PMID- 21681915 TI - Fate and transport of glyphosate and aminomethylphosphonic acid in surface waters of agricultural basins. AB - BACKGROUND: Glyphosate [N-(phosphonomethyl)glycine] is a herbicide used widely throughout the world in the production of many crops and is heavily used on soybeans, corn and cotton. Glyphosate is used in almost all agricultural areas of the United States, and the agricultural use of glyphosate has increased from less than 10 000 Mg in 1992 to more than 80 000 Mg in 2007. The greatest intensity of glyphosate use is in the midwestern United States, where applications are predominantly to genetically modified corn and soybeans. In spite of the increase in usage across the United States, the characterization of the transport of glyphosate and its degradate aminomethylphosphonic acid (AMPA) on a watershed scale is lacking. RESULTS: Glyphosate and AMPA were frequently detected in the surface waters of four agricultural basins. The frequency and magnitude of detections varied across basins, and the load, as a percentage of use, ranged from 0.009 to 0.86% and could be related to three general characteristics: source strength, rainfall runoff and flow route. CONCLUSIONS: Glyphosate use in a watershed results in some occurrence in surface water; however, the watersheds most at risk for the offsite transport of glyphosate are those with high application rates, rainfall that results in overland runoff and a flow route that does not include transport through the soil. PMID- 21681916 TI - Quantification of physical (roughness) and chemical (dielectric constant) leaf surface properties relevant to wettability and adhesion. AB - BACKGROUND: Spray droplet adhesion is dependent not only on formulation and droplet parameters but also on the surface properties (physical and chemical) of the leaf. Quantifying these leaf surface properties would aid understanding and modelling of adhesion, helping to optimise spray formulations. Fractal dimensions (FDs) were used to quantify the relative leaf surface roughness of ten plant species. Static droplet contact angles were measured on each leaf surface, and wetting tension was calculated. Chemical profiles of the leaf surfaces were developed by evaluating contact angle behaviour relative to solution dielectric constants. RESULTS: The FDs of Cryo-SEM micrographs taken at 300* magnification gave the best correlation with adhesion. The wetting tension intercept had a strong relationship with mean adhesion, and successfully accounted for the wettability of the outlier species. CONCLUSIONS: The microroughness of the leaf surface, as revealed by Cryo-SEM, can be quantified by fractal dimension analysis. However, the wetting tension intercept is a more useful universal measure of the surface properties of the leaf (including roughness) as they pertain to adhesion. The slope of the wetting tension versus dielectric constant plot allowed preliminary quantification of the chemical contribution of leaf surface dielectric behaviour to adhesion. PMID- 21681917 TI - Field leaching of pesticides at five test sites in Hawaii: modeling flow and transport. AB - BACKGROUND: Physically based tier-II models may serve as possible alternatives to expensive field and laboratory leaching experiments required for pesticide approval and registration. The objective of this study was to predict pesticide fate and transport at five different sites in Hawaii using data from an earlier field leaching experiment and a one-dimensional tier-II model. As the predicted concentration profiles of pesticides did not provide close agreement with data, inverse modeling was used to obtain adequate reactive transport parameters. The estimated transport parameters of pesticides were also utilized in a tier-I model, which is currently used by the state authorities to evaluate the relative leaching potential. RESULTS: Water flow in soil profiles was simulated by the tier-II model with acceptable accuracy at all experimental sites. The observed concentration profiles and center of mass depths predicted by the tier-II simulations based on optimized transport parameters provided better agreements than did the non-optimized parameters. With optimized parameters, the tier-I model also delivered results consistent with observed pesticide center of mass depths. CONCLUSION: Tier-II numerical modeling helped to identify relevant transport processes in field leaching of pesticides. The process-based modeling of water flow and pesticide transport, coupled with the inverse procedure, can contribute significantly to the evaluation of chemical leaching in Hawaii soils. PMID- 21681918 TI - Insecticide detoxification indicator strains as tools for enhancing chemical discovery screens. AB - BACKGROUND: Insecticide discovery screens carried out on whole organisms screen for potency resulting from chemical activity at the target site. However, many potentially insecticidal compounds are naturally detoxified in vivo and do not make it to the target site. It is hypothesised that insect strains with their xenobiotic detoxification machinery compromised could be used to identify such compounds that normally fail to show up in screens; these compounds could then be more rationally designed to increase their bioavailability. This strategy was tested with transgenic Drosophila lines with altered expression of Cyp6g1 and Dhr96. RESULTS: It was observed that Cyp6g1 knockdown transgenic lines have increased susceptibility to the test compound imidacloprid, while Dhr96 knockdown transgenic lines are resistant. Evidence was found for a systemic response to xenobiotic exposure, uncovered by piperonyl butoxide treatment and by gene expression profiling. Sex-specific gene expression regulated by DHR96 was also observed. CONCLUSION: The results confirm that this approach to chemical discovery could identify compounds that escape traditional screens. The complexity of the system means that a panel of single and multiple gene knockdown transgenic lines may be required. PMID- 21681919 TI - Spinosad resistance in female Musca domestica L. from a field-derived population. AB - BACKGROUND: Bait-formulated spinosad is currently being introduced for housefly (Musca domestica L.) control around the world. Spinosad resistance was evaluated in a multiresistant field population and strains derived from this by selection with insecticides. Constitutive and spinosad-induced expression levels of three cytochrome P450 genes, CYP6A1, CYP6D1 and CYP6D3, previously reported to be involved in insecticide resistance, were examined. RESULTS: In 2004 a baseline for spinosad toxicity of Danish houseflies where all field populations were considered to be susceptible was established. In the present study, females of a multiresistant field population 791a were, however, 27-fold spinosad resistant at LC(50), whereas 791a male houseflies were susceptible. Strain 791a was selected with spinosad, thiamethoxam, fipronil and imidacloprid, resulting in four strains with individual characteristics. Selection of 791a with spinosad did not alter spinosad resistance in either males or females, but counterselected against resistance to the insecticides thiamethoxam and imidacloprid targeting nicotinic acetylcholine receptors. A synergist study with piperonyl butoxide, as well as gene expression studies of CYP6A1, CYP6D1 and CYP6D3, indicated a partial involvement of cytochrome P450 genes in spinosad resistance. CONCLUSION: This study reports female-linked spinosad resistance in Danish houseflies. Negative cross-resistance was observed between spinosad and neonicotinoids in one multiresistant housefly strain. Spinosad resistance involved alterations of cytochrome P450 gene expression. PMID- 21681920 TI - Early oogenesis in the short-tailed fruit bat Carollia perspicillata: transient germ cell cysts and noncanonical intercellular bridges. AB - The ovaries of early embryos (40 days post coitum/p.c.) of the bat Carollia perspicillata contain numerous germ-line cysts, which are composed of 10 to 12 sister germ cells (cystocytes). Variability in the number of cystocytes within the cyst and between the cysts (defying the Giardina rule) indicates that the mitotic divisions of the cystoblast are asynchronous in this bat species. Serial section analysis showed that the cystocytes are interconnected via intercellular bridges that are atypical, strongly elongated, short-lived, and rich in microtubule bundles and microfilaments. During slightly later stages of embryonic development (44-46 days p.c.), somatic cells penetrate the cyst, and their cytoplasmic projections separate individual oocytes. Separated oocytes surrounded by a single layer of somatic cells constitute the primordial ovarian follicles. The oocytes of C. perspicillata are similar to mouse oocytes and are asymmetric. In both species, this asymmetry is clearly recognizable in the localization of the Golgi complexes. The presence of germ-line cysts and intercellular bridges (although noncanonical) in the fetal ovaries of C. perspicillata suggest that the formation of germ-line cysts is an evolutionarily conserved phase in the development of the female gametes in a substantial part of the animal kingdom. PMID- 21681921 TI - Soluble interleukin-2 receptor alpha activation in a Children's Oncology Group randomized trial of interleukin-2 therapy for pediatric acute myeloid leukemia. AB - PURPOSE: To assess associations of soluble IL-2 receptor alpha (sIL-2ralpha) concentration with outcomes in pediatric acute myeloid leukemia (AML) in a phase 3 trial of IL-2 therapy. PROCEDURES: We randomized 289 children with AML in first remission after intensive chemotherapy to receive IL-2 infused on days 0-3 and 8 17 (IL-2 group) or no further therapy (AML control group). We measured sequential serum sIL-2ralpha concentrations in both groups before, during and after therapy in both groups and in reference controls without AML. RESULTS: Before treatment, mean sIL-2ralpha concentrations were similar in the IL-2 group and AML controls, but significantly higher than in reference controls. Both AML groups experienced reduction in sIL-2ralpha concentration after chemotherapy. Thereafter in the IL-2 group, mean sIL-2ralpha concentration increased from 2,669 pg/ml before IL-2 to 15,534 pg/ml on day 4 (P < 0.001) and 10,585 pg/ml on day 18 (P < 0.001). In the control group sIL-2ralpha concentration did not change after 28 days of follow up. Five-year disease-free survival (DFS) was 51% in the IL-2 group and 58% in the controls (P = 0.489) and overall survival was 70% and 73%, respectively (P = 0.727). CONCLUSION: SIL-2ralpha concentration was elevated in AML at diagnosis and tended to normalize after chemotherapy. IL-2 infusion significantly increased sIL-2ralpha concentration, but did not improve DFS or survival in pediatric AML. Furthermore, sIL-2ralpha concentration was not predictive of outcome before, during or after treatment for AML. PMID- 21681922 TI - Clinical characteristics and treatment outcome of children with intraocular retinoblastoma: a report from a Chinese cooperative group. AB - BACKGROUND: To present the characteristics and treatment outcome of patients with intraocular retinoblastoma in a Chinese cooperative group. PROCEDURE: Between January 2005 and March 2009, 159 eyes of 133 patients with retinoblastoma were included in this retrospective study. The International Classification of Retinoblastoma (ICRB) staging system was noted for each patient. Cases with visible extraocular extension at diagnosis were excluded. The patient data were reviewed for demographic information, clinical findings, and managements. RESULTS: Of 133 cases, there were 83 (62%) male and 50 (38%) female, ranging in age from 2 months to 134 months (median, 23 months; mean, 26 months). There were 26 bilateral cases (20%). One hundred and twenty-four cases (93%) were deemed sporadic and nine cases (7%) were deemed familial. Leukocoria was the most common presenting symptom. One hundred and twenty-three eyes (77%) of 123 patients (92%) had no visual potential. Only 36 eyes (23%) of 30 patients (23%) utilized vision preserving treatments. The ocular salvage rate was 83% (30/36) for this group. The cumulative probability of survival was 98% (Kaplan-Meier method) at 60 months follow up. CONCLUSIONS: The overall survival rate of this study is in agreement with data from developed countries. In appropriate patients, systemic chemotherapy, and focal ophthalmic therapy are effective and carry little morbidity. Compared with more medically developed countries, there are still many challenges in the management of retinoblastoma in China. Early detection and doctor education should be an important future goal. Pediatr Blood Cancer 2011; 57: 1113-1116. (c) 2011 Wiley Periodicals, Inc. PMID- 21681923 TI - Ewing sarcoma/primitive neuroectodermal tumor arising from the adrenal gland in an adolescent. AB - We review the case of an adolescent who presented with flank pain, fatigue and a discrete nonfunctioning adrenal lesion which was found to be an adrenal Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET). The patient was treated with a minimally invasive adrenalectomy as a component of multimodal therapy, including seven courses of chemotherapy and whole abdominal radiation. She is currently disease free 14 months after the operation and 3 months off therapy. PMID- 21681924 TI - Reduced-intensity allogeneic stem cell transplantation for children with neuroblastoma who failed tandem autologous stem cell transplantation. AB - BACKGROUND: To date, no effective curative option is available for children with neuroblastoma (NB) who failed tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT). The present study evaluated the feasibility and efficacy of reduced-intensity allogeneic stem cell transplantation (RI alloSCT) in six children with NB who failed tandem HDCT/autoSCT. PROCEDURE: A cyclophosphamide/fludarabine regimen was used as a conditioning for HLA-matched SCT, and ATG was added for haploidentical SCT. Peripheral blood stem cells from four HLA-matched donors and two haploidentical donors were transplanted. Immune suppression was rapidly tapered if graft-versus-host disease (GVHD) was absent. RESULTS: Regimen-related short-term toxicity was manageable, and complete donor chimerism was achieved in the early period after transplant. Grade I/II acute GVHD developed or was induced in all patients. Tumor response, attributed to a graft-versus-tumor (GVT) effect, was observed in two of six patients after induction of acute GVHD. The other four patients with significant tumor burden prior to transplant had tumor progression despite presence of GVHD. However, it was difficult to effectively reduce the tumor burden prior to transplant through the use of conventional treatment modalities. CONCLUSION: Although regimen related short-term toxicity was manageable in intensively pretreated patients with NB, GVT effect was not sufficiently strong to control tumor progression in patients who had a significant tumor burden at transplant. Therefore, new treatment modalities to effectively reduce tumor burden prior to transplant in concert with post-transplant adjuvant treatment to enhance the GVT effect are needed to improve the outcome after RI alloSCT. PMID- 21681925 TI - Incidence of childhood leukemia in Yogyakarta, Indonesia, 1998-2009. AB - BACKGROUND: In most developing countries, incidence data for childhood cancers are less reliable, because very few population-based registries exist. The aim of this study was to present the epidemiology of childhood leukemia in the Dr. Sardjito Hospital (DSH) region, which catchment area extends beyond the boundaries of the Yogyakarta Special Province (YSP). PROCEDURE: Health records of children, 0-14 years of age, who were diagnosed with leukemia between January 1998 and December 2009, were reviewed. Diagnosis of leukemia was confirmed by morphological and histochemical examination of marrow samples. RESULTS: The estimated average annual incidence rate (AAIR) of childhood acute leukemia in DSH was 46.2 per million per year. Interestingly, the annual incidence rate (AIR) of childhood acute leukemia from the catchment area of DSH significantly increased from 35 in 1999 to 70 in 2009 (ANOVA, P = 0.003). The YSP population data, analyzed separately, showed an increase in AIR from 15.7 to 32.9 (ANOVA, P = 0.325) and an AAIR of 28.8. Remarkably, a relatively high frequency (25.5% in DSH and 27.7% in YSP) of children with AML was found in the group of acute leukemias. CONCLUSION: The DSH incidence calculations may be overestimated due to an underestimation of the population number. Since the population count for YSP is more precise, the data of YSP were used for comparison with developed countries. AAIR of ALL (20.8) is relatively low compared to Western countries (22.4-37.9). The AAIR of AML (8.0) is similar to Western countries (5.0-8.0) resulting a relatively high percentage of AML versus ALL (27.7%) in YSP. PMID- 21681926 TI - Sarcomas gone bad: what to do about recurrent Ewing sarcoma. PMID- 21681927 TI - Familial adenomatous polyposis with concurrent metastatic appendiceal carcinoid and ovarian cystoadenoma. PMID- 21681928 TI - A phase II study of amifostine in children with myelodysplastic syndrome: a report from the Children's Oncology Group study (AAML0121). AB - Based on its potential role in adult myelodysplastic syndrome (MDS), the Children's Oncology Group (COG) embarked on a phase II study using amifostine in pediatric MDS (WHO 2001 criteria) patients. Responses were evaluated after two cycles. Ten patients were enrolled; five were deemed ineligible, and four withdrew after the first course. Only one patient completed two courses, and was found to be in complete remission. The study was closed after being open for 2 years due to slow accrual. Studying a rare disease like MDS may pose insurmountable obstacles even in a large clinical trials group such as COG, in part because of the changing definitions of MDS and the rarity of adult type MDS in children. The role of amifostine in pediatric MDS was not known at the time of study. PMID- 21681929 TI - Initial testing (stage 1) of LCL161, a SMAC mimetic, by the Pediatric Preclinical Testing Program. AB - LCL161, a SMAC mimetic, was tested against the PPTP in vitro panel (1.0 nM to 10.0 uM) and the PPTP in vivo panels (30 or 75 mg/kg [solid tumors] or 100 mg/kg [ALL]) administered orally twice in a week. LCL161 showed a median relative IC(50) value of >10 uM, being more potent against several leukemia and lymphoma lines. In vivo LCL161 induced significant differences in EFS distribution in approximately one-third of solid tumor xenografts (osteosarcoma and glioblastoma), but not in ALL xenografts. No objective tumor responses were observed. In vivo LCL161 demonstrated limited single agent activity against the pediatric preclinical models studied. PMID- 21681930 TI - Immunophenotype and cytogenetic characteristics in the relationship between birth weight and childhood leukemia. AB - BACKGROUND: High birth weight increases the risk of childhood acute lymphoid leukemia (ALL) through unknown mechanisms. Whether this risk is specific to ALL subtypes is unknown, and low case numbers have prevented investigation of the rarer leukemias. Here we address these associations using a large population based dataset. PROCEDURE: Using the National Registry of Childhood Tumors, birth weights of 7,826 leukemia cases, defined by immunophenotype and cytogenetic subgroup, were compared with those of 10,785 controls born in England and Wales between 1980 and 2007. RESULTS: The risk for overall leukemia increases 7% with each 0.5 kg increase in birth weight (OR 1.07, 95%CI 1.04-1.10). This risk is limited to the lymphoid leukemias (OR 1.08, 95%CI 1.05-1.12) diagnosed between 1 and 9 years of age. Analysis by cytogenetic feature reveals that there appears to be association with specific chromosomal abnormality: the risk of tumors with high hyperdiploid karyotypes increases 12% per 0.5 kg increase in birth weight (OR 1.12, 95%CI 1.05-1.20), and t(1;19) tumors show an increased risk of 41% per 0.5 kg increase (OR 1.41, 95%CI 1.09-1.84). The risk of acute myeloid leukemia is elevated in high and low birth weight babies. There is no significant risk relationship to other leukemias or myeloproliferative diseases. CONCLUSIONS: Birth weight is a risk factor for ALL and AML. Other subtypes of the disease are not significantly affected. There appears to be association with specific chromosomal abnormality, which may aid our understanding of the development of childhood leukemia in utero. PMID- 21681931 TI - Exocrine pancreatic tumors in childhood in Germany. AB - BACKGROUND: Pancreatic tumors (PT) in childhood are rare. Standard therapeutic approaches are lacking. Our aim was to analyze treatment modalities and outcome in children with PT. PROCEDURE: Between 1980 and 2007, 55 patients with exocrine PT < 16 years old were registered. Data were obtained from the German Pediatric Tumour Registry. Medical records were evaluated and patient data were pseudonymized. RESULTS: Patient records of 29 children were available (9 male, 20 female, median age 11.2 years, range 3.1-16). In 18 patients a solid pseudopapillary tumor (SPT) was diagnosed, in 7 patients a pancreatic carcinoma (P-CA) (5 acinar cell carcinoma (ACC), 2 ductal adenocarcinoma (DCA)), and in 4 patients a pancreatoblastoma (PBL). In 69% of the patients the initial radiological findings led to an incorrect tentative diagnosis. Initial histopathological diagnoses were differing from the reference pathology in 50% of the SPT and 45% of the P-CA. In the group of SPT survival rate was 100%; all patients underwent surgical resection. There were two cases of tumor relapse and one late secondary malignancy of the pancreas (DCA). In P-CA patients, survival rate was 14%, in the PBL group the survival rate was 25%. Concepts of chemotherapy, radiotherapy, and surgical intervention in P-CA and PBL were varying widely. CONCLUSIONS: In all cases of pediatric PT reference pathology and reference radiology should be involved. Standardized treatment concepts as well as prospective data registrations need to be entrenched. PMID- 21681932 TI - "Risk adapted" assessments of health related quality of life in HSCT recipients. PMID- 21681933 TI - Successful pulmonary artery embolectomy in a patient with a saddle Wilms tumor embolus. AB - Denys-Drash syndrome is a genetic disorder characterized by ambiguous genitalia, cryptorchidism, nephrotic syndrome, and a high predilection for Wilms tumor with intravascular invasion. We report a 5-year-old male with Denys-Drash syndrome who rapidly developed Wilms tumor with vascular invasion, subsequent saddle tumor embolus, and required emergent embolectomy. This case illustrates the rapid emergence of Wilms tumor in a patient with Denys-Drash syndrome and the importance of considering embolectomy over thrombolytic therapy for PE in this population, given a high likelihood of tumor embolus. PMID- 21681934 TI - Constitutional tandem duplication of 9q34 that truncates EHMT1 in a child with ganglioglioma. AB - Point mutations of EHMT1 or deletions and duplications of chromosome 9q34.3 are found in patients with variable neurologic and developmental disorders. Here, we present a child with congenital cataract, developmental and speech delay who developed a metastatic ganglioglioma with progression to anaplastic astrocytoma. Molecular analysis identified a novel constitutional tandem duplication in 9q34.3 with breakpoints in intron 1 of TRAF2 and intron 16 of EHMT1 generating a fusion transcript predicted to encode a truncated form of EHMT1. The ganglioglioma showed complex chromosomal aberrations with further duplication of the dup9q34. Thus, this unique tandem 9q34.3 duplication may impact brain tumor formation. PMID- 21681935 TI - Rapamycin does not control hemophagocytic lymphohistiocytosis in LCMV-infected perforin-deficient mice. AB - Hemophagocytic lymphohistiocytosis (HLH) is an immunodysregulatory disorder for which more effective treatments are needed. The macrolide rapamycin has immunosuppressive properties, making it an attractive candidate for controlling the aberrant T cell activation that occurs in HLH. To investigate its therapeutic potential, we used rapamycin to treat Lymphocytic Choriomeningitis Virus (LCMV) infected perforin-deficient (Prf1(-/-)) mice according to a well-established model of HLH. At the regimens tested, rapamycin did not improve weight loss, splenomegaly, hemophagocytosis, cytopenias, or proinflammatory cytokine production in LCMV-infected Prf1(-/-) animals. Thus, single agent rapamycin appears ineffective in treating the clinical and laboratory manifestations of LCMV-induced HLH. PMID- 21681936 TI - First contact physicians and retinoblastoma in Mexico. AB - BACKGROUND: Early detection and timely referral are keys to improve survival in patients with retinoblastoma (Rb). In Mexico, one of the main obstacles for an early diagnosis is the lack of knowledge of the disease. The objective of this study was to evaluate Rb comprehension in students in their last year of medical school. PROCEDURE: A questionnaire was completed by 791 students from 12 universities. Descriptive statistics from the population were obtained and every answer to each question was analyzed. RESULTS: Only 3.3% of the students got a proficiency grade. Less than 50% diagnosed Rb when an image was shown. CONCLUSIONS: The students evaluated do not have the knowledge to detect the disease. It is necessary to develop continuous educational programs for first contact physicians. PMID- 21681937 TI - Lymphoblastic lymphoma with mature b-cell immunophenotype and MLL-AF9 in a child. PMID- 21681938 TI - Dengue Fever in patients with pediatric malignancy on chemotherapy: a concern in tropical countries. PMID- 21681939 TI - Rituximab and cyclosporine therapy for accelerated phase Chediak-Higashi syndrome. AB - A 19-month-old male with Chediak-Higashi syndrome developed Epstein-Barr virus (EBV)-associated accelerated phase. Real-time polymerase chain reaction showed high EBV-DNA levels in plasma and peripheral blood mononuclear cells. His condition was refractory to conventional treatments for hemophagocytic lymphohistiocytosis, including corticosteroids, cyclosporine, and etoposide. In situ hybridization revealed higher proportion of EBER-1-positive cells in CD19+ cell fraction than in CD8+ cell fraction. Complete remission was achieved by combination therapy with rituximab and cyclosporine; subsequent bone marrow transplantation was successful. Combination therapy with rituximab and cyclosporine could be effective in patients with EBV-infected T and B cells. PMID- 21681940 TI - Surface-modified gold nanoshells for enhanced cellular uptake. AB - Gold nanoshells have shown a great potential for use as agents in a wide variety of biomedical applications, and some of which require the delivery of large numbers of gold nanoshells onto or into the cells. Here, we develop a ready method to enhance the cellular uptake of gold nanoshells by modifying with meso 2,3-dimercaptosuccinic acid (DMSA). The quantifiable technique of inductively coupled plasma atomic emissions spectroscopy (ICP-AES) and transmission electron microscopy (TEM) were used to investigate the cellular uptake of unmodified and DMSA-modified gold nanoshells. Three cell lines (RAW 264.7, A549, and BEL-7402) were involved and the results indicated that the cellular uptake of the DMSA modified gold nanoshells was obviously enhanced versus the unmodified gold nanoshells. The reason possibly lies in the nonspecific adsorption of serum protein on the DMSA-modified gold nanoshells (DMSA-GNs), which consequently enhanced the cellular uptake. As a continued effort, in vitro experiments with endocytic inhibitors suggested the DMSA-GNs internalized into cells via receptor mediated endocytosis (RME) pathway. This study has provided a valuable insight into the effects of surface modification on cellular uptake of nanoparticles. PMID- 21681941 TI - Evaluation of the osteoconductivity of alpha-tricalcium phosphate, beta tricalcium phosphate, and hydroxyapatite combined with or without simvastatin in rat calvarial defect. AB - The purpose of this study is to evaluate the osteoconductivity of three different bone substitute materials: alpha-tricalcium phosphate (alpha-TCP), (beta-TCP), and hydroxyapatite (HA), combined with or without simvastatin, which is a cholesterol synthesis inhibitor stimulating BMP-2 expression in osteoblasts. We used 72 Wistar rats and prepared two calvarial bone defects of 5 mm diameter in each rat. Defects were filled with the particles of 500-750 MUm diameter combined with or without simvastatin at 0.1 mg dose for each defect. In the control group, defects were left empty. Animals were divided into seven groups: alpha-TCP, beta TCP, HA, alpha-TCP with simvastatin, beta-TCP with simvastatin, HA with simvastatin, and control. The animals were sacrificed at 6 and 8 weeks. The calvariae were dissected out and analyzed with micro CT. The specimens were evaluated histologically and histomorphometrically. In alpha-TCP group, the amount of newly formed bone was significantly more than both HA and control groups but not significantly yet more than beta-TCP group. Degradation of alpha TCP was prominent and beta-TCP showed slower rate while HA showed the least degradation. Combining the materials with Simvastatin led to increasing in the amount of newly formed bone. These results confirmed that alpha-TCP, beta-TCP, and HA are osteoconductive materials acting as space maintainer for bone formation and that combining these materials with simvastatin stimulates bone regeneration and it also affects degradability of alpha-TCP and beta-TCP. Conclusively, alpha-TCP has the advantage of higher rate of degradation allowing the more bone formation and combining alpha-TCP with simvastatin enhances this property. PMID- 21681942 TI - Quantifying the effect of pore size and surface treatment on epidermal incorporation into percutaneously implanted sphere-templated porous biomaterials in mice. AB - The sinus between skin and a percutaneous medical device is often a portal for infection. Epidermal integration into an optimized porous biomaterial could seal this sinus. In this study, we measured epithelial ingrowth into rods of sphere templated porous poly(2-hydroxyethyl methacrylate) implanted percutaneously in mice. The rods contained spherical 20-, 40-, or 60-MUm pores with and without surface modification. Epithelial migration was measured 3, 7, and 14 days post implantation utilizing immunohistochemistry for pankeratins and image analysis. Our global results showed average keratinocyte migration distances of 81 +/- 16.85 MUm (SD). Migration was shorter through 20-MUm pores (69.32 +/- 21.73) compared with 40 and 60 MUm (87.04 +/- 13.38 MUm and 86.63 +/- 8.31 MUm, respectively). Migration was unaffected by 1,1' carbonyldiimidazole surface modification without considering factors of pore size and healing duration. Epithelial integration occurred quickly showing an average migration distance of 74.13 +/- 12.54 MUm after 3 days without significant progression over time. These data show that the epidermis closes the sinus within 3 days, migrates into the biomaterial (an average of 11% of total rod diameter), and stops. This process forms an integrated epithelial collar without evidence of marsupialization or permigration. PMID- 21681943 TI - A chemically polymerized electrically conducting composite of polypyrrole nanoparticles and polyurethane for tissue engineering. AB - A variety of cell types respond to electrical stimuli; accordingly, many conducting polymers (CPs) have been used as tissue engineering (TE) scaffolds, and one such CP is polypyrrole (PPy). PPy is a well-studied biomaterial with potential TE applications because of its electrical conductivity and many other beneficial properties. Combining its characteristics with an elastomeric material, such as polyurethane (PU), may yield a hybrid scaffold with electrical activity and significant mechanical resilience. Pyrrole was in situ polymerized within a PU emulsion mixture in weight ratios of 1:100, 1:20, 1:10, and 1:5, respectively. Morphology, electrical conductivity, mechanical properties, and cytocompatibility with C2C12 myoblast cells were characterized. The polymerization resulted in a composite with a principle base of PU interspersed with an electrically percolating network of PPy nanoparticles. As the mass ratio of PPy to PU increased so did electrical conductivity of the composites. In addition, as the mass ratio of PPy to PU increased, stiffness of the composite increased while maximum elongation length decreased. Ultimate tensile strength was reduced by ~47% across all samples with the addition of PPy to the PU base. Cytocompatibility assay data indicated no significant cytotoxic effect from the composites. Static cellular seeding of C2C12 cells and subsequent differentiation showed myotube formation on the composite materials. PMID- 21681944 TI - Physicobiological properties and biocompatibility of biodegradable poly(oxalate co-oxamide). AB - The development of biodegradable and biocompatible materials is the basis for tissue engineering and drug delivery. The aims of this study are to develop the poly(oxalate-co-oxamide) (POXAM) and evaluate its physicochemical properties and biocompatibility as the initial step for the development of new biomaterials. POXAM had a molecular weight of ~70,000 Da and rapidly degraded under physiological condition with a half-hydrolysis of ~4 days. POXAM films exhibited relative hydrophilic nature because of the presence of oxamide linkages and induced a higher cell attachment and proliferation compared with poly(lactic-co glycolic acid) (PLGA) films. In vitro inflammatory responses to POXAM were evaluated using murine macrophage RAW 264.7 cells. POXAM films minimally stimulated the cells to generate less production of tumor necrosis factor-alpha (TNF-alpha) than PLGA films. We assessed the in vivo inflammatory responses to POXAM films implanted in the dorsal skin of rats. Histological studies revealed that POXAM provoked remarkably reduced inflammatory responses, evidenced by the less accumulation of inflammatory cells and giant cells, thinner fibrotic capsules, in comparison with PLGA. Given its excellent biocompatibility, fast degradation, and very mild inflammatory responses, POXAM has great potential for biomedical applications, such as scaffolds, wound dressing, and fast drug delivery. PMID- 21681945 TI - Endotoxin contamination delays the foreign body reaction. AB - Biomaterials are at continuous risk of bacterial contamination during production and application. In vivo, bacterial contamination of biomaterials delays the foreign body reaction (FBR). Endotoxins such as lipopolysaccharides (LPS), major constituents of the bacterial cell wall, are potent stimulators of the immune system in vitro and in vivo. In vitro, biomaterials contaminated with LPS induce the production of proinflammatory cytokines by adherent macrophages. This suggests that the presence of endotoxins on biomaterials will intensify the FBR. The effects of LPS on the course of the FBR have never been studied in vivo. In this study, the influence of LPS contamination on the FBR to subcutaneously implanted Puramatrix-loaded hexamethylenediisocyanate-crosslinked dermal sheep collagen (HDSC) disks was studied in rats. During the onset phase of the FBR, a massive influx of granulocytes was detected in LPS-contaminated disks, while their presence was prolonged. IL-10 production inside LPS-contaminated disks was increased at days 10 and 21. Macrophage densities were not affected by the presence of LPS. However, macrophage functionality was altered: giant cell formation and biomaterial degradation were delayed by LPS-contamination up to 21 days. On the basis of these results, we conclude that LPS delays the FBR. This finding indicates that endotoxin contamination has significant implications for the in vivo function of biomaterials and medical devices and emphasizes the importance of endotoxin testing. PMID- 21681946 TI - Poly(dimethyl siloxane) surface modification with biosurfactants isolated from probiotic strains. AB - Depending on the final application envisaged for a given biomaterial, many surfaces must be modified before use. The material performance in a biological environment is mainly mediated by its surface properties that can be improved using suitable modification methods. The aim of this work was to coat poly(dimethyl siloxane) (PDMS) surfaces with biosurfactants (BSs) and to evaluate how these compounds affect the PDMS surface properties. BSs isolated from four probiotic strains (Lactococcus lactis, Lactobacillus paracasei, Streptococcus thermophilus A, and Streptococcus thermophilus B) were used. Bare PDMS and PDMS coated with BSs were characterized by contact angle measurements, infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM). The influence of the surface modifications on the materials blood compatibility was studied through thrombosis and hemolysis assays. The cytotoxicity of these materials was tested against rat peritoneal macrophages. AFM results demonstrated the successful coating of the surfaces. Also, by contact angle measurements, an increase of the coated surfaces hydrophilicity was seen. Furthermore, XPS analysis indicated a decrease of the silicon content at the surface, and ATR-FTIR results showed the presence of BS characteristic groups as a consequence of the modification. All the studied materials revealed no toxicity and were found to be nonhemolytic. The proposed approach for the modification of PDMS surfaces was found to be effective and opens new possibilities for the application of these surfaces in the biomedical field. PMID- 21681947 TI - Studies on the hemocompatibility of bacterial cellulose. AB - Among the strategies to improve a material's hemocompatibility, pre-coating with the tripeptide Arg-Gly-Asp (RGD) is used to favor endothelialization thus lowering thrombogenicity. The blood compatibility of native and RGD-modified bacterial cellulose (BC) was studied in this work for the first time. The plasma recalcification time and whole blood clotting results demonstrate the hemocompatibility of BC. A significant amount of plasma protein adsorb to BC fibres, however, according to analysis by intrinsic tryptophan fluorescence techniques when albumin, gamma-globulin, and fibrinogen from pure protein solutions adsorb to BC do not undergo detectable conformational modifications. Human microvascular endothelial cells cultured on RGD-modified BC readily form a confluent cell layer, inhibiting the adhesion of platelets. As a general conclusion, both native and RGD-modified BCs may be classified as hemocompatible materials. PMID- 21681948 TI - Keratin hydrogels support the sustained release of bioactive ciprofloxacin. AB - Keratins are naturally derived proteins that can be fabricated into several biomaterial forms including hydrogels. These materials are a potential polymeric system for several tissue engineering and regenerative medicine applications due to their ability to support cell attachment, proliferation, and migration. However, little is known regarding their ability to support sustained release of therapeutic agents. This report describes the use of keratin hydrogels for sustained release of the antibiotic ciprofloxacin, which may prove useful to traumatic injury applications that would benefit from materials promoting tissue regeneration while also preventing acute infection. Hydrogels were formed from keratins obtained by oxidative extraction and known as keratose. We found that keratose hydrogels released ~60% of loaded ciprofloxacin over the first 10 days and that continued release was detectable over the course of 3 weeks. Released ciprofloxacin was bioactive, inhibiting growth of Staphylococcus aureus for 23 days in vitro and for 2 weeks in a mouse subcutaneous model. The rate of ciprofloxacin release was highly correlated with degradation of the keratin hydrogel and not consistent with simple diffusion. Further experiments indicated that ciprofloxacin binds to keratose through electrostatic interactions. These studies demonstrate the specific use of keratose hydrogels for the release of antibiotic and the potential for the more general use of this material in tissue engineering and regenerative medicine applications. PMID- 21681949 TI - Silk fibroin and polyethylene glycol-based biocompatible tissue adhesives. AB - Tissue sealants have emerged in recent years as strong candidates for hemostasis. A variety of formulations are currently commercially available and though they satisfy many of the markets' needs there are still key aspects of each that need improvement. Here we present a new class of blends, based on silk fibroin and chemically active polyethylene glycols (PEGs) with strong adhesive properties. These materials are cytocompatible, crosslink within seconds via chemical reaction between thiols and maleimides present on the constituent PEGs and have the potential to further stabilize through beta-sheet formation by silk. Based on the silk concentration in the final formulation, the adhesive properties of these materials are comparable or better than the current leading PEG-based sealant. In addition, the silk-PEG based materials show decreased swelling and longer degradation times. Such properties would make them suitable for applications for which the current sealants are contraindicated. PMID- 21681950 TI - Characteristics of hydroxyapatite film formed on human enamel with the powder jet deposition technique. AB - This study aimed to create hydroxyapatite (HAp) film by powder jet deposition with manipulating the blasting nozzle above human enamel and to examine the microstructural and mechanical properties of the HAp film and the bonding strength at the interface between the HAp film and the enamel substrate. HAp particles calcinated at 1200 degrees C with an average size of 4.7 MUm were used. The HAp particles were mixed with carrier gas (N2) to form an aerosol flow and was accelerated and blasted from the nozzle onto the enamel substrate at room temperature and atmospheric pressure. To evaluate the microstructure, scanning electron microscope (SEM) images of the surface and cross section of the HAp films and a three-dimensional profile of the HAp films were observed. To evaluate the mechanical properties, the micro-Vickers hardness and the bonding strength of the HAp films to the enamel substrate were measured. The deposition area of the HAp film was over 3 * 4 mm. The average and maximum thickness were about 30 and 40 MUm, respectively. No significant difference was observed between the hardness of the HAp film and the enamel (p > 0.05). The bonding strength of the HAp film was the same as the bonding strength between composite resin and enamel. Compared with previous reports, wider and thicker HAp film was created on the enamel substrate successfully. The HAp film, which has same hardness with enamel and same bonding strength to the enamel with composite resin, would be a candidate as dental restorative materials. PMID- 21681951 TI - A novel hydroxyapatite ceramic bone substitute transformed by ostrich cancellous bone: characterization and evaluations of bone regeneration activity. AB - Various biomaterials have been used for bone repair and reconstruction of bone defects. Inorganic xenogenic bone substitutes have been intensively studied because they possesses favorable regenerative properties. The purpose of this study was to evaluate the properties of a novel inorganic xenogenic bone substitute, sintered ostrich cancellous bone (SOCB). Bone regeneration capability was also comparing to that of other bone substitutes in rabbit calvarial defects. Biochemical and biomechanical properties of the SOCB ceramic closely resembled those of human bone. Bone regeneration was evaluated by radiograph, histology, and histomorphometry. Bone regeneration was significantly enhanced in defects treated with SOCB when compared with other bone substitutes. The biochemical and biomechanical properties of SOCB are favorable for bone regeneration. SOCB might be a promising biomaterial for the repair of bone defects. PMID- 21681952 TI - Single-step mineralization of woodpile chitosan scaffolds with improved cell compatibility. AB - A facile and efficient single-step mineralization approach was exploited for achieving nanoscopic hydroxyapatite (HAP) crystal layer in chitosan porous matrix, wherein a mixed water-ethanol solvent was used to control the growth of minerals. The crystallographic structure, morphology, and mechanical properties of the scaffold were analyzed with XRD, FTIR, environmental scanning electric microscopy (ESEM), TEM, and compression tests. The behaviors and responses of MC3T3-E1 pre-osteoblast cells on the scaffolds were studied as well. The results showed that the scaffolds kept woodpile structure with predefined and controlled hierarchical structure after mineralization. The inorganic phase in the mineralized chitosan scaffolds was determined as pure rod-like HAP, which settled densely on the matrix. The compression strength and compressive modulus of the scaffolds increased dramatically to 0.54 +/- 0.005 MPa and 5.47 +/- 0.65 MPa, respectively. During a culture period of 2 and 3 weeks, cell proliferation and in growth were observed by phase contrast light microscopy and SEM. The alkaline phosphatase (ALP) activity increased after 1 week. Cell viability and cell proliferation index (PI) obtained higher values than that of the chitosan scaffolds. The novel single-step mineralization approach and the porous hybrid scaffolds would be a promising method for designing hybrid bone graft. PMID- 21681953 TI - Guided orientation of cardiomyocytes on electrospun aligned nanofibers for cardiac tissue engineering. AB - Cardiac tissue engineering (TE) is one of the most promising strategies to reconstruct the infarct myocardium and the major challenge involves producing a bioactive scaffold with anisotropic properties that assist in cell guidance to mimic the heart tissue. In this study, random and aligned poly(epsilon caprolactone)/gelatin (PG) composite nanofibrous scaffolds were electrospun to structurally mimic the oriented extracellular matrix (ECM). Morphological, chemical and mechanical properties of the electrospun PG nanofibers were evaluated by scanning electron microscopy (SEM), water contact angle, attenuated total reflectance Fourier transform infrared spectroscopy and tensile measurements. Results indicated that PG nanofibrous scaffolds possessed smaller fiber diameters (239 +/- 37 nm for random fibers and 269 +/- 33 nm for aligned fibers), increased hydrophilicity, and lower stiffness compared to electrospun PCL nanofibers. The aligned PG nanofibers showed anisotropic wetting characteristics and mechanical properties, which closely match the requirements of native cardiac anisotropy. Rabbit cardiomyocytes were cultured on electrospun random and aligned nanofibers to assess the biocompatibility of scaffolds, together with its potential for cell guidance. The SEM and immunocytochemical analysis showed that the aligned PG scaffold greatly promoted cell attachment and alignment because of the biological components and ordered topography of the scaffolds. Moreover, we concluded that the aligned PG nanofibrous scaffolds could be more promising substrates suitable for the regeneration of infarct myocardium and other cardiac defects. PMID- 21681954 TI - Restoration of longitudinal growth by bioengineered cartilage pellet in physeal injury is not affected by low intensity pulsed ultrasound. AB - Physeal fracture is a common pediatric fracture that would result in premature physeal closure in long bones, and there is currently no gold standard for its management. In this study, we investigated the application of a Bioengineered Cartilage Pellet (BCP) in repairing a rabbit physeal fracture model, and the possible effects of Low Intensity Pulsed Ultrasound (LIPUS) treatment. Rabbits with physeal fracture created were assigned to the NC group (no BCP, no LIPUS), GC group (BCP, no LIPUS), and GT group (BCP and LIPUS). Femoral lengths and cartilage area were assessed at 4, 8, and 16 weeks post-defect. After transplantation, the BCP showed continuous growth in the host and demonstrated resemblance to a natural growth plate. The GC group showed 34.1, 32.1, and 41.1% advantage in lengthening over the NC group and the GT group showed 51.1, 41.6, and 26.9% improved lengthening than the NC group, at 4 (p = 0.203), 8 (p = 0.543) and 16 weeks (p = 0.049), respectively. Cartilage area was shown to be significantly higher in GC and GT group compared to NC group (p < 0.05). No significant difference was found between GC and GT group. Femoral longitudinal growth was shown to be improved by the BCP, however no additional enhancement effect was shown to be provided by LIPUS. PMID- 21681955 TI - Native polyacrylamide electrophoresis in the presence of Ponceau Red to study oligomeric states of protein complexes. AB - Native polyacrylamide electrophoresis in the presence of two reversible protein anionic stains (Ponceau S and Ponceau 2R) was used to study the oligomeric states of soluble proteins. A mild binding of the used protein stains to nondissociated protein oligomers imposed a charge shift on the proteins resulting into separation of protein species according to their size under physiological conditions. Adsorbed stains could be easily removed after electrophoresis by washing of polyacrylamide gel with buffer and protein complexes could be visualized either by the detection of their enzyme activity or by using a nonspecific protein stain. The specific detection of enzyme activity of glycosidases, lactate dehydrogenase, or phosphatases was shown as an example. PMID- 21681956 TI - Hollow fiber-based liquid-liquid-liquid microextraction followed by flow injection analysis using column-less HPLC for the determination of phenazopyridine in plasma and urine. AB - Hollow fiber-based liquid-liquid-liquid microextraction (HF-LLLME) followed by flow injection analysis and diode array detection (FIA-DAD) was applied as a simple and sensitive quantitative method for the determination of phenazopyridine in urine and plasma samples. Flow injection system included a conventional HPLC system (without a chromatographic column) and a diode array detector. The extraction of phenazopyridine was carried out using diphenyl ether as the organic phase for filling the pores of the hollow fiber wall, and 0.1 M H(2)SO(4) solution as acceptor phase in the lumen of the fiber. The factors affecting the HF-LLLME and flow injection analysis including type of organic solvent, pH of donor phase, extraction temperature, extraction time, stirring rate, and pH of mobile phase were investigated and the optimal extraction conditions were established. With the consumption of 5 mL of sample solution, the enrichment factor was about 230. The limit of detection was 0.5 MUg/L with inter- and intra day precision being (RSD%) 6.9 and 4.9, respectively. Excellent linearity was found between 5 and 200 MUg/L. PMID- 21681957 TI - Comments on the paper "Characterization of stationary phases by a linear solvation energy relationship utilizing supercritical fluid chromatography" by C. R. Mitchell, N. J. Benz, S. Zhang. AB - In a recent paper published by Mitchell et al. in this journal, some results obtained in supercritical fluid chromatography and interpreted with the solvation parameter model to characterize interactions for "novel stationary phases" were surprising to us. Indeed, we had already published results for most of the stationary phases reported, but, except for polar phases, our results were not in agreement with those, despite the use of identical mobile phases in both studies. These data were disturbing because they suggest that supercritical fluid chromatography is always a normal-phase mode, while we have shown that it is a reversed-phase mode when working with non-polar stationary phases. In the process of establishing the reason for the differences between our works, we examined several different factors. This paper deals with practice of linear solvation energy relationships: choice of dead-volume marker, choice of test-solutes to adequately probe the possible interactions and appropriate column length for characterization of chromatographic systems with highly eluting mobile phases are discussed. The importance of control experiments to validate retention models and confirm their accordance with the chromatographer's experience is evidenced. Recommendations for good linear solvation energy relationship practice are suggested in order to avoid the publication of results leading to erroneous conclusions. PMID- 21681958 TI - Synthesis of a difunctional orthogonal coupler for the preparation of carbohydrate-functionalized sP(EO-stat-PO) hydrogels. AB - The synthesis and characterization of a new difunctional coupler (4) based on trimethylolpropane (TMP) are described. The coupler is used to connect biologically active N-acetylglucosamine (GlcNAc) on amino-reactive microtiter plates and on star-shaped poly[(ethylene oxide)-stat-(propylene oxide)] hydrogel layers in microtiter plates. The biological activity of immobilized carbohydrates is determined using an enzyme-linked lectin assay. PMID- 21681959 TI - Synthesis of collagenase-sensitive polyureas for ligament tissue engineering. AB - Recently, poly(ester urethanes) were investigated for use as ligament grafts due to their exceptional mechanical properties and highly tunable structure; however, these grafts are susceptible to hydrolytic degradation that occurs independent of tissue regeneration. To address this limitation, polyureas containing collagen derived peptides were synthesized which enable cellular release of proteases to dictate degradation rate. It is hypothesized that this cell-responsive design will facilitate load transfer from the biodegradable scaffold to neotissue at a rate that promotes proper tissue orientation and function while maintaining construct integrity. PMID- 21681960 TI - Poly(D,L-lactide)-block-poly(2-hydroxyethyl acrylate) block copolymers as potential biomaterials for peripheral nerve repair: in vitro and in vivo degradation studies. AB - The properties of poly(D,L-lactide)-block-poly(2-hydroxyethyl acrylate) (PLA-b PHEA) block copolymers by means of in vitro / in vivo (rat) degradation are investigated and compared to those of PLA homopolymer. Over 12 weeks, we observe mass loss and molecular weight decrease. In vitro and in vivo findings are very similar for each polymer tested. When a short PHEA block is used (PLA-b-PHEA 15 000-3 000 g . mol(-1) , 85/15 wt%), the degradation process is found to be very similar to that of homo-PLA, and to be typical of a bulk erosion mechanism, with no mass loss observed until week 7 and continuous decrease of molar mass within this timeframe. For a longer PHEA block length within the block copolymer (PLA-b PHEA 15 000-7 500 g . mol(-1) , 65/35 wt%), the degradation mechanism is modified, with a significant mass loss observed at early times and only a slight decrease in molar mass. The latter finding is related to the pronounced hydrophilicity and softness of the material induced by the PHEA block, which allow easy diffusion and rapid leakage of the degradation residues from the material towards the aqueous medium. Schwann cells are found to better adhere on spin-coated films of PLA-b-PHEA (85/15 wt%) than on PLA ones. These results show the potential of such hydrophilized PLA-based copolymers for use in peripheral nerve repair. PMID- 21681961 TI - Parallel production and verification of protein products using a novel high throughput screening method. AB - Protein production and analysis in a parallel fashion is today applied in laboratories worldwide and there is a great need to improve the techniques and systems used for this purpose. In order to save time and money, a fast and reliable screening method for analysis of protein production and also verification of the protein product is desired. Here, a micro-scale protocol for the parallel production and screening of 96 proteins in plate format is described. Protein capture was achieved using immobilized metal affinity chromatography and the product was verified using matrix-assisted laser desorption ionization time-of-flight MS. In order to obtain sufficiently high cell densities and product yield in the small-volume cultivations, the EnBase(r) cultivation technology was applied, which enables cultivation in as small volumes as 150 MUL. Here, the efficiency of the method is demonstrated by producing 96 human, recombinant proteins, both in micro-scale and using a standard full-scale protocol and comparing the results in regard to both protein identity and sample purity. The results obtained are highly comparable to those acquired through employing standard full-scale purification protocols, thus validating this method as a successful initial screening step before protein production at a larger scale. PMID- 21681962 TI - Filtration kinetics of chitosan separation by electrofiltration. AB - Downstream processing of chitosan requires several technological steps that contribute to the total production costs. Precipitation and especially evaporation are energy-consuming processes, resulting in higher costs and limiting industrial scale production. This study investigated the filtration kinetics of chitosan derived from cell walls of fungi and from exoskeletons of arthropods by electrofiltration, an alternative method, thus reducing the downstream processing steps and costs. Experiments with different voltages and pressures were conducted in order to demonstrate the effect of both parameters on filtration kinetics. The concentration of the biopolymer was obtained by the average factor of 40 by applying an electric field of 4 V/mm and pressure of 4 bars. A series of analytical experiments demonstrated the lack of structural and functional changes in chitosan molecules after electrofiltration. These results, combined with the reduction of energy and processing time, define the investigated method as a promising downstream step in the chitosan production technology. PMID- 21681963 TI - Fast and easy protocol for the purification of recombinant S-layer protein for synthetic biology applications. AB - A goal of synthetic biology is to make biological systems easier to engineer. One of the aims is to design, with nanometer-scale precision, biomaterials with well defined properties. The surface-layer protein SbpA forms 2D arrays naturally on the cell surface of Lysinibacillus sphaericus, but also as the purified protein in solution upon the addition of divalent cations. The high propensity of SbpA to form crystalline arrays, which can be simply controlled by divalent cations, and the possibility to genetically alter the protein, make SbpA an attractive molecule for synthetic biology. To be a useful tool, however, it is important that a simple protocol can be used to produce recombinant wild-type and modified SbpA in large quantities and in a biologically active form. The present study addresses this requirement by introducing a mild and non-denaturing purification protocol to produce milligram quantities of recombinant, active SbpA. PMID- 21681964 TI - Multiplexing and demultiplexing logic functions for computing signal processing tasks in synthetic biology. AB - Building biological devices to perform computational and signal processing tasks is one of the main research issues in synthetic biology. Herein, two modular biological systems that could mimic multiplexing and demultiplexing logic functions are proposed and discussed. These devices, called multiplexer (mux) and demultiplexer (demux), respectively, have a remarkable importance in electronic, telecommunication, and signal processing systems and, similarly, they could play a crucial role if implemented in a living organism, such as Escherichia coli. BioBrick standard parts were used to design mux and demux and to construct two genetic circuits that could carry out the desired tasks. A modular approach, mimicking basic logic gates (AND, OR, and NOT) with protein/autoinducer or protein/DNA interactions and interconnecting them to create the final circuits, was adopted. A mathematical model of the designed gene networks was been defined and simulations performed to validate the expected behavior of the systems. In addition, circuit subparts were tested in vivo and the results used to determine some of the parameters of the mathematical model. According to both the experimental and simulated results, guidelines for future finalization of mux and demux are provided. PMID- 21681965 TI - Synthetic biology methodology and model refinement based on microelectronic modeling tools and languages. AB - In microelectronics, the design of new systems is based on a proven time-tested design flow. The goal of this paper is to determine to what extend this design flow can be adapted to biosystem design. The presented methodology is based on a top-down approach and consists of starting with a behavioral description of the system to progressively refine it to its final low-level system representation, composed of DNA parts. To preserve accuracy and simplicity, the design flow relies on refined models of biological mechanisms, which can be expressed by the hardware description languages and simulation tools traditionally used in microelectronics. A case study, the complete modeling of a priority encoder, is presented to demonstrate the effectiveness of the method. PMID- 21681966 TI - Empirical model and in vivo characterization of the bacterial response to synthetic gene expression show that ribosome allocation limits growth rate. AB - Synthetic biology uses modeling to facilitate the design of new genetic constructions. In particular, it is of utmost importance to model the reaction of the cellular chassis when expressing heterologous systems. We constructed a mathematical model for the response of a bacterial cell chassis under heterologous expression. For this, we relied on previous characterization of the growth-rate dependence on cellular resource availability (in this case, DNA and RNA polymerases and ribosomes). Accordingly, we estimated the maximum capacities of the cell for heterologous expression to be 46% of the total RNA and the 33% of the total protein. To experimentally validate our model, we engineered two genetic constructions that involved the constitutive expression of a fluorescent reporter in a vector with a tunable origin of replication. We performed fluorescent measurements using population and single-cell fluorescent measurements. Our model predicted cell growth for several heterologous constructions under five different culture conditions and various plasmid copy numbers with significant accuracy, and confirmed that ribosomes act as the limiting resource. Our study also confirmed that the bacterial response to synthetic gene expression could be understood in terms of the requirement for cellular resources and could be predicted from relevant cellular parameters. PMID- 21681967 TI - Programming microbial population dynamics by engineered cell-cell communication. AB - A major aim of synthetic biology is to program novel cellular behavior using engineered gene circuits. Early endeavors focused on building simple circuits that fulfill simple functions, such as logic gates, bistable toggle switches, and oscillators. These gene circuits have primarily focused on single-cell behaviors since they operate intracellularly. Thus, they are often susceptible to cell-cell variations due to stochastic gene expression. Cell-cell communication offers an efficient strategy to coordinate cellular behavior at the population level. To this end, we review recent advances in engineering cell-cell communication to achieve reliable population dynamics, spanning from communication within single species to multispecies, from one-way sender-receiver communication to two-way communication in synthetic microbial ecosystems. These engineered systems serve as well-defined model systems to better understand design principles of their naturally occurring counterparts and to facilitate novel biotechnology applications. PMID- 21681968 TI - First BRET-based screening assay performed in budding yeast leads to the discovery of CDK5/p25 interaction inhibitors. AB - The protein kinase CDK5 (cyclin-dependent kinase 5) is activated through its association with a cyclin-like protein p35 or p39. In pathological conditions (such as Alzheimer's disease and various other neuropathies), truncation of p35 leads to the appearance of the p25 protein. The interaction of p25 with CDK5 up regulates the kinase activity and modifies the substrate specificity. ATP-mimetic inhibitors of CDK5 have already been developed. However, the lack of selectivity of such inhibitors is often a matter of concern. An alternative approach can be used to identify highly specific inhibitors that disrupt protein interactions involving protein kinases. We have developed a bioluminescence resonance energy transfer (BRET)-based screening assay in yeast to discover protein-protein interaction inhibitors (P2I2). Here, we present the first use of BRET in yeast for the screening of small molecule libraries. This screening campaign led to the discovery of one molecule that prevents the interaction between CDK5 and p25, thus inhibiting the protein kinase activity. This molecule may give rise to high specificity drug candidates. PMID- 21681969 TI - An in silico approach for the discovery of CDK5/p25 interaction inhibitors. AB - The lack of selectivity of all existing ATP competitive inhibitors for a single cyclin-dependent kinase (CDK) has led us to redirect the structure-based molecule design from targeting the classic ATP-binding pocket in CDK5 toward the CDK5/p25 interface. The aim was to seek novel inhibition mechanisms to interrupt protein protein interactions. A combined strategy of alanine-scanning calculations for locating binding sites, virtual screening for small molecules, molecular dynamics simulations for examining the binding stability of virtual screening hits and bio assays for testing the level of inhibition was set up and used to explore novel inhibitors capable of interrupting the interactions between the proteins, and consequently of inhibiting the kinase activity. Two compounds were shown to inhibit the complex formation between CDK5 and p25 through p25 binding. They could open avenues for the discovery of new types of structures that prevent interactions between CDK5 and p25 or other CDK and activator proteins, and, more importantly, provide leads in the development of selective inhibitors among CDKs. PMID- 21681970 TI - Cytodiagnosis of primary thyroid lymphoma with histologic correlation: A case report. AB - Primary thyroid lymphoma is a very rare disease. Here, we present a case of primary diffuse large B-cell lymphoma (DLBCL) in a 48-year-old female involving thyroid gland. The patient had thyroid swelling for 15 years which rapidly increased during last 5 months. Fine needle aspiration cytology revealed monomorphic large cells arranged discretely. The cells have high nuclear cytoplasmic ratio with prominent single to multiple nucleoli. Aggregates of thyroid follicular cells were absent in the smears. A cytodiagnosis of DLBCL was made and a differential diagnosis of lymphocytic thyroiditis was also included. Subsequent histologic examination revealed a high-grade non-Hodgkin lymphoma (NHL). Immunohistochemistry showed the tumor cells expressing CD45, CD20, BCl-6, and tumor cells were negative for cytokeratin, epithelial membrane antigen, CD3, CD5, and CD30. Proliferative index (Ki-67) was very high (70%). Thus, a final diagnosis of NHL of DLBCL subtype was established. The patient was treated with R CHOP (rituximab, cyclophosphamide, doxorubicin, vincristin, prednisone) and radiotherapy. The patient is under one-year follow-up which is uneventful. PMID- 21681971 TI - Cytomorphologic features of advanced lung adenocarcinomas tested for EGFR and KRAS mutations: a retrospective review of 50 cases. AB - Associations between bronchioloalveolar carcinoma (BAC), mucinous differentiation, and epidermal growth factor receptor (EGFR) and KRAS mutations have been previously reported in studies of surgical specimens. We present the cytomorphology of lung adenocarcinomas, including metastases that were diagnosed by cytologic methods and the relationship to both EGFR and KRAS mutational status. We retrospectively reviewed the clinical and cytomorphologic features of 50 lung adenocarcinomas that were tested for both EGFR and KRAS mutations. Cytomorphologic features evaluated included cell size, architectural pattern, nucleoli, intranuclear cytoplasmic inclusions (INCI), mucin, necrosis, squamoid features, lymphocytic response, and histologic features of BAC differentiation. DNA was extracted from a paraffin-embedded cell block or frozen needle core fragments. Exon 19 deletions and the L858R mutation in exon 21 of EGFR were detected using PCR followed by capillary electrophoresis for fragment sizing. KRAS mutational analysis was performed by real-time PCR using a set of seven different Taqman(r) allelic discrimination assays to detect six mutations in codon 12 and one mutation in codon 13. Six cases (12%) showed EGFR mutations, 12 (24%) showed KRAS mutations, and 38 (62%) contained neither EGFR nor KRAS mutations. The majority of patients had stage IV disease (78%); 20 samples (40%) were from metastatic sites. The presence of prominent INCI (P = 0.036), papillary fragments (P = 0.041), and histologic features of BAC on paraffin block (P = 0.039) correlated with the presence of EGFR mutations. The presence of necrosis (P = 0.030), squamoid features (P = 0.048), and poorly differentiated tumors (P = 0.025) were more likely to be identified in the KRAS positive group. PMID- 21681972 TI - Ciliated cells in abdominal or pelvic fine needle aspirations: a case report and review of the literature. AB - Ciliated cells encountered outside of an expected anatomical location (e.g., the respiratory tract, fallopian tube, etc) can represent a diagnostic difficulty for the cytopathologist, especially during preliminary assessment of a fine needle aspiration (FNA) for adequacy or malignancy. We present the cytologic and histologic features of a FNA and needle core biopsy, respectively, of an abdominal mass, likely from a gastrointestinal duplication cyst, foregut cyst or a bronchogenic cyst. We also briefly review the differential diagnosis for ciliated cells encountered in abdominal or pelvic FNAs. PMID- 21681973 TI - Imprint cytological findings of acquired cystic disease-associated renal-cell carcinoma: a close relationship to papillary renal-cell carcinoma. PMID- 21681974 TI - Clinical and immunological characteristics associated with the presence of protozoa in sputum smears. AB - The objective of this study is to assess the relationship between protozoa in spontaneously expectorated sputum samples and a range of clinical and immunological variables. Clinical details including age, gender, smoking status, and use of oral or inhaled steroids were recorded for a cohort of 199 patients whose spontaneously expectorated sputum samples were submitted to a Cytology Laboratory in Spain between January 2005 and December 2006. Slides were scanned for protozoa under light microscopy and scanned for monocytes/small macrophages highlighted by immunocytochemistry (CD68 monoclonal antibody). One hundred ninety one patients provided adequate sputum samples, of whom 70 had protozoa in their sputum. There was a strong relationship between the presence of protozoa and monocytes/small macrophages identified under light microscopy (P < 0.001). A binary logistic regression model also indicated a relationship between protozoa and both smoking status and steroid use. The diagnoses in those with protozoa included infection (including tuberculosis), chronic obstructive pulmonary disease (COPD), lung fibrosis, asthma, chronic liver disease, immunosuppression, cancer, pancreatic or renal disease, heart failure, and AIDS. The identified association between protozoa and monocytes/small macrophages in sputum suggests an immune response and warrants further investigation to clarify whether or not these organisms have any pathological significance in this wide range of conditions. PMID- 21681975 TI - Modified technique of toluidine blue staining in rapid on-site evaluation. PMID- 21681976 TI - The Bethesda system for reporting thyroid cytopathology: An experience of 1,382 cases in a community practice setting with the implication for risk of neoplasm and risk of malignancy. AB - The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) has provided a set of uniform diagnostic terminology including benign (B), atypia of undetermined significance (AUS), follicular neoplasm (FN), suspicious for malignancy (SM), malignancy (M), and nondiagnostic (ND) for the interpretation of thyroid fine-needle aspiration (FNA). We applied this terminology on our 1,382 thyroid aspirates in a community practice setting, which included 539 cases of B (39%), 376 cases of AUS (27.2%), 116 cases of FN (8.4%), 37 cases of malignant (2.7%), 36 cases of SM (2.6%), and 278 cases of ND (20.1%). Two hundred twenty one cases (16%) of thyroid FNA had corresponding follow-up thyroidectomies. Each diagnostic category represented a unique association with risk of malignancy and risk of neoplasm. Based on histologic follow-up, the risk of neoplasm (including benign and malignant neoplasm) was B 14%, AUS 44%, FN 67%, SM 77%, and M 100% and the risk of malignancy was B 3%, AUS 6%, FN 22%, SM 56%, and M 100%. The classification and follow-up recommendation of TBSRTC are appropriate for each category. Both B and AUS are low-risk lesions with low probability of malignancy. FN predicts a higher rate for neoplasm but an intermediate rate for malignancy while SM carries a high risk for malignancy. PMID- 21681977 TI - Palpable lesions as a diagnostic tool in patients with thoracic pathology. AB - Palpable lesion(s) noticed in a patient with thoracic disease may be a useful diagnostic tool and it often gives a clue for further management. In this study, we searched the diagnostic value of palpable lesions in patients with thoracic pathology suspected clinically and/or radiologically. We prospectively examined the correlations of clinical/radiologic and pathologic findings of 72 palpable lesions from 68 patients who presented with suspect for a thoracic disease from two tertiary medical centers. Thirty-two lesions (44.4%) were diagnosed as malignant either by fine-needle aspiration (FNA) only or FNA with confirmatory biopsy. The most common malignancy was non-small-cell carcinoma (10) followed by adenocarcinoma (6), and small-cell carcinoma (5). The most common localization of the palpable lesions was cervical region (20.8%) followed by left supraclavicular (13.8%) and anterior chest wall (13.8%). FNA was effective in obtaining an accurate diagnosis in 66.6% of the patients. Tissue confirmation of FNA was performed in 54 patients. The sensitivity, specificity, negative predictive value, and positive predictive value of FNA in distinguishing a malignant lesion from a benign disease for these palpable lesions were 75, 97, 96, and 80, respectively. One false negativity and one false positivity were also found. Abnormal radiologic features were not correlated with having a malignant palpable lesion. Evaluation of the palpable lesions by FNA and tissue biopsy together is effective for initial triage of the patients with suspect for a thoracic pathology. FNA alone is a convenient and easy method for this purpose especially when the material is immediately assessed for specimen adequacy. PMID- 21681978 TI - Acute bronchial obstruction in preschool children: change from nebulizers to metered dose inhalers with spacers. PMID- 21681979 TI - Concordance between tuberculin skin test and interferon-gamma assay and interferon-gamma response to mitogen in pediatric tuberculosis contacts. AB - There is paucity of data on the usefulness of Interferon (IFN)-gamma release assays in the diagnosis of latent tuberculosis infection (LTBI) in children. The aim of this study was to evaluate the concordance between tuberculin skin test (TST) and QuantiFERON(r)-TB Gold in-tube (QFT-GIT) test, when used in contact screening to diagnose LTBI in asymptomatic children. We also aimed to determine if there is any correlation between age and the IFN-gamma response to the mitogen. Children assessed at Leicester Royal Infirmary and Glenfield hospital (Leicester, United Kingdom) as part of tuberculosis contact screening were studied. Two hundred and eighty three children (mean [SD] age 5.3 [4.1] years, 148 males) underwent clinical examination, chest radiograph, TST, and QFT-GIT test. In this group, there was good agreement (kappa = 0.70 [95%CI = 0.57-0.83], P < 0.0001) between TST and QFT-GIT. Of the 18 children in this group with an indeterminate QFT-GIT test result, all except one were < 5-years-old. To study the correlation between age and the IFN-gamma response to the mitogen, results of 282 children who had QFT-GIT test as part of tuberculosis contact screening during the study period were analyzed. A significant correlation was observed between age and the IFN-gamma response to the mitogen (r = 0.47, P < 0.001). Whilst our study re-emphasizes the good overall concordance between TST and QFT GIT, the high rate of indeterminate results and the low IFN-gamma response to the mitogen seen in young children raise some concerns about the performance of IGRAs in this group. PMID- 21681980 TI - Culture conditions' impact on succinate production by a high succinate producing Escherichia coli strain. AB - This work aimed to identify the key operational factors that significantly affect succinate production by the high succinate producing Escherichia coli strain SBS550MG (pHL413), which bears mutations inactivating genes adhE ldhA iclR ackpta::Cm(R) and overexpresses the pyruvate carboxylase from Lactococcus lactis. The considered factors included glucose concentration, cell density, CO(2) concentration in the gas stream, pH, and temperature. The results showed that high glucose concentrations inhibited succinate production and that there is a compromise between the total succinate productivity and succinate specific productivity, where the total productivity increased with the increase in cell density and the specific productivity decreased with cell density, probably due to mass transfer limitation. On the other hand, a CO(2) concentration of 100% in the gas stream showed the highest specific succinate productivity, probably by favoring pyruvate carboxylation, increasing the OAA pool that later is converted into succinate. A full factorial design of experiments was applied to analyze the pH and temperature effects on succinate production in batch bioreactors, where succinate yield was not significantly affected by either temperature (37 to 43 degrees C) or pH (6.5 to 7.5). Additionally, the temperature effect on succinate productivity and titer was not significant, in the range tested. On the other hand, a pH of 6.5 showed very low productivity, whereas pH values of 7.0 and 7.5 resulted in significantly higher specific productivities and higher titers. The increase on pH value from 7.0 to 7.5 did not show significant improvement. Then, pH 7.0 should be chosen because it involves a lower cost in base addition. PMID- 21681981 TI - Immobilization and stability of a Rhizopus oryzae lipase expressed in Pichia pastoris: comparison between native and recombinant variants. AB - The stability of a soluble extract containing a recombinant lipase from Rhizopus oryzae (Cursive) lipase (rROL) produced by Pichia pastoris (Cursive), as well as that for the commercial extract containing the lipase produced by the native organism (nROL), was investigated. The results showed higher residual activity values of the commercial protein compared with the recombinant one. Moreover, two different kinds of support, the polypropylene powder EP100 and Eupergit(r)C, were tested to immobilize the enzymes. The residual activity of the immobilizated derivatives was also tested to determine whether their stability was enhanced. The results showed a slight improvement in rROL using both supports but a decrease in nROL using Eupergit(r)C. The study of the residual activity of soluble and immobilized enzymes was performed by means of a central composite rotatable experiment design. In addition, EP100 adsorption isotherms were determined. PMID- 21681982 TI - Robust estimation and inference for bivariate line-fitting in allometry. AB - In allometry, bivariate techniques related to principal component analysis are often used in place of linear regression, and primary interest is in making inferences about the slope. We demonstrate that the current inferential methods are not robust to bivariate contamination, and consider four robust alternatives to the current methods -- a novel sandwich estimator approach, using robust covariance matrices derived via an influence function approach, Huber's M estimator and the fast-and-robust bootstrap. Simulations demonstrate that Huber's M-estimators are highly efficient and robust against bivariate contamination, and when combined with the fast-and-robust bootstrap, we can make accurate inferences even from small samples. PMID- 21681983 TI - Tailored single crystals of triisopropylsilylethynyl pentacene by selective contact evaporation printing. PMID- 21681984 TI - Evolution of eukaryotic genome architecture: Insights from the study of a rapidly evolving metazoan, Oikopleura dioica: Non-adaptive forces such as elevated mutation rates may influence the evolution of genome architecture. AB - Recent sequencing of the metazoan Oikopleura dioica genome has provided important insights, which challenges the current understanding of eukaryotic genome evolution. Many genomic features of O. dioica show deviation from the commonly observed trends in other eukaryotic genomes. For instance, O. dioica has a rapidly evolving, highly compact genome with a divergent intron-exon organization. Additionally, O. dioica lacks the minor spliceosome and key DNA repair pathway genes. Even with a compact genome, O. dioica contains tandem repeats, comparable to other eukaryotes, and shows lineage-specific expansion of certain protein domains. Here, we review its genomic features in the context of current knowledge, discuss implications for contemporary biology and identify areas for further research. Analysis of the O. dioica genome suggests that non adaptive forces such as elevated mutation rates might influence the evolution of genome architecture. The knowledge of unique genomic features and splicing mechanisms in O. dioica may be exploited for synthetic biology applications, such as generation of orthogonal splicing systems. PMID- 21681985 TI - Five years of siRNA delivery: spotlight on gold nanoparticles. AB - Gold nanoparticles have become widely used in scientific research due to their unique physical and chemical properties. In the last several years their use as siRNA delivery agents has been investigated. Here, progress made using gold nanoparticles for siRNA delivery is described and the different strategies employed are compared. PMID- 21681986 TI - Mechanism of the switchable photovoltaic effect in ferroelectric BiFeO3. PMID- 21681987 TI - Abstracts of the 25th International Conference on Yeast Genetics and Molecular Biology. Olsztyn, Poland. July 11-16, 2011. PMID- 21681988 TI - Single MWNT-glass fiber as strain sensor and switch. PMID- 21681989 TI - Cephalopod origin and evolution: A congruent picture emerging from fossils, development and molecules: Extant cephalopods are younger than previously realised and were under major selection to become agile, shell-less predators. AB - Cephalopods are extraordinary molluscs equipped with vertebrate-like intelligence and a unique buoyancy system for locomotion. A growing body of evidence from the fossil record, embryology and Bayesian molecular divergence estimations provides a comprehensive picture of their origins and evolution. Cephalopods evolved during the Cambrian (~530 Ma) from a monoplacophoran-like mollusc in which the conical, external shell was modified into a chambered buoyancy apparatus. During the mid-Palaeozoic (~416 Ma) cephalopods diverged into nautiloids and the presently dominant coleoids. Coleoids (i.e. squids, cuttlefish and octopods) internalised their shells and, in the late Palaeozoic (~276 Ma), diverged into Vampyropoda and the Decabrachia. This shell internalisation appears to be a unique evolutionary event. In contrast, the loss of a mineralised shell has occurred several times in distinct coleoid lineages. The general tendency of shell reduction reflects a trend towards active modes of life and much more complex behaviour. PMID- 21681990 TI - Discovery of biomarker candidates for coronary artery disease from an APOE-knock out mouse model using iTRAQ-based multiplex quantitative proteomics. AB - Due to the lack of precise markers indicative of its occurrence and progression, coronary artery disease (CAD), the most common type of heart diseases, is currently associated with high mortality in the United States. To systemically identify novel protein biomarkers associated with CAD progression for early diagnosis and possible therapeutic intervention, we employed an iTRAQ-based quantitative proteomic approach to analyze the proteome changes in the plasma collected from a pair of wild-type versus apolipoprotein E knockout (APOE(-/-) ) mice which were fed with a high fat diet. In a multiplex manner, iTRAQ serves as the quantitative 'in-spectra' marker for 'cross-sample' comparisons to determine the differentially expressed/secreted proteins caused by APOE knock-out. To obtain the most comprehensive proteomic data sets from this CAD-associated mouse model, we applied both MALDI and ESI-based mass spectrometric (MS) platforms coupled with two different schemes of multidimensional liquid chromatography (2-D LC) separation. We then comparatively analyzed a series of the plasma samples collected at 6 and 12 wk of age after the mice were fed with fat diets, where the 6- or 12-wk time point represents the early or intermediate phase of the fat induced CAD, respectively. We then categorized those proteins showing abundance changes in accordance with APOE depletion. Several proteins such as the gamma and beta chains of fibrinogen, apolipoprotein B, apolipoprotein C-I, and thrombospondin-4 were among the previously known CAD markers identified by other methods. Our results suggested that these unbiased proteomic methods are both feasible and a practical means of discovering potential biomarkers associated with CAD progression. PMID- 21681991 TI - The chlorosome of Chlorobaculum tepidum: size, mass and protein composition revealed by electron microscopy, dynamic light scattering and mass spectrometry driven proteomics. AB - Chlorosomes, the antenna complexes of green bacteria, are unique antenna systems in which pigments are organized in aggregates. Studies on isolated chlorosomes from Chlorobaculum tepidum based on SDS-PAGE, immunoblotting and molecular biology have revealed that they contain ten chlorosomal proteins, but no comprehensive information is available about the protein composition of the entire organelle. To extend these studies, chlorosomes were isolated from C. tepidum using three related and one independent isolation protocol and characterized by absorption spectroscopy, tricine SDS-PAGE, dynamic light scattering (DLS) and electron microscopy. Tricine SDS-PAGE showed the presence of more than 20 proteins with molecular weights ranging between 6 and 70 kDa. The chlorosomes varied in size. Their hydrodynamic radius (R(h) ) ranged from 51 to 75 nm and electron microscopy indicated that they were on average 140 nm wide and 170 nm long. Furthermore, the mass of 184 whole chlorosome organelles determined by scanning transmission electron microscopy ranged from 27 to 237 MDa being on average 88 (+/-28) MDa. In contrast their mass-per-area was independent of their size, indicating that there is a strict limit to chlorosome thickness. The average protein composition of the C. tepidum chlorosome organelles was obtained by MS/MS-driven proteomics and for the first time a detailed protein catalogue of the isolated chlorosomal proteome is presented. Based on the proteomics results for chlorosomes isolated by different protocols, four proteins that are involved in the electron or ion transport are proposed to be tightly associated with or incorporated into C. tepidum chlorosomes as well as the ten Csm proteins known to date. PMID- 21681992 TI - Proteomic changes in articular cartilage of human endemic osteoarthritis in China. AB - Kashin-Beck disease (KBD) is a chronic endemic osteochondropathy with unclear pathogenesis. It is a degenerative disease similar to osteoarthritis, but with different manifestations of cartilage damage. The aim of this investigation was to show the protein changes in KBD cartilage and to identify the candidate proteins in order to understand the pathogenesis of the disease. Proteins were extracted from the media of primary cell cultures of KBD and normal chondrocytes, and separated by two-dimensional fluorescence difference gel electrophoresis (2-D DIGE). MALDI-TOF/TOF analysis revealed statistically significant differences in 27 proteins from KBD chondrocyte cultures, which consisted of 17 up-regulated and ten down-regulated proteins. The results were further validated by Western blot analysis. The proteins identified are mainly involved in cellular redox homeostasis and stress response (MnSOD, Hsp27, Peroxiredoxin-1, and Cofilin-1), glycolysis (PGK-1, PGM-1, alpha-enolase), and cell motility and cytoskeletal organization (Actin, Calponin-2, and Keratin). These KBD-associated proteins indicate that cytoskeletal remodeling, glycometabolism, and oxidative stress are abnormal in KBD articular cartilage. PMID- 21681994 TI - Biologically inspired hierarchical design of nanocomposites based on poly(ethylene oxide) and cellulose nanofibers. AB - Attempts to create hierarchically structured, uniaxially oriented nanocomposites comprising cellulose nanowhiskers (CNWs), which promise anisotropic mechanical properties, are exceedingly rare. We report here the fabrication of uniaxially oriented arrays of microfibers based on poly(ethylene oxide) (PEO) and CNWs by electrospinning. Compared with the neat PEO fibers, the incorporation of CNWs within the fibers increased the storage modulus (E') of arrays along the fiber axis of the PEO/CNW nanocomposite fibers. Successful incorporation of the CNWs within each of the as-spun PEO/CNW nanocomposite fibers in the direction parallel to the fiber axis was verified by both scanning and transmission electron microscopy. PMID- 21681995 TI - Psychometric development and reliability analysis of a patient satisfaction with interpersonal relationship with navigator measure: a multi-site patient navigation research program study. AB - BACKGROUND: Patient navigation (PN) is a method for addressing racial-ethnic and socioeconomically based disparities in cancer-related care. Patient navigators provide logistic and emotional support to underserved patients to facilitate successful completion of diagnostic and treatment care. Yet, little is known about patient satisfaction with the relationship with a navigator due to a dearth of instruments measuring satisfaction. OBJECTIVE: The objective of this study was to validate the Patient Satisfaction with Interpersonal Relationship with Navigator (PSN-I) measure for patients undergoing diagnostic and/or therapeutic cancer care. METHODS: We administered the PSN-I to 783 participants from the nine different sites of the National Cancer Institute sponsored Patient Navigation Research Program. We evaluated the latent structure and internal consistency of the PSN-I using principal components analysis (PCA) and Cronbach coefficient alpha (alpha), respectively. We used correlation analyses to examine divergence and convergence of the PSN-I with the Patient Satisfaction with Cancer-related Care (PSCC), the Rapid Estimate of Adult Literacy in Medicine (REALM) Long Form, and patients' demographics. RESULTS: The PCA revealed a coherent set of items that explicates 76.6% of the variance in PSN-I. Reliability assessment revealed high internal consistency (alpha ranging from 0.95 to 0.96). The PSN-I had good face validity as well as convergent and divergent validities as indicated by moderate correlations with score on the PSCC (all ps < 0.0001) and non significant correlations with primary language, marital status, and scores on the REALM Long Form (all ps > 0.05). CONCLUSION: The PSN-I is a valid and suitable measure of satisfaction with a patient navigator for the present sample. PMID- 21681996 TI - pH sensitive hierarchically self-organized bioinspired films. AB - In the present manuscript, we have demonstrated that hierarchically structured smart porous polymer films based on honeycomb-patterned surface can be elaborated from PS-b-P4VP pH-responsive block copolymer using the breath figure process. Despite the fast film formation by a bottom-up process, the copolymer nanostructuration was observed inside the walls of the honeycomb porous film. Atomic force microscopy (AFM), small angle X-ray and neutron scattering (SAXS and SANS) measurements were used to reveal both the hexagonal arrays formed by the pores at the micrometer length scale and the hexagonal copolymer self-assembly at the nanometer length scale. Contact angle (CA) measurements were used to point out the reversible pH-responsive wettability character of the surface. The PS-b P4VP honeycomb film shows a contact angle variation of 20 degrees between pH 9 and pH 3. An increase of the roughness was obtained with the pincushions hexagonal array enhancing the pH responsiveness of the polymer film with a switching CA gap of 75 degrees when pH tuned from pH 9 to pH 3. This work presents the first report on honeycomb porous and pincushion films exhibiting a reversible pH-responsive character. PMID- 21681997 TI - Exploration of the rapid effects of personal fine particulate matter exposure on arterial hemodynamics and vascular function during the same day. AB - BACKGROUND: Levels of fine particulate matter [<= 2.5 MUm in aerodynamic diameter (PM(2.5))] are associated with alterations in arterial hemodynamics and vascular function. However, the characteristics of the same-day exposure-response relationships remain unclear. OBJECTIVES: We aimed to explore the effects of personal PM(2.5) exposures within the preceding 24 hr on blood pressure (BP), heart rate (HR), brachial artery diameter (BAD), endothelial function [flow mediated dilatation (FMD)], and nitroglycerin-mediated dilatation (NMD). METHODS: Fifty-one nonsmoking subjects had up to 5 consecutive days of 24-hr personal PM(2.5) monitoring and daily cardiovascular (CV) measurements during summer and/or winter periods. The associations between integrated hour-long total personal PM(2.5) exposure (TPE) levels (continuous nephelometry among compliant subjects with low secondhand tobacco smoke exposures; n = 30) with the CV outcomes were assessed over a 24-hr period by linear mixed models. RESULTS: We observed the strongest associations (and smallest estimation errors) between HR and TPE recorded 1-10 hr before CV measurements. The associations were not pronounced for the other time lags (11-24 hr). The associations between TPE and FMD or BAD did not show as clear a temporal pattern. However, we found some suggestion of a negative association with FMD and a positive association with BAD related to TPE just before measurement (0-2 hr). CONCLUSIONS: Brief elevations in ambient TPE levels encountered during routine daily activity were associated with small increases in HR and trends toward conduit arterial vasodilatation and endothelial dysfunction within a few hours of exposure. These responses could reflect acute PM(2.5)-induced autonomic imbalance and may factor in the associated rapid increase in CV risk among susceptible individuals. PMID- 21681998 TI - High prevalence of bla(CTX-M) extended-spectrum beta-lactamase genes in Escherichia coli isolates from pets and emergence of CTX-M-64 in China. AB - As a cause of community-acquired infections, extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli constitute an emerging public-health concern. Few data on the molecular epidemiology of ESBL-producing E. coli isolates from pets are available in China. Detection and characterization of ESBL genes (bla(CTX-M), bla(SHV) and bla(TEM)) was conducted among 240 E. coli isolates recovered from healthy and sick pets in South China from 2007 to 2008. The clonal relatedness of ESBL-producing E. coli isolates was assessed by pulsed field gel electrophoresis. ESBL-encoding genes were identified in 97 (40.4%) of the 240 isolates and 96 (40.0%) of them harbored CTX-M. The most common CTX-M types were CTX-M-14 (n = 45) and CTX-M-55 (n = 24). The recently reported CTX-M-64 was identified in three isolates. Isolates producing CTX-M-27, -15, -65, -24, -3 and 9 were also identified. Ten isolates carried two or three CTX-M types, with the combination of CTX-M-14 and CTX-M-55 being the most frequent (n = 6). ISEcp1 was identified in the upstream region of 93 out of the 107 bla(CTX-M) genes (86.9%). The sequence of the spacer region (45 bp) between ISEcp1 and the start codon of all bla(CTX-M-55) genes (except four) was identical to that of bla(CTX-M-64). No major clonal relatedness was observed among these CTX-M producers. It is suggested that the horizontal transfer of bla(CTX-M) genes, mediated by mobile elements, contributes to their dissemination among E. coli isolates from pets. Our finding of high prevalence of ESBL in E. coli of companion animal origin illustrates the importance of molecular surveillance in tracking CTX-M-producing E. coli strains in pets. PMID- 21681999 TI - Extending the vermilion glow. PMID- 21682000 TI - Clark Millikan, MD (1915-2011). PMID- 21682001 TI - Retraction notice to: "Electrical stimulation enhanced remyelination of injured sciatic nerves by increasing neurotrophins" [Neuroscience 169 (2010) 1029-1038]. PMID- 21682002 TI - Efficiency of glaucoma drug regulation in 5 European countries: a 1995-2006 longitudinal prescription analysis. AB - PURPOSE: To compare the evolution of prostaglandin analog (PGA) and beta-blocker (BB) prescriptions across 5 European countries. METHODS: Data were extracted from various sources: (1) IMS data for France, Germany, Italy, Spain, and the United Kingdom, (2) glaucoma-treated patients from the United Kingdom General Practice Research Database (UK-GPRD), (3) prescriptions delivered by the territorial pharmaceutical service of Monselice of the Padova region (Italy). Drugs were grouped into 3 classes: PGAs, BBs, and other drugs. Yearly market shares were calculated. Treatment persistence survival curves were estimated for Italian and UK data, and the 3 drug groups were compared using the Cochran Mantel Haenszel test. RESULTS: According to Padova data, BBs decreased in market share, whereas PGAs increased. A linear extrapolation of these market shares, based on 1998 to 2003 data, predicted that the 2 curves should cross in 2005, a prediction reinforced by the European Medicines Agency authorization (2002) of PGAs as first line glaucoma treatments. That this did not occur may be explained by Italy's refusal to reimburse PGAs as first-line therapy. IMS data identified Italy and Germany as 2 countries in which BBs are still more frequently prescribed than PGAs. Treatment persistence with PGAs as monotherapy, in PGA-naive patients, was longer than for BBs according to both Padova and UK-GPRD data. This held true for both first-line and second-line PGA prescriptions (UK-GPRD); the persistence of second-line PGA equalled first-line BB treatment. CONCLUSION: Health care regulations impacted upon glaucoma prescribing and may be one of the reasons for different annual evolution rates of PGA and BB prescriptions. PMID- 21682003 TI - Surveillance VLA disease surveillance report: Rare form of meningoencephalitis in young cattle. PMID- 21682005 TI - Abstracts of Perinatal Medicine 2011. June 15-17, 2011. Harrogate, United Kingdom. PMID- 21682004 TI - Fieldwork: Close quarters. PMID- 21682006 TI - Severe winter weather affects the health of scottish livestock. PMID- 21682007 TI - A fond farewell to Ernest A. McCulloch--a beacon who inspired generations of scientists and framed the foundation of modern stem cell biology. PMID- 21682008 TI - Abstracts of the 13th World Congress on the Menopause. June 8-11, 2011. Rome, Italy. PMID- 21682009 TI - [Research subject to approval or clinical patient care?]. PMID- 21682010 TI - Proceedings of Trauma Melbourne 2009 and the Trauma Research Methods and Practice Workshop. November 19-21, 2009. Melbourne, Australia. PMID- 21682011 TI - HIV in Europe--no longer business as usual. PMID- 21682012 TI - Surveillance, co-infection, resistance: tuberculosis in Europe. PMID- 21682013 TI - Vaccines and public health in Europe. PMID- 21682014 TI - Strontium ranelate: too many adverse effects. PMID- 21682015 TI - Fenofibrate: altered renal function. AB - In patients with type 2 diabetes, a subgroup analysis of a placebo-controlled trial of fenofibrate showed a significant decline in calculated creatinine clearance with fenofibrate. Most fibrates seem to have a detrimental effect on renal function, with the probable exception of gemfibrozil, which is the fibrate of choice in the few situations in which a fibrate is needed. PMID- 21682016 TI - Bevacizumab, sunitinib: osteonecrosis of the jaw. PMID- 21682017 TI - Venous sclerosants: distant ischaemic disorders. PMID- 21682018 TI - Even when regulated, advertising is still advertising. AB - The Swiss authorities have tried to make drug advertising less misleading by insisting that it be evidence-based. However, a study conducted 3 years after the legislation was enacted showed that half of the claims made in drug ads were not backed up by the references cited or were based on biased information. PMID- 21682019 TI - Tonsillectomy practice in South Africa. PMID- 21682020 TI - Baby friendly initiative. PMID- 21682021 TI - That personal touch. PMID- 21682023 TI - Will unity defeat parochialism? PMID- 21682022 TI - Case study. To tell or not to tell. Commentary. PMID- 21682024 TI - [Cord like thickening of both palms. Patient has no complaints. Dupuytren's disease]. PMID- 21682025 TI - [Not every abdominal discomfort is EHEC: when is truly threatening (interview by Dr. med. Brigitte Moreano)]. PMID- 21682026 TI - [Future work for health care. Complex illnesses need more than just drugs (interview by Wolfgang van den Bergh)]. PMID- 21682027 TI - [Even when the cancer has long been over, the late sequelae of therapy are a threat: after-care for life]. PMID- 21682028 TI - [Diabetic polyneuropathy. How do you relieve the pain?]. PMID- 21682029 TI - [Naturopathy consultation. Depressive symptoms]. PMID- 21682030 TI - [Incidental splenic cysts finding. How great is the risk of rupture?]. PMID- 21682031 TI - [Asbestos-induced diseases: an on-going problem]. PMID- 21682032 TI - [Benign asbestos related diseases]. PMID- 21682033 TI - [Asbestos-induced malignant pulmonary and pleural diseases]. PMID- 21682034 TI - [Emergency checklist: pelvic ring fractures]. PMID- 21682035 TI - [Attempted homicide or legal termination of treatment?]. PMID- 21682036 TI - [Can weight reduction normalize blood pressure?]. PMID- 21682037 TI - [Opioid-related bowel dysfunction]. PMID- 21682038 TI - [Distal aortic repair after aortic arch replacement]. AB - BACKGROUND: It is crucial to expose the proximal aorta in distal aortic repair, i.e., replacement of the descending thoracic aorta (DTA) or the thoracoabdominal aorta (TAA), after aortic arch replacement. With the elephant trunk (ET), it is usually easy to expose and clamp it. On the other hand, without the ET, it may be difficult or impossible to expose the proximal aorta and deep hypothermic circulatory arrest (DHCA) will be required. METHODS: Between April 1989 and March 2007, 17 patients underwent distal aortic repair after aortic arch replacement. Five patients underwent replacement of DTA and 12 of TAA. Five patients without the ET needed DHCA and open proximal anastomosis [OP (+) group], while in 12 patients, the ET or proximal aorta was successfully clamped [OP (-) group]. RESULTS: The mean extracorporeal circulation time in OP (+) group was significantly longer than that in OP (-) group (415 +/- 131 min v.s. 267 +/- 109 min, p < 0.05). There was no hospital death, cerebral infarction, fatal arrhythmia or low output syndrome in either group, and paraplegia in 2 patients and renal failure requiring hemodialysis in one were found only in OP (+) group. CONCLUSION: The ET procedure enables to avoid DHCA and may contribute to improving operative results in distal aortic repair after aortic arch replacement. PMID- 21682039 TI - [Clinical assessment of granulocyte colony-stimulating factor producing lung cancer]. AB - OBJECTIVE: The aim of this study was to reveal the clinicopathological feature of granulocyte colony-stimulating factor (G-CSF) producing lung cancer. METHOD: Nine cases of G-CSF producing lung cancer from July 2003 to July 2008 were retrospectively evaluated. RESULTS: All cases were male, 8 cases were poorly differentiated carcinoma. Average of leucocyte and serum G-CSF were 23,378/microl and 128.6 pg/ml respectively. Five cases had febrile symptom, average of serum C reactive protein (CRP) was 13.37 mg/dl. Immunohistological examination showed positive staining for G-CSF in 6 cases. Serum interleukin-6 (IL-6) level was elevated in 3 cases. Clinical stages were IB in 2, IIB in 2, IIIA in 3 and IIIB in 2 patients. Chemotherapy was performed for patients with stage IIIB. Operation was performed for the other cases. Five cases were died within 12 months, whereas 4 cases are surviving for 6 to 16 months. CONCLUSION: Generally, the prognosis of G-CSF producing lung cancer seems to be poor, but in our institute there were 2 cases who lived over 1 year without disease. It is important to establish more effective adjuvant therapy for G-CSF producing tumor. PMID- 21682040 TI - [Treatment strategy of cardiac rupture due to blunt trauma]. AB - Cardiac trauma is common in blunt injuries of the chest. However, survival after a cardiac rupture is not common, and only a certain percentage of the patients reach the hospital alive. We report on 3 cases of successful treatment of cardiac rupture due to blunt trauma; one by emergency surgical repair, and the others, conservative medical treatment. Echocardiography and computed tomography demonstrated pericardial effusion in all cases, and emergency pericardial drainage was performed. Gas analyses of arterial blood and pericardial effusion were made simultaneously. When the oxygen saturation levels of the pericardial effusion were lower than those of the arterial blood, we suspected the cardiac injury to be right-sided. When they were almost at the same level, we suspected it to be left-sided. Simultaneous gas analysis of arterial blood and pericardial effusion is considered to be an easy and useful diagnostic method to decide not only treatment strategy, but also operative approach and procedure in patients suffering from cardiac tamponade following cardiac injuries. PMID- 21682041 TI - [Acute forearm compartment syndrome after total arch replacement]. AB - A 61-year-old female presented with shortness of breath and was found to have moderate aortic regurgitation with annulo-aortic ectasia and an aneurysm involving the aortic arch. She underwent Bentall operation and total arch replacement with a branched prosthesis. The patient developed hypesthesia and paresis of the left forearm one day after the surgery. Computed tomography revealed complete occlusion of the left subclavian artery (LSA). An emergency operation was performed 15 hours after the initial operation. A new bypass graft to the axillary artery was placed since the LSA was occluded by the wide arterial dissection. However, her left forearm showed rapid swelling within a few hours. Under the diagnosis of acute compartment syndrome (ACS) of the forearm, emergency decompression fasciotomy was performed. She was discharged with a mild dysfunction of her forearm and hand 40 days after the operation. The rapid progression of ACS was thought to have been associated with not only the severe and prolonged ischemia but also the venous obstruction caused by the ligation of left brachiocephalic vein during the initial operation. Immediate and complete decompression, including the deep compartment of the forearm, was essential to achieve a full functional recovery from ACS. PMID- 21682042 TI - [Malignant lymphoma of lung with hypersensitivity pneumonitis]. AB - We report a resected case of malignant lymphoma with hypersensitivity pneumonitis. A 62-year-old woman, who presented with fever, wheeze and dry cough was referred to our department under the diagnosis of malignant B cell lymphoma in lower lobe of the left lung and hypersensitivity pneumonitis. She underwent left lower lobectomy as a therapy for malignant lymphoma. Pathological findings showed multiple small nodules macroscopically, which was observed as bronchiolocentric interstitial pneumonitis with lymphocytes microscopically. Post operative course was uneventful and no sign of acute exacerbation was seen. It is rare that lung with hypersensitivity pneumonitis is observed as a macroscopical specimen. Hypersensitivity pneumonitis differs from idiopathic pulmonary fibrosis, but we have to take care of post operative course because post operative acute exacerbation was reported. PMID- 21682043 TI - [Reconstruction of the superior vena cava by artificial graft bypass between right brachiocephalic vein and right atrial appendage preserving azygos vein circulation for mediastinal non-seminomatous germ cell tumor]. AB - A 24-year-old man was admitted to our hospital for surgical resection of mediastinal non-seminomatous germ cell tumor after 4 courses of BEP therapy (cisplatin, bleomycin, etoposide). Although it became markedly smaller after chemotherapy, the tumor invaded the superior vena cava (SVC) and the left brachiocephalic vein (LBCV). Venogram demonstrated SVC obstruction above the azygos vein and missing LBCV. A blood return from the left upper limb was shown through thoracodorsal vein, intercostal vein, and accessory hemi-azygos continuation. Excision of residual tumor with SVC and LBCV was done through a median sternotomy. Vascular reconstruction was performed between the right brachiocephalic vein and the right atrial appendage with ringed polytetrafluoroethylene graft. SVC was sutured just above the azygos vein to preserve collateral circulation. LBCV reconstruction was abandoned because distal end of LBCV was entirely surrounded by postchemotherapy scar tissue. Venous occlusive symptoms were not seen in both intraoperative and postoperative period. PMID- 21682044 TI - [Coronary artery bypass grafting after total esophagectomy]. AB - A 69-year-old male with a history of total esophagectomy and substernal placement of the gastric tube for esophageal carcinoma was admitted due to an unstable angina. Cardiac catheterization revealed a severe stenosis just proximal to the left anterior descending coronary artery and a 75% stenosis of the right coronary artery. Intraaortic balloon pumping was started in the catheter laboratory. Off pump coronary artery bypass grafting was performed through left thoracotomy. The left internal mammary artery could not be utilized as a bypass graft to the left anterior descending artery due to severe substernal adhesion. Percutaneous coronary intervention was selected for the revascularization of the right coronary artery lesion. PMID- 21682045 TI - [Hybrid procedure for combined descending thoracic and abdominal aortic aneurysms]. AB - In patients with previous infrarenal abdominal aortic aneurysm (AAA) repair, the risk of spinal cord ischemia increases after thoracic endovascular aortic repair (TEVAR) for a descending thoracic aortic aneurysm (DTAA). The case is a 67-year old man with a 60 mm infrarenal AAA and a 73 mm DTAA. We performed the staged hybrid procedure for these aortic aneurysms. First of all we underwent a conventional AAA repair. The bilateral internal iliac arteries and a inferior mesenteric artery were preserved. In addition, the right leg of the tube graft was anastomosed to the right superficial femoral artery to facilitate access of TEVAR. Two months later we performed TEVAR for the DTAA. DTAA extended from the level of the 7th thoracic vertebra to that of the 11th thoracic vertebra. Although there was a certain risk of paraplegia, no complications occurred. The hybrid procedure for combined DTAA and AAA may be a valuable option. PMID- 21682046 TI - [Radical resection following to concurrent chemoradiotherapy for eighty-five year old patient with superior sulcus tumor]. AB - An 85-year-old male with superior sulcus tumor was referred to our hospital complaining right brachial pain and omalgia. Chest computed tomography showed right apical lung tumor involving the 1st rib, and bronchoscopy established a diagnosis of squamous cell carcinoma, cT3NOM0. After concurrent chemoradiotherapy [cisplatin (CDDP) + 60 Gy], functional examination indicated him to be tolerable to lobectomy, and he underwent right upper lobectomy + chest wall resection (1st 3rd ribs) + lymph-node dissection. Pathological examination revealed that the effect of chemoradiotherapy was Ef. 3. The postoperative course was uneventful. He is free from recurrence for 7 years after the surgery. PMID- 21682047 TI - [Bronchioloalveolar carcinoma producing CA19-9]. AB - A 76-year-old man, who had underwent radiation for laryngeal cancer 5 years before, was pointed out abnormal pulmonary lesion on computed tomography. The 4.6 cm-sized lesion was seen in the upper lobe of the left lung. Endoscopic brushing cytology revealed adenocarcinoma. The patient was diagnosed as primary lung cancer of T2N0M0, clinical stage IB. Preoperative serum CA19-9 was elevated to 250 U/ml, although other tumor markers were within normal limits. The patient underwent left upper lobectomy with mediastinal lymph node dissection. Histologically, the lesion was diagnosed as well differentiated adenocarcinoma, mucinous subtype of bronchioloalveolar carcinoma (BAC) in World Health Organization (WHO) classification. Immunohistochemistry shows positive for CA19-9 and thyroid transcription factor-1 (TTF-1). PMID- 21682048 TI - [Diaphragmatic hernia complicated with perforated stomach during pregnancy]. AB - Diaphragmatic hernia complicating pregnancy is rare and results in a high mortality rate, if early surgical intervention is not undertaken. We report a case of a woman at 32 week's gestation who was admitted to our hospital due to severe epigastralgia. Diaphragmatic relaxation had been pointed out since her birth. The patient was initially diagnosed with acute gastritis, but she developed acute respiratory insufficiency on day 3 of hospitalization. Chest X ray and computed tomography showed niveau in the left pleural cavity. She was treated with chest tube drainage and an emergency caesarean was performed. The next day, gastric fiberscope demonstrated perforation of gastric ulcer in the left hemithorax. She was diagnosed as having diaphragmatic hernia complicated by a perforated stomach. Emergency thoracotomy was carried out and primary repair of both stomach and diaphragma was performed. PMID- 21682049 TI - [Successful repair of penetrating cardiac injury with chopstick; report of a case]. AB - We used percutaneous cardiopulmonary support (PCPS) to resuscitate a 54-year-old man who had stabbed himself in the left anterior chest with a chopstick. Chest computed tomography showed that the chopstick had penetrated the heart. As he was in shock due to the development of tamponade while waiting for emergency surgery, we immediately decided to initiate PCPS. After cardiopulmonary bypass was established through a median sternotomy replacing PCPS, the chopstick was removed and the stab wounds were closed by mattress sutures. The postoperative course was uneventful. PMID- 21682050 TI - [Combined double valve replacement and abdominal aortic aneurysm repair in a patient with infective endocarditis; report of a case]. AB - The choice of simultaneous or staged surgery in patients with valvular diseases and abdominal aortic aneurysms (AAA) remains controversial. We present a case of simultaneous surgery of double valve replacement and abdominal aorta replacement in a patient with infective endocarditis. A 74-year-old woman was admitted to our hospital because of general fatigue and appetite loss. Computed tomography (CT) scan showed a infrarenal AAA measuring 99 x 67 mm. Echocardiography showed severe regurgitation of mitral valve and aortic valve with vegetations. Electrocardiogram showed atrial fibrillation. She was diagnosed as heart failure due to infective endocarditis and treated with antibiotics, diuretics and catecholamine. However, heart failure did not improve; the patient underwent double valve replacement, pulmonary vein isolation and abdominal aorta replacement simultaneously. Postoperative course was uneventful. PMID- 21682051 TI - [Robot assisted tumor resection of an asymptomatic right atrial intracardiac lipoma; report of a case]. AB - Primary cardiac tumors are relatively rare. No therapeutic guidelines have been established for the surgical indications of such cases. This creates therapeutic dilemmas, especially when the patient is asymptomatic. We describe the robot assisted resection of an asymptomatic right atrial lipoma. A 63-year-old female was diagnosed to have a round mobile lipoma, measuring 27 mm in diameter in the right atrium near the junction with the inferior vena cava (IVC). Although she was asymptomatic, a surgical resection was indicated since the lipoma could cause an embolism or IVC obstruction due to its morbidity and potential to enlarge. Surgery was performed using the da Vinci Surgical System. A right-sided approach was used through 4 ports. The tumor was resected with a small portion of the right atrial wall. The total operation time was 214 minutes, and the total pump time was 84 minutes. The operation was performed while the heart was beating. PMID- 21682052 TI - [Crista terminalis bridge mimicking right atrial mass; report of a case]. AB - A 67-year-old female was operated upon because of transthoracic echocardiograms revealing a 13 x 8 mm mass in right atrium. However, there was no mass and was prominent crista terminalis (CT) instead. CT is the largest and strongest fibromuscular bundle in the right atrium, which separates primitive right atrium from the venous sinus. Prominent CT can mimic right atrial mass on transthoracic echocardiography. It was difficult to make a differential diagnosis because prominent CT formed a bridge-like shape in this case. To obtain certain diagnosis, transesophageal echocardiography (TEE) is necessary, and prevalence of three-dimensional (3D)-TEE is expected to improve the accuracy of diagnosis. We report this case as a pitfall of the diagnosis for the right atrial mass. PMID- 21682053 TI - [Simultaneous resection of lung and liver metastases due to uterine leiomyosarcoma; report of a case]. AB - We describe a case of simultaneous resection of lung and liver metastases from uterine leiomyosarcoma, with reference to previous reports. A 51-year-old female was admitted for treatment of nodules shadow in the right lung and in the left lateral side of the liver discovered by computed tomography (CT). She had been treated for uterine leiomyosarcoma 19 months earlier. Segmentectomy of the right S6 of the lung and left lateral segmentectomy of the liver were performed. The tumors pathologically diagnosed as metastases from uterine leiomyosarcoma. After 29 months, a metastasis to the left lung was detected and thoracoscopic resection was performed. The patient died due to multiple metastases from uterine leiomyosarcoma after 36 months. PMID- 21682054 TI - [Pleomorphic carcinoma of the lung; report of a case]. AB - Pleomorphic carcinoma is a rare primary lung cancer with a poor prognosis. We report a surgically treated case of pleomorphic carcinoma of the lung. An abnormal shadow was incidentally detected by computed tomography (CT) scan for an 80-year-old male. CT scan performed 1 month before the detection of tumor was normal. Right upper lobectomy with ND2a was performed after 5 months follow-up by CT scan because of the enlargement of the tumor. Histological examination showed numerous atypical spindle cells with massive necrosis, diagnosing as pleomorphic carcinoma. Only 2 months after operation, multiple metastases to the lung, chest wall, pleura, and small intestine were found. PMID- 21682055 TI - [Neurogenic tumors originated from vagus nerve and intercostal nerve simultaneously; report of a case]. AB - A 60-years-old man was presented with the posterior mediastinal tumor by chest computed tomography (CT) that had been taken for the examination of another disease. A well circumscribed mass of 9 x 6 x 5 cm in diameter between the body of the thoracic vertebra and pericardium and a well circumscribed mass of 2 x 2 x 0.8 cm in diameter in the 9th intercostal space were noted by chest CT. von Recklinghausen's disease was suspected by the presence of a lot of brown spots and subcutaneous small nodules in the whole body, and both was speculated as neurogenic tumors. Both tumors were removed by the operation, and the pathologic diagnosis of the neurofibroma was obtained. PMID- 21682056 TI - Krapina Neanderthal Museum as a well of medical information. AB - The new Krapina Neanderthal museum consists of two sections: a section reconstructing the life of the Krapina Neanderthal and a section bringing the latest knowledge about the evolution of life on Earth. It is a well of scientific information, a teaching tool, and the world's largest find of Neanderthal fossil remains. This article briefly reports a tour visit of members of the Croatian Scientific Society for the History of Health Culture to the Museum, describes the facets of the exhibition, and gives the most important facts about the life of the Krapina Neanderthal. PMID- 21682057 TI - Identifying, monitoring, and assessing promising innovations: using evaluation to support rapid-cycle change. AB - The Center for Medicare and Medicaid Innovation (Innovation Center) was created by the Affordable Care Act to identify, develop, assess, support, and spread new approaches to health care financing and delivery that can help improve quality and lower costs. Although the Innovation Center has been given unprecedented authority to take action, it is being asked to produce definitive results in an extremely short time frame. One particularly difficult task is developing methodological approaches that adhere to a condensed time frame, while maintaining the rigor required to support the extensive policy changes needed. The involvement and collaboration of the health services research community will be a key element in this endeavor. This issue brief reviews the mission of the Innovation Center and provides perspectives from the research community on critical issues and challenges. PMID- 21682058 TI - FPIN's clinical inquiries. Clinical indicators of obstructive sleep apnea. PMID- 21682059 TI - Labeling and effectiveness testing; sunscreen drug products for over-the-counter human use. Final rule. AB - The Food and Drug Administration (FDA) is issuing this document to address labeling and effectiveness testing for certain over-the counter (OTC) sunscreen products containing specified active ingredients and marketed without approved applications. This document addresses labeling and effectiveness testing issues raised by the nearly 2,900 submissions that we received in response to the sunscreen proposed rule of August 27, 2007 (2007 proposed rule). The document also identifies specific claims that render a product that is subject to this rule misbranded or would not be allowed on any OTC sunscreen product marketed without an approved application. The document does not address issues related to sunscreen active ingredients or certain other issues regarding the GRASE determination for sunscreen products. The document requires OTC sunscreen products to comply with the content and format requirements for OTC drug labeling contained in the 1999 Drug Facts final rule (published in the Federal Register of March 17, 1999, by lifting the delay of implementation date for that rule that we published on September 3, 2004). PMID- 21682061 TI - [The role of dendritic cells in the intestinal mucosa]. PMID- 21682060 TI - "The Women in Surgery Committee was established to encourage and support all trainees, but females in particular" - RACS Women in Surgery. PMID- 21682062 TI - [GERD and otorhinolaryngological diseases: gastro-duodenal reflux reaching as far as the middle ear]. PMID- 21682063 TI - [Surgical techniques in cervical lymph node dissection]. PMID- 21682064 TI - [Social factors that determine health (11). "Life course epidemiology"]. PMID- 21682065 TI - [Health service research (8). Child health service research]. PMID- 21682066 TI - [Public health for scientific study of society and health (4) Computer simulation to evaluate human exposure to environmental chemicals]. PMID- 21682067 TI - [Public health monitoring report (3) Children's health and social class: effects of low birth weight on health]. PMID- 21682068 TI - On to the appeals. Four ACA challenges make their way to next level. PMID- 21682069 TI - Working in concert. Effort seeks surgeon general posts for all states. PMID- 21682070 TI - Suffering a loss. James Mongan's death removes a wise and caring presence. PMID- 21682071 TI - Just watch us. FTC should allow mergers that further reform's goals, with monitoring for ill effects. PMID- 21682072 TI - Healthcare ahoy. Cruise lines using IT to improve seafaring care. PMID- 21682073 TI - The optimism bias. PMID- 21682074 TI - The effects of lipopolysaccharide-induced endogenous hyperthermia and different antipyretic treatment modalities on rat brain. AB - BACKGROUND: In the present study, the effects of fever and hyperthermia, and different anti hyperthermia treatment modalities on the brain by was investigated by using experimental animal model MATERIALS AND METHODS: Endogenous hyperthermia (41 degrees C) was induced by lipopolysaccharide (LPS) injection, and the signs of probable neuronal damage were evaluated by healthy, necrotic and apoptotic cells, and heat-shock proteins (HSP 27 and HSP 70) in cerebral cortex, cerebellum and hypothalamus. The animals were treated with widely used treatment modalities for high fever in pediatric practice, namely hypothermia, dexamethasone, paracetamol and diclofenac, and their effect on the hyperthermia-induced brain changes were evaluated. RESULTS: Generalized seizure was observed in fifteen rats of which rectal temperature achieved 41 degrees C (15/36, 41%); five of them died on second day (5/15, 33%). LPS-induced endogenous hyperthermia; (i) caused significant increase of necrotic cells in cerebral cortex and cerebellum and apoptotic cells in all three regions (p < 0.05), (ii) caused significant decrease of healthy cells in cerebral cortex (p < 0.05), and (iii) no significant change of HSP 27 and 70 in all three neuronal locations (p > 0.05). For the treatment modalities applied; (i) paracetamol had an effect of increasing the healthy cell count in cerebral cortex and hypothalamus and decreasing the necrotic cell count in cerebellum and hypothalamus (p < 0.05). CONCLUSION: The neuronal tissue in different regions of brain can show various degrees of damage in response to endogenous hyperthermia and the applied medications have varying degree of protection (Tab. 3, Fig. 6, Ref. 44). PMID- 21682075 TI - The study of biochemical and histopathological effects of spirulina in rats with TNBS-induced colitis. AB - OBJECTIVES: To evaluate the beneficial effects of spirulina on the treatment of experimental colitis. BACKGROUND: Spirulina, a planktonic blue green algae from oascillateriaceae family, has anti-inflammatory, antioxidant, antitumor, anti viral, and antimicrobial effects, rendering it a natural drug of prophylactic and therapeutic properties. The effects of spirulina on colitis are not known. METHODS: Wistar rats weighing 200-300 g were used. Experimental colitis was created during anesthesia using the trinitrobenzene sulfonic (TNBS) acid. The rats were randomly divided into the 3 groups. In the group 1 (sham; n = 8), saline was administered via oral gavage 7 days after 1 ml of rectal saline was administered. In the group 2 (experimental colitis + spirulina; n = 8), 2 g/kg spirulina was administered via oral gavage 7 days after the rectal 1 ml TNBS was administered. In group 3 (experimental colitis; n = 8), enema was administered via oral gavage 7 days after the rectal 1 ml TNBS was administered. Eight days after the instigation of TNBS colitis, the rats were sacrificed and blood and tissue samples were taken. Histopathologic and immunohistochemical evaluations were conducted, and malondialdehyde (MDA), advanced oxidation protein products (AOPP), catalase (CAT), total antioxidant status (TAS), and glutathione (GSH) levels were determined. RESULTS: Inflammation on mucosa and submucosa, hemorrhage, necrosis, cellular infiltration and crypt abscess formation, immunoreactivity and tissue MDA levels were decreased in the experimental colitis + spirulina group when compared to the experimental colitis group (p < 0.05). CONCLUSION: The results of the present study indicate the beneficial effects of spirulina on TNBS-induced inflammatory bowel disease (Tab. 6, Fig. 10, Ref. 40). PMID- 21682076 TI - Histochemical detection of monoamine oxidases in rat female genital organs during preimplantation period of pregnancy. AB - OBJECTIVE: Localization of monoamine oxidases (MAO) in rat female gonads during preimplantation period of pregnancy was determined. MATERIAL AND METHODS: Pregnant females were killed on their first, third, and fifth days of pregnancy and animals were transcardially perfused with PBS and fixative solutions. Ovaries, oviducts and uteri were immediately removed and they served for the determination of MAO localization employing the method of enzymatic histochemistry. RESULTS: MAO-A activity in ovary was visible in corpora lutea and in interstitial gland cells while MAO-B was detected predominantly in blood vessels. Both MAO enzymes were seen in the smooth muscle fibers of the ovarian hilum. The presence of MAO enzymes was however not detected in follicles at any stage of their development. In oviduct and uterus, both MAO enzymes were visible in similar places, namely in smooth muscle fibers, mast cells and blood vessels, with no MAO presence seen in the epithelium. CONCLUSIONS: Potential physiological importance of MAO localization in different cells of female reproductive organs during early period of pregnancy is proposed (Fig. 6, Ref. 29). PMID- 21682077 TI - Vacuum assisted closure in vascular surgery. AB - BACKGROUND: Vacuum assisted closure (VAC-therapy) is a well established method in nearly all surgical disciplines. The aim is to present the efficiency of vacuum assisted closure in the treatment of acute and chronic wounds in patients admitted in the department of vascular surgery. METHODS: Within the year 2008 there were 59 patients (44 men, 15 women) treated with VAC therapy in our Department of Vascular surgery (Landshut, Germany). VAC was used 22x (37.28 %) in therapy of ulcus cruris (venous, arterial, mixed genesis), 15x (25.42%) in patients with diabetic foot syndrome, 12x (20.33%) in secondary healing wounds and infected wounds, 5x (8.47%) in wounds after several injuries and soft skin tissue infections and 5x (8.47%) in wound infections connected with vascular graft infections after vascular revascularization. RESULTS: VAC therapy seems to be very effective in the management of patients with venous ulcers, especially after a proper surgical treatment (100%), patients with soft skin tissue infections (100%) and secondary healing wounds (100%) especially in combination with MESH-Grafting. In patients with diabetic foot syndrome (80%) and peripheral arterial occlusive disease (72.7%), an evaluation of peripheral blood perfusion and revascularization prior to VAC therapy is often necessary. Although VAC was used 5x in the therapy of infected vascular grafts, successful preservation of infected graft material was observed in only one case (infection of PTFE femoro popliteal bypass graft). CONCLUSION: Vacuum assisted closure in vascular surgery proved to be simple and efficient method in therapy of acute and chronic wounds. The efficiency of VAC systems in therapy of infected graft material after revascularization needs further studies (Tab. 3, Ref. 10). PMID- 21682078 TI - Diagnosing metabolic syndrome in type 2 diabetic Turkish patients: comparison of AHA/NHLBI and IDF definitions. AB - OBJECTIVES: The objective of this study was to determine the percentage of metabolic syndrome (MetS) in a Turkish population with type 2 diabetes mellitus (T2DM) according to the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) and International Diabetes Federation (IDF) definitions and to assess the agreement among these definitions. BACKGROUND: It is essential to identify the prevalence of MetS in diabetic patients, as MetS is a stronger risk factor for cardiovascular disease in patients with T2DM than in non-diabetic subjects. METHODS: 235 consecutive patients with T2DM were included in the study. The MetS was defined according to AHA/NHLBI and IDF definitions. Cohen's kappa was used as a measure of agreement between the two definitions. Logistic regression analysis was performed to calculate the odds ratios. RESULTS: The percentage of MetS was 85.1% by AHA/NHLBI and 87.2% by IDF criteria. The agreement between AHA/NHLBI and IDF was fairly good (kappa = 0.55). Females were more affected than males. When the frequencies of each individual feature of the MetS according the definitions were assessed, hypertension was the most common feature in males, whilst abdominal obesity was in females. Serum triglyceride and waist circumference had the highest predictive ability for MetS according to AHA/NHLBI and IDF definitions, respectively. CONCLUSION: The MetS is a common condition among diabetic patients. Since diabetic patients carry a cluster of cardiovascular risk factors, correct identification of the MetS among this population is of great importance, for an integrated approach to reduce the high costs and the associated disabilities (Tab. 5, Fig. 2, Ref. 54). PMID- 21682079 TI - Toll-like receptor 9 polymorphism in patients with erythema multiforme, Stevens Johnson syndrome and Stevens Johnson syndrome/toxic epidermal necrolysis overlap syndrome. AB - BACKGROUND: "Toll like receptor" (TLR) 9 functions in stepping in of native immune system against different viral and bacterial pathogens and induction of adaptive immune response effectively. TLR 9 gene polymorphism makes host predisposed to microbial pathogens by affecting thefunctional capabilities of the receptor. OBJECTIVE: We aimed to determine if TLR 9 gene polymorphism makes a predisposition to "erythema multiforme" (EM), "Stevens Johnson syndrome" (SJS) and "Stevens Johnson syndrome/toxic epidermal necrolysis overlap syndrome" (SJS/TEN). METHODS: Forty-two patients clinically and/or histopathologically diagnosed as EM, SJS, and SJS/TEN overlap syndrome and 50 healthy control subjects were enrolled in our study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was applied for TLR 9 gene 1237 thymine/cytosine (T/C) polymorphism. Genotypes were determined according to bands occurring on agarose gel electrophoresis. RESULTS: In patients group, the frequencies of TT and TC genotypes were 73.8% and 26.2% while CC genotype wasn't detected. In control group, the frequencies of TT, TC and CC genotypes were 74%, 24%, and 2%. There wasn't a statistically significant difference for TT, TC and CC genotypes between patients and controls. The frequencies of T and C alleles were 84.5% and 15.5% in patients and 86% and 14% in controls, respectively. CONCLUSION: Our results showed that there isn't any association between TLR gene polymorphism and EM, SJS, SJS/TEN overlap syndrome (Tab. 1, Fig. 1, Ref. 30). PMID- 21682080 TI - Surgical management of submandibulary gland diseases: ten years of experience. AB - OBJECTIVE: The surgical management of submandibular gland diseases has always been a challenge because it carries a considerable risk of nerve injury. The aim of the study was to evaluate the history, diagnostic procedure, extent and success of the surgical treatment as well as possible complications in patients with submandibulary gland disorder. METHODS: We carried out a retrospective analysis of 86 patients (42 males, 44 females) with submandibular gland disorder treated between 1999 and 2008 at the Department of Otorhinolaryngology, FD Roosevelt Faculty Hospital in Banska Bystrica, Slovakia. Average age of patients was 52.3 years (range 13-80 years). RESULTS: All patients in our study were treated surgically with the use of standard transcervical approach. The most common indication for submandibulary gland extirpation was sialolithiasis (39.6%). 33.7% of all lesions were sialadenitis, and 26.7% were neoplasms. The morbidity of surgical treatment was low. Transient palsy of marginal mandibular nerve was observed to be the most common complication after the surgery (14%). CONCLUSION: Surgical removal of entire submandibulary gland is a safe operation with a low rate of complications (Tab. 5, Fig. 1, Ref. 17). PMID- 21682081 TI - Acute motor axonal neuropathy cases in Van region. AB - Acute motor axonal neuropathy (AMAN) is a form of Guillain Barre Syndrome (GBS) seen in summer months in Northern China to cause epidemics. This form of the disease, which is also sporadically observed in other countries, constitutes less than 5% of GBS in Western countries. It usually develops with motor findings. No sensory findings are observed. In some of the cases, the severe impairments in tissues improve however slowly and inadequately. In the motor conduction studies of cases with AMAN, motor action potential values are lowered. On needle electromyography (EMG), motor unit potential (MUP) activity is diminished with spontaneous denervation findings. Investigations were conducted on nerve conduction of patients with GBS aged from 1 to 77 years. AMAN was detected in 25 of these patients. In our investigation, AMAN as a GBS variant was detected in 39.7% of the patients. The conduction velocities of motor nerves were in normal ranges whereas combined muscle action potentials were significantly lower. No F response could be obtained. Although AMAN is a rare variant of GBS and shows different clinical courses, it has been brought under intense scrutiny since there is high prevalance of acute inflammatory neuropathies in our region (Tab. 1, Ref. 7). PMID- 21682082 TI - Positive associations of nosocomial infections in surgical ward with etiological clinical factors. AB - This study was conducted in the surgical wards of Dhaka Medical College Hospital, Bangladesh (General Surgery Wards and burn unit) on nosocomial infection. Thirty percent of the study patients, of which, elderly patients constitute 62.5%, were infected with nosocomial infection. Among those patients, wound infection (38.7%) was the most common type of nosocomial infection, from which about 63.5% belonged to postoperative. The other common types were acute respiratory tract infection (19.2%), urinary infection (26.6%), and gastro-intestinal infection (12.5%). In this study, it was found that combined infection (36%), pseudomonas (33%) as well as E. coli (17%) had the greatest contribution of developing postoperative wound infection. Nosocomial infection was not significantly associated with sex distribution, but was significantly higher in postoperative patients (63.5%) than preoperative (36.5%). Another significant finding of this study was that there was a strong positive association between the frequency of nosocomial infections and increasing number of visitors per patient per day) (Tab. 6, Fig. 4, Graph 2, Ref. 26). PMID- 21682083 TI - Major beta-thalassemia, use of desferiexamine and renal proximal tubular damage. AB - BACKGROUND AND PURPOSE: Thalassemia is a quantitative hereditary hemoglobinopathy, which is one of common hereditary diseases in the Mediterranean region including Iran. Homozygotic beta-thalassemia patients have manifestations and complications such as severe anemia and multiorgan dysfunction. Recently there have been some concerns about renal complications in a-thalassemia but some controversies have been demonstrated. The aim of this study was to investigate the renal function of major a-thalassemia patients in comparison with control group. METHODS AND MATERIALS: This was a historical cohort. Study population consisted of major beta-thalassemia patients who were under a management plan of thalassemia ward of Bo Ali sina hospital sari, IRAN (case group ) and uninvolved brothers or sisters of the patients (the control group). Two groups (case and control) were matched. Renal function of patients was investigated by measurement of renal and serum markers. Demographic and therapeutic data of patients were extracted from medical records. The data were analyzed using SPSS 11. FINDINGS: Eighty-four samples were studied in total, while 42 of them were from the case group and the rest from the control group. The case and control groups were matched according to gender and age. Mean age of patients was 21.3 +/- 5.2 years. Desferiexamin was dosed in amount of 70 +/- 19 mg/kg. There was no significant difference in the measures of 24-hour urine protein (beta-2 microglobin and fraction excretion of Na and K between case and control groups. Significant differences were however in the measures of Bun serum and creatinin as well as K (from both urine and serum). Gender, Hb, and level of ferritin related significantly with differences. CONCLUSION: This study demonstrates no evidence of proximal tubular damage in major a-thalassemia patients. Nevertheless, the patients with severe anemia, high dose of desferal and high level of ferritin yielded an increase in the levels of Bun, serum K, and in some cases in uric acid (Tab. 4, Ref. 33). PMID- 21682084 TI - Laparoscopic management of spontaneous intraperitoneal perforation of urinary bladder. AB - The authors present two cases of spontaneous intraperitoneal perforation of urinary bladder. The first case was a 56-year old female patient with history of urothelial cancer with partial urinary bladder resection and subsequent radiotherapy six years ago. The diagnostic laparoscopy was indicated because of the clinical signs of peritonitis. The diagnostic laparoscopy revealed a perforation of urinary bladder and the management of perforation was done laparoscopically. The histological examination of specimen revealed urothelial cancer. The postoperative course was uncomplicated and the patient underwent further oncologic treatment. The second patient was a 61-year old man admitted with abdominal pain lasting for one day after excessive alcohol intake. An indication to diagnostic laparoscopy was done according to the clinical signs of peritonitis. Also in this case, perforation of urinary bladder was identified and laparoscopic management was carried out. The postoperative course was uncomplicated. Both patients denied any trauma. The diagnosis of urinary bladder perforation was not done preoperatively. The diagnosis of spontaneous perforation of urinary bladder is difficult. The case history data with no trauma do not lead to this diagnosis. It is important to consider this diagnosis in case of acute abdomen. The treatment of urinary bladder perforation is based on the identification of the defect, lavage of the peritoneal cavity, excision of the defect, reconstruction of the bladder with intact blood supply, bladder drainage supporting the defect healing, and exclusion of malignancy. The laparoscopic treatment of spontaneous perforation according to literature is not common, however very effective (Fig. 1, Ref. 41). PMID- 21682085 TI - Hydatid cyst in abdominal incisional hernia. AB - Recurrence of hydatid cyst is one of the important complications of primary hydatid surgery. Here we present a very rare case of recurrent hydatid cyst inside an incisional hernial sac. A 50-year old male operated on for hydatid disease of the liver twice in 1998 and 2001 was admitted to our hospital for an abdominal mass formed under the old median incisional scar. On physical examination, a painless mass of 15 cm in diameter, stretched, hard and well bordered was palpated. There was also a fascial defect inferior to the mass. A herniated hydatid cyst was imaged with both of ultrasonography (US) and abdominal computed tomography (CT). As a surgical treatment hydatid cyst was excised totally together with primary repair of the fascial defect. The patient received preoperative Albendazole therapy, administered at a dose of 10 mg/kg body weight per day from 3 weeks before surgery to 6 months postoperatively. He had no problems in the 1-year follow up (Fig. 2, Ref. 19). PMID- 21682086 TI - Reconstructive surgery after postraumatic infected talus necrosis. AB - OBJECTIVES: A case of a young female patient is presented who underwent a tibiocalcaneal arthodesis for infected necrosis of the talus after total talus extrusion. We report our surgical technique of tibiocalcaneal arthrodesis as a salvage procedure for this complex problem. It was performed in two stages. Total talectomy and implantation of antibiotic spacer was followed by tibiocalcaneal fusion using a blade plate. The bone loss was compensated with autodigested, antigen extracted allogeneic bone. BACKGROUND: Total extrusion of the talus is a rare and severe injury of the foot. The outcome is unpredictable and the presence of infection and bone loss is a challenge for the surgeon to achieve a successful outcome. METHODS: Union was defined both clinically and radiographically. The clinical outcomes were mesured using a AOFAS hindfoot score. The radiographic healing was determined by the presence of trabeculation across the arthrodesis. RESULTS: The time of follow up was 18 months and the fusion was achieved after 8 months. CONCLUSION: The presented technique for tibiocalcaneal arthrodesis is an option for the treatment of these serious lower extremity injuries and chemosterilized, antigen-extracted autolyzed allograft is appropriate for the reconstructive procedures of the foot and ankle (Fig. 2, Ref. 6). PMID- 21682087 TI - A preliminary survey of the median artery in human cadavers of South Indian origin. AB - BACKGROUND: The median artery is a transitory vessel that represents the arterial axis of the forearm during early embryonic life. It normally regresses in the second embryonic month. Its persistence in the human adult has been recorded in 2 different patterns: as a large, long vessel (palmar type) which reaches the hand; or as a small and short vessel (antebrachial type) which ends before reaching the wrist joint. The palmar type is of major clinical significance. OBJECTIVE: This study was undertaken to investigate the incidence and course of the palmar type of the median artery in South Indian cadavers. MATERIAL AND METHODS: 25 upper limbs of South Indian cadavers were taken to study the median artery. RESULTS: The occurrence of median artery was 8%; of which 4% was on the right side and the other 4% was on the left side. On both sides, the artery originated from the ulnar artery. On the right side, the artery was involved in the formation of superficial palmar arch, whereas the artery on the left side did not join the arch; it terminated as 1st and 2nd common palmar digital arteries. CONCLUSION: Persistent median artery is closely related to the anterior interosseous nerve, it is possible that the artery may compress the anterior interosseous nerve and cause the anterior interosseous nerve syndrome (Fig. 2, Ref. 17). PMID- 21682088 TI - The predictors of the efficacy of high-dose chemotherapy and stem cell support in the management of metastatic germ cell cancer. AB - OBJECTIVES: We aimed to analyze the predictors of outcome in metastatic germ cell cancer (MGCC) patients treated with High-dose Chemotherapy (HDC) and stem cell rescue. BACKGROUND: Various prognostic factors have been suggested in the treatment of metastatic germ cell cancer. However, there is no comprehensive evaluation of independent prognostic factors for the efficacy of HDC in published patient cohorts. METHODS: Thirty-two published patient cohorts with MGCC (encompassing 2176 patients; 510 patients treated upfront and 1666 at relapse) were identified from PUBMED and Cochrane Registry of Clinical Trials. Weighted Regression Analyses of these trials were conducted to define prognosticators. RESULTS: Independent correlates of overall survival (OAS) when all trials were considered were line of chemotherapy index, an indicator of line of HDC utilization (1st line: 71% vs 2nd or higher line: 40%, p < 0.001), and number of HDC cycles administered (1 cycle: 43%, 1 to 2 cycles: 43%, 2 or more cycles: 64%, p = 0.021). In cohorts having HDC for relapsed disease, lower line of chemotherapy index again (p = 0.004), and higher median age (p = 0.023) were independently associated with better OAS. In trials utilizing upfront HDC, higher number of chemotherapeutics in the HDC regimen was marginally linked with improved OAS (p = 0.047). CONCLUSION: The efficacy of various forms of HDC in MGCC patients with diverse prognostic factors may vary both as an initial or salvage therapy. Clinicians need to be aware of these factors for optimal patient selection for HDC in MGCC (Tab. 3, Fig. 2, Ref. 54). PMID- 21682089 TI - Personalized vaccination? II. The role of natural microbiota in a vaccine-induced immunity. AB - Inter-individual variation in immune response to widely used prophylactic vaccines against infectious diseases is strongly influenced by sex, MHC (Major Histocompatibility Complex), age and current hormones status of vaccinated individuals. Numerous findings showed that microorganisms residing at different sites of human or animal body (natural microbiota), especially in the gastrointestinal tract, appear to contribute to nearly every element of the host's physiology. Recently, the microbiota is also supposed to be an underappreciated yet, but very important factor responsible for diverse vaccine efficacy observed in humans from developing vs. developed countries. In the article, selected aspects of the microbiota-host relation are presented: importance of the gut microbiota in the development of both the intestinal mucosal and systemic immune responses, bacteria of a predominant role for the immunity (e.g., SFB, Segmented Filamentous Bacteria), and several clinical observations on the varied immunogenicity of the same vaccines in different human populations. In the light of our current knowledge, manipulation of the microbiota by probiotics and/or prebiotics is becoming a realistic therapeutic and prophylactic strategy for many infectious, inflammatory and even neoplastic diseases within the gut but it may be also used for improving vaccine efficacy. PMID- 21682090 TI - Babesia spp. infections transmitted through blood transfusion. AB - Babesiosis in humans is caused by infection with various species of Babesia (Apicomplexa, Piroplasmida), mainly transmitted by an arthropod vector--Ixodes spp. ticks. This review will focus on blood transfusion as another mode of Babesia transmission, especially in endemic areas, as well as the impact of human babesiosis on transfusion medicine. PMID- 21682091 TI - Terminology and practice in control of some parasitic zoonoses. AB - Some terminology, based on tradition and still widely used in practice, is still scientifically incorrect. PMID- 21682092 TI - Monitoring of plasma concentration of pyrimethamine (PYR) in infants with congenital Toxoplasma gondii infection--own observations. AB - The study objective was to determine plasma concentration of pyrimethamine in 24 infants aged 1-5 months, treated for congenital toxoplasmosis. Pyrimethamine was used in a single daily dose at an amount of 0.35-0.98 mg/kg daily, with sulfadiazine (50-100 mg/kg/day) in divided doses 2-3 times a day, and folinic acid given twice a week (7.5 mg). This regimen was continued for 2-6 months, then Fansidar was administered. Pyrimethamine concentration in plasma was measured using high-performance liquid chromatography method (HPLC). A total of 70 tests were performed. Concentration of pyrimethamine ranged from 0.01 to 1.2 microg/ml. In 14 children (58 tests) the concentration of pyrimethamine achieved therapeutic value. In 7 patients (8 tests) the concentration was below therapeutic level, and in 3 patients (4 tests) above therapeutic level. In 11/24 (46%) children transient moderate neutropenia was observed. Modification of therapy was necessary in 12 patients. Monitoring of pyrimethamine concentration in plasma improves safety and effectiveness of the therapy and is useful in obtaining correct individual dose of the drug. Neutropenia is the most common side-effect of pyrimethamine observed even when using the recommended dose. PMID- 21682093 TI - Evaluation of the frequency of Pneumocystis jirovecii occurrence in a group of children hospitalized for acute respiratory infections. AB - Primary infection with Pneumocystis jirovecii in small children may cause inflammation of the respiratory tract which requires hospitalization. Lack of characteristic clinical symptoms makes it impossible to recognize P. jirovecii infections without performing laboratory analyses. Nasopharyngeal swabs from 70 children with respiratory tract infections were screened for fragments of the P. jirovecii genome. Pneumocystis DNA was found in swabs taken from two (2.9%) of the tested children: a newborn who was infected in the hospital and a six month old baby admitted to hospital two days after pneumonia was diagnosed. The obtained results confirm that primary P. jirovecii infections may occur in the form of acute respiratory tract inflammations suggesting a viral infection. In differential diagnosis of Pneumocystis infections in children molecular methods are useful as their high sensitivity makes it possible to analyze samples obtained in a non-invasive way. PMID- 21682094 TI - Results of long-standing mycological analyses of biological materials originating from selected organ ontocenoses--yeast and yeast-like fungi. AB - This paper reviews the results of an extensive monitoring study, spanning 20 years of observation from three medical centres in Olsztyn on the dynamics and species diversity of fungi most frequently colonizing the respiratory and digestive systems of humans. The experimental materials were swabs and specimens from the gastrointestinal tract, swabs from the oral cavity and pharynx, as well as sputum and bronchial fluid from the respiratory system. The biological material was subjected to routine mycological diagnostics, taxonomic determination and identification. In total, 41 species of yeast and yeast-like fungi were isolated, including 34 from the respiratory and 25 from the digestive system. In the last decade, a significant increase has been noticed in the counts of fungi, especially the gastrointestinal tract, reported from people. As many as 18 species were isolated from both systems--they were predominated by fungi of the genus Candida and their perfect forms. Worthy of notice are also frequent isolations of yeast (Saccharomyces spp.) and detection of an endemic species, Paracoccidioides brasiliensis, in the respiratory system, and of the sexual stages of Rhodosporidium diobovatum and Rhodosporidium kratochvilovae from the gastrointestinal tract. PMID- 21682095 TI - Air-conditioning vs. presence of pathogenic fungi in hospital operating theatre environment. AB - Infections related to modern surgical procedures present a difficult problem for contemporary medicine. Infections acquired during surgery represent a risk factor related to therapeutical interventions. Eradication of microorganisms from hospital operating theatre environment may contribute to reduction of infections as the laminar flow air-conditioning considerably reduces the number of microorganisms in the hospital environment. The objective of the study was to evaluate the occurrence of fungi in air-conditioned operating theatre rooms. The study was carried out in one of the hospitals in Krak6w during December 2009. Indoor air samples and imprints from the walls were collected from five operating theatre rooms. A total of fifty indoor air samples were collected with a MAS-100 device, and twenty five imprints from the walls were collected using a Count Tact method. Fungal growth was observed in 48 air samples; the average numbers of fungi were within the range of 5-100 c.f.u. in one cubic metre of the air. Fungi were detected only in four samples of the wall imprints; the number of fungi was 0.01 c.f.u. per one square centimetre of the surface. The mould genus Aspergillus was most frequently isolated, and the species A. fumigatus and A. versicolor were the dominating ones. To ensure microbiological cleanness of hospital operating theatre, the air-conditioning system should be properly maintained. Domination of the Aspergillus fungi in indoor air as well as increase in the number of moulds in the samples taken in evenings (p < 0.05) may suggest that the room decontamination procedures were neglected. PMID- 21682096 TI - Quantitative evaluation of biofilm formation in yeast nitrogen base (YNB) broth and in bovine serum (BS) of Candida albicans strains isolated from mucosal infections. AB - Candida albicans is a major human fungal pathogen especially as an etiologic agent of opportunistic oral and genital infections. Moreover, C. albicans can be involved in the deep infections and recent evidence suggests that the majority of diseases produced by this pathogen are associated with biofilm growth. The aims of this study were to evaluate biofilm production ability of C. albicans strains isolated from different sources, and to evaluate the effect of serum for enhancement the growth of biofilm. The strains used in this study were obtained from three sources; 12 from feces of patients with gastrointestinal disturbances, 13 from the oral cavity of patients with oral candidiasis, and 16 from the vagina of patients with Candida vulvovaginitis (CVV). Polystyrene 96-well plates were used to grow biofilms and crystal violet (CV) staining method was used to evaluate the growth. There were no differences in biofilm growth expressed as CV absorbance between C. albicans strains from different origins neither in Yeast Nitrogen Base broth (YNB) or in bovine serum (BS) (ANOVA, P = 0.1648, P = 0.5106, respectively). In the BS, the biofilm production was greater than in YNB medium for all samples (ANOVA, P = 0.0003). PMID- 21682097 TI - In vitro antifungal susceptibility testing of Scopulariopsis brevicaulis strains using agar diffusion method. AB - The genus Scopulariopsis is a common soil saprotroph and has been isolated from air, organic waste and also from plant, animal and human tissues. Scopulariopsis has mainly been associated in humans with superficial mycoses, but it has also been described as the cause of subcutaneous and invasive infections. The most common aetiological agent of infections in humans is Scopulariopsis brevicaulis. This species has been reported to be resistant in vitro to broad-spectrum antifungal agents available today. The aim of the study was to establish in vitro antifungal susceptibility of 35 S. brevicaulis strains against amphotericin B (AMB), flucytosine (FC), caspofungin (CAS), terbinafine (TER), ciclopirox (CIC), voriconazole (VOR), clotrimazole (CTR), miconazole (MCZ), econazole (ECO), ketoconazole (KET), itraconazole (ITR), and fluconazole (FLU). Antifungal susceptibility tests were evaluated by an agar diffusion method (Neo-Sensitabs, Rosco, Denmark). AMB, FC, CAS, ITR and FLU showed no antifungal activity against S. brevicaulis. TER, CIC, CTR, KET, VOR, ECO, and MCZ revealed inhibitory activity for S. brevicaulis, but it varied for each of the drugs. The best antifungal effect was observed for TER and CIC. All isolates had large inhibition zones for TER and CIC. CTR was also inhibitory for all tested S. brevicaulis isolates, but the diameters of inhibition zones were smaller than for TER and CIC. Nearly 89% isolates showed inhibition zones for KET and the mean diameter of the inhibition zone was comparable to CTR. The least antifungal activity exhibited VQR, ECO and MCZ. Because of the multiresistance of S. brevicaulis, infections due to this species may not respond to particular antifungal treatment and other therapeutic approaches should be considered, e.g., combined therapy and/or surgery. PMID- 21682098 TI - Seasonal biodiversity of pathogenic fungi in farming air area. Case study. AB - Poultry production proved to be a significant source of bioaerosols. The exposure to high concentration of microorganisms in the air can cause primarily irritations, infections, allergies, and toxic effects. The aim of the present study was to investigate the seasonal biodiversity of airborne fungi in the poultry house, in the surrounding area, as well as to estimate health risk. Seasonal investigations were conducted in the spring, summer, autumn and winter 2010 in the poultry house located near Wroclaw in Lower Silesia (Poland). The air samples were collected with the use of a Merck MAS-100 onto nutrient Sabouraud agar and were incubated for 5 days at 26 degrees C. Subsequently the colony forming units (CFU) were determined. The identification of the isolated fungi was made in accordance with the standard procedures. In the summer and autumn when the weather conditions are most friendly for the spread and the development of numerous microorganisms, fungi were more abundant in the surrounding area than in early spring and winter, when both humidity and temperature were lower. The total of 26 species were analysed (10 in the poultry house and 17 in the surrounding areas). Among 12 fungal genera: Aspergillus, Penicilium, Alternaria, Exophiala, Mycelia sterilla, Fusarium, Cladosporium, Scopulariopsis, Chaetomium, Acremonium, Candida and Rhodotorula nearly everything occurred to be the potential respiratory allergens. PMID- 21682099 TI - Cloacotaenia megalops (Nitzsch in Creplin, 1829) (Cestoda, Hymenolepididae) in wild ducks in Western Pomerania, Poland. AB - Cloacotaenia megalops (Nitzsch in Creplin, 1892) is a polyxenic and cosmopolitan tapeworm from the family Hymenolepididae. Its generic name derives from their typical location (cloaca), and the typical final hosts which are birds typically associated with water and marsh environments: Anseriformes, Galliformes and Gruiformes. In Poland, the presence of C. megalops has been observed so far in 16 species of ducks from the Baltic coast, the Mazurian Lake District, Wielkopolsko Kujawska Lowland, Mazovian Lowland, and Podlasie Lowland. In Western Pomerania, quantitative structure analyses were only carried out on Anas platyrhynchos, and therefore the aim of this study was the detailed analysis of environmental populations of C. megalops in wild ducks. The examined tapeworms were isolated from the digestive tract of 1005 wild ducks representing 17 species belonging to three different eco-tribes: Anatini (n=225), Aythyini (n=413) and Mergini (n=367), from northwestern Poland. During the Study 187 C. megalops were found in 89 birds (8.8% of examined ducks) belonging to 7 species: Anas crecca (common teal), A. querquedula (garganey), A. platyrhynchos (mallard) (Anatini); Aythyaferina (pochard), A. fuligula (tufted duck), A. marila (greater scaup) (Aythyini) and Bucephala clangula (goldeneye) (Mergini). The results show the differences in the quantitative structure of C. megalops among the examined species of ducks. The highest prevalence was found in mallard (18.6%) and the lowest in greater scaup (3.2%). The highest mean intensity was observed in greater scaup (4.0), and the lowest in garganey and common teal (1.0). Relative density was at a similar level in the tested birds. Based on the ratio of dominance, it was found that C. megalops is a rare species in the cestodofauna in the examined birds. PMID- 21682100 TI - Prevalence of Fasciola hepatica L. infection in cattle in the Lublin province (Poland) in the years 2005-2008. AB - Prevalence of Fasciola hepatica L. infection among cattle slaughtered in the Lublin province in the years 2005-2008 was evaluated. The study draws its data from annual reports of the Veterinary Inspectorate in Lublin. The results of the study are as follows: the prevalence of Fasciola hepatica infection in the cattle of the Lublin province between 2005 and 2008 amounts to 21.24%. PMID- 21682101 TI - Anastomotic leakage and septic complications: impact on local recurrence in surgery of low rectal cancer. AB - PURPOSE: We thought to determine the influence of anastomotic leakages (AL) and septic complications (SC) on the incidence of local recurrence (LR) in patients undergoing curative surgery for rectal cancer. METHODS: The records of 479 patients (286 male, 193 female; median age 67 years) who received, between 1966 and 1975 (Group A) and 1976 and 1985 (Group B), curative surgery for middle to low rectal cancer were retrospectively reviewed. All patients received mesorectal excision in the course of abdominoperineal excision (Group A) and of anterior resection with colorectal anastomosis (Group B). The outcome of SC in both groups and that of AL in Group B were investigated. AL were divided into clinical leaks (CL) and radiological leaks (RL). All patients surviving surgery were followed up for a mean period of 71 months. The development of pelvic recurrence was registered. The effect of SC and AL on LR was statistically analyzed. RESULTS: LR was diagnosed in 24 (9.3%) patients of Group A. No difference was detected between patients with SC (9.3%) and those without (9.3%). In Group B, LR occurred in 28 (12.7%) patients: 12.5% without SC and 12.7% with SC. A significant difference in the prevalence of LR was found between patients with CL (14.2%) and those with RL (30.0%). When CL were excluded, RL resulted as an independent predictor of LR. DISCUSSION: Many factors have been shown to affect the rate of LR, including operative technique and surgeon expertise as well as margins of clearance and tumor stage. In our study, overall LR rate of Group B was 13.2%. The incidence of this event in patients with AL (24%) was significantly higher than that in the nonleakage group (11.1%). Correspondent results have been reported by some authors who evidenced RL as a negative prognostic factor for higher rates of LR. The mechanism by which AL affects LR remains to be elucidated. CONCLUSIONS: All were found to be associated with higher rates of LR, especially if associated with prolonged inflammatory local reaction. PMID- 21682102 TI - Role of FDG-PET/CT in follow-up of patients treated with resective gastric surgery for tumour. AB - INTRODUCTION: Gastric cancer has a poor prognosis and a high rate of recurrences after surgery. The optimal method for assessing early recurrences is not defined: conventional imaging (ultrasonography, CT and MRI) have difficulty in detecting them, because they don't give information regarding metabolic features or tumor response to chemotherapy. Actually 18F-fluorodeoxyglucose positron emission (18FDG-PET) has several indications for the primary staging and the follow-up of colon-rectal, lung, breast, neck cancers and lymphoma, but its clinical role in gastric cancer is not assessed. Our study analyzes the role of 18FDG-PET integrated with CT scan in the detection of gastric cancer recurrence. MATERIALS AND METHODS: We retrospectively reviewed 50 patients which underwent follow-up 18FDG-PET/CT from 2006 to 2009 after radical surgery for gastric adenocarcinoma. Each study was repeated every 6 months for the first two years after surgery and every 12 months for the subsequent three years. RESULTS: 18FDG-PET/CT was positive for suspected neoplastic disease in 29 (58%) and negative in 21 (42%) patients, with 3 false positive and 3 false negative results. 18FDG-PET/CT showed highly effectiveness in early detection of recurrences, as observed in 17 patients that were totally asymptomatic, allowing the initiation of multimodal treatment resulting in an important increasing of survival. CONCLUSIONS: 18FDG PET-CT has a very good sensitivity (89.7%) and specificity (85.7%) in detecting local and distant recurrences during post-operative follow-up. Positive 18FDG PET/CT findings may lead to an early change in the management of these patients, directing them towards rescue surgery or chemotherapy thereby improving their overall survival PMID- 21682103 TI - Metatypical carcinoma. A review of 327 cases. AB - INTRODUCTION: Metatypical cell carcinoma is a quite rare malignancy (5% of all non melanoma skin cancers), with features of basal cell carcinoma and squamous cell carcinoma. It is described as coexistence of basal cell carcinoma and squamous cell carcinoma with no transition zone between them. MATERIALS AND METHODS: We performed a retrospective study of 327 consecutive patients, diagnosed for metatypical carcinoma. Statistical analysis was made to determinate most affected areas, gender prevalence, average age, presence of ulceration and infiltration, peripheral clearance rate. RESULTS: A relevant difference came out between two genders. Chi-square test emphasized a relation between females and the presence of carcinoma on the scalp. In addition a strong correlation between mixed subtype and ulceration was evident. A strong relation between intermediate subtype and positive surgical margin was found; this data could identify a more aggressive behavior of intermediate type. DISCUSSION: Differently from melanoma that usually arises on sun exposed areas, no relation was found between sun exposion and this tumor. This characteristic stresses on the importance of other risks factor apart from sun exposition. CONCLUSIONS: We identify some correlation between our data that cannot be explained with previous interpretation of sun exposition. PMID- 21682104 TI - Uncommon cause of acute abdomen: volvulus of gallbladder with necrosis. Case report and review of literature. AB - Gallbladder volvulus is a rare condition which can mimic an acute cholecystitis. This condition is characterized from a rotation of the gallbladder on its mesentery along the axis of the cystic duct and cystic artery. Preoperative diagnosis is difficult. This is an acute surgical emergency that must be treated with immediate detorsion and cholecystectomy. We report a case of acute gallbladder torsion in an elderly man and review the clinical aspects of the disease in the context of the available literature. PMID- 21682105 TI - GIST mimicking an hyperplastic polyp of descending colon. AB - INTRODUCTION: The authors describe a case of a patient who underwent resection of a colonic GIST mimicking a hyperplastic polyp of the descending colon. CASE REPORT: We report the case of a colonic Gastrointestinal Stromal Tumor (GIST) of a 55 years old male patient who was admitted to us because of rectal bleeding and altered bowel habits. Patient was initially diagnosed for hyperplastic polyps of the descending colon and thus surgical treatment was proposed. Post operative histological examination of the polypsi revealed a GIST that was classified as one of a very low malignancy based on NIH consensus risk stratification system. Patient is followed-up and until today presents no sign of disease. DISCUSSION: Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tumor commonly occurring in the gastrointestinal track. It is usually found at the stomach and small bowel while colonic, rectal and esophageal GIST are rare. Diagnosis of GIST is based more on histological examination and less on clinical findings or radiological image since they are nonspecific. Complete surgical resection with negative margins remains the only effective treatment against GIST yet imatinib mesylate, a tyrosine kinase growth factor receptor inhibitor, is found to be effective against GIST and is currently used as treatment for metastatic, recurrent or non-operable GIST Although the diagnosis is difficult, especially in the less common sites, the Authors suggest that GIST should be included in the differential diagnosis of colonic masses. PMID- 21682106 TI - The surgical palliative treatment of myelofibrosis. Personal experience. AB - We report a case of significant splenomegaly by myelofibrosis, treated in our institution, that we believe relevant to the completeness parade of symptoms and the exceptional size. PMID- 21682107 TI - Laparoscopic proctocolectomy: analysis of long term complications. Case report. AB - Surgery can be a curative treatment for ulcerative colitis. The correct surgical procedure is a total proctocolectomy and ileo anal J pouch anastomosis (IPAA). This procedure is feasible also in laparoscopic approach after a correct learning curve. Pouchitis, pouch complications, intestinal occlusion, infertility are the most common long term complications. We present a case of a 37-year-old man treated with laparoscopic proctocolectomy and followed at 18 months. PMID- 21682108 TI - Incidental rectal carcinoid discovered after stapled hemorrhoidopexy: importance of histopathologic examination. AB - AIM: Haemorrhoids are the most common surgically-treated gastrointestinal disorder. Complications of this surgery are generally non-neoplastic. Because rectal tumours usually present demonstratively during endoscopic examination, it is perhaps tempting to omit histopathologic examination after haemorrhoidectomy, especially in younger patients. METHODS: The AA present a case of an early rectal carcinoid discovered after surgical treatment of haemorrhoids in a 27 years old man as an example of why it is essential to send all such specimens in the pathologist. RESULTS: The detection of early lesions permits the adequate follow up necessary to preclude more extensive surgery and eventually to prevent recurrence of tumour. CONCLUSION: All tissue resected by haemorrhoidopexy must be sent to the pathology laboratory to protect the life and health of the patient . PMID- 21682109 TI - Combined approach for the treatment of anorectal condyloma. Carbon dioxide laser excision and endoscopic argon plasma coagulation in a case report. AB - Condyloma acuminatum (CA) is a sexually transmitted disease caused by human papilloma virus (HPV). Infection with HPV is a major risk factor for development of anal squamous cell carcinoma. In clinical practice, it is frequently limited to the perianal skin or anal canal and it is rarely described a rectal mucosal extension. Several therapeutic options are developed for CA, including chemical or physical destruction, immunological therapy, or a surgical excision. However, these treatments still have some degree of limitations and important side effects compromising patient compliance and reducing treatment efficacy. CO2-laser emits a continuous beam, absorbed by biologic tissues, that vaporizing intracellular water, destroys target lesions. Argon plasma coagulator (APC) is a non-contact method of endoscopically delivered high-frequency thermal coagulation allowing well-controlled superficial tissue destruction. We present a case of a young female affected by anorectal condiloma extended to rectum, that was successfully treated with combined ginecological (carbon dioxide laser) and endoscopic approach (argon plasma coagulator), with no side effects during the follow up and complete remission after two applications. PMID- 21682110 TI - Surgical management of hemorrhoids. State of the art. AB - Most patients with hemorrhoidal disease may be treated conservatively Along the years several surgical options have been proposed. including closed open and semiclosed hemorrhoidectomy (HC), radiofrequency HC (LigaSure), piles' suture or Farag operation, manual and stapled haemorrhoidopexy (PPH) with or without excision of anal tags, doppler hemorrhoidal artery ligation with or without recto anal mucopexy ano-mucosal flap circumferential HC or Whitehead-Rand procedure. Randomized prospective trials and metanalyses have been carried out with the aim of finding the gold standard operation. When carried out for advanced disease, HC appears to be more effective than PPH, which achieves good results in third degree, but carries high reintervention rate in fourth degree piles. Almost all trials comparing open and closed HC show similar outcomes. None of the costly innovations appears to be superior when compared with conventional procedures in terms of cure of the disease in the long term. PPH carries less postoperative pain and a shorter convalescence than HC On the other hand, while carrying a higher rate of complications, it may be responsible of the so-called "PPH syndrome", consisting of proctalgia, tenesmus and urgency Occasional recto vaginal fistulas have been described after PPH, if not even of rectal perforation and other life-threatening complications. Postoperative pain is very rare after Doppler hemorrhoidal arteries ligation and may be reduced following HC using nitrate ointments and botulin toxin injection, aimed at releasing anal spasm after surgery, more safely than by an internal sphincterotomy LigaSure HC decreases the risk of severe postoperative bleeding, which may be effectively treated by rectal balloon tamponade. Permanent and gross anal incontinence are unlikely to follow both HC and PPH Most cases of anal stricture following HC may be treated by anal dilation. Societies' guidelines recommend a tailored surgery, i.e., the use of different procedures according to the grade of haemorrhoids, which suggests that patients should be operated by a specialist colorectal surgeon, able to perform different surgeries and to deal with complications and failures. PMID- 21682111 TI - Overlapping anal sphincteroplasty: impact of suture selection on bowel symptoms. AB - OBJECTIVE: To look at women who underwent overlapping anal sphincteroplasty (OAS) with the use of either permanent or absorbable sutures and to describe patient reported fecal continence and quality of life. STUDY DESIGN: A case series of 40 women who underwent OAS completed the Modified Manchester Health Questionnaire a mean of 50 months after surgery. Descriptive statistics were used to describe those who had permanent sutures and those who had absorbable sutures. RESULTS: The primary outcome, loss of solid stool, was similar at 50% for each group. Severity of incontinence symptoms, as measured by the Fecal Incontinence Severity Index, was lower in the permanent suture group (15.9 vs. 24.0). There was no difference in overall impact on quality of life. CONCLUSION: While overall patient-reported fecal incontinence was similar, permanent suture use at time of OAS was associated with decreased fecal incontinence severity. PMID- 21682112 TI - Is the diagnosis of atypical glandular cells of undetermined significance associated with greater risk at an inner city hospital? AB - OBJECTIVE: To test the hypothesis that the high-risk patients at an inner city hospital with atypical glandular cells of undetermined significance (AGC) on their Pap smears have a higher rate of underlying significant pathology than that reported in published data. STUDY DESIGN: This was an Institutional Review Board approved retrospective review of all AGC Pap smears performed at University Hospital, Newark, New Jersey, between January 1, 2001, and July 30, 2008. We defined significant pathology as cervical intraepithelial neoplasia 2 (CIN 2) or greater, endocervical adenocarcinoma in situ or greater, or simple hyperplasia or greater of the endometrium. RESULTS: Medical records of 126 patients were reviewed. Forty did not meet inclusion criteria; 86 patients were included in the analysis. Thirty of the 86 (34.9%) patients were found to have significant pathology. CONCLUSION: Patients with AGC Pap results at our inner city hospital have a high risk for underlying significant pathology. PMID- 21682113 TI - Exclusive breastfeeding rates in a multiethnic population at a community hospital. AB - OBJECTIVE: To evaluate exclusive breastfeeding (EB) rates in a multiethnic community population and study various factors that could influence selection of feeding method. STUDY DESIGN: Electronic medical records of 100 patients who delivered from January to August 2009 in a community hospital were reviewed retrospectively. Patients who breastfed exclusively were compared with those whose children obtained some or all nutrition from bottle-feeding during the hospitalization immediately following delivery (NEB). Continuation rates at the infant's initial follow-up examination were assessed. RESULTS: The Asian populations had the highest EB (50%) and continuity rate. Single status and educational status were the only factors other than ethnicity found on univariate analysis to have an impact on the mode of feeding (p < 0.05). Employment, obesity, mode of delivery, birth weight, and sex of newborn did not have a significant effect on the type of feeding. Using multiple regression, only educational status had a significant association with exclusive breastfeeding, with an odds ratio of 2.1 (p = 0.038). CONCLUSION: EB was not well accepted by non-Asian populations. Because educational level was associated with breastfeeding, ways of encouraging those with limited education to practice breastfeeding should be developed. PMID- 21682114 TI - Increased prevalence of celiac disease in patients with unexplained infertility in the United States. AB - OBJECTIVE: To determine whether there might be an increased prevalence of undiagnosed celiac disease among a population of infertile women using serologic screening. STUDY DESIGN: A prospective cohort study was performed at an academic infertility clinic in the United States. RESULTS: The overall prevalence of celiac disease in this population was 2.1% (4/188). There was a significantly increased prevalence (5.9%) of undiagnosed celiac disease among women presenting with unexplained infertility (n = 51). CONCLUSION: Women with unexplained infertility are at increased risk for having undiagnosed celiac disease, which may be a potentially modifiable (and treatable) risk factor. PMID- 21682115 TI - Knowledge of emergency contraception among women aged 15-49 years in Mersin, Turkey. AB - OBJECTIVE: To determine the knowledge of, use of and willingness to use emergency contraception (EC) among women in Turkey. STUDY DESIGN: This cross-sectional study was conducted among 1,298 women at 12 primary health care centers in Mersin. Chi-square, Student's t test, Mann-Whitney U and binary logistic regression tests were performed for statistical analysis. RESULTS: Overall, 18.1% of the women had heard of EC, and of those, 73.6% correctly identified the time limit for the method's use. Among women who had heard about EC, the most commonly cited source of information was health care centers. Knowledge of EC was independently associated with younger women, higher education, having received counseling about family planning, having had an unintended pregnancy, and being employed. Of women who had been sexually active, 4.4% reported having used EC. CONCLUSION: These data suggest that in general a low percentage of the study population has heard of EC. Health care providers and media have an important role to play in the education of women for accurate information about EC. Providing information about EC may help to prevent some unintended pregnancies and induced abortions. PMID- 21682116 TI - Mullerian and mesothelial lymph node involvement in patients with borderline ovarian tumors. AB - OBJECTIVE: To determine the true incidence of Mullerian and mesothelial lymph node involvement in serous and mucinous borderline ovarian tumors (BLOT) with serial sectioning and immunohistochemistry. STUDY DESIGN: Formalinfixed, paraffin embedded lymph node blocks from patients with serous (N = 21) and mucinous (N = 5) BLOT who underwent lymphadenectomy between 1995 and 2002 were serially sectioned at 5 microm levels with 3 consecutive sections taken at surface, 125 microm and 475 microm. One slide from each level was stained with hematoxylin eosin (H-E), cytokeratin (AE1-AE3, DAKO) and calretinin (DAKO). Lymph node involvement was defined as epithelioid cells recognized by H-E and confirmed by immunoreaction with keratin (Mullerian) and calretinin (mesothelial) or identified by immunohistochemistry alone. The results obtained by serial sectioning and immunohistochemistry were compared with those obtained by routine histologic examination at the time of the original surgery. RESULTS: A total of 240 lymph nodes (215 from patients with serous and 25 from patients with mucinous BLOT) were examined. Original pathologic examination identified lymph node involvement in 29/215 lymph nodes from 21 patients with serous BLOT. Twelve of the 21 patients with serous BLOT (57%) and none of the 5 patients with mucinous BLOT (0%) demonstrated Mullerian lymph node involvement. Serial sectioning and keratin immunostaining identified Mullerian involvement in 4 (1.6%) and 10 (4.2%) additional nodes not diagnosed in original sections, respectively. However, no additional node-positive patients were identified. Mesothelial involvement was identified in 2 patients (2/26, 7.6%). CONCLUSION: Patients with serous BLOT have a high incidence of Mullerian lymph node involvement. Distinction between Mullerian and mesothelial differentiation may require immunohistochemical study. Compared with routine histologic examination, serial sectioning and immunohistochemical examination yield a higher number of involved lymph nodes. PMID- 21682117 TI - Management of high-risk gestational trophoblastic neoplasia with etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine chemotherapy. AB - OBJECTIVE: To evaluate the efficacy and toxicity of etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO) chemotherapy for the treatment of high-risk gestational trophoblastic neoplasia (GTN). STUDY DESIGN: Thirty-five patients with high-risk GTN were treated with 196 cycles of EMA-CO between 1997 and 2006. Twenty-nine patients received EMA-CO in the primary setting and another 6 after failure of single-agent chemotherapy. Salvage chemotherapy was offered to selected patients. RESULTS: Of the 29 patients treated with EMA-CO in the primary setting, 22 (75.8%) had a complete clinical response, 5 (17.1%) progressed, and 2 (7.1%) had early deaths. Three patients relapsed after achieving initial complete response. Five were treated with salvage chemotherapy, of which only 2 survived. This translated to overall survival rate of 71% in the primary setting. Five of the 6 patients treated with EMA-CO as second line are survivors. Life threatening toxicity was not seen after EMA-CO. Nine subsequent normal pregnancies were reported after EMA-CO. CONCLUSION: EMA-CO was highly effective for the management of high-risk GTN, and the toxicities were minimal. Reproductive outcome after treatment with EMA-CO was excellent. PMID- 21682118 TI - Clinical usefulness of contrast-enhanced color Doppler ultrasonography in invasive and noninvasive gestational trophoblastic diseases: a preliminary study. AB - OBJECTIVE: To examine the usefulness of contrast-enhanced color Doppler ultrasonography (CDU) in differentiating between invasive and noninvasive gestational trophoblastic disease (GTD). STUDY DESIGN: In 23 patients with findings suggestive of GTD by transvaginal gray-scale ultrasonography, the presence or absence of blood flow within uterine lesions was assessed by contrast enhanced CDU using Levovist (Schering, Berlin, Germany) microbubble contrast agent. Intratumoral blood flow waveforms were analyzed using resistance indices. Tumor size in each invasive or malignant GTD was assessed by magnetic resonance imaging. RESULTS: Intratumoral blood flow was detected in all invasive or malignant GTDs (7/7: 5 invasive moles, 1 choriocarcinoma and 1 placental site trophoblastic tumor), whereas it was not seen in any noninvasive GTD (0/16:10 complete moles, 5 partial moles and 1 exaggerated placental site) (p <0.0001). A marked increase in uterine vascularity was thus shown in all invasive or malignant GTDs following enhancement. In small invasive moles (<2 cm) in the uterine myometrium, color flow was remarkably increased by contrast-enhanced CDU. Intratumoral blood flow waveforms showed low resistance indices in all invasive and malignant GTDs. CONCLUSION: Contrast-enhanced CDU may be useful in differentiating invasive or malignant GTDs from noninvasive GTDs. By enhancing color flow, this minimally invasive approach may be helpful for detecting small invasive GTD lesions within the uterine myometrium. PMID- 21682119 TI - Management of massive hemorrhage in patients with gestational trophoblastic neoplasia by angiographic embolization: a safer alternative. AB - OBJECTIVE: To assess the usefulness of angiographic embolization in hemorrhage due to gestational trophoblastic neoplasia (GTN). STUDY DESIGN: We conducted a retrospective analysis of data of patients with gestational trophoblastic disease within the time period 2002-2008. RESULTS: Eight women with GTN presented with massive hemorrhage during this time period. According to the International Federation of Gynecology and Obstetrics Scoring system 2000, 4 of those patients had high-risk GTN. Vaginal metastasis was present in 50% of the women. All women underwent angiography, and embolization was performed in 7 of the 8 patients. One patient could not undergo embolization due to technical reasons. Two patients underwent embolization of bilateral internal iliac arteries, 4 had bilateral uterine artery embolization and 1 had bilateral uterine and hepatic artery embolization. Embolization was successful in 85.7% of the patients. All patients received chemotherapy: high-risk patients received combined regimen chemotherapy (EMA-CO), while low-risk cases received methotrexate/folinic acid regimen. Out of the 8 patients, 5 are in remission and 3 succumbed to the disease. In 2 women who tried to conceive, 1 delivered a term infant and the other had a miscarriage. The most common side effect of embolization was pain requiring parenteral analgesia. CONCLUSION: Transcatheter embolization is a safe and quick procedure and should be considered in GTN patients with acute hemorrhagic life-threatening complications. PMID- 21682120 TI - Fetal heart rate parameters of anencephalic fetuses according to gestational age. AB - OBJECTIVE: To evaluate various fetal heart rate (FHR) parameters of anencephalic fetuses and to assess the effect of the fetal nervous system on FHR according to gestational age. STUDY DESIGN: The antepartum nonstress test was performed in 25 anencephalic fetuses. Each FHR parameter was analyzed using a computerized FHR analysis system for various gestational groups, and the results were compared with results from a normal control group (N = 25). RESULTS: The mean baseline FHR of anencephalic fetuses decreased with increasing gestational age, as in normal fetuses. FHR variability increased with increasing gestational age, as in normal fetuses. CONCLUSION: In anencephalic fetuses, baseline FHR and FHR variability changed significantly with gestational age. These results suggest that the autonomic nervous system is more likely to be preserved than the central nervous system in anencephalic fetuses in spite of malformed or insufficient central nervous system. PMID- 21682121 TI - Comparison of different preoperative sublingual misoprostol regimens for surgical termination of first trimester pregnancies: a prospective randomized trial. AB - OBJECTIVE: To determine the appropriate dose of sublingual misoprostol administration before dilation and curettage (D&C) of the uterus in first trimester pregnancies. STUDY DESIGN: Ninety nulliparous women who underwent surgical termination of first trimester pregnancy were analyzed prospectively. The first group (n = 30) received a single 200-microg dose, and the second (n = 30) and third (n = 30) groups were administered 2x 200 microg (400 microg) and 3 x 200 microg (600 microg) doses of misoprostol sublingually, respectively, with 1 hour intervals. The main outcomes evaluated were the degree of difficulty of cervical dilation, adverse effects of misoprostol according to dose administered, and participant satisfaction rate with the procedure. RESULTS: The improvement in cervical dilation and the ease of the D&C procedure were more significant in the 600-microg misoprostol arm (p = 0.008). Because the prevalence and severity of the side effects of misoprostol were increased in a dose-dependent manner, the 400-microg arm was found to be the most efficient dose of the study with its high satisfaction rate (p < 0.001). CONCLUSION: Premedication with misoprostol makes the D&C procedure easier by leading to cervical ripening. By sublingual route 400 microg of misoprostol regimen seems to be appropriate for planned first trimester surgical pregnancy termination under local anesthesia. Misoprostol should be administered only to select and hospitalized patients. PMID- 21682122 TI - Evaluation of IGF2 imprinting status and the levels of folate biomarkers in second trimester pregnant Chinese women. AB - OBJECTIVE: To assess the relationship between folate biomarkers levels and IGF2 imprinting status among second trimester pregnant Chinese women. STUDY DESIGN: Three hundred women in their second trimester were screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for analysis of IGF2 imprinting status. Statistical differences of folate biomarkers levels were calculated in the groups with different imprinting status. RESULTS: Of the 300 women analyzed, 133 (44.33%) cases were homozygous allele with A, 3 (1.00%) cases were homozygous allele with G, while 164 (54.67%) cases were heterozygous with A and G, qualifying them for analysis of loss of imprinting (LOI). Among the 164 cases undergoing LOI analysis, 44 (26.83%) were IGF2 LOI cases, while 120 (73.17%) were IGF2 retention of imprinting (ROI) ones. The mean level of serum folate, vitamin B12 and tHcy was 28.46 +/- 10.74 ng/mL, 380.20 +/- 206.13 pg/mL, 14.24 +/- 6.34 micromol/L among women with IGF2 ROI, and 30.89 +/- 9.97 ng/mL, 394.28 +/- 195.92 pg/ mL, and 13.12 +/- 6.23 micromol/L among women with IGF2 LOI, respectively. CONCLUSION: No significant difference of folate biomarkers levels was observed between IGF2 ROI and IGF2 LOI groups. PMID- 21682123 TI - Stage IIIB carcinoma of the cervix in a 19-year-old: a case report. AB - BACKGROUND: As of December 2009, the American College of Obstetricians and Gynecologists recommends that cervical cancer screening not be initiated until age 21. However, cases, although rare, do exist of advanced cervical cancer diagnosed in women younger than age 21. Our case describes one such rare event and questions whether women should be evaluated based on their individual social behaviors and risk factors. CASE: A 19-year-old, nulliparous, African American female presented to the Methodist Dallas Hospital emergency department with complaints of chronic abdominal and pelvic pain of 3 months' duration which had become acutely more painful 1 week prior to presentation. The patient stated that she had been diagnosed and treated the previous week at a different hospital with pelvic inflammatory disease. On examination the patient was noted to have a large,fungating mass distorting the external surface of her cervix. At that time a Pap smear and a tissue sample biopsy were collected. The patient was admitted with a pelvic mass and was subsequently staged with Stage IIIB cervical cancer. CONCLUSION: Our patient demonstrates the importance of evaluating young women at high risk for cervical pathology despite new recommendations from ACOG that cervical cytologic screening begin uniformly at age 21. PMID- 21682124 TI - Robotic-assisted laparoscopic repair of symptomatic cesarean scar defect: a report of two cases. AB - BACKGROUND: Symptomatic cesarean scar defect is one of the commonly reported long term complications of cesarean section. CASES: We present two cases of symptomatic cesarean scar defect treated conservatively by robotic-assisted laparoscopy at our institution. Both patients presented with hematocele, pelvic discomfort and secondary infertility. Transvaginal ultrasound revealed hematocele measuring 3.7 x 1.9 x 3.8 cm and 3.0 x 2.0 x 1.6 cm in the lower uterine segments, respectively. After surgery normal menses resumed in both patients, and their childbearing potential was preserved. The patients conceived 3 and 11 months after surgery, respectively. CONCLUSION: Recognition of cesarean scar defect is important in the explanation of certain menstrual disorders since surgical intervention can result in improvement of symptoms and prevent the related secondary obstetric and gynecologic complications. Robotic-assisted laparoscopic approach is a good minimally invasive alternative for the repair of cesarean scar defect. PMID- 21682125 TI - Gelatin-thrombin hemostatic matrix in the management of placental site postpartum hemorrhage: a case report. AB - BACKGROUND: Gelatin-thrombin matrix (FloSeal, Baxter Healthcare Corporation, Fremont, California), a biodegradable hemostatic sealant, has been shown to control bleeding in multiple intraoperative scenarios and surgical disciplines. However, limited data is available regarding its use in obstetrics. A case of placental-site obstetric hemorrhage controlled with gelatin-thrombin matrix at time of cesarean delivery is presented. CASE: A 28-year-old woman underwent a tertiary repeat cesarean delivery for complete placenta previa. The placenta was removed without evidence of placenta accreta. Profuse bleeding occurred over the placental implantation site, resulting in hemorrhage, uncontrolled by conservative uterine-sparing methods. Upon preparation for emergency hysterectomy, gelatin-thrombin matrix was applied, resulting in rapid control of hemorrhage. CONCLUSION: Abnormal placentation is a predisposing factor of postpartum hemorrhage. In the absence of placenta accreta, profuse hemorrhage can occur from large vascular sinuses associated with a denuded implantation site in the poorly contractile lower uterine segment. In the event of unsuccessful hemorrhage control with conservative techniques, emergency hysterectomy is performed as a life-saving procedure. Multiple unit blood transfusion is often encountered. In the case presented, the use of gelatin-thrombin matrix gel for placental site hemorrhage management at the time of cesarean delivery resulted in rapid control of hemorrhage, uterine preservation and avoidance of massive blood transfusion. PMID- 21682126 TI - Recurrent ectopic pregnancy with heterotopic pregnancy in a patient of hypogonadotropic hypogonadism: a case report. AB - BACKGROUND: Heterotopic pregnancy is the simultaneous occurrence of intrauterine and ectopic pregnancies. With an incidence reported to be between 1:8,000 and 1:30,000 pregnancies, heterotopic pregnancy is a rare entity. However, the increasing use of assisted reproductive techniques has contributed to the increasing incidence of heterotopic pregnancy during the past years. CASE: This is a rare case of a hypogonadotropic hypogonadism in a patient with a heterotopic pregnancy six months after successful medical management of tubal ectopic pregnancy. The heterotopic pregnancy was managed expectantly with successful pregnancy outcome. CONCLUSION: Heterotopic pregnancy should always be considered, especially in patients with prior history of ectopic pregnancy and those undergoing assisted reproduction. Its treatment is a challenge as serial beta-hCG is not useful in diagnosis or follow-up, and medical management with methotrexate is contraindicated with an intrauterine pregnancy. Heterotopic pregnancies in select cases can be managed expectantly with strict monitoring and serial ultrasounds, and the viable intrauterine pregnancy can be saved. PMID- 21682127 TI - Men behaving badly. What is it about power that makes men crazy? PMID- 21682128 TI - The turning point. Finally, French women start a conversation about inappropriate sexual conduct. PMID- 21682129 TI - Killing fields. How Asia's growing appetite for traditional medicine is threatening Africa's rhinos. PMID- 21682131 TI - Scanxiety. Fear of a postcancer ritual. PMID- 21682130 TI - What I learned from my cancer scare. PMID- 21682132 TI - Mobile alert. A new study fuels debate over cell phones and tumors. PMID- 21682133 TI - Screening dilemma. Are some cancers better left undiscovered? PMID- 21682134 TI - Cracking cancer's code. Tumor DNA holds the key to beating the disease. PMID- 21682135 TI - Refuseniks. Why some cancer patients reject their doctor's advice. PMID- 21682136 TI - Check your charity! There are too many lightweight nonprofits in cancer research. PMID- 21682137 TI - Role of PPARgamma, a nuclear hormone receptor in neuroprotection. AB - Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily. PPAR-alpha is involved in wound healing, stimulation of lipid and folic acid catabolism, inflammation control, inhibition of ureagenesis and peroxisome proliferation. The PPARgamma/delta is involved wound healing, cell proliferation, embryo implantation, adipocyte differentiation, myelination alteration and apoptosis. The PPARgamma is involved in fat, lipid and calorie utilization, sugar control, inflammation control and macrophage (MQ) matutation. Homocysteine (Hcy) binds to nuclear peroxisome proliferator activated receptor. Increase in PPAR expression decreases the level of nitrotyrosine and increases endothelial nitric oxide concentration, decreases metalloproteinase activity and expression as well as elastinolysis and reverses Hcy-mediated vascular dysfunction. The PPARgamma initially recognized as a regulator of adipocyte development has become a potential therapeutic target for the treatment of diverse disorders. In addition, the activation of PPARgamma receptor ameliorates neurodegenerative disease. This review focuses on the recent knowledge of PPARgamma in neuroprotection and deals with the mechanism of neuroprotection of central nervous system disorder by PPARgamma. PMID- 21682138 TI - Abnormality of circadian rhythm of serum melatonin and other biochemical parameters in fibromyalgia syndrome. AB - Fibromyalgia syndrome (FMS) is a complex chronic condition causing widespread pain and variety of other symptoms. It produces pain in the soft tissues located around joints throughout the body. FMS has unknown etiology and its pathophysiology is not fully understood. However, abnormality in circadian rhythm of hormonal profiles and cytokines has been observed in this disorder. Moreover, there are reports of deficiency of serotonin, melatonin, cortisol and cytokines in FMS patients, which are fully regulated by circadian rhythm. Melatonin, the primary hormone of the pineal gland regulates the body's circadian rhythm and normally its levels begin to rise in the mid-to-late evening, remain high for most of the night, and then decrease in the early morning. FMS patients have lower melatonin secretion during the hours of darkness than the healthy subjects. This may contribute to impaired sleep at night, fatigue during the day and changed pain perception. Studies have shown blunting of normal diurnal cortisol rhythm, with elevated evening serum cortisol level in patients with FMS. Thus, due to perturbed level of cortisol secretion several symptoms of FMS may occur. Moreover, disturbed cytokine levels have also been reported in FMS patients. Therefore, circadian rhythm can be an important factor in the pathophysiology, diagnosis and treatment of FMS. This article explores the circadian pattern of abnormalities in FMS patients, as this may help in better understanding the role of variation in symptoms of FMS and its possible relationship with circadian variations of melatonin, cortisol, cytokines and serotonin levels. PMID- 21682139 TI - Isolation of a laccase with HIV-1 reverse transcriptase inhibitory activity from fresh fruiting bodies of the Lentinus edodes (Shiitake mushroom). AB - A laccase with a molecular mass of 67 kDa and inhibitory activity toward HIV-1 reverse transcriptase (IC50 = 7.5 microM) was isolated from fresh fruiting bodies of the Lentinus edodes (Shiitake mushroom). Its characteristics were compared with those of laccases from cultured mushroom mycelia reported earlier. The laccase was unadsorbed on DEAE-cellulose, Affi-gel blue gel and CM-cellulose, but was adsorbed on Con A-Sepharose. About 50-fold purification was achieved with a 19.2% yield of the enzyme. The activity of the enzyme increased steadily from 20 degrees C to 70 degreesC. The activity disappeared after exposure to the boiling temperature for 10 min. Its optimal pH was 4 and very little enzyme activity remained at and above pH 10. The laccase inhibited HIV-1 reverse transcriptase with an IC50 of 7.5 microM, but did not demonstrate any antifungal or anti proliferative activity. PMID- 21682140 TI - Isolation and characterization of a metal ion-dependent alkaline protease from a halotolerant Bacillus aquimaris VITP4. AB - A halotolerant bacterium Bacillus acquimaris VITP4 was used for the production of extracellular protease. Fractional precipitation using ammonium chloride was used to obtain the enzyme. The protease exhibited optimum activity at pH 8.0 and 40 degrees C and retained 50% of its optimal proteolytic activity even in the presence of 4 M NaCl, suggesting that it is halotolerant. The molecular mass of protease, as revealed by SDS-PAGE was found to be 34 kDa and the homogeneity of the enzyme was confirmed by gelatin zymography and reverse-phase HPLC. Upon purification, the specific activity of th enzyme increased from 533 U/mg to 1719 U/mg. Protease inhibitors like phenyl methane sulphonyl fluoride and 2 mercaptoethanol did not affect the activity of the enzyme, but EDTA inhibited the activity, indicating the requirement of metal ions for activity. Cu2, Ni2+ and Mn2+ enhanced the enzyme activity, but Zn2+, Hg2+ and Fe2+ decreased the activity, while Mg2+, Ca2+ and K+ had no effect on the enzyme activity. The protease was quite stable in the presence of cationic (CTAB), anionic (SDS) and neutral detergents (Triton X-100 and Tween-20) and exhibited antimicrobial activity against selected bacterial and fungal strains. The stability characteristics and broad spectrum antimicrobial activity indicated the potential use of this protease in industrial applications. PMID- 21682141 TI - A molecular docking study of anticancer drug paclitaxel and its analogues. AB - Present study was aimed at finding a better alternative to paclitaxel, an anticancer chemotherapeutic drug. Two targets, tubulin beta-1 chain and apoptosis regulator Bcl-2 protein (202F) were used in the study. Of these, structure of tubulin beta-1 chain is not known and that of Bcl-2 was taken from protein data bank with ID 202F. Tertiary structure model of tubulin beta-1 chain was predicted and validated. The validated 3D structure of tubulin beta-1 chain and Bcl-2 protein was taken to study their interaction with paclitaxel. Molecular docking of paclitaxel and its analogues was performed with these targets separately. Results showed that out of 84 analogues taken from PubChem, CID_44322802 had glide score of -9.62, as compared to -5.86 of paclitaxel with tubulin beta-1 chain. It was also observed that CID_9919057 had glide score of -9.0, as compared to -8.24 of paclitaxel with Bcl-2 protein. However, further experimental and clinical verification is needed to establish these analogues as drug. PMID- 21682142 TI - MAPS: an interactive web server for membrane annotation of transmembrane protein structures. AB - The exact positioning of the membrane in transmembrane (TM) proteins plays important functional roles. Yet, the structures of TM proteins in protein data bank (pdb) have no information about the explicit position of the membrane. Using a simple hydrophobic lipid-protein mismatch energy function and a flexible lipid/water boundary, the position of lipid bilayer for representative TM proteins in pdb have been annotated. A web server called MAPS (Membrane Annotation of Protein Structures; available at: http://www.boseinst.ernet.in/gautam/maps) has been set up that allows the user to interactively analyze membrane-protein orientations of any uploaded pdb structure with user-defined membrane flexibility parameters. PMID- 21682143 TI - Development and validation of a robust QSAR model for prediction of carcinogenicity of drugs. AB - Carcinogenicity is one of the toxicological endpoints causing the highest concern. Also, the standard bioassays in rodents used to assess the carcinogenic potential of chemicals and drugs are extremely long, costly and require the sacrifice of large numbers of animals. For these reasons, we have attempted development of a global quantitative structure-activity relationship (QSAR) model using a data set of 1464 compounds (the Galvez data set available from http://www.uv.es/-galvez/tablevi.pdf), including many marketed drugs for their carcinogenesis potential. Though experimental toxicity testing using animal models is unavoidable for new drug candidates at an advanced stage of drug development, yet the developed global QSAR model can in silico predict the carcinogenicity of new drug compounds to provide a tool for initial screening of new drug candidate molecules with reduced number of animal testing, money and time. Considering large number of data points with diverse structural features used for model development (n(training) = 732) and model validation (n(test) = 732), the model developed in this study has an encouraging statistical quality (leave-one-out Q2 = 0.731, R2pred = 0.716). Our developed model suggests that higher lipophilicity values and conjugated ring systems, thioketo and nitro groups contribute positively towards drug carcinogenicity. On the contrary, tertiary and secondary nitrogens, phenolic, enolic and carboxylic OH fragments and presence of three-membered rings reduce the carcinogenicity. Branching, size and shape are found to be crucial factors for drug-induced carcinogenicity. One may consider all these points to reduce carcinogenic potential of the molecules. PMID- 21682144 TI - Cold-induced sweetening development in Indian potato (Solanum tuberosum L.) varieties. AB - Developing cold sweetening resistant processing varieties is one of the frontal areas of research all over the world. In India, first potato processing variety was released in the year 1998 and till 2005 three varieties have been developed. But, there is no information available regarding sugar accumulation response of Indian varieties to low temperature storage. Therefore, it is imperative to generate basic information on cold sweetening development in Indian processing varieties for the use of potato breeders. Development of cold-induced sweetening and its relation to phenolic content of the tuber was studied in three Indian potato varieties viz., Kufri Chipsona-1, Kufri Chipsona-3 and Kufri Jyoti. The reducing sugars decreased in initial phase of storage, followed by continuous increase to unacceptably higher levels after around two weeks of storage. The increase in reducing sugar contents took place subsequent to increase in sucrose content. The changes in phenol content were not in a fixed trend. The degree or number of folds increase in reducing sugar content was relatively less in Kufri Jyoti which contained highest phenol content among the three varieties investigated. It is suggested that development of processing varieties with higher anti-oxidant content and lower invertase activity may provide better cold induced sweetening resistance. PMID- 21682145 TI - Glycemic control and the outcomes of Hispanic patients with diabetes admitted to the general ward of a community hospital in Puerto Rico. AB - OBJECTIVE: Uncontrolled glucose, present in 40% of diabetic patients admitted to United States hospitals, has been associated with prolonged length of stay and poorer general outcomes in critically ill and surgical patients. However, past studies of general ward patients have shown there to be no consistent benefits of strict glucose control, and the Hispanic population has been underrepresented in such studies. This work evaluated the association between glycemic control and the outcomes of hospitalized Hispanics with diabetes and to describe physicians' interventions in the treatment of diabetes. METHODS: This is a retrospective chart review of all patients with diabetes admitted over a period of six months in the general ward of a community hospital in Puerto Rico. We evaluated glucose levels during the first 72 hours, length of stay, and reported complications during admission. Outcomes were evaluated with crude odds ratios and multivariate logistic regression. RESULTS: Uncontrolled blood glucose was observed in 59.1% of the 875 patients whose records were revised; of that 59.1%, treatment modification was not prescribed for 43.2%. Patients with poorly controlled glucose were more likely to develop acute coronary syndrome (corrected OR: 11.46; 95% CI = 1.48-88.50) as a complication and less likely to develop hypoglycemia (corrected OR: 0.57; 95% = CI 0.37-0.88). CONCLUSION: Our results suggest that hospitalized but non-critically ill Hispanic patients with diabetes are prone to poor outcomes secondary to uncontrolled glucose levels; in addition, those results support the creation of standardized protocols for the management of diabetes in this population. PMID- 21682146 TI - Outcomes of osteomyelitis in patients with diabetes: conservative vs. combined surgical management in a community hospital in Puerto Rico. AB - OBJECTIVE: Diabetes predisposes patients to multiple complications, such as osteomyelitis, which, if not managed adequately, may result in amputation, sepsis, or death. This study aimed to compare the rates of amputation associated with two different treatment plans for osteomyelitis being utilized with a group of Puerto Ricans with diabetes. METHODS: We reviewed the medical records of adult patients with diabetes and osteomyelitis who had been admitted to a community hospital within a two-year timeframe; a total of 169 records were reviewed. Data were analyzed using descriptive statistics, chi-square, odds ratios, and multivariate logistic regression to compare the amputation rate of patients receiving conservative management (antibiotics and/or local care alone) with that of patients receiving combined surgical treatment (any modality consisting of an initial surgical treatment plus antibiotics and/or local care). RESULTS: We found a general amputation rate of 34.5%. Amputation was less likely in patients undergoing combined surgical treatment (OR: 0.22; 95% IC: 0.08-0.59) than it was in those patients whose disease management was conservative. In addition, men (OR: 2.09; 95% CI: 1.04-4.23) and non-geriatric patients (OR: 3.38; 95% CI: 1.65 6.94) had higher probabilities of amputation than did women and geriatric patients, respectively. CONCLUSION: This study revealed an amputation rate among patients with diabetes that is higher than that reported in the United States (34.5% vs. 11.0% to 20.0%). We also found that the probability of amputation secondary to osteomyelitis among patients with diabetes is two times higher for men and three times higher for non-geriatric patients; combined surgical treatment was associated with a significant reduction (78%) of the probability of amputation. PMID- 21682147 TI - Validation and reproducibility of a semi-quantitative food frequency questionnaire for use in Puerto Rican children. AB - OBJECTIVE: Knowledge of the diet of specific populations is of importance in the assessment of nutrient intake. Herein, we assess the reproducibility and validity of an interviewer-administered food frequency questionnaire (FFQ) in Puerto Rican children at two educational levels--elementary (ES) and high school (HS). METHODS: The FFQ contained 97 items including supplements. It was administered twice (FFQ1 and FFQ2) within a 2 week interval between which three dietary food records (DFR's) were collected. In all, 94 ES children (40 boys and 54 girls) and 89 HS children (42 boys and 47 girls) participated in this IRB-approved study. RESULTS: Results showed correlations between FFQ1 and FFQ2 for representative macro- and micronutrients lower than reported in the literature. Correlation coefficients were higher for HS (mean R = 0.43) compared to ES (mean R = 0.21) and higher for girls than for boys at both school levels. Results for validation also showed lower correlations between the FFQ2 and DFR's compared to other studies, which was higher in HS students (mean R = 0.34) compared to ES students (mean R = 0.10). However, these same nutrients were cross-classified into equivalent quartiles for both the FFQ and DFR with an accuracy of about 66%. CONCLUSION: We have designed and validated a FFQ, appropriate for use in Puerto Rican schoolchildren to estimate energy intake in younger students and energy and micronutrients in older students. The significance of this research is that there is now an updated instrument for use in dietary studies in Puerto Rican youth. PMID- 21682148 TI - HIV-related risk behaviors among a sample of men who have sex with men in Puerto Rico: an overview of substance use and sexual practices. AB - OBJECTIVE: Despite the growing impact of the human immunodeficiency virus (HIV) epidemic in Puerto Rico (PR), limited epidemiological research on men who have sex with men (MSM) has been conducted. The aim of this study was to describe HIV related risk behaviors in a sample of MSM in PR. METHODS: A secondary data analysis of a household survey of the adult population of PR was performed in order to describe substance use and sexual practices related to HIV transmission and seropositivity for hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, and type 2 herpes simplex virus (HSV-2) in MSM. Data regarding substance use and sexual practices were collected using audio computer-assisted self-interviewing (A-CASI). Descriptive statistics were used to examine lifetime and recent (12 months) prevalence of substance use and sexual practices. RESULTS: Of the 640 men interviewed, 41 (6.4%) reported having ever had sex with another man on at least one occasion. Approximately one-fourth of MSM reported having used marijuana (24.4%) and cocaine (24.4%) in the past 12 months. Nearly 42% of the MSM reported an early age of sexual initiation (< 15 years), and 61% reported having had at least 10 sexual partners in their lifetime. Seropositivity rates for HAV, HSV-2, HIV, HCV, and HBV were 43.3%, 32.4%, 7.3%, 4.9%, and 4.9%, respectively. CONCLUSION: This is the first study to attempt to examine high-risk behaviors related to HIV in a population-based sample of MSM in PR. Concurrent efforts that will help to intensify research and prevention initiatives among MSM are necessary, especially those that will enhance awareness of screening for HIV, HCV, and other sexually transmitted infections, access to HAV and HBV vaccinations, substance use, and identification of social barriers. PMID- 21682149 TI - Extracranial carotid artery stenting: the Puerto Rico medical center endovascular neurosurgery service experience. AB - OBJECTIVE: Extracranial carotid artery stenting (CAS) represents a viable alternative for high-risk surgical patients. The aim of this study was to determine the clinical features and outcome of 25 patients that underwent CAS at the Puerto Rico Medical Center. METHODS: A retrospective review of a series of 25 high-risk surgical patients that underwent CAS from June 2005 to January 2010 was performed. Patients were followed-up at clinics with computed tomography angiography and/or digital subtraction angiography. RESULTS: Patient ages ranged from 52 to 88 years. Twenty-one of the patients had severe cervical carotid stenosis (more than 80%). Those with moderate stenosis (from 50% to 80%) were treated when they were symptomatic or when stenosis recurred after carotid endarterectomy. Among the 25 patients, only 2 presented with restenosis (more than 50% luminal diameter). Both had a history of radiation-induced disease, but neither required retreatment. Five patients required post-stenting angioplasty due to a less than 50% improvement in luminal diameter. There was 1 death, and 1 patient presented delayed neurocognitive deterioration. The combined long-term morbidity and mortality in the subgroup with at least two years of follow-up was 8.3%. There were no intracerebral hemorrhages or recurrent strokes/transient ischemic attacks. CONCLUSION: The restriction of post-stenting angioplasty to only those cases without significant revascularization appears to help reduce restenosis rates while ensuring a gradual increase in intracranial blood flow. The latter may not apply to patients with a prior history of radiotherapy. PMID- 21682150 TI - Renal cell carcinoma: molecularly targeted therapy. AB - Renal cell carcinoma is the most common cancer of the kidney and is among the tumors that are the most resistant to systemic therapy. Until recently, long term survival of this disease when it was not confined to the kidney was dismal, with the use of drugs such as interleukin-2 resulting in a 5-year survival rate of less than 10% for patients with advanced disease. Nearly 30% of patients present with metastatic disease, and recurrence develops in approximately 40% of patients with localized tumors. Since December 2005, the Food and Drug Administration (FDA) has approved 6 novel drugs that target advanced disease. These molecularly targeted drugs, representing the next generation of anticancer agents, inhibit angiogenesis and tumor growth factors. Small molecule tyrosine kinase inhibitors are the prototype of cancer therapy in this century, causing fewer toxic effects in the normal cells and with targeted inhibition of malignant cell proliferation. These therapies have emerged from the understanding of the molecular genetics and biology of this tumor. Further elucidation of the mechanisms of action of these drugs and those in development will lead to more effective therapies and increase the understanding of the best ways to combine them. PMID- 21682151 TI - Implantable cardioverter-defibrillators for primary prevention of sudden cardiac death in patients with left ventricular systolic dysfunction: 14 years after MADIT. AB - Sudden cardiac death (SCD) is the most common cause of death among patients with heart failure and left ventricular systolic dysfunction. Implantable cardioverter defibrillators (ICDs) have been shown to be the single most effective therapy for primary prevention of SCD in patients with heart failure. The superiority of this therapy was clearly established for patients with ischemic cardiomyopathy by large clinical trials, such as the Multicenter Automatic Defibrillator Implantation Trial (MADIT), Multicenter Unsustained Tachycardia Trial (MUSTT), and MADIT-II studies. On the other hand, there was much debate on whether these results could be extrapolated for patients with non-ischemic cardiomyopathy until the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated a significant benefit of this therapy. Given the high costs of this therapy and the limited resources allocated to health care multiple studies have attempted to identify patients at higher risk of suffering SCD, who in theory will benefit the most out of this therapy. However, these studies have not established a reliable way to predict which patients will receive a direct survival benefit from ICD therapy. Until we are capable of further defining which patients will derive the absolute highest benefit from an ICD, we must rely on the information available from published trials and adhere to current clinical practice guidelines regarding this pressing issue. PMID- 21682152 TI - Aborted sudden cardiac death as a presentation of isolated non-compaction cardiomyopathy. AB - Left ventricular non-compaction cardiomyopathy (LVNC) is a rare disorder characterized by a thick myocardial wall with two distinct layers consisting of compacted and noncompacted myocardium. The major clinical manifestations of LVNC have been described as heart failure, cardiac arrhythmias, and cardioembolic events. In this report we present a case of a young woman with LVNC who presented with aborted sudden cardiac death. This is the second case of LVNC reported in Puerto Rico, but the first presenting with this complication. Recent advances in the field of cardiology allow the identification and diagnosis of this disease; thus, preventive and treatment strategies could be established for this potentially life-threatening condition. LVNC has to be considered in young patients presenting with sudden cardiac death. PMID- 21682153 TI - Neonatal diabetes mellitus: description of two Puerto Rican children with KCNJ11 activating gene mutation. AB - Neonatal diabetes mellitus (NDM) is a rare disorder. A one-month-old boy presented with vomiting, hyperglycemia (968 mg/dl [53.8 mmol/L]), severe acetonemia, and metabolic acidosis (pH 6.95, HCO3-4.2 mmol/L). A second child (three months of age) presented with upper respiratory tract symptoms and a plasma glucose level of 835 mg/dl, without acetonemia or acidosis. Both were hospitalized and managed with intravenous fluids and then discharged on insulin. Genetic testing identified the presence of the de nova V59M and E322K activating mutations in the KCNJ11 gene encoding the sulphonylurea/potassium channel (Kir6.2 subunit) of the insulin beta cell. Both patients were switched to glibenclamide and remain off insulin. To our knowledge, these are the first children in Puerto Rico identified with NDM secondary to a KCNJ11 activating mutation. We conclude that NDM secondary to KCNJ11/Kir6.2 activating mutations, although unusual, should be considered in similar cases since patients with these mutations could come off insulin. PMID- 21682154 TI - Harold W. Brown, Dean-in-a-Pinch. AB - The creation of the University of Puerto Rico School of Medicine required someone who could recruit faculty, plan the curriculum, set up the admissions process, and insure that the school meet accreditation requirements. Despite setbacks, chancellor Jaime Benitez found in Dr. Harold W. Brown a person with the knowledge and abilities to accomplish these tasks. Although Brown would not accept the deanship of the school, he was detailed by Columbia University to serve as Benitez's special advisor. In this role, he intervened at key points in the school's development and was able to accomplish his mission. Benitez gave credit to Brown for the school's development, and Brown's contributions were duly recognized when the School graduated its first class in 1954. PMID- 21682155 TI - The search for savings. PMID- 21682156 TI - Efficiency. Wealth of opportunities for mental healthcare. PMID- 21682157 TI - Quality and performance. Embracing the era of the outcome. PMID- 21682158 TI - Workforce. Pay freeze for jobs--deal or no deal?. PMID- 21682159 TI - Nurses can prove safety in numbers. PMID- 21682160 TI - "Localism is a laudable aim but it may result in care factories". PMID- 21682161 TI - "Take a look at the real piggy banks, not nurses' pensions". PMID- 21682162 TI - "I can't be the only male nurse who gets asked to read the gas meter". PMID- 21682163 TI - Diagnosing and treating HIV infection. AB - In the past, HIV infection was regarded as synonymous with AIDS, but it is increasingly viewed as a long-term, treatable condition. This article identifies the main changes in diagnosing and treating HIV infection since testing was introduced in the UK 25 years ago. PMID- 21682164 TI - Stamping out stigma in HIV. AB - Despite significant developments in the treatment of HIV infection, it is still heavily stigmatised. This article discusses why this is so, what can be done to help change negative attitudes towards people with HIV, and how nurses can help reduce stigma. PMID- 21682165 TI - Blood cancers, chemotherapy and the risks of neutropenia. PMID- 21682166 TI - The drama of end of life care at home. AB - BACKGROUND: Many terminally ill patients want to die at home. Family carers are fundamental to achieving this, but often feel anxious and unprepared for the role. Supporting them is vital in palliative care. AIM: To explore the experiences of carers of patients dying at home, in particular their expectations and preparedness for the dying process. METHOD: The study followed a qualitative approach. In-depth, semi-structured interviews with 15 carers were carried out. RESULTS: Carers experienced uncertainty and felt unrehearsed for their role. They were reluctant to seek information to give them a script for their performance because it was too painful to contemplate the patient's death. The carers needed the direction of health and social care professionals, and the help of paid carers, but experiences of these services varied. CONCLUSION: The study highlighted the drama of the situation for carers, and the anxiety of being the leading player on stage with minimal preparation. Nurses play a crucial role in supporting carers and can use a "dramaturgical" perspective to guide them in giving carers the direction they need. PMID- 21682167 TI - Nursing's rock. PMID- 21682168 TI - How to recruit temporary staff. PMID- 21682169 TI - Final Jeopardy! Category: physician assistants. PMID- 21682170 TI - Comparing brand name drugs to their generic equivalents. PMID- 21682171 TI - What is this slow-growing preauricular lesion? PMID- 21682172 TI - A day in the life. PMID- 21682173 TI - Diagnosis and treatment of exercise-induced bronchospasm: a review. PMID- 21682174 TI - Polydactyly in a young boy: a cause of teasing and local tribal suspicion. PMID- 21682175 TI - PAs in the ED: do physicians think they increase the malpractice risk? AB - OBJECTIVE: This study evaluates emergency physicians' perceptions of the malpractice risk posed by utilization of physician assistants (PAs) in emergency departments (EDs) in 2004 and again in 2009. METHODS: A 16-question survey was mailed to a random sample of 1,000 active members of the American College of Emergency Physicians in 2004 and again in 2009. RESULTS: In both 2004 and 2009, 70% of the emergency physicians did not believe that PAs, when properly supervised, are more likely to commit malpractice than any other clinician. In both surveys, 80% of the respondents did not believe PAs were more likely to be sued for malpractice. A significant negative correlation was found between perceived risk of malpractice by PAs and the number of years physicians had worked with PAs or had worked in emergency medicine. From 2004 to 2009, the number of respondents practicing with PAs increased by 26%, the number directly supervising a PA in the ED increased by 19%, the number who thought PAs decreased patient wait times increased by 13%, and the number who reported that PAs increased patient satisfaction increased by 10%. CONCLUSION: As physicians gain clinical experience with PAs, their perceived risk of malpractice tends to decrease. These results may have implications for the utilization of PAs, particularly as EDs become more utilized for noncritical situations. PMID- 21682176 TI - Robotics for the surgical treatment of pediatric patients: an overview. PMID- 21682177 TI - The assessment of jaundice in adults: tests, imaging, differential diagnosis. PMID- 21682178 TI - Biomarkers and gene mutations as aids for detecting AD early. PMID- 21682179 TI - Generational medicine: the year of the great-grandmother. PMID- 21682180 TI - Is it better to give, receive, or decline? The ethics of accepting gifts from patients. PMID- 21682181 TI - Pain in a patient's pelvis and hip following a car accident. PMID- 21682182 TI - Case of the month. Grade I hepatic encephalopathy. PMID- 21682183 TI - Suicidal behaviour and physical illness. PMID- 21682184 TI - Epidemiology and histology of malignant thyroid nodules in North East Region of Romania (Moldavia) before and after alimentary salt universal iodination. AB - Research on the relationship between iodine exposure and thyroid cancer risk is limited and the findings are inconclusive. OBJECTIVES: Given this molecular data on iodine we decided to evaluate the changes of incidence and histology of thyroid cancer in the North-Eastern region of Romania (Moldavia) after the government decision from 2004 that introduced the universal iodination of alimentary salt. After this decision values of urinary iodine increased from 50 microg/L (2001-2002) to 117 microg/L (2006 -2008). MATERIAL AND METHODS: We compared the incidence and the histology of thyroid cancer in residents living in an area known as a mild endemic goiter region (Moldavia-Romania) between 2001 2004 with the incidence and the histology of thyroid cancer between 2005-2008 in the same region after the introduction of universal iodization of alimentary salt. RESULTS: The number of papillary cancers increased from 125 cases (2001 2004) to 276 cases (2005-2008). The number of follicular cancer decreased from 52 cases (2001-2004) to 27 cases (2005-2008). The ratio between papillary and follicular cancers increased from 4.80 / 1 (2001-2004) at 10.61 / 1 (2005-2008). The number of medullar thyroid carcinoma increased from six cases (2001-2004) to 24 cases (2005-2008). Thyroid anaplastic carcinomas number increased from 7 cases (2001-2004) to 12 cases (2005-2008). The total number of thyroid cancer has increased dramatically after the introduction of universal iodination of alimentary salt with 178% compared to 2001-2004 (from 190 cases in 2001-2004 to 339 cases in 2005-2008), despite the fact that the number thyroidectomies decreased from 1734 (2001-2004) to 1449 (2005-2008). CONCLUSION: After the introduction the universal iodination of alimentary salt starting from 2004 the total number of thyroid cancers increased comparative with the period before universal iodination of alimentary salt. PMID- 21682185 TI - Wilson's disease: a challenging diagnosis. Clinical manifestations and diagnostic procedures in 12 patients. AB - Wilson disease is a neurodegenerative disease of copper metabolism. The genetic defect, localized to chromosome arm 13q, has been shown to affect the copper transporting adenosine triphosphatase (ATPase) gene (ATP7B) in the liver. Our aim was to study the clinical and laboratory characteristics of 12 children and young adults diagnosed with WD and point out the diagnostic difficulties. MATERIAL AND METHOD: We retrospectively analyzed the patients diagnosed with Wilson's disease between 2001 and 2009 diagnosed in Constanta County Emergency Hospital. Evaluation included detailed physical examination, conventional laboratory testing, genetic analysis, and liver biopsy. RESULTS: Patients with hepatic symptoms showed a considerably earlier onset of symptoms and a shorter diagnostic delay before definitive diagnosis than those with neuropsychiatrical symptoms. The mean age at diagnosis was 9.12 +/- 2.59 years (range 5 years-20 years). 10 patients were symptomatic, 6 were referred because of abnormal liver function test results and/or hepatomegaly, 4 had neuropsychiatrical symptoms and 2 received their diagnoses after family screening. Hepatic copper concentration was between 250 and 1200 micrograms/g. 4 patients had liver cirrhosis, five chronic hepatitis and one had massive hepatic necrosis on necropsy. Any person with recurrent hepatic disease and unexplained neurological symptoms should be investigated to have Wilson's disease. CONCLUSIONS: Detection of WD in children and young adults remains very difficult. The most important investigation is liver biopsy with the assessment of liver copper. Genetic analysis may help in doubtful cases. PMID- 21682186 TI - The role of real-time elastography in the evaluation of post chemotherapy hepatotoxicity in children with cancer. AB - The drugs hepatotoxicity represents a major problem of the iatrogenic pathology, with various manifestations, directly through the hepatotoxic effect or through idiosycrasy reactions. The hepatic affection induced by chemotherapy appears in children in cases of prolonged therapy, chronic diseases, or other associated conditions. Hepatotoxicity clinically develops through hepatic disorder, cholestatic or mixed hepato-cholestatic manifestations and systematic affection. There are no specific hystological or biochemical characteristics for diagnostic of hepatotoxicity. The international criteria for asessing the hepatotoxicity includes the bilirubin, the transaminasis, GGT, FA, albumin and the flow on the vein. It has been noticed that these parameters are not enough for the right assesssment of the chemotherapics' hepatotoxicity. Thus it is required the abdominal ultrasonography and computerised tomography for the identification of billiary tract, vascularisation, associated conditions and the degree of fibrosis; also, the hepatic biopsy may be necessary. The ultrasound elastography is a method which can give information related to the elasticity/stiffness of the examined tissue and degree of fibrosis. Acustic radiation force imaging(ARFI) is an elastographic method which allows valid, accurate and flexible evaluation of liver stiffness, a quantification with a strong correlation with the fibrosis stage, not influenced by steatosis. In conclusion, the hepatic toxicity showed by alterated hepatic biochemical tests and by symptomes of hepatopathy needs a proper appreciation of the hepatic modifications, which can be obtained through hepatic biopsy or by assessing the hepatic elasticity through elastography. Thus, real-time elastography is an useful tool in assessing the chemotherapics hepatotoxicity in children with cancer. PMID- 21682187 TI - Spiral enteroscopy--a novel method for the management of small bowel diseases- case report and description of technique. AB - Small bowel diseases are associated with difficult management. Recently, new methods such as single or double balloon enteroscopy and capsule endoscopy have been implemented for the investigation of small bowel, but none is perfect. Spiral enteroscopy seems to be an alternative primising technique for the diagnosis and therapy of small bowel diseases. We report two cases in which spiral enetroscopy was useful both for diagnosis and therapy. One was the case of a man with repeated digestive bleeding of unknown cause and spiral enteroscopy helped for diagnosis and treatment with argon plasma coagulation of the vascular lesions. The later was a patient with Gartner Syndrome with multiple duodenal and intestinal polyps and spiral enteroscopy allowed small bowel evaluation. In conclusion, this novel method seems to allow a rapid and efficient diagnosis of small bowel diseases. PMID- 21682188 TI - Factors affecting early morbidity and mortality in non-small cell lung cancer surgery, the experience of Surgical Clinic No. 1, Tg. Mures. AB - INTRODUCTION: The incidence of lung cancer has increased alarmingly. Lung cancer represents the first cause of death in men. Thoracic surgery is engraved with increased morbidity and mortality. Therefore, a rigorous selection of patients undergoing such surgery is imposed. In order to establish the correct therapeutic attitude,paraclinical explorations are of the ulmost importance. MATERIAL AND METHODS: We conducted a retrospective observational study over a period of six years. We used the casuistry of Surgical Clinic no. 1, Mures County Emergency Hospital. We studied the observation sheets of all the patients admitted in the Surgical Clinic no. 1 over a period of six years (1th of January 2005 to the 31th of December 2010). We studied 197 patients admitted to surgery in our clinic for lung cancer. RESULTS: In the group studied, the majority of patients were in the 5th and 6th decade of life. The average age was 59.48 years. In our study group, most patients were in an advanced stage of the disease, probably due to the late stage diagnosis of lung cancer in general. The majority of the patients were in the stage IIB and IIIA of disease. The overall postoperative morbidity rate was 21.82% (43 cases), In the study group we registered 8 deaths (4.06%)--it should be noted that we considered in-hospital mortality within the first 30 days postoperatively. CONCLUSIONS: The main risk factors for postoperative complications are: late age, male gender, pneumonectomy, low FEV1 value. Certain risk factors are predictive of postoperative mortality. The most important of them are: late age, male gender, type of surgery, FEV value, associated diseases (especially cardiovascular and diabetes). PMID- 21682189 TI - Giant lipomatous tumors of the upper extremities--a series of 8 consecutive cases. AB - We present a series of eight consecutive patients evaluated in our department from 2002 to 2007 with giant lipomatous tumors (as defined in medical studies as greater than 5 cm) of upper extremities. There were three male and five female, ranged in age from 17 to 77 years (mean age of 55). The tumor's size ranged from 5 to 34 cm. All patients underwent total excision of the tumors with free margins. All specimens were sent to pathology: seven patients had benign tumors and one patient had liposarcoma. There were no recurrences of the tumors. Appropriate preoperative evaluation and complete surgical excision are mandatory for successful treatment of these tumors. PMID- 21682190 TI - Genetic and epigenetic biomarkers for early detection, therapeutic effectiveness and relapse monitoring in bladder cancer. AB - Urinary bladder cancer is the fifth most common cancer in the Western world and is responsible for about 3% of all cancer-related deaths. Because most advanced invasive or metastatic cancers have low cure rates, risk assessment and early detection of the clinically occult premalignant phases of neoplasia are a particular importance. Many tumor biomarkers for bladder cancer have been evaluated for use in detecting and monitoring bladder cancers tissue specimens, bladder washes, and urine specimens but, none of the biomarkers reported to date has shown sufficient sensitivity and specificity to detect the entire spectrum of bladder cancers in routine clinical practice. The limitations of established prognostic markers requires us to identify better molecular parameters that could be of interest in predicting the prognosis of bladder cancer patients, in particular, the high-risk patient groups that are at risk of progression and recurrence. Methylation is an important molecular mechanism in the development of bladder cancer and could be used as a prognostic and diagnostic biomarker, because hypermethylation of several gene promoters was detected in urine sediment DNA from bladder cancer patients. Aberrant patterns of epigenetic modification could be, in the near future, crucial indicators in cancer diagnosis, prognosis, and additionally could be good targets for developing novel therapies while maintaining quality of life. PMID- 21682191 TI - The importance of EDHF in endothelium-dependent relaxation increases distally in mesenteric arteries depending upon the contracting agent. AB - AIM: The importance of endothelium-derived hyperpolarizing factor (EDHF) in endothelium-dependent relaxation (EDR) is influenced by multiple factors, including vascular territory and caliber, pre-existing tone and its determining factors. METHOD: Using isometric myography we noticed that in rat mesenteric resistance arteries (RMA2; 2nd order branches) EDHF-mediated relaxation is increased when precontraction is induced by prostaglandin F2 (PGF) compared to phenylephrine (PHE) and we investigated the participation of certain K channels. Here we extend the study on more proximal vascular fragments; from mesenteric arcade and from 1st order branches. RESULTS: The EDHF component of EDR is stronger distally only when precontraction is induced by PHE. Moreover, morphometric analysis shows a strong inverse correlation between the magnitude of EDHF response and arterial caliber. CONCLUSIONS: Other authors have shown that EDHF increases in relative importance distally, but we show that this change in EDR profile depends upon the contracting agent used, with implications regarding the physiological relevance of accumulated data refering to EDHF and nitric oxide as mediators of EDR in resistance arteries. PMID- 21682192 TI - Food-drug interactions: grapefruit juice. AB - Food-drug interactions are increasingly recognized as important clinical events which may change significantly the bioavailability of oral administrated drugs. Grapefruit juice (GFJ) demonstrated multiple interactions with drugs leading to loss of the therapeutic effects or increased side-effects. GFJ decreases pre systemic metabolism through a) competitive or mechanism-based inhibition of gut wall CYP3A4 isoenzymes and b) P-glycoprotein (P-gp), c) multidrug resistance protein-2 (MRP2) or d) organic anion-transporting polypeptide (OATP) inhibition. Although, GFJ presents high amounts of flavonoids (e.g. naringin, naringenin), furanocoumarins (e.g. 6',7'-dihydroxybergamottin, bergamottin) are the main chemicals involved in the pharmacokinetic interactions. As compounds of GFJ show additive or synergistic effects, all the major furanocoumarins are necessary for the maximal inhibitory effect. Also, related citrus fruits (sweeties, pummelo and sour orange) or various plants containing furanocoumarins may present pharmacological interactions, yet to be discovered. PMID- 21682194 TI - Reclaiming 'a land of milk and honey'. PMID- 21682193 TI - Toxicologic screening of some surfactants using modern in vivo bioassays. AB - This paper aims to evaluate the degree of skin irritation using specific in vivo tests. The completion of the study is to develop models with wide applicability in toxicological area. HET-CAM or chorioallantoic membrane assay is a new method accepted as an INVITTOX protocol that is a substitute of Draize test. The methods applied in present study were CAM assay on embryonated egg and CD1 Nu/Nu experimental model. The evaluation of erythema that is an important toxic effect of surfactants was done using a Mexameter MX18 (Courage Khazaka research line). The main observations were that sodium lauryl sulphate is the most toxic compound on our series but the non-ionic surfactants are not completely non-noxious. Non invasive methods can be associated with other test such as CAM assay to evaluate irritant compounds. PMID- 21682195 TI - Keeping well in Christchurch. PMID- 21682196 TI - A place for natural remedies. PMID- 21682197 TI - NZNO confused over new qualification. PMID- 21682198 TI - Let's get lean. PMID- 21682199 TI - Understanding health access and equity. PMID- 21682200 TI - Home-based nursing service aims to reduce health inequalities. PMID- 21682201 TI - Warm 'n well--and reducing health inequalities. PMID- 21682202 TI - Earthquake 2011. PMID- 21682203 TI - Caring for aged-care residents in the earthquake aftermath. PMID- 21682204 TI - Take a stand--sign the charter for quality aged care. PMID- 21682205 TI - Pulse oximetry--what are we really measuring? PMID- 21682206 TI - What will future models of care look like? PMID- 21682207 TI - Nanotechnology--a beginner's guide. PMID- 21682208 TI - Managing respiratory conditions. PMID- 21682209 TI - Making the most of a clinical placement. PMID- 21682210 TI - Integrated family health centre proposed for Queenstown. PMID- 21682211 TI - The fine line between genius and insanity. PMID- 21682212 TI - Transforming community services. Building broader foundations. PMID- 21682213 TI - Transforming community services. The right stuff. PMID- 21682214 TI - Transforming community services. Perfectly cut out for each other. PMID- 21682215 TI - Evaluation of the preparation of the coronal part of the mesial canals of lower molars. AB - Canal entrances can be flared using specific, low speed, continuously rotating Ni Ti instruments. Two such instruments were evaluated for their capacity to flare the canal entrance while respecting the initial canal axis. Lower molars (n = 20) with two distinct mesial canals were prepared to within 2.5 mm of the pulp chamber floor using Bramante's technique. Canal entrances were flared with a QUANTEC FLARE LX or an ENDOFLARE. They both had a 0.12 taper and a #25 tip diameter. The instruments were first inserted in the canals using an axial movement and then withdrawn with a selective circumferential brushing action. Photographs taken before and after each preparation were compared. No ledging or significant modification of the working length was noted. The centre of mass was displaced on average by 0.138 mm with no brushing action and 0.274 mm with brushing action. In most cases (87.5%), the centre of mass was displaced mesially. The two instruments behaved in an identical mode, both before (p = 0.3497) and after (p = 0.9304) the brushing action. Ni-Ti flaring instruments can be used to flare the canal entrance with little displacement of the initial canal axis, even when a brushing action is used. PMID- 21682216 TI - Expectations and perceptions of Nigerian patients regarding infectious diseases in dentistry. AB - OBJECTIVE: To assess the expectations and perceptions of Nigerian patients regarding infectious diseases in dentistry. METHODS: A questionnaire based cross sectional survey of patients attending the dental centre of University of Benin Teaching Hospital, Nigeria was conducted in 2009. RESULTS: Out of the 405 patients that responded, 75.6% expressed worry about contracting infection during the dental treatment. Respondents felt that they are at risk of contracting the following infection from the dental clinic, HIV (47.4%), hepatitis B and C (15.5%), herpes (3.5%) and tuberculosis (1.7%). One-quarter (25.4%) of the respondents would avoid dental treatment because of fear of contracting HIV. Ninety-two (22.7%) would switch from dental clinic with HIV infected personnel and 37.8% would allow HIV-infected dentist to treat them. Only 10.4% of the respondents would expect the dentist to refuse to render dental treatment to the HIV-infected patients. CONCLUSION: This survey revealed that a high proportion of Nigerian patients are worried about contracting infectious disease during dental treatment and this impacted negatively on how they seek dental care. Improved public education and communication on the risk involved with dental treatments is needed to allay the fear of Nigerian patients. PMID- 21682217 TI - Can consortia bear the burden? PMID- 21682218 TI - Surgical workforce. We can build a better future. PMID- 21682219 TI - Service redesign: Part 2 of 2. Grand designs for freeing up money. PMID- 21682220 TI - Patient involvement. Sound out the younger user. PMID- 21682221 TI - Measuring excellence. Future of NICE. PMID- 21682222 TI - Disinventment. A question of cutting to the chase. PMID- 21682223 TI - Healthcare rationing. Decision time. PMID- 21682224 TI - Public involvement. Plugging into Joe public. PMID- 21682225 TI - The public health manifesto. PMID- 21682226 TI - Service redesign. Fitter, faster: improved pathways speed up recovery. PMID- 21682227 TI - Outreach services. Driving a change in services. PMID- 21682228 TI - Length of stay. No time to rest on reducing bed days. PMID- 21682229 TI - Information technology. Meaningful use funding: When should you apply? PMID- 21682230 TI - Patient safety. New Sentinel System aims to improve patient safety in real time. PMID- 21682231 TI - Payment. Value-based benefit programs grow, driving patient decisions. PMID- 21682232 TI - Other voice. An action plan to improve equity, quality. PMID- 21682233 TI - The extramile. Trying to give peace of mind to patients in a war zone. PMID- 21682234 TI - The attestation dilemma. AB - The meaningful use attestation period opened in April. Will hospitals be ready to apply? PMID- 21682235 TI - Health coaching. AB - Improving quality and outcomes requires hospitals to engage patients so they understand their conditions and medications and can self-manage their care. Hospitals engage patients by educating them before and during discharge, actively following up after they go home, by using new technology, and a variety of other ways. PMID- 21682236 TI - Rescuing the ED. AB - Emergency departments already are bursting at the seams, and things could get more intense when 32 million Americans gain coverage under the Affordable Care Act. Experts offer several ways to ease the problem, starting with triage and throughput. PMID- 21682237 TI - Rural hospitals look near and far for allied health professionals. AB - Filling certain types of jobs can be an enormous challenge for rural hospitals. Rural leaders and others offer practical ideas on how to recruit staff, sometimes from abroad and sometimes right in their own backyards. PMID- 21682238 TI - Value-based purchasing and bundled payments. AB - Bundled Medicare payments and value-based purchasing are intended to create integrated delivery systems that are more accountable to their communities and to make providers assume greater financial risk. Here's what hospitals should know. PMID- 21682239 TI - Automate your supply chain and reap the benefits. AB - Web-based materials management saves hospitals money by making the process more efficient. It also aids in contract negotiations with vendors and even helps boost quality of care by freeing up clinical staff time. PMID- 21682240 TI - Transforming health care. PMID- 21682241 TI - The evolution of measurement. PMID- 21682242 TI - Enhancing care, one community at a time. PMID- 21682243 TI - Integration through IT. PMID- 21682244 TI - Changing the way we deliver and pay for care. PMID- 21682245 TI - Demonstrating accountability, internally and externally. PMID- 21682246 TI - Creating a vision for the future. PMID- 21682247 TI - Using patient data to provide equitable care. PMID- 21682248 TI - Who's counting? PMID- 21682249 TI - Metal-free inorganic ligands for colloidal nanocrystals: S2-, HS-, Se2-, HSe-, Te2-, HTe-, TeS3(2-), OH-, and NH2- as surface ligands. AB - All-inorganic colloidal nanocrystals were synthesized by replacing organic capping ligands on chemically synthesized nanocrystals with metal-free inorganic ions such as S(2-), HS(-), Se(2-), HSe(-), Te(2-), HTe(-), TeS(3)(2-), OH(-) and NH(2)(-). These simple ligands adhered to the NC surface and provided colloidal stability in polar solvents. The versatility of such ligand exchange has been demonstrated for various semiconductor and metal nanocrystals of different size and shape. We showed that the key aspects of Pearson's hard and soft acids and bases (HSAB) principle, originally developed for metal coordination compounds, can be applied to the bonding of molecular species to the nanocrystal surface. The use of small inorganic ligands instead of traditional ligands with long hydrocarbon tails facilitated the charge transport between individual nanocrystals and opened up interesting opportunities for device integration of colloidal nanostructures. PMID- 21682250 TI - Perfluorochemical (PFC) exposure in children: associations with impaired response inhibition. AB - BACKGROUND: Perfluorinated chemicals (PFCs) have been used widely in consumer products since the 1950s and are currently found at detectable levels in the blood of humans and animals across the globe. In stark contrast to this widespread exposure to PFCs, there is relatively little research on potential adverse health effects of exposure to these chemicals. OBJECTIVES: We performed this cross-sectional study to determine if specific blood PFC levels are associated with impaired response inhibition in children. METHODS: Blood levels of 11 PFCs were measured in children (N = 83) and 6 PFCs: perfluorooctane sulfonate (PFOS), perfluorohexane sulfate (PFHxS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorooctanesulfonamide (PFOSA), and perfluorodecanoic acid (PFDA) - were found at detectable levels in most children (87.5% or greater had detectable levels). These levels were analyzed in relation to the differential reinforcement of low rates of responding (DRL) task. This task rewards delays between responses (i.e., longer inter-response times; IRTs) and therefore constitutes a measure of response inhibition. RESULTS: Higher levels of blood PFOS, PFNA, PFDA, PFHxS, and PFOSA were associated with significantly shorter IRTs during the DRL task. The magnitude of these associations was such that IRTs during the task decreased by 29-34% for every 1 SD increase in the corresponding blood PFC. CONCLUSIONS: This study suggests an association between PFC exposure and children's impulsivity. Although intriguing, there is a need for further investigation and replication with a larger sample of children. PMID- 21682251 TI - Bacterial attachment to RO membranes surface-modified by concentration polarization-enhanced graft polymerization. AB - Concentration polarization-enhanced radical graft polymerization, a facile surface modification technique, was examined as an approach to reduce bacterial deposition onto RO membranes and thus contribute to mitigation of biofouling. For this purpose an RO membrane ESPA-1 was surface-grafted with a zwitterionic and negatively and positively charged monomers. The low monomer concentrations and low degrees of grafting employed in modifications moderately reduced flux (by 20 40%) and did not affect salt rejection, yet produced substantial changes in surface chemistry, charge and hydrophilicity. The propensity to bacterial attachment of original and modified membranes was assessed using bacterial deposition tests carried out in a parallel plate flow setup using a fluorescent strain of Pseudomonas fluorescens. Compared to unmodified ESPA-1 the deposition (mass transfer) coefficient was significantly increased for modification with the positively charged monomer. On the other hand, a substantial reduction in bacterial deposition rates was observed for membranes modified with zwitterionic monomer and, still more, with very hydrophilic negatively charged monomers. This trend is well explained by the effects of surface charge (as measured by zeta potential) and hydrophilicity (contact angle). It also well correlated with force distance measurements by AFM using surrogate spherical probes with a negative surface charge mimicking the bacterial surface. The positively charged surface showed a strong hysteresis with a large adhesion force, which was weaker for unmodified ESPA-1 and still weaker for zwitterionic surface, while negatively charged surface showed a long-range repulsion and negligible hysteresis. These results demonstrate the potential of using the proposed surface- modification approach for varying surface characteristics, charge and hydrophilicity, and thus minimizing bacterial deposition and potentially reducing propensity biofouling. PMID- 21682252 TI - Nanostructured growth patterns and chaotic oscillations in potential during electropolymerization of aniline in the presence of surfactants. AB - Polyaniline nanoparticles were synthesized by simple electrochemical polymerization of aniline in systems (a) aniline-sodium dodecyl sulfate (NaDS) dodecylbenzene sulfonic acid (DBSA)-H(2)O and (b) aniline-NaDS-DBSA cetyltrimethyl ammonium bromide (CTAB)-H(2)O. Different morphologies including compact and fractal/dendrimer were observed at different experimental conditions. Fractal dimension was calculated by the box counting method. Growth kinetics during electropolymerization of aniline in both of the systems was studied by measuring the weight of polymer aggregates as a function of time. Growth rate was found to be reduced in system (b) due to coordination of CTAB with the growing polyaniline chain. The weight of polymer aggregates was found to depend on field intensity and attains a maximum value at a critical field intensity 4.0 V/cm. Beyond this critical field intensity, the growth rate was decreased due to loss of conjugation and degradation of the polymer backbone. Electropolymerized aggregates were characterized by transmission electron microscopy (TEM), powder X ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and electrical conductivity measurements. Nanosized polyaniline was formed, with particle diameters in the range of 10-200 nm, as evident by TEM studies and supported by XRD studies. FT-IR spectroscopy established the formation of hyperbranched polyaniline chains. During electropolymerization, oscillations in potential were monitored as a function of time at different experimental conditions. A suitable mechanism for fractal growth of polyaniline was also proposed. PMID- 21682253 TI - Immobilization of MP-11 into a mesoporous metal-organic framework, MP-11@mesoMOF: a new platform for enzymatic catalysis. AB - Microperoxidase-11 has for the first time been successfully immobilized into a mesoporous metal-organic framework (MOF) consisting of nanoscopic cages and it demonstrates superior enzymatic catalysis performances compared to its mesoporous silica counterpart. PMID- 21682254 TI - The missing C-17 O-methyltransferase in geldanamycin biosynthesis. AB - The biosynthetic gene clusters for the Hsp90 inhibitor geldanamycin (GDM, 1) have been cloned previously from three different Streptomyces strains, but the gene encoding the C-17 O-methyltransferase remains unknown. The cloning and sequencing of a new GDM biosynthetic gene cluster from Streptomyces autolyticus CGMCC 0516 was reported, identifying the gdmMT gene that encodes the missing C-17 O methyltransferase for 1 biosynthesis. PMID- 21682255 TI - Heterocyclic radical mediated synthesis and fluorescence properties of conjugated polyene ketones. AB - A straightforward route for the preparation of decatetraene diketone derivates is presented. The synthesis has been accomplished by a one-step procedure starting from phenyl-substituted pyrylium perchlorates, and an elaborate heterocyclic alpha-radical mechanism was proposed. This class of molecules displays a crystallization induced emission enhancement property. PMID- 21682256 TI - Polyphenolics from acai ( Euterpe oleracea Mart.) and red muscadine grape (Vitis rotundifolia ) protect human umbilical vascular Endothelial cells (HUVEC) from glucose- and lipopolysaccharide (LPS)-induced inflammation and target microRNA 126. AB - Endothelial anti-inflammatory effects of acai (Ac) and red muscadine grape (Gp) polyphenolics have not been extensively investigated. It was hypothesized that polyphenolics from Ac and Gp exert comparable protective effects in human vascular endothelial cells (HUVEC) upon inflammatory stress. Furthermore, this study investigated whether microRNAs relevant to endothelial function might be regulated by Ac and Gp. Results showed that Ac and Gp (5-20 mg gallic acid equivalent/L) protected HUVEC against glucose-induced oxidative stress and inflammation. Glucose-induced expression of interleukin-6 and -8 was down regulated by Ac and Gp at mRNA and protein levels. Upon lipopolysaccharide (LPS; 1 MUg/L)-induced inflammation, Ac and Gp inhibited gene expression of adhesion molecules and NF-kappaB activation to similar extents, although Gp was more effective in decreasing PECAM-1 and ICAM-1 protein. Of the screened microRNAs, only microRNA-126 expression was found to be modulated by Ac and Gp as the underlying mechanism to inhibit gene and protein expression of VCAM-1. PMID- 21682257 TI - Biphenyl-substituted oxazolidinones as cholesteryl ester transfer protein inhibitors: modifications of the oxazolidinone ring leading to the discovery of anacetrapib. AB - The development of the structure-activity studies leading to the discovery of anacetrapib is described. These studies focused on varying the substitution of the oxazolidinone ring of the 5-aryloxazolidinone system. Specifically, it was found that substitution of the 4-position with a methyl group with the cis stereochemistry relative to the 5-aryl group afforded compounds with increased cholesteryl ester transfer protein (CETP) inhibition potency and a robust in vivo effect on increasing HDL-C levels in transgenic mice expressing cynomolgus monkey CETP. PMID- 21682258 TI - Distinct conformations of DNA-stabilized fluorescent silver nanoclusters revealed by electrophoretic mobility and diffusivity measurements. AB - Silver-DNA nanoclusters (Ag:DNAs) are novel fluorophores under active research and development as alternative biomolecular markers. Comprised of a few-atom Ag cluster that is stabilized in water by binding to a strand of DNA, they are also interesting for fundamental explorations into the properties of metal molecules. Here, we use in situ calibrated electrokinetic microfluidics and fluorescence correlation spectroscopy to determine the size, charge, and conformation of a select set of Ag:DNAs. Among them is a pair of spectrally distinct Ag:DNAs stabilized by the same DNA sequence, for which it is known that the silver cluster differs by two atoms. We find these two Ag:DNAs differ in size by ~30%, even though their molecular weights differ by less than 3%. Thus a single DNA sequence can adopt very different conformations when binding slightly different Ag clusters. By comparing spectrally identical Ag:DNAs that differ in sequence, we show that the more compact conformation is insensitive to the native DNA secondary structure. These results demonstrate electrokinetic microfluidics as a practical tool for characterizing Ag:DNA. PMID- 21682260 TI - Breaking symmetry toward nonspherical Janus particles based on polyhedral oligomeric silsesquioxanes: molecular design, "click" synthesis, and hierarchical structure. AB - The design, synthesis, and self-assembly of a series of precisely defined, nonspherical, polyhedral oligomeric silsesquioxane (POSS)-based molecular Janus particles are reported. The synthesis aims to fulfill the "click" philosophy by using thiol-ene chemistry to efficiently install versatile functionalities on one of the POSS cages. In such a way, both the geometrical and chemical symmetries were broken to create the Janus feature. These particles self-organize into hierarchically ordered supramolecular structures in the bulk. For example, the Janus particle with isobutyl groups on one POSS and carboxylic groups on the other self-assembles into a bilayered structure with head-to-head, tail-to-tail arrangements of each particle, which further organize into a three-dimensional orthorhombic lattice. While the ordered structure in the layers was lost upon heating via a first-order transition, the bilayered structure persisted throughout. This study provides a model system of well-defined molecular Janus particles for the general understanding of their self-assembly and hierarchical structure formation in the condensed state. PMID- 21682261 TI - Controlled density patterning of tolylterpyridine-tagged oligonucleotides. AB - An efficient surface anchoring strategy of tolylterpyridine-tagged DNA single strands (ssDNA-ttpy) synthesized on gold electrodes is reported. The method is based on exchange reactions between Fe(II)bis-terpyridine complexed SAMs and ssDNA-ttpy, and allows efficient hybrydization of the cDNA strands. Moreover, by using low-current focused ion beam lithography, micropatterned arrays are obtained, homogeneously covered with ssDNA-ttpy. The surface adsorption kinetics of ssDNA-ttpy, as well as its hybridization efficiency, was monitored by in situ quartz crystal microbalance with dissipation monitoring (QCM-D) technique. The effective confinement of the ssDNA-ttpy at the micrometer level has been monitored by time of flight secondary ion mass spectrometry (ToF-SIMS) and ellipsometric surface imaging experiments, providing laterally resolved chemical and topographic mapping. PMID- 21682262 TI - Bioactive neo-clerodane diterpenoids from the whole plants of Ajuga ciliata Bunge. AB - Ten new neo-clerodane diterpenes, ajugaciliatins A-J (1-5, 8-12), along with 17 known analogues (6, 7, 13-27) were isolated from the whole plants of Ajuga ciliata Bunge. Their structures were elucidated by spectroscopic data analysis (IR, ESIMS, HRESIMS, 1D and 2D NMR), and the configuration of 1 was confirmed by X-ray crystallography. All of the compounds were assessed for neuroprotective effects against MPP(+)-induced neuronal cell death in dopaminergic neuroblastoma SH-SY5Y cells. Compounds 2, 6, 7, 9, 10, 15-17, 19, and 20 exhibited moderate neuroprotective effects. PMID- 21682263 TI - Crystallographic X-ray analyses of Yb@C(2v)(3)-C80 reveal a feasible rule that governs the location of a rare earth metal inside a medium-sized fullerene. AB - Single crystal X-ray diffraction studies of Yb@C(2v)(3) C(80).Ni(II)(OEP).CS(2).1.5C(6)H(6) (OEP = octaethylporphinate) reveal that a relatively flat region of the fullerene interacts with the Ni(II)(OEP) molecule, featuring shape-matching interactions. Surprisingly, it is found that the internal metal is located under a hexagonal carbon ring apart from the 2-fold axis of the C(2v)(3)-C(80) cage, presenting the first example of metallofullerenes with an asymmetrically positioned metal. Such an anomalous location of Yb(2+) is associated with its strong ability to pursue a large coordination number and the lack of hexagon along the C(2) axis of C(2v)(3) C(80). It is accordingly assumed that a suitable cage hexagon is most likely to be preferred by the single rare earth metal to stay behind inside a medium-sized fullerene, such as C(80) and C(82). PMID- 21682264 TI - Sesquiterpene glycosides from Cosmospora joca. AB - Five novel sesquiterpene glycosides, namely, cosmosporasides A-E (1-5), were isolated from the ethyl acetate extract of the fermented broth of Cosmospora joca. The structures of 1-5 were elucidated on the basis of spectroscopic data analyses, monosaccharide composition analyses, and monosaccharide chirality analyses. The relative configuration of the sesquiterpene moiety of 3-5 was determined by J-based configuration analyses and supported by NOESY assignments. The inhibitory effects of 1-5 on the nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW264.7 cells were evaluated; all except 3 inhibited NO production at 100 MUM. 4 was the most potent, with an average maximum inhibition and a median inhibitory concentration value of 71.70 +/- 1.23% and 65.98 +/- 0.53 MUM, respectively. PMID- 21682265 TI - Can we predict the spreading of a two-liquid system from the spreading of the corresponding liquid-air systems? AB - We present new data obtained from the spreading of a series of oil droplets, on top of a hydrophobic grafted silicon substrate, in air and immersed in water. We follow the contact angle and radius dynamics of hexane, dodecane, hexadecane, dibutyl phthalate, and squalane from the first milliseconds to approximately 1 s. Analysis of the images allows us to make several hundred contact angle and droplet radius measurements with great accuracy. The G-Dyna (Seveno et al. Langmuir 2010, 25, 13034) software is then used to fit the data with one of the wetting theories, the molecular-kinetic theory (MKT) (Blake et al. J. Colloid Interface Sci.1969, 30, 421), which takes into account the dissipation at the three-phase zone at the contact line. This theory allows us to extract the coefficient of friction of the contact line, which expresses the relationship between the driving force, that is, the unbalanced Young force, and the contact line velocity V. It is first shown that the MKT is appropriate to describe the experimental data and then that the contact-line friction is a linear function of the viscosity as theoretically predicted. This is checked for oil-air and oil water systems. A linear relation between the contact-line friction measured in oil-water systems and the contact-line frictions of the parent single liquid system seems plausible. To the best of our knowledge, this is the first trial to establish a link between the dynamics of wetting in liquid-liquid and in liquid air systems. PMID- 21682266 TI - Hydroxycarboxylic acid-derived organosulfates: synthesis, stability, and quantification in ambient aerosol. AB - Organosulfates have been proposed as contributors to aerosol growth and have been detected in both chamber and atmospheric aerosol samples. We present a simple method for the synthesis of quantitative analytical standards of two small hydroxycarboxylic acid-derived organosulfates, glycolic and lactic acid sulfate. Additionally, we discuss the stability of hydroxycarboxylic acid-derived organosulfates and their previously proposed sulfate hemiacetal isomers in commonly used solvents for filter extraction. The hydroxycarboxylic acid-derived organosulfates were found to be stable under acidic conditions comparable to those found in ambient aerosol. By using synthesized standards, quantitative organosulfate concentrations were measured from ambient particulate matter (PM(2.5)) collected in urban locations in the United States, Mexico City, and Pakistan. Lactic acid sulfate and glycolic acid sulfate concentrations ranged 0.4 3.8 ng/m(3) and 1.9-11.3 ng/m(3), respectively. We propose that glycolic acid sulfate represents an important tracer for atmospheric processes that form organosulfates in ambient particulate matter. PMID- 21682267 TI - Evidence of micro- and nanoscaled particles during starch nanocrystals preparation and their isolation. AB - Great work has been done to reduce the batch production time of starch nanocrystals (SNCs) and improve their compatibilization with different matrices. However, only one study was reported on SNC production kinetics and none on size distributions and isolation techniques. This study was designed to assess if nonsolubilized particles in the hydrolyzed starch suspension reflect the actual amount of SNC. It was observed that SNCs are produced from a very early stage. It suggests, for the first time, that (i) nanocrystals are mixed together with other microparticles and (ii) some nanocrystals might turn to sugar by the end of the batch production process explaining the low yields. An isolation process has been proposed, but limits of differential centrifugations as washing step and isolation technique were also evidenced. This study clearly shows the need for a continuous production and extraction process of SNC. PMID- 21682268 TI - Active site gating and substrate specificity of butyrylcholinesterase and acetylcholinesterase: insights from molecular dynamics simulations. AB - Butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) are highly homologous proteins with distinct substrate preferences. In this study we compared the active sites of monomers and tetramers of human BChE and human AChE after performing molecular dynamics (MD) simulations in water-solvated systems. By comparing the conformational dynamics of gating residues of AChE and BChE, we found that the gating mechanisms of the main door of AChE and BChE are responsible for their different substrate specificities. Our simulation of the tetramers of AChE and BChE indicates that both enzymes could have two dysfunctional active sites due to their restricted accessibility to substrates. The further study on catalytic mechanisms of multiple forms of AChE and BChE would benefit from our comparison of the active sites of the monomers and tetramers of both enzymes. PMID- 21682269 TI - Diketopyrrolopyrrole-containing oligothiophene-fullerene triads and their use in organic solar cells. AB - We report the characterization of a series of oligothiophene-diketopyrrolopyrrole fullerene triads and their use as active materials for solution processed organic solar cells (OSCs). By incorporating the diketopyrrolopyrrole (DPP) core with electron rich oligothiophene units and electron withdrawing fullerene units, multifunctional electronic molecules have been prepared; these molecules show high solubility in common organic solvents, excellent photophysical properties with high extinction coefficients (1 * 10(4) to 1 * 10(5) M(-1) cm(-1)) and broad absorption spectra coverage (250-800 nm), as well as suitable molecular orbital energy levels (HOMO of approximately -5.1 eV, LUMO of approximately -3.7 eV). Solution-processed thin-film organic field effect transistors (OFETs) from these triads revealed good n-type characteristics with electron mobilities up to 1.5 * 10(-3) cm(2) V(-1) s(-1). With these multifunctional triads, single-component OSCs have been fabricated, exhibiting power conversion efficiencies (PCEs) of up to 0.5 % under AM 1.5 G simulated 1 sun solar illumination. Blending these molecules with poly(3-hexylthiophene) (P3HT) afforded bulk heterojunction OSCs with PCEs reaching as high as 2.41%. PMID- 21682270 TI - A nonemissive iridium(III) complex that specifically lights-up the nuclei of living cells. AB - A nonemissive cyclometalated iridium(III) solvent complex, without conjugation with a cell-penetrating molecular transporter, [Ir(ppy)(2)(DMSO)(2)](+)PF(6)(-) (LIr1), has been developed as a first reaction-based fluorescence-turn-on agent for the nuclei of living cells. LIr1 can rapidly and selectively light-up the nuclei of living cells over fixed cells, giving rise to a significant luminescence enhancement (200-fold), and shows very low cytotoxicity at the imaging concentration (incubation time <10 min, LIr1 concentration 10 MUM). More importantly, in contrast to the reported nuclear stains that are based on luminescence enhancement through interaction with nucleic acids, complex LIr1 as a nuclear stain has a reaction-based mode of action, which relies on its rapid reaction with histidine/histidine-containing proteins. Cellular uptake of LIr1 has been investigated in detail under different conditions, such as at various temperatures, with hypertonic treatment, and in the presence of metabolic and endocytic inhibitors. The results have indicated that LIr1 permeates the outer and nuclear membranes of living cells through an energy-dependent entry pathway within a few minutes. As determined by an inductively coupled plasma atomic emission spectroscopy (ICP-AEC), LIr1 is accumulated in the nuclei of living cells and converted into an intensely emissive adduct. Such novel reaction-based nuclear staining for visualizing exclusively the nuclei of living cells with a significant luminescence enhancement may extend the arsenal of currently available fluorescent stains for specific staining of cellular compartments. PMID- 21682271 TI - Facile fabrication of functionalized graphene sheets (FGS)/ZnO nanocomposites with photocatalytic property. AB - Functionalized graphene sheets (FGS)/ZnO nanocomposites were fabricated via thermal treatment method, using graphene oxide as a precursor of graphene, Zn(NH(3))(4)CO(3) as a precursor of zinc oxide, and poly(vinyl pyrrolidone) as an intermediate to combine zinc with carbon materials. Thermogravimetric analysis, X ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), and scanning electron microscopy (SEM) were used to characterize crystal structure and morphology of FGS/ZnO nanocomposites. It was shown that the well-dispersed ZnO nanoparticles were deposited on FGS homogeneously. The composites exhibited photocatalytic activity to decompose rhodamine 6G efficiently under low-power ultraviolet (UV) light. This facile and low-cost method makes the composite a perfect candidate in applications of catalysis and other areas. PMID- 21682272 TI - Nondestructive Raman analysis of polyacetylenes in apiaceae vegetables. AB - Food plants from the Apiaceae family have been found to demonstrate health promoting properties. Polyacetylenes are bioactive compounds that are considered to contribute substantially to the beneficial properties of Apiaceae plants. This study applied a Raman mapping technique in the investigation of polyacetylene spatial distribution in fresh roots of some Apiaceae species. Fresh root sections were measured directly without any preliminary preparation. For three Apiaceae species, that is, parsnip ( Pastinaca sativa L.), celeriac ( Apium graveolens var. rapaceum L.), and parsley ( Petroselinum crispum ), the presence of polyacetylenes was confirmed due to the detection of strong and well-separated Raman signals of symmetric -C = C-C = C- stretching vibration in the range of 2200-2300 cm(-1). The spectra were used for generation of two-dimensional maps applying the integration and cluster analysis methods. The Raman maps visualized the distribution of total polyacetylenes as well as individual compounds. Heterogeneous and tissue-specific occurrence of polyacetylenes in roots is shown. PMID- 21682273 TI - Diverse fragment clustering and water exclusion identify protein hot spots. AB - Simulated annealing of chemical potential located the highest affinity positions of eight organic probes and water on eight static structures of hen egg white lysozyme (HEWL) in various conformational states. In all HELW conformations, a diverse set of organic probes clustered in the known binding site (hot spot). Fragment clusters at other locations were excluded by tightly-bound waters so that only the hot-spot cluster remained in each case. The location of the hot spot was correctly predicted irrespective of the protein conformation and without accounting for protein flexibility during the simulations. Any one of the static structures could have been used to locate the hot spot. A site on a protein where a diversity of organic probes is calculated to cluster, but where water specifically does not bind, identifies a potential small-molecule binding site or protein-protein interaction hot spot. PMID- 21682274 TI - Computational chemical analysis of [FeFe] hydrogenase H-cluster analogues to discern catalytically relevant features of the natural diatomic ligand configuration. AB - Density functional theoretical models of the electronic structure of several configurational isomers and analogues of the [2Fe](H) H-cluster in [FeFe] hydrogenase were analyzed to identify distinguishing features of the canonical cofactor structure potentially relevant to catalysis. Collective analysis of geometric changes over models of oxidized and reduced [2Fe] clusters highlighted movement of the bridging carbonyl and anticorrelation of the proximal and distal Fe-C(terminal) bonds as key explanatory factors for variance over the considered models. Charge and bond order analysis suggest that as the bridging carbonyl favors the distal iron upon reduction, bonding simultaneously becomes more ionic in nature, raising the possibility of simple electrostatic stabilization as a factor in charge accumulation prior to ultimate H(2) creation and release. Frontier orbital energies show cis and trans arrangements of cyanide on the Fe-Fe core to have distinctive energies from the other models, which may be important for redox poise. Altogether, few factors qualitatively distinguish the cis- from the trans-cyano configurations, which may in fact enhance catalytic robustness under conditions leading to exchange of the bridging and terminal carbonyl ligands. However, the naturally occurring trans configuration possesses two distinct donor-metal-acceptor S-Fe-C(O) interactions, which might play a role in enforcing a low-spin ground state for the hydridic mechanism of H(2) production. PMID- 21682276 TI - Mechanism of amyloid beta-protein aggregation mediated by GM1 ganglioside clusters. AB - It is widely accepted that the conversion of the soluble, nontoxic amyloid beta protein (Abeta) monomer to aggregated toxic Abeta rich in beta-sheet structures is central to the development of Alzheimer's disease. However, the mechanism of the abnormal aggregation of Abeta in vivo is not well understood. We have proposed that ganglioside clusters in lipid rafts mediate the formation of amyloid fibrils by Abeta, the toxicity and physicochemical properties of which are different from those of amyloids formed in solution. In this paper, the mechanism by which Abeta-(1-40) fibrillizes in raftlike lipid bilayers composed of monosialoganglioside GM1, cholesterol, and sphingomyelin was investigated in detail on the basis of singular-value decomposition of circular dichroism data and analysis of fibrillization kinetics. At lower protein densities in the membrane (Abeta:GM1 ratio of less than ~0.013), only the helical species exists. At intermediate protein densities (Abeta:GM1 ratio between ~0.013 and ~0.044), the helical species and aggregated beta-sheets (~15-mer) coexist. However, the beta-structure is stable and does not form larger aggregates. At Abeta:GM1 ratios above ~0.044, the beta-structure is converted to a second, seed-prone beta structure. The seed recruits monomers from the aqueous phase to form amyloid fibrils. These results will shed light on a molecular mechanism for the pathogenesis of the disease. PMID- 21682275 TI - Utilizing DART mass spectrometry to pinpoint halogenated metabolites from a marine invertebrate-derived fungus. AB - Prenylated indole alkaloids are a diverse group of fungal secondary metabolites and represent an important biosynthetic class. In this study we have identified new halogenated prenyl-indole alkaloids from an invertebrate-derived Malbranchea graminicola strain. Using direct analysis in real time (DART) mass spectrometry, these compounds were initially detected from hyphae of the fungus grown on agar plates, without the need for any organic extraction. Subsequently, the metabolites were isolated from liquid culture in artificial seawater. The structures of two novel chlorinated metabolites, named (-)-spiromalbramide and (+)-isomalbrancheamide B, provide additional insights into the assembly of the malbrancheamide compound family. Remarkably, two new brominated analogues, (+) malbrancheamide C and (+)-isomalbrancheamide C, were produced by enriching the growth medium with bromine salts. PMID- 21682277 TI - Ultrafast exciton energy transfer between nanoscale coaxial cylinders: intertube transfer and luminescence quenching in double-walled carbon nanotubes. AB - We study exciton energy transfer in double-walled carbon nanotubes using femtosecond time-resolved luminescence measurements. From direct correspondence between decay of the innertube luminescence and the rise behavior in outertube luminescence, it is found that the time constant of exciton energy transfer from the inner to the outer semiconducting tubes is ~150 fs. This ultrafast transfer indicates that the relative intensity of steady-state luminescence from the innertubes is ~700 times weaker than that from single-walled carbon nanotubes. PMID- 21682278 TI - Structural determinants of limited proteolysis. AB - Limited or regulatory proteolysis plays a critical role in many important biological pathways like blood coagulation, cell proliferation, and apoptosis. A better understanding of mechanisms that control this process is required for discovering new proteolytic events and for developing inhibitors with potential therapeutic value. Two features that determine the susceptibility of peptide bonds to proteolysis are the sequence in the vicinity of the scissile bond and the structural context in which the bond is displayed. In this study, we assessed statistical significance and predictive power of individual structural descriptors and combination thereof for the identification of cleavage sites. The analysis was performed on a data set of >200 proteolytic events documented in CutDB for a variety of mammalian regulatory proteases and their physiological substrates with known 3D structures. The results confirmed the significance and provided a ranking within three main categories of structural features: exposure > flexibility > local interactions. Among secondary structure elements, the largest frequency of proteolytic cleavage was confirmed for loops and lower but significant frequency for helices. Limited proteolysis has lower albeit appreciable frequency of occurrence in certain types of beta-strands, which is in contrast with some previous reports. Descriptors deduced directly from the amino acid sequence displayed only marginal predictive capabilities. Homology-based structural models showed a predictive performance comparable to protein substrates with experimentally established structures. Overall, this study provided a foundation for accurate automated prediction of segments of protein structure susceptible to proteolytic processing and, potentially, other post translational modifications. PMID- 21682280 TI - A fluorescent, shape-persistent dendritic host with photoswitchable guest encapsulation and intramolecular energy transfer. AB - A fluorescent and photoresponsive host based on rigid polyphenylene dendrimers (PPDs) has been synthesized. The key building block for the divergent dendrimer buildup is a complex tetracyclone 12 containing azobenzenyl, pyridyl, and ethynyl entities. The rigidity of polyphenylenes is of crucial importance for a site specific placement of different functions: eight azobenzene (AB) moieties into the rigid scaffold, a fluorescent perylenetetracarboxdiimide (PDI) into the core, and eight pyridin functions into the interior cavities. AB moieties of host-1 undergo reversible cis-trans photoisomerization and are photostable, as confirmed by various techniques: UV-vis, (1)H NMR, size exclusion chromatography, and fluorescence correlation (FCS). In this system, AB moieties act as photoswitchable hinges and enable control over (i) molecular size, (ii) intramolecular energy transfer between AB and PDI, and (iii) encapsulation and release of guest molecules. The presence of PDI allows not only following the effect of cis-trans photoisomerization on molecular size with highly sensitive FCS but also monitoring the efficiency of the intramolecular energy transfer process (from AB to PDI) by time-resolved optical spectroscopy. Pyridyl functions were incorporated to facilitate guest uptake via hydrogen bonds between the host and guests. Also, we have demonstrated that the photoswitchability of the host can be utilized to actively encapsulate guest molecules into its interior cavities. This novel, light-driven encapsulation mechanism could enable the design of new drug delivery systems. PMID- 21682279 TI - Dramatic destabilization of transmembrane helix interactions by features of natural membrane environments. AB - Membrane proteins have evolved to fold and function in a lipid bilayer, so it is generally assumed that their stability should be optimized in a natural membrane environment. Yet optimal stability is not always in accord with optimization of function, so evolutionary pressure, occurring in a complex membrane environment, may favor marginal stability. Here, we find that the transmembrane helix dimer, glycophorin A (GpATM), is actually much less stable in the heterogeneous environment of a natural membrane than it is in model membranes and even common detergents. The primary destabilizing factors are electrostatic interactions between charged lipids and charged GpATM side chains, and nonspecific competition from other membrane proteins. These effects overwhelm stabilizing contributions from lateral packing pressure and excluded volume. Our work illustrates how evolution can employ membrane composition to modulate protein stability. PMID- 21682281 TI - TiCl4-promoted cyclization reactions of aminoacetals and ethenetricarboxylates leading to nitrogen-containing heterocycles. AB - Lewis acid-catalyzed cyclization of aminoacetals 2 and triethyl ethenetricarboxylate (1a) has been examined. The reaction of 3 aminopropionaldehyde diethyl acetal (2a) and 1a in the presence of 1 equiv of TiCl(4) at room temperature gave 4-ethoxypiperidine-2,3,3-tricarboxylate 3a in 92% yield with a 2,4-diastereomer ratio of 1:1. The reaction in the presence of 3 equiv of TiCl(4) gave 2,4-trans-piperidine derivative 3a in 86% yield predominantly. The reaction of aminoacetaldehyde diethyl/dimethyl acetals 2c,d and 1a with 3 equiv of TiCl(4) gave 2,4-trans-4-pyrrolidine-2,3,3-tricarboxylates 5a,b predominantly. PMID- 21682282 TI - Identifying sources of Pb exposure in waterbirds and effects on porphyrin metabolism using noninvasive fecal sampling. AB - Waterbird feces (mainly mallard Anas platyrhynchos and coot Fulica atra) were collected from four wetlands in Southern Spain in the field or during capture (n = 558 and n = 59, respectively) to study lead (Pb) shot ingestion. Lead and aluminum (Al) concentrations along with Pb isotope signatures were used to identify sources of Pb exposure. The profile and concentrations of porphyrins and biliverdin in feces were used as biomarkers of toxicological effects. Feces with Pb concentrations >= 34 MUg/g d.w. showed higher Pb/Al ratios, together with lower (206)Pb/(207)Pb and (208)Pb/(207)Pb ratios, and higher (208)Pb/(206)Pb ratios, than feces with <34 MUg/g d.w. Isotope signatures and Pb/Al ratios together indicated that Pb shot ingestion was the likely cause of the high Pb levels in some samples, whereas sediment ingestion was linked to lower/background levels. Coproporphyrin I and protoporphyrin IX were also higher in feces with Pb >= 34 MUg/g d.w., indicating measurable disruption in heme synthesis. Noninvasive fecal sampling permits study of the degree and source of Pb exposure and physiological effects, with low-effort and minimal disturbance to waterbirds. PMID- 21682283 TI - Modeling spatial variation in microbial degradation of pesticides in soil. AB - Currently, no general guidance is available on suitable approaches for dealing with spatial variation in the first-order pesticide degradation rate constant k even though it is a very sensitive parameter and often highly variable at the field, catchment, and regional scales. Supported by some mechanistic reasoning, we propose a simple general modeling approach to predict k from the sorption constant, which reflects bioavailability, and easily measurable surrogate variables for microbial biomass/activity (organic carbon and clay contents). The soil depth was also explicitly included as an additional predictor variable. This approach was tested in a meta-analysis of available literature data using bootstrapped partial least-squares regression. It explained 73% of the variation in k for the 19 pesticide-study combinations (n = 212) in the database. When 4 of the 19 pesticide-study combinations were excluded (n = 169), the approach explained 80% of the variation in the degradation rate constant. We conclude that the approach shows promise as an effective way to account for the effects of bioavailability and microbial activity on microbial pesticide degradation in large-scale model applications. PMID- 21682284 TI - Concentration and size separation of DNA samples at liquid-liquid interfaces. AB - This report introduces a new analytical concept utilizing the mass transfer resistance of a liquid-liquid interface to concentrate and separate DNA samples. DNA molecules can be electrophoretically accumulated at a liquid-liquid interface of an aqueous two-phase system (ATPS) of poly(ethylene glycol) (PEG) and dextran, two polymers that form two immiscible phases in aqueous electrolyte solutions. The detachment of DNA from the interface into the other phase can be triggered by increasing the applied electric field. We experimentally study the size dependence of the detachment process for a broad spectrum of DNA fragments. In a regime where the coiling of the chains does not play a significant role, the process shows a linear dependence on the diffusion coefficient, with shorter DNA chains detaching at lower electric field strengths than larger ones. The concept may enable novel separation protocols for preparative and analytical purposes. PMID- 21682285 TI - Dinitrogen silylation and cleavage with a hafnocene complex. AB - Silylation of a hafnocene complex containing a strongly activated dinitrogen ligand, [(eta(5)-C(5)H(2)-1,2,4-Me(3))(2)Hf](2)(MU(2),eta(2),eta(2)-N(2)), by addition of CySiH(3) resulted in N-Si and Hf-H bond formation and a compound poised for subsequent N(2) cleavage. Warming the silane addition product to 75 degrees C triggered N-N scission, for which the requisite electrons were provided by silyl migration. Dinitrogen cleavage coupled to N-C bond formation was also accomplished by carbonylation of the silylated product, yielding an unprecedented MU-formamidide ([NC(H)O](2-)) ligand. Subsequent treatment with HCl yielded free formamide, demonstrating that an important organic molecule can be synthesized from N(2), CO, an organosilane, and protons. PMID- 21682286 TI - Toward functional carboxylate-bridged diiron protein mimics: achieving structural stability and conformational flexibility using a macrocylic ligand framework. AB - A dinucleating macrocycle, H(2)PIM, containing phenoxylimine metal-binding units has been prepared. Reaction of H(2)PIM with [Fe(2)(Mes)(4)] (Mes = 2,4,6 trimethylphenyl) and sterically hindered carboxylic acids, Ph(3)CCO(2)H or Ar(Tol)CO(2)H (2,6-bis(p-tolyl)benzoic acid), afforded complexes [Fe(2)(PIM)(Ph(3)CCO(2))(2)] (1) and [Fe(2)(PIM)(Ar(Tol)CO(2))(2)] (2), respectively. X-ray diffraction studies revealed that these diiron(II) complexes closely mimic the active site structures of the hydroxylase components of bacterial multicomponent monooxygenases (BMMs), particularly the syn disposition of the nitrogen donor atoms and the bridging MU-eta(1)eta(2) and MU-eta(1)eta(1) modes of the carboxylate ligands at the diiron(II) centers. Cyclic voltammograms of 1 and 2 displayed quasi-reversible redox couples at +16 and +108 mV vs ferrocene/ferrocenium, respectively. Treatment of 2 with silver perchlorate afforded a silver(I)/iron(III) heterodimetallic complex, [Fe(2)(MU OH)(2)(ClO(4))(2)(PIM)(Ar(Tol)CO(2))Ag] (3), which was structurally and spectroscopically characterized. Complexes 1 and 2 both react rapidly with dioxygen. Oxygenation of 1 afforded a (MU-hydroxo)diiron(III) complex [Fe(2)(MU OH)(PIM)(Ph(3)CCO(2))(3)] (4), a hexa(MU-hydroxo)tetrairon(III) complex [Fe(4)(MU OH)(6)(PIM)(2)(Ph(3)CCO(2))(2)] (5), and an unidentified iron(III) species. Oxygenation of 2 exclusively formed di(carboxylato)diiron(III) compounds, a testimony to the role of the macrocylic ligand in preserving the dinuclear iron center under oxidizing conditions. X-ray crystallographic and (57)Fe Mossbauer spectroscopic investigations indicated that 2 reacts with dioxygen to give a mixture of (MU-oxo)diiron(III) [Fe(2)(MU-O)(PIM)(Ar(Tol)CO(2))(2)] (6) and di(MU hydroxo)diiron(III) [Fe(2)(MU-OH)(2)(PIM)(Ar(Tol)CO(2))(2)] (7) units in the same crystal lattice. Compounds 6 and 7 spontaneously convert to a tetrairon(III) complex, [Fe(4)(MU-OH)(6)(PIM)(2)(Ar(Tol)CO(2))(2)] (8), when treated with excess H(2)O. PMID- 21682287 TI - Environmental impacts of cultured meat production. AB - Cultured meat (i.e., meat produced in vitro using tissue engineering techniques) is being developed as a potentially healthier and more efficient alternative to conventional meat. Life cycle assessment (LCA) research method was used for assessing environmental impacts of large-scale cultured meat production. Cyanobacteria hydrolysate was assumed to be used as the nutrient and energy source for muscle cell growth. The results showed that production of 1000 kg cultured meat requires 26-33 GJ energy, 367-521 m(3) water, 190-230 m(2) land, and emits 1900-2240 kg CO(2)-eq GHG emissions. In comparison to conventionally produced European meat, cultured meat involves approximately 7-45% lower energy use (only poultry has lower energy use), 78-96% lower GHG emissions, 99% lower land use, and 82-96% lower water use depending on the product compared. Despite high uncertainty, it is concluded that the overall environmental impacts of cultured meat production are substantially lower than those of conventionally produced meat. PMID- 21682288 TI - Quantitative analysis of the leaky expression of adenovirus genes in cells transduced with a replication-incompetent adenovirus vector. AB - Theoretically, adenovirus (Ad) genes should not be expressed following transduction with a replication-incompetent Ad vector because the E1A gene, which is essential for the expression of other viral gene, is deleted in a replication incompetent Ad vector. However, leaky expression of viral genes is known to occur following transduction with an E1-deleted Ad vector, leading to an induction of cellular immunity against Ad proteins. To date, no detailed analysis of the leaky expression profiles of Ad genes has been performed. In this study, we systematically examined the expression profiles of Ad genes in cells following transduction with a replication-incompetent Ad vector (Ad-L2) at multiplicities of infection (MOIs) of 10 and 100 using real-time RT-PCR. Significant expression was found for the E4 and pIX genes following transduction with Ad-L2 in cultured cells. The expression levels of the E4 and pIX genes were approximately 30- to 600-fold lower than those of the transgene (firefly luciferase), and 50- to 5000 fold lower than those of the E4 and pIX genes following transduction at the same MOI with the wild-type Ad. Unexpectedly, expression levels of the major capsid proteins were approximately the same as, or even slightly above, the background levels (Ad gene expression levels in mock-transduced cells). This study provides valuable information for the design of a safe and efficient replication incompetent Ad vector. PMID- 21682290 TI - Peculiarities of homooligonucleotides wrapping around carbon nanotubes: molecular dynamics modeling. AB - Spontaneous adsorption of homooligonucleotides dC(25), dT(25), dG(25), and dA(25) on the surface of the carbon nanotube (16,0) has been simulated by the molecular dynamics method. It was demonstrated that the rate of pyrimidine oligonucleotide wrapping around the nanotube is higher than that of purine ones which do not form a complete pitch even after the maximum simulation time (50 ns). This behavior can be explained by a stronger self-stacking between the purines than pyrimidines, which prevents the reorientation of the polymer required for the acquisition of a more energetically favored conformation on the nanotube. Estimations obtained from modeling allowed to establish the oligonucleotide row which demonstrates decreasing interaction energies between oligonucleotides and the carbon nanotube: d(T)(25) > d(C)(25) > d(A)(25) ~ d(G)(25). It was shown that the temperature growth increases the rate of oligonucleotides to reach the maximum binding energy mainly due to the destruction of nitrogen base self stacking. Ribonucleic oligonucleotides r(C)(25), r(A)(25), and r(G)(25) do not make a pitch around the nanotube for 50 ns. The presence of the additional hydroxyl group in ribose restricts the conformational flexibility of ribonucleic oligonucleotides in comparison with their deoxy analogues and this reduces the possibility of rapid occupation of the stable conformation on the nanotube surface. PMID- 21682289 TI - Synthesis of mercapto-(+)-methamphetamine haptens and their use for obtaining improved epitope density on (+)-methamphetamine conjugate vaccines. AB - This study reports the synthesis of the mercapto-hapten (S)-N-(2-(mercaptoethyl) 6-(3-(2-(methylamino)propyl)phenoxy)hexanamide [3, (+)-METH HSMO9] and its use to prepare METH-conjugated vaccines (MCV) from maleimide-activated proteins. MALDI TOF mass spectrometry analysis of the MCV synthesized using 3 showed there was a high and controllable epitope density on two different carrier proteins. In addition, the MCV produced a substantially greater immunological response in mice than previous METH haptens, and a monoclonal antibody generated from this MCV in mice showed a very high affinity for (+)-METH (K(D) = 6.8 nM). The efficient covalent coupling of (+)-METH HSMO9 to the activated carrier proteins suggests that this approach could be cost-effective for large-scale production of MCV. In addition, the general methods described for the synthesis of (+)-METH HSMO9 (3) and its use to synthesize MCV will be applicable for conjugated vaccines of small molecules and other substances of abuse such as morphine, nicotine, and cocaine. PMID- 21682291 TI - Preparation and assembly of poly(arginine)-coated liposomes to create a free standing bioscaffold. AB - We created a free-standing membrane as a novel bioscaffold through the assembly of polymer-coated liposomes. Polyarginine (P(Arg)) possessing a cell-penetrating activity was used to form the polymer layer onto a negatively charged liposome (lipo-P(Arg)). The capsule wall of P(Arg) over liposomes made it possible to improve the mechanical property of capsules and to display deoxyribonucleic acid (DNA) over the vesicle surface through the electrostatic attraction (lipo-P(Arg) DNA). The release rates of a fluorescent probe encapsulated in lipo-P(Arg) and lipo-P(Arg)-DNA were tunable by the number of polymeric layers of the capsule walls. To investigate the cell-membrane permeability of lipo-P(Arg)-DNA, polymer coated liposomes were incubated with human umbilical vein endothelial cells (HUVECs) at 4 degrees C. It was found that lipo-P(Arg) underwent a significant cellular uptake, whereas bare liposomes and liposomes modified with chitosan were incapable of overcoming the plasma membrane barrier. To prepare a free-standing membrane composed of polymer-coated liposomes, a suspension of lipo-P(Arg)-DNA was cast over a mesh hole and dried up. SEM observation revealed that a free standing membrane was obtained through drying-mediated assembly process without rupturing polymer-coated liposomes inside the membrane. On the other hand, it was not possible to obtain a complete membrane from a mixture of lipo-P(Arg) and DNA. In summary, lipo-P(Arg)-DNA capsules possess versatile functions as a drug carrier, and their assembly enables us to create a free-standing membrane applicable as a bioscaffold. PMID- 21682292 TI - Contact angle dependence of the resonant frequency of sessile water droplets. AB - The resonant vibrations of small (microliter) sessile water droplets supported on solid substrates were monitored using a simple optical detection technique. A small puff of air was used to apply an impulse to the droplets and their time dependent oscillations were monitored by passing a laser beam through the droplet and measuring the variations of the intensity of the scattered light using a simple photodiode arrangement. The resulting time dependent intensity changes were then Fourier transformed to obtain information about the vibrational frequencies of the droplets. The resonant frequencies of droplets with masses in the range 0.005-0.03 g were obtained on surfaces with water contact angles ranging from 12 +/- 4 degrees to 160 +/- 5 degrees . The contact angle dependence of the resonant frequency of the droplets was found to be in good agreement with a simple theory which considers standing wave states along the meridian profile length of the droplets. PMID- 21682294 TI - Poly (N-isopropylacrylamide) microgels for organic dye removal from water. AB - The ability of poly (N-isopropylacrylamide) (pNIPAm), and pNIPAm-co-acrylic acid (pNIPAm-co-AAc) microgels to remove an organic azo dye molecule, 4-(2-Hydroxy-1 naphthylazo) benzenesulfonic acid sodium salt (Orange II) from aqueous solutions at both room and elevated temperature was assessed. At room temperature, we found that the amount of Orange II removed from water (removal efficiency) increased with increasing AAc and microgel concentration. The removal of Orange II from water was also fit by a Langmuir sorption isotherm model. Furthermore, we found the extent of Orange II removal depended on solution temperature; more Orange II was removed from water at elevated temperature and as the microgels were held at that temperature for longer durations of time. Additionally, by increasing the cycles between high and ambient temperature, the removal of Orange II was enhanced, although this was only true for two temperature cycles. We hypothesize that this is a result of the thermoresponsive nature of pNIPAm-based microgels which deswell at elevated temperature expelling their solvating water and when the microgels are cooled back down they reswell with the Orange II containing water. We also hypothesize that the microgels become saturated after the second heating cycle and so the efficiency of removal did not increase further. Finally, we assessed the ability of the microgels to retain the Orange II after it is removed from the aqueous solution. We determined that the microgels "leak" 25.6% of the Orange II that was originally removed from the water. PMID- 21682293 TI - Surface reactivity from electrochemical lithography: illustration in the steady state reductive etching of perfluorinated surfaces. AB - The scanning electrochemical microscope (SECM) in the lithographic mode is used to assess quantitatively, from both theoretical and experimental points of view, the kinetics of irreversible transformation of electroactive molecular moieties immobilized on a surface as self-assembled monolayers (SAMs). The SECM tip allows the generation of an etchant that transforms the surface locally and irreversibly. The resulting surface patterning is detectable by different surface analyses. The quantification of the surface transformation kinetics is deduced from the evolution of the pattern dimensions with the etching time. The special case of slow etching kinetics is presented; it is predicted that the pattern evolution follows the expansion of the etchant at the substrate surface. The case of a chemically unstable etchant is considered. The model is then tested by inspecting the slow reductive patterning of a perfluorinated SAM. Good agreement is found with different independent SECM interrogation modes, depending on the insulating or conducting nature of the covered substrate. The surface transformation measurements are also compared to the reduction of solutions of perfluoroalkanes. The three-orders-of-magnitude-slower electron transfer observed at the immobilized molecules likely describes the large reorganization associated with the generation of a perfluoroalkyl-centered radical anion. PMID- 21682295 TI - Development of new antioxidant active packaging films based on ethylene vinyl alcohol copolymer (EVOH) and green tea extract. AB - Ethylene vinyl alcohol copolymer (EVOH) films containing green tea extract were successfully produced by extrusion. The films were brown and translucent, and the addition of the extract increased the water and oxygen barrier at low relative humidity but increased the water sensitivity, the glass transition temperature, and the crystallinity of the films and improved their thermal resistance. An analysis by HPLC revealed that the antioxidant components of the extract suffered partial degradation during extrusion, reducing the content of catechin gallates and increasing the concentration of free gallic acid. Exposure of the films to various food simulants showed that the liquid simulants increased their capacity to reduce DPPH(*) and ABTS(*+) radicals. The release of green tea extract components into the simulant monitored by HPLC showed that all compounds present in the green tea extract were partially released, although the extent and kinetics of release were dependent on the type of food. In aqueous food simulants, gallic acid was the main antioxidant component released with partition coefficient values ca. 200. In 95% ethanol (fatty food simulant) the K value for gallic acid decreased to 8 and there was a substantial contribution of catechins (K in the 1000 range) to a greatly increased antioxidant efficiency. Kinetically, gallic acid was released more quickly than catechins, owing to its faster diffusivity in the polymer matrix as a consequence of its smaller molecular size, although the most relevant effect is the plasticization of the matrix by alcohol, increasing the diffusion coefficient >10-fold. Therefore, the materials here developed with the combination of antioxidant substances that constitute the green tea extract could be used in the design of antioxidant active packaging for all type of foods, from aqueous to fatty products, the compounds responsible for the protection being those with the higher compatibility with the packaged product. PMID- 21682296 TI - Direct conversion of bio-ethanol to isobutene on nanosized Zn(x)Zr(y)O(z) mixed oxides with balanced acid-base sites. AB - We report the design and synthesis of nanosized Zn(x)Zr(y)O(z) mixed oxides for direct and high-yield conversion of bio-ethanol to isobutene (~83%). ZnO is addded to ZrO(2) to selectively passivate zirconia's strong Lewis acidic sites and weaken Bronsted acidic sites, while simultaneously introducing basicity. As a result, the undesired reactions of bio-ethanol dehydration and acetone polymerization/coking are suppressed. Instead, a surface basic site-catalyzed ethanol dehydrogenation to acetaldehyde, acetaldehyde to acetone conversion via a complex pathway including aldol-condensation/dehydrogenation, and a Bronsted acidic site-catalyzed acetone-to-isobutene reaction pathway dominates on the nanosized Zn(x)Zr(y)O(z) mixed oxide catalyst, leading to a highly selective process for direct conversion of bio-ethanol to isobutene. PMID- 21682297 TI - Bottom-up synthesis of gold octahedra with tailorable hollow features. AB - Gold octahedra with hollow features have been synthesized in high yield via the controlled overgrowth of preformed concave cube seeds. This Ag(+)-assisted, seed mediated synthesis allows for the average edge length of the octahedra and the size of the hollow features to be independently controlled. We propose that a high concentration of Ag(+) stabilizes the {111} facets of the octahedra through underpotential deposition while the rate of Au(+) reduction controls the dimensions of the hollow features. This synthesis represents a highly controllable bottom-up approach for the preparation of hollow gold nanostructures. PMID- 21682298 TI - Discovery of a selective allosteric M1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold. AB - One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M(1) muscarinic receptor. A number of nonselective M(1) muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M(2) to M(5) subtypes. One strategy to confer selectivity for M(1) is the identification of positive allosteric modulators, which would target an allosteric site on the M(1) receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have been previously identified as highly selective M(1) positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4 cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation. PMID- 21682299 TI - Strain effects in electron spin resonance spectroscopy of quintet 2,6-bis(4' nitrenophenyl)-4-phenylpyridine. AB - Photolysis of 2,6-bis(4'-azidophenyl)-4-phenylpyridine in 2-methyltetrahydrofuran (2MTHF) glass at 7 K leads to quintet 2,6-bis(4'-nitrenophenyl)-4-phenylpyridine as a mixture of rotational isomers. The electron spin resonance (ESR) spectrum of this mixture of rotamers shows a considerable broadening of many transitions in the range of 0-5000 G and cannot be reproduced by computer simulations solely based on the tuning of the spin Hamiltonian parameters g, D(Q), and E(Q) alone or on predictions of DFT calculations. The best modeling of the experimental ESR spectrum is obtained only when the large line-broadening parameter of Gamma(E(Q)) = 1200 MHz along with the spin Hamiltonian g = 2.003, D(Q) = 0.154 cm(-1), and E(Q) = 0.050 cm(-1) is used in the spectral simulations. The most accurate theoretical estimations of the magnetic parameters of the dinitrene in a 2MTHF glass are obtained from the B3LYP/6-311+G(d,p)+PBE/DZ/COSMO calculations of the spin-spin coupling parameters D(SS) and E(SS). Such calculations overestimate the E(Q) and D(Q) values of the dinitrene just by 1% and 10%, respectively, demonstrating that contributions of the spin-orbit coupling parameters D(SOC) and E(SOC) to the total D(Q) and E(Q) values are negligibly small. The research shows that ESR studies of polynuclear high-spin nitrenes, obtained by photolysis of rotational isomers of the starting azides, can only be successful if large E(Q) strain effects are taken into account in the spectral simulations. PMID- 21682300 TI - Laser desorption ionization-time-of-flight mass analysis of perfluoropolyether monolayer directly from hard disk medium surface. AB - Modern life is dependent on computer technology, and because the volume of digital data in the world is increasing rapidly, the importance of data storage devices is also increasing rapidly. Among them, demands for magnetic disk drive well-known as hard disk drives is quite huge and information recording density on the disk media is continuing to grow dramatically. For the research and development of the magnetic disk media, it is critical to investigate and characterize the lubricant layer formed on the disk media surface. However, it is difficult because the layer is only a monolayer which has only approximately 1 nm thickness in many cases. Although matrix-assisted laser desorption ionization time-of-flight-mass spectrometry (MALDI-TOF-MS) measurements of monolayers have already been reported (Su, J.; Mrksich, M. Langmuir, 2003, 19, 4867-4870), lubricants used here are (co)polymers which have molecular weight distributions and are mixtures of various degrees of polymerization. This can reduce the sensitivity of MS measurement because the number (or density) of distinct single molecular species is lower than for homogeneous samples. In this report, direct measurement and characterization of lubricant monolayers using the LDI-TOF-MS instrument is performed to gain insight into detailed information like average molecular weight, polymer distribution, and two-dimensional mapping directly from magnetic disk monolayers. To our knowledge, this is the first time such information was acquired directly from hard disk media. The technique reported here might open up new possibilities also for investigations of various electronic devices other than magnetic hard disks. PMID- 21682301 TI - Transpeptidase-mediated incorporation of D-amino acids into bacterial peptidoglycan. AB - The beta-lactams are the most important class of antibiotics in clinical use. Their lethal targets are the transpeptidase domains of penicillin binding proteins (PBPs), which catalyze the cross-linking of bacterial peptidoglycan (PG) during cell wall synthesis. The transpeptidation reaction occurs in two steps, the first being formation of a covalent enzyme intermediate and the second involving attack of an amine on this intermediate. Here we use defined PG substrates to dissect the individual steps catalyzed by a purified E. coli transpeptidase. We demonstrate that this transpeptidase accepts a set of structurally diverse D-amino acid substrates and incorporates them into PG fragments. These results provide new information on donor and acceptor requirements as well as a mechanistic basis for previous observations that noncanonical D-amino acids can be introduced into the bacterial cell wall. PMID- 21682302 TI - k-Restoring processes at carbon depleted ultralow-k surfaces. AB - In this study we investigate the silylation of OH groups with different silazanes. In particular we use density functional theory and the nudged elastic band method to study the different reaction mechanisms. For the silylation reaction of hexamethyldisilazane and trimethylaminosilane with silanol, the minimum energy paths as well as the activation and reaction energies are discussed in detail. From minimum energy reaction paths we found that all studied silazanes react exothermically. Bis(dimethylamino)dimethylsilane shows the most exothermic silylation reaction with the lowest activation energies. Therefore, it is a good candidate for the chemical repair of porous films in the semiconductor k-restoring process. PMID- 21682303 TI - Lubricant degradation and related wear of a steel pin in lubricated sliding against a steel disc. AB - In lubricated sliding contacts, components wear out and the lubricating oil ages with time. The present work explores the interactive influence between lubricant aging and component wear. The flat face of a steel pin is slid against a rotating steel disk under near isothermal conditions while the contact is immersed in a reservoir of lubricant (hexadecane). The chemical changes in the oil with time are measured by vibrational spectroscopy and gas chromatography. The corresponding chemistry of the pin surface is recorded using X-ray photoelectron spectroscopy while the morphology of the worn pins; surface and subsurface, are observed using a combination of focused ion beam milling and scanning electron microscopy. When compared to thermal auto-oxidation of the lubricant alone, steel on steel friction and wear are found to accentuate the decomposition of oil and to reduce the beneficial impact of antioxidants. The catalytic action of nascent iron, an outcome of pin wear and disk wear, is shown to contribute to this detrimental effect. Over long periods of sliding, the decomposition products of lubricant aging on their own, as well as in conjunction with their products of reaction with iron, generate a thick tribofilm that is highly protective in terms of friction and wear. PMID- 21682304 TI - Effective temperature of ions in traveling wave ion mobility spectrometry. AB - Traveling wave ion mobility spectrometers (TW IMS) operate at significantly higher fields than drift tube ion mobility spectrometers. Here we measured the fragmentation of the fragile p-methoxybenzylpyridinium ion inside the TW ion mobility cell of the first-generation SYNAPT HDMS spectrometer. The ion's vibrational internal energy was quantified by a vibrational effective temperature T(eff,vib), which is the mean temperature of the ions inside the cell that would result in the same fragmentation yield as observed experimentally. Significant fragmentation of the probe ion inside the TW IMS cell was detected, indicating that field heating of the ions takes place in TW IMS. For typical small molecule IMS conditions, T(eff,vib) = 555 +/- 2 K. The variations of the effective temperature were studied as a function of the IMS parameters, and we found that T(eff,vib) decreases when the wave height decreases, when the pressure increases, or when the wave speed increases. The energy transfer efficiency of argon is higher than for He, N(2), or CO(2). With T(eff,vib) being directly related to the ion speed inside the TW IMS, our results also provide new insight on the ion movement in TW IMS. We also discuss the influence of field heating of ions for calibration and structural studies in TW IMS. PMID- 21682305 TI - From platonic templates to Archimedean solids: successive construction of nanoscopic {V16As8}, {V16As10}, {V20As8}, and {V24As8} polyoxovanadate cages. AB - Supramolecular coordination cages provide unique restricted inner cavities that can be exploited for molecular recognition purposes and catalysis. Their syntheses often involve complex self-organization processes and rely on the identification of preorganized, kinetically stable building units that provide ligand-accessible coordination sites. Here we report a highly effective protocol for the successive buildup of symmetrical nanoscopic polyoxometalate (POM) cages. Our methodology takes advantage of a supramolecular templating effect and utilizes the structure-directing influence of octahedral {X(x)(H(2)O)(6-x)} (X = Br(-), Cl(-); x = 2, 4, 6) assemblies that reside inside the hollow cluster shells and determine the arrangement of di- and tetranuclear vanadate units. The approach allows the preparation of a series of high-nuclearity POM cages that are characterized by {V(16)As(8)}, {V(16)As(10)}, {V(20)As(8)}, and {V(24)As(8)} core structures. In the latter cluster cage, the vanadium centers adopt a truncated octahedral topology. The formation of this Archimedean body is the direct result of the assembly of six square {V(4)O(8)} units that cap the vertices of the encapsulated Platonic {Cl(6)} octahedron. To the best of our knowledge, this {V(24)As(8)} cage is the largest hybrid vanadate cluster reported to date. PMID- 21682306 TI - Modular ion mobility spectrometer for explosives detection using corona ionization. AB - Ion mobility spectrometry (IMS) has become the most widely used technology for trace explosives detection. A key task in designing IMS systems is to balance the explosives detection performance with size, weight, cost, and safety of the instrument. Commercial instruments are, by and large, equipped with radioactive (63)Ni ionization sources which pose inherent problems for transportation, safety, and waste disposal regulation. An alternative to a radioactive source is a corona discharge ionization source, which offers the benefits of simplicity, stability, and sensitivity without the regulatory problems. An IMS system was designed and built based on modeling and simulation with the goal to achieve a lightweight modular design that offered high performance for the detection of trace explosives using a corona ionization source. Modeling and simulations were used to investigate design alternatives and optimize parameters. Simulated spectra were obtained for 2,4,6-trinitrotoluene (TNT) and cyclo-1,3,5 trimethylene-2,4,6-trinitramine (RDX) and showed good agreement with experimentally measured spectra using a corona ionization source. The reduced mobilities for TNT and RDX obtained with corona ionization were 1.53 and 1.46 cm(2)/(V s), respectively, and this agreed well with literature values. PMID- 21682307 TI - Glutathione reductase-catalyzed cascade of redox reactions to bioactivate potent antimalarial 1,4-naphthoquinones--a new strategy to combat malarial parasites. AB - Our work on targeting redox equilibria of malarial parasites propagating in red blood cells has led to the selection of six 1,4-naphthoquinones, which are active at nanomolar concentrations against the human pathogen Plasmodium falciparum in culture and against Plasmodium berghei in infected mice. With respect to safety, the compounds do not trigger hemolysis or other signs of toxicity in mice. Concerning the antimalarial mode of action, we propose that the lead benzyl naphthoquinones are initially oxidized at the benzylic chain to benzoyl naphthoquinones in a heme-catalyzed reaction within the digestive acidic vesicles of the parasite. The major putative benzoyl metabolites were then found to function as redox cyclers: (i) in their oxidized form, the benzoyl metabolites are reduced by NADPH in glutathione reductase-catalyzed reactions within the cytosols of infected red blood cells; (ii) in their reduced forms, these benzoyl metabolites can convert methemoglobin, the major nutrient of the parasite, to indigestible hemoglobin. Studies on a fluorinated suicide-substrate indicate as well that the glutathione reductase-catalyzed bioactivation of naphthoquinones is essential for the observed antimalarial activity. In conclusion, the antimalarial naphthoquinones are suggested to perturb the major redox equilibria of the targeted infected red blood cells, which might be removed by macrophages. This results in development arrest and death of the malaria parasite at the trophozoite stage. PMID- 21682309 TI - Template-directed synthesis of ordered single-crystalline nanowires arrays of Cu2ZnSnS4 and Cu2ZnSnSe4. AB - Highly ordered quaternary semiconductor Cu(2)ZnSnS(4) nanowires array have been prepared via a facile solvothermal approach using anodic aluminum oxide (AAO) as a hard template. The as-prepared nanowires are uniform and single crystalline. They grow along either the crystalline [110] or [111] direction. The structure, morphology, composition, and optical absorption properties of the as-prepared Cu(2)ZnSnS(4) samples were characterized using X-ray powder diffraction, transmission electron microscopy, energy dispersive X-ray spectrometry, scanning electron microscopy, and UV-vis spectrometry. A possible formation mechanism of the nanowire arrays is proposed. Governed by similar mechanism, we show that Cu(2)ZnSnSe(4) nanowire array with similar structural characteristics can also be obtained. PMID- 21682310 TI - Influence of chain length of alcohols on Stokes' shift dynamics in catanionic vesicles. AB - In this paper, we explore the effects of the chain length of simple monohydroxy alcohol (C(n)OH, 2 <= n <= 8) and benzyl alcohol (C(6)H(5)CH(2)OH) upon the fluorescence dynamics of a dipolar solute probe, coumarin 153 (C153), in vesicles formed in aqueous solutions of two oppositely charged (cationic and anionic) surfactants in the presence of 0.05 mol kg(-1) alcohol. The catanionic vesicles are composed of 70 mol % sodium dodecyl sulfate (SDS) and 30 mol % cetyltrimethylammonium bromide (CTAB). The presence of alcohols of different chain length improves the stability of the catanionic vesicles. Dynamic light scattering (DLS) experiments suggest a gentle increase in the hydrodynamic diameter of the catanionic vesicle with alcohol chain length up to n=4 and then an abrupt increase for the rest of the alcohols considered. The polarity and dynamics of the catanionic vesicles, probed by the steady-state and time-resolved fluorescence spectroscopy, indicate a signature of confined water. Quantities measured from fluorescence experiments of these vesicles also show a mild variation for alcohols of chain length n <= 4, followed by a sudden variation for alcohols with n > 4. Interestingly, pentanol and benzyl alcohol in catanionic vesicles showed roughly similar effects due to their equivalent chain length. All of these data are remarkably correlated with the recently observed depression of the solubility temperature of catanionics with alcohol chain length (Langmuir2009, 25, 12516-12521). PMID- 21682308 TI - Structural basis of regiospecificity of a mononuclear iron enzyme in antibiotic fosfomycin biosynthesis. AB - Hydroxypropylphosphonic acid epoxidase (HppE) is an unusual mononuclear iron enzyme that uses dioxygen to catalyze the oxidative epoxidation of (S)-2 hydroxypropylphosphonic acid (S-HPP) in the biosynthesis of the antibiotic fosfomycin. Additionally, the enzyme converts the R-enantiomer of the substrate (R-HPP) to 2-oxo-propylphosphonic acid. To probe the mechanism of HppE regiospecificity, we determined three X-ray structures: R-HPP with inert cobalt containing enzyme (Co(II)-HppE) at 2.1 A resolution; R-HPP with active iron containing enzyme (Fe(II)-HppE) at 3.0 A resolution; and S-HPP-Fe(II)-HppE in complex with dioxygen mimic NO at 2.9 A resolution. These structures, along with previously determined structures of S-HPP-HppE, identify the dioxygen binding site on iron and elegantly illustrate how HppE is able to recognize both substrate enantiomers to catalyze two completely distinct reactions. PMID- 21682311 TI - Crystallinity enhancement of Nafion electrolyte membranes assisted by a molecular gelator. AB - Nanocrystallites, acting as physical cross-links in Nafion membranes, play a crucial role in building blocks for improving mechanical durability and stopping fuel crossover. However, Nafion membranes suffer from low crystallinity due to the irregular pendent side chains, which hinder self-aggregation of the poly(tetrafluoroethylene) (PTFE) backbones. For the first time, a molecular gelator was introduced in the membrane casting process to enhance the rate of self-assembly of PTFE backbones so as to increase the membrane's crystallinity as well as proton conductivity without sacrificing the purity of Nafion. The molecular gelator used was 3,4-dimethylbenzaldehyde (DMBA). Addition of 0.5 wt % DMBA led to a 42% increase in crystallinity, a 32% increase in yield strength, a 22% increase in tensile modulus and an 18% increase in proton conductivity at 60 degrees C and 90% relative humidity. Additionally, the membrane electrode assembly (MEA) prepared from the membranes cast from the solution containing 0.5 wt % DMBA also showed an increase of 17% in maximum power density in comparison to the MEA prepared from pure Nafion membrane in a single cell polarization test without any external humidification. Transmission electron microscopy (TEM) and molecular dynamics simulation were used to elucidate the structural changes in Nafion membrane due to the introduction of DMBA. It was observed that the presence of DMBA gives wider crystalline regions under TEM. The molecular dynamics simulation at 500 K shows that the PTFE backbones become elongated in the presence of DMBA due to the enhanced mobility. This is consistent with the observed increase in crystallinity in the membrane as it means reduced entropic change upon crystallization. PMID- 21682312 TI - Enzymatic probing of model lipid membranes: phospholipase A2 activity toward monolayers modified by oxicam NSAIDs. AB - Three nonsteroidal anti-inflammatory oxicam drugs, namely meloxicam, piroxicam, and tenoxicam, were used to modify the properties of monomolecular films formed with 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3 phosphoethanolamine, or 1,2-dilauroyl-sn-glycero-3-phospho-(1-rac-glycerol). These systems were examined via surface pressure and surface electrical potential measurements, polarization modulation infrared reflection absorption spectroscopy, and Brewster angle microscopy. Moreover, phospholipase A2 activity was used to differentiate between the three drugs. Our results reveal that the oxicams studied modify membrane properties, namely hydration of the lipid polar heads, orientation of the molecules, and morphology of the domains. Phospholipase A2 was shown to be sensitive to the presence of the drugs in the systems studied; the activity of the enzyme correlates with the effect of meloxicam, piroxicam, and tenoxicam on the monolayer properties. The latter indicates that the anti inflammatory action of oxicams may be related to interference with phospholipase activity in addition to cyclooxygenase inhibition. PMID- 21682313 TI - Interplay of three-dimensional morphologies and photocarrier dynamics of polymer/TiO2 bulk heterojunction solar cells. AB - In this study, we investigated the interplay of three-dimensional morphologies and the photocarrier dynamics of polymer/inorganic nanocrystal hybrid photoactive layers consisting of TiO(2) nanoparticles and nanorods. Electron tomography based on scanning transmission electron microscopy using high-angle annular dark-field imaging was performed to analyze the morphological organization of TiO(2) nanocrystals in poly(3-hexylthiophene) (P3HT) in optimal solar cell devices. The Three-dimensional (3D) morphologies of these hybrid films were correlated with the photocarrier dynamics of charge separation, transport, and recombination, which were comprehensively probed by various transient techniques. Visualization of these 3D bulk heterojunction morphologies clearly reveals that elongated and anisotropic TiO(2) nanorods in P3HT not only can significantly reduce the probability of the interparticle hopping transport of electrons by providing better connectivity with respect to the TiO(2) nanoparticles, but also tend to form a large-scale donor-acceptor phase-separated morphology, which was found to enhance hole transport. The results support the establishment of a favorable morphology for polymer/inorganic hybrid solar cells due to the presence of the dimensionality of TiO(2) nanocrystals as a result of more effective mobile carrier generation and more efficient and balanced transport of carriers. PMID- 21682314 TI - Oligoether carboxylates: task-specific room-temperature ionic liquids. AB - Recently, a new family of ionic liquids based on oligoether carboxylates was introduced. 2,5,8,11-Tetraoxatridecan-13-oate (TOTO) was shown to form room temperature ionic liquids (RTILs) even with small alkali ions such as lithium and sodium. However, the alkali TOTO salts suffer from their extremely high viscosities and relatively low conductivities. Therefore, we replaced the alkali cations by tetraalkylammonium (TAA) ions and studied the TOTO salts of tetraethyl (TEA), tetrapropyl- (TPA), and tetrabutylammonium (TBA). In addition, the environmentally benign quaternary ammonium ion choline (Ch) was included in the series. All salts were found to be ionic liquids at ambient temperatures with a glass transition typically at around -60 degrees C. Viscosities, conductivities, solvent polarities, and Kamlet-Taft parameters were determined as a function of temperature. When using quaternary ammonium ions, the viscosities of the resulting TOTO ionic liquids are >600 times lower, whereas conductivities increase by a factor of up to 1000 compared with their alkali counterparts. Solvent polarities further reveal that choline and TAA cations yield TOTO ionic liquids that are more polar than those obtained with the, per se, highly polar sodium ion. Results are discussed in terms of ion-pairing and structure-breaking concepts with regard to a possible complexation ability of the TOTO anion. PMID- 21682315 TI - Permanent electric dipole moments of carboxyamides in condensed media: what are the limitations of theory and experiment? AB - Electrostatic properties of proteins are crucial for their functionality. Carboxyamides are small polar groups that, as peptide bonds, are principal structural components of proteins that govern their electrostatic properties. We investigated the medium dependence of the molar polarization and of the permanent dipole moments of amides with different state of alkylation. The experimentally measured and theoretically calculated dipole moments manifested a solvent dependence that increased with the increase in the media polarity. We ascribed the observed enhancement of the amide polarization to the reaction fields in the solvated cavities. Chloroform, for example, caused about a 25% increase in the amide dipole moments determined for vacuum, as the experimental and theoretical results demonstrated. Another chlorinated solvent, 1,1,2,2-tetrachloroethane, however, caused an "abnormal" increase in the experimentally measured amide dipoles, which the theoretical approaches we used could not readily quantify. We showed and discussed alternatives for addressing such discrepancies between theory and experiment. PMID- 21682316 TI - Improving the lipid profile in hypercholesterolemia-induced rabbit by supplementation of germinated brown rice. AB - It is imperative that there be a diet designed specifically to improve lipid profile in order to impede the progress of atherosclerosis. Because rice is a staple food in Asia, it will be chosen as the diet of interest. This study sets out to discover whether consumption of different processed rice diets may result in a change of the lipid profile. The experiment was done on male New Zealand white rabbits after 10 weeks of treatment with diet containing 0.5% cholesterol. The experimental diets include white rice (WR), brown rice (BR), and germinated brown rice (GBR). Among them, rabbits fed a GBR diet demonstrated significantly lower levels of total cholesterol (TC), low-density lipoprotein (LDL), LDL/HDL, and atherogenic index (AI) and a higher level of high-density lipoprotein (HDL). Results from atherosclerotic plaque assessment further support the findings. The level of malondialdehyde (MDA), which acts as an indicator for oxidative stress, was also reduced by GBR diet. The positive change in lipid profile in the rabbits fed GBR appeared to correspond with the higher amounts of gamma-oryzanol, tocopherol, and monounsaturated fatty acid (MUFA) content. PMID- 21682317 TI - The role of electrochemical phenomena in scanning probe microscopy of ferroelectric thin films. AB - Applications of piezoresponse force microscopy and conductive atomic force microscopy to ferroelectric thin films necessitate understanding of the possible bias-induced electrochemical reactivity of oxide surfaces. These range from reversible ionic surface charging (possibly coupled to polarization) and vacancy and proton injection to partially reversible vacancy ordering, to irreversible electrochemical degradation of the film and bottom electrode. Here, the electrochemical phenomena induced by a biased tip are analyzed and both theoretical and experimental criteria for their identification are summarized. PMID- 21682318 TI - Imaging symmetry-selected corner plasmon modes in penta-twinned crystalline Ag nanowires. AB - Using dual-plane leakage radiation microscopy, we investigate plasmon propagation in individual penta-twinned crystalline silver nanowires. By measuring the wavevector content of the light emitted in the substrate, we unambiguously determine the effective index and the losses of the mode propagating in these structures. The experimental results, in particular, the unexpectedly low effective index, reveal the direct influence of the nanowire crystallinity and pentagonal structure on the observed plasmon modes. By analogy with molecular orbitals of similar symmetry, the plasmon modes are also determined numerically in good agreement with the observed values. We further investigate the effect of wire geometry (length, diameter) on the effective index and propagation loss. Our results show that, beyond dissipation concerns, the morphological and structural control obtained in crystalline colloidal plasmonic nanostructures can be exploited to finely tune their optical properties. PMID- 21682319 TI - The compositions of volatiles and aroma-active compounds in dried omija fruits (Schisandra chinensis Baillon) according to the cultivation areas. AB - Differences in the compositions of volatiles from dried omija fruits (Schisandra chinensis Baillon) cultivated in different areas (Mungyeong, Jangsu, Jechon, and Hoengseong) in South Korea were determined by applying principal component analysis to gas chromatography-mass spectrometry data sets. Quantitative assessments revealed that terpene hydrocarbons, such as germacrene D, beta selinene, alpha-ylangene, beta-elemene, alpha-selinene, and (E)-beta-farnesene, were the main volatiles in all omija fruit samples. On the other hand, (E)-beta ocimene, calarene, (E)-beta-farnesene, beta-selinene, nonanal, 2-methylbutanoic acid, benzoic acid, 2,3-butanediol, and phenethyl alcohol were the major volatile components that contributed to the discrimination between omija fruit samples from the four cultivation areas. In addition, aroma-active compounds in four dried omija fruits were investigated and compared by gas chromatography olfactometry using aroma extract dilution analysis. (E)-beta-Ocimene (floral and herbaceous), alpha-pinene (pine-like and woody), hexanal (cut grass-like), 5 methylfurfural (burnt sugar-like and sweet), and alpha-terpinene (minty, green, and fresh) were important aroma-active compounds in all omija samples. Interestingly, the flavor dilution factors of most aroma-active compounds were lower for omija sample cultivated in Hoengseong than for those cultivated in Mungyeong, Jangsu, and Jechon. PMID- 21682320 TI - Excited states in electron-transfer reaction products: ultrafast relaxation dynamics of an isolated acceptor radical anion. AB - The spectroscopy and ultrafast relaxation dynamics of excited states of the radical anion of a representative charge-transfer acceptor molecule, 2,3,5,6 tetrafluoro-7,7,8,8-tetracyanoquinodimethane, have been studied in the gas phase using time-resolved photoelectron spectroscopy. The photoelectron spectra reveal that at least two anion excited states are bound. Time-resolved studies show that both excited states are very short-lived and internally convert to the anion ground state, with the lower energy state relaxing within 200 fs and a near threshold valence-excited state relaxing on a 60 fs time scale. These excited states, and in particular the valence-excited state, present efficient pathways for electron-transfer reactions in the highly exergonic inverted region which commonly displays rates exceeding predictions from electron-transfer theory. PMID- 21682321 TI - Low-temperature self-catalytic growth of tin oxide nanocones over large areas. AB - Nanoscale texturing has been studied for various applications, but most of the methods used to make these nanostructures are expensive and not easily scalable. Some of these methods require etching steps or high-temperature processes, which limit the processes to certain materials, such as silicon. In this study, we report a non-etching nanoscale texturing technique that allows for controlled oxidation to create tin oxide nanocones over large areas. Similar results are obtained on different substrates, such as silicon, aluminum foil, quartz, and polyimide film, and this method can be employed at temperatures as low as 220 degrees C in ambient pressure. This simple and scalable nanotexturing process improves the anti-reflection effect in photovoltaic devices. The light absorption of a polycrystalline silicon substrate, a widely used photovoltaic material, is increased by 30% over the wavelength range of 400-850 nm after fabricating nanocones on the surface. PMID- 21682322 TI - Synthesis of substituted pyrazoles via tandem cross-coupling/electrocyclization of enol triflates and diazoacetates. AB - The synthesis of 3,4,5-trisubstituted pyrazoles via a tandem catalytic cross coupling/electrocyclization of enol triflates and diazoacetates is presented. The initial scope of this methodology is demonstrated on a range of differentially substituted acyclic and cyclic enol triflates as well as an elaborated set of diazoacetates to provide the corresponding pyrazoles with a high degree of structural complexity. PMID- 21682323 TI - Enantioselective synthesis of tertiary alcohols through a zirconium-catalyzed Friedel-Crafts alkylation of pyrroles with alpha-ketoesters. AB - Chiral complexes of 1,1'-bi-2-naphthol-based ligands with zirconium tert-butoxide catalyze the Friedel-Crafts alkylation of pyrroles with alpha-ketoesters to afford tertiary alcohols in good yields and ee up to 98%. The reaction is also of application to 4,7-dihydroindole to give C2-alkylated indoles after oxidation with p-benzoquinone. PMID- 21682324 TI - Symmetry in strain engineering of nanomembranes: making new strained materials. AB - Strain in a material changes the lattice constant and thereby creates a material with new properties relative to the unstrained, but chemically identical, material. The ability to alter the strain (its magnitude, direction, extent, periodicity, symmetry, and nature) allows tunability of these new properties. A recent development, crystalline nanomembranes, offers a powerful platform for using and tuning strain to create materials that have unique properties, not achievable in bulk materials or with conventional processes. Nanomembranes, because of their thinness, enable elastic strain sharing, a process that introduces large amounts of strain and unique strain distributions in single crystal materials, without exposing the material to the formation of extended defects. We provide here prescriptions for making new strained materials using crystal symmetry as the driver: we calculate the strain distributions in flat nanomembranes for two-fold and four-fold elastically symmetric materials. We show that we can controllably tune the amount of strain and the asymmetry of the strain distribution in elastically isotropic and anisotropic materials uniformly over large areas. We perform the experimental demonstration with a trilayer Si(110)/Si((1-x))Ge(x)(110)/Si(110) nanomembrane: an elastically two-fold symmetric system in which we can transfer strain that is biaxially isotropic. We are thus able to make uniformly strained materials that cannot be made any other way. PMID- 21682325 TI - Photo-cross-linked biodegradable poly(ester anhydride) networks prepared from alkenylsuccinic anhydride functionalized poly(epsilon-caprolactone) precursors. AB - Biodegradable poly(ester anhydride) networks based on linear and star-shaped poly(epsilon-caprolactone)-based precursors were synthesized with the aim of obtaining matrixes suitable for release of macromolecular active agents. The ring opening polymerization yielded hydroxyl telechelic oligomers, which were end functionalized with succinic anhydride or with alkenylsuccinic anhydrides containing 8, 12, or 18 carbons in their alkenyl chains. Before cross-linking, the acid-terminated oligomers were reacted with methacrylic anhydride to obtain methacrylated precursors containing labile anhydride bonds. The degrees of substitution for the acid functionalization and methacrylation were >93%. Cross linking of the precursors was carried out with visible light at room temperature. Gel contents and cross-linking densities were higher for networks cross-linked from the star-shaped precursors than for networks prepared from the linear precursors. In in vitro erosion tests, the presence of the alkenyl chain slowed down the erosion rate. The networks exhibited characteristic surface erosion: the mass loss was linear, whereas the dimensions of the specimens decreased steadily. A macromolecular release study showed the release of the model compound to be linear and in proportion to the mass loss. PMID- 21682326 TI - Dispersed and encapsulated gain medium in plasmonic nanoparticles: a multipronged approach to mitigate optical losses. AB - The performance of all metamaterial-based applications is significantly limited by the inherent and strong energy dissipation present in metals, especially in the visible range. In fact, these materials suffer from rather strong damping of the plasmon fields which can become obstructive for most optical and photonic applications. Therefore, eliminating losses in optical metamaterials is critical for enabling their numerous potential applications. We experimentally demonstrate that the incorporation of gain material (fluorophores) in the high-local-field areas of a metamaterial subunits (gold core/silica shell nanoparticles) makes it possible to induce resonant energy transfer processes from gain units to plasmonic nanoparticles. A comparison between gain-assisted (nanoparticle-dye dispersion) and gain-functionalized (dye encapsulated into the shell) systems is reported. Fluorescence quenching and time-resolved spectroscopy along with modification of Rayleigh scattering and transmission of a probe beam as a function of impinging energy are key evidence of the strong coupling occurring between NPs and gain medium. The multipronged approach used to compensate losses in these metal-based subunits permits one to obtain important advances in materials science and paves the way toward further promising scientific research aimed to enable the wide range of electromagnetic properties of optical metamaterials. PMID- 21682327 TI - Mapping the iron binding site(s) on the small tetraheme cytochrome of Shewanella oneidensis MR-1. AB - In the model microbe Shewanella oneidensis, multi-heme proteins are utilized for respiratory metabolism where metals serve as the terminal electron acceptor. Among those is the periplasm-localized small tetraheme cytochrome (STC). STC has been extensively characterized structurally and electrochemically to which electron flow in and out of the protein has been modeled. However, until the present work, no kinetic studies have been performed to probe the route of electron flow or to determine the iron-binding site on STC. Using iron chelated by EDTA, NTA, or citrate, we have used chemical modification, site-directed mutagenesis along with isothermal titration calorimetry (ITC), and stopped-flow measurements to identify the iron binding site of STC. Chemical modifications of STC revealed that carboxyl groups on STC are involved in binding of EDTA-Fe(3+). Scanning mutagenesis was performed on Asp and Glu to probe the putative iron binding site on STC. Two STC mutants (D21N; D80N) showed ~70% decrease in observed electron transfer rate constant with EDTA-Fe(3+) from transient-state kinetic measurements. The impaired reactivity of STC (D80N/D21N) with EDTA-Fe(3+) was further confirmed by a significant decrease (>10-fold) in iron binding affinity. PMID- 21682328 TI - Observation of reduced cytotoxicity of aggregated amyloidogenic peptides with chaperone-like molecules. AB - The pathogenesis of many neurodegenerative diseases is associated with different types of aggregates of amyloidogenic peptides, including senile plaques, fibrils, protofibrils, and oligomers. It is therefore valuable to explore diversity of approaches toward reducing the cytotoxicity of amyloidogenic peptides by modulating aggregation behaviors. Herein we report an approach toward reducing the neuronal cytotoxicity of amyloidogenic peptides by accelerating the aggregation process, which is different from prevalent methods via inhibiting the aggregation of peptides. The pyridyl derivatives behave like chaperones to dramatically change the assembling characteristics of the peptides via strong hydrogen bond formation with C-termini of amyloid beta (Abeta) peptides, which is revealed by using scanning probe microscopy. The light scattering experiments demonstrated the effect of the chaperone-like molecules on accelerating the aggregation process of Abeta peptides, accompanied by the reduced neuronal cytotoxicity of amyloidogenic peptides. These results would give rise to a complementary approach for modulating biological effects of the aggregates of amyloidogenic peptides. PMID- 21682330 TI - Combined ab initio/DFT and Monte Carlo calculation of relative standard chemical potentials in solution. AB - A method has been proposed for pure theoretical estimation of relative standard chemical potentials (1 mol/dm(3) standard state) and related K(c) equilibrium constants for tautomers/conformers dissolved in some solvents. The relative internal free energy could be obtained by means of in-solution ab initio/DFT methods. Using the free energy perturbation method for the transformation of the involved species, the solvation contribution to the relative standard chemical potential can be determined by considering 1 M solution models. Comparison of the DeltaG(solv)/MC value calculated for the 1 M solution with those obtained for the system at other concentrations helps explore the ratio of the activity coefficients in nonstandard states. The method has been applied for the study of the tautomeric pair of formaldoxime and nitrosomethane with large structural differences. It was pointed out that the DeltaG(solv)/MC values for the 1 and 0.11 M solutions differ by up to 0.2 kcal/mol, when atomic charges are derived on the basis of the in-solution IEF-PCM/B3LYP/aug-cc-pvtz molecular electrostatic potential. On the basis of calculated free energy differences, the ratio of the CH(3)NO and CH(2)NOH activity coefficients in 0.11 molar aqueous and dichloromethane solutions were predicted as of 1.4 and 0.8, respectively. The 0.11 M model is hypothetical by assuming that only one of the tautomers exists in the solution box. As an extension of the method, a procedure has been outlined where contributions to the change of the solvation free energy by terms related to relative activity coefficients might be assessed at physically relevant concentrations for the equilibrated tautomers. PMID- 21682329 TI - Single-walled carbon nanotubes deliver peptide antigen into dendritic cells and enhance IgG responses to tumor-associated antigens. AB - We studied the feasibility of using single-wall carbon nanotubes (SWNTs) as antigen carriers to improve immune responses to peptides that are weak immunogens, a characteristic typical of human tumor antigens. Binding and presentation of peptide antigens by the MHC molecules of antigen presenting cells (APCs) is essential to mounting an effective immune response. The Wilm's tumor protein (WT1) is upregulated in many human leukemias and cancers and several vaccines directed at this protein are in human clinical trials. WT1 peptide 427 induces human CD4 T cell responses in the context of multiple human HLA-DR.B1 molecules, but the peptide has a poor binding affinity to BALB/c mouse MHC class II molecules. We used novel, spectrally quantifiable chemical approaches to covalently append large numbers of peptide ligands (0.4 mmol/g) onto solubilized SWNT scaffolds. Peptide-SWNT constructs were rapidly internalized into professional APCs (dendritic cells and macrophages) within minutes in vitro, in a dose dependent manner. Immunization of BALB/c mice with the SWNT-peptide constructs mixed with immunological adjuvant induced specific IgG responses against the peptide, while the peptide alone or peptide mixed with the adjuvant did not induce such a response. The conjugation of the peptide to SWNT did not enhance the peptide-specific CD4 T cell response in human and mouse cells, in vitro. The solubilized SWNTs alone were nontoxic in vitro, and we did not detect antibody responses to SWNT in vivo. These results demonstrated that SWNTs are able to serve as antigen carriers for delivery into APCs to induce humoral immune responses against weak tumor antigens. PMID- 21682331 TI - A theoretical rationale for why azetidine has a faster rate of formation than oxetane in TC(6-4) photoproducts. AB - The mechanism of formation of azetidine and oxetane in (6-4) photoproducts between thymine and imine-type cytosine is studied using the MPWB1K and B3LYP functionals together with the 6-31G(d,p) and 6-311++G(d,p) basis sets, in vacuum and bulk solvent. The photoinduced cycloaddition displays favorable energy barriers in the triplet excited state for formation of both azetidine and oxetane. The stepwise cycloaddition in the triplet excited state involves the initial formation of a diradical followed by ring closure via singlet-triplet interaction. The distinguishing feature in the formation of azetidine compared to that of oxetane is an intermediate H3' back-transfer to N3', which is a low barrier exothermic reaction, and thus shifts the energy balance toward azetidine formation. PMID- 21682332 TI - Optical reflectivity and Raman scattering in few-layer-thick graphene highly doped by K and Rb. AB - We report the optical reflectivity and Raman scattering of few layer (L) graphene exposed to K and Rb vapors. Samples many tens of layers thick show the reflectivity and Raman spectra of the stage 1 bulk alkali intercalation compounds (GICs) KC(8) and RbC(8). However, these bulk optical and Raman properties only begin to appear in samples more than about 15 graphene layers thick. The 1 L to 4 L alkali exposed graphene Raman spectra are profoundly different than the Breit Wigner-Fano (BWF) spectra of the bulk stage 1 compounds. Samples less than 10 layers thick show Drude-like plasma edge reflectivity dip in the visible; alkali exposed few layer graphenes are significantly more transparent than intrinsic graphene. Simulations show the in-plane free electron density is lower than in the bulk stage 1 GICs. In few layer graphenes, alkalis both intercalate between layers and adsorb on the graphene surfaces. Charge transfer electrically dopes the graphene sheets to densities near and above 10(+14) electrons/cm(2). New intrinsic Raman modes at 1128 and 1264 cm(-1) are activated by in-plane graphene zone folding caused by strongly interacting, locally crystalline alkali adlayers. The K Raman spectra are independent of thickness for L = 1-4, indicating that charge transfer from adsorbed and intercalated K layers are similar. The Raman G mode is downshifted and significantly broadened from intrinsic graphene. In contrast, the Rb spectra vary strongly with L and show increased doping by intercalated alkali as L increases. Rb adlayers appear to be disordered liquids, while intercalated layers are locally crystalline solids. A significant intramolecular G mode electronic resonance Raman enhancement is observed in K exposed graphene, as compared with intrinsic graphene. PMID- 21682333 TI - Evaluation of the potential hypoglycemic and Beta-cell protective constituents isolated from Corni fructus to tackle insulin-dependent diabetes mellitus. AB - Corni fructus is the fruit of Cornus officinalis Sieb. et Zucc. and has attracted much interest due to its traditional applications and active fraction that reportedly possesses antidiabetic effects. In this study, we isolated 12 compounds from Corni fructus including three flavonoids, two iridoid glycosides, three phenolic compounds, and two triterpenoids, together with cornuside (11) and 2-butoxybutanedioic acid (12). Chemical structures were identified by (1)H, (13)C NMR, DEPT, COSY, HSQC, and HMBC spectral analyses. Furthermore, the glucose uptake efficiency, messenger (m)RNA expression of phosphoenolpyruvate carboxykinase (PEPCK), and prevention of cytokine-mediated cytotoxicity in the presence of test agents were evaluated. While CH and CB significantly increased glucose uptake from muscle, compounds 3 and 8, each at 50 MUM, significantly suppressed PEPCK mRNA expression. Finally, compound 5, at 50 and 100 MUM, effectively attenuated beta-cell death. In conclusion, those compounds could contribute to the antihyperglycemic and beta-cell-protective actions of Corni fructus against diabetes mellitus. PMID- 21682334 TI - Room-temperature ferroelectric resistive switching in ultrathin Pb(Zr 0.2 Ti 0.8)O3 films. AB - Spontaneous polarization of ferroelectric materials has been for a long time proposed as binary information support, but it suffers so far from destructive readout. A nondestructive resistive readout of the ferroelectric polarization state in a metal-ferroelectric-metal capacitor would thus be advantageous for data storage applications. Combing conducting force microscopy and piezoelectric force microscopy, we unambiguously show that ferroelectric polarization direction and resistance state are correlated for epitaxial ferroelectric Pb(Zr(0.2)Ti(0.8))O(3) nanoscale capacitors prepared by self-assembly methods. For intermediate ferroelectric layer thickness (~9 nm) sandwiched between copper and La(0.7)Sr(0.3)MnO(3) electrodes we achieved giant electroresistance with a resistance ratio of >1500 and high switching current densities (>10 A/cm(2)) necessary for effective resistive readout. The present approach uses metal ferroelectric-metal devices at room temperature and, therefore, significantly advances the use of ferroelectric-based resistive switching. PMID- 21682337 TI - Generalized theory for nanoscale voltammetric measurements of heterogeneous electron-transfer kinetics at macroscopic substrates by scanning electrochemical microscopy. AB - Here we report on a generalized theory for scanning electrochemical microscopy to enable the voltammetric investigation of a heterogeneous electron-transfer (ET) reaction with arbitrary reversibility and mechanism at the macroscopic substrate. In this theory, we consider comprehensive nanoscale experimental conditions where a tip is positioned at a nanometer distance from a substrate to detect the reactant or product of a substrate reaction at any potential in the feedback or substrate generation/tip collection mode, respectively. Finite element simulation with the Marcus-Hush-Chidsey formalism predicts that a substrate reaction under the nanoscale mass transport conditions can deviate from classical Butler-Volmer behavior to enable the precise determination of the standard ET rate constant and reorganization energy for a redox couple from the resulting tip current-substrate potential voltammogram as obtained at quasi-steady state. Simulated voltammograms are generalized in the form of analytical equations to allow for reliable kinetic analysis without the prior knowledge of the rate law. Our theory also predicts that a limiting tip current can be controlled kinetically to be smaller than the diffusion-limited current when a relatively inert electrode material is investigated under the nanoscale voltammetric conditions. PMID- 21682338 TI - Superlubricity behavior with phosphoric acid-water network induced by rubbing. AB - In present work, a superlubricity phenomenon of phosphoric acid (H(3)PO(4)) was found under ambient conditions. An ultralow friction coefficient of about 0.004 between glass/Si(3)N(4) and sapphire/sapphire tribopairs was obtained under the lubrication of a phosphoric acid aqueous solution (pH 1.5) at high contact pressure (the maximum pressure can reach about 1.65 GPa) after a running-in period of about 600 s. The experimental results indicate that the superlow friction state was very stable for more than 3 h. In such a state, solidlike films formed on the two sliding surfaces, which are hydrates of phosphoric acid with a hydrogen-bonded network according to the Raman spectrum. The superlubricity mechanism is mainly attributed to the hydrogen bond effect that forms a hydrated water layer with low shearing strength, and the dipole-dipole effects that form an interfacial Coulomb repulsion force also make some contributions to low friction. This work may help us to introduce a new approach to superlubricity and may lead to the wide application of superlubricity in future technological and biomedical areas. PMID- 21682339 TI - Synthesis and self-assembly of an amino-functionalized hybrid hydrocarbon/fluorocarbon double-chain phospholipid. AB - In this article, we designed and synthesized an amino-functionalized hybrid hydrocarbon/fluorocarbon double-chain phospholipid (ACFPC) containing one chain with the hydrophobic fluorocarbon chain and terminal amino, amide, and ether linkages and one chain with the hydrocarbon chain. The novel reactive phospholipid was fully characterized with Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS). Then the self-assembly behaviors of the hybrid double-chain phospholipid in aqueous and acidic media were investigated with transmission electron microscopy (TEM), the critical micelle concentration (cmc), dynamic light scattering (DLS), and the hydrocarbon double-chain phospholipid (ACCPC) for comparison. Moreover, their self-assembled structures in aqueous and acidic media were simulated using the dissipative particle dynamics (DPD) method. These results suggest that the fluorocarbon/hydrocarbon hybrid-chain phospholipid can self-assemble into a more stable microstructure compared to the double hydrocarbon chain phospholipid, which will have the potential ability to self-assemble into a more stable minicking biomembrane structure onto material surfaces to inhibit protein adsorption under complicated physiological conditions. PMID- 21682340 TI - Comparison of ERLIC-TiO2, HILIC-TiO2, and SCX-TiO2 for global phosphoproteomics approaches. AB - Reversible phosphorylations play a critical role in most biological pathways. Hence, in signaling studies great effort has been put into identification of a maximum number of phosphosites per experiment. Mass spectrometry (MS)-based phosphoproteomics approaches have been proven to be an ideal analytical method for mapping of phosphosites. However, because of sample complexity, fractionation of phosphopeptides prior to MS analysis is a crucial step. In the current study, we compare the chromatographic strategies electrostatic repulsion-hydrophilic interaction chromatography (ERLIC), hydrophilic interaction liquid chromatography (HILIC), and strong cation exchange chromatography (SCX) for their fractionation behavior of phosphopeptides. In addition, we investigate the use of repetitive TiO(2)-based enrichment steps for a maximum identification of phosphopeptides. On the basis of our results, SCX yields the highest number of identified phosphopeptides, whereas ERLIC is optimal for the identification of multiphosphorylated peptides. Consecutive incubations of fractions and flow through by TiO(2) beads enrich qualitatively different sets of phosphopeptides, increasing the number of identified phosphopeptides per analysis. PMID- 21682341 TI - Parinaric acid methyl ester polymer films with hill-structured features: fabrication and different sensitivities to normal and tumor cells. AB - Parinaric acid methyl ester (PnA-Me) polymer films with hill-structured features were fabricated by a solvent volatilization in situ cross-linking method. Moreover, nuclear magnetic resonance, Fourier transform infrared, and oxidation kinetic analyses were successfully applied to monitor the formation process of PnA-Me polymer films. The role of PnA-Me monomer concentrations for growth control of the hill structures on a glass matrix had also been investigated. Also, the results demonstrated that size control of the resulting hill structure ranging from 0.56 +/- 0.18 to 19.6 +/- 3.5 MUm could be realized by varying the concentration of the PnA-Me monomer from 0.0117 to 1.5 mg/mL. Additionally, the effects of polymer films with different surface topographical structures on the behaviors of rat mesenchymal stem cells and human pheochromocytoma cells were measured by morphological and metabolic methods. The results revealed that the cell activity of PnA-Me films was topographical structure- and cell-type dependent. Furthermore, the selective sensitivity of the PnA-Me films to normal and tumor cells supported the potential value as the coatings for the tissue engineering substitutes. PMID- 21682342 TI - Intrinsic proton-donating power of zinc-bound water in a carbonic anhydrase active site model estimated by NMR. AB - Using liquid-state NMR spectroscopy we have estimated the proton-donating ability of Zn-bound water in organometallic complexes designed as models for the active site of the metalloenzyme carbonic anhydrase (CA). This ability is important for the understanding of the enzyme reaction mechanism. The desired information was obtained by (1)H and (15)N NMR at 180 K of solutions of [Tp(Ph,Me)ZnOH] [1, Tp(Ph,Me) = tris(2-methyl-4-phenylpyrazolyl)hydroborate] in CD(2)Cl(2), in the absence and presence of the proton donors (C(6)F(5))(3)BOH(2) [aquatris(pentafluorophenyl)boron] and Col-H(+) (2,4,6-trimethylpyridine-H(+)). Col-H(+) forms a strong OHN hydrogen bond with 1, where the proton is located closer to nitrogen than to oxygen. (C(6)F(5))(3)BOH(2), which exhibits a pK(a) value of 1 in water, also forms a strong hydrogen bond with 1, where the proton is shifted slightly across the hydrogen-bond center toward the Zn-bound oxygen. Finally, a complex between Col and (C(6)F(5))(3)BOH(2) was identified, exhibiting a zwitterionic OHN hydrogen bond, where H is entirely shifted to nitrogen. The comparison with complexes of Col with carboxylic acids studied previously suggests that, surprisingly, the Zn-bound water exhibits in an aprotic environment a similar proton-donating ability as a carboxylic acid characterized in water by a pK(a) of 2.2 +/- 0.6. This value is much smaller than the value of 9 found for [Zn(OH(2))(6)](2+) in water and those between 5 and 8 reported for different forms of CA. Implications for the biological function of CA are discussed. PMID- 21682343 TI - Synthesis of sugars by hydrolysis of hemicelluloses--a review. PMID- 21682344 TI - Using ordered carbon nanomaterials for shedding light on the mechanism of the cathodic oxygen reduction reaction. AB - Insufficient understanding of the mechanism of the cathodic oxygen reduction reaction puts constraints on the improvement of the efficiency of polymer electrolyte fuel cells (PEMFCs). We apply ordered catalytic layers based on vertically aligned carbon nanofilaments and combine experimental rotating ring disk studies with mathematical modeling for shedding light on the mechanism of the oxygen reduction reaction on Pt nanoparticles. Based on the experimental and simulation evidence we propose a dual path ORR mechanism which comprises a "direct 4e(-)" and a "series 2e(-) + 2e(-)" pathway and explains switching between the two. For the first time we show that below 0.8 V the "direct" path may be discarded and the ORR predominantly occurs via H(2)O(2) mediated pathway, while in the potential interval between ca. 0.8 V and the onset of the ORR the "direct" path is dominating. PMID- 21682345 TI - Enantioselective oxidation of C-O and C-N bonds using oxidases. PMID- 21682346 TI - Formation of Maillard reaction products during heat treatment of carrots. AB - As indicators of the early stage of the Maillard reaction in carrots, N (furoylmethyl) amino acids (FMAAs) formed during acid hydrolysis of the corresponding Amadori products were analyzed using RP-HPLC with UV detection. N(epsilon)-FM-Lys (furosine), FM-Gly, FM-Ala, FM-Val, FM-Ile, FM-Leu, and FM-GABA were identified using synthesized standard material by means of mass spectrometry. Furthermore, N(epsilon)-carboxymethyllysine (CML) and pyrraline were analyzed as indicators for advanced stages of glycation. For commercial samples with high water content, the formation of Amadori compounds predominates, whereas the advanced stage of Maillard reaction plays only a minor part. Carrot juices, baby food, and tinned carrots showed quite low rates of amino acid modification up to 5%. For dehydrated carrots, significantly higher values for Amadori products were measured, corresponding to a lysine derivatization of up to 58% and nearly 100% derivatization of GABA. Drying experiments revealed great differences in reactivity between the amino acids studied. Whereas furosine reached constant values quite quickly, some FMAAs showed a continuous increase with heating time, indicating that selected FMAAs can be used as a hallmark for the early Maillard reaction to control processing conditions. PMID- 21682347 TI - Steered molecular dynamics simulations reveal important mechanisms in reversible monoamine oxidase B inhibition. AB - The monotopic membrane protein monoamine oxidase B (MAO B) is an important drug target for Parkinson's disease. In order to design more specific, and thereby more effective, inhibitors for this enzyme, it is necessary to determine what factors govern inhibitor specificity and the inhibitor binding process, including the roles of the lipid bilayer, the active site loop, and several key residues within the binding pocket. Atomistic molecular dynamics simulations of MAO B either embedded in a lipid bilayer or free in solution have been performed. The simulations suggest that the bilayer controls the availability of the active site cavity by regulating the degree of fluctuation in two key loops that form the greater part of the active site entrance (residues 85-110 and 155-165). In turn, the enzyme itself causes local thinning and a decrease in area per lipid of the surrounding bilayer environment. Additional MD simulations of MAO B in complex with seven different reversible inhibitors followed by nonequilibrium steered MD simulations of the inhibitor unbinding have also been performed. The simulations demonstrate that the average energy of interaction between inhibitor and MAO B residues during inhibitor egress is an effective indicator of inhibitor strength and is also useful for identifying key residues that govern inhibitor specificity. These data provide researchers with valuable tools for designing effective MAO B inhibitors as well as outline a method that can be translated to the study of other enzyme-inhibitor complexes. PMID- 21682348 TI - Organizing DNA origami tiles into larger structures using preformed scaffold frames. AB - Structural DNA nanotechnology utilizes DNA molecules as programmable information coding polymers to create higher order structures at the nanometer scale. An important milestone in structural DNA nanotechnology was the development of scaffolded DNA origami in which a long single-stranded viral genome (scaffold strand) is folded into arbitrary shapes by hundreds of short synthetic oligonucleotides (staple strands). The achievable dimensions of the DNA origami tile units are currently limited by the length of the scaffold strand. Here we demonstrate a strategy referred to as "superorigami" or "origami of origami" to scale up DNA origami technology. First, this method uses a collection of bridge strands to prefold a single-stranded DNA scaffold into a loose framework. Subsequently, preformed individual DNA origami tiles are directed onto the loose framework so that each origami tile serves as a large staple. Using this strategy, we demonstrate the ability to organize DNA origami nanostructures into larger spatially addressable architectures. PMID- 21682349 TI - Design of patient access schemes in the UK: influence of health technology assessment by the National Institute for Health and Clinical Excellence. AB - BACKGROUND: Patient Access Schemes (PAS) are alternative market access agreements between the UK Department of Health and drug manufacturers. They are implemented to enable the UK National Institute for Health and Clinical Excellence (NICE) to recommend expensive medicines for use in the UK NHS. OBJECTIVE: We aimed to analyse the extent to which NICE drug appraisals influence the construction of PAS and what rationale underlies the variety of approaches to their design. METHODS: We analysed publicly available documentation on PAS developed as a part of the NICE Health Technology Assessment process. RESULTS: We demonstrate how the design of PAS is determined by the kind of evidence that is available to model cost effectiveness of a drug and by the incremental cost-effectiveness ratio that is deemed acceptable in a given patient population. PAS aimed to reduce drug cost to the NHS by means of various discounts or rebates on a per-patient basis rather than by lowering the list price of drugs. While almost all schemes were proposed by the industry in reply to negative draft recommendations by NICE, motivations of the stakeholders to implement PAS are not disclosed in the publicly available documentation. CONCLUSION: A more transparent process might be necessary to protect against a perverse impact of PAS on international reference pricing that uses list prices rather than the real cost of purchasing medicines that the NHS incurs. PMID- 21682350 TI - Cost-efficacy analysis of the MONET trial using UK antiretroviral drug prices. AB - BACKGROUND: In virologically suppressed patients, switching to darunavir/ritonavir (DRV/r) monotherapy maintains HIV RNA suppression, and could also lower treatment costs. OBJECTIVE: The purpose of this analysis was to calculate the potential cost savings from the use of DRV/r monotherapy in the UK. METHODS: In the MONET trial, 256 patients with HIV RNA < 50 copies/mL on current highly active antiretroviral therapy (HAART) for over 24 weeks (non-nucleoside reverse-transcriptase inhibitor [NNRTI] based [43%] or protease inhibitor [PI] based [57%]), switched to DRV/r 800/100 mg once daily, either as monotherapy (n = 127) or with two NRTIs (n = 129). The UK costs per patient with HIV RNA < 50 copies/mL at week 48 (responders) were calculated using a 'switch included' analysis to account for additional antiretrovirals taken after initial treatment failure. By this analysis, efficacy was 93.5% versus 95.1% in the DRV/r monotherapy and triple therapy arms, respectively. British National Formulary 2009 values were used. RESULTS: Before the trial, the mean annual cost of antiretrovirals was L6906 for patients receiving NNRTI-based HAART, and L8348 for patients receiving PI-based HAART. During the MONET trial, the mean annual per patient cost of antiretrovirals was L8642 in the triple therapy arm, of which 55% was from NRTIs and 45% from PIs. The mean per-patient cost in the monotherapy arm was L4126, a saving of 52% versus triple therapy. The mean cost per responder was L9085 in the triple therapy arm versus L4413 in the DRV/r monotherapy arm. CONCLUSIONS: Based on the MONET results, the lower cost of DRV/r monotherapy versus triple therapy in the UK would allow more patients to be treated for fixed budgets, while maintaining HIV RNA suppression at < 50 copies/mL. If all patients meeting the inclusion criteria of the MONET trial in the UK were switched to DRV/r monotherapy, there is the potential to save up to L60 million in antiretroviral drug costs from the UK NHS budget. PMID- 21682351 TI - Ordering errors, objections and invariance in utility survey responses: a framework for understanding who, why and what to do. AB - BACKGROUND: Utilities are the quantification of the perceived quality of life associated with any health state. They are used to calculate QALYs, the outcome measure in cost-utility analysis. Generally measured through surveys of individuals, utilities often contain apparent or unapparent errors that can bias resulting values and QALYs calculated from these values. OBJECTIVE: The aim of this study was to improve direct health utility elicitation methodology through the identification of the types of survey responses that indicate errors and objections, and the reasons underlying them. METHODS: We conducted a systematic review of the medical (PubMed), economics (EconLit) and psychology (PsycINFO) literature from 1975 through June 2010 for articles describing the types and frequency of errors and objections in directly elicited utility survey responses, and strategies to address these responses. Primary data were collected through an internet-based utility survey (standard gamble) of community members to identify responses that indicate error or objections. A qualitative telephone survey was conducted among a subset of respondents with these types of responses using an open-ended protocol to elicit rationales for them. RESULTS: A total of 11 papers specifically devoted to errors, objections and invariance in utility responses have been published since the mid-1990s. Error/objection responses can be broadly categorized into ordering errors (which include illogical and inconsistent responses) and objections/invariance (which include missing data, protest responses and refusals to trade time or risk in utility questions). Reported frequencies of respondents making ordering errors ranged from 5% to 100%, and up to 35% of respondents have been reported as objecting to the survey or task in some manner. Changes in the design, administration and analysis of surveys can address these potentially problematic responses. Survey data (n = 398) showed that individuals who provided invariant responses (n = 26) reported the lowest level of difficulty with the survey and often identified as religious (23% of invariant responders found the survey difficult vs 63% of all responders, and 77% of invariant responders identified as religious compared with 56% of entire sample; p < 0.05 for both). Respondents who provided illogical responses (n = 50) were less likely to be college educated (56% of illogical responders vs 73% of entire sample; p < 0.05), and less likely to be confident in their responses (62% vs 75% of entire sample; p < 0.05). Qualitative interviews (n = 42) following the survey revealed that the majority of ordering errors were a result of confusion, lack of attention or difficulty in responding to the survey on the part of the respondent, while invariant responses were often considered and thoughtful reactions to the premise of valuing health using the standard gamble task. CONCLUSIONS: Rationales for error/objection responses include difficulty in articulating preferences or misunderstanding with a complex survey task, and also thoughtful and considered protestations to the task. Mechanisms to correct unintentional errors may be useful, but cannot address intentional responses to elements of the measurement task. Identification and analysis of the prevalence of errors and objections in responses in utility data sets are essential to understanding the accuracy and precision of utility estimates and analyses that depend thereon. PMID- 21682352 TI - The use of decision-analytic models in Parkinson's disease: a systematic review and critical appraisal. AB - The aims of this review were to review decision-analytic models used to evaluate interventions in idiopathic Parkinson's disease (PD), and to consider the future directions for development of methods to model the progression of PD over time. A systematic search of the healthcare literature up to June 2010 identified model based economic evaluations in PD. The modelling methods used in the identified studies were appraised using good practice guidelines for decision-analytic modelling. The review identified 18 model-based evaluations of interventions in PD. All models evaluated treatments targeted towards the motor symptoms of PD or the motor complications of PD treatment. There were no models identified that evaluated interventions targeted towards the non-motor symptoms of PD, such as neuropsychiatric problems or autonomic dysfunction. Consequently, models characterized disease progression in PD using clinical measures of motor functioning. Most studies (n = 13) evaluated medications, three evaluated diagnostic technologies and two examined surgical procedures. Overall, the models reported structural components and data inputs appropriately and clearly, although limited evidence was provided to support choices made on the structures used in the models or the data synthesis reported. Models did not adequately consider structural uncertainty or internal/external consistency. Modelling methods used to date do not capture the full impact of PD. The emphasis in the current literature is on the motor symptoms of PD, characterizing the clinical nature of disease progression, largely neglecting the important impacts of non motor symptoms. Modelling methods reported for the motor symptoms of PD may not be suitable for future interventions targeted towards modifying disease progression in PD across the entire spectrum of PD. More comprehensive models of disease progression, including both motor and non-motor symptoms will be needed where it is important to capture the effects of interventions more broadly. PMID- 21682353 TI - Cost effectiveness of secondary vs tertiary prevention for post-menopausal osteoporosis. AB - BACKGROUND: The aging of the population is likely to increase the number of osteoporosis-related fractures, such as hip fractures, and hence the economic burden for society. Therefore, strategies to identify women at increased risk are of major interest. OBJECTIVE: The aim of this study was to determine the cost effectiveness of preventive services for osteoporosis, comparing secondary plus tertiary prevention (SP/TP) versus tertiary prevention (TP) alone in post menopausal women in Germany. METHODS: A cost-utility analysis and a budget-impact analysis were performed from the perspective of the German statutory health insurance (SHI). A Markov model simulated costs and benefits discounted at 3% over a lifetime horizon. RESULTS: Cost effectiveness of TP compared with no screening was 669 Euros, 477 Euros and 385 Euros per QALY for women aged 60, 70 and 80 years, respectively (year 2010 values). In women aged 50 years, TP dominated no prevention. Cost effectiveness of SP/TP compared with TP was 4543 Euros, 19791 Euros, 8670 Euros and 3368 Euros for women aged 50, 60, 70 and 80 years, respectively. SP/TP resulted in additional costs of 109 million Euros or 0.10% of the SHI's annual budget (TP alone = 8 million Euros). CONCLUSION: Compared with TP, a strategy based on SP/TP appears to be more expensive but more effective in each age group. Given that cost effectiveness seems acceptable, allocation of resources to SP/TP to decrease post-menopausal osteoporotic fracture risk may be justified. PMID- 21682354 TI - Drugs for rare diseases: influence of orphan designation status on price. AB - The literature indicates that the expenditure on orphan drugs will be increasing over the coming years. The market for orphan drugs has inherent market characteristics that sometimes result in high prices. The aim of this study was to analyse whether awarding orphan designation status has an influence on the price setting of drugs for rare disease indications. To this effect, prices of designated orphan drugs were compared with other non-designated drugs for rare disease indications. We identified 28 designated orphan drugs and 16 comparable non-designated drugs for rare disease indications for which we collected official hospital prices (per defined daily dose) in Belgium in 2010. Orphan-designated drugs had a higher median price (138.56 Euros [interquartile range; IQR 406.57 Euros]) than non-designated drugs (16.55 Euros [IQR 28.05 Euros]) for rare disease indications (p < 0.01). In conclusion, our results suggest that awarding orphan designation status in itself is associated with higher prices for drugs for rare disease indications. In order to gain full insight into orphan drug pricing mechanisms, future research should focus on collecting information about the different factors influencing orphan drug pricing. PMID- 21682355 TI - Rupture of anterior cruciate ligament monitored by acoustic emission. AB - The scope of this study is to relate the acoustic emission (AE) during rupture of human soft tissue (anterior cruciate ligament, ACL) to the mechanisms leading to its failure. The cumulative AE activity highlights the onset of serious damage, while other parameters, show repeatable tendencies, being well correlated with the tissue's mechanical behavior. The frequency content of AE signals increases throughout the experiment, while other indices characterize between different modes of failure. Results of this preliminary study show that AE can shed light into the failure process of this tissue, and provide useful data on the ACL reconstruction. PMID- 21682356 TI - Engaging concert hall acoustics is made up of temporal envelope preserving reflections. AB - Strong, exciting, and engaging sound is perceived in the best concert halls. Here, it is shown that wideband early reflections that preserve the temporal envelope of sound contribute to the clear and open acoustics with strong bass. Such reflections are fused with the direct sound due to the precedence effect. In contrast, reflections that distort the temporal envelope render the sound weak and muddy because they partially break down the precedence. The presented findings are based on the earlier psychoacoustics research, and confirmed by a perceptual evaluation with six simulated concert halls that have same monaural room acoustical parameter values according to ISO3382-1. PMID- 21682357 TI - A statistical model of horizontal auditory localization performance data. AB - Horizontal localization experiments are used to evaluate the listener's ability to locate the position of a sound source, and determine how signal characteristics affect this ability. These experiments generate circular, bimodal, and repeated data that are challenging to statistically analyze. A two part mixture of wrapped Cauchys is proposed for these data, with the effects of signal type and position on localization bias, precision, and front-back confusion modeled using regression. The model is illustrated using mid- (1.0-2.0 kHz) and high- (3.0-6.0 kHz) frequency narrow band noises localization collected among ten normal hearing listeners. PMID- 21682358 TI - A particle filtering approach for spatial arrival time tracking in ocean acoustics. AB - The focus of this work is on arrival time and amplitude estimation from acoustic signals recorded at spatially separated hydrophones in the ocean. A particle filtering approach is developed that treats arrival times as "targets" and tracks their "location" across receivers, also modeling arrival time gradient. The method is evaluated via Monte Carlo simulations and is compared to a maximum likelihood estimator, which does not relate arrivals at neighboring receivers. The comparison demonstrates a significant advantage in using the particle filter. It is also shown that posterior probability density functions of times and amplitudes become readily available with particle filtering. PMID- 21682359 TI - Effects of speaking style on speech intelligibility for Mandarin-speaking cochlear implant users. AB - Cochlear implant (CI) users' speech understanding may be influenced by different speaking styles. In this study, speech recognition was measured in Mandarin speaking CI and normal-hearing (NH) subjects for sentences produced according to four styles: slow, normal, fast, and whispered. CI subjects were tested using their clinical processors; NH subjects were tested while listening to a four channel CI simulation. Performance gradually worsened with increasing speaking rate and was much poorer with whispered speech. CI performance was generally similar to NH performance with the four-channel simulation. Results suggest that some speaking styles, especially whispering, may negatively affect Mandarin speaking CI users' speech understanding. PMID- 21682360 TI - Limits of coherence-based aeroacoustic analysis in the presence of distributed sources. AB - Coherence-based analysis techniques utilizing a small number of microphones are often applied in aeroacoustic measurements. These techniques can remove statistically incoherent noise, electronic or hydrodynamic, from acoustic signals measured by microphones, at significantly lower cost than array methods. However, the assumptions involved in the usage of the ordinary coherence function technically limit analysis to a single-source field. In the presence of multiple sources the coherence function breaks down and ordinary analysis techniques under predict true acoustic levels. This phenomenon is demonstrated mathematically and illustrated using experimental trailing edge noise data. PMID- 21682361 TI - Eddy-current non-inertial displacement sensing for underwater infrasound measurements. AB - A non-inertial sensing approach for an Acoustic Vector Sensor (AVS), which utilizes eddy-current displacement sensors and operates well at Ultra-Low Frequencies (ULF), is described here. In the past, most ULF measurements (from mHertz to approximately 10 Hertz) have been conducted using heavy geophones or seismometers that must be installed on the seafloor; these sensors are not suitable for water column measurements. Currently, there are no readily available compact and affordable underwater AVS that operate within this frequency region. Test results have confirmed the validity of the proposed eddy-current AVS design and have demonstrated high acoustic sensitivity. PMID- 21682362 TI - Focused sound from three-dimensional sound propagation effects over a submarine canyon. AB - Ship noise data reveal an intensification of the near-surface sound field over a submarine canyon. Numerical modeling of sound propagation is used to study the effect. The noise data were collected during an ocean acoustic and physical oceanography experiment northeast of Taiwan in 2009. In situ measurements of water sound-speed profiles and a database of high-resolution bathymetry are used in the modeling study. The model results suggest that the intensification is caused by three-dimensional sound focusing by the concave canyon seafloor. Uncertainties in the model results from unsampled aspects of the environment are discussed. PMID- 21682363 TI - Development and validation of the Mandarin speech perception test. AB - Currently there are few standardized speech testing materials for Mandarin speaking cochlear implant (CI) listeners. In this study, Mandarin speech perception (MSP) sentence test materials were developed and validated in normal hearing subjects listening to acoustic simulations of CI processing. Percent distribution of vowels, consonants, and tones within each MSP sentence list was similar to that observed across commonly used Chinese characters. There was no significant difference in sentence recognition across sentence lists. Given the phonetic balancing within lists and the validation with spectrally degraded speech, the present MSP test materials may be useful for assessing speech performance of Mandarin-speaking CI listeners. PMID- 21682364 TI - Experimental validation of the sound transmission of rectangular baffled plates with general elastic boundary conditions. AB - Several prediction methods have recently been developed for systematically studying the effects of general boundary conditions on the sound transmission loss (STL) of plate-like structures. But corresponding experimental validation studies remain scarce owing to the difficulty of obtaining accurate boundary conditions for practical structures. This paper presents a convincing experiment conducted on a baffled plate system to validate the STL prediction model in a previous paper by Yu et al. [Noise Control Eng. J. 58(2), 187-200, 2010]. A method is proposed to determine the boundary conditions of this system, and experimental STL compares well with the predictions based on the identified boundary condition. PMID- 21682365 TI - Evaluation of similarity effects in informational masking. AB - The degree of similarity between signal and masker in informational masking paradigms has been hypothesized to contribute to informational masking. The present study attempted to quantify "similarity" using a discrimination task. Listeners discriminated various signal stimuli from a multitone complex and then detected the presence of those signals embedded in a multitone informational masker. Discriminability negatively correlated with detection threshold in an informational masking experiment, indicating that similarity between signal and the masker quality contributed to informational masking. These results suggest a method for specifying relevant signal attributes in informational masking paradigms involving similarity manipulations. PMID- 21682366 TI - The design of a harmonic percussion ensemble (L). AB - The primary oscillators of tuned percussion instruments are rigid structures that exhibit bending waves. Bending waves do not naturally occur at harmonically related frequencies, which may lead to uncertainty associated with the intended pitch of the instrument. Despite millennia of development across many cultures, tuned percussion instruments rarely exhibit harmonic tuning of the first three or more partials. This letter presents three percussion instruments that have three or more harmonically tuned partials, and provides an overview of the methods used to tune the partials and manufacture the instruments at relatively low production costs. These instruments form the basis of new percussion instrument ensembles for educational, recreational, and professional use. PMID- 21682368 TI - On the acoustic-radiation-induced strain and stress in elastic solids with quadratic nonlinearity (L). AB - This letter demonstrates that an eigenstrain is induced when a wave propagates through an elastic solid with quadratic nonlinearity. It is shown that this eigenstrain is intrinsic to the material, but the mean stress and the total mean strain are not. Instead, the mean stress and total means strain also depend on the boundary conditions, so care must be taken when using the static deformation to measure the acoustic nonlinearity parameter of a solid. PMID- 21682367 TI - Masked auditory thresholds in three species of birds, as measured by the auditory brainstem response (L). AB - Auditory brainstem responses (ABRs) were recorded in adult budgerigars, canaries, and zebra finches in quiet and in three levels of white noise for tone stimuli between 1 and 4 kHz. Similar to behavioral results, masked ABR thresholds increased linearly with increasing noise levels. When the three species are considered together, ABR-derived CRs were higher than behavioral CRs by 18-23 dB between 2 and 4 kHz and by about 30 dB at 1 kHz. This study clarifies the utility of using ABRs for estimating masked auditory thresholds in natural environmental noises in species that cannot be tested behaviorally. PMID- 21682369 TI - Forward scatter target strength extraction in a marine environment (L). AB - A 48 m rail with a moving receiver was used to measure forward scattering from a spherical shell lying on the bottom in the Gulf of Mexico. The target was mid-way between the source and rail, on a line from the source bisecting the rail. The major obstacle to the measurement of forward scattering is the much stronger source signal which overlaps the scattered signal in space and time. Here, forward scattered target strength is obtained by processing the received signals using a wavenumber filter to remove the incident wave. The result compares favorably to that obtained from numerical predictions. PMID- 21682370 TI - Bimodal listeners are not sensitive to interaural time differences in unmodulated low-frequency stimuli (L). AB - Sensitivity to interaural time differences (ITDs) with unmodulated low-frequency stimuli was assessed in bimodal listeners who had previously shown to be good performers in ITD experiments. Two types of stimuli were used: (1) an acoustic sinusoid combined with an electric transposed signal and (2) an acoustic sinusoid combined with an electric clicktrain. No or very low sensitivity to ITD was found for these stimuli, even though subjects were highly trained on the task and were intensively tested in multiple test sessions. In previous studies with users of a cochlear implant (CI) and a contralateral hearing aid (HA) (bimodal listeners), sensitivity was shown to ITD with modulated stimuli with frequency content between 600 and 3600 Hz. The outcomes of the current study imply that in speech processing design for users of a CI in combination with a HA on the contralateral side, the emphasis should be more on providing salient envelope ITD cues than on preserving fine-timing ITD cues present in acoustic signals. PMID- 21682371 TI - Near field acoustic holography with microphones on a rigid sphere (L). AB - Spherical near field acoustic holography (spherical NAH) is a technique that makes it possible to reconstruct the sound field inside and just outside a spherical surface on which the sound pressure is measured with an array of microphones. This is potentially very useful for source identification. The sphere can be acoustically transparent or it can be rigid. A rigid sphere is somewhat more practical than an open sphere. However, spherical NAH based on a rigid sphere is only valid if it can be assumed that the sphere has a negligible influence on the incident sound field, and this is not necessarily a good assumption when the sphere is very close to a radiating surface. This Letter examines the matter through simulations and experiments. PMID- 21682372 TI - Axisymmetric scattering of scalar waves by spheroids. AB - A phase shift formulation of scattering by oblate and prolate spheroids is presented, in parallel with the partial-wave theory of scattering by spherical obstacles. The crucial step is application of a finite Legendre transform to the Helmholtz equation in spheroidal coordinates. In the long-wavelength limit the spheroidal analog of the spherical scattering length immediately gives the cross section. Analytical results are readily obtained for scattering of Schrodinger particle waves by impenetrable spheroids, and for scattering of sound waves by acoustically soft spheroidal objects. The method is restricted to scattering by spheroids whose symmetry axis is coincident with the direction of the incident plane wave. PMID- 21682373 TI - An efficient method for computing backscattering from Born objects of arbitrary shape. AB - A method is presented for efficiently computing the propagating pressure field backscattered by an arbitrarily shaped, weakly scattering, three-dimensional object. This is accomplished by drawing upon a previously reported relationship between the boundary condition on a two-dimensional radiating aperture and the pressure propagating along an axis normal to the aperture, and the fundamental theorem of diffraction tomography, which relates the Fourier transform of an object function to its scattered pressure field. Together, these two results are used to derive an integral formula that expresses the pressure field backscattered from an object as a one-dimensional Fourier transform of its scattering amplitude. This formula is then utilized to compute the backscattered pressure field from a uniform fluid sphere in the first Born approximation; the results of which are compared to the rigorous partial wave expansion. PMID- 21682374 TI - Point mobility of a cylindrical plate incorporating a tapered hole of power-law profile. AB - The paper describes the results of experimental measurements of point mobility carried out on circular plates containing tapered holes of quadratic power-law profile with attached damping layers. The obtained results are compared to the developed numerical model, as a means of validation. The profiles of the tapered hole in the plates are designed to replicate near zero reflection of quasi-plane waves from a tapered hole in geometrical acoustics approximation, also known as acoustic black hole effect. The driving point mobility measurements are provided, showing a comparison of the results for a constant thickness circular plate, a constant thickness plate with a layer of damping film applied and a plate with a quadratic power-law profile machined into the center, which is tested with a thin layer of elastic damping material attached. The results indicate a substantial suppression of resonant peaks, agreeing with a numerical model, which is based on the analytical solution available for the vibration of a plate with a central quadratic power-law profile. The paper contains results for the case of free boundary conditions on all edges of the plates, with emphasis placed on the predictions of resonant frequencies and the amplitudes of vibration and loss factor. PMID- 21682375 TI - Two regimes of the parametrically self-exciting ultrasonic standing waves. AB - This paper discusses a nonlinear multi-wave mechanism for the parametrically self exciting standing waves in a plane-parallel liquid layer driven at one end of the layer. The dependence of this process on the number of parametrically self exciting waves and the frequency detuning between the frequency "f" of the pump wave and the nearest natural frequency are analyzed. It is found that two regimes with different thresholds are possible. One of them is characterized by self exciting subharmonic frequencies close to f/2 and the second has a much lower threshold and the presence of a self-exciting subharmonic at a frequency near to the smallest natural frequency. Three dimensionless parameters determining each regime are introduced. PMID- 21682376 TI - Theoretical and numerical calculations for the time-averaged acoustic force and torque acting on a rigid cylinder of arbitrary size in a low viscosity fluid. AB - In this paper, theoretical calculations as well as numerical simulations are performed for the time-averaged acoustic force and torque on a rigid cylinder of arbitrary size in a fluid with low viscosity, i.e., the acoustic boundary layer is thin compared to the cylinder radius. An exact analytical solution and its approximation are proposed in the form of an infinite series including Bessel functions. These solutions can be evaluated easily by a mathematical software package such as mathematica and matlab. Three types of incident waves, plane traveling wave, plane standing wave, and dual orthogonal standing waves, are investigated in detail. It is found that for a small particle, the viscous effects for an incident standing wave may be neglected but those for an incident traveling wave are notable. A nonzero viscous torque is experienced by the rigid cylinder when subjected to dual orthogonal standing waves with a phase shift even when the cylinder is located at equilibrium positions without imposed acoustic forces. Furthermore, numerical simulations are carried out based on the FVM algorithm to verify the proposed theoretical formulas. The theoretical results and the numerical ones agree with each other very well in all the cases considered. PMID- 21682377 TI - Closed form solutions for the acoustical impulse response over a masslike or an absorbing plane. AB - The transient sound field caused by a Dirac delta impulse function above an infinite locally reacting plane can be calculated by applying the inverse Fourier transform of the corresponding half-space Green's function in frequency domain. As a starting point, the representation given by Ochmann [J. Acoust. Soc. Am. 116(6), 3304-3311 (2004)] is used, which consists of discrete and continuous superposition of point sources. For a locally reacting plane with masslike character and also with pure absorbing behavior, it is possible to express the resulting impulse response in closed form. Such a result is surprising, because corresponding formulations in the frequency domain are not available yet. Hence, the first main result is the closed form solution Eq. (22) for an impulse response over an infinite plane with a pure imaginary impedance. The second main result is the closed form solution Eq. (53) for an impulse response over an infinite plane with a pure real impedance. As a particular application of both main results, a convolution technique is used for deriving formulas for point sources with a general time dependency. For special signals like an exponentially decaying time signal or a triangular shaped impulse, the resulting sound field can be presented in terms of elementary functions. PMID- 21682378 TI - Comparison of methods for calculating the sound field due to a rotating monopole. AB - A spherical harmonic expansion for the sound field due to a rotating oscillating point source has recently been derived. This paper provides further confirmation of the expansion results by comparing it with two known numerical approaches to determining the sound field. In the advanced time approach-applicable for Mach numbers below 1-the sound at transmission time determines the field at an observation point from the distance from source to observation point at the transmission time. In the retarded time approach the field at the observation point at the observation time is determined by solving for the retarded transmission times. The results from all three approaches are shown to be in good agreement. Expressions for the far-field instantaneous frequency are also derived and shown to agree with previous work. PMID- 21682379 TI - Comparison of sound power radiation from isolated airfoils and cascades in a turbulent flow. AB - An analytical model of the sound power radiated from a flat plate airfoil of infinite span in a 2D turbulent flow is presented. The effects of stagger angle on the radiated sound power are included so that the sound power radiated upstream and downstream relative to the fan axis can be predicted. Closed-form asymptotic expressions, valid at low and high frequencies, are provided for the upstream, downstream, and total sound power. A study of the effects of chord length on the total sound power at all reduced frequencies is presented. Excellent agreement for frequencies above a critical frequency is shown between the fast analytical isolated airfoil model presented in this paper and an existing, computationally demanding, cascade model, in which the unsteady loading of the cascade is computed numerically. Reasonable agreement is also observed at low frequencies for low solidity cascade configurations. PMID- 21682380 TI - Shear and compressional wave speeds in Hertzian granular media. AB - It is shown that the shear wave speed in a granular medium is less than that in an elastic solid of the same shear modulus-to-density ratio. Shear and compressional wave speeds are derived for granular media using a conservation of energy approach. The grains are assumed to be spherical with elastic Hertzian contacts of constant stiffness. The affine approximation is used to determine the relative displacements of grain centers, and it is also assumed that the grains are small compared to a wavelength, consistent with the effective medium approximation. Potential and kinetic energies associated with linear motion are the same as those in an elastic solid, but it is found that shear wave propagation in a granular medium involves additional energies associated with grain rotation. The partition of energies results in a reduction in the shear wave speed, relative to an elastic solid of the same shear modulus-to-density ratio. It is shown that the reduction is an inherent property of granular media, independent of any departure from the affine approximation or fluctuations in coordination number or contact stiffness. The predicted wave speed ratios are consistent with published measurements. PMID- 21682381 TI - Velocity dispersion and attenuation in granular marine sediments: comparison of measurements with predictions using acoustic models. AB - The large velocity dispersion recently reported could be explained by a gap stiffness model incorporated into the Biot model (the BIMGS model) proposed by the author. However, at high frequencies, some measured results have been reported for negative velocity dispersion and attenuation proportional to the first to fourth power of frequency. In this study, first, it is shown that the results of velocity dispersion and attenuation calculated using the BIMGS model are consistent with the results measured in two kinds of water-saturated sands with different grain sizes, except in the high-frequency range. Then, the velocity dispersion and attenuation in six kinds of water-saturated glass beads and four kinds of water-saturated silica sands with different grain sizes are measured in the frequency ranges of 80-140 and 300-700 kHz. The measured results are compared with those calculated using the BIMGS model plus some acoustic models. It is shown that the velocity dispersion and attenuation are well predicted by using the BIMGS model in the range of kd <= 0.5 (k: wavenumber in water, d: grain diameter) and by using the BIMGS model plus multiple scattering effects in the range of kd >= 0.5 in which negative velocity dispersion appears. PMID- 21682382 TI - On the two-point cross-correlation function of anisotropic, spatially homogeneous ambient noise in the ocean and its relationship to the Green's function. AB - It is well established that the free-space Green's function can be recovered from the two-point cross-correlation function of a random noise field if the noise is white and isotropic. Ambient noise in the ocean rarely satisfies either of these conditions. However, a non-uniform spectrum could be pre-whitened by the application of a suitable filter but anisotropy cannot be so readily eliminated. To investigate the effects of vertical anisotropy, three azimuthally uniform, spatially homogeneous noise fields are analyzed, two of which are idealized, while the third is representative of ambient noise in the deep ocean. In each case, the coherence function, the cross-correlation function, and the derivative of the latter with respect to the correlation delay, are derived for vertical and horizontal alignments of the sensor pair. With vertical sensors, any step function discontinuity in the directional density function is mapped into a delta function at an appropriate time delay in the derivative (with respect to time delay) of the cross-correlation function. No such mapping occurs with horizontal sensors. In this case, only horizontally traveling noise can generate delta functions in the derivative of the cross-correlation function, and these always appear at the retarded time on either side of the origin. PMID- 21682383 TI - Bayesian multiple-source localization in an uncertain ocean environment. AB - This paper considers simultaneous localization of multiple acoustic sources when properties of the ocean environment (water column and seabed) are poorly known. A Bayesian formulation is developed in which the environmental parameters, noise statistics, and locations and complex strengths (amplitudes and phases) of multiple sources are considered to be unknown random variables constrained by acoustic data and prior information. Two approaches are considered for estimating source parameters. Focalization maximizes the posterior probability density (PPD) over all parameters using adaptive hybrid optimization. Marginalization integrates the PPD using efficient Markov-chain Monte Carlo methods to produce joint marginal probability distributions for source ranges and depths, from which source locations are obtained. This approach also provides quantitative uncertainty analysis for all parameters, which can aid in understanding of the inverse problem and may be of practical interest (e.g., source-strength probability distributions). In both approaches, closed-form maximum-likelihood expressions for source strengths and noise variance at each frequency allow these parameters to be sampled implicitly, substantially reducing the dimensionality and difficulty of the inversion. Examples are presented of both approaches applied to single- and multi-frequency localization of multiple sources in an uncertain shallow-water environment, and a Monte Carlo performance evaluation study is carried out. PMID- 21682384 TI - Temporal coherence of acoustic signals in a fluctuating ocean. AB - Temporal coherence of acoustic signals propagating in a fluctuating ocean is important for many practical applications and has been studied intensively experimentally. However, only a few theoretical formulations of temporal coherence exist. In the present paper, a three-dimensional (3D) modal theory of sound propagation in a fluctuating ocean is used to derive closed-form equations for the spatial-temporal coherence function of a broadband signal. The theory is applied to the analysis of the temporal coherence of a monochromatic signal propagating in an ocean perturbed by linear internal waves obeying the Garrett Munk (G-M) spectral model. In particular, the temporal coherence function is calculated for propagation ranges up to 10(4) km and for five sound frequencies: 12, 25, 50, 75, and 100 Hz. Then, the dependence of the coherence time (i.e., the value of the time lag at which the temporal coherence decreases by a factor of e) on range and frequency is studied. The results obtained are compared with experimental data and predictions of the path-integral theory. PMID- 21682385 TI - Separation of sperm whale click-trains for multipath rejection. AB - In this paper an algorithm is described for grouping sperm whale clicks received at a single hydrophone into click-trains associated with a given whale and propagation path. To accomplish this, features are extracted from pairs of clicks in order to derive a statistical measure of click similarity. Then, the algorithm maximizes a global measure of similarity between the associated clicks. In addition to grouping clicks according to click-trains, it classifies click-trains into a propagation path (direct, surface, bottom reverberation). The propagation path is identified using a combination of (1) a statistical classifier operating on features extracted from individual clicks and (2) the cross-correlation of click-trains to identify the relative time delays. The algorithm is demonstrated on at-sea recorded data, showing the elimination of time-delay ambiguities associated with the reverberation paths observed at sensor pairs. PMID- 21682386 TI - Cetacean population density estimation from single fixed sensors using passive acoustics. AB - Passive acoustic methods are increasingly being used to estimate animal population density. Most density estimation methods are based on estimates of the probability of detecting calls as functions of distance. Typically these are obtained using receivers capable of localizing calls or from studies of tagged animals. However, both approaches are expensive to implement. The approach described here uses a MonteCarlo model to estimate the probability of detecting calls from single sensors. The passive sonar equation is used to predict signal to-noise ratios (SNRs) of received clicks, which are then combined with a detector characterization that predicts probability of detection as a function of SNR. Input distributions for source level, beam pattern, and whale depth are obtained from the literature. Acoustic propagation modeling is used to estimate transmission loss. Other inputs for density estimation are call rate, obtained from the literature, and false positive rate, obtained from manual analysis of a data sample. The method is applied to estimate density of Blainville's beaked whales over a 6-day period around a single hydrophone located in the Tongue of the Ocean, Bahamas. Results are consistent with those from previous analyses, which use additional tag data. PMID- 21682387 TI - Callback response of dugongs to conspecific chirp playbacks. AB - Dugongs (Dugong dugon) produce bird-like calls such as chirps and trills. The vocal responses of dugongs to playbacks of several acoustic stimuli were investigated. Animals were exposed to four different playback stimuli: a recorded chirp from a wild dugong, a synthesized down-sweep sound, a synthesized constant frequency sound, and silence. Wild dugongs vocalized more frequently after playback of broadcast chirps than that after constant-frequency sounds or silence. The down-sweep sound also elicited more vocal responses than did silence. No significant difference was found between the broadcast chirps and the down-sweep sound. The ratio of wild dugong chirps to all calls and the dominant frequencies of the wild dugong calls were significantly higher during playbacks of broadcast chirps, down-sweep sounds, and constant-frequency sounds than during those of silence. The source level and duration of dugong chirps increased significantly as signaling distance increased. No significant correlation was found between signaling distance and the source level of trills. These results show that dugongs vocalize to playbacks of frequency-modulated signals and suggest that the source level of dugong chirps may be manipulated to compensate for transmission loss between the source and receiver. This study provides the first behavioral observations revealing the function of dugong chirps. PMID- 21682388 TI - A spiral wave front beacon for underwater navigation: basic concept and modeling. AB - A spiral wave front source produces an acoustic field that has a phase that is proportional to the azimuthal angle about the source. The concept of a spiral wave front beacon is developed by combining this source with a reference source that has a phase that is constant with the angle. The phase difference between these sources contains information about the receiver's azimuthal angle relative to the beacon and can be used for underwater navigation. To produce the spiral wave front, two sources are considered: a "physical-spiral" source, which produces the appropriate phase by physically deforming the active element of the source into a spiral, and a "phased-spiral" source, which uses an array of active elements, each driven with the appropriate phase, to produce the spiral wave front. Using finite element techniques, the fields produced by these sources are examined in the context of the spiral wave front beacon, and the advantages of each source are discussed. PMID- 21682389 TI - Probing waveforms and adaptive receivers for active sonar. AB - Active sonar systems involve the transmission and reception of one or more probing sequences, which provide a basis for extraction of target information in a region of interest. The probing sequences at the transmitter and signal processing at the receiver play crucial roles in the overall system performance. In this paper, CAN (cyclic algorithm-new) is employed to synthesize probing sequences with good aperiodic autocorrelation properties. The performance of the CAN sequences will be compared with those of pseudo random noise and random phase sequences. Two adaptive receiver designs, namely the iterative adaptive approach (IAA) and the sparse learning via iterative minimization (SLIM) method, will also be considered. IAA and SLIM will be compared with the conventional matched filter method. The performances of the algorithms will be illustrated via numerical examples, which show that CAN, IAA, and SLIM can contribute to the overall performance improvement of the active sonar systems. PMID- 21682390 TI - A k-space Green's function solution for acoustic initial value problems in homogeneous media with power law absorption. AB - An efficient Green's function solution for acoustic initial value problems in homogeneous media with power law absorption is derived. The solution is based on the homogeneous wave equation for lossless media with two additional terms. These terms are dependent on the fractional Laplacian and separately account for power law absorption and dispersion. Given initial conditions for the pressure and its temporal derivative, the solution allows the pressure field for any time t>0 to be calculated in a single step using the Fourier transform and an exact k-space time propagator. For regularly spaced Cartesian grids, the former can be computed efficiently using the fast Fourier transform. Because no time stepping is required, the solution facilitates the efficient computation of the pressure field in one, two, or three dimensions without stability constraints. Several computational aspects of the solution are discussed, including the effect of using a truncated Fourier series to represent discrete initial conditions, the use of smoothing, and the properties of the encapsulated absorption and dispersion. PMID- 21682391 TI - Scattering of obliquely incident shear waves from a cylindrical cavity. AB - Prior work has proposed the use of ultrasonic angle-beam shear wave techniques to detect cracks of varying angular location around fastener sites by generating and detecting creeping waves. To better understand the nature of the scattering problem and quantify the role of creeping waves in fastener site inspections, a 3D analytical model was developed for the propagation and scattering of an obliquely incident plane shear wave from a cylindrical cavity with arbitrary shear wave polarization. The generation and decay of the spiral creeping waves was found to be dependent on both the angle of incidence and polarization of the plane shear wave. A difference between the angle of displacement in 3D and the direction of propagation for the spiral creeping wave was observed and attributed to differences in the curvature of the cavity surface for the tangential and vertical (z) directions. Using the model, practical insight was presented on measuring the displacement response in the far-field from the hole. Both analytical and experimental results highlighted the value of the diffracted and leaky spiral creeping wave signals for nondestructive evaluation of a crack located on the cavity. Last, array and signal processing methods are discussed to improve the resolution of the weaker creeping wave signals in the presence of noise. PMID- 21682392 TI - Characterization of a fiber-optic displacement sensor for measurements in high intensity focused ultrasound fields. AB - A fiber-optic sensor is presented that is capable of measuring the particle displacement in high-intensity focused ultrasound (HIFU) fields. For this probe, a secondary calibration was performed, and the resulting complex frequency response is discussed. As a first practical application, the setup was used to measure the pressure in the field of a weakly focusing ultrasound transducer. The result is compared with that of a membrane hydrophone measurement. The feasibility of measurements in HIFU fields is demonstrated by means of measurements of the spatial distribution of the peak particle velocity within the focus of a HIFU transducer and of the dependence of the peak values on the acoustical power level. PMID- 21682393 TI - Electret accelerometers: physics and dynamic characterization. AB - Electret microphones are produced in numbers that significantly exceed those for all other microphone types. This is due to the fact that air-borne electret sensors are of simple and low-cost design but have very good acoustical properties. In contrast, most of the discrete structure-borne sound sensors (or accelerometers) are based on the piezoelectric effect. In the present work, capacitive accelerometers utilizing the electret principle were constructed, built, and characterized. These electret accelerometers comprise a metallic seismic mass, covered by an electret film, a ring of a soft cellular polymer supplying the restoring force, and a metallic backplate. These components replace membrane, spacer, and back electrode, respectively, of the electret microphone. An adjustable static pressure to the seismic mass is generated by two metal springs. The dynamic characterization of the accelerometers was carried out by using an electrodynamic shaker and an external charge or voltage amplifier. Sensors with various seismic masses, air gap distances, and electret voltages were investigated. Charge sensitivities from 10 to 40 pC/g, voltage sensitivities from 600 to 2000 mV/g, and resonance frequencies from 3 to 1.5 kHz were measured. A model describing both the charge and the voltage sensitivity is presented. Good agreement of experimental and calculated values is found. The experimental results show that sensitive, lightweight, and inexpensive electret accelerometers can be built. PMID- 21682394 TI - Reflection and transmission of plane waves from a fluid-porous piezoelectric solid interface. AB - The reflection and transmission of plane waves from a fluid-porous piezoelectric solid interface is studied. The porous piezoelectric solid, having 6 mm symmetry, is supposed to be filled with viscous fluid. The expressions for amplitude ratios and energy ratios corresponding to reflected wave and transmitted waves are derived analytically. The Christoffel equation of a leaky wave propagating along the surface of a porous piezoelectric solid is derived. The effects of the angle of incidence, frequency, porosity, piezoelectric interaction, and anisotropy on the reflected and transmitted energy ratios are studied numerically for a particular model BaTiO(3). The porous piezoelectric solid half space is assumed to be loaded with water. The effects of porosity and frequency on the leaky wave velocity are also studied. PMID- 21682395 TI - Speech recognition in noise with active and passive hearing protectors: a comparative study. AB - The perceived negative influence of standard hearing protectors on communication is a common argument for not wearing them. Thus, "augmented" protectors have been developed to improve speech intelligibility. Nevertheless, their actual benefit remains a point of concern. In this paper, speech perception with active earplugs is compared to standard passive custom-made earplugs. The two types of active protectors included amplify the incoming sound with a fixed level or to a user selected fraction of the maximum safe level. For the latter type, minimal and maximal amplification are selected. To compare speech intelligibility, 20 different speech-in-noise fragments are presented to 60 normal-hearing subjects and speech recognition is scored. The background noise is selected from realistic industrial noise samples with different intensity, frequency, and temporal characteristics. Statistical analyses suggest that the protectors' performance strongly depends on the noise condition. The active protectors with minimal amplification outclass the others for the most difficult and the easiest situations, but they also limit binaural listening. In other conditions, the passive protectors clearly surpass their active counterparts. Subsequently, test fragments are analyzed acoustically to clarify the results. This provides useful information for developing prototypes, but also indicates that tests with human subjects remain essential. PMID- 21682396 TI - A field study of effects of road traffic and railway noise on polysomnographic sleep parameters. AB - The aim of this study was to explore and compare the effect of noise from railway and road traffic on sleep in subjects habitually exposed to nocturnal noise. Forty young and middle aged healthy subjects were studied with polysomnography (PSG) during two consecutive nights in their own bedroom. Noise measurements and recordings were conducted concurrently outside of the bedroom facade as well as inside the bedroom of each participant. Different noise exposure parameters were calculated (L(p,A,eq,night), L(p,A,Fmax,night), and L(AF5,night)) and analyzed in relation to whole-night sleep parameters. The group exposed to railway noise had significantly less Rapid eye movement, (REM) sleep than the group exposed to road traffic noise. A significant association was found between the maximum level (L(p,A,Fmax,night)) of railway noise and time spent in REM sleep. REM sleep was significantly shorter in the group exposed to at least a single railway noise event above 50 dB inside the bedroom. These results, obtained in an ecological valid setting, support previous laboratory findings that railway noise has a stronger impact than road traffic noise on physiological parameters during sleep, and that the maximum noise level is an important predictor of noise effects on sleep assessed by PSG, at least for railway noise. PMID- 21682397 TI - Low-frequency noise from large wind turbines. AB - As wind turbines get larger, worries have emerged that the turbine noise would move down in frequency and that the low-frequency noise would cause annoyance for the neighbors. The noise emission from 48 wind turbines with nominal electric power up to 3.6 MW is analyzed and discussed. The relative amount of low frequency noise is higher for large turbines (2.3-3.6 MW) than for small turbines (<= 2 MW), and the difference is statistically significant. The difference can also be expressed as a downward shift of the spectrum of approximately one-third of an octave. A further shift of similar size is suggested for future turbines in the 10-MW range. Due to the air absorption, the higher low-frequency content becomes even more pronounced, when sound pressure levels in relevant neighbor distances are considered. Even when A-weighted levels are considered, a substantial part of the noise is at low frequencies, and for several of the investigated large turbines, the one-third-octave band with the highest level is at or below 250 Hz. It is thus beyond any doubt that the low-frequency part of the spectrum plays an important role in the noise at the neighbors. PMID- 21682398 TI - Calibration of pressure-velocity probes using a progressive plane wave reference field and comparison with nominal calibration filters. AB - A procedure for calibrating pressure-velocity (p-v) sound intensity probes using a progressive plane wave as reference field is presented here. The procedure has been checked for a microelectromechanical system technology-based Microflown((r)) match-size probe by comparing the calibration results with the nominal correction curves available from the manufacturer. The reference field was generated along a wave guide by means of a dual cone loudspeaker supplying acoustic energy in the range 20 Hz-20 kHz through an impedance adaptor. Different from the current in field procedures, the one proposed here allows the calibration of probes under test to be executed at once up to 10 kHz without any change in the experimental setup. After a detailed review of the general principles of calibration, the procedure has been finalized with three main stages: (a) determination of the full coherence calibration bandwidth of the probe, (b) comparison calibration of the probe built-in pressure microphone over the full coherence frequency range, and (c) relative calibration of the velocity sensor over the calibrated pressure one. Calibration results for the probe under test have been best fitted against the calibration filters modeled by the manufacturer and the direct comparison of the obtained data with the factory ones has been reported. PMID- 21682399 TI - Improved signal processing to detect cancer by ultrasonic molecular imaging of targeted nanoparticles. AB - In several investigations of molecular imaging of angiogenic neovasculature using a targeted contrast agent, Renyi entropy [I(f)(r)] and a limiting form of Renyi entropy (I(f,infinity)) exhibited significantly more sensitivity to subtle changes in scattering architecture than energy-based methods. Many of these studies required the fitting of a cubic spline to backscattered waveforms prior to calculation of entropy [either I(f)(r) or I(f,infinity)]. In this study, it is shown that the robustness of I(f,infinity) may be improved by using a smoothing spline. Results are presented showing the impact of different smoothing parameters. In addition, if smoothing is preceded by low-pass filtering of the waveforms, further improvements may be obtained. PMID- 21682400 TI - Extraction of small boat harmonic signatures from passive sonar. AB - This paper investigates the extraction of acoustic signatures from small boats using a passive sonar system. Noise radiated from a small boats consists of broadband noise and harmonically related tones that correspond to engine and propeller specifications. A signal processing method to automatically extract the harmonic structure of noise radiated from small boats is developed. The Harmonic Extraction and Analysis Tool (HEAT) estimates the instantaneous fundamental frequency of the harmonic tones, refines the fundamental frequency estimate using a Kalman filter, and automatically extracts the amplitudes of the harmonic tonals to generate a harmonic signature for the boat. Results are presented that show the HEAT algorithms ability to extract these signatures. PMID- 21682401 TI - Regularization for improving the deconvolution in real-time near-field acoustic holography. AB - Near-field acoustic holography is a measuring process for locating and characterizing stationary sound sources from measurements made by a microphone array in the near-field of the acoustic source plane. A technique called real time near-field acoustic holography (RT-NAH) has been introduced to extend this method in the case of nonstationary sources. This technique is based on a formulation which describes the propagation of time-dependent sound pressure signals on a forward plane using a convolution product with an impulse response in the time-wavenumber domain. Thus the backward propagation of the pressure field is obtained by deconvolution. Taking the evanescent waves into account in RT-NAH improves the spatial resolution of the solution but makes the deconvolution problem "ill-posed" and often yields inappropriate solutions. The purpose of this paper is to focus on solving this deconvolution problem. Two deconvolution methods are compared: one uses a singular value decomposition and a standard Tikhonov regularization and the other one is based on optimum Wiener filtering. A simulation involving monopoles driven by nonstationary signals demonstrates, by means of objective indicators, the accuracy of the time dependent reconstructed sound field. The results highlight the advantage of using regularization and particularly in the presence of measurement noise. PMID- 21682402 TI - Frequency shifts with age in click-evoked otoacoustic emissions of preterm infants. AB - A previous study [Brienesse et al. (1997). Pediatr. Res. 42, 478-483] demonstrated a positive shift with increasing postmenstrual age (PMA) in the frequencies of synchronized spontaneous otoacoustic emissions (SSOAEs) in preterm infants. We used a mixed model approach to describe a shift with PMA in the spectra of click-evoked otoacoustic emissions (CEOAEs) measured in a group of 22 preterm infants. The rate in shift in CEOAE spectral components was found to be frequency dependent, with a mean estimate of 10 Hz/week for frequencies around 2 kHz and 30 Hz/week for frequencies around 4.25 kHz. This rate decreased with increasing PMA. Because SSOAEs are often part of the CEOAE response, a comparison was made between the shifts in SSOAEs and CEOAEs in a sub-group of 16 preterm infants. The results indicate that the shifts found for both types of OAE are similar, which supports a common mechanism for this change in OAE-characteristic. At present it is not clear to what extent developmental processes in the cochlea and the middle ear can account for these frequency shifts in the spectra of CEOAEs and SSOAEs during the preterm period. PMID- 21682403 TI - Human cochlear tuning estimates from stimulus-frequency otoacoustic emissions. AB - Two objective measures of human cochlear tuning, using stimulus-frequency otoacoustic emissions (SFOAE), have been proposed. One measure used SFOAE phase gradient delay and the other two-tone suppression (2TS) tuning curves. Here, it is hypothesized that the two measures lead to different frequency functions in the same listener. Two experiments were conducted in ten young adult normal hearing listeners in three frequency bands (1-2 kHz, 3-4 kHz and 5-6 kHz). Experiment 1 recorded SFOAE latency as a function of stimulus frequency, and experiment 2 recorded 2TS iso-input tuning curves. In both cases, the output was converted into a sharpness-of-tuning factor based on the equivalent rectangular bandwidth. In both experiments, sharpness-of-tuning curves were shown to be frequency dependent, yielding sharper relative tuning with increasing frequency. Only a weak frequency dependence of the sharpness-of-tuning curves was observed for experiment 2, consistent with objective and behavioural estimates from the literature. Most importantly, the absolute difference between the two tuning estimates was very large and statistically significant. It is argued that the 2TS estimates of cochlear tuning likely represents the underlying properties of the suppression mechanism, and not necessarily cochlear tuning. Thus the phase gradient delay estimate is the most likely one to reflect cochlear tuning. PMID- 21682404 TI - Is it necessary to penalize impulsive noise +5 dB due to higher risk of hearing damage? AB - It is studied whether the +5 dB penalty for impulsiveness established by ISO 1999:1990 accounts for a higher risk of noise-induced hearing loss. A total of 16 normal-hearing human subjects were exposed for 10 min to two types of binaural industrial-recordings: (1) a continuous broad-band noise normalized to L(EX,8 h)=80 dBA and (2) the combination of the previous stimulus with an impulsive noise normalized to L(EX,8 h)=75+5(db penalty)=80 dBA (peak level 117 dBC and repetition rate of 0.5 impacts per second). Distortion product otoacoustic emissions (DPOAEs) were measured in a broad frequency range before and in the following 90 min after the exposure. The group results show that the continuous exposure had a bigger impact on DPOAE levels, with a maximum DPOAE shift of approximately 5 dB in the frequency range of 2-3.15 kHz during the first 10 min of the recovery. No evident DPOAE shift is seen for the impulsive + continuous stimulus. The results indicate that the penalty overestimated the effects on DPOAE levels and support the concept that the risk of hearing loss from low-level impulses may be predicted on an equal-energy basis. PMID- 21682405 TI - Effects of stimulation configurations on place pitch discrimination in cochlear implants. AB - The present study aimed to examine the effect of electrode configuration, specifically monopolar (MP) or bipolar (BP) stimulation, on place pitch discrimination in cochlear implants (CIs). Twelve subjects implanted with the Nucleus Freedom device were presented with various pairs of stimulation across the electrode array, with varying degrees of distance between stimulation sites, and asked to judge the higher of the two in pitch. Each pair was presented either in the same mode or in different modes of stimulation for the within-mode or across-mode condition, respectively, at least 20 times. The result of the within mode condition revealed that subjects, on average, were able to discriminate pitches significantly better in MP than in BP, with the sensitivity index (d') for adjacent channels of 1.2 for MP and 0.8 for BP. The result of the across-mode condition revealed that while individual variability existed, there was a strong tendency for CI subjects to perceive a higher pitch in BP stimulation than in MP for a similar site of stimulation. In other words, an MP channel needed to be shifted in a basal direction by as much as two electrodes on average to elicit a pitch comparable to that of a BP channel. PMID- 21682406 TI - The just audible tonality of short exponential and Gaussian pure tone bursts. AB - This paper reports on listening tests performed to investigate the just audible tonality (JAT) of decaying pure tone bursts. Both exponential and Gaussian functions are used to shape the envelopes of the tone bursts and critical band center frequencies between 150 and 7000 Hz are studied. Loudness compensation is implemented to compensate for the reduced loudness of short tone bursts and attack functions are used for minimizing clicks. By using the method of limits, a sequence of tone bursts with increasing decay times and constant frequencies is presented to the listeners at 0.9 s intervals. The first burst in the sequence which is perceived as being tonal is indicated by the listeners. When that happens, the decay times of the tone bursts decrease and the listeners are asked to select the first tone burst with no audible tonality. The listeners are allowed to freely define tonality. No reference is given. For frequencies above 3.4 kHz, the results indicate that tonality is just audible for tone burst lengths of approximately 2.6-3.0 ms. For the lowest stimuli frequencies, the corresponding burst length is approximately 20-23 ms. PMID- 21682407 TI - Enhancing a tone by shifting its frequency or intensity. AB - When a test sound consisting of pure tones with equal intensities is preceded by a precursor sound identical to the test sound except for a reduction in the intensity of one tone, an auditory "enhancement" phenomenon occurs: In the test sound, the tone which was previously softer stands out perceptually. Here, enhancement was investigated using inharmonic sounds made up of five pure tones well resolved in the auditory periphery. It was found that enhancement can be elicited not only by increases in intensity but also by shifts in frequency. In both cases, when the precursor and test sounds are separated by a 500-ms delay, inserting a burst of pink noise during the delay has little effect on enhancement. Presenting the precursor and test sounds to opposite ears rather than to the same ear significantly reduces the enhancement resulting from increases in intensity, but not the enhancement resulting from shifts in frequency. This difference suggests that the mechanisms of enhancement are not identical for the two types of change. For frequency shifts, enhancement may be partly based on the existence of automatic "frequency-shift detectors" [Demany and Ramos, J. Acoust. Soc. Am. 117, 833-841 (2005)]. PMID- 21682408 TI - Subcomponent cues in binaural unmasking. AB - The addition of a signal in the N0Spi binaural configuration gives rise to fluctuations in interaural phase and amplitude. Sensitivity to these individual cues was measured by applying sinusoidal amplitude modulation (AM) or quasi frequency modulation (QFM) to a band of noise. Discrimination between interaurally in-phase and out-of-phase modulation was measured using an adaptive task for narrow bands of noise at center frequencies from 250 to 1500 Hz, for modulation rates of 2-40 Hz, and with or without flanking bands of diotic noise. Discrimination thresholds increased steeply for QFM with increasing center frequency, but increased only modestly for AM, and mainly for modulation rates below 10 Hz. Flanking bands of noise increased thresholds for AM, but had no consistent effect for QFM. The results suggest that two underlying mechanisms may support binaural unmasking: one most sensitive to interaural amplitude modulations that is susceptible to across-frequency interference, and a second, most sensitive to interaural phase modulations that is immune to such effects. PMID- 21682409 TI - The influence of different segments of the ongoing envelope on sensitivity to interaural time delays. AB - The auditory system is sensitive to interaural timing disparities in the fine structure and the envelope of sounds, each contributing important cues for lateralization. In this study, psychophysical measurements were conducted with customized envelope waveforms in order to investigate the isolated effect of different segments of a periodic, ongoing envelope on lateralization. One envelope cycle was composed of the four segments attack flank, hold duration, decay flank, and pause duration, which were independently varied to customize the envelope waveform. The envelope waveforms were applied to a 4-kHz sinusoidal carrier, and just noticeable envelope interaural time differences were measured in six normal hearing subjects. The results indicate that attack durations and pause durations prior to the attack are the most important stimulus characteristics for processing envelope timing disparities. The results were compared to predictions of three binaural lateralization models based on the normalized cross correlation coefficient. Two of the models included an additional stage to mimic neural adaptation prior to binaural interaction, involving either a single short time constant (5 ms) or a combination of five time constants up to 500 ms. It was shown that the model with the single short time constant accounted best for the data. PMID- 21682410 TI - Memory for the locations of environmental sounds. AB - The accuracy with which a single source of sound can be localized has been examined in many studies, but very few studies have examined the ability of participants to determine the absolute locations of multiple sources of sound. The current study assessed participants' abilities to determine and remember the locations of up to six sources of environmental sound that were positioned at a range of azimuths and elevations in virtual auditory space. In experiment 1, a sequence of one to six sounds was presented one, three, or five times in each trial and the target sound was nominated following presentation of the last sequence. In experiment 2, memory load was held constant by nominating the target sound prior to a single sequence presentation. Localization accuracy was observed to decrease as the number of sounds was increased to three or more under the conditions of experiment 1, but not those of experiment 2. In experiment 1, localization was more accurate when sequences were presented more than once. Pronounced primacy and recency effects were observed for the six sound conditions in experiment 1. An analysis of errors for those conditions indicated that immediate temporal errors, but not immediate spatial errors, were over represented. PMID- 21682411 TI - Temporal modulation transfer functions for listeners with real and simulated hearing loss. AB - A functional simulation of hearing loss was evaluated in its ability to reproduce the temporal modulation transfer functions (TMTFs) for nine listeners with mild to profound sensorineural hearing loss. Each hearing loss was simulated in a group of three age-matched normal-hearing listeners through spectrally shaped masking noise or a combination of masking noise and multiband expansion. TMTFs were measured for both groups of listeners using a broadband noise carrier as a function of modulation rate in the range 2 to 1024 Hz. The TMTFs were fit with a lowpass filter function that provided estimates of overall modulation-depth sensitivity and modulation cutoff frequency. Although the simulations were capable of accurately reproducing the threshold elevations of the hearing impaired listeners, they were not successful in reproducing the TMTFs. On average, the simulations resulted in lower sensitivity and higher cutoff frequency than were observed in the TMTFs of the hearing-impaired listeners. Discrepancies in performance between listeners with real and simulated hearing loss are possibly related to inaccuracies in the simulation of recruitment. PMID- 21682412 TI - Wind noise at microphones within and across hearing aids at wind speeds below and above microphone saturation. AB - The variation of wind noise at hearing-aid microphones with wind speed, wind azimuth, and hearing-aid style was investigated. Comparisons were made across behind-the-ear (BTE) and completely-in-canal (CIC) devices, and between microphones within BTE devices. One CIC device and two BTE devices were placed on a Knowles Electronics Manikin for Acoustic Research. The smaller BTE device had vented plastic windshields around its microphone ports while the larger BTE device had none. The microphone output signals were digitally recorded in wind generated at 0, 3, 6, and 12 m/s at 8 wind azimuths. The microphone output signals were saturated at 12 m/s with wind-noise levels of up to 116 dB SPL at the microphone output. Wind-noise levels differed by up to 12 dB between microphones within the same BTE device, and across BTE devices by up to 6 or 8 dB for front or rear microphones, respectively. On average, wind-noise levels were lowest with the CIC device and highest at the rear microphone of the smaller BTE device. Engineering and clinical implications are discussed. PMID- 21682413 TI - Effects of electrode configuration on cochlear implant modulation detection thresholds. AB - Cochlear implant function, as assessed by psychophysical measures, varies from one stimulation site to another within a patient's cochlea. This suggests that patient performance might be improved by selection of the best-functioning sites for the processor map. In evaluating stimulation sites for such a strategy, electrode configuration is an important variable. Variation across stimulation sites in loudness-related measures (detection thresholds and maximum comfortable loudness levels), is much larger for stimulation with bipolar electrode configurations than with monopolar configurations. The current study found that, in contrast to the loudness-related measures, magnitudes of across-site means and the across-site variances of modulation detection thresholds were not dependent on electrode configuration, suggesting that the mechanisms underlying variation in these various psychophysical measures are not all the same. The data presented here suggest that bipolar and monopolar electrode configurations are equally effective in identifying good and poor stimulation sites for modulation detection but that the across-site patterns of modulation detection thresholds are not the same for the two configurations. Therefore, it is recommended to test all stimulation sites using the patient's clinically assigned electrode configuration when performing psychophysical evaluation of a patient's modulation detection acuity to select sites for the processor map. PMID- 21682414 TI - Spatial tuning curves from apical, middle, and basal electrodes in cochlear implant users. AB - Forward-masked psychophysical spatial tuning curves (fmSTCs) were measured in 15 cochlear-implant subjects, 10 using monopolar stimulation and 5 using bipolar stimulation. In each subject, fmSTCs were measured at several probe levels on an apical, middle, and basal electrode using a fixed-level probe stimulus and variable-level maskers. Tuning curve slopes and bandwidths did not change significantly with probe level for electrodes located in the apical, middle, or basal region although a few subjects exhibited dramatic changes in tuning at the extremes of the probe level range. Average tuning curve slopes and bandwidths did not vary significantly across electrode regions. Spatial tuning curves were symmetrical and similar in width across the three electrode regions. However, several subjects demonstrated large changes in slope and/or bandwidth across the three electrode regions, indicating poorer tuning in localized regions of the array. Cochlear-implant users exhibited bandwidths that were approximately five times wider than normal-hearing acoustic listeners but were in the same range as acoustic listeners with moderate cochlear hearing loss. No significant correlations were found between spatial tuning parameters and speech recognition; although a weak relation was seen between middle electrode tuning and transmitted information for vowel second formant frequency. PMID- 21682415 TI - Binaural unmasking with multiple adjacent masking electrodes in bilateral cochlear implant users. AB - Bilateral cochlear implant (BiCI) users gain an advantage in noisy situations from a second implant, but their bilateral performance falls short of normal hearing listeners. Channel interactions due to overlapping electrical fields between electrodes can impair speech perception, but its role in limiting binaural hearing performance has not been well characterized. To address the issue, binaural masking level differences (BMLD) for a 125 Hz tone in narrowband noise were measured using a pair of pitch-matched electrodes while simultaneously presenting the same masking noise to adjacent electrodes, representing a more realistic stimulation condition compared to prior studies that used only a single electrode pair. For five subjects, BMLDs averaged 8.9 +/- 1.0 dB (mean +/- s.e.) in single electrode pairs but dropped to 2.1 +/- 0.4 dB when presenting noise on adjacent masking electrodes, demonstrating a negative impact of the additional maskers. Removing the masking noise from only the pitch-matched electrode pair not only lowered thresholds but also resulted in smaller BMLDs. The degree of channel interaction estimated from auditory nerve evoked potentials in three subjects was significantly and negatively correlated with BMLD. The data suggest that if the amount of channel interactions can be reduced, BiCI users may experience some performance improvements related to binaural hearing. PMID- 21682416 TI - Laryngeal electromyographic responses to perturbations in voice pitch auditory feedback. AB - The present study was conducted to test the hypothesis that intrinsic laryngeal muscles are involved in producing voice fundamental frequency (F(0)) responses to perturbations in voice pitch auditory feedback. Electromyography (EMG) recordings of the cricothyroid and thyroarytenoid muscles were made with hooked-wire electrodes, while subjects sustained vowel phonations at three different voice F(0) levels (conversational, high pitch in head register, and falsetto register) and received randomized pitch shifts (+/-100 or +/-300 cents) in their voice auditory feedback. The median latencies from stimulus onset to the peak in the EMG and voice F(0) responses were 167 and 224 ms, respectively. Among the three different F(0) levels, the falsetto register produced compensatory EMG responses that occurred prior to vocal responses and increased along with rising voice F(0) responses and decreased for falling F(0) responses. For the conversational and high voice levels, the EMG response timing was more variable than in the falsetto voice, and changes in EMG activity with relevance to the vocal responses did not follow the consistent trend observed in the falsetto condition. The data from the falsetto condition suggest that both the cricothyroid and thyroarytenoid muscles are involved in generating the compensatory vocal responses to pitch-shifted voice feedback. PMID- 21682417 TI - Vocal tract area functions and formant frequencies in opera tenors' modal and falsetto registers. AB - According to recent model investigations, vocal tract resonance is relevant to vocal registers. However, no experimental corroboration of this claim has been published so far. In the present investigation, ten professional tenors' vocal tract configurations were analyzed using MRI volumetry. All subjects produced a sustained tone on the pitch F4 (349 Hz) on the vowel /a/ (1) in modal and (2) in falsetto register. The area functions were estimated from the MRI data and their associated formant frequencies were calculated. In a second condition the same subjects repeated the same tasks in a sound treated room and their formant frequencies were estimated by means of inverse filtering. In both recordings similar formant frequencies were observed. Vocal tract shapes differed between modal and falsetto register. In modal as compared to falsetto the lip opening and the oral cavity were wider and the first formant frequency was higher. In this sense the presented results are in agreement with the claim that the formant frequencies differ between registers. PMID- 21682418 TI - Production of phonetic and phonological contrast by heritage speakers of Mandarin. AB - This study tested the hypothesis that heritage speakers of a minority language, due to their childhood experience with two languages, would outperform late learners in producing contrast: language-internal phonological contrast, as well as cross-linguistic phonetic contrast between similar, yet acoustically distinct, categories of different languages. To this end, production of Mandarin and English by heritage speakers of Mandarin was compared to that of native Mandarin speakers and native American English-speaking late learners of Mandarin in three experiments. In experiment 1, back vowels in Mandarin and English were produced distinctly by all groups, but the greatest separation between similar vowels was achieved by heritage speakers. In experiment 2, Mandarin aspirated and English voiceless plosives were produced distinctly by native Mandarin speakers and heritage speakers, who both put more distance between them than late learners. In experiment 3, the Mandarin retroflex and English palato-alveolar fricatives were distinguished by more heritage speakers and late learners than native Mandarin speakers. Thus, overall the hypothesis was supported: across experiments, heritage speakers were found to be the most successful at simultaneously maintaining language-internal and cross-linguistic contrasts, a result that may stem from a close approximation of phonetic norms that occurs during early exposure to both languages. PMID- 21682419 TI - Spectro-temporal envelope changes caused by temporal fine structure modification. AB - The study of speech from which the temporal fine structure (TFS) has been removed has become an important research area. Common procedures for removing TFS include noise and tone vocoders. In the noise vocoder, bands of noise are modulated by the envelope of the speech within each band, and in the tone vocoder the carrier is a sinusoid at the center of each frequency band. Five different procedures for removing TFS are evaluated in this paper: the noise vocoder, a low-noise noise approach in which the noise envelope is replaced by the speech envelope in each frequency band, phase randomization within each band, the tone vocoder, and sinusoidal modeling with random phase. The effects of TFS modification on the speech envelope are evaluated using an index based on the envelope time-frequency modulation. The results show that for all of the TFS techniques implemented in this study, there is a substantial loss in the accuracy of reproduction of the envelope time-frequency modulation. The tone vocoder gives the best accuracy, followed by the procedure that replaces the noise envelope with the speech envelope in each band. PMID- 21682420 TI - Perception of sinewave vowels. AB - There is a significant body of research examining the intelligibility of sinusoidal replicas of natural speech. Discussion has followed about what the sinewave speech phenomenon might imply about the mechanisms underlying phonetic recognition. However, most of this work has been conducted using sentence material, making it unclear what the contributions are of listeners' use of linguistic constraints versus lower level phonetic mechanisms. This study was designed to measure vowel intelligibility using sinusoidal replicas of naturally spoken vowels. The sinusoidal signals were modeled after 300 /hVd/ syllables spoken by men, women, and children. Students enrolled in an introductory phonetics course served as listeners. Recognition rates for the sinusoidal vowels averaged 55%, which is much lower than the ~95% intelligibility of the original signals. Attempts to improve performance using three different training methods met with modest success, with post-training recognition rates rising by ~5-11 percentage points. Follow-up work showed that more extensive training produced further improvements, with performance leveling off at ~73%-74%. Finally, modeling work showed that a fairly simple pattern-matching algorithm trained on naturally spoken vowels classified sinewave vowels with 78.3% accuracy, showing that the sinewave speech phenomenon does not necessarily rule out template matching as a mechanism underlying phonetic recognition. PMID- 21682422 TI - Processing speech signal using auditory-like filterbank provides least uncertainty about articulatory gestures. AB - Understanding how the human speech production system is related to the human auditory system has been a perennial subject of inquiry. To investigate the production-perception link, in this paper, a computational analysis has been performed using the articulatory movement data obtained during speech production with concurrently recorded acoustic speech signals from multiple subjects in three different languages: English, Cantonese, and Georgian. The form of articulatory gestures during speech production varies across languages, and this variation is considered to be reflected in the articulatory position and kinematics. The auditory processing of the acoustic speech signal is modeled by a parametric representation of the cochlear filterbank which allows for realizing various candidate filterbank structures by changing the parameter value. Using mathematical communication theory, it is found that the uncertainty about the articulatory gestures in each language is maximally reduced when the acoustic speech signal is represented using the output of a filterbank similar to the empirically established cochlear filterbank in the human auditory system. Possible interpretations of this finding are discussed. PMID- 21682423 TI - Development of a temporal fundamental frequency coding strategy for cochlear implants. AB - A sound-coding strategy for users of cochlear implants, named enhanced-envelope encoded tone (eTone), was developed to improve coding of fundamental frequency (F0) in the temporal envelopes of the electrical stimulus signals. It is based on the advanced combinational encoder (ACE) strategy and includes additional processing that explicitly applies F0 modulation to channel envelope signals that contain harmonics of prominent complex tones. Channels that contain only inharmonic signals retain envelopes normally produced by ACE. The strategy incorporates an F0 estimator to determine the frequency of modulation and a harmonic probability estimator to control the amount of modulation enhancement applied to each channel. The F0 estimator was designed to provide an accurate estimate of F0 with minimal processing lag and robustness to the effects of competing noise. Error rates for the F0 estimator and accuracy of the harmonic probability estimator were compared with previous approaches and outcomes demonstrated that the strategy operates effectively across a range of signals and conditions that are relevant to cochlear implant users. PMID- 21682421 TI - Predicted effects of sensorineural hearing loss on across-fiber envelope coding in the auditory nerve. AB - Cross-channel envelope correlations are hypothesized to influence speech intelligibility, particularly in adverse conditions. Acoustic analyses suggest speech envelope correlations differ for syllabic and phonemic ranges of modulation frequency. The influence of cochlear filtering was examined here by predicting cross-channel envelope correlations in different speech modulation ranges for normal and impaired auditory-nerve (AN) responses. Neural cross correlation coefficients quantified across-fiber envelope coding in syllabic (0-5 Hz), phonemic (5-64 Hz), and periodicity (64-300 Hz) modulation ranges. Spike trains were generated from a physiologically based AN model. Correlations were also computed using the model with selective hair-cell damage. Neural predictions revealed that envelope cross-correlation decreased with increased characteristic frequency separation for all modulation ranges (with greater syllabic-envelope correlation than phonemic or periodicity). Syllabic envelope was highly correlated across many spectral channels, whereas phonemic and periodicity envelopes were correlated mainly between adjacent channels. Outer-hair-cell impairment increased the degree of cross-channel correlation for phonemic and periodicity ranges for speech in quiet and in noise, thereby reducing the number of independent neural information channels for envelope coding. In contrast, outer-hair-cell impairment was predicted to decrease cross-channel correlation for syllabic envelopes in noise, which may partially account for the reduced ability of hearing-impaired listeners to segregate speech in complex backgrounds. PMID- 21682424 TI - Dynamics of communal vocalizations in a social songbird, the zebra finch (Taeniopygia guttata). AB - Colonies or communities of animals such as fishes, frogs, seabirds, or marine mammals can be noisy. Although vocal communication between clearly identified sender(s) and receiver(s) has been well studied, the properties of the noisy sound that results from the acoustic network of a colony of gregarious animals have received less attention. The resulting sound could nonetheless convey some information about the emitting group. Using custom-written software for automatic detection of vocalizations occurring over many hours of recordings, this study reports acoustic features of communal vocal activities in a gregarious species, the zebra finch (Taeniopygia guttata). By biasing the sex ratio and using two different housing conditions (individual versus communal housing), six groups of zebra finches were generated, with six different social structures that varied both in terms of sex-composition and proportion of paired individuals. The results showed that the rate of emission and the acoustic dynamic both depended on the social structure. In particular, the vocal activity of a group of zebra finches depended mainly on the number of unpaired birds, i.e., individuals not part of a stably bonded pair. PMID- 21682425 TI - North Pacific right whale up-call source levels and propagation distance on the southeastern Bering Sea shelf. AB - Call source levels, transmission loss, and ambient noise levels were estimated for North Pacific right whale (Eubalaena japonica) up-calls recorded in the southeastern Bering Sea in autumn of 2000 and 2001. Distances to calling animals, needed to estimate source levels, were based on two independent techniques: (1) arrival-time differences on three or more hydrophones and (2) shallow-water dispersion of normal modes on a single receiver. Average root-mean-square (rms) call source levels estimated by the two techniques were 178 and 176 dB re 1 MUPa at 1 m, respectively, over the up-call frequency band, which was determined per call and averaged 90 to 170 Hz. Peak-to-peak source levels were 14 to 22 dB greater than rms levels. Transmission loss was approximately 15*log(10)(range), intermediate between cylindrical and spherical spreading. Ambient ocean noise within the up-call band varied from 72 to 91 dB re 1 MUPa(2)/Hz. Under average noise conditions, call spectrograms were detectable for whales at distances up to 100 km, but propagation and detection distance may vary depending on environmental parameters and anthropogenic noise. Obtaining distances to animals and acoustic detection range is a step toward using long-term passive acoustic recordings to estimate abundance for this critically endangered whale population. PMID- 21682426 TI - A method for detecting whistles, moans, and other frequency contour sounds. AB - An algorithm is presented for the detection of frequency contour sounds-whistles of dolphins and many other odontocetes, moans of baleen whales, chirps of birds, and numerous other animal and non-animal sounds. The algorithm works by tracking spectral peaks over time, grouping together peaks in successive time slices in a spectrogram if the peaks are sufficiently near in frequency and form a smooth contour over time. The algorithm has nine parameters, including the ones needed for spectrogram calculation and normalization. Finding optimal values for all of these parameters simultaneously requires a search of parameter space, and a grid search technique is described. The frequency contour detection method and parameter optimization technique are applied to the problem of detecting "boing" sounds of minke whales from near Hawaii. The test data set contained many humpback whale sounds in the frequency range of interest. Detection performance is quantified, and the method is found to work well at detecting boings, with a false-detection rate of 3% for the target missed-call rate of 25%. It has also worked well anecdotally for other marine and some terrestrial species, and could be applied to any species that produces a frequency contour, or to non-animal sounds as well. PMID- 21682427 TI - Numerical simulation of ultrasonic wave propagation for the evaluation of dental implant biomechanical stability. AB - Osseointegration of dental implants remains poorly understood. The objective of this numerical study is to understand the propagation phenomena of ultrasonic waves in prototypes cylindrically shaped implants and to investigate the sensitivity of their ultrasonic response to the surrounding bone biomechanical properties. The 10 MHz ultrasonic response of the implant was calculated using a finite difference numerical simulation tool and was compared to rf signals taken from a recent experimental study by Mathieu et al. [Ultrasound Med. Biol. 37, 262 270 (2011a)]. Reflection and mode conversion phenomena were analyzed to understand the origin of the different echoes and the importance of lateral wave propagation was evidenced. The sensitivity of the ultrasonic response of the implant to changes of (i) amount of bone in contact with the implant, (ii) cortical bone thickness, and (iii) surrounding bone material properties, was compared to the reproducibility of the measurements. The results show that, either a change of 1 mm of bone in contact with the implant, or 1.1 mm of cortical thickness or 12% of trabecular bone mass density should be detectable. This study paves the way for the investigation of the use of quantitative ultrasound techniques for the evaluation of bone-implant interface properties and implant stability. PMID- 21682428 TI - Theoretical framework for quantitatively estimating ultrasound beam intensities using infrared thermography. AB - In the characterization of high-intensity focused ultrasound (HIFU) systems, it is desirable to know the intensity field within a tissue phantom. Infrared (IR) thermography is a potentially useful method for inferring this intensity field from the heating pattern within the phantom. However, IR measurements require an air layer between the phantom and the camera, making inferences about the thermal field in the absence of the air complicated. For example, convection currents can arise in the air layer and distort the measurements relative to the phantom-only situation. Quantitative predictions of intensity fields based upon IR temperature data are also complicated by axial and radial diffusion of heat. In this paper, mathematical expressions are derived for use with IR temperature data acquired at times long enough that noise is a relatively small fraction of the temperature trace, but small enough that convection currents have not yet developed. The relations were applied to simulated IR data sets derived from computed pressure and temperature fields. The simulation was performed in a finite-element geometry involving a HIFU transducer sonicating upward in a phantom toward an air interface, with an IR camera mounted atop an air layer, looking down at the heated interface. It was found that, when compared to the intensity field determined directly from acoustic propagation simulations, intensity profiles could be obtained from the simulated IR temperature data with an accuracy of better than 10%, at pre-focal, focal, and post-focal locations. PMID- 21682501 TI - Construction of CASCI-type wave functions for very large active spaces. AB - We present a procedure to construct a configuration-interaction expansion containing arbitrary excitations from an underlying full-configuration interaction-type wave function defined for a very large active space. Our procedure is based on the density-matrix renormalization group (DMRG) algorithm that provides the necessary information in terms of the eigenstates of the reduced density matrices to calculate the coefficient of any basis state in the many-particle Hilbert space. Since the dimension of the Hilbert space scales binomially with the size of the active space, a sophisticated Monte Carlo sampling routine is employed. This sampling algorithm can also construct such configuration-interaction-type wave functions from any other type of tensor network states. The configuration-interaction information obtained serves several purposes. It yields a qualitatively correct description of the molecule's electronic structure, it allows us to analyze DMRG wave functions converged for the same molecular system but with different parameter sets (e.g., different numbers of active-system (block) states), and it can be considered a balanced reference for the application of a subsequent standard multi-reference configuration-interaction method. PMID- 21682502 TI - Alternative single-reference coupled cluster approaches for multireference problems: the simpler, the better. AB - We report a general implementation of alternative formulations of single reference coupled cluster theory (extended, unitary, and variational) with arbitrary-order truncation of the cluster operator. These methods are applied to compute the energy of Ne and the equilibrium properties of HF and C(2). Potential energy curves for the dissociation of HF and the BeH(2) model computed with the extended, variational, and unitary coupled cluster approaches are compared to those obtained from the multireference coupled cluster approach of Mukherjee et al. [J. Chem. Phys. 110, 6171 (1999)] and the internally contracted multireference coupled cluster approach [F. A. Evangelista and J. Gauss, J. Chem. Phys. 134, 114102 (2011)]. In the case of Ne, HF, and C(2), the alternative coupled cluster approaches yield almost identical bond length, harmonic vibrational frequency, and anharmonic constant, which are more accurate than those from traditional coupled cluster theory. For potential energy curves, the alternative coupled cluster methods are found to be more accurate than traditional coupled cluster theory, but are three to ten times less accurate than multireference coupled cluster approaches. The most challenging benchmark, the BeH(2) model, highlights the strong dependence of the alternative coupled cluster theories on the choice of the Fermi vacuum. When evaluated by the accuracy to cost ratio, the alternative coupled cluster methods are not competitive with respect to traditional CC theory, in other words, the simplest theory is found to be the most effective one. PMID- 21682503 TI - The nature of electron correlation in a dissociating bond. AB - We have constructed the unrestricted Hartree-Fock (UHF), restricted Hartree-Fock (RHF), and full configuration interaction (FCI) position and momentum intracules and holes for H...H at bond lengths R from 1 to 10 bohrs. We trace the recently discovered inversion of the UHF position hole at intermediate R to over localization of the spin-orbitals, and support this by a correlation energy component analysis. The RHF and UHF momentum holes are found to be more complicated; however their features are explained through decomposition of electron correlation effects. The UHF momentum hole is also found to invert and exhibits interesting behavior at large R. The RHF (but not UHF) and FCI momentum intracules exhibit Young-type interference patterns related to recent double photoionization experiments. Our analyses yield the most comprehensive picture to date of the behavior of the electrons during homolytic bond fission. PMID- 21682504 TI - Some comments and corrections regarding the calculation of electrostatic potential derivatives using the Ewald summation technique. AB - A review of the literature on the calculation of electrostatic potentials, fields, and field gradients in systems consisting of charges and dipoles using the Ewald summation technique is presented. Discrepancies between the previous formulas are highlighted, and an error in the derivation of the reciprocal contributions to the electrostatic field and field gradient is corrected. The new formulas for the field and field gradient are shown to exhibit a termwise identity with the ones for the electrostatic energy. PMID- 21682505 TI - Molecular association of heteronuclear vibrating square-well dumbbells in liquid vapor phase equilibrium. AB - Molecular aggregates are formed by heteronuclear vibrating square-well dumbbells. In a recent article [G. A. Chapela and J. Alejandre, J. Chem. Phys., 132(10), 104704 (2010)], it is shown that heteronuclear vibrating square-well dumbbells with a diameter ratio between particles of 1/2 and interacting potential ratio of 4 form micelles of different sizes and shapes which manifest themselves in both the liquid and vapor phases, up to and above the critical point. This means that micellization and phase separation are present simultaneously in this simple model. These systems present a maximum in the critical temperature when plotted against the potential well depth of the second particle epsilon(2). In the same publication, it was speculated that the formation of micelles was responsible for the appearance of the maximum. A thorough study on this phenomena is presented here and it is found that there is a threshold on the size of the second particle and its corresponding depth of interaction potential, where the micelles are formed. If the diameter and well depth of the second particle are small enough for the first and deep enough for the second, micelles are formed. For sigma(2)/sigma(1) between 0.25 and 0.65 and epsilon(2)/epsilon(1) larger than 5.7, micelles are formed up to and above the critical temperature. Outside these ranges micelles appear only at temperatures lower than the critical point. There is a strong temperature dependence on the formation and persistence of the aggregates. For the deepest wells and large enough second particles, a gel interconnected aggregate is obtained. In this work, the micelles are formed at temperatures as low as the triple point and as high as the critical point and, in some cases, persist well above it. The presence of these maxima in critical temperatures T(c) when plotted against epsilon(2) as follows. At lower values of epsilon(2), an increase of T(c) is obtained as is expected by the increase of the attractive volume as indicated by the principle of corresponding states. As epsilon(2) increases further, the formation of molecular aggregates produce a saturation effect of the deepening of the potential well by encapsulating the particles of the second kind inside the micelles, so the resulting T(c) represents a new poly disperse system of molecular aggregates and not the original heteronuclear vibrating square-well dumbbells. The surface tension is also analyzed for these systems, and it is shown that decreases with increasing attraction due to the formation of molecular aggregates. PMID- 21682506 TI - Generalized Kubo relations and conditions for anomalous diffusion: physical insights from a mathematical theorem. AB - The paper describes an approach to anomalous diffusion within the framework of the generalized Langevin equation. Using a Tauberian theorem for Laplace transforms due to Hardy, Littlewood, and Karamata, generalized Kubo relations for the relevant transport coefficients are derived from the asymptotic form of the mean square displacement. In a second step conditions for anomalous diffusion are derived for the asymptotic forms of the velocity autocorrelation function and the associated memory function. Both spatially unconfined and confined diffusion processes are considered. The results are illustrated with semi-analytical examples. PMID- 21682507 TI - The multiscale coarse-graining method. VII. Free energy decomposition of coarse grained effective potentials. AB - The potential of mean force (PMF) with respect to coarse-grained (CG) coordinates is often calculated in order to study the molecular interactions in atomistic molecular dynamics (MD) simulations. The multiscale coarse-graining (MS-CG) approach enables the computation of the many-body PMF of an atomistic system in terms of the CG coordinates, which can be used to parameterize CG models based on all-atom configurations. We demonstrate here that the MS-CG method can also be used to analyze the CG interactions from atomistic MD trajectories via PMF calculations. In addition, MS-CG calculations at different temperatures are performed to decompose the PMF values into energetic and entropic contributions as a function of the CG coordinates, which provides more thermodynamic information regarding the atomistic system. Two numerical examples, liquid methanol and a dimyristoylphosphatidylcholine lipid bilayer, are presented. The results show that MS-CG can be used as an analysis tool, comparable to various free energy computation methods. The differences between the MS-CG approach and other PMF calculation methods, as well as the characteristics and advantages of MS-CG, are also discussed. PMID- 21682508 TI - The isotropic spectrum of the CO2 Raman 2nu3 overtone: a line-mixing band shape analysis at pressures up to several tens of atmospheres. AB - A line-mixing shape analysis of the isotropic remnant Raman spectrum of the 2nu(3) overtone of CO(2) is reported at room temperature and for densities, rho, rising up to tens of amagats. The analysis, experimental and theoretical, employs tools of non-resonant light scattering spectroscopy and uses the extended strong collision model (ESCM) to simulate the strong line mixing effects and to evidence motional narrowing. Excellent agreement at any pressure is observed between the calculated spectra and our experiment, which, along with the easy numerical implementation of the ESCM, makes this model stand out clearly above other semiempirical models for band shape calculations. The hitherto undefined, explicit rho-dependence of the vibrational relaxation rate is given. Our study intends to improve the understanding of pressure-induced phenomena in a gas that is still in the forefront of the news. PMID- 21682510 TI - On the correlation between bond-length change and vibrational frequency shift in halogen-bonded complexes. AB - The C-Hal (Hal = Cl, Br, or I) bond-length change and the corresponding vibrational frequency shift of the C-Hal stretch upon the C-Hal...Y (Y is the electron donor) halogen bond formation have been determined by using density functional theory computations. Plots of the C-Hal bond-length change versus the corresponding vibrational frequency shift of the C-Hal stretch all give straight lines. The coefficients of determination range from 0.94366 to 0.99219, showing that the correlation between the C-Hal bond-length change and the corresponding frequency shift is very good in the halogen-bonded complexes. The possible effects of vibrational coupling, computational method, and anharmonicity on the bond-length change-frequency shift correlation are discussed in detail. PMID- 21682509 TI - Unveiling the nonadiabatic rotational excitation process in a symmetric-top molecule induced by two intense laser pulses. AB - We experimentally investigate the nonadiabatic rotational excitation process of a symmetric-top molecule, benzene, in the electronic ground state irradiated by intense nonresonant ultrafast laser fields. The initial rotational-state distribution was restricted mostly to the five lowest levels with different nuclear spin modifications by an extensive adiabatic cooling with the rotational temperature well below 1 K, and distributions after the interaction with a femtosecond double-pulse pair (3-5 TW/cm(2) each with 160 fs duration) with time delays were probed in a quantum-state resolved manner by employing resonant enhanced multiphoton ionization via the S(1) <- S(0) 6(0) (1) vibronic transition. Populations of 10 rotational levels with J ranging from 0 to 4 and K from 0 to 3 were examined to show an oscillatory dependence on the time delay between the two pulses. Fourier analysis of the beat signals provides the coupling strengths between the constituent levels of the rotational wave packets created by the nonadiabatic excitation. These data are in good agreement with the results from quantum mechanical calculations, evidencing stepwise excitation pathways in the wave packet creation with DeltaJ = 2 in the K = 0 stack while DeltaJ = 1 and 2 in the K > 0 stacks. PMID- 21682511 TI - All-boron analogues of aromatic hydrocarbons: B17- and B18-. AB - We have investigated the structural and electronic properties of the B(17)(-) and B(18)(-) clusters using photoelectron spectroscopy (PES) and ab initio calculations. The adiabatic electron detachment energies of B(17)(-) and B(18)(-) are measured to be 4.23 +/- 0.02 and 3.53 +/- 0.05 eV, respectively. Calculated electron detachment energies are compared with experimental data, confirming the presence of one planar C(2v) ((1)A(1)) isomer for B(17)(-) and two nearly isoenergetic quasi-planar C(3v) ((2)A(1)) and C(s) ((2)A') isomers for B(18)(-). The stability and planarity/quasi-planarity of B(17)(-) and B(18)(-) are ascribed to sigma- and pi-aromaticity. Chemical bonding analyses reveal that the nature of pi-bonding in B(17)(-) and B(18)(-) is similar to that in the recently elucidated B(16)(2-) and B(19)(-) clusters, respectively. The planar B(17)(-) cluster can be considered as an all-boron analogue of naphthalene, whereas the pi-bonding in the quasi-planar B(18)(-) is reminiscent of that in coronene. PMID- 21682512 TI - Intramolecular proton transfer in malonaldehyde: accurate multilayer multi configurational time-dependent Hartree calculations. AB - Full-dimensional (multilayer) multi-configurational time-dependent Hartree calculations studying the intramolecular proton transfer in malonaldehyde based on a recent potential energy surface (PES) [Wang et al., J. Chem. Phys. 128, 224314 (2008)] are presented. The most accurate calculations yield a ground state tunneling splitting of 23.8 cm(-1) and a zero point energy of 14,678 cm(-1). Extensive convergence tests indicate an error margin of the quantum dynamics calculations for the tunneling splitting of about 0.2 cm(-1). These results are to be compared with the experimental value of the tunneling splitting of 21.58 cm(-1) and results of Monte Carlo calculations of Wang et al. on the same PES which yielded a zero point energy of 14,677.9 cm(-1) with statistical errors of 2 3 cm(-1) and a tunneling splitting of 21.6 cm(-1). The present data includes contributions resulting from the vibrational angular momenta to the tunneling splitting and the zero point energy of 0.2 cm(-1) and 2.4 cm(-1), respectively, which have been computed using a perturbative approach. PMID- 21682513 TI - Designing organic spin filters in the coherent tunneling regime. AB - Spin filters, that is, systems which preferentially transport electrons of a certain spin orientation, are an important element for spintronic schemes and in chemical and biological instances of spin-selective electronic communication. We study the relation between molecular structure and spin filtering functionality employing a theoretical analysis of both model and stable organic radicals based on substituted benzene, which are bound to gold electrodes, with a combination of density functional theory and the Landauer-Imry-Buttiker approach. We compare the spatial distribution of the spin density and of the frontier central subsystem molecular orbitals, and local contributions to the transmission. Our results suggest that the delocalization of the singly occupied molecular orbital and of the spin density onto the benzene ring connected to the electrodes, is a good, although not the sole indicator of spin filtering functionality. The stable radicals under study do not effectively act as spin filters, while the model phenoxy-based radicals are effective due to their much larger spin delocalization. These conclusions may also be of interest for electron transfer experiments in electron donor-bridge-acceptor complexes. PMID- 21682514 TI - Gas phase analogs of stable sodium-tin Zintl ions: anion photoelectron spectroscopy and electronic structure. AB - Mass spectrometry and photoelectron spectroscopy together with first principles theoretical calculations have been used to study the electronic and geometric properties of the following sodium-tin, cluster anion/neutral cluster combinations, (Na(n)Sn(4))(-)/(Na(n)Sn(4)), n = 0-4 and (NaSn(m))(-)/(NaSn(m)), m = 4-7. These synergistic studies found that specific Zintl anions, which are known to occur in condensed Zintl phases, also exist as stable moieties within free clusters. In particular, the cluster anion, (Na(3)Sn(4))(-) is very stable and is characterized as (Na(+))(3)(Sn(4))(-4); its moiety, (Sn(4))(-4) is a classic example of a Zintl anion. In addition, the cluster anion, (NaSn(5))(-) was the most abundant species to be observed in our mass spectrum, and it is characterized as Na(+)(Sn(5))(2-). Its moiety, (Sn(5))(2-) is also known to be present as a Zintl anion in condensed phases. PMID- 21682515 TI - Dynamics of H+ + N2 at E(Lab) = 30 eV. AB - The H(+) + N(2) system at E(Lab) = 30 eV, relevant in astrophysics, is investigated with the simplest-level electron nuclear dynamics (SLEND) method. SLEND is a time-dependent, direct, variational, non-adiabatic method that employs a classical-mechanics description for the nuclei and a single-determinantal wavefunction for the electrons. A canonical coherent-states procedure, intrinsic to SLEND, is used to reconstruct quantum vibrational properties from the SLEND classical mechanics. Present simulations employ three basis sets: STO-3G, 6-31G, and 6-31G**, to determine their effect on the results, which include reaction visualizations, product predictions, and scattering properties. Present simulations predict non-charge-transfer scattering and N(2) collision-induced dissociation as the main reactions. Average vibrational energy transfer, H(+) energy-loss spectra, rainbow angle, and elastic vibrational differential cross sections at the SLEND/6-31G** level agree well with available experimental data. SLEND/6-31G** results are comparable to those calculated with the vibrational close-coupling rotational infinite-order sudden approximation and the quasi classical trajectory method. PMID- 21682516 TI - Application of parametric equations of motion to study the laser induced multiphoton dissociation of H2+ in intense laser field. AB - We have applied parametric equations of motion (PEM) to study photodissociation dynamics of H(2)(+). The resonances are extracted using smooth exterior scaling method. This is the first application of PEM to non-Hermitian Hamiltonian that includes resonances and the continuum. Here, we have studied how the different resonance states behave with respect to the change in field amplitude. The advantage of this method is that one can easily trace the different states that are changing as the field parameter changes. PMID- 21682517 TI - Theoretical modeling of ionization energies of argon clusters: nuclear delocalization effects. AB - Temperature dependence of vertical ionization energies is modeled for small argon clusters (N <= 13) using classical parallel-tempering Monte Carlo methods and extended interaction models based on the diatomics-in-molecules approach. Quantum effects at the zero temperature are also discussed in terms of zero-point nuclear vibrations, either at the harmonic approximation level or at the fully anharmonic level using the diffusion Monte Carlo calculations. Both approaches lead to a considerable improvement of the theoretical predictions of argon clusters ionization energies and represent a realistic way of modeling of ionization energies for weakly bound and floppy complexes in general. A thorough comparison with a recent electron-impact experiment [O. Echt et al., J. Chem. Phys. 123, 084313 (2005)] is presented and a novel interpretation of the experimental data is proposed. PMID- 21682519 TI - On the mechanism of the highly viscous flow. AB - The asymmetry model for the highly viscous flow postulates thermally activated jumps from a practically undistorted ground state to strongly distorted, but stable structures, with a pronounced Eshelby backstress from the distorted surroundings. The viscosity is ascribed to those stable distorted structures which do not jump back, but relax by the relaxation of the surrounding viscoelastic matrix. It is shown that this mechanism implies a description in terms of the shear compliance, with a viscosity which can be calculated from the cutoff of the retardation spectrum. Consistency requires that this cutoff lies close to the Maxwell time. The improved asymmetry model compares well with experiment. PMID- 21682518 TI - The 1(5)Pi(g) state of C2. AB - We report ab initio spectroscopic constants for the recently identified 1(5)Pi(g) state of C(2) [P. Bornhauser, Y. Sych, G. Knopp, T. Gerber, and P. P. Radi, J. Chem. Phys. 134, 044302 (2011)]. The calculations are performed at the multi reference configuration interaction level of theory with Davidson's correction using aug-cc-pV6Z basis sets and include core-valence correlation and relativistic corrections obtained with quadruple-zeta bases. Such treatment accurately reproduces the experimentally observed constants of the a(3)Pi(u) and other states. Thus, we expect our calculated omega(e) value for the 1(5)Pi(g) state to be within a few cm(-1), and rotational constants to be within 0.1% of experiment. Agreement with available spectroscopic data is excellent, with the calculations strongly suggesting that the 1(5)Pi(g) vibrational level observed by Bornhauser et al. is v = 0. PMID- 21682520 TI - Renormalization-group analysis of the R(I)-R(V) rotator phase transition. AB - A model for coupled tilt angle and lattice distortion parameter is proposed to describe the R(I)-R(V) transition in n-alkane. The model is treated in the framework of a Landau mean-field theory and renormalization-group theory. The influence of gauche conformations and molecular flexibility on the R(I)-R(V) transition is discussed within the mean-field theory. The fluctuations on the R(I)-R(V) transition are discussed by the renormalization-group theory. Renormalization-group theory predicts that the R(I)-R(V) transition can be driven first order by fluctuations and becomes second order at a tricritical point. Available experimental data are consistent with our model. PMID- 21682522 TI - Simulation of multiple ordered phases in C23 n-alkane. AB - Normal alkanes display multiple ordered phases, including an orthorhombic crystal (X) and two partially ordered rotator phases (RI and RII). The rotator phase transitions X-RI and RI-RII are of interest because they are weakly first-order, and because experiments suggest that crystalline polyethylene may nucleate via a metastable rotator phase. We have performed heating and cooling scans of all-atom NsigmaT (isothermal, isostress) simulations of a pure C(23) solid. We find a sequence of phases, transition temperatures, structural and thermodynamic properties, all reasonably consistent with experiment, except that a monoclinic crystal is more stable in our simulations than the experimental orthorhombic structure. We find that the RI phase is well described as an orthorhombic crystal disordered by random +/-90 degrees rotations of molecules about their stem axis, and the RII phase can be represented as a loose hexagonal packing of parallel chain stems, which tend to orient with the in-plane projection of C-C bonds pointing between neighbors. To measure local orthorhombic, RI, or RII order, we define Potts- and Ising-like order parameters, from which global order parameters and correlation functions can be computed. We observe modest pretransitional fluctuations of local RI order in the RII phase near T(RI-RII), characteristic of this weakly first-order transition. PMID- 21682521 TI - Time-resolved luminescence spectroscopy of self-trapped excitons in ladder type Br-bridged Pt complexes. AB - The out-of-phase and in-phase ladder type Br-bridged Pt complexes are investigated by time-resolved luminescence spectroscopy in pico- and femtosecond time regions. The observed luminescence spectra have peaks at 0.87 and 0.94 eV in out-of-phase and in-phase materials, respectively, and are assigned to self trapped excitons. The wave-packet oscillations in self-trapped excitons (STE) are observed in both materials. The time-evolution curves are analyzed in terms of the secondary radiation theory of strongly coupled electron-phonon system. The period and dephasing time of oscillations as well as the lifetime and spectral shape of the STE luminescence are determined. The fast dephasing or cooling of the wave-packet motion observed in the in-phase type complex is ascribed to inter chain interactions within the ladder. PMID- 21682523 TI - Intermediate vibronic coupling in charge transfer states: comprehensive calculation of electronic excitations in sexithiophene crystal. AB - A comprehensive theory of linear vibronic coupling in a coupled manifold of Frenkel and charge-transfer states in an infinite molecular crystal is presented and applied for sexithiophene. The approach, valid in the intermediate-coupling regime, includes up to three-particle terms of the Philpott expansion, with the vibronic wavefunctions represented in the Lang-Firsov basis. As a stringent test, the scheme is used to reproduce the complete set of available sexithiophene absorption and electroabsorption spectra within a unified theoretical framework. The input is based primarily on independent calculations and to some extent on independent experiments, with explicit fitting contained within the limits set by the estimated inherent errors of a priori parameter estimates. Reasonably good quantitative agreement with experimental spectra is achieved. The results resolve some existing interpretational ambiguities and expose some peculiarities of electric field effect on vibronic eigenstates of Frenkel parentage, highlighting the role of charge-transfer interactions. PMID- 21682524 TI - CO2 solvation free energy using quasi-chemical theory. AB - Accumulation of greenhouse gases, especially carbon dioxide, is believed to be the key factor in global climate change. To develop effective ways to remove CO(2) from the atmosphere, it is helpful to understand the mechanism of CO(2) solvation first. Here we investigate the thermodynamics of CO(2) hydration using quasi-chemical theory. Two approaches for estimating hydration free energy are carried out. Both agree reasonably well with experimental measurements. Analysis of the free energy components reveals that the weak hydration free energy results from a balance of unfavorable molecular packing and favorable chemical association. PMID- 21682526 TI - A new grand canonical ensemble method to calculate first-order phase transitions. AB - A theory about first-order phase transition of pure fluids is proposed. The theory is developed by combining grand canonical ensemble with density functional for homogeneous fluids. It is based on the fact that the grand partition function of one macroscopic volume is the product of the grand partition functions of its subvolumes. Density fluctuations of molecules determine the relation between the grand partition function and the free energy density. By combining pairs of subvolumes successively, the free energy density is transformed and rapidly becomes stationary. The stationary curve versus molecule density is convex and its linear segments represent phase transitions. The transform leads to the new grand canonical method to calculate phase equilibrium, which is more robust than classic ones. The transform suggests that classical van der Waals loop is physical and essential to phase transition. PMID- 21682527 TI - Adsorption of organic molecules on the TiO2(011) surface: STM study. AB - High resolution scanning tunneling microscopy has been applied to investigate adsorption and self-assembly of large organic molecules on the TiO(2)(011) surface. The (011) face of the rutile titania has been rarely examined in this context. With respect to possible industrial applications of rutile, quite often in a powder form, knowledge on behavior of organic molecules on that face is required. In the presented study we fill in the gap and report on experiments focused on the self-assembly of organic nanostructures on the TiO(2)(011) surface. We use three different kinds of organic molecules of potential interest in various applications, namely, PTCDA and CuPc representing flat, planar stacking species, and Violet Landers specially designed for new applications in molecular electronics. In order to reach a complete picture of molecular behavior, extended studies with different surface coverage ranging from single molecule up to 2 monolayer (ML) thick films are performed. Our results show that the adsorption behavior is significantly different from previously observed for widely used metallic templates. Creation of highly ordered molecular lines, quasi ordered wetting layers, controlled geometrical reorientation upon thermal treatment, existence of specific adsorption geometries, and prospects for tip induced molecule ordering and manipulation provide better understanding and add new phenomena to the knowledge on the (011) face of rutile titania. PMID- 21682525 TI - Increased fraction of low-density structures in aqueous solutions of fluoride. AB - X-ray absorption spectroscopy (XAS) and small angle x-ray scattering (SAXS) were utilized to study the effect of fluoride (F(-)) anion in aqueous solutions. XAS spectra show that F(-) increases the number of strong H-bonds, likely between F( ) and water in the first hydration shell. SAXS data show a low-Q scattering intensity increase similar to the effect of a temperature decrease, suggesting an enhanced anomalous scattering behavior in F(-) solutions. Quantitative analysis revealed that fluoride solutions have larger correlation lengths than chloride solutions with the same cations but shorter compared to pure water. This is interpreted as an increased fraction of tetrahedral low-density structures in the solutions due to the presence of the F(-) ions, which act as nucleation centers replacing water in the H-bonding network and forming stronger H-bonds, but the presence of the cations restricts the extension of strong H-bonds. PMID- 21682528 TI - Hyperthermal organic thin film growth on surfaces terminated with self-assembled monolayers. I. The dynamics of trapping. AB - We have examined the initial stages of growth of a crystalline small molecule organic thin film, diindenoperylene (DIP), on SiO(2) surfaces terminated with a series of self-assembled monolayers (SAMs). In this study we make use of supersonic molecular beam techniques to vary the incident kinetic energy of the DIP molecules, and we use in situ, real time synchrotron x-ray scattering to monitor the buildup of each molecular layer in the growing thin film. We find that the effects of the SAMs are most apparent concerning growth in the sub monolayer regime, before the substrate is entirely covered by the DIP thin film. In this coverage regime on bare SiO(2), and SiO(2) terminated with either hexamethyldisilazane or perflurooctyltrichlorosilane the adsorption dynamics are consistent with trapping-mediated adsorption as observed in more simple systems, where the probability of adsorption decreases significantly with increasing kinetic energy. Once these surfaces are covered with DIP, however, the adsorption probability increases, particularly at the highest incident kinetic energy, and the probability of adsorption exhibits only a weak dependence on the incident kinetic energy. In contrast, on surfaces terminated by octyl- (OTS) and octadecyltrichlorosilane (ODTS) the trapping probability is high and exhibits little dependence on the incident kinetic energy, essentially the same as what is observed on these same surfaces covered by DIP. We postulate, which is backed by the results of molecular dynamics simulations, that direct molecular insertion into the OTS and ODTS layers is a primary explanation for efficient trapping on these surfaces. PMID- 21682529 TI - Hybrid density functional theory description of N- and C-doping of NiO. AB - The large intrinsic bandgap of NiO hinders its potential application as a photocatalyst under visible-light irradiation. In this study, we have performed first-principles screened exchange hybrid density functional theory with the HSE06 functional calculations of N- and C-doped NiO to investigate the effect of doping on the electronic structure of NiO. C-doping at an oxygen site induces gap states due to the dopant, the positions of which suggest that the top of the valence band is made up primarily of C 2p-derived states with some Ni 3d contributions, and the lowest-energy empty state is in the middle of the gap. This leads to an effective bandgap of 1.7 eV, which is of potential interest for photocatalytic applications. N-doping induces comparatively little dopant-Ni 3d interactions, but results in similar positions of dopant-induced states, i.e., the top of the valence band is made up of dopant 2p states and the lowest unoccupied state is the empty gap state derived from the dopant, leading to bandgap narrowing. With the hybrid density functional theory (DFT) results available, we discuss issues with the DFT corrected for on-site Coulomb description of these systems. PMID- 21682530 TI - Evaporation of Lennard-Jones fluids. AB - Evaporation and condensation at a liquid/vapor interface are ubiquitous interphase mass and energy transfer phenomena that are still not well understood. We have carried out large scale molecular dynamics simulations of Lennard-Jones (LJ) fluids composed of monomers, dimers, or trimers to investigate these processes with molecular detail. For LJ monomers in contact with a vacuum, the evaporation rate is found to be very high with significant evaporative cooling and an accompanying density gradient in the liquid domain near the liquid/vapor interface. Increasing the chain length to just dimers significantly reduces the evaporation rate. We confirm that mechanical equilibrium plays a key role in determining the evaporation rate and the density and temperature profiles across the liquid/vapor interface. The velocity distributions of evaporated molecules and the evaporation and condensation coefficients are measured and compared to the predictions of an existing model based on kinetic theory of gases. Our results indicate that for both monatomic and polyatomic molecules, the evaporation and condensation coefficients are equal when systems are not far from equilibrium and smaller than one, and decrease with increasing temperature. For the same reduced temperature T/T(c), where T(c) is the critical temperature, these two coefficients are higher for LJ dimers and trimers than for monomers, in contrast to the traditional viewpoint that they are close to unity for monatomic molecules and decrease for polyatomic molecules. Furthermore, data for the two coefficients collapse onto a master curve when plotted against a translational length ratio between the liquid and vapor phase. PMID- 21682531 TI - The adsorption and co-adsorption of oxygen and carbon monoxide on Pt3Ni(111): a vibrational study. AB - High-resolution electron energy loss spectroscopy has been used to investigate the adsorption and co-adsorption of oxygen and CO on the Pt(3)Ni(111) surface. For the sake of comparison, similar measurements have also been performed on the Pt(111) surface. We find that CO adsorbs at the same manner on both surfaces. By contrast, significant differences between the two surfaces exist concerning the adsorption of O and the co-adsorption of O with CO. PMID- 21682532 TI - Hybrid density functional theory band structure engineering in hematite. AB - We present a hybrid density functional theory (DFT) study of doping effects in alpha-Fe(2)O(3), hematite. Standard DFT underestimates the band gap by roughly 75% and incorrectly identifies hematite as a Mott-Hubbard insulator. Hybrid DFT accurately predicts the proper structural, magnetic, and electronic properties of hematite and, unlike the DFT+U method, does not contain d-electron specific empirical parameters. We find that using a screened functional that smoothly transitions from 12% exact exchange at short ranges to standard DFT at long range accurately reproduces the experimental band gap and other material properties. We then show that the antiferromagnetic symmetry in the pure alpha-Fe(2)O(3) crystal is broken by all dopants and that the ligand field theory correctly predicts local magnetic moments on the dopants. We characterize the resulting band gaps for hematite doped by transition metals and the p-block post-transition metals. The specific case of Pd doping is investigated in order to correlate calculated doping energies and optical properties with experimentally observed photocatalytic behavior. PMID- 21682533 TI - Oxygen adsorption on Pt/Ru(0001) layers. AB - Chemical properties of epitaxially grown bimetallic layers may deviate substantially from the behavior of their constituents. Strain in conjunction with electronic effects due to the nearby interface represent the dominant contribution to this modification. One of the simplest surface processes to characterize reactivity of these substrates is the dissociative adsorption of an incoming homo-nuclear diatomic molecule. In this study, the adsorption of O(2) on various epitaxially grown Pt films on Ru(0001) has been investigated using infrared absorption spectroscopy and thermal desorption spectroscopy. Pt/Ru(0001) has been chosen as a model system to analyze the individual influences of lateral strain and of the residual substrate interaction on the energetics of a dissociative adsorption system. It is found that adsorption and dissociative sticking depends dramatically on Pt film thickness. Even though oxygen adsorption proceeds in a straightforward manner on Pt(111) and Ru(0001), molecular chemisorption of oxygen on Pt/Ru(0001) is entirely suppressed for the Pt/Ru(0001) monolayer. For two Pt layers chemisorbed molecular oxygen on Pt terraces is produced, albeit at a very slow rate; however, no (thermally induced) dissociation occurs. Only for Pt layer thicknesses N(Pt) >= 3 sticking gradually speeds up and annealing leads to dissociation of O(2), thereby approaching the behavior for oxygen adsorption on genuine Pt(111). For Pt monolayer films a novel state of chemisorbed O(2), most likely located at step edges of Pt monolayer islands is identified. This state is readily populated which precludes an activation barrier towards adsorption, in contrast to adsorption on terrace sites of the Pt/Ru(0001) monolayer. PMID- 21682534 TI - Ordered structures of defect clusters in gadolinium-doped ceria. AB - The nano-domain, with short-range ordered structure, has been widely observed in rare-earth-doped ceria. Atomistic simulation has been employed to investigate the ordering structure of the nano-domain, as a result of aggregation and segregation of dopant cations and the associated oxygen vacancies in gadolinium-doped ceria. It is found that the binding energy of defect cluster increases as a function of cluster size, which provides the intrinsic driving force for the defect cluster growth. However, the ordered structures of the defect clusters are different from the chain model as previously reported. Adjacent oxygen vacancies prefer to locate along <110>/2 lattice vector, which results in a unique stable structure (isosceles triangle) formation. Such isosceles triangle structure can act as the smallest unit of cluster growth to form a symmetric dumbbell structure. This unique dumbbell structure is hence considered as a building block for the development of larger defect clusters, leading to nano-domain formation in rare earth-doped ceria. PMID- 21682535 TI - Thermal degradation of unstrained single polymer chain: non-linear effects at work. AB - We examine the thermally induced fracture of an unstrained polymer chain of discrete segments coupled by an anharmonic potential by means of molecular dynamics simulation with a Langevin thermostat. Cases of both under- and over damped dynamics are investigated, and a comparison with recent studies of bond scission in model polymers with harmonic interactions is performed. We find that the polymer degradation changes qualitatively between the inertial regime and that of heavily damped dynamics. The role of bond healing (recombination) is also studied and probability distributions for the recombination times and overstretched bond lengths are obtained. Our extensive simulations reveal many properties of the scission dynamics in agreement with the notion of random breakdown of independent bonds, e.g., the mean time of chain rupture, follows an Arrhenian behavior with temperature T, and depends on the number of bonds N in the polymer as ? N(-1). In contrast, the rupture rates of the individual bonds along the polymer backbone indicate clearly the presence of self induced inhomogeneity resulting from the interplay of thermal noise and nonlinearity. Eventually we examine the fragmentation kinetics during thermolysis. We demonstrate that both the probability distribution function of fragment sizes as well as the mean length of fragments at subsequent times t characterize degradation as predominantly a first order reaction. PMID- 21682536 TI - Simulations of the confinement of ubiquitin in self-assembled reverse micelles. AB - We describe the effects of confinement on the structure, hydration, and the internal dynamics of ubiquitin encapsulated in reverse micelles (RM). We performed molecular dynamics simulations of the encapsulation of ubiquitin into self-assembled protein/surfactant reverse micelles to study the positioning and interactions of the protein with the RM and found that ubiquitin binds to the RM interface at low salt concentrations. The same hydrophobic patch that is recognized by ubiquitin binding domains in vivo is found to make direct contact with the surfactant head groups, hydrophobic tails, and the iso-octane solvent. The fast backbone N-H relaxation dynamics show that the fluctuations of the protein encapsulated in the RM are reduced when compared to the protein in bulk. This reduction in fluctuations can be explained by the direct interactions of ubiquitin with the surfactant and by the reduced hydration environment within the RM. At high concentrations of excess salt, the protein does not bind strongly to the RM interface and the fast backbone dynamics are similar to that of the protein in bulk. Our simulations demonstrate that the confinement of protein can result in altered protein dynamics due to the interactions between the protein and the surfactant. PMID- 21682537 TI - The effect of Brownian motion of fluorescent probes on measuring nanoscale distances by Forster resonance energy transfer. AB - Forster resonance energy transfer (FRET) is a powerful optical technique to determine intra-molecular distances. However, the dye rotational motion and the linker flexibility complicate the relationship between the measured energy transfer efficiency and the distance between the anchoring points of the dyes. In this study, we present a simple model that describes the linker and dye dynamics as diffusion on a sphere. Single-pair energy transfer was treated in the weak excitation limit, photon statistics and scaffold flexibility were ignored, and different time-averaging regimes were considered. Despite the approximations, our model provides new insights for experimental designs and results interpretation in single-molecule FRET. Monte Carlo simulations produced distributions of the inter-dye distance, the dipole orientation factor, kappa(2), and the transfer efficiency, E, which were in perfect agreement with independently derived theoretical functions. Contrary to common perceptions, our data show that longer linkers will actually restrict the motion of dye dipoles and hence worsen the isotropic 2/3 approximation of kappa(2). It is also found that the thermal motions of the dye-linker system cause fast and large efficiency fluctuations, as shown by the simulated FRET time-trajectories binned on a microsecond time scale. A fundamental resolution limit of single-molecule FRET measurements emerges around 1-10 MUs, which should be considered for the interpretation of data recorded on such fast time scales. PMID- 21682538 TI - Reexamining protein-protein and protein-solvent interactions from Kirkwood-Buff analysis of light scattering in multi-component solutions. AB - The classic analysis of Rayleigh light scattering (LS) is re-examined for multi component protein solutions, within the context of Kirkwood-Buff (KB) theory as well as a more generalized canonical treatment. Significant differences arise when traditional treatments that approximate constant pressure and neglect concentration fluctuations in one or more (co)solvent/co-solute species are compared with more rigorous treatments at constant volume and with all species free to fluctuate. For dilute solutions, it is shown that LS can be used to rigorously and unambiguously obtain values for the osmotic second virial coefficient (B(22)), in contrast with recent arguments regarding protein interactions deduced from LS experiments. For more concentrated solutions, it is shown that conventional analysis over(under)-estimates the magnitude of B(22) for significantly repulsive(attractive) conditions, and that protein-protein KB integrals (G(22)) are the more relevant quantity obtainable from LS. Published data for alpha-chymotrypsinogen A and a series of monoclonal antibodies at different pH and salt concentrations are re-analyzed using traditional and new treatments. The results illustrate that while traditional analysis may be sufficient if one is interested in only the sign of B(22) or G(22), the quantitative values can be significantly in error. A simple approach is illustrated for determining whether protein concentration (c(2)) is sufficiently dilute for B(22) to apply, and for correcting B(22) values from traditional LS regression at higher c(2) values. The apparent molecular weight M(2, app) obtained from LS is shown to generally not be equal to the true molecular weight, with the differences arising from a combination of protein-solute and protein cosolute interactions that may, in principle, also be determined from LS. PMID- 21682540 TI - Highly porous electrospun nanofibers enhanced by ultrasonication for improved cellular infiltration. AB - A significant problem that affects tissue-engineered electrospun nanofibrous scaffolds is poor infiltration of cells into the three-dimensional (3D) structure. Physical manipulation can enhance cellular infiltration into electrospun scaffolds. The porosity of electrospun nanofibers was highly enlarged by ultrasonication in an aqueous solution. The porosity and related property changes on a series of nanofibers were observed to be dependent on ultrasonication time and energy. To evaluate cell infiltration into the scaffold, fibroblasts were seeded onto these nanofibers and cultured for different lengths of time. The penetration levels of these cells into the scaffold were monitored using confocal lazer scanning microscopy. The cell infiltration potential was greatly increased with regard to an increase in pore size and porosity. These 3D nanofibrous scaffolds fabricated by an ultrasonication process allowed cells to infiltrate easily into the scaffold. This approach shows great promise for design of cell permeable nanofibrous scaffolds for tissue-engineering applications. PMID- 21682542 TI - Aphasia friendly written health information: content and design characteristics. AB - People with aphasia need communicatively accessible written health information. Healthcare providers require knowledge of how to develop printed education materials (PEMs) in formats that people with aphasia prefer and can read. This study aimed to explore formatting characteristics considered to be barriers and facilitators to reading PEMs. Semi-structured in-depth interviews were conducted with 40 adults with aphasia who were selected using maximum variation sampling across aphasia severity, reading ability, and time post-stroke. Participants were shown stroke and aphasia PEMs obtained from the recruiting stroke services, asked to rank them from most liked to least liked, and comment on factors that made the PEMs easier and harder to read. The majority of participants ranked the aphasia friendly stroke (56.4%, n = 22) and aphasia (87.2%, n = 34) PEMs as most liked. Forty-five facilitator and 46 barrier codes were identified using qualitative content analysis and grouped into two categories; (1) content characteristics and (2) design characteristics. Findings support many of the recommendations found within the literature for developing best practice PEMs and accessible information for other patient groups. Routine consideration of the facilitators and barriers identified will contribute to making written information more accessible to people with aphasia. PMID- 21682541 TI - Stem cell-based meniscus tissue engineering. AB - Knee meniscus, a fibrocartilaginous tissue, is characterized by heterogeneity in extracellular matrix (ECM) and biomechanical properties, and critical for orthopedic stability, load transmission, shock absorption, and stress distribution within the knee joint. Most damage to the meniscus cannot be effectively healed by the body due to its partial avascular nature; thus, damage caused by injury or age impairs normal knee function, predisposing patients to osteoarthritis. Meniscus tissue engineering offers a possible solution to this problem by generating replacement tissue that may be implanted into the defect site to mimic the function of natural meniscal tissue. To address this need, a multiporous, multilamellar meniscus was formed using silk protein scaffolds and stem cells. The silk scaffolds were seeded with human bone marrow stem cells and differentiated over time in chondrogenic culture in the presence of transforming growth factor-beta 3 to generate meniscus-like tissue in vitro. High cellularity along with abundant ECM leading to enhanced biomechanics similar to native tissue was found. Higher levels of collagen type I and II, sulfated glycosaminoglycans along with enhanced collagen 1-alpha1, aggrecan, and SOX9 gene expression further confirmed differentiation and matured cell phenotype. The results of this study are a step forward toward biomechanically competent meniscus engineering, reconstituting both form and function of the native meniscus. PMID- 21682543 TI - Speech-language pathologists' informal learning in healthcare settings: behaviours and motivations. AB - The current research sought to identify the types of informal learning behaviours speech-language pathologists (SLPs) working in healthcare settings engage in as well as SLPs' motivations for engaging in informal learning. Twenty-four American Speech-Language-Hearing Association (ASHA)-certified SLPs participated in this qualitative study. Data collection consisted of computer-mediated interviews, online journaling, and a virtual focus group. These textual data were coded and collapsed into themes. All participant SLPs reported that they learned through collaboration (inter- and intra-disciplinary), worked with patients to learn through trial-and-error, and consulted non-peer-reviewed material on the internet as well as peer-reviewed research in order to learn informally in the workplace. Eighteen of the 24 participants reported being motivated to learn at work to meet a patient's need to meet therapy goals. Five of the 24 participants reported meeting their own personal learning needs was a motivating factor and 10 of the 24 participants reported learning informally to meet the needs of the healthcare organization/SLP profession. Results were compared to past research on SLPs' information retrieval behaviours. It was concluded that SLPs acknowledge their personal work-related gaps in knowledge and skills and actively seek to develop their knowledge and skill base through informal means. PMID- 21682544 TI - The impact of bilingual language learning on whole-word complexity and segmental accuracy among children aged 18 and 36 months. AB - This study investigates the phonological acquisition of 19 monolingual English children and 21 English?French bilingual children at 18 and 36 months. It contributes to the understanding of age-related changes to phonological complexity and to differences due to bilingual language development. In addition, preliminary normative data is presented for English children and English?French bilingual children. Five measures were targeted to represent a range of indices of phonological development: the phonological mean length of utterance (pMLU) of the adult target, the pMLU produced by the child, the proportion of whole-word proximity (PWP), proportion of consonants correct (PCC), and proportion of whole words correct (PWC). The measures of children's productions showed improvements from 18 to 36 months; however, the rate of change varied across the measures, with PWP improving faster, then PCC, and finally PWC. The results indicated that bilingual children can keep pace with their monolingual peers at both 18 months and 36 months of age, at least in their dominant language. Based on these findings, discrepancies with monolingual phonological development that one might observe in a bilingual child's non-dominant language could be explained by reduced exposure to the language rather than a general slower acquisition of phonology. PMID- 21682545 TI - Utilization of visual information and listener strategies in intelligibility impairment related to bilateral facial paresis. AB - This study investigated how intelligibility scores of a speaker with bilateral facial paresis differed in auditory-only and auditory-visual presentation modes. A speech sample was collected and movies were created in both auditory-only and auditory-visual modes. These movies were presented to listeners who were unfamiliar with the speaker (n=20) with 10 of the listeners randomly assigned to the auditory-only listening mode and 10 assigned to the auditory-visual mode. Listeners transcribed what they heard and also completed a scale to determine the strategies used to understand this speaker's utterances. Results of ANOVA revealed that intelligibility in the auditory-visual condition was significantly greater than intelligibility for the auditory-only condition. Listeners reported utilizing many strategies to transcribe the speaker's utterances and listeners in the auditory-visual mode utilized cognitive strategies significantly more than listeners in the auditory-only mode. Findings of this study highlight the importance of visual information provided to listeners, as well as the types of strategies that listeners may use or be taught to use in understanding speakers with dysarthria. PMID- 21682546 TI - Oral language competence in incarcerated young offenders: links with offending severity. AB - Previous research in Australia and overseas has shown that young offenders serving community-based orders are at high-risk for undetected but clinically significant oral language difficulties. However, this phenomenon has received little attention in incarcerated samples, and links with offending severity, mental health, and other markers of early risk have not previously been systemically examined. A cross-sectional examination of 100 young offenders (mean age 19.03 years) completing custodial sentences in Victoria, Australia was conducted. A range of standardized oral language, IQ, mental health, and offending severity measures was employed. Forty-six per cent of participants were classified as language impaired (LI), and these were compared with the non-LI sub group on background and offending variables. When the sub-group with high scores on a measure of offending severity was compared with those with (relatively) lower offending scores, significant differences on a range of language measures were identified. A range of early risk indicators (such as placement in Out of Home Care) was also examined with respect to language impairment in this high risk group. Results are discussed with respect to policy and practice pertaining to early intervention for vulnerable children, and implications for service delivery within the justice system. In particular, emphasis is placed on the need to closely examine the oral language skills of children who struggle with the transition to literacy and then display behavioural difficulties in the classroom. Once a young person is engaged with youth justice services, a high index of suspicion should be maintained with respect to their oral language skills; for example, in relation to forensic interviewing and the ability to benefit from verbally mediated interventions. PMID- 21682547 TI - Strontium- and zinc-alginate hydrogels for bone tissue engineering. AB - The development of bone replacement materials is an important healthcare objective due to the drawbacks of treating defects with bone autografts. In this work we propose a bone tissue engineering approach in which arginine-glycine aspartic acid (RGD)-modified alginate hydrogels are crosslinked with bioactive strontium and zinc ions as well as calcium. Strontium was chosen for its ability to stimulate bone formation, and zinc is essential for alkaline phosphatase (ALP) activity. Calcium and strontium gels had similar stiffnesses but different stabilities over time. Strontium gels made with alginate with a high percentage of guluronic acid residues (high G) were slow to degrade, whereas those made with alginate rich in mannuronic acid (high M) degraded more quickly, and supported proliferation of Saos-2 osteoblast-like cells. After an initial burst, strontium release from alginate gels was steady and sustained, and the magnitude of release from high M gels was biologically relevant. Saos-2 cultured within alginate gels upregulated the osteoblast phenotypic marker genes RUNX2, collagen I (COL1A1) and bone sialoprotein (BSP), and ALP protein activity was highest in alginate gels cast with strontium ions. This strategy has the potential to be combined with other alginate-based systems for bone tissue engineering, or adapted to other tissue engineering applications. PMID- 21682548 TI - Maternal-fetal proinflammatory cytokine gene polymorphism and preterm birth. AB - Association between maternal-fetal proinflammatory cytokine genotype and preterm birth was studied. Isolated genomic DNA from maternal and cord blood samples of 100 preterm and 101 term labors were used for TNFalpha (-238G/A, -308G/A), IL 1alpha (4845G/T), and IL-1beta (-511C/T) genotyping. TNFalpha -238 GA genotype in term neonates was significantly higher than the premature neonates (p<0.05). Maternal-fetal TNFalpha -238 heterozygosity was associated with term labor (p<0.05). TNFalpha -308 GA and AA genotypes were associated with term labor (mothers and neonates, respectively; p<0.05 and p<0.001). The incidence of term labor was significantly increased in TNFalpha -308 GA genotype. If a -308GA carrier has a fetus with GG genotype, the incidence of preterm labor increases (p<0.01). The 4845 T allele was significantly higher in preterm mothers and neonates (p<0.001 and p<0.001). The effect of maternal-fetal genotype for the pregnancy outcome reveals that maternal 4845GG and GT genotypes increase term labor incidence, whereas fetal 4845 TT genotype was a significant independent risk factor for preterm birth (p<0.01). IL-1beta -511 TT genotype was significantly higher in preterm neonates. The preterm labor risk was significantly increased in maternal -511 TT genotype and fetal CT genotypes, whereas with maternal -511 CT or TT genotypes or a -511 TT fetus, the incidence of term pregnancy increases (p<0.01). PMID- 21682549 TI - Effects of C-reactive protein on CC chemokine receptor 2-mediated chemotaxis of monocytes. AB - Periodontal infections can increase patients' serum C-reactive protein (CRP) level, which is a predictive marker of future cardiovascular events. Serum CRP may be a key mediator associating periodontitis with cardiovascular disease. It is not yet clarified whether the chemotactic activity of monocytes changes with increased serum CRP. This study investigated the influence of CRP on monocyte chemotaxis and the effects of CRP on CC chemokine receptor 2 (CCR2) expression by monocytes in vitro. Monocyte cell line THP-1 was cultured with human recombinant CRP of different final concentrations, which were 2, 4, 6, 8, and 10 mg/L, respectively. After 24 h incubation, Transwell chambers were applied to analyze the chemotactic activity of pretreated monocytes. Flow cytometry analysis and real-time reverse transcription-polymerase chain reaction (RT-PCR) were applied to detect the CCR2 protein and gene expression levels. In Transwell chambers, more cells were attracted in CRP-pretreated groups than that of blank control with no CRP (p<0.05). The chemotaxis activity was stronger in higher CRP concentration groups than lower ones (p<0.05). The CCR2 protein and mRNA expression was increased in a CRP concentration-dependent manner (p<0.05). CRP stimulation may induce CCR2 overexpression on monocytes and then promote the chemotaxis ability of monocytes. This result suggests that increased serum CRP concentration of periodontitis patients may be associated with high risk of cardiovascular disease. PMID- 21682550 TI - Trends in endometrial cancer incidence rates in the United States, 1999-2006. AB - BACKGROUND: Risk factors for endometrial cancer, such as hormone replacement therapy (HRT) and obesity, have changed significantly in the last decade. We investigated trends in endometrial cancer histologic subtypes on a national level during 1999-2006. METHODS: Data covering 88% of the U.S. population were from central cancer registries in the National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results (SEER) programs that met high-quality United States Cancer Statistics (USCS) criteria. Our analyses included females with microscopically confirmed invasive uterine cancer (n=257,039). Age-adjusted incidence rates and trends for all invasive uterine cancers and by endometrial cancer histologic subtypes (type I and II) were assessed. RESULTS: There were 145,922 cases of type I endometrial cancers and 15,591 cases of type II for 1999 2006. We found that type I endometrial cancers have been increasing, whereas type II endometrial cancers and all invasive uterine cancers have been relatively stable throughout the 1999-2006 period. CONCLUSIONS: During the past decade, the overall burden of uterine cancer has been stable, although there have been changes in underlying histologies (e.g., endometrial). Changes in trends for underlying histologies may be masked when reviewing trends irrespective of histologic subtypes. Our findings suggest the need to examine trends of uterine cancer by histologic subtype in order to better understand the burden of endometrial cancer in relation to these subtypes to help women at increased risk for developing more aggressive types of endometrial cancer (e.g., type II). PMID- 21682551 TI - Drug-drug interactions with statins: will pitavastatin overcome the statins' Achilles' heel? AB - BACKGROUND: As the clinical complexity of patients at high cardiovascular risk and with multiple comorbid conditions increases, so does the potential for drug drug interactions (DDIs). Large retrospective studies in various clinical settings have shown that an unacceptably large proportion of patients are coprescribed a statin with potentially interacting therapies, suggesting that the impact of polypharmacy on the safety profile of statins may be underappreciated. SCOPE: To assess the evidence for the burden of DDIs and related adverse drug reactions (ADRs) with current statins relative to pitavastatin, a new agent recently approved in the USA and EU. METHODS: Structured review of the PubMed and EMBASE databases (to 15 October 2010) for literature on statins in the areas of ADRs, polypharmacy and DDIs; pharmacokinetics, and pitavastatin clinical safety and efficacy. FINDINGS: Patients who are on statin therapy are often receiving multiple medications for comorbid conditions, and so are at increased risk of ADRs, such as myopathy, because of pharmacokinetic interactions at the level of cytochrome P450 (CYP) enzymes and/or organic anion-transporting polypeptides. Pitavastatin has a distinctive metabolic profile that means it is marginally metabolised by CYP enzymes, and is therefore expected to have a low risk of DDIs and related ADRs. A large post-marketing study conducted in more than 20,000 patients in Japan has demonstrated that the rate of DDIs with pitavastatin treatment may compare favourably with that observed with atorvastatin and rosuvastatin. CONCLUSIONS: The addition of pitavastatin to the range of available statins provides prescribing physicians with a new treatment option that is expected to have a low risk of DDIs and related ADRs. This, coupled with the demonstrated efficacy of pitavastatin in reducing low-density lipoprotein cholesterol, should help physicians individualise lipid-lowering regimens based on the patient profile and concomitant medications. PMID- 21682552 TI - Simplifying anemia management in hemodialysis patients: ESAs administered at longer dosing intervals can enhance opportunities to provide patient-focused care. AB - OBJECTIVE: To review issues and challenges in caring for hemodialysis patients with anemia of chronic kidney disease, specifically focusing on the effects of longer erythropoiesis-stimulating agent (ESA) dosing intervals on processes of care. METHODS: PubMed searches were performed limited to the last 10 years to February 2011, focusing on articles in English that were 'clinical trials,' assessed processes of care, measured associations of hemoglobin (Hb) with outcomes, and explored/analyzed extended dosing intervals of ESAs in hemodialysis patients and recommendations for increasing the quality of care of these patients. Some limitations included the fact that a meta-analysis was not conducted; many studies were associative and therefore unable to prove causality; and none of the clinical trials directly compared the impact of more frequent or less frequent ESA dosing strategies on patient care and outcomes. FINDINGS: Progress over the past several decades has been substantial; however, unmet needs remain and there is room for improvement in efficiencies of care. Many patients fail to meet Hb targets, and nephrology professionals' time is consumed with preparing, administering, and monitoring therapy. Direct interaction between patients and care providers has been lost as attention has shifted to 'cost effective' (not necessarily patient-centered) ways to deliver care. Use of ESAs at longer dosage intervals represents one opportunity to improve efficiency of care. Newer ESAs have been developed for less frequent dosing. Once-monthly dosing decreases time spent administering/monitoring therapy and allows nephrology professionals to provide comprehensive renal care, wherein the patient rather than task-oriented processes becomes the primary focus. CONCLUSIONS: A fragmented, uncoordinated care-delivery model heightens the urgency to systematically address issues related to delivery of care and improve efficiencies in anemia management as part of the patient-centered approach. ESAs designed for administration at longer intervals may effectively and reliably achieve Hb targets with once-monthly dosing, thereby decreasing time spent administering/monitoring therapy. PMID- 21682553 TI - Effects of a secondary prevention combination therapy with an aspirin, an ACE inhibitor and a statin on 1-year mortality of patients with acute myocardial infarction treated with a beta-blocker. Support for a polypill approach. AB - OBJECTIVE: Large randomized clinical trials have shown the efficacy of aspirin, ACE (angiotensin converting enzyme) inhibitors and statins as secondary prevention measures in patients after an acute coronary syndrome with and without ST elevations. Therefore we aimed to determine the effect of a combination therapy with these three drugs on 1-year mortality after acute myocardial infarction (AMI). METHODS: We prospectively followed 9998 survivors of acute myocardial infarction treated with a beta-blocker for 1 year. Patients were divided into three groups according to their therapy with aspirin, ACE inhibitors and statins: 3 drugs, 2 drugs or 0-1 drug. RESULTS: The majority of patients (n = 6260, 62.6%) were treated with 3 drugs, 2986 (29.9%) with 2 drugs and 752 (7.5%) with 0-1 drug. In the univariate analysis 1-year mortality was 4.9%, 9.7% and 13.6%, respectively. After adjusting for confounding factors in the propensity score analysis the odds ratios for 1-year mortality were significantly increased with 0-1 drug (odds ratio 1.67, 95% CI 1.24-2.27) and with 2 drugs (odds ratio 1.54, 95% CI 1.26-1.87) in comparison with the group treated with all 3 drugs. However, in the ACOS registry the treatment was left to the discretion of the physician. This could lead to a selection bias, which cannot be fully eliminated by using multiple regression analysis. CONCLUSIONS: A combination therapy with aspirin, an ACE inhibitor and a statin reduces 1-year mortality in patients after AMI. Therefore a polypill approach with these three agents should be considered to increase drug compliance and reduce mortality after acute myocardial infarction. PMID- 21682554 TI - Association between sexual behavior and cervical cancer screening. AB - BACKGROUND: Not much is known about whether women who follow Pap testing recommendations report the same pattern of sexual behavior as women who do not. METHODS: Data come from part of a larger population-based computer-assisted telephone survey of 8656 Australians aged 16-64 years resident in Australian households with a fixed telephone line (Australian Longitudinal Study of Health and Relationships [ALSHR]). The main outcome measure in the current study was having had a Pap test in the past 2 years. RESULTS: Data on a weighted sample of 4052 women who reported sexual experience (ever had vaginal intercourse) were analyzed. Overall, 73% of women in the sample reported having a Pap test in the past 2 years. Variables individually associated with Pap testing behavior included age, education, occupation, cohabitation status, residential location, tobacco and alcohol use, body mass index (BMI), lifetime and recent number of opposite sex partners, sexually transmitted infection (STI) history, and condom reliance for contraception. In adjusted analyses, women in their 30s, those who lived with their partner, and nonsmokers were more likely to have had a recent Pap test. Those who drank alcohol at least weekly were more likely to have had a recent test than irregular drinkers or nondrinkers. Women with no sexual partners in the last year were less likely to have had a Pap test, and women who reported a previous STI diagnosis were more likely to have had a Pap test in the past 2 years. CONCLUSIONS: There are differences in Pap testing behavior among Australian women related to factors that may affect their risk of developing cervical abnormalities. Younger women and regular smokers were less likely to report a recent test. Screening programs should consider the need to focus recruitment strategies for these women. PMID- 21682556 TI - Identification and characterization of a mitochondrial manganese superoxide dismutase of Spirometra erinacei. AB - A gene encoding the manganese superoxide dismutase (Mn-SOD) of Spirometra erinacei was identified, and the biochemical properties of the recombinant enzyme were partially characterized. The S. erinacei Mn-SOD gene consisted of 669 bp, which encoded 222 amino acids. A sequence analysis of the gene showed that it had typical molecular structures, including characteristic metal-binding residues and motifs that were conserved in Mn-SODs. An analysis of the N-terminal presequence of S. erinacei Mn-SOD revealed that it had physiochemical characteristics commonly found in mitochondria-targeting sequences and predicted that the enzyme is located in the mitochondria. A biochemical analysis also revealed that the enzyme is a typical Mn-SOD. The enzyme was consistently expressed in both S. erinacei plerocercoid larvae and adult worms. Our results collectively suggested that S. erinacei Mn-SOD is a typical mitochondrial Mn-SOD and may play an important role in parasite physiology, detoxifying excess superoxide radicals generated in the mitochondria. PMID- 21682557 TI - Discovery of Opisthorchis lobatus (Trematoda: Opisthorchiidae): a new record of small liver flukes in the Greater Mekong Sub-region. AB - Metacercariae, morphologically similar to those of small liver flukes, were found to parasitize red-tailed snakehead fish, Channa limbata, collected from the city of Vientiane, Lao People's Democratic Republic. Adult worms that were recovered from experimentally-infected hamsters showed characteristics distinctly different from Opisthorchis viverrini, but closely similar to Opisthorchis lobatus, which was first reported in poultry (Anas sp.) from Pakistan. The present study aimed to redescribe O. lobatus based on the adult worms recovered from experimentally infected hamsters. Additionally, it aimed to document the genetic relationships among O. lobatus and other opisthorchiid liver flukes using the mitochondrial cytochrome c oxidase subunit 1 (COI) gene and the internal transcribed spacer 2 (ITS2) region. DNA alignment of the O. lobatus and O. viverrini COI partial sequences (330 bp) showed 3.03% fixed differences (2.72% of amino acids changed) while the ITS2 region (350 bp) indicated a 0.86% difference for nucleotides. Species boundaries between the 2 parasites were determined by neighbor-joining analysis using the molecular sequence data. The phenogram confirmed that O. lobatus was distinctly different from O. viverrini, representing the first reported instance of O. lobatus in the Greater Mekong Sub-region (GMS) and the first record of C. limbata as the second intermediate host of a small liver fluke. Questions regarding human infection and the extent of the geographic distribution of these species should be investigated further. PMID- 21682558 TI - Effect of deep wound infection following lumbar arthrodesis for degenerative disc disease on long-term outcome: a prospective study: clinical article. AB - OBJECT: Deep wound infections are one of the most common and serious complications of spinal surgery. The impact of such infections on long-term outcomes is not well understood. The purpose of this study was to evaluate the functional status and satisfaction in patients who suffered a deep wound infection after undergoing lumbar arthrodesis for symptomatic degenerative disc disease. METHODS: The authors conducted a prospective study in 13 patients with a clinical and radiological diagnosis of symptomatic degenerative lumbar stenosis and instability; after undergoing decompression and instrumentation-augmented arthrodesis, the patients suffered a deep wound infection (infection group). A 3:1 (39-patient) matched cohort was selected for comparison (control group). All surgeries were performed during the same period and by a single surgeon. The postoperative infections were all treated in a similar manner and the instrumentation was not removed. Both groups were followed up and assessed with validated outcome instruments: Numerical Rating Scale of pain, Oswestry Disability Index, 36-Item Short Form Health Survey, Beck Depression Inventory, and Hospital Anxiety and Depression Scale. Patient satisfaction was also determined. RESULTS: The median follow-up duration was 22 months (range 6-108 months). The mean patient age was 62 +/- 10 years, and 59.6% of the patients were female. There was no significant difference between the groups in pain, functional disability, quality of life, or depression and anxiety. However, 53.8% of the patients with infection were not satisfied with the procedure at the final evaluation, compared with 15.4% of the patients without a deep wound infection (p = 0.003). CONCLUSIONS: Patients with successfully treated postoperative deep wound infections do not have a difference in functional outcome compared with patients who underwent an identical operation but did not suffer a complicating infection. Patients who suffered an infection were more likely to be unsatisfied with the procedure than patients who did not. PMID- 21682559 TI - Expression of water channel aquaporin-4 during experimental syringomyelia: laboratory investigation. AB - OBJECT: Aquaporins (aqp) are protein channels providing water transport across cell membranes. The main member of this family expressed in the CNS is aqp-4. The pattern and amount of expression of this channel suggest a dominant role in bulk water movement into the nervous tissue. It has also been shown to play a role in several water balance disorders in the CNS. In this study, the authors investigated the possible role of aqp-4 in syringomyelia. METHODS: Twenty-five male Wistar-Hannover rats were divided into experimental (20 rats) and control (5 rats) groups. Syringomyelia was induced in the experimental group by kaolin injection into the cisterna magna. Eight weeks later, the animals were killed, and their spinal cords were removed. Central canal dilations were noted in all experimental animals. Immunohistochemistry and Western blot analysis were performed to evaluate aqp-4 expression. RESULTS: Both groups demonstrated positive immunoreactive signals to aqp-4. Western blot analysis revealed a slight decrease in the mean aqp-4 value in the experimental group; however, the difference did not reach statistical significance (p > 0.05). Immunohistochemical analysis showed a similar pattern and intensity of aqp-4 staining in both groups. CONCLUSIONS: The results of this study indicate that aqp-4 most likely does not play a major role in chronic syringomyelia. Its slight downregulation during the initial stage of syrinx formation is possibly a compensatory mechanism. This effect is not present during the late stage of syringomyelia, and aqp-4 is most likely not involved in the pathophysiology of syrinx cavity formation. PMID- 21682561 TI - A new transvenous approach to the carotid-cavernous sinus via the inferior petrooccipital vein. AB - OBJECT: The transvenous approach via the inferior petrosal sinus (IPS) is commonly used as the most appropriate for carotid-cavernous fistula (CCF) or cavernous sinus sampling. However, sometimes the IPS is not accessible because of anatomical problems and/or complications, therefore an alternative route is needed. In this paper, the authors present and discuss the utility of a transvenous approach to the cavernous sinus via the inferior petrooccipital vein. METHODS: Four patients, 3 with dural CCFs and the other with Cushing disease, in whom endovascular surgical attempts failed using a conventional venous approach via the IPS, underwent a transvenous approach to the cavernous sinus via the inferior petrooccipital vein (IPOV). One dural CCF case had only cortical venous drainage, the second CCF also mainly drained into the cortical vein with slight inflow into the superior ophthalmic vein and inferior ophthalmic vein, and the third demonstrated drainage into the superior and inferior ophthalmic veins and IPOV. RESULTS: In all cases, the cavernous sinus could be accessed successfully via this route and without complications. CONCLUSIONS: The transvenous approach to the cavernous sinus via the IPOV should be considered as an alternative in cases when use of the IPS is precluded by an anatomical problem and there are no other suitable venous approach routes. PMID- 21682562 TI - Facial nerve function after vestibular schwannoma surgery. AB - OBJECT: The object of this study was to evaluate long-term postoperative facial nerve (FN) function in patients undergoing vestibular schwannoma (VS) surgery. METHODS: The authors retrospectively reviewed the clinical course of patients affected by isolated VSs with normal preoperative FN function, with no previous surgical or radiotherapeutic treatment, and who underwent surgery between 1987 and 2007. Facial nerve function was clinically evaluated according to the House Brackmann (HB) scale. The minimum postoperative follow-up was 12 months. RESULTS: Among the 1550 patients surgically treated at the authors' center, 1151 matched inclusion criteria for the present study. The FN was anatomically interrupted in 48 cases (4.2%), and 51 patients (4.4%) underwent subtotal tumor removal and were considered separately. Among the 1052 patients with anatomically preserved FNs and total tumor removal, 684 (65%) enjoyed postoperative HB Grade I or II and 309 (29.4%) enjoyed Grade III, with the remaining 59 cases (5.6%) suffering unsatisfactory results (HB Grades IV-VI). As expected, FN function results deteriorated in cases of larger tumors. CONCLUSIONS: The main factor influencing postoperative FN function was tumor size. Although there was a progressive deterioration in FN function outcome in relation to tumor size, a cutoff point between satisfactory and unsatisfactory results could be identified at around 2 cm in maximum extrameatal tumor diameter, with the "optimal size" for surgery identified at < 1 cm. This finding emphasizes the importance of an early diagnosis and should be kept in mind when selecting the correct timing for VS removal. For small lesions, the results following a middle cranial fossa approach were significantly worse as compared with those following the translabyrinthine and retrosigmoidretrolabyrinthine approaches. PMID- 21682563 TI - Dr. Harvey Cushing's attempts to cure migraine based on theories of pathophysiology. AB - A multitude of theories characterized medical thought on migraine in the early 20th century. Newly discovered historical case files revealed Dr. Harvey Cushing's previously unpublished early attempts at surgical cure of migraine. Following institutional review board approval, and through the courtesy of the Alan Mason Chesney Archives, the authors reviewed the microfilm surgical records for The Johns Hopkins Hospital from 1896 to 1912. Patients undergoing surgical intervention by Dr. Harvey Cushing for the treatment of migraine were selected for further review. All 4 patients in the series were women and ranged in age from 29 to 41 years old. The women were admitted and observed in the hospital until a migraine occurred. Surgeries were performed while the women were in the midst of an attack. Cushing used surgical strategies including decompression, temporal artery ligation, and removal of the spine of the second vertebra. In each case, the patients' headaches eventually returned following surgery. Cushing relied on a combination of contemporary theories on migraine including humeral science, vasospastic theory, organic cause, and increased intracranial pressure. His unpublished efforts foreshadowed future surgical efforts at curing migraines. PMID- 21682564 TI - Acute subdural hematoma. PMID- 21682565 TI - Immunoliposomal drug-delivery system targeting lectin-like oxidized low-density lipoprotein receptor-1 for carotid plaque lesions in rats. AB - OBJECT: Targeted drug delivery with immunoliposomes has been applied to various in vivo animal models and is newly focused as a novel therapeutic target. Lectin like oxidized low-density lipoprotein receptor-1 (LOX1) is a potent regulator of systemic atherosclerosis, and the authors focused on its effect on carotid plaques. The authors developed a LOX1-targeted liposomal rho-kinase inhibitor and examined the therapeutic effect on carotid intimal hypertrophy in rats. METHODS: LOX1-targeted rho-kinase inhibitor fasudil-containing liposomes, composed of hydrogenated soy phosphatidylcholine/cholesterol/PEG(2000)-DSPE, were prepared by conjugating anti-LOX1 antibodies on the surface and by remote loading of fasudil. Carotid intimal hypertrophy was induced by balloon injury, and the drugs were intravenously administered on Day 3 postinjury. The rats were divided into 4 groups: nontreatment, treatment with intravenous fasudil (2 mg), treatment with liposomal fasudil (2 mg), and treatment with LOX1-targeted liposomal fasudil (2 mg). The authors compared intimal hypertrophy, atherosclerotic factor, and matrix metalloproteinase-9 expression among groups. RESULTS: DiI-labeled LOX1-targeted liposomes were prominently observed in the lesions on Day 7 after the surgery. The intimal thickness was significantly reduced in the LOX1-targeted liposomal fasudil-treated group (mean 81.6 +/- 13.9 MUm) compared with the other groups (no treatment 105.4 +/- 16.8 MUm; fasudil treatment 102.4 +/- 20.0 MUm; and liposomal fasudil treatment 102.8 +/- 22.2 MUm; p = 0.046). Matrix metalloproteinase-9 expression was also significantly reduced in the LOX1-targeted liposomal fasudil group. CONCLUSIONS: Liposomes conjugated with anti-LOX1 antibody effectively reached carotid artery lesions, and liposomal rho-kinase significantly inhibited intimal hypertrophy. The new liposomal drug delivery system targeting LOX1 may become a therapeutic strategy for atherosclerotic diseases. PMID- 21682566 TI - Cruveilhier plexus: an anatomical study and a potential cause of failed treatments for occipital neuralgia and muscular and facet denervation procedures. AB - OBJECT: The nerves of the posterior neck are often encountered by the neurosurgeon and are sometimes the focus of denervation procedures for muscular, joint, or nervous pathologies. One collection of fibers in this region that has not been previously investigated is the Cruveilhier plexus, interneural connections between the dorsal rami of the upper cervical nerves. METHODS: Fifteen adult cadavers (30 sides) were subjected to dissection of the upper cervical and occipital regions with special attention given to identifying potential connections between adjacent extradural dorsal rami of the cervical nerves. When connections were identified, measurements were made and random samples were immunohistochemically stained. RESULTS: At least one communicating branch was identified on 86.7% of sides. Sampled nervous loops were composed primarily of sensory fibers, but occasional motor fibers were identified. For C 1, a communicating loop joined the medial branches of C-2 on 65.4% of sides. On 29.4% of sides, this loop pierced the obliquus capitis inferior muscle before joining C-2. On 54% of sides, a communicating loop joined the medial branches of the dorsal rami of C-2 and C-3; and on 15.4% of sides, a communicating loop joined the medial branches of the dorsal rami of C-3 and C-4. No specimen had communicating branches between the dorsal rami of cervical nerves C-5 to C-8. Articular branches arose from the deep surface of the interneural connections as they crossed the adjacent facet joint on 34.6% of sides. Loops giving rise to fibers that terminated into surrounding musculature were seen on 35% of sides. CONCLUSIONS: Physical examinations that reveal unexpected results, such as altered sensory dermatome findings, may be attributed to the Cruveilhier plexus. Based on findings in the present study, surgical procedures, such as those aimed at completely denervating the upper posterior cervical musculature, facets, or nerves supplying the skin of the occiput, must also transect the Cruveilhier plexus. PMID- 21682568 TI - Delayed diagnosis of aneurysmal subarachnoid hemorrhage in patients: a community based study. AB - OBJECT: A community-based study was conducted to estimate the frequency of and evaluate the clinical features related to delayed diagnosis of aneurysmal subarachnoid hemorrhage (SAH). METHODS: Between 1980 and 1998, 358 patients with aneurysmal SAH underwent treatment in Izumo, Japan. The diagnosis of SAH was delayed in 76 patients (21%) and was early in 282 (79%). Among the 76 patients whose diagnosis was delayed, the condition was misdiagnosed by clinicians in 46 cases (Subgroup A), and in the remaining 30 the patients were unaware that SAH had occurred and failed to seek prompt treatment (Subgroup B). RESULTS: The proportion of Subgroup A patients decreased significantly from 18% (30 of 170 patients) between 1980 and 1989 to 9% (16 of 188 patients) between 1990 and 1998 (p = 0.0098), whereas the proportion of Subgroup B patients during the same periods was 8% (13 of 170 patients) and 9% (17 of 188 patients), respectively (p = 0.6341). With regard to Subgroup A, the misdiagnosis rate in private clinics decreased from 14% (23 of 170 patients) between 1980 and 1989 to 5% (10 of 188 patients) between 1990 and 1998 (p = 0.0073), whereas the misdiagnosis rate in hospitals during the same periods was 4% (7 of 170 patients) and 3% (6 of 188 patients), respectively (p = 0.6399). Multivariate analysis revealed that World Federation of Neurosurgical Societies Grade I or II was the main risk factor for delayed diagnosis of SAH (OR 3.97 [95% CI 1.69-10.37]), and that the timing of SAH onset, that is, between 12:00 a.m. and 6:00 a.m., was an important reason for the condition in Subgroup B patients (OR 9.29 [95% CI 2.66-33.93]). Rebleeding before admission occurred in 26% of the patients in whom diagnosis was delayed, and in 3% of those who were diagnosed early (p < 0.0001). CONCLUSIONS: Although the rate of SAH misdiagnosis seems to be decreasing, failure of patients to present for prompt treatment is unlikely to decrease unless the public becomes better educated about SAH and the importance of getting prompt medical attention, even in the middle of the night. PMID- 21682567 TI - Proteomic identification of glutamine synthetase as a differential marker for oligodendrogliomas and astrocytomas. AB - OBJECT: Astrocytomas and oligodendrogliomas are primary CNS tumors that remain a challenge to differentiate histologically because of their morphological variability and because there is a lack of reliable differential diagnostic markers. To identify proteins that are differentially expressed between astrocytomas and oligodendrogliomas, the authors analyzed the proteomic expression patterns and identified uniquely expressed proteins in these neoplasms. METHODS: Proteomes of astrocytomas and oligodendrogliomas were analyzed using 2D gel electrophoresis and subsequent computerized gel analysis to detect differentially expressed proteins. The proteins were identified using high performance liquid chromatography accompanied by tandem mass spectrometry. To determine the role of the differentially expressed proteins in astrocytes, undifferentiated glial cell cultures were treated with dibutyryl-cyclic adenosine monophosphate (cAMP). RESULTS: Two-dimensional gel electrophoresis revealed that glutamine synthetase was differentially expressed in astrocytomas and oligodendrogliomas. Western blot and immunohistochemical analyses confirmed the increased expression of glutamine synthetase in astrocytomas compared with oligodendrogliomas. Whereas glutamine synthetase expression was demonstrated across all grades of astrocytomas (Grade II-IV [15 tumors]) and oligoastrocytomas (4 tumors), it was expressed in only 1 oligodendroglioma (6% [16 tumors]). Treatment of undifferentiated glial cell cultures with dibutyryl-cAMP resulted in astrocyte differentiation that was associated with increased levels of glial fibrillary acidic protein and glutamine synthetase. CONCLUSIONS: These data indicate that glutamine synthetase expression can be used to distinguish astrocytic from oligodendroglial tumors and may play a role in the pathogenesis of astrocytomas. PMID- 21682569 TI - Temporizing treatment of hyperacute subdural hemorrhage by subdural evacuation port system placement. AB - An acute subdural hematoma (SDH) requiring surgical intervention is treated with craniotomy or craniectomy, in part because it is generally accepted that coagulated blood present in the acute phase cannot be adequately evacuated by less-invasive means such as bur hole drainage. However, a hyperacute SDH in the first few hours after trauma can have mixed-density components on CT scans that are thought to represent subdural blood that is not yet fully coagulated. The authors report a case in which a hyperacute SDH in a patient receiving antiplatelet therapy was treated with the novel technique of temporizing subdural evacuation port system (SEPS) placement. Placement of an SEPS in the intensive care unit allowed for rapid surgical treatment of the patient's elevated intracranial pressure (ICP) by drainage of 70 ml of fresh subdural blood. After initial SEPS-induced stabilization, the patient underwent operative treatment of the SDH by craniotomy. The combined approach of emergency SEPS placement followed by craniotomy resulted in a dramatic recovery, with improvement from coma and extensor posturing to a normal status on neurological evaluation 5 weeks later. In appropriately selected cases, patients with a hyperacute SDH may benefit from SEPS placement to quickly treat elevated ICP, as a bridge to definitive surgical treatment by craniotomy. PMID- 21682570 TI - Influence of surgical or endovascular treatment on visual symptoms caused by intracranial aneurysms: single-center series and systematic review. AB - OBJECT: Intracranial aneurysms of the anterior circulation might become symptomatic by causing visual deficits. The influence of treatment modality on improvement is still unclear. The objective of this study was to analyze the recovery of visual deficits caused by the mass effect of intracranial aneurysms after surgical clipping or endovascular treatment. METHODS: Between June 1999 and December 2009, 20 patients with unruptured intracranial aneurysms causing visual dysfunction due to compression of the optical nerve were treated at the authors' institution. Visual deficits were recorded at admission and at follow-up. To evaluate a larger number of patients, MEDLINE was searched for published studies involving visual disturbance caused by an aneurysm. A multivariate analysis was performed to find independent predictors for favorable visual outcome. RESULTS: Nine (75%) of 12 patients treated surgically achieved improvement of visual symptoms, compared with 3 (38%) of 8 patients treated endovascularly. A literature review, including the current series, revealed a total of 165 patients with UIAs causing visual dysfunction. Surgical treatment was associated with a significantly higher rate of visual improvement (p = 0.002) compared with endovascular treatment. According to the multivariate analysis, surgical clipping was the only variable significantly associated with improvement of visual outcome (p = 0.02). CONCLUSIONS: Aneurysm-related visual dysfunction developed from direct mechanical compression may improve after surgical clipping and endovascular coiling. However, based on the present series combined with pooled analysis of data from the literature, the only factor significantly associated with improvement of visual dysfunction was surgical clipping. PMID- 21682571 TI - Trans sodium crocetinate: functional neuroimaging studies in a hypoxic brain tumor. AB - OBJECT: Intratumoral hypoxia is believed to be exhibited in high-grade gliomas. Trans sodium crocetinate (TSC) has been shown to increase oxygen diffusion to hypoxic tissues. In this research, the authors use oxygen-sensitive PET studies to evaluate the extent of hypoxia in vivo in a glioblastoma model and the effect of TSC on the baseline oxygenation of the tumor. METHODS: The C6 glioma cells were stereotactically implanted in the right frontal region of rat brains. Formation of intracranial tumors was confirmed on MR imaging. Animals were injected with Copper(II) diacetyl-di(N4-methylthiosemicarbazone) (Cu-ATSM) and then either TSC or saline (6 rats each). Positron emission tomography imaging was performed, and relative uptake values were computed to determine oxygenation within the tumor and normal brain parenchyma. Additionally, TSC or saline was infused into the animals, and carbonic anhydrase 9 (CA9) and hypoxia-inducing factor-1alpha (HIF-1alpha) protein expression were measured 1 day afterward. RESULTS: On PET imaging, all glioblastoma tumors demonstrated a statistically significant decrease in uptake of Cu-ATSM compared with the contralateral cerebral hemisphere (p = 0.000002). The mean relative uptake value of the tumor was 3900 (range 2203-6836), and that of the contralateral brain tissue was 1017 (range 488-2304). The mean relative hypoxic tumor volume for the saline group and TSC group (6 rats each) was 1.01 +/- 0.063 and 0.69 +/- 0.062, respectively (mean +/- SEM, p = 0.002). Infusion of TSC resulted in a 31% decrease in hypoxic volume. Immunoblot analysis revealed expression of HIF-1alpha and CA9 in all tumor specimens. CONCLUSIONS: Some glioblastomas exhibit hypoxia that is demonstrable on oxygen-specific PET imaging. It appears that TSC lessens intratumoral hypoxia on functional imaging. Further studies should explore relative hypoxia in glioblastoma and the potential therapeutic gains that can be achieved by lessening hypoxia during delivery of adjuvant treatment. PMID- 21682573 TI - Intergenerational relations and the family food environment in families with a child with obesity. AB - BACKGROUND: Implicit in much of the literature on childhood obesity is a hierarchical, unidirectional understanding of intergenerational relations, which highlights parents' responsibility for children's food and eating practices. AIM: Drawing upon alternative understandings from the social science literature, which offer more nuanced insights into family life and generational relations, this paper explores, through parents' narratives, the construction of family food environments and family eating practices in families with a child with obesity. SUBJECTS AND METHODS: Data were generated through individual, semi-structured interviews with parents of children attending a community-based obesity intervention programme in an inner city area in the North of England. Forty-nine interviews were conducted with 25 parental adults from 19 families. RESULTS: Parent's own concerns over their body weight and size and children's social experiences in a fat-averse society can both work to flatten the traditional familial, adult-child hierarchy. Both parents and children actively contribute to the construction of family life and family eating practices. CONCLUSION: Findings may pose challenges for contemporary health promotion and policy agendas which presume that parents have the ability and resources to control and direct children's eating in a unidirectional and authoritative manner. PMID- 21682574 TI - A whole family approach to childhood obesity management (GOALS): relationship between adult and child BMI change. AB - BACKGROUND: A growing body of evidence advocates a multidisciplinary, family focused approach to childhood obesity management, but there is a need to explore familial factors associated with intervention success. AIM: This study explored the relationship between adult BMI change and child BMI SDS change following completion of a community-based, lifestyle change intervention for obese children and families (Getting Our Active Lifestyles Started (GOALS)). METHOD: Sixty of 121 families with overweight children completed the GOALS intervention between September 2006 and March 2009.Complete pre- and post-intervention (6 months) BMI data was available for 47 of these families, 26 of whom attended 12-month follow up. Child BMI was converted to age- and sex-specific standard deviation scores (SDS) using the 1990 UK growth references. RESULTS: There was a strong correlation between adult BMI change and child BMI SDS change from pre- to post intervention (r = 0.53, p < 0.001) and from pre-intervention to 12-month follow up (r = 0.72, p < 0.001). Over both time periods, children with adults who reduced BMI were more likely to reduce BMI SDS (p < 0.01) and showed a greater reduction in BMI SDS (p < 0.01) than children with adults who maintained or increased BMI. CONCLUSION: The results showed a strong positive association between adult BMI change and child BMI SDS change, particularly during the post intervention period where therapeutic contact was minimal. The findings suggest active involvement of adult family members in the weight loss process improves child treatment outcomes. PMID- 21682572 TI - Evidence for the intra-uterine programming of adiposity in later life. AB - AIM: Research in animals has shown that altering foetal nutrition by under nourishing or over-nourishing the mother or rendering her diabetic or foetal exposure to glucocorticoids and toxins can programme obesity in later life. The increased adiposity is mediated by permanent changes in appetite, food choices, physical activity and energy metabolism. In humans, increased adiposity has been shown in people who experienced foetal under-nutrition due to maternal famine or over-nutrition due to maternal diabetes. Lower birth weight (a proxy for foetal under-nutrition) is associated with a reduced adult lean mass and increased intra abdominal fat. Higher birth-weight caused by maternal diabetes is associated with increased total fat mass and obesity in later life. There is growing evidence that maternal obesity, without diabetes, is also a risk factor for obesity in the child, due to foetal over-nutrition effects. Maternal smoking is associated with an increased risk of obesity in the children, although a causal link has not been proven. Other foetal exposures associated with increased adiposity in animals include glucocorticoids and endocrine disruptors. CONCLUSIONS: Reversing the current obesity epidemic will require greater attention to, and better understanding of, these inter-generational (mother-offspring) factors that programme body composition during early development. PMID- 21682575 TI - A myocardial patch made of collagen membranes loaded with collagen-binding human vascular endothelial growth factor accelerates healing of the injured rabbit heart. AB - Tissue-engineered myocardial patches could be useful in the repair of myocardial injuries. The aim of the present study was to evaluate a collagen targeting delivery system for myocardial repair. A specific peptide collagen-binding domain (CBD) was fused to human vascular endothelial growth factor (VEGF) to enhance the binding of VEGF to collagen. In this study, collagen membranes loaded with CBD VEGF, natural VEGF, or phosphate-buffered saline are used as cardiac patches to repair the infarcted myocardium in a rabbit model. CBD-VEGF/collagen group could effectively induce more cells to penetrate into the collagen membrane after 4 weeks and promote more vascularization in infarcted myocardium after 12 weeks compared with the other two control groups. Echocardiography and hemodynamic studies both show cardiac function improvement in the CBD-VEGF/collagen group. These results reveal that implantation of CBD-VEGF collagen membrane patch into the infarcted myocardium could effectively improve left ventricle cardiac function and increase the vascular density. PMID- 21682576 TI - FOXL2 and SOX9 distinguish the lineage of the sex cord-stromal cells in gonadoblastomas. AB - Gonadoblastomas are mixed germ cell sex cord-stromal tumors that arise in dysgenetic gonads and are composed of immature germ cells and sex cord-stromal cells of indeterminate differentiation. FOXL2 is one of the first genes expressed in female gonad development, and it is required for proper granulosa cell differentiation during folliculogenesis. SOX9 , a downstream target of SRY , the gene in the Y chromosomal sex-determining region, is required for testicular development and for the formation and maintenance of (pre-)Sertoli cells. This study characterized the sex cord-stromal cells of gonadoblastoma by evaluating the expression of these counteracting transcription factors. Archival paraffin embedded material of 7 gonadoblastomas, 5 of which were overgrown by dysgerminoma, was examined by immunohistochemistry for expression and localization of FOXL2 and SOX9. The sex cord-stromal cells revealed strong nuclear staining for FOXL2 and were negative for SOX9 expression. Germ cells in the gonadoblastoma and dysgerminoma components showed no FOXL2 and SOX9 expression. Areas of transition between gonadoblastoma and dysgerminoma revealed nests with a gradual reduction of FOXL2 expression. Our results support the hypothesis that the sex cord-stromal cell component of gonadoblastomas is of granulosa cell origin. In addition, FOXL2 appears to be a useful marker for the evaluation of overgrowth by dysgerminomas and for the identification of the transition zone of "dysgerminoma in situ." As FOXL2 and SOX9 are differentially expressed, they also should be useful for distinguishing gonadoblastomas from intratubular germ cell neoplasias and can help to differentiate those with a Sertoli cell component from gonadoblastoma with a granulosa cell component. PMID- 21682577 TI - Urinary lithogenesis risk tests: comparison of a commercial kit and a laboratory prototype test. AB - OBJECTIVE: Renal stone formation is a multifactorial process depending in part on urine composition. Other parameters relate to structural or pathological features of the kidney. To date, routine laboratory estimation of urolithiasis risk has been based on determination of urinary composition. This process requires collection of at least two 24 h urine samples, which is tedious for patients. The most important feature of urinary lithogenic risk is the balance between various urinary parameters, although unknown factors may be involved. The objective of this study was to compare data obtained using a commercial kit with those of a laboratory prototype, using a multicentre approach, to validate the utility of these methods in routine clinical practice. MATERIAL AND METHODS: A simple new commercial test (NefroPlus(r); Sarstedt AG & Co., Numbrecht, Germany) evaluating the capacity of urine to crystallize calcium salts, and thus permitting detection of patients at risk for stone development, was compared with a prototype test previously described by this group. Urine of 64 volunteers produced during the night was used in these comparisons. The commercial test was also used to evaluate urine samples of 83 subjects in one of three hospitals. RESULTS: Both methods were essentially in complete agreement (98%) with respect to test results. The multicentre data were: sensitivity 94.7%; specificity 76.9%; positive predictive value (lithogenic urine) 90.0%; negative predictive value (non-lithogenic urine) 87.0%; test efficacy 89.2%. CONCLUSION: The new commercial NefroPlus test offers fast and cheap evaluation of the overall risk of development of urinary calcium-containing calculi. PMID- 21682578 TI - Sun protection advice mediated by the general practitioner: an effective way to achieve long-term change of behaviour and attitudes related to sun exposure? AB - OBJECTIVE: To investigate, in primary health care, differentiated levels of prevention directed at skin cancer, and how the propensity of the patients to change sun habits/sun protection behaviour and attitudes towards sunbathing were affected, three years after intervention. Additionally, the impact of the performance of a phototest as a complementary tool for prevention was evaluated. DESIGN: Randomized controlled study. Setting and subjects. During three weeks in February, all patients >= 18 years of age registering at a primary health care centre in southern Sweden were asked to fill in a questionnaire mapping sun exposure habits, attitudes towards sunbathing, and readiness to increase sun protection according to the Transtheoretical Model of Behaviour Change (TTM) (n = 316). They were randomized into three intervention groups, for which sun protection advice was given, in Group 1 by means of a letter, and in Groups 2 and 3 orally during a personal GP consultation. Group 3 also underwent a phototest to demonstrate individual skin UV sensitivity. MAIN OUTCOME MEASURES: Change of sun habits/sun protection behaviour and attitudes, measured by five-point Likert scale scores and readiness to increase sun protection according to the TTM, three years after intervention, by a repeated questionnaire. RESULTS: In the letter group, almost no improvement in sun protection occurred. In the two doctor's consultation groups, significantly increased sun protection was demonstrated for several items, but the difference compared with the letter group was significant only for sunscreen use. The performance of a phototest did not appear to reinforce the impact of intervention. CONCLUSION: Sun protection advice, mediated personally by the GP during a doctor's consultation, can lead to improvement in sun protection over a prolonged time period. PMID- 21682579 TI - The relationship of height and body fat to gender-assortative weight gain in children. A longitudinal cohort study (EarlyBird 44). AB - OBJECTIVE: Height, body fat and body mass index (BMI) are correlated in children, so we hypothesized that the gender-assortative associations in BMI recently reported in contemporary children might extend to their height and body fat. DESIGN: Prospective longitudinal cohort study. SUBJECTS: A total of 226 healthy trios (mother, father and child) from a 1995?1996 birth cohort randomly recruited in the city of Plymouth, UK. MEASUREMENTS: Height, weight, and BMI (kg/m(2)) were measured in each of the parents and, in addition, sum of five skin-folds (SF) in their children at 5, 6, 7 and 8 y. RESULTS: BMI and SF were strongly height dependent in the children by 8 y (r = 0.41-0.56). SF was gender-assortative insofar as the mean SF was significantly greater in the daughters (but not the sons) of obese mothers (obese vs. normal weight: +2.5 cm p < 0.001) and in the sons (but not the daughters) of obese fathers (obese vs. normal: +1.3 cm p < 0.001). As expected, offspring height correlated with that of their parents, but overweight/obese children were systematically taller than normal weight children (boys: +1.02 SDS, girls: +1.14 SDS, p < 0.01), and this difference was independent of parental height or BMI. CONCLUSIONS: Height is transmitted by both parents, and the body fat of overweight/obese children largely by the same-sex parent, but the extra height associated with more fat in the child is unrelated to the height or weight of either parent. The secular trend in height among contemporary children may simply reflect their rising body fat. Excess fat is unhealthy, so the trend in height may not be healthy either. PMID- 21682580 TI - Intrasession and interrater reliability of rehabilitative ultrasound imaging measures of the deep neck flexors: A pilot study. AB - The purpose of this investigation was to examine the intrasession and interrater reliability of rehabilitative ultrasound imaging (RUSI) to measure the deep neck flexors (DNF). Two investigators traced the DNF muscle borders in eight female subjects aged 33 +/- 11.2 years. Of the eight subjects, five subjects reported a greater than 6-month history of neck pain, and three subjects were asymptomatic healthy controls. Cross-sectional area (CSA) (cm(2)) of right and left muscle groups were calculated. The intraclass correlation coefficients (ICC) for CSA measures were 0.67 (95% CI: 0.27-0.87) for rater 1 with a standard error of measurement (SEM) of 0.06 cm(2); 0.87 (95% CI: 0.65-0.96) for rater 2 with an SEM of 0.09 cm(2); and 0.68 (95% CI: 0.44-0.87) for interrater reliability between rater 1 and rater 2 with an SEM of 0.11 cm(2). The mean difference between CSA (cm(2)) measures were 0.00 +/- 0.10 cm(2) for rater 1 and 0.09 +/- 0.13 cm(2) for rater 2. The mean differences for CSA were 0.04 +/- 0.12 cm(2). This pilot investigation suggests that RUSI could be used to reliably assess the size of the deep neck flexors. PMID- 21682581 TI - Maximal respiratory pressures in healthy boys who practice swimming or indoor soccer and in healthy sedentary boys. AB - The purpose of this study was to investigate respiratory muscle strength in boys who practice swimming or indoor soccer and in their sedentary counterparts. Seventy-five 7- and 8-year-old boys were included; 25 were swimmers (group 1), 25 played indoor soccer (group 2), and 25 were sedentary (group 3). All subjects underwent anthropometric evaluation. Maximal respiratory pressures were measured by manometry. Data were analyzed by using ANOVA and the Tukey-Kramer post hoc test (significance level: p < 0.05). Mean maximal inspiratory pressures in groups 1, 2, and 3 were -109.67 +/- 11.06, -90.74 +/- 16.06, and -90.67 +/- 19.93 cm H(2)O, respectively (p < 0.001 by ANOVA; group 1 * group 2: p < 0.001; group 1 * group 3: p < 0.001; group 2 * group 3: p > 0.05 by Tukey-Kramer). Mean maximal expiratory pressures in groups 1, 2, and 3 were 108.17 +/- 9.90, 92.32 +/-11.67, and 91.33 +/-15.17 cm H(2)O, respectively (p < 0.0001 by ANOVA; group 1 * group 2: p < 0.001; group 1 * group 3: p < 0.001; group 2 * group 3: p > 0.05 by Tukey Kramer). Swimmers showed better maximal respiratory pressures than indoor soccer players and sedentary subjects. No significant difference was observed between the results for soccer players and sedentary subjects. PMID- 21682582 TI - Community ambulation: perceptions of rehabilitation physiotherapists in rural and regional communities. AB - Research has highlighted the impact of the external environment on the ability to walk in the community but little research exists about the abilities, skills, or contextual factors that physiotherapists identify as important to enable a client to return to walking in their rural or regional community. This article investigates the abilities, skills, and contextual factors that rehabilitation physiotherapists practicing in rural and regional communities in Australia perceive significant in enabling clients post stroke to return to walking in their rural or regional community. Physiotherapists involved in treating clients with stroke were interviewed about their perceptions of the skills and abilities required by clients post stroke with a mobility problem that are significant in enabling a return to walking in the community. Data were interpreted by using a grounded theory methodology that involved coding and analysing observational notes and interview transcripts to develop an understanding of the emergent themes. Six key themes were identified: 1) ability to walk at speed and physical fitness, 2) the ability to negotiate different terrains, 3) ambient conditions, 4) the ability to reason and monitor the environment, 5) to have support of a person or aid, and 6) to have the drive (internal and external) to walk in the community. Some of these abilities are described in the current literature, but others are not. The findings of this research will add to the existing body of knowledge on physiotherapist's decision making around the emerging topic of community ambulation. PMID- 21682583 TI - Perceptions of Norwegian physiotherapy students: cultural diversity in practice. AB - At the Faculty of Health Sciences, Oslo University College there is a growing recognition of the need for cultural competency training among students at the bachelor programmes. At the Mensendieck-physiotherapy bachelor programme the students are engaged in leading physical activity groups for Muslim women. This qualitative study describes ethnically Norwegian students experiencing cultural diversity in practice. Twenty-two female physiotherapy students participated in the interviews; 6 students were interviewed individually by telephone, and 16 students were interviewed in person in 8 pairs. The students' framework for dealing with diversity is based on preconceived notions about Muslim women and is reflected in two particular ways. One is how the values and norms of Norwegian "ideology of sameness" are pursued by the students. The other is how the students constructed images of the women as "the others." The interview responses indicate difficulties in uniting the reality of diversity and the "need" for integration. The curriculum requires additional attention on cultural competency for health care professionals in a multicultural society. PMID- 21682584 TI - Development of the movement domain in the global body examination. AB - The purpose of this study was to develop a new Movement domain, based on 16 items from the Global Physiotherapy Examination-52 (GPE-52) and 18 items from the Comprehensive Body Examination (CBE). Furthermore, we examined how well the new domain and its scales would discriminate between healthy individuals and different groups of patients, compared to the original methods. Two physiotherapists, each using one method, independently examined 132 individuals (34 healthy, 32 with localized pain, 32 with generalized pain, and 34 with psychoses). The number of items was reduced by means of correlational and exploratory factor analysis. Internal consistency was examined with Cronbach's alpha. For examination of discriminative validity, Mann-Whitney U-test and Area under the Curve (AUC) were used. The initial 34 items were reduced to two subscales with 13 items: one for range of movement and balance and one for flexibility. Cronbach's alpha was 0.84 and 0.87 for the two subscales. The new subscales showed very good to excellent discriminating ability between healthy persons and the different patient groups (p < 0.001; AUC 0.82-0.95). Furthermore, patients with localized pain had significantly less movement aberrations than the other patient groups. The new Movement domain had fewer items than the GPE-52 and CBE, without losing discriminative validity. PMID- 21682585 TI - Evidence and individualization: Important elements in treatment for women with postpartum pelvic girdle pain. AB - The aim of our study was to elucidate patients' experiences of a treatment program for postpartum pelvic girdle pain. The written information given by 47 women regarding their experiences with the treatment program was analyzed by qualitative content analysis. Three categories were identified from the patients' experiences: 1) "Treatment means involvement"; 2) "The interchange of knowledge and experience"; and 3) "Perceived change and meaning." The treatment required the participants' involvement, individual adaptation, and focusing on the importance of building their capacity to master daily activities. The therapists were skilled, interested in each patient, and listened attentively. The program was evidence based and put into practice on a personalized basis. The dialogs of the therapist and patient were experienced as meaningful, creating insight, knowledge, and hope. The treatment facilitated a feeling of being in charge of their own bodies. The dialog and the individualized guidance seemed to be experienced as positive for the women's coping of their daily life. By being active agents in managing their pelvic girdle pain and therapy, they learned to set proximal goals. Perceived hope and self-efficacy appeared to be essential for developing a capacity for self-management and an enhanced ability to benefit from appropriate learning experiences. PMID- 21682586 TI - Internet health information seeking behavior and antiretroviral adherence in persons living with HIV/AIDS. AB - Abstract While the Internet has the potential to educate persons living with HIV/AIDS (PLWHA), websites may contain inaccurate information and increase the risk of nonadherence with antiretroviral therapy (ART). The objectives of our study were to determine the extent to which PLWHA engage in Internet health information seeking behavior (IHISB) and to determine whether IHISB is associated with ART adherence. We conducted a survey of adult, English-speaking HIV-infected patients at four HIV outpatient clinic sites in the United States (Baltimore, Maryland; Detroit, Michigan; New York, and Portland, Oregon) between December 2004 and January 2006. We assessed IHISB by asking participants how much information they had received from the Internet since acquiring HIV. The main outcome was patient-reported ART adherence over the past three days. Data were available on IHISB for 433 patients, 334 of whom were on ART therapy. Patients had a mean age of 45 (standard error [SE] 0.45) years and were mostly male (66%), African American (58%), and had attained a high school degree (73%). Most (55%) reported no IHISB, 18% reported some, and 27% reported "a fair amount" or "a great deal." Patients who reported higher versus lower levels of IHISB were significantly younger, had achieved a higher level of education, and had higher medication self-efficacy. In unadjusted analyses, higher IHISB was associated with ART adherence (odds ratio [OR], 2.96, 95% confidence interval [CI] 1.27 6.94). This association persisted after adjustment for age, gender, race, education, clinic site, and medication self-efficacy (adjusted odds ratio [AOR] 2.76, 95% CI 1.11-6.87). Our findings indicate that IHISB is positively associated with ART adherence even after controlling for potentially confounding variables. Future studies should investigate the ways in which Internet health information may promote medication adherence among PLWHA. PMID- 21682587 TI - Sexual behaviors of racial/ethnic minority young men who have sex with men. AB - We assessed changes in sexual behaviors from baseline to 12-month follow-up among a multisite cohort of HIV-positive racial/ethnic minority young men who have sex with men enrolled in an outreach, linkage, and retention study. In the 3 months prior to their baseline interview, more than three-quarters of participants (78.5%) reported sex with at least one man (mean: 2.3 partners). Among sexually active participants, 44.2% had one partner; 50.5% had 2-9 partners; and 5.3% had 10 or more partners. Over three-quarters (77.5%) reported engaging in sex with at least one steady partner, 43.5% with at least one casual partner, and 29.5% with both casual and steady partners. Exchanging sex for money, drugs, or other needs was reported by 13.2%. Use of condoms during oral and anal sex increased significantly from baseline to 12-month follow-up (oral sex: 29.1-42.5%, p=0.02; anal sex: 67.8-76.2%, p=0.05). While unprotected anal sex significantly decreased among individuals who were new to care (34.8-18.3%, p<0.0001), it significantly increased among individuals who were previously in care (26.7-37.5%, p=0.03). Overall, exchange sex decreased from 13.3% at baseline to 5.0% at 12 months (p=0.001). Despite reductions in unprotected sexual encounters and exchange sex through one year of follow-up, many participants continued to engage in high-risk sexual behaviors. Retention within this study appeared to be associated with decreases in high-risk sexual behaviors, especially among participants who were new to care, although more research is needed. Future studies should investigate sexual network characteristics and the prevalence of behaviors such as serosorting. PMID- 21682589 TI - Proteomic analysis of the mode of antibacterial action of trans-cinnamaldehyde against Cronobacter sakazakii 415. AB - Cronobacter sakazakii is an opportunistic foodborne pathogen that contaminates powdered infant formula, causing a rare but life-threatening infection in neonates and infants. Contaminated powdered infant formula represents the only known source of infection in infants. We previously reported that trans cinnamaldehyde (TC), an ingredient in cinnamon, inactivated C. sakazakii in powdered infant formula. Although the antimicrobial properties of TC have been well established, only limited information is available on its antimicrobial mechanisms, especially at the molecular level. Therefore, we performed a proteomic analysis of the outer membrane and whole cell proteins from TC-treated C. sakazakii to investigate its potential antimicrobial mechanisms against C. sakazakii. The proteomic data revealed that TC exerts antimicrobial effects by several mechanisms, including disruption of carbohydrate, amino acid, and lipid metabolism. Additionally, TC compromises motility, attachment, and invasion ability and cellular defenses of C. sakazakii against oxidative stress, thereby reducing its virulence. The results of this study suggest that TC could be potentially used for controlling C. sakazakii. PMID- 21682588 TI - Sex position, marital status, and HIV risk among Indian men who have sex with men: clues to optimizing prevention approaches. AB - A divide exists between categories of men who have sex with men (MSM) in India based on their sex position, which has consequences for the design of novel HIV prevention interventions. We examine the interaction between sex position and other attributes on existing HIV risk including previous HIV testing, unprotected anal intercourse (UAI), and HIV serostatus among MSM recruited from drop-in centers and public cruising areas in the twin cities of Hyderabad and Secunderabad, India. A survey was administered by trained research assistants and minimally invasive HIV testing was performed by finger-stick or oral testing. HIV seropositive MSM underwent CD4+ lymphocyte count measurement. In our sample (n = 676), 32.6% of men were married to women, 22.2% of receptive only participants were married, and 21.9% of men were HIV seropositive. In bivariate analysis, sex position was associated with previous HIV testing, UAI, HIV serostatus, and CD4+ lymphocyte count at diagnosis. In multivariate analysis with interaction terms, dual unmarried men were more likely to have undergone an HIV test than insertive unmarried men (odds ratio [OR] 2.8; 95% confidence interval [CI] 1.2-6.5), a relationship that did not hold among married men. Conversely, dual married men were less likely than insertive married men to engage in UAI (OR 0.3; 95% CI 0.1 0.6), a relationship that did not hold among unmarried men. Further implementation research is warranted in order to best direct novel biologic and behavioral prevention interventions towards specific risk behaviors in this and other similar contexts. PMID- 21682590 TI - Intravitreal bevacizumab for exudative age-related macular degeneration in clinical practice. AB - PURPOSE: The purpose of this study was to evaluate whether baseline visual acuity and baseline anatomy of the macula influence visual outcome in patients receiving intravitreal bevacizumab as treatment of exudative age-related macular degeneration (AMD) in clinical practice. METHODS: This clinical case series study included 319 patients (406 eyes) who consecutively received intravitreal injections of bevacizumab for treatment of exudative AMD. The intervals between injections were 6 weeks and postinjection examinations were performed at 4 weeks after injection. Mean follow-up was 3.6 months. RESULTS: After 3 injections of bevacizumab, best-corrected visual acuity (BCVA) significantly (P<0.01) improved in eyes with a baseline BCVA of less than 0.2 (group 1; 138 eyes; -0.10+/-0.43 LogMAR) and in eyes with a baseline BCVA >=0.2 and <0.4 (group 2; 117 eyes; 0.06+/-0.24 LogMAR), but BCVA deteriorated in eyes with a baseline BCVA of >=0.4 (group 3; 151 eyes; 0.09+/-0.32 LogMAR). Correspondingly, regression analysis revealed that improvement in BCVA after 3 intravitreal bevacizumab injections was significantly (P=0.001) associated with a low baseline BCVA. After the first injection of bevacizumab, changes in optical coherent tomography measurements of the macula (height of subretinal fluid, macular tissue thickness) were statistically significant for group 1 (P=0.03, P=0.03, respectively) and group 2 (P=0.01, P=0.02, respectively), but not for group 3 (P=0.85, P=0.22, respectively). CONCLUSIONS: In clinical practice, patients with exudative AMD and a baseline BCVA of <0.2 have a better prognosis for an increase in BCVA after intravitreal bevacizumab injections than patients with a higher baseline BCVA. PMID- 21682591 TI - Discontinuous release of bone morphogenetic protein-2 loaded within interconnected pores of honeycomb-like polycaprolactone scaffold promotes bone healing in a large bone defect of rabbit ulna. AB - The choice of an appropriate carrier and its microarchitectural design is integral in directing bone ingrowth into the defect site and determining its subsequent rate of bone formation and remodeling. We have selected a three dimensional polycaprolactone (PCL) scaffold with an interconnected honeycomb-like porous structure to provide a conduit for vasculature ingrowth as well as an osteoconductive pathway to guide recruited cells responding to a unique triphasic release of osteoinductive bone morphogenetic proteins (BMP) from these PCL scaffolds. We hypothesize that the use of recombinant human bone morphogenetic protein 2 (rhBMP2)-PCL constructs promotes rapid union and bone regeneration of a large defect. Results of our pilot study on a unilateral 15 mm mid-diaphyseal segmental rabbit ulna defect demonstrated enhanced bone healing with greater amount of bone formation and bridging under plain radiography and microcomputed tomography imaging when compared with an empty PCL and untreated group after 8 weeks postimplantation. Quantitative measurements showed significantly higher bone volume fraction and trabecular thickness, with lower trabecular separation in the rhBMP2-treated groups. Histology evaluation also revealed greater mature bone formation spanning across the entire scaffold region compared with other groups, which showed no bone regeneration within the central defect zone. We highlight that it is the uniqueness of the scaffold having a highly porous network of channels that promoted vascular integration and allowed for cellular infiltration, leading to a discontinuous triphasic BMP2 release profile that mimicked the release profile during natural repair mechanisms in vivo. This study serves as preclinical evidence demonstrating the potential of combining osteoinductive rhBMP2 with our PCL constructs for the repair of large defects in a large animal model. PMID- 21682592 TI - Comparison of two approaches to retroperitoneoscopic renal pedicle lymphatic disconnection for chyluria. AB - BACKGROUND AND PURPOSE: The retroperitoneoscopic renal pedicle lymphatic disconnection has been performed mainly via a renal adipose (RA) capsule approach. In this study, we reported a novel technique via extra-adipose (EA) capsule approach and compared the two approaches for intractable chyluria. PATIENTS AND METHODS: From December 2002 to March 2008, retroperitoneoscopic renal pedicle lymphatic disconnection was performed on 41 patients with 23 EA and 18 RA. The stripping of hilar vessels and ureterolympholysis were performed in both approaches, while the mobilization of the kidney was only performed in RA. Comparisons of the two approaches were conducted, including mean operative time, intraoperative blood loss, postoperative bed rest, and hospital stay, as well as operative outcome. RESULTS: Patients were treated successfully without major complications. EA showed the same advantages as RA in terms of intraoperative blood loss (54.9+/-19.3 mL vs 59.3+/-26.5 mL, P>0.05), postoperative hospital stay (6.6+/-1.0 d vs 7.2+/-0.9 d, P>0.05). Chyluria disappeared in all patients immediately after the operations. EA was significantly superior to RA in operative time (78.9+/-18.3 min vs 101.8+/-20.6 min, P<0.05) and the postoperative bed rest time (20.7+/-1.7 h vs 72.0+/-0.0 h, P<0.05). No recurrence or nephroptosis was diagnosed in any patient within the follow-up of 21 to 84 months. CONCLUSIONS: Retroperitoneoscopic renal pedicle lymphatic disconnection for chyluria is safe and efficacious. EA offers significantly shorter operative time and earlier return to postoperative ambulation. PMID- 21682593 TI - A study of haptoglobin levels in groups of cattle and pigs with and without abnormalities at meat inspection. AB - A total of 96 bovines originating from 36 farms and 97 pigs from five farms were slaughtered in two multispecies abattoirs and subjected to official meat inspection and haptoglobin (Hp) testing using a single radial immunodiffusion method. No direct correlation between Hp level and specific postmortem abnormalities was found at individual cattle/pig level. However, at animal group level, the mean of Hp values (in both cattle and pigs) were statistically significantly higher in animals with abnormalities than in those without. The study indicated that the mean Hp value in groups of cattle or pigs can be useful as an overall objective indicator of the overall status of cattle/pig batches when analyzing the food chain information as a part of the antemortem inspection at abattoirs, but related specific Hp criteria are currently missing. Because of the large variability and nonspecific nature of Hp-related responses in cattle and pigs, establishing a single, reliable cutoff Hp value differentiating batches that may pose public health risks does not appear as a realistic approach presently. Rather, establishing wider, unsatisfactory/marginal/satisfactory ranges of batch-based Hp values indicating general appropriateness of the cattle/pigs source appears more promising. For that, wider Hp baseline studies are necessary at abattoir. PMID- 21682594 TI - Designing the next generation of vaccines for global public health. AB - Vaccine research and development are experiencing a renaissance of interest from the global scientific community. There are four major reasons for this: (1) the lack of efficacious treatment for many devastating infections; (2) the emergence of multidrug resistant bacteria; (3) the need for improving the safety of the more traditional licensed vaccines; and finally, (4) the great promise for innovative vaccine design and research with convergence of omics sciences, such as genomics, proteomics, immunomics, and vaccinology. Our first project based on omics was initiated in 2000 and was termed reverse vaccinology. At that time, antigen identification was mainly based on bioinformatic analysis of a singular genome. Since then, omics-guided approaches have been applied to its full potential in several proof-of-concept studies in the industry, with the first reverse vaccinology-derived vaccine now in late stage clinical trials and several vaccines developed by omics in preclinical studies. In the meantime, vaccine discovery and development has been further improved with the support of proteomics, functional genomics, comparative genomics, structural biology, and most recently vaccinomics. We illustrate in this review how omics biotechnologies and integrative biology are expected to accelerate the identification of vaccine candidates against difficult pathogens for which traditional vaccine development has thus far been failing, and how research will provide safer vaccines and improved formulations for immunocompromised patients in the near future. Finally, we present a discussion to situate omics-guided rational vaccine design in the broader context of global public health and how it can benefit citizens in both developed and developing countries. PMID- 21682595 TI - XRCC1 Arg399Gln gene polymorphism and the risk of systemic lupus erythematosus in the Polish population. AB - It has been shown that DNA repair is reduced in patients with systemic lupus erythematosus (SLE) and that the X-ray repair cross-complementing (XRCC1) Arg399Gln (rs25487) polymorphism may contribute to DNA repair. We evaluated the frequency of the XRCC1 Arg399Gln substitution in patients with SLE (n=265) and controls (n=360) in a sample of the Polish population. The odds ratio (OR) for SLE patients with the Gln/Gln versus Gln/Arg or Arg/Arg genotypes was 1.553 (95% confidence interval [CI]=0.9573-2.520; p=0.0729). OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.551 (95% CI=1.122-2.144, p=0.0077). The OR for the 399 Gln allele in patients with SLE was 1.406 (95% CI=1.111-1.779, p=0.0045). There was also a statistically significant p-value of the chi(2) test for the trend observed in the XRCC1 Arg399Gln polymorphism (ptrend=0.0048). We also found a significant contribution of the Gln/Gln or Arg/Gln versus Arg/Arg genotype to the presence of either the malar rash or photosensitivity manifestations of SLE OR=2.241 (1.328-3.781, p=0.0023, pcorr=0.0414). Moreover, the meta-analysis of Taiwanese Han Chinese, Brazilian, and Polish populations showed that the Gln/Gln or Gln/Arg genotype and Gln allele were associated with SLE incidence. OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.440 (95% CI=1.15-1.80, p=0.0019) and OR for the Gln allele was 1.27 (95% CI=1.08-1.51, p=0.0051). Our studies may confirm that the XRCC1 Arg399Gln polymorphism may increase the risk of incidence of SLE and the occurrence of some SLE manifestations. PMID- 21682597 TI - Randomized prospective trial comparing immediate versus delayed ureteroscopy for patients with ureteral calculi and normal renal function who present to the emergency department. AB - PURPOSE: To compare the safety and efficacy of emergency vs scheduled ureteroscopy with a prospective study that included patients who presented to the emergency department (ED) with renal colic from ureteral stones. PATIENTS AND METHODS: There were 271 consecutive patients who were enrolled in this prospective study. Patients were randomized to emergency ureteroscopy (group A) or delayed ureteroscopy (group B). All patients underwent helical unenhanced CT (HUCT). Stone-free status was defined as the complete absence of residual fragments at 1 week postoperatively, assessed with HUCT, with no need for ancillary interventions after ureteroscopy. RESULTS: Group A included 139 assessable patients. The overall stone-free rate was 93%. Neither location nor size was a significant prognostic factor (P>0.05). Single-session ureteroscopy failed to clear nine ureteral stones. A Double-J stent was placed in 27/139 patients. Group B included 100 assessable patients. Patients in the control group were scheduled for ureteroscopy after their departure from the ED. The overall stone-free rate was 90%. Single-session ureteroscopy failed to clear 10 ureteral stones. A Double-J stent was placed in 80/100 patients. There were no statistical differences with regard to stone diameter and location, complications, and stone free rate between group A and group B patients. The rate of Double-J stent positioning was significantly higher (P<0.05) in group B patients. CONCLUSIONS: In our experience, emergency ureteroscopy showed equal efficacy and safety compared with the elective procedure. It has the main advantage of providing both immediate relief from pain and stone fragmentation. PMID- 21682596 TI - Gene expression profiling-based identification of CD28 and PI3K as new biomarkers for chronic graft-versus-host disease. AB - Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Currently, no reliable biomarkers are available to predict the onset or progression of cGVHD. Therefore, in this study, we collected peripheral blood mononuclear cells from four patients with cGVHD and four ones with non-GVHD after hematopoietic stem cell transplantation and employed Affymetrix GeneChip Human U133 Plus 2.0 microarrays to screen the genes differentially expressed in cGVHD versus non-GVHD groups, with the aim to identify potential clinical biomarkers to predict cGVHD risk or progression. Microarray analysis demonstrated that the expression of 3180 genes changed significantly in cGVHD versus non-GVHD, with 879 genes upregulated and 2301 genes downregulated. Among them we chose CD28 and PI3K as candidates for further verification. Flow cytometry and quantitative real-time polymerase chain reaction analysis confirmed the significant upregulation of CD28 and PI3K in samples from patients with cGVHD compared with patients with non-GVHD, respectively. In conclusion, our study suggested that the upregulation of CD28 and PI3K contributed to the onset and progression of cGVHD and provided evidence that CD28 and PI3K may serve as promising biomarkers for cGVHD. PMID- 21682598 TI - Objective assessment of working tool impact on irrigation flow and visibility in flexible ureterorenoscopes. AB - BACKGROUND AND PURPOSE: Impaired irrigation causes reduced visibility in flexible ureteroscopy. The aim of this ex-vivo study was to investigate the impact of working tools on light transmission in a medium as an objective measurement of visibility in flexible ureteroscopes. MATERIALS AND METHODS: Five ureteroscopes (Viper, Cobra, FlexX(2), URF-P5, DUR-8 Elite) were evaluated. The endoscopes were placed into a dark chamber with a photo diode, measuring light transmission. Light transmission was measured in a clear liquid and a 2% ink solution to simulate impaired vision. The time needed to restore light transmission by clear irrigation inflow was measured. Measurements were carried out five times, with empty and loaded ureteroscopes (1.7F, 2.2F basket, 273 MUm laser fiber). RESULTS: The time needed to restore light transmission as a measurement of visibility depends on tool size and the length of the working channel. The presented setup provides more sensitive results than the measurement of the irrigation flow rate. With empty working channels, the fastest restoration of light transmission (increase by 1000 units) was achieved with the Cobra dual channel device (25 s), followed by single channel DUR-8 (28 s), Viper (38.5), and Flex X(2) (40 s). The ureteroscope with the longest working channel (URF-P5) needed the longest irrigation time to restore light transmission (66.5 s). These results become even more obvious with the use of different working tools. CONCLUSION: Measurement of light transmission is a sensitive tool to evaluate irrigation performance. Double irrigation is superior to single irrigation in terms of light transmission. PMID- 21682599 TI - In vitro evaluation of nitinol stone retrieval baskets for flexible ureteroscopy. AB - BACKGROUND AND PURPOSE: Because of increased clinical relevance of retrograde intrarenal surgery (RIRS), a variety of stone retrieval baskets have been introduced into endourology. Differences in shape and material may have consequences in performance and efficacy of RIRS. The aim of the study was to evaluate the in vitro performance of multiple commercially available nitinol retrieval baskets. MATERIALS AND METHODS: Ten manufacturers of baskets for RIRS were invited to participate in this evaluation. The evaluation included measurement of the basket's internal resistance toward deflection, the influence on the deflection angle of a flexible ureteroscope (URF-P5, Olympus), and basket function in maximum deflection of the scope. All measurements were performed five times. RESULTS: Nine manufacturers, providing a total of 15 baskets, decided to participate in this evaluation. Maximum deflection of the ureteroscope (275 degrees) was achieved in 12 baskets and reduced in 3. In maximum deflection, complete opening of the basket was possible in 13 samples. In one case, partial opening of the basket was possible; one basket failed. The measurement of the basket's internal resistance showed wide variations (5.97 to 38 mm deflection/g), consecutively leading to increased inner radius of the fully deflected scope in 10 of 15 tested samples. CONCLUSIONS: The tested baskets showed wide variations in their resistance toward bending. Influence on overall deflection capacity seems minor, however. On the other hand, higher resistance leads to increased inner radius of the fully deflected renoscope, which may alter functionality. Knowledge about the basket's key feature and differences in basket performance may be crucial to choose the best tool for the patient. PMID- 21682600 TI - Using zebrafish to learn statistical analysis and Mendelian genetics. AB - This project was developed to promote understanding of how mathematics and statistical analysis are used as tools in genetic research. It gives students the opportunity to carry out hypothesis-driven experiments in the classroom: students generate hypotheses about Mendelian and non-Mendelian inheritance patterns, gather raw data, and test their hypotheses using chi-square statistical analysis. In the first protocol, students are challenged to analyze inheritance patterns using GloFish, brightly colored, commercially available, transgenic zebrafish that express Green, Yellow, or Red Fluorescent Protein throughout their muscles. In the second protocol, students learn about genetic screens, microscopy, and developmental biology by analyzing the inheritance patterns of mutations that cause developmental defects. The difficulty of the experiments can be adapted for middle school to upper level undergraduate students. Since the GloFish experiments use only fish and materials that can be purchased from pet stores, they should be accessible to many schools. For each protocol, we provide detailed instructions, ideas for how the experiments fit into an undergraduate curriculum, raw data, and example analyses. Our plan is to have these protocols form the basis of a growing and adaptable educational tool available on the Zebrafish in the Classroom Web site. PMID- 21682601 TI - HeNe laser (633 nm)-coupled confocal microscope allows simulating magnetic resonance imaging/computed tomography scan of the brain and eye: a noninvasive optical approach applicable to small laboratory animals. AB - Magnetic resonance imaging (MRI) and computed tomography (CT) are noninvasive medical imaging techniques used for the detailed visualization of internal organs of the human body. Because CT uses X-rays for imaging, there is a risk of radiation exposure. In contrast, MRI uses radiowaves and magnetic fields for imaging; thus, there are no reported biological hazards. However, neither MRI nor CT is suitable as a noninvasive imaging tool applicable in small laboratory animals such as zebrafish embryos or larvae. The recently established micro-CT scanner is only suitable for scanning adult fish and a staining procedure is required for imaging. In addition, CT-based scanning is generally more suitable for skeletal imaging but not for visualization of soft tissues because of its lower contrast. In this study, we evaluated whether 633 nm HeNe laser-coupled confocal microscope allows simulating MRI/CT scan and imaging soft tissues such as brain and eye in zebrafish embryos/larvae. We show that the 633 nm HeNe laser can penetrate well into intact brain and eye of zebrafish. It represents a noninvasive imaging method with high resolution while not requiring contrast agents, enabling the detection of differential signals from normal and pathological organs such as brain and eye. PMID- 21682602 TI - Heal thyself: using endogenous regeneration to repair bone. AB - Bone has the capacity to repair itself after an injury, and this occurs in normal fracture repair. This reparative process can be harnessed to regenerate segments of bone using distraction osteogenesis, in which the healing bone is slowly stretched. The use of animal models is identifying the important sources of cells for this endogenous bone regeneration, signaling molecules that regulate this reparative process, and the environmental cues important for success bone regeneration. A more complete understanding of the cells and pathways involved in this process can be applied to improve the outcome of distraction osteogenesis and to the development of methods to enhance endogenous bone regeneration. PMID- 21682603 TI - Altered obstacle negotiation after low thoracic hemisection in the cat. AB - Following a lateralized spinal cord injury (SCI) in humans, substantial walking recovery occurs; however, deficits persist in adaptive features of locomotion critical for community ambulation, including obstacle negotiation. Normal obstacle negotiation is accomplished by an increase in flexion during swing. If an object is unanticipated or supraspinal input is absent, obstacle negotiation may involve the spinally organized stumbling corrective response. How these voluntary and reflex components are affected following partial SCI is not well studied. This study is the first to characterize recovery of obstacle negotiation following low-thoracic spinal hemisection in the cat. Cats were trained pre- and post-injury to cross a runway with an obstacle. Assessments focused on the hindlimb ipsilateral to the lesion. Pre-injury, cats efficiently cleared an obstacle by increasing knee flexion during swing. Post-injury, obstacle clearance permanently changed. At 2 weeks, when basic overground walking ability been recovered, the hindlimb was dragged over the obstacle (~90%). Surprisingly, the stumbling corrective response was not elicited until after 2 weeks. Despite a notable increase, between 4 and 8 weeks, in the ability to modify limb trajectory when approaching an obstacle, limb lift during obstacle approach was insufficient during ~50% of encounters and continued to evoke the stumbling corrective response even at 16 weeks. A post-injury lead limb bias identified during negotiations with complete clearance, suggests a potential training strategy to increase the number of successful clearances. Therefore, following complete severing of half of the spinal cord, the ability to modify ipsilateral hindlimb trajectory shows significant recovery and by 16 weeks permits effective clearing of an obstacle, without contact, ~50% of the time. Although this suggests plasticity of supporting circuitry, it is insufficient to support consistent clearance. This inconsistency, even at the most chronic time point assessed (16 weeks), is probably a contributing factor to falls reported for people with SCI. PMID- 21682605 TI - Randall-Selitto test: a new approach for the detection of neuropathic pain after spinal cord injury. AB - In this work we assess the usefulness of the Randall-Selitto test as a method to detect and quantify neuropathic pain responses in rats subjected to different spinal cord injuries. The mechanical nociceptive thresholds were significantly reduced during follow-up after spinal cord contusion or transection. Our results demonstrate that the Randall-Selitto test allows the detection of neuropathic pain both in forepaws and hindpaws, as well as in dorsal and plantar surfaces. Moreover, it does not require weight support capacity, so it can be used at early time points after the injury. This is the first time that this method has been used to describe the changes in nociceptive thresholds that take place after spinal cord injuries of different severities over time. PMID- 21682604 TI - Potential for imaging engineered tissues with X-ray phase contrast. AB - As the field of tissue engineering advances, it is crucial to develop imaging methods capable of providing detailed three-dimensional information on tissue structure. X-ray imaging techniques based on phase-contrast (PC) have great potential for a number of biomedical applications due to their ability to provide information about soft tissue structure without exogenous contrast agents. X-ray PC techniques retain the excellent spatial resolution, tissue penetration, and calcified tissue contrast of conventional X-ray techniques while providing drastically improved imaging of soft tissue and biomaterials. This suggests that X-ray PC techniques are very promising for evaluation of engineered tissues. In this review, four different implementations of X-ray PC imaging are described and applications to tissues of relevance to tissue engineering reviewed. In addition, recent applications of X-ray PC to the evaluation of biomaterial scaffolds and engineered tissues are presented and areas for further development and application of these techniques are discussed. Imaging techniques based on X-ray PC have significant potential for improving our ability to image and characterize engineered tissues, and their continued development and optimization could have significant impact on the field of tissue engineering. PMID- 21682606 TI - Clinical comorbidities, treatment patterns, and direct medical costs of patients with osteoarthritis in usual care: a retrospective claims database analysis. AB - OBJECTIVE: Comorbidities and resource utilization among patients with osteoarthritis (OA) in clinical practice have been infrequently characterized. The purpose of this study was to examine comorbidities, pain-related pharmacotherapy, and direct medical costs of patients with OA in clinical practice. METHOD: This retrospective cohort analysis used medical and pharmacy claims data from the LifeLinkTM Database. OA patients (ICD-9-CM codes 715.XX) were matched (age, gender, and region) with individuals without OA. Comorbidities, pain-related pharmacotherapy, and direct medical costs (pharmacy, outpatient, inpatient, total) were examined for the calendar year 2008. RESULTS: The sample consisted of 112,951 OA patients and 112,951 controls (mean age: 56.9 [SD=9.5] years; 62% female). Relative to controls, OA patients were significantly more likely (p<0.0001) to have comorbidities, including musculoskeletal (84.3 vs. 37.1%) and neuropathic pain (22.0 vs. 6.1%) conditions, depression (12.4 vs. 6.4%), anxiety (6.6 vs. 3.5%), and sleep disorders (11.9 vs. 4.2%). OA patients were significantly more likely (p<0.0001) to receive pain-related medications, including opioids (40.7 vs. 17.1%), NSAIDs (37.1 vs. 11.5%), tramadol (9.8 vs. 1.8%), and adjunctive medications for treating depression, anxiety, and insomnia. Mean [SD] total direct medical costs were more than two times higher among OA patients ($12,905 [$21,884] vs. $5099 [$13,855]; p<0.001) and median costs were more than three times higher ($6188 vs. $1879; p<0.0001). Study limitations include potential errors in coding and recording; overestimation of the comorbidity burden; inability to link condition of interest, OA, with prescribed medications; and possible underestimation of the true costs of OA, because indirect costs were not considered and the direct costs were from a third party payer (commercial insurance) perspective. CONCLUSION: The patient burden of OA was characterized by a high prevalence of comorbidities. The payer burden was also substantial, with significantly greater use of pain-related and adjunctive medications, and higher direct medical costs. PMID- 21682607 TI - Barriers to the clinical translation of orthopedic tissue engineering. AB - Tissue engineering and regenerative medicine have been the subject of increasingly intensive research for over 20 years, and there is concern in some quarters over the lack of clinically useful products despite the large sums of money invested. This review provides one perspective on orthopedic applications from a biologist working in academia. It is suggested that the delay in clinical application is not atypical of new, biologically based technologies. Some barriers to progress are acknowledged and discussed, but it is also noted that preclinical studies have identified several promising types of cells, scaffolds, and morphogenetic signals, which, although not optimal, are worth advancing toward human trials to establish a bridgehead in the clinic. Although this transitional technology will be replaced by more sophisticated, subsequent systems, it will perform valuable pioneering functions and facilitate the clinical development of the field. Some strategies for achieving this are suggested. PMID- 21682608 TI - Regeneration in, and properties of, extracted peripheral nerve allografts and xenografts. AB - When not enough conventional autologous nerve grafts are available, alternatives are needed to bridge nerve defects. Our aim was to study regeneration of nerves in chemically-extracted acellular nerve grafts from frogs, mice, humans (fresh and stored sural nerve), pigs and rats when defects in rat sciatic nerves were bridged. Secondly, we compared two different extraction procedures (techniques described by Sondell et al. and Hudson et al.) with respect to how efficiently they supported axonal outgrowth, and remaining laminin and myelin basic protein (MBP), after extraction. Isografts (rat) and xenografts (mouse) were transplanted into defects in rat sciatic nerves. Acellular nerve allografts from rats, extracted by the Sondell et al's technique, had an appreciably longer axonal outgrowth based on immunohistochemical staining of neurofilaments, than acellular nerve xenografts except those from the pig. Among acellular xenografts there was considerably longer axonal outgrowth in the grafts from pigs compared with those from humans (fresh), but there were no other differences among the xenografts with respect to axonal outgrowth. Axonal outgrowth in acellular nerve xenografts from mice, extracted by the method described by Sondell et al. was longer than in those extracted by Hudson et al's method, while there was no difference in outgrowth between extracted nerve isografts from rats. Electrophoretic analysis of extracted acellular nerve grafts showed remaining laminin, but not MBP, after both extraction procedures. These preserved laminin and removed MBP in acellular nerve grafts. Such grafts can be used to reconstruct short defects in nerves irrespective of their origin. However, selecting and matching a suitable combination of graft and host species may improve axonal outgrowth. PMID- 21682609 TI - Initial size of cleft does not correlate with size and function of nasal airway in adults with unilateral cleft lip and palate. AB - The noses of patients with clefts are often functionally inadequate. The aim of the present study was to evaluate the correlation between size of the maxillary cleft in infancy and size and function of the nasal airway in adults with unilateral cleft lip and palate (UCLP). This is a long-term follow up study including 53 patients with UCLP born between 1960 and 1987 and treated at the Cleft Lip and Palate Centre, Uppsala University Hospital, Sweden. Lip repair was performed at 3-4 months of age followed by either a one-stage or a two-stage palatal closure. The size of the cleft was measured on infant maxillary dental casts. Nasal minimum cross-sectional area (cm(2)) and volume (cm(3)) (acoustic rhinometry), air flow resistance (Pa s/cm(3)) (rhinomanometry), peak inspiratory flow (l/min) (peak nasal inspiratory flow) and number of identified odours (Scandinavian odor-identification test) were assessed in adulthood. The size of the maxillary cleft varied considerably at infancy. The size of the nasal airway and its function on the cleft side in adulthood were reduced compared with the non-cleft side, but no correlations were found between size of the initial cleft in infancy and size and function of the nasal airway in adulthood. In adults born with UCLP, therefore, size of the maxillary cleft in infancy does not seem to affect size and function of the nasal airway in adulthood. PMID- 21682610 TI - Videofluorographic evaluation of dysphagia before and after modification of the flap and scar in patients with oral cancer. AB - Dysphagia is an important postoperative problem in patients with oral cancer. We evaluated the usefulness of a technique to modify the flap and scar for the alleviation of swallowing disorders. The modifications were made while tongue pressure was being measured to improve excursion of the residual tongue in nine patients. They had been operated on for oral cancer and reconstruction was with a forearm free flap, or the wound was closed primarily. After a 5 ml bolus of liquid barium had been given orally, lingual movement, barium inflow into the pharynx before swallowing, stasis in the epiglottic valleculae, and stasis in the oral cavity after swallowing, were evaluated by videofluorography before and after modification. Oral transit time, pharyngeal transit time, and total transit time were also measured. Lingual movement improved in eight patients. Barium inflow into the pharynx before swallowing improved slightly in all patients. Stasis in the epiglottic valleculae was improved in six patients. Stasis in the oral cavity improved in all patients. Oral transit time and total transit time were significantly shorter after modification of the flap and scar than before operation. Pharyngeal transit time was unchanged. We conclude that our technique for modification of the flap and scar can alleviate postoperative swallowing dysfunction in patients with oral cancer. PMID- 21682611 TI - Microcirculatory evaluation of deep inferior epigastric artery perforator flaps with laser Doppler perfusion imaging in breast reconstruction. AB - We have made a quantitative analysis of the microcirculation in the classic perfusion zones of the deep inferior epigastric artery perforator (DIEAP) flap on 10 consecutive women having breast reconstruction with a unilateral DIEAP. Laser Doppler perfusion imaging was used for operative scans. Data were recorded 10 minutes after successful microanastomosis. The mean (SD) perfusion for each perfusion zone was calculated. Zone I = 44.2 (6.2); zone II = 35.1 (10.3); zone III = 39.9 (9.2); and zone IV = 21.9 (10.0). There were significant differences between zones I, II, and III and zone IV (p < 0.001), and zones I and II (p = 0.02). However, there was no significance between zones I and III (p = 0.9), and zones II and III (p = 0.6). The perfusion of zone IV was significantly lower than those in all other zones, which is in keeping with clinical practice in which zone IV is normally discarded to avoid partial necrosis of the flap in unilateral breast reconstruction. Higher values are expected in zone I than zone III, and in zone II than zone III. However, we could not confirm this. We conclude that there are no differences in skin perfusion between zones I and III, and zones II and III. However, the perfusion of zone IV was significantly less than that in all other zones immediately after revascularisation of the DIEAP flap. PMID- 21682612 TI - New concept for total wrist replacement. AB - Wrist prostheses have never achieved the sort of clinical outcomes found with those of hips and knees. We have developed a novel uncemented modular wrist prosthesis with screw fixation, metal-on-metal coupling, and ball-and-socket articulation. Eight patients admitted for wrist arthrodesis to treat primary or secondary osteoarthritis (not rheumatoid) were operated on. The prosthesis reduced the amount of bone removed and spared the distal radioulnar joint. After 7 to 9 years we found that the fixed centre of the ball-and-socket articulation provided good stability and mobility, and relief of pain and grip strength were satisfactory. We saw no luxations, metacarpal fractures or cut-outs, or mechanical failures of the implants. Two distal screws loosened (revised with new distal screws), and one early inflammation and one late infection occurred (revised to arthrodesis). We propose modifications to the implant with reduction in the diameter of the screws and the height of the threads, and rounding of the distal tip. The technique should include release of the third carpometacarpal joint, alignment of the capitate and the third metacarpal, and arthrodesis of the joint with bone chips. PMID- 21682613 TI - Improved postoperative outcome of segmental fasciectomy in Dupuytren disease by insertion of an absorbable cellulose implant. AB - In this case-control prospective study, we investigated if we could improve the surgical outcome of interrupting strands in Dupuytren disease by creating a blocking effect with an absorbable cellulose implant, a known absorbable adhesion barrier. We studied 33 operations in 29 patients who had the potential for recurrent disease. The cellulose was implanted in the first 15 patients. An intraindividual control was added in 4 patients, who were given the implant in 1 of 2 operated hands. Goniometric evolution was monitored on digital photography, and satisfaction was measured on a visual analogue scale (VAS) with a preliminary one year follow-up. With the implant the postoperative range of movement improved significantly (by 33%) and remained unchanged after three months to a one year follow-up. The VAS for satisfaction also improved. We conclude that cellulose implants may improve the outcome of segmental fasciectomy in Dupuytren disease by achieving a better extension of fingers and a higher patients' satisfaction. PMID- 21682614 TI - Atypical squamous cell carcinoma of the nail bed with phalangeal involvement. AB - We report an atypical presentation of squamous cell carcinoma (SCC) of the distal phalanx of the left thumb. On physical examination, there was no clinical evidence of a local lesion, but magnetic resonance imaging (MRI) showed multiple intraosseous cavities filled with fluid. A biopsy specimen showed a well differentiated SCC, which was treated by amputation of the distal phalanx. PMID- 21682615 TI - Doctors and medical students case managed by an Australian Doctors Health Program: characteristics and outcomes. AB - OBJECTIVE: The aim of this paper is to describe the characteristics and outcomes of participants with an Australian physician health program, the Victorian Doctors Health Program (VDHP), for case management of substance use disorder (SUD) and/or significant mental illness. METHOD: As part of quality assurance, processes data, including demographic information, care plan components and outcomes, were analysed. RESULTS: Between 2001 and 2008, 115 participants undertook case management plans with the VDHP. The majority (n = 71, 62%) had some involvement with the Medical Practitioners Board of Victoria (MPBV). Case management included facilitating referrals to addiction specialists, psychiatrists, counsellors and peer-based support. Ninety (78%) participants reported SUD, the remainder having mental illness (n = 25, 22%). Alcohol was the main drug reported by the SUD group (n = 44, 49%). Most of the SUD participants undertook biochemical monitoring. On commencement with the VDHP, 39 (34%) participants were on leave due to illness. The majority of participants case managed for 5 years were in medical work (n = 31, 84%). CONCLUSIONS: Case management by an independent physician health program may protect the health of the doctor and the community, and could be considered in other jurisdictions. PMID- 21682616 TI - Hermine Hug-Hellmuth, the first child psychoanalyst: legacy and dilemmas. AB - OBJECTIVE: Despite being the first psychoanalyst of children, Hermine Hug Hellmuth's history and writings remain relatively unknown. This paper endeavours to examine the way in which the history of the psychoanalysis of children is marked by the history of its protagonists. In particular, Hug-Hellmuth's treatment of children is divided between an educational approach and a more properly psychoanalytical aspect. Her theory and practice heavily influenced the directions taken after her, in particular by Anna Freud and Melanie Klein, even if this influence is essentially unacknowledged by these authors. CONCLUSIONS: Hug-Hellmuth's contribution to the psychoanalysis of children and consequently to child psychiatry are considerable and include technical innovation with the introduction of play into the treatment of children, the elaboration of the place of the analyst in regard to the child and notably the establishment of the place of the parents in regard to the treatment of the child. It is proposed that the very duality of her approach is what allowed her to be able to distinguish the place of the parent from that of the analyst. Nonetheless, her insistence on the place of education within the treatment and its effects on later theorists continue to raise dilemmas today. PMID- 21682617 TI - The suicidal desire of Tolstoy. AB - AIM: To explore whether a healthy, successful individual may experience suicidal desires. METHOD: Examination of "A Confession" by Leo Tolstoy. RESULTS: Confirmation that a physically and mentally healthy, well resourced individual may experience suicidal desires. CONCLUSION: To reduce suicide rates, a broader understanding of the factors which contribute to suicidal desires is required. PMID- 21682618 TI - Benchmarking adult mental health organizations. AB - OBJECTIVE: This paper describes the adult mental health forums that were conducted as part of the National Mental Health Benchmarking Project (NMHBP). METHOD: Eight adult mental health forums were attended by staff from eight adult mental health services from around the country. The forums provided an avenue for these participants to document their organizations' performances against previously agreed key performance indicators (KPIs), and to compare this performance with that of their peers. The forums also encouraged discussion about appropriate targets. RESULTS: Forum participants found that the inter organizational range for many of the KPIs was substantial, and they used this to inform practice change within their own organizations. They also found that they could set "alert targets" and "good practice targets" for some KPIs but not others. The discussion that ensued informed participants' understanding of factors that were within the control of their organizations that could be modified to improve service quality. CONCLUSIONS: Benchmarking in adult mental health services is not only possible but also likely to be extremely worthwhile as an exercise in improving service quality. For benchmarking to realize its potential, it requires strong national and local leadership, and a spirit of openness on the part of participating organizations. PMID- 21682619 TI - An examination of risk factors for readmission to acute adult mental health services within 28 days of discharge in the Australian setting. AB - OBJECTIVE: The aim of this paper was to identify risk factors associated with readmission within 28 days of discharge from eight Australian adult acute mental health inpatient services. METHOD: A detailed file audit was conducted comparing 222 patients readmitted within 28 days of discharge with 253 patients not readmitted during the same period. RESULTS: There was an association between early readmission and having had contact with the service in the previous 12 months (51% vs 21%), having been admitted in the previous 12 months (65% vs 36%), and having been diagnosed with an emotionally unstable personality disorder (14% vs 4%). Those who were not readmitted had a significantly higher score in the Health of the Nation Outcome Scales on index admission than those who were readmitted. Those who had community team contact on the day of discharge and those who received follow up by the mental health team within 7 days of discharge were more likely to be readmitted (55% vs 45% and 29% vs 19% respectively). CONCLUSIONS: Significant determinants of early readmission identified were a history of recent previous admissions and a diagnosis of unstable personality disorder. The usefulness of this performance measure to Area Mental Health Services and clinicians is discussed. PMID- 21682621 TI - Weight gain and metabolic syndrome among young patients on antipsychotic medication: what do we know and where do we go? AB - OBJECTIVE: Childhood obesity and its sequelae, including metabolic syndrome, are reaching epidemic proportions worldwide. Young people treated with antipsychotic medication are particularly at risk as they experience significant weight gain as a side effect of second generation antipsychotics (SGAs) with consequent increased risk of type 2 diabetes, cardiovascular morbidity and metabolic syndrome. However, surveillance for these side effects is not carried out nor intervention offered in routine clinical prctice. This paper examines the current state of evidence on this topic and suggests directions for future research and clinical practice. CONCLUSIONS: Systematic monitoring and preventative programs aimed at weight gain and metabolic side effects should form an integral part of the comprehensive management of adolescents on SGAs. PMID- 21682620 TI - Benchmarking the cost efficiency of community care in Australian child and adolescent mental health services: implications for future benchmarking. AB - OBJECTIVE: The purpose of this study was to benchmark the cost efficiency of community care across six child and adolescent mental health services (CAMHS) drawn from different Australian states. METHOD: Organizational, contact and outcome data from the National Mental Health Benchmarking Project (NMHBP) data sets were used to calculate cost per "treatment hour" and cost per episode for the six participating organizations. We also explored the relationship between intake severity as measured by the Health of the Nations Outcome Scales for Children and Adolescents (HoNOSCA) and cost per episode. RESULTS: The average cost per treatment hour was $223, with cost differences across the six services ranging from a mean of $156 to $273 per treatment hour. The average cost per episode was $3349 (median $1577) and there were significant differences in the CAMHS organizational medians ranging from $388 to $7076 per episode. HoNOSCA scores explained at best 6% of the cost variance per episode. CONCLUSIONS: These large cost differences indicate that community CAMHS have the potential to make substantial gains in cost efficiency through collaborative benchmarking. Benchmarking forums need considerable financial and business expertise for detailed comparison of business models for service provision. PMID- 21682622 TI - Improving patient return to general practice after specialist assessment. AB - OBJECTIVE: The aim of this study was to evaluate the impact of a two-pronged, letter intervention strategy to improve the follow-up after referral (FAR) rate to general practitioners of patients referred for a psychiatric assessment. METHODS: The FAR rate of patients referred to the Inner South East Primary Mental Health Team (PMHT) between June 2007 and June 2008 was examined via telephone call, before and after the implementation of a process sending letters to patients and practice managers advising them to make an appointment to discuss recommendations resulting from the psychiatric assessment. RESULTS: A statistically significant improvement (chi2 (1, n = 44) = 5.81, p = 0.016) in FAR rate was observed for patients post-intervention, with 11/25 (44%) pre intervention patients not returning to their referring general practitioner within 1 month of assessment, compared to 2/19 (10.5%) patients post intervention. CONCLUSIONS: The implementation of two simple and inexpensive measures resulted in a fourfold improvement in the return rate of patients to their referring general practitioner post-psychiatric assessment. PMID- 21682623 TI - The Early Motherhood Service: an acceptable and accessible perinatal mental health service. AB - OBJECTIVES: The aims of this paper are to quantify the effect of an innovative perinatal mental health program, the Early Motherhood Service, to identify factors contributing to its success, and to make recommendations as to its general applicability across other rural services. METHOD: The study involved stakeholder evaluation, analysis of available outcome data and analysis of consumer feedback data. RESULTS: Service functions were grouped into four key areas: increasing awareness of perinatal mental health problems; providing information and advice; providing treatment and support; and education, training and capacity building. Women accessing the service showed significant improvement in outcomes as measured by change over time in the Edinburgh Postnatal Depression Scale and the Health of the Nation Outcome Scale. Consumer feedback demonstrated that the service was highly valued. Key factors identified as contributing to the service's success were broad coverage of perinatal mental health problems; inclusion of early intervention and prevention; outreach capacity; partnership with, support for and capacity building of other health providers; a location which is accessible and non-stigmatizing; and staff comprising senior and skilled clinicians. CONCLUSIONS: The Early Motherhood Service is an innovative perinatal mental health service. It provides a useful model for the development of such services in rural communities. PMID- 21682624 TI - The multiple uses of routine mental health outcome measures in Australia and New Zealand: experiences from the field. AB - OBJECTIVE: The aim of this paper is to describe the way in which particular Australian and New Zealand mental health services are making use of routine outcome data to foster clinical improvements for consumers. METHOD: We invited individuals who are responsible for implementing outcome data collection across the two countries to describe exemplary practices occurring within their own services, and present the resultant information in the form of case studies. RESULTS: Outcome measurement is being used to guide clinical decision-making, engage consumers in treatment, foster a collaborative approach to care planning and goal setting, review consumers' progress with treatment, inform questions about consumers' eligibility for given programs, assist with discharge planning, improve the evidence-base on which services are founded, and evaluate particular models of service delivery. CONCLUSIONS: A number of mental health services are deriving useful information from routine outcome measurement, and using this to guide clinical practice. The examples provided here may offer some lessons for other services wishing to make better use of outcome data, and there may be some opportunities for the sharing of resources or infrastructure. Services that are already using outcome data to inform their clinical activities, and services that are keen to do so, will need ongoing support. PMID- 21682625 TI - Service use in consultation-liaison psychiatry: guidelines for baseline staffing. AB - OBJECTIVE: The aim of this study was to determine how referrals and clinical activity in consultation-liaison psychiatry (C-L) vary according to unit type and size, length of stay and psychiatric diagnosis, and to use these data to inform recommendations for the minimum levels of staffing required to conduct consultations in a general hospital. METHOD: Data were collected across three urban teaching hospitals over a 5-year period. The data included hospital admission data, referrals, psychiatric diagnosis, clinical contact time, clinical equivalent full time (EFT) and a measure of 'busyness'. RESULTS: Mean clinical staffing was 0.84 EFT per 100 beds. Services received a mean of 2.4 referrals per 100 hospital admissions. On average, each referral generated 3.9 contacts and a total contact time of 2.6 hours. The contact time was greater in patients with multiple psychiatric diagnoses as compared with a single or no diagnosis. CONCLUSION: In order to provide a minimum level of service for consultations to the expected range of serious and immediate psychiatric disorders present in the general hospital, a C-L service requires about 1.0 clinical EFT per 100 beds. For services to be able to address more complex elements of illness behaviour, provide education, conduct research, contribute to comprehensive care in specialist areas and undertake other liaison activities, greater and more multi disciplinary EFT is required. PMID- 21682626 TI - Acceptability of Internet treatment of anxiety and depression. AB - OBJECTIVE: The Internet is increasingly used to deliver treatment programs for common mental disorders. However, little is known about the acceptability of online interventions. The present study used an online survey to explore levels of acceptability of Internet-based treatment programs for anxiety and depression. METHODS: Visitors to websites operated by the Clinical Research Unit for Anxiety and Depression (CRUfAD), were invited to complete an online questionnaire during 16 weeks in 2008. RESULTS: Of 1543 people who began the survey, 1104 (72%) Australian health professionals and lay people completed it. Internet treatment programs for people with mild or moderate symptoms were more acceptable than programs for people with severe symptoms. There were no differences between health professionals and non-health professionals in acceptability ratings. As expected, previous users of Internet treatments reported significantly greater acceptability and preference for Internet treatments than non-users. CONCLUSIONS: Respondents rated Internet-based treatment programs as acceptable, with higher ratings from previous users. In order to facilitate implementation, program developers need to implement strategies for increasing knowledge about the efficacy and effectiveness of such programs, and engage therapists and consumers in establishing ethical and professional guidelines for their safe and responsible use. PMID- 21682627 TI - Something to hang my life on: the health benefits of writing poetry for people with serious illnesses. AB - OBJECTIVE: We aimed to explore the effect of a poetry writing program for people who had experienced a serious illness. METHOD: For this study we randomly assigned 28 volunteer participants with a history of serious illness, usually cancer, to one of two poetry writing workshops. Each group met weekly for 2 hours for 8 weeks. The second group was wait-listed to enable comparison between the two groups. We used the Kessler-10, a measure of wellbeing, before and after the workshops and also interviewed the participants at these times. RESULTS: Participants responded enthusiastically and each group demonstrated an increase in wellbeing over the course of their workshop, moving them from medium to low risk on the K10. Participants enjoyed the challenge of writing and the companionship of other group members. CONCLUSIONS: Psychiatrists, especially those working in liaison psychiatry, are in a position to encourage patients who have experienced a serious illness to explore writing as a way of coming to terms with their experiences. PMID- 21682628 TI - Dangerous myths about suicide. PMID- 21682629 TI - Defusing the "time-bomb": clarifying annotation 3.13. PMID- 21682630 TI - Risk assessment and resource allocation. PMID- 21682632 TI - Legal requirements to change gender: an abuse of human rights? PMID- 21682633 TI - Support workers for patients in borderline personality disorder. PMID- 21682634 TI - Risky management. PMID- 21682635 TI - Medical student teaching 'on the run' in a busy hospital. PMID- 21682640 TI - Turning hepatitis C into a real virus. AB - The reality of hepatitis C is inescapable for the estimated 130 million people worldwide chronically infected with the virus. Yet this pathogen has been notoriously difficult to move from the infected individual into experimental systems, and each advance--from the identification of the infectious agent to its culture and study--has been a significant challenge. As a result of unrelenting technical hurdles, preventative and therapeutic options have been slow to reach hepatitis C patients. More than 35 years since the recognition of the disease, there is no vaccine available, and the only approved treatment, a combination of pegylated interferon-alpha (IFN-alpha) and ribavirin, is frequently ineffective. Decades of research, however, have resulted in systematic progress and much is now known about this once elusive pathogen. Most importantly, key breakthroughs have stimulated drug discovery, and the first generation of specifically targeted antiviral inhibitors is poised to enter the market. This review provides a look back at progress in developing tractable model systems for this important agent of chronic hepatitis. PMID- 21682642 TI - Kin discrimination and cooperation in microbes. AB - Recognition of relatives is important in microbes because they perform many behaviors that have costs to the actor while benefiting neighbors. Microbes cooperate for nourishment, movement, virulence, iron acquisition, protection, quorum sensing, and production of multicellular biofilms or fruiting bodies. Helping others is evolutionarily favored if it benefits others who share genes for helping, as specified by kin selection theory. If microbes generally find themselves in clonal patches, then no special means of discrimination is necessary. Much real discrimination is actually of kinds, not kin, as in poison antidote systems, such as bacteriocins, in which cells benefit their own kind by poisoning others, and in adhesion systems, in which cells of the same kind bind together. These behaviors can elevate kinship generally and make cooperation easier to evolve and maintain. PMID- 21682643 TI - How viruses and toxins disassemble to enter host cells. AB - Many viruses and toxins disassemble to enter host cells and cause disease. These conformational changes must be orchestrated temporally and spatially during entry to avoid premature disassembly leading to nonproductive pathways. Although viruses and toxins are evolutionarily distinct toxic agents, emerging findings in their respective fields have revealed that the cellular locations supporting disassembly, the host factors co-opted during disassembly, the nature of the conformational changes, and the physiological function served by disassembly are strikingly conserved. Here, we examine some of the shared disassembly principles observed in model viruses and toxins. Where appropriate, we also underscore their differences. Our major intention is to draw together the fields of viral and toxin cell entry by using lessons gleaned from each field to inform and benefit one another. PMID- 21682641 TI - Recombination and DNA repair in Helicobacter pylori. AB - All organisms have pathways that repair the genome, ensuring their survival and that of their progeny. But these pathways also serve to diversify the genome, causing changes at the nucleotide, whole gene, and genome structure levels. Sequencing of bacteria has revealed wide allelic diversity and differences in gene content within the same species, highlighting the importance of understanding pathways of recombination and DNA repair. The human stomach pathogen Helicobacter pylori is an excellent model system for studying these pathways. H. pylori harbors major recombination and repair pathways and is naturally competent, facilitating its ability to diversify its genome. Elucidation of DNA recombination, repair, and diversification programs in this pathogen will reveal connections between these pathways and their importance to infection. PMID- 21682644 TI - Dinoflagellate genome evolution. AB - The dinoflagellates are an ecologically important group of microbial eukaryotes that have evolved many novel genomic characteristics. They possess some of the largest nuclear genomes among eukaryotes arranged on permanently condensed liquid crystalline chromosomes. Recent advances have revealed the presence of genes arranged in tandem arrays, trans-splicing of messenger RNAs, and a reduced role for transcriptional regulation compared to other eukaryotes. In contrast, the mitochondrial and plastid genomes have the smallest gene content among functional eukaryotic organelles. Dinoflagellate biology and genome evolution have been dramatically influenced by lateral transfer of individual genes and large-scale transfer of genes through endosymbiosis. Next-generation sequencing technologies have only recently made genome-scale analyses of these organisms possible, and these new methods are helping researchers better understand the biology and evolution of this enigmatic group of eukaryotes. PMID- 21682645 TI - Biology of Clostridium difficile: implications for epidemiology and diagnosis. AB - Clostridium difficile is an anaerobic, spore-forming, gram-positive rod that causes a spectrum of antibiotic-associated colitis through the elaboration of two large clostridial toxins and other virulence factors. Since its discovery in 1978 as the agent responsible for pseudomembranous colitis, the organism has continued to evolve into an adaptable, aggressive, hypervirulent strain. Advances in molecular methods and improved animal models have facilitated an understanding of how this organism survives in the environment, adapts to the gastrointestinal tract of animals and humans, and accomplishes its unique pathogenesis. The advances in microbiology have been accompanied by some important clinical observations including increased rates of C. difficile infection, increased virulence, and multiple outbreaks. The major new risk is fluoroquinolone use; there is also an association with proton pump inhibitors and increased recognition of cases in outpatients, pediatric patients, and patients without recent antibiotic use. The combination of more aggressive strains with mobile genomes in a setting of an expanded pool of individuals at risk has refocused attention on and challenged assumptions regarding diagnostic gold standards. Future research is likely to build upon the advancements in phylogenetics to create novel strategies for diagnosis, treatment, and prevention. PMID- 21682646 TI - The human gut microbiome: ecology and recent evolutionary changes. AB - The human gastrointestinal tract is divided into sections, allowing digestion and nutrient absorption in the proximal region to be separate from the vast microbial populations in the large intestine, thereby reducing conflict between host and microbes. In the distinct habitats of the gut, environmental filtering and competitive exclusion between microbes are the driving factors shaping microbial diversity, and stochastic factors during colonization history and in situ evolution are likely to introduce intersubject variability. Adaptive strategies of microbes with different niches are genomically encoded: Specialists have smaller genomes than generalists, and microbes with environmental reservoirs have large accessory genomes. A shift toward a Neolithic diet increased loads of simple carbohydrates and selected for their increased breakdown and absorption in the small intestine. Humans who outcompeted microbes for the new substrates obtained more energy from their diets and prospered, an evolutionary process reflected in modern population genetics. The three-way interactions between human genetics, diet, and the microbiota fundamentally shaped modern populations and continue to affect health globally. PMID- 21682647 TI - Approaches to capturing and designing biologically active small molecules produced by uncultured microbes. AB - Bacteria are one of the most important sources of bioactive natural products for drug discovery. Yet, in most habitats only a small percentage of all existing prokaryotes is amenable to cultivation and chemical study. There is strong evidence that the uncultivated diversity represents an enormous resource of novel biosynthetic enzymes and secondary metabolites. In addition, many animal-derived drug candidates that are structurally characterized but difficult to access seem to be produced by uncultivated, symbiotic bacteria. This review provides an overview about established and emerging techniques for the investigation and exploitation of the environmental metabolome. These include metagenomic library construction and screening, heterologous expression, community sequencing, and single-cell methods. Such tools, the advantages and shortcomings of which are discussed, have just begun to reveal the full metabolic potential of free-living and symbiotic bacteria, providing exciting new avenues for natural product research and environmental microbiology. PMID- 21682648 TI - The genetics of atrial fibrillation: from the bench to the bedside. AB - Atrial fibrillation (AF) has become a growing global epidemic and a financial burden for society. The past 10 years have seen significant advances in our understanding of the genetic aspects of AF: At least 2 chromosomal loci and 17 causal genes have been identified in familial AF, and an additional 7 common variants and single-nucleotide polymorphisms in 11 different genes have been indicated in nonfamilial AF. However, the current management strategies for AF are suboptimal. The integration of genetic information into clinical practice may aid the early identification of AF patients who are at risk as well as the characterization of molecular pathways that culminate in AF, with the eventual result of better treatment. Never before has such an opportunity arisen to advance our understanding of the biology of AF through the translation of genetics findings from the bench to the bedside. PMID- 21682649 TI - Experience of stress in childhood negatively correlates with plasma oxytocin concentration in adult men. AB - Early life experience is known to affect responses to stress in adulthood. Adverse experience in childhood and/or adolescence sensitises to life events that precipitate depression in later life. Published evidence suggests a relationship between depression and oxytocin (OT), but the extent to which early life experience influences OT disposition in adulthood deserves further exploration. This study hypothesised that early life stress (ELS) has a long-term negative effect on OT system activity. The study was performed on 90 male volunteers (18 56 years; mean +/- standard deviation = 27.7 +/- 7.09 years). Several questionnaires were used to assess: health, early life stressful experiences in childhood (ELS-C, up to 12 years) and early life stressful adolescence (13-18 years), recent stressful life events, depressive symptoms, state-trait anxiety and social desirability. Plasma OT concentration was estimated by means of a competitive enzyme immunoassay. Lower OT concentrations were significantly associated with higher levels of ELS-C (p < 0.01), and with depressive symptoms and trait anxiety (both p < 0.05). The interaction between ELS-C and trait anxiety was significant (p < 0.05), indicating that the link between ELS-C and plasma OT concentration is moderated by trait anxiety. These results contribute to the evidence that early life adverse experience is negatively associated with OT system activity in adulthood, and offer further insight into mediator and moderator effects on this link. PMID- 21682650 TI - Interleukin-18 expression in pig salivary glands and salivary content changes during acute immobilization stress. AB - Interleukin-18 (IL-18) has recently been considered a promising marker of stress responses. In this study, to evaluate IL-18 as a noninvasive stress marker in pigs, we investigated the expression of IL-18 in porcine salivary glands and its presence in saliva, and its dynamics during acute immobilization stress in pigs. IL-18 mRNA was detected robustly in the pig salivary glands by RT-PCR. Immunohistochemical staining of IL-18 protein expression revealed that the expression patterns differed among the three types of salivary glands (parotid, submandibular, and sublingual gland). IL-18 was also detected in pig saliva by ELISA, and a diurnal rhythm with a peak in the afternoon was observed. The IL-18 concentration in saliva was significantly increased during a 60-min acute immobilization stress in thirteen 5-month-old pigs. These results are the first evidence of a stress-related change of IL-18 in pig saliva. Salivary IL-18 may thus become a useful noninvasive marker for the evaluation of acute stress in pigs. PMID- 21682651 TI - Andrographolide induces apoptosis in B16F-10 melanoma cells by inhibiting NF kappaB-mediated bcl-2 activation and modulating p53-induced caspase-3 gene expression. AB - Cancer is a disorder characterized by uncontrolled proliferation and reduced apoptosis. Inducing apoptosis is an efficient method of treating cancers. In this study, we investigated the effect of andrographolide on the induction of apoptosis as well as its regulatory effect on the activation of transcription factors in B16F-10 melanoma cells. Treatment of B16F-10 cells with nontoxic concentration of andrographolide showed the presence of apoptotic bodies and induced DNA fragmentation in a dose-dependent manner. Cell cycle analysis and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays also confirmed the observation. The proapoptotic genes p53, Bax, caspase-9, and caspase-3 were found upregulated in andrographolide-treated cells, whereas the antiapoptotic gene bcl-2 was downregulated. This study also reveals that andrographolide treatment could alter the production and expression of proinflammatory cytokines and could inhibit the activation and nuclear translocation of p65, p50, and c-Rel subunits of nuclear factor-kappaB (NF kappaB), and other transcription factors such as c-fos, activated transcription factor-2, and cyclic adenosine monophosphate response element-binding protein in B16F-10 melanoma cells. These results suggest that andrographolide induces apoptosis via inhibiting NF-kappaB-induced bcl-2-mediated survival signaling and modulating p53-induced caspase-3-mediated proapoptotic signaling. PMID- 21682652 TI - Behavioral and physiological correlates of stress related to examination performance in college chemistry students. AB - This study was designed to assess physiological and behavioral correlates of academic stress during a college course in organic chemistry in the USA. Participants (45 females, 46 males, mean age 19.88 years) were screened for their basal hypothalamic-pituitary-adrenocortical activity using saliva samples collected at the beginning of the course and after each major test. Displacement activities (DAs) were observed during each test by videotaping students' behavior when they were taking the tests. These variables were then used as predictors of the students' achievement as measured by their grade point average (GPA) scores, American College Testing (ACT) scores, and their final grade in the class. Ninety one students, enrolled in Organic Chemistry I at Marshall University during the summer of 2009, were recruited for this study. It was found that individual differences in the physiological stress responses are a factor in predicting the students' ability to pass a challenging class. A logistic model built on GPA, DAs during stress, and salivary hormone (cortisol and dehydroepiandrosterone) concentrations was able to correctly classify almost 90% of the students passing the class. The same model was not nearly as successful in determining the possible factors behind failing the class, because the classification success was just 52%, a figure close to chance. We conclude that a clear set of characteristics related to the students' ability and resilience to psychological stress are necessary to succeed in a challenging class. The reason behind dropping or failing a class could be less defined. These data indicated that investigating the physiological and behavioral propensities associated with psychological stress can help us better understand an individual's coping responses to a long-term challenging situation. PMID- 21682653 TI - Fast high-throughput screening of temoporfin-loaded liposomal formulations prepared by ethanol injection method. AB - A new strategy for fast, convenient high-throughput screening of liposomal formulations was developed, utilizing the automation of the so-called ethanol injection method. This strategy was illustrated by the preparation and screening of the liposomal formulation library of a potent second-generation photosensitizer, temoporfin. Numerous liposomal formulations were efficiently prepared using a pipetting robot, followed by automated size characterization, using a dynamic light scattering plate reader. Incorporation efficiency of temoporfin and zeta potential were also detected in selected cases. To optimize the formulation, different parameters were investigated, including lipid types, lipid concentration in injected ethanol, ratio of ethanol to aqueous solution, ratio of drug to lipid, and the addition of functional phospholipid. Step-by-step small liposomes were prepared with high incorporation efficiency. At last, an optimized formulation was obtained for each lipid in the following condition: 36.4 mg.mL(-1) lipid, 13.1 mg.mL(-1) mPEG(2000)-DSPE, and 1:4 ethanol:buffer ratio. These liposomes were unilamellar spheres, with a diameter of approximately 50 nm, and were very stable for over 20 weeks. The results illustrate this approach to be promising for fast high-throughput screening of liposomal formulations. PMID- 21682654 TI - Unpredictable chronic stress in juvenile or adult rats has opposite effects, respectively, promoting and impairing resilience. AB - We evaluated the effects of early maternal deprivation (MD; age 7-14 days) alone or in combination with unpredictable chronic stress (UCS; MDUN; 28-84 days) on anxiety and learning in 90 days old adult rats. We hypothesized that exposure to both stressors (MDUN) would be more detrimental than exposure to one or neither. Unexpectedly, adult rats from the MDUN group did not differ from control animals, whereas adult MD animals exhibited impaired avoidance learning. We next investigated the effect of juvenile-onset (30-90 days) versus adult-onset (60-90 days) stress on avoidance learning in adulthood (90 days). We found that adult onset chronic stress impaired avoidance learning and memory whereas juvenile onset stress did not. Thus, the results again indicate that juvenile exposure to UCS induces resilience rather than impairment. PMID- 21682655 TI - Physiological and psychological impacts on male medical interns during on-call duty. AB - This study aimed to explore the physiological and psychological impacts on male medical interns during on-call duty (OCD). A prospective study of 13 medical interns was carried out using repeated testing during an on-call internal medicine and a duty-free course. There are 10 OCDs per month and each duty is composed of 33.5 consecutive work hours followed by 2 duty-free days for a time period of 3 months. Spectral analysis of R-R intervals was performed to evaluate the participants' heart rate variability. Among the three main spectral components distinguished, a high-frequency (HF) component of 0.15-0.4 Hz and a low-frequency component (LF) of 0.04-0.15 Hz were analyzed. The ratio of LF and HF (LF/HF) was also calculated. Reduced LF/HF, which suggests reduced cardiac sympathetic modulation, was found during duty night work. Increased HF was identified during the first sleep after OCD, which corresponded to the sleepiness scales. The OCD causes temporary emotional influence by the findings of higher anxiety and depression scores. In addition, inattention and impulsiveness, as represented by the continuous performance test score and lower nocturnal sympathetic modulation, were found, which indicated the differences between the internal medicine course and duty-free course. Our study suggests that 10 stressful on-call duties monthly result in reduced sympathetic modulation during duty night work, high anxiety and depression state, and a persistent inattention. PMID- 21682656 TI - Perceived stress correlates with disturbed sleep: a link connecting stress and cardiovascular disease. AB - The association between stress and cardiovascular disease (CVD) risk is becoming established. A mechanistic link clarifying the intermediate steps between the experience of stress and the development of CVD would support this association. We sought to examine the role of perceived stress as a factor associated with disturbed sleep with the goal of providing an explanation for the stress-CVD connection. We performed a cross-sectional analysis of data recorded by subjects at entry to our CVD prevention program. Data collection included questionnaire surveys, anthropometrics, and a CVD-relevant laboratory panel. Of 350 consecutively enrolled subjects (mean age 54.4 +/- 12.4 [SD] years, 138 men, 39%), 165 (47%) scored above the mean for stress measures. These high-stress subjects displayed an increased cardiovascular risk profile including elevated body mass index (mean +/- SD 31.1 +/- 5.9 vs. 29.0 +/- 5.9, r(s) = 0.175), increased waist circumference (102 +/- 17 cm vs. 98 +/- 14, r(s) = 0.135), and elevated high-sensitivity serum C-reactive protein (0.384 mg/dl vs. 0.356, r(s) = 0.109). High-stress subjects also demonstrated greater daytime sleepiness (Epworth Sleepiness Scale: 10.4 +/- 5.0 vs. 7.8 +/- 4.8, r(s) < 0.316), greater fatigue (fatigue scale: 5.4 +/- 2.2 vs. 3.4 +/- 2.4, r(s) = 0.484), poorer sleep quality (Pittsburgh Sleep Quality Index: 8.5 +/- 4.4 vs. 5.9 +/- 4.0, r(s) = 0.416), and shorter sleep duration (20 min less/24 h, r(s) = negative 0.177) with a higher risk for sleep apnea (60% at high risk vs. 40%, p = 0.003) than low stress subjects. High stress was associated with significant disturbances in sleep duration and sleep quality. Stress levels also correlated with daytime consequences of disturbed sleep. The stress-sleep connection may be an important mechanistic mediator of the association between stress and CVD. PMID- 21682657 TI - Pharmacotherapy of haemophilia A. AB - INTRODUCTION: Haemophilia A is due to factor VIII (FVIII) deficiency. The main treatment is replacement therapy with FVIII concentrates. However, these concentrates carried a high risk of blood-borne viral infections and still have a high risk of inducing anti-FVIII inhibitors. AREAS COVERED: An overview of products available and therapeutic options for haemophilia A management in order to help in decision making. A literature search using Medline with the keywords: 'haemophilia', 'factor VIII', 'therapy', 'inhibitor', 'concentrate', 'bleeding', 'prophylaxis', 'on demand', 'plasma-derived', 'recombinant', 'coagulation factors', 'immunotolerance' was performed. The years 1960 - 2010 are included. EXPERT OPINION: Progress in management of patients with haemophilia A has allowed increased life expectancy and quality of life. There is evidence that prophylaxis prevents or, at least, slows down arthropathy development when started early in childhood. FVIII concentrates have achieved high levels of blood-borne pathogen safety. However, treatment is frequently complicated by development of FVIII neutralizing inhibitors, which prevent control of bleeding and predispose to a high morbidity and mortality risk. Bypassing agents are effective in bleeding treatment in a high percentage of cases. Prophylaxis with bypassing agents and their use in combination are offering opportunities in management of inhibitor patients. More evidence is necessary to understand how to prevent and manage this complication. PMID- 21682658 TI - Nanocarriers: a tool to overcome biological barriers in siRNA delivery. AB - INTRODUCTION: siRNA has poor in vivo stability and has a plasma half life of only a few minutes after intravenous administration. These problems can be overcome by conjugating/encapsulating siRNA with various nanosystems. Surface modifications of such nanosystems can further improve the cellular uptake of siRNA-nanosystems. In this review, the authors have highlighted the problems encountered in siRNA delivery, conjugation strategies and nanosystems for siRNA delivery and for improving their in vivo delivery performance. AREAS COVERED: The authors briefly cover various problems encountered in siRNA delivery and discuss nanocarriers for overcoming these biological barriers. EXPERT OPINION: siRNA binding and unpacking are important factors for optimizing the interactions between siRNA and nanosystems. Several crucial conjugation parameters, such as the conjugation site of siRNA, and the nature of molecules to be conjugated (charge, molecular weight and hydrophobicity), should be carefully considered for maximising delivery efficiency of siRNA conjugated nanosystems. PMID- 21682659 TI - Glucocorticoid response to changes in enclosure size and human proximity in the Persian onager (Equus hemionus onager). AB - This study investigated glucocorticoid (GC) responses to season and changes in enclosure size and human proximity in the Persian onager (Equus hemionus onager). Enzyme immunoassays were validated to measure GC metabolites in urine and feces (fGCM). Fecal samples were collected from 10 female onagers while in a large pasture, after transport to smaller yards (in greater proximity to people), and 2 months thereafter. Urine samples were collected for 1 year while females were in smaller yards to examine seasonal GC activity. Approximately, 2-fold increases (P < 0.05) were observed in fGCM levels after transport from pasture to yards with increased human exposure, followed by a rapid decline (within -17 days) to baseline (pasture) values. However, responses varied among onagers during the 30 days after translocation, with one female failing to acclimate. Mean fGCM concentrations in smaller yards 2 months after transport were comparable to those in pasture. Seasonal GC concentrations were lowest (P < 0.05) during winter, indicating modest seasonal variability. Results demonstrate an acute increase in GC secretion in Persian onagers that moved from large to small enclosures coincident with increased human activities. Most animals acclimated within 3 weeks, suggesting that this rare equid has retained mechanisms to acclimate to marked alterations in an ex situ environment. PMID- 21682660 TI - The effects of dynamic ankle-foot orthoses on functional ambulation activities, weight bearing and spatio-temporal characteristics of hemiparetic gait. AB - PURPOSE: To investigate the effects of dynamic ankle-foot orthoses (DAFOs) on functional ambulation activities, weight bearing and spatio-temporal characteristics of hemiparetic gait and to inquire whether wearing a DAFO for 3 months has a carryover effect. METHOD: Fourteen chronic hemiparetic patients who could walk independently with or without a cane were the subjects of the study. Patients were assessed initially with tennis shoes and were given custom fabricated DAFOs which they wore for three months and were retested under two conditions: with tennis shoes only and with DAFOs worn in these shoes. All patients were assessed for weight bearing percentage of the affected side, cadence, step length of the involved and uninvolved sides, step width, functional reach, timed up and go, timed down stairs, timed up stairs, physiologic cost index and velocity. RESULTS: Comparison of initial and third month assessments with shoes only condition showed that there was no significant improvement for the measured parameters. When comparison was made at the third month while patients were wearing tennis shoes only and when they were wearing DAFO's in their shoes there was a significant difference in favour of the condition where patients were wearing DAFOs. CONCLUSION: The benefits of using DAFOs in chronic hemiparetic patients are lost when the patients are not wearing their orthoses. PMID- 21682661 TI - Recent advances in the treatment of chronic hepatitis B. AB - INTRODUCTION: At present, two strategies exist for the treatment of chronic hepatitis B (CHB): i) standard or pegylated interferon alpha (IFN) with mainly immune modulatory effects; and ii) nucleos(t)ide analogues (NA) with direct antiviral effects. The optimal treatment for an individual patient remains controversial. AREAS COVERED: The treatment efficacy and prediction of response to antiviral agents for chronic hepatitis B are reviewed and discussed. EXPERT OPINION: The rates of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) loss or seroconversion are continuously increasing in CHB patients after stopping a finite course of IFN, whereas long-term NA therapy is usually required to improve the adverse outcomes of CHB. Lower baseline HBV DNA level is a strong predictor for both sustained viral suppression and HBeAg seroconversion in patients receiving IFN-based as well as NAs therapy. In addition, HBeAg-positive patients with genotype A or B infection have better responses to IFN-based therapy than those with genotypes C or D infection. Furthermore, on-treatment predictors such as declines of serum HBV DNA, HBsAg and HBeAg levels may be helpful in making decisions of subsequent therapy. Regarding the association of host genetic factors with responses to antiviral therapy, current evidence is limited. PMID- 21682662 TI - Brivaracetam for the treatment of epilepsy. AB - INTRODUCTION: Epilepsy is one of the most common neurological disorders, affecting about 1% of the population worldwide. With currently available antiepileptic drugs, one-third of patients continue to suffer from seizures even when treated at maximally tolerated dosages, either in monotherapy or in various drug combinations. Pharmacoresistance is associated with physical risks, reduced life expectancy, reduced quality of life and impairments in social opportunities. The acetamide derivate levetiracetam (LEV) that primarily targets the synaptic vesicle protein 2A has been one of the most successful second-generation antiepileptic drugs. AREAS COVERED: This article reviews a rationally designed LEV derivative, brivaracetam (BRV), which has an increased affinity to the LEV binding site. BRV has shown some efficacy in the treatment of progressive myoclonus epilepsy and is under development to be used as an add-on treatment of focal epilepsy. Evidence is given for possible advantages related to the higher intrinsic antiepileptic efficacy of BRV and its antiepileptic potential in relation to a wide spectrum of epilepsy forms and for possible disadvantages related to hepatic metabolism and to a lower therapeutic index related to additional intrinsic activity at the sodium channel. An update on pharmacodynamic, pharmacokinetic and study data published until 2010 on BRV is given. EXPERT OPINION: BRV is a rationally developed third-generation antiepileptic drug with higher binding to SV2A and additional mechanisms of actions. Animal studies are promising regarding its efficacy in a wide spectrum of epilepsy models. Clinical studies have shown good tolerability at dosages of up to 50 mg/day but have yet to identify the optimal dose range and to prove an additional value of the drug in terms of seizure control. PMID- 21682663 TI - Triple reuptake inhibitors for treating subtypes of major depressive disorder: the monoamine hypothesis revisited. AB - INTRODUCTION: Major depression is one of the most prevalent forms of mental illnesses and is among the leading causes of disability, affecting about 121 million people worldwide. Approximately 30% of patients fail to respond to present therapies. Therefore, the search for novel antidepressant drugs continues. AREAS COVERED: The most prescribed antidepressants are serotonin reuptake inhibitors and/or noradrenaline reuptake inhibitors, which only indirectly affect dopaminergic neurotransmission. As a consequence, residual symptoms remain, including impaired motivation and impaired pleasure. This article reviews the development of new broad-spectrum antidepressants, the triple reuptake inhibitors, which also increase brain dopamine levels. EXPERT OPINION: In this review, a distinction is made between the subtypes of melancholic and atypical depressions and their associated brain abnormalities and dysfunctions in neurotransmitter systems. Subsequently, we propose a hypothetical model: 'the monoamine hypothesis revisited' to predict what kind of pharmacological treatment will be effective in the different subtypes of depression. It is expected that the triple reuptake inhibitors, inhibiting the reuptake of all three monoamines, can produce a greater efficacy than traditional antidepressants especially in atypical depression. Since triple reuptake inhibitors may also dampen states of hyperglutamatergic activity and subsequent excitotoxicity, it is suggested that these new drugs have a considerable neuroprotective potential in major depression, especially in melancholic depression. PMID- 21682664 TI - Cisplatin induces production of reactive oxygen species via NADPH oxidase activation in human prostate cancer cells. AB - This study aimed to examine the roles of reactive oxygen species (ROS) in cisplatin treatment of human prostate cancer cells; hormone-sensitive LNCaP and hormone-refractory PC3 and DU145 cells. Intracellular levels of ROS and H(2)O(2) were measured and visualized using specific fluorescent probes. NADPH oxidase (NOX) activity was detected by lucigenin chemiluminescence assay. Expression levels of NOX isoforms were determined by semi-quantitative RT-PCR. Cisplatin treatment increased the intracellular levels of ROS and H(2)O(2) in three prostate cancer cell lines. The increase was transient and robust in hormone sensitive LNCaP cells compared with hormone-refractory PC3 and DU145 cells. Consistent with these findings, the NOX activity induced by cisplatin was higher in LNCaP cells than in PC3 and DU145 cells. Expression pattern of NOX isoforms varied among three cell lines and the NOX activity was independent of NOX expression. Taken together, we have shown that cisplatin induces production of ROS and H(2)O(2) via NOX activation in human prostate cancer cell lines, which is most prominent in hormone-sensitive LNCaP cells. PMID- 21682665 TI - "From herb to kitchen and bedside: food factors are pharmacological molecules with antioxidant activity". PMID- 21682666 TI - Insulin targets the Na(+)/K(+) ATPase in enterocytes via PI3K, PKC, and MAPKS. AB - The effect of insulin on intestinal Na(+)/K(+) ATPase is till now undetermined, and it is still unclear whether insulin exerts any modulatory effect on glucose absorption by targeting the ATPase. This work attempted to address this question and to unravel the signaling pathway involved using Caco-2 cells as a model. After an overnight starvation, cells were treated with insulin in presence and absence of specific inhibitors of some known mediators. The activity of the pump was assayed by measuring the ouabain-inhibitable inorganic phosphate (P(i)) released, whereas changes in its abundance were determined by western blot analysis. Insulin decreased the activity and abundance of the ATPase in a crude membrane homogenate. This effect disappeared completely upon inhibition of either phosphotidylinositol-3 kinase (PI3K) or protein kinase C (PKC), but was partially abolished when p38MAPK or MEK/ERK were inhibited separately. Activation of PKC with phorbol-12-myristate-13-acetate (PMA) imitated the effect of insulin and was not affected by inhibition of PI3K. The data suggest that PI3K and PKC are along the same pathway that branches into two separate ones involving each either p38MAP kinase or MEK/ERK. This hypothesis was confirmed by the data obtained from the treatment of Caco-2 cells with PMA, when p38MAPK and MEK/ERK were inhibited simultaneously. Concomitant inhibition of p38MAPK and MEK/ERK abrogated fully the effect of insulin, indicating that no other pathways are present in addition to the ones proposed above. PMID- 21682667 TI - Screening and appraisal for immunological adjuvant-active fractions from Platycodon grandiflorum total saponins. AB - In this study, the total saponins from the root of Platycodon grandiflorum (PGS(t)) was subjected to D101 macroreticular resin column chromatography to afford four fractions (PGS30, PGS50, PGS75 and PGS95). PGS(t) and its four fractions were evaluated and compared for the haemolytic activities and adjuvant potentials on the specific cellular and humoral immune responses of ICR mice against recombinant hepatitis B surface antigen (HBsAg). PGS(t), PGS30, PGS50, PGS75, and PGS75 showed a slight haemolytic effect, with their concentration inducing 50% of the maximum haemolysis (HD50) being 16.13 +/- 0.81, >200, 17.53 +/- 0.24, 20.16 +/- 0.76, 76.31 +/- 2.20 MUg/mL against 0.5% rabbit red blood cell, respectively. PGS(t), PGS50, and PGS75 significantly not only enhanced the Con A-, lipopolysaccharide-, and HBsAg-induced splenocyte proliferation, but promoted the killing activities of natural killer (NK) cells from splenocytes in HBsAg-immunized mice (P < 0.01 or P < 0.001). HBsAg-specific IgG, IgG1, IgG2a, and IgG2b antibody levels in serum were also significantly enhanced by PGS(t), PGS50, and PGS75 compared with HBsAg control group (P < 0.05, P < 0.01, or P < 0.001). Moreover, the adjuvant effects of PGS50 and PGS75 on the cellular immune responses and HBsAg-specific IgG2a and IgG2b antibody responses were more significant than those of Alum, PGS30, and PGS95. The results indicated that PGS50 and PGS75 could improve both cellular and humoral immune responses, and elicit a balanced Th1/Th2 response to HBsAg in mice, and that PGS75 may be developed as an ideal candidate adjuvant for hepatitis B vaccine. PMID- 21682668 TI - Understanding paediatric rehabilitation therapists' lack of use of outcome measures. AB - PURPOSE: Despite widespread educational and promotional efforts, paediatric rehabilitation therapists still do not systematically or routinely use outcome measures. METHOD: A review of contextual and psychosocial factors affecting therapists' use of outcome measures was performed, incorporating information from past studies of barriers to therapists' use of measures and more recent information about measure use, knowledge brokering and expert practice. RESULTS: This cumulative and contextual overview provided insights into how many therapists may approach practice. Therapists' beliefs in the importance of establishing effective relationships may lead them to place less value on formal measurement, to adopt a less rigorous and more pragmatic approach to ascertaining whether outcomes are achieved, and to avoid measures that may show little improvement. CONCLUSIONS: A relational goal-oriented approach to practice is proposed in which therapists adopt a broader facilitative and educational role with families about the importance of the measurement process. PMID- 21682669 TI - Reliability and validity of Short Form 36 Version 2 to measure health perceptions in a sub-group of individuals with fatigue. AB - PURPOSE: To determine the validity and reliability of Short Form 36 Version 2 (SF36v2) in sub-groups of individuals with fatigue. METHOD: Thirty subjects participated in this study, including n = 16 subjects who met case definition criteria for chronic fatigue syndrome (CFS) and n = 14 non-disabled sedentary matched control subjects. SF36v2 and Multidimensional Fatigue Inventory (MFI-20) were administered before two maximal cardiopulmonary exercise tests (CPETs) administered 24 h apart and an open-ended recovery questionnaire was administered 7 days after CPET challenge. The main outcome measures were self-reported time to recover to pre-challenge functional and symptom status, frequency of post exertional symptoms and SF36v2 sub-scale scores. RESULTS: Individuals with CFS demonstrated significantly lower SF36v2 and MFI-20 sub-scale scores prior to CPET. Between-group differences remained significant post-CPET, however, there were no significant group by test interaction effects. Subjects with CFS reported significantly more total symptoms (p < 0.001), as well as reports of fatigue (p < 0.001), neuroendocrine (p < 0.001), immune (p < 0.01), pain (p < 0.01) and sleep disturbance (p < 0.01) symptoms than control subjects as a result of CPET. Many symptom counts demonstrated significant relationships with SF36v2 sub-scale scores (p < 0.05). SF36v2 and MFI-20 sub-scale scores demonstrated significant correlations (p < 0.05). Various SF36v2 sub-scale scores demonstrated significant predictive validity to identify subjects who recovered from CPET challenge within 1 day and 7 days (p < 0.05). Potential floor effects were observed for both questionnaires for individuals with CFS. CONCLUSION: Various sub-scales of SF36v2 demonstrated adequate reliability and validity for clinical and research applications. Adequacy of sensitivity to change of SF36v2 as a result of a fatiguing stressor should be the subject of additional study. PMID- 21682670 TI - Investigations on feasibility of in situ development of amphotericin B liposomes for industrial applications. AB - Amphotericin B (AmB) liposome formulations are very successful in the treatment of fungal infections and leishmaniasis. But higher cost limits its widespread use among people in developing countries. Therefore, we have developed a modified ethanol-injection method for the preparation of AmB liposomes. Two liposomal formulations were developed with dimyristoyl phosphatidylcholine [F-1a] and soya phosphatidylcholine [F-2a], along with egg phosphatidyl glycerol and cholesterol. AmB was dissolved in acidified dimethyl acetamide and mixed with ethanolic lipid solution and rapidly injected in 5% dextrose to prepare liposomes. Liposomes were characterized on the basis of size (~100 nm), zeta (-43.3 +/- 2.8 mV) and percent entrapment efficiency (>95%). The in vitro release study showed an insignificant difference (P >= 0.05) for 24-hour release between marketed AmB liposomes (AmBisome) and F-1a and F-2a. Proliposome concentrate, used for the preparation of in situ liposomes, was physically stable for more than 3 months at experimental conditions. Similarly, AmB showed no sign of degradation in reconstituted liposomes stored at 2-8 degrees C for more than 3 months. IC(50) value of Ambisome (0.18 ug/mL) was comparatively similar to F-1a (0.17 ug/mL) and F-2a (0.16 ug/mL) against intramacrophagic amastigotes. Under experimental conditions, a novel modified method for AmB liposomes is a great success and generates interest for development as a platform technology for many therapeutic drug products. PMID- 21682671 TI - Adopting extensive intra-operative peritoneal lavage (EIPL) as the standard prophylactic strategy for peritoneal recurrence. AB - EIPL (extensive intra-operative peritoneal lavage) therapy was developed as a prophylactic strategy for peritoneal recurrence, with the goal of improving the quality of life and survival span for advanced gastric cancer patients with peritoneal free cancer cells. The purpose of this article is to review the therapy's contribution to a remarkable improvement in the 5-year survival for patients with positive lavage cytology on prospective randomized controlled clinical trials. We also advocate for the adoption of the EIPL as the optimal treatment protocol for advanced gastric cancer. PMID- 21682673 TI - Sex-related differences in QTc effects potential of drugs. AB - The objective of this study was to examine the drug-induced sex differences in corrected QT (QTc) interval by re-analyzing the data collected in thorough QT studies submitted to the US Food and Drug Administration (FDA). We examined 64 studies available in the FDA database by performing a time-matched, baseline adjusted ANCOVA on the QTc response stratified by sex. We used several summaries to capture the differences between males and females in drug response QTc effects. They included sample means, upper confidence intervals, and areas under the curves. At baseline, females tend to have a higher QTc response than males. After treatment, various summaries suggest that females tend to have a higher QTc effect than males. However, the magnitude of the difference is small and is often not statistically significant. Several limitations can be raised about these available data: 1) available QT studies were not designed to examine the sex differences in QTc effects, 2) the findings were undermined by large variations seen in QT data, and 3) our summary statistics are descriptive in nature and are not for inferential purposes. Nonetheless, the results suggest that females tend to have a higher QTc effect than males, although the difference tends to be small. Further research is needed to formally address the question. PMID- 21682672 TI - Recent advances of kinesin motor inhibitors and their clinical progress. AB - Antimitotic chemotherapy remains the most effective approach to treat a variety of human neoplasms. Since the discovery of tubulin-targeting agents, vinca alkaloids and the taxanes including paclitaxel and docetaxel are used clinically to treat several solid tumors of the head and neck, breast, lung, ovary, and bladder. Despite the preclinical and clinical success of tubulin-targeting agents, the ability of tumors to develop an acquired resistance to drugs used for treatment and neurotoxicity severely limited their long-term effectiveness to cancer cure. Lately, advances in antimitotic treatments led to the identification of novel mitosis-specific agents that are expected to show higher selectivity and less cytotoxicity compared to known antimitotics. This review focuses on the progress of kinesin motor inhibitors that target proteins that function predominantly in mitosis. PMID- 21682674 TI - Clinical trials in relapsing-remitting multiple sclerosis /a new proposal for dealing with basic problems and restrictions. AB - The natural course of multiple sclerosis is characterized by a high variability of pattern, relapse rate and different progression indices. They also present a dramatic impact on the interpretation of treatment trials. Reports, based on uncontrolled observations are therefore of little value. Currently it is generally accepted that a proper treatment trial should be double blinded and, although probably controversial, that it should be compared with a group of MS patients treated with placebo. Currently MS is considered as a generalized degenerative disease. The lesions are persistent, which is the reason why immunomodulatory treatment has to be started as early as possible. An alternative approach, somewhat suggestive for the use of placebo trials, seems to be a comparison of proposed new drug therapy group with a group of patients treated with a generally accepted reference drug. PMID- 21682675 TI - Targeted-therapy and imaging response: a new paradigm for clinical evaluation? AB - Clinical management of patients with malignant tumors has dramatically changed over the last years with the introduction of novel therapeutics, such as receptor targeted therapies, downstream effectors and antiangiogenic compounds. This has created a need to re-evaluate the existing criteria used to assess treatment response. Emerging diagnostic techniques, combining functional and structural data may play a relevant role in planning new treatment strategies in individual cancer patients. In the new scenario where biological treatment results in stable disease, standard Response Evaluation Criteria in Solid Tumors (RECIST) and RECIST 1.1 criteria have limitations. Moreover, functional 18- fluorodeoxyglucose ((18)FDG)-positron emission tomography (PET) imaging provides an additional tool to assess tumor activity, particularly consistent in some settings, such as Gastro Intestinal Solid Tumors (GIST), hepatocarcinoma, nonsmall lung cancer, and colorectal cancer. The integration of (18)FDG-PET and computed tomography (CT) enhances the evaluation of oncologic patients treated with molecularly targeted drugs, and accelerates drug development in many types of tumors. PMID- 21682676 TI - Nosocomial MRSA pneumonia: data from recent clinical trials. AB - MRSA infections, especially pneumonia have been associated with considerable morbidity and mortality and the management of MRSA infections is considered as an issue of high priority for scientific societies. Many studies which have been published during the last 10 years have provided evidence for MRSA pneumonia epidemiology, diagnosis and treatment. The main regime of antibiotic treatment recommended for MRSA pneumonia is either vancomycin or linezolid. Despite its pK/pD superiority over vancomycin, linezolid has to date failed to show clear advantage over vancomycin in recent clinical trials. PMID- 21682677 TI - Clinical trials using vasodilators in pulmonary arterial hypertension: where do we go from here? AB - BACKGROUND: The impact of treatment with vasodilators on the survival of patients with pulmonary arterial hypertension (PAH) remains uncertain. Despite several clinical trials have been carried out in the last 15 years, their primary objective was not to assess mortality but the changes on surrogate end points. METHODS AND RESULTS: We reviewed the results of all clinical trials with vasodilators in PAH and the main results of different metaanalysis. Clinical trials and systematic reviews confirm that vasodilator therapies in patients with PAH who are non-vasoreactive produce a consistent, statistically significant but a marginal effect on exercise capacity assessed by the six-minute walk test. The weighted mean difference (95% CI) achieved with epoprostenol (EPO) or other prostacyclin analogues (PCA), endothelin receptor antagonists (ETRA) and phosphodiesterase-type-5 inhibitors (PDE5-I) was 35.4 m (17.3-53.5), 46.1 m (38.1 54.2) and 33.8 m (24.8-42.7), respectively. When considering the cumulative effects within each drug family, no class of drug produced a statistically significant reduction in all cause mortality. The relative risk rates (95% CI) conferred by EPO or PCA, ETRA and PDE5-I were 0.66 (0.36-1.21), 0.48 (0.19-1.23) and 0.65 (0.16-2.67), respectively. INTERPRETATION: Further trials utilizing similar classes of drugs, and following similar trial designs are unlikely to yield different results or offer any more clinical benefits. Given that PAH is a fatal disease this raises concerns about whether they are ethical to conduct or not. Future trials will need to utilize clinical endpoints rather than the ones that are easy to administer and will need to include longer durations of study and other strategies to test the durability of effect. PMID- 21682678 TI - Inhibition of hemorrhagic activity of viper venoms by N-acetyl cysteine: involvement of N-acetyl and thiol groups. AB - The mortality rate due to snakebite is reduced markedly by the use of anti venoms, which are the only medically approved remedial agents available. The anti venoms effectively neutralize the systemic toxicity but offer no protection towards local tissue degradation. In viperid snake envenomations, SVMPs and SVHYs are the major agents responsible for brutal local tissue damage as they degrade ECM and basement membrane surrounding the blood vessels. Thus, the usage of inhibitor(s) against ECM degrading enzymes in the treatment of viper bites is an affirmative therapeutic choice. The present study assessed the efficacy of N acetyl cysteine (NAC) to inhibit gelatinase, hyaluronidase, hemorrhagic and defibrinogenating activities of Vipera russelli and Echis carinatus venoms. NAC inhibited these activities dosedependently, but it did not inhibit the PLA2, 5' nucleotidase, procoagulant and edema inducing activities of both the venoms. NAC showed complete inhibition of hemorrhagic activity when incubated with venom prior to testing. Whereas little inhibition was observed when venom and NAC were injected independently. Inhibition of the basement membrane degradation and accumulation of inflammatory leukocytes at the site of venom injection in histological sections further corroborate the inhibitory property of NAC. The observed inhibition of hemorrhage was likely due to zinc chelation as supported by spectral studies. Further, docking predictions suggested the role of -SH and NH-CO-CH3 groups of NAC in the inhibition of SVMPs and SVHYs. Future studies related to the protective role of NAC against the venom induced systemic hemorrhage and secondary complications are highly exciting. PMID- 21682679 TI - Characterization of major zinc containing myonecrotic and procoagulant metalloprotease 'malabarin' from non lethal trimeresurus malabaricus snake venom with thrombin like activity: its neutralization by chelating agents. AB - A major myonecrotic zinc containing metalloprotease 'malabarin' with thrombin like activity was purified by the combination of gel permeation and anion exchange chromatography from T. malabaricus snake venom. MALDI-TOF analysis of malabarin indicated a molecular mass of 45.76 kDa and its N-terminal sequence was found to be Ile-Ile-Leu- Pro(Leu)-Ile-Gly-Val-Ile-Leu(Glu)-Thr-Thr. Atomic absorption spectral analysis of malabarin raveled the association of zinc metal ion. Malabarin is not lethal when injected i.p. or i.m. but causes extensive hemorrhage and degradation of muscle tissue within 24 hours. Sections of muscle tissue under light microscope revealed hemorrhage and congestion of blood vessel during initial stage followed by extensive muscle fiber necrosis with elevated levels of serum creatine kinase and lactate dehydrogenase activity. Malabarin also exhibited strong procoagulant action and its procoagulant action is due to thrombin like activity; it hydrolyzes fibrinogen to form fibrin clot. The enzyme preferentially hydrolyzes Aalpha followed by B subunits of fibrinogen from the N terminal region and the released products were identified as fibrinopeptide A and fibrinopeptide B by MALDI. The myonecrotic, fibrinogenolytic and subsequent procoagulant activities of malabarin was neutralized by specific metalloprotease inhibitors such as EDTA, EGTA and 1, 10-phenanthroline but not by PMSF a specific serine protease inhibitor. Since there is no antivenom available to neutralize local toxicity caused by T. malabaricus snakebite, EDTA chelation therapy may have more clinical relevance over conventional treatment. PMID- 21682680 TI - Protective effect of schizolobium parahyba flavonoids against snake venoms and isolated toxins. AB - Four compounds (isoquercitrin, myricetin-3-O-glucoside, catechin and gallocatechin) were isolated from lyophilized aqueous extract of Schizolobium parahyba leaves by chromatography on Sephadex LH-20, followed by semipreparative HPLC using a C-18 column, and identified by 1H and 13C NMR. The compounds were then, tested against hemorrhagic and fibrinogenolytic activities of Bothrops crude venoms and isolated metalloproteinases. The inhibitors neutralized the biological and enzymatic activities of Bothrops venoms and toxins isolated from B. jararacussu and B. neuwiedi venoms. The results showed that gallocatechin and myricetin-3-O-glucoside are good inhibitors of hemorrhagic and fibrinogenolytic activities of metalloproteinases, respectively. Gallocatechin also inhibited the myotoxic activity of both B. alternatus venom and BnSP-6 (Lys49 PhospholipaseA2 from B. neuwiedi). Circular dichroism and docking simulation studies were performed in order to investigate the possible interaction between BnSP-6 and gallocatechin. This is the first time these compounds and their anti-ophidian properties are reported for S. parahyba species. Forthcoming studies involving X ray co-crystallization, will be of great importance for the development of new therapeutic agents for the treatment of ophidian accidents and for the better understanding of the structure/function relationship of venom toxins. PMID- 21682681 TI - Daboia russelli venom hyaluronidase: purification, characterization and inhibition by beta-3-(3-hydroxy-4-oxopyridyl) alpha-amino-propionic Acid. AB - The present study describes the purification and characterization of a hyaluronidase (DRHyal-II) from Daboia/Vipera russelli venom and its inhibition by beta-3-(3-hydroxy-4-oxopyridyl) alpha-amino-propionic acid, the mimosine. Gel permeation and ion exchange chromatography were employed to isolate DRHyal-II. The molecular mass by MALDITOF mass spectrometry was found to be 28.3 kDa. Single band in reduced SDS-PAGE suggested the monomeric nature. It was optimally active at pH 5.5 and at 37C and require 150 mM NaCl in the reaction mixture. It was specific to hyaluronan substrate and belongs to class-I or the neutral active enzymes. DRHyal-II was non-toxic by itself but, it potentiated the myotoxicity of VRV-PL-VIII myotoxin and hemorrhagic activity of hemorrhagic complex (HC). In in vitro experiments, mimosine inhibited the activity of DRHyal-II and the hyaluronidase activity of whole venom dose dependently. In in vivo experiments, mimosine inhibited the DRHyal-II potentiated myotoxicity of VRV-PL-VIII myotoxin and hemorrhagic activity of HC. The inhibition was due to the formation of DRHyal II-mimosine inhibitory complex that resulted in significant structural changes at secondary and tertiary levels as evidenced by fluorescence emission and CD spectral studies. Hence, in this study an attempt was made to establish the possible role of hyaluronidase activity in the pathology of Daboia/Vipera russelli venom and the beneficial effects of its inhibition with special emphasis on the management of local toxicity. PMID- 21682682 TI - Therapeutic potential of peptides with neutralizing ability towards the venom and toxin (CaTx-I) of crotalus adamanteus. AB - The CaTx-I (PLA2) toxin of Crotalus adamanteus venom is responsible for most of the symptoms observed during envenomation. Synthetic peptides were designed and screened for venom (0.8 MUg/ml) and CaTx-I (0.1 MUM) inhibition at varying doses of the peptide (10000- 0.0001 MUM) using a Cayman chemical human secretory phospholipase A2 (sPLA2, Type II) assay kit. Further, in vitro neutralization studies were evaluated by a fixed dose of peptide (1 MUM) against venom (0.8 MUg/ml) and toxin (0.1 MUM). Among the linear peptides (PIP-18, cyclic C and PIP59-67) that showed potent neutralizing effects against the venom/toxin of C. adamanteus. PIP-18 [IC50, 1.23 MUM] and cyclic C [IC50, 1.27 MUM] peptides possessed the strongest inhibitory effect against CaTx-I. A fixed dose of CaTx-I (75 MUg/kg) was administered intraperitoneally (i.p.) into mice followed by an i.p. injection of peptides PIP-18 and cyclic C at (6 MUg/mouse), venom (150 MUg/kg) and toxin CaTx-I alone served as references. Mice treated with PIP-18 and cyclic C showed a very strong neutralizing effect and markedly reduced mortality compared to the control after 24 h. The CA venom and CaTx-I injected mice showed severe toxicity after 24 h. Peptides PIP-18 and cyclic C were non-hemolytic at 100 MUM. They produced a significant decrease in lipid peroxidase (LPx) and enhancement of superoxide dismutase (SOD), catalase (CAT) and Glutathione-s transferase (GST) levels indicating their antioxidant property against venom induced changes in mice. This study confirmed the potent snake venom neutralizing properties of peptides. PMID- 21682683 TI - Neutralization of local toxicity induced by vipera russelli phospholipase A2 by lipophilic derivative of ascorbic acid. AB - L-ascorbic acid upon condensation with palmitic acid in the presence of sulphuric acid results in L-ascorbic acid-6-palmitate (AP). The effect of L-ascorbic acid derivative, AP on the pharmacological activities of purified basic multi-toxic PLA2 enzyme, VRV-PL-VIIIa from Vipera russelli snake venom along with in vitro activities is described. AP inhibited VRV-PL-VIIIa enzyme activity in a concentration dependent manner with IC50 value of 48.85 MUM and the inhibition is found to be independent of substrate and calcium concentration. Upon investigating the in vivo pharmacological activities, it has been found that AP inhibited VRV-PL-VIIIa induced mouse paw edematogenic activity in a dose dependant manner. Intramuscular co-injection of AP with VRV-PL-VIIIa (1:10 w:w) neutralized the VRV-PL-VIIIa induced myotoxocity. Sections of mouse thigh muscle showed normal intact musculature with normal levels of serum creatine kinase and lactate dehydrogenase. Histopathological studies showed that administration of VRV-PL-VIIIa (i.p) along with AP mixture inhibited VRV-PL-VIIIa induced lung haemorrhage in mouse indicated that enzyme activity is responsible for all these observed pathological and pharmacological activities. The biophysical interaction studies showed that AP interacted directly with the enzyme and decreased the relative intrinsic fluorescence intensity. CD spectral analysis showed an apparent shift in the far UV-CD spectra of VRV-PL-VIIIa with AP. Docking study also confirmed the interaction of AP with enzyme directly. These results demonstrate that AP neutralizes VRV-PL-VIIIa induced pharmacological activities by inhibiting the enzyme with direct interactions. This compound along with other inhibitors of snake venom hydrolytic enzymes might be of use to neutralize local toxicity of V. russelli venom where antivenoms have failed. PMID- 21682684 TI - The polyphenol 3, 4, 5 - tri-hydroxy benzoic acid inhibits indian daboia russelli venom and its hemorrhagic complex induced local toxicity. AB - Despite a long history on treatment and management of snakebite, as of now, no satisfactory cure exists to treat local toxicity, including anti-venom therapy. Several natural compounds from plants and their synthetic analogs have shown to be protective. In this study 3, 4, 5-tri-hydroxy benzoic acid, the gallic acid (GA) was tested against the local toxicity of Daboia russelli (DR) venom and its purified hemorrhagic complex (HC). GA inhibited in vitro proteolytic activity of both DR venom and HC but, it did not inhibit phospholipase activity of DR venom. GA inhibited hemorrhage, edema forming, dermo- and myonecrotic activities of both HC and DR venom in in vivo experiments. GA was particularly effective against hemorrhagic activity but, GA inhibition had a greater effect on HC when compared to DR venom. The inhibition was likely due to GA induced structural changes in HC as revealed by alterations in fluorescence emission and CD spectral properties. However, the inhibition was not due to chelating property of GA as suggested by UV-visible spectral studies. Inhibition of collagen type IV, laminin and fibronectin degradation essentially provided the biochemical basis for GA which inhibited local effects of HC as well as DR venom. Thus, the study appears highly promising to explore GA and its generics against ruthless local effects and perhaps systemic hemorrhage of DR and other snake bites as well. Further, these agents will possibly find an immense value in the regulation of matrix metalloproteases (MMPs) in processes such as wound healing, inflammation and in the treatment of cancer. PMID- 21682686 TI - Snakebite management: time for strategic approach. PMID- 21682685 TI - Structural and functional characterization of a gamma-type phospholipase A2 inhibitor from bothrops jararacussu snake plasma. AB - Phospholipases A2 (PLA2s) from snake venoms comprise a group of 14-18 kDa proteins, responsible for several toxic effects induced by the whole venom. Considering this, studies aiming at the search for natural inhibitors of these proteins are very important. The present work had as objectives the isolation and functional/structural characterization of a gamma-type phospholipase A2 inhibitor (PLI) from Bothrops jararacussu snake plasma, named gammaBjussuMIP. This acidic glycoprotein was isolated in a high purity level through affinity chromatography on CNBr-Sepharose 4B coupled with BthTXII, showing a pI ~ 5.5 and molecular weight of 23,500 for the monomer (determined by SDS-PAGE), and 160,000 for the oligomer (determined by molecular exclusion chromatography on Sephacryl S-200). The interaction between gammaBjussuMIP (MIP) and Phospholipase A2 (PLA2) was confirmed using circular dichroism (CD) and emission fluorescence techniques. The helical content of the 1:1 molar mixture was higher than that calculated for the addition of the spectra of the unbound proteins indicating binding. The emission fluorescence experiments pointed that Trp residues in PLA2 participate in proteins interaction as blue shift of 4 nm was observed. The gammaBjussuMIP cDNA, obtained by PCR of the liver of B. jararacussu snake, revealed 543 bp codifying for a mature protein of 181 amino acid residues. Alignment of its amino acid sequence with those of other snake gammaPLIs showed 89-94% of similarity. gammaBjussuMIP mainly inhibited the pharmacological properties of Asp49 PLA2s, such as phospholipase, anticoagulant, myotoxic, edema inducing, cytotoxic, bactericidal and lethal activities. In addition, it showed to be able to supplement Bothrops antivenom, potentiating its antimyotoxic effect. The aspects broached in this work will be able to provide complementary information on possible mechanisms of action, relating structure and function, which could result in a better understanding of the inhibitory effects induced by gammaBjussuMIP. PMID- 21682687 TI - Posaconazole: a new antifungal weapon. AB - The last twenty years, the incidence of invasive fungal infections (IFI) has risen dramatically due to the prolongation of survival of patients with multiple risk factors for fungal infections. Amphotericin B was for more than 40 years the gold standard for almost all IFI, but toxicity and resistance, especially of new and emerging pathogens remained important issues. Fluconazole and itraconazole have also the same disadvantage of resistance. Voriconazole, a new triazole antifungal has offered an additional option, but the problem of resistant aspergillosis, and zygomycosis remains. Echinocandins (caspofungin, micafungin and anidulafungin) are active only against Candida and Aspergillus spp., but not against Fusarium, Scedosporium and Zygomycetes. Posaconazole is the most recently approved triazole with broad spectrum activity against Candida spp., Aspergillus spp., Cryptococcus neoformans, Zygomycetes, dermatiaceous, dimorphic, and other fungal pathogens. Interestingly, posaconazole is active against Candida spp., resistant to fluconazole and itraconazole, and Aspergillus fumigatus resistant to fluconazole itraconazole, amphotericin B, and voriconazole. The results from clinical trials of posaconazole as salvage treatment are encouraging. Multicenter clinical trials have also established its role in the prophylaxis of (IFI) in the severely immunocompromised patients such as those after hematopoietic stem cell transplantation (HSCT) who developed graft versus host disease (GVHD), as well as the neutropenic patients with an acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after myeloablative chemotherapy. Posaconazole has pharmacokinetic advantages and low side effect profile, which are very important, especially in the seriously ill population. PMID- 21682688 TI - A critical systematic review of recent clinical trials comparing open retropubic, laparoscopic and robot-assisted laparoscopic radical prostatectomy. AB - The surgical treatment of prostate cancer has evolved rapidly, driven by technological advances that have made minimally-invasive prostatectomy feasible. The contemporary surgical approaches are laparoscopic radical prostatectomy (LRP) and robot-assisted laparoscopic radical prostatectomy (RALP). These are now considered standard modalities of treatment in urology departments across North America, Europe and centres of excellence world-wide. However, despite the widespread adoption of minimally-invasive approaches there are only a handful of robust studies directly comparing the results of these techniques with the gold standard approach of open radical prostatectomy (ORP). Of note, uncertainty remains over exactly which men with localised prostate cancer will benefit from radical treatment and the reduction of surgical side-effects is paramount in optimising outcomes. This systematic review examines the current status of minimally- invasive prostatectomy focussing on peri-operative, oncological and urogenital functional outcomes. PMID- 21682689 TI - Sugammadex, a promising reversal drug. A review of clinical trials. AB - According to published data, sugammadex, rapidly reverses (2-5 min) shallow and profound NM block induced by rocuronium and vecuronium, without being connected with serious adverse events. It is accepted that in order to reverse shallow block, the suggested dose of sugammadex comes up to 2 mg/kg. Profound level of NM block demands 4 mg/kg in order to defy few responses at the post titanic count. Doses of sugammadex lower than 1 mg/kg may lead to rebound of rocuronium's effect. Higher doses of sugammadex (12 16 mg/g) are used in rescue reversal. In children and adolescents the 2 mg/kg dose is both effective and well tolerated, while, to date, data regarding infants are scarce. In patients with renal failure, 2 mg/kg of sugammadex resulted in a mean time to recovery of TOF ratio to 0.9 in 2 min, which was quicker than the time of reversal by acetylcholinesterase inhibitors. Investigations in cardiac patients undergoing noncardiac surgery suggest that 2 and 4 mg/kg of sugammadex are both safe and effective. Compared with neostigmine, sugammadex has no need to use muscarinic antagonists and therefore is not associated with variations in heart rate. Trials indicate that sugammadex acts faster than edrophonium and neostigmine. Sugammadex is a promising, well tolerated agent that enables fast reversal in different depths of NM block -shallow and profound- and in different patients populations. After completion of trial probation and settlement of issues concerning estimated cost and cost impact, it is believed to play a leading part in future anesthesiology. PMID- 21682691 TI - Management of exercise-induced glycemic imbalances in type 1 diabetes. AB - Regular moderate-intensity exercise is strongly recommended for its beneficial effects in all people. In patients with type 1 diabetes, however, the exercise associated glycemic imbalances remain an unresolved clinical challenge. Current guidelines require an in-depth understanding of the glycemic responses to exercise and each patient has to discover, by trial-and-error, his/her own strategy, several attempts being usually required to gain sufficient experience. Consequently, fear of hypoglycemia remains the strongest barrier to physical activity. This paper explores the potential strategies that may be employed to minimize the risk of exercise related glycemic imbalances. Moreover, a newly developed algorithm (ECRES, Exercise Carbohydrate Requirement Estimating Software) is described, which estimates on a patient- and situation-specific basis the glucose supplement required by the patient to maintain safe blood glucose levels. The algorithm was tested on 27 patients who performed three 1-hr constant intensity walks (each starting at a different time interval following insulin injection). Results showed that in 70.4% of the trials, independent of the time of day, the algorithm provided a satisfactory estimate of the carbohydrates needed by patients to complete the exercise with a glucose level within safe thresholds (i.e. 3.9 - 10 mmol.L-1). Despite the algorithm requires further experimental testing to be applied by the majority of patients, these results indicate its potential usefulness as a tool for preventing immediate exercise-induced glycemic imbalances (i.e. during exercise) in type 1 diabetic patients, in particular for spontaneous activities not planned in advance, thus allowing all insulin-dependent patients to safely enjoy the benefits of exercise. PMID- 21682692 TI - Heat shock response regulates insulin sensitivity and glucose homeostasis: pathophysiological impact and therapeutic potential. AB - A large and increasing number of people in all over the world suffer from obesity, metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Attenuation of the heat shock response (HSR), which was originally identified as a cellular defense mechanism, is one of the key factors involved in the deterioration of metabolic abnormalities. On the other hand, activating the HSR increases heat shock protein 72 (HSP72) expression and improves insulin resistance and glucose homeostasis in rodents and humans, possibly by inhibiting the activation of stress kinases such as c-jun terminal kinase (JNK) and inhibitor of kappa B kinase beta (IKKbeta). These approaches may also reduce inflammatory cytokine production and prevent the onset of atherogenic complications. This review focuses on the physiological effects of HSR in regulating insulin sensitivity and hyperglycemia, and the potential to target the HSR system for the treatment of MS and T2DM, as well as other cellular stress-related diseases. PMID- 21682693 TI - Gastric bypass and diabetes: past, present and future. AB - CONTEXT: Owing to the pathogenic role of insulin resistance and beta-cell dysfunction in type 2 diabetes, the clinical manifestation of this disease is extremely complex and is often associated with obesity. In recent years, Roux-en Y gastric bypass (RYGB) surgery, which was originally developed to treat morbid obesity, has been found to have therapeutic potential for diabetes. However, the underlying mechanisms of the therapeutic application of this technique are not fully known. OBJECTIVE: This review describes the technique of RYGB, including the advantages and disadvantages of the procedure. The advantages include metabolic improvement, obesity resolution, and reduction in morbidity. The disadvantages include short-term perioperative complications and long-term nutritional disorders. Finally, we provide a review of the possible underlying mechanisms leading to the resolution of type 2 diabetes symptoms after the RYGB procedure. CONCLUSIONS: While some complications are found after RYGB, there have also been reports showing a remarkable decrease in mortality, successful weight loss, and resolution of type 2 diabetes. The actual mechanism leading to diabetes resolution remains unknown. Gastric bypass surgery is certainly an effective method to increase remission rate in a subgroup of type 2 diabetes patients with morbid obesity. PMID- 21682694 TI - New spectroscopic and electrochemical insights on a class I superoxide reductase: evidence for an intramolecular electron-transfer pathway. AB - SORs (superoxide reductases) are enzymes involved in bacterial resistance to reactive oxygen species, catalysing the reduction of superoxide anions to hydrogen peroxide. So far three structural classes have been identified. Class I enzymes have two iron-centre-containing domains. Most studies have focused on the catalytic iron site (centre II), yet the role of centre I is poorly understood. The possible roles of this iron site were approached by an integrated study using both classical and fast kinetic measurements, as well as direct electrochemistry. A new heterometallic form of the protein with a zinc-substituted centre I, maintaining the iron active-site centre II, was obtained, resulting in a stable derivative useful for comparison with the native all-iron from. Second-order rate constants for the electron transfer between reduced rubredoxin and the different SOR forms were determined to be 2.8 * 107 M-1 . s-1 and 1.3 * 106 M-1 . s-1 for SORFe(IIII)-Fe(II) and for SORFe(IIII)-Fe(III) forms respectively, and 3.2 * 106 M-1 . s-1 for the SORZn(II)-Fe(III) form. The results obtained seem to indicate that centre I transfers electrons from the putative physiological donor rubredoxin to the catalytic active iron site (intramolecular process). In addition, electrochemical results show that conformational changes are associated with the redox state of centre I, which may enable a faster catalytic response towards superoxide anion. The apparent rate constants calculated for the SOR mediated electron transfer also support this observation. PMID- 21682695 TI - Sunlight exposure is important for preventing hip fractures in patients with Alzheimer's disease, Parkinson's disease, or stroke. AB - OBJECTIVES: Hypovitaminosis D as a result of malnutrition or sunlight deprivation, increased bone resorption, low bone mineral density (BMD), or an increased risk of falls may contribute to an increased risk of hip fractures in patients with neurological diseases, including Alzheimer's disease, Parkinson's disease, and stroke. The purpose of this study was to clarify the efficacy of sunlight exposure for reducing the risk of hip fractures in patients with such neurological diseases. METHODS: The English literature was searched using PubMed, and randomized controlled trials evaluating the efficacy of sunlight exposure for reducing the risk of hip fractures in patients with Alzheimer's disease, Parkinson's disease, and stroke were identified. The relative risk and the 95% confidence interval were calculated for individual randomized controlled trials, and a pooled data analysis (meta-analysis) was performed. RESULTS: Three randomized controlled trials were identified. Sunlight exposure improved hypovitaminosis D and increased the BMD. The relative risk (95% confidence interval) of hip fractures was 0.22 (0.05, 1.01) for Alzheimer's disease, 0.27 (0.08, 0.96) for Parkinson's disease, and 0.17 (0.02, 1.36) for stroke. The relative risk (95% confidence interval) calculated for the pooled data analysis was 0.23 (0.10, 0.56) (P = 0.0012), suggesting a significant risk reduction rate of 77%. CONCLUSION: The present meta-analysis added additional evidence indicating the efficacy of sunlight exposure for reducing the risk of hip fractures in patients with Alzheimer's disease, Parkinson's disease, and stroke. PMID- 21682696 TI - Maternal and obstetric factors associated with delayed postpartum eclampsia: a national study population. AB - OBJECTIVE: To estimate the incidence of delayed postpartum eclampsia and to investigate whether maternal characteristics and outcomes were different between women with delayed or early postpartum eclampsia. DESIGN: Prospective population based study. SETTING: All 229 UK hospitals with consultant-led maternity units in the UK. POPULATION: All women delivering between February 2005 and February 2006. METHODS: Maternal characteristics and outcomes were compared between women with delayed (>= 12 hours between delivery and eclampsia) and early postpartum eclampsia. MAIN OUTCOME MEASURES: Rates with 95% confidence intervals (CIs). Adjusted odds ratio estimates. RESULTS: Seventy-six women had postpartum eclampsia, representing an incidence of 1.0/10 000 (95% CI 0.7-1.2/10 000) maternities. Among the women having postpartum eclampsia, 53 (70%; 95% CI 59-79) occurred in the first 12 hours following delivery, eight (11%; 95% CI 3-20) during hours 12-24, four (5%; 95% CI 2-13) during the 24-48 hours after delivery and 11 (14%; 95% CI 7-24) more than 48 hours after delivery. Maternal characteristics, biological and clinical symptoms in the week preceding eclampsia and neonatal outcomes were not significantly different in the delayed eclampsia group in comparison with the early postpartum eclampsia group. However, the cesarean delivery rate was higher in women with delayed eclampsia in comparison with earlier postpartum eclampsia [13 (57%) vs. 6 (11%); odds ratio 10.1, 95% CI 3.12-33.3]. CONCLUSIONS: Close follow-up should be performed in the 12 hours following delivery in women with hypertensive disorders of pregnancy. Beyond this, the risk of eclampsia is very low, and eclampsia occurs mainly among women who have had a cesarean delivery. PMID- 21682697 TI - Risk factors for cerebral palsy in children born at term. AB - OBJECTIVE: To provide an overview of current research on risk factors for cerebral palsy (CP) in children born at term and hypothesize how new findings can affect the content of the CP registers worldwide. DESIGN: A systematic search in PubMed for original articles, published from 2000 to 2010, regarding risk factors for CP in children born at term was conducted. METHODS: Full text review was made of 266 articles. MAIN OUTCOME MEASURES: Factors from the prenatal, perinatal and neonatal period considered as possible contributors to the causal pathway to CP in children born at term were regarded as risk factors. RESULTS: Sixty-two articles met the criteria for an original report on risk factors for CP in children born at term. Perinatal adverse events, including stroke, were the focus of most publications, followed by genetic studies. Malformations, infections, perinatal adverse events and multiple gestation were risk factors associated with CP. The evidence regarding, for example, thrombophilic factors and non-CNS abnormalities was inconsistent. CONCLUSIONS: Information on maternal and neonatal infections, umbilical cord blood gases at birth, mode of delivery and placental status should be collected in a standardized way in CP registers. Information on social factors, such as education level, family income and area of residence, is also of importance. More research is needed to understand the risk factors of CP and specifically how they relate to causal pathways of cerebral palsy. PMID- 21682698 TI - Beyond maternal mortality: obstetric hemorrhage in a Malawian district. AB - OBJECTIVE: To identify substandard care factors in the management of obstetric hemorrhage at district hospital level in rural Malawi. DESIGN: Retrospective hospital-based cohort study. SETTING: Thyolo District Hospital. POPULATION: Women who delivered at this facility in 2005. METHODS: All cases of obstetric hemorrhage were included according to the following criteria: any antepartum hemorrhage, postpartum hemorrhage with more than 500 ml of blood loss within 24 hours after delivery, uterine rupture, retained placenta and peripartum blood transfusion. MAIN OUTCOME MEASURES: Incidence of antepartum and postpartum hemorrhage, related maternal and perinatal mortality and mode of delivery. RESULTS: A total of 133 hemorrhage cases occurred among 3 085 hospital deliveries (43.1 per 1 000 deliveries), six of which resulted in maternal death (case fatality rate 4.5%). Twenty of 95 postpartum hemorrhage cases (21%) were peri cesarean hemorrhages. Sixteen cesareans delivered lifeless fetuses, where a maternal indication for operative delivery was present in only four. Monitoring of pregnant women was regularly insufficient, including monitoring of women in waiting homes, and the use of uterotonics was often inconsistent. CONCLUSIONS: Morbidity review revealed important substandard care factors, including unnecessary cesarean sections. These factors may be modified against affordable cost, which could make an important improvement in maternal outcome. PMID- 21682699 TI - Circulating levels of the anti-angiogenic thrombospondin 2 are elevated in pre eclampsia. AB - An imbalance of maternal circulating pro- and anti-angiogenic factors may play a role in the pathogenesis of pre-eclampsia. Thrombospondin 2 (TSP-2) is a protein expressed mainly by activated endothelial cells, which acts as a potent anti angiogenic agent. Our aim was to determine whether serum TSP-2 levels are altered in pre-eclampsia. We enrolled 35 pre-eclamptic patients and 35 healthy pregnant women in the study. Thrombospondin 2 levels were determined by enzyme-linked immunosorbent assay, while soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) concentrations were determined by electrochemiluminescence immunoassay. In patients with PE, we demonstrated 1.7 fold higher TSP-2 [13.2 (9.4-18.1) vs. 7.9 (7.2-11.2) ng/ml, p<0.001], 3.8-fold higher sFlt-1 and 4.3-fold lower PlGF levels compared with the control group. There were no associations between TSP-2 and sFlt-1 or PlGF concentrations. We suggest that circulating TSP-2 levels may contribute to the pathogenesis of PE via its anti-angiogenic properties, but in a distinct way from sFlt-1 and PlGF. PMID- 21682700 TI - External cephalic version of non-cephalic presentation; is it worthwhile? AB - A retrospective study of 186 consecutive external cephalic versions (ECV) late in the third trimester was done. Logistic regression analysis of background factors leading to a successful ECV showed that multiparity, a larger amount of amniotic fluid, measured as amniotic fluid index, and a transverse fetal position were each significantly correlated with a successful version. The total success rate was 62%, and after a successful ECV 84% of the fetuses were delivered vaginally. No severe complications were registered during the ECVs, and all babies had normal Apgar scores at delivery. Attempting ECV at least once or even twice seems to be appropriate because a successful ECV can decrease the rate of cesarean section in this group of patients and by so doing may also decrease the risk of cesarean section in future pregnancies. PMID- 21682701 TI - Who requires irradiated blood products? PMID- 21682702 TI - Accuracy of surface landmark identification for cannula cricothyroidotomy. PMID- 21682703 TI - Resuscitation guidelines 2010. PMID- 21682705 TI - Elective use of cannula cricothyroidotomy. PMID- 21682706 TI - All of a sudden the screen went blank! PMID- 21682708 TI - Complications associated with introduction of new neuraxial equipment. PMID- 21682709 TI - Equipment changes and magnetic resonance imaging compatibility. PMID- 21682710 TI - An unusual source of air during regional anaesthesia. PMID- 21682711 TI - Blood clot causing airway obstruction and the use of jet ventilation. PMID- 21682713 TI - Accidental arterial cannulation in a child. PMID- 21682714 TI - Litigation relating to central and peripheral venous access by anaesthetists. PMID- 21682715 TI - Videolaryngoscopy and Cormack and Lehane grading. PMID- 21682716 TI - Never events and the dangers of distraction. PMID- 21682717 TI - Use of the iPad in paediatric anaesthesia. PMID- 21682718 TI - Survey of iPhone usage among anaesthetists in England. PMID- 21682719 TI - Retraction. Physostigmine for the prevention of postanaesthetic shivering following general anaesthesia--a placebo-controlled comparison with nefopam. PMID- 21682720 TI - Activation of natural killer cells by hepatitis C virus particles in vitro. AB - Little is known about the ability of hepatitis C virus (HCV) to alter early innate immune responses in infected patients. Previous studies have shown that natural killer (NK) cells are functionally impaired after interaction of recombinant HCV glycoprotein E2 with the co-stimulatory CD81 molecule in vitro; however, the functional consequences of a prolonged contact of NK cells with HCV particles have remained unclear. We have examined the phenotypes of purified, interleukin-2-activated NK cells from healthy donors and HCV genotype 1b patients after culture for 5 days with HCV pseudoparticles (HCVpp) and serum samples containing HCV genotype 1b. NK cells from healthy donors and chronic HCV patients were found to up-regulate receptors associated with activation (NKp46, NKp44, NKp30, NKG2D), while NK receptors from the killer cell immunoglobulin-like receptor family (KIR/CD158), predominantly having an inhibitory function, were significantly down-modulated after culture in the presence of HCV particles compared with control cultures of NK cells. HCV-infected sera and HCVpp elicited significantly higher secretion of the NK effector lymphokines interferon-gamma and tumour necrosis factor-alpha. Furthermore, HCV stimulated the cytotoxic potential of NK cells from normal donors and patients. The enhanced activation of NK cells after prolonged culture with HCVpp or HCV-containing sera for 5 days suggests that these innate effector cells may play an important role in viral control during early phases of HCV infection. PMID- 21682722 TI - Diet-induced elevations in serum cholesterol are associated with alterations in hippocampal lipid metabolism and increased oxidative stress. AB - The structure and function of the hippocampus, a brain region critical for learning and memory, is impaired by obesity and hyperlipidemia. Peripheral cholesterol and sphingolipids increase progressively with aging and are associated with a range of age-related diseases. However, the mechanisms linking peripheral cholesterol metabolism to hippocampal neuroplasticity remain poorly understood. To determine whether diets that elevate serum cholesterol influence lipid metabolism in the hippocampus, we maintained rats on a diet with high amounts of saturated fat and simple sugars for 3 months and then analyzed hippocampal lipid species using tandem mass spectrometry. The high fat diet was associated with increased serum and liver cholesterol and triglyceride levels, and also promoted cholesterol accumulation in the hippocampus. Increases in hippocampal cholesterol were associated with elevated galactosyl ceramide and sphingomyelin. To determine whether changes in lipid composition exerted biological effects, we measured levels of the lipid peroxidation products 4 hydroxynonenal-lysine and 4-hydroxynonenal-histidine; both were increased locally in the hippocampus, indicative of cell membrane-associated oxidative stress. Taken together, these observations support the existence of a potentially pathogenic relationship between dietary fat intake, peripheral cholesterol and triglyceride levels, brain cell sphingolipid metabolism, and oxidative stress. PMID- 21682721 TI - Effect of medium/omega-6 long chain triglyceride-based emulsion on leucocyte death and inflammatory gene expression. AB - Lipid emulsion (LE) containing medium/omega-6 long chain triglyceride-based emulsion (MCT/omega-6 LCT LE) has been recommended in the place of omega-6 LCT based emulsion to prevent impairment of immune function. The impact of MCT/omega 6 LCT LE on lymphocyte and neutrophil death and expression of genes related to inflammation was investigated. Seven volunteers were recruited and infusion of MCT/omega-6 LCT LE was performed for 6 h. Four volunteers received saline and no change was found. Blood samples were collected before, immediately afterwards and 18 h after LE infusion. Lymphocytes and neutrophils were studied immediately after isolation and after 24 and 48 h in culture. The following determinations were carried out: plasma-free fatty acids, triacylglycerol and cholesterol concentrations, plasma fatty acid composition, neutral lipid accumulation in lymphocytes and neutrophils, signs of lymphocyte and neutrophil death and lymphocyte expression of genes related to inflammation. MCT/omega-6 LCT LE induced lymphocyte and neutrophil death. The mechanism for MCT/omega-6 LCT LE dependent induction of leucocyte death may involve changes in neutral lipid content and modulation of expression of genes related to cell death, proteolysis, cell signalling, inflammatory response, oxidative stress and transcription. PMID- 21682724 TI - Interpersonal impact messages associated with different forms of achievement motivation. AB - Two studies evaluated relations between different forms of achievement motivation and transactional interpersonal impact messages during a dyadic puzzle-solving task. In Study 1,400 college students received no formal competence feedback during the task. In Study 2, competence feedback was manipulated for 600 college students and used to create high-, low-, and mixed-status dyads. Expectancies of success had robust actor and partner effects on submission in both studies. Competence valuation was linked with communal partner effects in Study 1 and a generalized interpersonal sensitivity in Study 2. When competence was ambiguous, approach and avoidance achievement motives exhibited affectively driven actor and partner effects consistent with their roots in pride and shame, respectively; however, when competence was established formally, motives had more cognitively driven effects on person perception and behavior (e.g., rejection sensitivity). Collectively, these findings highlight the importance of the achievement motivation system for organizing interpersonal impact messages during competence pursuits. PMID- 21682725 TI - The circumplex structure of interpersonal sensitivities. AB - Previous research on aversive interpersonal behavior has provided limited links between interpersonal sensitivities and comprehensive models of personality and social behavior. Study 1 (N = 1,336) of this article demonstrated that interpersonal sensitivities can be mapped onto the interpersonal circumplex and that people generally find others' behavior that is least similar to their own generally most aversive. In Study 2 (N = 299), a broader array of correlates with interpersonal sensitivities was investigated, and results again suggested that interpersonal opposites are generally perceived as most aversive. Study 3 (N = 315) specified romantic, platonic, or nonclose relationships and again found this pattern. Conceptualizing sensitivities with the interpersonal circumplex model permits investigators to distinguish general from specific kinds of sensitivity, allows for tests of the convergent and discriminant validity of interpersonal sensitivities, and integrates sensitivities into a well-established nomological net composed of multiple constructs relevant to social behavior and interpersonal dysfunction. PMID- 21682723 TI - In vivo electrochemical evidence for simultaneous 5-HT and histamine release in the rat substantia nigra pars reticulata following medial forebrain bundle stimulation. AB - Exploring the mechanisms of serotonin [5-hydroxytryptamine (5-HT)] in the brain requires an in vivo method that combines fast temporal resolution with chemical selectivity. Fast-scan cyclic voltammetry is a technique with sufficient temporal and chemical resolution for probing dynamic 5-HT neurotransmission events; however, traditionally it has not been possible to probe in vivo 5-HT mechanisms. Recently, we optimized fast-scan cyclic voltammetry for measuring 5-HT release and uptake in vivo in the substantia nigra pars reticulata (SNR) with electrical stimulation of the dorsal raphe nucleus (DRN) in the rat brain. Here, we address technical challenges associated with rat DRN surgery by electrically stimulating 5-HT projections in the medial forebrain bundle (MFB), a more accessible anatomical location. MFB stimulation elicits 5-HT in the SNR; furthermore, we find simultaneous release of an additional species. We use electrochemical and pharmacological methods and describe physiological, anatomical and independent chemical analyses to identify this species as histamine. We also show pharmacologically that increasing the lifetime of extracellular histamine significantly decreases 5-HT release, most likely because of increased activation of histamine H-3 receptors that inhibit 5-HT release. Despite this, under physiological conditions, we find by kinetic comparisons of DRN and MFB stimulations that the simultaneous release of histamine does not interfere with the quantitative 5-HT concentration profile. We therefore present a novel and robust electrical stimulation of the MFB that is technically less challenging than DRN stimulation to study 5-HT and histamine release in the SNR. PMID- 21682726 TI - Impulsivity partially mediates the relationship between BIS/BAS and risky health behaviors. AB - Several theorists have suggested that impulsivity can be understood as a joint function of the behavioral approach (BAS) and behavioral inhibition systems (BIS). After resolving questions concerning the measurement of impulsivity and BAS, this study examined the relationships among risky health behaviors, impulsivity, BIS, and BAS. Utilizing a sample of undergraduates (N = 904), a structural model was tested in which BAS and BIS predicted impulsivity, which, in turn, predicted risky behavior. Fit indices were acceptable, but not good. A modified version of the model showed a statistically significant negative relationship between BAS and risky behaviors. However, the fit indices were not unequivocally supportive of the need to include that path. Overall, the data suggest that impulsivity is the joint result of countervailing motivational forces and that it partially or fully mediates the influence of BIS and BAS on risky health behavior. PMID- 21682727 TI - Influence of social desirability on age differences in self-reports of mood and personality. AB - ABSTRACT Increased age has been found to be associated with differences in affect and personality that have been interpreted in terms of better emotional regulation and increased maturity. However, these findings have largely been based on self-report data, and the primary goal of the current research was to investigate the hypothesis that age-related differences in affect and in certain desirable personality traits might, at least partially, reflect age differences in social desirability. As expected, increased age was associated with lower levels of negative affect and Neuroticism and higher levels of positive affect, life satisfaction, Agreeableness, and Conscientiousness, and scores on the social desirability scale were positively related to age and to desirable self-report characteristics but negatively related to undesirable self-report characteristics. Importantly, controlling for the variance in the social desirability measure resulted in less positive age trends in both types of self report measures. PMID- 21682729 TI - Religiosity and social welfare: competing influences of cultural conservatism and prosocial value orientation. AB - This research examines the hypothesis that religiosity has two competing psychological influences on the social welfare attitudes of contemporary Americans. On the one hand, religiosity promotes a culturally based conservative identity, which in turn promotes opposition to federal social welfare provision. On the other hand, religiosity promotes a prosocial value orientation, which in turn promotes support of federal social welfare provision. Across two national samples (Ns = 1,513 and 320) and one sample of business employees (N = 710), reliable support for this competing pathways model was obtained. We argue that research testing influences of nonpolitical individual differences on political preferences should consider the possibility of competing influences that are rooted in a combination of personality processes and contextual-discursive surroundings. PMID- 21682728 TI - Trajectories of religious coping from adolescence into early adulthood: their form and relations to externalizing problems and prosocial behavior. AB - Little is known about changes in religious coping and their relations to adolescents' and young adults' functioning. In 686 Italian youths, trajectories of religious coping were identified from age 16-17 years to age 22-23 years; cohorts of youths reported at 3 of the 4 assessments. Four trajectories of religious coping were identified: decreasing, low stable, high stable, and increasing. A decline in religious coping was associated with high levels of externalizing problems at age 16-17, whereas an increase in religious coping was associated with higher externalizing problems at ages 18-19 and 20-21 years and with relatively high involvement with deviant peers. High stable religious copers were high in prosocial behavior at three ages; low stable religious copers were higher than people undergoing change in their religious coping from mid adolescence into early adulthood. These results can expand our current thinking about religious coping and adolescent adjustment. PMID- 21682730 TI - A cross-cultural study of relationships between daily social interaction and the five-factor model of personality. AB - Two studies, one in the United States (N = 130) and another in Germany (N = 100), examined relationships between daily social interaction and the traits of the Five-Factor Model. In both studies, student participants described their social interactions for 2 weeks using the Rochester Interaction Record. In both countries, Agreeableness and Conscientiousness were positively related to reactions to social interaction, whereas Neuroticism was unrelated to reactions to interactions. In the United States, Extraversion and Openness were positively related to reactions to interactions, whereas these factors were not related to reactions to interactions in Germany. In the United States, Extraversion was positively related to how socially active participants were, whereas none of the FFM traits was related to amount of social interaction in the German sample. In both countries, Extraversion was positively related to percent of interactions involving friends. The results highlight the importance of taking into account the sociocultural milieus within which personality unfolds. PMID- 21682731 TI - Hepatitis B virus nucleic acid testing in Chinese blood donors with normal and elevated alanine aminotransferase. AB - BACKGROUND: Nucleic acid testing (NAT) is currently not a routine donor test in China. The aim of this study was to evaluate the current residual risk of hepatitis B virus (HBV) transmission and the value of ALT testing in preventing HBV infection. STUDY DESIGN AND METHODS: From January 2008 to September 2009, a total of 5521 qualified donations by routine screening and 5034 deferred donations due to elevated ALT alone were collected from five blood centers. Samples were tested for HBV DNA by triplex individual-donation (ID)-NAT (ULTRIO assay, on the TIGRIS system, Novartis Diagnostics). HBV NAT-reactive samples were further analyzed by HBV serology, alternative NAT, and viral load and were diluted to simulate if they could be detected in a minipool-NAT. RESULTS: There was no significant difference in the HBV NAT-yield rate between the qualified donations group (5/5521) and the deferred donations group (4/5034). Of these nine potential HBV-yield cases, one donor (11%) was a possible HBV window-period donor, one (11%) was a chronic HBV carrier, and seven (78%) had probable or confirmed occult HBV infections. Of seven potential HBV-yield cases quantified, the viral loads were less than or equal to 70.0 IU/mL. Minipool testing (minipools of 4, 8, and 16 donations) would miss 43% to 79% of the nine HBV-yield donations. CONCLUSIONS: Based on our findings in qualified donations, we estimate that the nationwide implementation of ID-NAT testing for HBV DNA in China would detect an additional 9964 viremic donations per year. ALT testing seems to have no significant value in preventing transfusion-transmitted HBV infection. ID-NAT versus simulated minipool-NAT using the ULTRIO test demonstrates the benefit to implement a more sensitive NAT strategy in regions of high HBV endemicity. PMID- 21682733 TI - Hemolysis and red blood cell mechanical fragility in shed blood after total knee arthroplasty. AB - BACKGROUND: There are several options for the salvage of postoperative shed red blood cells (RBCs). This study compared the characteristics of the returned RBCs collected using two different devices: one that washes and one that does not wash the collected RBCs. STUDY DESIGN AND METHODS: Forty patients undergoing first time total knee arthroplasty consented to participate. Twenty patients were operated on by a surgeon who routinely uses a device that does not wash the shed RBCs (unwashed group), the other 20 patients were operated on by surgeons who routinely use a device that washes and concentrates the collected RBCs (washed group). A small quantity of postprocessing RBCs were collected immediately before reinfusion and the amount of plasma-free hemoglobin (PFHb), and the mechanical fragility index (MFI) of the returned RBCs were determined. RESULTS: The patients in both groups were well matched for age, sex, and length of stay. The mean percent hemolysis of the returned RBCs was not different between the unwashed and washed groups (1.22+/-0.30 vs. 1.24+/-0.42, p=0.895), while the mean total amount of returned PFHb was not different (0.51+/-0.12 g vs. 0.55+/-0.35 g, p<0.615). The ratio of total PFHb:total returned Hb was significantly lower for the washed group (0.0087+/-0.0023 vs. 0.0035+/-0.0011, p<0.0001). The MFI was higher in the washed group (1.71+/-0.55 vs. 0.53+/-0.42, p<0.001). CONCLUSIONS: The washing device returned more Hb to the patients relative to the amount of free Hb. PMID- 21682732 TI - Adverse reactions and other factors that impact subsequent blood donation visits. AB - BACKGROUND: The importance of adverse reactions in terms of donor safety recently has received significant attention, but their role in subsequent donation behavior has not been thoroughly investigated. STUDY DESIGN AND METHODS: Six REDS II blood centers provided data for this analysis. Summary minor and major adverse reaction categories were created. The influence of adverse reactions on donation was examined in two ways: Kaplan-Meier curves were generated to determine the cumulative pattern of first return, and adjusted odds ratios (AORs) for demographic and other factors positively and negatively associated with return were estimated using multivariable logistic regression. RESULTS: Donors who had major reactions had longer times to return than donors with minor or no reactions. The AOR of returning for donors with major reactions was 0.32 (95% confidence interval [CI], 0.28-0.37) and with minor reactions 0.59 (95% CI, 0.56 0.62) when compared to donors who did not have reactions. Conversely, the most important factors positively associated with return were the number of donations in the previous year and increasing age. Subsequent return, whether a major, minor, or no reaction occurred, varied by blood center. Factors that are associated with the risk of having adverse reactions were not substantial influences on the return after adverse reactions. CONCLUSION: Having an adverse reaction leads to significantly lower odds of subsequent donation irrespective of previous donation history. Factors that have been associated with a greater risk of adverse reactions were not important positive or negative predictors of return after a reaction. PMID- 21682734 TI - A family study of the Chinese Rhnull individual of the regulator type: a novel single missense mutation identified in RHAG gene. AB - BACKGROUND: Rh(null) is a rare autosomal recessive disorder, and Rh(null) of the regulator type may result from mutation of the RHAG gene, which encodes RhAG glycoprotein and modulates Rh antigen expression. This study described the molecular genetic analysis of a Chinese Rh(null) family and identified a novel mutation in the RHAG gene. STUDY DESIGN AND METHODS: RBCs from the Rh(null) family members were analyzed for Rh phenotype by standard methods. DNA sequences of all 10 exons of RHAG gene were analyzed using genomic DNA by polymerase chain reaction and direct DNA sequencing. RESULTS: Genomic DNA analyses showed that a 672C>A mutation in Exon 5 of the RHAG gene was present at the homozygous state in DH and at the heterozygous state in the other members of the Rh(null) family. The 672C>A missense mutation converted serine into arginine at Position 224 in the Transmembrane Segment 7 of RhAG glycoprotein. CONCLUSION: These findings provide evidence that the 672C>A missense mutation in the RHAG gene could result in Rh(null) of the regulator type, and the single-amino-acid change (Ser to Arg) might be critical for assembly of the Rh antigen complex within the membrane. PMID- 21682735 TI - The role of allergy in disease. PMID- 21682737 TI - Pathophysiology of allergic inflammation. AB - Allergic inflammation is due to a complex interplay between several inflammatory cells, including mast cells, basophils, lymphocytes, dendritic cells, eosinophils, and sometimes neutrophils. These cells produce multiple inflammatory mediators, including lipids, purines, cytokines, chemokines, and reactive oxygen species. Allergic inflammation affects target cells, such as epithelial cells, fibroblasts, vascular cells, and airway smooth muscle cells, which become an important source of inflammatory mediators. Sensory nerves are sensitized and activated during allergic inflammation and produce symptoms. Allergic inflammatory responses are orchestrated by several transcription factors, particularly NF-kappaB and GATA3. Inflammatory genes are also regulated by epigenetic mechanisms, including DNA methylation and histone modifications. There are several endogenous anti-inflammatory mechanisms, including anti-inflammatory lipids and cytokines, which may be defective in allergic disease, thus amplifying and perpetuating the inflammation. Better understanding of the pathophysiology of allergic inflammation has identified new therapeutic targets but developing effective novel therapies has been challenging. Corticosteroids are highly effective with a broad spectrum of anti-inflammatory effects, including epigenetic modulation of the inflammatory response and suppression of GATA3. PMID- 21682738 TI - Allergens and their role in the allergic immune response. AB - Allergens are recognized as the proteins that induce immunoglobulin E (IgE) responses in humans. The proteins come from a range of sources and, not surprisingly, have many different biological functions. However, the delivery of allergens to the nose is exclusively on particles, which carry a range of molecules in addition to the protein allergens. These molecules include pathogen associated molecular patterns (PAMPs) that can alter the response. Although the response to allergens is characterized by IgE antibodies, it also includes other isotypes (IgG, IgA, and IgG4), as well as T cells. The challenge is to identify the characteristics of these exposures that favor the production of this form of response. The primary features of the exposure appear to be the delivery in particles, such as pollen grains or mite feces, containing both proteins and PAMPs, but with overall low dose. Within this model, there is a simple direct relationship between the dose of exposure to mite or grass pollen and the prevalence of IgE responses. By contrast, the highest levels of exposure to cat allergen are associated with a lower prevalence of IgE responses. Although the detailed mechanisms for this phenomenon are not clear, it appears that enhanced production of interleukin-10 in response to specific Fel d 1 peptides could influence the response. However, it is striking that the animal sources that are most clearly associated with decreased responses at high allergen dose are derived from animals from which humans evolved more recently (~65 million years ago). Although the nose is still recognized as the primary route for sensitization to inhalant allergens, there is increasing evidence that the skin is also an important site for the generation of IgE antibody responses. By contrast, it is now evident that delivery of foreign proteins by the oral route or sublingually will favor the generation of tolerance. PMID- 21682736 TI - The genetics of asthma and allergic disease: a 21st century perspective. AB - Asthma and allergy are common conditions with complex etiologies involving both genetic and environmental contributions. Recent genome-wide association studies (GWAS) and meta-analyses of GWAS have begun to shed light on both common and distinct pathways that contribute to asthma and allergic diseases. Associations with variation in genes encoding the epithelial cell-derived cytokines, interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), and the IL1RL1 gene encoding the IL-33 receptor, ST2, highlight the central roles for innate immune response pathways that promote the activation and differentiation of T helper 2 cells in the pathogenesis of both asthma and allergic diseases. In contrast, variation at the 17q21 asthma locus, encoding the ORMDL3 and GSDML genes, is specifically associated with risk for childhood onset asthma. These and other genetic findings are providing a list of well-validated asthma and allergy susceptibility genes that are expanding our understanding of the common and unique biological pathways that are dysregulated in these related conditions. Ongoing studies will continue to broaden our understanding of asthma and allergy and unravel the mechanisms for the development of these complex traits. PMID- 21682740 TI - The role of oxidative stress and innate immunity in O(3) and endotoxin-induced human allergic airway disease. AB - Ozone (O(3)) and endotoxin are common environmental contaminants that cause asthma exacerbation. These pollutants have similar phenotype response characteristics, including induction of neutrophilic inflammation, changes in airway macrophage immunophenotypes, and ability to enhance response to inhaled allergen. Evoked phenotyping studies of volunteers exposed to O(3) and endotoxin were used to identify the response characteristics of volunteers to these pollutants. New studies support the hypotheses that similar innate immune and oxidant processes modulate response to these agents. These include TLR4 and inflammasome-mediated signaling and cytokine production. Innate immune responses are also impacted by oxidative stress. It is likely that continued discovery of common molecular processes which modulate response to these pollutants will occur. Understanding the pathways that modulate response to pollutants will also allow for discovery of genetic and epigenetic factors that regulate response to these pollutants and determine risk of disease exacerbation. Additionally, defining the mechanisms of response will allow rational selection of interventions to examine. Interventions focused on inhibition of Toll-like receptor 4 and inflammasome represent promising new approaches to preventing pollutant-induced asthma exacerbations. Such interventions include specific inhibitors of innate immunity and antioxidant therapies designed to counter the effects of pollutants on cell signaling. PMID- 21682741 TI - Innate immunity in allergic disease. AB - The innate immune system consists of multiple cell types that express germline encoded pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Allergens are frequently found in forms and mixtures that contain PAMPs and DAMPs. The innate immune system is interposed between the external environment and the internal acquired immune system. It is also an integral part of the airways, gut, and skin. These tissues face continuous exposure to allergens, PAMPs, and DAMPs. Interaction of allergens with the innate immune system normally results in immune tolerance but, in the case of allergic disease, this interaction induces recurring and/or chronic inflammation as well as the loss of immunologic tolerance. Upon activation by allergens, the innate immune response commits the acquired immune response to a variety of outcomes mediated by distinct T-cell subsets, such as T-helper 2, regulatory T, or T-helper 17 cells. New studies highlighted in this review underscore the close relationship between allergens, the innate immune system, and the acquired immune system that promotes homeostasis versus allergic disease. PMID- 21682739 TI - Rhinoviruses, allergic inflammation, and asthma. AB - Viral infections affect wheezing and asthma in children and adults of all ages. In infancy, wheezing illnesses are usually viral in origin, and children with more severe wheezing episodes are more likely to develop recurrent episodes of asthma and to develop asthma later in childhood. Children who develop allergen specific immunoglobulin E (allergic sensitization) and those who wheeze with human rhinoviruses (HRV) are at especially high risk for asthma. In older children and adults, HRV infections generally cause relatively mild respiratory illnesses and yet contribute to acute and potentially severe exacerbations in patients with asthma. These findings underline the importance of understanding the synergistic nature of allergic sensitization and infections with HRV in infants relative to the onset of asthma and in children and adults with respect to exacerbations of asthma. This review discusses clinical and experimental evidence of virus-allergen interactions and evaluates theories which relate immunologic responses to respiratory viruses and allergens to the pathogenesis and disease activity of asthma. Greater understanding of the relationship between viral respiratory infections, allergic inflammation, and asthma is likely to suggest new strategies for the prevention and treatment of asthma. PMID- 21682743 TI - Basophils: emerging roles in the pathogenesis of allergic disease. AB - After approximately 130 years since their discovery as rare granulocytes that circulate in blood, basophils are just now gaining respect as significant contributors in the pathogenesis underlying allergic inflammation and disease. While long known for secreting preformed and newly synthesized mediators and for selectively infiltrating tissue during immunoglobulin E (IgE)-mediated inflammation, their role has largely been viewed as redundant to that of tissue mast cells in functioning as effector cells. This line of thought has persisted even though it has been known in humans for approximately 20 years that basophils additionally produce relatively large quantities of cytokines, e.g. interleukin-4 (IL-4)/IL-13, that are central for the manifestations of allergic disease. Studies using novel IL-4 reporter mice have significantly added to the in vivo importance of basophils as IL-4 producing cells, with recent findings indicating that these cells also function as antigen-presenting cells essential in initiating T-helper 2 responses. If confirmed and translated to humans, these provocative findings will give new meaning to the role basophils have in allergic disease, and in immunology overall. PMID- 21682742 TI - Beyond immediate hypersensitivity: evolving roles for IgE antibodies in immune homeostasis and allergic diseases. AB - Immunoglobulin E (IgE) antibodies have long been recognized as the antigen specific triggers of allergic reactions. This review briefly introduces the established functions of IgE in immediate hypersensitivity and then focuses on emerging evidence from our own investigations as well as those of others that IgE plays important roles in protective immunity against parasites and exerts regulatory influences in the expression of its own receptors, FcepsilonRI and CD23, as well as controlling mast cell homeostasis. We provide an overview of the multifaceted ways in which IgE antibodies contribute to the pathology of food allergy and speculate regarding potential mechanisms of action of IgE blockade. PMID- 21682745 TI - Airway smooth muscle and immunomodulation in acute exacerbations of airway disease. AB - Airway smooth muscle (ASM) manifests a hyperresponsive phenotype in airway disorders such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. Current evidence also suggests that ASM modulates immune responses by secreting mediators and expressing cell surface molecules. Such processes amplify or dampen inflammation by inflammatory cells in the airways or by altering cellular responses to viruses, bacteria, or pathogens known to exacerbate airways diseases. PMID- 21682744 TI - Eosinophils: multifaceted biological properties and roles in health and disease. AB - Eosinophils are leukocytes resident in mucosal tissues. During T-helper 2 (Th2) type inflammation, eosinophils are recruited from bone marrow and blood to the sites of immune response. While eosinophils have been considered end-stage cells involved in host protection against parasite infection and immunopathology in hypersensitivity disease, recent studies changed this perspective. Eosinophils are now considered multifunctional leukocytes involved in tissue homeostasis, modulation of adaptive immune responses, and innate immunity to certain microbes. Eosinophils are capable of producing immunoregulatory cytokines and are actively involved in regulation of Th2-type immune responses. However, such new information does not preclude earlier observations showing that eosinophils, in particular human eosinophils, are also effector cells with proinflammatory and destructive capabilities. Eosinophils with activation phenotypes are observed in biological specimens from patients with disease, and deposition of eosinophil products is readily seen in the affected tissues from these patients. Therefore, it would be reasonable to consider the eosinophil a multifaceted leukocyte that contributes to various physiological and pathological processes depending on their location and activation status. This review summarizes the emerging concept of the multifaceted immunobiology of eosinophils and discusses the roles of eosinophils in health and disease and the challenges and perspectives in the field. PMID- 21682746 TI - Epithelial cells and airway diseases. AB - The airway epithelial cell is the initial cell type impacted both by inhaled environmental factors, such as pathogens, allergens, and pollutants, and inhaled medications for airway diseases. As such, epithelial cells are now recognized to play a central role in the regulation of airway inflammatory status, structure, and function in normal and diseased airways. This article reviews our current knowledge regarding the roles of the epithelial cell in airway inflammation and host defense. The interactions of inhaled environmental factors and pathogens with epithelial cells are also discussed, with an emphasis on epithelial innate immune responses and contributions of epithelial cells to immune regulation. Recent evidence suggesting that epithelial cells play an active role in inducing several of the structural changes, collectively referred to airway remodeling, seen in the airways of asthmatic subjects is reviewed. Finally, the concept that the epithelium is a major target for the actions of a number of classes of inhaled medications is discussed, as are the potential mechanisms by which selected drugs may alter epithelial function. PMID- 21682747 TI - The sentinel role of the airway epithelium in asthma pathogenesis. AB - The adoption of the concept that asthma is primarily a disease most frequently associated with elaboration of T-helper 2 (Th2)-type inflammation has led to the widely held concept that its origins, exacerbation, and persistence are allergen driven. Taking aside the asthma that is expressed in non-allergic individuals leaves the great proportion of asthma that is associated with allergy (or atopy) and that often has its onset in early childhood. Evidence is presented that asthma is primarily an epithelial disorder and that its origin as well as its clinical manifestations have more to do with altered epithelial physical and functional barrier properties than being purely linked to allergic pathways. In genetically susceptible individuals, impaired epithelial barrier function renders the airways vulnerable to early life virus infection, and this in turn provides the stimulus to prime immature dendritic cells toward directing a Th2 response and local allergen sensitization. Continued epithelial susceptibility to environmental insults such as viral, allergen, and pollutant exposure and impaired repair responses leads to asthma persistence and provides the mediator and growth factor microenvironment for persistence of inflammation and airway wall remodeling. Increased deposition of matrix in the epithelial lamina reticularis provides evidence for ongoing epithelial barrier dysfunction, while physical distortion of the epithelium consequent upon repeated bronchoconstriction provides additional stimuli for remodeling. This latter response initially serves a protective function but, if exaggerated, may lead to fixed airflow obstruction associated with more severe and chronic disease. Dual pathways in the origins, persistence, and progression of asthma help explain why anti-inflammatory treatments fail to influence the natural history of asthma in childhood and only partially does so in chronic severe disease. Positioning the airway epithelium as fundamental to the origins and persistence of asthma provides a rationale for pursuit of therapeutics that increase the resistance of the airways to environmental insults rather than concentrating all effort on suppressing inflammation. PMID- 21682748 TI - Human asthma phenotypes: from the clinic, to cytokines, and back again. AB - A large body of experimental evidence supports the hypothesis that T-helper 2 (Th2) cytokines orchestrate allergic airway inflammation in animal models. However, human asthma is heterogeneous with respect to clinical features, cellular sources of inflammation, and response to common therapies. This disease heterogeneity has been investigated using sputum cytology as well as unbiased clustering approaches using cellular and clinical data. Important differences in cytokine-driven inflammation may underlie this heterogeneity, and studies in human subjects with asthma have begun to elucidate these molecular differences. This molecular heterogeneity may be assessed by existing biomarkers (induced sputum evaluation or exhaled nitric oxide testing) or may require novel biomarkers. Effective testing and application of emerging therapies that target Th2 cytokines will depend on accurate and easily obtained biomarkers of this molecular heterogeneity in asthma. Furthermore, whether other non-Th2 cytokine pathways underlie airway inflammation in specific subsets of patients with asthma is an unresolved question and an important goal of future research using both mouse models and human studies. PMID- 21682749 TI - Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. AB - Atopic dermatitis (AD) is an important chronic or relapsing inflammatory skin disease that often precedes asthma and allergic disorders. New insights into the genetics and pathophysiology of AD point to an important role of structural abnormalities in the epidermis as well as immune dysregulation not only for this skin disease but also for the development of asthma and allergies. Patients with AD have a unique predisposition to colonization or infection by microbial organisms, most notably Staphylococcus aureus and herpes simplex virus. Measures directed at healing and protecting the skin barrier and addressing the immune dysregulation are essential in the treatment of patients with AD, and early intervention may improve outcomes for both the skin disease as well as other target organs. PMID- 21682751 TI - Immune modulation for treatment of allergic disease. AB - Immune modulation for treatment of allergic diseases aims to decrease the pathologic immune response rather than to cause a return to an immunologically naive or unresponsive state. Our expanding knowledge of innate and adaptive immune responses at the molecular level has led to development of immunomodulators for several allergic diseases, particularly asthma, allergic rhinitis, and eosinophilic esophagitis. Although successful immune modulation in mouse models of allergic disease have often failed to translate into significant results in human clinical trials, much has been learned about the pleotropic nature of cytokines and their effector mechanisms and of the varied phenotypes of allergic disease. We examine strategies of immune modulation in allergic diseases that have undergone human clinical trials, all with the common goal of decreasing the T-helper 2 (Th2) response, but through different mechanisms: blocking critical Th2 cytokines, inhibiting Th2 cytokine synthesis, blocking critical Th2 effector molecules, inhibiting important cells in the Th2 response, and stimulating Th1 responses. Therapies directed against specific effector molecules, such as immunoglobulin E and prostaglandin D2, hold promise in immune modulation of allergic disease, as do targeting the IL-4/IL-13 receptor and augmenting Th1/Th2 balance with Toll-like receptor agonists. PMID- 21682752 TI - Synergistic effect of alcohol consumption and body mass on serum concentrations of cytokeratin-18. AB - BACKGROUND: Cytokeratin-18 is an essential component of the cytoskeleton of epithelial cells (including hepatocytes). Serum concentrations of cytokeratin-18 (tissue polypeptide-specific antigen [TPS]) are used as a marker of epithelial neoplasms. Here, we investigated the potential interaction between alcohol and obesity in relation to serum TPS concentrations. METHODS: Alcohol consumption, body mass index, and components of metabolic syndrome were measured in a random sample (n = 420) of the adult population (aged 18 to 92 years, 45% men) from a single municipality. Regular alcohol intake of >20 g/d (women) or >30 g/d (men) was considered risky drinking. Serum TPS was measured with a commercial immunoassay. RESULTS: Risky drinking was associated with increased serum concentrations of TPS, which was particularly evident among obese individuals. Among individuals without risky drinking, TPS concentrations were similar for all levels of body mass. Conversely, among risky drinkers, serum TPS concentrations increased in parallel with body mass (p = 0.002). The odds ratio of a high (>100 U/l) TPS concentration for the combination of risky drinking and obesity was greater than the additive effect of the 2 separate factors, after adjusting for age and sex. A similar interaction was observed between risky drinking and abdominal adiposity, a major component of the metabolic syndrome. Serum TPS concentrations were correlated with markers of liver damage. Serum TPS was not superior to standard markers (gamma-glutamyl transferase and red blood cell mean volume) for the detection of risky drinking. CONCLUSIONS: There is a synergism between risky alcohol consumption and common metabolic disorders (particularly obesity) in relation to serum concentrations of cytokeratin-18 (TPS), which probably reflect liver disease. PMID- 21682750 TI - Anaphylaxis: a history with emphasis on food allergy. AB - In the century since Paul Portier and Charles Richet described their landmark findings of severe fatal reactions in dogs re-exposed to venom after vaccination with sea anemone venom, treatment for anaphylaxis continues to evolve. The incidence of anaphylaxis continues to be difficult to measure. Underreporting due to patients not seeking medical care as well as failure to identify anaphylaxis affects our understanding of the magnitude of the disease. Treatment with intramuscular epinephrine continues to be the recommended first-line therapy, although studies indicate that education of both the patients and the medical community is needed. Adverse food reactions continue to be the leading cause of anaphylaxis presenting for emergency care. Current therapy for food-induced anaphylaxis is built on the foundation of strict dietary avoidance, rapid access to injectable epinephrine, and education to recognize signs and symptoms of anaphylaxis. Investigation into therapy with oral and sublingual immunotherapy as well as other modalities holds hope for improved treatment of food-induced anaphylaxis. PMID- 21682753 TI - Differential effects of ethanol on spectral binding and inhibition of cytochrome P450 3A4 with eight protease inhibitors antiretroviral drugs. AB - BACKGROUND: Cytochrome P450 3A4 (CYP3A4) is the most abundant CYP enzyme in the liver, which metabolizes approximately 50% of the marketed drugs including antiretroviral agents. CYP3A4 induction by ethanol and its impact on drug metabolism and toxicity is known. However, CYP3A4-ethanol physical interaction and its impact on drug binding, inhibition, or metabolism is not known, except that we have recently shown that ethanol facilitates the binding of a protease inhibitor (PI), nelfinavir, with CYP3A4. The current study was designed to examine the effect of ethanol on spectral binding and inhibition of CYP3A4 with all currently used PIs that differ in physicochemical properties. METHODS: We performed type I and type II spectral binding with CYP3A4 at 0 and 20 mM ethanol and varying PIs' concentrations. We also performed CYP3A4 inhibition using 7 benzyloxy-4-trifluoromethylcoumarin substrate and NADPH at varying concentrations of PIs and ethanol. RESULTS: Atazanavir, lopinavir, saquinavir, and tipranavir showed type I spectral binding, whereas indinavir and ritonavir showed type II. However, amprenavir and darunavir did not show spectral binding with CYP3A4. Ethanol at 20 mM decreased the maximum spectral change (deltaA(max)) with type I lopinavir and saquinavir, but it did not alter deltaA(max) with other PIs. Ethanol did not alter spectral binding affinity (K(D)) and inhibition constant (IC(50)) of type I PIs. However, ethanol significantly decreased the IC(50) of type II PIs, indinavir and ritonavir, and markedly increased the IC(50) of amprenavir and darunavir. CONCLUSIONS: Overall, our results suggest that ethanol differentially alters the binding and inhibition of CYP3A4 with the PIs that have different physicochemical properties. This study has clinical relevance because alcohol has been shown to alter the response to antiretroviral drugs, including PIs, in HIV-1-infected individuals. PMID- 21682755 TI - Review article: faecal transplantation therapy for gastrointestinal disease. AB - BACKGROUND: Evidence is emerging regarding the relationship between a dysbiosis of the human gut microbiota and a number of gastrointestinal diseases as well as diseases beyond the gut. Probiotics have been investigated in many gastrointestinal disease states, with variable and often modest outcomes. Faecal transplantation is an alternative approach to manipulate the gut microbiota. AIM: To review the use of faecal transplantation therapy for the management of gastrointestinal disorders. METHODS: Available articles on faecal transplantation in the management of gastrointestinal disorders were identified using a Pubmed search and bibliographies of review articles on the subject were collated. RESULTS: A total of 239 patients who had undergone faecal transplantation were reported. Seventeen of 22 studies of faecal transplantation were in fulminant or refractory Clostridium difficile. Studies of faecal transplantation are heterogeneous regarding the patients, donors, screening, methods of administration and definition of response. Faecal transplantation for C. difficile has been demonstrated to be effective in 145/166 (87%) patients. Small numbers of patients are reported to have undergone successful faecal transplantation for irritable bowel syndrome and inflammatory bowel disease. CONCLUSIONS: Faecal transplantation has been reported with good outcomes for fulminant and refractory C. difficile. No adverse effects of faecal transplantation have been reported. However, there are no level 1 data of faecal transplantation and reports to date may suffer from reporting bias of positive outcomes and under-reporting of adverse effects. This therapy holds great promise, where a dysbiosis of the gut microbiota is responsible for disease and further studies are necessary to explore this potential. PMID- 21682754 TI - Race affects healing of erosive oesophagitis in patients treated with proton pump inhibitors. AB - BACKGROUND: Erosive oesophagitis appears to be more common in white vs. nonwhite patients with gastro-oesophageal reflux disease (GERD). AIM: To evaluate the association between race and erosive oesophagitis healing in patients with GERD treated with once-daily proton pump inhibitors (PPIs). METHODS: Data from five double-blind trials of once-daily treatment with esomeprazole 40mg vs. omeprazole 20mg or lansoprazole 30mg for erosive oesophagitis healing (evaluated at weeks 4 and 8 by endoscopy) were pooled and stratified by baseline race and Los Angeles (LA) severity grade. Multiple logistic regression models were fit with erosive oesophagitis healing (dependent variable) and race (independent variable), with adjustments for treatment, study, baseline LA grade, age, gender, BMI, Helicobacter pylori status, hiatal hernia and interactions of these factors with race. RESULTS: Of 11,027 patients, 91% were white. Nonwhite (n=978) and black (n=613) patients were less likely to have severe baseline erosive oesophagitis (LA grade C or D) than white patients [adjusted OR: 0.69 (95% CI, 0.61-0.79) and 0.67 (0.57-0.78), respectively; P<0.0001]. At week 8, nonwhite and black patients had lower healing rates than white patients [OR: 0.75 (0.63-0.89) and 0.67 (0.54 0.83), respectively; P<=0.001]. Greater odds of healing were associated with less severe baseline LA grade, increasing age, hiatal hernia, esomeprazole treatment (vs. lansoprazole or omeprazole) and lansoprazole treatment (vs. omeprazole) (all P<=0.0009); no factor interacted significantly with race. CONCLUSIONS: Nonwhite patients with GERD had less severe baseline erosive oesophagitis, but were less likely than white patients to have erosive oesophagitis healing after 8-week PPI therapy. PMID- 21682756 TI - Anti-viral therapy in haemodialysed HCV patients: efficacy, tolerance and treatment strategy. AB - BACKGROUND: In end-stage renal disease (ESRD) patients, hepatitis C virus (HCV) eradication improves patient and graft survival. AIM: To determine optimal use of erythropoietin (EPO) and ribavirin, to compare ribavirin concentrations with those of HCV patients having normal renal function and to evaluate sustained virological response (SVR) in a prospective observatory of ESRD candidates for renal transplantation. METHODS: Thirty-two naive patients were treated with Peg IFN-alpha2a and ribavirin. Two different schedules of ribavirin and EPO administration were used: starting ribavirin at 600mg per week and adapting EPO when haemoglobin (Hb) fell below 10g/dL (adaptive strategy) or starting ribavirin at 1000mg per week while increasing EPO from the start of treatment (preventive strategy). RESULTS: Patients treated with the adaptive strategy had lower median Hb levels (9.6 vs. 10.9g/dL, P=0.02) and more frequent median Hb levels below 10g/dL (58 vs. 5%, P=0.0007) despite lower median ribavirin doses (105 vs. 142mg/day, P<0.0001) than patients treated with the preventive strategy. There was a trend for more frequent transfusion in patients treated with the adaptive strategy than in patients treated with preventive strategy (50 vs. 20%, P=0.08). Compared to patients with normal renal function, ESRD patients had lower ribavirin concentrations during the first month (0.81 vs. 1.7mg/L, P=0.007) and similar concentrations thereafter. SVR was reached in 50%. CONCLUSIONS: Pegylated interferon (Peg-IFN) and an adapted schedule of ribavirin are effective in ESRD patients. Increasing EPO from the start of treatment provides better haematological tolerance. The optimal dosage of ribavirin remains unresolved, in light of frequent side effects. PMID- 21682757 TI - Effects on metabolic variables after 12-month treatment with a new once-a-week sustained-release recombinant growth hormone (GH: LB03002) in patients with GH deficiency. AB - INTRODUCTION: GH substitution in GH deficiency (GHD) must be subcutaneously administered daily. A new sustained-release formulation of GH (LB03002) has been developed, which has to be injected once a week. As a substudy to the phase III study, we performed this prospective study to evaluate the influence of LB03002 on metabolic variables and hormones. METHODS: Eleven patients with GHD [four women/seven men, 58 years (29-69 years)] without GH therapy were included in the study. Eight patients were treated with LB03002 for 12 months and three patients received placebo for 6 months followed by LB03002 for 6 months. A 3-h oral glucose tolerance test (OGTT) was performed at study entry and at study end. Additionally, IGF-I, cholesterol, LDL, HDL, triglycerides, leptin, ghrelin, HbA1c and C-peptide were measured. Body composition was evaluated by dual-energy X-ray absorptiometry (DXA), and waist/hip ratio (WHR) and waist/height (WHtR) ratio were measured by tape and scale. RESULTS: Multiple of upper limit of normal (xULN) of IGF-I (0.23 (0.09-0.4) vs 0.71 (0.4-1.04), P < 0.01), WHR (0.98 (0.86 1.04) vs 1.01 (0.86-1.05), P < 0.05) and ghrelin levels [119.8 ng/l (67.7-266.6) vs 137 ng/l (67-289.5), P < 0.05] were significantly higher, whereas fat mass (FM) [34.7% (20.4-49.2) vs 32.4% (16.7-48.5), P < 0.05] and leptin [11.2 MUg/l (3.3-55.7) vs 7.05 MUg/l (2.4-54.3), P < 0.05] were significantly lower at study end. Glucose, insulin, HOMA-IR, ISI, HOMA-beta, C-peptide and HbA1c during OGTT were not significantly different before and after GH substitution, neither were BMI, WHtR, bone mineral density and lipid variables. CONCLUSION: Substitution with LB03002 showed statistically significant reduction in FM, which reduces leptin levels and increases ghrelin levels but does not seem to influence glucose and lipid metabolism. PMID- 21682758 TI - Vitamin D, cardiovascular disease and mortality. AB - A poor vitamin D status, i.e. low serum levels of 25-hydroxyvitamin D [25(OH)D], is common in the general population. This finding is of concern not only because of the classic vitamin D effects on musculoskeletal outcomes, but also because expression of the vitamin D receptor (VDR) and vitamin D metabolizing enzymes in the heart and blood vessels suggests a role of vitamin D in the cardiovascular system. VDR-knockout mice suffer from cardiovascular disease (CVD), and various experimental studies suggest cardiovascular protection by vitamin D, including antiatherosclerotic, anti-inflammatory and direct cardio-protective actions, beneficial effects on classic cardiovascular risk factors as well as suppression of parathyroid hormone (PTH) levels. In epidemiological studies, low levels of 25(OH)D are associated with increased risk of CVD and mortality. Data from randomized controlled trials (RCTs) are sparse and have partially, but not consistently, shown some beneficial effects of vitamin D supplementation on cardiovascular risk factors (e.g. arterial hypertension). We have insufficient data on vitamin D effects on cardiovascular events, but meta-analyses of RCTs indicate that vitamin D may modestly reduce all-cause mortality. Despite accumulating data suggesting that a sufficient vitamin D status may protect against CVD, we still must wait for results of large-scale RCTs before raising general recommendations for vitamin D in the prevention and treatment of CVD. In current clinical practice, the overall risks and costs of vitamin D supplementation should be weighed against the potential adverse consequences of untreated vitamin D deficiency. PMID- 21682759 TI - Association between 25-OH vitamin D and insulin is independent of lipoatrophy in HIV. AB - OBJECTIVE: Vitamin D deficiency (VDD) is prevalent in HIV, and following antiretroviral therapy (ART), increased rates of lipoatrophy and metabolic abnormalities are described. We investigated the relationships between 25 hydroxyvitamin D [25(OH)D] and other metabolic parameters in a group of HIV patients with and without lipoatrophy to examine whether lipoatrophy could explain the high prevalence of VDD and metabolic abnormalities. BACKGROUND: Vitamin D receptors are expressed in adipose tissue implicating vitamin D, through paracrine/autocrine mechanism, in exerting effects on fat metabolism. HIV patients frequently suffer from VDD, and those treated with thymidine analogues frequently suffer from lipoatrophy so we investigated whether lipoatrophy could explain these associations. DESIGN AND PATIENTS: Cross-sectional study of HIV infected male patients (n = 107; 39 with lipoatrophy) from the West Australian cohort with measurements of 25(OH)D, adiponectin, insulin, lipids and leg fat as a percentage of mass. RESULTS: Reduced 25(OH)D levels were common and significantly associated with higher serum insulin in the entire cohort (P = 0.006), but there was no difference in 25(OH)D between untreated and antiretroviral-treated patients with or without lipoatrophy. Treated patients with lipoatrophy were more likely to take thymidine analogue therapy, were older and on therapy longer than treated patients without lipoatrophy. Adiponectin levels did not correlate with 25(OH)D, but lipoatrophic-treated patients had lower levels of adiponectin compared with nonlipoatrophic-treated patients. CONCLUSIONS: Lower 25(OH)D is associated with higher serum insulin but not lipoatrophy or hypoadiponectinemia in HIV-infected patients. The association between VDD and insulin resistance is likely to be mediated by independent mechanisms. PMID- 21682760 TI - Association of the aldosterone synthase gene -344T>C polymorphism with essential hypertension and glucose homeostasis: a case-control study in a Han Chinese population. AB - 1. Aldosterone is a hormone that affects both blood pressure and glucose homeostasis. We studied the association of the aldosterone synthase gene (CYP11B2) polymorphism -344T>C with essential hypertension (EH) and glucose homeostasis in people in China. 2. We investigated the polymorphism -344T>C in CYP11B2 using a case-control study design (1059 cases and 1120 controls). Genotyping was carried out by matrix-assisted laser desorption/ionization time-of flight mass spectroscopy using a MassARRAY platform. 3. The aldosterone synthase gene -344T>C polymorphism was found to be associated with EH (odds ratio 1.252; 95% confidence interval 1.067-1.468; P(add) = 0.006). The -344C variant was found to be significantly associated with increased systolic blood pressure (P(add) = 0.003) and diastolic blood pressure (P(add) = 0.024) in controls and increased plasma aldosterone levels (P(add) = 0.0001) in EH cases. The -344C variant was also found to be significantly associated with increased fasting glucose (P(rec) = 0.003) in controls. In the subgroup containing 893 EH cases without a history of diabetes or hypoglycaemia medications, the -344C variant was found to be associated with increased fasting and postprandial plasma glucose levels (P(add) = 0.0001, P(add) = 0.001, respectively) and decreased pancreatic beta-cell function and insulin sensitivity (P(add) = 0.030, P(dom) = 0.019, respectively) by homeostasis model assessments. 4. In this Han Chinese population, the -344T/C polymorphism of the CYP11B2 gene was found to be associated with EH and glucose homeostasis, both of which might be mediated by plasma aldosterone levels, insulin sensitivity and beta-cell function. PMID- 21682761 TI - N-Methyl-D-aspartate receptor modulators block hyperalgesia induced by acute low dose morphine. AB - 1. Following opioid-induced antinociception in mice, hyperalgesic responses may be observed. The present study was designed to evaluate the effect of different N methyl-d-aspartate (NMDA) receptor modulators (magnesium, dextromethorphan, d serine) on the development of morphine-induced hyperalgesia in mice. The tail flick test was used to assess the effects of morphine alone and in combination with the NMDA receptor modulators. 2. Administration of a single low dose (2 mg/kg) of morphine to mice produced antinociception that was followed by hyperalgesia. 3. Administration of magnesium sulphate (5 mg/kg) and d-serine (10 mg/kg) alone produced a transient antinociceptive response, whereas dextromethorphan (10 mg/kg) alone produced a prolonged antinociceptive response that had a relatively delayed onset after 4 h. 4. When coadministered with morphine, the NMDA receptor blockers magnesium (2 mg/kg) and dextromethorphan (2 and 5 mg/kg) and the NMDA receptor agonist d-serine (2, 5 and 10 mg/kg), maintained the duration of the antinociceptive response to morphine and inhibited the development of the hyperalgesic response. Coadministration of dextromethorphan (10 mg/kg) with morphine produced antinociception at 30-120 min and at 4-24 h. 5. The results of the present study suggest that coadministration of low-dose NMDA receptor antagonists, as well as the NMDA receptor agonist d serine, with morphine can inhibit morphine-induced hyperalgesia. PMID- 21682762 TI - Disclosure: a concept analysis. AB - AIM: This article is a report of a concept analysis of disclosure. BACKGROUND: Disclosure of health concerns is often delayed or incomplete, resulting in a lack of appropriate care or inability to avoid complications. Disclosure is a poorly understood phenomenon in nursing, however, an understanding of the concept is critical to providing effective nursing care. DATA SOURCES: Literature from the humanities, social sciences, business, law, nursing and allied health fields in five search engines was reviewed for insight into a patient's decision to disclose health information to a healthcare provider. REVIEW METHODS: Wilson's method of concept analysis guided this study into the meaning of disclosure from the point of view of a patient seeking healthcare. Inclusive years of search ranged from 1991 to 2010. RESULTS: Disclosure is defined as the act of seeking care by revealing personally significant information that exposes the bearer to the risk of rejection or negative judgment. Attributes of disclosure are identified as: holding significant health-related information, assistance needed to cope, tolerance for unpredictable result, divulgence and expectation of serious response. Consequences of disclosure include resolution, reassurance or assistance gained, but may also include suffering rejection or negative repercussions. CONCLUSION: Implications for nursing practice are explored and include focused questioning, providing for safety concerns, acknowledging significance and sensitivity of disclosed information and acting on the disclosure. PMID- 21682764 TI - Model of the molecular basis for hydroxylamine oxidation and nitrous oxide production in methanotrophic bacteria. AB - Many methane-oxidizing bacteria (MOB) have been shown to aerobically oxidize ammonia and hydroxylamine (NH(2)OH) to produce nitrite and nitrous oxide (N(2)O). Genome sequences of alphaproteobacterial, gammaproteobacterial, and verrucomicrobial methanotrophs revealed the presence of haoAB, cytL, cytS, nirS or nirK, and norCB genes that may be responsible for N(2)O production, and additional haoAB genes were sequenced from two strains of Methylomicrobium album. The haoAB genes of M. album ATCC 33003 were inducible by ammonia and NH(2)OH, similar to haoAB induction by ammonia in Methylococcus capsulatus Bath. Increased expression of genes encoding nitric oxide reductase (cNOR; norCB) was measured upon exposure of M. capsulatus Bath to NaNO(2) and NO-releasing sodium nitroprusside. Only incubations of M. capsulatus Bath with methane, ammonia, and nitrite produced N(2)O. The data suggest a possible pathway of nitrite reduction to NO by reversely operating NH(2)OH oxidoreductase and NO reduction to N(2)O by cNOR independently or in conjunction with ammonia-induced enzymes (i.e. HAO or cytochrome c'-beta). Results of this study show that MOB likely have diverse mechanisms for nitrogen oxide metabolism and detoxification of NH(2)OH that involve conventional and unconventional enzymes. PMID- 21682763 TI - Genome sequence of Staphylococcus lugdunensis N920143 allows identification of putative colonization and virulence factors. AB - Staphylococcus lugdunensis is an opportunistic pathogen related to Staphylococcus aureus and Staphylococcus epidermidis. The genome sequence of S. lugdunensis strain N920143 has been compared with other staphylococci, and genes were identified that could promote survival of S. lugdunensis on human skin and pathogenesis of infections. Staphylococcus lugdunensis lacks virulence factors that characterize S. aureus and harbours a smaller number of genes encoding surface proteins. It is the only staphylococcal species other than S. aureus that possesses a locus encoding iron-regulated surface determinant (Isd) proteins involved in iron acquisition from haemoglobin. PMID- 21682765 TI - Advances in equine dentistry: 2009 and 2010. PMID- 21682766 TI - Penile anthropometry of normal prepubertal boys in Turkey. AB - AIM: The age-related values of penile length must be known to determine abnormal penis sizes and to follow the treatment of underlying diseases. The aim of this study is to evaluate abnormal penile length in Turkish children by establishing novel reference values for Turkish population and to compare the mean penile length and other parameters with alternates from different ethnic populations and geography. METHODS: This cross-sectional study was conducted on a voluntary basis between November 2008 and November 2009 from four centres in Turkey and comprised of 1278 healthy volunteered prepubertal children. Complete stretched penile length and penis circumference measurements were used for penile length and penis circumference evaluations, respectively. All measurements were taken twice by only one investigator, and mean values were recorded. RESULTS: Penile length and penis circumference for every age group were obtained, percentile curves were established and these findings were compared with the results of previous studies. Significant differences were found between penile length of Turkish children and recently used reference values. CONCLUSION: With this study, novel reference values for penile length in prepubertal children were presented to the literature. PMID- 21682767 TI - Lack of spatial remapping of the visual field surrounding a monocular scotoma. AB - BACKGROUND: Changes in cortical receptive fields following deafferentation raise the question of whether interruption of optic nerve fibres engenders spatial distortion in the region bordering the resulting scotoma. METHODS: The regularity and uniformity of the spatial metric surrounding a monocular Bjerrum scotoma were studied in both the affected and unaffected eyes of a glaucoma patient, using rigorous psychometric measurements and Amsler grid observations. RESULTS: No expansion of distances towards the edge of the scotoma was found; however, such a change occurs at the border of the normal blind spot, though not binocularly and not in the corresponding field of the other eye. CONCLUSION: The findings argue against cortical reorganisation following monocular retinal deafferentation in the adult. PMID- 21682768 TI - Limiting iron supplementation for anemia in dialysis patients--the Basis for Japan's conservative guidelines. AB - Both the Kidney Disease Outcomes Quality Initiative (KDOQI) Guidelines and the European Best Practice Guidelines (EBPG) support the use of substantial doses of iron supplementation when iron overload cannot be confirmed. However, excessive iron reduces iron utilization and is involved in the generation of intracellular reactive oxygen species, which induce cell injury; the risk of subtle toxicity from iron excess exists. Unnecessary iron supplementation also accelerates hepcidin (HP) production. HP, via its effect on ferroportin 1 (FP-1), keeps intracellular iron from being carried even if the iron storage is adequate; it also decreases iron absorption from the intestine. The Japanese Society for Dialysis Therapy Guidelines propose that a minimal amount of iron should be given to chronic kidney disease patients with anemia and only in cases of evident iron deficiency. Japanese clinicians believe that the risk/benefit ratio for iron supplementation is higher than that accepted in Western countries. When erythropoiesis-stimulating agent hyporesponsiveness exists, we should consider conditions other than iron deficiency and treat these conditions to improve iron utilization. PMID- 21682769 TI - Implications of a nephrology workforce shortage for dialysis patient care. AB - Recent dramatic decreases in US medical graduate and International Medical Graduate interest in nephrology as a career suggest that delivery of care to the vulnerable population of dialysis patients in the United States could be negatively affected in coming years. Demographic shifts and changes to national health policy are also likely to exacerbate challenges to provide adequate care to people on dialysis or at risk of end-stage renal disease. Training an adequate number of nephrologists is imperative and will require both reconfiguring current approaches to training and certain aspects of care delivery as well as highlighting bright spots of innovation within the field of nephrology. PMID- 21682770 TI - Effects of aortic stiffness abnormalities on the heart. PMID- 21682771 TI - Targeting the renin angiotensin system in dialysis patients. AB - Patients on chronic dialysis therapy have a dramatic excess cardiovascular risk compared to any other population, including those with overt diabetic nephropathy. Despite this, patients on dialysis are almost invariably excluded from trials evaluating the cardioprotective effect of novel treatments. Consistent evidence is available that inhibitors of the renin-angiotensin system, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), are more cardioprotective than other antihypertensive agents in patients with chronic renal disease or diabetes (with or without renal involvement), but whether this applies also to patients on dialysis is unknown. However, clear evidence is available that ACE inhibitors and ARBs reduce morbidity and mortality in patients on dialysis with heart failure (HF) or atrial fibrillation (AF). Moreover, these drugs may preserve residual renal function in those with preterminal kidney failure as well as vascular access and peritoneal membrane function in those on extracorporeal or peritoneal dialysis, respectively. These drugs also show an excellent tolerability profile in this population. Thus, ACE inhibitors and ARBs are indicated in patients on dialysis with HF or AF. Available evidence suggests that they should be first-choice therapy in patients on dialysis with hypertension, though trials are still needed to formally demonstrate their superior cardioprotective effect over other antihypertensives in this population. PMID- 21682772 TI - Does it matter how parathyroid hormone levels are suppressed in secondary hyperparathyroidism? AB - Because secondary hyperparathyroidism is associated with morbidity and mortality in patients with chronic kidney disease, suppression of parathyroid hormone (PTH) and minimization of associated derangements in mineral metabolism are cardinal therapeutic goals. There is an ongoing debate regarding the proper treatment strategy for PTH suppression in this population. While some practitioners believe that calcitriol analogues should be the primary therapy in this setting, others contend that calcimimetics offer unique treatment benefits. Recent advancements in the understanding of the pathophysiology of secondary hyperparathyroidism and the secondary effects of these agents may help clarify this debate. Here, we review the classical actions of calcitriol analogues and calcimimetics on mineral metabolism. We also examine the potential nonclassical effects of these therapies on the renin-angiotensin-aldosterone system, proteinuria, vascular calcification, fibroblast growth factor-23, inflammation, and overall survival. PMID- 21682773 TI - Vascular incompetence in dialysis patients--protein-bound uremic toxins and endothelial dysfunction. AB - Patients with chronic kidney disease (CKD) have a much higher risk of cardiovascular diseases than the general population. Endothelial dysfunction, which participates in accelerated atherosclerosis, is a hallmark of CKD. Patients with CKD display impaired endothelium-dependent vasodilatation, elevated soluble biomarkers of endothelial dysfunction, and increased oxidative stress. They also present an imbalance between circulating endothelial populations reflecting endothelial injury (endothelial microparticles and circulating endothelial cells) and repair (endothelial progenitor cells). Endothelial damage induced by a uremic environment suggests an involvement of uremia-specific factors. Several uremic toxins, mostly protein-bound, have been shown to have specific endothelial toxicity: ADMA, homocysteine, AGEs, and more recently, p-cresyl sulfate and indoxyl sulfate. These toxins, all poorly removed by hemodialysis therapies, share mechanisms of endothelial toxicity: they promote pro-oxidant and pro inflammatory response and inhibit endothelial repair. This article (i) reviews the evidence for endothelial dysfunction in CKD, (ii) specifies the involvement of protein-bound uremic toxins in this dysfunction, and (iii) discusses therapeutic strategies for lowering uremic toxin concentrations or for countering the effects of uremic toxins on the endothelium. PMID- 21682776 TI - Single site with multichannel transumbilical laparoscopic implantation of long term peritoneal dialysis catheters: initial clinical experience of two cases. PMID- 21682774 TI - Pruritic rash and eosinophilia in a patient receiving peritoneal dialysis. AB - A 28-year-old woman with end-stage renal disease maintained on peritoneal dialysis developed a hyperpigmented macular pruritic rash on multiple parts of her body associated with an eosinophilia of 22%. The consulting allergist suspected a silicone allergy from the peritoneal dialysis catheter. A patch test confirmed this diagnosis. Treatment with both topical and systemic steroids was ineffective. Following a living nonrelated renal transplant and removal of the catheter the rash and eosinophilia resolved. PMID- 21682777 TI - Neuronal correlates of normal and drug-potentiated Pavlovian-instrumental transfer (Commentary on Saddoris et al.). PMID- 21682778 TI - Maternal and paternal transmission of type 2 diabetes. PMID- 21682779 TI - Multiparameter phenotyping of T-cell subsets in distinct subgroups of patients with pulmonary sarcoidosis. AB - OBJECTIVES: Sarcoidosis is an inflammatory disorder in which elevated numbers of activated T cells are found in the lung. HLA-DRB1*0301(pos) (DR3(pos) ) patients are characterized by good prognosis and an accumulation of lung CD4(pos) T cells expressing the T-cell receptor (TCR) gene segment AV2S3. Our aim was to phenotype lung and blood T-cell subsets in distinct patient groups to better understand the function of these subsets. DESIGN: Bronchoalveolar lavage (BAL) fluid and whole blood were obtained from a total of 22 patients with sarcoidosis, of whom 11 were DR3(pos) . Using eight-colour flow cytometry, phenotyping of T cells was performed with regard to CD3, CD4, CD8, CD25, CD27, CD45RO, CD57, CD69, CD103, FOXP3 and TCR AV2S3. RESULTS: DR3(pos) patients had fewer FOXP3(pos) (regulatory) CD45RO(pos) (memory) BAL T cells than DR3(neg) patients. Fewer AV2S3(pos) T cells were FOXP3(pos) , compared with AV2S3(neg) cells, thus indicating an effector function and not a regulatory role for this subset. Fewer lung and blood AV2S3(pos) T cells were CD25(pos) CD27(pos) , and more were CD25(neg) CD27(neg) and CD69(pos) , compared with AV2S3(neg) T cells, indicating a higher degree of differentiation and activation in both compartments. CONCLUSION: Our main findings were a lower proportion of regulatory T cells in DR3(pos) patients, together with the accumulation of AV2S3(pos) T cells with a highly activated effector phenotype in the lungs of these patients. This may provide for efficient elimination of a harmful antigen in DR3(pos) patients and could thus help to explain the spontaneous recovery typically seen in these patients. PMID- 21682780 TI - Climate change: present and future risks to health, and necessary responses. AB - Recent observed changes in Earth's climate, to which humans have contributed substantially, are affecting various health outcomes. These include altered distributions of some infectious disease vectors (ticks at high latitudes, malaria mosquitoes at high altitudes), and an uptrend in extreme weather events and associated deaths, injuries and other health outcomes. Future climate change, if unchecked, will have increasing, mostly adverse, health impacts - both direct and indirect. Climate change will amplify health problems in vulnerable regions, influence infectious disease emergence, affect food yields and nutrition, increase risks of climate-related disasters and impair mental health. The health sector should assist society understand the risks to health and the needed responses. PMID- 21682781 TI - Replacing dairy fat with rapeseed (canola) oil improves hyperlipidaemia- editorial. PMID- 21682782 TI - Integrated medicine. PMID- 21682783 TI - MTR4, a putative RNA helicase and exosome co-factor, is required for proper rRNA biogenesis and development in Arabidopsis thaliana. AB - The exosome is a conserved protein complex that is responsible for essential 3' >5' RNA degradation in both the nucleus and the cytosol. It is composed of a nine subunit core complex to which co-factors confer both RNA substrate recognition and ribonucleolytic activities. Very few exosome co-factors have been identified in plants. Here, we have characterized a putative RNA helicase, AtMTR4, that is involved in the degradation of several nucleolar exosome substrates in Arabidopsis thaliana. We show that AtMTR4, rather than its closely related protein HEN2, is required for proper rRNA biogenesis in Arabidopsis. AtMTR4 is mostly localized in the nucleolus, a subcellular compartmentalization that is shared with another exosome co-factor, RRP6L2. AtMTR4 and RRP6L2 cooperate in several steps of rRNA maturation and surveillance, such as processing the 5.8S rRNA and removal of rRNA maturation by-products. Interestingly, degradation of the Arabidopsis 5' external transcribed spacer (5' ETS) requires cooperation of both the 5'->3' and 3'->5' exoribonucleolytic pathways. Accumulating AtMTR4 targets give rise to illegitimate small RNAs; however, these do not affect rRNA metabolism or contribute to the phenotype of mtr4 mutants. Plants lacking AtMTR4 are viable but show several developmental defects, including aberrant vein patterning and pointed first leaves. The mtr4 phenotype resembles that of several ribosomal protein and nucleolin mutants, and may be explained by delayed ribosome biogenesis, as we observed a reduced rate of rRNA accumulation in mtr4 mutants. Taken together, these data link AtMTR4 with rRNA biogenesis and development in Arabidopsis. PMID- 21682784 TI - Nursing home caregivers' explanations for and coping strategies with residents' aggression: a qualitative study. AB - AIMS AND OBJECTIVES: This study explored caregivers' perspectives regarding the conditions and situations of resident aggression and practical strategies caregivers use to deal with aggression. BACKGROUND: Working in a nursing home is associated with a high risk to experience aggression from residents or patients. Despite existing recommendations for dealing with aggression there is a lack of information about caregivers' ways of dealing with it in practice. DESIGN: A qualitative study with focus group method was conducted. METHOD: Five focus group interviews, with a total of 30 participants, from nursing homes in Switzerland were undertaken employing a semi-structured interview guideline. For analysing the data, qualitative content analysis was employed. RESULTS: Analysis of the data produced three themes with additional sub-themes. One main theme concerns the explanations of the caregivers in regard to the occurrence of aggressive behaviour. This theme is subdivided into two areas, the contributory resident related factors and the caregiver related factors. The measures for handling aggressive behaviour are illustrated in the second theme 'dealing with residents'. The third theme refers to the strategies of the caregivers when confronted with aggressive behaviour -'self-protection' and 'coping with the situation'. CONCLUSION: Caregivers use a broad spectrum of interventions for reducing aggression, some of which are recommended by guidelines but often ignore the link between aggressive behaviour and physiological issues like pain or elimination. The caregivers only very rarely linked their practical knowledge about aggressive behaviour with theoretical knowledge. RELEVANCE TO CLINICAL PRACTICE: The results give insight into the caregivers' perspectives on factors leading to aggression and their coping strategies. Caregivers are informed about relevant reasons for aggressive behaviour and its management, but do not apply a systematic approach. Furthermore, the anxiety of caregivers involved in aggression incidents is an under examined area. PMID- 21682785 TI - Same... same but different: expectations of graduates from two midwifery education courses in Australia. AB - AIMS AND OBJECTIVES: To identify the expectations and workforce intentions of new graduate midwives from two different pre-registration educational courses at one Australian university. BACKGROUND: In Australia there are two different educational pathways to midwifery qualification, one offered for registered nurses, commonly at a postgraduate level and the other for non-nurses, at an undergraduate level. The knowledge about midwifery graduates in general is reasonably limited and there is no specific research that examines the similarities and differences between graduates from the two different courses. DESIGN: A cross-sectional design was used. METHOD: Data were collected by questionnaire from both undergraduate and postgraduate midwifery graduates in 2007 and 2008 at one Australian university. Data were analysed using descriptive statistics. RESULTS: Almost all the graduates from the two different pre registration courses intended to enter the midwifery workforce with both groups rating the factors that influenced this decision similarly. There were, however, significant differences in graduates age and their intention to work part time. Their views of their ideal roles and subsequent uptake into formal new graduate transition programmes differed. Graduates from the two courses also reported philosophical differences regarding their concepts of job satisfaction and ways their jobs could be improved. CONCLUSIONS: The graduates from the two different courses showed sufficient significant differences to warrant consideration in current workforce planning for midwifery. RELEVANCE TO CLINICAL PRACTICE: The factors that influence the career decisions of new graduate midwives can positively impact educational and workforce planning. The findings may be able to help inform strategies to address turnover and attrition in midwifery. PMID- 21682786 TI - Environmental factors associated with genetic and phenotypic divergence among sympatric populations of Arctic charr (Salvelinus alpinus). AB - The mechanisms by which phenotypic and genetic divergence may occur among sympatric, conspecific populations have been widely discussed but are still not well understood. Possible mechanisms include assortative mating based on morphology or variation in the reproductive behaviour of phenotypes, and both have been suggested to be relevant to the differentiation of salmonid populations in post-glacial lakes. Here, we studied Arctic charr (Salvelinus alpinus) in Windermere, where putative populations are defined by spatial and temporal variation in spawning. Genetic differentiation was assessed based on nine microsatellite loci, and phenotypic variation was assessed from morphometric characters. We test hypotheses about the relative role of morphology, spawning season and spawning habitat in the evolution of genetic divergence among these populations. Distinct from other lake systems, we find that both morphological and genetic differentiation are restricted primarily to one of two interconnecting basins, that genetic and morphological differentiation are decoupled in this lake and that both phenotype and environment have changed over the last 20 years. The implication is that breeding habitat plays a primary role in isolating populations that differentiate by drift and that phenotypically plastic changes, potentially related to foraging specializations, have either become secondarily decoupled from the genetically defined populations or were never fundamental in driving the evolution of genetic diversity in the Windermere system. PMID- 21682787 TI - A quantitative genetic analysis of hibernation emergence date in a wild population of Columbian ground squirrels. AB - The life history schedules of wild organisms have long attracted scientific interest, and, in light of ongoing climate change, an understanding of their genetic and environmental underpinnings is increasingly becoming of applied concern. We used a multi-generation pedigree and detailed phenotypic records, spanning 18 years, to estimate the quantitative genetic influences on the timing of hibernation emergence in a wild population of Columbian ground squirrels (Urocitellus columbianus). Emergence date was significantly heritable [h(2) = 0.22 +/- 0.05 (in females) and 0.34 +/- 0.14 (in males)], and there was a positive genetic correlation (r(G) = 0.76 +/- 0.22) between male and female emergence dates. In adult females, the heritabilities of body mass at emergence and oestrous date were h(2) = 0.23 +/- 0.09 and h(2) = 0.18 +/- 0.12, respectively. The date of hibernation emergence has been hypothesized to have evolved so as to synchronize subsequent reproduction with upcoming peaks in vegetation abundance. In support of this hypothesis, although levels of phenotypic variance in emergence date were higher than oestrous date, there was a highly significant genetic correlation between the two (r(G) = 0.98 +/- 0.01). Hibernation is a prominent feature in the annual cycle of many small mammals, but our understanding of its influences lags behind that for phenological traits in many other taxa. Our results provide the first insight into its quantitative genetic influences and thus help contribute to a more general understanding of its evolutionary significance. PMID- 21682788 TI - Impact of selection on genes involved in regulatory network: a modelling study. AB - Complex phenotypes are often controlled by many interacting genes. One question emerging from such organization is how selection, acting at the phenotypic level, shapes the evolution of genes involved in regulatory networks controlling the phenotypes. We studied this issue through a matrix model of such networks. In a population submitted to selection, we simulated the evolution of a quantitative trait controlled by a set of loci that regulate each other through positive or negative interactions. Investigating several levels of selection intensity on the trait, we studied the evolution of regulation intensity between the genes and the evolution of the genetic diversity of those genes as an indirect measure of the strength of selection acting on them. We show that an increasing intensity of selection on the phenotype leads to an increased level of regulation between the loci. Moreover, we found that the genes responding more strongly to selection within the network were those evolving towards stronger regulatory action on the other genes and/or those that are the less regulated by the other genes. This observation is strongest for an intermediate level of selection. This may explain why several experimental studies have shown evidence of selection on regulatory genes inside gene networks. PMID- 21682789 TI - A possible coagulation-independent mechanism for pregnancy loss involving beta(2) glycoprotein 1-dependent antiphospholipid antibodies and CD1d. AB - PROBLEM beta(2) glycoprotein1 (beta(2) GP1)-dependent antiphospholipid antibodies (aPL) increase the risk for recurrent pregnancy loss. We address whether anti-beta(2) GP1 antibodies can interact with phosphatidylserine (PS) bearing CD1d on trophoblast cells and induce local inflammation. METHODS CD1d bearing choriocarcinoma cells were used in flow cytometry and immunoprecipitation experiments. CD1d-mediated cytokine induction was assessed using antibody cross linking. Cytokine production during co-culture of decidual lymphocytes with CD1d bearing cells was also examined. RESULTS Trophoblast surface-expressed CD1d forms a complex with PS-bound beta(2) GP1. Anti-beta(2) GP1 mAb cross-linking causes IL12p70 release from CD1d-bearing cells. IL12p70 release from CD1d-bearing trophoblast cells was also induced during co-culture with human decidual lymphocytes. The addition of anti-beta2GP1 mAb to co-cultures resulted in a three fold increase in IL12p70 secretion. IFNgamma secretion from decidual lymphocytes was also induced during co-culture with anti-beta2GP1 mAbs. CONCLUSIONS beta(2) GP1-dependent IL12 release from CD1d-bearing trophoblast in the presence of aPL may link the antiphospholipid syndrome to pregnancy loss via an inflammatory mechanism. PMID- 21682790 TI - Commitment of decidual haematopoietic progenitor cells in first trimester pregnancy. AB - PROBLEM The aim of this study was to investigate the phenotype and commitment of decidual haematopoietic progenitor cells (HPCs) in healthy pregnant women and in women with early miscarriage. METHOD OF STUDY Peripheral blood and decidual tissue from healthy and pathological pregnant women were examined for HPCs and lymphoid progenitors using flow cytometric analysis. RESULTS Compared with peripheral blood, we found a significant increase in decidual HPCs in both healthy pregnant women and women with spontaneous abortion. T/NK, natural killer (NK), gamma-delta and NKT cell progenitors were identified in all peripheral blood and decidual samples. In pathologic pregnant women, the ratios of decidual T/NK and NK cell progenitors were significantly increased compared with healthy pregnant controls. CONCLUSION We demonstrated decidual cells with haematopoietic progenitor cell phenotype in human decidua. Increased levels of NK progenitors in the decidua of women with early spontaneous abortion suggest a dysregulation of this pathway that may contribute to pregnancy failure. PMID- 21682791 TI - Anti-prothrombin antibodies are associated with adverse pregnancy outcome. AB - PROBLEM: Women with antiphospholipid antibodies (aPL) such as lupus anticoagulant, anticardiolipin antibodies, and anti-beta(2) glycoprotein-1 antibodies are at high risk of late pregnancy complications, such as severe pre eclampsia, placental insufficiency, and fetal loss. It has been observed that aPL consists of a heterogeneous group of antibodies targeting several phospholipid binding plasma proteins, including also anti-prothrombin (anti-PT), anti-protein S (anti-PS), and anti-protein C (anti-PC) antibodies. Their potential role in late pregnancy complications is not known. The aim of this work was to investigate the association between those autoantibodies and histories for adverse pregnancy outcome. METHOD OF STUDY: Anti-PT, anti-PS, and anti-PC antibodies were evaluated in 163 patients with previous severe pre-eclampsia, fetal death, and/or placental abruption and in as many women with previous uneventful pregnancies, negative for aPL. RESULTS: The prevalence of anti-PT antibodies was higher in cases than in controls (OR, 95% CI: 10.92, 4.52-26.38). The highest prevalence was observed in subjects with fetal death. CONCLUSION: Anti-PT antibodies appear to be associated with adverse pregnancy outcome, irrespectively of aPL. PMID- 21682792 TI - Influence of mid-trimester amniotic fluid on endogenous and lipopolysaccharide mediated responses of mononuclear lymphoid cells. AB - PROBLEM We evaluated the influence of amniotic fluid (AF) on immune mediator production by mononuclear leukocytes. METHOD OF STUDY Thirty mid-gestation AFs were incubated with peripheral blood mononuclear cells (PBMCs) in the presence or absence of lipopolysaccharide (LPS). Supernatants were tested for interleukin (IL) - 6, 10, 12, 23, tumor necrosis factor-alpha (TNF-alpha) and monocyte chemotactic protein (MCP)-1. RESULTS Endogenous mediator production was minimal or non-detectable. AF stimulated endogenous MCP-1, IL-6 and TNF-alpha release. In the presence of LPS, production of MCP-1 and IL-10 by PBMCs was enhanced eight- to ninefold by AF. Release of IL-6 and IL-23 was enhanced less than twofold by the addition of AF while TNF-alpha production was unchanged. AF-stimulated mediator production was similar irrespective of pregnancy outcome. CONCLUSION Selective AF stimulation of LPS-mediated MCP-1 and IL-10 release may be a mechanism to promote antibody production and the influx of phagocytic cells to engulf pathogens while downregulating the production of pro-inflammatory cytokines. PMID- 21682793 TI - Vertebral artery anomaly causing C2 suboccipital neuralgia, relieved by neurovascular decompression. AB - We report imaging and surgical findings of a symptomatic 40-year-old male with an anomalous left vertebral artery. MR, CT myelography, angiography, and intraoperative photos demonstrate the vertebral artery entering the thecal sac at the C1-C2 intervertebral foramen and compressing the dorsal C2 nerve rootlets against the cord. Open microvascular decompression alleviated the patient's long standing suboccipital and posterior cervical neck pain. An embryologic review of the vertebral and lateral spinal artery systems reveals possible developmental explanations for this variant. Intradural course of the vertebral artery at C2 is one of the few symptomatic developmental vertebral artery anomalies. Recognition of this condition is important because surgical intervention can alleviate associated neck pain. PMID- 21682794 TI - Radiotherapy and immediate expander/implant breast reconstruction: should reconstruction be delayed? AB - Chest wall irradiation is very common for mastectomy patients that have opted for immediate breast reconstruction. We reviewed a 6 year experience with tissue expander implant reconstruction with and without radiotherapy in 97 patients. All patients were evaluated with respect to aesthetic outcome, infection, implant exposure, capsular contracture, displacement and failure of the reconstruction; more than 50% of our irradiated patients resulted in a complication. The findings of this study demonstrate that the rate of complications and the rate of patients requiring corrective surgeries in irradiated patients is significant in early follow up. PMID- 21682795 TI - Treatment of acne scarring using a dual-spot-size ablative fractionated carbon dioxide laser: review of the literature. AB - BACKGROUND: Fractional photothermolysis has been reported in the literature to improve pigmentary and textural changes associated with acne scarring. OBJECTIVE: To review the literature for the treatment of acne scarring using nonablative fractional laser (NAFL) and ablative fractional laser (AFL) resurfacing. METHODS: Review of the Medline literature evaluating NAFL and AFL for acne scarring. RESULTS: NAFL and AFL are safe and effective treatments for acne scarring. It is likely that the controlled, limited dermal heating of fractional resurfacing initiates a cascade of events in which normalization of the collagenesis collagenolysis cycle occurs. We present the results of a patient treated using a novel dual-spot-size AFL device. Three months after the final treatment, the patient reported 75% improvement in acne scarring and 63% overall improvement in photoaging. CONCLUSIONS: Fractionated resurfacing for the treatment of acne scarring is associated with lesser risks of side effects of prolonged erythema and risks of delayed-onset dyspigmentation and scarring which complicate traditional ablative laser resurfacing approaches. We present herein preliminary data suggesting that a dual-spot-size AFL device presents novel advantages of improving texture and pigmentation in acne scarring and photoaging. PMID- 21682796 TI - Periorbital hyperpigmentation in Asians: an epidemiologic study and a proposed classification. AB - BACKGROUND: Periorbital hyperpigmentation (POH) presents with a dark area surrounding the eyelids. It is an ill-defined condition, and the pathogenesis can be multifactorial. OBJECTIVE: This epidemiologic study was conducted to assess the prevalence of periorbital hyperpigmentation in Singapore in an attempt to propose a classification. MATERIALS AND METHODS: One thousand consecutive patients attending the general dermatology clinic at the National Skin Center were enrolled in the study to assess for POH, of whom 200 with POH were examined and investigated to define the cause of POH. The possible causes were determined according to a detailed history, clinical examination, and assessment by three dermatologists. The extent of the POH was measured using a mexameter. RESULTS: The commonest form of POH was the vascular type (41.8%), followed by constitutional (38.6%), postinflammatory hyperpigmentation (12%), and shadow effects (11.4%). The vascular type was seen predominantly in Chinese, whereas as the constitutional type was most common in Indians and Malays. CONCLUSION: The vascular form of POH was the predominant type. We propose a comprehensive classification for POH that we hope will influence the choice of treatment modalities used in managing POH in the future. PMID- 21682797 TI - A better way to repair torn earlobes using a modified z-plasty. PMID- 21682798 TI - Measles, a re-emerging disease in France? PMID- 21682799 TI - Tuberculosis: an unpredictable long-standing human companion still in need of rapid diagnostic tests. PMID- 21682800 TI - Molecular epidemiology of multidrug-resistant strains of Mycobacterium tuberculosis. AB - Genotyping of Mycobacterium tuberculosis has been extensively used for investigating epidemics of multidrug-resistant strains of M. tuberculosis, in order to identify the factors involved in the transmission of such strains and determine effective control programmes to limit their expansion at both the individual and population levels. Here, we review the methods currently used to study the molecular epidemiology of multidrug-resistant M. tuberculosis strains, and the insights provided by these techniques regarding global trends and the transmission dynamics of multidrug-resistant tuberculosis at a world scale. PMID- 21682801 TI - Guidelines on interferon-gamma release assays for tuberculosis infection: concordance, discordance or confusion? AB - Identification of latent tuberculosis (TB) infection and preventive therapy is important for TB control, especially in high-risk populations. Since the advent of interferon-gamma release assays (IGRAs), many studies have evaluated their role in the diagnosis of active and latent TB. With the growing evidence base, many guidelines now include IGRAs. We surveyed the literature and contacted experts to identify 33 guidelines and position papers from 25 countries and two supranational organizations. The results show considerable diversity in the recommendations on IGRAs, with four approaches commonly proposed: (i) two-step approach of tuberculin skin test (TST) first, followed by IGRA either when the TST is negative (to increase sensitivity, mainly in immunocompromised individuals), or when the TST is positive (to increase specificity, mainly in bacillus Calmette-Guerin-vaccinated individuals); (ii) Either TST or IGRA, but not both; (iii) IGRA and TST together (to increase sensitivity); and (iv) IGRA only, replacing the TST. Overall, the use of IGRAs is increasingly recommended, but most of the current guidelines do not use objective, transparent methods to grade evidence and recommendations, and do not disclose conflicts of interests. Future IGRA guidelines must aim to be transparent, evidence-based, periodically updated, and free of financial conflicts and industry involvement. PMID- 21682802 TI - Strain diversity, epistasis and the evolution of drug resistance in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis harbours little DNA sequence diversity compared with other bacteria. However, there is mounting evidence that strain-to-strain variation in this organism has been underestimated. We review our current understanding of the genetic diversity among M. tuberculosis clinical strains and discuss the relevance of this diversity for the ongoing global epidemics of drug resistant tuberculosis. Based on findings in other bacteria, we propose that epistatic interactions between pre-existing differences in strain genetic background, acquired drug-resistance-conferring mutations and compensatory changes could play a role in the emergence and spread of drug-resistant M. tuberculosis. PMID- 21682803 TI - Insights gained from palaeomicrobiology into ancient and modern tuberculosis. AB - The direct detection of ancient Mycobacterium tuberculosis molecular biomarkers has profoundly changed our understanding of the disease in ancient and historical times. Initially, diagnosis was based on visual changes to skeletal human remains, supplemented by radiological examination. The introduction of biomolecular methods has enabled the specific identification of tuberculosis in human tissues, and has expanded our knowledge of the palaeopathological changes associated with the disease. We now realize that the incidence of past tuberculosis was greater than previously estimated, as M. tuberculosis biomarkers can be found in calcified and non-calcified tissues with non-specific or no visible pathological changes. Modern concepts of the origin and evolution of M. tuberculosis are informed by the detection of lineages of known location and date. PMID- 21682804 TI - Lower incidence of catheter-related bloodstream infection in subclavian venous access in the presence of tracheostomy than in femoral venous access: prospective observational study. AB - Guidelines for the prevention of catheter-related bloodstream infection (CRBSI) recommend subclavian rather than femoral venous access to minimize the risk of CRBSI. However, they do not address the issue of CRBSI with subclavian venous access in the presence of tracheostomy, where the incidence of CRBSI has been found to be higher than without tracheostomy. In this study, we found lower CRBSI in subclavian venous access in the presence of tracheostomy than in femoral venous access (3.9 vs. 10.1 CRBSI per 1000 catheter-days; odds ratio = 0.39; 95% confidence interval <=0.001-0.91; p 0.03). PMID- 21682805 TI - Occurrence of Bartonella henselae and Borrelia burgdorferi sensu lato co infections in ticks collected from humans in Germany. AB - Bartonella (B.) henselae is the zoonotic agent of cat scratch disease. B. henselae has been associated with therapy-resistant Lyme disease in humans suggesting that B. henselae and Borrelia burgdorferi sensu lato might be transmitted concurrently by ticks. In the present study we found that 16 (6.9%) of 230 Ixodes ricinus collected from humans harboured DNA of Bartonella spp. Fifteen positive ticks were infected with B. henselae and one tick with B. clarridgeiae. Twenty-five percent of the 16 Bartonella positive ticks were co infected with Borrelia burgdorferi sensu lato. Our data show that B. henselae is present in Ixodes ricinus and that ticks may serve as source of infection for humans. PMID- 21682806 TI - Methicillin-resistant Staphylococcus aureus (MRSA) ST398 in a farmer with skin lesions and in pigs of his farm: clonal relationship and detection of lnu(A) gene. AB - Skin infection associated with methicillin-resistant Staphylococcus aureus (MRSA) ST398 was detected in a pig-farmer, and MRSA-ST398 isolates were also detected in nasal samples of the patient and of 11/12 pigs on his farm. Twelve MRSA isolates were obtained from skin lesions (n = 6) and nasal samples (n = 6) of the patient in two sampling moments and 11 MRSA isolates from nasal samples of pigs. They were typed as t011-SCCmecIVa-agrI and t108-SCCmecV-agrI (patient and pigs) and t588-SCCmecV-agrI (patient). The following resistance genes were detected (number isolates): tet(K) (1), tet(L) (23), tet(M) (13), erm(A) (13), erm(C) (13), msr(A) (11), lnu(A) (21), aph(2'')-acc(6') (3), ant(4') (13), aph(3') (12), dfrS1 (15) and dfrK (22). Seventeen human and animal MRSA-ST398 isolates showed indistinguishable PFGE patterns (A1-spa-t011 or B2-spa-t108) and similar phenotypic-genotypic characteristics, including the presence of the lnu(A) gene, associated with lincomycin resistance. Potential pig-to-human transference of ST398 is suggested in this study. The first detection of the lnu(A) gene in MRSA ST398 is reported. PMID- 21682807 TI - HBV subgenotype misclassification expands quasi-subgenotype A3. AB - Recently, we proposed a new classification for 'subgenotype A' of hepatitis B virus (HBV), in which the novel 'quasi-subgenotype A3' group comprising HBV 'subgenotype A3', 'tentative A4', and A5 was introduced. Newly 'Tentative subgenotype A7' strains from Cameroon were introduced by Hubschen et al. However, our meticulous phylogenetic analysis demonstrated that these isolates should also be classified into 'quasi-subgenotype A3'. Such misclassification can be avoided by following established principles for HBV subgenotyping. Moreover, their close evolutionary relationship with A3 highlights our hypothesis that geographical origin may be an important factor in further classification of HBV subgenotypes. PMID- 21682808 TI - Unmanageable norovirus outbreak in a single resort located in the Dominican Republic. AB - Noroviruses constitute an important cause of acute gastroenteritis, mainly in semi-closed populations such as hospitals, hotels and cruise ships. This study records the most important norovirus outbreak in the Dominican Republic in a single resort, with more than 800 people being affected in a 15-day period. Analysis of clinical and environmental samples demonstrated that norovirus was the aetiological agent responsible for the outbreak. Although enhanced hygiene and disinfection measures were achieved, the outbreak was only controlled after suspension of entry into the resort. PMID- 21682809 TI - Case reports in psychiatry and clinical neurosciences. PMID- 21682810 TI - Reception of Kraepelin's ideas 1900-1960. AB - Kraepelin's system of mental diseases has contributed substantially to the foundation of modern psychiatric diagnosis in the DSM-IV and ICD-10. Considering Kraepelin's influence in the creation of these diagnostic tools, the question arises as to how Kraepelin's contemporaries and successors reacted to his nosology. Historical libraries and archives in Munich, Berlin and Paris were searched for European and American psychiatric literature using the keywords 'Kraepelin', 'dichotomy' and 'manic-depressive disorder'. Literature from 1900 to 1960 was examined and compared to the current literature regarding Kraepelin's impact on modern classification systems. The sixth edition of Kraepelin's 'Lehrbuch' (1899) presented the dichotomy in its entirety and led to three different periods of critical comment on dichotomy and methodology between 1900 and 1960. But on the whole, Kraepelin's system was quickly and completely adopted in clinical diagnosis. The publications appearing on and following Kraepelin's centenary in 1956 represent his work as generally being the foundation of modern psychiatry. The neo-Kraepelinian movement, beginning in the late 1960s, developed more differentiated views of Kraepelin's scientific background and methodology. Notwithstanding all the criticism of Kraepelin's dichotomy, it remains more than ever the basis of psychiatric diagnosis. The criticism today shows parallels to the statements made during Kraepelin's era, mainly concerning the issue of diagnostic overlapping of the two disease entities, manic-depressive disorder and schizophrenia, and includes the question of syndromatology. PMID- 21682811 TI - Correlations between the offensive subtype of social anxiety disorder and personality disorders. AB - AIMS: Recent studies have revealed the possibility that the offensive subtype of social anxiety disorder (SAD) may no longer be a culture-bound syndrome; however, detailed clinical pictures have never been reported. This study investigated the differences between the offensive and non-offensive subtypes of SAD in terms of the background and axis I and II comorbidity. METHODS: A total of 139 patients with SAD based on DSM-IV criteria were studied by conducting a semi-structured interview including the Structured Clinical Interview for DSM-IV axis I and II disorders, and the Liebowitz Social Anxiety Scale. RESULTS: Fifty-two (37%) patients were classified with the offensive subtype. There were no significant differences in most demographic variables and axis I lifetime comorbidity between offensive and non-offensive subtype patients. On logistic regression analysis, offensive subtype patients showed a more frequent history of parental physical abuse, higher Liebowitz Social Anxiety Scale scores, and more frequently exhibited obsessive--compulsive personality disorders than non-offensive subtype patients. CONCLUSION: Yamashita (1977) reported that the majority of offensive subtype patients were doted on by their parents, although current offensive subtype patients are more likely to have had a troubled childhood, show severer forms of SAD, and more frequently exhibit an inflexible personality. This study suggested that the offensive subtype might not be essentially different from the non-offensive subtype (quantitative rather than qualitative). PMID- 21682812 TI - Midbrain volume increase in patients with panic disorder. AB - AIM: Although recent studies suggest abnormalities of the cerebral cortex, limbic structures, and brain stem regions in panic disorder (PD), the extent to which the midbrain is associated with PD pathophysiology is unclear. The aim of this study was to investigate structural abnormalities of the midbrain using magnetic resonance imaging and to determine if there is a clinical correlation between midbrain volume and clinical measurements in patients with PD. METHODS: Thirty eight patients with PD (PD group) and 38 healthy controls (HC group) participated in this study. The midbrain was measured with a manual tracing method with high spatial resolution magnetic resonance imaging. The Panic Disorder Severity Scale and Global Assessment of Functioning were used to examine the correlation between volume abnormality and clinical symptoms and functioning in the PD group. RESULTS: Relative midbrain volume was larger in the PD group than in the HC group. The relative volume of the dorsal midbrain was larger in the PD group, while the volume of the ventral midbrain was not. We found a significant positive correlation between relative dorsal midbrain volume and total Panic Disorder Severity Scale score, and a significant negative correlation between relative dorsal midbrain volume and Global Assessment of Functioning score in the PD group. CONCLUSIONS: Our findings suggest that the dorsal midbrain is associated with PD pathophysiology. The midbrain volume increase may reflect PD severity. PMID- 21682813 TI - Pedometer walking plus motivational interviewing program for Thai schizophrenic patients with obesity or overweight: a 12-week, randomized, controlled trial. AB - AIM: The aim of this study was to design and examine a program called the 'pedometer walking plus motivational interviewing (PWMI) program' in schizophrenic patients who are obese or overweight. METHODS: This was a 12-week, randomized, parallel, open-label, controlled trial in mildly ill schizophrenic patients with a body mass index (BMI) of 23.0 kg/m(2) or more. Each participant in the intervention or control group was given a leaflet entitled 'What is a healthy lifestyle?' The 1-week, PWMI program consisted of five 1-h sessions of individual motivational interviewing, group education, goal-setting, and practising of pedometer walking. The pedometers were given to the intervention group only. Weight, height, BMI and waist circumference were assessed at baseline, week 4, week 8, and week 12. The primary outcome of this trial was the changed bodyweight at week 4, week 8, and week 12. RESULTS: Of 64 participants, 32 each were randomly allocated to intervention and control groups. All participants completed the study. Only the means of changed bodyweight at week 12 were significantly different between groups (P = 0.03). At this week, the bodyweight of the intervention group decreased significantly more than that of the control group with a mean difference of 2.21 kg (95% confidence interval of 4.12-0.29). CONCLUSION: Increased physical activity by pedometer walking plus individual motivational interviewing may be an effective program for the reduction of bodyweight and BMI in Thai schizophrenic patients who are obese or overweight. Its efficacy may be comparable to other cognitive/behavioral programs. Further studies in larger sample sizes are warranted. PMID- 21682814 TI - Superficial siderosis of the central nervous system presenting with hallucination and delusion: a case report. PMID- 21682815 TI - Reduced thalamus volume in non-right-handed male patients with autism spectrum disorders. PMID- 21682817 TI - Case of undiagnosed catecholaminergic polymorphic ventricular tachycardia presenting with ventricular fibrillation after administration of succinylcholine during anesthesia for modified electroconvulsive therapy. PMID- 21682816 TI - Three cases of schizophrenia showing improvement after switching to blonanserin. PMID- 21682819 TI - Reduced early prophylaxis of children with haemophilia in a developing country, Turkey. PMID- 21682818 TI - Pharmacokinetics and ex vivo whole blood clot formation of a new recombinant FVIII (N8) in haemophilia A dogs. AB - N8, a new recombinant factor VIII (rFVIII) compound developed for the treatment of haemophilia A, is produced in Chinese hamster ovary (CHO) cells and formulated without human- or animal-derived materials. The aim of the present study was to compare the pharmacokinetics (PK) and the procoagulant effect, measured by ex vivo whole blood clot formation, of N8 and a commercial rFVIII in a cross-over study in haemophilia A dogs. N8 and Advate(r) (100 IU kg-1) were administered intravenously to three haemophilia A dogs. Blood was sampled between 0 and 120 h postdose and FVIII:C analysed. PK parameters maximum plasma concentration, area under the curve, half-life (t(1/2)), clearance, mean residence time (MRT) and volume of distribution and incremental recovery were calculated. Whole blood clotting time (WBCT) and thromboelastography (TEG(r)) were used to determine the haemostatic potential. No adverse reactions were observed with N8 or Advate (r). N8 and Advate(r) exhibited similar PK parameters, with t(1/2) 7.7-11 h and MRT 11 14 h. Both rFVIII compounds corrected the prolonged WBCT (> 48 min) to the range of normal dogs (8-12 min), i.e. N8 to 7.5-10.5 min and Advate(r) to 7.5-11.5 min. N8 and Advate(r) also normalized the whole blood clot formation according to TEG(r). The native whole blood clotting assays (WBCT, TEG(r)) appeared to be more sensitive to low concentrations of FVIII than assays in citrated plasma samples. In conclusion, comparison of N8 and Advate (r) in haemophilia A dogs revealed similar safety, similar PK and similar effects in whole blood clot formation assays. PMID- 21682820 TI - Factor X deficiency and intracranial bleeding: who is at risk? AB - Very few mutations of the gene encoding for coagulation factor X (FX) have been found associated with intracranial haemorrhage (ICH) due to FX deficiency (FXD). No guidelines exist as to when prophylaxis in FXD should be started and how patients at risk for ICH can be identified. We report on a novel mutation causative for ICH in a family of Iranian origin and provide a summary of all published mutations in the FX gene related to ICH. The index patient is an infant with umbilical bleeding requiring blood transfusion in the postnatal period. The international normalized ratio (6.01) and activated partial thromboplastin time (117 s) were prolonged. Coagulation factor analysis was normal except for FX activity (<1%). At 4 months, the child suffered a spontaneous severe intracranial haemorrhage. The child was the product of a consanguineous union. Four of five available family members from three generations displayed minor bleeding symptoms and mildly reduced FX. Sequencing of FX gene demonstrated homozygosity for a novel duplication A (c.1402_1403dupA)* in exon 8 and heterozygosity in four family members. We compare this case to all 15 patients with FXD and ICH and their 11 known mutations described so far. This case illustrates a pattern of FXD (a male neonate with umbilical or gastrointestinal bleeding, very low FX:C (<1%) and an underlying homozygous genotype) who may be at high risk for ICH. In these cases, we recommend to start early prophylactic substitution of FX to prevent a possible life-threatening haemorrhage. PMID- 21682821 TI - FVIII administration in surgery. PMID- 21682822 TI - An uncommon cause of knee haemarthrosis in an adult haemophilia patient suffering from long-term paraplegia. PMID- 21682823 TI - Evaluation of the host response to endotoxemia of FVIII and FIX deficient mice. AB - For several years, coagulation has been implicated in the pathogenesis of sepsis. However, results from clinical trials with natural anticoagulants, as well as studies with knock-out mice for specific coagulation factors yielded conflicting results on the role of coagulation in the pathogenesis of sepsis. The aim of this study was to evaluate the impact of severe The factor VIII:C (FVIII:C) and factor IX:C (FIX:C) deficiency on a lipopolysaccharide (LPS)-induced murine model of sepsis. FVIII:C and FIX:C deficient mice, and their haemostatic normal littermate controls were challenged with LPS, and several parameters of the host response were evaluated: seven-day survival experiments were performed using two dose levels of LPS; biochemical and histological markers of tissue damage, coagulation parameters, and pro-inflammatory cytokines were evaluated at baseline and after 3 h and 6 h after an injection of LPS. Severe FVIII and FIX deficiency were compatible with normal survival in experimental sepsis. In addition, LPS-induced tissue damage and coagulation activation were similar in FVIII or FIX deficient mice compared to their respective controls. A lower release of pro-inflammatory cytokines was observed in FIX but not in FVIII deficient mice. Severe FIX or FVIII deficiency does not protect mice from mortality or from tissue damage in the endotoxemia model, supporting the hypothesis that FVIII and FIX are not critical to the pathogenesis of experimental sepsis. PMID- 21682824 TI - An analysis of factors affecting the incidence of inhibitor formation in patients with congenital haemophilia in Japan. AB - Studies conducted in European and North American countries have demonstrated that various factors including races affect the frequency of inhibitor formation in haemophilia patients. The present study was undertaken to analyse factors affecting the incidence of inhibitor formation in Japanese haemophilia A and B patients. Analytical data were retrospectively collected from haemophilia A and B patients born after 1988, the year when monoclonal antibody-purified factor VIII products were first marketed in Japan. Various data were collected from 184 patients (153 cases of haemophilia A; 31 cases of haemophilia B). The sample size of haemophilia B cases was too small to reveal any significant differences between the inhibitor formation group and the inhibitor-free group in any of background variables. For patients with haemophilia A, on the other hand, univariate analysis identified the severity of haemophilia and a positive family history of inhibitor development as risk factors for the formation of inhibitors. In analyses of the clotting factor products used, the incidence of inhibitor formation did not differ significantly between the group treated with plasma derived products (29.7%) and the group treated with recombinant products (25.0%). When background variables were compared, age was higher in the group treated with plasma-derived products but none of the other background variables differed between the two groups. These results suggest that in Japanese haemophilia patients, the type of clotting factor preparations used for therapy has not influenced the incidence of inhibitor formation. PMID- 21682825 TI - Platelets significantly modify procoagulant activities in haemophilia A. AB - Haemophilia A replacement therapy is dosed according to patient's weight and plasma FVIII activity (FVIII:C). The FVIII interacts with platelet membrane but limited data on the impact of platelet procoagulant activity (PCA) are available in haemophilia A. Our aim was to characterize individual PCA in vitro in 20 adult haemophilia A patients at various FVIII:C levels. We detected thrombin generation in platelet-poor (PPP) and platelet-rich plasma (PRP) using: (i) calibrated automated thrombography (CAT) triggered with tissue factor, (ii) adhesion-induced PCA upon collagen and (iii) annexin V binding, expression of P-selectin and active glycoprotein (GP) IIbIIIa on platelets after stimulation of GPVI with collagen-related peptide. The FVIII:C levels varied between <1% and 37%. Thrombin generation was individual and strongly enforced by platelets and associated within the three methods. Range of thrombin generation was maximal (up to 30 fold) at FVIII:C levels 1-5%, underlining the impact of platelets in the presence of traces of replacement therapy. At FVIII:C > 5% platelet contribution in the variance faded. Platelet PCA and P-selectin exposure lead to a fivefold variation. Intriguingly, at FVIII:C < 1% thrombin generation in PPP associated negatively with platelet GPVI activation, suggestive of a regulatory interplay between plasma and platelets. In haemophilia A, the variability in thrombin generation is partially related to plasma FVIII:C, but mainly dependent on platelet procoagulant capacity. Annexin V binding and PCA in response to activation by collagen receptors contribute to this variability. In all, platelet PCA at least following collagen interaction significantly impacts thrombin generation in haemophilia A. PMID- 21682826 TI - Sustained virological response of patients with hepatitis C virus genotype 2 depends on pegylated interferon compliance. AB - AIM: Patients infected with hepatitis C virus (HCV) genotype 2 are more sensitive to interferon (IFN) therapy than those infected with genotype 1, but 10 20% of patients do not achieve a sustained viral response (SVR) to combination therapy with pegylated (PEG) IFN and ribavirin (RBV). This study examines the prognostic factors associated with SVR in patients infected with HCV genotype 2 treated with PEG IFN and RBV. METHODS: We treated 149 patients with chronic hepatitis C caused by HCV genotype 2. The patients received s.c. PEG IFN-alpha-2b (1.5 ug/kg) and a weekly weight-adjusted dose of RBV (600, 800 and 1000 mg per <60, 60-80 and >80 kg, respectively) for 24 weeks and then prognostic factors associated with the SVR were examined. RESULTS: Among the 149 patients, 138 completed the combination therapy and a sustained viral response was achieved in 71.8% of them. Univariate analysis showed that age, as well as mean RBV and PEG IFN doses were factors affecting the SVR (P = 0.012, =0.021, =0.014). Multivariate analysis identified age and mean PEG IFN dose (P = 0.021, =0.018, respectively) as factors involved in the SVR, but not mean RBV dose. CONCLUSION: The SVR of patients infected with HCV genotype 2 depended on the dosage of PEG IFN, but not of RBV. Selecting sufficient doses of PEG IFN for combination with RBV is critical for treating such patients. PMID- 21682827 TI - Molecular characteristics of non-cancerous liver tissue in non-B non-C hepatocellular carcinoma. AB - Although chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) are the most important risk factors for the development of hepatocellular carcinoma (HCC) worldwide, the proportion of HCC patients negative for the hepatitis B surface antigen and hepatitis C antibody, so-called "non-B non-C HCC", is rapidly increasing, especially in Japan. The background liver diseases of non-B non-C HCC patients can be multifactorial, including occult HBV infection and non-alcoholic steatohepatitis. It is reasonable to investigate the non cancerous liver tissues to identify the potential molecular mechanisms responsible for the processes of hepatocarcinogenesis of non-B non-C HCC. However, to date, only a few studies have focused on this research concept based on the idea of "field cancerization". This review highlights the potential importance of the molecular analysis of non-cancerous liver tissues to clarify the molecular characteristics in patients with non-B non-C HCC. A better understanding of the molecular mechanisms underlying the individual predisposition to non-B non-C HCC will lead to improvements in the prevention, early diagnosis and treatment of this neoplastic disease. PMID- 21682828 TI - Activator protein-2alpha functions as a master regulator of multiple transcription factors in the mouse liver. AB - AIM: Activator protein 2alpha (AP-2alpha) belongs to the AP-2 family of transcription factors that are involved in the regulation of cell proliferation, differentiation, apoptosis and carcinogenesis and has been suggested to function as a tumor suppressor in many cancers. However, the physiological role of AP 2alpha in hepatocytes is unknown. The present study is to characterize the expression and function of AP-2alpha in the liver of conscience mouse. METHODS: Exogenous AP-2alpha was overexpressed in the mouse liver by in vivo gene delivery and changes in transcription factor expression were identified by using protein DNA arrays and immunoblotting. RESULTS: Western blotting and protein/DNA arrays showed that AP-2alpha is expressed in the nuclei of mouse hepatocytes. Overexpression of AP-2alphain vivo significantly suppressed transcription factors AP-1, CREB and c-Myc, and markedly increased CBF, c-Myb, NF-1, Pax-5, RXR, Smad3/4, TR(DR-4), USF-1 and GATA. Among all GATA proteins, only GATA-4 level was dramatically elevated and there was a concomitant loss of phospho-GATA-4. Corresponding changes were detected in upstream kinases Akt, GSK-3beta and PKA, which regulates the phosphorylation status and stability of GATA-4 protein. CONCLUSIONS: AP-2alpha is expressed in mouse hepatocytes and it acts as a master regulator of numerous transcription factors in the liver. PMID- 21682829 TI - Therapeutic effects of the oriental herbal medicine Sho-saiko-to on liver cirrhosis and carcinoma. AB - The traditional Chinese herbal medicine Sho-saiko-to is a mixture of seven herbal preparations that has long been used in the treatment of chronic liver disease. Various clinical trials have shown that Sho-saiko-to protects against the development of hepatocellular carcinoma in cirrhotic patients. However, the mechanism by which Sho-saiko-to protects hepatocytes against hepatic fibrosis and carcinoma is not yet known. Basic science studies have demonstrated that Sho saiko-to reduces hepatocyte necrosis and enhances liver function. Sho-saiko-to significantly inhibits hepatic fibrosis by inhibiting the activation of stellate cells, the major producers of collagen in the liver, as well as by inhibiting hepatic lipid peroxidation, promoting matrix degradation, and suppressing extracellular matrix (ECM) accumulation. Furthermore, clinical trials have shown that Sho-saiko-to lowers the rate of hepatocellular carcinoma (HCC) development in patients with cirrhosis and increases the survival of patients with HCC. Unfortunately, some case reports have shown the side effects of Sho-saiko-to. Most of the side effects were interstitial pneumonia and acute respiratory failure induced by Sho-saiko-to in Japan. As a result of analyzing these case reports, the incidence and risk are increased by co-administration of interferon, duration of medication, and, high in an elderly population. This review discusses the properties of Sho-saiko-to with regards to the treatment of chronic liver diseases and suggests the side effects of Sho-saiko-to. PMID- 21682830 TI - Cholesterol and chronic hepatitis C virus infection. AB - Cholesterol is an essential molecule for the life cycle of the hepatitis C virus (HCV). This review focuses on the roles of cholesterol in HCV infection and introduces HCV events related to cholesterol metabolism and applications for cholesterol metabolism as a therapeutic target. HCV appears to alter host lipid metabolism into its preferable state, which is clinically recognized as steatosis and hypocholesterolemia. While hepatic fatty acid and triglyceride syntheses are upregulated in chronic hepatitis C patients, no direct evidence of increased hepatic de novo cholesterol biosynthesis has been obtained. Impaired VLDL secretion from hepatocytes is suggested to increase intracellular cholesterol concentrations, which may lead to hypocholesterolemia. Clinically, lower serum cholesterol levels are associated with lower rates of sustained virological responses (SVR) to pegylated-interferon plus ribavirin therapy, but the reason remains unclear. Clinical trials targeting HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, are being conducted using statins. Anti-HCV actions by statins appear to be caused by the inhibition of geranylgeranyl pyrophosphate synthesis rather than their cholesterol lowering effects. Other compounds that block various steps of cholesterol metabolic pathways have also been studied to develop new strategies for the complete eradication of this virus. PMID- 21682831 TI - Close correlation of liver stiffness with collagen deposition and presence of myofibroblasts in non-alcoholic fatty liver disease. AB - AIM: Transient elastography is known as a rapid, objective, and highly reliable technique for staging hepatic fibrosis caused by hepatitis C virus infection; however, the relationship between degree of fibrosis and the collagen deposition or the accumulation of myofibroblasts in non-alcoholic fatty liver disease (NAFLD) remains to be further elucidated. METHODS: The subjects were 36 patients with NAFLD who received liver biopsy and liver stiffness measurement using transient elastography. Their clinical data and laboratory values were collected. Morphometric analyses of liver fibrosis indicated by collagen deposition and the relative numbers of myofibroblasts were performed. RESULTS: Liver stiffness measured by transient elastography correlated with histopathological fibrosis staging of NAFLD determined by Brunt's scoring system (P = 0.000149). The fibrosis staging correlated with the ratios of the Sirius red positive area (P = 0.000032) and alpha-smooth muscle actin-positive area (P = 0.000898). Finally, liver stiffness significantly correlated with the ratios of the Sirius red-positive area (r = 0.390, P = 0.0184) and alpha-smooth muscle actin-positive area (r = 0.333, P = 0.0471). CONCLUSIONS: Liver stiffness measurement by transient elastography is valuable for evaluating fibrotic progression in NAFLD. PMID- 21682832 TI - Species coexistence in a variable world. AB - The contribution of deterministic and stochastic processes to species coexistence is widely debated. With the introduction of powerful statistical techniques, we can now better characterise different sources of uncertainty when quantifying niche differentiation. The theoretical literature on the effect of stochasticity on coexistence, however, is often ignored by field ecologists because of its technical nature and difficulties in its application. In this review, we examine how different sources of variability in population dynamics contribute to coexistence. Unfortunately, few general rules emerge among the different models that have been studied to date. Nonetheless, we believe that a greater understanding is possible, based on the integration of coexistence and population extinction risk theories. There are two conditions for coexistence in the presence of environmental and demographic variability: (1) the average per capita growth rates of all coexisting species must be positive when at low densities, and (2) these growth rates must be strong enough to overcome negative random events potentially pushing densities to extinction. We propose that critical tests for species coexistence must account for niche differentiation arising from this variability and should be based explicitly on notions of stability and ecological drift. PMID- 21682833 TI - Efficacy and safety of alogliptin added to pioglitazone in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label long-term extension study. AB - AIM: To assess the efficacy and safety of alogliptin added to pioglitazone versus pioglitazone monotherapy, in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus diet/exercise. METHODS: Patients were stabilized on pioglitazone 15 or 30 mg/day plus diet/exercise during a 16-week screening period. Patients with HbA1c of 6.9-10.4% were randomized to 12 weeks' double-blind treatment with alogliptin 12.5 or 25 mg once daily or placebo, added to their stable pioglitazone regimen. The primary endpoint was the change in HbA1c from baseline to week 12. Patients had an option to continue in a 40-week, open-label extension study, with those originally randomized to alogliptin remaining on the same dosage regimen while patients treated with placebo were randomly allocated to alogliptin 12.5 or 25 mg (added to their stable pioglitazone). RESULTS: The change from baseline in HbA1c after 12 weeks was significantly greater with alogliptin 12.5 mg added to pioglitazone and alogliptin 25 mg added to pioglitazone than with placebo added to pioglitazone (-0.91 and -0.97% vs. -0.19%; p < 0.0001). Responder rates (HbA1c <6.9% and HbA1c <6.2%) and changes in fasting and postprandial blood glucose levels showed a similar positive trend in terms of glycaemic control. The benefits seen with alogliptin were sustained during the 40-week extension period. Alogliptin added to pioglitazone was generally well tolerated; hypoglycaemia was infrequent and increases in body weight were minor. CONCLUSIONS: Once-daily alogliptin was effective and generally well tolerated when given as add-on therapy to pioglitazone in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus lifestyle measures. Clinical benefits were maintained for 52 weeks. PMID- 21682834 TI - A randomized, parallel group, double-blind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long term glycaemic control and bone mineral density after 80 weeks of treatment in drug-naive type 2 diabetes mellitus patients. AB - AIM: The purpose of this study was to evaluate if superior glycaemic control could be achieved with Avandamet(r) (rosiglitazone/metformin/AVM) compared with metformin (MET) monotherapy, and if glycaemic effects attained with AVM are durable over 18 months of treatment. Bone mineral density (BMD) and bone biomarkers were evaluated in a subgroup of patients. METHODS: This was a phase IV, randomized, double-blind, multi-centre study in 688, drug naIve, male and female patients who had an established clinical diagnosis of type 2 diabetes mellitus (T2DM). Patients were randomized in a 1 : 1 ratio either to AVM or MET. RESULTS: As initial therapy in patients with T2DM, AVM was superior to MET in achieving statistically significant reductions in glycated haemoglobin (HbA1c) (p < 0.0001) and fasting plasma glucose (FPG) (p < 0.001), with more patients reaching recommended HbA1c and FPG targets for intensive glycaemic control. The glycaemic effects attained with AVM compared to MET monotherapy were durable over 18 months of treatment. In the bone substudy, AVM was associated with a significantly lower BMD in comparison with MET at week 80 in the lumbar spine and total hip (p < 0.0012 and p = 0.0005, respectively). Between-treatment differences were not statistically significant for distal one-third of radius BMD, femoral neck BMD or total BMD. CONCLUSION: Superior glycaemic control was achieved with AVM compared with MET monotherapy. The superior glycaemic effects were shown to be durable over 18 months of treatment. AVM was associated with a significantly reduced BMD in comparison with MET at week 80 in the lumbar spine and total hip. PMID- 21682835 TI - Anabolic steroids and male infertility: a comprehensive review. AB - What's known on the subject? and What does the study add? The negative impact of AAS abuse on male fertility is well known by urologists. The secondary hypogonadotropic hypogonadism is often highlighted when AAS and fertility are being discussed. On the other hand, the patterns of use, mechanisms of action and direct effects over the testicle are usually overseen. The present study reviews the vast formal and "underground" culture of AAS, as well as their overall implications. Specific considerations about their impact on the male reproductive system are made, with special attention to the recent data on direct damage to the testicle. To our knowledge this kind of overview is absolutely unique, offering a distinguished set of information to the day-by-day urologists. For several decades, testosterone and its synthetic derivatives have been used with anabolic and androgenic purposes. Initially, these substances were restricted to professional bodybuilders, becoming gradually more popular among recreational power athletes. Currently, as many as 3 million anabolic-androgenic steroids (AAS) users have been reported in the United States, and considering its increasing prevalence, it has become an issue of major concern. Infertility is defined as the failure to achieve a successful pregnancy after 12 months or more of regular unprotected intercourse, with male factor being present in up to 50% of all infertile couples. Several conditions may be related to male infertility. Substance abuse, including AAS, is commonly associated to transient or persistent impairment on male reproductive function, through different pathways. Herein, a brief overview on AAS, specially oriented to urologists, is offered. Steroids biochemistry, patterns of use, physiological and clinical issues are enlightened. A further review about fertility outcomes among male AAS abusers is also presented, including the classic reports on transient axial inhibition, and the more recent experimental reports on structural and genetic sperm damage. PMID- 21682836 TI - ADARs: allies or enemies? The importance of A-to-I RNA editing in human disease: from cancer to HIV-1. AB - Adenosine deaminases acting on RNA (ADARs) are enzymes that convert adenosine (A) to inosine (I) in nuclear-encoded RNAs and viral RNAs. The activity of ADARs has been demonstrated to be essential in mammals and serves to fine-tune different proteins and modulate many molecular pathways. Recent findings have shown that ADAR activity is altered in many pathological tissues. Moreover, it has been shown that modulation of RNA editing is important for cell proliferation and migration, and has a protective effect on ischaemic insults. This review summarises available recent knowledge on A-to-I RNA editing and ADAR enzymes, with particular attention given to the emerging role played by these enzymes in cancer, some infectious diseases and immune-mediated disorders. PMID- 21682837 TI - The evolution of endothermy in Cenozoic mammals: a plesiomorphic-apomorphic continuum. AB - The evolution of endothermy in birds and mammals was one of the most important events in the evolution of the vertebrates. Past tests of hypotheses on the evolution of endothermy in mammals have relied largely on analyses of the relationship between basal and maximum metabolic rate, and artificial selection experiments. I argue that components of existing hypotheses, as well as new hypotheses, can be tested using an alternative macrophysiological modeling approach by examining the development of endothermy during the Cenozoic. Recent mammals display a 10 degrees C range in body temperature which is sufficiently large to identify the selective forces that have driven the development of endothermy from a plesiomorphic (ancestral) Cretaceous or Jurassic condition. A model is presented (the Plesiomorphic-Apomorphic Endothermy Model, PAE Model) which proposes that heterothermy, i.e. bouts of normothermy (constant body temperature) interspersed with adaptive heterothermy (e.g. daily torpor and/or hibernation), was the ancestral condition from which apomorphic (derived), rigid homeothermy evolved. All terrestrial mammal lineages are examined for existing data to test the model, as well as for missing data that could be used to test the model. With the exception of Scandentia and Dermoptera, about which little is known, all mammalian orders that include small-sized mammals (<500 g), have species which are heterothermic and display characteristics of endothermy which fall somewhere along a plesiomorphic-apomorphic continuum. Orders which do not have heterothermic representatives (Cetartiodactyla, Perissodactyla, Pholidota, and Lagomorpha) are comprised of medium- to large-sized mammals that have either lost the capacity for heterothermy, or in which heterothermy has yet to be measured. Mammalian heterothermy seems to be plesiomorphic and probably evolved once in the mammalian lineage. Several categories of endothermy are identified (protoendothermy, plesioendothermy, apoendothermy, basoendothermy, mesoendothermy, supraendothermy, and reversed mesoendothermy) to describe the evolution of endothermy during the Cenozoic. The PAE Model should facilitate the testing of hypotheses using a range of macrophysiological methods (e.g. the comparative method and the reconstruction of ancestral states). PMID- 21682839 TI - Greenhouse warming by nitrous oxide and methane in the Proterozoic Eon. AB - An anoxic, sulfidic ocean that may have existed during the Proterozoic Eon (0.54 2.4 Ga) would have had limited trace metal abundances because of the low solubility of metal sulfides. The lack of copper, in particular, could have had a significant impact on marine denitrification. Copper is needed for the enzyme that controls the final step of denitrification, from N(2) O to N(2) . Today, only about 5-6% of denitrification results in release of N(2) O. If all denitrification stopped at N(2) O during the Proterozoic, the N(2) O flux could have been 15-20 times higher than today, producing N(2) O concentrations of several ppmv, but only if O(2) levels were relatively high (>0.1 PAL). At lower O(2) levels, N(2) O is rapidly photodissociated. Methane concentrations may also have been elevated during this time, as has been previously suggested. A lack of dissolved O(2) and sulfate in the deep ocean could have produced a high methane flux from marine sediments, as much as 10-20 times today's methane flux from land. The photochemical lifetime of CH(4) increases as more CH(4) is added to the atmosphere, so CH(4) concentrations of up to 100 ppmv are possible during this time. The combined greenhouse effect of CH(4) and N(2) O could have provided up to 10 degrees of warming, thereby keeping the surface warm during the Proterozoic without necessitating high CO(2) levels. A second oxygenation event near the end of the Proterozoic would have resulted in a reduction in both atmospheric N(2) O and CH(4) , perhaps triggering the Neoproterozoic "Snowball Earth" glaciations. PMID- 21682840 TI - Carotenoid biomarkers as an imperfect reflection of the anoxygenic phototrophic community in meromictic Fayetteville Green Lake. AB - Organic biomarkers in marine sedimentary rocks hold important clues about the early history of Earth's surface environment. The chemical relicts of carotenoids from anoxygenic sulfur bacteria are of particular interest to geoscientists because of their potential to signal episodes of marine photic-zone euxinia such as those proposed for extended periods in the Proterozoic as well as brief intervals during the Phanerozoic. It is therefore critical to constrain the environmental and physiological factors that influence carotenoid production and preservation in modern environments. Here, we present the results of coupled pigment and nucleic acid clone library analyses from planktonic and benthic samples collected from a microbially dominated meromictic lake, Fayetteville Green Lake (New York). Purple sulfur bacteria (PSB) are abundant and diverse both in the water column at the chemocline and in benthic mats below oxygenated shallow waters, with different PSB species inhabiting the two environments. Okenone (from PSB) is an abundant carotenoid in both the chemocline waters and in benthic mats. Green sulfur bacteria and their primary pigment Bchl e are also represented in and below the chemocline. However, the water column and sediments are devoid of the green sulfur bacteria carotenoid isorenieratene. The unexpected absence of isorenieratene and apparent benthic production of okenone provide strong rationale for continued exploration of the microbial ecology of biomarker production in modern euxinic environments. PMID- 21682841 TI - Relationship among Schneiderian membrane, Underwood's septa, and the maxillary sinus inferior border. AB - BACKGROUND: Osseo-integrated implants are increasingly being used to restore functional dentition; however, in the posterior region, implant placement can be problematic because of inadequate bone height. In this condition, maxillary sinus floor elevation surgery has become the treatment of choice. The presence of anatomic variations within the maxillary sinus such as Underwood's septa and thin Schneiderian membrane decreases the success of the sinus floor elevation. PURPOSE: In this study, we tried to determine the relationship between the anatomic variations of the maxillary sinus: Underwood's septa, Schneiderian membrane thickness, and the cortical thickness of the inferior border of the maxillary sinus. MATERIAL AND METHODS: The left and right maxillary sinus images of 74 patients were obtained by using dental computed tomography (CT). The Schneiderian membrane and the cortical thickness of the inferior border of the maxillary sinus were measured on the coronal images of dental CT scans at the deepest portion of the sinus cavity. The presence of Underwood's septa was identified on the axial images. The correlations between these variables were assessed. RESULTS: We found that there was only a negative correlation between the Schneiderian membrane thickness and the presence of Underwood's septa (r = 0.168 p = .042). CONCLUSION: It is suggested that Underwood's septa may be the reason for the thinness of the Schneiderian membrane. However, future studies among larger groups are necessary for confirming the finding by using well designed clinical studies. PMID- 21682842 TI - Displacement of dental implants in trabecular bone under a static lateral load in fresh bovine bone. AB - AIM: The study aims to provide objective data for the displacement of titanium screw implants in trabecular bone specimens. One hundred Semados implants (Bego, Bremen, Germany) were inserted in bovine type IV bone specimens. All implants had a diameter of 3.75 mm; 50 implants had a length of 8.5 mm and 50 implants had a length of 15 mm. Insertion torque was determined at intervals of 10, 20, and 30 Ncm. Implants were loaded horizontally with 10, 20, and 30 N for 2 seconds. An indicator strip was attached to the implant abutment to allow direct observation of implant movement relative to the bone surface. Horizontal displacement was assessed with an accuracy of measurement of 10 um. Seven implants got lost by visible loosening. Degree of displacement was subject to evaluation with all others. Those implants showed a mean displacement of 59 um for 10 N (n = 100), 173 um for 20 N (n = 99), and 211 um for 30 N (n = 93). The mean displacement of 15-mm implants (16, 37, 51 um) was significantly lower compared with 8.5-mm implants (103, 311, 396 um) corresponding to 10, 20, and 30 N as lateral loads. CONCLUSIONS: Displacement of screw implants in trabecular bone can be detected and visualized using commercially available endoscopes with a high magnification. A lateral load of 20 N indicates a mean displacement of over 100 um and therefore results in a critical displacement. PMID- 21682843 TI - Submicron scale-structured hydrophilic titanium surfaces promote early osteogenic gene response for cell adhesion and cell differentiation. AB - BACKGROUND AND PURPOSE: Titanium (Ti) surface roughness and surface hydrophilicity are key factors to regulate osteogenic cell responses during dental implant healing. In detail, specific integrin-mediated interactions with the extracellular environment trigger relevant osteogenic cell responses like differentiation and matrix synthesis via transcriptions factors. Aim of this study was to monitor surface-dependent osteogenic cell adhesion dynamics, proliferation, and specific osteogenic cell differentiation over a period of 7 days. MATERIALS AND METHODS: Ti disks were manufactured to present smooth pretreatment (PT) surfaces and rough sandblasted/acid-etched (SLA) surfaces. Further processing to isolate the uncontaminated TiO(2) surface from contact with atmosphere provided a highly hydrophilic surface without alteration of the surface topography (modSLA). Tissue culture polystyrene (TCPS) served as control. Human osteogenic cells were cultivated on the respective substrates. After 24 hours, 48 hours, 72 hours, and 7 days, cell morphology on the Ti substrates was visualized by scanning transmission electron microscopy. As a marker of cellular proliferation, cell count was assessed. For the analysis of cell adhesion and differentiation, specific gene expression levels of the integrin subunits beta1 and alphav, runx-2, collagen type Ialpha (COL), alkaline phosphatase (AP), and osteocalcin (OC) were obtained by real-time RT-PCR for the respective time points. Data were normalized to internal controls. RESULTS: TCPS and PT surfaces preserved a rather immature, dividing osteogenic phenotype (high proliferation rates, low integrin levels, and low specific osteogenic cell differentiation). SLA and especially modSLA surfaces promoted both cell adhesion as well as the maturation of osteogenic precursors into post-mitotic osteoblasts. In detail, during the first 48 hours, modSLA resulted in lowest cell proliferation rates but exhibited highest levels of the investigated integrins, runx-2, COL, AP, and OC. CONCLUSION: Our results revealed a strong synergistic effect between submicron scale roughness and surface hydrophilicity on early osteogenic cell adhesion and maturation. PMID- 21682844 TI - Changes in implant stability using different site preparation techniques: twist drills versus piezosurgery. A single-blinded, randomized, controlled clinical trial. AB - PURPOSE: The objective of the present investigation was to longitudinally monitor stability changes of implants inserted using traditional rotary instruments or piezoelectric inserts, and to follow their variations during the first 90 days of healing. MATERIALS AND METHODS: A randomized, controlled trial was conducted on 20 patients. Each patient received two identical, adjacent implants in the upper premolar area: the test site was prepared with piezosurgery, and the control site was prepared using twist drills. Resonance frequency analysis measurements were taken by a blinded operator on the day of surgery and after 7, 14, 21, 28, 42, 56, and 90 days. RESULTS: At 90 days, 39 out of 40 implants were osseointegrated (one failure in the control group). Both groups showed an initial decrease in mean implant stability quotient (ISQ) values: a shift in implant stability to increasing ISQ values occurred after 14 days in the test group and after 21 days in the control group. The lowest mean ISQ value was recorded at 14 days for test implants (97.3% of the primary stability) and at 21 days for the control implants (90.8% of the primary stability). ISQ variations with respect to primary stability differed significantly between the two groups during the entire period of observation: from day 14 to day 42, in particular, the differences were extremely significant (p < .0001). All 39 implants were in function successfully at the visit scheduled 1 year after insertion. CONCLUSIONS: The findings from this study suggest that ultrasonic implant site preparation results in a limited decrease of ISQ values and in an earlier shifting from a decreasing to an increasing stability pattern, when compared with the traditional drilling technique. From a clinical point of view, implants inserted with the piezoelectric technique demonstrated a short-term clinical success similar to those inserted using twist drills. PMID- 21682845 TI - Heart rate variability in domestic chicken lines genetically selected on feather pecking behavior. AB - Domestic chicken lines of the White Leghorn type differing in their level of feather pecking were developed by divergent genetic selection specifically on feather pecking behavior. We determined parameters of heart rate variability to elucidate the relative activation of the sympathetic and parasympathetic nervous systems during rest and stressful situations. A total of 48 hens were tested in 8 batches. Segments of 2 min were extracted from electrocardiograms recorded by radio-transmitter implants, before (basal undisturbed conditions) and during physical restraint and a social test. Under basal conditions mean distance between R-waves were shorter in the low and high lines compared to the control. During physical restraint, stress reactions [reduced root of the mean squares of successive differences (RMSSD), reduced high frequency (HF), high low frequency (LF/HF) and low vagal-sympathetic effect (VSE) compared to basal levels] were significant in all lines. During the physical restraint the high feather pecking (HFP) line reacted significantly stronger than control (CON) and low feather pecking (LFP) line. During social test the LFP line reacted different than the other two lines. Seemingly birds from LFP conceived the social test as less stressful than birds from the CON and HFP lines. From this it follows that (1) physical restraint generally induced higher stress reactions than the social test and (2) genetic selection for higher levels of feather pecking increased the autonomic nervous system reaction to physical restraint whereas selection against feather pecking has reduced the response to increased social contact. PMID- 21682846 TI - Near-fatal outcome of late cardiac perforation by a pacemaker lead in a young woman with transposition of the great arteries. AB - We report a case of ventricular perforation by an active-fixation permanent pacemaker lead in a young woman with congenital heart defect and pacemaker because of atrioventricular block. The rarity of the case is based not only upon the late perforation (as opposed to the more common acute perforations) but also on the near-fatal outcome. The patient experienced sharp chest pain and 1 week later passed out with cardiac arrest. PMID- 21682847 TI - Alcohol consumption after laryngectomy. AB - OBJECTIVE: The aim of the study was the analysis of drinking behaviour in laryngectomised patients and its concomitants in quality of life and mental health. STUDY DESIGN: Multi-centered cross-sectional study. PARTICIPANTS AND SETTING: Two hundred and twenty-five laryngectomised patients were asked to participate in the study. One hundred and seventy nine patients (80%) were interviewed after laryngectomy at six different ENT clinics in Germany. MAIN OUTCOME MEASURES: 'Questionnaire of Health Behaviour' (FEG), 'Short Questionnaire of Alcohol Risk', Hospital Anxiety and Depression Scale (HADS), Hornheider Questionnaire (HFB), Visual Analogue Scales (VAS) and the Quality of Life Questionnaires of the European Organization of Research and Treatment of Cancer (EORTC) (EORTC QLQ-C30, EORTC QLQ-H & N35). RESULTS: Alcohol dependence was found in 7% of the patients. Half of the respondents showed a constant consumption of alcohol with 6% of the patients who wanted to change their consumption. Patients with alcohol dependence indicated in comparison with non-dependent persons increased anxiety (p = 0.03), problems in coping with illness (p = 0.03), increased psychosocial care needs (p = 0.02), fatigue (p = 0.04), shortness of breath (p = 0.04), diarrhoea (p = 0.02) and a worse emotional functioning level (p = 0.03). Alcohol intake was independent of tumour stage (p = 0.48), employment status (p = 0.54), social class (p = 0.82), the time interval since laryngectomy (p = 0.64) and type of voice substitute (p = 0.76). The quality of life and mental state were independent of the amount of alcohol consumed. CONCLUSIONS: The results show that alcohol dependence is associated with adverse psychosocial and medical consequences, which require treatment. Socio-demographic and medical parameters do not allow any conclusions to alcoholism risk. Therefore, an individual exploration of the patients' drinking behaviour is needed, which could prepare the ground to specific treatment. PMID- 21682848 TI - Clinical, laboratory and radiologic characteristics of 2009 pandemic influenza A/H1N1 pneumonia: primary influenza pneumonia versus concomitant/secondary bacterial pneumonia. AB - BACKGROUND: Although influenza virus usually involves the upper respiratory tract, pneumonia was seen more frequently with the 2009 pandemic influenza A/H1N1 than with seasonal influenza. METHODS: From September 1, 2009, to January 31, 2010, a specialized clinic for patients (aged >=15 years) with ILI was operated in Korea University Guro Hospital. RT-PCR assay was performed to diagnose 2009 pandemic influenza A/H1N1. A retrospective case-case-control study was performed to determine the predictive factors for influenza pneumonia and to discriminate concomitant/secondary bacterial pneumonia from primary influenza pneumonia during the 2009-2010 pandemic. RESULTS: During the study period, the proportions of fatal cases and pneumonia development were 0.12% and 1.59%, respectively. Patients with pneumonic influenza were less likely to have nasal symptoms and extra-pulmonary symptoms (myalgia, headache, and diarrhea) compared to patients with non-pneumonic influenza. Crackle was audible in just about half of the patients with pneumonic influenza (38.5% of patients with primary influenza pneumonia and 53.3% of patients with concomitant/secondary bacterial pneumonia). Procalcitonin, C-reactive protein (CRP), and lactate dehydrogenase were markedly increased in patients with influenza pneumonia. Furthermore, procalcitonin (cutoff value 0.35 ng/ml, sensitivity 81.8%, and specificity 66.7%) and CRP (cutoff value 86.5 mg/IU, sensitivity 81.8%, and specificity 59.3%) were discriminative between patients with concomitant/secondary bacterial pneumonia and patients with primary influenza pneumonia. CONCLUSIONS: Considering the subtle manifestations of 2009 pandemic influenza A/H1N1 pneumonia in the early stage, high clinical suspicion is required to detect this condition. Both procalcitonin and CRP would be helpful to differentiate primary influenza pneumonia from concomitant/secondary bacterial pneumonia. PMID- 21682849 TI - Interpol: An R package for preprocessing of protein sequences. AB - BACKGROUND: Most machine learning techniques currently applied in the literature need a fixed dimensionality of input data. However, this requirement is frequently violated by real input data, such as DNA and protein sequences, that often differ in length due to insertions and deletions. It is also notable that performance in classification and regression is often improved by numerical encoding of amino acids, compared to the commonly used sparse encoding. RESULTS: The software "Interpol" encodes amino acid sequences as numerical descriptor vectors using a database of currently 532 descriptors (mainly from AAindex), and normalizes sequences to uniform length with one of five linear or non-linear interpolation algorithms. Interpol is distributed with open source as platform independent R-package. It is typically used for preprocessing of amino acid sequences for classification or regression. CONCLUSIONS: The functionality of Interpol widens the spectrum of machine learning methods that can be applied to biological sequences, and it will in many cases improve their performance in classification and regression. PMID- 21682850 TI - Lytic activity of the virion-associated peptidoglycan hydrolase HydH5 of Staphylococcus aureus bacteriophage vB_SauS-phiIPLA88. AB - BACKGROUND: Staphylococcus aureus is a food-borne pathogen and the most common cause of infections in hospitalized patients. The increase in the resistance of this pathogen to antibacterials has made necessary the development of new anti staphylococcal agents. In this context, bacteriophage lytic enzymes such as endolysins and structural peptidoglycan (PG) hydrolases have received considerable attention as possible antimicrobials against gram-positive bacteria. RESULTS: S. aureus bacteriophage vB_SauS-phiIPLA88 (phiIPLA88) contains a virion associated muralytic enzyme (HydH5) encoded by orf58, which is located in the morphogenetic module. Comparative bioinformatic analysis revealed that HydH5 significantly resembled other peptidoglycan hydrolases encoded by staphylococcal phages. The protein consists of 634 amino acid residues. Two putative lytic domains were identified: an N-terminal CHAP (cysteine, histidine-dependent amidohydrolase/peptidase) domain (135 amino acid residues), and a C-terminal LYZ2 (lysozyme subfamily 2) domain (147 amino acid residues). These domains were also found when a predicted three-dimensional structure of HydH5 was made which provided the basis for deletion analysis. The complete HydH5 protein and truncated proteins containing only each catalytic domain were overproduced in E. coli and purified from inclusion bodies by subsequent refolding. Truncated and full-length HydH5 proteins were all able to bind and lyse S. aureus Sa9 cells as shown by binding assays, zymogram analyses and CFU reduction analysis. HydH5 demonstrated high antibiotic activity against early exponential cells, at 45 degrees C and in the absence of divalent cations (Ca2+, Mg2+, Mn2+). Thermostability assays showed that HydH5 retained 72% of its activity after 5 min at 100 degrees C. CONCLUSIONS: The virion-associated PG hydrolase HydH5 has lytic activity against S. aureus, which makes it attractive as antimicrobial for food biopreservation and anti-staphylococcal therapy. PMID- 21682851 TI - Towards patient-specific cardiovascular modeling system using the immersed boundary technique. AB - BACKGROUND: Previous research shows that the flow dynamics in the left ventricle (LV) reveal important information about cardiac health. This information can be used in early diagnosis of patients with potential heart problems. The current study introduces a patient-specific cardiovascular-modelling system (CMS) which simulates the flow dynamics in the LV to facilitate physicians in early diagnosis of patients before heart failure. METHODS: The proposed system will identify possible disease conditions and facilitates early diagnosis through hybrid computational fluid dynamics (CFD) simulation and time-resolved magnetic resonance imaging (4-D MRI). The simulation is based on the 3-D heart model, which can simultaneously compute fluid and elastic boundary motions using the immersed boundary method. At this preliminary stage, the 4-D MRI is used to provide an appropriate comparison. This allows flexible investigation of the flow features in the ventricles and their responses. RESULTS: The results simulate various flow rates and kinetic energy in the diastole and systole phases, demonstrating the feasibility of capturing some of the important characteristics of the heart during different phases. However, some discrepancies exist in the pulmonary vein and aorta flow rate between the numerical and experimental data. Further studies are essential to investigate and solve the remaining problems before using the data in clinical diagnostics. CONCLUSIONS: The results show that by using a simple reservoir pressure boundary condition (RPBC), we are able to capture some essential variations found in the clinical data. Our approach establishes a first-step framework of a practical patient-specific CMS, which comprises a 3-D CFD model (without involving actual hemodynamic data yet) to simulate the heart and the 4-D PC-MRI system. At this stage, the 4-D PC-MRI system is used for verification purpose rather than input. This brings us closer to our goal of developing a practical patient-specific CMS, which will be pursued next. We anticipate that in the future, this hybrid system can potentially identify possible disease conditions in LV through comprehensive analysis and facilitates physicians in early diagnosis of probable cardiac problems. PMID- 21682852 TI - Querying large read collections in main memory: a versatile data structure. AB - BACKGROUND: High Throughput Sequencing (HTS) is now heavily exploited for genome (re-) sequencing, metagenomics, epigenomics, and transcriptomics and requires different, but computer intensive bioinformatic analyses. When a reference genome is available, mapping reads on it is the first step of this analysis. Read mapping programs owe their efficiency to the use of involved genome indexing data structures, like the Burrows-Wheeler transform. Recent solutions index both the genome, and the k-mers of the reads using hash-tables to further increase efficiency and accuracy. In various contexts (e.g. assembly or transcriptome analysis), read processing requires to determine the sub-collection of reads that are related to a given sequence, which is done by searching for some k-mers in the reads. Currently, many developments have focused on genome indexing structures for read mapping, but the question of read indexing remains broadly unexplored. However, the increase in sequence throughput urges for new algorithmic solutions to query large read collections efficiently. RESULTS: Here, we present a solution, named Gk arrays, to index large collections of reads, an algorithm to build the structure, and procedures to query it. Once constructed, the index structure is kept in main memory and is repeatedly accessed to answer queries like "given a k-mer, get the reads containing this k-mer (once/at least once)". We compared our structure to other solutions that adapt uncompressed indexing structures designed for long texts and show that it processes queries fast, while requiring much less memory. Our structure can thus handle larger read collections. We provide examples where such queries are adapted to different types of read analysis (SNP detection, assembly, RNA-Seq). CONCLUSIONS: Gk arrays constitute a versatile data structure that enables fast and more accurate read analysis in various contexts. The Gk arrays provide a flexible brick to design innovative programs that mine efficiently genomics, epigenomics, metagenomics, or transcriptomics reads. The Gk arrays library is available under Cecill (GPL compliant) license from http://www.atgc-montpellier.fr/ngs/. PMID- 21682853 TI - Long-term changes of spine dynamics and microglia after transient peripheral immune response triggered by LPS in vivo. AB - BACKGROUND: An episode of peripheral immune response may create long-lasting alterations in the neural network. Recent studies indicate a glial involvement in synaptic remodeling. Therefore it is postulated that both synaptic and glial changes could occur under the peripheral inflammation. RESULTS: We tested this possibility by in vivo two-photon microscopy of dendritic spines after induction of a peripheral immune response by lipopolysaccharide (LPS) treatment of mice.We observed that the spines were less stable in LPS-treated mice. The accumulation of spine changes gradually progressed and remained low over a week after LPS treatment but became significantly larger at four weeks. Over eight weeks after LPS treatment, the fraction of eliminated spines amounted to 20% of the initial population and this persistent destabilization resulted in a reduction of the total spine density.We next evaluated glial activation by LPS administration. Activation of microglia was confirmed by a persistent increase of Iba1 immunoreactivity. Morphological changes in microglia were observed two days after LPS administration and were partially recovered within one week but sustained over a long time period. CONCLUSIONS: These results indicate long-lasting aggravating effects of a single transient peripheral immune response on both spines and microglia. The parallel persistent alterations of both spine turnover and the state of microglia in vivo suggest the presence of a pathological mechanism that sustains the enhanced remodeling of neural networks weeks after peripheral immune responses. This pathological mechanism may also underlie long lasting cognitive dysfunctions after septic encephalopathy in human patients. PMID- 21682854 TI - Phenotypic and genetic characterization of a cohort of pediatric Wilson disease patients. AB - BACKGROUND: In Egypt, Wilson disease seems to be under diagnosed and clinical data on large cohorts are limited. The aim of this study is to highlight the clinical, laboratory and genetic characteristics of this disease in our pediatric population as well as to report our experience with both treatment options and outcome. METHODS: The study included 77 patients from 50 unrelated families (62 were followed up for a mean period of 58.9 +/- 6.4 months and 27 were asymptomatic siblings). Data were collected retrospectively by record analysis and patient interviews. Diagnosis was confirmed by sequencing of the ATP7B gene in 64 patients. RESULTS: Our patients had unique characteristics compared to other populations. They had a younger age of onset (median: 10 years), higher prevalence of Kayser-Fleischer rings (97.6% in the symptomatic patients), low ceruloplasmin (93.5%), high rate of parental consanguinity (78.9%) as well as a more severe course. 71.42% of those on long term D-penicillamine improved or were stable during the follow up with severe side effects occurring in only 11.5%. Preemptive treatment with zinc monotherapy was an effective non-toxic alternative to D-penicillamine. Homozygous mutations were found in 85.7%, yet limited by the large number of mutations detected, it was difficult to find genotype-phenotype correlations. Missense mutations were the most common while protein-truncating mutations resulted in a more severe course with higher incidence of acute liver failure and neurological symptoms. CONCLUSIONS: Egyptian children with Wilson disease present with early Kayser-Fleischer rings and early onset of liver and neurological disease. The mutational spectrum identified differs from that observed in other countries. The high rate of homozygous mutations (reflecting the high rate of consanguinity) may potentially offer further insights on genotype-phenotype correlation. PMID- 21682855 TI - The cost of emergency hospital admissions for falls on snow and ice in England during winter 2009/10: a cross sectional analysis. AB - BACKGROUND: In the UK, the 2009/10 winter was characterised by sustained low temperatures; grit stocks became depleted and surfaces left untreated. We describe the relationship between temperature and emergency hospital admissions for falls on snow and ice in England, identify the age and gender of those most likely to be admitted, and estimate the inpatient costs of these admissions during the 2009/10 winter. METHODS: Hospital Episode Statistics were used to identify episodes of emergency admissions for falls on snow and ice during winters 2005/06 to 2009/10; these were plotted against mean winter temperature. By region, the logs of the rates of weekly emergency admissions for falls on snow and ice were plotted against the mean weekly temperature for winters 2005/06 to 2009/10 and a linear regression analysis undertaken. For the 2009/10 winter the number of emergency hospital admissions for falls on snow and ice were plotted by age and gender. The inpatient costs of admissions in the 2009/10 winter for falls on snow and ice were calculated using Healthcare Resource Group costs and Admitted Patient Care 2009/10 National Tariff Information. RESULTS: The number of emergency hospital admissions due to falls on snow and ice varied considerably across years; the number was 18 times greater in 2009/10 (N = 16,064) than in 2007/08 (N = 890). There is an exponential increase [Ln(rate of admissions) = 0.456 - 0.463*(mean weekly temperature)] in the rate of emergency hospital admissions for falls on snow and ice as temperature falls. The rate of admissions in 2009/10 was highest among the elderly and particularly men aged 80 and over. The total inpatient cost of falls on snow and ice in the 2009/10 winter was 42 million GBP. CONCLUSIONS: Emergency hospital admissions for falls on snow and ice vary greatly across winters, and according to temperature, age and gender. The cost of these admissions in England in 2009/10 was considerable. With responsibility for health improvement moving to local councils, they will have to balance the cost of public health measures like gritting with the healthcare costs associated with falls. The economic burden of falls on snow and ice is substantial; keeping surfaces clear of snow and ice is a public health priority. PMID- 21682856 TI - Phylogeography and demographic history of Lacerta lepida in the Iberian Peninsula: multiple refugia, range expansions and secondary contact zones. AB - BACKGROUND: The Iberian Peninsula is recognized as an important refugial area for species survival and diversification during the climatic cycles of the Quaternary. Recent phylogeographic studies have revealed Iberia as a complex of multiple refugia. However, most of these studies have focused either on species with narrow distributions within the region or species groups that, although widely distributed, generally have a genetic structure that relates to pre Quaternary cladogenetic events. In this study we undertake a detailed phylogeographic analysis of the lizard species, Lacerta lepida, whose distribution encompasses the entire Iberian Peninsula. We attempt to identify refugial areas, recolonization routes, zones of secondary contact and date demographic events within this species. RESULTS: Results support the existence of 6 evolutionary lineages (phylogroups) with a strong association between genetic variation and geography, suggesting a history of allopatric divergence in different refugia. Diversification within phylogroups is concordant with the onset of the Pleistocene climatic oscillations. The southern regions of several phylogroups show a high incidence of ancestral alleles in contrast with high incidence of recently derived alleles in northern regions. All phylogroups show signs of recent demographic and spatial expansions. We have further identified several zones of secondary contact, with divergent mitochondrial haplotypes occurring in narrow zones of sympatry. CONCLUSIONS: The concordant patterns of spatial and demographic expansions detected within phylogroups, together with the high incidence of ancestral haplotypes in southern regions of several phylogroups, suggests a pattern of contraction of populations into southern refugia during adverse climatic conditions from which subsequent northern expansions occurred. This study supports the emergent pattern of multiple refugia within Iberia but adds to it by identifying a pattern of refugia coincident with the southern distribution limits of individual evolutionary lineages. These areas are important in terms of long-term species persistence and therefore important areas for conservation. PMID- 21682857 TI - Visual recovery in a patient with total hyphema, neovascular glaucoma, long standing retinal detachment and no light perception vision: a case report. AB - INTRODUCTION: We report the case of a patient with total hyphema, neovascular glaucoma, long-standing retinal detachment and no light perception vision, who regained counting fingers vision with complete regression of neovascularization following anterior chamber washout, intravitreal bevacizumab, pars plana vitrectomy, and silicone oil placement. This represents a rare case in which a patient with no light perception vision was able to regain functional vision. CASE PRESENTATION: A 63-year-old Caucasian man with a 55-year history of long standing retinal detachment after trauma presented to our facility with pain and redness, a total hyphema, no light perception vision and an intraocular pressure of 60 mmHg (right eye). He had a history of diabetes mellitus and coronary artery disease. Following anterior chamber washout, he was found to have neovascular glaucoma, for which intravitreal bevacizumab was administered. After washout and intraocular pressure control, his visual acuity improved to light perception. He subsequently underwent vitrectomy, membrane peeling, endolaser and silicone oil placement to reattach his retina, and then a second retinal reattachment procedure. Following these procedures, he had visual recovery to counting fingers vision in his right eye at five metres, complete regression of neovascularization, and intraocular pressure of 10 to 12 mmHg on one antiglaucoma medication. CONCLUSION: Functional vision can be regained despite long-standing retinal detachment. PMID- 21682859 TI - The prevalence of the term subluxation in North American English-Language Doctor of chiropractic programs. AB - BACKGROUND: The subluxation construct has been a divisive term in the chiropractic profession. There is a paucity of evidence to document the subluxation. Some authors have questioned the propriety of continuing to use the term. AIM: The purpose of this study is to examine current North American English language chiropractic college academic catalogs and determine the prevalence of the term subluxation in the respective chiropractic program curricula. METHODS: Sixteen current English-language North American chiropractic college academic catalogs were studied. The term subluxation was searched for in each of the catalogs. Categories were developed for the usage of the term. These included "total times mentioned", "subluxation mentioned in a course description", "subluxation mentioned in a course title", "subluxation mentioned in a technique course description", and "subluxation mentioned in a philosophy course description." The prevalence of the "subluxation mentioned in a course description" was compared to the total programmatic curriculum. RESULTS: Palmer College in Florida devoted 22.72% of its curriculum to courses mentioning the subluxation followed by Life University (Marietta, GA) and Sherman College with 16.44% and 12.80% respectively. As per specific coursework or subjects, an average of 5.22 courses or subjects have descriptions mentioning the term subluxation. Three schools made no mention of the term subluxation in their academic catalogs; they were National University of Health Sciences, Canadian Memorial Chiropractic College, and Southern California University of Health Sciences. CONCLUSION: Despite the controversies and paucity of evidence the term subluxation is still found often within the chiropractic curricula of most North American chiropractic programs. Future research should determine if changes in accreditation standards and research on evidence based practice will affect this prevalence. PMID- 21682858 TI - A comparison of online versus on-site training in health research methodology: a randomized study. AB - BACKGROUND: Distance learning may be useful for building health research capacity. However, evidence that it can improve knowledge and skills in health research, particularly in resource-poor settings, is limited. We compared the impact and acceptability of teaching two distinct content areas, Biostatistics and Research Ethics, through either on-line distance learning format or traditional on-site training, in a randomized study in India. Our objective was to determine whether on-line courses in Biostatistics and Research Ethics could achieve similar improvements in knowledge, as traditional on-site, classroom based courses. METHODS: SUBJECTS: Volunteer Indian scientists were randomly assigned to one of two arms. INTERVENTION: Students in Arm 1 attended a 3.5-day on-site course in Biostatistics and completed a 3.5-week on-line course in Research Ethics. Students in Arm 2 attended a 3.5-week on-line course in Biostatistics and 3.5-day on-site course in Research Ethics. For the two course formats, learning objectives, course contents and knowledge tests were identical. MAIN OUTCOME MEASURES: Improvement in knowledge immediately and 3-months after course completion, compared to baseline. RESULTS: Baseline characteristics were similar in both arms (n = 29 each). Median knowledge score for Biostatistics increased from a baseline of 49% to 64% (p < 0.001) 3 months after the on-site course, and from 48% to 63% (p = 0.009) after the on-line course. For the on-site Research Ethics course, median score increased from 69% to 83% (p = 0.005), and for the on-line Research Ethics course from 62% to 80% (p < 0.001). Three months after the course, median gains in knowledge scores remained similar for the on site and on-line platforms for both Biostatistics (16% vs. 12%; p = 0.59) and Research Ethics (17% vs. 13%; p = 0.14). CONCLUSION: On-line and on-site training formats led to marked and similar improvements of knowledge in Biostatistics and Research Ethics. This, combined with logistical and cost advantages of on-line training, may make on-line courses particularly useful for expanding health research capacity in resource-limited settings. PMID- 21682860 TI - Identification of 11-amino acid peptides that disrupt Notch-mediated processes in Drosophila. AB - BACKGROUND: The conserved Notch signaling pathway regulates cell fate decisions and maintains stem cells in multicellular organisms. Up-regulation of Notch signaling is observed in several types of cancer and is causally involved in proliferation and survival of cancer cells. Thus, it is of great interest to look for anti-Notch reagents for therapeutic purposes. In model animal Drosophila, Notch signaling restricts selection of sensory organ precursors (SOPs) during external sensory (ES) organ development. To look for novel genes that can suppress Notch signaling, we performed a gain-of-function modifier screen to look for genes that enhance the phenotype of ectopic ES organs induced by overexpression of phyllopod, a gene required for SOP specification. RESULTS: From the gain-of-function screen, we discovered that overexpression of polished rice/tarsal-less (pri/tal) increases the numbers of ES organs as well as SOPs. pri/tal is a polycistronic gene that contains four short open reading frames encoding three 11-amino acid and one 32-amino acid peptides. Ectopic expression of the 11 amino-acid peptides recapitulates the pri/tal misexpression phenotype in ectopic ES organ formation. In situ hybridization experiment reveals that pri/tal mRNA is expressed in the SOPs of the chemosensory organs and the stretch sensing chordotonal organs.In Drosophila wing development, the Notch signaling pathway mediates the formation of the dorsal-ventral (DV) compartmental boundary and the restriction of the vein width from the primordial veins, the proveins. We also found that pri/tal mRNA is expressed in the DV boundary and the longitudinal proveins, and overexpression of Pri/Tal peptides disrupts the DV boundary formation and helps to expand the width of the wing vein. Genetic analyses further show that a Notch loss-of-function allele strongly enhances these two phenotypes. Cut and E(spl)mbeta are target genes of the Notch pathway in DV boundary formation and vein specification, respectively. We also found that overexpression of Pri/Tal peptides abolishes Cut expression and co-expression of Pri/Tal peptides with phyl strongly reduces E(spl)mbeta expression. CONCLUSIONS: We show for the first time that the overexpression of Pri/Tal 11-amino acid peptides disrupts multiple Notch-mediated processes and reduces Notch target gene expression in Drosophila, suggesting that these peptides have novel antagonistic activity to the Notch pathway. Thus, our discovery might provide insights into designing new therapeutic reagents for Notch-related diseases. PMID- 21682861 TI - Balancing selection is common in the extended MHC region but most alleles with opposite risk profile for autoimmune diseases are neutrally evolving. AB - BACKGROUND: Several susceptibility genetic variants for autoimmune diseases have been identified. A subset of these polymorphisms displays an opposite risk profile in different autoimmune conditions. This observation open interesting questions on the evolutionary forces shaping the frequency of these alleles in human populations.We aimed at testing the hypothesis whereby balancing selection has shaped the frequency of opposite risk alleles. RESULTS: Since balancing selection signatures are expected to extend over short genomic portions, we focused our analyses on 11 regions carrying putative functional polymorphisms that may represent the disease variants (and the selection targets). No exceptional nucleotide diversity was observed for ZSCAN23, HLA-DMB, VARS2, PTPN22, BAT3, C6orf47, and IL10; summary statistics were consistent with evolutionary neutrality for these gene regions. Conversely, CDSN/PSORS1C1, TRIM10/TRIM40, BTNL2, and TAP2 showed extremely high nucleotide diversity and most tests rejected neutrality, suggesting the action of balancing selection. For TAP2 and BTNL2 these signatures are not secondary to linkage disequilibrium with HLA class II genes. Nonetheless, with the exception of variants in TRIM40 and CDSN, our data suggest that opposite risk SNPs are not selection targets but rather have accumulated as neutral variants. CONCLUSION: Data herein indicate that balancing selection is common within the extended MHC region and involves several non-HLA loci. Yet, the evolutionary history of most SNPs with an opposite effect for autoimmune diseases is consistent with evolutionary neutrality. We suggest that variants with an opposite effect on autoimmune diseases should not be considered a distinct class of disease alleles from the evolutionary perspective and, in a few cases, the opposite effect on distinct diseases may derive from complex haplotype structures in regions with high genetic diversity. PMID- 21682862 TI - A dual adaptive watermarking scheme in contourlet domain for DICOM images. AB - BACKGROUND: Nowadays, medical imaging equipments produce digital form of medical images. In a modern health care environment, new systems such as PACS (picture archiving and communication systems), use the digital form of medical image too. The digital form of medical images has lots of advantages over its analog form such as ease in storage and transmission. Medical images in digital form must be stored in a secured environment to preserve patient privacy. It is also important to detect modifications on the image. These objectives are obtained by watermarking in medical image. METHODS: In this paper, we present a dual and oblivious (blind) watermarking scheme in the contourlet domain. Because of importance of ROI (region of interest) in interpretation by medical doctors rather than RONI (region of non-interest), we propose an adaptive dual watermarking scheme with different embedding strength in ROI and RONI. We embed watermark bits in singular value vectors of the embedded blocks within lowpass subband in contourlet domain. RESULTS: The values of PSNR (peak signal-to-noise ratio) and SSIM (structural similarity measure) index of ROI for proposed DICOM (digital imaging and communications in medicine) images in this paper are respectively larger than 64 and 0.997. These values confirm that our algorithm has good transparency. Because of different embedding strength, BER (bit error rate) values of signature watermark are less than BER values of caption watermark. Our results show that watermarked images in contourlet domain have greater robustness against attacks than wavelet domain. In addition, the qualitative analysis of our method shows it has good invisibility. CONCLUSIONS: The proposed contourlet-based watermarking algorithm in this paper uses an automatically selection for ROI and embeds the watermark in the singular values of contourlet subbands that makes the algorithm more efficient, and robust against noise attacks than other transform domains. The embedded watermark bits can be extracted without the original image, the proposed method has high PSNR and SSIM, and the watermarked image has high transparency and can still conform to the DICOM format. PMID- 21682863 TI - Efficacy and long-term follow-up of IL-1R inhibitor anakinra in adults with Still's disease: a case-series study. AB - INTRODUCTION: To assess the efficacy and safety of the interleukin-1 receptor (IL 1R) inhibitor anakinra in adult patients with refractory Still's disease. METHODS: Twenty-five patients (13 males and 12 females, median age 32 years, median disease duration seven months) with Still's disease were treated with subcutaneous injections of anakinra (100 mg/day). Treatment was given as adjunct therapy in 16 patients and as standalone in 9 patients for a median time of 15 months (range 1.5-71). The clinical and laboratory parameters during follow-up were recorded. RESULTS: In 84% of patients the clinical activity resolved completely within a few days (median time 0.2 months), and response was maintained until the last visit in all but one patient. A complete response of all disease-related symptoms (clinical and laboratory) occurred subsequently within a median time of three months in 80% of patients. A partial clinical and laboratory improvement was shown in 12% and 16% of patients, respectively. The Visualized Analogue Scale and Health Assessment Questionnaire scores significantly decreased during treatment. The proportion of patients achieving the American College of Rheumatology 20 (ACR20) score (20% improvement) was 82% at one month and improved to 100% at one year. The mean oral corticosteroid dose was significantly reduced at each visit. Anakinra was discontinued due to unresponsiveness in one patient and due to relapsing disease in another. Treatment was also withdrawn in three patients with severe skin reactions (urticaria). Seven patients experienced an infection during follow-up. CONCLUSIONS: The rapid and sustained response in the majority of our patients encourages the use of anakinra in adults with Still's disease. PMID- 21682864 TI - COPE-ICD: a randomised clinical trial studying the effects and meaning of a comprehensive rehabilitation programme for ICD recipients -design, intervention and population. AB - BACKGROUND: Growing evidence exists that living with an ICD can lead to fear and avoidance behaviour including the avoidance of physical activity. It has been suggested that psychological stress can increase the risk of shock and predict death. Small studies have indicated a beneficial effect arising from exercise training and psychological intervention, therefore a large-scale rehabilitation programme was set up. METHODS/DESIGN: A mixed methods embedded experimental design was chosen to include both quantitative and qualitative measures. A randomised clinical trial is its primary component. 196 patients (power calculated) were block randomised to either a control group or intervention group at a single centre. The intervention consists of a 1-year psycho-educational component provided by two nurses and a 12-week exercise training component provided by two physiotherapists. Our hypothesis is that the COPE-ICD programme will reduce avoidance behaviour, sexual dysfunction and increase quality of life, increase physical capability, reduce the number of treatment-demanding arrhythmias, reduce mortality and acute re-hospitalisation, reduce sickness leading to absence from work and be cost-effective. A blinded investigator will perform all physical tests and data collection. DISCUSSION: Most participants are men (79%) with a mean age of 58 (range 20-85). Most ICD implantations are on primary prophylactic indication (66%). 44% is NYHA II. Mean walk capacity (6MWT) is 417 m. Mean perception of General Health (SF-36) is PCS 42.6 and MCS 47.1.A large-scale ICD rehabilitation trial including psycho-educational intervention and exercise training has been initiated and will report findings starting in 2011. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00569478. PMID- 21682865 TI - Immobilized Rhizopus oryzae lipase catalyzed synthesis of palm stearin and cetyl alcohol wax esters: optimization by response surface methodology. AB - BACKGROUND: Waxes are esters of long-chain fatty acids and long-chain alcohols. Their principal natural sources are animals (sperm whale oil) and vegetables (jojoba) which are expensive and not easily available. Wax esters synthesized by enzymatic transesterification, using palm stearin as raw material, can be considered as an alternative to natural ones. RESULTS: Palm stearin is a solid fraction obtained by fractionation of palm oil. Palm stearin was esterified with cetyl alcohol to produce a mixture of wax esters. A non-commercial immobilized lipase from Rhizopus oryzae was used as biocatalyst. Response surface methodology was employed to determine the effects of the temperature (30-50 degrees C), the enzyme concentration (33.34-300 IU/mL), the alcohol/palm stearin molar ratio (3-7 mol/mol) and the substrate concentration (0.06-0.34 g/mL) on the conversion yield of palm stearin. Under optimal conditions (temperature, 30 degrees C; enzyme concentration, 300 IU/mL; molar ratio 3 and substrate concentration 0.21 g/mL) a high conversion yield of 98.52% was reached within a reaction time of 2 h. CONCLUSIONS: Response surface methodology was successfully applied to determine the optimum operational conditions for synthesis of palm stearin based wax esters. This study may provide useful tools to develop economical and efficient processes for the synthesis of wax esters. PMID- 21682866 TI - Anti-Inflammatory mechanisms of the proteinase-activated receptor 2-inhibiting peptide in human synovial cells. AB - BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease which affects the entire joint structure, including the synovial membrane. Disease progression was shown to involve inflammatory changes mediated by proteinase-activated receptor (PAR)-2. Previous studies demonstrated that PAR-2 messenger (m)RNA and protein levels increased in OA synovial cells, suggesting that PAR-2 is a potential therapeutic target of the disease. METHODS: We designed a PAR-2-inhibiting peptide (PAR2-IP) by changing an isoleucine residue in the PAR-2-activating peptide (PAR2-AP), SLIGKV, to alanine, generating the SLAGKV peptide. We used it to test PAR-2-mediated inflammatory responses, including the expressions of cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-1 and activation of nuclear factor (NF)-kappaB in human synovial cells. As a control, expressions of COX-2 and MMP-1 were induced by trypsin at both the mRNA and protein levels. RESULTS: The PAR2-AP increased the expression of COX-2 more dramatically than that of MMP-1. When we treated cells with the designed PAR2-IP, the trypsin induced COX-2 level was completely inhibited at a moderate concentration of the PAR2-IP. With further examination of trypsin-induced NF-kappaB activation, we observed sufficient inhibitory effects of the PAR2-IP in synoviosarcoma cells and primary synovial cells from OA patients. CONCLUSIONS: Our study suggests that the PAR2-IP inhibits trypsin-induced NF-kappaB activation, resulting in a reduction in inflammatory COX-2 expression in synovial cells. Application of PAR2-IP is suggested as a potential therapeutic strategy for OA. PMID- 21682868 TI - Plasma intact fibroblast growth factor 23 levels in women with bulimia nervosa: A cross-sectional pilot study. AB - Fibroblast growth factor (FGF) 23, a circulating 26-kDa peptide produced by osteogenic cells, is a novel phosphaturic factor. In our previous study, binge eating/purging type anorexia nervosa (AN-BP) patients had elevated plasma intact FGF23 (iFGF23) levels, while restricting type (AN-R) patients had plasma iFGF23 levels similar to healthy controls. Although bulimia nervosa (BN) patients as well as some patients with AN-BP regularly engage in binge eating, there have been no studies regarding plasma iFGF23 levels in BN patients. Therefore, this study was performed to determine plasma iFGF23 concentrations in BN patients and healthy controls. The study population consisted of 13 female BN patients and 11 healthy female controls. Blood samples were collected from all subjects after overnight fasting. Plasma iFGF23 was measured using an ELISA kit in a cross sectional manner. The two-tailed Mann-Whitney U-test was used to assess differences between BN patients and healthy controls. In addition, BN patients were divided into two groups based on questionnaire-reported binge eating frequency immediately prior to participation in this study: high frequency of binge eating (once a week or more; HF group; n = 8) and low frequency of binge eating (less than once a week; LF group; n = 5). Two-tailed Mann-Whitney U-test with Bonferroni's correction was performed after the Kruskal-Wallis test to assess differences between HF group, LF group, and healthy controls. Median (quartiles) plasma iFGF23 levels were greater in BN patients (35.5 [14.8-65.0] pg/ml) than in controls (3.8 [not detected-5.3] pg/ml; p = 0.002). In addition, median (quartiles) plasma iFGF23 levels were greater in the HF group (62.3 [44.4 73.4] pg/ml) than in controls (p < 0.001) and in the LF group (12.9 [not detected 30.3] pg/ml; p = 0.011), while there were no differences between the LF group and controls (p = 0.441). This is the first study to show that BN patients have elevated plasma iFGF23 levels. Moreover, this study showed that BN patients with a high frequency of binge eating have elevated plasma iFGF23 levels, while iFGF23 levels are similar to healthy controls in those with a low frequency of binge eating. Plasma iFGF23 level may be a suitable indicator of binge eating in BN patients. PMID- 21682867 TI - Best practice for motor imagery: a systematic literature review on motor imagery training elements in five different disciplines. AB - BACKGROUND: The literature suggests a beneficial effect of motor imagery (MI) if combined with physical practice, but detailed descriptions of MI training session (MITS) elements and temporal parameters are lacking. The aim of this review was to identify the characteristics of a successful MITS and compare these for different disciplines, MI session types, task focus, age, gender and MI modification during intervention. METHODS: An extended systematic literature search using 24 databases was performed for five disciplines: Education, Medicine, Music, Psychology and Sports. References that described an MI intervention that focused on motor skills, performance or strength improvement were included. Information describing 17 MITS elements was extracted based on the PETTLEP (physical, environment, timing, task, learning, emotion, perspective) approach. Seven elements describing the MITS temporal parameters were calculated: study duration, intervention duration, MITS duration, total MITS count, MITS per week, MI trials per MITS and total MI training time. RESULTS: Both independent reviewers found 96% congruity, which was tested on a random sample of 20% of all references. After selection, 133 studies reporting 141 MI interventions were included. The locations of the MITS and position of the participants during MI were task-specific. Participants received acoustic detailed MI instructions, which were mostly standardised and live. During MI practice, participants kept their eyes closed. MI training was performed from an internal perspective with a kinaesthetic mode. Changes in MI content, duration and dosage were reported in 31 MI interventions. Familiarisation sessions before the start of the MI intervention were mentioned in 17 reports. MI interventions focused with decreasing relevance on motor-, cognitive- and strength-focused tasks. Average study intervention lasted 34 days, with participants practicing MI on average three times per week for 17 minutes, with 34 MI trials. Average total MI time was 178 minutes including 13 MITS. Reporting rate varied between 25.5% and 95.5%. CONCLUSIONS: MITS elements of successful interventions were individual, supervised and non-directed sessions, added after physical practice. Successful design characteristics were dominant in the Psychology literature, in interventions focusing on motor and strength-related tasks, in interventions with participants aged 20 to 29 years old, and in MI interventions including participants of both genders. Systematic searching of the MI literature was constrained by the lack of a defined MeSH term. PMID- 21682869 TI - Exercise Training in Pregnancy for obese women (ETIP): study protocol for a randomised controlled trial. AB - BACKGROUND: Both maternal pre-pregnancy obesity and excessive gestational weight gain are increasing in prevalence and associated with a number of adverse pregnancy outcomes for both mother and child. Observational studies regarding physical activity in pregnancy have found reduced weight gain in active mothers, as well as reduced risk of adverse pregnancy outcomes. There is however a lack of high quality, randomized controlled trials on the effects of regular exercise training in pregnancy, especially those with a pre-pregnancy body mass index (BMI) at or above 30 kg/m2. METHODS: We are conducting a randomised, controlled trial in Norway with two parallel arms; one intervention group and one control group. We will enroll 150 previously sedentary, pregnant women with a pre pregnancy BMI at or above 30 kg/m2. The intervention group will meet for organized exercise training three times per week, starting in gestation week 14 (range 12-16). The control group will get standard antenatal care. The main outcome measure will be weight gain from baseline to delivery. Among the secondary outcome measures are changes in exercise capacity, endothelial function, physical activity level, body composition, serum markers of cardiovascular risk, incontinence, lumbopelvic pain and cardiac function from baseline to gestation week 37 (range 36-38). Offspring outcome measures include anthropometric variables at birth, Apgar score, as well as serum markers of inflammation and metabolism in cord blood. DISCUSSION: The results of this trial will provide knowledge about effects of regular exercise training in previously sedentary, obese pregnant women. If the program proves effective in reducing gestational weight gain and adverse pregnancy outcomes, such programs should be considered as part of routine pregnancy care for obese women. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01243554. PMID- 21682870 TI - The Global Evidence Mapping Initiative: scoping research in broad topic areas. AB - BACKGROUND: Evidence mapping describes the quantity, design and characteristics of research in broad topic areas, in contrast to systematic reviews, which usually address narrowly-focused research questions. The breadth of evidence mapping helps to identify evidence gaps, and may guide future research efforts. The Global Evidence Mapping (GEM) Initiative was established in 2007 to create evidence maps providing an overview of existing research in Traumatic Brain Injury (TBI) and Spinal Cord Injury (SCI). METHODS: The GEM evidence mapping method involved three core tasks:1. Setting the boundaries and context of the map: Definitions for the fields of TBI and SCI were clarified, the prehospital, acute inhospital and rehabilitation phases of care were delineated and relevant stakeholders (patients, carers, clinicians, researchers and policymakers) who could contribute to the mapping were identified. Researchable clinical questions were developed through consultation with key stakeholders and a broad literature search. 2. Searching for and selection of relevant studies: Evidence search and selection involved development of specific search strategies, development of inclusion and exclusion criteria, searching of relevant databases and independent screening and selection by two researchers. 3. Reporting on yield and study characteristics: Data extraction was performed at two levels - 'interventions and study design' and 'detailed study characteristics'. The evidence map and commentary reflected the depth of data extraction. RESULTS: One hundred and twenty-nine researchable clinical questions in TBI and SCI were identified. These questions were then prioritised into high (n = 60) and low (n = 69) importance by the stakeholders involved in question development. Since 2007, 58 263 abstracts have been screened, 3 731 full text articles have been reviewed and 1 644 relevant neurotrauma publications have been mapped, covering fifty-three high priority questions. CONCLUSIONS: GEM Initiative evidence maps have a broad range of potential end-users including funding agencies, researchers and clinicians. Evidence mapping is at least as resource-intensive as systematic reviewing. The GEM Initiative has made advancements in evidence mapping, most notably in the area of question development and prioritisation. Evidence mapping complements other review methods for describing existing research, informing future research efforts, and addressing evidence gaps. PMID- 21682871 TI - Time-of-day dependence of neurological deficits induced by sodium nitroprusside in young mice. AB - Sodium nitroprusside (SNP) is widely used in pharmacological studies as a potent vasodilator or a nitric oxide donor. SNP-induced ataxic effects were assessed in mice by the Joulou-Couvoisier test. Swiss albino mice of both genders, 2-8 weeks of age, were acclimated at least for 2 weeks to 12 h light (rest span)/12 h dark (activity span). In 2 and 4 week old mice, maxima of ataxia were found following intraperitoneal administration of a dose ranging from 3 to 3.6 mg.kg-1 SNP at ~ 1 and 13 HALO (Hours After Light Onset). The sublethal toxicity was statistically dosing-time dependent (chi2 test: P < 0.005). No rhythm was validated in neurotoxicity by cosinor analyses. At the 8th week of post-natal development (PND), SNP-induced ataxia was greatest at ~ 1 HALO (69% in males vs. 49% in females) and lowest at ~ 13 HALO (21% in males vs. 11% in females) (chi2 test: P < 0.00001). Cosinor analysis also revealed no statistically significant rhythm in mice injected with 3 or 3.3 mg.kg-1. However, a significant circadian (tau = 24 h) rhythm was detected by adjusted cosinor in 3.6 mg.kg-1-treated mice (P < 0.004). In all studied groups, SNP-induced motor impairment (expressed in %) was lower during the dark than the light phase. Furthermore, there was a non significant gender-related difference in SNP-induced neuronal toxicity with the males more sensitive than females at every studied PND. The ataxic effects were inversely proportional to the lag time from injection and to the age of animals (with P < 0.05 only between 2 and 8 week old mice). These data indicate that both the administration time and age of the animal significantly affect the neurotoxic effects of SNP. PMID- 21682872 TI - Including the urban heat island in spatial heat health risk assessment strategies: a case study for Birmingham, UK. AB - BACKGROUND: Heatwaves present a significant health risk and the hazard is likely to escalate with the increased future temperatures presently predicted by climate change models. The impact of heatwaves is often felt strongest in towns and cities where populations are concentrated and where the climate is often unintentionally modified to produce an urban heat island effect; where urban areas can be significantly warmer than surrounding rural areas. The purpose of this interdisciplinary study is to integrate remotely sensed urban heat island data alongside commercial social segmentation data via a spatial risk assessment methodology in order to highlight potential heat health risk areas and build the foundations for a climate change risk assessment. This paper uses the city of Birmingham, UK as a case study area. RESULTS: When looking at vulnerable sections of the population, the analysis identifies a concentration of "very high" risk areas within the city centre, and a number of pockets of "high risk" areas scattered throughout the conurbation. Further analysis looks at household level data which yields a complicated picture with a considerable range of vulnerabilities at a neighbourhood scale. CONCLUSIONS: The results illustrate that a concentration of "very high" risk people live within the urban heat island, and this should be taken into account by urban planners and city centre environmental managers when considering climate change adaptation strategies or heatwave alert schemes. The methodology has been designed to be transparent and to make use of powerful and readily available datasets so that it can be easily replicated in other urban areas. PMID- 21682873 TI - Hypericum lanceolatum (Hypericaceae) as a potential source of new anti-malarial agents: a bioassay-guided fractionation of the stem bark. AB - BACKGROUND: Malaria is a major public health threat in Africa, and traditional medicine continues to play a key role in its control especially in rural areas. A bioassay-guided fractionation was carried out in order to evaluate the anti malarial potential and the safety of the methanol extract of the Hypericum lanceolatum stem bark. METHODS: The anti-plasmodial activity was assayed by the lactate dehydrogenase method (pLDH) against the multidrug-resistant W2mef laboratory strain, and a field isolate (SHF4) of Plasmodium falciparum. Cytotoxicity tests were carried out using the LLC-MK2 monkey kidney epithelial cells. RESULTS: Five compounds were isolated from the most active and least cytotoxic ethylacetate sub-extract: betulinic acid (HLT1), 2,2',5,6' tetrahydroxybenzophenone (HLT2), 5-hydroxy-3-methoxyxanthone (HLT3), 3-hydroxy-5 methoxyxanthone (HLT4) and HLT0 (yet to be identified). Three of the tested compounds presented significant anti-plasmodial activities (with 50% inhibitory concentration, IC50 < 5 MUM), with 5-hydroxy-3-methoxyxanthone exerting the highest activity, followed by HLT0 and betulinic acid. All the compounds with significant anti-plasmodial activity were non-cytotoxic, except betulinic acid which showed a 50% cytotoxic concentration, CC50 of 25 MUg/mL. CONCLUSIONS: These findings justify the use of H. lanceolatum stem bark as anti-malarial by traditional healers of Western Cameroon, and could constitute a good basis for further studies towards development of new drug candidates or phytomedicines for malaria. PMID- 21682874 TI - Phylogeography of Francisella tularensis subspecies holarctica from the country of Georgia. AB - BACKGROUND: Francisella tularensis, the causative agent of tularemia, displays subspecies-specific differences in virulence, geographic distribution, and genetic diversity. F. tularensis subsp. holarctica is widely distributed throughout the Northern Hemisphere. In Europe, F. tularensis subsp. holarctica isolates have largely been assigned to two phylogenetic groups that have specific geographic distributions. Most isolates from Western Europe are assigned to the B.Br.FTNF002-00 group, whereas most isolates from Eastern Europe are assigned to numerous lineages within the B.Br.013 group. The eastern geographic extent of the B.Br.013 group is currently unknown due to a lack of phylogenetic knowledge about populations at the European/Asian juncture and in Asia. In this study, we address this knowledge gap by describing the phylogenetic structure of F. tularensis subsp. holarctica isolates from the country of Georgia, and by placing these isolates into a global phylogeographic context. RESULTS: We identified a new genetic lineage of F. tularensis subsp. holarctica from Georgia that belongs to the B.Br.013 group. This new lineage is genetically and geographically distinct from lineages previously described from the B.Br.013 group from Central-Eastern Europe. Importantly, this new lineage is basal within the B.Br.013 group, indicating the Georgian lineage diverged before the diversification of the other known B.Br.013 lineages. Although two isolates from the Georgian lineage were collected nearby in the Ukrainian region of Crimea, all other global isolates assigned to this lineage were collected in Georgia. This restricted geographic distribution, as well as the high levels of genetic diversity within the lineage, is consistent with a relatively older origin and localized differentiation. CONCLUSIONS: We identified a new lineage of F. tularensis subsp. holarctica from Georgia that appears to have an older origin than any other diversified lineages previously described from the B.Br.013 group. This finding suggests that additional phylogenetic studies of F. tularensis subsp. holarctica populations in Eastern Europe and Asia have the potential to yield important new insights into the evolutionary history and phylogeography of this broadly dispersed F. tularensis subspecies. PMID- 21682875 TI - Evaluation of two methods of estimating larval habitat productivity in western Kenya highlands. AB - BACKGROUND: Malaria vector intervention and control programs require reliable and accurate information about vector abundance and their seasonal distribution. The availability of reliable information on the spatial and temporal productivity of larval vector habitats can improve targeting of larval control interventions and our understanding of local malaria transmission and epidemics. The main objective of this study was to evaluate two methods of estimating larval habitat productivity in the western Kenyan highlands, the aerial sampler and the emergence trap. METHODS: The study was conducted during the dry and rainy seasons in 2008, 2009 and 2010. Aerial samplers and emergence traps were set up for sixty days in each season in three habitat types: drainage ditches, natural swamps, and abandoned goldmines. Aerial samplers and emergence traps were set up in eleven places in each habitat type. The success of each in estimating habitat productivity was assessed according to method, habitat type, and season. The effect of other factors including algae cover, grass cover, habitat depth and width, and habitat water volume on species productivity was analysed using stepwise logistic regression RESULTS: Habitat productivity estimates obtained by the two sampling methods differed significantly for all species except for An. implexus. For for An. gambiae s.l. and An. funestus, aerial samplers performed better, 21.5 and 14.6 folds, than emergence trap respectively, while the emergence trap was shown to be more efficient for culicine species. Seasonality had a significant influence on the productivity of all species monitored. Dry season was most productive season. Overall, drainage ditches had significantly higher productivity in all seasons compared to other habitat types. Algae cover, debris, chlorophyll-a, and habitat depth and size had significant influence with respect to species. CONCLUSION: These findings suggest that the aerial sampler is the better of the two methods for estimating the productivity of An. gambiae s.l. and An. funestus in the western Kenya highlands and possibly other malaria endemic parts of Africa. This method has proven to be a useful tool for monitoring malaria vector populations and for control program design, and provides useful means for determining the most suitable sites for targeted interventions. PMID- 21682876 TI - Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland. AB - BACKGROUND: Kallmann syndrome (KS), comprised of congenital hypogonadotropic hypogonadism (HH) and anosmia, is a clinically and genetically heterogeneous disorder. Its exact incidence is currently unknown, and a mutation in one of the identified KS genes has only been found in ~30% of the patients. METHODS: Herein, we investigated epidemiological, clinical, and genetic features of KS in Finland. RESULTS: The minimal incidence estimate of KS in Finland was 1:48 000, with clear difference between males (1:30 000) and females (1:125 000) (p = 0.02). The reproductive phenotype of 30 probands (25 men; 5 women) ranged from severe HH to partial puberty. Comprehensive mutation analysis of all 7 known KS genes (KAL1, FGFR1, FGF8, PROK2, PROKR2, CHD7, and WDR11) in these 30 well-phenotyped probands revealed mutations in KAL1 (3 men) and FGFR1 (all 5 women vs. 4/25 men), but not in other genes. CONCLUSIONS: Our results suggest that Finnish KS men harbor mutations in gene(s) yet-to-be discovered with sex-dependent penetrance of the disease phenotype. In addition, some KS patients without CHD7 mutations display CHARGE-syndrome associated phenotypic features (e.g. ear or eye anomalies), possibly implying that, in addition to CHD7, there may be other genes associated with phenotypes ranging from KS to CHARGE. PMID- 21682877 TI - Mature autologous dendritic cell vaccines in advanced non-small cell lung cancer: a phase I pilot study. AB - BACKGROUND: Overall therapeutic outcomes of advanced non-small-cell lung cancer (NSCLC) are poor. The dendritic cell (DC) immunotherapy has been developed as a new strategy for the treatment of lung cancer. The purpose of this study was to evaluate the feasibility, safety and immunologic responses in use in mature, antigen-pulsed autologous DC vaccine in NSCLC patients. METHODS: Five HLA-A2 patients with inoperable stage III or IV NSCLC were selected to receive two doses of 5 * 107 DC cells administered subcutaneous and intravenously two times at two week intervals. The immunologic response, safety and tolerability to the vaccine were evaluated by the lymphoproliferation assay and clinical and laboratorial evolution, respectively. RESULTS: The dose of the vaccine has shown to be safe and well tolerated. The lymphoproliferation assay showed an improvement in the specific immune response after the immunization, with a significant response after the second dose (p = 0.005). This response was not long lasting and a tendency to reduction two weeks after the second dose of the vaccine was observed. Two patients had a survival almost twice greater than the expected average and were the only ones that expressed HER-2 and CEA together. CONCLUSION: Despite the small sample size, the results on the immune response, safety and tolerability, combined with the results of other studies, are encouraging to the conduction of a large clinical trial with multiples doses in patients with early lung cancer who underwent surgical treatment. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN45563569. PMID- 21682878 TI - Identifying subtypes of patients with neovascular age-related macular degeneration by genotypic and cardiovascular risk characteristics. AB - BACKGROUND: One of the challenges in the interpretation of studies showing associations between environmental and genotypic data with disease outcomes such as neovascular age-related macular degeneration (AMD) is understanding the phenotypic heterogeneity within a patient population with regard to any risk factor associated with the condition. This is critical when considering the potential therapeutic response of patients to any drug developed to treat the condition. In the present study, we identify patient subtypes or clusters which could represent several different targets for treatment development, based on genetic pathways in AMD and cardiovascular pathology. METHODS: We identified a sample of patients with neovascular AMD, that in previous studies had been shown to be at elevated risk for the disease through environmental factors such as cigarette smoking and genetic variants including the complement factor H gene (CFH) on chromosome 1q25 and variants in the ARMS2/HtrA serine peptidase 1 (HTRA1) gene(s) on chromosome 10q26. We conducted a multivariate segmentation analysis of 253 of these patients utilizing available epidemiologic and genetic data. RESULTS: In a multivariate model, cigarette smoking failed to differentiate subtypes of patients. However, four meaningfully distinct clusters of patients were identified that were most strongly differentiated by their cardiovascular health status (histories of hypercholesterolemia and hypertension), and the alleles of ARMS2/HTRA1 rs1049331. CONCLUSIONS: These results have significant personalized medicine implications for drug developers attempting to determine the effective size of the treatable neovascular AMD population. Patient subtypes or clusters may represent different targets for therapeutic development based on genetic pathways in AMD and cardiovascular pathology, and treatments developed that may elevate CV risk, may be ill advised for certain of the clusters identified. PMID- 21682879 TI - RegNetB: predicting relevant regulator-gene relationships in localized prostate tumor samples. AB - BACKGROUND: A central question in cancer biology is what changes cause a healthy cell to form a tumor. Gene expression data could provide insight into this question, but it is difficult to distinguish between a gene that causes a change in gene expression from a gene that is affected by this change. Furthermore, the proteins that regulate gene expression are often themselves not regulated at the transcriptional level. Here we propose a Bayesian modeling framework we term RegNetB that uses mechanistic information about the gene regulatory network to distinguish between factors that cause a change in expression and genes that are affected by the change. We test this framework using human gene expression data describing localized prostate cancer progression. RESULTS: The top regulatory relationships identified by RegNetB include the regulation of RLN1, RLN2, by PAX4, the regulation of ACPP (PAP) by JUN, BACH1 and BACH2, and the co-regulation of PGC and GDF15 by MAZ and TAF8. These target genes are known to participate in tumor progression, but the suggested regulatory roles of PAX4, BACH1, BACH2, MAZ and TAF8 in the process is new. CONCLUSION: Integrating gene expression data and regulatory topologies can aid in identifying potentially causal mechanisms for observed changes in gene expression. PMID- 21682881 TI - Substrate texture properties induce triatomine probing on bitten warm surfaces. AB - BACKGROUND: In this work we initially evaluated whether the biting process of Rhodnius prolixus relies on the detection of mechanical properties of the substrate. A linear thermal source was used to simulate the presence of a blood vessel under the skin of a host. This apparatus consisted of an aluminium plate and a nickel-chrome wire, both thermostatized and presented at 33 and 36 degrees C, respectively. To evaluate whether mechanical properties of the substrate affect the biting behaviour of bugs, this apparatus was covered by a latex membrane. Additionally, we evaluated whether the expression of probing depends on the integration of bilateral thermal inputs from the antennae. RESULTS: The presence of a latex cover on a thermal source induced a change in the biting pattern shown by bugs. In fact, with latex covered sources it was possible to observe long bites that were never performed in response to warm metal surfaces. The total number of bites was higher in intact versus unilaterally antennectomized insects. These bites were significantly longer in intact than in unilaterally antennectomized insects. CONCLUSIONS: Our results suggest that substrate recognition by simultaneous input through thermal and mechanical modalities is required for triggering maxillary probing activity. PMID- 21682880 TI - Novel gene expression responses in the ovine abomasal mucosa to infection with the gastric nematode Teladorsagia circumcincta. AB - Infection of sheep with the gastric nematode Teladorsagia circumcincta results in distinct Th2-type changes in the mucosa, including mucous neck cell and mast cell hyperplasia, eosinophilia, recruitment of IgA/IgE producing cells and neutrophils, altered T-cell subsets and mucosal hypertrophy. To address the protective mechanisms generated in animals on previous exposure to this parasite, gene expression profiling was carried out using samples of abomasal mucosa collected pre- and post- challenge from animals of differing immune status, using an experimental model of T. circumcincta infection. Recently developed ovine cDNA arrays were used to compare the abomasal responses of sheep immunised by trickle infection with worm-naive sheep, following a single oral challenge of 50 000 T. circumcincta L3. Key changes were validated using qRT-PCR techniques. Immune animals demonstrated highly significant increases in levels of transcripts normally associated with cytotoxicity such as granulysin and granzymes A, B and H, as well as mucous-cell derived transcripts, predominantly calcium-activated chloride channel 1 (CLCA1). Challenge infection also induced up-regulation of transcripts potentially involved in initiating or modulating the immune response, such as heat shock proteins, complement factors and the chemokine CCL2. In contrast, there was marked infection-associated down-regulation of gene expression of members of the gastric lysozyme family. The changes in gene expression levels described here may reflect roles in direct anti-parasitic effects, immuno-modulation or tissue repair. PMID- 21682882 TI - Expressed sequence tags from Atta laevigata and identification of candidate genes for the control of pest leaf-cutting ants. AB - BACKGROUND: Leafcutters are the highest evolved within Neotropical ants in the tribe Attini and model systems for studying caste formation, labor division and symbiosis with microorganisms. Some species of leafcutters are agricultural pests controlled by chemicals which affect other animals and accumulate in the environment. Aiming to provide genetic basis for the study of leafcutters and for the development of more specific and environmentally friendly methods for the control of pest leafcutters, we generated expressed sequence tag data from Atta laevigata, one of the pest ants with broad geographic distribution in South America. RESULTS: The analysis of the expressed sequence tags allowed us to characterize 2,006 unique sequences in Atta laevigata. Sixteen of these genes had a high number of transcripts and are likely positively selected for high level of gene expression, being responsible for three basic biological functions: energy conservation through redox reactions in mitochondria; cytoskeleton and muscle structuring; regulation of gene expression and metabolism. Based on leafcutters lifestyle and reports of genes involved in key processes of other social insects, we identified 146 sequences potential targets for controlling pest leafcutters. The targets are responsible for antixenobiosis, development and longevity, immunity, resistance to pathogens, pheromone function, cell signaling, behavior, polysaccharide metabolism and arginine kynase activity. CONCLUSION: The generation and analysis of expressed sequence tags from Atta laevigata have provided important genetic basis for future studies on the biology of leaf cutting ants and may contribute to the development of a more specific and environmentally friendly method for the control of agricultural pest leafcutters. PMID- 21682883 TI - Blocking premature reverse transcription fails to rescue the HIV-1 nucleocapsid mutant replication defect. AB - BACKGROUND: The nucleocapsid (NC) protein of HIV-1 is critical for viral replication. Mutational analyses have demonstrated its involvement in viral assembly, genome packaging, budding, maturation, reverse transcription, and integration. We previously reported that two conservative NC mutations, His23Cys and His44Cys, cause premature reverse transcription such that mutant virions contain approximately 1,000-fold more DNA than wild-type virus, and are replication defective. In addition, both mutants show a specific defect in integration after infection. RESULTS: In the present study we investigated whether blocking premature reverse transcription would relieve the infectivity defects, which we successfully performed by transfecting proviral plasmids into cells cultured in the presence of high levels of reverse transcriptase inhibitors. After subsequent removal of the inhibitors, the resulting viruses showed no significant difference in single-round infective titer compared to viruses where premature reverse transcription did occur; there was no rescue of the infectivity defects in the NC mutants upon reverse transcriptase inhibitor treatment. Surprisingly, time-course endogenous reverse transcription assays demonstrated that the kinetics for both the NC mutants were essentially identical to wild-type when premature reverse transcription was blocked. In contrast, after infection of CD4+ HeLa cells, it was observed that while the prevention of premature reverse transcription in the NC mutants resulted in lower quantities of initial reverse transcripts, the kinetics of reverse transcription were not restored to that of untreated wild-type HIV-1. CONCLUSIONS: Premature reverse transcription is not the cause of the replication defect but is an independent side-effect of the NC mutations. PMID- 21682884 TI - Immunohistochemical detection and regulation of alpha5 nicotinic acetylcholine receptor (nAChR) subunits by FoxA2 during mouse lung organogenesis. AB - BACKGROUND: alpha5 nicotinic acetylcholine receptor (nAChR) subunits structurally stabilize functional nAChRs in many non-neuronal tissue types. The expression of alpha5 nAChR subunits and cell-specific markers were assessed during lung morphogenesis by co-localizing immunohistochemistry from embryonic day (E) 13.5 to post natal day (PN) 20. Transcriptional control of alpha5 nAChR expression by FoxA2 and GATA-6 was determined by reporter gene assays. RESULTS: Steady expression of alpha5 nAChR subunits was observed in distal lung epithelial cells during development while proximal lung expression significantly alternates between abundant prenatal expression, absence at PN4 and PN10, and a return to intense expression at PN20. alpha5 expression was most abundant on luminal edges of alveolar type (AT) I and ATII cells, non-ciliated Clara cells, and ciliated cells in the proximal lung at various periods of lung formation. Expression of alpha5 nAChR subunits correlated with cell differentiation and reporter gene assays suggest expression of alpha5 is regulated in part by FoxA2, with possible cooperation by GATA-6. CONCLUSIONS: Our data reveal a highly regulated temporal spatial pattern of alpha5 nAChR subunit expression during important periods of lung morphogenesis. Due to specific regulation by FoxA2 and distinct identification of alpha5 in alveolar epithelium and Clara cells, future studies may identify possible mechanisms of cell differentiation and lung homeostasis mediated at least in part by alpha5-containing nAChRs. PMID- 21682885 TI - Understanding managerial behaviour during initial steps of a clinical information system adoption. AB - BACKGROUND: While the study of the information technology (IT) implementation process and its outcomes has received considerable attention, the examination of pre-adoption and pre-implementation stages of configurable IT uptake appear largely under-investigated. This paper explores managerial behaviour during the periods prior the effective implementation of a clinical information system (CIS) by two Canadian university multi-hospital centers. METHODS: Adopting a structurationist theoretical stance and a case study research design, the processes by which CIS managers' patterns of discourse contribute to the configuration of the new technology in their respective organizational contexts were longitudinally examined over 33 months. RESULTS: Although managers seemed to be aware of the risks and organizational impact of the adoption of a new clinical information system, their decisions and actions over the periods examined appeared rather to be driven by financial constraints and power struggles between different groups involved in the process. Furthermore, they largely emphasized technological aspects of the implementation, with organizational dimensions being put aside. In view of these results, the notion of 'rhetorical ambivalence' is proposed. Results are further discussed in relation to the significance of initial decisions and actions for the subsequent implementation phases of the technology being configured. CONCLUSIONS: Theoretical and empirically grounded, the paper contributes to the underdeveloped body of literature on information system pre-implementation processes by revealing the crucial role played by managers during the initial phases of a CIS adoption. PMID- 21682886 TI - Sociodemographic gradients in breast and cervical cancer screening in Korea: the Korean National Cancer Screening Survey (KNCSS) 2005-2009. AB - BACKGROUND: Cancer screening rates in Korea for five cancer types have increased steadily since 2002. With regard to the life-time cancer screening rates in 2009 according to cancer sites, the second highest was breast cancer (78.1%) and the third highest was cervical cancer (76.1%). Despite overall increases in the screening rate, disparities in breast and cervical cancer screening, based on sociodemographic characteristics, still exist. METHODS: Data from 4,139 women aged 40 to 74 years from the 2005 to 2009 Korea National Cancer Screening Survey were used to analyze the relationship between sociodemographic characteristics and receiving mammograms and Pap smears. The main outcome measures were ever having had a mammogram and ever having had a Pap smear. Using these items of information, we classified women into those who had had both types of screening, only one screening type, and neither screening type. We used logistic regression to investigate relationships between screening history and sociodemographic characteristics of the women. RESULTS: Being married, having a higher education, a rural residence, and private health insurance were significantly associated with higher rates of breast and cervical cancer screening after adjusting for age and sociodemographic factors. Household income was not significantly associated with mammograms or Pap smears after adjusting for age and sociodemographic factors. CONCLUSIONS: Disparities in breast and cervical cancer screening associated with low sociodemographic status persist in Korea. PMID- 21682887 TI - Differential effect of CLK SR Kinases on HIV-1 gene expression: potential novel targets for therapy. AB - BACKGROUND: RNA processing plays a critical role in the replication of HIV-1, regulated in part through the action of host SR proteins. To explore the impact of modulating SR protein activity on virus replication, the effect of increasing or inhibiting the activity of the Cdc2-like kinase (CLK) family of SR protein kinases on HIV-1 expression and RNA processing was examined. RESULTS: Despite their high homology, increasing individual CLK expression had distinct effects on HIV-1, CLK1 enhancing Gag production while CLK2 inhibited the virus. Parallel studies on the anti-HIV-1 activity of CLK inhibitors revealed a similar discrepant effect on HIV-1 expression. TG003, an inhibitor of CLK1, 2 and 4, had no effect on viral Gag synthesis while chlorhexidine, a CLK2, 3 and 4 inhibitor, blocked virus production. Chlorhexidine treatment altered viral RNA processing, decreasing levels of unspliced and single spliced viral RNAs, and reduced Rev accumulation. Subsequent experiments in the context of HIV-1 replication in PBMCs confirmed the capacity of chlorhexidine to suppress virus replication. CONCLUSIONS: Together, these findings establish that HIV-1 RNA processing can be targeted to suppress virus replication as demonstrated by manipulating individual CLK function and identified chlorhexidine as a lead compound in the development of novel anti-viral therapies. PMID- 21682888 TI - Midazolam suppresses interleukin-1beta-induced interleukin-6 release from rat glial cells. AB - BACKGROUND: Peripheral-type benzodiazepine receptor (PBR) expression levels are low in normal human brain, but their levels increase in inflammation, brain injury, neurodegenerative states and gliomas. It has been reported that PBR functions as an immunomodulator. The mechanisms of action of midazolam, a benzodiazepine, in the immune system in the CNS remain to be fully elucidated. We previously reported that interleukin (IL)-1beta stimulates IL-6 synthesis from rat C6 glioma cells and that IL-1beta induces phosphorylation of inhibitory kappa B (IkappaB), p38 mitogen-activated protein (MAP) kinase, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription (STAT)3. It has been shown that p38 MAP kinase is involved in IL-1beta-induced IL-6 release from these cells. In the present study, we investigated the effect of midazolam on IL 1beta-induced IL-6 release from C6 cells, and the mechanisms of this effect. METHODS: Cultured C6 cells were stimulated by IL-1beta. IL-6 release from C6 cells was measured using an enzyme-linked immunosorbent assay, and phosphorylation of IkappaB, the MAP kinase superfamily, and STAT3 was analyzed by Western blotting. RESULTS: Midazolam, but not propofol, inhibited IL-1beta stimulated IL-6 release from C6 cells. The IL-1beta-stimulated levels of IL-6 were suppressed by wedelolactone (an inhibitor of IkappaB kinase), SP600125 (an inhibitor of SAPK/JNK), and JAK inhibitor I (an inhibitor of JAK 1, 2 and 3). However, IL-6 levels were not affected by PD98059 (an inhibitor of MEK1/2). Midazolam markedly suppressed IL-1beta-stimulated STAT3 phosphorylation without affecting the phosphorylation of p38 MAP kinase, SAPK/JNK or IkappaB. CONCLUSION: These results strongly suggest that midazolam inhibits IL-1beta-induced IL-6 release in rat C6 glioma cells via suppression of STAT3 activation. Midazolam may affect immune system function in the CNS. PMID- 21682889 TI - High-resolution time series of Pseudomonas aeruginosa gene expression and rhamnolipid secretion through growth curve synchronization. AB - BACKGROUND: Online spectrophotometric measurements allow monitoring dynamic biological processes with high-time resolution. Contrastingly, numerous other methods require laborious treatment of samples and can only be carried out offline. Integrating both types of measurement would allow analyzing biological processes more comprehensively. A typical example of this problem is acquiring quantitative data on rhamnolipid secretion by the opportunistic pathogen Pseudomonas aeruginosa. P. aeruginosa cell growth can be measured by optical density (OD600) and gene expression can be measured using reporter fusions with a fluorescent protein, allowing high time resolution monitoring. However, measuring the secreted rhamnolipid biosurfactants requires laborious sample processing, which makes this an offline measurement. RESULTS: Here, we propose a method to integrate growth curve data with endpoint measurements of secreted metabolites that is inspired by a model of exponential cell growth. If serial diluting an inoculum gives reproducible time series shifted in time, then time series of endpoint measurements can be reconstructed using calculated time shifts between dilutions. We illustrate the method using measured rhamnolipid secretion by P. aeruginosa as endpoint measurements and we integrate these measurements with high resolution growth curves measured by OD600 and expression of rhamnolipid synthesis genes monitored using a reporter fusion. Two-fold serial dilution allowed integrating rhamnolipid measurements at a ~0.4 h-1 frequency with high time resolved data measured at a 6 h-1 frequency. We show how this simple method can be used in combination with mutants lacking specific genes in the rhamnolipid synthesis or quorum sensing regulation to acquire rich dynamic data on P. aeruginosa virulence regulation. Additionally, the linear relation between the ratio of inocula and the time-shift between curves produces high-precision measurements of maximum specific growth rates, which were determined with a precision of ~5.4%. CONCLUSIONS: Growth curve synchronization allows integration of rich time-resolved data with endpoint measurements to produce time-resolved quantitative measurements. Such data can be valuable to unveil the dynamic regulation of virulence in P. aeruginosa. More generally, growth curve synchronization can be applied to many biological systems thus helping to overcome a key obstacle in dynamic regulation: the scarceness of quantitative time-resolved data. PMID- 21682890 TI - Zangfu zheng (patterns) are associated with clinical manifestations of zang shang (target-organ damage) in arterial hypertension. PMID- 21682891 TI - Implication of next-generation sequencing on association studies. AB - BACKGROUND: Next-generation sequencing technologies can effectively detect the entire spectrum of genomic variation and provide a powerful tool for systematic exploration of the universe of common, low frequency and rare variants in the entire genome. However, the current paradigm for genome-wide association studies (GWAS) is to catalogue and genotype common variants (5% < MAF). The methods and study design for testing the association of low frequency (0.5% < MAF <= 5%) and rare variation (MAF <= 0.5%) have not been thoroughly investigated. The 1000 Genomes Project represents one such endeavour to characterize the human genetic variation pattern at the MAF = 1% level as a foundation for association studies. In this report, we explore different strategies and study designs for the near future GWAS in the post-era, based on both low coverage pilot data and exon pilot data in 1000 Genomes Project. RESULTS: We investigated the linkage disequilibrium (LD) pattern among common and low frequency SNPs and its implication for association studies. We found that the LD between low frequency alleles and low frequency alleles, and low frequency alleles and common alleles are much weaker than the LD between common and common alleles. We examined various tagging designs with and without statistical imputation approaches and compare their power against de novo resequencing in mapping causal variants under various disease models. We used the low coverage pilot data which contain ~14 M SNPs as a hypothetical genotype-array platform (Pilot 14 M) to interrogate its impact on the selection of tag SNPs, mapping coverage and power of association tests. We found that even after imputation we still observed 45.4% of low frequency SNPs which were untaggable and only 67.7% of the low frequency variation was covered by the Pilot 14 M array. CONCLUSIONS: This suggested GWAS based on SNP arrays would be ill-suited for association studies of low frequency variation. PMID- 21682893 TI - Pricing and reimbursement of orphan drugs: the need for more transparency. AB - Pricing and reimbursement of orphan drugs are an issue of high priority for policy makers, legislators, health care professionals, industry leaders, academics and patients. This study aims to conduct a literature review to provide insight into the drivers of orphan drug pricing and reimbursement. Although orphan drug pricing follows the same economic logic as drug pricing in general, the monopolistic power of orphan drugs results in high prices: a) orphan drugs benefit from a period of marketing exclusivity; b) few alternative health technologies are available; c) third-party payers and patients have limited negotiating power; d) manufacturers attempt to maximise orphan drug prices within the constraints of domestic pricing and reimbursement policies; and e) substantial R&D costs need to be recouped from a small number of patients. Although these conditions apply to some orphan drugs, they do not apply to all orphan drugs. Indeed, the small number of patients treated with an orphan drug and the limited economic viability of orphan drugs can be questioned in a number of cases. Additionally, manufacturers have an incentive to game the system by artificially creating monopolistic market conditions. Given their high price for an often modest effectiveness, orphan drugs are unlikely to provide value for money. However, additional criteria are used to inform reimbursement decisions in some countries. These criteria may include: the seriousness of the disease; the availability of other therapies to treat the disease; and the cost to the patient if the medicine is not reimbursed. Therefore, the maximum cost per unit of outcome that a health care payer is willing to pay for a drug could be set higher for orphan drugs to which society attaches a high social value. There is a need for a transparent and evidence-based approach towards orphan drug pricing and reimbursement. Such an approach should be targeted at demonstrating the relative effectiveness, cost-effectiveness and economic viability of orphan drugs with a view to informing pricing and reimbursement decisions. PMID- 21682894 TI - Targeted metabolomic analyses of cellular models of pelizaeus-merzbacher disease reveal plasmalogen and myo-inositol solute carrier dysfunction. AB - BACKGROUND: Leukodystrophies are devastating diseases characterized by dys- and hypo-myelination. While there are a number of histological and imaging studies of these disorders, there are limited biochemical data available. We undertook targeted lipidomic analyses of Pelizaeus-Merzbacher disease (PMD) fibroblasts, PMD lymphocytes, and 158JP oligodendrocytes, a murine model of PMD, to define the lipid changes in these cell models. Further targeted metabolomics analyses were conducted to obtain a preliminary evaluation of the metabolic consequences of lipid changes and gene mutations in these cell models. RESULTS: In both PMD fibroblasts and lymphocytes, and 158JP oligodendrocytes, ethanolamine plasmalogens were significantly decreased. Labeling studies with 158JP oligodendrocytes further demonstrated a decreased rate of lipid remodeling at sn 2. Targeted metabolomics analyses of these cells revealed dramatic increases in cellular levels of myo-inositol. Further uptake studies demonstrated increased rates of myo-inositol uptake by PMD lymphocytes. CONCLUSIONS: Our data demonstrating PlsEtn decrements, support previous studies indicating leukodystrophy cells possess significant peroxisomal deficits. Our data for the first time also demonstrate that decrements in peroxisomal function coupled with the PLP1 gene defects of PMD, result in changes in the function of membrane myo inositol solute carriers resulting in dramatic increases in cellular myo-inositol levels. PMID- 21682895 TI - HomPPI: a class of sequence homology based protein-protein interface prediction methods. AB - BACKGROUND: Although homology-based methods are among the most widely used methods for predicting the structure and function of proteins, the question as to whether interface sequence conservation can be effectively exploited in predicting protein-protein interfaces has been a subject of debate. RESULTS: We studied more than 300,000 pair-wise alignments of protein sequences from structurally characterized protein complexes, including both obligate and transient complexes. We identified sequence similarity criteria required for accurate homology-based inference of interface residues in a query protein sequence.Based on these analyses, we developed HomPPI, a class of sequence homology-based methods for predicting protein-protein interface residues. We present two variants of HomPPI: (i) NPS-HomPPI (Non partner-specific HomPPI), which can be used to predict interface residues of a query protein in the absence of knowledge of the interaction partner; and (ii) PS-HomPPI (Partner-specific HomPPI), which can be used to predict the interface residues of a query protein with a specific target protein.Our experiments on a benchmark dataset of obligate homodimeric complexes show that NPS-HomPPI can reliably predict protein-protein interface residues in a given protein, with an average correlation coefficient (CC) of 0.76, sensitivity of 0.83, and specificity of 0.78, when sequence homologs of the query protein can be reliably identified. NPS-HomPPI also reliably predicts the interface residues of intrinsically disordered proteins. Our experiments suggest that NPS-HomPPI is competitive with several state-of-the art interface prediction servers including those that exploit the structure of the query proteins. The partner-specific classifier, PS-HomPPI can, on a large dataset of transient complexes, predict the interface residues of a query protein with a specific target, with a CC of 0.65, sensitivity of 0.69, and specificity of 0.70, when homologs of both the query and the target can be reliably identified. The HomPPI web server is available at http://homppi.cs.iastate.edu/. CONCLUSIONS: Sequence homology-based methods offer a class of computationally efficient and reliable approaches for predicting the protein-protein interface residues that participate in either obligate or transient interactions. For query proteins involved in transient interactions, the reliability of interface residue prediction can be improved by exploiting knowledge of putative interaction partners. PMID- 21682896 TI - Toxoplasma gondii infection and abdominal hernia: evidence of a new association. AB - BACKGROUND: We performed a retrospective, observational study in 1156 adult subjects from the general population of Durango City, Mexico, Fifty five subjects with a history of abdominal hernia repair and 1101 subjects without hernia were examined with enzyme-linked immunoassays for the presence of anti-Toxoplasma IgG and IgM antibodies. RESULTS: The seroprevalence of anti-Toxoplasma IgG antibodies and IgG titers was significantly higher in subjects with abdominal hernia repair than those without hernia. There was a tendency for subjects with hernia repair to have a higher seroprevalence of anti-Toxoplasma IgM antibodies than subjects without hernia. The seroprevalence of anti-Toxoplasma IgG antibodies in subjects with hernia repair was significantly higher in subjects >= 50 years old than those < 50 years old. Further analysis in subjects aged >= 50 years showed that the seroprevalence of anti-Toxoplasma IgG antibodies was also significantly higher in individuals with hernia repair than those without hernia (OR = 2.72; 95% CI: 1.10-6.57). Matching by age and sex further showed that the seroprevalence of Toxoplasma infection was significantly higher in patients with hernia repair than those without hernia (OR: 4.50; 95% CI: 1.22-17.33). CONCLUSIONS: Results indicate that infection with Toxoplasma is associated with abdominal hernia. The contributing role of infection with Toxoplasma in abdominal hernia was observed mainly in subjects aged >= 50 years old. Our results might have clinical, prevention and treatment implications and warrant for further investigation. PMID- 21682897 TI - Anti-inflammatory activity of monogalactosyldiacylglycerol in human articular cartilage in vitro: activation of an anti-inflammatory cyclooxygenase-2 (COX-2) pathway. AB - INTRODUCTION: The mono- and digalactosyldiacylglycerol (MGDG and DGDG) galactolipids have been purified from the thermophilic blue-green alga Phormidium sp. ETS-05 that colonizes the therapeutic thermal mud of Abano Terme and Montegrotto Terme, Italy. Both compounds present a marked composition in polyunsaturated fatty acids, mainly omega-3. The therapeutic thermal mud is applied mainly to osteoarthritic cartilage patients. In the present study the effect of MGDG treatment on proteins and factors expressed by human articular cartilage cells in culture and on pathways activated in inflammatory conditions was studied. METHODS: Primary cultures of human articular chondrocytes were used at cell passage number 1 (P1). Cells were treated in serum-free medium with inflammatory cytokines in the presence and in the absence of MGDG. Western blot was performed on collected medium and on cell layers. At least three different experiments were performed on primary cultures. The quantitation of the MGDG effect was performed by densitometric scanning of Western blots. p38 Mitogen Activated Protein Kinase (p38) activation, Nuclear Factor-kappaB (NF-kB) activation and Prostaglandin E(2) (PGE(2)) quantitation were performed by commercially available assays. Results are given as the mean values +/- SD. All statistical analyses were performed using GraphPad software. The two-tailed Student's t -test was performed. RESULTS: We report that MGDG: 1) represses the expression of interleukin-6 (IL-6) and interleukin-8 (IL-8) induced by interleukin-1alpha (IL-1alpha) or IL-1alpha + tumor necrosis factor alpha (TNFalpha) interfering with the p38 and NF-kB pathways; 2) is not toxic for the cells and does not affect the cell phenotype; 3) strongly enhances COX-2 expression induced by IL-1alpha or IL-1alpha + TNFalpha; 4) represses mPGES expression induced by IL-1alpha and the synthesis of PGE(2) and induces the synthesis of 15-deoxy-Delta 12,14-prostaglandin J(2) (15DeltaPGJ(2)). In addition, the COX-2 product 15DeltaPGJ(2) added to the cells: 1) strongly represses IL-6 and IL-8 induced by IL-1alpha; 2) represses mPGES expression induced by IL-1alpha and the synthesis of PGE(2). CONCLUSIONS: All together these data suggest that MGDG has an anti-inflammatory activity in human articular cartilage and possibly activates an anti-inflammatory loop triggered by COX-2 via 15DeltaPGJ(2) production, indicating a possible role of COX-2 in resolution of inflammation. The purified compound is a novel anti-inflammatory agent potentially active for human articular cartilage pathologies related to inflammation. PMID- 21682899 TI - Assessing young unmarried men's access to reproductive health information and services in rural India. AB - BACKGROUND: We investigated the accessibility of reproductive health information and contraceptives in a relatively less developed area of rural central India and assessed the risks facing young unmarried men. METHODS: This cross-sectional study used both qualitative and quantitative methods. Participants included 38 unmarried rural men in four focus-group discussions and a representative sample of 316 similarly profiled men, aged 17-22 years, in a survey. Information was collected on the men's socioeconomic characteristics; awareness, knowledge, and perceptions of family planning; attitudes toward future contraceptive use; intra family communication; knowledge about STIs/HIV/AIDS; and access and use of condoms. Content analysis for qualitative information and descriptive analysis for survey data were used to draw conclusions. RESULTS: Young unmarried rural Indian men's sexual and reproductive health (SRH) knowledge is limited, although the majority is familiar with condoms (99%). The young men identified electronic mass media (67%) as the prime source of reproductive health information, yet they lacked detailed knowledge of various contraceptives and felt ignored by health providers, who, they felt, would be capable of providing SRH information through interpersonal communication. Young men are more concerned about avoiding infections and securing sexual pleasure and less concerned about avoiding potential pregnancies. For example, 68% of the young men were aware of condoms and their HIV/AIDS preventive role, but only about two-fifths mentioned condom use to prevent unwanted pregnancies. Although most young men (96%) knew where to access a condom, they felt uncomfortable or embarrassed doing so in their own villages or close by because of socio-cultural norms that prevented them from using contraceptives. Very few respondents (4%) disclosed using condoms themselves, but 59% said they knew someone from their peer group who had used them. CONCLUSIONS: Young unmarried men in rural India are underserved with regard to SRH information and services, because they are not recognized as key targets under the public health system, and they receive their limited knowledge and information mainly from the mass media; this situation could be greatly improved by public health service providers. It is important that programmers involve young men with effective communication strategies to enable them to act responsibly with regard to their own sexual health needs. PMID- 21682898 TI - Epigallocatechin-3-gallate suppresses the global interleukin-1beta-induced inflammatory response in human chondrocytes. AB - INTRODUCTION: Epigallocatechin-3-gallate (EGCG) is a bioactive polyphenol of green tea and exerts potent anti-inflammatory effects by inhibiting signaling events and gene expression. Interleukin-1beta (IL-1beta) is the principal cytokine linked to cartilage degradation in osteoarthritis (OA). The objective of this study was to evaluate the global effect of EGCG on IL-1beta-induced expression of proteins associated with OA pathogenesis in human chondrocytes. METHODS: Primary OA chondrocytes were pretreated with EGCG (10 to 100 uM) and then stimulated with IL-1beta (5 ng/ml) for 24 hours. Culture supernatants were incubated with cytokine antibody arrays and immunoreactive proteins (80 proteins) were visualized by enhanced chemiluminiscence. Effect of EGCG on IL-1beta-induced expression of 18 selected genes was verified by Real time-PCR and effect on IL-6, IL-8 and tumor necrosis factor-alpha (TNF-alpha) production was determined using specific ELISAs. Western immunoblotting was used to analyze the effect of EGCG on the interleukin-1 receptor-associated kinase 1 (IRAK-1) and TNF receptor associated factor 6 (TRAF-6) proteins in IL-1beta-stimulated chondrocytes. The role of nuclear factor kappa-B (NF-kappaB) and mitogen activated protein kinases (MAPKs) in the regulation of selected genes and the mechanism involved in EGCG mediated modulation of these genes was determined by using specific inhibitors for NF- kappaB (MG132) and MAPKs (p38-MAPK, SB202190; JNK-MAPK, SP600125, ERK MAPK, PD98059). RESULTS: Out of 80 proteins present on the array, constitutive expression of 14% proteins was altered by EGCG treatment. No significant stimulatory effect was observed on the proteins associated with cartilage anabolic response. Stimulation with IL-1beta enhanced the expression of 29 proteins. Expression of all 29 proteins up-regulated by IL-1beta was found to be suppressed by EGCG. EGCG also inhibited the expression of the signaling intermediate TRAF-6 at 50 and 100 uM concentrations (P < 0.05). Our results identified several new targets of EGCG, including epithelial neutrophil activating peptide-78 (ENA-78), granulocyte macrophage colony stimulation factor (GM-CSF), growth- related oncogene (GRO), GRO-alpha, IL-6, IL-8, monocyte chemotactic protein-1 (MCP-1), MCP-3, macrophage inflammatory protein-1beta (MIP 1beta), granulocyte chemotactic protein-2 (GCP-2), MIP-3alpha, interferon-gamma inducible protein-10 (IP-10), nucleosome assembly protein-2 (NAP-2) and leukemia inhibitory factor (LIF). The inhibitory effects of EGCG were mainly mediated by inhibiting the activation of NF-kappaB and c-Jun N-terminal Kinase (JNK)-MAPK in human chondrocytes. CONCLUSIONS: Our results suggest that the potential of EGCG in OA treatment/prevention may be related to its ability to globally suppress the inflammatory response in human chondrocytes. These results identify additional new targets of EGCG and advocate that EGCG may be a potent chondroprotective agent in OA. PMID- 21682900 TI - Factor VIII haplotypes frequencies in Tunisian hemophiliacs A. AB - BACKGROUND: The development of inhibitors against factor 8 (F8) is the most serious complication of replacement therapy with F8 in children with severe hemophilia. It was suggested that mismatched F8 replacement therapy may be a risk factor for the development of anti-factor F8 alloantibodies. Recently four single nucleotide polymorphisms (SNPs) encoding six distinct haplotypes, designated H1 through H6, were studied in different populations. Two SNPs are components of the A2 and C2 immunodominant-inhibitor epitopes.The aim of this study is to determine the different types of haplotypes in relation with inhibitors developments and their frequencies in our Tunisian hemophiliac population. MATERIALS AND METHODS: 95/116 Tunisian patients with hemophilia A undergoing treatment at Hemophilia Treatment Center, Aziza Othmana hospital, participate in this study. Among them only six patients develop inhibitors. The four SNPs were amplified and sequenced. RESULTS AND DISCUSSION: In a total of 77 patients, we identified the H1, H2, H3 and the infrequent H5 haplotypes. The H1 and H2 haplotypes, which have the same amino acid sequence in the recombinant F8 molecules used clinically, are the most represented with the frequency of 0.763 and 0.157 respectively. This distribution is almost similar to that of Caucasians in which the frequencies are respectively 0.926 and 0.074, whereas it is 0.354 and 0.374 among Subsaharians. Four patients with inhibitors studied here have the H1 haplotype. For one patient who has a large deletion including the exon 10 we can't identify his haplotype. Theses frequencies may explain partially the low level of inhibitors in our patients. PMID- 21682901 TI - Diagnostic challenge for ovarian malignant melanoma in premenopausal women: primary or metastatic? AB - BACKGROUND: In the ovary, metastatic malignant melanoma may be confused with primary malignant melanoma and presents a diagnosis challenge. Most cases are associated with disseminated diseases and poor prognosis. We present this case report of a metastatic ovarian malignant melanoma simulating primary ovarian cancer. CASE REPORT: A 45-year-old premenopausal woman was incidentally found to have an abdominal mass, 3 years after removal of a cutaneous melanoma lesion. Ultrasound and CT scan revealed left two solid masses, which were found to be an ovarian tumor at laparotomy. Left oophorectomy was performed. Histopathology and immunohistochemistry showed melanoma metastasis to the ovary. Nine months later, the patient developed epilepsy and confusion. Magnetic Resonance Imaging showed unique Wright frontal lobe lesion. She underwent stereotactic radio surgery and dacarbazine monotherapy. For months later, the patient is died from disseminate disease progression. CONCLUSION: Ovarian metastasis is an unusual presentation of cutaneous melanoma and the prognosis was dismal. As illustrated by this case report, a differential diagnosis of a metastatic malignant melanoma must be considered. PMID- 21682903 TI - Comprehensive analysis of human microRNA target networks. AB - BACKGROUND: MicroRNAs (miRNAs) mediate posttranscriptional regulation of protein coding genes by binding to the 3' untranslated region of target mRNAs, leading to translational inhibition, mRNA destabilization or degradation, depending on the degree of sequence complementarity. In general, a single miRNA concurrently downregulates hundreds of target mRNAs. Thus, miRNAs play a key role in fine tuning of diverse cellular functions, such as development, differentiation, proliferation, apoptosis and metabolism. However, it remains to be fully elucidated whether a set of miRNA target genes regulated by an individual miRNA in the whole human microRNAome generally constitute the biological network of functionally-associated molecules or simply reflect a random set of functionally independent genes. METHODS: The complete set of human miRNAs was downloaded from miRBase Release 16. We explored target genes of individual miRNA by using the Diana-microT 3.0 target prediction program, and selected the genes with the miTG score ? 20 as the set of highly reliable targets. Then, Entrez Gene IDs of miRNA target genes were uploaded onto KeyMolnet, a tool for analyzing molecular interactions on the comprehensive knowledgebase by the neighboring network-search algorithm. The generated network, compared side by side with human canonical networks of the KeyMolnet library, composed of 430 pathways, 885 diseases, and 208 pathological events, enabled us to identify the canonical network with the most significant relevance to the extracted network. RESULTS: Among 1,223 human miRNAs examined, Diana-microT 3.0 predicted reliable targets from 273 miRNAs. Among them, KeyMolnet successfully extracted molecular networks from 232 miRNAs. The most relevant pathway is transcriptional regulation by transcription factors RB/E2F, the disease is adult T cell lymphoma/leukemia, and the pathological event is cancer. CONCLUSION: The predicted targets derived from approximately 20% of all human miRNAs constructed biologically meaningful molecular networks, supporting the view that a set of miRNA targets regulated by a single miRNA generally constitute the biological network of functionally-associated molecules in human cells. PMID- 21682902 TI - In-silico prediction of disorder content using hybrid sequence representation. AB - BACKGROUND: Intrinsically disordered proteins play important roles in various cellular activities and their prevalence was implicated in a number of human diseases. The knowledge of the content of the intrinsic disorder in proteins is useful for a variety of studies including estimation of the abundance of disorder in protein families, classes, and complete proteomes, and for the analysis of disorder-related protein functions. The above investigations currently utilize the disorder content derived from the per-residue disorder predictions. We show that these predictions may over-or under-predict the overall amount of disorder, which motivates development of novel tools for direct and accurate sequence-based prediction of the disorder content. RESULTS: We hypothesize that sequence-level aggregation of input information may provide more accurate content prediction when compared with the content extracted from the local window-based residue level disorder predictors. We propose a novel predictor, DisCon, that takes advantage of a small set of 29 custom-designed descriptors that aggregate and hybridize information concerning sequence, evolutionary profiles, and predicted secondary structure, solvent accessibility, flexibility, and annotation of globular domains. Using these descriptors and a ridge regression model, DisCon predicts the content with low, 0.05, mean squared error and high, 0.68, Pearson correlation. This is a statistically significant improvement over the content computed from outputs of ten modern disorder predictors on a test dataset with proteins that share low sequence identity with the training sequences. The proposed predictive model is analyzed to discuss factors related to the prediction of the disorder content. CONCLUSIONS: DisCon is a high-quality alternative for high-throughput annotation of the disorder content. We also empirically demonstrate that the DisCon's predictions can be used to improve binary annotations of the disordered residues from the real-value disorder propensities generated by current residue-level disorder predictors. The web server that implements the DisCon is available at http://biomine.ece.ualberta.ca/DisCon/. PMID- 21682904 TI - Successful twin pregnancy in a patient with parkin-associated autosomal recessive juvenile parkinsonism. AB - BACKGROUND: Pregnancy in patients with Parkinson disease is a rare occurrence. To the best of our knowledge, the effect of pregnancy as well as treatment in genetically confirmed autosomal recessive juvenile parkinsonism (ARJP) has never been reported. Here, we report the first case of pregnancy in a patient with ARJP associated with a parkin gene mutation, ARJP/PARK2. CASE PRESENTATION: A 27-year old woman with ARJP/PARK2 was diagnosed as having a spontaneous dichorionic/diamniotic twin pregnancy. Exacerbation of motor disability was noted between ovulation and menstruation before pregnancy as well as during late pregnancy, suggesting that her parkinsonism might have been influenced by fluctuations in the levels of endogenous sex hormones. During the organogenesis period, she was only treated with levodopa/carbidopa, although she continued to receive inpatient hospital care for assistance in the activities of daily living. After the organogenesis period, she was administered sufficient amounts of antiparkinsonian drugs. She delivered healthy male twins, and psychomotor development of both the babies was normal at the age of 2 years. CONCLUSION: Pregnancy may worsen the symptoms of ARJP/PARK2, although appropriate treatments with antiparkinsonian drugs and adequate assistance in the activities of daily living might enable successful pregnancy and birth of healthy children. PMID- 21682905 TI - Kinetic modeling and exploratory numerical simulation of chloroplastic starch degradation. AB - BACKGROUND: Higher plants and algae are able to fix atmospheric carbon dioxide through photosynthesis and store this fixed carbon in large quantities as starch, which can be hydrolyzed into sugars serving as feedstock for fermentation to biofuels and precursors. Rational engineering of carbon flow in plant cells requires a greater understanding of how starch breakdown fluxes respond to variations in enzyme concentrations, kinetic parameters, and metabolite concentrations. We have therefore developed and simulated a detailed kinetic ordinary differential equation model of the degradation pathways for starch synthesized in plants and green algae, which to our knowledge is the most complete such model reported to date. RESULTS: Simulation with 9 internal metabolites and 8 external metabolites, the concentrations of the latter fixed at reasonable biochemical values, leads to a single reference solution showing beta amylase activity to be the rate-limiting step in carbon flow from starch degradation. Additionally, the response coefficients for stromal glucose to the glucose transporter k(cat) and KM are substantial, whereas those for cytosolic glucose are not, consistent with a kinetic bottleneck due to transport. Response coefficient norms show stromal maltopentaose and cytosolic glucosylated arabinogalactan to be the most and least globally sensitive metabolites, respectively, and beta-amylase k(cat) and KM for starch to be the kinetic parameters with the largest aggregate effect on metabolite concentrations as a whole. The latter kinetic parameters, together with those for glucose transport, have the greatest effect on stromal glucose, which is a precursor for biofuel synthetic pathways. Exploration of the steady-state solution space with respect to concentrations of 6 external metabolites and 8 dynamic metabolite concentrations show that stromal metabolism is strongly coupled to starch levels, and that transport between compartments serves to lower coupling between metabolic subsystems in different compartments. CONCLUSIONS: We find that in the reference steady state, starch cleavage is the most significant determinant of carbon flux, with turnover of oligosaccharides playing a secondary role. Independence of stationary point with respect to initial dynamic variable values confirms a unique stationary point in the phase space of dynamically varying concentrations of the model network. Stromal maltooligosaccharide metabolism was highly coupled to the available starch concentration. From the most highly converged trajectories, distances between unique fixed points of phase spaces show that cytosolic maltose levels depend on the total concentrations of arabinogalactan and glucose present in the cytosol. In addition, cellular compartmentalization serves to dampen much, but not all, of the effects of one subnetwork on another, such that kinetic modeling of single compartments would likely capture most dynamics that are fast on the timescale of the transport reactions. PMID- 21682906 TI - Single-trial classification of motor imagery differing in task complexity: a functional near-infrared spectroscopy study. AB - BACKGROUND: For brain computer interfaces (BCIs), which may be valuable in neurorehabilitation, brain signals derived from mental activation can be monitored by non-invasive methods, such as functional near-infrared spectroscopy (fNIRS). Single-trial classification is important for this purpose and this was the aim of the presented study. In particular, we aimed to investigate a combined approach: 1) offline single-trial classification of brain signals derived from a novel wireless fNIRS instrument; 2) to use motor imagery (MI) as mental task thereby discriminating between MI signals in response to different tasks complexities, i.e. simple and complex MI tasks. METHODS: 12 subjects were asked to imagine either a simple finger-tapping task using their right thumb or a complex sequential finger-tapping task using all fingers of their right hand. fNIRS was recorded over secondary motor areas of the contralateral hemisphere. Using Fisher's linear discriminant analysis (FLDA) and cross validation, we selected for each subject a best-performing feature combination consisting of 1) one out of three channel, 2) an analysis time interval ranging from 5-15 s after stimulation onset and 3) up to four Delta[O2Hb] signal features (Delta[O2Hb] mean signal amplitudes, variance, skewness and kurtosis). RESULTS: The results of our single-trial classification showed that using the simple combination set of channels, time intervals and up to four Delta[O2Hb] signal features comprising Delta[O2Hb] mean signal amplitudes, variance, skewness and kurtosis, it was possible to discriminate single-trials of MI tasks differing in complexity, i.e. simple versus complex tasks (inter-task paired t-test p <= 0.001), over secondary motor areas with an average classification accuracy of 81%. CONCLUSIONS: Although the classification accuracies look promising they are nevertheless subject of considerable subject-to-subject variability. In the discussion we address each of these aspects, their limitations for future approaches in single-trial classification and their relevance for neurorehabilitation. PMID- 21682907 TI - Rural-urban differences of neonatal mortality in a poorly developed province of China. AB - BACKGROUND: The influence of rural-urban disparities in children's health on neonatal death in disadvantaged areas of China is poorly understood. In this study of rural and urban populations in Gansu province, a disadvantaged province of China, we describe the characteristics and mortality of newborn infants and evaluated rural-urban differences of neonatal death. METHODS: We analyzed all neonatal deaths in the data from the Surveillance System of Child Death in Gansu Province, China from 2004 to 2009. We calculated all-cause neonatal mortality rates (NMR) and cause-specific death rates for infants born to rural or urban mothers during 2004-09. Rural-urban classifications were determined based on the residence registry system of China. Chi-square tests were used to compare differences of infant characteristics and cause-specific deaths by rural-urban maternal residence. RESULTS: Overall, NMR fell in both rural and urban populations during 2004-09. Average NMR for rural and urban populations was 17.8 and 7.5 per 1000 live births, respectively. For both rural and urban newborn infants, the four leading causes of death were birth asphyxia, preterm or low birth weight, congenital malformation, and pneumonia. Each cause-specific death rate was higher in rural infants than in urban infants. More rural than urban neonates died out of hospital or did not receive medical care before death. CONCLUSIONS: Neonatal mortality declined dramatically both in urban and rural groups in Gansu province during 2004-09. However, profound disparities persisted between rural and urban populations. Strategies that address inequalities of accessibility and quality of health care are necessary to improve neonatal health in rural settings in China. PMID- 21682908 TI - Dealing with Alcohol-related problems in the Night-Time Economy: A Study Protocol for Mapping trends in harm and stakeholder views surrounding local community level interventions. AB - BACKGROUND: This project will provide a comprehensive investigation into the prevalence of alcohol-related harms and community attitudes in the context of community-based interventions being implemented to reduce harm in two regional centres of Australia. While considerable experimentation and innovation to address these harms has occurred in both Geelong and Newcastle, only limited ad hoc documentation and analysis has been conducted on changes in the prevalence of harm as a consequence, leaving a considerable gap in terms of a systematic, evidence-based analysis of changes in harm over time and the need for further intervention. Similarly, little evidence has been reported regarding the views of key stakeholder groups, industry, government agencies, patrons or community regarding the need for, and the acceptability of, interventions to reduce harms. This project will aim to provide evidence regarding the impact and acceptability of local initiatives aimed at reducing alcohol-related harms. METHODS/DESIGN: This study will gather existing police data (assault, property damage and drink driving offences), Emergency Department presentations and Ambulance attendance data. Further, the research team will conduct interviews with licensed venue patrons and collect observational data of licensed venues. Key informant interviews will assess expert knowledge from key industry and government stakeholders, and a community survey will assess community experiences and attitudes towards alcohol-related harm and harm-reduction strategies. Overall, the project will assess: the extent of alcohol-related harm in the context of harm-reduction interventions, and the need for and acceptability of further intervention. DISCUSSION: These findings will be used to improve evidence-based practice both nationally and internationally. ETHICAL APPROVAL: This project has been approved by Deakin University HREC. PMID- 21682909 TI - Evaluation of the Frails' Fall Efficacy by Comparing Treatments (EFFECT) on reducing fall and fear of fall in moderately frail older adults: study protocol for a randomised control trial. AB - BACKGROUND: Falls are common in frail older adults and often result in injuries and hospitalisation. The Nintendo(r) WiiTM is an easily available exercise modality in the community which has been shown to improve lower limb strength and balance. However, not much is known on the effectiveness of the Nintendo(r) WiiTM to improve fall efficacy and reduce falls in a moderately frail older adult. Fall efficacy is the measure of fear of falling in performing various daily activities. Fear contributes to avoidance of activities and functional decline. METHODS: This randomised active-control trial is a comparison between the Nintendo WiiActive programme against standard gym-based rehabilitation of the older population. Eighty subjects aged above 60, fallers and non-fallers, will be recruited from the hospital outpatient clinic. The primary outcome measure is the Modified Falls Efficacy Scale and the secondary outcome measures are self reported falls, quadriceps strength, walking agility, dynamic balance and quality of life assessments. DISCUSSIONS: The study is the first randomised control trial using the Nintendo Wii as a rehabilitation modality investigating a change in fall efficacy and self-reported falls. Longitudinally, the study will investigate if the interventions can successfully reduce falls and analyse the cost effectiveness of the programme. PMID- 21682910 TI - From rehabilitation to recovery: protocol for a randomised controlled trial evaluating a goal-based intervention to reduce depression and facilitate participation post-stroke. AB - BACKGROUND: There is much discourse in healthcare about the importance of client centred rehabilitation, however in the realm of community-based therapy post stroke there has been little investigation into the efficacy of goal-directed practice that reflects patients' valued activities. In addition, the effect of active involvement of carers in such a rehabilitation process and their subsequent contribution to functional and emotional recovery post-stroke is unclear. In community based rehabilitation, interventions based on patients' perceived needs may be more likely to alter such outcomes. In this paper, we describe the methodology of a randomised controlled trial of an integrated approach to facilitating patient goal achievement in the first year post-stroke. The effectiveness of this intervention in reducing the severity of post-stroke depression, improving participation status and health-related quality of life is examined. The impact on carers is also examined. METHODS/DESIGN: Patients (and their primary carers, if available) are randomly allocated to an intervention or control arm of the study. The intervention is multimodal and aims to screen for adverse stroke sequelae and address ways to enhance participation in patient valued activities. Intervention methods include: telephone contacts, written information provision, home visitation, and contact with treating health professionals, with further relevant health service referrals as required. The control involves treatment as usual, as determined by inpatient and community rehabilitation treating teams. Formal blinded assessments are conducted at discharge from inpatient rehabilitation, and at six and twelve months post stroke. The primary outcome is depression. Secondary outcome measures include participation and activity status, health-related quality of life, and self efficacy. DISCUSSION: The results of this trial will assist with the development of a model for community-based rehabilitation management for stroke patients and their carers, with emphasis on goal-directed practice to enhance home and community participation status. Facilitation of participation in valued activities may be effective in reducing the incidence or severity of post-stroke depression, as well as enhancing the individual's perception of their health related quality of life. The engagement of carers in the rehabilitation process will enable review of the influence of the broader social context on recovery. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12608000042347. PMID- 21682911 TI - Determinants of use and non-use of a web-based communication system in cerebral palsy care: evaluating the association between professionals' system use and their a priori expectancies and background. AB - BACKGROUND: Previously we described parents' and professionals' experiences with a web-based communication system in a 6-month pilot in three Dutch cerebral palsy care settings. We found that half of the participating professionals had not used the system, and of those who had used the system one third had used it only once. The present study aimed to evaluate whether professionals' system use was associated with their a priori expectancies and background. METHODS: Professionals who had not used the system (n = 54) were compared with professionals who had used the system more than once (n = 46) on the basis of their questionnaire responses before the pilot, their affiliation and the number of patients which they represented in the study. The questionnaire items comprised professionals' expectancies regarding the system's performance and ease of use, as well as the expected time availability and integration into daily care practice. RESULTS: Overall, users had higher a priori expectancies than non users. System use was associated with expected ease of use (p = .046) and time availability (p = .005): 50% of the users (vs. 31% of the non-users) expected that the system would be easy to use and 93% of the users (vs. 72% of the non users) expected that they would be able to reserve a time slot each week for responding to submitted questions. With respect to professionals' affiliation, system use was associated with professionals' institution (p = .003) and discipline (p = .001), with more (para-) medical professionals among users (93% vs. 63% among non-users), and more education professionals among non-users (37% vs. 7% among users). In addition, users represented more patients (mean 2, range 1-8) than non-users (mean 1.1, range 1-2) (p = .000). CONCLUSIONS: Professionals' system use was associated with expected ease of use and time availability, professionals' affiliation and the number of represented patients, while no association was found with expected performance of the system. To achieve higher adoption rates in the future, it is important to further develop the technology by optimizing the system's ease of use and interoperability and including advanced consultation options. In addition, better identified end users should be more extensively informed about the system's possibilities through tailored education. PMID- 21682912 TI - Applying the revised Chinese Job Content Questionnaire to assess psychosocial work conditions among Taiwan's hospital workers. AB - BACKGROUND: For hospital accreditation and health promotion reasons, we examined whether the 22-item Job Content Questionnaire (JCQ) could be applied to evaluate job strain of individual hospital employees and to determine the number of factors extracted from JCQ. Additionally, we developed an Excel module of self evaluation diagnostic system for consultation with experts. METHODS: To develop an Excel-based self-evaluation diagnostic system for consultation to experts to make job strain assessment easier and quicker than ever, Rasch rating scale model was used to analyze data from 1,644 hospital employees who enrolled in 2008 for a job strain survey. We determined whether the 22-item Job Content Questionnaire (JCQ) could evaluate job strain of individual employees in work sites. The respective item responding to specific groups' occupational hazards causing job stress was investigated by using skewness coefficient with its 95% CI through item-by-item analyses. RESULTS: Each of those 22 items on the questionnaire was examined to have five factors. The prevalence rate of Chinese hospital workers with high job strain was 16.5%. CONCLUSIONS: Graphical representations of four quadrants, item-by-item bar chart plots and skewness 95% CI comparison generated in Excel can help employers and consultants of an organization focusing on a small number of key areas of concern for each worker in job strain. PMID- 21682913 TI - Comparative analysis of macrophage associated vectors for use in genetic vaccine. AB - BACKGROUND: Antigen presentation by non professional antigen presenting cells (APC) can lead to anergy. In genetic vaccines, targeting the macrophages and APC for efficient antigen presentation might lead to balanced immune response. One such approach is to incorporate APC specific promoter in the vector to be used. METHODS: Three promoters known to be active in macrophage were selected and cloned in mammalian expressing vector (pAcGFP1-N1) to reconstruct (pAcGFP-MS), (pAcGFP-EMR) and (pAcGFP-B5I) with macrosialin, EmrI and Beta-5 Integrin promoters respectively. As a positive control (pAcGFP-CMV) was used with CMV promoter and promoterless vector (pAcGFP-NIX) which served as a negative control. GFP gene was used as readout under the control of each of the promoter. The expression of GFP was analyzed on macrophage and non-macrophage cell lines using Flow cytometry and qRT-PCR with TaqMan probe chemistries. RESULTS: All the promoters in question were dominant to macrophage lineage cell lines as observed by fluorescence, Western blot and quantitative RT-PCR. The activity of macrosialin was significantly higher than other macrophage promoters. CMV promoter showed 1.83 times higher activity in macrophage cell lines. The expression of GFP driven by macrosialin promoter after 24 hours was 4.40 times higher in macrophage derived cell lines in comparison with non macrophage cell lines. CONCLUSIONS: Based on this study, macrosialin promoter can be utilized for targeting macrophage dominant expression. In vivo study needs to be carried out for its utility as a vaccine candidate. PMID- 21682914 TI - On the importance of long-term functional assessment after stroke to improve translation from bench to bedside. AB - Despite extensive research efforts in the field of cerebral ischemia, numerous disappointments came from the translational step. Even if experimental studies showed a large number of promising drugs, most of them failed to be efficient in clinical trials. Based on these reports, factors that play a significant role in causing outcome differences between animal experiments and clinical trials have been identified; and latest works in the field have tried to discard them in order to improve the scope of the results. Nevertheless, efforts must be maintained, especially for long-term functional evaluations. As observed in clinical practice, animals display a large degree of spontaneous recovery after stroke. The neurological impairment, assessed by basic items, typically disappears during the firsts week following stroke in rodents. On the contrary, more demanding sensorimotor and cognitive tasks underline other deficits, which are usually long-lasting. Unfortunately, studies addressing such behavioral impairments are less abundant. Because the characterization of long-term functional recovery is critical for evaluating the efficacy of potential therapeutic agents in experimental strokes, behavioral tests that proved sensitive enough to detect long-term deficits are reported here. And since the ultimate goal of any stroke therapy is the restoration of normal function, an objective appraisal of the behavioral deficits should be done. PMID- 21682915 TI - 'The smoking toolkit study': a national study of smoking and smoking cessation in England. AB - BACKGROUND: Up-to-date data tracking of national smoking patterns and cessation related behaviour is required to evaluate and inform tobacco control strategies. The Smoking Toolkit Study (STS) was designed for this role. This paper describes the methodology of the STS and examines as far as possible the representativeness of the samples. METHODS: The STS consists of monthly, cross sectional household interviews of adults aged 16 and over in England with smokers and recent ex smokers in each monthly wave followed up by postal questionnaires three and six months later. Between November 2006 and December 2010 the baseline survey was completed by 90,568 participants. STS demographic, prevalence and cigarette consumption estimates are compared with those from the Health Survey for England (HSE) and the General Lifestyle Survey (GLF) for 2007-2009. RESULTS: Smoking prevalence estimates of all the surveys were similar from 2008 onwards (e.g 2008 STS=22.0%, 95% C.I.=21.4% to 22.6%, HSE=21.7%, 95% C.I.=20.9% to 22.6%, GLF=20.8%, 95% C.I.=19.7% to 21.9%), although there was heterogeneity in 2007 (chi-square=50.30, p<0.001). Some differences were observed across surveys within sociodemographic sub-groups, although largely in 2007. Cigarette consumption was virtually identical in all surveys and years. CONCLUSION: There is reason to believe that the STS findings (see http://www.smokinginengland.info) are generalisable to the adult population of England. PMID- 21682916 TI - Unlimited access to health care--impact of psychosomatic co-morbidity on utilisation in German general practices. AB - BACKGROUND: The effect of psychosomatic co-morbidity on resource use for systems with unlimited access remains unclear. The aim of this study was to evaluate the impact on practice visits, referrals and periods of disability in German general practices and to identify predictors of health care utilisation. METHODS: Cross sectional observational study in 13 practices in Upper Bavaria. Patients were included consecutively and filled in the Patients Health Questionnaire (PHQ). Numbers of practice visits, referrals and periods of disability within the last twelve months and permanent mental and somatic diagnoses were extracted manually by review of the computerised charts. Physicians in Germany are obliged to document repetitive reasons of encounter as permanent diagnoses in terms of ICD 10-codes. These ICD-10-codes are used for legitimisation of reimbursement in German general practices. RESULTS: 1005 patients were included (58.6% female). On average, patients had 15.3 (sd 16.3) practice contacts, 3.8 (sd 4.2) referrals and 7.5 (sd 23.1) days of disability per year. The mean number of coded permanent diagnoses was 0.4 (sd 0.7) for mental and 4.0 (sd 4.0) for somatic diagnoses. Patients with mental diagnoses scored higher in depression, anxiety, panic and somatoform disorder scales of PHQ. Frequent practice visits were associated stronger with coded permanent mental diagnoses (OR 20.0; 95%CI 7.5-53.9) than with coded permanent somatic diagnoses (OR 14.4; 95%CI 5.9-35.4). Frequent referrals were associated stronger with somatic diagnoses (OR 4.9; 95%CI 2.0 11.9) than with mental diagnoses (OR 3.6; 95%CI 1.4-9.8). Periods of disability were predicted by mental diagnoses (OR 5.0; 95%CI 1.6-15.8) but not by somatic diagnoses (OR 2.5; 95%CI 0.7-8.1). CONCLUSIONS: Psychosomatic co-morbidity has a stronger impact on health care utilisation in German general practices with respect to practice visits and periods of disability whereas somatic disorders play a stronger role for referrals. Time constraints in the practices might lead to frequent contacts as too little time is left for patients with mental problems. Therefore, structural changes in the health care reimbursement systems might be necessary. Mental diagnoses might be helpful to identify patients at risk for high health care utilisation. However, the use of routinely coded diagnoses for reimbursement might lead to distorted estimation of resource use. PMID- 21682917 TI - Novel norovirus recombinants and of GII.4 sub-lineages associated with outbreaks between 2006 and 2010 in Belgium. AB - BACKGROUND: Noroviruses (NoVs) are an important cause of acute gastroenteritis in humans worldwide. To gain insight into the epidemiologic patterns of NoV outbreaks and to determine the genetic variation of NoVs strains circulating in Belgium, stool samples originating from patients infected with NoVs in foodborne outbreak investigations were analysed between December 2006 and December 2010. RESULTS: NoVs were found responsible of 11.8% of all suspected foodborne outbreaks reported in the last 4 years and the number of NoV outbreaks reported increased along the years representing more than 30% of all foodborne outbreaks in 2010. Genogroup II outbreaks largely predominated and represented more than 90% of all outbreaks. Phylogenetic analyses were performed with 63 NoV-positive samples for the partial polymerase (N = 45) and/or capsid gene (N = 35) sequences. For 12 samples, sequences covering the ORF1-ORF2 junction were obtained. A variety of genotypes was found among genogroups I and II; GII.4 was predominant followed in order of importance by GII.2, GII.7, GII.13, GI.4 and GI.7. In the study period, GII.4 NoVs variants 2006a, 2006b, 2007, 2008 and 2010 were identified. Moreover, phylogenetic analyses identified different recombinant NoV strains that were further characterised as intergenotype (GII.e/GII.4 2007, GII.e/GII.3 and GII.g/GII.1) and intersub-genotype (GII.4 2006b/GII.4 2007 and GII.4 2010/GII.4 2010b) recombinants. CONCLUSIONS: NoVs circulating in the last 4 years in Belgium showed remarkable genetic diversity either by small-scale mutations or genetic recombination. In this period, GII.4 2006b was successfully displaced by the GII.4 2010 subtype, and previously reported epidemic GII.b recombinants seemed to have been superseded by GII.e recombinants in 2009 and GII.g recombinants in 2010. This study showed that the emergence of novel GII.4 variants together with novel GII recombinants could lead to an explosion in NoV outbreaks, likewise to what was observed in 2008 and 2010. Among recombinants detected in this study, two hitherto unreported strains GII.e/GII.3 and GII.g/GII.1 were characterised. Surveillance will remain important to monitor contemporaneously circulating strains in order to adapt preventive and curative strategies. PMID- 21682918 TI - Nuclear and cytoplasmic LIMK1 enhances human breast cancer progression. AB - BACKGROUND: LIM kinase 1 (LIMK1) is expressed in both cytoplasmic and nuclear compartments, and is a key regulator of cytoskeletal organization involved in cell migration and proliferation. LIMK1 levels are increased in several human cancers, with LIMK1 over-expression in prostate and breast cancer cells leading to tumor progression. While it has been presumed that the mechanism by which LIMK1 promotes cancer progression is via its cytoplasmic effects, the role of nuclear vs cytoplasmic LIMK1 in the tumorigenic process has not been examined. RESULTS: To determine if cytoplasmic or nuclear LIMK1 expression correlated with breast cancer, we performed immunohistochemical (IHC) analysis of breast tissue microarrays (TMAs), The IHC analysis of breast TMAs revealed that 76% of malignant breast tissue samples strongly expressed LIMK1 in the cytoplasm, with 52% of these specimens also expressing nuclear LIMK1. Only 48% of benign breast samples displayed strong cytoplasmic LIMK1 expression and 27% of these expressed nuclear LIMK1. To investigate the respective roles of cytoplasmic and nuclear LIMK1 in breast cancer progression, we targeted GFP-LIMK1 to cytoplasmic and nuclear subcellular compartments by fusing nuclear export signals (NESs) or nuclear localization sequences (NLS), respectively, to the amino-terminus of GFP LIMK1. Stable pools of MDA-MB-231 cells were generated by retroviral transduction, and fluorescence microscopy revealed that GFP alone (control) and GFP-LIMK1 were each expressed in both the cytoplasm and nucleus of MDA-MB-231 cells, whereas NLS-GFP-LIMK1 was expressed in the nucleus and NES-GFP-LIMK1 was expressed in the cytoplasm. Western blot analyses revealed equal expression of GFP-LIMK1 and NES-GFP-LIMK1, with NLS-GFP-LIMK1 expression being less but equal to endogenous LIMK1. Also, Western blotting revealed increased levels of phospho cofilin, phospho-FAK, phospho-paxillin, phospho-Src, phospho-AKT, and phospho Erk1/2 in cells expressing all GFP-LIMK1 fusions, compared to GFP alone. Invasion assays revealed that all GFP-LIMK1 fusions increased MDA-MB-231 cell invasion ~1.5-fold, compared to GFP-only control cells. Tumor xenograft studies in nude mice revealed that MDA-MB-231 cells stably expressing GFP-LIMK, NLS-GFP-LIMK1 and NES-GFP-LIMK1 enhanced tumor growth 2.5-, 1.6- and 4.7-fold, respectively, compared to GFP-alone. CONCLUSION: Taken together, these data demonstrate that LIMK1 activity in both the cytoplasmic and nuclear compartments promotes breast cancer progression, underscoring that nuclear LIMK1 contributes to the transforming function of LIMK1. PMID- 21682919 TI - Insecticide-treated net (ITN) ownership, usage, and malaria transmission in the highlands of western Kenya. AB - BACKGROUND: Insecticide-treated bed nets (ITNs) are known to be highly effective in reducing malaria morbidity and mortality. However, usage varies among households, and such variations in actual usage may seriously limit the potential impact of nets and cause spatial heterogeneity on malaria transmission. This study examined ITN ownership and underlying factors for among-household variation in use, and malaria transmission in two highland regions of western Kenya. METHODS: Cross-sectional surveys were conducted on ITN ownership (possession), compliance (actual usage among those who own ITNs), and malaria infections in occupants of randomly sampled houses in the dry and the rainy seasons of 2009. RESULTS: Despite ITN ownership reaching more than 71%, compliance was low at 56.3%. The compliance rate was significantly higher during the rainy season compared with the dry season (62% vs. 49.6%). Both malaria parasite prevalence (11.8% vs. 5.1%) and vector densities (1.0 vs.0.4 female/house/night) were significantly higher during the rainy season than during the dry season. Other important factors affecting the use of ITNs include: a household education level of at least primary school level, significantly high numbers of nuisance mosquitoes, and low indoor temperatures. Malaria prevalence in the rainy season was about 30% lower in ITN users than in non-ITN users, but this percentage was not significantly different during the dry season. CONCLUSION: In malaria hypo mesoendemic highland regions of western Kenya, the gap between ITNownership and usage is generally high with greater usage recorded during the high transmission season. Because of the low compliance among those who own ITNs, there is a need to sensitize households on sustained use of ITNs in order to optimize their role as a malaria control tool. PMID- 21682920 TI - Two logistic models for the prediction of hypothyroidism in pregnancy. AB - BACKGROUND: The mounting evidence linking hypothyroidism during pregnancy with poor pregnancy outcome underscores the need for screening and, therefore, a search for more reliable and cheaper screening methods. METHODS: The study was conducted in two phases. The phase one study comprised of healthy women in different stages of pregnancy who attended routine antenatal clinic at St Theresa's Maternity Hospital, Enugu, Nigeria from September 6 to October 18 1994. In this study the variables compared between the hypothyroid and non-hypothyroid pregnant women were maternal age, the number of the pregnancy or gravidity, gestational age, social class, body weight, height, the clinically assessed size of the thyroid gland, serum free thyroxin (FT4) and serum thyrotrophin (TSH). Based on the parameter differences between the two comparison groups of pregnant women two Logistic models, Model I and Model 11, were derived to differentiate the hypothyroid group from their non-hypothyroid counterparts. The two logistic models were then applied in a prospective validation study involving 197 pregnant women seen at presentation in Mother of Christ Specialist Hospital and Maternity, Ogui Road, Enugu from March 2002 to November 2007 FINDINGS: The findings were that 82 (50.3%) of the 163 pregnant women had thyroid gland enlargement while 60 (36.8%) had hypothyroidism as defined by FT4 values below and/or TSH above their laboratory reference ranges. The pregnant subjects with hypothyroidism, compared with their non-hypothyroid counterparts, were characterized by a higher gravidity (p < 0.01), a higher body weight (p < 0.01), a higher goiter prevalence rate (p < 0.01) and a more advanced gestational age (p < 0.0001). A significant, positive correlation was also found between body weight and gestational age (r = 0.5; p < 0.01) At the cut-off point for Model l (fitted with gravidity, thyroid size and gestational age) it had a sensitivity of 100%, a specificity of 72.8% and an overall predictive accuracy of 82.9%; whereas for Model II (fitted with gravidity, thyroid size and body weight) the sensitivity was 100%, the specificity was 59.2% and the overall accuracy of discrimination was 74.8%. In the prospective validation study both models showed a sensitivity of 100% each with specificities of 85.5% for Model I and 76.2% for Model II. CONCLUSION: It is concluded that logistic models fitting gravidity, thyroid gland size and gestational age or body weight are useful alternatives in screening for hypothyroidism during pregnancy. There is, however, a need for further independent confirmation of these findings. PMID- 21682921 TI - Enhancements to the ADMIXTURE algorithm for individual ancestry estimation. AB - BACKGROUND: The estimation of individual ancestry from genetic data has become essential to applied population genetics and genetic epidemiology. Software programs for calculating ancestry estimates have become essential tools in the geneticist's analytic arsenal. RESULTS: Here we describe four enhancements to ADMIXTURE, a high-performance tool for estimating individual ancestries and population allele frequencies from SNP (single nucleotide polymorphism) data. First, ADMIXTURE can be used to estimate the number of underlying populations through cross-validation. Second, individuals of known ancestry can be exploited in supervised learning to yield more precise ancestry estimates. Third, by penalizing small admixture coefficients for each individual, one can encourage model parsimony, often yielding more interpretable results for small datasets or datasets with large numbers of ancestral populations. Finally, by exploiting multiple processors, large datasets can be analyzed even more rapidly. CONCLUSIONS: The enhancements we have described make ADMIXTURE a more accurate, efficient, and versatile tool for ancestry estimation. PMID- 21682922 TI - Isolation and characterization of a novel alphanodavirus. AB - BACKGROUND: Nodaviridae is a family of non-enveloped isometric viruses with bipartite positive-sense RNA genomes. The Nodaviridae family consists of two genera: alpha- and beta-nodavirus. Alphanodaviruses usually infect insect cells. Some commercially available insect cell lines have been latently infected by Alphanodaviruses. RESULTS: A non-enveloped small virus of approximately 30 nm in diameter was discovered co-existing with a recombinant Helicoverpa armigera single nucleopolyhedrovirus (HearNPV) in Hz-AM1 cells. Genome sequencing and phylogenetic assays indicate that this novel virus belongs to the genus of alphanodavirus in the family Nodaviridae and was designated HzNV. HzNV possesses a RNA genome that contains two segments. RNA1 is 3038 nt long and encodes a 110 kDa viral protein termed protein A. The 1404 nt long RNA2 encodes a 44 kDa protein, which exhibits a high homology with coat protein precursors of other alphanodaviruses. HzNV virions were located in the cytoplasm, in association with cytoplasmic membrane structures. The host susceptibility test demonstrated that HzNV was able to infect various cell lines ranging from insect cells to mammalian cells. However, only Hz-AM1 appeared to be fully permissive for HzNV, as the mature viral coat protein essential for HzNV particle formation was limited to Hz AM1 cells. CONCLUSION: A novel alphanodavirus, which is 30 nm in diameter and with a limited host range, was discovered in Hz-AM1 cells. PMID- 21682923 TI - MLPAstats: an R GUI package for the integrated analysis of copy number alterations using MLPA data. AB - BACKGROUND: Multiplex-Dependent Probe Amplification (MLPA) is a cost-effective experimental method for candidate gene studies, aimed at the identification of copy number alterations. The analysis of such genetic variants, from electropherogram peak intensities, involves two main stages. First, peak normalization for each probe is required to remove the contribution of probe size to peak intensity. Second, the statistical significance of peak alteration between case and control samples is estimated. A number of methods have been proposed in each step with varying levels of complexity and precision. However, there is no single framework from which the results of each method and possible combinations at each step can be assessed. RESULTS: We present MLPAstats, an R package designed to integrate the methods for exploring different analysis scenarios in a reliable way. A GUI has been developed to allow researchers to find their optimal analysis strategy. CONCLUSIONS: MLPAstats is an analysis tool that promotes the use of cost-effective MLPA suitable for candidate gene studies. Its R implementation allows future methods to be easily incorporated, while its GUI will facilitate its use by non-expert analysts. A vignette describing a set by-step tutorial is also available with the package. PMID- 21682924 TI - Analysis of the construct of dignity and content validity of the patient dignity inventory. AB - BACKGROUND: Maintaining dignity, the quality of being worthy of esteem or respect, is considered as a goal of palliative care. The aim of this study was to analyse the construct of personal dignity and to assess the content validity of the Patient Dignity Inventory (PDI) in people with an advance directive in the Netherlands. METHODS: Data were collected within the framework of an advance directives cohort study. This cohort study is aiming to get a better insight into how decisions are made at the end of life with regard to advance directives in the Netherlands. One half of the cohort (n = 2404) received an open-ended question concerning factors relevant to dignity. Content labels were assigned to issues mentioned in the responses to the open-ended question. The other half of the cohort (n = 2537) received a written questionnaire including the PDI. The relevance and comprehensiveness of the PDI items were assessed with the COSMIN checklist ('COnsensus-based Standards for the selection of health status Measurement INstruments'). RESULTS: The majority of the PDI items were found to be relevant for the construct to be measured, the study population, and the purpose of the study but the items were not completely comprehensive. The responses to the open-ended question indicated that communication and care related aspects were also important for dignity. CONCLUSIONS: This study demonstrated that the PDI items were relevant for people with an advance directive in the Netherlands. The comprehensiveness of the items can be improved by including items concerning communication and care. PMID- 21682925 TI - Aortic valve tear with severe aortic regurgitation following blunt chest trauma. AB - An aortic valve tear associated with aortic regurgitation following blunt chest trauma is seldom seen. In this case, a 55-year-old man sustained a non penetrating chest injury caused by a sudden fall from 10 meters. This led to a sizable tear in the left coronary cusp associated with severe aortic insufficiency. The case was treated successfully by surgical replacement of the aortic valve with a mechanical prosthesis. PMID- 21682926 TI - Long- term outcome of paediatric patients with ANCA vasculitis. AB - BACKGROUND: Primary systemic vasculitis presenting in childhood is an uncommon but serious condition. As these patients transfer to adult clinics for continuing care, defining long term outcomes with emphasis on disease and treatment- related morbidity and mortality is important. The aim of this study is to describe the long- term clinical course of paediatric patients with ANCA vasculitis. METHODS: The adult patients in our vasculitis clinics who had presented in childhood, with a follow up time of greater than 10 years were included. We also reviewed the literature for articles describing the clinical outcome of paediatric patients with ANCA vasculitis. RESULTS: We describe the clinical course of 8 adults who presented in childhood with ANCA vasculitis. 7 patients had Wegener's granulomatosis and 1 had microscopic polyangiitis. The median age at presentation was 11.5 years, and follow up time ranged form 11 to 30 years. Induction therapy for all patients was steroids and/or cyclophosphamide. Maintenance therapy was with azathioprine or mycophenolate mofetil. Biological agents were used in 3 patients for relapsed disease in adulthood only.Seven patients achieved complete remission. All patients experienced disease relapse, with a median of 4 episodes. Kidney function was generally well preserved, with median eGFR 76 ml/min. Only one patient developed end-stage renal failure and one patient died after 25 years of disease. Treatment-related morbidity rates were high; 7 suffered from infections, 4 were infertile, 2 had skeletal complications, and 1 developed malignancy. CONCLUSION: Close long- term follow up of paediatric patients with ANCA vasculitis is imperative, as this patient cohort is likely to live long enough to develop significant treatment and disease- related morbidities. Prospective cohort studies with novel therapies including paediatric patients are crucial to help us determine the best approach to managing this complex group of patients. In addition, although not yet observed in our series, late cardiovascular morbidity remains a major longer-term potential concern for adult survivors of paediatric vasculitis. PMID- 21682927 TI - Development and validation of a novel molecular biomarker diagnostic test for the early detection of sepsis. AB - INTRODUCTION: Sepsis is a complex immunological response to infection characterized by early hyper-inflammation followed by severe and protracted immunosuppression, suggesting that a multi-marker approach has the greatest clinical utility for early detection, within a clinical environment focused on Systemic Inflammatory Response Syndrome (SIRS) differentiation. Pre-clinical research using an equine sepsis model identified a panel of gene expression biomarkers that define the early aberrant immune activation. Thus, the primary objective was to apply these gene expression biomarkers to distinguish patients with sepsis from those who had undergone major open surgery and had clinical outcomes consistent with systemic inflammation due to physical trauma and wound healing. METHODS: This was a multi-centre, prospective clinical trial conducted across four tertiary critical care settings in Australia. Sepsis patients were recruited if they met the 1992 Consensus Statement criteria and had clinical evidence of systemic infection based on microbiology diagnoses (n = 27). Participants in the post-surgical (PS) group were recruited pre-operatively and blood samples collected within 24 hours following surgery (n = 38). Healthy controls (HC) included hospital staff with no known concurrent illnesses (n = 20). Each participant had minimally 5 ml of PAXgene blood collected for leucocyte RNA isolation and gene expression analyses. Affymetrix array and multiplex tandem (MT)-PCR studies were conducted to evaluate transcriptional profiles in circulating white blood cells applying a set of 42 molecular markers that had been identified a priori. A LogitBoost algorithm was used to create a machine learning diagnostic rule to predict sepsis outcomes. RESULTS: Based on preliminary microarray analyses comparing HC and sepsis groups, a panel of 42 gene expression markers were identified that represented key innate and adaptive immune function, cell cycling, WBC differentiation, extracellular remodelling and immune modulation pathways. Comparisons against GEO data confirmed the definitive separation of the sepsis cohort. Quantitative PCR results suggest the capacity for this test to differentiate severe systemic inflammation from HC is 92%. The area under the curve (AUC) receiver operator characteristics (ROC) curve findings demonstrated sepsis prediction within a mixed inflammatory population, was between 86 and 92%. CONCLUSIONS: This novel molecular biomarker test has a clinically relevant sensitivity and specificity profile, and has the capacity for early detection of sepsis via the monitoring of critical care patients. PMID- 21682928 TI - The impact of socio-economic disadvantage on rates of hospital separations for diabetes-related foot disease in Victoria, Australia. AB - BACKGROUND: Information describing variation in health outcomes for individuals with diabetes related foot disease, across socioeconomic strata is lacking. The aim of this study was to investigate variation in rates of hospital separations for diabetes related foot disease and the relationship with levels of social advantage and disadvantage. METHODS: Using the Index of Relative Socioeconomic Disadvantage (IRSD) each local government area (LGA) across Victoria was ranked from most to least disadvantaged. Those LGAs ranked at the lowest end of the scale and therefore at greater disadvantage (Group D) were compared with those at the highest end of the scale (Group A), in terms of total and per capita hospital separations for peripheral neuropathy, peripheral vascular disease, foot ulceration, cellulitis and osteomyelitis and amputation. Hospital separations data were compiled from the Victorian Admitted Episodes Database. RESULTS: Total and per capita separations were 2,268 (75.3/1,000 with diabetes) and 2,734 (62.3/1,000 with diabetes) for Group D and Group A respectively. Most notable variation was for foot ulceration (Group D, 18.1/1,000 versus Group A, 12.7/1,000, rate ratio 1.4, 95% CI 1.3, 1.6) and below knee amputation (Group D 7.4/1,000 versus Group A 4.1/1,000, rate ratio 1.8, 95% CI 1.5, 2.2). Males recorded a greater overall number of hospital separations across both socioeconomic strata with 66.2% of all separations for Group D and 81.0% of all separations for Group A recorded by males. However, when comparing mean age, males from Group D tended to be younger compared with males from Group A (mean age; 53.0 years versus 68.7 years). CONCLUSION: Variation appears to exist for hospital separations for diabetes related foot disease across socioeconomic strata. Specific strategies should be incorporated into health policy and planning to combat disparities between health outcomes and social status. PMID- 21682929 TI - Can improving working memory prevent academic difficulties? A school based randomised controlled trial. AB - BACKGROUND: Low academic achievement is common and is associated with adverse outcomes such as grade repetition, behavioural disorders and unemployment. The ability to accurately identify these children and intervene before they experience academic failure would be a major advance over the current 'wait to fail' model. Recent research suggests that a possible modifiable factor for low academic achievement is working memory, the ability to temporarily store and manipulate information in a 'mental workspace'. Children with working memory difficulties are at high risk of academic failure. It has recently been demonstrated that working memory can be improved with adaptive training tasks that encourage improvements in working memory capacity. Our trial will determine whether the intervention is efficacious as a selective prevention strategy for young children at risk of academic difficulties and is cost-effective. METHODS/DESIGN: This randomised controlled trial aims to recruit 440 children with low working memory after a school-based screening of 2880 children in Grade one. We will approach caregivers of all children from 48 participating primary schools in metropolitan Melbourne for consent. Children with low working memory will be randomised to usual care or the intervention. The intervention will consist of 25 computerised working memory training sessions, which take approximately 35 minutes each to complete. Follow-up of children will be conducted at 6, 12 and 24 months post-randomisation through child face-to-face assessment, parent and teacher surveys and data from government authorities. The primary outcome is academic achievement at 12 and 24 months, and other outcomes include child behaviour, attention, health-related quality of life, working memory, and health and educational service utilisation. DISCUSSION: A successful start to formal learning in school sets the stage for future academic, psychological and economic well-being. If this preventive intervention can be shown to be efficacious, then we will have the potential to prevent academic underachievement in large numbers of at-risk children, to offer a ready-to-use intervention to the Australian school system and to build international research partnerships along the health-education interface, in order to carry our further studies of effectiveness and generalisability. PMID- 21682930 TI - Melittin restores proteasome function in an animal model of ALS. AB - Amyotrophic lateral sclerosis (ALS) is a paralyzing disorder characterized by the progressive degeneration and death of motor neurons and occurs both as a sporadic and familial disease. Mutant SOD1 (mtSOD1) in motor neurons induces vulnerability to the disease through protein misfolding, mitochondrial dysfunction, oxidative damage, cytoskeletal abnormalities, defective axonal transport- and growth factor signaling, excitotoxicity, and neuro-inflammation.Melittin is a 26 amino acid protein and is one of the components of bee venom which is used in traditional Chinese medicine to inhibit of cancer cell proliferation and is known to have anti-inflammatory and anti-arthritic effects.The purpose of the present study was to determine if melittin could suppress motor neuron loss and protein misfolding in the hSOD1G93A mouse, which is commonly used as a model for inherited ALS. Meltittin was injected at the 'ZuSanLi' (ST36) acupuncture point in the hSOD1G93A animal model. Melittin-treated animals showed a decrease in the number of microglia and in the expression level of phospho-p38 in the spinal cord and brainstem. Interestingly, melittin treatment in symptomatic ALS animals improved motor function and reduced the level of neuron death in the spinal cord when compared to the control group. Furthermore, we found increased of alpha-synuclein modifications, such as phosphorylation or nitration, in both the brainstem and spinal cord in hSOD1G93A mice. However, melittin treatment reduced alpha synuclein misfolding and restored the proteasomal activity in the brainstem and spinal cord of symptomatic hSOD1G93A transgenic mice.Our research suggests a potential functional link between melittin and the inhibition of neuroinflammation in an ALS animal model. PMID- 21682931 TI - Cyclic Tetrapyrrolic Photosensitisers from the leaves of Phaeanthus ophthalmicus. AB - BACKGROUND: Twenty-seven extracts from 26 plants were identified as photo cytotoxic in the course of our bioassay guided screening program for photosensitisers from 128 extracts prepared from 64 terrestrial plants in two different collection sites in Malaysia - Royal Belum Forest Reserve in the State of Perak and Gunung Nuang in the State of Selangor. One of the photo-cytotoxic extracts from the leaves of Phaeanthus ophtalmicus was further investigated. RESULTS: The ethanolic extract of the leaves from Phaeanthus ophtalmicus was able to reduce the in vitro viability of leukaemic HL60 cells to < 50% when exposed to 9.6 J/cm2 of a broad spectrum light at a concentration of 20 MUg/mL. Dereplication of the photo-cytotoxic fractions from P. ophthalmicus extracts based on TLC Rf values and HPLC co-injection of reference tetrapyrrolic compounds enabled quick identification of known photosensitisers, pheophorbide-a, pheophorbide-a methyl ester, 132-hydroxypheophorbide-a methyl ester, pheophytin-a and 151-hydroxypurpurin 7-lactone dimethyl ester. In addition, compound 1 which was not previously isolated as a natural product was also identified as 7-formyl 151-hydroxypurpurin-7-lactone methyl ester using standard spectroscopic techniques. CONCLUSIONS: Our results suggest that the main photosensitisers in plants are based on the cyclic tetrapyrrole structure and photosensitisers with other structures, if present, are present in very minor amounts or are not as active as those with the cyclic tetrapyrrole structure. PMID- 21682932 TI - Comparison between elementary flux modes analysis and 13C-metabolic fluxes measured in bacterial and plant cells. AB - BACKGROUND: (13)C metabolic flux analysis is one of the pertinent ways to compare two or more physiological states. From a more theoretical standpoint, the structural properties of metabolic networks can be analysed to explore feasible metabolic behaviours and to define the boundaries of steady state flux distributions. Elementary flux mode analysis is one of the most efficient methods for performing this analysis. In this context, recent approaches have tended to compare experimental flux measurements with topological network analysis. RESULTS: Metabolic networks describing the main pathways of central carbon metabolism were set up for a bacteria species (Corynebacterium glutamicum) and a plant species (Brassica napus) for which experimental flux maps were available. The structural properties of each network were then studied using the concept of elementary flux modes. To do this, coefficients of flux efficiency were calculated for each reaction within the networks by using selected sets of elementary flux modes. Then the relative differences - reflecting the change of substrate i.e. a sugar source for C. glutamicum and a nitrogen source for B. napus - of both flux efficiency and flux measured experimentally were compared. For both organisms, there is a clear relationship between these parameters, thus indicating that the network structure described by the elementary flux modes had captured a significant part of the metabolic activity in both biological systems. In B. napus, the extension of the elementary flux mode analysis to an enlarged metabolic network still resulted in a clear relationship between the change in the coefficients and that of the measured fluxes. Nevertheless, the limitations of the method to fit some particular fluxes are discussed. CONCLUSION: This consistency between EFM analysis and experimental flux measurements, validated on two metabolic systems allows us to conclude that elementary flux mode analysis could be a useful tool to complement (13)C metabolic flux analysis, by allowing the prediction of changes in internal fluxes before carbon labelling experiments. PMID- 21682933 TI - miR-200c at the nexus of epithelial-mesenchymal transition, resistance to apoptosis, and the breast cancer stem cell phenotype. AB - Decreased expression of miRNAs of the miR-200 family has been implicated in the growth and metastasis of breast cancer cells. Of this family, miR-200c has garnered particular attention as a consequence of its ability to target ZEB1 and ZEB2, mediators of epithelial- mesenchymal transition. An article in the previous issue of Breast Cancer Research identifies additional targets of miR-200c that link increased cancer cell invasiveness, resistance to apoptosis, and induction of breast cancer stem cell characteristics. PMID- 21682934 TI - Genome-wide mapping of the sixth base. AB - Mapping of 5-hydroxylmethylcytosine in mammalian genomes has unveiled its unique role in the epigenetic regulation of gene expression. PMID- 21682935 TI - Grand network convergence. AB - A report of the Systems Biology: Networks meeting, Cold Spring Harbor, USA, 22-26 March 2011.The success of the human genome project has provided a model for an analogous interactome project to map how proteins, genes, metabolites and other regulatory components interact to transform a biochemical soup into a living system. These maps promise to serve as a framework for models that predict how a biological system responds to a perturbation or an input, which is relevant to gene mutations and therapeutic treatment in human disease, and as a framework for designing new systems in synthetic biology.Three major themes arose during the 2011 meeting: technological drivers and data generation, algorithmic advances, and convergence on biological applications with context-sensitive networks. PMID- 21682936 TI - Pluripotent stem cells and reprogrammed cells in farm animals. AB - Pluripotent cells are unique because of their ability to differentiate into the cell lineages forming the entire organism. True pluripotent stem cells with germ line contribution have been reported for mice and rats. Human pluripotent cells share numerous features of pluripotentiality, but confirmation of their in vivo capacity for germ line contribution is impossible due to ethical and legal restrictions. Progress toward derivation of embryonic stem cells from domestic species has been made, but the derived cells were not able to produce germ line chimeras and thus are termed embryonic stem-like cells. However, domestic animals, in particular the domestic pig (Sus scrofa), are excellent large animals models, in which the clinical potential of stem cell therapies can be studied. Reprogramming technologies for somatic cells, including somatic cell nuclear transfer, cell fusion, in vitro culture in the presence of cell extracts, in vitro conversion of adult unipotent spermatogonial stem cells into germ line derived pluripotent stem cells, and transduction with reprogramming factors have been developed with the goal of obtaining pluripotent, germ line competent stem cells from domestic animals. This review summarizes the present state of the art in the derivation and maintenance of pluripotent stem cells in domestic animals. PMID- 21682937 TI - Restoration of uneven illumination in light sheet microscopy images. AB - Light microscopy images suffer from poor contrast due to light absorption and scattering by the media. The resulting decay in contrast varies exponentially across the image along the incident light path. Classical space invariant deconvolution approaches, while very effective in deblurring, are not designed for the restoration of uneven illumination in microscopy images. In this article, we present a modified radiative transfer theory approach to solve the contrast degradation problem of light sheet microscopy (LSM) images. We confirmed the effectiveness of our approach through simulation as well as real LSM images. PMID- 21682938 TI - Prescribing pattern of psychotropic drugs in nursing home residents with dementia. AB - BACKGROUND: The goal of this study is to determine patterns of psychotropic drug use (PDU), the association with neuropsychiatric symptoms (NPS), and the variability across dementia types in nursing home residents with dementia. In addition, PDU was analyzed across multiple indications. METHODS: This was a prospective cohort study over a two-year period from 2006 to 2008, which involved 14 dementia special care units in nine nursing homes. A total of 117 residents with dementia participated in the study, of whom 35% had Alzheimer's dementia (AD) and 11% vascular dementia (VaD). PDU was classified according to anatomical therapeutic chemical-classification as either "present" or "absent". RESULTS: The majority of residents had moderately severe to severe dementia. At all successive assessments, almost two-thirds of residents received any psychotropic drug (PD) and almost one-third continued to receive any PD. Of all PDs, antipsychotics (APs) were prescribed most frequently. Fewer residents started with antidepressants, but continued to receive antidepressants at higher percentages. Anxiolytics showed an intermittent course, but a subgroup of 9% showed two-year continuation. Once started on PDs at baseline, residents continued to use PDs at high percentages: three-quarters continued to receive APs for at least six months. Half of residents received at least one PD; one-fifth received at least two PDs simultaneously. Residents with AD received more hypnotics and antidementia drugs; residents with VaD received more antipsychotics, antidepressants, anxiolytics and anticonvulsants. CONCLUSIONS: PDs have different utilization patterns, but overall, consistently high continuation rates were found. These results warrant scrutiny of continuous PDU. PMID- 21682939 TI - Stakeholders' perspective on issues and challenges associated with care and treatment of aging-related cognitive impairment disorders in Singapore. AB - BACKGROUND: An expanding elderly population poses challenges for the provision of care and treatment for age-related physical and mental disorders. Cognitive impairment (CI)/dementia is one such mental disorder that is on the rise in Singapore and has concomitant implications for social and health systems. The objective of this study is to understand the perspectives of prominent stakeholders about current and future issues and challenges associated with CI/dementia among the elderly in Singapore. METHODS: Using indepth interviews, this qualitative study obtained the views of multiple stakeholders on issues and challenges associated with CI/dementia in Singapore. The 30 individuals interviewed as part of the study included clinicians, policy-makers, researchers, community workers, administrators, and caregivers. Using a framework approach, interview texts were indexed into domains and issues by utilizing NVivo 9.0 software. RESULTS: The stakeholders expressed concerns related to multiple domains of the CI/dementia care system: attitude and awareness, economics, education, family caregiving, inputs to care system, living arrangements, prevention, screening and diagnosis, and treatment and management of care. Within each domain, multiple issues and challenges were identified by respondents. CONCLUSIONS: The study identifies a complex set of inter-related issues and challenges that are associated with the care and treatment of people with CI/dementia. The results suggest that CI and dementia profoundly affect patients, families, and communities and that the issues related to the two disorders are truly system-wide. These findings lay the foundation for utilization of a systems approach to studying CI/dementia and provide an analytic framework for future research on complex health care issues. PMID- 21682940 TI - Stability of the factor structure of the Neuropsychiatric Inventory in a 31-month follow-up study of a large sample of nursing-home patients with dementia. AB - BACKGROUND: Neuropsychiatric symptoms (NPS) are highly prevalent among nursing home patients with dementia. Several studies have investigated subsyndromes of NPS but the stability of these subsyndromes over time has rarely been examined. We have examined the stability over time of the factor structure of the Neuropsychiatric Inventory-Nursing Home version (NPI-NH) in a large sample of nursing-home patients with dementia. METHODS: Nursing-home patients with dementia were assessed with the NPI-NH at baseline (n = 895), and at 12-month (n = 592) and 31-month (n = 278) follow-up assessments, giving three partly overlapping samples. Exploratory factor analysis was done to investigate neuropsychiatric subsyndromes of the NPI-NH at each assessment in these samples. RESULTS: Three- or four-factor solutions were found, termed agitation, psychosis, apathy, and affective symptoms. Depression and anxiety (affective), delusion and hallucination (psychosis), and agitation and irritability (agitation) were the symptoms that most often co-occurred in the same factor. Apathy did not load together with affective symptoms at any of the assessments. CONCLUSIONS: Subsyndromes of the NPI-NH are relatively stable over 31-month follow-up assessments in nursing-home patients with dementia, indicating that these subsyndromes may be useful for following the natural course of symptoms as well as observing the effect of interventions. Our findings lend support to the distinction between apathy and affective symptoms, which may have important clinical implications. PMID- 21682941 TI - Delirium superimposed on dementia: defining disease states and course from longitudinal measurements of a multivariate index using latent class analysis and hidden Markov chains. AB - BACKGROUND: The study of mental disorders in the elderly presents substantial challenges due to population heterogeneity, coexistence of different mental disorders, and diagnostic uncertainty. While reliable tools have been developed to collect relevant data, new approaches to study design and analysis are needed. We focus on a new analytic approach. METHODS: Our framework is based on latent class analysis and hidden Markov chains. From repeated measurements of a multivariate disease index, we extract the notion of underlying state of a patient at a time point. The course of the disorder is then a sequence of transitions among states. States and transitions are not observable; however, the probability of being in a state at a time point, and the transition probabilities from one state to another over time can be estimated. RESULTS: Data from 444 patients with and without diagnosis of delirium and dementia were available from a previous study. The Delirium Index was measured at diagnosis, and at 2 and 6 months from diagnosis. Four latent classes were identified: fairly healthy, moderately ill, clearly sick, and very sick. Dementia and delirium could not be separated on the basis of these data alone. Indeed, as the probability of delirium increased, so did the probability of decline of mental functions. Eight most probable courses were identified, including good and poor stable courses, and courses exhibiting various patterns of improvement. CONCLUSION: Latent class analysis and hidden Markov chains offer a promising tool for studying mental disorders in the elderly. Its use may show its full potential as new data become available. PMID- 21682942 TI - Low-molecular-weight fucoidan regulates myogenic differentiation through the mitogen-activated protein kinase pathway in C2C12 cells. AB - Low-molecular-weight fucoidan (LMWF) has been broadly studied in recent years due to its numerous biological properties. Nevertheless, there have been no reports about the effects of LMWF on myogenic differentiation (MyoD). The objective of the present study was to demonstrate the impact of LMWF on myogenesis in C2C12 cells. The ultimate aim was to establish whether LMWF regulates myogenesis similar to heparin as a partial regulator of myogenesis. LMWF was prepared at a minimal size by ultra-filtration compared with crude fucoidan. We treated C2C12 cells with LMWF and/or heparin during MyoD. The data from the present study are the first to suggest that LMWF suppresses the expression of the myogenic regulatory factors and the myocyte enhancer factors as well as the morphological changes that occur during differentiation. Additionally, the expression of the mitogen-activated protein kinase (MAPK) family was significantly inhibited by LMWF when compared with controls. The LMWF-treated group showed significantly decreased expression of reactive oxygen species (ROS) enzymes compared with control cells. Heparin was used as a positive control because it has been reported to activate MyoD. Taken together, these results suggest that LMWF might regulate MyoD through the MAPK pathway and by regulating ROS activity in C2C12 cells. PMID- 21682943 TI - Regionally selective activation and differential regulation of ERK, JNK and p38 MAP kinase signalling pathway by protein kinase C in mood modulation. AB - A growing body of evidence indicates that the extracellular signal-regulated kinase (ERK) pathway may participate in the neuronal modulation of depression. p38MAPK and c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) also belong to the MAPK family which mainly function as mediators of cellular stresses. Since increasing evidence implicates stress as an important factor in vulnerability to depressive illnesses, the involvement of ERK, JNK and p38MAPK pathways in the modulation of mood was investigated in the forced swim test (FST) and tail suspension test (TST). The effect produced by a single acute session of FST and TST on hippocampal and cortical MAPK expression and phosphorylation was investigated by immunoblotting experiments. In the hippocampus of animals exposed to FST and TST, an intensive, PKC-dependent, ERK1, ERK2, JNK, and p38MAPK phosphorylation was observed. In the frontal cortex, the FST and TST produced a PKC-dependent increase of ERK2 and p38MAPK phosphorylation, a PKC-independent activation of JNK and cAMP response element-binding protein (CREB) whereas any involvement of ERK1 was detected. The PKC blocker calphostin C (0.05-0.1 MUg i.c.v.), the MEK inhibitor U0126 (10-20 MUg i.c.v.), the p38MAPK inhibitor SB203580 (5-20 MUg i.c.v.) and the JNK inhibitor II (0.5-5 MUg i.c.v.), produced antidepressant-like behaviour without altering locomotor activity. These results illustrate a differentially mediated activation of MAPK in hippocampus and frontal cortex of animals exposed to behavioural despair paradigms. An antidepressant-like phenotype produced by acute blockade of MAPK signalling was also demonstrated. PMID- 21682944 TI - DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population. AB - It is well accepted that schizophrenia has a strong genetic component. Several genome-wide association studies (GWASs) of schizophrenia have been published in recent years; most of them population based with a case-control design. Nevertheless, identifying the specific genetic variants which contribute to susceptibility to the disorder remains a challenging task. A family-based GWAS strategy may be helpful in the identification of schizophrenia susceptibility genes since it is protected against population stratification, enables better accounting for genotyping errors and is more sensitive for identification of rare variants which have a very low frequency in the general population. In this project we implemented a family-based GWAS of schizophrenia in a sample of 107 Jewish-Israeli families. We found one genome-wide significant association in the intron of the DOCK4 gene (rs2074127, p value=1.134*10-7) and six additional nominally significant association signals with p<1*10-5. One of the top single nucleotide polymorphisms (p<1*10-5) which is located in the predicted intron of the CEACAM21 gene was significantly replicated in independent family-based sample of Arab-Israeli origin (rs4803480: p value=0.002; combined p value=9.61*10-8), surviving correction for multiple testing. Both DOCK4 and CEACAM21 are biologically reasonable candidate genes for schizophrenia although generalizability of the association of DOCK4 with schizophrenia should be investigated in further studies. In addition, gene-wide significant associations were found within three schizophrenia candidate genes: PGBD1, RELN and PRODH, replicating previously reported associations. By application of a family-based strategy to GWAS, our study revealed new schizophrenia susceptibility loci in the Jewish-Israeli population. PMID- 21682945 TI - Increased Cdk5/p35 activity in the dentate gyrus mediates depressive-like behaviour in rats. AB - Depression is one of the most pervasive and debilitating psychiatric diseases, and the molecular mechanisms underlying the pathophysiology of depression have not been elucidated. Cyclin-dependent kinase 5 (Cdk5) has been implicated in synaptic plasticity underlying learning, memory, and neuropsychiatric disorders. However, whether Cdk5 participates in the development of depressive diseases has not been examined. Using the chronic mild stress (CMS) procedure, we examined the effects of Cdk5/p35 activity in the hippocampus on depressive-like behaviour in rats. We found that CMS increased Cdk5 activity in the hippocampus, accompanied by translocation of neuronal-specific activator p35 from the cytosol to the membrane in the dentate gyrus (DG) subregion. Inhibition of Cdk5 in DG but not in the cornu ammonis 1 (CA1) or CA3 hippocampal subregions inhibited the development of depressive-like symptoms. Overexpression of p35 in DG blocked the antidepressant-like effect of venlafaxine in the CMS model. Moreover, the antidepressants venlafaxine and mirtazapine, but not the antipsychotic aripiprazole, reduced Cdk5 activity through the redistribution of p35 from the membrane to the cytosol in DG. Our results showed that the development of depressive-like behaviour is associated with increased Cdk5 activity in the hippocampus and that the Cdk5/p35 complex plays a key role in the regulation of depressive-like behaviour and antidepressant actions. PMID- 21682946 TI - Antidepressant treatment is associated with epigenetic alterations in the promoter of P11 in a genetic model of depression. AB - P11 (S100A10) has been associated with the pathophysiology of depression both in human and rodent models. Different types of antidepressants have been shown to increase P11 levels in distinct brain regions and P11 gene therapy was recently proven effective in reversing depressive-like behaviours in mice. However, the molecular mechanisms that govern P11 gene expression in response to antidepressants still remain elusive. In this study we report decreased levels of P11, associated with higher DNA methylation in the promoter region, in the prefrontal cortex of the Flinders Sensitive Line (FSL) genetic rodent model of depression. This hypermethylated pattern was reversed to normal, as indicated by the control line, after chronic administration of escitalopram (a selective serotonin reuptake inhibitor; SSRI). The escitalopram-induced hypomethylation was associated with both an increase in P11 gene expression and a reduction in mRNA levels of two DNA methyltransferases that have been shown to maintain DNA methylation in adult forebrain neurons (Dnmt1 and Dnmt3a). In conclusion, our data further support a role for P11 in depression-like states and suggest that this gene is controlled by epigenetic mechanisms that can be affected by antidepressant treatment. PMID- 21682948 TI - The structure of depression, anxiety and somatic symptoms in primary care. AB - BACKGROUND: Observed co-morbidity among the mood and anxiety disorders has led to the development of increasingly sophisticated dimensional models to represent the common and unique features of these disorders. Patients often present to primary care settings with a complex mixture of anxiety, depression and somatic symptoms. However, relatively little is known about how somatic symptoms fit into existing dimensional models. METHOD: We examined the structure of 91 anxiety, depression and somatic symptoms in a sample of 5433 primary care patients drawn from 14 countries. One-, two- and three-factor lower-order models were considered; higher order and hierarchical variants were studied for the best-fitting lower-order model. RESULTS: A hierarchical, bifactor model with all symptoms loading simultaneously on a general factor, along with one of three specific anxiety, depression and somatic factors, was the best-fitting model. The general factor accounted for the bulk of symptom variance and was associated with psychosocial dysfunction. Specific depression and somatic symptom factors accounted for meaningful incremental variance in diagnosis and dysfunction, whereas anxiety variance was associated primarily with the general factor. CONCLUSIONS: The results (a) are consistent with previous studies showing the presence and importance of a broad internalizing or distress factor linking diverse emotional disorders, and (b) extend the bounds of internalizing to include somatic complaints with non-physical etiologies. PMID- 21682949 TI - Depressive symptom dimensions and cardiac prognosis following myocardial infarction: results from the ENRICHD clinical trial. AB - BACKGROUND: Depression following myocardial infarction (MI) independently increases risk for early cardiac morbidity and mortality. Studies suggest that somatic, but not cognitive, depressive symptoms are responsible for the increased risk. However, the effects of somatic depressive symptoms at follow-up, after sufficient time has elapsed to allow for physical recovery from the initial infarction, are not known. Our aim was to examine the relationship between cognitive and somatic depressive symptom dimensions at baseline and 12 months post-MI and subsequent mortality and cardiovascular morbidity. METHOD: Patients were 2442 depressed and/or socially isolated men and women with acute MI included in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial. We used principal components analysis (PCA) of the Beck Depression Inventory (BDI) items to derive subscales measuring cognitive and somatic depressive symptom dimensions, and Cox regression with Bonferroni correction for multiple testing to examine the contribution of these dimensions to all-cause mortality, cardiovascular mortality, and first recurrent non-fatal MI. RESULTS: After adjusting for medical co-morbidity and Bonferroni correction, the somatic depressive symptom dimension assessed proximately following MI did not significantly predict any endpoints. At 12 months post-MI, however, this dimension independently predicted subsequent all-cause [hazard ratio (HR) 1.43, 95% confidence interval (CI) 1.13-1.81] and cardiovascular mortality (HR 1.60, 95% CI 1.17-2.18). No significant associations were found between the cognitive depressive symptom dimension and any endpoints after Bonferroni correction. CONCLUSIONS: Somatic symptoms of depression at 12 months post-MI in patients at increased psychosocial risk predicted subsequent mortality. Psychosocial interventions aimed at improving cardiac prognosis may be enhanced by targeting somatic depressive symptoms, with particular attention to somatic symptom severity at 12 months post-MI. PMID- 21682951 TI - Peptidyl-prolyl cis-trans isomerase Pin1 in ageing, cancer and Alzheimer disease. AB - Phosphorylation of proteins on serine or threonine residues preceding proline is a key signalling mechanism in diverse physiological and pathological processes. Pin1 (peptidyl-prolyl cis-trans isomerase) is the only enzyme known that can isomerise specific Ser/Thr-Pro peptide bonds after phosphorylation and regulate their conformational changes with high efficiency. These Pin1-catalysed conformational changes can have profound effects on phosphorylation signalling by regulating a spectrum of target activities. Interestingly, Pin1 deregulation is implicated in a number of diseases, notably ageing and age-related diseases, including cancer and Alzheimer disease. Pin1 is overexpressed in most human cancers; it activates numerous oncogenes or growth enhancers and also inactivates a large number of tumour suppressors or growth inhibitors. By contrast, ablation of Pin1 prevents cancer, but eventually leads to premature ageing and neurodegeneration. Consistent with its neuroprotective role, Pin1 has been shown to be inactivated in neurons of patients with Alzheimer disease. Therefore, Pin1 mediated phosphorylation-dependent prolyl isomerisation represents a unique signalling mechanism that has a pivotal role in the development of human diseases, and might offer an attractive new diagnostic and therapeutic target. PMID- 21682950 TI - Using electronic medical records to enable large-scale studies in psychiatry: treatment resistant depression as a model. AB - BACKGROUND: Electronic medical records (EMR) provide a unique opportunity for efficient, large-scale clinical investigation in psychiatry. However, such studies will require development of tools to define treatment outcome. METHOD: Natural language processing (NLP) was applied to classify notes from 127 504 patients with a billing diagnosis of major depressive disorder, drawn from out patient psychiatry practices affiliated with multiple, large New England hospitals. Classifications were compared with results using billing data (ICD-9 codes) alone and to a clinical gold standard based on chart review by a panel of senior clinicians. These cross-sectional classifications were then used to define longitudinal treatment outcomes, which were compared with a clinician-rated gold standard. RESULTS: Models incorporating NLP were superior to those relying on billing data alone for classifying current mood state (area under receiver operating characteristic curve of 0.85-0.88 v. 0.54-0.55). When these cross sectional visits were integrated to define longitudinal outcomes and incorporate treatment data, 15% of the cohort remitted with a single antidepressant treatment, while 13% were identified as failing to remit despite at least two antidepressant trials. Non-remitting patients were more likely to be non Caucasian (p<0.001). CONCLUSIONS: The application of bioinformatics tools such as NLP should enable accurate and efficient determination of longitudinal outcomes, enabling existing EMR data to be applied to clinical research, including biomarker investigations. Continued development will be required to better address moderators of outcome such as adherence and co-morbidity. PMID- 21682952 TI - Portable pulse-dose oxygen concentrators should not be used with noninvasive ventilation. AB - An increasing number of patients, mainly COPD and overlap-syndrome patients, simultaneously use home oxygen therapy and noninvasive ventilation (NIV) at night. Usually the oxygen source is a stationary concentrator. We report a patient who, without a medical recommendation, was using a portable oxygen concentrator during nocturnal NIV. In the laboratory, with the patient, we tested the portable oxygen concentrator's triggering and oxygen delivery, with the supplemental oxygen connected at 3 different positions: near the ventilator, near the exhalation valve, and on the nasal mask port. We also tested the concentrator's triggering capacity by placing the nasal prongs and the nasal mask independently. We tested ventilator inspiratory pressures of 10, 14, and 18 cm H(2)O, and expiratory pressures of 4 and 6 cm H(2)O. The portable oxygen concentrator did not detect the patient's inspiratory effort or deliver the required oxygen flow at any of the tested settings. We recommended that the patient not use the portable oxygen concentrator during nocturnal NIV. PMID- 21682953 TI - Prolonged slow expiration technique in infants: effects on tidal volume, peak expiratory flow, and expiratory reserve volume. AB - BACKGROUND: Prolonged slow expiration (PSE) is a physiotherapy technique often applied in infants to reduce pulmonary obstruction and clear secretions, but there have been few studies of PSE's effects on the respiratory system. OBJECTIVE: To describe PSE's effects on respiratory mechanics in infants. METHODS: We conducted a cross-sectional study with 18 infants who had histories of recurrent wheezing. The infants were sedated for lung-function testing, which was followed by PSE. The PSE consisted of 3 sequences of prolonged manual thoraco abdominal compressions during the expiratory phase. We measured peak expiratory flow (PEF), tidal volume (V(T)), and the frequency of sighs during and immediately after PSE. We described the exhaled volume during PSE as a fraction of expiratory reserve volume (%ERV). We quantified ERV with the raised-volume rapid-thoracic-compression technique. RESULTS: The cohort's mean age was 32.2 weeks, and they had an average of 4.8 previous wheezing episodes. During PSE there was significant V(T) reduction (80 +/- 17 mL vs 49 +/- 11 mL, P < .001), no significant change in PEF (149 +/- 32 mL/s vs 150 +/- 32 mL/s, P = .54), and more frequent sighs (40% vs 5%, P = .03), compared to immediately after PSE. The exhaled volume increased in each PSE sequence (32 +/- 18% of ERV, 41 +/- 24% of ERV, and 53 +/- 20% of ERV, P = .03). CONCLUSIONS: It was possible to confirm and quantify that PSE deflates the lung to ERV. PSE caused no changes in PEF, induced sigh breaths, and decreased V(T), which is probably the main mechanical feature for mucus clearance. PMID- 21682954 TI - Dyspnea associated with dermatomyositis. PMID- 21682955 TI - The Role of a Vibration Response Imaging Device in the Selection of Patients for Lung Resection Surgery. AB - BACKGROUND: Simpler and radiation free alternatives have been researched to estimate postoperative lung functions. Objective of the study is to investigate the reliability of predicted postoperative (ppo) forced expiratory volume in 1 second (FEV1) and carbon monoxide diffusion capacity (DLCO) calculated by vibration response imaging (VRI) to guide the selection of patients for lung resection surgery in comparison with quantitative perfusion scintigraphy (Q scan). METHODS: 35 candidates for lung resection were enrolled in the study for preoperative and postoperative evaluation of FEV1 and DLCO. RESULTS: Totally 25 patients had preoperative tests. VRI measurements showed strong correlation with Q scan measurements of predicted postoperative (ppo) FEV1% (r= .87, p<.001), ppo FEV1(L) (r=.90, p<.001) and ppo DLCO% (r=.90, p<.001). There was a correlation between ppo FEV1 (% and L) calculated by Q scan and postoperative actual FEV1 (% and L) (r=.47, p<.05; r=.73, p<.001). There was no difference between VRI measurements of ppo FEV1(% and L) and postoperative actual FEV1 values. There was a correlation between ppo FEV1 (% and L) calculated by VRI and postoperative actual FEV1(% and L) (r= .52, p<.05; r= .79, p<.001). The mean differences between ppo and postoperative actual FEV1 values was 49ml for VRI versus 230ml for Q scan. Both VRI and Q scan ppo DLCO% did not show agreement with postoperative actual DLCO%. CONCLUSIONS: VRI, which is a non-invasive, radiation free and simple test, may be valuable in the preoperative evaluation of lung resection surgery. It may be a good alternative to Q scan. PMID- 21682956 TI - The effects of low and high tidal volume and pentoxifylline on intestinal blood flow and leukocyte-endothelial interactions in mechanically ventilated rats. AB - BACKGROUND: The combination of high PEEP and low tidal volume (V(T)) decreases some risks of mechanical ventilation, including pulmonary overdistention, damage due to cyclic opening and closing of the alveoli, and inflammatory responses that can lead to multiple-organ dysfunction. We hypothesized that high V(T) and high PEEP induce mesenteric microcirculatory disturbances and that those disturbances would be attenuated by pentoxifylline, which is anti-inflammatory. METHODS: We anesthetized (isoflurane 1.5%), tracheostomized, and mechanically ventilated 57 male Wistar rats with PEEP of 10 cm H(2)O and F(IO(2)) of 0.21 for 2 hours. One group received low V(T) (7 mL/kg), another group received high V(T) (10 mL/kg), and a third group received high V(T) plus pentoxifylline (25 mg/kg). We measured mean arterial pressure, respiratory mechanics, mesenteric blood flow, and leukocyte-endothelial interactions. RESULTS: The mean arterial pressure was similar among the groups at baseline (108 mm Hg [IQR 94-118 mm Hg]) and after 2 hours of mechanical ventilation (104 mm Hg [IQR 90-114 mm Hg]). Mesenteric blood flow was also similar between the groups: low V(T) 15.1 mL/min (IQR 12.4-17.7 mL/min), high V(T) 11.3 mL/min (IQR 8.6-13.8 mL/min), high-V(T)/pentoxifylline 12.4 mL/min (10.8-13.7 mL/min). Peak airway pressure after 2 hours was lower (P = .03) in the low-V(T) group (10.4 cm H(2)O [IQR 10.2-10.4 cm H(2)O]) than in the high-V(T) group (12.6 cm H(2)O [10.2-14.9 cm H(2)O]) or the high V(T)/pentoxifylline group (12.8 cm H(2)O [10.7-16.0 cm H(2)O]). There were fewer adherent leukocytes (P = .005) and fewer migrated leukocytes (P = .002) in the low-V(T) group (5 cells/100 MUm length [IQR 4-7 cells/100 MUm length] and 1 cell/5,000 MUm(2) [IQR 1-2 cells/5,000 MUm(2)], respectively) and the high V(T)/pentoxifylline group (5 cells/100 MUm length [IQR 3-10 cells/100 MUm length] and 1 cell/5,000 MUm(2) [IQR 1-3 cells/5,000 MUm(2)], respectively) than in the high-V(T) group (14 cells/100 MUm length [IQR 11-16 cells/100 MUm length] and 9 cells/5,000 MUm(2) [IQR 8-12 cells/5,000 MUm(2)], respectively). CONCLUSIONS: Low V(T) with high PEEP was lung-protective, and early pentoxifylline reduced the inflammatory response to high V(T) with high PEEP (and presumed lung overdistention) during mechanical ventilation. PMID- 21682957 TI - Helping the poor access innovation in tuberculosis control: using evidence from implementation research. PMID- 21682958 TI - You have to find TB to treat TB. PMID- 21682959 TI - A neglected research approach to prevent acquired drug resistance when treating new tuberculosis patients. AB - The occurrence of significant drug resistance in many countries, coupled with known problems in delivering directly observed therapy (DOT), calls for a re examination of tuberculosis (TB) treatment delivery strategies. Electronic medication monitors, devices that determine when medication is removed from containers, and videophone-based strategies are being introduced to determine if they can effectively differentiate 1) patients who are adequately adherent to self-administered treatment (SAT), 2) less reliable patients who could be successfully treated with SAT if given more intensive counseling and 3) patients who require DOT. The adherence record could be used in deciding on compensatory longer treatment when poor adherence occurs. The time saved not giving DOT to all patients could be used to retrieve defaulters. Together these components constitute a monitor-based strategy. The program could be extended to supervise the adherence of private patients to medication provided by trained and subsidized pharmacies with the physicians or, when necessary, health departments managing poorly adherent patients. When patients move, the device could transfer essential data to the new care giver. To obtain optimal results, the requirements for the best possible devices and procedures for dealing with poor adherence need to be carefully evaluated. PMID- 21682960 TI - Making innovations accessible to the poor through implementation research. AB - Within countries, poorer populations have greater health needs and less access to good medical care than better-off populations. This is particularly true for tuberculosis (TB), the archetypal disease of poverty. Innovations also tend to become available to better-off populations well before they become available to those who need them the most. In a new era of innovations for TB diagnosis and treatment, it is increasingly important not only to be sure that these innovations can work in terms of accuracy and efficacy, but also that they will work, especially for the poor. We argue that after an innovation or a group of innovations has been endorsed, based on demonstrated accuracy and/or efficacy, introduction into routine practice should proceed through implementation by research. Cluster-randomised pragmatic trials are suited to this approach, and permit the prospective collection of evidence needed for full impact assessment according to a previously published framework. The novel approach of linking transmission modelling with operational modelling provides a methodology for expanding and enhancing the range of evidence, and can be used alongside evidence from pragmatic implementation trials. This evidence from routine practice should then be used to ensure that innovations in TB control are used for positive action for all, and particularly the poor. PMID- 21682961 TI - Countrywide management of pulmonary tuberculosis reverses increasing incidence. AB - OBJECTIVE: To evaluate the impact of countrywide management of tuberculosis (TB) and the availability of second-line drugs (SLDs) on the notification rates of pulmonary TB (PTB) overall and of multidrug-resistant TB (MDR-TB), taking into account human immunodeficiency virus (HIV) co-infection and the national economy in Estonia. DESIGN: Retrospective analysis of notification rates and treatment outcomes of PTB and MDR-TB during 1998-2006. RESULTS: The annual notification rates of both PTB and MDR-TB decreased significantly, by on average 3.3 (P = 0.007) and 1.7 (P = 0.008) cases per 100,000 population, respectively. The accelerating impact of SLD availability on the annual decline was significant for both PTB overall and MDR-TB (P = 0.003 and P = 0.025, respectively). During 1998 2006, an increase in TB-HIV co-infection (P = 0.009) significantly affected the notification rates of both PTB overall and MDR-TB (P < 0.001 and P < 0.001, respectively). The negative impact of TB-HIV co-infection was counterbalanced by the availability of SLDs, the decrease in the MDR-TB rate and the increase in gross domestic product (GDP) per capita, as confirmed by multivariate analysis. CONCLUSION: Countrywide access to SLDs and the coordinated effect of programmatic conditions can, in parallel with increasing GDP, reverse the increasing notification rates of PTB and MDR-TB in the context of an HIV epidemic. PMID- 21682962 TI - Local epidemic history as a predictor of tuberculosis incidence in Saskatchewan Aboriginal communities. AB - BACKGROUND: Average tuberculosis (TB) incidence rates are high in Canadian Aboriginal communities, but there is significant variability within this group. OBJECTIVE: To determine whether local history of post-contact TB epidemics is predictive of contemporary epidemiology among Aboriginal communities in Saskatchewan, Canada. METHODS: TB incidence, age-specific morbidity patterns and rates of clustering of TB genotypes from 1986 to 2004 were compared between two groups of communities: Group 1, in which post-contact epidemics of TB were established around 1870, and Group 2, in which they were delayed until after 1920. Concomitant effects of socio-economic and geographic variables were explored with multivariate models. RESULTS: Group 2 communities were characterized by higher annual incidence of TB (median 431 per 100,000 population vs. 38/100,000). In multivariate models that included socio-economic and geographic variables, historical grouping remained a significant independent predictor of community incidence of TB. Clustering of TB genotypes was associated with Group 2 (OR 8.7, 95%CI 3.3-22.7) and age 10-34 years (OR 2.5, 95%CI 1.1 5.7). CONCLUSIONS: TB transmission dynamics can vary significantly as a function of a population's historical experience with TB. Populations at different stages along the epidemic trajectory may be amenable to different types of interventions. PMID- 21682963 TI - Chronic lung disease and HIV infection are risk factors for recurrent tuberculosis in a low-incidence setting. AB - SETTING: Programmatic data from the United States on tuberculosis (TB) recurrence are limited. OBJECTIVES: To determine the TB recurrence rate and to determine if chronic lung disease (CLD) and human immunodeficiency virus (HIV) infection are risk factors for recurrence in this population. DESIGN: Nested case-control study among TB cases reported to the Tennessee Department of Health between 1 January 2000 and 31 December 2006. Time at risk for recurrence was through 31 December 2007. Multiple imputation accounted for missing data. RESULTS: Of 1431 TB cases, 20 cases recurred (1.4%, 95%CI 0.9-2.1). Median time at risk for recurrence was 4.5 years (interquartile range 2.7-6.1). Initial and recurrent Mycobacterium tuberculosis isolates were available for genotyping for 15 patients; 12 were consistent with relapse (0.8%, 95%CI 0.4-1.5) and three with re-infection (0.2%, 95%CI 0.04-0.6). HIV infection (OR 5.01, P = 0.04) and CLD (OR 5.28, P = 0.03) were independently associated with recurrent TB, after adjusting for a disease risk score. HIV infection was a risk factor for TB re-infection (P < 0.001). CONCLUSIONS: In this low-incidence US population, the TB recurrence rate was low, but CLD and HIV were independent risk factors for recurrence. HIV infection was also a risk factor for TB re-infection. PMID- 21682964 TI - Tuberculosis surveillance in Cape Town, South Africa: an evaluation. AB - SETTING: Cape Town, South Africa. OBJECTIVE: To evaluate the current system of tuberculosis surveillance in the Cape Metro region. DESIGN: This evaluation was based on the 'Updated Guidelines for Evaluating Public Health Surveillance Systems' of the Centers for Disease Control and Prevention, modified to render the framework applicable to the context of tuberculosis (TB) surveillance. The evaluation incorporated qualitative exploration of perceptions and experiences of system users. RESULTS: System users were very accepting of the system and were committed to seeing it achieve its purpose within public health. Some individuals expressed concerns about the rigidity of the Electronic TB Register software and its analysis capabilities. Dissemination of TB data and evidence-based action within the Cape Metro region are strong attributes of Cape Town's TB surveillance system. At the time of the evaluation, integration of TB and human immunodeficiency virus (HIV) data was weak, as was multidrug-resistant TB (MDR TB) surveillance; the South African Tuberculosis Control Programme is developing initiatives to improve these areas. CONCLUSIONS: Cape Metro's TB surveillance is strong, although it would be strengthened by increasing availability of data reflecting TB-HIV co-infection and MDR-TB. Systems operations could be improved by increasing software flexibility, and increased integration of electronic data across health regions would enhance the capacity and assessment of control efforts. PMID- 21682965 TI - Evaluation of the World Health Organization algorithm for the diagnosis of HIV associated sputum smear-negative tuberculosis. AB - BACKGROUND: Outcomes from the World Health Organization's (WHO's) recommendations for the diagnosis of smear-negative tuberculosis (SNTB) in high human immunodeficiency virus prevalence settings are unknown. METHODS: We retrospectively applied the WHO algorithm for SNTB without danger signs to a prospectively enrolled cohort of ambulatory adult SNTB suspects in KwaZulu-Natal, South Africa. Participants fulfilling specified criteria for SNTB started empiric anti-tuberculosis treatment; the rest of the cohort was observed. All were followed for 8 weeks. Confirmed TB was defined as positive culture or granulomata plus acid-fast bacilli on histology. RESULTS: In total, 221 participants retrospectively fulfilled the WHO ambulatory SNTB algorithm entry criteria. The diagnostic performance of the WHO algorithm was: positive predictive value 0.34 (95%CI 0.26-0.43), negative predictive value 0.86 (95%CI 0.76-0.92), positive likelihood ratio 1.43 (95%CI 1.34-1.48), negative likelihood ratio 0.46 (95%CI 0.38-0.56) and diagnostic odds 3.1 (95%CI 1.52-6.34). Losses to follow-up (n = 4), hospitalisations (n = 6) and deaths (n = 5) did not differ significantly in those who were and were not diagnosed with SNTB. CONCLUSIONS: The WHO ambulatory SNTB algorithm had a reasonably high negative predictive value but low positive predictive value. Mortality over an 8-week period was low in participants who met the entry criteria for the WHO algorithm. PMID- 21682966 TI - Anemia in adults with tuberculosis is associated with HIV and anthropometric status in Dar es Salaam, Tanzania. AB - SETTING: Tuberculosis (TB) infected adults attending out-patient TB clinics in Dar es Salaam, Tanzania. OBJECTIVE: To examine the association of anemia with human immunodeficiency virus (HIV) co-infection, indicators of socio-economic status (SES) and anthropometric status in TB-infected adults. DESIGN: Cross sectional data collection during screening for a clinical trial. RESULTS: Overall, 750 females and 1693 males participated in this study, of whom respectively 49% and 24% were co-infected with HIV-1. Hemoglobin levels were significantly lower in females than in males and in HIV-positive than in HIV negative participants. HIV co-infection in this antiretroviral-naive population was also associated with severe anemia (hemoglobin < 85 g/l) in both women (prevalence ratio [PR] = 2.07, 95%CI 1.65-2.59) and men (PR 3.45, 95%CI 2.66 4.47). Although severe anemia was negatively associated with indicators of SES, especially in males, adjustment for SES indicators only marginally changed its association with HIV co-infection. In both sexes, anemia was inversely associated with anthropometric status, independently of HIV infection and SES. CONCLUSION: Among TB-infected adults, anemia is strongly associated with HIV co-infection and anthropometric status, independently of SES indicators. As anemia is a risk factor for morbidity and mortality in both infections, the management of anemia in TB-HIV co-infected patients warrants special attention. PMID- 21682967 TI - Reduced tuberculosis case notification associated with scaling up antiretroviral treatment in rural Malawi. AB - OBJECTIVE: To report on the trends in new and recurrent tuberculosis (TB) case notifications in a rural district of Malawi that has embarked on large-scale roll out of antiretroviral treatment (ART). METHODS: Descriptive study analysing TB case notification and ART enrolment data between 2002 and 2009. RESULTS: There were a total of 10,070 new and 755 recurrent TB cases. ART scale-up started in 2003, and by 2007 an estimated 80% ART coverage had been achieved and was sustained thereafter. For new TB cases, an initial increase in case notifications in the first years after starting ART (2002-2005) was followed by a highly significant and sustained decline from 259 to 173 TB cases per 100,000 population (chi(2) for trend 261, P < 0.001, cumulative reduction for 2005-2009 = 33%, 95%CI 27-39). For recurrent TB, the initial increase was followed by a significant drop, from 20 to 15 cases/100,000 (chi(2) for linear trend = 8.3, P = 0.004, constituting a 25% (95%CI 9-49) cumulative reduction between 2006 and 2009. From 2005 to 2009, ART averted an estimated 1164 (95%CI 847-1480) new TB cases and 78 (95%CI 23-151) recurrent TB cases. CONCLUSIONS: High ART implementation coverage is associated with a very significant declining trend in new and recurrent TB case notifications at population level. PMID- 21682968 TI - Tuberculosis knowledge, attitudes and health-seeking behaviour in rural Uganda. AB - OBJECTIVES: To assess tuberculosis (TB) knowledge, attitudes and health-seeking behaviour to inform the design of communication and social mobilisation interventions. SETTING: Iganga/Mayuge Demographic Surveillance Site, Uganda. DESIGN: Between June and July 2008, 18 focus group discussions and 12 key informant interviews were conducted, including parents of infants and adolescents and key informant interviews with community leaders, traditional healers and patients with TB. RESULTS: People viewed TB as contagious, but not necessarily an airborne pathogen. Popular TB aetiologies included sharing utensils, heavy labour, smoking, bewitchment and hereditary transmission. TB patients were perceived to seek care late or to avoid care. Combining care from traditional healers and the biomedical system was common. Poverty, drug stock-outs, fear of human immunodeficiency virus (HIV) testing and length of TB treatment negatively affect health-seeking behaviour. Stigma and avoidance of persons with TB often reflects an assumption of HIV co-infection. CONCLUSION: The community's concerns about pill burden, quality of care, financial barriers, TB aetiology, stigma and preference for pluralistic care need to be addressed to improve early detection. Health education messages should emphasise the curability of TB, the feasibility of treatment and the engagement of traditional healers as partners in identifying cases and facilitating adherence to treatment. PMID- 21682969 TI - Health-seeking norms for tuberculosis symptoms in southern Angola: implications for behaviour change communications. AB - SETTING: A passive case-finding strategy as present in the DOTS strategy presupposes a patient's willingness to seek care. This requires awareness of tuberculosis (TB) symptoms and the diagnostic process, and positive attitudes towards access and probability of cure. OBJECTIVE: To measure parameters of health-seeking intention in Southern Angola and to inform the design of context specific interventions to improve case detection. DESIGN: A survey in four communities based on the cough-to-cure pathway represented by five domains with either one or two proxy measures. These were assessed for association with appropriate health-seeking behaviour (visiting a medical institution or service). RESULTS: In total, 805 individuals were included in the study. Appropriate health seeking behaviour was positively associated with knowing the disease (OR 3.1, 95%CI 1.4-6.8), knowing key symptoms (OR 1.4, 95%CI 1.0-1.9), perceived curability (OR 1.3, 95%CI 1.0-1.6), and the perception that TB services were free of charge (OR 1.9, 95%CI 1.4-2.7). Respondents who perceived a personal risk for TB were less likely to have an appropriate intended health-seeking behaviour (OR 0.7, 95%CI 0.5-0.9). CONCLUSION: Knowledge about TB should include key symptoms, perceived curability and information on access to services when designing interventions to improve case detection. The study highlights the importance of advocacy, social mobilisation and communication strategies. PMID- 21682971 TI - Hydrochloric vs. sulphuric acid in water for Ziehl-Neelsen staining of acid-fast bacilli. AB - SETTING: Damien Foundation Bangladesh tuberculosis (TB) control projects. OBJECTIVES: To compare 25% sulphuric acid in water (H(2)SO(4)) with hydrochloric acid in water (HCl) to differentiate acid-fast bacilli in sputum smears stained with 1% carbolfuchsin. DESIGN: For 1 year, all 158 microscopy laboratories used either H(2)SO(4) or 3%/6%/10% HCl for their routine work, alternating monthly between H(2)SO(4) and HCl. Each month a sample of five smears per laboratory was rechecked blind. After recording qualitative staining aspects, all sample smears were restained before rechecking, using H(2)SO(4) for destaining. RESULTS: A total of 368,059 H(2)SO(4) and 335,436 HCl smears were routinely read, yielding 7.2% positive or scanty results in both groups. Of these, 9492 were rechecked. There was no difference in false-negatives detected (0.66%, 95%CI 0.44-0.95 for H(2)SO(4) vs. 0.68%, 95%CI 0.46-0.98 for HCl), but apparently there were more false-positives with H(2)SO(4) (2.12%, 95%CI 0.92-4.14 vs. 0.28%, 95%CI 0.00 1.54, P = 0.05). Qualitatively, only 3% HCl yielded significantly inferior differentiation results. CONCLUSIONS: HCl 6-10% in water can be recommended for Ziehl-Neelsen destaining above H(2)SO(4). Diluting is easier and safer, and it may cause less confusion with false-positives during rechecking, including a restaining step. PMID- 21682970 TI - Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients. AB - BACKGROUND: Delamanid (OPC-67683) is a novel mycolic acid biosynthesis inhibitor active against Mycobacterium tuberculosis at a low minimum inhibitory concentration. METHODS: Forty-eight patients with smear-positive tuberculosis (63% male; 54.7 +/- 9.9 kg; 30.7 +/- 10.8 years) were randomly assigned to receive delamanid 100, 200, 300 or 400 mg daily for 14 days. Colony forming units (cfu) of M. tuberculosis were counted on agar plates from overnight sputum collections to calculate early bactericidal activity (EBA), defined as fall in log(10) cfu/ml sputum/day. RESULTS: The EBA of delamanid was monophasic and not significantly different between dosages; however, more patients receiving 200 mg (70%) and 300 mg (80%) experienced a response of >=0.9 log(10) cfu/ml sputum decline over 14 days than those receiving 100 mg (45%) and 400 mg (27%). The average EBA of all dosages combined (0.040 +/- 0.056 log(10) cfu/ml sputum/day) was significant from day 2 onward. Delamanid exposure was less than dosage proportional, reaching a plateau at 300 mg, likely due to dose-limited absorption. Moderate but significant correlation was found between C(max) and EBA, indicating exposure dependence. Delamanid was well tolerated without significant toxicity. CONCLUSIONS: Delamanid at all dosages was safe, well tolerated and demonstrated significant exposure-dependent EBA over 14 days, supporting further investigation of its pharmacokinetics and anti-tuberculosis activity. PMID- 21682972 TI - Evaluation of the Genotype(r) MTBDRplus assay as a tool for drug resistance surveys. AB - SETTING: A national tuberculosis (TB) drug resistance survey in Tanzania. OBJECTIVE: To compare the performance of the Genotype(r) MTBDRplus line-probe assay (LPA) on smear-positive sputum specimens with conventional culture and isoniazid (INH) plus rifampicin (RMP) drug susceptibility testing (DST). DESIGN: Mycobacterium tuberculosis isolates tested at the Tanzanian Central TB Reference Laboratory (CTRL) were submitted for quality assurance of phenotypic DST to its supranational reference laboratory (SRL), together with ethanol-preserved sputum specimens for LPA DST. RESULTS: Only 321 samples could be tested using LPA; of these, three were identified as being non-tuberculous mycobacteria using CTRL DST. Both tests had 269 sets with interpretable results. CTRL DST yielded almost the same number of interpretable results as LPA, with 90% concordance (kappa = 0.612, P < 0.001). Five (1.9%) multidrug-resistant (MDR) strains, 46 (17.1%) resistant to INH only and 0 RMP only, were found by CTRL DST. For the LPA, these results were respectively 5 (1.9%), 26 (9.7%) and 2 (0.7%). With SRL DST as the gold standard, LPA was more accurate than CTRL DST for RMP, but missed almost half the INH-resistant samples. CONCLUSION: LPA applied directly on ethanol preserved sputum specimens was similar to phenotypic DST in terms of yield of interpretable results. Although probably more accurate for RMP and MDR-TB, it appears to seriously underestimate INH resistance. Considering speed, easy and safe specimen transportation and low infrastructure requirements, LPA DST from sputum can be recommended for surveys in resource-poor settings. PMID- 21682974 TI - Second-hand smoke in indoor hospitality venues in Pakistan. AB - BACKGROUND: Second-hand smoke (SHS) constitutes a significant public health threat in countries with a high smoking prevalence. However, data assessing the quality of indoor air at public venues in Pakistan are limited. OBJECTIVES: To measure mean concentrations of PM(2.5) (particulate matter <=2.5 microns in diameter), a sensitive indicator of SHS, in hospitality venues in Pakistan. SETTING AND DESIGN: Data were collected discreetly from 39 indoor venues such as cafes, restaurants and shisha (water-pipe) bars from three major cities in Pakistan. Data were recorded using a portable air quality monitoring device. RESULTS: The overall mean PM(2.5) value for the visited venues was 846 MUg/m(3) (95%CI 484-1205). The mean PM(2.5) value was 101 MUg/m(3) (95%CI 69-135 MUg/m(3)) for non-smoking venues, 689 MUg/m(3) (95%CI 241-1138) for cigarette smoking venues and 1745 MUg/m(3) (95%CI 925-2565) for shisha smoking venues. CONCLUSION: The significant levels of SHS recorded in this study, in particular from shisha smoking venues, could represent a major public health burden in Pakistan. Appropriate legislation needs to be enforced to protect the health of those exposed to the hazards of second-hand tobacco smoke. PMID- 21682973 TI - Reliability and validity of the St George's Respiratory Questionnaire for asthma. AB - BACKGROUND: The St George's Respiratory Questionnaire (SGRQ) is a self administered questionnaire that has been used to evaluate the health-related quality of life of patients with chronic respiratory diseases. OBJECTIVE: To assess the validity and reliability of the SGRQ for a large population with asthma. DESIGN: We used the previously developed Korean version of the SGRQ (SGRQ K) to assess 676 asthma patients enrolled from the Cohort for Reality and Evolution of Adult Asthma in Korea study. Cronbach's alpha was used to assess test reliability and Pearson's correlation coefficient was used to assess the correlation between SGRQ scores and various clinical factors. RESULTS: The total SGRQ-K score had acceptable reliability (Cronbach's alpha = 0.92). The total SGRQ K score was significantly correlated with symptom duration (r = 0.157, P < 0.001), pulmonary function (% FEV(1) of predicted r = -0.314, P < 0.001; % FVC of predicted r = -0.224, P < 0.001; FEV(1)/FVC r = -0.224, P < 0.001), asthma severity (r = 0.278, P < 0.001) and history of asthma exacerbation. CONCLUSION: With the exception of the SGRQ-K symptoms, SGRQ-K is a reliable and valid test for evaluation of the quality of life of patients with asthma. Scores were well correlated with duration of symptoms, lung function and previous history of asthma exacerbation. PMID- 21682975 TI - Tuberculosis treatment outcomes and socio-economic status: a prospective study in Duque de Caxias, Brazil. AB - A prospective study was conducted to evaluate tuberculosis treatment outcomes according to socio-economic status (SES) using different classification criteria. Patients aged >=18 years under treatment for <=8 weeks were interviewed. Outcomes were classified as successful (cure/completed) or unsuccessful (default/failure/death). The overall treatment default ratio was 20.9% and the unsuccessful outcome rate was 24.1%. Unsuccessful treatment was associated with SES according to any criteria used, except for the definition of poverty line. Poverty seems to be hampering the achievement of the World Health Organization targeted 90% cure rate in developing settings. PMID- 21682976 TI - Diabetes and tuberculosis, US National Health Interview Survey, 2000-2005. AB - Blacks and Hispanics are disproportionately affected by diabetes, which may confound ethnic association with tuberculosis (TB). We analyzed 2000-2005 National Health Interview Survey data. We present adjusted odds ratios (aORs) and 99% confidence intervals (CIs) for the association of diabetes with history of TB disease, controlling for race/ethnicity and age. Diabetics had an aOR of 1.4 (99%CI 1.0-2.0) for history of TB, controlling for being foreign-born non Hispanic (aOR 2.2, 99%CI 1.6-3.2), US-born Hispanic (aOR 2.1, 99%CI 1.4-3.2), age >=65 years (aOR 2.0, 99%CI 1.5-2.6), and being Black (aOR 1.6, 99%CI 1.1-2.4). After controlling for race/ethnicity, self-identified diabetics had an increased aOR for history of TB. PMID- 21682977 TI - Advancing the development of diagnostic tests and biomarkers for tuberculosis. AB - High costs and limited returns on investment have hampered progress in developing new diagnostic tests and treatments for tuberculosis (TB). We need new biomarkers to develop assays that can rapidly, efficiently and reliably detect Mycobacterium tuberculosis infection and disease, identify drug resistance and expedite drug and vaccine development. This can only be accomplished through cross-disciplinary collaborations to facilitate access to human specimens. The Food and Drug Administration, Centers for Disease Control and Prevention, National Institutes of Health, the industry and academia experts came together in a June 2010 workshop to examine the field of TB diagnostic test development and biomarker discovery, identify areas of most urgent need and formulate strategies to address those needs. PMID- 21682978 TI - Xpert MTB/RIF(r), a novel automated polymerase chain reaction-based tool for the diagnosis of tuberculosis. AB - There is an urgent need for new point of care tests for tuberculosis (TB). Xpert MTB/RIF(r) is a real-time polymerase chain reaction-based system that detects Mycobacterium tuberculosis DNA and rifampicin (RMP) resistance modulating mutations directly from clinical samples in 2 h. The sensitivity for detecting M. tuberculosis in culture-positive samples was 93.8% (60/64) and exceeded smear microscopy (40/64, 62.5%). The specificity for detecting M. tuberculosis was 92.0% (23/25) and for RMP resistance it was 100% (8/8). The test is simple to conduct and requires basic sputum handling facilities only. These characteristics render it a promising close-to-patient test for TB in various settings. PMID- 21682979 TI - Low-level rifampicin-resistant Mycobacterium tuberculosis strains raise a new therapeutic challenge. AB - In an outbreak of multidrug-resistant tuberculosis, the outbreak strain had an Asp516Tyr rpoB gene mutation. Phenotypically, low-level rifampicin (RMP) resistance (minimum inhibitory concentration [MIC] 1-2 mg/l) was observed. Based on drug susceptibility test results, three patients were treated with 12-15 month rifabutin-based regimens and one with a 12-month RMP-based regimen. We retrospectively performed pharmacokinetic calculations to assess the potential for RMP treatment, from which we conclude that MICs for RMP up to 1 MUg/ml may be safely overcome by applying 20 mg/kg RMP doses in treatment regimens. PMID- 21682980 TI - Mycobacterium kansasii cutaneous abscesses occurring as immune reconstitution inflammatory syndrome. PMID- 21682981 TI - Focus on primary prevention of tobacco smoking. PMID- 21682982 TI - High flow through a nasal cannula and CPAP effect in a simulated infant model. AB - BACKGROUND: Limited data are available to describe the CPAP effects that can be expected when using high flow with a traditional nasal cannula. OBJECTIVE: To describe the relationship between the pressure generated at the airway opening and flow through a nasal cannula using a simulated infant model. We hypothesized that positive pressure generated by a standard cannula at flows > 2 L/min would be minimal and clinically unimportant. METHODS: Nares were simulated with holes drilled in a plastic fixture. A nares template for CPAP prongs served as a sizing template for the holes. Small, medium, and large nares fixtures were constructed and connected to a lung simulator that simulated spontaneous breathing. Respiratory muscle pressure was simulated by setting a waveform and adjusting the amplitude to deliver a range of tidal volumes (V(T)) from 3 mL to 12 mL. Lung compliance and resistance were set at 0.5 mL/cm H(2)O and 125 cm H(2)O/L/s, respectively. Nasal cannulas were inserted in the model nares. We assured that the prong occlusion of the nares did not exceed 50%. Cannula flow was adjusted from 2-6 L/min in 1-L/min increments. Data were averaged over 20 breaths. Mean airway pressure and percent change in V(T) were recorded. RESULTS: The greatest effect on V(T) (mean +/- SD 0.16 +/- 0.10 mL) and pressure change (mean +/- SD 0.7 +/- 0.5 cm H(2)O) occurred with the premature cannula. The least effect on pressure (mean +/- SD 0.3 +/- 0.22 cm H(2)O) and V(T) change (mean +/- SD 0.01 +/ 0.02 mL) occurred with the infant cannula. CONCLUSIONS: Clinically important pressures were not generated by high flows with a standard nasal cannula. The differences in spontaneous V(T) across all flows were negligible. PMID- 21682983 TI - User error with Diskus and Turbuhaler by asthma patients and pharmacists in Jordan and Australia. AB - BACKGROUND: Use of inhalers requires accurate completion of multiple steps to ensure effective medication delivery. OBJECTIVE: To evaluate the most problematic steps in the use of Diskus and Turbuhaler for pharmacists and patients in Jordon and Australia. METHODS: With standardized inhaler-technique checklists, we asked community pharmacists to demonstrate the use of Diskus and Turbuhaler. We asked patients with asthma to demonstrate the inhaler (Diskus or Turbuhaler) they were currently using. RESULTS: Forty-two community pharmacists in Jordan, and 31 in Australia, participated. In Jordan, 51 asthma patients demonstrated use of Diskus, and 40 demonstrated use of Turbuhaler. In Australia, 53 asthma patients demonstrated use of Diskus, and 42 demonstrated use of Turbuhaler. RESULTS: The pharmacists in Australia had received inhaler-technique education more recently than those in Jordan (P = .03). With Diskus, few pharmacists in either country demonstrated correct technique for step 3 (exhale to residual volume) or step 4 (exhale away from the device), although there were somewhat fewer errors in Australia than Jordan (16% vs 0% in step 3, P = .007, and 20% vs 0% in step 4, P = .003 via chi-square test). With Turbuhaler there were significant differences between the pharmacists from Australia and Jordan, mainly in step 2 (hold the device upright while loading, 45% vs 2% correct, P < .001). Few of the patients had received inhaler-technique education in the previous year. The patients made errors similar to those of the pharmacists in individual steps with Diskus and Turbuhaler. The essential steps with Diskus were performed correctly more often by the Jordanian patients, and with Turbuhaler by the Australian patients. CONCLUSIONS: Despite differences in Jordan's and Australia's health systems, pharmacists from both Australia and Jordan had difficulty with the same Diskus and Turbuhaler steps. In both countries, the errors made by the asthma patients were similar to those made by the pharmacists. PMID- 21682984 TI - Intrapleural streptokinase for the treatment of chylothorax. AB - Chylothorax is suspected when milky white turbid fluid is obtained from thoracocentesis. Conservative management usually involves intercostal tube drainage, dietary restriction, and total parenteral nutrition. Surgery is indicated when conservative management fails. We describe a young woman with idiopathic chylothorax who failed conservative therapy but refused surgery. We instilled intrapleural streptokinase, which improved her condition. PMID- 21682985 TI - Use of hypothermia to allow low-tidal-volume ventilation in a patient with ARDS. AB - Low-tidal-volume ventilation reduces mortality in patients with ARDS, but there are often challenges in implementing lung-protective ventilation, such as acidosis from hypercapnia. In a patient with severe ARDS we achieved adequate ventilation with a very low tidal volume (4 mL/kg ideal body weight) by inducing mild hypothermia (body temperature 35-36 degrees C). PMID- 21682986 TI - Do commonly used ventilator settings for mechanically ventilated adults have the potential to embed secretions or promote clearance? AB - BACKGROUND: Intubation and mechanical ventilation can impair mucociliary clearance and cause secretion retention, airway occlusion, atelectasis, and pneumonia. Animal and laboratory work has demonstrated that mechanical ventilator settings can generate a flow bias (inspiratory or expiratory) that may result in mucus movement either away from the ventilator (deeper into the lungs) or toward the ventilator (toward the mouth), respectively. An absolute difference of 17 L/min, and a relative difference of >= 10%, between the expiratory and inspiratory flow have been reported as thresholds for mucus movement. METHODS: We measured baseline peak inspiratory and expiratory flows during quiet mechanical ventilation in a convenience sample of 20 intubated and ventilated adult patients. RESULTS: Nineteen patients had an inspiratory flow bias of >= 10%. Eight patients had an absolute mean inspiratory flow bias of >= 17 L/min. CONCLUSIONS: Commonly used mechanical ventilator settings generate an inspiratory flow bias that may promote secretion retention. PMID- 21682987 TI - Organizing pneumonia and non-necrotizing granulomata on transbronchial biopsy: coexistence or bronchiolitis obliterans organizing pneumonia secondary to Mycobacterium kansasii disease. AB - Mycobacterium kansasii disease was diagnosed in an 85-year-old woman admitted to the hospital for cough and gradually worsening breathlessness. Transbronchial biopsy indicated either non-necrotizing granulomata or bronchiolitis obliterans organizing pneumonia (BOOP). She was cured with combined therapy of specific anti-mycobacterial medications and systemic steroids. To our knowledge, this is the first report of M. kansasii non-tuberculous mycobacterium disease with a BOOP like pattern on lung biopsy. PMID- 21682988 TI - Lung abscesses in 2 patients with Lancefield group F streptococci (Streptococcus milleri group). PMID- 21682989 TI - Highly sensitive determination and validation of gabapentin in pharmaceutical preparations by HPLC with 4-fluoro-7-nitrobenzofurazan derivatization and fluorescence detection. AB - A sensitive HPLC method with pre-column fluorescence derivatization using 4 Fluoro-7-Nitrobenzofurazan (NBD-F) has been developed for the determination of gabapentin in pharmaceutical preparations. The method is based on the derivatization of gabapentin with (NBD-F) in borate buffer of pH 9.5 to yield a yellow, fluorescent product. The HPLC separation was achieved on a Inertsil C(18) column (250 mm * 4.6 mm) using a mobile phase of methanol water (80:20, v/v) solvent system at 1.2 mL/min flow rate. Mexiletine was used as the internal standard. The fluorometric detector was operated at 458 nm (excitation) and 521 nm (emission). The assay was linear over the concentration range of 5 50 ng/mL. The method was validated for specificity, linearity, limit of detection, limit of quantification, precision, accuracy, robustness. Moreover, the method was found to be sensitive with a low limit of detection (0.85 ng/mL) and limit of quantitation (2.55 ng/mL). The results of the developed procedure for gabapentin content in capsules were compared with those by the official method (USP 32). Statistical analysis by t- and F-tests, showed no significant difference at 95 confidence level between the two proposed methods. PMID- 21682990 TI - HPLC method for determination of diclofenac in human plasma and its application to a pharmacokinetic study in Turkey. AB - A simple high-performance liquid chromatography (HPLC) method has been developed for determination of diclofenac in human plasma. The method was validated on Ace C(18) column using UV detection. The mobile phase consisted of 20 mM phosphate buffer (pH 7) containing 0.1% trifluoroacetic acid-acetonitrile (65:35, v/v). Calibration curve was linear between the concentration range of 75-4000 ng/mL. Intra- and inter-day precision values for diclofenac in plasma were less than 3.6, and accuracy (relative error) was better than 5.3%. The limits of detection and quantification of diclofenac were 25 and 75 ng/mL, respectively. Also, this assay was applied to determine the pharmacokinetic parameters of diclofenac in healthy Turkish volunteers who had been given 50 mg diclofenac. PMID- 21682991 TI - Direct UPLC-MS-MS validated method for the quantification of 5-aminolevulinic acid: application to in-vitro assessment of colonic-targeted oral tablets. AB - A reliable, sensitive, specific, and rapid ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS-MS) method was developed for the determination of 5-aminolevulinic acid (5-ALA) in orally-administered colonic delivery system. The prepared system is a compression-coated tablet using granulated chitosan as the coat layer. L-Tyrosine (TYR) was used as an internal standard with no need for derivatization. The chromatographic system consisted of Acquity UPLC BEH C18 column and isocratic mobile phase composed of acetonitrile and 0.1% formic acid with a flow rate of 2.5 min. The assay was based on ESI+ mode in a multiple reaction monitoring (MRM) transitions at m/z 132.08 > 86.0 and m/z 132.08 > 114.0 and m/z 182.1 > 91.2 for 5-ALA and TYR, respectively. Limit of quantification was 5.0 ng/mL and the calibration curve was linear (r(2) = 0.994). Within-run precision and between-run repeatability were expressed as relative standard deviation and were lower than 2.5%. The recoveries from control samples were > 95%. The method was successfully applied for evaluation in assay and release profile of 5-ALA colon targeted tablets media containing suspended rat cecal contents pH 6.8 medium (colonic) for colonic delivery. PMID- 21682992 TI - Validated stability indicating LC method for carprofen: characterization of degradation products by MS. AB - A simple, sensitive, and selective stability indicating high performance liquid chromatographic method has been developed and validated for quantitative analysis of carprofen (CPF) in presence of its degradation products. All degradation products in acid hydrolysis and photolysis were separated, identified by mass spectroscopic method and probable structures were elucidated. The forced degradation studies were performed on a bulk sample of CPF by using various methods like 0.1 M hydrochloric acid, 0.1 M sodium hydroxide, 0.33% hydrogen peroxide (H(2)O), heating at 60 degrees C and exposure to UV light at 254 nm. A 5 MUm particle octa desyl silane (ODS) column (150 mm * 4.6 mm) was used with acetonitrile-ammonium acetate (100 mM, pH-6.7) 40:60 (v/v) as a mobile phase at flow rate of 1.2 mL/min. Column oven temperature was maintained at 30 degrees C and quantitation was achieved at 239 nm on the basis of peak area. The linear range and correlation coefficient (r(2)) was found 0.5-60 MUg/mL and 0.9999 respectively. The limit of detection (LOD) and limit of quantitation (LOQ) were obtained 0.066 MUg/mL and 0.20 MUg/mL respectively . The proposed method was found to be suitable and accurate for quantitative analysis, stability study and characterisation of degradation product of CPF. PMID- 21682993 TI - Quality by design (QbD) based development of a stability indicating HPLC method for drug and impurities. AB - In this paper, an application of Quality by Design (QbD) concepts to the development of a stability indicating HPLC method for a complex pain management drug product containing drug substance, two preservatives, and their degradants is described. The QbD approach consisted of (i) developing a full understanding of the intended purpose, (ii) developing predictive solutions, (iii) designing a meaningful system suitability solution that helps to identify failure modes, and (iv) following design of experiments (DOE) approach. The starting method lacked any resolution among drug degradant and preservative oxidative degradant peaks, and peaks for preservative and another drug degradant. The method optimization was accomplished using Fusion AETM software (S-Matrix Corporation, Eureka, CA) that follows a DOE approach. Column temperature (50 +/- 5 degrees C), mobile phase buffer pH (2.9 +/- 0.2), initial % acetonitrile (ACN, 2 +/- 1%), and initial hold time (2.5, 5, or 10 min) of the HPLC method were simultaneously studied to optimize separation of the unresolved peaks. The optimized HPLC conditions (column temperature of 50 degrees C, buffer pH of 3.1, 3% initial ACN with 2.5 min initial hold) resulted in fully resolved peaks in the two critical pairs. The QbD based method development helped in generating a design space and operating space with knowledge of all method performance characteristics and limitations and successful method robustness within the operating space. PMID- 21682994 TI - Polyimide polymer glass-free capillary columns for gas chromatography. AB - Polymeric polyimide capillary tubing, both uncoated and coated with stationary phases of two polarities, is explored for use as capillary columns for gas chromatography (GC). These glass-free polyimide columns are flexible and their small winding diameter of less than a cm around a solid support makes them compatible for potential use in portable GC instruments. Polyimide columns with dimensions of 0.32 mm i.d. * 3 m are cleaned, annealed at 300 degrees C, and coated using the static method with phenylmethylsilicone (PMS). Separations of volatile organics are investigated isothermally on duplicate sets of polyimide columns by GC with a flame ionization detector using split injection. Unlike the uncoated ones, the coated polyimide columns successfully separate Grob test mix classes of alkanes, amines, and fatty acid methyl esters. The relative standard deviations for retention time and peak area are 0.5 and 2.5 , respectively. With the 3 m PMS-coated column connected to a retention gap to permit operation at its optimum flow rate of 30 cm/s, a plate count of 3200 or plate height of 1 mm is possible. Lack of retention and tailing peaks are evident for the polyimide polymer capillary columns as compared to that of a 3 m commercial cross-linked PMS fused silica capillary. However, headspace analyses of an aromatic hydrocarbon mix and a Clearcoat automotive paint sample are viable applications on the PMS polyimide polymer column. PMID- 21682995 TI - Determination of total polyvinylpyrrolidone (PVP) in ophthalmic solutions by size exclusion chromatography with ultraviolet-visible detection. AB - A straightforward size exclusion chromatography (SEC) method was developed and validated for the determination of total polivinylpyrrolidone (PVP) in ophthalmic solutions using the unusual combination of size exclusion chromatography (SEC), ultraviolet-visible detection and quantitation of an analyte peak that elutes in the total exclusion volume of the column. Samples of opthalmic solutions are diluted with water and injected onto a TSKgel G1000PW, 7.5 mm i.d. * 30 cm, 12 MUm column at 50 degrees C, with 80:20 0.1M sodium acetate-methanol mobile phase and UV detection at 220 nm. Validation was successful for a stability indicating pharmaceutical method, with parameters including specificity, accuracy, linearity, and precision within typical pharmaceutical acceptance criteria. A stress study with acid, base, peroxide, heat, and light indicates that there is no interference from drug, product, or excipients. PMID- 21682996 TI - Quantification of total and free carnitine in human plasma by hydrophilic interaction liquid chromatography tandem mass spectrometry. AB - Carnitine is an endogenous quaternary amine whose primary function is to shuttle long chain fatty acids to the mitochondrial matrix, where they subsequently undergo beta oxidation. Accurate quantification of total and free carnitine is essential for the accurate diagnosis of a number of inborn errors of metabolism, including disorders of fatty acid oxidation as well as various organic acidurias. Early methods for carnitine measurement were enzyme based. Recently, liquid chromatography tandem mass spectrometry has become the method of choice for carnitine measurement. Typically, carnitine is derivitized to from a butyl ester, thus improving its ionization and retention characteristics. A potential problem with this approach is that the acidic conditions used to carry out the reaction may hydrolyze other acyl esters, resulting in ex-vivo artifacts. Consequently, we developed a hydrophobic interaction chromatography (HILIC) tandem mass spectrometry method for the quantification of carnitine. The use of HILIC allows for the derivitization step to be circumvented, while still allowing for favorable chromatographic performance. The method was shown to be accurate, precise, and robust. PMID- 21682997 TI - Rapid analysis of dissolved methane, ethylene, acetylene and ethane using partition coefficients and headspace-gas chromatography. AB - Analysis of dissolved methane, ethylene, acetylene, and ethane in water is crucial in evaluating anaerobic activity and investigating the sources of hydrocarbon contamination in aquatic environments. A rapid chromatographic method based on phase equilibrium between water and its headspace is developed for these analytes. The new method requires minimal sample preparation and no special apparatus except those associated with gas chromatography. Instead of Henry's Law used in similar previous studies, partition coefficients are used for the first time to calculate concentrations of dissolved hydrocarbon gases, which considerably simplifies the calculation involved. Partition coefficients are determined to be 128, 27.9, 1.28, and 96.3 at 30 degrees C for methane, ethylene, acetylene, and ethane, respectively. It was discovered that the volume ratio of gas-to-liquid phase is critical to the accuracy of the measurements. The method performance can be readily improved by reducing the volume ratio of the two phases. Method validation shows less than 6% variation in accuracy and precision except at low levels of methane where interferences occur in ambient air. Method detection limits are determined to be in the low ng/L range for all analytes. The performance of the method is further tested using environmental samples collected from various sites in Nova Scotia. PMID- 21682998 TI - Predictions of retention factors for some organic nucleuphiles in complexation gas chromatography. AB - In the present work, the quantitative structure-retention relationship (QSRR) was used to predict the gas chromatographic retention factors of some organic nucleuphile on chemically modified stationary phase by complexes of Cu (II) with amino groups. The gravitation index, relative negative charge surface area, C component of moment of inertia and weighted negative charged partial surface area are selected as the most relevant descriptors from the pool of descriptors. These descriptors were used for developing multiple linear regression (MLR) and artificial neural network (ANN) models as linear and nonlinear feature mapping techniques. The root mean square errors (RMES) in calculation of retention factors for training, internal and external test set are 0.242, 0.295, and 0.240, respectively for MLR model, and for ANN model the RMSE for training, internal and external test set are; 0.084, 0.108, and 0.176. The ANN and MLR model were further examined by cross validation test, which obtained statistics of Q2 = 0.82 and SPRESS = 0.22 for MLR model and Q2 = 0.97, SPRESS = 0.07 for ANN model. Comparison between these results and other statistics of ANN and MLR models revealed the superiority of ANN over MLR model. PMID- 21682999 TI - beta-cyclodextrin-bonded silica particles as novel sorbent for stir bar sorptive extraction of phenolic compounds. AB - A stir bar coated with beta-cyclodextrin-bonded-silica (CDS) as novel sorbent has been developed and used to analyze seven phenolic compounds in aqueous samples, followed by thermal desorption and gas chromatography-mass spectrometric detection. Significant parameters affecting sorption process such as the time and temperature of sorption and desorption, ionic strength, pH and stirring rate have been optimized and discussed. The coating has a high thermal stability up to 300 degrees C and long application lifetime (80 times). The porous structure of CDS coating provides high surface area and allows high extraction efficiency. Under the selected conditions, linearity range of 0.1-400 MUg/L, limit of quantifications of 0.08-3.3 MUg/L and method detection limits of 0.02-1.00 MUg/L have been obtained. A satisfactory repeatability (RSD <= 6.5, n = 7) with good linearity (0.9975 <= r(2) <= 0.9996) of results illustrated a good performance of the present method. The recovery of different natural water samples was higher than 81.5%. PMID- 21683000 TI - Unusual sequelae of blunt liver injury: laparoscopic resection of a liver abscess and stent failure of an ischemic common bile duct stricture. PMID- 21683001 TI - Operative intervention for diagnosis and management of autoimmune sclerosing pancreatitis confined to the pancreatic tail. PMID- 21683002 TI - Elastofibroma of the posterior thoracic wall. PMID- 21683003 TI - Gastric mucormycosis as a cause of life-threatening upper gastrointestinal bleeding in a trauma patient. PMID- 21683004 TI - Solitary fibrous tumor of the liver. PMID- 21683005 TI - Maxillary sinus carcinoma metastases mimicking malignant pleural mesothelioma. PMID- 21683006 TI - Celiac artery avulsion and right atrial rupture after blunt multisystem trauma. PMID- 21683007 TI - Renal cell carcinoma metastatic to the pancreas. PMID- 21683008 TI - A rare but important cause for appendicitis: actinomyces. PMID- 21683009 TI - Penetrating foreign body mimicking an infected choledochal cyst: can plastic forks be dangerous? PMID- 21683010 TI - Malignant transformation of an anterior mediastinal dermoid cyst in an HIV patient. PMID- 21683011 TI - Comparative study of an electrothermal bipolar vessel sealing system (LigaSure(r)), a harmonic curved shears (Harmonic FocusTM), and traditional technique in total thyroidectomy. PMID- 21683012 TI - Laparoscopic resection of a schwannoma of the ascending colon. PMID- 21683013 TI - Modified single incision laparoscopic fundoplication is feasible: a technical description. PMID- 21683014 TI - Negative pressure post-extubation pulmonary edema after laparoscopic appendectomy. PMID- 21683016 TI - An investigation of exercise and the placebo effect. AB - OBJECTIVE: To replicate previous research that concluded exercise affects health via a placebo effect: simply telling workers with physically active jobs that their "work is exercise" improves health. METHOD: A convenience sample of university building service workers (n=53) learned "their work is exercise" or about job safety. RESULTS: Groups demonstrated similar outcomes at 4 and 8 weeks for weight, percent fat, waist circumference, and behavioral measures. Both groups increased self-perception as "regular exercisers"; blood pressure was reduced only in the intervention group. CONCLUSION: This research did not support the placebo effect. Although enticing, simply changing mind-set does not alter the relationship between exercise and health. PMID- 21683017 TI - Family context as it relates to weight-related behaviors in preadolescent African American girls. AB - OBJECTIVE: To examine family context in relation to body image, weight concerns, and weight control behaviors in preadolescent African American girls. METHODS: Cross-sectional baseline data were analyzed from 303 African American girls 8 to 10 years old and a caregiver in the Girls health Enrichment Multi-site Studies Phase 2(GEMS), an obesity prevention intervention trial. RESULTS: Fruit, juice, and vegetable accessibility and family support for healthy eating and physical activity were significantly related to girls' body image and weight control behaviors. CONCLUSIONS: A comprehensive understanding of family factors may improve future programs aimed at preadolescent girls. PMID- 21683018 TI - Health-related quality of life and nicotine dependence, Florida 2007. AB - OBJECTIVE: To explore the relationship between health-related quality of life (HRQOL) and nicotine dependence in a representative sample of 3560 Florida smokers. METHODS: Data from the 2007 Behavioral Risk Factor Surveillance System Florida Tobacco Callback Survey were used. Logistic regression models were conducted to identify factors independently associated with HRQOL measures. RESULTS: Greater nicotine dependence was associated with poor/fair self-rated health, 1-29 days of poor physical health, and poor mental health, and inactivity in the past 30 days. CONCLUSIONS: The consequences of long-term smoking, and thus nicotine dependence, may not be confined to traditional morbidity measures but may include poor perceived health and overall well-being. PMID- 21683019 TI - Racial/ethnic differences in US health behaviors: a decomposition analysis. AB - OBJECTIVE: To quantify contributions of individual sociodemographic factors, neighborhood socioeconomic status (NSES), and unmeasured factors to racial/ethnic differences in health behaviors for non-Hispanic (NH) whites, NH blacks, and Mexican Americans. METHODS: We used linear regression and Oaxaca decomposition analyses. RESULTS: Although individual characteristics and NSES contributed to racial/ethnic differences in health behaviors, differential responses by individual characteristics and NSES also played a significant role. CONCLUSIONS: There are racial/ethnic differences in the way that individual-level determinants and NSES affect health behaviors. Understanding the mechanisms for differential responses could inform community interventions and public health campaigns that target particular groups. PMID- 21683020 TI - Exercise DVD improves exercise expectations in cardiovascular outpatients. AB - OBJECTIVE: To assess impact of exercise education intervention on exercise frequency and attitudes. METHODS: Cardiovascular outpatients (N=509) were randomized to receive an education DVD or standard care. Outcome measures (baseline and 6 weeks) assessed exercise frequency and cognitive variables. RESULTS: There was no difference between groups on exercise frequency change from baseline, but DVD group reported greater exercise outcome expectations than control group (P=0.01). There was a greater increase in relapse-prevention behavior in the DVD group, compared to control, for those with low relapse prevention behavior at baseline (P=0.02). CONCLUSION: A minimal intervention improves outcome expectations for exercise. PMID- 21683021 TI - Older adults' common sense models of diabetes. AB - OBJECTIVE: To investigate the importance of viewing belief systems about health maintenance holistically. METHODS: Qualitative (N=74) and quantitative data (N=95) were obtained from a multi-ethnic rural-dwelling sample of older adults with diabetes to characterize their common sense models (CSMs) of diabetes. RESULTS: There is a discrete number of CSMs held by older adults, each characterized by unique clusters of diabetes-related knowledge and beliefs. Individuals whose CSM was shaped by biomedical knowledge were better able to achieve glycemic control. CONCLUSIONS: Viewing individuals' health beliefs incrementally or in a piece-meal strategy may be less effective for health behavior change than focusing on beliefs holistically. PMID- 21683022 TI - Exercise engagement is differentially motivated by age-dependent factors. AB - OBJECTIVES: To examine exercise engagement motives from adolescence throughout the adult life span using the Exercise Motivation Inventory 2 questionnaire. METHODS: Two hundred fifty-five (255) participants, 13 - 84 years and equally representing both genders, were grouped by age and sex. RESULTS: An age-dependent engagement in voluntary exercise was observed. Young adults engage in exercise based on interpersonal motives, whereas exercise engagement in middle age is associated with body-related motives and psychological motives. Health motives influence exercise engagement beyond middle age whereas fitness motives underpin exercise engagement throughout the life span beyond childhood. CONCLUSIONS: Data indicate age-dependent motivational factors for exercise engagement that may hold important implications for exercise adherence and engagement strategies. PMID- 21683023 TI - A clinic-based, youth development approach to teen pregnancy prevention. AB - OBJECTIVE: To provide a description of Prime Time, an intervention to reduce pregnancy risk behaviors among high-risk adolescent girls. METHODS: Prime Time, a clinic-based, multicomponent youth development intervention aims to reduce sexual risk behaviors, violence involvement, and school disconnection. RESULTS: We highlight key considerations in conceptualization, design, and methods for a Prime Time randomized trial. CONCLUSIONS: Prime Time comes at a time of great interest in restructuring adolescent health services. This study represents an important effort to expand preventive and youth development services among young people most vulnerable to early pregnancy, for whom services must go beyond traditional problem-oriented approaches. PMID- 21683024 TI - Predictors of physical activity in adults with type 2 diabetes. AB - OBJECTIVES: To determine demographic, medical, social cognitive, and environmental predictors of aerobic physical activity and resistance training in a population sample of adults with type 2 diabetes. METHODS: Two hundred forty four (244) participants completed questionnaires with a 3-month follow-up. Multiple and logistic regression models examined predictors of aerobic activity and resistance training. RESULTS: Several factors were associated with higher levels of both aerobic physical activity and resistance training; self-efficacy was the strongest predictor for both modes of activity. CONCLUSIONS: The findings can guide physical activity promotion interventions and programs for this population, profiling those who are least active. PMID- 21683025 TI - Predicting osteoporosis prevention behaviors: health beliefs and knowledge. AB - OBJECTIVES: To investigate whether the expanded Health Belief Model (EHBM) could predict calcium intake and physical activity in adolescent girls. METHODS: Participants self-reported calcium intake, physical activity, and osteoporosis health beliefs. Regression analysis examined the relationship between these beliefs and behaviors. RESULTS: Calcium self-efficacy, calcium barriers, and osteoporosis knowledge predicted calcium intake, whereas exercise self-efficacy and health motivation predicted physical activity. CONCLUSIONS: The EHBM appears to be useful in predicting osteoporosis prevention behaviors in adolescent girls. Interventions should focus on identifying barriers to calcium consumption and physical activity and increasing beliefs in the ability overcome them. PMID- 21683026 TI - Metastases to the mouth and jaws: a contemporary Canadian experience. AB - BACKGROUND AND OBJECTIVE: The types of cancers that most frequently metastasize to the mouth and jaws reflect, for the most part, the relative incidence of cancers in a given population at a given time. We report a retrospective, but relatively contemporary study of 38 cases of metastatic oral tumours in a Canadian population to compare the Canadian experience with that of nearby and distant countries. METHODS: Thirty-eight cases of metastatic disease to the mouth and jaws in a Canadian population were analyzed. Data about patients' age, sex, site of metastatic deposits, clinical history, including the presence of a known primary cancer, and radiographic features were collected from the files (1992 2010) of the oral pathology diagnostic service at the University of Western Ontario, and the hospital archives (2002-2010) of the department of pathology, London Health Sciences Centre, London, Ontario. RESULTS: Most metastases were to the mandible, although oral soft tissues were also involved, most frequently, the gingiva and mucosa of the alveolar ridge. Prostate, lung and breast cancers were the most common primary sites, but a variety of cancer types were found. CONCLUSIONS: The relative frequency of types of metastatic cancer to the oral region is similar in Canada, the United States and Northern Europe, but differs significantly from those reported in South East Asia and Japan. The relative frequency of types of cancer that metastasize to the mouth and jaws reflects the relative incidence of cancers in the population. PMID- 21683028 TI - Oral manifestations of a systemic disease. PMID- 21683027 TI - Osseous (cemento-osseous) dysplasia of the jaws: clinical and radiographic analysis. AB - OBJECTIVES: To explore the demographic characteristics and clinical features among patients with osseous (cemento-osseous) dysplasia (OD/COD) of the jaws and to determine the frequency of particular radiographic characteristics. METHODS: The charts and radiographic reports of 118 patients with OD/COD, obtained from the archives of the University of Toronto discipline of oral and maxillofacial radiology, were reviewed. Demographic and clinical data, radiographic findings and final diagnoses were collected and analyzed to determine typical characteristics. RESULTS: Of the 117 patients for whom age and sex were known, the majority (97 [82.9%]) were female; these female patients had a mean age (+/- standard deviation) of 44.3 +/- 13.4 years. Eighty-three (72.2%) of the 115 patients for whom symptoms were known were clinically asymptomatic. Ninety-three patients (78.8%) had OD/COD at single sites (i.e., periapical OD/COD), and 25 (21.2%) had OD/COD at multiple sites (i.e., florid OD/COD). In addition, 15 (12.7%) of the cases were associated with one or more simple bone cysts, and 13 (11.0%) were associated with osteomyelitis. In most cases, the OD/COD was unilateral, with the lesion being located in the mandible, usually associated only with the posterior teeth. The lesions exhibited well-defined, sclerotic or corticated margins (108 patients [91.5%]) and were surrounded by a radiolucent border. Minimal effects on surrounding structures were observed. As well, 85 (72.0%) of the lesions were in the mixed radiolucent-radiopaque stage, with dense, cementum-like radiopacities. CONCLUSIONS: The majority of cases of OD/COD occurred in women in the fifth decade of life, and most cases were asymptomatic. OD/COD was more likely to present as solitary lesions but also occurred in association with simple bone cysts or osteomyelitis. PMID- 21683029 TI - Some thoughts on our profession. PMID- 21683030 TI - Dr. Robert MacGregor: a legacy of caring. PMID- 21683031 TI - An unusual red lesion of the gingiva: differential diagnosis and management. PMID- 21683032 TI - Mentoring: key to a collegial culture. PMID- 21683033 TI - Parents know best, but are they accurate? Parental normative misperceptions and their relationship to students' alcohol-related outcomes. AB - OBJECTIVE: Parents often look to other parents for guidance, but how accurate are their perceptions? Expanding on existing normative literature to include parents of college students, this study first sought to determine whether parents accurately estimated the attitudes of other parents concerning their college student's alcohol-related behaviors. The effect of these (mis)perceived injunctive norms on the alcohol-related attitudes and behaviors of the parents' own children was then examined. METHOD: Participants were 270 college student parent dyadic pairs who completed independent online surveys. The student sample was 59% female; the parent sample was 78% female. RESULTS: A structural equation model demonstrated that parents significantly overestimated other parents' approval of alcohol use by their respective child and, further, that these misperceptions strongly influenced parental attitudes toward their own child's drinking. Parental attitudes were subsequently found to be significantly associated with their child's attitudes toward drinking but were only marginally associated with the child's actual drinking, thereby underscoring the mediational effect of the child's attitudes. CONCLUSIONS: This is the first study to document the influence of parental normative misperceptions regarding alcohol use by their college-age children, reinforcing the importance of parental attitudes on children's alcohol-related attitudes and behaviors in college. These findings support the need to complement student-based interventions with parent-based interventions aimed at increasing parental awareness and involvement. Further, the current findings indicate that normative interventions targeting parents offer a promising avenue by which to indirectly and positively influence college students' alcohol use. PMID- 21683034 TI - Evaluation of a service provider short course for prevention of fetal alcohol syndrome. AB - OBJECTIVE: South Africa has among the highest reported rates of Fetal Alcohol Syndrome (FAS) globally. Primary prevention targeting women at risk for alcohol exposed pregnancies could substantially reduce the incidence of FAS. We evaluated the effectiveness of a short training intervention to improve service providers' screening, identification, and management of women at risk for alcohol-exposed pregnancies. METHOD: Training to screen and counsel women at risk for alcohol exposed pregnancies was offered to 86 service providers (95% of whom were female) in two municipalities in the Western Cape Province, South Africa. Effectiveness was evaluated through a before-after study of service providers' knowledge and confidence levels and a comparison of service providers' practices (assessed indirectly via service user exit interviews) at intervention and control clinics. RESULTS: The proportion of service providers indicating that alcohol use during pregnancy is harmful to the fetus increased after training (23% vs. 67%; p < .001). After training, providers expressed significantly more confidence for four skills indicators related to the identification and management of women at risk for an alcohol-exposed pregnancy. Female clients at intervention clinics were more likely than those at the control clinics to receive alcohol advice (odds ratio [OR] = 2.13, 95% CI [1.27, 3.53]), counseling (OR = 1.3, 95% CI [1.05, 1.56]), and an offer of family planning (OR = 1.1, 95% CI [1.06, 2.10]) after the training. Time * Group interaction variable analysis in multiple logistic regression modeling confirmed these effects as related to training. CONCLUSIONS: A short training course based on brief motivational interviewing principles appears to be effective in building service provider capacity to better prevent and manage women at risk for alcohol-exposed pregnancies. PMID- 21683035 TI - Paternal drinking, intimate relationship quality, and alcohol consumption in pregnant Ukrainian women. AB - OBJECTIVE: Maternal alcohol consumption during pregnancy and fetal alcohol spectrum disorders (FASDs) represent a significant public health problem. The influence of the male partner's alcohol consumption patterns and the quality of the partner's intimate relationship might be important factors to consider in the design of successful FASD prevention programs. METHOD: As part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, 166 pregnant women in two regions in Ukraine participated in an in-person interview at an average gestational age of 18-19 weeks. Subjects were classified cross-sectionally as abstainers/light drinkers (n = 80), defined as low or no consumption of alcohol in the periconceptional period and none in the most recent 2 weeks of pregnancy; discontinuers (n = 43), defined as moderate to heavy alcohol use in the periconceptional period but none during the most recent 2 weeks of pregnancy; or continuing drinkers (n = 43), defined as continued moderate to heavy alcohol use within the most recent 2 weeks of pregnancy. Women also reported on their partner's drinking behavior and on the quality of their intimate relationship. RESULTS: Heavy paternal drinking was significantly associated with both continuing maternal drinking in the most recent 2 weeks (adjusted odds ratio [OR] = 34.1; 95% CI [5.9, 195.8]) and being a risky drinker only around conception (adjusted OR = 27.0; 95% CI [5.0, 147.7]). In addition, women who consumed alcohol during pregnancy had lower mean scores for satisfaction with partners' relationship and ability to discuss problems (p < .05) compared with light drinkers/abstainers. CONCLUSIONS: This study suggests that development of partner based interventions, as opposed to those solely focused on maternal drinking, might be warranted as a strategy to prevent FASD. PMID- 21683036 TI - Trait and state hostile rumination facilitate alcohol-related aggression. AB - OBJECTIVE: This investigation attempted to determine whether trait and state hostile rumination functioned as risk factors for the relation between acute alcohol intoxication and aggression. METHOD: Participants were 516 social drinkers (252 men and 264 women). Trait hostile rumination was assessed using Caprara's Dissipation-Rumination Scale. Following the consumption of either an alcohol or a placebo beverage, participants were tested on a laboratory task in which electric shocks were received from and administered to a fictitious opponent under the guise of a competitive reaction-time task. Aggression was operationalized as the combined mean responses for shock intensity and duration across all trials. In a subset of the sample (n = 320), state hostile rumination was assessed following the aggression task using a self-report measure. RESULTS: As expected, both trait and state measures acted as moderators. Specifically, acute alcohol intoxication was more likely to increase aggression in persons with higher trait and state hostile rumination scores compared with their equally intoxicated lower rumination counterparts. CONCLUSIONS: This was the first investigation to demonstrate that trait or state rumination significantly heighten the risk of intoxicated aggression. We believe that hostile rumination facilitates intoxicated aggression because ruminators have difficulty diverting their attention away from anger-provoking stimuli and related thoughts, thus making violent reactions more likely. Clinical and public health interventions would benefit by developing strategies to distract ruminative attention away from violence-promoting messages, especially when persons are under the influence of alcohol. PMID- 21683037 TI - Drinking style and dating violence in a sample of urban, alcohol-using youth. AB - OBJECTIVE: This study examined childhood abuse, problem behavior, drinking style, and dating violence (DV). Our goal was to assess whether (a) alcohol use-related beliefs and behaviors ("drinking style") would be associated with DV perpetration and victimization, (b) drinking style would mediate the relationship between childhood abuse and DV, and (c) the drinking style-DV relationship would be attributable to propensity for problem behavior. METHOD: Cross-sectional survey data were collected from 456 youth ages 14-21 years who were patients in an urban emergency department. Participants were eligible if they were unmarried and reported past-month alcohol use and dating in the past year. By design, the sample was 50% female. Data were analyzed using structural equation modeling. RESULTS: For both males and females, past-year DV was associated with a more risky drinking style, characterized by more frequent alcohol use, alcohol aggression expectancies, drinking to cope, and beliefs that alcohol is disinhibiting and that being drunk provides a "time-out" from behavioral expectations. Drinking style mediated the childhood victimization-DV relationship for males and females. However, when propensity for problem behavior was included in the model, the effect of drinking style on DV was no longer significant. Substantial path differences for males and females were observed. CONCLUSIONS: The current study examined adolescent drinking style as a potential mediator between childhood victimization and DV. Drinking style was associated with DV for males and females and mediated the relationship between childhood victimization and DV. The relationship between drinking style and DV appeared to reflect adolescents' propensity for problem behavior. Variations in males' and females' pathways to DV were observed. The implications of these findings are discussed. PMID- 21683038 TI - Drug and alcohol involvement in four types of fatal crashes. AB - OBJECTIVE: The aim of this study was to explore the relationship of drunk and drugged driving to the occurrence of fatal crashes associated with speeding, failure to obey/yield, inattention, and seat belt nonuse. METHOD: We examined data for fatally injured drivers involved in single-vehicle crashes killed in states in which more than 79% of the drivers were tested for drugs other than alcohol and had a known result. RESULTS: About 25% of the drivers tested positive for drugs, a figure almost double that estimated by the 2007 National Roadside Survey. Cannabinoids and stimulants each contributed to about 23% of the drugpositive results (6% among all fatally injured single-vehicle drivers). Stimulants more than cannabinoids were found to be associated with the four types of crashes under study. Some drugs showed a protective effect over the four crash types under study. Significant interactions between drugs and alcohol were observed. Stimulants contributed to the different types of fatal crashes irrespective of the levels of alcohol consumed by the drivers. CONCLUSIONS: This study provides further evidence of a link between drug consumption and fatal crashes. It also opens the door to some interesting and sometimes unexpected questions regarding the way drugs contribute to crashes, which we found varies depending on the type of crash considered, the class of drug, and the presence of alcohol. Research is also needed on drugs that could have a protective effect on the occurrence of fatal crashes. These findings could be highly relevant to the design of drug-related traffic laws and programs targeted at curbing drugged driving. PMID- 21683039 TI - Economic analysis of methamphetamine prevention effects and employer costs. AB - OBJECTIVE: The goal of this research was to evaluate economically three interventions designed to prevent substance use in general populations of adolescents, specifically focusing on the prevention of methamphetamine use and its subsequent benefits to employers. METHOD: In a randomized, controlled trial, three preventive interventions were delivered to 6th- or 7th-grade youth in 58 Iowa school districts, with 905 of these youth (449 girls) providing follow-up assessments as 12th graders. Intervention conditions included the family-focused Iowa Strengthening Families Program (ISFP), the school-based Life Skills Training (LST) program, and a combined condition of both the Strengthening Families Program: For Parents and Youth 10-14 (SFP10- 14; an ISFP revision) plus LST (LST + SFP10-14). Analyses based on intervention costs, 12th-grade methamphetamine use rates, and methamphetamine- related employer costs yielded estimates of intervention cost, cost-effectiveness, benefit-cost ratio, and net benefit. RESULTS: The ISFP lowered methamphetamine use by 3.9%, cost $25,385 to prevent each case, and had a benefit-cost ratio of 3.84, yielding a net benefit of $2,813 per youth. The LST program reduced methamphetamine use by 2.5%, required $5,122 per prevented case, and had a benefit-cost ratio of 19.04, netting $2,273 per youth. The combined LST + SFP10-14 prevention condition lowered methamphetamine use rates by 1.8%, cost $62,697 to prevent each case, had a benefit-cost ratio of 1.56, and netted $620 per youth. Findings were robust after varying a number of key parameters across a range of plausible values. CONCLUSIONS: Substance use prevention programming is economically feasible, particularly for effective interventions that have lower per person treatment delivery costs. PMID- 21683040 TI - Risk of marijuana use in male and female college student athletes and nonathletes. AB - OBJECTIVE: A large minority of collegiate athletes report past-year marijuana use even though there is a significant possibility of experiencing negative athlete specific consequences related to performance, eligibility, and scholarship. The present study examined risk factors that can drive or curb marijuana use in college athletes and nonathletes. METHOD: Logistic regressions, performed separately for men and for women, assessed the relationship of past-year marijuana use to sensation seeking, negative mood, perceptions of peer marijuana use, motivations for marijuana use, and stress related to body image and academics in athletes (233 men, 156 women) and nonathletes (184 men, 313 women). Risk factors also were compared for male past-year marijuana users who reported using (n = 26) or not using (n = 61) the substance during their competitive season. RESULTS: For athletes and nonathletes of both genders, being White, being past-year cigarette smokers, having higher sensation-seeking scores, and having exaggerated perceptions of student use norms were associated with past-year marijuana use. Enhancement motivations for use were higher among athletes compared with their same-gender nonathlete peers. In women, but not in men, greater body image stress and lower academic stress were associated with past year marijuana use. Male athletes who continued using marijuana into their competitive season demonstrated a qualitatively different risk profile compared with athlete past-year users who reported no in-season use, including greater coping motivations for marijuana use. CONCLUSIONS: This preliminary study suggests that although the overall risk profile of college athletes and nonathletes is similar, athletes appear to be particularly motivated to use marijuana because of its enhancement or pleasurable properties. PMID- 21683041 TI - Comparison of the concurrent and predictive validity of three measures of readiness to change marijuana use in a clinical sample of adolescents. AB - OBJECTIVE: The measurement of readiness to change has become common practice in alcohol and drug treatment of both adults and adolescents. Nevertheless, there is relatively little research on the validity of measures of readiness to change among treated adolescents. The purpose of this study was to compare three measures of readiness to change marijuana use commonly used in clinical research and practice with adolescents: the Readiness Ruler, the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES; Factors 1 and 2, Recognition and Taking Steps, respectively), and a staging algorithm. METHOD: The participants were 174 adolescents presenting for intensive outpatient alcohol and drug treatment who reported current marijuana use at the initial assessment. Evidence for concurrent validity was assessed by computing simple correlations among readiness measures, and correlations of each readiness measure with marijuana involvement (percentage of days abstinent in the last 30 days, problem severity score, and marijuana abuse and dependence symptom count [based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria]) at both the initial/baseline assessment and at a 6-month follow-up assessment. Evidence for predictive validity was based on the results of multilevel regression models of the readiness measures in predicting frequency of marijuana use, symptoms, and problems at 6 months from the initial readiness assessment and then in predicting marijuana use, symptoms, and problems at 12 months from the readiness assessment at 6 months. RESULTS: The results showed evidence for good concurrent and predictive validity for the ruler, the staging algorithm, and Taking Steps but poor evidence for the validity of Recognition. The ruler emerged as the measure with the most clinical utility when brevity and ease of administration are taken into account. CONCLUSIONS: Research and clinical implications of the findings are discussed. PMID- 21683042 TI - A comprehensive longitudinal test of the acquired preparedness model for alcohol use and related problems. AB - OBJECTIVE: According to the acquired preparedness model (APM), personality traits related to disinhibition (i.e., impulsivity and sensation seeking) may influence the learning process, contributing to individual differences in cognitions (e.g., expectations about outcomes) that may contribute to engagement in and consequences of risk behaviors, including alcohol use. Although there is strong support for the APM, longitudinal studies have involved short-term follow-ups, and the relevance of the APM for alcohol-related consequences has not been clearly established. METHOD: Participants were 2,245 (59.9% female) incoming freshmen who completed the first of eight web-based surveys during the summer before college matriculation. Structural equation modeling was used to test a comprehensive longitudinal APM for both alcohol use and related consequences. Multigroup models were used to examine measurement and structural invariance by gender. RESULTS: Positive (but not negative) alcohol expectancies during freshman year of college partially mediated the relation between senior year of high school disinhibition and both alcohol use and related problems during the fourth year of college, and multigroup models suggested that the relationships proposed in the APM operated similarly for women and men. CONCLUSIONS: This study demonstrates the temporal relations proposed in the APM across a longer period (4 years) than in previous studies among a large sample of ethnically diverse students. Further, the results are the first to validate the APM with respect to drinking consequences while controlling for levels of alcohol use. The results lend support for brief interventions targeting positive alcohol expectancies, particularly for individuals high in trait disinhibition. PMID- 21683043 TI - Differential relationships between continuity of care practices, engagement in continuing care, and abstinence among subgroups of patients with substance use and psychiatric disorders. AB - OBJECTIVE: We examined whether patient subgroups with differing substance use disorders (SUDs) and psychiatric severity levels varied on engagement in continuing care and abstinence outcomes, the association of continuity of care practices to engagement, and the association of engagement to abstinence. METHOD: Staff in 28 Veterans Affairs SUD treatment programs used the Addiction Severity Index to assess 865 (98% male) patients' alcohol, other drug, and psychiatric problems at treatment entry. At discharge, staff supplied data on patients' treatment, motivation, and continuity of care practices. Administrative data assessed continuing care engagement. Six months after discharge, 673 patients completed a self-reported Addiction Severity Index. The sample comprised four SUD subgroups (abstinent from alcohol and other drugs, used alcohol only, used other drugs only, used alcohol and other drugs) and two psychiatric severity subgroups (high and moderate to low). RESULTS: Patients receiving more continuity of care services engaged in continuing care longer. This association was weaker for the high psychiatric severity subgroup than for the moderate-to-low psychiatric severity subgroup. Engagement in continuing care was the most important predictor of abstinence overall. The positive association between engagement in continuing care and abstinence was strongest for the SUD subgroup using both alcohol and other drugs. This group had the lowest likelihood of abstinence if they engaged in little or no continuing care but showed the greatest increase in abstinence with longer continuing care engagement. CONCLUSIONS: Subgroups' differential responsiveness to continuity of care services and engagement highlights the crucial importance of continuing care interventions to improve abstinence outcomes for certain subgroups of patients who use both alcohol and other drugs. PMID- 21683044 TI - Alcohol use and related problems among college students and their noncollege peers: the competing roles of personality and peer influence. AB - OBJECTIVE: Although alcohol use and related problems are highly prevalent in emerging adulthood overall, college students drink somewhat more than do their peers who do not attend college. The personal or social influences underlying this difference, however, are not yet well understood. The present study examined whether personality traits (i.e., self-regulation and sensation seeking) and peer influence (i.e., descriptive drinking norms) contributed to student status differences. METHOD: At approximately age 22, 4-year college students (n = 331) and noncollege emerging adults (n = 502) completed web-based surveys, including measures of alcohol use, alcohol-related problems, personality, and social norms. RESULTS: College students drank only slightly more heavily. This small difference, however, reflected personality suppression. College students were lower in trait-based risk for drinking, and accounting for traits revealed a stronger positive association between attending college and drinking more heavily. Although noncollege emerging adults reported greater descriptive drinking norms for social group members, norms appeared to more strongly influence alcohol use among college students. Finally, despite drinking less, noncollege individuals experienced more alcohol-related problems. CONCLUSIONS: The association between attending college and drinking heavily may be larger than previously estimated, and it may be masked by biased selection into college as a function of both self-regulation and sensation seeking. Differing patterns of alcohol use, its predictors, and its consequences emerged for the college and noncollege samples, suggesting that differing intervention strategies may best meet the needs of each population. PMID- 21683045 TI - Daily relationship between event-specific drinking norms and alcohol use: a four year longitudinal study. AB - OBJECTIVE: This study examined how social-influence processes operate during specific drinking contexts as well as the stability and change in these processes throughout the college years. METHOD: Using a measurement-burst design, a hybrid of longitudinal and daily diary methods, we assessed the relationship between event-specific descriptive drinking norms and personal drinking. College students (N = 523) completed a baseline survey followed by a 30-day daily diary each year for up to the 4 study years. The baseline survey assessed participant gender and social anxiety, and the daily survey assessed personal drinking and perceived peer drinking (i.e., event-specific descriptive norms) during social drinking events. RESULTS: Multilevel modeling revealed that men's social drinking slightly increased over the 4 years, whereas women's drinking remained steady. Further, on social drinking days when event-specific descriptive norms were high, students drank more, but this relationship was stronger for men than women and did not change over time. However, men's drinking norm perceptions increased across years, whereas women's decreased. Social anxiety did not moderate the relationship between norms and drinking. CONCLUSIONS: We demonstrate that although gender differences exist in the stability and change of personal drinking, norms, and normative influence on drinking across the years of college, the acute social influence of the norm on personal drinking remains a stable and important predictor of drinking throughout college. Our findings can assist with the identification of how, when, and for whom to target social influence-based interventions aimed at reducing drinking. PMID- 21683046 TI - Effects of AlcoholEdu for college on alcohol-related problems among freshmen: a randomized multicampus trial. AB - OBJECTIVE: AlcoholEdu for College is a 2- to 3-hour online course for incoming college freshmen. This study was the first multicampus trial to examine effects of AlcoholEdu for College on alcohol-related problems among freshmen. METHOD: Thirty universities participated in the study. Fifteen were randomly assigned to receive AlcoholEdu, and the other 15 were assigned to the control condition. AlcoholEdu was implemented by intervention schools during the summer and/or fall semester. Cross-sectional surveys of freshmen were conducted at each university beginning before the intervention in spring 2008/2009; post-intervention surveys were administered in fall 2008/2009 and spring 2009/2010. The surveys included questions about the past-30-day frequency of 28 alcohol-related problems, from which we created indices for the total number of problems and problems in seven domains: physiological, academic, social, driving under the influence/ riding with drinking drivers, aggression, sexual risk taking, and victimization. Multilevel Poisson regression analyses were conducted to examine intent-to-treat and dosage effects of AlcoholEdu for College on these outcomes. RESULTS: Multilevel intent-to-treat analyses indicated significant reductions in the risk for past-30-day alcohol problems in general and problems in the physiological, social, and victimization domains during the fall semester immediately after completion of the course. However, these effects did not persist in the spring semester. Additional analyses suggested stronger AlcoholEdu effects on these outcomes at colleges with higher rates of student course completion. No AlcoholEdu effects were observed for alcohol-related problems in the other four domains. CONCLUSIONS: AlcoholEdu for College appears to have beneficial short term effects on victimization and the most common types of alcohol-related problems among freshmen. Universities may benefit the most by mandating AlcoholEdu for College for all incoming freshmen and by implementing this online course along with environmental prevention strategies. PMID- 21683047 TI - Neighborhood variation in adolescent alcohol use: examination of socioecological and social disorganization theories. AB - OBJECTIVE: Risk factors for adolescent alcohol use are typically conceptualized as individual and interpersonal level factors; however, these factors do not fully explain adolescent drinking behavior. We used a socioecological model to examine the contribution of neighborhood factors in a risk and promotive model of adolescent alcohol use among urban high school youth (N = 711; 52% female; 82% African American; M = 18 years old). METHOD: Using a multilevel model, we considered the role of neighborhood disadvantage on youth alcohol use, after accounting for risk (e.g., peer and parental substance use) and promotive factors (e.g., social support and participation in prosocial activities). RESULTS: Peer alcohol use and peer support were associated with more alcohol use, and maternal support was negatively associated with alcohol use. Despite significant variation at the neighborhood level, neighborhood disadvantage was not directly associated with adolescent drinking. CONCLUSIONS: Our study contributes to a mixed body of literature on social context and adolescent health. Although our research highlights the importance of interpersonal relationships, we found no support for neighborhood influences. We conclude with future directions for research examining the link between adolescent drinking and neighborhood contexts. PMID- 21683048 TI - Six-month changes in spirituality and religiousness in alcoholics predict drinking outcomes at nine months. AB - OBJECTIVE: Although spiritual change is hypothesized to contribute to recovery from alcohol dependence, few studies have used prospective data to investigate this hypothesis. Prior studies have also been limited to treatment-seeking and Alcoholics Anonymous (AA) samples. This study included alcohol-dependent individuals, both in treatment and not, to investigate the effect of spiritual and religious (SR) change on subsequent drinking outcomes, independent of AA involvement. METHOD: Alcoholics (N = 364) were recruited for a panel study from two abstinence-based treatment centers, a moderation drinking program, and untreated individuals from the local community. Quantitative measures of SR change between baseline and 6 months were used to predict 9-month drinking outcomes, controlling for baseline drinking and AA involvement. RESULTS: Significant 6-month changes in 8 of 12 SR measures were found, which included private SR practices, beliefs, daily spiritual experiences, three measures of forgiveness, negative religious coping, and purpose in life. Increases in private SR practices and forgiveness of self were the strongest predictors of improvements in drinking outcomes. Changes in daily spiritual experiences, purpose in life, a general measure of forgiveness, and negative religious coping also predicted favorable drinking outcomes. CONCLUSIONS: SR change predicted good drinking outcomes in alcoholics, even when controlling for AA involvement. SR variables, broadly defined, deserve attention in fostering change even among those who do not affiliate with AA or religious institutions. Last, future research should include SR variables, particularly various types of forgiveness, given the strong effects found for forgiveness of self. PMID- 21683049 TI - A longitudinal examination of alcohol pharmacotherapy adoption in substance use disorder treatment programs: patterns of sustainability and discontinuation. AB - OBJECTIVE: The objectives of this study were to (a) identify the patterns of disulfiram (Antabuse) and tablet naltrexone (Revia) adoption over a 48-month period in a nationally representative sample of privately funded programs that deliver substance use disorder treatment; (b) examine predictors of sustainability, later adoption, discontinuation, and nonadoption of disulfiram and tablet naltrexone; and (c) measure reasons for medication discontinuation. METHOD: Two waves of data were collected via face-to-face structured interviews with 223 program administrators. RESULTS: These data demonstrated that adoption of medications for alcohol use disorders (AUDs) was a dynamic process. Although nonadoption was the most common pattern, approximately 20% of programs sustained use of the AUD medications and 30% experienced organizational change in adoption over the study period. Bivariate multinomial logistic regression models revealed that organizational characteristics were associated with sustainability including location in a hospital setting, program size, accreditation, revenues from private insurance, referrals from the criminal justice system, number of medical staff, and use of selective serotonin reuptake inhibitors at baseline. Two patterns of discontinuation were found: Programs either discontinued use of all substance use disorder medications or replaced disulfiram/tablet naltrexone with a newer AUD medication. CONCLUSIONS: These findings suggest that adoption of AUD medications may be positively affected by pressure from accreditation bodies, partnering with primary care physicians, medication-specific training for medical staff, greater availability of resources to cover the costs associated with prescribing AUD medications, and amending criminal justice contracts to include support for AUD medication use. PMID- 21683050 TI - Alcohol use and problem severity: associations with dual systems of self-control. AB - OBJECTIVE: The current study tested the associations between a dual-systems model of self-control and alcohol use and problem severity. METHOD: The sample consisted of 491 college students (77.0% women) from a rural state university. Participants completed a series of online surveys that assessed aspects of self control, alcohol consumption, and alcohol-related problems. RESULTS: A confirmatory factor analysis model indicated two moderately correlated factors of poor control and good self-control. Poor control was positively associated with both alcohol use and problem severity. Good self-control had a negative association with problem severity. Good self-control moderated the association between poor control and alcohol use as well as between poor control and problem severity. The association between poor control and alcohol use was stronger at low levels of good self-control, whereas at high levels of good self-control, the effect of poor control was weaker and not significant. The interaction predicting problem severity was different: There was a negative association between good self-control and problem severity at low levels of poor control, and this effect diminished as poor control increased. CONCLUSIONS: The results suggest that multidimensional models of self-control may be useful in understanding problematic alcohol use and may be beneficial for prevention and intervention efforts. PMID- 21683051 TI - Hazardous use should not be a diagnostic criterion for substance use disorders in DSM-5. PMID- 21683052 TI - "Gray area" alcohol consumption and the U.S. Dietary Guidelines: a comment on Dawson and Grant (2011). PMID- 21683053 TI - The enhancement of beneficial effects following audio feedback by cognitive preparation in the treatment of social anxiety: a single-session experiment. AB - BACKGROUND AND OBJECTIVES: According to cognitive models, negatively biased processing of the publicly observable self is an important aspect of social phobia; if this is true, effective methods for producing corrective feedback concerning the public self should be strived for. Video feedback is proven effective, but since one's voice represents another aspect of the self, audio feedback should produce equivalent results. This is the first study to assess the enhancement of audio feedback by cognitive preparation in a single-session randomized controlled experiment. METHOD: Forty socially anxious participants were asked to give a speech, then to listen to and evaluate a taped recording of their performance. Half of the sample was given cognitive preparation prior to the audio feedback and the remainder received audio feedback only. Cognitive preparation involved asking participants to (1) predict in detail what they would hear on the audiotape, (2) form an image of themselves giving the speech and (3) listen to the audio recording as though they were listening to a stranger. To assess generalization effects all participants were asked to give a second speech. RESULTS: Audio feedback with cognitive preparation was shown to produce less negative ratings after the first speech, and effects generalized to the evaluation of the second speech. More positive speech evaluations were associated with corresponding reductions of state anxiety. Social anxiety as indexed by the Implicit Association Test was reduced in participants given cognitive preparation. LIMITATIONS: Small sample size; analogue study. CONCLUSION: Audio feedback with cognitive preparation may be utilized as a treatment intervention for social phobia. PMID- 21683054 TI - Mitochondrial DNA diversity in the populations of great gerbils, Rhombomys opimus, the main reservoir of cutaneous leishmaniasis. AB - Accurate identification of animal reservoirs of transmissible diseases is an absolute requirement to any epidemiological survey of zoonoses and is essential for predicting species-specific population outbreaks and therefore to develop accurate ecological control strategies. The systematic status of the great gerbil (Rhombomys opimus) remains unclear, despite the fundamental role of these rodents as the main known reservoir hosts of the protozoan parasite Leishmania major in the epidemiology of zoonotic cutaneous leishmaniasis (ZCL) in central and south Asia. In the present work, we represent molecular evidence supporting the identification of at least two major lineages (subspecies) within the species of R. opimus in Iran. Analysis of the mitochondrial cytochrome b (cyt b) gene, revealed a range of 1-10% genetic variation among populations, which were well associated with biogeographic origins and subspecies. Results of laboratory cross hybridization between the subspecies and finding sympatric haplotypes of the two subspecies suggested that no pre- or post-zygotic barriers exist between the subspecies indicating that they still belong to a single taxon. However, the amount of genetic variations between populations/subspecies is high enough to lead them to speciation in future. Implications of such findings on the eco epidemiology of ZCL in Iran are discussed. PMID- 21683055 TI - Passive Ca(2+) overload in H9c2 cardiac myoblasts: assessment of cellular damage and cytosolic Ca(2+) transients. AB - Increase of resting Ca(2+) levels and amplitude of vasopressin-induced Ca(2+) transients were observed when cells in serum-free medium were exposed to 5mM Ca(2+) for 2h. Small effect on cell viability was also observed. A rapid cytotoxic effect was developed in the presence of 10mM Ca(2+) and absence of serum. However, cells exposed to 10mM Ca(2+) in the presence of serum were protected from damage for at least 2days. Resting Ca(2+) levels and cytosolic Ca(2+) transients in serum-containing medium with 10mM Ca(2+) displayed lower increases and a tendency to recover control values. When serum was absent, cells preincubated with 10mM Ca(2+) were more sensitive to thapsigargin-induced damage than cells preincubated with lower Ca(2+). The sensitivity was similar when serum was present. Tolerance to high Ca(2+) in the presence of serum was linked to potentiation of the mitochondrial Ca(2+) entry to decrease the sarcoplasmic reticulum Ca(2+) overload. PMID- 21683056 TI - Interaction between sodium dodecyl sulfate and membrane reconstituted aquaporins: a comparative study of spinach SoPIP2;1 and E. coli AqpZ. AB - This study describes the interaction between sodium dodecyl sulfate (SDS) and membrane proteins reconstituted into large unilamellar lipid vesicles and detergent micelles studied by circular dichroism (CD) and polarity sensitive probe labeling. Specifically, we carried out a comparative study of two aquaporins with high structural homology SoPIP2;1 and AqpZ using identical reconstitution conditions. Our CD results indicate that SDS, when added to membrane-reconstituted aquaporins in concentrations below the SDS critical micelle concentration (CMC, ~8mM), causes helical rearrangements of both aquaporins. However, we do not find compelling evidence for unfolding. In contrast when SDS is added to detergent stabilized aquaporins, SoPIP2;1 partly unfolds, while AqpZ secondary structure is unaffected. Using a fluorescent polarity sensitive probe (Badan) we show that SDS action on membrane reconstituted SoPIP2;1 as well as AqpZ is associated with initial increased hydrophobic interactions in protein transmembrane (TM) spanning regions up to a concentration of 0.1* CMC. At higher SDS concentrations TM hydrophobic interactions, as reported by Badan, decrease and reach a plateau from SDS CMC up to 12.5* CMC. Combined, our results show that SDS does not unfold neither SoPIP2;1 nor AqpZ during transition from a membrane reconstituted form to a detergent stabilized state albeit the native folds are changed. PMID- 21683057 TI - Renal connexins and blood pressure. AB - The kidneys are centrally involved in the regulation of blood pressure. Kidney function requires the coordinated actions of a number of different vascular and tubular cell types in the renal vasculature and in the renal tubular system. The intrarenal coordination of these actions is not well understood. Since gap junctions have been identified in the kidneys, possible pathways involved in this context could be direct intercellular communication via gap junctions or via connexin hemichannels. In this context nine different connexins have been found to be expressed in the kidney, either localized to the vasculature or to the tubular system. Evidence is arising that malfunctions of certain connexins have an impact on the capability of the kidney to maintain blood pressure homeostasis. Findings reported in this context will be outlined and discussed in this review. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics. PMID- 21683058 TI - Angiotensin II modulates interleukin-1beta-induced inflammatory gene expression in vascular smooth muscle cells via interfering with ERK-NF-kappaB crosstalk. AB - Angiotensin II is implicated in cardiovascular diseases, which is associated with a role in increasing vascular inflammation. The present study investigated how angiotensin II modulates vascular inflammatory signaling and expression of inducible nitric oxide synthase (iNOS) and vascular cell adhesion molecule (VCAM) 1. In cultured rat aortic vascular smooth muscle cells (VSMCs), angiotensin II suppressed interleukin-1beta-induced prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and ribosomal S6 kinase (RSK)-1, and nuclear translocation of nuclear factor (NF)-kappaB, leading to decreased iNOS but enhanced VCAM-1 expression, associated with an up-regulation of mitogen-activated protein kinase phosphatase-1 expression. Knock-down of RSK1 selectively down regulated interleukin-1beta-induced iNOS expression without influencing VCAM-1 expression. In vivo experiments showed that interleukin-1beta, iNOS, and VCAM-1 expression were detectable in the aortic arches of both wild-type and apolipoprotein E-deficient (ApoE(-/-)) mice. VCAM-1 and iNOS expression were higher in ApoE(-/-) than in wild type mouse aortic arches. Angiotensin II infusion (3.2 mg/kg/day, for 6 days, via subcutaneous osmotic pump) in ApoE(-/-) mice enhanced endothelial and adventitial VCAM-1 and iNOS expression, but reduced medial smooth muscle iNOS expression associated with reduced phosphorylation of ERK and RSK-1. These results indicate that angiotensin II can differentially modulate inflammatory gene expression in aortic smooth muscle cells through influencing ERK-NF-kappaB crosstalk, which may contribute to angiotensin II induced inflammatory disorders related to cardiovascular diseases. PMID- 21683059 TI - Suppression of ovalbumin-induced allergic diarrhea by diminished intestinal peristalsis in RAMP1-deficient mice. AB - Recent studies have revealed that various neurotransmitters regulate the immune system via their receptors expressed on the immune cells. Calcitonin gene-related peptide (CGRP), a sensory nerve C-fiber neuropeptide, is also known to have the ability to modulate the functions of immune cells in vitro. However, the contribution of CGRP to the immune regulation in vivo remains to be fully elucidated. Here we report that mice deficient in receptor activity-modifying protein 1 (RAMP1), which is a subunit of the CGRP receptor, showed a significantly lower incidence of diarrhea compared with wild-type (WT) mice in the ovalbumin (OVA)-induced food allergic model. Serum OVA-specific IgE levels and the differentiation of T helper cells was comparable in WT mice and RAMP1 deficient mice. Moreover, there were no significant differences between recruitment and degranulation of mast cells in the small intestine of these mice. In contrast, significantly diminished intestinal peristalsis was observed by the allergy induction in RAMP1-deficient mice compared with WT mice. These results suggest that this suppression of allergic diarrhea is due to the diminished intestinal peristalsis in RAMP1-deficient mice. PMID- 21683060 TI - BRG1 is indispensable for IFN-gamma-induced TRIM22 expression, which is dependent on the recruitment of IRF-1. AB - The modification of chromatin structure is increasingly recognized to be an important facet of transcriptional regulation. Here, we report that Brahma related gene 1 (BRG1), a chromatin remodeling enzyme, plays a crucial role in IFN gamma-induced TRIM22 expression. Our results showed that IFN-gamma failed to induce TRIM22 expression in BRG1-deficient SW-13 cells, and reconstitution of BRG1 in this cell line could restore IFN-gamma induction of TRIM22. Furthermore, it was revealed that BRG1 absence, per se, did not impair IFN-gamma-induced IRF-1 expression, but blocked its access to TRIM22 promoter, and BRG1-dependent induction of TRIM22 perfectly correlated with BRG1-dependent recruitment of IRF-1 to TRIM22 promoter. We also found that the DNA-dependent ATPase domain of BRG1 was required for TRIM22 expression and IRF-1 recruitment in response to IFN-gamma stimulation, suggesting that BRG1-mediated chromatin remodeling is critical for the IFN-gamma-inducibility of TRIM22 gene. PMID- 21683061 TI - Delphinidin, a specific inhibitor of histone acetyltransferase, suppresses inflammatory signaling via prevention of NF-kappaB acetylation in fibroblast-like synoviocyte MH7A cells. AB - Histone acetyltransferase (HAT) inhibitors (HATi) isolated from dietary compounds have been shown to suppress inflammatory signaling, which contributes to rheumatoid arthritis. Here, we identified a novel HATi in Punica granatum L. known as delphinidin (DP). DP did not affect the activity of other epigenetic enzymes (histone deacetylase, histone methyltransferase, or sirtuin1). DP specifically inhibited the HAT activities of p300/CBP. It also inhibited p65 acetylation in MH7A cells, a human rheumatoid arthritis synovial cell line. DP induced hypoacetylation was accompanied by cytosolic accumulation of p65 and nuclear localization of IKBalpha. Accordingly, DP treatment inhibited TNFalpha stimulated increases in NF-kappaB function and expression of NF-kappaB target genes in these cells. Importantly, DP suppressed lipopolysaccharide-induced pro inflammatory cytokine expression in Jurkat T lymphocytes, demonstrating that HATi efficiently suppresses cytokine-mediated immune responses. Together, these results show that the HATi activity of DP counters anti-inflammatory signaling by blocking p65 acetylation and that this compound may be useful in preventing inflammatory arthritis. PMID- 21683062 TI - Stable knockdown of MYCN by lentivirus-based RNAi inhibits human neuroblastoma cells growth in vitro and in vivo. AB - Neuroblastoma is the most common childhood solid tumor, yet current treatment approaches have not been able to effectively control this cancer. Amplification and overexpression of MYCN have been shown to be closely related with high risk and poor prognosis in neuroblastoma. This suggests that MYCN is an important target for the antitumor therapy. Recently, vector-based RNA interference (RNAi) systems have been successfully used to eliminate gene expression, but knockdown of MYCN by vector-based RNAi as a therapeutic model for neuroblastoma has not been fully established. In this study, we used a lentivirus vector-based RNAi approach which expresses short hairpin RNA (shRNA) to knockdown MYCN in neuroblastoma cell lines IMR-32 and LAN-1. Western blotting analysis showed that expressions of MYCN were efficiently downregulated after infection with MYCN shRNA expression vector. The stable suppression of MYCN expression induced differentiation and apoptosis in neuroblastoma cell lines. Furthermore, we demonstrated that these changes were associated with caspase-3 activation, p27 upregulation as well as Bcl-2 and MDM2 downregulation. Finally, we demonstrated that downregulation of MYCN expression significantly reduced colony formation in vitro and tumor growth in nude mice. Our data indicate that lentivirus vector mediated silencing of MYCN in neuroblastoma cells could efficiently and significantly inhibit tumor growth both in vitro and in vivo. Therefore we demonstrate the therapeutic potential of lentivirus-delivered shRNA as a novel approach for treatment of neuroblastoma and other malignant tumors with MYCN overexpression. PMID- 21683063 TI - IP3 signaling is required for cilia formation and left-right body axis determination in Xenopus embryos. AB - Vertebrate left-right (LR) body axis is manifested as an asymmetrical alignment of the internal organs such as the heart and the gut. It has been proposed that the process of LR determination commonly involves a cilia-driven leftward flow in the mammalian node and its equivalents (Kupffer's vesicle in zebrafish and the gastrocoel roof plate in Xenopus). Recently, it was reported that Ca(2+) flux regulates Kupffer's vesicle development and is required for LR determination. As a basis of Ca(2+) flux in many cell types, inositol 1,4,5-trisphosphate (IP(3)) receptor-mediated calcium release from the endoplasmic reticulum (ER) plays important roles. However, its involvement in LR determination is poorly understood. We investigated the role of IP(3) signaling in LR determination in Xenopus embryos. Microinjection of an IP(3) receptor-function blocking antibody that can inhibit IP(3) calcium channel activity randomized the LR axis in terms of left-sided Pitx2 expression and organ laterality. In addition, an IP(3) sponge that could inhibit IP(3) signaling by binding IP(3) more strongly than the IP(3) receptor impaired LR determination. Examination of the gastrocoel roof plate revealed that the number of cilia was significantly reduced by IP(3) signal blocking. These results provide evidence that IP(3) signaling is involved in LR asymmetry formation in vertebrates. PMID- 21683064 TI - Sphingolipid long chain base phosphates can regulate apoptotic-like programmed cell death in plants. AB - Sphingolipids are ubiquitous components of eukaryotic cells and sphingolipid metabolites, such as the long chain base phosphate (LCB-P), sphingosine 1 phosphate (S1P) and ceramide (Cer) are important regulators of apoptosis in animal cells. This study evaluated the role of LCB-Ps in regulating apoptotic like programmed cell death (AL-PCD) in plant cells using commercially available S1P as a tool. Arabidopsis cell cultures were exposed to a diverse array of cell death-inducing treatments (including Cer) in the presence of S1P. Rates of AL-PCD and cell survival were recorded using vital stains and morphological markers of AL-PCD. Internal LCB-P levels were altered in suspension cultured cells using inhibitors of sphingosine kinase and changes in rates of death in response to heat stress were evaluated. S1P reduced AL-PCD and promoted cell survival in cells subjected to a range of stresses. Treatments with inhibitors of sphingosine kinase lowered the temperature which induced maximal AL-PCD in cell cultures. The data supports the existence of a sphingolipid rheostat involved in controlling cell fate in Arabidopsis cells and that sphingolipid regulation of cell death may be a shared feature of both animal apoptosis and plant AL-PCD. PMID- 21683065 TI - The role of SNM1 family nucleases in etoposide-induced apoptosis. AB - DNA double strand breaks (DSBs) induced by etoposide, an inhibitor of DNA topoisomerase II, are repaired mainly by non-homologous end joining (NHEJ). Unexpectedly, it was found that at high doses of etoposide, proteins involved in NHEJ, such as KU70/80, DNA-PKcs and ARTEMIS/SNM1C, trigger apoptosis rather than repair of DSBs. Because ARTEMIS is a member of the SNM1 protein family that includes SNM1A and APOLLO/SNM1B, this study examined whether SNM1A and/or APOLLO are also involved in etoposide-induced apoptosis. Using SNM1A(-/-) and APOLLO(-/ ) cells, it was found that both SNM1A and APOLLO participate in etoposide-induced apoptosis. Although cell viability monitored by MTT assay did not differ between SNM1A(-/-)/APOLLO(-/-)/ARTEMIS(-/-), SNM1A(-/-)/APOLLO(-/-), and single gene knockout cells, DNA fragmentation monitored by TUNEL assay differed between these cells, suggesting that the three SNM1 family nucleases function independently, at least during the induction of apoptotic DNA fragmentation. PMID- 21683066 TI - Novel protein tyrosine phosphatase 1B inhibitors: interaction requirements for improved intracellular efficacy in type 2 diabetes mellitus and obesity control. AB - Resistance to the hormones insulin and leptin are hallmarks in common for type 2 diabetes mellitus and obesity. Both conditions are associated with increased activity and expression of protein tyrosine phosphatase (PTP)1B. Therefore, inhibition of PTP1B activity or down-regulation of its expression should ameliorate insulin and leptin resistance, and may hold therapeutic utility in type 2 diabetes mellitus and obesity control. This background has motivated the fervent search for PTP1B inhibitors, carried out in the recent years. The purpose of this review is to provide the most recent advances in understanding the structural details of PTP1B molecule relevant to the interactions with inhibitors, and the progress towards compounds with enhanced membrane permeability, affinity, specificity, and potency on intracellular PTP1B; several inhibitors of benefit in type 2 diabetes mellitus and obesity control are presented and discussed. PMID- 21683067 TI - The anti-inflammatory effects of soluble epoxide hydrolase inhibitors are independent of leukocyte recruitment. AB - Excess leukocyte recruitment to the lung plays a central role in the development or exacerbation of several lung inflammatory diseases including chronic obstructive pulmonary disease. Epoxyeicosatrienoic acids (EETs) are cytochrome P 450 metabolites of arachidonic acid reported to have multiple biological functions, including blocking of leukocyte recruitment to inflamed endothelium in cell culture through reduction of adhesion molecule expression. Inhibition of the EET regulatory enzyme, soluble epoxide hydrolase (sEH) also has been reported to have anti-inflammatory effects in vivo including reduced leukocyte recruitment to the lung. We tested the hypothesis that the in vivo anti-inflammatory effects of sEH inhibitors act through the same mechanisms as the in vitro anti-inflammatory effects of EETs in a rat model of acute inflammation following exposure to tobacco smoke. Contrary to previously published data, we found that sEH inhibition did not reduce tobacco smoke-induced leukocyte recruitment to the lung. Furthermore, sEH inhibition did not reduce tobacco smoke-induced adhesion molecule expression in the lung vasculature. Similarly, concentrations of EETs greater than or equal to their reported effective dose did not reduce TNFalpha induced expression of the adhesion molecules. These results suggest that the anti inflammatory effects of sEH inhibitors are independent of leukocyte recruitment and EETs do not reduce the adhesion molecules responsible for leukocyte recruitment in vitro. This demonstrates that the widely held belief that sEH inhibition prevents leukocyte recruitment via EET prevention of adhesion molecule expression is not consistently reproducible. PMID- 21683068 TI - Single-nucleotide polymorphisms (SNPs) of the IRF6 and TFAP2A in non-syndromic cleft lip with or without cleft palate (NSCLP) in a northern Chinese population. AB - Non-syndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect that is presumably caused by genetic factors alone or gene alterations in combination with environmental changes. A number of studies have shown an association between NSCLP and single-nucleotide polymorphisms (SNPs) in the interferon regulatory factor 6 (IRF6) gene in several populations. The transcription factor AP-2a (TFAP2A), which is involved in regulating mid-face development and upper lip fusion, has also be considered a candidate gene contributing to the etiology of NSCLP. The potential importance of IRF6 and TFAP2A in the NSCLP is further highlighted by a study showing that the two molecules are in the same developmental pathway. To further assess the roles of the IRF6 and TFAP2A in NSCLP, we investigated two identified IRF6 SNPs (rs2235371, rs642961) and three TFAP2A tag SNPs (rs3798691, rs1675414, rs303050) selected from HapMap data in a northern Chinese population, a group with a high prevalence of NSCLP. These SNPs were examined for association with NSCLP in 175 patients and 160 healthy controls. We observed a significant correlation between IRF6 rs642961 and NSCLP, and a lack of association between IRF6 rs2235371 polymorphisms and NSCLP in this population. This investigation indicated that there is no association between the three SNPs in the TFAP2A and NSCLP, suggesting that TFAP2A may not be involved in the development of NSCLP in the northern Chinese population. Our study provides further evidence regarding the role of IRF6 variations in NSCLP development and finds no significant association between TFAP2A and NSCLP in this northern Chinese population. PMID- 21683069 TI - 15-Deoxy-Delta12,14-prostaglandin J2 enhanced the anti-tumor activity of camptothecin against renal cell carcinoma independently of topoisomerase-II and PPARgamma pathways. AB - Renal cell carcinoma (RCC) is chemoresistant cancer. Although several clinical trials were conducted to explore effective medications, the chemoresistance of RCC has not yet been conquered. An endogenous ligand for peroxisome proliferator activated receptor-gamma (PPARgamma), 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), induces apoptosis in RCC. Here, we examined synergistic effects of several carcinostatics on the anti-tumor activity of 15d-PGJ(2) in Caki-2 cell line by MTT assay. A topoisomerase-I inhibitor, camptothecin (CPT), exhibited synergistically toxicity with 15d-PGJ(2), but neither 5-fluorouracil nor cisplatin did. The combination of 15d-PGJ(2) and a topoisomerase-II inhibitor, doxorubicine, did not cause synergistic cell growth inhibition. The synergistic effect of topoisomerase-I and II inhibitors was not also detected. A PPARgamma antagonist, GW9662, did not prevent Caki-2 from undergoing 15d-PGJ(2)-induced cytotoxicity. The treatment of CPT combined with 15d-PGJ(2) activated caspase-3 more than the separate treatment. These results suggest that 15d-PGJ(2) exhibited the anti-tumor activity synergistically with CPT independent of topoisomerase-II and PPARgamma. PMID- 21683070 TI - Polymorphisms in CYP1B1 modify the risk of idiopathic male infertility with abnormal semen quality. AB - BACKGROUND: It is acknowledged that Cytochrome P450 1B1 (CYP1B1) plays a crucial role in metabolism and is involved in lots of diseases. We carried out this study to evaluate the association between CYP1B1 single nucleotide polymorphisms (SNPs) and male infertility in the Han-Chinese population with abnormal semen parameters. METHODS: We genotyped five CYP1B1 polymorphisms by using TaqMan allelic discrimination assay and Genome Lab SNP-stream. A total of 591 idiopathic infertile men and 419 fertile controls were comprised in the research. Semen quality analysis was performed using computer assisted sperm analysis. According to semen parameters, we divided cases into 3 subgroups in the stratified analysis. RESULTS: In our study, we only found genetic variant rs1056836 is correlated with idiopathic male infertility (P=0.012). Additionally, in strategy analysis, rs1056836 may decrease the risk of abnormal sperm motility (OR=0.11, 95% CI=0.01, 0.86). While other four variants showed no significant association with male infertility. CONCLUSIONS: Our results suggested that polymorphism of CYP1B1 modified the risk of male infertility, and men harboring this polymorphism had lower risk of abnormal sperm parameters. These findings should be validated by more epidemiological and functional studies. PMID- 21683071 TI - Alterations in cyclic GMP levels in preeclampsia may reflect increased B-type natriuretic peptide levels and not impaired nitric oxide activity. AB - OBJECTIVES: We compared nitrite, B-type natriuretic peptide (BNP), and cGMP levels in preeclamptic with those found in healthy pregnant. METHODS: We studied 21 healthy pregnant and 27 preeclamptic. Plasma cGMP and BNP levels were determined by ELISA. Nitrite levels were determined by chemiluminescence. RESULTS: Higher cGMP and BNP, and lower nitrite levels were found in preeclamptic versus healthy pregnant. CONCLUSIONS: Altered cGMP levels reflect increased BNP levels and not impaired nitric oxide activity in preeclampsia. PMID- 21683072 TI - Mouse thymic epithelial cell lines expressing "Aire" and peripheral tissue specific antigens reproduce in vitro negative selection of T cells. AB - In the human thymus, AIRE (autoimmune regulator) gene is expressed in a very limited type of medullary thymic epithelial cells (mTECs) and no cognate cell lines are available, hence the molecular analysis of AIRE gene function has been difficult. To improve this situation, we attempted to isolate Aire-expressing cells and established three cell lines (Aire+TEC1, Aire+TEC2, Aire+DC) from the abnormally enlarged thymus, which was developed in the transgenic mice expressing SV40 T-antigen driven by the mouse Aire gene promoter. When these Aire+ cell lines were co-cultured with fresh thymocytes, they adhered to the majority of thymocytes and induced apoptosis as if negative selection of T-cells in the thymus is occurring in vitro. Further analysis revealed that these Aire+ cell lines are derived from mTECs and exhibit characteristic natures of "antigen presenting cells" including several distinct abilities: to express a variety of peripheral tissue-specific antigens, to produce immunoproteasome and immunological synapse, and to express some of TNFSFs (tumor necrosis factor super families). Thus, the newly established Aire+ cell lines will be invaluable for the further detailed analysis of AIRE gene function in the central tolerance of immunity and autoimmune disease. PMID- 21683073 TI - High frequency stimulation of the subthalamic nucleus acutely rescues motor deficits and neocortical movement representations following 6-hydroxydopamine administration in rats. AB - Loss of frontal neocortical activation is one of the main neurophysiological abnormalities of Parkinson's disease (PD) and can be observed in rodent models of nigrostriatal degeneration. High-frequency deep brain stimulation (DBS) of the subthalamic nucleus improves motor deficits in PD. However, it is unknown whether this general therapeutic effect is associated with a restoration of frontal output function. To address this question, chronic stimulating electrodes were implanted bilaterally into the subthalamic nuclei of adult rats that received either bilateral intrastriatal 6-hydroxydopamine (6-OHDA) or vehicle infusion to induce nigrostriatal degeneration. Forelimb use and locomotor activity were assessed based on the cylinder and open field tests in intact, post-lesion+sham DBS, and post-lesion+DBS conditions. Intracortical microstimulation was then used to probe frontal output function of forelimb motor areas. DBS was found to improve motor deficits arising from 6-OHDA lesions, increase forelimb map area, and decrease movement thresholds relative to baseline. These effects were significantly greater in 6-OHDA lesion rats compared to vehicle controls. Results indicate that changes in motor map expression can take place during subthalamic DBS following dopamine depletion in a rodent model of PD. PMID- 21683074 TI - Substrate positioning in chitinase A, a processive chito-biohydrolase from Serratia marcescens. AB - The contributions of the -3 subsite and a putative +3 subsite to substrate positioning in ChiA from Serratia marcescens have been investigated by comparing how ChiA and its -3 subsite mutant W167A interact with soluble substrates. The data show that Trp - GlcNAc stacking in the -3 subsite rigidifies the protein backbone supporting the formation of the intermolecular interaction network that is necessary for the recognition and positioning of the N-acetyl groups before the -1 subsite. The +3 subsite exhibits considerable substrate affinity that may promote endo-activity in ChiA and/or assist in expelling dimeric products from the +1 and +2 subsites during processive hydrolysis. PMID- 21683075 TI - Oxaliplatin sensitizes human colon cancer cells to TRAIL through JNK-dependent phosphorylation of Bcl-xL. AB - BACKGROUND & AIMS: Oxaliplatin sensitizes drug-resistant colon cancer cell lines to tumor necrosis factor-related apoptosis inducing ligand (TRAIL), a death receptor ligand that is selective for cancer cells. We investigated the molecular mechanisms by which oxaliplatin sensitizes cancer cells to TRAIL-induced apoptosis. METHODS: We incubated the colon cancer cell lines HT29 and V9P, which are resistant to TRAIL, with TRAIL or with oxaliplatin for 2 hours, followed by TRAIL. Annexin V staining was used to measure apoptosis; RNA silencing and immunoblot experiments were used to study the roles of apoptosis-related proteins. Site-directed mutagenesis experiments were used to determine requirements for phosphorylation of Bcl-xL; co-immunoprecipitation experiments were used to analyze the interactions among Bcl-xL, Bax, and Bak, and activation of Bax. RESULTS: Oxaliplatin-induced sensitivity to TRAIL required activation of the mitochondrial apoptotic pathway; reduced expression of Bax, Bak, and caspase 9, and stable overexpression of Bcl-xL, reduced TRAIL-induced death of cells incubated with oxaliplatin. Mitochondrial priming was induced in cells that were sensitized by oxaliplatin and required signaling via c-Jun N-terminal kinase and phosphorylation of Bcl-xL. Mimicking constitutive phosphorylation of Bcl-xL by site-directed mutagenesis at serine 62 restored sensitivity of cells to TRAIL. Co immunoprecipitation experiments showed that oxaliplatin-induced phosphorylation of Bcl-xL disrupted its ability to sequestrate Bax, allowing Bax to interact with Bak to induce TRAIL-mediated apoptosis. CONCLUSIONS: Oxaliplatin facilitates TRAIL-induced apoptosis in colon cancer cells by activating c-Jun N-terminal kinase signaling and phosphorylation of Bcl-xL. Oxaliplatin-induced sensitivity to TRAIL might be developed as an approach to cancer therapy. PMID- 21683076 TI - Mycobacterium bovis Bacillus Calmette-Guerin killed by extended freeze-drying reduces colitis in mice. AB - BACKGROUND & AIMS: Mycobacterium bovis Bacillus Calmette-Guerin (BCG), killed by extended freeze-drying (EFD), induces secretion of interleukin-10 and reduces lung inflammation in a mouse model of asthma. We investigated the effects of EFD BCG in mouse models of inflammatory bowel disease. METHODS: EFD BCG was administered subcutaneously to mice with colitis induced by dextran sodium sulfate (DSS), oxazolone, or adoptive transfer of CD4(+)CD45RB(high)Foxp3(-) T cells from C57Bl/6 Foxp3GFP mice to RAG2(-/-) mice. RESULTS: EFD BCG, administered either before induction of DSS and oxazolone colitis or after development of acute or chronic DSS-induced colitis, reduced symptom scores, loss of body weight, and inflammation. Although transfer of CD4(+)CD45RB(high)Foxp3(-) cells induced colitis in RAG2(-/-) mice, administration of EFD BCG at the time of the transfer converted Foxp3(-) T cells to Foxp3(+) T cells and the mice did not develop colitis. EFD BCG protected mice from colitis via a mechanism that required expansion of T regulatory cells and production of interleukin-10 and transforming growth factor beta. EFD BCG activated the retinoid X receptor (RXR) alpha-peroxisome proliferator-activated receptor (PPAR)-gamma heterodimer, blocked translocation of nuclear factor kappaB to the nucleus, and reduced colonic inflammation; it did not increase the number of colon tumors that formed in mice with chronic DSS-induced colitis. CONCLUSIONS: EFD BCG controls severe colitis in mice by expanding T regulatory cell populations and PPAR-gamma and might be developed to treat patients with inflammatory bowel disease. PMID- 21683077 TI - The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. AB - BACKGROUND & AIMS: Alterations in the microbial composition of the gastrointestinal tract (dysbiosis) are believed to contribute to inflammatory and functional bowel disorders and psychiatric comorbidities. We examined whether the intestinal microbiota affects behavior and brain biochemistry in mice. METHODS: Specific pathogen-free (SPF) BALB/c mice, with or without subdiaphragmatic vagotomy or chemical sympathectomy, or germ-free BALB/c mice received a mixture of nonabsorbable antimicrobials (neomycin, bacitracin, and pimaricin) in their drinking water for 7 days. Germ-free BALB/c and NIH Swiss mice were colonized with microbiota from SPF NIH Swiss or BALB/c mice. Behavior was evaluated using step-down and light preference tests. Gastrointestinal microbiota were assessed using denaturing gradient gel electrophoresis and sequencing. Gut samples were analyzed by histologic, myeloperoxidase, and cytokine analyses; levels of serotonin, noradrenaline, dopamine, and brain-derived neurotropic factor (BDNF) were assessed by enzyme-linked immunosorbent assay. RESULTS: Administration of oral antimicrobials to SPF mice transiently altered the composition of the microbiota and increased exploratory behavior and hippocampal expression of BDNF. These changes were independent of inflammatory activity, changes in levels of gastrointestinal neurotransmitters, and vagal or sympathetic integrity. Intraperitoneal administration of antimicrobials to SPF mice or oral administration to germ-free mice did not affect behavior. Colonization of germ free BALB/c mice with microbiota from NIH Swiss mice increased exploratory behavior and hippocampal levels of BDNF, whereas colonization of germ-free NIH Swiss mice with BALB/c microbiota reduced exploratory behavior. CONCLUSIONS: The intestinal microbiota influences brain chemistry and behavior independently of the autonomic nervous system, gastrointestinal-specific neurotransmitters, or inflammation. Intestinal dysbiosis might contribute to psychiatric disorders in patients with bowel disorders. PMID- 21683078 TI - Pregabalin reduces pain in patients with chronic pancreatitis in a randomized, controlled trial. AB - BACKGROUND & AIMS: Pain is a disabling symptom for patients with chronic pancreatitis (CP) and difficult to treat. Evidence from basic science and human studies indicates that pain processing by the central nervous system is abnormal and resembles that observed in patients with neuropathic pain disorders. We investigated whether agents used to treat patients with neuropathic pain are effective in CP. METHODS: We conducted a randomized, double-blind, placebo controlled trial to evaluate the effects of the gabapentoid pregabalin as an adjuvant analgesic. We measured pain relief, health status, quality of life, and tolerability in 64 patients with pain from CP; they were randomly assigned to groups given increasing doses of pregabalin or placebo (control) for 3 consecutive weeks. The primary end point was pain relief, based on a visual analogue scale documented by a pain diary. Secondary end points included Patients' Global Impression of Change (PGIC) score, changes in physical and functional scales, pain character, quality of life, and tolerability. RESULTS: Pregabalin, compared with placebo, caused more effective pain relief after 3 weeks of treatment (36% vs 24%; mean difference, 12%; 95% confidence interval, 22%-2%; P = .02). The percentage of patients with much or very much improved health status (PGIC score) at the end of the study was higher in the pregabalin than the control group (44% vs 21%; P = .048). Changes in physical and functional scales, pain character, quality of life, and number of serious adverse events were comparable between groups. CONCLUSIONS: In a placebo-controlled trial, pregabalin is an effective adjuvant therapy for pain in patients with CP. PMID- 21683079 TI - Tolerance to ingested deamidated gliadin in mice is maintained by splenic, type 1 regulatory T cells. AB - BACKGROUND & AIMS: Patients with celiac disease have permanent intolerance to gluten. Because of the high frequency of this disorder (approximately 1 in 100 individuals), we investigated whether oral tolerance to gluten differs from that to other food proteins. METHODS: Using transgenic mice that express human HLA-DQ2 and a gliadin-specific, humanized T-cell receptor, we compared gluten-specific T cell responses with tolerogenic mucosal T-cell responses to the model food protein ovalbumin. RESULTS: Consistent with previous findings, the ovalbumin specific response occurred in the mesenteric lymph nodes and induced Foxp3(+) regulatory T cells. In contrast, ingestion of deamidated gliadin induced T-cell proliferation predominantly in the spleen but little in mesenteric lymph nodes. The gliadin-reactive T cells had an effector-like phenotype and secreted large amounts of interferon gamma but also secreted interleukin-10. Despite their effector-like phenotype, gliadin-reactive T cells had regulatory functions, because transfer of the cells suppressed a gliadin-induced, delayed-type hypersensitivity response. CONCLUSIONS: Ingestion of deamidated gliadin induces differentiation of tolerogenic, type 1 regulatory T cells in spleens of HLA-DQ2 transgenic mice. These data indicate that under homeostatic conditions, the T cell response to deamidated gliadin is tolerance, which is not conditioned by the mucosal immune system but instead requires interleukin-10 induction by antigen presentation in the spleen. PMID- 21683080 TI - Glucocorticoid receptor blockade inhibits brain cell addition and aggressive signaling in electric fish, Apteronotus leptorhynchus. AB - When animals are under stress, glucocorticoids commonly inhibit adult neurogenesis by acting through glucocorticoid receptors (GRs). However, in some cases, conditions that elevate glucocorticoids promote adult neurogenesis, and the role of glucocorticoid receptors in these circumstances is not well understood. We examined the involvement of GRs in social enhancement of brain cell addition and aggressive signaling in electric fish, Apteronotus leptorhynchus. In this species, long-term social interaction simultaneously elevates plasma cortisol, enhances brain cell addition and increases production of aggressive electrocommunication signals ("chirps"). We implanted isolated and paired fish with capsules containing nothing (controls) or the GR antagonist, RU486, recorded chirp production and locomotion for 7d, and measured the density of newborn cells in the periventricular zone. Compared to isolated controls, paired controls showed elevated chirping in two phases: much higher chirp rates in the first 5h and moderately higher nocturnal rates thereafter. Treating paired fish with RU486 reduced chirp rates in both phases to those of isolated fish, demonstrating that GR activation is crucial for socially induced chirping. Neither RU486 nor social interaction affected locomotion. RU486 treatment to paired fish had a partial effect on cell addition: paired RU486 fish had less cell addition than paired control fish but more than isolated fish. This suggests that cortisol activation of GRs contributes to social enhancement of cell addition but works in parallel with another GR-independent mechanism. RU486 also reduced cell addition in isolated fish, indicating that GRs participate in the regulation of cell addition even when cortisol levels are low. PMID- 21683081 TI - Genetic diversity of the feminising microsporidian parasite Dictyocoela: new insights into host-specificity, sex and phylogeography. AB - Microsporidia of the genus Dictyocoela are parasites of gammarid amphipod Crustacea. They typically exhibit low virulence and efficient vertical transmission and at least some strains are capable of feminising their hosts. Sequencing of a region of the 16S rDNA of Dictyocoela spp. from various gammarid host species and localities in Europe and northern Asia indicates that Dictyocoela is genetically diverse and that different strains predominate in different host species. However, the presence of intermediate sequences casts doubt upon previous attempts to describe Dictyocoela spp. on the basis of rDNA divergence alone. Phylogenetic analysis provides little support for coevolution between gammarids and Dictyocoela. Furthermore, observations of heavily infected individuals, together with genetic evidence of recombination, suggest that some strains of Dictyocoela may be horizontally transmitted and are sexually reproducing. These findings suggest that Dictyocoela may be phenotypically, as well as genotypically, diverse, with the potential to exhibit a range of different interactions with its host populations. PMID- 21683082 TI - Hippoboscid-transmitted Haemoproteus parasites (Haemosporida) infect Galapagos Pelecaniform birds: evidence from molecular and morphological studies, with a description of Haemoproteus iwa. AB - Haemosporidian parasites are widely distributed and common parasites of birds, and the application of molecular techniques has revealed remarkable diversity among their lineages. Four haemosporidian genera infect avian hosts (Plasmodium, Haemoproteus, Leucocytozoon and Fallisia), and Haemoproteus is split into two sub genera based on morphological evidence and phylogenetic support for two divergent sister clades. One clade (Haemoproteus (Parahaemoproteus)) contains parasites developing in birds belonging to several different orders, except pigeons and doves (Columbiformes), while the other (Haemoproteus (Haemoproteus)) has previously been shown to only infect dove hosts. Here we provide molecular and morphological identification of Haemoproteus parasites from several seabird species that are closely related to those found in dove hosts. We also document a deeply divergent clade with two haemosporidian lineages recovered primarily from frigatebirds (Fregatidae, Pelecaniformes) that is sister to the hippoboscid (Hippoboscidae) transmitted dove parasites. One of the lineages in this new clade of parasites belongs to Haemoproteus iwa and is distributed in two species of frigatebird (Fregata) hosts from Hawaii, the Galapagos Islands, the eastern Pacific and throughout the Caribbean Basin. Haemosporidian parasites are often considered rare in seabirds due in part to the lack or low activity of some dipteran vectors (e.g., mosquitos, biting midges) in marine and coastal environments; however, we show that H. iwa is prevalent and is very likely vectored among frigatebirds by hippoboscid flies which are abundant on frigatebirds and other seabirds. This study supports the existence of two sister clades of avian Haemoproteus in accord with the subgeneric classification of avian hemoproteids. Description of H. iwa from Galapagos Fregata minor is given based on morphology of blood stages and segments of the mitochondrial cytochrome b gene, which can be used for identification. This study shows that hippoboscid flies warrant more attention as vectors of avian Haemoproteus spp., particularly in marine and coastal environments. PMID- 21683083 TI - HOXC6 Is transcriptionally regulated via coordination of MLL histone methylase and estrogen receptor in an estrogen environment. AB - Homeobox (HOX)-containing gene HOXC6 is a critical player in mammary gland development and milk production, and is overexpressed in breast and prostate cancers. We demonstrated that HOXC6 is transcriptionally regulated by estrogen (E2). HOXC6 promoter contains two putative estrogen response elements (EREs), termed as ERE1(1/2) and ERE2(1/2). Promoter analysis using luciferase-based reporter assay demonstrated that both EREs are responsive to E2, with ERE1(1/2) being more responsive than ERE2(1/2). Estrogen receptors (ERs) ERalpha and ERbeta bind to these EREs in an E2-dependent manner, and antisense-mediated knockdown of ERs suppressed the E2-dependent activation of HOXC6 expression. Similarly, knockdown of histone methylases MLL2 and MLL3 decreased the E2-mediated activation of HOXC6. However, depletion of MLL1 or MLL4 showed no significant effect. MLL2 and MLL3 were bound to the HOXC6 EREs in an E2-dependent manner. In contrast, MLL1 and MLL4 that were bound to the HOXC6 promoter in the absence of E2 decreased upon exposure to E2. MLL2 and MLL3 play key roles in histone H3 lysine-4 trimethylation and in the recruitment of general transcription factors and RNA polymerase II in the HOXC6 promoter during E2-dependent transactivation. Nuclear receptor corepressors N-CoR and SAFB1 were bound in the HOXC6 promoter in the absence of E2, and that binding was decreased upon E2 treatment, indicating their critical roles in suppressing HOXC6 gene expression under nonactivated conditions. Knockdown of either ERalpha or ERbeta abolished E2-dependent recruitment of MLL2 and MLL3 into the HOXC6 promoter, demonstrating key roles of ERs in the recruitment of these mixed lineage leukemias into the HOXC6 promoter. Overall, our studies demonstrated that HOXC6 is an E2-responsive gene, and that histone methylases MLL2 and MLL3, in coordination with ERalpha and ERbeta, transcriptionally regulate HOXC6 in an E2-dependent manner. PMID- 21683085 TI - Resurgent Na+ current: a new avenue to neuronal excitability control. AB - Integrative and firing properties are important characteristics of neuronal circuits and these responses are determined in large part by the repertoire of ion channels they express, which can vary considerably between cell types. Recently, a new mode of operation of voltage dependent sodium channels has been described that generates a so-called resurgent Na+ current. Accumulating evidence suggests resurgent Na current participates in the generation of sub-threshold inward Na+ current causing membrane depolarization which provides the necessary drive to fire high-frequency action potentials. Recent studies indicate that resurgent Na+ current could be a more widespread feature than previously thought. PMID- 21683084 TI - Cooperative RNP assembly: complementary rescue of structural defects by protein and RNA subunits of archaeal RNase P. AB - Ribonuclease P (RNase P) is a ribonucleoprotein complex that utilizes a Mg(2+) dependent RNA catalyst to cleave the 5' leader of precursor tRNAs (pre-tRNAs) and generate mature tRNAs. The bacterial RNase P protein (RPP) aids RNase P RNA (RPR) catalysis by promoting substrate binding, Mg(2+) coordination and product release. Archaeal RNase P comprises an RPR and at least four RPPs, which have eukaryal homologs and function as two binary complexes (POP5.RPP30 and RPP21.RPP29). Here, we employed a previously characterized substrate-enzyme conjugate [pre-tRNA(Tyr)-Methanocaldococcus jannaschii (Mja) RPR] to investigate the functional role of a universally conserved uridine in a bulge-helix structure in archaeal RPRs. Deletion of this bulged uridine resulted in an 80-fold decrease in the self-cleavage rate of pre-tRNA(Tyr)-MjaDeltaU RPR compared to the wild type, and this defect was partially ameliorated upon addition of either RPP pair. The catalytic defect in the archaeal mutant RPR mirrors that reported in a bacterial RPR and highlights a parallel in their active sites. Furthermore, an N terminal deletion mutant of Pyrococcus furiosus (Pfu) RPP29 that is defective in assembling with its binary partner RPP21, as assessed by isothermal titration calorimetry and NMR spectroscopy, is functional when reconstituted with the cognate Pfu RPR. Collectively, these results indicate that archaeal RPPs are able to compensate for structural defects in their cognate RPR and vice-versa, and provide striking examples of the cooperative subunit interactions critical for driving archaeal RNase P toward its functional conformation. PMID- 21683086 TI - Short- and long-term treatment with estradiol or progesterone modifies the expression of GFAP, MAP2 and Tau in prefrontal cortex and hippocampus. AB - AIMS: We analyzed the effects of the short- and long-term administration of estradiol (E2) or progesterone (P4) after ovariectomy on the expression of MAP2, Tau and GFAP in prefrontal cortex and hippocampus. MAIN METHODS: Sprague Dawley rats were ovariectomized and immediately treated with E2 or P4 for 2 or 18 weeks. At the end of treatments, hippocampus and prefrontal cortex were excised, proteins were extracted and MAP2, Tau and GFAP were analyzed by Western blot. KEY FINDINGS: MAP2 and Tau content was not modified by E2 in the prefrontal cortex. On the contrary, P4 decreased MAP2 content after a short-term treatment, while it increased that of MAP2 and TAU in this brain region after a long-term treatment. E2 increased MAP2 content in hippocampus. In this region, short-term administration of P4 increased that of MAP2. GFAP content was diminished after a long-term administration of P4 in hippocampus. SIGNIFICANCE: Current data emphasize the importance of short- and long-term sex steroid treatment on neuronal and glial cytoskeletal proteins expression. PMID- 21683087 TI - Dopaminergic modulation of oscillatory network inhibition in the rat basolateral amygdala depends on initial activity state. AB - The amygdala receives dopaminergic innervation, and dopamine (DA) enhances various activities in cognitive and emotional behaviors. Periodic bursts of spontaneous inhibitory postsynaptic currents (IPSCs) with a low (<1 Hz) inter event frequency have been observed in projection neurons of the basolateral nucleus of the amygdala (BL). Blockade of ionotropic glutamate receptors or GABA(A) receptors abolishes these oscillatory IPSC bursts in the BL, suggesting that the activity has a network origin. Here, we investigated dopaminergic modulation of the oscillatory network inhibition in rat brain slices. We evaluated the effects of DA receptor agonists and antagonists on the network inhibition; the resultant changes were quantified by integrated power spectral density (0.1-3.0 Hz). DA enhanced the power when its initial activity was low, but reduced it when the activity was initially robust. These changes in the power were accompanied by changes in burst IPSC amplitude. D1-like receptor agonist SKF 38393, or DA together with the D2-like receptor antagonist sulpiride, reproduced DA's facilitatory actions. D2-like receptor agonist quinpirole did not change the periodic IPSC burst activity of the high baseline power, though D(4) receptor agonist PD 168077, or DA together with the D1-like receptor antagonist SCH 23390, reduced its activity. These results suggest that: 1) dopaminergic modulation of the oscillatory network inhibition depends on its initial activity; and 2) facilitatory and suppressing effects of DA in the BL are mediated by D1-like receptors and D(4) receptors, respectively. PMID- 21683088 TI - The environmental chemical tributyltin chloride (TBT) shows both estrogenic and adipogenic activities in mice which might depend on the exposure dose. AB - Exposure during early development to chemicals with hormonal action may be associated with weight gain during adulthood because of altered body homeostasis. It is known that organotins affect adipose mass when exposure occurs during fetal development, although no knowledge of effects are available for exposures after birth. Here we show that the environmental organotin tributyltin chloride (TBT) exerts adipogenic action when peripubertal and sexually mature mice are exposed to the chemical. The duration and extent of these effects depend on the sex and on the dose of the compound, and the effects are relevant at doses close to the estimated human intake (0.5MUg/kg). At higher doses (50-500MUg/kg), TBT also activated estrogen receptors (ERs) in adipose cells in vitro and in vivo, based on results from acute and longitudinal studies in ERE/luciferase reporter mice. In 3T3-L1 cells (which have no ERs), transiently transfected with the ERE dependent reporter plus or minus ERalpha or ERbeta, TBT (in a dose range of 1 100nM) directly targets each ER subtype in a receptor-specific manner through a direct mechanism mediated by ERalpha in undifferentiated preadipocytic cells and by ERbeta in differentiating adipocytes. The ER antagonist ICI-182,780 inhibits this effect. In summary, the results of this work suggest that TBT is adipogenic at all ages and in both sexes and that it might be an ER activator in fat cells. These findings might help to resolve the apparent paradox of an adipogenic chemical being also an estrogen receptor activator by showing that the two apparently opposite actions are separated by the different doses to which the organism is exposed. PMID- 21683089 TI - Synergistic antiemetic interactions between serotonergic 5-HT3 and tachykininergic NK1-receptor antagonists in the least shrew (Cryptotis parva). AB - Significant electrophysiological and biochemical findings suggest that receptor cross-talk occurs between serotonergic 5-HT(3)- and tachykininergic NK(1) receptors in which co-activation of either receptor by ineffective doses of their corresponding agonists (serotonin (5-HT) or substance P (SP), respectively) potentiates the activity of the other receptor to produce a response. In contrast, selective blockade of any one of these receptors attenuates the increase in abdominal vagal afferent activity caused by either 5-HT or SP. This interaction has important implications in chemotherapy-induced nausea and vomiting (CINV) since 5-HT(3)- and NK(1)-receptor antagonists are the major classes of antiemetics used in cancer patients receiving chemotherapy. The purpose of this study was to demonstrate whether the discussed interaction produces effects at the behavioral level in a vomit-competent species, the least shrew. Our results demonstrate that pretreatment with either a 5-HT(3) (tropisetron)- or an NK(1) (CP99,994)-receptor specific antagonist, attenuates vomiting caused by a selective agonist (2-methyl 5-HT or GR73632, respectively) of both emetic receptors. In addition, relative to each antagonist alone, their combined doses were 4-20 times more potent against vomiting caused by each emetogen. Moreover, combined sub-maximal doses of the agonists 2-methyl 5-HT and GR73632, produced 8-12 times greater number of vomits relative to each emetogen tested alone. However, due to large variability in vomiting caused by the combination doses, the differences failed to attain significance. The antiemetic dose-response curves of tropisetron against both emetogens were U-shaped probably because larger doses of this antagonist behave as a partial agonist. The data demonstrate that 5-HT(3)- and NK(1)-receptors cross-talk to produce vomiting, and that synergistic antiemetic effects occur when both corresponding antagonists are concurrently used against emesis caused by each specific emetogen. PMID- 21683090 TI - Regulation of the equilibrium between G-quadruplex and duplex DNA in promoter of human c-myc oncogene by a pyrene derivative. AB - It has been established that the equilibrium between duplex and G-quadruplex of the nuclease hypersensitivity element III1 (NHE III1) in human c-myc promoter is linked with this gene's transcription. Using NMR and ESI-MS, we have found a pyrene derivative, DMAPP, is able to modulate this equilibrium and, thus, might have the potential to regulate this oncogene's transcription. DMAPP has shown as a G-quadruplex binding agent and could induce c-myc G-quadruplex formation out of duplex. These results provide new clue for rational drug design to target transcription control of c-myc. PMID- 21683091 TI - Differential expression and intrachromosomal evolution of the sghC1q genes in zebrafish (Danio rerio). AB - The secreted globular head C1q (sghC1q) genes can be characterized as a family of genetic loci encoding signal peptides followed by single complement component 1q globular (gC1q) motifs. Members of this family have been referred to as precerebellin-like (Cblnl), C1q-like or ovary specific C1q-like factors, and are transcribed in response to infection and/or during early development. This study was primarily undertaken to identify the zebrafish sghC1q (or DrsghC1q) genes that increase their transcription in response to infection and to examine their transcriptional patterns during early development. Twenty sghC1q genes were found in the zebrafish (Danio rerio) genome (Zv9). Two of the examined twenty genes showed significant up-regulation within 24h of infection with the fish pathogen Streptococcus iniae, and eleven of the examined twenty were expressed during early development. Due to the clustered nature of these genes on chromosomes two and seven, intrachromosomal duplication events are hypothesized and explored. PMID- 21683093 TI - How common is the non-nucleoside reverse transcriptase inhibitor mutation E138K in clinical practice? PMID- 21683092 TI - Neuroprotective effects of MAPK/ERK1/2 and calpain inhibitors on lactacystin induced cell damage in primary cortical neurons. AB - The dysfunction of the proteasome system is implicated in the pathomechanism of several chronic neurodegenerative diseases. Lactacystin (LC), an irreversible proteasome inhibitor, induces cell death in primary cortical neurons, however, the molecular mechanisms of its neurotoxic action has been only partially unraveled. In this study we aimed to elucidate an involvement of the key enzymatic pathways responsible for LC-induced neuronal cell death. Incubation of primary cortical neurons with LC (0.25-50 MUg/ml) evoked neuronal cell death in concentration- and time-dependent manner. Lactacystin (2.5 MUg/ml; 6.6MUM) enhanced caspase-3 activity, but caspase-3 inhibitor, Ac-DEVD-CHO did not attenuate the LC-evoked cell damage. Western blot analysis showed a time dependent, prolonged activation of MAPK/ERK1/2 pathway after LC exposure. Moreover, inhibitors of MAPK/ERK1/2 signaling, U0126 and PD98052 attenuated the LC-evoked cell death. We also found that LC-treatment resulted in the induction of calpains and calpain inhibitors (MDL28170 and calpeptin) protected neurons against the LC-induced cell damage. Neuroprotective action of MAPK/ERK1/2 and calpain inhibitors were connected with attenuation of LC-induced DNA fragmentation measured by Hoechst 33342 staining and TUNEL assay. However, only MAPK/ERK1/2 but not calpain inhibitors, attenuated the LC-induced AIF (apoptosis inducing factor) release. Further studies showed no synergy between neuroprotective effects of MAPK/ERK1/2 and calpain inhibitors given in combination when compared to their effects alone. The obtained data provided evidence for neuroprotective potency of MAPK/ERK1/2 and calpain, but not caspase 3 inhibition against the neurotoxic effects of LC in primary cortical neurons and give rationale for using these inhibitors in the treatment of neurodegenerative diseases connected with proteasome dysfunction. PMID- 21683094 TI - Common occurrence of anaemia at the end of pregnancy following exposure to zidovudine-free regimens. AB - OBJECTIVE: Although zidovudine-free regimens are increasingly used in pregnancy, their haematological effects in mothers and newborns are incompletely defined. METHODS: The haematological profiles of 119 HIV-infected women and their neonates with highly active antiretroviral regimens (HAART) in pregnancy including or not zidovudine (ZDV) were investigated. Three groups were compared: 1) women who started ZDV-lamivudine (3TC)-based HAART during pregnancy (ZDVs, n = 60); 2) women on ZDV-3TC-based HAART from conception (ZDVc, n = 18); 3) women on ZDV-free HAART from conception (ZDVf, n = 41). RESULTS: At the beginning of pregnancy, haemoglobin levels were similar in the three groups. By week 36 compared to baseline, haemoglobin levels had a significantly greater decrease in ZDVf women compared to ZDVs women (ZDVf: -2.03 g/dl; ZDVs: -1.36 g/dl, p = 0.036). A similar trend was observed for occurrence of maternal anaemia at 36 weeks. Newborns with no prenatal ZDV exposure had significantly higher haemoglobin levels at birth (ZDVf: 16.1 +/- 1.4 g/dl, ZDVs: 14.3 +/- 2.0 g/dl; ZDVc: 14.6 +/- 2.4 g/dl, p = 0.044 and 0.003, respectively). CONCLUSIONS: Half of ZDV-unexposed mothers had anaemia at the end of pregnancy, but their neonates had normal haemoglobin levels. ZDV initiation was associated with a lower occurrence of maternal anaemia during the third trimester and decreased haemoglobin levels in the newborns. We hypothesize that foetal iron requirements could represent a major determinant of maternal anaemia at the end of pregnancy. PMID- 21683095 TI - Continuous monitoring of hypothalamic neurotransmitters and thermoregulatory responses in exercising rats. AB - The purpose of the present study was to investigate the relationship between thermoregulation and catecholamine release in the preoptic area and anterior hypothalamus (PO/AH) during incremental treadmill running in the rat. To this aim, we combined in vivo brain microdialysis, biotelemetry and metabolic measurements for continuous monitoring of core body temperature (T(core)), neurotransmitters and thermoregulatory responses. The animals were exercised for 1h at 23 degrees C. Treadmill speed was increased every 20 min (10, 20 and 26 m min-1). T(core), oxygen consumption (VO2, an index of heat production) and tail skin temperature (T(tail), an index of heat loss) were simultaneously measured. Brain microdialysis samples were collected every 10 min, and these samples were analyzed for noradrenaline (NA), dopamine (DA) and serotonin (5-HT). T(core) and VO(2)2 significantly increased during treadmill and were exercise intensity dependent. After an initial drop T(tail) increased significantly during exercise. Both NA and DA levels in the PO/AH increased significantly during exercise. There was no effect on serotonin release. T(core), VO2 and T(tail) were positively correlated with the levels of NA and DA. Our data suggest that thermoregulatory responses are dependent on the intensity of the exercise and that these responses are associated with changes in NA and DA release, but not in 5-HT release in the PO/AH. PMID- 21683096 TI - Early identification of availability issues for poorly water-soluble microbicide candidates in biorelevant media: a case study with saquinavir. AB - In the search for a successful HIV microbicide, many poorly water-soluble antiviral agents are currently being investigated. Unfortunately, solubility and precipitation issues may limit intravaginal concentrations and thus availability of these agents upon application of an aqueous gel formulation. In the present study, we evaluated the in vitro precipitation behavior of the HIV protease inhibitor saquinavir in vaginal and seminal fluid simulants (VFS and SFS). Despite its limited solubility, the mesylate salt of saquinavir enables formulation of sufficiently high concentrations (2.5 mM, i.e. ca. 10(5)-fold in vitro IC(50) values) in a standard aqueous vehicle. While saquinavir stays in solution upon dilution with VFS, SFS induces precipitation of saquinavir, resulting in a 5-fold reduced availability and antiviral potency. Inclusion of the solubilizing excipients polyethylene glycol 1000 (12%) and hydroxypropyl-beta cyclodextrin (2.5%) was required to avoid saquinavir precipitation in SFS and to restore the antiviral potency of the formulation. This study illustrates the importance of identifying solubility and precipitation issues of microbicide candidates in biorelevant media and provides a simple in vitro procedure to implement this evaluation in early microbicide development. PMID- 21683097 TI - Thiated derivatives of 2',3'-dideoxy-3'-fluorothymidine: synthesis, in vitro anti HIV-1 activity and interaction with recombinant drug resistant HIV-1 reverse transcriptase forms. AB - Various thiated analogues of thymine 2',3'-dideoxy-3'-fluoronucleoside (FLT) and their 5'-monophosphates and 5'-triphosphates were prepared with the use of modified multistep procedures. The thiated analogues of FLT and FLTMP were evaluated against the wild type and drug- and multidrug-resistant strains of HIV 1, using the replicative phenotyping format of the deCIPhR assay, and showed potent inhibition of drug-resistant HIV-1 strains at low cytotoxicity. Additionally, inhibition of recombinant drug resistant forms of reverse transcriptase from single and multiple HIV-1 mutants by the synthesized 5' triphosphates was investigated. The strongest inhibition was observed for K103N and Delta67 mutants and the most potent anti-HIV-1 activity against drug resistant strains and the lowest cytotoxicity was exerted by S4FLTMP and FLTMP which may be regarded as potential anti-HIV/AIDS agents. PMID- 21683098 TI - Detection of Legionella species in potting mixes using fluorescent in situ hybridisation (FISH). AB - This study used Fluorescent in situ Hybridisation (FISH) with rRNA targeted oligonucleotide probes combined with scanning confocal laser microscopy to successfully detect Legionella spp. in commercially available potting mix. A range of techniques were explored to optimise the FISH method by reducing background fluorescence and preventing non-specific binding of probes. These techniques included the use of a blocking agent, UV light treatment, image subtraction of a nonsense probe and spectral unmixing of specific probes fluorescence and autofluorescence dependent on the specific emission spectra of probe fluorophores. Spectral unmixing was the best microscopy technique for reducing background fluorescence and non-specific binding of probes was not observed. The rapid turnaround time and increased sensitivity of the FISH provides as an alternative to traditional culture methods, which are tedious and often give varied results. FISH is also advantageous compared to PCR methods as it provides information on the structure of the microbial community the bacteria is situated in. This study demonstrates that FISH could provide an alternative method for Legionella detection and enumeration in environmental samples. PMID- 21683100 TI - Marine actinomycetes as an emerging resource for the drug development pipelines. AB - Many representatives of the order Actinomycetales are prolific producers of thousands of biologically active secondary metabolites. Actinomycetes from terrestrial sources have been studied and screened since the 1950s, yielding many important anti-infective and anti-cancer drugs. However, frequent re-discovery of the same compounds in terrestrial actinomycetes have made them less attractive for screening programs in the recent years. At the same time, actinomycetes isolated from the marine environment currently receive considerable attention due to the structural diversity and unique biological activities of their secondary metabolites. This review highlights achievements and challenges in the isolation of marine actinomycetes, some examples of bioactive metabolites identified by conventional screening, and presents new developments in the field of genome mining and heterologous expression of biosynthetic gene clusters leading to the discovery of novel compounds. PMID- 21683099 TI - Production of glutathione using a bifunctional enzyme encoded by gshF from Streptococcus thermophilus expressed in Escherichia coli. AB - Glutathione (GSH) is one of the most ubiquitous non-protein thiols that is involved in numerous cellular activities. The gene coding for a novel bifunctional enzyme catalyzing the reaction for glutathione synthesis, gshF, was cloned from Streptococcus thermophilus SIIM B218 and expressed in Escherichia coli JM109. In the presence of the precursor amino acids and ATP, the induced cells of E. coli JM109 (pTrc99A-gshF) could accumulate 10.3 mM GSH in 5 h. The S. thermophilus GshF was insensitive to feedback inhibition caused by GSH even at 20 mM. At elevated concentrations of the precursor amino acids and ATP, E. coli JM109 (pTrc99A-gshF) produced 36 mM GSH with a molar yield of 0.9 mol/mol based on added cysteine and of 0.45 mol/mol based on added ATP. When ATP was replaced with glucose, E. coli JM109 (pTrc99A-gshF) produced 7 mM in 3h. Saccharomyces cerevisiae was used to generate ATP for GSH production. In the presence of glucose and the pmr1 mutant of S. cerevisiae BY4742, JM109 (pTrc99A-gshF) produced 33.9 mM GSH in 12h with a yield of 0.85 mol/mol based on added l cysteine. It is shown that the S. thermophilus GshF can be successfully used for GSH production. PMID- 21683101 TI - Cationic polyacrylamides promote binding of cellulase and amylase. AB - Cationic polyacrylamides (c-PAMs) increase the binding of cellulase to cellulose and of alpha-amylase to cornstarch. The c-PAMs increase the rate of hydrolysis of both substrates by about the same amount, which suggests that the increased binding is responsible for the enhanced rates. These results support our proposed mechanism where the c-PAM neutralizes the charge of the substrate through a "patching" mechanism, which reduces the charge repulsion between fiber and enzyme. PMID- 21683102 TI - Topology and cellular localization of the small hydrophobic protein of avian metapneumovirus. AB - The small hydrophobic protein (SH) is a type II integral membrane protein that is packaged into virions and is only present in certain paramyxoviruses including metapneumovirus. In addition to a highly divergent primary sequence, SH proteins vary significantly in size amongst the different viruses. Human respiratory syncytial virus (HRSV) encodes the smallest SH protein consisting of only 64 amino acids, while metapneumoviruses have the longest SH protein ranging from 174 to 179 amino acids in length. Little is currently known about the cellular localization and topology of the metapneumovirus SH protein. Here we characterize for the first time metapneumovirus SH protein with respect to topology, subcellular localization, and transport using avian metapneumovirus subgroup C (AMPV-C) as a model system. We show that AMPV-C SH is an integral membrane protein with N(in)C(out) orientation located in both the plasma membrane as well as within intracellular compartments, which is similar to what has been described previously for SH proteins of other paramyxoviruses. Furthermore, we demonstrate that AMPV-C SH protein localizes in the endoplasmic reticulum (ER), Golgi, and cell surface, and is transported through ER-Golgi secretory pathway. PMID- 21683103 TI - The role of the lymphatic system in vaccine trafficking and immune response. AB - The development and improvement of vaccines has been a significant endeavor on the part of the medical community for more than the last two centuries, and the success of these efforts is obvious when one considers the millions of lives that have been saved. Recent work in the field of vaccines, however, indicates that vaccines may be developed for even more challenging diseases than those previously addressed. It will be important in achieving this feat to account for the physical and chemical processes related to vaccine trafficking, rather than solely relying on our knowledge of the pathogen and our empirical experience. A thorough understanding of the lymphatic system is essential considering the role it plays in antigen trafficking and all immunological activity. This review describes the results of recent work that provides insight into the physiological processes of the lymphatic system and its various components with an emphasis on vaccine antigen trafficking from the administration site to secondary lymphoid tissues and the ensuing immune response. The review also discusses current challenges in designing vaccines and presents modern strategies for designing vaccines to better interface with the lymphatic system. PMID- 21683104 TI - Corilagin prevents tert-butyl hydroperoxide-induced oxidative stress injury in cultured N9 murine microglia cells. AB - Oxidative stress plays an important role in neurodegenerative diseases. Reactive oxygen species (ROS)-mediated stress in microglia in vivo could result in cellular injuries and preferentially induces neuronal injury. Corilagin, a novel member of the phenolic tannin family, has been shown to possess antioxidant properties. In this study, we investigated the effects of corilagin on tert-butyl hydroperoxide (TBHP)-induced injury in cultured N9 murine microglial cells and the underlying mechanisms by a methyltetrazolium assay and oxidative damage assay. We found that exposure of N9 cells to TBHP induced cytotoxicity as demonstrated by cell shrinkage, loss of cell viability, increased lactate dehydrogenase (LDH) leakage, and increased intracellular levels of ROS. By contrast, TBHP reduced both superoxide dismutase activity and total cell anti oxidation capacity, but glutathione was not reduced. Moreover, TBHP treatment was associated with the loss of mitochondrial membrane potential, and it induced cell apoptosis through the mitochondrial-mediated pathway involving the down regulation of Bcl-2 expression and up-regulation of the Bax/Bcl-2 ratio. Interestingly, pre-treatment with corilagin reversed these reactions. These data collectively indicated that corilagin could attenuate TBHP-induced oxidative stress injury in microglial cells, and its protective effects may be ascribed to its antioxidant and antiapoptotic properties. Our findings suggest that corilagin should be a potential candidate for the treatment of oxidative stress-induced neurodegenerative diseases. PMID- 21683105 TI - Study of the pathways involved in apoptosis induced by PI3K inhibition in cerebellar granule neurons. AB - In the present study we focused in the PI3K/Akt pathway which plays a key role in neuronal survival. Here we show that inhibition of PI3K/Akt by means of LY294002 induces apoptosis via a caspase-dependent and calpain-independent pathway in cerebellar granule neurons (CGNs). This finding was confirmed using zVAD-fmk, a widely caspase inhibitor that prevents apoptosis. For this purpose, we compared two models of apoptosis in CGNs, namely inhibition of PI3K/Akt, and serum potassium deprivation (S/K deprivation). In contrast to the S/K deprivation model, caspase-3 was not activated when PI3K is inhibited. Likewise, CDK5 activation was not involved in this apoptotic process, because calpain activation is responsible for the formation of CDK5/p25 neurotoxic form. However, S/K deprivation activated calpain, as it is shown by alpha-spectrin breakdown, and favoured the formation of CDK5/p25. Moreover, although PI3K/Akt inhibition enhanced pRbser780 phosphorylation, no increase in the expression of cell-cycle proteins, namely: cyclin D, cyclin E, CDK2 or CDK4, was detected. Furthermore, BrdU incorporation assay did not shown any increase in DNA synthesis. Likewise, PI3K/Akt inhibition increased GSK3beta activity and c-Jun phosphorylation, which implicates these two pathways in this apoptotic route. Although previous reports suggest that apoptosis induced in CGNs by LY294002 and S/K deprivation causes PI3K inhibition and increases GSK3beta activity and c-Jun phosphorylation activation, our results demonstrate substantial differences between them and point to a key role of GSK3beta in the apoptosis induced in CGNs in the two models tested. PMID- 21683106 TI - The pathological prion protein forms ionic conductance in lipid bilayer. AB - Transmissible spongiform encephalopathies (TSEs) are neurodegenerative pathologies characterized by the accumulation of amyloid fibrils mainly composed of the pathological isoform of the prion protein (PrP(TSE)). PrP(TSE) pre-amyloid fibrils are supposed to induce neurodegenerative lesions possibly through the alteration of membrane permeability. The effect of PrP(TSE) on cellular membranes has been modeled in vitro by synthetic peptides that are, however, only partially representative of PrP(TSE) isoforms found in vivo. In the present work we show that a synthetic membrane exposed to PrP27-30 extracted from TSE-infected hamster brains changes its permeability because of the formation of molecular pores that alter the conductance of the synthetic lipid bilayer. Synthetic membrane challenged with the recombinant prion peptide PrP90-231 shows a much lower conductance. Elevation of calcium ion concentration not only increases the current amplitude due to the action of both PrP27-30 and PrP90-231 on the membrane, but also amplifies the interaction of PrP90-231 with the lipid bilayer. PMID- 21683107 TI - Expression and localization of the iron-siderophore binding protein lipocalin 2 in the normal rat brain and after kainate-induced excitotoxicity. AB - Lipocalin 2 (LCN2) is produced by mammalian hosts to bind bacterial siderophore and sequester free iron as part of an innate immune response, and could also play a role in tissue iron homeostasis, but thus far, little is known about its expression in the CNS. The present study was carried out to study the expression of the lipocalin in the normal rat brain and after neuronal injury induced by kainate (KA). Low levels of LCN2 mRNA and protein expression were detected in most regions of the normal brain except the olfactory bulb, brainstem and cerebellum. KA lesions resulted in damage to the hippocampus, leading to an early increase at three days and a sustained elevation in LCN2 mRNA level of 16-fold, and protein expression at 80-fold in the lesioned tissue compared to controls at 2 weeks post-KA injection. The sustained elevation in mRNA expression was not detected among other lipocalins surveyed using real-time RT-PCR - apoD, PGDS, Rbp4 and LCN5. Single and double immunostaining confirmed that LCN2 is present in astrocytes in the olfactory bulb, brainstem and cerebellum of the normal brain, and reactive astrocytes in the KA-lesioned hippocampus. In conclusion, the present study showed LCN2 to be present in select brain regions, and is upregulated in astrocytes after neuronal injury induced by kainate. We postulate that, as in the periphery, LCN2 may have a role in iron transport or trafficking in the CNS. PMID- 21683108 TI - Multiplex sequence-specific polymerase chain reaction reveals new MASP2 haplotypes associated with MASP-2 and MAp19 serum levels. AB - Deficiency of mannan-binding lectin-associated serine protease 2 (MASP-2) has been associated with infections, whereas high levels appear to increase the risk of inflammatory disorders. Nevertheless, MASP2 haplotypes have been poorly investigated. To overcome haplotyping cost and time consumption, we developed multiplex polymerase chain reactions with sequence-specific primers (PCR-SSP) for 8 single nucleotide polymorphisms (SNPs), reducing the number of necessary reactions from 18 to 7. SNPs were distributed from the promoter to the last exon, and a single PCR-SSP was used for p.D120G. We evaluated the phylogenetic relationships and global distribution of 10 identified haplotypes in 338 Danish individuals with known MASP-2 and MAp19 levels and 309 South Brazilians. Four haplotypes were associated with reduced MASP-2 levels in plasma (lower than 200 ng/mL). Simultaneous association with the highest MASP-2 (over 600 ng/mL) and lowest MAp19 levels (lower than 200 ng/mL) was demonstrated with the intron 9 mutation (Kruskal-Wallis p < 0.0001). Cumulative genotype frequencies predict approximately 0.4% severely deficient and 25% overproducing individuals in both populations. Rapid and low-cost screening of patients with multiplex MASP2 PCR SSP could be used to identify clinical conditions where MASP-2 (or MAp19) levels may be disease modifying, possibly improving disease outcome through early therapeutic and preventive measures. PMID- 21683109 TI - Attenuated interleukin-8/leukocyte immunoresponse in preterm infants compared with term infants hospitalized with respiratory syncytial virus bronchiolitis: a pilot study. AB - Decreased transplacental transfer of antibodies and altered immunoresponsiveness may place preterm (PT) infants at higher risk for serious consequences from respiratory syncytial virus (RSV) bronchiolitis. We hypothesize that among infants hospitalized with RSV bronchiolitis, immune response in PT infants may be different when compared with that of term infants. Nasal-wash samples were collected from 11 PT (<37 weeks of gestation) and 13 term infants (>=37 weeks of gestation) hospitalized with RSV bronchiolitis. Severity of illness (clinical score [CS]), admission peripheral oxygen saturation, and days subjects required supplemental oxygen were compared. Nasal-wash leukocyte count as well as cytokines for interleukin (IL)-8, IL-4, and interferon-gamma (IFN-gamma) were assayed. No significant differences in CS, admission SaO(2), and O(2) days were seen between PT and term infants. Nasal-wash leukocyte counts and IL-8 levels were higher in term infants compared with PT and correlated with severity (higher CS) in term (p < 0.05) but not in PT (p > 0.05) infants. IL-4 and IFN-gamma levels did not differ between the 2 groups (p > 0.05). PT infants hospitalized with RSV bronchiolitis have lower nasal-wash leukocyte counts and a less robust IL-8 response than term infants, and only in term infants did IL-8 levels correlate with clinical disease severity. PMID- 21683110 TI - A new oral vaccine candidate based on the microencapsulation by spray-drying of inactivated Vibrio cholerae. AB - The aim of this work was to evaluate the microencapsulation by spray-drying of inactivated Vibrio cholerae, using methacrylic copolymers Eudragit(r) L30D-55 and FS30D. The microparticles obtained presented a particle size around 3.0 MUm. The preparation temperature affected the morphology and the antigenicity of microparticles, but it did not affect the V. cholerae content. In vitro release studies showed that in acid medium less than 5% of bacteria was released, and in neutral medium, Eudragit(r) L30D-55 microparticles released 86% after 24 h, whereas FS30D released less than 30%. Rats inoculated with microparticles exhibited vibriocidal antibody titres. Microencapsulation by spray-drying of inactivated V. cholerae could be proposed as a method to obtain an oral vaccine which provides controlled release of the bacteria. PMID- 21683112 TI - Invasive pneumococcal disease: association between serotype, clinical presentation and lethality. AB - To ascertain the factors linked to invasive pneumococcal disease (IPD) caused by the different serotypes in the period 2007-2009, following the conjugate vaccine's inclusion in the childhood vaccination schedule, a total of 2013 IPD cases were reviewed. The mean annual incidence in this period was 10.74 cases per 100,000 inhabitans and the lethality was 8.8%. Overall serotype distribution displayed certain peculiarities, such as the high frequency of serotype 5. Serotype 3, male gender, sepsis and presence of risk factors were significantly associated with lethality. Vaccinated children under 5 years of age had a higher risk of disease due to serotype 19A. Serotype 8 was associated with the presence of underlying risk factors. PMID- 21683111 TI - Mucosal immune features to phosphorylcholine by nasal Flt3 ligand cDNA-based vaccination. AB - Phosphorylcholine (PC) is an immunodominant epitope in some pathogens including Streptococcus pneumoniae and it is well-known that PC-specific antibodies (Abs) play a key role in the induction of protective immunity against pneumococcal infection. In this study, we examined whether nasal administration of DNA plasmid encoding Flt3 ligand gene (pFL) as a mucosal adjuvant plus PC-conjugated keyhole limpet hemocyanin (PC-KLH), would elicit PC-specific immune responses, and characterized mucosal immune responses to PC induced by this nasal vaccination. Nasal immunization with pFL plus PC-KLH enhanced induction of PC-specific IgA and IgM Abs in airway secretions when compared with mice given PC-KLH with or without empty plasmid gene (pORF) as controls; in addition to the mucosal immune responses, PC-specific immune responses in serum were also induced. Furthermore, the mucosal and serum IgA and IgM Abs in mice given pFL plus PC-KLH nasally, exhibited high-specificity for the PC molecule. Of interest, the PC-specific Abs bound dose-dependently to anti-T15 idiotype (AB1-2). Thus, the inhibition of S. pneumoniae colonization on the nasal cavity and lungs after nasal challenge with the live organism was significantly elicited in mice immunized with pFL plus PC KLH compared to that of mice immunized with antigen with pORF. Taken together, these findings show that nasal administration of pFL with PC-KLH elicited T15 like anti-PC IgA and IgM Abs in the respiratory tracts, and further attenuated S. pneumoniae colonization on the respiratory tracts. Nasal administration of Flt3 ligand cDNA with PC may contribute to the development of nasal vaccination for prevention of S. pneumoniae infection. PMID- 21683113 TI - Polyphenol contents and radical scavenging capacities of red maple (Acer rubrum L.) extracts. AB - The crude ethanol and water extracts of different red maple (Acer rubrum L.) tissues: whole branches (WB), wood of branches (BW), bark of branches (BB), stem bark (SB) and whole twigs (T), were examined in order to determine their phenolic contents as well as their radical scavenging capacities. The total phenols (TP), total extractable tanins (TET) and non-precipitable phenols (NPP), were determined by combination of spectrophotometric and precipitation methods, while total flavonoids, hydroxy cinanmic acids and proanthocyanidins were determined spectrophotometrically. The radical scavenging activities of the extracts were determined against five reactive oxygen species (ROS): superoxide anion (O(2)(. )), hydroxyl radical (HO(.)), peroxyl radical (ROO(.)), hypochlorite ion (ClO( )), and hydrogen peroxide (H(2)O(2)) and one reactive nitrogen species (RNS): nitric oxide (NO). The extracts of stem bark were significantly more efficient (exhibiting the highest antioxidant efficiencies, AE) than the other studied extracts against all ROS (at p<0.05, Duncan statistical tests), except against NO. The correlation coefficients determined between total phenolic (TP) content and antiradical efficiencies were R(2)=0.12 for O(2)(.-); R(2)=0.29 for HO(.); R(2)=0.40 for H(2)O(2); R(2)=0.86 for ROO(.); R(2)=0.03 for NO(.) and R(2)=0.73 for ClO(-). Our results indicate potential utilisation of extracts as natural antioxidants. PMID- 21683114 TI - State of the art in benefit-risk analysis: consumer perception. AB - Benefit and risk perception with respect to food consumption, have been a part of human daily life from beginning of time. In today's society the food chain is long with many different types of actors and low degree of transparency. Making informed food choices where knowledge of benefits and risks is part of the decision making process are therefore complicated for consumers. Thus, to understand how consumers perceive benefits and risks of foods, their importance in relation to quality evaluations are aspects that need to be addressed. The objective of this paper is to discuss state of the art in understanding consumer perceptions of benefits and risks of foods in order to improve understanding of consumer behaviour in the food domain. Risks may be associated with both acute and long term consequences, some of which may have serious effects. Perceived risks are connected to morbidity and mortality along two dimensions relating to unknown risk, and to which extent the risk is dreaded by the consumer. Unfamiliar, uncertain, unknown, uncontrollable, and severe consequences are some factors associated with risk perception. Novel food processing techniques, for instance, score high on several of these parameters and are consequently regarded with suspicion and perceived as risky by consumers. On a daily basis, benefits of foods and food consumption are more important in most consumers' minds than risks. Benefits are often associated with food's ability to assuage hunger, and to provide pleasure through eating and socialising. In addition, two main categories of benefits that are important for acceptance of product innovations are health and environmental benefits. Benefit and risk perception of foods seem to be inversely correlated, so when something is perceived as being highly beneficial, it is correspondingly perceived as having low risk. However, slightly different paths are used in the formation of these perceptions; benefit perception is based on heuristics and experience, while risk perception is to a larger extent the result of cognitive information processing. Consumers are particularly conservative when it comes to perception and acceptance of foods compared to other products. Benefit-risk evaluations tend to be skewed towards acceptance of all that is traditional and well-known (benefits), and rejection or suspicion towards anything that is novel or highly processed (risks) regardless of actual risk. Knowledge of how consumers perceive benefits and risks of foods, may contribute to understanding benefit-risk perception in other areas related to personal, societal or environmental perspectives. PMID- 21683115 TI - State of the art in benefit-risk analysis: medicines. AB - Benefit-risk assessment in medicine has been a valuable tool in the regulation of medicines since the 1960s. Benefit-risk assessment takes place in multiple stages during a medicine's life-cycle and can be conducted in a variety of ways, using methods ranging from qualitative to quantitative. Each benefit-risk assessment method is subject to its own specific strengths and limitations. Despite its widespread and long-time use, benefit-risk assessment in medicine is subject to debate and suffers from a number of limitations and is currently still under development. This state of the art review paper will discuss the various aspects and approaches to benefit-risk assessment in medicine in a chronological pathway. The review will discuss all types of benefit-risk assessment a medicinal product will undergo during its lifecycle, from Phase I clinical trials to post-marketing surveillance and health technology assessment for inclusion in public formularies. The benefit-risk profile of a drug is dynamic and differs for different indications and patient groups. In the end of this review we conclude benefit-risk analysis in medicine is a developed practice that is subject to continuous improvement and modernisation. Improvement not only in methodology, but also in cooperation between organizations can improve benefit-risk assessment. PMID- 21683116 TI - Non-clinical safety and pharmacokinetic evaluations of propylene glycol aerosol in Sprague-Dawley rats and Beagle dogs. AB - Aerosolized propylene glycol (PG) was generated as log-normally distributed particulate clouds in different concentrations using a novel capillary aerosol generator (CAG) and evaluated in a battery of non-clinical studies intended to assess its potential inhalation and systemic toxicity in 2 species before ICH compliant "first-time-in-man" studies. Exposures were nose-only in rats, and via face mask with oropharyngeal tube in dogs. The CAG-generated PG aerosol had a mass median aerodynamic diameter (MMAD) of 2.29MUm, with a 1.56 geometric standard deviation (GSD) in the rat studies, and a MMAD of 1.34MUm (1.45 GSD) in the dog studies, consistent with expected particle size exposures in man. International Congress on Harmonization (ICH) Guidelines were followed, which recommend preliminary non-clinical safety studies using the vehicle and device (CAG-PG) prior to the first human exposure including safety pharmacology, pharmacokinetic (PK) studies, single dose toxicity studies, and repeated dose toxicity studies in two species. In the rat, the only biologically relevant findings included clinical signs of ocular and nasal irritation indicated by minor bleeding around the eyes and nose, and minimal laryngeal squamous metaplasia. This finding is commonly observed in inhalation studies in the rat, and likely related to the unique sensitivity of the tissue, as well as the circuitous airflow pathway through the larynx which increases particle deposition. In the female Beagle dog, treatment-related decreases in hemoglobin, red blood cells and hematocrit were observed in the two highest exposure groups, equivalent to approximately 18 and 60mg/kg/day. In male dogs from the high dose group, similar small decreases, albeit, non-statistically significant decreases were observed in these hematological markers as well. PK studies in rats and dogs showed that the absorption of PG following pulmonary inhalation exposure occurs rapidly, and equilibrium between lung tissue and plasma is achieved quickly. With daily inhalations of PG aerosols, there is evidence of minor tissue accumulation of PG in each species. Inhalation exposure to CAG-generated PG aerosols achieved PG concentrations in the systemic circulation that were similar to those attained via the oral route. Systemic elimination of PG appears to be saturable, presumably via hepatic metabolism. PG elimination in the high dose groups for both species showed terminal plasma and lung concentration-time profiles suggesting a zero-order elimination process. There was no apparent tissue toxicity of the lung, liver and kidney in these studies. Under the conditions of these studies, the NOEL for the rat was determined to be 20mg/kg/day for the 28 day study. In the Beagle dog, the NOEL was approximately 6.05mg/kg/day for the 28 day study. Overall, these studies allowed us to conclude that PG aerosol generated with the capillary aerosol generator could be administered safely in man, with an adequate margin of safety needed to conduct "first-time-in-man" human exposure studies. PMID- 21683117 TI - Extramitochondrial tricarboxylic acid cycle in retinal rod outer segments. AB - Vertebrate retinal rod Outer Segments (OS) are the site of visual transduction, an energy demanding process for which mechanisms of ATP supply are still poorly known. Glycolysis or diffusion of either ATP or phosphocreatine from the Inner Segment (IS) does not seem to display adequate timing to supply ATP for phototransduction. We have previously reported data suggesting an aerobic metabolism in OS, which would largely account for the light-stimulated ATP need of the photoreceptor. Here, by oxymetry and biochemical analyses we show that: (i) disks isolated by Ficoll flotation consume O(2) in the presence of physiological respiring substrates either in coupled or uncoupled conditions; (ii) OS homogenates contain the whole biochemical machinery for the degradation of glucose, i.e. glycolysis and the tricarboxylic acid cycle (TCA cycle), consistently with the results of our previous proteomic study. Activities of the 8 TCA cycle enzymes in OS were comparable to those in retinal mitochondria enriched fractions. Disk and OS preparations were subjected to TEM analysis, and while they can be considered free of inner segment contaminants, immunogold with specific antibodies demonstrate the expression therein of both the visual pigment rhodopsin and F(o)F(1)-ATP synthase. Finally, double immunofluorescence on mouse retina sections demonstrated a colocalization of some respiratory complex mitochondrial proteins with rhodopsin in rod OS. Data, suggestive of the exportability of the mitochondrial machinery for aerobic metabolism, may shed light on those retinal pathologies related to energy supply impairment in OS and to mutations in TCA enzymes. PMID- 21683118 TI - Nuclear calcium signaling: an emerging topic in plants. AB - The calcium ion is probably one of the most studied second messenger both in plant and animal fields. A large number of reviews have browsed the diversity of cytosolic calcium signatures and evaluated their pleiotropic roles in plant and animal cells. In the recent years, an increasing number of reviews has focused on nuclear calcium, especially on the possible roles of nuclear calcium concentration variations on nuclear activities. Experiments initially performed on animal cells gave conflicting results that brought about a controversy about the ability of the nucleus to generate its own calcium signals and to regulate its calcium level. But in plant cells, several converging scientific pieces of evidence support the hypothesis of nucleus autonomy. The present review briefly summarizes data supporting this hypothesis and tries to put forward some possible roles for these nucleus-generated calcium signals in controlling nuclear activity. PMID- 21683119 TI - Quantum-like model of processing of information in the brain based on classical electromagnetic field. AB - We propose a model of quantum-like (QL) processing of mental information. This model is based on quantum information theory. However, in contrast to models of "quantum physical brain" reducing mental activity (at least at the highest level) to quantum physical phenomena in the brain, our model matches well with the basic neuronal paradigm of the cognitive science. QL information processing is based (surprisingly) on classical electromagnetic signals induced by joint activity of neurons. This novel approach to quantum information is based on representation of quantum mechanics as a version of classical signal theory which was recently elaborated by the author. The brain uses the QL representation (QLR) for working with abstract concepts; concrete images are described by classical information theory. Two processes, classical and QL, are performed parallely. Moreover, information is actively transmitted from one representation to another. A QL concept given in our model by a density operator can generate a variety of concrete images given by temporal realizations of the corresponding (Gaussian) random signal. This signal has the covariance operator coinciding with the density operator encoding the abstract concept under consideration. The presence of various temporal scales in the brain plays the crucial role in creation of QLR in the brain. Moreover, in our model electromagnetic noise produced by neurons is a source of superstrong QL correlations between processes in different spatial domains in the brain; the binding problem is solved on the QL level, but with the aid of the classical background fluctuations. PMID- 21683120 TI - Genetic analysis of lysosomal alpha-galactosidase A gene in sporadic Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disease. Majority of PD cases are sporadic, resulting from interaction of genetic and environmental factors. Accumulating evidence indicates that autophagy, which delivers alpha synuclein to lysosomes for degradation, is involved in the PD pathogenesis. Some lysosomal hydrolases, such as glucocerebrosidase gene and ATP13A2, a lysosomal ATPase gene, have been implicated in PD. We have previously screened the activities of a group of lysosomal hydrolases in sporadic PD patients and found that alpha-galactosidase A (GLA) activities are significantly decreased. In this study, we analyzed GLA gene in sporadic PD patients by sequencing its promoter and exon regions. One single-nucleotide polymorphism (SNP) in the promoter region, rs3027580 (NG_007119.1:g.4292G>C), and two SNPs in the GLA 5' untranslated region, rs2071225 (NM_000169.2:c.-10C>T) and rs3027585 (NM_000169.2:c.-12G>A), were identified with similar frequencies in sporadic PD patients and healthy controls. A novel variant (NG_007119.1:g.4488C>G) within the promoter region, at the -573 site upstream of the translation start codon (ATG), was found in one male PD patient, but not in female PD patients or healthy controls. Our data suggest that the sequence variant may affect GLA gene expression by altering transcription factor binding sites, contributing to the pathogenesis of sporadic PD. PMID- 21683121 TI - Novel RPGR-ORF15 mutations in X-linked retinitis pigmentosa patients. AB - X-linked retinitis pigmentosa (XLRP) is the most severe type of retinitis pigmentosa (RP), with patients consistently showing early onset and rapid deterioration. Obtaining a genetic diagnosis for a family with XLRP is important for counseling purposes. In this study, we aimed to identify disease-causing mutations in two unrelated XLRP families. Genetic analysis was performed on two unrelated XLRP families. Genomic DNA was extracted from peripheral blood or amniotic fluid samples. The coding regions and intron/exon boundaries of the Retinitis Pigmentosa GTPase Regulator (RPGR) and RP2 genes were amplified by PCR and then sequenced directly. A clinically unaffected pregnant female and the four month old fetus were found to have a hemizygous 2 base pair deletion (g.ORF15+484_485delAA) in the exon ORF15 of RPGR gene. In another XLRP family, a nonsense mutation (g.ORF15+810G>T) was identified. Neither mutation has been reported previously. Both are predicted to cause premature termination of the protein. In conclusion, we identified a micro-deletion through prenatal genetic diagnosis and another novel nonsense mutation in RPGR-ORF15. Identifying a disease-causing mutation facilitated early diagnosis and genetic counseling for the patients. Discovery of novel mutations also broadens knowledge of XLRP and the spectrum of its pathogenic genotypes. PMID- 21683122 TI - When far is near: ERP correlates of crossmodal spatial interactions between tactile and mirror-reflected visual stimuli. AB - Visuo-tactile integration occurs in a privileged way in peripersonal space, namely when visual and tactile stimuli are in spatial proximity. Here, we investigated whether crossmodal spatial effects (i.e. stronger crossmodal interactions for spatially congruent compared to incongruent visual and tactile stimuli) are also present when visual stimuli presented near the body are indirectly viewed in a mirror, thus appearing in far space. Participants had to attend to one of their hands throughout a block of stimuli in order to detect infrequent tactile target stimuli at that hand while ignoring tactile targets at the unattended hand, all tactile non-target stimuli, and any visual stimuli. Visual stimuli were presented simultaneously with tactile stimuli, in the same (congruent) or opposite (incongruent) hemispace with respect to the tactile stimuli. In one group of participants the visual stimuli were delivered near the participants' hands and were observed as indirect mirror reflections ('mirror' condition), while in the other group these were presented at a distance from the hands ('far' condition). The main finding was that crossmodal spatial modulations of ERPs recorded over and close to somatosensory cortex were present in the 'mirror' condition but not the 'far' condition. That is, ERPs were enhanced in response to tactile stimuli coupled with spatially congruent versus incongruent visual stimuli when the latter were viewed through a mirror. These effects emerged around 190 ms after stimuli onset, and were modulated by the focus of spatial attention. These results provide evidence that visual stimuli observed in far space via a mirror are coded as near-the-body stimuli according to their known rather than to their perceived location. This suggests that crossmodal interactions between vision and touch may be modulated by previous knowledge of reflecting surfaces (i.e. top-down processing). PMID- 21683123 TI - The GABA(A)rho receptors in hippocampal spontaneous activity and their distribution in hippocampus, amygdala and visual cortex. AB - A bicuculline-resistant and TPMPA-sensitive GABAergic component was identified in hippocampal neurons in culture and in acute isolated brain slices. In both preparations, total GABAergic activity showed two inactivation kinetics: fast and slow. RT-PCR, in situ hybridization (ISH) and immunohistochemistry detected expression of GABArho subunits. Immunogold and electron microscopy indicated that the receptors are mostly extrasynaptic. In addition, by RT-PCR and immunofluorescence we found GABArho present in amygdala and visual cortex. PMID- 21683124 TI - Increased cellular iron levels affect matrix metalloproteinase expression and phagocytosis in activated microglia. AB - Activation of microglia could be beneficial and yet simultaneously harmful depending upon nature of pathological milieu. Regardless of disease-specific etiology, iron accumulation, particularly in activated microglia, is a notable feature associated with a series of neuropathologies, including Alzheimer's diseases. Although mounting evidence supports the role of iron in oxidative brain injury, knowledge on its regulatory role in neuroinflammation is still scarce. Here, we hypothesize that cellular iron status may be involved in determining the roles of activated microglia in neuroinflammatory processes. In this study, we examined effects of iron on expression of MMPs known to be involved in nervous system inflammation and degeneration using rat microglial cell line (HAPI). Stimulation experiments were performed using lipopolysaccharide (LPS). We demonstrated by RT-PCR that increased cellular iron levels enhanced the expression of MMP-9 in activated microglia, but had no effect on MMP-1. Studies using western blot and gelatin zymography analyses demonstrated that increased cellular iron levels in activated microglia enhanced the secretion of MMP-9 and MMP-1. Taken together, these results demonstrated regulatory roles of iron in the expression of MMPs by activated microglia at the transcription and translation levels. Using a colorimetric NBT reduction assay, we showed that increased cellular iron levels impaired zymosan phagocytic activity in activated microglia. Thus, these findings further our understanding toward the consequences of iron accumulation by activated microglia in neurodegeneration and suggest a possible link between iron metabolism in activated microglia and neuroinflammation. PMID- 21683125 TI - Continuous theta burst stimulation over the contralesional sensory and motor cortex enhances motor learning post-stroke. AB - The current study investigated the contributions of contralesional primary somatosensory cortex (S1c) to motor learning deficits post-stroke. For three days, continuous theta burst (cTBS) was delivered over the contralesional hemisphere prior to practicing a serial targeting task. cTBS was delivered over either S1c, contralesional primary motor cortex (M1c) or as control stimulation (n=4/group). Change in motor ability was assessed from initial performance to a delayed retention test using a serial targeting task and a subset of items from the Wolf Motor Function Test. Practice preceded by cTBS over either M1c or S1c resulted in large decreases in movement time compared to practice preceded by control stimulation. M1c cTBS resulted in larger decreases in peak velocity and peak acceleration compared to control and S1c cTBS. In contrast, S1c cTBS resulted in larger reductions in time to initiate movement and time to complete the WMFT compared to control and M1c cTBS. These preliminary findings suggest that stimulation of either M1c or S1c can enhance the benefits of practice. However, changes in M1c and S1c excitability may contribute to different aspects of post-stroke motor deficits that may differentially impact rehabilitation. PMID- 21683126 TI - Transmigration of beta amyloid specific heavy chain antibody fragments across the in vitro blood-brain barrier. AB - Previously selected amyloid beta recognizing heavy chain antibody fragments (VHH) affinity binders derived from the Camelid heavy chain antibody repertoire were tested for their propensity to cross the blood-brain barrier (BBB) using an established in vitro BBB co-culture system. Of all tested VHH, ni3A showed highest transmigration efficiency which is, in part, facilitated by a three amino acid substitutions in its N-terminal domain. Additional studies indicated that the mechanism of transcellular passage of ni3A is by active transport. As VHH ni3A combines the ability to recognize amyloid beta and to cross the BBB, it has potential as a tool for non-invasive in vivo imaging and as efficient local drug targeting moiety in patients suffering from cerebral amyloidosis such as Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). PMID- 21683128 TI - Effect of crystallisation conditions and feedstock morphology on the aerosolization performance of micronised salbutamol sulphate. AB - Salbutamol sulphate (SS) used in dry powder inhalers requires drug particles in the respirable size range of 1-5 MUm to achieve a suitable therapeutic effect. The aim of this study was therefore to determine strategies for controlling drug substance characteristics pre and post-crystallisation to facilitate the production of micronised SS with desirable particle attributes for optimal delivery as an inhaled aerosol. SS batches were crystallised using an antisolvent method to produce a range of crystal morphologies. Air jet milling was then used to reduce the size of crystallised SS particles. Starting materials and micronised batches of SS were characterised in the solid state using a range of techniques with subsequent assessment of aerosol properties. Assessment of the aerodynamic characteristics of micronised SS delivered by DPI (without any carrier) indicated that fine particle fraction and emitted dose as a percentage of the total recovered dose were dependent on the quality attributes of the micronised SS, which were directly linked to the degree of imperfections and the morphology of the crystalline feedstock used in micronisation. Aerosolization performance of micronised SS can be optimised by manipulation of feedstock characteristics through crystal engineering and through definition of optimal processing conditions for micronisation. PMID- 21683127 TI - Mitochondrial genome-maintaining activity of mouse mitochondrial transcription factor A and its transcript isoform in Saccharomyces cerevisiae. AB - Mitochondrial transcription factor A (Tfam) binds to and organizes mitochondrial DNA (mtDNA) genome into a mitochondrial nucleoid (mt-nucleoid) structure, which is necessary for mtDNA transcription and maintenance. Here, we demonstrate the mtDNA-organizing activity of mouse Tfam and its transcript isoform (Tfam(iso)), which has a smaller high-mobility group (HMG)-box1 domain, using a yeast model system that contains a deletion of the yeast homolog of mouse Tfam protein, Abf2p. When the mouse Tfam genes were introduced into the ABF2 locus of yeast genome, the corresponding mouse proteins, Tfam and Tfam(iso), can functionally replace the yeast Abf2p and support mtDNA maintenance and mitochondrial biogenesis in yeast. Growth properties, mtDNA content and mitochondrial protein levels of genes encoded in the mtDNA were comparable in the strains expressing mouse proteins and the wild-type yeast strain, indicating that the proteins have robust mtDNA-maintaining and -expressing function in yeast mitochondria. These results imply that the mtDNA-organizing activities of the mouse mt-nucleoid proteins are structurally and evolutionary conserved, thus they can maintain the mtDNA of distantly related and distinctively different species, such as yeast. PMID- 21683129 TI - Development and characterization of immuno-nanocarriers targeting the cancer stem cell marker AC133. AB - In the context of targeted therapy, we addressed the possibility of developing a drug delivery nanocarrier capable to specifically reach cancer cells that express the most prominent marker associated with cancer stem cell (CSC) phenotype, AC133. For this purpose, 100nm lipid nanocapsules (LNCs) were functionalized with a monoclonal antibody (mAb) directed against AC133 according to two distinct methods: firstly, post-insertion within 100nm LNCs of a lipid poly(ethylene glycol) functionalized with reactive-sulfhydryl maleimide groups (DSPE-PEG(2000) maleimide) followed by thiolated mAb coupling, and, secondly, creation of a thiolated lipo-immunoglobulin between DSPE-PEG(2000)-maleimide and AC133, then post-inserted within LNCs. Due to the reduced number of purification steps, lower amounts of DSPE-PEG(2000)-maleimide that were necessary as well as lower number of free maleimide functions present onto the surface of immuno-LNC, the second method was found to be more appropriate. Thus, 126nm AC133-LNC with a zeta potential of -22mV while keeping a narrow distribution were developed. Use of the IgG1kappa isotype control-immunoglobulins produced similar control IgG1-LNCs. Micro-Bradford colorimetric assay indicated a fixation of about 40 immunoglobulins per LNC. Use of human Caco-2 cells that constitutively express AC133 (Caco-2-AC133(high)) allowed addressing the behavior of the newly functionalized immuno-LNCs. siRNA knockown strategy permitted to obtain Caco-2 AC133(low) for comparison. Immunofluorescence-combined flow cytometry analysis demonstrated that the epitope-recognition function of AC133 antibody was preserved when present on immuno-LNCs. Although grafting of immunoglobulins onto the surface of LNCs repressed their internalization within Caco-2 cells as evaluated by flow cytometry, AC133-specific cellular binding was obtained with AC133-LNC as assessed by computer-assisted fluorescence microscopy. In conclusion, interest of AC133-LNCs as niche carriers is discussed toward the development of CSC targeted chemo- or radio-nanomedicines. PMID- 21683130 TI - Chloride cotransporters, chloride homeostasis, and synaptic inhibition in the developing auditory system. AB - The role of glycine and GABA as inhibitory neurotransmitters in the adult vertebrate nervous system has been well characterized in a variety of model systems, including the auditory, which is particularly well suited for analyzing inhibitory neurotransmission. However, a full understanding of glycinergic and GABAergic transmission requires profound knowledge of how the precise organization of such synapses emerges. Likewise, the role of glycinergic and GABAergic signaling during development, including the dynamic changes in regulation of cytosolic chloride via chloride cotransporters, needs to be thoroughly understood. Recent literature has elucidated the developmental expression of many of the molecular components that comprise the inhibitory synaptic phenotype. An equally important focus of research has revealed the critical role of glycinergic and GABAergic signaling in sculpting different developmental aspects in the auditory system. This review examines the current literature detailing the expression patterns and function (chapter 1), as well as the regulation and pharmacology of chloride cotransporters (chapter 2). Of particular importance is the ontogeny of glycinergic and GABAergic transmission (chapter 3). The review also surveys the recent work on the signaling role of these two major inhibitory neurotransmitters in the developing auditory system (chapter 4) and concludes with an overview of areas for further research (chapter 5). PMID- 21683131 TI - Health benefits of marine foods and ingredients. AB - The health benefits of seafood consumption have primarily been associated with protective effects against cardiovascular diseases (CVD). However, intake of seafood has also been associated with improved foetal and infant development, as well as several other diseases and medical conditions. The health promoting effects have chiefly been attributed to the long-chain n-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In addition, the general fatty acid profile is considered favourable. On the other hand, recent and emerging research on seafood proteins and other seafood derived components suggest that these nutritional components contribute to the health effects. In this paper we review the nutritional characteristics and health benefits of marine foods and ingredients, and discuss some current and future trends in marine food production. PMID- 21683132 TI - Repeat traumatic brain injury in the developing brain. AB - The Center for Disease Control estimates that there are 1.7 million brain injuries in the US each year with 51% of these injuries occurring during periods of cerebral development. Among this population there is a growing population of individuals with repeat traumatic brain injury (RTBI). While the exact incidence is unknown, estimates range from 5.6 to 36% of the TBI population. This review summarizes the clinical problems/challenges and experimental research models that currently exist. It is intended to reveal the critical areas that need to be addressed so that age-relevant clinical management guidelines can be established to protect this population. PMID- 21683133 TI - Gene conversions in the growth hormone gene family of primates: stronger homogenizing effects in the Hominidae lineage. AB - In humans, the growth hormone/chorionic somatomammotropin gene family is composed of five highly similar genes. We characterized the gene conversions that occurred between the growth hormone genes of 11 primate species. We detected 48 conversions using GENECONV and others were only detected using phylogenetic analyses. Gene conversions were detected in all species analyzed, their average size (+/-standard deviation) is 197.8+/-230.4 nucleotides, the size of the conversions is correlated with sequence similarity and converted regions are significantly more GC-rich than non-converted regions. Gene conversions have a stronger homogenizing effect in Hominidae genes than in other primate species. They are also less frequent in conserved gene regions and towards functionally important genes. This suggests that the high degree of sequence similarity observed between the growth hormone genes of primate species is a consequence of frequent gene conversions in gene regions which are under little selective constraints. PMID- 21683134 TI - Developmental toxicity of albendazole and its three main metabolites in zebrafish embryos. AB - Albendazole (ABZ) is used as an anthelmintic drug in humans and animals. ABZ has been shown to cause developmental toxicity in experimental animals, however it is not clear if this is caused by the parent compound or a metabolite. Zebrafish embryos were exposed from 1 to 144hpf (hours post fertilization) to investigate the developmental toxicity of ABZ, the first metabolite albendazole sulphoxide and the subsequent metabolites albendazole sulphone (ABZSO(2)) and albendazole-2 aminosulphone (ABZSO(2)NH(2)). The results showed that ABZ caused malformations of head and tail and embryonic lethality from 0.3MUM. In contrast, the metabolites did not display developmental toxicity at any tested concentration. Dechorionation did not influence the developmental toxic potential of ABZ and ABZSO, indicating that bioavailability was not a limiting factor. Chemical analysis showed that at sublethal concentrations, most of ABZ was metabolized to ABZSO. The results demonstrate that in zebrafish embryos ABZ rather than ABZSO displays developmental toxicity. PMID- 21683136 TI - Central serotonergic system. PMID- 21683137 TI - The amylin peptide implicated in type 2 diabetes stimulates copper-mediated carbonyl group and ascorbate radical formation. AB - Human amylin (hA), which is toxic to islet beta-cells, can self-generate H(2)O(2), and this process is greatly enhanced in the presence of Cu(II) ions. Here we show that carbonyl groups, a marker of oxidative modification, were formed in hA incubated in the presence of Cu(II) ions or Cu(II) ions plus H(2)O(2), but not in the presence of H(2)O(2) alone. Furthermore, under similar conditions (i.e., in the presence of both Cu(II) ions and H(2)O(2)), hA also stimulated ascorbate radical formation. The same observations concerning carbonyl group formation were made when the histidine residue (at position 18) in hA was replaced by alanine, indicating that this residue does not play a key role. In complete contrast to hA, rodent amylin, which is nontoxic, does not generate H(2)O(2), and binds Cu(II) ions only weakly, showed none of these properties. We conclude that the hA-Cu(II)/Cu(I) complex is redox active, with electron donation from the peptide reducing the oxidation state of the copper ions. The complex is capable of forming H(2)O(2) from O(2) and can also generate (*)OH via Fenton chemistry. These redox properties of hA can explain its ability to stimulate copper-mediated carbonyl group and ascorbate radical formation. The formation of reactive oxygen species from hA in this way could hold the key to a better understanding of the damaging consequences of amyloid formation within the pancreatic islets of patients with type 2 diabetes mellitus. PMID- 21683138 TI - Nucleoporins: leaving the nuclear pore complex for a successful mitosis. AB - The nuclear envelope (NE) separates the cytoplasm and the cell nucleus of interphase eukaryotic cells and nuclear pore complexes (NPCs) mediate the macromolecular exchange between these two compartments. The NE and the NPCs of vertebrate cells disassemble during prophase and the nuclear pore proteins (nucleoporins) are distributed within the mitotic cytoplasm. For an increasing number of them active mitotic functions have been assigned over the past few years. Nucleoporins are participating in spindle assembly, kinetochore organisation, and the spindle assembly checkpoint, all processes that control chromosome segregation and are important for maintenance of genome integrity. But nucleoporins are also engaged in early and late mitotic events, such as centrosome positioning and cytokinesis. Here we will highlight recent progress in deciphering the roles for nucleoporins in the distinct steps of mitosis. PMID- 21683135 TI - Effects of citalopram on serotonin and CRF systems in the midbrain of primates with differences in stress sensitivity. AB - This chapter reviews the neurobiological effects of stress sensitivity and s citalpram (CIT) treatment observed in our nonhuman primate model of functional hypothalamic amenorrhea (FHA). This type of infertility, also known as stress induced amenorrhea, is exhibited by cynomolgus macaques. In small populations, some individuals are stress-sensitive (SS) and others are highly stress-resilient (HSR). The SS macaques have suboptimal secretion of estrogen and progesterone during normal menstrual cycles. SS monkeys also have decreased serotonin gene expression and increased CRF expression compared to HSR monkeys. Recently, we found that CIT treatment improved ovarian steroid secretion in SS monkeys, but had no effect in HSR monkeys. Examination of the serotonin system revealed that SS monkeys had significantly lower Fev (fifth Ewing variant, rodent Pet1), TPH2 (tryptophan hydroxylase 2), 5HT1A autoreceptor and SERT (serotonin reuptake transporter) expression in the dorsal raphe than SR monkeys. However, CIT did not alter the expression of either Fev, TPH2, SERT or 5HT1A mRNAs. In contrast, SS monkeys tended to have a higher density of CRF fiber innervation of the dorsal raphe than HSR monkeys, and CIT significantly decreased the CRF fiber density in SS animals. In addition, CIT increased CRF-R2 gene expression in the dorsal raphe. We speculate that in a 15-week time frame, the therapeutic effect of S citalopram may be achieved through a mechanism involving extracellular serotonin inhibition of CRF and stimulation of CRF-R2, rather than alteration of serotonin related gene expression. PMID- 21683139 TI - Rac1 signalling towards GLUT4/glucose uptake in skeletal muscle. AB - Small Rho family GTPases are important regulators of cellular traffic. Emerging evidence now implicates Rac1 and Rac-dependent actin reorganisation in insulin induced recruitment of glucose transporter-4 (GLUT4) to the cell surface of muscle cells and mature skeletal muscle. This review summarises the current thinking on the regulation of Rac1 by insulin, the role of Rac-dependent cortical actin remodelling in GLUT4 traffic, and the impact of Rac1 towards insulin resistance in skeletal muscle. PMID- 21683140 TI - Myelin genes are downregulated in canine fucosidosis. AB - The processes regulating the complex neurodegenerative cascade of vacuolation, neuroinflammation, neuronal loss and myelin deficits in fucosidosis, a neurological lysosomal storage disorder, remain unclear. To elucidate these processes the gene expression profile of the cerebral cortex from untreated and intrathecal enzyme replacement therapy treated fucosidosis pups and age-matched unaffected controls were examined. Neuroinflammation and cell death processes were identified to have a major role in fucosidosis pathophysiology with 37% of differentially expressed (DE) genes involved in these processes. Critical, specific, early decreases in expression levels of key genes in myelin assembly were identified by gene expression profiling, including myelin-associated glycoprotein (MAG), myelin and lymphocyte protein (MAL), and oligodendrocyte myelin paranodal and inner loop protein (OPALIN). These gene expression changes may be indicative of early neuronal loss causing reduced electrical impulses required for oligodendrocyte maturation. PMID- 21683141 TI - Emerging roles for ADAMTS5 during development and disease. PMID- 21683142 TI - Celastrol regulates innate immunity response via NF-kappaB and Hsp70 in human retinal pigment epithelial cells. AB - Elevated nuclear factor kappa B (NF-kappaB) activity and interleukin-6 (IL-6) secretion participates in the pathology of several age and inflammatory-related diseases, including age-related macular degeneration (AMD), in which retinal pigment epithelial cells are the key target. Recent findings reveal that heat shock protein 70 (Hsp70) may affect regulation of NF-kappaB. In the current study, effects of Hsp70 expression on NF-kappaB RelA/p65 activity were evaluated in human retinal pigment epithelial cells (ARPE-19) by using celastrol, a novel anti-inflammatory compound. Anti-inflammatory properties of celastrol were determined by measuring expression levels of IL-6 and endogenous NF-kappaB levels during lipopolysaccharide (LPS) exposure by using enzyme-linked immunosorbent assays (ELISA). Cell viability was measured by MTT and LDH assay, and Hsp70 expression levels were analyzed by Western blotting. ARPE-19 cells were transfected with hsp70 small interfering RNA (siRNA) in order to attenuate Hsp70 expression and activity of NF-kappaB RelA/p65 was measured using NF-kappaB consensus bound ELISA. Simultaneous exposures to LPS and celastrol reduced IL-6 expression levels as well as activity of phosphorylated NF-kappaB at serine 536 (Ser536) in ARPE-19 cells when compared to LPS exposure alone. In addition, inhibition of NF-kappaB RelA/p65 activity by celastrol was attenuated when Hsp70 response was silenced by siRNA. Favorable anti-inflammatory concentrations of celastrol showed no signs of cytotoxic response. Our findings reveal that celastrol is a novel plant compound which suppresses innate immunity response in human retinal pigment epithelial cells via NF-kappaB and Hsp70 regulation, and that Hsp70 is a critical regulator of NF-kappaB. PMID- 21683143 TI - Much excitement about antidepressants, DBI and c-FOS. AB - This article briefly outlines the background and major findings of the research projects in which, together with a number of skilled and enthusiastic collaborators, I was involved at FGIN under the mentorship of the late Dr. Erminio Costa.The topics covered are (i) our search for an endogenous ligand of the [3H]-imipramine binding site, as an approach to shed light on the still today elusive mechanisms underlying the therapeutic action of antidepressant drugs; (ii) our attempt to correlate psychopathological states, characterized by dysfunctions of the GABAergic neurotransmission, with an altered brain content of Diazepam binding inhibitor (DBI), a peptide that exerts a direct negative modulation of GABAA receptor function and also, by binding to the mitochondrial benzodiazepine receptor, increases the brain content of GABAA receptor-active neurosteroids; (iii) our demonstration that the activation of the glutamate/NMDA receptor, throughstimulation of several intracellular signaling pathways, induces the expression of the early inducible gene c-fos, a mechanism proposed to underlie glutamate-mediated neuronal plasticity. PMID- 21683144 TI - Hepatocyte growth factor acts as a mitogen and chemoattractant for postnatal subventricular zone-olfactory bulb neurogenesis. AB - Neural progenitor cells persist throughout life in the forebrain subventricular zone (SVZ). They generate neuroblasts that migrate to the olfactory bulb and differentiate into interneurons, but mechanisms underlying these processes are poorly understood. Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic factor that influences cell motility, proliferation and morphogenesis in neural and non-neural tissues. HGF and its receptor, c-Met, are present in the rodent SVZ-olfactory bulb pathway. Using in vitro neurogenesis assays and in vivo studies of partially HGF-deficient mice, we find that HGF promotes SVZ cell proliferation and progenitor cell maintenance, while slowing differentiation and possibly altering cell fate choices. HGF also acts as a chemoattractant for SVZ neuroblasts in co-culture assays. Decreased HGF signaling induces ectopic SVZ neuroblast migration and alters the timing of migration to the olfactory bulb. These results suggest that HGF influences multiple steps in postnatal forebrain neurogenesis. HGF is a mitogen for SVZ neural progenitors, and regulates their differentiation and olfactory bulb migration. PMID- 21683145 TI - The importance of the digest: proteolysis and absolute quantification in proteomics. AB - Virtually all mass spectrometric-based methods for quantitative proteomics are at the peptide level, whether label-mediated or label-free. Absolute quantification in particular is based on the measurement of limit peptides, defined as those peptides that cannot be further fragmented by the protease in use. Complete release of analyte and (stable isotope labelled) standard ensures that the most reliable quantification data are recovered, especially when the standard peptides are in a different primary sequence context, such as sometimes occurs in the QconCAT methodology. Moreover, in label-free methods, incomplete digestion would diminish the ion current attributable to limit peptides and lead to artifactually low quantification data. It follows that an essential requirement for peptide based absolute quantification in proteomics is complete and consistent proteolysis to limit peptides. In this paper we describe strategies to assess completeness of proteolysis and discuss the potential for variance in digestion efficiency to compromise the ensuing quantification data. We examine the potential for kinetically favoured routes of proteolysis, particularly at the last stages of the digestion, to direct products into 'dead-end' mis-cleaved products. PMID- 21683147 TI - The recent paper "Multimodal imaging demonstrates concomitant changes in bone and cartilage after destabilization of the medial meniscus and increased joint laxity". PMID- 21683146 TI - In vivo imaging of rat coronary arteries using bi-plane digital subtraction angiography. AB - INTRODUCTION: X-ray based digital subtraction angiography (DSA) is a common clinical imaging method for vascular morphology and function. Coronary artery characterization is one of its most important applications. We show that bi-plane DSA of rat coronary arteries can provide a powerful imaging tool for translational safety assessment in drug discovery. METHODS: A novel, dual tube/detector system, constructed explicitly for preclinical imaging, supports image acquisition at 10 frames/s with 88-micron spatial resolution. Ventilation, x-ray exposure, and contrast injection are all precisely synchronized using a biological sequence controller implemented as a LabVIEW application. A set of experiments were performed to test and optimize the sampling and image quality. We applied the DSA imaging protocol to record changes in the visualization of coronaries and myocardial perfusion induced by a vasodilator drug, nitroprusside. The drug was infused into a tail vein catheter using a peristaltic infusion pump at a rate of 0.07 mL/h for 3 min (dose: 0.0875 mg). Multiple DSA sequences were acquired before, during, and up to 25 min after drug infusion. Perfusion maps of the heart were generated in MATLAB to compare the drug effects over time. RESULTS: The best trade-off between the injection time, pressure, and image quality was achieved at 60 PSI, with the injection of 150 ms occurring early in diastole (60 ms delay) and resulting in the delivery of 113 MUL of contrast agent. DSA images clearly show the main branches of the coronary arteries in an intact, beating heart. The drug test demonstrated that DSA can detect relative changes in coronary circulation via perfusion maps. CONCLUSIONS: The methodology for DSA imaging of rat coronary arteries can serve as a template for future translational studies to assist in safety evaluation of new pharmaceuticals. Although x-ray imaging involves radiation, the associated dose (0.4 Gy) is not a major limitation. PMID- 21683148 TI - The patellofemoral joint: the forgotten joint in knee osteoarthritis. PMID- 21683149 TI - The D-galacturonic acid catabolic pathway in Botrytis cinerea. AB - D-galacturonic acid is the most abundant component of pectin, one of the major polysaccharide constituents of plant cell walls. Galacturonic acid potentially is an important carbon source for microorganisms living on (decaying) plant material. A catabolic pathway was proposed in filamentous fungi, comprising three enzymatic steps, involving D-galacturonate reductase, L-galactonate dehydratase, and 2-keto-3-deoxy-L-galactonate aldolase. We describe the functional, biochemical and genetic characterization of the entire D-galacturonate-specific catabolic pathway in the plant pathogenic fungus Botrytis cinerea. The B. cinerea genome contains two non-homologous galacturonate reductase genes (Bcgar1 and Bcgar2), a galactonate dehydratase gene (Bclgd1), and a 2-keto-3-deoxy-L galactonate aldolase gene (Bclga1). Their expression levels were highly induced in cultures containing GalA, pectate, or pectin as the sole carbon source. The four proteins were expressed in Escherichia coli and their enzymatic activity was characterized. Targeted gene replacement of all four genes in B. cinerea, either separately or in combinations, yielded mutants that were affected in growth on D galacturonic acid, pectate, or pectin as the sole carbon source. In Aspergillus nidulans and A. niger, the first catabolic conversion only involves the Bcgar2 ortholog, while in Hypocrea jecorina, it only involves the Bcgar1 ortholog. In B. cinerea, however, BcGAR1 and BcGAR2 jointly contribute to the first step of the catabolic pathway, albeit to different extent. The virulence of all B. cinerea mutants in the D-galacturonic acid catabolic pathway on tomato leaves, apple fruit and bell peppers was unaltered. PMID- 21683150 TI - Phospholipid acylhydrolases trigger membrane degradation during fungal sporogenesis. AB - Armillaria ostoyae is a phytopathogen infecting coniferous trees. Fruiting bodies of this basidiomycete contain high phospholipase A(1) (PLA(1)) activity. In this paper, the role of phospholipid-deacylating activity, which was also detected in fruiting bodies of other basidiomycetes, in the fungal lipid metabolism is elucidated. For A. ostoyae the occurrence of PLA(1) activity is shown to be restricted to the late reproductive phase, correlating with the release of mature spores. Specific expression in the spore-producing tissue provides evidence for the involvement of PLA(1) in spore formation. Based on lipid analysis, the degradation of membrane phospholipids in this tissue can be ascribed mainly to PLA(1) activity because other enzymes such as phospholipases C and D, triglyceride lipase and phosphatidic acid phosphatase had only low activities. A concomitant increase in the concentration of fatty acids and their anabolites (di and triglycerides), which are used as storage lipids in the developing fungal spore cells, was observed. Therefore, PLA(1) contributes to the formation of spores by providing membrane constituents as a source of fatty acids. PMID- 21683151 TI - Molecular ontogenesis of digestive capability and associated endocrine control in Atlantic cod (Gadus morhua) larvae. AB - We have profiled the expression of twelve genes, in order to provide an overview on the molecular ontogeny of digestive capability with the associated endocrine control during Atlantic cod (Gadus morhua) larval development. Enzyme activity levels for the key digestive enzyme, trypsin, was also measured. Specifically, transcripts for trypsin, amylase, lipolytic enzymes: bile salt activated lipase (BAL), phospholipase A2 (PLA2) and Acyl CoA dehydrogenase (ACADM), regulatory peptides: neuropeptide Y (NPY), orexin (OX) cholecystokinin (CCK) and cocaine and amphetamine-related transcript (CART), the somatotropic factors: growth hormone (GH), preprosomatostatin 1 (PPSS1) and thyroid hormone receptors (TRalpha and TRbeta) were analyzed using quatitative (real-time) polymerase chain reaction (qPCR). Trypsin and BAL mRNA levels peaked at approximately day 17 and 25 post hatch, respectively, and thereafter displayed a decreasing pattern until metamorphosis. GH mRNA levels decreased moderately from 3 to 33dph, and thereafter, an increase was observed until 46dph. TRalpha mRNA levels showed a fluctuating pattern peaking at day 39 post-hatch. TRbeta mRNA levels were too low to obtain quantitative measurements. Amylase mRNA slightly increased from day 3 to 17 post-hatch, and thereafter showed a steady decrease until day 60. Interestingly, PLA2 mRNA expression showed a consistent increase throughout the study period, indicating an increasingly important role during larval development. Overall, data from this study indicate that cod larvae show differential developmental mode of expression patterns for key genes and endocrine factors that regulate digestive capability, growth and development. These data are discussed in relation to larval trypsin enzyme activity and previous reports for other teleost species. PMID- 21683152 TI - Reactive oxygen species participate in the p38-mediated apoptosis induced by potassium deprivation and staurosporine in cerebellar granule neurons. AB - Apoptosis induced by low potassium (K5) or staurosporine in cerebellar granule neurons triggers an increase in reactive oxygen species (ROS) levels. ROS inhibition by antioxidants or inhibitors of the NADPH oxidase (NOX) activity reduces the apoptosis induced by both stimuli. It has been reported that JNK mediates the apoptosis induced by K5 but not by staurosporine. No information is available about the role of other signaling pathways such as p38 in staurosporine induced apoptosis, and whether p38 activation could be related to ROS levels induced by both K5 and staurosporine. Here, we explored this possibility and found that K5 activates p38 and ATF2 and that the inhibition of p38 activity prevents the apoptosis induced by this treatment. We also found that p38 is downstream of ROS generation induced by K5. On the other hand, staurosporine promotes a sustained activation of p38. We found that p38 inhibition markedly decreases ROS generation, NOX activity and apoptosis induced by staurosporine. Furthermore, antioxidants inhibit p38 activation induced by staurosporine. These data indicate that apoptosis induced by both K5 and staurosporine is dependent on p38 activation, which is mediated by ROS. In addition, p38 activation by staurosporine induces a further production of ROS through NOX activation. PMID- 21683153 TI - Patches for improving gastrointestinal absorption: an overview. AB - The oral route is probably the preferred method for drug administration, owing to simplicity and positive safety aspects. Despite these advantages, this route of administration presents limitations relating to difficult absorption for some molecules, such as peptides, proteins and nucleic acids. Numerous approaches have been proposed to circumvent this drawback and improve the absorption of these active substances, but today, these approaches are often inefficient. Therefore, the use of patches for oral delivery was proposed, realized by using traditional techniques or microfabrication procedures. This review will focus on the rationale underlying the development of these dosage forms, critically discussing their performance and potential. PMID- 21683154 TI - Phytanic acid metabolism in health and disease. AB - Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid which cannot be beta-oxidized due to the presence of the first methyl group at the 3-position. Instead, phytanic acid undergoes alpha-oxidation to produce pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) plus CO(2). Pristanic acid is a 2-methyl branched-chain fatty acid which can undergo beta-oxidation via sequential cycles of beta-oxidation in peroxisomes and mitochondria. The mechanism of alpha-oxidation has been resolved in recent years as reviewed in this paper, although some of the individual enzymatic steps remain to be identified. Furthermore, much has been learned in recent years about the permeability properties of the peroxisomal membrane with important consequences for the alpha-oxidation process. Finally, we present new data on the omega oxidation of phytanic acid making use of a recently generated mouse model for Refsum disease in which the gene encoding phytanoyl-CoA 2-hydroxylase has been disrupted. PMID- 21683155 TI - Profiling of acylcarnitines and sterols from dried blood or plasma spot by atmospheric pressure thermal desorption chemical ionization (APTDCI) tandem mass spectrometry. AB - Free carnitine and acylcarnitines play an important role in the metabolism of fatty acids. Sterols are structural lipids found in the membranes of many eukaryotic cells, and they also have functional roles such as the regulation of membrane permeability and fluidity, activity of membrane-bound enzymes and signals transduction. Abnormal profiles of these compounds in biological fluids may be useful markers of metabolic changes. In this review, we describe the subset of the lipidome represented by acylcarnitines and sterols, and we summarize how these compounds have been analyzed in the past. Over the last 50years, lipid mass spectrometry (MS) has evolved to become one of the most useful techniques for metabolic analysis. Today, the introduction of new ambient ionization techniques coupled to MS (AMS), which are characterized by the direct desorbing/ionizing of molecules from solid samples, is generating new possibilities for in situ analysis. Recently, we developed an AMS approach called APTDCI to desorb/ionize using a heated gas flow and an electrical discharge to directly analyze sterols and indirectly investigate acylcarnitines in dried blood or plasma spot samples. Here, we also describe the APTDCI method and some of its clinical applications, and we underline the common complications and issues that remain to be resolved. PMID- 21683156 TI - Ezetimibe restores biliary cholesterol excretion in mice expressing Niemann-Pick C1-Like 1 only in liver. AB - Niemann-Pick C1-Like 1 (NPC1L1) is highly expressed in the small intestine across mammalian species and is the target of ezetimibe, a potent cholesterol absorption inhibitor. In humans, NPC1L1 is also expressed in the liver. We found that transgenic overexpression of NPC1L1 in the wild-type mouse liver inhibits biliary cholesterol secretion and raises blood cholesterol, which can be reversed by ezetimibe treatment. Unfortunately, the high expression of endogenous NPC1L1 in the intestine hampered a definitive establishment of the role of hepatic NPC1L1 in cholesterol metabolism and ezetimibe action in the liver because intestinal NPC1L1 dramatically influences cholesterol homeostasis and is a target of ezetimibe. To circumvent this obstacle, we crossed liver-specific NPC1L1 transgenic mice to NPC1L1 knockout (L1-KO) mice and created a mouse line expressing no endogenous NPC1L1, but human NPC1L1 in liver only (L1(LivOnly) mice). Compared to L1-KO mice, L1(LivOnly) mice on a 0.2% cholesterol diet showed significantly increased hepatic and plasma cholesterol, and despite a 90% reduction in biliary cholesterol excretion, their fecal cholesterol excretion remained completely unaltered. Remarkably, 4days of ezetimibe treatment significantly restored biliary cholesterol secretion in L1(LivOnly) mice. These findings demonstrated a direct role of hepatic NPC1L1 in regulating biliary cholesterol excretion and hepatic/blood cholesterol levels, and unequivocally established hepatic NPC1L1 as a target of ezetimibe. PMID- 21683158 TI - Type II interleukin-1 receptor expression is reduced in monocytes/macrophages and atherosclerotic lesions. AB - Type II interleukin-1 receptor (IL-1R2) is a non-signaling decoy receptor that negatively regulates the activity of interleukin-1 (IL-1), a pro-inflammatory cytokine involved in atherogenesis. In this article we assessed the relevance of IL-1R2 in atherosclerosis by studying its expression in monocytes from hyperlipidemic patients, in THP-1 macrophages exposed to lipoproteins and in human atherosclerotic lesions. Our results showed that the mRNA and protein expression of IL-1R2 was reduced in monocytes from patients with familial combined hyperlipidemia (-30%, p<0.05). THP-1 macrophages incubated with increasing concentrations of acetylated low density (ac-LDL) and very low density (VLDL) lipoproteins also exhibit a decrease in IL-1R2 mRNA and protein levels. Pre-incubation with agents that block intracellular accumulation of lipids prevents the decrease in IL-1R2 mRNA caused by lipoproteins. Lipoproteins also prevented the increase in IL-1R1 and IL-1R2 caused by a 4-h stimulation with LPS and reduced protein expression of total and phosphorylated IL-1 receptor associated kinase-1. Finally, IL-1R2 expression in human atherosclerotic vessels was markedly lower than in non-atherosclerotic arteries (-80%, p<0.0005). Overall, our results suggest that under atherogenic conditions, there is a decrease in IL-1R2 expression in monocytes/macrophages and in the vascular wall that may facilitate IL-1 signaling. PMID- 21683157 TI - Quantitative analysis of glycerophospholipids by LC-MS: acquisition, data handling, and interpretation. AB - As technology expands what it is possible to accurately measure, so too the challenges faced by modern mass spectrometry applications expand. A high level of accuracy in lipid quantitation across thousands of chemical species simultaneously is demanded. While relative changes in lipid amounts with varying conditions may provide initial insights or point to novel targets, there are many questions that require determination of lipid analyte absolute quantitation. Glycerophospholipids present a significant challenge in this regard, given the headgroup diversity, large number of possible acyl chain combinations, and vast range of ionization efficiency of species. Lipidomic output is being used more often not just for profiling of the masses of species, but also for highly targeted flux-based measurements which put additional burdens on the quantitation pipeline. These first two challenges bring into sharp focus the need for a robust lipidomics workflow including deisotoping, differentiation from background noise, use of multiple internal standards per lipid class, and the use of a scriptable environment in order to create maximum user flexibility and maintain metadata on the parameters of the data analysis as it occurs. As lipidomics technology develops and delivers more output on a larger number of analytes, so must the sophistication of statistical post-processing also continue to advance. High dimensional data analysis methods involving clustering, lipid pathway analysis, and false discovery rate limitation are becoming standard practices in a maturing field. PMID- 21683159 TI - Total pancreatectomy with autologous islet cell transplantation in children: making a difference. PMID- 21683161 TI - Education by a nurse increases response of patients with chronic hepatitis C to therapy with peginterferon-alpha2a and ribavirin. AB - BACKGROUND & AIMS: Education of patients with chronic hepatitis C has been proposed to increase response to therapy with peginterferon and ribavirin. We performed a prospective study to determine the effects of systematic consultation by a nurse on patient adherence and the efficacy of therapy. METHODS: We analyzed data from 244 patients who received either systematic consultation after each medical visit from a nurse who used a standard evaluation grid and provided information about the disease and treatment (group A [GrA], n = 123) or the conventional clinical follow-up procedure (group B [GrB], n = 121). Treatment lasted 24 to 48 weeks. RESULTS: Characteristics of each group were similar at baseline, including prior treatment (42.6% in GrA and 36.0% in GrB). Overall, GrA had significantly better adherence to treatment than GrB (74.0% vs 62.8%), especially among patients who received 48 weeks of treatment (69.7% vs 53.2%; P < .03). Significantly more patients in GrA had a sustained virologic response, compared with GrB overall (38.2% vs 24.8%; P < .02), as well as treatment-naive patients (47.1% vs 30.3%; P < .05), and those with genotypes 1, 4, or 5 infections (31.6% vs 13.3%; P < .007). There were no differences between GrA and GrB in response of patients with genotypes 2 or 3 infections or advanced fibrosis. Prognostic factors for a sustained virologic response (based on bivariate and multivariate analyses) were virologic response at week 12 (odds ratio [OR], 1.9; P < .0001), genotypes 2 or 3 (OR, 2.9; P < .0001), therapeutic education (OR, 2.5; P < .02), and lack of previous treatment (OR, 2.3; P < .005). CONCLUSIONS: Therapeutic education by a specialized nurse increases the response of patients with hepatitis C to therapy, particularly in difficult-to-treat patients. PMID- 21683160 TI - Quality of life improves for pediatric patients after total pancreatectomy and islet autotransplant for chronic pancreatitis. AB - BACKGROUND & AIMS: Total pancreatectomy (TP) and islet autotransplant (IAT) have been used to treat patients with painful chronic pancreatitis. Initial studies indicated that most patients experienced significant pain relief, but there were few validated measures of quality of life. We investigated whether health-related quality of life improved among pediatric patients undergoing TP/IAT. METHODS: Nineteen consecutive children (aged 5-18 years) undergoing TP/IAT from December 2006 to December 2009 at the University of Minnesota completed the Medical Outcomes Study 36-item Short Form (SF-36) health questionnaire before and after surgery. Insulin requirements were recorded. RESULTS: Before TP/IAT, patients had below average health-related quality of life, based on data from the Medical Outcomes Study SF-36; they had a mean physical component summary (PCS) score of 30 and mental component summary (MCS) score of 34 (2 and 1.5 standard deviations, respectively, below the mean for the US population). By 1 year after surgery, PCS and MCS scores improved to 50 and 46, respectively (global effect, PCS P < .001, MCS P = .06). Mean scores improved for all 8 component subscales. More than 60% of IAT recipients were insulin independent or required minimal insulin. Patients with prior surgical drainage procedures (Puestow) had lower yields of islets (P = .01) and greater incidence of insulin dependence (P = .04). CONCLUSIONS: Quality of life (physical and emotional components) significantly improve after TP/IAT in subsets of pediatric patients with severe chronic pancreatitis. Minimal or no insulin was required for most patients, although islet yield was reduced in patients with previous surgical drainage operations. PMID- 21683162 TI - Nonalcoholic fatty liver disease: what are the odds your patient will get a transplant? PMID- 21683163 TI - Intestinal obstruction as manifestation of a multifocal colonic endometriosis. PMID- 21683164 TI - Symptoms, stones, and surgery: predicting pain relief after cholecystectomy for gallstones. PMID- 21683165 TI - Impact of homoplasy on variable numbers of tandem repeats and spoligotypes in Mycobacterium tuberculosis. AB - Homoplasy is the occurrence of genotypes that are identical by state but not by descent. It arises through a number of means including convergent and reverse evolution, and horizontal gene transfer. When using molecular markers that are based on sequences possessing a finite number of character states, such as VNTR or spoligotypes, this is an unavoidable phenomenon. Here we discuss the extent of homoplasy and its impact on inferences drawn from spoligotypes and VNTR in epidemiological studies of tuberculosis. To further explore this problem, we developed a computer simulation model combining the processes of mutation and transmission. Our results show that while the extent of homoplasy is not negligible, its effect on the proportion of isolates clustered ("n-1 method") is likely to be relatively low for spoligotyping. For VNTR-typing, homoplasy occurs at a low rate provided the number of loci used is high and the mutation rate is relatively high. However, deep phylogenetic inferences using spoligotypes or VNTRs with a small number of loci are likely to be unreliable. PMID- 21683166 TI - The effect of nano-silver on the activation of nasal polyp epithelial cells by Alternaria, Der P1 and staphylococcal enterotoxin B. AB - Nano-silver is used for its anti-bacterial, anti-viral and anti-fungal properties. The aim of this study was to investigate the potential clinical efficacy of nano-silver for its anti-inflammatory effect on respiratory epithelial cell inflammation. Primary nasal polyp epithelial cells (NPECs) were exposed to Alternaria alternata, Der P1, and staphylococcal enterotoxin B for 48 h with or without various concentration of nano-silver, then the supernatants were collected. Cell cytotoxicities were measured using a CellTiter-96(r) aqueous cell proliferation assay kit. The interleukin (IL)-6, IL-8 and granulocyte macrophage colony stimulating factor were measured to evaluate the inflammatory effects on the epithelial cells. Nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) were analyzed using western blot and ELISA method. Cell survival was found to be significantly decreased at nano-silver concentrations exceeding 10 ppm. Alternaria, Der P1 and SEB activated NPECs with increased cytokine production. Alternaria induced NPECs not inhibited by nano-silver. However, Der P1 and SEB induced cytokine production was significantly affected by concentrations over 1 ppm. Alternaria, Der P1 and SEB enhanced nuclear NF-kappaB expression and nano-silver inhibited NF-kappaB expression in SEB and Der P1 treated group. Although nano-silver is cytotoxic at higher concentrations, at safe concentrations it can inhibit the activation of NPECs. This finding suggests a novel pharmacological rationale for the treatment of airway inflammation and/or immunological disease. PMID- 21683167 TI - Unraveling the structural and functional differences between purine nucleoside phosphorylase and 5'-deoxy-5'-methylthioadenosine phosphorylase from the archaeon Pyrococcus furiosus. AB - Purine nucleoside metabolism in the archaeon Pyrococcus furiosus is catalyzed by purine nucleoside phosphorylase (PfPNP) and 5'-deoxy-5'-methylthioadenosine phosphorylase (PfMTAP). These enzymes, characterized by 50% amino acid sequence identity, show non-common features of thermophilicity and thermostability and are stabilized by intramolecular disulfide bonds. PfPNP is highly specific for 6 oxopurine nucleosides while PfMTAP is characterized by a broad substrate specificity with 6-aminopurine nucleosides as preferred substrates. Amino acid sequence comparison clearly shows that the hypothetical active sites of PfPNP and PfMTAP are almost identical and that, in analogy with human 5'-deoxy-5' methylthioadenosine phosphorylase and human purine nucleoside phosphorylase, residue changes at level of the same crucial positions could be responsible for the switch of substrate specificity. To validate this hypothesis we changed the putative active site of PfPNP by site-directed mutagenesis. Substrate specificity and catalytic efficiency of PfPNP mutants were then analyzed by kinetic studies and compared with the wild-type enzyme. We carried out the molecular modeling of PfPNP and PfMTAP to obtain a picture of the overall enzyme structure and to identify structural features as well as interactions playing critical roles in thermostability. Finally, we utilized the structural models of mutant enzyme substrate complex to rationalize the functional effects of the mutations. PMID- 21683168 TI - Intercellular communication via the endo-lysosomal system: translocation of granzymes through membrane barriers. AB - Cytotoxic lymphocytes (CLs) are responsible for the clearance of virally infected or neoplastic cells. CLs possess specialised lysosome-related organelles called granules which contain the granzyme family of serine proteases and perforin. Granzymes may induce apoptosis in the target cell when delivered by the pore forming protein, perforin. Here we follow the perforin-granzyme pathway from synthesis and storage in the granule, to exocytosis and finally delivery into the target cell. This review focuses on the controversial subject of perforin mediated translocation of granzymes into the target cell cytoplasm. It remains unclear whether this occurs at the cell surface with granzymes moving through a perforin pore in the plasma membrane, or if it involves internalisation of perforin and granzymes and subsequent release from an endocytic compartment. The latter mechanism would represent an example of cross talk between the endo lysosomal pathways of individual cells. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome. PMID- 21683170 TI - Roles of avian herpesvirus microRNAs in infection, latency, and oncogenesis. AB - MicroRNAs have been reported for the avian herpesviruses Marek's disease virus 1 (MDV1; oncogenic), Marek's disease virus 2 (MDV2; non-oncogenic), herpesvirus of turkeys (HVT), and infectious laryngotracheitis virus (ILTV). No obvious phylogenetic relationships exist among the avian herpesvirus microRNAs, but the general genomic locations of microRNA clusters are conserved, with microRNAs being located in the repeat regions of the genomes. In some cases, microRNAs are antisense to open reading frames. Among MDV1 field isolates with different virulence properties, microRNAs are highly conserved, and variations that have been observed lie in putative promoter regions. One cluster of MDV1 microRNAs lies upstream of the meq gene, and this cluster is more highly expressed in tumors caused by an extremely virulent MDV1 isolate compared to tumors caused by a less virulent isolate. Several of the avian herpesvirus microRNAs are orthologs of microRNAs in other species. For example, mdv1-miR-M4 shares a seed sequence with gga-miR-155 (also shared with Kaposi sarcoma herpesvirus (KSHV) kshv-miR K12), mdv2-miR-M21 shares a seed with miR-29b, and hvt-miR-H14 shares a seed sequence with miR-221. Functional analyses of avian herpesvirus microRNAs include a variety of in vitro assays to demonstrate potential function as well as the use of mutants that can exploit the ability to assess phenotypes experimentally in the natural host. This article is part of a Special Issue entitled:MicroRNA's in viral gene regulation. PMID- 21683171 TI - From the third month of pregnancy to 1 year postpartum. Prevalence, incidence, recurrence, and new onset of depression. Results from the perinatal depression research & screening unit study. AB - OBJECTIVE: Perinatal depression is a particular challenge to clinicians, and its prevalence estimates are difficult to compare across studies. Furthermore, to our knowledge, there are no studies that systematically assessed the incidence of perinatal depression. The aim of this study is to estimate the prevalence, incidence, recurrence, and new onset of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, minor and major depression (mMD) in an unselected population of women recruited at the third month of pregnancy and followed up until the 12th month postpartum. METHOD: One thousand sixty-six pregnant women were recruited. Minor and major depression was assessed in a naturalistic, longitudinal study. The Edinburgh Postnatal Depression Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Disorders were administered at different time points during pregnancy and in the postpartum period. RESULTS: The period prevalence of mMD was 12.4% in pregnancy and 9.6% in the postpartum period. The cumulative incidence of mMD in pregnancy and in the postpartum period was 2.2% and 6.8%, respectively. Thirty-two (7.3%) women had their first episode in the perinatal period: 1.6% had a new onset of depression during pregnancy, 5.7% in the postpartum period. CONCLUSIONS: Our postpartum prevalence figures, which are lower than those reported in the literature, may reflect treatment during the study, suggesting that casting a multiprofessional network around women in need of support may be potentially useful for reducing the effects of this disorder on the mother and the newborn child. Furthermore, our results indicate that women with a history of depression have a 2-fold risk of developing mMD in the perinatal period. PMID- 21683169 TI - Proteases as regulators of pathogenesis: examples from the Apicomplexa. AB - The diverse functional roles that proteases play in basic biological processes make them essential for virtually all organisms. Not surprisingly, proteolysis is also a critical process required for many aspects of pathogenesis. In particular, obligate intracellular parasites must precisely coordinate proteolytic events during their highly regulated life cycle inside multiple host cell environments. Advances in chemical, proteomic and genetic tools that can be applied to parasite biology have led to an increased understanding of the complex events centrally regulated by proteases. In this review, we outline recent advances in our knowledge of specific proteolytic enzymes in two medically relevant apicomplexan parasites: Plasmodium falciparum and Toxoplasma gondii. Efforts over the last decade have begun to provide a map of key proteotolyic events that are essential for both parasite survival and propagation inside host cells. These advances in our molecular understanding of proteolytic events involved in parasite pathogenesis provide a foundation for the validation of new networks and enzyme targets that could be exploited for therapeutic purposes. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome. PMID- 21683172 TI - Suicide attempts in anorexia nervosa subtypes. AB - OBJECTIVE: The risk for suicide attempts is elevated in anorexia nervosa (AN), yet we know little about the relation between suicide and personality in this group. We explored the prevalence of lifetime suicide attempts in women with AN and compared those who had and had not attempted suicide on eating disorder symptoms, general psychopathology, and personality both relative to a healthy control group and then across AN subtypes. METHOD: One hundred four outpatients with restricting AN, 68 outpatients with purging AN, and 146 comparison individuals participated in the study. RESULTS: The prevalence of suicide attempts differed significantly across the 3 groups (P = .003), with 0% in the controls, 8.65% in the restricting AN group, and 25.0% in the purging AN group. Depression measures were elevated in those with suicide attempts. Within the restricting AN group, those who attempted suicide scored significantly higher on Phobic Anxiety, measured by means of the Symptom Checklist-Revised, than those who did not (P = .001). CONCLUSION: The presence of purging and depressive symptoms in individuals with AN should increase vigilance for suicidality; and among restrictors, greater anxiety may index greater suicide risk. PMID- 21683174 TI - Comorbidities and factors related to discontinuation of pharmacotherapy among outpatients with major depressive disorder. AB - OBJECTIVE: Although many studies have researched adherence to pharmacotherapy among patients with major depressive disorder (MDD), the effects of chronic depression, anxiety comorbidities, migraine, and other factors on adherence have rarely been studied. This study investigated which comorbidities and factors independently predicted discontinuation of pharmacotherapy among psychiatric outpatients with MDD. METHODS: One hundred thirty-five subjects (34 men, 101 women) with MDD were enrolled. MDD and anxiety comorbidities were diagnosed using the Structured Clinical Interview for DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision), migraine was diagnosed based on the International Classification of Headache Disorders, 2nd Edition, and depression severity was evaluated using the Hamilton Depression Rating Scale. Six months later, subjects' reasons for discontinuation were investigated, and Cox proportional hazards regression and logistic regression were used to investigate the independent factors predicting discontinuation. RESULTS: Subjects with chronic depression, migraine, panic/agoraphobia, or posttraumatic stress disorder attended follow-up for longer before discontinuation than those without. Chronic depression and greater age independently predicted a longer follow-up before discontinuation. Concern about and intolerance of the side effects of antidepressants and lack of insight into MDD independently predicted discontinuation within 2 months. "Self-reported recovery" was the most common reason for discontinuation; however, 53.8% of the subjects who cited this reason did not reach full remission. CONCLUSIONS: The impact of the duration of depression (chronic depression) on adherence may be more important than the severity of depression, anxiety comorbidities, and migraine. Education of MDD patients and society in general to improve understanding of MDD and antidepressants is needed to enhance adherence to pharmacotherapy. PMID- 21683173 TI - Parent-reported mental health in preschoolers: findings using a diagnostic interview. AB - Previous research suggests that many preschoolers meet criteria for psychiatric diagnoses; still, relatively little is known about preschool mental health, particularly emotional problems, in the community. This study investigated the rates of parent-reported DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) disorders in a large community sample of preschoolers using the Preschool Age Psychiatric Assessment (PAPA). Five hundred forty-one parents were interviewed with the PAPA. Of the children, 27.4% met criteria for a PAPA/DSM-IV diagnosis; 9.2% met criteria for 2 or more diagnoses. Oppositional defiant disorder (ODD) (9.4%), specific phobia (9.1%), and separation anxiety disorder (5.4%) were the most common diagnoses; depression (1.8%), selective mutism (1.5%), and panic disorder (0.2%) were the least common. In addition, there was significant comorbidity/covariation between depression, anxiety, and ODD and between ODD and attention-deficit/hyperactivity disorder (odds ratios = 1.81-18.44; P < .05), and significant associations with measures of psychosocial functioning. The stability and clinical significance of diagnoses and patterns of comorbidity must be elucidated in future research. PMID- 21683175 TI - Impulse control disorder comorbidity among patients with bipolar I disorder. AB - OBJECTIVE: Impulsivity is associated with mood instability, behavioral problems, and action without planning in patients with bipolar disorder. Increased impulsivity levels are reported at all types of mood episodes. This association suggests a high comorbidity between impulse control disorders (ICDs) and bipolar disorder. The aim of this study is to compare the prevalence of ICDs and associated clinical and sociodemographic variables in euthymic bipolar I patients. METHOD: A total of 124 consecutive bipolar I patients who were recruited from regular attendees from the outpatient clinic of our Bipolar Disorder Unit were included in the study. All patients were symptomatically in remission. Diagnosis of bipolar disorder was confirmed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Impulse control disorders were investigated using the modified version of the Minnesota Impulsive Disorders Interview. Impulsivity was measured with the Barratt Impulsiveness Scale Version 11. Furthermore, all patients completed the Zuckerman Sensation-Seeking Scale Form V. RESULTS: The prevalence rate of all comorbid ICDs in our sample was 27.4% (n = 34). The most common ICD subtype was pathologic skin picking, followed by compulsive buying, intermittent explosive disorder, and trichotillomania. There were no instances of pyromania or compulsive sexual behavior. There was no statistically significant difference between the sociodemographic characteristics of bipolar patients with and without ICDs with regard to age, sex, education level, or marital status. Comorbidity of alcohol/substance abuse and number of suicide attempts were higher in the ICD(+) group than the ICD(-) group. Length of time between mood episodes was higher in the ICD(-) group than the ICD(+) group. There was a statistically significant difference between the total number of mood episodes between the 2 groups, but the number of depressive episodes was higher in the ICD(+) patients as compared with the ICD(-) patients. There was no statistically significant difference between the age of first episode, seasonality, presence of psychotic features, and chronicity of illness. A statistically significant difference was observed between the ICD(+) and ICD(-) groups in terms of total impulsivity, attention, nonplanning, and motor impulsivity scores as determined by the Barratt Impulsiveness Scale Version 11. CONCLUSION: The present study revealed that there is a high comorbidity rate between bipolar disorder and ICDs based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria. Alcohol/substance use disorders, a high number of previous suicide attempts, and depressive episodes should alert the physician to the presence of comorbid ICDs among bipolar patients that could affect the course and treatment of the disorder. PMID- 21683176 TI - Medical students as patients: implications of their dual role as explored in a vignette-based survey study of 1027 medical students at nine medical schools. AB - OBJECTIVE: Medical students experience a range of mental and physical illnesses during training and may encounter significant barriers in seeking health care. Little is known about the issues surrounding the dual role as both learner and patient when a medical student seeks care at his or her training institution. METHOD: A confidential survey examining medical students' health care needs, practices, and concerns was administered at 9 US medical schools. One part of the survey focused on responses to 4 medical student-patient vignettes. The vignettes systematically varied preexisting student vs preexisting patient status before assuming a medical student-patient role, and the vignettes also varied illness situations that were more vs less stigmatizing. Responses were analyzed using chi(2) and multivariate analysis of variance tests. RESULTS: A total of 1027 students participated. We found that students were more likely to accept the dual role as medical student-patient in vignettes depicting a preexisting patient role than a preexisting student role. Students sought to avoid the dual role as student-patient in the context of stigmatizing health concerns. Women students were more likely than men to reject the dual role in all cases. CONCLUSION: Medical students appear to be sensitive to the conflicts that may be associated with the dual role as both medical student and patient when seeking care at their training institution. Our data suggest the importance of substantive efforts to promote the health, interests, and well-being of medical student-patients. PMID- 21683177 TI - Depersonalization and personality in panic disorder. AB - BACKGROUND: Prevalence and clinical correlates of depersonalization symptoms have been associated with panic disorder. Personality traits might increase the likelihood of experiencing depersonalization symptoms or depersonalization disorder in panic patients. AIMS: The objectives of this study are to establish the prevalence of depersonalization symptoms during the panic attack and in depersonalization disorder and to examine the personality factors associated with the presence of depersonalization in patients with panic disorder. METHODS: The sample comprised 104 consecutive adult outpatients with panic disorder, diagnosed according to the Semistructured Clinical Interview for DSM-IV (Axis I/II disorders). Participants were assessed with the Cambridge Depersonalization Scales, the Temperament and Character Inventory, and the Panic and Agoraphobia Scale. RESULTS: Forty-eight percent of the sample had depersonalization symptoms during the panic attack, whereas 20% of patients had a depersonalization disorder. Women presented more depersonalization disorders than did men (P = .036). Patients with panic disorder with depersonalization disorder had a more severe panic disorder (P = .002). Logistic regression analysis showed that self transcendence trait (odds ratio, 1.089; 95% confidence interval, 1.021-1.162; P = .010) and severity of panic (odds ratio, 1.056; 95% confidence interval, 1.005 1.110; P = .032) were independently associated with depersonalization disorder. CONCLUSIONS: A high prevalence of depersonalization symptoms and depersonalization disorder was confirmed in patients with panic disorder, supporting a dosage effect model for understanding depersonalization pathology. Self-transcendence trait and severity of panic disorder were reported as risk factors for depersonalization disorder. PMID- 21683178 TI - Depression, materialism, and excessive Internet use in relation to compulsive buying. AB - OBJECTIVE: The objective of the study was to examine the relationship between compulsive buying (CB), depression, materialism, and excessive Internet use. METHODS: An online survey of 387 consumers was conducted including questions about demographics and shopping venues, the Compulsive Buying Scale, the Patient Health Questionnaire Depression Scale, the Materialistic Values Scale, and questions concerning excessive Internet use. RESULTS: Seventeen percent of the participants reported Compulsive Buying Scale scores less than -1.34 and were considered to be having CB. Participants with CB did not significantly differ from those without CB regarding age, sex, marital status, annual household income, and shopping preferences. Individuals with CB reported more depressive symptoms, higher materialistic values endorsement, and more severe excessive Internet use compared with those without CB. Results of a stepwise logistic regression analysis with CB as the dependent variable showed that materialism and depression were associated with CB, whereas excessive Internet use was not. CONCLUSIONS: Materialism and depression jointly influence CB. Further research is needed to examine the influence of materialism on CB in a clinical sample consisting of patients with diagnosed CB. PMID- 21683179 TI - Temperament, character, and quality of life in patients with schizophrenia and their first-degree relatives. AB - The aim of this study was to investigate the associations between the temperament, character dimensions, and quality of life (QOL) of patients with schizophrenia; their first-degree, nonaffected relatives; and healthy control subjects. One hundred twenty patients, the same number of first-degree relatives, and the same number of control subjects were assessed using the Temperament and Character Inventory and the Quality of Life Enjoyment and Satisfaction Questionnaire. Patients were also assessed using the Positive and Negative Syndrome Scale. Patients and relatives had a significantly lower QOL than control subjects, controlled for temperament and character dimensions. Patients scored significantly higher than control subjects in harm avoidance and self transcendence and lower in novelty seeking and self-directedness. First-degree relatives had lower results for novelty seeking and scored higher on self transcendence than control subjects. Harm avoidance, self-directedness, and self transcendence were the dimensions of Temperament and Character Inventory shown to be the most significant predictors of QOL. Psychopathology and age were also significant predictors of QOL. Our understanding of an individual patient's QOL must include personality evaluation. PMID- 21683180 TI - Posttraumatic stress disorder among survivors of the Wenchuan earthquake 1 year after: prevalence and risk factors. AB - Exposure to earthquakes has been associated with psychological distress in particular, the development of posttraumatic stress disorder (PTSD). The aims of this study are to estimate the prevalence of PTSD, explore the associated risk factors among survivors 1 year after the Wenchuan earthquake in China, and compare the findings in our study to other disasters. Cross-sectional sample survey was conducted to collect data in severely affected counties. We use the PTSD Check List-Civilian Version, which consists of 17 items corresponding to each symptom in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition PTSD criteria B, C, and D. The prevalence estimates of probable PTSD in our sample ranged from 21.5% (based on Check List-Civilian Version score of 50 or higher) to 40.1% (based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria). The prevalence of PTSD was high, compared with rates of PTSD in previous studies. Low social support, feeling fear during the earthquake, female, young people, Han nationality, low monthly income, and low educational level were risk factors significantly related to the development of PTSD. Postdisaster mental health recovery interventions including early identification, ongoing monitoring, and sustained psychosocial support are required for the high risk population with PTSD. Existing rural and urban health care services should be convenient for people, and special measures need to be designed, such as home visits and mobile clinics. PMID- 21683182 TI - Cross-cultural validity of the I7 impulsiveness-venturesomeness-empathy scales: evidence from the Italian I7. AB - The cross-cultural generalizability of Impulsiveness-Venturesomeness-Empathy questionnaire (I(7)) is investigated with a sample of 578 Italian adults, mostly nonstudents. Results indicate that Italian I(7) scale intercorrelations and reliabilities were similar to those obtained in other cultural contexts; furthermore, the 3-factor structure is generalizable across sexes and invariant compared with the English normative structure, as well as with those found in the French, Dutch, and Spanish versions. Impulsiveness was positively correlated with Barratt Impulsiveness Scale and with Dickman's dysfunctional impulsivity scale but independent of the functional impulsivity scale. Plotting the scale onto the Eysenck's psychoticism-extraversion-neuroticism factor space, impulsiveness was more strongly related to psychoticism and neuroticism than to extraversion. We remark that the impulsiveness measure of I(7) is fairly stable across languages and cultures and can be used reliably in Italian speaking samples. PMID- 21683183 TI - Gastric dissociation for the treatment of congenital microgastria with paraesophageal hiatal hernia. AB - Microgastria is a rare but well-described congenital anomaly of the alimentary tract that presents in the neonatal period with vomiting, aspiration, and failure to thrive. Based on a relatively small number of case reports, gastric augmentation with a double-barrel loop of jejunum, known as a Hunt-Lawrence pouch, has been advocated as the reconstructive procedure of choice in affected children who fail nonoperative management. In this report, we present a novel method of foregut reconstruction in an infant with congenital microgastria and a paraesophageal hiatal hernia. In this procedure, the stomach was transected 1 cm below the gastroesophageal junction with construction of a straight Roux-en-Y jejunal anastomosis to the gastric fundic cuff. A feeding gastrostomy tube was placed into the distal remnant stomach for enteral access. The patient did well and eventually transitioned to full oral feeds by 3 years of age. PMID- 21683181 TI - The differential effects of child abuse and posttraumatic stress disorder on schizotypal personality disorder. AB - OBJECTIVE: Previous findings suggest a relation between trauma exposure and risk for schizotypal personality disorder (SPD). However, the reasons for this relationship are not well understood. Some research suggests that exposure to trauma, particularly early trauma and child abuse, as well as posttraumatic stress disorder (PTSD) may play a role. METHODS: We examined subjects (n = 541) recruited from the primary care clinics of an urban public hospital as part of an National Institute of Mental Health-funded study of trauma-related risk and resilience. We evaluated childhood abuse with the Childhood Trauma Questionnaire and the Early Trauma Inventory and SPD with the Schedule for Nonadaptive and Adaptive Personality. We assessed for lifetime PTSD using the Clinician Administered PTSD Scale. RESULTS: We found that of the 3 forms of abuse analyzed (emotional, physical, and sexual), only emotional abuse significantly predicted SPD (P < .001, R = 0.28) when all 3 abuse types were simultaneously entered into a regression model. Lifetime PTSD symptoms also significantly predicted SPD (P < .001, R = 0.26). Posttraumatic stress disorder was specifically predictive of 4 of the 8 SPD symptoms (P <= .001): excessive social anxiety, a lack of close friends or confidants, unusual perceptual experiences, and eccentric behavior or appearance. Using a Sobel test, we also found a partial mediation effect of PTSD on the relation between emotional abuse and SPD (z = 3.45, P < .001). CONCLUSIONS: These findings point to the important influence of emotional abuse on SPD and suggest that PTSD symptoms may provide a link between damaging childhood experiences and SPD symptoms in traumatized adults. PMID- 21683184 TI - Gastric antrum hypertrophy causing outlet obstruction in an infant with congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia (CDH) is associated with multiple congenital anomalies affecting several organ systems, including the gastrointestinal system. Pyloric stenosis and bands are known and previously reported etiologies of gastric outlet obstruction in infants with CDH. We report the first case of gastric antrum hypertrophy causing gastric outlet obstruction in an infant with CDH. PMID- 21683185 TI - Cervical cystic swelling in an adolescent: unusual association of a cervical mature teratoma with vertebral anomalies and a history of gastric duplication cyst. AB - A 14-year-old girl presented with a cervical cystic swelling in association with deformity of cervical vertebrae. As a child, she had been treated for gastric duplication. Pathologic examination of the resected cervical swelling revealed a mature teratoma. We discuss possible embryologic associations, which could explain the unusual combination of a mature teratoma with vertebral anomalies and gastric duplication. PMID- 21683186 TI - Balloon-occluded retrograde transvenous obliteration for a portosystemic shunt after pediatric living-donor liver transplantation. AB - Portosystemic shunts may cause steal phenomenon after liver transplantation, which can lead to graft loss without proper management. Portal vein stenosis is one of the causes for the occurrence of portosystemic shunts after liver transplantation. Recently, new interventional radiologic techniques have been developed in the field of liver transplantation. Balloon-occluded retrograde transvenous obliteration (B-RTO) is a novel interventional technique for gastric varices and portosystemic shunts and also is effective for increasing portal vein flow. We herein report a pediatric case of portal vein stenosis with a large shunt successfully treated with a combination of balloon dilatation and B-RTO. If enlarged collateral vessels cause steal phenomenon, then B-RTO should be considered as an additional therapy. PMID- 21683187 TI - Giant cecal diverticulum in a child. AB - A 12-year-old girl with abdominal pain and fever underwent urgent surgery. As was suspected on computed tomographic scan, a large diverticular mass adherent to the cecum was identified. A diverticulectomy was performed. We report this rare case of a giant cecal diverticulum and provide an overview of known literature. PMID- 21683188 TI - Management of a hypoplastic lower urinary tract: a case report. AB - This case relates to a child with an antenatal diagnosis of severe bilateral hydronephrosis with congenital anomalies of the ureters, bladder, and urethra. We describe the presentation and surgical management, highlighting the complexity of this anomaly and the surgical technique used to reconstruct the lower urinary tract. To our knowledge, there has not been a similar case in the literature and the use of a segment of colon for ureteric substitution in children has not been previously reported in the literature. PMID- 21683189 TI - Papillary renal cell carcinoma: report of a rare entity in childhood with review of the clinical management. AB - We present the case of a 9-year-old boy who presents with gross hematuria and is subsequently diagnosed with a papillary (type 1) renal cell carcinoma. Management of renal cell carcinoma in the pediatric population represents a unique challenge, owing to the potential for a genetic predisposition and screening. Herein we discuss novel discoveries with respect to pediatric renal cell carcinoma and their potential impact on screening. PMID- 21683190 TI - Robotic lateral pancreaticojejunostomy (Puestow). AB - A lateral pancreaticojejunostomy (LPJ), also known as the Puestow procedure, is a complex procedure performed for chronic pancreatitis when the pancreatic duct is dilated and unable to drain properly. Traditionally, these procedures are performed with open surgery. A minimally invasive approach to the LPJ using rigid handheld nonarticulating instruments is tedious and rarely performed. In fact, there are no prior laparoscopic case reports for LPJ in children and only a small handful of cases in the adult literature. This lack of laparoscopic information may be an indication of the difficulty in performing this complex operation with nonarticulating laparoscopic instruments. The advantages of robotic surgery may help overcome these difficulties. We present the first robotic LPJ ever reported in a 14-year-old child with idiopathic chronic pancreatitis. This case demonstrates the utility of this advanced surgical technology and may lead to a new minimally invasive option for both adults and children with chronic pancreatitis requiring surgical intervention. PMID- 21683191 TI - Sequestrated tubular duplications of small bowel. AB - Duplications of bowel are well-known gastrointestinal tract anomalies. However, sequestrated duplications are very uncommon. Two sequestrated tubular duplications of the small bowel, separate from the ileum with autonomous blood supply and classic histologic features of small bowel are presented. Two sequestrated duplications in the same child are quite rare and have not been previously reported. PMID- 21683192 TI - Altered intestinal microcirculation is the critical event in the development of necrotizing enterocolitis. AB - PURPOSE: The pathophysiology of necrotizing enterocolitis (NEC) includes prematurity, enteral feeds, hypoxia, and hypothermia. We hypothesized that vasoconstriction of the neonatal intestinal microvasculature is the essential mechanistic event in NEC and that these microvascular changes correlate with alterations in mediators of inflammation. METHODS: Sprague-Dawley rat pups were separated into groups by litter. Necrotizing enterocolitis was induced in experimental groups, whereas control animals were delivered vaginally and dam fed. Neonatal pups underwent intravital videomicroscopy of the terminal ileum with particular attention to the inflow and premucosal arterioles. Reverse transcriptase-polymerase chain reaction was performed to evaluate for messenger RNA of mediators of inflammation. RESULTS: Necrotizing enterocolitis animals demonstrated statistically significant smaller inflow and premucosal arterioles than control animals (P < .05). Necrotizing enterocolitis animals had an altered intestinal arteriolar flow with a distinct "stop-and-go" pattern, suggesting severe vascular dysfunction. Reverse transcriptase-polymerase chain reaction confirmed elevation of Toll-like receptor 4 (P = .01) and high-mobility group box protein 1 (P = .001) in the ileum of animals with NEC. CONCLUSION: Intestinal arterioles were significantly smaller at baseline in animals with NEC compared with controls, and expression of inflammatory mediators was increased in animals with NEC. This represents a novel method of defining the pathophysiology of NEC and allows real-time evaluation of novel vasoactive strategies to treat NEC. PMID- 21683193 TI - Bacterial DNA content in the intestinal wall from infants with necrotizing enterocolitis. AB - PURPOSE: The objective of our study was to quantify mucosal bacterial DNA within specimens from neonates undergoing small bowel resection for necrotizing enterocolitis (NEC). METHODS: We obtained clinical information and pathologic specimens from all infants diagnosed with NEC who underwent surgical treatment at our institution from 1999 to 2008. Bacterial and human DNA were isolated from paraffin-embedded surgical specimens, and real time polymerase chain reaction was used to amplify bacterial and human genes. Linear regression was used to quantify the amount of human and bacterial DNA in our specimens. RESULTS: From a cohort of 50 infants, we identified 23 infants who underwent both surgical resection and subsequent intestinal reanastomosis. Thirteen (59%) of the neonates had Bell stage III NEC, and 9 (41%) had stage II. There was significantly more bacterial DNA in the resection specimens than in the reanastomosis specimens. This corresponds to a median (interquartile range) increase of 1.81 (1.11-4.69)-fold bacterial DNA in the resection specimen compared with the reanastomosis specimen (P < .05). CONCLUSION: There is more bacterial DNA in infants with acute NEC compared with the same infants after the NEC had clinically resolved. These findings underscore the potential relevance of adherent or invasive bacteria across the bowel wall in the pathogenesis of NEC. PMID- 21683194 TI - Near-infrared spectroscopy measurement of abdominal tissue oxygenation is a useful indicator of intestinal blood flow and necrotizing enterocolitis in premature piglets. AB - PURPOSE: A major objective of necrotizing enterocolitis (NEC) research is to devise a noninvasive method of early detection. We hypothesized that abdominal near-infrared spectroscopy (A-NIRS) readings will identify impending NEC in a large animal model. METHODS: Piglets were prematurely delivered and received parenteral nutrition followed by enteral feedings. Serial A-NIRS readings were obtained for 5 days, and animals were monitored for NEC. Separately, A-NIRS readings were obtained in healthy piglets to validate the correlation of A-NIRS with splanchnic oxygen delivery. RESULTS: Of 29 piglets, 3 developed NEC. Eleven piglets without NEC died prematurely. Fifteen piglets remained healthy, had normal histologic assessment of their intestines, and served as controls. Abdominal near-infrared spectroscopy readings within 12 hours of birth were significantly lower in animals that developed NEC compared with healthy littermates (4% vs 33%, P = .02). For all time-points measured, A-NIRS readings were significantly lower in the NEC group compared with controls (21% vs 55%, P < .001). Abdominal near-infrared spectroscopy readings correlated with both decreased pulse oximetry readings during apneic episodes (r = 0.96) and increased superior mesenteric artery flow in response to glucagon-like peptide 2 (r = 0.67). CONCLUSION: Abdominal near-infrared spectroscopy is capable of detecting alterations in intestinal oxygenation and perfusion in neonatal piglets and may allow early detection of neonates at risk for NEC. PMID- 21683195 TI - Outcomes of diverting jejunostomy for severe necrotizing enterocolitis. AB - BACKGROUND/PURPOSE: A diverting jejunostomy without bowel resection is an option for surgical management of extensive necrotizing enterocolitis (NEC). We aimed to determine outcomes of infants who underwent this operation. METHODS: We collected clinical and outcome data on infants undergoing a diverting jejunostomy with no bowel resection as a primary procedure for extensive NEC. Data are median (range). RESULTS: Seventeen neonates underwent a diverting jejunostomy. Eleven (65%) had multifocal disease, whereas 6 (35%) had pan-intestinal involvement. Perforation was seen in 7 (41%), all with multifocal disease. The stoma was placed 12 cm (8-45) from the duodenojejunal flexure. Six infants (35%) died, 4 of these within a day of operation, owing to persisting instability. Intestinal continuity was achieved in all survivors after 52 (17-83) days, and only 1 infant (9%) had a colonic stricture. Seven infants recovered without the need for further intestinal resection distal to the jejunostomy. In those that survived, parenteral nutrition was needed for 2.2 months (1.3-18.0). A single patient had short bowel syndrome. CONCLUSIONS: A diverting jejunostomy is a useful surgical procedure that allows high survival and enteral autonomy in the treatment of extensive NEC. In most patients, the affected intestine recovers without further intestinal resection. PMID- 21683196 TI - Intestinal adaptation after small bowel resection in human infants. AB - PURPOSE: In animal models, the small intestine responds to massive small bowel resection (SBR) through a compensatory process termed adaptation, characterized by increases in both villus height and crypt depth. This study seeks to determine whether similar morphologic alterations occur in humans after SBR. METHODS: Clinical data and pathologic specimens of infants who had both an SBR for necrotizing enterocolitis and an ostomy takedown from 1999 to 2009 were reviewed. Small intestine mucosal morphology was compared in the same patients at the time of SBR and at the time of ostomy takedown. RESULTS: For all samples, there was greater villus height (453.6 +/- 20.4 vs 341.2 +/- 12.4 MUm, P < .0001) and crypt depth (178.6 +/- 7.2 vs 152.6 +/- 6 MUm, P < .01) in the ostomy specimens compared with the SBR specimens. In infants with paired specimens, there was an increase of 31.7% +/- 8.3% and 22.1% +/- 10.0% in villus height and crypt depth, respectively. There was a significant correlation between the amount of intestine resected and the percent change in villus height (r = 0.36, P < .05). CONCLUSION: Mucosal adaptation after SBR in human infants is similar to what is observed in animal models. These findings validate the use of animal models of SBR used to understand the molecular mechanisms of this important response. PMID- 21683197 TI - The optimal timing of referral to an intestinal failure program: the relationship between hyperbilirubinemia and mortality. AB - PURPOSE: Multidisciplinary treatment of pediatric intestinal failure has shown promising results. However, there are limited data as to the optimal time frame for referral of patients to intestinal failure programs. The aim of this study was to explore the relationship of hyperbilirubinemia at referral with patient outcomes in a multidisciplinary program. METHODS: A retrospective analysis was performed of a prospectively collected database from a multidisciplinary intestinal failure program. Multivariable logistic regression adjusted for age at referral was used to model the association between the conjugated bilirubin at referral and risk of mortality. Median values with range are reported. RESULTS: Sixty-two patients were referred from 2005 to 2009. Patients presented at age 6.4 months (0.4-261.4 months) and were followed up for 16.8 (0.3-53.0) months. Nine subjects (14.5%) died, and 12 subjects (19.4%) were listed for combined liver intestine transplant. A 50% mortality was seen in patients referred with a conjugated bilirubin >= 7.2 mg/dL (n = 12), whereas mortality at referral bilirubin levels <7.2 mg/dL was 6%. After adjusting for age at referral, patients with a conjugated bilirubin >= 7.2 mg/dL at referral were 15.4 times more likely to die than patients who presented with lower bilirubin levels (P = .001; 95% confidence interval, 2.8-83.4). CONCLUSION: Within a pediatric intestinal failure program, mortality is associated with the degree of hyperbilirubinemia at time of referral. These data strongly suggest that these patients should be referred to a multidisciplinary program early in the evolution of their liver disease. PMID- 21683198 TI - Utility of liver function tests including aminotransferase-to-platelet ratio index in monitoring liver dysfunction in short-gut infants of varying ages and intestinal lengths. AB - BACKGROUND/PURPOSE: Aspartate aminotransferase-to-platelet ratio index (APRI) has good correlation with liver fibrosis progression in the infant and toddler short gut population. This study applies laboratory liver function testing, including APRI, to monitor liver dysfunction over time for short-gut infants, with further analysis of at-risk subpopulations. METHODS: Study inclusion criteria included infants younger than 1 year at initial intestinal resection with subsequent continuous parenteral nutrition dependence of 3 months minimum. Bilirubin, aspartate aminotransferase, alanine aminotransferase, APRI, and biopsies were collected for 26 weeks postresection. Subgroup analysis was stratified by (1) estimated gestational age, (2) age at intestinal resection (AGE), and (3) remaining intestinal length. RESULTS: Thirty-one children were included, all with AGE younger than 2 months at initial intestinal resection (mean, 13 days). Aminotransferase-to-platelet ratio index was the only marker associated with fibrosis progression (median, APRI by METAVIR grade: F0/F1/F2, 1.9; F3, 5.7; F4, 14.7 [P = .02]). At 8 and 18 weeks postresection, there are separations seen within study subgroups, indicating the onset and progression of liver dysfunction. CONCLUSION: Aminotransferase-to-platelet ratio index is associated with liver fibrosis progression in this population. There are marked changes in liver dysfunction at 8 and 18 weeks postresection, with subgroup differences within estimated gestational age, AGE, and remaining intestinal length. PMID- 21683199 TI - Chlorhexidine antisepsis significantly reduces the incidence of sepsis and septicemia during parenteral nutrition in surgical infants. AB - BACKGROUND/PURPOSE: After a change in national policy, central venous catheter (CVC) antisepsis with chlorhexidine was introduced in our hospital. Our aim was to evaluate whether this change reduced the rate of infection seen during parenteral nutrition (PN) in infants requiring gastrointestinal surgery. METHODS: Two groups of consecutive infants were compared: control, 98 infants who had CVC antisepsis with 70% isopropanol alone, and chlorhexidine, 112 infants who had CVC antisepsis with 2% chlorhexidine in 70% isopropanol. Incidence rates of sepsis (blood cultures taken) and septicemia (blood cultures positive) were compared by Poisson regression. RESULTS: Seventy-one percent of infants experienced clinically suspected sepsis. The incidence of septicemia was 32%. The incidence rate ratio for sepsis was 0.72 (95% confidence interval, 0.61-0.84) for the chlorhexidine group vs control (P < .0005). The incidence rate ratio for septicemia was 0.49 (95% confidence interval, 0.36-0.67; P < .0005); that is, over a given period of PN, patients had half the rate of positive blood cultures after the introduction of chlorhexidine antisepsis compared with before. CONCLUSION: (1) The incidence of sepsis and septicemia among surgical infants on PN for gastrointestinal anomalies is high. (2) Chlorhexidine CVC antisepsis has significantly reduced this incidence, and we advocate its use in this group of patients. PMID- 21683200 TI - Antenatal diagnosis of bowel dilatation in gastroschisis is predictive of poor postnatal outcome. AB - PURPOSE: Although gastroschisis infants usually have a good outcome, there remains a cohort of babies who fare poorly. We inquired whether the presence of bowel dilatation in utero is predictive of postnatal course in infants with gastroschisis. METHODS: We compared the clinical course of infants who had bowel dilatation with those who did not. Bowel dilatation was defined as more than 20 mm in cross-sectional diameter on ultrasound at any gestational age. Outcome measures used were length of time of parenteral nutrition, death, and surgery for intestinal failure. RESULTS: A review of 170 infants with gastroschisis identified 74 who had dilatation of more than 20 mm (43.5%). There was no significant difference in the incidence of intestinal atresia in those with bowel dilatation and those without (P = .07). Those with bowel dilatation spent a longer period on parenteral nutrition. There were significantly more deaths in the group with bowel dilatation (P = .01). There was no significant difference in the number of infants requiring surgery for intestinal failure between the 2 groups (P = .47). CONCLUSIONS: We found that sonographically detected bowel dilatation more than 20 mm in utero in fetuses with gastroschisis may have value in predicting clinically significant adverse postnatal outcomes. PMID- 21683201 TI - A comparison of circumumbilical and transverse abdominal incisions for neonatal abdominal surgery. AB - PURPOSE: Although neonatal bowel surgery traditionally involves a transverse abdominal incision, several authors have reported that the circumumbilical incision is effective and cosmetically appealing. We report the first study comparing the circumumbilical incision to the transverse abdominal incision for a variety of neonatal abdominal operations. METHODS: Retrospective cohort analysis comparing the circumumbilical incision to the transverse abdominal incision for neonates who underwent surgical repair of malrotation, duodenal atresia/web, or intestinal atresia/web was performed between 1999 and 2009. RESULTS: One hundred thirty-two patients underwent a laparotomy through a transverse abdominal incision (n = 106) or a circumumbilical incision (n = 26). Baseline characteristics between groups were similar. No differences were found when comparing operative time, postoperative days on a ventilator, narcotic infusion, time to full feeds, length of hospital stay, incidence of surgical site infection, and bowel obstruction. Although more incisional hernias occurred in the circumumbilical incision group (38%) than the transverse abdominal incision group (6%), all hernias in the circumumbilical group resolved without intervention, whereas 33% required surgical repair in the transverse abdominal group. CONCLUSIONS: Because of its cosmetic advantages and similar outcomes to the transverse abdominal incision, the circumumbilical incision should be considered as an alternative to the transverse abdominal approach in neonatal surgery. PMID- 21683202 TI - Safety of ketorolac in surgical neonates and infants 0 to 3 months old. AB - BACKGROUND: Ketorolac is a nonsteroidal antiinflammatory drug widely used as an adjunct to postoperative pain control in adult and pediatric patients. Minimal safety data exist regarding the use of ketorolac in neonates. METHODS: The charts of 57 postsurgical neonates between 0 and 3 months of age were retrospectively reviewed for bleeding events associated with ketorolac. Data included gestational age (GA), corrected gestational age (CGA) at the time of ketorolac, serum creatinine, platelet count, urine output (in milliliters per kilogram per hour), concomitant medications, enteral feeds, number of ketorolac doses, and surgical procedure performed. RESULTS: Of 57 patients, 10 (17.2%) demonstrated a bleeding event. Mean CGA and serum creatinine for those with bleeding events was 39.4 weeks (P = .69) and 0.64 mg/dL (P = .03), respectively. Patients with a bleeding event received ketorolac at a mean of 20.7 days of life with 70% receiving the drug at less than 14 days of age, whereas those without a bleeding event received ketorolac at a mean of 31.9 days (P = .04). Bleeding events correlated with glomerular filtration rate of less than 30 mL/min/1.73 m(2) or concomitant medications in all but 1 patient. CONCLUSIONS: Infants younger than 21 days and less than 37 weeks CGA are at significantly increased risk for bleeding events and should not be candidates for ketorolac therapy. PMID- 21683203 TI - Prophylactic antibiotics do not decrease the incidence of wound infections after laparoscopic pyloromyotomy. AB - PURPOSE: Although laparoscopic pyloromyotomy is considered to be a clean case, many surgeons administer prophylactic preoperative antibiotics. The aim of this study was to evaluate the impact of prophylactic antibiotics on the wound infection rate after laparoscopic pyloromyotomy. METHODS: We conducted a retrospective review of all patients who underwent laparoscopic pyloromyotomy at our institution between August 2002 and December 2009. Data included patient age, sex, weight, serum HCO(3) at admission and at operation, and if the patient received prophylactic antibiotics. The rate of wound infection or other wound complications, including suture granuloma, umbilical granuloma, umbilical hernia, skin dehiscence, and omental evisceration, was determined. RESULTS: Two hundred ninety-nine patients underwent 301 consecutive laparoscopic pyloromyotomies. Sixty-four percent (n = 194) of patients returned for follow-up and were included in the study. Fifty-seven percent (group A, n = 111) received antibiotics, and 43% (group B, n = 84) did not. There were 3 wound infections in each of the equally matched groups (group A, 2.7%; group B, 3.5%; P = .73). Other wound complications occurred in 4.5% of patients (n = 5) in group A and 8.3% of patients (n = 7) in group B (P = .27). CONCLUSION: The use of prophylactic antibiotics does not significantly decrease the rate of wound infection or other wound complications after laparoscopic pyloromyotomy. PMID- 21683204 TI - Geographic distribution of community-acquired methicillin-resistant Staphylococcus aureus soft tissue infections. AB - PURPOSE: The goal of this study is to look at the geographic growth patterns of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections in our local region and to determine if specific geographic areas are at increased risk. METHODS: After Institution Review Board approval (132603-3), a retrospective chart review was conducted of 614 patients who underwent incision and drainage of an abscess by a single pediatric surgical practice from January 2004 to December 2008. In addition, previously published data from 195 patients who underwent incision and drainage of an abscess from January 2000 to December 2003 were reviewed. RESULTS: The most commonly cultured organism found in the pediatric population undergoing incision and drainage was S aureus (n = 388), of which 258 (66%) were methicillin resistant. This is a 21% increase from the rate of MRSA cultures identified from 2000 to 2003. Geographic information system space-time analysis showed that a cluster of 14 MRSA cases was located within a 1.44-km radius between 2000 and 2003, and 5 separate clusters of more than 20 MRSA infection cases each were identified in 3 separate cities over the 8-year time span using geographic information system spatial analysis (P value = .001). CONCLUSION: Methicillin-resistant S aureus has now become the most prevalent organism isolated from cultures of community-acquired abscesses requiring incision and drainage in the pediatric population in our local region. Significant clustering of MRSA infections has appeared in several different cities within our geographic region. PMID- 21683205 TI - Variations in preoperative decision making for antireflux procedures in pediatric gastroesophageal reflux disease: a survey of pediatric surgeons. AB - BACKGROUND/PURPOSE: The purpose of the study was to identify influential factors contributing to the variation with which antireflux procedures (ARPs) are performed at freestanding children's hospitals in the United States. METHODS: We conducted an online survey of pediatric surgeons working in Child Health Corporation of America (CHCA) member hospitals in which we examined decision making for ARPs. RESULTS: Thirty-six percent (n = 121) of contacted surgeons responded. Eighty percent reported requiring preoperative upper gastrointestinal series before ARPs, and 13% require a pH probe study. Although surgeons ranked their own opinion as the most important in preoperative decision making, parents and referring physicians played significant roles in hypothetical scenarios. In children with negative/equivocal objective studies, more than half of surgeons reported offering ARP when the referring specialist felt that ARP was indicated. Despite equivocal studies, 20% of the surgeons reported offering ARP when the parents were convinced that ARP would help. In a patient with both a positive pH probe and upper gastrointestinal series, 46% of surgeons reported declining ARP if parents were hesitant. CONCLUSIONS: These data suggest that a surgeon's final decision to perform ARP may be just as influenced by nonobjective factors, such as referring physician and parental opinions, as it is by objective studies. Our survey reinforces the need for further examination of specific factors in preoperative decision making for ARPs in the pediatric population. PMID- 21683206 TI - Intussusception in children: cost-effectiveness of ultrasound vs diagnostic contrast enema. AB - PURPOSE: The aim of the study was to compare the cost-effectiveness of different imaging strategies for the diagnosis of pediatric intussusception using a decision analytic model. METHODS: A Markov decision model was constructed to model effects of radiation exposure at the time of intussusception in a hypothetical cohort of 2-year-old children. The 2 strategies compared were ultrasound followed conditionally by contrast enema (US/CE) vs contrast enema (CE) alone. The model simulated short-term and long-term outcomes of the patients, calculating the average quality-adjusted life years (QALYs) and health care costs associated with each arm. RESULTS: The use of ultrasound as a first line diagnostic modality would result in a decrease of 79.3 and 59.7 cases of radiation-induced malignancy per 100,000 male and female children evaluated, respectively. For male and female children with intussusception, US/CE was both the most costly initial imaging strategy and the most effective compared with CE. The incremental cost-effectiveness ratios of US/CE to CE was $70,100 (boy) and $92,227 (girl) per quality-adjusted life years gained. CONCLUSIONS: In a Markov decision model of pediatric acute intussusception, initial US/CE was both the most costly and the most effective strategy. PMID- 21683207 TI - Pediatric appendicitis in New England: epidemiology and outcomes. AB - BACKGROUND: Acute appendicitis is among the most common indications for surgery in children in the Western world. The epidemiology of acute appendicitis in the United States has not been recently analyzed in a population-based cohort study. METHODS: Here, we describe the epidemiology of acute appendicitis in the pediatric population in New England from 2000 to 2006. RESULTS: Our results show that there is clustering of perforated and nonperforated appendicitis by hospital catchment area (Moran I index 0.01 and 0.03, respectively). The overall incidence of nonperforated appendicitis decreased over our study period by 9.7% (P < .05), the proportion of perforated appendicitis did not change significantly over our study period, and there was a 38% decrease in the proportion of negative appendectomies (P < .05). CONCLUSIONS: There were trends toward increased operative volume for pediatric surgeons as well as sharp increases in the use of laparoscopy and early discharge with home health services. Our results demonstrate that the epidemiology, outcomes, and trends in treatment of acute appendicitis continue to change. PMID- 21683208 TI - Surgeon-performed ultrasound as a diagnostic tool in appendicitis. AB - PURPOSE: Diagnosing appendicitis may require adjunct studies such as computed tomography or ultrasound (US). Combining a clinical examination with surgeon performed US (SPUS) may increase diagnostic accuracy and decrease radiation exposure and costs. METHODS: A prospective study was conducted including children with a potential diagnosis of appendicitis. A surgery resident performed a clinical examination and US to make a diagnosis. Final diagnosis of appendicitis was confirmed by operative findings and pathology. Results were compared with radiology department US (RDUS) and a large randomized trial. Analysis was performed using Fisher exact test. RESULTS: Fifty-four patients were evaluated and underwent SPUS. Twenty-nine patients (54%) had appendicitis. Overall accuracy was 89%, with accuracy increasing from 85% to 93% between the 2 halves of the study. Radiology department US was performed on 21 patients before surgical evaluation, yielding an accuracy of 81%. Surgeon-performed US on those 21 patients yielded an accuracy of 90%. No statistical differences were found between any groups (P > .05). CONCLUSION: Accuracy of SPUS was similar to RDUS and that of a large prospective randomized trial performed by radiologists. Furthermore, when the same clinician performs the clinical examination and US, a high level of accuracy can be achieved. With this degree of accuracy, SPUS may be used as a primary diagnostic tool and computed tomography reserved for challenging cases, limiting costs, and radiation exposure. PMID- 21683209 TI - Quality of life assessment between laparoscopic appendectomy at presentation and interval appendectomy for perforated appendicitis with abscess: analysis of a prospective randomized trial. AB - PURPOSE: The current study examined the impact of immediate laparoscopic surgery vs nonoperative initial management followed by interval appendectomy for appendicitis with abscess on child and family psychosocial well-being. METHODS: After obtaining Internal Review Board approval, 40 patients presenting with a perforated appendicitis and a well-formed abscess were randomized to surgical condition. Parents were asked to complete child quality of life and parenting stress ratings at presentation, at 2 weeks postadmission, and at approximately 12 weeks postadmission (2 weeks postoperation for the interval appendectomy group). RESULTS: Children in the interval arm experienced trends toward poorer quality of life at 2 and 12 weeks postadmission. However, no group differences in parenting stress were observed at 2 weeks postoperation. At 12 weeks postadmission, participants in the interval condition demonstrated significant impairment in both frequency and difficulty of problems contributing to parenting distress. CONCLUSION: Families experience significant parenting distress related to the child's functioning and disruption in the child's quality of life that may be because of the delay in fully resolving the child's medical condition. In addition, parents experience negative consequences to their own stress as a result of the delay before the child's appendectomy. PMID- 21683210 TI - Is it necessary to drain all postoperative fluid collections after appendectomy for perforated appendicitis? AB - PURPOSE: Children treated for perforated appendicitis can have significant morbidity. Management often includes looking for and draining postoperative fluid collections. We sought to determine if drainage hastens recovery. METHODS: Children with perforated appendicitis treated with appendectomy from 2006 to 2009 were reviewed. Patients with postoperative fluid that was drained were compared with patients with undrained fluid with regard to preoperative features and postoperative outcomes. Statistical analyses included paired Student's t tests, Mann-Whitney U test, and linear regression. RESULTS: Five hundred ninety-one patients were reviewed. Seventy-one patients had postoperative fluid, of whom 36 had a drainage procedure and 35 did not. There was no significant difference in white blood cell count at the time of assessment for drainage (16.4 +/- 4.0 vs 14.6 +/- 4.9, P = .14), days with fever (3.5 +/- 3.0 vs 2.9 +/- 2.5, P = .35), or readmission rate (19% vs 31%, P = .28). After multivariate linear regression, larger fluid volumes were associated with prolonged length of stay (LOS) (P = .03). For fluid collections between 30-100 mL, there was no significant difference in LOS between the drain and no-drain groups (9.8 +/- 3.5 vs 10.9 +/- 5.2 days, P = .51). CONCLUSION: After appendectomy for perforated appendicitis, larger postoperative fluid collections are associated with prolonged LOS. Drainage of collections less than 100 mL may not hasten recovery. PMID- 21683211 TI - Disaster response in a pediatric field hospital: lessons learned in Haiti. AB - PURPOSE: This study outlines the evolution of a pediatric field hospital after the January 2010 Haiti earthquake. METHODS: Project Medishare set up a field hospital in Port-au-Prince 48 hours after the event. Our institution staffed the pediatric component for 45 days, with sequential deployment of 9 volunteer medical teams. Evolving facility and manpower requirements and changing patient demographics over time were evaluated. RESULTS: Delegations consisted of surgeons, pediatricians, nurses, operating room (OR) personnel, physical therapists, pharmacists, and support staff. Primary goals involved creation of a child-specific ward, pediatric OR, and a wound care center. Major inpatient demographic changes occurred as time from the disaster elapsed. Initial census showed that 93% of the patients were surgical admissions with 40% undergoing operations, mostly fracture and wound care, over the first week. Eight weeks later, medical illnesses accounted for 70% of inpatients, whereas OR volume dropped by more than 50%. A second trend involved increasing acuity of care. Initially, children were admitted for serious or limb-threatening, but usually not life-threatening, injuries. Within 2 months, one third of the patients were housed in the developing NICU/PICU; and only 12% were admitted for injuries related to the earthquake. This change in patient needs led to alterations in facility requirements and in staffing and leadership needs. CONCLUSION: A disaster involving significant casualties in a populated area demands the rapid development of a field facility with pediatric personnel. Requirements for equipment, manpower, medical records, and systems addressing volunteer stress and ethical dilemmas can be anticipated. PMID- 21683212 TI - The management of pancreatic injuries in children: operate or observe. AB - PURPOSE: The critical management decision in pediatric pancreatic injuries involves whether or not to operate on patients with grade II or III injuries. Because of the rarity of these injuries, no one hospital cares for enough patients to determine the outcome of this decision. Given this, the American Pediatric Surgical Association accrued a series of patients with pancreatic injuries from the members of its Trauma Committee. METHODS: A retrospective review of concurrent pancreatic injuries from 9 level 1 pediatric trauma centers was performed. RESULTS: Data on 131 children were submitted. Forty-three patients suffered grade II or grade III injuries. Twenty patients underwent an operation, and 23 were observed. Patients who underwent an operation had an average length of stay of 16.1 days compared with 14.2 days. Two in the operative group received total parenteral nutrition compared with 12 in the nonoperative group. Eight in the nonoperative group developed a pseudocyst compared with 3 in the operative group. CONCLUSIONS: Children with grade II or grade III pancreatic injuries managed nonoperatively had a higher rate of pseudocyst, lower rate of reoperation, and a comparable length of stay compared with those who underwent surgery. These data will be used to help design a prospective study of pancreatic injury management. PMID- 21683213 TI - Acute pancreatitis in children: spectrum of disease and predictors of severity. AB - BACKGROUND: The aim of this study was to describe the spectrum of disease in children with acute pancreatitis and assess predictors of severity. METHODS: Children (<= 18 years) admitted to a single institution with acute pancreatitis from 2000 to 2009 were included. The accuracy of the Ranson, modified Glasgow, and pediatric acute pancreatitis severity (PAPS) scoring systems for predicting major complications was assessed. RESULTS: The etiology of pancreatitis in these 211 children was idiopathic (31.3%), medication-induced (19.9%), gallstones (11.8%), trauma (7.6%), transplantation (7.6%), structural (5.2%), and hemolytic uremic syndrome (3.3%). Fifty-six patients (26.5%) developed severe complications. Using the cutoff thresholds in the PAPS scoring system, only admission white blood cell count more than 18,500/MUL (odds ratio [OR], 3.1; P = .010), trough calcium less than 8.3 mg/dL (OR, 3.0; P = .019), and blood urea nitrogen rise greater than 5 mg/dL (OR, 4.1; P = .004) were independent predictors of severe outcome in a logistic regression model. The sensitivity (51.8%, 51.8%, 48.2%) and negative predictive value (83.2%, 83.5%, 80.5%) of the Ranson, modified Glasgow, and PAPS scores were, respectively, insufficient to guide clinical decision making. CONCLUSION: Commonly used scoring systems have limited ability to predict disease severity in children and adolescents with acute pancreatitis. Careful and repeated evaluations are essential in managing these patients who may develop major complications without early signs. PMID- 21683214 TI - Dynamic tracheal occlusion improves lung morphometrics and function in the fetal lamb model of congenital diaphragmatic hernia. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) is associated with significant neonatal morbidity and mortality. Although prenatal complete tracheal occlusion (cTO) causes hypoplastic CDH lungs to enlarge, improved lung function has not been demonstrated. Furthermore, cTO interferes with the dynamic pressure change and fluid flow associated with fetal breathing. PURPOSE: The purpose of the study was to assess a novel dynamic tracheal occlusion (dTO) device that preserves pressure changes and fluid flow. METHODS: In this pilot study, CDH was created in fetal lambs at 65 days of gestational age (GA). At 110 days GA, a cTO device (n = 3) or a dTO device (n = 4) was placed in the fetal trachea. At 135 days GA, lambs were delivered and resuscitated. Unoperated lamb co-twins (n = 5), sham thoracotomy lambs (n = 2), and untreated CDH lambs (n = 3) served as controls. RESULTS: Tracheal opening pressure, lung volume, lung fluid total protein, and phospholipid were significantly higher in the cTO group than in the dTO and unoperated control groups. Maximal oxygenation and lung compliance were significantly lower in the cTO group when compared with the unoperated control and dTO groups. CONCLUSION: Preliminary results suggest that in the fetal lamb CDH model, dTO restores normal lung morphometrics and function, whereas cTO leads to enlarged but less functional lungs. PMID- 21683215 TI - Minimally invasive repair of congenital diaphragmatic hernia. AB - PURPOSE: Operative approach, including minimally invasive surgery (MIS) in the repair of congenital diaphragmatic hernia (CDH), is variable among institutions. The short-term recurrent hernia rate is not well described. We evaluated the in hospital recurrence rate of MIS repairs of infants with CDH from the Congenital Diaphragmatic Hernia Registry. METHODS: Prospectively collected data from infants with CDH were analyzed from the Congenital Diaphragmatic Hernia Registry from January 1995 to January 2010. Recurrent hernia was defined as reoperations during initial hospitalization. Operative approaches included abdominal, thoracic, laparoscopic, and thoracoscopic techniques. RESULTS: Five thousand four hundred eighty infants with CDH were identified, of which 4516 (82.4%) were repaired. Operative data were available in 4390 infants. One hundred fifty-one infants (3.4%) underwent MIS repairs with 12 reported recurrences (7.9%) compared with 114 for open techniques (2.7%, P < .05). Minimally invasive surgery demonstrated a significant increased odds for recurrence (odds ratio, 3.59; 95% confidence interval, 1.92-6.71) after adjusting for gestational age, birth weight, patch repair, and extracorporeal membrane oxygenation. CONCLUSION: Minimally invasive techniques appear to have a significant higher recurrent hernia rate, with thoracoscopy being the highest. Although adjusted for patch repair, other factors with regard to disease severity may contribute to differences in outcomes among centers. This study is limited to short-term recurrence during initial hospitalization. PMID- 21683216 TI - Late gestation fetal magnetic resonance imaging-derived total lung volume predicts postnatal survival and need for extracorporeal membrane oxygenation support in isolated congenital diaphragmatic hernia. AB - PURPOSE: Magnetic resonance imaging (MRI) has been used as an imaging modality to assess pulmonary hypoplasia in congenital diaphragmatic hernias (CDHs). The objective of this study was to determine if there is a correlation between late gestational fetal MRI-derived total lung volumes (TLVs) and CDH outcomes. METHODS: From 2006 to 2009, 44 patients met criteria of an isolated CDH with a late gestational MRI evaluation. The prenatal TLV (in milliliters) was obtained between 32 and 34 weeks gestation. The measured study outcomes included survival, need for extracorporeal membrane oxygenation (ECMO), and length of stay. RESULTS: There were 39 left and 5 right CDH patients. The average TLV was significantly lower for nonsurvivors (P = .01), and there was a significant association between lower TLV and the need for ECMO (P = .0001). When stratified by TLV, patients with a TLV of greater than 40 mL had a 90% survival vs 35% survival for a TLV of less than 20 mL. Furthermore, patients with a TLV greater than 40 mL had a lower rate of ECMO use (10%) than patients with a TLV of less than 20 mL (86%). Shorter length of stay was found to correlate with increasing TLV (P = .022). CONCLUSION: Late gestation fetal MRI-derived TLV significantly correlates with postnatal survival and need for ECMO. Fetal MRI may be useful for the evaluation of patients who present late in gestation with a CDH. PMID- 21683217 TI - Regional chest wall motion dysfunction in patients with pectus excavatum demonstrated via optoelectronic plethysmography. AB - BACKGROUND: Paradoxical chest wall motion is recognized clinically in pectus excavatum (PE). We report chest wall volume and motion differences between PE patients and unaffected individuals. METHODS: A prospective, institutional review board-approved study compared nonoperated PE patients with normal controls (C). Subjects had deep breathing maneuvers captured by infrared cameras. Chest wall volume and excursion were calculated using optoelectronic plethysmography marker reconstruction combined with proprietary software (BTS Bioengineering, Milan, Italy). RESULTS: One hundred nineteen patients underwent optoelectronic plethysmography analysis (PE: 64, C: 5). Total chest wall volume at rest was similar in both groups (PE: 13.6 L, C: 14.1 L, P = .55). During maximal inspiration, PE patients had a significant increase in the volume within the abdominal rib cage compartment (PE: 0.77 L, C: 0.6 L, P < .01). Patients with PE had 51% less midline marker excursion at the angle of Louis (P < .01), a 46% decrease at the level of the nipples (P < .01), and 28% less excursion at the xiphoid process (P = .02). At the level of the umbilicus, PE patients had 147% increase in midline marker excursion compared with controls (P < .01). CONCLUSIONS: Optoelectronic plethysmography kinematic analysis allows for quantification of focal chest wall motion dysfunction. Patients with PE demonstrate significantly decreased chest wall motion at the area of the pectus defect and increased abdominal contributions to respiration compared with controls. This finding may help to explain exertional symptoms of easy fatigability or shortness of breath in PE. PMID- 21683218 TI - One hundred patients with recurrent pectus excavatum repaired via the minimally invasive Nuss technique--effective in most regardless of initial operative approach. AB - PURPOSE: Controversy exists as to the best operative approach to use in patients with failed pectus excavatum (PE) repair. We examined our institutional experience with redo minimally invasive PE repair along with the unique issues related to each technique. METHODS: We conducted an institutional review board approved review of a prospectively gathered database of all patients who underwent minimally invasive repair of PE. RESULTS: From June 1987 to January 2010, 100 patients underwent minimally invasive repair for recurrent PE. Previous repairs included 42 Ravitch (RAV) procedures, 51 Nuss (NUS) procedures, 3 Leonard procedures, and 4 with previous NUS and RAV repairs. The median Haller index at reoperation was 4.99 (range, 2.4-20). Fifty-five percent of RAV patients and 25% of NUS patients required 2 or more bars (P = .01). Two RAV patients had intraoperative nonfatal cardiac arrest owing to thoracic chondrodystrophy--1 at insertion and 1 upon removal. Bar displacements occurred in 12% RAV and 7.8% NUS patients (P = .05). Overall reoperation for bar displacement is 9%. CONCLUSIONS: The minimally invasive NUS technique is safe and effective for the correction of recurrent PE. Patients with prior NUS repair can have extensive pleural adhesions necessitating decortication during secondary repair. Patients with a previous RAV repair may have acquired thoracic chondrodystrophy that may require a greater number of pectus bars to be placed at secondary repair and greater risk for complications. We have a greater than 95% success rate regardless of initial repair technique. PMID- 21683219 TI - Tumor volume to fetal weight ratio as an early prognostic classification for fetal sacrococcygeal teratoma. AB - PURPOSE: This study was designed to develop a prognostic factor for fetuses with sacrococcygeal teratoma (SCT) that may be useful to predict outcome and guide counseling early in pregnancy. We hypothesize that, in fetuses with SCT, the ratio of tumor size to estimated fetal weight in the second trimester predicts outcome. METHODS: We retrospectively reviewed charts of all patients evaluated at our Fetal Center for SCT between 2004 and 2009. Estimated fetal weight and tumor volume were calculated based on prenatal ultrasound or fetal magnetic resonance imaging. Patients were stratified based on tumor volume to fetal weight ratio (TFR), and their outcomes were analyzed by Fisher's Exact test. RESULTS: Tumor volume to fetal weight ratio before 24 weeks' gestation was predictive of outcome. Those with a TFR less than or equal to 0.12 (n = 5) had a significantly better outcome than patients with a TFR greater than 0.12 (n = 5, P < .05). All patients with poor outcomes had a TFR greater than 0.12 by 24 weeks' gestation. A TFR greater than 0.12 predicted poor outcome with 100% sensitivity and 83% specificity. All 4 patients who developed hydrops had a TFR greater than 0.12. CONCLUSION: In our series of fetuses with SCT, TFR before 24 weeks' gestation correlates with outcome. This novel, prenatal diagnostic tool may be useful in prenatal counseling and for early identification of high-risk fetuses. PMID- 21683220 TI - Prenatal and postnatal urologic complications of sacrococcygeal teratomas. AB - PURPOSE: Urologic complications are an underappreciated sequelae of the mass effect of sacrococcygeal teratoma (SCT) and its resection. The goal of this study was to evaluate the incidence and severity of urologic complications in patients with SCT. METHODS: A retrospective review of patients with a prenatal diagnosis of SCT and postnatal referral for SCT at a single institution during a 5-year period (2004-2009) was performed. The presence of prenatal and postnatal urologic abnormalities were collected and analyzed. RESULTS: Thirty patients were identified for inclusion in the study. Twenty-two patients were diagnosed prenatally, 3 patients were referred for resection of the tumor, and 5 patients were initially treated elsewhere and referred after resection for urologic complications. Of the 20 patients with subsequent follow-up included in this study, 9 had neurogenic bladder, 5 of whom also had associated renal injury. All patients with renal injury had a higher grade Altman type II/III lesion. CONCLUSION: Urologic problems appear to be common in patients with SCT. Higher grade SCTs should alert the surgeon to possible urologic sequelae, particularly neurogenic bladder and renal injury. Careful urologic evaluation and management of the genitourinary tract should be included in prenatal and preoperative counseling. PMID- 21683221 TI - The role of nerve growth factor in caspase-dependent apoptosis in human BE(2)C neuroblastoma. AB - PURPOSE: The purpose of the study was to determine if nerve growth factor (NGF) stimulation induces apoptosis in the BE(2)C neuroblastoma cell line in vitro. METHODS: The LPCX retroviral vector was used to achieve stable transduction of NGF complementary DNA into BE(2)C neuroblastoma cells. Wild-type and NGF transduced cells were then incubated with varying concentrations of NGF for varying periods. A laddering assay was performed to determine the presence of DNA fragments characteristic of apoptosis. The expression of various cleaved and total caspases was determined by Western immunoblotting. RESULTS: p75 receptor expression in the NGF-transduced cell line was equivalent to that in the wild type cell line, but Trk A receptor expression was significantly decreased in BE(2)C-NGF cells. DNA laddering assay demonstrated that only BE(2)C-NGF cells underwent apoptosis after stimulation with exogenous NGF. BE(2)C-NGF cells have increased expression of cleaved caspase-3 when compared with wild-type cells. Cleaved caspase-3 expression is further increased with exogenous NGF stimulation in the transduced cells. CONCLUSION: This study confirms that NGF stimulation of BE(2)C neuroblastoma cells can induce apoptosis through activation of the caspase cascade in vitro. The differential expression of the receptors Trk A and p75 between the wild-type and NGF-transduced cell lines may explain the differing effects observed. PMID- 21683222 TI - Brain lipid-binding protein: a marker of differentiation in neuroblastic tumors. AB - PURPOSE: Neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN) are neuroblastic tumours (NT) of sympathetic nervous system origin. Brain lipid binding protein (BLBP) has potential morphogenic activity during nervous system development but has not been studied in these tumours. We analyzed the expression of BLBP in NT according to histological subtypes and extent of differentiation. METHODS: Thirty cases of NT (10 each of NB, intermixed GNB, and GN) were identified from the histopathology archive of a single center. Tissue sections were obtained from representative paraffin blocks and immunohistochemistry for BLBP performed. RESULTS: Brain lipid-binding protein was not expressed in any NB case. In all cases of GN, BLBP was strongly expressed in the cytoplasm of mature ganglion cells but negative in Schwannian stroma. In the intermixed GNB, there was similar strong BLBP immunoreactivity in the cytoplasm of fully differentiated and differentiating ganglion cells but no BLBP expression in immature neuroblasts. CONCLUSION: Brain lipid-binding protein is strongly expressed in mature and maturing ganglion cells in NT (GN and GNB), whereas it is absent in poorly differentiated neuroblasts of GNB and NB. Cytoplasmic expression of BLBP in NT increases as the cells undergo neural differentiation and is therefore associated with the extent of tumour differentiation and favorable histology. PMID- 21683223 TI - Adrenal cortical tumors in children: factors associated with poor outcome. AB - PURPOSE: The purpose of this study was to evaluate recurrence and survival outcomes in pediatric adrenal cortical neoplasms. METHODS: A 90-year retrospective review of children with adrenal cortical neoplasms was performed using multivariate Cox regression analysis to identify factors associated with recurrence and tumor-related mortality. RESULTS: The evaluable cohort included 29 patients. Twenty-seven underwent resection. Twenty-two (81%) had localized disease, and 5 (19%) had locally advanced disease (all received chemotherapy and 2 of 5 were cured). Two patients presenting with metastatic disease died despite treatment. There were 4 recurrences; all patients died. Tumor-related mortality was 24% (7/29). Kaplan-Meier freedom from recurrence was 85% at 1 year (95% confidence interval, 75%-95%). Multivariate Cox regression revealed that older age (P = .01), higher mitotic rate (P = .005), and necrosis (P < .001) were independent predictors of tumor-related death. Higher mitotic rate (P = .007) and larger tumor size (P = .03) were significant predictors of tumor recurrence. CONCLUSION: Risk factors for poor outcomes in patients with adrenocortical tumors include older age, higher mitotic rate, higher percent necrosis, and larger tumor size. Therefore, the presence of these factors may warrant consideration of adjuvant chemotherapy, even in the absence of advanced disease. PMID- 21683225 TI - Vascular anomalies of the male genitalia. AB - PURPOSE: Vascular tumors and malformations of the male genitalia can affect urinary, sexual, reproductive, and emotional function. METHODS: Male patients with a genital lesion evaluated or treated at our center from 1995 to 2010 were reviewed to analyze presentation, diagnosis, treatment modalities, and outcome. RESULTS: Of the 3889 male patients, 117 had a vascular anomaly of the genitalia: 12 tumors and 105 malformations. The referring diagnosis was accurate in 72.7% of patients with a tumor, whereas 46.3% of malformations were misdiagnosed. Tumors included infantile hemangioma (n = 10) and kaposiform lymphatic anomaly (n = 2). Common vascular malformations were lymphatic (n = 46), venous (n = 33), and capillary-lymphatic-venous (n = 16). Presenting signs for tumors included ulceration (33.0%) and ambiguous genitalia (25.0%). Malformations manifested with swelling (40.0%), fluid leakage (16.2%), and pain (16.2%). Treatment was necessary for 69.9% (79/113) of patients. The remaining lesions (34/113) were observed. Tumor management included observation, pharmacotherapy, and excision. Malformations were largely treated with sclerotherapy and/or surgical procedures. CONCLUSIONS: Vascular anomalies of the male genitalia are uncommon and frequently misdiagnosed. Accurate diagnosis can be made and appropriate treatment can be instituted based on presentation, natural history, and radiographic imaging. Observation and pharmacotherapy are the mainstays of tumor management. Malformations require sclerotherapy and/or resection. Interdisciplinary care optimizes outcomes for males with these often-disfiguring vascular lesions. PMID- 21683224 TI - Adrenocortical cell transplantation reverses a murine model of adrenal failure. AB - PURPOSE: Although adrenal insufficiency can be managed with steroid replacement, transplantation of adrenocortical cells may represent a more definitive therapy. METHODS: An adrenal failure model was created by adding stress to mice that underwent staged bilateral adrenalectomy. Murine adrenocortical cells were seeded onto collagen sponges. The grafts were implanted under the renal capsule during the first adrenalectomy. Some mice had an additional graft placed next to the kidney. A contralateral adrenalectomy and a laparotomy were performed 1 week after the first adrenalectomy. Two weeks later, blood was collected for corticosterone measurement; and implants were retrieved for adrenal-specific messenger RNA analysis and histology. Mice that underwent the same procedures but received a graft without cells served as controls. RESULTS: Control group mortality was 100%. Mice that had only one cell-seeded implant had 42% survival, whereas mice that had 2 cell-seeded implants had 100% survival. Retrieved implants demonstrated viable cells and expression of adrenocortical genes. The plasma corticosterone concentration in animals that survived was similar to that in normal mice. CONCLUSION: Cells transplantation restored the adrenocortical function in these mice. Further optimization of this technique could bring a curative therapy to patients with adrenal insufficiency. PMID- 21683226 TI - The utility of routine pouchogram before ileostomy reversal in children and adolescents following ileal pouch anal anastomosis. AB - INTRODUCTION: Pouchograms are used to assess the integrity of the ileal pouch anal anastomosis (IPAA) in patients who have undergone restorative proctocolectomy. Its benefits have been questioned, and there are no data to support the routine use in children. METHODS: We retrospectively reviewed the charts of 26 patients who had an IPAA and pouchogram at our institution between 2001 and 2009. Each patient also underwent an examination under anesthesia to assess the integrity of the IPAA on the day of the ileostomy closure. RESULTS: The mean age of the patients was 13.8 (+/- 0.7) years. The pouchogram was performed at a median of 6 weeks after the IPAA (range, 4-20 weeks). The findings were normal in 26 (89.7%) and demonstrated stricture in 2 (6.9%) and leak in 1 (3.4%). History was suggestive and physical examination was confirmatory in these 3 problematic cases. CONCLUSIONS: A contrast enema is not routinely required to evaluate the integrity of the IPAA before ileostomy reversal in pediatric patients. Complications can be detected by history and rectal examination before ileostomy closure. We recommend the use of contrast enema only in symptomatic patients where a leak is suspected, thereby limiting radiation exposure and inconvenience. PMID- 21683227 TI - Management of H-type rectovestibular and rectovaginal fistulas. AB - INTRODUCTION: H-type rectovestibular or rectovaginal fistulas are rare entities in the spectrum of anorectal malformations seen in North America. Management options described in the literature have included perineal repair, anterior perineal anorectoplasty, vestibuloanal pull-through, and limited or formal posterior sagittal anorectoplasty, with a reported recurrence rate of 5% to 30%. We describe our approach and outcome in the management of these patients. METHODS: In a series of 1170 females with anorectal malformation, we cared for 8 patients who had an H-type rectovestibular or rectovaginal fistula and reviewed their clinical presentation, diagnosis, operative technique, and postoperative course. RESULTS: The patients' presenting symptoms included passage of stool per vagina (6), constipation (3), labial abscess (1), and recurrent urinary tract infection (1). There was associated anorectal stenosis in 3 patients. The remaining 5 patients had normal anal openings. Endoscopy was not helpful in locating the fistulas, but the fistulas were all demonstrated on direct inspection under anesthesia. The fistula was located in the vestibule (4), vagina (3), or labia (1). One patient had an associated presacral mass. Two patients had been operated on twice previously using a perineal repair and a protective colostomy and presented with third recurrences. In 5 cases, a posterior sagittal approach was used, placing sutures circumferentially around the fistulous opening on the rectal side, ligating the fistula, and pulling down a normal segment of rectum to be placed in front of the repaired vaginal wall. In our last 3 cases, we performed a transanal mobilization of the anterior rectal wall, leaving the perineal body intact. After our repairs, the patients have been followed up for 3 months to 15 years with a median of 15 months, and we have seen no recurrences. CONCLUSIONS: In addition to vaginal passage of stool, an H-type fistula should be suspected when there is a labial abscess in an infant, and an associated anal stenosis or presacral mass must be checked for. Direct inspection is the key, with a careful look in the vestibule, because endoscopy may miss the fistula. The essential technical point for repair is to get healthy anterior rectal wall to cover the area of fistula on the posterior vagina. A transanal approach, leaving the perineal body intact, is an excellent option for this repair. PMID- 21683228 TI - Acquired posterior urethral diverticulum following surgery for anorectal malformations. AB - PURPOSE: Despite significant advances in the surgical management of anorectal malformations (ARMs), many children still experience significant debilities from potentially avoidable complications. One complication, the posterior urethral diverticulum, may have untoward consequences if not recognized and treated. METHODS: A retrospective cohort review was undertaken of male patients who presented to us with persistent problems after being operated on elsewhere for ARM. Twenty-nine patients presented with a urethral diverticulum. Their charts were reviewed for the type of malformation, prior repair, presentation, treatment, and postoperative follow-up. RESULTS: Twenty-nine patients were identified that fit the criteria for this study. To date, 28 patients have been managed with reoperation. Urinary complaints were the most common presenting symptoms. All patients were repaired using a posterior sagittal approach. Pathology of the diverticulum in one patient revealed a well-differentiated mucinous adenocarcinoma. CONCLUSION: The incidence of acquired posterior urethral diverticulum has decreased with the popularization of the posterior sagittal incision. There is a theoretical concern that the incidence may increase with the use of laparoscopy for the treatment of ARMs especially those where the fistula is below the peritoneal reflection. Once detected, the diverticulum should be excised. PMID- 21683229 TI - The appendix as a conduit for antegrade continence enemas in patients with anorectal malformations: lessons learned from 163 cases treated over 18 years. AB - INTRODUCTION: The antegrade continence enema (ACE) has been shown to be a safe and effective method for managing fecal incontinence in the pediatric population. The purpose of this study was to examine our experience with the ACE procedure using the appendix as a catheterizable conduit in children with anorectal malformations (ARMs). METHODS: We reviewed the charts of all patients who underwent an ACE procedure using the appendix as a catheterizable conduit between January 1992 and January 2010. Preoperative diagnosis (ARM type), operative details, functional outcomes, and postoperative complications were assessed. Technical modifications over time included selective cecoplication, implementation of the umbilical V-V appendicoplasty technique, and laparoscopy for cecal mobilization. RESULTS: Mean age was 9.9 +/- 0.6 years, and 67% were male. The most common preoperative diagnosis was rectourethral fistula in boys (39%) and persistent cloaca in girls (61%). Forty-five complications occurred in 41 patients with an overall incidence of 25.6% (stricture, 18%; leakage, 6%; prolapse, 4%; intestinal obstruction, 0.6%). The incidence of stomal leakage was lower in patients when a cecoplication was performed (2.9% [4/138] vs 29.4% [5/17]; P < .01), and the incidence of stricture was lower in patients when the umbilical anastomosis was created using the V-V appendicoplasty technique (11% [11/100] vs 30% [18/60]; P < .01). Successful management of incontinence was reported by 96% of all patients. CONCLUSIONS: The ACE procedure using the umbilical V-V appendicoplasty provides an effective and cosmetically superior means for bowel management in children with ARMs. The rate of late complications is not insignificant however, and preventative strategies should focus on careful operative technique and ensuring compliance with catheterization protocols well past the initial postoperative period. PMID- 21683230 TI - Neoappendicostomy in the management of pediatric fecal incontinence. AB - PURPOSE: The Malone appendicostomy, for antegrade enemas, has improved the quality of life for many children with fecal incontinence. In patients whose appendix has been removed, a neo-appendix can be created. We describe our approach and experience with this procedure as an option for surgeons managing children with fecal incontinence. METHODS: The procedure involves creating a transverse flap of cecum that receives its blood supply by a transverse mesenteric branch. This flap is then tubularized around a feeding tube. The surrounding colon is plicated around the neo-appendix to prevent leakage of stool. The tip of the flap is then anastomosed to the deepest portion of the umbilicus. We reviewed our experience with this procedure, including results and complications. IRB approval was obtained. RESULTS: Eighty patients required a neo appendicostomy. Sixty-six patients (82%) had an anorectal malformation, four had spina bifida, and ten had other diagnoses. The reasons for not having an appendix available included: "incidental" appendectomy (34, 42.5%), use of the appendix for a Mitrofanoff procedure (20, 25%), and Ladd's procedure (5, 6%). In fifteen patients (19%) we could find no appendix and assume that it was removed previously. Following neoappendicostomy, nine patients (11%) developed a stricture, and seven patients had leakage (9%). In 2004, we modified the appendiceal-umbilical anastomosis and among these patients, only one patient (3%) developed a stricture, compared with eight patients (18%) without the modification. All seven patients with leakage were within the first forty cases. No patient in the last forty cases had a leakage. CONCLUSIONS: In patients with the potential for fecal incontinence, the appendix should be preserved. In patients without an appendix, the neo-appendicostomy is a valuable tool for fecally incontinent patients. We have found that the V-V anastomosis had a reduced rate of stricture, and the rate of leakage seems to be related to surgical experience. PMID- 21683231 TI - Pitfalls and challenges of cloaca repair: how to reduce the need for reoperations. AB - PURPOSE: Cloacal malformations represent the most complex of genitourinary/anorectal anomalies. We have encountered a unique group of complications in referred patients after failed attempted repairs elsewhere and chose to review this experience with the hope of identifying pitfalls to avoid during the primary repair. METHODS: In our series of 509 cloacas, 95 were repaired elsewhere but required reoperation. These cases were reviewed for specific indications for reoperation and methods used for reoperative repair. Key findings at reoperation to explain the complication(s) were specifically sought. RESULTS: Indications for reoperation included the following: persistent urogenital sinus (46), rectal stricture or acquired atresia (45), acquired vaginal atresia or stricture (45), mislocated rectum (36), urethrovaginal fistula (16), rectal prolapse (12), urethral atresia or stricture (7), and rectovaginal fistula (5). Most patients had more than one indication. In cases of persistent urogenital sinus, the surgeons were unaware of the presence of a cloaca, referring instead to the malformation as a "rectovaginal fistula." From our reading of the operative reports of the original operations, we ascertain that rectal stricture, atresia, or fistula that occurred was most likely related to tension or ischemia. Prolapse was associated with poor pelvic musculature. The average length of the common channel of those patients with vaginal and urethral problems was 4.1 cm. CONCLUSION: We have observed key complications requiring reoperation in a large series of cloacal malformations that are potentially avoidable. A persistent urogenital sinus can be avoided by properly diagnosing a cloaca and repairing the entire malformation and not just the rectum during the initial repair. Vaginal and urethral complications occurred mainly in patients with a common channel longer than 3 cm. Repair of cloacas with common channels longer than 3 cm requires familiarity with a complex decision-making process, and atresias, strictures, and fistulae can be avoided with adequate mobilization of structures and preservation of blood supply. Rectal prolapse occurrence relates to the quality of the perineal muscles. Reoperations can restore the anatomy, but the functional results are not as good as those achieved after primary repair. PMID- 21683232 TI - A comparison of the cleft lift procedure vs wide excision and packing for the treatment of pilonidal disease in adolescents. AB - BACKGROUND/PURPOSE: The cleft lift for pilonidal disease is a flap procedure designed to counteract suspected causes of closed-technique failure. This study compares cleft lift with wide excision and packing in adolescents with respect to complications, healing, and recurrence. METHODS: Charts of all patients surgically treated for pilonidal disease at our institution from August 2000 to August 2009 were reviewed retrospectively. Wide excision was routinely performed until May 2007 when the cleft lift as described by Bascom was instituted here. Factors examined were postoperative complications, wound healing, and disease recurrence. RESULTS: Seventy patients (49 males, 21 females; mean age, 16 years; mean weight, 170.5 lb) with pilonidal disease underwent a total of 39 cleft lift procedures and 34 wide excision procedures. All but 1 cleft lift patient (97.4%) healed completely, whereas 25 (73.5%) of 34 patients in the excision group healed (P < .001). The remaining 9 excision patients had chronic wounds, 3 of whom have undergone cleft lift with full healing. One cleft lift patient had recurrent disease (2.5%) compared with 7 (20.6%) of 34 excision patients (P < .02). CONCLUSIONS: The cleft lift procedure is a superior treatment method of pilonidal disease in adolescents, resulting in primary healing, lower likelihood of recurrent disease, and simplified wound care. PMID- 21683233 TI - Report of the 62 nd Meeting of the American Academy of Pediatrics, Section on Surgery, San Francisco, CA, October 1-2, 2010. PMID- 21683234 TI - Fetal lung interstitial tumor: a cause of late gestation fetal hydrops. AB - Most fetal lung masses present by mid gestation, grow during the canalicular phase of lung development (18-26 weeks of gestation), and plateau in growth or shrink after 26 weeks of gestation. We describe the unique case of a fetal lung mass presenting at 37 weeks of gestation with hydrops and fetal heart failure. The late growth of this lesion and resultant hydrops prompted resection as part of the ex utero intrapartum treatment. Histopathology revealed a rare, recently described fetal lung interstitial tumor. This case demonstrates that a subset of fetal lung masses may continue to grow later in gestation and emphasizes the need for late gestation imaging and close follow-up in this patient cohort. PMID- 21683235 TI - Development of hepatic angiomyolipoma accompanied with focal nodular hyperplasia long after treatment of pelvic rhabdomyosarcoma. AB - Survivors of childhood cancer have a higher risk of developing a secondary neoplasm in their lifetime. The increased risk of a second malignant neoplasm is related to treatment of the primary tumor and genetic predisposition. We describe a 19-year-old man with 2 hepatic masses, one of which was diagnosed as a hepatic angiomyolipoma and the other as focal nodular hyperplasia 14 years after the treatment of stage IV pelvic rhabdomyosarcoma. The combination of these tumors has not previously been reported in the literature. PMID- 21683236 TI - Primary yolk sac tumor of the common bile duct. AB - Yolk sac tumor (YST) is a germ cell neoplasm usually arising from the gonads. Extragonadal YST has been reported in the mediastinum, retroperitoneum, liver, and pelvis. Primary YST of the common bile duct (CBD) has not been previously reported. We describe an 11-month-old girl with a YST arising from the CBD who presented with obstructive jaundice. Imaging studies revealed an intraluminal CBD mass with intrahepatic biliary dilatation and extraluminal infiltration of the head of the pancreas. A complete resection was carried out, and postoperative chemotherapy with cisplatin, etoposide and bleomycin was administered. PMID- 21683237 TI - Gastroschisis and extreme prematurity: a report of two survivors. AB - Extreme prematurity is not commonly associated with gastroschisis, and there are no reports of babies surviving with both gastroschisis and extreme prematurity. We report 2 such cases. PMID- 21683238 TI - Prepubertal presentation of Herlyn-Werner-Wunderlich syndrome: a case report. AB - Herlyn-Werner-Wunderlich syndrome represents a complex female genital malformation with uterus didelphys, unilateral low vaginal obstruction, and ipsilateral renal agenesis, all 3 being secondary to mesonephric duct-induced mullerian anomalies. Clinically, this usually presents in postpubertal adolescent or adult women where hematometrocolpos produces a more pronounced mass effect and pain on the side of the obstructed hemivagina. It is extremely rare for this to present in infancy and early childhood because imaging may not show the small prepubertal uteri and vaginas clearly. We describe a 4-year-old girl with all of the features of this syndrome. Ipsilateral renal agenesis with a pelvic mass should raise the level of suspicion for this syndrome. Magnetic resonance imaging will confirm the diagnosis, so that early endoscopic resection of the obstructing vaginal septum can be carried out as definitive treatment. Long-term outcome is quite good with expectation of normal fertility. PMID- 21683239 TI - The first case of renal lipoma in a child. AB - Lipoma of the kidney is a rare benign renal tumor that previously had been reported only in adults. We present a case of this tumor in a 2-year-old boy. Serial imaging studies revealed a tumor with high fat content arising from the right kidney. Radical nephrectomy was performed for tumor excision. Macroscopically, the tumor consisted of a yellow fatty mass, which was surrounded by a thin fibrous capsule. The tumor was about 600 g, and the kidney was compressed laterally by the tumor. Microscopically, the tumor consisted of large fat cells that did not express human melanoma black-45 (HMB-45). It was diagnosed as a renal lipoma. Postoperatively, there has been no recurrence of tumor in the 10 months since the surgical excision. PMID- 21683240 TI - Cystic lymphatic malformation of bladder presenting as a pelvic mass. AB - We report a 5-year-old boy with a cystic lymphatic malformation (LM) of bladder, and the imaging characteristics of the lesion are reported. Cystic LM of the urinary system is rare, and a location in the bladder is extremely rare. The exact mechanism of the lesion that occurs in bladder is unknown. This case is different from the 3 cases reported before, for it is only presented with a palpable pelvic mass and the lesion did not penetrate full thickness of bladder. Although imaging examinations are helpful in the definition of cystic LMs, no characteristic findings are available to diagnose a cystic LM of the bladder before surgery. The diagnosis is always made after surgical intervention. Surgical excision is ideal, and an extensive operation is not warranted because the lesion is benign. Once excised completely, the prognosis of the disease is good. PMID- 21683241 TI - Living donor liver transplantation for multiple intrahepatic portosystemic shunts after involution of infantile hepatic hemangiomas. AB - We describe a 6-year-old girl presenting with multiple intrahepatic portosystemic shunts after the involution of infantile hepatic hemangiomas (IHHs), who successfully underwent living donor liver transplantation. The chronological changes of radiologic findings indicated that remnant portovenous shunts at the time of IHHs involution developed gradually on the background of atrophic intrahepatic portal veins. This suggests that patients should be carefully followed up for the late onset of intrahepatic portosystemic shunts after the involution of IHHs. PMID- 21683242 TI - Lung nodules in children: video-assisted thoracoscopic surgical resection after computed tomography-guided localization using a microcoil. AB - BACKGROUND: Lung nodules that develop in children with cancer may represent metastatic disease or other conditions potentially requiring aggressive treatment. Thoracoscopic methods have been used for nodule resection; however, lesions deep in the lung parenchyma can be difficult to visualize. Fluoroscopic guided thoracoscopic surgical resection after computed tomography (CT)-guided localization using microcoils has been described in the adult literature and has the potential to assist in the resection of deep pulmonary nodules in children. METHODS: Six patients (ages 6-15 years) with an undiagnosed pulmonary nodule were treated using a combined CT-guided microcoil localization/fluoroscopic video assisted thoracoscopic surgical technique. Preoperatively, a platinum-fibered microcoil was deployed with the deep end of the coil placed either through or in the vicinity of the pulmonary nodule and the superficial end coiled on the pleural surface. The nodule and coil were then resected with endoscopic staplers guided by fluoroscopy and video-assisted thoracoscopic surgical. RESULTS: Computed tomography-guided microcoil localization and fluoroscopic-guided thoracoscopic resection were successful and critically influenced the management of all patients. Three patients were diagnosed with malignancy (2 metastatic diseases and 1 Hodgkin disease). A diagnosis of nonmalignant disease was made in 3 patients (granuloma, eosinophilic granuloma, and aspergilloma). CONCLUSION: In the pediatric population, we have successfully applied a previously described adult technique using CT-localized microcoils to direct fluoroscopic-guided thoracoscopic surgical resection of pulmonary nodules. PMID- 21683243 TI - Re: Early developmental outcome of infants with infantile hypertrophic stenosis. PMID- 21683245 TI - Biology of serpins. Preface. PMID- 21683246 TI - Analysis of serpin secretion, misfolding, and surveillance in the endoplasmic reticulum. AB - Biological checkpoints are known to function in the cellular nucleus to monitor the integrity of inherited genetic information. It is now understood that posttranslational checkpoint systems operate in numerous biosynthetic compartments where they orchestrate the surveillance of encoded protein structures. This is particularly true for the serpins where opposing, but complementary, systems operate in the early secretory pathway to initially facilitate protein folding and then selectively target the misfolded proteins for proteolytic elimination. A current challenge is to elucidate how this posttranslational checkpoint can modify the severity of numerous loss-of-function and gain-of-toxic-function diseases, some of which are caused by mutant serpins. This chapter provides a description of the experimental methodology by which the fate of a newly synthesized serpin is monitored, and how the processing of asparagine-linked oligosaccharides helps to facilitate both the protein folding and disposal events. PMID- 21683247 TI - Serpin-Enzyme Receptors LDL Receptor-Related Protein 1. AB - Early studies suggested the existence of an hepatic receptor that is involved in the clearance of serpin:enzyme complexes. Subsequent work has identified this receptor as the LDL receptor-related protein 1 (LRP1). LRP1 is a multifunctional receptor that serves to transport numerous molecules into the cell via endocytosis and also serves as a signaling receptor. LRP1 plays diverse roles in biology, including roles in lipoprotein metabolism, regulation of protease activity, activation of lysosomal enzymes, and cellular entry of bacterial toxins and viruses. Deletion of the Lrp1 gene leads to lethality in mice, revealing a critical, but as of yet undefined, role in development. Its identification as a receptor for serpin:enzyme complexes confirms a major role for LRP1 in regulating protease activity. PMID- 21683248 TI - The role of autophagy in alpha-1-antitrypsin deficiency. AB - In the classical form of alpha-1-antitrypsin (AT) deficiency, a mutant protein accumulates in the endoplasmic reticulum of liver cells, causing hepatic fibrosis and hepatocellular carcinoma by a gain-of-toxic function mechanism. Autophagy is specifically activated by the accumulation of mutant AT, and the autophagy plays a key role in intracellular degradation of this mutant protein. Our recent study indicates that an autophagy enhancer drug can decrease the hepatic load of mutant AT and reduce hepatic fibrosis in a mouse model of AT deficiency. In this chapter, we discuss what is known about autophagy in AT deficiency and methods for characterizing autophagy in cell lines and animal models. PMID- 21683249 TI - Serpins and the complement system. AB - C1-inhibitor (serpin G1) is a 105 kDa inhibitor which functions as a major antiinflammatory protein in the body. It has its effects via inhibition of the proteases of the complement system and contact system of coagulation, as well as several direct effects mediated by its unique highly glycosylated N-terminal domain. The serpin controls a number of different proteases very efficiently and for some of these the function is augmented by the cofactor, heparin. Here, we describe the preparation of human plasma and recombinant C1-inhibitor and the basic methods required for their characterization, using the complement enzyme C1s as an example of a target enzyme. PMID- 21683250 TI - Use of mouse models to study plasminogen activator inhibitor-1. AB - Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) and therefore plays an important role in the plasminogen/plasmin system. PAI-1 is involved in a variety of cardiovascular diseases (mainly through inhibition of t PA) as well as in cell migration and tumor development (mainly through inhibition of u-PA and interaction with vitronectin). PAI-1 is a unique member of the serpin superfamily, exhibiting particular unique conformational and functional properties. Since its involvement in various biological and pathophysiological processes PAI-1 has been the subject of many in vivo studies in mouse models. We briefly discuss structural and physiological differences between human and mouse PAI-1 that should be taken into account prior to extrapolation of data obtained in mouse models to the human situation. The current review provides an overview of the various models, with a focus on cardiovascular disease and cancer, using wild-type mice or genetically modified mice, either deficient in PAI-1 or overexpressing different variants of PAI-1. PMID- 21683251 TI - Plasminogen activator inhibitor type 2: still an enigmatic serpin but a model for gene regulation. AB - Plasminogen activator inhibitor type-2 (PAI-2; SERPINB2) is an atypical member of the Ov-serpin family of serine protease inhibitors. While it is an undisputed inhibitor of urokinase and tissue-type plasminogen activator in the extracellular space and on the cell surface, the weight of circumstantial evidence suggests that PAI-2 also fulfills an intracellular role which is independent of plasminogen activator inhibition and indeed may not even involve protease inhibition at all. More and more data continue to implicate a role for PAI-2 in many settings, the most recent associating it as a modulator of the innate immune response. Further to the debates concerning its physiological role, there are few genes, if any, that display the regulation profile of the PAI-2 gene: PAI-2 protein and mRNA levels can be induced in the order of, not hundred-, but thousand-folds in a process that is controlled at many levels including gene transcription and mRNA stability while an epigenetic component is also likely. The ability of some cells, including monocytes, fibroblasts, and neurons to have the capacity to increase PAI-2 synthesis to such high levels is intriguing enough. So why do these cells have the capacity to synthesize so much of this protein? While tantalizing clues continue to be revealed to the field, an understanding of how this gene is regulated so profoundly has provided insights into the broader mechanics of gene expression and regulation. PMID- 21683252 TI - The SerpinB1 knockout mouse a model for studying neutrophil protease regulation in homeostasis and inflammation. AB - SerpinB1 is a clade B serpin, or ov-serpin, found at high levels in the cytoplasm of neutrophils. SerpinB1 inhibits neutrophil serine proteases, which are important in killing microbes. When released from granules, these potent enzymes also destroy host proteins and contribute to morbidity and mortality in inflammatory diseases including emphysema, chronic obstructive pulmonary disease, cystic fibrosis, arthritis, and sepsis. Studies of serpinB1-deficient mice have established a crucial role for this serpin in Pseudomonas aeruginosa infection by preserving lung antimicrobial proteins from proteolysis and by protecting lung recruited neutrophils from a premature death. SerpinB1-/- mice also have a severe defect in the bone marrow reserve of mature neutrophils demonstrating a key role for serpinB1 in cellular homeostasis. Here, key methods used to generate and characterize serpinB1-/- mice are described including intranasal inoculation, myeloperoxidase activity, flow cytometry analysis of bone marrow myeloid cells, and elastase activity. SerpinB1-knockout mice provide a model to dissect the pathogenesis of inflammatory disease characterized by protease:antiprotease imbalance and may be used to assess the efficacy of therapeutic compounds. PMID- 21683253 TI - Investigating maspin in breast cancer progression using mouse models. AB - Clade B serpin family of proteins regulate a variety of cellular functions including cell adhesion and motility. One key member of the clade B serpin family is maspin (SERPINB5). Maspin is classified as a type II tumor suppressor that regulates cell adhesion and invasion. It is expressed in normal mammary epithelial cells but is reduced in benign breast tumors and absent in invasive breast carcinomas. Although maspin regulates cell apoptosis, cell adhesion, migration, and invasion in breast cancer cell culture systems, mouse models are necessary to verify this in vivo. In this chapter, we review the development of transgenic and syngeneic mouse models to study the role of maspin in mammary tumorigenesis and in normal mammary development. PMID- 21683254 TI - Hsp47 as a collagen-specific molecular chaperone. AB - Heat shock protein (HSP) 47 is a 47 kDa collagen-binding glycoprotein localized in the endoplasmic reticulum (ER). It belongs to the serpin family and contains a serpin loop, although it does not have serine protease inhibitory activity. The induction of Hsp47 by heat shock is regulated by a heat shock element in its promoter region, while the constitutive and tissue-specific expression of Hsp47 correlates with that of collagen and is regulated via enhancer elements located in the promoter and intron regions. Hsp47 transiently binds to procollagen in the ER and dissociates in the cis-Golgi or ER-Golgi intermediate compartment region (ERGIC). Gene ablation studies indicated that Hsp47 is essential for embryonic development and the maturation of several types of collagen. The requirement for Hsp47 in collagen maturation may reflect its ability to inhibit collagen aggregation by binding procollagen in the ER and facilitate triple helix formation. In Hsp47-deficient cells, misfolded procollagen aggregates in the ER are degraded by the autophagy-lysosome pathway but not through the ubiquitin proteasome pathway. Hsp47 may be a therapeutic target for collagen-related disorders such as fibrosis, which feature abnormal accumulations of collagen and increased expression of Hsp47. This is supported by mouse models of fibrosis in which knockdown of Hsp47 clearly decreased the accumulation of collagen in fibrotic tissues and prevented the promotion of fibrosis. On the other hand, mutations in Hsp47 cause collagen-related genetic diseases such as osteogenesis imperfecta. Thus, Hsp47 is an indispensible molecular chaperone specific for collagen that is important in several major human diseases. PMID- 21683255 TI - Assays for the antiangiogenic and neurotrophic serpin pigment epithelium-derived factor. AB - Pigment epithelium-derived factor (PEDF) is a secreted serpin that exhibits a variety of interesting biological activities. The multifunctional PEDF has neurotrophic and antiangiogenic properties, and acts in retinal differentiation, survival, and maintenance. It is also antitumorigenic and antimetastatic, and has stem cell self-renewal properties. It is widely distributed in the human body and exists in abundance in the eye as a soluble extracellular glycoprotein. Its levels are altered in diseases characterized by retinopathies and angiogenesis. Its mechanisms of neuroprotection and angiogenesis are associated with receptor interactions at cell-surface interfaces and changes in protein expression. This serpin lacks demonstrable serine protease inhibitory activity, but has binding affinity to extracellular matrix components and cell-surface receptors. Here we describe purification protocols, methods to quantify PEDF, and determine interactions with specific molecules, as well as neurotrophic and angiogenesis assays for this multifunctional protein. PMID- 21683256 TI - The Drosophila serpins: multiple functions in immunity and morphogenesis. AB - Members of the serpin superfamily of proteins have been found in all living organisms, although rarely in bacteria or fungi. They have been extensively studied in mammals, where many rapid physiological responses are regulated by inhibitory serpins. In addition to the inhibitory serpins, a large group of noninhibitory proteins with a conserved serpin fold have also been identified in mammals. These noninhibitory proteins have a wide range of functions, from storage proteins to molecular chaperones, hormone transporters, and tumor suppressors. In contrast, until recently, very little was known about insect serpins in general, or Drosophila serpins in particular. In the last decade, however, there has been an increasing interest in the serpin biology of insects. It is becoming clear that, like in mammals, a similar wide range of physiological responses are regulated in insects and that noninhibitory serpin-fold proteins also play key roles in insect biology. Drosophila is also an important model organism that can be used to study human pathologies (among which serpinopathies or other protein conformational diseases) and mechanisms of regulation of proteolytic cascades in health or to develop strategies for control of insect pests and disease vectors. As most of our knowledge on insect serpins comes from studies on the Drosophila immune response, we survey here the Drosophila serpin literature and describe the laboratory techniques that have been developed to study serpin-regulated responses in this model genetic organism. PMID- 21683257 TI - Modeling serpin conformational diseases in Drosophila melanogaster. AB - Transgenic Drosophila melanogaster have been used to model both the physiological and pathological behavior of serpins. The ability to generate flies expressing serpins and to rapidly assess associated phenotypes contributes to the power of this paradigm. While providing a whole-organism model of serpinopathies the powerful toolkit of genetic interventions allows precise molecular dissection of important biological pathways. In this chapter, we summarize the contribution that flies have made to the serpin field and then describe some of the experimental methods that are employed in these studies. In particular, we will describe the generation of transgenic flies, the assessment of phenotypes, and the principles of how to perform a genetic screen. PMID- 21683258 TI - Using Caenorhabditis elegans to study serpinopathies. AB - Protein misfolding, polymerization, and/or aggregation are hallmarks of serpinopathies and many other human genetic disorders including Alzheimer's, Huntington's, and Parkinson's disease. While higher organism models have helped shape our understanding of these diseases, simpler model systems, like Caenorhabditis elegans, offer great versatility for elucidating complex genetic mechanisms underlying these diseases. Moreover, recent advances in automated high throughput methodologies have promoted C. elegans as a useful tool for drug discovery. In this chapter, we describe how one could model serpinopathies in C. elegans and how one could exploit this model to identify small molecule compounds that can be developed into effective therapeutic drugs. PMID- 21683259 TI - Using C. elegans to identify the protease targets of serpins in vivo. AB - Most serpins inhibit serine and/or cysteine proteases, and their inhibitory activities are usually defined in vitro. However, the physiological protease targets of most serpins are unknown despite many years of research. This may be due to the rapid degradation of the inactive serpin:protease complexes and/or the conditions under which the serpin inhibits the protease. The model organism Caenorhabditis elegans is an ideal system for identifying protease targets due to powerful forward and reverse genetics, as well as the ease of creating transgenic animals. Using combinatorial approaches of genetics and biochemistry in C. elegans, the true in vivo protease targets of the endogenous serpins can be elucidated. PMID- 21683261 TI - Human SCCA serpins inhibit staphylococcal cysteine proteases by forming classic "serpin-like" covalent complexes. AB - Proteolytic enzymes secreted by Staphylococcus aureus are considered important virulence factors. Here, we present data showing that staphylococci-derived cysteine proteases (staphopains) are efficiently inhibited by squamous cell carcinoma antigen 1 (SCCA1), a serpin abundant on the epithelial surfaces. The high association rate constant (k(ass)) for inhibitory complex formation (1.9 * 104 and 5.8 *104 M-1 s-1 for staphopain A and staphopain B interaction with SCCA1, respectively) argues that SCCA1 can restrain staphopain activity in vivo at epithelial sites colonized by S. aureus. The mechanism of staphopain inhibition by SCCA1 is apparently the same as for serpin interaction with target serine proteases. The formation of a covalent complex results in cleavage of the SCCA1 reactive site peptide bond, and it is associated with the release of the C terminal peptide of 37 amino acid residues from the serpin. Significantly, the SCCA1 reactive site closely resembles a motif in the reactive site loop of natural S. aureus-derived inhibitors of the staphopains (staphostatins). Taking into account that SCCA1 is predominantly expressed in epithelial tissues, including respiratory pathways, hair follicles and skin [Kato, H. (1996). Expression and function of squamous cell carcinoma antigen. Anticancer Res.16, 2149-2153.], all of which are regularly colonized by S. aureus, the physiological relevance of SCCA1-staphopain B interaction as a defense mechanism seems to be very well substantiated. PMID- 21683260 TI - Viral serpin therapeutics from concept to clinic. AB - Over the past 19 years, we have developed a novel myxoma virus-derived anti inflammatory serine protease inhibitor, termed a serpin, as a new class of immunomodulatory therapeutic. This review will describe the initial identification of viral serpins with anti-inflammatory potential, beginning with preclinical analysis of viral pathogenesis and proceeding to cell and molecular target analyses, and successful clinical trial. The central aim of this review is to describe the development of two serpins, Serp-1 and Serp-2, as a new class of immune modulating drug, from inception to implementation. We begin with an overview of the approaches used for successful mining of the virus for potential serpin immunomodulators in viruses. We then provide a methodological overview of one inflammatory animal model used to test for serpin anti-inflammatory activity followed by methods used to identify cells in the inflammatory response system targeted by these serpins and molecular responses to serpin treatment. Finally, we provide an overview of our findings from a recent, successful clinical trial of the secreted myxomaviral serpin, Serp-1, in patients with unstable inflammatory coronary arterial disease. PMID- 21683262 TI - Plants and the study of serpin biology. AB - Serpins appear to be ubiquitous in the Plant Kingdom and have several unique properties when compared to the substantial number of other families of protease inhibitors in plants. Serpins in plants are likely to have functions distinct from those of animal serpins, partly because plants and animals developed multicellularity independently and partly because most animal serpins are involved in animal-specific processes, such as blood coagulation and the activation of complement. To encourage and facilitate the discovery of plant serpin functions, here we provide a set of protocols for detection of serpins in plant extracts, localization of serpins in plant tissues and cells, purification of serpins from a range of organs from monocot and eudicot plants, production and purification of recombinant plant serpins, and analysis of plant-protease interactions including identification of in vivo target proteases. PMID- 21683263 TI - [Importance of geriatric centres or long-stay health institutions due to the endemic persistence of MRSA]. PMID- 21683264 TI - Changes after surgically-assisted maxillary expansion (SARME) to the dentoalveolar, palatal and nasal structures by using tooth-borne distraction devices. AB - Different devices are available to aid surgically-assisted maxillary expansion. In this study we have evaluated the changes to the anchoring teeth, the hard palate, and the lower nasal passage made by tooth-borne distraction devices. Thirty-one patients (mean (SD) age 28 (2) years) with deficiencies in the transverse width of the maxilla were examined by computed tomography and cone beam scans before and after operation. The data were analysed with the help of Wilcoxon's signed rank test and Spearman's r correlation. The mean (SD) distraction width was 6.5 (2.3) mm. All anchorage teeth were tilted (p<0.01). The axes changed by a mean (SD) of 4.8 (0.9) degrees in the first premolar and 3.1 (0.8) degrees in the first molar. The nasal isthmus increased by a mean (SD) of 2.5 (0.3) mm. The hard palate adjacent to the anchoring teeth increased anteriorly by a mean (SD) of 2.8 (0.4) mm and posteriorly by 2.7 (0.4) mm. The hard palate was lowered by 1.2 (0.8) mm. There was a significant correlation in the distraction width, with changes in the intercoronal and interapical distances of the anchoring premolars (p<0.05) and with the interapical distance of the anchoring molars (p<0.01). There was also a correlation between the distraction width and the overall gain in width of the lower nasal passage (p<0.05). The results suggested that surgically-assisted maxillary expansion with tooth-borne devices has significant effects on the anchoring teeth, the nasal floor, and the hard palate. Both tilting of the teeth and an evenly distributed movement of the segments were seen. PMID- 21683265 TI - DnaJ sequences of Bacillus cereus strains isolated from outbreaks of hospital infection are highly similar to Bacillus anthracis. AB - Bacillus cereus is becoming an important nomosomial pathogen because of frequent isolation from blood cultures and from severe systemic infections. To differentiate highly pathogenic outbreak strain of B. cereus from other sources of the Bacillus cereus, we attempted to analyze their dnaJ sequences. Assays indicated that dnaJ sequence similarity of all of 52 blood culture isolates of B. cereus ranged from 92.8% to 100%. The distance between B. anthracis and B. cereus except six outbreak isolates ranged from 3.8% to 6.4%. The dnaJ sequences of six outbreak strains of B. cereus (GTC 02891, GTC 02896, GTC 02916, GTC 02917, GTC 03221, and GTC 03222) were closely related to those of B. anthracis (99.2%-99.5% sequence similarity). Ba813 sequences were only found in the six outbreak strains of B. cereus. The other pathogenic factors of B. anthracis were not found in these six outbreak strains, with the exception of GTC 02891 (cap-positive). The six outbreak strains formed clear beta-hemolytic colonies on a sheep blood agar plate. Our findings suggest that outbreak strains of B. cereus isolated from blood cultures are likely to have the risk of causing serious infection, and dnaJ and Ba813 are important markers to identify such strains. Phylogenetic analysis of dnaJ and MLST revealed that the six outbreak strains of B. cereus are closely related to B. anthracis. PMID- 21683266 TI - Fasciola hepatica saposin-like protein-2-based ELISA for the serodiagnosis of chronic human fascioliasis. AB - An indirect enzyme-linked immunosorbent assay (ELISA) was developed and evaluated for its diagnostic ability to detect human IgG antibodies against Fasciola hepatica saposin-like protein-2. The assay was compared with an indirect ELISA with excretory-secretory products (FhES) from adult F. hepatica. In an analysis of the sera of 37 patients infected with F. hepatica, 40 patients with other parasitic infections, and 50 healthy controls, the sensitivity of both ELISA assays was 100%. However, the FhSAP2-based ELISA was more specific (95.6%) than the FhES-ELISA (91.9%). These results demonstrated that FhSAP2 can be used in the serodiagnosis of chronic human fascioliasis with the additional advantage of being relatively cheap and easy to produce. Studies are in progress to evaluate this FhSAP2-ELISA assay in a large-scale prevalence surveys in endemic areas. PMID- 21683267 TI - Contribution of laboratory methods in diagnosing clinically suspected ocular toxoplasmosis in Brazilian patients. AB - This prospective study evaluated the value of laboratorial diagnosis in ocular toxoplasmosis analyzing peripheral blood samples from a group of Brazilian patients by immunologic and molecular methods. We analyzed blood samples from 184 immunocompetent patients with ocular disorders divided into 2 groups: Group I, composed of samples from 49 patients with ocular toxoplasmosis diagnosed by clinical features; Group II, samples from 135 patients with other ocular diseases. Samples were assayed by conventional polymerase chain reaction (cnPCR), real-time PCR (qPCR) for Toxoplasma gondii, indirect immunofluorescence reaction (IF), avidity test (crude tachyzoite lysate as antigen), and excreted-secreted tachyzoite proteins as antigen (ESA-ELISA). cnPCR and qPCR profiles were concordant in all samples. Positive PCR was shown in 40.8% of group I patients. The majority of the positive blood samples (75%) were taken from patients with toxoplasmic retinochoroiditis scars, and the others (25%), from patients with retinal exudative lesions. Despite that 86 of the 135 patients from Group II had asymptomatic toxoplasmosis, all DNA blood samples had negative PCR. Concordant results were shown in the data obtained by serologic methods. Around 24% of the patients with ocular toxoplasmosis had high antibody titers determined by ESA ELISA and IF. Anti-ESA antibodies are shown principally in patients with active infection. Collectively, these data demonstrate the presence of tachyzoites in the blood of patients with chronic infection, supporting the idea of recurrent disease. Circulating parasites in blood of immunocompetent individuals may be associated with the reactivation of the ocular disease. PMID- 21683268 TI - The effects of group 1 versus group 2 carbapenems on imipenem-resistant Pseudomonas aeruginosa: an ecological study. AB - Use of the group 2 carbapenems, imipenem and meropenem, may lead to emergence of Pseudomonas aeruginosa resistance. The group 1 carbapenem ertapenem has limited activity against P. aeruginosa and is not associated with imipenem-resistant P. aeruginosa (IMP-R PA) in vitro. This retrospective, group-level, longitudinal study collected patient, antibiotic use, and resistance data from 2001 to 2005 using a hospital database containing information on 9 medical wards. A longitudinal data time series analysis was done to evaluate the association between carbapenem use (defined daily doses, or DDDs) and IMP-R PA. A total of 139 185 patient admissions were included, with 541 150 antibiotics DDDs prescribed: 4637 DDDs of group 2 carbapenems and 2130 DDDs of ertapenem. A total of 779 IMP-R PA were isolated (5.6 cases/1000 admissions). Univariate analysis found a higher incidence of IMP-R PA with group 2 carbapenems (P < 0.001), aminoglycosides (P = 0.034), and penicillins (P = 0.05), but not with ertapenem. Multivariate analysis showed a yearly increase in incidence of IMP-R-PA (3.8%, P < 0.001). Group 2 carbapenem use was highly associated with IMP-R PA, with a 20% increase in incidence (P = 0.0014) for each 100 DDDs. Group 2 carbapenem use tended to be associated with an increased proportion of IMP-R PA (P = 0.0625) in multivariate analysis. Ertapenem was not associated with IMP-R PA. These data would support preferentially prescribing ertapenem rather than group 2 carbapenems where clinically appropriate. PMID- 21683270 TI - A study on erm(B)-mediated MLS resistance in Streptococcus pyogenes clinical isolates. AB - The constitutive or inducible macrolide-lincosamide-streptogramin (MLS) phenotype of 30 erm(B)-positive Streptococcus pyogenes isolates was determined by different methods and under various growth conditions and correlated to the sequence of the 5'-untranslated regions of erm(B). The MLS phenotype of one-third of the isolates could not be classified. In liquid medium, some of these isolates responded to induction only during the logarithmic phase of growth, while others expressed clindamycin resistance even under noninducing conditions. By increasing the growth rate, we observed a shift from a constitutive towards an inducible pattern of resistance. All data were confirmed by analysis of the 23S rRNA methylation level. The erm(B)-5'-untranslated region was 99% similar in sequence. In erm(B) positive S. pyogenes, the MLS phenotype is strongly influenced by culture conditions and control of its expression does not depend exclusively on the sequence of the erm(B)-5'-untranslated region. PMID- 21683271 TI - Accuracy of MIC determination for Streptococcus pneumoniae using the Sirscan2000automatic MIC determination system. AB - The Sirscan2000automatic MIC determination (SIR-MD) system is a new system for MIC determination based on the automatic detection of growth of bacteria spotted onto agar medium using a camera scan. To evaluate its accuracy, 3608 Streptococcus pneumoniae clinical isolates yielding 18,165 MICs were tested in parallel with the SIR-MD and a standard interpretive antibiogram procedure. The overall percent agreement between the 2 methods within 1 log(2) dilution was 86.9%. After exclusion of the 11.8% noninterpretable results, errors in the deduction of susceptibilities were very major in 0.03%, major in 0.2%, and minor in 1.3%. PMID- 21683269 TI - Comparative activities of daptomycin and several agents against staphylococcal blood isolates. Glycopeptide tolerance. AB - The activity of daptomycin was evaluated against 702 staphylococcal blood isolates (316 methicillin-susceptible Staphylococcus aureus, 187 methicillin resistant S. aureus [MRSA], and 199 coagulase-negative staphylococci [CoNS]) collected in 41 Spanish hospitals. Glycopeptide tolerance and the incidence of heterogeneous glycopeptide-intermediate (hGISA) isolates were also examined. Vancomycin MICs determined by the Etest were compared with those obtained by the reference broth microdilution method. Daptomycin exhibited good activity, and only 2 isolates were nonsusceptible to this antibiotic. Resistance to linezolid was observed in 2 MRSA isolates and in 16 CoNS. The cfr gene was detected in 7 of these 18 isolates. Vancomycin and teicoplanin tolerance was 9.6% and 21.9%, respectively, in MRSA isolates. We detected the hGISA phenotype in 5.8% of MRSA isolates. Vancomycin MICs by the Etest were slightly higher than those obtained by broth microdilution. Daptomycin retained activity against isolates that were not susceptible to linezolid, teicoplanin, or quinupristin-dalfopristin. PMID- 21683272 TI - Lack of effect of strain type on detection of toxigenic Clostridium difficile by glutamate dehydrogenase and polymerase chain reaction. AB - Glutamate dehydrogenase (GDH) is popular as a preliminary test for the detection of Clostridium difficile. Recent work has suggested that GDH sensitivity may vary according to ribotype and may be lower for ribotypes 002, 027, and 106 compared with polymerase chain reaction (PCR). We investigated this effect using a dilution series of 64 isolates tested by GDH and Cepheid GeneXpert PCR. PCR was significantly more sensitive than GDH overall; however, there was no difference in detection according to specific ribotype. PMID- 21683273 TI - Are we foodies? PMID- 21683275 TI - Location of food stores near schools does not predict the weight status of Maine high school students. AB - OBJECTIVE: To examine the relationship between stores selling calorie-dense food near schools and student obesity risk, with the hypothesis that high availability predicts increased risk. METHODS: Mail surveys determined height, weight, and calorie-dense food consumption for 552 students at 11 Maine high schools. Driving distance from all food stores within 2 km (1.24 miles) of schools (or the closest store) was computed, and the impact of food store density and proximity to schools on student body mass index was determined by logistic regression. RESULTS: Ten schools had >= 1 store selling soda, and 8 schools had >=1 fast-food restaurant within 1 km (0.62 miles). There were no significant relationships between the proximity or density of food stores around schools and student obesity risk. Students obtained sugar-sweetened beverages in many locations including at school. CONCLUSIONS AND IMPLICATIONS: Unhealthful food choices are ubiquitous. Consequently, stores selling these food items near schools have no significant affect on student obesity. PMID- 21683277 TI - Youth Can! results of a pilot trial to improve the school food environment. AB - OBJECTIVE: This study evaluated the potential of youth partnerships to improve the school environment and child nutrition. METHODS: A quasi-experimental trial was conducted with 2 intervention and 3 control schools. Intervention schools selected student leaders to participate in youth-led interventions in their schools. Students (n = 104) were included in the evaluation if they were in the fourth grade at baseline and had complete baseline and follow-up data. The intervention trained student leaders in research, advocacy, and nutrition. Leaders implemented interventions appropriate to their schools. Changes in children's reported dietary intake were examined. Data were analyzed using multivariable regression. RESULTS: Children's diets changed in response to the interventions offered at the schools, although the dietary changes differed by the types of interventions selected. CONCLUSIONS AND IMPLICATIONS: Partnering with youth, even at the elementary school level, is a promising avenue for developing tailored interventions for schools. PMID- 21683276 TI - Self-efficacy scale for weight loss among multi-ethnic women of lower income: a psychometric evaluation. AB - OBJECTIVE: This study examined test-retest reliability, internal consistency, and construct and predictive validity of the Physical Activity and Nutrition Self Efficacy (PANSE) scale, an 11-item instrument to assess weight-loss self-efficacy among postpartum women of lower income. METHODS: Seventy-one women completed the PANSE scale and psychosocial measures at baseline and at 7 and 13 weeks of a pilot study of weight loss. RESULTS: Test-retest reliability of PANSE scores was r = 0.55 (P < .01). Cronbach alpha was r = 0.89. Construct validity was supported by correlations with less-healthful behaviors (r = -0.33, P = .005), perceived stress (r = -0.24, P = .04), and decisional balance (r = 0.25, P = .03). PANSE change scores correlated with intervention group weight changes (r = -0.54, P < .01), although baseline scores did not. One factor emerged (loadings .80 to .57). CONCLUSIONS AND IMPLICATIONS: The PANSE scale demonstrated adequate reliability, internal consistency, construct validity, and moderate predictive validity. Replication is needed to confirm study findings. PMID- 21683278 TI - Nutritionopoly: let healthy choices "monopolize" your lifestyle. PMID- 21683279 TI - Reliability of a retail food store survey and development of an accompanying retail scoring system to communicate survey findings and identify vendors for healthful food and marketing initiatives. AB - OBJECTIVE: To develop a retail grocery instrument with weighted scoring to be used as an indicator of the food environment. PARTICIPANTS/SETTING: Twenty six retail food stores in low-income areas in California. INTERVENTION: Observational. MAIN OUTCOME MEASURE(S): Inter-rater reliability for grocery store survey instrument. Description of store scoring methodology weighted to emphasize availability of healthful food. ANALYSIS: Type A intra-class correlation coefficients (ICC) with absolute agreement definition or a kappa test for measures using ranges as categories. RESULTS: Measures of availability and price of fruits and vegetables performed well in reliability testing (kappa = 0.681 0.800). Items for vegetable quality were better than for fruit (ICC 0.708 vs 0.528). Kappa scores indicated low to moderate agreement (0.372-0.674) on external store marketing measures and higher scores for internal store marketing. "Next to" the checkout counter was more reliable than "within 6 feet." Health departments using the store scoring system reported it as the most useful communication of neighborhood findings. CONCLUSIONS AND IMPLICATIONS: There was good reliability of the measures among the research pairs. The local store scores can show the need to bring in resources and to provide access to fruits and vegetables and other healthful food. PMID- 21683280 TI - Effect of fresh fruit availability at worksites on the fruit and vegetable consumption of low-wage employees. AB - OBJECTIVE: To examine the impact of fresh fruit availability at worksites on the fruit and vegetable consumption and related psychosocial determinants of low-wage employees. DESIGN: A prospective, randomized block experimental design. SETTING: Seven apparel manufacturing and 2 food processing worksites. PARTICIPANTS: A convenience sample of 391 low-wage employees in 6 intervention worksites and 137 low-wage employees in 3 control worksites in Los Angeles, CA. INTERVENTION: Fresh fruit deliveries with enough for 1 serving per employee, 3 days a week for 12 consecutive weeks. The control worksites did not receive the fruit deliveries. MAIN OUTCOME MEASURES: Participants' fruit and vegetable consumption, fruit and vegetable purchasing habits, self-efficacy, job satisfaction, and overall health were measured at baseline, weeks 4 and 8, and following the 12-week intervention. ANALYSIS: Descriptive statistics and growth curve analysis using hierarchical linear modeling were employed to analyze the data. RESULTS: Participants in the intervention worksites showed a significant increase in fruit, vegetable, and total fruit and vegetable consumption, purchasing of fruit, family purchasing of vegetables, and self-efficacy toward eating 2 servings of fruit each day compared to the control worksites. CONCLUSIONS AND IMPLICATIONS: Improving access to fruit during the workday can improve fruit and vegetable consumption, purchasing habits, and self-efficacy of low-income employees. PMID- 21683281 TI - The Power Play! Campaign's School Idea & Resource Kits improve determinants of fruit and vegetable intake and physical activity among fourth- and fifth-grade children. AB - OBJECTIVE: Examine the effect of the California Children's Power Play! Campaign's School Idea & Resource Kits for fourth/fifth grades on the psychosocial determinants of fruit and vegetable (FV) intake and physical activity (PA). METHODS: Randomized, controlled trial (n = 31 low-resource public schools; 1,154 children). Ten grade-specific, 50-minute nutrition and PA lessons over an 8-week period. Pre/post surveys measuring knowledge, outcome expectations, and self efficacy (SE) were analyzed using analysis of covariance, controlling for baseline values; chi-square comparing positive/negative changes, adjusted for cluster design effects. RESULTS: Intervention children made significant gains for FV knowledge (4 items, P < .05 to P < .001); positive outcome expectations (fifth grade only, P < .001); asking/shopping and eating SE (P = .04 and P < .001); PA knowledge (2 items, P < .01 to P < .001); outcome expectations (P < .05); and support seeking SE (P = .04); but not SE to overcome barriers. CONCLUSIONS AND IMPLICATIONS: The Power Play! Campaign's School Idea & Resource Kits improved the determinants of FV intake and PA. PMID- 21683282 TI - Building evaluation capacity in local programs for multisite nutrition education interventions. AB - From 2004-2008, capacity to conduct program evaluation was built among the Network for a Healthy California's 48 largest local partners. Capacity building was done within a framework of Empowerment Evaluation and Utility-Focused evaluation. Tools included: a Scope of Work template, a handbook, a compendium of surveys, an evaluation plan and report template, data entry and analysis templates, teleconferences, workshops, and technical assistance. Over time, more programs completed an evaluation, used a more rigorous design, and reported statistically significant results. Acting as an evaluation guide, rather than a funder, Network staff built rapport with local programs that annually undertake new evaluations. PMID- 21683283 TI - Community health centers: a promising venue for supplemental nutrition assistance program education in the Central Valley. AB - Health care providers could help achieve the necessary shift to healthful eating and active living; however, lack of coverage or reimbursement, lack of time, and limited information about appropriate interventions are some of the documented barriers. This report highlights the potential for Supplemental Nutrition Assistance Program Education (SNAP-Ed) implementation in the relatively nontraditional setting of Federally Qualified Health Centers based on the experience of the Central Valley Health Network's Nutrition Education Demonstration Project. The report provides a brief overview of the primary prevention role(s) suggested for health care providers, relevant SNAP-Ed policies, how SNAP-Ed has been implemented in Federally Qualified Health Center settings, and recommendations for similar efforts. PMID- 21683284 TI - Impact of a kindergarten through eighth-grade nutrition education program on student, teacher, and schoolwide practices. PMID- 21683285 TI - Enhancing the delivery of Supplemental Nutrition Assistance Program education through geographic information systems. PMID- 21683286 TI - Impact of the Harvest of the Month program on low-income Hmong and white middle school students. PMID- 21683287 TI - Catering trucks in California promote healthful eating in low-wage worksites. PMID- 21683288 TI - Cultural adaptation of a nutrition education curriculum for Latino families to promote acceptance. PMID- 21683289 TI - Curriculum intervention in preschool children: Nutrition Matters! PMID- 21683290 TI - Raising the bar for practice and research collaborations. PMID- 21683291 TI - From the Network for a Healthy California. PMID- 21683292 TI - Using an opinion poll to build an obesity-prevention social marketing campaign for low-income Asian and Hispanic immigrants: report of findings. AB - OBJECTIVE: To gain opinions from low-income, limited-English-speaking Hispanic and Asian immigrants for formative research in a social marketing campaign. DESIGN: Nineteen questions on obesity prevention-related topics were embedded into a larger random digit-dial survey investigating the effects of language and cultural barriers on health care access. Participants were selected by ethnic encoding from consumer databases. SETTING: California's northern, southern, and Central Valley regions. PARTICIPANTS: Nine hundred and five adult Hispanic, Chinese, Vietnamese, Hmong, and Korean Californians from households < 130% of the Federal Poverty Level interviewed in 2005. VARIABLES MEASURED: Media usage, food stamp participation, health insurance, health problems, access and availability of fruits and vegetables (FVs) and physical activity, beliefs about overweight, and related regulation and policy change. ANALYSIS: Descriptive statistics and percentages for all questions. RESULTS: Latinos reported receiving most information from television; Hmong from radio. Hispanics, Koreans, and Vietnamese thought diabetes was the greatest health issue in California. Among Hmong, 83% thought FVs were too expensive, and 49% of Vietnamese thought good quality, affordable fresh FVs were too hard to find. CONCLUSIONS AND IMPLICATIONS: Identifying characteristics and opinions that distinguish these ethnic immigrant populations better enables the Network for a Healthy California to develop culturally relevant social marketing campaigns and materials. PMID- 21683293 TI - Evaluating form and function of regional partnerships: applying social network analysis to the Network for a Healthy California, 2001-2007. AB - OBJECTIVE: To evaluate the partnership structure of the Network for a Healthy California (Network), a social marketing program, from 2001-2007, to determine if California's program was able to establish and maintain partnerships that (1) provided access to a local audience, (2) facilitated regional collaboration, (3) included new and nontraditional partners, and (4) strengthened regional networks over time, even with significant administrative changes in 2003 and 2006. DESIGN: An outcome evaluation using 5 years of cross-sectional data. SETTING: Data drawn from annual progress reports. PARTICIPANTS: Funded local agencies and regional lead agencies. MAIN OUTCOME MEASURES: Regional sociograms offered a visual assessment. Social network statistics (fragmentation and density) were calculated from sociogram data for changes over time. ANALYSIS: A social network analysis and time-series regression analysis. RESULTS: Sociograms demonstrated that more counties participated, more local agencies worked together, and networks were more integrated in 2007 than in 2001. Increased cohesion of Network partners was demonstrated by decreased fragmentation, and reaching out to new and existing partners was demonstrated by density. CONCLUSIONS AND IMPLICATIONS: The Network developed in a way consistent with program goals. Social network analysis offers great potential for partnership and systems research. PMID- 21683294 TI - Using a Toolbox of tailored educational lessons to improve fruit, vegetable, and physical activity behaviors among African American women in California. AB - OBJECTIVE: Evaluate the effectiveness of the Fruit, Vegetable, and Physical Activity Toolbox for Community Educators (Toolbox), an intervention originally designed for Spanish- and English-speaking audiences, in changing knowledge, attitudes, and behavior among low-income African American women. DESIGN: Quasi experimental design with treatment and control groups. SETTING: Four community based organizations and direct health service provider sites. PARTICIPANTS: African American women ages 18-54 (156 treatment, 171 control), 75% of whom were low income. INTERVENTION: Six 1-hour Toolbox classes. MAIN OUTCOME MEASURES: Knowledge, attitudes, self-efficacy, empowerment, and behavior change related to fruits and vegetables and physical activity. ANALYSIS: Dependent t tests pre- to posttest and chi-square test between control and treatment groups. RESULTS: Women in the treatment group reported significant changes in 9 measures of attitude, compared to 1 measure in the control group, as well as 12 measures of confidence and 5 measures of empowerment for which the control group showed no changes. Compared to those in the control group, women in the treatment group were also more likely to make behavioral changes to meet recommendations for fruit and vegetable consumption and physical activity. CONCLUSIONS AND IMPLICATIONS: Toolbox lessons were effective in increasing participants' knowledge, attitudes, self-efficacy, empowerment, and reported fruit and vegetable- and physical activity-related behaviors. PMID- 21683295 TI - Usage and recall of the Food Stamp Office Resource Kit (FSORK) by food stamp applicants in 4 California counties. AB - OBJECTIVE: To evaluate recall and usage of the Food Stamp Office Resource Kit (FSORK), a set of nutrition education materials designed for use in food stamp offices. DESIGN: Client intercept exit surveys, an environmental scan, and individual observations of clients in the food stamp office. SETTING: Four food stamp offices in California. PARTICIPANTS: People applying for food stamps in community social service offices: exit survey (n = 419), environmental scan (n = 308), individual observations of video (n = 111). INTERVENTION: FSORK includes a video, poster, recipe cards, and brochures for the waiting room. MAIN OUTCOME MEASURE(S): Aided and unaided recall of FSORK materials, self-efficacy, video attention (eyes on screen), and observations of materials usage. ANALYSIS: Descriptive statistics for recall, usage, and video attention. RESULTS: Nearly 70% of clients recalled, unaided, at least 1 FSORK element with the video recalled the most. In the observation study, of clients who initially engaged with the video, 40% of their viewing time was spent "watching" it. CONCLUSIONS AND IMPLICATIONS: Food stamp offices are a useful setting for nutrition education in offices that are willing and able to display the materials and show the video. PMID- 21683296 TI - California adults increase fruit and vegetable consumption from 1997-2007. AB - OBJECTIVE: To determine whether fruit and vegetable consumption among California adults significantly increased from 1997-2007. DESIGN: Biennial telephone surveillance surveys of California adults' dietary practices. PARTICIPANTS: California adults (n = 9,105 total all 6 surveys). INTERVENTION: Surveillance data reporting. MAIN OUTCOME MEASURES: Changes in fruit and vegetable consumption over time between 1997-2007, measured by mean servings and percentage of adults eating >= 5 servings on any given day. ANALYSIS: Comparisons of subsets both within the same year and across years were made using t tests, chi-square, and Tukey Studentized Range tests at 5% procedure-wise error rate. RESULTS: California adults significantly increased mean daily servings of fruits and vegetables from 3.8 servings in 1997 to 5.2 servings in 2007. CONCLUSIONS AND IMPLICATIONS: Since 1998, notable improvements in fruit and vegetable consumption have occurred to California populations, including the target audience groups of the Network for a Healthy California. PMID- 21683297 TI - Air pollution: An environmental factor contributing to intestinal disease. AB - The health impacts of air pollution have received much attention and have recently been subject to extensive study. Exposure to air pollutants such as particulate matter (PM) has been linked to lung and cardiovascular disease and increases in both hospital admissions and mortality. However, little attention has been given to the effects of air pollution on the intestine. The recent discovery of genes linked to susceptibility to inflammatory bowel diseases (IBD) explains only a fraction of the hereditary variance for these diseases. This, together with evidence of increases in incidence of IBD in the past few decades of enhanced industrialization, suggests that environmental factors could contribute to disease pathogenesis. Despite this, little research has examined the potential contribution of air pollution and its components to intestinal disease. Exposure of the bowel to air pollutants occurs via mucociliary clearance of PM from the lungs as well as ingestion via food and water sources. Gaseous pollutants may also induce systemic effects. Plausible mechanisms mediating the effects of air pollutants on the bowel could include direct effects on epithelial cells, systemic inflammation and immune activation, and modulation of the intestinal microbiota. Although there is limited epidemiologic evidence to confirm this, we suggest that a link between air pollution and intestinal disease exists and warrants further study. This link may explain, at least in part, how environmental factors impact on IBD epidemiology and disease pathogenesis. PMID- 21683298 TI - Comprehensive study of cardiovascular morbidity in hospitalized inflammatory bowel disease patients. AB - BACKGROUND: The full extent of cardiovascular morbidity in inflammatory bowel disease is not well understood. OBJECTIVE: To comprehensively study the association of different cardiovascular diseases in hospitalized patients with inflammatory bowel disease (IBD) using a large database. METHODS: We used the Nationwide Inpatient Sample (NIS) database to perform a cross-sectional study. The study group was defined as all hospitalized patients between ages 18-60 years included in the NIS 2006 database with a discharge diagnosis of IBD, as per the International Classification of Diseases - Clinical Modification, 9th revision (ICD-9-CM) codes. Individuals in the same age group whose hospital discharge records did not note IBD were identified as the control group. Cardiovascular diseases, identified by the ICD-9-CM codes, were studied comprehensively for their association with IBD using multivariate logistic regression analysis. Odds ratios were calculated adjusting for relevant patient comorbidities. RESULTS: IBD was found to be strongly associated with mesenteric ischemia (adjusted odds ratio (aOR), 3.4; 95% confidence interval (CI), 2.9-4.0) and venous thrombotic diseases (aOR, 1.38; 95% CI, 1.25-1.53). Age and gender stratified analysis revealed that IBD is positively associated with dysrhythmias in females aged 18-39 years (aOR, 2.05; 95% CI, 1.72-2.44). We did not find an increased risk of other cardiovascular diseases in IBD patients. CONCLUSIONS: Our study substantiates the previously reported associations of mesenteric ischemia and venous thrombotic disorders with IBD. Our study also suggests that young females with IBD might have an increased risk for dysrhythmias. PMID- 21683299 TI - Measurement of reticulocyte and red blood cell indices in the evaluation of anemia in inflammatory bowel disease. AB - BACKGROUND: The commonest types of anemia in inflammatory bowel disease (IBD) are iron deficiency (IDA) and anemia of chronic disease. The differentiation between these two conditions is important for the management of the patient. The aim of this study was to investigate the usefulness of reticulocyte and red blood cell indices in the evaluation of anemia in IBD. METHODS: One hundred IBD patients [49 ulcerative colitis (UC), 51 Crohn's disease (CD)] and 102 healthy controls were enrolled. Measurement of reticulocyte and red blood cell indices was performed using the Coulter LH780 Hematology Analyzer (Beckman Coulter). Additionally, serum levels of ferritin, transferrin saturation (Tsat) and soluble transferrin receptor (sTfR) were analyzed in all patients and controls. RESULTS: The prevalence of anemia was 41.2% for UC and 42.9% for CD, whereas 30 IBD patients (30%) had IDA. Red cell Distribution Width (RDW), Red blood cell Size Factor (RSF), and Reticulocyte Distribution Width-Coefficient of Variation (RDWR-CV) were found significantly correlated with both Tsat and sTfR but not with ferritin levels. Patients with IDA had significantly higher RDW and RDWR-CV and significantly lower RSF levels compared with those without IDA. High values of RDW (sensitivity 93%, specificity 81%) and low values of RSF (sensitivity 83%, specificity 82%) were the best markers for the diagnosis of IDA. Both RDWR-CV and RDWR-SD were significantly correlated with disease activity and CRP levels. CONCLUSION: RDW, RSF and RDWR, could be useful markers for the evaluation of anemia and disease activity in IBD. PMID- 21683300 TI - Managing the long term care of inflammatory bowel disease patients: The cost to European health care providers. AB - BACKGROUND AND AIMS: Inflammatory Bowel Disease (which includes Crohn's Disease and Ulcerative Colitis), is a chronic condition characterised by substantial morbidity. Inflammatory Bowel Disease patients are considered expensive to manage, hence accurate estimates of care costs are crucial to help healthcare providers plan clinical management. The aim of this study is to estimate the cost of care for Crohn's Disease and Ulcerative Colitis patients in the United Kingdom and Western mainland Europe. METHODS: Decision models were built to simulate the natural disease history of Crohn's Disease and Ulcerative Colitis, informed by United Kingdom and European clinical pathways. A healthcare provider perspective was adopted, model inputs were informed by published sources and expert opinion, and UK healthcare costs were used (2008 prices). Cohorts of 25 year old patients presenting with symptoms of varying severity were modelled over ten years, and annual treatment costs calculated per patient. RESULTS: The average annual cost of care per Crohn's Disease/Ulcerative Colitis patient was L631/L762 (United Kingdom) and L838/L796 (Europe). Most costs were incurred immediately following diagnosis, particularly in European Crohn's patients, reflecting the earlier use of more aggressive treatments. Surgery, hospitalisation, and the use of biological therapies and mesalazine (in Ulcerative Colitis) were key cost drivers. The total annual cost to the United Kingdom National Health Service of caring for Inflammatory Bowel Disease patients was estimated to be L131million. CONCLUSIONS: This study confirms that Inflammatory Bowel Disease patients are expensive to manage and illustrates the importance of differentiating between alternative clinical management scenarios. PMID- 21683301 TI - Conception and pregnancy outcome in women with inflammatory bowel disease: A multicentre study from Japan. AB - BACKGROUND: Neither conceptions and pregnancy outcomes nor the safety of medications for childbearing inflammatory bowel disease (IBD) patients has been investigated in Asia. The aim of this study is to analyse conception and pregnancy outcomes of Japanese female IBD patients. METHODS: We conducted a retrospective cohort study of pregnant IBD patients at 6 institutions. The incidences of abortion, Caesarean delivery, low birth weight (LBW) (<2500g), and congenital malformation were analysed in these patients. Risk factors associated with adverse outcomes in IBD patients were also assessed. RESULTS: A total of 325 patients experienced 534 conceptions. Among these, 303 conceptions (57%) were observed during/after disease onset. Although conceptions and pregnancy outcomes after disease onset were comparable to the observed levels prior to disease onset in UC patients, the incidences of spontaneous abortion (OR 5.3; 95%CI 1.1-25.0) and Caesarean delivery (OR 4.8; 95%CI 1.5-15.0) were significantly higher in Crohn's disease (CD) patients whose conceptions occurred after disease onset compared to CD patients whose conceptions occurred before disease onset. The incidences of spontaneous abortion, LBW, and Caesarean delivery were higher in CD patients who had a history of surgery for perianal lesions than in those who did not have perianal lesions or who had ulcerative colitis (UC). In the IBD patients studied after disease onset, independent risk factors for spontaneous abortions included a history of previous treatment for sterility (OR 2.9; 95%CI 1.2-7.0). Independent risk factors for Caesarean operation (OR 4.1, 95% CI: 1.7-10.1) and LBW (OR 3.5, 95% CI: 1.3-9.1) included a history of bowel resection for the treatment of IBD. Congenital malformation was not associated with the factors of type of disease, smoking, and previous surgery. CONCLUSION: In Japanese UC patients, conception and pregnancy outcomes after disease onset were comparable to the outcomes observed prior to disease onset, whereas CD appeared to be associated with adverse outcomes. Caesarean operation and LBW were more frequently observed in CD patients who had a history of surgery for perianal lesions and bowel resection. PMID- 21683302 TI - Adalimumab as second line anti-tumour necrosis factor alpha therapy for Crohn's disease: A single centre experience. AB - BACKGROUND AND AIMS: Non-response, loss of response, or intolerance to anti tumour necrosis factor alpha (anti-TNFalpha) therapy is well recognised in Crohn's disease (CD) patients. Data concerning outcomes following the use of a second anti-TNFalpha therapy, particularly in patients who do not respond to a first anti-TNFalpha agent, are still emerging. The aim of this study was to assess response and tolerability to adalimumab following infliximab failure in a single centre cohort of CD patients. METHODS: Data were collected prospectively on 44 patients who received adalimumab therapy following infliximab failure. Initial response to adalimumab therapy at 6weeks following induction was defined using a two point decrease in the Harvey-Bradshaw Index, with remission at this point defined using a Harvey Bradshaw index<=4. Sustained clinical benefit at the last point of follow up was determined using a physician's global assessment. Corticosteroid-free sustained clinical benefit was also assessed at this point. RESULTS: Thirty-four (77%) patients had initial response to adalimumab therapy, with 28 (64%) having sustained clinical benefit. Corticosteroid-free sustained clinical benefit was achieved in nine (53%) of 17 patients requiring steroids at commencement of adalimumab. Four (44%) of the 9 patients who were primary non responders to infliximab responded to adalimumab. The majority of CD patients who failed adalimumab therapy required surgery. CONCLUSIONS: Second-line anti TNFalpha therapy with adalimumab is effective at both inducing remission and maintaining response in CD patients who have failed infliximab, regardless of the reason for infliximab failure. PMID- 21683303 TI - High prevalence of fatigue in inflammatory bowel disease: A case control study. AB - BACKGROUND AND AIMS: Many outpatients with Inflammatory Bowel Disease (IBD) complain about fatigue, even in a quiescent disease. The aim of this study is to examine prevalence of fatigue in IBD outpatients and define possible determinants of fatigue. METHODS: A case-control study was conducted in consecutive IBD outpatients, with Lynchsyndrome gene carriers (Lynch) as a control group. Demographics, laboratory results and Harvey Bradshaw Index (HBI) were obtained from medical records. Subjective fatigue was measured by the revised Piper Fatigue Scale (PFS). Mean PFS scores were compared between groups. Secondly, possible determinants of fatigue were assessed. RESULTS: Three hundred patients were enrolled. 74% returned the questionnaires (117 CD; 55 UC; and 50 Lynch). Demographics were not different between groups. Mean overall PFS is 4.03. PFS score in IBD patients was significantly higher compared to Lynch. Mean (SD) PFS score was 4.8 (2.09) for CD, 4.2 (2.3) for UC versus 1.9 (2.03) for Lynch (P<0.01). Fatigue was present in 40% of the IBD patients in remission. HBI was positively, but not significantly, correlated with PFS scores (r=0.37). CONCLUSION: We found a high prevalence of fatigue in IBD patients, compared to a control group, even in a quiescent disease. None of the studied determinants was significantly associated with fatigue. PMID- 21683304 TI - Perianal disease in patients with ulcerative colitis: A case-control study. AB - BACKGROUND: Patients with ulcerative colitis (UC) and concomitant perianal disease (PAD) are occasionally seen, but the impact of PAD on UC outcome has been scarcely assessed. AIMS: To evaluate the prevalence, clinical features and outcomes of PAD among UC patients. METHODS: Patients with an initial diagnosis of UC who ever developed PAD were identified from three IBD hospital databases. Each case was matched by age, disease extent at diagnosis, and year of diagnosis, with two UC patients who never developed PAD. RESULTS: Thirty-seven UC patients (5% of the whole series) developed PAD (complex in about a half of them), being more frequent among men (62%), with distal (50%) or extense (34%) disease. Proximal spread of UC occurred in 19% of cases. No differences in demographic features, rate of proximal spread or colectomy during follow-up were found as compared to controls, but greater requirements of steroids (P=0.019) were detected in UC-PAD patients. A change in disease diagnosis occurred in 6 patients mainly because of transmural involvement in colectomy specimen, small intestinal involvement, and/or endoscopic appearance. CONCLUSIONS: PAD may occur in up to 5% of UC patients. When complex it leads to a change in disease diagnosis in one third of cases. UC-related therapeutic requirements are not increased in these patients, except for steroids. PMID- 21683305 TI - Construction and validation of a web-based epidemiological database for inflammatory bowel diseases in Europe An EpiCom study. AB - BACKGROUND: The EpiCom-study investigates a possible East-West-gradient in Europe in the incidence of IBD and the association with environmental factors. A secured web-based database is used to facilitate and centralize data registration. AIM: To construct and validate a web-based inception cohort database available in both English and Russian language. METHOD: The EpiCom database has been constructed in collaboration with all 34 participating centers. The database was translated into Russian using forward translation, patient questionnaires were translated by simplified forward-backward translation. Data insertion implies fulfillment of international diagnostic criteria, disease activity, medical therapy, quality of life, work productivity and activity impairment, outcome of pregnancy, surgery, cancer and death. Data is secured by the WinLog3 System, developed in cooperation with the Danish Data Protection Agency. Validation of the database has been performed in two consecutive rounds, each followed by corrections in accordance with comments. RESULTS: The EpiCom database fulfills the requirements of the participating countries' local data security agencies by being stored at a single location. The database was found overall to be "good" or "very good" by 81% of the participants after the second validation round and the general applicability of the database was evaluated as "good" or "very good" by 77%. In the inclusion period January 1st -December 31st 2010 1336 IBD patients have been included in the database. CONCLUSION: A user-friendly, tailor-made and secure web-based inception cohort database has been successfully constructed, facilitating remote data input. The incidence of IBD in 23 European countries can be found at www.epicom-ecco.eu. PMID- 21683306 TI - Depression and mucosal proinflammatory cytokines are associated in patients with ulcerative colitis and pouchitis - A pilot study. AB - BACKGROUND AND AIMS: Recent studies demonstrated that depression was associated with mucosal inflammation in patients with ulcerative colitis (UC). This association had not been studied in patients with UC with ileal pouch-anal anastomosis (IPAA) after restorative proctocolectomy. We hypothesized that depression and mucosal proinflammatory cytokines in UC-patients with pouchitis were associated. METHODS: We assessed 18 IPAA-UC-patients with pouchitis and 19 IPAA-UC-patients without pouchitis. Mucosal biopsies were taken from the areas with maximal inflammation in the pouch or from the posterior wall of the pouch if the pouch had a normal endoscopic appearance. Disease activity was assessed by the Pouch Disease Activity Index. The expression of mucosal proinflammatory gene transcripts (interleukin-8 [IL-8] and interleukin-1beta [IL-1b]) was quantified by real-time polymerase chain reaction. Depression was assessed by the Hospital Anxiety and Depression Scale (HADS). Pearson correlations between depression and cytokine transcripts were calculated. RESULTS: The correlation of HADS depression scores of patients with pouchitis with IL-8 was r=0.51 (p=0.03) and with IL-1beta was r=0.47 (p=0.04). The correlation between the HADS depression scores of patients without pouchitis with IL-8 was r=-0.19; (p=0.21) and with IL-1beta was r=-0.12 (p=0.30). CONCLUSION: Depression is associated with mucosal proinflammatory cytokines in patients with pouchitis after restorative proctocolectomy in patients with UC. PMID- 21683307 TI - Cytomegalovirus ileitis in a patient after liver transplantation-differentiating from de novo IBD. AB - Cytomegalovirus (CMV) infection of the gastrointestinal (GI) tract has been reported in immunocompromised patients and is seen following liver transplantation. Although CMV infection can affect any part of the GI tract, involvement of the terminal ileum is rarely encountered after liver transplantation. We report a case of a 32-year-old male who developed CMV infection of the terminal ileum while receiving immunosuppression for liver transplantation. Initial ganciclovir treatment did not improve the patient's symptoms and therapy was then switched to foscarnet which ultimately resulted in resolution of infection. However the patient continued to have symptoms because of intermittent small bowel obstruction because of ulcerations and fibrosis ultimately requiring surgical resection. CMV DNA polymerase chain reaction (PCR) was negative throughout the course of infection. Surgical resected specimen revealed no evidence of inflammatory bowel disease (IBD). Follow up colonoscopy up to a year after infection also did not reveal any evidence of IBD. Compartmentalization in the clinical presentation of CMV involving GI tract can be seen with a negative blood DNA PCR. Histological diagnosis thus forms an important part in the clinical follow-up of liver transplant patients undergoing intense immunosuppression and should be aggressively pursued in patients with GI symptoms. De novo IBD should be considered in the differential diagnosis in these patients who do not improve with anti-viral treatment. PMID- 21683308 TI - Liver abscess of the caudate lobe due to Staphylococcus aureus in an ulcerative colitis patient: First case report. AB - Liver abscesses are very rare complications of ulcerative colitis, with only nine cases described in the literature, to our knowledge. We report a case where a recurrence of liver abscess occurred in an ulcerative colitis patient, in two different hepatic lobes, which has not been previously described. The recurrence was in the caudate lobe having the cultures yielded Staphylococcus aureus. This is also the first case report of liver abscess in this location and caused by this microorganism in an ulcerative colitis patient. A review of the literature concerning liver abscesses involving ulcerative colitis patients is also provided. PMID- 21683309 TI - Successful treatment with adalimumab in a familial case of gastrointestinal Behcet's disease. AB - We present here two siblings with a history of recurrent oral and genital ulcers, neurological and gastrointestinal manifestations. The diagnosis of Behcet's disease in a context of familial aggregation was assumed. Facing repeated steroid dependent flares and failure of maintenance therapies with colchicine and intolerance to pentoxifilline and disulone, adalimumab was started. Rapid response was observed in both patients, with clinical remission after induction therapy, which currently sustains under maintenance schedule. This case report suggests the effectiveness of adalimumab as first anti-TNFalpha in case of steroid-dependent/resistant gastrointestinal BD. PMID- 21683310 TI - Concomitant presentation of collagenous sprue and HFE hemochromatosis. AB - Collagenous sprue (CS) is a progressive malabsorptive disorder characterized by collagen deposition beneath the basement membrane of small bowel epithelium in refractory celiac sprue. CS is a pathologically distinct entity from celiac disease, despite a similar clinical presentation. The etiology of CS is unclear, although there are speculations that CS and celiac disease may share similar pathogenetic pathways. On the other hand, HFE hemochromatosis (HH) is a distinct disease entity. Celiac disease and HH are common HLA-associated genetic disorders in Northern European populations. There are a few case reports linking celiac disease and HH. We present a patient diagnosed with concurrent CS and HH. PMID- 21683311 TI - Considered "negative" for MAP, these results would be very "positive" for tuberculoid leprosy. PMID- 21683313 TI - Effects of corticosteroid therapy on depression and inflammation in ulcerative colitis patients. PMID- 21683315 TI - Increased pancreatic enzymes and inflammatory bowel diseases: What correlation? PMID- 21683316 TI - Oculopharyngeal muscular dystrophy: a case report and review of the literature. AB - Oculopharyngeal muscular dystrophy is an infrequent, not widely known entity. Of genetic origin, it usually shows up in the 5th or 6th decade of life. Most cases are referred directly to the gastroenterologist by their general practitioner and not to the otolaryngologist, so it is essential to be aware of this disease to suspect it. We report a case diagnosed and treated in our hospital and we review the literature. PMID- 21683317 TI - Laryngeal manifestation of B-cell non-Hodgkin lymphoma. AB - Laryngeal lymphomas are rare, involving less than 1% of all laryngeal tumours. Extranodal non-Hodgkin lymphomas generally appear in places where lymphoid tissue exists, such as the small bowel or parotid; they are very unusual in organs with little or no presence of lymphoid tissue, such as the larynx. When advanced stages are established, initial lymphoma manifestation at the laryngeal level has rarely been documented. We present a case of a small cell lymphocytic lymphoma at stage IV/E with initial laryngeal symptoms and indicate its management and follow up. PMID- 21683318 TI - [Fournier gangrene: description of 37 cases and analysis of associated health care costs]. AB - BACKGROUND AND OBJECTIVES: Fournier gangrene is a urological emergency associated with a high mortality. It is a necrotizing fasciitis caused by polymicrobial infection originating in the anorectal or genitourinary area. The aim of this study was to analyze the epidemiological and clinical characteristics of Fournier gangrene along with the variables that influence disease course and mortality in patients treated in our department. MATERIAL AND METHODS: We carried out a retrospective study of 37 patients diagnosed with Fournier gangrene between January 2001 and October 2010. RESULTS: All of the patients were men, 43.2% had diabetes, and the mean age of the patients was 57.68 years. Statistically significant differences were observed between the age of surviving patients and that of patients who died (55.8 and 69.6 years, respectively). The mean hospital stay was 27.54 days and 32.4% of patients required admission to the intensive care unit. Etiology was unknown in 39.8% of cases. Polymicrobial infection was observed in 59.5% of cases. The mean health care cost associated with a patient diagnosed with Fournier gangrene admitted to intensive care and requiring at least 1 procedure in the operating room was ?25,108.67. Mortality was 13.5%. Based on analysis of individual comorbid conditions, only ischemic heart disease displayed a statistically significant association with mortality due to Fournier gangrene; ischemic heart disease was also associated with longer hospital stay. CONCLUSIONS: Fournier gangrene is associated with high mortality despite appropriate early treatment. Although the condition is infrequent, the high associated health care costs suggest that primary and secondary prevention measures should be implemented. PMID- 21683319 TI - [Analysis of phenotypic characteristics and exposure to UV radiation in a group of patients with cutaneous melanoma]. AB - BACKGROUND: Melanoma is the most serious type of skin cancer and is caused by a combination of endogenous and exogenous risk factors. Here were describe the clinical and anatomical characteristics of melanoma along with the endogenous and exogenous risk factors in 120 patients diagnosed with cutaneous melanoma in a health care area of the province of Santa Cruz de Tenerife in Spain. PATIENTS AND METHODS: A descriptive, cross-sectional study was undertaken in patients diagnosed with melanoma between January 1999 and July 2005 in the health care area served by Hospital Universitario de Canarias. Data were collected on demographic characteristics, phenotype, sun exposure, sun protection, and actinic damage. RESULTS: Melanoma was most commonly diagnosed in women (62.5%) and lesions were most frequently located on the trunk. The most frequent tumor subtype was superficial spreading melanoma (63.3%) and 51.5% of patients were classified as having skin phototype II. Intermittent sun exposure was reported by 81.8% of patients and 50% had a moderate cumulative sun exposure (50-120 h/y). Multiple melanomas were present in 3.3% of patients. In 43% of patients, the time to diagnosis of melanoma was more than 24 months. CONCLUSIONS: A substantial percentage of melanomas were associated with actinic damage. Differences were observed in the level of sun exposure according to melanoma subtype. The most common causes for concern were growth and color changes in the lesion, and a substantial number of patients waited for some time between observing these changes and consulting a doctor. PMID- 21683320 TI - Silver polymeric nanocomposites as advanced antimicrobial agents: classification, synthetic paths, applications, and perspectives. AB - Utilization of metallic nanoparticles in various biotechnological and medical applications represents one of the most extensively investigated areas of the current materials science. These advanced applications require the appropriate chemical functionalization of the nanoparticles with organic molecules or their incorporation in suitable polymer matrices. The intensified interest in polymer nanocomposites with silver nanoparticles is due to the high antimicrobial effect of nanosilver as well as the unique characteristics of polymers which include their excellent structural uniformity, multivalency, high degree of branching, miscellaneous morphologies and architectures, and highly variable chemical composition. In this review, we explore several aspects of antimicrobial polymer silver nanocomposites, giving special focus to the critical analysis of the reported synthetic routes including their advantages, drawbacks, possible improvements, and real applicability in antibacterial and antifungal therapy. A special attention is given to "green" synthetic routes exploiting the biopolymeric matrix and to the methods allowing preparing magnetically controllable antimicrobial polymers for targeting to an active place. The controversial mechanism of the action of silver against bacteria, fungi and yeasts as well as perspectives and new applications of silver polymeric nanocomposites is also briefly discussed. PMID- 21683321 TI - Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). AB - AMR101 is an omega-3 fatty acid agent containing >=96% eicosapentaenoic acid ethyl ester and no docosahexaenoic acid. Previous smaller studies suggested that highly purified eicosapentaenoic acid lowered triglyceride (TG) levels without increasing low-density lipoprotein (LDL) cholesterol levels. TG-lowering therapies such as fibrates, and fish oils containing both eicosapentaenoic acid and docosahexaenoic acid, can substantially increase LDL cholesterol levels when administered to patients with very high TG levels (>=500 mg/dl). The present double-blind study randomized 229 diet-stable patients with fasting TG >=500 mg/dl and <=2,000 mg/dl (with or without background statin therapy) to AMR101 4 g/day, AMR101 2 g/day, or placebo. The primary end point was the placebo corrected median percentage of change in TG from baseline to week 12. The baseline TG level was 680, 657, and 703 mg/dl for AMR101 4 g/day, AMR101 2 g/day, and placebo. AMR101 4 g/day reduced the placebo-corrected TG levels by 33.1% (n = 76, p <0.0001) and AMR101 2 g/day by 19.7% (n = 73, p = 0.0051). For a baseline TG level >750 mg/dl, AMR101 4 g/day reduced the placebo-corrected TG levels by 45.4% (n = 28, p = 0.0001) and AMR101 2 g/day by 32.9% (n = 28, p = 0.0016). AMR101 did not significantly increase the placebo-corrected median LDL cholesterol levels at 4 g/day (-2.3%) or 2 g/day (+5.2%; both p = NS). AMR101 significantly reduced non-high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein-associated phospholipase A(2), very low-density lipoprotein cholesterol, and total cholesterol. AMR101 was generally well tolerated, with a safety profile similar to that of the placebo. In conclusion, the present randomized, double-blind trial of patients with very high TG levels demonstrated that AMR101 significantly reduced the TG levels and improved other lipid parameters without significantly increasing the LDL cholesterol levels. PMID- 21683322 TI - Mutations in the TGFbeta binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. AB - Geleophysic (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group and are both characterized by severe short stature, short extremities, and stiff joints. Although AD has an unknown molecular basis, we have previously identified ADAMTSL2 mutations in a subset of GD patients. After exome sequencing in GD and AD cases, we selected fibrillin 1 (FBN1) as a candidate gene, even though mutations in this gene have been described in Marfan syndrome, which is characterized by tall stature and arachnodactyly. We identified 16 heterozygous FBN1 mutations that are all located in exons 41 and 42 and encode TGFbeta-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFbeta signaling were consistent features in GD and AD fibroblasts. Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGFbeta signaling caused by FBN1 mutations can trigger either Marfan syndrome or GD and AD, our findings support the fact that TB5 mutations in FBN1 are responsible for short stature phenotypes. PMID- 21683323 TI - Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement. AB - Autosomal-dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders. In this study, we performed genetic analysis of a unique form of SCA (SCA36) that is accompanied by motor neuron involvement. Genome-wide linkage analysis and subsequent fine mapping for three unrelated Japanese families in a cohort of SCA cases, in whom molecular diagnosis had never been performed, mapped the disease locus to the region of a 1.8 Mb stretch (LOD score of 4.60) on 20p13 (D20S906-D20S193) harboring 37 genes with definitive open reading frames. We sequenced 33 of these and observed a large expansion of an intronic GGCCTG hexanucleotide repeat in NOP56 and an unregistered missense variant (Phe265Leu) in C20orf194, but we found no mutations in PDYN and TGM6. The expansion showed complete segregation with the SCA phenotype in family studies, whereas Phe265Leu in C20orf194 did not. Screening of the expansions in the SCA cohort cases revealed four additional occurrences, but none were revealed in the cohort of 27 Alzheimer disease cases, 154 amyotrophic lateral sclerosis cases, or 300 controls. In total, nine unrelated cases were found in 251 cohort SCA patients (3.6%). A founder haplotype was confirmed in these cases. RNA foci formation was detected in lymphoblastoid cells from affected subjects by fluorescence in situ hybridization. Double staining and gel-shift assay showed that (GGCCUG)n binds the RNA-binding protein SRSF2 but that (CUG)(6) does not. In addition, transcription of MIR1292, a neighboring miRNA, was significantly decreased in lymphoblastoid cells of SCA patients. Our finding suggests that SCA36 is caused by hexanucleotide repeat expansions through RNA gain of function. PMID- 21683324 TI - Transfusion-transmitted babesiosis in an immunocompromised patient: a case report and review. AB - Babesiosis is a tick- and transfusion-borne disease caused by intraerythrocytic Babesia parasites. In 2009, a 61-year-old Minnesota woman with chronic lymphocytic leukemia and a history of recent chemotherapy and numerous blood transfusions for gastrointestinal bleeding became febrile and anemic 12 days postsplenectomy. Babesia were visualized on blood smears, confirmed by polymerase chain reaction as B. microti. She developed respiratory failure despite initiation of clindamycin and quinine, and required 12 weeks of azithromycin and atovaquone before blood smear and polymerase chain reaction findings were negative. Serologic evidence of B. microti infection was identified in 1 associated blood donor and 1 other recipient of that donor's blood. Babesia infection can be asymptomatic or cause mild to fulminant disease resulting in multiorgan failure or death. Patients with advanced age, asplenia, or other immune compromise are at risk for severe babesiosis and may require prolonged treatment to eradicate parasitemia. Incidence of transfusion-transmitted babesiosis has increased over the past decade. PMID- 21683327 TI - Biomarkers in clinical practice. PMID- 21683328 TI - Use of the patient acceptable symptom state and the minimal clinically important difference to evaluate the outcomes of cataract extraction. AB - PURPOSE: To determine the minimal clinically important difference and the patient acceptable symptom state for visual acuity and visual function, 2 key visual outcomes for patients undergoing cataract extraction, as an aid for evaluating the outcome of cataract extraction. DESIGN: Prospective cohort study. METHODS: SETTING: Multicenter study of 17 hospitals. PATIENTS: A total of 4335 consecutive patients advised to undergo cataract extraction. MAIN OUTCOME MEASURES: Sociodemographic and clinical data, including visual acuity (VA), patient satisfaction, and responses to the Visual Function Index 14 (VF-14) and transitional questions were collected before and after cataract extraction. The patient acceptable symptom state and minimal clinically important difference were estimated for the entire sample and for subgroups by preintervention status and presence of ocular comorbidities. RESULTS: Among patients with simple cataract, postintervention patient acceptable symptom state values for VA ranged from 0.67 to 0.80, depending on preintervention VA, while VF-14 scores ranged from 88 to 90. For patients with any additional ocular comorbidity, VA ranged from 0.63 to 0.75, depending on preintervention VA, while VF-14 scores ranged from 86 to 92. For the entire sample, postintervention patient acceptable symptom state values were 0.75 for VA and 86.1 for VF-14 scores. Minimal clinically important difference for patients who reported being a little better ranged from 0.17 to 0.5 in VA and 0.41 to 37.46 in VF-14 scores, depending on preintervention status and presence of ocular comorbidities. CONCLUSION: The minimal clinically important difference and patient acceptable symptom state values are complementary parameters that may help in the clinical decision-making process by providing more meaningful estimates of the impact of cataract extraction on 2 important outcomes, visual acuity and visual function. PMID- 21683329 TI - Risk of late intraocular lens dislocation after cataract surgery, 1980-2009: a population-based study. AB - PURPOSE: To estimate the long-term cumulative risk of late posterior chamber intraocular lens (IOL) dislocation after cataract extraction in a population based cohort. DESIGN: Retrospective cohort study and nested case-control study. METHODS: The records of all residents of Olmsted County, Minnesota, who underwent cataract extraction from January 1, 1980, through May 31, 2009, (14 471 cases in 9577 residents) and who were diagnosed with late posterior chamber IOL dislocation in the same period were reviewed. Cases were identified through the Rochester Epidemiology Project. Three controls chosen from the cataract surgery cohort were matched to each IOL dislocation case by age, gender, and duration of follow-up. Records were reviewed to confirm case status and to ascertain risk factor information. The cumulative risk of IOL dislocation was estimated by using the Kaplan-Meier method. Logistic regression models assessed differences between cases and controls. RESULTS: We identified 16 cases of late posterior chamber IOL dislocation, 9 with in-the-bag dislocations and 7 with out-of-the-bag dislocations. At 5, 10, 15, 20, and 25 years after cataract extraction, the cumulative risk of IOL dislocation was 0.1%, 0.1%, 0.2%, 0.7%, and 1.7%, respectively. There was no significant difference in the risk of late IOL dislocation after extracapsular cataract extraction when compared with phacoemulsification (P = .21) or between different decades of surgery (P = .92). Pseudoexfoliation and zonular laxity at surgery were associated significantly with late IOL dislocation (P = .01). CONCLUSIONS: The long-term cumulative risk of late IOL dislocation after cataract extraction was low and did not significantly change over our nearly 30-year study period. PMID- 21683330 TI - Vitrectomy timing for retained lens fragments after surgery for age-related cataracts: a systematic review and meta-analysis. AB - PURPOSE: To evaluate the effect of vitrectomy timing on outcomes for patients with crystalline retained lens fragments receiving vitrectomy 3+ days after cataract surgery. DESIGN: Systematic review and meta-analysis of retrospective interventional cases series. METHODS: Searches of MEDLINE (English, 1/1/85 through 7/30/2010) and article reference lists. Articles were screened for patients with crystalline retained lens fragments after surgery for age-related cataracts, discussion of vitrectomy timing, and, for the meta-analysis, patient totals for at least 1 outcome and multiple time periods, 10+ patients, and mean follow-up >=3 months. Outcomes included visual acuity, retinal detachment, increased intraocular pressure, intraocular infection/inflammation, cystoid macular edema, and corneal edema. Data extraction was performed twice and quality assessed. Logistic regression estimated study-level odds ratios for each additional 1-week vitrectomy delay. Meta-analysis estimated summary odds ratios using random-effects models. RESULTS: Of 257 articles identified, there were 43 unique studies (53 articles) for the systematic review, including 27 (31 articles) for the meta-analysis. Early vitrectomies were statistically significantly associated with better outcomes for not good visual acuity (odds ratio: 1.13; 95% CI: 1.04-1.22, P = .005); bad visual acuity (odds ratio: 1.05; 95% CI: 1.01-1.09, P = .009); previtrectomy retinal detachment (odds ratio: 1.29; 95% CI: 1.01-1.65, P = .038); postvitrectomy retinal detachment (odds ratio: 1.13; 95% CI: 1.02-1.26, P = .024); increased intraocular pressure (odds ratio: 1.23; 95% CI: 1.07-1.41, P = .003); and intraocular infection/inflammation (odds ratio: 1.20; 95% CI: 1.01-1.42, P = .041). Results were robust to sensitivity analyses. CONCLUSIONS: This systematic review and meta-analysis found significantly better outcomes (visual acuity, retinal detachment, increased intraocular pressure, intraocular infection/inflammation) with earlier vitrectomy for retained lens fragments. Reduced vitrectomy delays may yield better patient outcomes. PMID- 21683331 TI - Facial nerve injury: a complication of superficial temporal artery biopsy. AB - PURPOSE: To describe 4 patients who sustained facial nerve injury during temporal artery biopsy. DESIGN: Retrospective, observational case series. METHODS: The medical records were reviewed of 4 patients (2 men, 2 women; mean age 72.8 years, range 60 to 87), referred for evaluation of palsy of the frontal branch of the facial nerve following temporal artery biopsy. Main outcomes measured were site of incision, length of follow-up, and degree of recovery. RESULTS: In all cases, incisions were made in the preauricular region or on the pretrichial temple within 3 cm of the lateral canthal angle. Follow-up ranged from 1 month to over 5 years. No patient recovered completely; 2 had partial return of function, and 2 reported no improvement. CONCLUSIONS: Branch facial nerve palsy can occur with temporal artery biopsy and is likely to result in permanent disability. In all cases the incision was placed within the known course of the frontal branch of the facial nerve. To prevent this rare complication, we advocate biopsy of the parietal, rather than the frontal, branch of the superficial temporal artery. PMID- 21683332 TI - Quality of vision after femtosecond laser-assisted descemet stripping endothelial keratoplasty and penetrating keratoplasty: a randomized, multicenter clinical trial. AB - PURPOSE: To compare the quality of vision (straylight and contrast sensitivity) after femtosecond laser-assisted Descemet stripping endothelial keratoplasty (FS DSEK) and penetrating keratoplasty (PK). DESIGN: Prospective, randomized clinical trial. METHODS: setting: Multicenter (5 ophthalmic centers in The Netherlands). study population: Eighty eyes of 80 patients with corneal endothelial dysfunction were included and were randomized to FS DSEK or PK. observation procedures: FS DSEK and PK. main outcome measures: Straylight, contrast sensitivity, astigmatism, uncorrected visual acuity, best spectacle-corrected visual acuity (BSCVA), and visual symptom score. RESULTS: Straylight at 12 months was 1.37 +/- 0.2 logarithm of straylight for FS DSEK and 1.46 +/- 0.2 logarithm of straylight for PK (P = .151). During 12 months of follow-up, there was a significant improvement of straylight and contrast sensitivity after FS DSEK (P < .001) and PK (P < .001). The change of straylight and contrast sensitivity correlated significantly with the change of BSCVA after FS DSEK (r = -0.645; r = 0.580) and PK (r = -0.370; r = 0.659). The visual symptom score was comparable between the 2 groups during the 12 months of follow-up. CONCLUSIONS: Improvement of straylight and contrast sensitivity was significantly correlated with an improvement of BSCVA. Straylight and contrast sensitivity were improved significantly after FS DSEK and were comparable with those after PK, although BSCVA was slightly better in the PK group. PMID- 21683333 TI - Elevated intraocular pressure is a common complication during active microbial keratitis. AB - PURPOSE: To determine the incidence, risk factor, and outcomes of elevated intraocular pressure (IOP) during active microbial keratitis. DESIGN: Retrospective cohort study. METHODS: One hundred eighty-four patients with culture-proven microbial keratitis examined from January 2003 through December 2007 were included. High IOP was defined as IOP of 22 mm Hg or higher measured during the episode of active keratitis. The control group consisted of eyes with microbial keratitis whose IOP remained less than 22 mm Hg. Twelve factors were evaluated by univariate and multivariate analyses to determine whether any were associated with increased IOP. The incidence, risk factors, microbial profile, the necessity of therapeutic surgery, time to resolution, and final visual acuity were compared between the high IOP group and the control group. RESULTS: High IOP (mean, 29.1 mm Hg; range, 22 to 51 mm Hg) occurred in 52 (28%) of 184 patients with active corneal infection. Prior ocular surgery, diabetes mellitus, and ulcer size of 4.0 mm or larger were associated with IOP elevation (P <= .013). Surgical interventions were necessary in 19 (39%) of 49 patients in the high IOP group and in 14 (11%) of 129 patients in the control group (P < .0001). Time to ulcer resolution was longer in the high IOP group (mean, 50.1 +/- 53.2 days) than in the control (mean, 31.6 +/- 42.0 days; P = .005). Final visual acuity of 20/40 or better was achieved by more patients in the control group (47%) than in the high IOP group (20%; P < .001). CONCLUSIONS: Elevated IOP was detected in a significant proportion of patients with active microbial keratitis and was associated with poorer outcomes. Routine IOP check should be performed to avoid possible optic nerve damage. PMID- 21683334 TI - Oral mucosal graft to correct lid margin pathologic features in cicatricial ocular surface diseases. AB - PURPOSE: To evaluate the efficacy of oral mucosal graft to correct not only lid margin keratinization and trichiasis or distichiasis, but also incomplete closure in severe cicatricial ocular surface diseases. DESIGN: Retrospective, noncomparative, interventional case series. METHODS: Twenty-two eyes (39 eyelids) of 19 patients received an oral mucosal graft during lid margin reconstruction from September 2007 through February 2010. Relief of symptoms, conjunctival inflammation, corneal epithelial abnormalities, and visual acuity were compared before and after surgeries as outcome measures. RESULTS: Among 22 eyes, 10 eyes (45.5%) had lid margin keratinization, trichiasis or distichiasis, or both, resulting in blink-related microtrauma. The oral mucosal graft resulted in successful correction in 6 eyes; in the remaining eyes, trichiasis in 3 eyes and distichiasis in 1 eye were away from the corneal surface. Incomplete closure present in 12 (54.5%) eyes was completely corrected in 9 eyes and was much improved in the remaining 3 eyes. During a mean follow-up of 16.2 months, reports of foreign body sensation, photophobia, pain, burning, tearing, and discharge were relieved significantly in 17 (77.3%) of 22 eyes. The visual acuity was improved in 13 eyes (59.1%) and was maintained in 8 eyes. Conjunctival inflammation was reduced markedly in 19 eyes (86.4%). Corneal epithelial defect and superficial punctate keratopathy were healed rapidly or improved in 14 eyes, and regression of superficial vascularization was noted in 1 eye. CONCLUSIONS: Oral mucosal graft can reduce not only blink-related microtrauma caused by lid margin keratinization and trichiasis or distichiasis, but also exposure caused by cicatricially induced incomplete closure, thus preventing further deterioration of the ocular surface. PMID- 21683335 TI - Factors influencing outcomes of the treatment of allograft corneal rejection. AB - PURPOSE: To identify patient characteristics influencing treatment outcomes of allograft corneal rejection. DESIGN: Retrospective case file review. METHODS: Files containing details of first episode of corneal allograft rejections in patients who underwent penetrating keratoplasty at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia from 1991 to 2006 were reviewed. Cases were divided into 2 groups based on the response to treatment for graft rejection: treatment responders and failures. Main parameters evaluated were demographic characteristics, preoperative clinical profile, donor characteristics, surgical technique, presentation, and treatment of rejection episode. RESULTS: A total of 235 cases of graft rejection were identified, of which 195 cases (83%) were successfully treated and 40 (17%) failed to respond. Age (P = .08) and gender (P = .61) were comparable in both groups. On univariate analysis, primary diagnosis of keratoconus (P = .04) and phakic lens status at the time of surgery (P = .02) were more common in treatment responders whereas aphakic bullous keratopathy (P <= .01), history of glaucoma (P < .01), aphakia (P < .01), and previous grafts (P < .01) were more common among treatment failures. Multivariate analysis revealed that preoperative corneal neovascularization (adjusted odds ratio [aOR] 3.6, 95% CI: 1.3-9.7, P = .01), a larger (>9 mm) donor size (aOR 5.7, 95% CI: 1.3-24.9, P = .02), and corneal edema at presentation (aOR 4.7, 95% CI: 1.7-13.2, P < .01), were independently associated with failure of treatment of graft rejection. CONCLUSIONS: Treatment failure in cases of corneal allograft rejection is more likely to occur among patients with corneal neovascularization, large donor graft buttons, and corneal edema at presentation. PMID- 21683336 TI - Femtosecond sub-bowman keratomileusis: a prospective, long-term, intereye comparison of safety and outcomes of 90- versus 100-MUm flaps. AB - PURPOSE: To analyze the long-term safety profile, visual and refractive results, and incidence of complications between sub-Bowman keratomileusis with 90- and 100 MUm flaps. DESIGN: Prospective, randomized, comparative clinical study. METHOD: A total of 385 candidates (770 eyes) underwent bilateral, single-sitting, sub Bowman keratomileusis, with flap creation (90 or 100 MUm) on IntraLase 60-kHz (Abott Medical Optics) and ablation on Technolas 217z100 (Technolas PV) . Right and left eyes were randomized to undergo 90- or 100-MUm flap procedures. Preoperative and postoperative assessment included uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), refraction, and topographic analysis. All cases were followed up until 12 months after surgery. After excluding cases lost to follow-up, a final analysis of 368 patients was carried out (368 eyes in each of the 2 groups). The main outcome measures were BSCVA, UCVA, complication rates, and residual spherical equivalent refractive error. RESULTS: The mean preoperative values were: spherical equivalent, -6.08 +/ 2.7 diopters (D; 90-MUm group) and -5.99 +/- 2.8 D (100-MUm group; P = .7); and logarithm of the minimal angle of resolution BSCVA, 0.01 +/- 0.03 (90-MUm group) and 0.01 +/- 0.04 (100-MUm group: P = .8). Postoperative 12-month values were: spherical equivalent, -0.02 +/- 0.4 D (90-MUm group) and -0.01 +/- 0.4 D (100-MUm group; P = .8); logarithm of the minimal angle of resolution BSCVA, -0.05 +/- 0.07 (90-MUm group) and -0.04 +/- 0.07 (100-MUm group; P = .8); and logarithm of the minimal angle of resolution UCVA, 0.012 +/- 0.01 (90-MUm group) and 0.017 +/- 0.02 (100-MUm group; P = .2). No loss of BSCVA was seen in any case. The efficacy indices were 1.039 +/- 0.21 (90-MUm group) and 1.014 +/- 0.24 (100-MUm group; P = .2); safety indices were 1.163 +/- 0.21 (90-MUm group) and 1.158 +/- 0.22 (100 MUm group; P = .6); and vision difference indices were 0.09 +/- 0.14 (90-MUm group) and 0.10 +/- 0.15 (100-MUm group; P = .1). Both groups had a low but comparable incidence of diffuse lamellar keratitis and microstriae. However, the incidence of microstriae (although visually asymptomatic) was significantly higher in ablation with spherical equivalent of -9 D or more compared with lesser ablations (6.7% vs 0.8%; P < .001). CONCLUSIONS: The 1-year follow-up of femtosecond sub-Bowman keratomileusis with 90- and 100-MUm flaps suggests that both the flap options have comparable outcomes. PMID- 21683337 TI - Who is the high-risk recipient? Predicting mortality after heart transplant using pretransplant donor and recipient risk factors. AB - BACKGROUND: In this study we sought the following: (1) To objectively assess the risk related to various pretransplant recipient and donor characteristics; (2) to devise a preoperative risk stratification score (RSS) based on pretransplant recipient and donor characteristics predicting graft loss at 1 year; and (3) to define different risk strata based on RSS. METHODS: The United Network for Organ Sharing provided de-identified patient-level data. Analysis included 11,703 orthotopic heart transplant recipients aged 18 years or greater and transplanted between January 1, 2001 and December 31, 2007. The primary outcome was 1-year graft failure. Multivariable logistic regression analysis (backward p value<0.20) was used to determine the relationship between pretransplant characteristics and 1-year graft failure. Using the odds ratio for each identified variable, an RSS was devised. The RSS strata were defined by calculating receiver operating characteristic curves and stratum specific likelihood ratios. RESULTS: The strongest negative predictors of 1-year graft failure included the following: right ventricular assist device only, extracorporeal membrane oxygenation, renal failure, extracorporeal left ventricular assist device, total artificial heart, and advanced age. Threshold analysis identified 5 discrete RSS strata: low risk (LR, RSS: <2.55; n=3242, 27.7%), intermediate risk (IR, RSS: 2.55-5.72; n=6,347, 54.2%), moderate risk (MR, RSS: 5.73-8.13; n=1,543, 13.2%), elevated risk (ER, RSS: 8.14-9.48; n=310, 2.6%), and high risk (HR, RSS: >9.48; n=261, 2.2%). The 1 year actuarial survival (%) in the LR, IR, MR, ER, and HR groups were 93.8, 89.2, 81.3, 67.0, and 47.0, respectively. CONCLUSIONS: Pretransplant recipient variables significantly influence early and late graft failure after heart transplantation. The RSS may improve organ allocation strategies by reducing the potential negative impact of transplanting candidates who are at a high risk for poor postoperative outcomes. PMID- 21683338 TI - Effects of heated seats in vehicles on thermal comfort during the initial warm-up period. AB - Eight subjects participated in a subjective experiment of eight conditions to investigate the effects of heated seats in vehicles on skin temperature, thermal sensation and thermal comfort during the initial warm-up period. The experimental conditions were designed as a combination of air temperature in the test room (5, 10, 15, or 20 degrees C) and heated seat (on/off). The heated seat was effective for improving thermal comfort during the initial warm-up period when air temperature was lower than 15 degrees C. Use of heated seats prevented decreases in or increased toe skin temperature. Heated seats also increased foot thermal sensation at 15 and 20 degrees C. Optimal thermal sensation in contact with the seat was higher when air temperature was lower. Optimal skin temperature in contact with the seat back was higher than that with the seat cushion. Moreover, these optimal skin temperatures were higher when air temperature was lower. PMID- 21683339 TI - Interleukin-1 beta affects cyclooxygenase-2 expression and cartilage metabolism in mandibular condyle. AB - Extracellular matrix degradation in mandibular condylar cartilage is mediated by various cytokines in the temporomandibular joint (TMJ). Interleukin-1 beta (IL 1beta) is detected in joint structures with pathologic status, and participates in catabolic action in the extracellular matrix. The purpose of this study was to investigate the effects of IL-1beta on cyclooxygenase-2 (COX-2) expression and cartilage metabolism using cultured chondrocytes from mandibular condyle. Articular chondrocytes from the porcine mandibular condylar cartilage around the surface were cultured and treated with 0-10 ng/ml IL-1beta or 0-1000 ng/ml prostaglandin (PGE(2)) for 0-24h. The mRNA levels of COX-2, MMP-1, -3, and -13 were evaluated by real-time PCR analysis. The protein levels of PGE(2) and MMPs were examined by ELISA and Western blot analysis, respectively. The expression levels of COX-2 and PGE(2) were enhanced by exogenous IL-1beta in chondrocytes. The mRNA levels of MMP-1, -3, and -13 were up-regulated by PGE(2) treatment dose dependently. It is shown that the expression of COX-2/PGE(2) was enhanced by IL 1beta in articular chondrocytes from mandibular condyle, and that MMP-1, -3, and 13 were induced by PGE(2), suggesting that IL-1beta-induced COX-2/PGE(2) play a crucial role in catabolic processes of mandibular condylar cartilage under inflammatory conditions. PMID- 21683340 TI - Comparative immunohistochemical expression of RANK, RANKL and OPG in radicular and dentigerous cysts. AB - OBJECTIVE: Receptor activator of nuclear factor-kappaB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) are members of the superfamily of ligands and receptors of tumour necrosis factor family involved in bone metabolism. The formation, differentiation and activity of osteoclasts are regulated by these proteins. To clarify the roles of osteoclast regulatory factors in cystic expansion of odontogenic cysts, expression of these proteins were analysed in radicular and dentigerous cysts. DESIGN: The immunohistochemistry expression of these biomarkers were evaluated and measured in lining epithelium and fibrous capsule of the radicular (n=20) and dentigerous cysts (n=20). RESULTS: A similar expression in lining epithelium was observed in the lesions. The fibrous capsule of dentigerous cyst showed a higher content of RANK-positive and RANKL-positive cells than fibrous capsule of radicular cyst. In the lining epithelium the RANKL/OPG ratio showed higher numbers of OPG-positive than RANKL-positive cells, whereas fibrous capsule of the cysts had a tendency to present a similar expression (OPG=RANKL). CONCLUSION: Ours findings indicate the presence of RANK, RANKL and OPG in cysts. Moreover, increased expression of OPG compared to RANKL in the lining epithelium could contribute to the differential bone resorption activity in theses lesions. PMID- 21683341 TI - Mesenchymal and embryonic characteristics of stem cells obtained from mouse dental pulp. AB - OBJECTIVE: Several studies have demonstrated that human dental pulp is a source of mesenchymal stem cells. To better understand the biological properties of these cells we isolated and characterized stem cells from the dental pulp of EGFP transgenic mice. METHODS: The pulp tissue was gently separated from the roots of teeth extracted from C57BL/6 mice, and cultured under appropriate conditions. Flow cytometry, RT-PCR, light microscopy (staining for alkaline phosphatase) and immunofluorescence were used to investigate the expression of stem cell markers. The presence of chromosomal abnormalities was evaluated by G banding. RESULTS: The mouse dental pulp stem cells (mDPSC) were highly proliferative, plastic adherent, and exhibited a polymorphic morphology predominantly with stellate or fusiform shapes. The presence of cell clusters was observed in cultures of mDPSC. Some cells were positive for alkaline phosphatase. The karyotype was normal until the 5th passage. The Pou5f1/Oct-4 and ZFP42/Rex-1, but not Nanog transcripts were detected in mDPSC. Flow cytometry and fluorescence analyses revealed the presence of a heterogeneous population positive for embryonic and mesenchymal cell markers. Adipogenic, chondrogenic and osteogenic differentiation was achieved after two weeks of cell culture under chemically defined in vitro conditions. In addition, some elongated cells spontaneously acquired a contraction capacity. CONCLUSIONS: Our results reinforce that the dental pulp is an important source of adult stem cells and encourage studies on therapeutic potential of mDPSC in experimental disease models. PMID- 21683342 TI - Porphyromonas gingivalis induces myocarditis and/or myocardial infarction in mice and IL-17A is involved in pathogenesis of these diseases. AB - OBJECTIVES: Although an association between periodontitis and cardiovascular diseases has been suggested, the role of Porphyromonas gingivalis in cardiovascular diseases is not clear. In this study, we examined whether experimental bacteremia of P. gingivalis causes cardiovascular diseases and investigated the mechanism of pathogenesis of cardiovascular diseases induced by P. gingivalis. DESIGN: C57BL/6 mice were intravenously inoculated with 2.0 * 10(8)CFU of P. gingivalis A7436 strain. Mice were sacrificed at specified days and their hearts were collected. The collected organs were divided into two halves and used for histological evaluation and cytokine analysis. IL-17A(-/-), IFN-gamma(-/-) and TNF-alpha(-/-) mice were also intravenously inoculated and the histological changes of hearts in mice were examined. RESULTS: Myocarditis and/or myocardial infarction were observed in mice injected with P. gingivalis. The levels of IL1-beta, IL-6, IL-17A, IL-18, TNF-alpha and IFN-gamma mRNA increased significantly after P. gingivalis injection. In particular, high levels of IL-17A and IFN-gamma mRNA expression were observed in hearts of mice after P. gingivalis injection in comparison with these levels before injection. Furthermore, the production of IL-17A was detected in hearts of wild-type mice after P. gingivalis injection. In wild-type, TNF-alpha(-/-) and IFN-gamma(-/-) mice, moderate infiltration of neutrophils and monocytes was observed in hearts at 5 days after injection. In contrast, no inflammatory findings were observed in hearts of IL 17A(-/-) mice. CONCLUSION: We have demonstrated that an experimental bacteremia of P. gingivalis could induce myocarditis and/or myocardial infarction in mice, and IL-17A plays an important role in the pathogenesis of these diseases. PMID- 21683343 TI - Retrieval properties of negative vs. positive mental images and autobiographical memories in social anxiety: outcomes with a new measure. AB - High (n=41) and low (n=39) socially anxious (SA) participants completed the Waterloo Images and Memories Interview (WIMI), a new assessment tool that measures the accessibility and properties of mental images and associated autobiographical memories that individuals may experience across both anxiety provoking (negative) and non-anxiety-provoking (positive) social situations. Results indicated that both high and low SA individuals experience negative images and associated autobiographical memories in anxiety-provoking social situations, but the rates of endorsement of such images and memories among high SA participants were substantially lower than those reported in recent studies. Moreover, whereas low SA individuals were capable of accessing a relatively balanced array of both negative and positive self-representations that were rich in episodic detail, high SA individuals retrieved a higher, more unbalanced ratio of negative-to-positive images and memories, as well as impoverished positive images that were significantly degraded in episodic detail. Finally, negative images influenced the two groups differently, with high SA individuals experiencing more negative emotional and cognitive consequences associated with bringing such images to mind. These results are discussed in relation to theoretical models of learning and memory within the context of contemporary cognitive behavioral models of social anxiety. PMID- 21683345 TI - Human umbilical mesenchymal stem cells enhance the expression of neurotrophic factors and protect ataxic mice. AB - Cerebellar ataxias, which comprise a wide spectrum of progressive disorders, are incurable at present. It has been reported that human umbilical mesenchymal stem cell (HU-MSC) transplantation has a protective effect on neurodegenerative diseases. In this study, we investigated the effect of HU-MSCs on ataxic mice induced by cytosine beta-D-arabinofuranoside (Ara-C). The ataxic mouse received an intravenous injection of 2*10(6) HU-MSCs once a week for three consecutive weeks. Neurological function was scored weekly by rotarod test and open field test. The mouse cerebellar volume and weight were also measured. The apoptotic cells, pathological alternations and distribution of HU-MSCs were determined by TUNEL assay and immunohistochemistry staining respectively. Double immunostaining was carried out to investigate the dynamics of HU-MSCs in the host animals. Neurotrophic factors in cerebellar tissue and serum were measured by Q-PCR and ELISA. Our results showed that HU-MSCs implantation significantly improved the motor skills of ataxic mice 8 weeks after application. HU-MSCs also alleviated cerebellar atrophy and decreased the number of apoptotic cells in the therapeutic group. Implanted HU-MSCs stayed in cerebellum for at least three months with no obvious differentiation. HU-MSC treated mice had enhanced expression of insulin like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) in cerebellum extraction and blood serum. Double immunostaining revealed that a few MAB1287 positive cells co-localized with IGF-1 or VEGF express cells. Our results suggest that HU-MSC treatment is capable of alleviating the motor impairments and cerebellar atrophy in the ataxic mouse model, probably via promoting particular neurotrophic factors. PMID- 21683346 TI - EEG-based motor imagery classification using enhanced active segment selection and adaptive classifier. AB - In this study, an adaptive electroencephalogram (EEG) analysis system is proposed for a two-session, single-trial classification of motor imagery (MI) data. Applying event-related brain potential (ERP) data acquired from the sensorimotor cortices, the adaptive linear discriminant analysis (LDA) is used for classification of left- and right-hand MI data and for simultaneous and continuous update of its parameters. In addition to the original use of continuous wavelet transform (CWT) and Student's two-sample t-statistics, the 2D anisotropic Gaussian filter is proposed to further refine the selection of active segments. The multiresolution fractal features are then extracted from wavelet data by means of modified fractal dimension. The classification in session 2 is performed by adaptive LDA, which is trial-by-trial updated using the Kalman filter after the trial is classified. Compared with original active segment selection and non-adaptive LDA on six subjects from two data sets, the results indicate that the proposed method is helpful to realize adaptive BCI systems. PMID- 21683344 TI - Rare nonsynonymous variants in alpha-4 nicotinic acetylcholine receptor gene protect against nicotine dependence. AB - BACKGROUND: Several studies report association of alpha-4 nicotinic acetylcholine receptors (encoded by CHRNA4) with nicotine dependence (ND). A meta-analysis of genomewide linkage studies for ND implicated a single chromosomal region, which includes CHRNA4, as genome-wide significant. METHODS: After establishing that common variants are unlikely to completely account for this linkage, we investigated the distribution of CHRNA4 rare variants by sequencing the coding exons and flanking intronic regions of CHRNA4 in 209 European American (EA) ND cases and 183 EA control subjects. Because most of the rare variants that we detected (and all nonsynonymous changes) were in Exon 5, we sequenced Exon 5 in an additional 1000 ND cases and 1000 non-ND comparison subjects, both of which included equal numbers of EAs and African Americans. RESULTS: Comparison subjects had a higher frequency of rare nonsynonymous variants in the Exon 5 region (encoding the large intercellular loop of the alpha4 subunit; Fisher's Exact Test p = .009; association test p = .009, odds ratio = .43; weighted-sum method p = .014), indicating a protective effect against ND. Considering data from the two stages combined and only nonsynonymous variants predicted to alter protein function, the association was stronger (Fisher's Exact Test p = .005; association test p = .008, odds ratio = .29; weighted-sum method p = .005). Single-photon emission computed tomography imaging results were consistent with functionality. CONCLUSIONS: CHRNA4 functional rare variants may reduce ND risk. This is the first demonstration that rare functional variants at a candidate locus protect against substance dependence to our knowledge, suggesting a novel mechanism of substance dependence heritability that is potentially of general importance. PMID- 21683347 TI - Mast cells in human testicular biopsies from patients with mixed atrophy: increased numbers, heterogeneity, and expression of cyclooxygenase 2 and prostaglandin D2 synthase. AB - OBJECTIVE: To determine intratesticular abundance and distribution of tryptase positive mast cells (MCs) and to examine the expression of key enzymes of prostaglandin (PG) synthesis, cyclooxygenase 2 (COX2), and PGD2 synthase in the testes of men with mixed atrophy (MA) syndrome and in normal samples. DESIGN: Retrospective study. SETTING: Academic research institute and andrology practice. PATIENT(S): Nineteen men. INTERVENTION(S): Testicular biopsies. MAIN OUTCOME MEASURE(S): Immunohistochemistry and evaluation of COX2 and tryptase-positive MCs, laser microdissection of immunoreactive cells followed by reverse transcriptase polymerase chain reaction for COX2 and PGDS-H mRNA, and transmission electron microscopy. RESULT(S): In line with previous studies, few tryptase-positive MCs, but no COX2-positive cells, were observed in testes with normal spermatogenesis. In MA samples, the number of tryptase-positive MCs was significantly increased and the cells accumulated in the walls of the seminiferous tubules. In 11 of 13 MA samples, COX2 protein was detected. In 2 cases, Leydig cells were positive; however, in all 11 of 13 cases, COX2 was localized to MCs, coexpressing tryptase. The proportion of MCs coexpressing COX2 varied from 4% to 35%. Laser microdissection of tryptase/COX2-positive MCs followed by reverse transcriptase polymerase chain reaction revealed PGDS-H mRNA. Transmission electron microscopy identified typical MCs with abundant granules and another subtype with only a few granules, implying that MCs may differentiate in the testes. CONCLUSION(S): In patients with MA, testicular MC numbers and phenotypes change with respect to the ability to express COX2 and synthesize PGs. MCs and PGs have emerged as players in spermatogenic dysfunction. PMID- 21683349 TI - Five-day anastrozole group in infertility needs supplemental human chorionic gonadotropin. PMID- 21683350 TI - An observational study of women with mullerian agenesis and their need for vaginal dilator therapy. AB - OBJECTIVE: To assess vaginal development, sexual activity, and the efficacy of vaginal dilator therapy in women with vaginal agenesis (Mayer-Rokitansky-Kuster Hauser syndrome). DESIGN: Retrospective case review. SETTING: Tertiary referral university teaching hospital clinic for disorders of sexual development and differentiation (DSDD). PATIENT(S): Eighty cases of Rokitansky syndrome. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Sexual activity and vaginal dimensions. RESULT(S): The retrospective case review examined vaginal dimensions and sexual activity at presentation with further evaluation at completion of vaginal dilator therapy. Eleven of 80 patients had undergone surgery in the past; six of these 80 women had received dilator training elsewhere, and four were sexually active. Sixty-three of 80 patients had not undergone any previous treatment. Seventeen were having satisfactory sexual intercourse, 16 were having unsatisfactory sexual intercourse, and 26 had never been sexually active; for four women, no information had been recorded. A total of 32 patients underwent vaginal dilator treatment, and 25 completed the therapy. Their vaginal length increased from 3.2 cm (range: 0 to 7 cm) to 6.1 cm (range: 3 to 9 cm). CONCLUSION(S): Diagnosis and management of mullerian agenesis may be achieved without the need for surgery in the majority of cases. Dilator treatment for vaginal agenesis should be offered as first-line treatment, coordinated by a specialist nurse with input from a psychologist. PMID- 21683352 TI - Fluid dynamics during embryo transfer. AB - OBJECTIVE: To study fluid dynamics during ET. DESIGN: Computational fluid dynamics were applied to calculate fluid velocity changes, dynamic pressure differences, and shear stress in the transferred load for the following injection speeds: 0.1, 1, 6, 12, and 20 m/sec. SETTING: Academic research institute of mechanical engineering and reproduction biotechnology and private centers of reproductive medicine. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Fluid velocity, dynamic pressure, and shear stress during injection of the transferred load. RESULT(S): An increase of injection speed for the transferred load increased the shear stress, dynamic pressure, and velocity differences acting on the embryo. The narrowing of the catheter lumen diameter by 20% amplified the transferred fluid velocity by 78%. An embryo positioned in proximity to the catheter's wall was exposed to considerably higher shear stress, dynamic pressure, and velocity difference than an embryo in the center of the catheter's lumen. CONCLUSION(S): The transfer of an embryo should be conducted gently and with minimal injection speed. Any narrowing of the catheter lumen should be eliminated. Preferably the embryo should be kept far from the catheter's wall during injection of the transferred load. PMID- 21683351 TI - The association of reproductive senescence with mitochondrial quantity, function, and DNA integrity in human oocytes at different stages of maturation. AB - OBJECTIVE: To determine the impact of reproductive aging on oocyte mitochondrial quantity, function, and DNA (mtDNA) integrity. DESIGN: Prospective observational study. SETTING: IVF clinic in a tertiary academic care center. PATIENT(S): One hundred two oocytes from 32 women undergoing IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Adenosine triphosphate (ATP) levels, mtDNA number, and mtDNA deletion occurrence in individual oocytes. RESULT(S): Oocyte ATP content increases with maturation (786 +/- 87 fmol, 1,037 +/- 57 fmol, and 1,201 +/- 59 fmol for prophase 1 [P1], metaphase 1 [M1], and metaphase 2 [M2] oocytes, respectively), whereas mtDNA copy numbers do not change (64,500 +/- 20,440, 180,000 +/- 44,040, and 143,000 +/- 31,210 for P1, M1, and M2 oocytes, respectively). Stepwise multiple regression analysis identified developmental stage as a determinant of oocyte ATP, whereas number of oocytes retrieved and cycle day 3 FSH level were determinants of mtDNA copy number. Of the 15 oocytes found to possess the 5-kb mtDNA deletion, 10 were arrested or degenerated oocytes. CONCLUSION(S): Although no direct association was found between female age and oocyte mitochondrial quantity and function, the number of mitochondria was predicted by ovarian reserve indicators. As the oocyte matures, ATP content increases. PMID- 21683353 TI - Challenging clinical paradigms of common bile duct diameter. PMID- 21683354 TI - Meta-analysis of randomized trials comparing the patency of covered and uncovered self-expandable metal stents for palliation of distal malignant bile duct obstruction. AB - BACKGROUND: Self-expandable metal stents (SEMSs) are used for palliation of malignant biliary obstruction. OBJECTIVE: We performed a meta-analysis to compare stent patency and stent survival of covered SEMSs (CSEMSs) and uncovered SEMSs (USEMSs) in patients with unresectable distal malignant biliary obstruction. DESIGN: Meta-analysis. SETTING: Tertiary-care facility. PATIENTS: A comprehensive search of several databases (from each database's earliest inclusive dates to November 2010, any language, and any population) was conducted. The search identified 337 potential abstracts and titles, of which 16 were retrieved in full text. Review of references identified 17 additional studies. We found 5 multicenter, randomized trials involving 781 patients. INTERVENTION: Placement of covered and uncovered SEMSs for treatment of distal malignant biliary obstruction. MAIN OUTCOME MEASUREMENTS: Stent patency, stent survival, patient survival, and cause for stent dysfunction (ingrowth, overgrowth, migration, and sludge formation). RESULTS: The median length of follow-up was 212 days. Compared with USEMSs, CSEMSs were associated with significantly prolonged stent patency (weighted mean difference [WMD] 60.56 days; 95% confidence interval [CI], 25.96, 95.17; I2 = 0%) and longer stent survival (WMD 68.87 days; 95% CI, 25.64, 112.11; I(2) = 79%). Stent migration, tumor overgrowth, and sludge formation were significantly higher with CSEMSs (relative risk [RR] 8.11; 95% CI, 1.47, 44.76; I2 = 0%), (RR 2.02; 95% CI, 1.08, 3.78; I2 = 0%), (RR 2.89; 95% CI, 1.27, 6.55; I2 = 0%). LIMITATIONS: Relatively low number of studies available and the fact that 2 of the 5 studies were from one institution. Also, the limited availability of some stents used in the trials may limit the applicability of these results. CONCLUSION: CSEMSs have a significantly longer duration of patency compared with USEMSs in patients with distal malignant biliary obstruction. Stent dysfunction occurs at a similar rate, although there is a trend toward later obstruction with CSEMSs. PMID- 21683355 TI - Preoperative predictors for mortality following hip fracture surgery: a systematic review and meta-analysis. AB - BACKGROUND: Hip fractures are always associated with a high postoperative mortality, the preoperative predictors for mortality have neither been well identified or summarised. This systematic review and meta-analysis was performed to identify the preoperative non-interventional predictors for mortality in hip fracture patients, especially focused on 1 year mortality. METHODS: Non interventional studies were searched in Pubmed, Embase, Cochrane central database (all to February 26th, 2011). Only prospective studies and retrospective studies with prospective collected data were included. Qualities of included studies were assessed by a standardised scale previous reported for observational studies. The effects of individual studies were combined with the study quality score using a previous reported model of best-evidence synthesis. The hazard ratios of strong evidence predictors were combined only by high quality studies. RESULTS: 75 included studies with 94 publications involving 64,316 patients were included and the available observations was a heterogeneous group. The overall inpatient or 1 month mortality was 13.3%, 3-6 months was 15.8%, 1 year 24.5% and 2 years 34.5%. There were strong evidence for 12 predictors, including advanced age, male gender, nursing home or facility residence, poor preoperative walking capacity, poor activities of daily living, higher ASA grading, poor mental state, multiple comorbidities, dementia or cognitive impairment, diabetes, cancer and cardiac disease. We also identified 7 moderate evidence and 12 limited evidence mortality predictors, and only the race was identified as the conflicting evidence predictor. CONCLUSION: Whilst there is no conclusive evidence of the preoperative predictors for mortality following hip fractures, special attention should be paid to the above 12 strong evidence predictors. Future researches were still needed to evaluate the effects of these predictors. PMID- 21683356 TI - Cervical status after neck sprains in frontal and rear-end car impacts. AB - OBJECTIVE: To compare the cervical status after neck sprains in frontal and rear end car impacts with respect to earlier proposed neck-sprain injury mechanisms, rotated head at impact, and the seat-belt geometry. METHODS: A prospective, multidisciplinary, in-depth study was made based on 23 car occupants injured in frontal impacts and 108 injured in rear-end impacts. The active neck mobility was measured in protraction-retraction, flexion-extension, side bending right-left, and rotation right-left. This was done in the acute phase and then three and twelve months later. The maximum range, increase in pain, and level of pain were recorded for each movement. A subgroup with increased pain during movements towards the impact direction, but not in the opposite one, so-called isolated contra-directional pain (ICP), was further analysed. The side bending and rotation mobility were studied in another subgroup, in which the head was rotated inwards or outwards relative the car, i.e. away from or towards the diagonal part of the seat belt. RESULTS: Rear-end impacts more often than frontal impacts caused greater restrictions of the cervical mobility and more frequently increased pain at the three different times that measurements were recorded, but, with few exceptions, the differences for each movement were not statistically significant. Increased pain during extension was more often noted after rear-end impacts. ICP during pro-/retraction was also more often noted after rear-end impacts. Head-inward rotation in rear-end impacts caused a more restricted mobility in the same direction at the primary examination than head-outward rotation. CONCLUSIONS: The cervical status after neck sprains in frontal and rear end car impacts is very similar, and the cervical range of movement in different directions and increased pain during cervical motions do not reveal any specific isolated injury mechanisms. Combined injury mechanisms should be considered, and further studies are recommended to investigate asymmetric loading during impact. PMID- 21683357 TI - Obstetrician-gynecologists' beliefs about safe-sex and abstinence counseling. AB - OBJECTIVE: To examine obstetrician-gynecologists' beliefs about safe-sex and abstinence counseling. METHODS: Between October 2008 and January 2009, a survey was mailed to a national randomized sample of 1800 practicing US obstetrician gynecologists. Study variables were agreement with 2 statements. (1) "If physicians counsel patients about safe-sex practices, the patients will be less likely to engage in risky sexual behaviors". (2) "If physicians counsel patients about abstinence, the patients will be much less likely to engage in sexual activity". Covariates included demographic, clinical, and religious characteristics of the physician. RESULTS: The response rate was 66% (1154/1760 eligible physicians). Most respondents somewhat (62%) or strongly (25%) agreed that counseling patients about safe-sex practices makes patients less likely to engage in risky sexual behaviors. Fewer agreed strongly (3%) or somewhat (28%) that counseling patients about abstinence makes patients less likely to engage in sexual activity. The belief that safe-sex counseling reduces risky behaviors was less common among males (odds ratio [OR] 0.6) and more common among immigrants (OR 2.0). Religious physicians were more likely to believe that abstinence counseling reduces sexual activity (OR 2.2-5.3). CONCLUSIONS: Most obstetrician gynecologists believed that counseling about safe sex is effective, and a significant minority endorsed abstinence counseling. PMID- 21683358 TI - Retrospective analysis of follicle loss after laparoscopic excision of endometrioma compared with benign nonendometriotic ovarian cysts. AB - OBJECTIVE: To evaluate follicle loss in ovarian tissue after laparoscopic excision by the stripping technique in endometriomas versus benign nonendometriotic ovarian cysts. METHODS: Cystectomy samples obtained from 127 ovaries from 104 patients (mean age, 29.05 +/- 05 years; range, 19-40 years) by laparoscopic excision (61 endometriomas and 66 benign nonendometriotic cysts) were evaluated for follicle loss. The samples including normal ovarian tissue were graded on a semiquantitative scale from 0 to 4, where 0 was complete absence of follicles and 4 was the pattern of primary and secondary follicles seen in a normal ovary. The results from endometriomas were compared with those from nonendometriotic cysts. RESULTS: There were no differences in mean tissue thickness, or number of primordial, primary, or secondary follicles between the endometriomas and the nonendometriotic cysts (P > 0.05). Ovarian cortex was detected in 92% and 82% of the endometriomas and nonendometriotic samples, respectively, (P = 0.081). Semiquantitative scoring of ovarian tissue was significantly higher in endometriomas (1.64 +/- 1.35 versus 1.11 +/- 1.22, P = 0.022). CONCLUSION: In up to 92% of the cystectomy samples, normal ovarian tissue was found adjacent to the benign cyst; however, functional follicle loss was slightly, but significantly, higher in the endometriomas. PMID- 21683359 TI - Bacterial vaginosis as a risk factor for high-grade cervical lesions and cancer in HIV-seropositive women. AB - OBJECTIVE: To assess the effect of bacterial vaginosis (BV) on the risk of high grade squamous intraepithelial lesions (HSIL) among HIV-seropositive women. METHODS: A hospital-based prospective cohort study of HIV-seropositive women was conducted in Johannesburg, South Africa from January 2005 to September 2009. Multivariate log-binomial and Poisson regressions were used to estimate prevalence and rate ratios, respectively. RESULTS: Among 1954 HIV-seropositive women, the baseline prevalence of HSIL was 17%. BV prevalence was high (54%) and showed no association with prevalence of HSIL (adjusted prevalence ratio, 1.12; 95% confidence intervals (CI), 0.92-1.35) nor with cervical lesion progression at follow-up visit (n=503) (adjusted rate ratio: 1.00; 95% CI, 0.65-1.53). CONCLUSION: Among HIV-seropositive women, BV was not associated with an increased risk of HSIL or cervical lesion progression. PMID- 21683360 TI - Relationships among depression, anxiety, self-care behaviour and diabetes education difficulties in patients with type-2 diabetes: a cross-sectional questionnaire survey. AB - BACKGROUND: Since psychosocial issues appear to be common among people with diabetes, addressing these problems may improve outcomes. Specifically, it is important to understand the factors associated with anxiety and depression in patients with diabetes. OBJECTIVE: The purpose of this study was to investigate the relationships between self-care behaviour, diabetes education difficulties, depression and anxiety among patients with type-2 diabetes in Taiwan. DESIGN: This study was cross-sectional and consisted of descriptive statistics and correlations in terms of analyses. SETTING: Three teaching hospitals, one from each of the northern, middle and southern parts of Taiwan, were selected for data collection. PARTICIPANT: A total of 312 patients diagnosed with type-2 diabetes were recruited to participate in this study. The inclusion criteria of the study subjects included a diagnosis of type-2 diabetes beyond the age of 18 years and the ability to communicate in Mandarin. METHODS: Various questionnaires were used to assess demographic, disease characteristics, self-care behaviour, diabetes education difficulty, depression and anxiety data. RESULTS: (1) Rates of disturbance for depression (10.6%) and anxiety (20.5%) among type-2 diabetes patients were lower than those in Western countries. (2) Anxiety was positively correlated with age (r=0.15, p<0.01), complications (r=0.27, p<0.01), diabetes education difficulty (r=0.39, p<0.01) and depression (r=0.54, p<0.01), but negatively correlated with body mass index (BMI) (r=0.20, p<0.01). (3) A total of 50.5% of variance in anxiety was explained by age, complications, BMI, diabetes education difficulty and depression. (4) A total of 42.8% of variance in depression was explained by BMI, diabetes education difficulty and anxiety. CONCLUSION: Depression and anxiety are common among patients with diabetes and can have significant effects on the outcome of their medical illness. Addressing psychosocial factors of people with diabetes may improve effects of patient education and disease self-management. PMID- 21683361 TI - Modeling leaflet correction techniques in aortic valve repair: A finite element study. AB - In aortic valve sparing surgery, cusp prolapse is a common cause of residual aortic insufficiency. To correct cusp pathology, native leaflets of the valve frequently require adjustment which can be performed using a variety of described correction techniques, such as central or commissural plication, or resuspension of the leaflet free margin. The practical question then arises of determining which surgical technique provides the best valve performance with the most physiologic coaptation. To answer this question, we created a new finite element model with the ability to simulate physiologic function in normal valves, and aortic insufficiency due to leaflet prolapse in asymmetric, diseased or sub optimally repaired valves. The existing leaflet correction techniques were simulated in a controlled situation, and the performance of the repaired valve was quantified in terms of maximum leaflets stress, valve orifice area, valve opening and closing characteristics as well as total coaptation area in diastole. On the one hand, the existing leaflet correction techniques were shown not to adversely affect the dynamic properties of the repaired valves. On the other hand, leaflet resuspension appeared as the best technique compared to central or commissural leaflet plication. It was the only method able to achieve symmetric competence and fix an individual leaflet prolapse while simultaneously restoring normal values for mechanical stress, valve orifice area and coaptation area. PMID- 21683362 TI - Biomechanical effects of flow and coculture on human aortic and cord blood derived endothelial cells. AB - Human endothelial cells derived from umbilical cord blood (hCB-ECs) represent a promising cell source for endothelialization of tissue engineered blood vessels. hCB-ECs cultured directly above human aortic smooth muscle cells (SMCs), which model native and tissue engineered blood vessels, produce a confluent endothelium that responds to flow like normal human aortic endothelial cells (HAECs). The objective of this study was to quantify the elastic modulus of hCB-ECs cocultured with SMCs under static and flow conditions using atomic force microscopy (AFM). Cytoskeleton structures were assessed by AFM cell surface imaging and immunofluorescence of F-actin. The elastic moduli of hCB-ECs and HAECs were similar and significantly smaller than the value for SMCs in monoculture under static conditions (p<0.05). In coculture, hCB-ECs and HAECs became significantly stiffer with moduli 160-180% larger than their corresponding values in monoculture. While the moduli of hCB-ECs and HAECs almost doubled in monoculture and flow condition, their corresponding values in coculture declined after exposure to flow. Both the number and diameter of cortical stress fiber per cell width increased in coculture and/or flow conditions, whereas the subcortical stress fiber density throughout the cell interior increased by a smaller amount. These findings indicate that changes to biomechanical properties in coculture and/or exposure to flow are correlated with changes in the cortical stress fiber density. For ECs, fluid shear stress appeared to have greater effect on the elastic modulus than the presence of SMCs and changes to the elastic modulus in coculture may be due to EC-SMC communication. PMID- 21683363 TI - Protein adsorption and transport in dextran-modified ion-exchange media. II. Intraparticle uptake and column breakthrough. AB - Protein transport behavior was compared for the traditional SP Sepharose Fast Flow and the dextran-modified SP Sepharose XL and Capto S resins. Examination of the dynamic binding capacities (DBCs) revealed a fundamental difference in the balance between transport and equilibrium capacity limitations when comparing the two resin classes, as reflected by differences in the locations of the maximum DBCs as a function of salt. In order to quantitatively compare transport behavior, confocal microscopy and batch uptake experiments were used to obtain estimates of intraparticle protein diffusivities. For the traditional particle, such diffusivity estimates could be used to predict column breakthrough behavior accurately. However, for the dextran-modified media, neither the pore- nor the homogeneous-diffusion model was adequate, as experimental dynamic binding capacities were consistently lower than predicted. In examining the shapes of breakthrough curves, it was apparent that the model predictions failed to capture two features observed for the dextran-modified media, but never seen for the traditional resin. Comparison of estimated effective pore diffusivities from confocal microscopy and batch uptake experiments revealed a discrepancy that led to the hypothesis that protein uptake in the dextran-modified resins could occur with a shrinking-core-like sharp uptake front, but with incomplete saturation. The reason for the incomplete saturation is speculated to be that protein initially fills the dextran layer with inefficient packing, but can rearrange over time to accommodate more protein. A conceptual model was developed to account for the partial shrinking-core uptake to test whether the physical intuition led to predictions consistent with experimental behavior. The model could correctly reproduce the two unique features of the breakthrough curves and, in sample applications, parameters found from the fit of one breakthrough curve could be used to adequately match breakthrough at a different flow rate or batch uptake behavior. PMID- 21683364 TI - Fast determination of the functional peptide soymetide in different soybean derived foods by capillary-high performance liquid chromatography. AB - The determination of bioactive peptides derived from food sources is gaining special attention in last years, due to their ability to promote health and their potential to reduce the risk of chronic diseases. In this work, a new analytical methodology has been developed enabling for the first time the determination of soymetide, a new immunostimulating peptide derived from soybean, in different soybean derived foodstuffs. Capillary-HPLC was employed for peptide separation after accelerated tryptic digestion of soybean proteins. Two different capillary HPLC columns were tested and chromatographic separation was optimized in each case. The use of a 300 MUm fused-core technology C18 column enabled a suitable separation of soymetide from the other peptides in less than 18 min. Different analytical characteristics of the method were evaluated: selectivity, linearity, accuracy, precision, limit of detection and quantitation, and stability. The developed method was applied to the determination of soymetide content in different soybean dairy-like products for human consumption (powdered milks and infant formulas). PMID- 21683365 TI - Determination of quinolone residues in infant and young children powdered milk combining solid-phase extraction and ultra-performance liquid chromatography tandem mass spectrometry. AB - The present work describes a method based on solid-phase extraction (SPE) and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for the simultaneous determination of three quinolones (pipemidic acid, oxolinic acid and flumequine) and twelve fluoroquinolones (marbofloxacin, fleroxacin, pefloxacin, levofloxacin, norfloxacin, ciprofloxacin, enrofloxacin, danofloxacin, lomefloxacin, difloxacin, sarafloxacin, and moxifloxacin) in different infant and young children powdered milks. After suitable deproteination of the reconstituted powdered samples, a SPE procedure was developed providing recovery values higher than 84% (RSDs lower than 13%) for all the analytes, with limits of detection between 0.04 and 0.52 MUg/kg. UPLC-MS/MS analyses were carried out in less than 10 min. Sixteen infant and young children powdered milk samples of different origin, type and composition bought at Spanish markets were analyzed. Residues of the selected antibiotics were not detected in any of the analyzed samples. PMID- 21683366 TI - Antibody purification by affinity chromatography based on small molecule affinity ligands identified by SPR-based screening of chemical microarrays. AB - Libraries of small molecules were searched for Fc-fragment selective binders to a recombinant human antibody ("MDJ8", IgG(1)-subtype, kappa-light chain) via SPR based screening of chemical microarrays. Identified hit structures were immobilised on NHS-activated Sepharose for the determination of MDJ8 binding and selectivity versus typical proteineous impurities represented by the spend cell culture supernatant. Columns were packed and the most promising ligands further characterized in terms of binding constants, binding kinetics, as well as dynamic and equilibrium binding capacities. The performance of the best ligand, 2A10, was compared to standard Protein A chromatography. Using ligand 2A10 antibody capture from unprocessed cell culture supernatants was possible at similar recovery yield (>90%), purity (>80%), and eluting concentration (approximately 1 g/L) as with Protein A. Affinity constants (K(d)) of 2A10 were an order of magnitude higher than for the Protein A material, but still in the nM-range, while maximum binding capacities and binding kinetics were in the same order of magnitude. Ligand 2A10 was also able to capture a murine monoclonal antibody, again with similar efficiency as Protein A, as well as a number of humanised therapeutic antibodies. Antibody elution from the 2A10 column was possible using the Protein A standard protocol, i.e. 100mM glycine HCl pH 3.0, but also at near physiological pH, when some organic solvent or modifiers were present. Ligand 2A10 thus constitutes a cheaper, more robust alternative to Protein A as possible generic antibody binder. Moreover, the outlined approach to ligand selection could in principle by used to create suitable affinity ligands for other high value biotech products. PMID- 21683367 TI - Mass spectrometric characterization of urinary toremifene metabolites for doping control analyses. AB - Toremifene is a selective estrogen receptor modulator included in the list of prohibited substances in sport by the World Anti-doping Agency. The aim of the present study was to investigate toremifene metabolism in humans in order to elucidate the structures of the most abundant urinary metabolites and to define the best marker to detect toremifene administration through the analysis of urine samples. Toremifene (Fareston) was administered to healthy volunteers and the urine samples were subjected to different preparation methods to detect free metabolites as well as metabolites conjugated with glucuronic acid or sulphate. Urinary extracts were analyzed by LC-MS/MS with triple quadrupole analyzer using selected reaction monitoring mode. Transitions for potential metabolites were selected by using the theoretical [M+H](+) as precursor ion and m/z 72 or m/z 58 as product ions for N,N-dimethyl and N-desmethyl metabolites, respectively. Toremifene and 20 metabolites were detected in excretion study samples, excreted free or conjugated with glucuronic acid or sulphate. Structures for most abundant phase I metabolites were proposed using accurate mass measurements performed by QTOF MS, based on fragmentation pattern observed for those metabolites available as reference standards. Several metabolic pathways including mono- and di hydroxylation, N-desmethylation, hydroxymethylation, oxidation, dehalogenation and combinations were proposed. All metabolites were detected up to one month after toremifene administration; the most abundant metabolites were detected in the free fraction and they were metabolites resulting from dehalogenation. Several of the metabolites elucidated in this work have not been reported until now in the scientific literature. PMID- 21683368 TI - Profiles of phenolic compounds in modern and old common wheat varieties determined by liquid chromatography coupled with time-of-flight mass spectrometry. AB - The health-promoting properties of common wheat (Triticum aestivum L.) have been largely attributed to the presence of unique phytochemicals of whole grains. The aim of this study was to profile the phenolic content of 16 old and 6 modern Italian wheat varieties, cropped in the same location and growing season. High variability was observed among the investigated wheat genotypes, both in the free and bound phenolic extracts. The total polyphenol content ranged from 885.5 to 1715.9 MUmol GAE/100 g of grain and, on average, the bound fraction contributed for 72.0% to the total phenolic content. As regards the flavonoid content, the free fraction ranged from 50.7 to 106.1 MUmol CE/100 g of grain and the bound fraction from 78.3 to 148.9 MUmol CE/100 g of grain. Moreover, the interpretation of the mass spectra allowed the characterization of 34 phenolic compounds (104 including isomer forms) belonging to the phenolic acid, flavonoid, coumarin, stilbene, proanthocyanidin and lignan chemical classes. HPLC-ESI-TOF-MS analysis highlighted remarkable differences in the phytochemical fingerprints of old and modern wheat varieties. Six ancient wheat genotypes (Bianco Nostrale, Frassineto, Gentil Rosso, Gentil Rosso Mutico, Marzuolo d'Aqui, Verna) showed phenolic profiles with a number of total compounds and isomer forms much higher than that identified in the modern cultivars. The present findings confirm that ancient wheat may represent a valuable source of biodiversity, especially as regards phenolic compounds. The investigated old wheat genotypes may be successfully used in breeding programs for developing bread wheat varieties with added value in terms of health-promoting phytochemicals. PMID- 21683369 TI - Sensitive determination of phenylarsenic compounds based on a dual preconcentration method with capillary electrophoresis/UV detection. AB - A novel method based on off-line hollow fiber based liquid liquid liquid microextraction (HF-LLLME) combined with on-column anion selective exhaustive injection (ASEI)-capillary electrophoresis/ultraviolet (CE/UV) detection was proposed for the speciation of five phenylarsenic compounds including phenylarsonic acid (PAA), 4-aminophenylarsonic acid (4-APAA), 4 hydroxyphenylarsonic acid (4-HPAA), 4-nitrophenylarsonic acid (4-NPAA) and 3 nitro-4-hydroxyphenylarsonic acid (NHPAA) in this paper. In HF-LLLME, the target analytes were extracted from 5 mL aqueous samples (donor solution pH 2.15) through a thin phase of tributyl phosphate (TBP) inside the pores of a polypropylene hollow fiber and finally into an 18 MUL 0.8 mmol/L Tris acceptor solution inside the lumen of the hollow fiber. Following HF-LLLME, the acceptor solutions were directly analyzed by ASEI-CE/UV. For ASEI, a large plug of water (91% length of total capillary) was introduced into the separation capillary before sample injection in order to prolong the sample injection time, and thus enhance the stacking efficiency. Under the optimized ASEI conditions, up to 236 fold of enrichment factor (EF) was obtained for the ASEI-CE/UV determination of target phenylarsenic compounds. By combining HF-LLLME with ASEI-CE/UV, EFs ranging from 155 to 1780-fold were achieved and the limits of detection (LODs) (at a signal-to-noise ratio of 3) were in the range of 0.68-6.90 MUg/L for five phenylarsenic compounds; the relative standard deviations (RSDs) of corrected peak area were 5.6-11.8%. The proposed HF-LLLME-ASEI-CE/UV method was applied for the determination of five target phenylarsenic compounds in pig feed from a local pig farm, and storage pig litter, soil in agricultural field and lake water collected near this pig farm, the recoveries for the spiked samples were in the range of 85.7-104.5%, 66.7-96.2%, 28.9-46.9% and 86.9-107.8% for pig feed, pig litter, soil and lake water, respectively. PMID- 21683370 TI - Neonatal necrotizing tracheobronchitis. PMID- 21683371 TI - Quality of early mother-child interaction associated with depressive psychopathology in the offspring: a prospective study from infancy to adulthood. AB - Evidence from animal research has revealed that less maternal care results in disturbed emotionality in the offspring. In the present study, the long-term impact of maternal responsiveness and stimulation during early mother-child interaction on depressive psychopathology was examined until adulthood. Data are from an epidemiological cohort study of the long-term outcome of early risk factors assessed at birth. At age 3 months, mothers and infants were videotaped during a nursing and playing situation. Maternal responsiveness and stimulation as well as infant responsiveness were evaluated by trained raters. At age 19 years, 314 participants (145 males, 169 females) were characterized on measures of depression through interview and questionnaire. In addition, measures of depression and anxiety were available from assessments in childhood. Results indicated that less maternal stimulation during early interaction was associated with a higher risk of depression in the offspring until the age of 19 years. In addition, children of less stimulating mothers showed more depressive symptoms at age 19 years and displayed more anxiety and depressive symptoms between the ages of 4.5 and 15 years. In contrast, maternal responsiveness was unrelated to children's outcome. In accordance with findings from animal research, the present study provides first longitudinal evidence in humans of a continuous and long term influence of early maternal interaction behavior on the offspring's psychological adjustment until adulthood. The results suggest that the amount of maternally initiated contact behavior in a very early developmental stage may be crucial for children's mental health, regardless of child and maternal responsiveness. PMID- 21683372 TI - Perceptions of student-observers in the operating room. AB - BACKGROUND: Student observation of surgical procedures is standard practice performed at the discretion of the attending surgeon and the participating medical facility. The goal of our study was to evaluate patient, physician, and operating room (OR) staff opinions concerning student observation of surgical procedures at different levels of academic training. MATERIALS AND METHODS: Following Institutional Review Board approval, patients undergoing elective surgery were consented to participate in the survey. An anonymous online survey was sent to attending surgeons and OR staff. RESULTS: The majority of patients (97), physicians (91), and OR staff (71) believe that OR observational experience is important to medical student training. Patients (92%) and OR staff (97%) more so than physicians (72%) rated OR observational experience as important for nursing student education (P < 0.001). Comparatively, all groups believe this experience is less important for college and high school students (P < 0.01). When asked if patients should be informed preoperatively of student-observer presence during procedures, more patients and OR staff replied affirmatively compared with physicians (P < 0.001). Similarly, patients and OR staff more frequently believed that informed consent for OR student-observers was necessary (P < 0.0001). CONCLUSION: All groups acknowledged the educational value of student observational experience, although significant disparity was noted relative to academic level and the group responding. Additionally, opinions of the OR staff were more closely aligned with those of patients. Further assessment of the role of informed consent for student-observer OR presence and potential implications is needed. PMID- 21683373 TI - Five primary human pancreatic adenocarcinoma cell lines established by the outgrowth method. AB - BACKGROUND: Pancreatic ductal adenocarcinoma is an aggressive tumor; treatment remains a challenge because of the lack of effective therapeutic strategies. Basic research in this field is dependent on the availability of model systems. New pancreatic cancer cell lines are therefore important for the study of its biology. In the present study, we report the establishment and characterization of five new pancreatic cancer cell lines (PaCaDD-43, -60, -119, -135, -137). MATERIAL AND METHODS: All cell lines were derived from pancreatic ductal adenocarcinomas by the Dresden outgrowth protocol. The five cell lines originated from primary pancreatic tumors, lymph node metastases, or malignant pleural effusions. We characterized the cell lines by examining their morphology and their cytostructural and functional profiles. RESULTS: All cell lines grew as adherent monolayers and were cultured in optimized Dresden-medium. The doubling time ranged from 22 to 47 h. v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were detected in four of the five cell lines. KRAS mutations were identical between each primary tumor and the cell line derived from it. Immunohistochemical staining showed cytoplasmic expression of CK8/18, mostly membrane and partially cytoplasmic expression of E-cadherin and strong expression of ezrin in all cell lines. Three cell lines showed nuclear p53 accumulation and heterogeneous expression of vimentin. SMAD4 was heterogeneously expressed in four of the cell lines. CONCLUSIONS: We were able to establish five new primary pancreatic carcinoma cell lines. As applicable tools for basic research, these cell lines might contribute to a better understanding and treatment of this aggressive tumor. PMID- 21683374 TI - Does statin in the acute phase of ischemic stroke improve outcome after intravenous thrombolysis? A retrospective study. AB - BACKGROUND: In recent years, the medical literature has shown that statin treatment before and in the acute phase of ischemic stroke has a positive impact on outcome. The possible effect of statins during the acute phase has never been assessed in thrombolysed patients, and the few studies investigating a possible association between prior statin use and outcome after thrombolysis have reported controversial results. The aim of the present study was to assess whether statin treatment started in the acute phase of stroke (within 24h) or before stroke and continued during the acute phase may influence short- and long-term outcome in patients receiving intravenous (IV) thrombolysis. METHODS: We conducted a retrospective analysis of 250 patients treated with IV thrombolysis. Outcome measures were 3-month good functional outcome (modified Rankin Scale <= 2); neurological improvement (reduction >= 4 points on the National Institutes of Health Stroke Scale [NIHSS]) between 24 and 72 h; and symptomatic intracerebral hemorrhage (brain hematoma associated with NIHSS deterioration >= 4 points) within 72 h. RESULTS: Multivariate analysis showed that statin treatment started in the acute phase of stroke was associated with both good functional outcome (OR: 6.18; 95% CI: 1.43-26.62; P=0.015) and neurological improvement (OR: 9.47; 95% CI: 1.98-45.37; P=0.005), whereas statin treatment started before stroke and continued in the acute phase was associated with symptomatic intracerebral hemorrhage (OR: 6.65; 95% CI: 1.58-29.12; P=0.010). CONCLUSIONS: Our data suggest that statin treatment started within 24h after IV thrombolysis, but not statin treatment started before stroke and continued in the acute phase, may improve short- and long-term outcome. PMID- 21683375 TI - Impulsive and compulsive behaviors in Parkinson's disease: a one-year follow-up study. AB - Impulsive and compulsive behaviors (ICBs) have been reported to occur frequently in Parkinson's disease (PD) and include impulse control disorders (ICDs), punding and dopamine dysregulation syndrome (SSD). We report on the outcomes of 25 PD patients who developed ICBs. Information was collected on changes in parkinsonian and psychiatric medication follow-up (median=12.1 months). At time 1, only 18 patients (72%) were taking dopamine agonists (DA). At time 2, fifteen patients (83.33%) either discontinued or decreased their DA treatment. Of these patients, thirteen (86.67%) reported experiencing full or partial remission of their ICBs symptoms. When analyzing separately the 11 patients with punding, these symptoms remained unchanged in 9 patients (81.82%) independently of changes in dopaminergic drugs. In conclusion, the current study suggests that there are clear similarities, but also important differences, between punding and ICDs over time. Pathological gambling, binge or compulsive eating, pathological hypersexuality and compulsive shopping in PD were robustly associated with the use of DA but the relationship between dopaminergic medications and punding is less clear. It is important to determine if other treatment strategies may be effective for punding in PD. PMID- 21683376 TI - Aortic no-touch technique makes the difference in off-pump coronary artery bypass grafting. AB - OBJECTIVES: Both off-pump surgery (OPCAB) and aortic no-touch technique reduce stroke after coronary artery bypass grafting (CABG). We evaluate the impact of partial aortic clamping (PC) versus a no-touch technique using either the HEARTSTRING system (HS) or total arterial revascularization (TAR) on the incidence of stroke. METHODS: From 1999 [corrected] to 2009, 4314 patients underwent myocardial revascularization. Patients either underwent OPCAB (n = 2203) or conventional on-pump CABG (n = 2111). The OPCAB cohort was divided into 2 subgroups: patients requiring proximal anastomosis applying PC (n = 567) or a "no-touch" technique with the HS (n = 1365). Patients who received TAR (n = 271) served as a control group (gold-standard). Data collection was performed prospectively using a propensity score (PS)-adjusted regression analysis. End points were stroke, mortality, major adverse cardiac and cerebrovascular events (MACCE), and a noncardiac composite end point including respiratory failure, renal failure, and bleeding. RESULTS: The mortality rate (1.6% vs 2.4%; propensity-adjusted odds ratio [PAOR] = 0.51; CI 95%, 0.26-0.99; P = .047), MACCE (7.9% vs 17.1%; PAOR = 0.67; CI 95%, 0.52-0.84; P = .001) including myocardial infarction (1.1% vs 2.2%; PAOR = 0.50; CI 95%, 0.26-0.98; P = .044) and stroke (1.1% vs 2.4%; PAOR = 0.35; CI 95%, 0.17-0.72; P = .005) as well as the noncardiac composite (PAOR = 0.46; CI 95%, 0.35-0.91; P < .001) were significantly lower for OPCAB when compared with on-pump CABG. In comparison with PC, OPCAB patients undergoing the HS approach had significantly lower frequencies of stroke (0.7% vs 2.3%; PAOR = 0.39; CI 95%, 0.16-0.90; P = .04) and MACCE (6.7% vs 10.8%; PAOR = 0.55; CI 95%, 0.38-0.79; P = .001), and these results were similar to those of the control group, who underwent no-touch TAR (stroke rate, 0.8%; MACCE, 7.9%). CONCLUSIONS: Our results confirm that OPCAB is superior with regard to risk-adjusted outcomes. There is no difference in the stroke rate when comparing on-pump CABG versus applying partial aortic crossclamping in OPCAB. Whenever a proximal anastomosis is needed, a no-touch technique should be applied, that is, using the HS device. PMID- 21683377 TI - Renal cell carcinoma with rhabdoid features. PMID- 21683378 TI - Urodynamic score in children with lipomyelomeningocele: a prospective study. AB - PURPOSE: We assessed the correlation between urodynamic score and presence of symptoms in children with lipomyelomeningocele, and the usefulness of this measure in monitoring these children. MATERIALS AND METHODS: We prospectively evaluated 29 patients 1 month to 13 years old (mean 1.9 years) with lipomyelomeningocele from 1995 to 2010. A 4-parameter urodynamic score ranging from 0 to 17 was assigned to each patient at diagnosis and followup. Indications for surgery were presence of symptoms and signs or abnormal urodynamic score. Children were divided into 2 groups, symptomatic and asymptomatic. The latter group was further divided into operated and conservatively managed cases. Average followup was 6.7 years (range 2 to 16). RESULTS: The symptomatic group contained 11 children (38%) operated on at a mean age of 2.9 years. Mean followup was 6.7 years (range 2 to 12). All patients presented with an abnormal urodynamic score. Postoperative urodynamic score improved in 6 patients (55%), remained abnormal in 4 (36%) and deteriorated in 1 (9%). The asymptomatic group contained 18 patients, of whom 7 (39%) were operated on at a mean age of 1.4 years. Mean followup was 10 years (range 3 to 16). Postoperative score improved in 6 patients (86%) and remained unchanged in 1 (14%). A total of 11 cases (61%) were managed conservatively, with a mean followup 4.3 years (range 2 to 7). Of these patients 3 (27%) presented with late urodynamic score deterioration at 3, 5 and 6 years of followup while remaining asymptomatic. CONCLUSIONS: Urodynamic score is a useful tool in monitoring children with lipomyelomeningocele because it has a good correlation with the presence of symptoms. PMID- 21683379 TI - Cost-effectiveness of primary prevention strategies for nephrolithiasis. AB - PURPOSE: Stone disease is a highly prevalent condition associated with substantial cost and morbidity. We evaluated the cost-effectiveness of a primary prevention strategy. MATERIALS AND METHODS: A decision analysis model was constructed to compare the cost of ad hoc management of symptomatic stones vs the cost of primary prevention. A literature search was performed to determine the incidence of stone disease, the effectiveness of nonmedical prevention strategies and cost associated with stone management. One and 2-way sensitivity analyses were performed to determine conditions under which a strategy of primary prevention might be cost-effective. RESULTS: Assuming a 1% incidence of stones, a 50% risk reduction and a $100 cost per individual per year for primary prevention, the model was used to calculate the overall costs per individual per year without and with a primary prevention strategy of $46 and $123, respectively. One-way sensitivity analyses indicated that primary prevention was cost-effective if the incidence of stones exceeded 4.3% yearly or the cost of prevention was less than $23 per person yearly. Varying other factors (risk reduction, probability of requiring surgery, hours of lost work, emergency room cost) failed to reach cost equivalence under any circumstances or required unrealistic assumptions. Preventive strategies were more costly than no prevention unless the incidence of stone disease was at least 1%, the cost did not exceed $20 per person per year and the prevention strategy was at least 50% effective in preventing stones. CONCLUSIONS: Primary prevention strategies for stone disease have not been sufficiently evaluated but can theoretically be cost effective if the population has a sufficiently high incidence of stone disease and the strategy is of low cost and moderately effective. PMID- 21683380 TI - Robotic flexible ureteroscopy for renal calculi: initial clinical experience. AB - PURPOSE: We report what is to our knowledge the initial clinical experience with remote robotic ureterorenoscopy and laser lithotripsy for renal calculi using a novel flexible robotic system. MATERIALS AND METHODS: After institutional review board approval and informed consent 18 patients with renal calculi underwent flexible robotic ureteroscopy. Study inclusion criteria were 5 to 15 mm renal calculi. Patients with ureteral calculi or obstruction, uncontrolled infection, renal insufficiency or solitary kidney were excluded from analysis. The flexible robotic catheter system was manually introduced into the renal collecting system over a guidewire under fluoroscopic control. All intrarenal maneuvers, including stone relocation and fragmentation into 1 to 2 mm particles, were done exclusively from the remote robotic console. RESULTS: All procedures were technically successful without conversion to manual ureteroscopy. Mean stone size was 11.9 mm, mean robot docking time was 7.3 minutes, mean stone localization time was 8.7 minutes, mean total robot time was 41.4 minutes and mean total operative time was 91 minutes. The mean visual analog scale rating on a scale of 1-worst to 10-best was 8.5 for robotic control, 9.0 for stability and 9.2 for fragmentation ease. There were no intraoperative complications. Postoperative complications included transient fever in 2 cases and temporary limb paresis in 1. One patient required secondary percutaneous nephrolithotomy for residual stone. Based on computerized tomogram/excretory urogram the complete stone clearance rate at 2 and 3 months was 56% and 89%, respectively. At 3 months all patients had stable renal function and unobstructed drainage. CONCLUSIONS: We present a novel flexible robotic platform for retrograde ureteroscopic treatment for intrarenal calculi. Initial experience is encouraging. PMID- 21683381 TI - Sacral neuromodulation as a treatment for chronic pelvic pain. AB - PURPOSE: Chronic pelvic pain syndrome is a debilitating disease which often has a major impact on quality of life. A significant number of patients do not respond to conservative treatment and often no good alternative can be offered except radical surgery. Sacral neuromodulation is a well established therapy for patients with lower urinary tract dysfunction. This therapy has also been suggested to be useful in the treatment of chronic pelvic pain. Although currently no Food and Drug Administration approval exists for this indication, several studies have demonstrated promising results. We provide an overview of the published literature on sacral neuromodulation as a treatment for chronic pelvic pain. MATERIALS AND METHODS: A PubMed(r) search was performed to identify articles in English from 1990 to February 2010 reporting treatment of pelvic pain with sacral neuromodulation. In addition, the current definitions of pelvic pain syndromes and the mechanisms of action are discussed. RESULTS: A total of 12 relevant articles were identified. Of these articles 10 mainly addressed the efficacy of sacral neuromodulation in patients with interstitial cystitis/bladder pain. The percentage of patients who responded to test stimulation was reported between 51% and 77%. Of the 10 articles 7 reported treatment outcome after implantation. The duration of followup ranged between 5 and 87 months. The mean reduction in pain scores was reported between 40% and 72%. The reoperation rate ranged between 27% and 50% after long-term followup. Two articles included patients with miscellaneous urogenital pain syndromes. The success rates after implantation ranged from 60% to 77% with followup ranging between 19 and 36 months. CONCLUSIONS: Currently there is insufficient evidence to determine the role of sacral neuromodulation in the treatment of chronic pelvic pain. Larger prospective trials with long-term evaluation are required to determine the ultimate efficacy of this treatment. PMID- 21683382 TI - Prospective evaluation of clinical voiding reeducation or voiding school for lower urinary tract conditions in children. AB - PURPOSE: We conducted a prospective controlled study evaluating the results of a clinical voiding reeducation program (voiding school) for treatment of lower urinary tract conditions in children compared to no treatment. MATERIALS AND METHODS: A total of 38 children with nonneurogenic lower urinary tract conditions were included in the study. Controls, consisting of 15 children on the waiting list for the same program, received no treatment. The clinical voiding reeducation program consisted of instruction on voiding and drinking, individualized voiding diaries, pelvic floor biofeedback training, uroflowmetry, alarm therapy, cognitive therapy and psychological support. Data on voiding, drinking, pelvic floor control, voided volume, uroflow, incontinence and stool habits were gathered before the program, during the program and 6 months after the program. In the control group the same data were gathered. RESULTS: In the study group a positive effect of voiding school was observed in 92% of children, with 42% becoming completely dry, 24% improving from incontinence during the day and night to incontinence during the day or night only, and 26% remaining incontinent. In all patients the number and amount of incontinence episodes decreased. In the control group no differences were observed between the start of study and 6 months later. The study group did significantly better on voided volume and incontinence compared to controls. CONCLUSIONS: In this prospective controlled study a positive effect was noted on voided volume and incontinence with a clinical voiding reeducation program (voiding school). PMID- 21683384 TI - Re: Glanuloplasty with urethral flap after partial penectomy. J. J. Belinky, G. M. Cheliz, C. A. Graziano and H. M. Rey. J Urol 2011; 185: 204-206. PMID- 21683385 TI - Role of calcitonin gene-related peptide in inhibitory neurotransmission to the pig bladder neck. AB - PURPOSE: We studied the role of calcitonin gene-related peptide in nonadrenergic, noncholinergic neurotransmission to the pig bladder neck. MATERIALS AND METHODS: We used immunohistochemical techniques to determine the distribution of calcitonin gene-related peptide immunoreactive fibers as well as organ baths for isometric force recording. We investigated relaxation due to endogenously released or exogenously applied calcitonin gene-related peptide in urothelium denuded phenylephrine precontracted strips treated with guanethidine, atropine and NG-nitro-L-arginine to block noradrenergic neurotransmission, muscarinic receptors and nitric oxide synthase, respectively. RESULTS: Rich calcitonin gene related peptide immunoreactive innervation was found penetrating through the adventitia and distributed in the suburothelial and muscle layers. Numerous, variable size, varicose calcitonin gene-related peptide immunopositive terminals were seen close below the urothelium. In the muscle layer calcitonin gene-related peptide immunopositive nerves usually appeared as varicose terminals running along muscle fibers. Electrical field stimulation (2 to 16 Hz) and exogenous calcitonin gene-related peptide (0.1 nM to 0.3 MUM) evoked frequency and concentration dependent relaxation, respectively. Nerve responses were potentiated by capsaicin, decreased by calcitonin gene-related peptide (8-37) and abolished by tetrodotoxin, capsaicin sensitive primary afferent blockers, calcitonin gene-related peptide receptors and neuronal voltage gated Na+ channels. Calcitonin gene-related peptide-induced relaxation was potentiated by the neuronal voltage gated Ca2+ channels blocker omega-conotoxin-GVIA and decreased by calcitonin gene-related peptide (8-37). Calcitonin gene-related peptide relaxation was not modified by blockade of endopeptidases, nitric oxide synthase, guanylyl cyclase and cyclooxygenase. CONCLUSIONS: Results suggest that calcitonin gene-related peptide is involved in the nonadrenergic, noncholinergic inhibitory neurotransmission of the pig bladder neck, producing relaxation through neuronal and muscle calcitonin gene-related peptide receptors. Nitric oxide/cyclic guanosine monophosphate and cyclooxygenase pathways do not seem to be involved in such responses. PMID- 21683386 TI - Re: Assessing the usefulness of delayed imaging in routine followup for renal trauma. P. Davis, M. F. Bultitude, J. Koukounaras, P. L. Royce and N. M. Corcoran. J Urol 2010; 184: 973-977. PMID- 21683387 TI - Risk factors for end stage renal disease in non-WT1-syndromic Wilms tumor. AB - PURPOSE: We assessed risk factors for end stage renal disease in patients with Wilms tumor without known WT1 related syndromes. We hypothesized that patients with characteristics suggestive of a WT1 etiology (early onset, stromal predominant histology, intralobar nephrogenic rests) would have a higher risk of end stage renal disease due to chronic renal failure. We predicted a high risk of end stage renal disease due to progressive bilateral Wilms tumor in patients with metachronous bilateral disease. MATERIALS AND METHODS: End stage renal disease was ascertained in 100 of 7,950 nonsyndromic patients enrolled in a National Wilms Tumor Study during 1969 to 2002. Risk factors were evaluated with cumulative incidence curves and proportional hazard regressions. RESULTS: The cumulative incidence of end stage renal disease due to chronic renal failure 20 years after Wilms tumor diagnosis was 0.7%. For end stage renal disease due to progressive bilateral Wilms tumor the incidence was 4.0% at 3 years after diagnosis in patients with synchronous bilateral Wilms tumor and 19.3% in those with metachronous bilateral Wilms tumor. For end stage renal disease due to chronic renal failure stromal predominant histology had a HR of 6.4 relative to mixed (95% CI 3.4, 11.9; p<0.001), intralobar rests had a HR of 5.9 relative to no rests (95% CI 2.0, 17.3; p=0.001), and Wilms tumor diagnosis at less than 24 months had a HR of 1.7 relative to 24 to 48 months and 2.8 relative to greater than 48 months (p=0.003 for trend). CONCLUSIONS: Metachronous bilateral Wilms tumor is associated with high rates of end stage renal disease due to surgery for progressive Wilms tumor. Characteristics associated with a WT1 etiology markedly increased the risk of end stage renal disease due to chronic renal failure despite the low risk in non-WT1 syndromic cases overall. PMID- 21683388 TI - Endovascular stenting for treatment of Nutcracker syndrome: report of 61 cases with long-term followup. AB - PURPOSE: We report the efficacy and safety of endovascular stenting for nutcracker syndrome at long-term followup. MATERIALS AND METHODS: We retrospectively evaluated the endovascular stenting experience with 61 patients with a median age of 26 years. Symptoms were hematuria, proteinuria or flank pain. Median followup was 66 months. RESULTS: Peak velocity in the aortomesenteric portion, and the anteroposterior diameter ratio of the renal hilum and the aortomesenteric portion of the left renal vein on Duplex ultrasound after stenting was significantly decreased compared to that on Duplex ultrasound before stenting (p<0.05). However, peak velocity in the hilar portion did not statistically differ (p>0.05). Symptoms resolved or improved in 15, 24 and 20 of the 61 patients within 1 week, and 1 and 6 months, respectively, after endovascular stenting. Symptoms remained unchanged in 2 patients and recurred in 1. A perioperative complication was noted in 1 patient, that is a stent that was mistakenly moved and poorly deployed in a left renal vein collateral required operative intervention. Postoperative complications included stent migration into the right atrium, stent protrusion into the inferior vena cava and stent migration into the hilar left renal vein in 1 case each. CONCLUSIONS: Based on our long-term followup endovascular stenting is a safe, effective procedure in select adults. We recommend endovascular stenting as primary option for nutcracker syndrome. PMID- 21683389 TI - Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States. AB - PURPOSE: Bladder pain syndrome/interstitial cystitis is a poorly understood condition that can cause serious disability. We provide the first population based symptom prevalence estimate to our knowledge among United States adult females. MATERIALS AND METHODS: We developed and validated 2 case definitions to identify bladder pain syndrome/interstitial cystitis symptoms. Beginning in August 2007 we telephoned United States households, seeking adult women with bladder symptoms or a bladder pain syndrome/interstitial cystitis diagnosis. Second stage screening identified those subjects who met case definition criteria. Each completed a 60-minute interview on the severity and impact of bladder symptoms, health care seeking and demographics. Data collection ended in April 2009. Using population and nonresponse weights we calculated prevalence estimates based on definitions spanning a range of sensitivity and specificity. We used United States Census counts to estimate the number of affected women in 2006. The random sample included 146,231 households, of which 131,691 included an adult female. Of these households 32,474 reported an adult female with bladder symptoms or diagnosis, of which 12,752 completed the questionnaire. RESULTS: Based on the high sensitivity definition 6.53% (95% CI 6.28, 6.79) of women met symptom criteria. Based on the high specificity definition 2.70% (95% CI 2.53, 2.86) of women met the criteria. These percentages translated into 3.3 to 7.9 million United States women 18 years old or older with bladder pain syndrome/interstitial cystitis symptoms. Symptom severity and impact were comparable to those of adult women with established diagnoses. However, only 9.7% of the women reported being assigned a bladder pain syndrome/interstitial cystitis diagnosis. CONCLUSIONS: Bladder pain syndrome/interstitial cystitis symptoms are widespread among United States women and associated with considerable disability. These results suggest bladder pain syndrome/interstitial cystitis may be underdiagnosed. PMID- 21683390 TI - Mixed epithelial and stromal tumor of the kidney. PMID- 21683391 TI - Do chief resident scores on the in-service examination predict their performance on the American Board of Urology Qualifying Examination? AB - PURPOSE: The American Urological Association In-Service Examination and the American Board of Urology Qualifying Examination are written multiple choice tests that cover all domains in urology. We investigated whether In-Service Examination performance could identify chief residents who scored in the lowest quartile on the Qualifying Examination. MATERIALS AND METHODS: All urology chief residents in the United States and Canada in 2008 and 2009 were eligible to participate in this study. In-Service Examination 2008 and Qualifying Examination 2009 performance data were obtained from the American Urological Association and American Board of Urology, respectively. Data were analyzed with the Pearson correlation and descriptive statistics. RESULTS: Of the 257 American and Canadian chief residents who completed the Qualifying Examination 2009, 194 (75%) enrolled in this study and were included in analysis. Overall In-Service Examination 2008 scores correlated significantly with Qualifying Examination 2009 scores (r=0.55, p<0.001), accounting for 30% of score variance. Substantial variability in In Service Examination-Qualifying Examination rankings was notable among individual residents. An In-Service Examination 2008 cutoff percentile rank of 40% identified chief residents in the lowest quartile on the Qualifying Examination 2009 with 71% sensitivity, 77% specificity, and a likelihood ratio of 3.1 and 0.4 (positive and negative likelihood ratios, respectively). CONCLUSIONS: The substantial variability of In-Service Examination-Qualifying Examination performance among individual chief residents limits In-Service Examination predictive utility. A single In-Service Examination score should not be used to make a high stakes judgment about an individual resident. In-Service Examination scores should be used as 1 part of an overall evaluation program to prospectively identify residents who could benefit from additional educational support. PMID- 21683393 TI - Lower urinary tract symptoms in adults treated for posterior urethral valves in childhood: matched cohort study. AB - PURPOSE: We compared the prevalence and bother of lower urinary tract symptoms in adults treated for posterior urethral valves in childhood and population based controls. MATERIALS AND METHODS: Questionnaires were mailed to patients 18 years and older treated at our institution for posterior urethral valves. Of the 124 patients 68 (64.2%) participated, 18 were unavailable and 38 did not participate. Age and sex matched controls were randomly identified from a population based study (response proportion 62.4%). Danish Prostatic Symptom Score was used to assess occurrence (never/rarely/often/always) and bother (none/small/moderate/major) of 12 different lower urinary tract symptoms. Chi square test was used for the analyses stratified by patient/control status, with the 4-point ordinal scale as the outcome. RESULTS: Median age of 68 patients with posterior urethral valves and 272 controls (ratio 1:4) was 38.5 years (range 18 to 57). Overall, at least 1 moderate or severe lower urinary tract symptom was reported by 32.4% of patients with posterior urethral valves and 15.8% of controls (p=0.002). Mild hesitancy, weak stream, incomplete emptying and straining were reported twice as often by patients with posterior urethral valves as by controls (p<0.05). Prevalence of any urgency incontinence (14.7% vs 4.8%, p=0.014) and any stress incontinence (11.8% vs 3.0%, p=0.005) was increased at least 3-fold in patients with posterior urethral valves compared to controls. Furthermore, prevalence of bother from several lower urinary tract symptoms was increased approximately 2-fold in patients with posterior urethral valves compared to controls (p<0.05). However, most patients and controls reported no or small bother. CONCLUSIONS: In adulthood the occurrence and bother of most lower urinary tract symptoms are increased approximately 2-fold in patients with posterior urethral valves compared to the general population. However, in this cohort of young and middle-aged men most symptoms are mild. PMID- 21683395 TI - Editorial comment. PMID- 21683396 TI - Specific protein patterns characterize metastatic potential of advanced bladder cancer. AB - PURPOSE: The prognosis in patients with metastasized bladder cancer is still poor. Clinical and histopathological parameters have limited ability to predict the risk of tumor progression. Thus, we identified specific protein patterns associated with tumor progression to differentiate specimens with and without metastasis. MATERIALS AND METHODS: We analyzed 46 metastasized and 42 nonmetastasized muscle invasive bladder cancers by ProteinChip(r) technology surface enhanced laser desorption/ionization time of flight mass spectrometry. Cell lysis was done after laser capture microdissection from cryostat sections to achieve high tumor cell purity. Surface enhanced laser desorption/ionization time of flight mass spectrometry was completed with 2 matrices (Q10 and CM10). Bioinformatic analysis was performed by XLMiner(r) clustering using the Fuzzy c means method. Differentially expressed proteins were identified and verified by 2 dimensional gel electrophoresis, tryptic in gel digest, peptide mapping, immunodepletion assay and Western blot analysis. RESULTS: By combining data on 2 chip surfaces (Q10 and CM10) results showed 86% sensitivity and 89% specificity in the training set, and 63% sensitivity and 88% specificity in the validation set. The relevant protein peaks 10.83, 14.68, 16.15 and 27.85 Da were identified as S100A8, MAP-1LC3, MUC-1S1 and GST-M1, respectively. CONCLUSIONS: We defined specific protein patterns with ProteinChip technology using bioinformatic evaluation software, which allowed differentiation between nonmetastasized and metastasized bladder tumor samples with high sensitivity and specificity. We identified 4 differentially expressed proteins. Thus, it seems possible to identify patients at high metastasized risk even at a clinically localized stage, leading to individual therapy decisions. PMID- 21683397 TI - Optimization of nonmuscle invasive bladder cancer recurrence detection using a urine based FGFR3 mutation assay. AB - PURPOSE: FGFR3 mutations occur in 70% of nonmuscle invasive bladder tumors. Although urine based FGFR3 mutation analysis can detect recurrence, its sensitivity may be limited if samples have few or no tumor cells. We determined whether test sensitivity depends on tumor size and the time point of urine collection, and how to increase sensitivity. MATERIALS AND METHODS: A total of 440 urine samples from 18 patients with a suspicious bladder lesion at cystoscopy were collected during 6 days before surgery. Eight patients (300 samples) had an FGFR3 mutant tumor, including 4 each with a tumor greater than 3 and less than 1.5 cm. Polymerase chain reaction based FGFR3 analysis was done on all tumors and urine samples. RESULTS: FGFR3 mutations were detected in 257 of the 300 urine samples (86%) from patients with an FGFR3 mutant tumor. Assay sensitivity was 100% for tumors greater than 3 cm and 75% for tumors less than 1.5 cm. It increased to 100% in patients with a less than 1.5 cm tumor when samples were pooled during 24 hours. Sensitivity was not influenced by the time of urine collection. All urine samples from patients with an FGFR3 wild-type tumor were negative for FGFR3 mutation. CONCLUSIONS: The sensitivity of tumor detection increased with tumor size. FGFR3 assay sensitivity depends on the number of shed tumor cells and improves by increasing urine volume. These findings suggest that there is an upper limit to the sensitivity of the FGFR3 assay when 1 urine sample is analyzed. This may also apply to other DNA or RNA based assays. PMID- 21683398 TI - Implantation of autologous urine derived stem cells expressing vascular endothelial growth factor for potential use in genitourinary reconstruction. AB - PURPOSE: We evaluated the effects of vascular endothelial growth factor overexpression on urine derived stem cell survival and myogenic differentiation to determine whether these cells could be used as a novel cell source for genitourinary reconstruction. MATERIALS AND METHODS: Urine derived stem cells were isolated from 31 urine samples of 6 healthy individuals 3 to 27 years old. Urine derived stem cells were infected with an adenoviral vector containing the mouse VEGF gene. These cells were then mixed with human umbilical vein endothelial cells (total 5*10(6)) in a collagen-I gel. These cell containing gels were subcutaneously implanted along with 6 other controls into 18 athymic mice. The grafts were assessed up to 28 days after injection for gross appearance and immunocytochemistry. RESULTS: Vascular endothelial growth factor levels in the media from infected urine derived stem cell cultures reached a peak value on day 10 after infection. Grafts composed of urine derived stem cell/adenoviral vector containing the mouse VEGF gene and human umbilical vein endothelial cells were larger and better vascularized compared to uninfected urine derived stem cell control grafts. Additionally more implanted cells expressed human nuclear markers in the vascular endothelial growth factor expressing grafts. Vascular endothelial growth factor expressing grafts also contained more cells expressing the endothelial markers CD-31 and von Willebrand factor, and smooth muscle markers (alpha-smooth muscle actin, desmin and myosin). Also, more nerve fibers were present in urine derived stem cell/adenoviral vector containing mouse VEGF gene plus human umbilical vein endothelial cell grafts than in controls. CONCLUSIONS: Vascular endothelial growth factor overexpression combined with human umbilical vein endothelial cells enhanced in vivo survival and myogenic differentiation of urine derived stem cells. Neovascularization and nerve regeneration were also enhanced within the implanted grafts. PMID- 21683399 TI - Low incidence of urinary tract infections following renal transplantation in children with bladder augmentation. AB - PURPOSE: Children with end-stage renal disease and bladder dysfunction may require augmentation cystoplasty before kidney transplantation. Previous reports have suggested unacceptable urinary tract infection rates in these immunosuppressed patients. We reviewed our experience in this population. MATERIALS AND METHODS: We retrospectively studied patients undergoing augmentation cystoplasty and subsequent renal transplantation by a single surgeon between 1989 and 2007. This cohort was compared with a control group on clean intermittent catheterization who had undergone transplantation without augmentation. Patient demographics, etiology of renal failure, surgical details, surgical/allograft outcomes and occurrence of urinary tract infection were analyzed. RESULTS: The augmented group included 17 patients with a median age at reconstruction of 6.4 years. Stomach was used in 15 patients and colon in 2. Median time between reconstruction and transplantation was 1.2 years. Median followup after transplantation was 7.7 years. The control group included 17 patients with a median age at transplantation of 10.9 years. Median followup in the controls was 6.1 years. All ureteral reimplantations were antirefluxing. Patients on clean intermittent catheterization were maintained on oral antibiotic suppression and/or gentamicin bladder irrigations. In the augmented group 35 episodes of urinary tract infection were noted, and the number of documented infections per patient-year of followup was 0.22, compared to 32 episodes of urinary tract infection and 0.28 infections per patient-year of followup in the controls. No allograft was lost to infectious complications. CONCLUSIONS: In our series there was no increase in urinary tract infection rate following renal transplantation in patients with augmented bladders compared to controls. This finding may be due to the use of gastric augmentation, antirefluxing reimplantation and gentamicin irrigations. PMID- 21683401 TI - Aliskiren ameliorates renal inflammation and fibrosis induced by unilateral ureteral obstruction in mice. AB - PURPOSE: Renin-angiotensin system activation is involved in inflammation and fibrosis in the kidney. Aliskiren, a direct renin inhibitor, decreases renin angiotensin system activation, including plasma renin activity and angiotensin II, but increases the prorenin level, which may promote inflammation and fibrosis in renal tissue. Thus, we evaluated whether inhibiting the renin-angiotensin system by aliskiren would decrease renal inflammation and fibrosis in a mouse model of unilateral ureteral obstruction. MATERIALS AND METHODS: Ten-week-old male C57BL/6 mice (Samtako, Kyoung Gi-Do, Korea) weighing 30 to 33 gm were divided into 4 groups, including vehicle or aliskiren treated sham operated and vehicle or aliskiren treated unilateral ureteral obstruction groups. We evaluated plasma renin activity, and plasma renin and renal mRNA expression levels of renin and (pro)renin receptor. To evaluate inflammation and fibrosis renal mRNA expression of monocyte chemotactic protein-1, osteopontin and transforming growth factor-beta was measured. Hematoxylin and eosin, Masson's trichrome staining, and immunohistochemical staining for CD68, transforming growth factor-beta and alpha smooth muscle actin were performed. RESULTS: Plasma renin activity was significantly lower in the aliskiren treated obstruction group than in the vehicle treated obstruction group. Aliskiren treatment increased renal mRNA expression of renin. The number of CD68 positive cells, and renal monocyte chemotactic protein-1 and osteopontin mRNA levels were significantly higher in mice with unilateral ureteral obstruction than in sham operated mice. Aliskiren decreased the increased levels of these inflammation markers. Aliskiren also decreased renal transforming growth factor-beta mRNA expression, transforming growth factor-beta and alpha-smooth muscle actin immunostaining, and Masson's trichrome stained areas of unilateral ureteral obstruction kidneys. CONCLUSIONS: Aliskiren has anti-inflammatory and antifibrotic effects in an experimental unilateral ureteral obstruction mouse model. PMID- 21683402 TI - Nonvoiding activity of the guinea pig bladder. AB - PURPOSE: Detrusor nonvoiding contractions occur in up to 70% of healthy individuals. These contractions increase in those with pathological detrusor function and may be associated with afferent activity. We examined nonvoiding contractions in the urethane anesthetized guinea pig bladder and studied the effect of filling rate and intravesical volume. MATERIALS AND METHODS: A total of 14 guinea pigs were anesthetized and underwent bladder catheterization at the dome. In 6 guinea pigs bladder infusion was continuous and 2 physiological filling rates were used, including 25 (0.75 HD) and 50 MUl per minute (1.5 HD). In another 8 guinea pigs isovolumetric cystometry was done by filling the bladder incrementally and recording at low, medium and high intravesical volume. RESULTS: Nonvoiding contractions were apparent in all animals. Contractions increased in frequency and amplitude as the bladder filled. Different phases were identified. Immediately after a void no nonvoiding contractions were observed, followed by continuous activity, first with small contractions, and later with small and large contractions. Small nonvoiding contractions showed a phasic pattern in frequency while the frequency of large nonvoiding contractions slowly increased or remained stable. The frequency and amplitude of nonvoiding contractions were higher at a faster filling rate and a higher intravesical volume. CONCLUSIONS: Nonvoiding contractions are present in the anesthetized guinea pig. Under normal physiological conditions they increase in amplitude and frequency with the increase in the filling rate and in intravesical volume. Small and large nonvoiding contractions differ in frequency pattern and occur at different bladder filling periods. This may illustrate different afferents functioning during bladder filling, which could be important for understanding bladder pathology. PMID- 21683403 TI - Routine drain placement after partial nephrectomy is not always necessary. AB - PURPOSE: To our knowledge the benefit of routine drainage after partial nephrectomy has never been investigated, although a drain after partial nephrectomy can be associated with morbidity. We report our initial experience with omitting the drain in select cases of superficial renal cortical tumors. MATERIALS AND METHODS: From a surgery database we identified 512 consecutive open partial nephrectomies performed by a single surgeon between January 2005 and May 2009 using standardized technique. The study group included 75 evaluable patients (14.6%) who did not have a drain placed. Clinical data, surgical information, histological type and postoperative complications within 90 days of the procedure using the modified Clavien system were included in analysis. RESULTS: Median patient age was 64 years (IQR 49, 70) and 56.8% of the patients were male. Median tumor size was 2.0 cm (IQR 1.5, 3.0) and more than 70% were malignant. A total of 38 patients (50.7%) underwent renal artery clamping and cold ischemia with a median clamp time of 30 minutes. The overall complication rate was 13.3% (10 patients). In 4 patients (5.3%) complications were related to an absent drain, including grade I urinary leak, grade II perirenal collection, grade III urinoma requiring percutaneous drainage and grade III urinary leak with urosepsis, respectively. No deaths occurred in this cohort. CONCLUSIONS: Omitting drainage after partial nephrectomy in a select group of patients without collecting system entry is feasible and safe. The decision to place a drain after partial nephrectomy for small renal cortical tumors must be made intraoperatively and should be tailored to each case. PMID- 21683404 TI - Editorial comment. PMID- 21683405 TI - P2X receptor currents in smooth muscle cells contribute to nerve mediated contractions of rabbit urethral smooth muscle. AB - PURPOSE: Adenosine triphosphate is capable of relaxing and contracting urethral smooth muscle. The mechanisms responsible for the relaxing effects of adenosine triphosphate have been well studied but those involved in the contractile response are still unclear. We investigated the contributions of interstitial cells of Cajal and smooth muscle cells to nerve mediated, adenosine triphosphate dependent contractions of urethral smooth muscle. MATERIALS AND METHODS: Tension recordings were made from strips of rabbit urethral smooth muscle. Recordings were made of membrane potential and ionic currents from freshly isolated smooth muscle cells and interstitial cells of Cajal using the patch clamp technique. RESULTS: Stimulating intramural nerves in urethral smooth muscle yielded contractions that were inhibited by the broad spectrum P2 receptor inhibitor pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate and the P2X receptor agonist alpha,beta-methylene adenosine triphosphate but not by the P2Y receptor antagonist MRS2500. When studied under voltage clamp at a holding potential of 60 mV, interstitial cells of Cajal showed spontaneous transient inward currents that were increased in frequency by adenosine triphosphate but not by alpha,beta methylene adenosine triphosphate. In contrast, smooth muscle cells were quiescent but responded to adenosine triphosphate and alpha,beta-methylene adenosine triphosphate by producing a single transient inward current. Currents evoked by adenosine triphosphate in smooth muscle cells were inhibited by alpha,beta methylene adenosine triphosphate, pyridoxal-phosphate-6-azophenyl-2',4' disulfonate and suramin, and by a decrease in extracellular Na+ from 130 to 13 mM. CONCLUSIONS: Stimulating purinergic nerves in rabbit urethral smooth muscle induces contractions via the activation of P2X receptors on smooth muscle cells. PMID- 21683406 TI - Diphosphate regulation of adenosine triphosphate sensitive potassium channel in human bladder smooth muscle cells. AB - PURPOSE: To clarify the properties of adenosine triphosphate sensitive K+ channel in human detrusor smooth muscle we examined the effect of the representative nicotinic acid derivatives beta-nicotinamide adenine dinucleotide, cyclic adenosine diphosphate ribose and nicotinic acid adenine dinucleotide phosphate (Sigma-Aldrich(r)) on human detrusor adenosine triphosphate sensitive K+ channels. MATERIALS AND METHODS: Patch clamp procedures were done in human detrusor cells. Reverse transcriptase and real-time polymerase chain reaction were performed to clarify the subunit components of adenosine triphosphate sensitive K+ channels. RESULTS: The K+ channel opener levcromakalim induced a long lasting outward current that was inhibited by glibenclamide (Sigma-Aldrich) under the whole cell configuration. The single channel study revealed that the unitary conductance of the adenosine triphosphate sensitive K+ channel in the human detrusor was 11 pS and nucleotide diphosphates increased its open probability. Applying beta-nicotinamide adenine dinucleotide also activated the adenosine triphosphate sensitive K+ channel but applying cyclic adenosine diphosphate ribose or nicotinic acid adenine dinucleotide phosphate had little effect on channel activation. Molecular studies indicated that Kir6.1 and SUR2B were the predominant components of the adenosine triphosphate sensitive K+ channel in the human detrusor. CONCLUSIONS: To our knowledge we report the first single channel study of the adenosine triphosphate sensitive K+ channel in the human detrusor. The properties of this channel, ie unitary conductance, adenosine triphosphate sensitivity and diphosphate activation, were consistent with those of other smooth muscle organs. beta-Nicotinamide adenine dinucleotide has the potency to activate adenosine triphosphate sensitive K+ channels in the human detrusor. This channel likely has some role during ischemic conditions as well as physiological muscle motion leading to the activation of cell metabolism. PMID- 21683407 TI - Gradient changes in porcine renal arterial vascular anatomy and blood flow after cryoablation. AB - PURPOSE: We quantified temporal changes in vascular structure and blood flow after cryosurgery of the porcine kidney in vivo. MATERIALS AND METHODS: We studied 5 groups of 4 kidneys each with a survival time of 20 minutes, 4 hours, 2 days, and 1 and 2 weeks after cryoablation, respectively. Before harvesting the kidneys, fluorescently labeled microspheres were administrated in the descending aorta. After harvest the kidney and its vasculature were casted with fluorescently dyed elastomer, frozen and processed in an imaging cryomicrotome to reveal the 3-dimensional arterial branching structure and microsphere distribution. In regions of interest vessels were segmented by image analysis software and histograms were constructed to reveal the total summed vessel length as a function of diameter. A characteristic diameter of the ablated area was measured. RESULTS: The 20-minute survival group histograms showed a significant shift of the peak to larger diameters (p<0.002), indicating that smaller vessels were destroyed. Microsphere density was decreased to 2% in the ablated region but not in the nonablated border zone, depending on the remaining crater crossing larger vessels. After 2 weeks neither vessels nor microspheres were left in the ablated area, which had shrunk by about 40% in diameter. Study limitations are the lack of histological confirmation and the use of normal rather than cancerous tissue. CONCLUSIONS: Larger vessels remain patent just after ablation and transport blood to the border of the ablation crater but perfusion within the crater is halted instantly. Characteristic crater diameter increases initially but decreases thereafter. Destruction of vessels and tissue is complete 2 weeks after cryoablation. PMID- 21683408 TI - Re: Annual surgical caseload and open radical prostatectomy outcomes: improving temporal trends. L. Budaus, F. Abdollah, M. Sun, M. Morgan, R. Johal, R. Thuret, K. C. Zorn, H. Isbarn, S. F. Shariat, F. Montorsi, P. Perrotte, M. Graefen and P. I. Karakiewicz. J Urol 2010; 184: 2285-2290. PMID- 21683409 TI - Re: Validity of administrative coding in identifying patients with upper urinary tract calculi. M. J. Semins, B. J. Trock and B. R. Matlaga. J Urol 2010; 184: 190 192. PMID- 21683410 TI - A comparative study of the inhibiting effects of mitomycin C and polyphenolic catechins on tumor cell implantation/growth in a rat bladder tumor model. AB - PURPOSE: Mitomycin C (Novaplus(r)) is often instilled intravesically in the postoperative period to prevent tumor cell implantation/regrowth after transurethral tumor resection. In an earlier study EGCG prevented tumor cell implantation/growth in an experimental bladder tumor model simulating clinical transurethral bladder resection. We compared the efficacy of EGCG (Polyphenon E(r)) to that of mitomycin C to prevent tumor cell implantation/growth in this model. MATERIALS AND METHODS: Mitomycin C and EGCG were studied for their in vitro and in vivo effects. The AY-27 rat urothelial tumor cell line was used for in vitro and in vivo studies. In vitro cell viability studies included trypan blue exclusion, MTT proliferation assay and clonal growth assay. Fischer 344 female rats were used for intravesical tumor implantation/growth assay using an electrocautery injury model. Tumor growth in vivo was assessed in controls treated with phosphate buffered saline and in bladders treated with mitomycin C or EGCG by standard histological techniques using hematoxylin and eosin 4 weeks after injury. RESULTS: Mitomycin C and EGCG showed cytotoxicity on all in vitro assays. They were equivalent for preventing intravesical tumor growth. CONCLUSIONS: EGCG prevents intravesical tumor growth with efficacy equivalent to that of mitomycin C in this experimental model. PMID- 21683411 TI - Re: Expression of estrogen related proteins in hormone refractory prostate cancer: association with tumor progression. O. Celhay, M. Yacoub, J. Irani, B. Dore, O. Cussenot and G. Fromont. J Urol 2010; 184: 2172-2178. PMID- 21683413 TI - Assessing Internet health information on female pelvic floor disorders. AB - PURPOSE: While health information on the Internet on female pelvic floor disorders is abundant, to our knowledge there has been no comprehensive evaluation of the quality of this material. We assessed health information on the Internet using Health on the Net Foundation principles as they pertain to female pelvic floor disorders. MATERIALS AND METHODS: Web sites were searched using the key words urinary incontinence, vaginal, uterine or pelvic organ prolapse and overactive bladder. The first 150 websites identified for each female pelvic disorder were assessed for Health on the Net Foundation certification using an automated toolbar function. The specific sponsorship of each web site was also recorded. RESULTS: All searched domains for female pelvic floor disorders revealed that most websites were not certified. The certification rate for urinary incontinence, pelvic organ prolapse and overactive bladder was 29%, 27% and 27%, respectively. Overall websites were sponsored by for profit commercial entities (44%), urologist/specialty societies (30%), government/educational organizations (16%), nonprofit organizations (9%) and law firms (1%). Nonprofit organizations (40%) and government/educational organization (38%) sponsored websites were more likely to be certified than those sponsored by commercial entities (25%) and urologist/specialty societies (23%) (p=0.036). CONCLUSIONS: The Internet has become a heavily used resource for the distribution and acquisition of health information. Availability notwithstanding, certification and validation are lacking for most sites related to information on female pelvic floor disorders. As we move forward, improvement in the quality of information on the Internet is imperative along with proper guidance to patients using the Internet as a reference. PMID- 21683414 TI - Editorial comment. PMID- 21683412 TI - Baseline urodynamic predictors of treatment failure 1 year after mid urethral sling surgery. AB - PURPOSE: We determined whether baseline urodynamic study variables predict failure after mid urethral sling surgery. MATERIALS AND METHODS: Preoperative urodynamic study variables and postoperative continence status were analyzed in women participating in a randomized trial comparing retropubic to transobturator mid urethral sling. Objective failure was defined by positive standardized stress test, 15 ml or greater on 24-hour pad test, or re-treatment for stress urinary incontinence. Subjective failure criteria were self-reported stress symptoms, leakage on 3-day diary or re-treatment for stress urinary incontinence. Logistic regression was used to assess associations between covariates and failure controlling for treatment group and clinical variables. Receiver operator curves were constructed for relationships between objective failure and measures of urethral function. RESULTS: Objective continence outcomes were available at 12 months for 565 of 597 (95%) women. Treatment failed in 260 women (245 by subjective criteria, 124 by objective criteria). No urodynamic variable was significantly associated with subjective failure on multivariate analysis. Valsalva leak point pressure, maximum urethral closure pressure and urodynamic stress incontinence were the only urodynamic variables consistently associated with objective failure on multivariate analysis. No specific cut point was determined for predicting failure for Valsalva leak point pressure or maximum urethral closure pressure by ROC. The lowest quartile (Valsalva leak point pressure less than 86 cm H2O, maximum urethral closure pressure less than 45 cm H2O) conferred an almost 2-fold increased odds of objective failure regardless of sling route (OR 2.23, 1.20-4.14 for Valsalva leak point pressure and OR 1.88, 1.04-3.41 for maximum urethral closure pressure). CONCLUSIONS: Women with a Valsalva leak point pressure or maximum urethral closure pressure in the lowest quartile are nearly 2-fold more likely to experience stress urinary incontinence 1 year after transobturator or retropubic mid urethral sling. PMID- 21683415 TI - Induction of effective antitumor response after mucosal bacterial vector mediated DNA vaccination with endogenous prostate cancer specific antigen. AB - PURPOSE: The induction of systemic immune responses against antigenic targets that are over expressed by cancer cells represents a powerful therapeutic strategy to target metastatic cancer. We generated specific antitumor immune responses in a murine model of prostate cancer by oral administration of an attenuated strain of Salmonella typhimurium containing a plasmid coding for murine prostate stem cell antigen. MATERIALS AND METHODS: Trafficking of S. typhimurium SL7207 in the initial 10 hours after gavage feeding was determined using a bacterial lux expressing strain and live bioluminescence imaging. For vaccination trials male C57 BL/6 mice were gavage fed SL7207/murine prostate stem cell antigen expressing plasmid or controls twice at 2-week intervals. One week after the last feeding the mice were challenged subcutaneously with TRAMPC1 murine prostate carcinoma cells. Tumor dynamics and animal survival were recorded. RESULTS: Clearance of bacterial vector from animals was complete 9 hours after feeding. Delivery of vector transformed with a firefly luciferase reporter plasmid resulted in maximal eukaryotic reporter gene expression in splenocytes 48 hours after feeding. Induction of tumor protective immunity was achieved by feeding the mice murine prostate stem cell antigen expressing plasmid bearing bacteria and greater than 50% of immunized mice remained tumor free. No significant toxicity was observed. Induction of T-helper type 1 immune responses was determined by measuring interferon-gamma produced by splenocytes from vaccinated mice. When adoptively transferred to naive animals, splenocytes from vaccinated mice prevented tumor growth in 66% of challenged animals. CONCLUSIONS: Endogenous prostate cancer antigen gene delivery using a bacterial vector resulted in breaking immune tolerance to murine prostate stem cell antigen and significant retardation of tumor growth. PMID- 21683416 TI - Surgical anatomy of the 10th and 11th intercostal, and subcostal nerves: prevention of damage during lumbotomy. AB - PURPOSE: In a descriptive, inventorial anatomical study we mapped the course of the 10th and 11th intercostal nerves, and the subcostal nerve in the abdominal wall to determine a safe zone for lumbotomy. MATERIALS AND METHODS: We dissected 11 embalmed cadavers, of which 10 were analyzed. The 10th and 11th intercostal nerves, and the subcostal nerve were dissected from the intercostal space to the rectus sheath. Analysis was done using computer assisted surgical anatomy mapping. A safe zone and an incision line with a minimum of nerve crossings were determined. RESULTS: The 10th and 11th intercostal nerves were invariably positioned subcostally. The subcostal nerve lay subcostally but caudal to the rib in 4 specimens. The main branches were located between the internal oblique and transverse abdominal muscles. The nerves branched and extensively varied in the abdominal wall. A straight line extended from the superior surface of the 11th and 12th ribs indicated a zone with lower nerve density. In 5 specimens the 10th and 11th intercostal nerves crossed this line from the superior surface of the 11th rib. In 5 specimens neither the 11th intercostal nerve nor the subcostal nerve crossed this extended line from the superior surface of the 12th rib up to 15 cm from the tip of the rib. CONCLUSIONS: Damage is inevitable to branches of the 10th or 11th intercostal nerve, or the subcostal nerve during lumbotomy. However, an incision extending from the superior surface of the 11th or 12th rib is less prone to damage these nerves. Closing the abdominal wall in 3 layers with the transverse abdominal muscle separately might prevent damage to neighboring nerves. PMID- 21683417 TI - Endocrine disrupting compounds: can they target the immune system of fish? AB - Endocrine disruption, in particular disruption by estrogen-active compounds, has been identified as an important ecotoxicological hazard in the aquatic environment. Research on the impact of endocrine disrupting compounds (EDCs) on wildlife has focused on disturbances of the reproductive system. However, there is increasing evidence that EDCs affect a variety of physiological systems other than the reproductive system. Here, we discuss if EDCs may be able to affect the immune system of fish, as this would have direct implications for individual fitness and population growth. Evidence suggesting an immunomodulatory role of estrogens in fish comes from the following findings: (a) estrogen receptors are expressed in piscine immune organs, (b) immune gene expression is modulated by estrogen exposure, and (c) pathogen susceptibility of fish increases under estrogen exposure. PMID- 21683418 TI - Using a macroalgal delta15N bioassay to detect cruise ship waste water effluent inputs. AB - Green macroalgae bioassays were used to determine if the delta15N signature of cruise ship waste water effluent (CSWWE) could be detected in a small harbor. Opportunistic green macroalgae (Ulva spp.) were collected, cultured under nutrient depleted conditions and characterized with regard to N content and delta15N. Samples of algae were used in controlled incubations to evaluate the direction of isotope shift from exposure to CSWWE. Algae samples exposed to CSWWE exhibited an increase of 1-2.50/00 in delta15N values indicating that the CSWWE had an enriched isotope signature. In contrast, algae samples exposed to field conditions exhibited a significant decrease in the observed delta15N indicating that a light N source was used. Isotopically light, riverine nitrogen derived from N2-fixing trees in the watershed may be a N source utilized by algae. These experiments indicate that the delta15N CSWWE signature was not detectable under the CSWWE loading conditions of this experiment. PMID- 21683419 TI - Differential kinetics and temperature dependence of abiotic and biotic processes controlling the environmental fate of TNT in simulated marine systems. AB - This work seeks to understand how the balance of abiotic and biotic kinetic processes in sediments control the residual concentration of TNT in marine systems after release from ocean-dumped source. Kinetics of TNT disappearance were followed using marine sediments at different temperatures and under both biotic and presumably abiotic conditions (through sodium azide addition). Sediments exhibiting the highest rate of TNT disappearance under biotic conditions also exhibited the highest sorption affinity for TNT under abiotic conditions. Significant temperature dependence in the abiotic processes was observed in the diffusion coefficient of TNT and not sediment sorption affinity. At higher temperature, kinetics of biotic processes outpaced abiotic processes, but at low temperature, kinetics of abiotic processes were much more significant. We concluded that the differential influence of temperature on the kinetics of abiotic and biotic processes could provide distinguishing predictions for the potential residual concentration of TNT contamination in marine-sediment systems. PMID- 21683420 TI - Critical appraisal on the identification of Reference Conditions for the evaluation of ecological quality status along the Emilia-Romagna coast (Italy) using M-AMBI. AB - According to the European Water Framework Directive, the ecological status (ES) of a water body is determined by comparing observation data with undisturbed Reference Conditions (RCs). Defining RCs is crucial when evaluating the ES of a water body as it strongly affects the final outcome of any index application. Identifying RCs by observing real sites is not feasible in many marine environments, such as the Emilia-Romagna coast (Italy, N-Adriatic Sea). We used a statistical approach on a large dataset to derive RCs for the application of the benthic index M-AMBI in this area. We then applied M-AMBI to samples collected along a gradient of presumed environmental disturbance. The results put 14.8% of the Emilia-Romagna samples in "High" ES, 60.2% in "Good", 23.0% in "Moderate" and 2.0% in "Poor", showing a spatial gradient of improving quality. These results are in agreement with the extensive ecological knowledge available for this area. PMID- 21683421 TI - Spatial modeling of environmental vulnerability of marine finfish aquaculture using GIS-based neuro-fuzzy techniques. AB - Combining GIS with neuro-fuzzy modeling has the advantage that expert scientific knowledge in coastal aquaculture activities can be incorporated into a geospatial model to classify areas particularly vulnerable to pollutants. Data on the physical environment and its suitability for aquaculture in an Irish fjard, which is host to a number of different aquaculture activities, were derived from a three-dimensional hydrodynamic and GIS models. Subsequent incorporation into environmental vulnerability models, based on neuro-fuzzy techniques, highlighted localities particularly vulnerable to aquaculture development. The models produced an overall classification accuracy of 85.71%, with a Kappa coefficient of agreement of 81%, and were sensitive to different input parameters. A statistical comparison between vulnerability scores and nitrogen concentrations in sediment associated with salmon cages showed good correlation. Neuro-fuzzy techniques within GIS modeling classify vulnerability of coastal regions appropriately and have a role in policy decisions for aquaculture site selection. PMID- 21683422 TI - Matrix-bound phosphine in sediments from Lake Illawarra, New South Wales, Australia. AB - Matrix-bound phosphine (MBP) has been measured in sediment from two cores in Lake Illawarra on the south east coast of Australia. The sediments were also dated in the upper layers. MBP concentrations found range from 142 to 1813 ng kg(-1), dw (dry weight of sediment) with some values being amongst the highest ever measured. Values of MBP in deeper sediments were higher than for near surface samples, but the patterns with depth were not consistent. Strong correlations were noted between MBP and organic phosphorus (OP, r>0.8) and with total phosphorus (TP, r>0.7), but only moderate correlations were found with organic carbon (OC, r>0.5). No correlations were found between MBP concentrations and the age of the sediments. It was confirmed that high MBP concentrations are indicative of a phosphorus rich environment. The results tend to support the premise that MBP is generated by microbial attack on OP under anaerobic conditions. PMID- 21683423 TI - The marine medaka Oryzias melastigma--a potential marine fish model for innate immune study. AB - The objective of this study is to develop the marine medaka Oryzias melastigma as a potential marine fish model for innate immune and immunotoxicological studies. Hepcidin plays an important role in innate immune system. Two hepcidin genes (OM hep1 and OM-hep2) were identified and characterized in the O. melastigma, which were highly conserved with other reported hepcidins. During embryogenesis, significant elevation of OM-hep1 and OM-hep2 transcripts were coincided with liver development in the embryos. In adult medaka, differential tissue expressions of both hepcidin transcripts were evident: high in liver, moderate in spleen and low in non-immune tissues. After bacterial challenge, the two hepcidin mRNAs were rapidly and remarkably induced in liver and spleen, suggesting the two OM-hepcidins in O. melastigma play a complementary role in innate defense. Gender difference in time of induction and extent of the two hepcidin mRNAs elevation in infected O. melastigma should be considered in immunotoxicological studies. PMID- 21683424 TI - Genetics for understanding and predicting clinical progression in multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) is a dys-immune disease of the central nervous system with highly variable and unpredictable long-term outcome. STATE OF THE ART: In the early 1970s association between HLA alleles and MS was established. Very recently, the power of Genome Wide Association Studies (GWAS) enabled the identification of several loci involved in immune functions as genetic risk factors in MS. Recent data suggest that common genetic variations might modulate the clinical phenotype of MS through a regulation of key pathophysiological pathways. PERSPECTIVES: Identification of modifier genes might offer an opportunity to explore new relevant therapeutic targets and early prognostic markers. To date, studies of modifier genes in MS are numerous but results are still unclear. This research field may now benefit from large cohorts of patients available for association studies. CONCLUSION: In this context, we propose a review of epidemiological and association studies of genetic modifying effect in MS. PMID- 21683425 TI - [Vaccination anti-H1N1 and narcolepsy]. PMID- 21683426 TI - Integrating statistical and experimental protocols to model and design novel Gemini surfactants with promising critical micelle concentration and low environmental risk. AB - A paradigmatic study of integrating statistical modeling and experimental analysis to investigate the critical micelle concentration (CMC) and environmental risk of 120 structurally diverse Gemini surfactants is performed. In this procedure, the structural profiles of studied compounds are characterized using hundreds of constitutional, topological, geometrical and electrostatic descriptors, and the resulting variables of the characterization are then calibrated on the basis of experimentally measured properties via a variety of regression techniques, including MLR, PLS, SVM, RF, and GP, in conjunction with two sophisticated variable selection methods, i.e. empirical heuristic strategy and nonnumerical genetic algorithm. Among all the built models the most predictable one is constructed based on the simplest combination of heuristic variable selection and MLR modeling, with its predictive coefficient of determination (r(pred)(2)) and root-mean-square error of prediction (RMSP) on external independent test set of 0.90 and 0.39, respectively. Subsequently, this model is used to explain the structural factors that fundamentally govern the self-assembly behavior of Gemini surfactant molecules in solution and to design several new Gemini surfactants with potentially high CMC activity and low environmental risk. Further, these designed compounds are synthesized by diquaternary ammonium reaction and characterized by elemental analysis, (1)H NMR, (13)C NMR and mass spectrum. Found a promising candidate that possesses particularly high CMC potency as 0.83 mmol L(-1) at 25 degrees C. This experimentally measured value is in agreement with the model-predicted 0.89 mmol L(-1) fairly well. PMID- 21683427 TI - Electrocoagulation of wastewater from almond industry. AB - This work was carried out to study the treatment of almond industry wastewater by the electrocoagulation process. First of all, laboratory scale experiments were conducted in order to determine the effects of relevant wastewater characteristics such as conductivity and pH, as well as the process variables such as anode material, current density and operating time on the removal efficiencies of the total organic carbon (TOC) and the most representative analytical parameters. Next, the wastewater treatment process was scaled up to pre-industrial size using the best experimental conditions and parameters obtained at laboratory scale. Finally, economic parameters such as chemicals, energy consumption and sludge generation have been discussed. PMID- 21683428 TI - New reconstruction and morphological description of a Homo erectus cranium: skull IX (Tjg-1993.05) from Sangiran, Central Java. AB - Skull IX (Tjg-1993.05) was unearthed from the upper stratigraphic zone (Bapang-AG levels) of the hominin-bearing sequence in Sangiran. This remarkably complete cranial specimen of Homo erectus from the early Pleistocene of Java preserves substantial portions of the vault and face. However, the distortion present in the original reconstruction has hampered detailed documentation of its morphological characteristics. We here report a new reconstruction of Skull IX that successfully recovers the original morphology and significantly differs from previous reconstructions. Detailed morphological description and the results of initial comparative analyses based on this new reconstruction are provided. The endocranial volume of Skull IX was measured as 870 cc using micro-CT data. The neurocranium of Skull IX is slightly smaller than the so far recorded smallest cranium from this zone, suggesting this individual was female. In most, but not all, aspects of the cranial vault form, details of the external surface structures, and facial morphology, Skull IX exhibits numerous similarities to the other Bapang-AG H. erectus specimens, indicating that it belonged to the Bapang AG H. erectus population. Drawing on the expanded fossil sample of this chronoregional H. erectus group, we discuss their evolutionary status, degree of sexual dimorphism, and facial morphological variation in Afro-Asian earlier Homo specimens. PMID- 21683429 TI - A reassessment of the Neanderthal teeth from Taddeo cave (southern Italy). AB - The Middle Paleolithic fossil human teeth from Taddeo cave in southwestern Italy were discovered in 1967, but to date only scanty and partially incorrect information has been published about them. The teeth were recovered in a reddish sandy layer from the cave's floor, which is attributed either to an early phase of Wurm I (OIS 5c or 5d) or a transition phase between Wurm I and Wurm II (OIS 5a). In this paper, we present a revised morphological description and morphometric comparisons of the four dental remains discovered. Apart from a classic morphometric comparison, we also provide a qualitative and quantitative assessment of the internal morphology with the aid of micro-CT imaging. In addition, virtual restoration and matching of adjacent teeth were performed with 3D digital modeling and Computer-Aided Design techniques. Occlusal Fingerprint Analysis was also employed to help correctly identify each tooth. While in the previous studies, Taddeo 1 was considered either an upper right canine or a lower right canine, in the present work it has been definitely identified as lower left canine. Taddeo 2 has been reclassified as a right P(4) instead of a right P(3). Based on the occlusal and interproximal wear, we have also shown that Taddeo 2 and Taddeo 3 (right M(1)) belong to the same individual. All of the teeth show characteristic Neanderthal features in crown morphology and fissure pattern. However, although Taddeo 4 shows morphological features typical of Neanderthal M(1)s, some morphometric results (large enamel thickness, low dentine volume) recall more modern humans than Neanderthals. This result might suggest that, at least for lower first molars, the Neanderthal range of variation is large and still not clearly understood. PMID- 21683430 TI - Expression of cyclooxygenase-2 (COX-2) and p53 in neighboring invasive and in situ components of breast tumors. AB - The aim of the study was to assess the relationship between the expression of COX 2 and p53, hormone receptors and HER-2 in the in situ (DCIS) and invasive components of ductal carcinomas (IDC) of the same breast. The expression of COX 2, p53, and hormone receptors was assessed in 87 cases of IDC with contiguous areas of DCIS. Results showed that there was no difference in COX-2 expression comparing the in situ and invasive components of the tumors. In the in situ component, there was a statistically borderline increase in p53 expression in tumors that also expressed COX-2. ER-positive specimens were more common in the group of tumors that expressed COX-2 in the invasive component. From this study we conclude that the expression of COX-2 was similar in the in situ and invasive components of the breast carcinomas. COX-2 positivity was marginally related with the expression of p53 in the in situ components, and with the ER expression in the invasive components. PMID- 21683431 TI - Is there a real standard for stage IVa cervical cancer? PMID- 21683432 TI - Adaptive cytokine production in early life differentially predicts total IgE levels and asthma through age 5 years. AB - BACKGROUND: Although it has been postulated that allergic disease is associated with a predominance of T(H)2 cells, whether IgE levels and asthma might differ in their relation to early-life cytokine production is not known. OBJECTIVE: We sought to assess the relationship between first-year adaptive immune cytokine production with asthma and total IgE levels through age 5 years in a nonselected birth cohort. METHODS: Mitogen (concanavalin A/phorbol 12-myristate 13-acetate) stimulated IL-4, IL-5, IL-13, and IFN-gamma levels were measured in supernatants from cord blood mononuclear cells and PBMCs at birth, 3 months, and 12 months. Total serum IgE levels and physician-diagnosed active asthma were assessed at 1, 2, 3, and 5 years. Longitudinal models that adjust for both T(H)1 and T(H)2 cytokine production were used to determine relations of outcomes. RESULTS: Relations of cytokines to total IgE levels and asthma were strikingly different. Total IgE levels through age 5 years were positively associated with 12-month IL 4 (P < .001), IL-5 (P < .001), and IL-13 (P = .02) levels when adjusted for IFN gamma levels and inversely associated with 12-month IFN-gamma levels after IL-4 adjustment (P = .01). Active asthma through age 5 years was positively associated with 3-month IL-13 levels adjusted for IFN-gamma (odds ratio, 2.6; P < .001) and inversely associated with 3-month IFN-gamma levels adjusted for IL-13 (odds ratio, 0.5; P = .001). These relations were strongest for nonatopic asthma. CONCLUSION: Total IgE levels and active asthma through age 5 years are associated with adaptive cytokine production in early life, although relations vary temporally and with regard to the relative importance of individual cytokines. PMID- 21683433 TI - An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme. AB - In the ubiquitin-proteasome system (UPS), E2 enzymes mediate the conjugation of ubiquitin to substrates and thereby control protein stability and interactions. The E2 enzyme hCdc34 catalyzes the ubiquitination of hundreds of proteins in conjunction with the cullin-RING (CRL) superfamily of E3 enzymes. We identified a small molecule termed CC0651 that selectively inhibits hCdc34. Structure determination revealed that CC0651 inserts into a cryptic binding pocket on hCdc34 distant from the catalytic site, causing subtle but wholesale displacement of E2 secondary structural elements. CC0651 analogs inhibited proliferation of human cancer cell lines and caused accumulation of the SCF(Skp2) substrate p27(Kip1). CC0651 does not affect hCdc34 interactions with E1 or E3 enzymes or the formation of the ubiquitin thioester but instead interferes with the discharge of ubiquitin to acceptor lysine residues. E2 enzymes are thus susceptible to noncatalytic site inhibition and may represent a viable class of drug target in the UPS. PMID- 21683434 TI - Evidence for right hemisphere phonology in a backward masking task. AB - The extent to which orthographic and phonological processes are available during the initial moments of word recognition within each hemisphere is under specified, particularly for the right hemisphere. Few studies have investigated whether each hemisphere uses orthography and phonology under constraints that restrict the viewing time of words and reduce overt phonological demands. The current study used backward masking in the divided visual field paradigm to explore hemisphere differences in the availability of orthographic and phonological word recognition processes. A 20ms and 60ms SOA were used to track the time course of how these processes develop during pre-lexical moments of word recognition. Nonword masks varied in similarity to the target words such that there were four types: orthographically and phonologically similar, orthographically but not phonologically similar, phonologically but not orthographically similar and unrelated. The results showed the left hemisphere has access to both orthography and phonology early in the word recognition process. With more time to process the stimulus, the left hemisphere is able to use phonology which benefits word recognition to a larger extent than orthography. The right hemisphere also demonstrates access to both orthography and phonology in the initial moments of word recognition, however, orthographic similarity improves word recognition to a greater extent than phonological similarity. PMID- 21683435 TI - Language and syntactic impairment following stroke in late bilingual aphasics. AB - PURPOSE: Bilingual aphasia generally affects both languages. However, the age of acquisition of the second language (L2) seems to play a role in the anatomo functional correlation of the syntactical/grammatical processes, thus potentially influencing the L2 syntactic impairment following a stroke. The present study aims to analyze the influence of late age of acquisition of the L2 on syntactic impairment in bilingual aphasic patients. METHODS: Twelve late bilingual participants (speaking French as L2 and either English, German, Italian or Spanish as L1) with stroke-induced aphasia participated in the study. The MAST or BAT aphasia batteries were used to evaluate overall aphasia score. An auditory syntactic judgement task was developed and used to test participants syntactic performance. RESULTS: The overall aphasia scores did not differ between L1 and L2. In a multiple case analysis, only one patient had lower scores in L2. However, four patients presented significantly lower performances in syntactic processing in the late L2 than in their native language (L1). In these four patients the infarct was localized, either exclusively or at least partially, in the pre-rolandic region. CONCLUSION: This pilot study suggests that, in late bilingual aphasics, syntactic judgment abilities may be more severely impaired in L2, and that this syntactic deficit is most likely to occur following anterior lesions. PMID- 21683436 TI - What the African fluid-bolus trial means. PMID- 21683437 TI - Controlled biodegradation of self-assembling beta-hairpin peptide hydrogels by proteolysis with matrix metalloproteinase-13. AB - Controlled biodegradation specific to matrix metalloproteinase-13 was incorporated into the design of self-assembling beta-hairpin peptide hydrogels. Degrading Peptides (DP peptides) are a series of five peptides that have varying proteolytic susceptibilities toward MMP-13. These peptides undergo environmentally triggered folding and self-assembly under physiologically relevant conditions (150 mm NaCl, pH 7.6) to form self-supporting hydrogels. In the presence of enzyme, gels prepared from distinct peptides are degraded at rates that differ according to the primary sequence of the single peptide comprising the gel. Material degradation was monitored by oscillatory shear rheology over the course of 14 days, where overall degradation of the gels vary from 5% to 70%. Degradation products were analyzed by HPLC and identified by electrospray-ionization mass spectrometry. This data shows that proteolysis of the parent peptides constituting each gel occurs at the intended sequence location. DP hydrogels show specificity to MMP-13 and are only minimally cleaved by matrix metalloproteinase-3 (MMP-3), another common enzyme present during tissue injury. In vitro migration assays performed with SW1353 cells show that migration rates through each gel differs according to peptide sequence, which is consistent with the proteolysis studies using exogenous MMP-13. PMID- 21683438 TI - Tailoring the porosity and pore size of electrospun synthetic human elastin scaffolds for dermal tissue engineering. AB - We obtained low and high porosity synthetic human elastin scaffolds by adapting low (1 mL/h) and high (3 mL/h) flow rates respectively during electrospinning. Physical, mechanical and biological properties of these scaffolds were screened to identify the best candidates for the bioengineering of dermal tissue. SHE scaffolds that were electrospun at the higher flow rate presented increased fiber diameter and greater average pore size and over doubling of overall scaffold porosity. Both types of scaffold displayed Young's moduli comparable to that of native elastin, but the high porosity scaffolds possessed higher tensile strength. Low and high porosity scaffolds supported early attachment, spreading and proliferation of primary dermal fibroblasts, but only high porosity scaffolds supported active cell migration and infiltration into the scaffold. High porosity SHE scaffolds promoted cell persistence and scaffold remodeling in vitro with only moderate scaffold contraction. The scaffolds persisted for at least 6 weeks in a mouse subcutaneous implantation study with fibroblasts on the exterior and infiltrating, evidence of scaffold remodeling including de novo collagen synthesis and early stage angiogenesis. PMID- 21683439 TI - The role of poly(ethylene glycol) brush architecture in complement activation on targeted microbubble surfaces. AB - Complement fixation to surface-conjugated ligands plays a critical role in determining the fate of targeted colloidal particles after intravenous injection. In the present study, we examined the immunogenicity of targeted microbubbles with various surface architectures and ligand surface densities using a flow cytometry technique. Targeted microbubbles were generated using a post-labeling technique with a physiological targeting ligand, cyclic arginine-glycine asparagine (RGD), attached to the distal end of the poly(ethylene glycol) (PEG) moieties on the microbubble surface. Microbubbles were incubated in human serum, washed and then mixed with fluorescent antibodies specific for various serum components. We found that complement C3/C3b was the main human serum factor to bind in vitro to the microbubble surface, compared to IgG or albumin. We also investigated the effect of PEG brush architecture on C3/C3b fixation to the microbubble surface. RGD peptide was able to trigger a complement immune response, and complement C3/C3b fixation depended on microbubble size and RGD peptide surface density. When the targeting ligand was attached to shorter PEG chains that were shielded by a PEG overbrush layer (buried-ligand architecture), significantly less complement activation was observed when compared to the more traditional exposed-ligand motif. The extent of this protective role by the PEG chains depended on the overbrush length. Taken together, our results confirm that the buried-ligand architecture may significantly reduce ligand-mediated immunogenicity. More generally, this study illustrates the use of flow cytometry and microbubbles to analyze the surface interactions between complex biological media and surface-engineered biomaterials. PMID- 21683440 TI - The generation of iPS cells using non-viral magnetic nanoparticle based transfection. AB - Induced pluripotent stem (iPS) cells have been generated from various somatic cells; however, a major restriction of the technology is the use of potentially harmful genome-integrating viral DNAs. Here, without a viral vector, we generated iPS cells from fibroblasts using a non-viral magnetic nanoparticle-based transfection method that employs biodegradable cationic polymer PEI-coated super paramagnetic nanoparticles (NP). Our findings support the possible use of transient expression of iPS genes in somatic cells by magnet-based nanofection for efficient generation of iPS cells. Results of dynamic light scattering (DLS) analysis and TEM analyses demonstrated efficient conjugation of NP with iPS genes. After transfection, nanofection-mediated iPS cells showed ES cell-like characteristics, including expression of endogenous pluripotency genes, differentiation of three germ layer lineages, and formation of teratomas. Our results demonstrate that magnet-based nanofection may provide a safe method for use in generation of virus-free and exogenous DNA-free iPS cells, which will be crucial for future clinical applications in the field of regenerative medicine. PMID- 21683441 TI - Toxicity to Eisenia andrei and Folsomia candida of a metal mixture applied to soil directly or via an organic matrix. AB - Regulatory limits for chemicals and ecological risk assessment are usually based on the effects of single compounds, not taking into account mixture effects. The ecotoxicity of metal-contaminated sludge may, however, not only be due to its metal content. Both the sludge matrix and the presence of other toxicants may mitigate or promote metal toxicity. To test this assumption, the toxicity of soils recently amended with an industrial sludge predominantly contaminated with chromium, copper, nickel, and zinc and soils freshly spiked with the same mixture of metals was evaluated through earthworm (Eisenia andrei) and collembolan (Folsomia candida) reproduction tests. The sludge was less toxic than the spiked metal mixture for E. andrei but more toxic for F. candida. Results obtained for the earthworms suggest a decrease in metal bioavailability promoted by the high organic matter content of the sludge. The higher toxicity of the sludge for F. candida was probably due to the additive toxic effect of other pollutants. PMID- 21683442 TI - Radioactive impact of Fukushima accident on the Iberian Peninsula: evolution and plume previous pathway. AB - High activity concentrations of several man-made radionuclides (such as (131)I, (132)I, (132)Te, (134)Cs and (137)Cs) have been detected along the Iberian Peninsula from March 28th to April 7th 2011. The analysis of back-trajectories of air masses allowed us to demonstrate that the levels of manmade radionuclide activity concentrations in the southwest of the Iberian Peninsula come from the accident produced in the nuclear power plant of Fukushima. The pathway followed by the radioactive plume from Fukushima into Huelva (southwest of the Iberian Peninsula) was deduced through back-trajectories analysis, and this fact was also verified by the activity concentrations measured of those radionuclides reported in places crossed by this radioactive cloud. In fact, activity concentrations reported by E.P.A., and by IAEA, in several places of Japan, Pacific Ocean and United States of America are according to the expected ones from the air mass trajectory arriving at Huelva province. PMID- 21683443 TI - Thyroid hormone disrupting activities associated with phthalate esters in water sources from Yangtze River Delta. AB - Thyroid hormone disrupting compounds in water sources is a concern. Thyroid hormone (TH) agonist and antagonist activities of water sources from the Yangtze River, Huaihe River, Taihu Lake and ground water in the Yangtze River Delta region were evaluated by use of a TH reporter gene assay based on the green monkey kidney fibroblast (CV-1). While weak TH receptor (TR) agonist potency was observed in only one of 15 water sources, antagonist potency was present in most of the water sources. TR antagonist equivalents could be explained by the presence of dibutyl phthalate (DBP), with concentrations ranging from 2.8*10(1) to 1.6*10(3) MUg DBP /L (ATR-EQ(50)s). None of the ground waters exhibited TH agonist potencies while all of the samples from Taihu Lake displayed notable TR antagonist potencies. To identify the responsible thyroid active compounds, instrumental analysis was conducted to measure a list of potential thyroid disrupting chemicals, including organochlorine (OC) pesticides and phthalate esters. Combining the results of the instrumental analysis with those of the bioassay, DBP was determined to account for 17% to 144% of ATR-EQ(50)s in water sources. Furthermore, ATR-EQ(20-80) ranges for TR antagonist activities indicated that samples from locations WX-1 and WX-2 posed the greatest health concern and the associated uncertainty may warrant further investigation. PMID- 21683444 TI - Refined sewer epidemiology mass balances and their application to heroin, cocaine and ecstasy. AB - The detection of illicit drugs in environmental matrices may be a cause for concern, both from the perspective of their potential environmental impacts and the fact that their presence in detectable concentrations would be an indicator of significant drug use. The primary goal behind recent studies on this subject has been to use measured influent concentrations of selected illicit drugs or their in vivo metabolites in the environment as a means of estimating the abuse level of these drugs and patterns of consumption. Thus-far, such calculations have hinged on the use of solitary excretion estimates from single studies of limited scope and/or studies of limited applicability. Therefore, the need exists to conduct a comprehensive meta-analysis of metabolic disposition studies to construct excretions profiles for the various illicit drugs and their in vivo metabolites. The constructed excretory profiles should not only provide mean excretion values but also indicate the expected variations in excreted fractions that arise due to differences not only in the metabolic capacity of users but also in the efficiencies of various routes of administration for a given illicit drug. Therefore, the primary goal of the research presented here was to refine sewer epidemiology extrapolation mass balances for various illicit drugs of interest by constructing their excretory profiles segregated by route-of administration. After conducting such a study with a multi-national scope on illicit drugs including cocaine, heroin and ecstasy, the results obtained clearly indicate that extrapolation factors currently being used in literature for these drugs to enumerate prevalence of abuse required significant refinement to increase their reliability. PMID- 21683445 TI - Empirical analyses of the influence of diet on human concentrations of persistent organic pollutants: a systematic review of all studies conducted in Spain. AB - BACKGROUND: Numerous studies analyzed concentrations of persistent organic pollutants (POPs) in human samples, and in many types of foods; however, food consumption is less commonly included in studies on the determinants of POP concentrations in humans, and these approaches are rarely integrated with surveys of food intake to estimate the amount and safety of human POP intake from food. OBJECTIVE: To analyze the main characteristics and findings of all studies conducted in Spain that quantitatively assessed the influence of diet on human concentrations of POPs. METHODS: Studies published until December 2010 (with no other time restrictions) were identified through Medline/PubMed, ISI-Thomson, ScienceDirect, and SciELO databases. RESULTS: We identified 25 papers, from 19 different studies. Twelve papers were published in 2009-2010. All studies but one were based on subgroups not representative of the general population, and over half were limited to women. Serum was the most used biological matrix, while p,p' DDE, HCB and PCBs were the most frequently analyzed compounds. Food intakes were measured with heterogeneous food frequency questionnaires. The most consistent association was between fish consumption and PCBs and HCB, followed by dairy products and PCBs. A few studies observed a relationship between meat and some POPs, whilst intake of vegetables, fruits and cereals was rarely related to POP levels. Only 3 studies did not find any relationship between dietary habits and POP concentrations. CONCLUSIONS: In spite of methodological heterogeneity, the studies were able to quantify to what extent consumption of foods from animal origin (fish, milk, dairy products and meat) is related to higher body concentrations of POPs. As in a few other countries, in Spain food consumption is increasingly analyzed as a major determinant of human POP intake. PMID- 21683446 TI - Spying for the enlightenment. AB - According to Enlightenment ideology, knowledge was shared openly in the international Republic of Letters. In reality, the owners of lucrative new technologies were determined to keep their discoveries hidden from industrial spies. PMID- 21683447 TI - Electrostatic exploration of the C3d-FH4 interaction using a computational alanine scan. AB - The complement system is a component of innate immunity and is activated by a cascade of protein interactions whose function is vital to our ability to fight infection. When proper regulation fails, the complement system is unable to recognize "self" from "nonself" and, therefore, attacks own tissues leading to autoimmune diseases. The central protein of the complement system is C3, which is the convergence point of three independently activated but communicating pathways. Regulation of C3 occurs through modular proteins which consist of many repeats of complement control protein (CCP) modules. CCP modules have diverse sequences, similar structures, and diverse physicochemical compositions, with excess of charge being a predominant characteristic. The goal of our study is to understand the electrostatic mechanism that underlies the interaction between the C3d domain of C3 and the fourth module of the complement regulator Factor H (FH4). We have performed a computational alanine scan in which we have replaced every ionizable amino acid, one at a time, with an alanine to generate a family of mutants for the C3d-FH4 complex. We have used Poisson-Boltzmann electrostatic calculations in combination with clustering of spatial distributions of electrostatic potentials and free energy calculations to delineate the contribution of each replaced amino acid to the C3d-FH4 interaction. We have analyzed our data in view of a two-step model which separates association into long-range recognition and short-range binding and we have identified key amino acids that contribute to association. We discuss the complex role of C3d in binding FH4 and the bacterial proteins Efb/Ehp from Staphylococcus aureus. PMID- 21683448 TI - Natural and synthetic estrogens modulate the inflammatory response in the gilthead seabream (Sparus aurata L.) through the activation of endothelial cells. AB - Sex steroids are known to deeply alter processes other than fish reproduction, including fish growth, intermediary metabolism, osmoregulation and immunity. We have previously reported that 17beta-estradiol (E(2)), the main fish estrogen, promotes the mobilization of acidophilic granulocytes from the head kidney, the bone marrow equivalent in fish, to the gonad in the bony fish gilthead seabream (Sparus aurata L.). The aim of this study was to investigate the effects of E(2) and 17alpha-ethinylestradiol (EE(2)), an endocrine disruptor with strong estrogenic effects commonly found in the aquatic environment, on the ability of gilthead seabream endothelial cells (ECs) to promote leukocyte infiltration. E(2) and EE(2) were seen to affect ECs in different ways. Thus, E(2) was able to increase the production of nitric oxide (NO) and up-regulate the expression of the key activation markers, interleukin-1beta, CC chemokine ligand 4, interleukin 8, E-selectin and matrix metalloproteinase 9, when used alone or combined with bacterial DNA. In contrast, EE(2) failed to affect NO release and reduced the up regulation of the above genes promoted by bacterial DNA. Moreover, we found that leukocyte adhesion to ECs was enhanced by E(2) treatment. Collectively, these results suggest that estrogens modulate fish leukocyte trafficking during an inflammatory process by activating ECs. PMID- 21683449 TI - Extreme positive and negative appraisals of activated states interact to discriminate bipolar disorder from unipolar depression and non-clinical controls. AB - BACKGROUND: This research aimed to test whether positive, negative, or conflicting appraisals about activated mood states (e.g., energetic and high states) predicted bipolar disorder. METHODS: A sample of individuals from clinical and control groups (171 with bipolar disorder, 42 with unipolar depression, and 64 controls) completed a measure of appraisals of internal states. RESULTS: High negative appraisals related to a higher likelihood of bipolar disorder irrespective of positive appraisals. High positive appraisals related to a higher likelihood of bipolar disorder only when negative appraisals were also high. Individuals were most likely to have bipolar disorder, as opposed to unipolar depression or no diagnosis, when they endorsed both extremely positive and extremely negative appraisals of the same, activated states. LIMITATIONS: Appraisals of internal states were based on self-report. CONCLUSIONS: The results indicate that individuals with bipolar disorder tend to appraise activated, energetic internal states in opposing or conflicting ways, interpreting these states as both extremely positive and extremely negative. This may lead to contradictory attempts to regulate these states, which may in turn contribute to mood swing symptoms. Psychological therapy for mood swings and bipolar disorder should address extreme and conflicting appraisals of mood states. PMID- 21683450 TI - Sleep matters: sleep functioning and course of illness in bipolar disorder. AB - BACKGROUND: Few studies have prospectively examined the relationships of sleep with symptoms and functioning in bipolar disorder. METHODS: The present study examined concurrent and prospective associations between total sleep time (TST) and sleep variability (SV) with symptom severity and functioning in a cohort of DSM-IV bipolar patients (N = 468) participating in the National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder (STEP BD), all of whom were recovered at study entry. RESULTS: Concurrent associations at study entry indicated that shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity. Mixed-effects regression modeling was used to examine prospective associations in the 196 patients for whom follow-up data were available. Consistent with findings at study entry, shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity over 12 months. DISCUSSION: These findings highlight the importance of disrupted sleep patterns in the course of bipolar illness. PMID- 21683451 TI - Epidemiology of depression in an urban population of Turkish children and adolescents. AB - BACKGROUND: In Turkey, studies of childhood depression have been limited to those using only scales. METHODS: This is a two-stage cross-sectional epidemiological study. Three schools in Fatih, Istanbul, Turkey were selected by cluster sampling. The study included 1482 students between the fourth and eighth grades. The Child Depression Inventory (CDI) was used for screening in the first stage. According to test results, 320 children were interviewed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Depressive disorders were diagnosed in 62 students, constituting the case group. The control group was matched to the case group on school, grade, age, gender, and socioeconomic status (SES). RESULTS: The prevalence rate was 4.2% for some form of depressive disorder, 1.55% for major depressive disorder, 1.75% for dysthymic disorder, 0.26% for double depression, and 0.60% for depressive disorder-not otherwise specified. According to the logistic regression analysis, increasing age, having a working mother and low maternal education were all positively associated with CDI score. Low SES, perception of paternal health and relations with father as negatively, low popularity and behavior subscales of the Piers-Harris self-concept scale, and high trait anxiety were associated with the presence of a depressive disorder. LIMITATIONS: Parents were not included in the diagnostic interviews. CONCLUSIONS: Dysthymic disorder was the most common depressive disorder. Low maternal education, low SES, dysfunctional interaction with the father, anxiety, and low self-esteem, which were all associated with depression, may be the target of interventions for prevention and treatment of depression. PMID- 21683452 TI - Recent advances in understanding immunology of reproductive failure. AB - Aspects of the immunological relationship between mother and conceptus still remain a mystery, although the recent advances in molecular biology have enlightened some of the parameters that participate in fetomaternal cross-talk during implantation. The atypical expression of major histocompatibility complex (MHC), the specific role of some hormones and cytokines, as well as the temporal and spatial distributions of uterine natural killer cells, represent substantive parameters of fetomaternal immunotolerance during implantation. Although human maternal and fetal immunology is difficult to investigate, aberrant immune responses and an imbalanced cytokine network may be related to infertility, implantation failures after IVF and recurrent pregnancy losses. In this review, immunological and interacting factors involved in human reproductive failure are summarized and critically evaluated. PMID- 21683453 TI - Dysfunctional distracter inhibition and facilitation for sad faces in depressed individuals. AB - Depression is a commonly occurring mental disorder, which is characterized by dysfunctional inhibition and facilitation for emotional stimuli. The aim of the present study was to investigate distracter inhibition and facilitation for emotional faces in depressed individuals in a negative affective priming task. Control participants who had never suffered from depression (NC), sub-clinically depressed participants, and participants diagnosed with a current major depressive disorder (MDD), Anxiety Inventory, the Hamilton Depression Rating Score were recruited using the Beck Depression Inventory, the Beck and DSM-IV as tools. Twenty-four participants in each group completed a negative affective priming task. The main finding was that there were no significant differences among the three groups in the positive and negative priming effects of happy faces. However, there were significant differences for positive and negative priming effects of sad faces between each pair of groups, with the effects being lowest for MDD and highest for NC participants. It can be concluded that depressed individuals are characterized by enhanced facilitation and deficient inhibition for negative materials, which is a stable cognitive vulnerability risk, possibly associated with the occurrence of depression. There are differences in the cognitive dysfunction for negative stimuli between clinically depressed and sub-clinically depressed individuals. PMID- 21683455 TI - Cardiovascular disease risk factors and depression in Korean women: results from the fourth Korean National Health and Nutrition Examination Survey. AB - Depression is the fourth leading factor of disease burden for the global female population, but while increasing evidence has supported a contributing role of depression in cardiovascular disease, little is known about this association within the female population of Korea. We examined the association in a study of 5658 Korean women who participated in the fourth Korean National Health and Nutrition Examination Survey. A logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). A total of 279 cases of depression were included. Cardiovascular disease risk factors were associated with higher odds of depression: ORs (95% CIs) were 3.99 (2.25-7.05) for current smokers with <5 pack-years vs. never-smokers, 1.97 (1.18-3.30) for >=28 vs. <20kg/m(2) of body mass index, 1.42 (1.03-1.95) for 100-125 vs. <100mg/dL of fasting serum glucose levels, and 2.10 (1.46-3.03) for a history of hyperlipidemia. Women with a history of two or three comorbid disorders (diabetes, hypertension, and cardiovascular disease) had a 1.63-fold higher OR for depression than women without any of these diseases. Korean women with depression had a greater prevalence of major risk factors for cardiovascular disease than women without depression. PMID- 21683454 TI - Cross-cultural comparisons on Wisconsin Card Sorting Test performance in euthymic patients with bipolar disorder. AB - We compared executive dysfunction with the Wisconsin Card Sorting Test (WCST) among distinct national and ethnic patients with bipolar disorder in euthymia. Bipolar patients, aged 16-45years, from the United States (n=25) and Taiwan (n=30) did not differ significantly on any measure. The WCST score for number Failure to Maintain Set was significantly positively correlated with residual affective symptoms in Taiwanese and US patients. Selective executive dysfunction in euthymia is inherent to bipolar disorder. Euthymic bipolar patients of various ethnic groups may exhibit similar executive dysfunction. PMID- 21683456 TI - A lack of antibody formation against inactivated influenza virus after aerosol vaccination in presence or absence of adjuvantia. AB - In the poultry industry, infections with avian influenza virus (AIV) can result in significant economic losses. The risk and the size of an outbreak might be restricted by vaccination of poultry. A vaccine that would be used for rapid intervention during an outbreak should be safe to use, highly effective after a single administration and be suitable for mass application. A vaccine that could be applied by spray or aerosol would be suitable for mass application, but respiratory applied inactivated influenza is poorly immunogenic and needs to be adjuvanted. We chose aluminum OH, chitosan, cholera toxin B subunit (CT-B), and Stimune as adjuvant for an aerosolized vaccine with inactivated H9N2. Each adjuvant was tested in two doses. None of the adjuvanted vaccines induced AIV specific antibodies after single vaccination, measured 1 and 3 weeks after vaccination by aerosol, in contrast to the intramuscularly applied vaccine. The aerosolized vaccine did enter the chickens' respiratory tract as CT-B-specific serum antibodies were detected after 1 week in chickens vaccinated with the CT-B adjuvanted vaccine. Chickens showed no adverse effects after the aerosol vaccination based on weight gain and clinical signs. The failure to detect AIV specific antibodies might be due to the concentration of the inactivated virus. PMID- 21683457 TI - The human caveolin 1 gene upstream purine complex and neurodegeneration--a common signature. AB - The caveolin 1 gene (CAV1) is over-expressed in experimental animal models of multiple sclerosis (MS). Increased expression of this gene has also been reported in the Alzheimer's disease (AD) brain. Loss of this gene, on the other hand, has recently been reported to be associated with neruodegeneration. We have recently reported skew in the homozygote haplotypes of the human CAV1 gene -1.5 kb upstream purine complex in patients afflicted with MS and late-onset AD vs. controls. In order to examine reproducibility of those findings, we sequenced the region in independent groups of MS patients (n=120) and controls (n=150). We report two novel extreme homozygote haplotypes at 86-bp and 142-bp in the patients vs. controls. The above haplotypes were also detected in the previously reported cases of late-onset AD. The range of homozygote haplotypes in the controls was detected at between 106-bp to 122-bp. Following pooling of the neurodegenerative (n=486) and non-neurodegenerative (n=610) subjects studied for the human CAV1 purine complex to date, twenty haplotypes were found to be homozygous in the neurodegenerative, and not in the control pool (p<0.000001). Six overlapping haplotypes were detected in the MS and AD patients (p<0.007), strengthening the role of this region as a common etiological factor in the pathophysiology of neurodegenerative disorders, possibly through inflammatory mechanisms. Those overlapping haplotypes contained motif lengths that were non existent in the control homozygote pool. The CAV1 purine complex GGAA and GAAA motifs are binding sites for numerous inflammatory transcription factors including the Ets, STAT, and IRF family members. Further work on the functionality of this region will shed light on the downstream events to the disease-linked haplotypes. PMID- 21683458 TI - Novel bronchodilators for the treatment of chronic obstructive pulmonary disease. AB - Because of the central role of bronchodilators in the treatment of respiratory diseases, there is still considerable interest in finding novel classes of broncholytic drugs. It can be hypothesized that a longer duration of bronchodilation with a once-daily agent might be associated with superior and more consistent efficacy over a range of endpoints than is achieved with a twice daily agent. Several novel beta(2)-adrenoceptor (AR) agonists, antimuscarinic agents, new combination platforms such as dual-acting muscarinic antagonist beta(2)-AR agonist bronchodilators, xanthine drugs and phosphodiesterase inhibitors, and their combination with another bronchodilator class, or an inhaled corticosteroid are currently under development with the aim of achieving once-daily dosing and, therefore, increasing the likelihood of compliance with therapy. This review paper mainly focuses on recent results of preclinical studies that have used human tissue and clinical trials of new bronchodilators in patients with chronic obstructive pulmonary disease. PMID- 21683459 TI - Integrating contact network structure into tuberculosis epidemiology in meerkats in South Africa: Implications for control. AB - Empirical studies that integrate information on host contact patterns with infectious disease transmission over time are rare. The aims of this study were to determine the relative importance of intra-group social interactions in the transmission of tuberculosis (TB; Mycobacterium bovis infection) in a population of wild meerkats (Suricata suricatta) in South Africa, and to use this information to propose an evidence-based intervention strategy to manage this disease. Detailed behavioural observations of all members of eight meerkat groups (n=134 individuals) were made over 24 months from January 2006 to December 2007. Social network analysis of three types of interaction (aggression, foraging competitions and grooming) revealed social structure to be very stable over time. Clustering of interactions was positively correlated with group size for both aggression (r=0.73) and grooming interactions (r=0.71), suggesting that infections may spread locally within clusters of interacting individuals but be limited from infecting all members of large groups by an apparent threshold in connections between different clusters. Repeated biological sampling every three months of all members of one social group (n=37 meerkats) was undertaken to quantify individual changes in M. bovis infection status. These empirical data were used to construct a dynamic network model of TB transmission within a meerkat group. The results indicated that grooming (both giving and receiving) was more likely than aggression to be correlated with M. bovis transmission and that groomers were at higher risk of infection than groomees. Intervention strategies for managing TB in meerkats that focus on those individuals engaging in the highest amount of grooming are therefore proposed. PMID- 21683460 TI - How payment systems affect physicians' provision behaviour--an experimental investigation. AB - Understanding how physicians respond to incentives from payment schemes is a central concern in health economics research. We introduce a controlled laboratory experiment to analyse the influence of incentives from fee-for-service and capitation payments on physicians' supply of medical services. In our experiment, physicians choose quantities of medical services for patients with different states of health. We find that physicians provide significantly more services under fee-for-service than under capitation. Patients are overserved under fee-for-service and underserved under capitation. However, payment incentives are not the only motivation for physicians' quantity choices, as patients' health benefits are of considerable importance as well. We find that patients in need of a high (low) level of medical services receive larger health benefits under fee-for-service (capitation). PMID- 21683461 TI - Opportunities and benefits as determinants of the direction of scientific research. AB - Scientific research and private-sector technological innovation differ in objectives, constraints, and organizational forms. Scientific research may thus not be driven by the direct practical benefit to others in the way that private sector innovation is. Alternatively, some - yet largely unexplored - mechanisms drive the direction of scientific research to respond to the expected public benefit. We test these two competing hypotheses of scientific research. This is important because any coherent specification of what constitutes the socially optimal allocation of research requires that scientists take the public practical benefit of their work into account in setting their agenda. We examine whether the composition of medical research responds to changes in disease prevalence, while accounting for the quality of available research opportunities. We match biomedical publications data with disease prevalence data and develop new methods for estimating the quality of research opportunities from textual information and structural productivity parameters. PMID- 21683462 TI - Measuring socioeconomic inequality in health, health care and health financing by means of rank-dependent indices: a recipe for good practice. AB - The tools to be used and other choices to be made when measuring socioeconomic inequalities with rank-dependent inequality indices have recently been debated in this journal. This paper adds to this debate by stressing the importance of the measurement scale, by providing formal proofs of several issues in the debate, and by lifting the curtain on the confusing debate between adherents of absolute versus relative health differences. We end this paper with a 'matrix' that provides guidelines on the usefulness of several rank-dependent inequality indices under varying circumstances. PMID- 21683464 TI - Interpersonal coordination and ball dynamics in futsal (indoor football). AB - Here, we report an investigation of the patterned movement behavior of players for a specific sub-phase of the game of futsal, namely when the goalkeeper for the attacking team is substituted with an extra outfield player. The movement trajectories of the ball and players were recorded in both lateral and longitudinal directions and investigated using relative phase analysis. Some differences in phase relations between different playing dyads were noted, indicating specificity of phase attractions, or otherwise, for certain players. In general terms, the defenders demonstrated strong in-phase attractions with the ball and with each other, whereas weaker phase attractions, indicated by increased relative phase variability, were observed for the attackers and ball, as well as between attackers themselves. These results demonstrate different coordination dynamics for the defending and attacking dyads, from which we interpret evidence for different playing sub-systems consistent with different team objectives linked together in an overarching game structure. In keeping with dynamical systems theory for complex systems, we view this sub-phase of futsal as being characterized by coordinated behavior patterns that emerge as a result of self-organizing processes. These dynamic patterns are generated within functional constraints, with players and teams exerting mutual influence on each other. PMID- 21683463 TI - Cellulases: ambiguous nonhomologous enzymes in a genomic perspective. AB - The key material for bioethanol production is cellulose, which is one of the main components of the plant cell wall. Enzymatic depolymerization of cellulose is an essential step in bioethanol production, and can be accomplished by fungal and bacterial cellulases. Most of the biochemically characterized bacterial cellulases come from only a few cellulose-degrading bacteria, thus limiting our knowledge of a range of cellulolytic activities that exist in nature. The recent explosion of genomic data offers a unique opportunity to search for novel cellulolytic activities; however, the absence of clear understanding of structural and functional features that are important for reliable computational identification of cellulases precludes their exploration in the genomic datasets. Here, we explore the diversity of cellulases and propose a genomic approach to overcome this bottleneck. PMID- 21683465 TI - The inhibitory effects of wine phenolics on lysozyme activity against lactic acid bacteria. AB - The lysozyme of hen's egg white is used in winemaking to control spontaneous lactic acid bacteria (LAB). A total of eight LAB strains, isolated from grape must and wine, were used to assess the inhibitory effects of wine phenolics on lysozyme activity. The presence of phenolics, extracted from grape pomace, in growth medium reduced the mortality rate due to the lysozyme activity. This effect was especially clear in the case of strains belonging to Lactobacillus uvarum, Pediococcus parvulus and Oenococccus oeni, which are more sensitive to lysozyme than L. plantarum and L. hilgardii strains. Cell lysis assays carried out on four strains sensitive to lysozyme and Micrococcus lysodeikticus ATCC 4698, used as a reference strain, confirmed the inhibition of grape pomace phenolics on the muramidase. There was no interference from non-flavonoids, flavanols and flavonol compounds, when they were tested individually, on the lysozyme activity against the strains. Anthocyanins extracted from grape skins slightly inhibited the activity only against M. lysodeikticus. However, proanthocyanidins extracted from seed berries, strongly inhibited the lysozyme. In this extract, dimers were the predominant oligomers of flavan-3-ol. The study demonstrated that the effectiveness of lysozyme against LAB in red winemaking is related to the amount of low molecular weight proanthocyanidins that are released when the grapes are macerating. PMID- 21683466 TI - Role of flhA and motA in growth of Listeria monocytogenes at low temperatures. AB - While temperature-dependent induction of flagella is a well-characterized phenomenon in Listeria monocytogenes, the essentiality of increased flagellum production during growth at low temperatures remains unclear. To study this relationship, we compared the relative expression levels of two motility genes, flhA and motA, at 3 degrees C, 25 degrees C and 37 degrees C in L. monocytogenes strain EGD-e by using qRT-PCR, and compared the growth curves, motility, and flagellation between the wild-type and flhA and motA deletion mutants. The relative expression levels of flhA and motA at 3 degrees C were significantly higher than at 37 degrees C (p<0.01). At 3 degrees C, the level of flhA transcripts was also significantly higher than at 25 degrees C (p<0.01). Growth curve analysis showed that at 3 degrees C both the growth rates and maximum optical densities of DeltaflhA and DeltamotA strains at 600 nm were significantly lower than those of the wild-type (p<0.001), while no significant differences were observed between the wild-type and the mutants at 37 degrees C, and 25 degrees C. Mutant strains DeltaflhA and DeltamotA were nonmotile at all three temperatures. At 25 degrees C, the number of flagellated cells of DeltamotA was notably reduced compared with the wild-type, whereas DeltaflhA appeared nonflagellated at all temperatures. The results suggest that flhA and motA play a role in the cold tolerance of L. monocytogenes strain EGD-e, and that motile flagella may be needed for optimal cold stress response of L. monocytogenes. PMID- 21683467 TI - Adaptation of the Audit of Diabetes-Dependent Quality of Life questionnaire to people with diabetes in China. AB - AIM: This study was intended to cross-culturally adapt and evaluate the Chinese version of the Audit of Diabetes Dependent Quality of Life (ADDQoL)--the Chinese Normal Audit of Diabetes-Dependent Quality of Life (CN-ADDQoL) in Mainland, China. METHODS: The standard procedure for cross-culture adaptation was used to develop the Chinese version CN-ADDQoL. After the linguistic validation, the validity and reliability of CN-ADDQoL questionnaire were evaluated based on a sample of 697 Type 2 diabetes patients. The Cronbach's alpha coefficient, correlation analysis and the structural equation model (SEM) were applied, respectively. RESULTS: We developed 19 items for the CN-ADDQoL questionnaire. The estimated Cronbach's alpha coefficient was 0.941, indicating an excellent internal consistency of the scale. All items had high performance in the structural validity evaluation, with most factor loading values being larger than 0.40 (varied from 0.44 to 0.88). CONCLUSIONS: The Chinese version CN-ADDQoL has maintained its original psychometric properties and achieved adequate reliability and validity. Therefore, it could be efficiently used to evaluate the current trend of diabetes self-management education programs and multinational clinical research trials. PMID- 21683468 TI - Demography, kinship, and the evolving theory of genomic imprinting. AB - Genomic imprinting is the differential expression of an allele based on the parent of origin. Recent transcriptome-wide evaluations of the number of imprinted genes reveal complex patterns of imprinted expression among developmental stages and cell types. Such data demand a comprehensive evolutionary framework in which to understand the effect of natural selection on imprinted gene expression. We present such a framework for how asymmetries in demographic parameters and fitness effects can lead to the evolution of genomic imprinting and place recent theoretical advances in this framework. This represents a modern interpretation of the kinship theory, is well suited to studying populations with complex social interactions, and provides predictions which can be tested with forthcoming transcriptomic data. To understand the intricate phenotypic patterns that are emerging from the recent deluge of data, future investigations of genomic imprinting will require integrating evolutionary theory, transcriptomic data, developmental and functional genetics, and natural history. PMID- 21683469 TI - Membrane dynamics and fusion at late endosomes and vacuoles--Rab regulation, multisubunit tethering complexes and SNAREs. AB - Membrane fusion at late endosomes and vacuoles depends on a conserved machinery, which includes Rab GTPases, their binding to tethering complexes and SNAREs. Fusion is initiated by the interaction of Rabs with tethering complexes. At the endosome, the CORVET complex interacts with the Rab5 GTPase Vps21, whereas the homologous HOPS complex binds the Rab7-like Ypt7 at the late endosome and vacuole. Activation of Ypt7 requires the recruitment of the Mon1-Ccz1 complex to the late endosome, which occurs via the CORVET complex. The interaction of Rab and the tethering complex is followed by the assembly of SNAREs, which leads to bilayer mixing. In this review, we will summarize our current knowledge on the mechanisms and regulation of endosome and vacuole membrane dynamics, and their role in organelle physiology. PMID- 21683470 TI - Suppression of telomere-binding protein gene expression represses seed and fruit development in tomato. AB - Tomato (Solanum lycopersicum L.) plants were transformed with an antisense construct of a cDNA encoding tomato telomere-binding protein (LeTBP1) to describe the role of a telomere-binding protein at the whole plant level. Fruit size decreased corresponding to the degree of suppression of LeTBP1 expression. This inhibition of fruit development was likely due to a decrease in the number of seeds in the LeTBP1 antisense plants. Pollen fertility and pollen germination rate decreased in accordance with the degree of suppression of LeTBP1 expression. Ovule viability was also reduced in the LeTBP1 antisense plants. Although plant height was somewhat reduced in the antisense plants compared to the control plants, the number and weight of leaves were unaffected by LeTBP1 suppression. The number and morphology of flowers were also normal in the antisense plants. These indicate that reduced fertility in the antisense plants is not an indirect effect of altered vegetative growth. LeTBP1 expression was sensitive to temperature stress in wild-type plants. We conclude that LeTBP1 plays a critical role in seed and fruit development rather than vegetative growth and flower formation. PMID- 21683471 TI - [Corneal lesions in Kindler syndrome: a case report]. AB - INTRODUCTION: Kindler syndrome is a rare autosomal recessive genodermatosis belonging to the class of bullous poikiloderma. Corneal lesions are rare. We report a case of ocular lesions in this syndrome. OBSERVATION: We report the case of a 57-year-old patient followed since childhood in dermatology with the diagnosis of Kindler syndrome. He presented to the ophthalmology department with decreased vision. Ophthalmologic examination showed symblepharon, ectropion in both eyes, and corneal deformation. CONCLUSION: The role played by the abnormal protein in epithelial integrity suggests that ocular and more particularly corneal involvement is not rare in Kindler syndrome. In fact, it is less known by ophthalmologists and dermatologists are not aware of the ophthalmologic manifestations. PMID- 21683472 TI - Benefits of total body photography and digital dermatoscopy ("two-step method of digital follow-up") in the early diagnosis of melanoma in patients at high risk for melanoma. AB - BACKGROUND: Early detection of melanoma is the best way to improve prognosis. Digital follow-up (DFU) programs of populations at high risk could be an efficient strategy for detecting early melanomas with low morbidity. OBJECTIVE: We sought to report the added value of the use of the "two-step method" (digital total body photography and digital dermatoscopy). METHODS: This was an analysis of the surveillance of 618 patients at high risk for melanoma included in our DFU program from 1999 to 2008. RESULTS: A total of 11,396 lesions were monitored (mean 18.44/patient) during a median follow-up of 96 months (median 10 visits/patient). A total of 1152 lesions, 1.86 per patient, were excised. Almost 70% (798) were lesions previously registered at least twice, whereas 356 (30%) were detected and removed in the same visit. During follow-up, 98 melanomas (8.5% of excised lesions) were diagnosed in 78 patients (12.6%). In all, 53 melanomas were in situ (53.3%), whereas invasive (45) showed a Breslow index of less than 1 mm (median 0.5 mm) and none were ulcerated. LIMITATIONS: Because there are no control groups we cannot determine if the combined use of total body photography and digital dermatoscopy is more beneficial than these techniques used separately. CONCLUSION: DFU with total body photography and dermatoscopy in a selected population at high risk demonstrated the early detection of melanomas with a low rate of excisions. Long-term follow-up is required to allow the detection of slow-growing melanomas. Based on our 10-year experience, melanomas can be diagnosed at any time, suggesting that in a population at high risk for melanoma, DFU should be maintained over time. PMID- 21683473 TI - Diabetes is not associated with increased mortality in emergency department patients with sepsis. AB - STUDY OBJECTIVE: Despite its high prevalence, the influence of diabetes on outcomes of emergency department (ED) patients with sepsis remains undefined. Our aim is to investigate the association of diabetes and initial glucose level with mortality in patients with suspected infection from the ED. METHODS: Three independent, observational, prospective cohorts from 2 large US tertiary care centers were studied. We included patients admitted to the hospital from the ED with suspected infection. We investigated the association of diabetes and inhospital mortality within each cohort separately and then overall with logistic regression and generalized estimating equations adjusted for age, sex, disease severity, and sepsis syndrome. We also tested for an interaction between diabetes and hyperglycemia/hypoglycemia. RESULTS: A total of 7,754 patients were included. The mortality rate was 4.3% (95% confidence interval [CI] 3.9% to 4.8%) and similar in diabetic and nondiabetic patients (4.1% versus 4.4%; absolute risk difference 0.4%; 95% CI -0.7% to 1.4%). There was no significant association between diabetes and mortality in adjusted analysis (odds ratio [OR] overall 0.85; 95% CI 0.71 to 1.01). Diabetes significantly modified the effect of hyperglycemia and hypoglycemia with mortality; initial glucose levels greater than 200 mg/dL were associated with higher mortality in nondiabetic patients (OR 2.1; 95% CI 1.4 to 3.0) but not in diabetic patients (OR 1.0; 95% CI 0.2 to 4.7), whereas glucose levels less than 100 mg/dL were associated with higher mortality mainly in the diabetic population (OR 2.3; 95% CI 1.6 to 3.3) and to a lesser extent in nondiabetic patients (OR 1.1; 95% CI 1.03 to 1.14). CONCLUSION: We found no evidence for a harmful association of diabetes and mortality in patients across different sepsis severities. High initial glucose levels were associated with adverse outcomes in the nondiabetic population only. Further investigation is warranted to determine the mechanism for these effects. PMID- 21683475 TI - Different beta-amyloid oligomer assemblies in Alzheimer brains correlate with age of disease onset and impaired cholinergic activity. AB - In this study, we examined the relationship between various beta-amyloid (Abeta) oligomer assemblies in autopsy brain with the levels of fibrillar Abeta and cholinergic synaptic function. Brain tissues obtained from the frontal cortex of 14 Alzheimer's disease (AD) patients grouped into early-onset AD (EOAD) and late onset AD (LOAD) and 12 age-matched control subjects were used to extract and quantify Abeta oligomers in soluble (TBS), detergent soluble (TBST), and insoluble (GuHCl) fractions. The predominant oligomeric Abeta assemblies detected were dodecamers, decamers, and pentamers, and different patterns of expression were observed between EOAD and LOAD patients. There was no association between any of the detected Abeta oligomer assemblies and fibrillar Abeta levels measured by N-methyl[(3)H] 2-(40-methylaminophenyl)-6-hydroxy-benzothiazole ([(3)H]PIB) binding. Levels of pentamers in the soluble fraction significantly correlated with a reduction in choline acetyltransferase activity in AD patients. The number of nicotinic acetylcholine receptors negatively correlated with the total amount of Abeta oligomers in the insoluble fraction in EOAD patients, and with decamers in the soluble fraction in LOAD patients. These novel findings suggest that distinct Abeta oligomers induce impairment of cholinergic neurotransmission in AD pathogenesis. PMID- 21683478 TI - [Pneumonia as a result of infection with parainfluenza virus type 4 and thrombotic thrombocytopenic purpura]. PMID- 21683476 TI - Perimenopausal regulation of steroidogenesis in the nonhuman primate. AB - Human aging is characterized by a marked decrease in circulating levels of dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS), hormonal changes associated with cognitive decline. Despite beneficial effects of DHEA supplementation in rodents, studies in elderly humans have generally failed to show cognitive improvement after treatment. In the present study we evaluate the effects of age and estradiol supplementation on expression of genes involved in the de novo synthesis of DHEA and its conversion to estradiol in the rhesus macaque hippocampus. Using reverse transcription polymerase chain reaction (RT PCR) we demonstrate the expression of genes associated with this synthesis in several areas of the rhesus brain. Furthermore, real-time PCR reveals an age related attenuation of hippocampal expression level of the genes CYP17A1, STS, and 3BHSD1/2. Additionally, short-term administration of estradiol is associated with decreased expression of CYP17A1, STS, SULT2B1, and AROMATASE, consistent with a downregulation not only of estrogen synthesis from circulating DHEA, but also of de novo DHEA synthesis within the hippocampus. These findings suggest a decline in neurosteroidogenesis may account for the inefficacy of DHEA supplementation in elderly humans, and that central steroidogenesis may be a function of circulating hormones and menopausal status. PMID- 21683479 TI - [Splenic hydatidosis: 5 cases of this location]. PMID- 21683474 TI - Do children with blunt head trauma and normal cranial computed tomography scan results require hospitalization for neurologic observation? AB - STUDY OBJECTIVE: Children evaluated in the emergency department (ED) with minor blunt head trauma, defined by initial Glasgow Coma Scale (GCS) scores of 14 or 15, are frequently hospitalized despite normal cranial computed tomography (CT) scan results. We seek to identify the frequency of neurologic complications in children with minor blunt head trauma and normal ED CT scan results. METHODS: We conducted a prospective, multicenter observational cohort study of children younger than 18 years with blunt head trauma (including isolated head or multisystem trauma) at 25 centers between 2004 and 2006. In this substudy, we analyzed individuals with initial GCS scores of 14 or 15 who had normal cranial CT scan results during ED evaluation. An abnormal imaging study result was defined by any intracranial hemorrhage, cerebral edema, pneumocephalus, or any skull fracture. Patients with normal CT scan results who were hospitalized were followed to determine neurologic outcomes; those discharged to home from the ED received telephone/mail follow-up to assess for subsequent neuroimaging, neurologic complications, or neurosurgical intervention. RESULTS: Children (13,543) with GCS scores of 14 or 15 and normal ED CT scan results were enrolled, including 12,584 (93%) with GCS scores of 15 and 959 (7%) with GCS scores of 14. Of 13,543 patients, 2,485 (18%) were hospitalized, including 2,107 of 12,584 (17%) with GCS scores of 15 and 378 of 959 (39%) with GCS scores of 14. Of the 11,058 patients discharged home from the ED, successful telephone/mail follow-up was completed for 8,756 (79%), and medical record, continuous quality improvement, and morgue review was performed for the remaining patients. One hundred ninety-seven (2%) children received subsequent CT or magnetic resonance imaging (MRI); 5 (0.05%) had abnormal CT/MRI scan results and none (0%; 95% confidence interval [CI] 0% to 0.03%) received a neurosurgical intervention. Of the 2,485 hospitalized patients, 137 (6%) received subsequent CT or MRI; 16 (0.6%) had abnormal CT/MRI scan results and none (0%; 95% CI 0% to 0.2%) received a neurosurgical intervention. The negative predictive value for neurosurgical intervention for a child with an initial GCS score of 14 or 15 and a normal CT scan result was 100% (95% CI 99.97% to 100%). CONCLUSION: Children with blunt head trauma and initial ED GCS scores of 14 or 15 and normal cranial CT scan results are at very low risk for subsequent traumatic findings on neuroimaging and extremely low risk of needing neurosurgical intervention. Hospitalization of children with minor head trauma after normal CT scan results for neurologic observation is generally unnecessary. PMID- 21683480 TI - [Intracerebral hemorrhage in anticoagulated patients: what do we do afterwards?]. AB - INTRODUCTION: The management of antithrombotic therapy after intracerebral hemorrhage (ICH) in anticoagulated patients is not well defined. We analyzed the risks and benefits of antiplatelet therapy (AG) against the resumption of anticoagulation with vitamin K antagonists (AVK) in a series of patients. MATERIAL AND METHODS: Retrospective study of ICH in anticoagulated patients. We registered demographic data, history of hypertension (HT), time of follow-up and new cerebral vascular events (ICH, stroke [IC]). RESULTS: We evaluated 88 patients, mean age 69+/-9 years, 50% men, 73% hypertensive. During the acute phase 18 patients died and the follow-up was lost in 31. Of the remaining (n=39), AVKs were resumed in 25 and changed to AG in 14. Comparing the characteristics of both groups, the anticoagulated group was younger (P=.005) and the embolic sources were more often of higher risk (P=.003). After an average follow-up of 54+/-31 months, the distribution of events was: IC (AVKs 8%, AG 14.3%, P=.6), ICH (AVKs 24%, AG 7.1%, P=.38), IC or ICH (AVKs 32%, AG 21.4%, P=.48) and death (AVKs 29%, AG 7.1%, P=.21). This trend of increased risk of new events in patients with AVKs was confirmed by Kaplan-Meier curves, although without statistical differences. CONCLUSIONS: Restarting AVK treatment after ICH in anticoagulated patients could increase the risk of new bleeding events and mortality. Prospective studies are needed to define a better and appropriate antithrombotic therapy after ICH related with anticoagulation. PMID- 21683481 TI - [Letter with reference to the article "Importance of electromyographic studies in the diagnosis of orthostatic tremor"]. PMID- 21683482 TI - [The pineal gland as physical tool of the soul faculties: a persistent historical connection]. AB - INTRODUCTION: The anatomic seat of the human soul has been a controversial matter of discussion in the philosophical, theological and scientific fields throughout history. One of more known hypotheses on this subject was proposed by Descartes, for whom the soul would host in the pineal gland, a brain body with a special location that would adequately address the functionalism of the human body. DEVELOPMENT: In this work, we discuss the historical influences which made possible the Cartesian model of the relationship between spirit (res cogitans) and body-machine (res extensa) and the technical bases of his dualism doctrine. In philosophical terms, Descartes supported Augustine approaches and in physiological and anatomical terms adopted some theories of the classical Antiquity, essentially the proposals of Alexandrian pneumatic school (Herophilos, Erasistratus) in relation to the animal spirits. Descartes might also have known the hypotheses of some contemporary anatomists (Diemerbroeck) which established the location of sensorium commune in the pineal gland. CONCLUSIONS: Although Cartesian theories had strong criticism even in his time, some aspects of these postulates remained up to mid 19th century. PMID- 21683483 TI - Synthesis, characterization and biological evaluation of novel 2,4,6 trisubstituted bis-pyrimidine derivatives. AB - A new series of 2,4,6-trisubstituted bis-pyrimidines were synthesized and evaluated for in vitro antiamoebic activity against HM1:IMSS strain of Entamoeba histolytica. Out of 16 compounds 8 compounds have shown IC(50) values in the range of 0.10-1.86 MUM. Bis-pyrimidine having methyl-, methoxy-, thiomethyl- and dimehyl-phenyl substituents, exhibited higher antiamoebic activity than the reference drug metronidazole (IC(50) = 1.9 MUM). The toxicological studies of active compounds on PC12-rat pheochoromocytoma cell line showed that all compounds were non-toxic at a concentration of 100 MUM. 4-4'-Benzene-1,3 diylbis[6-(4-methylphenyl-2-(piperidin-1-yl)pyrimidine] (4c) was found most active (IC(50) = 0.10 MUM) and least toxic among all the compounds. PMID- 21683484 TI - Application of Ullmann and Ullmann-Finkelstein reactions for the synthesis of N aryl-N-(1H-pyrazol-3-yl) acetamide or N-(1-aryl-1H-pyrazol-3-yl) acetamide derivatives and pharmacological evaluation. AB - Ullmann-type reactions are becoming a major tool in medicinal chemistry. In this article, we describe the use of these Copper-catalyzed reactions with various precursors, acyl-heteroarylamines or pyrazoles of interest for pharmacomodulation. To the medicinal chemist they offer new, usually untapped disconnection approaches to compounds of interest. They thus open the way to new original analogues of bioactive compounds possibly not patented, from common building-blocks. They also allow C to N bioisosteric replacements, which sometimes are synthetically challenging. We report for the first time the critical effect of acetylamino substituents on the regioselective arylation of unsymmetrical pyrazoles that are useful for medicinal chemists. Finally, we have applied this strategy to the design of novel AT(1) receptor antagonists. Though this family has been extensively investigated in the past 30 years, N-arylation and C to N replacement made possible by Ullmann chemistry, can produce original antagonists. PMID- 21683486 TI - Sorption of selenate on soils and pure phases: kinetic parameters and stabilisation. AB - This study was conducted to identify the principle selenate carrier phases for two selected soils, by comparing their reactivity with selenate to that of pure phases of the solids. Silica, calcium carbonate, aluminium hydroxide, goethite, bentonite and humic acid were selected as the main soil carrier phases. Comparisons were made first on the parameter values obtained with the best fit of a kinetic sorption model which can discriminate instantaneous sorption from kinetically limited sorption. Then comparisons were made of the ability for each solid to stabilise selenate by measuring the ratio of the partition coefficient for sorption (Kd(sorption)) over that of the desorption (Kd(desorption)). Kinetics and stabilisation were used to help elucidate the nature of interactions with the test solid phases for a large range of selenate concentrations. The experiments were conducted over 165 h in batch reactors, the solid being isolated from the solution by dialysis tubing, at two pH (5.4 and 8) and three selenate concentrations (1 * 10(-3), 1 * 10(-6) and 1 * 10(-8) mol L(-1)). The results obtained showed that only aluminium hydroxide can sorb selenate throughout the studied pH range (pH 5.4 to 8.0). The sorption capacity on this mineral was high (Kd(sorption) > 100 to 1 * 10(4) L kg(-1)) and the selenate was mainly stabilized by the formation of inner sphere complexes. The sorption on goethite occurred at pH 5.4 (Kd(sorption) 52 L kg(-1)), mainly as outer sphere complexes, and was null at pH 8. On silica, a weak sorption was observed only at pH 5.4 and at 165 h (Kd(sorption) 4 L kg(-1)). On bentonite, calcium carbonate and humic acid no significant sorption was observed. Concerning the two soils studied, different behaviours were observed for selenate. For soil Ro (pH 5.4), Kd(sorption) was low (8 L kg(-1)) compared to soil Bu (pH 8) (70 L kg(-1)). The sorption behaviour of selenate on soil Ro was mainly due to outer sphere complexes, as for goethite, whereas for soil Bu the sorption was mainly attributed to inner sphere complexes followed by reduction mechanisms, probably initiated by microorganisms, in which no steady state was reached at the end of the 165 h experiments. The sorption of selenate decreased when concentrations reached 1 * 10(-3) mol L(-1), due to solid saturation, except for aluminium hydroxide. Reduction of selenate seemed also to occur on goethite and soil Ro, for the same concentration, but without preventing a decrease in sorption. Thus, this work shows that the comparison of selenate behaviour between soil and pure phases helps to elucidate the main carrier phases and sorption mechanisms in soil. PMID- 21683487 TI - Women's perceptions of their right to choose the place of childbirth: an integrative review. AB - OBJECTIVE: to provide a critical synthesis of published research concerning women's experiences in choosing where to give birth. METHOD: an integrative literature review was conducted using three databases (MEDLINE, CINAHL and Ovid) for 1997-2009. Inclusion criteria were: (1) publication in the English language; (2) research article; (3) focus on women's perceptions for their birthplace choices; and (4) data collected during pregnancy, at birth and post partum. FINDINGS: twenty-one research-based papers met the inclusion criteria, and these used a range of approaches and methods. Four themes were derived from the data: choice of birthplace and medicalisation of childbirth; the midwifery model of care and the rhetoric of birthplace choices; perceptions of safety shaped women's preferences; and choice is related to women's autonomy. CONCLUSION: there is considerable evidence that women worldwide wish to be able to exercise their rights and make informed choices about where to give birth. The medical model remains a strong and powerful influence on women's decisions in many countries. The midwifery model offers birthplace choices to women, while policies and culture in some countries affect midwifery practise. Perceptions of safety shaped women's preferences, and women's autonomy facilitated birthplace choices. IMPLICATIONS FOR PRACTISE: these findings can be seen as a challenge for health professionals and policy makers to improve perinatal care based on women's needs. Local research is advisable due to cultural and health system differences. PMID- 21683485 TI - Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food. AB - OBJECTIVE: Maintenance of muscle mass is crucial to improving outcome and quality of life in cancer patients. Stimulating muscle protein synthesis is the metabolic basis for maintaining muscle mass, but in cancer patients normal dietary intake has minimal effects on muscle protein synthesis. Adding leucine to high protein supplements stimulates muscle protein synthesis in healthy older subjects. The objective was to determine if a specially formulated medical food, high in leucine and protein, stimulates muscle protein synthesis acutely in individuals with cancer to a greater extent than a conventional medical food. DESIGN: A randomized, controlled, double-blind, parallel-group design was used in 25 patients with radiographic evidence of cancer. Patients were studied before their cancer treatment was started or 4 weeks after their treatment was completed or halted. The fractional rate of muscle protein synthesis (FSR) was measured using the tracer incorporation technique with L-[ring-(13)C(6)]-phenylalanine. The experimental group (n = 13) received a medical food containing 40 g protein, based on casein and whey protein and enriched with 10% free leucine and other specific components, while the control group (n = 12) was given a conventionally used medical food based on casein protein alone (24 g). Blood and muscle samples were collected in the basal state and 5h hours after ingestion of the medical foods. RESULTS: The cancer patients were in an inflammatory state, as reflected by high levels of C-reactive protein (CRP), IL-1 beta and TNF-alpha, but were not insulin resistant (HOMA). After ingestion of the experimental medical food, plasma leucine increased to about 400 MUM as compared to the peak value of 200 MUM, after the control medical food (p < 0.001). Ingestion of the experimental medical food increased muscle protein FSR from 0.073 (SD: 0.023) to 0.097 (SD: 0.033) %/h (p = 0.0269). In contrast, ingestion of the control medical food did not increase muscle FSR; 0.073 (SD: 0.022) and 0.065 (SD: 0.028) %/h. CONCLUSIONS: In cancer patients, conventional nutritional supplementation is ineffective in stimulating muscle protein synthesis. This anabolic resistance can be overcome with a specially formulated nutritional supplement. PMID- 21683488 TI - Spatial and temporal patterns of mercury accumulation in lacustrine sediments across the Laurentian Great Lakes region. AB - Data from 104 sediment cores from the Great Lakes and "inland lakes" in the region were compiled to assess historical and recent changes in mercury (Hg) deposition. The lower Great Lakes showed sharp increases in Hg loading c. 1850 1950 from point-source water dischargers, with marked decreases during the past half century associated with effluent controls and decreases in the industrial use of Hg. In contrast, Lake Superior and inland lakes exhibited a pattern of Hg loading consistent with an atmospheric source - gradual increases followed by recent (post-1980) decreases. Variation in sedimentary Hg flux among inland lakes was primarily attributed to the ratio of watershed area:lake area, and secondarily to a lake's proximity to emission sources. A consistent region-wide decrease (~20%) of sediment-Hg flux suggests that controls on local and regional atmospheric Hg emissions have been effective in decreasing the supply of Hg to Lake Superior and inland lakes. PMID- 21683489 TI - Contrasting controls on arsenic and lead budgets for a degraded peatland catchment in Northern England. AB - Atmospheric deposition of trace metals and metalloids from anthropogenic sources has led to the contamination of many European peatlands. To assess the fate and behaviour of previously deposited arsenic and lead, we constructed catchment scale mass budgets for a degraded peatland in Northern England. Our results show a large net export of both lead and arsenic via runoff (282 +/- 21.3 gPb ha(-1) y(-1) and 60.4 +/- 10.5 gAs ha(-1) y(-1)), but contrasting controls on this release. Suspended particulates account for the majority of lead export, whereas the aqueous phase dominates arsenic export. Lead release is driven by geomorphological processes and is a primary effect of erosion. Arsenic release is driven by the formation of a redox-dynamic zone in the peat associated with water table drawdown, a secondary effect of gully erosion. Degradation of peatland environments by natural and anthropogenic processes has the potential to release the accumulated pool of legacy contaminants to surface waters. PMID- 21683490 TI - Do changes in parent mental health explain trends in youth emotional problems? AB - There is evidence of a long-term rise in the prevalence of adolescent emotional problems in the U.K. and in other countries. The aim of this study was to test whether time trends in parents' emotional difficulties contributed to these increases using data from two national surveys of English teenagers and parents studied twenty years apart (1986 and 2006). The 1986 sample is the age 16 follow up of the 1970 British Cohort Study (N = 4524 adolescents, N = 7169 parents). The 2006 sample included 16/17-year-olds and their parents drawn from the 2002 and 2003 Health Surveys for England (N = 711). Both studies used identical self complete questionnaire assessments of adolescent (GHQ-12 and Malaise Inventory) and parent (Malaise) symptoms of depression and anxiety. Follow-up data on emotional problems and psychiatric service use at age 30 years (N = 2785) for adolescents in the first cohort was used to validate the role of parent emotional problems as risk factors for offspring mental health. We found that maternal emotional problems increased across all socio-demographic groups between 1986 and 2006, mirroring increases in adolescent emotional problems over this period. They were cross-sectionally and prospectively associated with adolescent emotional problems. Cohort differences in adolescent emotional problems were attenuated when accounting for the increase in maternal emotional problems. Rising rates of maternal emotional problems have likely contributed to, but do not fully explain, recent time trends in adolescent emotional problems. PMID- 21683491 TI - Changes in reciprocal support provision and need-based support from partners of patients undergoing radical prostatectomy. AB - We examined need-related and reciprocal provision of support in couples facing radical prostatectomy and its sequelae, including patients' urinary incontinence. Partners' reciprocal support provision to patients was assumed to drop from prior to until after patients' surgeries and increase again in the following months, while need-related indicators were assumed to remain unique correlates throughout. In this study of German prostatectomy patients and their partners, N = 141 couples provided data on 4 measurement occasions from presurgery to 1-year postsurgery. Need-based predictors of partners' support provision were patients' mobilized support, such as efforts to obtain advice or comfort, and degree of postsurgery incontinence. Strength of association between partner-received and provided supports served as an indicator of reciprocal support provision. Data suggested that partners' reciprocal support provision dropped significantly postsurgery and then increased again in the following months. This was true for emotional as well as instrumental reciprocal support provision. Findings also indicated that one need-based predictor of partners' support provision, patients' mobilization of support from their partners, remained a unique correlate of partners' support provision to patients. Reciprocal support provision in couples may vary during the adaptation to illness-related functional impairment and coexist with need-oriented support provision. PMID- 21683492 TI - Stock options, tax credits or employment contracts please! The value of deliberative public disagreement about human tissue donation. AB - 'Deliberative democracy' is increasingly popular globally, as a means of securing public engagement with emerging health technologies and democratizing their governance. Architects of deliberative 'mini-publics' have tended, however, to privilege consensus within deliberation and the generation of 'action commitments' within a 'decisional context', despite widespread critique. Less attention has been paid to the phenomenon of persistent disagreement within constructed deliberative fora. This paper addresses this lacuna, performing a narrative analysis of four days of deliberation within one small group of demographically diverse public participants at the BC Biobank Deliberation (Vancouver, Canada, 2007). It reveals the value of listening to persistent deliberative disagreements. First, this paper argues that disagreements enable identification of deliberation and evaluation of its quality. Second, they generate insight into the deliberative process and the discursive means through which consensus can be achieved. Third, persistent deliberative disagreements can be creative of innovative governance solutions. In the case of the BC Biobank Deliberation, disagreements about compensation for biobank donors generated a range of suggestions for mediating between donor rights, corporate interests and societal needs--from tissue sample rentals to donor tax credits--suggestions that are unique to the existing academic and policy literature. Finally, this paper argues that practitioners should present persistent disagreements to public and policy audiences as an 'output' of deliberative democracy events. PMID- 21683493 TI - Determinants and beliefs of health information mavens among a lower-socioeconomic position and minority population. AB - People of lower-socioeconomic position (SEP) and most racial/ethnic minorities face significant communication challenges which may negatively impact their health. Previous research has shown that these groups rely heavily on interpersonal sources to share and receive health information; however, little is known about these lay sources. The purpose of this paper is to apply the concept of a market maven to the public health sector with the aims of identifying determinants of high health information mavenism among low-SEP and racial/ethnic minority groups and to assess the information they may be sharing based on their own health beliefs. Data for this study were drawn from the baseline survey (n = 325) of a US randomized control intervention study aimed at eliciting an understanding of Internet-related challenges among lower-SEP and minority individuals. Regression models were estimated to distinguish significant determinants of health information mavenism among the sample. Similarly, bivariate and logistic multivariable models were estimated to determine the association between health information mavenism and accurate health beliefs relating to diet, physical activity and smoking. The data illustrate that having a larger social network, being female and being older were important factors associated with higher mavenism scores. Additionally being a moderate consumer of general media as well as fewer years in the US and lower language acculturation were significant predictors of higher mavenism scores. Mavens were more likely than non-mavens to maintain accurate beliefs regarding diet; however, there was no distinction between physical activity and smoking beliefs between mavens and non-mavens. These results offer a unique understanding of health information mavenism which could better leverage word-of-mouth health communication efforts among lower-SEP and minority groups in order to reduce communication inequalities. Moreover, the data indicate that health information mavens may serve as an ideal point of intervention in attempts to modify health beliefs with the goal of reducing health disparities among these populations. PMID- 21683494 TI - Policy and practice in the use of root cause analysis to investigate clinical adverse events: mind the gap. AB - This paper examines the challenges of investigating clinical incidents through the use of Root Cause Analysis. We conducted an 18-month ethnographic study in two large acute NHS hospitals in the U.K. and documented the process of incident investigation, reporting, and translation of the results into practice. We found that the approach has both strengths and problems. The latter stem, in part, from contradictions between potentially incompatible organizational agendas and social logics that drive the use of this approach. While Root Cause Analysis was originally conceived as an organisational learning technique, it is also used as a governance tool and a way to re-establish organisational legitimacy in the aftermath of incidents. The presence of such diverse and partially contradictory aims creates tensions with the result that efforts are at times diverted from the aim of producing sustainable change and improvement. We suggest that a failure to understand these inner contradictions, together with unreflective policy interventions, may produce counterintuitive negative effects which hamper, instead of further, the cause of patient safety. PMID- 21683495 TI - Anterior versus posterior approach to iliac crest for alveolar cleft bone grafting. AB - PURPOSE: The goal of this study was to compare perioperative outcomes for the anterior versus posterior approach to the iliac crest for alveolar bone grafting in patients with cleft lip and palate (CLP). MATERIALS AND METHODS: A retrospective cohort study of patients with CLP who had an anterior or posterior iliac crest bone graft during a 10-year period was performed. Available medical records were reviewed and the outcome variables documented included the operation site for bone graft procurement (anterior or posterior), estimated blood loss, duration of operation, concurrent procedures, and length of hospital stay. The 2 groups were compared by t test, Fisher exact test, and multivariate regression to show differences. RESULTS: There were 239 patients with CLP who had an iliac crest bone graft to the alveolar cleft; 133 had an anterior and 106 a posterior approach for bone graft procurement. The mean estimated blood loss was significantly less with the posterior approach (85 vs 177 mL; P < .0001). The mean operation duration with the posterior approach was longer (4.6 vs 3.5 hours; P < .0001). Most patients in this group (67%), however, had 2 or more additional procedures during the same anesthetic, whereas only 16% of patients in the anterior group had 2 or more additional procedures. The mean length of stay was significantly shorter for the posterior approach (1.7 vs 2.2 days; P < .0001). CONCLUSIONS: These results suggest that patients having a bone graft from the posterior iliac crest have a smaller estimated blood loss and a shorter length of stay. In addition, this approach permits repair of the alveolar cleft and additional procedures, including augmentation of the median tubercle and correction of nasolabial distortions, which are often present in patients with CLP. PMID- 21683496 TI - Bilateral parotid duct obstruction after rhytidectomies: case report. PMID- 21683497 TI - Maxillofacial fractures in older patients. AB - PURPOSE: The purpose of the present study was to analyze the trends and characteristic features of maxillofacial fractures in older patients. PATIENTS AND METHODS: The data from 247 patients aged 65 years old or older, who were treated for maxillofacial fractures at the Department of Oral and Maxillofacial Surgery, Nara Medical University, from October 1981 to March 2010, were retrospectively analyzed. RESULTS: Of the 247 patients, 127 were men and 120 were women; 50 patients had been treated in the first third of the period, 87 in the second, and 110 in the third. Injury had most frequently occurred because of falling on a level surface (n = 126), followed by a traffic accident (n = 84). Of the fractures, 140 were in the mandible, 90 in the midface, and 17 in both. In the mandible, the fracture lines were most frequently observed at the condyle, followed by the body, exclusively in edentulous patients. In the midface, the zygoma was mostly involved. The facial injury severity scale score ranged from 1 to 10 (average 1.81). Injury at other sites of the body was found in 45 patients. Observation was most frequently chosen (n = 127), primarily for those of older age, followed by open reduction and internal fixation in 46 and maxillomandibular fixation in 41 patients. The facial injury severity scale score was greatest in patients treated by open reduction and internal fixation, followed by those treated by maxillomandibular fixation. CONCLUSION: Maxillofacial fractures in older patients have been increasing and showed the characteristic features of etiology, patterns, and treatment modalities. PMID- 21683498 TI - A rare case of mediastinal and cervical emphysema secondary mandibular angle fracture: a case report. PMID- 21683499 TI - Epidemiology of facial fracture injuries. AB - PURPOSE: Injuries resulting from accidents are a leading cause of mortality and morbidity. The objective of this study was to present epidemiologic estimates of hospital-based emergency department (ED) visits for facial fractures in the United States. MATERIALS AND METHODS: The Nationwide Emergency Department Sample for 2007 was used. All ED visits with facial fractures were selected. Demographic characteristics of these ED visits, causes of injuries, presence of concomitant injuries, and resource use in hospitals were examined. All estimates were projected to national levels and each ED visit was the unit of analysis. RESULTS: During 2007 in the United States, 407,167 ED visits concerned a facial fracture. Patients' average age for each ED visit was 37.9 years. Sixty-eight percent of all ED visits concerned male patients, and 85,759 ED visits resulted in further treatment in the same hospital. Three hundred fourteen patients died in EDs, and 2,717 died during hospitalization. Mean charge per each ED visit was $3,192. Total United States ED charges were close to $1 billion. Mean hospitalization charges (ED and inpatient charges) amounted to $62,414. Mean length of stay was 6.23 days, and total hospitalization time in the entire United States was 534,322 days. Frequently reported causes of injuries included assaults (37% of all ED visits), falls (24.6%), and motor vehicle accidents (12.1%). CONCLUSIONS: The management of maxillofacial fractures in EDs across the United States uses considerable resources. The public health impact of facial fractures is highlighted in the present study. PMID- 21683500 TI - Differentially tuned responses to restricted versus prolonged awareness of threat: a preliminary fMRI investigation. AB - Responses to threat occur via two known independent processing routes. We propose that early, reflexive processing is predominantly tuned to the detection of congruent combinations of facial cues that signal threat, whereas later, reflective processing is predominantly tuned to incongruent combinations of threat. To test this prediction, we examined responses to threat-gaze expression pairs (anger versus fear expression by direct versus averted gaze). We report on two functional magnetic resonance imaging (fMRI) studies, one employing prolonged presentations (2s) of threat-gaze pairs to allow for reflective processing (Study 1), and one employing severely restricted (33 ms), backward masked presentations of threat-gaze pairs to isolate reflexive neural responding (Study 2). Our findings offer initial support for the conclusion that early, reflexive responses to threat are predominantly tuned to congruent threat-gaze pairings, whereas later reflective responses are predominantly tuned to ambiguous threat-gaze pairings. These findings highlight a distinct dual function in threat perception. PMID- 21683502 TI - Cervical cytology of atypical squamous cells, cannot exclude high-grade squamous intra-epithelial lesion: significance of age, human papillomavirus DNA detection and previous abnormal cytology on follow-up outcomes. AB - OBJECTIVE: Despite the usefulness of Pap tests for cancer screening, outcomes can be difficult to predict when atypical squamous cells (ASCs) are identified. According to the 2001 Bethesda system, ASCs can be subdivided into two groups: ASCs of undetermined significance (ASC-US); and ASCs, cannot exclude high-grade squamous intra-epithelial lesion (ASC-H). ASC-H interpretations are uncommon, and studies involving this type of lesion are based on small numbers of cases. STUDY DESIGN: Cross-sectional, retrospective study of 392 ASC-H cases. The follow-up outcomes of ASC-H cases that were diagnosed during routine primary screening between 2002 and 2008 were investigated, and relationships between clinicopathological parameters were assessed, particularly positive test for high risk HPV (HPV) DNA, patient age at diagnosis and previous abnormal cytology. RESULTS: Of the 392 cases, high-grade squamous intra-epithelial lesion (HSIL) was detected in 111 (28.3%) cases, squamous cell carcinoma was detected in 15 (3.8%) cases, low-grade squamous intra-epithelial lesion was detected in 37 (9.4%) cases, reactive change was detected in 178 (45.4%) cases, atrophy was detected in 47 (12.0%) cases, and adenocarcinoma was detected in four (1.0%) cases. The prevalence of HSIL or greater was 27.8% for women aged >= 40 years, and 52.3% for women aged <40 years (p<0.001). HPV positivity in ASC-H smears was significantly associated with HSIL or greater, irrespective of age (<40 years, p=0.003; >= 40 years, p<0.001). ASC-H with previous abnormal cytology greater than ASC-US showed a significantly higher detection rate for HSIL or greater at follow-up (p<0.001). CONCLUSIONS: Patient age, positive HPV DNA test and previous abnormal cytology are useful predictors of underlying HSIL or greater in women with ASC-H. PMID- 21683503 TI - Prognostic significance of human epididymis protein 4 in epithelial ovarian cancer. AB - OBJECTIVE: The purpose of this study was to evaluate the prognostic significance of serum human epididymis protein 4 (HE4) level in patients with epithelial ovarian cancer. STUDY DESIGN: A total of 78 women diagnosed with a pelvic mass and operated on in our institute comprised our cohort. Forty-five of these were diagnosed with epithelial ovarian cancer and treated with debulking surgery, followed by taxane and platinum-based chemotherapy as clinically indicated. Preoperatively obtained serum samples were analyzed for levels of HE4 and CA125. RESULTS: The elevated serum HE4 level was related to advanced stage and serous type of cancer. The median duration of the follow-up was 35.1 months. In advanced stage, the median progression-free survival (PFS) of patients with elevated serum HE4 levels was 20.1 months (95% CI, 15.7-24.6 months), whereas that of patients with normal serum HE4 level was 24.2 months (95% CI, 13.9-34.6 months) (p=0.029). Independent predictors for PFS in patients with advanced stage EOC included serum HE4 level (hazard ratio 2.24; 95% CI, 1.14 to 6.84; p=0.048). CONCLUSIONS: Our results demonstrated that an elevated serum HE4 level was related to the advanced stage of epithelial ovarian cancer. An elevated serum level of HE4 is a poor prognostic factor for PFS in patients with epithelial ovarian cancer who were treated with debulking surgery and adjuvant taxane and platinum-based chemotherapy. The serum HE4 level is a promising indicator for the progression of cancer as well as a biomarker for the detection of epithelial ovarian cancer. PMID- 21683504 TI - Osmolyte effects on protein stability and solubility: a balancing act between backbone and side-chains. AB - In adaptation biology the discovery of intracellular osmolyte molecules that in some cases reach molar levels, raises questions of how they influence protein thermodynamics. We've addressed such questions using the premise that from atomic coordinates, the transfer free energy of a native protein (DeltaG(tr,N)) can be predicted by summing measured water-to-osmolyte transfer free energies of the protein's solvent exposed side chain and backbone component parts. DeltaG(tr,D) is predicted using a self avoiding random coil model for the protein, and DeltaG(tr,D)-DeltaG(tr,N), predicts the m-value, a quantity that measures the osmolyte effect on the N?D transition. Using literature and newly measured m values we show 1:1 correspondence between predicted and measured m-values covering a range of 12 kcal/mol/M in protein stability for 46 proteins and 9 different osmolytes. Osmolytes present a range of side chain and backbone effects on N and D solubility and protein stability key to their biological roles. PMID- 21683505 TI - Transcranial sonographic localization of deep brain stimulation electrodes is safe, reliable and predicts clinical outcome. AB - In patients with deep brain stimulation (DBS), poor postoperative outcome or unexpected clinical change require brain imaging to check the lead location. Here, we studied safety, reliability and prognostic value of transcranial sonography (TCS) for DBS lead localization applying predefined TCS criteria. After measuring thermal effects of TCS and imaging artefact sizes of DBS lead using a skull phantom, we prospectively enrolled 34 patients with DBS of globus pallidus internus, ventro-intermediate thalamic or subthalamic nucleus. TCS had no influence on lead temperature, electrical parameters of DBS device or clinical state of patients. TCS measures of lead coordinates agreed with MRI measures in anterior-posterior and medial-lateral axis. Lead dislocation requiring reinsertion was reliably detected. Only patients with optimal lead position on TCS had favorable clinical 12-month outcome (>50% improvement), whereas unfavorable outcome (<25% improvement) was associated with suboptimal lead position. TCS may therefore become a first-choice modality to monitor lead location. PMID- 21683506 TI - The diastolic function to cyclic variation of myocardial ultrasonic backscatter relation: the influence of parameterized diastolic filling (PDF) formalism determined chamber properties. AB - Myocardial tissue characterization represents an extension of currently available echocardiographic imaging. The systematic variation of backscattered energy during the cardiac cycle (the "cyclic variation" of backscatter) has been employed to characterize cardiac function in a wide range of investigations. However, the mechanisms responsible for observed cyclic variation remain incompletely understood. As a step toward determining the features of cardiac structure and function that are responsible for the observed cyclic variation, the present study makes use of a kinematic approach of diastolic function quantitation to identify diastolic function determinants that influence the magnitude and timing of cyclic variation. Echocardiographic measurements of 32 subjects provided data for determination of the cyclic variation of backscatter to diastolic function relation characterized in terms of E-wave determined, kinematic model-based parameters of chamber stiffness, viscosity/relaxation and load. The normalized time delay of cyclic variation appears to be related to the relative viscoelasticity of the chamber and predictive of the kinematic filling dynamics as determined using the parameterized diastolic filling formalism (with r-values ranging from .44 to .59). The magnitude of cyclic variation does not appear to be strongly related to the kinematic parameters. PMID- 21683507 TI - Model system using controlled receptor expression for evaluating targeted ultrasound contrast agents. AB - This report details a model system for evaluating targeted ultrasound (US) contrast agents using adenoviral (Ad) vectors to regulate target receptor expression. Receptor density in vitro was modulated in breast cancer cells by varying the multiplicity of infection (MOI) from 0 to 100. Target receptors were induced using a green fluorescent protein (GFP) reporter Ad vector for gene transfer and expression of the hemagglutinin (HA) tag. These reporter genes were under the control of the ubiquitous cytomegalovirus (CMV) promoter. Subsequently, receptor expression and anti-HA antibody (Ab) binding was examined with flow cytometry. Targeted US contrast agents, or microbubbles (MB), were created by conjugating either biotinylated anti-HA or isotype control Ab to the surface of biotin coated MBs via a streptavidin bridge. Targeted MBs were incubated with Ad infected 2LMP cells to evaluate in vitro MB binding. Experimental results found GFP expression to be directly correlated with Ad MOI (r2 = 0.96). Increasing the Ad MOI produced a corresponding increase in binding and accumulation of anti-HA Ab on the cell surface (p < 0.01). However, no difference was found between Cy5 labeled anti-HA Ab exposed cell groups at an MOI of 0 (p > 0.29). Additionally, no difference was found between the isotype control Ab group (p > 0.44) indicating minimal nonspecific binding. No difference was found between cell groups incubated with isotype-targeted MBs (p > 0.42) regardless of receptor density. However, cells exposed to HA-targeted MBs showed increased levels of cell binding proportional to induced receptor expression levels (p < 0.02). PMID- 21683508 TI - Improved flow measurement using microbubble contrast agents and disruption replenishment: clinical application to tumour monitoring. AB - Dynamic contrast-enhanced ultrasound (DCE-US) and the method of disruption replenishment has been used for the past 10 years to measure flow noninvasively in the microcirculation. However, the method's perceived poor reproducibility remains a major impediment to widespread clinical acceptance. Poor reproducibility can be attributed, in part, to the curve fitting model that is used to quantify microbubble enhancement. Flow measurement in tumours is further complicated by the spatial and temporal heterogeneity of tumour blood flow. In this work, we evaluate three models of microbubble disruption and replenishment (mono-exponential, a simplified multivessel model by Krix and the lognormal perfusion model) using clinical data (11 patients, 41 sessions) from an antiangiogenic drug trial for metastatic renal cell carcinoma (RCC) and evaluate their contribution to the measurement's variability. Compared with the mono exponential model, the lognormal perfusion model decreased the variability of intra-session velocity and blood volume measurements by 33% and 34%, respectively. Blood volume assessment using the lognormal perfusion model was comparable to Krix's mutlivessel model. Flow velocity measurement was 18% less variable for the lognormal perfusion model compared with the multivessel model. To further decrease flow measurement variability, we examine a method that exploits microbubble flow dynamics to discard the contribution of flow in large arteries and isolate the portion of the tumour microvasculature that is most sensitive to vessel targeting therapies. The method is validated with an in vitro phantom study prior to its application to the RCC clinical data set. Combined with the lognormal perfusion model, this method decreased the inter-plane variability of clinical measurements of relative tumour blood volume, in some cases by up to 20%. PMID- 21683509 TI - Sonographic appearances of Morton's neuroma: differences from other interdigital soft tissue masses. AB - The purpose of the study was to evaluate the ultrasonographic characteristics of Morton's neuroma (MNs) and the usefulness of the "ginkgo leaf sign" for differentiating MNs from other interdigital soft tissue masses. The inclusion criteria were 27 patients with the masses in the intertarsal region with surgical proof. Fourteen masses in the 10 patients (mean age, 46) were MNs and nine cases of nine patients were ganglion cysts, seven cases (seven patients) of epidermoid tumors and one case of fibroma were included. Ultrasonographic examinations were performed by a musculoskeletal radiologist using the HDI 5000 (Philips, Bothell, WA, USA) or the Logiq E9 (GE Medical Systems, Milwaukee, WI, USA) equipped with a linear 6-15 MHz probe, and the findings were interpreted in consensus by two musculoskeletal radiologists. The ultrasonographic findings such as margin, size, echogenicity and deepness of the MNs were compared with those for other interdigital soft tissue masses. The ginkgo leaf sign was defined as the appearance of a biconcave shape of the mass from compression by adjacent structures. The mean size of the MNs was 5.6 mm. There was a significant difference in incidence between males and females (female dominant, p = 0.003). There was no difference in incidence with regard to age (p = 0.259). All lesions were hypoechoic (100%, 14/14) and 10 cases exhibited the ginkgo leaf sign (71%, 10/14, p < 0.001). The lesions were either well marginated (43%, 6/14) or poorly marginated (57%, 8/14, p = 0.075). None of the lesions abutted adjacent bony structures (p < 0.001). Interdigital MNs are primarily found in middle-aged women and often demonstrate the ginkgo leaf sign. MNs are hypoechoic and do not abut adjacent bony structures. Based on our findings, we believe ultrasound of interdigital soft tissue masses may provide useful information with respect to their location to adjacent soft tissue structures. Detection of our Gingko leaf sign may be specific for Morton's neuromas and more studies are needed to confirm its value as a sonographic sign. PMID- 21683510 TI - Improvement of freehand ultrasound calibration accuracy using the elevation beamwidth profile. AB - This article presents a novel approach that incorporates an ultrasound slice thickness profile into a filtered, weighted-least-square framework to improve the reconstruction accuracy of a real-time freehand calibration system. An important part of the system is a slice-thickness calibration device that aids in the extraction of the slice thickness across a wide range of imaging depths. Extensive experiments were conducted on a 10,000-image dataset to evaluate the effects of the framework on the calibration accuracy. The results showed that three-dimensional (3-D) reconstruction errors were significantly reduced in every experiment (p < 0.001). Real-time testing showed that the proposed method worked effectively with a small number of input images, suggesting great potential for intraoperative use where only a limited number of data may be available. This new framework can enable efficient quality control of calibration accuracy in real time operating-room use. PMID- 21683511 TI - Four-year experience with a clinical ultrasound quality control program. AB - Ultrasound (US) quality control (QC) program data over a 4-year period from more than 45 scanners and more than 265 transducers were reviewed to optimize the program in terms of efficiency and effectiveness. Our program included evaluations of mechanical integrity, image uniformity, distance measurement accuracy and maximum depth of penetration (DOP). We computed failure rates and fraction of failures detected by each test. A total of 187 equipment problems were identified. Average annual scanner component and transducer failure rates were 10.5% and 13.9%, respectively. The mechanical integrity and uniformity evaluations detected 25.1% and 66.3% of all failures, respectively. Those evaluations plus defects detected by sonographers accounted for 98.4% of all detected failures. DOP and distance measurement accuracy were not effective at detecting equipment failures. For routine US QC, we recommend quarterly mechanical integrity and uniformity assessments of all transducers. A scanner with five transducers could be tested in an estimated 30 min or less. PMID- 21683512 TI - Correlation based 3-D segmentation of the left ventricle in pediatric echocardiographic images using radio-frequency data. AB - Clinical diagnosis of heart disease might be substantially supported by automated segmentation of the endocardial surface in three-dimensional (3-D) echographic images. Because of the poor echogenicity contrast between blood and myocardial tissue in some regions and the inherent speckle noise, automated analysis of these images is challenging. A priori knowledge on the shape of the heart cannot always be relied on, e.g., in children with congenital heart disease, segmentation should be based on the echo features solely. The objective of this study was to investigate the merit of using temporal cross-correlation of radio frequency (RF) data for automated segmentation of 3-D echocardiographic images. Maximum temporal cross-correlation (MCC) values were determined locally from the RF-data using an iterative 3-D technique. MCC values as well as a combination of MCC values and adaptive filtered, demodulated RF-data were used as an additional, external force in a deformable model approach to segment the endocardial surface and were tested against manually segmented surfaces. Results on 3-D full volume images (Philips, iE33) of 10 healthy children demonstrate that MCC values derived from the RF signal yield a useful parameter to distinguish between blood and myocardium in regions with low echogenicity contrast and incorporation of MCC improves the segmentation results significantly. Further investigation of the MCC over the whole cardiac cycle is required to exploit the full benefit of it for automated segmentation. PMID- 21683513 TI - Ultrasound-triggered drug release and enhanced anticancer effect of doxorubicin loaded poly(D,L-lactide-co-glycolide)-methoxy-poly(ethylene glycol) nanodroplets. AB - A novel ultrasound-responsive doxorubicin (DOX)-loaded nanoparticulate system was prepared in this study. The DOX-loaded polymeric micelles were first prepared using poly(D,L-lactide-co-glycolide)-methoxy-poly(ethylene glycol) (PLGA-mPEG) with a high encapsulation efficiency of 89.2%. After filling with perfluoropentane (boiling point 29 degrees C), the micelles were transformed into nanodroplets that were stable as a result of the PEG shell. The nanodroplets were transformed into nanobubbles at 37 degrees C, and little drug was released if no ultrasound was exerted. Ultrasound-triggered drug release, with pH dependency, was shown. The DOX release percentage was 9.59% at pH 6.5 (also appeared in tumor) and only 2.22% at pH 7.4 after sonicating for 0.5 min at 37 degrees C. The tumor inhibitory rate of Group III (DOX-loaded nanodroplets combined with ultrasound) was 84.3%, more than that of Group II (DOX-loaded nanodroplets), which was 60.4%. Moreover, the nanodroplets showed much lower toxicity than free drugs. The novel nanodroplets could be a promising anticancer drug delivery system. PMID- 21683514 TI - Localized harmonic motion imaging for focused ultrasound surgery targeting. AB - Recently, an in vivo real-time ultrasound-based monitoring technique that uses localized harmonic motion (LHM) to detect changes in tissues during focused ultrasound surgery (FUS) has been proposed to control the exposure. This technique can potentially be used as well for targeting imaging. In the present study, we evaluated the potential of using LHM to detect changes in stiffness and the feasibility of using it for imaging purposes in phantoms and in vivo tumor detection. A single-element FUS transducer (80 mm focal length, 100 mm diameter, 1.485 MHz) was used for inducing a localized harmonic motion and a separate ultrasound diagnostic transducer excited by a pulser/receiver (5 kHz PRF, 5 MHz) was used to track motion. The motion was estimated using cross-correlation techniques on the acquired radio-frequency (RF) signal. Silicon phantom studies were performed to determine the size of inclusion that was possible to detect using this technique. Inclusions were discerned from the surroundings as a reduction on LHM amplitude and it was possible to depict inclusions as small as 4 mm. The amplitude of the induced LHM was always lower at the inclusions compared with the one obtained at the surroundings. Ten New Zealand rabbits had VX2 tumors implanted on their thighs and LHM was induced and measured at the tumor region. Tumors (as small as 10 mm in length and 4 mm in width) were discerned from the surroundings as a reduction on LHM amplitude. PMID- 21683516 TI - Resveratrol enhances the expression of death receptor Fas/CD95 and induces differentiation and apoptosis in anaplastic large-cell lymphoma cells. AB - Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a phytoalexin found in grapes and other plants, plays a protective role in human atherosclerosis and carcinogenesis. We examined the effects of resveratrol on the anaplastic large cell lymphoma (ALCL) cell line SR-786. Resveratrol inhibited growth and induced cellular differentiation, as demonstrated by morphological changes and elevated expression of T cell differentiation markers CD2, CD3, and CD8. Resveratrol also triggered cellular apoptosis, as demonstrated by morphological observations, DNA fragmentation, and cell cycle analyses. Further, the surface expression of the death receptor Fas/CD95 was increased by resveratrol treatment. Our data suggest that resveratrol may have potential therapeutic value for ALCL. PMID- 21683517 TI - Lipoxin A4 and its analog suppress hepatocellular carcinoma via remodeling tumor microenvironment. AB - Macrophages play an important role in tumor inflammatory microenvironment, lipoxin (LX), the 'stop signal' for inflammation, has been extensively studied preclinically for its anti-inflammatory or inflammatory pro-resolving effect. Here, we showed that LXA(4) could promote the apoptosis and inhibit the proliferation, migration and angiogenesis of HepG2 hepatocarcinoma cells stimulated by lipopolysaccharide (LPS) or activated macrophage-conditioned media (ACM). Moreover, BML-111, the analog of LXA(4), effectively inhibited the proliferation, invasion and angiogenesis of tumor in H22 hepatocarcinoma cell bearing mice. These results showed that LXA(4) could be a possible candidate for liver cancer therapy, and blocking the activation of macrophages would be an effective drug target. PMID- 21683518 TI - Stem cells in endometrium and endometrial cancer: accumulating evidence and unresolved questions. AB - The human endometrium undergoes cyclical process of regeneration, growing from less than 1mm in thickness just after menstruation to 7-8 mm in only 2 weeks, which is accompanied by functional differentiation, followed by shedding of the functional layer. Since endometrium can fully regenerate even after complete physical shedding, there may be a cell population residing in the basal layer that can continue to provide daughter cells with high proliferative potential. Such a cell population is assumed to have stem cell characteristics. This review article aims to introduce evidence of the presence of stem cells not only in normal endometrium but also in endometrial cancer and discusses their roles in physiological regeneration and in carcinogenesis of the endometrium. Accumulating evidence revealed that there are rare individual cells that display adult stem cell properties of self-renewal and differentiation in both epithelium and stroma of the human endometrium, probably responsible for in its immense regenerative capacity. Epithelial stem cells might be located in the basal layer of endometrium. Prospectively isolated CD133(+) cells and/or side population (SP) cells in endometrial cancer were capable of initiating tumor formation and of recapitulating the phenotype of the original tumor, and therefore are candidate for endometrial cancer stem cells. These studies help us to understand the mechanisms of endometrial regeneration as well as endometrial carcinogenesis and will hopefully help in establishing novel molecular-based cancer therapies targeting stem cells. PMID- 21683520 TI - Surface modification of coconut shell based activated carbon for the improvement of hydrophobic VOC removal. AB - In this study, coconut shell based carbons were chemically treated by ammonia, sodium hydroxide, nitric acid, sulphuric acid, and phosphoric acid to determine suitable modification for improving adsorption ability of hydrophobic volatile organic compounds (VOCs) on granular activated carbons (GAC). The saturated adsorption capacities of o-xylene, a hydrophobic volatile organic compound, were measured and adsorption effects of the original and modified activated carbons were compared. Results showed that GAC modified by alkalis had better o-xylene adsorption capacity. Uptake amount was enhanced by 26.5% and reduced by 21.6% after modification by NH(3)H(2)O and H(2)SO(4), respectively. Compared with the original, GAC modified by acid had less adsorption capacity. Both SEM/EDAX and BET were used to identify the structural characteristics of the tested GAC, while IR spectroscopy and Boehm's titration were applied to analysis the surface functional groups. Relationships between physicochemical characteristics of GAC and their adsorption performances demonstrated that o-xylene adsorption capacity was related to surface area, pore volume, and functional groups of the GAC surface. Removing surface oxygen groups, which constitute the source of surface acidity, and reducing hydrophilic carbon surface favors adsorption capacity of hydrophobic VOCs on carbons. The performances of modified GACs were also investigated in the purification of gases containing complex components (o-xylene and steam) in the stream. PMID- 21683519 TI - Differential dependency of human cancer cells on vascular endothelial growth factor-mediated autocrine growth and survival. AB - Analysis using the public microarray database Gene Expression Omnibus indicates significantly higher mRNA expression of VEGF and VEGFRs in colorectal cancer and high grade astrocytoma but not in hepatocellular carcinoma compared to normal tissue. Human malignant astrocytoma cell lines (U251-MG and U373-MG) and HT-1080 fibrosarcoma cells expressed relatively higher levels of VEGF and VEGFRs compared to hepatocellular and colorectal cancer cell lines. Administration of exogenous VEGF-A induced cell growth in a dose-dependent fashion in astrocytoma and fibrosarcoma cells but not in colorectal and hepatocellular cancer cells. The blockade of VEGF inhibited cell survival only in U251-MG, U373-MG and HT-1080 cells. These results collectively suggest the role of autocrine VEGF signaling in various cancer cells and provide a basis for the variable clinical responses to antiangiogenic therapy observed in different types of malignancies. PMID- 21683521 TI - Bioleaching of metal concentrates of waste printed circuit boards by mixed culture of acidophilic bacteria. AB - Metal concentrates of printed circuit boards (PCBs) are the residue valuable metals from which non-metallic components are removed. The non-metallic components show bacterial toxicity in bioleaching process and can be recycled as well. In this study, the effects of initial pH, initial Fe(II) concentration, metal concentrate dosage, particle size, and inoculation quantity on the bioleaching were investigated so as to determine the optimum conditions and evaluate the feasibility of bioleaching of metal concentrates of PCBs by mixed culture of acidophilic bacteria (MCAB). The results showed that the initial pH and Fe(II) concentration played an important role in copper extraction and precipitate formation. Under the optimized conditions of initial pH 2.00, 12g/L initial Fe(II), 12g/L metal concentrate dosage, 10% inoculation quantity, and 60 80 mesh particle size, 96.8% the copper leaching efficiency was achieved in 45h, and aluminum and zinc 88.2% and 91.6% in 98h, respectively. All findings demonstrated that metals could be efficiently leached from metal concentrates of waste PCBs by using the MCAB, and the leaching period was shorten from about 8 days to 45h. PMID- 21683522 TI - A combination of bioleaching and bioprecipitation for deep removal of contaminating metals from dredged sediment. AB - A linked microbial process comprising bioleaching with sulfate-oxidizing bacteria and bioprecipitation with sulfate-reducing bacteria operating sequentially was investigated to deeply remove contaminating metals from dredged sediment. The results showed that sediment bioleaching resulted in a sharp decrease in sediment pH from an initial pH ~ 7.6 to pH ~ 2.5 within 10-20 days, approximately 65% of the main heavy metals present (Zn+Cu+Cr) were solubilized, and most of the unsolubilized metals existed in residual form of sediment. The acidic leachate that resulted from sediment bioleaching was efficiently stripped of metal sulfates using a bioprecipitation reactor when challenged with influent as low as pH ~ 3.7. More than 99% of Zn(2+), 99% of Cu(2+) and 90% of Cr(3+) were removed from the leachate, respectively, due to the formation of ZnS, Cu(2)S and CrOOH precipitates, as confirmed by SEM-EDS and XRD detection. It was also found that alkalization of bioleached sediment using Ca(OH)(2) excluded the risk of sediment re-acidification. The ability of the combined process developed in this study to deeply remove heavy metals in insoluble sulfides or hydroxides forms makes it particularly attractive for the treatment of different types of metal contaminants. PMID- 21683523 TI - Adsorptive removal of fluoride from aqueous solution using orange waste loaded with multi-valent metal ions. AB - Adsorption gels for fluoride ion were prepared from orange waste by saponification followed by metal loading. The pectin compounds contained in orange waste creates ligand exchange sites once it is loaded with multi-valent metal ions such as Al(3+), La(3+), Ce(3+), Ti(4+), Sn(4+), and V(4+) to be used for fluoride removal from aqueous solution. The optimum pH for fluoride removal depends on the type of loaded metal ions. The isotherm experiments showed the Langmuir type monolayer adsorption. Among all kinds of metal loaded gels tested, Al loaded gel appeared to exhibit the most favorable adsorption behavior. The adsorption kinetics of fluoride on loaded gel demonstrated fast adsorption process. The presence of NO(3)(-), Cl(-) and Na(+) ions has negligible effect on fluoride removal whereas SO(4)(2-) and HCO(3)(-) retarded the fluoride removal capacity in some extent. Fluoride removal at different adsorbent doses showed that fluoride concentration can be successfully lowered down to the acceptable level of environmental standard. The fluoride adsorption mechanism was interpreted in terms of ligand exchange mechanism. The complete elution of adsorbed fluoride from the gel was successfully achieved using NaOH solution. PMID- 21683524 TI - Application of fly ash as a catalyst for synthesis of carbon nanotube ribbons. AB - The larger diameter-based carbon nanotube (CNT) ropes and ribbons are currently synthesized by catalytic decomposition of hydrocarbons with transition metal based catalysts e.g., Co, Ni, Fe and Mo at 1100-1200 degrees C, using chemical vapour deposition (CVD) and electric arc methods. We produced CNT ribbons by fly ash (FA) catalyzed pyrolysis of a composite film of poly (vinyl alcohol) (PVA) with FA at 500 degrees C for 10min under a nitrogen flow of 2L/min. Different geometrical structures, e.g.; knotted and twisted, U- and spiral-shaped CNT ribbons were observed in the images of scanning and transmission electron microscopy. The widths of the CNT ribbons measured varied in the ranges 18-80nm. X-ray photoelectron spectroscopy analysis showed five types of carbon binding peaks, C-C/C-H (~77%), C-O-H (~9%), -C-O-C (~5%), C=O (~5%) and -O-C=O (~3%). The ratio of intensities of G and D bands, IG/ID was 1.61 analysed by Raman Spectroscopy. CNT ribbons grown on the surface of FA have potential for the fabrication of high-strength composite materials with polymer and metal. PMID- 21683525 TI - The azo dye Disperse Orange 1 induces DNA damage and cytotoxic effects but does not cause ecotoxic effects in Daphnia similis and Vibrio fischeri. AB - Azo dyes constitute the largest group of colorants used in industry and can pass through municipal waste water plants nearly unchanged due to their resistance to aerobic treatment, which potentially exposes humans and local biota to adverse effects. Unfortunately, little is known about their environmental fate. Under anaerobic conditions, some azo dyes are cleaved by microorganisms forming potentially carcinogenic aromatic amines. In the present study, the azo dye Disperse Orange 1, widely used in textile dyeing, was tested using the comet, Salmonella/microsome mutagenicity, cell viability, Daphnia similis and Microtox((r)) assays. The human hepatoma cell line (HepG2) was used in the comet assay and for cell viability. In the mutagenicity assay, Salmonella typhimurium strains with different levels of nitroreductase and o-acetyltransferase were used. The dye showed genotoxic effects with respect to HepG2 cells at concentrations of 0.2, 0.4, 1.0, 2.0 and 4.0MUg/mL. In the mutagenicity assay, greater responses were obtained with the strains TA98 and YG1041, suggesting that this compound mainly induces frameshift mutations. Moreover, the mutagenicity was greatly enhanced with the strains overproducing nitroreductase and o acetyltransferase, showing the importance of these enzymes in the mutagenicity of this dye. In addition, the compound induced apoptosis after 72h in contact with the HepG2 cells. No toxic effects were observed for either D. similis or Vibrio fischeri. PMID- 21683527 TI - A randomized, controlled trial of acceptance and commitment therapy and cognitive behavioral therapy for chronic pain. AB - Individuals reporting chronic, nonmalignant pain for at least 6 months (N=114) were randomly assigned to 8 weekly group sessions of acceptance and commitment therapy (ACT) or cognitive-behavioral therapy (CBT) after a 4-6 week pretreatment period and were assessed after treatment and at 6-month follow-up. The protocols were designed for use in a primary care rather than specialty pain clinic setting. All participants remained stable on other pain and mood treatments over the course of the intervention. ACT participants improved on pain interference, depression, and pain-related anxiety; there were no significant differences in improvement between the treatment conditions on any outcome variables. Although there were no differences in attrition between the groups, ACT participants who completed treatment reported significantly higher levels of satisfaction than did CBT participants. These findings suggest that ACT is an effective and acceptable adjunct intervention for patients with chronic pain. PMID- 21683528 TI - Chronic idiopathic pain in adolescence--high prevalence and disability: the young HUNT Study 2008. AB - The aim of this study was to determine the prevalence of self-reported chronic idiopathic pain among adolescents in relation to age and gender, and to explore how pain interferes with daily activities. The study was performed in Nord Trondelag County, Norway in 2006-2008. All adolescents were invited to participate; the response rate was 78%. Participants completed a comprehensive questionnaire, including questions about pain and interference with everyday life. Chronic idiopathic pain was defined as pain at least once a week during the last 3 months, not related to any known disease or injury. The final study population, with complete pain questionnaires, consisted of 7373 adolescents aged 13-18 years. Chronic pain was reported by 44.4% of the participants, and 25.5% reported pain in at least 2 locations. Chronic idiopathic musculoskeletal pain was most prevalent (33.4%), and the neck/shoulder was most commonly affected. Musculoskeletal pain in 3 or more locations was reported by 8.5%. Pain almost daily was reported by 10.2%. More girls than boys reported pain. In girls, the prevalence of pain increased with age. A high number of pain-associated disabilities were reported, and 58.5% described difficulties doing daily activities in leisure time. Subjective disabilities were higher in girls, and increased with the frequency of pain and the number of pain locations, as shown by high disability in adolescents with musculoskeletal pain in 3 or more locations. Chronic idiopathic pain, especially multisite pain, is common among adolescents, and those suffering from it report a major impact on several areas of daily living. PMID- 21683529 TI - Methamphetamine laboratory-related burns in Western Australia--why the explosion? AB - INTRODUCTION: With increasing numbers of illicit drug users in both urban and rural communities, users and producers are becoming increasingly enterprising in their sourcing of mind altering drugs. An example of this is the 'amateur' production of methamphetamine in domestic dwellings. We describe the mechanism of burn seen in methamphetamine production, the pattern of clinical injury, and the difficulties in treating these patients. METHODS: A 12 month retrospective study of five patient groups presenting to our burn service with injuries following methamphetamine laboratory explosion. RESULTS: Out of five patient groups we have treated 9 individual patients (with one patient presenting on two different occasions) with burns following methamphetamine laboratory explosion. All patients were male and required hospital admission. The cause of the explosive injury was initially reported as barbeque or oven related, assault, or accident in all patients. Two patients (in separate events) required intubation for associated inhalation injury. Burn size varied from 1% to 40% BSA. 7 patients required surgical debridement and skin grafting. Injury type was thermal and chemical. All patients had difficult follow-up due to low levels of clinic attendance. CONCLUSION: Methamphetamine laboratory explosion burns are difficult injuries from the start. Invariably the true circumstances surrounding the injury are not clear, and clinicians should be suspicious of a meth lab explosion in suspect individuals with burns plus airway injury. Patient management is complex and often requires substantial analgesic and anxiolytic medication in conjunction with clinical psychology and psychiatry as an inpatient. PMID- 21683530 TI - Radionuclide treatment of painful bone metastases in patients with breast cancer: a systematic review. AB - Bone-seeking radionuclides, such as Sr-89, Sm-153, and Re-186, have been shown to have an effect on pain from bone metastasis in prostate cancer. The effect on bone pain in other cancer types, including breast cancer, remains unclear. The purpose of the study was to perform a systematic review of the use of radioisotopes for pain relief in metastatic breast cancer. A literature search was performed in PubMed, EMBASE, and Web of Science (1970 to September 2009) for clinical studies with a primary outcome of pain, performance status, or quality of life. Eligibility criteria were the following: (1) the trial must include at least 10 breast cancer patients with painful bone metastasis, (2) the radionuclide has been approved by regulatory authorities in Europe or the United States and is commercially available (Sr-89, Sm-153, and Re-186), (3) the dose of radionuclides must be clinically effective, (4) the primary endpoint must be pain, performance status or quality of life, and (5) separate reporting of efficacy should be available for breast cancer patients provided the trial included patients with various types of cancer. The literature search identified 189 individual studies of which 19 trials fulfilled the eligibility criteria. There were three randomized controlled trials of which two trials compared two different radionuclides, and one trial compared two doses of Sm-153. In addition, there were 16 uncontrolled trials. Reporting of trial research methodology in the randomized as well as the uncontrolled trials was low (median Jadad score of 1, range 1-2). Key trial details, such as patient recruitment, description of prior palliative therapies, baseline characteristics, follow up, and reporting of outcome was insufficient in a large proportion of the trials. According to Center of Evidence-based Medicine criteria, there is level 4 documentation for the effect of radionuclides in painful bone metastasis in breast cancer. It has been concluded that there is limited clinical evidence supporting the clinical effect of radionuclides in relieving pain from bone metastasis in breast cancer. Large, randomized controlled trials are needed to establish the utility of bone-seeking radionuclides in the palliative care of breast cancer patients. PMID- 21683531 TI - Targeting the kynurenine pathway as a potential strategy to prevent and treat Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the elderly accounting for the vast majority of dementia. Recently, many studies have implicated the role of inflammatory response, especially neuroinflammatory response in the development and progression of AD. However, the underlying mechanism of how inflammatory response induces AD is unknown. Kynurenine pathway is a major route of the amino acid tryptophan catabolism, resulting in the production of nicotine adenine dinucleotide and other neuroactive intermediates: quinolinic acid (QA) and kynurenic acid (KA). QA exerts different toxic effects, including over-activation of N-methyl-d-aspartate (NMDA) receptor and excitotoxicity, synaptic dysfunction and neuronal death. On the other hand, KA is identified as the only endogenous NMDA receptor antagonist and could modulate neurotoxic effects of QA. We hypothesize that an activated kynurenine pathway induced by inflammatory cytokines would generate more neurotoxic metabolites, which could be closely related to the pathogenesis of AD in elderly patients. Moreover, some measures, which facilitate KA synthesis and reduce the formation of QA, may emerge as a new therapeutic strategy against AD. PMID- 21683532 TI - Functional recovery in cerebral palsy may be potentiated by administration of selective serotonin reuptake inhibitors. AB - Cerebral palsy is a disorder of movement and posture caused by a non-progressive lesion to the brain. The incidence of cerebral palsy is over 2 per 1000 live births in Europe. Management of cerebral palsy is primarily supportive--none of the current treatments offered attempt to correct the primary problem of a brain lesion. Neurological problems may be treated by upregulating cerebral plasticity. Evidence suggests that this is the mechanism of action of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression. Encouraging evidence of motor improvements in stroke patients treated with SSRIs suggest the possibility of similar improvements in cerebral palsy. Patients with less severe cerebral palsy show more evidence of plasticity than patients with more severe forms. Evidence should initially come from animal models, and thereafter case reports and case series in selected cases, before progression to large scale trials. SSRIs would have to be used in conjunction with cooling, which prevents secondary damage. Due consideration is needed to prevent harmful side-effects. PMID- 21683533 TI - Near infrared reflectance spectroscopy predicts the content of polyunsaturated fatty acids and biohydrogenation products in the subcutaneous fat of beef cows fed flaxseed. AB - This study examined the ability of near infrared reflectance spectroscopy (NIRS) to estimate the concentration of polyunsaturated fatty acids and their biohydrogenation products in the subcutaneous fat of beef cows fed flaxseed. Subcutaneous fat samples at the 12th rib of 62 cows were stored at -80 degrees C, thawed, scanned over a NIR spectral range from 400 to 2498 nm at 31 degrees C and 2 degrees C, and subsequently analysed for fatty acid composition. Best NIRS calibrations were with samples at 31 degrees C, showing high predictability for most of the n-3 (R(2): 0.81-0.86; RMSECV: 0.11-1.56 mg g(-1) fat) and linolenic acid biohydrogenation products such as conjugated linolenic acids, conjugated linoleic acids (CLA), non-CLA dienes and trans-monounsaturated fatty acids with R(2) (RMSECV, mgg(-1) fat) of 0.85-0.85 (0.16-0.37), 0.84-0.90 (0.21-2.58), 0.90 (5.49) and 0.84-0.90 (4.24-8.83), respectively. NIRS could discriminate 100% of subcutaneous fat samples from beef cows fed diets with and without flaxseed. PMID- 21683534 TI - RAPD and VNTR analyses demonstrate genotypic heterogeneity of Mycoplasma hyopneumoniae isolates from pigs housed in a region with high pig density. AB - Since differences in the virulence of Mycoplasma (M.) hyopneumoniae strains have been described, the isolation of field strains followed by genotypic and phenotypic characterisation has become a major goal in epidemiological studies. The aim of this study was to compare various M. hyopneumoniae isolates from different pig herds and numerous pigs within the same herd. Therefore, pigs of 109 herds located in North-Western Germany were sampled either on-farm or during necropsies. Overall, 52 isolates of M. hyopneumoniae were recovered from 45 pigs originating from 21 herds. The identity of cultures was confirmed by PCR targeting the 16S-23S intergenic spacer region. Typing of isolates was achieved by random amplified polymorphic DNA (RAPD) analysis and multi-locus analysis of variable number of tandem repeats (VNTR) and demonstrated a high degree of heterogeneity of M. hyopneumoniae isolates. Differences among isolates recovered from animals of the same herd or even from the same pig revealed a grouping into different genotypic clusters. This outcome was observed with both methods. It was concluded that more than one strain of M. hyopneumoniae might be present in a pig herd and even in a single pig, suggesting high genetic heterogeneity between isolates of the same epidemiological source. These factors should be considered when applying nucleic amplification techniques for characterising M. hyopneumoniae strains to specify the epidemiology of infection and to evaluate virulence factors triggering the corresponding disease. PMID- 21683535 TI - Cardiorespiratory fitness and its association with body composition and physical activity in Hong Kong Chinese women aged from 55 to 94 years. AB - BACKGROUND: Low levels of cardiorespiratory fitness have proven to be associated with a higher risk of premature death from all causes, specifically from cardiovascular disease. However, there has been no study conducted to describe the cardiorespiratory fitness normative values in Chinese midlife and elderly. OBJECTIVES: To provide normative values of cardiorespiratory fitness expressed as maximal oxygen uptake (VO(2max)) and its association with body composition and physical activity in Chinese midlife and elderly women in Hong Kong. METHODS: 659 Chinese women aged from 55 to 94 years were recruited from two existing cohorts: the carotid atherosclerosis in women Hong Kong cohort study and the Osteoporotic Fractures in Women (MsOS) Hong Kong cohort study. Symptom-limited maximal exercise testing on an electrically braked bicycle ergometer was performed to assess VO(2max), where the subject was connected to a calibrated metabolic cart for gas analysis. Their body composition and physical activity data were also assessed. RESULTS: The body mass index was 23.4 kg/m(2) and the mean fat mass and lean body mass were 16.6 kg and 37.3 kg, respectively. The mean VO(2max) was 20.3+/-4.1 ml/kg/min (range, 7.9-35.7 ml/kg/min). VO(2max) decreased with age, with the rate of decline 0.25 ml/kg/min/yr (7.1% per decade). In a subgroup of 475 women from the MsOS study, the decline in VO(2max) was found to depend on ageing (beta=0.31, P<0.001), body mass index (beta=-0.30, P<0.001) and levels of physical activity (beta=0.02, P<0.001). Fat mass was also independently associated with VO(2max) (beta=-0.20, P<0.001). CONCLUSIONS: This study describes the normative values of VO(2max) in a sample of Chinese midlife and elderly women which provides a valuable reference to assess health and fitness in Chinese elderly. Results from this study also suggested that body composition and levels of physical activity were important determinants of the age-related decline in VO(2max). PMID- 21683536 TI - Seasonal and habitat abundance and distribution of some forensically important blow flies (Diptera: Calliphoridae) in Central California. AB - Seasonal and habitat calliphorid abundance and distribution were examined weekly for two years (2001-2003) in Santa Clara County, California, using sentinel traps baited with bovine liver. Of the 34,389 flies examined in three defined habitats (rural, urban, and riparian), 38% of the total catch represented Compsomyiops callipes (Bigot) and 23% represented Phormia regina (Meigen). Other flies collected in this survey included Calliphora vomitoria (Linnaeus), Calliphora latifrons (Hough), Lucilia sericata (Meigen), Lucilia cuprina (Wiedemann), and Lucilia mexicana (Macquart), which is a new record for the area. Multivariate MANOVA and ANOVA (P <= 0.05) analysis indicate significant seasonal habitat preference for all fly species examined. This information may be used to identify potentially forensically impo rtant fly species within Santa Clara County, California. PMID- 21683537 TI - Fatal tolperisone poisoning: autopsy and toxicology findings in three suicide cases. AB - Tolperisone (Mydocalm) is a centrally acting muscle relaxant with few sedative side effects that is used for the treatment of chronic pain conditions. We describe three cases of suicidal tolperisone poisoning in three healthy young subjects in the years 2006, 2008 and 2009. In all cases, macroscopic and microscopic autopsy findings did not reveal the cause of death. Systematic toxicological analysis (STA) including immunological tests, screening for volatile substances and blood, urine and gastric content screening by GC-MS and HPLC-DAD demonstrated the presence of tolperisone in all cases. In addition to tolperisone, only the analgesics paracetamol (acetaminophen), ibuprofen and naproxen could be detected. The blood ethanol concentrations were all lower than 0.10 g/kg. Tolperisone was extracted by liquid-liquid extraction using n chlorobutane as the extraction solvent. The quantification was performed by GC NPD analysis of blood, urine and gastric content. Tolperisone concentrations of 7.0 mg/l, 14 mg/l and 19 mg/l were found in the blood of the deceased. In the absence of other autopsy findings, the deaths in these three cases were finally explained as a result of lethal tolperisone ingestion. To the best of our knowledge, these three cases are the first reported cases of suicidal tolperisone poisonings. PMID- 21683538 TI - MRI patterns in recurrence of primary CNS lymphoma in immunocompetent patients. AB - PURPOSE: Primary CNS lymphomas (PCNSL) are highly malignant non-Hodgkin's B-cell lymphoma restricted to the CNS. While MRI features of PCNSL at initial presentation have been comprehensively described, literature on MRI characteristics at relapse is sparse. The purpose of this study was to investigate anatomic location and contrast enhancement patterns at PCNSL recurrence by cranial MRI. METHODS: Sixteen immunocompetent patients (9 men, 7 women, median age 65 years) with histologically proven PCNSL and initial response to a standardized polychemotherapy, but suffering from a relapse were consecutively recorded. Native and contrast-enhanced MRI examinations carried out at initial presentation and at time of relapse were compared. Anatomical site of parenchymal enhancement, frequency and presence of non-parenchymal contrast enhancement (i.e. ventricular, superficial, subependymal) patterns at initial presentation and at relapse were recorded and compared. RESULTS: Local recurrence was found at the site of the initial tumor presentation in four of the 16 cases. Six of 11 patients presenting a unilateral PCNSL at initial presentation had a bilateral involvement at relapse. In two cases, recurrence appeared solely on the contralateral side without involvement of the hemisphere initially affected. At both dates, subependymal enhancement was the most often found non-parenchymal pattern (six at initial presentation, and five at relapse). The number of patients with a ventricular contrast enhancement increased from one at initial presentation to four at relapse. CONCLUSIONS: PCNSL tend to recur in different parenchymal anatomic sites as compared with the site of the initial tumor presentation. Contrast-enhancing non-parenchymal lesions are also frequent and might change their pattern at relapse. PMID- 21683539 TI - Comparison of 3D vs. 2D fast spin echo imaging for evaluation of articular cartilage in the knee on a 3T system scientific research. AB - PURPOSE: We sought to retrospectively compare the accuracy of a three-dimensional fat-suppressed, fast spin-echo sequences acquired in the sagittal plane, with multiplanar reconstructions to that of two-dimensional fat-suppressed, fast spin echo sequences acquired in three planes on a 3T MR system for the evaluation of articular cartilage in the knee. MATERIALS AND METHODS: Our study group consisted of all patients (N=34) that underwent 3T MR imaging of the knee at our institution with subsequent arthroscopy over an 18-month period. There were 21 males and 13 females with an average age of 36 years. MR images were reviewed by 3 musculoskeletal radiologists, blinded to operative results. 3D and 2D sequences were reviewed at different sittings separated by 4 weeks to prevent bias. Six cartilage surfaces were evaluated both with MR imaging and arthroscopically with a modified Noyes scoring system and arthroscopic results were used as the gold standard. Sensitivity, specificity, and accuracy were calculated for each reader along with Fleiss Kappa assessment agreement between the readers. Accuracies for each articular surface were compared using a difference in proportions test with a 95% confidence interval and statistical significance was calculated using a Fisher's Exact Test. RESULTS: Two hundred and four articular surfaces were evaluated and 49 articular cartilage lesions were present at arthroscopy. For the patellofemoral surfaces, the sensitivity, specificity, and accuracy were 76.5%, 83%, and 78.2% for the 3D sequences and were 82.3%, 76%, and 82% respectively for the 2D sequences. For the medial compartment surfaces, the sensitivity, specificity, and accuracy were 81.1%, 65.1%, and 78.5% for the 3D sequences and were 82.5%, 48%, and 76.7% respectively for the 2D sequences. For the lateral compartment surfaces, the sensitivity, specificity, and accuracy were 89.3%, 39%, and 79.5% for the 3D sequences and were 94.7%, 18.8%, and 79.5% respectively for the 2D sequences. The accuracies were not significantly different between 3D and 2D sequences. Fleiss Kappa agreement values for the assessment of inter-observer agreement ranged from substantial for the patella and medial femur to moderate for the trochlea and fair for the medial tibia and lateral compartment. CONCLUSION: There was no significant difference in accuracy for the evaluation of articular cartilage of a single three-dimensional, fast spin echo sequence with multi-planar reformatted images vs. two-dimensional, fast spin echo sequences acquired in all three imaging planes in the knee. PMID- 21683540 TI - HPLC determination of hesperidin, diosmin and eriocitrin in Iranian lime juice using polyamide as an adsorbent for solid phase extraction. AB - Solid phase extraction (SPE) and HPLC were used for simultaneous determination of hesperidin, diosmin and eriocitrin in Iranian lime juice samples. The method involved very simple efficient SPE with polyamide cartridge, the use of mixture of water/acetonitrile/acetic acid (78:19:3, v/v) as a mobile phase at a flow rate of 0.8 mL/min and UV detection at 280 nm. Optimum conditions for SPE were achieved using 8 mL water/methanol (85:15, v/v, pH=3) as the washing solution and 4 mL methanol for elution. SPE parameters, such as maximum loading capacity and breakthrough volume, were also determined for each analyte. Good clean-up and high>90% were observed for all analytes. Limits of detection, limits of quantification, linear range, recovery, repeatability of retention times, and peak areas for hesperidin, diosmin and eriocitrin were 0.0283-0.0512 MUg/mL, 0.0857-0.155 MUg/mL, 0.0283-105.0 MUg/mL (R2 > 0.99), 93.3-98.1%, 3.2-4.7% and 2.8-3.6%, respectively. The method was applied to analysis of lime juice samples obtained from different locations of Iran. PMID- 21683541 TI - Development of a method for the determination of glycine in human cerebrospinal fluid using pre-column derivatization and LC-MS/MS. AB - An LC-MS/MS method using pre-column derivatization with phenylisothiocyanate (PITC) was developed to quantify glycine in human cerebrospinal fluid (CSF) and applied to the determination of glycine in human samples collected during clinical testing. The calibration curve range for the assay was 50-10,000 ng/mL and 13C215N-glycine was used as an internal standard. Artificial CSF was used as a surrogate matrix for standards due to the presence of endogenous glycine in human CSF and this approach was validated with additional experiments involving either standard addition, or stable labeled glycine as an alternate calibration standard for endogenous glycine. Interday bias (% RE) and precision (% CV) were 4.2 and 12.3% at the LLOQ, and less than +/-0.9 and 8.3% for higher concentrations, respectively. Glycine was stable in artificial CSF for at least 5h at room temperature, 55 days at -70 degrees C (-60 to -80 degrees C range), and through three freeze-thaw cycles. PMID- 21683542 TI - Whole fentanyl patch ingestion: a multi-center case series. AB - BACKGROUND: Fentanyl is a potent synthetic opioid with large abuse potential. A common preparation of fentanyl is a sustained-release transdermal patch. To our knowledge, there are only two published case reports of whole patch ingestion. A case series of 76 patients with a history of whole patch ingestion is reported. STUDY OBJECTIVES: To characterize whole fentanyl patch ingestion to develop a clinical guideline for management. METHODS: This was a retrospective review of all patients who ingested intact fentanyl patches as reported to three regional poison information centers (RPIC) from 2000 to 2008. The three RPIC medical record databases were queried for all exposures with a substance code matching the Micromedex(r) (Thomson Reuters, New York, NY) fentanyl product codes. Collected data included: age, gender, reason for the exposure, number of patches ingested, dose (MUg/h), symptoms, symptom onset and duration, treatment hospital flow (level of care), and outcome. RESULTS: A total of 76 patients met the inclusion criteria. Two patients had both time of onset and symptom duration documented. In both patients, the signs and symptoms developed within 2 h of the exposure, and the patients were asymptomatic at 61/2 and 9 h, respectively. Fifty eight (78.3%) patients were admitted. Of those patients who were admitted, 56 (96.5%) were admitted to a critical care unit. Fourteen patients required intubation, and naloxone infusions were documented in eight cases. CONCLUSION: Ingestion of whole fentanyl patches may lead to prolonged and significant toxicity based on these poison center data. PMID- 21683543 TI - Maximizing the clinical usefulness of a nomogram to select patients candidate to sentinel node biopsy for cutaneous melanoma. AB - AIMS: Investigators from the Memorial Sloan Kettering Cancer Centre (MSKCC) have proposed a nomogram for predicting the sentinel node (SN) status in patients with cutaneous melanoma. The negative predictive value (NPV) of this test, which might help identify low-risk patients who might be safely spared SN biopsy (SNB), has not been yet investigated. METHODS: We tested the discrimination (area under the curve [AUC]), the calibration (linear regression) and the NPV of MSKCC nomogram in 543 patients treated at our institution. Different cut-off values were tested to assess the NPV, the reduction of SNB performed and the overall error rate obtained with the MSKCC nomogram. RESULTS: SN was positive in 147 patients (27%). Mean predicted probability was 17.8% (95%CI: 16.8-18.8%). Nomogram discrimination was significant (area under the curve = 0.68; P < 0.0001) and mean predicted probabilities of SN positivity well correlated with the observed risk (R(2) = 0.99). Cut-off values between 4% and 9% led to a NPV, SNB reduction and overall error rates ranging between 100 and 91.2%, 2.2 and 27.2%, and 0 and 2.3%, respectively. CONCLUSION: In our series, the nomogram showed a significant predictive accuracy, although the incidence of SN metastasis was higher than that observed in the MSKCC series (27% vs 16%). Using the nomogram, a NPV greater than 90% could be obtained, which would be associated with a clinically meaningful reduction of the SNB rate and an acceptable error rate. If validated in large prospective series, this tool might be implemented in the clinical setting for SNB patient selection. PMID- 21683545 TI - Optimization of portal placement for endoscopic calcaneoplasty. AB - PURPOSE: The purpose of our study was to determine an anatomic landmark to help locate portals in endoscopic calcaneoplasty. METHODS: The device for optimal portal placement (DOPP) was developed to measure the distance from the distal fibula tip to the calcaneus (DFC) in 28 volunteers to determine the location of the posterosuperior calcaneal border in relation to this line. RESULTS: The DOPP showed an interobserver reliability of 0.99 (95% confidence interval, 0.97 to 0.99). We found that portals should be placed at a mean of 15 mm (SD, 4.5 mm) distal to the tip of the fibula in patients with flat feet, at a mean of 20 mm (SD, 4.8 mm) in normal feet, and at a mean of 22 mm (SD, 5.4 mm) in cavus feet. The difference in the DFC within the 3 different foot type groups was significant (P < .05). CONCLUSIONS: The DOPP was shown to be highly reliable in measuring the DFC (intraclass coefficient, 0.99). A numeric distance scale for use in all different foot morphologies could not be constructed. There is a direct relation between portal location and foot morphology (P < .05): in flat feet the portal location is significantly more proximal (15 mm) to the tip of the fibula when compared with cavus feet (22 mm). CLINICAL RELEVANCE: These results may help with portal placement in endoscopic calcaneoplasty for all different foot morphologies. PMID- 21683546 TI - A catastrophic complication of hip arthroscopy. AB - We present the case of an unusual and serious complication of hip arthroscopy due to the severance of the inferior gluteal artery. The lesion induced a severe anemic condition and the formation of a large pseudoaneurysm, which compressed the sciatic nerve and left permanent neurologic sequelae. To our knowledge, this is the first reported case of its kind. We also describe how to establish a safe posterior hip joint arthroscopic portal to avoid such a complication. PMID- 21683548 TI - The Egyptian technique revisited (Sersar-Mansoura technique). How to remove some inhaled foreign bodies through rigid bronchoscopy without using a forceps. PMID- 21683547 TI - Regional differential expression of TREK-1 at left ventricle in myocardial infarction. AB - BACKGROUND: Altered membrane electrophysiology contributes to arrhythmias after myocardial infarction (MI). TREK-1 channel is essential in various physiological and pathological conditions through its regulation on resting membrane potential and voltage-dependent action potential duration. OBJECTIVES: The aim of this study was to investigate changes in gene expression and electrophysiology of TREK 1 in the left ventricle in a MI model. METHODS: Fifty-five rats were divided into 5 groups: sham-operated group, 6 hours, 24 hours, 3 days, and 7 days post MI group (n=11 per group). TREK-1 messenger RNA (mRNA) expression level in the infarct region (IR) and infarct border region (IBR) were quantified by real-time polymerase chain reaction (PCR), and TREK-1 current density at the IBR was recorded with whole-cell patch-clamp technique. RESULTS: TREK-1 mRNA expression decreased significantly in both endocardial and epicardial cells in the infarct region after MI. Conversely, TREK-1 increased significantly in endocardial and epicardial cells from the IBR (P<0.01). Current density of TREK-1 at IBR increased significantly in both epicardial and endocardial cells after MI (P<0.01). CONCLUSIONS: TREK-1 demonstrates specific changes in expression and electrophysiological function in left ventricle post MI. These results suggest that TREK-1 may participate in pathophysiologic alteration and electrical remodelling of left ventricular myocardium after MI, which may eventually lead to post-MI ventricular arrhythmias. PMID- 21683549 TI - Dendritic gates for signal integration with excitability-dependent responsiveness. AB - The shape and excitability of neuronal dendrites are expected to be responsible for the functional characteristics of information processing in the brain. In the present study, we proposed that excitable media with branching patterns mimicked the multi-signal integration of neuronal computation. We initially examined the conditions of the coincidence detection of two inputs as the simplest form of signal integration. We considered a gate with two channels that was bound by a circular joint with uniform excitability and demonstrated that the time window for the coincidence detection was controlled by the geometry and excitability of the gate. The functions of the gate were due to the unique property of the excitation waves, known as the curvature effect. The expanded spatial spread diluted the incoming excitation signals to insufficient levels to sustain wave advancement. Next, we applied dendritic gates that were reminiscent of neuronal dendrites for multi-signal integration. The irregular dendritic patterns were produced by a cellular automaton model of self-organizing pattern formation that adopted the semi-random grid in numerical simulations. We demonstrated that the threshold operation for multiple inputs was conducted by the dendritic pattern. The thresholds varied among gates owing to their irregular patterns, and were adjusted by changing the excitability without changing the gate geometry. The materializable model may provide a novel biomimetic approach for developing fuzzy hardware with adjustable responsiveness. PMID- 21683550 TI - The genetics of autoimmune thyroiditis: the first decade. AB - Most of our current understanding of the genetic predisposition to autoimmune disease can be traced to experiments performed in the decade from 1971 to 1981. Chella David was a key contributor to this research. Many of these early steps came from studies of experimental autoimmune thyroiditis. This model has been especially valuable because essentially the same disease can occur spontaneously in selected strains of animals or can be induced by deliberate immunization. From a genetic point of view, the disease has been investigated in three different species: mice, rats and chickens. The same antigen, thyroglobulin, initiates the disease in all three species. Among the main discoveries were the relationship of autoimmune disease to the major histocompatibility complex (MHC), the interplay of different subregions within the MHC in promoting or retarding development of disease, the differing roles of MHC class II and MHC I class genes in induction and effector phases, respectively, and the cumulative effect of non-MHC genes, each of which represents a small addition to overall susceptibility. Other experiments revealed that genetic differences in thyroglobulin allotypes influence susceptibility to thyroiditis. Thyroid glands differed in different strains in vulnerability to passive transfer of antibody. The first evidence of modulatory genes on the sex-related X chromosome emerged. All of these genetic findings were concurrently translated to the human disease, Hashimoto's thyroiditis, where thyroglobulin is also the initiating antigen. PMID- 21683552 TI - Transferable plasmid-mediated quinolone resistance in association with extended spectrum beta-lactamases and fluoroquinolone-acetylating aminoglycoside-6'-N acetyltransferase in clinical isolates of Vibrio fluvialis. AB - Vibrio fluvialis, which causes cholera-like diarrhoea in humans, is one of the aetiological agents of acute diarrhoea in Kolkata, India, and is resistant to many antimicrobial agents. Two V. fluvialis isolates resistant to fluoroquinolones and beta-lactam antimicrobials were found to have mutations in the quinolone resistance-determining regions (QRDRs) of GyrA at position 83 and of ParC at position 85 as well as carrying a 150 kb plasmid harbouring the quinolone resistance gene qnrA1, the ciprofloxacin-modifying enzyme-encoding gene aac(6')-Ib-cr and genes encoding for extended-spectrum beta-lactamases such as bla(SHV) and bla(CTX-M-3). When this large plasmid was transferred to Escherichia coli by conjugation, the transconjugants showed a 10-75-fold increase in the minimum inhibitory concentrations of ciprofloxacin and norfloxacin. The qnrA1 gene was identified in a complex sul1-type integron in a plasmid of the transconjugants. Southern hybridisation and sequence analysis of qnrA1 and its flanking regions confirmed the presence of aac(6')-Ib-cr and bla(CTX-M-3) but these were not associated with the sul1-type integron. Pulsed-field gel electrophoresis (PFGE) revealed that the two V. fluvialis isolates belonged to different clones. Although the presence of many qnr alleles has been reported amongst enteric bacteria in Asian countries, this is the first report on the emergence of qnrA1 in India. qnrA1 along with aac(6')-Ib-cr and bla(CTX-M-3) genes on a mobile plasmid may spread to other bacterial species that are under the selective pressure of fluoroquinolones and beta-lactam antimicrobials in this region. PMID- 21683551 TI - Efficacy of HLA-DRB1*03:01 and H2E transgenic mouse strains to correlate pathogenic thyroglobulin epitopes for autoimmune thyroiditis. AB - Thyroglobulin (Tg), a homodimer of 660 kD comprising 2748 amino acids, is the largest autoantigen known. The prevalence of autoimmune thyroid disease, including Hashimoto's thyroiditis and Graves' disease, has provided the impetus for identifying pathogenic T cell epitopes from human Tg over two decades. With no known dominant epitopes, the search has long been a challenge for investigators. After identifying HLA-DRB1*03:01 (HLA-DR3) and H2E(b) as susceptibility alleles for Tg-induced experimental autoimmune thyroiditis in transgenic mouse strains, we searched for naturally processed T cell epitopes with MHC class II-binding motif anchors and tested the selected peptides for pathogenicity in these mice. The thyroiditogenicity of one peptide, hTg2079, was confirmed in DR3 transgenic mice and corroborated in clinical studies. In H2E(b) expressing transgenic mice, we identified three T cell epitopes from mouse Tg, mTg179, mTg409 and mTg2342, based on homology to epitopes hTg179, hTg410 and hTg2344, respectively, which we and others have found stimulatory or pathogenic in both DR3- and H2E-expressing mice. The high homology among these peptides with shared presentation by DR3, H2E(b) and H2E(k) molecules led us to examine the binding pocket residues of these class II molecules. Their similar binding characteristics help explain the pathogenic capacity of these T cell epitopes. Our approach of using appropriate human and murine MHC class II transgenic mice, combined with the synthesis and testing of potential pathogenic Tg peptides predicted from computational models of MHC-binding motifs, should continue to provide insights into human autoimmune thyroid disease. PMID- 21683553 TI - Clinical and economic burden of community-acquired pneumonia amongst adults in the Asia-Pacific region. AB - Community-acquired pneumonia (CAP) is an important cause of mortality and morbidity amongst adults in the Asia-Pacific region. Literature published between 1990 and May 2010 on the clinical and economic burden of CAP amongst adults in this region was reviewed. CAP is a significant health burden with significant economic impact in this region. Chronic obstructive pulmonary disease, cardiovascular disease, diabetes mellitus and advanced age were risk factors for CAP. Aetiological agents included Streptococcus pneumoniae, Klebsiella pneumoniae, Gram-negative bacteria, Mycobacterium tuberculosis, Burkholderia pseudomallei, Staphylococcus aureus and atypical pathogens (Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella spp.), with important differences in the prevalence of these pathogens within the region. Antibiotic resistance was significant but was not linked to excess mortality. Aetiological pathogens remained susceptible to newer antimicrobial agents. Rational antibiotic use is essential for preventing resistance, and increased surveillance is required to identify future trends in incidence and aetiology and to drive treatment and prevention strategies. PMID- 21683554 TI - Time-dependent effect analysis of antipsychotic treatment in a naturalistic cohort study of patients with schizophrenia. AB - OBJECTIVE: Evidence based treatment of schizophrenia as well as antipsychotic drug utility patterns have changed considerably in recent years and the present study aims to investigate the current level of unplanned hospital readmissions in a cohort of patients with schizophrenia, and to determine the risk-reducing effects of current antipsychotic drug treatment. METHOD: An open cohort study included all consecutively discharged patients with schizophrenia in a 3-year period (n=277). The treatment-dependent variables were entered in a multivariate Cox survival analyses with time to unplanned readmission as the dependent variable. RESULTS: 11.2% of patients were readmitted within 30 days of discharge, and 44.8% were readmitted within 12 months. Antipsychotic monotherapy reduced the risk of readmission by 74.9%. Treatment in CMHC also had a risk-reducing effect. The prescription rate of clozapine in this sample was 10.1%. DISCUSSION: The over all level of unplanned readmissions was in correspondence with the findings of others. Current antipsychotic drug treatment independently offers strong protection against unplanned readmissions. There may be a potential for further optimalizing antipsychotic drug treatment according to treatment guidelines. CONCLUSIONS: Unplanned readmissions are very common for patients with schizophrenia but antipsychotic drug treatment is associated with a strong risk reducing effect in this regard. PMID- 21683555 TI - Neurochemical alteration in the caudate: implications for the pathophysiology of bipolar disorder. AB - Several lines of evidence suggest that the neuropathophysiology of bipolar disorder is marked by structural and functional abnormalities in the caudate. We used magnetic resonance spectroscopy imaging (MRSI) to examine potential neurochemical changes in the caudate of adult bipolar patients (BP). 2D-MRSI scans including the caudate were obtained from 25 BP and 9 healthy subjects (HS). BP patients were further divided into medicated (n=14) and unmedicated (n=11) groups; the majority of medicated patients received atypical antipsychotics (AAP). Ratios of Cr/Cho, Cho/NAA and Cr/NAA in the caudate were compared between groups, controlling for age, gender and gray/white ratio. BP and HS did not significantly differ on any ratios. The Cr/Cho ratio, however, was significantly greater in medicated BP compared to HS. Conversely, the Cho/NAA ratio was non significantly lower in medicated BP vs. HS. Medicated BP also showed significantly greater Cr/Cho and significantly smaller Cho/NAA ratios than unmedicated BP. Although we did not observe significant overall differences between BP and HS, our findings suggest the presence of reduced choline levels in the caudate of medicated BP receiving AAP. While speculative, these results suggest that AAP do not cause oxidative injury to neuronal membranes. PMID- 21683557 TI - WITHDRAWN: Biosynthesis of silver nanoparticles: Parameter optimization using response surface method. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21683556 TI - Changes in brain anatomy during the course of posttraumatic stress disorder. AB - The goal of this study was to determine whether posttraumatic stress disorder (PTSD) was associated with an increase in time-related decline in macrostructural brain volume and whether these changes were associated with accelerated cognitive decline. To quantify brain structure, three-dimensional T1-weighted MRI scans were performed at baseline and again after a minimum of 24months in 25 patients with PTSD (PTSD+) and 22 controls (PTSD-). Longitudinal changes in brain volume were measured using deformation morphometry. For the group as a whole, PTSD+ patients did not show significant ongoing brain atrophy compared to PTSD-. PTSD+ patients were then subgrouped into those with decreasing or increasing symptoms. We found little evidence for brain markers of accelerated atrophy in PTSD+ veterans whose symptoms improved over time, with only a small left parietal region showing greater ongoing tissue loss than PTSD-. PTSD patients whose symptoms increased over time showed accelerated atrophy throughout the brain, particularly brainstem and frontal and temporal lobes. Lastly, for the sample as a whole, greater rates of brain atrophy were associated with greater rates of decline in verbal memory and delayed facial recognition. PMID- 21683558 TI - Selective determination of 3,4-dihydroxyphenylacetic acid in the presence of ascorbic acid using 4-(dimethylamino)pyridine capped gold nanoparticles immobilized on gold electrode. AB - 4-(Dimethylamino)pyridine capped gold nanoparticles (DMAP-AuNPs) were synthesized in aqueous medium and then immobilized on 1,6-hexanedithiol (HDT) modified Au electrode for the selective determination of 3,4-dihydroxyphenylacetic acid (DOPAC) in the presence of ascorbic acid (AA). The synthesized DMAP-AuNPs were characterized by UV-visible spectroscopy and high resolution-transmission electron microscopy (HR-TEM). The HR-TEM images showed that the nanoparticles are spherical in shape with a diameter of ~12 nm. The DMAP-AuNPs immobilized on HDT modified electrode was characterized by cyclic voltammetry and impedance spectroscopy. Impedance spectra show that the electron transfer reaction was more facile at the AuNPs modified electrode when compared to bare and HDT modified Au electrodes. The application of DMAP-AuNPs modified electrode was demonstrated by selective determination of DOPAC in the presence of high concentration of AA at pH 4. Using amperometry method, 40 nM detection of each AA and DOPAC was achieved. The current response was increased linearly with increasing AA and DOPAC in the concentration range of 40*10(-9) to 10*10(-5) M and a detection limit was found to be 5.6*10(-10) M and 3.7*10(-10) M (S/N=3) for AA and DOPAC, respectively. The present modified electrode was also successfully used for the determination of 40 nM DOPAC in the presence of 2500-fold excess of common interferents such as Na(+), Mg(2+), Cu(2+), Ca(2+), NH(4)(+) urea and glucose. PMID- 21683559 TI - Fabrication strategy for amphiphilic microcapsules with narrow size distribution by premix membrane emulsification. AB - Amphiphilic co-polymer, which can maintain the stability of proteins and increase the protein loading efficiency, is considered as an exploring-worthy biodegrade polymer for drug delivery. However, amphiphilic microcapsules prepared by conventional methods, such like mechanical stirring and spray-drying methods, exhibit broad size distributions due to its hydrophilic sequences, leading to poor reproducibility. In this study, we employed poly(monomethoxypoly ethylene glycol-co-D,L-lactide) (mPEG-PLA, PELA), one of common amphiphilic polymers, as model to focus on investigating the process parameters and mechanisms to prepare PELA microcapsules with narrow size distribution and regular sphericity by combining premix membrane emulsification and double emulsion technique. The coarse double emulsion with broad size distribution was repeatedly pressed through Shirasu Porous Glass (SPG) membrane with relatively high pressure to form the fine emulsion with narrow size distribution. Then, the microcapsules with narrow size distribution can be obtained by solvent extraction method. It was found that it was more difficult to obtain PELA microcapsules with narrow size distribution and smooth surface due to its amphiphilic property, compared with the cases of PLA and PLGA. The smooth surface morphology was found to be related to several factors including internal water phase with less volume, slower stirring rate during solidification and using ethyl acetate as oil phase. It was also found that mass ratio of hydrophilic mPEG, stabilizer PVA concentration in external water phase and transmembrane pressure played important role on the distribution of microcapsules size. The suitable preparation conditions were determined as follows: for the membrane with pore size of 2.8 MUm, the mass ratio of PLA/mPEG was 19:1, volume ratio of W(1)/O was 1:10 and O/W(2) was 1:5, PVA concentration (w/v) was 1.0%, magnetic stirring rate during solidification was 60 rpm and 300 kPa was chosen as transmembrane pressure. There was a linear relationship between the diameter of microcapsules and the pore size of the membranes. Finally, by manipulating the process parameters, PELA microcapsules with narrow size distributions (coefficient of variation was less than 15%), smooth morphology and various sizes, were obtained. Most importantly, the key factors affecting fabrication have been revealed and mechanisms were illustrated in detail, which would shed light on the research of amphiphilic polymer formulation. PMID- 21683561 TI - Increasing rates of head melanoma in Nordic countries. PMID- 21683560 TI - Water soluble carbon nanoparticles: hydrothermal synthesis and excellent photoluminescence properties. AB - Water-soluble carbon nanoparticles (CNPs) were fabricated by a facile, one step hydrothermal synthetic route using acid/alkali as additives. These CNPs emit bright photoluminescence (PL) covering the entire visible-near infrared (NIR) spectral range. PL measurements confirmed that the CNPs have up-conversion of PL properties, and that the NIR PL of the CNPs can also be observed by NIR excitation. Control experiments indicated that different additives can strongly affect the PL properties of the CNPs. With a combination of free dispersion in water and attractive PL properties, these CNPs hold promise for applications in nanotechnology. PMID- 21683562 TI - [Child food refusal: when will we call a child psychiatrist?]. AB - Food refusal is a frequent symptom in infants and toddlers. Many difficulties resolve with pediatric treatment. In some cases of feeding disorders it is necessary to involve child psychiatrist intervention. This indication depends of child characteristics (medical and psychiatric diagnosis, failure to thrive, psycho-affective development) and also of family functioning and parental psychopathology. PMID- 21683563 TI - Feasibility of case-based beam generation for robotic radiosurgery. AB - OBJECTIVE: Robotic radiosurgery uses the kinematic flexibility of a robotic arm to target tumors and lesions from many different directions. This approach allows to focus the dose to the target region while sparing healthy surrounding tissue. However, the flexibility in the placement of treatment beams is also a challenge during treatment planning. We study an approach to make the search for treatment beams more efficient by considering previous treatment plans. METHODS AND MATERIAL: Conventionally, a beam generation heuristic based on randomly selected candidate beams has been proven to be most robust in clinical practice. However, for prevalent types of cancer similarities in patient anatomy and dose prescription exist. We present a case-based approach that introduces a problem specific measure of similarity and allows to generate candidate beams from a database of previous treatment plans. Similarity between treatments is established based on projections of the organs and structures considered during planning, and the desired dose distribution. Solving the inverse planning problem a subset of treatment beams is determined and adapted to the new clinical case. RESULTS: Preliminary experimental results indicate that the new approach leads to comparable plan quality for substantially fewer candidate beams. For two prostate cases, the dose homogeneity in the target region and the sparing of critical structures is similar for plans based on 400 and 600 candidate beams generated with the novel and the conventional method, respectively. However, the runtime for solving the inverse planning problem for could be reduced by up to 47%, i.e., from approximately 19 min to less than 11 min. CONCLUSION: We have shown the feasibility of case-based beam generation for robotic radiosurgery. For prevalent clinical cases with similar anatomy the cased-based approach could substantially reduce planning time while maintaining high plan quality. PMID- 21683564 TI - Mechanisms of cancer-induced bone pain. AB - Cancer-induced bone pain (CIBP) is common and challenging to treat. Common therapies, such as opioids, radiotherapy and bisphosphonates, are often only partially effective. CIBP is a different entity to inflammatory or neuropathic pain and needs to be considered as such. This overview examines the mechanisms of CIBP; the imbalance of bone turnover, peripheral and central nervous involvement and key neurochemical mediators. The current understanding of the underlying pathophysiology of CIBP is discussed. PMID- 21683565 TI - Effects of cuticle structure and crystalline wax coverage on the coloration in young and old males of Calopteryx splendens and Calopteryx virgo. AB - Male secondary sexual characters, such as color patterns, are often investigated at the macroscale level. However, micro- and nanoscale levels of morphological investigations may reveal functional features responsible for a particular coloration, thus providing more information, e.g., about the condition dependence of male sexual characters. The aim of this paper was to investigate cuticle color and its structure in males of two congeneric damselfly species, Calopteryx splendens and Calopteryx virgo, and reveal possible color changes with age. According to spectrometer measurements, C. splendens males were bluer and had a greater saturation of blue in their abdomen than C. virgo males, which were, in turn, greener and had more green saturation. Although the two species differed in the number of structural layers and the spacing of the layers, it seems that intactness of the wax crystals covering the epicuticle was most often the morphological trait which was related to the color parameters measured from males' cuticles. The effect of the crystalline wax coverage on cuticle color was also confirmed by removing the wax using chloroform: after the treatment, the hue was bluer, the cuticle had a greater brightness and greater blue saturation, but less green saturation. Age differences influencing the color and structure of the cuticle were also observed: older males had more blue and green saturation and had more intact wax coverage than did younger males. Although multilayer reflection should be responsible for the iridescent color of males, our results suggest that wax coverage plays an important role in the color tuning of the male cuticle. This may have a considerable signal function, indicating the males' viability to competing males or to females. PMID- 21683566 TI - A preliminary categorization of end-of-life electrical and electronic equipment as secondary metal resources. AB - End-of-life electrical and electronic equipment (EEE) has recently received attention as a secondary source of metals. This study examined characteristics of end-of-life EEE as secondary metal resources to consider efficient collection and metal recovery systems according to the specific metals and types of EEE. We constructed an analogy between natural resource development and metal recovery from end-of-life EEE and found that metal content and total annual amount of metal contained in each type of end-of-life EEE should be considered in secondary resource development, as well as the collectability of the end-of-life products. We then categorized 21 EEE types into five groups and discussed their potential as secondary metal resources. Refrigerators, washing machines, air conditioners, and CRT TVs were evaluated as the most important sources of common metals, and personal computers, mobile phones, and video games were evaluated as the most important sources of precious metals. Several types of small digital equipment were also identified as important sources of precious metals; however, mid-size information and communication technology (ICT) equipment (e.g., printers and fax machines) and audio/video equipment were shown to be more important as a source of a variety of less common metals. The physical collectability of each type of EEE was roughly characterized by unit size and number of end-of-life products generated annually. Current collection systems in Japan were examined and potentially appropriate collection methods were suggested for equipment types that currently have no specific collection systems in Japan, particularly for video games, notebook computers, and mid-size ICT and audio/video equipment. PMID- 21683567 TI - Liberation characteristic and physical separation of printed circuit board (PCB). AB - Recycling of printed circuit board (PCB) is an important subject and to which increasing attention is paid, both in treatment of waste as well as recovery of valuable material terms. Precede physical and mechanical method, a good liberation is the premise to further separation. In this study, two-step crushing process is employed, and standard sieve is applied to screen crushed material to different size fractions, moreover, the liberation situation and particles shape in different size are observed. Then metal of the PCB is separated by physical methods, including pneumatic separation, electrostatic separation and magnetic separation, and major metal contents are characterized by inductively coupled plasma emission spectrometry (ICP-AES). Results show that the metal and nonmetal particles of PCB are dissociated completely under the crush size 0.6mm; metal is mainly enriched in the four size fractions between 0.15 and 1.25 mm; relatively, pneumatic separation is suitable for 0.6-0.9 mm size fraction, while the electrostatic separation is suitable for three size fractions that are 0.15 0.3mm, 0.3-0.6mm and 0.9-1.25 mm. The whole process that involves crushing, electrostatic and magnetic separation has formed a closed cycle that can return material and provide salable product. PMID- 21683569 TI - The strategy of signal amplification for ultrasensitive detection of hIgE based on aptamer-modified poly(di-acetylene) supramolecules. AB - Herein, we demonstrate three strategies of signal amplification for ultrasensitive detection of human immunoglobulin E (hIgE) based on poly(di acetylene) supramolecules. To fabricate the ultrasensitive PDA biosensor, ethylenediamine as an interlinker and aptamer as a receptor were introduced into the chip fabrication process. Using the prepared PDA liposome biosensor, the hIgE could be detected up to below 1.0 ng/ml by a primary response. In order to accomplish more ultrasensitive detection of protein on a PDA biosensor, polyclonal hIgE antibody was employed as an external mechanical force for the inducement of a secondary response. As a result, a PDA liposome biosensor sensitivity as high as 0.01 ng/ml for the target hIgE was obtained, with a sensitivity which is one hundred times of that of the method without signal amplification. These results indicate that the proposed strategies were capable of ultrasensitive quantitative and qualitative analyses of biomolecules without non-specific binding of non-target proteins. PMID- 21683568 TI - Myoglobin-biomimetic electroactive materials made by surface molecular imprinting on silica beads and their use as ionophores in polymeric membranes for potentiometric transduction. AB - Myoglobin (Mb) is among the cardiac biomarkers playing a major role in urgent diagnosis of cardiovascular diseases. Its monitoring in point-of-care is therefore fundamental. Pursuing this goal, a novel biomimetic ionophore for the potentiometric transduction of Mb is presented. It was synthesized by surface molecular imprinting (SMI) with the purpose of developing highly efficient sensor layers for near-stereochemical recognition of Mb. The template (Mb) was imprinted on a silane surface that was covalently attached to silica beads by means of self assembled monolayers. First the silica was modified with an external layer of aldehyde groups. Then, Mb was attached by reaction with its amine groups (on the external surface) and subsequent formation of imine bonds. The vacant places surrounding Mb were filled by polymerization of the silane monomers 3 aminopropyltrimethoxysilane (APTMS) and propyltrimethoxysilane (PTMS). Finally, the template was removed by imine cleavage after treatment with oxalic acid. The results materials were finely dispersed in plasticized PVC selective membranes and used as ionophores in potentiometric transduction. The best analytical features were found in HEPES buffer of pH 4. Under this condition, the limits of detection were of 1.3 * 10(-6)mol/L for a linear response after 8.0 * 10(-7) mol/L with an anionic slope of -65.9 mV/decade. The imprinting effect was tested by preparing non-imprinted (NI) particles and employing these materials as ionophores. The resulting membranes showed no ability to detect Mb. Good selectivity was observed towards creatinine, sacarose, fructose, galactose, sodium glutamate, and alanine. The analytical application was conducted successfully and showed accurate and precise results. PMID- 21683570 TI - Classification and prediction of rice wines with different marked ages by using a voltammetric electronic tongue. AB - A voltammetric electronic tongue (VE-tongue) was developed to discriminate the difference between Chinese rice wines in this research. Three types of Chinese rice wine with different marked ages (1, 3, and 5 years) were classified by the VE-tongue by principal component analysis (PCA) and cluster analysis (CA). The VE tongue consisted of six working electrodes (gold, silver, platinum, palladium, tungsten, and titanium) in a standard three-electrode configuration. The multi frequency large amplitude pulse voltammetry (MLAPV), which consisted of four segments of 1 Hz, 10 Hz, 100 Hz, and 1000 Hz, was applied as the potential waveform. The three types of Chinese rice wine could be classified accurately by PCA and CA, and some interesting regularity is shown in the score plots with the help of PCA. Two regression models, partial least squares (PLS) and back-error propagation-artificial neural network (BP-ANN), were used for wine age prediction. The regression results showed that the marked ages of the three types of Chinese rice wine were successfully predicted using PLS and BP-ANN. PMID- 21683571 TI - An electrochemical impedance spectroscopy (EIS) assay measuring the calcification inhibition capacity in biological fluids. AB - Pathological calcification of the cardiovascular system is one of the major causes of high mortality and morbidity in dialysis patients. The inhibition of ectopic calcification relies (I) on the formation of calciprotein particles (CPPs), nanospherical complexes of calcium phosphate mineral, fetuin-A and other acidic serum proteins, and (II) on the stabilization of calcium phosphate prenucleation clusters by fetuin-A monomers. In supersaturated serum, mineral ion aggregation leads to a change in the electrical impedance. In this work, we present a method based on electrochemical impedance spectroscopy (EIS) to establish an impedance trace of mineral ion clustering in vitro. In the presence of 20 MUM of serum protein fetuin-A, a prototypic calcification inhibitor, we measured a change in impedance (Delta(R)) of 195.52 +/- 27.78%Omega compared to 430.41 +/- 11.36%Omega in inhibitor-free samples. We also identified a CPP formation dependency on the actual content of ions and protein in the samples under investigation. Two-step ripening of CPP was also observed. The presented method may form the basis of a simple label-free bedside or online test to be used in routine clinical practice for estimating the calcification risk in serum. PMID- 21683572 TI - Recent advances in graphene-based biosensors. AB - A detailed overview towards the advancement of graphene based biosensors has been reviewed. The large surface area and excellent electrical conductivity of graphene allow it to act as an "electron wire" between the redox centers of an enzyme or protein and an electrode's surface. Rapid electron transfer facilitates accurate and selective detection of biomolecules. This review discusses the application of graphene for the detection of glucose, Cyt-c, NADH, Hb, cholesterol, AA, UA, DA, and H(2)O(2). GO and RGO have been used for the fabrication of heavy metal ion sensors, gas sensors, and DNA sensors. Graphene based FETs have also been discussed in details. In all these cases, the biosensors performed well with low working potentials, high sensitivities, low detection limits, and long-term stabilities. PMID- 21683573 TI - Current state of biotechnology in Turkey. AB - Biotechnology is an interdisciplinary branch of science that encompasses a wide range of subjects like genetics, virology, microbiology, immunology, engineering to develop vaccines, and so on and plays a vital role in health systems, crop and seed management, yield improvement, agriculture, soil management, ecology, animal farming, cellular process, bio statistics, and so on. This article is about activities in medical and pharmaceutical biotechnology, environmental biotechnology, agricultural biotechnology and nanobiotechnology carried out in Turkey. Turkey has made some progress in biotechnology projects for research and development. PMID- 21683574 TI - Efficient computation via sparse coding in electrosensory neural networks. AB - The electric sense combines spatial aspects of vision and touch with temporal features of audition. Its accessible neural architecture shares similarities with mammalian sensory systems and allows for recordings from successive brain areas to test hypotheses about neural coding. Further, electrosensory stimuli encountered during prey capture, navigation, and communication, can be readily synthesized in the laboratory. These features enable analyses of the neural circuitry that reveal general principles of encoding and decoding, such as segregation of information into separate streams and neural response sparsification. A systems level understanding arises via linkage between cellular differentiation and network architecture, revealed by in vitro and in vivo analyses, while computational modeling reveals how single cell dynamics and connectivity shape the sparsification process. PMID- 21683576 TI - Overexpression of matrix metalloproteinase-12 (MMP-12) correlates with poor prognosis of hepatocellular carcinoma. AB - Tumour recurrence and metastasis are pressing issues of hepatocellular carcinoma (HCC) patients who receive surgical treatments. Matrix metalloproteinase-12 (MMP 12), previously identified from our animal model, is involved in tumour invasiveness of rat hepatoma. We aimed to investigate the significance and prognostic value of MMP-12 expression in human HCC. MMP-12 mRNA level of 139 pairs of tumour and non-tumour liver tissues of HCC patients after hepatectomy were investigated by quantitative real-time RT-PCR. MMP-12 mRNA was significantly elevated in tumour liver tissues of HCC patients compared to non-tumour and normal liver tissues. By comparing paired tumour and non-tumour liver tissues, MMP-12 mRNA was overexpressed in 58% of tumour tissue of HCC patients. Overexpression of MMP-12 mRNA was significantly correlated with presence of venous infiltration (p=0.004), high serum AFP level (p=0.012), early tumour recurrence (p=0.018) and poor overall survival (p=0.02) of HCC patients. Moreover, MMP-12 mRNA was an independent factor in predicting the 1- and 3-year overall survival of HCC patients after hepatectomy. Our data demonstrated that MMP-12 mRNA may be a valuable prognostic marker for both overall survival and tumour recurrence of HCC patients after liver resection. PMID- 21683575 TI - Spikes alone do not behavior make: why neuroscience needs biomechanics. AB - Neural circuits do not function in isolation; they interact with the physical world, accepting sensory inputs and producing outputs via muscles. Since both these pathways are constrained by physics, the activity of neural circuits can only be understood by considering biomechanics of muscles, bodies, and the exterior world. We discuss how animal bodies have natural stable motions that require relatively little activation or control from the nervous system. The nervous system can substantially alter these motions, by subtly changing mechanical properties such as body or leg stiffness. Mechanics can also provide robustness to perturbations without sensory reflexes. By considering a complete neuromechanical system, neuroscientists and biomechanicians together can provide a more integrated view of neural circuitry and behavior. PMID- 21683577 TI - Regulation of the organic pollution level in anaerobic digesters by using off line COD measurements. AB - A sampled delayed scheme is proposed to regulate the organic pollution level in anaerobic digestion processes by using off-line COD measurements. The proposed scheme is obtained by combining an error feedback control with a steady state estimator to track constant references and attenuate process load disturbances. The controller performance is tested experimentally for the treatment of tequila vinasses over a period of 68days under different set-point values and several uncertain scenarios which include badly known kinetic parameters and load disturbances. Experimental results show that the COD concentration can be effectively regulated under the influence of set-point changes and high load disturbances by using only a daily off-line COD measurement, which makes the industrial application of the proposed control scheme feasible. PMID- 21683578 TI - Whole-cell oxidation of omeprazole sulfide to enantiopure esomeprazole with Lysinibacillus sp. B71. AB - Production of enantiopure esomeprazole by biocatalysis is of great demand by pharmaceutical industry. A Gram-positive bacterium oxidizing omeprazole sulfide 1a (5-methoxy-2-[((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio]-1H benzoimidazole) to (S)-sulfoxide esomeprazole 2a (S)-5-methoxy-2-[(4-methoxy-3,5 dimethylpyridin-2-yl) methylsulfinyl]-3H-benzoimidazole was isolated from soil polluted with elemental sulfur. The strain exhibited the highest identity with the genus Lysinibacillus and catalyzed oxidation of 1a into enantiopure esomeprazole with conversion of 77% in a stirred bioreactor, fed-batch culture. No consecutive oxidation of (S)-sulfoxide to sulfone was observed during whole cell catalysis. The unique characteristics of the catalyst provide a solid basis for further improvement and development of sustainable green bioprocess. PMID- 21683579 TI - Conversion for Avicel and AFEX pretreated corn stover by Clostridium thermocellum and simultaneous saccharification and fermentation: insights into microbial conversion of pretreated cellulosic biomass. AB - In this study, efforts were taken to compare solubilization of Avicel and AFEX pretreated corn stover (AFEX CS) by SSF and Clostridium thermocellum fermentation, with an aim to gain insights into microbial conversion of pretreated cellulosic biomass. Solubilization rates for AFEX CS are comparable for the two systems while solubilization of Avicel is much faster by C. thermocellum. Initial catalyst loading impacts final cellulose conversion for SSF but not for C. thermocellum. Hydrolysis of the two substrates using cell-free C. thermocellum fermentation broth revealed much smaller difference in cellulose conversion than the difference observed for growing cultures. Tests on hemicellulose removal and particle size reduction for AFEX CS indicated that substrate accessibility is very important for enhanced solubilization by C. thermocellum. PMID- 21683580 TI - Assessment of a bioaugmentation strategy with polyphosphate accumulating organisms in a nitrification/denitrification sequencing batch reactor. AB - Different alternative configurations and strategies for the simultaneous biological removal of organic matter and nutrients (N and P) in wastewater have been proposed in the literature. This work demonstrates a new successful strategy to bring in enhanced biological phosphorus removal (EBPR) to a conventional nitrification/denitrification system by means of bioaugmentation with an enriched culture of phosphorus accumulating organisms (PAO). This strategy was tested in a sequencing batch reactor (SBR), where an 8h configuration with 3h anoxic, 4.5h aerobic and 25 min of settling confirmed that nitrification, denitrification and PAO activity could be maintained for a minimum of 60 days of operation after the bioaugmentation step. The successful bioaugmentation strategy opens new possibilities for retrofitting full-scale WWTP originally designed for only nitrification/denitrification. These systems could remove P simultaneously to COD and N if they were bioaugmented with waste purge of an anaerobic/aerobic SBR operated in parallel treating part of the influent wastewater. PMID- 21683581 TI - Wavelength specificity of growth, photosynthesis, and hydrocarbon production in the oil-producing green alga Botryococcus braunii. AB - The effect of monochromatic light on growth, photosynthesis, and hydrocarbon production was tested in Botryococcus braunii Bot-144 (race B), which produces triterpenoid hydrocarbons. The growth was higher in order of red, blue, and green light. The color of red light-grown cells became more orange-yellow and their shape dominantly changed to grape-like with long branches. Photosynthetic carbon fixation activity was higher in order of blue, red, and green light-grown cells, but photosystem activities showed no difference. In the pulse-chase experiments with (14)CO(2), no major difference was observed in the production of lipids, hydrocarbons, polysaccharides, or proteins among the three kinds of cells, although hydrocarbon production was slightly lower in green light-grown cells. These results indicate that blue and red light were more effective for growth, photosynthetic CO(2) fixation, and hydrocarbon production than green light, and that red light is the most efficient light source when calculated based on photoenergy supplied. PMID- 21683582 TI - Industrial yeast strain engineered to ferment ethanol from lignocellulosic biomass. AB - In this study an industrial Saccharomyces cerevisiae yeast strain capable of fermenting ethanol from pretreated lignocellulosic material was engineered. Genes encoding cellulases (endoglucanase, exoglucanase and beta-glucosidase) were integrated into the chromosomal ribosomal DNA and delta regions of a derivative of the K1-V1116 wine yeast strain. The engineered cellulolytic yeast produces ethanol in one step through simultaneous saccharification and fermentation of pretreated biomass without the addition of exogenously produced enzymes. When ethanol fermentation was performed with 10% dry weight of pretreated corn stover, the recombinant strain fermented 63% of the cellulose in 96 h and the ethanol titer reached 2.6% v/v. These results demonstrate that cellulolytic S. cerevisiae strains can be used as a platform for developing an economical advanced biofuel process. PMID- 21683583 TI - Removal of enzymatic and fermentation inhibitory compounds from biomass slurries for enhanced biorefinery process efficiencies. AB - Within the biorefinery paradigm, many non-monomeric sugar compounds have been shown to be inhibitory to enzymes and microbial organisms that are used for hydrolysis and fermentation. Here, two novel separation technologies, polyelectrolyte polymer adsorption and resin-wafer electrodeionization (RW-EDI), have been evaluated to detoxify a dilute acid pretreated biomass slurry. Results showed that detoxification of a dilute acid pretreated ponderosa pine slurry by sequential polyelectrolyte and RW-EDI treatments was very promising, with significant removal of acetic acid, 5-hydroxymethyl furfural, and furfural (up to 77%, 60%, and 74% removed, respectively) along with >97% removal of sulfuric acid. Removal of these compounds increased the cellulose conversion to 94% and elevated the hydrolysis rate to 0.69 g glucose/L/h. When using Saccharomyces cerevisiae D(5)A for fermentation of detoxified slurry, the process achieved 99% of the maximum theoretical ethanol yield and an ethanol production rate nearly five-times faster than untreated slurry. PMID- 21683584 TI - The effect of hydraulic retention time on the performance and fouling characteristics of membrane sequencing batch reactors used for the treatment of synthetic petroleum refinery wastewater. AB - The use of membrane sequencing batch reactors, operated at HRT of 8, 16 and 24h, was considered for the treatment of a synthetic petroleum wastewater. Increase in HRT resulted in statistically significant decrease in MLSS. Removal efficiencies higher than 97% were found for the three model hydrocarbon pollutants at all HRTs, with air stripping making a small contribution to overall removal. Particle size distribution (PSD) and microscopic analysis showed reduction in the protozoan populations in the activated sludge with decreasing HRT. PSD analysis also showed a higher proportion of larger and smaller sized particles at the lowest HRT. The rate of membrane fouling was found to increase with decreasing HRT; SMP, especially carbohydrate SMP, and mixed liquor apparent viscosity also showed a pronounced increase with decreasing HRT, whereas the concentration of EPS and its components decreased. FTIR analysis identified organic compounds as the main component of membrane pore fouling. PMID- 21683585 TI - Effects of carbonization and solvent-extraction on change in fuel characteristics of sewage sludge. AB - Urban sewage sludge was carbonized at 300-500 degrees C for 1h, and combustible components were extracted through the solvent-extraction process. N-methyl-2 pyrrolidinone (NMP) was used as the solvent for extraction, and the extraction temperature was fixed at 360 degrees C. The atomic ratios of the solvent extracted sludge of CS300 (ECS300) were shown to be 1.04 for H/C and 0.11 for O/C, which represented the characteristics of its coal band. Thus, its coal band was similar to that of a high-rank fuel such as bituminous coal. FT-IR analysis showed that the absorbance band of ECS300 was considerably different from that of dried sludge (RS) or the carbonized sludge at 300 degrees C (CS300) but similar to that of coal, although the ash content absorbance band of 800-1200 cm(-1) was of very low intensity. The combustion profile showed that combustion of ESC300 occurred at a temperature higher than the ignition temperature (T(i)) or maximum weight loss rate (DTG(max)) of coal. PMID- 21683586 TI - Bermuda grass as feedstock for biofuel production: a review. AB - Bermuda grass is a promising feedstock for the production of fuel ethanol in the Southern United States. This paper presents a review of the significant amount of research on the conversion of Bermuda grass to ethanol and a brief discussion on the factors affecting the biomass production in the field. The biggest challenge of biomass conversion comes from the recalcitrance of lignocellulose. A variety of chemical, physico-chemical, and biological pretreatment methods have been investigated to improve the digestibility of Bermuda grass with encouraging results reported. The subsequent enzymatic hydrolysis and fermentation steps have also been extensively studied and effectively optimized. It is expected that the development of genetic engineering technologies for the grass and fermenting organisms has the potential to greatly improve the economic viability of Bermuda grass-based fuel ethanol production systems. Other energy applications of Bermuda grass include anaerobic digestion for biogas generation and pyrolysis for syngas production. PMID- 21683587 TI - Ethanol production from the enzymatic hydrolysis of non-detoxified steam-exploded corn stalk. AB - To reduce water consumption and equipment investment, and simplify the technological process, a Pichia stipitis-adapted strain with improved tolerance against inhibitors and ethanol was used in ethanol production. The steam-exploded corn stalk was directly enzymatically hydrolyzed without detoxification, and then the enzymatic hydrolysate was used as the fermentation substrate. Results from laboratory experiments in shake flasks and fermentation tanks indicated that, after fermentation for 48 h, ethanol concentration reached to 43.42 g/L; the ethanol yield was 0.47 g(p)/g(s), which was 92.16% of the theoretical ethanol yield. The results of the present research demonstrated that the application of this strain avoided detoxification of the steam-pretreated material through washing, thus simplifying the technological process. In addition, the application of the adapted strain reduced water consumption and lowered the equipment investment of ethanol production from corn stalk, which are important factors in further promotion of the development of ethanol production from straw. PMID- 21683588 TI - Production of spent mushroom substrate hydrolysates useful for cultivation of Lactococcus lactis by dilute sulfuric acid, cellulase and xylanase treatment. AB - Spent mushroom substrate (SMS) was treated with dilute sulfuric acid followed by cellulase and xylanase treatment to produce hydrolysates that could be used as the basis for media for the production of value added products. A L9 (3(4)) orthogonal experiment was performed to optimize the acid treatment process. Pretreatment with 6% (w/w) dilute sulfuric acid at 120 degrees C for 120 min provided the highest reducing sugar yield of 267.57 g/kg SMS. No furfural was detected in the hydrolysates. Exposure to 20PFU of cellulase and 200 XU of xylanase per gram of pretreated SMS at 40 degrees C resulted in the release of 79.85 g/kg or reducing sugars per kg acid pretreated SMS. The dilute sulfuric acid could be recycled to process fresh SMS four times. SMS hydrolysates neutralized with ammonium hydroxide, sodium hydroxide, or calcium hydroxide could be used as the carbon source for cultivation of Lactococcus lactis subsp. lactis W28 and a cell density of 2.9*10(11)CFU/mL could be obtained. The results provide a foundation for the development of value-added products based on SMS. PMID- 21683589 TI - Factors in the determination of methanogenic potential of manure. AB - The influence of the substrate concentration, the micro and macro nutrients and buffer requirements, the sludge origin (biomass that is acclimatized or not acclimatized to waste) and the inoculum/substrate ratio (ISR) were studied to determine their effects in the methanogenic potential of turkey manure, which is a solid waste. According to the results obtained, the methane production determination does not require the addition of nutrients (additional to the contents in the waste) and a buffer for this type of assay. The methane yield (gamma(CH) 4) performance is given by the substrate concentration and the sludge origin, therefore it is better to carry out the assay with biomass that is already adapted to the waste. The methanogenic potential of this type of waste is not determined by the amount of sludge and it does not need an external inoculum (external to the waste contents). PMID- 21683590 TI - Production of ferulic acid from lignocellulolytic agricultural biomass by Thermobifida fusca thermostable esterase produced in Yarrowia lipolytica transformant. AB - A gene (axe) encoding the AXE thermostable esterase in Thermobifida fusca NTU22 was cloned into a Yarrowia lipolytica P01g host strain. Recombinant expression resulted in extracellular esterase production at levels as high as 70.94 U/ml in Hinton flask culture broth, approximately 140 times higher than observed in a Pichia pastoris expression system. After 72 h of fermentation by the Y. lipolytica transformant in the fed-batch fermentor, the fermentation broth accumulated 41.11 U/ml esterase activity. Rice bran, wheat bran, bagasse and corncob were used as hydrolysis substrates for the esterase, with corncob giving the best ferulic acid yield. The corncob was incubated with T. fusca xylanase (Tfx) for 12h and then with the AXE esterase for an additional 12h. Ferulic acid accumulated to 396 MUM in the culture broth, a higher concentration than with esterase alone or with Tfx and esterase together for 24 h. PMID- 21683591 TI - Comparative studies on lignin and polycyclic aromatic hydrocarbons degradation by basidiomycetes fungi. AB - A total of 130 wild basidiomycetes fungi were collected and identified. The polycyclic aromatic hydrocarbons (PAHs) degradation by the potential Phellinus sp., Polyporus sulphureus (in liquid state fermentation (LSF), solid state fermentation (SSF), in soil) and lignin biodegradation were compared with those of a bacterial isolate and their corresponding cocultures. The PAHs degradation was higher in LSF and the efficiency of the organisms declined in SSF and in soil treatment. Phellinus sp. showed better degradation in SSF and in soil. Bacillus pumilus showed higher degradation in LSF. B. pumilus was seen to have lower lignin degradation than the fungal cultures and the cocultures could not enhance the degradation. Phellinus sp. which had higher PAHs and lignin degradation showed higher biosurfactant production than other organism. Manganese peroxidase (MnP) was the predominant enzyme in Phellinus sp. while lignin peroxidase (Lip) was predominant in P. sulphureus. PMID- 21683592 TI - Anti-leishmanial activity of disubstituted purines and related pyrazolo[4,3 d]pyrimidines. AB - We report here results of screening directed to finding new anti-leishmanial drugs among 2,6-disubstituted purines and corresponding 3,7-disubstituted pyrazolo[4,3-d]pyrimidines. These compounds have previously been shown to moderately inhibit human cyclin-dependent kinases. Since some compounds reduced viability of axenic amastigotes of Leishmania donovani, we screened them for interaction with recombinant leishmanial cdc-2 related protein kinase (CRK3/CYC6), an important cell cycle regulator of the parasitic protozoan. Eighteen pairs of corresponding isomers were tested for viability of amastigotes and for inhibition of CRK3/CYC6 kinase activity. Some compounds (9A, 12A and 13A) show activity against amastigotes with EC(50) in a range 1.5-12.4MUM. Structure activity relationships for the tested compounds are discussed and related to the lipophilicity of the compounds. PMID- 21683593 TI - New muramyl dipeptide (MDP) mimics without the carbohydrate moiety as potential adjuvant candidates for a therapeutic hepatitis B vaccine (HBV). AB - A series of new muramyl dipeptide (MDP) mimics were designed and synthesized via a solid-phase synthetic route. Their adjuvant activities were evaluated ex vivo for investigation of the synergism of the S(28-39) peptide, which is an MHC class I binding epitope of recombinant hepatitis B surface antigen (HBsAg) for both humans and mice. Several compounds without the carbohydrate moiety exerted better adjuvanticity than the MDP-C that has been reported by our laboratory previously. A primary screening test revealed that compounds 6, 14 and 16 exhibited stronger adjuvanticity compared with other MDP mimics. PMID- 21683594 TI - A study of FHL1, BAG3, MATR3, PTRF and TCAP in Australian muscular dystrophy patients. AB - FHL1, BAG3, MATR3 and PTRF are recently identified myopathy genes associated with phenotypes that overlap muscular dystrophy. TCAP is a rare reported cause of muscular dystrophy not routinely screened in most centres. We hypothesised that these genes may account for patients with undiagnosed forms of muscular dystrophy in Australia. We screened a large cohort of muscular dystrophy patients for abnormalities in FHL1 (n=102) and TCAP (n=100) and selected patients whose clinical features overlapped the phenotypes previously described for BAG3 (n=9), MATR3 (n=15) and PTRF (n=7). We found one FHL1 mutation (c.311G>A, p.C104Y) in a boy with rapidly progressive muscle weakness and reducing body myopathy who was initially diagnosed with muscular dystrophy. We identified no pathogenic mutations in BAG3, MATR3, PTRF or TCAP. In conclusion, we have excluded these five genes as common causes of muscular dystrophy in Australia. Patients with reducing body myopathy may be initially diagnosed as muscular dystrophy. PMID- 21683596 TI - From part- to whole-body ownership in the multisensory brain. AB - The question of how we experience ownership of an entire body distinct from the external world is a fundamental problem in psychology and neuroscience [1-6]. Earlier studies suggest that integration of visual, tactile, and proprioceptive information in multisensory areas [7-11] mediates self-attribution of single limbs. However, it is still unknown how ownership of individual body parts translates into the unitary experience of owning a whole body. Here, we used a "body-swap" illusion [12], in which people experienced an artificial body to be their own, in combination with functional magnetic resonance imaging to reveal a coupling between the experience of full-body ownership and neural responses in bilateral ventral premotor and left intraparietal cortices, and left putamen. Importantly, activity in the ventral premotor cortex reflected the construction of ownership of a whole body from the parts, because it was stronger when the stimulated body part was attached to a body, was present irrespective of whether the illusion was triggered by stimulation of the hand or the abdomen, and displayed multivoxel patterns carrying information about full-body ownership. These findings suggest that the unitary experience of owning an entire body is produced by neuronal populations that integrate multisensory information across body segments. PMID- 21683595 TI - Modularity of the bacterial cell cycle enables independent spatial and temporal control of DNA replication. AB - BACKGROUND: Complex regulatory circuits in biology are often built of simpler subcircuits or modules. In most cases, the functional consequences and evolutionary origins of modularity remain poorly defined. RESULTS: Here, by combining single-cell microscopy with genetic approaches, we demonstrate that two separable modules independently govern the temporal and spatial control of DNA replication in the asymmetrically dividing bacterium Caulobacter crescentus. DNA replication control involves DnaA, which promotes initiation, and CtrA, which silences initiation. We show that oscillations in DnaA activity dictate the periodicity of replication while CtrA governs the asymmetric replicative fates of daughter cells. Importantly, we demonstrate that DnaA activity oscillates independently of CtrA. CONCLUSIONS: The genetic separability of spatial and temporal control modules in Caulobacter reflects their evolutionary history. DnaA is the central component of an ancient and phylogenetically widespread circuit that governs replication periodicity in Caulobacter and most other bacteria. By contrast, CtrA, which is found only in the asymmetrically dividing alpha proteobacteria, was integrated later in evolution to enforce replicative asymmetry on daughter cells. PMID- 21683597 TI - Phosphorylation of Groucho mediates RTK feedback inhibition and prolonged pathway target gene expression. AB - BACKGROUND: Signaling by receptor tyrosine kinase (RTK) pathways plays fundamental roles in processes of cell-fate determination, often through the induction of specific transcriptional responses. Yet it is not fully understood how continuous target gene expression, required for irreversible cell-fate specification, is preserved after RTK signaling has ended. Here we address this question using the Drosophila embryo, a model system that has been instrumental in elucidating the developmental functions of RTK signal transduction. RESULTS: The Groucho corepressor is phosphorylated and downregulated in response to RTK signaling. Here we show that RTK pathways use Groucho phosphorylation as a general mechanism for inducing expression of pathway target genes encoding cell fate determinants as well as feedback antagonists, indicating that relief of Groucho-dependent repression is an integral element of RTK signaling networks. We further demonstrate that after mitogen-activated protein kinase (MAPK) has been deactivated, sustained phosphorylation of Groucho is essential for persistent RTK induced target gene expression and cell-fate determination in several developmental contexts. CONCLUSIONS: Phosphorylation of Groucho by MAPK plays a dual role in the regulation of RTK responses: (1) it mediates rapid feedback inhibition, and (2) it provides a stable memory mechanism of past MAPK activity. We propose that, in this manner, phosphorylation of Groucho enables transiently active RTK pathways to fix the spatiotemporal expression profiles of downstream targets over time. PMID- 21683598 TI - Molecular evidence for ancient asexuality in timema stick insects. AB - Asexuality is rare in animals in spite of its apparent advantage relative to sexual reproduction, indicating that it must be associated with profound costs [1 9]. One expectation is that reproductive advantages gained by new asexual lineages will be quickly eroded over time [3, 5-7]. Ancient asexual taxa that have evolved and adapted without sex would be "scandalous" exceptions to this rule, but it is often difficult to exclude the possibility that putative asexuals deploy some form of "cryptic" sex, or have abandoned sex more recently than estimated from divergence times to sexual relatives [10]. Here we provide evidence, from high intraspecific divergence of mitochondrial sequence and nuclear allele divergence patterns, that several independently derived Timema stick-insect lineages have persisted without recombination for more than a million generations. Nuclear alleles in the asexual lineages displayed significantly higher intraindividual divergences than in related sexual species. In addition, within two asexuals, nuclear allele phylogenies suggested the presence of two clades, with sequences from the same individual appearing in both clades. These data strongly support ancient asexuality in Timema and validate the genus as an exceptional opportunity to attack the question of how asexual reproduction can be maintained over long periods of evolutionary time. PMID- 21683599 TI - Comparison of elliptical training, stationary cycling, treadmill walking and overground walking. AB - The extent to which therapeutic, exercise or robotic devices can maximize gait function is a major unresolved issue in neurorehabilitation. Several factors may influence gait outcomes such as similarity of the task to overground walking, degree of coordination within and across limbs, and cycle-to-cycle variability in each device. Our objective was to compare lower extremity kinematics, coordination and variability during four locomotor tasks: overground walking, treadmill walking, elliptical training and stationary cycling in 10 non-disabled adults (6 male; mean age 22.7+/-2.9 yrs, range 20-29). All first performed four overground walking trials at self-selected speed with mean temporal-spatial data used to pace the other conditions. Joint positions, excursions, and the Gait Deviation Index (GDI) were compared across conditions to evaluate kinematic similarity. Time-series data were correlated within and across limbs to evaluate intralimb and interlimb coordination, respectively. Variability in cadence was quantified to assess how constrained the locomotor rhythm was compared to overground walking. Treadmill walking most closely resembled overground with GDI values nearly overlapping, reinforcing its appropriateness for gait training. Cycling showed the largest GDI difference from overground, with elliptical closer but still a significant distance from all three. Cycling showed greater hip reciprocation Cycling and elliptical showed stronger intralimb synergism at the hip and knee than the other two. Based on kinematics, results suggest that elliptical training may have greater transfer to overground walking than cycling and cycling may be more useful for enhancing reciprocal coordination. Further evaluation of these devices in neurological gait disorders is needed. PMID- 21683600 TI - Relationship between foot sensation and standing balance in patients with multiple sclerosis. AB - The aims of the present study were to investigate the relationship between the foot sensations and standing balance in patients with Multiple Sclerosis (MS) and find out the sensation, which best predicts balance. Twenty-seven patients with MS (Expanded Disability Status Scale 1-3.5) and 10 healthy volunteers were included. Threshold of light touch-pressure, duration of vibration, and distance of two-point discrimination of the foot sole were assessed. Duration of static one-leg standing balance was measured. Light touch-pressure, vibration, two-point discrimination sensations of the foot sole, and duration of one-leg standing balance were decreased in patients with MS compared with controls (p<0.05). Sensation of the foot sole was related with duration of one-leg standing balance in patients with MS. In the multiple regression analysis conducted in the 27 MS patients, 47.6% of the variance in the duration of one-leg standing balance was explained by two-point discrimination sensation of the heel (R(2)=0.359, p=0.001) and vibration sensation of the first metatarsal head (R(2)=0.118, p=0.029). As the cutaneous receptors sensitivity decreases in the foot sole the standing balance impairs in patients with MS. Two-point discrimination sensation of the heel and vibration sensation of the first metatarsal head region are the best predictors of the static standing balance in patients with MS. Other factors which could be possible to predict balance and effects of sensorial training of foot on balance should be investigated. PMID- 21683601 TI - Synthesis and biological evaluation of novel 5-alkyl-2-arylthio-6-((3,4 dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV 1 reverse transcriptase inhibitors. AB - A series of novel S-DABO analogues of 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin 1(2H)-yl)methyl)pyrimidin-4(3H)-ones were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were compounds 6c1,6c6, and 6b1 (EC(50)=0.24 +/- 0.05, 0.38 +/- 0.13, 0.39 +/- 0.05 MUM, respectively), which possess improved or similar HIV-1 inhibitory activity compared with nevirapine (NVP) (EC(50)=0.21 MUM) and delavirdine (DLV) (EC(50)=0.32 MUM). None of these compounds were active against HIV-2 replication. Furthermore, enzyme inhibitory assays were performed with selected derivatives against HIV-1 wtRT, confirming that the main target of these compounds is the HIV-1 RT and these new S-DABOs are acting as NNRTIs. The preliminary structure-activity relationship (SAR) of these new congeners is discussed briefly and rationalized by docking studies. PMID- 21683602 TI - Synthesis and evaluation of hermitamides A and B as human voltage-gated sodium channel blockers. AB - Hermitamides A and B are lipopeptides isolated from a Papau New Guinea collection of the marine cyanobacterium Lyngbya majuscula. We hypothesized that the hermitamides are ligands for the human voltage-gated sodium channel (hNa(V)) based on their structural similarity to the jamaicamides. Herein, we describe the nonracemic total synthesis of hermitamides A and B and their epimers. We report the ability of the hermitamides to displace [(3)H]-BTX at 10 MUM more potently than phenytoin, a clinically used sodium channel blocker. We also present a potential binding mode for (S)-hermitamide B in the BTX-binding site and electrophysiology showing that these compounds are potent blockers of the hNav1.2 voltage-gated sodium channel. PMID- 21683603 TI - Heating rate effect on thermoluminescence glow curves of LiF:Mg,Cu,P+PTFE phosphor. AB - The influence of heating rate on the thermoluminescence (TL) property of LiF:Mg,Cu,P+PTFE was analyzed. The activation energy and the frequency factor as a function of the heating rate were determined. The kinetic parameters and their dependence on the heating rate were evaluated using the sequential quadratic programming glow curve deconvolution (SQPGCD). The results showed that as the heating rate increases, the peak intensity at the maximum (I(M)) decreases and shifts to higher temperature; similar behavior of the kinetics parameters was observed. PMID- 21683604 TI - Comparison of the soil losses from (7)Be measurements and the monitoring data by erosion pins and runoff plots in the Three Gorges Reservoir region, China. AB - The potential for using (7)Be measurements to document soil redistribution associated with a heavy rainfall was estimated using (7)Be method on a bare purple soil plot in the Three Gorges Reservoir region of China. The results were compared with direct measurement from traditional approaches of erosion pins and runoff plots. The study shows that estimation of soil losses from (7)Be are comparable with the monitoring results provided by erosion pins and runoff plots, and are also in agreement with the existing knowledge provided by 137Cs measurements. The results obtained from this study demonstrated the potential for using (7)Be technique to quantify short-term erosion rates in these areas. PMID- 21683605 TI - Radiation inactivation of Paenibacillus larvae and sterilization of American Foul Brood (AFB) infected hives using Co-60 gamma rays. AB - The effectiveness of gamma radiation in inactivating the Philippine isolate of Paenibacillus larvae was investigated. Spores of P. larvae were irradiated at incremental doses (0.1, 0.2, 0.4, 0.8 and 1.6 kGy) of gamma radiation emitted by a 60Co source. Surviving spores were counted and used to estimate the decimal reduction (D10) value. A dose of 0.2 kGy was sufficient to inactivate 90% of the total recoverable spores from an initial count of 105- 9 * 103 spores per glass plate. The sterilizing effect of high doses of gamma radiation on the spores of P. larvae in infected hives was determined. In this study, a minimum dose (D(min)) of 15 kGy was tested. Beehives with sub-clinical infections of AFB were irradiated and examined for sterility. All the materials were found to be free of P. larvae indicating its susceptibility to gamma-rays. After irradiation, there were no visible changes in the physical appearance of the hives' body, wax and frames. Thus, a dose of 15 kGy is effective enough for sterilization of AFB infected materials. PMID- 21683606 TI - CXCL12-binding receptors expression in non-small cell lung cancer relates to tumoral microvascular density and CXCR4 positive circulating tumoral cells in lung draining venous blood. AB - OBJECTIVES: Lung cancer is the main cause of cancer-related death in Western countries. Despite early diagnosis, approximately 40% of patients have undergone surgical resection for localized non-small cell lung cancer relapse within 24 months after surgery. Current prognostic criteria for patients with non-small cell lung cancer are gradually enriched by the discovery of critical biological markers in surgical samples to better stratify patients with high risk for recurrent and metastatic disease after surgical manipulation. In fact, specific biological features are needed to drive metastasis development and, among these chemokine receptors, when activated, seem to play a relevant role, promoting both neovessels formation and tumoral cell migration. METHODS: To this purpose, blood samples from the closed stumps of the pulmonary veins were drawn immediately after major pulmonary surgery in 45 patients with resectable non-small cell lung cancer to evaluate the expression of chemokine CXCL12 receptor, CXCR4, in circulating tumor cells. In addition, primary tumor sections have been used to assess microvascular density (MVD) and vessels invasion and build prognostic tissue micro-array to investigate the expression of CXCL12 receptors CXCR4 and CXCR7. RESULTS: Cells positive for cytokeratins from tumor draining pulmonary venous blood were detectable in 11 cases (23.9%). In 8 out of 11 cases, CK positive cells coexpressed CXCR4. Moreover, in tumoral tissue high CXCR4 expression was significantly associated to high mMVD (p = 0.046), high CXCR7 expression (p = 0.001), adenocarcinoma histotype (p = 0.023), and to the presence of circulating tumoral cells in pulmonary veins (p = 0.001). Finally, vessel invasions relate to high MVD. CONCLUSION: In conclusion, the results of our study underline the significant potential role of CXCL12 receptors in determining both vessel formation and tumoral cell migration to blood stream, favoring metastasis development. PMID- 21683607 TI - Anticalcification effects of decellularization, solvent, and detoxification treatment for genipin and glutaraldehyde fixation of bovine pericardium. AB - OBJECTIVE: Calcification plays a major role in the failure of bioprosthetic and other tissue heart valve substitutes. The objective of this study was to evaluate the anticalcification effect of decellularization and detoxification in glutaraldehyde (GA)/genipin- and solvent-fixed bovine pericardium using a rabbit intramuscular model which is effective for assessing calcification in bioprosthetic tissue. METHODS: Bovine pericardial tissues were fixed with 0.5% GA/0.4% genipin in organic solvent (75% ethanol + 5% octanol, 75% ethanol + 5% octanediol, or 70% ethanol + 10% isopropanol) and post-treated with glycine, glutamic acid, or sodium bisulfite. Decellularization was performed with 0.25% sodium dodecylsulfate prior to fixation. The material characteristics of the treated tissues were assessed by thermal stability test, uniaxial mechanical test, and light microscopy. Stability of the treated tissue was measured by the resistance to enzymatic degradation using protease. The tissues were intramuscularly implanted into 4-week-old rabbits for 8 weeks, and the anti-alpha Gal(Gal[alpha]1,3-Gal[beta]1,4GlcNAc-R) antibodies (immunoglobulin G) were measured at various time intervals after implantation. Explanted tissues were examined by light microscopy and calcium contents of the explanted tissues were measured. RESULTS: Differently treated tissues resulted in no significant alterations in material characteristics and morphology. GA groups are superior to genipin groups in tissue cross-linking without difference according to addition of decellularization, organic solvent treatment, and detoxification by resistance toward pronase degradation. The titer of anti-alpha-Gal antibodies gradually increased after implantation in all study groups. The titer of anti-alpha-Gal antibodies increased less in genipin groups than in GA groups, and less with decellularization than without decellularization. The calcium contents of genipin groups (n = 75) were significantly lower than those of GA groups (n = 118) (28.55 +/- 11.22 MUg mg(-1) vs 37.16 +/- 7.75 MUg mg(-1), p < 0.001). Calcium contents decreased with decellularization, organic solvent treatment, and detoxification, irrespective of the type of organic solvent and amino acids. Inorganic phosphorus contents of genipin groups (n = 66) were significantly lower than those of GA groups (n = 103) (55.36 +/- 26.98 MUg mg(-1) vs 75.67 +/- 23.44 MUg mg(-1), p = 0.000). CONCLUSIONS: Genipin fixation is a novel alternative to conventional GA fixation in vitro material assessment and in vivo anticalcification effect. The addition of decellularization, organic solvent treatment, and detoxification prevented calcification of GA/genipin-fixed bovine pericardium in the rabbit intramuscular implantation model, irrespective of the type of organic solvent and amino acids. PMID- 21683608 TI - An unusual ectopic calcification in the left atrium. PMID- 21683609 TI - Prospective study of percutaneous radiofrequency sympathicolysis in severe hyperhidrosis and facial blushing: efficacy and safety findings. AB - OBJECTIVE: Hyperhidrosis (Hh) and facial blushing (Fb) are conditions caused by hyperactivity of the sympathetic system; they affect around 2% of the population. Severe cases have been typically treated with thoracic sympathectomy through a minimally invasive approach. We sought to determine if severe Hh and/or Fb patients, who are reluctant to go through an operation with general anaesthesia, could benefit from receiving percutaneous radiofrequency ablation of the sympathetic chain. METHODS: Prospectively collected data obtained from May 2007 to May 2010 were analysed to compare the treatment efficacy and effects on quality of life of the two procedures. RESULTS: From a total of 58 patients enrolled in the study, 31 were treated with radiofrequency procedures, whereas 27 received surgical sympathectomy. Patients with Hh had better results with surgery than with radiofrequency sympathicolysis in terms of efficacy (p=0.0001) and quality of life (p=0.0002). However, there was still a significant improvement in quality of life in the group of patients treated with radiofrequency sympathicolysis (p=0.004). Patients with Fb had good results with surgical procedures and poor outcomes with radiofrequency ablation, resulting in significant differences in treatment efficacy (p=0.005) and in quality of life (p=0.003). Fb patients treated with radiofrequency procedures had no improvement in quality of life after the intervention (p=0.28). CONCLUSION: Our results support the view of surgical sympathectomy as the gold-standard treatment in severe cases of Hh and Fb. Radiofrequency sympathicolysis is useful as a second treatment choice for Hh patients. Fb patients do not benefit from radiofrequency sympathicolysis. PMID- 21683610 TI - Position article for the use of extracorporeal life support in adult patients. AB - Extracorporeal life support (ECLS) is one of the recent fields in cardiac surgery which has improved significantly the quality of patient care in acute or chronic end-stage heart disease. The safe use of this new technology requires many different prerequisites which are summarized in this position article. It includes the necessary personnel and their qualifications, the structural assumptions, the required equipment, and the parameters which have to be monitored for the safe usage of these devices. In addition, indications and contraindications for ECLS, the management and control of a wide range of parameters related to the extracorporeal circulation, as well as the necessary equipment are described. Quality assurance and education are also described in this position article. PMID- 21683611 TI - Aortic stiffness and aortic dilation in infants and children with tetralogy of Fallot before corrective surgery: evidence for intrinsically abnormal aortic mechanical property. AB - OBJECTIVE: The present study tested the hypothesis that there is an intrinsic abnormality of aortic elasticity in infants/children with tetralogy of Fallot (TOF) before corrective surgery. The study also determined the independent and quantitative effects of aortic volume load on aortic dilation in this group of TOF patients. METHODS: Aortic stiffness (pulse wave velocity; PWV) and aortic volume load (aortic volume flow) were measured during catheterization in 37 infants and children with TOF before corrective surgery and in 55 control subjects. RESULTS: PWV was significantly higher in TOF patients than in controls, irrespective of age, sex, hemodynamic burden on the aortic wall, and existence of aorto-pulmonary shunt. Aortic diameter was also significantly greater in TOF patients than in controls. Multivariate regression analysis identified aortic volume load as an independent determinant of aortic dilation (aortic diameter = 0.72 aortic flow + 26.1 body surface area + 2.79, r(2) = 0.58, p < 0.001). Increased aortic-wall stiffness correlated with the increase in aortic diameter in patients with dominant left-to-right shunt (without aortic volume load); aortic diameter = 0.007 PWV + 13.5 body surface area (BSA) + 6.3 (r(2) = 0.73, p < 0.05). CONCLUSIONS: The present study highlighted the intrinsic abnormality of the mechanical property of the aortic wall as a feature of aortopathy in TOF. The study also indicated that aortic volume overload and, to a lesser extent, intrinsically high aortic stiffness correlated significantly with aortic dilation in TOF. PMID- 21683612 TI - Thrombectomy for massive bioprosthetic valve thrombosis. PMID- 21683613 TI - Could targeting bone delay cancer progression? Potential mechanisms of action of bisphosphonates. AB - Although dissemination may occur early in the course of many cancers, the development of overt metastases depends upon a variety of factors inherent to the cancer cells and the tissue(s) they colonize. The time lag between initial dissemination and established metastases could be several years, during which period the bone marrow may provide an unwitting sanctuary for disseminated tumor cells (DTCs). Survival in a dormant state within the bone marrow may help DTCs weather the effects of anticancer therapies and seed posttreatment relapses. The importance of the bone marrow for facilitating DTC survival may vary depending on the type of cancer and mechanisms of tumor cell dissemination. By altering the bone microenvironment, bisphosphonates may reduce DTC viability. Moreover, some bisphosphonates have demonstrated multiple anticancer activities. These multiple mechanisms may help explain the improvement in disease outcomes with the use of zoledronic acid in malignancies like breast cancer and multiple myeloma. PMID- 21683614 TI - beta2-Adrenergic agonists bias TLR-2 and NOD2 activated dendritic cells towards inducing an IL-17 immune response. AB - This study tested the hypothesis that activation of beta2-adrenoceptors on DCs influences NOD2 signaling along with its cross-talk with Toll-like receptor-2 resulting in altered Th cell priming ability. Th17 cells are a newly discovered lineage of CD4(+) T cells involved in defense against extracellular bacteria and also implicated in autoimmune disorders. Initiation and polarization of the adaptive immune response is controlled by innate immune recognition mediated by DCs. Previous studies demonstrated that adrenergic receptors modulate cytokine production by DCs and affect their Th cell priming ability. We show that the beta2-adrenoceptor agonist salbutamol enhanced IL-6 production in murine bone marrow-derived DCs stimulated with the nucleotide-binding oligomerization domain 2 ligand muramyl dipeptide. However, when the Toll-like receptor-2 ligand Pam3CysSK4 was added, salbutamol inhibited IL-12 but did not alter IL-6 and IL-23 expression. Gene expression analysis showed that salbutamol inhibited the p40 subunit as well as IL-12p35, while IL-23p19 and IL-6 were stimulated. Therefore, beta2-adrenoceptors modulated cytokine production resulting in a Th17 cell priming cytokine pattern. Indeed, when antigen-pulsed DCs stimulated by muramyl dipeptide or Pam3CysSK4+muramyl dipeptide in the presence of salbutamol were used for in vivo immunization, the resulting Th17/Th1 cell ratio was increased as evaluated by IL-17 and IFN-gamma production. In addition, intradermal injection of norepinephrine along with Pam3CysSK4+muramyl dipeptide increased the Th17 response to an immunogenic protein and this effect was reversed by a beta2 adrenoceptor antagonist. Thus, beta2-adrenoceptors may be involved in the regulation of defense against extracellular bacteria and the pathogenesis of inflammatory diseases. PMID- 21683615 TI - Reply: "age at menopause: imputing age at menopause for women with a hysterectomy with application to risk of postmenopausal breast cancer". PMID- 21683616 TI - Combined impact of lifestyle factors on cancer mortality in men. AB - PURPOSE: The impact of lifestyle factors on cancer mortality in the U.S. population has not been thoroughly explored. We examined the combined effects of cardiorespiratory fitness, never smoking, and normal waist girth on total cancer mortality in men. METHODS: We followed a total of 24,731 men ages 20-82 years who participated in the Aerobics Center Longitudinal Study. A low-risk profile was defined as never smoking, moderate or high fitness, and normal waist girth, and they were further categorized as having 0, 1, 2, or 3 combined low-risk factors. RESULTS: Over an average of 14.5 years of follow-up, there were a total of 384 cancer deaths. After adjustment for age, examination year, and multiple risk factors, men who were physically fit, never smoked, and had a normal waist girth had a 62% lower risk of total cancer mortality (95% confidence interval [CI], 45% 73%) compared with men with no low-risk factors. Men with all 3 low-risk factors had a 12-year (95% CI, 8.6-14.6) longer life expectancy compared with men with no low-risk factors. Approximately 37% (95% CI, 17%-52%) of total cancer deaths might have been avoided if the men had maintained all 3 low-risk factors. CONCLUSIONS: Being physically fit, never smoking, and maintaining a normal waist girth is associated with lower risk of total cancer mortality in men. PMID- 21683617 TI - Previous antiplatelet use is associated with hematoma expansion in patients with spontaneous intracerebral hemorrhage. AB - BACKGROUND: Patients with intracerebral hemorrhage (ICH) often report the use of antiplatelet medications, even more commonly than the use of anticoagulants. The effect of antiplatelet drugs on the course of ICH is controversial. In this study, our aim was to determine the effects of previous antiplatelet therapy on admission hematoma volume and hematoma expansion in patients with spontaneous ICH. METHODS: A consecutive series of patients with a diagnosis of ICH who underwent brain computed tomographic (CT) scans within 12 hours of symptom onset and a follow-up CT scan within 72 hours were included in the study. Hematoma volume was calculated by using the ABC/2 method on admission and follow-up images. Univariate and multivariate analyses were performed to determine the independent role of antiplatelet use on baseline hematoma volume and hematoma expansion (defined as an increase in hematoma volume >12.5 mL or 33% of the baseline ICH volume). RESULTS: A total of 153 patients were included in the study. Fifty-two (34%) patients were using antiplatelet drugs at the time of symptom onset. Antiplatelet users tend to have a larger baseline hematoma volume; however, this difference failed to reach statistical significance (P = .17). Antiplatelet therapy was found to be a significant determinant of substantial hematoma expansion, both in univariate and multivariate analyses (P < .01). CONCLUSIONS: Previous antiplatelet use significantly contributes to hematoma expansion in patients with ICH. PMID- 21683618 TI - Prediction of outcome in neurogenic oropharyngeal dysphagia within 72 hours of acute stroke. AB - BACKGROUND: Stroke is the most frequent cause of neurogenic oropharyngeal dysphagia (NOD). In the acute phase of stroke, the frequency of NOD is greater than 50% and, half of this patient population return to good swallowing within 14 days while the other half develop chronic dysphagia. Because dysphagia leads to aspiration pneumonia, malnutrition, and in-hospital mortality, it is important to pay attention to swallowing problems. The question arises if a prediction of severe chronic dysphagia is possible within the first 72 hours of acute stroke. METHODS: On admission to the stroke unit, all stroke patients were screened for swallowing problems by the nursing staff within 2 hours. Patients showing signs of aspiration were included in the study (n = 114) and were given a clinical swallowing examination (CSE) by the swallowing/speech therapist within 24 hours and a swallowing endoscopy within 72 hours by the physician. The primary outcome of the study was the functional communication measure (FCM) of swallowing (score 1-3, tube feeding dependency) on day 90. RESULTS: The grading system with the FCM swallowing and the penetration-aspiration scale (PAS) in the first 72 hours was tested in a multivariate analysis for its predictive value for tube feeding dependency on day 90. For the FCM level 1 to 3 (P < .0022) and PAS level 5 to 8 (P < .00001), the area under the curve (AUC) was 72.8% and showed an odds ratio of 11.8 (P < .00001; 95% confidence interval 0.036-0.096), achieving for the patient a 12 times less chance of being orally fed on day 90 and therefore still being tube feeding-dependent. CONCLUSIONS: We conclude that signs of aspiration in the first 72 hours of acute stroke can predict severe swallowing problems on day 90. Consequently, patients should be tested on admission to a stroke unit and evaluated with established dysphagia scales to prevent aspiration pneumonia and malnutrition. A dysphagia program can lead to better communication within the stroke unit team to initiate the appropriate diagnostics and swallowing therapy as soon as possible. PMID- 21683619 TI - Metabolic profile of sub-Saharan African patients presenting with first-ever-in lifetime stroke: association with insulin resistance. AB - BACKGROUND: To assess the pattern of metabolic profile associated with first stroke episode in a hospital setting in Cameroon. METHODS: All patients admitted for first-ever-in-lifetime stroke over a 6-month period were eligible for inclusion in the study. The 84% participation rate yielded 57 of 68 patients between 16 and 85 years of age. Fifty-seven control subjects were selected to match patients included for age range, sex, and known hypertension and diabetes. We measured fasting serum glucose, insulin, and lipids in controls and in patients between days 3 and 7 after admission. RESULTS: Total cholesterol was comparable in patients and controls (172.6 +/- 39.5 v 175.4 +/- 49.7 mg/dL; P = .75), as were triglycerides (129.4 +/- 56.1 v 122.4 +/- 60.7 mg/dL; P = .53). high-density lipoprotein cholesterol (HDL-C) levels were lower in patients than in controls (37.4 +/- 20.6 v 50.2 +/- 18.0 mg/dL; P = .001), with comparable levels of low-density lipoprotein cholesterol (LDL-C; 109.4 +/- 43.0 v 100.7 +/- 48.8 mg/dL; P = .32). The LDL-C/HDL-C ratio was higher in patients compared to controls (4.0 +/- 3.0 v 2.3 +/- 1.7; P = .0001), as was the total cholesterol/HDL C ratio (5.9 +/- 3.5 v 3.9 +/- 1.8; P = .0001). Compared to controls, stroke patients had higher fasting insulin levels (5.9 +/- 5.4 v 2.3 +/- 3.2 IU/mL; P < .001) and higher insulin resistance as measured by the homeostatic model assessment of insulin resistance (1.9 +/- 2.2 v 0.7 +/- 1.0; P = .001). CONCLUSIONS: Stroke is associated with markers of insulin resistance, low serum levels of HDL, and high total cholesterol/HDL ratio in this African population. Studies with a larger sample size and cohort designs are warranted to explore the causal pathways, persistence of these abnormalities, and population-specific cut points. PMID- 21683620 TI - Organ storage with University of Wisconsin solution is associated with improved outcomes after orthotopic heart transplantation. AB - BACKGROUND: Despite significant advances in cardiac allograft preservation, the optimal preservative solution is unknown. We evaluated the impact of the most commonly used solutions in the USA, the University of Wisconsin solution (UW) and Celsior solution (CS), on outcomes after orthotopic heart transplantation (OHT). METHODS: We retrospectively reviewed adult OHT recipients in the United Network for Organ Sharing (UNOS) database. Primary stratification was by preservation solution. The primary end-point was short-term survival (30 days and 1 year). Secondary end-points included common post-operative complications. Subgroup analysis was performed in high-risk allografts (donor age >50 years or ischemic time >4 hours). Risk-adjusted multivariate Cox proportional hazard regression was used to assess survival. RESULTS: From 2004 to 2009, 4,910 patients (3,107 UW and 1,803 CS) with sufficient preservation solution information for analysis underwent OHT. Baseline characteristics were well-matched between the two groups. UW was associated with a small but significantly improved survival compared with CS at 30 days (96.7% vs 95.4%, p = 0.02) and 1 year (89.6% vs 87.0%, p < 0.01). These survival differences persisted on multivariate analysis at 30 days (HR 1.47 [1.02 to 2.13], p < 0.05) and 1 year (HR 1.40 [1.14 to 1.73], p < 0.01). In the 1,455 patients with high-risk allografts, preservation with UW was associated with improved survival compared with CS at 30 days (94.3% vs 91.3%, p < 0.01) and at 1 year (84.2% vs 80.19%, p < 0.01), a difference that was significant according to multivariate Cox analysis at 30 days (HR 2.29 [1.39 to 3.76], p < 0.01) and 1 year (HR 1.61 [1.17 to 2.21], p < 0.01). CONCLUSIONS: Preservation with UW solution is associated with improved short-term survival compared with CS. Patients undergoing OHT with high-risk allografts have a similar survival benefit. PMID- 21683621 TI - Radiographic evaluation of navicular position in the sagittal plane-correction following an extraosseous talotarsal stabilization procedure. AB - The navicular drop in the sagittal plane on weight-bearing is a valid indicator of foot pronation. Dislocation of the talus on the tarsal mechanism results in hyperpronation, which can lead to excessive navicular drop. The purpose of the present study was to radiographically determine the efficacy of HyProCure((r)) in realigning the navicular bone in hyperpronating feet. We hypothesized that following the placement of HyProCure((r)), the navicular height would increase significantly compared to its preoperative value. Radiographs of 61 adult patients (86 feet) who received HyProCure((r)) without adjunctive hindfoot or midfoot soft tissue or osseous procedures were analyzed. The distance of the navicular with respect to the cuboid was measured from the pre- and postoperative weight-bearing lateral radiographs. Additionally, we measured foot length to normalize the navicular to cuboid distance. The postoperative radiographs were taken at an average follow-up of 17 days. The mean preoperative true navicular to cuboid distance was 19 +/- 6 mm as compared to a mean postoperative value of 24 +/- 5 mm. The mean pre- and postoperative normalized navicular to cuboid distances were 0.098 +/- 0.029 and 0.125 +/- 0.027, respectively (+/- 1 SD). The postoperative increase in the true and normalized navicular to cuboid distance was statistically significant (p < .001). HyProCure((r)) was effective in improving the anatomic alignment of the talonavicular joint by reducing excessive navicular drop. This indicates reduction of excessive abnormal pronation and stabilization of the medial column of the foot, which can also lead to reduction in the excessive forces placed on the supporting soft tissue structures. PMID- 21683622 TI - Interval changes in postoperative range of motion of Salto-Talaris total ankle replacement. AB - The purpose of the present study was to identify changes in the range of motion during the first year after placement of the Salto-Talaris total ankle implant. The first 97 cases were assessed throughout the year at 6 weeks and 3, 6, and 12 months. Data were extracted through retrospective chart review, operative reports, and electronic goniometry of the implant in maximal dorsiflexion and plantarflexion. The range of motion incrementally improved through the treatment course, with the greatest increases occurring between 6 weeks and 6 months. The mean range of motion at 6 weeks was 11.85 degrees +/- 0.824 degrees standard error, which had increased by 3.07 degrees +/- 0.862 degrees to 14.92 degrees (p < .0001) at 3 months postoperatively. From 3 to 6 months, it increased 3.96 degrees +/- 0.981 degrees to 18.88 degrees (p < .0001) at 6 months postoperatively. From 6 to 12 months, the mean range of motion increased to 20.11 degrees +/- 1.243 degrees (p = .3765). The overall mean increase in the range of motion from 6 weeks to 12 months was 8.25 degrees (p < .0001). These results have demonstrated a predictable incremental increase in motion over time, with the largest percentage of improvement occurring from 6 weeks to 6 months. This information will aid surgeons in guiding patient expectations after implant arthroplasty of the ankle. PMID- 21683623 TI - Outcomes after the Stainsby procedure in the lesser toes: an alternative procedure for the correction of rigid claw toe deformity. AB - Clawing of the digits is a deformity seen both in patients with and without rheumatoid arthritis, resulting in pain and deformity in the forefoot. After failure of conservative treatment, the Stainsby procedure is one surgical option for severe clawing and metatarsalgia in both rheumatoid and nonrheumatoid feet. Results from the originating authors (G.D. Stainsby and P.J. Briggs) are consistent and reliable; however, there is little material outside of the originating center. This article reviews our experience in the Western Sussex Hospitals NHS Trust. Sixteen consecutive patients who underwent Stainsby procedure between 2006 and 2009 were reviewed. All operations were performed by a single consultant surgeon, the senior author (S.P.). All patients were scored using the Manchester Oxford Foot and Ankle score preoperatively and postoperatively. Minimum follow-up was 6 months, with a mean follow-up of 14 months. Significant improvements in all scores were seen postoperatively. Walking scores dropped from a mean of 22 preoperatively to 12.7 postoperatively (p = 0.007). Pain scores dropped from a mean of 13.3 to 7.1 (p = 0.001). Social scores dropped from a mean 11 to 6 (p = 0.001). Overall patient satisfaction was high. The Stainsby procedure has been shown to improve function and reduce pain in patients from its originating center in both rheumatoid and nonrheumatoid feet. This study demonstrates this simple technique is reproducible and effective in reducing morbidity. PMID- 21683624 TI - Structural and functional modulation of early healing of full-thickness superficial digital flexor tendon rupture in rabbits by repeated subcutaneous administration of exogenous human recombinant basic fibroblast growth factor. AB - The present study was designed to investigate the effects of basic fibroblast growth factor on the healing of the acute phase of complete superficial digital flexor tendon rupture in rabbits. A total of 40 skeletally mature female white New Zealand rabbits were randomly divided into 2 equal groups of injured treated and injured control. After tenotomy and surgical anastomosis, using a modified Kessler and running pattern, the injured legs were placed in casts for 14 days, and basic fibroblast growth factor was injected subcutaneously over the lesion on days 3, 7, and 10 after injury. The injured control rabbits received a normal saline injection in a similar protocol. The rabbits' weight, tendon diameter, clinical signs, radiographs, and ultrasound scans were evaluated weekly. The rabbits were killed 28 days after injury, and the tendons were evaluated at the macroscopic, histopathologic, and ultrastructural levels and for biomechanical and the percentage of dry weight analysis. Treatment significantly reduced the diameter and increased the echogenicity and dry weight content and enhanced the maturation rate of the tenoblasts, fibrillogenesis, collagen fibril diameter, fibrillar density, tensile strength, and stiffness and stress of the injured tendons. Treatment with basic fibroblast growth factor was effective in restoring the morphologic and biomechanical properties of the injured superficial digital flexor tendon and could be valuable in clinical trial studies. PMID- 21683625 TI - Influence of socioeconomic status on trauma center performance evaluations in a Canadian trauma system. AB - BACKGROUND: Trauma center performance evaluations generally include adjustment for injury severity, age, and comorbidity. However, disparities across trauma centers may be due to other differences in source populations that are not accounted for, such as socioeconomic status (SES). We aimed to evaluate whether SES influences trauma center performance evaluations in an inclusive trauma system with universal access to health care. STUDY DESIGN: The study was based on data collected between 1999 and 2006 in a Canadian trauma system. Patient SES was quantified using an ecologic index of social and material deprivation. Performance evaluations were based on mortality adjusted using the Trauma Risk Adjustment Model. Agreement between performance results with and without additional adjustment for SES was evaluated with correlation coefficients. RESULTS: The study sample comprised a total of 71,784 patients from 48 trauma centers, including 3,828 deaths within 30 days (4.5%) and 5,549 deaths within 6 months (7.7%). The proportion of patients in the highest quintile of social and material deprivation varied from 3% to 43% and from 11% to 90% across hospitals, respectively. The correlation between performance results with or without adjustment for SES was almost perfect (r = 0.997; 95% CI 0.995-0.998) and the same hospital outliers were identified. CONCLUSIONS: We observed an important variation in SES across trauma centers but no change in risk-adjusted mortality estimates when SES was added to adjustment models. Results suggest that after adjustment for injury severity, age, comorbidity, and transfer status, disparities in SES across trauma center source populations do not influence trauma center performance evaluations in a system offering universal health coverage. PMID- 21683626 TI - A single T cell receptor bound to major histocompatibility complex class I and class II glycoproteins reveals switchable TCR conformers. AB - Major histocompatibility complex class I (MHCI) and MHCII proteins differ in structure and sequence. To understand how T cell receptors (TCRs) can use the same set of variable regions to bind both proteins, we have presented a comparison of a single TCR bound to both MHCI and MHCII ligands. The TCR adopts similar orientations on both ligands with TCR amino acids thought to be evolutionarily conserved for MHC interaction occupying similar positions on the MHCI and MHCII helices. However, the TCR antigen-binding loops use different conformations when interacting with each ligand. Most importantly, we observed alternate TCR core conformations. When bound to MHCI, but not MHCII, Valpha disengages from the Jalpha beta strand, switching Valpha's position relative to Vbeta. In several other structures, either Valpha or Vbeta undergoes this same modification. Thus, both TCR V-domains can switch among alternate conformations, perhaps extending their ability to react with different MHC-peptide ligands. PMID- 21683627 TI - Unc93B1 restricts systemic lethal inflammation by orchestrating Toll-like receptor 7 and 9 trafficking. AB - Toll-like receptor-7 (TLR7) and 9, innate immune sensors for microbial RNA or DNA, have been implicated in autoimmunity. Upon activation, TLR7 and 9 are transported from the endoplasmic reticulum (ER) to endolysosomes for nucleic acid sensing by an ER-resident protein, Unc93B1. Little is known, however, about a role for sensor transportation in controlling autoimmunity. TLR9 competes with TLR7 for Unc93B1-dependent trafficking and predominates over TLR7. TLR9 skewing is actively maintained by Unc93B1 and reversed to TLR7 if Unc93B1 loses preferential binding via a D34A mutation. We here demonstrate that mice harboring a D34A mutation showed TLR7-dependent, systemic lethal inflammation. CD4(+) T cells showed marked differentiation toward T helper 1 (Th1) or Th17 cell subsets. B cell depletion abolished T cell differentiation and systemic inflammation. Thus, Unc93B1 controls homeostatic TLR7 activation by balancing TLR9 to TLR7 trafficking. PMID- 21683628 TI - Phospholipase C-beta3 regulates FcERI-mediated mast cell activation by recruiting the protein phosphatase SHP-1. AB - Mast cells are major effectors in high-affinity IgE receptor (FcERI)-dependent allergic reactions. Here we show that phospholipase C (PLC)-beta3 is crucial for FcERI-mediated mast cell activation. Plcb3(-/-) mice showed blunted FcERI dependent late-phase, but not acute, anaphylactic responses and airway inflammation. Accordingly, FcERI stimulation of Plcb3(-/-) mast cells exhibited reduced cytokine production but normal degranulation. Reduced cytokine production in Plcb3(-/-) cells could be accounted for by increased activity of the negative regulatory Src family kinase Lyn and reduced activities of the positive regulatory protein kinases MAPKs. Mechanistically, PLC-beta3 constitutively interacts with FcERI, Lyn, and SHP-1 (protein phosphatase). SHP-1 probably recognizes its substrates Lyn and MAPKs via the recently described kinase tyrosine-based inhibitory motif, KTIM. Consistent with PLC-beta3- and SHP-1 mediated repression of Lyn activity by dephosphorylation at Tyr396, FcERI mediated phenotypes were similar in Plcb3(-/-) and SHP-1 mutant mast cells. Thus, we have defined a PLC-beta3- and SHP-1-mediated signaling pathway for FcERI mediated cytokine production. PMID- 21683630 TI - Management and outcome of fractures of the distal phalanx: a retrospective study of 285 horses with a long term outcome in 223 cases. AB - A multicentre study of 285 cases was performed to enhance the management of distal phalangeal fractures on the basis of clinical evidence. The outcome after treatment was available for 223 of the cases. Horses with a non-articular type I fracture had a better prognosis (91.7%) for return to original or expected level of use than horses with an articular type II or III fracture (69.6% and 74.1%, respectively). The prognosis for types IV and V fractures was fair (57.7% and 57.1%, respectively) and for type VI good (80%). Horses with a hindlimb fracture had a significantly greater chance of a successful outcome. No significant association between age or time to start treatment and success rate was noted. The best treatment option for types I-III fractures was a conservative approach (box rest). Type IV fractures were best treated by arthroscopic removal of the fragment. Immobilisation of the hoof did not seem to influence outcome. Radiological findings and clinical healing were not accurately correlated and the re-commencement of training should be based on clinical rather than radiological findings. Complete osseous union of the fracture was not essential for a successful return to athletic activity. PMID- 21683629 TI - Anthrax toxin induces macrophage death by p38 MAPK inhibition but leads to inflammasome activation via ATP leakage. AB - Detection of microbial constituents by membrane associated and cytoplasmic pattern recognition receptors is the essence of innate immunity, leading to activation of protective host responses. However, it is still unclear how immune cells specifically respond to pathogenic bacteria. Using virulent and nonvirulent strains of Bacillus anthracis, we have shown that secretion of ATP by infected macrophages and the sequential activation of the P2X7 purinergic receptor and nucleotide binding oligomerization domain (NOD)-like receptors are critical for IL-1-dependent host protection from virulent B. anthracis. Importantly, lethal toxin produced by virulent B. anthracis blocked activation of protein kinases, p38 MAPK and AKT, resulting in opening of a connexin ATP release channel and induction of macrophage death. Prevention of cell death or ATP release through constitutive p38 or AKT activation interfered with inflammasome activation and IL 1beta production, thereby compromising antimicrobial immunity. PMID- 21683631 TI - Levetiracetam reduces the frequency of interictal epileptiform discharges during NREM sleep in children with ADHD. AB - BACKGROUND: Symptoms of attention deficit hyperactivity disorder (ADHD) are more common in children with epilepsy than in the general paediatric population. Epileptiform discharges in EEG may be seen in children with ADHD also in those without seizure disorders. Sleep enhances these discharges which may be suppressed by levetiracetam. AIM: To assess the effect of levetiracetam on focal epileptiform discharges during sleep in children with ADHD. METHOD: In this retrospective study a new semi-automatic quantitative method based on the calculation of spike index in 24-h ambulatory EEG recordings was applied. Thirty five ADHD children, 17 with focal epilepsy, one with generalised epilepsy, and 17 with no seizure disorder were evaluated. Follow-up 24-h EEG recordings were performed after a median time of four months. RESULTS: Mean spike index was 50 prior to levetiracetam treatment and 21 during treatment. Seventeen children had no focal interictal epileptiform discharges in EEG at follow-up. Five children had a more than 50% reduction in spike index. Thus, a more than 50% reduction in spike index was found in 22/35 children (63%). Out of these an improved behaviour was noticed in 13 children (59%). CONCLUSION: This study shows that treatment with levetiracetam reduces interictal epileptiform discharges in children with ADHD. There is a complex relationship between epilepsy, ADHD and epileptiform activity, why it is a need for prospective studies in larger sample sizes, also to ascertain clinical benefits. PMID- 21683632 TI - On the inversion of diffusion NMR data: Tikhonov regularization and optimal choice of the regularization parameter. AB - The analysis of diffusion NMR data in terms of distributions of diffusion coefficients is hampered by the ill-posed nature of the required inverse Laplace transformation. Naive approaches such as multiexponential fitting or standard least-squares algorithms are numerically unstable and often fail. This paper updates the CONTIN approach of the application of Tikhonov regularization to stabilise this numerical inversion problem and demonstrates two methods for automatically choosing the optimal value of the regularization parameter. These approaches are computationally efficient and easy to implement using standard matrix algebra techniques. Example analyses are presenting using both synthetic data and experimental results of diffusion NMR studies on the azo-dye sunset yellow and some polymer molecular weight reference standards. PMID- 21683633 TI - Exchange enhanced sensitivity gain for solvent-exchangeable protons in 2D 1H-15N heteronuclear correlation spectra acquired with band-selective pulses. AB - Conformational or chemical exchange can cause significant sensitivity loss in NMR spectroscopy through resonance broadening for nuclear spins involved in these processes. While this effect may sometimes be alleviated by manipulating experimental conditions such as temperature, pH, and buffers, conditions optimal for all resonances are not always achievable. As a consequence, any means of recovering or minimizing this exchange-induced sensitivity loss is potentially of significant value in regaining information otherwise lost. We report the experimental observation of significant sensitivity gain for nuclear spins undergoing chemical exchange with solvent (water) at exchange rates ca 1-10 s(-1) in (1)H-(15)N correlation spectra of proteins acquired with band-selective pulses (the SOFAST-HMQC sequence). PMID- 21683634 TI - Optic nerve abnormalities in children: a practical approach. AB - Evaluation of children with optic nerve abnormalities is challenging. Fundus photography, ocular coherence tomography, visual field testing, color vision evaluation, neuroimaging, and genetic testing are helpful in the diagnosis and management of these patients. Importantly, many optic nerve problems are not isolated but occur in association with systemic and central nervous system anomalies. The ophthalmologist thus plays a critical role in recognizing patients who warrant systemic and neurologic assessment. PMID- 21683635 TI - Negative social reaction to strabismus in school children ages 8-12 years. AB - PURPOSE: To investigate children's willingness to sit next to a child with noticeable exotropia as a measure of social alienation. METHODS: This was a cross sectional, mixed-design study. Children in primary grades 3-6 (8-12 years old) were asked to view 8 digitally modified images of exotropic or orthotropic children in classroom settings and rate their willingness to sit next to the child in each image. RESULTS: A total of 157 children participated. A 4 * 2 * 2 mixed-design analysis of variance revealed a significant main effect for primary level (F [3, 151] = 4.06, P = .01, partial eta(2) = .08) and for image type, exotropic versus orthotropic, (F [1, 151] = 108.45, P = .00, partial eta(2) = .42). The results of the main effects were qualified by a significant primary level X image type interaction (F [3, 151] = 4.00, P = .01, partial eta(2) = .08). Children were less willing to sit next to a person with noticeable exotropia. Although this phenomenon was consistent across all primary levels, the magnitude of the effect diminished in strength for children in higher primary levels. CONCLUSIONS: This study further strengthens existing evidence for strabismus-related prejudice that suggests that children with noticeable strabismus may be subjected to social alienation by other children. PMID- 21683637 TI - Completeness of reporting and case ascertainment for neonatal tetanus in rural Pakistan. AB - OBJECTIVES: The objectives of this study were to assess the case ascertainment and completeness of neonatal tetanus (NT) reporting and to estimate the incidence of NT in Dadu District, Pakistan. METHODS: We conducted active surveillance and hospital record reviews for suspected NT cases. We compared the cases of NT reported to the routine surveillance system with the cases identified through the hospital record reviews for 1993 through 2003. The two-source capture-recapture method was used to evaluate case ascertainment in the routine surveillance system and to estimate the incidence of cases of NT. RESULTS: Active surveillance and hospital record reviews identified 134 cases in addition to 274 cases in the routine surveillance system. The two-source capture-recapture method indicated that there would have been 463 cases during this period (95% confidence interval (CI)=418-508), representing an average annual incidence of 0.62 per 1000 live births. The overall completeness of routine reporting was 59.2%. The proportions of cases reported were 68.1% for government hospitals and 53.8% for private reporting sites. CONCLUSIONS: Reporting of NT cases is incomplete. Active promotion of private sector participation, community involvement, and strengthening of the government sector as a way of improving NT reporting and surveillance is strongly suggested. PMID- 21683636 TI - Structural insights to how mammalian capping enzyme reads the CTD code. AB - Physical interaction between the phosphorylated RNA polymerase II carboxyl terminal domain (CTD) and cellular capping enzymes is required for efficient formation of the 5' mRNA cap, the first modification of nascent mRNA. Here, we report the crystal structure of the RNA guanylyltransferase component of mammalian capping enzyme (Mce) bound to a CTD phosphopeptide. The CTD adopts an extended beta-like conformation that docks Tyr1 and Ser5-PO(4) onto the Mce nucleotidyltransferase domain. Structure-guided mutational analysis verified that the Mce-CTD interface is a tunable determinant of CTD binding and stimulation of guanylyltransferase activity, and of Mce function in vivo. The location and composition of the CTD binding site on mammalian capping enzyme is distinct from that of a yeast capping enzyme that recognizes the same CTD primary structure. Thus, capping enzymes from different taxa have evolved different strategies to read the CTD code. PMID- 21683638 TI - Human African trypanosomiasis: a review of non-endemic cases in the past 20 years. AB - Human African trypanosomiasis (HAT) is caused by sub-species of the parasitic protozoan Trypanosoma brucei and is transmitted by tsetse flies, both of which are endemic only to sub-Saharan Africa. Several cases have been reported in non endemic areas, such as North America and Europe, due to travelers, ex-patriots or military personnel returning from abroad or due to immigrants from endemic areas. In this paper, non-endemic cases reported over the past 20 years are reviewed; a total of 68 cases are reported, 19 cases of Trypanosoma brucei gambiense HAT and 49 cases of Trypanosoma brucei rhodesiense HAT. Patients ranged in age from 19 months to 72 years and all but two patients survived. Physicians in non-endemic areas should be aware of the signs and symptoms of this disease, as well as methods of diagnosis and treatment, especially as travel to HAT endemic areas increases. We recommend extension of the current surveillance systems such as TropNetEurop and maintaining and promotion of existing reference centers of diagnostics and expertise. Important contact information is also included, should physicians require assistance in diagnosing or treating HAT. PMID- 21683639 TI - Identification of HNF1A-MODY and HNF4A-MODY in Irish families: phenotypic characteristics and therapeutic implications. AB - AIM: The prevalence of hepatocyte nuclear factor (HNF)-1A and HNF4A mutations, and the clinical implications following the genetic diagnosis of maturity-onset diabetes of the young (MODY) in the Irish population, remain unknown. The aim of this study was to establish the occurrence of HNF1A and HNF4A mutations in subjects classified clinically as MODY to identify novel mutations, and to determine the phenotypic features and response to therapy. METHODS: A total of 36 unrelated index cases with a clinical diagnosis of MODY were analyzed for HNF1A/HNF4A mutations. OGTT was performed to determine the degree of glucose tolerance and insulin secretory response. Also, 38 relatives underwent OGTT and were tested for the relevant known mutations. HNF1A-/HNF4A-MODY subjects were compared with nine HNF1A mutation-negative relatives and 20 type 2 diabetic (T2DM) patients. RESULTS: Seven different HNF1A mutations were identified in 11/36 (30.5%) index cases, two of which were novel (S352fsdelG and F426X), as well as two novel HNF4A mutations (M1? and R290C; 6%). Family screening revealed 20 subjects with HNF1A and seven with HNF4A mutations. Only 51.6% of HNF1A mutation carriers were diagnosed with diabetes by age 25 years; 11 of the mutation carriers were overweight and four were obese. Insulin secretory response to glucose was significantly lower in HNF1A-MODY subjects than in T2DM patients and HNF1A mutation-negative relatives (P=0.01). Therapeutic changes occurred in 48% of mutation carriers following genetic diagnosis. CONCLUSION: There was an HNF1A-MODY pick-up rate of 30.5% and an HNF4A-MODY pick-up rate of 6% in Irish MODY families. Genetically confirmed MODY has significant therapeutic implications. PMID- 21683640 TI - [Radiation biology: major advances and perspectives for radiotherapy]. AB - At the beginning of the 21st century, radiation biology is at a major turning point in its history. It must meet the expectations of the radiation oncologists, radiologists and the general public, but its purpose remains the same: to understand the molecular, cellular and tissue levels of lethal and carcinogenic effects of ionizing radiation in order to better protect healthy tissues and to develop treatments more effective against tumours. Four major aspects of radiobiology that marked this decade will be discussed: technological developments, the importance of signalling and repair of radiation-induced deoxyribonucleic acid (DNA) damage, the impact of individual factor in the response to radiation and the contribution of radiobiology to better choose innovative therapies such as protontherapy or stereotactic body radiation therapy (SBRT). A translational radiobiology should emerge with the help of radiotherapists and radiation physicists and by facilitating access to the new radio and/or chemotherapy modalities. PMID- 21683642 TI - Diatom extraction with HCl from animal tissues: a technical note. AB - Identification of diatoms from human or animal tissue may be affected by factors concerning techniques of extraction and analysis which cause fragmentation or loss of diatoms. In this brief technical note a novel efficient method of extraction of diatoms from animal tissues is presented. The authors have tested an H(2)O(2) plus HCl and HCl method to detect diatoms in several tissues from pig immersed in water rich in diatoms; they have also compared this method to other methods of extraction including enzymatic ones. The experiment showed that all siliceous frustules of fresh water diatoms are resistant to the treatment proposed and are still recognizable after the digestion. Among the different tests, treatment by 20% HCl (T1) proved to be more simple and time-saving, and seems to be a valuable diagnostic tool for routine forensic procedures in the extraction and detection of diatoms. The positive results obtained in all cases should lead to further studies in order to evaluate the reliability of the proposed methods also from a quantitative point of view. PMID- 21683641 TI - Anti-mutated citrullinated vimentin (anti-MCV) and anti-65 kDa heat shock protein (anti-hsp65): new biomarkers in ankylosing spondylitis. AB - INTRODUCTION: Citrullination as well as anti-citrullinated protein/peptide antibodies (ACPA) have been implicated in the pathogenesis of rheumatoid arthritis (RA). While ACPAs are specific and sensitive markers for RA, there have been hardly any reports regarding ACPAs in ankylosing spondylitis (AS). The possible role of antibodies to Mycobacterial 65 kDa heat shock protein (hsp65) has not been characterized in AS. As new laboratory biomarkers of AS are needed, we investigated the prevalence of anti-mutated citrullinated vimentin (MCV) and anti-hsp65 antibodies in AS. METHODS: Altogether 43 AS and 44 healthy controls were included in the study. Anti-MCV and anti-hsp65 were determined in sera by commercial and in-house ELISA, respectively. Serum autoantibody levels were correlated with ESR, CRP, HLA-B27 status, smoking habits, pain intensity, BASDAI, BASFI and BASMI indices. RESULTS: Patients with AS had significantly higher serum anti-MCV levels (17.3 U/mL, range: 8.3-31.5 U/mL) in comparison to healthy subjects (8.9 U/mL, range: 5.4-13.3 U/mL) (p<0.01). Sixteen of the 43 AS patients (37%) and none of the 44 healthy controls (0%) were anti-MCV positive using the cut-off value recommended by the manufacturer (>20 U/mL). The mean anti-hsp65 concentration in AS sera was 124.8 AU/mL (range: 27.2-1000 AU/mL), while controls exerted significantly lower anti-hsp65 levels (mean: 51.8 AU/mL; range: 22.5-88.5 AU/mL) (p<0.001). Correlation analysis revealed that both anti-MCV positivity (r=0.613; p=0.012) and absolute serum anti-MCV levels (r=0.553; p=0.021) correlated with anti-hsp65 levels. Anti-MCV positivity also correlated with ESR (r=0.437; p=0.03). CONCLUSIONS: Anti-MCV and anti-hsp65 may be novel biomarkers in AS. PMID- 21683643 TI - Combined analyses of creatine kinase MB, cardiac troponin I and myoglobin in pericardial and cerebrospinal fluids to investigate myocardial and skeletal muscle injury in medicolegal autopsy cases. AB - Creatine kinase-MB (CK-MB), cardiac troponin I (cTnI) and myoglobin (Mb) are biochemical markers of myocardial injury; however, Mb is more abundant in skeletal muscles. The present study involved analysis of these markers in pericardial and cerebrospinal fluids (PCF and CSF) from serial medicolegal autopsy cases (n=295, within 48h) to examine their efficacy in determining the cause of death. Although these markers showed a slight postmortem time-dependent elevation, except for CK-MB in CSF, the distribution depended on the cause of death. Mb levels in PCF and CSF were higher in fatal hyperthermia (heat stroke) and methamphetamine abuse, and CK-MB in both fluids was also higher in the latter. In psychotropic drug intoxication, CK-MB, cTnI and Mb were higher in PCF, but only cTnI was elevated in CSF. In electrocution and cerebrovascular disease, each marker was higher in PCF and also relatively high in CSF. PCF cTnI level was higher in acute pulmonary embolism without significant elevation of any other markers, whereas CSF CK-MB was higher in acute blunt brain injury death and methamphetamine abuse. In most cases of delayed brain injury death, hypothermia (cold exposure) and pneumonia, these markers were low or intermediate in both PCF and CSF; however, sudden cardiac death, asphyxiation and fire fatality cases showed few characteristic findings. These observations suggest that combined analyses of these markers in postmortem PCF and CSF, in addition to blood samples, are helpful for evaluating the severity of myocardial and/or skeletal muscle damage in death processes, in particular for investigating deaths due to hyperthermia, hypothermia, electrocution and intoxication. PMID- 21683644 TI - Expression of Bcl2l1, Clcf1, IL-28ra and Pias1 in the mouse heart after single and repeated administration of chlorpromazine. AB - Several chlorpromazine (CPZ)-related deaths have been suspected in forensic autopsies but these are difficult to identify precisely because only low concentrations of CPZ can usually be detected. Patients on CPZ therapy exhibit various cardiovascular diseases, such as arrhythmia and cardiomyopathy. As our previous study revealed that CPZ administration affects the expression of immediate early genes that are induced before any other genes, we expected that CPZ probably affects the heart and, in particular, the gene expression in heart. CPZ changes tumor necrosis factor (TNF) production. After stimulation of TNF, the Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling pathway is activated via TNF receptor (TNF-R), and the pathway participates in the regulation of cellular responses such as apoptosis [1]. We used semi-arrays to determine the JAK-STAT signaling pathway in a mouse cardiomyocyte cell line, HL-1, and real-time quantitative-PCR to determine whether the semi-array data applied in vivo in mouse heart after single and once daily repeated (1-4weeks) low-dose (0.75mg/kg) or high-dose (7.5mg/kg) CPZ treatment. We found that expression of B cell lymphoma 2 like 1 (Bcl2l1), Cardiotrophin-like cytokine factor 1 (Clcf1), Interleukin-28 receptor alpha (IL 28ra) and Protein inhibitor of activated STAT-1 (Pias1) were significantly changed in vivo. All these genes are associated with apoptosis. The expression level of Bcl2l1 was elevated after a single high-dose CPZ treatment and after 1week of repeated high doses, but returned to baseline from week 2 to week 4. Clcf1 and IL-28ra expression increased from week 2 or 3 after low-dose CPZ treatment. Pias1 also increased from week 2 after low-dose CPZ treatment. Our results indicate that different doses of CPZ can induce distinct patterns of gene expression for preventing the apoptotic progression in mouse cardiomyocytes, suggesting that CPZ can affect cardiomyocytes via the JAK-STAT signaling pathway and that this might lead to cardiomyopathy. In addition, our data may help to clarify the pathophysiology of cardiomyopathy induced by CPZ and to diagnose cardiac sudden death following CPZ treatment. PMID- 21683645 TI - Cessation of refractory post-traumatic tremor after convulsive status epilepticus. PMID- 21683646 TI - Malignant transformation of proliferative verrucous leukoplakia to oral squamous cell carcinoma: a series of 55 cases. AB - In this study, we compared clinical differences between patients with proliferative verrucous leukoplakia (PVL) who did and did not develop oral cancer. This was a retrospective study of 55 PVL cases. All patients were followed for at least 1year, with a mean follow-up of 7.53 (SD=4.18) years. The mean age of the patients was 61.69 (SD=11.76) years. There were 36 (65.5%) females and 19 (34.5%) males. Group 1 included the 28 PVL patients who did not develop oral squamous cell carcinoma (OSCC) during the period. Group 2 included the 27 PVL patients who developed at least one OSCC during the period. The latter group was subdivided into patients with PVL who developed one (Subgroup 2a; n=16) or more than one (Subgroup 2b; n=11) OSCC during follow-up. There was no statistical difference in age or oral location of the PVL between Groups 1 and 2. Females had a greater tendency to develop cancer than males (58.3% vs. 31.6%). In Group 2, only six (22.2%) were smokers. There was no difference between Subgroups 2a and b in terms of age, gender, and oral location of the PVL. Subgroup 2b included fewer smokers, had higher gingival involvement rate, and lower frequency of PVL on the tongue. The PVL patients who develop oral cancers were more commonly female and non-smokers. Those patients who developed more than one OSCC were most likely to develop lesions of the gingiva. PMID- 21683647 TI - The impact of late treatment-toxicity on generic health-related quality of life in head and neck cancer patients after radiotherapy. AB - To examine the impact of late treatment-related xerostomia and dysphagia on health-related quality of life (HRQOL) in head and neck cancer (HNC) patients after radiotherapy. A multi-center cross-sectional survey was performed. Patients with a follow-up of at least 6months after curative radiotherapy, without evidence of recurrent disease were eligible for inclusion. The Euroqol-5D questionnaire (EQ-5D) was filled out and toxicity was scored and converted to the RTOG scale. The EQ-5D measures generic HRQOL in terms of utility and visual analogue scale (VAS) scores. Missing data on the EQ-5D were imputed using multiple imputation. HRQOL was compared between subgroups of patients with and without toxicity. Subsequently, the impact of xerostomia and dysphagia on HRQOL was analyzed using multivariate regression analyses. Both analyses were performed separately for utility scores and VAS scores. The study population was composed of 396 HNC patients. The average utility and VAS scores were 0.85 (scale 0-1) and 75 (scale 0-100). Subgroups of patients with xerostomia and/or dysphagia showed statistically significantly lower utility and VAS scores (P=0.000-0.022). The multivariate regression model showed that xerostomia and dysphagia were negative predictors of both utility and VAS scores. Other factors which influenced HRQOL in at least one of the two regression models were: sex, tumor location and the addition of surgery to radiotherapy. Xerostomia and dysphagia diminish generic HRQOL. Moreover dysphagia affects patients' HRQOL stronger than xerostomia. PMID- 21683648 TI - A study on quantum chemical calculations of 3-, 4-nitrobenzaldehyde oximes. AB - The molecular geometry, vibrational frequencies, 1H and 13C NMR chemical shifts, UV-vis spectra, HOMO-LUMO analyses, molecular electrostatic potentials (MEPs), , thermodynamic properties and atomic charges of 3- and 4-Nitrobenzaldehyde oxime (C7H6N2O3) molecules have been investigated by using Hartree-Fock (HF) and density functional theory (DFT/B3LYP) methods with the 6-311++G(d, p) basis set. The calculated optimized geometric parameters (bond lengths and bond angles), the vibrational frequencies calculated and 13C and 1H NMR chemical shifts values for the mentioned compounds are in a very good agreement with the experimental data. Furthermore, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) have been simulated and the transition states, energy band gaps and molecular electrostatic potential (MEP) maps for each oxime compound have been determined. Additionally, we also report the infrared intensities and Raman activities for the compounds under study. PMID- 21683649 TI - Rectal swabs can be used for diagnosis of viral gastroenteritis with a multiple real-time PCR assay. AB - BACKGROUND: Viral agents, especially norovirus, are the most common cause of nosocomial spread of epidemic gastroenteritis (GE). Rapid and reliable detection of these agents could reduce the risk of outbreaks. OBJECTIVE: To evaluate the diagnostic performance of rectal swab samples compared to standard stool samples for detection of agents causing viral GE by PCR. STUDY DESIGN: Complete pairs of rectal swab and stool samples, obtained simultaneously from patients with symptoms of acute onset GE, were analysed with a multiple real-time PCR targeting six different gastroenteritis agents (astro-, adeno-, rota-, sapo- and norovirus GI and II). Cycle threshold (Ct) values were registered for positive samples. A positive PCR result in either sample for any virus was considered gold standard. RESULTS: 69 sample pairs were included of which 29 were negative in both sample types and 38 were positive in both sample types. One pair was positive in the stool sample only and another pair was positive in the rectal swab sample only. Sensitivity for both sample types was 97.5% (39/40). CONCLUSION: Rectal swab samples are as reliable as stool samples for PCR-based diagnosis of viral gastroenteritis in patients with a short duration of symptoms and may be used as a complement to stool samples, especially when immediate sampling is desirable. PMID- 21683650 TI - Intra- and inter-rater reliability of motor unit number estimation and quantitative motor unit analysis in the upper trapezius. AB - OBJECTIVE: To collect normative data and assess the intra- and inter-rater reliability of decomposition-enhanced spike-triggered averaging (DE-STA) motor unit number estimation (MUNE) and quantitative MU analysis obtained using decomposition-based quantitative electromyography (DQEMG) in the upper trapezius (UT). METHODS: In 10 control subjects, the experimental protocol was performed twice by the same examiner, and once by a second examiner. RESULTS: Mean MUNE values were 339+/-121 (rater 1a), 320+/-131 (rater 1b), and 262+/-115 (rater 2) MUs. Intra- and inter-rater reliability was good for maximum CMAP (ICC=0.77 and 0.79, respectively) and moderate for MUNE (ICC=0.69 and 0.73, respectively), with poor inter-rater reliability for mean S-MUP (ICC=0.42). Significant differences between rater 1a and 2 were found for mean S-MUP (p=0.014) and MUNE (p=0.002), and moderate to good levels of reliability found for quantitative needle-detected MUP parameters. CONCLUSIONS: Various components of the protocol may have contributed to mean S-MUP variability, and may require particular attention in a large, proximal muscle like the UT. SIGNIFICANCE: This study has established preliminary data using DQEMG in a novel muscle which may be relevant to study in patients with ALS. PMID- 21683651 TI - Associations between activity-related behaviours and standardized BMI among Australian adolescents. AB - OBJECTIVES: To examine the relationships between physical activity, sedentary behaviour and body mass index (BMI) among a sample of Australian adolescents. METHODS: Anthropometric, demographic and behavioural data were collected from students (n=3040 mean age 14.6, 44% female) from 12 secondary schools in South West Victoria, Australia (response rate=48.6%). The appropriate descriptive, univariate and regression analysis were used to examine the strength of the associations between physical activity, sedentary behaviour and odds of overweight or obese and the effect of interaction between physical activity and sedentary behaviour on odds of overweight and obese. RESULTS: Males were more likely to be active during the school day than females and had higher median hours of screen time per school day. Physical activity during the school day was associated with higher standardized BMI (BMI-z) among males. Higher levels of activity after school were associated with lower BMI-z for males and females. For both males and females the odds of overweight or obese were higher among the least active. An interaction was observed for females whereby the prevalence of overweight and obesity among the most physically active was lowest for the least sedentary and highest for the most sedentary. CONCLUSIONS: The relationships between physical activity, sedentary behaviour and BMI-z were complex. Interventions to reduce BMI through increasing physical activity or decreasing sedentary behaviour need to consider the complex inter-relationships between these variables and moderating factors such as age, sex and socio economic status in their design and interpretation. PMID- 21683652 TI - External validation of nomogram for the decline in serum anti-Mullerian hormone in women: a population study of 15,834 infertility patients. AB - The value of anti-mullerian hormone (AMH) as a marker of the ovarian reserve is becoming clear in a range of clinical contexts.This study reports the external validation of a quadratic model-based AMH-age nomogram using a cohort of 15,834 US women. All models previously investigated for the decline in ovarian reserve (i.e. linear, bi-linear, decay curve, power and quadratic models) tended to overestimate AMH by approximately 11% versus the published nomogram, indicating some between-population heterogeneity. Bootstrapping of 1000 datasets indicated that the quadratic model provided the best fit, confirming the choice of this model in the AMH-age nomogram. This nomogram can therefore be used with confidence for the interpretation of AMH in clinical populations. PMID- 21683653 TI - Effectiveness of interventions to improve screening for syphilis in pregnancy: a systematic review and meta-analysis. AB - BACKGROUND: About 2.1 million pregnant women have active syphilis every year. Without screening and treatment, 69% of these women will have an adverse outcome of pregnancy. The objectives of this study were to review the literature systematically to determine the effectiveness of screening interventions to prevent congenital syphilis and other adverse pregnancy outcomes. METHODS: We searched four electronic databases and selected studies to examine evidence for effectiveness of interventions on three outcomes: increased uptake of syphilis testing, increased treatment rates, and reduction in adverse pregnancy outcomes. We used fixed effects meta-analysis to estimate pooled relative risks if no or little evidence of heterogeneity between trials existed. FINDINGS: Ten studies met the inclusion criteria, including two randomised trials. Only two studies aimed to encourage women to seek care earlier in pregnancy. Nine studies included decentralisation of screening and treatment. The effects of the interventions on uptake of testing for antenatal syphilis and receiving at least one dose of penicillin were variable and could not be combined statistically. Study interventions were associated with a reduction in perinatal death (pooled risk ratio [RR] from three studies 0.46, 95% CI 0.26-0.82) and stillbirth (pooled RR from three studies 0.42, 95% CI 0.19-0.93). The incidence of congenital syphilis was reduced in all four studies that measured this outcome with heterogeneous results. INTERPRETATION: Interventions to improve the coverage and effect of screening programmes for antenatal syphilis could reduce the syphilis attributable incidence of stillbirth and perinatal death by 50%. The resources required to roll out antenatal screening programmes would be a worthwhile investment for reduction of adverse pregnancy outcomes and improvement of neonatal and child survival. FUNDING: None. PMID- 21683654 TI - Syphilis, still a major cause of infant mortality. PMID- 21683655 TI - Meaningfulness is not the most important component for changes in sense of coherence. AB - BACKGROUND: Sense of coherence is a theoretical construct which is used to measure the degree to which a person finds the world comprehensible, manageable and meaningful. AIM: The main aim of the present study was to assess the hypothesis of Antonovsky that meaningfulness is the most crucial component in sense of coherence. The second aim was to explore the importance of its components and factors at baseline on sense of coherence changes and if the findings can be used in cardiac rehabilitation. METHODS: One hundred patients, who suffered a primary myocardial infarction were followed during two years. The instruments used were; sense of coherence questionnaire-13, 12-item short-form health survey questionnaire, the Seattle angina questionnaire and health curve. RESULTS: Thirty-nine percent of the participants fulfilled Antonovsky's hypothesis. Comprehensibility and the baseline factors of smoking, alcohol use, marital status and disease perception proved to be of importance for sense of coherence changes over time. CONCLUSION: The hypothesis that meaningfulness is the most crucial component in sense of coherence is rejected for patients with primary myocardial infarction. Comprehensibility is more important than meaningfulness for changes in sense of coherence. Nurses therefore have an important task to increase comprehensibility and sense of coherence by providing information and knowledge about myocardial infarction and lifestyle changes at an early stage. The information should be given in an individualized and easily understandable way from a salutogenic perspective, which means to identify and work with factors that can contribute to preserving and promoting health. PMID- 21683656 TI - Prediction of the outcome of antenatally diagnosed hydronephrosis: a multivariable analysis. AB - PURPOSE: The majority of cases of antenatal hydronephrosis (ANH) resolve postnatally. The purpose of this study was to determine independent predictors for resolution of ANH using a multivariable analysis model. METHODS: A retrospective study was performed on 100 children (80 males and 20 females, 118 renal units) referred to a single pediatric urology clinic with the diagnosis of ANH. Patients with ultimately resolved ANH were compared to unresolved cases in a univariate analysis in terms of sex, laterality, severity of ANH using Society for Fetal Urology (SFU) grading, antero-posterior pelvic diameter (APD), parenchymal thickness, renographic differential function and development of clinical complications, followed by a Cox proportional hazard model for multivariable analysis. RESULTS: Median follow up was 34 months (range 3-204). Hydronephrosis in 62 units resolved spontaneously and pyeloplasty was done in 29. The remaining 27 units had persistent uncomplicated hydronephrosis at last follow up. Multivariate analysis showed larger APD (hazard ratio 0.54; 95%CI 0.36-0.80) and SFU grade 4 (HR 0.34; 95%CI 0.13-0.90) to be associated with a significantly lower likelihood of resolution. The mean initial APD in resolved cases was 9.4mm as opposed to 29.0mm in cases requiring surgery. CONCLUSION: Large initial APD has predictive value for surgical intervention. This model is helpful in counseling families about the potential outcomes of ANH. PMID- 21683657 TI - Incorporating human papillomavirus testing into cytological screening in the era of prophylactic vaccines. AB - Screening for, and treatment of, pre-cancerous cervical lesions has lead to dramatic reductions in cervical cancer in many countries. In all cases, cervical screening has been based on cytology, but that is beginning to change. Research studies, including randomised trials, clearly show that human papillomavirus (HPV) testing could be used to prevent a greater proportion of cervical cancer within a practical screening programme. Meanwhile, young adolescents are being vaccinated against HPV in developed countries, but cervical screening should continue for many years because it will take decades before most of those targeted by screening have been vaccinated. In the HPV vaccination era, the rate of cervical disease will decrease, and so will the positive predictive value of cytology. The screening characteristics of HPV testing make it the preferred choice for primary screening. However, questions regarding how to use HPV testing to screen vaccinated and unvaccinated women in the future remain unanswered. PMID- 21683658 TI - Personality traits in patients with juvenile myoclonic epilepsy. AB - There is evidence of personality disorders in patients with juvenile myoclonic epilepsy (JME). To date, there have been no published quantitative studies on personality traits in JME. The aim of the work described here was to study a group of patients with JME and quantitatively measure personality traits. We evaluated 42 patients (mean age: 26.57 years, SD: 8.38) and 42 controls (mean age: 26.96, SD: 8.48) using a validated personality inventory, the Temperament and Character Inventory (TCI). We applied two scores, one for the Beck Depression Inventory and one for the State-Trait-Anxiety Inventory, as depression and anxiety may impact the performance of these patients on the TCI. We compared both groups on TCI scales using analysis of covariance with Beck Depression Inventory and State-Trait-Anxiety Inventory scores as covariates. Patients with JME obtained significantly higher scores on Novelty Seeking (P=0.001) and Harm Avoidance (P=0.002) and significantly lower scores on Self-Directedness (P=0.001). Patients with JME have a higher expression of impulsive personality traits that demand early recognition to avoid further consequences and facilitate social insertion, consequently avoiding future stigma. PMID- 21683659 TI - Selective mGluR5 antagonism attenuates the stress-induced reduction of MK-801's antiseizure potency in the genetically inbred Balb/c mouse. AB - The ability of MK-801 (dizocilpine), a noncompetitive N-methyl D-aspartate (NMDA) antagonist, to antagonize electrical seizures is reduced in stressed mice. Stress associated alterations in seizure susceptibility and diminished efficacy of antiseizure medications in humans have been reported [Joels, 2009; Haut et al., 2007; Moshe et al., 2008]; thus, these experimental observations implicate altered endogenous tone of NMDA receptor-mediated neurotransmission in clinically adverse effects of stress on seizure proneness and treatment. The current exploratory experiment examined the effect of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an antagonist of mGluR5, administered prior to stress on the stress induced reduction of MK-801's antiseizure effect in Swiss-Webster and Balb/c mice; the Balb/c mouse is behaviorally hypersensitive to MK-801. Interestingly, the data suggest that MPEP can attenuate the severity of the stress-induced reduction of MK-801's antiseizure effect in the Balb/c strain. Thus, mGluR5 could serve as a target for strategies for adjuvant treatment of seizures exacerbated by stress. PMID- 21683660 TI - Light therapy for seniors in long term care. AB - OBJECTIVES: To investigate the effects of light therapy on cognition, depression, sleep, and circadian rhythms in a general, nonselected population of seniors living in a long term care facility. DESIGN: A double-blind, placebo-controlled trial. SETTING: The experiment took place at a long term care facility in Pennsylvania. PARTICIPANTS: Study participants (15 treatment, 13 placebo) were residents receiving either personal care or skilled nursing care. INTERVENTION: Treatment consisted of approximately 400 lux of blue light administered for 30 minutes per day, Monday through Friday, for 4 weeks. The placebo was approximately 75 lux of red light generated from the same device. MEASUREMENTS: Behavioral assessments were made using the MicroCog Assessment of Cognitive Functioning, Geriatric Depression Scale, and Profile of Mood States. Daytime sleepiness was evaluated using the Epworth Sleepiness Scale. RESULTS: Three of the 4 composite scores from the MicroCog as well as the mean Tension/Anxiety score from the Profile of Mood States showed a significant treatment versus placebo effect. CONCLUSION: Blue light treatment led to significant cognitive improvements compared with placebo red light and may be a promising environmental intervention to reduce cognitive symptoms in elderly, long-term care residents. PMID- 21683661 TI - Scope and severity index: a metric for quantifying nursing home survey deficiency number, scope, and severity adjusted for the state-related measurement bias. AB - OBJECTIVES: To develop a metric (scope and severity index [SSI]) to measure nursing home deficiency number, scope, and severity adjusted for the state related bias and to test its convergent and predictive validity. DESIGN: We assigned scope and severity weights to each level of scope and severity (A-L). SSI was calculated as a sum of all weights per survey which was further corrected for the state-level bias by dividing by the state average number of health deficiencies and multiplying by the national average number of health deficiencies. Data source - National Online Survey, Certification, and Reporting system. SETTING: All Medicare/Medicaid-certified skilled nursing facilities. MEASUREMENTS: We correlated SSI with nursing home staffing levels (convergent validity) and denial of payment for new admissions (predictive validity). RESULTS: The expert panel reached agreement on the scope and severity weights: Level A = 5, B = 10, C = 15, D = 20, E = 30, F = 40, G = 35, H = 50, I = 65, J = 55, K = 75, and L = 100 points. Scope and severity per deficiency was positively correlated with the number of deficiencies in that survey. SSI contained almost no state-related bias, but yet related state-level variability. It demonstrated strong face, convergent, and predictive validity. CONCLUSIONS: SSI rendered a valuable metric to conduct quantitative analyses of nursing home deficiency number, scope, and severity across states. Future research should investigate the positive relationship between scope and severity of deficiencies and their number. Better understanding and correction of other factors introducing systematic bias to the survey results (e.g. regional impact) can further improve the accuracy of survey result evaluation. PMID- 21683662 TI - Minimal trauma fractures: lifting the specter of misconduct by identifying risk factors and planning for prevention. AB - Minimal trauma fractures are an unfortunate, yet not uncommon, event for frail elderly individuals in long term care facilities. These fractures result in significant morbidity including pain and loss of function along with significantly increased mortality. Further concern exists for the medico-legal issues raised after a minimal trauma fracture is discovered. The controversy at hand is whether such fractures are primarily the result of inadequate, careless, or abusive care practices. We build a case to the contrary. Although the data regarding this condition are limited, there exists a reasonable evidence base to identify an at-risk patient population. We present a representative case and subsequent literature review of minimal trauma fractures to illustrate the condition, including risk factors, mode of presentation, and patient outcomes. No direct research has been conducted on the pathophysiology of these fractures. Extrapolating from other similar conditions and likely associated comorbid illnesses, we explore possible physiologic explanations for their occurrence. Again, no direct investigation into prevention or treatment of minimal trauma fractures has been published. Instead, we consider a variety of pharmacologic and nonpharmacologic interventions that may modify the risk for minimal trauma fractures considering the previously identified risk factors and probable pathophysiologic changes leading to fracture development. We propose that reducing minimal trauma fractures in the frail elderly nursing home population will require careful staff education, close attention to identify at-risk patients, and implementation of select interventions aimed at preventing such fractures. PMID- 21683663 TI - The constructal law and the evolution of design in nature. AB - The constructal law accounts for the universal phenomenon of generation and evolution of design (configuration, shape, structure, pattern, rhythm). This phenomenon is observed across the board, in animate, inanimate and human systems. The constructal law states the time direction of the evolutionary design phenomenon. It defines the concept of design evolution in physics. Along with the first and second law, the constructal law elevates thermodynamics to a science of systems with configuration. In this article we review the more recent work of our group, with emphasis on the advances made with the constructal law in the natural sciences. Highlighted are the oneness of animate and inanimate designs, the origin of finite-size organs on animals and vehicles, the flow of stresses as the generator of design in solid structures (skeletons, vegetation), the universality and rigidity of hierarchy in all flow systems, and the global design of human flows. Noteworthy is the tapestry of distributed energy systems, which balances nodes of production with networks of distribution on the landscape, and serves as key to energy sustainability and empowerment. At the global level, the constructal law accounts for the geography and design of human movement, wealth and communications. PMID- 21683664 TI - [Enteral nutrition for management of diabetic enteropathy: a case report]. PMID- 21683665 TI - [Changes in the international recommendations on neonatal resuscitation, 2010: comments]. AB - Since previous publication in 2005, the most significant changes that have been addressed in the 2010 International Liaison Committee on Resuscitation (ILCOR) recommendations are as follows: (i) use of 2 vital characteristics (heart rate and breathing) to initially evaluate progression to the following step in resuscitation; (ii) oximetry monitoring for the evaluation of oxygenation (assessment of color is unreliable); (iii) for babies born at term it is better to start resuscitation with air rather than 100% oxygen; (iv) administration of supplementary oxygen should be regulated by blending oxygen and air; (v) controversy about endotraqueal suctioning of depressed infants born through meconium-stained amniotic fluid; (vi) chest compression-ventilation ratio should remain at 3/1 for neonates unless the arrest is known to be of cardiac etiology, in which case a higher ratio should be considered; (vii) use of therapeutic hypothermia for infants born at term or near term evolving to moderate or severe hypoxic-ischemic encephalopathy, with protocol and follow-up coordinated through a regional perinatal system (post-resuscitation management); (viii) cord clamping delay for at least 1 minute in babies who do not require resuscitation (there is insufficient evidence to recommend a time for clamping in those who require resuscitation) and, (ix) it is appropriate to consider discontinuing resuscitation if there has been no detectable heart rate for 10 minutes, although many factors contribute to the decision to continue beyond 10 minutes. Under certain circumstances, non-initiation of resuscitation could be proposed taking into consideration general recommendations, own results and parents' opinion. PMID- 21683666 TI - Indocyanine green (ICG)-enhanced lymphography for evaluation of facial lymphoedema. PMID- 21683667 TI - Comparative analysis of human mitochondrial DNA from World War I bone samples by DNA sequencing and ESI-TOF mass spectrometry. AB - Mitochondrial DNA is commonly used in identity testing for the analysis of old or degraded samples or to give evidence of familial links. The Abbott T5000 mass spectrometry platform provides an alternative to the more commonly used Sanger sequencing for the analysis of human mitochondrial DNA. The robustness of the T5000 system has previously been demonstrated using DNA extracted from volunteer buccal swabs but the system has not been tested using more challenging sample types. For mass spectrometry to be considered as a valid alternative to Sanger sequencing it must also be demonstrated to be suitable for use with more limiting sample types such as old teeth, bone fragments, and hair shafts. In 2009 the Commonwealth War Graves Commission launched a project to identify the remains of 250 World War I soldiers discovered in a mass grave in Fromelles, France. This study characterises the performance of both Sanger sequencing and the T5000 platform for the analysis of the mitochondrial DNA extracted from 225 of these remains, both in terms of the ability to amplify and characterise DNA regions of interest and the relative information content and ease-of-use associated with each method. PMID- 21683668 TI - Use of a brief standardized screening instrument in a primary care setting to enhance detection of social-emotional problems among youth in foster care. AB - OBJECTIVE: To determine whether systematic use of a validated social-emotional screening instrument in a primary care setting is feasible and improves detection of social-emotional problems among youth in foster care. METHODS: Before-and after study design, following a practice intervention to screen all youth in foster care for psychosocial problems using the Strengths and Difficulties Questionnaire (SDQ), a validated instrument with 5 subdomains. After implementation of systematic screening, youth aged 11 to 17 years and their foster parents completed the SDQ at routine health maintenance visits. We assessed feasibility of screening by measuring the completion rates of SDQ by youth and foster parents. We compared the detection of psychosocial problems during a 2-year period before systematic screening to the detection after implementation of systematic screening with the SDQ. We used chart reviews to assess detection at baseline and after implementing systematic screening. RESULTS: Altogether, 92% of 212 youth with routine visits that occurred after initiation of screening had a completed SDQ in the medical record, demonstrating high feasibility of systematic screening. Detection of a potential mental health problem was higher in the screening period than baseline period for the entire population (54% vs 27%, P < .001). More than one-fourth of youth had 2 or more significant social-emotional problem domains on the SDQ. CONCLUSIONS: Systematic screening for potential social-emotional problems among youth in foster care was feasible within a primary care setting and doubled the detection rate of potential psychosocial problems. PMID- 21683669 TI - Prospecting for adipose progenitor cell biomarkers: biopanning for gold with in vivo phage display. AB - In this issue of Cell Stem Cell, Daquinag et al. (2011) take a lesson from the oncology field to search for stromal progenitor cells within adipose tissue. Their use of phage display biopanning in vivo identified an isoform of the extracellular matrix protein decorin as a receptor for the adipokine resistin. PMID- 21683671 TI - Mental illness stigma and ethnocultural beliefs, values, and norms: an integrative review. AB - The current literature on the problem of mental illness stigma in the United States must be expanded to better account for the role of culture. This article examines the relationship between mental illness stigma and culture for Americans of American Indian, Asian, African, Latino, Middle Eastern, and European descent. In this review, culture refers to the shared beliefs, values, and norms of a given racial or ethnic group. The reviewed literature indicates that there are differences in stigma among the various cultural groups; however, explanations as to why these differences exist are scant. Qualitative and quantitative studies indicate that cultural values are important with regard to stigma, particularly for Asian Americans and African Americans. Less is known about the interaction between cultural values and mental illness stigma for other cultural groups. Continued research in the area requires better organization and more exploration of the role of cultural history and values as they relate to mental illness stigma. To that end, a detailed, systematic approach to future research in the area is proposed. PMID- 21683670 TI - An isoform of decorin is a resistin receptor on the surface of adipose progenitor cells. AB - Adipose stromal cells (ASCs) serve as mesenchymal progenitors in white adipose tissue (WAT). Intercellular interactions involving ASCs have remained obscure. By merging phage display technology with fluorescence-activated cell sorting (FACS), we screened a combinatorial library for peptides that target mouse ASCs in vivo. We isolated peptide CSWKYWFGEC that specifically homes to ASCs, used it as bait to purify the corresponding ASC surface receptor, and identified it as a previously unreported cleavage product of decorin (DCN) lacking the glycanation site (termed DeltaDCN). We demonstrate that DeltaDCN is differentially expressed on ASC surface. In a screen for DeltaDCN-binding proteins, we identified resistin, an adipokine for which the receptor has been unknown. Expression of DeltaDCN in 3T3-L1 cells promoted proliferation and migration but suppressed lipid accumulation upon adipogenesis induction, which was resistin dependent. We conclude that DeltaDCN serves as a functional receptor of resistin in adipocyte progenitors and may regulate WAT expansion. PMID- 21683672 TI - KISS1 methylation and expression as tumor stratification biomarkers and clinical outcome prognosticators for bladder cancer patients. AB - KISS1 is a metastasis suppressor gene that is lost in several malignancies, including bladder cancer. We tested the epigenetic silencing hypothesis and evaluated the biological influence of KISS1 methylation on its expression and clinical relevance in bladder cancer. KISS1 hypermethylation was frequent in bladder cancer cells analyzed by methylation-specific PCR and bisulfite sequencing and was associated with low gene expression, being restored in vitro by demethylating azacytidine. Hypermethylation was also frequently observed in a large series of bladder tumors (83.1%, n = 804). KISS1 methylation was associated with increasing stage (P = 0.001) and tumor grade (P = 0.010). KISS1 methylation was associated with low KISS1 transcript expression by quantitative RT-PCR (P = 0.037). KISS1 transcript expression was also associated with histopathological tumor stage (P < 0.0005). Low transcript expression alone (P = 0.003) or combined with methylation (P = 0.019) was associated with poor disease-specific survival (n = 205). KISS1 transcript expression remained an independent prognosticator in multivariate analyses (P = 0.017). KISS1 hypermethylation was identified in bladder cancer, providing a potential mechanistic explanation (epigenetic silencing) for the observed loss of KISS1 in uroepithelial malignancies. Associations of KISS1 methylation and its expression with histopathological variables and poor survival suggest the utility of incorporating KISS1 measurement using paraffin-embedded material for tumor stratification and clinical outcome prognosis of patients with uroepithelial neoplasias. PMID- 21683673 TI - Visualization of mouse pancreas architecture using MR microscopy. AB - Pancreatic diseases, which include diabetes, pancreatitis, and pancreatic cancer, are often difficult to detect and/or stage, contributing to a reduced quality of life and lifespan for patients. Thus, there is need for a technology that can visualize tissue changes in the pancreas, improve understanding of disease progression, and facilitate earlier detection in the human population. Because of low spatial resolution, current clinical magnetic resonance imaging (MRI) at low field strength has yet to fully visualize the exocrine, endocrine, vascular, and stromal components of the pancreas. We used high field strength magnetic resonance microscopy (MUMRI) to image mouse pancreas ex vivo without contrast agents at high spatial resolution. We analyzed the resulting high-resolution images using volume rendering to resolve components in the pancreas, including acini, islets, blood vessels, and extracellular matrix. Locations and dimensions of pancreatic components as seen in three-dimensional MUMRI were compared with histological images, and good correspondence was found. Future longitudinal studies could expand on the use of in vivo MUMRI in mouse models of pancreatic diseases. Capturing three-dimensional structural changes through MUMRI could help to identify early cellular and tissue changes associated with pancreatic disease, serving as a mode of improved detection in the clinic for endocrine and exocrine pathologies. PMID- 21683674 TI - Intermediate volume on computed tomography imaging defines a fibrotic compartment that predicts glomerular filtration rate decline in autosomal dominant polycystic kidney disease patients. AB - Total kidney and cyst volumes have been used to quantify disease progression in autosomal dominant polycystic kidney disease (ADPKD), but a causal relationship with progression to renal failure has not been demonstrated. Advanced image processing recently allowed to quantify extracystic tissue, and to identify an additional tissue component named "intermediate," appearing hypoenhanced on contrast-enhanced computed tomography (CT). The aim of this study is to provide a histological characterization of intermediate volume, investigate its relation with renal function, and provide preliminary evidence of its role in long-term prediction of functional loss. Three ADPKD patients underwent contrast-enhanced CT scans before nephrectomy. Histological samples of intermediate volume were drawn from the excised kidneys, and stained with hematoxylin and eosin and with saturated picrosirius solution for histological analysis. Intermediate volume showed major structural changes, characterized by tubular dilation and atrophy, microcysts, inflammatory cell infiltrate, vascular sclerosis, and extended peritubular interstitial fibrosis. A significant correlation (r = -0.69, P < 0.001) between relative intermediate volume and baseline renal function was found in 21 ADPKD patients. Long-term prediction of renal functional loss was investigated in an independent cohort of 13 ADPKD patients, followed for 3 to 8 years. Intermediate volume, but not total kidney or cyst volume, significantly correlated with glomerular filtration rate decline (r = -0.79, P < 0.005). These findings suggest that intermediate volume may represent a suitable surrogate marker of ADPKD progression and a novel therapeutic target. PMID- 21683675 TI - Prostaglandin E2 produced by Entamoeba histolytica signals via EP4 receptor and alters claudin-4 to increase ion permeability of tight junctions. AB - Entamoeba histolytica is a protozoan parasite that causes amebic dysentery characterized by severe watery diarrhea. Unfortunately, the parasitic factors involved in the pathogenesis of diarrhea are poorly defined. Prostaglandin E(2) (PGE(2)) is a host lipid mediator associated with diarrheal diseases. Intriguingly, E. histolytica produces and secretes this inflammatory molecule. We investigated the mechanism whereby ameba-derived PGE(2) induces the onset of diarrhea by altering ion permeability of paracellular tight junctions (TJs) in colonic epithelia. PGE(2) decreased barrier integrity of TJs in a dose- and time dependent manner, as measured by transepithelial resistance. PGE(2) signals were selectively transduced via the EP4 receptor. Furthermore, PGE(2) signaling decreased TJ integrity, as revealed by EP receptor-specific agonist and antagonist studies. Loss of mucosal barrier integrity corresponded with increased ion permeability across TJs. Subcellular fractionation and confocal microscopy studies highlighted a significant spatial alteration of an important TJ protein, claudin-4, that corresponded with increased sodium ion permeability through TJs toward the lumen. Moreover, PGE(2)-induced luminal chloride secretion was a prerequisite for alterations at TJs. Thus, the gradient of NaCl created across epithelia could serve as a trigger for osmotic water flow that leads to diarrhea. Our results highlight a pathological role for E. histolytica-derived PGE(2) in the onset of diarrhea. PMID- 21683676 TI - Selective permeabilization for the high-throughput measurement of compartmented enzyme activities in mammalian cells. AB - Permeabilization was evaluated as a rapid method to prepare mammalian cells for subcellular enzyme activity measurement. It was observed that enzymes can be measured directly in cell suspensions permeabilized by Triton X-100 and digitonin with various concentrations. Total enzyme activities measured in permeabilized cells were identical to those measured in sonicated cells showing that permeabilization can replace the more complicated sonication method. Tuning of digitonin concentration allowed selective permeabilization of plasma and mitochondrial membranes. This was studied by analyzing the release of extramitochondrial and mitochondrial marker enzymes on treatment with different concentrations of the agent. Solely the plasma membrane was permeabilized by using 0.01-0.02% (w/v) digitonin. Access to all cellular enzymes was achieved by using 0.05% (v/v) Triton X-100. This selective permeabilization was further evaluated in a 96-well plate format by testing additional marker enzymes and additional cell lines, Hep G2 and CHO-K1, applying the developed protocol. The presented method is well suited for the high-throughput analysis of subcellular localization and activity of enzymes. The method is simple and enables one to distinguish between mitochondrial and extramitochondrial activities, which is usually achieved only by much more complicated and time-consuming cell preparation. PMID- 21683677 TI - Improved agarose gel electrophoresis method and molecular mass calculation for high molecular mass hyaluronan. AB - The molecular mass of the polysaccharide hyaluronan (HA) is an important determinant of its biological activity and physicochemical properties. One method currently used for the analysis of the molecular mass distribution of an HA sample is gel electrophoresis. In the current work, an improved agarose gel electrophoresis method for analysis of high molecular mass HA is presented and validated. HA mobility in 0.5% agarose minigels was found to be linearly related to the logarithm of molecular mass in the range from approximately 200 to 6000 kDa. A sample load of 2.5 MUg for polydisperse HA samples was employed. Densitometric scanning of stained gels allowed analysis of the range of molecular masses present in the sample as well as calculation of weight-average and number average values. The method was validated for a polydisperse HA sample with a weight-average molecular mass of approximately 2000 kDa. Excellent agreement was found between the weight-average molecular mass determined by electrophoresis and that determined by rheological measurement of the solution viscosity. The revised method was then used to show that heating solutions of HA at 100 degrees C, followed by various cooling procedures, had no effect on the HA molecular mass distribution. PMID- 21683679 TI - 5-Ethynyl-2'-deoxycytidine as a new agent for DNA labeling: detection of proliferating cells. AB - The labeling of newly synthesized DNA in cells to identify cell proliferation is an important experimental technique. The most accurate methods incorporate [(3)H]thymidine or 5-bromo-2'-deoxyruidine (BrdU) into dividing cells during S phase, which is subsequently detected by autoradiography or immunohistochemistry, directly measuring the newly synthesized DNA. Recently, a novel method was developed to detect DNA synthesis in proliferating cells based on a novel thymidine analog, 5-ethynyl-2'-deoxyuridine (EdU). EdU is incorporated into DNA and subsequently detected with a fluorescent azide via "click" chemistry. This novel technique is highly sensitive and does not require DNA denaturation. However, it was also found that EdU exhibits time-dependent inhibition effects on cell growth. Therefore, here we report a novel deoxycytidine analog, 5-ethynyl-2' deoxycytidine (EdC), that can be used to detect DNA synthesis in vitro and in vivo at a similar sensitivity level compared with EdU. Furthermore, the EdC induced cytotoxicity is much less than that of EdU when combined with thymidine. This will be a potential application for the long-term detection of proliferating cells. PMID- 21683678 TI - Chiral capillary electrophoresis-mass spectrometry of 3,4-dihydroxyphenylalanine: evidence for its enantioselective metabolism in PC-12 nerve cells. AB - A fully automated chiral capillary electrophoresis-tandem mass spectrometry (CE MS/MS) method was developed for enantiomeric quantification of 3,4 dihydroxyphenylalanine (DOPA) and its precursors, phenylalanine (Phe) and tyrosine (Tyr). To avoid MS source contamination, a negatively charged chiral selector, sulfated beta-cyclodextrin (sulfated beta-CD), that migrated away from the detector was used in combination with the partial filling technique. The six stereoisomers were simultaneously quantified in less than 12 min. Detection limits were 0.48 and 0.51 MUM for l- and d-DOPA enantiomers, respectively. Assay reproducibility values (relative standard deviations [RSDs], n=6) were 4.43, 3.15, 4.91, 5.16, 3.96, and 3.25% for l- and d-DOPA, l- and d-Tyr, and l- and d Phe at 10 MUM, respectively. Thanks to the high enantioseparation efficiency, detection of trace d-DOPA in l-/d-DOPA mixtures could be achieved. The assay was employed to study the metabolism of DOPA, a well-known therapeutic drug for treating Parkinson's disease. It was found that l-DOPA was metabolized effectively in PC-12 cells. Approximately 88% of l-DOPA disappeared after incubation at a cell density of 2*10(6)cells/ml for 3 h. However, d-DOPA coexisting with l-DOPA in the incubation solution remained intact. The enantiospecific metabolism of DOPA in this neuronal model was demonstrated. PMID- 21683680 TI - Comparative analysis of microbial DNA extraction protocols for groundwater samples. AB - A comparative analysis of four different DNA extraction protocols was performed to determine the best choice for groundwater microbial diversity studies using temperature gradient gel electrophoresis (TGGE) analysis. The methods used were a chelex-based method, a modified salting out procedure (MSOP), and the commercial kits Epicentre and FastDNA. Both commercial kits exhibited the greatest reproducibility in their methods; however, their band patterns were very different. The protocol that showed the highest diversity was the chelex-based method, and the one that showed the lowest diversity was the FastDNA kit. PMID- 21683681 TI - Physical and functional interaction between D-ribokinase and topoisomerase I has opposite effects on their respective activity in Mycobacterium smegmatis and Mycobacterium tuberculosis. AB - d-ribose is an essential component of multiple important biological molecules and must first be phosphorylated by ribokinase before entering metabolic pathways. However, the function and regulation of ribokinases in Mycobacterium tuberculosis, the causative agent of tuberculosis, and its related species are largely unknown. In this study, we have characterized the activities of two putative ribokinases, Rv2436 and Ms4585, from M. tuberculosis and Mycobacterium smegmatis, respectively. The mycobacterial topoisomerase I (TopA) was found to physically interact with its ribokinase both in vitro and in vivo. By creating two ribokinase mutants that showed defective interactions with TopA, we further showed that the interaction between ribokinase and TopA had opposite effects on their respective function. While the interaction between the two proteins inhibited the ability of TopA to relax supercoiled DNA, it stimulated ribokinase activity. A cross-regulation assay revealed that the interaction between the two proteins was conserved in the two mycobacterial species. Thus, we uncovered an interplay between ribokinase and topoisomerase I in mycobacteria, which implies the existence of a novel regulatory strategy for efficient utilization of d ribose in M. tuberculosis that may be useful in stressful environments with restricted access to nutrients. PMID- 21683682 TI - The effect of variable liposome brightness on quantifying lipid-protein interactions using fluorescence correlation spectroscopy. AB - Fluorescence correlation spectroscopy (FCS) has been increasingly used to study the binding of fluorescently-labeled peptides and proteins to phospholipid vesicles. In this work, we present a new method to analyze partition data obtained by this technique based on the assumption that the number of fluorescently-labeled protein molecules bound per liposome follows a Poisson distribution. To not overestimate the recovered partition coefficients, we first show that the variation in liposome brightness caused by this statistical distribution must be considered explicitly in data analysis when the parameter used to establish the partition curves is the fractional instead of the absolute amplitudes associated with the slowest diffusing particles in the system (lipid vesicles), a choice frequently made in FCS partition studies. We further extend the theoretical model describing the membrane partition of a fluorescently labeled protein by considering the presence of a trace amount of free fluorescent dye (non-binding component) in the system. We show that this situation can account for an apparent maximal binding level lower than 100% in the experimental partitioning curves obtained for Alexa 488 fluorescently-labeled lysozyme and liposomes prepared with variable anionic phospholipid content. The extreme sensitivity of the FCS technique allowed uncoupling lysozyme partition from the protein-induced liposome aggregation, confirming that lysozyme binding to negatively charged liposomes is dominantly driven by electrostatic interactions. PMID- 21683684 TI - Activation of phospholipase A2 by Hsp70 in vitro. AB - We recently suggested a novel mechanism for the activation of phospholipase A2 (PLA2), with a (catalytically) highly active oligomeric state, which subsequently becomes inactivated by conversion into amyloid. This process can be activated by lysophosphatidylcholine which promotes both oligomerization and amyloid activation/inactivation. The heat shock protein 70 (Hsp70), has been demonstrated to be able to revert the conversion of alpha-synuclein and Alzheimer beta-peptide to amyloid fibrils in vitro. Accordingly, we would expect Hsp70 to sustain the lifetime of the active state of the enzyme oligomer by attenuating the conversion of the enzyme oligomers into inactive amyloid. Here we show that Hsp70 activates PLA2 in vitro, in a manner requiring ATP and Mg(2+). PMID- 21683683 TI - Towards understanding the Tat translocation mechanism through structural and biophysical studies of the amphipathic region of TatA from Escherichia coli. AB - The twin-arginine translocase (Tat) system is used by many bacteria and plants to move folded proteins across the cytoplasmic or thylakoid membrane. In most bacteria, the TatA protein is believed to form a defined pore in the membrane through homo-oligomerization with other TatA protomers. The predicted secondary structure of TatA includes a transmembrane helix, an amphipathic helix, and an unstructured C-terminal region. Here biophysical and structural investigations were performed on a synthetic peptide representing the amphipathic region of TatA (residues 22 to 44, abbreviated TatAH2). The C-terminal region of TatA (residues 44-89) was previously shown to be accessible from both the cytoplasmic and periplasmic sides of the membrane only when the membrane potential was intact, suggesting dependence of its topology on an energized membrane (Chan et al. 2007 Biochemistry 46: 7396-404). Such observation suggests that the TatAH2 region would have unique lipid interactions that may be related to the function of TatA during translocation and thus warranted further investigations. NMR and CD spectroscopy of TatAH2 show that it adopts a predominantly helical structure in a membrane environment while remaining unstructured in aqueous solution. Differential scanning calorimetry studies also reveal that TatAH2 interacts with DPPG lipids but not with DPPC, suggesting that negatively charged phospholipid head groups contribute to the membrane interactions with TatA. PMID- 21683685 TI - Mobility of late endosomal and lysosomal markers on phagosomes analyzed by fluorescence recovery after photobleaching. AB - During phagosome maturation, the late endosomal marker Rab7 and the lysosomal marker LAMP1 localize to the phagosomes. We investigated the mobility of Rab7 and LAMP1 on the phagosomes in macrophages by fluorescence recovery after photobleaching (FRAP) analysis. Rab7 was mobile between the phagosomal membrane and the cytosol in macrophages that ingested latex beads during phagosome maturation. The addition of interferon-gamma (IFN-gamma) restricted this mobility, suggesting that Rab7 is forced to bind to the phagosomal membrane by IFN-gamma-mediated activation. Immobilization of LAMP1 on the phagosomes was observed irrespective of IFN-gamma-activation. We further examined the mobility of Rab7 on the phagosomes containing Mycobacterium bovis BCG by FRAP analysis. The rate of fluorescence recovery for Rab7 on mycobacterial phagosomes was lower than that on the phagosomes containing latex beads, suggesting that mycobacteria impaired the mobility of Rab7 and arrested phagosome maturation. PMID- 21683686 TI - AhR deficiency impairs expression of LPS-induced inflammatory genes in mice. AB - Recent reports suggest the participation of the aryl hydrocarbon receptor (AhR) in the induction mechanism of the NF-kappaB signaling pathway. In the current study we challenged C57BL/6 wild-type (WT) and AhR deficient (AhR(-/-)) mice with bacterial lipopolysaccharide (LPS) to investigate the role of the AhR in expression profiles of LPS and NF-kappaB target genes. Further, we analyzed the effect of LPS on the DNA binding activity of NF-kappaB, C/EBP and AP-1 transcription factors in liver and lung from WT and AhR(-/-) mice. The results show that the LPS-induced expression of several target genes was impaired in AhR( /-) mice compared to WT mice. Depending on the target gene, the target tissue as well as the time of treatment, the deficiency of AhR may cause an inhibition or increase of the LPS-induced gene expression. The binding activity of NF-kappaB, C/EBP and AP-1 transcription factors was also affected in a time- and tissue dependent manner. The current study shows that the AhR is implemented in LPS induced inflammatory gene expression in vivo even in the absence of exogenous ligands of the AhR. The main implication of this finding is that the AhR functions in Toll-like receptor (TLR) and NF-kappaB signaling after activation by a classical stimulus, such as LPS. PMID- 21683687 TI - FcepsilonRI-induced mast cell cytokine production critically involves an aspartic acid residue (D234) in the C-terminal intracellular domain of the FcepsilonRIbeta chain. AB - The high affinity IgE Fc receptor (FcepsilonRI) beta chain is well implicated as a signal amplifier through the immunoreceptor tyrosine-based activation motif (ITAM) in its C-terminal intracellular region. Our previous study, however, demonstrated that mutation in all of the three tyrosine residues within the FcepsilonRIbeta ITAM did not impair FcepsilonRI-induced cytokine production, suggesting a possible functional region other than the ITAM. To investigate the ITAM-independent mechanism by which FcepsilonRIbeta regulates FcepsilonRI-induced cytokine production, mouse mast cells expressing various FcepsilonRIbeta mutants were generated. We observed that truncation of the FcepsilonRIbeta C-terminus downstream of the ITAM resulted in a considerable decrease in FcepsilonRI-induced IL-6 production but not degranulation. Furthermore, mutagenesis of a single C terminal aspartic acid (D234) to alanine (beta-D234A) also significantly impaired IL-6 production. In addition, the similarity between the circular dichroism (CD) spectra of the wild type and beta-D234A suggests that the secondary structure of the FcepsilonRIbeta C-terminus was not affected by the D234A mutation. Consistently, we did not observe any effect of this mutation on FcepsilonRI induced tyrosine phosphorylation of FcepsilonRIbeta. These observations strongly suggest a novel signaling pathway mediated by the cytoplasmic tail downstream of the FcepsilonRIbeta ITAM. PMID- 21683688 TI - Glutamate residue 90 in the predicted transmembrane domain 2 is crucial for cation flux through channelrhodopsin 2. AB - Channelrhodopsin 2 (ChR2) is a microbial-type rhodopsin with a putative heptahelical structure that binds all-trans-retinal. Blue light illumination of ChR2 activates an intrinsic leak channel conductive for cations. Sequence comparison of ChR2 with the related ChR1 protein revealed a cluster of charged amino acids within the predicted transmembrane domain 2 (TM2), which includes glutamates E90, E97 and E101. Charge inversion substitutions of these residues significantly altered ChR2 function as revealed by two-electrode voltage-clamp recordings of light-induced currents from Xenopus laevis oocytes expressing the respective mutant proteins. Specifically, replacement of E90 by lysine or alanine resulted in differential effects on H(+)- and Na(+)-mediated currents. Our results are consistent with this glutamate side chain within the proposed TM2 contributing to ion flux through and the cation selectivity of ChR2. PMID- 21683689 TI - Tumor-targeting magnetic lipoplex delivery of short hairpin RNA suppresses IGF-1R overexpression of lung adenocarcinoma A549 cells in vitro and in vivo. AB - Liposomal magnetofection potentiates gene transfection by applying a magnetic field to concentrate magnetic lipoplexes onto target cells. Magnetic lipoplexes are self-assembling ternary complexes of cationic lipids with plasmid DNA associated with superparamagnetic iron oxide nanoparticles (SPIONs). Type1 insulin-like growth factor receptor (IGF-1R), an important oncogene, is frequently overexpressed in lung cancer and mediates cancer cell proliferation and tumor growth. In this study, we evaluated the transfection efficiency (percentage of transfected cells) and therapeutic potential (potency of IGF-1R knockdown) of liposomal magnetofection of plasmids expressing GFP and shRNAs targeting IGF-1R (pGFPshIGF-1Rs) in A549 cells and in tumor-bearing mice as compared to lipofection using Lipofectamine 2000. Liposomal magnetofection provided a threefold improvement in transgene expression over lipofection and transfected up to 64.1% of A549 cells in vitro. In vitro, IGF-1R specific-shRNA transfected by lipofection inhibited IGF-1R protein by 56.1+/-6% and by liposomal magnetofection by 85.1+/-3%. In vivo delivery efficiency of the pGFPshIGF-1R plasmid into the tumor was significantly higher in the liposomal magnetofection group than in the lipofection group. In vivo IGF-1R specific-shRNA by lipofection inhibited IGF-1R protein by an average of 43.8+/-5.3%; that by liposomal magnetofection inhibited IGF-1R protein by 43.4+/-5.7%, 56.3+/-9.6%, and 72.2+/ 6.8%, at 24, 48, and 72 h, respectively, after pGFPshIGF-1R injection. Our findings indicate that liposomal magnetofection may be a promising method that allows the targeting of gene therapy to lung cancer. PMID- 21683690 TI - SUMO1 attenuates stress-induced ROS generation by inhibiting NADPH oxidase 2. AB - Small ubiquitin-like modifier 1 (SUMO1) is a member of the superfamily of ubiquitin-like proteins. Despite its structural similarity with ubiquitin, SUMO1 does not seem to play any role in protein degradation and its precise biological function is poorly understood. During our studies on heat-shock responses, we found that heat-shock stress increased SUMO1 conjugation in a dose-dependent manner. Intriguingly, SUMO1 conjugation resulted in decrease of intracellular ROS generation and protection cells from death under heat-shock stress. We showed that NADPH oxidase 2 (NOX2) is a target protein of sumoylation by SUMO1 using immunoprecipitation and is colocalized with SUMO1 at plasma membrane. Additionally, we demonstrated that the attenuation in intracellular ROS generation resulted from inhibition of NADPH oxidase complex (NOX) activity. These results suggested that SUMO1 plays an important role in modulation of NOX activity required for ROS generation. PMID- 21683692 TI - Cytochrome b(5) shifts oxidation of the anticancer drug ellipticine by cytochromes P450 1A1 and 1A2 from its detoxication to activation, thereby modulating its pharmacological efficacy. AB - Ellipticine is a pro-drug, whose activation is dependent on its oxidation by cytochromes P450 (CYP) and peroxidases. Cytochrome b(5) alters the ratio of ellipticine metabolites formed by isolated reconstituted CYP1A1 and 1A2, favoring formation of 12-hydroxy- and 13-hydroxyellipticine metabolites implicated in ellipticine-DNA adduct formation, at the expense of 9-hydroxy- and 7 hydroxyellipticine that are detoxication products. Cytochrome b(5) enhances the production of 12-hydroxy and 13-hydroxyellipticine. The change in metabolite ratio results in an increased formation of covalent ellipticine-DNA adducts, one of the DNA-damaging mechanisms of ellipticine antitumor action. This finding explains previous apparent discrepancies found with isolated enzymes and in vivo, where CYP1A enzymatic activation correlated with ellipticine-DNA-adduct levels while isolated CYP1A1 or 1A2 in reconstituted systems were much less effective than CYP3A4. The effect of cytochrome b(5) might be even more pronounced in vivo, since, as we show here, ellipticine increases levels of cytochrome b(5) in rat liver. Our results demonstrate that both the native 3D structure of cytochrome b(5) and the presence of the heme as an electron transfer agent in this protein enable a shift in ellipticine metabolites formed by CYP1A1/2. PMID- 21683691 TI - Valine 44 and valine 45 of human glutathione synthetase are key for subunit stability and negative cooperativity. AB - It was hypothesized that residues Val44 and Val45 serve as important residues for human glutathione synthetase (hGS) function and stability given their location at the dimer interface of this enzyme. Computational studies suggest that mutation at Val45 has more impact on the structure and stability of hGS than does mutation at Val44. Experimentally, enzymes with mutations at the 44 and or 45 positions of hGS were prepared, purified and assayed for initial activity. Val45 position mutations (either to alanine or tryptophan) have a greater impact on enzyme activity than do mutations at Val44. Differential scanning calorimetry experiments reveal a loss of stability in all mutant enzymes, with V45 mutations being less stable than the corresponding Val44 mutations. The gamma-GluABA substrate affinity remains unaltered in V44A and V45A mutant enzymes, but increases when tryptophan is introduced at either of these positions. Hill coefficients trend towards less negative cooperativity with the exception of V45W mutant hGS. These results imply that residues V44 and V45 are located along the allosteric pathway of this negatively cooperative dimeric enzyme, that their mutation impacts the allosteric pathway more than it does the active site of hGS, and that these residues (and by extension the dimer interface in which they are located) are integral to the stability of human glutathione synthetase. PMID- 21683693 TI - Oxidized LDL-induced endolysosomal phospholipidosis and enzymatically modified LDL-induced foam cell formation determine specific lipid species modulation in human macrophages. AB - Recruitment of circulating monocytes and formation of macrophage foam cells in the arterial intima are characteristic features of atherogenesis. Foam cells are formed by cellular uptake and storage of atherogenic lipoproteins, including oxidized LDL (oxLDL) and enzymatically modified LDL (eLDL). Dissection of oxLDL- and eLDL-induced cellular phenotypes indicates that these two LDL-modifications are coupled with two fundamentally different cellular responses in macrophages. Oxidized LDL preferentially up-regulates scavenger receptors required for its internalization, induces preferential lipid storage in the acidic compartment resembling drug-induced endolysosomal phospholipidosis, parallel with increased cellular content of the endolysosomal signature lipid bis(monoacylglycero)phosphate, pro-apoptotic signalling and appearance of ceramide-enriched surface membrane microdomains. By contrast, challenge of macrophages by eLDL leads to expanded cholesterol- and sphingomyelin-enriched surface membrane microdomains, up-regulation of diverse pattern recognition receptors required for phagocytosis of eLDL, parallel with extensive lipid droplet formation, increased endoplasmic reticulum (ER)-stress and membrane contact site formation for interorganelle trafficking and signalling, and enhanced cellular content of the mitochondrial lipid cardiolipin. This review focuses on biological activities of oxLDL and eLDL in human macrophages, and discusses some lipidomic considerations related to foam cell formation and phospholipidosis. PMID- 21683694 TI - Suitability of a transport box for blood sample shipment over a long period. AB - BACKGROUND: Safety transport boxes are increasingly used to ship laboratory specimens but there is little information on their capacity to maintain suitable transportation temperatures. MATERIALS AND METHODS: Inner temperature was assessed using a commercially available transport box during an 8-h transportation period in the heat. RESULTS: Temperature stability was unsatisfactory during approximately 64% of the transportation time (i.e., from 125 to 450 min). CONCLUSIONS: Transport boxes might be unsuitable for shipping specimens over long periods. PMID- 21683696 TI - Disturbance of perineuronal nets in the perilesional area after photothrombosis is not associated with neuronal death. AB - Perineuronal nets (PNNs) are a condensed form of extracellular matrix that covers the surface of a subset of neurons. Their presence limits neuronal plasticity and may protect neurons against harmful agents. Here we analyzed the relationship between spatiotemporal changes in PNN expression and cell death markers after focal cortical photothrombotic stroke in rats. We registered a substantial decrease in PNN density using Wisteria floribunda agglutinin staining and CAT-315 and brevican immunoreactivity; the decrease occurred not only in the lesion core but also in the perilesional and remote cortex as well as in homotopic contralateral cortical regions. Fluoro Jade C and TUNEL staining in perilesional and remote areas, however, showed a low density of dying cells. Our results suggest that the PNN reduction was not a result of cellular death and could be considered an attempt to create conditions favorable for synaptic remodeling. PMID- 21683695 TI - Growth of limb muscle is dependent on skeletal-derived Indian hedgehog. AB - During embryogenesis, muscle and bone develop in close temporal and spatial proximity. We show that Indian Hedgehog, a bone-derived signaling molecule, participates in growth of skeletal muscle. In Ihh(-/-) embryos, skeletal muscle development appears abnormal at embryonic day 14.5 and at later ages through embryonic day 20.5, dramatic losses of hindlimb muscle occur. To further examine the role of Ihh in myogenesis, we manipulated Ihh expression in the developing chick hindlimb. Reduction of Ihh in chicken embryo hindlimbs reduced skeletal muscle mass similar to that seen in Ihh(-/-) mouse embryos. The reduction in muscle mass appears to be a direct effect of Ihh since ectopic expression of Ihh by RCAS retroviral infection of chicken embryo hindlimbs restores muscle mass. These effects are independent of bone length, and occur when Shh is not expressed, suggesting Ihh acts directly on fetal myoblasts to regulate secondary myogenesis. Loss of muscle mass in Ihh null mouse embryos is accompanied by a dramatic increase in myoblast apoptosis by a loss of p21 protein. Our data suggest that Ihh promotes fetal myoblast survival during their differentiation into secondary myofibers by maintaining p21 protein levels. PMID- 21683698 TI - Arachidonyl trifluoromethyl ketone ameliorates experimental autoimmune encephalomyelitis via blocking peroxynitrite formation in mouse spinal cord white matter. AB - Inhibition of phospholipase A(2) (PLA(2)) has recently been found to attenuate the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of multiple sclerosis (MS). However, the protective mechanisms that underlie PLA(2) inhibition are still not well understood. In this study, we found that cytosolic PLA(2) (cPLA(2)) was highly expressed in infiltrating lymphocytes and macrophages/microglia in mouse spinal cord white matter. Although cPLA(2) is also expressed in spinal cord neurons and oligodendrocytes, there were no differences observed in these cell types between EAE and control animals. Arachidonyl trifluoromethyl ketone (AACOCF3), a cPLA(2) inhibitor, significantly reduced the clinical symptoms and inhibited the body weight loss typically found in EAE mice. AACOCF3 also attenuated the loss of mature, myelin producing, oligodendrocytes, and axonal damage in the spinal cord white matter. Nitrotyrosine immunoreactivity, an indicator of peroxynitrite formation, was dramatically increased in EAE mice and attenuated by treatment with AACOCF3. These protective effects were not evident when AA861, an inhibitor of lipoxygenase, was used. In primary cultures of microglia, lipopolysaccharide (LPS) induced an upregulation of cPLA(2), inducible nitric oxide synthase (iNOS) and components of the NADPH oxidase complex, p47phox and p67phox. AACOCF3 significantly attenuated iNOS induction, nitric oxide production and the generation of reactive oxygen species in reactive microglia. Similar to the decomposition catalyst of peroxynitrite, AACOCF3 also blocked oligodendrocyte toxicity induced by reactive microglia. These results suggest that AACOCF3 may prevent oligodendrocyte loss in EAE by attenuating peroxynitrite formation in the spinal cord white matter. PMID- 21683697 TI - Breathing patterns after mid-cervical spinal contusion in rats. AB - Respiratory failure is the leading cause of death after cervical spinal injury. We hypothesized that incomplete cervical spinal injuries would alter respiratory pattern and initiate plasticity in the neural control of breathing. Further, we hypothesized that the severity of cervical spinal contusion would correlate with changes in breathing pattern. Fourteen days after C4-C5 contusions, respiratory frequency and tidal volume were measured in unanesthetized Sprague Dawley rats in a whole body plethysmograph. Phrenic motor output was monitored in the same rats which were anesthetized, vagotomized, paralyzed and ventilated to eliminate and/or control sensory feedback that could alter breathing patterns. The extent of spinal injury was approximated histologically by measurements of the injury induced cyst area in transverse sections; cysts ranged from 2 to 28% of spinal cross-sectional area, and had a unilateral bias. In unanesthetized rats, the severity of spinal injury correlated negatively with tidal volume (R(2)=0.85; p<0.001) and positively with breathing frequency (R(2)=0.65; p<0.05). Thus, the severity of C4-C5 spinal contusion dictates post-injury breathing pattern. In anesthetized rats, phrenic burst amplitude was decreased on the side of injury, and burst frequency correlated negatively with contusion size (R(2)=0.51; p<0.05). A strong correlation between unanesthetized breathing pattern and the pattern of phrenic bursts in anesthetized, vagotomized and ventilated rats suggests that changes in respiratory motor output after spinal injury reflect, at least in part, intrinsic neural mechanisms of CNS plasticity initiated by injury. PMID- 21683699 TI - Structural and functional differences between neuropathy with and without pain? AB - We aimed to find functional and structural differences in neuropathy between patients with and without chronic pain following nerve injury. We included 30 patients requiring hand surgery after a trauma, with 21 reporting chronic pain for more than one year after the injury, while 9 did not suffer from injury related chronic pain. We assessed mechanical sensitivity, thermal thresholds, electrically induced pain and axon reflex erythema and cutaneous nerve fiber density in skin biopsies of the injured site and its contralateral control. Epidermal fiber density of the injured site was reduced similarly in both patient groups. Thresholds for cold and heat pain and axon reflex areas were reduced in the injured site, but did not differ between the patient groups. Only warmth thresholds were better preserved in the pain patients (35.2 vs. 38.4 degrees C). Neuronal CGRP staining did not reveal any difference between pain and non-pain patients. Epidermal innervation density correlated best to warmth detection thresholds and deeper dermal innervation density to the area of the axon reflex erythema. No specific pattern of subjective, functional or structural parameters was detected that would separate the neuropathy patients into pain and non-pain patients. Specific staining of additional targets may help to improve our mechanistic understanding of pain development. PMID- 21683700 TI - Stimulation of the subthalamic region at 20 Hz slows the development of grip force in Parkinson's disease. AB - Excessive synchronization of basal ganglia neuronal activity at ~20 Hz is characteristic of patients with untreated Parkinson's disease (PD). Correlative evidence suggests that this activity may contribute to bradykinesia. Attempts to demonstrate causality through stimulation imposed synchronization at 20 Hz in the region of the subthalamic nucleus (STN) have had limited success. Finger-tapping is slowed by about 8% and only in those PD patients that have a relatively normal baseline performance in this task. Here we investigate whether greater performance decrements might be seen in a reaction time grip task. We studied 32 sides in 16 patients with PD after overnight withdrawal of medication. Patients were asked to grip as hard and as fast as possible without STN stimulation and during bilateral stimulation at 5 Hz, 10 Hz, 20 Hz, 50 Hz and 130 Hz. Stimulation at 20 Hz slowed the development of force by 14.7+/-8.3% (P=0.044) across all patients. Slowing increased by 22+/-7% (P=0.005) in those patients with the best performance in the task without stimulation. The effect was frequency specific. These data provide direct interventional evidence of a mechanistic link between excessive neuronal synchronization in the beta range and motor impairment in PD. PMID- 21683702 TI - Host parasite interactions and pathophysiology in Giardia infections. AB - Giardia is a protozoan parasite of the small intestine, and a leading cause of diarrhoeal disease worldwide in a variety of animals, including humans. The host parasite interaction and pathophysiological processes of giardiasis remain incompletely understood. Current research suggests that Giardia-induced diarrhoeal disease is mediated by small intestinal malabsorption and maldigestion, chloride hypersecretion and increased rates of small intestinal transit. Small intestinal malabsorption and maldigestion results from the CD8+ lymphocyte-induced diffuse shortening of brush border microvilli. Activation of CD8+ lymphocytes occurs secondary to small intestinal barrier dysfunction, which results from heightened rates of enterocyte apoptosis and disruption of epithelial tight junctions. Both host and parasite factors contribute to the pathogenesis of giardiasis and ongoing research in this field may elucidate genotype/assemblage-specific pathogenic mechanisms. Giardia infections can result in chronic gastrointestinal disorders such as post-infectious Irritable Bowel Syndrome and symptoms may manifest at extra-intestinal sites, even though the parasite does not disseminate beyond the gastrointestinal tract. The infection can cause failure to thrive in children. Furthermore, there is now evidence suggesting that Giardia symptoms may vary between industrialised and developing areas of the world, for reasons that remain obscure. More research is needed to improve our understanding of this parasitic infection which was recently included in the World Health Organisation "Neglected Disease Initiative". PMID- 21683701 TI - Differential, type I interferon-mediated autophagic trafficking of hepatitis C virus proteins in mouse liver. AB - BACKGROUND & AIMS: The hepatitis C virus (HCV) serine protease NS3/4A can cleave mitochondria-associated antiviral signaling protein (MAVS) and block retinoic acid-inducible gene I-mediated interferon (IFN) responses. Although this mechanism is thought to have an important role in HCV-mediated innate immunosuppression, its significance in viral persistence is not clear. METHODS: We generated transgenic mice that express the HCV NS3/4A proteins specifically in the liver and challenged the animals with a recombinant vesicular stomatitis virus, a synthetic HCV genome, IFN alfa, or IFN beta. We evaluated the effects of HCV serine protease on the innate immune responses and their interactions. RESULTS: Expression of HCV NS3/4A resulted in cleavage of intrahepatic MAVS; challenge of transgenic mice with vesicular stomatitis virus or a synthetic HCV genome induced strong, type I IFN-mediated responses that were not significantly lower than those of control mice. Different challenge agents induced production of different ratios of IFN alfa and beta, resulting in different autophagic responses and vesicular trafficking patterns of endoplasmic reticulum- and mitochondria-associated viral proteins. IFN beta promoted degradation of the viral proteins by the autolysosome. Variant isoforms of MAVS were associated with distinct, type I IFN-mediated autophagic responses; these responses have a role in trafficking of viral components to endosomal compartments that contain Toll like receptor-3. CONCLUSIONS: IFN beta mediates a distinct autophagic mechanism of antiviral host defense. MAVS has an important role in type I IFN-induced autophagic trafficking of viral proteins. PMID- 21683703 TI - Small worms, big appetites: ratios of different functional morphs in relation to interspecific competition in trematode parasites. AB - Animals living in colonies or collectives composed of highly-related individuals often produce morphs that are physically and behaviourally specialised to perform specific tasks. Because such morphs are often sterile, their production represents a fitness cost for the colony and there should be an optimal ratio of the numbers of sterile specialists and reproductive members that may be adjustable to environmental conditions. Trematode parasites undergo asexual multiplication within their snail intermediate host, resulting in large numbers of clonal stages known as rediae or sporocysts, depending on the trematode species. In areas with high prevalences of infection, the host can be infected by multiple species, which can lead to intense competition for limited resources. Here, we describe the existence of specialised 'mini-rediae' in the trematode Philophthalmus sp. that are morphologically and functionally specialised for interspecific competition. Mini-rediae were observed feeding on the sporocysts of a co-occurring trematode species -Maritrema novaezealandensis. In addition, in larger snails - which are less likely to have M. novaezealandensis infections Philophthalmus sp. produces relatively fewer mini-rediae than expected. Our findings support results from a prior study which demonstrated the existence of morphs that perform specialised functions in antagonistic interspecific interactions in trematodes, and additionally shows that the number of these morphs in each host is associated with the likelihood of encountering other species within the same host. Trematodes may thus provide interesting models for studying morphological specialisation in colonial organisms. PMID- 21683704 TI - Altered avr-14B gene transcription patterns in ivermectin-resistant isolates of the cattle parasites, Cooperia oncophora and Ostertagia ostertagi. AB - Ivermectin (IVM) resistance is an emerging problem for the control of gastrointestinal nematodes of cattle such as Cooperia oncophora and Ostertagia ostertagi. Although there is still a poor understanding of the molecular basis of macrocyclic lactone (ML)-resistance, it is clear that IVM exerts its activity by binding to glutamate-gated chloride (GluCl) channels within the parasite's neuromuscular system. One of the GluCl genes (avr-14) encodes, via alternative splicing, two subunits, AVR-14A and AVR-14B; the latter is suggested to be the main target for IVM. The genomic DNA (gDNA) sequence of avr-14 in C. oncophora contains 21 exons separated by 20 introns and spans approximately 10 kb of gDNA. Intron 13 contains a sequence with high homology to a mammalian mariner transposase. The L256F polymorphism in the avr-14 gene, which was shown to be associated with IVM resistance in a UK isolate of C. oncophora, was not found in the IVM-resistant C. oncophora and O. ostertagi isolates investigated in this study. However, genetic analyses on C. oncophora indicated a loss in allelic diversity of the avr-14 gene in the resistant isolates compared with the susceptible isolate. This suggests that the avr-14 gene, or another genetically linked locus, is under selection in these Belgian C. oncophora isolates. Comparison of the full-length avr-14B coding sequence in the susceptible and resistant C. oncophora isolates did not show any polymorphisms specifically linked to IVM resistance, although a decrease in the number of avr-14B isoforms was observed in the resistant isolates compared with the susceptible one. Measuring the transcription levels of avr-14B in adult male and female C. oncophora and O. ostertagi worms showed significantly lower levels in resistant worms compared with susceptible ones. Whether the down-regulation of this IVM target actually contributes to the resistance mechanism in these worms remains unclear. PMID- 21683705 TI - Gene expression changes in a P-glycoprotein (Tci-pgp-9) putatively associated with ivermectin resistance in Teladorsagia circumcincta. AB - Anthelmintic resistance in parasitic nematodes of small ruminants is widespread and, in some parts of the world, threatens the sustainability of sheep production. The genetic changes underlying resistance to anthelmintics, particularly ivermectin (IVM), remain to be determined. The majority of studies to date have investigated target site mutations; relatively little attention has been paid to the role of changes in gene expression. In this study, we investigated the expression of putative drug transporter molecules, P glycoproteins (Pgps), in Teladorsagia circumcincta, the predominant parasitic nematode species of sheep in the UK and the major anthelmintic resistant species. Utilising a degenerate PCR approach, 11 partial Pgp sequences were identified. Constitutive differences in gene expression between an IVM-susceptible (MTci2) and a multidrug-resistant (MTci5) isolate were determined for 10 of the Pgps using the DeltaDeltaCt TaqMan(r) real-time PCR method. Gene expression differences were particularly marked in one of these genes, namely Tci-pgp-9. In the MTci5 isolate, statistically significant increases in Tci-pgp-9 expression, at the mRNA level, were observed across all life-cycle stages and most notably in eggs (55-fold increase). Comparison of the partial Tci-pgp-9 nucleotide sequences from MTci2 and MTci5 also identified high levels of polymorphism. This work has shown that constitutively increased expression in Tci-pgp-9, coupled with increased sequence polymorphism, could play a role in allowing multidrug resistant T. circumcincta to survive IVM exposure. The genetic changes underpinning these gene expression changes remain to be elucidated and need to be investigated in other isolates. These changes could form the basis of an IVM resistance marker to monitor the spread of resistance and to evaluate management practices aimed at delaying its spread. PMID- 21683706 TI - Mapmi gene contributes to stress tolerance and virulence of the entomopathogenic fungus, Metarhizium acridum. AB - Phosphomannose isomerase (PMI) catalyzes the reversible interconversion of fructose 6-phosphate (Fru-6-P) and mannose 6-phosphate (Man-6-P), providing a link between glycolysis and the mannose metabolic pathway. In this study, we identified pmi gene (Mapmi) from the entomopathogenic fungus, Metarhizium acridum, and analyzed its functions using RNA interference (RNAi). Amending the growth medium with cell stress chemicals significantly reduced growth, conidial production and percent germination in Mapmi-RNAi mutant strain, compared to the wild-type strain. Growth of RNAi mutant was lower than the wild type strain with glucose or fructose as sole carbon source. RNAi mutant exhibited a normal growth phenotype with mannose at low concentrations, while trace or high concentration of mannose was more negatively impacted the growth of RNAi mutant than the wild type strain. Infection with Mapmi-RNAi mutant against Locusta migratoria manilensis (Meyen) led to a significantly reduced virulence compared to infection with the wild-type strain. These results suggest that Mapmi plays essential roles in stress tolerance and pathogenicity of M. acridum. PMID- 21683707 TI - Musty odor of entomopathogens enhances disease-prevention behaviors in the termite Coptotermes formosanus. AB - Termites often eliminate pathogens directly through mutual grooming, and are thereby prevent infections from entomopathogenic fungi. Our previous study confirmed that the antennae of Coptotermesformosanus sensitively responded to the musty odor of entomopathogenic fungi. However, it is unclear if this odor has any effect on termite behavior. The purpose of this study was to clarify the effects of fungal odor on termite behavior, especially on conidia removal. The musty odor was prepared as an aqueous solution by immersing conidia in distilled water. When untreated termites were mixed with fungal-odor-treated termites at a ratio of 4:1, mutual grooming and attack of treated termites were frequently observed. This indicated that the fungal odor triggered these behavioral responses. While some components of the fungal odor were found in all of the entomopathogenic fungi tested, the odor profiles differed among the isolates. PMID- 21683708 TI - Myosin cross-bridges do not form precise rigor bonds in hypertrophic heart muscle carrying troponin T mutations. AB - Distribution of orientations of myosin was examined in ex-vivo myofibrils from hearts of transgenic (Tg) mice expressing Familial Hypertrophic Cardiomyopathy (FHC) troponin T (TnT) mutations I79N, F110I and R278C. Humans are heterozygous for sarcomeric FHC mutations and so hypertrophic myocardium contains a mixture of the wild-type (WT) and mutated (MUT) TnT. If mutations are expressed at a low level there may not be a significant change in the global properties of heart muscle. In contrast, measurements from a few molecules avoid averaging inherent in the global measurements. It is thus important to examine the properties of only a few molecules of muscle. To this end, the lever arm of one out of every 60,000 myosin molecules was labeled with a fluorescent dye and a small volume within the A-band (~1 fL) was observed by confocal microscopy. This volume contained on average 5 fluorescent myosin molecules. The lever arm assumes different orientations reflecting different stages of acto-myosin enzymatic cycle. We measured the distribution of these orientations by recording polarization of fluorescent light emitted by myosin-bound fluorophore during rigor and contraction. The distribution of orientations of rigor WT and MUT myofibrils was significantly different. There was a large difference in the width and of skewness and kurtosis of rigor distributions. These findings suggest that the hypertrophic phenotype associated with the TnT mutations can be characterized by a significant increase in disorder of rigor cross-bridges. PMID- 21683709 TI - A eukaryotic-like interaction of soluble cyanobacterial sensory rhodopsin transducer with DNA. AB - Anabaena sensory rhodopsin is a recently discovered membrane photosensor with a unique signal transduction cascade. It interacts with a soluble tetrameric transducer [Anabaena sensory rhodopsin transducer (ASRT)] that can bind to promoter regions of several genes related to the utilization of light energy. Even though the X-ray crystal structure of ASRT is available, the mechanism of its interaction with DNA is still unknown. We used solution NMR to understand the mechanism of the DNA binding. Both X-ray crystal structures and solution NMR data reveal seven beta-strands forming a rigid scaffold (beta-face) and a flexible, partially disordered alpha-face, comprised by the C-termini and loops. We found that the conformation of the alpha-face in solution is very different from that in the crystals. While the C-termini of crystalline ASRT are solvent exposed and either alpha-helical or disordered, about half of ASRT monomers in solution feature buried C-terminal beta-strand, with another half of C-tails being random coils. Titration of ASRT with a 20-bp fragment of the pec operon promoter showed that only monomers with beta-structured C-tails bind the DNA. NMR signals suggest that specific Arg and Asn/Gln residues are involved in the interaction with DNA. The DNA binding occurs with micromolar affinity and a 1:1 stoichiometry (DNA:ASRT tetramer) and results in a significant ordering of the alpha-face involving the extension of the C-terminal beta-strand and reorganization of the first loop. Such induced-fit type of interaction, which mainly utilizes loops between beta strands and results in the increase in their order, is typical for eukaryotic transcription factors of the immunoglobulin-like fold. PMID- 21683710 TI - A conserved acidic amino acid mediates the interaction between modulators and co chaperones in enterobacteria. AB - Hsp40-like co-chaperones are ubiquitous enzymes that stimulate the protein refolding activity of Hsp70 family chaperones. They are widespread in prokaryotic and eukaryotic systems. In bacteria, the best characterized co-chaperone is the Escherichia coli DnaJ protein. Many gamma-proteobacteria encode a functional homologue of DnaJ, known as CbpA, which is expressed in response to starvation and environmental stress. The activity of CbpA is regulated by the "modulator" protein CbpM. Here, we have used a combination of genetics and biochemistry to identify the co-chaperone contact determinant of CbpM. We show that the nature of the interaction is conserved in enterobacteria. PMID- 21683711 TI - Restricted occupancy models for neutralization of HIV virions and populations. AB - HIV virions infect cells by attaching to target cell receptors, fusing membranes with the cell and by finally releasing their genetic material into the target cells. Antibodies can hinder the infection by attaching to the HIV envelope glycoprotein trimers before or during attachment. The exact mechanisms and the quantitative requirements of antibody neutralization are still debated. Recently, the number of antibodies rendering one trimer non-functional, called stoichiometry of (trimer) neutralization, was studied with mathematical models. Here we extend this theoretical framework to calculate the stoichiometries of neutralizing a single virion and a whole virion population. We derive mathematical equations for antibody neutralization based on restricted occupancy theory. Additionally we simulate these processes when a direct calculation is not possible. We find that the number of trimers needed for cell entry and the number of antibodies neutralizing one trimer strongly influence the mean number of antibodies needed for virion and population neutralization. Further we show that the mean number of antibodies needed to neutralize a virion population exceeds the product of the number of virions in the population and the mean number of antibodies needed to neutralize one virion. PMID- 21683712 TI - L-type Ca(2+) channel agonist inhibits RANKL-induced osteoclast formation via NFATc1 down-regulation. AB - AIMS: BayK 8644 is an L-type Ca(2+) channel agonist that enhances Ca(2+) influx and elevates cytosolic Ca(2+). As intracellular calcium plays a key role in osteoclast formation, we investigated the effects of BayK 8644 in cultures of bone marrow-derived precursor cells with macrophage colony-stimulating factor (M CSF) and receptor activator of nuclear factor kappaB ligand (RANKL). MAIN METHODS: We performed an osteoclast formation assay, a pit formation assay, real time PCR, and Western blot analysis. KEY FINDINGS: BayK 8644 concentration dependently suppressed osteoclastogenesis, as well as the expression of osteoclastic marker genes. It also decreased osteoclastic bone resorption on a dentine slice. While the RANKL-stimulated induction of IL-1beta and IL-6 was not affected, TNF-alpha induction was reduced by BayK 8644 treatment. In addition, BayK 8644 blocked IkappaB degradation and the induction of nuclear factor of activated T cells c1 (NFATc1), the master regulator of osteoclast differentiation, following RANKL stimulation. Finally, forced expression of NFATc1 reversed the inhibitory effect of BayK 8644 on osteoclastogenesis, suggesting that NFATc1 is a downstream target for the anti-osteoclastogenic action of BayK 8644. Taken together, our data suggest that BayK 8644 has an anti osteoclastogenic effect by inhibiting RANKL-induced activation of NF-kappaB pathways, thereby suppressing the gene expression of NFATc1 in osteoclast precursors. SIGNIFICANCE: Our results provide a molecular understanding of the inhibitory effect of the L-type Ca(2+) channel agonist, BayK 8644, on osteoclastogenesis. PMID- 21683715 TI - Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers. AB - Mitochondria are key organelles in eukaryotic cells principally responsible for multiple cellular functions. In addition to a plethora of somatic mutations as well as polymorphic sequence variations in mitochondrial DNA (mtDNA), the identification of increased or reduced mtDNA copy number has been increasingly reported in a broad range of primary human cancers, underscoring that accumulation of mtDNA content alterations may be a pivotal factor in eliciting persistent mitochondrial deficient activities and eventually contributing to cancer pathogenesis and progression. However, the detailed roles of altered mtDNA amount in driving the tumorigenic process remain largely unknown. This review outlines mtDNA content changes present in various types of common human malignancies and briefly describes the possible causes and their potential connections to the carcinogenic process. The present state of our knowledge regarding how altered mtDNA quantitative levels could be utilized as a diagnostic biomarker for identifying genetically predisposed population that should undergo intensive screening and early surveillance program is also discussed. Taken together, these findings strongly indicate that mtDNA copy number alterations may exert a crucial role in the pathogenic mechanisms of tumor development. Continued insights into the functional significance of altered mtDNA quantities in the etiology of human cancers will hopefully help in establishing novel potential targets for anti-tumor drugs and intervention therapies. PMID- 21683713 TI - Mechanisms of methylmercury-induced neurotoxicity: evidence from experimental studies. AB - Neurological disorders are common, costly, and can cause enduring disability. Although mostly unknown, a few environmental toxicants are recognized causes of neurological disorders and subclinical brain dysfunction. One of the best known neurotoxins is methylmercury (MeHg), a ubiquitous environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. In the aquatic environment, MeHg is accumulated in fish, which represent a major source of human exposure. Although several episodes of MeHg poisoning have contributed to the understanding of the clinical symptoms and histological changes elicited by this neurotoxicant in humans, experimental studies have been pivotal in elucidating the molecular mechanisms that mediate MeHg-induced neurotoxicity. The objective of this mini-review is to summarize data from experimental studies on molecular mechanisms of MeHg-induced neurotoxicity. While the full picture has yet to be unmasked, in vitro approaches based on cultured cells, isolated mitochondria and tissue slices, as well as in vivo studies based mainly on the use of rodents, point to impairment in intracellular calcium homeostasis, alteration of glutamate homeostasis and oxidative stress as important events in MeHg-induced neurotoxicity. The potential relationship among these events is discussed, with particular emphasis on the neurotoxic cycle triggered by MeHg-induced excitotoxicity and oxidative stress. The particular sensitivity of the developing brain to MeHg toxicity, the critical role of selenoproteins and the potential protective role of selenocompounds are also discussed. These concepts provide the biochemical bases to the understanding of MeHg neurotoxicity, contributing to the discovery of endogenous and exogenous molecules that counteract such toxicity and provide efficacious means for ablating this vicious cycle. PMID- 21683714 TI - Endogenous sphingosine 1-phosphate regulates spontaneous glutamate release from mossy fiber terminals via S1P(3) receptors. AB - AIMS: Previous studies have shown that sphingosine 1-phosphate (S1P) stimulates glutamate release from hippocampal neurons. The present study was designed to understand the mechanism underlying S1P-induced spontaneous glutamate release from mossy fiber terminals in the hippocampus. MAIN METHODS: Slice patches were made from three different regions of neurons in rat hippocampal slices, and spontaneous alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor mediated miniature excitatory postsynaptic currents (AMPA-mEPSCs) were monitored. KEY FINDINGS: Inhibitors of sphingosine kinase such as dimethylsphingosine (DMS) and 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (HACPT), to suppress endogenous S1P production, significantly decreased the rate of spontaneous AMPA mEPSCs elicited from CA3 pyramidal neurons, but not CA1 pyramidal neurons or dentate granular neurons. A similar decrease was also obtained with VPC23019, an inhibitor of S1P receptors, suramin, an inhibitor of S1P(3) receptor, U73122, an inhibitor of phospholipase C, or GF109203X, an inhibitor of protein kinase C. SIGNIFICANCE: The results of the present study show that endogenous S1P regulates spontaneous glutamate release in a restricted hippocampal area, i.e., the release from mossy fiber terminals, via S1P(3) receptors linked to G(q) protein. This may represent fresh insight into the regulatory mechanism of spontaneous transmitter release. PMID- 21683716 TI - Signal transducer and activator of transcription 4 gene polymorphisms associated with rheumatoid arthritis in Northwestern Chinese Han population. AB - AIMS: Signal transducer and activator of transcription 4 (STAT4) gene encode a transcriptional factor that transmits signals induced by several key cytokines which play important roles in the development of autoimmune diseases. Recently, several single nucleotide polymorphisms (SNPs) in STAT4 gene have been reported to be significantly associated with Rheumatoid arthritis (RA) in different ethnic populations. We undertook this study to investigate whether the association of STAT4 genetic polymorphisms with RA is present in Northwestern Chinese Han population. MAIN METHODS: A case-control association study in individuals with RA (n=208) and healthy controls (n=312) was conducted. Four SNPs (rs7574865, rs8179673, rs10181656, rs11889341) in STAT4 gene were genotyped by using polymerase chain reaction followed by denaturing high-performance liquid chromatography (PCR-DHPLC) and DNA sequencing. KEY FINDINGS: The genotype and allele distributions of four polymorphisms were significantly different in individuals with RA compared to controls, with SNP rs7574865 T allele and T/T genotype showing the most significant association with susceptibility to RA (uncorrected P=1*10(-4), OR=1.645, 95% CI=1.272-2.129; uncorrected P=4.8*10(-5), OR=3.111, 95% CI=1.777-5.447, respectively). Stratification studies showed that STAT4 gene polymorphisms were significantly associated with anti-cyclic citrullinated peptide (anti-CCP) positive subgroup in Northwestern Chinese Han population. SIGNIFICANCE: These findings strongly suggest that STAT4 genetic polymorphisms are associated with RA in Northwestern Chinese Han population, and support the hypothesis of STAT4 gene polymorphisms increasing the risk for RA across major populations. PMID- 21683717 TI - Synthetic isoforms of endogenous sulfatides differently modulate indoleamine 2,3 dioxygenase in antigen presenting cells. AB - AIMS: To investigate whether sulfatides modulate indoleamine 2,3-dioxygenase (IDO)1, a fine-tuned enzymatic mechanism for controlling immune responses, gene expression/function in antigen presenting cells (APC). The relationship between structure and activity (SAR) of newly synthesized sulfatide isoforms (C16:0, C18:0, C22:0, C24:1) was also evaluated. MAIN METHODS: CD1d-transfected THP-1 human cells were used as APC and treated with increasing concentrations (0.01 10MUMU) of each compound for an appropriate period of time. The gene expression and the enzymatic activity of IDO1 were examined using reverse transcription polymerase chain reaction (RT-PCR) and high performance liquid chromatography (HPLC). Compound-untreated cells were taken as negative, while 1000U/ml interferon (IFN)-gamma-treated cells as positive controls. KEY FINDINGS: Not all sulfatides induced the same effect: the basal IDO1 expression was significantly reduced (-48 +/- 3% at 0.01MUMU) by C16:0 sulfatide, while it was increased by C18:0 or C24:1 sulfatide (+87 +/- 7% and +50 +/- 5% at 1MUMU, respectively) over negative controls; C22:0 sulfatide resulted ineffective at all concentrations tested. These effects functionally correlated with changes in IDO1 activity: l kynurenine contents in the culture media were significantly reduced by C16:0 sulfatide (-29 +/- 4% at 0.01MUM), while it was increased by C18:0 or C24:1 sulfatide (+61 +/- 8% and +48 +/- 4% at 1MUM, respectively) over negative controls. C22:0 sulfatide resulted ineffective at all concentration tested. SIGNIFICANCE: The overall data demonstrate that specific sulfatide isoforms differently modulate IDO1 in APC. The sulfatide-induced effects are structurally dependent on the length/saturation of their fatty acid chain. PMID- 21683718 TI - Cell signaling in NMDA preconditioning and neuroprotection in convulsions induced by quinolinic acid. AB - The search for novel, less invasive therapeutic strategies to treat neurodegenerative diseases has stimulated scientists to investigate the mechanisms involved in preconditioning. Preconditioning has been report to occur in many organs and tissues. In the brain, the modulation of glutamatergic transmission is an important and promising target to the use of effective neuroprotective agents. The glutamatergic excitotoxicity is a factor common to neurodegenerative diseases and acute events such as cerebral ischemia, traumatic brain injury and epilepsy. In this review we focus on the neuroprotection and preconditioning by chemical agents. Specially, chemical preconditioning models using N-methyl-d-aspartate (NMDA) pre-treatment, which has demonstrated to lead to neuroprotection against seizures and damage to neuronal tissue induced by quinolinic acid (QA). Here we attempted to gather important results obtained in the study of cellular and molecular mechanisms involved in NMDA preconditioning and neuroprotection. PMID- 21683719 TI - Transcriptional regulation of mouse TREM-1 gene in RAW264.7 macrophage-like cells. AB - AIMS: Triggering receptor expressed on myeloid cells (TREM)-1 is expressed in macrophages, and functions as an amplifying molecule in inflammatory responses. TREM-1 is constitutively expressed in macrophage, and upregulated by bacterial components, such as lipopolysaccharide (LPS). In this present study, we investigated the regulatory mechanism for the basal and LPS-induced transcription of mouse TREM-1 gene in mononuclear cells using RAW264.7 macrophage-like cells. MAIN METHODS: To elucidate the potential role of cis-acting elements in the basal and LPS-induced transcription of mouse TREM-1 gene, the luciferase vector containing the promoter with 5' deletion and adenine substitution mutants was transfected into RAW264.7 cells and incubated in the absence or presence of LPS. To further identify the transcription factor(s), gel shift/supershift analysis was performed. KEY FINDINGS: The CRE (cAMP response element) and NF-kappaB-1 (a distal NF-kappaB site) in the mouse TREM-1 promoter are positively and negatively regulating the basal TREM-1 transcription via the interaction with C/EBPalpha and NF-kappaB p50/p50 homodimer, respectively. In addition, the CRE and NF-kappaB-1 likely participate in the LPS-induced upregulation of TREM-1 promoter activity possibly via the interaction with phosphorylated CREB and NF-kappaB p65/p50 heterodimer. Furthermore, the AP-1-1 (a distal AP-1 site) is likely to be involved in the LPS-induced TREM-1 transcription via the interaction with phosphorylated c-fos/c-jun. SIGNIFICANCE: The present study has demonstrated for the first time the detailed mechanism for the basal and LPS-induced expression of TREM-1, an amplifying molecule in inflammation. PMID- 21683721 TI - Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways. AB - Insulin and its receptor are broadly expressed throughout the brain and have been postulated to play a crucial role in synaptic plasticity. Although structural remodeling of dendritic spines is associated with stable expression of synaptic plasticity, the role of insulin receptor (IR) signaling in the establishment and dynamic changes of dendritic spines remains unclear. Here we report that insulin promotes dendritic spine formation in primary cultures of rat hippocampal neurons. Conversely, downregulation of IR signaling using a blocking antibody or short hairpin RNAs (shRNAs) resulted in a decrease in number of dendritic spines and caused a significant reduction in the frequency of miniature excitatory postsynaptic currents (mEPSCs) without affecting the distribution of their amplitudes. Pharmacological blockade of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway and the small GTPase Rac1 specifically prevented the insulin-induced increase in dendritic spine density. In parallel, genetic ablation of Rac1 expression by lentiviral infection with shRNA abrogated the increase in dendritic spines induced by insulin. More importantly, the increase in dendritic spine density by insulin was accompanied by increasing in presynaptic marker staining density and displayed an increase in mEPSC frequency. Taken together, these results reveal a novel role for IR signaling in the regulation of dendritic spine formation and excitatory synapse development in hippocampal neurons through activation of the PI3K/Akt/mTOR and Rac1 signaling pathways. PMID- 21683720 TI - Scaffold-mediated nucleation of protein signaling complexes: elementary principles. AB - Proteins with multiple binding sites play important roles in cell signaling systems by nucleating protein complexes in which, for example, enzymes and substrates are co-localized. Proteins that specialize in this function are called by a variety names, including adapter, linker and scaffold. Scaffold-mediated nucleation of protein complexes can be either constitutive or induced. Induced nucleation is commonly mediated by a docking site on a scaffold that is activated by phosphorylation. Here, by considering minimalist mathematical models, which recapitulate scaffold effects seen in more mechanistically detailed models, we obtain analytical and numerical results that provide insights into scaffold function. These results elucidate how recruitment of a pair of ligands to a scaffold depends on the concentrations of the ligands, on the binding constants for ligand-scaffold interactions, on binding cooperativity, and on the milieu of the scaffold, as ligand recruitment is affected by competitive ligands and decoy receptors. For the case of a bivalent scaffold, we obtain an expression for the unique scaffold concentration that maximally recruits a pair of monovalent ligands. Through simulations, we demonstrate that a bivalent scaffold can nucleate distinct sets of ligands to equivalent extents when the scaffold is present at different concentrations. Thus, the function of a scaffold can potentially change qualitatively with a change in copy number. We also demonstrate how a scaffold can change the catalytic efficiency of an enzyme and the sensitivity of the rate of reaction to substrate concentration. The results presented here should be useful for understanding scaffold function and for engineering scaffolds to have desired properties. PMID- 21683722 TI - Coherent illusory contours reduce microsaccade frequency. AB - Synchronized high-frequency gamma band oscillations (30-100 Hz) are thought to mediate the binding of single visual features into whole-object representations. For example, induced gamma band oscillations (iGBRs) have been recorded ~ 280 ms after the onset of a coherent Kanizsa triangle, but not after an incoherent equivalent shape. However, several recent studies have provided evidence that the EEG-recorded iGBR may be a by-product of small saccadic eye movements (microsaccades). Considering these two previous findings, one would hypothesis that there should be more microsaccades following the onset of a coherent Kanizsa triangle. However, we found that microsaccade rebound rate was significantly higher after an incoherent triangle was presented. This result suggests that microsaccades are not a reliable indicator of perceptual binding, and, more importantly, implies that iGBR cannot be universally produced by ocular artefacts. PMID- 21683723 TI - Functional specialisation in the hippocampus and perirhinal cortex during the encoding of verbal associations. AB - Functional magnetic resonance imaging (fMRI) was employed to investigate the contributions of medial temporal lobe (MTL) regions to encoding operations underpinning recollection and familiarity. Participants first studied word pairs. Words in pairs were either weakly or strongly semantically related. In a subsequent retrieval task, participants distinguished between studied pairs, unstudied pairs, and recombined pairs formed from words taken from different studied pairs. Greater activity at encoding for correct judgments to studied pairs with strong, rather than weak, semantic relationships was assumed to index processes supporting subsequent familiarity-based responding. Greater activity for correct judgments to studied pairs than for recombined pairs identified incorrectly as studied pairs was assumed to index processes contributing to recollection-based responding. Evidence that these assumptions were reasonable was obtained in independent behavioural studies, while the outcomes of these fMRI contrasts indicated links between perirhinal cortex and familiarity, and anterior hippocampus and recollection. This functional separation is consistent with models in which the hippocampus and perirhinal cortex support two separable processes that contribute to memories for verbal associations. PMID- 21683724 TI - Abnormal sense of intention preceding voluntary movement in patients with psychogenic tremor. AB - Psychogenic tremor is the commonest psychogenic movement disorder, yet little is known of its pathophysiology. Given the presence of movements that appear from their physiological properties to be voluntarily produced, and yet are not experienced as such by the patients, we hypothesised that patients might have an abnormal conscious experience of volition with regard to self-generated movement. Nine patients with psychogenic tremor were asked to judge the timing of a self paced button press relative to a clock displayed on a computer screen. In separate trials they were asked to judge the timing of their internal feeling of intention to move. These results were compared to those of healthy control participants. Patients with psychogenic tremor judged their feeling of intention to move significantly later compared to control participants. As a result, the interval between the perceived time of intention and the perceived time of action, which was highly significant in the control participants, was numerically smaller and non-significant in the patients. This study provides novel data that the sense of volition prior to movement is impaired in patients with psychogenic tremor. This fits with a pathophysiological explanation for this disorder based on an impairment of neural mechanisms that generate the conscious experience of action: actions that are voluntary in terms of their physiological origin might be experienced as involuntary. PMID- 21683725 TI - Corticosteroids stimulate the amphibious behavior in mudskipper: potential role of mineralocorticoid receptors in teleost fish. AB - It has long been held that cortisol, a glucocorticoid in many vertebrates, carries out both glucocorticoid and mineralocorticoid actions in teleost fish. However, 11-deoxycorticosterone (DOC) has been identified as a specific endogenous ligand for the teleostean mineralocorticoid receptor (MR). Furthermore, the expressions of MR mRNA are modest in the osmoregulatory organs, but considerably higher in the brain of most teleosts. These recent findings suggest that the mineralocorticoid system (DOC/MR) may carry out some behavioral functions in fish. To test this possibility, we examined the effects of cortisol and DOC administration in the amphibious behavior in mudskipper (Periophthalmus modestus) in vivo. It was found that mudskippers remained in the water for an increased period of time when they were immersed into 5 MUM DOC or cortisol for 8h. Additionally, an exposure to 25 MUM DOC for 4 to 8 h caused a decreased migratory frequency of mudskippers to the water, reflected a tendency to remain in the water. It was further observed that after 8 h of intracerebroventricular (ICV) injection with 0.3 pmol DOC or cortisol the staying period in the water increased in fish. The migratory frequency was decreased after ICV DOC injection which indicated that fishes stayed in the water. Concurrent ICV injections of cortisol with RU486 [a specific glucocorticoid-receptor (GR) antagonist] inhibited only the partial effects of cortisol. Together with no changes in the plasma DOC concentrations under terrestrial conditions, these results indicate the involvement of brain MRs as cortisol receptors in the preference for an aquatic habitat of mudskippers. Although the role of GR signaling cannot be excluded in the aquatic preference, our data further suggest that the MR may play an important role in the brain dependent behaviors of teleost fish. PMID- 21683726 TI - Similar effects of roux-en-Y gastric bypass and vertical sleeve gastrectomy on glucose regulation in rats. AB - Bariatric surgery is the most efficacious procedure for eliciting weight loss in humans, and many patients undergoing the procedure experience significant lessening of their symptoms of type-2 diabetes in addition to losing weight. We have adapted two bariatric surgical procedures commonly employed in humans to a rat model to begin to understand the mechanisms underlying the improvements in energy homeostasis. Young adult male rats received either roux-en-Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG) and were assessed for body weight, food intake and parameters of glucose homeostasis over a 28-week period. Control rats received either a sham surgical procedure or else were unoperated. RYGB and VSG had comparable beneficial effects relative to controls. They ate less food and lost more weight, and they both had improved glucose parameters. The most intriguing aspect of the findings is that the two surgical procedures had such similar effects in spite of quite different rearrangements of the gastrointestinal system. PMID- 21683727 TI - Removal of intra-abdominal visceral adipose tissue improves glucose tolerance in rats: role of hepatic triglyceride storage. AB - Epidemiological studies have demonstrated a strong link between increased visceral fat and metabolic syndrome. In rodents, removal of intra-abdominal but non-visceral fat improves insulin sensitivity and glucose homeostasis, though previous studies make an imprecise comparison to human physiology because actual visceral fat was not removed. We hypothesize that nutrient release from visceral adipose tissue may have greater consequences on metabolic regulation than nutrient release from non-visceral adipose depots since the latter drains into systemic but not portal circulation. To assess this we surgically decreased visceral white adipose tissue (~0.5 g VWATx) and compared the effects to removal of non-visceral epididymal fat (~4 g; EWATx), combination removal of visceral and non-visceral fat (~4.5 g; EWATx/VWATx) and sham-operated controls, in chow-fed rats. At 8 weeks after surgery, only the groups with visceral fat removed had a significantly improved glucose tolerance, although 8 times more fat was removed in EWATx compared with VWATx. This suggests that mechanisms controlling glucose metabolism are relatively more sensitive to reductions in visceral adipose tissue mass. Groups with visceral fat removed also had significantly decreased hepatic lipoprotein lipase (LPL) and triglyceride content compared with controls, while carnitine palmitoyltransferase (CPT-1A) was decreased in all fat-removal groups. In a preliminary experiment, we assessed the opposite hypothesis; i.e., we transplanted excess visceral fat from a donor rat to the visceral cavity (omentum and mesentery), which drains into the hepatic portal vein, of a recipient rat but observed no major metabolic effect. Overall, our results indicate surgical removal of intra-abdominal fat improves glucose tolerance through mechanism that may be mediated by reductions in liver triglyceride. PMID- 21683728 TI - Molecular and electrophysiological changes in the prefrontal cortex-amygdala dorsal periaqueductal grey pathway during persistent pain state and fear conditioned analgesia. AB - Fear-conditioned analgesia (FCA) is the reduction in pain responding which is expressed upon re-exposure to a context previously paired with an aversive stimulus. Projections along the prefrontal cortex (PFC)-amygdala-dorsal periaqueductal grey (dPAG) pathway may mediate FCA. However, there is a paucity of studies measuring both molecular and electrophysiological changes in this pathway in rats expressing persistent pain-related behaviour or FCA. Male Lister hooded rats, with stimulating and recording electrodes implanted in the amygdala and dPAG, respectively, either received or did not receive footshock (0.4 mA) paired with context, followed 23.5 h later by an intraplantar injection of saline or formalin (50 MUL, 2.5%) into the right hindpaw. Thirty minutes post formalin/saline, rats were re-exposed to the context for 15 min, during which pain-related behaviours were assessed in addition to evoked field potential recordings in the amygdala-dPAG pathway. Immediately after the 15-minute trial, PFC tissue was isolated for measurement of total and phosphorylated extracellular signal regulated kinase (ERK) by western blotting. Formalin-evoked nociceptive behaviour in non-fear-conditioned rats was associated with increased field potential amplitude in the dPAG and increased relative expression of phospho-ERK in the PFC. These effects were abolished in rats expressing FCA. Fear conditioning in non-formalin treated rats was associated with increased phospho ERK in the PFC but no change in field potential amplitude in the dPAG. Together, these data suggest differential, state-dependent alterations in electrophysiological activity and ERK phosphorylation along the PFC-amygdala-dPAG pathway during pain, conditioned fear, and FCA. PMID- 21683729 TI - Characterisation of chocolate eating behaviour. AB - Knowledge concerning variation in chocolate eating behaviour amongst consumers, and the impact that differences in the physical properties of chocolate could have on such behaviour is limited. The eating behaviour of individuals, consuming two chocolate samples (A and B), of comparable melt viscosity but with different textural attributes, was investigated. Surface electromyography (sEMG) was used to evaluate masticator muscle activity and electroglottography (EGG) was used to record swallowing events. Results showed that observed differences in mouthcoating affected the in-mouth residence time: chocolate A, perceived as more mouthcoating, showed an increased total chewing time and time of last swallow. Key differences across subjects were: time and number of chews, time of last swallow and total number of swallows. Subjects were grouped into three clusters of eating behaviour characterised as, "fast chewers", "thorough chewers" and "suckers". The main differences between clusters were the time chocolate was kept in mouth, chew rate and muscle work. PMID- 21683730 TI - Time course of discrimination between emotional facial expressions: the role of visual saliency. AB - Saccadic and manual responses were used to investigate the speed of discrimination between happy and non-happy facial expressions in two-alternative forced-choice tasks. The minimum latencies of correct saccadic responses indicated that the earliest time point at which discrimination occurred ranged between 200 and 280ms, depending on type of expression. Corresponding minimum latencies for manual responses ranged between 440 and 500ms. For both response modalities, visual saliency of the mouth region was a critical factor in facilitating discrimination: The more salient the mouth was in happy face targets in comparison with non-happy distracters, the faster discrimination was. Global image characteristics (e.g., luminance) and semantic factors (i.e., categorical similarity and affective valence of expression) made minor or no contribution to discrimination efficiency. This suggests that visual saliency of distinctive facial features, rather than the significance of expression, is used to make both early and later expression discrimination decisions. PMID- 21683732 TI - Promoting men's health within barbershops: barber/owner survey results and implications for intervention planning. PMID- 21683731 TI - Disparate effects of pramipexole on locomotor activity and sensorimotor gating in Sprague-Dawley rats. AB - Prepulse inhibition (PPI) of acoustic startle and locomotor activity are both widely studied in the preclinical development of dopaminergic agents, including those acting at D3 dopamine receptors. In mice, the dopamine D3 receptor preferential agonist pramipexole (PPX) alters locomotor activity in a biphasic manner at doses that have no effect on PPI. The present study examined the time course of PPX effects on locomotion and PPI in rats. In adult male Sprague-Dawley rats, PPX (0, 0.1, 0.3, 1.0mg/kg) was injected prior to measurement of locomotor activity for 90 min in photobeam chambers. Based on disparate early vs. late effects of PPX on locomotion, the effects of PPX (0 vs. 0.3mg/kg) on PPI were tested 20 and 80 min after injection. All doses of PPX decreased locomotor activity for 30 min compared to vehicle, and the higher doses stimulated hyperlocomotion later in the session; the late hyperlocomotion, but not the early hypolocomotion, was blocked by the D2-selective antagonist, L741626 (1.0mg/kg sc). In contrast to its locomotor effects, PPX caused a similar reduction in PPI at 20 and 80 min after administration. These findings suggest both a temporal and pharmacological dissociation between PPX effects on locomotor activity and PPI; these two behavioral measures contribute non-redundant information to the investigation of D3-related behavioral pharmacology. PMID- 21683733 TI - Molecular identification of interleukin-2 in the lymphoid tissues of the common brushtail possum, Trichosurus vulpecula. AB - The common brushtail possum (Trichosurus vulpecula) is an Australian marsupial. Here we describe the identification of possum interleukin-2 in mitogen-stimulated lymph node cells. We used a strategy of Rapid amplification of cDNA ends using probes designed from recently-sequenced marsupial genomes to identify the IL2 gene and then confirmed that IL-2 expression in possum immune tissue occurs in a similar manner to that in their eutherian counterparts. The predictive possum IL 2 peptide showed 28% and 35% amino acid sequence homology with the mouse and human IL-2 molecules, respectively, consistent with the divergence found within this cytokine family. Despite this low sequence identity, possum IL-2 still possessed the characteristic hallmarks of mammalian IL-2, such as a predicted signal peptide and conserved family motifs. PMID- 21683734 TI - Molecular cloning and expression analysis of two distinct F-type lectins from the rock bream, Oplegnathus fasciatus. AB - Several lectin families characterized by distinct signature sequence motifs and structural folds, such as C-type, peptidoglycan recognition protein, ficolin, pentraxins, and most recently galectins, have been implicated in immune surveillance. In this study, two distinct F-type lectins RbFTL-1 and RbFTL-2, from the rock bream (Oplegnathus fasciatus), were identified and their expression was analyzed. The full-length cDNA of RbFTL-1 was composed of 1204 bp with a 945 bp open reading frame (ORF) that encoded a 314 amino-acid protein, while that of RbFTL-2 consisted of 1614 bp with a 951-bp ORF encoding a 316 amino-acid protein. RbFTL-1 and RbFTL-2 mRNAs were predominately expressed in the head-kidney and in the liver, respectively. Levels of the RbFTL-1 mRNA transcript increased up to 5.0- and 2.8-fold in the head-kidney and trunk-kidney compared to the muscle, respectively, while those of the RbFTL-2 mRNA transcript increased up to 12.0 fold in liver. The expression of RbFTL-1 and RbFTL-2 were differentially up regulated in rock bream challenged with Edwardsiella tarda, Streptococcus iniae, and RSIV, with significant increases at 1 and 3h post-challenge compared to the controls. PMID- 21683735 TI - The large episomes of Butyrivibrio proteoclasticus B316T have arisen through intragenomic gene shuttling from the chromosome to smaller Butyrivibrio-specific plasmids. AB - The genome of Butyrivibrio proteoclasticus B316(T) contains three large episomes including a 302 kb chromid (BPc2) and two large plasmids of 361 (pCY360) and 186 kb (pCY186). The two plasmids are largely cryptic and it is therefore difficult to gauge their contributions or importance to the biology of B. proteoclasticus. Here, we provide evidence that at least BPc2 and pCY360 are essential as neither could be cured using several previously described curing techniques. We show that BPc2 exists at a copy number of 1, while pCY360 and pCY186 exist at copy numbers of 4 and 0.9, respectively. Yet the transcriptional activities of each episome are much less than that of the 3.5 Mb chromosome. Codon usage analyses did not support the hypothesis that the genes of all three episomes were acquired horizontally. Instead our analyses suggest that the vast majority of genes on each episome were transferred from the 3.5 Mb B. proteoclasticus chromosome. Analysis of their replication origins, however, suggests the plasmid backbones share an evolutionary lineage with the smaller Butyrivibrio specific plasmids, pRJF1 and pRJF2. A survey of 13 species of the Butyrivibrio/Pseudobutyrivibrio assemblage identified similar large episomes in nine strains. DNA hybridization experiments revealed none contained an rRNA operon and only a 145 kb episome from Pseudobutyrivibrioruminis possessed an ortholog of the pCY360 plasmid replication initiation protein. The size and distribution of episomes within the nine strains of Butyrivibrio/Pseudobutyrivibrio showed no correlation with 16S rRNA based phylogeny, leading to a hypothesis that the large episomes of Butyrivibrio spp., have arisen through intragenomic gene transfer events from the chromosome to small horizontally acquired elements. PMID- 21683736 TI - L-DOPA neurotoxicity is prevented by neuroprotective effects of erythropoietin. AB - The neurotoxicity of L-3,4-dihydroxyphenylalanine (L-DOPA), one of the most important drugs for the treatment of Parkinson's disease, still remains controversial, although much more data on L-DOPA neurotoxicity have been presented. Considering the well known neuroprotective effects of erythropoietin (EPO), the inhibitory effects of EPO on L-DOPA neurotoxicity need to be evaluated. Neuronally differentiated PC12 (nPC12) cells were treated with different concentrations of L-DOPA and/or EPO for 24h. Cell viability was evaluated using trypan blue, 4',6-diamidino-2-phenylindole (DAPI) and TUNEL staining, and cell counting. Free radicals and intracellular signaling protein levels were measured with 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and Western blotting, respectively. L-DOPA reduced nPC12 cell viability at higher concentrations, but combined treatment with EPO and L-DOPA significantly restored cell viability. Free radicals and hydroxyl radical levels increased by L-DOPA were decreased after combined treatment of L-DOPA and EPO. Levels of survival related intracellular signaling proteins decreased in nPC12 cells treated with 200 MUM L-DOPA but increased significantly in cells treated with 200MUM L-DOPA and 5 MUM EPO. However, cleaved caspase-3, a death-related protein, increased in nPC12 cells treated with 200 MUM L-DOPA but decreased significantly in cells treated with 200 MUM L-DOPA and 5 MUM EPO. Pretreatment with LY294002, a phosphatidylinositol 3-kinase inhibitor, prior to combined treatment with EPO and L-DOPA almost completely blocked the protective effects of EPO. These results indicate that EPO can prevent L-DOPA neurotoxicity by activating the PI3K pathway as well as reducing oxidative stress. PMID- 21683737 TI - Liprin-alpha is involved in exocytosis and cell spreading in mast cells. AB - The active zone is a specialized region of the presynaptic plasma membrane where the neurotransmitter release occurs by exocytosis. Mast cells also release inflammatory mediators by exocytosis resulting in induction of allergic responses. In our previous reports, we found that active zone proteins, Munc13-1 and ELKS regulates exocytosis of mast cell positively. In this study, we investigated the involvement of liprin-alpha, another active zone protein, in exocytosis in mast cells. We found that three isoforms of liprin-alpha, liprin alpha1, -alpha2 and -alpha3 were expressed. Immunocytochemical experiments revealed that liprin-alpha1 resided both in the cytoplasm and on the plasma membrane. Upon stimulation with antigen, the area of a cell increased remarkably due to cell spreading and the distribution of liprin-alpha1 became punctuated. Interestingly, knockdown of liprin-alpha1 caused decrease in exocytotic release and cell spreading. These results suggest that liprin-alpha1 facilitates exocytosis and cell spreading, and these events might have correlated each other in mast cells. PMID- 21683738 TI - Direct detection of highly pathogenic avian influenza A/H5N1 virus from mud specimens. AB - Contaminated mud and soil may play roles as reservoirs and sources of transmission for avian influenza A virus. However, the persistence of highly pathogenic avian influenza (HPAI) H5N1 virus in soil or mud has not been well documented, and specific methods of H5N1 virus detection in mud and soil specimens have not been described. The aim of this work was to evaluate the capacities of five different commercial kits and one elution-concentration technique to extract nucleic acids from H5N1 virus and to detect infectious viral particles in experimentally infected mud specimens. The viral RNA detection thresholds for the QIAamp kit, Trizol LS and the MagNA Pure LC kit were 5 * 10(2)RNA copies per gram of mud. Trizol reagent and the RNA PowerSoilTM kit were unsuccessful in recovering any viral RNA from mud. When the elution-concentration technique was performed prior to nucleic acid extraction, the performance of the MagNA Pure kit increased to a level that allowed the detection of H5N1 nucleic acids in naturally contaminated environmental samples that had previously tested negative after direct extraction using commercial kits. The levels of detection of infectious virus after inoculation into embryonated eggs were higher in concentrates than in eluates. PMID- 21683739 TI - Timing behavior in streptozotocin-induced diabetic rats. AB - There is evidence of deterioration of spatial cognition in streptozotocin (STZ) induced diabetic rats. Here, we evaluate a possible dissociation in the cognitive deficits due to diabetes by examining another crucial aspect of animal cognition: temporal perception. Timing behavior and temporal memory were evaluated in STZ induced diabetic rats employing two timing tasks: the peak-interval procedure, with its Gap variant, and the interval bisection task. A spatial memory task, rewarded alternation in the T-maze, was also evaluated to explore spatial cognition. The two timing tasks employed coincide in the finding of a normal timing performance in STZ-induced diabetic rats. The peak-interval procedure provided results that suggest that the timing behavior is equally accurate and precise than in control subjects; in the Gap procedure, an equal change in peak time in both groups indicates that temporal working memory is also intact. In the interval bisection task, we analyzed the acquisition of a temporal discrimination and the sensitivity to changes in the duration of the stimulus; no differences were found in either the acquisition process or the sensitivity index. In contrast, in the rewarded alternation task, STZ-induced diabetic rats exhibited a significant deficit in spatial cognition. The cognitive processes involved in timing behavior and temporal memory are not deteriorated as a consequence of diabetes; the cognitive deficits associated to diabetes thus seem to be restricted to the spatial domain. PMID- 21683740 TI - Lrp of Corynebacterium glutamicum controls expression of the brnFE operon encoding the export system for L-methionine and branched-chain amino acids. AB - Corynebacterium glutamicum possesses export systems for various amino acids including BrnFE, a two-component export system for L-methionine and the branched chain amino acids L-valine, L-isoleucine and L-leucine. A gene for a putative transcriptional regulator of the Lrp family is transcribed divergently to the brnFE operon and is required for L-isoleucine export. By comparing global gene expression changes due to L-isoleucine addition we revealed increased brnFE expression in response to L-isoleucine in C. glutamicum wild type but not in an lrp deletion mutant. ChIP-to-chip analysis, band shift experiments and DNAse footprint analysis demonstrated that Lrp binds to the intergenic region between lrp and brnF. Expression analysis of transcriptional fusions with the lrp and brnFE promoters indicated that branched-chain amino acids and L-methionine when added to the growth medium stimulated brnFE expression in the order L-leucine > L methionine > L-isoleucine > L-valine and that Lrp was required for activation of brnFE expression. Thus, regulation of brnFE by Lrp ensures that BrnFE is synthesized only if its substrate amino acids accumulate in cells which is commensurate with its role to counteract such situations of metabolic imbalance. PMID- 21683741 TI - Development of high-speed and highly efficient butanol production systems from butyric acid with high density of living cells of Clostridium saccharoperbutylacetonicum. AB - Living cells are alive and have the butanol-producing ability but not much proliferation under nitrogen source-limited condition. We investigated various butanol production systems with high density of living cells of Clostridium saccharoperbutylacetonicum N1-4 supplemented with methyl viologen (MV) as an electron carrier and nutrient dosing for activity regeneration. In continuous butanol production with high density of living cells, butanol yield was drastically increased from 0.365 C-mol/C-mol with growing cells to 0.528 C-mol/C mol at a dilution rate of 0.85 h-1, being increased with the butanol to total solvent ratio. This yield was increased to 0.591 C-mol/C-mol by adding 0.01 mM MV. MV addition increased not only butanol yield but also butanol concentration and productivity as compared to those without MV addition. However, living cells lost their activity with incubation time, which lowered the operational stability of the system. Therefore, to maintain constant stability, activity regeneration was carried out with high density of living cells and MV. This system produced butanol at high concentration (9.40 g l-1) and productivity (7.99 g l-1 h-1) for approximately 100 h with maintenance of considerably high yield of butanol (0.686 C-mol/C-mol). Thus, we established a high-speed and highly efficient butanol production system. PMID- 21683742 TI - Genomic and phylogenetic analyses of murine adenovirus 2. AB - Murine adenoviruses (MAdV) are supposedly the oldest members of the genus Mastadenovirus. Currently, there are three distinct MAdV types known with rather different tropism and pathology. Here we report and annotate the DNA sequence of the full genome of MAdV-2. It was found to consist of 35,203 bp thus being considerably larger than the genomes of the other two MAdV types. The increased size of the MAdV-2 genome is generally due to larger genes and ORFs, although some differences in the number of ORFs were observed for the early regions E1, E3 and E4. The homologue of the 19K gene of E1B from MAdV-2 codes for 330 amino acids (aa) and is almost twice as large as from other mastadenoviruses. Accordingly, only the N-terminal half (155aa) has homology to the 19K protein. A homologue of the gene of the 12.5K protein was identified in the E3 region of MAdV-2, but not in MAdV-1 or MAdV-3. The other gene of yet unknown function in the E3 region of MAdV-2 seems to be unique. The E4 region of MAdV-2 contains three ORFs. One has similarity to the 34K gene of other AdVs. Two unique ORFs in the E4 region of MAdV-2 have no homology to any of the five and six ORFs in the E4 region of MAdV-1 or MAdV-3, respectively. Phylogenetic analyses showed that the three murine AdVs have a close common ancestor. They likely formed the first branching of the lineage of mastadenoviruses, and seem to be the most ancient representatives of this genus. PMID- 21683743 TI - The E3 CR1-gamma gene in human adenoviruses associated with epidemic keratoconjunctivitis. AB - Human adenovirus species D type 37 (HAdV-D37) is an important etiologic agent of epidemic keratoconjunctivitis. Annotation of the whole genome revealed an open reading frame (ORF) in the E3 transcription unit predicted to encode a 31.6kDa protein. This ORF, also known as CR1-gamma, is predicted to be an integral membrane protein containing N-terminal signal sequence, luminal, transmembrane, and cytoplasmic domains. HAdV-D19 (C), another viral pathogen causing epidemic keratoconjunctivitis, contains an ORF 100% identical to its HAdV-D37 homologue but only 66% identical to other HAdV-D homologues. Kinetics of RNA expression and confirmation of splicing to the adenovirus tripartite leader sequence suggest a role for the protein product of CR1-gamma in the late stages of the viral replication cycle. Confocal microscopy is consistent with expression in the cytoplasm. Sequence analysis reveals a hypervariable luminal domain and a conserved cytoplasmic domain. The luminal domain is predicted to contain multiple N-glycosylation sites. The cytoplasmic domain contains a putative protein kinase C phosphorylation site and potential YXXphi and dileucine (LL) motifs suggesting a potential role in modification of host proteins. PMID- 21683744 TI - Comparative structural studies of bovine viral diarrhea virus IRES RNA. AB - The internal ribosomal entry site (IRES) RNA of bovine viral diarrhea virus (BVDV) has been implicated in virus propagation. To gain insight into the structure and potential function of the BVDV IRES RNA, we collected and aligned 663 of its sequences. Compensatory Watson-Crick and wobble G.U pairs were investigated to establish phylogenetically supported secondary structures for each of the BVDV IRES RNA sequences. The extensively folded BVDV IRES RNAs were composed of helices 2, 3 and 4. Helix 2 consisted of five helical sections. Helix 3 contained sections 3a to 3j as well as six helical insertions 3.1-3.6. Sections 3a and 3b together with helices 3.6 and 4 formed an RNA pseudoknot. Two highly variable regions corresponded to hairpins 3j and 3.4. Three-dimensional modeling of the BVDV-1b strain Osloss IRES RNA predicted an elongated structure with approximate dimensions of 170 A by 65 A by 90 A. The model of the IRES RNA ribosome complex suggested proximity between helix 2 of the BVDV IRES and ribosomal proteins S5 and S25. PMID- 21683745 TI - Translational imaging of lymphatics in cancer. AB - Imaging in the lymphatic system has gone through much advancement over the past 70 years since its beginnings. In this review, we will examine the modalities available for lymphatic imaging. We will explore the modern uses of early modalities, such as ultrasound as well as more modern modalities, such as Positron-Emission Tomography (PET). We will also describe some of the new modalities currently in development and their potential uses for the future as well as some of the current imaging modalities being studied in animal models. PMID- 21683746 TI - Targeting the lymphatics using dendritic polymers (dendrimers). AB - Dendrimers are unique biomaterials that are constructed by the stepwise addition of layers (generations) of polymer around a central core. They can be constructed with a range of molecular weights and have a polyfunctional surface that facilitates the attachment of drugs and pharmacokinetic modifiers such PEG or targeting moieties. These properties have led to considerable interest in the development of dendrimers for a range of biomedical applications. After subcutaneous administration, larger dendrimers in particular (> 8 nm), preferentially drain from the injection site into the peripheral lymphatic capillaries and therefore have potential as lymphatic imaging agents for magnetic resonance and optical fluorescence lymphangiography and as vectors for drug targeting to lymphatic sites of disease progression. In general, lymphatic targeting of dendrimers is enhanced by increasing size although ultimately larger constructs may be incompletely absorbed from the injection site. Increasing hydrophilicity and reducing surface charge enhances drainage from subcutaneous injection sites, but the reverse is true of uptake into lymph nodes where charge and hydrophobicity promote retention. Larger hydrophilic dendrimers are also capable of extravasation from the systemic circulation, absorption into the lymphatic system and recirculation into the blood. Lymphatic recirculation may therefore be a characteristic of PEGylated dendrimers with long systemic circulation times. PMID- 21683747 TI - Increasing food familiarity without the tears. A role for visual exposure? AB - Research has established the success of taste exposure paradigms as a means of increasing children's acceptance, and liking, of previously unfamiliar or disliked foods. Yet, parents report that they tend to avoid the stress associated with repeatedly offering their children foods that are likely to be rejected. Given that successful taste exposure programmes often enhance children's familiarity with a food's appearance, as well as its taste, this article reviews the potential for exposure interventions that do not require repeated tastings to bring about positive attitude changes towards healthy foods. Recent evidence from studies that expose toddlers to picture books about fruit and vegetables suggest that familiarity with the origins and appearance of unfamiliar foods might increase children's willingness to accept these into their diets. PMID- 21683748 TI - Food dependence in rats selectively bred for low versus high saccharin intake. Implications for "food addiction". AB - The "food addiction" concept implies that proneness to drug dependence and to food dependence should covary. The latter was studied in low- (LoS) and high- (HiS) saccharin-consuming rats, who differ in drug self-administration (HiS>LoS) and withdrawal (LoS>HiS). Sugary food intake in the first 1-2 h was higher in HiS than LoS rats. Sugar intake predicted startle during abstinence only among LoS rats. These results may suggest bingeing-proneness in HiS rats and withdrawal proneness among LoS rats. However, intake escalation and somatic withdrawal did not differ between lines. Further study with selectively bred rats, with attention to definitions and measures, is warranted. PMID- 21683749 TI - Determinants of fast-food consumption. An application of the Theory of Planned Behaviour. AB - This study applied and extended the Theory of Planned Behaviour (TPB; Ajzen, 1988) in an examination of the variables influencing fast-food consumption in an Australian sample. Four hundred and four participants responded to items measuring TPB constructs and retrospective and prospective measures of fast-food consumption. Additional independent variables included: Consideration of Future Consequences (Strathman, Gleicher, Boninger, & Edwards, 1994), Fear of Negative Evaluation (Leary, 1983), and Self-Identification as a Healthy Eater Scale (Armitage & Conner, 1999a). Structural Equation Modeling (SEM) was used to examine predictors of consumption. SEM indicated that the TPB successfully predicted fast-food consumption. Factor analyses assisted in the definition of constructs that underlay attitudes towards fast foods. These constructs were included in an 'extended' TPB model which then provided a richer source of information regarding the nature of the variables influencing fast-food consumption. Findings suggest that fast-food consumption is influenced by specific referent groups as well as a general demand for meals that are tasty, satisfying, and convenient. These factors reflect immediate needs and appear to override concerns about longer-term health risks associated with fast food. Results are discussed in the context of possible applications. PMID- 21683750 TI - Evaluation of satiety enhancement, including compensation, by blends of gum arabic. A methodological approach. AB - In the present study a potential satiating effect by two blends of gum arabic (EmulGold((r)) (EG) and PreVitae((r)) (PV)) was investigated in healthy humans applying a regression analysis on the change of values throughout the interval of the study. Two studies were thus conducted: a feasibility study using doses between 10 and 40 g and a dose-finding study of 5 or 10 g of only EG. The gums were dissolved in 250 ml of water (negative control). In both studies energy intake was determined 3 h after consumption, while Visual Analogue Scale (VAS) scores were recorded every 30 min from the time of consumption onwards. At doses of 40 g both EG and PV yielded a significant reduction in energy intake of more than 100 and 200 kcal, respectively. At doses of 10 or 20 g the reduction in energy intake amounted to more than 100 kcal for both. The second study demonstrated a significant reduction in caloric intake of more than 60 kcal at doses of 5 and 10 g of EG. With respect to the subjective perception of satiety, VAS scores revealed a significant increase as compared to the negative control of all doses of both gums. The regression analysis was sensitive in identifying not only the intensity of the perception during the time interval of the study but also the change in this intensity over time. The results of this study show that both blends of gum arabic are able to decrease the caloric intake significantly 3 h after consumption, and increase subjective ratings of feeling satiated, and could therefore be used in a dietary approach to control body weight development. PMID- 21683751 TI - Developmental overfeeding alters hypothalamic neuropeptide mRNA levels and response to a high-fat diet in adult mice. AB - It has been suggested that nutritional manipulations during the first weeks of life can alter the development of the hypothalamic circuits involved in energy homeostasis. We studied the expression of a large number of the hypothalamic neuropeptide mRNAs that control body weight in mice that were overfed during breastfeeding (mice grown in a small litter, SL) and/or during adolescence (adolescent mice fed a high-fat diet, AHF). We also investigated possible alterations in mRNA levels after 50 days of a high-fat diet (high-fat challenge, CHF) at 19 weeks of age. Both SL and AHF conditions caused overweight during the period of developmental overfeeding. During adulthood, all of the mouse groups fed a CHF significantly gained weight in comparison with mice fed a low-fat diet, but the mice that had undergone both breast and adolescent overfeeding (SL-AHF CHF mice) gained significantly more weight than the control CHF mice. Of the ten neuropeptide mRNAs studied, only neuropeptide Y (NPY) expression was decreased in all of the groups of developmentally overfed adult mice, but CHF during adulthood by itself induced a decrease in NPY, agouti-related protein (AgRP) and orexin (Orx) mRNA levels. Moreover, in the developmentally overfed CHF mice NPY, AgRP, galanin (GAL) and galanin-like peptide (GalP) mRNA levels significantly decreased in comparison with the control CHF mice. These results show that, during adulthood, hypothalamic neuropeptide systems are altered (NPY) and/or abnormally respond to a high-fat diet (NPY, AgRP, GAL and GalP) in mice overfed during critical developmental periods. PMID- 21683752 TI - Lack of association between translin-associated factor X gene (TSNAX) and methamphetamine dependence in the Japanese population. AB - OBJECTIVES: Recently, we detected that the prokineticin 2 receptor gene was associated with not only major depressive disorder (MDD) but also methamphetamine dependence. Therefore, it is possible that mood disorders and drug addiction have shared susceptibility genes. The translin-associated factor X gene (TSNAX)/disrupted-in-schizophrenia-1 gene (DISC1) has been associated with psychiatric disorders, including schizophrenia, MDD and bipolar disorder. TSNAX is located immediately upstream of DISC1 and has been shown to undergo intergenic splicing with DISC1. Based on this evidence, we hypothesized that TSNAX might be a good candidate gene for methamphetamine dependence. METHODS: We conducted a case-control study of Japanese individuals (215 with methamphetamine dependence and 318 age- and sex-matched controls) with three tagging SNPs (rs1630250, rs766288 and rs6662926) selected by HapMap database. RESULTS: rs1630250 was associated in males with methamphetamine dependence in the allele analysis (P value: 0.0253). However, these results did not remain significant after Bonferroni correction to adjust for multiple comparisons (corrected P-value: 0.152). CONCLUSION: Our findings suggest that TSNAX does not play a role in methamphetamine dependence in the Japanese population. A replication study using larger samples needs to be conducted to obtain conclusive results. PMID- 21683753 TI - Increased frequency of micronuclei in diabetes mellitus patients using pioglitazone and glimepiride in combination. PMID- 21683754 TI - Transcriptome of tributyltin-induced apoptosis of the cultured rat mesencephalic neural stem cells. AB - Exposure to environmental neurotoxic chemicals both in utero and during the early postnatal period can cause neurodevelopmental disorders. To evaluate the disruption of neurodevelopmental programming, we previously established an in vitro neurosphere assay system, using rat mesencephalic neural stem cells (mNSC). Here, we examined the developmental neurotoxicity of tributyltin (TBT) in an in vitro neurosphere assay. A neurosphere was driven from rat E16 mesencephalon and seeded in a poly-l-ornithine/laminin-coated plate. Exposure to TBT increased the number of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL)-positive cells in time-dependent and dose-dependent manner: it was significantly detectable with treatment of 100pM TBT for 90min, or of 1MUM TBT for 30min. Disruption of mitochondrial membrane potential and activation of caspase-3/7 were concomitantly observed. Furthermore, DNA microarray analyses using Affymetrix GeneChip revealed that as early as 0.5h after exposure to the metal (1MUM), the expression levels of 71 genes were increased by more than 2 fold, whereas those of 8 genes were decreased by 2-fold or less: it was notably altered in expression of Ca(2+)-mobilizing-related genes, and retinoic-acid signal-related genes, as well as bifunctional apoptosis-related genes. The levels of gene expression of Wnt family were also significantly changed. Thus, we established transcriptome of TBT-induced apoptosis of mNSC. This would help to evaluate developmental neurotoxicity of TBT in vivo, contributing to the risk assessment methods based on infant physiology. PMID- 21683755 TI - Primary sensory cortices, top-down projections and conscious experience. AB - Beginning with a prominent article by Crick and Koch in 1995 (Nature 375, 121 123), cognitive neuroscience has witnessed an intensive debate about whether or not neural activity in primary visual cortex correlates with conscious visual experience. While some studies--especially those employing functional magnetic resonance imaging--imply that this is the case, others--particularly those recording from single neurons--suggest that it is not. In the light of this ongoing controversy, it is surprising that the analogous question in other sensory modalities has received far less attention. The first part of the present article reviews studies relevant to the role of primary auditory and primary somatosensory cortices in conscious auditory and tactile experience. As will become evident, the results of these studies, at least at first sight, appear no less contradictory than those obtained in the visual modality--in fact, they evidence discrepancies that resemble those found in the visual system to an impressive degree. The second part of the article attempts to reconcile the seemingly contradictory data by suggesting that only activity induced in the primary sensory cortices through cortico-cortical top-down signals can become consciously accessible, whereas activity induced by bottom-up signals from the thalamus cannot. This conclusion is in line with the earlier proposals of several prominent neuroscientists that portrayed conscious perception as the result of an active interpretative process by the brain, rather than a passive reflection of the environment. PMID- 21683756 TI - Affective and neuroendocrine stress reactivity to an academic examination: influence of the 5-HTTLPR genotype and trait neuroticism. AB - The current study examined the singular and interactive effects of the 5-HTTLPR genotype and trait neuroticism on affective and physiological stress responses to an academic examination in healthy undergraduate students. From 771 students, 46 short/short (S/S)-allele carriers and 48 long/long (L/L)-allele carriers with the lowest and the highest neuroticism scores (80 females, 14 males; mean age+/-SD: 20.3+/-1.7 years) were selected. Salivary cortisol concentrations, mood and perceived stress were assessed before and after a 2-h written examination and compared with a control day. Negative mood, perceived stress and cortisol significantly increased during the examination compared to the control day. Negative stress effects on mood and perceived stress were significantly larger for S/S-allele carriers compared to L/L-allele carriers, regardless of trait neuroticism. Since vulnerability to real-life stressors is an important risk factor for depression pathogenesis, this may be a mediating factor making S/S allele carriers more susceptible for depression symptoms. PMID- 21683757 TI - Bifurcation analysis and effects of changing ionic conductances on pacemaker rhythm in a sinoatrial node cell model. AB - The electrical excitation (action potential generation) of sinoatrial node (cardiac pacemaker) cells is directly related to various ion channels (pore forming proteins) in cell membranes. In order to analyze the relation between action potential generation and ion channels, we use the Yanagihara-Noma-Irisawa (YNI) model of sinoatrial node cells, which is described by the Hodgkin-Huxley type equations with seven variables. In this paper, we analyze the global bifurcation structure of the YNI model by varying various conductances of ion channels, and examine the effects of these conductance changes on pacemaker rhythm (frequency of action potential generation). The coupling effect on pacemaker rhythm is also examined approximately by applying external current to the YNI model. PMID- 21683758 TI - Cell biology of H2O2 generation in the thyroid: investigation of the control of dual oxidases (DUOX) activity in intact ex vivo thyroid tissue and cell lines. AB - H2O2 generation by dual oxidase (DUOX) at the apex of thyroid cells is the limiting factor in the oxidation of iodide and the synthesis of thyroid hormones. Its characteristics have been investigated using different in vitro models, from the most physiological thyroid slices to the particulate fraction isolated from transfected DUOX expressing CHO cells. Comparison of the models shows that some positive controls are thyroid specific (TSH) or require the substructure of the in vivo cells (MbetaCD). Other controls apply to all intact cell models such as the stimulation of the PIP(2) phospholipase C pathway by ATP acting on purinergic receptors, the activation of the Gq protein downstream (NaF), or surrogates of the intracellular signals generated by this cascade (phorbol esters for protein kinase C, Ca(++) ionophore for Ca(++)). Still, other controls, exerted by intracellular Ca(++) or its substitute Mn(++), the intracellular pH, or arachidonate bear directly on the enzyme. Iodide acts at the apical membrane of the cell through an oxidized form, presumably iodohexadecanal. Cooling of the cells to 22 degrees C blocks the activation of the PIP(2) phospholipase C cascade. All these effects are reversible. Their kinetics and concentration effect characteristics have been defined in the four models. A general scheme of the thyroid signaling pathways regulating this metabolism is proposed. The probes characterized could be applied to other H2O2 producing cells and to pathological material. PMID- 21683759 TI - Histamine evokes excitatory response of neurons in the cerebellar dentate nucleus via H2 receptors. AB - Previous studies have shown an excitatory effect of histamine on neurons in two cerebellar nuclei, the fastigial nucleus and the interposed nucleus. Here we investigated action of histamine on the dentate nucleus (DN), another nucleus of the cerebellum, and provided more evidence for motor control by histamine via the cerebellum. Spontaneous unitary discharge of neurons in the DN was extracellularly recorded by use of cerebellar slice preparations. In total 79 recorded neurons, which were from 53 cerebellar slices, 67 neurons (84.8%) had an excitatory response to histamine stimulation, and the rest (15.2%) were not reactive. The histamine-induced excitation of the DN neurons was not blocked by low-Ca(2+)/high-Mg(2+) medium, demonstrating that this effect of histamine was postsynaptic. Triprolidine, an antagonist of histamine H(1) receptors, did not block the excitatory effect of histamine, but ranitidine, an antagonist for H(2) receptors, blocked the excitatory response to histamine in a concentration dependent manner. Further, histamine H(1) receptor agonist 2-pyridylethylamine did not elicit any response of DN neurons, but H(2) receptor agonist dimaprit had an excitatory action on the DN cells and this action was blocked by ranitidine. These results indicate that histamine excites cerebellar DN neurons via histamine H(2) receptors. Since the DN receives hypothalamocerebellar histaminergic projections and plays a role in initiation and planning of somatic movement, the postsynaptic excitation of the DN neurons by histamine suggests the possibility that the initiation and planning of movement may be modulated by the histaminergic projections. PMID- 21683760 TI - Genetic association study of GABRA2 single nucleotide polymorphisms and electroencephalography in alcohol dependence. AB - The gamma aminobutyric acid (GABA) system has been implicated in the susceptibility to develop alcohol dependence and in determining electroencephalogram (EEG) beta activity. The role of the GABA receptor alpha-2 gene (GABRA2) in human alcohol dependence was determined in a genetic and electrophysiological study. The study population comprised 586 white UK individuals with alcohol dependence but a very low prevalence of co-morbid drug dependence, and 603 ancestrally matched healthy controls. Genotyping for seven GABRA2 single nucleotide polymorphisms (SNPs), identified from the literature as positively associated with alcohol dependence, was performed with success rates of 90% or greater. EEGs were available in 32 selected patients who had been abstinent from alcohol for a minimum of 24 months and in 138 ancestrally matched healthy controls. None of the SNPs showed allelic or haplotypic association with alcohol dependence. All markers were in Hardy Weinberg equilibrium (HWE) in the controls. HWE for marker rs279841 in the alcohol dependent sample was p=0.0199 and combined p=0.0166. Linkage disequilibrium patterns appear to be very similar to that observed in the HapMap CEU data. A significantly higher prevalence of excess EEG fast activity was found in the patients (31 vs. 14%, p=0.018). A significant relationship was found between the presence of excess EEG fast activity and GABRA2 SNPs rs548583, rs279871 and rs279841. This allelic association study provides no evidence for an association between GABRA2 polymorphisms and alcohol dependence. However, a significant relationship was identified between GABRA2 and excess EEG fast activity. This dissociation of effect may reflect the fact that the EEG is a more direct marker of phenotypic GABRA2 expression than the more heterogeneous alcohol dependence phenotype. PMID- 21683761 TI - Impairment of long-term potentiation in the hippocampus of alcohol-treated OLETF rats. AB - Type 2 diabetes and chronic heavy alcohol consumption each have been known to be associated with the impairment of hippocampus-dependent cognitive functions. Although both conditions often coexist clinically and there is accumulated evidence of a relationship between the two, the combined effect on hippocampal long-term potentiation (LTP) has not yet been investigated. We compared the effect of type 2 diabetes itself with that of type 2 diabetes with chronic heavy alcohol consumption on the hippocampal LTP using Otsuka Long-Evans Tokushima Fatty (OLETF) rat model, which resembles the characteristics of human type 2 diabetes. Ten of 16-week-old male OLETF rats were randomized into two treatment groups according to weight: the OLETF-Alcohol (O-A, n=5) and the OLETF-Control (O C, n=5). The rats in the O-A group were fed Lieber-DeCarli Regular EtOH over a 10 week period and the amount of alcohol consumption was 8.42+/-2.52g/kg/day. To ensure the effect of poor glycemic control on LTP, intraperitoneal glucose tolerance test was performed after a 10-week treatment. The hippocampal LTP was measured by extracellular field excitatory post-synaptic potentials at Shaffer collateral (SC) synapses in the CA1 region. Although the O-A group showed significantly lower fasting and postprandial glucose (P<0.01 and P=0.02, respectively), the hippocampal LTP was more significantly attenuated in the O-A group than the O-C group (P=0.032). The results of this study suggested that chronic heavy alcohol consumption could potentiate the impairment of hippocampal LTP in individuals with impaired glucose tolerance or early type 2 diabetes, even though it did not aggravate, but did improve glycemic control. Clinical attention to chronic heavy drinking will be required in preventing cognitive impairment in individuals with type 2 diabetes. PMID- 21683762 TI - The eccentricity effect of inhibition of return is resistant to practice. AB - Inhibition of return (IOR) refers to a delayed responding to targets appeared at previously cued location relative to an uncued novel location. In a recent study, Bao and Poppel reported a functional dissociation of inhibitory processing in the visual field with much stronger IOR magnitude in the far periphery relative to the perifoveal visual field up to 15 degrees eccentricity. The present study aimed to examine whether this effect is sensitive to participant experience or practice. Consistent with previous findings, our data demonstrated a larger IOR magnitude at 21 degrees relative to 7 degrees stimulus eccentricity. More importantly, no practice-related IOR magnitude changes were observed for both perifoveal and peripheral stimuli, although response times did decrease significantly with practice. These results suggest that the eccentricity effect of IOR is a robust phenomenon which is resistant to practice. PMID- 21683763 TI - The abnormal cannabidiol analogue O-1602 reduces nociception in a rat model of acute arthritis via the putative cannabinoid receptor GPR55. AB - Cannabinoids classically act via CB1 and CB2 receptors to modulate nociception; however, recent findings suggest that some cannabinoids bind to atypical receptors. One such receptor is GPR55 which is activated by the abnormal cannabidiol analogue O-1602. This study investigated whether the synthetic GPR55 agonist O-1602 can alter joint nociception in a rat model of acute joint inflammation. Acute (24 h) inflammatory joint pain was induced in male Wistar rats by intra-articular injection of 2% kaolin and 2% carrageenan. Single unit extracellular recordings were made from arthritic joint afferents in response to mechanical rotation of the knee. Peripheral administration of O-1602 significantly reduced movement-evoked firing of nociceptive C fibres and this effect was blocked by the GPR55 receptor antagonist O-1918. Co-administration of the CB1 and CB2 antagonists (AM281 and AM630 respectively) had no effect on O 1602 responses. This study clearly shows that atypical cannabinoid receptors are involved in joint nociception and these novel targets may be advantageous for the treatment of inflammatory pain. PMID- 21683764 TI - Amelioration of hypoxia-induced striatal 5-HT(2A) receptor, 5-HT transporter and HIF1 alterations by glucose, oxygen and epinephrine in neonatal rats. AB - Alterations in neurotransmitters and its receptors expression induce brain injury during neonatal hypoxic insult. Molecular processes regulating the serotonergic receptors play an important role in the control of respiration under hypoxic insult. The present study focused on the serotonergic regulation of neonatal hypoxia and its resuscitation methods. Receptor binding assays and gene expression studies were done to evaluate the changes in 5HT(2A) receptors and its transporter in the corpus striatum of hypoxic neonatal rats and hypoxic rats resuscitated with glucose, oxygen and epinephrine. Total 5HT and 5HT(2A) receptor number was increased in hypoxic neonates along with an up regulation of 5HT(2A) receptor and 5HT transporter gene. The enhanced striatal 5HT(2A) receptors modulate the ventilatory response to hypoxia. Immediate glucose resuscitation was found to ameliorate the receptor and transporter alterations. Hypoxia induced ATP depletion mediated reduction in blood glucose levels can be encountered by glucose administration and oxygenation helps in overcoming the anaerobic condition. The adverse effect of immediate oxygenation and epinephrine supplementation was also reported. This has immense clinical significance in establishing a proper resuscitation for the management of neonatal hypoxia. PMID- 21683765 TI - Immunohistochemical characterization of superior cervical ganglion neurons supplying porcine parotid salivary gland. AB - The main goal of our study was to investigate the chemical coding of the superior cervical ganglion (SCG) sympathetic neurons supplying the porcine parotid gland. Additionally, the chemical nature of the vicinal nerve fibers surrounding the parotid SCG perikarya was investigated. Fast blue (FB) retrograde tracing of the parotid gland and immunofluorescent labelling of SCG neurons were studied in juvenile female pigs. Microscopic analysis revealed that only ipsilateral SCG neurons were retrogradely labelled. The labelled neurons formed a discrete cluster in the middle and caudal region of the ganglion. Immunofluorescent labelling revealed that virtually all of the FB-positive parotid gland neurons were immunoreactive to tyrosine hydroxylase (TH), confirming their sympathetic nature. In addition to TH, the majority of the FB-positive neurons were found to be immunoreactive to calbindin (CB) and to a lesser extent for neuropeptide Y (NPY), leu-enkephalin (LENK) and galanin (GAL). In the close proximity of the FB traced perikarya, a large number of immunoreactive (IR) vasoactive intestinal peptide (VIP-IR), pituitary adenylate cyclase-activating polypeptide (PACAP-IR), nitric oxide synthase (NOS-IR) processes were identified. Moreover, calcitonin gene related peptide-immunoreactive (CGRP-IR), substance P-immunoreactive (SP IR), vesicular acetylcholine transporter (VAChT-IR), calretinin (CRT-IR), GAL-IR, LENK-IR and CB-IR protrusions were observed. The results of the present study provide a detailed characteristic of the location and neurochemical coding of sympathetic SCG neurons innervating the parotid salivary gland of the pig and lay ground for more advanced, clinical studies on salivary gland innervations. PMID- 21683766 TI - Transcranial direct current stimulation (tDCS) produces localized and specific alterations in neurochemistry: a 1H magnetic resonance spectroscopy study. AB - Transcranial direct current stimulation (tDCS) has been found to produce significant changes in behavior, including a large increase of learning and performance for a difficult visual perceptual task (Clark et al., NeuroImage 2010). The mechanisms by which tDCS produces these behavioral effects are currently uncertain. One hypothesis is that anodal tDCS leads to increased metabolic activity in the brain, which enhances cognitive and memory processes. Here we examined the neuronal mechanisms by which tDCS influences learning by measuring changes in brain metabolite concentrations using proton magnetic resonance spectroscopy (1H MRS). As perception and learning can also influence neurochemistry, here we applied tDCS during rest. MRS data was obtained before and after 2.0 mA of anodal tDCS was applied for 30 min over electrode site P4, with the cathode placed on the contralateral arm. MRS data were acquired from the right parietal lobe beneath the anodal tDCS electrode, and from the homologous regions of the left hemisphere once before and once after tDCS. Significantly higher combined glutamate and glutamine levels were found in right parietal cortex, beneath the stimulating electrode, with non-significant increases in homologous regions of the opposite hemisphere. In addition, a significant interaction between hemispheres was found for tDCS effects on tNAA. These results suggest that changes in glutamatergic activity and tNAA may be related to the mechanisms by which tDCS influences learning and behavior. PMID- 21683767 TI - Effects of increasing durations of immobilization stress on plasma corticosterone level, learning and memory and hippocampal BDNF gene expression in rats. AB - Stress effects on learning and memory are widely recognized, but less agreement exists on whether they are positive or negative as well as on their neuronal and neuromolecular correlates. Stress involves expression of certain genes such as neurotrophin BDNF (brain derived neurotrophic factor), which is also involved in learning, but results are not consistent. Here effects of stress on memory and BDNF expression were studied using on adult male rats exposed to "immobilization stress" for various "short" durations, i.e., 1-h, 3-h, 5-h and "long-term" ones (2-h/day for 1 week). Learning and memory was measured using passive avoidance testing (STL=step-through-latency scores) as well as plasma corticosterone (CSt) levels and hippocampal BDNF gene expression. CSt increased in the 3-h and longer stressed groups but differences were significant in the 5-h and 1-week stressed subgroups. Three and 5-h of stress markedly and significantly (60-69%, p<0.01) decreased memory retention in the stressed animals, while 1-h of stress had no effect; prolonged stress (2-h daily for 1-week) increased memory significantly (33%, p<0.05). Hippocampal BDNF gene expression increased in the 1-h and 3-h stressed groups (44%, p<0.05 and 71%, p<0.01); but this parameter steadily declined in the 5-h stressed group (26%, p<0.05) and weeklong stressed group (6%, not significant). Statistical analysis revealed an apparent but significant negative correlation between changes in memory and those of BDNF gene expression, indicating that BDNF may possibly play a compensatory role, reversing deleterious effects of stress on hippocampal memory functions. PMID- 21683768 TI - Muscle recovery after repair of short and long peripheral nerve gaps using fibrin conduits. AB - Peripheral nerve injuries with loss of nervous tissue are a significant clinical problem and are currently treated using autologous nerve transplants. To avoid the need for donor nerve, which results in additional morbidity such as loss of sensation and scarring, alternative bridging methods have been sought. Recently we showed that an artificial nerve conduit moulded from fibrin glue is biocompatible to nerve regeneration. In this present study, we have used the fibrin conduit or a nerve graft to bridge either a 10 mm or 20 mm sciatic nerve gap and analyzed the muscle recovery in adult rats after 16 weeks. The gastrocnemius muscle weights of the operated side were similar for both gap sizes when treated with nerve graft. In contrast, muscle weight was 48.32 +/- 4.96% of the contra-lateral side for the 10 mm gap repaired with fibrin conduit but only 25.20 +/- 2.50% for the 20 mm gap repaired with fibrin conduit. The morphology of the muscles in the nerve graft groups showed an intact, ordered structure, with the muscle fibers grouped in fascicles whereas the 20 mm nerve gap fibrin group had a more chaotic appearance. The mean area and diameter of fast type fibers in the 20 mm gap repaired with fibrin conduits were significantly (P<0.01) worse than those of the corresponding 10 mm gap group. In contrast, both gap sizes treated with nerve graft showed similar fiber size. Furthermore, the 10 mm gaps repaired with either nerve graft or fibrin conduit showed similar muscle fiber size. These results indicate that the fibrin conduit can effectively treat short nerve gaps but further modification such as the inclusion of regenerative cells may be required to attain the outcomes of nerve graft for long gaps. PMID- 21683769 TI - Sexually dimorphic effects of estrogen on spines in cultures of accessory olfactory bulb. AB - A sex difference has been reported in the responsiveness of the vomeronasal (VN) system to pheromones. In the present study, to clarify a direct and acute influence of 17beta-estradiol (E2) on the accessory olfactory bulb (AOB) neurons, we investigated the effect of E2 on dendritic spines in cultured AOB cells derived from male and female neonatal rats. After 17-18 days in vitro (DIV), cultured AOB cells were transfected with GFP expression vectors. At 21-23 DIV, cells were treated with E2, and time-lapse images of transfected AOB neurons identified as granule cells were taken under a confocal laser scanning microscope for 3h. The dendritic spine head area of granule cells was quantitatively evaluated, and spine heads were classified into larger (>= 1 MUm2) and smaller (<1 MUm2) ones before E2-treatment (0 h). In cultured cells derived from both sexes, the larger spines were not significantly changed at 1, 2 and 3 h after E2 treatment. In contrast, E2-treatment significantly enlarged the head area of the smaller spines of granule cells derived from the female, whereas E2 did not cause any significant effects on those from the male. Our results provide evidence for the sexually-dimorphic effect of E2 on spine development in AOB granule cells. PMID- 21683770 TI - Niaspan reduces high-mobility group box 1/receptor for advanced glycation endproducts after stroke in type-1 diabetic rats. AB - OBJECTIVE: High-mobility group box 1 (HMGB1), an active receptor for advanced glycation endproducts (RAGE), functions as a potent proinflammatory cytokine-like factor that contributes to the pathogenesis of vasculature. Diabetes mellitus (DM) is associated with accelerated development of both microvascular and macrovascular disease and increases the risk of ischemic stroke. Using a model of streptozotocin-induced type-1 diabetes (T1DM) in rats, we investigated the changes in HMGB and RAGE and tested the effects of Niaspan, a slow release form of niacin, on the expression of pro-inflammatory proteins in rats after stroke. RESEARCH DESIGN AND METHODS: T1DM rats were subjected to transient middle cerebral artery occlusion (MCAo) and treated without or with Niaspan (40 mg/kg) daily for 14 days after MCAo. Non-streptozotocin rats (WT) were also subjected to MCAo. Immunostaining for inflammatory mediators including HMGB1, RAGE, matrix metalloproteinase-9 (MMP-9) and toll-like receptor 4 (TLR4) immunostaining (n=8/group) and Western blotting (n=4/group) were performed. RESULTS: Compared to WT-MCAo rats, T1DM-MCAo rats showed an increased expression of HMGB1 (0.82+/-0.07 vs. 1.81+/-0.98, P<0.05), RAGE (1.31+/-0.22 vs. 3.77+/-0.72, P<0.05), MMP-9 (0.74+/-0.08 vs. 1.61+/-0.09, P<0.05) and TLR4 (2.85+/-0.22 vs. 6.72+/-0.44, P<0.05) after stroke. Niaspan treatment significantly attenuated the expression of HMGB1 (1.80+/-0.98 vs. 1.31+/-0.01, P<0.05), RAGE (3.77+/-0.71 vs. 1.78+/ 0.45, P<0.05), MMP-9 (1.61+/-0.09 vs. 0.97+/-0.07, P<0.05) and TLR4 (6.72+/-0.44 vs. 2.28+/-0.43, P<0.05) in the ischemic brain in T1DM-MCAo rats. CONCLUSIONS: T1DM increases HMGB1/RAGE, TLR4 and MMP-9 expression after stroke. Niaspan treatment of stroke in T1DM rats inhibits HMGB1/RAGE, TLR4 and MMP-9 expression which may contribute to the reduced inflammatory response after stroke in T1DM rats. PMID- 21683771 TI - Outbred ICR/CD1 mice display more severe neuroinflammation mediated by microglial TLR4/CD14 activation than inbred C57Bl/6 mice. AB - Neuroinflammation mediated by microglia is a pathological hallmark of many CNS disorders. Cell lines derived from inbred C57Bl/6 and outbred ICR/CD1 mice (BV-2 and N9 respectively), are often used to study microglial inflammatory activities. Although many studies demonstrate different responses of these cell lines to the same stimulus, no comparisons have been done in vivo. Because inbreeding reduces resistance to pathogens and parasites, we hypothesized that microglia from outbred ICR/CD1 mice would have a stronger response to centrally administered LPS than microglia from inbred C57Bl/6 mice. The evaluation of gene expression in freshly isolated CD11b+ cells from brain revealed that microglia from ICR/CD1 mice were more pro-inflammatory than those from C57Bl/6 mice, although these differences did not appear to result from alterations in the expression levels of the LPS receptors TLR4 or CD14. Notably, the timing of inflammatory gene expression did not correlate with CD11b+ cell proliferation/infiltration. The highest expression of TNFalpha, IL-6 and iNOS occurred 3 h after LPS injection when the number of CD11b+ cells was not changed. Whereas the expression of these pro-inflammatory genes had returned to basal by 48 h when the highest number of CD11b+ cells in the brain was found, the expression of the anti-inflammatory cytokine IL-10 was still significantly up-regulated. This is important because the increased presence of CD11b+ cells in the CNS is often used as an indicator of neuroinflammation. While LPS did not affect the expression of the growth factors VEGF or BDNF, we observed that mechanical injury (caused by intraparenchymal injection) induced distinct patterns of microglial activation characterized by increased expression of VEGF and down-regulation of BDNF. It remains to be determined which type of microglia is more beneficial/detrimental to the CNS, but our data suggest that genetic traits determining microglial properties may have profound effect on many CNS pathologies. PMID- 21683772 TI - Aging influences adaptations of the neuromuscular junction to endurance training. AB - This investigation sought to determine if aging affected adaptations of the neuromuscular junction (NMJ) to exercise training. Twenty young adult (8 months) and 20 aged (24 months) rats were assigned to either a program of treadmill exercise, or sedentary conditions. Following the 10-week experimental period, rats were euthanized, and soleus and plantaris muscles were removed and frozen. Longitudinal sections of the muscles were fluorescently stained to visualize pre synaptic nerve terminals and post-synaptic endplates on both slow- and fast twitch fibers. Images were collected with confocal microscopy and quantified. Muscle cross-sections were histochemically stained to assess muscle fiber profiles (size and fiber type). Our analysis of NMJs revealed a high degree of specificity and sensitivity to aging, exercise training, and their interaction. In the soleus, slow-twitch NMJs demonstrated significant (P <= 0.05) training induced adaptations in young adult, but not aged rats. In the fast-twitch NMJs of the soleus, aging, but not training, was associated with remodeling. In the plantaris, aging, but not training, remodeled the predominant fast-twitch NMJs, but only pre-synaptically. In contrast, the slow-twitch NMJs of the plantaris displayed morphologic adaptations to both aging and exercise in pre- and post synaptic components. Muscle fiber profiles indicated that changes in NMJ size were unrelated to adaptations of their fibers. Our data show that aging interferes with the ability of NMJs to adapt to exercise training. Results also reveal complexity in the coordination of synaptic responses among different muscles, and different fiber types within muscles, in their adaptation to aging and exercise training. PMID- 21683773 TI - Leucoanthocyanidin Dioxygenase in Arabidopsis thaliana: characterization of mutant alleles and regulation by MYB-BHLH-TTG1 transcription factor complexes. AB - In Arabidopsis thaliana, most mutants impaired in flavonoid accumulation were identified through screens for altered seed pigmentation. Mutations in more than 20 loci have been described that can result in a transparent testa (tt) or tannin deficient seed (tds) phenotype. For some of these mutants it is still unclear if they represent additional loci or if they are allelic to known mutations. In this study, we found that tt17 is allelic to tt11 and tds4 and identified a point mutation in tt17 that affects the gene encoding Leucoanthocyanidin Dioxygenase (LDOX). The mutation results in replacement of a cysteine close to the active site of the enzyme by the hydrophobic amino acid tyrosine. Effects of this mutation on protein structure and activity are discussed in the context of LDOX sequences from various genotypes. Regulation of the LDOX promoter was analyzed and found to be directly controlled by different MYB-BHLH-TTG1 transcription factor complexes containing the BHLH factors EGL3 and TT8. Experiments with single and double loss-of-function mutants identified EGL3 and TT8 as necessary regulators of anthocyanin accumulation in developing A. thaliana seedlings. PMID- 21683774 TI - Organophosphate hydrolases as catalytic bioscavengers of organophosphorus nerve agents. AB - Bioscavengers are molecules able to neutralize neurotoxic organophosphorus compounds (OP) before they can reach their biological target. Human butyrylcholinesterase (hBChE) is a natural bioscavenger each molecule of enzyme neutralizing one molecule of OP. The amount of natural enzyme is insufficient to achieve good protection. Thus, different strategies have been envisioned. The most straightforward consists in injecting a large dose of highly purified natural hBChE to increase the amount of bioscavenger in the bloodstream. This proved to be successful for protection against lethal doses of soman and VX but remains expensive. An improved strategy is to regenerate prophylactic cholinesterases (ChE) by administration of reactivators after exposure. But broad spectrum efficient reactivators are still lacking, especially for inhibited hBChE. Cholinesterase mutants capable of reactivating spontaneously are another option. The G117H hBChE mutant has been a prototype. We present here the Y124H/Y72D mutant of human acetylcholinesterase; its spontaneous reactivation rate after V-agent inhibition is increased up to 110 fold. Catalytic bioscavengers, enzymes capable of hydrolyzing OP, present the best alternative. Mesophilic bacterial phosphotriesterase (PTE) is a candidate with good catalytic efficiency. Its enantioselectivity has been enhanced against the most potent OP isomers by rational design. We show that PEGylation of this enzyme improves its mean residence time in the rat blood stream 24-fold and its bioavailability 120 fold. Immunogenic issues remain to be solved. Human paraoxonase 1 (hPON1) is another promising candidate. However, its main drawback is that its phosphotriesterase activity is highly dependent on its environment. Recent progress has been made using a mammalian chimera of PON1, but we provide here additional data showing that this chimera is biochemically different from hPON1. Besides, the chimera is expected to suffer from immunogenic issues. Thus, we stress that interest for hPON1 must not fade away, and in particular, the 3D structure of the hPON1 eventually in complex with OP has to be solved. PMID- 21683775 TI - Fusarin C acts like an estrogenic agonist and stimulates breast cancer cells in vitro. AB - Fusarin C is a mycotoxin produced by several Fusarium species and has been associated with esophageal cancer due to its carcinogenic effects. Here, we report that fusarin C stimulates growth of the breast cancer cell line MCF-7. This suggests that fusarin C can act as an estrogenic agonist and should be classified as a mycoestrogen. MCF-7 cells were stimulated in the range between 0.1 and 20MUM and inhibited when the concentration exceeded 50MUM. The toxicity of fusarin C is comparable to other mycoestrogens such as zearalenone, but the chemical structure of fusarin C is very different from other known estrogen agonists. Furthermore, the toxicity of fusarin C was tested in five additional human cell lines Caco 2, U266, PC3, MDA-MB-231 and MCF-10a which were all inhibited when the concentration of fusarin C exceeded 10MUM. To the best of our knowledge this is the first report on the mycoestrogenic properties of fusarin C. PMID- 21683776 TI - Comminution of ibuprofen to produce nano-particles for rapid dissolution. AB - A critical problem associated with poorly soluble drugs is low and variable bioavailability derived from slow dissolution and erratic absorption. The preparation of nano-formulations has been identified as an approach to enhance the rate and extent of drug absorption for compounds demonstrating limited aqueous solubility. A new technology for the production of nano-particles using high speed, high efficiency processes that can rapidly generate nano-particles with rapid dissolution rate has been developed. Size reduction of a low melting ductile model compound was achieved in periods less than 1h. Particle size reduction of ibuprofen using this methodology resulted in production of crystalline particles with average diameter of approximately 270nm. Physical stability studies showed that the nano-suspension remained homogeneous with slight increases in mean particle size, when stored at room temperature and under refrigerated storage conditions 2-8 degrees C for up to 2 days. Powder containing crystalline drug was prepared by spray-drying ibuprofen nano-suspensions with mannitol dissolved in the aqueous phase. Dissolution studies showed similar release rates for the nano-suspension and powder which were markedly improved compared to a commercially available drug product. Ibuprofen nano-particles could be produced rapidly with smaller sizes achieved at higher suspension concentrations. Particles produced in water with stabilisers demonstrated greatest physical stability, whilst rapid dissolution was observed for the nano particles isolated in powder form. PMID- 21683777 TI - Improvement of the wettability and dissolution of fenofibrate compacts by plasma treatment. AB - The goal of this study was to investigate the effect of plasma treatment on the wettability and dissolution of fenofibrate compacts. Contact angle measurements and intrinsic dissolution rate studies of untreated and plasma-treated fenofibrate compacts were conducted. The contact angle data clearly show that the wettability of the tablet surface increased with the duration of plasma treatment. Analyses of stability revealed that the surfaces which were plasma treated for more than 1min regained some degree of hydrophobicity after storage in air. Since their hydrophobic recovery finally reached the level observed with 1min plasma-treated fenofibrate compacts it was deduced that permanent incorporation of hydrophilic groups had already attained saturation upon plasma irradiation for 1min. Dissolution studies revealed the advantages of the hydrophilized surface of plasma-treated fenofibrate compacts. Due to the improved wettability of plasma-treated fenofibrate its intrinsic dissolution rate was vastly increased compared to untreated fenofibrate. This study thus demonstrates the potential of plasma treatment to enhance the wettability and dissolution behavior of poorly water-soluble drugs. PMID- 21683778 TI - The role of temporal regularity in auditory segregation. AB - The idea that predictive modelling and extraction of regularities plays a pivotal role in auditory segregation has recently attracted considerable attention. The present study investigated the effect of one basic form of regularity, rhythmic regularity, on auditory stream segregation. We departed from the classic streaming paradigm and developed a new stimulus, Rand-AB, consisting of two, concurrently presented, temporally uncorrelated, tone sequences (with frequencies A and B). To evaluate segregation, we used an objective measure of the extent to which listeners are able to selectively attend to one of the sequences in the presence of the other. Performance was quantified on a difficult pattern detection task which involves detecting a rarely occurring pattern of amplitude modulation applied to three consecutive A or B tones. In all cases the attended sequence was temporally irregular (with a random inter-tone-interval (ITI) between 100 and 400 ms) and the regularity status of the competing sequence was set to one of four conditions: (1) random ITI between 100 and 400 ms (2) isochronous with ITI = 400 ms. (3) isochronous with ITI = 250 ms (equal to the mean rate of the attended sequence) (4) isochronous with ITI = 100 ms. For a frequency separation of 2 (but not 4) semi tones we observed improved performance in conditions (3) and (4) relative to (1), suggesting that stream segregation is facilitated when the distracter sequence is temporally regular, but that the effect of temporal regularity as a cue for segregation is limited to relatively fast rates and to situations where frequency separation is insufficient for segregation. These findings provide new evidence to support models of streaming that involve segregation based on the formation of predictive models. PMID- 21683779 TI - Antimicrobial peptides from marine invertebrates: challenges and perspectives in marine antimicrobial peptide discovery. AB - The emergence of pathogenic bacteria resistance to conventional antibiotics calls for an increased focus on the purification and characterization of antimicrobials with new mechanisms of actions. Antimicrobial peptides are promising candidates, because their initial interaction with microbes is through binding to lipids. The interference with such a fundamental cell structure is assumed to hamper resistance development. In the present review we discuss antimicrobial peptides isolated from marine invertebrates, emphasizing the isolation and activity of these natural antibiotics. The marine environment is relatively poorly explored in terms of potential pharmaceuticals, and it contains a tremendous species diversity which evolved in close proximity to microorganisms. As invertebrates rely purely on innate immunity, including antimicrobial peptides, to combat infectious agents, it is believed that immune effectors from these animals are efficient and rapid inhibitors of microbial growth. PMID- 21683780 TI - Effects of genome architecture and epigenetic factors on susceptibility of promoter CpG islands to aberrant DNA methylation induction. AB - Aberrant DNA methylation is induced at specific promoter CpG islands (CGIs) in contrast with mutations. The specificity is influenced by genome architecture and epigenetic factors, but their relationship is still unknown. In this study, we isolated promoter CGIs susceptible and resistant to aberrant methylation induction during prostate and breast carcinogenesis. The effect of genome architecture was more evident for promoter CGIs susceptible in both of the two tissues than for promoter CGIs susceptible only in one tissue. Multivariate analysis of promoter CGIs with tissue-nonspecific susceptibility showed that genome architecture, namely a remote location from SINE (OR=5.98; 95% CI=2.33 15.34) and from LINE (OR=2.08; 95% CI=1.03-4.21), was associated with increased susceptibility, independent of epigenetic factors such as the presence of RNA polymerase II (OR=0.09; 95% CI=0.02-0.48) and H3K27me3 (OR=3.28; 95% CI=1.17 9.21). These results showed that methylation susceptibility of promoter CGIs is determined both by genome architecture and epigenetic factors, independently. PMID- 21683782 TI - Toxicity testing. PMID- 21683784 TI - Neuroprotective effects of overexpressed cyclophilin B against Abeta-induced neurotoxicity in PC12 cells. AB - Accumulated amyloid-beta (Abeta) is a well-known cause of neuronal apoptosis in Alzheimer disease and functions in part by generating oxidative stress. Our previous work suggested that cyclophilin B (CypB) protects against endoplasmic reticulum (ER) stress. Therefore, in this study we examined the ability of CypB to protect against Abeta toxicity. CypB is present in the neurons of rat and mouse brains, and treating neural cells with Abeta(25-35) mediates apoptotic cell death. Abeta(25-35)-induced neuronal toxicity was inhibited by the overexpression of CypB as measured by cell viability, apoptotic morphology, sub-G1 cell population, intracellular reactive oxygen species accumulation, activated caspase 3, PARP cleavage, Bcl-2 proteins, mitogen-activated protein kinase (MAPK) activation, and phosphoinositide 3-kinase (PI-3-K) activation. CypB/R95A PPIase mutants did not reduce Abeta(25-35) toxicity. We showed that Abeta(25-35)-induced apoptosis is more severe in a CypB knockdown model, confirming that CypB protects against Abeta(25-35)-induced toxicity. Consequently, these findings suggest that CypB may protect against Abeta toxicity by its antioxidant properties, by regulating MAPK and PI-3-K signaling, and through the ER stress pathway. PMID- 21683783 TI - Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy. AB - Beyond an inert oxidation product of nitric oxide (NO) metabolism, current thinking posits a key role for nitrite as a mediator of NO signaling, especially during hypoxia. This concept has been discussed in the context of nitrite serving a role as an endogenous modulator of NO homeostasis, but also from a novel clinical perspective whereby nitrite therapy may replenish NO signaling and prevent ischemic tissue injury. Indeed, the relatively rapid translation of studies delineating mechanisms of action to ongoing and planned clinical trials has been critical in fuelling interest in nitrite biology, and several excellent reviews have been written on this topic. In this article we limit our discussions to current concepts and what we feel are questions that remain unanswered within the paradigm of nitrite being a mediator of NO biology. PMID- 21683785 TI - Specific recognition of malondialdehyde and malondialdehyde acetaldehyde adducts on oxidized LDL and apoptotic cells by complement anaphylatoxin C3a. AB - Oxidatively modified low-density lipoproteins (Ox-LDL) and complement anaphylatoxins C3a and C5a are colocalized in atherosclerotic lesions. Anaphylatoxin C3a also binds and breaks bacterial lipid membranes and phosphatidylcholine liposomes. The role of oxidized lipid adducts in C3a binding to Ox-LDL and apoptotic cells was investigated. Recombinant human C3a bound specifically to low-density lipoprotein and bovine serum albumin modified with malondialdehyde (MDA) and malondialdehyde acetaldehyde (MAA) in chemiluminescence immunoassays. No binding was observed to native proteins, LDL oxidized with copper ions (CuOx-LDL), or phosphocholine. C3a binding to MAA-LDL was inhibited by two monoclonal antibodies specific for MAA-LDL. On agarose gel electrophoresis, C3a comigrated with MDA-LDL and MAA-LDL, but not with native LDL or CuOx-LDL. C3a bound to apoptotic cells in flow cytometry. C3a opsonized MAA LDL and was taken up by J774A.1 macrophages in immunofluorescence analysis. Complement-activated human serum samples (n=30) showed increased C3a binding to MAA-LDL (P<0.001) and MDA-LDL (P<0.001) compared to nonactivated samples. The amount of C3a bound to MAA-LDL was associated with total complement activity, C3a desArg concentration, and IgG antibody levels to MAA-LDL. Proteins containing MDA adducts or MAA adducts may bind C3a in vivo and contribute to inflammatory processes involving activation of the complement system in atherosclerosis. PMID- 21683786 TI - Clinical trials of antioxidants as cancer prevention agents: past, present, and future. AB - The purpose of this review is to summarize the most important human clinical trials of antioxidants as cancer prevention agents conducted to date, provide an overview of currently ongoing studies, and discuss future steps needed to advance research in this field. To date there have been several large (at least 7000 participants) trials testing the efficacy of antioxidant supplements in preventing cancer. The specific agents (diet-derived direct antioxidants and essential components of antioxidant enzymes) tested in those trials included beta carotene, vitamin E, vitamin C, selenium, retinol, zinc, riboflavin, and molybdenum. None of the completed trials produced convincing evidence to justify the use of traditional antioxidant-related vitamins or minerals for cancer prevention. Our search of ongoing trials identified six projects at various stages of completion. Five of those six trials use selenium as the intervention of interest delivered either alone or in combination with other agents. The lack of success to date can be explained by a variety of factors that need to be considered in the next generation research. These factors include lack of good biological rationale for selecting specific agents of interest; limited number of agents tested to date; use of pharmacological, rather than dietary, doses; and insufficient duration of intervention and follow-up. The latter consideration underscores the need for alternative endpoints that are associated with increased risk of neoplasia (i.e., biomarkers of risk), but are detectable prior to tumor occurrence. Although dietary antioxidants are a large and diverse group of compounds, only a small proportion of candidate agents have been tested. In summary, the strategy of focusing on large high-budget studies using cancer incidence as the endpoint and testing a relatively limited number of antioxidant agents has been largely unsuccessful. This lack of success in previous trials should not preclude us from seeking novel ways of preventing cancer by modulating oxidative balance. On the contrary, the well demonstrated mechanistic link between excessive oxidative stress and carcinogenesis underscores the need for new studies. It appears that future large-scale projects should be preceded by smaller, shorter, less expensive biomarker-based studies that can serve as a link from mechanistic and observational research to human cancer prevention trials. These relatively inexpensive studies would provide human experimental evidence for the likely efficacy, optimum dose, and long-term safety of the intervention of interest that would then guide the design of safe, more definitive large-scale trials. PMID- 21683787 TI - Behavioral and physiological effects of acute ketamine exposure in adult zebrafish. AB - Ketamine is a non-competitive glutamatergic antagonist used to induce sedation and analgesia. In sub-anesthetic doses, it induces hyperlocomotion, impairs memory and evokes stereotypic circling in rodents. Zebrafish (Danio rerio) emerged as a promising new animal model to screen the effects of psychotropic compounds. Here, we investigated the effects of sub-anesthetic doses of ketamine on anxiety, locomotion, habituation and social behavior of adult zebrafish. Acute 20-min exposure to 20 and 40 mg/L (but not 2 mg/L) of ketamine reduced anxiety, impaired intra-session habituation, evoked circular swimming and disrupted zebrafish shoaling. Additionally, ketamine reduced whole-body cortisol levels and elevated brain c-fos expression in zebrafish. Our findings demonstrate the sensitivity of zebrafish to behavioral and physiological effects of sub anesthetic doses of ketamine, further supporting the utility of this species as a model for neuropharmacological research, including testing ketamine and related drugs. PMID- 21683788 TI - The regulation of mitochondrial morphology: intricate mechanisms and dynamic machinery. AB - Mitochondria typically form a reticular network radiating from the nucleus, creating an interconnected system that supplies the cell with essential energy and metabolites. These mitochondrial networks are regulated through the complex coordination of fission, fusion and distribution events. While a number of key mitochondrial morphology proteins have been identified, the precise mechanisms which govern their activity remain elusive. Moreover, post translational modifications including ubiquitination, phosphorylation and sumoylation of the core machinery are thought to regulate both fusion and division of the network. These proteins can undergo several different modifications depending on cellular signals, environment and energetic demands of the cell. Proteins involved in mitochondrial morphology may also have dual roles in both dynamics and apoptosis, with regulation of these proteins under tight control of the cell to ensure correct function. The absolute reliance of the cell on a functional mitochondrial network is highlighted in neurons, which are particularly vulnerable to any changes in organelle dynamics due to their unique biochemical requirements. Recent evidence suggests that defects in the shape or distribution of mitochondria correlate with the progression of neurodegenerative diseases such as Alzheimer's, Huntington's and Parkinson's disease. This review focuses on our current understanding of the mitochondrial morphology machinery in cell homeostasis, apoptosis and neurodegeneration, and the post translational modifications that regulate these processes. PMID- 21683789 TI - Inhibitory effects of GL-V9 on the invasion of human breast carcinoma cells by downregulating the expression and activity of matrix metalloproteinase-2/9. AB - Cancer cell invasion plays a crucial role in growth and local spreading of tumors. GL-V9 is a newly synthesized flavonoid that has been shown to possess an antitumor effect. However, the mechanism of GL-V9 in preventing tumor growth is still unclear. The purpose of this study is to investigate the anti-invasive and anti-metastatic activity of this novel compound in MDA-MB-231 and MCF-7 human breast carcinoma cells. In this study, GL-V9 caused a concentration-dependent suppression of cell adhesive ability by cell adhesion assay, it also inhibited the migration and invasion of cells by wound healing assay and transwell invasion assay in a concentration-dependent manner. Considering matrix metalloproteinases (MMPs) play an important role in metastatic process, we used western blotting and gelatin zymography to examine the effect of GL-V9 on the expression and activity of MMPs. The mechanism revealed that GL-V9 significantly suppressed the expression and activity of MMP-2 and MMP-9. Furthermore, GL-V9 suppressed their upstream protein kinases activation by reducing phosphorylated forms of serine/threonine kinase AKT and c-Jun N-terminal kinase. These findings suggested that GL-V9 could inhibit the invasion of tumor cells by downregulating the expression and activity of MMP-2 and MMP-9, potentially associating with the suppression of phosphorylation of AKT and JNK. PMID- 21683790 TI - Enhanced transbuccal salmon calcitonin (sCT) delivery: effect of chemical enhancers and electrical assistance on in vitro sCT buccal permeation. AB - This study investigates the combined effect of absorption enhancers and electrical assistance on transbuccal salmon calcitonin (sCT) delivery, using fresh swine buccal tissue. We placed 200 IU (40 MUg/mL) of each sCT formulation- containing various concentrations of ethanol, N-acetyl-L-cysteine (NAC), and sodium deoxyglycocholate (SDGC)--onto the donor part of a Franz diffusion cell. Then, 0.5 mA/cm(2) of fixed anodal current was applied alone or combined with chemical enhancers. The amount of permeated sCT was analyzed using an ELISA kit, and biophysical changes of the buccal mucosa were investigated using FT-IR spectroscopy, and hematoxylin-eosin staining methods were used to evaluate histological alteration of the buccal tissues. The flux (J(s)) of sCT increased with the addition of absorption enhancer groups, but it was significantly enhanced by the application of anodal iontophoresis (ITP). FT-IR study revealed that all groups caused an increase in lipid fluidity but only the groups containing SDGC showed statistically significant difference. Although the histological data of SDGC groups showed a possibility for tissue damage, the present enhancing methods appear to be safe. In conclusion, the combination of absorption enhancers and electrical assistance is a potential strategy for the enhancement of transbuccal sCT delivery. PMID- 21683791 TI - Vaspin prevents TNF-alpha-induced intracellular adhesion molecule-1 via inhibiting reactive oxygen species-dependent NF-kappaB and PKCtheta activation in cultured rat vascular smooth muscle cells. AB - Vaspin (visceral adipose tissue-derived serine protease inhibitor) was recently identified as a novel adipocytokine with insulin-sensitizing effects. We hypothesized that vaspin could play a role in vascular inflammation. To test the hypothesis, we investigated the effects of vaspin on TNF-alpha-stimulated vascular smooth muscle cells (SMCs) focusing on inflammatory signal transduction. Vascular SMCs from mesenteric artery of male Wistar rats were treated with TNF alpha (5-10 ng/ml, 20 min-6 h) in the absence or presence of vaspin (1-300 ng/ml, pretreatment for 24 h). Western blotting was performed to analyze the cellular signal. Reactive oxygen species (ROS) generation was fluorometrically measured using 2',7'-diclorofluorescein diacetate. Vaspin alone treatment had no effect on vascular SMCs morphology and cellular signal. Vaspin significantly decreased the TNF-alpha-induced monocyte adhesion to SMCs. Vaspin significantly inhibited the protein expression of intracellular adhesion molecule (ICAM)-1 and the phosphorylation of NF-kappaB and protein kinase C (PKC)theta induced by TNF alpha. Both of NF-kappaB and novel PKC inhibitors significantly attenuated the TNF-alpha-induced ICAM-1 expression. Moreover, vaspin inhibited TNF-alpha-induced ROS generation. An anti-oxidant, N-acetyl-L-cysteine blocked the TNF-alpha induced activation of NF-kappaB, PKCtheta and expression of ICAM-1. The present results demonstrated for the first time that vaspin inhibits TNF-alpha-induced expression of ICAM-1 via preventing the ROS generation and subsequent activation of NF-kappaB and PKCtheta. Consequently, vaspin could play inhibitory roles on inflammatory states of vascular SMCs. PMID- 21683792 TI - The Fidia-Georgetown Institute for the Neurosciences (FGIN) 1985-1994. AB - This article describes briefly the history and activities of the Fidia-Georgetown Institute for the Neurosciences (FGIN), from its establishment in 1985 to its closure in 1994. It also provides a list of those colleagues and students who worked at FGIN and contributed to various research projects. PMID- 21683793 TI - The extraction, isolation and purification of an endogenous regulator for the 5 HT2 receptor. AB - Early studies indicated that serotonin, a primary transmitter in the central nervous system, may not represent the primary endogenous regulator for the 5-HT2 receptor labeled by [3H]-ketanserin. Instead, an endogenous ligand may be responsible for modulating the [3H]-ketanserin site. Through different isolation and purification procedures, a pronase-sensitive peptide with activity on [3H] ketanserin binding was identified in the rat brain. This peptide seems specific for the 5-HT2 receptor since it does not displace the binding of [3H]-imipramine or [3H]-mianserin from rat cortical membranes and is able to stimulate PI turnover in a ketanserin sensitive fashion. Given the role of 5-HT2 receptors in the action of antidepressants, this finding may help understand some of the molecular mechanisms involved in antidepressant effect. PMID- 21683794 TI - The correlation between white-matter microstructure and the complexity of spontaneous brain activity: a difussion tensor imaging-MEG study. AB - The advent of new signal processing methods, such as non-linear analysis techniques, represents a new perspective which adds further value to brain signals' analysis. Particularly, Lempel-Ziv's Complexity (LZC) has proven to be useful in exploring the complexity of the brain electromagnetic activity. However, an important problem is the lack of knowledge about the physiological determinants of these measures. Although a correlation between complexity and connectivity has been proposed, this hypothesis was never tested in vivo. Thus, the correlation between the microstructure of the anatomic connectivity and the functional complexity of the brain needs to be inspected. In this study we analyzed the correlation between LZC and fractional anisotropy (FA), a scalar quantity derived from diffusion tensors that is particularly useful as an estimate of the functional integrity of myelinated axonal fibers, in a group of sixteen healthy adults (all female, mean age 65.56+/-6.06 years, intervals 58 82). Our results showed a positive correlation between FA and LZC scores in regions including clusters in the splenium of the corpus callosum, cingulum, parahipocampal regions and the sagittal stratum. This study supports the notion of a positive correlation between the functional complexity of the brain and the microstructure of its anatomical connectivity. Our investigation proved that a combination of neuroanatomical and neurophysiological techniques may shed some light on the underlying physiological determinants of brain's oscillations. PMID- 21683796 TI - Direct delayed human adenoviral BMP-2 or BMP-6 gene therapy for bone and cartilage regeneration in a pony osteochondral model. AB - OBJECTIVE: To evaluate healing of surgically created large osteochondral defects in a weight-bearing femoral condyle in response to delayed percutaneous direct injection of adenoviral (Ad) vectors containing coding regions for either human bone morphogenetic proteins 2 (BMP-2) or -6. METHODS: Four 13mm diameter and 7mm depth circular osteochondral defects were drilled, 1/femoral condyle (n=20 defects in five ponies). At 2 weeks, Ad-BMP-2, Ad-BMP-6, Ad-green fluorescent protein (GFP), or saline was percutaneously injected into the central drill hole of the defect. Quantitative magnetic resonance imaging (qMRI) and computed tomography (CT) were serially performed at 12, 24, and 52 weeks. At 12 (one pony) or 52 weeks, histomorphometry and microtomographic analyses were performed to assess subchondral bone and cartilage repair tissue quality. RESULTS: Direct delivery of Ad-BMP-6 demonstrated delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) and histologic evidence of greater Glycosaminoglycan (GAG) content in repair tissue at 12 weeks, while Ad-BMP-2 had greater non-mineral cartilage at the surface at 52 weeks (p<0.04). Ad-BMP-2 demonstrated greater CT subchondral bone mineral density (BMD) by 12 weeks and both Ad-BMP-2 and -6 had greater subchondral BMD at 52 weeks (p<0.05). Despite earlier (Ad-BMP-6) and more persistent (Ad-BMP-2) chondral tissue and greater subchondral bone density (Ad BMP-2 and -6), the tissue within the large weight-bearing defects at 52 weeks was suboptimal in all groups due to poor quality repair cartilage, central fibrocartilage retention, and central bone cavitation. Delivery of either BMP by this method had greater frequency of subchondral bone cystic formation (p<0.05). CONCLUSIONS: Delivery of Ad-BMP-2 or Ad-BMP-6 via direct injection supported cartilage and subchondral bone regeneration but was insufficient to provide long term quality osteochondral repair. PMID- 21683797 TI - Macroscopic and histopathologic analysis of human knee menisci in aging and osteoarthritis. AB - OBJECTIVE: Meniscus lesions following trauma or associated with osteoarthritis (OA) have been described, yet meniscus aging has not been systematically analyzed. The objectives of this study were to (1) establish standardized protocols for representative macroscopic and microscopic analysis, (2) improve existing scoring systems, and (3) apply these techniques to a large number of human menisci. DESIGN: Medial and lateral menisci from 107 human knees were obtained and cut in two different planes (triangle/cross section and transverse/horizontal section as well) in three separate locations (middle portion, anterior and posterior horns). All sections included vascular and avascular regions and were graded for (1) surface integrity, (2) cellularity, (3) matrix/fiber organization and collagen alignment, and (4) Safranin-O staining intensity. The cartilage in all knee compartments was also scored. RESULTS: The new macroscopic and microscopic grading systems showed high inter-reader and intra-reader intraclass correlation coefficients. The major age-related changes in menisci in joints with no or minimal OA included increased Safranin-O staining intensity, decreased cell density, the appearance of acellular zones, and evidence of mucoid degeneration with some loss of collagen fiber organization. The earliest meniscus changes occurred predominantly along the inner rim. Menisci from OA joints showed severe fibrocartilaginous separation of the matrix, extensive fraying, tears and calcification. Abnormal cell arrangements included decreased cellularity, diffuse hypercellularity along with cellular hypertrophy and abnormal cell clusters. In general, the anterior horns of both medial and lateral menisci were less affected by age and OA. CONCLUSIONS: New standardized protocols and new validated grading systems allowed us to conduct a more systematic evaluation of changes in aging and OA menisci at a macroscopic and microscopic level. Several meniscus abnormalities appear to be specific to aging in the absence of significant OA. With aging the meniscal surface can be intact but abnormal matrix organization and cellularity were observed within the meniscal substance. The increased Safranin-O staining appears to represent a shift from fibroblastic to chondrocytic phenotype during aging and early degeneration. PMID- 21683798 TI - Outcome of myeloablative conditioning and unrelated donor hematopoietic cell transplantation for childhood acute lymphoblastic leukemia in third remission. AB - We conducted a retrospective study of 155 children who underwent unrelated donor hematopoietic cell transplantation (HCT) between 1990 and 2005 for acute lymphoblastic leukemia in third remission. The median patient age was 11 years, the median time from diagnosis to first relapse was 36 months, and the median time from first relapse to second relapse was 26 months. Stem cell sources were bone marrow (n = 115), peripheral blood (n = 11), and cord blood (n = 29). All patients received a myeloablative pretransplantation conditioning regimen. The 5 year estimates of leukemia-free survival, relapse, and nonrelapse mortality were 30%, 25%, and 45%, respectively. In multivariate analysis, the only risk factor associated with relapse was the interval between the first relapse and the second relapse. Second relapses occurring >26 months from the first relapse were associated with lower risk for post-HCT relapse compared with second relapses occurring at <=26 months (relative risk, 0.4; P = .01). Relapse risk was lowest when late second relapse was preceded by late first relapse (>36 months from diagnosis), as demonstrated by a 3-year relapse rate of 9% (P = .0009). Our data indicate that long-term leukemia-free survival can be achieved in children with acute lymphoblastic leukemia in third remission using unrelated donor HCT, especially when the second relapse occurs late. PMID- 21683799 TI - In vitro transcriptome analysis of porcine choroid plexus epithelial cells in response to Streptococcus suis: release of pro-inflammatory cytokines and chemokines. AB - The Gram-positive zoonotic bacterium Streptococcus suis (S. suis) is responsible for a wide range of diseases including meningitis in pigs and humans. The blood cerebrospinal fluid (CSF) barrier is constituted by the epithelial cells of the choroid plexus, which execute barrier function also after bacteria have entered the central nervous system (CNS). We show that the bacterial capsule, a major virulence factor, strongly attenuates adhesion of S. suis to the apical side of porcine choroid plexus epithelial cells (PCPEC). Oligonucleotide microarray analysis and quantitative PCR surprisingly demonstrated that adherent wild-type and capsule-deficient S. suis influenced expression of a pronounced similar pattern of genes in PCPEC. Investigation of purified capsular material provided no evidence for a significant role of the capsule. Enriched among the regulated genes were those involved in "inflammatory response", "defense response" and "cytokine activity". These comprised several cytokines and chemokines including the interleukins 6 and 8, which could be detected on protein level. We show that after infection with S. suis the choroid plexus contributes to the immune response by actively producing cytokines and chemokines. Other virulence factors than the bacterial capsule may be relevant in inducing a strong inflammatory response in the CNS during S. suis meningitis. PMID- 21683800 TI - Trypanocidal action of eupomatenoid-5 is related to mitochondrion dysfunction and oxidative damage in Trypanosoma cruzi. AB - Because of its severe side effects and variable efficacy, the current treatment for Chagas disease is unsatisfactory. Natural compounds are good alternative chemotherapeutic agents for the treatment of this infection. Recently, our group reported the antiproliferative activity and morphological alterations in epimastigotes and intracellular amastigotes of Trypanosoma cruzi treated with eupomatenoid-5, a neolignan isolated from leaves of Piper regnellii var. pallescens. Here, we demonstrate that eupomatenoid-5 exhibited activity against trypomastigotes, the infective form of T. cruzi (EC50 40.5 MUM), leading to ultrastructural alteration and lipoperoxidation in the cell membrane. Additionally, eupomatenoid-5 induced depolarization of the mitochondrial membrane, lipoperoxidation and increased G6PD activity in epimastigotes of T. cruzi. These findings support the possibility that different mechanisms may be targeted, according to the form of the parasite, and that the plasma membrane and mitochondria are the structures that are most affected in trypomastigotes and epimastigotes, respectively. Thus, the trypanocidal action of eupomatenoid-5 may be associated with mitochondrial dysfunction and oxidative damage, which can trigger destructive effects on biological molecules of T. cruzi, leading to parasite death. PMID- 21683802 TI - Improving MeSH classification of biomedical articles using citation contexts. AB - Medical Subject Headings (MeSH) are used to index the majority of databases generated by the National Library of Medicine. Essentially, MeSH terms are designed to make information, such as scientific articles, more retrievable and assessable to users of systems such as PubMed. This paper proposes a novel method for automating the assignment of biomedical publications with MeSH terms that takes advantage of citation references to these publications. Our findings show that analysing the citation references that point to a document can provide a useful source of terms that are not present in the document. The use of these citation contexts, as they are known, can thus help to provide a richer document feature representation, which in turn can help improve text mining and information retrieval applications, in our case MeSH term classification. In this paper, we also explore new methods of selecting and utilising citation contexts. In particular, we assess the effect of weighting the importance of citation terms (found in the citation contexts) according to two aspects: (i) the section of the paper they appear in and (ii) their distance to the citation marker. We conduct intrinsic and extrinsic evaluations of citation term quality. For the intrinsic evaluation, we rely on the UMLS Metathesaurus conceptual database to explore the semantic characteristics of the mined citation terms. We also analyse the "informativeness" of these terms using a class-entropy measure. For the extrinsic evaluation, we run a series of automatic document classification experiments over MeSH terms. Our experimental evaluation shows that citation contexts contain terms that are related to the original document, and that the integration of this knowledge results in better classification performance compared to two state-of the-art MeSH classification systems: MeSHUP and MTI. Our experiments also demonstrate that the consideration of Section and Distance factors can lead to statistically significant improvements in citation feature quality, thus opening the way for better document feature representation in other biomedical text processing applications. PMID- 21683803 TI - Unusual colonoscopic finding: a penetrating ventriculoperitoneal shunt. PMID- 21683801 TI - Ubiquitin-dependent mitochondrial protein degradation. AB - Progressive mitochondrial failure is tightly associated with the onset of many age-related human pathologies. This tight connection results from the double edged sword of mitochondrial respiration, which is responsible for generating both ATP and ROS, as well as from risks that are inherent to mitochondrial biogenesis. To prevent and treat these diseases, a precise understanding of the mechanisms that maintain functional mitochondria is necessary. Mitochondrial protein quality control is one of the mechanisms that protect mitochondrial integrity, and increasing evidence implicates the cytosolic ubiquitin/proteasome system (UPS) as part of this surveillance network. In this review, we will discuss our current understanding of UPS-dependent mitochondrial protein degradation, its roles in diseases progression, and insights into future studies. PMID- 21683804 TI - Erroneous diagnosis of gastroesophageal reflux disease in achalasia. AB - BACKGROUND & AIMS: Most experienced gastroenterologists have seen one or several cases of achalasia patients who have been erroneously diagnosed with gastroesophageal reflux disease (GERD) or even underwent antireflux surgery. We aim to describe the current knowledge about the diagnostic features of achalasia and their overlap with GERD. Furthermore, we present 3 cases in which achalasia was mistaken for GERD. METHODS: Search of the literature published in English using the PubMed database and relevant abstracts presented at international conventions. RESULTS: Typical features of GERD such as heartburn, retrosternal pain, esophagitis, and pathologic acid exposure can be observed in achalasia patients. Diagnostic tests such as endoscopy and radiography lack sensitivity and specificity for achalasia. Current diagnostic guidelines for antireflux surgery do not stipulate that achalasia should be ruled out preoperatively. CONCLUSIONS: Clinical presentation as well as the diagnostic work-up of achalasia patients can show overlap with GERD. Mistaking achalasia for GERD can be avoided by esophageal manometry and this should therefore be performed in all patients undergoing surgical fundoplication. PMID- 21683805 TI - Population-based estimates of cancer and mortality in Barrett's esophagus: implications for the future. PMID- 21683806 TI - Should industry share a greater burden for the cost of device recalls? PMID- 21683807 TI - Targeted extracellular nanoparticles enable intracellular detection of activated epidermal growth factor receptor in living brain cancer cells. AB - Mechanistic study of biological processes via Quantum Dots (QDs) remain constrained by inefficient QD delivery methods and consequent altered cell function. Here the authors present a rapid method to label activated receptor populations in live cancer cells derived from medulloblastoma and glioma tumors. The authors used QDs to bind the extracellular domain of Epidermal Growth Factor Receptor (EGF-R) proteins and then induced receptor activation to facilitate specific detection of intracellular, activated EGF-R subpopulations. Such labeling enables rapid identification of biological markers characteristic of tumor type, grade and chemotherapy resistance. FROM THE CLINICAL EDITOR: In this paper, a rapid, quantum dot-based method is presented with the goal of labeling activated receptor populations in live cancer cells. More accurate characterization of medulloblastoma and glioma cancer cells using this biomarker detection technique may lead to a more specific targeted therapy. PMID- 21683808 TI - Inhibition of H1N1 influenza A virus growth and induction of inflammatory mediators by the isoquinoline alkaloid berberine and extracts of goldenseal (Hydrastis canadensis). AB - In this study we tested whether the isoquinoline alkaloid berberine can inhibit the growth of influenza A. Our experiments showed strong inhibition of the growth of H1N1 influenza A strains PR/8/34 or WS/33 in RAW 264.7 macrophage-like cells, A549 human lung epithelial-derived cells and murine bone marrow derived macrophages, but not MDCK canine kidney cells. Studies of the mechanism underlying this effect suggest that berberine acts post-translationally to inhibit virus protein trafficking/maturation which in turn inhibits virus growth. Berberine was also evaluated for its ability to inhibit production of TNF-alpha and PGE(2) from A/PR/8/34 infected-RAW 264.7 cells. Our studies revealed strong inhibition of production of both mediators and suggest that this effect is distinct from the anti-viral effect. Finally, we asked whether berberine containing ethanol extracts of goldenseal also inhibit the growth of influenza A and production of inflammatory mediators. We found strong effectiveness at high concentrations, although upon dilution extracts were somewhat less effective than purified berberine. Taken together, our results suggest that berberine may indeed be useful for the treatment of infections with influenza A. PMID- 21683809 TI - Dynamics of polymerization shed light on the mechanisms that lead to multiple amyloid structures of the prion protein. AB - It is generally accepted that spongiform encephalopathies result from the aggregation into amyloid of a ubiquitous protein, the so-called prion protein. As a consequence, the dynamics of amyloid formation should explain the characteristics of the prion diseases: infectivity as well as sporadic and genetic occurrence, long incubation time, species barriers and strain specificities. The success of this amyloid hypothesis is due to the good qualitative agreement of this hypothesis with the observations. However, a number of difficulties appeared when comparing quantitatively the in vitro experimental results with the theoretical models, suggesting that some differences should hide important discrepancies. We used well defined quantitative models to analyze the experimental results obtained by in vitro polymerization of the recombinant hamster prion protein. Although the dynamics of polymerization resembles a simple nucleus-dependent fibrillogenesis, neither the initial concentration dependence nor off-pathway hypothesis fit with experimental results. Furthermore, seeded polymerization starts after a long time delay suggesting the existence of a specific mechanism that takes place before nucleus formation. On the other hand, polymerization dynamics reveals a highly stochastic mechanism, the origin of which appears to be caused by nucleation heterogeneity. Moreover, the specific structures generated during nucleation are maintained during successive seeding although a clear improvement of the dynamics parameters (polymerization rate and lag time) is observed. We propose that an additional on-pathway reaction takes place before nucleation and it is responsible for the heterogeneity of structures produced during prion protein polymerization in vitro. These amyloid structures behave like prion strains. A model is proposed to explain the genesis of heterogeneity among prion amyloid. PMID- 21683811 TI - Separation of clavulanic acid from fermented broth of amino acids by an aqueous two-phase system and ion-exchange adsorption. AB - The clavulanic acid is a substance which inhibits the beta-lactamases used with penicillins for therapeutic treatment. After the fermentation, by-products of low molecular weight such as amino acids lysine, histidine, proline and tyrosine are present in the fermented broth. To remove these impurities the techniques of extraction by an aqueous two-phase system of 17% polyethylene glycol molecular weight 600 and 15% potassium phosphate were used for a partial purification. A subsequent ion-exchange adsorption was used for the recuperation of the clavulanic acid of the top phase and purification getting a concentration factor of 2 and purification of 100% in relation to the amino acids lysine, histidine, proline and tyrosine. PMID- 21683810 TI - Gel-based proteomics of liver cancer progression in rat. AB - A significant challenge in proteomics biomarker research is to identify the changes that are of highest diagnostic interest, among the many unspecific aberrations associated with disease burden and inflammation. In the present study liver tissue specimens (n=18) from six experimental stages were collected from the resistant hepatocyte (RH) rat model of liver cancer and analyzed by 2D DIGE. The study included triplicates of regenerating liver, control "sham-operated" liver, three distinct premalignant stages and hepatomas. Out of 81 identified proteins two-thirds were differentially abundant in rat hepatomas compared to control rat liver and, secondly, the majority of proteins were also changed in precursor stages. This underscores the importance of adequate control samples in explorative cancer biomarker research. We confirm several proteomic changes previously identified in human hepatocellular carcinoma (HCC) and we identify novel candidate proteomic aberrations for further analysis in human HCC. In particular, increased levels of HSP70, HSP90, AKR1B1, AKR7A3, GCLM, ANXA5, VDBP, RGN and SULT1E1 were associated specifically with rat hepatomas, or with liver cancer progression in rat. In addition, we examine an integrated gel-based workflow for analysis of protein post-translational modifications (PTMs) and microtubule-association. We highlight differential PTM and localization of HSP60 as an interesting target for further analysis in liver cancer. PMID- 21683812 TI - The nuclear exporter, Crm1, is regulated by NFY and Sp1 in cancer cells and repressed by p53 in response to DNA damage. AB - The nuclear exporter protein, Crm1, plays a key role in normal cell functioning, mediating the nucleo-cytoplasmic transport of cargo proteins. Elevated Crm1 expression has recently been identified in various tumours; however, the mechanisms driving its expression have not been investigated to date. In this study we identified the Crm1 promoter and factors associated with its elevated expression and with its repression under conditions of DNA damage. The -1405 to +99 Crm1 promoter region was found to be significantly more active in cancer and transformed cells compared to normal, and the -175 to +99 region identified as responsible for the differential activity. Mutation of two CCAAT boxes and a GC box within this region significantly diminished Crm1 promoter activity and ChIP analysis revealed binding of NFY and Sp1 to these sites, with increased binding in transformed and cancer cells. In addition, p53 was found to repress Crm1 promoter activity, after induction with doxorubicin, with p53 siRNA blocking the effect. Crm1 promoter constructs with mutated CCAAT boxes were significantly less responsive to p53 repression, and in vivo binding of NFY to the CCAAT boxes was diminished upon p53 binding, suggesting that p53 mediates repression of the Crm1 promoter via interfering with NFY. This was confirmed using NFY knock-down cells, in which Crm1 promoter activity was significantly less responsive to p53. In vitro EMSAs revealed that NFY and p53 bind the CCAAT boxes as a single complex under conditions of DNA damage. In summary, this study is a first to analyse Crm1 promoter regulation and reveals NFY and Sp1 as contributors to Crm1 overexpression in cancer. In addition, this study reveals that Crm1 transcription is inhibited by DNA damage and that the mechanism of inhibition involves p53 interfering with NFY function. PMID- 21683813 TI - Dickkopf homolog 1, a Wnt signaling antagonist, is transcriptionally up-regulated via an ATF4-independent and MAPK/ERK-dependent pathway following amino acid deprivation. AB - Amino acid response (AAR) pathway is activated when cells are deprived of amino acids. In the present study, using the human colon cancer cell line SW480, we observed that DKK1, an antagonist of the Wnt pathway, was significantly induced at the mRNA level after the removal of amino acids from the medium. Addition of the amino alcohol histidinol, which prevents the formation of histidinyl tRNA(His), also increased DKK1 mRNA to a level similar to that observed when cells were deprived of all amino acids. Transcriptional activity and stability of DKK1 mRNA were both increased in the amino acid-deprived condition. The induction of DKK1 gene expression was confirmed by the increased immunofluorescent staining of the DKK1 protein in the amino acid deprived condition. Although chromatin immunoprecipitation assays showed increased RNA Polymerase II binding at the DKK1 promoter in amino acid-limited conditions, ATF4 binding to the promoter is absent. Luciferase reporter assays did not detect any functional AARE within the DKK1 gene structure. Knockdown of ATF4 by siRNA did not affect the increase of DKK1 mRNA during amino acid limitation. Inhibition of ERK phosphorylation abolished the induction of DKK1. Our study revealed that DKK1 is a novel target gene in the response to amino acid deficiency and that the expression of DKK1 is up-regulated through an ATF4-independent and an ERK-dependent pathway. PMID- 21683814 TI - Drosha processing controls the specificity and efficiency of global microRNA expression. AB - microRNAs (miRNAs) are a large family of approximately 22-nucleotide-long RNAs that regulate gene expression. They are first transcribed as long, primary transcripts, which then undergo a series of processing steps to generate the single-stranded, mature miRNAs. Here, we showed that Drosha cleaved hundreds of human primary miRNA transcript substrates with different efficiencies in vitro. The differential Drosha susceptibility of the primary miRNA transcripts significantly correlated with the expression of the corresponding, mature miRNAs in vivo. Conserved miRNAs were more efficiently expressed in vivo, and their primary transcripts were also better Drosha substrates in vitro. Combining secondary structure prediction and statistical analyses, we identified features in human primary miRNA transcripts that predisposed miRNAs to efficient Drosha processing in vitro as well as to better expression in vivo. We propose that the selectivity of Drosha action contributes greatly to the specificity and efficiency of miRNA biogenesis. Moreover, this study serves as an example of substrate specificity of a biochemical reaction regulating gene expression at a global scale in vivo. This article is part of a Special Issue entitled: MicroRNA's in viral gene regulation. PMID- 21683815 TI - RNA silencing pathways of plants: silencing and its suppression by plant DNA viruses. AB - RNA silencing refers to processes that depend on small (s)RNAs to regulate the expression of eukaryotic genomes. In plants, these processes play critical roles in development, in responses to a wide array of stresses, in maintaining genome integrity and in defense against viral and bacterial pathogens. We provide here an updated view on the array of endogenous sRNA pathways, including microRNAs (miRNAs), discovered in the model plant Arabidopsis, which are also the basis for antiviral silencing. We emphasize the current knowledge as well as the recent advances made on understanding the defense and counter-defense strategies evolved in the arms race between plants and DNA viruses on both the nuclear and the cytoplasmic front. This article is part of a Special Issue entitled: MicroRNA's in viral gene regulation. PMID- 21683816 TI - Reduction of protein phosphatase 2A Calpha enhances bone formation and osteoblast differentiation through the expression of bone-specific transcription factor Osterix. AB - The serine/threonine protein phosphatase 2A (PP2A) participates in regulating many important physiological processes such as control of cell cycle, growth, and division. On the other hand, Osterix is a zinc-finger-containing transcription factor that is essential for the differentiation of osteoblasts and regulation of many bone-related genes. Here we examined the effect of okadaic acid (OA), a specific inhibitor of PP2A, on bone formation in vivo and the molecular mechanism regulated by PP2A Calpha in osteoblast differentiation. Administration of 1nM OA to the calvarial region in mice increased bone mineral density, as shown by MUCT, while histomorphological analysis showed an increase in mineral apposition and bone thickness in the same region. In addition, treatment with 1nM OA stimulated osteoblast differentiation and the expression of Osterix, bone sialoprotein (Bsp), and osteocalcin (OCN) in mouse osteoblastic MC3T3-E1 cells. Moreover, the expression and phosphatase activity of PP2A Calpha was decreased in the initial step of osteoblast differentiation, which was in parallel with an increase in Osterix expression. To further clarify the role of PP2A Calpha in osteoblast differentiation, we constructed PP2A knock-down cells by infecting MC3T3-E1 cells with a lentivirus expressing shRNA specific for the PP2A Calpha. Accordingly, the silencing of PP2A Calpha in MC3T3-E1 cells dramatically increased osteoblast differentiation and mineralization, which were accompanied with expressions of Osterix, Bsp, and OCN. Our data indicate that PP2A Calpha plays an important role in the regulation of bone formation and osteoblast differentiation through the bone-related genes. PMID- 21683817 TI - The causes of finger clubbing: a list worth learning. PMID- 21683818 TI - Anticoagulation for atrial fibrillation: underuse? PMID- 21683820 TI - Antidepressant compliance and incident myocardial infarction. PMID- 21683822 TI - Unusual cause of cellulitis in a patient with hepatitis C and cirrhosis. PMID- 21683823 TI - Establishing diagnosis of Haemophilus parainfluenzae as etiology of culture negative endocarditis using DNA sequence analysis on tissue specimen. PMID- 21683824 TI - Should the affordable care act of 2010 be repealed? PMID- 21683825 TI - Testosterone deficiency. AB - Testosterone deficiency (TD) afflicts approximately 30% of men aged 40-79 years, with an increase in prevalence strongly associated with aging and common medical conditions including obesity, diabetes, and hypertension. A strong relationship is noted between TD and metabolic syndrome, although the relationship is not certain to be causal. Repletion of testosterone (T) in T-deficient men with these comorbidities may indeed reverse or delay their progression. While T repletion has been largely thought of in a sexual realm, we discuss its potential role in general men's health concerns: metabolic, body composition, and all-cause mortality through the use of a single clinical vignette. This review examines a host of studies, with practical recommendations for diagnosis of TD and T repletion in middle-aged and older men, including an analysis of treatment modalities and areas of concerns and uncertainty. PMID- 21683826 TI - Surveillance and monitoring of adult cancer survivors. AB - Advances in early detection and treatment have improved survival in common adult cancers. Surveillance for late recurrence and secondary primary malignancies is recommended for most patients. Initial treatment with surgery, radiation, chemotherapy, or hormonal therapy can result in both local and systemic sequelae, including treatment-related new cancers. Patients with head and neck, lung, breast, colorectal, and prostate cancers constitute the largest groups requiring long-term monitoring and follow-up care. PMID- 21683827 TI - Terry's nails: a window to systemic diseases. PMID- 21683828 TI - Heart failure, aneurysms and telangiectases, oh my! PMID- 21683829 TI - An enlarging solitary mass in an asymptomatic patient. PMID- 21683830 TI - Predictors of nonadherence to national hospital quality measures for heart failure and pneumonia. AB - BACKGROUND: Understanding factors associated with process measure nonadherence may improve both patient care and future measure design. METHODS: We analyzed 3401 patients with heart failure and 2186 patients with pneumonia who were eligible for at least 1 National Hospital Quality Measure at an urban tertiary medical center from July 1, 2004, to June 30, 2008. We investigated the association of socioeconomic, demographic, clinical, and care delivery factors with process measure nonadherence, using multivariable analysis. RESULTS: Demographic and socioeconomic variables were unrelated to heart failure measure adherence. Nonadherence with angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use was more common in patients with renal failure (odds ratio [OR] 2.56; 95% confidence interval [CI], 1.46-4.49), and patients admitted to noncardiac units more often failed the heart failure all-or-none measure (OR 2.22; 95% CI, 1.79-2.75). Patients with pneumonia who were admitted via the emergency department were less likely to fail antibiotic timing (OR 0.41; 95% CI, 0.27-0.63), whereas those with a history of methicillin-resistant Staphylococcus aureus (OR 2.63; 95% CI, 1.31-5.28) or requiring intensive care unit admission (OR 11.4; 95% CI, 6.3-20.8) were more likely to fail the antibiotic selection measure. CONCLUSION: Demographic and socioeconomic factors were generally unrelated to process measure nonadherence, demonstrating that excellent inpatient care can be delivered even to vulnerable populations. Clinical predictors suggest opportunities for improving both medical record documentation of appropriate exclusions and future measure specifications, especially for complex patients. Care delivery factors substantially affect process adherence. PMID- 21683831 TI - Reduction in acute myocardial infarction hospitalization after implementation of a smoking ordinance. AB - BACKGROUND: Smoking ordinances have been associated with reduced acute myocardial infarction rates, but nearly all studies lack patient-level data. OBJECTIVE: We determined whether a smoking ordinance was associated with a reduction in hospitalizations for acute myocardial infarction, irrespective of smoking status and infarct presentation (ST elevation vs. non-ST elevation). METHODS: Detailed chart abstraction of biomarkers to confirm first acute myocardial infarction events was performed from the single community hospital serving Greeley, Colorado and adjacent zip codes, 17 months before and 31 months after implementing a public smoking ordinance. Poisson regression analysis, adjusted for population growth, was used to assess changes in mean incidence rates. RESULTS: A total of 706 hospitalizations were identified from July 2002 through June 2006: 482 among Greeley city residents and 224 within adjacent zip code areas. A postordinance reduction in hospitalizations was observed in Greeley (relative risk [RR] 0.73; 95% confidence interval [CI], 0.59-0.90). A smaller, nonsignificant decrease was noted in the area immediately surrounding Greeley (RR 0.83; 95% CI, 0.61-1.14). However, the comparison of relative risk reductions between Greeley and the surrounding area was not significant (P=.48). The reduction in Greeley was more pronounced among smokers (RR 0.44; 95% CI, 0.29-0.65) than nonsmokers (RR 0.86; 95% CI, 0.67-1.09) and did not differ by acute myocardial infarction presentation (P=.38). CONCLUSIONS: A smoking ordinance was associated with a decrease in acute myocardial infarction hospitalizations of a magnitude similar to previous reports, but could not be distinguished from the adjacent geographic area. Reductions were greatest among smokers, despite previous studies suggesting that benefits accrue primarily among nonsmokers. Smoke-free policy may therefore exert a beneficial effect among smokers, who are disproportionately exposed to direct and sidestream smoke. PMID- 21683833 TI - Educating clerkship students in the era of resident duty hour restrictions. PMID- 21683832 TI - Elevated natriuretic peptide levels and cognitive function in community-dwelling older adults. AB - BACKGROUND: Natriuretic peptides have prognostic value across a wide spectrum of cardiovascular diseases and may predict cognitive dysfunction in patients with cardiovascular disease, even in the absence of previous stroke. Little is known about the association of natriuretic peptides with cognitive function in community-dwelling adults. We assessed the association between N-terminal pro B type natriuretic peptide (NT-proBNP) levels and cognitive function in community dwelling ambulatory older adults in the Rancho Bernardo Study. METHODS: We studied 950 men and women, aged 60 years and older, who attended a research clinic visit where a medical history and examination were performed, and blood for cardiovascular disease risk factors and NT-proBNP levels were obtained. Three cognitive function tests were administered: the Mini Mental State Examination (MMSE), Trail-Making Test B (Trails B), and Category Fluency. RESULTS: Participants with high NT-proBNP levels (>=450 pg/mL; n=198) were older and had a higher prevalence of coronary heart disease (12% vs 30%), and stroke (5% vs 11%; P<=.001 for both). In unadjusted analyses, all 3 cognitive function test scores were significantly associated with NT-proBNP levels (P<.001). After adjusting for age, sex, education, hypertension, body mass index, exercise, alcohol use, smoking, low density lipoprotein cholesterol, creatinine clearance, and previous cardiovascular disease, elevated NT-proBNP levels remained independently associated with poor cognitive performance on MMSE (odds ratio [OR] 2.0; 95% confidence interval [CI], 1.1-3.6; P=.02) and Trails B (OR 1.7; 95% CI, 1.2-2.7; P=.01), but not Category Fluency (OR 1.4; 95% CI, 0.9-2.2; P=.19). Results were unchanged after excluding the 6% of participants with a history of stroke. CONCLUSIONS: NT-proBNP levels were strongly and independently associated with poor cognitive function in community-dwelling older adults. PMID- 21683834 TI - An unusual case of chyloptysis. PMID- 21683835 TI - Historical perspectives of The American Association for Thoracic Surgery: Richard H. Sweet (1901-1962). PMID- 21683836 TI - Cardiothoracic surgery and the National Institutes of Health and National Heart, Lung, and Blood Institute. PMID- 21683837 TI - Esophageal stents for anastomotic leaks and perforations. AB - OBJECTIVE: Intrathoracic esophageal anastomotic leaks and perforations are very morbid and challenging problems. Esophageal stents are increasingly playing an integral role in the management of these patients. Our objective was to report our experience with esophageal stent placement for anastomotic leaks and perforations and to provide a treatment algorithm. METHODS: We performed a review of patients with stent placement for esophagogastric anastomotic leaks or esophageal perforation from March 2005 to August 2009. A prospective database was used to collect data. Success was defined as endoscopic defect closure, negative esophagram, and resumption of oral intake. Failure was defined as no change in leak size or clinical signs of ongoing infection. We collected and analyzed patient demographics, diagnosis, clinical history, and poststent outcomes using descriptive statistics. RESULTS: Thirty-seven patients underwent esophageal stent placement for anastomotic leaks (n = 22) and perforations (n = 15). The median time from original procedure to diagnosis of leak or perforation was 6 days (0 420 days). Nineteen patients (51%) had 21 associated procedures for source control. We placed 94 stents (mean = 2.7 stents/patient); 16 patients (43%) required more than 1 stenting procedure (mean = 1.8 procedures/patient). The median time to restoration of esophageal integrity was 33 days (7-120 days). There were 22 successes (59%); 2 failures were secondary to undrained abscess. Only 2 failures occurred in the last 15 patients (88% success). Strictures did not develop in any patients. Serious complications occurred in 3 patients (stent erosion, leak enlargement, fatal gastroaortic fistula). CONCLUSIONS: Esophageal stents can potentially play an integral role in the management of anastomotic leaks and perforations. Success depends on appropriate procedures for source control and surgeon experience. PMID- 21683838 TI - Pretransplant gastroesophageal reflux compromises early outcomes after lung transplantation. AB - OBJECTIVES: Gastroesophageal reflux disease (GERD) is implicated as a risk factor for bronchiolitis obliterans syndrome after lung transplantation, but its effects on acute rejection, early allograft function, and survival are unclear. Therefore, we sought to systematically understand the time-related impact of pretransplant GERD on graft function (spirometry), mortality, and acute rejection early after lung transplantation. METHODS: From January 2005 to July 2008, 215 patients underwent lung transplantation; 114 had preoperative pH testing, and 32 (28%) had objective evidence of GERD. Lung function was assessed by forced 1 second expiratory volume (FEV(1); percent of predicted) in 97 patients, mortality by follow-up (median, 2.2 years), and acute rejection by transbronchial biopsy. RESULTS: Pretransplant GERD was associated with decreased FEV(1) early after lung transplantation (P = .01) such that by 18 months, FEV(1) was 70% of predicted in double lung transplant patients with GERD versus 83% among non-GERD patients (P = .05). A similar decrease was observed in single lung transplantation (50% vs 60%, respectively; P = .09). GERD patients had lower survival early after transplant ( P = .02)-75% versus 90%. Presence of GERD did not affect acute rejection (P = .6). CONCLUSIONS: For lung transplant recipients, pretransplant GERD is associated with worse early allograft function and survival, but not increased acute rejection. The compromise in lung function is substantial, such that FEV(1) after double lung transplant in GERD patients approaches that of single lung transplant in non-GERD patients. We advocate thorough testing for GERD before lung transplantation; if identified, aggressive therapy early after transplant, including fundoplication, may prove efficacious. PMID- 21683839 TI - Endovascular fenestration in aortic dissection with acute malperfusion syndrome: immediate and late follow-up. AB - OBJECTIVE: To evaluate the immediate and long-term results of fenestration in aortic dissection with acute malperfusion syndrome. METHODS: Between 1999 and 2007, 35 patients (31 men; age, 57 +/- 11 years) with aortic dissection (19 with type A and 16 with type B) were treated by fenestration for malperfusion syndrome (27 renal, 27 bowel, and 14 lower limb) due to dynamic compression. Fenestration was performed with 2 rigid guidewires inserted in one 8F sheath (45 cm long). The mean interval between aortic dissection and fenestration was 5 days (28 patients within 3 days and 7 patients between 9 and 41 days). RESULTS: Fenestration (100% technical success rate) with an additional endovascular procedure (29 peripheral stents and 1 thoracic stent graft) resulted in angiographic success in 97% of the patients. Bowel surgery was performed in 7 patients. Mortality within the first month (12/35) was related to bowel ischemia (n = 5), neurologic complications (n = 3), type A surgery (n = 2), and late treatment (n = 2). At a mean follow-up of 48 +/- 30 months, 4 of the remaining 23 patients had died and 2 had withdrawn from the study. The diameter of the aorta, as measured using computed tomography/magnetic resonance imaging, remained stable in 12 of the remaining 17 patients and had increased in 5 (1 with Marfan syndrome and 4 with multiple arterial ectasia). CONCLUSIONS: In emergencies, fenestration saved 69% of the patients with acute malperfusion syndrome in complicated aortic dissection. During the follow-up period, the aortic diameter remained stable in most of the surviving patients. PMID- 21683840 TI - Continued controversy regarding adverse events after Amplatzer septal device closure: mass hysteria or tip of the iceberg? PMID- 21683842 TI - Methods, outcomes, and relationships. PMID- 21683844 TI - Cardiac xenotransplantation technology provides materials for improved bioprosthetic heart valves. PMID- 21683846 TI - Continuous tracheal intubation in patients with myasthenia gravis after thymectomy to prevent tracheal incision for myasthenic crisis. PMID- 21683848 TI - The Gordian knot of revascularization for multivessel coronary artery disease. PMID- 21683850 TI - Simulating video-assisted thoracoscopic lung resection using a virtual 3 dimensional pulmonary model on a personal computer. PMID- 21683851 TI - Extended durability of noncryopreserved aortic allografts. PMID- 21683852 TI - Social media in surgical education and practice. PMID- 21683853 TI - Social media in medical school education. PMID- 21683854 TI - How surgical residents use social media. PMID- 21683855 TI - Social networking in surgery: the residency program director's view. PMID- 21683856 TI - Social networking in health care: surgeons and their patients. PMID- 21683857 TI - American College of Surgeons and social media efforts. PMID- 21683858 TI - Social networking services: implications for the next generation of physicians. PMID- 21683859 TI - Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. AB - BACKGROUND: Tumor size is a criterion of staging in nonfunctioning pancreatic endocrine tumors as well as a predictor of outcome after curative resection. This study analyzes the correlation between tumor size and malignancy in patients with nonfunctioning pancreatic endocrine tumors. METHODS: All patients with nonfunctioning pancreatic endocrine tumors who underwent curative resection (R0) at our institution between 1990 and 2008 were considered. Their clinicopathologic characteristics were compared among 3 different groups according to tumor size. Univariate and multivariable analyses were performed. RESULTS: Over the study period, 177 patients were identified. Overall, 90 patients (51%) had a tumor size <=2 cm (group 1), 46 (26%) had tumor size between >2 cm and <=4 cm (group 2), and 41 (23%) had tumor size >4 cm (group 3). Tumors <=2 cm were more frequently incidentally discovered (group 1, 57% vs group 2, 51% vs group 3, 32%; P = .014) and benign (group 1, 81% vs group 2, 65% vs group 3, 5%; P < .0001). The presence of a nonfunctioning pancreatic endocrine tumor >2 cm and a nonincidental diagnosis of the tumor were independent predictors of malignancy at multivariable analysis. None of the 51 patients (29%) with a pancreatic endocrine tumor <=2 cm that was incidentally diagnosed died of disease. CONCLUSION: A strict correlation between tumor size and malignancy in nonfunctioning pancreatic endocrine tumors was demonstrated. A nonoperative management could be advocated for tumors <=2 cm when discovered incidentally. PMID- 21683860 TI - Validation of the prognostic value of lymph node ratio in patients with cutaneous melanoma: a population-based study of 8,177 cases. AB - BACKGROUND: The proportion of positive among examined lymph nodes (lymph node ratio [LNR]) has been recently proposed as an useful and easy-to-calculate prognostic factor for patients with cutaneous melanoma. However, its independence from the standard prognostic system TNM has not been formally proven in a large series of patients. METHODS: Patients with histologically proven cutaneous melanoma were identified from the Surveillance Epidemiology End Results database. Disease-specific survival was the clinical outcome of interest. The prognostic ability of conventional factors and LNR was assessed by multivariable survival analysis using the Cox regression model. RESULTS: Eligible patients (n = 8,177) were diagnosed with melanoma between 1998 and 2006. Among lymph node-positive cases (n = 3,872), most LNR values ranged from 1% to 10% (n = 2,187). In the whole series (>=5 lymph nodes examined) LNR significantly contributed to the Cox model independently of the TNM effect on survival (hazard ratio, 1.28; 95% confidence interval, 1.23-1.32; P < .0001). On subgroup analysis, the significant and independent prognostic value of LNR was confirmed both in patients with >=10 lymph nodes examined (n = 4,381) and in those with TNM stage III disease (n = 3,658). In all cases, LNR increased the prognostic accuracy of the survival model. CONCLUSION: In this large series of patients, the LNR independently predicted disease-specific survival, improving the prognostic accuracy of the TNM system. Accordingly, the LNR should be taken into account for the stratification of patients' risk, both in clinical and research settings. PMID- 21683861 TI - Support surfaces for intraoperative prevention of pressure ulcers in patients undergoing surgery: a cost-effectiveness analysis. AB - BACKGROUND: Patients who undergo prolonged surgical procedures are at risk of developing pressure ulcers. Recent systematic reviews suggest that pressure redistribution overlays on operating tables significantly decrease the associated risk. Little is known about the cost effectiveness of using these overlays in a prevention program for surgical patients. METHODS: Using a Markov cohort model, we evaluated the cost effectiveness of an intraoperative prevention strategy with operating table overlays made of dry, viscoelastic polymer from the perspective of a health care payer over a 1-year period. We simulated patients undergoing scheduled surgical procedures lasting >=90 min in the supine or lithotomy position. RESULTS: Compared with the current practice of using standard mattresses on operating tables, the intraoperative prevention strategy decreased the estimated intraoperative incidence of pressure ulcers by 0.51%, corresponding to a number-needed-to-treat of 196 patients. The average cost of using the operating table overlay was $1.66 per patient. Compared with current practice, this intraoperative prevention strategy would increase slightly the quality adjusted life days of patients and by decreasing the incidence of pressure ulcers, this strategy would decrease both hospital and home care costs for treating fewer pressure ulcers originated intraoperatively. The cost savings was $46 per patient, which ranged from $13 to $116 by different surgical populations. Intraoperative prevention was 99% likely to be more cost effective than the current practice. CONCLUSION: In patients who undergo scheduled surgical procedures lasting >=90 min, this intraoperative prevention strategy could improve patients' health and save hospital costs. The clinical and economic evidence support the implementation of this prevention strategy in settings where it has yet to become current practice. PMID- 21683862 TI - "Double common bile duct: a pitfall during liver transplantation and cholecystectomy". PMID- 21683863 TI - Latissimus dorsi flap herniation: is it really that rare? PMID- 21683864 TI - On being a pathologist: Maria Dabska--the woman behind the eponym, a pioneer in pathology. AB - There is only one cancer to our knowledge named in honor of its female describer, the Dabska tumor. Maria Dabska was a brave hero of the Warsaw Resurrection of 1944 who survived deportation to Germany to graduate from medical school in Gdansk and pursue a career in pathology, for which her research on the Dabska tumor, breast cancer, sweat gland tumors, keratoacanthoma, soft tissue sarcomas, bone pathology, parachordoma, melanoma, and other entities remains salient. Working behind the Iron Curtain, she nevertheless achieved international recognition, yet few today are cognizant of her and her accomplishments. This vibrant distinguished professor is celebrating her 90th birthday. PMID- 21683865 TI - Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer- shifting the paradigm. AB - Recent morphologic, immunohistochemical, and molecular genetic studies have led to the development of a new paradigm for the pathogenesis and origin of epithelial ovarian cancer based on a dualistic model of carcinogenesis that divides epithelial ovarian cancer into 2 broad categories designated types I and II. Type I tumors comprise low-grade serous, low-grade endometrioid, clear cell and mucinous carcinomas, and Brenner tumors. They are generally indolent, present in stage I (tumor confined to the ovary), and are characterized by specific mutations, including KRAS, BRAF, ERBB2, CTNNB1, PTEN, PIK3CA, ARID1A, and PPP2R1A, which target specific cell signaling pathways. Type I tumors rarely harbor TP53 mutations and are relatively stable genetically. Type II tumors comprise high-grade serous, high-grade endometrioid, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas. They are aggressive, present in advanced stage, and have a very high frequency of TP53 mutations but rarely harbor the mutations detected in type I tumors. In addition, type II tumors have molecular alterations that perturb expression of BRCA either by mutation of the gene or by promoter methylation. A hallmark of these tumors is that they are genetically highly unstable. Recent studies strongly suggest that fallopian tube epithelium (benign or malignant) that implants on the ovary is the source of low-grade and high-grade serous carcinoma rather than the ovarian surface epithelium as previously believed. Similarly, it is widely accepted that endometriosis is the precursor of endometrioid and clear cell carcinomas and, as endometriosis, is thought to develop from retrograde menstruation; these tumors can also be regarded as involving the ovary secondarily. The origin of mucinous and transitional cell (Brenner) tumors is still not well established, although recent data suggest a possible origin from transitional epithelial nests located in paraovarian locations at the tuboperitoneal junction. Thus, it now appears that type I and type II ovarian tumors develop independently along different molecular pathways and that both types develop outside the ovary and involve it secondarily. If this concept is confirmed, it leads to the conclusion that the only true primary ovarian neoplasms are gonadal stromal and germ cell tumors analogous to testicular tumors. This new paradigm of ovarian carcinogenesis has important clinical implications. By shifting the early events of ovarian carcinogenesis to the fallopian tube and endometrium instead of the ovary, prevention approaches, for example, salpingectomy with ovarian conservation, may play an important role in reducing the burden of ovarian cancer while preserving hormonal function and fertility. PMID- 21683866 TI - Thyroid transcription factor-1 expression in endometrioid tumors: a note of caution. PMID- 21683868 TI - Do mast cell phenotypes play a role in concomitantly increased microvessel density and progression of non-small cell lung cancer? PMID- 21683870 TI - An overview on plant cuticle biomechanics. AB - Plant biomechanics combines the principles of physics, chemistry and engineering to answer questions about plant growth, development and interaction with the environment. The epidermal-growth-control theory, postulated in 1867 and verified in 2007, states that epidermal cells determine the rate of organ elongation since they are under tension, while inner tissues are under compression. The lipid cuticle layer is deposited on the surface of outer epidermal cell walls and modifies the chemical and mechanical nature of these cell walls. Thus, the plant cuticle plays a key role in plant interaction with the environment and in controlling organ expansion. Rheological analyses indicate that the cuticle is a mostly viscoelastic and strain-hardening material that stiffens the comparatively more elastic epidermal cell walls. Cuticle stiffness can be attributed to polysaccharides and flavonoids present in the cuticle whereas a cutin matrix is mainly responsible for its extensibility. Environmental conditions such as temperature and relative humidity have a plasticizing effect on the mechanical properties of cuticle since they lower cuticle stiffness and strength. The external appearance of agricultural commodities, especially fruits, is of great economic value. Mechanical properties of the cuticle can have a positive or negative effect on disorders like fruit cracking, fungal pathogen penetration and pest infestation. Cuticle rheology has significant variability within a species and thus can be subjected to selection in order to breed cultivars resistant to pests, infestation and disorders. PMID- 21683871 TI - Boron deficiency and transcript level changes. AB - Boron (B) is an essential element for plant growth whose deficiency causes an alteration in the expression of a wide range of genes involved in several physiological processes. However, our understanding of the signal transduction pathways that trigger the B-deficiency responses in plants is still poor. The aims of this review are (i) to summarize the genes whose transcript levels are affected by B deficiency and (ii) to provide an update on recent findings that could help to understand how the signal(s) triggered by B deficiency is transferred to the nucleus to modulate gene expression. In this contribution we review the effects of B deficiency on the transcript level of genes related to B uptake and translocation, maintenance of cell wall and membrane function, nitrogen assimilation and stress response. In addition, we discuss the possible mediation of calcium, arabinogalactan-proteins and other cis-diol containing compounds in the signaling mechanisms that transfer the signal of B deficiency to nuclei. Finally, we conclude that the advance in the knowledge of the molecular basis of B deficiency response in plants will allow improving the tolerance of crops to B deficiency stress. PMID- 21683872 TI - Photosynthetic response of clusterbean chloroplasts to UV-B radiation: energy imbalance and loss in redox homeostasis between Q(A) and Q(B) of photosystem II. AB - The effects of ultraviolet-B (UV-B: 280-320 nm) radiation on the photosynthetic pigments, primary photochemical reactions of thylakoids and the rate of carbon assimilation (P(n)) in the cotyledons of clusterbean (Cyamopsis tetragonoloba) seedlings have been examined. The radiation induces an imbalance between the energy absorbed through the photophysical process of photosystem (PS) II and the energy consumed for carbon assimilation. Decline in the primary photochemistry of PS II induced by UV-B in the background of relatively stable P(n), has been implicated in the creation of the energy imbalance(.) The radiation induced damage of PS II hinders the flow of electron from Q(A) to Q(B) resulting in a loss in the redox homeostasis between the Q(A) to Q(B) leading to an accumulation of Q(A)(-). The accumulation of Q(A)(-) generates an excitation pressure that diminishes the PS II-mediated O(2) evolution, maximal photochemical potential (F(v)/F(m)) and PS II quantum yield (Phi(PS II)). While UV-B radiation inactivates the carotenoid-mediated protective mechanisms, the accumulation of flavonoids seems to have a small role in protecting the photosynthetic apparatus from UV-B onslaught. The failure of protective mechanisms makes PS II further vulnerable to the radiation and facilitates the accumulation of malondialdehyde (MDA) indicating the involvement of reactive oxygen species (ROS) metabolism in UV-B-induced damage of photosynthetic apparatus of clusterbean cotyledons. PMID- 21683873 TI - Double-filter identification of vascular-expressed genes using Arabidopsis plants with vascular hypertrophy and hypotrophy. AB - Genes expressed in vascular tissues have been identified by several strategies, usually with a focus on mature vascular cells. In this study, we explored the possibility of using two opposite types of altered tissue compositions in combination with a double-filter selection to identify genes with a high probability of vascular expression in early organ primordia. Specifically, we generated full-transcriptome microarray profiles of plants with (a) genetically strongly reduced and (b) pharmacologically vastly increased vascular tissues and identified a reproducible cohort of 158 transcripts that fulfilled the dual requirement of being underrepresented in (a) and overrepresented in (b). In order to assess the predictive value of our identification scheme for vascular gene expression, we determined the expression patterns of genes in two unbiased subsamples. First, we assessed the expression patterns of all twenty annotated transcription factor genes from the cohort of 158 genes and found that seventeen of the twenty genes were preferentially expressed in leaf vascular cells. Remarkably, fifteen of these seventeen vascular genes were clearly expressed already very early in leaf vein development. Twelve genes with published leaf expression patterns served as a second subsample to monitor the representation of vascular genes in our cohort. Of those twelve genes, eleven were preferentially expressed in leaf vascular tissues. Based on these results we propose that our compendium of 158 genes represents a sample that is highly enriched for genes expressed in vascular tissues and that our approach is particularly suited to detect genes expressed in vascular cell lineages at early stages of their inception. PMID- 21683874 TI - Aberrant vegetative and reproductive development by overexpression and lethality by silencing of OsHAP3E in rice. AB - We generated transgenic rice plants overexpressing OsHAP3E which encodes a subunit of a CCAAT-motif binding HAP complex. The OsHAP3E-overexpressing plants showed various abnormal morphologies both in their vegetative and reproductive phases. The OsHAP3E-overexpressing plants were dwarf with erected leaves and similar to brassinosteroid mutants in the vegetative phase. In the reproductive phase, dense panicle was developed, and occasionally successive generation of lateral rachises and formation of double flowers were observed. These phenotypes indicate association of OsHAP3E with determination of floral meristem identity. On the other hand, repression of OsHAP3E by RNAi or by overexpressing chimeric repressor fusion constructs brought about lethality to transformed cells, and almost no transformant was obtained. This suggests that the OsHAP3E function is essential for rice cells. Altogether, our loss-of-function and gain-of-function analyses suggest that OsHAP3E plays important pleiotropic roles in vegetative and reproductive development or basic cellular processes in rice. PMID- 21683875 TI - Cloning of FaPAL6 gene from strawberry fruit and characterization of its expression and enzymatic activity in two cultivars with different anthocyanin accumulation. AB - The accumulation of anthocyanin pigments is one of the most important traits that turn strawberry fruit attractive to consumers. During ripening, strawberry fruit color development is associated to anthocyanin synthesis through the phenylpropanoid pathway. Phenylalanine ammonia-lyase (PAL) is a key enzyme in this pathway, having a determining role in strawberry fruit quality. In this work, we studied the level of anthocyanins during fruit ripening of two cultivars that differ in color development (Camarosa and Toyonoka). Toyonoka showed a lower anthocyanin accumulation that was limited to external fruit tissue, while Camarosa accumulated higher amount of anthocyanins in both internal and external sections. In addition, we cloned a full-length gene (FaPAL6) and analyzed its expression in different strawberry plant tissues. The expression of this gene is fruit specific, and increases during fruit ripening in both cultivars along with anthocyanin accumulation. The mRNA level of FaPAL6 was higher in Camarosa. PAL enzyme activity increased at similar rates in both cultivars at early ripening stages, but at the end of ripening PAL activity diminished in Toyonoka while it rose markedly in Camarosa. PAL activity was higher in internal fruit tissue, showing no correlation with anthocyanin level of the same section in both cultivars. The higher FaPAL6 expression and activity detected in Camarosa could be associated to the enhanced anthocyanin accumulation found in this cultivar. PMID- 21683876 TI - The 1-Cys peroxiredoxin, a regulator of seed dormancy, functions as a molecular chaperone under oxidative stress conditions. AB - Peroxiredoxins are antioxidative enzymes that catalyze the reduction of alkyl hydroperoxides to alcohols and hydrogen peroxide to water. 1-Cys peroxiredoxins (1-Cys Prxs) perform important roles during late seed development in plants. To characterize their biochemical functions in plants, a 1Cys-Prx gene was cloned from a Chinese cabbage cDNA library and designated as "C1C-Prx". Glutamine synthetase (GS) protection and hydrogen peroxide reduction assays indicated that C1C-Prx was functionally active as a peroxidase. Also C1C-Prx prevented the thermal- or chemical-induced aggregation of malate dehydrogenase and insulin. Hydrogen peroxide treatment changed the mobility of C1C-Prx on a two-dimensional gel, which implies overoxidation of the conserved Cys residue. Furthermore, after overoxidation, the chaperone activity of C1C-Prx increased approximately two fold, but its peroxidase activity decreased to the basal level of the reaction mixture without enzyme. However, according to the structural analysis using far UV circular dichroism spectra, intrinsic tryptophan fluorescence spectra, and native-PAGE, overoxidation did not lead to a conformational change in C1C-Prx. Therefore, our results suggest that 1-Cys Prxs function not only to relieve mild oxidative stresses but also as molecular chaperones under severe conditions during seed germination and plant development, and that overoxidation controls the switch in function of 1-Cys-Prxs from peroxidases to molecular chaperones. PMID- 21683877 TI - Genetic analysis of cysteine-poor prolamin polypeptides reduced in the endosperm of the rice esp1 mutant. AB - The esp1 mutant CM21 specifically exhibits reduced levels of cysteine-poor (CysP) prolamin bands with pIs of 6.65, 6.95, 7.10, and 7.35 in rice seed. Matrix assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis demonstrated that the bands with pIs 6.65, 6.95, and 7.35 are encoded by different structural genes. These results suggest that the Esp1 locus encodes a regulatory factor involved in the synthesis and/or accumulation of CysP prolamin molecules. Isoelectric focusing (IEF) analysis of CysP prolamins in chromosome substitution lines showed that structural genes for bands with pI values of 6.95, 7.10, and 7.35, which are reduced in esp1 mutant lines, are located as a gene cluster in the 44.2 cM region on chromosome 5. PMID- 21683878 TI - Screening of valid reference genes for real-time RT-PCR data normalization in Hevea brasiliensis and expression validation of a sucrose transporter gene HbSUT3. AB - Real-time RT-PCR (RT-qPCR) is a sensitive and precise method of quantifying gene expression, however, suitable reference genes are required. Here, a systematic reference gene screening was performed by RT-qPCR on 22 candidate genes in Hevea brasiliensis. Two ubiquitin-protein ligases (UBC2a and UBC4) were the most stable when all samples were analyzed together. A mitosis protein (YLS8) and a eukaryotic translation initiation factor (eIF1Aa) were the most stable in response to tapping. UBC2b and UBC1 were the most stable among different genotypes. UBC2b and a DEAD box RNA helicase (RH2b) were the most stable across individual trees. YLS8 and RH8 were most stably expressed in hormone-treated samples. Expression of the candidate reference genes varied significantly across different tissues, and at least four genes (RH2b, RH8, UBC2a and eIF2) were needed for expression normalization. In addition, examination of relative expression of a sucrose transporter HbSUT3 in different RNA samples demonstrated the importance of additional reference genes to ensure accurate quantitative expression analysis. Overall, our work serves as a guide for selection of reference genes in RT-qPCR gene expression studies in H. brasiliensis. PMID- 21683879 TI - Elevation of free proline and proline-rich protein levels by simultaneous manipulations of proline biosynthesis and degradation in plants. AB - Proline-rich proteins (PRP) are cell wall and plasma membrane-anchored factors involved in cell wall maintenance and its stress-induced fortification. Here we compare the synthesis of P5C as the proline (Pro) precursor in the cytosol and chloroplast by an introduced alien system and evaluate correlation between PRP synthesis and free Pro accumulation in plants. We developed a Pro over-producing system by generating transgenic tobacco plants overexpressing E. coli P5C biosynthetic enzymes; Pro-indifferent gamma-glutamyl kinase 74 (GK74) and gamma glutamylphosphate reductase (GPR), as well as antisensing proline dehydrogenase (ProDH) transcription. GK74 and GPR enzymes were targeted either to the cytosol or plastids. Molecular analyses indicated that the two bacterial enzymes are efficiently expressed in plant cells, correctly targeted to the cytosol or chloroplasts, and processed to active enzymatic complexes in the two compartments. Maximal Pro increase is obtained when GK74 and GPR are active in chloroplasts, and ProDH mRNA level is reduced by anti-sense silencing, resulting in more than 50-fold higher Pro content compared to that of wild type tobacco plants. The Pro over-producing system efficiently works in tobacco and Arabidopsis. The elevation of Pro levels promotes accumulation of ectopically expressed Cell Wall Linker Protein (AtCWLP), a membrane protein with an external Pro-rich domain. These results suggest that the Pro-generating system can support endogenous or alien PRP production in plants. PMID- 21683880 TI - Metabolic changes of iron uptake in N(2)-fixing common bean nodules during iron deficiency. AB - Iron is an important nutrient in N(2)-fixing legume nodules. The demand for this micronutrient increases during the symbiosis establishment, where the metal is utilized for the synthesis of various iron-containing proteins in both the plant and the bacteroid. Unfortunately, in spite of its importance, iron is poorly available to plant uptake since its solubility is very low when in its oxidized form Fe(III). In the present study, the effect of iron deficiency on the activity of some proteins involved in Strategy I response, such as Fe-chelate reductase (FC-R), H(+)-ATPase, and phosphoenolpyruvate carboxylase (PEPC) and the protein level of iron regulated transporter (IRT1) and H(+)-ATPase proteins has been investigated in both roots and nodules of a tolerant (Flamingo) and a susceptible (Coco blanc) cultivar of common bean plants. The main results of this study show that the symbiotic tolerance of Flamingo can be ascribed to a greater increase in the FC-R and H(+)-ATPase activities in both roots and nodules, leading to a more efficient Fe supply to nodulating tissues. The strong increase in PEPC activity and organic acid content, in the Flamingo root nodules, suggests that under iron deficiency nodules can modify their metabolism in order to sustain those activities necessary to acquire Fe directly from the soil solution. PMID- 21683881 TI - Tissue specificity and diurnal change in gene expression of the sucrose phosphate synthase gene family in rice. AB - The rice genome contains 5 isogenes for sucrose phosphate synthase (SPS), the key enzyme in sucrose synthesis; however, little is known about their transcriptional regulation. In order to determine the expression patterns of the SPS gene family in rice plants, we conducted an expression analysis in various tissues and developmental stages by real-time quantitative RT-PCR. At the transcript level, the rice SPS genes, particularly SPS1, were preferentially expressed in source tissues, whereas SPS2, SPS6, and SPS8 were expressed equally in source and sink tissues. We also investigated diurnal changes in SPS gene expression, SPS activity, and soluble sugar content in leaf blades. Interestingly, the expression of all the SPS genes, particularly that of SPS1 and SPS11, tended to be higher at night when the activation state of the SPS proteins was low, and the mRNA levels of SPS1 and SPS6 were negatively correlated with sucrose content. Furthermore, the temporal patterns of SPS gene expression and sugar content under continuous light conditions suggested the involvement of endogenous rhythm and/or sucrose sensing in the transcriptional regulation of SPS genes. Our data revealed differential expression patterns in the rice SPS gene family and part of the complex mechanisms of their transcriptional control. PMID- 21683882 TI - Carbon partitioning and the impact of starch deficiency on the initial response of Arabidopsis to chilling temperatures. AB - Metabolites and stress related transcripts were measured in Arabidopsis thaliana in response to chilling temperatures. Rates of carbon assimilation increased 17% on average in response to cold treatment. Sucrose, glucose and fructose accumulation consumed 42% of the carbon from A but leaf starch only could synthesize ~10% of observed changes in soluble sugars. Carbohydrates were the only major class of metabolites that accumulated during the first 24 h of cold treatment. Except maltose and raffinose, carbohydrate accumulation was abolished when cold treatments were in darkness. Starch hydrolysis was correlated with maltose accumulation and increased expression of BAM3, which encodes a beta amylase necessary for starch mobilization. Hexose accumulation was delayed 6 h and raffinose accumulation was not observed in a starchless (pgm1) mutant. Changes of expression of five stress-induced transcripts in response to cold were similar in the wild type and in the pgm1 mutant. Three of five stress related transcripts had decreased expression when cold treatments were performed in the dark compared to the light. Therefore, starch hydrolysis may augment hexose and raffinose accumulations during the first 24 h after a cold shock and a partial cold stress response was observed in Arabidopsis during cold treatments in the dark. PMID- 21683883 TI - The role of a putative peroxisomal-targeted epoxide hydrolase of Nicotiana benthamiana in interactions with Colletotrichum destructivum, C. orbiculare or Pseudomonas syringae pv. tabaci. AB - Motif analysis among 30 EH1 and EH2 epoxide hydrolases from Solanaceaeous plants showed differences primarily in the lid region around the catalytic site. Based on in silico models of 3D structures, EH1 proteins lack a catalytic triad because of the orientation of one of the conserved lid tyrosines, while the orientation of that tyrosine in EH2 proteins fomed a catalytic triad inside a hydrophobic tunnel. Two similar EH2 protein genes from Nicotiana benthamiana, NbEH2.1 and NbEH2.2, have a predicted peroxisomal targeting sequence, catalytic triad, and structural similarities to a potato cutin monomer-synthesizing epoxide hydrolase. NbEH2.1 expression increased with infections by the hemibiotrophs, Colletotrichum destructivum, Colletotrichum orbiculare or Pseudomonas syringae pv. tabaci only during their biotrophic phases, while there was only a slight increase during the hypersensitive response to P. syringae pv. tabaci (avrPto). In contrast, among the four pathogens, NbEH2.2 expression increased only in response to P. syringae pv. tabaci. Virus-induced gene silencing of NbEH2.1 significantly affected only the interaction with C. destructivum, resulting in a delay in the appearance of necrosis that may be related to its biotrophic phase being restricted to single epidermal cells, which is unique among these pathogens. These results differed from that of a previously reported EH1 gene of N. benthamiana for these interactions, demonstrating specialization among EH genes in basal resistance. PMID- 21683884 TI - The modified castor bean catalase intron is incompletely spliced in tobacco and Arabidopsis. AB - In an attempt to insert the modified castor bean catalase intron (mCBC intron) into the coding sequence of the Cre recombinase gene, we found that the mCBC intron was not completely spliced from the resulting iCre gene in tobacco and Arabidopsis. Sequencing and allele-specific PCR analyses indicated that six nucleotides (UUACAG) at the 3' terminus of the mCBC intron were retained in the mature mRNA of the iCre gene. Moreover, the mCBC intron was incompletely spliced from the Gus gene in pCAMBIA vectors. A mutational analysis of the mCBC intron demonstrated that the incomplete splicing was due to an artificial 3' splice site introduced by the insertion of an adenine, which created a TAG (stop) codon near the 3' splice site of the original CBC intron. Deletion of the inserted adenine or the six nucleotides that were retained from the mCBC intron led to the complete removal of the intron from the resulting iCre2 and iCre3 genes. Thus, in this study, we not only characterized the incomplete splicing event of the mCBC intron in tobacco and Arabidopsis, but also reported the construction of two intron-containing Cre recombinase genes that are useful for plant biotechnology applications. PMID- 21683885 TI - Beneficial effects of exogenous iodine in lettuce plants subjected to salinity stress. AB - Salinity inhibits plant growth due to ionic and osmotic effects on metabolic processes and nutritional balance, leading to impaired physiological functions. Selenium (Se) and silicon (Si) can be partially alleviated by the effects wrought by NaCl on the plant metabolism. Iodine (I), applied as iodate (IO(3)(-)) in biofortification programmes, has been confirmed to improve the antioxidant response in lettuce plants. Thus, the aim of this study was to determine whether the application of IO(3)(-) can improve the response to severe salinity stress in lettuce (Lactuca sativa cv. Philipus). In this work, the application of IO(3)(-) (20-80 MUM) in lettuce plants under salinity stress (100mM of NaCl) exerted a significantly positive effect on biomass and raised the levels of soluble sugars while lowering the Na(+) and Cl(-) concentrations as well as boosting the activity of antioxidant enzymes such as SOD, APX, DHAR and GR. Therefore, IO(3)( ) could be considered a possibly beneficial element to counteract the harmful effects of salinity stress. PMID- 21683886 TI - [Advances in a two year adventure]. PMID- 21683887 TI - Acute versus chronic hypoxia: why a simplified classification is simply not enough. PMID- 21683889 TI - Intraoperative radiotherapy during a second breast-conserving procedure for relapsed breast cancer after previous external beam radiotherapy. PMID- 21683888 TI - Stereotactic radiosurgical treatment of brain metastases to the choroid plexus. AB - PURPOSE: Choroid plexus metastases (CPM) are uncommon lesions. Consequently, optimal management of CPM is uncertain. We summarize our experience with stereotactic radiosurgery (SRS) of CPM. METHODS AND MATERIALS: Sixteen consecutive patients with presumed CPM treated with SRS between 1997 and 2007 were examined. Twelve were men with a median age at diagnosis of CPM of 61.9 +/- 9.9 years; 14 had metastases from renal cell carcinoma (RCC). All patients had controlled primary disease at the time of treatment for CPM. Four patients with RCC and 1 with non-small-cell lung cancer had undergone whole-brain radiotherapy (WBRT) previously and 2 had received SRS to other brain metastases. The disease free interval from the primary diagnosis to CPM diagnosis averaged 39.3 +/- 46.2 months (range, 1.0-156.3). Five patients were asymptomatic; of the remaining 11, none had symptoms related to CPM. All presented with a single CPM. RESULTS: Average maximum diameter of the CPMs was 2.0 +/- 1.0 cm (range, 0.9-4.1 cm); mean volume was 2.4 +/- 2.6 cm(3) (range, 0.2-9.3). Median SRS dose was 24 Gy to the 53% isodose line (range, 14-24 Gy). Survival after SRS to the CPM was 25.3 +/- 23.4 months (range, 3.2-101.6). Patients in Recursive Partitioning Analysis (RPA) class I (n = 10) had improved survival compared to those in class II (n = 6), as did those with better GPA scores. There were no local failures. After SRS, 1 patient underwent WBRT, 3 patients had one, and another had two subsequent SRS treatments to other brain lesions. Of the 14 patients who have died, 11 succumbed to systemic disease progression, 2 to progressive, multifocal central nervous system disease, and 1 to systemic disease with concurrent, stable central nervous system disease. There were no complications related to SRS. CONCLUSIONS: Most CPMs are associated with RCC. SRS represents a safe and viable treatment option as primary modality for these metastases, with excellent outcomes. PMID- 21683890 TI - In reply to Dr. King (Adjuvant radiotherapy after prostatectomy: does waiting for a detectable prostate-specific antigen level make sense?). PMID- 21683892 TI - Response to "Patient selection and activity planning guide for selective internal radiotherapy with Yttrium-90 resin microspheres." (Int J Radiat Oncol Biol Phys 2010;Oct 13). PMID- 21683893 TI - Argonaute proteins. PMID- 21683894 TI - Reproductive interference. PMID- 21683895 TI - Antarctic marine biology. PMID- 21683896 TI - Could Scott have survived with today's physiological knowledge? AB - In 1911, members of a British expedition walked across the Antarctic to the South Pole, but in the punishingly hostile environment, retracing their steps back to the edge of the continent proved fatal. Over the last 100 years, knowledge about human physiology has greatly increased and, on the centenary of this most extreme of all journeys, this essay explores the true extent of the physiological stress experienced by the men involved and whether their fate was inevitable. PMID- 21683897 TI - Rocking synchronizes brain waves during a short nap. PMID- 21683898 TI - Animal behaviour: emotion in invertebrates? AB - Bees exposed to vigorous shaking designed to simulate a dangerous event judge ambiguous stimuli as predicting a negative outcome - a 'pessimistic' cognitive bias that is characteristic of anxious or depressed humans and other vertebrates in putative negative emotional states. PMID- 21683899 TI - Thermal robustness: lessons from bacterial chemotaxis. AB - Temperature changes affect reaction kinetics. How do signaling pathways cope with such global perturbation? A recent study dissects the solution found by bacterial chemotaxis. PMID- 21683900 TI - Conservation biology: the many ways to protect biodiversity. AB - Protecting hotspots of marine species richness may not be an effective strategy to conserve biodiversity because these sites do not coincide with hotspots of functional and phylogenetic diversity. PMID- 21683901 TI - Behavioral neurobiology: the bitter life of male flies. AB - Male fruit flies demonstrate aggression and even courtship towards other male flies. A new study reveals that these behaviors are induced via a bitter gustatory receptor. PMID- 21683902 TI - Tendon homeostasis: the right pull. AB - Mechanotransduction, the conversion of a biophysical force into a cellular response, allows cells and tissues to respond to their mechanical milieu. How muscle force is translated through TGF-beta signaling to regulate tendon homeostasis offers an interesting in vivo example of mechanotransduction. PMID- 21683903 TI - Innate immunity: unfolding the neuro-immuno connections. AB - The innate immune system maintains health and fitness during infection by eliminating infectious agents and by limiting damage caused by pathogens or immune activation. The nervous system contributes to innate immunity by modulating the expression of antimicrobial peptides and by regulating the unfolded protein response. PMID- 21683904 TI - Development: a pathway to plant female germ cells. AB - Plant germ cells form late in development, but little is known about the molecular basis for germline specification in plants. Recent results have identified components of a regulatory pathway controlling female germ cell determination, including a key transcription factor and some putative signaling proteins. PMID- 21683905 TI - Mitochondrial dynamics: a strategy for avoiding autophagy. AB - Cells normally respond to a lack of nutrients by activating autophagy, a prominent pro-survival pathway that involves the catabolism and recycling of cytoplasmic material. Recent results indicate that mitochondria actively elongate during autophagy, thereby avoiding their degradation and sustaining cell viability. PMID- 21683906 TI - Introduction. Histone ubiquitylation. PMID- 21683907 TI - Chronic kidney disease: nutrition basics. PMID- 21683908 TI - "You can't handle the truth!". PMID- 21683909 TI - Forensic psychiatry. PMID- 21683910 TI - Juveniles who sexually offend: recommending a treatment program and level of care. AB - Specialized interventions for juveniles who have committed sex offenses have been widely available for 25 years. These interventions initially were based largely on adult sex offender interventions, with little consideration of developmental and other differences that distinguish juveniles from adult offenders. More recently, interventions have been developed that address youth-specific factors associated with problem sexual behaviors and that include a stronger family focus. This article reviews the history of intervention approaches, summarizes specialized evaluation methods and addresses the assessment of juvenile recidivism risk. PMID- 21683911 TI - The supreme court and the sentencing of juveniles in the United States: reaffirming the distinctiveness of youth. AB - The US Supreme Court has set 2 key constitutionally based limits to punishment of juveniles; a bar on the imposition of the death penalty for crimes committed by juveniles and of life imprisonment without possibility of parole for juveniles who commit nonhomicide offenses. Both decisions held that these penalties were disproportionate given juveniles' distinctive characteristics. The Court's adoption of a developmental model of culpability may produce future challenges to lengthy juvenile sentences, broad provisions allowing transfer of juveniles for trial as adults, and even possibly to younger juveniles'competence to stand trial. PMID- 21683912 TI - Cornered: an approach to school bullying and cyberbullying, and forensic implications. AB - Bullying is an abuse of power and control that can cause significant harm to individuals. School systems have the difficult task of trying to police this behavior to maintain a safe learning environment for their students. Although there may be an identified bully, the ramifications of the behavior affect the system as a whole. Bullies, targeted victims, and bystanders play an integral role in ameliorating this problem. A change of culture within the school system is often the best, yet often the most difficult, intervention. In addition, cyberbullying has become a powerful avenue for bullying, resulting in significant morbidity within schools. PMID- 21683913 TI - Children of divorce: the differential diagnosis of contact refusal. AB - Contact refusal is a common phenomenon that can occur during the course of, or after, divorce, which affects the relationship between a child and the parent. This article defines the concept of contact refusal and discusses the importance of its recognition. The concept is further narrowed to focus on the child as the one refusing contact, not the parent, which can happen as well. Various types of contact refusals are illustrated in the article through clinical vignettes, and an approach to categorizing the various types of contact refusal is presented. PMID- 21683914 TI - The psychosocial treatment of parental alienation. AB - Parental alienation occurs in divorces when one parent indoctrinates the child to dislike, fear, and avoid contact with the other parent. Mental health professionals who treat children and adolescents are likely to encounter victims of parental alienation in clinical practice, and it is important to identify and treat these youngsters earlier, when the condition is mild, rather than later, when the parental alienation is almost intractable. This article presents an overview of the treatment of parental alienation, which is called reunification therapy. All the parties involved in the case have a role in the prevention and treatment of parental alienation. PMID- 21683915 TI - Visitation arrangements for impaired parents. AB - Forensic mental health professionals are frequently asked to evaluate the parenting skills of divorcing parents because the court seeks help in determining the custody, visitation, and parenting time arrangements for the children. When one of the parents is impaired, the court wants to know the way to help the children have a good relationship with that parent and keep the children safe. There is little empirical research to answer such questions. In this article, the authors describe their methodology for providing useful clinical information to the court to help guide their decisions regarding visitation with impaired parents. PMID- 21683916 TI - Estimating present and future damages following child maltreatment. AB - The child psychiatric forensic evaluation of children and adolescents who are plaintiffs in civil lawsuits regarding their present and future damages from child maltreatment requires knowledge of current research findings on the short term and long-term consequences of child maltreatment, evidence-based treatments for psychological trauma, and relevant professional guidelines, along with knowledge of the ethics and laws governing mental health expert practice and testimony in personal injury litigation. This article reviews current research and recommends an approach to these evaluations and expert testimony that is informed by current research findings, recently developed professional guidelines, and many years of professional experience. PMID- 21683917 TI - Forensic psychiatry in France: the Outreau case and false allegations of child sexual abuse. AB - During the Outreau case in France, 13 individuals were falsely accused of child sexual abuse and incarcerated. The author of this article testified as a psychiatric expert when the convictions were appealed. He explains how purposeful false statements by adults, inept expert witnesses, and the judicial assumption that children do not lie converged to create a tragic legal outcome. This article explains how psychiatric experts should conduct evaluations in cases of alleged child sexual abuse. PMID- 21683918 TI - On the use and misuse of genomic and neuroimaging science in forensic psychiatry: current roles and future directions. AB - Dramatic advances in the understanding of the neurobiological bases of human behavior have prompted excitement and controversy surrounding the ethical, legal, and social applications of this knowledge. The authors critically examine the promise and challenges of integrating genomic and neuroimaging techniques into legal settings. They suggest criteria for enhancing the viability of incorporating these data within a legal context and highlight several recent developments that may eventually allow genetic and neuroimaging evidence to meet these criteria and play a more prominent role in forensic science and law. PMID- 21683919 TI - Malingering in children: fibs and faking. AB - Research has established that children can make efforts to deceive others and that malingering or underperformance in psychiatric and psychological evaluations is common. Clinicians often resist the idea that children can successfully fake mental disorders and formal assessment for malingering is rare in clinical practice. The author suggests that screening tests be performed during the initial evaluation of all children to identify deceptive behavior. Children who behave in a suspect fashion and children who have known motivations to present as more pathologic than they are should be formally assessed with psychological techniques to rule out the presence of malingering. PMID- 21683920 TI - Ridiculous statements by mental health experts. AB - When mental health experts express their opinions in testimony, reports, and articles in professional literature, it is expected that their statements will accurately reflect the current state of knowledge. Experts may disagree about the data that they collected. In some cases, however, disagreement occurs because an expert has employed a methodology that is far outside usual procedures or simply disregarded objective facts. When that occurs, the expert's opinions may be considered ridiculous. The author presents examples of ridiculous statements by mental health experts and provides suggestions for how a forensic practitioner might address ridiculous statements by mental health experts. PMID- 21683921 TI - The child and adolescent track in the forensic fellowship. AB - Exposure to child and adolescent forensic issues is limited in general psychiatry residency and child and adolescent psychiatry residency programs. There is no Graduate Medical Education Program for child and adolescent forensic psychiatry that is approved by the American Council on Graduate Medical Education (ACGME). Forensic psychiatry residency directors can create a child-focused forensic training opportunity that meets the needs of the ACGME program in forensic psychiatry. By creating didactic, clinical, and research experiences relevant to child and adolescent forensic psychiatric issues, this much-needed training can be provided to qualified psychiatrists. PMID- 21683922 TI - An annotated bibliography for the testifying child and adolescent psychiatrist. AB - To persuade a fact finder that a forensic opinion has a scientific basis, it is often useful to cite professional literature that supports one's opinions or procedures. If the admissibility of one's opinion is challenged in a Daubert hearing, citing literature is almost always required to support the claim that the expert's opinion relies on scientific facts or proceeds from scientific methodology. This annotated bibliography provides a sampling of articles that may be useful in bolstering testimony. The sample selected here is not comprehensive, but provides examples of literature that may be cited by forensic child and adolescent psychiatric experts. PMID- 21683923 TI - EURAP signals a new era in epilepsy research. PMID- 21683924 TI - The multiple sclerosis mystery: is there a vascular component? PMID- 21683925 TI - Revised criteria for Alzheimer's disease: what are the lessons for clinicians? PMID- 21683926 TI - Is the economic crisis affecting the quality of neurological services? PMID- 21683927 TI - Giovanni Frisoni: an innovator with his head in the cloud. PMID- 21683930 TI - Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. AB - The rationale for use of adult stem cells as a treatment for neurological diseases such as multiple sclerosis arose from the hope that they had the capacity to foster repair of the CNS through tissue integration and differentiation into neural cells. Evidence from preclinical studies suggested that mesenchymal stem cells (MSCs), a subset of adult progenitor cells, are an effective therapy in preclinical animal models of neurological diseases such as experimental autoimmune encephalomyelitis, a model for multiple sclerosis, and stroke. In experimental autoimmune encephalomyelitis, intravenous injection of MSCs ameliorates clinical course and decreases demyelination, immune infiltrates, and axonal loss. Surprisingly, these effects do not require full CNS engraftment by MSCs, but rely on the capacity of MSCs to inhibit pathogenic immune responses and release neuroprotective and pro-oligodendrogenic molecules favouring tissue repair. These results led to the conclusion that therapeutic use of MSCs should initially focus on individuals with multiple sclerosis and persistent inflammation. Small clinical studies in different neurological diseases have suggested that MSCs are safe, paving the road for larger phase 2 studies addressing the effect of MSCs on clinical outcomes and markers of disease activity. PMID- 21683929 TI - Clinical features and pathophysiology of complex regional pain syndrome. AB - A complex regional pain syndrome (CRPS)--multiple system dysfunction, severe and often chronic pain, and disability--can be triggered by a minor injury, a fact that has fascinated scientists and perplexed clinicians for decades. However, substantial advances across several medical disciplines have recently improved our understanding of CRPS. Compelling evidence implicates biological pathways that underlie aberrant inflammation, vasomotor dysfunction, and maladaptive neuroplasticity in the clinical features of CRPS. Collectively, the evidence points to CRPS being a multifactorial disorder that is associated with an aberrant host response to tissue injury. Variation in susceptibility to perturbed regulation of any of the underlying biological pathways probably accounts for the clinical heterogeneity of CRPS. PMID- 21683931 TI - Vascular aspects of multiple sclerosis. AB - Three types of vascular dysfunction have been described in multiple sclerosis (MS). First, findings from epidemiological studies suggest that patients with MS have a higher risk for ischaemic stroke than people who do not have MS. The underlying mechanism is unknown, but might involve endothelial dysfunction secondary to inflammatory disease activity and increased plasma homocysteine concentrations. Second, patients with MS have global cerebral hypoperfusion, which might predispose them to the development of ischaemic stroke. The widespread decrease in perfusion in normal-appearing white matter and grey matter in MS seems not to be secondary to axonal degeneration, but might be a result of reduced axonal activity, reduced astrocyte energy metabolism, and perhaps increased blood concentrations of endothelin-1. Data suggest that a subtype of focal MS lesions might have an ischaemic origin, and there seems to be a link between reduced white matter perfusion and cognitive dysfunction in MS. Third, the pathology of MS might be the consequence of a chronic state of impaired venous drainage from the CNS, for which the term chronic cerebrospinal venous insufficiency (CCSVI) has been coined. A number of recent vascular studies do not support the CCSVI theory, but some elements of CCSVI might be explained by slower cerebral venous blood flow secondary to the reduced cerebral perfusion in patients with MS compared with healthy individuals. PMID- 21683932 TI - Clinical amyloid imaging in Alzheimer's disease. AB - BACKGROUND: The hypothesis that amyloid deposition is the leading cause of Alzheimer's disease (AD) is supported by findings in transgenic animal models and forms the basis of clinical trials of anti-amyloid agents. According to this theory, amyloid deposition causes severe damage to neurons many years before onset of dementia via a cascade of several downstream effects. This hypothesis has, however, not yet been directly tested in human beings because of the very limited possibility of diagnosing amyloid deposition in vivo, which until recently required either brain biopsy or PET imaging with an on-site cyclotron and radiochemistry laboratory. Moreover, a clinical diagnosis of AD requires that patients have dementia, at which stage any effective treatment aimed at reducing amyloid deposition will probably be too late. RECENT DEVELOPMENTS: The amyloid imaging tracers flutemetamol, florbetapir, and florbetaben labelled with (18)F have been developed for PET; they can be produced commercially at central cyclotron sites and subsequently delivered to clinical PET scanning facilities. These tracers are currently undergoing formal clinical trials to establish whether they can be used to accurately image fibrillary amyloid and to distinguish patients with AD from normal controls and those with other diseases that cause dementia. They might also be used as biomarkers to predict development of AD before onset of dementia and to assess the effect of anti-amyloid therapy. Negative amyloid scans indicate absence of AD with a high level of accuracy, but healthy elderly volunteers might have positive amyloid scans, so their predictive value in isolation is less clear. Close association of in-vivo amyloid imaging results with post-mortem histopathological findings was shown with florbetapir in a phase 3 study. WHERE NEXT?: Therapeutic studies of anti-amyloid agents that include amyloid tracers as biomarkers are expected to be useful for drug development and to clarify the relation between amyloid removal and clinical effects. Once the (18)F tracers become available for diagnostic use, large-scale longitudinal studies will be needed to clarify their prognostic and diagnostic power in relation to age, risk factors, and AD subtypes. Ultimately, these tracers will hopefully clarify the pathophysiological role of amyloid in AD and contribute to development of new treatments. PMID- 21683933 TI - [Endoscopic management of paranasal sinus mucoceles: experience with 46 patients]. AB - OBJECTIVE: The purpose of this study was to determine changes in the surgical treatment of patients with the diagnosis of paranasal mucoceles managed in a Latin American hospital. We hypothesised that endonasal endoscopic surgeries had emerged as the main treatment option for this disease in the last five years. METHODS: A retrospective chart review of all patients who were diagnosed with paranasal sinus mucoceles and treated at the Otorhinolaryngology Head and Neck Department of our hospital from 2002 to 2010 was performed. Patient demographic data, mucoceles location, symptoms, surgical approach and complications were recorded. RESULTS: A total of 46 patients were included (27 males; 19 females). This series include 29 patients (63%) with frontal or frontoethmoidal mucoceles, 14 (30.4%) with maxillary and 3 (6.5%) with sphenoid mucoceles. Ninety-five percent of the patients were treated with intranasal endoscopic surgery. Complications occurred only in 7 cases (15.2%). CONCLUSIONS: This study confirms that over the last 9 years significant changes have occurred in the surgical treatment of paranasal mucocele in our hospital, as endoscopic surgeries increased from 34% to over 90% as the first option of treatment for mucoceles. PMID- 21683934 TI - [Radiological anatomy of the ethmoidal arteries: CT cadaver study]. AB - INTRODUCTION AND OBJECTIVES: Our aim was to study the radiological anatomy of the ethmoidal arteries. METHODS: A descriptive study was performed including CT images of 20 cadaver heads. The specimens were perfused with a radiopaque material and various anatomical parameters were analysed. RESULTS: The anterior ethmoidal artery was found in 95% (38/40) of cases. It originated from the ophthalmic artery in 87.5% (34/40) of nasal cavities. In six cases, normal variants were found. The mean length of the anterior ethmoidal canal was 8.43 +/- 0.74 mm. The angle performed into the skull base was 37.3 +/- 5.48 degrees . In 90% of cases (36/40), it was located between the second and third lamella. The posterior ethmoidal artery was localised only in 14/40 cases, with 28.5% (4/14) of them showing normal variants. The mean length of the posterior ethmoidal canal was 7.1 +/- 1.02 mm. The angle performed into the skull base was 7.11 +/- 4.07 degrees . The distance from sill to the anterior ethmoid artery was 55.51 +/- 5.52 mm. The angle between the nasal spine and the anterior ethmoidal canal was 57.67 +/- 1.68 degrees . The distance between the nasion and the anterior ethmoidal canal was 29.31 +/- 2.53 mm, the distance was 11.24 +/- 2.14 mm from the anterior ethmoid artery to the posterior ethmoid artery and from the posterior ethmoid artery to the optic nerve, 7.26 +/- 1.33 mm. Supraorbital cells were observed in 15% (6/40) of the cases. CONCLUSIONS: A complete vascular study of the ethmoidal arteries was possible by using this technique. PMID- 21683935 TI - [Analysis of unofficial consultations in a tertiary-level hospital]. AB - BACKGROUND: Dermatologists are regularly consulted in their place of work by patients without an official appointment (individuals accompanying other patients, doctors from other specialties, hospital workers, etc). OBJECTIVES: To describe the characteristics of consulting patients, reasons for consultation, severity of complaint, diagnostic and therapeutic approach taken, and level of care provided by the consulted professionals. RESULTS: The typical patient would be a middle-aged female nurse consulting for the first time for a benign melanocytic lesion. In general, the dermatologist will take an empirical or informative therapeutic approach and consider the care provided to be similar to that offered to patients with an official appointment. CONCLUSIONS: Unofficial appointments, although commonly for trivial complaints, represent an additional workload in daily clinical practice. PMID- 21683936 TI - Two decades of progress in vascular medicine. PMID- 21683937 TI - Gestational weight and intraoperative management in the obese gravida. PMID- 21683938 TI - A novel technique for the transplantation of pancreatic islets within a vascularized device into the greater omentum to achieve insulin independence. AB - BACKGROUND: The greater omentum with its vascularization and blood flow has been considered as a location for islet transplantation; however, there is a need to provide a controlled and protected site for the islets within the omentum that would be applicable to donor islets and future stem cell technologies. Here we describe the use of a novel device implanted within the omentum with a subcutaneous delivery port that offers an environment for donor islets. METHODS: A prototype cell pouch device was wrapped in the greater omentum and an islet implantation port was exposed subcutaneously in diabetic Lewis rats. After tissue growth throughout the device, islet isografts were implanted and long-term glucose control was evaluated. RESULTS: By using this technique, 7 of 10 diabetic rat recipients showed long-term normal blood glucose levels after minimal islet dose transplants. Histologic assessment revealed collagen formation and vascularization within the device. CONCLUSIONS: The implanted device assessed using this technique provides a safe and efficacious environment for the support of pancreatic islets contained within a removable device as a cell therapy in a highly vascularized setting. PMID- 21683939 TI - Changing trend in surgical indication and management for Graves' disease. AB - BACKGROUND: Although thyroidectomy for Graves' disease (GD) is well established, surgical indications remain less well defined. This study aimed to evaluate the changes in surgical indication, type of resection, and surgical outcomes at a single institution. METHODS: A total of 346 patients who underwent thyroidectomy for GD were divided into 2 time periods: period 1 (1995-2001) and period 2 (2002 2008). Their surgical indication, type of resection, and surgical outcomes were compared. RESULTS: Patients in the earlier period were significantly younger, suffered more previous relapses, and were on a longer duration of antithyroid drugs before surgery. Graves' ophthalmopathy and refusal for radioactive iodine were the indications that changed significantly between the 2 periods. Total/near total thyroidectomy was performed more commonly and resulted in a higher temporary hypoparathyroidism rate in the latter period (P < .001). CONCLUSIONS: Over the study period, significant changes in surgical indication, type of resection, and surgical outcomes were noted. Graves' ophthalmopathy became one of the most common surgical indications. Total thyroidectomy became the preferred surgery but that resulted in a higher temporary hypoparathyroidism rate. PMID- 21683941 TI - Keeping new antifungals as second-line agents only. PMID- 21683940 TI - [Recurrent pericarditis as an initial manifestation of Wegener's granulomatosis]. AB - Recurrent pericarditis occur in around a quarter of patients after a first episode of acute pericarditis. Most of the cases are idiopathic or viral pericarditis or post-pericardial injury syndromes. Recurrent pericarditis are most likely to occur in patients with known systemic lupus erythematosus or rheumatoid arthritis but are rare in other systemic auto-immune diseases. We report here an unusual case of a patient with a 5-year history of four acute myopericarditis revealing Wegener's granulomatosis. Clinicians should consider the possibility of Wegener's granulomatosis in case of recurrent pericarditis and look for features suggestive of granulomatous disease affecting the upper and lower respiratory tract. In this setting, antineutrophil cytoplasmic autoantibodies (ANCA) testing and/or biopsy of involved organs appear of particular interest to confirm the diagnosis. PMID- 21683942 TI - The default mode network and EEG alpha oscillations: an independent component analysis. AB - The default mode network (DMN) has been principally investigated using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) and has received mixed support in electroencephalographic (EEG) studies. In particular, the existing evidence is too inconsistent to allow formulation of specific hypotheses linking DMN activity to traditional EEG frequency bands. In this study, we aimed to test whether blind decomposition methods are able to identify in EEG data spatial patterns resembling the DMN as it is described in PET and fMRI studies. Further we aimed to test a degree of task-relatedness of DMN patterns identified in the traditional EEG frequency bands. To answer these questions we collected data both in a resting state and during performance of two experimental tasks: an explicit judgment of facial affect and a social game task. Individual differences in amount of self-referential thoughts during the resting state were measured by a short self-report scale. Only alpha band spatial patterns simultaneously showed a considerable overlap with the DMN and high correlations with presumptive DMN function-related outcomes both in the resting state and during the social game task. Spontaneous self-referential thoughts were associated with enhanced alpha activity in the posterior DMN hub, whereas processing of DMN function-related external stimuli disrupted this activity and simultaneously caused partial alpha phase-locking to external events. This evidence implies that synchronization of internal mental processes, as opposed to the processing of external stimuli, might be the primary function of alpha oscillations which is bound to be related to activity of the DMN. PMID- 21683943 TI - The main and accessory olfactory systems of female mice are activated differentially by dominant versus subordinate male urinary odors. AB - Previous studies have shown that female preferences for male pheromones depend on the female's reproductive condition and the dominance status of the male. However, it is unknown which olfactory system detects the odors that result in a preference for a dominant male. Therefore, in the present study, we asked whether dominant versus subordinate male urinary odors differentially activate the main and accessory olfactory systems in female (C57Bl/6j) mice by monitoring the induction of the immediate early gene, c-fos. A more robust induction of Fos was observed in female mice which had direct nasal contact with dominant male urinary odors in four specific segments of the accessory olfactory system, i.e., the posteroventral part of the medial amygdala, the bed nucleus of the stria terminalis, the medial part of the preoptic nucleus and the ventrolateral part of the ventromedial hypothalamus, compared to females that were exposed to subordinate male urine. This greater activation of the accessory olfactory pathway by dominant male urine suggests that there are differences in the nonvolatile components of dominant versus subordinate male urine that are detected by the vomeronasal organ. By contrast, subordinate male urinary odors induced a greater activation in the piriform cortex which is part of the main olfactory system, suggesting that female mice discriminate between dominant and subordinate male urine using their main olfactory system as well. PMID- 21683944 TI - Maturational changes and effects of chronic hypoxemia on electrocortical activity in the ovine fetus. AB - We have studied the maturation of electrocortical (ECoG) activity in fetal sheep and the impact of chronic hypoxemia using a growth restriction model with placental embolizations. Twenty chronically catheterized fetal sheep (control, n=9; hypoxemic, n=11) were monitored at 116-119, 121-126 and 128-134 days gestational age (term=145 days), with ECoG activity scored using automated analysis of amplitude and frequency components to distinguish low-voltage/high frequency (LV/HF) and high-voltage/low frequency (HV/LF) state epochs, along with indeterminate voltage/frequency (IV/F) and transition period activities. We have shown that multiple aspects of ECoG state activity in the ovine fetus undergo maturational change as electrophysiologic measures of brain development. With chronic fetal hypoxemia, some maturational changes continue to occur, i.e. ECoG activity amplitude and 95% SEF, indicating the resiliency of these parameters to adverse conditioning. However, some maturational changes were altered, i.e. LV/HF and HV/LF incidence and duration, and likely regulated and adaptive with a decrease in the brain's nonessential energy needs, while some were altered, i.e. IV/F incidence and duration, and state transition times, and likely indicating a degree of aberrant development in associated control circuitries. This may then have consequences for disturbed sleep-wake patterns during later life and for adverse neurologic sequelae known to be increased in humans born with growth restriction. PMID- 21683945 TI - Expression of a new disialyllacto structure in the lipopolysaccharide of non typeable Haemophilus influenzae. AB - The structure of lipopolysaccharide (LPS) expressed by non-typeable Haemophilus influenzae (NTHi) strains 1008 and 1247 has been investigated by mass spectrometry and NMR analyses on O-deacylated LPS and core oligosaccharide material. Both strains express the conserved triheptosyl inner core, [l-alpha-d Hepp-(1->2)-[PEtn->6]-l-alpha-d-Hepp-(1->3)-l-alpha-d-Hepp-(1->5)-[PPEtn->4] alpha-Kdo-(2->6)-Lipid A] with PCho->6)-beta-d-Glcp (GlcI) substituting the proximal heptose (HepI) at O-4. Strain 1247 expresses the common structural motifs of H. influenzae; globotetraose [beta-d-GalpNAc-(1->3)-alpha-d-Galp-(1->4) beta-d-Galp-(1->4)-beta-d-Glcp-(1->] and its truncated versions globoside [alpha d-Galp-(1->4)-beta-d-Galp-(1->4)-beta-d-Glcp-(1->] and lactose [beta-d-Galp-(1 >4)-beta-d-Glcp-(1->] linked to the terminal heptose of the inner core and GlcI. A genetically distinct NTHi strain, 1008, expresses identical structures to strain 1247 with the exception that it lacks GalNAc. A lpsA mutant of strain 1247 expressed LPS of reduced complexity that facilitated unambiguous structural determination of the oligosaccharide from HepI. By CE-ESI-MS/MS we identified disialylated glycoforms indicating disialyllactose [alpha-Neu5Ac-(2->8)-alpha Neu5Ac-(2->3)-beta-d-Gal-(1->4)-beta-d-Glcp-(1->] as an extension from GlcI which is a novel finding for NTHi LPS. PMID- 21683946 TI - Apocynin stimulates osteoblast differentiation and inhibits bone-resorbing mediators in MC3T3-E1 cells. AB - Apocynin is a naturally occurring methoxy-substituted catechol, experimentally used as an inhibitor of NADPH-oxidase. In the present study, the effect of apocynin on the function of osteoblastic MC3T3-E1 cells was studied. Apocynin caused a significant elevation of alkaline phosphatase (ALP) activity, collagen content, and mineralization in the cells (P<0.05). Antimycin A (AMA), which inhibits complex III of the electron transport system, has been used as a reactive oxygen species (ROS) generator in biological systems. We exposed cultured osteoblastic MC3T3-E1 cells to AMA with or without pretreatment with apocynin. Apocynin significantly (P<0.05) increased cell survival, calcium deposition, and osteoprotegerin release and decreased the production of ROS and osteoclast differentiation inducing factors such as TNF-alpha, IL-6, and receptor activator of nuclear factor-kB ligand (RANKL) in the presence of AMA. These results demonstrate that apocynin can protect osteoblasts from mitochondrial dysfunction-induced toxicity and may have positive effects on skeletal structure. PMID- 21683947 TI - Multidimensional scaling of emotional responses to music in patients with temporal lobe resection. AB - The present study investigated emotional responses to music by using multidimensional scaling (MDS) analysis in patients with right or left medial temporal lobe (MTL) lesions and matched normal controls (NC). Participants were required to evaluate emotional dissimilarities of nine musical excerpts that were selected to express graduated changes along the valence and arousal dimensions. For this purpose, they rated dissimilarity between pairs of stimuli on an eight point scale and the resulting matrices were submitted to an MDS analysis. The results showed that patients did not differ from NC participants in evaluating emotional feelings induced by the musical excerpts, suggesting that all participants were able to distinguish refined emotions. We concluded that the ability to detect and use emotional valence and arousal when making dissimilarity judgments was not strongly impaired by a right or left MTL lesion. This finding has important clinical implications and is discussed in light of current neuropsychological studies on emotion. It suggests that emotional responses to music can be at least partially preserved at a non-verbal level in patients with unilateral temporal lobe damage including the amygdala. PMID- 21683948 TI - Modality-specific alterations in the perception of emotional stimuli in Bipolar Disorder compared to Healthy Controls and Major Depressive Disorder. AB - OBJECTIVES: Affect identification accuracy paradigms have increasingly been utilized to understand psychiatric illness including Bipolar Disorder (BD) and Major Depressive Disorder (MDD). This investigation focused on perceptual accuracy in affect identification in both visual and auditory domains among patients with BD, relative to Healthy Controls (HC) and patients with MDD. Demographic and clinical variables, in addition to medications were also investigated. METHOD: The visual Facial Emotion Perception Test (FEPT) and auditory Emotional Perception Test (EPT) were administered to adults with BD (n=119) and MDD (n=78) as well as HC (n=66). RESULTS: Performance on the FEPT was significantly stronger than on the EPT irrespective of group. Performance on the EPT did not significantly differentiate the groups. On the FEPT, BD samples had the greatest difficulty relative to HC in identification of sad and fearful faces. BD participants also had greater difficulty identifying sad faces relative to MDD participants though not after controlling for severity of illness factors. For the BD (but not MDD) sample several clinical variables were also correlated with FEPT performance. CONCLUSIONS: The findings suggest that disruptions in identification of negative emotions such as sadness and fear may be a characteristic trait of BD. However, this effect may be moderated by greater illness severity found in our BD sample. PMID- 21683949 TI - The inhibitory effect of celecoxib and rosiglitazone on experimental endometriosis. AB - OBJECTIVE: To evaluate the effects of celecoxib and rosiglitazone on the implantation and growth of endometriotic-like lesions in a murine model of endometriosis. DESIGN: Prospective experimental study. SETTING: Animal research and laboratory facility. ANIMAL(S): Two-month-old female BALB/c mice. INTERVENTION(S): Surgically induced endometriosis in female BALB/C mice; 28 days of treatment with celecoxib, rosiglitazone, or their combination; counting, measuring, excising, and fixing lesions. MAIN OUTCOME MEASURE(S): Immunohistochemical examination for proliferating cell nuclear antigen (PCNA), CD31, and CD34 to assess cell proliferation and vascularization, with the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) technique for apoptosis evaluation. RESULT(S): Celecoxib and the combined treatment (celecoxib and rosiglitazone) statistically significantly reduced the mean number of lesions established per mouse, and all treatments diminished the implant volume. In addition, cell proliferation within the implants was statistically significantly reduced, and apoptosis was statistically significantly enhanced by all treatments. Also, we found that all treatments diminished the vascularized area in the lesion. CONCLUSION(S): These results are promising and reveal that celecoxib and rosiglitazone, combined or separately, have a beneficial effect on overall endometriotic growth. PMID- 21683951 TI - Prevalence of physical activity among healthy pregnant women in Ireland. PMID- 21683950 TI - Inherited mutation of the luteinizing hormone/choriogonadotropin receptor (LHCGR) in empty follicle syndrome. AB - OBJECTIVE: To test by genomic analysis whether empty follicle syndrome (EFS) in a family with two affected sisters has a genetic basis. DESIGN: Whole-exome sequencing in the context of clinical genetics. SETTING: University hospital. PATIENT(S): Two women (36 and 32 years old at the time of the study) with EFS. INTERVENTION(S): Genetic counseling based on autosomal recessive inheritance. MAIN OUTCOME MEASURE(S): Discovery of a mutation in the LH/choriogonadotropin receptor (LHCGR) as the cause of EFS. RESULT(S): A novel missense mutation in LHCGR, p.N400S, was homozygous in sisters with EFS and/or infertility, but not in their unaffected siblings or parents. The mutation was not present in 500 ancestry-matched control subjects. Asparagine at residue 400 is highly conserved and its substitution by serine predicted to alter critical interactions that stabilize LHCGR. CONCLUSION(S): We describe a genetic basis for EFS and provide strong evidence for the existence of genuine EFS in some patients. A mutation impairing the function of LHCGR explains the lack of response of these patients to repeated administration of beta-hCG. PMID- 21683952 TI - Forced and coerced sterilization of women in Europe. AB - Human rights provisions in laws set by international treaties and national legislatures make individuals' informed and freely given consent a precondition to the legality of their sterilization. Nevertheless, evidence shows that sterilizations have been undertaken by forceful means or coerced acceptance, to which women do not genuinely consent. The women are often members of ethnic minorities in their countries, such as Roma women, or adolescent or disabled women. Some European governments have acknowledged their responsibility for human rights abuses by forced and coerced sterilization of vulnerable women, and committees established by international human rights treaties to monitor states' compliance with their standards are increasingly vigilant to expose and condemn wrongful sterilization. For instance, the committee monitoring compliance with the Convention on the Elimination of All Forms of Discrimination against Women and the Council of Europe's Commissioner for Human Rights provide guidance for the prevention of violations. PMID- 21683953 TI - Effect of age and stage of endometriosis on ovarian follicular loss during laparoscopic cystectomy for endometrioma. AB - OBJECTIVE: To identify the risk factors associated with inadvertent follicular loss during laparoscopic cystectomy for endometrioma. METHODS: Between April 2008 and April 2010, 114 patients who underwent laparoscopic cystectomy for endometrioma were enrolled in the study. Clinical data were collected, together with a retrospective review of medical records. Ovarian follicular loss and the thickness of the cystic wall removed were evaluated by pathologic slide review. RESULTS: Ovarian follicular loss was more frequently observed among younger patients (P < 0.001) and those with stage 3 endometriosis than among those with stage 4 (P = 0.027), in addition to having an inverse correlation with age (P < 0.001). The thickness of the removed ovarian tissue correlated with inadvertent follicular loss (P < 0.001); however, there was no correlation between any clinical parameter tested and the thickness of the removed ovarian tissue. There was a correlation between ovarian follicular loss and the thickness of the removed ovarian tissue among patients younger than 40 years (P < 0.001), but not among patients aged 40 years or older (P = 0.123). CONCLUSION: Ovarian follicular loss was more common among younger patients and patients with lower-stage endometriosis. The thickness of the removed ovarian tissue did not differ among patients, despite varying clinical factors. PMID- 21683954 TI - Forkhead box protein P1 as a downstream target of transforming growth factor-beta induces collagen synthesis and correlates with a more stable plaque phenotype. AB - OBJECTIVE: Atherosclerosis is an inflammatory disease, modulated by plaque stabilizing and de-stabilizing cell populations such as infiltrating monocytes and vascular smooth muscle cells (vSMCs). Transcription factors regulating proliferation and differentiation of atherosclerosis relevant cell types are of interest in this context. The forkhead box transcription factor FoxP1 modulates monocyte differentiation. We studied FoxP1 expression in atherosclerotic tissue, correlated FoxP1 expression with plaque characteristics and identified associations between FoxP1 and plaque proteins. METHODS: 116 Atherosclerotic plaques from carotid endarterectomy samples were histologically classified (fibrous, fibroatheromatous, atheromatous) and subjected to semi-quantitative protein analysis. Macrophage, SMC content and intraplaque thrombus amount were determined histologically. FoxP1 expression was investigated by western blotting and immunohistochemistry. In addition FoxP1 was overexpressed in vitro to identify causal relations between FoxP1 and plaque proteins. RESULTS: FoxP1 expression was observed in SMCs, macrophages, endothelial cells and T-cells within the plaque. High SMC and collagen content correlated with increased FoxP1 isoform (72 kD and 95 kD) levels. 72 kD FoxP1 expression was lower in plaques containing intraplaque thrombus. FoxP1 correlated with active intraplaque TGFbeta signaling. In vitro stimulation of SMCs with TGFbeta resulted in increased FoxP1 levels. 72 kD FoxP1 correlated with expression of pro-fibrotic EGR-1 and increased Col1A1 expression. CONCLUSION: FoxP1 is expressed by different cell types in atherosclerotic lesions and associated with more stable plaque characteristics and intraplaque TGFbeta signaling. FoxP1 expression in vitro is induced by TGFbeta, resulting in increased collagen and EGR-1 expression, providing a mechanism for the observed association with a more stable plaque phenotype. PMID- 21683955 TI - High-performance liquid chromatography coupled to direct analysis in real time mass spectrometry: investigations on gradient elution and influence of complex matrices on signal intensities. AB - Direct analysis in real time (DART) time-of-flight mass spectrometry (TOF-MS) has been tested for its suitability as a detector for gradient elution HPLC. Thereby a strong dependency of signal intensity on the amount of organic solvent present in the eluent could be observed. Adding a make-up liquid (iso-propanol) post column to the HPLC effluent greatly enhanced detection limits for early eluting compounds. Limits of detection achieved employing this approach were in the range of 7-27 MUg L(-1) for the parabene test mixture and 15-87 MUg L(-1) for the pharmaceuticals. In further investigations DART ionization was compared to several other widely used atmospheric pressure ionization methods with respect to signal suppression phenomena occurring in when samples with problematic matrices are analyzed. For this purpose extracts from environmental and waste water samples were selected as model matrices which were subsequently spiked with a set of six substances commonly present in personal care products as well as six pharmaceuticals at concentration levels between 100 MUg L(-1) and 500 MUg L(-1) corresponding to 100 ng L(-1) and 500 ng L(-1) respectively in the original sample. With ionization suppression of less than 11% for most analytes investigated, DART ionization showed similar to even somewhat superior behavior compared to atmospheric pressure chemical ionization (APCI) and atmospheric pressure photo ionization (APPI) for the Danube river water extract; for the more challenging matrix of the sewage plant effluent extract DART provided better results with ion suppression being less than 11% for 9 out of 12 analytes while values for APCI were lying between 20% and >90%. Electrospray ionization (ESI) was much more affected by suppression effects than DART with values between 26% and 80% for Danube river water; in combination with the sewage plant effluent matrix suppression >50% was observed for all analytes. PMID- 21683956 TI - On-chip pre-concentration and complexation of [18F]fluoride ions via regenerable anion exchange particles for radiochemical synthesis of Positron Emission Tomography tracers. AB - Microfluidic approaches have demonstrated a relevant impact on radiochemical reactions involving Positron Emission Tomography (PET) nuclides, due to shorter reaction times and smaller precursor quantities. However, little attention has been given to the integration of the initial pre-concentration and drying of radioactive [(18)F]fluoride ions, required for the labeling of radiotracer compounds. In this work we report the design, fabrication and implementation of a glass microfluidic device filled with recyclable anion exchange particles for the repeated recovery of [(18)F] and [(19)F]fluoride ions. The device was first tested with non radioactive [(19)F]fluoride ions and it was shown to repeatedly trap and elute >95% fluoride over 40 successive experimental runs with no decrease in efficiency. The same device was then tested for the trapping and release of [(18)F]fluoride ions over 20 experiments with no measurable decrease in performance. Finally, the [(18)F]fluoride ions were eluted as a K(18)F/K2.2.2 complex, dried by repeated dissolution in acetonitrile and evaporation of residual water, and reacted with ethyl ditosylate (EtDT) leading to the desired product ([(18)F]fluoroethyltosylate) with 96 +/- 3% yield (RCY). The overall time needed for conditioning, trapping, elution and regeneration was less than 6 min. This approach will be of great benefit towards an integrated platform able to perform faster and safer radiochemical synthesis on the micro-scale. PMID- 21683957 TI - Evaluating the solvation properties of functionalized ionic liquids with varied cation/anion composition using the solvation parameter model. AB - Ionic liquids (ILs) are promising gas chromatography (GC) stationary phases due to their high thermal stability, negligible vapor pressure, and ability to solvate a broad range of analytes. The tunability of ILs allows for structure modification in pursuit of enhanced separation selectivity and control of analyte elution order. In this study, the solvation parameter model is used to characterize the solvation interactions of fifteen ILs containing various cationic functional groups (i.e., dimethylamino, hydroxyl, and ether) and cation types paired with various counter anions, namely, tris(pentafluoroethyl)trifluorophosphate (FAP(-)), bis[(trifluoromethyl)sulfonyl]imide (NTf(2)(-)), thiocyanate (SCN(-)), tricyanomethide (C(CN)(3)(-)), tetracyanoborate (B(CN)(4)(-)), and bis[oxalate(2 )]borate (BOB(-)). The presence of functional groups affected the hydrogen bond basicity, hydrogen bond acidity, as well as dispersion interactions of the resulting ILs, while the change of cation type yielded modest influence on the dipolarity. The switch of counter anions in unfunctionalized ILs produced compounds with higher dipolarity and hydrogen bond basicity. The dipolarity and hydrogen bond basicity of ILs possessing cyano-containing anions appeared to be inversely proportional to the cyano content of the anion. The modification of IL structure resulted in a significant effect on the retention behavior as well as separation selectivity for many solutes, including reversed elution orders of some analytes. This study provides one of the most comprehensive examinations up to-date on the relation between IL structure and the resulting solvation characteristics and gives tremendous insight into choosing suitable ILs as GC stationary phases for solute specific separations. PMID- 21683958 TI - Coordination of executive functions in monolingual and bilingual children. AB - Two groups of 8-year-old children who were monolingual or bilingual completed a complex classification task in which they made semantic judgments on stimuli that were presented either visually or auditorily. The task requires coordinating a variety of executive control components, specifically working memory, inhibition, and shifting. When each of the visual and auditory tasks was presented alone, performance was comparable for children in the two groups. Combining the two modalities into a dual-task paradigm made the task more difficult, and on this combined task bilingual children maintained better accuracy than monolingual children, especially on the visual task. The results are interpreted in terms of the enhanced ability of bilingual children to coordinate the executive control components required in performing this complex task. PMID- 21683959 TI - Disseminated skin manifestations in a neonate with incontinentia pigmenti. PMID- 21683961 TI - Trajectory and predictors of depression in a 12-month prospective study after the Madrid March 11 terrorist attacks. AB - BACKGROUND: Few longitudinal studies have examined the trajectory of and the risk factors for depression in a representative sample of the population exposed to terrorism. A 12 month prospective study was conducted among a sample of Madrid city residents after the March 11, 2004 terrorist attacks. We aimed to document the trajectories of depressive symptoms and determine the risk factors associated with these trajectories. METHODS: We conducted telephone surveys among a representative sample of Madrid citizens (N = 1589) to recruit baseline respondents approximately 1 month after the March 11 terrorist attacks. Participants were re-contacted at 6 and 12 months after baseline for further telephone interviews. RESULTS: Findings reveal heterogeneity in the longitudinal trajectories of depression ranging from the absence of depressive symptoms over time, to transient or chronic depression. Life and recent stressors, experiencing direct exposure to the attacks, personality traits, poor physical health and other psychological disorders were principally associated with a worse trajectory of depression after this event. CONCLUSIONS: Consistent with a stress diathesis model, ongoing stressors and intense event exposure are key drivers of a chronic depression trajectory after a mass traumatic event. PMID- 21683960 TI - High level of persistence of pediatric bipolar-I disorder from childhood onto adolescent years: a four year prospective longitudinal follow-up study. AB - OBJECTIVE: To examine the longitudinal course of pediatric bipolar (BP)-I disorder in youth transitioning from childhood into adolescence. METHODS: We conducted a four year prospective follow-up study of 78 youth with BP-I disorder 6-17 years old at ascertainment followed up into adolescent years (13.4 +/- 3.9 years). All subjects were comprehensively assessed with structured diagnostic interviews, neuropsychological testing, psychosocial, educational and treatment history assessments. BP disorder was considered persistent if subjects met full criteria for DSM-IV BP-I disorder at follow-up. RESULTS: Of 78 BP-I participating youth subjects, 57 (73.1%), continued to meet full diagnostic criteria for BP-I Disorder. Of those with a non-persistent course, only 6.4% (n = 5) were euthymic (i.e., syndromatic and symptomatic remission) at the 4-year follow-up and were not receiving pharmacotherapy for the disorder. The other non-persistent cases either continued to have subthreshold BP-I disorder (n = 5, 6.4%), met full (n = 3, 3.8%) or subthreshold (n = 1, 1.3%) criteria for major depression, or were euthymic but were treated for the disorder (n = 7, 9.0%). Full persistence was associated with higher rates of major depression and disruptive behavior disorders at the follow-up assessment and higher use of stimulant medicines at the baseline assessment. Non-Peristent BP-I was also characterized by high levels of dysfunction and morbidity. CONCLUSIONS: This four year follow-up shows that the majority of BP-I disorder youth continue to experience persistent disorder into their mid and late adolescent years and its persistence is associated with high levels of morbidity and disability. Persistence of subsyndromal forms of bipolar disorder was also associated with dysfunction and morbidity. PMID- 21683962 TI - Up-regulation of major vault protein in the frontal cortex of patients with intractable frontal lobe epilepsy. AB - Major vault protein (MVP) is a vesicular drug transporter and may participate in multidrug resistance (MDR). The aim of this study was to determine the expression and cellular localization of MVP in refractory frontal lobe epilepsy (FLE). We detected MVP expression in tissue samples from the refractory frontal cortex of 30 patients who had been surgically treated for refractory epilepsy. We compared these tissues with twelve histologically normal frontal lobe samples from controls. In the control group, the expression of MVP was faint in the cortex. The expression of MVP protein increased dramatically in the refractory epilepsy group; MVP immunoreactivity (IR) was observed in the cytoplasm of neurons. Thus, MVP protein was increased in the frontal cortex of patients with refractory epilepsy. Further research is necessary to determine whether or not MVP plays a role in the mechanisms underlying drug resistance in refractory FLE. PMID- 21683963 TI - Alpha- and beta-synuclein expression in Parkinson disease with and without dementia. AB - Parkinson disease (PD) is the most important movement disorder and about 50% of patients develop dementia over the time. PD belongs to the group of Lewy body disorders. Alpha-synuclein (AS) is the main component of Lewy bodies and its aggregation is a key event in the pathogenesis of PD. Beta-synuclein (BS) inhibits AS aggregation in vitro and in vivo and has been shown to interact directly with AS regulating its functionality and preventing its oligomerization. Recently, we have described a molecular subgroup of DLB characterized by the drastic BS reduction in cortical areas. In this study we have analyzed the expression of two BS transcripts and the main AS transcript SNCA140, in frozen samples of three brain areas, temporal cortex, caudate nucleus and pons, from patients with PD and PDD in comparison with controls. Relative mRNA expression was determined by real-time PCR with SybrGreen, neuron-specific-enolase as housekeeping gene and the deltadeltaCt method. The most important difference in BS and AS mRNA expression between PD and PDD was found in the caudate nucleus, where BS mRNA was overexpressed in PD and AS mRNA diminished in PDD. Our findings provide new insights into the pathogenesis of dementia in PD, indicating that differential BS and AS expression in the caudate nucleus may represent one of the molecular mechanisms involved in these complex diseases. PMID- 21683965 TI - Results of matching valve and root repair to aortic valve and root pathology. AB - OBJECTIVE: For patients with aortic root pathology and aortic valve regurgitation, aortic valve replacement is problematic because no durable bioprosthesis exists, and mechanical valves require lifetime anticoagulation. This study sought to assess outcomes of combined aortic valve and root repair, including comparison with matched bioprosthesis aortic valve replacement. METHODS: From November 1990 to January 2005, 366 patients underwent modified David reimplantation (n = 72), root remodeling (n = 72), or valve repair with sinotubular junction tailoring (n = 222). Active follow-up was 99% complete, with a mean of 5.6 +/- 4.0 years (maximum 17 years); follow-up for vital status averaged 8.5 +/- 3.6 years (maximum 19 years). Propensity-adjusted models were developed for fair comparison of outcomes. RESULTS: Thirty-day and 5-, 10-, and 15-year survivals were 98%, 86%, 74%, and 58%, respectively, similar to that of the US matched population and better than that after bioprosthesis aortic valve replacement. Propensity-score-adjusted survival was similar across procedures (P > .3). Freedom from reoperation at 30 days and 5 and 10 years was 99%, 92%, and 89%, respectively, and was similar across procedures (P > .3) after propensity score adjustment. Patients with tricuspid aortic valves were more likely to be free of reoperation than those with bicuspid valves at 10 years (93% vs 77%, P = .002), equivalent to bioprosthesis aortic valve replacement and superior after 12 years. Bioprostheses increasingly deteriorated after 7 years, and hazard functions for reoperation crossed at 7 years. CONCLUSIONS: Valve preservation (rather than replacement) and matching root procedures have excellent early and long-term results, with increasing survival benefit at 7 years and fewer reoperations by 12 years. We recommend this procedure for experienced surgical teams. PMID- 21683964 TI - Impulsivity and Parkinson's disease: more than just disinhibition. AB - In the last few years it has become clear that impulsivity is a complex behaviour composed of different domains and dependent on different neural networks. The proposed pathogenetic mechanisms for the emergence of impulsivity disorders in Parkinson's Disease (PD) can be broadly separated into three potentially interacting processes: the contribution of premorbid susceptibility to impulsivity, the contribution of the disease itself to the behaviour and the potential contribution of therapeutic agents. Growing evidence suggests that dopamine and the subthalamic nucleus are playing a certain role in the pathophysiology of different aspects of impulsivity. In this review, we summarise the main concepts defining various components of impulsivity both in healthy subjects and patients affected by PD. PMID- 21683967 TI - Eutrophication assessment of the Baltic Sea Protected Areas by available data and GIS technologies. AB - Concerning increased degradation of marine ecosystems, there is a great political and institutional demand for an array of different tools to restore a good environmental status. Thereby, eutrophication is acknowledged as one of the major human induced stressors which has to be monitored and reduced. The present study concentrates on an assessment of the eutrophication status of the Baltic Sea Protected Areas by use of available data and GIS technologies. Two geodata layers were used for analysis: (1) a map on the eutrophication status of the Baltic Sea generated by the Helsinki Commission applying the HELCOM Eutrophication Assessment Tool (HEAT), and (2) modelled data on atmospheric nitrogen deposition made available by the European Monitoring and Evaluation Programme (EMEP). The results yielded comprehensive and conclusive data indicating that most of the BSPAs may be classified as being 'affected by eutrophication' and underlining the need to decrease the overall emissions of nutrients. PMID- 21683968 TI - Perfluorinated compounds in estuarine and coastal areas of north Bohai Sea, China. AB - Perfluorinated compounds (PFCs) in water, sediment, soil, and biota collected from estuarine and coastal areas of the north Bohai Sea, China, were determined by use of HPLC-MS/MS. Significant concentrations of PFCs were found in water (mean: 18.4 ng/l) and biologic samples (fish: 265 ng/g dw), while concentrations of PFCs in soils and sediments were less. The predominately detected compound was perfluorooctanesulfonate (PFOS), with a maximum concentration of 30.9 ng/l in water and 791 ng/g dw in fish. Concentrations of PFCs were significantly greater in the Liaohe River system than other locations, which suggests point sources in this urbanized and industrialized region. PFOS concentrations in water and biota were both less than the reported threshold concentrations. Detection of PFCs at relatively great concentrations in various environmental matrices from this region suggested that further studies characterizing concentrations of PFCs, their sources and potential risk to both humans and wildlife are needed. PMID- 21683969 TI - Progress in molecular typing of Mycobacterium avium subspecies paratuberculosis. AB - Mycobacterium avium subspecies paratuberculosis (M. a. paratuberculosis) is responsible for paratuberculosis or Johne's disease, a chronic inflammation of the gastrointestinal tract in different animal species. Some studies have also established a link between this microorganism and Crohn's disease in humans. Although, M. a. paratuberculosis is a difficult microorganism to cultivate in the laboratory (occasionally is non-cultivable), a proper molecular characterization of M. a. paratuberculosis is necessary to better understand the epidemiology of the disease, and design strategies to eradicate it. In the present review, we compile and discuss the recent progress attained in the diagnostic and characterization of this pathogen. PMID- 21683970 TI - [Free floating thrombus on carotid megabulb or suspended bulb: what kind of dysplasia?]. AB - Floating carotid thrombi are a rare cause of stroke mostly associated with atheromatous plaques, cardiogenic emboli, arterial dissections and systemic diseases related to coagulopathic states or iron deficiency anaemia. We report the cases of two patients with stroke and carotid megabulb or suspended bulb associated with floating thrombus. These findings are rarely described probably related to a form of arterial dysplasia and seem to be responsible of local haemodynamic modifications. PMID- 21683971 TI - Parametric model of the BAW resonator phase-noise. AB - Excepted for the very short terms the frequency stability of ultra-stable oscillators is mainly limited by the resonator noise. In this work we proposed a parametric model of the bulk acoustic wave (BAW) resonator phase noise based on an equivalent circuit. This model explains phase noise generated by a BAW crystal from a point of view of parametric fluctuations and proves the f(-1) dependences of the crystal noise. The model performance is verified with simulation. Simulation results are compared to experimental data and discussed. Comparison of three existing models is made. PMID- 21683972 TI - A fast tissue stiffness-dependent elastography for HIFU-induced lesions inspection. AB - To monitor HIFU-induced lesion with elastography in quasi-real time, a fast correlation based elastographic algorithm using tissue stiffness-dependent displacement estimation (SdDE) is developed in this paper. The high time efficiency of the proposed method contributes to the reduction on both the number of the displacement points and the computational time of most of the points by utilizing local uniformity of the tissue under HIFU treatment. To obtain admirable comprehensive performance, the key algorithm parameter, a threshold to densify the displacement points, is optimized with simulation over a wedge inclusion tissue model by compromising the axial resolution (AR) and the computational cost. With the optimum parameter, results from both simulations and phantom experiments show that the SdDE is faster in about one order of magnitude than the traditional correlation based algorithm. At the same time, other performance parameters, such as the signal-to-noise ratio (SNRe), the contrast-to noise ratio (CNRe) and the axial resolution (AR), are superior to or comparable with that obtained from the traditional algorithm. In vitro experiments on bovine livers validate the improvement on the time efficiency under the circumstances of real tissue and real radio frequency (RF) signal. This preliminary work implies potential of the SdDE in dynamic or close real time guidance and monitoring of HIFU treatment. PMID- 21683973 TI - Transgenic expression of full-length 2',5'-oligoadenylate synthetase 1b confers to BALB/c mice resistance against West Nile virus-induced encephalitis. AB - Susceptibility of inbred strains to infection with West Nile virus (WNV) has been genetically associated with an arginine-to-a nonsense codon substitution at position 253 (R253X) in the predicted sequence of the murine 2',5'-oligoadenylate synthetase 1B (OAS1B) protein. We introduced by transgenesis the Oas1b cDNA from MBT/Pas mice carrying the R253 codon (Oas1b(MBT)) into BALB/c mice homozygous for the X253 allele (Oas1b(BALB/c)). Overexpression of Oas1b(MBT) mRNA in the brain of transgenic mice prior and in the time course of infection provided protection against the neuroinvasive WNV strain IS-98-ST1. A 200-fold induction of Oas1b(MBT) mRNA in the brain of congenic BALB/c mice homozygous for a MBT/Pas segment encompassing the Oas1b gene was also efficient in reducing both viral growth and mortality, whereas a 200-fold induction of Oas1b(BALB/c) mRNA was unable to prevent virally-induced encephalitis, confirming the critical role of the R253X mutation on Oas1b activity in live mice. PMID- 21683974 TI - Synergistic effect of nickel ions on the coupled dechlorination of trichloroethylene and 2,4-dichlorophenol by Fe/TiO2 nanocomposites in the presence of UV light under anoxic conditions. AB - The coupled removal of priority pollutants by nanocomposite materials has recently been receiving much attention. In this study, trichloroethylene (TCE) and 2,4-dichlorophenol (DCP) in aqueous solutions were simultaneously removed by Fe/TiO2 nanocomposites under anoxic conditions in the presence of nickel ions and UV light at 365 nm. Both TCE and DCP were effectively dechlorinated by Fe/TiO2 nanocomposites, and the pseudo-first-order rate constants (k(obs)) for TCE and DCP dechlorination were (1.39 +/- 0.05)*10-2 and (1.08 +/- 0.05)*10-2 h-1, respectively, which were higher than that by nanoscale zerovalent iron alone. In addition, the k(obs) for DCP dechlorination was enhanced by a factor of 77 when Fe/TiO2 was illuminated with UV light for 2 h. Hydrodechlorination was found to be the major reaction pathway for TCE dechlorination, while DCP could undergo reductive dechlorination or react with hydroxyl radicals to produce 1,4 benzoquinone and phenol. TCE was a stronger electron acceptor than DCP, which could inhibit the dechlorination efficiency and rate of DCP during simultaneous removal processes. The addition of nickel ions significantly enhanced the simultaneous photodechlorination efficiency of TCE and DCP under the illumination of UV light. The k(obs) values for DCP and TCE photodechlorination by Fe/TiO2 in the presence of 20-100 MUM Ni(II) were 30.4-136 and 13.2-192 times greater, respectively, when compared with those in the dark. Electron spin resonance analysis showed that the photo-generated electron-hole pairs could be effectively separated through Ni ions cycling, leading to the improvement of electron transfer efficiency of TCE and DCP by Fe/TiO2. PMID- 21683975 TI - Effect of two simultaneous aza-beta3-amino acid substitutions on recognition of peptide substrates by cAMP dependent protein kinase catalytic subunit. AB - Peptidomimetic analogs of the hexapeptide RRASVA, containing simultaneously two aza-beta(3)-amino acid residues in different positions of this sequence, except for the phosphorylatable serine residue, were synthesized and tested as substrates for the cAMP-dependent protein kinase catalytic subunit. All these peptidomimetics were phosphorylated by the enzyme and this reaction was characterized by the K(m) and k(cat) values as well as by the second-order rate constants k(II). Affinity and reactivity of all peptidomimetics was lower than that for the parent peptide RRASVA. The effect of backbone modification was dependent upon the positions where these two aza-beta(3) residues were located, although the sequence of amino acid side groups remained the same in all compounds. It was found that the influence of two backbone modifications in the substrate structure was not described additively, i.e. the effect of each structural alteration was dependent upon the position of the second modification. The results were in agreement with the concept of specificity-determining clusters in the sequence of peptide and peptidomimetic ligands, which predominantly determine the molecular recognition of these ligands by their target sites and therefore serve as major modification points for the design of activity of peptidomimetic ligands. PMID- 21683976 TI - Biochemical biomarkers in Nile tilapia (Oreochromis niloticus) after short-term exposure to diesel oil, pure biodiesel and biodiesel blends. AB - Fossil fuels such as diesel are being gradually replaced by biodiesel, a renewable energy source, cheaper and less polluting. However, little is known about the toxic effects of this new energy source on aquatic organisms. Thus, we evaluated biochemical biomarkers related to oxidative stress in Nile tilapia (Oreochromis niloticus) after two and seven exposure days to diesel and pure biodiesel (B100) and blends B5 and B20 at concentrations of 0.01 and 0.1 mL L( 1). The hepatic ethoxyresorufin-O-deethylase activity was highly induced in all groups, except for those animals exposed to B100. There was an increase in lipid peroxidation in liver and gills in the group exposed to the higher concentration of B5. All treatments caused a significant increase in the levels of 1 hydroxypyrene excreted in the bile after 2 and 7d, except for those fish exposed to B100. The hepatic glutathione-S-transferase increased after 7d in animals exposed to the higher concentration of diesel and in the gill of fish exposed to the higher concentration of pure diesel and B5, but decreased for the two tested concentrations of B100. Superoxide dismutase, catalase and glutathione peroxidase also presented significant changes according to the treatments for all groups, including B100. Biodiesel B20 in the conditions tested had fewer adverse effects than diesel and B5 for the Nile tilapia, and can be suggested as a less harmful fuel in substitution to diesel. However, even B100 could activate biochemical responses in fish, at the experimental conditions tested, indicating that this fuel can also represent a risk to the aquatic biota. PMID- 21683977 TI - Epstein-Barr virus-positive T-cell lymphoma cells having chromosome 22q11.2 deletion: an autopsy report of DiGeorge syndrome. AB - Reported herein was the first autopsy case of Epstein-Barr virus-associated T cell lymphoma in a 25-year-old man with DiGeorge syndrome. Systemic lymph nodes demonstrated diffuse encasement by large lymphoma cells positive for CD45, CD2, CD3, CD5, CD7, CD8, TIA1, and granzyme B, accompanied with marked hemophagocytosis. Almost 100% of lymphoma cells were both EBER- and LMP-1 positive, and EBNA2-negative. The rearrangement of T-cell receptor beta gene was proved by polymerase chain reaction. Clinical and pathologic features coincided with Epstein-Barr virus-associated T/NK-cell lymphoproliferative disorder preceded by chronic active Epstein-Barr virus infection. A fluorescence in situ hybridization using paraffin-embedded tissues demonstrated a mosaic chromosome 22q11.2 deletion with both host cardiac myocytes and lymphoma cells, suggesting that Epstein-Barr virus-associated T-cell lymphoma was associated with and derived from the cells carrying the chromosomal abnormality. Furthermore, the lymphomagenesis of our case correlated with defect of cellular immunity in DiGeorge syndrome. PMID- 21683978 TI - Hepatosplenic T-cell lymphoma: clinicopathologic, immunophenotypic, and molecular characterization of 17 Chinese cases. AB - Hepatosplenic T-cell lymphoma is a highly aggressive tumor with a poor outcome. About 210 cases were identified through PubMed, of which fewer than 20 originated in Asia. We reviewed 17 Chinese cases of hepatosplenic T-cell lymphoma, including an unusual one with cutaneous pink papules, for clinicopathologic, immunophenotypic, and genotypic features; Epstein-Barr virus status; treatment; and outcome. The median age of the patients was 23 years. All patients had splenomegaly, and 88.2% of them had hepatomegaly as well. Bone marrow involvement was present in 53.3%. Eleven patients underwent splenectomy for diagnosis and treatment. Twelve specimens were collected by image-guided liver core biopsy or wedge resection. Histologically, the homogeneous small- to medium-size neoplastic lymphoid cells infiltrated the sinuses or sinusoids of the spleen, bone marrow, and liver. Diagnosis was based on image-guided core-needle biopsy of the liver alone in 41.2% of the cases. Immunohistochemically, 15 of the lesions were hepatosplenic gammadelta T-cell lymphoma, and the remaining 2 were hepatosplenic alphabeta T-cell lymphoma. Epstein-Barr virus was detected in both cases of hepatosplenic alphabeta T-cell lymphoma and one case of hepatosplenic gammadelta T-cell lymphoma. Most of the patients received cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or regimens similar to it. Follow-up data were available in 70.6% of the patients; half of them died of the tumor, and the median survival time was 6 months. The frequency of bone marrow involvement was lower than that reported in the literature. Image-guided core-needle biopsy of the liver is recommended for diagnosis. PMID- 21683979 TI - Illumina whole-genome complementary DNA-mediated annealing, selection, extension and ligation platform: assessing its performance in formalin-fixed, paraffin embedded samples and identifying invasion pattern-related genes in oral squamous cell carcinoma. AB - High-throughput gene expression profiling from formalin-fixed, paraffin-embedded tissues has become a reality, and several methods are now commercially available. The Illumina whole-genome complementary DNA-mediated annealing, selection, extension and ligation assay (Illumina, Inc) is a full-transcriptome version of the original 512-gene complementary DNA-mediated annealing, selection, extension and ligation assay, allowing high-throughput profiling of 24,526 annotated genes from degraded and formalin-fixed, paraffin-embedded RNA. This assay has the potential to allow identification of novel gene signatures associated with clinical outcome using banked archival pathology specimen resources. We tested the reproducibility of the whole-genome complementary DNA-mediated annealing, selection, extension and ligation assay and its sensitivity for detecting differentially expressed genes in RNA extracted from matched fresh and formalin fixed, paraffin-embedded cells, after 1 and 13 months of storage, using the human breast cell lines MCF7 and MCF10A. Then, using tumor worst pattern of invasion as a classifier, 1 component of the "risk model," we selected 12 formalin-fixed, paraffin-embedded oral squamous cell carcinomas for whole-genome complementary DNA-mediated annealing, selection, extension and ligation assay analysis. We profiled 5 tumors with nonaggressive, nondispersed pattern of invasion, and 7 tumors with aggressive dispersed pattern of invasion and satellites scattered at least 1 mm apart. To minimize variability, the formalin-fixed, paraffin-embedded specimens were prepared from snap-frozen tissues, and RNA was obtained within 24 hours of fixation. One hundred four down-regulated genes and 72 up-regulated genes in tumors with aggressive dispersed pattern of invasion were identified. We performed quantitative reverse transcriptase polymerase chain reaction validation of 4 genes using Taqman assays and in situ protein detection of 1 gene by immunohistochemistry. Functional cluster analysis of genes up-regulated in tumors with aggressive pattern of invasion suggests presence of genes involved in cellular cytoarchitecture, some of which already associated with tumor invasion. Identification of these genes provides biologic rationale for our histologic classification, with regard to tumor invasion, and demonstrates that the whole genome complementary DNA-mediated annealing, selection, extension and ligation assay is a powerful assay for profiling degraded RNA from archived specimens when combined with quantitative reverse transcriptase polymerase chain reaction validation. PMID- 21683980 TI - Low activated leukocyte cell adhesion molecule expression is associated with advanced tumor stage and early prostate-specific antigen relapse in prostate cancer. AB - Activated leukocyte cell adhesion molecule (CD166) is a member of the immunoglobulin superfamily and is aberrantly expressed in different tumors, including prostate cancer. To learn more on the prevalence and clinical significance of activated leukocyte cell adhesion molecule expression in prostate cancer, a tissue microarray containing 3261 primary prostate cancers treated by radical prostatectomy was used. A total of 2390 different prostate cancers were analyzed by immunohistochemistry in a tissue microarray format. Activated leukocyte cell adhesion molecule immunostaining in cancers was compared with clinical follow-up, which was available for 1746 patients. Membranous activated leukocyte cell adhesion molecule immunostaining was recorded in 1663 (69.6%) of cases. High activated leukocyte cell adhesion molecule expression levels were significantly associated with favorable tumor features (pT: P = .0015; pN: P = .0008; preoperative prostate-specific antigen: P = .0057) and a lower risk of a biochemical recurrence (P = .0067). Cytoplasmatic activated leukocyte cell adhesion molecule staining was usually associated with membranous staining. The small number of cancers with pure cytoplasmatic staining did not reveal any particularities with respect to clinical outcome or tumor phenotype. It is concluded that activated leukocyte cell adhesion molecule protein is almost always expressed in prostate cancer and that decreased levels of activated leukocyte cell adhesion molecule expression may lead to an aggressive behavior of tumor cells. The abundant presence of activated leukocyte cell adhesion molecule and its membranous localization in prostate cancer epithelium make activated leukocyte cell adhesion molecule a potentially attractive structure for targeted therapy. PMID- 21683981 TI - Prognostic significance of mitotic figures in metastatic mammary ductal carcinoma to the lymph nodes. AB - We previously reported that the number of mitotic figures in metastatic mammary carcinoma to the lymph nodes accurately predicted the outcome of patients with invasive ductal carcinoma with nodal metastasis. To confirm these previous findings, the present study investigated the number of mitotic figures and other histologic characteristics in metastatic mammary carcinoma to the lymph nodes and their associations with patient outcome according to nodal status and the histologic grade of primary invasive ductal carcinomas in a different series of 1039 patients with invasive ductal carcinoma. Multivariate analyses examining well-known clinicopathologic factors, the number of mitotic figures in the primary invasive ductal carcinomas, the grading system for lymph vessel tumor emboli, the p53 Allred score risk classes of tumor-stromal fibroblasts forming and not forming a fibrotic focus, and 9 histologic features of metastatic mammary carcinoma to the lymph nodes were performed. The presence of 6 or more mitotic figures in metastatic mammary carcinoma to the lymph nodes significantly increased the hazard ratios for tumor recurrence and tumor-related death among patients with invasive ductal carcinoma as a whole, those with nodal metastasis, and those with a histologic grade of 2 or 3. The presence of 6 or more mitotic figures in metastatic mammary carcinoma to the lymph nodes also significantly increased the hazard ratio for tumor recurrence among patients with histologic grade 1 invasive ductal carcinoma. In conclusion, this study clearly confirmed the excellent outcome predictive power of the number of mitotic figures in metastatic mammary carcinoma to the lymph nodes. PMID- 21683982 TI - Multiple chromosomal monosomies are characteristic of giant cell ependymoma. AB - Giant cell ependymoma, a rare ependymoma subtype, was recently recognized as a separate diagnostic entity with variations both in malignant potential and course of disease. We analyzed the first supratentorial giant cell ependymoma using G band karyotyping, DNA ploidy analysis, and array comparative genomic hybridization. The tumor was hypodiploid, and the karyotype showed multiple monosomies. This novel cytogenetic pattern seems specific for giant cell ependymoma as the only previous cytogenetic analysis of a giant cell ependymoma found similar monosomies. We were also able to analyze cytogenetically the subsequent recurrent tumor, phenotypically an anaplastic ependymoma, allowing a first insight into the genetic events involved in disease progression. PMID- 21683983 TI - Limited smoothelin expression within the muscularis mucosae: validation in bladder diverticula. AB - Smoothelin, a marker of differentiated smooth muscle, is diffusely expressed by bladder muscularis propria and is negative to only weakly and focally expressed in muscularis mucosae. We used bladder diverticula, which lack muscularis propria and frequently demonstrate hyperplastic muscularis mucosae, to evaluate the use of smoothelin immunoreactivity in diagnostic pathology. Diverticula from 40 patients (21 with benign features, 19 with neoplastic features) were studied. Immunohistochemistry was performed using smoothelin antibody (clone R4A, 1:150 dilution; Abcam, Cambridge, MA); and tissue was scored as 0 (no expression), 1+ (moderate expression b10% of cells), 2+ expression (moderate expression N10% of cells), and 3+ (robust diffuse expression). All diverticula contained muscularis mucosae of varying caliber; staining in diverticular muscularis mucosae was compared with historic results in the muscularis mucosae of cystectomy specimens. Hyperplastic muscularis mucosae occurred in 31 (78%) of 40 cases. Smoothelin immunoreactivity in the diverticular muscularis mucosae included 0 (16/40, or 40%); 1+ (11/40, or 27.5%); 2+ (13/40, or 32.5%); and 3+ (0/40, or 0%), with a slightly higher 2+ expression level in hyperplastic versus nonhyperplastic muscularis mucosae (35% versus 22%). Adjacent normal muscularis propria, present in 12 specimens, demonstrated 3+ muscularis propria immunoreactivity. Comparison between diverticula with benign and neoplastic features showed no significant difference in smoothelin immunoreactivity. No correlation was evident with smoothelin immunohistochemistry and muscle caliber. Smoothelin immunoreactivity in bladder diverticula confirms the limited nature of smoothelin expression in the muscularis mucosae and represents a useful ancillary technique in the proper histopathologic evaluation of diverticular and nondiverticular bladder carcinomas. A strong and robust staining of smooth, rounded muscle with smoothelin remains a useful diagnostic adjunct in the reliable recognition of muscularis propria. PMID- 21683984 TI - Regenerating I messenger RNA and protein expression in the failing human testis: a potential molecular prognostic marker of seminoma. AB - Infertility has been stated as a risk factor for testicular cancer; but currently, there is no prognostic indicator of tumor development from the pathologic testis with impaired spermatogenesis. Regenerating proteins are expressed in many human tissues including the testis, and their role in carcinogenesis has been well documented. In the present work, regenerating I messenger RNA and protein expression and cellular protein localization were studied in testicular biopsies of patients with normal (obstructive azoospermia) or impaired spermatogenesis (nonobstructive azoospermia) and in seminoma testis by quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunofluorescence analyses. No significant differences in regenerating I transcripts were reported between the 3 groups studied. However, regenerating I protein was highly expressed in pure seminoma and in placental-like alkaline phosphatase-positive seminiferous tubules with in situ carcinoma. Regenerating I protein levels measured by Western blotting increased from the placental-like alkaline phosphatase-negative distal region of the seminoma to the pure placental like alkaline phosphatase-positive tumoral region. Importantly, although cells localized in seminiferous tubules of obstructive azoospermic patients with normal spermatogenesis were very slightly labeled, persisting germ, Sertoli, and myoid cells and fibrous tissues were strongly regenerating I positive in seminiferous tubules of nonobstructive azoospermia. These results suggest the possibility to use regenerating I as a prognostic marker of tumoral development in the infertile testis. PMID- 21683985 TI - Centrosome amplification as a putative prognostic biomarker for the classification of urothelial carcinomas. AB - Recent studies have reported that centrosome amplification is closely related to chromosomal instability and patient prognosis in human malignancies. The purpose of this study was to elucidate the relationship between centrosome amplification and genomic alterations in urothelial carcinomas. Centrosomes were evaluated by immunohistochemistry using anti-gamma-tubulin antibody. Array-based comparative genomic hybridization technology using DNA chips spotted with 4030 bacterial artificial chromosome clones was applied to 70 urothelial carcinomas to examine DNA copy number aberrations. Studying aberrations in the number of chromosomes 7, 9, and 17 using fluorescence in situ hybridization allowed the estimation of the degree of chromosomal instability. DNA copy number gains at 20p12.2, 5p15.2, 5p15.31, and 17q25.3 and losses at 17p12, 8p22, 2q37.3, 5q31.1, and 2q37.3 were more frequent in tumors with centrosome amplification than in those without it. The total numbers of DNA copy number aberrations and frequency of chromosomal instability were also larger in tumors with centrosome amplification than in those without it (P = .0263 and P < .0001, respectively). These parameters were more closely associated with centrosome amplification than with the subjectively assigned tumor grade (P = .0405 and P = .0020, respectively). Thus, these data suggest that centrosome amplification may have great potential as a biomarker for improved objective classification of urothelial carcinoma and estimation of prognosis. PMID- 21683987 TI - Distributed lag effects in the relationship between temperature and mortality in three major cities in South Korea. AB - In many cases, the effect of an environmental exposure event is not restricted to the period when it occurs. Understanding the extent to which high-temperature exposure hastens the occurrence of health outcomes is a key to interpreting public health risks correctly and developing appropriate intervention programs related to heat. We explored distributed lag effects in the relationship between high temperature and mortality in summer (June-August) in Seoul, Daegu, and Incheon, South Korea, from 1991 to 2008. A Poisson regression model adapted for time-series data was used to estimate short-term heat-related mortality impacts. To examine the distributed lag effects, we fitted a constrained distributed lag model that included lagged exposure variables as covariates, applying a function of days of lag according to B-spline bases. The effects on mortality caused by high-temperature exposure continued for about 5 days, and slight deficit effects after the initial mortality increases were observed, even if not initially apparent. Thirty days after high-temperature exposure, the cumulative effects were still high in Seoul and Incheon. This study shows a pattern of distributed lag effects of high-temperature exposure that the single-day model could not identify. Our results confirm that summer high temperature has an effect on mortality, not advancing the date of adverse events by a few days. Ultimately, it suggests that public health programs be amended to allow for differential high temperature effects spread over multiple days. PMID- 21683986 TI - Prenatal exposure to organochlorine pesticides and TSH status in newborns from Southern Spain. AB - OBJECTIVE: To investigate the association between prenatal exposure to organochlorine pesticides (OCPs) and thyroid-stimulating hormone (TSH) levels in male newborns. METHODS: Exposure to 17 OCPs was analyzed in 220 placentas from a male birth cohort in Southern Spain, and TSH was measured in the umbilical cord blood. OCP concentrations were quantified by gas chromatography and mass spectrometry. Multivariate regression analysis was conducted to examine the association between pesticide exposure and neonatal TSH levels, adjusting for confounders. RESULTS: Newborn boys with higher exposure to endrin in placenta had higher odds of TSH cord blood levels >= 5 mU/L (80th percentile) (OR=2.05; 95% CI=1.01, 4.18; p=0.05), whereas higher prenatal exposure to endosulfan-sulfate was associated with lower odds of TSH >= 5 mU/L (OR=0.36; 95% CI=0.17, 0.77; p=0.008). A marginally significant negative association was found between TSH and hexachlorobenzene levels (beta=-0.15; 95% CI=-0.31, 0.02; p=0.09), and exposure to p,p'-DDE showed a marginally-significant higher odds of TSH >= 5 mU/L (OR=1.32; 95% CI=0.95, 1.83; p=0.09). No association was found between TSH and the remaining pesticides. CONCLUSIONS: Early exposure to certain environmental chemicals with endocrine-disruption activity may interfere with neonatal thyroid hormone status; however, the pattern of interference is not yet clearly elucidated. PMID- 21683988 TI - Safety of coronary artery bypass surgery during therapeutic oral anticoagulation. AB - INTRODUCTION: Therapeutic (international normalized ratio, INR 2.0-3.5) oral anticoagulation (TOAC) is assumed to increase perioperative bleeding complications and a standard recommendation is to discontinue warfarin before coronary bypass grafting (CABG). MATERIALS AND METHODS: To assess the safety of TOAC we retrospectively analyzed consecutive patients (n=270) with long-term warfarin therapy referred for CABG in two centers where TOAC strategy is employed. The main in-hospital outcomes of interest were death, stroke, acute myocardial infarction, new onset renal failure, resternotomy, and their composite. In the TOAC group of 103 patients CABG was performed during therapeutic oral anticoagulation and in the control group (81 patients) preoperative INR was lowered to a subtherapeutic (<=1.5) level. RESULTS: The patients in TOAC group were more often operated on an emergency basis (p=0.02) and their EuroSCORE was higher (p=0.02). There were no significant differences in the major outcome events or their composite (17.5 vs. 11.1%, p=0.30) between the groups. Patients in the TOAC group had more postoperative blood loss (941+/-615 vs. 754+/-610 ml, p<0.01) and received more fresh frozen plasma (2.8+/-3.0 vs. 1.3+/-2.4 units, p<0.001), but transfused red blood cells (2.1+/-2.8 vs. 2.1+/ 3.4 units) were comparable in the groups. Preoperative clopidogrel (OR 4.8, 95% CI 1.4-16.2, p=0.01) and enoxaparin therapy (OR 2.6, 95% CI 1.1-6.5, p=0.04) were the only significant independent predictors for any major adverse event. CONCLUSIONS: Our study suggests that CABG is a safe procedure during TOAC with no excess bleeding or major complications. Prospective trials are needed to confirm this observation. PMID- 21683989 TI - Utility of percent free prostate-specific antigen in repeat prostate biopsy. AB - OBJECTIVES: To assess the utility of the percent free prostate-specific antigen (%fPSA) for the prediction of prostate cancer in men undergoing repeat biopsy. METHODS: A retrospective review was performed of 1037 patients in an institutional review board-approved repeat prostate biopsy database. A total of 617 patients who underwent 683 biopsies had all their data available for analysis. The patients were categorized as having undergone 1 repeat biopsy or >1 repeat biopsy. RESULTS: The overall cancer detection rate was 27% and 22% in men who underwent 1 and >1 repeat biopsy, respectively. The area under the receiver operating characteristic curve for the %fPSA was 0.65 for men who underwent 1 repeat biopsy. Multivariate analysis demonstrated that a positive family history, decreasing %fPSA, and presence of high-grade intraepithelial neoplasia and/or atypical small acinar proliferation predicted for cancer. The univariate odds ratio for every 5% decrease in the %fPSA was 1.5 (95% confidence interval 1.2 1.7). The performance of %fPSA was further improved in men who underwent >1 repeat biopsy, with an area under the curve of 0.72. In men who underwent >1 repeat biopsy, multivariate analysis showed that a decreasing %fPSA, >20 cores removed, and high-grade intraepithelial neoplasia predicted for cancer. The univariate odds ratio for every 5% decrease in the %fPSA was 1.8 (95% confidence interval 1.4-2.3). A %fPSA cutoff of 10% achieved 90% and 91% specificity in the 1 repeat biopsy and >1 repeat biopsy groups, respectively. CONCLUSIONS: %fPSA is useful in predicting for prostate cancer in the repeat biopsy population, particularly for those who have undergone multiple repeat biopsies. A persistently low %fPSA should prompt additional investigation in these men. PMID- 21683990 TI - Recurrent metanephric stromal tumor in an infant. AB - A 9-month-old boy underwent nephrectomy for a renal mass. Congenital mesoblastic nephroma was diagnosed, and the patient received postoperative chemotherapy. Tumor recurred 6 months later as a scrotal mass. After orchiectomy, diagnosis of metanephric stromal tumor (MST) was made; review of the nephrectomy specimens confirmed this diagnosis. No additional treatment was given, and the child is alive and well 31 months later. Taking into account the histopathological entity of MST in the differential diagnosis of stromal renal tumors in childhood can spare the patient further, potentially toxic, treatment even in the case of relapse, as reported here for the first time. PMID- 21683991 TI - Multicenter randomized controlled trial of bacterial interference for prevention of urinary tract infection in patients with neurogenic bladder. AB - OBJECTIVES: To compare the effectiveness of bacterial interference versus placebo in preventing urinary tract infection (UTI). METHODS: The main outcome measure was the numbers of episodes of UTI/patient-year. Randomization was computer generated, with allocation concealment by visibly indistinguishable products distributed from a core facility. The healthcare providers and those assessing the outcomes were unaware of the group allocation. Adult patients (n = 65) with neurogenic bladder after spinal cord injury and a history of recurrent UTI were randomized in a 3:1 ratio to receive either Escherichia coli HU2117 or sterile saline. Urine cultures were obtained weekly during the first month and then monthly for 1 year. The patients were evaluable if they remained colonized with E. coli HU2117 for >4 weeks (experimental group). The trial is closed to follow up. RESULTS: Of the 59 patients who received bladder inoculations, 27 were evaluable (17 in the experimental group and 10 in the placebo group). The 2 study groups had comparable clinical characteristics. Of 17 patients colonized with E. coli HU2117 and the 10 control patients, 5 (29%, 95% confidence interval 0.11 0.56) and 7 (70%, 95% confidence interval 0.35-0.92) developed >1 episode of UTI (P = .049; 1-sided Fisher's exact test), respectively. The average number of episodes of UTI/patient-year was also lower (P = .02, Wilcoxon rank sum test) in the experimental (0.50) than in the control group (1.68). E. coli HU2117 did not cause symptomatic UTI. CONCLUSIONS: Bladder colonization with E. coli HU2117 safely reduces the risk of symptomatic UTI in patients with spinal cord injury. Effective, but less complex, methods for achieving bladder colonization with E. coli HU2117 are under investigation. PMID- 21683992 TI - Stathmin 1, a marker of PI3K pathway activation and regulator of microtubule dynamics, is expressed in early pelvic serous carcinomas. AB - BACKGROUND: Most high-grade pelvic serous carcinomas (HGPSCs) arise from fallopian tube epithelium (FTE). To date, few markers have been shown to characterize FTE transformation. Stathmin 1 (STMN1) is a candidate oncogene whose activity is influenced by p53, p27Kip1 (p27), and PI3K/Akt pathway activation. As a microtubule destabilizing protein, STMN1 regulates cytoskeletal dynamics, cell cycle progression, mitosis, and cell migration. This study examines the expression of STMN1 and its negative regulator p27 along the morphologic continuum from normal FTE to invasive carcinoma. METHODS: STMN1 and p27 expression were examined by immunohistochemistry (IHC) in benign (n=12) and malignant (n=13) fallopian tubes containing normal epithelium, morphologically benign putative precursor lesions ("p53 signatures"), potential transitional precursor lesions ("proliferative p53 signatures"), tubal intraepithelial carcinoma (TIC), and/or invasive serous carcinoma. STMN1 expression was further assessed in 131 late-stage HGPSCs diagnosed as primary ovarian and in 6 ovarian cancer cell lines by IHC and Western blot, respectively. RESULTS: STMN1 expression was absent in benign FTE and infrequently detected in p53 signatures. However, it was weakly expressed in proliferative p53 signatures and robustly induced upon progression to TIC and invasive carcinoma, typically accompanied by decreased p27 levels. STMN1 was expressed in >80% of high-grade serous ovarian carcinomas and cell lines. CONCLUSIONS: STMN1 is a novel marker of early serous carcinoma that may play a role in FTE tumor initiation. Our data are consistent with a model by which STMN1 overexpression, resulting from loss of p27-mediated regulation, may potentiate aberrant cell proliferation, migration, and/or loss of polarity during early tumorigenesis. PMID- 21683995 TI - Shadows of music-language interaction on low frequency brain oscillatory patterns. AB - Electrophysiological studies investigating similarities between music and language perception have relied exclusively on the signal averaging technique, which does not adequately represent oscillatory aspects of electrical brain activity that are relevant for higher cognition. The current study investigated the patterns of brain oscillations during simultaneous processing of music and language using visually presented sentences and auditorily presented chord sequences. Music-syntactically regular or irregular chord functions were presented in sync with syntactically or semantically correct or incorrect words. Irregular chord functions (presented simultaneously with a syntactically correct word) produced an early (150-250 ms) spectral power decrease over anterior frontal regions in the theta band (5-7 Hz) and a late (350-700 ms) power increase in both the delta and the theta band (2-7 Hz) over parietal regions. Syntactically incorrect words (presented simultaneously with a regular chord) elicited a similar late power increase in delta-theta band over parietal sites, but no early effect. Interestingly, the late effect was significantly diminished when the language-syntactic and music-syntactic irregularities occurred at the same time. Further, the presence of a semantic violation occurring simultaneously with regular chords produced a significant increase in later delta-theta power at posterior regions; this effect was marginally decreased when the identical semantic violation occurred simultaneously with a music syntactical violation. Altogether, these results show that low frequency oscillatory networks get activated during the syntactic processing of both music and language, and further, these networks may possibly be shared. PMID- 21683993 TI - The impact of disease distribution on survival in patients with stage III epithelial ovarian cancer cytoreduced to microscopic residual: a Gynecologic Oncology Group study. AB - OBJECTIVE: To assess the survival impact of initial disease distribution on patients with stage III epithelial ovarian cancer (EOC) cytoreduced to microscopic residual. METHODS: We reviewed data from 417 stage III EOC patients cytoreduced to microscopic disease and given adjuvant intravenous platinum/paclitaxel on one of three randomized Gynecologic Oncology Group (GOG) trials. We subdivided patients into three groups based on preoperative disease burden: (1) minimal disease (MD) defined by pelvic tumor and retroperitoneal metastasis (2) abdominal peritoneal disease (APD) with disease limited to the pelvis, retroperitoneum, lower abdomen and omentum; and (3) upper abdominal disease (UAD) with disease affecting the diaphragm, spleen, liver or pancreas. We assessed the survival impact of potential prognostic factors, focusing on initial disease distribution using a proportional hazards model and estimated Kaplan Meier survival curves. RESULTS: The study groups had similar clinicopathologic characteristics. Median overall survival (OS) was not reached in MD patients compared to 80 and 56 months in the APD and UAD groups (P<0.05). The five-year survival percentages for MD, APD, and UAD were 67%, 63%, and 45%. In multivariate analysis, the UAD group had a significantly worse prognosis than MD and APD both individually and combined (Progression Free Survival (PFS) Hazards Ratio (HR) 1.44; P=0.008 and OS HR 1.77; P=0.0004 compared to MD+APD). CONCLUSION: Stage III EOC patients with initial disease in the upper abdomen have a worse prognosis despite cytoreductive surgery to microscopic residual implying that factors beyond cytoreductive effort are important in predicting survival. PMID- 21683996 TI - Spontaneous aneurysm of the superficial temporal artery. PMID- 21683997 TI - Introduction to the Department for Environment, Food and Rural Affairs (Defra) PREDICT 2 Tamar Estuary Research Workshop: pathological risk evaluation using "health status-related" biomarkers. PMID- 21683998 TI - Integration of biochemical, histochemical and toxicogenomic indices for the assessment of health status of mussels from the Tamar Estuary, U.K. AB - The aim of this study was to examine whether a combination of biochemical, histopathological and toxicogenomic data could be used as a valuable tool for the assessment of biological risk associated with pollutants within the Tamar River and Estuary, S.W. England, U.K. Accordingly, biochemical and histopathological biomarkers (protein carbonyls, lipofuscin, neutral lipids, lysosomal stability [N acetyl-beta-hexosaminidase and neutral red], lysosomal volume, ferric reducing antioxidant power [FRAP] and malonaldehyde [MDA]) and gene expression profiles were assessed in 5 sites from the Tamar River and Estuary (Neal Point, Town Quay, Wilcove, Cremyll Ferry and Whitsand; and a reference site, Trebarwith Strand, N. Cornwall). PAHs were measured in mussel tissue and sediment and metals were measured in mussel tissue only. Data from the biomarkers was integrated into a Mussel Expert System (MES) model to produce a simple assessment of mussel stress. Clear gradients of mussel toxicity were identified by the biomarkers (with the exception of neutral lipids) with the highest impacted animals found furthest up the Tamar, whilst the MES was unable to identify a gradient of effect. Gene expression profiles also indicated a gradient of stress with the greatest number of significantly up- or down- regulated genes found at the uppermost 2 sites. The MES did, however, determine that mussels from all sites, except the reference site, were highly stressed; a conclusion that could not be inferred from the biomarker data alone. It is concluded that the MES is a valuable tool that permits integration and interpretation of complex sets of biomarker data by identifying the biological meaning of biomarker changes. PMID- 21683999 TI - Hydrogel-based biomimetic environment for in vitro modulation of branching morphogenesis. AB - The mechanical properties of the cellular microenvironment dramatically alter during tissue development and growth. Growing evidence suggests that physical microenvironments and mechanical stresses direct cell fate in developing tissue. However, how these physical cues affect the tissue morphogenesis remains a major unknown. We explain here that the physical properties of the cell and tissue microenvironment, biomimetically reproduced by using hydrogel, guide the tissue morphogenesis in the developmental submandibular gland (SMG). In particular, the softer gel enhances the bud expansion and cleft formation of SMG, whereas the stiffer gel attenuates them. These morphological changes in SMG tissue are led by soluble factors (FGF7/10) induction regulated by cell traction force derived from the tissue deformation. Our findings suggest that cells sense the mechanics of their surrounding environment and alter their properties for self-organization and the following tissue morphogenesis. Also, physically designed hydrogel material is a valuable tool for producing the biomimetic microenvironment to explore how physical cues affect tissue morphogenesis and to modulate tissue morphogenesis for in vitro tissue synthesis. PMID- 21684000 TI - Surfactant-assisted controlled release of hydrophobic drugs using anionic surfactant templated mesoporous silica nanoparticles. AB - A series of mesoporous silica nanoparticles (MSNs) were synthesized using the co structure directing method. A non-cytotoxic anionic surfactant, undec-1-en-11 yltetra(ethylene glycol) phosphate monoester surfactant (PMES), was used as a structure directing agent (SDA) together with aminopropyltrimethoxysilane that functioned as a co-structure directing agent (CSDA). The morphology and mesoporous structure of these materials were tuned by changing the molar ratio of CSDA and SDA. These mesoporous nanomaterials containing PMES inside the pores showed excellent biocompatibility in vitro. The cellular internalization and endosome escape of PMES-MSNs in cervical cancer cells (HeLa) was demonstrated by flow cytometry and confocal microscopy, respectively. The PMES-MSNs were used as drug delivery carriers for resveratrol, a low water solubility drug, by taking advantage of the hydrophobic environment created by the PMES micelle inside the pores. This surfactant-assisted delivery strategy was tested under physiological conditions showing an increase of the drug loading compared to the material without surfactant and steady release of resveratrol. Finally, the therapeutic properties of resveratrol-loaded PMES-MSNs were evaluated in vitro using HeLa and Chinese hamster ovarian cells. We envision that this surfactant-assisted drug delivery method using MSNs as nanovehicles would lead to a new generation of carrier materials for intracellular delivery of a variety of hydrophobic therapeutic agents. PMID- 21684002 TI - Affinity hydrogels for controlled protein release using nucleic acid aptamers and complementary oligonucleotides. AB - Biomaterials for the precise control of protein release are important to the development of new strategies for treating human diseases. This study aimed to fundamentally understand aptamer--protein dissociation triggered by complementary oligonucleotides, and to apply this understanding to develop affinity hydrogels for controlled protein release. The results showed that the oligonucleotide tails of the aptamers played a critical role in inducing intermolecular hybridization and triggering aptamer--protein dissociation. In addition, the attachment of the oligonucleotide tails to the aptamers and the increase of hybridizing length could produce a synergistic effect on the dissociation of bound proteins from their aptamers. More importantly, pegylated complementary oligonucleotides could successfully trigger protein release from the aptamer-functionalized hydrogels at multiple time points. Based on these results, it is believed that aptamer functionalized hydrogels and complementary oligonucleotides hold great potential of controlling the release of protein drugs to treat human diseases. PMID- 21684001 TI - Infusion pressure and pain during microneedle injection into skin of human subjects. AB - Infusion into skin using hollow microneedles offers an attractive alternative to hypodermic needle injections. However, the fluid mechanics and pain associated with injection into skin using a microneedle have not been studied in detail before. Here, we report on the effect of microneedle insertion depth into skin, partial needle retraction, fluid infusion flow rate and the co-administration of hyaluronidase on infusion pressure during microneedle-based saline infusion, as well as on associated pain in human subjects. Infusion of up to a few hundred microliters of fluid required pressures of a few hundred mmHg, caused little to no pain, and showed weak dependence on infusion parameters. Infusion of larger volumes up to 1 mL required pressures up to a few thousand mmHg, but still usually caused little pain. In general, injection of larger volumes of fluid required larger pressures and application of larger pressures caused more pain, although other experimental parameters also played a significant role. Among the intradermal microneedle groups, microneedle length had little effect; microneedle retraction lowered infusion pressure but increased pain; lower flow rate reduced infusion pressure and kept pain low; and use of hyaluronidase also lowered infusion pressure and kept pain low. We conclude that microneedles offer a simple method to infuse fluid into the skin that can be carried out with little to no pain. PMID- 21684003 TI - The Goldilocks surface. AB - A minimum in the biological response to materials that is observed to occur within a narrow surface energy range is related to the properties of water at these biology-contacting surfaces. Wetting energetics are calculated using a published theory from which it is further estimated that water molecules bind to these special surfaces through a single hydrogen bond, leaving three other hydrogen bonds to interact with proximal water molecules. It is concluded that, at this Goldilocks Surface, the local chemical environment of surface-bound water is nearly identical to that experienced in bulk water; neither deprived of hydrogen bond opportunities, as it is in contact with a more hydrophobic surface, nor excessively hydrogen bonded to a more hydrophilic surface. A minimum in the biological response occurs because water vicinal (near) to the Goldilocks Surface is not chemically different than bulk water. A more precise definition of the relative terms hydrophobic and hydrophilic for use in biomaterials becomes evident from calculations: >1.3 kJ/mole-of-surface-sites is expended in wetting a hydrophilic surface whereas <1.3 kJ/mole-of-surface-sites is expended in wetting hydrophobic surfaces; hydrophilic surfaces wet with >1 hydrogen bond per water molecule whereas hydrophobic surfaces wet with <1 hydrogen bond per water molecule. PMID- 21684004 TI - Voltage-gated calcium channel types in cultured C. elegans CEPsh glial cells. AB - The four cephalic sensilla sheath (CEPsh) glial cells are important for development of the nervous system of Caenorhabditis elegans. Whether these invertebrate glia can generate intracellular Ca(2+) increases, a hallmark of mammalian glial cell excitability, is not known. To address this issue, we developed a transgenic worm with the specific co-expression of genetically encoded red fluorescent protein and green Ca(2+) sensor in CEPsh glial cells. This allowed us to identify CEPsh cells in culture and monitor their Ca(2+) dynamics. We show that CEPsh glial cells, in response to depolarization, generate various intracellular Ca(2+) increases mediated by voltage-gated Ca(2+) channels (VGCCs). Using a pharmacological approach, we find that the L-type is the preponderant VGCC type mediating Ca(2+) dynamics. Additionally, using a genetic approach we demonstrate that mutations in three known VGCC alpha(1)-subunit genes, cca-1, egl-19 and unc-2, can affect Ca(2+) dynamics of CEPsh glial cells. We suggest that VGCC-mediated Ca(2+) dynamics in the CEPsh glial cells are complex and display heterogeneity. These findings will aid understanding of how CEPsh glial cells contribute to the operation of the C. elegans nervous system. PMID- 21684005 TI - Deletion of TET2 gene in an acute myeloid leukemia case with a t(4;15)(q24;q26) characterized by glass needle based chromosome microdissection and oligonucleotide array. PMID- 21684006 TI - Infections in relapsed or refractory acute myeloid leukemia patients given clofarabine+cytarabine. PMID- 21684007 TI - Partitioning of polar and non-polar neutral organic chemicals into human and cow milk. AB - The aim of this work was to develop a predictive model for milk/water partition coefficients of neutral organic compounds. Batch experiments were performed for 119 diverse organic chemicals in human milk and raw and processed cow milk at 37 degrees C. No differences (<0.3 log units) in the partition coefficients of these types of milk were observed. The polyparameter linear free energy relationship model fit the calibration data well (SD=0.22 log units). An experimental validation data set including hormones and hormone active compounds was predicted satisfactorily by the model. An alternative modelling approach based on log K(ow) revealed a poorer performance. The model presented here provides a significant improvement in predicting enrichment of potentially hazardous chemicals in milk. In combination with physiologically based pharmacokinetic modelling this improvement in the estimation of milk/water partitioning coefficients may allow a better risk assessment for a wide range of neutral organic chemicals. PMID- 21684008 TI - The role of locomotor posture and experience on handedness and footedness in infancy. AB - This research examined the development of handedness and footedness in infancy. We measured footedness by documenting the limb infants used to "lead-out" as they crawled or walked down a path several times. We measured handedness by documenting the hand infants used to reach for a goal at the end of each trial. Study 1 showed that locomotor skill affects limb lateralization preferences and that most 13-month-old infants demonstrated a side preference for reaching and leading out "in the moment." Study 2 longitudinally examined the developmental trajectories of handedness and footedness as they related to locomotor posture and experience. The findings suggest high variability in the developmental trajectory of footedness, with frequent fluctuation between side preferences. The developmental trajectory of handedness was more stable over the transition between locomotor milestones. The transition between crawling and walking decreased the proportion of infants demonstrating side preferences for leading out and the onset of walking decreased the proportion of infants demonstrating side preferences for reaching. These findings demonstrate the importance of making behavioral observations at multiple time scales to understand underlying developmental trajectories, specifically the stability or instability of the motor system associated with the acquisition of new motor abilities. PMID- 21684009 TI - The public health impact of antidepressants: an instrumental variable analysis. AB - BACKGROUND: There has been a marked increase in antidepressant medication prescription and use over the past three decades with unclear effects on the mental health status of the population. This study examined the impact of expansion of antidepressant use on prevalence and characteristics of depression and suicidal ideations in the community. METHOD: Instrumental variable models were used to assess the impact of antidepressant treatments on the prevalence of depressive episodes, mixed anxiety and depression states and suicidal ideations in 22,845 participants of the 1993, 2000 and 2007 National surveys of psychiatric morbidity of Great Britain who were between 16 and 64 years of age. RESULTS: Increased prevalence of antidepressant treatment did not impact the prevalence of depressive episodes or mixed anxiety and depression states. However, antidepressant treatment was associated with decreased prevalence of severe and, to a lesser extent, mild depressive episodes and suicidal ideations and a corresponding increase in prevalence of moderate depressive episodes. LIMITATIONS: The data were cross-sectional and based on self-report of symptoms in the past month and current medication use with no information on dose and duration of medication treatment. CONCLUSIONS: Expansion of antidepressant treatments in recent years has not changed the community prevalence of depression overall, but it has reduced the prevalence of more severe depression and suicidal ideations. The findings call for better targeting and more judicious use of antidepressants in cases of more severe depressive episodes which are more likely to respond to such treatments. PMID- 21684010 TI - A predictive model for diagnosing bipolar disorder based on the clinical characteristics of major depressive episodes in Chinese population. AB - BACKGROUND: A correct timely diagnosis of bipolar depression remains a big challenge for clinicians. This study aimed to develop a clinical characteristic based model to predict the diagnosis of bipolar disorder among patients with current major depressive episodes. METHODS: A prospective study was carried out on 344 patients with current major depressive episodes, with 268 completing 1 year follow-up. Data were collected through structured interviews. Univariate binary logistic regression was conducted to select potential predictive variables among 19 initial variables, and then multivariate binary logistic regression was performed to analyze the combination of risk factors and build a predictive model. Receiver operating characteristic (ROC) curve was plotted. RESULTS: Of 19 initial variables, 13 variables were preliminarily selected, and then forward stepwise exercise produced a final model consisting of 6 variables: age at first onset, maximum duration of depressive episodes, somatalgia, hypersomnia, diurnal variation of mood, irritability. The correct prediction rate of this model was 78% (95%CI: 75%-86%) and the area under the ROC curve was 0.85 (95%CI: 0.80 0.90). The cut-off point for age at first onset was 28.5 years old, while the cut off point for maximum duration of depressive episode was 7.5 months. LIMITATIONS: The limitations of this study include small sample size, relatively short follow up period and lack of treatment information. CONCLUSION: Our predictive models based on six clinical characteristics of major depressive episodes prove to be robust and can help differentiate bipolar depression from unipolar depression. PMID- 21684011 TI - Ongoing or re-emerging subjective insomnia symptoms after full/partial remission or recovery of major depressive disorder mainly with the selective serotonin reuptake inhibitors and risk of relapse or recurrence: a 52-week follow-up study. AB - BACKGROUND: Many patients who remit fully/partially or recover from an episode of major depression continue to suffer from sleep problems, mainly insomnia. Our study assesses the frequency and types of ongoing or re-emerging subjective insomnia symptoms and their relationship to subsequent depressive relapse or recurrence in a group of full/partial remitters or recoverers. METHOD: Sixty patients, 18 to 65 years of age, with current MDD defined using DSM-IV-TR criteria were participated in the study. They began a 24-week course of open label acute plus continuation phase treatment mainly with SSRIs. Maintenance treatment was not planned for not affecting natural relapse or recurrence rates. All participants were evaluated by CGI-S, BDI, HAMD-17, PSQI, and ISI at weeks 0, 4, 12, 24, and 52. RESULTS: Majority of the participants (83.33%) had subjective sleep disturbance, insomnia prior to relapse or recurrence. Repeated measures ANOVA was used to evaluate changes in scores of depression and sleep scales over time between recurred (N = 12) and non-recurred groups (N = 48). Differences between means were calculated with post hoc Bonferroni comparison test. The changes in scores of entire clinical scales over time between recurred and non recurred groups were statistically significant. LIMITATIONS: The limitations of this study include the use of a relatively small, mostly young female sample and the lack of an objective sleep measure to corroborate self-report scales. CONCLUSIONS: Early recognition and treatment of disturbances of the sleep-wake cycle may be important for treatment and prevention of recurrence of depression. PMID- 21684012 TI - Elevated macrophage migration inhibitory factor and decreased transforming growth factor-beta levels in major depression--no influence of celecoxib treatment. AB - OBJECTIVES: The involvement of an immune process in the pathophysiology of major depression disorder (MDD) was substantiated by studies demonstrating elevated levels of proinflammatory cytokines and prostaglandin E(2) (PGE(2)). Cyclooxygenase-2 (COX-2) inhibitors lead to a reduced production of PGE(2) and have been shown to improve depressive symptoms. We investigated the three immune parameters macrophage migration inhibitory factor (MIF), transforming growth factor-beta (TGF-beta) and soluble CD14 (sCD14) in a randomized, placebo controlled trial of the COX-2 inhibitor celecoxib as add-on therapy in patients with MDD treated with reboxetine. METHODS: Thirty-two patients with depression and 20 healthy controls participated in the study. The patients were treated with reboxetine and celecoxib or placebo. Immune parameters were measured from serum at baseline, after three and five weeks using ELISA. RESULTS: Celecoxib as add-on strategy resulted in a significant reduction of Hamilton Depression Scale scores compared to placebo. Depressed patients showed significantly elevated MIF (p < 0.001) and reduced TGF-beta (p = 0.006) concentrations at baseline. There was no difference in sCD14-concentrations. There was no difference between the placebo and the celecoxib group and no change over time. LIMITATIONS: Limitations of the study are the relatively small sample size and lack of functional assessment of HPA axis in parallel. CONCLUSIONS: MIF is a promising new candidate in the neuro immune interplay that may link depressive symptoms, altered immune state and HPA axis dysregulation. Reduced levels of TGF-beta replicate previous findings and support the importance of this regulatory cytokine in major depressive disorder. PMID- 21684013 TI - Inflammatory mediator gene polymorphisms and gestational diabetes: a review of the literature. AB - The incidence of gestational diabetes (GD) is rising worldwide, in parallel with obesity and type 2 diabetes. Obesity and GD are conditions that have in common a state of chronic, low-grade subclinical inflammation characterized by abnormal production of cytokines and mediators. Genetic polymorphisms may influence the production of inflammatory mediators and predispose to different disorders, including diabetes. The aim of this study was to review the existing literature on the relationship between inflammatory mediator gene polymorphisms and GD. The search in PubMed was restricted to articles published in English, from January 1990 to December 2010. Eight studies were included. These publications evaluated 13 different SNPs and six inflammatory mediators in the blood of women with GD. Gene polymorphisms related to leptin, mannose-binding lectin (MBL) and RAGE (receptor for advanced glycation end products) were individually evaluated in a single study each. Leptin and MBL plasma levels were also evaluated in two studies. The participants included in the studies were ethnically different, but matched with controls. Different criteria were adopted to select the participants. Seven of the eight studies included took into consideration the BMI of patients and controls. Due to the heterogeneity and limited number of studies on GD and inflammatory gene polymorphisms, we could not pool together any of the results or perform any additional analyses of the existing data. Since the existing findings come from isolated studies with mostly small sample sizes, there is a need for new, larger, properly designed studies of good methodological quality. PMID- 21684014 TI - The effect of trauma on stress reactivity in aggressive youth. AB - To address gaps in the literature related to the contribution of childhood trauma on aggression, we evaluated salivary cortisol and heart rate changes to psychological challenge in aggressive children with various degrees of trauma. We hypothesized that traumatized and aggressive youths will exhibit higher responsiveness to an active challenge (Violent film-VF) than aggressive youth with no trauma but will not differ when viewing a Non-Violent film (NVF). A total of 25 children (aged 9-12; M=15, F=9) with history of aggression were assessed for trauma exposure. Children viewed the two films in randomized order. Four salivary cortisol and pulse measurements were obtained before (T1), 15 min after the start (T2), at the end (T3), and 15 min following the end of the movie (T4). Repeated measures Analysis of Covariance (ANCOVA) using Film (VF/NVF), Cortisol/Time at T1-T4, Group (Trauma/Non-Trauma), and Film Order were performed with age and gender as covariates. There were significant main effects for Group and Cortisol/Time for the Trauma group showing greater cortisol responsiveness than the Non-Trauma group that was most pronounced during the NVF. These results suggest that aggressive youth with personal history of trauma may exhibit unique biological characteristics, which may have important implications for classification and treatment. PMID- 21684015 TI - Increase in C-reactive protein and lipids in adolescents with psychiatric disease. AB - Eighteen adolescent patients with severe psychiatric disorders were compared with healthy, eutrophics adolescents for the presence of inflammation and cardiovascular risk factors. We found significant differences in high-sensitivity C-reactive protein, total cholesterol, and triglycerides. Our results show, evidence of an inflammatory status and a deleterious lipid profile, in a very early state of psychiatric disease. PMID- 21684016 TI - Development, item analysis, and initial reliability and validity of a multiple choice knowledge of mental illnesses test for lay samples. AB - The public's level of mental health literacy remains low, despite growing access to information regarding mental illnesses. Because few measures exist to assess the level of knowledge of mental illnesses in lay samples, the Multiple-Choice Knowledge of Mental Illnesses Test (MC-KOMIT) was developed, initially for use in a study involving police officers, some of whom received 40 h of training focused on recognizing mental illnesses, using verbal de-escalation techniques, and making mental health referrals when appropriate. This report details the initial development of the 100 questions in the item bank and the eventual selection of the final 33 items that were retained. For these 33 items, internal consistency was demonstrated, and test-retest reliability was examined among officers not in the mental health-related training who completed the test on Monday morning and again on Friday afternoon. Construct validity was examined by three hypothesis tests: the MC-KOMIT was sensitive to change related to the educational intervention, scores were significantly correlated with years of educational attainment, and officers reporting past or current treatment for a mental health problem scored higher than those without such a history. This initial report suggests that the MC-KOMIT may be useful in quantifying knowledge of mental illnesses in police officers and other diverse lay samples. PMID- 21684017 TI - Development of a clinician questionnaire and patient interview to assess reasons for antipsychotic discontinuation. AB - Time to treatment discontinuation and rates of discontinuation are commonly used when evaluating effectiveness of antipsychotic medication. However, less is known about reasons for discontinuation. The purpose of this study was to develop two measures of reasons for discontinuation or continuation of antipsychotics for the treatment of schizophrenia. Based on literature review, a patient interview pilot study, and expert panel input, two measures were drafted: the clinician-reported Reasons for Antipsychotic Discontinuation/Continuation Questionnaire (RAD-Q) and the patient-reported Reasons for Antipsychotic Discontinuation/Continuation Interview (RAD-I). Patients and clinicians completed the draft measures and structured cognitive debriefing interviews. For the draft instruments, reasons for discontinuation/continuation were divided into 3 categories: therapeutic benefits (positive symptoms, negative symptoms, mood, cognition, functional status), adverse events, and reasons other than direct effects of the medication (e.g., cost, inadequate social support). In cognitive debriefings, 10 clinicians and 15 patients indicated that the RAD-Q and RAD-I were clear, easy to complete, and comprehensive. Clinicians and patients suggested minor revisions, and the instruments were revised accordingly. The RAD-Q and RAD-I appear to be useful instruments for assessing reasons for antipsychotic discontinuation and continuation. The next step is a psychometric evaluation of the measures in a larger sample. PMID- 21684018 TI - Preliminary investigation of web-camera delivered cognitive-behavioral therapy for youth with obsessive-compulsive disorder. AB - This study reports a waitlist controlled randomized trial of family-based cognitive-behavioral therapy delivered via web-camera (W-CBT) in children and adolescents with obsessive-compulsive disorder (OCD). Thirty-one primarily Caucasian youth with OCD (range=7-16years; 19 male) were randomly assigned to W CBT or a Waitlist control. Assessments were conducted immediately before and after treatment, and at 3-month follow-up (for W-CBT arm only). Primary outcomes included the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), clinical global improvement rates, and remission status. When controlling for baseline group differences, W-CBT was superior to the Waitlist control on all primary outcome measures with large effect sizes (Cohen's d>=1.36). Thirteen of 16 youth (81%) in the W-CBT arm were treatment responders, versus only 2/15 (13%) youth in the Waitlist arm. Similarly, 9/16 (56%) individuals in the W-CBT group met remission criteria, versus 2/15 (13%) individuals in the Waitlist control. Gains were generally maintained in a naturalistic 3-month follow-up for those randomized to W-CBT. This preliminary study suggests that W-CBT may be helpful in reducing obsessive-compulsive symptoms in youth with OCD. Given considerable access issues, such findings hold considerable promise for treatment dissemination. PMID- 21684019 TI - Immunomodulatory effect of swine CCL20 chemokine in DNA vaccination against CSFV. AB - The objective of this work was to explore whether a plasmid expressing CCL20 chemokine could improve the immune response against CSFV in co-administration with a DNA vaccine expressing the E2 protein. The immunization of pigs with the DNA vaccine formulation, that contains swine CCL20 chemokine, resulted in the homogenous induction of detectable levels of CSFV antibodies at 36 days after the first injection. Remarkably, immunized animals with E2 DNA vaccine in co administration with the plasmid containing swine CCL20 developed high titers of neutralizing antibodies against homologous and heterologous CSFV strains and were totally protected upon a lethal viral challenge (sterilizing protection). Our results confirm the role of CCL20 to increase antibody-mediated responses. At the same time suggest the ability of CCL20 to enhance the T helper cell response associated with the induction of neutralizing antibodies against CSFV in pigs previously reported. Systemic replication of virulent CSFV in vivo during the acute phase of infection induces type I IFN. Lower average values of IFN alpha were detected in the serum of pigs immunized with pE2 and pCCL20 at 3 days after challenge. The levels of IFN-alpha detected in pigs immunized with pE2 and principally in non-vaccinated challenged animals can be related to viral load in serum at 3 and 7 days post infection and the clinical signs observed. Our results emphasized the capacity of swine CCL20 chemokine to enhance cellular, humoral and anti viral response with an adjuvant effect in the immune response elicited by E2 DNA vaccination against CSFV. To our knowledge, this is the first report demonstrating the adjuvant effect of swine CCL20 to effectively enhance the potential of DNA vaccine in the immune induction and protection against virus challenge in swine infection model. PMID- 21684020 TI - A role for reactive oxygen species in endotoxin-induced elevation of MOR expression in the nervous and immune systems. AB - This study examined the mechanism by which exposure to lipopolysaccharide (LPS) alters mu-opioid receptor (MOR) expression in immune and neuronal cells using an in vitro conditioned medium model system. We found that LPS stimulated the intracellular accumulation of reactive oxygen species (ROS) and MOR expression in macrophage-like TPA-HL-60 cells. Conditioned medium from the LPS-stimulated TPA HL-60 cells increased MOR expression in SH-SY5Y cells, a neuronal cell model, through actions mediated by TNF-alpha and GM-CSF. These data suggest that the endotoxin, LPS, modulates MOR expression in nervous and immune cells via ROS signaling, and demonstrates the crosstalk that exists within the neuroimmune axis. PMID- 21684022 TI - Physical therapy intervention (PTI) increases plasma brain-derived neurotrophic factor (BDNF) levels in non-frail and pre-frail elderly women. AB - Biomarkers are important factors in the identification of the frail elderly (higher risk of developing disease) and in assessing the impact of PTI. On the other hand, BDNF has been related to neuroprotection in a series of central nervous system diseases in older age. The levels of BDNF in groups of elderly women classified according to Fried phenotype (non-frail and pre-frail) were compared. We assessed the impact of a PTI on BDNF levels. A convenience sample of 48 elderly women was randomly selected. The PTI group was composed by 20 elderly women selected from this group. Plasma neurotrophic factors, such as BDNF, glial derived neutrophic factor (GDNF), and nerve growth factor (NGF) were measured by enzyme-linked immunosorbent assay (ELISA). Timed-up-and-go (TUG) test, hand-grip and work/body weight were evaluated before and after the intervention. Plasma concentrations of BDNF were significantly higher in non-frail in comparison to pre-frail elderly women. After the PTI, higher levels of BDNF were found in elderly women (before 351+/-68 pg/ml and after 593+/-79 pg/ml; p<0.001). Both groups had an increase in BDNF levels after the PTI. The low levels of BDNF in pre-frail elderly women suggest that this neurotrophic factor may be a key pathophysiological mediator in the syndrome of frailty. The fact that PTI increased BDNF levels in both groups suggests that it may be possible to modify this phenotype. PMID- 21684021 TI - Is hyperhomocysteinemia an Alzheimer's disease (AD) risk factor, an AD marker, or neither? AB - Alzheimer's disease (AD) is the most common form of neurodegenerative disease. The vast majority cases of AD are sporadic, without clear cause, and a combination of environmental and genetic factors has been implicated. The hypothesis that homocysteine (Hcy) is a risk factor for AD was initially prompted by the observation that patients with histologically confirmed AD had higher plasma levels of Hcy, termed hyperhomocysteinemia (HHcy), than age-matched controls. Most evidence accumulated so far implicates HHcy as a risk factor for AD onset, but there are also conflicting results. In this review we summarize reports on the relationship between HHcy and AD from epidemiological investigations, including observational studies and randomized controlled clinical trials. We also examine recent in vivo and in vitro studies of potential mechanisms whereby HHcy could influence AD development. Finally, we discuss possible reasons for the existing conflicting data and provide suggestions for future studies. PMID- 21684023 TI - Elderly patients with acute kidney injury (AKI): clinical features and risk factors for mortality. AB - PURPOSE: Elderly patients with AKI are associated with considerable mortality. The clinical features and risk factors predicting poor outcomes of these patients are not known. The aim of this study is to investigate the clinical features and risk factors affecting mortality in elderly patients with AKI. METHODS: A prospective study on the elderly patients with AKI (age >=65 years old) was conducted. A consecutive sample of 99 elderly patients with AKI was evaluated. These patients were divided into survivor group and non-survivor group according their outcomes. Factors including clinical characteristics and laboratory features were compared between these two groups. Analysis of correlations between death and categorized risk factors was done by means of Pearson's chi-squared test (or Fisher's exact test). Multivariate logistic regression was performed to analyze the possible risk factors for death. RESULTS: The main causes of the elderly patients with AKI were ischemia (53.34%), surgery (33.33%), sepsis/infection (10.10%), nephrotoxic drug (3.03%). The mortality rate of the elderly patients with AKI was 42%. Significant differences were found between the survival group and non-survival group of the elderly patients in concomitant disease, complicated with multiple organ dysfunction syndrome (MODS), albumin, etc. Concomitant disease and MODS were found to be the independent risk factors for death of the elderly patients with AKI after adjusting for age, sex, pre albumin, sepsis/infection, and serum creatinine (SCr). CONCLUSION: This study found that concomitant disease and MODS were the independent risk factors for the death of elderly patients with AKI. PMID- 21684024 TI - Normative study of the category fluency test (CFT) from nationwide data on community-dwelling elderly in Korea. AB - OBJECTIVES: We determined the influence of demographic characteristics on the categorical verbal fluency and to provided its' normative data for the community dwelling elderly with diverse educational attainment. METHODS: We administered the CFT using the animal category to 3025 (1420 men and 1605 women) non-demented community-dwelling Koreans aged 60-96 years who had educational levels ranging from 0 to 22 years. RESULTS: Age and education were associated significantly with performance of CFT, with education showing the stronger association. Education accounted for 14.0% of CFT score variance and age accounted for 3.2%. However, gender did not influence performance of the test. We present normative data for CFT stratified by age (60-64, 65-69, 70-74, 75-79, 80-84, and >=85 years) and education (0, 1-3, 4-6, 7-9, 10-12, and >=13 years). CONCLUSIONS: The CFT norms should provide clinically useful data for evaluating elderly people and help improve the interpretation of verbal fluency tasks and allow for greater diagnostic accuracy for cognitive disorders such as Alzheimer's disease (AD). PMID- 21684025 TI - Mucosal tolerance induction in autoimmune myocarditis and myocardial infarction. AB - BACKGROUND: Antigen-specific therapy is a compelling approach for the treatment of autoimmune conditions. Primary goal is to induce the specific tolerization of self-reactive immune cells without altering host immunity against pathogens. We studied the effects of mucosal tolerance induction on cTnI-induced experimental autoimmune myocarditis (EAM) and post-infarct remodeling. METHODS: Mucosal tolerance was induced by intranasal application of cTnI, alternatively anti-CD3 p.o. Protocols varied in frequency, dosage and time point of application before EAM. We then applied the most effective regimen to mice undergoing myocardial infarction in order to verify its effectiveness in post-infarct cardiac remodeling. The myocardium was evaluated on histological slides and for the cytokine secretion pattern, while echocardiography determined cardiac function. RESULTS: A single dose of 100 MUg of cTnI 7 days prior to myocarditis appeared to be most effective in suppressing inflammation and fibrosis (p = 0.03), while improving fractional shortening (p = 0.02). Treatment with intranasal cTnI upregulated IL-10 expression. On the other hand, frequent intranasal application of high doses of cTnI increased myocardial inflammation. Anti-CD3 p.o. showed the propensity to reduce myocardial inflammation and improve cardiac function. The single dose regimen of i.n. cTnI applied 7 days before a myocardial infarction reduced inflammation by trend (p=0.07) and improved heart function (p=0.002). Moreover, expression of matrix metalloproteinases 9 and 14 significantly decreased when treated with intranasal cTnI (p<0.01). CONCLUSIONS: Depending on the optimal amount, the time period and the choice of antigen, effective mucosal tolerance can be achieved and represents an appealing therapeutic approach in the inflammatory process of cardiac remodeling. PMID- 21684026 TI - Ruminant brucellosis in Upper Egypt (2005-2008). AB - Brucellosis is endemic among humans and ruminant in Egypt and recent reports suggest that its incidence may be increasing. In this study we describe the frequency of brucellosis among different ruminant species in Upper Egypt and its spatial distribution using the data generated by a large-scale control campaign undertaken between 2005 and 2008. A total of 120,090 individual animals of different ruminant species were tested during the campaign. The true proportions of brucellosis were estimated as 0.79% (CI: 0.71%-0.87%), 0.13% (CI: 0.08% 0.18%), 1.16% (1.05%-1.27%) and 0.44% (0.34%-0.54%) among cattle, buffaloes, sheep and goats respectively. We estimated that 0.2% (CI: 0.16%-0.23%) of households in the study area keep at least one seropositive animal. Spatial autocorrelation of the proportions of seropositive households and seropositive animals was assessed using Global Univariate Moran's I and Local Univariate LISA. These analyses showed that the distribution of seropositive animals has considerable spatial heterogeneity with clustering in the northern governorates of the study area. Our results show that brucellosis is widespread and heterogeneously distributed in Upper Egypt. At the current level of available resources it is very unlikely that test and slaughter could be implemented with the intensity needed to be effective and other control measures that could replace or complement the test and slaughter policy in place should be considered. Also, this study illustrates some of the challenges faced by bilateral projects that have to accommodate an externally funded intervention with an ongoing national official disease control program. PMID- 21684027 TI - Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. AB - INTRODUCTION: The recently updated meta-analysis of chemotherapy in head and neck cancer (MACH-NC) demonstrated the benefit of the addition of chemotherapy in terms of overall survival in head and neck squamous cell carcinoma (HNSCC). The magnitude of the benefit according to tumour site is unknown as well as their potential interactions with patient or trial characteristics. METHODS: Eighty seven randomized trials performed between 1965 and 2000 were included in the present analysis. Patients were divided into four categories according to tumour location: oral cavity, oropharynx, hypopharynx and larynx. Patients with other tumour location were excluded (999, 5.7%). For each tumour location and chemotherapy timing, the logrank-test, stratified by trial, was used to compare treatments. The hazard ratios of death or relapse were calculated. Interactions between patient or trial characteristics and chemotherapy effect were studied. RESULTS: Individual patient data of 16,192 patients were analysed, with a median follow-up of 5.6years. The benefit of the addition is consistent in all tumour locations, with hazard ratios between 0.87 and 0.88 (p-value of interaction=0.99). Chemotherapy benefit was higher for concomitant administration for all tumour locations, but the interaction test between chemotherapy timing and treatment effect was only significant for oropharyngeal (p<0.0001) and laryngeal tumours (p=0.05), and not for oral cavity (p=0.15) and hypopharyngeal tumours (p=0.30). The 5-year absolute benefits associated with the concomitant chemotherapy are 8.9%, 8.1%, 5.4% and 4% for oral cavity, oropharynx, larynx and hypopharynx tumours, respectively. CONCLUSION: The benefit of the addition of chemotherapy to locoregional treatment is consistent in all tumour locations of HNSCC. The higher benefit of concomitant schedule was demonstrated only for oropharyngeal and laryngeal tumours but this may be only a consequence of a lack of power. PMID- 21684028 TI - Vortex re-capturing and kinematics in human underwater undulatory swimming. AB - To maximize swimming speed athletes copy fish undulatory swimming during the underwater period after start and turn. The anatomical limitations may lead to deviations and may enforce compensating strategies. This has been investigated by analyzing the kinematics of two national female swimmers while swimming in a still water pool. Additionally, the flow around and behind the swimmers was measured with the aid of time-resolved particle image velocimetry (TR-2D-PIV). As compared to fish, the swimmers used undulatory waves characterized by much higher Strouhal numbers but very similar amplitude distributions along the body and Froude efficiencies. Vortices generated in the region of strongly flexing joints are suitable to be used pedally to enhance propulsion (vortex re-capturing). Complementing studies using numerical and technical modeling will help us to probe the efficiency of observed mechanisms and further improvements of the human strategy. PMID- 21684029 TI - Reprint of "Nanobody--shell functionalized thermosensitive core-crosslinked polymeric micelles for active drug targeting". AB - The aim of this study was to develop poly(ethylene glycol)-b-poly[N-(2 hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAm-Lac(n))) core-crosslinked thermosensitive biodegradable polymeric micelles suitable for active tumor targeting, by coupling the anti-EGFR (epidermal growth factor receptor) EGa1 nanobody to their surface. To this end, PEG was functionalized with N succinimidyl 3-(2-pyridyldithio)-propionate (SPDP) to yield a PDP-PEG-b-p(HPMAm Lac(n)) block copolymer. Micelles composed of 80% mPEG-b-p(HPMAm-Lac(n)) and 20% PDP-PEG-b-p(HPMAm-Lac(n)) were prepared and lysozyme (as a model protein) was modified with N-succinimidyl-S-acetylthioacetate, deprotected with hydroxylamine hydrochloride and subsequently coupled to the micellar surface. The micellar conjugates were characterized using SDS-PAGE and gel permeation chromatography (GPC). Using the knowledge obtained with lysozyme conjugation, the EGa1 nanobody was coupled to mPEG/PDP-PEG micelles and the conjugation was successful as demonstrated by western blot and dot blot analysis. Rhodamine labeled EGa1 micelles showed substantially higher binding as well as uptake by EGFR over expressing cancer cells (A431 and UM-SCC-14C) than untargeted rhodamine labeled micelles. Interestingly, no binding of the nanobody micelles was observed to EGFR negative cells (3T3) as well as to14C cells in the presence of an excess of free nanobody. This demonstrates that the binding of the nanobody micelles is indeed by interaction with the EGF receptor. In conclusion, EGa1 decorated (mPEG/PDP PEG)-b-(pHPMAm-Lac(n)) polymeric micelles are highly promising systems for active drug targeting. PMID- 21684030 TI - Hospital admissions, emergency department utilisation and patient activation for self-management among people with diabetes. AB - AIMS: To assess the relationship between patient activation for self-management and admissions to hospital or attendances at emergency departments among people with diabetes, after controlling for other known associations. METHODS: Patients were randomly selected from Australia's National Diabetes Services Scheme and invited to participate in the Living with Diabetes Study, which is a longitudinal survey providing a comprehensive examination of health care utilisation, well being and disease progression. Data was collected for 3951 participants. RESULTS: Outcome events were defined as 1 or more hospitalization and 1 or more visits to an emergency department in the preceding 12 months. Logistic regression analyses showed six variables remained significantly associated with both outcomes: age, income, disease duration and severity, current depression and PAM stage. Patients at PAM stage 1 were 1.4 times more likely to be hospitalised (p=0.023) and 1.3 times more likely to have visited emergency (p=0.049) compared to those at stage 4. CONCLUSIONS: Low levels of activation are associated with higher utilisation of hospital resources even after controlling for relevant factors such as disease severity and co-morbid depression. Most will be gained by moving patients from PAM stage 1 to a higher level of activation. PMID- 21684031 TI - Climate change impacts on the leaching of a heavy metal contamination in a small lowland catchment. AB - The Keersop catchment (43km(2)) in the south of The Netherlands has been contaminated by the emissions of four zinc ore smelters. The objective of this study was to assess the effects of future projected climate change on the hydrology and the leaching of heavy metals (i.e. Cd and Zn) in the catchment. The numerical, quasi-2D, unsaturated zone Soil Water Atmosphere Plant model was used with 100-year simulated daily time series of precipitation and potential evapotranspiration. The time series are representative of stationary climates for the periods 1961-1990 ("baseline") and 2071-2100 ("future"). The time series of future climate were obtained by downscaling the results of eight regional climate model (RCM) experiments, driven by the SRES A2 emissions scenario, using change factors for a series of climate statistics and applying them to stochastic weather generator models. The time series are characterized by increased precipitation in winter, less precipitation in summer, and higher air temperatures (between 2 degrees C and 5 degrees C) throughout the year. Future climate scenarios project higher evapotranspiration rates, more irrigation, less drainage, lower discharge rates and lower groundwater levels, due to increased evapotranspiration and a slowing down of the groundwater system. As a result, lower concentrations of Cd and Zn in surface water are projected. The reduced leaching of heavy metals, due to drying of the catchment, showed a positive impact on a limited aspect of surface water quality. PMID- 21684032 TI - Effect of temperature on the containment properties of argillaceous rocks: The case study of Callovo-Oxfordian claystones. AB - Heat generated by high level radioactive wastes could alter the performance of a clay repository. It was intended to investigate the effect of such a thermal period on the diffusive properties of Callovo-Oxfordian claystones. Thus, through diffusion experiments with HTO, Cl-36, Na-22 and Cs-137 were performed before, during and after stages of heating at 80 degrees C that lasted for up to one year. A special attention was paid to limit the occurrence of any chemical disturbance. Therefore (i) the temperature was raised to 80 degrees C, then progressively brought back to 21 degrees C, thanks to three intermediate temperature stages, and (ii) specific synthetic solutions were used for each temperature, chemistry of which being close to the equilibrium state, especially with respect to the carbonate and sulphate minerals. It was found that experiments carried out at 80 degrees C showed a clear increase of the effective diffusion coefficient values for the four tracers with respect to those obtained at 21 degrees C (by a factor of 3 for HTO and Cl-36, 5 for Na-22 and 2 for Cs 137). On the other hand, the porosity and rock capacity values did not exhibit any significant discrepancy between 21 degrees C and 80 degrees C, indicating no observable damage of both the pore conducing network and the sorption properties of clay minerals. The Stokes-Einstein relationship, based on the temperature dependency of the viscosity of bulk water, could be used to describe the temperature dependence of the diffusion of HTO and Cl-36 but failed to describe the diffusive evolution of the two sorbing cations, Na-22 and Cs-137. Furthermore, experiments performed after the thermal period led to diffusive properties well matching those obtained before heating. All these results suggest that at the lab scale the heating of rock samples would not alter the claystone containment properties. PMID- 21684033 TI - Cell wall oxalate oxidase modifies the ferulate metabolism in cell walls of wheat shoots. AB - Oxalate oxidase (OXO) utilizes oxalate to generate hydrogen peroxide, and thereby acts as a source of hydrogen peroxide. The present study was carried out to investigate whether apoplastic OXO modifies the metabolism of cell wall-bound ferulates in wheat seedlings. Histochemical staining of OXO showed that cell walls were strongly stained, indicating the presence of OXO activity in shoot walls. When native cell walls prepared from shoots were incubated with oxalate or hydrogen peroxide, the levels of ester-linked diferulic acid (DFA) isomers were significantly increased. On the other hand, the level of ester-linked ferulic acid (FA) was substantially decreased. The decrease in FA level was accounted neither by the increases in DFA levels nor by the release of FA from cell walls during the incubation. After the extraction of ester-linked ferulates, considerable ultraviolet absorption remained in the hemicellulosic and cellulose fractions, which was increased by the treatment with oxalate or hydrogen peroxide. Therefore, a part of FA esters may form tight linkages within cell wall architecture. These results suggest that cell wall OXO is capable of modifying the metabolism of ester-linked ferulates in cell walls of wheat shoots by promoting the peroxidase action via supply of hydrogen peroxide. PMID- 21684035 TI - Targeted mining of drought stress-responsive genes from EST resources in Cleistogenes songorica. AB - Cleistogenes songorica is an important perennial grass found in the pastoral steppe of Inner Mongolia. C. songorica flourishes in drought prone environments, and therefore provides an ideal candidate plant system for the identification of drought-tolerance conferring genes. We constructed cDNA libraries from leaves and roots of drought-stressed C. songorica seedlings. Expressed sequence tag (EST) sequencing of 5664 random cDNA clones produced 3579 high quality, trimmed sequences. The average read length of trimmed ESTs was 613bp. Clustering and assembly identified a non-redundant set of 1499 contigs, including 805 singleton unigenes and 694 multi-member unigenes. The resulting unigenes were functionally categorized according to the Gene Ontology (GO) hierarchy using the in house Bioinformatic Advanced Scientific Computing (BASC) annotation pipeline. Among the total 2.2Mbp of EST sequence data, 161 putative SSRs were found, a frequency similar to that previously observed in oat and Arabidopsis ESTs. Sixty-three unigenes were functionally annotated as being stress responsive, of which 22 were similar to genes implicated in drought stress response. Using quantitative real time RT-PCR, transcripts of 13 of these 22 genes were shown to be at least three fold more, or less abundant in drought-stressed leaves or roots, with 8 increased and 5 decreased in relative transcript abundance. The C. songorica EST and cDNA collections generated in this study are a valuable resource for microarray-based expression profiling, and functional genomics in order to elucidate their role, and to understand the underlying mechanisms of drought-tolerance in C. songorica. PMID- 21684034 TI - Phytochrome interacting factors (PIFs) are essential regulators for sucrose induced hypocotyl elongation in Arabidopsis. AB - Phytochrome interacting factors (PIFs) are members of a subfamily of basic helix loop-helix transcript factors and have been proposed to act as positive regulators of hypocotyl elongation under normal condition. Here, we show that PIF1, 3, 4, 5 together play a central role in sucrose-induced hypocotyl elongation. When seedlings grown in light were transferred to darkness, exogenously applied sucrose significantly induced hypocotyl elongation in wild type Col-0, but this effect was impaired in all tested pif mutants, especially in the quadruple mutant pif1pif3pif4pif5 (pifq). Subsequent experiments showed that under various light/dark (L/D) cycle conditions sucrose still markedly induced hypocotyl elongation in Col-0, but exhibited little effects in pifq. Phytohormone gibberellins (GAs) have been proven to be required for sucrose-induced hypocotyl elongation, but application of GA(3) (an active form of GAs) was not able to rescue the impairment observed in pifq, suggesting that impairment of sucrose induced hypocotyl elongation in pifq is not due to the reduced endogenous GAs. Interestingly, through RT-PCR assay, we found that sucrose up-regulated the transcript level of PIF1, 3, 4, 5 in darkness. Furthermore, this effect was dependent on the presence of GAs. Additionally, under continuous light condition, sucrose markedly inhibited the hypocotyl elongation in Col-0 but not in pifq, whereas exogenous GA(3) could recover the repression in Col-0 but only showed slight effect in pifq. These results collectively indicate that PIFs together with GAs control the effect of sucrose on hypocotyl elongation in Arabidopsis seedlings. PMID- 21684036 TI - Melanocytes in nonlesional sun-exposed skin: a multicenter comparative study. AB - BACKGROUND: There are limited data regarding melanocyte density and distribution on sun-exposed skin of the head and neck, in particular, comparing morphology (hematoxylin-eosin [H&E] staining) and immunohistochemistry (Melan-A staining) on formalin-fixed tissue. Furthermore, comparisons of melanocyte density between distinct geographic populations have not been made using these methods. This information would be useful for physicians who use histologic criteria to diagnose and treat lentigo maligna. OBJECTIVE: We aimed to characterize the density and distribution of melanocytes using Melan-A and H&E stains on nonlesional sun-exposed skin of the face and neck, and compare the results between patients seen in Florida and Minnesota. We also aimed to quantify the presence and extent of features considered characteristic of melanoma in these noncancerous specimens of sun-damaged skin. The overall goal was to be able to provide this information to physicians who perform histopathologic interpretations of skin biopsy specimens to potentially prevent the overdiagnosis of melanoma. METHODS: In all, 100 patients undergoing Mohs micrographic and reconstructive surgery for basal cell and squamous cell carcinoma were enrolled, 50 each at the two sites. Permanent tissue sections were prepared from sun exposed skin without clinical lesions. Melanocyte density and distribution were quantified. RESULTS: The overall median and 90th percentile, respectively, of melanocytes per high-power field was 9 and 14 on the H&E-stained sections and 11 and 19 on the Melan-A-stained sections. The means were 9.3 and 12.0, respectively (P < .001). There was evidence that melanocyte densities were higher in patients in Florida than in Minnesota, at least using H&E staining. There was evidence of lower melanocyte densities with increasing age, more so for Melan-A than H&E staining, and higher densities in men using Melan-A. Confluence was noted in 24% of cases using H&E and 45% using Melan-A. More than two thirds of these were classified as having mild confluence, whereas the others demonstrated higher amounts of confluence (3-8 melanocytes). Only 37 patients had a follicle present; of these, 7 patients had follicular extension although this did not extend beyond 1 mm in depth. Cytologic atypia was noted in 19 of the 100 patients; pagetoid spread was found in 3. LIMITATIONS: This was a selected population of patients; results may not be generalizable to the wider population. Variables such as contours of the epidermis (rete density), density of hair follicles, and epidermal thickness may affect the reproducibility of the results. Melanomas were not included for comparison. CONCLUSION: Relatively high melanocyte density, mild to moderate confluence of melanocytes, focal pagetosis, superficial follicular extension (<1.0 mm), and mild or moderate cytologic atypia may be observed in the absence of a melanocytic neoplasm. It is important for physicians to be aware of these findings so that such features are interpreted appropriately when making a histologic assessment that may ultimately influence therapy and outcome. PMID- 21684037 TI - Histologic features of alopecia areata other than peribulbar lymphocytic infiltrates. AB - BACKGROUND: Histologic features other than a lymphocytic infiltrate around follicular bulbs are now recognized as helpful clues to the diagnosis of alopecia areata, especially in long-standing lesions where the peribulbar lymphocytic infiltrate may be sparse or absent. OBJECTIVES: We sought to determine the frequency of peribulbar lymphocytic infiltrates, eosinophils, lymphocytes, and melanin in fibrous tracts, pigment casts in follicles, the presence of catagen/telogen follicles, follicular miniaturization, and dystrophic ("nanogen") follicles in alopecia areata. Secondly, we sought to compare the diagnostic use of transversely sectioned versus horizontally sectioned specimens in those cases for which both were available (15 of 109 cases). METHODS: The pathology archives of Geisinger Medical Center (Danville, PA), Wilford Hall US Air Force Medical Center (San Antonio, TX), and Brooke US Army Medical Center (San Antonio, TX) were searched for the term "alopecia areata" in the diagnostic field from the period of 1991 to 2006, which yielded 109 cases with sections suitable for review. Cases from the two military institutions from 1997 or earlier were excluded to avoid any overlap with data previously reported by our group. RESULTS: A peribulbar lymphocytic infiltrate was present in 92 specimens (84%), eosinophils in fibrous tracts in 48 (44%), lymphocytes in fibrous tracts in 102 (94%), melanin within fibrous tracts in 92 (84%), pigment casts within follicular canals in 46 (44%), catagen follicles in 101 (93%), and miniaturized follicles in 98 (90%). Dystrophic miniaturized follicles were rare (4 cases). In 14 of 15 cases with both vertical and transverse sections, either was diagnostic. One case showed diagnostic features only in vertical sections. LIMITATIONS: Comparable vertical and transverse sections were only available for a limited number of the cases. We did not correlate duration of disease with individual findings. Our results were correlated with the clinical diagnosis but not with serologic tests for syphilis. CONCLUSIONS: Although most specimens showed evidence of a peribulbar lymphocytic infiltrate (84%), a higher percentage showed evidence of follicles in catagen/telogen phase (93%) and evidence of miniaturization of follicles (90%). This could lead to an incorrect diagnosis of trichotillomania or pattern alopecia. Pigment casts within the hair canal were also found in a significant number of follicles, especially in catagen follicles, creating further potential for misdiagnosis as trichotillomania. A significant percentage showed evidence of eosinophils (44%), melanin (84%), and lymphocytes (94%) in fibrous tracts. These features are particularly helpful when a peribulbar lymphocytic infiltrate is lacking. Vertical and transverse sections appear comparable. PMID- 21684038 TI - Is closure of entire wards necessary to control norovirus outbreaks in hospital? Comparing the effectiveness of two infection control strategies. AB - The standard approach for norovirus control in hospitals in the UK, as outlined by the Health Protection Agency guidance and implemented previously by Lancashire Teaching Hospitals, involves the early closure of affected wards. However, this has a major impact on bed-days lost and cancelled admissions. In 2008, a new strategy was introduced in the study hospital, key elements of which included closure of affected ward bays (rather than wards), installation of bay doors, enhanced cleaning, a rapid in-house molecular test and an enlarged infection control team. The impact of these changes was assessed by comparing two norovirus seasons (2007-08 and 2009-10) before and after implementation of the new strategy, expressing the contrast between seasons as a ratio (r) of expected counts in the two seasons. There was a significant decrease in the ratio of confirmed hospital outbreaks to community outbreaks (r = 0.317, P = 0.025), the number of days of restricted admissions on hospital wards per outbreak (r = 0.742, P = 0.041), and the number of hospital bed-days lost per outbreak (r = 0.344, P <0.001). However, there was no significant change in the number of patients affected per hospital outbreak (r = 1.080, P = 0.517), or the number of hospital staff affected per outbreak (r = 0.651, P = 0.105). Closure of entire wards during norovirus outbreaks is not always necessary. The changes implemented at the study hospital resulted in a significant reduction in the number of bed days lost per outbreak, and this, together with a reduction in outbreak frequency, resulted in considerable cost savings. PMID- 21684039 TI - Mechanisms underlying altered striatal synaptic plasticity in old A53T-alpha synuclein overexpressing mice. AB - The interactions between certain alpha-synuclein (SNCA) conformations and dopamine (DA) metabolism cause selective DA neuron degeneration in Parkinson's disease (PD). Preclinical research on PD took advantage of increasing studies involving different animal models which express different forms of mutated SNCA. Transgenic animals expressing mutant alpha-synucleins such as mice transgenic for A53T-SNCA (TG) are considered valuable models to assess specific aspects of the pathogenesis of synucleinopathies and PD. In this study we performed electrophysiological recordings in corticostriatal slice preparations from young TG overexpressing mice, in which extracellular striatal DA levels appeared to be normal, and in old TG mice, characterized by abnormalities in striatal DA signaling and impaired long-term depression (LTD). We report no difference in TG mice from the two groups of age of either the basal membrane properties and synaptic striatal excitability in respect to age-matched wild-type mice. Furthermore, in old TG mice, showing plastic abnormalities and motor symptoms, we investigated the mechanisms at the basis of the altered LTD. In old TG mice LTD could not be restored by treatments with acute application of DA or by subchronic treatment with L-3,4-dihydroxyphenylalanine (L-DOPA). Conversely, the application of the phosphodiesterase inhibitor zaprinast fully restored LTD to normal conditions via the stimulation of a cyclic guanosine monophosphate (GMP)-protein kinase G-dependent intracellular signaling pathway. These results suggest that, in addition to the dopaminergic alterations reported in this genetic model of PD, other signal transduction pathways linked to striatal synaptic plasticity are altered in an age-dependent manner. PMID- 21684040 TI - Non-invasive brain stimulation improves object-location learning in the elderly. AB - Remembering the location of objects, an integral part of everyday life, is known to decline with advancing age and early in the course of neurodegenerative dementia. Here, we aimed to test if object-location learning and its retention could be modified by noninvasive brain stimulation. In a group of 20 elderly (mean age 62.1 years) right-handed individuals, we applied transcranial direct current stimulation (tDCS; 20 minutes, 1 mA) over the right temporoparietal cortex, while subjects acquired the correct position of buildings on a street map using an associative learning paradigm. Each subject participated in a randomized and balanced order in 1 session of anodal tDCS and 1 session of sham stimulation, in a double-blind design with 2 parallel versions of the task. Outcome measures were learning success at the end of each session, and immediate as well as delayed (1 week) free recall. We found that subjects performed comparably in the learning task in the 2 conditions, but showed improved recall 1 week after learning with anodal tDCS compared with learning with sham stimulation. In conclusion, retention of object-location learning in the elderly may be modulated by noninvasive brain stimulation, a finding of potential relevance not only for normal aging but also for memory deficits in pathological aging. PMID- 21684042 TI - [Antiplatelet agents and proton pump inhibitors. How can the risk-benefit balance be optimized in patients at risk for cardiovascular disease and gastrointestinal bleeding?]. AB - Antiplatelet agents are routinely used in both primary and secondary prevention of cardiovascular events. The development of new antiplatelet agents and the strong growth of interventional cardiology have led to this therapy being more widely prescribed and for longer periods. The most important secondary effect is the rise in the incidence of hemorrhagic complications, the most prevalent being gastrointestinal bleeding. In this context, the balance between the cardiovascular benefits and bleeding risk of these agents must be optimized. This review provides specific management recommendations and highlights important practical aspects related to antiplatelet therapy, including the interaction between clopidogrel and proton pump inhibitors. The benefits and hazards in distinct clinical settings are outlined within the context of optimizing the balance between the cardiovascular benefits and bleeding risk of antiplatelet therapy. PMID- 21684043 TI - [Detection of low-avidity specific IgG antibody in the diagnosis of hepatitis C virus acute primary infection]. PMID- 21684044 TI - [Bacterial identification methods in the microbiology laboratory]. AB - In order to identify the agent responsible of the infectious process and understanding the pathogenic/pathological implications, clinical course, and to implement an effective antimicrobial therapy, a mainstay in the practice of clinical microbiology is the allocation of species to a microbial isolation. In daily routine practice microbiology laboratory phenotypic techniques are applied to achieve this goal. However, they have some limitations that are seen more clearly for some kinds of microorganism. Molecular methods can circumvent some of these limitations, although its implementation is not universal. This is due to higher costs and the level of expertise required for thei implementation, so molecular methods are often centralized in reference laboratories and centers. Recently, proteomics-based methods made an important breakthrough in the field of diagnostic microbiology and will undoubtedly have a major impact on the future organization of the microbiology services. This paper is a short review of the most noteworthy aspects of the three bacterial identification methods described above used in microbiology laboratories. PMID- 21684046 TI - [Epidural abscess caused by Pasteurella pneumotropica]. PMID- 21684045 TI - An outbreak of cutaneous infection due to Mycobacterium abscessus associated to mesotherapy. AB - INTRODUCTION: In February 2009 an outbreak of subcutaneous abscesses due to Mycobacterium abscessus was detected in Spain which affected healthy women who had undergone mesotherapy procedures in an aesthetic clinic. METHODS: Epidemiological research, health inspection and microbiological studies were conducted. The patients were given antibiotic treatment (according to susceptibility testing) with clarithromycin, and in some cases, combined with amikacin. RESULTS: Seventeen out of 77 patients treated in the clinic were affected. The products used for the injections were homeopathic drugs in multi dose vials. The environmental samples were negative. The sterile injection equipment and the clinical procedures were evaluated as correct. The storage conditions for the drugs were also correct, and all the samples tested negative for Mycobacteria. However Paenibacillus provencensis was isolated from samples of unused multi-dose vials and the withdrawal of the product from distribution was ordered. Deficiencies were detected in the sterile products process of at the homeopathic drug factory, so the production line was suspended. CONCLUSIONS: The results of environmental investigation suggest the most likely cause of the outbreak could have been the contamination of the products in the factory, although there was no laboratory confirmation. The widespread use of homeopathic products in invasive procedures requires extreme control during the manufacturing, handling and packaging process. It is important to consider mesotherapy and parenteral use of homeopathic medicines as potential sources of infection and therefore the same precautions in the procedures and quality assurance of products should be applied as with any other drug or medical activity. PMID- 21684047 TI - Anticancer activity and cDNA microarray studies of a (RS)-1,2,3,5-tetrahydro-4,1 benzoxazepine-3-yl]-6-chloro-9H-purine, and an acyclic (RS)-O,N-acetalic 6-chloro 7H-purine. AB - Completing a SAR study, a series of (RS)-6-substituted-7- or 9-(1,2,3,5 tetrahydro-4,1-benzoxazepine-3-yl)-7H or 9H-purines was previously prepared. The most potent antiproliferative agent against the MCF-7 adenocarcinoma cell line that belongs to the benzoxazepine O,N-acetalic family is (RS)-9-[1-(9H-fluorenyl 9-methoxycarbonyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl]-6-chloro-9H-purine (16, IC(50) = 0.67 +/- 0.18 MUM), whilst (RS)-7-{2-(N-hydroxymethylphenyl)-2 nitrobenzenesulfonamido]-1-methoxyethyl}-6-chloro-7H-purine (37) shows the lowest IC(50) value between the family of acyclic O,N-acetals (IC(50) = 3.25 +/- 0.23 MUM). Moreover, 16 showed the better in vitro Therapeutic Index in breast cell lines (3.19), whilst 37 was found to be 3.69-fold more active against HT-29 human colon cancer cell line than versus IEC-6 normal rat intestinal epithelial cell line. The global apoptotic cells caused by 16 and 37 against MCF-7 were 80.08% and 54.85% of cell population after 48 h, respectively. cDNA microarray technology reveals potential drug targets, which are mainly centred on positive apoptosis regulatory pathway genes, and the repression of genes involved in carcinogenesis, proliferation and tumour invasion. PMID- 21684048 TI - Probing the difference between BH3 groove of Mcl-1 and Bcl-2 protein: Implications for dual inhibitors design. AB - Based on our previous discovery of a dual inhibitor of Mcl-1 and Bcl-2, 3 thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (1, S1), and guided by structure insight of 1 complex with Mcl-1 and Bcl-2, we exploited the spatial orientation of BH3 groove of the two proteins by a series of analogues of 1. These analogues contain substitutes with various steric hindrance designed to explore the width and length of the p2 pocket. The structure-activity relationships (SARs) studies together with docking studies and cell-based assays proved that the p2 pocket of Mcl-1 is relatively wider and shorter than that of Bcl-2. A novel dual inhibitor 6 was obtained based on these new findings that it exhibited nanomalar affinities toward Mcl-1 and Bcl-2, as well as nanomalar cytotoxicity activity against multiple cancer cell lines. PMID- 21684049 TI - Student nurses' perceptions of mental health care: validation of a questionnaire. AB - AIM: This article describes the results of a study into the psychometric properties of a questionnaire about student nurses' perceptions of mental health care. The questionnaire was constructed in 2008, but has not yet been tested in terms of construct validity and reliability. A validated questionnaire is essential as a standardized method of analyzing student nurses' perceptions of mental health care. METHOD: To investigate the construct validity, an exploratory factor analysis was performed. Reliability was determined by measuring the internal consistency of the questionnaire. RESULTS: A principal component analysis (PCA) yielded a two-factor solution. The first factor comprised 9 items referring to the views of student nurses on psychiatric patients; the second factor comprised 6 items referring to the views of the students about professional careers in mental health care. CONCLUSION: The factor analysis and questionnaire produced two easily interpretable factors covering the same categories as those identified in the literature as determinants of a student nurse's choice for or against a career in mental health care. The questionnaire's construct validity was rated as sufficient, its reliability as acceptable. The problem is the low explained variance (25.6%). The usefulness of the questionnaire is therefore questionable. The usefulness might be improved through the expansion of some of the categories by additional items. Relevant suggestions are made in this article. PMID- 21684050 TI - Design and manufacture of customised protective facial sports splints. PMID- 21684041 TI - Body mass index is associated with biological CSF markers of core brain pathology of Alzheimer's disease. AB - Weight changes are common in aging and Alzheimer's disease (AD) and postmortem findings suggest a relation between lower body mass index (BMI) and increased AD brain pathology. In the current multicenter study, we tested whether lower BMI is associated with higher core AD brain pathology as assessed by cerebrospinal fluid (CSF)-based biological markers of AD in 751 living subjects: 308 patients with AD, 296 subjects with amnestic mild cognitive impairment (MCI), and 147 elderly healthy controls (HC). Based upon a priori cutoff values on CSF concentration of total tau and beta-amyloid (Abeta(1-42)), subjects were binarized into a group with abnormal CSF biomarker signature (CSF+) and those without (CSF-). Results showed that BMI was significantly lower in the CSF+ when compared with the CSF- group (F = 27.7, df = 746, p < 0.001). There was no interaction between CSF signature and diagnosis or apolipoprotein E (ApoE) genotype. In conclusion, lower BMI is indicative of AD pathology as assessed with CSF-based biomarkers in demented and nondemented elderly subjects. PMID- 21684051 TI - Incidence of the occipital artery arising from the internal carotid artery identified by three-dimensional computed tomographic angiography. AB - Variants of the branches of the external carotid artery are common, but it is extremely rare that the occipital artery arises from the internal carotid artery. We investigated the incidence using three-dimensional computed tomographic (CT) angiography. In 265 patients with cancer of the head and neck, we did CT angiography for vascular mapping of the external carotid artery and its branches before reconstruction or superselective intra-arterial chemotherapy. The origin of the occipital artery was detected in 514 of 530 carotid arteries (97%); the incidence of it arising from the internal carotid artery was 0.2%. PMID- 21684052 TI - Shoulder dystocia: a qualitative exploration of what works. AB - OBJECTIVE: to explore expert practitioners' methods of managing shoulder dystocia. DESIGN AND SETTING: a qualitative interpretive study enabled a descriptive, hermeneutic analysis of data collected. Data were collected via tape recorded interviews, transcribed and analysed to explore themes and meanings. PARTICIPANTS: five clinicians (four midwives and one obstetrician) who have significant experience in the management of shoulder dystocia and work in high risk maternity practice. KEY FINDINGS: IMPLICATIONS FOR PRACTICE: the results of this study demonstrate that the actions to be taken in the event of shoulder dystocia should be further examined and possibly reviewed. The three simple steps of McRoberts Manoeuvre - Suprapubic Pressure - Axillary Traction could revolutionise the way in which shoulder dystocia is managed. PMID- 21684053 TI - Arthroscopic rotator cuff repair: a biomechanical comparison of the suture-bridge technique vs. a new transosseous technique using SutureButtons((r)). AB - BACKGROUND: The suture-bridge technique using anchors as established transosseous equivalent technique in arthroscopic rotator cuff repair was compared to a modified transosseous technique suitable for arthroscopic cuff repair. METHODS: In 10 fresh-frozen matched pairs of human cadaveric shoulders (mean age 67.1, SD 8.5 years), two different surgical techniques of cuff repair were tested: Group 1, using the suture-bridge technique with suture anchors, and Group 2, using two transosseous tunnels with SutureButtons((r)). Lateral row fixation was performed in both groups using knotless implants. Cyclic displacement to gap formation of 2 and 5mm, linear stiffness, yield load, ultimate load, and mode of failure were recorded. FINDINGS: Gap formation at the tendon-to-bone interface of 2mm occurred after a mean of 219.5 (SD 590.7) cycles in Group 1 and after 750.0 (SD 1566.1) cycles in Group 2. Gap formation of 5mm occurred after 2331.6 (SD 2033.9) cycles (Group 1) and 2364.5 (SD 1994.2) cycles (Group 2), respectively. The yield and ultimate loads were 316.9 (SD 114.1)N and 375.9 (SD 131.2)N in Group 1, and 311.0 (SD 97.2)N and 363.8 (SD 107.6)N in Group 2, respectively. The linear stiffness was 40.3 (SD 10.4)N/mm in Group 1, and 41.6 (SD 13.2)N/mm in Group 2. There were no statistically significant intergroup differences. INTERPRETATION: The new transosseous technique using SutureButtons((r)) achieves equivalent biomechanical properties to the established suture-bridge technique using anchors. A tendentially reduced primary gap formation may be of importance for repair healing during the early phase of rehabilitation. PMID- 21684054 TI - Price subsidies and the market for mosquito nets in developing countries: A study of Tanzania's discount voucher scheme. AB - This study uses a partial equilibrium simulation model to explore how price subsidies for insecticide-treated mosquito nets (ITNs) affect households' purchases of ITNs. The model describes the ITN market in a typical developing country and is applied to the situation in Tanzania, where the Tanzania National Voucher Scheme (TNVS) provides a targeted subsidy to vulnerable population groups by means of a discount voucher. The data for this study come from a nationally representative household survey completed July-August 2006 covering over 4300 households in 21 districts. The simulation results show the impact of the voucher program on ITN coverage among target households, namely those that experienced the birth of a child. More specifically, the share of target households purchasing an ITN increased from 18 to 62 percent because of the discount voucher. The model also suggests that the voucher program could cause the retail ITN price to rise due to an overall increase in demand. As a result, ITN purchases by households without a voucher may actually decline. The simulation model suggests that additional increases toward the stated goal of 80 percent ITN coverage for pregnant women and children could best be achieved through a combination of "catch up" mass distribution programs and expanding the target group for the voucher program to cover additional households. The model can be employed in other countries considering use of a targeted price subsidy for ITNs, and could be adapted to assess the impact of subsidies for other public health commodities. PMID- 21684055 TI - Undocumented immigrants and their use of medical services in Orange County, California. AB - Does an undocumented immigration status predict the use of medical services? To explore this question, this paper examines medical care utilization of undocumented Latino immigrants compared to Latino legal immigrants and citizens, and non-Latino whites in Orange County, California. Data were collected through a random sample telephone survey of 805 Latinos and 396 non-Hispanic whites between January 4 and January 30, 2006. Findings show that undocumented immigrants had relatively low incomes and were less likely to have medical insurance; experience a number of stresses in their lives; and underutilize medical services when compared to legal immigrants and citizens. Predictors of use of medical services are found to include undocumented immigration status, medical insurance, education, and gender. Undocumented Latinos were found to use medical services less than legal immigrants and citizens, and to rely more on clinic-based care when they do seek medical services. PMID- 21684056 TI - [Conchal flap with a superior pedicle to reconstruct the middle or upper third of the auricle]. AB - The middle or upper third of the auricle can be reconstructed with a composite chondro-cutaneous peninsular flap of the conchal part of the auricle. This peninsular flap is based on the anastomotic network between the posterior auricular and the superficial temporal artery. The authors report their experience about 24 clinical cases. Most of the cases were partial auricular amputations for squamous cell carcinoma. The surgical procedure allows a hidden cartilaginous donor site, the concha, allowing in a single operation a color- and texture-matched reconstruction. This flap represents an alternative to more complex surgical procedures, and can easily be realised under local anaesthesia. PMID- 21684057 TI - Vascular risk, diabetes and the ankle-brachial index. PMID- 21684059 TI - A prize worth the effort: a common European registry of out-of-hospital cardiac arrest. PMID- 21684058 TI - The improved but unfinished business of stroke risk stratification in atrial fibrillation. PMID- 21684060 TI - Inhibition of FGF signaling converts dorsal mesoderm to ventral mesoderm in early Xenopus embryos. AB - In early vertebrate development, mesoderm induction is a crucial event regulated by several factors including the activin, BMP and FGF signaling pathways. While the requirement of FGF in Nodal/activin-induced mesoderm formation has been reported, the fate of the tissue modulated by these signals is not fully understood. Here, we examined the fate of tissues when exogenous activin was added and FGF signaling was inhibited in animal cap explants of Xenopus embryos. Activin-induced dorsal mesoderm was converted to ventral mesoderm by inhibition of FGF signaling. We also found that inhibiting FGF signaling in the dorsal marginal zone, in vegetal-animal cap conjugates or in the presence of the activin signaling component Smad2, converted dorsal mesoderm to ventral mesoderm. The expression and promoter activities of a BMP responsive molecule, PV.1 and a Spemann organizer, noggin, were investigated while FGF signaling was inhibited. PV.1 expression increased, while noggin decreased. In addition, inhibiting BMP-4 signaling abolished ventral mesoderm formation induced by exogenous activin and FGF inhibition. Taken together, these results suggest that the formation of dorso ventral mesoderm in early Xenopus embryos is regulated by a combination of FGF, activin and BMP signaling. PMID- 21684061 TI - Public engagement in neighbourhood level wildfire mitigation and preparedness: case studies from Canada, the US and Australia. AB - This study examined neighbourhood level wildfire mitigation programs being implemented in neighbourhoods in Canada (FireSmart-ForestWise), Australia (Community Fireguard) and the US (Firewise Communities). Semi-structured interviews were completed with 19 residents participating in the programs. A wide range of activities were completed as part of the three programs. Despite differences between the three programs, participants appeared to participate in the programs for three main reasons: Fire experience, agency involvement, and personal and family protection. A fire therefore provides a window of opportunity to engage residents in neighbourhood level wildfire mitigation programs. The neighbourhood level wildfire mitigation programs helped to reduce the wildfire risk, but also enhanced both community resilience and relationships between residents and government agencies. PMID- 21684062 TI - Real-time texture analysis for identifying optimum microbubble concentration in 2 D ultrasonic particle image velocimetry. AB - Many recent studies on ultrasonic particle image velocimetry (Echo PIV) showed that the accuracy of two-dimensional (2-D) flow velocity measured depends largely on the concentration of ultrasound contrast agents (UCAs) during imaging. This article presents a texture-based method for identifying the optimum microbubble concentration for Echo PIV measurements in real-time. The texture features, standard deviation of gray level, and contrast, energy and homogeneity of gray level co-occurrence matrix were extracted from ultrasound contrast images of rotational and pulsatile flow (10 MHz) in vitro and in vivo mouse common carotid arterial flow (40 MHz) with UCAs at various concentrations. The results showed that, at concentration of 0.8~2 * 103 bubbles/mL in vitro and 1~5 * 105 bubbles/mL in vivo, image texture features had a peak value or trough value, and velocity vectors with high accuracy can be obtained. Otherwise, poor quality velocity vectors were obtained. When the texture features were used as a feature set, the accuracy of K-nearest neighbor classifier can reach 86.4% in vitro and 87.5% in vivo, respectively. The texture-based method is shown to be able to quickly identify the optimum microbubble concentration and improve the accuracy for Echo PIV imaging. PMID- 21684063 TI - Newtonian viscous effects in ultrasonic emboli removal from blood. AB - We have modeled the removal of emboli from cardiopulmonary bypass circuits via acoustic radiation force. Unless removed, emboli can result in cognitive deficit for those undergoing heart surgery with the use of extracorporeal circuits. There are a variety of mathematical formulations in the literature describing acoustic radiation force, but a lingering question that remains is how important viscosity of the blood and/or embolus is to the process. We implemented both inviscid and viscous models for acoustic radiation force on a sphere immersed in a fluid. We found that for this specific application, the inviscid model seems to be sufficient for predicting acoustic force upon emboli when compared with the chosen viscous model. Thus, the much simpler inviscid model could be used to optimize experimental techniques for ultrasonic emboli removal. PMID- 21684064 TI - Late gastrointestinal toxicities following radiation therapy for prostate cancer. AB - BACKGROUND: Radiation therapy is commonly used to treat localized prostate cancer; however, representative data regarding treatment-related toxicities compared with conservative management are sparse. OBJECTIVE: To evaluate gastrointestinal (GI) toxicities in men treated with either primary radiation or conservative management for T1-T2 prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: We performed a population-based cohort study, using Medicare claims data linked to the Surveillance Epidemiology and End Results data. Competing risk models were used to evaluate the risks. MEASUREMENTS: GI toxicities requiring interventional procedures occurring at least 6 mo after cancer diagnosis. RESULTS AND LIMITATIONS: Among 41,737 patients in this study, 28,088 patients received radiation therapy. The most common GI toxicity was GI bleeding or ulceration. GI toxicity rates were 9.3 per 1000 person-years after three-dimensional conformal radiotherapy, 8.9 per 1000 person-years after intensity-modulated radiotherapy, 5.3 per 1000 person-years after brachytherapy alone, 20.1 per 1000 person-years after proton therapy, and 2.1 per 1000 person-years for conservative management patients. Radiation therapy is the most significant factor associated with an increased risk of GI toxicities (hazard ratio [HR]: 4.74; 95% confidence interval [CI], 3.97-5.66). Even after 5 yr, the radiation group continued to experience significantly higher rates of new GI toxicities than the conservative management group (HR: 3.01; 95% CI, 2.06-4.39). Because our cohort of patients were between 66 and 85 yr of age, these results may not be applicable to younger patients. CONCLUSIONS: Patients treated with radiation therapy are more likely to have procedural interventions for GI toxicities than patients with conservative management, and the elevated risk persists beyond 5 yr. PMID- 21684065 TI - Re: Bayan Alsaid, Thomas Bessede, Djibril Diallo, et al. Division of autonomic nerves within the neurovascular bundles distally into corpora cavernosa and corpus spongiosum components: immunohistochemical confirmation with three dimensional reconstruction. Eur Urol 2011;59:902-9. PMID- 21684066 TI - Mechanical stimuli-induced urothelial differentiation in a human tissue engineered tubular genitourinary graft. AB - BACKGROUND: A challenge in urologic tissue engineering is to obtain well differentiated urothelium to overcome the complications related to other sources of tissues used in ureteral and urethral substitution. OBJECTIVE: We investigated the effects of in vitro mechanical stimuli on functional and morphologic properties of a human tissue-engineered tubular genitourinary graft (TTGG). DESIGN, SETTING, AND PARTICIPANTS: Using the self-assembly technique, we developed a TTGG composed of human dermal fibroblasts and human urothelial cells without exogenous scaffolding. Eight substitutes were subjected to dynamic flow and hydrostatic pressure for up to 2 wk compared to static conditions (n=8). MEASUREMENTS: Stratification and cell differentiation were assessed by histology, electron microscopy, immunostaining, and uroplakin gene expression. Barrier function was determined by permeation studies with carbon 14-urea. RESULTS AND LIMITATIONS: Dynamic conditions showed well-established stratified urothelium and basement membrane formation, whereas no stratification was observed in static culture. The first signs of cell differentiation were perceived after 7 d of perfusion and were fully expressed at day 14. Superficial cells under perfusion displayed discoidal and fusiform vesicles and positive staining for uroplakin 2, cytokeratine 20, and tight junction protein ZO-1, similar to native urothelium. Mechanical stimuli induced expression of the major uroplakin transcripts, whereas expression was low or undetectable in static culture. Permeation studies showed that mechanical constraints significantly improved the barrier function compared to static conditions (p<0.01 at 14 d, p<0.05 at 7 d) and were comparable to native urothelium. CONCLUSIONS: Mechanical stimuli induced in vitro terminal urothelium differentiation in a human genitourinary substitute displaying morphologic and functional properties equivalent to a native urologic conduit. PMID- 21684068 TI - Prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma: a prospective, multicentre, randomised clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT-C Trial). AB - BACKGROUND: Standard treatment for upper urinary tract urothelial carcinoma (UUTUC) is nephroureterectomy. Subsequently, around 40% of patients will develop a bladder tumour potentially because of implantation from the primary tumour. OBJECTIVE: To prevent bladder tumour after nephroureterectomy with a single postoperative dose of intravesical mitomycin C (MMC). DESIGN, SETTING, AND PARTICIPANTS: A prospective, randomised, nonblinded trial (ODMIT-C: One Dose Mitomycin C) was undertaken in 46 British centres between July 2000 and December 2006. The study recruited 284 patients with no previous or concurrent history of bladder cancer undergoing nephroureterectomy for suspected UUTUC. INTERVENTION: A single postoperative intravesical dose of MMC (40 mg in 40 ml saline) or standard management on removal of the urinary catheter. MEASUREMENTS: Bladder tumour formation was judged by visual appearance at cystoscopy at 3, 6, and 12 mo following nephroureterectomy. RESULTS AND LIMITATIONS: One hundred forty-four patients were randomised to receive MMC and 140 patients to receive standard care. In the MMC arm, 105 of 144 patients (73%) and 115 of 140 patients (82%) in the standard care arm received their allocated treatment. Thirteen of 105 patients who received MMC and 20 of 115 patients allocated to standard treatment did not complete follow-up. By modified intention-to-treat analysis, 21 of 120 patients (17%) in the MMC arm developed a bladder recurrence in the first year compared to 32 of 119 patients (27%) in the standard treatment arm (p=0.055). By treatment as per protocol analysis, 17 of 105 patients (16%) in the MMC arm and 31 of 115 patients (27%) in the standard treatment arm developed a recurrence (p=0.03). No serious adverse events were reported. A limitation is that histologic proof of recurrence was not required in this trial. CONCLUSIONS: A single postoperative dose of intravesical MMC appears to reduce the risk of a bladder tumour within the first year following nephroureterectomy for UUTUC. The absolute reduction in risk is 11%, the relative reduction in risk is 40%, and the number needed to treat to prevent one bladder tumour is nine. PMID- 21684069 TI - Laparoendoscopic single-site surgery in urology: worldwide multi-institutional analysis of 1076 cases. AB - BACKGROUND: Laparoendoscopic single-site surgery (LESS) has gained popularity in urology over the last few years. OBJECTIVE: To report a large multi-institutional worldwide series of LESS in urology. DESIGN, SETTING, AND PARTICIPANTS: Consecutive cases of LESS done between August 2007 and November 2010 at 18 participating institutions were included in this retrospective analysis. INTERVENTION: Each group performed a variety of LESS procedures according to its own protocols, entry criteria, and techniques. MEASUREMENTS: Demographic data, main perioperative outcome parameters, and information related to the surgical technique were gathered and analyzed. Conversions to reduced-port laparoscopy, conventional laparoscopy, or open surgery were evaluated, as were intraoperative and postoperative complications. RESULTS AND LIMITATIONS: Overall, 1076 patients were included in the analysis. The most common procedures were extirpative or ablative operations in the upper urinary tract. The da Vinci robot was used to operate on 143 patients (13%). A single-port technique was most commonly used and the umbilicus represented the most common access site. Overall, operative time was 160+/-93 min and estimated blood loss was 148+/-234 ml. Skin incision length at closure was 3.5+/-1.5 cm. Mean hospital stay was 3.6+/-2.7 d with a visual analog pain score at discharge of 1.5+/-1.4. An additional port was used in 23% of cases. The overall conversion rate was 20.8%; 15.8% of patients were converted to reduced-port laparoscopy, 4% to conventional laparoscopy/robotic surgery, and 1% to open surgery. The intraoperative complication rate was 3.3%. Postoperative complications, mostly low grade, were encountered in 9.5% of cases. CONCLUSIONS: This study provides a global view of the evolution of LESS in the field of minimally invasive urologic surgery. A broad range of procedures have been effectively performed, primarily in the academic setting, within diverse health care systems around the world. Since LESS is performed by experienced laparoscopic surgeons, the risk of complications remains low when stringent patient-selection criteria are applied. PMID- 21684070 TI - Does the extent of lymphadenectomy in radical cystectomy for bladder cancer influence disease-free survival? A prospective single-center study. AB - BACKGROUND: Controversy exists regarding the optimal extent of lymphadenectomy and the number of lymph nodes to be retrieved at radical cystectomy (RC). OBJECTIVE: To compare the disease-free survival of patients with standard lymphadenectomy (endopelvic region composed of the internal, external iliac, and obturator groups of lymph nodes) versus extended lymphadenectomy (up to the level of origin of the inferior mesenteric artery) at RC in a prospective cohort of patients at a single, high-volume center. DESIGN, SETTING, AND PARTICIPANTS: Prospective data were collected from 400 consecutive patients treated with RC for bladder cancer by two high-volume surgeons at Mansoura Urology and Nephrology Center. Of the 400 patients, 200 (50%) received extended lymphadenectomy and the other 200 (50%) underwent standard lymphadenectomy at RC. The patients did not receive any neoadjuvant or adjuvant therapy. MEASUREMENTS: Patient characteristics and outcomes are evaluated. RESULTS AND LIMITATIONS: Median patient age for the entire group was 53.0 yr. Ninety-six patients (24.0%) had lymph node metastases. Median follow-up was 50.2 mo. Estimates of 5-yr disease free survival in the extended lymphadenectomy group were 66.6% compared with 54.7% for patients with standard lymphadenectomy (p = 0.043). Extended lymphadenectomy was associated with better disease-free survival after adjusting for the effects of standard pathologic features (p = 0.02). When restricting the analyses to lymph node-positive patients, patients with extended lymphadenectomy had much better 5-yr disease-free survival compared with patients with standard lymphadenectomy (48.0% vs 28.2%; p = 0.029). The study was nonrandomized. CONCLUSIONS: Extended lymphadenectomy is associated with better disease-free survival for bladder cancer patients with endopelvic lymph node involvement and should be considered in these patients. PMID- 21684071 TI - Urine markers for detection and surveillance of non-muscle-invasive bladder cancer. AB - CONTEXT: Bladder cancer diagnosis and surveillance includes cystoscopy and cytology. The limitation of urinary cytology is its low sensitivity for low-grade recurrences. As of now, six urine markers are commercially available to complement cystoscopy in the detection of bladder cancer. Several promising tests are under investigation. OBJECTIVE: In this nonsystematic review, we summarize the existing data on commercially available and promising investigational urine markers for the detection of bladder cancer. EVIDENCE ACQUISITION: A PubMed search was carried out. We reviewed the recent literature on urine-based markers for bladder cancer. Articles were considered between 1997 and 2011. Older studies were included selectively if historically relevant. EVIDENCE SYNTHESIS: Although different studies have shown the superiority of urine markers regarding sensitivity for bladder cancer detection as compared with cytology, none of these tests is ideal and can be recommended unrestrictedly. CONCLUSIONS: Urine markers have been studied extensively to help diagnose bladder cancer and thereby decrease the need for cystoscopy. However, no marker is available at present that can sufficiently warrant this. Several urinary markers have higher but still insufficient sensitivity compared with cytology. Urinary cytology or markers cannot safely replace cystoscopy in this setting. To identify an optimal marker that can delay cystoscopy in the diagnosis of bladder cancer, large prospective and standardized studies are needed. PMID- 21684073 TI - Safety issues and rationale for neoadjuvant approaches in renal cell carcinoma. PMID- 21684072 TI - Sequelae of treatment in long-term survivors of testis cancer. AB - CONTEXT: Testicular cancer patients are often diagnosed at a young age, and because of the advances in the treatment of this disease, the vast majority have a normal life expectancy after therapy. Thus, recognition of the long-term sequelae of treatment (ie, surgery, radiation therapy, and chemotherapy) is particularly important in these patients. OBJECTIVE: To review the adverse effects and the risk of secondary malignancy in long-term survivors of testicular cancer. EVIDENCE ACQUISITION: We conducted a Medline search to identify original articles and reviews on the long-term effects of testicular cancer treatment. Although the search included articles from January 1948 to February 2011, the majority of the included articles were published in the last two decades. EVIDENCE SYNTHESIS: All studies examining the long-term sequelae of treatment in testicular cancer are retrospective in nature, with most classified as cohort, case-control, and/or epidemiologic studies. Given that no standardized method of reporting long-term complications exists, evidence synthesis is limited. CONCLUSIONS: Recent evidence suggests an increased risk of cardiovascular disease, neurotoxicity, and mild reductions in renal function in survivors of testicular cancer. Treatment of testicular malignancy can also negatively affect gonadal function and fertility and has been shown to result in an increased risk of solid malignancy and leukemia. PMID- 21684074 TI - OCT4B1, a novel spliced variant of OCT4, generates a stable truncated protein with a potential role in stress response. AB - A novel variant of OCT4, OCT4B1, is highly expressed in pluripotent cells. OCT4B1 is also upregulated in various tumors and cell lines. Here, we have constructed a HA-tagged OCT4B1 construct, which could be translated into an N-terminally tagged protein, detectable by HA antibody. Western blotting revealed that OCT4B1 can act as a precursor for OCT4B, and it can also produce a truncated protein with a molecular size corresponding to that of predicted OCT4B1. Furthermore, our data demonstrated a cytoplasmic distribution for both isoforms. Interestingly, the expression ratio of OCT4B1/OCT4B transcripts and proteins was significantly elevated under the heat-stress condition. PMID- 21684075 TI - Arsenic (III,V) removal from aqueous solution by ultrafine alpha-Fe2O3 nanoparticles synthesized from solvent thermal method. AB - Ultrafine iron oxide (alpha-Fe(2)O(3)) nanoparticles were synthesized by a solvent thermal process and used to remove arsenic ions from both lab-prepared and natural water samples. The alpha-Fe(2)O(3) nanoparticles assumed a near sphere shape with an average size of about 5 nm. They aggregated into a highly porous structure with a high specific surface area of ~ 162 m(2)/g, while their surface was covered by high-affinity hydroxyl groups. The arsenic adsorption experiment results demonstrated that they were effective, especially at low equilibrium arsenic concentrations, in removing both As(III) and As(V) from lab prepared and natural water samples. Near the neutral pH, the adsorption capacities of the alpha-Fe(2)O(3) nanoparticles on As(III) and As(V) from lab prepared samples were found to be no less than 95 mg/g and 47 mg/g, respectively. In the presence of most competing ions, these alpha-Fe(2)O(3) nanoparticles maintained their arsenic adsorption capacity even at very high competing anion concentrations. Without the pre-oxidation and/or the pH adjustment, these alpha Fe(2)O(3) nanoparticles effectively removed both As(III) and As(V) from a contaminated natural lake water sample to meet the USEPA drinking water standard for arsenic. PMID- 21684076 TI - Facile synthesis of ZnO nanorod arrays and hierarchical nanostructures for photocatalysis and gas sensor applications. AB - A facile one-step hydrothermal route was demonstrated to grow ZnO nanorod arrays and hierarchical nanostructures on arbitrary substrates without any catalysts and seeds coated before the reaction, which are prerequisite in the current two-step protocol. Meanwhile, ZnO nanoflowers composed of nanorods were obtained at the bottom of the autoclaves in the absence of substrates. An in situ spontaneous seeds-assisted growth mechanism was tentatively proposed on the basis of the experimental data to explain the growth process of ZnO nanostructures. Moreover, the obtained ZnO nanorod arrays exhibited superior photocatalytic activity for decomposing methyl orange, and the nanoflowers showed better gas sensing performance towards some flammable gases and corrosive vapors with high sensitivity, rapid response-recovery characteristics, good selectivity and long term stability. PMID- 21684077 TI - Electrochemical EDTA recycling after soil washing of Pb, Zn and Cd contaminated soil. AB - Recycling of chelant decreases the cost of EDTA-based soil washing. Current methods, however, are not effective when the spent soil washing solution contains more than one contaminating metal. In this study, we applied electrochemical treatment of the washing solution obtained after EDTA extraction of Pb, Zn and Cd contaminated soil. A sacrificial Al anode and stainless steel cathode in a conventional electrolytic cell at pH 10 efficiently removed Pb from the solution. The method efficiency, specific electricity and Al consumption were significantly higher for solutions with a higher initial metal concentration. Partial replacement of NaCl with KNO(3) as an electrolyte (aggressive Cl(-) are required to prevent passivisation of the Al anode) prevented EDTA degradation during the electrolysis. The addition of FeCl(3) to the acidified washing solution prior to electrolysis improved Zn removal. Using the novel method 98, 73 and 66% of Pb, Zn and Cd, respectively, were removed, while 88% of EDTA was preserved in the treated washing solution. The recycled EDTA retained 86, 84 and 85% of Pb, Zn and Cd extraction potential from contaminated soil, respectively. PMID- 21684078 TI - Microemulsion-mediated solvothermal synthesis and photocatalytic properties of crystalline titania with controllable phases of anatase and rutile. AB - Titanium oxide with different ratios of anatase to rutile has been prepared by the microemulsion-mediated solvothermal method. The resulting samples were investigated by X-ray diffraction, Raman spectroscopy, scanning electron microscopy, UV-vis diffuse reflectance spectra, transmission electron microscopy and Brunauer-Emmett-Teller analysis. The contents of anatase and rutile in the TiO(2) particles have been successfully controlled by simply adjusting the amount of urea in the aqueous phase of the microemulsion. Both the degradation of Rhodamine B in aqueous solutions and mineralization of TOC revealed that the catalyst containing 47.6% anatase have presented the highest photocatalytic activity. A proposed mechanism is discussed to interpret the evolution of the phases based on the effect of different amount of urea. PMID- 21684079 TI - Influence of injection conditions on EDDS-flushing of metal-contaminated soil. AB - This study evaluated the design of step-gradient, single-pulse, multi-pulse, and continuous injection of biodegradable EDDS ([S,S]-ethylene-diamine-disuccinic acid, under the same total dosage) and the significance of pore-water velocities during in situ soil flushing. In view of the metal breakthrough and extraction efficiency of each injection mode, single-pulse injection was found to be the least effective for all metals. Multi-pulse injection was consistently more effective than single-pulse injection, although the efficiency of second and third pulse injections significantly diminished. Continuous injection offered a simple operation and the greatest Ni and Cu extraction, whereas step-gradient injection was the best option for Zn and Pb extraction because it mitigated the influence of metal exchange. Moreover, a rinsing step with a background solution following the initial injection of the multi-pulse injection removed newly formed metal-EDDS complexes from soil pores effectively before further EDDS-flushing. A decrease in pore-water velocity provided a longer residence time for greater Ni and Cu extraction, but also enhanced the rate-limited metal exchange of Zn-EDDS and Pb-EDDS complexes and thus hindered Zn and Pb extraction. These results suggest a slower and continuous injection for the best Ni or Cu removal, but a faster and step-gradient injection for Zn or Pb removal. PMID- 21684080 TI - Speciation of heavy metals by modified BCR sequential extraction procedure in different depths of sediments from Sungai Buloh, Selangor, Malaysia. AB - The sequential extraction procedure proposed by the European Standard, Measurements and Testing (SM&T) program, formerly the Community Bureau of Reference (BCR), was applied for partitioning of heavy metals (HMs) in river sediments collected along the course of Sungai Buloh and the Straits of Malacca in Selangor, Malaysia. Eight elements (V, Pb, Cd, Cr, Co, Ni, Cu and Zn) from seven stations (S1-S7) and at different depths were analyzed using the modified BCR Sequential Extraction Procedure (SEP) in combination with ICP-MS to obtain the metal distribution patterns in this region. The results showed that heavy metal contaminations at S2 and S3 was more severe than at other sampling sites, especially for Zn, Cu, Ni and Pb. Nevertheless, the element concentrations from top to bottom layers decreased predominantly. The samples from the Straits of Malacca (S4-S7) the highest contamination factors obtained were for Co, Zn and Pb while the lowest were found for V and Cr, similar to Sungai Buloh sediments. The sediments showed a low risk for V, Cr, Cu and Pb with RAC values of less than 10%, but medium risk for Co, Zn (except S3), Cd at S1 and S2 and Ni at S1, S3 and S5. Zn at S3 and Cd at S3-S7 showed high risk to our sediment samples. There is not any element of very high risk conditions in the selected samples. PMID- 21684081 TI - Reutilization of Cr-Y zeolite obtained by biosorption in the catalytic oxidation of volatile organic compounds. AB - This work aims at the reutilization of a Cr-loaded NaY zeolite obtained by biorecovery of chromium from water as catalyst in the oxidation of volatile organic compounds (VOC). Cr-NaY catalysts were obtained after biosorption of Cr(VI) using a bacterium, Arthrobacter viscosus, supported on the zeolite. The biosorption experiments were conducted at different pH values in the range 1-4. The catalysts were characterized by several techniques, namely ICP-AES, SEM-EDS, XRD, XPS, Raman, H(2)-TPR and N(2) adsorption. The zeolite obtained at pH 4 has the highest content of chromium, 0.9%, and was selected as the best catalyst for the oxidation of different VOC, namely ethyl acetate, ethanol and toluene. For all VOC tested, the catalyst with chromium showed higher activity and selectivity to CO(2), in comparison with the starting zeolite NaY. The presence of chromium shifted also the reaction pathways. In terms of selectivity to CO(2), the following sequence was observed: ethyl acetate>toluene>ethanol. PMID- 21684082 TI - Interaction of silver nanoparticles (SNPs) with bacterial extracellular proteins (ECPs) and its adsorption isotherms and kinetics. AB - Indiscriminate and increased use of silver nanoparticles (SNPs) in consumer products leads to the release of it into the environment. The fate and transport of SNPs in environment remains unknown. We have studied the interaction of SNPs with extracellular protein (ECP) produced by two environmental bacterial species and the adsorption behavior in aqueous solutions. The effect of pH and salt concentrations on the adsorption was also investigated. The adsorption process was found to be dependent on surface charge (zeta potential). The capping of SNPs by ECP was confirmed by Fourier transform infrared spectroscopy and X-ray diffraction. The adsorption of ECP on SNPs was analyzed by Langmuir and Freundlich models, suggesting that the equilibrium adsorption data fitted well with Freundlich model. The equilibrium adsorption data were modeled using the pseudo-first-order and pseudo-second-order kinetic equations. The results indicated that pseudo-second-order kinetic equation would better describe the adsorption kinetics. The capping was stable at environmental pH and salt concentration. The destabilization of nanoparticles was observed at alkaline pH. The study suggests that the stabilization of nanoparticles in the environment might lead to the accumulation and transport of nanomaterials in the environment, and ultimately destabilizes the functioning of the ecosystem. PMID- 21684083 TI - The first survey of Theileria orientalis infection in Mongolian cattle. AB - In the present study, we have surveyed the presence of a bovine Theileria protozoan, Theileria orientalis, in Mongolian cattle and engorging tick populations from selected provinces and districts in Mongolia. The percentages of infection in the cattle and ticks ranged from 8.8 to 66.6 and from 3.7 to 73.3, respectively, on a per district basis. The genetic diversity of T. orientalis isolates was also studied, based on the protozoan gene encoding a major piroplasm surface protein (MPSP). At least five genotypes (types 1, 3, 5, 7, and N-3) of T. orientalis were found to be circulating among the Mongolian cattle and tick populations. In particular, types 3 and N-3 were common in most of the districts examined, while a strong geographical relationship among the genotypes was not detected in the present study. This is the first epidemiological report describing the presence of T. orientalis infection in Mongolian cattle. PMID- 21684084 TI - Emerging perspectives in the research of bovine babesiosis and anaplasmosis. AB - The Babesia bovis and B. bigemina apicomplexan protozoa in conjunction with the rickettsia Anaplasma marginale are intraerythrocytic pathogens that are responsible for the most prevalent and costly tick borne diseases (TBD's) of cattle worldwide. These organisms are historically associated as they can cause clinically related hemolytic diseases in cattle, are all transmitted by Rhiphicephallus (Boophilus) ticks, and share an uncanny ability to evade the immune systems of the vertebrate hosts, causing persistent disease. In addition, acute babesiosis and anaplasmosis can be prevented quite effectively by combining tick control and vaccination with living attenuated organisms. However these methods of control have numerous limitations and improved approaches are needed. Importantly, immunizations of cattle with inactivated experimental Babesia and Anaplasma vaccines can elicit variable degrees of protection, indicating the feasibility for the development of inactivated or subunit vaccines. A new research toolbox that includes full genome sequencing combined with the improved ability to genetically modify the organisms is enhancing our understanding of their biology. An emerging paradigm is the use of recently developed Babesia and Anaplasma transfection methods for functional gene characterizations and for vaccine development. Promising recently identified subunit vaccine candidates are also emerging, including babesial proteases, putative rhoptry, microneme, and sexual stage antigens, as well as subdominant, conserved, A. marginale outer membrane major surface proteins. However, significant knowledge gaps on the role of key parasite molecules involved in cell invasion, adhesion, asexual and sexual reproduction, tick transmission, and evasion of the immune system, remain. A better understanding of the biology of these organisms and the protective immune responses will positively contribute toward the goal of developing improved immunological and pharmacological interventions against these elusive pathogens that are responsible for the most devastating TBD's of cattle. Importantly, the currently available research toolbox provides basic research instruments for helping close current knowledge gaps which will aid the design and production of effective vaccines and alternative pharmacological interventions. PMID- 21684085 TI - Can natural antibodies to VIP or VIP-like HIV-1 glycoprotein facilitate prevention and supportive treatment of breast cancer? AB - OBJECTIVES: The incidence of non-AIDS-defining cancer is remarkably higher in HIV infected than in the general population. In contrast, breast cancer risk is significantly reduced in the HIV-infected population. The molecular mechanisms underlying the phenomenon of suppression of breast cancer in the HIV-infected population may serve as a basis for development of a new platform for prevention and treatment of breast cancer. HYPOTHESIS: Various evidences indicate that vasoactive intestinal peptide (VIP) plays an important role in growth, and differentiation of breast cancer. We previously showed (i) that natural antibodies recognizing VIP and the gp120-derived peptide NTM significantly contribute to the control of HIV disease progression by suppression of VIP-like activity of HIV-1 gp120 and (ii) that physical exercise stimulates production of these natural antibodies. These findings suggest that natural anti-VIP/NTM antibodies could contribute to a decrease of breast cancer in the HIV-infected population by suppression of VIP, which may play a pro/oncogenic function. Aerobic exercise which stimulates production of anti-VIP/NTM antibodies could be used as prevention and supportive treatment of breast cancer. IMPACT: Immunotherapy based on natural anti-VIP/NTM antibodies could serve as an effective adjunct therapy for the treatment of breast cancer. Similarly, aerobic exercise, which stimulates production of these antibodies, should be considered as an inexpensive and safe preventive and supportive breast cancer therapy. Natural anti-VIP/NTM antibodies also represent promising prognostic marker for breast cancer. PMID- 21684086 TI - Total antioxidant capacities of raw and cooked meats. AB - This study investigated the total antioxidant capacity (TAC) of meats (beef, chicken, pork and fish) and its changes on thermal treatment. The QUENCHER procedure, which is performed directly on the solid material without extraction, was selected and proved to be particularly suitable for meat samples. The ABTS(+) scavenging capacity of raw meats ranged between 25.9+/-1.0 and 51.7+/-1.2 mmol Trolox Eq./kg. Raw chicken had the highest TAC followed by pork, beef and fish. Upon heating at 180 degrees C, TAC of meats increased to an apparent maximum at 5 min followed by sudden decreases until 15 min, while the final stage of heating was characterized by slight increases. The modifications of TAC during cooking can be explained considering factors such as denaturation and exposure of reactive protein sites, degradation of endogenous antioxidants and the formation of Maillard reaction products having antioxidant properties. PMID- 21684087 TI - [Umbilical endometriosis in women free of abdominal surgical antecedents]. AB - Primary umbilical endometriosis represents a very rare localization of the disease and is represented by blue, papular, nodular or cystic lesions whose symptoms are related to ovarian cycle. We report the management of three women, free of surgical antecedents presenting with primary umbilical endometriosis. In each woman, abdominal laparoscopy revealed peritoneal pelvic endometriosis. The excision of umbilical lesions was performed with satisfactory esthetical outcomes. In our experience, umbilical endometriosis responsible for highly characteristic features appears playing the role of clinical marker for pelvic endometriosis. PMID- 21684088 TI - Treatment of adolescents with a cannabis use disorder: main findings of a randomized controlled trial comparing multidimensional family therapy and cognitive behavioral therapy in The Netherlands. AB - BACKGROUND: To meet the treatment needs of the growing number of adolescents who seek help for cannabis use problems, new or supplementary types of treatment are needed. We investigated whether multidimensional family therapy (MDFT) was more effective than cognitive behavioral therapy (CBT) in treatment-seeking adolescents with a DSM-IV cannabis use disorder in The Netherlands. METHODS: One hundred and nine adolescents participated in a randomized controlled trial, with study assessments at baseline and at 3, 6, 9 and 12 months following baseline. They were randomly assigned to receive either outpatient MDFT or CBT, both with a planned treatment duration of 5-6 months. Main outcome measures were cannabis use, delinquent behavior, treatment response and recovery at one-year follow-up, and treatment intensity and retention. RESULTS: MDFT was not found to be superior to CBT on any of the outcome measures. Adolescents in both treatments did show significant and clinically meaningful reductions in cannabis use and delinquency from baseline to one-year follow-up, with treatment effects in the moderate range. A substantial percentage of adolescents in both groups met the criteria for treatment response at month 12. Treatment intensity and retention was significantly higher in MDFT than in CBT. Post hoc subgroup analyses suggested that high problem severity subgroups at baseline may benefit more from MDFT than from CBT. CONCLUSIONS: The current study indicates that MDFT and CBT are equally effective in reducing cannabis use and delinquent behavior in adolescents with a cannabis use disorder in The Netherlands. PMID- 21684089 TI - Depressive mood and tobacco use: moderating effects of gender and emotional attention. AB - INTRODUCTION: Depressive symptomatology is a predictive variable of tobacco use. The objective of the present study was to evaluate the influence that this symptomatology has on tobacco use when moderated by emotional attention. METHODS: A total of 289 participants (127 males, 162 females) completed a survey to measure perceived emotional intelligence, depressive symptomatology, tobacco use and sociodemographic variables. Results were analyzed using a multiple regression model that included self-perceived emotional attention as a moderating variable. RESULTS: In women, an interaction was found between depressive symptomatology and gender for predicting the number of cigarettes smoked (t=2.45; p=.01), but not in men (t=-.74; p=.45). This interaction was moderated by emotional attention (t=2.83; p=.005), such that women with medium and high levels of attention consumed a larger number of cigarettes. CONCLUSIONS: In women, the effect of depressive symptomatology on tobacco use was moderated by the amount of attention that women paid to those symptoms. Such a moderating effect of attention was not observed in men. We recommend that smoking cessation programs incorporate interventions designed specifically for women, in particular to help them manage depressive symptomatology. PMID- 21684090 TI - Immunization of chickens with Salmonella enterica subspecies enterica serovar Enteritidis pathogenicity island-2 proteins. AB - Several structural components of the type III secretion systems (T3SS) encoded by Salmonella pathogenicity island (SPI)-1 and SPI-2 are exposed to the host's immune system prior to/during the infection/invasion process, making them potential vaccine candidates. In this study we evaluated whether chickens vaccinated with SPI-2 T3SS components could mount a significant humoral immune response (as measured by serum IgG titres) and whether these antibodies could be transferred to progeny (as measured by egg yolk IgG titres), and whether vaccinates and progeny of vaccinates could be protected against challenge with SE. The results of our studies show that vaccinated chickens do produce high levels of SPI-2 T3SS specific serum IgG that they are able to transfer to their progeny. It was demonstrated that vaccinates and progeny of vaccinates had lower overall countable recovered Salmonella enterica subspecies enterica serovar Enteritidis (SE) per bird in most situations. PMID- 21684091 TI - Emergence and genetic variability of Anaplasma species in small ruminants and ticks from Central Europe. AB - Anaplasmoses are common tick-borne zoonotic bacterial diseases of livestock and free-living ungulates from the genus Anaplasma that are recently emerging in Central Europe. The main aim of this study was to analyze the prevalence and genetic variability of Anaplasma phagocytophilum and Anaplasma ovis in small ruminants and questing ticks from six different sites in Slovakia and the Czech Republic using the PCR of the msp4 gene followed by the sequence analysis. At two farms from southeastern Slovakia, 66.1% small ruminants were infected with A. ovis in contrast to one positive animal from both sites in northern Slovakia. It was represented by two different genotypes. A. phagocytophilum was present in all tested flocks with the infection prevalence ranging from 0.9% to 5.7%. None of the tested questing ticks carried A. ovis. A. phagocytophilum was detected in 1.1% and 7.8% of questing Ixodes ricinus ticks collected around the farms located in southeastern and northern Slovakia, respectively. A. phagocytophilum revealed higher intraspecific diversity than A. ovis. PMID- 21684092 TI - Genetic differentiation of infected from vaccinated animals after implementation of an emergency vaccination strategy against classical swine fever in wild boar. AB - Oral emergency vaccination against classical swine fever is a powerful tool to control disease outbreaks among European wild boar and thus to safeguard domestic pigs in affected regions. In the past, when virus detection was mainly done using virus isolation in cell culture or antigen enzyme-linked immunosorbent assays, modified live vaccine strains like C-strain "Riems", were barely detectable after oral vaccination campaigns. Nowadays, the use of highly sensitive molecular techniques has given rise to an increase in vaccine virus detections. This was also the case during the 2009 outbreak among German wild boar and the subsequent vaccination campaigns. To guarantee a rapid differentiation of truly infected from C-strain vaccinated animals, a combination of differentiating multiplex rRT PCR assays with partial sequencing was implemented. Here, we report on the rational and use of this approach and the lessons learned during execution. It was shown that positive results in the recently developed vaccine strain (genotype) specific rRT-PCR assay can be taken as almost evidentiary whereas negative results should be confirmed by partial sequencing. Thus, combination of multiplex rRT-PCR assays as a first line differentiation with partial sequencing can be recommended for a genetic DIVA strategy in areas with oral vaccination against classical swine fever in wild boars. PMID- 21684093 TI - Transcriptional profiling of peripheral lymphoid tissue reveals genes and networks linked to SSBP/1 scrapie pathology in sheep. AB - Transmissible spongiform encephalopathies (TSEs) are slow and progressive neurodegenerative diseases of humans and animals. The major target organ for all TSEs is the brain but some TSE agents are associated with prior accumulation within the peripheral lymphoid system. Many studies have examined the effects of scrapie infection on the expression of central nervous system (CNS) genes, but this study examines the progression of scrapie pathology in the peripheral lymphoid system and how scrapie infection affects the transcriptome of the lymph nodes and spleen. Infection of sheep with SSBP/1 scrapie resulted in PrP(Sc) deposition in the draining prescapular lymph node (PSLN) by 25 days post infection (dpi) in VRQ/VRQ genotype sheep and 75 dpi in tonsils and spleen. Progression of PrP(Sc) deposition in VRQ/ARR animals was 25 dpi later in the PSLN and 250 dpi later in spleen. Microarray analysis of 75 dpi tissues from VRQ/VRQ sheep identified 52 genes in PSLN and 37 genes in spleen cells that showed significant difference (P <= 0.05) between scrapie-infected and mock-infected animals. Transcriptional pathway analysis highlighted immunological disease, cell death and neurological disease as the biological pathways associated with scrapie pathogenesis in the peripheral lymphoid system. PrP(Sc) accumulation of lymphoid tissue resulted in the repression of genes linked to inflammation and oxidative stress, and the up-regulation of genes related to apoptosis. PMID- 21684094 TI - The central role of lipoproteins in the pathogenesis of mycoplasmoses. AB - Mycoplasmas are a diverse group of pathogens responsible for disease in a wide range of animal species. In recent years there have been considerable advances in knowledge of the proteins and structures involved in adherence in some mycoplasmas, but understanding of the biochemical functions and roles in virulence of another central feature of mycoplasmas, their lipoproteins, continues to develop. The aim of this review is to examine current knowledge of the roles of lipoproteins in the pathogenicity and the evolution of virulence in those mycoplasmas causing disease in domestic animals. Those lipoproteins that have been characterised have roles in adherence, in transport of nutrients into the mycoplasma cell, and in enzymatic interactions with the host. Furthermore they appear to play a prominent role in both inducing the host immune response to infection and in facilitating evasion of this response, particularly through the generation of dramatic levels of antigenic variation on the cell surface. Recent genomic comparisons of several pathogenic mycoplasmas have identified a further level of interaction between lipoproteins and pathogenicity. In several pathogens large scale horizontal gene transfer between distantly related mycoplasma species has resulted in the acquisition of a large number of genes, including those encoding lipoproteins thought to play a role in virulence, by one mycoplasma from another inhabiting the same host species. The interactions between these horizontally transferred genes, their new mycoplasma host and the animal that it infects may be an important contributing factor in the pathogenesis of some mycoplasmoses. PMID- 21684095 TI - Polymorphisms in follicle stimulation hormone receptor, inhibin alpha, inhibin bata A, and prolactin genes, and their association with sperm quality in Chinese Holstein bulls. AB - Candidate genes follicle stimulation hormone receptor (FSHR), inhibin alpha (INHA), inhibin bata A (INHBA) and prolactin (PRL) were investigated for their association with sperm quality traits of semen volume per ejaculate (VOL), sperm concentration (SCON), motility (MOT), sperm motility in frozen semen (FMOT), acrosome integrity rate (AIR) and abnormal sperm rate (ASR) in a total of 123 normal mature Holstein bulls. Three reported single nucleotide polymorphisms (SNPs) of FSHR A-234500T (rs43676359), IHNA A192G (rs41257116), and IHNBA C7639T (rs43408735), and 3 novel SNPs (G7550A, C7661T, and T8370C) in exons 4 and 5 of bovine PRL gene (NC 007324) were analyzed. Analysis of variance revealed that FSHR A-234500T and INHBA C7639T polymorphisms significantly associated with VOL (P<0.05) and SCON (P<0.05), and the polymorphism of INHBA C7639T also had significant effects on MOT (P<0.05). Furthermore, the INHA A192G polymorphism significantly associated with AIR (P<0.05). No significant differences were found between the polymorphisms of PRL gene and sperm quality traits. PMID- 21684096 TI - The effect of hysterectomy or levonorgestrel-releasing intrauterine system on cardiovascular disease risk factors in menorrhagia patients: a 10-year follow-up of a randomised trial. AB - OBJECTIVE: To compare, whether women with menorrhagia, treated with either hysterectomy or LNG-IUS, differ in their cardiovascular risk profile during 10 year follow-up. STUDY DESIGN: A total of 236 women were randomized to treatment by hysterectomy (n=117) or LNG-IUS (n=119). Their cardiovascular risk factors were analyzed at baseline, at 5 years, and at 10 years. As 55 originally randomized to the LNG-IUS group had hysterectomy during the follow-up, all analyzes were performed by actual treatment modality. MAIN OUTCOME MEASURES: Waist circumference, body-mass index (BMI), blood pressure, and the levels of blood lipids, serum high-sensitivity CRP (hsCRP) and tumor necrosis factor alpha (TNF-alpha) were measured, and the use of medication for hypertension, diabetes, hypercholesterolemia, and ischemic heart disease was analyzed. RESULTS: After 5 years, an increase in the use of diabetes medication during the follow-up was only detected in the hysterectomy group (from 1.7% to 6.7%, P=0.008 vs from 5.1% to 8.4%, P=0.08), as well as they had significantly higher serum levels of TNF alpha (108.59 pg/ml vs 49.02 pg/ml, P=0.001) and hsCRP (1.55 MUg/ml vs 0.78 MUg/ml, P=0.038) at 5- and 10-years. There was no difference between the groups in the use of cardiovascular medication, neither was there difference in blood pressure, waist circumference, BMI, or concentrations of blood lipids. CONCLUSIONS: Hysterectomy seems to be associated with increased levels of serum inflammatory markers and increased diabetes medication, which in turn, may predispose individual to future cardiovascular events. PMID- 21684097 TI - The co-occurrence of autism and epilepsy and the lack of a targeted therapeutical approach. PMID- 21684098 TI - Radiological evaluation of cartilage after microfracture treatment: a long-term follow-up study. AB - INTRODUCTION: Recent literature revealed good short-term results after microfracturing (MFX) of isolated focal cartilage defects in the knee joint. Study purpose was a long-term evaluation of patients who received MFX through a multimodal approach, correlating clinical scores and morphological pre- and postoperative MRI-scans. MATERIALS AND METHODS: Between 2000 and 2007 158 patients were treated with MFX for focal femoral or tibial defects at our department. Patients with instabilities, secondary surgical intervention, patellofemoral lesions, a plica mediopatellaris or more than one cartilage defect site and age >55 were excluded. 15 patients were included. Minimum postoperative follow-up (FU) was 18 months (18-78 m). Mean age at surgery was 45 years (27-54), mean FU-interval 48 months (18-78 m). Male to female ratio was 9:6. For clinical assessment the Knee Osteoarthritis Ou tcome Score (KOOS) and Lysholm Score were used, radiological evaluation was performed with radiographs and 3Tesla-MRI. RESULTS: Clinical knee function was rated good to excellent in 1 patient, fair in 2 and poor in 10 patients. 2/15 patients received full knee replacement due to insufficient cartilage repair through MFX during FU period. Evaluation of pre- and postoperative MRI showed good cartilage repair tissue in 1 (7.7%), moderate repair in 2 (15.4%) and poor fill in 10 patients (76.9%). In these 10 patients the defect size increased. Average defect size preoperatively was 187 mm(2) (range 12-800 mm(2)) and postoperatively 294 mm(2) (40-800 mm(2)). The KOOS-Pain averaged 60 (39-94), KOOS-Symptoms 60.6 (21-100), KOOS-ADL 69 (21-91), KOOS Sports 35.7 (5-60) and KOOS-QUL 37.2 (6-81). The average Lysholm Score was 73.9 (58-94). 10 patients showed a varus leg axis deviation (O 5.9 degrees ), 3 had a neutral alignment. The alignment correlated positively with KOOS and especially with the Lysholm Score. CONCLUSION: Our study demonstrated that MFX as a treatment option for cartilage defect in the knee did not show the anticipated clinical and radiological long-term results. In 12 of 15 patients the cartilage defect size had increased after MFX, in 2 patients indicating full-knee replacement. Especially those with a leg malalignment >5 degrees in varus were more prone to suffer from an increase in defect size. In our cohort the clinical scores correlated with the radiological findings. PMID- 21684099 TI - A review of patient dose and optimisation methods in adult and paediatric CT scanning. AB - An increasing number of publications and international reports on computed tomography (CT) have addressed important issues on optimised imaging practice and patient dose. This is partially due to recent technological developments as well as to the striking rise in the number of CT scans being requested. CT imaging has extended its role to newer applications, such as cardiac CT, CT colonography, angiography and urology. The proportion of paediatric patients undergoing CT scans has also increased. The published scientific literature was reviewed to collect information regarding effective dose levels during the most common CT examinations in adults and paediatrics. Large dose variations were observed (up to 32-fold) with some individual sites exceeding the recommended dose reference levels, indicating a large potential to reduce dose. Current estimates on radiation-related cancer risks are alarming. CT doses account for about 70% of collective dose in the UK and are amongst the highest in diagnostic radiology, however the majority of physicians underestimate the risk, demonstrating a decreased level of awareness. Exposure parameters are not always adjusted appropriately to the clinical question or to patient size, especially for children. Dose reduction techniques, such as tube-current modulation, low-tube voltage protocols, prospective echocardiography-triggered coronary angiography and iterative reconstruction algorithms can substantially decrease doses. An overview of optimisation studies is provided. The justification principle is discussed along with tools that assist clinicians in the decision-making process. There is the potential to eliminate clinically non-indicated CT scans by replacing them with alternative examinations especially for children or patients receiving multiple CT scans. PMID- 21684100 TI - [Anaesthesia for HIV-infected patients]. AB - France is one of main countries affected by the HIV-outbreak in Europe with more than 120,000 cases, among which 34,600 patients having developed an AIDS. The antiretroviral combination therapies (combined antiretroviral therapy [cART]) reduced by half the mortality. A low compliance to cART alters the virologic control and increases the morbimortality. If required, the therapeutic break should be the shortest possible, including the whole treatment (to limit the risk of viral resistance). The perioperative care should take into account the underlying conditions. During the preoperative period, the clinical picture could combine various complications: 1: respiratory impairment; 2: impairment of neuronal functions (related to viral factors, host response and environmental factors such as alcohol, drug addiction, HCV co-infection) inducing a cognitive dysfunction or a peripheral neuropathy; 3: lipodystrophy, dyslipidemia and insulin resistance are the main metabolic cART-related side effects, responsible for atherosclerosis and coronaropathy; 4: major nutritional impairment. Anesthesia for HIV patients is almost the same than usual, without HIV-related contraindication to regional anesthesia. Anesthetic drugs can be associated to cART. The main restriction belongs to the protease inhibitors, which could affect the metabolic pathways of opioids, NSAIDs and benzodiazepines (over dosage risks). During the postoperative period, the follow-up should include the thromboembolism prevention (increased risk compared to main people), the cardiovascular side effects, the nutritional status and the continuation of the treatment. Moreover, the psychological status related and a close collaboration with the corresponding physician is critical. PMID- 21684101 TI - [Cervical disc hernia decompensation complicated by postoperative transitory tetraparesia about long-term haemodialysis patient]. AB - We report a case of a 51-year-old man who underwent a third kidney transplantation that was complicated by tetraparesia due to a C5-C6 cervical disc hernia decompensation in the immediate postoperative period. Preoperative consultation for long-term haemodialysis patients could be perfected by further neurological investigation and additional imagery. PMID- 21684102 TI - Tissue inhibitor of metalloproteinase-1 decreased chemosensitivity of MDA-435 breast cancer cells to chemotherapeutic drugs through the PI3K/AKT/NF-kB pathway. AB - TIMP-1 is well known to be capable of inhibiting apoptosis. Elevated levels of TIMP-1 in tumor tissue have been shown to be strongly associated with a poor response to chemotherapy. In this study, using conventional cytotoxic drugs commonly used in the treatment of breast cancer, we investigated how TIMP-1 influenced the efficacy using breast cell lines. Our data demonstrated that overexpression of TIMP-1 could significantly decrease the sensitivity of MDA-435 breast cancer cells to epirubicin and paclitaxel. TIMP-1 can potently activate phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappaB (NF-kB) signaling. Furthermore, the TIMP-1-induced attenuation of the effect of epirubicin and paclitaxel was reversed by the PI3K/Akt chemical inhibitor LY294002 and the NF-kB inhibitor pyrrolidine dithiocarbamate (PDTC), showing that the PI3K/Akt and NF-kB signaling pathway was involved in the TIMP-1-induced effect on chemoresistance. Taken together, our results indicate that TIMP-1 decreased chemosensitivity through the PI3K/Akt/NF-kB signal transduction pathway in MDA-435 breast cancer cells. PMID- 21684103 TI - [Mechanisms of gout inflammation]. AB - Gout inflammation is an acute and self-resolving reaction. MSU crystals can stimulate cells through either crystal-cell membrane interaction or after their phagocytosis. The onset of gout inflammation relies on non-hematopoietic resident cells whereas the amplification of the reaction is driven by phagocytic cells of immune innate system. Interleukin-1beta (IL-1beta) and polynuclear neutrophils play central role in gout inflammation. In vitro, MSU crystal-induced IL-1beta secretion is secondary mainly to NLRP3 inflammasome activation although numerous proteases are also involved. Mechanisms of NLRP3 inflammasome activation remain unclear involving mostly reactive oxygen species production. Gout resolution involves several mechanisms including monocyte differentiation into macrophage, clearance of apoptotic neutrophils by macrophages, production of Transforming Growth Factor (TGF-beta) and modification of protein coating on MSU crystal surface. PMID- 21684104 TI - [New therapeutic options for gout]. AB - Chronic hyperuricemia and acute arthritis in severe gouty patients can be difficult to manage, in particular in patients with renal failure or with history of cardio vascular conditions. Hopefully, new drugs have been approved or will emerge, and will help to overcome these situations. Febuxostat has been recently approved in France for the treatment of chronic hyperuricemia in conditions where urate deposition has already occurred. Febuxostat is a novel non-purine, selective inhibitor of xanthine oxidase, metabolized and excreted by the liver, so no dose adjustment appears to be necessary in patients with mild-to-moderate renal impairment. Other novel hypouricemic drugs are the PEG-uricase (pegloticase), recently approved by the FDA, and a novel uricosuric drug (RDEA594), which is currently under development. The discovery that interleukin 1beta (IL- beta) plays a key role in the pathogenesis of acute attacks of gout has prompted to assess the efficacy of IL-1 beta blockers in patients with acute gout. Biologic agents that inhibit IL-1 beta such as canakinumab, rilonacept and anakinra have shown promising results for the treatment of gouty arthritis. PMID- 21684105 TI - [Sugar-sweetened beverages and cardiometabolic risk]. AB - The observation of parallel increase in the prevalence of obesity and consumption of sweet beverages has drawn the attention of the scientific community on the possibility of a link between these tendencies at the population level. Clinical and epidemiological evidence support the possibility of a relationship between consumption of sweet beverages and the occurrence of obesity and diabetes. The precise mechanisms of these associations need further clarification. Nutritional education programs aiming at reducing sweet beverage intake in experimental schools have lowered the occurrence of obesity as compared to control schools. Energy intake via beverages is less efficiently regulated than energy from solid foods. Strategies for obesity and diabetes prevention should incorporate not only increasing physical activity, improving fatty acid quality of food items, but also reducing energy intake from beverages. PMID- 21684106 TI - [Hyperuricemia and uro-nephrological disorders]. AB - Hyperuricemia is a specific risk factor for cardiovascular morbidity and mortality. Uric acid lithiasis is urological symptom of hyperuricemia. In case of uric acid lithiasis, you must search a metabolic syndrome, an insulin resistance, a type 2 diabetes. Chronic tubular interstitial nephropathy is the renal disease of hyperuricemia. Hyperuricemia is a specific risk factor for chronic renal failure. Metabolism of uric acid involves the uromodulin. PMID- 21684107 TI - [Cutaneous manifestations of male breast cancer]. AB - OBJECTIVE: The appearance of skin symptoms in male breast is the main reason for consultation in our context. The aim of this study is to describe the various cutaneous manifestations of male breast cancer through a series of cases collected in a dermatology department. METHODS: A retrospective study was conducted in the dermatology department at the CHU Ibn Rochd January 1988 to December 2009. All cases of male breast cancer initially diagnosed in dermatology were included. The various epidemiological, clinical, histological and therapeutic data were collected from medical records. RESULTS: Twenty cases were collected. The mean age was 61.25 years. Skin invasion by tumor was found in all patients, and it was the reason for consultation. It was a cutaneous involvement at the nipple and areola (17 cases) and at the periareolar skin (three cases). The clinical appearance of skin involvement was vegetative type in 12 cases, infiltrating with nipple retraction in five cases and nodule with skin change in three cases. The average period of consultation was 25 months. The axillary lymph nodes were noted in 11 patients and distant metastases in eight patients. The cutaneous metastases outside breast were noted in six patients. The histological types were: infiltrating ductal carcinoma in 15 cases (75%), papillary carcinoma in two cases (10%) and non-specific carcinoma in three cases (15%). The treatment was surgery in 14 patients and consisted of radical mastectomy with complete axillary nodal dissection according to Patey. Complementary therapies, chemotherapy or radiotherapy, were indicated in 14 patients. CONCLUSION: Our single-center study with dermatological recruitment illustrates the frequency and variety of skin disease in male breast cancer and demonstrates that they are still the main reason for consultation in our context. Better information for public and practitioners would allow earlier diagnosis and a more favourable prognosis. PMID- 21684108 TI - [Calcium pyrophosphate deposition disease]. AB - Definitive diagnosis of chondrocalcinosis (CC) is allowed by identification of calcium pyrophosphate (CPP) crystals in synovial fluid. In daily practice, X-Rays are the most frequent imaging used to detect CC. Most cases of CC are sporadic. If CC occurs before 60 years of age, primary metabolic disorders such as hyperparathyroidism, hypomagnesemia, and hemochromatosis or a familial predisposition should be particularly considered. Treatment of CPP arthritis includes application of ice, rest, joint aspiration and intra-articular injection of corticosteroids. Oral NSAIDs can be used cautiously, in particular in the elderly. Prophylaxis against frequent recurrent acute CPP crystal arthritis can be achieved with low-dose oral colchicine. PMID- 21684109 TI - Dry eye after laser in situ keratomileusis with femtosecond laser and mechanical keratome. AB - PURPOSE: To prospectively compare dry-eye symptoms after laser in situ keratomileusis (LASIK) with mechanical keratome-created flaps and femtosecond laser keratome-created flaps. SETTING: Department of Ophthalmology, Stanford University School of Medicine, Stanford, California, USA. DESIGN: Randomized clinical trial. METHODS: Fellow eyes were prospectively randomized to the mechanical keratome group and femtosecond laser keratome group. Patients had wavefront-guided LASIK using a mechanical keratome in 1 eye and a femtosecond laser keratome in the fellow eye. They completed dry-eye questionnaires preoperatively and 1, 3, 6, and 12 months postoperatively. The effect of laser ablation depth, sex, age, and flap thickness on dry-eye symptoms was also analyzed. RESULTS: The study enrolled 51 patients. There was no statistically significant change in dry-eye symptoms except in the femtosecond group 1 month postoperatively (mean increase 1.08) (P=.03). There were no significant differences in symptoms between the 2 groups (P=.7). The dry-eye score was 1.3 points lower in women than in men (P=.01). Central ablation depth, flap thickness, and age did not significantly affect the reported dryness. CONCLUSION: There appeared to be no statistically significant difference in self-reported dry eye symptoms between the mechanical keratome group and the femtosecond laser keratome group. PMID- 21684110 TI - Cataract surgery in eyes with low corneal endothelial cell density. AB - PURPOSE: To compare corneal endothelial damage after cataract surgery in eyes with low endothelial cell density (ECD) and eyes with normal ECD. SETTING: Hayashi Eye Hospital, Fukuoka, Japan. DESIGN: Case-control study. METHODS: Cataract surgery was performed in eyes with a low ECD (500 to 1000 cells/mm(2)) (low-density group) and control eyes with a normal ECD. The ECD and central corneal thickness (CCT) were measured preoperatively and 1 and 3 months postoperatively, and the percentage cell loss and increase in CCT were compared. RESULTS: The low-density group and control group each comprised 50 eyes. In the low-density group, 39 eyes had nonprogressive endothelial pathology and 11 had Fuchs dystrophy. The mean ECD was significantly less and the CCT significantly greater in the low-density group than in the control group throughout the follow up (P <=.0066). However, no significant difference in the percentage of cell loss was found between groups at 1 or 3 months (5.1%, low-density group; 4.2%, control group) (P >=.1477). The percentage increase in CCT was significantly greater in the low-density group than in the control group at 1 month (P<.0001), although there was no significant difference at 3 months (0.4% and -0.4%, respectively) (P=.2172). CONCLUSION: Corneal endothelial damage after cataract surgery in eyes with low ECD was slight and comparable to that in healthy eyes, which suggests that cataract surgery alone (without corneal transplantation) should be performed first. PMID- 21684111 TI - Risk assessment of simple phacoemulsification in patients on combined anticoagulant and antiplatelet therapy. AB - PURPOSE: To assess the safety of phacoemulsification cataract extraction in patients on combined anticoagulant and antiplatelet treatment. SETTING: Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Israel. DESIGN: Prospective interventional case series. METHODS: Consecutive patients with simple cataract on combined anticoagulant (warfarin) and antiplatelet (aspirin or clopidogrel) treatment who were unable to discontinue the treatment because of a high risk for thromboembolic events were included. Patients had cataract extraction under topical anesthesia with a clear corneal incision (CCI), phacoemulsification, and implantation of a foldable posterior chamber intraocular lens. Prothrombin time-international normalized ratio and platelet functions were evaluated immediately before surgery. Patients were also examined 1 day and 7 days postoperatively. Intraoperative and postoperative ocular bleeding and other related complications were assessed. RESULTS: Forty patients (51 eyes) with a mean age of 72 years (range 51 to 90 years) had phacoemulsification. Hemorrhagic complications were not observed at surgery or during the 1-week follow-up. Surgical complications included 1 rupture of the capsulorhexis and 1 implantation of a capsular tension ring due to partial zonulysis. No patient had a thromboembolic event. CONCLUSIONS: In patients with uncomplicated cataract at high risk for thromboembolic events, phacoemulsification cataract surgery using a CCI under topical needle-free anesthesia was safely performed without discontinuing systemic anticoagulant and antiplatelet treatment. PMID- 21684112 TI - Determinants of patient satisfaction after orthopedic interventions to the hand: a review of the literature. AB - Treatment effectiveness is increasingly evaluated from the patients' perspective. However, the interpretation of satisfaction is complex because the patient's perception of a satisfactory outcome is influenced by numerous factors. The objective of this study was to identify which factors are associated with patient satisfaction after orthopedic interventions to the hand. A literature review was conducted, including studies on determinants of satisfaction with treatment outcome or unspecified overall satisfaction of patients with hand problems. The results indicate that patient satisfaction is determined by multiple factors. There is moderate evidence that pain/symptoms, activities of daily living/function, aesthetics, and embodiment influence patient satisfaction. Furthermore, data indicate a correlation of strength, range of motion, fulfillment of expectations, deformity, workers' compensation, and length of follow-up with satisfaction. Knowledge about these determinants may lead to a more detailed decision-making process, thus contributing to improved treatment outcomes and cost-effectiveness. LEVEL OF EVIDENCE: V. PMID- 21684113 TI - Tissue doppler imaging and plasma BNP levels to assess the prognosis in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: In addition to sudden death, heart failure and stroke due to atrial fibrillation are important in patients with hypertrophic cardiomyopathy (HCM). The aim of the present study was to determine whether Doppler tissue imaging findings and plasma B-type natriuretic peptide (BNP) levels, which are widely used for risk stratification in several cardiovascular diseases, are useful for risk stratification in patients with HCM in a regional cohort. METHODS: One hundred thirty patients (82 men; mean age, 60 +/- 16 years) with HCM were enrolled in this study. RESULTS: Twenty end points were observed during a mean follow-up period of 3.7 +/- 1.7 years. Septal E/e' ratios and BNP levels in patients with events were higher than those in patients without events (17.4 +/- 6.3 vs 10.6 +/- 4.3, P < .0001, and 441 +/- 304 vs 202 +/- 174 pg/mL, P < .0001, respectively). By multivariate logistic regression analysis, a high septal E/e' ratio, in addition to a history of syncope and documentation of atrial fibrillation, was a significant predictor of combined end points. In contrast, plasma BNP levels were not a significant predictor of combined end points. CONCLUSION: Assessment by Doppler tissue imaging is useful for further risk stratification of patients with HCM. PMID- 21684114 TI - Updating comparative effectiveness reviews: current efforts in AHRQ's Effective Health Care Program. AB - OBJECTIVES: To review the current knowledge and efforts on updating systematic reviews (SRs) as applied to comparative effectiveness reviews (CERs). STUDY DESIGN AND SETTING: This article outlines considerations for updating CERs by including a definition of the updating process, describing issues around assessing whether to update, and providing general guidelines for the update process. Key points to consider include (1) identifying when to update CERs, (2) how to update CERs, and (3) how to present, report, and interpret updated results in CERs. RESULTS: Currently, there is little information about what proportion of SRs needs updating. Similarly, there is no consensus on when to initiate updating and how best to carry it out. CONCLUSION: CERs need to be regularly updated as new evidence is produced. Lack of attention to updating may lead to outdated and sometimes misleading conclusions that compromise health care and policy decisions. The article outlines several specific goals for future research, one of them being the development of efficient guideline for updating CERs applicable across evidence-based practice centers. PMID- 21684115 TI - Finding evidence for comparing medical interventions: AHRQ and the Effective Health Care Program. AB - OBJECTIVE: This article discusses search methodology to identify evidence for comparative effectiveness reviews (CERs) as practiced by the Effective Health Care program. STUDY DESIGN AND SETTING: Review. RESULTS: Search methods described attempt to overcome the bias inherent in the publication and distribution of clinical evidence. Bibliographic databases and search strategies are discussed with special emphasis on searching for observational studies and harms data. Other techniques described include the use of key articles, citation tracking, hand searching, and personal communications. Strategies for locating gray literature, such as clinical trial protocols and regulatory information, are described. Search reporting and other practical matters are also discussed. CONCLUSION: Better reporting and further research on search strategies is needed to develop additional evidence-based recommendations. PMID- 21684116 TI - Boosting qualifies capture-recapture methods for estimating the comprehensiveness of literature searches for systematic reviews. AB - OBJECTIVE: Capture-recapture methods were proposed to evaluate the comprehensiveness of systematic literature searches. We investigate the statistical feasibility of capture-recapture techniques with model selection for estimating the number of missing references in literature searches using two systematic reviews in gastroenterology and hematology. STUDY DESIGN AND SETTING: First, we compared manually selected Poisson regression models that differ with respect to included interactions. Secondly, we performed selection via componentwise boosting, which provides automatic variable selection. The proposed boosting technique is a regularized, stepwise procedure allowing to distinguish between mandatory and optional variables. Results from all models were compared based on Akaike's Information Criterion and the Bayesian Information Criterion. RESULTS: For the first example, the best manually selected model suggested a number of 82 missing articles (95% CI: 52-128), whereas the boosting technique provided 127 (95% CI: 86-186) missing articles. For the second example, 140 (95% CI: 116-168) missing articles were estimated for the manually selected and 188 (95% CI: 159-223) for the automatically selected model. CONCLUSION: Capture recapture analysis requires the selection of an appropriate model. Because of problems of variable selection and overfitting, manual model selection yielded large estimates, varying markedly, with broad confidence intervals. By contrast, boosting was robust against overfitting and automatically created an appropriate model for inference. PMID- 21684119 TI - Pharmaconutrition: how has this concept evolved in the last two decades? PMID- 21684117 TI - Accurate reporting of expected delivery date by mothers 9 months after birth. AB - OBJECTIVE: To measure agreement between gestational age based on maternal report of expected date of delivery (EDD) 9 months after birth and gestational age at birth in routine hospital data. Furthermore, to examine whether sociodemographic and perinatal factors influenced agreement and whether disagreement affected classification of infants in preterm groups. STUDY DESIGN AND SETTING: The study used data on 8,058 singleton infants from the UK Millennium Cohort Study. Women were interviewed 9 months after birth and interviews were linked to routine hospital data. The infant's date of birth and EDD were used to calculate gestational age in completed weeks. RESULTS: Agreement between maternal report and hospital data was 72% for exact number of weeks' gestation and 94% for agreement within 1 week. Disagreement was associated with the infant not being firstborn, unplanned pregnancy, late or no antenatal care, and low socioeconomic status. Maternal report of gestational age resulted in slightly more children being classified as preterm (6.4%) than gestational age based on hospital data (6.1%). Agreement was found to be poor for postterm births. CONCLUSION: Gestational age based on retrospective maternal reporting of EDD is reliable within 1 week or when used to assign infants to broad gestational groups. PMID- 21684120 TI - Effects of flavonoids on alpha-glucosidase activity: potential targets for glucose homeostasis. AB - OBJECTIVE: Flavonoids are naturally occurring compounds widely distributed in plants, which have hypoglycemic potential and have been described as glucosidase inhibitors. This study evaluated the effect of flavonoids on intestinal glucosidase activity after in vivo and in vitro treatment. METHODS: For the in vivo studies animals received quercetin by gavage and for the in vitro assays a segment of the small intestine was used. To obtain the oral glucose tolerance curve fasted normal rats were loaded with glucose plus flavonoids. The glycemia was measured by the glucose oxidase method. RESULTS: Quercetin reduced the effect of sucrase and maltase in the in vivo and in vitro treatments. It was observed in the in vitro studies that the maximum inhibitory effect of kaempferitrin was around 23% for maltase activity. Also, for the sucrose substrate the specific enzyme activity was significantly decreased. Aglycone, flavonoids, and kaempferol decreased significantly the maltase activity at all concentrations assayed. Finally, rutin reduced maltase-specific activity at all concentrations studied. According to the oral glucose tolerance curve, rutin reduced the serum glucose levels at 15, 30, and 60 min when administered by oral gavage 30 min before glucose overload in rats. CONCLUSION: Based on these results, we can conclude that disaccharidases are targets of flavonoids in the regulation of glucose absorption and consequently glucose homeostasis. PMID- 21684121 TI - Topiramate-induced weight loss: a review. AB - BACKGROUND: Weight loss can occur during topiramate (TPM) treatment and it should be evaluated by clinicians, especially in children, whose growth could be compromised. In international literature, the reported body weight loss incidences linked to TPM therapy vary widely and, in some cases, are very conflicting. AIMS: The aims of this review are to quantify TPM-induced weight loss, analyze the pathogenetic mechanisms and evaluate its clinical implications in patients with epilepsy. RESULTS: The amount of weight loss appears to be related to some factors such as the duration of the treatment and a high baseline body mass index (BMI), while the role of daily dosage and gender of patients is controversial. The mechanism through which TPM may induce weight loss is still unclear. INTERPRETATION: TPM is able to induce weight loss, especially in high baseline BMI patients, not strictly depending on daily dosage and perhaps not influenced by gender. This makes TPM a good choice, especially in obese patients suffering from seizures. However, TPM can make nutritionally vulnerable children or adult patients, with epilepsy associated with other neuropsychiatric diseases, who cannot voluntarily increase their caloric intake. PMID- 21684122 TI - Sex-specific associations between peripheral oxytocin and emotion perception in schizophrenia. AB - BACKGROUND: We previously reported that higher levels of peripheral oxytocin are associated with lower levels of positive, general, and overall symptoms in women but not in men with schizophrenia. Here we investigate the influence of sex, sex steroid hormone fluctuations, and peripheral oxytocin levels on emotional processing in men and women with schizophrenia. METHOD: Twenty-two women with schizophrenia and 31 female controls completed the Penn Emotion Acuity Test (PEAT), a facial emotion recognition and perception task, during two menstrual cycle phases: 1) early follicular (Days 2-4; low estrogen/progesterone) and 2) midluteal (Days 20-22; high estrogen/progesterone). Twenty-six males with schizophrenia and 26 male controls completed testing at comparable intervals. We obtained plasma hormone assays of estrogen, progesterone, testosterone, and oxytocin. RESULTS: No sex differences were noted on the PEAT. Plasma oxytocin levels did not fluctuate across phases of the menstrual cycle. However, female patients and controls more accurately identified facial emotions during the early follicular versus midluteal phase (p<0.05). Higher oxytocin levels related to perceiving faces as happier in both female patients (r=-0.46, p=0.04) and controls (r=-0.40, p=0.04) but not in men. CONCLUSION: Like healthy women, women with schizophrenia demonstrate menstrual-cycle dependent fluctuations in recognizing emotional cues. Like healthy women, female patients with higher levels of oxytocin perceived faces as happier. Future studies need to address whether this sex-specific relationship is associated with trust and other positive emotions, and whether exogenous oxytocin might enhance mood states and social interaction in female or all schizophrenia patients. PMID- 21684123 TI - Neural basis of semantic priming in schizophrenia during a lexical decision task: a magneto-encephalography study. AB - Numerous behavioral and electrophysiological studies have provided evidence of abnormal semantic processing in schizophrenia. However, the neural basis of these deficits is poorly understood. We investigated magnetic cortical responses elicited by a word-pair lexical decision task in 20 patients with schizophrenia and 12 healthy control subjects. The task involved presentation of a prime word (200 ms), followed by a blank (250 ms), and then a target stimulus (1200 ms); the subject had to decide whether the target was a real word or not. During this task, bilateral temporal and left prefrontal activations were observed in both groups. However, in contrast to controls, patients with schizophrenia did not show increased activation in the left temporal and anterior cingulate cortices between 200 and 450 ms in response to semantic incongruity. These results suggested that schizophrenia was associated with a functional disturbance in some semantic regions that gave rise to the N400 component. Moreover, a significant modulation in the right temporal cortex was observed in patients, but not in controls. This suggested the existence of alternative processes in patients because both groups showed similar behavioral priming. Finally, we elucidated some functional abnormalities in the semantic network during prime word processing in patients, indicated by prolonged activation compared to healthy controls. Thus, in addition to context integration impairment, abnormal activations during the prime word provided new evidence of context processing deficits in schizophrenia. PMID- 21684124 TI - Voxel-based morphometry (VBM) studies in schizophrenia-can white matter changes be reliably detected with VBM? AB - Voxel-based morphometry (VBM) is a hypothesis-free, whole-brain, voxel-by-voxel analytic method that attempts to compare imaging data between populations. Schizophrenia studies have utilized this method to localize differences in diffusion tensor imaging (DTI) derived fractional anisotropy (FA), a measure of white matter integrity, between patients and healthy controls. The number of publications has grown, although it is unclear how reliable and reproducible this method is, given the subtle white matter abnormalities expected in schizophrenia. Here we analyze and combine results from 23 studies published to date that use VBM to study schizophrenia in order to evaluate the reproducibility of this method in DTI analysis. Coordinates of each region reported in DTI VBM studies published thus far in schizophrenia were plotted onto a Montreal Neurological Institute atlas, and their anatomical locations were recorded. Results indicated that the reductions of FA in patients with schizophrenia were scattered across the brain. Moreover, even the most consistently reported regions were reported independently in less than 35% of the articles studied. Other instances of reduced FA were replicated at an even lower rate. Our findings demonstrate striking inconsistency, with none of the regions reported in much more than a third of the published articles. This poor replication rate suggests that the application of VBM to DTI data may not be the optimal way for finding the subtle microstructural abnormalities suggested in schizophrenia. PMID- 21684125 TI - Modulation of aggregation behavior of amphiphilic drug AMT under the influence of polymer molecular weight and composition. AB - The purpose of this study was to determine the aggregation behavior of amphiphilic drug amitriptyline hydrochloride (AMT) and to search for means which boost/suppress the aggregation behavior. Polyethylene glycols (PEGs) nonionic polymers (which are used as pharmaceutical excipients) of varying molecular weights from 400 to 35,000 were tested. To know their effect on the micellization and interfacial behavior of the drug, the critical micelle concentration (CMC) and critical aggregation concentration (CAC) were determined in presence of various polymers by tensiometric and conductivity methods. The CAC values were found to decrease while the CMC values increased with increase in the polymer concentration. The thermodynamic parameters were evaluated where DeltaG degrees (mic) and DeltaG degrees (agg) are found to be negative, confirming the feasibility of interaction between AMT and polymers. PMID- 21684126 TI - Electrophoretic deposition of chiral polymers and composites. AB - Electrophoretic deposition (EPD) method has been developed for the deposition of thin films of chiral polymers. EPD of poly-L-lysine (PLL) and poly-L-ornithine (PLO) films was performed for the first time on conductive substrates from aqueous and ethanol-water solutions. The deposition yield was monitored using a quartz crystal microbalance. The results demonstrated that the deposition yield can be varied by variation of the deposition time, voltage and polymer concentration in the solutions. It was shown that PLL and PLO provided stabilization and charging of hydroxyapatite (HA) nanoparticles in suspensions. Composite PLL-HA and PLO-HA films of controlled thickness were prepared by EPD. Electron microscopy investigations showed that the thickness of the PLL, PLO and composite films was varied in the range of 0-3 MUm. The polymer and composite films can be used for biomedical applications. PMID- 21684127 TI - Swelling-shrinking behavior of chemically cross-linked polypeptide gels from poly(alpha-L-lysine), poly(alpha-DL-lysine), poly(E-L-lysine) and thermally prepared poly(lysine): effects of pH, temperature and additives in the solution. AB - We synthesized the glutaraldehyde cross-linked hydrogels using four kinds of poly(lysine)s (PLs) and measured the equilibrium swelling ratio (Q) as a function of pH. Also measured was the temperature change of Q at a fixed pH (11.6) in the absence and presence of additives (LiBr, methanol and urea) that affect the secondary structure of PLs. The swelling data were examined using a force balance approach in which the repulsive and attractive interactions among the cross linked PL chains were considered based on the conformational properties of PLs in aqueous solutions. It was found that the formation of the helical segments in the cross-linked chain has little effect in the gel collapse, but their association acts as the attractive interaction causing the gel to shrink. The formation of the beta-sheet structure within the network also acts as the attractive interaction. These attractive interactions are mainly due to the hydrogen bonding, but hydrophobic interactions between the lysine side chains should be considered. In addition, in the swelling behavior of all the PL gels the polyampholyte nature appears due to electrostatic interactions of the basic groups with the C-terminal carboxyl group. PMID- 21684128 TI - [Primary ciliary dyskinesia: who and how to confirm the diagnosis?]. AB - Primary ciliary dyskinesia (PCD) is a rare genetic disease associated with abnormal ciliary structure and function, which results in retention of mucus and bacteria in the respiratory tract, leading to chronic oto-sino-pulmonary disease from early childhood, situs abnormalities and abnormal sperm motility. The diagnosis of PCD can be difficult and is based on the presence of the characteristic clinical phenotype, evidence of abnormal ciliary function and specific ultrastructural ciliary defects identified by transmission electron microscopy. Because prognosis of the disease is related to the age of diagnosis, we suggest in this article, elements that should early orientate diagnostic evaluation of patients suspected of having PCD. PMID- 21684129 TI - Neoadjuvant chemoradiotherapy for resectable oesophageal and gastro-oesophageal junction cancer--do we need another randomised trial? AB - AIMS: The optimal neoadjuvant therapy option for locally advanced oesophageal cancer remains elusive. Neoadjuvant chemoradiotherapy (CRT) is the preferred modality of choice in the USA. In contrast, neoadjuvant chemotherapy is commonly used in the UK. We provide a comprehensive overview of the available evidence for defining the ideal neoadjuvant treatment algorithm. MATERIALS AND METHODS: The PubMed database combined with American Society of Clinical Oncology and American Society for Therapeutic Radiology and Oncology websites were searched online to identify randomised studies and published meta-analyses that have compared these modalities compared with surgery alone. In particular, we searched for randomised trials that may have directly compared outcomes after neoadjuvant CRT or chemotherapy. RESULTS: We identified 17 published randomised studies of neoadjuvant CRT (n = 9) and chemotherapy (n = 8) compared with surgery alone and one prospective series that compared the above modalities against each other. Studies evaluating CRT have reported pathological complete response rates of 15 40% and no increase in postoperative mortality was observed, except in one study that used a hypofractionated radiation schedule. Two randomised studies showed significant survival benefit and the remaining (n = 7) were negative, but showed a trend towards improved survival. Furthermore, at least four meta-analyses have shown improved survival in favour of CRT extending up to an absolute benefit of 13% at 2 years. In comparison, five studies of neoadjuvant chemotherapy showed no survival difference and two of the remaining studies that showed significant benefit included gastric adenocarcinomas and used peri-operative chemotherapy. All the above studies have shown uniformly poor pathological complete response rates of less than 10 percent. Moreover, three meta-analyses were negative, but two showed up to 7% absolute survival benefit at 2 years in favour of chemotherapy. The trial comparing the above modalities showed a trend towards improved survival in favour of CRT, but closed early due to poor recruitment. CONCLUSION: Data from the above studies are potentially conflicting and inconclusive for defining the optimal neoadjuvant treatment schedule. In our opinion, the above question can only be answered within the context of a randomised control trial. We have included a proposal for a trial design for direct comparison of these modalities. PMID- 21684130 TI - Vasoprotective activity of standardized Achillea millefolium extract. AB - We investigated the effects of Achillea millefolium extract in vitro on the growth of primary rat vascular smooth muscle cells (VSMCs) as well as the potential involvement of estrogen receptors (ERs) in this process. In addition, the ability of A. millefolium extract to modulate the NF-kappaB pathway was tested in human umbilical vein endothelial cells (HUVECs). The fingerprinting of the extract was carried out by HPLC-DAD and LC-MS(n) and main constituents were flavonoids (10%) and dicaffeolylquinic acid derivatives (12%). The extract enhanced VSMC growth at least in part by acting through ERs and impaired NF kappaB signaling in HUVECs. The various compounds may act with different mode of actions thus contributing to the final effect of the extract. Our findings support some of the traditional uses of A. millefolium, and suggest potential modes of action as related to its effects on vascular inflammation. Therefore, A. millefolium may induce novel potential actions in the cardiovascular system. PMID- 21684131 TI - Al and Fe levels in mixed saliva of children related to elution behavior from teeth and restorations. AB - OBJECTIVES: The levels of trace elements in mixed saliva were not well-defined. This study was performed to determine Al and Fe concentrations in mixed saliva of children and to investigate the relationship between these levels and dental caries. METHODS: Among 562 collected mixed saliva specimens, 514 and 548 samples for analyses of Al and Fe levels were obtained, respectively. The Al and Fe concentrations were determined using flameless atomic absorption spectrometry. RESULTS: The Al and Fe concentrations in children without a history of caries were 0.093+/-0.136 and 0.121+/-0.128 MUg/mL, respectively. The Fe level depended on sex. The Fe level in girls who experienced caries was significantly higher than that without caries history. The Al and Fe levels were significantly higher in children with treated caries than children without caries history. The Fe concentrations were affected by restoration type. Composite resin increased the Fe level significantly especially in girls, and the Fe level was also higher in boys treated with both composite resin and metal restorations. In children without caries history, the Al level was inversely proportional to the number of deciduous teeth and increased with the number of permanent teeth. In contrast, the Fe level showed the reverse tendency. CONCLUSIONS: The Fe level in mixed saliva of children was influenced by the restoration type. It was suggested that Al was eluted more from sound permanent teeth than sound deciduous teeth, while Fe was eluted in the opposite manner. PMID- 21684132 TI - Regulatory mechanism for the stimulatory action of genistein on glucose uptake in vitro and in vivo. AB - Genistein, an isoflavone, is known to possess diverse biological functions such as antioxidative and anti-inflammatory actions. It also acts like estrogen and inhibits several tyrosine kinases. Genistein was reported to suppress insulin mediated glucose uptake in adipocytes. In this study, we investigated the effects of genistein on glucose uptake in vitro and in vivo as well as the mechanisms associated with the glucose uptake. We found that genistein decreased nonfasting blood glucose levels in KK-Ay/Ta Jcl mice, a type 2 diabetic animal model. It also dose-dependently induced insulin secretion by Rin-5F cells. In L6 myotubes, it directly stimulated glucose uptake independently of insulin under normal and high glucose conditions in dose-dependent manners. It promoted the translocation of glucose transporter 4 to the cell membrane under both glucose conditions. Based on studies using inhibitors of signaling molecules related to glucose uptake, the stimulatory effect of genistein on glucose uptake appeared to be dependent on the phosphatidylinositol 3-kinase, mammalian target of rapamycin, protein kinase C and 5'-adenosine-monophosphate-activated protein kinase pathway under both glucose conditions. In addition, O-GlcNAcylation by O-(2-acetamido-2 deoxy-D-glucopyranosylidene) amino N-phenyl carbamate, an inhibitor of N acetylglucosaminidase, reduced the stimulatory effect of genistein on glucose uptake under both glucose conditions. Taken together, genistein may regulate glucose uptake by increasing the phosphorylation and decreasing the O GlcNAcylation of proteins related to glucose homeostasis. PMID- 21684133 TI - Estrogen status alters tissue distribution and metabolism of selenium in female rats. AB - A reported association between estrogen and selenium status may be important in the regulation of selenium metabolism. In this study, the effect of estrogen status on the metabolism of orally administered (75)Se-selenite and tissue selenium status was investigated. Female Sprague-Dawley rats were bilaterally ovariectomized at 7 weeks of age and implanted with either a placebo pellet (OVX) or pellet containing estradiol (OVX+E2), or were sham operated (Sham). At 12 weeks of age, 60 uCi of (75)Se as selenite was orally administered to OVX and OVX+E2 rats. Blood and organs were collected 1, 3, 6 and 24 h after dosing. Estrogen status was associated with time-dependent differences in distribution of (75)Se in plasma, red blood cell (RBC), liver, heart, kidney, spleen, brain and thymus and incorporation of (75)Se into plasma selenoprotein P (Sepp1) and glutathione peroxidase (GPx). Estrogen treatment also significantly increased selenium concentration and GPx activity in plasma, liver and brain, selenium concentration in RBC and hepatic Sepp1 and GPx1 messenger RNA. These results suggest that estrogen status affects tissue distribution of selenium by modulating Sepp1, as this protein plays a central role in selenium transport. PMID- 21684135 TI - Naringin, the major grapefruit flavonoid, specifically affects atherosclerosis development in diet-induced hypercholesterolemia in mice. AB - Naringin (NAR) from grapefruit has exhibited potential protective effects against atherosclerosis development. However, specific mechanisms responsible for such effects are poorly understood. Thus, we aimed to investigate the antiatherogenic effects of NAR in different mouse models of hypercholesterolemia and decipher its molecular targets in the aorta using transcriptomic approach. Two mouse models of hypercholesterolemia, wild-type mice fed a high-fat/high-cholesterol diet and apolipoprotein E-deficient mice fed a semisynthetic diet, were studied. Mice were fed a respective control diets supplemented or not for 18 weeks with 0.02% of NAR, that is, nutritional supplementation. NAR supplementation reduced plaque progression only in wild-type mice fed the high-fat/high-cholesterol diet (-41%). Consistent with this protective effect, NAR reduced plasma non-high-density lipoprotein cholesterol concentrations as well as biomarkers of endothelial dysfunction. Microarray studies performed on aortas demonstrated differentially expressed genes encoding proteins involved in cell adhesion, actin cytoskeleton organization and cell division. Thus, the changes in gene expression induced by NAR could suggest a limited atherosclerosis progression by preventing immune cell adhesion and infiltration in the intima of vascular wall, as well as smooth muscle cell proliferation. Furthermore, this hypothesis was strengthened by in vitro experiments, which showed the ability of naringenin to reduce monocyte adhesion to endothelial cells and smooth muscle cell proliferation. In conclusion, this study revealed the antiatherogenic effect of NAR supplemented at a nutritionally achievable dose, specifically toward diet-induced atherosclerosis, and depicted its multitarget mode of action at the vascular level. PMID- 21684134 TI - Dietary supplementation with high dose of epigallocatechin-3-gallate promotes inflammatory response in mice. AB - Epigallocatechin-3-gallate (EGCG) from green tea has been indicated to have anti inflammatory activity. However, most of the evidence is in vitro studies in which EGCG is often added at levels unachievable by oral intake. With few exceptions, in vivo studies along this line have been conducted in animal models of diseases, and the results are inconclusive. In this study, we fed C57BL/6 mice a diet containing 0%, 0.15%, 0.3% or 1% (w/w) EGCG for 6 weeks. Contrary to the assumption that EGCG would reduce inflammatory response, mice fed 0.15% and 0.3% EGCG diet exhibited no change while those fed 1% EGCG diet produced more proinflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-6, and IL 1beta and lipid inflammatory mediator prostaglandin E(2) in their splenocytes and macrophages (MPhi) and less IL-4 in splenocytes. Spleens from the mice fed 1% EGCG diet also had higher proportions of regulatory T cells, MPhi, natural killer (NK) cells and NKT cells compared to those from mice fed the other diets. These results suggest that high intake of EGCG may induce a proinflammatory response, and this change may be associated with a disturbed homeostasis of immune cells involving changes in both function and number of specific immune cell populations. While the mechanisms and clinical significance for this effect of EGCG remain to be investigated further, these data suggest the need for defining accurate EGCG dose limits to induce an anti-inflammatory effect since current data indicate that higher doses would produce an inflammatory response. PMID- 21684136 TI - A novel mechanism of coenzyme Q10 protects against human endothelial cells from oxidative stress-induced injury by modulating NO-related pathways. AB - BACKGROUND: Atherosclerosis is a chronic inflammatory disease of the vessel wall associated with oxidized low-density lipoprotein (oxLDL)-induced apoptosis of endothelial cells. Coenzyme Q10 (CoQ10), a potent antioxidant and a critical intermediate of the electron transport chain, has been reported to inhibit LDL oxidation and thus the progression of atherosclerosis. However, its molecular mechanisms on endothelial cells remain still unclarified. METHODS: In this study, primary human umbilical vein endothelial cell cultures treated with oxLDL were used to explore the protective effects of CoQ10. RESULTS: Our results showed that CoQ10 attenuated the oxLDL-induced generation of reactive oxygen species and improved the antioxidant capacity. CoQ10 also attenuated the oxLDL-mediated down regulation of endothelial nitric oxide synthase (eNOS) and up-regulation of inducible nitric oxide synthase (iNOS). In addition, CoQ10 suppressed oxLDL activated NF-kappaB and downstream inflammatory mediators, including expression of adhesion molecules, release of proinflammatory cytokines and the adherence of monocytic THP-1 cells. Moreover, CoQ10 attenuated oxLDL-altered proapoptotic responses. The inhibitor of eNOS (L-NIO 10 MUM) and iNOS (1400W 10 MUM) as well as NO enhancer (SNP 10 MUM) were used to clean up the mechanism. CONCLUSION: These results provide new insight into the possible molecular mechanisms by which CoQ10 protects against atherogenesis by NO-related pathways. PMID- 21684137 TI - Zebrafish (Danio rerio) fed vitamin E-deficient diets produce embryos with increased morphologic abnormalities and mortality. AB - Vitamin E (alpha-tocopherol) is required to prevent fetal resorption in rodents. To study alpha-tocopherol's role in fetal development, a nonplacental model is required. Therefore, the zebrafish, an established developmental model organism, was studied by feeding the fish a defined diet with or without added alpha tocopherol. Zebrafish (age, 4-6 weeks) were fed the deficient (E-), sufficient (E+) or lab diet up to 1 years. All groups showed similar growth rates. The exponential rate of alpha-tocopherol depletion up to ~80 day in E- zebrafish was 0.029+/-0.006 nmol/g, equivalent to a depletion half-life of 25+/-5 days. From age ~80 days, the E- fish (5+/-3 nmol/g) contained ~50 times less alpha tocopherol than the E+ or lab diet fish (369+/-131 or 362+/-107, respectively; P<.05). E-depleted adults demonstrated decreased startle response suggesting neurologic deficits. Expression of selected oxidative stress and apoptosis genes from livers isolated from the zebrafish fed the three diets were evaluated by quantitative polymerase chain reaction and were not found to vary with vitamin E status. When E-depleted adults were spawned, they produced viable embryos with depleted alpha-tocopherol concentrations. The E- embryos exhibited a higher mortality (P<.05) at 24 h post-fertillization and a higher combination of malformations and mortality (P<.05) at 120 h post-fertillization than embryos from parents fed E+ or lab diets. This study documents for the first time that vitamin E is essential for normal zebrafish embryonic development. PMID- 21684138 TI - Sulforaphane, a natural constituent of broccoli, prevents cell death and inflammation in nephropathy. AB - Cisplatin (cis-diamminedichloroplatinum II, CIS) is a potent and widely used chemotherapeutic agent to treat various malignancies, but its therapeutic use is limited because of dose-dependent nephrotoxicity. Cell death and inflammation play a key role in the development and progression of CIS-induced nephropathy. Sulforaphane (SFN), a natural constituent of cruciferous vegetables such as broccoli, Brussels sprouts, etc., has been shown to exert various protective effects in models of tissue injury and cancer. In this study, we have investigated the role of prosurvival, cell death and inflammatory signaling pathways using a rodent model of CIS-induced nephropathy, and explored the effects of SFN on these processes. Cisplatin triggered marked activation of stress signaling pathways [p53, Jun N-terminal kinase (JNK), and p38-alpha mitogen-activated protein kinase (MAPK)] and promoted cell death in the kidneys (increased DNA fragmentation, caspases-3/7 activity, terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick-end labeling), associated with attenuation of various prosurvival signaling pathways [e.g., extracellular signal regulated kinase (ERK) and p38-beta MAPK]. Cisplatin also markedly enhanced inflammation in the kidneys [promoted NF-kappaB activation, increased expression of adhesion molecules ICAM and VCAM, enhanced tumor necrosis factor-alpha (TNF alpha) levels and inflammatory cell infiltration]. These effects were significantly attenuated by pretreatment of rodents with SFN. Thus, the cisplatin induced nephropathy is associated with activation of various cell death and proinflammatory pathways (p53, JNK, p38-alpha, TNF-alpha and NF-kappaB) and impairments of key prosurvival signaling mechanisms (ERK and p38-beta). SFN is able to prevent the CIS-induced renal injury by modulating these pathways, providing a novel approach for preventing this devastating complication of chemotherapy. PMID- 21684140 TI - Docosahexaenoic acid inhibits invasion of human RT112 urinary bladder and PT45 pancreatic carcinoma cells via down-modulation of granzyme B expression. AB - Fish oil-derived n-3 polyunsaturated fatty acids (n-3 PUFAs) inhibit invasion of some tumor cell types in vitro and in vivo. The mechanisms underlying this activity are unclear. Here, we examined the capability of n-3 PUFA docosahexaenoic acid (22:6n-3; DHA) to affect the invasiveness of human RT112 urinary bladder and PT45 pancreatic carcinoma cell lines in vitro and the mechanism underlying this activity; n-6 PUFA-arachidonic acid (20:4n-6; AA) served as control. We showed that, in contrast to AA, 25, 50 and 100 MUM DHA significantly inhibited in a dose-dependent manner the invasion through Matrigel of both RT112 and PT45 cells. Then, we analyzed whether the serine proteinase granzyme B (GrB), originally known as cytotoxic molecule of lymphocytes and recently also characterized for its extracellular functions such as invasion promotion of bladder cancer cells, might be involved in the invasion inhibitory activity exerted by DHA. We demonstrated that, accordingly to RT112 bladder cancer cells, PT45 cells expressed GrB and GrB promoted their invasion, since stealth RNA interference-mediated down-regulation of GrB dramatically suppressed PT45 cell invasion. Notably, we also showed that, in contrast to AA, 25, 50 and 100 MUM DHA induced a dose-dependent down-modulation of GrB expression in both RT112 and PT45 cells. In conclusion, DHA can reduce the invasive phenotype of bladder and pancreatic carcinoma cells, and we provide the first evidence for a possible causative role of GrB in DHA-induced inhibition of cancer cell invasion. The potential use of fish oil as adjuvant antibladder and antipancreatic cancer agent may be suggested. PMID- 21684139 TI - ATP-binding cassette transporter A1 and HDL metabolism: effects of fatty acids. AB - Ample evidence indicates that dietary fatty acids alter the plasma levels of high density lipoprotein cholesterol (HDL-C). However, the mechanisms underlying the effects of fatty acids still remain elusive. Recent advances in our understanding of ATP-binding cassette transporter A1 (ABCA1) function and regulation have provided a valuable insight into the mechanisms by which fatty acids may affect plasma HDL-C levels. ABCA1 mediates the assembly of phospholipids and free cholesterol with apolipoprotein A-I, which is a critical step for HDL biogenesis. Studies have shown that unsaturated fatty acids, but not saturated fatty acids, repress the expression of ABCA1 in vitro. Although information on mechanisms for the fatty-acid-mediated regulation of ABCA1 expression is still limited and controversial, recent evidence suggests that unsaturated fatty acids inhibit the expression of ABCA1 at the transcriptional and posttranscriptional levels. The transcriptional repression of ABCA1 expression by unsaturated fatty acids is likely liver X receptor dependent. Evidence also suggests that histone deacetylation may play a role in the repression. Posttranscriptionally, unsaturated fatty acids may facilitate ABCA1 protein degradation, which may involve phosphorylation of ABCA1 by protein kinases. Further studies are warranted to better understand the role of dietary fatty acids in HDL metabolism and their effects on cardiovascular health. PMID- 21684141 TI - Conjugated linoleic acid improves blood pressure by increasing adiponectin and endothelial nitric oxide synthase activity. AB - Conjugated linoleic acid (CLA) has been reported to reduce blood pressure in obese insulin-resistant rats, but its mechanism of action has not been identified. The objective of this study was to determine whether CLA isomers can reduce obesity-related hypertension in the fa/fa Zucker rat in relation to adiponectin production and endothelial nitric oxide synthase (eNOS) activation. Obese fa/fa Zucker rats were randomly assigned to one of four groups: (1) cis 9,trans-11-CLA, (2) trans-10,cis-12 (t10,c12)-CLA, (3) control or (4) captopril. After 8 weeks, systolic blood pressure increased 30% in control obese rats. This increase was attenuated 11%-13% in the t10,c12-CLA isomer and captopril groups, respectively. The t10,c12-CLA isomer concurrently elevated adiponectin levels in both plasma and adipose tissue and increased phosphorylated eNOS in adipose tissue as well as the aorta. Although a direct effect of CLA was not observed in cultured endothelial cells, direct adiponectin treatment increased phosphorylation of eNOS. Endothelial nitric oxide synthase phosphorylation was also increased in adipose of fa/fa Zucker rats infused with adiponectin in parallel with improvements in blood pressure. Our results suggest that the t10,c12-CLA isomer attenuates development of obesity-related hypertension, at least in part, by stimulating adiponectin production, which subsequently activates vascular eNOS. PMID- 21684143 TI - Biomaterials based on photosynthetic membranes as potential sensors for herbicides. AB - In this study, ultrathin film multilayers of Photosystem II-enriched photosynthetic membranes (BBY) were prepared and immobilized on quartz substrates by means of a Layer by Layer procedure exploiting electrostatic interactions with poly(ethylenimine) as polyelectrolyte. The biomaterials thus obtained were characterized by means of optical techniques and Atomic Force Microscopy, highlighting the fact that the Layer by Layer approach allowed the BBYs to be immobilized with satisfactory results. The activity of these hybrid materials was evaluated by means of optical assays based on the Hill Reaction, indicating that the biosamples, which preserved about 65% of their original activity even ten weeks after preparation, were both stable and active. Furthermore, an investigation of the biochips' sensitivity to the herbicide terbutryn, as a model analyte, gave interesting results: inhibition of photosynthetic activity was observed at terbutryn concentrations higher than 10(-7)M, thus evidencing the potential of such biomaterials in the environmental biosensor field. PMID- 21684144 TI - Impedance analysis of adherent cells after in situ electroporation: non-invasive monitoring during intracellular manipulations. AB - In this study adherent animal cells were grown to confluence on circular gold film electrodes of 250 MUm diameter that had been deposited on the surface of a regular culture dish. The impedance of the cell-covered electrode was measured at designated frequencies to monitor the behavior of the cells with time. This approach is referred to as electric cell-substrate impedance sensing or short ECIS in the literature. The gold-film electrodes were also used to deliver well defined AC voltage pulses of several volts amplitude and several hundred milliseconds duration to the adherent cells in order to achieve reversible membrane electroporation (in situ electroporation=ISE). Electroporation-assisted introduction of membrane impermeable molecules into the cytoplasm was studied by using FITC-labeled dextran molecules of different molecular weights. Probes as big as 2MDa were successfully loaded into the cells residing on the electrode surface. Time-resolved impedance measurements before and immediately after the electroporation pulse revealed the kinetics of membrane resealing as well as subsequent changes in cell morphology. Cells recovered from the electroporation pulse within less than 90 min. When membrane-impermeable, bioactive compounds like N(3)(-) or bleomycin were introduced into the cells by in situ electroporation, concomitant ECIS readings sensitively reported on the associated response of the cells to these toxins as a function of time (ISE-ECIS). PMID- 21684142 TI - Interest in low-threshold employment among people who inject illicit drugs: implications for street disorder. AB - BACKGROUND: Income generation opportunities available to people who use illicit drugs have been associated with street disorder. Among a cohort of injection drug users (IDU) we sought to examine street-based income generation practices and willingness to forgo these sources of income if other low-threshold work opportunities were made available. METHODS: Data were derived from a prospective community recruited cohort of IDU. We assessed the prevalence of engaging in disorderly street-based income generation activities, including sex work, drug dealing, panhandling, and recycling/salvaging/vending. Using multivariate logistic regressions based on Akaike information criterion and the best subset selection procedure, we identified factors associated with disorderly income generation activities, and assessed willingness to forgo these sources of income during the period of November 2008 to July 2009. RESULTS: Among our sample of 874 IDU, 418 (48%) reported engaging in a disorderly income generation activity in the previous six months. In multivariate analyses, engaging in disorderly income generation activities was independently associated with high intensity stimulant use, as well as binge drug use, having encounters with police, being a victim of violence, sharing used syringes, and injecting in public areas. Among those engaged in disorderly income generation, 198 (47%) reported a willingness to forgo these income sources if given opportunities for low-threshold employment, with sex workers being most willing to engage in alternative employment. CONCLUSION: Engagement in disorderly street-based income generation activities was associated with high intensity stimulant drug use and various markers of risk. We found that a high proportion of illicit drug users were willing to cease engagement in these activities if they had options for causal low-threshold employment. These findings indicate that there is a high demand for low-threshold employment that may offer important opportunities to reduce drug-related street disorder and associated harms. PMID- 21684145 TI - Electrical immunosensor based on a submicron-gap interdigitated electrode and gold enhancement. AB - We demonstrated that the detection of human interleukin 5 (IL5) with a higher sensitivity than the enzyme-linked immunosorbent assay (ELISA) was possible using mass-producible submicron-gap interdigitated electrodes (IDEs) combined with signal amplification by a gold nanoparticle (AuNP) and gold enhancement. IDEs, facing comb-shape electrodes, can act as simple and miniaturized devices for immunoassay. An IDE with a gap size of 400nm was fabricated by a stepper photolithography process and was applied for the immunoassay of human IL5. A biotinylated anti-human IL5 was immobilized on the streptavidin-modified IDE, and biotin-bovine serum albumin (BSA) and BSA were added sequentially to reduce non specific binding between the streptavidin-immobilized IDE surface and other proteins. The immunoassay procedure included three main steps: the reaction of human IL5 to form antigen-antibody complexes, the binding of AuNP conjugation with an antibody against human IL5 for the sandwich immunoassay, and gold enhancement for electrical signal amplification. The measurement of electrical current at each step showed that the gold enhancement step was very critical in detection of the concentration of human IL5. Analysis by scanning electron microscope (SEM) showed that close to 1MUm particles were formed from 10nm AuNP by the gold enhancement reaction using gold ions and hydroxylamine. Under optimized conditions, human IL5 could be analyzed at 1pgmL(-1) with a wide dynamic range (from 10(-3) to 100ngmL(-1) concentrations). PMID- 21684146 TI - Electron-transfer quenching of nucleic acid-functionalized CdSe/ZnS quantum dots by doxorubicin: a versatile system for the optical detection of DNA, aptamer substrate complexes and telomerase activity. AB - The optical detection of DNA or the sensing of low-molecular-weight substrates or proteins by aptamer nucleic acids is a long term challenge in the design of biosensors. Similarly, the detection of the telomerase activity, a versatile biomarker of cancer cells, is important for rapid cancer diagnostics. We implement the luminescence quenching of the CdSe/ZnS quantum dots (QDs) as a versatile process to develop DNA sensors and aptasensors, and to design an analytical platform for the detection of telomerase activity. The formation of nucleic acid duplexes on QDs, or the assembly of aptamer-substrate complexes on the QDs (substrate=cocaine or thrombin) is accompanied by the intercalation of doxorubicin (DB) into the duplex domains of the resulting recognition complexes. The intercalated DB quenches the luminescence of the QDs, thus leading to the detection readout signal. Similarly, the telomerase-induced formation of the telomere chains on the QDs is followed by the hybridization of nucleic-acid units complementary to the telomere repeat units, and the intercalation of DB into the resulting duplex structure. The resulting luminescence quenching of the QDs provides an indicating signal for the activity of telomerase. PMID- 21684147 TI - The multiple roles of Purkinje cells in sensori-motor calibration: to predict, teach and command. AB - Neurophysiological recordings in the cerebellar cortex of awake-behaving animals are revolutionizing the way we think about the role of Purkinje cells in sensori motor calibration. Early theorists suggested that if a movement became miscalibrated, Purkinje cell output would be changed to adjust the motor command and restore good performance. The finding that Purkinje cell activity changed in many sensori-motor calibration tasks was taken as strong support for this hypothesis. Based on more recent data, however, it has been suggested that changes in Purkinje cell activity do not contribute to the motor command directly; instead, they are used either as a teaching signal, or to predict the altered kinematics of the movement after calibration has taken place. I will argue that these roles are not mutually exclusive, and that Purkinje cells may contribute to command generation, teaching, and prediction at different times during sensori-motor calibration. PMID- 21684148 TI - Modeling developmental patterns of spontaneous activity. AB - Spontaneous activity is found in many regions of the developing nervous system; such activity is thought to be instructive for guiding developmental processes. In particular, the developing retina generates correlated patterns of activity known as retinal waves. We review the main theoretical models that have been developed to study the mechanisms for generation and propagation of retinal waves. Much of the progress in this field has been due to the close interaction between experimentalists and theorists in analyzing and modeling spontaneous activity. We conclude by describing spontaneous activity models in other systems and suggestions for future modeling work. PMID- 21684149 TI - Protein design with fragment databases. AB - Structure-based computational methods are popular tools for designing proteins and interactions between proteins because they provide the necessary insight and details required for rational engineering. Here, we first argue that large-scale databases of fragments contain a discrete but complete set of building blocks that can be used to design structures. We show that these structural alphabets can be saturated to provide conformational ensembles that sample the native structure space around energetic minima. Second, we show that catalogs of interaction patterns hold the key to overcome the lack of scaffolds when computationally designing protein interactions. Finally, we illustrate the power of database-driven computational protein design methods by recent successful applications and discuss what challenges remain to push this field forward. PMID- 21684150 TI - Strategy and success for the directed evolution of enzymes. AB - Directed evolution is widely used to improve enzymes, particularly for industrial biocatalytic processes. Molecular biology advances present many new strategies for directed evolution. Commonly used techniques have led to many successful examples of enzyme improvement, yet there is still a need to improve both the efficiency and capability of directed evolution. Recent strategies aimed at making directed evolution faster and more efficient take better advantage of available structural and sequence information. The underlying principles that lead to early dead-ends for directed evolution experiments are also discussed along with recent strategies designed to by-pass them. Several emerging methods for creating novel enzymes are also discussed including examples of catalytic activity for which there is no precedent in nature. Finally, the combined use of several strategies is likely to be required in practice to improve multiple target properties of an enzyme, as successfully shown by a recent industrial example. PMID- 21684151 TI - Randomised phase II study of amrubicin as single agent or in combination with cisplatin versus cisplatin etoposide as first-line treatment in patients with extensive stage small cell lung cancer - EORTC 08062. AB - PURPOSE: The EORTC 08062 phase II randomised trial investigated the activity and safety of single agent amrubicin, cisplatin combined with amrubicin, and cisplatin combined with etoposide as first line treatment in extensive disease (ED) small cell lung cancer (SCLC). PATIENTS AND METHODS: Eligible patients with previously untreated ED-SCLC, WHO performance status (PS) 0-2 and measurable disease were randomised to 3 weekly cycles of either amrubicin alone 45mg/m(2) i.v. day(d) 1-3 (A), cisplatin 60mg/m(2) i.v. d1 and amrubicin 40mg/m(2) i.v. d1 3 (PA), or cisplatin 75mg/m(2) i.v. d1 and etoposide 100mg/m(2) d1, d2-3 i.v./po (PE). The primary end-point was overall response rate (ORR) as assessed by local investigators (RECIST1.0 criteria). Secondary end-points were treatment toxicity, progression-free survival and overall survival. RESULTS: The number of randomised/eligible patients who started treatment was 33/28 in A, 33/30 in PA and 33/30 in PE, respectively. Grade (G) ?3 haematological toxicity in A, PA and PE was neutropenia (73%, 73%, 69%); thrombocytopenia (17%, 15%, 9.4%), anaemia (10%, 15%, 3.1%) and febrile neutropenia (13%, 18%, 6%). Early deaths, including treatment related, occurred in 1, 3 and 3 patients in A, PA and PE arms, respectively. Cardiac toxicity did not differ among the 3 arms. Out of 88 eligible patients who started treatment, ORR was 61%, (90% 1-sided confidence intervals [CI] 47-100%), 77% (CI 64-100%) and 63%, (CI 50-100%) for A, PA and PE respectively. CONCLUSION: All regimens were active and PA met the criteria for further investigation, despite slightly higher haematological toxicity. PMID- 21684152 TI - Under usage of zoledronic acid in non-small cell lung cancer patients with metastatic bone disease--a short communication. AB - BACKGROUND AND AIM: The use of zoledronic acid (ZA) is now recommended for patients with NSCLC and metastatic bone disease (MBD). We thus examined the rates of ZA administration in NSCLC looking specifically at the use of this drug with systemic chemotherapy (ZCt) and comparing overall survival between patients who had ZCt from diagnosis to those who had chemotherapy (Ct) alone. METHOD: In this retrospective audit, we analysed the data of 114 consecutive patients with stage IV NSCLC and MBD at presentation. Forty-three of these patients had received zoledronic acid and chemotherapy (ZCt) and 71 had received chemotherapy alone (Ct). RESULTS: Forty-three (37.7%, 43/114) of NSCLC patients diagnosed with MBD received ZA with their first chemotherapy (ZCt). Patients on ZCt, after adjustment for the planned prognostic factors (sites of disease, histology and PS), had better overall survival (OS), with a median of 34 weeks, compared to those who received chemotherapy alone, who had a median of 19 weeks (p = 0.03), HR = 0.60 (95%CI: 0.38-0.96). After adjusting for prognostic factors (sex, age. single versus doublet chemotherapy), ZCt patients still maintained a trend to better OS (p = 0.06) HR 0.63 (95%CI: 0.39-1.02) 34 versus 21 weeks. CONCLUSIONS: The percentage of patients with MBD treated with ZA at first chemotherapy (37.7%) is low. The addition of ZA increased OS in NSCLC patients with MBD in this audit. More formal policies and dedicated trials on the treatment of MBD in NSCLC patients need to be put in place. PMID- 21684153 TI - Early stopping rules in oncology: considerations for clinicians. AB - The number of cancer-related clinical trials has been rapidly increasing over the past decade. Along with this increase, oncology studies stopped early for benefit or harm have also been more common. Clinicians treating cancer patients often are faced with the challenge of having to decide whether or not to incorporate information from these new studies into their daily clinical practice. This review article explains the role of the Data and Safety Monitoring Committee in stopping trials early; provides examples of oncology trials stopped early; and reviews some of the controversies and statistical concepts associated with early stopping rules. In addition, a simple and practical approach to interpreting the findings of trials that are stopped early is provided to assist clinicians in deciding how to incorporate information from these studies into their daily practice. PMID- 21684154 TI - miR-429 modulates the expression of c-myc in human gastric carcinoma cells. AB - AIM: MicroRNAs (miRNAs) are a recently discovered class of small non-coding RNAs that regulate gene expression and may contribute to the development and progression of many cancers. In this study, our goal was to investigate the regulation of miR-429 in gastric cancer and explored the mechanism/s by which it influenced pathogenesis of gastric cancer. METHODS: We used real-time reverse transcriptase-polymerase chain reaction to quantify the expression level of miR 429 in 52 gastric cancer tissues and their paracancerous tissues. Bioinformatics was used to predict downstream target genes of miR-429. SGC-7901 gastric cancer cells were transfected with miR-429 mimics and endogenous c-myc expression was detected by western blots. We performed functional assays using the 3'UTR of the c-myc gene as a miR-429 target in a luciferase reporter assay system. RESULTS: We showed that miR-429 was downregulated in human gastric carcinoma tissue and in SGC-7901 cells. Cell viability, proliferation and attachment were inhibited in miR-429-transfected cells. miR-429 significantly downregulated endogenous c-myc expression in SGC-7901 cells. Action of miR/429 on c-myc 3'UTR was confirmed. The levels of miR-429 in tumour tissue of patients with lymph node metastasis were significantly lower than in those without lymph node metastasis. CONCLUSIONS: Our results suggested that miR-429 played a role in the pathogenesis of gastric carcinoma and may function as a recessive cancer gene. c-myc is an important miR 429 target gene. PMID- 21684155 TI - Techno-economical study of ethanol and biogas from spruce wood by NMMO pretreatment and rapid fermentation and digestion. AB - Given that N-methylmorpholine-N-oxide (NMMO) is a promising alternative for the pretreatment of lignocelluloses, a novel process for ethanol and biogas production from wood was developed. The solvent, NMMO, is concentrated by multistage evaporation, and the wood is pretreated with the concentrated NMMO. Thereafter, ethanol is produced by the non-isothermal simultaneous saccharification and fermentation (NSSF) method, which is a rapid and efficient process. The wastewater is treated by upflow anaerobic sludge blanket (UASB) digester for rapid production of biogas. The process was simulated by Aspen plus(r). Using mechanical vapor recompression for evaporators in the pretreatment and multi-pressure distillation columns, the energy requirements for the process were minimized. The economical feasibility of the developed biorefinery for five different plant capacities was studied by Aspen Icarus Process Evaluator. The base case was designed to utilize 200,000 tons of spruce wood per year and required M? 58.3 as the total capital investment, while the production cost of ethanol is calculated to be ?/l 0.44. PMID- 21684156 TI - Addition of ammonia and/or oxygen to an ionic liquid for delignification of miscanthus. AB - Ammonia and/or oxygen were used to enhance the delignification of miscanthus dissolved in 1-ethyl-3-methylimidazolium acetate at 140 degrees C. After dissolution of the gas at 9 bar, water was added as antisolvent to regenerate the dissolved biomass. In a next step, an acetone/water mixture was used to remove carbohydrate-free lignin from the regenerated biomass. The lignin content in the final product was around 10%, much lower than the ca. 23% lignin content of the raw dry miscanthus. This lignin reduction is achieved without diminution of cellulose or of total carbohydrates recovered, relative to the recovery achieved with the ionic liquid pretreatment in contact with air or nitrogen. PMID- 21684157 TI - Novel nanomolar imidazo[4,5-b]pyridines as selective nitric oxide synthase (iNOS) inhibitors: SAR and structural insights. AB - Inducible arginine oxidation and subsequent NO production by correspondent synthase (iNOS) are important cellular answers to proinflammatory signals. Prolonged NO production has been proved in higher organisms to cause stroke or septic shock. Several classes of potent NOS inhibitors have been reported, most of them targeting the arginine binding site of the oxygenase domain. Here we disclose the SAR and the rational design of potent and selective iNOS inhibitors which may be useful as anti-inflammatory drugs. PMID- 21684158 TI - Synthesis and evaluation of chromenyl barbiturates and thiobarbiturates as potential antitubercular agents. AB - A novel series of barbiturate and thiobarbiturate analogs of 2-benzoyl-3-methyl-5 oxo-5H-furo[3,2-g]chromene-6-carbaldehydes (3a-g and 4a-d, respectively) and 6 methyl-4,8-dioxo-4,8-dihydropyrano[3,2-g]chromenes (7a-c), were synthesized and evaluated for their antitubercular activities against Mycobacterium tuberculosis H37RV, and cytotoxicity (CC(50)) in the VERO cell MABA assay. The results indicate that the furanochromene series of compounds (3a-g and 4a-d) showed only weak to moderate antitubercular activity. However, the pyranochromene analog 7b showed good antitubercular activity (IC(90): 5.9MUg/mL) and cytotoxicity (CC(50): 14.27MUg/mL). The antitubercular activity of 7b was superior to the antituberculosis drug, pyrazinamide (PZA; IC(90): >20MUg/mL). Analog 7b was considered to be a lead compound for subsequent structural optimization. PMID- 21684159 TI - Novel quinoxaline derivatives for in vivo imaging of beta-amyloid plaques in the brain. AB - In a search for new probes to detect beta-amyloid plaques in the brain of patients with Alzheimer's disease (AD), we have synthesized and evaluated a series of quinoxaline derivatives containing a '6+6-6' ring system. These quinoxaline derivatives showed excellent affinity for Abeta(1-42) aggregates with K(i) values ranging from 2.6 to 10.7nM. Autoradiography with sections of brain tissue from an animal model of AD mice (APP/PS1) and AD patients revealed that [(125)I]5 labeled beta-amyloid plaques specifically. In biodistribution experiments using normal mice, [(125)I]5 displayed high uptake (6.03% ID/g at 2min) into and a moderately fast washout from the brain. Although additional refinements are needed to decrease the lipophilicity and improve the washout rate, the quinoxaline scaffold may be useful as a backbone structure to develop novel beta-amyloid imaging agents. PMID- 21684160 TI - SAR studies of 9-norbornylpurines as Coxsackievirus B3 inhibitors. AB - Coxsackievirus and related enteroviruses are important human pathogens that cause various diseases with clinical manifestations ranging from trivial flu-like syndromes to dangerous or even fatal diseases such as myocarditis, meningitis and encephalitis. Here, we report on our continuous SAR study focused on 9 (bicyclo[2.2.1]hept-2-yl)-9H-purines as anti-enteroviral inhibitors. The purine moiety was modified at positions 2, 6 and 8. Several analogues inhibited Coxsackievirus B3 as well as other enteroviruses at low-micromolar concentrations. The 6-chloropurine derivative was confirmed as the most active compound in this series. PMID- 21684161 TI - Discovery of novel SecA inhibitors of Candidatus Liberibacter asiaticus by structure based design. AB - Candidatus Liberibacter asiaticus is the causal agent of Huanglongbing (HLB) disease of citrus. Current management practices have not been able to control HLB and stop the spread of HLB. The current study is focused on screening small molecule inhibitors against SecA protein of Ca. L. asiaticus. Homology modeling, structure based virtual screening and molecular docking methods have been used to find the novel inhibitory compounds against SecA activity at ATP binding region. At 20MUm 17 compounds showed >50% inhibition and four compounds had more than 65% inhibition. The most active compound has IC(50) value of 2.5MUM. The differences between the activities of the compounds are explained by their inter-molecular interactions at ATP binding site. PMID- 21684162 TI - BODIPY-modified 2'-deoxyguanosine as a novel tool to detect DNA damages. AB - BODIPY-modified 2'-deoxyguanosine was synthesized for use as a detection reagent for genotoxic compounds. BODIPY-FL is a well known fluorescence reagent whose fluorescent light emission diminishes near a guanine base by a photo-induced electron transfer process. We attached BODIPY-Fl to the 5' position of the deoxyribose moiety of 2'-deoxyguanosine. Although this compound has low fluorescence activity, when depurination by the action of alkylating reagents and dG oxidation by singlet oxygen occurred, the emission of strong fluorescence was observed. BODIPY-dG was found, therefore, to be a very useful tool for selectively detecting DNA damaging activity particularly in natural environmental extracts. PMID- 21684163 TI - Synthesis and evaluation of nitric oxide-releasing derivatives of 3-n butylphthalide as anti-platelet agents. AB - Most ischemic stroke results from brain blood vessel blockage by platelet mediated thrombus, and anti-platelet therapy has been demonstrated clinical benefits in the treatment of this disease. In the present work, novel nitric oxide (NO)-releasing derivatives of an anti-ischemic stroke drug 3-n butylphthalide (NBP) were synthesized. Compounds 7a and 7c exhibited more potent anti-platelet activity than NBP and aspirin, and released a moderate amount of NO, which is beneficial in improving cardiovascular and cerebral circulation. These findings provide an alternative approach to the development of drugs more potent than NBP for the intervention of ischemic stroke. PMID- 21684164 TI - Consensus based clinical guideline for oral hygiene in the critically ill. AB - OBJECTIVES: Oropharyngeal colonisation has been identified as a factor contributing to ventilator associated pneumonia (VAP) in the Intensive Care Unit (ICU). We sought to develop a clinical practice guideline for providing oral hygiene in the critically ill. RESEARCH METHODOLOGY: Following a systematic literature review a prospectively derived consensus development conference was convened and sponsored by a clinical governance unit. RESULTS: The consensus development conference generated 12 recommendations for tools and solutions; frequency and duration of cleaning; oral assessment tools and oral hygiene protocols. These recommendations underwent a validation process. CONCLUSIONS: In light of sparse high level evidence to inform guidelines, further research is needed inform clinical practice. Oral hygiene is a critical element of nursing care and a standardised approach has the potential to improve clinical outcomes. PMID- 21684165 TI - Energy cost of walking in transfemoral amputees: Comparison between Marlo Anatomical Socket and Ischial Containment Socket. AB - OBJECTIVE: To compare energy cost of walking (ECW) and prosthesis-related perceived mobility with the Marlo Anatomical Socket (MAS((r))) and the Ischial Containment (IC) Socket. METHOD: Transfemoral (TF) amputees were enrolled in the study. ECW tests were conducted inside, in a hallway with a regular floor surface. Subjects had to walk back and forth on a 61m linear course at their own self-selected speed. Metabolic and heart rate data were collected during the walking test using a portable gas analyzer. All measurements were made at steady state (SS). The tests were performed first using the IC socket and then after 30 days of MAS((r)) use; the last test was carried out after 60 days of MAS((r)) use. The amputees were also administered the Prosthetic Evaluation Questionnaire Mobility Section (PEQ MS) at the first and the last test to assess perceived potential for mobility using the prosthesis. RESULTS: Seven long-term prosthesis users were analyzed. Their mean age was 33.9+/-9.3 years; all were employed, active, and used IC sockets. At the third walking test, the ECW with the MAS((r)) was significantly lower than that with the IC socket (p=.016). PEQ MS data also improved significantly at the last evaluation (p<.018). CONCLUSION: Results suggest that using the MAS((r)), lowering the ECW and improving PEQ MS, could be a valid prosthesis design for active TF amputees compared to their usual IC socket. PMID- 21684166 TI - Bendigoles D-F, bioactive sterols from the marine sponge-derived Actinomadura sp. SBMs009. AB - Marine derived actinomycetes have become an important source of bioactive natural products. Here we report the structure and bioactivity of the bendigoles D-F (1 3), 3-keto sterols isolated from the new marine sponge derived bacterium, Actinomadura sp. SBMs009. The isolation of these compounds was guided by a novel high-content screen for NF-kappaB and glucocorticoid receptor (GR) activity, and cytotoxicity assays. The structures of 1-3 were determined by detailed analysis of NMR, MS, and single crystal X-ray diffraction data. Interestingly, 1 displayed cytotoxicity against the L929 (mouse fibroblast) cell line with an IC(50) approximated to 30 MUM and was the most active inhibitor of GR-translocation, while 3 was the most effective inhibitor of NF-kappaB nuclear translocation with an IC(50) of 71 MUM. PMID- 21684167 TI - 5-Ethynyl-1-beta-D-ribofuranosyl-1H-[1,2,3]triazole-4-carboxylic acid amide (ETCAR) and its analogues: synthesis and cytotoxic properties. AB - Efficient Pd(0)-catalysed synthesis of 5-alkynyl-1-beta-D-ribofuranosyl-1H [1,2,3]triazole-4-carboxylic acid amide depends on the presence of different protecting groups of the ribose moiety. Peracetylated 5-iodo substrate (15) couples with terminal alkynes or trimethyl-[(tributylstannyl)ethynyl]silane in 50 71% and 72% yield (ETCAR), respectively, although its hydrodehalogenation to 19 is noticeable. On the other hand, hydrodehalogenation of acetonide (16) predominates over coupling with terminal alkyne and slightly decreases a yield of cross-coupling reaction with trimethyl[(tributylstannyl)ethynyl]silane. Alternative conditions of reaction with terminal alkynes, to exclude so far identified hydride sources to produce hydridopalladium species, have been established for acetonide 16 and allowed to achieve 72% of coupling. Fluoromethyl derivative (42) was prepared from its 5-hydroxymethyl precursor by fluorination with DAST. Additionally, X-ray structural analysis of 42 was performed. All 1,2,3 triazolonucleosides and two synthesized cycloSal-pronucleotides were evaluated for cytotoxic activity against K562, HeLa and HUVEC cells. PMID- 21684168 TI - Design and synthesis of 4-amino-2-phenylquinazolines as novel topoisomerase I inhibitors with molecular modeling. AB - 4-Amino-2-phenylquinazolines 7 were designed as bioisosteres of 3 arylisoquinolinamines 6 that were energy minimized to provide stable conformers. Interestingly, the 2-phenyl ring of 4-amino-2-phenylquinazolines was parallel to the quinazoline ring and improved their DNA intercalation ability in the DNA-topo I complex. Among the synthesized 4-amino group-substituted analogs, 4 cyclohexylamino-2-phenylquinazoline 7h exhibited potent topo I inhibitory activity and strong cytotoxicity. Interestingly, consistency was observed between the cytotoxicities and topo I activities in these quinazoline analogs, suggesting that the target of 4-amino-2-phenylquinazolines is limited to topo I. Molecular docking studies were performed with the Surflex-Dock program to afford the ideal interaction mode of the compound into the binding site of the DNA-topo I complex in order to clarify the topo I activity of 7h. PMID- 21684169 TI - Natural radionuclides in major aquifer systems of the Parana sedimentary basin, Brazil. AB - This paper describes the natural radioactivity of groundwater occurring in sedimentary (Bauru and Guarani) and fractured rock (Serra Geral) aquifer systems in the Parana sedimentary basin, South America that is extensively used for drinking purposes, among others. The measurements of gross alpha and gross beta radioactivity as well the activity concentration of the natural dissolved radionuclides 40K, 238U, 234U, 226Ra, 222Rn, 210Po and 210Pb were held in 80 tubular wells drilled in 21 municipalities located at Sao Paulo State and its border with Mato Grosso do Sul State in Brazil. Most of the gross alpha radioactivity data were below 1 mBq/L, whereas values exceeding the gross beta radioactivity detection limit of 30 mBq/L were found. The radioelement solubility in the studied systems varied according to the sequence radon>radium>other radionuclides and the higher porosity of sandstones relatively to basalts and diabases could justify the enhanced presence of dissolved radon in the porous aquifer. The implications of the data obtained in terms of standards established for defining the drinking water quality have also been discussed. The population weighted average activity concentration for these radionuclides was compared to the guideline value of 0.1 mSv/yr for the total effective dose and discussed in terms of the choice of the dose conversion factors. PMID- 21684170 TI - Clinical results of boron neutron capture therapy (BNCT) for glioblastoma. AB - The purpose of this study was to evaluate the clinical outcome of BSH-based intra operative BNCT (IO-BNCT) and BSH and BPA-based non-operative BNCT (NO-BNCT). We have treated 23 glioblastoma patients with BNCT without any additional chemotherapy since 1998. The median survival time (MST) of BNCT was 19.5 months, and 2-year, 3-year and 5-year survival rates were 26.1%, 17.4% and 5.8%, respectively. This clinical result of BNCT in patients with GBM is superior to that of single treatment of conventional radiotherapy compared with historical data of conventional treatment. PMID- 21684171 TI - Intra-operative conversion is a cause of masked mortality in off-pump coronary artery bypass: a meta-analysis. AB - Coronary artery bypass surgery can offer excellent results when performed with cardiopulmonary bypass (on pump) or without cardiopulmonary bypass (off pump). The debate as to which technique is superior remains unanswered. Intra-operative conversion from off- to on-pump coronary surgery is a relatively unexplored phenomenon, which cannot be assessed within randomised controlled trial design. We aimed to assess the effect of off-pump conversion on patient mortality. Medline, Embase, Cochrane and Google Scholar databases were systematically reviewed for studies published between 1980 and 2010 that compared the incidence of mortality between converted and non-converted off-pump patients. Publication bias and heterogeneity were assessed and data were extracted independently by multiple observers. We undertook a meta-analysis of these studies using random effects modelling. A total of 17 studies fulfilled our inclusion criteria, containing data for 18,870 off-pump coronary artery bypass operations spanning a decade (1998-2008), involving 920 cases of conversion. Overall, conversion increased mortality by an odds ratio of 6.18 (95% confidence interval 4.65-8.20), whereas emergency conversion further raised the odds ratio of mortality to 6.99 (95% confidence interval 5.18-9.45). The conversion from off- to on-pump cardiac surgery may significantly increase the chance of an adverse outcome, whereas emergency conversion confers a significant rise in mortality. The risk of conversion should be discussed when obtaining the patient's informed consent and its prevention warrants serious consideration by cardiac surgeons and cardiac surgical training programmes. PMID- 21684172 TI - Surgical treatment efficacy in 172 cases of tuberculosis-destroyed lungs. AB - OBJECTIVES: Compared to the use of anti-TB drugs for the treatment of tuberculosis (TB), surgery is destructive and is associated with higher risk. Whether surgery is needed for the treatment of TB-destroyed lungs (for short: destroyed lungs) is still controversial and unresolved in the clinic. METHODS: Retrospective analysis of treatment efficacy was performed on 172 cases of destroyed lungs (176 surgeries) in the Thoracic Surgery Department of our hospital from April 1992 to June 2010. RESULTS: A total of 83 male and 89 female patients was analyzed. The youngest patient was 7 years old, and the oldest was 72 years old, with a mean age of 38.4 years. A total of 120 cases had a preoperative cough, 31 cases had fever, and 42 cases had hemoptysis. A total of 49 cases was positive for Mycobacterium tuberculosis by sputum test before surgery, yielding a positive TB rate of 28.5% (49/172). A total of 116 patients had a destroyed left lung and 56 cases had a destroyed right lung. In all, 110 cases underwent total pneumonectomy, 37 pleuropneumonectomy, one lobectomy, 10 residual lobectomy, two total pneumonectomy and tracheoplasty, 11 cases bronchopleural fistula (BPF) repair and other surgeries, and one case underwent thoracoplasty. A total of four patients underwent thoracoplasty 30 days after surgery due to a thoracic cavity infection or empyema. The overall perioperative mortality rate was 2.9% (5/172). The surgical complication rate was 18.6% (32/172). The sputum negative conversion rate was 87.8% (43/49), and the clinical cure rate was 91.9% (158/172). CONCLUSIONS: Our findings suggested that surgical treatment efficacy in destroyed lungs was satisfactory with strict surgical indications, standard preoperative anti-TB treatment, adequate preoperative preparation, and careful intraoperative operations. PMID- 21684173 TI - Spinal analgesia for advanced cancer patients: an update. AB - In the nineties, spinal analgesia has been described as an useful means to control pain in advanced cancer patients. The aim of this review was to update this information with a systematic analysis of studies performed in the last 10 years. 27 papers pertinent with the topic selected for review were collected according to selection criteria. Few studies added further information on spinal analgesia in last decade. Despite a lack of a clinical evidence, spinal analgesia with a combination of opioids, principally morphine, and local anesthetics may allow to achieve analgesia in patients who had been intensively treated unsuccessfully with different trials of opioids. Some adjuvant drugs such as clonidine, ketamine, betamethasone, meperidine, and ziconotide may be promising agents, but several problems have to be solved before they can be used in the daily practice. In complex pain situations, spinal analgesia should not be negated to cancer patients, and oncologists should address this group of patients to other specialists. PMID- 21684174 TI - Mixture analysis of heterogeneous physical activity outcomes. AB - PURPOSE: The health benefits of physical activity (PA) are well established. PA outcomes, being semicontinuous in nature, often exhibit a large portion of zero values together with continuous positive values that are right-skewed. We propose a novel two-part mixture regression model with random effects to characterize heterogeneity of the clustered PA data. METHODS: In the binary part, the odds of PA participation are modeled with the use of a logistic mixed regression model. In the continuous part, the PA intensity conditional on those individuals engaging in PA is assessed by a gamma mixture regression model. Random effects are incorporated within the two parts to account for correlation of the observations. RESULTS: Model fitting and inference are performed through the Gaussian quadrature technique, which is implemented conveniently in the SAS PROC NLMIXED. The development of mixture methodology for analyzing PA is motivated by a study of PA in the daily life of patients with chronic obstructive pulmonary disease. CONCLUSIONS: The findings demonstrate the usefulness of the mixture analysis, which enables the separate identification of pertinent factors affecting PA participation and PA intensity for different patient subgroups. PMID- 21684175 TI - alcohol, smoking, and caffeine in relation to fecundability, with effect modification by NAT2. AB - PURPOSE: Common polymorphisms in the N-acetyltransferase-2 (NAT2) metabolic enzyme determine slow or rapid acetylator phenotypes. We investigated the effects of alcohol, smoking, and caffeine on fecundability, and determined whether the effects were modified by NAT2. METHODS: Three NAT2 polymorphisms were genotyped in 319 women office workers participating in a prospective pregnancy study (1990 1994). Women were ages 20-41 and at risk for pregnancy. Discrete-time survival analysis was used to determine the effects of alcohol, smoking, and caffeine on fecundability and evaluate effect modification by NAT2. RESULTS: We followed 319 women (161 slow acetylators, 158 rapid) for an average of 8 menstrual cycles, resulting in 124 pregnancies. There was no effect of caffeine on fecundability. Drinking >=1 alcoholic drink per day and current smoking were significantly associated with reduced fecundability, but only among slow acetylators (adjusted fecundability odds ratio [FOR] for smoking = 0.34; 95% confidence interval, 0.22 0.90; adjusted FOR for >=1 drink per day = 0.20; 0.05-0.92). There was no effect among rapid acetylators. CONCLUSIONS: NAT2 status significantly modified the effects of alcohol and smoking on fecundability, emphasizing the importance of incorporating genetic and metabolic information in studies of reproductive health. Replication of this study is warranted. PMID- 21684177 TI - "Warriors": impact of a powerful television drama on the psychological health of U.K. Bosnia peacekeepers. AB - PURPOSE: The impact of secondary trauma, such as watching powerful images on television, on the etiology of posttraumatic stress disorder in adults remains controversial. We explored the impact of a powerful TV drama ("Warriors") on the psychological health of U.K. peacekeeping troops compared with other military personnel who also saw the program but did not deploy on the same mission. METHODS: Psychological health (health perception, fatigue, posttraumatic stress reactions and common mental disorders) was assessed via questionnaire in a group of 1463 U.K. Armed Forces personnel before and after the televising of an award winning dramatic reconstruction ("Warriors") of events in Former Yugoslavia, a deployment in which some of the respondents had participated (Bosnia group) and some who had not (Era group). Information was also collected on whether participants had seen Warriors. RESULTS: Those who had deployed to Bosnia were more likely to have watched the drama, and viewers were more likely to be posttraumatic stress reactions and common mental disorders cases before transmission of the program. There were few health differences between viewers and nonviewers, and Bosnia viewers and Era viewers, posttransmission. Viewing status and group status (Bosnia/Era) restricted to viewers only did not predict posttransmission health outcomes, with one exception. Group status (viewers only) was a significant predictor of posttransmission fatigue, with Bosnia viewers more likely to be cases. Additional analyses, however, revealed the same finding for nonviewers. CONCLUSIONS: We found no evidence that those with symptoms of traumatic distress avoided watching a drama relevant to their experiences and no evidence of adverse effects on mental health. PMID- 21684176 TI - Are current law enforcement strategies associated with a lower risk of repeat speeding citations and crash involvement? A longitudinal study of speeding Maryland drivers. AB - PURPOSE: To determine whether traffic court appearances and different court verdicts were associated with risk of subsequent speeding citations and crashes. METHODS: A cohort of 29,754 Maryland drivers ticketed for speeding who either went to court or paid fines by mail in May/June 2003 was followed for 3 years. Drivers appearing in court were categorized by verdicts: 1) not guilty, 2) suspension of prosecution/no prosecution (STET/NP), 3) case dismissed, 4) probation before judgment (PBJ) and fines, or 5) fines and demerit points. Cox proportional hazard models were used to estimate adjusted hazard ratios (AHR). RESULTS: Court appearances were associated with lower risk of subsequent speeding citations (AHR = 0.92; 95% confidence interval [CI], 0.88-0.96), but higher risk of crashes (AHR = 1.25; 95% CI, 1.16-1.35). PBJ was associated with significantly lower repeat speeding tickets (AHR = 0.83; 95% CI, 0.75-0.91) and a non significant decrease in crashes (AHR = 0.87; 95% CI, 0.75-1.02). Both repeat speeding tickets and subsequent crashes were significantly lower in the STET/NP group. CONCLUSIONS: PBJ and STET/NP may reduce speeding and crashes, but neither verdict eliminated excess crash risk among drivers who choose court appearances. Randomized, controlled evaluations of speeding countermeasures are needed to inform traffic safety policies. PMID- 21684178 TI - Relationship between appetite and symptoms of depression and anxiety in patients on chronic hemodialysis. AB - OBJECTIVE: We aimed at evaluating the association between appetite and symptoms of depression and anxiety, cognitive dysfunction, fatigue, and comorbidities in patients on hemodialysis (HD). DESIGN: A cross-sectional study was conducted. SETTING: The study was conducted in an outpatient HD service of a tertiary level academic hospital. PATIENTS: A total of 90 patients on HD were evaluated for appetite (during the past week, how would you rate your appetite?), symptoms of depression (Beck Depression Inventory [BDI]) and anxiety (Hamilton Anxiety Rating Scale [HARS]), cognitive dysfunction (Mini Mental State Examination [MMSE]), and comorbidities (Charlson Comorbidity Index). MAIN OUTCOME MEASURE: Relationship between appetite and symptoms of depression and/or anxiety, cognitive dysfunction, and comorbidities was assessed. RESULTS: In 43 patients, the appetite was very good/good (group 1), in 22, it was fair (group 2), and in 25, it was poor/very poor (group 3). Mean and median BDI were significantly higher in group 3 as well as the percentage of patients with BDI >=16. Mean and median HARS and the percentage of patients with HARS >13 were significantly higher in group 3. MMSE was significantly lower in group 3 as well as the percentage of patients with MMSE <=23. Multiple linear regression analysis showed a dependence of appetite by age and BDI (P = .007 and P = .002, respectively). CONCLUSIONS: Anorexia is associated with older age and symptoms of depression in patients on HD. PMID- 21684179 TI - Interoceptive awareness and unaware fear conditioning: are subliminal conditioning effects influenced by the manipulation of visceral self-perception? AB - Research has shown repeatedly that attention influences implicit learning effects. In a similar vein, interoceptive awareness might be involved in unaware fear conditioning: The fact that the CS is repeatedly presented in the context of aversive bodily experiences might facilitate the development of conditioned responding. We investigated the role of interoceptive attention in a subliminal conditioning paradigm. Conditioning was embedded in a spatial cueing task with subliminally presented cues that were followed by a masking stimulus. Response times to the targets that were either validly or invalidly predicted by the cues served as index of conditioning. Interoceptive attention was manipulated between subjects. Half the participants completed a heartbeat detection task before conditioning. This task tunes attention to one's own bodily signals. We found that conditioned responding was facilitated in this latter group of participants. These results are in line with the hypothesis that a rise interoceptive attention enhances unaware conditioned responding. PMID- 21684180 TI - Synaesthesia in a logographic language: the colouring of Chinese characters and Pinyin/Bopomo spellings. AB - Studies of linguistic synaesthesias in English have shown a range of fine-grained language mechanisms governing the associations between colours on the one hand, and graphemes, phonemes and words on the other. However, virtually nothing is known about how synaesthetic colouring might operate in non-alphabetic systems. The current study shows how synaesthetic speakers of Mandarin Chinese come to colour the logographic units of their language. Both native and non-native Chinese speakers experienced synaesthetic colours for characters, and for words spelled in the Chinese spelling systems of Pinyin and Bopomo. We assessed the influences of lexical tone and Pinyin/Bopomo spelling and showed that synaesthetic colours are assigned to Chinese words in a non-random fashion. Our data show that Chinese-speaking synaesthetes with very different native languages can exhibit both differences and similarities in the ways in which they come to colour their Chinese words. PMID- 21684181 TI - Treatment of Jones fracture nonunion with isolated intramedullary screw fixation. AB - Although the treatment of acute Jones fractures is well described in published studies, the Jones fracture nonunion is more controversial with regard to treatment. Although nonoperative treatment is an option, surgery is the usual course. We conducted a retrospective case series of 7 patients (1 man and 6 women; age range 39 to 54 years), who were initially treated nonoperatively for acute Jones fractures. They went on to develop nonunions and were treated with intramedullary screw fixation. All patients had healed radiographically by 11 weeks postoperatively. One screw (14.29%) required removal because of irritation. None of the patients to date have experienced a new fracture. Our results indicate that intramedullary screw fixation alone without bone grafting is a viable option for Jones fracture nonunions. PMID- 21684182 TI - Sebaceous adenoma arising within an ovarian mature cystic teratoma in Muir-Torre syndrome. AB - This is the first reported case of a sebaceous adenoma arising within an ovarian mature cystic teratoma in a patient with Muir-Torre syndrome. The pathologic findings and a literature review are presented, including the importance and possible benefits of an early diagnosis of Muir-Torre syndrome. It is proposed that the presence of a sebaceous adenoma in an ovarian cystic teratoma may serve as a useful trigger to consider further history and investigations, with the goal of identifying an important genetic cancer predisposition syndrome. PMID- 21684183 TI - Metastatic renal mucinous tubular and spindle cell carcinoma. Atypical behavior of a rare, morphologically bland tumor. AB - Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare, distinctive renal neoplasm characterized by an admixture of cuboidal cells in tubules and sheets of spindle cells, typically with low-grade nuclei and a myxoid or mucinous background. It is characteristically of low malignant potential, and only rare metastatic cases have been reported. We describe a case in which the patient presented with extensive regional and distant metastases, but both primary and metastatic tumor showed the typical histomorphology of bland cuboidal or spindle cells lacking pleomorphism, mitoses, and necrosis. Almost all previous cases of metastatic MTSCCs have shown nuclear atypia or sarcomatoid morphology of the primary tumor; and metastatic renal MTSCC in which the primary neoplasm does not display atypical features is exceptional, serving to highlight that these rare tumors can behave aggressively even with "indolent" histological appearances. PMID- 21684184 TI - Lymphoepithelial carcinoma of the parotid gland arising in an intraglandular lymph node: report of a rare case mimicking metastasis. AB - We present a case (female patient aged 40 years) with a primary Epstein-Barr virus-associated lymphoepithelial carcinoma of the parotid gland that was confined to an intraparotid lymph node. This appearance of the tumor simulated a metastasis that was excluded by exhaustive radiologic and clinicopathologic investigations. PMID- 21684185 TI - Atypical polypoid adenomyoma of the uterus: an immunohistochemical study on 5 cases. AB - Immunohistochemical studies of atypical polypoid adenomyoma (APA) of the uterus are very rare. Five cases of APA were retrieved from the surgical cases of our laboratory. The ages were 38, 41, 54, 65, and 77 years (mean +/- SD, 55 +/- 14.6 years). The diameters of APA were 1.2, 1.9, 2.3, 3.2, and 7.0 cm (mean +/- SD, 3.12 +/- 2.00 cm). Histologically, APA consisted of complex glandular element and mesenchymal fibromuscular element. No endometrial stroma was present. Mucins were found in the glands but not in the mesenchyma. The glands were consistently positive for pancytokeratin (AE1/3, CAM5.2), cytokeratin (CK) 7, CK8, CK18, CK19, vimentin, CA125, estrogen receptor, progesterone receptor, MUC1, and MUC6. The glands were consistently negative for CK14, CK20, CEA, epithelial membrane antigen, S100 protein, p53, CD10, MUC2, and MUC5AC. Some cases were positive for CK34betaE12 (4/5), CK5/6 (4/5), and CA19-9 (4/5). The Ki-67 labeling ranged from 3% to 10%. The mesenchymal element was consistently positive for vimentin, alpha smooth muscle actin, estrogen receptor, progesterone receptor, and CD10, while consistently negative for pancytokeratin (AE1/3, CAM5.2), CK34betaE12, CK5/6, CK7, CK8, CK14, CK18, CK19, CK20, CEA, epithelial membrane antigen, S100 protein, CA125, CA19-9, p53, MUC1, MUC2, MUC5AC, and MUC6. Some cases were positive for desmin (2/5). Ki-67 labeling ranged from 1% to 8%. In conclusion, the immunoprofile of APA was reported. The findings provide basic knowledge of APA of the uterus. PMID- 21684187 TI - Trials of the detection of semen and vaginal fluid RNA using the genome profiling method. AB - The identification of sperm at the scene of a sexual crime is important evidence that can be used to prove that a crime took place. We used the new genome profiling (GP) method in this study to identify sperm and vaginal fluid from RNA extracted from bodily fluids. We randomly amplified genes via a PCR approach from these semen and vaginal fluid samples and performed temperature gradient gel electrophoresis between 15-65 degrees C. We identified specific species identification dots (spiddos) for semen and vaginal fluid. The results showed that the GP method is effective for the identification of bodily fluids at the scene of a sex crime. PMID- 21684186 TI - Deciphering the RNA polymerase II CTD code in fission yeast. AB - The RNA polymerase II carboxy-terminal domain (CTD) consists of tandem Y(1)S(2)P(3)T(4)S(5)P(6)S(7) repeats. Dynamic remodeling of the CTD, especially its serine phosphorylation pattern, conveys informational cues about the transcription apparatus to a large ensemble of CTD-binding proteins. Our genetic dissection of fission yeast CTD function provides insights to the "CTD code." Two concepts stand out. First, the Ser2 requirement for transcription during sexual differentiation is bypassed by subtracting Ser7, signifying that imbalance in the phosphorylation array, not absence of a phospho-CTD cue, underlies a CTD associated pathology. Second, the essentiality of Ser5 for vegetative growth is circumvented by covalently tethering mRNA capping enzymes to the CTD, thus proving that capping enzyme recruitment is a chief function of the Ser5-PO(4) mark. This illustrates that a key "letter" in the CTD code can be neutralized by delivering its essential cognate receptor to the transcription complex via an alternative route. PMID- 21684188 TI - AuxV: a database of auxin transport velocities. AB - One of the most widely used techniques to quantify polar auxin transport is the measurement of auxin speed. To date there have been more than 90 published reports of auxin speed in 44 species. We have collected available speed measurements into a database, along with information on plant growth conditions and growth rate. Measured auxin speeds have a range of 1.2-18 mm/h, and show notable correlations with organ type, growth rate, and plant clade. PMID- 21684189 TI - Meta-awareness, perceptual decoupling and the wandering mind. AB - Mind wandering (i.e. engaging in cognitions unrelated to the current demands of the external environment) reflects the cyclic activity of two core processes: the capacity to disengage attention from perception (known as perceptual decoupling) and the ability to take explicit note of the current contents of consciousness (known as meta-awareness). Research on perceptual decoupling demonstrates that mental events that arise without any external precedent (known as stimulus independent thoughts) often interfere with the online processing of sensory information. Findings regarding meta-awareness reveal that the mind is only intermittently aware of engaging in mind wandering. These basic aspects of mind wandering are considered with respect to the activity of the default network, the role of executive processes, the contributions of meta-awareness and the functionality of mind wandering. PMID- 21684190 TI - Effector proteins that modulate plant--insect interactions. AB - Insect herbivores have highly diverse life cycles and feeding behaviors. They establish close interactions with their plant hosts and suppress plant defenses. Chewing herbivores evoke characteristic defense responses distinguishable from general mechanical damage. In addition, piercing-sucking hemipteran insects display typical feeding behavior that suggests active suppression of plant defense responses. Effectors that modulate plant defenses have been identified in the saliva of these insects. Tools for high-throughput effector identification and functional characterization have been developed. In addition, in some insect species it is possible to silence gene expression by RNAi. Together, this technological progress has enabled the identification of insect herbivore effectors and their targets that will lead to the development of novel strategies for pest resistances in plants. PMID- 21684191 TI - Colorimetric detection of cyanide with phenyl thiourea derivatives. AB - Three structurally simple thiourea derivatives 1-3 were prepared, and their chromogenic behaviors toward various anions were investigated in aqueous solution. Among them 1 showed good sensitivity and selectivity for cyanide ion and also can distinguish it from other anions by different color changes. Besides that, the receptor 1 has a sensitive detection limit (1.27 MUM) for cyanide ion accordingly it can be used as a colorimetric sensor for the determination of cyanide ion. The use of the test strip of sensor 1 to detect cyanide ion was also reported. PMID- 21684192 TI - Dynamic NMR and computational study of 5,5-dimethyl-3,4-di-p-tolyl-2-cylopenten-1 one. AB - The restricted rotation of p-tolyl moiety in 5,5-dimethyl-3,4-di-p-tolyl-2 cyclopenten-1-one was studied by variable temperature NMR spectroscopy at a temperature range of 218-368 K. A free rotation, in NMR time scale, was observed at temperatures higher than 368 K; while, the rotation froze below 248 K. From dynamic NMR analysis, the Arrhenius energy of activation DeltaG? was calculated as 56.37 kJ mol(-1). The experimental results were confirmed by theoretical calculation using the density functional theory method B3LYP with basis sets, 6 31G and 6-31+G. PMID- 21684193 TI - Spectroscopic and spectrofluorimetric studies on the interaction of irbesartan with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and iodine. AB - Raman, UV-vis, 1H NMR, FT-IR, mass and fluorescence spectral techniques were employed to investigate the mechanism of interaction of irbesartan (IRB) drug with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and iodine. Interaction of IRB with iodine yields triiodide ion and its formation was confirmed by electronic and Raman spectra. The peaks appeared in Raman spectrum of the isolated product at 143, 113 and 76 cm(-1) are assigned to nuas(I-I), nus(I-I) and delta(I3-) respectively, confirmed the presence of I3- ion. The interaction of DDQ with irbesartan was found to proceed through the formation of outer complex and its conversion to the CT complex. Formation constant (K), molar extinction coefficient (E) and thermodynamic properties DeltaH#, DeltaS# and DeltaG# were determined and discussed. Fluorescence quenching studies indicated that the interaction between the IRB and the acceptors are spontaneous and the IRB-DDQ interaction is found to be stronger than that the other system. Solvent variation studies indicated that the binding constant increased with an increase in polarity of the medium. PMID- 21684194 TI - Vibrational spectral investigation of four second order nonlinear optical azobenzene-containing materials: a combination of experimental and density functional theoretical (DFT) study. AB - In this work, four-second order nonlinear optical (NLO) azobenzene-containing materials are studied in-depth by using vibrational spectra and density functional theory (DFT). The Fourier transform infrared (FT-IR) spectra and FT Raman spectra are recorded in the range of 50-4000 and 100-3600cm(-1), respectively. Meanwhile, the DFT computations are performed at B3LYP/6-31G (d, p) level to derive equilibrium geometry, vibrational wavenumbers and intensities, and first hyperpolarizability, and the scaled theoretical wavenumbers are also shown to be in good agreement with experimental data. The calculated results show that these four azobenzene-containing compounds are good materials and the compound with nitro substituent groups possesses a larger first molecular hyperpolarizability (beta) value. Moreover, the simultaneous infrared and Raman activation of R1 group and CC stretching suggest that the charge transfer interaction might occur between the R1 group and phenyl ring, and the HOMO-LUMO gap analysis also supports this viewpoint. PMID- 21684195 TI - Spectrofluorimetric determination of glutathione in human plasma by solid-phase extraction using graphene as adsorbent. AB - An efficient solid phase extraction-spectrofluorimetric method using graphene as adsorbent was developed to sensitively determine glutathione (GSH) in biological samples. Fluorescent probe N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s indacene-3-yl)methyl)iodoacetamide (BODIPY Fl-C1-IA) was applied for the derivatization of GSH. The procedure was based on BODIPY Fl-C1-IA selective reaction with GSH to form highly fluorescent product BODIPY Fl-C1-IA-GSH, its extraction to the graphene-packed SPE cartridge and spectrofluorimetric determination. Some factors affecting the extraction efficiency, such as the type of the eluent and its volume, sample pH, extraction time, and sample volume were optimized. Comparative studies were also performed between graphene and other adsorbents including C18 silica, graphitic carbon, and multi-walled carbon nanotubes for the extraction of analyte. The calibration graph using the pretreatment system for GSH was linear over the range of 0.5-200 nM. The limit of detection was 0.01 nM (signal-to-noise ratio=3). Relative standard deviation for six replicate determinations of GSH at 80 nM concentration level was lower than 5.0%. The developed method was applied to the determination of GSH in human plasma with recoveries of 92-108%. This work revealed the great potentials of graphene as an excellent sorbent material in the analysis of biological samples. PMID- 21684196 TI - Experimental and theoretical assessment of the mechanism involved in the reaction of steroidal ketone semicarbazone with hydrogen peroxide. AB - 3beta-Acetoxy-5alpha-cholestan-6-one semicarbazone 1 on reaction with hydrogen peroxide affords selectively 3beta-acetoxy-5alpha-cholestan-6-spiro-1',2',4' triazolidine-3'-one 2. The structural assignment of the product was confirmed by spectral data and elemental analysis. A free radical mechanism of the present reaction was described successfully by calculating theoretical models of 1, A, B and 2, using DFT with B3LYP/6-31G* basis set. It was found that the reaction undergoes through the formation of two radical intermediates and the only one isomer of the product in which -NH-CO- group is cis with respect C5alpha-H, was selectively obtained. Frontier molecular orbital, spin electronic density, electrostatic potential and atomic charges were discussed. PMID- 21684197 TI - Unique role of ionic liquid [bmin][BF4] during curcumin-surfactant association and micellization of cationic, anionic and non-ionic surfactant solutions. AB - Hydrophilic ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroburate, modified the properties of aqueous surfactant solutions associated with curcumin. Because of potential pharmaceutical applications as an antioxidant, anti-inflammatory and anti-carcinogenic agent, curcumin has received ample attention as potential drug. The interaction of curcumin with various charged aqueous surfactant solutions showed it exists in deprotonated enol form in surfactant solutions. The nitro and hydroxyl groups of o-nitrophenol interact with the carbonyl and hydroxyl groups of the enol form of curcumin by forming ground state complex through hydrogen bonds and offered interesting information about the nature of the interactions between the aqueous surfactant solutions and curcumin depending on charge of head group of the surfactant. IL[bmin][BF4] encouraged early formation of micelle in case of cationic and anionic aqueous surfactant solutions, but slightly prolonged micelle formation in the case of neutral aqueous surfactant solution. However, for curcumin IL [bmin][BF4] favored strong association (7-fold increase) with neutral surfactant solution, marginally supported association with anionic surfactant solution and discouraged (~2-fold decrease) association with cationic surfactant solution. PMID- 21684198 TI - Synthesis and thermal studies of tetraaza macrocylic ligand and its transition metal complexes. DNA binding affinity of copper complex. AB - A Tetraaza Macrocylic Ligand (H2L) and its complexes, [Cd(H2L)(OH2)2](NO3)(2).1/2OH2 (I), [Co(H2L)(OH2)](NO3)(2).1/2OH2 (II), [Cu(H2L)(NO3)2].3/2OH2 (III) and [Ni(H2L)(NO3)(OH2)]NO3.OH2 (IV), have been synthesized and characterized on the basis of elemental analysis, molar conductivity, 1H NMR, UV-vis, FT-IR and mass spectroscopy. All results confirm that the prepared compounds have 1:1 metal-to-ligand stoichiometry, octahedral configuration and the ligand behaves as a neutral tetradendate towards the metal ions. [CdL(OH2)2] (V), [CoL(OH2)2] (VI), [CuL(OH2)2] (VII) and [Ni(H2L)(NO3)2] (VIII) were synthesized pyrolytically in solid state from corresponding compounds (I-IV). Analytical results of complexes (V-VIII) show that the ligand behaves either as a neutral tetradendate or dianionic tetradentate ligand towards the metal ions. The binding of H2L and its copper complex (III) to DNA has been investigated by ultraviolet absorption spectroscopy. The experiments indicate that H2L and its copper complex (III) can bind to DNA through an intercalative mode. The H2L and its copper complex (III) exhibited anti-tumor activity against Ehrlich Acites Carcinoma (E.A.C) at the concentration of 100 MUg/ml. PMID- 21684199 TI - Study on the interaction between thiazolopyrimidine analogues and bovine serum albumin. AB - Fluorescence and ultraviolet spectroscopy were used to explore the interaction between thiazolopyrimidines (TAPM) and bovine serum albumin (BSA) under imitated physiological conditions. The experimental results show that thiazolopyrimidines can quench the fluorescence of BSA through a static quenching process. The binding constants, binding sites, and thermodynamic parameters at different temperatures were calculated. The calculated results indicate that the interaction between thiazolopyrimidines and BSA is driven mainly by Van der Waals' force and hydrogen bonds. The binding distances r was obtained based on Forster theory of non-radiation energy transfer. The comparison of binding potency of thiazolopyrimidines and BSA suggests that the substituent on the benzene ring promotes the binding process of thiazolopyrimidines and BSA. PMID- 21684200 TI - B-cell polyclonal activation and Epstein-Barr viral abortive lytic cycle are two key features in acute infectious mononucleosis. AB - BACKGROUND: Acute infectious mononucleosis (AIM) is generally associated with a large EBV B cell reservoir cells and an intense B-cell polyclonal activation whereas the number of quiescent EBV-infected memory B cells in chronically EBV infected healthy controls is very low. OBJECTIVES: To evaluate the extent and functionality of ex vivo B-cell polyclonal activation, quantify the EBV DNA integrated in B cells, enumerate the functional EBV DNA reservoir in B cells and circulating B cells spontaneously secreting EBV antigens in AIM. STUDY DESIGN: Circulating B cells and B cells differentiating into plamablasts and plasma cells, early (BZLF1)- and late viral antigen (gp350)-secreting-cells (SCs) were enumerated in six AIM patients and seven healthy EBV carriers. RESULTS: In vitro B-cell polyclonal activation induced 8000-24,000 BZLF1- and 1000-3000gp350 SCs/10(6) B cells, respectively. These data suggest that only 11.1-19.5% of cells expressing BZLF1 synthesized gp350 and so completed the EBV-lytic cycle. Furthermore, circulating spontaneous BZLF1- and gp350-SCs that reflect ongoing viral replication were rare (20-120 and 10-30/10(6) B cells, respectively), and their low numbers contrasted with the high levels of circulating plasma cells (1.1-10.2% of CD19(+) B cells). CONCLUSION: The in vivo terminal-B-cell differentiation into plasma cells could unmask EBV B-cell reservoir to specific cytotoxic T-cell response and combined with a predominant abortive functional-EBV reservoir, strongly contribute to rapid decay of cellular EBV reservoir in AIM. PMID- 21684201 TI - Acute myositis associated with the initial phase of tick-borne encephalitis. AB - We present a case of clinically overt acute myositis associated with the initial phase of tick-borne encephalitis in a ten-year-old boy. The diagnosis of the disease was confirmed by detection of tick-borne encephalitis virus RNA in blood prior to the development of serum specific antibodies and the second phase of the disease. PMID- 21684202 TI - Emerging oseltamivir resistance in seasonal and pandemic influenza A/H1N1. AB - The emergence of oseltamivir resistance in seasonal and pandemic influenza A/H1N1 has created challenges for diagnosis and clinical management. This review discusses how clinical virology laboratories have handled diagnosis of oseltamivir-resistant H1N1 and what we have learned from clinical studies and case series. Immunocompetent patients infected with oseltamivir-resistant H1N1 have similar outcomes as patients infected with oseltamivir-susceptible H1N1. However, immunocompromised patients infected with oseltamivir-resistant H1N1 experience potentially more risks of complication and transmissibility with few therapeutic options. PMID- 21684203 TI - Testing procedures for SLAP lesions of the shoulder involving contraction and torsion of biceps long head and glenohumeral glides. AB - Testing procedures for SLAP lesions of the shoulder can combine resisted elbow flexion, forearm pronation and supination, and glenohumeral glides. These procedures reproduce symptoms by increasing biceps long head active tension or passive torsion, and by placing the shoulder in an unstable position. We compared activation of biceps long head and pain intensity, between supinated and pronated forearm positions, between different glides, and between individuals with and without shoulder impairment. A case control study. Twelve participants with suspected SLAP lesions and twelve with no history of shoulder injury volunteered. Electromyography measured muscle activity in biceps long head, normalised against maximum voluntary isometric contraction (MVIC). Subjective pain intensity scores were recorded. Biceps long head activity was greater in forearm supination (mean 39% MVIC) than pronation (mean 24% MVIC), but pain was higher in pronation (mean 4.5/10) than supination (3.2/10). Biceps long head activity was greater when testing without a glide, but there was no difference in pain comparing the glide conditions. The impaired group experienced more pain (mean 3.9/10) than controls (mean 0.3/10) but there was no difference in shoulder muscle activity. No one combination of testing procedures appeared to be diagnostic of SLAP lesions in our sample. This study supports the theory that biceps long head acts as a stabiliser of the shoulder, and suggests that clinical testing procedures for SLAP lesions may need to inhibit biceps long head activity. The addition of glides to SLAP testing procedures did not affect the reproduction of pain. PMID- 21684204 TI - Negative ionotropic agents for the treatment of left ventricular outflow tract obstruction due to sigmoid septum and concentric left ventricular hypertrophy. AB - BACKGROUND: Negative ionotropic agents are established treatments for left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM). However, their benefit in those with LVOTO without typical HCM is unclear. We evaluated if negative ionotropic agents are beneficial in treatment of LVOTO in patients without typical HCM. METHOD: In this retrospective cohort study, we evaluated echocardiograms and reviewed records of 15 patients with resting LVOT obstruction due to sigmoid septum (SS, n=9) and mild concentric left ventricular hypertrophy (LVH, n=6). Patients received treatment with sequential negative ionotropic agents (beta-blockers and disopyramide). Initial symptoms, presentation characteristics and echocardiographic characteristics pre and post treatment were evaluated. RESULTS: Fifteen patients (mean age 66.2 years, 46.7% male) were included. Dyspnoea (NYHA Class II/III) was reported as the initial symptom in all patients with four patients reporting chest pain. All patients had hypercontractile LV function at baseline (fractional shortening 46.29+/-8.77%) but had normal LVS/PW ratio (1.03+/-0.10). The mean resting LVOT gradient was 74.4+/-55.2 mmHg. Fourteen patients received initial beta-blocker therapy with a mean reduction in peak LVOT gradient of 40.9 mmHg seen in 11 patients that responded to therapy (p=0.02). Nine patients received disopyramide with a further 24.2+/-25.8 mmHg reduction in peak LVOT gradient observed in eight patients who tolerated treatment (p=0.04). Symptomatic improvement occurred in 80% of treated patients. CONCLUSIONS: In patients with LVOTO without typical HCM, sequential treatment with negative ionotropes is associated with a significant reduction in the degree of LVOTO and leads to symptomatic improvement. PMID- 21684205 TI - Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. AB - BACKGROUND: In a previous meta-analysis, we identified a survival benefit from neoadjuvant chemotherapy or chemoradiotherapy before surgery in patients with resectable oesophageal carcinoma. We updated this meta-analysis with results from new or updated randomised trials presented in the past 3 years. We also compared the benefits of preoperative neoadjuvant chemotherapy compared with neoadjuvant chemoradiotherapy. METHODS: To identify additional studies and published abstracts from major scientific meetings, we searched Medline, Embase, and Central (Cochrane clinical trials database) for studies published since January, 2006, and also manually searched for abstracts from major conferences from the same period. Only randomised studies analysed by intention to treat were included, and searches were restricted to those databases citing articles in English. We used published hazard ratios (HRs) if available or estimates from other survival data. We also investigated treatment effects by tumour histology and relations between risk (survival after surgery alone) and effect size. FINDINGS: We included all 17 trials from the previous meta-analysis and seven further studies. 12 were randomised comparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1854), nine were randomised comparisons of neoadjuvant chemotherapy versus surgery alone (n=1981), and two compared neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy (n=194) in patients with resectable oesophageal carcinoma; one factorial trial included two comparisons and was included in analyses of both neoadjuvant chemoradiotherapy (n=78) and neoadjuvant chemotherapy (n=81). The updated analysis contained 4188 patients whereas the previous publication included 2933 patients. This updated meta analysis contains about 3500 events compared with about 2230 in the previous meta analysis (estimated 57% increase). The HR for all-cause mortality for neoadjuvant chemoradiotherapy was 0.78 (95% CI 0.70-0.88; p<0.0001); the HR for squamous-cell carcinoma only was 0.80 (0.68-0.93; p=0.004) and for adenocarcinoma only was 0.75 (0.59-0.95; p=0.02). The HR for all-cause mortality for neoadjuvant chemotherapy was 0.87 (0.79-0.96; p=0.005); the HR for squamous-cell carcinoma only was 0.92 (0.81-1.04; p=0.18) and for adenocarcinoma only was 0.83 (0.71-0.95; p=0.01). The HR for the overall indirect comparison of all-cause mortality for neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy was 0.88 (0.76-1.01; p=0.07). INTERPRETATION: This updated meta-analysis provides strong evidence for a survival benefit of neoadjuvant chemoradiotherapy or chemotherapy over surgery alone in patients with oesophageal carcinoma. A clear advantage of neoadjuvant chemoradiotherapy over neoadjuvant chemotherapy has not been established. These results should help inform decisions about patient management and design of future trials. FUNDING: Cancer Australia and the NSW Cancer Institute. PMID- 21684206 TI - A new approach to cervical screening. PMID- 21684208 TI - Oesophageal cancer: who needs neoadjuvant therapy? PMID- 21684207 TI - Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. AB - BACKGROUND: Concurrent testing for human papillomavirus (HPV) and cervical cytology (co-testing) is an approved alternative to cytology alone in women aged 30 years and older. We aimed to assess the safety in routine clinical practice of 3-year screening intervals for women testing negative for HPV with normal cytology and to assess if co-testing can identify women at high risk of cervical cancer or cervical intraepithelial neoplasia grade 3 (CIN3) or worse over 5 years. METHODS: We assessed the 5-year cumulative incidence, starting in 2003-05, of cervical cancer and CIN3 or worse for 331,818 women aged 30 years and older who enrolled in co-testing at Kaiser Permanente Northern California (Berkeley, CA, USA) and had adequate enrolment co-test results. Follow-up continued until Dec 31, 2009. We defined cumulative incidence to include prevalence at enrolment and incidence after enrolment. Prevalence at enrolment was defined as the ratio of women diagnosed with each outcome on the biopsy visit immediately after their enrolment screening visit to the total enrolled women. At screening visits only HPV test and Pap smear samples were collected, and at biopsy visits colposcopically directed biopsies were taken. To estimate post-enrolment incidence, we used Weibull survival models. FINDINGS: In 315,061 women negative by HPV testing, the 5-year cumulative incidence of cancer was 3.8 per 100,000 women per year, slightly higher than for the 306,969 who were both negative by HPV and Pap testing (3.2 per 100,000), and half the cancer risk of the 319,177 who were negative by Pap testing (7.5 per 100,000). 313,465 (99.5%) women negative by HPV testing had either normal cytology or equivocal abnormalities. Abnormal cytology greatly increased cumulative incidence of CIN3 or worse over 5 years for the 16,757 positive by HPV testing (12.1%vs 5.9%; p<0.0001). By contrast, although statistically significant, abnormal cytology did not increase 5-year risk of CIN3 or worse for women negative by HPV testing to a substantial level (0.86%vs 0.16%; p=0.004). 12,208 (73%) of the women positive by HPV testing had no cytological abnormality, and these women had 258 (35%) of 747 CIN3 or adenocarcinoma in situ, [corrected] 25 (29%) of 87 cancers, and 17 (63%) of 27 adenocarcinomas. INTERPRETATION: For women aged 30 years and older in routine clinical practice who are negative by co-testing (both HPV and cytology), 3-year screening intervals were safe because a single negative test for HPV was sufficient to reassure against cervical cancer over 5 years. Incorporating HPV testing with cytology also resulted in earlier identification of women at high risk of cervical cancer, especially adenocarcinoma. Testing for HPV without adjunctive cytology might be sufficiently sensitive for primary screening for cervical cancer. FUNDING: Intramural Research Program of the US National Cancer Institute/NIH/DHHS, and the American Cancer Society. PMID- 21684209 TI - Survival benefit in hepatocellular carcinoma: when an innovative transplant strategy might benefit oncology. PMID- 21684210 TI - Barcelona Clinic Liver Cancer staging and transplant survival benefit for patients with hepatocellular carcinoma: a multicentre, cohort study. AB - BACKGROUND: Allocation of deceased-donor livers to patients with chronic liver failure is improved by prioritising patients by 5-year liver transplantation survival benefit. The Barcelona Clinic Liver Cancer (BCLC) staging has been proposed as the standard means to assess for prognosis of patients with hepatocellular carcinoma. We aimed to create a prediction model linking the BCLC stage of patients with hepatocellular carcinoma to their 5-year liver transplant benefit. METHODS: A large cohort of consecutive patients with hepatocellular carcinoma (n=1328) from the ITA.LI.CA database (n=2951) were judged as potentially eligible for liver transplantation according to the following criteria: absence of macroscopic vascular invasion or metastases, age 70 years or younger, and absence of relevant extra-hepatic comorbidities. To assess the correlation between BCLC staging and non-liver transplantation survival, we did Cox univariate and multivariate analyses including the following covariates: BCLC stage, year of diagnosis, age, sex, cause of cirrhosis, model for end-stage liver disease score, alpha-fetoprotein concentrations, and treatment. Liver transplantation survival benefit for patients was calculated, using Monte Carlo simulation analysis, as the patient's 5-year life expectancy with liver transplantation (estimated by the Metroticket model) minus the 5-year life expectancy without liver transplantation according to BCLC stage. FINDINGS: 83 (6%) of 1328 patients had BCLC 0 stage disease, 614 (46%) had BCLC A, 500 (38%) had BCLC B-C, and 131 (10%) had BCLC D. In the Cox non-liver transplantation survival multivariate model, hazard ratios associated with increasing BCLC stages were 1.530 (95% CI 1.107-2.116) for BCLC A versus BCLC 0, 1.572 (1.350-1.830) for BCLC B-C versus BCLC A, and 1.470 (1.164-1.856) for BCLC D versus BCLC B-C. Results of the Monte Carlo simulation analysis confirmed the significant effect of BCLC classification on transplant benefit; in the adjusted model, a median 5 year transplant benefit of 11.19 months (IQR 10.73-11.67) for BCLC 0, 13.49 months (11.51-15.57) for BCLC A, 17.36 months (15.06-19.28) for BCLC B-C, and 28.46 months (26.38-30.34) for BCLC D. INTERPRETATION: Liver transplantation could result in survival benefit for patients with hepatocellular carcinoma and advanced liver cirrhosis (BCLC stage D) and in those with intermediate tumours (BCLC stages B-C), regardless of the nodule number-size criteria (ie, Milan criteria), provided that macroscopic vascular invasion and extra-hepatic disease are absent. FUNDING: None. PMID- 21684211 TI - Using the patchwork text assessment as a vehicle for evaluating students' perceptions of their clinical leadership development. AB - A shift in universities world wide in providing theoretical post graduate programmes of study underpinned by traditional assessment strategies to work based learning programmes supported by innovative assessment strategies is required if Higher education institutions are to effectively educate contemporary healthcare leaders. Concurrently generating the evidence to evaluate the effectiveness of educational programmes is required by commissioners of healthcare education (DH, 2010). This paper reports on the perceptions of twelve post graduate students attending a clinical leadership masters programme of their leadership development through analysis of the critical commentary provided by students as part of assessment strategy that utilised the Patchwork Text Assessment. Following a thematic content analysis six themes emerged: programme philosophy and its impact on the success of the Patchwork Text Assessment; leadership development targeted against leadership frameworks; application and applicability of learning to the students own healthcare organisation; integrating theory to practice through theoretical development and work based activities; the value of networking; and the importance of multi-professional reflective groups. This study has clearly demonstrated how the success of the Patchwork Text Assessment in promoting deep learning is determined by its integration into the overall philosophy of the programme. Concurrently systems needed to be in place to ensure that Patchwork text Assessment is operationalised effectively and embedded within the day to day management of the programme. PMID- 21684212 TI - Gene-environment interactions in cardiovascular disease. AB - BACKGROUND: Historically, models to describe disease were exclusively nature based or nurture-based. Current theoretical models for complex conditions such as cardiovascular disease acknowledge the importance of both biologic and non biologic contributors to disease. A critical feature is the occurrence of interactions between numerous risk factors for disease. The interaction between genetic (i.e., biologic, nature) and environmental (i.e. non-biologic, nurture) causes of disease is an important mechanism for understanding both the etiology and public health impact of cardiovascular disease. OBJECTIVES: The purpose of this paper is to describe theoretical underpinnings of gene-environment interactions, models of interaction, methods for studying gene-environment interactions, and the related concept of interactions between epigenetic mechanisms and the environment. DISCUSSION: Advances in methods for measurement of genetic predictors of disease have enabled an increasingly comprehensive understanding of the causes of disease. In order to fully describe the effects of genetic predictors of disease, it is necessary to place genetic predictors within the context of known environmental risk factors. The additive or multiplicative effect of the interaction between genetic and environmental risk factors is often greater than the contribution of either risk factor alone. PMID- 21684213 TI - Cigarette smoke alters the invariant natural killer T cell function and may inhibit anti-tumor responses. AB - Invariant natural killer T (iNKT) cells are a minor subset of human T cells which express the invariant T cell receptor Valpha24 Jalpha18 and recognize glycolipids presented on CD1d. Invariant NKT cells are important immune regulators and can initiate anti-tumor responses through early potent cytokine production. Studies show that iNKT cells are defective in certain cancers. Cigarette smoke contains many carcinogens and is implicated directly and indirectly in many cancers. We investigated the effects of cigarette smoke on the circulating iNKT cell number and function. We found that the iNKT cell frequency is significantly reduced in cigarette smoking subjects. Invariant NKT cells exposed to cigarette smoke extract (CSE) showed significant defects in cytokine production and the ability to kill target cells. CSE inhibits the upregulation of CD107 but not CD69 or CD56 on iNKT cells. These findings suggest that CSE has a specific effect on iNKT cell anti-tumor responses, which may contribute to the role of smoking in the development of cancer. PMID- 21684214 TI - Cognitive and neurodevelopmental effects of antiepileptic drugs. AB - This article primarily represents the contributions of two young investigators to the understanding of the neuropsychological consequences of epilepsy and its treatment. The authors have reviewed two key areas of importance: the complex relationship between cognitive dysfunction and epilepsy and the risks of cognitive dysfunction in children as a consequence of in utero exposure to antiepileptic drug treatment. The work of two young investigators is presented and future research needs are outlined. PMID- 21684215 TI - Steroid-induced hallucination following intra-articular administration: a case report and brief review. AB - Amidst the ubiquitous use of steroids, psychiatric side-effects are not uncommon, though the presentation may be curiously diverse. The case of an elderly lady who had 40 mg of methylprednisolone injected in each knee for treatment of suprapatellar bursitis is presented. After 3 days, she reported visual hallucinations, which resolved without treatment 6 days after the steroid injections. We found considerable interest in this case as there were very few reported cases of adverse psychiatric events triggered by intra-articular steroid administration. We follow with a brief review of the incidence, risk factors, presentation, and treatment of steroid-induced psychiatric side-effects. PMID- 21684216 TI - Overexpression of GDNF in the uninjured DRG exerts analgesic effects on neuropathic pain following segmental spinal nerve ligation in mice. AB - Glial cell line-derived neurotrophic factor (GDNF), a survival-promoting factor for a subset of nociceptive small-diameter neurons, has been shown to exert analgesic effects on neuropathic pain. However, its detailed mechanisms of action are still unknown. In the present study, we investigated the site-specific analgesic effects of GDNF in the neuropathic pain state using lentiviral vector mediated GDNF overexpression in mice with left fifth lumbar (L5) spinal nerve ligation (SNL) as a neuropathic pain model. A lentiviral vector expressing both GDNF and enhanced green fluorescent protein (EGFP) was constructed and injected into the left dorsal spinal cord, uninjured fourth lumbar (L4) dorsal root ganglion (DRG), injured L5 DRG, or plantar skin of mice. In SNL mice, injection of the GDNF-EGFP-expressing lentivirus into the dorsal spinal cord or uninjured L4 DRG partially but significantly reduced the mechanical allodynia in association with an increase in GDNF protein expression in each virus injection site, whereas injection into the injured L5 DRG or plantar skin had no effects. These results suggest that GDNF exerts its analgesic effects in the neuropathic pain state by acting on the central terminals of uninjured DRG neurons and/or on the spinal cells targeted by the uninjured DRG neurons. PERSPECTIVE: This article shows that GDNF exerts its analgesic effects on neuropathic pain by acting on the central terminals of uninjured DRG neurons and/or on the spinal cells targeted by these neurons. Therefore, research focusing on these GDNF-dependent neurons in the uninjured DRG would provide a new strategy for treating neuropathic pain. PMID- 21684217 TI - Chronic pain in adolescents is associated with suicidal thoughts and behaviors. AB - Adults who suffer from chronic pain are at increased risk for suicide ideation and attempts, but it is not clear whether adolescents with chronic pain are similarly at elevated risk. This study investigates whether chronic pain is associated with an increase in suicidal ideation/attempts independent of depression in a population sample of adolescents. We analyzed data from the National Longitudinal Study of Adolescent Health, a longitudinal study of a nationally representative sample of adolescents in the United States (N = 9,970). Most chronic pain was related to suicide ideation/attempt both in the last year (odds ratio [OR] 1.3-2.1) and during the subsequent year (OR 1.2-1.8). After controlling for depressive symptoms, headaches (OR = 1.3 last year, OR = 1.2 subsequent year) and muscle aches (OR = 1.3 last year) remained associated with suicide ideation but not suicide attempt. These findings show that chronic pain in adolescence is a risk factor for suicide ideation; this effect is partly but not fully explained by depression. Youth with comorbid depression and chronic pain are at increased risk of thinking about and attempting suicide. Clinicians should be alert to suicide ideation/attempt and comorbid depression in this at risk population. PERSPECTIVE: Adolescents who suffer from chronic pain are at increased risk for suicide ideation and attempt. Depressive symptoms account for the link between chronic pain and suicide attempt, but do not completely explain why adolescents with chronic pain show suicide ideation. PMID- 21684218 TI - Occurrence and characteristics of chronic pain in a community-based cohort of indigent adults living with HIV infection. AB - Pain is common among people living with HIV/AIDS (PLWHA), but little is known about chronic pain in socioeconomically disadvantaged HIV-infected populations with high rates of substance abuse in the postantiretroviral era. This cross sectional study describes the occurrence and characteristics of pain in a community-based cohort of 296 indigent PLWHA. Participants completed questionnaires about sociodemographics, substance use, depression, and pain. Cut point analysis was used to generate categories of pain severity. Of the 270 participants who reported pain or the use of a pain medication in the past week, 8.2% had mild pain, 38.1% had moderate pain, and 53.7% had severe pain. Female sex and less education were associated with more severe pain. Depression was more common among participants with severe pain than among those with mild pain. Increasing pain severity was associated with daily pain and with chronic pain. Over half of the participants reported having a prescription for an opioid analgesic. Findings from this study suggest that chronic pain is a significant problem in this high risk, socioeconomically disadvantaged group of patients with HIV disease and high rates of previous or concurrent use of illicit drugs. PERSPECTIVE: This article presents epidemiological data showing that unrelieved chronic pain is a significant problem for indigent people living with HIV. Participants reported pain severity similar to those with metastatic cancer. Despite high rates of substance use disorders, approximately half received prescriptions for opioid analgesics, although few for long-acting agents. PMID- 21684220 TI - Chronic intermittent hypoxia augments sympatho-excitatory response to ATP but not to L-glutamate in the RVLM of rats. AB - The development of sympathetic overactivity and hypertension in rats submitted to chronic intermittent hypoxia (CIH) involve alterations in the central mechanisms controlling respiratory and autonomic functions. Herein, we assessed whether CIH alters glutamatergic and/or purinergic signaling in the ventrolateral medulla (VLM), a region that encompasses the pre-sympathetic neurons and respiratory neurons of the ventral respiratory column. Groups of juvenile rats were exposed for 10 days to CIH (6% O(2) for 40s, every 9min, 8h/day) or normoxia (controls). Following treatment, in situ working heart-brainstem preparations were performed to record simultaneously respiratory and sympathetic motor outputs. In separate CIH and control groups, the VLM was dissected for western-blot analyses of ionotropic glutamatergic and P2 receptors. l-glutamate microinjections (1, 3 or 10mM) into VLM of control (n=6) and CIH groups (n=10) produced similar increases of sympathetic and abdominal activities associated with phrenic nerve inhibition; immunoreactive NMDAR1 and GluR2/3 densities at the VLM were also alike between groups (n=4). In contrast, VLM microinjections of ATP (1, 10 or 50mM) evoked larger sympatho-excitatory responses in CIH (n=8) than in control rats (n=7, P<0.05) whilst the abdominal increase and phrenic nerve inhibition were of comparable magnitudes. The immunoreactive densities of P2X3 and P2X4 receptors, but not P2X1 and P2Y2, were 20% higher in VLM of CIH (n=8; P<0.05) than controls (n=8). Altogether, our findings suggest that CIH augments purinergic signaling in the VLM, supporting the concept that nucleotides play a role in the dynamic central control of the sympathetic autonomic function. PMID- 21684219 TI - Predicting sleep apnea in bariatric surgery patients. AB - BACKGROUND: Because of the high prevalence and potentially serious complications of obstructive sleep apnea (OSA) in obese individuals, several prediction models have been developed to detect moderate-to-severe OSA in patients undergoing bariatric surgery. Using commonly collected variables (body mass index [BMI], age, observed sleep apnea, hemoglobin A1c, fasting plasma insulin, gender, and neck circumference), Dixon et al. developed a model with a sensitivity of 89% and specificity of 81% for patients undergoing laparoscopic adjustable gastric band surgery suspected to have OSA. The present study evaluated the prediction model of Dixon et al. in 310 gastric bypass patients (mean BMI 46.8 kg/m(2), age 41.6 years, 84.5% women), with no preselection for OSA symptoms in a bariatric surgery partnership. METHODS: The patients underwent overnight limited polysomnography to determine the presence and severity of OSA as measured using the apnea-hypopnea index. RESULTS: Of the 310 patients, 44.2% had moderate-to-severe OSA (apnea hypopnea index >= 15/h). Most variables in the Dixon model were associated with a greater prevalence of OSA. The sensitivity (75%) and specificity (57%) for the model-based classification of OSA were considerably lower in the present sample than originally reported. An alternate prediction model identified 10 unique predictors of OSA. The presence of >= 5 of these predictors modestly improved the sensitivity (77%) and greatly improved the specificity (77%) in predicting an apnea-hypopnea index of >= 15/h. When applied to the validation sample, the sensitivity (76%) and specificity (72%) were essentially the same. CONCLUSION: Although the Dixon model and our model included overlapping predictors (BMI, gender, age, neck circumference), when applied in our sample of gastric bypass patients, neither model achieved the sensitivity and specificity for predicting OSA previously reported by Dixon et al. PMID- 21684221 TI - The xeroderma pigmentosum pathway: decision tree analysis of DNA quality. AB - The nucleotide excision repair (NER) system is a fundamental cellular stress response that uses only a handful of DNA binding factors, mutated in the cancer prone syndrome xeroderma pigmentosum (XP), to detect an astounding diversity of bulky base lesions, including those induced by ultraviolet light, electrophilic chemicals, oxygen radicals and further genetic insults. Several of these XP proteins are characterized by a mediocre preference for damaged substrates over the native double helix but, intriguingly, none of them recognizes injured bases with sufficient selectivity to account for the very high precision of bulky lesion excision. Instead, substrate versatility as well as damage specificity and strand selectivity are achieved by a multistage quality control strategy whereby different subunits of the XP pathway, in succession, interrogate the DNA double helix for a distinct abnormality in its structural or dynamic parameters. Through this step-by-step filtering procedure, the XP proteins operate like a systematic decision making tool, generally known as decision tree analysis, to sort out rare damaged bases embedded in a vast excess of native DNA. The present review is focused on the mechanisms by which multiple XP subunits of the NER pathway contribute to the proposed decision tree analysis of DNA quality in eukaryotic cells. PMID- 21684222 TI - Direct monitoring changes of salbutamol concentration in serum by chemiluminescent imaging. AB - We report in this manuscript, the use of direct ammonium persulfate-enhanced chemiluminescence (CL) imaging, to monitor changes to measure serum salbutamol concentration in subjects of different haptoglobin (Hp) phenotypes at different dosing time. It was noted that CL generated from Hp was decreased due to salbutamol's reducibility, which was used for monitoring salbutamol concentration in serum. The serum from the subjects treated by oral administration of salbutamol, was collected at different dosing time and was separated by polyacrylamide gel electrophoresis (PAGE) prior to the CL detection. According to CL images, samples were separated into three groups based on the Hp phenotypes. The curves of CL signal intensity versus time were obtained for each group, and we demonstrated that there were more significant variables on binding ability between groups. The maximum salbutamol concentration in the serum appeared after 4h, which was in agreement with the literature. In addition, the binding constants of salbutamol to Hp were determined by a fluorescence-based method, whose results were in agreement with the phenomenon of the greater salbutamol metabolism rate for Group Hp 1-1 than Group Hp 2-2. The presented method can monitor changes of salbutamol concentration in serum directly, making the procedures much simple, convenient, rapid and has the property of lower cost. It provided us with excellent reference information for the individual dosage regimen of different Hp groups, which hopefully could become a potential method for further pharmaceutical research. PMID- 21684223 TI - Development and validation of a sample stabilization strategy and a UPLC-MS/MS method for the simultaneous quantitation of acetylcholine (ACh), histamine (HA), and its metabolites in rat cerebrospinal fluid (CSF). AB - A UPLC-MS/MS assay was developed and validated for simultaneous quantification of acetylcholine (ACh), histamine (HA), tele-methylhistamine (t-mHA), and tele methylimidazolacetic acid (t-MIAA) in rat cerebrospinal fluid (CSF). The biological stability of ACh in rat CSF was investigated. Following fit-for purpose validation, the method was applied to monitor the drug-induced changes in ACh, HA, t-mHA, and t-MIAA in rat CSF following administration of donepezil or prucalopride. The quantitative method utilizes hydrophilic interaction chromatography (HILIC) Core-Shell HPLC column technology and a UPLC system to achieve separation with detection by positive ESI LC-MS/MS. This UPLC-MS/MS method does not require extraction or derivatization, utilizes a stable isotopically labeled internal standard (IS) for each analyte, and allows for rapid throughput with a 4 min run time. Without an acetylcholinesterase (AChE) inhibitor present, ACh was found to have 1.9+/-0.4 min in vitro half life in rat CSF. Stability studies and processing modification, including the use of AChE inhibitor eserine, extended this half life to more than 60 min. The UPLC-MS/MS method, including stabilization procedure, was validated over a linear concentration range of 0.025-5 ng/mL for ACh and 0.05-10 ng/mL for HA, t-mHA, and t-MIAA. The intra-run precision and accuracy for all analytes were 1.9-12.3% CV and -10.2 to 9.4% RE, respectively, while inter-run precision and accuracy were 4.0-16.0% CV and -5.3 to 13.4% RE, respectively. By using this developed and validated method, donepezil caused increases in ACh levels at 0.5, 1, 2, and 4h post dose as compared to the corresponding vehicle group, while prucalopride produced approximately 1.6- and 3.1-fold increases in the concentrations of ACh and t-mHA at 1h post dose, respectively, compared to the vehicle control. Overall, this methodology enables investigations into the use of CSF ACh and HA as biomarkers in the study of these neurotransmitter systems and related drug discovery efforts. PMID- 21684224 TI - The meanings of semantics: Comment on "Towards a neural basis of processing musical semantics" by Stefan Koelsch. PMID- 21684225 TI - [Astrocytoma in a patient with multiple endocrine neoplasia type 2A syndrome. May the coexistence of glial tumors and multiple endocrine neoplasia 2A not be casual?]. PMID- 21684226 TI - Regulation of immune responses, apoptosis, and tumorigenesis by separate FOXP-3 dependent genes: connection with clinical manifestations. AB - Recently, forkhead/winged-helix family box protein P3 (FOXP-3) was described as the main regulator of regulatory T cells' activity. This transcription factor has the ability to control the immunosuppressive response of regulatory T cells. FOXP 3 has binding sites for different genes specific for proteins with various important functions. In this article, selected FOXP-3-dependent genes with known functions were divided into two groups. The first group of genes has main immunoregulatory functions, and the second group has the ability to regulate apoptosis and tumorigenesis. Investigation of the functions of all FOXP-3 dependent genes opens perspectives for applications in different fields of basic and clinical research. PMID- 21684227 TI - Predictive model for bacteremia in adult patients with blood cultures performed at the emergency department: a preliminary report. AB - BACKGROUND: Useful predictive models for identifying patients at high risk of bacteremia at the emergency department (ED) are lacking. This study attempted to provide useful predictive models for identifying patients at high risk of bacteremia at the ED. METHODS: A prospective cohort study was conducted at the ED of a tertiary care hospital from October 1 to November 30, 2004. Patients aged 15 years or older, who had at least two sets of blood culture, were recruited. Data were analyzed on selected covariates, including demographic characteristics, predisposing conditions, clinical presentations, laboratory tests, and presumptive diagnosis, at the ED. An iterative procedure was used to build up a logistic model, which was then simplified into a coefficient-based scoring system. RESULTS: A total of 558 patients with 84 episodes of true bacteremia were enrolled. Predictors of bacteremia and their assigned scores were as follows: fever greater than or equal to 38.3 degrees C [odds ratio (OR), 2.64], 1 point; tachycardia greater than or equal to 120/min (OR, 2.521), 1 point; lymphopenia less than 0.5*10(3)/MUL (OR, 3.356), 2 points; aspartate transaminase greater than 40IU/L (OR, 2.355), 1 point; C-reactive protein greater than 10mg/dL (OR, 2.226), 1 point; procalcitonin greater than 0.5 ng/mL (OR, 3.147), 2 points; and presumptive diagnosis of respiratory tract infection (OR, 0.236), -2 points. The area under the receiver operating characteristic curves of the original logistic model and the simplified scoring model using the aforementioned seven predictors and their assigned scores were 0.854 (95% confidence interval, 0.806-0.902) and 0.845 (95% confidence interval, 0.798-0.894), respectively. CONCLUSION: This simplified scoring system could rapidly identify high-risk patients of bacteremia at the ED. PMID- 21684228 TI - [Palmoplantar hyperkeratosis in an infant]. PMID- 21684229 TI - [Changes in nutritional state, metabolic control and treatment of type 1 diabetes in the last 20 years]. AB - OBJECTIVE: The aim of this study is to describe changes in anthropometric characteristics, metabolic control, treatment and prevalence of overweight in diabetic children (DM1) from 2007 compared with another similar group from 1986. PATIENTS AND METHODS: Observational retrospective study of two groups of diabetic children (n=90). The collection of variables has been made at two cross-sections, 1986 and 2007. The studied variables were: age, years of DM1, sex, weight, height, BMI (and their Z values), HbA(1c) and treatment with insulin (type, number of doses, IU/day and IU/kg/day). RESULTS: In 2007 group there is a significant increase in Z-weight and Z-BMI (P=.001) when compared with the 1986 group. There was a negative relationship between the years with DM1 and Z-height (P=.05) in the 1986 group. The value of HbA(1c) was lower in the 2007 group (P=.001), but the dose of insulin (IU/day and IU/kg/day) was similar in both groups. The number of daily doses of insulin was higher in the 2007 group (P<.001), the use of insulin analogues dominated overall. A statistically significant relationship between HbA(1c) and treatment with insulin (dose injections, insulin type) was not found. The prevalence of overweight (14.6% vs 2.4%) was significantly higher in the 2007 Group (P=.001). CONCLUSIONS: The metabolic control (HbA(1c)) had improved and the use of multiple daily doses of insulin has been become the standard, but the prevalence of overweight has increased. We must monitor the emergence of insulin resistance and cardiovascular risk factors in this sensitive population to prevent early cardiovascular disease. PMID- 21684230 TI - [Short-term complications of late preterm infants]. AB - INTRODUCTION: Late preterm infants, born at 34-36(+6) weeks gestation, are physiologically more immature than term infants. As a consequence, they have an increased risk of morbidity and mortality. Since health outcomes in prematurity may change depending on local factors we have proposed determine the short-term medical problems of these infants in our hospital. PATIENTS AND METHODS: A retrospective observational study was carried out on all newborn >= 34 weeks gestation admitted to Virgen del Rocio hospital from May 2005 to December 2008. We divided this cohort into late preterm (34-36(+6) weeks, n=769) and term (37 41(+6) weeks, n=1460) groups. We compared mortality and morbidity data between the 2 groups. RESULTS: Late preterm group was associated with assisted reproduction, twin pregnancy, caesarean delivery and preeclampsia during pregnancy. The risk of hospitalization was six times greater in these infants and neonatal intensive care admissions were twice as common. The hospital stay was double in this group. Neonatal respiratory morbidity and jaundice were greater in the preterm group. The use of surfactant, oxygen and respiratory support (CPAP and CMV) was also higher. There were no significant differences in hypoglycaemia and neonatal mortality between both groups. CONCLUSIONS: Late preterm infants represent a well-defined risk group for developing complications and should be available the necessary resources should be made available for their special care. PMID- 21684231 TI - [Treatment of iron deficiency in predialysis state by low molecular weight iron dextran high doses intravenously]. AB - Anemia is a common complication of chronic kidney disease (CKD) in predialysis stage. Iron deficiency is more common than in normal patients and plays a key role in the genesis of anemia. Its correction avoids the use of erythropoiesis stimulating agents (ESA) or reduces their dosage. Treatment with oral iron is often poorly tolerated and ineffective, necessitating the use of intravenous iron. New forms of injectable iron allow the use of high doses and correct iron deficiency in a single administration with consequent preservation of venous capital and lower costs. We studied the effectiveness of iron dextran of low molecular weight (LMWID) in high doses to correct iron deficiency and treat anemia in predialysis CKD patients. Twenty-nine doses of 500 to 1600 mg were administered to 25 patients followed for CKD (GFR between 60 and 10 ml/min per 1.73 m(2)), selected on biological criteria of iron deficiency defined by a ratio of transferrin saturation (TSAT) <20% and/or serum ferritin of less than 100 MUg/L. Patients received treatment by ESA in 16 cases out of 29. One month after treatment, hemoglobin (Hb) increased significantly (11.4+/-1.6 vs 10.4+/-1.4 g/dL, P=0.0003) along with a significant increase in TSAT (21.3+/-7.3 vs 13.3+/ 3.8%, P=0.000003) and serum ferritin (286+/-253 vs 91+/-60 MUg/L, P=0.00005). Six patients had a serum ferritin greater than 500 MUg/L after treatment, which may put them at risk of iron overload. Their serum ferritin was higher than the rest of the population before treatment, while the TSAT was no different, reflecting a functional deficiency. Their hemoglobin did not increase after treatment in contrast to the rest of the population suggesting the unavailability of iron for erythropoiesis with accumulation in the reticuloendothelial system. Renal function did not change significantly and there were no cases of acute renal failure. No immediate side effect was observed. Three patients presented delayed reactions to such self-limiting myalgia and arthralgia. No venous inflammatory reaction was noted. The administration of high doses of LMWID is effective in treating anemia of CKD in the predialysis stage with a satisfactory tolerance, without affecting kidney function and helps preserve the venous capital. It should be reserved for patients whose serum ferritin is less than or equal to 150 MUg/L. PMID- 21684232 TI - Observation of resident clinical skills: outcomes of a program of direct observation in the continuity clinic setting. AB - OBJECTIVE: To assess the feasibility of a new multi-institutional program of direct observation and report what faculty observed and the feedback they provided. METHODS: A program of direct observation of real patient encounters was implemented in 3 pediatric residency programs using a structured clinical observation (SCO) form to document what was observed and the feedback given. Outcome variables included the number of observations made, the nature of the feedback provided, resident attitudes about direct observation before and after implementation, and the response of the faculty. RESULTS: Seventy-nine preceptors and 145 residents participated; 320 SCO forms were completed. Faculty provided feedback in 4 areas: content, process of the encounter, patient-centered attitudes and behaviors, and interpersonal skills. Feedback was 85% specific and 41% corrective. Corrective feedback was most frequent for physical examination skills. After program implementation, residents reported an increase in feedback and a decrease in discomfort with direct observation; in addition, they agreed that direct observation was a valuable component of their education. Participation rates among faculty were high. CONCLUSIONS: Direct observation using SCOs results in timely and specific feedback to residents about behaviors rarely observed in traditional precepting models. Resident competency in these clinical skill domains is critical for assessing, diagnosing, and managing patients. The SCO methodology is a feasible way to provide formative feedback to residents about their clinical skills. PMID- 21684233 TI - Digital image correlation analysis on the influence of crown material in implant supported prostheses on bone strain distribution. AB - PURPOSE: A digital image correlation (DIC) method for full-field surface strain measurement was used to analyze the effect of two veneering materials for implant supported crowns on the strain distribution within the surrounding bone. METHODS: An epoxy resin model of a bone block was made by housing acrylic resin replicas of a mandibular first premolar and second molar together with threaded implants replacing the second premolar and first molar. Porcelain-veneered (G1 and G3) and resin-veneered (G2 and G4) screw-retained splinted crowns were fabricated and loaded with (G1 and G2) and without (G3 and G4) the presence of the second molar replica. A 2-dimensional DIC measuring system was used to record surface deformation of the bone block model at a frequency of 1.0 Hz during application of a 250-N load. RESULTS: Maximum compressive strains (E(XX), %) were found for the following regions: between molars, G1 (-0.21), G2 (-0.18), G3 (-0.26), and G4 (-0.25); between implants, G1 (-0.19), G2 (-0.13), G3 (-0.19), and G4 (-0.14). The magnitude of strains in the simulated bone block with the resin-veneered crowns was lower than that with porcelain-veneered crowns, irrespective of the presence or absence of the second molar. CONCLUSIONS: The softer resin veneer helped to spread the load more evenly amongst the supporting teeth and implants, thus reducing the strains in the simulant bone block. Conversely, using the harder porcelain veneer resulted in the load being concentrated within one or two teeth or implants, thus leading to higher strain values in the bone block. PMID- 21684234 TI - Immediate implant placement in the maxillary central incisor region: a case report. AB - PATIENT: A 67-year-old female with root fracture of the maxillary central incisor underwent implant placement immediately after extraction, with the goal of shortening the treatment period. The superstructure was placed on the implant after a 4-month healing period. Review 5 years after implant loading revealed no clinical problems. DISCUSSION AND CONCLUSION: The treatment time was shortened effectively by the flapless immediate post-extraction placement procedure. Immediate post-extraction implant placement based on proper examination and diagnosis would reduce the patient burden. PMID- 21684235 TI - Schizotypy and emotional memory. AB - BACKGROUND: Emotional dysfunction is a core feature of psychotic disorders. One expression of such dysfunction is a reduction of the emotion-induced enhancement of memory which is normally found in healthy individuals. Less severe disruption of emotional processing may also be present in individuals prone to 'unusual' psychosis-like experiences. In this study we investigate voluntary declarative (i.e. explicit or episodic) emotional memory performance, primarily in relation to positive schizotypy (as measured by the unusual experiences scale of the O LIFE). The effect of negative schizotypy (introvertive anhedonia scale of the O LIFE) was also explored. We hypothesized that schizotypal individuals (scoring highly on Unusual Experiences) would show reduced memory enhancement. METHODS: One hundred and two healthy participants viewed a narrated slide-show containing neutral and negative emotional content. They rated the story on a number of affective dimensions and completed a variety of trait measures, including a multi dimensional measure of schizotypy. Seven days later, a memory test was performed and frequency of involuntary memories related to the slide-show assessed. RESULTS: The voluntary declarative emotional memory advantage in recall seen in low scorers (25%ile) on unusual experiences was absent in high scorers (75%ile), despite greater subjective fearfulness and emotionality in that group. However, the high scoring group did report experiencing more involuntary memories related to the story. There was no effect of negative schizotypy on declarative emotional memory. CONCLUSIONS: The emotional memory difficulties seen in studies of schizophrenia may extend to those with a vulnerability to positive psychosis-like experiences. This vulnerability may be expressed in both voluntary declarative - as well as involuntary - emotional memory performance. PMID- 21684236 TI - Decreased vitellogenin inducibility and 17beta-estradiol levels correlated with reduced egg production in killifish (Fundulus heteroclitus) from Newark Bay, NJ. AB - Aquatic species inhabiting polluted estuaries are exposed to complex mixtures of xenobiotics which can alter normal reproduction. We previously reported that female Atlantic killifish (Fundulus heteroclitus) from the highly contaminated Newark Bay, NJ (USA) exhibited an inhibition of oocyte development due to reduced vitellogenin (egg-yolk precursor) levels. Our hypothesis was that the inhibition of oocyte development in Newark Bay killifish is due to (1) deficient levels of circulating 17beta-estradiol, and (2) a decreased sensitivity of the vitellogenin pathway to physiological doses of 17beta-estradiol. In the first study, adult naive killifish from Tuckerton, NJ (reference) were caged at Tuckerton and Newark Bay. After 1 month, males caged at Newark Bay exhibited inductions of hepatic vitellogenin and estrogen receptor alpha, which were transient and returned to basal levels after 2 months (p<=0.05). In the second study, fecundity and 17beta estradiol levels were measured in reproductively active adult females from Tuckerton and Newark Bay. Tuckerton females produced 140 eggs per female and Newark Bay females produced 11 eggs per female. Embryos from Newark Bay had 34% greater mortality and 28% less hatch, relative to Tuckerton. In addition, embryo mass and yolk-volume of Newark Bay embryos compared to Tuckerton embryos was 16% and 25% lower, respectively. Circulating 17beta-estradiol levels in Newark Bay females (0.26 ng/mL) were measured to be 8-fold lower than Tuckerton females (2.25 ng/mL). In the third study, adult killifish from both sites were dosed with 17beta-estradiol to assess the sensitivity of the vitellogenin pathway. At doses of 0.01, 0.1, 1 and 10 ng/g body weight, induction levels of circulating vitellogenin in Newark Bay males were significantly inhibited by 97, 99, 98 and 44%, respectively, compared to Tuckerton males. At doses of 0.01, 0.1, 1, 10 and 100 ng/g body weight, induction levels of circulating vitellogenin in Newark Bay females were inhibited by 89, 79, 61, 40 and 30%, respectively, compared to Tuckerton females. These differences in inducibility could not be explained by altered hepatic expression of estrogen receptors alpha, betaa or betab. Based on the caged and dose-response studies, contaminants that down-regulate vitellogenin would interfere with its ability to be used as a biomarker for xeno-estrogen exposures. These studies demonstrate that contaminants within Newark Bay exert both estrogenic and anti-estrogenic responses which results in an overtly anti estrogenic phenotype (reduced egg production due to inhibition of vitellogenesis). PMID- 21684237 TI - Generation of fluorescent zebrafish to study endocrine disruption and potential crosstalk between thyroid hormone and corticosteroids. AB - Several environmental chemicals disrupt thyroid function, a key regulator of normal development involved in many physiological processes in fish. We studied the effects of such chemicals in vivo using transient transgenic zebrafish (Danio rerio), expressing Green Fluorescent Protein (GFP) under the control of a TH/bZIP promoter from Xenopus laevis. Exposure to thyroid hormone (T3) at 10(-8)M increased GFP fluorescence in F0 embryos and larvae. Transient transgenic embryos were exposed to a T3 signaling agonist (TRIAC) or antagonists (NH(3) or NaClO(4)), or to the endocrine disruptor Bisphenol A (BPA). When tested alone, TRIAC increased fluorescence, confirming the specificity of our model. Exposure to NH(3) or NaClO(4) decreased fluorescence, reflecting inhibition of thyroid function. When tested alone, BPA did not modify fluorescence, but when tested with T3, it significantly reduced T3-induced fluorescence, suggesting disruption of the thyroid function by BPA. The expression of genes involved in the TH axis (TR-alpha, TR-beta, TSH) and the corticoid axis (GR and MR) was followed by q-PCR after T3 or BPA exposure (24 or 48h) and at different developmental stages (0, 1, or 5 days post-fertilization). Expression of TR-alpha, TR-beta, and TSH genes increased after 48h T3 exposure in 1-day-old larvae. When tested alone, BPA only slightly affected gene expression. When applied with T3, BPA decreased expression of all candidate genes in 1-day-old embryos compared to the T3 treated group, in agreement with data obtained with the TH/bZIP-eGFP zebrafish model. Finally, we show that T3 exposure leads to up-regulation of MR and GR genes. This study provides a new rapid diagnostic tool for characterizing the disrupting effects of toxicants on thyroid function and suggests possible crosstalk between the TR and Corticoid Signaling system. PMID- 21684238 TI - Physiological response to a metal-contaminated invertebrate diet in zebrafish: importance of metal speciation and regulation of metal transport pathways. AB - Dietary metal uptake in fish is determined by metal bioavailability in prey and the metal requirements of the fish. In this study zebrafish were fed the intertidal polychaete worm Nereis diversicolor (3% wet weight day(-1)) collected from Ag, Cd and Cu-impacted Restronguet Creek (RC) or a reference site, Blackwater estuary (BW), for 21 days. On days 0, 7, 14 and 21 fish were fed a single meal of RC or BW N. diversicolor labeled with (110m)Ag or (109)Cd for measurements of metal assimilation efficiency (AE). Zebrafish intestines were also taken for mRNA expression analysis of copper transporter 1 (ctr1), divalent metal transporter 1 (dmt1) and metallothionein 2 (mt2). No significant difference was observed in the AE of (109)Cd in metal naive fish at day 0 between RC and BW worms, 11.8+/-2.1 and 15.3+/-2.8%, respectively. However, AE of (110m)Ag was significantly greater in fish fed worms from BW compared to RC, 5+/-1.2% and 1.6+/-0.5%, respectively at day 0. Fractionation analysis of radiolabeled metal partitioned in N. diversicolor from RC revealed a greater proportion of Ag (40+/ 1.1%) in a fraction containing protein and organelle bound metal, associated with high trophic availability, compared to BW polychaetes (24+/-2.5%). Lower AE of (110m)Ag from RC polychaetes is therefore unlikely due to speciation of (110m)Ag in N. diversicolor from RC, but to the high concentration of Cu, a potential Ag antagonist. Exposure to RC polychaetes significantly increased the AE of (110m)Ag (6.2+/-1%), but not (109)Cd, from RC worms, after 21 days. AE of (110m)Ag and (109)Cd was unaffected by pre-exposure to BW. Elevated concentration of intestinal Cu and increased expression of ctr1, dmt1 and mt2 after 14 days exposure in fish fed worms from RC suggest altered Cu handling strategy of these fish which may increase AE of Ag via shared Ag and Cu transport pathways. These data suggest metal exposure history of invertebrates may affect metal bioavailability to fish, and fish may alter intestinal uptake physiology during chronic dietary exposure with implications for the assimilation and toxicity of dietary metals. PMID- 21684240 TI - 17alpha-Ethinyl estradiol affects anxiety and shoaling behavior in adult male zebra fish (Danio rerio). AB - Ethinyl estradiol is a potent endocrine disrupting compound in fish and ubiquitously present in the aquatic environment. In this study, we exposed adult zebra fish (Danio rerio) males to 0, 5 or 25 ng Ethinyl estradiol/L for 14 days and analyzed the effects on non-reproductive behavior. Effects of treatment of the exposed males was shown by vitellogenin induction, while brain aromatase (CYP 19B) activity was not significantly altered. Both concentrations of Ethinyl estradiol significantly altered the behavior in the Novel tank test, where anxiety is determined as the tendency to stay at the bottom when introduced into an unfamiliar environment. The effects were, however, opposite for the two concentrations. Fish that were exposed to 5 ng/L had longer latency before upswim, fewer transitions to the upper half and shorter total time spent in the upper half compared with control fish, while 25 ng Ethinyl estradiol treatment resulted in shorter latency and more and longer visits to the upper half. The swimming activity of 25, but not 5 ng-exposed fish were slightly but significantly reduced, and these fish tended to spend a lot of time at the surface. We also studied the shoaling behavior as the tendency to leave a shoal of littermates trapped behind a Plexiglas barrier at one end of the test tank. The fish treated with Ethinyl estradiol had significantly longer latency before leaving shoal mates and left the shoal fewer times. Further, the fish exposed to 5 ng/L also spent significantly less time away from shoal than control fish. Fertilization frequency was higher in males exposed to 5 ng/L Ethinyl estradiol when compared with control males, while no spawning was observed after treatment with 25 ng/L. The testes from both treatment groups contained a normal distribution of spermatogenesis stages, and no abnormality in testis morphology could be observed. In conclusion, we have observed effects on two behaviors not related to reproduction in zebra fish males after treatment with Ethinyl estradiol, adding to the ecological consequences of contamination of aquatic environments with estrogenic substances. PMID- 21684239 TI - Methyl tert butyl ether targets developing vasculature in zebrafish (Danio rerio) embryos. AB - Disruption of vascular endothelial growth factor (VEGF) signaling during early development results in abnormal angiogenesis and increased vascular lesions. Embryonic exposure to 0.625-10mM methyl tert butyl ether (MTBE), a highly water soluble gasoline additive, resulted in a dose dependent increase in pooled blood in the common cardinal vein (CCV), cranial hemorrhages and abnormal intersegmental vessels (ISVs). The EC50s for the lesions ranked in terms of likelihood to occur with MTBE exposure were: pooled blood in the CCV, 3.2 mM [95% CI: 2.2-4.7]>cranial hemorrhage, 11 mM [5.9-20.5]>abnormal ISV, 14.5 mM [6.5 32.4]. Organ systems other than the vascular system appear to develop normally, which suggests MTBE toxicity targets developing blood vessels. Equal molar concentrations (0.625-10mM) of the primary metabolites, tertiary butyl alcohol (TBA) and formaldehyde, did not result in vascular lesions, which suggested that the parent compound is responsible for the toxicity. Stage specific exposures were carried out to determine the developmental period most sensitive to MTBE vascular disruption. Embryos treated until 6-somites or treated after Prim-5 stages did not exhibit a significant increase in lesions, while embryos treated between 6-somites and Prim-5 had a significant increase in vascular lesions (p<=0.05). During the critical window for MTBE-induced vascular toxicity, expression of vegfa, vegfc, and flk1/kdr were significantly decreased 50, 70 and 40%, respectively. This is the first study to characterize disruption in vascular development following embryonic exposure to MTBE. The unique specificity of MTBE to disrupt angiogenesis may be mediated by the down regulation of critical genes in the VEGF pathway. PMID- 21684241 TI - Differential proteomic responses in hepatopancreas and adductor muscles of the green-lipped mussel Perna viridis to stresses induced by cadmium and hydrogen peroxide. AB - This study aimed to reveal the proteomic responses in the hepatopancreas and adductor muscle of a common biomonitor, Perna viridis after 14-day exposure to two model chemicals, cadmium (Cd; a toxic metal) and hydrogen peroxide (H(2)O(2); a pro-oxidant), using two-dimensional gel electrophoresis coupled with multivariate statistical analyses. Unique sets of tissue-specific protein expression signatures were revealed corresponding to the two treatment groups. In the hepatopancreas, 15 and 2 spots responded to Cd and H(2)O(2) treatments respectively. 6 and 7 spots were differentially expressed in the adductor muscle for Cd and H(2)O(2) treatments, respectively. 15 differentially expressed spots were successfully identified by MALDI-TOF/TOF MS analysis. These proteins are involved in glycolysis, amino acid metabolism, energy homeostasis, oxidative stress response, redox homeostasis and protein folding, heat-shock response, and muscle contraction modulation. This is the first time, to have demonstrated that Cd exposure not only leads to substantial oxidative stress but also results in endoplasmic reticulum stress in hepatopancreas of the mussel. Such notable stress responses may be attributable to high Cd accumulation in this tissue. Our results suggested that investigations on these stress-associated protein changes could be used as a new and complementary approach in pollution monitoring by this popular biomonitor species. PMID- 21684242 TI - Comparative effects of butyl benzyl phthalate (BBP) and di(2-ethylhexyl) phthalate (DEHP) on the aquatic larvae of Chironomus riparius based on gene expression assays related to the endocrine system, the stress response and ribosomes. AB - In this work, the effects of butyl benzyl phthalate (BBP) and di(2-ethylhexyl) phthalate (DEHP), two of the most extensively used phthalates, were studied in Chironomus riparius under acute short-term treatments, to compare their relative toxicities and identify genes sensitive to exposure. The ecotoxicity of these phthalates was assessed by analysis of the alterations in gene expression profiles of selected inducible and constitutive genes related to the endocrine system, the cellular stress response and the ribosomal machinery. Fourth instar larvae, a model system in aquatic toxicology, were experimentally exposed to five increasing concentrations (0.01, 0.1, 1, 10, and 100mg/L) of DEHP and BBP for 24h. Gene expression was analysed by the changes in levels of transcripts, using RT-PCR techniques with specific gene probes. The exposures to DEHP or BBP were able to rapidly induce the hsp70 gene in a concentration-dependent manner, whereas the cognate form hsc70 was not altered by either of these chemicals. Transcription of ribosomal RNA as a measure of cell viability, quantified by the levels of ITS2, was not affected by DEHP, but was slightly, yet significantly, downregulated by BBP at the highest concentrations tested. Finally, as these phthalates are classified as endocrine disruptor chemicals (EDCs), their potential effect on the ecdysone endocrine system was studied by analysing the two genes, EcR and usp, of the heterodimeric ecdysone receptor complex. It was found that BBP provoked the overexpression of the EcR gene, with significant increases from exposures of 0.1mg/L and above, while DEHP significantly decreased the activity of this gene at the highest concentration. These data are relevant as they show for the first time the ability of phthalates to interfere with endocrine marker genes in invertebrates, demonstrating their potential capacity to alter the ecdysone signalling pathway. Overall, the study clearly shows a differential gene-toxin interaction for these two phthalates and adds novel genomic tools for biomonitoring environmental xenobiotics in insects. PMID- 21684243 TI - Perfluorooctane sulfonate impairs the cardiac development of a marine medaka (Oryzias melastigma). AB - Perfluorooctane sulfonate (PFOS) is a persistent organic contaminant and has been widely detected in the sea water. However, toxic effects of PFOS on cardiac development in marine organisms have not been reported. In the present study, we investigated the toxicity of PFOS on the cardiac development using Oryzias melastigma embryos. The embryos at 2 days post-fertilization (dpf) were continuous exposed to PFOS (1, 4 and 16 mg/L) for various periods, cardiac function and morphology were examined at different developmental stages. The results showed that exposure to 4 and 16 mg/L PFOS resulted in enlarged the sinus venosus (SV)-bulbus arteriosus (BA) distance and altered the heart rate. We further investigated eight heart-development related genes to test the effects of PFOS on molecular level. Seven genes were first cloned in O. melastigma and their temporal expression patterns were assayed. Most of the genes were highly expressed in the 6dpf, which is the critical stage for heart development. Their expression levels upon PFOS exposure were studied. The expressions of GATA4 and NKX2.5 were significantly down-regulated while COX-2, FGF8 and ATPase were significantly up-regulated at 6dpf. Our results showed for the first time that PFOS exposure affected the expression of cardiac development-related genes, development and function of heart in the marine medaka. PMID- 21684244 TI - Short-term exposure to a treated sewage effluent alters reproductive behaviour in the three-spined stickleback (Gasterosteus aculeatus). AB - Some UK sewage treatment work (STW) effluents have been found to contain high levels of anti-androgenic activity, but the biological significance of this activity to fish has not been determined. The aim of this study was to investigate the effects of exposure to a STW effluent with anti-androgenic activity on the reproductive physiology and behaviour of three-spined sticklebacks (Gasterosteus aculeatus). Fish were exposed to a STW effluent (50 and 100%, v/v) with a strong anti-androgenic activity (328.56+/-36.83 MUgl(-1) flutamide equivalent, as quantified in a recombinant yeast assay containing the human androgen receptor) and a low level of oestrogenic activity (3.32+/-0.66 ngl(-1) oestradiol equivalent, quantified in a recombinant yeast assay containing the human oestrogen receptor) for a period of 21 days in a flow-through system in the laboratory. Levels of spiggin, an androgen-regulated protein, were not affected by the STW effluent exposure, nor were levels of vitellogenin (a biomarker of oestrogen exposure), but the reproductive behaviour of the males was impacted. Males exposed to full strength STW effluent built fewer nests and there was a significant reduction in male courtship behaviour for exposures to both the 50 and 100% STW effluent treatments compared with controls. The effect seen on the reproduction of male sticklebacks may not necessarily have been as a consequence of the endocrine active chemicals present in the STW effluent alone, but could relate to other features of the effluent, such as turbidity that can impair visual signalling important for courtship interactions. Regardless the specific causation, the data presented show that effluents from STW have an impact on reproductive behaviour in male sticklebacks which in turn affects reproductive performance/outcome. The study further highlights the use of fish behaviour as a sensitive endpoint for assessing potential effects of contaminated water bodies on fish reproduction. PMID- 21684245 TI - Promotion of liver and lung tumorigenesis in DEN-treated cytoglobin-deficient mice. AB - Cytoglobin (Cygb) is a recently discovered vertebrate globin with molecular characteristics that are similar to myoglobin. To study the biological function of Cygb in vivo, we generated Cygb knockout mice and investigated their susceptibility to N,N-diethylnitrosamine (DEN)-induced tumorigenesis. Four-week old male mice were administered DEN in drinking water at a dose of 25 ppm for 25 weeks or 0.05 ppm for 36 weeks. Cygb deficiency promoted the DEN-induced development of liver and lung tumors. All Cygb(+/-) and Cygb(-/-) mice treated with 25-ppm DEN exhibited liver tumors, compared with 44.4% of their wild-type counterparts. Lung tumors were present only in Cygb-deficient mice. More than 40% of Cygb(-/-) mice developed liver and lung tumors at the nontoxic dose of DEN (0.05 ppm), which did not induce tumors in wild-type mice. Cygb loss was associated with increased cancer cell proliferation, elevated extracellular signal-regulated kinase and Akt activation, overexpression of IL-1beta, IL-6, Tnfalpha, and Tgfbeta3 mRNAs, and hepatic collagen accumulation. Cygb-deficient mice also exhibited increased nitrotyrosine formation and dysregulated expression of cancer-related genes (cyclin D2, p53, Pak1, Src, Cdkn2a, and Cebpa). These results suggest that Cygb deficiency induces susceptibility to cancer development in the liver and lungs of mice exposed to DEN. Thus, globins such as Cygb will shed new light on the biological features of organ carcinogenesis. PMID- 21684246 TI - Slow-adhering stem cells derived from injured skeletal muscle have improved regenerative capacity. AB - A wide variety of myogenic cell sources have been used for repair of injured and diseased muscle including muscle stem cells, which can be isolated from skeletal muscle as a group of slow-adhering cells on a collagen-coated surface. The therapeutic use of muscle stem cells for improving muscle regeneration is promising; however, the effect of injury on their characteristics and engraftment potential has yet to be described. In the present study, slow-adhering stem cells (SASCs) from both laceration-injured and control noninjured skeletal muscles in mice were isolated and studied. Migration and proliferation rates, multidifferentiation potentials, and differences in gene expression in both groups of cells were compared in vitro. Results demonstrated that a larger population of SASCs could be isolated from injured muscle than from control noninjured muscle. In addition, SASCs derived from injured muscle demonstrated improved migration, a higher rate of proliferation and multidifferentiation, and increased expression of Notch1, STAT3, Msx1, and MMP2. Moreover, when transplanted into dystrophic muscle in MDX/SCID mice, SASCs from injured muscle generated greater engraftments with a higher capillary density than did SASCs from control noninjured muscle. These data suggest that traumatic injury may modify stem cell characteristics through trophic factors and improve the transplantation potential of SASCs in alleviating skeletal muscle injuries and diseases. PMID- 21684247 TI - Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis. AB - Aberrantly hyperactivated STAT3 has been found in human liver cancers as an oncogene; however, STAT3 has also been shown to exert hepatoprotective effects during liver injury. The balancing act that STAT3 plays between hepatoprotection and liver tumorigenesis remains poorly defined. In this study, the diethylnitrosamine (DEN)-induced liver tumor model and the chronic carbon tetrachloride (CCl(4))-induced liver fibrosis model were both used to investigate the role of STAT3 in liver tumorigenesis. Hepatocyte-specific STAT3 knockout mice were resistant to liver tumorigenesis induced by a single DEN injection, whose tumorigenesis was associated with minimal chronic liver inflammation, injury, and fibrosis. In contrast, long-term CCl(4) treatment resulted in severe hepatic oxidative damage, inflammation, and fibrosis but rarely induced liver tumor formation in wild-type mice. Despite the oncogenic function of STAT3 in DEN induced liver tumor, hepatocyte-specific STAT3 knockout mice were more susceptible to liver tumorigenesis after 16 weeks of CCl(4) injection, which was associated with higher levels of liver injury, inflammation, fibrosis, and oxidative DNA damage compared with wild-type mice. These findings suggest that the hepatoprotective feature of STAT3 prevents hepatic damage and fibrosis under the condition of persistent inflammatory stress, consequently suppressing injury driven liver tumor initiation. Once liver tumor cells have developed, STAT3 likely acts as an oncogenic factor to promote tumor growth. PMID- 21684249 TI - Scanning electron microscopy preparation protocol for differentiated stem cells. AB - The lack of an established protocol for scanning electron microscopy (SEM) studies on stem cells differentiating into adipogenic lineage led us to develop a protocol for the preparation of differentiated adult bone marrow-derived mesenchymal stem cells (BMSC) for SEM. This protocol describes the procedure to maintain and preserve the structural organization of cellular components following differentiation, for morphological and physical characterization. The fixation of the differentiated cells was followed by dehydration using methanol, and vacuum desiccation before microscopy. The use of longer chain alcohols as dehydrating agents was avoided in our method to reduce the dissolution of lipid deposits in cells, thus allowing the maintenance of their structural integrity. The time period for the processing of samples was reduced by avoiding the osmium tetroxide postfixation and critical point drying. Thus, this protocol helps in determining the potential, fate, and degree of stem cell differentiation. This may be useful for SEM analysis of differentiated cells, especially those grown on various scaffolds. PMID- 21684248 TI - Agarose and polyacrylamide gel electrophoresis methods for molecular mass analysis of 5- to 500-kDa hyaluronan. AB - Agarose and polyacrylamide gel electrophoresis systems for the molecular mass dependent separation of hyaluronan (HA) in the size range of approximately 5-500 kDa were investigated. For agarose-based systems, the suitability of different agarose types, agarose concentrations, and buffer systems was determined. Using chemoenzymatically synthesized HA standards of low polydispersity, the molecular mass range was determined for each gel composition over which the relationship between HA mobility and logarithm of the molecular mass was linear. Excellent linear calibration was obtained for HA molecular mass as low as approximately 9 kDa in agarose gels. For higher resolution separation, and for extension to molecular masses as low as approximately 5 kDa, gradient polyacrylamide gels were superior. Densitometric scanning of stained gels allowed analysis of the range of molecular masses present in a sample as well as calculation of weight-average and number-average values. The methods were validated for polydisperse HA samples with viscosity-average molecular masses of 112, 59, 37, and 22 kDa at sample loads of 0.5 MUg (for polyacrylamide) to 2.5 MUg (for agarose). Use of the methods for electrophoretic mobility shift assays was demonstrated for binding of the HA-binding region of aggrecan (recombinant human aggrecan G1-IGD-G2 domains) to a 150-kDa HA standard. PMID- 21684250 TI - Differential apoptotic staining of mammalian blastocysts based on double immunofluorescent CDX2 and active caspase-3 staining. AB - Several approaches have been described for differential staining of blastocysts, but these methods are often time-consuming and unreliable. Here we describe a method for simultaneous differential staining and detection of apoptosis. The differential staining is based on the transcription factor CDX2 which is localized in the nucleus of trophectoderm (TE) cells but absent in the inner cell mass (ICM). Apoptosis is detected by staining of active caspase-3, a key player in several apoptotic pathways. This new approach represents a robust method for quantifying simultaneously ICM/TE ratio and apoptotic cell ratio in bovine, murine, porcine, and human blastocysts. PMID- 21684252 TI - FOXP2 promotes the nuclear translocation of POT1, but FOXP2(R553H), mutation related to speech-language disorder, partially prevents it. AB - FOXP2 is a forkhead box-containing transcription factor with several recognizable sequence motifs. However, little is known about the FOXP2-associated proteins except for C-terminal binding protein (CtBP). In the present study, we attempted to isolate the FOXP2-associated protein with a yeast two-hybrid system using the C-terminal region, including the forkhead domain, as a bait probe, and identified protection of telomeres 1 (POT1) as a FOXP2-associated protein. Immunoprecipitation assay confirmed the association with FOXP2 and POT1. POT1 alone localized in the cytoplasm but co-localized with FOXP2 and the forkhead domain of FOXP2 in nuclei. However, both FOXP2 with mutated nuclear localization signals and (R553H) mutated forkhead, which is associated with speech-language disorder, prevented the nuclear translocation of POT1. These results suggest that FOXP2 is a binding partner for the nuclear translocation of POT1. As loss of POT1 function induces the cell arrest, the impaired nuclear translocation of POT1 in the developing neuronal cells may be associated with the pathogenesis of speech language disorder with FOXP2(R553H) mutation. PMID- 21684251 TI - Differential effects of glutamate-286 mutations in the aa(3)-type cytochrome c oxidase from Rhodobacter sphaeroides and the cytochrome bo(3) ubiquinol oxidase from Escherichia coli. AB - Both the aa(3)-type cytochrome c oxidase from Rhodobacter sphaeroides (RsCcO(aa3)) and the closely related bo(3)-type ubiquinol oxidase from Escherichia coli (EcQO(bo3)) possess a proton-conducting D-channel that terminates at a glutamic acid, E286, which is critical for controlling proton transfer to the active site for oxygen chemistry and to a proton loading site for proton pumping. E286 mutations in each enzyme block proton flux and, therefore, inhibit oxidase function. In the current work, resonance Raman spectroscopy was used to show that the E286A and E286C mutations in RsCcO(aa3) result in long range conformational changes that influence the protein interactions with both heme a and heme a(3). Therefore, the severe reduction of the steady-state activity of the E286 mutants in RsCcO(aa3) to ~0.05% is not simply a result of the direct blockage of the D-channel, but it is also a consequence of the conformational changes induced by the mutations to heme a and to the heme a(3) Cu(B) active site. In contrast, the E286C mutation of EcQO(bo3) exhibits no evidence of conformational changes at the two heme sites, indicating that its reduced activity (3%) is exclusively a result of the inhibition of proton transfer from the D-channel. We propose that in RsCcO(aa3), the E286 mutations severely perturb the active site through a close interaction with F282, which lies between E286 and the heme-copper active site. The local structure around E286 in EcQO(bo3) is different, providing a rationale for the very different effects of E286 mutations in the two enzymes. This article is part of a Special Issue entitled: Allosteric cooperativity in respiratory proteins. PMID- 21684253 TI - Soft matrix supports osteogenic differentiation of human dental follicle cells. AB - The differentiation of stem cells can be directed by the grade of stiffness of the developed tissue cells. For example a rigid extracellular matrix supports the osteogenic differentiation in bone marrow derived mesenchymal stem cells (MSCs). However, less is known about the relation of extracellular matrix stiffness and cell differentiation of ectomesenchymal dental precursor cells. Our study examined for the first time the influence of the surface stiffness on the proliferation and osteogenic differentiation of human dental follicle cells (DFCs). Cell proliferation of DFCs was only slightly decreased on cell culture surfaces with a bone-like stiffness. The osteogenic differentiation in DFCs could only be initiated with a dexamethasone based differentiation medium after using varying stiffness. Here, the softest surface improved the induction of osteogenic differentiation in comparison to that with the highest stiffness. In conclusion, different to bone marrow derived MSCs, soft ECMs have a superior capacity to support the osteogenic differentiation of DFCs. PMID- 21684254 TI - iNOS potentiates mouse Ig isotype switching through AID expression. AB - The IgA antibody plays an important role in protecting mucosal surfaces against pathogens. It has recently been shown that nitric oxide (NO) plays a critical role in mouse IgA synthesis. In the present study, we further characterized inducible-nitric oxide synthase-deficient (iNOS(-/-)) mice in the context of Ig expression. The amount of IgA in fecal pellets was substantially diminished in iNOS(-/-) mice and was paralleled by a decrease in IgA production by Peyer's patch cells. Interestingly, the amount of all IgG subisotypes, as well as IgA, was substantially diminished in sera and in cultured spleen B cells from iNOS(-/ ) mice. Moreover, the synthesis of TGF-beta1-inducible IgA and IgG2b in iNOS(-/-) mice was also lower than that in WT mice. However, levels of Ig germ-line transcripts, and expression of TGF-beta receptor type II (TbetaRII) and BAFF/APRIL, were comparable between iNOS(-/-) and WT mice. Expression of activation-induced cytidine deaminase (AID) was diminished in iNOS(-/-) B cells, but restored by a NO donor, SNAP. These results indicate that iNOS regulates Ig isotype switching events at the level of AID gene expression. PMID- 21684255 TI - Impairment of survival signaling and efferocytosis in TRPC3-deficient macrophages. AB - We have recently shown that in macrophages proper operation of the survival pathways phosphatidylinositol-3-kinase (PI3K)/AKT and nuclear factor kappa B (NFkB) has an obligatory requirement for constitutive, non-regulated Ca(2+) influx. In the present work we examined if Transient Receptor Potential Canonical 3 (TRPC3), a member of the TRPC family of Ca(2+)-permeable cation channels, contributes to the constitutive Ca(2+) influx that supports macrophage survival. We used bone marrow-derived macrophages obtained from TRPC3(-/-) mice to determine the activation status of survival signaling pathways, apoptosis and their efferocytic properties. Treatment of TRPC3(+/+) macrophages with the pro apoptotic cytokine TNFalpha induced time-dependent phosphorylation of IkappaBalpha, AKT and BAD, and this was drastically reduced in TRPC3(-/-) macrophages. Compared to TRPC3(+/+) cells TRPC3(-/-) macrophages exhibited reduced constitutive cation influx, increased apoptosis and impaired efferocytosis. The present findings suggest that macrophage TRPC3, presumably through its constitutive function, contributes to survival signaling and efferocytic properties. PMID- 21684256 TI - Pancreatic exocrine enzyme-producing cell differentiation via embryoid bodies from human embryonic stem cells. AB - Mouse embryonic stem cells (ESCs) can be induced to form pancreatic exocrine enzyme-producing cells in vitro in a stepwise fashion that recapitulates the development in vivo. However, there is no protocol for the differentiation of pancreatic-like cells from human ESCs (hESCs). Based upon the mouse ESC model, we have induced the in vitro formation of pancreatic exocrine enzyme-producing cells from hESCs. The protocol took place in four stages. In Stage 1, embryoid bodies (EBs) were formed from dissociated hESCs and then treated with the growth factor activin A, which promoted the expression of Foxa2 and Sox17 mRNAs, markers of definitive endoderm. In Stage 2, the cells were treated with all-trans retinoic acid which promoted the transition to cells that expressed gut tube endoderm mRNA marker HNF1b. In Stage 3, the cells were treated with fibroblast growth factor 7 (FGF7), which induced expression of Pdx1 typical of pancreatic progenitor cells. In Stage 4, treatment with FGF7, glucagon-like peptide 1, and nicotinamide induced the expression amylase (AMY) mRNA, a marker for mature pancreatic exocrine cells. Immunohistochemical staining showed the expression of AMY protein at the edges of cell clusters. These cells also expressed other exocrine secretory proteins including elastase, carboxypeptidase A, chymotrypsin, and pancreatic lipase in culture. Production of these hESC-derived pancreatic enzyme producing cells represents a critical step in the study of pancreatic organogenesis and in the development of a renewable source of human pancreatic like exocrine cells. PMID- 21684257 TI - Generation of mice deficient in RNA-binding motif protein 3 (RBM3) and characterization of its role in innate immune responses and cell growth. AB - The activation of innate immune responses is critical to host defense against microbial infections, wherein nucleic acid-sensing pattern recognition receptors recognize DNA or RNA from viruses or bacteria and activate downstream signaling pathways. In a search for new DNA-sensing molecules that regulate innate immune responses, we identified RNA-binding motif protein 3 (RBM3), whose role has been implicated in the regulation of cell growth. In this study, we generated Rbm3 deficient (Rbm3(-/-)) mice to study the role of RBM3 in immune responses and cell growth. Despite evidence for its interaction with immunogenic DNA in a cell, no overt phenotypic abnormalities were found in cells from Rbm3(-/-) mice for the DNA-mediated induction of cytokine genes. Interestingly, however, Rbm3(-/-) mouse embryonic fibroblasts (MEFs) showed poorer proliferation rates as compared to control MEFs. Further cell cycle analysis revealed that Rbm3(-/-) MEFs have markedly increased number of G2-phase cells, suggesting a hitherto unknown role of RBM3 in the G2-phase control. Thus, these mutant mice and cells may provide new tools with which to study the mechanisms underlying the regulation of cell cycle and oncogenesis. PMID- 21684258 TI - Effects of length and amino acid sequence of O-mannosyl peptides on substrate specificity of protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase 1 (POMGnT1). AB - Protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) catalyzes the transfer of GlcNAc to O-mannose of glycoproteins. Mutations in the POMGnT1 gene cause muscle-eye-brain disease (MEB). POMGnT1 is a typical type II membrane protein, which is localized in the Golgi apparatus. However, details of the catalytic and reaction mechanism of POMGnT1 are not understood. To develop a better understanding of POMGnT1, we examined the substrate specificity of POMGnT1 using a series of synthetic O-mannosyl peptides based on the human alpha dystroglycan (alpha-DG) sequence as substrates. O-Mannosyl peptides consisting of three to 20 amino acids are recognized as substrates. Enzyme kinetics improved with increasing peptide length up to a length of 8 amino acids but the kinetics of peptides longer than 8 amino acids were similar to those of octapeptides. Our results also show that the amino acid sequence affects POMGnT1 activity. These data suggest that both length and amino acid sequence of mannosyl peptides are determinants of POMGnT1 substrate specificity. PMID- 21684259 TI - Role of yeast JmjC-domain containing histone demethylases in actively transcribed regions. AB - In budding yeast, there are five JmjC domain-containing proteins, Jhd1, Jhd2, Rph1, Ecm5, and Gis1, which have been suggested to directly remove histone lysine methylation via a hydroxylation reaction. Of these demethylases, the ability of Jhd1 or Rph1 to demethylate histone H3 as a substrate has been identified in vivo. However, the overall roles of endogenous JmjC demethylases in the demethylation of histones encompassed by genes that are constitutively transcribed or their specificities towards histone H3 lysine modification at mono , di-, or trimethylation states are still unclear. Using chromatin immunoprecipitation with nine specific antibodies directed against mono-, di-, or trimethylated histone H3 at lysines 4, 36, or 79, we show the whole patterns of histone H3 lysine methylation and the net changes in methylations that are caused by the deletion of each of the five JmjC demethylases in actively transcribed regions. Our results show that of the JmjC-containing proteins, Rph1 is the demethylase that is specific for histone H3K36 trimethylation during transcription elongation in vivo, and the abilities of other endogenous JmjC demethylasesto demethylate histone H3 are weak toward histone H3in actively transcribed regions. PMID- 21684260 TI - Caffeine lengthens circadian rhythms in mice. AB - Although caffeine alters sleep in many animals, whether or not it affects mammalian circadian clocks remains unknown. Here, we found that incubating cultured mammalian cell lines, human osteosarcoma U2OS cells and mouse fibroblast NIH3T3 cells, with caffeine lengthened the period of circadian rhythms. Adding caffeine to ex vivo cultures also lengthened the circadian period in mouse liver explants from Per2::Luciferase reporter gene knockin mice, and caused a phase delay in brain slices containing the suprachiasmatic nucleus (SCN), where the central circadian clock in mammals is located. Furthermore, chronic caffeine consumption ad libitum for a week delayed the phase of the mouse liver clock in vivo under 12 h light-dark conditions and lengthened the period of circadian locomotor rhythms in mice under constant darkness. Our results showed that caffeine alters circadian clocks in mammalian cells in vitro and in the mouse ex vivo and in vivo. PMID- 21684261 TI - Endothelial cell-specific aryl hydrocarbon receptor knockout mice exhibit hypotension mediated, in part, by an attenuated angiotensin II responsiveness. AB - Hypotension in aryl hydrocarbon receptor knockout mice (ahr(-/-)) is mediated, in part, by a reduced contribution of angiotensin (Ang) II to basal blood pressure (BP). Since AHR is highly expressed in endothelial cells (EC), we hypothesized that EC-specific ahr(-/-) (ECahr(-/-)) mice would exhibit a similar phenotype. We generated ECahr(-/-) mice by crossing AHR floxed mice (ahr(fx/fx)) to mice expressing Cre recombinase driven by an EC-specific promoter. BP was assessed by radiotelemetry prior to and following an acute injection of Ang II or chronic treatment with an angiotensin converting enzyme inhibitor (ACEi). ECahr(-/-) mice were hypotensive (ECahr(+/+): 116.1+/-1.4; ECahr(-/-): 107.4+/-2.0 mmHg, n=11, p<0.05) and exhibited significantly different responses to Ang II and ACEi. While Ang II increased BP in both genotypes, the increase was sustained in ECahr(+/+), whereas the increase in ECahr(-/-) mice steadily declined. Area under the curve analysis showed that Ang II-induced increase in diastolic BP (DBP) over 30 min was significantly lower in ECahr(-/-) mice (ECahr(+/+) 1297+/-223 mmHg/30 min; ECahr(-/-)(AUC): 504+/-138 mmHg/30 min, p<0.05). In contrast, while ACEi decreased BP in both genotypes, the subsequent rise in DBP after treatment was significantly delayed in the ECahr(-/-) mice. ECahr(-/-) mice also exhibited reduced vascular and adipose Ang II type 1 receptor (AT1R) expression, and reduced aortic Ang II-dependent vasoconstriction in the presence of vascular adipose. Taken together these data suggest that hypotension in ECahr(-/-) mice results from reduced vascular responsiveness to Ang II that is influenced by AT1R expression and adipose. PMID- 21684262 TI - Functional brain imaging of nicotinic effects on higher cognitive processes. AB - Significant advances in human functional brain imaging offer new opportunities for direct observation of the effects of nicotine, novel nicotinic agonists and nicotinic antagonists on human cognitive and behavioral performance. Careful research over the last decade has enabled investigators to explore the role of nicotinic systems on the functional neuroanatomy and neural circuitry of cognitive tasks in domains such as selective attention, working memory, episodic memory, cognitive control, and emotional processing. In addition, recent progress in understanding functional connectivity between brain regions utilized during cognitive and emotional processes offers new opportunities for examining drug effects on network-related activity. This review will critically summarize available nicotinic functional brain imaging studies focusing on the specific cognitive domains of attention, memory, behavioral control, and emotional processing. Generally speaking, nicotine appears to increase task-related activity in non-smokers and deprived smokers, but not active smokers. By contrast, nicotine or nicotinic stimulation decreases the activity of structures associated with the default mode network. These particular patterns of activation and/or deactivation may be useful for early drug development and may be an efficient and cost-effective method of screening potential nicotinic agents. Further studies will have to be done to clarify whether such activity changes correlate with cognitive or affective outcomes that are clinically relevant. The use of functional brain imaging will be a key tool for probing pathologic changes related to brain illness and for nicotinic drug development. PMID- 21684263 TI - Acute in vivo nicotine administration enhances synchrony among dopamine neurons. AB - Altered functional interactions among midbrain dopamine (DA) neurons contribute to the reinforcing properties of environmental stimuli and addictive drugs. To examine correlations among DA neurons, acute nicotine was administrated to rats via an intraperitoneal catheter and unit activity was measured using multi tetrode in vivo recordings. Nicotine administration enhanced the correlated activity of simultaneously recorded DA neurons from the ventral tegmental area (VTA). The strength of the correlations between DA neuron pairs, as measured by cross covariance among two spike trains, showed dynamic changes over time. Nicotine produced a gradual rise in firing rate and burst activity that reached a stable plateau approximately 20 min after the intraperitoneal nicotine infusion. Shortly after that time the cross correlations measured using 5-ms bins increased significantly above baseline. In addition, nicotine increased the firing rates of DA neurons in the posterior VTA more than in the anterior VTA. Unlike nicotine, eticlopride administration also boosted DA neuron firing activity but did not enhance synchronization, indicating that the cross correlations induced by nicotine were not due to a non-specific increase in firing rate. The overall results show that nicotine induces nearly synchronous firing by a subset of DA neurons, and those changes in correlative firing will enhance the DA signal that contributes to nicotine-induced behavioral reinforcement. PMID- 21684264 TI - Hypoxia modulates the effect of dihydroartemisinin on endothelial cells. AB - Artemisinin derivatives, the current cornerstone of malaria treatment, possess also anti-angiogenic and anti-tumor activity. Hypoxia plays a crucial role both in severe malaria (as a consequence of the cytoadherence of infected erythrocytes to the microvasculature) and in cancer (due to the restricted blood supply in the growing tumor mass). However, the consequences of hypoxia onto the effects of artemisinins is under-researched. This study aimed at assessing how the inhibition of microvascular endothelial cell (HMEC-1) growth induced by dihydroartemisinin (DHA, an antimalarial drug and the active metabolite of currently in-use artemisinins) is affected by oxygen tension. Low doses of DHA (achieved in the patients' plasma when treating malaria) were more inhibitory in hypoxia, whereas high doses (required for anti-angiogenic or anti-tumor activity) were more effective in normoxia. The peroxide bridge is essential for cellular toxicity (deoxyDHA was inactive). High doses of DHA caused HMEC-1 apoptosis and G2 cell cycle arrest. Effects were mediated by the generation of oxidative stress as demonstrated by DCF-DA fluorescence and membrane lipid peroxidation analysis. Overall, these results suggest that DHA inhibition of endothelial cell growth is related to the level of tissue oxygenation and drug concentration. This should be considered when studying both the effects of artemisinin derivatives as antimalarials and the potential therapeutic applications of these drugs as anti tumor agents. PMID- 21684265 TI - Neurobiology of nAChRs and cognition: a mini review of Dr. Jerry J. Buccafusco's contributions over a 25 year career. AB - This review highlights some of the many contributions of the late Dr. Jerry J. Buccafusco to the neurobiology of nicotinic acetylcholine receptors (nAChRs) and cognition over a 25 year period. The article is written by two of Dr. Buccafusco's professional colleagues, one from academia and one from the pharmaceutical industry. While Dr. Buccafusco's expertise in the cholinergic field was extensive, his insights into the practical relevance of his work (with a long-term goal of formulating new drug development strategies) were unique, and a great asset to both the basic science community and pharmaceutical companies. In 1988, Dr. Buccafusco's laboratory was the first to report the cognitive enhancing action of low doses of nicotine in non-human primates. Since that time he studied a large number of novel pro-cognitive agents from several pharmacological classes in rodents as well as monkeys. Based on years of observing paradoxical effects of nicotinic ligands in vitro and in vivo, Dr. Buccafusco made the provocative argument that it might be possible to develop new chemical entities (with pro-cognitive actions) that have the ability to desensitize nAChRs without producing an antecedent agonist action. Some of his more recent work focused on development of single molecular entities that act on multiple CNS targets (including nAChRs) to enhance cognition, provide neuroprotection, and/or provide additional therapeutic actions (e.g., antipsychotic effects). Dr. Buccafusco's influence will live on in the work of the numerous graduate students, postdoctoral fellows, and junior faculty that he mentored over the years who now serve in prestigious positions throughout the world. PMID- 21684267 TI - Heteromerization of human cytomegalovirus encoded chemokine receptors. AB - Human cytomegalovirus (HCMV) is a widespread pathogen that infects up to 80% of the human population and causes severe complications in immunocompromised patients. HCMV expresses four seven transmembrane (7TM) spanning/G protein coupled receptors (GPCRs) - US28, US27, UL33 and UL78 - that show close homology to human chemokine receptors. While US28 was shown to bind several chemokines and to constitutively activate multiple signaling cascades, the function(s) of US27, UL33 and UL78 in the viral life cycle have not yet been identified. Here we investigated the possible interaction/heteromerization of US27, UL33 and UL78 with US28 and the functional consequences thereof. We provide evidence that these receptors not only co-localize, but also heteromerize with US28 in vitro. While the constitutive activation of the US28-mediated Galphaq/phospholipase C pathway was not affected by receptor heteromerization, UL33 and UL78 were able to silence US28-mediated activation of the transcription factor NF-kappaB. Summarized, we provide evidence that these orphan viral receptors have an important regulatory capacity on the function of US28 and as a consequence, may ultimately impact on the viral life cycle of HCMV. PMID- 21684268 TI - Influence of HSA and IgG on LDL oxidation studied by size-exclusion chromatography and phospholipid profiling using MALDI tandem-mass spectrometry. AB - In the present study a direct detection approach combining size-exclusion chromatography (SEC) and matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight tandem-mass spectrometry (MALDI-QIT-TOF-MS/MS) was applied to investigate the influence of HSA and IgG on LDL oxidation in vitro. SEC analysis showed an increase of protein aggregation during LDL-oxidation that could be essentially suppressed in the presence of HSA. In parallel, lipid peroxidation measured by TBARS assay over 24h was inhibited by 95-100% in the presence of HSA but only 0-34% by IgG, respectively. MALDI phospholipid profiles showed considerable decrease of signals from PCs containing sn-2 PUFAs (18:2 or 20:4) accompanied by increase of sn-2 LPCs indicating for specific breakdown of PUFA-containing PLs during LDL-oxidation. These effects were nearly 100% inhibited in the presence of HSA but not by IgG, respectively. Among known pro atherogenic PL species present in human plasma sphingomyelin (SM16:0) was bound in significant amounts to HSA but not IgG after incubation with oxLDL. Moreover, our investigation showed that LPCs containing SAFAs (16:0 or 18:0) were specifically bound to HSA, while those containing PUFAs (18:2 and 18:3) were preferentially associated with IgG. In summary, the presented methodology provides a promising platform for studying lipid-protein interactions in vivo. PMID- 21684266 TI - Role of alpha6 nicotinic receptors in CNS dopaminergic function: relevance to addiction and neurological disorders. AB - Although a relative newcomer to the nicotinic acetylcholine receptor (nAChR) family, substantial evidence suggests that alpha6 containing nAChRs play a key role in CNS function. This subtype is unique in its relatively restricted localization to the visual system and catecholaminergic pathways. These latter include the mesolimbic and nigrostriatal dopaminergic systems, which may account for the involvement of alpha6 containing nAChRs in the rewarding properties of nicotine and in movement. Here, we review the literature on the role of alpha6 containing nAChRs with a focus on the striatum and nucleus accumbens. This includes molecular, electrophysiological and behavioral studies in control and lesioned animal models, as well as in different genetic models. Converging evidence suggest that the major alpha6 containing nAChRs subtypes in the nigrostriatal and mesolimbic dopamine system are the alpha6beta2beta3 and alpha6alpha4beta2beta3 nAChR populations. They appear to have a dominant role in regulating dopamine release, with consequent effects on nAChR-modulated dopaminergic functions such as reinforcement and motor behavior. Altogether these data suggest that drugs directed to alpha6 containing nAChRs may be of benefit for the treatment of addiction and for neurological disorders with locomotor deficits such as Parkinson's disease. PMID- 21684269 TI - Practical and reliable enzyme test for the detection of mucopolysaccharidosis IVA (Morquio Syndrome type A) in dried blood samples. AB - BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA), or Morquio Syndrome type A, is an autosomal recessive disease caused by deficiency of the lysosomal enzyme N acetylgalactosamine-6-sulfatase (GALNS), resulting in excessive lysosomal storage of keratan sulfate in many tissues and organs. This accumulation causes a severe skeletal dysplasia with short stature, and affects the eye, heart and other organs, with many signs and symptoms. Morquio A syndrome is estimated to occur in 1 in 200,000 to 300,000 live births. Clinical trials with enzyme replacement therapy for this disease are in progress, and it is probable that the treatment, when available, would be more effective if started early. We describe an innovative fluorometric method for the assay of GALNS in dried blood spots (DBS). METHODS: We used dried blood spots (DBS) as the enzyme source and compared it with leukocytes samples, having studied 25 MPS IVA patients and 54 healthy controls. We optimized the assay conditions, including incubation time and stability of DBS samples. To eppendorf type tubes containing a 3-mm diameter blood spot we added elution liquid and substrate solution. After 2 different incubations at 37 degrees C, the amount of hydrolyzed product was compared with a calibrator to allow the quantification of the enzyme activity. Results in DBS were compared to the ones obtained in leukocytes using the standard technique. RESULTS: The fluorescent methodology was validated in our laboratory and the assay was found sensitive and specific, allowing reliable detection of MPS IVA patients. The use of DBS simplifies the collection and transport steps, and is especially useful for testing patients from more remote areas of large countries, and when samples need to cross country borders. CONCLUSION: This assay could be easily incorporated into the protocol of reference laboratories and play a role in the screening for MPS IVA, contributing to earlier detection of affected patients. PMID- 21684270 TI - Osteogenic differentiation of GFP-labeled human umbilical cord blood derived mesenchymal stem cells after cryopreservation. AB - The osteogenic capacity of human umbilical cord blood derived mesenchymal stem cells (UCB-MSCs) has been demonstrated both in vitro and in vivo. Therefore, cell labeling and storage are becoming necessary for researching the potential therapeutic use of UCB-MSCs for bone tissue engineering. The aim of this study was to determine the effect of cryopreservation on the osteogenic differentiation of green fluorescent protein (GFP)-marked UCB-MSCs in vitro. MSCs were isolated from full-term human UCB, expanded, transfected with the GFP gene, and then cryopreserved in liquid nitrogen for 4 weeks. After thawing, cell surface antigen markers and osteogenic potential were analyzed, and the luminescence of these cells was observed by fluorescence microscopy. The results demonstrate that cryopreservation has no effect on the cell phenotype, GFP expression or osteogenic differentiation of UCB-MSCs, showing that cryopreserved GFP-labeled UCB-MSCs might be applied for bone tissue engineering. PMID- 21684271 TI - miR-203 modulates epithelial differentiation of human embryonic stem cells towards epidermal stratification. AB - The molecular mechanisms controlling the differentiation of human basal keratinocyte stem cells towards the epidermis are well characterized, whereas the earliest process leading to the specification of embryonic stem cells into keratinocytes is still not well understood. MicroRNAs are regulators of many cellular events, but evidence for microRNA acting on the differentiation of human embryonic stem cells into a specific lineage has been elusive. By using our recent protocol for obtaining functional keratinocytes from hESC, we attempted to analyze the role of microRNAs in the early stages of epidermal differentiation. Thus, we identified a set of 5 microRNAs, namely miR-200a, miR-200b, miR-203, miR 205 and miR-429, that are specifically overexpressed during the early stages of the differentiation process. Interestingly, our functional analyses revealed an instrumental role of miR-203, which had been previously shown to play a key role during the formation of the pluristratified epidermis by basal keratinocyte stem cells, in the early keratinocyte commitment. These results highlight the determinant and unique role of miR-203 during the entire process of epidermal development by extending its spectrum of action from the early commitment of embryonic stem cells to ultimate differentiation of the organ. PMID- 21684272 TI - PRKX critically regulates endothelial cell proliferation, migration, and vascular like structure formation. AB - Angiogenesis is a fundamental step in several important physiological events and pathological conditions including embryonic development, wound repair, tumor growth and metastasis. PRKX was identified as a novel type-I cAMP-dependent protein kinase gene expressed in multiple developing tissues. PRKX has also been shown to be phylogenetically and functionally distinct from PKA. This study presents the first evidence that PRKX stimulates endothelial cell proliferation, migration, and vascular-like structure formation, which are the three essential processes for angiogenesis. In contrast, classic PKA demonstrated an inhibitory effect on endothelia vascular-like structure formation. Our findings suggest that PRKX is an important protein kinase engaged in the regulation of angiogenesis and could play critical roles in various physiological and pathological conditions involving angiogenesis. PRKX binds to Pin-1, Magi-1 and Bag-3, which regulate cell proliferation, apoptosis, differentiation and tumorigenesis. The interaction of PRKX with Pin-1, Magi-1 and Bag-3 could contribute to the stimulating role of PRKX in angiogenesis. PMID- 21684274 TI - Reduced reciprocal inhibition during assisted stepping in human spinal cord injury. AB - The aim of this study was to establish the modulation pattern of the reciprocal inhibition exerted from tibialis anterior (TA) group I afferents onto soleus motoneurons during body weight support (BWS) assisted stepping in people with spinal cord injury (SCI). During assisted stepping, the soleus H-reflex was conditioned by percutaneous stimulation of the ipsilateral common peroneal nerve at one fold TA M-wave motor threshold with a single pulse delivered at a short conditioning-test interval. To counteract movement of recording and stimulating electrodes, a supramaximal stimulus at 80-100 ms after the test H-reflex was delivered. Stimuli were randomly dispersed across the step cycle which was divided into 16 equal bins. The conditioned soleus H-reflex was significantly facilitated throughout the stance phase, while during swing no significant changes on the conditioned H-reflex were observed when compared to the unconditioned soleus H-reflex recorded during stepping. Spontaneous clonic activity in triceps surae muscle occurred in multiple phases of the step cycle at a mean frequency of 7 Hz for steps with and without stimulation. This suggests that electrical excitation of TA and soleus group Ia afferents did not contribute to manifestation of ankle clonus. Absent reciprocal inhibition is likely responsible for lack of soleus H-reflex depression in swing phase observed in these patients. The pronounced reduced reciprocal inhibition in stance phase may contribute to impaired levels of co-contraction of antagonistic ankle muscles. Based on these findings, we suggest that rehabilitation should selectively target to transform reciprocal facilitation to inhibition through computer controlled reflex conditioning protocols. PMID- 21684273 TI - Retinal pigment epithelial expression of complement regulator CD46 is altered early in the course of geographic atrophy. AB - In geographic atrophy (GA), the non-neovascular end stage of age-related macular degeneration (AMD), the macular retinal pigment epithelium (RPE) progressively degenerates. Membrane cofactor protein (MCP, CD46) is the only membrane-bound regulator of complement expressed on the human RPE basolateral surface. Based on evidence of the role of complement in AMD, we hypothesized that altered CD46 expression on the RPE would be associated with GA development and/or progression. Here we report the timeline of CD46 protein expression changes across the GA transition zone, relative to control eyes, and relative to events in other chorioretinal layers. Eleven donor eyes (mean age 87.0 +/- 4.1 yr) with GA and 5 control eyes (mean age 84.0 +/- 8.9 yr) without GA were evaluated. Macular cryosections were stained with PASH for basal deposits, von Kossa for calcium, and for CD46 immunoreactivity. Internal controls for protein expression were provided by an independent basolateral protein, monocarboxylate transporter 3 (MCT3) and an apical protein, ezrin. Within zones defined by 8 different semi quantitative grades of RPE morphology, we determined the location and intensity of immunoreactivity, outer segment length, and Bruch's membrane calcification. Differences between GA and control eyes and between milder and more severe RPE stages in GA eyes were assessed statistically. Increasing grades of RPE degeneration were associated with progressive loss of polarity and loss of intensity of staining of CD46, beginning with the stages that are considered normal aging (grades 0-1). Those GA stages with affected CD46 immunoreactivity exhibited basal laminar deposit, still-normal photoreceptors, and concomitant changes in control protein expression. Activated or anteriorly migrated RPE (grades 2-3) exhibited greatly diminished CD46. Changes in RPE CD46 expression thus occur early in GA, before there is evidence of morphological RPE change. At later stages of degeneration, CD46 alterations occur within a context of altered RPE polarity. These changes precede degeneration of the overlying retina and suggest that therapeutic interventions be targeted to the RPE. PMID- 21684275 TI - Depression, stress, epilepsy and adult neurogenesis. AB - Epilepsy and depression share an unusually high coincidence suggestive of a common etiology. Disrupted production of adult-born hippocampal granule cells in both disorders may contribute to this high coincidence. Chronic stress and depression are associated with decreased granule cell neurogenesis. Epilepsy is associated with increased production - but aberrant integration - of new cells early in the disease and decreased production late in the disease. In both cases, the literature suggests these changes in neurogenesis play important roles in their respective diseases. Aberrant integration of adult-generated cells during the development of epilepsy may impair the ability of the dentate gyrus to prevent excess excitatory activity from reaching hippocampal pyramidal cells, thereby promoting seizures. Effective treatment of a subset of depressive symptoms, on the other hand, may require increased granule cell neurogenesis, indicating that adult-generated granule cells can modulate mood and affect. Given the robust changes in adult neurogenesis evident in both disorders, competing effects on brain structure are likely. Changes in relative risk, disease course or response to treatment seem probable, but complex and changing patterns of neurogenesis in both conditions will require sophisticated experimental designs to test these ideas. Despite the challenges, this area of research is critical for understanding and improving treatment for patients suffering from these disorders. PMID- 21684277 TI - Bioenergetic dysfunction in Huntington's disease human cybrids. AB - In this work we studied the mitochondrial-associated metabolic pathways in Huntington's disease (HD) versus control (CTR) cybrids, a cell model in which the contribution of mitochondrial defects from patients is isolated. HD cybrids exhibited an interesting increase in ATP levels, when compared to CTR cybrids. Concomitantly, we observed increased glycolytic rate in HD cybrids, as revealed by increased lactate/pyruvate ratio, which was reverted after inhibition of glycolysis. A decrease in glucose-6-phosphate dehydrogenase activity in HD cybrids further indicated decreased rate of the pentose-phosphate pathway. ATP levels of HD cybrids were significantly decreased under glycolysis inhibition, which was accompanied by a decrease in phosphocreatine. Nevertheless, pyruvate supplementation could not recover HD cybrids' ATP or phosphocreatine levels, suggesting a dysfunction in mitochondrial use of that substrate. Oligomycin also caused a decrease in ATP levels, suggesting a partial support of ATP generation by the mitochondria. Nevertheless, mitochondrial NADH/NAD(t) levels were decreased in HD cybrids, which was correlated with a decrease in pyruvate dehydrogenase activity and protein expression, suggesting decreased tricarboxylic acid cycle (TCA) input from glycolysis. Interestingly, the activity of alpha ketoglutarate dehydrogenase, a critical enzyme complex that links the TCA to amino acid synthesis and degradation, was increased in HD cybrids. In accordance, mitochondrial levels of glutamate were increased and alanine was decreased, whereas aspartate and glutamine levels were unchanged in HD cybrids. Conversely, malate dehydrogenase activity from total cell extracts was unchanged in HD cybrids. Our results suggest that inherent dysfunction of mitochondria from HD patients affects cellular bioenergetics in an otherwise functional nuclear background. PMID- 21684278 TI - Use of a fluorescent stain for evaluating in vitro infection with Leishmania panamensis. AB - Leishmaniasis is a group of endemic diseases produced by infection with Leishmania parasites and affects tropical and subtropical regions of the world. Due to the severe problems related to the treatment of this condition (resistance and toxicity), further studies are needed to evaluate new antileishmanial compounds. The activity of antileishmanial prototypes should be analyzed in models that allow a better interpretation of the findings with respect to natural infection. In this sense, the use of an infection model with macrophages and dendritic cells is a better than using promastigotes alone, in order to establish the potential leishmanicidal activity of a prototype compound. For infection analysis, staining with polychromatic dyes such as Giemsa plus microscopic examination is the gold standard. However, it is common to find problems associated with color uniformity, expertise of the observer, sensitivity and specificity of the technique. For this reason, it's necessary to develop tools and protocols to overcome such limitations. This study assessed the utility of the SYBR(r) Safe fluorescent dye, considering its affinity for nucleic acids as a useful property for staining the nucleus and kinetoplast of Leishmania parasites within an infected cell. Infection (and subsequent treatment) assays were performed in dendritic cells and macrophages infected with Leishmania panamensis parasites to compare SYBR(r) Safe and Giemsa stain for the same assay. Correlation coefficients were found to be above 0.9 for both techniques; however, unlike Giemsa, SYBR(r) Safe staining was easier and provided a clearer observation of internalized parasites. These results support the use of SYBR(r) Safe as a promising tool for evaluating potential antileishmanials given its advantages over the traditional technique. PMID- 21684276 TI - Progesterone treatment normalizes the levels of cell proliferation and cell death in the dentate gyrus of the hippocampus after traumatic brain injury. AB - Traumatic brain injury (TBI) increases cell death in the hippocampus and impairs hippocampus-dependent cognition. The hippocampus is also the site of ongoing neurogenesis throughout the lifespan. Progesterone treatment improves behavioral recovery and reduces inflammation, apoptosis, lesion volume, and edema, when given after TBI. The aim of the present study was to determine whether progesterone altered cell proliferation and short-term survival in the dentate gyrus after TBI. Male Sprague-Dawley rats with bilateral contusions of the frontal cortex or sham operations received progesterone or vehicle at 1 and 6 h post-surgery and daily through post-surgery Day 7, and a single injection of bromodeoxyuridine (BrdU) 48 h after injury. Brains were then processed for Ki67 (endogenous marker of cell proliferation), BrdU (short-term cell survival), doublecortin (endogenous marker of immature neurons), and Fluoro-Jade B (marker of degenerating neurons). TBI increased cell proliferation compared to shams and progesterone normalized cell proliferation in injured rats. Progesterone alone increased cell proliferation in intact rats. Interestingly, injury and/or progesterone treatment did not influence short-term cell survival of BrdU-ir cells. All treatments increased the percentage of BrdU-ir cells that were co labeled with doublecortin (an immature neuronal marker in this case labeling new neurons that survived 5 days), indicating that cell fate is influenced independently by TBI and progesterone treatment. The number of immature neurons that survived 5 days was increased following TBI, but progesterone treatment reduced this effect. Furthermore, TBI increased cell death and progesterone treatment reduced cell death to levels seen in intact rats. Together these findings suggest that progesterone treatment after TBI normalizes the levels of cell proliferation and cell death in the dentate gyrus of the hippocampus. PMID- 21684279 TI - Regucalcin (RGN/SMP30) alters agonist- and thapsigargin-induced cytosolic [Ca2+] transients in cells by increasing SERCA Ca(2+)ATPase levels. AB - Regucalcin (RGN), also reported as senescence marker protein-30 (SMP30), plays a role in Ca(2+) homeostasis by modulating a number of Ca(2+)-dependent proteins. RGN also plays a cyto-protective role and its decrease is linked to age-related diseases and cell death. This study shows that RGN reduces agonist (histamine) induced Ca(2+) transients in RGN(+) transfected COS-7 cells (RGN(+)) and also increases their Ca(2+) storage capacity. These observations are explained by RGN(+) cells having increased mRNA and protein expression levels of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA). Therefore down-regulation of RGN expression may contribute to characteristics of age-dependent Ca(2+) homeostasis dis-regulation, by decreasing SERCA levels. PMID- 21684280 TI - Abnormal resting brain activity in patients with functional dyspepsia is related to symptom severity. AB - BACKGROUND & AIMS: Abnormal processing of visceral sensation at the level of the central nervous system is believed to be involved in functional dyspepsia. However, compared with studies of stimulation-related changes in brain activity, few studies have focused on resting brain activity, which also is important in pathogenesis. We mapped changes in resting brain glucometabolism of patients with functional dyspepsia, compared with healthy subjects, and attempted to correlate abnormal brain activity with symptom severity. METHODS: We performed fluorodeoxyglucose positron emission tomography-computed tomography on 40 patients with functional dyspepsia and 20 healthy subjects who were in resting states. The symptom index of dyspepsia and the Nepean dyspepsia index were used to determine symptom severity. The positron emission tomography-computed tomography data were analyzed using statistical parametric mapping software. RESULTS: Compared with healthy subjects, patients with functional dyspepsia had higher levels of glycometabolism in the bilateral insula, anterior cingulate cortex (ACC), middle cingulate cortex (MCC), cerebellum, thalamus, prefrontal cortex, precentral gyrus, postcentral gyrus, middle temporal gyrus, superior temporal gyrus, putamen, right parahippocampal gyrus, claustrum, and left precuneus (P < .001). The signal increase in the ACC, insula, thalamus, MCC, and cerebellum was correlated with symptom index of dyspepsia scores and Nepean dyspepsia index scores (P < .01). The glycometabolism in ACC, insula, thalamus, MCC, and cerebellum of patients with more severe functional dyspepsia was significantly higher than that of patients with less severe functional dyspepsia (P < .005). CONCLUSIONS: In patients with functional dyspepsia, resting cerebral glycometabolism differs significantly from that of healthy subjects. The ACC, insula, thalamus, MCC, and cerebellum might be the key regions that determine the severity of symptoms. PMID- 21684281 TI - The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with nonconstipating irritable bowel syndrome. AB - BACKGROUND & AIMS: Serotonin (5-hydroxytryptamine [5-HT]) has an important role in gastrointestinal function. LX1031 is an oral, locally acting, small molecule inhibitor of tryptophan hydroxylase (TPH). Local inhibition of TPH in the gastrointestinal tract might reduce mucosal production of serotonin (5-HT) and be used to treat patients with nonconstipating irritable bowel syndrome (IBS). METHODS: We evaluated 2 dose levels of LX1031 (250 mg or 1000 mg, given 4 times/day) in a 28-day, multicenter, randomized, double-blind, placebo-controlled study of 155 patients with nonconstipating IBS. 5-hydroxyindoleacetic acid (5 HIAA), a biomarker of pharmacodynamic activity, was measured in urine samples at baseline (24 hours after LX1031 administration), and at weeks 4 and 6 (n = 76). RESULTS: Each dose of LX1031 was safe and well-tolerated. The primary efficacy end point, relief of IBS pain and discomfort, improved significantly in patients given 1000 mg LX1031 (25.5%), compared with those given placebo, at week 1 (P = .018); with nonsignificant improvements at weeks 2, 3, and 4 (17.9%, 16.3%, and 11.6%, respectively). Symptom improvement correlated with a dose-dependent reduction in 5-HIAA, a marker for TPH inhibition, from baseline until week 4. This suggests the efficacy of LX1031 is related to the extent of inhibition of 5 HT biosynthesis. Stool consistency significantly improved, compared with the group given placebo, at weeks 1 and 4 (P < .01) and at week 2 (P < .001). CONCLUSIONS: In a phase 2 study, LX1031 was well tolerated, relieving symptoms and increasing stool consistency in patients with nonconstipating IBS. Symptom relief was associated with reduced levels of 5-HIAA in urine samples. This marker might be used to identify patients with nonconstipating IBS who respond to inhibitors of 5-HT synthesis. PMID- 21684282 TI - 5' Triphosphorylated small interfering RNAs control replication of hepatitis B virus and induce an interferon response in human liver cells and mice. AB - BACKGROUND & AIMS: Approved therapies for chronic hepatitis B include systemic administration of interferon (IFN)-alfa and inhibitors of hepatitis B virus (HBV) reverse-transcription. Systemic application of IFN-alfa is limited by side effects. Reverse-transcriptase inhibitors effectively control HBV replication, but rarely eliminate the virus and can select drug-resistant variants. We aimed to develop an alternative therapeutic approach that combines gene silencing with induction of IFN in the liver. METHODS: To stimulate an immune response while inhibiting HBV activity, we designed 3 small interfering (si)RNAs that target highly conserved sequences and multiple HBV transcripts of all genotypes. A 5' triphosphate (3p) was added to the siRNAs, turning them into a ligand for the cytosolic helicase retinoic acid-inducible protein I, which becomes activated and induces expression of type-I IFNs. Antiviral activity was investigated in cell lines that replicate HBV, in HBV-infected primary human hepatocytes, and in HBV transgenic mice. RESULTS: 3p-double-stranded RNA (3p-RNA) activated retinoic acid inducible protein I, induced a strong type I IFN response (expression of IFN beta) in liver cells and showed transient but strong antiviral activity. Bifunctional, HBV-specific, 3p-siRNAs controlled replication of HBV more efficiently and for longer periods of time than 3p-RNAs without silencing capacity or siRNAs that targeted identical sequences but did not contain 3p. CONCLUSIONS: HBV-specific 3p-siRNAs are bifunctional antiviral molecules that induce production of type I IFNs in the liver and target HBV RNAs to inhibit viral replication. PMID- 21684283 TI - Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. AB - BACKGROUND & AIMS: Gastric cancer (GC) is a heterogeneous disease comprising multiple subtypes that have distinct biological properties and effects in patients. We sought to identify new, intrinsic subtypes of GC by gene expression analysis of a large panel of GC cell lines. We tested if these subtypes might be associated with differences in patient survival times and responses to various standard-of-care cytotoxic drugs. METHODS: We analyzed gene expression profiles for 37 GC cell lines to identify intrinsic GC subtypes. These subtypes were validated in primary tumors from 521 patients in 4 independent cohorts, where the subtypes were determined by either expression profiling or subtype-specific immunohistochemical markers (LGALS4, CDH17). In vitro sensitivity to 3 chemotherapy drugs (5-fluorouracil, cisplatin, oxaliplatin) was also assessed. RESULTS: Unsupervised cell line analysis identified 2 major intrinsic genomic subtypes (G-INT and G-DIF) that had distinct patterns of gene expression. The intrinsic subtypes, but not subtypes based on Lauren's histopathologic classification, were prognostic of survival, based on univariate and multivariate analysis in multiple patient cohorts. The G-INT cell lines were significantly more sensitive to 5-fluorouracil and oxaliplatin, but more resistant to cisplatin, than the G-DIF cell lines. In patients, intrinsic subtypes were associated with survival time following adjuvant, 5-fluorouracil-based therapy. CONCLUSIONS: Intrinsic subtypes of GC, based on distinct patterns of expression, are associated with patient survival and response to chemotherapy. Classification of GC based on intrinsic subtypes might be used to determine prognosis and customize therapy. PMID- 21684284 TI - Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis. AB - BACKGROUND & AIMS: RAC1 is a guanosine triphosphatase that has an evolutionarily conserved role in coordinating immune defenses, from plants to mammals. Chronic inflammatory bowel diseases are associated with dysregulation of immune defenses. We studied the role of RAC1 in inflammatory bowel diseases using human genetic and functional studies and animal models of colitis. METHODS: We used a candidate gene approach to HapMap-Tag single nucleotide polymorphisms in a discovery cohort; findings were confirmed in 2 additional cohorts. RAC1 messenger RNA expression was examined from peripheral blood cells of patients. Colitis was induced in mice with conditional disruption of Rac1 in phagocytes by administration of dextran sulfate sodium. RESULTS: We observed a genetic association between RAC1 with ulcerative colitis in a discovery cohort, 2 independent replication cohorts, and in combined analysis for the single nucleotide polymorphisms rs10951982 (P(combined UC) = 3.3 * 10(-8), odds ratio = 1.43 [95% confidence interval: 1.26-1.63]) and rs4720672 (P(combined UC) = 4.7 * 10(-6), odds ratio = 1.36 [95% confidence interval: 1.19-1.58]). Patients with inflammatory bowel disease who had the rs10951982 risk allele had increased expression of RAC1 compared to those without this allele. Conditional disruption of Rac1 in macrophage and neutrophils of mice protected against dextran sulfate sodium-induced colitis. CONCLUSIONS: Human studies and knockout mice demonstrated a role for the guanosine triphosphatase RAC1 in the development of ulcerative colitis; increased expression of RAC1 was associated with susceptibility to colitis. PMID- 21684285 TI - Early requirement of Rac1 in a mouse model of pancreatic cancer. AB - BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease without effective chemopreventive or therapeutic approaches. Although the role of oncogenic Kras in initiating development of PDAC is well established, downstream targets of aberrant Ras signaling are poorly understood. Acinar-ductal metaplasia (ADM) appears to be an important prerequisite for development of pancreatic intraepithelial neoplasia (PanIN), a common precursor to PDAC. RAS-related C3 botulinum substrate 1 (Rac1), which controls actin reorganization, can be activated by Ras, is up-regulated in several human cancers, and is required for cerulein-induced morphologic changes in acini. We investigated effects of loss of Rac1 in Kras-induced pancreatic carcinogenesis in mice. METHODS: Using a Cre/lox approach, we deleted Rac1 from pancreatic progenitor cells in different mouse models of PDAC and in mice with cerulein-induced acute pancreatitis. Acinar epithelial explants of mutant mice were used to investigate the role of Rac1 in vitro. RESULTS: Rac1 expression increased in mouse and human pancreatic tumors, particularly in the stroma. Deletion of Rac1 in Kras(G12D)-induced PDAC in mice reduced formation of ADM, PanIN, and tumors and significantly prolonged survival. Pancreatic epithelial metaplasia was accompanied by apical-basolateral redistribution of F-actin, along with basal expression of Rac1. Acinar epithelial explants that lacked Rac1 or that were incubated with inhibitors of actin polymerization had a reduced ability to undergo ADM in 3-dimensional cultures. CONCLUSIONS: In mice, Rac1 is required for early metaplastic changes and neoplasia-associated actin rearrangements in development of pancreatic cancer. Rac1 might be developed as a diagnostic marker or therapeutic target for PDAC. PMID- 21684286 TI - Dietary intake and nutritional deficiencies in patients with diabetic or idiopathic gastroparesis. AB - BACKGROUND & AIMS: Gastroparesis can lead to food aversion, poor oral intake, and subsequent malnutrition. We characterized dietary intake and nutritional deficiencies in patients with diabetic and idiopathic gastroparesis. METHODS: Patients with gastroparesis on oral intake (N = 305) were enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Registry and completed diet questionnaires at 7 centers. Medical history, gastroparesis symptoms, answers to the Block Food Frequency Questionnaire, and gastric emptying scintigraphy results were analyzed. RESULTS: Caloric intake averaged 1168 +/- 801 kcal/day, amounting to 58% +/- 39% of daily total energy requirements (TER). A total of 194 patients (64%) reported caloric-deficient diets, defined as <60% of estimated TER. Only 5 patients (2%) followed a diet suggested for patients with gastroparesis. Deficiencies were present in several vitamins and minerals; patients with idiopathic disorders were more likely to have diets with estimated deficiencies in vitamins A, B(6), C, K, iron, potassium, and zinc than diabetic patients. Only one-third of patients were taking multivitamin supplements. More severe symptoms (bloating and constipation) were characteristic of patients who reported an energy-deficient diet. Overall, 32% of patients had nutritional consultation after the onset of gastroparesis; consultation was more likely among patients with longer duration of symptoms and more hospitalizations and patients with diabetes. Multivariable logistic regression analysis indicated that nutritional consultation increased the chances that daily TER were met (odds ratio, 1.51; P = .08). CONCLUSIONS: Many patients with gastroparesis have diets deficient in calories, vitamins, and minerals. Nutritional consultation is obtained infrequently but is suggested for dietary therapy and to address nutritional deficiencies. PMID- 21684287 TI - Genotypic variation among Douglas-fir tussock moth nucleopolyhedrovirus (OpNPV) isolates in the western United States. AB - Periodic outbreaks of the Douglas-fir tussock moth (Orgyia pseudotsugata) in forests of western North America generally end with a sudden collapse due primarily to an epizootic caused by a nucleopolyhedrovirus (NPV) that occurs naturally within O. pseudotsugata populations. We genotypically characterized NPV populations from Washington State, Oregon, Idaho, New Mexico and California for the first time. Of 159 infected tussock moth samples, restriction fragment length polymorphism (RFLP) analysis showed that 125 (78.6%) contained single nucleopolyhedrovirus (OpSNPV), 28 (17.6%) contained multiple nucleopolyhedrovirus (OpMNPV), and six (3.8%) contained both OpSNPV and OpMNPV. In comparison, our previous studies in the southern interior of British Columbia showed that all 298 samples examined were infected with OpMNPV, and none were infected with OpSNPV. More than half of the Washington OpSNPV samples shared the same genotype, but most OpSNPV genotypes were rare or unique: across the five states, 31 of the 43 different OpSNPV genotypes were each only found in a single sample. In contrast, only four different OpMNPV genotypes were found, and 29 of the 34 OpMNPV samples shared the same genotype, designated genotype AA. This strain of OpMNPV has been developed, registered and used in both Canada and the United States to control outbreaks of the Douglas-fir tussock moth. It is also the most common genotype in southern British Columbia. The estimated degree of genetic divergence ranged from 0% to 4.19% for the various OpSNPV genotypes and from 0% to 3.16% for the OpMNPV genotypes (based on number of shared bands). This is the first description of the genotypic diversity in a population of OpSNPV, and the first genotypic characterization of NPVs infecting O. pseudotsugata in the USA. PMID- 21684288 TI - MicroRNA-9 is an activation-induced regulator of PDGFR-beta expression in cardiomyocytes. AB - The platelet derived growth factor receptor (PDGFR) is an important target for novel anti-cancer therapeutics, but agents targeting PDGFR have been associated with cardiotoxicity. Cardiomyocyte PDGFR-beta signaling in pressure-overloaded hearts induces compensatory angiogenesis via a paracrine-signaling cascade. Tight regulation of receptor tyrosine kinases in response to ligand stimulation is a critical part of any such cascade. The objective of the present study was to characterize the early and late regulation of PDGFR-beta following ligand stimulation and define a potential role for microRNAs (miRNAs) predicted to interact with the 3'UTR of PDGFR-beta in feedback regulation. Using two in-vitro model systems (U87 glioblastoma cells and neonatal cardiomyocytes), we observed that in response to stimulation with PDGF-BB, levels of PDGFR-beta declined beginning at one hour, persisting for 48 h. PDGFR-beta mRNA levels declined beginning at 6h after receptor activation. Early, but not late activation-induced receptor downregulation was proteasome dependent. Levels of miRNA-9 (miR-9) were significantly increased in U87 cells and cardiomyocytes beginning 6h after addition of ligand. In response to pressure overload, miR-9 levels were significantly reduced in the hearts of cardiac-specific PDGFR-beta knockout mice. Luciferase reporter assays demonstrate that miR-9 directly interacts with its predicted seed in the 3'UTR of PDGFR-beta. Increasing miR-9 levels reduces levels of PDGFR-beta, resulting in a reduction in the paracrine angiogenic capacity of cardiomyocytes, consistent with the established function of cardiomyocyte PDGFR beta. Importantly, increase of anti-miR-9 in cardiomyocytes attenuates ligand induced PDGFR-beta downregulation. In conclusion, we have identified miR-9 as an activation-induced regulator of PDGFR-beta expression in cardiomyocytes that is part of a negative feedback loop which serves to modulate PDGFR-beta expression upon ligand-stimulation through direct interaction with the 3'UTR of PDFGR-beta. This article is part of a Special Issue entitled 'Possible Editorial'. PMID- 21684290 TI - iLoc-Virus: a multi-label learning classifier for identifying the subcellular localization of virus proteins with both single and multiple sites. AB - In the last two decades or so, although many computational methods were developed for predicting the subcellular locations of proteins according to their sequence information, it is still remains as a challenging problem, particularly when the system concerned contains both single- and multiple-location proteins. Also, among the existing methods, very few were developed specialized for dealing with viral proteins, those generated by viruses. Actually, knowledge of the subcellular localization of viral proteins in a host cell or virus-infected cell is very important because it is closely related to their destructive tendencies and consequences. In this paper, by introducing the "multi-label scale" and by hybridizing the gene ontology information with the sequential evolution information, a predictor called iLoc-Virus is developed. It can be utilized to identify viral proteins among the following six locations: (1) viral capsid, (2) host cell membrane, (3) host endoplasmic reticulum, (4) host cytoplasm, (5) host nucleus, and (6) secreted. The iLoc-Virus predictor not only can more accurately predict the location sites of viral proteins in a host cell, but also have the capacity to deal with virus proteins having more than one location. As a user friendly web-server, iLoc-Virus is freely accessible to the public at http://icpr.jci.edu.cn/bioinfo/iLoc-Virus. Meanwhile, a step-by-step guide is provided on how to use the web-server to get the desired results. Furthermore, for the user's convenience, the iLoc-Virus web-server also has the function to accept the batch job submission. It is anticipated that iLoc-Virus may become a useful high throughput tool for both basic research and drug development. PMID- 21684289 TI - The molecular refractive function of lens gamma-Crystallins. AB - gamma-Crystallins constitute the major protein component in the nucleus of the vertebrate eye lens. Present at very high concentrations, they exhibit extreme solubility and thermodynamic stability to prevent scattering of light and formation of cataracts. However, functions beyond this structural role have remained mostly unclear. Here, we calculate molecular refractive index increments of crystallins. We show that all lens gamma-crystallins have evolved a significantly elevated molecular refractive index increment, which is far above those of most proteins, including nonlens members of the betagamma-crystallin family from different species. The same trait has evolved in parallel in crystallins of different phyla, including S-crystallins of cephalopods. A high refractive index increment can lower the crystallin concentration required to achieve a suitable refractive power of the lens and thereby reduce their propensity to aggregate and form cataracts. To produce a significant increase in the refractive index increment, a substantial global shift in amino acid composition is required, which can naturally explain the highly unusual amino acid composition of gamma-crystallins and their functional homologues. This function provides a new perspective for interpreting their molecular structure. PMID- 21684291 TI - Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system. AB - Microglia and astrocytes in the central nervous system are now recognized as active participants in various pathological conditions such as trauma, stroke, or chronic neurodegenerative disorders. Their activation is closely related with the development and severity of diseases. Interestingly, activation of microglia and astrocytes occurs with a spatially and temporarily distinct pattern. The present review explores the cross talk in the process of their activation. Microglia, activated earlier than astrocytes, promote astrocytic activation. On the other hand, activated astrocytes not only facilitate activation of distant microglia, but also inhibit microglial activities. Molecules contributing to their intercommunication include interleukin-1 (IL-1), adenosine triphosphate (ATP), and transforming growth factor beta (TGF-beta). A better understanding about the cross talk between activation of microglia and astrocytes would be helpful to elucidate the role of glial cells in pathological conditions, which could accelerate the development of treatment for various diseases. PMID- 21684292 TI - Cytotoxic and antitumor effects of brucine on Ehrlich ascites tumor and human cancer cell line. AB - AIMS: Brucine (BRU), a natural plant alkaloid is reported to possess cytotoxic and antiproliferative activities. In this study we aimed to investigate its in vitro and in vivo antitumor and antiangiogenic effects. MAIN METHODS: Cell proliferation and viability was assessed using microculture tetrazolium tests (MTT). As predictive markers we determined intracellular levels of vascular endothelial growth factor (VEGF), Interleukin-12 (IL-12), tumor necrosis factor (TNF-alpha), caspase-3, -8 and -9 by ELISA and enzymatic activity assays. In addition, anti-VEGF neutralization effect was evaluated to assess whether it could result in augmented anticancer efficacy than the single agent. Antitumor activity was evaluated against Ehrlich ascites and solid tumor models. 15*10(6) EAC cells were implanted intraperitoneally (i.p., ascites tumor) and subcutaneous (s.c., solid tumor) in Swiss albino mice. Mice with established tumors received brucine i.p. at 12.5, 25, and 50mg/kg for 14days in ascites tumor and 50mg/kg in solid tumor for 30days. Tumor volume, cell viability, angiogenic, anti angiogenic, anti-inflammatory factors and antioxidant parameters were determined. Immunohistochemistry analysis for VEGF and CD-31 was also performed. KEY FINDINGS: BRU produced time and dose-dependent inhibition of MCF-7 in vitro and EAC tumors in vivo. The anti-angiogenic effects were accompanied with decreased VEGF and TNF-alpha and increased IL-12 expression. BRU reduced peritoneal angiogenesis and microvessel density in vivo. CONCLUSION: Our findings suggest that BRU possesses antitumor and anti-angiogenic activities in vitro and in vivo. The above results showed that BRU can be used as a potential anticancer agent as an antimetastatic and anti-angiogenic agent. PMID- 21684293 TI - Eicosapentaenoic acid reduces the pulmonary vein arrhythmias through nitric oxide. AB - AIMS: Omega-3 polyunsaturated fatty acids can modulate cardiac electrophysiology and reduce the genesis of atrial fibrillation. This study investigates the potential mechanisms through which eicosapentaenoic acid (EPA) reduces pulmonary vein (PV) arrhythmogenesis. MAIN METHODS: Conventional microelectrodes were used to record the action potentials (APs), before and after the EPA (0.1 MUM and 1.0 MUM) administration with and without the presence of a nitric oxide (NO) synthase inhibitor (L-NAME, 100 MUM) in isolated rabbit PV tissue preparations. Furthermore, indo-1 fluorimetric ratio technique was used to evaluate intracellular calcium in isolated single PV cardiomyocytes with or without incubation of EPA (1.0 MUM, 30 min). KEY FINDINGS: EPA concentration-dependently reduced the PV spontaneous beating rate (P<0.05). EPA (1.0 MUM) also reduced the amplitude of delayed afterdepolarizations (P<0.05). EPA hyperpolarized the maximal diastolic potential (MDP), shortened AP duration, increased AP amplitude (APA), and reduced diastolic tension and contractility. However, EPA in the presence of L-NAME or omega-9 fatty acids (oleic acid, 1.0 MUM) did not have any effect on PV spontaneous activity, AP morphology, or contractile force. A linear regression shows that the decrease in PV spontaneous beating rates induced by EPA correlated well with the changes of MDP, APA, diastolic tension, and contractile force of PVs. In addition, intracellular Ca(2+) transient and sarcoplasmic reticulum Ca(2+) content were significantly more decreased in the EPA-treated cardiomyocytes than in control PV cardiomyocytes as observed by indo-1 fluorescence. SIGNIFICANCE: EPA reduces PV arrhythmogenesis through the mechanoelectrical feedback generated by NO production. PMID- 21684294 TI - Expression of XRCC5 in peripheral blood lymphocytes is upregulated in subjects from a heavily polluted region in the Czech Republic. AB - Air pollution causes oxidative damage to macromolecules, chromosomal aberrations and changes in gene expression. We investigated the levels of oxidative stress markers [8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), 15-F(2t)-isoprostane (15 F2t-IsoP), protein carbonyls] and cytogenetic parameters [genomic frequency of translocations (F(G)/100), percentage of aberrant cells (%AB.C.) and acentric fragments (ace)] in subjects living in Prague and in the heavily polluted Ostrava region. We also compared the expression of genes participating in base excision repair (BER) and non-homologous end-joining (NHEJ). We analyzed 64 subjects from Prague and 75 subjects from Ostrava. We measured oxidative stress markers by ELISA, cytogenetic parameters by fluorescence in situ hybridization and gene expression by quantitative PCR. The levels of air pollutants (benzo[a]pyrene, B[a]P; carcinogenic polycyclic aromatic hydrocarbons, c-PAHs; benzene) measured by personal monitors were significantly elevated in Ostrava compared to Prague (p<0.001). Despite this fact, we observed no differences in biomarkers of oxidative stress between the two locations. Moreover, subjects from Ostrava were less likely to have above-median levels of %AB.C. (OR; 95% CI: 0.18; 0.05-0.67; p=0.010). Multivariate analyses revealed that subjects living in Ostrava had increased odds of having above-median levels of XRCC5 expression (OR; 95% CI: 3.33; 1.03-10.8; q=0.046). Above-median levels of 8-oxodG were associated with decreased levels of vitamins C (OR; 95% CI: 0.37; 0.16-0.83; p=0.016) and E (OR; 95% CI: 0.25; 0.08-0.75; p=0.013), which were elevated in subjects from Ostrava. We suggest that air pollution by c-PAHs affects XRCC5 gene expression, which probably protects subjects from Ostrava against the induction of a higher frequency of translocations; elevated vitamin C and E levels in the Ostrava subjects decrease the levels of 8-oxodG. PMID- 21684295 TI - Are effects of emotion in single words non-lexical? Evidence from event-related brain potentials. AB - Emotional meaning impacts word processing. However, it is unclear, at which functional locus this influence occurs and whether and how it depends on word class. These questions were addressed by recording event-related potentials (ERPs) in a lexical decision task with written adjectives, verbs, and nouns of positive, negative, and neutral emotional valence. In addition, word frequency (high vs. low) was manipulated. The early posterior negativity (EPN) in ERPs started earlier for emotional nouns and adjectives than for verbs. Depending on word class, EPN onsets coincided with or followed the lexicality effects. Main ERP effects of emotion overlapped with effects of word frequency between 300 and 550 ms but interacted with them only after 500 ms. These results indicate that in all three word classes examined, emotional evaluation as represented by the EPN has a post-lexical locus, starting already after a minimum of lexical access. PMID- 21684296 TI - Preface to the special issue of Physiology and Behavior from the 2010 Annual Meeting of the Society for the Study of Ingestive Behavior (SSIB). PMID- 21684297 TI - Allostasis: a model of predictive regulation. AB - The premise of the standard regulatory model, "homeostasis", is flawed: the goal of regulation is not to preserve constancy of the internal milieu. Rather, it is to continually adjust the milieu to promote survival and reproduction. Regulatory mechanisms need to be efficient, but homeostasis (error-correction by feedback) is inherently inefficient. Thus, although feedbacks are certainly ubiquitous, they could not possibly serve as the primary regulatory mechanism. A newer model, "allostasis", proposes that efficient regulation requires anticipating needs and preparing to satisfy them before they arise. The advantages: (i) errors are reduced in magnitude and frequency; (ii) response capacities of different components are matched -- to prevent bottlenecks and reduce safety factors; (iii) resources are shared between systems to minimize reserve capacities; (iv) errors are remembered and used to reduce future errors. This regulatory strategy requires a dedicated organ, the brain. The brain tracks multitudinous variables and integrates their values with prior knowledge to predict needs and set priorities. The brain coordinates effectors to mobilize resources from modest bodily stores and enforces a system of flexible trade-offs: from each organ according to its ability, to each organ according to its need. The brain also helps regulate the internal milieu by governing anticipatory behavior. Thus, an animal conserves energy by moving to a warmer place - before it cools, and it conserves salt and water by moving to a cooler one before it sweats. The behavioral strategy requires continuously updating a set of specific "shopping lists" that document the growing need for each key component (warmth, food, salt, water). These appetites funnel into a common pathway that employs a "stick" to drive the organism toward filling the need, plus a "carrot" to relax the organism when the need is satisfied. The stick corresponds broadly to the sense of anxiety, and the carrot broadly to the sense of pleasure. This design constrains anxieties to be non-adapting and pleasures to be brief -- fast-adapting -- to make way for the next anxiety. The stick/carrot mechanisms evolved early and expanded so that in humans they govern higher level learning and social organization. Correspondingly, the "funnel" widened to allow innumerable activities and experiences to each provide non-adapting anxieties and brief pleasures, their reward values depending partly on the effort expended. But modern life narrows the variety of small pleasures and reduces effort, thereby reducing their reward value and requiring larger portions for equivalent satisfaction - a cycle that generates addictive behaviors. Homeostasis and allostasis locate pathology at different levels. Homeostasis identifies proximate causes; for example, it attributes essential hypertension to excess salt water in too small a vascular reservoir. Thus it directs pharmacotherapy toward reducing salt and water, expanding the reservoir, and blocking feedbacks that would counteract these measures. Allostasis attributes essential hypertension to the brain. Chronically anticipating a need for higher pressure, the brain mobilizes all the low level mechanisms in concert: kidney to retain salt and water, vascular system to tighten, and salt appetite to rise. Correspondingly, allostasis would direct therapy toward higher levels - to reduce demand and increase sense of control -- so that the brain can down-shift its prediction and relax all the low-level mechanisms in concert. For disorders of addiction homeostasis pursues pharmacological treatments: drugs to treat drug addiction, obesity, and other compulsive behaviors. Allostasis suggests broader approaches - such as re-expanding the range of possible pleasures and providing opportunities to expend effort in their pursuit. PMID- 21684298 TI - The relation between dietary fructose, dietary fat and leptin responsiveness in rats. AB - Others reported that rats fed a high-fructose diet for 6 months were leptin resistant. We tested peripheral and/or central leptin responses in rats fed fructose for shorter time periods. Rats fed a diet containing 60% energy (% kcal) fructose and 10% kcal fat diet for 21 days had the same serum triglycerides (TG), gained less weight than controls, decreased their food intake and weight gain in response to central injections of 0.5 or 1.0 ug leptin, but were resistant to an i.p. injection of 2.0 mg leptin/kg. An i.p. injection of 1 mg leptin/kg increased phosphorylation of hypothalamic signal transducer and activator of transcription 3 (PSTAT3) implying resistance was not a failure of leptin to cross the blood brain barrier. The effects of dietary fructose were compared with those of dietary fat. Rats fed a 10%kcal fructose and 30%kcal fat diet for 39 days were leptin resistant whereas rats fed a 40%kcal fructose and 30%kcal fat diet responded to i.p. leptin. Another monosaccharide, glucose, replicated the effects of fructose in the 30% kcal fat diet. Surprisingly, none of the rats showed a reliable response to third ventricle leptin and peripheral leptin failed to stimulate hypothalamic PSTAT3 although it did increase PSTAT3 in the brainstem of rats fed the 40%kcal fructose or glucose diets. Thus a high-fructose, low-fat diet induces peripheral leptin resistance in less than 4 weeks, but high dietary concentrations of fructose or glucose prevent peripheral leptin resistance in rats fed a high-fat diet. PMID- 21684299 TI - Caveats and limitations of plate reader-based high-throughput kinetic measurements of intracellular calcium levels. AB - Calcium plays a crucial role in virtually all cellular processes, including neurotransmission. The intracellular Ca(2+) concentration ([Ca(2+)](i)) is therefore an important readout in neurotoxicological and neuropharmacological studies. Consequently, there is an increasing demand for high-throughput measurements of [Ca(2+)](i), e.g. using multi-well microplate readers, in hazard characterization, human risk assessment and drug development. However, changes in [Ca(2+)](i) are highly dynamic, thereby creating challenges for high-throughput measurements. Nonetheless, several protocols are now available for real-time kinetic measurement of [Ca(2+)](i) in plate reader systems, though the results of such plate reader-based measurements have been questioned. In view of the increasing use of plate reader systems for measurements of [Ca(2+)](i) a careful evaluation of current technologies is warranted. We therefore performed an extensive set of experiments, using two cell lines (PC12 and B35) and two fluorescent calcium-sensitive dyes (Fluo-4 and Fura-2), for comparison of a linear plate reader system with single cell fluorescence microscopy. Our data demonstrate that the use of plate reader systems for high-throughput real-time kinetic measurements of [Ca(2+)](i) is associated with many pitfalls and limitations, including erroneous sustained increases in fluorescence, limited sensitivity and lack of single cell resolution. Additionally, our data demonstrate that probenecid, which is often used to prevent dye leakage, effectively inhibits the depolarization-evoked increase in [Ca(2+)](i). Overall, the data indicate that the use of current plate reader-based strategies for high throughput real-time kinetic measurements of [Ca(2+)](i) is associated with caveats and limitations that require further investigation. PMID- 21684300 TI - Protective effects of antioxidants and anti-inflammatory agents against manganese induced oxidative damage and neuronal injury. AB - Exposure to excessive manganese (Mn) levels leads to neurotoxicity, referred to as manganism, which resembles Parkinson's disease (PD). Manganism is caused by neuronal injury in both cortical and subcortical regions, particularly in the basal ganglia. The basis for the selective neurotoxicity of Mn is not yet fully understood. However, several studies suggest that oxidative damage and inflammatory processes play prominent roles in the degeneration of dopamine containing neurons. In the present study, we assessed the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates and associated neuronal dysfunctions both in vitro and in vivo. Results from our in vitro study showed a significant (p<0.01) increase in biomarkers of oxidative damage, F(2)-isoprostanes (F(2)-IsoPs), as well as the depletion of ATP in primary rat cortical neurons following exposure to Mn (500 MUM) for 2h. These effects were protected when neurons were pretreated for 30 min with 100 of an antioxidant, the hydrophilic vitamin E analog, trolox (6-hydroxy-2,5,7,8 tetramethylchroman-2-carboxylic acid), or an anti-inflammatory agent, indomethacin. Results from our in vivo study confirmed a significant increase in F(2)-IsoPs levels in conjunction with the progressive spine degeneration and dendritic damage of the striatal medium spiny neurons (MSNs) of mice exposed to Mn (100mg/kg, s.c.) 24h. Additionally, pretreatment with vitamin E (100mg/kg, i.p.) or ibuprofen (140 MUg/ml in the drinking water for two weeks) attenuated the Mn-induced increase in cerebral F(2)-IsoPs? and protected the MSNs from dendritic atrophy and dendritic spine loss. Our findings suggest that the mediation of oxidative stress/mitochondrial dysfunction and the control of alterations in biomarkers of oxidative injury, neuroinflammation and synaptodendritic degeneration may provide an effective, multi-pronged therapeutic strategy for protecting dysfunctional dopaminergic transmission and slowing of the progression of Mn-induced neurodegenerative processes. PMID- 21684301 TI - Sulforaphane prevents microcystin-LR-induced oxidative damage and apoptosis in BALB/c mice. AB - Microcystins (MCs), the products of blooming algae Microcystis, are waterborne environmental toxins that have been implicated in the development of liver cancer, necrosis, and even fatal intrahepatic bleeding. Alternative protective approaches in addition to complete removal of MCs in drinking water are urgently needed. In our previous work, we found that sulforaphane (SFN) protects against microcystin-LR (MC-LR)-induced cytotoxicity by activating the NF-E2-related factor 2 (Nrf2)-mediated defensive response in human hepatoma (HepG2) and NIH 3T3 cells. The purpose of this study was to investigate and confirm efficacy the SFN induced multi-mechanistic defense system against MC-induced hepatotoxicity in an animal model. We report that SFN protected against MC-LR-induced liver damage and animal death at a nontoxic and physiologically relevant dose in BALB/c mice. The protection by SFN included activities of anti-cytochrome P450 induction, anti oxidation, anti-inflammation, and anti-apoptosis. Our results suggest that SFN may protect mice against MC-induced hepatotoxicity. This raises the possibility of a similar protective effect in human populations, particularly in developing countries where freshwaters are polluted by blooming algae. PMID- 21684302 TI - Regional brain c-fos activation associated with penile erection and other symptoms induced by the spider toxin Tx2-6. AB - Brain areas expressing c-fos messenger RNA were mapped by quantitative in situ hybridization after 1-2 h of intoxication with 10 MUg/kg Tx2-6, a toxin obtained from the venom of the spider Phoneutria nigriventer. Relative to saline-treated controls, brains from toxin-treated animals showed pronounced c-fos activation in many brain areas, including the supraoptic nucleus, the paraventricular nucleus of the hypothalamus, the motor nucleus of the vagus, area postrema, paraventricular and paratenial nuclei of the thalamus, locus coeruleus, central amydaloid nucleus and the bed nucleus of the stria terminalis. The paraventricular hypothalamus and the bed nucleus of the stria terminalis have been implicated in erectile function in other studies. A possible role for central NO is considered. Acute stress also activates many brain areas activated by Tx2-6 as well as with NOstimulated Fos transcription. Brain areas that appear to be selectively activated by Tx2-6, include the paratenial and paraventricular thalamic nuclei, the bed nucleus of the stria terminalis and the area postrema and the dorsal motor n. of vagus in the medulla. However, direct injections of different doses of the toxin into the paraventricular hypothalamic n. failed to induce penile erection, arguing against CNS involvement in this particular effect. PMID- 21684303 TI - Spatial frequency and visual discomfort. AB - Images created from noise filtered to have an approximately 1/f amplitude spectrum were altered by adding excess energy concentrated at various spatial frequencies. The effects of this manipulation on judgements of visual discomfort were studied. Visual noise with a 1/f amplitude spectrum (typical of natural images) was judged more comfortable than any image with a relative increase in contrast energy within a narrow spatial frequency band. A peak centred on 0.375 1.5cycles/degree of spatial frequency was consistently judged as more uncomfortable than a peak at a higher spatial frequency. This finding was robust to slight differences in eccentricity, and when stimuli were matched for perceived contrast across spatial frequency. These findings are consistent with the idea that deviation from the statistics of natural images could cause discomfort because the visual system is optimised to encode images with the particular statistics typical of natural scenes. PMID- 21684304 TI - Adsorption of Cr(VI) and As(V) ions by modified magnetic chitosan chelating resin. AB - Cross-linked magnetic chitosan anthranilic acid glutaraldehyde Schiff's base (CAGS) was prepared for adsorption of both As(V) and Cr(VI) ions and their determination by ICP-OES. Prepared cross-linked magnetic CAGS was investigated by means of SEM, FTIR, wide angle X-ray diffraction (WAXRD) and TGA analysis. The adsorption properties of cross-linked magnetic CAGS resin toward both As(V) and Cr(VI) were evaluated. Various factors affecting the uptake behavior such as pH, temperature, contact time, initial concentration of metal ions, effect of other ions and desorption were studied. The equilibrium was achieved after about 110 min and 120 min for As(V) and Cr(VI), respectively at pH=2. The adsorption kinetics followed the mechanism of the pseudo-second order equation for all systems studied, evidencing chemical sorption as the rate-limiting step of adsorption mechanism and not involving a mass transfer in solution. The equilibrium data were analyzed using the Langmuir, Freundlich, and Tempkin isotherm models. The best interpretation for the equilibrium data was given by Langmuir isotherm, and the maximum adsorption capacities were 58.48 and 62.42 mg/g for both Cr(VI) and As(V), respectively. Cross-linked magnetic CAGS displayed higher adsorption capacity for Cr(VI). The adsorption capacity of the metal ions increased with increasing temperature under optimum conditions in case of Cr(VI), but decreased in case of As(V). The metal ion-loaded cross-linked magnetic CAGS were regenerated with an efficiency of greater than 88% using 0.2M sodium hydroxide (NaOH). PMID- 21684305 TI - Inhibition of protein kinase C decreases sensitivity of GABA receptor subtype to fipronil insecticide in insect neurosecretory cells. AB - Phosphorylation by serine/threonine kinases has been described as a new mechanism for regulating the effects of insecticides on insect neuronal receptors and channels. Although insect GABA receptors are commercially important targets for insecticides (e.g. fipronil), their modulation by kinases is poorly understood and the influence of phosphorylation on insecticide sensitivity is unknown. Using the whole-cell patch-clamp technique, we investigated the modulatory effect of PKC and CaMKinase II on GABA receptor subtypes (GABAR1 and GABAR2) in DUM neurons isolated from the terminal abdominal ganglion (TAG) of Periplaneta americana. Chloride currents through GABAR2 were selectively abolished by PMA and PDBu (the PKC activators) and potentiated by Go6983, an inhibitor of PKC. Furthermore, using KN-62, a specific CaMKinase II inhibitor, we demonstrated that CaMKinase II activation was also involved in the regulation of GABAR2 function. In addition, using CdCl(2) (the calcium channel blocker) and LOE-908, a blocker of TRPgamma, we revealed that calcium influx through TRPgamma played an important role in kinase activations. Comparative studies performed with CACA, a selective agonist of GABAR1 in DUM neurons confirmed the involvement of these kinases in the specific regulation of GABAR2. Furthermore, our study reported that GABAR1 was less sensitive than GABAR2 to fipronil. This was demonstrated by the biphasic concentration-response curve and the current-voltage relationship established with both GABA and CACA. Finally, we demonstrated that GABAR2 was 10-fold less sensitive to fipronil following inhibition of PKC, whereas inhibition of CaMKinase II did not alter the effect of fipronil. PMID- 21684306 TI - Autoantibody detection with indirect immunofluorescence on HEp-2 cells: starting serum dilutions for systemic rheumatic diseases. AB - Antinuclear antibodies (ANA) are determined, among other reasons, to identify samples which need a second test to detect the associated specificities. Our aim was to evaluate the clinical and economic impact generated by using an initial dilution for ANA of 1:160. We analyzed all samples for which ANA, anti-ENA and anti-dsDNA were requested over a 1-year period. ANA were detected by indirect immunofluorescence. Anti-ENA were analyzed with a combination of techniques. Anti dsDNA were detected by radioimmunoassay. Cost analysis was performed by calculating the difference between two cut-offs (ANA 1:40 and 1:160). A total of 13,233 samples were processed for ANA, of which 59.9% were positive with the 1:40 cut-off and 39.2% with the 1:160 cut-off. At ANA titer 1:40, 0.2% of the samples were anti-ENA-positive and 2.2% were anti-dsDNA positive. Only ANA dilutions of 1:160 and higher showed significantly increased positive predictive value for anti-ENA (1.5 versus 0.2, p=0.029) and anti-dsDNA (8.3 versus 2.2, p<0.001) compared to the 1:40 titer. With the 1:160 cut-off, 16.6% fewer ANA tests, 41.8% fewer anti-ENA determinations and 36.4% fewer anti-dsDNA tests would have been needed. The average saving was 0.87 cost-units per sample (1 unit=2.06euro). We conclude that setting the starting dilution for ANA at 1:160 avoids unnecessary studies, increases the positive predictive values of ANA for anti-ENA and anti dsDNA, and generates clinical and economic benefits. PMID- 21684307 TI - Neonatal paternal deprivation or early deprivation reduces adult parental behavior and central estrogen receptor alpha expression in mandarin voles (Microtus mandarinus). AB - Previous studies on parental behavior have primarily focused on maternal behavior, with little research directed at observing paternal behavior. The effects of neonatal paternal deprivation and early deprivation on adult parental behavior and estrogen receptor alpha (ERalpha) especially remain unclear. This study examined whether paternal deprivation or early deprivation has long-term effects on the parental behavior and central ERalpha expression of adult mandarin vole offspring. The parental behaviors of adult mandarin voles that suffered paternal deprivation or early deprivation were observed with their own pups at 0, 13 and 21 days of age. Central ERalpha expression was also examined in adult virgin voles with different neonatal treatments using immunocytochemistry. The results indicated that (1) levels of parental care and sociability in adult offspring were reduced due to paternal deprivation and early deprivation; (2) ERalpha expression in the stria terminalis (BNST), medial preoptic area (MPOA), ventromedial hypothalamic nucleus (VMH) and arcuate hypothalamic nucleus (Arc) were also reduced by paternal deprivation and early deprivation; (3) ERalpha expression in the BNST, MPOA, and VMH of control females was higher than that of control males, but ERalpha expression in the Arc was lower. Our findings show that paternal care plays an important role in the development of parental behavior in offspring. Also, because paternal deprivation and early deprivation impaired sexual differences, the alteration of parental behavior may be associated with decreased ERalpha expression. PMID- 21684308 TI - Green odor and depressive-like state in rats: toward an evidence-based alternative medicine? AB - It is widely accepted that mental stress is an important factor in the development of psychological disorders such as depression. On pre-existing evidence, the so-called green odor may have a relieving and sedative effect on animals exposed to stressful situations. Using two behavioral models of depression, the forced-swim test and learned helplessness paradigm, we investigated whether inhalation of green odor (a 50:50 mixture of trans-2-hexenal and cis-3-hexenol) might alleviate and/or prevent experimentally induced depressive-like states in rats. A 3-min swim every day for 7 days resulted in significant prolongation of immobility time (vs. day 1). Inhaling green odor, but not vehicle, thereafter for 10 days (without swimming) led to the prolonged immobility time being significantly reduced and the hippocampal level of brain derived neurotrophic factor (BDNF) being significantly increased. In the learned helplessness paradigm, the failure number and time spent in the shock compartment seen in the active avoidance test were both significantly attenuated in those rats that inhaled green odor for 11 days after the postshock screening test (vs. vehicle-exposed rats). Finally, for 10 consecutive days rats continuously exposed to green odor or vehicle swam for 3 min/day. Immobility time was significantly shorter in the green-odor group than in the vehicle-exposed group on days 6-10. These results suggest that green odor has not only a therapeutic, but also a preventive effect on depressive-like states in rats. These effects may be at least in part due to a green odor-induced upregulation of BDNF in the hippocampus. PMID- 21684309 TI - Ca2+-activated transbilayer movement of plasma membrane phospholipids in Leishmania donovani during ionomycin or thapsigargin stimulation. AB - The protozoan parasite Leishmania causes serious infections in humans all over the world. After being inoculated into the skin through the bite of an infected sandfly, Leishmania promastigotes must gain entry into macrophages to initiate a successful infection. Specific, surface exposed phospholipids have been implicated in Leishmania-macrophage interaction but the mechanisms controlling and regulating the plasma membrane lipid distribution remains to be elucidated. Here, we provide evidence for Ca(2+)-induced phospholipid scrambling in the plasma membrane of Leishmania donovani. Stimulation of parasites with ionomycin increases intracellular Ca(2+) levels and triggers exposure of phosphatidylethanolamine at the cell surface. We found that increasing intracellular Ca(2+) levels with ionomycin or thapsigargin induces rapid transbilayer movement of NBD-labelled phospholipids in the parasite plasma membrane that is bidirectional, independent of cellular ATP and not specific to the polar lipid head group. The findings suggest the presence of a Ca(2+) dependent lipid scramblase activity in Leishmania parasites. Our studies further show that lipid scrambling is not activated by rapid exposure of promastigotes to higher physiological temperature that increases intracellular Ca(2+) levels. PMID- 21684310 TI - Baseline autonomic nervous system arousal and physical and relational aggression in preschool: the moderating role of effortful control. AB - The current study investigates whether established associations between physical aggression and low autonomic nervous system arousal, as indexed by heart rate and blood pressure, also apply to the study of the development of relational aggression. Baseline heart rate and blood pressure were collected in two samples of preschoolers, and teachers reported on classroom physical and relational aggression. In Study 1, lower systolic and diastolic blood pressure were related to increased engagement in relational aggression among older preschoolers. In Study 2, lower heart rate and blood pressure predicted increased engagement in classroom physical and relational aggression concurrently and across a preschool year in some cases. Low baseline arousal-aggression associations were strongest for children with poorer self-regulation abilities, whereas high self-regulation appeared to protect children with low heart rate and blood pressure from engagement in aggressive classroom behavior. These findings suggest the utility of examining baseline physiological measures in the study of relational aggression as well as physical aggression. Implications for interventions targeted to physical and relational aggression in early childhood are discussed. PMID- 21684311 TI - Chronological changes in prosaposin in the developing rat brain. AB - Prosaposin is the precursor protein of four glycoproteins, saposins A, B, C, and D, which activate sphingolipid hydrolases in lysosomes. Besides this role, intact prosaposin is also known as a potent neurotrophic factor that prevents neuronal cell death and stimulates neurite outgrowth in in vivo and in vitro experiments. In the present study, we examined chronological changes in prosaposin immunoreactivity in the rat brain using immunofluorescence staining and Diaminobenzidine (DAB) immunohistochemistry. In the hippocampal regions CA1, CA3, and dentate gyrus, the strongest staining of prosaposin was observed on postnatal day 1. The prosaposin immunoreactivity then decreased gradually until postnatal day 28. But in the cerebral cortex, prosaposin staining intensity increased from postnatal day 1 to 14, then decreased until postnatal day 28. The prosaposin immunoreactivity co-localized with the lysosomal granules labeled by an anti Cathepsin D antibody, indicating that prosaposin mainly localized in the lysosomes of the neurons. We also examined the chronological changes in prosaposin mRNA and its two alternatively spliced variants using in situ hybridization. We found that both the mRNA forms, especially the one without a nine-base insertion, increased significantly from embryonic day 15 to postnatal day 7, then decreased gradually until postnatal day 28. Abundant prosaposin expression in the perinatal stages indicates a potential role of prosaposin in the early development of the rat brain. PMID- 21684312 TI - Effect of molecular mobility on coupled enzymatic reactions involving cofactor regeneration using nanoparticle-attached enzymes. AB - Cofactor-dependent multi-step enzymatic reactions generally require dynamic interactions among cofactor, enzyme and substrate molecules. Maintaining such molecular interactions can be quite challenging especially when the catalysts are tethered to solid state supports for heterogeneous catalysis for either biosynthesis or biosensing. The current work examines the effects of the pattern of immobilization, which presumably impacts molecular interactions on the surface of solid supports, on the reaction kinetics of a multienzymic system including glutamate dehydrogenase, glucose dehydrogenase and cofactor NAD(H). Interestingly, particle collision due to Brownian motion of nanoparticles successfully enabled the coupled reactions involving a regeneration cycle of NAD(H) even when the enzymes and cofactor were immobilized separately onto superparamagnetic nanoparticles (124 nm). The impact of particle motion and collision was evident in that the overall reaction rate was increased by over 100% by applying a moderate alternating magnetic field (500 Hz, 17 Gs), or using additional spacers, both of which could improve the mobility of the immobilized catalysts. We further observed that integrated immobilization, which allowed the cofactor to be placed in the molecular vicinity of enzymes on the same nanoparticles, could enhance the reaction rate by 1.8 fold. These results demonstrated the feasibility in manipulating molecular interactions among immobilized catalyst components by using nanoscale fabrication for efficient multienzymic biosynthesis. PMID- 21684313 TI - Polymer assemblies for controlled delivery of bioactive molecules from surfaces. AB - Localized delivery of bioactive compounds from surfaces of biomedical devices affords significant therapeutic benefits, and often relies on the capability of surface coatings to provide spatial and temporal control over release rate. The layer-by-layer technique presents a unique means to construct surface coatings that can conform to a variety of biomaterial surfaces and serve as matrices enabling controlled delivery of bioactive molecules from surfaces. The versatility of layer-by-layer assembly enables construction of surface coatings of diverse chemistry and internal architecture with controlled release properties. This review focuses on recent developments in constructing such layered matrices using linear polymers, polymer nanoparticles and block copolymer micelles, including micelles with stimuli-responsive cores, as film building blocks and in controlling release rate of therapeutics from these matrices via degradation, application of pH, ionic strength, temperature, light, electric field and chemical or biological stimuli. Challenges and opportunities associated with fabrication of stratified multilayer films capable of multi-stage delivery of multiple drugs are also discussed. PMID- 21684314 TI - beta-Hydroxybutyrate is the preferred substrate for GABA and glutamate synthesis while glucose is indispensable during depolarization in cultured GABAergic neurons. AB - The ketogenic diet has multiple beneficial effects not only in treatment of epilepsy, but also in that of glucose transporter 1 deficiency, cancer, Parkinson's disease, obesity and pain. Thus, there is an increasing interest in understanding the mechanism behind this metabolic therapy. Patients on a ketogenic diet reach high plasma levels of ketone bodies, which are used by the brain as energy substrates. The interaction between glucose and ketone bodies is complex and there is still controversy as to what extent it affects the homeostasis of the neurotransmitters glutamate, aspartate and GABA. The present study was conducted to study this metabolic interaction in cultured GABAergic neurons exposed to different combinations of (13)C-labeled and unlabeled glucose and beta-hydroxybutyrate. Depolarization was induced and the incorporation of (13)C into glutamate, GABA and aspartate was analyzed. The presence of beta hydroxybutyrate together with glucose did not affect the total GABA content but did, however, decrease the aspartate content to a lower value than when either glucose or beta-hydroxybutyrate was employed alone. When combinations of the two substrates were used (13)C-atoms from beta-hydroxybutyrate were found in all three amino acids to a greater extent than (13)C-atoms from glucose, but only the (13)C contribution from [1,6-(13)C]glucose increased upon depolarization. In conclusion, beta-hydroxybutyrate was preferred over glucose as substrate for amino acid synthesis but the total content of aspartate decreased when both substrates were present. Furthermore only the use of glucose increased upon depolarization. PMID- 21684315 TI - Analysis of the influence of two CD24 genetic variants in Crohn's disease and ulcerative colitis. AB - The aim of this study was to evaluate the possible implication of CD24 gene in the genetic predisposition to inflammatory bowel disease (IBD). Our study population consisted of 1321 female Spanish individuals (369 Crohn's disease [CD] patients, 323 ulcerative colitis [UC] patients, and 629 healthy matched controls). Two putative functional polymorphisms, a C to T coding polymorphism (rs8734) and a TG deletion in the 3' untranslated region (rs3838646), were used as CD24 genetic markers and genotyped using a Taqman 5' allelic discrimination assay. The "del" allele of the dinucleotide deletion was associated with an increased risk of CD (odds ratio = 1.61, 95% confidence interval = 1.17-2.21, p(FDR) = 6.4E-03) but not with UC. Moreover, this allele was significant associated with the age of CD diagnosis between 17 and 40 years, the ileocolonic location, and the inflammatory behavior of CD. We observed no significant differences between the allelic or genotypic frequencies of the A57V polymorphism in our studied IBD cohort. Our results suggest that the rs3838646 CD24 polymorphism is part of the genetic background of CD. PMID- 21684316 TI - Hsp70 expression as biomarkers of oxidative stress: mycotoxins' exploration. AB - The environment represents a key contributor to human health and disease. Exposure to many substances such as pollutants, toxins and chemicals, has detrimental effects on health and are considered to contribute substantially to most diseases of major public health significance. Environmental diseases as mycotoxicosis are those in general aroused or exacerbated by exposure to environmental stressors as mycotoxins. These hazardous compounds are secondary metabolites produced by fungi and occurred simultaneously in food, feed and raw materials. The present investigation was conducted to assess if (i) Hsp70 induction, a parameter of protective and adaptive response, is a systematic biomarker to mycotoxin intoxications and (ii) all mycotoxins undergo oxidative stress in there toxic signalling pathways, as the omnipresent process playing a role in the initiation or progression of numerous disorders. Overall, observations to date evoke that Hsp70 can act as biomarkers of oxidative injury instead they are not systematic to mycotoxin exposure. PMID- 21684317 TI - Evaluation of PPARgamma agonists on rodent endothelial cell proliferation. AB - The PPARgamma agonist troglitazone (TG) induced an increased incidence of hemangiosarcomas in mice but was not carcinogenic in rats. In contrast, pioglitazone (PIO) did not induce hemangiosarcomas or any other tumors in mice. We previously demonstrated that TG increased the proliferation of endothelial cells (ECs) in liver and adipose tissue in mice, and acted as a mitogenic stimulant and an inhibitor of apoptosis in vitro in mouse, but not human, ECs. In the present study, we investigated whether TG had any effect on the proliferation of ECs in rats. We also evaluated the in vivo and in vitro effects of PIO on ECs in mice. In rats, TG did not increase the Ki-67 labeling index (LI) of ECs in liver or adipose tissue at doses used in the two-year bioassay, and did not increase hepatocyte proliferation. PIO administered to mice did not increase the Ki-67 LI of hepatocytes or ECs in liver or white adipose tissue, but slightly increased the EC proliferation in brown adipose tissue. PIO was slightly mitogenic on cultured mouse ECs after 3 days of treatment but not after 6 days, and there was no inhibition of apoptosis, in contrast to what was seen with TG. The data support the conclusion that sustained EC proliferation in mice is necessary, for the induction of hemangiosarcomas by TG, and these short-term and long-term effects are not seen with TG in the rat or with PIO in mice, treatments that also are not related to the induction of hemangiosarcomas in two-year bioassays. PMID- 21684318 TI - Interaction of minor groove ligands with G-quadruplexes: thermodynamic contributions of the number of quartets, T-U substitutions, and conformation. AB - In the presence of specific metal ions, DNA oligonucleotides containing guanine repeat sequences can adopt G-quadruplex structures. In this work, we used a combination of spectroscopic and calorimetric techniques to investigate the conformation and unfolding thermodynamics of the K(+)-form of five G-quadruplexes with sequences: d(G(2)T(2)G(2)TGTG(2)T(2)G(2)), G2, d(G(3)T(2)G(3)TGTG(3)T(2)G(3)), G3, their analogs where T is replaced with U, G2 U and G3-U, and r(G(2)U(2)G(2)UGUG(2)U(2)G(2)), rG2. These G-quadruplexes show CD spectra characteristic of the "chair" conformation (G2 and G2-U), or "basket" conformation (rG2); or a mixture of these two conformers (G3 and G3-U). Thermodynamic profiles show that the favorable folding of each G-quadruplex results from the typical compensation of a favorable enthalpy and unfavorable entropy contributions. G-quadruplex stability increase in the following order (in DeltaG degrees (20)): rG2 (-1.3 kcal/mol) < G2 < G2-U =100 * 10(9)/L, is associated with inferior outcomes following chemotherapy. The prognostic importance of CRp before allogeneic stem cell transplantation (allo SCT) remains unknown. We analyzed a cohort of AML (n = 334) and myelodysplastic syndrome (MDS; n = 10) patients to determine the prognostic significance of achieving CR versus CRp before allo-SCT. At time of transplantation, 266 patients were in CR (CR1 and >=CR2) and 78 in CRp (CR1p and >=CR2p). Median follow-up was 38 months (3-131 months). Overall survival, progression-free survival, and nonrelapse mortality (NRM) were most favorable in patients transplanted in CR (CR1 or >=CR2) compared with CRp (CR1p or >=CR2p). Achieving CR is therefore associated with improved posttransplantation outcomes compared with achieving CRp and is a significant prognostic factor that needs to be considered when evaluating AML/MDS patients for clinical trials and allo-SCT. PMID- 21684344 TI - Selectively T cell-depleted allografts from HLA-matched sibling donors followed by low-dose posttransplantation immunosuppression to improve transplantation outcome in patients with hematologic malignancies. AB - We evaluated a photodepletion technique to selectively deplete host-reacting T cells from human leukocyte antigen (HLA)-matched sibling stem cell transplantations with the goal of reducing posttransplantation immunosuppression to improve antimalignancy effects postallografting. Donor lymphocytes were stimulated with irradiated expanded recipient T lymphocytes in an ex vivo mixed lymphocyte reaction. Alloactivated T cells preferentially retaining the photosensitizer 4,5-dibromorhodamine 123 (TH9402) were eliminated by exposure to visible light. Twenty-four patients with hematologic malignancies (16 high risk) conditioned with fludarabine, cyclophosphamide, and totalbody irradiation received a CD34-selected stem cell allograft from an HLA-matched sibling along with 5 * 10(6)/kg selectively depleted donor T cells. Low-dose cyclosporine was used for posttransplantation immunosuppression. Eleven patients survived at a median of 30 months. Probabilities (+/- SEM) for overall and disease-free survival are 39% +/- 12% and 30% +/- 12%, respectively, whereas grade III-IV acute graft-versus-host disease (aGVHD) was 13% +/- 7%. Six patients relapsed, with a relapse probability of 27% +/- 10%. These results suggest that selectively photodepleted allografts in matched sibling transplantations followed by low-dose immunosuppression may protect against severe aGVHD but is associated with delayed immune recovery. PMID- 21684345 TI - Immune reconstitution in recipients of photodepleted HLA-identical sibling donor stem cell transplantations: T cell subset frequencies predict outcome. AB - We evaluated an ex vivo photodepletion (PD) technique to selectively deplete graft-versus-host disease (GVHD) alloreacting T cells given to 24 human leukocyte antigen (HLA)-identical sibling stem cell transplantation (SCT) recipients. Donor lymphocytes were activated by 72-hour exposure to irradiated in vitro expanded recipient T lymphocytes and pulsed with a TH9402 photosensitizer. Alloactivated T cells preferentially retaining the photosensitizer were eliminated by light exposure. The PD product showed an inverted CD4(+)/CD8(+) ratio with greatest depletion occurring in the CD4(+) naive and central memory populations. In contrast, the CD8(+) naive and effector cells were relatively conserved, reflecting the differential extrusion of TH9402 by T cell subsets. Cytomegalovirus reactive T cells were reduced in the PD product and in recipient blood 100 days after SCT when compared with contemporaneous HLA-identical sibling donor T cell-depleted SCT recipients. Although PD SCT recipients experienced similar absolute lymphocyte counts during the first 100 days after SCT, they achieved 100% donor T cell chimerism more rapidly and had higher CD8(+) naive T cell counts early after SCT. SCT recipients of PD products with the lowest CD4 central memory content had the highest risk of developing chronic GVHD (cGVHD) (P = .04) and a poorer survival (P = .03). Although the persistence of CD8(+) naive T cells may have contributed to important antileukemia responses resulting in a relatively low relapse rate, our findings emphasize the role of donor memory T cells and CD4 cells in establishing immune competence post-SCT. Although PD is associated with excellent outcomes in the haploidentical setting, the low frequency of alloactivations in HLA-matched pairs makes the PD approach used by our group for allodepletion in HLA-matched sibling transplantations an inefficient technique. PMID- 21684346 TI - Increasing free-energy (ATP) conservation in maltose-grown Saccharomyces cerevisiae by expression of a heterologous maltose phosphorylase. AB - Increasing free-energy conservation from the conversion of substrate into product is crucial for further development of many biotechnological processes. In theory, replacing the hydrolysis of disaccharides by a phosphorolytic cleavage reaction provides an opportunity to increase the ATP yield on the disaccharide. To test this concept, we first deleted the native maltose metabolism genes in Saccharomyces cerevisiae. The knockout strain showed no maltose-transport activity and a very low residual maltase activity (0.03 MUmol mg protein(-1)min( 1)). Expression of a maltose phosphorylase gene from Lactobacillus sanfranciscensis and the MAL11 maltose-transporter gene resulted in relatively slow growth (MU(aerobic) 0.09 +/- 0.03 h(-1)). Co-expression of Lactococcus lactis beta-phosphoglucomutase accelerated maltose utilization via this route (MU(aerobic) 0.21 +/- 0.01 h(-1), MU(anaerobic) 0.10 +/- 0.00 h(-1)). Replacing maltose hydrolysis with phosphorolysis increased the anaerobic biomass yield on maltose in anaerobic maltose-limited chemostat cultures by 26%, thus demonstrating the potential of phosphorolysis to improve the free-energy conservation of disaccharide metabolism in industrial microorganisms. PMID- 21684347 TI - Cryptococcus gattii: an emerging fungal pathogen infecting humans and animals. AB - Infectious fungi are among a broad group of microbial pathogens that has and continues to emerge concomitantly due to the global AIDS pandemic as well as an overall increase of patients with compromised immune systems. In addition, many pathogens have been emerging and re-emerging, causing disease in both individuals who have an identifiable immune defect and those who do not. The fungal pathogen Cryptococcus gattii can infect individuals with and without an identifiable immune defect, with a broad geographic range including both endemic areas and emerging outbreak regions. Infections in patients and animals can be severe and often fatal if untreated. We review the molecular epidemiology, population structure, clinical manifestations, and ecological niche of this emerging pathogen. PMID- 21684348 TI - TLR-mediated induction of pro-allergic cytokine IL-33 in ocular mucosal epithelium. AB - Interleukin (IL) 33 has been recently identified as a ligand to the ST2 receptor that mediates Th2-dominant allergic inflammation. The purpose of this study was to explore the role of toll-like receptor (TLR)-mediated innate immunity in IL-33 induction by mucosal epithelium. Human corneal tissues and cultured primary human corneal epithelial cells (HCECs) were treated with a variety of viral or bacterial components without or with different inhibitors to evaluate the IL-33 regulation and signaling pathways. The level of mRNA expression was determined by reverse transcription and real time PCR, and protein was measured by ELISA, immunostaining and Western blotting. IL-33 mRNA and protein were largely induced by various microbial components, mainly by polyI:C and flagellin, the ligands to TLR3 and TLR5, respectively in human corneal epithelium ex vivo and in vitro cultures. Pro-IL-33 protein was normally restricted inside cells, and could be secreted outside when activated by ATP. The PolyI:C induced IL-33 production was blocked by TLR3 antibody or TRIF Inhibitory peptide, while flagellin stimulated IL-33 was blocked by TLR5 antibody or MyD88 Inhibitory peptide. Interestingly, IkappaB-alpha inhibitor (BAY11-7082) or NF-kappaB inhibitor (quinazoline) blocked NF-kappaB p65 protein nuclear translocation, and suppressed IL-33 production induced by PolyI:C and flagellin. These findings demonstrate that IL-33, an epithelium-derived pro-allergic cytokine, is induced by microbial ligands through TLR-mediated innate signaling pathways, suggesting a possible role of mucosal epithelium in Th2-dominant allergic inflammation. PMID- 21684350 TI - MeSHy: Mining unanticipated PubMed information using frequencies of occurrences and concurrences of MeSH terms. AB - MOTIVATION: PubMed is the most widely used database of biomedical literature. To the detriment of the user though, the ranking of the documents retrieved for a query is not content-based, and important semantic information in the form of assigned Medical Subject Headings (MeSH) terms is not readily presented or productively utilized. The motivation behind this work was the discovery of unanticipated information through the appropriate ranking of MeSH term pairs and, indirectly, documents. Such information can be useful in guiding novel research and following promising trends. METHODS: A web-based tool, called MeSHy, was developed implementing a mainly statistical algorithm. The algorithm takes into account the frequencies of occurrences, concurrences, and the semantic similarities of MeSH terms in retrieved PubMed documents to create MeSH term pairs. These are then scored and ranked, focusing on their unexpectedly frequent or infrequent occurrences. RESULTS: MeSHy presents results through an online interactive interface facilitating further manipulation through filtering and sorting. The results themselves include the MeSH term pairs, along with MeSH categories, the score, and document IDs, all of which are hyperlinked for convenience. To highlight the applicability of the tool, we report the findings of an expert in the pharmacology field on querying the molecularly-targeted drug imatinib and nutrition-related flavonoids. To the best of our knowledge, MeSHy is the first publicly available tool able to directly provide such a different perspective on the complex nature of published work. IMPLEMENTATION AND AVAILABILITY: Implemented in Perl and served by Apache2 at http://bat.ina.certh.gr/tools/meshy/ with all major browsers supported. PMID- 21684352 TI - Narrow complex tachycardia with cycle length variability--what is the mechanism? PMID- 21684349 TI - Gene-class analysis of expression patterns induced by psychoactive pharmaceutical exposure in fathead minnow (Pimephales promelas) indicates induction of neuronal systems. AB - Psychoactive pharmaceuticals are among the most frequently prescribed drugs, contributing to persistent measurable concentrations in aquatic systems. Typically, it is assumed that such contaminants have no human health implications because they exist in extremely low concentrations. We exposed juvenile fathead minnows (Pimephales promelas) to three pharmaceuticals, fluoxetine, venlafaxine and carbamazepine, individually and in a mixture, and measured their effect on the induction of gene expression in fish brains using microarray analysis. Gene expression changes were accompanied by behavioral changes and validated by qPCR analysis. Gene Set Enrichment Analysis was used to perform gene-class analysis of gene expression, testing for enrichment of gene sets known to be involved in human neuronal development, regulation and growth. We found significant enrichment of gene sets for each of the treatments, with the largest induction of expression by the mixture treatment. These results suggest that the psychoactive pharmaceuticals are able to alter expression of fish genes associated with development, regulation and differentiation of synapses, neurons and neurotransmitters. The results provide a new perspective for the consideration of potential consequence for human health due to environmental exposure to unmetabolized psychoactive pharmaceuticals. PMID- 21684353 TI - Rationale and design of STOP DVT study: rosuvastatin for the prevention of deep vein thrombosis in patients undergoing total knee replacement arthroplasty--a prospective randomized open-label controlled trial. AB - BACKGROUND: Deep vein thrombosis (DVT) frequently occurs in high-risk cardiovascular patients receiving orthopedic surgery, despite prophylactic measures for its prevention. Statins, a class of drugs used to lower cholesterol levels, have been reported to help prevent the development of DVT. METHODS: We will conduct a prospective randomized clinical trial to compare the effects of high-dose rosuvastatin plus a low-molecular-weight heparin (LMWH), enoxaparin, with conventional LMWH therapy in the prevention of DVT. Patients will be naive to both statins and anti-coagulants and then underwent total knee replacement arthroplasty (TKRA). In total, 180 patients will be randomized into two groups of 90, consisting of a LMWH group (40 mg enoxaparin subcutaneously beginning at 12h prior to surgery and continuing for 7 days every 24h after surgery) and a statin plus LMWH group (20mg rosuvastatin orally for 14 days, 7 days before and after surgery in combination with LMWH). All patients will undergo computed tomography angiography of both extremities 7 days after index surgery to assess the development of DVT. DISCUSSION: DVT remains prevalent despite the use of conventional prophylactic measures, in part because certain patients (particularly the elderly) are unable to receive preventive treatment because of a high risk of bleeding complications and co-morbidity. Statins have been shown to have beneficial effects in arterial atherothrombosis and are frequently administered to elderly patients to treat coronary artery. We hypothesize that peri-operative statin treatment may be beneficial in those patients restricted from the conventional prophylaxis for DVT. PMID- 21684354 TI - Phylogeny of the genus Mycobacterium: many doubts, few certainties. AB - The genus Mycobacterium is characterized by very limited interspecies genetic variability and this makes the definition of a robust phylogeny problematic. In this study a twofold phylogenetic approach was adopted. Phylogenetic trees were constructed using as targets the almost complete 16S rRNA gene sequences and the concatenated amino acid sequences coded by fragments of hsp65 and rpoB genes. The comparison of the results made it possible to identify clusters of species sharing common phylogenetic pathway but for the majority of mycobacteria the definition of a robust phylogeny remained unreached. PMID- 21684355 TI - Atherosclerosis in psoriatic arthritis. AB - The atherosclerotic process is accelerated in several autoimmune rheumatic diseases. Effector cells of innate and adaptive immunity along with pro inflammatory cytokines and other immune mediators are found in atherosclerotic lesions, where they play an important role in induction, progression and rupture of plaques. Psoriatic arthritis (PsA) is a chronic inflammatory disease, characterized by arthritis, enthesitis, dactilytis, osteitis, and axial involvement, along with skin manifestations. PsA is frequently associated with obesity, diabetes, dyslipidemia, hypertension, accelerated atherosclerosis and with increased cardiovascular morbidity and mortality. Disease-specific and traditional risk factors seem to account for the atherosclerotic burden in PsA patients. Some immunological factors which are involved in PsA can also contribute to atherosclerosis including C reactive protein (CRP), TNF-alpha, IFN gamma, IL-1, Il 6, IL23, and Th17. PMID- 21684356 TI - Sternocleidomastoid muscle deoxygenation in response to incremental inspiratory threshold loading measured by near infrared spectroscopy. AB - This study investigated the pattern of changes in muscle oxygenation, deoxygenation and blood volume in the sternocleidomastoid (SCM) in comparison with the parasternal (PS) and intercostal (IC) muscles during a bout of incremental inspiratory threshold loading (ITL) in healthy subjects using near infrared spectroscopy. During progressive loading, the PS and IC showed a significant increase in oxygenated hemoglobin (5.9 +/- 2.3 and 6.8 +/- 2.4 MUM, P<0.05) and the SCM showed an increase in deoxygenated hemoglobin (17.3 +/- 3.8 MUM, P<0.05). Total hemoglobin also steadily increased in the SCM whereas it decreased in the quiescent vastus lateralis muscle (20.7 +/- 6.1MUM vs. -6.6 +/- 2.4 MUM, P<0.05), which was used as the control muscle during the ITL. Our data suggests that the SCM is recruited progressively during progressive ITL and is accompanied by an increased blood volume and maintenance of O(2)Hb. Blood redistribution away from the nonactive limb muscles during the ITL may provide one source of maintaining inspiratory muscle blood volume and oxygenation during high respiratory motor output. PMID- 21684357 TI - Identification of amino acid residues responsible for taurocyamine binding in mitochondrial taurocyamine kinase from Arenicola brasiliensis. AB - In order to investigate the residues associated with binding of the substrate taurocyamine in Arenicola mitochondrial taurocyamine kinase (TK), we performed Ala-scanning of the amino acid sequence HTKTV at positions 67-71 on the GS loop, and determined apparent K(m) and V(max) (appK(m) and appV(max), respectively) of the mutant forms for the substrates taurocyamine and glycocyamine. The appK(m) values for taurocyamine of the K69A, T70A and V71A mutants were significantly increased as compared with wild-type, suggesting that these residues are associated with taurocyamine binding. Of special interest is a property of V71A mutant: its catalytic efficiency for glycocyamine was twice that for taurocyamine, indicating that the V71A mutant acts like a glycocyamine kinase, rather than a TK. The role of the amino acid residue K95 of Arenicola MiTK was also examined. K95 was replaced with R, H, Y, I, A and E. K95R, K95H and K95I have a 3-fold higher affinity for taurocyamine, and activity was largely lost in K95E. On the other hand, the K95Y mutant showed a rather unique feature; namely, an increase in substrate concentration caused a decrease in initial velocity of the reaction (substrate inhibition). This is the first report on the key amino acid residues responsible for taurocyamine binding in mitochondrial TK. PMID- 21684358 TI - 9 Mb familial duplication in chromosome band Xp22.2-22.13 associated with mental retardation, hypotonia and developmental delay, scoliosis, cardiovascular problems and mild dysmorphic facial features. AB - We report on a family with syndromic X-linked mental retardation (XLMR) caused by an Xp22.2-22.13 duplication. This family consists of a carrier mother and daughter and four affected sons, presenting with mental retardation, developmental delay, cardiovascular problems and mild dysmorphic facial features. Female carriers have normal intelligence and some common clinical features, as well as different clinical abnormalities. Cytogenetic analysis of the mother showed an Xp22.2 duplication which was passed to all her offspring. Fluorescence In Situ Hybridization (FISH) using whole chromosome paint and Bacterial Artificial Chromosome (BAC) clones covering Xp22.12-Xp22.3 region, confirmed the X chromosome origin and the size of the duplication. Two different targeted microarray methodologies were used for breakpoint confirmation, resulting in the localization of the duplication to approximately 9.75-18.98 Mb. Detailed description of such rare duplications provides valuable data for the investigation of genetic disease etiology. PMID- 21684359 TI - Changes in gene expression induced by Sp1 knockdown differ from those caused by challenging Sp1 binding to gene promoters. AB - C/G-rich DNA regions, which include those recognized by the Sp1 transcription factor in several gene promoters, also encompass potential binding sites for the DNA-intercalating anthracyclines doxorubicin and WP631. We explored the differences between changes in gene expression caused by the ability of these drugs to compete with Sp1 for binding to DNA and those produced by Sp1 knockdown. By quantitative RT-PCR of around 100 genes, most of them involved in control of cell cycle progression, we found that the treatment of human MDA-MB231 breast carcinoma cells with bis-anthracycline WP631 for 24 h produced a profile of gene down-regulation markedly different from the profile caused by doxorubicin treatment or by stable Sp1 knockdown. These observations are rationalized by considering a near-specific effect of WP631 on Sp1 interaction with several gene promoters, thus representing potential therapeutic targets for WP631, in contrast to a less specific effect of reducing the availability of Sp1 through RNA interference. Genes down-regulated upon each treatment were mapped to their molecular and biological functions, which documented the down-regulation, among other things, of genes involved in mRNA transcription regulation, granting us insights into the effects of challenging the transactivation of gene expression by Sp1. PMID- 21684360 TI - trans-Fatty acids, insulin resistance/diabetes, and cardiovascular disease risk: should policy decisions be based on observational cohort studies, or should we be waiting for results from randomized placebo-controlled trials? PMID- 21684364 TI - A strategic revolution in HIV and global health. PMID- 21684365 TI - Health concerns of adolescents who are in a sexual minority. PMID- 21684361 TI - Ophthalmic manifestations and histopathology of xeroderma pigmentosum: two clinicopathological cases and a review of the literature. AB - Xeroderma pigmentosum is a rare, autosomal recessive disease caused by a defect in DNA repair. Patients with xeroderma pigmentosum often have cutaneous and ocular sun sensitivity, freckle-like skin pigmentation, multiple skin and eye cancers, and, in some patients, progressive neurodegeneration. Xeroderma pigmentosum predominantly affects the ultraviolet (UV) exposed ocular surface, resulting in eyelid atrophy and cancers, corneal dryness, exposure keratopathy, and conjunctival tumors. We report the clinical history and ocular pathology of two white women who had xeroderma pigmentosum with neurological degeneration: Case 1 (died at age 44 years) and Case 2 (died at age 45 years). Case 1, with mutations in the XPA gene, had more than 180 basal cell carcinomas of her skin and eyelids and died from complications of neurodegeneration. Case 2, with mutations in the XPD gene, was sun-protected and had three skin cancers. She died from complications of neurodegeneration and pneumonia. Both patients had bilateral pinguecula, corneal pannus, and exposure keratopathy. Case 1 had bilateral optic atrophy, and Case 2 had bilateral peripheral retinal pigmentary degeneration. Both patients developed retinal gliosis. The ophthalmic manifestations and pathology of xeroderma pigmentosum are discussed and reviewed with respect to this report and other cases in the literature. These cases illustrate the role of DNA repair in protection of the eyes from UV damage and neurodegeneration of the retina. PMID- 21684366 TI - Russia's punitive drug laws. PMID- 21684367 TI - HPV vaccine effect: is the glass half full or half empty? PMID- 21684368 TI - Health initiatives by Indigenous people in Australia. PMID- 21684369 TI - Clinical Series and our clinical content. PMID- 21684371 TI - Leonard Hayflick and the limits of ageing. PMID- 21684372 TI - Belimumab for systemic lupus erythematosus. PMID- 21684374 TI - Belimumab for systemic lupus erythematosus. PMID- 21684375 TI - Milestones in treatment: the tipping point and the ResQ Trial. PMID- 21684376 TI - Milestones in treatment: the tipping point and the ResQ Trial. PMID- 21684378 TI - Facebook use leads to health-care reform in Taiwan. PMID- 21684379 TI - Social networking and health. PMID- 21684380 TI - Social networking and health. PMID- 21684381 TI - Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. AB - BACKGROUND: Australia introduced a human papillomavirus (HPV) vaccination programme with the quadrivalent HPV vaccine for all women aged 12-26 years between 2007 and 2009. We analysed trends in cervical abnormalities in women in Victoria, Australia, before and after introduction of the vaccination programme. METHODS: With data from the Victorian Cervical Cytology Registry between 2003 and 2009, we compared the incidence of histopathologically defined high-grade cervical abnormalities (HGAs, lesions coded as cervical intraepithelial neoplasia of grade 2 or worse or adenocarcinoma in situ; primary outcome) and low-grade cytological abnormalities (LGAs) in five age groups before (Jan 1, 2003, to March 31, 2007) and after (April 1, 2007, to Dec 31, 2009) the vaccination programme began. Binary comparisons between the two periods were done with Fisher's exact test. Poisson piecewise regression analysis was used to compare incident rate trends. FINDINGS: After the introduction of the vaccination programme, we recorded a decrease in the incidence of HGAs by 0.38% (95% CI 0.61-0.16) in girls younger than 18 years. This decrease was progressive and significantly different to the linear trend in incidence before introduction of the vaccination (incident rate ratio 1.14, 1.00-1.30, p=0.05). No similar temporal decline was recorded for LGAs or in older age groups. INTERPRETATION: This is the first report of a decrease in incidence of HGAs within 3 years after the implementation of a population-wide HPV vaccination programme. Linkage between vaccination and screening registers is needed to confirm that this ecological observation is attributable to vaccination and to monitor participation in screening among vaccinated women. FUNDING: None. PMID- 21684382 TI - Osteoarthritis: an update with relevance for clinical practice. AB - Osteoarthritis is thought to be the most prevalent chronic joint disease. The incidence of osteoarthritis is rising because of the ageing population and the epidemic of obesity. Pain and loss of function are the main clinical features that lead to treatment, including non-pharmacological, pharmacological, and surgical approaches. Clinicians recognise that the diagnosis of osteoarthritis is established late in the disease process, maybe too late to expect much help from disease-modifying drugs. Despite efforts over the past decades to develop markers of disease, still-imaging procedures and biochemical marker analyses need to be improved and possibly extended with more specific and sensitive methods to reliably describe disease processes, to diagnose the disease at an early stage, to classify patients according to their prognosis, and to follow the course of disease and treatment effectiveness. In the coming years, a better definition of osteoarthritis is expected by delineating different phenotypes of the disease. Treatment targeted more specifically at these phenotypes might lead to improved outcomes. PMID- 21684383 TI - Spondyloarthritis. AB - Spondyloarthritis is a group of several related but phenotypically distinct disorders: psoriatic arthritis, arthritis related to inflammatory bowel disease, reactive arthritis, a subgroup of juvenile idiopathic arthritis, and ankylosing spondylitis (the prototypic and best studied subtype). The past decade yielded major advances in the recognition of spondyloarthritis as an entity, the classification of the disease, and understanding of the genetic and pathophysiological mechanisms of disease-related inflammation and tissue damage. In parallel, new clinical and imaging outcomes have allowed the assessment of various therapeutic modalities. Blockers of tumour necrosis factor are a major therapeutic advance, but the exact roles of physiotherapy, and treatment with non steroidal anti-inflammatory drugs and other biological treatments are unknown. The major challenges with direct relevance for clinical practice for the next decade are the development of techniques for early diagnosis, therapeutic modulation of structural damage, and, ultimately, induction of long-term, drug free remission. PMID- 21684384 TI - Juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis is a heterogeneous group of diseases characterised by arthritis of unknown origin with onset before age of 16 years. Pivotal studies in the past 5 years have led to substantial progress in various areas, ranging from disease classification to new treatments. Gene expression profiling studies have identified different immune mechanisms in distinct subtypes of the disease, and can help to redefine disease classification criteria. Moreover, immunological studies have shown that systemic juvenile idiopathic arthritis is an acquired autoinflammatory disease, and have led to successful studies of both interleukin 1 and interleukin-6 blockade. In other forms of the disease, synovial inflammation is the consequence of a disturbed balance between proinflammatory effector cells (such as T-helper-17 cells), and anti-inflammatory regulatory cells (such as FOXP3-positive regulatory T cells). Moreover, specific soluble biomarkers (S100 proteins) can guide individual treatment. Altogether these new developments in genetics, immunology, and imaging are instrumental to better define, classify, and treat patients with juvenile idiopathic arthritis. PMID- 21684385 TI - Return of the usual suspect. PMID- 21684386 TI - HIV screening in emergency departments. Introduction. PMID- 21684387 TI - HIV testing in emergency departments in the United States: a national survey. AB - OBJECTIVES: In 2006, the Centers for Disease Control and Prevention (CDC) published recommendations for HIV testing in health care settings, calling for nontargeted opt-out rapid HIV screening in most settings, including emergency departments (EDs). Although a number of ED-based testing strategies exist, it is unclear to what extent they are used. The objective of this study is to survey academic and community EDs throughout the United States to determine ED-based HIV testing practices. METHODS: This was a cross-sectional survey study of all academic EDs and a weighted random sample of all community-based EDs in the United States. A standardized survey instrument was developed and administered with an Internet-based survey platform, followed by direct contact and mail. The survey included domains related to perceived HIV testing barriers, whether HIV testing was performed and methods used, and familiarity with the CDC recommendations and whether they had been adopted. RESULTS: Of the 131 total academic sites and the 435 community sites, 99 (76%) and 150 (35%) completed the survey, respectively. A larger proportion of academic sites believed HIV testing was needed (P=.02) and a larger proportion actually provided HIV testing (65% versus 50%; P=.04). Among the academic and community EDs that provided testing, 74% and 62% performed diagnostic testing, 26% and 22% performed targeted screening, and 16% and 6% performed nontargeted screening, respectively. A larger proportion of academic EDs reported receiving external funding to support testing (23% versus 4%; P=.001), whereas a large proportion of community sites considered costs a significant barrier to testing (P=.03). A larger proportion of academic EDs reported being familiar with the 2006 CDC recommendations (64% versus 40%; P<.001), although only 26% and 37% reported having implemented any part of them, respectively. CONCLUSION: Academic EDs only make up approximately 3% of all EDs in the United States. Significant differences exist between academic and community EDs as they relate to performing HIV testing. Increased efforts should be made to improve the ability of community EDs to provide this service. PMID- 21684388 TI - HIV screening programs in US emergency departments: a cross-site comparison of structure, process, and outcomes. AB - OBJECTIVE: We present findings from a multisite evaluation that systematically compares HIV screening programs in 6 emergency departments (EDs). METHODS: From 2007 to 2008, we collected previous-year data on structural factors, process attributes, testing outcomes, and cost-effectiveness from 6 ED HIV testing programs operating for 6 months or longer. We administered questionnaires to program directors, conducted site visits, and interviewed key informants. RESULTS: HIV care providers (n=3 sites), emergency physicians (n=2), or health departments (n=1) initiated the testing programs. ED leadership and providers helped design and implement the programs (n=5), and emergency physicians or administrators provided daily oversight (n=5). Testing strategies included targeted (patients selected from at-risk populations; n=2), nontargeted (patients selected without regard to risk or intention of testing all; n=3), and universal (all patients selected; n=1) screening. Testing was conducted by supplemental staff (n=4) and existing hospital staff (n=2). ED testing programs were funded by grants (n=3), city HIV prevention/care budgets (n=2), or the hospital (n=1). The median percentage of census tested was 4.7% (range 2.1% to 8.4%). The median rate of preliminary positive test results was 1.2% (range 1.0% to 7.3%). The median confirmed new HIV diagnosis rate was 0.9% (range 0.8% to 6.4%). The median linkage to care rate was 92.0% (range 50% to 100%). The median cost per patient receiving a new diagnosis and linked to care was $10,200 (range $3,400 to $12,300). CONCLUSION: Although structure and process of screening programs varied across EDs, outcomes were similar, which suggests that with current ED environments, testing methods, and resources available, the capacity and structure to increase testing in EDs has limits. These ED HIV screening programs were cost-effective according to standard thresholds. PMID- 21684389 TI - Can computer-based feedback improve emergency department patient uptake of rapid HIV screening? AB - OBJECTIVE: We determine whether (1) an audiocomputer-delivered tailored feedback intervention increases emergency department (ED) patient uptake of opt-in, nontargeted rapid HIV screening; and (2) uptake is greater among patients who report more HIV risk and among those whose self-perceived HIV risk increases from baseline after completion of an HIV risk assessment. METHODS: ED patients aged 18 to 64 years were randomly assigned to receive either an assessment about reported and self-perceived HIV risk or an identical assessment plus feedback about their risk for having or acquiring an HIV infection, tailored according to their reported risk. All participants were offered a fingerstick rapid HIV test. Two sample tests of binomial proportions were used to compare screening uptake by study arm. Multivariable logistic regression was used to assess the relationship of reported HIV risk and an increase in self-perceived HIV risk with uptake of HIV screening. RESULTS: Of the 566 participants, the median age was 29 years, 62.2% were women, and 66.9% previously had been tested for HIV. Uptake of HIV screening was similar in the intervention and no intervention arms (54.1% versus 55.5% [Delta=-0.01%; 95% confidence interval {CI} -0.09% to 0.07%]). An increase in self-perceived HIV risk predicted greater uptake of HIV screening for women (odds ratio 2.15; 95% CI 1.08 to 4.28) but not men (odds ratio 1.61; 95% CI 0.60 to 4.30). Uptake of HIV screening was not related to reported HIV risk. CONCLUSION: Uptake of rapid HIV screening in the ED was not improved by this feedback intervention. Other methods need to be investigated to improve uptake of HIV screening by ED patients. PMID- 21684390 TI - Preliminary program evaluation of emergency department HIV prevention counseling. AB - OBJECTIVE: Controversy surrounds the linkage of prevention counseling with emergency department (ED)-based HIV testing. Further, the effectiveness and feasibility of prevention counseling in the ED setting is unknown. We investigate these issues by conducting a preliminarily exploration of several related aspects of our ED's HIV prevention counseling and testing program. METHODS: Our urban, academic ED provides formal client-centered prevention counseling in conjunction with HIV testing. Five descriptive, exploratory observations were conducted, involving surveys and analysis of electronic medical records and programmatic data focused on (1) patient perception and feasibility of prevention counseling in the ED, (2) patient perceptions of the need to link prevention counseling with testing, and (3) potential effectiveness of providing prevention counseling in conjunction with ED-based HIV testing. RESULTS: Of 110 ED patients surveyed after prevention counseling and testing, 98% believed privacy was adequate, and 97% reported that their questions were answered. Patients stated that counseling would lead to improved health (80%), behavioral changes (72%), follow-up testing (77%), and discussion with partners (74%). However, 89% would accept testing without counseling, 32% were willing to seek counseling elsewhere, and 26% preferred not to receive the counseling. Correct responses to a 16-question knowledge quiz increased by 1.6 after counseling (95% confidence interval 1.3 to 12.0). The program completed counseling for 97% of patients tested; however, 6% of patients had difficulty recalling the encounter and 13% denied received testing. Among patients undergoing repeated testing, there was no consistent change in self-reported risk behaviors. CONCLUSION: Participants in the ED prevention counseling and testing program considered counseling acceptable and useful, though not required. Given adequate resources, prevention counseling can be provided in the ED, but it is unlikely that all patients benefit. PMID- 21684391 TI - Counselor- versus provider-based HIV screening in the emergency department: results from the universal screening for HIV infection in the emergency room (USHER) randomized controlled trial. AB - OBJECTIVE: We compare rates of rapid HIV testing, test offer, and acceptance in an urban emergency department (ED) when conducted by dedicated HIV counselors versus current members of the ED staff. METHODS: The Universal Screening for HIV Infection in the Emergency Room [USHER] trial is a prospective randomized controlled trial that implemented an HIV screening program in the ED of an urban tertiary medical center. ED patients were screened and consented for trial enrollment by an USHER research assistant. Eligible subjects were randomized to rapid HIV testing (oral OraQuick) offered by a dedicated counselor (counselor arm) or by an ED provider (provider arm). In the counselor arm, counselors without other clinical responsibilities-assumed nearly all testing-related activities (consent, counseling, delivery of test results). In the provider arm, trained ED emergency service assistants (nursing assistants) consented and tested the participant in the context of other ED-related responsibilities. In this arm, ED house officers, physician assistants, or attending physicians provided HIV test results to trial participants. Outcome measures were rates of HIV testing and test offer among individuals consenting for study participation. Among individuals offered the test, test acceptance was also measured. RESULTS: From February 2007 through July 2008, 8,187 eligible patients were approached in the ED, and 4,855 (59%) consented and were randomized to trial participation. The mean age was 37 years, 65% were women, and 42% were white. The overall testing rate favored the counselor arm (57% versus 27%; P<.001); 80% (1,959/2,446) of subjects in the counselor arm were offered an HIV test compared with 36% (861/2,409) in the provider arm (P<.001). HIV test acceptance was slightly higher in the provider arm (counselor arm 71% versus provider arm 75%; P = .025). CONCLUSION: Routine rapid HIV testing in the ED was accomplished more frequently by dedicated HIV counselors than by ED staff in the course of routine clinical work. Without dedicated staff, HIV testing in this setting may not be truly routine. PMID- 21684392 TI - Outcomes and cost analysis of 3 operational models for rapid HIV testing services in an academic inner-city emergency department. AB - OBJECTIVE: We compare the outcomes and costs of alternative staffing models for an emergency department (ED) rapid HIV testing program. METHODS: A rapid oral fluid HIV testing program was instituted in an inner-city ED in 2005. Three staffing models were compared during 24.5 months: indigenous medical staff only, exogenous staff only, or exogenous staff plus medical staff (hybrid). Personnel obtained written consent and provided brief pretest counseling, obtained kits, collected specimens, returned specimens to the ED satellite laboratory, and performed posttest counseling and referral to care. Cost analysis was performed to estimate cost per patient tested and cost per patient linked to care. RESULTS: Overall, 44 of 2,958 (1.5%) patients tested received confirmed positive results and 30 (68%) were linked to care. The exogenous staff only model yielded the highest number tested per month (587), and indigenous medical staff only yielded the lowest (57). Significantly higher positivity rates were found in both indigenous medical staff only (2.2%) and hybrid (2.0%) models versus the exogenous staff only model (0.6%) (prevalence rate ratio: 3.7 [95% confidence interval {CI}1.5 to 9.3] versus 3.4 [95% CI 1.5 to 7.8], respectively). All patients with confirmed positive results were linked to care in the indigenous medical staff only model but only approximately 60% were linked to care in the 2 other models (linked to care rate ratio versus exogenous staff only: 1.8 [95% CI 1.1 to 4.4]; versus hybrid: 1.7 [95% CI 1.2 to 2.5]). The indigenous medical staff only model had the highest cost ($109) per patient tested, followed by the hybrid ($87) and the exogenous staff only ($39). However, the indigenous medical staff only model had the lowest cost ($4,937) per patient linked to care, followed by the hybrid ($7,213) and exogenous staff only ($11,454). CONCLUSION: The exogenous staff only model tested the most patients at the least cost per patient tested. The indigenous medical staff only model identified the fewest patients with unrecognized HIV infection and had the highest cost per patient tested but the lowest cost per patient linked to care. PMID- 21684393 TI - Effect of an emergency department HIV testing program on the proportion of emergency department patients who have been tested. AB - OBJECTIVE: The lack of well-described population-level outcome measures for emergency department (ED) HIV testing is one barrier to translation of screening into practice. We demonstrate the impact of an ED diagnostic testing and targeted screening program on the proportion of ED patients ever tested for HIV and explore cumulative effects on testing rates over time. METHODS: Data were extracted from electronic HIV testing program records and administrative hospital databases for January 2003 to December 2008 to obtain the monthly number of ED visits and HIV tests. We calculated the proportions of (1) patients tested in the program who reported a previous HIV test or had been previously tested in the program, and (2) the cumulative number of unique ED patients who were tested in our program. RESULTS: During the study period, 165,665 unique patients made 491,552 ED visits and the program provided 13,509 tests to 11,503 unique patients. From 2003 to 2008, tested patients who reported a history of an HIV test increased by 0.085% per month (95% confidence interval [CI] 0.037% to 0.133%), from 67.7% to 74.4%; the percentage of tested patients who had previous testing in the program increased by 0.277% per month (95% CI 0.245% to 0.308%), from 3.2% to 21.2%; and the percentage of unique ED patients previously tested in the program increased by 0.100% per month (95% CI 0.096% to 0.105%), reaching a cumulative proportion of 6.9%. CONCLUSION: Our HIV testing program increased the proportion of ED patients who have been tested for HIV at least once and repeatedly tested a subset of individuals. HIV screening, even during a minority of ED visits, can have important cumulative effects over time. PMID- 21684394 TI - Cost-effectiveness analysis and HIV screening: the emergency medicine perspective. AB - Cost-effectiveness analysis is a useful tool for decisionmakers charged with prioritizing of the myriad medical interventions in the emergency department (ED). This analytic approach may be especially helpful for ranking programs that are competing for scarce resources while attempting to maximize net health benefits. In this article, we review the health economics literature on HIV screening in EDs and introduce the methods of cost-effectiveness analysis for medical interventions. We specifically describe the incremental cost effectiveness ratio--its calculation, the derivation of ratio components, and the interpretation of these ratios. PMID- 21684396 TI - Rethinking how we perform HIV testing in the emergency department. PMID- 21684397 TI - Assessing the population-level prevention effect of emergency department-based HIV testing in the United States: a research framework and commentary. PMID- 21684395 TI - Public health and clinical impact of increasing emergency department-based HIV testing: perspectives from the 2007 conference of the National Emergency Department HIV Testing Consortium. AB - OBJECTIVE: Understanding perceived benefits and disadvantages of HIV testing in emergency departments (EDs) is imperative to overcoming barriers to implementation. We codify those domains of public health and clinical care most affected by implementing HIV testing in EDs, as determined by expert opinion. METHODS: Opinions were systematically collected from attendees of the 2007 National ED HIV Testing Consortium meeting. Structured evaluation of strengths, weaknesses, opportunities, and threats analysis was conducted to assess the impact of ED-based HIV testing on public health. A modified Delphi method was used to assess the impact of ED-based HIV testing on clinical care from both individual patient and individual provider perspectives. RESULTS: Opinions were provided by 98 experts representing 42 academic and nonacademic institutions. Factors most frequently perceived to affect public health were (strengths) high volume of ED visits and high prevalence of HIV, (weaknesses) undue burden on EDs, (opportunities) reduction of HIV stigma, and (threats) lack of resources in EDs. Diagnostic testing and screening for HIV were considered to have a favorable impact on ED clinical care from both individual patient and individual provider perspectives; however, negative test results were not perceived to have any benefit from the provider's perspective. The need for HIV counseling in the ED was considered to have a negative impact on clinical care from the provider's perspective. CONCLUSION: Experts in ED-based HIV testing perceived expanded ED HIV testing to have beneficial impacts for both the public health and individual clinical care; however, limited resources were frequently cited as a possible impediment. Many issues must be resolved through further study, education, and policy changes if the full potential of HIV testing in EDs is to be realized. PMID- 21684398 TI - Emergency department HIV testing: reflections forward. PMID- 21684400 TI - Processes and models for HIV screening in the emergency department: can and should we do this? PMID- 21684399 TI - Comparison of missed opportunities for earlier HIV diagnosis in 3 geographically proximate emergency departments. AB - OBJECTIVE: Differences in the prevalence of undiagnosed HIV between different types of emergency departments (EDs) are not well understood. We seek to define missed opportunities for HIV diagnosis within 3 geographically proximate EDs serving different patient populations in a single metropolitan area. METHODS: For an urban academic, an urban community, and a suburban community ED located within 10 miles of one another, we reviewed visit records for a cohort of patients who received a new diagnosis of HIV between July 1999 and June 2003. Missed opportunities for earlier HIV diagnosis were defined as ED visits in the year before diagnosis, during which there was no documented ED HIV testing offer or test. Outcomes were the number of missed opportunity visits and the number of patients with a missed opportunity for each ED. We secondarily reviewed medical records for missed opportunity encounters, using an extensive list of indications that might conceivably trigger testing. RESULTS: Among 276 patients with a new HIV diagnosis, 123 (44.5%) visited an ED in the year before diagnosis or received a diagnosis in the ED. The urban academic ED HIV testing program diagnosed 23 (8.3%) cases and offered testing to 24 (8.7%) patients who declined. Missed opportunities occurred during 187 visits made by 76 (27.5%) patients. These included 70 patients with 157 visits at the urban academic ED, 9 patients with 24 visits at the urban community ED, and 4 patients with 6 visits at the suburban community ED. Medical records were available for 172 of the 187 missed opportunity visits. Visits were characterized by the following potential testing indicators: HIV risk factors (58; 34%), related diagnosis indicating risk (7; 4%), AIDS-defining illness (8; 5%), physician suspicion of HIV (29; 17%), and nonspecific signs or symptoms of illness potentially consistent with HIV (126; 73%). CONCLUSION: Geographically proximate EDs differ in their opportunities for earlier HIV diagnosis, but all 3 sites had missed opportunities. Many ED patients with undiagnosed HIV have potential indications for testing documented even in the absence of a dedicated risk assessment, although most of these are nonspecific signs or symptoms of illness that may not be clinically useful selection criteria. PMID- 21684401 TI - Perspective from the NYC Assistant Commissioner of the Department of Health. PMID- 21684402 TI - HIV screening in emergency departments. Editors' introduction. PMID- 21684403 TI - A simple method for estimating the prevalence of undiagnosed HIV infection in an emergency department. AB - OBJECTIVES: Estimating the prevalence of undiagnosed HIV in emergency departments (EDs) is not straightforward. Regional epidemiologic data are unlikely to translate directly to a single ED setting, and the prevalence of undiagnosed HIV likely differs between EDs within a region. We propose a simple method for estimating the prevalence of undiagnosed HIV in individual EDs. METHODS: First, incident cases are grouped by zip codes and combined with census data to calculate zip code-specific case rates. Second, the proportion of ED patients living in each zip code is determined. Third, the prevalence of undiagnosed disease is estimated as the mean zip code case rate, weighted by the proportion of ED patients living in each zip code, multiplied by the estimated time from infection to diagnosis. We applied this method to 3 EDs in a metropolitan region with an annual HIV/AIDS case rate of 6.2 per 100,000. RESULTS: From 1999 through 2003, the annual HIV case rate was estimated to range from 6.4 to 12.7 at an urban academic ED, 5.9 to 10.2 at an urban community ED, and 2.1 to 4.9 at a suburban community ED. The estimated prevalence of undiagnosed disease was 0.05% (urban academic), 0.04% (urban community), and 0.02% (suburban community). CONCLUSION: Publicly reported regional AIDS or HIV statistics do not reflect ED specific HIV epidemiology, but ED-specific case rates can be crudely estimated from readily available data. This method promises to be a valuable aid for translating HIV screening to ED settings. PMID- 21684404 TI - A comparison of patient and staff attitudes about emergency department-based HIV testing in 2 urban hospitals. AB - OBJECTIVE: This study compares and contrasts emergency department (ED) patient and staff attitudes towards ED-based HIV testing in 2 major hospitals in a single city, with an attempt to answer the following: Should routine ED-based HIV testing be offered? If so, who should be responsible for disclosing HIV test results? And what barriers might prevent ED-based HIV testing? METHODS: Paper based surveys were presented to a convenience sample of ED patients and staff at 2 urban, academic, tertiary care hospitals between December 2007 and June 2009. Descriptive statistics were derived with SAS and MicroSoft Excel. Data are reported in percentages, fractions, and graphs. RESULTS: A total of 457 patients and 85 staff completed the surveys. The majority of patients favor ED-based HIV testing. Only a minority of ED staff support ED-based HIV testing. In both hospitals, patients prefer to have HIV test results delivered by a physician. This was true for both positive and negative results. However, only about one third of attending physicians feel comfortable disclosing a positive HIV test result. Patients and staff both view privacy and confidentiality as significant barriers to ED-based HIV testing. CONCLUSION: Although ED patients are overwhelmingly in favor of ED-based HIV testing, the staff is not. Patients and staff agree that physicians should deliver HIV test results to patients, but a significant number of physicians are not comfortable doing so. Historical barriers continue to hinder ED-based HIV testing programs. PMID- 21684405 TI - 2009 US emergency department HIV testing practices. AB - OBJECTIVES: We characterize HIV testing practices and programs in US emergency departments (EDs) in 2009. METHODS: A national Web-based survey of members of the National ED HIV Testing Consortium, participants in the 2007 Centers for Disease Control and Prevention (CDC)-sponsored ED HIV Testing Workshops, all US academic EDs, and a weighted random sample of US community EDs with snowball sampling to recruit additional testing sites was conducted. Data collected included geographic location, estimated seroprevalence, indications for testing, method of consent, weekly number of tests, funding, and costs. RESULTS: Of 619 sites surveyed, 338 (54.6%) responded. A total of 277 (82.0%) reported conducting any HIV testing, and 75 (22.2%) reported systematic HIV testing programs, operationally defined as having testing or screening organized at the departmental or institutional level. systematic HIV testing programs were concentrated in the Northeast, at high-volume urban EDs, and in regions with higher HIV/AIDS prevalence. Most systematic HIV testing programs had existed for less than or equal to 3 years, and nearly one third reported using an opt-out approach for consent. Among systematic HIV testing programs, the number of patients tested ranged from less than 1 to 2,100 tests per week. Overall, universal screening was the most commonly reported screening method reported overall, and rates of HIV positivity were consistently above the CDC threshold of 0.1%. CONCLUSION: The number of EDs conducting HIV testing has grown substantially since release of the 2006 CDC HIV testing recommendations. Although many EDs have systematic HIV testing programs, the majority do not. Ongoing surveillance will be required to quantify the evolution of ED-based HIV testing and the factors that facilitate or impede expanded translation. PMID- 21684406 TI - Ethical, financial, and legal considerations to implementing emergency department HIV screening: a report from the 2007 conference of the National Emergency Department HIV Testing Consortium. AB - OBJECTIVES: We seek to identify and analyze, from a group of participants experienced with HIV screening, the perceived challenges and solutions to the ethical, financial, and legal considerations of emergency department (ED)-based HIV screening. METHODS: We performed a qualitative analysis of the focus group discussions from the ethical, financial, and legal considerations portion of the inaugural National Emergency Department HIV Testing Consortium conference. Four groups composed of 20 to 25 consortium participants engaged in semistructured, facilitated focus group discussions. The focus group discussions were audiotaped and transcribed. A primary reader identified major themes and subthemes and representative quotes from the transcripts and summarized the discussions. Secondary and tertiary readers reviewed the themes, subthemes, and summaries for accuracy. RESULTS: The focus group discussions centered on the following themes. Ethical considerations included appropriateness of HIV screening in the ED and ethics of key elements of the 2006 Centers for Disease Control and Prevention HIV testing recommendations. Financial considerations included models of payment and support, role of health care insurance, financial ethics and downstream financial burdens, and advocacy approaches. Legal considerations included the adequacy of obtaining consent, partner notification, disclosure of HIV results, difficulties in addressing special populations, failure of not performing universal screening, failure to notify a person of being tested, failure to notify someone of their test results, liability of inaccurate tests, and failure to link to care. CONCLUSION: This qualitative analysis provides a broadly useful foundation to the ethical, financial, and legal considerations of implementing HIV screening programs in EDs throughout the United States. PMID- 21684407 TI - Less encouraging lessons from the front lines: barriers to implementation of an emergency department-based HIV screening program. AB - OBJECTIVE: We describe barriers to, and discuss recommendations for, implementing a limited emergency department (ED)-based HIV screening program. METHODS: A pilot program was designed to study the feasibility of integrating HIV screening into ED care among patients aged 18 to 64 years at an urban academic emergency department with an annual census of 50,000 patients. RESULTS: During the first 12 weeks of the pilot program, 395 patients were screened. Of those, 2 (0.5%; 95% confidence interval 0.06% to 1.8%) received a positive test result for HIV. Both were contacted by telephone, and one was seen for result notification, posttest counseling, and further care in the local health department. Of the patients who received a negative test result, 98% were contacted about their results. We encountered numerous barriers to implementation, which we categorized as departmental, public health, legal, institutional, test limitations, and infrastructure. CONCLUSION: Understanding potential barriers and making plans for dealing with them are critical to the successful implementation of an HIV screening program in the ED. PMID- 21684408 TI - Patient satisfaction with rapid HIV testing in the emergency department. AB - OBJECTIVE: Patient satisfaction with HIV screening is crucial for sustainable implementation of the Centers for Disease Control and Prevention (CDC) HIV testing recommendations. This investigation assesses patient satisfaction with rapid HIV testing in the emergency department (ED) of an urban tertiary academic medical center. METHODS: After receiving HIV test results, participants in the Universal Screening for HIV Infection in the Emergency Room (USHER) randomized controlled trial were offered a patient satisfaction survey. Questions concerned overall satisfaction with ED visit, time spent on primary medical problem, time spent on HIV testing, and test provider's ability to answer HIV-related questions. Responses were reported on a 4-point Likert scale, ranging from very dissatisfied to very satisfied (defined as optimal satisfaction). RESULTS: Of 4,860 USHER participants, 2,025 completed testing and were offered the survey: 1,616 (79.8%) completed the survey. Overall, 1,478 (91.5%) were very satisfied. Satisfaction was less than optimal for 34.5% (10 of 29) of participants with reactive results and for 7.5% (115 of 1,542) with nonreactive results. The independent factors associated with less than optimal satisfaction were reactive test result, aged 60 years or older, black race, Hispanic/Latino ethnicity, and testing by ED provider instead of HIV counselor. CONCLUSION: Most participants were very satisfied with the ED-based rapid HIV testing program. Identification of independent factors that correlate with patient satisfaction will help guide best practices as EDs implement CDC recommendations. It is critical to better understand whether patients with reactive results were negatively affected by their results or truly had concerns about the testing process. PMID- 21684409 TI - Physician-initiated rapid HIV testing in an urban emergency department: comparison of testing using a point-of-care versus a laboratory model. AB - STUDY OBJECTIVE: We compare the outcomes of 2 models of physician-initiated rapid HIV testing in an emergency department (ED). METHODS: One-year retrospective cohort comparing 2 6-month models of physician-initiated rapid HIV testing, point of-care versus laboratory. Patients aged 12 years or older and able to give verbal consent were eligible for physician-initiated rapid HIV testing if their treating physician believed testing was clinically indicated. During the point-of care phase, nursing staff performed oral fluid testing. During the laboratory phase, the laboratory performed whole-blood testing. The proportion of potentially eligible patients who had physician-initiated rapid HIV testing ordered (order rate), proportion of ordered tests completed (test completion rate), and proportion of potentially eligible patients who completed testing (overall testing rate) during each phase were assessed. ED length of stay and testing times were also compared. RESULTS: For the point-of-care versus laboratory phase, respectively, there were 24,345 potentially eligible patients versus 26,363; order rate was 3.3% versus 2.4% (P<.001); test completion rate was 75.3% versus 86.8% (P<.001); overall testing rate was 2.5% versus 2.1% (P=.009). Eighteen (3.0%) of the point-of-care-tested patients and 15 (2.7%) of the laboratory-tested patients had reactive tests (P=0.02). The total testing time was greater in the laboratory phase (88 versus 66 minutes; P<.001); however, there was no significant difference in the length of stay between phases (6.2 versus 6.9 hours; P=.15). CONCLUSION: Relatively few ED patients undergo physician-initiated rapid HIV testing regardless of whether a point-of-care or laboratory approach is used. Differences exist in most outcome measures when point-of-care and laboratory models are compared, which should be considered when testing is implemented. PMID- 21684410 TI - Rapid HIV testing in a southeastern emergency department serving a semiurban semirural adolescent and adult population. AB - OBJECTIVE: We determine the feasibility and yield of universal opt-out HIV screening among adolescents and adults in a southeastern emergency department (ED) serving a semiurban-semirural population. METHODS: Individuals aged 13 to 64 years who visited the ED during specified hours received the OraQuick rapid HIV test (administered by trained counselors) if they did not opt out. Western blot was used to confirm reactive results. Patients were excluded if they had a history of HIV, had been tested within the past year, were physically or mentally incapacitated, did not understand their right to opt out, or did not speak English or Spanish. Basic demographic information was analyzed by using standard descriptive statistics. Measures of diagnostic test performance were calculated for all valid tests. RESULTS: From March 2008 through August 2009, 91% (n=8,493) of eligible patients accepted testing, and results were valid. Of 41 reactive results, 35 were confirmed HIV positive, 2 were indeterminate by Western blot, and 4 were false positive. Blacks accounted for the largest percentage (0.65%) of newly detected infections, and the percentage among black men (1%) was more than twice the percentage among black women (0.42%). Rapid-test specificity was estimated at 99.95% (95% confidence interval 99.88% to 99.98%). Nearly 75% of patients confirmed as HIV positive kept their first HIV clinic appointment. CONCLUSION: High rates of acceptance of testing in an ED and linkage to HIV care for adolescents and adults with newly detected infection can be achieved by using opt-out testing and trained HIV counselors. PMID- 21684411 TI - Routine, rapid HIV testing of medicine service admissions in the emergency department. AB - OBJECTIVE: We identify undiagnosed HIV among adult emergency department (ED) patients awaiting medicine admission through rapid testing, expedite their redirection to the inpatient HIV service, and improve linkage to ambulatory HIV care. METHODS: Two ED health educators offered rapid testing to patients aged 18 to 64 years from the high-acuity ED area from which most medicine admissions originate. Heath educators obtained consent, obtained fingerstick blood, and performed point-of-care testing. Patients with reactive results received counseling, confirmatory testing, and appointments at the affiliated HIV clinic. RESULTS: Between March 1, 2008, and February 28, 2009, 4,755 patients received testing. Thirty patients (0.6%) had received a new diagnosis of HIV; 26 were admitted and redirected to the HIV service. Characteristics of HIV positive patients were mean age 38 years, 87% men, 64% black, and 33% Hispanic; 76% had CD4 counts less than 200 cells/mm(3); 67% had HIV-related diagnoses; and 93% reported for ambulatory HIV care in a median of 10 days. During 2 preceding years, these patients had a mean of 3 previous health system visits without testing. During a 6-month quality assurance interval of the 5,340 ED medicine admissions, 31% of patients were eligible for testing, of whom 88% received testing (1% positive) and 12% declined; 29% of the 5,340 were not approached for testing; and 40% were deemed ineligible. Common reasons for ineligibility included older age, recent previous test, and known HIV-positive status. CONCLUSION: Patients who receive a diagnosis of HIV in our ED before admission are extremely ill, most having AIDS. Targeted HIV screening of ED patients awaiting hospital admission facilitated timely diagnosis and reliable linkage to inpatient and outpatient HIV care. PMID- 21684412 TI - The use of a computer reminder system in an emergency department universal HIV screening program. AB - OBJECTIVE: We describe electronic medical record use in automated eligibility determination for an emergency department (ED)-based nontargeted HIV screening program. METHODS: We reviewed the electronic medical record system at an urban, inner-city ED from March 17 to April 14, 2008. During that period, patient eligibility for HIV screening was electronically determined according to preprogrammed criteria: (1) age between 18 and 64 years; (2) no known history of HIV disease; and (3) no known HIV screening in the previous year. This populated an electronic work list used by HIV testing counselors. RESULTS: Of 8,489 ED patients during the study period, the electronic medical record system determined 5,794 (68.3%) as eligible. Of 1,484 (25.6%) patients approached for screening, 1,121 (75.5%) consented, and 5 received confirmed positive results (0.4%). Reasons for ineligibility, as determined by the electronic medical record system, were previous screening 1,125 (41.7%), age 890 (33.0%), known HIV 111 (4.1%), and reason unknown 569 (21.1%). CONCLUSION: Clinical informatics solutions can provide automated delineation of ED subpopulations eligible for HIV screening, according to predetermined criteria, which could increase program efficiency and might accelerate integration of HIV screening into clinical practice. PMID- 21684413 TI - Will patients "opt in" to perform their own rapid HIV test in the emergency department? AB - OBJECTIVE: We evaluate the feasibility and accuracy of existing point-of-care HIV tests performed by an untrained patient compared with the routinely used HIV point-of-care test offered to patients in 2 urban emergency departments (EDs). METHODS: From April 2008 through December 2009, patients who had completed a standard HIV oral fluid test performed by a trained health care professional and who were unaware of their results were recruited to perform a rapid point-of-care HIV test. Patients were given a choice of the oral fluid or the fingerstick blood point-of-care test. Evaluation of acceptability to perform the mechanics of the test was accessed by questionnaire. For the "self-test," the participant obtained his or her own sample and performed the test. The patient's results were compared with standard oral fluid results obtained by the health care professional. RESULTS: Overall, 478 of 564 (85%) patients receiving a standard oral fluid HIV test volunteered, with a mean age of 38 to 39 years. Ninety-one percent of participants chose oral fluid and 9% chose blood (P<.05). Self-test results were 99.6% concordant with health care professionals' test results. For the self testers, 94% of oral fluid testers and 84.4% of blood testers reported trusting the self-administered test result "very much." Furthermore, 95.6% of the oral fluid group and 93.3% of the blood group would "probably" or "definitely" perform a test at home, if available. CONCLUSION: This study demonstrated that a significant proportion of patients offered a self-HIV point-of-care test volunteered and preferred using oral fluid. Patients' results agreed with standard HIV point-of-care results. The majority of participants trusted their results and would perform a point-of-care HIV test at home, given the opportunity. PMID- 21684414 TI - Using nonrapid HIV technology for routine, opt-out HIV screening in a high-volume urban emergency department. AB - OBJECTIVE: We implement an opt-out routine screening program in a high-volume, urban emergency department (ED), using conventional (nonrapid) technology as an alternative to rapid HIV tests. METHODS: We performed a retrospective cohort study. Since October 2008, all patients who visited Ben Taub General Hospital ED and had blood drawn were considered eligible for routine opt-out HIV screening. The hospital is a large, publicly funded, urban, academic hospital in Houston, TX. The ED treats approximately 8,000 patients monthly. Screening was performed with standard chemiluminescence technology, batched hourly. Patients with positive screening test results were informed of their likely status, counseled by a service linkage worker, and offered follow-up care at an HIV primary care clinic. Confirmatory Western blot assays were automatically performed on all new HIV-positive samples. RESULTS: Between October 1, 2008, and April 30, 2009, 14,093 HIV tests were performed and 39 patients (0.3%) opted out. Two hundred sixty-two (1.9%) HIV test results were positive and 80 new diagnoses were made, for an incidence of new diagnoses of 0.6%. There were 22 false-positive chemiluminescence results and 7 indeterminate Western blot results. Nearly half the patients who received a new diagnosis were not successfully linked to HIV care in our system. CONCLUSION: Opt-out screening using standard nonrapid technology, rather than rapid testing, is feasible in a busy urban ED. This method of HIV screening has cost benefits and a low false-positivity rate, but aggressive follow-up and referral of patients with new diagnoses for linkage to care is required. PMID- 21684415 TI - A targeted, conventional assay, emergency department HIV testing program integrated with existing clinical procedures. AB - OBJECTIVE: Various HIV testing models have been described, but widespread implementation has lagged. We describe a clinical HIV testing program notable for its use of conventional (nonrapid) assays, native hospital personnel, and an electronic system to aid targeted patient selection. METHODS: Clinical HIV testing program records and hospital emergency department (ED) and laboratory records were reviewed and linked for the period from January 2007 until November 5, 2008. RESULTS: There were 103,475 visits to the ED, for which 1,258 (1.2%) resulted in HIV testing, and 54 (4.3%) were positive for HIV antibody. Result notification was successful for 52 (96%) individuals with positive test results. After reporting to the health department, it was determined that 28 (2.2%) individuals had received a new diagnosis, of whom 89% were linked with care. Mean baseline CD4 counts for new diagnoses for periods 1 through 3, respectively, were (1) unavailable, (2) 138 cells/MUL (95% confidence interval [CI] 34 to 242 cells/MUL), and (3) 222 cells/MUL (95% CI 119 to 325 cells/MUL). Overall, mean calculated to be 180 cells/MUL (95% CI 16 to 345 cells/MUL). CONCLUSION: This ED HIV testing model successfully expanded new patient identification, result notification, and linkage to care. Although this effort falls short of Centers for Disease Control and Prevention recommendations, the model can be implemented widely without external funding for parallel staffing or rapid assays. PMID- 21684416 TI - HIV screening in an urban emergency department: comparison of screening using an opt-in versus an opt-out approach. AB - OBJECTIVE: We compare outcomes of opt-in and opt-out HIV screening approaches in an urban emergency department. METHODS: This was a 1-year prospective observational study comparing 2 6-month screening approaches. Eligibility for opt in and opt-out screening was identical: aged 15 years or older, medically stable, and able to complete general consent. During the opt-in phase, triage nurses referred patients to HIV testers stationed at triage, who obtained separate opt in written consent and performed rapid oral fluid tests. During the opt-out phase, registration staff conducted integrated opt-out consent and then referred patients to HIV testers. We assessed the proportion of potentially eligible patients who were offered screening (screening offer rate), the proportion offered screening who accepted (screening acceptance rate), the proportion who accepted screening and subsequently completed testing (test completion rate), and the proportion of potentially eligible patients who completed testing (overall screening rate) during each phase. RESULTS: For the opt-in versus the opt-out phases, respectively, there were 23,236 potentially eligible patients versus 26,757, screening offer rate was 27.9% versus 75.8% (P<.001), screening acceptance rate was 62.7% versus 30.9% (P<.001), test completion rate was 99.8% versus 74.6% (P<.001), and overall screening rate was 17.4% versus 17.5% (P = .90). CONCLUSION: A significantly higher proportion of patients were offered HIV screening with an opt-out approach at registration. However, this was offset by much higher screening acceptance and test completion rates with the opt-in approach at triage. Overall screening rates with the 2 approaches were nearly identical. PMID- 21684418 TI - [Massive gastrointestinal bleeding due to gastric ulcer in a patient with amyloidosis]. AB - Gastrointestinal amyloidosis may occur as part of the systemic manifestations of primary amyloidosis or in a localized form. The symptoms and signs that may occur are numerous and nonspecific, hampering clinical suspicion when this disease has not already been diagnosed. Gastric ulcers presenting as massive bleeding are an uncommon manifestation of this disease. We report the case of a patient with primary amyloidosis who developed massive gastrointestinal bleeding complicated by an amyloid gastric ulcer. Emergency surgery was required to control the bleeding. PMID- 21684419 TI - Technology transfer to developing country vaccine manufacturers to improve global influenza vaccine production: a success story and a window into the future. PMID- 21684417 TI - Operational methods of HIV testing in emergency departments: a systematic review. AB - OBJECTIVES: Casual review of existing literature reveals a multitude of individualized approaches to emergency department (ED) HIV testing. Cataloging the operational options of each approach could assist translation by disseminating existing knowledge, endorsing variability as a means to address testing barriers, and laying a foundation for future work in the area of operational models and outcomes investigation. The objective of this study is to provide a detailed account of the various models and operational constructs that have been described for performing HIV testing in EDs. METHODS: Systematic review of PUBMED, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Web of Science through February 6, 2009 was performed. Three investigators independently reviewed all potential abstracts and identified all studies that met the following criteria for inclusion: original research, performance of HIV testing in an ED in the United States, description of operational methods, and reporting of specific testing outcomes. Each study was independently assessed and data from each were abstracted with standardized instruments. Summary and pooled descriptive statistics were reported by using recently published nomenclature and definitions for ED HIV testing. RESULTS: The primary search yielded 947 potential studies, of which 25 (3%) were included in the final analysis. Of the 25 included studies, 13 (52%) reported results using nontargeted screening as the only patient selection method. Most programs reported using voluntary, opt-in consent and separate, signed consent forms. A variety of assays and communication methods were used, but relatively limited outcomes data were reported. CONCLUSION: Currently, limited evidence exists to inform HIV testing practices in EDs. There appears to be recent progression toward the use of rapid assays and nontargeted patient selection methods, with the rate at which reports are published in the peer-reviewed literature increasing. Additional research will be required, including controlled clinical trials, more structured program evaluation, and a focus on an expanded profile of outcome measures, to further improve our understanding of which HIV testing methods are most effective in the ED. PMID- 21684420 TI - Influenza vaccine production for Brazil: a classic example of successful North South bilateral technology transfer. AB - Technology transfer is a promising approach to increase vaccine production at an affordable price in developing countries. In the case of influenza, it is imperative that developing countries acquire the technology to produce pandemic vaccines through the transfer of know-how, as this will be the only way for the majority of these countries to face the huge demand for vaccine created by influenza pandemics. Access to domestically produced influenza vaccine in such health crises is thus an important national defence strategy. However, technology transfer is not a simple undertaking. It requires a committed provider who is willing to transfer a complete production process, and not just the formulation and fill-finish parts of the process. It requires a recipient with established experience in vaccine production for human use and the ability to conduct research into new developments. In addition, the country of the recipient should preferably have sufficient financial resources to support the undertaking, and an internal market for the new vaccine. Technology transfer should create a solid partnership that results in the joint development of new competency, improvements to the product, and to further innovation. The Instituto Butantan-sanofi pasteur partnership can be seen as a model for successful technology transfer and has led to the technological independence of the Instituto Butantan in the use a strategic public health tool. PMID- 21684421 TI - A pandemic influenza vaccine in India: from strain to sale within 12 months. AB - In the event of a highly pathogenic influenza pandemic, the Indian subcontinent would need 1.2 billion doses of vaccine to immunize its entire population, double if two doses were required to assure immunity. Serum Institute of India Limited (SII) thus became one of six initial grantees of the World Health Organization (WHO) technology transfer initiative to create capacity in developing countries to manufacture H5N1 pandemic influenza vaccine. At the outbreak of the A(H1N1) 2009 influenza pandemic, experience gained from the H5N1 project was used to develop a live attenuated influenza vaccine (LAIV), since this was the only option for the level of surge capacity required for a large-scale immunization campaign in India. SII took <12 months to develop and market its LAIV intranasal vaccine from receipt of the seed strain from WHO. As of November 2010, over 2.5 million persons have been vaccinated with Nasovac((r)) with no serious adverse reactions or vaccine failure after 3 months' post-marketing surveillance. The product has been submitted for prequalification by WHO for purchase by United Nations agencies. In parallel, SII also developed an inactivated influenza vaccine, and is currently looking to ensure the sustainability of its influenza vaccine manufacturing capacity. PMID- 21684422 TI - WHO initiative to increase global and equitable access to influenza vaccine in the event of a pandemic: supporting developing country production capacity through technology transfer. AB - Should a highly pathogenic avian influenza virus, such as the H5N1 virus type currently circulating in birds, become transmissible among humans, an effective vaccine, rapidly available in vast quantities, would be the best tool to prevent high case-fatalities and the breakdown of health and social services. The number of vaccine doses that could be produced on demand has risen sharply over the last few years; however, it is still alarmingly short of the 13 billion doses that would be needed if two doses were required to protect fully the world's population. Most developing countries would be last in the queue to benefit from a pandemic vaccine. The World Health Organization, together with governments, the pharmaceutical industry and other stakeholders, has been implementing the global pandemic influenza action plan to increase vaccine supply since 2006. Building capacity in developing countries to manufacture influenza vaccine is an integral part of this plan, as well as research and development into more efficacious technologies, e.g. those that allow significant dose-sparing. To this end, the influenza vaccine technology transfer initiative was launched in 2007 and, to date, vaccine manufacturers in 11 developing countries have received grants to acquire the capacity to produce inactivated or live attenuated influenza vaccine for their populations. In addition, a centralized 'hub' has been established to facilitate training in the new technologies for scientists and regulators in the countries. This supplement of Vaccine is devoted to showcasing the interim results of the WHO initiative and the impressive progress made by the developing country manufacturers. PMID- 21684423 TI - Establishment of pandemic influenza vaccine production capacity at Bio Farma, Indonesia. AB - In Indonesia, avian influenza A(H5N1) virus started to spread in humans in June 2005, with an alarming case-fatality rate of more than 80%. Considering that global influenza vaccine production capacity would barely have covered 10% of the world's pandemic vaccine needs, and that countries with no production facilities or prearranged contracts would be without access to a vaccine, the Government of Indonesia embarked on a programme to increase its readiness for a future influenza pandemic. This included the domestic production of influenza vaccine, which was entrusted to Bio Farma. This health security strategy consists of developing trivalent influenza vaccine production capacity in order to be able to convert immediately to monovalent production of up to 20 million pandemic doses for the Indonesian market upon receipt of the seed strain from the World Health Organization (WHO). For this purpose, a dedicated production facility is being constructed within the Bio Farma premises in Bandung. As an initial stage of influenza vaccine development, imported seasonal influenza bulk has been formulated and filled in the Bio Farma facility. Following three consecutive batches and successful clinical trials, the product was licensed by the Indonesian National Regulatory Authority and distributed commercially for the Hajj programme in 2009. With continued support from its technology transfer partners, Bio Farma is now advancing with the development of upstream processes to produce its own bulk for seasonal and pandemic use. PMID- 21684424 TI - Domestic influenza vaccine production in Mexico: a state-owned and a multinational company working together for public health. AB - The Mexican Government developed a plan in 2004 for pandemic influenza preparedness that included local production of influenza vaccine. To achieve this, an agreement was concluded between Birmex - a state-owned vaccine manufacturer - and sanofi pasteur, a leading developer of vaccine technology. Under this agreement, sanofi pasteur will establish a facility in Mexico to produce antigen for up to 30 million doses of egg-based seasonal vaccine per year, and Birmex will build a facility to formulate, fill and package the inactivated split-virion influenza vaccine. As at November 2010, the sanofi pasteur facility has been completed and the Birmex plant is under construction. Most of the critical equipment has been purchased and is in the process of validation. In addition to intensive support from sanofi pasteur for the transfer of the technology, the project is supported by the Mexican Ministry of Health, complemented by Birmex's own budget and grants from the WHO developing country influenza technology transfer project. PMID- 21684426 TI - Development of pandemic influenza vaccine production capacity in Viet Nam. AB - The Institute of Vaccines and Medical Biologicals (IVAC), a state-owned vaccine manufacturer, initiated research into avian influenza vaccines in the early 1990 s in response to the threat of a highly pathogenic avian influenza pandemic. Successful results from laboratory studies on A(H5N1) influenza virus attracted seed funds and led to participation in the WHO technology transfer project to enhance influenza vaccine production in developing countries. IVAC's goal is to produce 500,000 doses of inactivated monovalent whole-virion influenza vaccine per year by 2012, and progressively increase capacity to more than 1 million doses to protect essential populations in Viet Nam in the event of an influenza pandemic. The WHO seed grants, supplemented by other international partner support, enabled IVAC to build in a very short time an influenza vaccine manufacturing plant under Good Manufacturing Practice and relevant biosafety standards, a waste treatment system and a dedicated chicken farm for high-quality eggs. Much of the equipment and instrumentation required for vaccine production has been installed and tested for functional operation. Staff have been trained on site and at specialized courses which provided comprehensive manuals on egg based manufacturing processes and biosafety. Following process validation, clinical trials will start in 2011 and the first domestic influenza vaccine doses are expected in 2012. PMID- 21684425 TI - Development of influenza vaccine production capacity by the Government Pharmaceutical Organization of Thailand: addressing the threat of an influenza pandemic. AB - In 2005, a year after highly pathogenic avian influenza outbreaks in Thailand, the Thai Government issued a National Strategy Plan for Pandemic Influenza Preparedness, a major objective of which was the domestic production of seasonal influenza vaccine. It was considered that sustained influenza vaccine production was the best guarantee of a pandemic vaccine in the event of a future pandemic. The Government decided to provide funds to establish an industrial-scale influenza vaccine production plant, and gave responsibility for this challenging project to the Government Pharmaceutical Organization (GPO). In 2007, with support from the World Health Organization (WHO), the GPO started to develop egg based, trivalent inactivated influenza vaccine (IIV) in a renovated pilot plant. In early 2009, during the second year of the project, the GPO turned its attention to develop a pandemic live attenuated influenza vaccine (PLAIV) against the influenza A (H1N1) virus. By December 2010, the H1N1 PLAIV had successfully completed Phase II clinical trials and was awaiting registration approval from the Thai Food and Drug Administration (TFDA). The GPO has also started to develop an H5N2 PLAIV, which is expected to enter clinical trials in January 2011. The next step in 2011 will be the development and clinical evaluation of seasonal LAIV. To meet the needs of the national seasonal influenza vaccination programme, the GPO aims to produce 2 million doses of trivalent IIV in 2012 and progressively increase production to the maximum annual capacity of 10 million doses. This article relates how influenza vaccine production capacity was developed and how major challenges are being met in an expeditious manner, with strong local and global commitment. PMID- 21684427 TI - The Vaccine Formulation Laboratory: a platform for access to adjuvants. AB - Adjuvants are increasingly used by the vaccine research and development community, particularly for their ability to enhance immune responses and for their dose-sparing properties. However, they are not readily available to the majority of public sector vaccine research groups, and even those with access to suitable adjuvants may still fail in the development of their vaccines because of lack of knowledge on how to correctly formulate the adjuvants. This shortcoming led the World Health Organization to advocate for the establishment of the Vaccine Formulation Laboratory at the University of Lausanne, Switzerland. The primary mission of the laboratory is to transfer adjuvants and formulation technology free of intellectual property rights to academic institutions, small biotechnology companies and developing countries vaccine manufacturers. In this context, the transfer of an oil-in-water emulsion to Bio Farma, an Indonesian vaccine manufacturer, was initiated to increase domestic pandemic influenza vaccine production capacity as part of the national pandemic influenza preparedness plan. PMID- 21684428 TI - Live attenuated pandemic influenza vaccine: clinical studies on A/17/California/2009/38 (H1N1) and licensing of the Russian-developed technology to WHO for pandemic influenza preparedness in developing countries. AB - In February 2009, Nobilon granted the World Health Organization (WHO) a non exclusive licence to develop, register, manufacture, use and sell seasonal a pandemic live attenuated influenza vaccine (LAIV) produced on embryonated chicken eggs. WHO was permitted to grant sub-licences to vaccine manufacturers in developing countries within the framework of its influenza vaccine technology transfer initiative. In parallel, the Institute of Experimental Medicine (IEM), Russia, concluded an agreement with WHO for the supply of Russian LAIV reassortants for use by these manufacturers. Also in 2009, IEM carried out a study on a novel A/17/California/2009/38 (H1N1) pandemic LAIV candidate derived from the pandemic-related A/California/07/2009 (H1N1) influenza virus and the attenuated A/Leningrad/134/17/57 (H2N2) master donor virus, using routine reassortant technique in embryonated chicken eggs. Following successful preclinical studies in eggs and in ferrets, a double-blind, controlled, randomized clinical trial was carried out in immunologically naive study participants between 12-18 and 18-60 years old. Collectively, the immunogenicity data (haemagglutinin inhibition test, ELISA and cytokine tests for the detection of memory T cells) support the use of a single dose of the pandemic H1N1 LAIV in 12-60 year olds. The outcome of the studies showed no significant adverse reactions attributable to the vaccine, and suggests that the vaccine is as safe and immunogenic as seasonal influenza vaccines. Importantly, it was clearly demonstrated that reliance on the HAI assay alone is not recommended for testing LAIV. To date, via the licence agreement with WHO, the H1N1 LAIV has been transferred to the Government Pharmaceutical Organization in Thailand, the Serum Institute of India, and the Zhejiang Tianyuan Bio-Pharmaceutical Co., Ltd. in China. PMID- 21684429 TI - WHO influenza vaccine technology transfer initiative: role and activities of the Technical Advisory Group. AB - In May 2006, the WHO published a Global Pandemic Influenza Action Plan. A significant part of that plan involves the transfer of technology necessary to build production capacity in developing countries. The WHO influenza technology transfer initiative has been successful. Clearly the relatively small WHO investments made in these companies to develop their own influenza vaccine production facilities have had quite dramatic results. A few companies are already producing large amounts of influenza vaccine. Others will soon follow. Whether they are developing egg-based or planning non-egg based influenza vaccine production, all companies are optimistic that their efforts will come to fruition. PMID- 21684430 TI - United States of America Department of Health and Human Services support for advancing influenza vaccine manufacturing in the developing world. AB - Since 2005, the Government of the United States of America has provided more than US$ 50 million to advance influenza vaccine development in low-resourced countries. This programme has provided a unique opportunity for the US Government to develop a comprehensive view of, and to understand better the challenges and future needs for influenza vaccines in the developing world. The funding for this programme has been primarily through a cooperative agreement with the World Health Organization (WHO) to support directly its capacity-building grants to government-owned or -supported vaccine manufacturers in developing countries. A second cooperative agreement with the Program for Appropriate Technologies in Health (PATH) was initiated to accelerate the completion of a current Good Manufacturing Practice cGMP production facility, along with supporting facilities to obtain a reliable source of eggs, and to conduct clinical trials of influenza vaccine manufactured in Vietnam. This mechanism of utilizing cooperative agreements to support capacity-building for vaccine development in low-resourced settings has been novel and unique and has yielded fruitful returns on minimal investment. The information derived from this programme helps to clarify not only the development challenges for influenza vaccines and how the United States may assist in meeting those challenges, but also other vaccine development issues common to manufacturers in developing countries. While building the initial capacity to produce influenza vaccines can be a straightforward exercise, the sustainability of the enterprise and expansion of subsequent markets will be the key to future usefulness. There is hope for expansion of the global influenza vaccine market. Ongoing burden of disease studies are elucidating the impact of influenza infections, particularly in children, and more countries will take note and respond accordingly, since respiratory diseases are now the number one killer of children under five years of age. In addition to achievements described in this issue of Vaccine, the programme has been successful from the US perspective because the working relationships established between the US Department of Health and Human Services' (HHS) Assistant Secretary for Preparedness and Response Biomedical Advanced Research and Development Authority (BARDA) and its partners have assisted in advancing influenza vaccine development at many different levels. A few examples of BARDA's support include: establishment of egg-based influenza vaccine production from "scratch", enhancement of live attenuated influenza vaccine (LAIV) production techniques and infrastructure, completion of fill/finish operations for imported bulk vaccine, and training in advanced bio manufacturing techniques. These HHS-supported programmes have been well-received internationally, and we and our partners hope the successes will stimulate even more interest within the international community in maximizing global production levels for influenza vaccines. PMID- 21684431 TI - An international technology platform for influenza vaccines. AB - Since 2008, the World Health Organization has provided seed grants to 11 manufacturers in low- and middle-income countries to establish or improve their pandemic influenza vaccine production capacity. To facilitate this ambitious project, an influenza vaccine technology platform (or "hub") was established at the Netherlands Vaccine Institute for training and technology transfer to developing countries. During its first two years of operation, a robust and transferable monovalent pilot process for egg-based inactivated whole virus influenza A vaccine production was established under international Good Manufacturing Practice standards, as well as in-process and release assays. A course curriculum was designed, including a two-volume practical handbook on production and quality control. Four generic hands-on training courses were successfully realized for over 40 employees from 15 developing country manufacturers. Planned extensions to the curriculum include cell-culture based technology for viral vaccine production, split virion influenza production, and generic adjuvant formulation. We conclude that technology transfer through the hub model works well, significantly builds vaccine manufacturing capacity in developing countries, and thereby increases global and equitable access to vaccines of high public health relevance. PMID- 21684432 TI - The 12th "emed Scientific Meeting ESM", Providence (RI), USA, 14 to 17 August 2010. PMID- 21684433 TI - Abdominal pain, a palpable mass, and anemia in a woman treated with long-term dialysis. PMID- 21684434 TI - Urine dipstick to detect trace proteinuria: an underused tool for an underappreciated risk marker. PMID- 21684435 TI - Cardiovascular mortality in the general population versus dialysis: a glass half full or empty? PMID- 21684436 TI - The malnutrition-inflammation score: a valid nutritional tool to assess mortality risk in kidney transplant patients. PMID- 21684437 TI - Clinical and histologic resolution of poststreptococcal glomerulonephritis with large subendothelial deposits and kidney failure. AB - A 16-year-old male adolescent who had fallen and scratched his knee developed cold-like symptoms. Gross hematuria, oliguria, and peripheral edema appeared about 2 weeks after his fall. Tests showed hypocomplementemia, increased antistreptolysin O titers, and severe kidney failure with hematuria/proteinuria. Kidney biopsy showed endocapillary proliferative glomerulonephritis visible using light microscopy and deposits of complement C3 on capillary walls, detectable using immunofluorescence microscopy. Although these findings suggested that he had acute poststreptococcal glomerulonephritis (APSGN), electron microscopy failed to detect subepithelial humps, a feature typical of APSGN; instead, massive electron-dense deposits were visible in the subendothelial space. A second biopsy performed 3 months later showed mesangial cell proliferation without endocapillary proliferation using light microscopy and the disappearance of subendothelial electron-dense deposits in electron micrographs, suggesting that APSGN had resolved. Glomerular deposition of nephritis-associated plasmin receptor, a nephritogenic streptococcal antigen, was observed in the first biopsy specimen, but not the second. The patient required 4 hemodialysis treatments, and within 1 year of supportive therapy only, kidney function and urinalysis had normalized. This is an interesting case of APSGN presenting with acute kidney injury and atypical massive subendothelial deposits, but no subepithelial deposits on electron microscopy, a pattern resembling that in membranoproliferative glomerulonephritis type I. PMID- 21684438 TI - Human cytomegalovirus and kidney transplantation: a clinician's update. AB - Infection with human cytomegalovirus (CMV) is an important cause of morbidity and mortality in kidney transplant recipients. CMV disease is diagnosed based on the detection of viral replication by phosphoprotein 65 antigenemia or CMV DNA polymerase chain reaction in combination with typical signs and symptoms. Risk factors include CMV-seronegative recipients receiving a CMV-seropositive transplant, older donor age, exposure to cyclosporine and/or antilymphocyte antibody, rejection episodes, and impaired transplant function. Current preventive strategies in kidney transplant recipients include pre-emptive therapy with valganciclovir or intravenous ganciclovir and universal prophylaxis with valacyclovir, valganciclovir, or ganciclovir for 3-6 months after kidney transplantation and for 1-3 months after treatment with antilymphocyte antibody. Established disease should be treated using either intravenous ganciclovir or oral valganciclovir until CMV replication can no longer be detected. In addition to direct effects, CMV infection also induces a wide range of indirect effects, such as decreased transplant and recipient survival and susceptibility to rejection and opportunistic infections. In this review, we highlight the most relevant topics on CMV and kidney transplantation based on current evidence and guidelines. PMID- 21684439 TI - Early nephrologic consultation after acute kidney injury. PMID- 21684440 TI - Was it the nephrologists or the fluid? PMID- 21684442 TI - Science, not politics, delivers wisdom. PMID- 21684443 TI - Re: Evidence-based oral and maxillofacial surgery: some pitfalls and limitations. PMID- 21684445 TI - Rubber dam clamp trauma, root canal therapy, and osteonecrosis of the jaw. PMID- 21684446 TI - Re: Survey of faculty educator development award recipients. PMID- 21684449 TI - Re: Sagittal split genioplasty: a new technique. PMID- 21684450 TI - Use of colostomy bag in maxillofacial surgery. PMID- 21684451 TI - Outcome study of computer-aided surgical simulation in the treatment of patients with craniomaxillofacial deformities. AB - PURPOSE: The purpose of this study was to determine whether the surgical outcomes achieved with computer-aided surgical simulation (CASS) are better than those achieved with traditional methods. MATERIALS AND METHODS: Twelve consecutive patients with craniomaxillofacial (CMF) deformities were enrolled. According to the CASS clinical protocol, a 3-dimensional computer composite skull model for each patient was generated and reoriented to the neutral head posture. These models underwent 2 virtual surgeries: 1 was based on CASS (experimental group) and the other was based on traditional methods 1 year later (control group). Once the 2 virtual surgeries were completed, 2 experienced oral and maxillofacial surgeons at 2 different settings evaluated the 2 surgical outcomes. They were blinded to the planning method used on the virtual models and each other's evaluation results. The primary outcome was overall CMF skeletal harmony. The secondary outcomes were individual maxillary, mandibular, and chin harmonies. Statistical analyses were performed. RESULTS: Overall CMF skeletal harmony achieved with CASS was statistically significantly better than that achieved with traditional methods. In addition, the maxillary and mandibular surgical outcomes achieved with CASS were significantly better. Furthermore, although not included in the statistical model, the chin symmetry achieved by CASS tended to be better. A regression model was established between mandibular symmetry and overall CMF skeletal harmony. CONCLUSION: The surgical outcomes achieved with CASS are significantly better than those achieved with traditional planning methods. In addition, CASS enables the surgeon to better correct maxillary yaw deformity, better place proximal/distal segments, and better restore mandibular symmetry. The critical step in achieving better overall CMF skeletal harmony is to restore mandibular symmetry. PMID- 21684452 TI - Multiview fusion 3-D echocardiography: improving the information and quality of real-time 3-D echocardiography. AB - The advent of real-time 3-D echocardiography (RT3DE) promised dynamic 3-D image acquisition with the potential of a more objective and complete functional analysis. In spite of that, 2-D echocardiography remains the backbone of echocardiography imaging in current clinical practice, with RT3DE mainly used for clinical research. The uptake of RT3DE has been slow because of missing anatomic information, limited field-of-view (FOV) and tedious analysis procedures. This paper presents multiview fusion 3D echocardiography, where multiple images with complementary information are acquired from different probe positions. These multiple images are subsequently aligned and fused together for preserving salient structures in a single, multiview fused image. A novel and simple wavelet based fusion algorithm is proposed that exploits the low- and high-frequency separation capability of the wavelet analysis. The results obtained show that the proposed multiview fusion considerably improves the contrast (31.1%), contrast-to noise ratio (46.7%), signal-to-noise ratio (44.7%) and anatomic features (12%) in 3-D echocardiography, and enlarges the FOV (28.2%). This indicates that multiview fusion substantially enhances the image quality and information. PMID- 21684453 TI - Premature cardiac contractions produced efficiently by external high-intensity focused ultrasound. AB - Exposure of myocardium to a mechanical impact may produce premature ventricular contractions (PVCs). High-intensity focused ultrasound was reported to generate PVCs, while microbubbles at the target increased absorption, thus, promoting energy localization and decreased PVC threshold. The objective was to investigate the benefit of a two-stage ultrasonic transmission: (1) asymmetric mostly negative waveform at the focus (microbubbles generation) and (2) asymmetric mostly positive waveform at the microbubbles (impact generation). Optimization of transmission parameters was performed by measuring passive cavitation and attenuation. In vivo intact rat studies were performed while measuring electrocardiograph (ECG) and blood pressure. Most PVCs with blood injection were created while applying 3.06 MPa peak negative pressure during 1 ms, followed by 5.1 MPa peak positive pressure during 50 ms. Increasing the second stage from 5 ms to 50 ms increased the occurrence of PVCs. This study demonstrates that creation of localized microbubble population at the target promotes generation of PVCs without the need to inject contrast agents. PMID- 21684454 TI - An adaptive spectral estimation technique to detect cavitation in HIFU with high spatial resolution. AB - In ultrasound-guided high-intensity focused ultrasound (HIFU) therapy, the changes observed on tissue are subtle during treatment; some ultrasound-guided HIFU protocols rely on the observation of significant brightness changes as the indicator of tissue lesions. The occurrence of a distinct hyperechogenic region ("bright-up") around the focus is often associated with acoustic cavitation resulting in microbubble formation, but it may indicate different physical events such as larger bubbles from boiling (known to alter acoustic impedance) or sometimes lesion formation. A reliable method to distinguish and spatially localize these causes within the tissue would assist the control of HIFU delivery, which is the subject of this paper. Spectral analysis of the radio frequency (RF) signal underlying the B-mode image provides more information on the physical cause, but the usual techniques that are methods on the Fourier transform require a long series for good spectral resolution and so they give poor spatial resolution. This paper introduces an active spectral cavitation detection method to attain high spatial resolution (0.15 * 0.15 mm per pixel) through a parametric statistical method (ARMA modeling) used on finite-length data sets, which enables local changes to be identified more easily. This technique uses the characteristics of the signal itself to optimize the model parameters and structure. Its performance is assessed using synthesized cavitation RF data, and it is then demonstrated in ex vivo bovine liver during and after HIFU exposure. The results suggest that good spatial and spectral resolution can be obtained by the design of suitable algorithms. In ultrasound guided HIFU, the technique provides a useful supplement to B-mode analysis, with no additional time penalty in data acquisition. PMID- 21684455 TI - ECNP Summit on the future of CNS drug research in Europe 2011: report prepared for ECNP by David Nutt and Guy Goodwin. PMID- 21684457 TI - Pancreaticobiliary and gastrointestinal stents. PMID- 21684458 TI - Expandable metal stents: principles and tissue responses. AB - Expandable stents are widely used in gastroenterology. The basic principle of all of these devices is that they can be constrained onto a delivery system of small diameter and then deployed in an area of stenosis without the risk of complications due to excessive dilation. Understanding tissue responses to stents is important both for the design of new stents and for clinicians to balance the benefits and risks of covered and uncovered stents. With biodegradable stents and removable stents, understanding tissue responses provides the basis for timing of removal and assessing treatment response. PMID- 21684459 TI - Expandable stents for benign esophageal disease. AB - Partially covered self-expandable esophageal stents have been associated with unacceptable complications when used for benign esophageal disorders. With the introduction of removable or potentially removable fully covered stents and biodegradable stents, interest in using expandable stents for benign indications has been revived. Although expandable stents can offer a minimally invasive alternative to surgery, they can be associated with serious complications; hence, this approach should be considered in carefully selected patients, preferably on a protocol basis. PMID- 21684460 TI - Expandable stents for malignant esophageal disease. AB - Esophageal cancer is diagnosed in about 400,000 patients each year worldwide, and its incidence is increasing faster than that of any other malignancy. This makes it the ninth most common malignancy and sixth on the list of cancer mortality causes. Most patients with esophageal cancer present at a stage that is too advanced for curative therapy, and many die within a few months. Treatment of dysphagia is the main goal of palliative care in more than 50% of incurable cases. Although many different palliative options for malignant dysphagia are available, expandable stent placement is the most commonly performed treatment modality. PMID- 21684461 TI - Enteral stents for malignant gastric outlet obstruction. AB - Malignant gastric outlet obstruction (GOO) is a commonly encountered entity, defined as the inability of the stomach to empty because of mechanical obstruction at the level of either the stomach or the proximal small bowel. In this article, current literature on GOO is reviewed with a focus on enteral stents to include symptoms and diagnosis, stent and nonstent treatment, types of enteral stents, indications and contraindications to stent placement, and technical and clinical success rates. In comparison with gastrojejunostomy, enteral stent placement is better suited for patients with a shorter life expectancy and/or those who are poor surgical candidates. PMID- 21684462 TI - Plastic biliary stents for benign biliary diseases. AB - Biliary plastic stenting plays a key role in the endoscopic management of benign biliary diseases. Complications following surgery of the biliary tract and liver transplantation are amenable to endoscopic treatment by plastic stenting. Insertion of an increasing number of plastic stents is currently the method of choice to treat postoperative biliary strictures. Benign biliary strictures secondary to chronic pancreatitis or primary sclerosing cholangitis may benefit from plastic stenting in select cases. There is a role for plastic stent placement in nonoperative candidates with acute cholecystitis and in patients with irretrievable bile duct stones. PMID- 21684463 TI - Plastic biliary stents for malignant biliary diseases. AB - Plastic biliary endoprostheses have not changed much since their introduction more than 3 decades ago. Although their use has been challenged by the introduction of metal stents, plastic stents still remain commonly used. Much work has been done to improve the problem of stent obstruction but without substantial clinical success. In this review, the authors discuss the history of plastic biliary stent development and the current use of plastic stents for malignant biliary diseases. PMID- 21684464 TI - Expandable metal stents for benign biliary disease. AB - Benign biliary diseases include benign biliary strictures (BBS), choledocholithiasis, and leaks. BBS encompass postoperative injury, anastomotic stricture, chronic pancreatitis, primary sclerosing cholangitis, and gallstone related stricture. Therapeutic options for benign biliary diseases include surgical, percutaneous, and endoscopic interventions. Endoscopic options include placement of plastic stents as well as self-expanding metal stents (SEMS). SEMS can be uncovered, partially covered, and fully covered, and have been used with some success in resolution of strictures and leaks; however, complications limit their use. This article reviews the currently published experience on SEMS and attempts to define their current role in the treatment of benign biliary diseases. PMID- 21684465 TI - Self-expandable metal stents for malignant distal biliary strictures. AB - Obstructive jaundice can result from benign or malignant etiologies. The common benign conditions include primary sclerosing cholangitis, chronic pancreatitis, and gallstones. Malignant biliary obstruction can be caused by direct tumor infiltration, extrinsic compression by enlarged lymph nodes or malignant lesions, adjacent inflammation, desmoplastic reaction from a tumor, or a combination of these factors. Malignant diseases causing biliary obstruction include pancreatic cancer, ampullary cancer, cholangiocarcinoma, and metastatic diseases. This article focuses on malignant distal biliary obstruction and its management. PMID- 21684466 TI - Expandable metal stents for malignant hilar biliary obstruction. AB - Most patients with malignant hilar stenoses are candidates for palliation. For this purpose, biliary drainage plays a major role in improving liver function and managing or avoiding cholangitis. Endoscopic interventions are less invasive than the percutaneous approach and should be considered as the first-line drainage procedures in most cases. Transhepatic interventions should be reserved for endoscopic failures or performed as a complementary approach in a combined procedure. After successful endoscopic access to biliary obstruction, implantation of self-expandable metal stents offers advantages over plastic endoprostheses in terms of stent patency and number of reinterventions. PMID- 21684467 TI - Pancreatic stents. AB - Use of stents in the pancreas has been confined and limited to referral centers that specialize in the treatment of patients with severe pancreatitis and acute relapsing pancreatitis. With therapeutic development in endoscopic treatment of pancreatic diseases and a better understanding of the cause and prevention of ERCP related complications, the use of stents has been extended to transmural drainage of pancreatic fluid collection or of pancreatic ducts has well as to prophylaxis of post-ERCP pancreatitis. As a result, indication for pancreatic stenting and the kind of stents to be used as well as the followup after placement varies. This article reviews the major indication for pancreatic stent placement and focuses on the choice of stent, technique of implantation and followup. PMID- 21684468 TI - Expandable metal stents for malignant colorectal strictures. AB - The surgical management of malignant colorectal obstruction is still controversial and has higher associated mortality and complication rates compared with elective surgery. Placement of self-expanding metallic stents (SEMS) has been proposed as an alternative therapeutic approach for colonic decompression of patients with acute malignant obstruction. SEMS placement may be used both as a bridge to surgery in patients who are good candidates for curative resection and for palliation of those patients presenting with advanced stage disease or with severe comorbid medical illnesses. PMID- 21684469 TI - Expandable stents: unique devices and clinical uses. AB - The use of stents throughout the gastrointestinal tract has evolved over the past century. The evolution of endoscopic ultrasound and significant improvements in stent design are key factors that have allowed endoscopists to drive the use of stents in gastroenterology into new directions. Endoscopic creativity remains crucial in the evolution of any new endoscopic technology. Finally, the use of multidisciplinary teams, including endoscopists, radiologists, and surgeons, allows for the exchange of ideas and procedural planning necessary for successful innovation. PMID- 21684470 TI - Foreword. Fetal origins of adult disease. PMID- 21684473 TI - Building up a research pipeline in gastroenterology. PMID- 21684474 TI - Screening for minimal hepatic encephalopathy in asymptomatic drivers with liver cirrhosis. AB - BACKGROUND AND STUDY AIMS: Minimal hepatic encephalopathy (MHE) represents a part of the spectrum of hepatic encephalopathy (HE). It can have a far-reaching impact on quality and ability to function in daily life and may progress to overt HE. This study was designed to screen for MHE in drivers with liver cirrhosis in Mansoura, a city in the Nile delta in Egypt. PATIENTS AND METHODS: A total of 174 consecutive drivers with positive serology for viral markers and cirrhosis were screened for MHE. Questionnaires and standard psychometric tests and well informed consent were performed at the same setting. The diagnosis of MHE was made when one or both symbol digit test (SDT) and number connection test (NCT) appeared abnormal. Beck's inventory and Mini Mental State Examination questionnaires were performed for those diagnosed as MHE. After overnight fasting, venous blood samples were taken for haematologic tests and routine liver function tests by conventional methods. Arterial ammonia was also measured. RESULTS: A total of 66 patients showed evidence for MHE out of 139 patients who fulfilled the inclusion criteria. No significant differences were present, apart from a significantly elevated arterial ammonia level (p-value <0.001) and a bad self-reported driving history (p<0.05) in the MHE-positive group when compared with the MHE-negative group. Multivariate logistic regression revealed that advanced Child-Pugh grade (p<0.001), hepatitis B virus (HBV)-related aetiology (p<0.001) and smoking are significant risk factors for MHE. MHE is significantly commoner among Child-Pugh C patients (p<0.05) when compared with the other Child Pugh grades. CONCLUSION: Our data revealed a high prevalence of MHE (47%) among Egyptian drivers with liver cirrhosis. It is hence recommended to include the driving history as well as regular pencil-paper standard psychometric testing in evaluating those at risk, especially in the outpatient setting, for early detection and proper management. PMID- 21684475 TI - Can serum fibrosis markers predict medium/large oesophageal varices in patients with liver cirrhosis? AB - BACKGROUND AND STUDY AIMS: Non-invasive predictors of medium/large oesophageal varices (LOVs) could reduce the number of screening endoscopies. As portal hypertension is a consequence of liver fibrosis, serum fibrosis markers were evaluated together with other variables as possible non-invasive predictors of medium OV/LOV. PATIENTS AND METHODS: A total of 154 cirrhotic patients with splenomegaly and 30 healthy control subjects were recruited in a prospective study in two gastroenterology centres in Upper Egypt. Clinical parameters assessed included Child-Pugh class, liver size and ascites. Laboratory parameters included complete blood count, liver function tests, and aspartate aminotransferase (AST)/platelet ratio. Transforming growth factor-beta(1) (TGF beta(1)), alpha(2) macroglobulin (A(2)M) and hyaluronic acid (HA) were assayed. Ultrasonographic examination was done for assessment of liver span, portal vein diameter and detection of minimal ascites. Oesophageal varices were diagnosed and graded by oesophagogastroduodenoscopy. RESULTS: Fifty-four patients (35%) had no or small varices and 100 (65%) patients had medium OV/LOV by endoscopy. On multivariate analysis, the independent predictors of medium OV/LOV were the presence of ascites (beta=0.258, p=0.047) and serum HA (beta=0.449, p=0.009). The receiver operating characteristic curve for HA showed the area under the curve to be 0.916. The sensitivity, specificity, positive and negative predictive values and diagnostic accuracy of HA at a cut-off value of 207MUgl(-1) were 94%, 77.8%, 88.7%, 87.5% and 88.3%, respectively. CONCLUSIONS: The presence of ascites and serum HA level higher than 207MUgl(-1) can predict the presence of medium OV/LOV in cirrhotic patients. This would help physicians to identify patients who would most likely benefit from screening endoscopy and thus, reduce costs and discomfort from unnecessary endoscopic procedures. PMID- 21684471 TI - Fetal origins of adult disease. AB - Dr. David Barker first popularized the concept of fetal origins of adult disease (FOAD). Since its inception, FOAD has received considerable attention. The FOAD hypothesis holds that events during early development have a profound impact on one's risk for development of future adult disease. Low birth weight, a surrogate marker of poor fetal growth and nutrition, is linked to coronary artery disease, hypertension, obesity, and insulin resistance. Clues originally arose from large 20th century, European birth registries. Today, large, diverse human cohorts and various animal models have extensively replicated these original observations. This review focuses on the pathogenesis related to FOAD and examines Dr. David Barker's landmark studies, along with additional human and animal model data. Implications of the FOAD extend beyond the low birth weight population and include babies exposed to stress, both nutritional and nonnutritional, during different critical periods of development, which ultimately result in a disease state. By understanding FOAD, health care professionals and policy makers will make this issue a high health care priority and implement preventive measures and treatment for those at higher risk for chronic diseases. PMID- 21684476 TI - Fibrosis severity and mannan-binding lectin (MBL)/MBL-associated serine protease 1 (MASP-1) complex in HCV-infected patients. AB - BACKGROUND AND STUDY AIMS: Mannan-binding lectin (MBL) is a collectin synthesised in the liver and secreted into the bloodstream. It binds micro-organisms via interactions with glycans on the target surface. Bound MBL subsequently activates MBL-associated serine protease proenzymes (MASPs). Several studies have investigated the possible role for MBL in hepatitis C virus (HCV) infection by examining MBL levels and polymorphisms in relation to disease progression and in response to treatment. The aim of this study was to investigate the relation of the activity of MBL and MBL/MASP-1 complex in sera of patients with mild and severe chronic HCV infection and outcome of HCV infection. PATIENTS AND METHODS: Serum level of MBL and functional assays for MBL/MASP-1 complex activity were assayed in sera of 80 patients with chronic HCV infection. Patients were divided into two groups according to the results of the liver biopsy, group I (40 HCV patients had mild hepatic fibrosis, Ishak fibrosis stages 0-1) and group II (40 HCV patients had severe hepatic fibrosis, Ishak fibrosis stages 5-6), in addition to 20 control subjects as group III. The analysis of the MBL/MASP-1 complex activity at 0, 3 and 6 months was performed in all patients. RESULTS: Serum levels of MBL and MBL/MASP-1 complex activity were higher in sera of patients with chronic HCV liver disease compared to those in control subjects. There was a correlation between the activity of the MBL/MASP-1 complex and the severity of fibrosis (P=0.003). MBL/MASP-1 complex activity was associated more significantly with severe fibrosis in comparison to MBL concentration. CONCLUSION: MBL and MBL/MASP-1 complex activities play a key role in first-line host defence mechanism against certain infectious agents including HCV infection. However, it is also likely that the role of MBL and MBL/MASP-1 complex activity extends beyond this restricted infection-related view in that it appears to be a key regulator of inflammation. PMID- 21684477 TI - Fibro-alpha score as a simple and useful non-invasive test for predicting significant liver fibrosis in chronic hepatitis C patients. AB - BACKGROUND AND STUDY AIMS: Non-invasive methods for the assessment of liver fibrosis are clinically important where hepatitis C virus (HCV) is common in Egypt. Our aim was to evaluate the diagnostic performance of a panel of simple blood markers of liver fibrosis in chronic hepatitis C (CHC) patients. PATIENTS AND METHODS: A total of 199 patients with CHC evaluated for eligibility for antiviral therapy were included. Liver biochemical profile including transaminases, bilirubin, alkaline phosphatase, serum albumin, complete blood count prothrombin time and AFP were estimated. Liver biopsy was done. Statistical analyses were performed by logistic regression and receiver operating characteristic (ROC) curves to assess and compare diagnostic accuracy of blood markers. A stepwise combination algorithm was developed and validated prospectively in 135 additional patients. RESULTS: alpha-Foetoprotein (AFP) was the most efficient marker among other markers tested. The areas under the curves (AUCs) of AFP were 0.77 for significant liver fibrosis (F2-F4), 0.75 for advanced liver fibrosis (F3-F4) and 0.76 for liver cirrhosis (F4). The stepwise multivariate discriminant analysis (MDA) selected a novel non-invasive index for discriminating patients with significant liver fibrosis, named Fibro-alpha score. Fibro-alpha score=(1.35 (numeric constant) +AFP (IUml(-1))*0.009584+aspartate aminotransferase (AST)/alanine aminotransferase (ALT)*0.243-platelet count (*10(9)l(-1))*0.001624). The Fibro-alpha score was used for patients with advanced liver fibrosis and liver cirrhosis. The AUCs of Fibro-alpha score were 0.82 for patients with advanced liver fibrosis and 0.80 for those with cirrhosis. These results were reproduced in a validation study with no significant difference. CONCLUSION: While liver biopsy is invasive, expensive and, in some settings, impossible to do, Fibro-alpha score is simple, cheap, non-invasive and may be useful for predicting significant liver fibrosis. PMID- 21684478 TI - Paraoxonase-1 activity, malondialdehyde and glutathione peroxidase in non alcoholic fatty liver disease and the effect of atorvastatin. AB - BACKGROUND AND STUDY AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) appears to be increasing. The aim of the present study was to investigate the relationship between hepatic antioxidant paraoxonase 1 (PON1) activity, lipid peroxidation and antioxidant enzymes in patients with NAFLD and the effect of atorvastatin. PATIENTS AND METHODS: This study was conducted on 50 patients with NAFLD and 20 normal subjects matched for age and sex. All of them were subjected to the following investigations: abdominal ultrasonography, serum PON1 activity level, liver function tests, serum lipid profile, fasting and postprandial blood glucose and serum levels of malondialdehyde (MDA) and glutathione peroxidase (GP). NAFLD patients were further randomly classified into two groups (25 patients each), groups Ia and Ib. Only group Ia received atorvastatin 40mg tablet for 8months. RESULTS: Obesity, dyslipidaemia and impaired glucose tolerance were prevalent in group I. There was a significant decrease in serum PON1 activity with a significant increase in MDA and GP activity (i.e., there is a significant increase in lipid peroxidation rate) in group I compared with group II. After atorvastatin therapy, there was a significant increase in serum PNO1 activity and significant decrease in serum MDA levels. CONCLUSION: Patients with NAFLD show enhanced oxidative stress which may lead to non-alcoholic steatohepatitis (NASH). Reduced PON1 activity and increased MDA could be considered a biochemical marker for lipid peroxidation, which require follow-up in patients with NAFLD. Atorvastatin may have a role in prevention of, or delay, the transformation of liver steatosis into NASH. PMID- 21684479 TI - Economic burden of gastro-oesophageal reflux disease and dyspepsia: A community based study. AB - BACKGROUND AND STUDY AIMS: Gastro-oesophageal reflux disease (GERD) and dyspepsia are common digestive disorders that inflict serious harm, burden and economic consequences on individuals worldwide. The aim of this study was to estimate the direct and indirect economic burden of GERD and dyspepsia in the whole population of Tehran, the capital of Iran. PATIENTS AND METHODS: The study was performed on a total of 18,180 adult subjects (age>18 years) taken as a random sample in Tehran province, Iran (2006-2007). A valid and reliable questionnaire was used to enquire about the symptoms of GERD, dyspepsia and the frequency of the utilization of health services including physician visits, hospitalisations and productivity loss due to GERD/dyspepsia symptoms in the preceding 6 months. RESULTS: GERD was found in 518 (41.9% males) patients and dyspepsia in 404 patients (38.9% males). Further 1007 subjects had both GERD and dyspepsia. The total direct costs of disease per patient for GERD, dyspepsia and their overlap were PPP$97.70, PPP$108.10 and PPP$101.30, respectively (PPP, purchasing power parity dollars). The total indirect cost of disease per patient was PPP$13.7, PPP$12.1 and PPP$32.7, for GERD, dyspepsia and their overlap, respectively. CONCLUSION: According to our results, hospitalisation and physician visits were the main cost of disease that could be minimised by revision of the insurance business in Iran. PMID- 21684480 TI - Simple mesenteric cyst in a child: presentation and management. PMID- 21684481 TI - Mature teratoma of the pancreas diagnosed by fine-needle aspiration. PMID- 21684482 TI - Isolated corrosive pyloric stenosis without oesophageal involvement: an experience of 21 years. AB - BACKGROUND AND STUDY AIMS: Corrosive ingestion is common in Asia and it is a frequent cause of morbidity secondary to intense fibrotic reaction and stricture formation of the oesophagus. Isolated corrosive pyloric stenosis without oesophageal involvement is an uncommon phenomenon. PATIENTS AND METHODS: All consecutive patients, with corrosive ingestion in the last two decades, were reviewed and analysed. Eleven out of 201 patients with corrosive ingestion had isolated gastric outlet obstruction. RESULTS: Patients' age ranged from 11 to 29 years with a male:female ratio of 1.75:1. All patients developed pyloric stenosis following ingestion of solution of acids. Barium study revealed complete/near complete gastric outlet obstruction in all patients. On laparotomy, there was gastric dilatation in 10 patients, who underwent posterior gastrojejunostomy, whereas the stomach was contracted in one patient, and hence anterior gastrojejunostomy was performed. Seven patients were completely relieved of their symptoms; persistent postprandial epigastric fullness and/or dyspepsia was observed in four patients whose gastrojejunostomy stoma was found adequate on barium study, suggestive of gastric motility disorder. We did not encounter gastrojejunostomy-related complication of stomal ulcer/stenosis in our patients. CONCLUSION: Isolated corrosive pyloric stenosis is not as rare as is commonly thought. Gastrojejunostomy is effective, although a fair percentage of patients appear to develop gastric motility disorder secondary to corrosive injury. PMID- 21684483 TI - Open haemorrhoidectomy under local anaesthesia for symptomatic haemorrhoids: An experience from Nigeria. AB - BACKGROUND AND STUDY AIMS: Ligation-excision haemorrhoidectomy is considered to be the gold-standard treatment for prolapsed haemorrhoids. The procedure is commonly done under general or regional anaesthesia. This study aimed to assess the feasibility and tolerability of open haemorrhoidectomy under local anaesthesia. PATIENTS AND METHODS: This is a prospective study carried out in Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, Nigeria, over a 5 year period. All consenting adult patients with prolapsing haemorrhoids were offered Milligan-Morgan haemorrhoidectomy under local anaesthesia. They were assessed for tolerance and complications. RESULTS: More than 95% of the patients tolerated the procedure with manageable complications. CONCLUSION: Open excisional haemorrhoidectomy under local anaesthesia is feasible, safe and well tolerated in our environment, and may encourage early presentation of patients with piles to hospital. PMID- 21684484 TI - Coeliac disease in Iraqi type 1 diabetic patients. AB - BACKGROUND AND STUDY AIMS: High prevalence rates of coeliac disease (CD) in patients with type 1 diabetes mellitus (T1DM) have been reported. The aim of this study was to evaluate the frequency of silent CD in a sample of Iraqi patients with T1DM. PATIENTS AND METHODS: This is a cross-sectional study done in Baghdad Teaching Hospital, Baghdad Medical City, Baghdad, Iraq, on 62 patients with T1DM. For all patients, immunoglobulin A (IgA) anti-tissue transglutaminase antibodies (IgA tTG), IgG anti-tissue transglutaminase antibodies (IgG tTG), IgA endomysial antibody (IgA EMA), IgA antigliadin antibodies (IgA AGA) and IgG antigliadin antibodies (IgG AGA) tests were done, with duodenoscopy, and at least four biopsies were taken from the second part of the duodenum. RESULTS: A total of 27 patients (43.5%) had normal small-intestinal histopathology (Marsh 0), one of them had a positive result for all serological markers used in the study, and another patient was positive for IgA tTG only. Ten patients (16.1%) had Marsh grade I, one of them was positive for IgA tTG, IgG tTG and IgA EMA, another patient was IgA deficient and had positive IgG tTG only and another patient with Marsh I had positive IgA tTG and IgG tTG only. Two patients (3.2%) had Marsh IIIA; three patients (4.8%) had Marsh IIIB histopathology, two of them were positive for all tests and one had positive IgA tTG and IgA EMA only. Two patients (3.2%) had Marsh IIIC histopathological features; they were positive for all serological tests, hence, the frequency of CD was 11.2%. CONCLUSION: The frequency of silent CD in Iraqi patients with T1DM is not rare, reaching up to 11.2%. Both EMA and tTG antibodies are useful as screening tests. PMID- 21684485 TI - Mediastinal ganglioneuroblastoma-secreting vasoactive intestinal peptide causing secretory diarrhoea. AB - In this case report we describe a case of mediastinal ganglioneuroblastoma secreting vasoactive intestinal peptide (VIP), causing secretory diarrhoea in an 18-month-old child. An 18-month-old girl presented with a 2-month history of diarrhoea, abdominal distension and weight loss. Investigations revealed secretory diarrhoea with hypokalaemia, hyponatraemia and hypochloraemia and metabolic acidosis. Her stool output was 2.5-3.lday(-1) with increased stool sodium. VIP levels were strikingly high with normal glucagon and gastrin levels. X-ray of the chest revealed a well-defined mass in the right upper zone with tracheal shift, which was confirmed with computed tomography (CT) of the chest. The mass was resected and the patient became asymptomatic. This case shows that secretory diarrhoea caused by VIP and produced by ganglioneuroblastoma indicates a favourable prognosis, provided it is resectable. PMID- 21684486 TI - Vitiligo in a patient receiving infliximab for refractory ulcerative colitis. AB - Infliximab is a chimerical monoclonal antibody that inhibits pro-inflammatory activity of tumour-necrosis factor alpha (TNFalpha) and it is the primary biological agent used in the treatment of moderate-to-severe ulcerative colitis (UC). We report a case of vitiligo following infliximab administration in a patient with refractory UC. The case serves as a reminder of adverse cutaneous reactions induced by TNFalpha-antagonist therapy. PMID- 21684488 TI - Exercise reduces impairment and improves activity in people after some upper limb fractures: a systematic review. AB - QUESTION: What is the effect of exercise on reducing impairment and increasing activity in the rehabilitation of people with upper limb fractures? DESIGN: Systematic review of controlled trials. PARTICIPANTS: Adults following an upper limb fracture. INTERVENTION: Any exercise therapy program, including trials where exercise was delivered to both groups providing there was an expectation of different amounts of exercise. OUTCOME MEASURES: Body structure and function, and activity limitations. RESULTS: 13 relevant trials involving 781 participants with an upper limb fracture were identified. 12 of the 13 trials included exercise of different duration and administration in both intervention and comparison groups. In support of the role of exercise there is evidence that: exercise and advice compared to no intervention reduce pain and improve upper limb activity in the short term after distal radius fracture; starting exercise earlier after conservatively managed proximal humeral fractures can reduce pain and improve shoulder activity; and physiotherapy that included supervised exercise and home exercise increased wrist movement after distal radius fracture when compared to home exercise alone. There is contrary evidence from two trials one after distal radius fracture and one after proximal humeral fracture that a home exercise program was superior to a supervised plus home exercise program. Only a single meta-analysis was conducted due to clinical heterogeneity and a lack of common outcome measures among the included trials. CONCLUSION: There is evidence to support the role of specific exercise regimens in reducing impairments and improving upper limb function following specific upper limb fractures. PMID- 21684489 TI - Training unsupported sitting does not improve ability to sit in people with recently acquired paraplegia: a randomised trial. AB - QUESTION: Do people with recently acquired paraplegia benefit from a six-week motor retraining program aimed at improving their ability to sit unsupported? DESIGN: A randomised controlled trial with concealed allocation, assessor blinding, and intention-totreat analysis. PARTICIPANTS: 32 people with recently acquired paraplegia and limited ability to sit unsupported. INTERVENTION: All participants undertook standard inpatient rehabilitation over a six-week period. Experimental participants received three additional 30-minute sessions per week of motor retraining directed at improving their ability to sit unsupported. OUTCOME MEASURES: The three primary outcomes were the Maximal Lean Test, Maximal Sideward Reach Test, and the Performance Item of the Canadian Occupational Performance Measure (COPM). The secondary outcomes were the Satisfaction Item of the COPM, Participants' Impressions of Change, Clinicians' Impressions of Change, the T-shirt Test, and the Spinal Cord Injury Falls Concern Scale. RESULTS: The mean between-group differences for the Maximal Lean Test, Maximal Sideward Reach Test and the Performance Item of the COPM were -20 mm (95% CI -64 to 24), 5% arm length (95% CI -3 to 13) and 0.5 points (95% CI -0.5 to 1.5), respectively. The secondary outcomes did not differ significantly between groups. CONCLUSION: People with recently acquired paraplegia do not benefit from a six-week motor retraining program directed specifically at improving their ability to sit unsupported. Their ability to sit unsupported does, however, improve over time, suggesting that the practice of activities of daily living has important carry over effects on unsupported sitting, rendering additional training redundant. TRIAL REGISTRATION: ACTRN12608000464369. PMID- 21684490 TI - Strain-Counterstrain therapy combined with exercise is not more effective than exercise alone on pain and disability in people with acute low back pain: a randomised trial. AB - QUESTION: Is Strain-Counterstrain treatment combined with exercise therapy more effective than exercise alone in reducing levels of pain and disability in people with acute low back pain? DESIGN: Randomised trial with concealed allocation, assessor blinding, and intention-to-treat analysis. PARTICIPANTS: 89 (55 female) participants between 18 and 55 years experiencing acute low back pain were randomised to experimental (n = 44) and control (n = 45) groups. INTERVENTION: Participants attended four treatments in two weeks. The experimental group received Strain-Counterstrain treatment and review of standardised exercises (abdominal bracing, knee to chest, and lumbar rotation). The control group performed the standardised exercises under supervision. Following the intervention period, all participants received exercise progression, manual therapy, and advice. OUTCOME MEASURES: The primary outcome was the modified Oswestry low back pain disability questionnaire, measured at 2 weeks (ie, end of treatment), 6 weeks, and 28 weeks. Secondary outcome measures included the SF-36, visual analogue scale pain ratings, and a 7-point global rating of change. RESULTS: The experimental intervention was not more effective than exercise alone in reducing levels of pain and disability. Mean between-group differences in change from baseline for the Oswestry Disability Index were 0 (95% CI -6 to 7) after treatment, -1 (95% CI -7 to 6) at 6 weeks, and 2 (95% CI -4 to 8) at 28 weeks. Other outcomes did not differ significantly between groups. CONCLUSION: There is no advantage in providing Strain- Counterstrain treatment to patients with acute low back pain, although further studies could examine whether a subset of these patients can benefit from the treatment. TRIAL REGISTRATION: ACTRN 12609000084280. PMID- 21684491 TI - Real-time visual feedback can be used to activate scapular upward rotators in people with scapular winging: an experimental study. AB - QUESTION: Can real-time visual feedback facilitate the activity of serratus anterior in individuals with scapular winging during shoulder flexion? DESIGN: Comparative, repeated-measures experimental study. PARTICIPANTS: Nineteen subjects with scapular winging. INTERVENTION: Participants performed isometric shoulder flexion at 60 degrees and 90 degrees with and without real-time visual feedback using a video camera to monitor scapular winging. OUTCOME MEASURES: Activity in the upper trapezius, lower trapezius, and serratus anterior muscles was measured using surface electromyography. A video motion analysis system measured the displacement of a marker attached to the acromion in the frontal and sagittal planes. RESULTS: Visual feedback significantly increased activity in the upper trapezius at 60 degrees of shoulder flexion by 2.3% of maximum voluntary isometric contraction (95% CI 0.7 to 4.0). Visual feedback also significantly increased activity in the serratus anterior at 60 degrees and 90 degrees of shoulder flexion, by 3.0% (95% CI 2.3 to 3.6) and 5.9% (95% CI 3.3 to 8.5) of maximum voluntary isometric contraction respectively. These effects equated to effect sizes from 0.29 to 0.46. Visual feedback also significantly improved movement of the acromion superiorly at 60 degrees of shoulder flexion and anteriorly at 60 degrees and 90 degrees of shoulder flexion. CONCLUSION: Real time visual feedback can be used to activate the upper trapezius and serratus anterior muscles and to improve movement of the scapula during shoulder flexion in people with scapular winging. PMID- 21684492 TI - The de Morton Mobility Index (DEMMI) provides a valid method for measuring and monitoring the mobility of patients making the transition from hospital to the community: an observational study. AB - QUESTION: Is the de Morton Mobility Index (DEMMI) valid for measuring the mobility of patients making the transition from hospital to the community? DESIGN: Observational cohort study. PARTICIPANTS: 696 consecutive patients admitted to 11 Transition Care Programs for multidisciplinary care in Victoria and Tasmania during a 6-month period. The DEMMI and Modified Barthel Index were administered within 5 working days of admission and discharge from the Transition Care Program. OUTCOME MEASURES: The DEMMI and Modified Barthel Index. RESULTS: Neither the DEMMI nor the Modified Barthel Index had a floor or ceiling effect. Similar evidence of convergent, discriminant and known-groups validity were obtained for each instrument. The DEMMI was significantly more responsive to change than the Modified Barthel Index using criterion- and distribution-based methods. The minimum clinically important difference estimates represented similar proportions of the scale width for the DEMMI and Modified Barthel Index and were similar using criterion- and distribution-based estimates. Rasch analysis identified the DEMMI as essentially unidimensional in a Transition Care Program cohort and therefore can be applied to obtain interval level measurement. Rasch analysis demonstrated that the DEMMI was administered similarly by physiotherapists and allied health assistants under the direction of a physiotherapist. CONCLUSION: The DEMMI and Modified Barthel Index are both valid measures of activity limitation for Transition Care Program patients. The DEMMI has a broader scale width, provides interval level measurement, and is significantly more responsive to change than the Modified Barthel Index for measuring the mobility of Transition Care Program patients. PMID- 21684493 TI - Many participants in inpatient rehabilitation can quantify their exercise dosage accurately: an observational study. AB - QUESTION: Are inpatients undergoing rehabilitation who appear able to count exercises able to quantify accurately the amount of exercise they undertake? DESIGN: Observational study. PARTICIPANTS: Inpatients in an aged care rehabilitation unit and a neurological rehabilitation unit, who appeared able to count their exercises during a 1-2 min observation by their treating physiotherapist. MEASUREMENTS: Participants were observed for 30 min by an external observer while they exercised in the physiotherapy gymnasium. Both the participants and the observer counted exercise repetitions with a hand-held tally counter and the two tallies were compared. RESULTS: Of the 60 people admitted for aged care rehabilitation during the study period, 49 (82%) were judged by their treating therapist to be able to count their own exercise repetitions accurately. Of the 30 people admitted for neurological rehabilitation during the study period, 20 (67%) were judged by their treating therapist to be able to count their repetitions accurately. Of the 69 people judged to be accurate, 40 underwent observation while exercising. There was excellent agreement between these participants' counts of their exercise repetitions and the observers' counts, ICC (3,1) of 0.99 (95% CI 0.98 to 0.99). Eleven participants (28%) were in complete agreement with the observer. A further 19 participants (48%) varied from the observer by less than 10%. CONCLUSION: Therapists were able to identify a group of rehabilitation participants who were accurate in counting their exercise repetitions. Counting of exercise repetitions by therapist-selected patients is a valid means of quantifying exercise dosage during inpatient rehabilitation. PMID- 21684494 TI - Telephone-based patient self-management program might be effective in reducing osteoarthritis-related pain. PMID- 21684495 TI - Supervised aerobic and resistance exercise improves glycaemic control and modifiable cardiovascular risk factors in people with Type 2 diabetes mellitus. PMID- 21684496 TI - Patients with chronic obstructive pulmonary disease (COPD) who are not hypoxaemic at rest do not benefit from home oxygen. PMID- 21684497 TI - The six-minute walk test in paediatric populations. PMID- 21684498 TI - International Standards for the Neurological Classification of Spinal Cord Injury. PMID- 21684501 TI - Publications are welcome but mechanisms underlying the effects of new technologies have yet to be delineated. PMID- 21684502 TI - Was the effect of sitting time interpreted appropriately? PMID- 21684505 TI - Comparison of grasping movements made by healthy subjects in a 3-dimensional immersive virtual versus physical environment. AB - Virtual reality (VR) technology is being used with increasing frequency as a training medium for motor rehabilitation. However, before addressing training effectiveness in virtual environments (VEs), it is necessary to identify if movements made in such environments are kinematically similar to those made in physical environments (PEs) and the effect of provision of haptic feedback on these movement patterns. These questions are important since reach-to-grasp movements may be inaccurate when visual or haptic feedback is altered or absent. Our goal was to compare kinematics of reaching and grasping movements to three objects performed in an immersive three-dimensional (3D) VE with haptic feedback (cyberglove/grasp system) viewed through a head-mounted display to those made in an equivalent physical environment (PE). We also compared movements in PE made with and without wearing the cyberglove/grasp haptic feedback system. Ten healthy subjects (8 women, 62.1+/-8.8years) reached and grasped objects requiring 3 different grasp types (can, diameter 65.6mm, cylindrical grasp; screwdriver, diameter 31.6mm, power grasp; pen, diameter 7.5mm, precision grasp) in PE and visually similar virtual objects in VE. Temporal and spatial arm and trunk kinematics were analyzed. Movements were slower and grip apertures were wider when wearing the glove in both the PE and the VE compared to movements made in the PE without the glove. When wearing the glove, subjects used similar reaching trajectories in both environments, preserved the coordination between reaching and grasping and scaled grip aperture to object size for the larger object (cylindrical grasp). However, in VE compared to PE, movements were slower and had longer deceleration times, elbow extension was greater when reaching to the smallest object and apertures were wider for the power and precision grip tasks. Overall, the differences in spatial and temporal kinematics of movements between environments were greater than those due only to wearing the cyberglove/grasp system. Differences in movement kinematics due to the viewing environment were likely due to a lack of prior experience with the virtual environment, an uncertainty of object location and the restricted field-of-view when wearing the head-mounted display. The results can be used to inform the design and disposition of objects within 3D VEs for the study of the control of prehension and for upper limb rehabilitation. PMID- 21684506 TI - Metamemory for faces, names, and common nouns. AB - This study examined the metacognitive aspects of face-name learning with the goal of providing a comprehensive profile of monitoring performance during this task. Four types of monitoring judgments were solicited during encoding and retrieval of novel face-name associations. Across all of the monitoring judgments, relative accuracy was significantly above chance for face and name targets. Furthermore, metamemory performance was similar between both target conditions, even though names were more difficult to recognize than faces. As a preliminary test of the stability of monitoring accuracy across different categories of stimuli, we also compared metamemory performance between face-name pairs and noun-noun pairs. Prospective monitoring accuracy was similar across the categories of stimuli, but retrospective monitoring accuracy was superior for noun targets compared with face or name targets. Altogether, our results indicate that participants can monitor their memory for face-name associations at a level above chance, and retrospective monitoring is more accurate with nouns compared with faces and names. PMID- 21684507 TI - [Mohs micrographic surgery for repeat excision of basal cell carcinomas on the head with positive margins]. AB - BACKGROUND: There is debate in the literature regarding the management of basal cell carcinoma following excision with positive surgical margins. While in some cases recurrence is not observed even after many years of follow-up, those in which recurrence does occur are at an increased risk of complications. Factors may exist that help to choose the best therapeutic approach for basal cell carcinomas on the head in which positive margins are observed following excision. MATERIAL AND METHODS: A total of 46 patients were selected who had been treated by Mohs micrographic surgery as a result of positive surgical margins being present following previous tumor excision. The factors associated with the absence of tumor nests and the occurrence of negative margins following a single Mohs stage were analyzed. RESULTS: No associations were observed with sex, tumor size, affected margin (lateral, deep, or both), time since diagnosis, number of previous treatments, histological type, or tumor site. There was a certain trend towards more frequent identification of tumor nests when both surgical margins were affected and towards a requirement for a single Mohs stage in tumors less than 1.2 cm and in which less than 5 years had elapsed since diagnosis. CONCLUSIONS: Conclusive data are unavailable with which to define cases in which repeat excision is necessary or those in which conventional excision could be sufficient. The best option for the treatment of these tumors is Mohs micrographic surgery, although conventional excision could be reasonable in small tumors located at low-risk sites and in which long periods have not elapsed since diagnosis. PMID- 21684508 TI - Platelet response to aspirin 50 and 100 mg in patients with coronary heart disease over a five-year period. AB - Aspirin has been shown to decrease cardiovascular (CV) events by ~25%. Despite aspirin therapy 10% to 20% of patients with arterial vascular disease develop atherothrombotic events. A meta-analysis of antiplatelet therapy showed a progressive decrease in clinical efficacy of aspirin after 2 years. Whether this is due to a decreased sensitivity to aspirin during long-term therapy remains unclear. A prospective randomized clinical trial with serial monitoring over 5 years was conducted in 100 patients with documented coronary heart disease. We investigated whether long-term treatment with aspirin 50 and 100 mg affects platelet response similarly. Occurrence of CV events was documented. Platelet sensitivity to aspirin, prostacyclin, and adenosine diphosphate-, collagen-, and epinephrine-induced platelet aggregation were evaluated over time. In addition, beta-thromboglobulin and inflammatory markers were measured. Four patients were lost to follow-up and 10 patients died. Eleven patients developed nonfatal CV events. In the 2 groups platelet response to aspirin and the referenced variables remained unchanged over 5 years. In patients who developed CV events, the last monitoring interval revealed no difference in platelet response to aspirin. However, patients with nonfatal and fatal CV events showed increased inflammatory markers versus patients without CV events independent of aspirin 50 or 100 mg intake. In conclusion, our study revealed no difference in antiplatelet response to aspirin 50 versus 100 mg or CV events over 5 years in patients with coronary heart disease. PMID- 21684509 TI - Comparison of the relation between the calcium score and plaque characteristics in patients with acute coronary syndrome versus patients with stable coronary artery disease, assessed by computed tomography angiography and virtual histology intravascular ultrasound. AB - A considerable number of patients with an acute coronary syndrome (ACS) who present with a 0 or low calcium score (CS) still demonstrate coronary artery disease (CAD) and significant stenosis. The aim of the present study was to evaluate the relation between the CS and the degree and character of atherosclerosis in patients with suspected ACS versus patients with stable CAD obtained by computed tomography angiography and virtual histology intravascular ultrasound (VH IVUS). Overall 112 patients were studied, 53 with ACS and 59 with stable CAD. Calcium scoring and computed tomography angiography were performed and followed by VH IVUS. On computed tomography angiography each segment was evaluated for plaque and classified as noncalcified, mixed, or calcified. Vulnerable plaque characteristics on VH IVUS were defined by percent necrotic core and presence of thin-cap fibroatheroma. If the CS was 0, patients with ACS had a higher mean number of plaques (5.0 +/- 2.0 vs 2.0 +/- 1.9, p <0.05) and noncalcified plaques (4.6 +/- 3.5 vs 1.3 +/- 1.9, p <0.05) on computed tomography angiography than those with stable CAD. If the CS was 0, VH IVUS demonstrated that patients with ACS had a larger amount of necrotic core area (0.58 +/- 0.73 vs 0.22 +/- 0.43 mm(2), p <0.05) and a higher mean number of thin-cap fibroatheromas (0.6 +/- 0.7 vs 0.1 +/- 0.3, p <0.05) than patients with stable CAD. In conclusion, even in the presence of a 0 CS, patients with ACS have increased plaque burden and increased vulnerability compared to patients with stable CAD. Therefore, absence of coronary calcification does not exclude the presence of clinically relevant and potentially vulnerable atherosclerotic plaque burden in patients with ACS. PMID- 21684510 TI - Hypertrophic cardiomyopathy with left ventricular apical aneurysm in brothers. AB - The investigators report similar phenotypes of hypertrophic cardiomyopathy with left ventricular apical aneurysm and thrombus in 2 brothers aged 8 years apart. This report highlights the genetic predisposition for this unique, high-risk phenotype, the issue of prophylactic anticoagulation, and the importance of nonstandard echocardiographic imaging views in the assessment of these patients. PMID- 21684511 TI - Comparison of drug-eluting versus bare metal stents in cardiac allograft vasculopathy. AB - Although not a definitive treatment, percutaneous coronary intervention offers a palliative benefit to patients with cardiac allograft vasculopathy. Given the superior outcomes with drug-eluting stents (DESs) over bare metal stents (BMSs) in native coronary artery disease, similar improvements might be expected in transplant patients; however, the results have been mixed. Consecutive cardiac transplantation recipients at a single center receiving a stent for de novo cardiac allograft vasculopathy from 1997 to 2009 were retrospectively analyzed according to receipt of a DES versus a BMS. The angiographic and clinical outcomes were subsequently evaluated at 1 year. The baseline clinical and procedural characteristics were similar among those receiving DESs (n = 18) and BMSs (n = 16). Quantitative coronary angiography revealed no difference in the reference diameter, lesion length, or pre-/postprocedural minimal luminal diameter. At the 12-month angiographic follow-up visit, the mean lumen loss was significantly lower in the DES group than in the BMS group (0.19 +/- 0.73 mm vs 0.76 +/- 0.97 mm, p = 0.02). The DES group also had a lower rate of in-stent restenosis (12.5% vs 33%, p = 0.18), as well as a significantly lower rate of target lesion revascularization (0% vs 19%, p = 0.03). At 1 year, DESs were associated with a lower composite rate of cardiac death and nonfatal myocardial infarction (12% vs 38%, p = 0.04). In conclusion, DESs are safe and effective in the suppression of neointimal hyperplasia after percutaneous coronary intervention for cardiac allograft vasculopathy, resulting in significantly lower rates of late lumen loss and target lesion revascularization, as well as a reduced combined rate of cardiac death and nonfatal myocardial infarction. PMID- 21684512 TI - Identifying high risk in adults with congenital heart disease and atrial arrhythmias. AB - Atrial arrhythmias are associated with an increased mortality risk in adults with congenital heart disease (CHD). However, little is known about risk stratification in the specific group of adult patients with CHD and atrial arrhythmias. We sought to identify predictors of mortality in adult with CHD and atrial arrhythmias and to establish a risk score. The study involved 378 adult patients with CHD (mean age 39 +/- 13 years) and atrial arrhythmias who had serial follow-up in a tertiary referral center from 1999 through 2009. During a median follow-up of 5.2 years, there were 40 deaths (11%). Overall mortality rate was 2.0% per patient-year. Common modes of death included heart failure-related death (35%), sudden cardiac death (20%), and perioperative death (18%). Independent predictors of mortality were poor functional class (hazard ratio 3.69, 95% confidence interval [CI] 1.69 to 8.03, p = 0.001), single-ventricle physiology (hazard ratio 3.33, 95% CI 1.51 to 7.35, p = 0.003), pulmonary hypertension (hazard ratio 2.96, 95% CI 1.41 to 6.19, p = 0.004), and valvular heart disease (hazard ratio 2.73, 95% CI 1.33 to 5.59, p = 0.006). A risk score was constructed using these predictors in which patients were assigned 1 point for the presence of each risk factor. Mortality rates in the low-risk (no risk factor), moderate-risk (1 risk factor), and high-risk (>1 risk factor) groups were 0.5%, 1.9%, and 6.5% per patient-year, respectively (log-rank p <0.001). In conclusion, in adult with CHD and atrial arrhythmias specific clinical variables identify patients at high risk for death. Importantly, the absence of any of these risk factors is associated with an excellent survival despite the presence of atrial arrhythmias. PMID- 21684513 TI - Single-center experience with implantable cardioverter-defibrillators in adults with complex congenital heart disease. AB - Adults with congenital heart disease are at risk of lethal ventricular arrhythmias and are candidates for implantable cardiac defibrillator (ICD) therapy, yet implant risks, long-term outcomes, and rates of appropriate and inappropriate ICD therapies are not well characterized. We reviewed clinical, implantation, and follow-up data on all transvenous ICDs in adults with congenital heart disease at the Mayo Clinic from 1991 through 2008. Seventy-three adults with congenital heart disease received 85 ICDs. Implantation diagnoses included tetralogy of Fallot (44%) and congenitally corrected transposition of the great arteries (17%). Implantation indication was occurrence of sustained ventricular arrhythmias (secondary prevention) in 36% and prophylactic (primary prevention) in the remainder. There were no major implant-related complications. During follow-up (2.2 +/- 2.8 years, range 0 to 15) 11 patients died and 4 patients received heart or heart/lung transplants. An appropriate shock for a ventricular arrhythmia was observed in 19% of patients and an inappropriate shock was observed in 15% of patients. Likelihood of an appropriate shock was associated with increased subpulmonic ventricular pressure. In conclusion, implantation of transvenous ICDs in adults with congenital heart disease is associated with a low risk of implant complications. In this high-risk adult population the rate of inappropriate ICD shocks is low, whereas the likelihood of appropriate therapy for potentially lethal ventricular arrhythmias is high. These data suggest overall benefit of ICD therapy in adults with congenital heart disease. PMID- 21684514 TI - Bridging the gap between research and practice. PMID- 21684515 TI - A device that measures the pulling force and vector of delivering a baby. AB - OBJECTIVE: I sought to demonstrate a new device that measures the pulling on an infant during a vaginal delivery. STUDY DESIGN: The Peisner Platform (US Patent 6,684,165; Canadian patent 2,436,154) utilizes Newton's Third Law to measure the force/vector of delivering a baby. Ten patients at term with a singleton fetus in the vertex presentation were recruited for this pilot study. The platform measured the forces/vectors on the fetal head during the delivery. The primary outcomes were the graphs of the force/vector on the fetus and duration of that force. RESULTS: The pulling force exerted on the fetus ranged from 31.7-135.4 N over 8-51 seconds. Force vectors were often negative early, and positive later. CONCLUSION: This new device, which measures the pulling force and vector of delivering a baby, has been successfully demonstrated. PMID- 21684516 TI - Does treatment of premature labor with terbutaline increase the risk of autism spectrum disorders? PMID- 21684517 TI - The influence of surgical volume on morbidity and mortality of radical hysterectomy for cervical cancer. AB - OBJECTIVE: We examined the influence of physician and hospital volume on the morbidity and mortality of radical hysterectomy for cervical cancer. STUDY DESIGN: Women who underwent radical hysterectomy for cervical cancer between 2003 and 2007 were examined. The effect of surgeon and hospital volume on morbidity and mortality was examined using multivariable generalized estimating equations. RESULTS: A total of 1536 women who underwent radical hysterectomy were identified. Patients treated by high-volume surgeons had fewer medical complications (odds ratio, 0.55; 95% confidence interval, 0.34-0.88) and shorter lengths of stay (odds ratio, 0.49; 95% confidence interval, 0.25-0.98). After adjustment for case mix and surgeon volume, hospital volume had no independent effect on any of the variables of interest. CONCLUSION: High-volume surgeons have fewer postoperative medical complications, shorter lengths of stay, and lower transfusion requirements. Hospital volume appears to have only a minor influence on outcomes after radical hysterectomy. PMID- 21684518 TI - Association between genital intraepithelial lesions and anal squamous intraepithelial lesions in HIV-negative women. AB - OBJECTIVE: The objective of the study was to evaluate the risk of anal squamous intraepithelial lesions (ASILs) in immunocompetent women with genital squamous intraepithelial lesions (GSILs). STUDY DESIGN: This was a cross-sectional study that included 260 immunocompetent women divided into 2 study groups: 1 group included 184 women diagnosed with GSIL by genital colposcopy and biopsy, and the other included 76 controls. All subjects were submitted to anoscopy followed by a biopsy if pertinent. RESULTS: Of 184 GSIL women, 32 (17.4%) had ASIL (P<.001). The risk of ASIL was 13.1 times greater for GSIL women when there were 3 or 4 genital sites involved. All cases of high-grade ASIL were found in women with cervical GSILs. Among risk factors, anal intercourse without a condom demonstrated an important association with ASIL (prevalence ratio adjusted for age=2.6). CONCLUSION: There seems to be a strong association between ASIL and multicentric GSIL. Another factor related to ASIL was the practice of unprotected anal intercourse. PMID- 21684519 TI - ER-alpha36, a novel variant of estrogen receptor alpha, is involved in EGFR related carcinogenesis in endometrial cancer. AB - OBJECTIVE: To explore the role of estrogen receptor-alpha36 (ER-alpha36) in epidermal growth factor receptor (EGFR)-related carcinogenesis in endometrial cancer. STUDY DESIGN: The expression of ER-alpha36, EGFR, and phospho extracellular signal-regulated kinase was analyzed using immunohistochemistry in endometrial cancer samples. The cellular localization of ER-alpha36 and EGFR was determined using immunofluorescence in the endometrial cancer Hec1A cells. The level of phospho-extracellular signal-regulated kinase of Hec1A cells was determined using Western blotting after treatment with epidermal growth factor. RESULTS: Positive rate of ER-alpha36 was increased in high-stage (P = .03) and high-grade (P = .224) endometrial cancer; expression of ER-alpha36 and EGFR exhibited a significant positive correlation (r = 0.334, P = .025) and they showed substantial colocalization on the plasma membrane of glandular cells; phospho-extracellular signal-regulated kinase positive rate in ER-alpha36 positive group and EGFR positive group was higher than that of ER-alpha36 negative group (P = .014) and EGFR negative group (P = .016); finally, ER-alpha36 mediated epidermal growth factor-stimulated extracellular signal-regulated kinase activation in Hec1A cells. CONCLUSION: ER-alpha36 mediates EGFR-related extracellular signal-regulated kinase activation in endometrial cancer. PMID- 21684520 TI - Fresh muscle fiber fragments on a scaffold in rats-a new concept in urogynecology? AB - OBJECTIVE: To investigate if a synthetic, biodegradable scaffold with either autologous in vitro cultured muscle-derived cells or autologous fresh muscle fiber fragments could be used for tissue repair. STUDY DESIGN: Twenty scaffolds with muscle-derived cells and 20 scaffolds with muscle fiber fragments were implanted subcutaneously on the abdomen of rats, 2 in each rat, and examined after 3 weeks (10 of each preparation) and 8 weeks (10 of each preparation). Immonohistochemistry and histopathology was undertaken for assessment of growth pattern and biocompatibility, respectively. RESULTS: At 3 weeks, both muscle derived cells and muscle fiber fragments could be identified. At 8 weeks, the muscle fiber fragments generated fragmented, striated muscle tissue in 6 of 10 explants, whereas the muscle-derived cells and all scaffolds had vanished. CONCLUSION: Autologous fresh muscle fiber fragments on a biodegradable scaffold seem useful for tissue repair. This study introduces a promising new concept with possible implications for the surgical reconstruction of pelvic organ prolapse. PMID- 21684522 TI - Prevalence and risk factors of dry eye syndrome in a United States veterans affairs population. AB - PURPOSE: To evaluate the prevalence of dry eye syndrome (DES) and its associated risk factors in a US Veterans Affairs population receiving ocular care services. DESIGN: Retrospective study. METHODS: settings: Patients were seen in the Miami and Broward Veterans Affairs eye clinics between 2005 and 2010. patients population: Patients were divided into cases and controls with regard to their dry eye status (cases = ICD9 code for DES plus dry eye therapy; controls = patients without ICD9 code plus no therapy). main outcome measures: The prevalence of DES and its associated risk factors. RESULTS: A total of 16 862 patients were identified as either a dry eye case (n = 2056) or control (n = 14 806). Overall, 12% of male and 22% of female patients had a diagnosis of DES, with female gender imparting a 2.40 increased risk (95% confidence interval [CI] 2.04-2.81) over male gender. Several medical conditions were found to increase DES risk including post-traumatic stress disorder (odds ratio [OR] 1.97, 95% CI 1.75-2.23), depression (OR 1.91, 95% CI 1.73-2.10), thyroid disease (OR 1.81, 95% CI 1.46-2.26), and sleep apnea (OR 2.20, 95% CI 1.97-2.46) (all analyses adjusted for gender and age). The use of several systemic medications, including anti depressant medications (OR 1.97, 95% CI 1.79-2.17), anti-anxiety medication (OR 1.74, 95% CI 1.58-1.91), and anti-benign prostatic hyperplasia medications (OR 1.68, 95% CI 1.51-1.86), was likewise associated with an increased risk of DES. CONCLUSIONS: The prevalence of DES was found to be high in both men and women in our eye care population. This is the first study to demonstrate that in a veteran population, several diagnoses were significantly associated with DES, including post-traumatic stress disorder and depression. PMID- 21684523 TI - Outcomes of radial incision of the tricuspid valve for ventricular septal defect closure. AB - BACKGROUND: Adequate exposure of a ventricular septal defect (VSD) is critically important to obtaining a satisfactory repair. Some surgeons have advocated a circumferential incision on the tricuspid valve. For 20 years we have used a radial incision of the tricuspid valve when added exposure is required. METHODS: All patients undergoing VSD repair at Children's Memorial Hospital (Chicago, IL) were identified from our database. Operative records were reviewed to determine details of exposure. Follow-up patient and echocardiography data were obtained from the medical record. RESULTS: Between January 1995 and March 2010, 366 isolated VSDs were repaired, including 341 perimembranous, 15 muscular, 5 inlet, and 5 inlet-muscular VSDs. A radial tricuspid valve incision was used in 230 patients (63%). Mean times (minutes) were 97+/-24 for cardiopulmonary bypass and 66+/-18 for cross-clamp, with no significant difference between groups (p=0.59 and p=0.96, respectively). No operative deaths occurred. Follow-up echocardiograms were available for 150 patients at a mean of 3.5 years. Tricuspid regurgitation was rated as none or trivial in 97 (65%), mild in 45 (30%), and moderate in 8 (5%). The degree of tricuspid regurgitation was similar between patients whose tricuspid valve was and was not incised. CONCLUSIONS: Radial incision of the tricuspid valve enhances exposure for safe VSD closure and adds little complexity to the case. Its use in our series did not lead to increased tricuspid valve dysfunction, and it was durable at midterm echocardiographic assessment. PMID- 21684524 TI - Developing safety signs for children on board trains. AB - Every year a number of young children are injured as a result of accidents that occur on board trains in Great Britain. These accidents range from being caught in internal doors, through to injuries caused by using seats. We describe our efforts to design a new set of safety signs in order to help prevent the occurrence of these types of accident. The research was funded under a Rail Safety and Standards Board (RSSB) managed UK Department for Transport research programme and was carried out in collaboration with Loughborough University. The study involved analysis of industry accident incidence data and running a set of classroom discussions with young school children (aged 5-10, n=210). The classroom discussions initially involved showing them examples of a new design prototype sign alongside existing train signs and gathering the requirements for new designs. A second set of classroom discussions with these children was used to evaluate the new signs based on the outcomes from earlier discussions. We describe our findings alongside a set of outline guidelines for the design of safety signs for young children. A final section considers the main methodological and other lessons learnt from the study, alongside study limitations and possibilities for future research. PMID- 21684525 TI - Emotional working memory capacity in posttraumatic stress disorder (PTSD). AB - Participants with a lifetime history of posttraumatic stress disorder (PTSD) and trauma-exposed controls with no PTSD history completed an emotional working memory capacity (eWMC) task. The task required them to remember lists of neutral words over short intervals while simultaneously processing sentences describing dysfunctional trauma-related thoughts (relative to neutral control sentences). The task was designed to operationalise an everyday cognitive challenge for those with mental health problems such as PTSD; namely, the ability to carry out simple, routine tasks with emotionally benign material, while at the same time tackling emotional laden intrusive thoughts and feelings. eWMC performance, indexed as the ability to remember the word lists in the context of trauma sentences, relative to neutral sentences, was poorer overall in the PTSD group compared with controls, suggestive of a particular difficulty employing working memory in emotion-related contexts in those with a history of PTSD. The possible implications for developing affective working memory training as an adjunctive treatment for PTSD are explored. PMID- 21684526 TI - Safety signals mitigate the consequences of uncontrollable stress via a circuit involving the sensory insular cortex and bed nucleus of the stria terminalis. AB - BACKGROUND: Safety signals exert a powerful buffering effect when provided during exposure to uncontrollable stressors. We evaluated the role of the sensory insular cortex (Si) and the extend amygdala in this "safety signal effect." METHODS: Rats were implanted with microinjection cannula, exposed to inescapable tailshocks either with or without a safety signal, and later tested for anxiety like behavior or neuronal Fos expression. RESULTS: Exposure to the uncontrollable stressor reduced later social exploration but not when safety signals were present. Temporary inhibition of Si during stressor exposure but not during later behavioral testing blocked the safety signal effect on social exploration. The stressor induced Fos in all regions of the amygdala, but safety signals significantly reduced the number of Fos immunoreactive cells in the basolateral amygdala and ventrolateral region of the bed nucleus of the stria terminalis (BNSTlv). Inhibition of BNSTlv neuronal activity during uncontrollable stressor exposure prevented the later reduction in social exploration. Finally, safety signals reduced the time spent freezing during uncontrollable stress. CONCLUSIONS: These data suggest that safety signals inhibit the neural fear or anxiety response that normally occurs during uncontrollable stressors and that inhibition of the BNSTlv is sufficient to prevent later anxiety. These data lend support to a growing body of evidence that chronic fear is mediated in the basolateral amygdala and BNSTlv and that environmental factors that modulate fear during stress will alter the long-term consequences of the stressor. PMID- 21684527 TI - Rare copy number deletions predict individual variation in human brain metabolite concentrations in individuals with alcohol use disorders. AB - BACKGROUND: Although variations in neurometabolite concentrations occur in diverse neuropsychiatric and neurodegenerative disorders, little is known about the nature of underlying genetic influences. The current study investigated the importance of a specific type of genetic mutation, copy number variation (CNV), for neurometabolite concentrations in a bilateral anterior cingulate voxel. METHODS: These neurometabolic signals were quantified using proton magnetic resonance spectroscopy ((1)H-MRS): N-acetylaspartate (NAA), creatine phosphocreatine (Cre), glutamate/glutamine (Glx), myoinositol (mI), and phosphorylcholine-glycerol phosphorylcholine (Cho). Genetic data were collected using the Illumina 1MDuoBeadChip Array from a sample adults with alcohol use disorders (n = 146). RESULTS: The number of base pairs lost through rare copy number deletions (occurring in less than 5% of our sample) predicted lower NAA, Cre, mI, and Glx. More total rare deletions also predicted lower NAA, Cre, and Glx. Principal components analyses of the five neurometabolites identified two correlated components, the first comprised of NAA, Glx, and Cre, and the second comprised of Cho, mI, and to a lesser extent, Cre. The number and length of rare deletions were correlated with the first component, capturing approximately 10% of phenotypic variance, but not the second component. CONCLUSIONS: These results suggest that mutation load affects neurometabolite concentrations, potentially increasing risk for neuropsychiatric disorders. The greater effect of CVNs on NAA, Glx, and Cre may reflect a greater sensitivity to the effects of mutations (i.e., reduced canalization) for neurometabolites related to metabolic activity and cellular energetics, due to extensive recent selection pressure on these phenotypes in the human lineage. PMID- 21684528 TI - Differential role of anandamide and 2-arachidonoylglycerol in memory and anxiety like responses. AB - BACKGROUND: Cannabinoid agonists are potential therapeutic agents because of their antinociceptive and anxiolytic-like effects, although an important caveat to their use is the possible adverse responses related to memory impairment. An alternative approach to circumvent this limitation consists of enhancing the concentration of the endocannabinoids anandamide and 2-arachidonoylglycerol. METHODS: Using low doses of the specific inhibitors of the endocannabinoid metabolizing enzymes fatty acid amide hydrolase, URB597, and monoacylglycerol lipase, JZL184, we analyzed their acute and chronic effects on memory consolidation, anxiolytic-like effects, and nociception in mice (n = 6-12 per experimental group). RESULTS: We show that anandamide is a central component in the modulation of memory consolidation, whereas 2-arachidonoylglycerol is not involved in this process. Interestingly, both URB597 and JZL184 induce anxiolytic like effects through different cannabinoid receptors. In addition, the results show that the antinociceptive and anxiolytic-like responses of both inhibitors, as well as their acute effects on memory consolidation, are maintained after chronic treatment. CONCLUSIONS: These results dissociate the role of anandamide and 2-arachidonoylglycerol in memory consolidation and anxiety and reveal the interest of cannabinoid receptor 2 as a novel target for the treatment of anxiety related disorders. PMID- 21684529 TI - Autophagy activation is involved in neuroprotection induced by hyperbaric oxygen preconditioning against focal cerebral ischemia in rats. AB - Our previous studies have demonstrated that hyperbaric oxygen (HBO) preconditioning induces tolerance to focal cerebral ischemia. The present study aimed to investigate whether autophagy is involved in the neuroprotection elicited by HBO preconditioning in a rat model of transient focal cerebral ischemia. Twenty-four hours after the completion of HBO preconditioning (2.5 atm absolute in 100% oxygen for 60 min per day for 5 consecutive days), male Sprague Dawley rats were subjected to focal cerebral ischemia by middle cerebral artery occlusion (MCAO) for 120 min. The neurobehavioral score and infarct volume were used to evaluate cerebral ischemic injury. An intracerebroventricular injection of the autophagy inhibitor 3-methyladenine (3-MA) or the autophagy inducer rapamycin was administered before HBO preconditioning or MCAO. We found that after reperfusion the protein expression of LC3-II and Beclin 1 and the formation of autophagosomes were increased by HBO preconditioning or ischemia, but the increase following HBO preconditioning was higher than the increase following ischemia. 3-MA suppressed the increases in LC3-II and Beclin 1 induced by HBO preconditioning and attenuated the neuroprotection of HBO preconditioning against cerebral ischemia. Furthermore, 3-MA treatment before MCAO aggravated subsequent cerebral ischemic injury. In contrast, pretreatment with rapamycin up-regulated LC3-II and Beclin 1 after reperfusion and mimicked the neuroprotective effect of HBO preconditioning. These results indicate that HBO preconditioning elevates autophagic activity, which elicits a neuroprotective effect against ischemic injury in the brain, and suggest a novel mechanism of HBO preconditioning-induced tolerance against transient focal cerebral ischemia. PMID- 21684530 TI - Ca2+ modulation in dorsal raphe plays an important role in NREM and REM sleep regulation during pentobarbital hypnosis. AB - Our previous studies indicated that L-type calcium channel blocker diltiazem could potentiate pentobarbital-induced hypnosis through serotonergic system. In view of the important role of dorsal raphe nucleus (DRN) on the sleep regulation and the pharmacological actions of calcium channel blocker, we presumed that Ca(2+) in the DRN may play an important role in sleep regulation in pentobarbital treated rats. Therefore, we investigated whether the Ca(2+) modulation in DRN by the microinjection of L-type Ca(2+) channel antagonist diltiazem, agonist BAY-K 8644, Ca(2+) chelator EGTA and CaCl(2) would alter the sleep parameters in pentobarbital treated rats. Results showed that perfusion of the agents attenuating Ca(2+) function, such as diltiazem (5 or 20 nmol) or EGTA (3 or 6 pmol) into DRN significantly increased pentobarbital (35 mg/kg, i.p.)-induced total sleep (TS), non-rapid eye movement (NREM) sleep and the slow wave sleep (SWS) ratio in NREM sleep. On the contrary, the DRN injection of the agents improving Ca(2+) function, such as BAY-K-8644 (10 nmol) or CaCl(2) (50 or 100 nmol) significantly reduced pentobarbital (35 mg/kg, i.p.)-induced TS, NREM sleep, rapid eye movement (REM) sleep and REM sleep ratio in TS without influence on SWS. These results suggested that the suppression of Ca(2+) function in DRN could increase NREM sleep including SWS, and the elevation of Ca(2+) function could reduce both NREM and REM sleep in pentobarbital treated rats. PMID- 21684531 TI - Levels of conflict in reasoning modulate right lateral prefrontal cortex. AB - Right lateral prefrontal cortex (rlPFC) has previously been implicated in logical reasoning under conditions of conflict. A functional magnetic resonance imaging (fMRI) study was conducted to explore its role in conflict more precisely. Specifically, we distinguished between belief-logic conflict and belief-content conflict, and examined the role of rlPFC under each condition. The results demonstrated that a specific region of rlPFC is consistently activated under both types of conflict. Moreover, the results of a parametric analysis demonstrated that the same region was modulated by the level of conflict contained in reasoning arguments. This supports the idea that this specific region is engaged to resolve conflict, including during deductive reasoning. This article is part of a Special Issue entitled "The Cognitive Neuroscience of Thought". PMID- 21684532 TI - [Myopericytoma with a lipomatous component]. PMID- 21684533 TI - Comparison of cardiac magnetic resonance imaging features of isolated left ventricular non-compaction in adults versus dilated cardiomyopathy in adults. AB - AIM: To compare cardiac magnetic resonance imaging (MRI) features between isolated left ventricular non-compaction (IVNC) and dilated cardiomyopathy (DCM) in adults. MATERIALS AND METHODS: A consecutive series of 50 patients with IVNC from a single institution were reviewed. During the same period, 50 patients with DCM who had prominent trabeculations, who were matched for age, gender, and body surface area, were prospectively included. Left ventricular (LV) morphology and function were assessed using cardiac MRI. RESULTS: Compared with patients with DCM, patients with IVNC had a significantly lower LV sphericity index and end diastolic volume index (LVEDVI) and a greater LV ejection fraction (LVEF), number of trabeculated segments, and ratio of non-compacted to compacted myocardium (NC/C ratio). There were no significant differences in stroke volume index, cardiac output, and cardiac index between the two patient groups. In patients with IVNC, the number of trabeculated segments and the NC/C ratio correlated positively with LVEDVI (r=0.626 and r=0.559, respectively) and negatively with LVEF (r=-0.647 and r=-0.521, respectively, p<0.001 for all). In patients with DCM, the number of non-compacted segments and the NC/C ratio had no correlation with either the LVEDVI (r=-0.082 and r=-0.135, respectively) or the LVEF (r=0.097 and r=0.205, respectively). CONCLUSION: There are demonstrable morphological and functional differences between IVNC and DCM at LV assessment using cardiac MRI. The occurrence of trabeculated myocardium might be due to a different pathophysiological mechanism. PMID- 21684534 TI - Omental infarction caused by laparoscopy-assisted gastrectomy for gastric cancer: CT findings. AB - AIM: To investigate the computed tomography (CT) imaging features of omental infarction in patients who underwent laparoscopy-assisted gastrectomy (LAG) for gastric cancer. MATERIALS AND METHODS: A retrospective study was performed on 390 patients who underwent LAG for gastric cancer. Two radiologists evaluated the CT images for the presence of omental infarction. The CT pattern was characterized at initial presentation and the evolutional changes were evaluated. The initial CT appearance of omental infarctions were categorized into the following four types: type 1 (ill-defined, heterogeneous, fat density lesion); type 2 (well defined fat density lesion with rim enhancement); type 3 (well-defined heterogeneous lesion with fat component); and type 4 (well-defined heterogeneous lesion without a fat component). RESULTS: Of the 390 patients involved, nine patients (2.3%; six male and three female with a mean age of 57 years) were diagnosed with omental infarction. Infarctions averaged 4.1 cm (range 2-7.3 cm) in diameter. Among nine patients with omental infarction, two patients had type 1 lesions, two had type 2, two had type 3, and three type 4. All infarctions became smaller and better defined with evolution. In two patients who presented with type 1 lesions on initial CT, each lesion was progressed to type 2 and type 3 on follow-up CT. In two patients with type 3 lesions on initial CT, the lesions changed to type 4 on follow-up CT. CONCLUSION: An awareness of the various CT features and evolutional changes in omental infarction after LAG for gastric cancer can help ensure the correct diagnosis and to avoid misdiagnosis for omental implants. PMID- 21684535 TI - Anatomical analysis of incidental left atrial diverticula in patients with suspected coronary artery disease using 64-channel multidetector CT. AB - AIM: To describe and evaluate anatomical characterizations of incidental left atrial (LA) diverticula in patients with suspected coronary artery disease using 64-channel multidetector computed tomography (MDCT). MATERIALS AND METHODS: From October 2008 to June 2009, 2059 patients with suspected coronary artery disease underwent electrocardiogram-gated 64-channel MDCT. Five hundred and thirty-two LA diverticula were identified in 377 patients (18.3%, male to female ratio: 216:161, mean age 59+/-10.89 years, range from 20 to 91 years). Two radiologists retrospectively analysed the number (single or multiple), size (diameter and length), shape (cystiform or tubiform), surface (smooth or irregular), and location (right or mid or left/upper or lower/lateral or posterior). If the length/diameter was <1.5, the diverticular shape was considered to be cystiform. RESULTS: Among 532 LA diverticula, single (270/532, 51.1%), cystiform (411/532, 77.3%), and smooth (332/532, 62.4%) diverticula were found. The right upper region (255/532, 47.9%) was the most common location, followed by the left lateral area (172/532, 32.3%). The average diameter was 4.7+/-2 mm (range from 1 19 mm), and the average length was 4.7+/-2.1 mm (range 1-13 mm). The average ratio of length to diameter was 1.15 (range 0.25-1.45). The average number of diverticula was 2+/-1.06 (range 1-5). CONCLUSION: Incidental LA diverticulum is not an uncommon finding in patients with suspected coronary artery disease. MDCT can provide anatomical details of LA diverticula. However, further studies are needed to determine their clinical significance. PMID- 21684536 TI - Quality of life in major depressive disorder: the role of pain and pain catastrophizing cognition. AB - OBJECTIVE: Pain symptoms are frequent complaints in patients with major depressive disorder (MDD). Although it is known that pain intensity and pain related cognition predict quality of life (QOL) in patients with chronic pain, limited studies have examined their roles in MDD. The study aimed to determine whether pain and pain catastrophizing were independent predictors of QOL in MDD after accounting for the impact of anxiety and depression. METHODS: This is a prospective, naturalistic follow-up study. Ninety-one Chinese patients were enrolled during an acute episode of MDD, 82 of them were reassessed 3 months later using the same assessment on pain, anxiety, depression, and QOL. Pain intensity was evaluated using a verbal rating scale and a visual analog scale. Quality of life was assessed using the 36-item Short Form Health Survey. Pain related cognition was assessed at baseline with the Pain Catastrophizing Scale. RESULTS: There was significant improvement in pain, anxiety, depression, and QOL from baseline to 3-month follow-up. Hierarchical regression analyses showed that pain intensity was significantly associated with QOL at baseline and 3 months. Pain complaint was more important than anxiety and depressive symptoms in predicting changes in both physical and psychosocial domains of QOL. After controlling for the severity of pain, anxiety, and depression, Pain Catastrophizing Scale score was independently associated with QOL in MDD. CONCLUSION: The study supports the specific role of pain and pain-related cognition in predicting QOL in depressed patients. Further studies targeting pain related cognition for improving the outcome of MDD are necessary. PMID- 21684537 TI - John Hughlings Jackson and the clinico-anatomical correlation method. PMID- 21684538 TI - Associations of polychlorinated biphenyl exposure and endogenous hormones with diabetes in post-menopausal women previously employed at a capacitor manufacturing plant. AB - There is an increasing body of literature showing associations of organochlorine exposure with risk of diabetes and insulin resistance. Some studies suggest that associations differ by gender and that diabetes risk, in turn, may be affected by endogenous steroid hormones. This report examines the relationships of serum PCBs and endogenous hormones with history of diabetes in a cohort of persons previously employed at a capacitor manufacturing plant. A total of 118 women were post-menopausal with complete data, of whom 93 were not using steroid hormones in 1996, at the time of examination, which included a survey of exposure and medical history, height, weight and collection of blood and urine for measurements of lipids, liver function, hematologic markers and endogenous hormones. This analysis examines relationships of serum polychlorinated biphenyls (PCBs), work exposure and endogenous hormones with self-reported history of diabetes after control for potential confounders. All PCB exposure groups were significantly related to history of diabetes, but not to insulin resistance as measured by the homeostatic model assessment of insulin resistance (HOMA-IR) in non-diabetics. Diabetes was also independently and inversely associated with follicle stimulating hormone (FSH), dehydroepiandrosterone sulfate (DHEAS) and triiodothyronine (T3) uptake. HOMA-IR was positively associated with body mass index (BMI) and C-reactive protein (CRP) and inversely associated with sex hormone binding globulin (SHBG) and T3 uptake after control for PCB exposure. Possible biologic mechanisms are discussed. This study confirms previous reports relating PCB exposure to diabetes and suggests possible hormonal pathways deserving further exploration. PMID- 21684539 TI - The short-term influence of temperature on daily mortality in the temperate climate of Montreal, Canada. AB - The purpose of this study was to determine whether short-term changes in ambient temperature were associated with daily mortality among persons who lived in Montreal, Canada, and who died in the urban area between 1984 and 2007. We made use of newly developed distributed lag non-linear Poisson models, constrained to a 30 day lag period, and we adjusted for temporal trends and nitrogen dioxide and ozone. We found a strong non-linear association with high daily maximum temperatures showing an apparent threshold at about 27 degrees C; this association persisted until about lag 5 days. For example, we found across all lag periods that daily non-accidental mortality increased by 28.4% (95% confidence interval: 13.8-44.9%) when temperatures increased from 22.5 to 31.8 degrees C (75-99th percentiles). This association was essentially invariant to different smoothers for time. Cold temperatures were not found to be associated with daily mortality over 30 days, although there was some evidence of a modest increased risk from 2 to 5 days. The adverse association with colder temperatures was sensitive to the smoother for time. For cardio-respiratory mortality we found increased risks for higher temperatures of a similar magnitude to that of non accidental mortality but no effects at cold temperatures. PMID- 21684540 TI - Determinants of serum concentrations of 1,1-dichloro-2,2-bis(p chlorophenyl)ethylene and polychlorinated biphenyls among French women in the CECILE study. AB - BACKGROUND: Dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) are persistent organochlorine compounds bioaccumulating in human tissues. Body burden of organochlorines may be influenced by individual characteristics such as age, weight variations, breastfeeding, dietary habits and place of residence. OBJECTIVES: To assess the current serum concentrations of 1,1-dichloro 2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), the main DDT breakdown product, and of PCBs in women from two French administrative areas (Ille-et-Vilaine and Cote d'Or). To identify determinants of the current serum levels among individual characteristics related to intake, metabolism, and excretion of organochlorines. METHODS: We measured serum p,p'-DDE and PCB levels in 1055 general population women who were recruited in 2005-2007 to serve as controls in a case-control study on breast cancer. Associations between organochlorine levels and age, current body mass index (BMI), BMI change during the last 10 years, dietary habits, breastfeeding history, residence area and education were assessed in multivariate analyses. RESULTS: Median concentrations of p,p'-DDE and total PCBs were 85 and 240ng/g lipid, respectively. Based on multivariate analyses, the main predictors of high p,p'-DDE levels included age and frequent consumption of saltwater fish in women below 50 years, and high BMI in older women. Total PCB levels increased markedly with age. Among older women, other important predictors of high PCB levels included frequent consumption of saltwater fish and low BMI. Our results are also suggestive of an inverse association between PCB levels and BMI gain during the last ten years. Women in Cote d'Or had significantly higher PCB levels than women in Ille-et-Vilaine. CONCLUSION: The patterns of associations between determinants and serum organochlorine concentrations suggest that human PCB contamination is still ongoing in France. The most important predictors of serum p,p'-DDE and PCB concentrations among French women include age, body mass index, dietary habits, and place of residence. PMID- 21684541 TI - Bisphenol-A and phthalates contamination of urine samples by catheters in the Elfe pilot study: implications for large-scale biomonitoring studies. AB - Exposure to phthalates and Bisphenol A could cause developmental and reproductive toxicity. This study provides a first assessment of these exposures for more than 250 French pregnant women. The median concentrations of total and free Bisphenol A in urine were similar to those in other studies except the highest concentrations (5% of women had total and free Bisphenol A >50MUg/L). Our study highlights high levels of Di-(2-ethylhexyl)-phthalate metabolites in pregnant women, suggesting recent exposure, probably in hospital. Differences between types of delivery (caesarean vs. natural) support this hypothesis. This is a significant implication for large-scale biomonitoring studies among this population. PMID- 21684542 TI - Simvastatin improves morphological and functional recovery of sciatic nerve injury in Wistar rats. AB - AIM: The purpose of this work is to investigate the effects of simvastatin on sciatic nerve regeneration in male Wistar Rats. MATERIALS AND METHODS: Forty animals were allocated into four groups: (1) control (C); (2) control+simvastatin (CS); (3) lesioned animals+sterile PBS (LC) and (4) lesioned animals+simvastatin (LS). Lesioned animals were submitted to crushing lesion of right sciatic nerve. Simvastatin (20mg/kg/day, i.p.) was administered for five days. Footprints were obtained weekly for evaluation of functional locomotor recovery by means of the Sciatic Function Index (SFI). Blood samples were obtained weekly for quantifying circulating leukocytes. Animals were sacrificed after 21 days for histological analyses of sciatic nerve and spleen. RESULTS: LS Animals presented increased SFI scores, decreased areas of oedema and mononuclear cell infiltration during Wallerian degeneration and nerve regeneration (7,14 and 21 days; P<0.05). Spleen weight and white pulp areas was increased in LC animals after 21 days. Increased numbers of circulating neutrophils were observed in simvastatin treated animals (CS e LS) at seven, 14 and 21 days, compared to non-treated groups (C and LC). CONCLUSION: The study suggests that simvastatin accelerates the morphological and functional recovery process of the peripheral nervous system interfering with innate and acquired immunity. PMID- 21684543 TI - Validity of outcome measures used to assess one and six month outcomes in orthopaedic trauma patients. AB - INTRODUCTION: To evaluate the validity of the 12-item Short Form Health Survey (SF-12), Sickness Impact Profile (SIP) and the Short Musculoskeletal Functional Assessment Questionnaire (SMFA) for use in an orthopaedic trauma population. MATERIALS AND METHODS: A prospective validation trial was completed at a Level 1 adult trauma centre in Melbourne, Australia. One hundred and fifty four patients with orthopaedic trauma managed or followed-up by an orthopaedic unit were prospectively recruited. Patients with pathological fractures related to metastatic disease and/or an isolated orthopaedic injury, a documented history of mental illness or dementia or those for whom follow-up was likely to be difficult were excluded. The SF-12, SIP and SMFA were administered by a trained interviewer at one and six months. Each questionnaire was scored for the physical and mental components and then compared for content and construct validity at each time point. RESULTS: Complete data were collected for 134 patients at one and six months. The one and six month component scores correlated strongly between the SF 12 physical, SIP physical (r=0.513-0.669) and SMFA dysfunction (r=0.529-0.778); the SF-12 mental, SIP mental (r=0.643-0.719) and SMFA bother (r=0.564-0.602) components. The strength of association was greater for the six month time point compared to the one month measure. The SF-12 demonstrated no ceiling or floor effects, and provided a lower time burden on participants and researchers when compared to the SIP and SMFA. CONCLUSIONS: For large population-based surveillance research into orthopaedic injury the SF-12 provides a valid and versatile tool. PMID- 21684544 TI - Myoglobin clearance by continuous venous-venous haemofiltration in rhabdomyolysis with acute kidney injury: reply to letter. PMID- 21684545 TI - Levels of service user satisfaction in secure settings--a survey of the association between perceived social climate, perceived therapeutic relationship and satisfaction with forensic services. AB - BACKGROUND: The interests of users should lead service developments. However, it has been claimed that forensic mental health services have largely ignored examining users' views on the nature and quality of the service offered to them. Perceived social climate and perceived therapeutic relationship are viewed as important indicators of treatment outcome; however previous findings about how these variables may be associated with satisfaction with forensic services are equivocal. OBJECTIVES: This study aims to assess the levels of service user satisfaction in forensic in-patient settings in one mental health trust and explore how the perceived therapeutic relationship of the service users with their key-workers and the perceived social climate of the wards are associated with service user satisfaction. DESIGN: A cross-sectional survey design was chosen and an independent researcher facilitated the completion of three standardised assessments measuring service user satisfaction, therapeutic relationships and the social climate of the ward. METHOD: Forty-four service users detained in secure settings completed the standardised assessments. The study was conducted in four medium secure and three low secure units in one NHS mental health trust. The data was analysed to examine the level of satisfaction with services and how both the therapeutic relationship and the ward environment were related to levels of satisfaction. RESULTS: The majority of service users who responded were generally satisfied with services; "rehabilitation" and "perceived safety" were viewed most positively. Service users' perceptions about the social climate of the ward were found to have a significant relationship with service users' satisfaction with forensic services. However, the variables with the strongest association with satisfaction with forensic services are service users' perceptions about the nature of therapeutic relations with staff. CONCLUSIONS: This study indicates that service users' satisfaction with forensic services is strongly associated with their experiences of the therapeutic relationship with their key-workers and the social climate of the ward. The findings emphasize the importance of forming and maintaining effective therapeutic relations and reinforce the need to maintain a therapeutic environment free of aggressive tension and threats of violence. The results also highlight the potential for service users to be dissatisfied with their financial situation following admission. PMID- 21684546 TI - Impact of omega-3 polyunsaturated fatty acids on coronary plaque instability: an integrated backscatter intravascular ultrasound study. AB - OBJECTIVE: To assess the impact of omega-3 polyunsaturated fatty acids (omega3 PUFAs) on coronary plaque instability. METHODS: Serum content of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) was measured in 336 of 368 consecutive patients suspected of having coronary artery disease who underwent coronary angiography. Conventional and integrated backscatter intravascular ultrasound (IB-IVUS) parameters were analyzed in 116 patients with 128 coronary plaques, using a 43-MHz (motorized pullback 0.5mm/s) intravascular catheter (View It, Terumo Co., Japan). Lipid-rich plaques were classified into two categories according to their components. RESULTS: Patients with acute coronary syndrome had significantly lower levels of omega3 PUFAs (especially of EPA and DPA) than those without it. IB-IVUS analyses showed that omega3 PUFAs correlated inversely with % lipid volume and positively with % fibrous volume. Patients with low EPA levels, low DPA levels, and low DHA levels had a significantly higher % lipid volume (p=0.048, p=0.008, and p=0.036, respectively) and a significantly lower % fibrous volume (p=0.035, p=0.008, and p=0.034, respectively) than those with high levels of these fatty acids. Even after adjustment for confounders, the presence of both low EPA and low DPA levels proved to be an independent predictor for lipid-rich plaques in any of the two categories. CONCLUSIONS: A lower serum content of omega3 PUFAs (especially of EPA and DPA) was significantly associated with lipid-rich plaques, suggesting the contribution to the incidence of acute coronary syndrome. PMID- 21684547 TI - Influence of protein and stationary phase properties on protein-matrix interaction in cation exchange chromatography. AB - A large number of different stationary phases for ion-exchange chromatography from different manufacturers are available, which vary significantly in a number of chemical and physical properties. As a consequence, binding mechanisms may be different as well. In the work reported here, the retention data of model proteins (lysozyme, cytochrome c and two monoclonal antibodies) were determined for nine commercially available cation-exchange adsorbents. The linear gradient elution model in combination with a thermodynamic approach was used to analyse the characteristic parameters of the protein-stationary phase-interactions. Based on the pH dependency of the characteristic charge and the equilibrium constant for binding the differences between the standard Gibbs energies in the adsorbed and the solute state for the protein DeltaG(P) degrees and the salt DeltaG(S) degrees were calculated. The characteristic charge B of the proteins strongly depends on the molecular mass of the protein. For small proteins like lysozyme there is almost no influence of the stationary phase chemistry on B, while for the Mabs the surface modification strongly influences the B value. Surface extenders or tentacles usually increase the B values. The variation of the characteristic charge of the MABs is more pronounced the lower the pH value of the mobile phase is, i.e. the higher the negative net charge of the protein is. The standard Gibbs energy changes for the proteins DeltaG(P) degrees are higher for the Mabs compared to lysozyme and more strongly depend on the stationary phase properties. Surface modified resins usually show higher DeltaG(P) degrees and higher B values. A correlation between DeltaG(P) degrees and B is not observed, indicating that non-electrostatic interactions as well as entropic factors are important for DeltaG(P) degrees while for the B values the accessibility of binding sites on the protein surface is most important. PMID- 21684548 TI - The three-dimensional model for helical columns on type-J synchronous counter current chromatography. AB - Unlike the existing 2-D pseudo-ring model for helical columns undergoing synchronous type-J planetary motion of counter-current chromatograph (CCC), the 3 D "helix" model developed in this work shows that there is a second normal force (i.e. the binormal force) applied virtually in the axial direction of the helical column. This force alternates in the two opposite directions and intensifies phase mixing with increasing the helix angle. On the contrary, the 2-D spiral column operated on the same CCC device lacks this third-dimensional mixing force. The (principal) normal force quantified by this "helix" model has been the same as that by the pseudo-ring model. With beta>0.25, this normal centrifugal force has been one-directional and fluctuates cyclically. Different to the spiral column, this "helix" model shows that the centrifugal force (i.e. the hydrostatic force) does not contribute to stationary phase retention in the helical column. Between the popular helical columns and the emerging spiral columns for type-J synchronous CCC, this work has thus illustrated that the former is associated with better phase mixing yet poor retention for the stationary phase whereas the latter has potential for better retention for the stationary phase yet poor phase mixing. The methodology developed in this work may be regarded as a new platform for designing optimised CCC columns for analytical and engineering applications. PMID- 21684549 TI - A theoretical plate model accounting for slow kinetics in chromatographic elution. AB - The chromatographic elution has been studied from different perspectives. However, in spite of the simplicity and evident deficiencies of the plate model proposed by Martin and Synge, it has served as a basis for the characterization of columns up-to-date. This approach envisions the chromatographic column as an arbitrary number of theoretical plates, each of them consisting of identical repeating portions of mobile phase and stationary phase. Solutes partition between both phases, reaching the equilibrium. Mobile phase transference between the theoretical plates is assumed to be infinitesimally stepwise (or continuous), giving rise to the mixing of the solutions in adjacent plates. This yields an additional peak broadening, which is added to the dispersion associated to the equilibrium conditions. It is commonly assumed that when the solute concentration is sufficiently small, chromatographic elution is carried out under linear conditions, which is the case in almost all analytical applications. When the solute concentration increases above a value where the stationary phase approximates saturation (i.e. becomes overloaded), non-linear elution is obtained. In addition to overloading, another source of non-linearity can be a slow mass transfer. An extended Martin and Synge model is here proposed to include slow mass-transfer kinetics (with respect to flow rate) between the mobile phase and stationary phase. We show that there is a linear relationship between the variance and the ratio of the kinetic constants for the mass transfer in the flow direction (tau) and the mass transfer between the mobile phase and stationary phase (nu), which has been called the kinetic ratio (kappa=tau/nu). The proposed model was validated with data obtained according to an approach that simulates the solute migration through the theoretical plates. An experimental approach to measure the deviation from the equilibrium conditions using the experimental peak variances and retention times at several flow rates is also proposed. PMID- 21684550 TI - Nanoscale repulsive forces between mica and silica surfaces in aqueous solutions. AB - Nanoscale repulsive forces between mineral surfaces in aqueous solutions were measured for the asymmetric mica-silica system. The force measured with an atomic force microscope (AFM) has universal character in the short range, less than ~1 nm or about 3-4 water molecules, independent of solution conditions, that is, electrolyte ion (Na, Ca, Al), concentration (10(-6)-10(-2)M), and pH (3.9-8.2). Notably, the force is essentially the same as for the glass-silica system. Single force curves for a mica-silica system in a 10(-4)M aqueous NaCl solution at pH ~ 5.1 show oscillations with a period of about 0.25 nm, roughly the diameter of a water molecule, a consequence of a layer-by-layer dehydration of the surfaces when pushed together. This result provides additional support to the idea that nanoscale repulsive forces between mineral surfaces in aqueous solutions arise from a surface-induced water effect; the water between two mineral plates that are pushed together becomes structured and increasingly anchored to the surface of the plates by the creation of a hydrogen-bonding network that prevents dehydration of the surfaces. PMID- 21684551 TI - Isolation and partial characterization of a biosurfactant mixture produced by Sphingobacterium sp. isolated from soil. AB - Strain 6.2S, isolated from soil and identified as a Sphingobacterium sp., is the first strain in this genus to be reported as a biosurfactant producer, being able to reduce the surface tension of its culture supernatant to 32 mN/m. In this work, biosurfactants from the culture supernatant were purified and partially characterized. The crude extract (10 g/L) was very effective in reducing surface tension (22 mN/m). Thin layer chromatography (TLC) indicated that a mixture of various biosurfactants was present in the 6.2S crude extract. After purification, Fraction A, a phospholipid mixture, reduced surface tension to 33 mN/m. Fraction B was a mixture of lipopetides and at least one glycolipid. The surface tension concentration curve showed two plateaux, the first of which can be attributed to a critical aggregation concentration of the biosurfactant with a protein (2.7 g/L) and the second to the true cmc in water (6.3g/L). PMID- 21684552 TI - Neuroanatomical correlates of depression and apathy in Parkinson's disease: magnetic resonance imaging studies. AB - Depression and apathy are among the most common neuropsychiatric disturbances in Parkinson's disease (PD), and among the most important factors associated with a poor quality of life. However, their neural bases remain unclear. The results of the magnetic resonance imaging (MRI) studies on depression in PD differ dramatically. Some of them proposed a role of morphologic changes in the mediodorsal thalamus. In contrast to previous voxel-based morphometry (VBM) data, our study did not confirm a decrease in gray matter (GM) density in any brain region of depressed PD patients. Instead, a more severe white matter (WM) loss in the right frontal lobe was found, including the anterior cingulate bundle and the inferior orbitofrontal (OF) region. We suggested that the negative correlation between the severity of depression and WM density in the right OF region reinforces the hypothesis of depression in PD as a "disconnection syndrome". Only one MRI study using VBM found that high apathy scores correlated with low GM density values in the right (posterior) cingulate gyrus and the bilateral inferior frontal gyrus, in line with the findings in Alzheimer's disease and elderly adults with major depression. PMID- 21684554 TI - Lobectomy leads to optimal survival in early-stage small cell lung cancer: a retrospective analysis. AB - OBJECTIVE: Stage I or II small cell lung cancer is rare. We evaluated the contemporary incidence of early-stage small cell lung cancer and defined its optimal local therapy. METHODS: We analyzed the incidence, treatment patterns, and outcomes of 2214 patients with early-stage small cell lung cancer (1690 with stage I and 524 with stage II) identified from the Surveillance, Epidemiology, and End Results database from 1988 to 2005. RESULTS: Early-stage small cell lung cancer constituted a stable proportion of all small cell lung cancers (3%-5%), lung cancers (0.10%-0.17%), and stage I lung cancers (1%-1.5%) until 2003 but, by 2005, increased significantly to 7%, 0.29%, and 2.2%, respectively (P < .0001). Surgery for early-stage small cell lung cancer peaked at 47% in 1990 but declined to 16% by 2005. Patients treated with lobectomy or greater resections (lobe) without radiotherapy had longer median survival (50 months) than those treated with sublobar resections (sublobe) without radiotherapy (30 months, P = .006) or those treated with radiotherapy alone (20 months, P < .0001). Patients undergoing sublobe without radiotherapy also demonstrated superior survival than patients receiving radiotherapy alone (P = .002). The use or omission of radiotherapy made no difference after limited resection (30 vs 28 months, P = .6). Multivariable analysis found survival independently related to age, year of diagnosis, tumor size, stage, and treatment (lobe vs sublobe vs radiotherapy alone). CONCLUSIONS: Surgery is an underused modality in the management of early-stage small cell lung cancer. Lobectomy provides optimal local control and leads to superior survival. Although sublobar resection proved inferior to lobectomy, it conferred a survival advantage superior to radiotherapy alone. The addition of radiotherapy to resection provided no additional benefit. PMID- 21684555 TI - Prevalence and trends of urinary incontinence in adults in the United States, 2001 to 2008. AB - PURPOSE: We estimate trends in the prevalence of urinary incontinence in the adult population of the United States from 2001 through 2008 before and after adjusting for other potential associated factors. MATERIALS AND METHODS: We analyzed data on 17,850 adults 20 years old or older who participated in the 2001 to 2008 cycles of the National Health and Nutrition Examination Survey. Any urinary incontinence was defined as a positive response to questions on urine leakage during physical activity, before reaching the toilet and during nonphysical activity. During this period changes in demographic and clinical factors associated with urinary incontinence included age, race/ethnicity, obesity, diabetes and chronic medical conditions (prostate disease in men). Age standardized prevalence estimates and prevalence ORs of urinary incontinence trends were determined using adjusted multivariate models with appropriate sampling weights. RESULTS: The age standardized prevalence of urinary incontinence in the combined surveys was 51.1% in women and 13.9% in men. Prevalence in women increased from 49.5% in 2001 to 2002, to 53.4% in 2007 to 2008 (Ptrend=0.01) and in men from 11.5% to 15.1%, respectively (Ptrend=0.01). In women increased prevalence was partially explained by differences in age, race/ethnicity, obesity, diabetes and select chronic diseases across the survey periods. After adjustment the prevalence OR for 2007 to 2008 vs 2001 to 2002 decreased from 1.22 (95% CI 1.03-1.45) to 1.16 (95% CI 0.99-1.37). In men adjustment for potentially associated factors did not explain the increasing prevalence of urinary incontinence. CONCLUSIONS: The age standardized prevalence of urinary incontinence increased in men and women from 2001 through 2008. Decreasing obesity and diabetes may lessen the burden of urinary incontinence, especially in women. PMID- 21684556 TI - Lower urinary tract changes in young adults using ketamine. AB - PURPOSE: We identified the profile of lower urinary tract changes in ketamine users in the community. In addition, we identified the relative risks of dose, frequency of ingestion and duration of ketamine use for changes in lower urinary tract function. MATERIALS AND METHODS: A mobile medical assessment service was established at specific youth centers, and subjects who were known to social workers and who had a history of ketamine use were invited to participate in health screening. Lower urinary tract function was evaluated using the Pelvic Pain, Urgency and Frequency questionnaire, and uroflowmetry and ultrasonography. RESULTS: Use of ketamine more than 3 times weekly was significantly associated with lower voided volumes. Pelvic Pain, Urgency and Frequency questionnaire scores were significantly higher for ketamine use for more than 24 months compared to use for short durations (7.82 vs 6.00). The scores on the symptom and bother subscales of the Pelvic Pain, Urgency and Frequency questionnaire decreased progressively with increased duration of abstinence. For individuals after 1 year of abstinence the Pelvic Pain, Urgency and Frequency questionnaire scores were significantly lower and voided volumes were higher than those for active users. CONCLUSIONS: Ketamine users with at least a 2-year habit of 3 or more hits per week have altered bladder function that can be recognized and that causes bother. These early functional changes have the potential to normalize after 1 year of ketamine abstinence. This study provides a basis for the development of health promotion material that can be used in the community by welfare workers seeking to encourage drug cessation. PMID- 21684557 TI - A clinical nomogram to predict the successful shock wave lithotripsy of renal and ureteral calculi. AB - PURPOSE: Although shock wave lithotripsy is dependent on patient and stone related factors, there are few reliable algorithms predictive of its success. In this study we develop a comprehensive nomogram to predict renal and ureteral stone shock wave lithotripsy outcomes. MATERIALS AND METHODS: During a 5-year period data from patients treated at our lithotripsy unit were reviewed. Analysis was restricted to patients with a solitary renal or ureteral calculus 20 mm or less. Demographic, stone, patient, treatment and 3-month followup data were collected from a prospective database. All patients were treated using the Philips Lithotron(r) lithotripter. RESULTS: A total of 422 patients (69.7% male) were analyzed. Mean stone size was 52.3+/-39.3 mm2 for ureteral stones and 78.9+/ 77.3 mm2 for renal stones, with 95 (43.6%) of the renal stones located in the lower pole. The single treatment success rates for ureteral and renal stones were 60.3% and 70.2%, respectively. On univariate analysis predictors of shock wave lithotripsy success, regardless of stone location, were age (p=0.01), body mass index (p=0.01), stone size (p<0.01), mean stone density (p<0.01) and skin to stone distance (p<0.01). By multivariate logistic regression for renal calculi, age, stone area and skin to stone distance were significant predictors with an AUC of 0.75. For ureteral calculi predictive factors included body mass index and stone size (AUC 0.70). CONCLUSIONS: Patient and stone parameters have been identified to create a nomogram that predicts shock wave lithotripsy outcomes using the Lithotron lithotripter, which can facilitate optimal treatment based decisions and provide patients with more accurate single treatment success rates for shock wave lithotripsy tailored to patient specific situations. PMID- 21684558 TI - Early versus late maturation arrest: reproductive outcomes of testicular failure. AB - PURPOSE: There is a paucity of data characterizing infertile men with maturation arrest. We hypothesized that men with early stage maturation arrest could be clinically distinguished from men with late maturation arrest and would have worse reproductive outcomes. MATERIALS AND METHODS: We retrospectively reviewed the records of all patients with nonobstructive azoospermia and cryptozoospermia who underwent testis mapping and sperm extraction from 2002 to 2009 and for whom histopathological findings were available. Patients had uniform maturation arrest if multiple biopsies revealed maturation arrest at the spermatogonia/spermatocyte (early maturation arrest) or the spermatid (late maturation arrest) stage. Clinical parameters and pregnancy outcomes of in vitro fertilization/intracytoplasmic sperm injection were examined. Statistical analysis consisted of univariate and multivariate analysis. RESULTS: Uniform maturation arrest was identified in 49 of 219 men (22.3%) undergoing testicular sperm extraction. On multivariate analysis men with maturation arrest had significantly larger testes (p=0.01), decreased follicle-stimulating hormone (p=0.05) and more detectable genetic abnormalities (p=0.01) than men with other histopathological conditions. Men with late maturation arrest had decreased follicle-stimulating hormone (p=0.02), increased testosterone (p=0.03) and a higher sperm retrieval rate at testicular sperm extraction (p=0.01) than men with early maturation arrest. Predictors of successful sperm retrieval were larger testes, cryptozoospermia, late maturation arrest and hypospermatogenesis (each p<=0.05). Pregnancy outcomes for men with maturation arrest were not significantly different from those for men with other histopathological conditions. CONCLUSIONS: Maturation arrest is a common, diverse histopathological subtype of severe male infertility. Compared to men with late maturation arrest those with early maturation arrest have increased follicle-stimulating hormone, decreased testosterone and a decreased probability of mature spermatozoa. In vitro fertilization/intracytoplasmic sperm injection outcomes were similar when spermatozoa were discovered during testicular sperm extraction. PMID- 21684559 TI - Mid-term complications after placement of the male adjustable suburethral sling: a single center experience. AB - PURPOSE: In recent years various sling systems have been proposed as a successful treatment option for male stress urinary incontinence. Reports about complication rates and failures are still scarce. MATERIALS AND METHODS: We systematically reevaluated 29 male patients who received an Argus(r) suburethral sling for stress urinary incontinence between October 2006 and July 2007. RESULTS: Overall 24 patients (83%) experienced a total of 37 complications at a median followup of 35 months (range 29 to 45), including 10 (35%) in acute urinary retention. The sling was removed in 10 patients (35%) due to urethral erosion (3), infection (2), system dislocation (2), urinary retention (2) and persistent pain (1). Eight men (27%) complained of significant perineal pain, necessitating continuous oral analgesics. In 1 patient ureteral reimplantation was done due to ureteral erosion from a dislocated sling. At followup only 5 men (17%) remained dry while 21 (72%) were dissatisfied with the clinical outcome. No available clinical variables were statistically significantly associated with any grade or high grade complications even on univariate analysis. CONCLUSIONS: In our study cohort the Argus suburethral sling was associated with serious mechanical and infectious complications, and sparse functional results with negative impact on patient quality of life. Based on the results of this study significant changes are warranted in the sling system and in the implantation technique. PMID- 21684560 TI - Early evaluation of coastal nutrient over-enrichment: new procedures and indicators. AB - Recent studies have provided compelling evidence for an accelerated anthropogenic impact on coastal systems, resulting in intense inputs of materials and nutrients from the continent. This has led scientists and policymakers to encourage the implementation of monitoring programmes, which have resulted in the multiplicity of datasets. However surprisingly, only a few attempts have been made to couple observations with statistical and mathematical tools to detect, as soon as the data become available perturbations in coastal systems. Here, we propose new mathematical procedures to evaluate the state of a system, based on the building of relative reference state and indicators of nutrient over-enrichment. The techniques were tested in some French coastal systems using data from the programme SOMLIT. Applied to this dataset, the multivariate procedures rapidly identified and evaluated anthropogenic nutrient anomalies from the continent on three sites (Wimereux, Roscoff and Villefranche-sur-Mer) from 1997 onwards. PMID- 21684561 TI - The Department of Veterans Affairs Nursing Academy (VANA): forging strategic alliances with schools of nursing to address nursing's workforce needs. AB - In 2007, the Department of Veterans Affairs (VA) established the VA Nursing Academy (VANA), a 5-year, $60-million pilot program funding 15 partnerships between schools of nursing and local VA health care facilities nationwide, to expand nursing faculty, enhance clinical faculty development, increase nursing student enrollment, and promote educational innovations. VA is an ideal setting for educating nursing students owing to a well-educated registered nurse staff, an array of traditional and nontraditional settings, a state-of-the-art computerized electronic health record system, and a unique patient population. Challenges related to the complex nature of VANA partnerships, conceptualized as strategic alliances created between disparate subunits, each embedded in a larger organization, require careful governance to ensure smooth implementation. To ensure the program's aims are met, a 6-year national evaluation has been funded to help identify which strategies best achieve VANA's goals. The speed of economic recovery and the resulting changes in the nursing workforce are important determinants of VANA's future. PMID- 21684562 TI - Nursing documentation: how meaning is obscured by fragmentary language. AB - This article looks at the effect of using fragmentary language in nursing documentation. Fragmentary language is defined as phrases and abbreviations found in records of nursing care that are understood at the local ward level but would make it difficult for anyone reading the documentation beyond this local level to construct meaning. Sixty-seven entries of nursing documentation were investigated using textual analysis. Each entry was examined to determine how grammatical and linguistic features of the text could impede meaning. Three entries are discussed in detail to demonstrate possible difficulty for readers in understanding the patient's condition and care. Education programs that encourage nurses to view their documentation as a crucial aspect of care are recommended. Writing nursing documentation in a manner that allows readers from both within and outside the profession to understand the patient's condition and care required is supported. If readers cannot understand what is written in nursing documentation, there is a danger that misinterpretations could lead to clinical errors and adverse events. PMID- 21684563 TI - Graduate nursing education in China. AB - Despite the relatively long history of nursing education, the development of graduate nursing education in the People's Republic of China is slow compared to western countries. Yet, rapid social changes call for higher quality nursing care. Consequently, the Chinese government has acknowledged the need to upgrade nursing education in China. The first master of nursing program was established in 1992. Since then graduate programs have grown dramatically in the past 17 years and this growth has had a vital impact on nursing development. However, a number of issues have been raised concerning the focus of graduate programs. This article presents a comprehensive description on the current status, problems, and strategies used in graduate nursing education in mainland China. PMID- 21684564 TI - Coping styles relate to health and work environment of Norwegian and Dutch hospital nurses: a comparative study. AB - Nurses exposed to high nursing stress report no health complaints as long as they have high coping abilities. The purpose of this study was to investigate coping styles in relation to the health status and work environment of Norwegian and Dutch hospital nurses. This comparative study included a random sample of 5400 Norwegian nurses and a convenience sample of 588 Dutch nurses. Coping, health, and work environment were assessed by questionnaire in both samples and associations were investigated bivariately and multivariately. We found that active problem-solving coping was associated with the health and work environment of Norwegian nurses but not with the health and work environment of Dutch. Passive coping (avoiding problems or waiting to see what happens) was found to relate to poor general health, poor mental health, low job control, and low job support in both Norwegian and Dutch nurses. Improvements in the nursing work environment may not only result in better mental health, but may also reduce passive coping. PMID- 21684565 TI - Design element alternatives for stress-management intervention websites. AB - Typical public and military-sponsored websites on stress and depression tend to be prescriptive. Some require users to complete lengthy questionnaires. Others reproduce printed flyers, papers, or educational materials not adapted for online use. Some websites require users to follow a prescribed path through the material. Stress Gym was developed as a first-level, evidence-based, website intervention to help U.S. military members learn how to manage mild to moderate stress and depressive symptoms using a self-help intervention with progress tracking and 24/7 availablility. It was designed using web-based, health management intervention design elements that have been proven effective and users reported they prefer. These included interactivity, self-pacing, and pleasing aesthetics. Users learned how to manage stress by accessing modules they choose, and by practicing proven stress management strategies interactively immediately after login. Test results of Stress Gym with Navy members demonstrated that it was effective, with significant decreases in reported perceived stress levels from baseline to follow-up assessment. Stress Gym used design elements that may serve as a model for future websites to emulate and improve upon, and as a template against which to compare and contrast the design and functionality of future online, health-intervention websites. PMID- 21684566 TI - Molecular data of UL24 homolog gene (ORF37) from Brazilian isolates of equine herpesvirus type 1. AB - Equine herpesvirus type 1 (EHV-1) is associated with abortions, respiratory distress, and neurological disturbances in horses. The ORF37 of EHV-1 encodes a protein homolog to UL24 gene product of human herpesvirus that has been associated with neurovirulence. In the present work, ORF37 PCR fragments derived from two Brazilian EHV-1 isolates, a German isolate and an American reference strain were sequenced and characterized by molecular phylogenetic analysis. This genomic region is highly conserved an allowed to infer genetic distances between EHV-1 strains and other animal herpesvirus. PMID- 21684567 TI - Accuracy of routine diagnostic tests used in paracoccidioidomycosis patients at a university hospital. AB - The identification of appropriate laboratory measures to confirm clinical hypotheses is important in routine paracoccidioidomycosis medical care. The clinical records and laboratory reports of 401 paracoccidioidomycosis patients attended at the Tropical Diseases Area, Faculdade de Medicina de Botucatu, from 1974 to 2008 were reviewed. Direct mycological (DM), cell block (CB), histopathological (HP), and double immunodiffusion (DID) tests were evaluated before treatment. Typical Paracoccidioides brasiliensis yeast forms were observed in clinical specimens of 86% of the patients, but 14% were detected only by serological test. DM of 51 different tissue specimens produced 74.5% sensitivity, and 62.5% sensitivity was observed in 112 sputum samples. CB in 483 sputum samples generated 55.3% sensitivity. HP performed in 239 samples from different tissues revealed 96.7% sensitivity. Serology carried out in 351 patients and 200 healthy controls provided 90.0% sensitivity, 100.0% specificity, 100.0% positive predictive value, 85.1% negative predictive value and 93.6% accuracy. Comparisons of laboratory measurements performed in the same patient showed that sensitivity decreases from HP to DID to CB and DM, with the last two assays providing similar sensitivities. This study demonstrated that P. brasiliensis identification by HP, CB, and/or DM associated with DID is sufficient to establish the laboratorial diagnosis of paracoccidioidomycosis in practically all cases. PMID- 21684568 TI - Development of a 64 channel ultrasonic high frequency linear array imaging system. AB - In order to improve the lateral resolution and extend the field of view of a previously reported 48 element 30 MHz ultrasound linear array and 16-channel digital imaging system, the development of a 256 element 30 MHz linear array and an ultrasound imaging system with increased channel count has been undertaken. This paper reports the design and testing of a 64 channel digital imaging system which consists of an analog front-end pulser/receiver, 64 channels of Time-Gain Compensation (TGC), 64 channels of high-speed digitizer as well as a beamformer. A Personal Computer (PC) is used as the user interface to display real-time images. This system is designed as a platform for the purpose of testing the performance of high frequency linear arrays that have been developed in house. Therefore conventional approaches were taken it its implementation. Flexibility and ease of use are of primary concern whereas consideration of cost effectiveness and novelty in design are only secondary. Even so, there are many issues at higher frequencies but do not exist at lower frequencies need to be solved. The system provides 64 channels of excitation pulsers while receiving simultaneously at a 20-120 MHz sampling rate to 12-bits. The digitized data from all channels are first fed through Field Programmable Gate Arrays (FPGAs), and then stored in memories. These raw data are accessed by the beamforming processor to re-build the image or to be downloaded to the PC for further processing. The beamformer that applies delays to the echoes of each channel is implemented with the strategy that combines coarse (8.3 ns) and fine delays (2 ns). The coarse delays are integer multiples of the sampling clock rate and are achieved by controlling the write enable pin of the First-In-First-Out (FIFO) memory to obtain valid beamforming data. The fine delays are accomplished with interpolation filters. This system is capable of achieving a maximum frame rate of 50 frames per second. Wire phantom images acquired with this system show a spatial resolution of 146 MUm (lateral) and 54 MUm (axial). Images with excised rabbit and pig eyeball as well as mouse embryo were also acquired to demonstrate its imaging capability. PMID- 21684569 TI - Superior human leukocyte reconstitution and susceptibility to vaginal HIV transmission in humanized NOD-scid IL-2Rgamma(-/-) (NSG) BLT mice. AB - Humanized Bone marrow/Liver/Thymus (BLT) mice recapitulate the mucosal transmission of HIV, permitting study of early events in HIV pathogenesis and evaluation of preexposure prophylaxis methods to inhibit HIV transmission. Human hematopoiesis is reconstituted in NOD-scid mice by implantation of human fetal liver and thymus tissue to generate human T cells plus intravenous injection of autologous liver-derived CD34(+) hematopoietic stem cells to engraft the mouse bone marrow. In side-by-side comparisons, we show that NOD-scid mice homozygous for a deletion of the IL-2Rgamma-chain (NOD-scid IL-2Rgamma(-/-)) are far superior to NOD-scid mice in both their peripheral blood reconstitution with multiple classes of human leukocytes (e.g., a mean of 182 versus 14 CD4(+) T cells per MUl 12 weeks after CD34(+) injection) and their susceptibility to intravaginal HIV exposure (84% versus 11% viremic mice at 4 weeks). These results should speed efforts to obtain preclinical animal efficacy data for new HIV drugs and microbicides. PMID- 21684570 TI - Phytoplankton community succession shaping bacterioplankton community composition in Lake Taihu, China. AB - PCR-denaturing gradient gel electrophoresis (DGGE) and canonical correspondence analysis (CCA) were used to explore the relationship between succession of phytoplankton community and temporal variation of bacterioplankton community composition (BCC) in the eutrophic Lake Taihu. Serious Microcystis bloom was observed in July-December 2008 and Bacillariophyta and Cryptophyta dominated in January-June 2009. BCC was characterized by DGGE of 16S rRNA gene with subsequent sequencing. The DGGE banding patterns revealed a remarkable seasonality which was closely related to phytoplankton community succession. Variation trend of Shannon Wiener diversity index in bacterioplankton community was similar to that of phytoplankton community. CCA revealed that temperature and phytoplankton played key roles in structuring BCC. Sequencing of DGGE bands suggested that the majority of the sequences were affiliated with common phylogenetic groups in freshwater: Alphaproteobacteria, Betaproteobacteria, Bacteroidetes and Actinobacteria. The cluster STA2-30 (affiliated with Actinobacteria) was found almost across the sampling time at the two study sites. We observed that the family Flavobacteriaceae (affiliated with Bacteroidetes) tightly coupled to diatom bloom and the cluster ML-5-51.2 (affiliated with Actinobacteria) dominated the bacterioplankton communities during Microcystis bloom. These results were quite similar at the two sampling sites, indicating that BCC changes were not random but with fixed pattern. Our study showed insights into relationships between phytoplankton and bacterioplankton communities at species level, facilitating a better understanding of microbial loop and ecosystem functioning in the lake. PMID- 21684571 TI - Redistribution of free tropospheric chemical species over West Africa: radicals (OH and HO2), peroxide (H2O2) and acids (HNO3 and H2SO4). AB - The purpose of this paper is to study the redistribution of chemical species (OH, HO(2), H(2)O(2), HNO(3) and H(2)SO(4)) over West Africa, where the cloud cover is ubiquitously present, and where deep convection often develops. In this area, because of these cloud systems, chemical species are redistributed by the ascending and descending flow, or leached if they are soluble. So, we carry out a mesoscale study using the Regional Atmospheric Modelling System (RAMS) coupled to a code of gas and aqueous chemistry (RAMS_Chemistry). It takes into account all processes under mesh. We examine several cases following the period (November and July), with inputs emissions (anthropogenic, biogenic and biomass burning). The radicals OH and HO(2) are an indicator of possibilities for chemical activity. They characterize the oxidizing power of the atmosphere and are very strong oxidants. The acids HNO(3) and H(2)SO(4) are interesting in their transformation into nitrates and sulfates in precipitation. In November, when photochemistry is active during an event of biomass burning, concentrations of chemical species are higher than those of November in the absence of biomass burning. The concentrations of nitric acid double and sulfuric acid increases 70times. In addition, the concentrations are even lower in July if there is a deep convection. Compared to measures of the African Monsoon Multidisciplinary Analysis (AMMA), the results and observations of radicals OH and HO(2) are the same order of magnitude. Emissions from biomass burning increase the concentrations of acid and peroxide, and a deep convection cloud allows the solubility and the washing out of species, reducing their concentration. Rainfalls play a major role in solubility and washing out acids, peroxides and radicals in this region. PMID- 21684572 TI - Biodegradation and bio-sorption of antibiotics and non-steroidal anti inflammatory drugs using immobilized cell process. AB - In the present study, the removal mechanisms of four antibiotics (sulfamethoxazole, sulfadimethoxine, sulfamethazine, and trimethoprim) and four non-steroidal anti-inflammatory drugs (acetaminophen, ibuprofen, ketoprofen, and naproxen) in immobilized cell process were investigated using batch reactors. This work principally explores the individual or collective roles of biodegradation and bio-sorption as removal routes of the target pharmaceuticals and the results were validated by various experimental and analytical tools. Biodegradation and bio-sorption were found as dominant mechanisms for the drug removal, while volatilization and hydrolysis were negligible for all target pharmaceuticals. The target pharmaceuticals responded to the two observed removal mechanisms in different ways, typically: (1) strong biodegradability and bio sorption by acetaminophen, (2) strong biodegradability and weak bio-sorption by sulfamethoxazole, sulfadimethoxine, ibuprofen and naproxen, (3) low biodegradability and weak bio-sorption by sulfamethazine and ketoprofen, and (4) low biodegradability and medium bio-sorption by trimethoprim. In the sorption/desorption experiment, acetaminophen, sulfamethoxazole and sulfadimethoxine were characterized by strong sorption and weak desorption. A phenomenon of moderate sorption and well desorption was observed for sulfamethazine, trimethoprim and naproxen. Both ibuprofen and ketoprofen were weakly sorbed and strongly desorbed. PMID- 21684573 TI - Chemical composition of rainwater at a coastal town on the southwest of Europe: what changes in 20 years? AB - Rainwater was collected at the Portuguese west coast between September 2008 and September 2009, and analysed for pH, conductivity, and Cl-, NO3-, SO42-, and NH4+ concentrations. Results of rainwater chemical composition were compared with those obtained at the same site between 1986 and 1989. In both collection periods rainwater was predominantly (~ 80%) associated to oceanic air masses. The rainwater concentration of H+ was in the same range as twenty years ago. A clear decrease of non sea salt sulphate (NSS-SO42-) was observed in 2008-2009 relatively to 1986-1989, not only in samples with origin in central and northern Europe, but also in samples from Atlantic Ocean and Mediterranean. This decrease indicates that SO2 emissions were reduced, which may be due to a lower content of sulphur in oil by-products. A decrease was also observed in NH4+ concentration in 2008-2009. On the contrary an increase of NO3- concentration was observed for samples of all origins in 2008-2009 relatively to 1986-1989, which was particularly high (more than 3 fold) for samples with origin in Atlantic Ocean, suggesting the incorporation of this ion by rainout at the sampling site. The contribution of local sources is indeed suggested by the moderate negative correlation of NH4+, NO3- and NSS-SO42- with rainwater volume. The high increase of NO3- concentration can be attributed to the increase of local vehicular and industrial emissions in the sampling area. PMID- 21684574 TI - Temporal trends of Hg in Arctic biota, an update. AB - A statistically robust method was applied to 83 time-series of mercury in Arctic biota from marine, freshwater and terrestrial ecosystems with the purpose of generating a 'meta-analysis' of temporal trend data collected over the past two to three decades, mostly under the auspices of the Arctic Monitoring and Assessment Program (AMAP). Sampling locations ranged from Alaska in the west to northern Scandinavia in the east. Information from recently published temporal trend studies was tabulated to supplement the results of the statistical analyses. No generally consistent trend was evident across tissues and species from the circumpolar Arctic during the last 30years or so. However, there was a clear west-to-east gradient in the occurrence of recent increasing Hg trends, with larger numbers and a higher proportion of biotic datasets in the Canadian and Greenland region of the Arctic showing significant increases than in the North Atlantic Arctic. Most of the increasing datasets were for marine species, especially marine mammals. A total of 16 (19%) out of the 83 time-series could be classified as "adequate", where adequate is defined as the number of actual monitoring years in a time-series being equal to or greater than the number of years of sampling required to detect a 5% annual change in Hg concentrations, with a significance level of P<0.05 and 80% statistical power. At the time of the previous AMAP Assessment, only 10% of the Hg time-series were deemed adequate. If an additional 5years of data were to be added to the current set of time-series, it is predicted that 53% of time-series would become adequate. PMID- 21684575 TI - Biomonitoring of Cd, Cr, Hg and Pb in the Baluarte River basin associated to a mining area (NW Mexico). AB - With the purpose of knowing seasonal variations of Cd, Cr, Hg and Pb in a river basin with past and present mining activities, elemental concentrations were measured in six fish species and four crustacean species in Baluarte River, from some of the mining sites to the mouth of the river in the Pacific Ocean between May 2005 and March 2006. In fish, highest levels of Cd (0.06 MUg g -1 dry weight) and Cr (0.01 MUg g-1) were detected during the dry season in Gobiesox fluviatilis and Agonostomus monticola, respectively; the highest levels of Hg (0.56 MUg g-1) were detected during the dry season in Guavina guavina and Mugil curema. In relation to Pb, the highest level (1.65 MUg g-1) was detected in A. monticola during the dry season. In crustaceans, highest levels of Cd (0.05 MUg g-1) occurred in Macrobrachium occidentale during both seasons; highest concentration of Cr (0.09 MUg g-1) was also detected in M. occidentale during the dry season. With respect to Hg, highest level (0.20 MUg g-1) was detected during the rainy season in Macrobrachium americanum; for Pb, the highest concentration (2.4 MUg g 1) corresponded to Macrobrachium digueti collected in the dry season. Considering average concentrations of trace metals in surficial sediments from all sites, Cd (p<0.025), Cr (p<0.10) and Hg (p<0.15) were significantly higher during the rainy season. Biota sediment accumulation factors above unity were detected mostly in the case of Hg in fish during both seasons. On the basis of the metal levels in fish and crustacean and the provisional tolerable weekly intake of studied elements, people can eat up to 13.99, 0.79 and 2.34 kg of fish in relation to Cd, Hg and Pb, respectively; regarding crustaceans, maximum amounts were 11.33, 2.49 and 2.68 kg of prawns relative to levels of Cd, Hg and Pb, respectively. PMID- 21684576 TI - Extremely low frequency magnetic field measurements in buildings with transformer stations in Switzerland. AB - The aim of this study was to evaluate an exposure assessment method that classifies apartments in three exposure categories of extremely low frequency magnetic fields (ELF-MF) based on the location of the apartment relative to the transformer room. We completed measurements in 39 apartments in 18 buildings. In each room of the apartments ELF-MF was concurrently measured with 5 to 6 EMDEX II meters for 10 min. Measured arithmetic mean ELF-MF was 0.59 MUT in 8 apartments that were fully adjacent to a transformer room, either directly above the transformer or touching the transformer room wall-to-wall. In apartments that only partly touched the transformer room at corners or edges, average ELF-MF level was 0.14 MUT. Average exposure in the remaining apartments was 0.10 MUT. Kappa coefficient for exposure classification was 0.64 (95%-CI: 0.45-0.82) if only fully adjacent apartments were considered as highly exposed (>0.4 MUT). We found a distinct ELF-MF exposure gradient in buildings with transformer. Exposure classification based on the location of the apartment relative to the transformer room appears feasible. Such an approach considerably reduces effort for exposure assessment and may be used to eliminate selection bias in future epidemiologic studies. PMID- 21684577 TI - Acute non-cancer mortality excess after polychlorinated biphenyls and polychlorinated dibenzofurans mixed exposure from contaminated rice oil: Yusho. AB - In Japan in 1968, rice-oil contaminated by polychlorinated biphenyls and polychlorinated dibenzofurans caused severe food poisoning, termed "Yusho" (oil disease). Several previous studies attempted to evaluate the effects targeting officially-certified Yusho patients. However, these studies have several limitations such as the left-truncated nature of the registry or residual confounding arising from the referent population selection. We thus conducted an area-based standardized mortality ratios (SMRs) study using vital statistics. A severely affected area (Tamanoura area) was adopted as the exposure group, with a reference population from Nagasaki prefecture in Kyushu, which included the Tamanoura. A large number of residents in Tamanoura were exposed to the rice-oil (28% of all the certified cases as of 2009). We estimated SMRs of non-cancer and cancer diseases for the years 1968-2002. Shortly after the exposure, SMRs of all causes, diabetes mellitus, cardiovascular disease, pneumonia/bronchitis, and bronchus/lung cancer were elevated. In particular, SMRs of heart disease were 1.97 [95% confidence intervals (CI): 1.09-3.56] in 1968, 2.05 (95% CI: 1.16-3.60) in 1969, and 1.89 (95% CI: 1.05-3.41) in 1975. However, we did not observe clear increase in SMRs more than 10 years after the exposure. This study provides further evidence in Yusho, especially on acute effects on non-cancer mortality. PMID- 21684578 TI - Health risk associated with dietary co-exposure to high levels of antimony and arsenic in the world's largest antimony mine area. AB - Like arsenic (As), antimony (Sb) is known to be a genotoxic element in vitro and in vivo. Sb is now recognized as a global contaminant and has aroused the global concerns recently. However, knowledge is scarce concerning the transfer of Sb from the environment to humans and the related hazards to human health. In this pilot study, the health risk and main pathway of long-term human exposure to Sb and As for residents around Chinese Xikuangshan (XKS) Sb mine, the world's largest Sb mine, were evaluated by dietary exposure and hair accumulations survey. The concentrations and species of Sb and As in food samples (n=209) from three main categories and six subcategories, and in hair samples (n=89) were determined. Residents in the vicinity of XKS had an estimated dietary intake of Sb (554 MUg/day) which was 1.5 times higher than the tolerable daily intake (TDI) (Sb, 360 MUg/day), whereas their dietary intake of inorganic As (107 MUg/day) was slightly lower than the provisional tolerable weekly intake (PTWI) of 15 MUg/kg BW/week (equal to 129 MUg As/day). Hair Sb and As concentrations (Sb, 15.7 mg/kg, DW; As, 3.99 mg/kg, DW) in XKS residents are both above the normal/toxic level. Rice, vegetables (especially leafy vegetable), drinking water, and meat/poultry were the dominant dietary intake sources of Sb for the residents. In contrast, rice was the uniquely dominant dietary intake source of As. Antimonate (Sb(V)) was the dominant Sb species in vegetables, drinking water and residents' hairs. This study highlighted the difference of exposure characteristics between Sb and As. The preliminary results suggested that dietary exposures to Sb, rather than As, was the dominant health risk to local residents. Nevertheless, the adverse effects of As levels on the health of residents still can not be ignored since the elevated As concentrations in human hair have reached the critical level for health risks. In addition, this pilot study did not consider the possible Sb and As combined effects. PMID- 21684579 TI - Exploring an ecotoxicity database with the OECD (Q)SAR Toolbox and DRAGON descriptors in order to prioritise testing on algae, daphnids, and fish. AB - The European regulation on chemicals (REACh) places emphasis on reduction of systematic toxicity testing, thus fostering development of alternative methods. Consequently, we analysed acute toxicity data gathered by the Japanese Ministry of Environment for three species belonging to three different trophic levels (i.e., Pseudokirchneriella subcapitata 72-hour EC50, Daphnia magna 48-hour EC50 and Oryzias latipes 96-hour LC50). This paper investigates the relationships between the chemical structure and both the toxicity of the chemicals and the cross-species differences in sensitivity. The physicochemical properties of the chemicals were represented by the categories they belonged to in several widely used categorisation schemes implemented by the freely available OECD (Q)SAR Toolbox and by quantitative molecular descriptors using DRAGON software. The outputs of these software products were analysed and compared in terms of quality of prediction and biological interpretation. Amongst the categorisations implemented by the OECD Toolbox, those focussing on bioaccumulation or biotransformation appeared to be the most interesting in terms of environmental prediction on a whole set of chemicals, in particular as the predicted biotransformation half-life is strongly dependent on hydrophobicity. In predicting toxicity towards each species, simple linear regression on logP performed better than PLS regression of toxicity on a very large set of molecular descriptors. However, the predictions based on the interspecies correlations performed better than the QSAR predictions. The results in terms of cross-species comparisons encourage the use of test strategies focussing on reducing the number of tests on fish. PMID- 21684580 TI - Occurrence and concentrations of pharmaceutical compounds in groundwater used for public drinking-water supply in California. AB - Pharmaceutical compounds were detected at low concentrations in 2.3% of 1231 samples of groundwater (median depth to top of screened interval in wells=61 m) used for public drinking-water supply in California. Samples were collected statewide for the California State Water Resources Control Board's Groundwater Ambient Monitoring and Assessment (GAMA) Program. Of 14 pharmaceutical compounds analyzed, 7 were detected at concentrations greater than or equal to method detection limits: acetaminophen (used as an analgesic, detection frequency 0.32%, maximum concentration 1.89 MUg/L), caffeine (stimulant, 0.24%, 0.29 MUg/L), carbamazepine (mood stabilizer, 1.5%, 0.42 MUg/L), codeine (opioid analgesic, 0.16%, 0.214 MUg/L), p-xanthine (caffeine metabolite, 0.08%, 0.12 MUg/L), sulfamethoxazole (antibiotic, 0.41%, 0.17 MUg/L), and trimethoprim (antibiotic, 0.08%, 0.018 MUg/L). Detection frequencies of pesticides (33%), volatile organic compounds not including trihalomethanes (23%), and trihalomethanes (28%) in the same 1231 samples were significantly higher. Median detected concentration of pharmaceutical compounds was similar to those of volatile organic compounds, and higher than that of pesticides. Pharmaceutical compounds were detected in 3.3% of the 855 samples containing modern groundwater (tritium activity>0.2 TU). Pharmaceutical detections were significantly positively correlated with detections of urban-use herbicides and insecticides, detections of volatile organic compounds, and percentage of urban land use around wells. Groundwater from the Los Angeles metropolitan area had higher detection frequencies of pharmaceuticals and other anthropogenic compounds than groundwater from other areas of the state with similar proportions of urban land use. The higher detection frequencies may reflect that groundwater flow systems in Los Angeles area basins are dominated by engineered recharge and intensive groundwater pumping. PMID- 21684581 TI - Copper clean-up procedure for ultrasonic extraction and analysis of pyrethroid and phenylpyrazole pesticides in sediments by gas chromatography-electron capture detection. AB - A rapid ultrasonic extraction method coupled with a heated-copper clean-up procedure for removing interfering constituents was developed for analyzing pyrethroid and phenylpyrazole pesticides in sediments. Incubation of the 60 mL extract with 12 g copper granules at 60 degrees C for 2h was determined to be the optimal conditions for removing the interfering constituents. Eleven pyrethroid and phenylpyrazole pesticides were spiked into sediment samples to determine the effectiveness of the ultrasonic extraction method. The average recoveries of pyrethroids and phenylpyrazoles in sediment at 4 degrees C storage on day 0, 1, 7, 14, and 21 ranged from 98.6 to 120.0%, 79.2 to 116.0%, 85.0 to 119.7%, 93.6 to 118.7%, and 92.1 to 118.2%, respectively, with all percent relative standard deviations less than 10% (most <6%). This illustrated the stability of pyrethroids and phenylpyrazoles in sediment during sediment aging at 4 degrees C. Recoveries of the pesticides ranged from 98.6% to 120.0% for lowest fortification level (2-16 MUg kg-1), from 97.8% to 117.9% for middle fortification level (10-80 MUg kg-1), and from 94.3% to 118.1% for highest fortification level (20-160 MUg kg-1). Relative standard deviations of pesticide recoveries were usually less than 7%. Method detection limits of target pesticides ranged from 0.22 MUg kg-1 to 3.72 MUg kg-1. Furthermore, field sediment samples collected from four residential lakes during a three-month monitoring period were analyzed to evaluate the effectiveness of this method. Bifenthrin was detected in all of sediment samples (highest concentration 260.33+/-41.71 MUg kg-1, lowest concentration 5.68+/-0.38 MUg kg-1, and fipronil sulfone was detected at least once in sediment samples collected from three sites with concentrations ranging from 1.73+/-0.53 to 7.53+/-0.01 MUg kg-1. PMID- 21684582 TI - Geography and stage of development affect persistent organic pollutants in stranded and wild-caught harbor seal pups from central California. AB - Persistent organic pollutants have been associated with disease susceptibility and decreased immunity in marine mammals. Concentrations of polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane and its metabolites (DDTs), polybrominated diphenyl ethers (PBDEs), chlordanes (CHLDs), and hexachlorocyclohexane isomers (HCHs) were evaluated in terms of stage of development and likely exposure routes (in utero, suckling, fasting) in the blubber of 202 stranded and wild-caught, primarily young of the year (n=177), harbor seals (Phoca vitulina) in the central California coast. This is the first report of HCH concentrations in the blubber of California seals. Lipid normalized concentrations ranged from 200 to 330,000 ng/g for sum PCBs, 320-1,500,000 ng/g for sum DDTs, 23-63,000 ng/g for sum PBDEs, 29-29,000 ng/g for sum CHLDs, and 2 780 ng/g for sum HCHs. The highest concentrations were observed in harbor seal pups that suckled in the wild and then lost mass during the post-weaning fast. Among the pups sampled in the wild and those released from rehabilitation, there were no differences in mass, blubber depth, or percent lipid although contaminant concentrations were significantly higher in the pups which nursed in the wild. When geographic differences were evaluated in a subset of newborn animals collected near their birth locations, the ratio of sum DDTs to sum PCBs was significantly greater in samples from an area with agricultural inputs (Monterey), than one with industrial inputs (San Francisco Bay). A principal components analysis distinguished between seals from San Francisco Bay and Monterey Bay based on specific PCB and PBDE congeners and DDT metabolites. These data illustrate the important influence of life stage, nutritional status, and location on blubber contaminant levels, and thus the need to consider these factors when interpreting single sample measurements in marine mammals. PMID- 21684584 TI - Differential expression patterns of CXCR3 variants and corresponding CXC chemokines in clear cell ovarian cancers and endometriosis. AB - OBJECTIVES: Carcinogenesis of the ovary is often associated with endometriosis. We previously demonstrated that antitumor chemokine receptor CXCR3 was upregulated both in endometriosis and ovarian cancers. Currently, little is known about the roles of CXCR3 variants in these ovarian diseases. In this study, we investigated the expression of CXCR3 variants and their corresponding ligands in endometriosis and ovarian cancers. METHODS: The expression patterns of CXCR3 variants (CXCR3A, CXCR3B and CXCR3-alt) and their corresponding ligands were investigated by quantitative RT-PCR, Western blot and in situ hybridization in normal ovaries (n=16), endometriosis (n=12), and clear cell ovarian cancers (n=22) including endometriosis-coexisting cases (n=11). RESULTS: Sequence analysis of purified RT-PCR products confirmed the presence of three CXCR3 variants in human ovaries. Quantitative RT-PCR analysis revealed differential expression patterns of these variants depending on conditions. CXCR3A was upregulated both in endometriosis and cancers. On the other hand, CXCR3-alt was upregulated and CXCR3B was downregulated in cancers compared with endometriosis. The corresponding ligand CXCL11 was upregulated only in the cancers with elevated CXCR3-alt. Another ligand CXCL4 was downregulated in the cancers with suppressed CXCR3B. In situ hybridization demonstrated preferential expression of CXCR3A in cancer cells and infiltrating lymphocytes. CXCR3B and CXCR3-alt were detectable mainly in microvessels. CONCLUSIONS: Collective data suggest that differential expression patterns of CXC chemokines and CXCR3 variants are involved in specific inflammatory microenvironment of ovarian cancers. Altered balance of CXCR3 variants may become helpful information for better understanding of the pathogenesis of ovarian cancers arising from endometriosis. PMID- 21684583 TI - Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. AB - PURPOSE: The Gynecologic Oncology Group (GOG) conducted a phase II trial to assess the efficacy and tolerability of the anti-EGFR antibody cetuximab, in persistent or recurrent carcinoma of the cervix. PATIENTS AND METHODS: Eligible patients had cervical cancer, measurable disease, and GOG performance status <=2. Treatment consisted of cetuximab 400 mg/m(2) initial dose followed by 250 mg/m(2) weekly until disease progression or prohibitive toxicity. The primary endpoints were progression-free survival (PFS) at 6 months and response. The study used a 2 stage group sequential design. RESULTS: Thirty-eight patients were entered with 3 exclusions, leaving 35 evaluable for analysis. Thirty-one patients (88.6%) received prior radiation as well as either 1 (n=25, 71.4%) or 2 (n=10) prior cytotoxic regimens. Twenty-four patients (68.6%) had a squamous cell carcinoma. Grade 3 adverse events possibly related to cetuximab included dermatologic (n=5), GI (n=4), anemia (n=2), constitutional (n=3), infection (n=2), vascular (n=2), pain (n=2), and pulmonary, neurological, vomiting and metabolic (n=1 each). No clinical responses were detected. Five patients (14.3%; two-sided 90% CI, 5.8% to 30%) survived without progression for at least 6 months. The median PFS and overall survival (OS) times were 1.97 and 6.7 months, respectively. In this study, all patients with PFS at 6 months harbored tumors with squamous cell histology. CONCLUSION: Cetuximab is well tolerated but has limited activity in this population. Cetuximab activity may be limited to patients with squamous cell histology. PMID- 21684585 TI - Predicting gestational trophoblastic neoplasia (GTN): is urine hCG the answer? AB - BACKGROUND: Previous studies on the significance of hCG to predict gestational trophoblastic neoplasia (GTN) have been too small for robust conclusions to be reached. Our aim in this study was to analyse the significance of urine hCG in predicting GTN in a large population. METHODS: Details of 3926 patients were available for analysis. Information regarding age, dates of diagnosis and registration, urine hCG levels, antecedent pregnancy and chemotherapy were prospectively collected and used for analyses. Patients were stratified into different groups according to urine hCG level (IU/L); < 50, 50-99, 100-249, 250 499, 500-999, 1000-9999 and >=10,000. Multivariate analyses were used to identify the prognostic indicators of GTN. RESULTS: Urine hCG and antecedent pregnancy were the most powerful indicators for developing GTN (P<0.01). None of the patients with partial mole and urine hCG <50 IU/L (Normal level=40 IU/L) developed GTN. The risk of GTN was >35% in all patients with urine hCG >=500 IU/L. GTN developed in 70% of patients with complete mole and urine hCG >=10,000 IU/L. CONCLUSION: Urine hCG is sensitive test for GTN. Urine hCG level is a powerful prognostic indicator for the GTN. Patients with partial mole could be safely discharged from the surveillance programme once their hCG have normalised. Patients with urine hCG >=249 IU/L, whether partial or complete molar pregnancy, appear to benefit from intensive surveillance. Prophylactic chemotherapy could be considered when there are problems with surveillance. PMID- 21684586 TI - Asthma is not a syndrome. PMID- 21684587 TI - Regulatory B-cell induction by helminths: implications for allergic disease. AB - Chronic helminth infections are often associated with a reduced prevalence of inflammatory disorders, including allergic diseases. Helminths influence the host immune system by downregulating T-cell responses; the cytokine IL-10 appears to play a central role in this process. Over the last decade, evidence has emerged toward a new regulatory cell type: IL-10-producing B cells, capable of regulating immunity and therefore termed regulatory B cells. Initially, regulatory B cells have been described in autoimmunity models where they dampen inflammation, but recently they were also found in several helminth infection models. Importantly, regulatory B cells have recently been identified in humans, and it has been suggested that patients suffering from autoimmunity have an impaired regulatory B cell function. As such, it is of therapeutic interest to study the conditions in which IL-10-producing B cells can be induced. Chronic helminth infections appear to hold promise in this context as emerging evidence suggests that helminth induced regulatory B cells strongly suppress allergic inflammation. In this review, we will discuss the conditions under which regulatory B cells are present, leading to a state of tolerance, as well as the conditions where their absence or functional impairment leads to exacerbated disease. We will summarize their phenotypic characteristics and their mechanisms of action and elaborate on possible mechanisms whereby regulatory B cells can be induced or expanded, as this may open novel avenues for the treatment of inflammatory diseases, such as allergic asthma. PMID- 21684588 TI - Depression, anxiety, and dermatologic quality of life in adolescents with atopic dermatitis. PMID- 21684589 TI - Possession of epinephrine auto-injectors by Canadians with food allergies. PMID- 21684590 TI - Literal, fictive and metaphorical motion sentences preserve the motion component of the verb: a TMS study. AB - We used Transcranial Magnetic Stimulation (TMS) to assess whether reading literal, non-literal (i.e., metaphorical, idiomatic) and fictive motion sentences modulates the activity of the motor system. Sentences were divided into three segments visually presented one at a time: the noun phrase, the verb and the final part of the sentence. Single pulse-TMS was delivered at the end of the sentence over the leg motor area in the left hemisphere and motor evoked potentials (MEPs) were recorded from the right gastrocnemius and tibialis anterior muscles. MEPs were larger when participants were presented with literal, fictive and metaphorical motion sentences than with idiomatic motion or mental sentences. These results suggest that the excitability of the motor system is modulated by the motor component of the verb, which is preserved in fictive and metaphorical motion sentences. PMID- 21684591 TI - The role of acute and early HIV infection in the spread of HIV and implications for transmission prevention strategies in Lilongwe, Malawi: a modelling study. AB - BACKGROUND: HIV transmission risk is higher during acute and early HIV infection than it is during chronic infection, but the contribution of early infection to the spread of HIV is controversial. We estimated the contribution of early infection to HIV incidence in Lilongwe, Malawi, and predict the future effect of hypothetical prevention interventions targeted at early infection only, chronic infection only, or both stages. METHODS: We developed a deterministic mathematical model describing heterosexual HIV transmission, informed by detailed behavioural and viral-load data collected in Lilongwe. We included sexual contact within and outside of steady pairs and divided the infectious period into intervals to allow for changes in transmissibility by infection stage. We used a Bayesian melding approach to fit the model to HIV prevalence data collected between 1987 and 2005 at Lilongwe antenatal clinics. We assessed interventions that reduced the per-contact transmission probability to 0.00003 in people receiving them, and varied the proportion of individuals receiving the intervention in each stage. FINDINGS: We estimated that 38.4% (95% credible interval 18.6-52.3) of HIV transmissions in Lilongwe are attributable to sexual contact with individuals with early infection. Interventions targeted at only early infection substantially reduced HIV prevalence, but did not lead to elimination, even with 100% coverage. Interventions targeted at only chronic infections also reduced HIV prevalence, but coverage levels of 95-99% were needed for the elimination of HIV. In scenarios with less than 95% coverage of interventions targeted at chronic infections, additional interventions reaching 25-75% of individuals with early infection reduced HIV prevalence substantially. INTERPRETATION: Our results suggest that early infection plays an important part in HIV transmission in this sub-Saharan African setting. Without near-complete coverage, interventions during chronic infection will probably have incomplete effectiveness unless complemented by strategies targeting individuals with early HIV infection. FUNDING: National Institutes of Health, University of North Carolina Center for AIDS Research. PMID- 21684592 TI - Test and treat in HIV: success could depend on rapid detection. PMID- 21684593 TI - Magnetic brain tumor targeting and biodistribution of long-circulating PEG modified, cross-linked starch-coated iron oxide nanoparticles. AB - Magnetic iron oxide nanoparticles (MNPs) have been studied to circumvent the limitations of status-quo brain tumor therapy and can be targeted by applying an external magnetic field to lesions. To address the pharmacokinetic shortcomings of MNPs that can limit targeting efficiency, we recently reported a long circulating polyethylene glycol modified, cross-linked starch MNP (PEG-MNP) suitable for magnetic targeting. Using a rat model, this work explores the biodistribution patterns of PEG-MNPs in organs of elimination (liver, spleen, lung, and kidney) and shows proof-of-concept that enhanced magnetic brain tumor targeting can be achieved due to the relatively long circulation lifetime of the nanoparticles. Reductions in liver (~12-fold) and spleen (~2.5-fold) PEG-MNP concentrations at 1h compared to parent starch-coated MNPs (D) confirm plasma pharmacokinetics observed previously. While liver concentrations of PEG-MNPs remained considerably lower than those observed for D at 1h through 60 h, spleen values continue to increase and are markedly higher at later time points--a trend also observed with histology. Limited to no distribution of PEG-MNPs was visualized in lung or kidney throughout the 60 h course evaluated. Enhanced, selective magnetic brain tumor targeting (t = 1 h) of PEG-MNPs (12 mg Fe/kg) was confirmed in 9L-glioma tumors, with up to 1.0% injected dose/g tissue nanoparticle delivery achieved--a 15-fold improvement over targeted D (0.07% injected dose/g tissue). MRI and histological analyses visually confirmed enhanced targeting and also suggest a limited contribution of passive mechanisms to tissue retention of nanoparticles. Our results are exciting and justify both further development of PEG-MNP as a drug delivery platform and concurrent optimization of the magnetic brain tumor targeting strategy utilized. PMID- 21684594 TI - Uridine-based paramagnetic supramolecular nanoaggregate with high relaxivity capable of detecting primitive liver tumor lesions. AB - The water soluble uridine-based paramagnetic self-assembled amphiphilic molecules (LGd2-5) with DTTA binding site were synthesized and have been characterized in regard to their T(1) magnetic resonance imaging (MRI) contrast agent (CA) properties. The water proton relaxivities have been measured in phosphate buffered saline (PBS) at 36 degrees C at 3 different magnetic fields. Among the self-assembled CAs, LGd3 showed unprecedented, high relaxivities of 30.3 and 23.4 mM(-1) s(-1) in PBS solution at 36 degrees C at 0.47 and 1.41 T, respectively. The non-covalent interactions between the new CAs and human serum albumin (HSA) have been investigated and the relaxivity was further increased by 135-215% depending on alkyl chain lengths. The chemically inertness of these complexes (LGd1, LGd2, LGd3, LGd4) against biologically most abundant metal ion (i.e. Zn(2+)) have shown within the range of commercial DTPA-based CAs. In vivo pharmacokinetics of the complex LGd3 showed highly specific for hepatocytes resulting in increase of contrast noise ratio by ~240% in T(1)-weighted MR images of mouse liver 2 h after injection of the LGd3. It is capable to detect small hepatocellular carcinoma (HCC) with diameter of 1.5 mm. PMID- 21684596 TI - Early and mature endothelial progenitors and VEGFR2+-cells in multiple myeloma: association with disease characteristics and variation in different cell compartments. AB - We analyzed (1) early endothelial progenitors (EPCs; CD34(+)/AC133(+)/VEGFR2(+)), mature EPCs (CD34(+)/VEGFR2(+)) and VEGFR2(+)-cells in bone marrow (BM)-specimens of multiple myeloma (MM)- vs. monoclonal gammopathy (MGUS)-patients and healthy controls; (2) differences of BM-, peripheral blood (PB)- and leukapheresis (LP) samples; and (3) the association of EPCs and VEGFR2(+)-cells with MM-parameters. MM patients demonstrated highest early and mature EPCs and VEGFR2(+)-cells in the BM, particularly with advanced and active disease. Endothelial cells differed in BM-, PB- and LP-specimens, albeit seemed less associated with unfavorable prognostic MM-parameters. Our data suggest that especially VEGFR2(+)-cells and mature EPCs in MM are of value to explore further. PMID- 21684595 TI - Anisotropic material synthesis by capillary flow in a fluid stripe. AB - We present a simple bench-top technique to produce centimeter long concentration gradients in biomaterials incorporating soluble, material, and particle gradients. By patterning hydrophilic regions on a substrate, a stripe of prepolymer solution is held in place on a glass slide by a hydrophobic boundary. Adding a droplet to one end of this "pre-wet" stripe causes a rapid capillary flow that spreads the droplet along the stripe to generate a gradient in the relative concentrations of the droplet and pre-wet solutions. The gradient length and shape are controlled by the pre-wet and droplet volumes, stripe thickness, fluid viscosity and surface tension. Gradient biomaterials are produced by crosslinking gradients of prepolymer solutions. Demonstrated examples include a concentration gradient of cells encapsulated in three dimensions (3D) within a homogeneous biopolymer and a constant concentration of cells encapsulated in 3D within a biomaterial gradient exhibiting a gradient in cell spreading. The technique employs coated glass slides that may be purchased or custom made from tape and hydrophobic spray. The approach is accessible to virtually any researcher or student and should dramatically reduce the time required to synthesize a wide range of gradient biomaterials. Moreover, since the technique employs passive mechanisms it is ideal for remote or resource poor settings. PMID- 21684597 TI - Interventricular septal rupture caused by vehicular trauma. AB - We report the case of a patient admitted at the emergency unit after a severe car accident. As ECG showed a ST segment elevation in all leads, the working diagnosis was coronary dissection. Coronary angiography revealed a large interventricular septal rupture, confirmed by echocardiography. After discussion and as haemodynamics permitted, 6 weeks of medical observation were decided. A surgical repair was then performed, and provided a perfect repair of the shunt. We discuss about the prevalence and management of this rare traumatic complication. PMID- 21684598 TI - Right heart and pulmonary thromboembolism from extensive splanchnic vein thrombosis after splenectomy for myeloproliferative disease. AB - BACKGROUND: Splenectomy is a risk factor for both portal-vein and chronic thromboembolic pulmonary hypertension. The underlying mechanism is unclear, but may involve a hypercoagulable state. METHODS: We describe 1 patient with polycythemia vera who developed extensive portal thrombosis of the portal, suprahepatic, and inferior cava veins, leading to right heart thromboembolism, with a resultant pulmonary embolism subsequent to splenectomy despite heparin prophylaxis. RESULTS: In this patient, several mechanisms may have played a role, including perioperative stress, thrombocytosis, thrombophilia, and associated chronic liver disease. Nevertheless, combined treatment with intravenous heparin and thrombolysis and the myeloproliferative inhibitor hydroxyurea was associated with a favorable outcome. CONCLUSION: The risk of pulmonary thromboembolic complications and their management after splenectomies for hematologic disease warrant further study. PMID- 21684599 TI - Suppression of hepatitis B virus replication in Tupaia hepatocytes by tumor necrosis factor alpha of Tupaia belangeri. AB - Recently, Tupaia belangeri was used to study the full replication cycle of hepatitis B virus (HBV) in the primary hepatocyte cultures. Thus, the Tupaia model represents a suitable model to study the effects of cytokines on HBV infection. Here, Tupaia tumor necrosis factor-alpha (TNF-alpha) was molecularly cloned and expressed in mammalian cells. A test system for the biological activity of Tupaia TNF-alpha was established on the basis of its cytotoxic effect to the murine fibrosarcoma cell line L929. Recombinant Tupaia TNF-alpha was able to suppress HBV replication in primary Tupaia hepatocytes (PTH). However, the formation of HBV covalently closed circular DNA (cccDNA) and viral RNA was not completely prevented. Therefore, Tupaia TNF-alpha may contribute significantly to the control of HBV infection though it is not able to completely inhibit HBV replication alone. The characterization of this important cytokine allows further studies on its antiviral actions in the Tupaia model. PMID- 21684600 TI - Potential health care cost savings associated with early treatment of multiple sclerosis using disease-modifying therapy. AB - BACKGROUND: Clinical trials have shown that treatment with disease-modifying therapies (DMTs), such as interferon, at the time of clinically isolated syndrome can delay the onset of multiple sclerosis (MS). OBJECTIVES: The objective of this study was to assess health care utilization and expenditures associated with treating patients early with DMTs rather than delaying until patients meet the full diagnostic criteria of MS. METHODS: A retrospective study used insurance claims data (2000-2008) of enrolled patients before documented MS (1 inpatient or 2 outpatient claims with International Classification of Diseases, 9th Revision, Clinical Modification 340 coding). Treatment cohorts were early DMT (DMT claim before the first documented MS; N = 227) and delayed DMT (DMT started after documented MS; N = 3724). Comparisons during 1 year of follow-up were adjusted for confounding using multivariate methods. RESULTS: Adjusted annual per-patient expenditures (including patient out of pocket) for early versus delayed were as follows: total ($28,280 vs $29,102; P = 0.44), excluding DMT cost ($15,214 vs $17,630; P < 0.01), and MS-related ($9365 vs $13,661; P < 0.01). Hospitalizations were 10.1% versus 16.5% (adjusted odds ratio [OR] = 0.51; 95% CI, 0.32-0.81). CONCLUSIONS: Analysis indicated that early DMT treatment was associated with fewer hospitalizations than delayed treatment, and there was no statistically significant difference in annual health care expenditures. This suggests that the drug costs of early therapy were offset by savings in other medical expenditures. PMID- 21684601 TI - Survey of Trachoma within school students in the state of Roraima, Brazil. AB - PURPOSE: Trachoma, a blinding conjunctivitis, is the result of repeated infection with Chlamydia trachomatis. There are no recent data for the state of Roraima, Brazil, where it was thought that trachoma no longer existed. These data are derived from school children sampled in this state, with additional data collected from the contacts of children with trachoma. DESIGN: A population-based cross-sectional study with random sampling of students in grades 1 through 4 of all public schools within municipalities where the human development index was less than the national average in 2003. The sample was stratified according to population size. PARTICIPANTS: A sample size of 7200 was determined and a total of 6986 (93%) students were examined, along with an additional 2152 contacts. METHODS: All students were examined for trachoma according to World Health Organization criteria. Demographic data and contact information also was collected. The family and school contacts of students with trachoma then were located and examined. MAIN OUTCOME MEASURES: Prevalence and grade of trachoma, age, gender, race, and municipality location. RESULTS: The overall prevalence of trachoma was 4.5% (95% confidence interval [CI], 3.7%-5.3%), but there were municipalities within the state where the prevalence of inflammatory trachoma was more than 10%. The prevalence was greater in rural areas (4.9%; 95% CI, 3.7% 6.0%) compared with urban areas (3.9%; 95% CI, 2.9%-4.9%). Living in indigenous communities was associated with trachoma (odds ratio, 1.6; 95% CI, 0.9-2.6). An additional 2152 contacts were examined, and the overall trachoma prevalence was 9.3% (95% CI, 8.1-10.5). CONCLUSIONS: Trachoma continues to exist in Roraima, Brazil, where there are municipalities with a significant prevalence of disease. The indigenous population is highly mobile, crossing state and international borders, raising the possibility of trachoma in neighboring countries. Trachoma prevalence among the contacts of students with trachoma was higher than the school population, highlighting the importance of contact tracing. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21684603 TI - Myopia as a risk factor for open-angle glaucoma: a systematic review and meta analysis. AB - OBJECTIVE: To determine the association between myopia and open-angle glaucoma. DESIGN: Systematic review and meta-analysis of observational studies. PARTICIPANTS: Thirteen studies involving 48 161 individuals. METHODS: Articles published between 1994 and 2010 were identified in PubMed, Embase, and reference lists. Study-specific odds ratios (ORs) were pooled using a random effects model. MAIN OUTCOME MEASURES: Odds ratios with 95% confidence intervals (CIs) of myopia as a risk factor for open-angle glaucoma. RESULTS: Data from 11 population-based cross-sectional studies were included in the main analyses. The pooled OR of the association between myopia and glaucoma based on 11 risk estimates was 1.92 (95% CI, 1.54-2.38). On the basis of 7 risk estimates, the pooled ORs of the associations between low myopia (myopia up to -3 D) and glaucoma and between high myopia (<=-3 D myopic) and glaucoma were 1.65 (1.26-2.17) and 2.46 (1.93-3.15), respectively. There was considerable heterogeneity among studies that reported an association between any myopia and glaucoma (I(2)=53%) and low myopia and glaucoma (I(2)=29%), but not for high myopia and glaucoma (I(2)=0%). After omitting studies that contributed significantly to the heterogeneity, the pooled ORs were 1.88 (1.60-2.20) for any myopia and glaucoma and 1.77 (1.41-2.23) for low myopia and glaucoma. CONCLUSIONS: Individuals with myopia have an increased risk of developing open-angle glaucoma. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21684602 TI - Risk factors associated with incident cataracts and cataract surgery in the Age related Eye Disease Study (AREDS): AREDS report number 32. AB - OBJECTIVE: To investigate potential risk factors associated with incident nuclear, cortical, and posterior subcapsular (PSC) cataracts and cataract surgery in participants in the Age-Related Eye Disease Study (AREDS). DESIGN: Clinic based prospective cohort study. PARTICIPANTS: Persons (n = 4425) 55 to 80 years of age enrolled in a controlled clinical trial of antioxidant vitamins and minerals, AREDS, for age-related macular degeneration and cataract. METHODS: Lens photographs were graded centrally for nuclear, cortical, and PSC opacities using the AREDS system for classifying cataracts. Type-specific incident cataracts were defined as an increase in cataract grade from none or mild at baseline to a grade of moderate at follow-up, also with a grade of at least moderate at the final visit, or cataract surgery. Cox regression analyses were used to assess baseline risk factors associated with type-specific opacities and cataract surgery. MAIN OUTCOME MEASURES: Moderate cataract was defined as a grade of 4.0 or more for nuclear opacity, 10% or more involvement within the full visible lens for cortical opacity, and 5% or more involvement of the central 5-mm circle of the lens for PSC opacity. These were graded on baseline and annual lens photographs. RESULTS: A clinic-based cohort of 4425 persons 55 to 80 years of age at baseline was followed up for an average of 9.8+/-2.4 years. The following associations were found: increasing age with increased risk of all types of cataract and cataract surgery; males with increased risk of PSC and decreased risk of cortical cataracts; nonwhite persons with increased risk of cortical cataract; hyperopia with decreased risk of PSC, nuclear cataract, and cataract surgery; Centrum (Wyeth Consumer Healthcare, Madison, NJ) use with decreased risk of nuclear cataract; diabetes with increased risk of cortical, PSC cataract, and cataract surgery; higher educational level with decreased risk of cortical cataract; and smoking with increased risk of cortical cataract and cataract surgery. Estrogen replacement therapy in female participants increased the risk of cataract surgery. CONCLUSIONS: These findings largely are consistent with the results of previous studies, providing further evidence for possible modifiable risk factors for age-related cataract. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21684604 TI - Orbital blowout fractures and race. AB - PURPOSE: To examine the type of orbital blowout fracture and its variation with race. DESIGN: Retrospective review of computed tomography (CT) scans and demography in an unselected cohort of patients with orbital blowout fractures. PARTICIPANTS: Patients with a high-resolution CT scan of adequate quality for analysis who presented with an orbital blowout fracture to the Orbital Clinic at Moorfields Eye Hospital. Patients with fractures involving the orbital rim or the cranium, or with penetrating injuries of the globe or orbit, were omitted from the study. METHODS: Demographic and ethnic information was collected for each patient, and the orbital scans were reviewed by a single observer. On the basis of coronal and axial imaging, a fracture was classified as affecting up to 4 areas: the floor lateral to the infraorbital canal (area 1, "A1"), the floor medial to the canal ("A2"), the maxillo-ethmoidal strut ("inferomedial" strut, "A3"), and the medial wall blowout fracture ("A4"); with fractures involving the inferomedial strut, it was noted whether there was displacement or rotation of the strut. Ethnic origin was classified as Caucasian, Afro-Caribbean, or Asian (Oriental or Indian). MAIN OUTCOME MEASURES: The proportion of different walls involved in orbital blowout fractures within 3 ethnic groups. RESULTS: A total of 152 patients (125 men, 82%) had imaging adequate for analysis; 103 (68%) were Caucasian, 19 (12%) were Afro-Caribbean, and 30 (20%) were Asian. Caucasians most commonly had floor fractures (A1 or A2 in 56 orbits, 54%) compared with 10 of 103 purely medial fractures (A4, 10%); in contrast, medial fractures were the most common type in Afro-Caribbean patients (7/19 cases, 37%), and purely floor fractures occurred in only 2 cases (10%) (P<0.005). Asian patients had results similar to those for Caucasian patients, with isolated floor fractures being the most common (14/30 cases, 47%). CONCLUSIONS: Most blowout fractures involve the orbital floor in Caucasian and Asians, whereas in Afro-Caribbeans the most common site for fracture is the medial wall. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21684605 TI - Clinical relevance of thyroid-stimulating immunoglobulins in graves' ophthalmopathy. AB - PURPOSE: Thyroid-stimulating immunoglobulins (TSIs) likely mediate Graves' ophthalmopathy (GO). The clinical relevance of these functional autoantibodies was assessed in GO. DESIGN: Cross-sectional trial. PARTICIPANTS: A total of 108 untreated patients with GO. METHODS: Thyroid-stimulating immunoglobulins, assessed with a novel bioassay, bind to the thyrotropin receptor (TSHR) and transmit signals for cyclic adenosine monophosphate (cAMP)-dependent activation of luciferase gene expression. The cAMP/cAMP response element-binding protein/cAMP-regulatory element complex induces luciferase that is quantified after cell lysis. The TSI levels were correlated with activity and severity of GO and compared with a TSHR binding inhibitory immunoglobulin (TBII) assay. MAIN OUTCOME MEASURES: Thyroid-stimulating immunoglobulins, activity and severity of GO, diplopia, and TBII. RESULTS: Thyroid-stimulating immunoglobulins were detected in 106 of 108 patients (98%) with GO. All 53 hyperthyroid patients were TSI positive versus 47 patients (89%) who were TBII positive. All 69 patients with active GO were TSI positive, whereas only 58 of 69 patients (84%) were TBII positive. Thyroid-stimulating immunoglobulins correlated with the activity (r=0.83, P < 0.001) and severity (r=0.81, P < 0.001) of GO. All 59 patients with GO with diplopia were TSI positive, and 50 of 59 patients (85%) were TBII positive. Among patients with moderate-to-severe and mild GO, 75 of 75 (100%) and 31 of 33 (94%) were TSI positive compared with TBII positivity in 63 of 75 (84%) and 24 of 33 (73%), respectively. The TSI levels were higher in moderate-to severe versus mild GO (489%+/-137% vs. 251%+/-100%, P < 0.001). Chemosis and GO activity predicted TSI levels alone (P < 0.001, multivariable analysis). The TSI levels were higher in patients with chemosis (527%+/-131%) than in patients without chemosis (313%+/-127%, P < 0.001). CONCLUSIONS: Thyroid-stimulating immunoglobulins show more significant association with clinical features of GO than TBII and may be regarded as functional biomarkers for GO. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21684606 TI - Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. AB - PURPOSE: Assess 12-month efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after branch retinal vein occlusion (BRVO). DESIGN: Prospective, randomized, sham injection-controlled, double-masked, multicenter trial. PARTICIPANTS: A total of 397 patients with macular edema after BRVO. METHODS: Eligible patients were randomized 1:1:1 to 6 monthly injections of 0.3 mg or 0.5 mg ranibizumab or sham injections. After 6 months, all patients with study eye best-corrected visual acuity (BCVA) <=20/40 or central subfield thickness >=250 MUm were to receive ranibizumab. Patients could receive rescue laser treatment once during the treatment period and once during the observation period if criteria were met. MAIN OUTCOME MEASURES: The main efficacy outcome reported is mean change from baseline BCVA letter score at month 12. Additional visual and anatomic parameters were assessed. RESULTS: Mean (95% confidence interval) change from baseline BCVA letter score at month 12 was 16.4 (14.5-18.4) and 18.3 (15.8-20.9) in the 0.3 mg and 0.5 mg groups, respectively, and 12.1 (9.6-14.6) in the sham/0.5 mg group (P<0.01, each ranibizumab group vs. sham/0.5 mg). The percentage of patients who gained >=15 letters from baseline BCVA at month 12 was 56.0% and 60.3% in the 0.3 mg and 0.5 mg groups, respectively, and 43.9% in the sham/0.5 mg group. On average, there was a marked reduction in central foveal thickness (CFT) after the first as needed injection of 0.5 mg ranibizumab in the sham/0.5 mg group, which was sustained through month 12. No new ocular or nonocular safety events were identified. CONCLUSIONS: At month 12, treatment with ranibizumab as needed during months 6-11 maintained, on average, the benefits achieved by 6 monthly ranibizumab injections in patients with macular edema after BRVO, with low rates of ocular and nonocular safety events. In the sham/0.5 mg group, treatment with ranibizumab as needed for 6 months resulted in rapid reduction in CFT to a similar level as that in the 0.3 mg ranibizumab treatment group and an improvement in BCVA, but not to the extent of that in the 2 ranibizumab groups. Intraocular injections of ranibizumab provide an effective treatment for macular edema after BRVO. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21684607 TI - Prevalence of glaucoma in a rural northern china adult population: a population based survey in kailu county, inner mongolia. AB - PURPOSE: To assess the prevalence and types of glaucoma in a rural population in northern China. DESIGN: Population-based cross-sectional study. PARTICIPANTS: Subjects randomly selected from the population 40 years of age and older in Kailu County, Tongliao, Inner Mongolia. METHODS: Each subject underwent a screening examination consisting of an interview and ophthalmic examinations, including applanation tonometry, central corneal thickness, gonioscopy, slit-lamp examination, dilated fundus evaluation, and a screening visual field test using frequency-doubling technology. MAIN OUTCOME MEASURES: Glaucoma was diagnosed using International Society of Geographical and Epidemiological Ophthalmology criteria. RESULTS: Of 5949 individuals 40 years of age and older, 5197 (87.36%) were examined. Of these, 169 (3.28%) had diagnosed glaucoma, giving an age- and gender-standardized prevalence of 2.90% (95% confidence interval, 2.02%-3.78%). The age- and gender-standardized prevalence of primary angle-closure glaucoma (PACG) was 1.42% (95% confidence interval, 0.82%-2.02%) and that for primary open angle glaucoma (POAG) was 1.41% (95% confidence interval, 0.79%-2.02%). Of the 169 subjects with glaucoma, 54 (60%) and 3 (4.1%) had a previous known history of PACG or POAG, respectively. Unilateral blindness resulting from primary glaucoma was observed in 27 subjects (16.56%; 19 PACG/8 POAG), and bilateral blindness was present in 12 subjects (7.36%; 6 PACG/6 POAG). The prevalence of all types of glaucoma was increased with older age. CONCLUSIONS: The adjusted prevalence of glaucoma in this Chinese population was 2.90%, comparable with other data from Asia. The ratio of PACG to POAG was approximately equal. More than 90% of POAG cases previously were undetected, and nearly 30% of subjects with glaucoma were blind in at least 1 eye. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21684608 TI - Retinal video recording a new way to image and diagnose diabetic retinopathy. AB - PURPOSE: To validate the use of retinal video recording for diabetic retinopathy screening by comparing with standard retinal photography and slit-lamp examination. DESIGN: Evaluation of a new diagnostic technique. PARTICIPANTS: One hundred patients. METHODS: All fundus images were captured using standard retinal still photography (FF 450 plus; Carl Zeiss) and retinal video (EyeScan; Ophthalmic Imaging System, Sacramento, CA), followed by a gold standard slit-lamp biomicroscopy examination. All videos and still images were de-identified, randomized, and interpreted by 2 senior consultant ophthalmologists (M.L.T-K. and L.L.). Kappa statistics, sensitivity, and specificity for all the diabetic retinopathy signs and grades were calculated with reference to slit-lamp examination results as the gold standard. MAIN OUTCOME MEASURES: Sensitivity and specificity of video recording for detecting diabetic retinopathy signs and grades. RESULTS: The mean age (+/- standard deviation [SD]) of participants was 52.8 +/- 15.1 years, mean duration of diabetes (+/- SD) was 13.7 +/- 9.7 years, and the mean glycosylated hemoglobin level was 8.0 +/- 1.7%. Compared with the gold standard slit-lamp examination results, the sensitivity and specificity of video recording for detecting the presence of any diabetic retinopathy was 93.8% and 99.2%, respectively (ophthalmologist 1), and 93.3% and 95.2%, respectively (ophthalmologist 2). In contrast, the sensitivity and specificity of retinal photography was 91.8% and 98.4%, respectively (ophthalmologist 1), and 92.1% and 96.8%, respectively (ophthalmologist 2), for detection of any diabetic retinopathy. Both imaging methods had 100% sensitivity and specificity in detecting sight-threatening diabetic retinopathy. For overall diabetic retinopathy grading by both ophthalmologists, the measurements of agreement (Cohen's kappa coefficient) between the overall grading obtained from the retinal video versus slit-lamp examination and retinal photography versus slit-lamp examination were more than 0.90. Technical failure rate for retinal video recording and retinal photography were 7.0% and 5.5%, respectively. CONCLUSIONS: This study demonstrated that retinal video recording was equally as effective as retinal photography in the subjects evaluated in this study. It is a novel alternative diabetic retinopathy screening technique that not only offers primary eye care providers the opportunity to view numerous retinal fields within a short period but also is easy to learn by nonexperienced personnel with minimal training. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21684609 TI - Recurrent lacrimal gland pleomorphic adenoma: clinical and computed tomography features. AB - OBJECTIVE: To report the clinical and computed tomography (CT) features of recurrent lacrimal gland pleomorphic adenoma (LGPA). DESIGN: Retrospective observational case series. PARTICIPANTS: Five patients with recurrent LGPA. METHODS: Clinical records and CT findings in 5 patients with recurrent LGPA were reviewed. MAIN OUTCOME MEASURES: Clinical and CT features, malignant transformation, and disease-free survival. RESULTS: Five patients presented at intervals of 9 to 19 years after initial surgery for LGPA with symptoms and signs of recurrent tumor centered on the lacrimal gland fossa. Four patients underwent surgery to remove recurrent tumor, and 1 patient declined surgical intervention. One of the 4 operated patients was found to have malignant transformation and required craniofacial resection for tumor clearance. One patient had benign recurrence in a previously exenterated orbit and also required a craniofacial resection. Two patients with benign but multifocal recurrence had en bloc resection of tumor, but remain at risk of further recurrence. Computed tomography in all 5 patients revealed irregular bone erosion and remodeling in relation to nodules of recurrent tumor, despite only 1 of these patients having confirmed malignant transformation. Four patients were free of disease at their last follow up at intervals of 9 months to 18 years, including the patient with malignant transformation (14 years follow-up). One patient who declined treatment has been lost to follow-up. CONCLUSIONS: Recurrent LGPA tends to develop multifocally and may be widespread in the operative field. Computed tomography shows recurrent tumor nodules that are often associated with irregular bony erosion and remodeling despite these recurrences being usually benign. Repeated recurrence requiring further surgery with potential significant morbidity remains a lifelong risk, and malignant transformation in recurrent LGPA may also occur. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21684610 TI - Therapeutic processes in multi-family groups for major depression: results of an interpretative phenomenological study. AB - BACKGROUND: Recent research indicates that different couple and family interventions are effective in the treatment of depressed patients. However, how these psychosocial interventions work, has been less well investigated. In order to better understand the underlying treatment processes, helpful treatment experiences of depressive patients and their partners were examined in a multi family therapy group. METHOD: 24 patients hospitalized for depression and 20 partners participated in this study. Therapeutic factors were assessed using an open-ended questionnaire. Responses were analyzed using interpretative phenomenological approach (IPA). RESULTS: Eight recurring therapeutic factors were reported by both the patients and their partners: (1) Presence of others, (2) cohesion and understanding, (3) self-disclosure, (4) openness, (5) discussion, (6) insights, (7) observational experiences and (8) guidance from the therapist. LIMITATIONS: Results were not fed back to the participants following analysis and only therapeutic factors that operate on a conscious level could be identified. CONCLUSIONS: Several important therapeutic factors were identified in multi-family therapy groups for depression. These factors help to gain understanding into the processes, which should be emphasized in treatment and ought to be explored in future outcome and process research. PMID- 21684611 TI - Unmet needs of outpatients with late-life depression; a comparison of patient, staff and carer perceptions. AB - BACKGROUND: There is evidence that late life depression is associated with high levels of unmet needs. Only a minority of the depressed patients appears to be adequately treated. METHODS: Ninety-nine older patients (58-92 years), 96 informal carers and 85 health-care professionals were recruited from six outpatient facilities for old age psychiatry in the Netherlands and interviewed to identify met and unmet needs, using the Camberwell Assessment of Needs for the Elderly (CANE). The severity of depression was measured with the Montgomery Asberg Depression Rating Scale (MADRS). RESULTS: On average patients scored more unmet needs than staff and carers. On item level, patients and staff showed the highest agreement in the psychological needs category. Patient and carers showed the highest agreement on physical health needs. Logistic regression showed that severe depression is a significant predictor of low concordance between stakeholders on a substantial number of CANE items. LIMITATIONS: Kappa coefficients were computed to determine agreement between parties involved. However, Kappa coefficients should be interpreted with caution, especially when obvious disparity in unmet needs scores between groups of interest can be observed. CONCLUSION: Home dwelling older patients with major depressive disorder, their practitioners and their informal carers have different perceptions of the older patients unmet needs.Practitioners should be aware of the negative impact of depression severity on reaching agreement regarding unmet needs and its possible consequences for mutual goal setting and compliance. PMID- 21684612 TI - Prevalence and predictors of posttraumatic growth among adult survivors one year following 2008 Sichuan earthquake. AB - BACKGROUND: The aim of this study was to explore prevalence and predictors of posttraumatic growth, including its relationship with PTSD symptoms among adult survivors of a severe earthquake. METHODS: A stratification random sampling strategy was adopted and 2080 adult survivors of the 2008 Sichuan earthquake were surveyed. Posttraumatic Growth Inventory and Impact of Event Scale - Revised were used in the assessment of posttraumatic growth (PTG) and posttraumatic stress disorder (PTSD) symptoms, respectively. Hierarchical multiple regression analyses were used to explore the best predictors. RESULTS: At one year following the earthquake, prevalence rates for posttraumatic growth and PTSD symptoms were 51.1% and 56.8%, respectively. Best predictors of posttraumatic growth were being female, younger age, higher level of education, higher degree of earthquake related exposure and PTSD symptoms, including intrusion and hyperarousal symptoms. LIMITATIONS: The limitations of this study lie in that no comparison was made due to the lack of pre-disaster data, so it is very hard to conclude to what extent did this earthquake affect the people there. Our participants were mainly workers from different fields. Survey of affected population in rural and remote areas was unavailable. More representative samples are needed to examine the generalizability of these findings. CONCLUSIONS: Psychological interventions and care for survivors of Sichuan earthquake disaster should focus on females and older people who can be more affected by disasters. Besides, in order to produce positive outcomes after disasters, programs on adjustment and management of posttraumatic stress disorder symptoms should be implemented. PMID- 21684614 TI - Gender differences in firesetting: results from the national epidemiologic survey on alcohol and related conditions (NESARC). AB - This study presents gender differences in sociodemographics and in psychiatric correlates of firesetting in the United States. Data were derived from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a representative sample of U.S. adults. Face-to-face interviews of more than 43,000 adults were conducted in the 2001-2002 period. This study focused on the 407 subjects with a lifetime history of firesetting. The prevalence of lifetime firesetting in the U.S. was 1.7% in men and 0.4% in women. Firesetting was significantly associated with a wide range of antisocial behaviors that differed by gender. Multivariate logistic regression analyses indicated associations in both genders with psychiatric and addictive disorders. Men with a lifetime history of firesetting were significantly more likely than men without such history to have lifetime generalized anxiety disorder as well as a diagnosis of conduct disorder, antisocial personality disorder, alcohol or cannabis use disorder, and obsessive-compulsive personality disorder. Women with a lifetime history of firesetting were significantly more likely than women without such history to have lifetime alcohol or cannabis use disorder, conduct disorder, and antisocial or obsessive compulsive personality disorder, as well as psychotic disorder, bipolar disorder or schizoid personality disorder. Women with a lifetime history of firesetting were significantly more likely than men with such history to have a lifetime diagnosis of alcohol abuse and antisocial personality disorder as well as a diagnosis of schizoid personality disorder. Our findings indicate that firesetting in women could represent a behavioral manifestation of a broader spectrum than firesetting in men. PMID- 21684613 TI - Increased health burden associated with comorbid depression in older Brazilians with diabetes. AB - BACKGROUND: The health burden associated with comorbid depression and diabetes in older community residents in middle income countries is unclear. METHODS: Data came from a statewide representative sample (N = 6963, age >= 60) in Brazil. Controlled polytomous logistic regression was used to determine whether four mutually exclusive groups (all possible combinations of the presence or absence of depression and diabetes) differed in sociodemographic characteristics, social resources, health behaviors, and selected health conditions. RESULTS: While 2.37% were expected to have comorbid depression/diabetes given sample base rates (depression: 20.92% [1457/6963]; diabetes: 11.35% [790/6959]), comorbidity was present in 3.62% (52.5% beyond expectation; P<0.0001; OR = 1.58, 95% Confidence Interval 1.29-1.95). Depression without diabetes was reported by 17.3%, and diabetes without depression by 7.7%. In controlled analyses, the depression group had poorer socioeconomic status and health behaviors, and a greater likelihood of vascular, respiratory, and musculoskeletal problems than the diabetes group. Vascular, respiratory, and urinary problems were exacerbated in comorbid depression/diabetes; the comorbid group was also more likely to be female and younger. LIMITATIONS: Cross-sectional design. CONCLUSIONS: To our knowledge, this is the first study that explicitly reports on all four possible depression/diabetes combinations in an older representative community-resident sample, using controlled analyses to identify unique associations with sociodemographic characteristics and other health conditions. The burden of comorbid depression/diabetes in Brazil, a middle income country, appears to be comparable to that found in higher income countries. So, similarly, depression without diabetes had a greater odds of adverse sociodemographic and health conditions than diabetes without depression; comorbid depression/diabetes was more likely in women and young elderly, and the odds of vascular, respiratory, and urinary conditions was increased significantly. Attention to comorbid depression/diabetes as a unique entity is needed. PMID- 21684615 TI - Altering the expression balance of hnRNP C1 and C2 changes the expression of myelination-related genes. AB - The expression level of hnRNP C1/C2 protein has been reported to be significantly decreased in the post-mortem brain of schizophrenic patients. In this study, we investigated whether overexpression of the hnRNP C variants hnRNP C1 and C2 changed the expression of myelination-related genes in the human neuroblastoma cell line SK-N-SH. In both hnRNP C1- and C2-overexpressing cells, the expression of quaking (QKI)-6 and QKI-7 significantly increased or decreased compared to the control, respectively. Intriguingly, QKI-5 and myelin basic protein were markedly up- or down-regulated by overexpressing hnRNP C2, respectively. Our findings are the first to demonstrate distinct functions of hnRNP C1 and C2, and may be helpful in understanding the functions of these molecules. These findings indicate that altered expression levels of hnRNP C in the brain of patients with schizophrenia could be involved in the pathophysiology of this disease through alteration of the QKI isoform and myelin basic protein expression. PMID- 21684616 TI - Lesional skin in atopic dogs shows a mixed Type-1 and Type-2 immune responsiveness. AB - Canine atopic dermatitis (AD) is a chronic inflammatory and pruritic skin disease which shares several characteristics with its human counterpart. In chronic patch test lesions of human with AD mainly a Th1-type cellular response is found. Besides, non-lesional AD skin is already skewed for inflammation and therefore different from healthy skin. The goal of this study was to characterize local immune responsiveness in chronic canine AD lesions as compared to that in non lesional AD skin by defining T cell subset relevant cytokine- and transcription factor expression profiles. The gene expression of the Th1 cytokines IL-12p35, IL 12p40 and IFN-gamma and their related transcription factors STAT4, SOCS5 and T bet, the Th2 cytokines IL-4 and IL-13 and transcription factors STAT6, SOCS3 and GATA-3 and the regulatory cytokines IL-10 and TGF-beta and the transcription factor FOXP3 was evaluated in healthy control and atopic dogs. In non-lesional (NLS) and chronic lesional skin (LS) of atopic dogs and control skin (CS) from healthy dogs mRNA expression of cytokines and transcription factors were measured by quantitative real-time PCR. Significantly different values were found for the following factors: IL-12p40 mRNA was lower in LS when compared to NLS. Expression of STAT4 was higher in LS compared to CS and NLS. More IL-13 and SOCS3 were found in LS and NLS when compared to CS and also in LS compared to NLS. GATA-3 was lower in LS compared to NLS. IL-10 expression was higher in both LS and NLS compared to CS and more IL-10 was present in LS compared to NLS. These findings indicate that both Th1- and Th2-type as well as T regulatory cells are present in NLS and LS in canine atopic skin. PMID- 21684617 TI - Expression of E-cadherin and vimentin correlates with metastasis formation in head and neck squamous cell carcinoma patients. AB - PURPOSE: E-cadherin is a transmembrane glycoprotein, involved in cell-cell adhesion and epithelial-mesenchymal transition (EMT). Vimentin is highly expressed in mesenchymal cells and is positively correlated with increased metastasis. Here we set out to determine the expression of E-cadherin and vimentin in head and neck squamous cell carcinomas (HNSCC). PATIENTS AND METHODS: Twenty-six patients with primary stage II-IV HNSCC were included. E-cadherin and vimentin were visualised using immunohistochemistry, semi-automatically analysed for expression patterns and correlated with the clinical behaviour of these tumours. RESULTS: A large variation in E-cadherin and vimentin expression was observed between tumours (median 17% range 0-51% respectively median 0% range 0 20%). Tumours with low E-cadherin expression showed a significantly higher incidence of metastasis formation compared to tumours with high expression (81% versus 19%, p=0.004). Enhanced expression of vimentin was associated with a trend towards a higher metastatic risk (33% versus 77%) compared to tumours without expression of vimentin. All patients with low E-cadherin and high vimentin expression (an EMT-phenotype) developed distant metastases versus only 44% of the other patients (p=0.008). CONCLUSION: Loss of E-cadherin and gain of vimentin may be associated with enhanced migration of tumour cells, leading to higher metastatic risk of HNSCC patients. PMID- 21684618 TI - The influence of monetary reward and punishment on psychological, physiological, behavioral and performance aspects of a golf putting task. AB - The primary purpose of the present study was to examine kinematic characteristics and force control during a golf-putting task under a pressure condition. The secondary purpose was to provide an exploratory investigation of the relationship between changes in behavior (kinematics and force control) and performance on the one hand, and psychological (attention and affect) and physiological (arousal level) changes on the other hand. Twenty male novices performed 150 acquisition trials, followed by 10 test trials during a pressure condition induced by performance-contingent distracters: a cash reward or punishment. A three dimensional motion analysis revealed that, during the pressure test, angular displacements of rotational movements at the horizontal plane and movement time of the arms and club during the backswing and downswing phases all decreased, while acceleration of the elbows during the downswing phase increased. Mean performance indices in all participants' were unchanged in spite of the kinematic changes under the pressure condition. Multiple regression analyses indicated that the decrement in performance, as well as increased variability of movement time and speed, were more likely to increase when participants shifted their attention to movements. Furthermore, changes in heart rate and negative affect were related to both the increase in movement acceleration and a decrease in grip force. These findings suggest that performance and behavioral changes during golf-putting under pressure can be associated with attentional changes, along with the influences of physiological-emotional responses. PMID- 21684619 TI - Antimicrobial silver-montmorillonite nanoparticles to prolong the shelf life of fresh fruit salad. AB - In this work, silver-montmorillonite (Ag-MMT) antimicrobial nanoparticles have been obtained by allowing silver ions from nitrate solutions to replace the Na(+) of natural montmorillonite and then to be reduced by a thermal treatment. Ag-MMT were used as active antimicrobial compounds to improve the shelf life of fresh fruit salad. In order to assess their influence on product shelf life, sensorial and microbiological quality has been monitored during the storage. The microbiological quality was determined by monitoring the principal spoilage microorganisms (mesophilic and psychrotrophic bacteria, coliforms, lactic acid bacteria, yeasts and molds). Additionally, the evolution of sensorial quality was assessed by monitoring color, odor, firmness and product overall quality. The Ag MMT nanoparticles seemed to be effective in inhibiting microbial growth, above all at the highest tested concentration. Consequently, the sensorial quality of samples stored in the active packaging appeared to be better preserved. Thus, experimental results showed that a significant shelf life prolongation of fresh fruit salad can be obtained by a straightforward new packaging system. PMID- 21684620 TI - Street smoking bans in Japan: a hope for smoke-free cities? AB - OBJECTIVES: This study analysed 112 municipalities enforcing municipal smoking restrictions on streets in Japan to examine anti-smoking measures implemented in urban settings from a health perspective and derive lessons for future tobacco control. METHODS: Municipal governments implementing ordinances which restrict smoking on streets were identified through grey literature review. Implementation period, characteristics, scope, and department responsible were examined. RESULTS: Since the first municipal regulation was introduced in 1997, many other municipalities have followed. Enforcement of fines started in 2002, which is now a common practice nationwide. Nevertheless, the health impact of exposure to secondhand smoke is not clearly articulated in the ordinances. Street smoking bans have been developed in connection with "beautification" and littering prevention for environmental purposes, and local health departments do not have responsibility for these ordinances. CONCLUSIONS: There is potential to further prevent secondhand smoke exposure if such measures are expanded to indoor environments and integrated into broader policies. For policy-makers and advocates, the Japanese experience provides information on an additional tobacco control intervention as well as clues in the process of design, implementation and enforcement of such municipal measures. A more comprehensive and health driven approach is required to effectively address the harm of secondhand smoke in Japan. PMID- 21684621 TI - Molecular mechanisms of epistasis within and between genes. AB - 'Disease-causing' mutations do not cause disease in all individuals. One possible important reason for this is that the outcome of a mutation can depend upon other genetic variants in a genome. These epistatic interactions between mutations occur both within and between molecules, and studies in model organisms show that they are extremely prevalent. However, epistatic interactions are still poorly understood at the molecular level, and consequently difficult to predict de novo. Here I provide an overview of our current understanding of the molecular mechanisms that can cause epistasis, and areas where more research is needed. A more complete understanding of epistasis will be vital for making accurate predictions about the phenotypes of individuals. PMID- 21684622 TI - STAT3 expression in activating EGFR-driven adenocarcinoma of the lung. AB - Bronchioloalveolar carcinoma (BAC) pattern is often seen at the margin of invasive adenocarcinomas. We investigated EGFR signaling abnormalities involved in the progression of adenocarcinoma. Fifty tumors were obtained from patients who underwent surgery for lung adenocarcinoma seen as dense areas in ground glass opacity on computed tomography. Six, 18, and 26 tumors <1cm, 1-2 cm, and >=2 cm in diameter, respectively, were analyzed. Of the 24 tumors <=2 cm in diameter, nine were preinvasive and 15 were invasive. EGFR, pAKT, and pMAPK were overexpressed in the center of the adenocarcinoma compared to the BAC component (p<0.01) by immunohistochemistry, while pSTAT3 expression was reversed (p=0.017). In the tumors <=2 cm in diameter, pSTAT3 expression in the central area was higher in preinvasive tumors than in invasive tumors (p=0.005). pSTAT3 was identified in the BAC component of 88% of the EGFR mutant (n=17) and 82% of the wild-type tumors (n=33). Transgenic mice expressing delE748-A752 EGFR and two lung cancer cell lines (PC-9 mutant and A549 wild-type EGFR) were also investigated. In transgenic mice, pSTAT3 was overexpressed in the BAC component around the adenocarcinoma center. Two lung cancer cell lines that overexpressed pSTAT3 were equally sensitive to a JAK2/STAT3 inhibitor (JSI-124). The role of STAT3 in the progression of adenocarcinoma should be further pursued. PMID- 21684623 TI - Establishment and comparative characterization of novel squamous cell non-small cell lung cancer cell lines and their corresponding tumor tissue. AB - BACKGROUND: Cell lines play an important role for studying tumor biology and novel therapeutic agents. Particularly in pulmonary squamous cell carcinoma (SCC) the availability of cell lines is limited and knowledge about their representativeness for corresponding tumor tissue is scanty. MATERIALS AND METHODS: We established three novel SCC cell lines from fresh tumor tissue of 28 donors, including 8 SCC. Two cell lines were derived from different localizations of the same donor, i.e. primary tumor and lymph node metastasis. This represents a so far unique combination in lung cancer. The genotypes, gene expression profiles and mutational status of epidermal growth factor receptor (EGF-R) and Kirsten rat sarcoma (k-ras) of the cell lines and their corresponding tumor tissue were analyzed and compared. Moreover, the molecular characteristics were related to functional properties of the cell lines. Those comprised proliferation, motility and chemosensitivity. The cell lines were authenticated by single tandem repeat DNA typing. Tumorigenicity was analyzed in a murine xenograft model. RESULTS: Comparative genomic hybridization and multiplex fluorescence in situ hybridization revealed essential genetic similarities between the cell lines and their corresponding tumor tissue, but indicated also some genetic evolution and clonal selection. EGF-R or k-ras mutations were not detected. Gene expression profiling showed various differences between tumor tissue and cell lines affecting gene clusters associated with immune response, adhesion, proliferation, differentiation and angiogenesis. However, there were also common gene expression patterns reflecting the relationship between cell lines and their corresponding tumor tissue. Moreover, the molecular characteristics of the tumor tissue and the descendent cell line were associated with functional properties of the latter. All cell lines showed a unique, heterozygous human DNA profile and one cell line displayed rapid tumor formation in mice. CONCLUSIONS: Here, we demonstrate that cell lines represent a useful in vitro system for studying basic mechanisms in lung cancer, but cover only distinct molecular characteristics of the original tumor. Moreover, we present three novel, comprehensively characterized SCC cell lines. PMID- 21684624 TI - Detection of the EGFR mutation in exhaled breath condensate from a heavy smoker with squamous cell carcinoma of the lung. AB - A 61-year-old male smoker (40 pack-years) presented with right chest pain. Computed tomography of the chest revealed a cavitary mass in the right lower lobe. A transbronchial biopsy showed squamous cell carcinoma. We examined epidermal growth factor receptor (EGFR) mutations in exhaled breath condensate (EBC). The DNA extracted from his EBC showed a deletion mutation in exon 19. Subsequently, the del E746-A750 mutation in exon 19 in a transbronchial tissue specimen was confirmed. Although he underwent whole-brain irradiation against multiple brain metastases, he had paralysis of the left side of the body and his performance status was 3. The patient was treated with gefitinib. He had marked tumor regression and no symptoms. Although only a small percentage of heavy smokers with squamous cell carcinoma harbor EGFR mutations, they probably benefit from EGFR-tyrosine kinase inhibitors. EGFR mutation status in the patients having such clinical features might be examined. PMID- 21684625 TI - Insights into the achaete-scute homolog-1 gene (hASH1) in normal and neoplastic human lung. AB - Achaete-scute homolog-1 (ASH1) is pivotal for the development of pulmonary neuroendocrine (NE) cells. We examined human ASH1 (hASH1) expression across a comprehensive panel of human lung cancer cell lines, primary human lung tumors and normal fetal and post-natal lungs. While hASH1 was a cardinal feature of NE carcinomas, a subgroup of non-NE lung cancers also exhibited expression of this factor. Twenty lung cancer cell lines out of 33 were positive for hASH1 mRNA by reverse transcription PCR, including 6/6 small cell carcinomas (SCLC), 5/5 carcinoids, 6/7 non-SCLC with NE features, and 3/14 other non-SCLC. Among human primary tumors, 2/2 SCLC, 5/5 pulmonary carcinoids, and 10/41 non-SCLC (only 4 of which had NE features) were positive for hASH1 by immunohistochemistry and RNA RNA in situ hybridization. In normal human fetal lung, the expression of hASH1 and the neural marker synaptophysin was highly concordant in neuroepithelial bodies and solitary NE cells, while the rest of the epithelium was negative. In childhood and adulthood, the markers became progressively discordant, with a majority of hASH1-immunoreactive foci (69%) being negative for synaptophysin in adults, potentially representing dormant NE cell progenitors. We conclude that hASH1 provides an early indication of NE program in human lung. PMID- 21684626 TI - Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy. AB - PURPOSE: Gefitinib and erlotinib are potent EGFR TKIs, with antitumor activity. In this randomized, single-center, non-comparative phase II trial, the efficacy and safety of gefitinib and erlotinib was evaluated as the second-line therapy for advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with locally advanced, metastatic stage IIIB/IV NSCLC who failed first-line chemotherapy and had either EGFR mutation or at least two out of three clinical factors associated with higher incidence of EGFR mutations (female, adenocarcinoma histology, and never-smoker) were eligible. RESULTS: A total of 96 (48 per arm) patients were randomly assigned to gefitinib- or erlotinib-arm, respectively. Baseline characteristics were well-balanced between the two arms. The response rates (RR) were 47.9% in the gefitinib arm and 39.6% in the erlotinib arm. Median PFS was 4.9 months (95% CI, 1.3-8.5) in the gefitinib arm and 3.1 months (95% CI, 0.0-6.4) in the erlotinib arm. The most common grade 3/4 toxicity was skin rash. Exploratory analyses showed that there was no significant difference in RR and PFS in the gefitinib arm compared to the erlotinib arm (RR (%) 47.9 vs. 39.6, p=0.269; median survival (months) 4.9 vs. 3.1, p=0.336). There was no significant difference in QOL between the two arms. CONCLUSION: Both gefitinib and erlotinib showed effective activity and tolerable toxicity profiles as second-line treatment for the selected population of NSCLC. We may consider conducting a phase III trial to directly compare the efficacy and toxicity between gefitinib and erlotinib in an enriched patient population. PMID- 21684627 TI - The KdpFABC complex from Escherichia coli: a chimeric K+ transporter merging ion pumps with ion channels. AB - The KdpFABC complex represents a multi-subunit ATP-driven potassium pump, which is only found in bacteria and archaea. Based on the properties of the ATP hydrolyzing subunit (KdpB) the transporter has been classified as a type IA P type ATPase. However, structural and functional properties of the remaining subunits clearly show homologies to members of the potassium channel as well as the ABC transporter family, thus rendering the KdpFABC complex to represent an inimitable chimera of ion pumps and ion channels. Accordingly, this striking juxtaposition entails special features of KdpFABC with respect to typical members of each of the transporter families, involving not only the concepts but also the structures of ion channels and ion pumps. For example, the sites of ATP hydrolysis and substrate transport are spatially separated on two different polypeptides, which, in turn, leads to a unique coupling mechanism. During catalysis, the KdpFABC complex cycles between two main conformational states, each of which comprises different structural properties together with different binding affinities for both ATP and the transport substrate. These structural configurations have recently been directly visualized in the working enzyme. Translocation of potassium is mediated by the KdpA subunit, which comprises structural as well as functional homologies to potassium channels of the MPM type. The KdpC subunit participates in the binding of ATP, thus acting as a catalytic chaperone, which increases the ATP binding affinity of the KdpB subunit via a mechanism typical of nucleotide binding in ABC transporters. PMID- 21684628 TI - Exploring protein import pores of cellular organelles at the single molecule level using the planar lipid bilayer technique. AB - Proteins of living cells carry out their specialized functions within various subcellular membranes or aqueous spaces. Approximately half of all the proteins of a typical cell are transported into or across membranes. Targeting and transport to their correct subcellular destinations are essential steps in protein biosynthesis. In eukaryotic cells secretory proteins are transported into the endoplasmic reticulum before they are transported in vesicles to the plasma membrane. Virtually all proteins of the endosymbiotic organelles, chloroplasts and mitochondria, are synthesized on cytosolic ribosomes and posttranslationally imported. Genetic and biochemical techniques led to rather detailed knowledge on the subunit composition of the various protein transport complexes which carry out the membrane transport of the preproteins. Conclusive concepts on targeting and cytosolic transport of polypeptides emerged, while still few details on the molecular nature and mechanisms of the channel moieties of protein translocation complexes have been achieved. In this paper we will describe the history of how the individual subunits forming the channel pores of the chloroplast, mitochondrial and endoplasmic reticulum protein import machineries were identified and characterized by single channel electrophysiological techniques in planar bilayers. We will also highlight recent developments in the exploration of the molecular properties of protein translocating channels and the regulation of the diverse protein translocation systems using the planar bilayer technique. PMID- 21684629 TI - Drosophila metalloproteases in development and differentiation: the role of ADAM proteins and their relatives. AB - ADAM metalloproteases are membrane bound glycoproteins that control many biological processes during development and differentiation, mainly by acting as ectodomain sheddases. The Drosophila genome contains five genes that code for classical ADAM proteins which are characterized by a highly conserved domain structure with the respective catalytic domains facing the extracellular space. More than 50 genes encode related proteins such as those that have lost their primary enzymatic activity while retaining, e.g., their adhesive properties. The physiological relevance of many Drosophila ADAMs and their relatives is still unknown, however for others, a striking role during organogenesis and tissue maintenance has been demonstrated during the last few years. We have carried out genetic screenings combined with candidate approaches, aiming to identify new components involved in cardiogenesis and muscle differentiation. Herein we summarize our results with a particular focus on metalloproteases with known or potential roles in tissue differentiation. PMID- 21684630 TI - Centromere regulation: new players, new rules, new questions. AB - Centromeres support the assembly of the kinetochore on every chromosome and are therefore essential for the proper segregation of sister chromatids during cell division. Centromere identity is regulated epigenetically through the presence of the histone H3 variant CENP-A. CENP-A regulation and incorporation specifically into centromeric nucleosomes are the matter of intensive studies in many different model organisms. Here we briefly review the current knowledge in centromere biology with a focus on Drosophila melanogaster and how these insights lead to new rules and challenges. PMID- 21684631 TI - Transmembrane signal transduction in archaeal phototaxis: the sensory rhodopsin II-transducer complex studied by electron paramagnetic resonance spectroscopy. AB - Archaeal photoreceptors, together with their cognate transducer proteins, mediate phototaxis by regulating cell motility through two-component signal transduction pathways. This sensory pathway is closely related to the bacterial chemotactic system, which has been studied in detail during the past 40 years. Structural and functional studies applying site-directed spin labelling and electron paramagnetic resonance spectroscopy on the sensory rhodopsin II/transducer (NpSRII/NpHtrII) complex of Natronomonas pharaonis have yielded insights into the structure, the mechanisms of signal perception, the signal transduction across the membrane and provided information about the subsequent information transfer within the transducer protein towards the components of the intracellular signalling pathway. Here, we provide an overview about the findings of the last decade, which, combined with the wealth of data from research on the Escherichia coli chemotaxis system, served to understand the basic principles microorganisms use to adapt to their environment. We document the time course of a signal being perceived at the membrane, transferred across the membrane and, for the first time, how this signal modulates the dynamic properties of a HAMP domain, a ubiquitous signal transduction module found in various protein classes. PMID- 21684632 TI - Fatal nosocomial myiasis caused by Lucilia sericata. PMID- 21684633 TI - Mucosal surveillance cultures in predicting Gram-negative late-onset sepsis in neonatal intensive care units. AB - This study aimed to examine the spectrum and time course of gut and nasopharyngeal colonization with Gram-negative micro-organisms, and to define the value of surveillance cultures in predicting late-onset sepsis in neonates admitted to neonatal intensive care units. Nasopharyngeal and rectal swabs were collected on admission and twice weekly thereafter in 278 neonates admitted within the first 72 h of life with risk factors of early-onset sepsis. Sterile body fluid cultures were obtained on admission and subsequently as clinically indicated. Approximately half of the rectal (693/1250, 55%) and nasopharyngeal (558/1153, 48%) samples but only 6% (32/555) of the sterile fluid samples in 26 patients were culture positive for Gram-negative organisms. In total, 2108 invasive and mucosal culture pairs were analysed. The overall sensitivity, specificity, and positive and negative predictive values of a mucosal sample to predict late-onset sepsis were 27%, 66%, 4% and 94%, respectively. Patients with pre-existing colonization with Klebsiella pneumoniae (P = 0.011), Klebsiella oxytoca (P = 0.002), Escherichia coli (P = 0.003), Stenotrophomonas spp. (P = 0.003) and Pseudomonas spp. (P <= 0.001) were more likely to develop late-onset sepsis. No such association was found for Acinetobacter baumannii, Serratia spp. or Enterobacter cloacae. In conclusion, routine mucosal cultures are inefficient for the prediction of Gram-negative late-onset sepsis in neonatal intensive care units. However, targeted screening for specific organisms in an outbreak (e.g. Klebsiella spp., E. coli, Stenotrophomonas spp. and Pseudomonas spp.) may offer an opportunity to improve infection control measures and enable timely initiation of appropriate antibiotic therapy. PMID- 21684634 TI - [Single-session extracorporeal shock wave lithotripsy for urinary calculi: factors predicting success after three weeks of follow-up]. AB - INTRODUCTION: The aim of this study was to identify predictive factors of success following a single-session of shock wave lithotripsy (SWL) at 3 weeks of follow up in our center. MATERIAL AND METHODS: The medical records of 116 patients with solitary urinary calculi who underwent single-session SWL in our department between October 2007 and August 2009 were reviewed. All preoperative unenhanced computed axial tomographies were reviewed by two radiologists blinded to clinical outcome. Success was defined as complete clearance or the persistence of fragments <= 2 mm on a plain film at 3 weeks of follow-up. The impact of clinical and radiological factors on success was assessed by univariate and multivariate analyses. RESULTS: The single-session SWL success rate at 3 weeks was 49.1%. Stone size <8 mm, stone area < 30 mm(2), stone location (mid- and distal ureter), stone density <1000 HU and intraoperative fragmentation showed a significant association with SWL success in the univariate analysis (p<0.05). Stone area (OR 2.9), ureteral stone location (OR 3.4) and intraoperative fragmentation (OR 4.2) were the only predictors of success in the multivariate analysis. CONCLUSIONS: Stone area and ureteral stone location provide important information when deciding about the indication of a SWL in a patient with stone disease. However, successful resolution of only half of the cases after a single session at 3 weeks in our series undermines the relevance of informing patients about the potential need for additional treatment. PMID- 21684635 TI - [From genetics to genomics in the rational design of new Mycobacterium tuberculosis vaccines]. AB - Tuberculosis (TB) is an infectious disease affecting people from all ages all over the world. It is estimated that one third of the world population lives infected with the causal agent: Mycobacterium tuberculosis. Despite availability and systematic administration of BCG vaccine in endemic areas, TB transmission remains elusive to control, partly because BGC efficacy has been shown to have wide variability (0-80%). Such variability in protection is attributed to factors including: the BCG strain used for immunization, pre-existing exposure to environmental saprophytic Mycobacterium species, and host genetic factors. In this context, efforts regarding to re-engineering BCG vaccines with the ability to prevent latent TB reactivation, providing long lasting protection, and devoid from collateral effects in immunosuppressed people are urgent. In this work we review the actual molecular "gene-by-gene" strategies aimed at generating BCG alternatives, and discuss the urgent necessity of high throughput technology methods for a rational design for a new TB vaccine. PMID- 21684636 TI - Arylamides hybrids of two high-affinity sigma2 receptor ligands as tools for the development of PET radiotracers. AB - 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine 1 (PB28) and 2-Methoxy-5-methyl-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2 yl)butyl]benzamide 2 (RHM-1) represent leads for tumor diagnosis, given their high affinity at sigma(2) receptors. With the purpose of obtaining good candidates for sigma(2) PET tracers development, hybrid structures between 1 and 2 were designed. Excellent sigma(1)/sigma(2) selectivities were reached when 6,7 dimethoxytetrahydroisoquinoline was linked to an o-methoxy substituted arylamide (11a, 12a, 15a), and for these benzamides an intramolecular H-bond in the active conformation at the sigma sites, was hypothesized. However these excellent sigma(2) ligands were accompanied by interaction with P-gp, which may limit their use as sigma(2) receptor PET agents when tumors overexpress P-gp. Compound 15a whose P-gp interaction was just moderate represents an interesting tool for the development of sigma(2) PET tracers useful in tumors overexpressing P-gp. PMID- 21684637 TI - Daring to be different: a qualitative study exploring the education needs of the nurse consultant. AB - Nurse consultants are recognised experts and are one of the most senior nursing 'clinical' grades. How these roles have developed has varied but all require an armoury of expanded and extended skills. However, since their introduction in the UK little has been written about how they should be effectively prepared for the role. This study used a multi-method approach to establish a rich picture of the nurse consultant role (specialising in safeguarding children) in relation to their existing skills and perceived education needs. The job descriptions and specifications of a sample of consultant nurses (n=4) established role expectations and content, whilst in-depth individual semi-structured interviews with the nurses and six key 'stakeholders' explored perspectives about the educational preparation and ongoing learning needs of those either in the role or aspiring to be. The findings suggest that whilst there are differences there is also some convergence in their developmental needs. For example, that mentorship and academic and leadership support were integral to meeting their learning needs, to optimise effectiveness and to enhance future role development. It is vital therefore that those wishing to 'grow' consultant nurses implement a range of educational strategies to support the continued professional and clinical development of current and future post holders. PMID- 21684638 TI - Characterisation of prompt and delayed atmospheric radioactivity releases from underground nuclear tests at Nevada as a function of release time. AB - A database with information on about 500 cases of atmospheric radioactivity releases from underground nuclear tests is analysed. The data are statistically evaluated and systematically aggregated in order to characterise prompt uncontrolled as well as delayed operational releases of radioactivity into the atmosphere. The focus is put on the latter. The reported data compare well with theoretically derived xenon activities for reasonable nuclear test scenarios. Conclusions are drawn on the main features of releases that can be expected from underground nuclear tests as a function of release time. These findings are relevant for developing and validating methods to be applied in global monitoring of atmospheric radioactivity with respect to indications of an underground nuclear explosion. PMID- 21684639 TI - Quantitative and qualitative verification of data quality in the childbirth registers of two rural district hospitals in Western Kenya. AB - OBJECTIVE: to verify the data quality of childbirth registers and explore factors that influence quality at two rural district hospitals in Western Kenya. DESIGN: a retrospective comparative case study for data quality of the 2006 childbirth registers by quantitative and qualitative methods. SETTING: Siaya and Bondo District Hospitals. METHODS: after confirming the physical condition and availability of childbirth registers, the total number of births; number of complete/incomplete data; and number of complete data that were illegible, incorrectly coded, inappropriate and unrecognised were verified quantitatively to evaluate accuracy and completeness. Data categories and instructions were examined qualitatively to assess the relevance, completeness and accuracy of the data. Semi-structured interviews were conducted with key informants to capture their views and factors that influence data quality. FINDINGS: the childbirth registers used by the two hospitals were not developed by the Ministry of Health, and their supply to Bondo was interrupted. Of the 30 data categories in the registers, five for Siaya and 23 for Bondo were more than 20% incomplete. Data for number of antenatal consultations and use of human immunodeficiency virus drugs were at least 50% incomplete for both hospitals. The percentage of illegible, incorrectly coded and inappropriate data was relatively low, and only the place of residence had unrecognised data. Data categories in the registers did not correspond well with those of monthly reports, and inappropriate instructions suggested hidden inaccuracy among apparently valid data. Organisational impediments of the health information system in general, perinatal and intrapartum contexts were identified. KEY CONCLUSIONS: data quality of the childbirth registers was unsatisfactory. Influential factors were primarily organisational and technical, which may have had an adverse effect on midwives' record keeping behaviour. IMPLICATIONS FOR PRACTICE: data quality of the registers can be improved by re-examining technical challenges and organisational impediments at different levels. Midwives' awareness of data quality needs to be increased by sharing the purpose of the childbirth registers. Strong political commitment is also indispensable for putting these findings into action. PMID- 21684640 TI - From hospital to home: the quality and safety of a postnatal discharge system used for remote dwelling Aboriginal mothers and infants in the top end of Australia. AB - OBJECTIVE: to examine the transition of care in the postnatal period from a regional hospital to a remote health service and describe the quality and safety implications for remote dwelling Aboriginal mothers and infants. DESIGN: a retrospective cohort study of maternal health service utilisation and birth outcomes, key informant interviews with health service providers and participant observation in a hospital and two remote health centres. Data were analysed using descriptive statistics and content analysis. SETTING: a maternity unit in a regional public hospital and two remote health centres within large Aboriginal communities in the Top End of the Northern Territory, Australia. FINDINGS: poor discharge documentation, communication and co-ordination between hospital and remote health centre staff occurred. In addition, the lack of clinical governance and a specific position holding responsibility for the postnatal discharge planning process in the hospital system were identified as serious risks to the safety of the mother and infant. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: the quality and safety of discharge practices for remote dwelling mothers and their infants in the transition from hospital to their remote health service following birth need to be improved. The discharge process and service delivery model must be restructured to reduce the adverse effects of poor standards of care on mothers and infants. PMID- 21684641 TI - Degradability of aged aquatic suspensions of C60 nanoparticles. AB - In this study, aged aqueous suspensions of C(60) (nC(60)) were investigated in the respirometric OECD test for ready biodegradability. Two suspensions of nC(60) were prepared by stirring and aged under indirect exposure to sunlight for 36 months. ATR-FTIR analyses confirmed the presence of C(60)-structures in the suspensions. Samples of the nC(60) suspensions (20mg/l) were inoculated with activated sludge (30 mgTSS/L) and incubated in a mineral medium under aerobic conditions. Since no mineralisation of nC(60) was observed after 28 days of incubation, 5mg/l sodium acetate was added to the media. After additional 20 days, no mineralisation of nC(60) was observed. However, within a few days sodium acetate was completely mineralised, showing that the biomass was not inhibited by the presence of nC(60). Based on results from this simple approach, aged nC(60) can be classified as not ready biodegradable according to the standard OECD test procedure. PMID- 21684642 TI - The impact of heavy metal pollution gradients in sediments on benthic macrofauna at population and community levels. AB - The effect of sediment pollution on benthos was investigated in the vicinity of a large sewage treatment outflow at Incheon North Harbor, Korea. Animal size, vertical distribution and standard community parameters were analyzed along a 3 km transect line (n = 7). Univariate parameters showed a general trend of increasing species diversity with increasing distance from the pollution source. Multi-dimensional scaling analysis led to the clear separation of 3 locational groups, supporting gradient-dependent faunal composition. The innermost location was dominated by small sub-surface dwellers while the outer locations by large mid to deep burrowers. Looking for the size-frequency distribution, most abundance species (Heteromastus filiformis) showed the presence of larger size animals with increasing proximity to the pollution source. Meanwhile, species specific vertical distributions, regardless of the pollution gradient, indicated that such shifts were due to species replacement resulting from a higher tolerance to pollutants over some species. PMID- 21684643 TI - The use of standard contracts in the English National Health Service: a case study analysis. AB - The use of contracts is vital to market transactions. The introduction of market reforms in health care in the U.K. and other developed countries twenty years ago meant greater use of contracts. In the U.K., health care contracting was widely researched in the 1990s. Yet, despite the changing policy context, the subject has attracted less interest in recent years. This paper seeks to fill a gap by reporting findings from a study of contracting in the English National Health Service (NHS) after the introduction of the national standard contract in 2007. By using economic and socio-legal theories and two case studies we examine the way in which the new contract was implemented in practice and the extent to which implementation conformed to policy intentions and to our theoretical predictions. Data were collected using non-participant observation of 36 contracting meetings, 24 semi-structured interviews, and analysis of documents. We found that despite efforts to introduce a more detailed ('complete') contract, in practice, purchasers and providers often reverted to a more relational style of contracting. Frequently reliance on the NHS hierarchy proved to be indispensable; in particular, formal dispute resolution was avoided and financial risk was re allocated in compromises that sometimes ignored contractual provisions. Serious data deficiencies and shortages of skilled personnel still caused major difficulties. We conclude that contracting for health care continues to raise serious problems, which may be exacerbated by the impending transfer of responsibility to groups of general practitioners (GPs) who generally lack experience and expertise in large-scale, secondary care contracting. PMID- 21684644 TI - Empowerment in drug treatment: dilemmas in implementing policy in welfare institutions. AB - This article analyzes how and why welfare policies focusing on empowerment as users' self-management create dilemmas in medically assisted drug treatment in Denmark. Drawing on ethnographic fieldwork, the article points to two sets of dilemmas by focusing on the relationship between legal and institutional setups and staff and user possibilities for agency. The first dilemma concerns how to provide user self-management and individualized services and the actual possibilities of effectuating this in welfare institutions imbued by limited resources, manpower, and local rules. The second, how to create a balance between notions of user self-management and legal demands of control regarding substitution medicine. The article analyzes empowerment as a policy arguing that implementation of policy--also called policy in practice--is integral to policy studies, rather than a domain that is separate from policy making. PMID- 21684645 TI - A disorder of anger and aggression: children's perspectives on attention deficit/hyperactivity disorder in the UK. AB - This article investigates the social and moral dimensions of Attention Deficit/Hyperactivity Disorder (ADHD) diagnosis, asking what ADHD means in UK children's everyday lives, and what children do with this diagnosis. Drawing on interviews with over 150 children, the analysis examines the influence of a UK state school-based culture of aggression on the form and intensity of diagnosed children's difficulties with behavioral self-control. Diagnosed children's mobilization of ADHD behaviors and their exploitation of the diagnosis shows how children's active moral agency can support and compromise cognitive, behavioral and social resilience. The findings support a proposal for a complex sociological model of ADHD diagnosis and demonstrate the relevance of this model for national policy initiatives related to mental health and wellbeing in children. PMID- 21684646 TI - Familial instability and young children's physical health. AB - This paper uses recent longitudinal data about a cohort of young children born in the United States to mostly unmarried parents to examine the association between increasingly-complex patterns of family instability and physical health in early childhood. The analyses assess whether, and how, the association between family instability and child health varies across a number of family types. We consider several measures of children's health at age five (overweight/obesity, asthma diagnosis and overall health) and examine to what extent the association between family instability and child health varies across outcomes and depends on the number and timing of any familial transitions. We also explore a number of potential mechanisms through which family instability may affect child health. The results suggest that familial instability is related to worse child health, particularly among children born to coresident (married or cohabiting) biological parents and for children who experience high levels of residential instability. PMID- 21684647 TI - Deliberate self-harm in rural and urban regions: a comparative study of prevalence and patient characteristics. AB - In countries like the U.K., people living in urban regions are more likely to suffer poor physical and mental health than rural populations, and to have increased rates of psychiatric disorder. Urban/rural differences in suicidal behaviour have most frequently focussed on variations in the occurrence of suicide. We have investigated rates of deliberate self-harm (DSH) in urban and rural districts of Oxfordshire, England, and compared characteristics of DSH patients resident in these two areas. Information was collected on 6833 DSH episodes by 4054 persons aged 15 years and over presenting to the local general hospital between 2001 and 2005. We found that urban DSH rates were substantially higher than rural rates amongst both males and females aged between 15 and 64 years. This relationship was sustained even when socio-economic deprivation and social fragmentation were taken into account. There was little difference between urban and rural rates for patients aged 65 years and over. Urban DSH patients were more likely to be younger, non-white in ethnic origin, unemployed, living alone, to have a criminal record, to have previously engaged in DSH, and to report problems with housing. Rural DSH patients were more likely to suffer from physical illness, and to have higher suicide intent scores. Results of studies such as this can help identify where resources for preventive initiatives should be primarily directed and also what types of individuals may be at most risk in different areas. However, since variation by area will in part be due to differences at the individual level, further research utilising multi-level modelling techniques would be useful. PMID- 21684648 TI - Assessing validity of actual tooth height and width from cone beam images of cadavers with subsequent dissection to aid oral surgery. AB - PURPOSE: Cone-beam computed technology (CBCT) is a relatively new medium for maxillofacial conditions. Developed in 1998, commercial cone beam technology has been commonly used since 2000. CBCT offers less radiation than computed tomography (CT) in 3D image construction. With the meteoric rise in the number of dental implant surgeries, CBCT could become a common machine in dental offices. The objective of this study is to validate the accuracy of CBCT tooth measurements. MATERIALS: Twelve embalmed cadavers had a complete CBCT of the head and neck region. Ninety-six teeth (8 per cadaver) were extracted in total, but only 69 were collected and measured. CEN-TECH electronic calipers were used to measure the extracted teeth. iCAT measurements were used for imaged teeth. METHODS: A literature search was conducted on the validity and use of CBCT regarding tooth measurements for implant surgery. Extracted teeth were measured in the vertical, facial to lingual, and mesial to distal dimensions. Exclusion factors included crown or root fracture damage during extraction. RESULTS: A literature search revealed studies that validated bone measurements using 14 different location points on the maxilla and 17 anatomical landmarks on the skull. Both studies validated bone measurements on CBCT. However, no studies were identified measuring teeth lengths for implant surgery. Three, two-tailed, paired t-test compared the iCAT image measurements to the extracted teeth measurements for each dimension. There was no statistical significance for each dimension. CONCLUSION: This study suggests using iCAT measurements on teeth from CBCT imaging would reflect the actual tooth length and could be beneficial for implant surgery. PMID- 21684649 TI - Hourglass mandibular anatomic variant incidence and treatment considerations for all-on-four implant therapy: report of 10 cases. AB - PURPOSE: The purpose of this study was to determine the incidence and treatment of hour glass variant mandibles for All On Four implant placement. MATERIALS AND METHODS: Cone beam CAT scans were analyzed for 719 patients to determine the incidence of alveolar constriction in the mandible. Ten patients with alveolar constriction were treated over a 2-year period and retrospectively studied after 1 year in function. RESULTS: Of 719 mandibles studied, 28 have "hour glass" variants identified for an incidence of 3.89%. Treatment of these cases were variously done including the use of guided bone regeneration, the use of long implants, bone reduction, and angulation strategies. CONCLUSIONS: The hour glass mandibular finding is a developmental or genetic variant that poses a significant anatomic difficulty for dental implant surgery for All On Four immediate function. PMID- 21684650 TI - Orthognathic and TMJ surgery: postsurgical patient management. AB - Postsurgical patient management is a critical factor for high-quality patient treatment and predictable outcomes in orthognathic and temporomandibular joint (TMJ) surgery. Lack of understanding of proper patient management on the part of the surgeon and orthodontist can result in compromised or even disastrous results. Surgeons and orthodontists must have the knowledge and ability to implement postsurgical management protocols and strategies to provide the best care and outcomes possible for their orthognathic and TMJ surgery patients. Information is presented here in reference to postsurgical orthodontics, healing process, dietary considerations, activities, and potential complications to aid the clinician in understanding the postsurgical processes that patients will encounter. PMID- 21684651 TI - Odontogenic choristoma: report of a case. PMID- 21684652 TI - Cephalometric soft tissue analysis of combined elliptical-window genioglossus advancement and hyoid suspension for obstructive sleep apnea. AB - PURPOSE: This study sought to determine the changes in cephalometric facial profile soft tissue measurements after simultaneous elliptical-window genioglossus advancement and hyoid suspension procedures for obstructive sleep apnea. PATIENTS AND METHODS: A retrospective analysis of preoperative and postoperative lateral cephalometric soft tissue changes in 23 consecutive patients who had undergone combined elliptical-window genioglossus advancement and hyoid bone suspension for polysomnogram-confirmed obstructive sleep apnea. Six cephalometric soft tissue measurements of the lower face were evaluated: pogonion (Pg'-Pg), menton (Me'-Me), gnathion (G'-G), lower lip (LI-L1i), B point (B-B'), and horizontal distance from subnasale perpendicular to the soft tissue chin at the level of pogonion (SN-Pg'). Statistical analysis was conducted with the paired Student t test (with 95% confidence interval of difference between means) and found significant for P < .05. Post hoc power analysis was conducted. RESULTS: There were no statistically significant differences among all 6 preoperative and postoperative cephalometric, radiographic soft tissue measurements of the lower facial profile. CONCLUSIONS: The combined elliptical window genioglossus advancement and hyoid suspension procedures for obstructive sleep apnea do not significantly change the cephalometric lower facial profile. In patients with an adequate lower facial profile with base-of-tongue obstruction who require surgical management of obstructive sleep apnea without alteration of their lower facial profile, this procedure does not significantly alter the preoperative facial profile. PMID- 21684653 TI - Transoral open reduction with rigid internal fixation for subcondylar fractures of the mandible using a small angulated screwdriver system: is endoscopic assistance necessary? AB - PURPOSE: Although endoscopically assisted transoral open reduction and internal fixation of condylar mandible fractures is currently a popular technique, the need for it and its benefits remains unclear. This prospective study evaluated the efficacy and safety of open reduction and rigid internal fixation of subcondylar fractures of the mandible using a new small angulated screwdriver system without endoscopic assistance. PATIENTS AND METHODS: Fifteen patients with 15 linear subcondylar fractures were treated using this intraoral approach from June 2007 through March 2010 at the Division of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, Kagawa, Japan. The anatomic reduction of the displaced condylar segments and rigid fixation with 2 2.0-mm locking miniplates were performed using a small angulated screwdriver system, with an average follow up of 13 months (range, 6 to 30 months). RESULTS: Correct anatomic reduction of the condylar segments at centric occlusion followed by immediate functional recovery was achieved in all patients. Mean operating time was 50 minutes (range, 35 to 70 minutes) when performed by the consultant surgeon and the residents. In addition, all patients had good temporomandibular joint articular function, with no harmful clinical symptoms or deviation. CONCLUSIONS: The surgical treatment of linear subcondylar fractures of the mandible can be achieved with an intraoral approach alone, using a small angulated screwdriver system, without endoscopic assistance, offering reliable clinical results and safe and minimally invasive surgery. PMID- 21684654 TI - Targeted dendrimer chemotherapy in an animal model for head and neck squamous cell carcinoma. AB - PURPOSE: Nanoparticle drug delivery offers a potential solution in the treatment of cancer. Using a heterotopic tumor model for head and neck squamous cell carcinoma (HNSCC), tumors of variable folate binding protein-alpha (FBP-alpha) have been treated to delineate receptor necessity as well as efficacy and toxicity of folate targeted chemotherapy. MATERIALS AND METHODS: University of Michigan Squamous Cell Carcinoma (UM-SCC) and American Type Culture Collection (ATCC) cell lines were screened using quantitative real-time polymerase chain reaction for FBP-alpha expression. Acetylated generation 5 dendrimers conjugated to the targeting moiety folic acid and the therapeutic moiety methotrexate were fabricated and administered to severe combined immunodeficiency (SCID) CB-17 mice inoculated with UM-SCC-1, UM-SCC-17B, and UM-SCC-22B cancer cells. Mice were injected with targeted therapy, free methotrexate, or saline control and monitored for drug efficacy and toxicity. RESULTS: Targeted therapy was effective relative to receptor level expression. Targeted therapy could be delivered in molar doses 3 times that of free drug. The treatment of a high folate expression tumor cell population was noted to have increased efficacy over saline (P < .01) and free methotrexate (P = .03) as well as decreased systemic toxicity. CONCLUSIONS: This report represents the first translation of dendrimer-based chemotherapy to HNSCC and underscores its effectiveness as an antitumor agent in human cancer cell lines with lower levels of FBP-alpha than the in vitro and in vivo models previously reported. PMID- 21684655 TI - Extracellular matrix as an inductive template for temporomandibular joint meniscus reconstruction: a pilot study. AB - PURPOSE: A device consisting of powdered porcine urinary bladder extracellular matrix (UBM-ECM) encapsulated within sheets of the same material was investigated as a scaffold for temporomandibular joint (TMJ) meniscus reconstruction. MATERIALS AND METHODS: Five dogs underwent unilateral resection of the native meniscus and replacement with a UBM-ECM device. Necropsies were performed at 3, 4, 8, 12, and 24 weeks. Two additional dogs underwent bilateral resection of the meniscus with replacement with a UBM-ECM device on 1 side, leaving the contralateral side empty as a control. Necropsies were performed at 24 weeks for bilaterally treated animals. RESULTS: Macroscopically, the UBM-ECM implants were remodeled rapidly and were indistinguishable from newly deposited host tissue at all time points. Microscopically, remodeling was characterized by a dense infiltration of predominantly CD68(+) mononuclear cells and smooth muscle actin positive fibroblast-like cells at early time points changing with time to a sparse population of smooth muscle actin-negative spindle-shaped cells resembling those of the native fibrocartilaginous TMJ meniscus. Furthermore, the remodeling process showed deposition of predominantly type I collagen, the density and organization of which resembled those of the native meniscus by the 24-week time point. Ingrowth of calsequestrin-positive skeletal muscle tissue was also observed at the periphery of the remodeled UBM-ECM device and was similar to that found at the attachment site of the native meniscus to the surrounding soft tissues. Histologic results were identical for samples excised from both unilaterally and bilaterally treated animals. No adverse changes in the articulating surfaces of the condyle or fossa were observed in UBM-ECM-implanted joints. In the bilaterally treated animals, the unimplanted control side was characterized by degeneration and pitting of the articulating surfaces of both the condyle and the fossa, with disorganized bands of fibrous connective tissue observed within the joint space. CONCLUSION: Results of this study suggest that the UBM-ECM device provides an effective interpositional material while serving as an inductive template for reconstruction of the TMJ meniscus. PMID- 21684656 TI - Characteristics of oral and maxillofacial surgery residencies that result in graduating residents entering academic positions. PMID- 21684657 TI - Revisiting the supraforaminal horizontal oblique osteotomy of the mandible. AB - PURPOSE: Today, the most common orthognathic procedure for correction of mandibular deformities is the bilateral sagittal split osteotomy, also called sagittal ramus osteotomy. Permanent injury to the mandibular nerve (V3) is one of the main complications, with a reported incidence between 5% and 30%. Orthognathic surgery using sagittal ramus osteotomy of the mandible as the procedure of choice should be re-evaluated because of the complexity and the relatively high risk of damage to the inferior alveolar nerve. Surgical techniques that allow for accurate condylar positioning with a lower risk of inferior alveolar nerve injury should be considered. The aim of this study is to present a retrospective case series using the previously described horizontal osteotomy of the mandibular rami along with modern-day technical advances that make this procedure safe, reliable, and reproducible. MATERIALS AND METHODS: We performed a modified approach to the supraforaminal horizontal oblique osteotomy of the mandible with a condylar positioning device, endoscopy, and a surgical navigation system. This technique was performed in 17 consecutive patients. Postoperatively, we measured the amount of surgical movement of the mandible, monitored the mandibular nerve, and evaluated bone healing during removal of the osteosynthesis plates. RESULTS: In all 17 treated patients there was uneventful wound healing, and no patient had permanent nerve alteration. The mean movement of the mandible was 7.48 mm (SD, 2.1 mm), with a range from 3.0 to 10.5 mm. The mean follow-up was 19 months. The main purpose of the surgical navigation was the translation of the planned osteotomy line from the computed tomography scan to the surgical site during the operation. This was performed to prevent a large gap between the bone segments at the osteotomy site. CONCLUSION: The supraforaminal approach with a condylar positioning device appears to be an appropriate way to prevent injury to the inferior alveolar nerve during orthognathic surgery of the mandible while maintaining centric positioning of the condyle and obtaining good bony union. PMID- 21684658 TI - Survival after free flap reconstruction in patients with advanced oral squamous cell carcinoma. AB - PURPOSE: The purpose of the present study was to assess the effect of free-flap reconstruction on the survival of patients treated for oral squamous cell carcinoma. PATIENTS AND METHODS: The present study was based on a retrospective cohort of 98 patients. Of the 98 patients, 49 underwent surgical reconstruction with microvascular tissue transfer (test group) and in 49 (control group), only local or regional flaps were used. RESULTS: For the free-flap group, the average follow-up period was 34.6 months. For the control group, the average follow-up was 39.8 months. At the end of the follow-up period, 23 (47%) and 33 (67.3%) patients had died of oral squamous cell carcinoma in the microvascular reconstructive and control group, respectively. The difference in the final status between the 2 groups was statistically significant (P = .03). In the free flap group, the mean and median survival time was 65 and 60 months. In the locoregional flap group, the mean and median survival time was 54 and 24 months, respectively. No difference was seen in the survival time between the free-flap and local flap groups (P = .2). Univariate Kaplan-Meier analysis revealed that positive surgical margins were significantly associated with shortened survival in the free-flap group and that recurrence was significant in both reconstructive groups. On multivariate Cox regression analysis, the status of the resection margin (P = .07) and tumor recurrence (P < .0005) showed a significant relationship with survival. CONCLUSION: Patients with free-flap reconstruction of surgically created defects after oral cancer resection showed a trend toward better 5-year survival. PMID- 21684659 TI - Immediate loading in ectodermal dysplasia: clinical case. AB - The aim of the present report is to describe a clinical case of ectodermal dysplasia (ED) treated with an immediate implant-loading protocol. Six implants were placed in freshly extracted sockets of a 55-year-old patient with ED and immediately loaded in 48 hours. No immediate implant-loading protocol in a patient with ED has been reported. Implant management is difficult because of knife-edge ridges and pathologic 3-dimensional relation of the jaws. In the present case, implant non-parallelism caused by alveolar ridge atrophy was managed using a specific prosthetic connection device that simplified the surgical and prosthetic procedure and allowed a low-risk immediate-loading protocol. PMID- 21684660 TI - Airway space changes after nasopharyngeal adenoidectomy in conjunction with Le Fort I osteotomy. AB - PURPOSE: The purpose of the present study was to evaluate the nasopharyngeal airway changes after transnasal adenoidectomy and to determine whether a specific facial morphologic type is associated with hypertrophied nasopharyngeal adenoids. The nasopharyngeal adenoid tissues are present during childhood but usually spontaneously atrophy by 12 to 14 years of age. However, some patients have hypertrophied nasopharyngeal adenoid tissues that can remain after 14 years of age and can cause dysfunction of the eustachian tubes, cause nasal airway obstruction, affect speech, and adversely alter facial growth. In these cases, nasopharyngeal adenoidectomy could be indicated. In patients requiring orthognathic surgery, the adenoidectomy can be performed using a transnasal approach in conjunction with maxillary Le Fort I osteotomy, eliminating the need for a separate surgical procedure. PATIENTS AND METHODS: The records of 40 patients, 27 females and 13 males, with an average age of 16.77 years (range, 13 to 20) who had undergone transnasal adenoidectomy in conjunction with orthognathic surgery that included Le Fort I osteotomy were analyzed. The pre- and postoperative lateral cephalograms were analyzed for airway changes after surgery, with an average interval between surgery and the postoperative radiographs of 7.36 months. The measurements of the airway changes were taken from the junction of the atlas and the base of the skull to the most anterior area of the adenoid tissue before surgery and to the posterior pharyngeal wall postoperatively, parallel to the Frankfort horizontal plane. The maxillary depth, mandibular depth, and occlusal plane angulation measurements were recorded preoperatively to assess the most common skeletal type presenting with hyperplastic nasopharyngeal adenoid tissues. RESULTS: All patients showed an increased airway space after adenoidectomy, with an average improvement of 8.71 mm (range, 3 to 18). Of the 40 patients, 21 were skeletal Class II (ANB >4 degrees ), 6 skeletal Class III (ANB <0 degrees ), and 13 skeletal Class I (ANB 0 degrees to 4 degrees ). Also, 29 patients had a high occlusal plane angle (>12 degrees ), 1 a low occlusal plane angle (<4 degrees ), and 10 a normal occlusal plane angle (4 degrees to 12 degrees ). Statistical analysis was performed using the paired t test to validate the results. No complications were identified with the surgical technique in any patient. CONCLUSION: Nasopharyngeal adenoidectomy can be peformed safely through a transnasal approach in conjunction with orthognathic surgery providing predictable improvement in the nasopharyngeal airway. PMID- 21684661 TI - An analysis of 101 primary cosmetic rhinoplasties. AB - PURPOSE: Primary cosmetic rhinoplasty is one of the most complex of cosmetic surgical procedures in the maxillofacial area that requires precise consideration to both form and function. The complex and variable anatomy, highly visible position of the nose, and distinct patient desires contribute to the complexity of this procedure. This study reports the combined results of 101 consecutive primary cosmetic rhinoplasties at 2 centers. PATIENTS AND METHODS: A retrospective chart review was completed on all patients who had primary cosmetic rhinoplasty with or without septoplasty and who were operated on by the senior authors (S.C.B. and H.M.) from June 2006 through December 2008. A standard physical examination, including photo documentation, was completed on each patient preoperatively. All patients were followed periodically after surgery for at least 12 months. Outcome was measured by both subjective and objective measures of cosmetic and functional (breathing) outcome. The following data were collected and analyzed: age of patient, gender, chief cosmetic and functional complaint, details of surgical procedure (including septoplasty, grafts, and donor sites), complications, and report of subjective outcome at final evaluation. RESULTS: One hundred one patients (n = 101, average age 24.4 +/- 6.8 years old) were enrolled in the study. Most patients presented for consultation regarding cosmetic rhinoplasty (80%) versus septorhinoplasty (20%). Although most of the patients (63%) were treated with septorhinoplasty, the open rhinoplasty (transcollumellar) incision was used in 61% of patients versus the closed rhinoplasty (39%) technique. The most commonly performed combination of techniques used was the combination of nasal tip modification, with dorsal reduction and nasal osetotomies (54%), followed by tip modification with dorsal reduction (19%), and dorsal reduction with osteotomies (18%) and no tip modification. In the 50 patients who required a graft, in 80% the donor site was the nasal septum. Spreader grafts were used in 14% of patients, and a combination of shield/tip graft was used in 52%. The following complications were observed: unhappy patient 16%, dehiscence at incision 5%, asymmetry requiring revision 6%, and infection 1%. In the 63 patients that had septoplasty, 6 (9.5%) reported that their breathing was not improved. In this series 11 patients (11%) received a revision rhinoplasty. CONCLUSIONS: Primary cosmetic rhinoplasty is 1 of the more complex facial cosmetic procedures. The vast majority of complications can be avoided with careful and extensive treatment planning. In this series we found a complication and revision rate similar to that reported in the literature. PMID- 21684662 TI - [Closure of ventricular septal defect after surgical septal myectomy by hybrid procedure in an adult patient]. PMID- 21684663 TI - Determination of normalized values of the tricuspid annular plane systolic excursion (TAPSE) in 405 Spanish children and adolescents. AB - INTRODUCTION AND OBJECTIVES: Tricuspid annular plane systolic excursion (TAPSE) is an echocardiographic measure that allows us to assess right ventricular systolic function. TAPSE measurement is common in adults but reference values for children are scarce. Our objective was to establish reference values for TAPSE in Spanish children and to determine the relationship of these values with age and body surface. METHODS: This prospective study included 405 patients (from newborn to age 18 years, 53% male) referred for assessment of cardiac murmurs. Patients with confirmed cardiac or any other disease were excluded. We collected TAPSE measurements by M-mode echocardiography and recorded anthropometric variables. We analyzed the intra- and interobserver reproducibility of these measurements. RESULTS: Mean TAPSE values were 17.09 +/- 5.09 cm with nonsignificant differences between sexes. A curvilinear regression model proved appropriate, with values increasing in proportion to age group, height, weight, body mass index, and body surface. Body surface showed a strong positive correlation with TAPSE values (r = 0.81), whereas frequency had a negative correlation (r = -0.74). Multivariate analysis confirmed these correlations and the interactions between variables (age, height, weight, body surface). Graphs of estimated normal population-based TAPSE values adjusted by age and body surface are provided. CONCLUSIONS: We present reference values for TAPSE in Spanish children and adolescents. The TAPSE measurement was reproducible and associated directly with age and body surface. These reference values could guide decision making in daily clinical practice. PMID- 21684664 TI - [Phrenic nerve identification with cardiac multidetector computed tomography]. AB - Cryoballoon ablation of the pulmonary veins is a new technique that has proven useful in preventing paroxysmal and persistent atrial fibrillation recurrence. One of the most serious complications of this method is right phrenic nerve palsy. The usefulness of multidetector computed tomography to locate the right phrenic nerve and artery and predict the risk of phrenic nerve palsy during cryoablation according to the distance between the right phrenic neurovascular bundle and the right superior pulmonary vein ostium has recently been described. Fifty-five consecutive patients with paroxysmal atrial fibrillation (52 +/- 12 years) underwent balloon cryoablation, following multidetector computed tomography to measure the pulmonary veins. We were able to identify segments of the right pericardiacophrenic artery (mean length 25 mm [range 7-68 mm]) in only 10 patients (20%). PMID- 21684665 TI - [Aortic intramural hematoma and pulmonary embolism. Diagnostic challenge and therapeutic dilemma]. PMID- 21684666 TI - [Area strain: normal values for a new parameter in healthy people]. AB - The echocardiographic technology known as three-dimensional wall motion tracking offers three-dimensional images of the myocardium and provides multiple measures of deformation, one of which is known as "area strain" (AS), which combines left ventricular longitudinal and circumferential deformations. Our aim was to describe the normal maximum systolic reference AS value in a sample of healthy subjects. Sixty consecutive subjects without known cardiovascular risk factors or diseases were enrolled, and left ventricular AS was measured. Overall mean AS was -38.87 +/- 5.89%. Mean values at the level of the basal, middle, and apical segments were -38.42 +/- 7.58%, -38.74 +/- 6.34%, and -43.18 +/- 12.81%, respectively. Thus, our results show for the first time the reference values for AS in healthy subjects. PMID- 21684667 TI - Immediate angiography for everyone after cardiac arrest? How can we find the patients who will not benefit? PMID- 21684668 TI - Tracheal rapid ultrasound exam (T.R.U.E.) for confirming endotracheal tube placement during emergency intubation. AB - OBJECTIVES: This study aimed to assess the diagnostic accuracy and timeliness of using tracheal ultrasound to examine endotracheal tube placement during emergency intubation. METHODS: This was a prospective, observational study, conducted at the emergency department of a national university teaching hospital. Patients received emergency intubation because of impending respiratory failure, cardiac arrest, or severe trauma. The tracheal rapid ultrasound exam (T.R.U.E.) was performed during emergency intubation with the transducer placed transversely at the trachea over the suprasternal notch. Quantitative waveform capnography was used as the criterion standard for confirmation of tracheal intubation. The main outcome was the concordance between the T.R.U.E. and the capnography. RESULTS: A total of 112 patients were included in the analysis, and 17 (15.2%) had esophageal intubations. The overall accuracy of the T.R.U.E. was 98.2% (95% confidence interval [CI]: 93.7-99.5%). The kappa (kappa) value was 0.93 (95% CI: 0.84-1.00), indicating a high degree of agreement between the T.R.U.E. and capnography. The sensitivity, specificity, positive predictive value, and negative predictive value of the T.R.U.E. were 98.9% (95% CI: 94.3-99.8%), 94.1% (95% CI: 73.0-99.0%), 98.9% (95% CI: 94.3-99.8%) and 94.1% (95% CI: 73.0-99.0%). The median operating time of the T.R.U.E. was 9.0s (interquartile range [IQR]: 6.0, 14.0). CONCLUSIONS: The application of the T.R.U.E. to examine endotracheal tube placement during emergency intubation is feasible, and can be rapidly performed. PMID- 21684669 TI - Upper esophageal lesion following laryngeal mask airway resuscitation in a very low birth weight infant. PMID- 21684670 TI - Lung involvement in rheumatologic diseases in children. AB - BACKGROUND: Lung involvement in rheumatologic disease in children has been described with low frequency. OBJECTIVE: To describe the lung function test and the radiological findings in a group of paediatric patients with rheumatologic diseases. METHODS: Descriptive study. Pulmonary function was evaluated with spirometry, carbon monoxide diffusing capacity, blood arterial gas at rest and post exercise in addition to chest radiography and high resolution computed tomography were performed in children with rheumatologic disease. RESULTS: Of the fourteen patients studied: 11 were diagnosed with juvenile idiopathic arthritis (JIA), two with systemic lupus erythematosus (SLE), and one with juvenile dermatomyositis (JDM). Mean age: 13 years (range 7-18 years). Nine females, duration of disease 4 +/- 2.8 years (range 1-11 years). Four patients had any grade of abnormalities in one or more lung function tests and/or radiological test. CONCLUSION: We recommend routine checks of pulmonary function in all patients with rheumatologic diseases even in the absence of respiratory symptoms. PMID- 21684671 TI - Human U2B" protein binding to snRNA stemloops. AB - The human U2B" protein is one of the unique proteins that comprise the U2 snRNP, but it is also a representative of the U1A/U2B" protein family. In the U2 snRNP, it is bound to Stem-Loop IV (SLIV) of the U2 snRNA. We find that in vitro it binds not only to human SLIV, but also to Stem-Loop II (SLII) from human U1 snRNA and to Drosophila U2 snRNA SLIV. The thermodynamics of these binding interactions show a striking similarity, leading to the conclusion that U2B" has a relaxed specificity for its RNA targets. The binding properties of U2B" are distinct from those of human U1A and of Drosophila SNF, despite its high homology to those proteins, and so provide important new information on how this protein family has modulated its target preferences. PMID- 21684672 TI - The role of protein conformational fluctuations in allostery, function, and evolution. AB - It is now well-known that proteins exist at equilibrium as ensembles of conformational states rather than as unique static structures. Here we review from an ensemble perspective important biological effects of such spontaneous fluctuations on protein allostery, function, and evolution. However, rather than present a thorough literature review on each subject, we focus instead on connecting these phenomena through the ensemble-based experimental, theoretical, and computational investigations from our laboratory over the past decade. Special emphasis is given to insights that run counter to some of the prevailing ideas that have emerged over the past 40 years of structural biology research. For instance, when proteins are viewed as conformational ensembles rather than as single structures, the commonly held notion of an allosteric pathway as an obligate series of individual structural distortions loses its meaning. Instead, allostery can result from energetic linkage between distal sites as one Boltzmann distribution of states transitions to another. Additionally, the emerging principles from this ensemble view of proteins have proven surprisingly useful in describing the role of intrinsic disorder in inter-domain communication, functional adaptation mediated by mutational control of fluctuations, and evolutionary conservation of the energetics of protein stability. PMID- 21684674 TI - Isolation and cellular properties of mesenchymal cells derived from the decidua of human term placenta. AB - The clinical promise of cell-based therapies is generally recognized, and has driven an intense search for good cell sources. In this study, we isolated plastic-adherent cells from human term decidua vera, called decidua-derived mesenchymal cells (DMCs), and compared their properties with those of bone marrow derived-mesenchymal stem cells (BM-MSCs). The DMCs strongly expressed the mesenchymal cell marker vimentin, but not cytokeratin 19 or HLA-G, and had a high proliferative potential. That is, they exhibited a typical fibroblast-like morphology for over 30 population doublings. Cells phenotypically identical to the DMCs were identified in the decidua vera, and genotyping confirmed that the DMCs were derived from the maternal components of the fetal adnexa. Flow cytometry analysis showed that the expression pattern of CD antigens on the DMCs was almost identical to that on BM-MSCs, but some DMCs expressed the CD45 antigen, and over 50% of them also expressed anti-fibroblast antigen. In vitro, the DMCs showed good differentiation into chondrocytes and moderate differentiation into adipocytes, but scant evidence of osteogenesis, compared with the BM-MSCs. Gene expression analysis showed that, compared with BM-MSCs, the DMCs expressed higher levels of TWIST2 and RUNX2 (which are associated with early mesenchymal development and/or proliferative capacity), several matrix metalloproteinases (MMP1, 3, 10, and 12), and cytokines (BMP2 and TGFB2), and lower levels of MSX2, interleukin 26, and HGF. Although DMCs did not show the full multipotency of BM-MSCs, their higher proliferative ability indicates that their cultivation would require less maintenance. Furthermore, the use of DMCs avoids the ethical concerns associated with the use of embryonic tissues, because they are derived from the maternal portion of the placenta, which is otherwise discarded. Thus, the unique properties of DMCs give them several advantages for clinical use, making them an interesting and attractive alternative to MSCs for regenerative medicine. PMID- 21684675 TI - Re: Robert B. Nadler. Words of wisdom re: A randomized comparison of totally tubeless and standard percutaneous nephrolithotomy in elderly patients. Kara C, Resorlu B, Bayindir M, Unsal A. Urology 2010;76:289-93. Eur Urol 2011;59:1070. PMID- 21684677 TI - Phosphodiesterase type 5 inhibitors in the management of non-neurogenic male lower urinary tract symptoms: critical analysis of current evidence. AB - CONTEXT: A large body of epidemiologic data suggests a causal relationship between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED). Recently reported studies on phosphodiesterase type 5 inhibitors (PDE5-Is) and LUTS have further contributed to the understanding of mechanisms involved in this relationship and of potential treatment options. OBJECTIVE: A nonsystematic descriptive review was performed to summarize the literature concerning the role of PDE5-Is in men with LUTS, particularly looking at data derived from clinical trials in relation to the different PDE5-Is or their association with alpha blockers. EVIDENCE ACQUISITION: A comprehensive electronic search was conducted in October 2010 using the Medline database to identify all publications relating to ED and BPH and treatment with sildenafil, vardenafil, tadalafil, udenafil, UK 369003, and combination therapy with alfuzosin and tamsulosin. EVIDENCE SYNTHESIS: In studies in which either ED or LUTS was the entry criterion, sildenafil appears to improve both erectile function and LUTS in subjects with ED. Placebo-controlled trials of tadalafil and vardenafil showed improvement of LUTS secondary to benign prostatic hyperplasia (BPH), but none of the studies showed a significant effect on urodynamic measures. Exploratory studies with UK 369003 showed improvements in LUTS and ED. Sildenafil or tadalafil associated with alfuzosin or tamsulosin showed greater benefits for the combination therapy for both LUTS and ED. The coadministration of udenafil and an alpha-blocker in patients with BPH and ED also appeared to improve both LUTS and ED severity. CONCLUSIONS: Consistent evidence of improvements in LUTS has been shown with PDE5 Is, either alone or in combination with alpha-blockers. However, effects on urodynamics or objective measures of urinary flow are lacking. Further areas of research include investigation of mechanism of PDE5-Is, urodynamic studies, identification of new efficacy end points, head-to-head comparison with standard of care, potential benefit of add-on treatment, and long-term outcomes. PMID- 21684673 TI - Potential protective mechanisms of aryl hydrocarbon receptor (AHR) signaling in benign prostatic hyperplasia. AB - The aryl hydrocarbon receptor (AHR) is an evolutionarily conserved ligand activated transcription factor best known for its role in mediating toxic responses to dioxin-like environmental contaminants. However, AHR signaling has also emerged as an active participant in processes of normal development and disease progression. Here, we review the role of AHR signaling in prostate development and disease processes, with a particular emphasis on benign prostatic hyperplasia (BPH). Inappropriate AHR activation has recently been associated with a decreased risk of symptomatic BPH in humans and has been shown to impair prostate development and disrupt endocrine signaling in rodents. We highlight known physiological responses to AHR activation in prostate and other tissues and discuss potential mechanisms by which it may act in adult human prostate to protect against symptomatic BPH. PMID- 21684678 TI - Anterior expandable cylindrical cage reconstruction after cervical spinal metastasis resection. AB - Surgical therapy of cervical spine metastases had evolved a in the last years from posterior decompressive approaches to a direct anterior reconstructive approaches. Indication for surgery included intractable neck pain, spinal cord compression and stabilization of impending pathological fractures. We report our experience with expandable cylindrical cages in order to reconstruct and to stabilize cervical spine with metastasis. Between June 2004 and January 2006, a consecutive series of six patients underwent to resection of metastatic tumor in the cervical spine followed by expandable cylindrical cage reconstruction of the anterior vertebral column. All patients achieved immediate stability with neurological preservation. There were no significant complications related to the expandable cages in a mean follow up period of 10.5 months. Expandable cylindrical cages are effective resources for functional reconstruction after tumor resection in patients with cervical metastasis with advantages in the quality of life. PMID- 21684679 TI - Burden of care among caregivers of patients with Parkinson disease: a cross sectional study. AB - OBJECTIVE: Parkinson disease (PD) affects the lives of both the individuals and their family members. This study aims at investigating for clinical as well as socio-demographic factors associated with the perception of burden among the caregivers of individuals with PD in Malaysia. METHODS: This is a descriptive, cross-sectional study on PD patients and their caregivers who attended the neurology clinics of 2 tertiary hospitals in Kuala Lumpur. Socio-demographic and clinical data of the patients were obtained, including caregivers' perception of burden using the Caregiver's Burden Scale (CBS). RESULTS: The patients' mean age was 62.12+/-9.69 years, almost half of them were in stage 2 of their illness, had developed PD at the age of 50-69 and had duration of illness of less than 5 years. The caregivers were mostly females and a third of them were wives. Factors which were significantly associated with increased caregiver burden were patients' advancing age, later stage of illness and those having longer duration of caring. Caregivers' perceived burden was related to their race gender, social status, kinship with patient or duration of care-giving. CONCLUSION: Burden of care is significantly more in PD patients of advanced age and stage of illness. PMID- 21684680 TI - Enhancement of non-homologous end joining DNA repair capacity confers cancer cells resistance to the novel selenophene compound, D-501036. AB - D-501036 is a promising anti-cancer compound that exhibits potent anti proliferative activity against various types of human cancers through the induction of double strand DNA breaks. To determine drug resistance mechanism related to this class of DNA-damaging agents, a KB-derived D-501036-resistant cell line (S4) was established. Results showed that S4 cells exhibit enhanced DNA rejoining ability as compare to KB cells, through up-regulation of the non homologous end joining activity. In conclusion, enhancement of NHEJ activity plays important role in the development of D-501036-resistance and targeting NHEJ related molecules maybe able to overcome drug resistance to DNA damaging agents. PMID- 21684681 TI - GPx3 promoter hypermethylation is a frequent event in human cancer and is associated with tumorigenesis and chemotherapy response. AB - Glutathione peroxidase 3 (GPx3), a plasma antioxidant enzyme, maintains genomic integrity by inactivating reactive oxygen species (ROS), known DNA-damaging agents and mediators of cancer chemotherapy response. In this study, we demonstrate that loss of GPx3 expression by promoter hypermethylation is frequently observed in a wide spectrum of human malignancies. Furthermore, GPx3 methylation correlates with head and neck cancer (HNC) chemoresistance and may serve as a potential prognostic indicator for HNC patients treated with cisplatin based chemotherapy. Our findings support the hypothesis that defects in the antioxidant system may contribute to tumorigenesis of a wide spectrum of human malignancies. GPx3 methylation may have implications in chemotherapy response and clinical outcome of HNC patients. PMID- 21684682 TI - Development of graded Ni-YSZ composite coating on Alloy 690 by Pulsed Laser Deposition technique to reduce hazardous metallic nuclear waste inventory. AB - Alloy 690 based 'nuclear waste vitrification furnace' components degrade prematurely due to molten glass-alloy interactions at high temperatures and thereby increase the volume of metallic nuclear waste. In order to reduce the waste inventory, compositionally graded Ni-YSZ (Y(2)O(3) stabilized ZrO(2)) composite coating has been developed on Alloy 690 using Pulsed Laser Deposition technique. Five different thin-films starting with Ni80YSZ20 (Ni 80 wt%+YSZ 20 wt%), through Ni60YSZ40 (Ni 60 wt%+YSZ 40 wt%), Ni40YSZ60 (Ni 40 wt%+YSZ 60 wt%), Ni20YSZ80 (Ni 20 wt%+YSZ 80 wt%) and Ni0YSZ100 (Ni 0 wt%+YSZ 100 wt%), were deposited successively on Alloy 690 coupons. Detailed analyses of the thin-films identify them as homogeneous, uniform, pore free and crystalline in nature. A comparative study of coated and uncoated Alloy 690 coupons, exposed to sodium borosilicate melt at 1000 degrees C for 1-6h suggests that the graded composite coating could substantially reduced the chemical interactions between Alloy 690 and borosilicate melt. PMID- 21684683 TI - Clean hydrometallurgical route to recover zinc, silver, lead, copper, cadmium and iron from hazardous jarosite residues produced during zinc hydrometallurgy. AB - A hydrometallurgical process for treating the hazardous jarosite residue from zinc hydrometallurgy was proposed, for not only detoxifying the residue, but also recovering the contained valuable metal components. The jarosite was initially activated and decomposed by sintering at 650 degrees C for 1h. The sintered residue was leached in 6mol L(-1) aqueous NH(4)Cl solution at 105 degrees C, followed by filtration. The leaching extraction of Zn, Pb, Cu, Cd and Ag are more than 95%. During reduction with Zn powder, more than 93% of Pb, Cu, Ag and Cd can be simultaneously recovered. Then the NH(4)Cl leaching residue were leached again in 30wt% aqueous NaOH solution for 1h at 160 degrees C, and about 94% of As and 73% of Si were removed from the residue. The final residue was almost completely detoxified, and contains about 55wt% Fe, which can be used as an iron concentration. PMID- 21684684 TI - Environmental optimization of chromium recovery from tannery sludge using a life cycle assessment approach. AB - Life cycle assessment (LCA) was used to evaluate the environmental impact of an oxidative chromium recovery method from tannery sludge, in comparison with the usual landfilling process. Three improvement options (water reduction, byproduct use and anaerobic sludge digestion) were considered. The results showed that the proposed chromium recovery process would be better environmentally than conventional landfilling in all the evaluated impact categories if the amount of chromium recovered was 43 kg per ton of sludge. This amount could be recovered if the chromium concentration was about 20 times higher than that considered in this study. Alternatively, a lower chromium concentration would produce a better result if the recovery method was optimized and implemented at industrial rather than laboratory scale, and if more accurate data were provided on environmental credits for avoiding the chromium production process. Thus, the recovery method is environmentally beneficial when tannery sludge contains a chromium concentration of about 100,000 ppm. According to the literature, such concentrations are not unusual. The results could serve as the basis for further environmental improvements in chromium recovery and tannery sludge management and should be used in decision-making processes, especially for end-of-pipe treatments. PMID- 21684686 TI - Response to the commentary "You may (not always) experience what you expect: in search of the limits of the placebo and nocebo effect". PMID- 21684687 TI - Ultrastructure of the sporocysts of Eurytrema coelomaticum (Giard Et Billet, 1892) Looss, 1907. AB - The digenetic trematode Eurytrema coelomaticum is a parasite of pancreatic ducts of ruminants. The ultrastructure of the mother and daughter sporocysts of E. coelomaticum was analyzed. The mother sporocyst was attached to the coelome of the intestine wall of intermediate snail host Bradybaena similaris, intimately adhered in some regions. It presents a highly folded tegument with granules and the body wall was composed by an outer syncitial layer, basal lamina, and circular and longitudinal muscle layer. Below was the cell body (cyton) with the nucleus. The daughter sporocysts obtained by dissection exhibited many granules and secretory vesicle in the outer layer indicating an intense secretory activity. The body wall presented the same layers of the mother sporocysts, but the outer syncitial layer invaginated and an amorphous layer was present between the syncitial and circular muscle layers. The protonephridial excretory system was viewed. The anterior and posterior end of the expelled sporocyst exhibit a degenerated structure, but biological activity still occurred in these regions. The swollen middle of the body was filled by a lamellar structure formed by degenerating membranes, but the excretory system was preserved. The endocyst wall was fibrilar and filled by cercariae and amorphous, membranous and secretory material inside it. These results were discussed. PMID- 21684689 TI - Helminth parasites in pigs: new challenges in pig production and current research highlights. AB - Helminths in pigs have generally received little attention from veterinary parasitologists, despite Ascaris suum, Trichuris suis, and Oesophagostomum sp. being common worldwide. The present paper presents challenges and current research highlights connected with these parasites. In Danish swine herds, new indoor production systems may favour helminth transmission and growing knowledge on pasture survival and infectivity of A. suum and T. suis eggs indicates that they may constitute a serious threat to outdoor pig production. Furthermore, it is now evident that A. suum is zoonotic and the same may be true for T. suis. With these 'new' challenges and the economic impact of the infections, further research is warranted. Better understanding of host-parasite relationships and A. suum and T. suis egg ecology may also improve the understanding and control of human A. lumbricoides and T. trichiura infections. The population dynamics of the three parasites are well documented and may be used to study phenomena, such as predisposition and worm aggregation. Furthermore, better methods to recover larvae have provided tools for quantifying parasite transmission. Thus, an on going study using helminth naive tracer pigs has surprisingly demonstrated that soil infectivity with A. suum and T. suis increases during the first 2-3 years after pasture contamination. Though all three helminth species stimulate the Th2 arm of the immune system, Oesophagostomum seems weakly immunogenic, perhaps via specific modulation of the host immune system. A. suum and T. suis potently modulate the host immune response, up-regulating Th2 and down-regulating Th1. As a consequence, A. suum may compromise the efficacy of certain bacterial vaccines, whereas T. suis, which establish only short-term in humans, is a favourite candidate for down-regulating autoimmune Th1-related diseases in man. Some basic research findings have offered new possibilities for future sustainable control measures. For example, the heredity of host resistance to A. suum and T. suis is so high that breeding for resistant pigs may be a possibility. Experimental studies have demonstrated that fermentable dietary carbohydrates have an antagonistic effect on Oesophagostomum and to a lesser extent on T. suis and A. suum, whereas egg-destroying microfungi may be used to inactivate the hard shelled A. suum and T. suis eggs in the environment. Helminth control in Denmark has previously relied solely on anthelmintic treatment in herds with low helminth transmission. When indoor transmission rates increase, or in outdoor herds with high pasture contamination levels, medication may advantageously be combined with sustainable control measures, such as selected pig genomes, bioactive forages, and egg-destroying microfungi. PMID- 21684690 TI - Challenges of nematode control in ruminants: focus on Latin America. AB - Gastrointestinal nematodes (GIN) of ruminants (cattle, sheep and goats) are ubiquitous and can cause severe injuries to infected animals and significant losses in farming revenues. GIN are able to survive severe environmental and host conditions, but mankind has developed a number of ingenious methods for parasite control. The commerce and use of modern anthelmintic drugs with a broad spectrum of activity has been a solid tool for nearly 40 years, however the continuous use of these drugs, has led to the selection of populations of drug-resistant worms worldwide. At present, the ever-growing agricultural systems in Latin America are facing many challenges and cannot rely on the far-reaching objective of parasitic elimination from the host or the environment. The lack of extensive programs for monitoring drug resistance exacerbates the negative consequences of reduced efficacy, which is evident in some areas with the increase in mortality rate even after treatment. Experts agree that new schemes of parasitic control are needed and should be based on the strategy of targeted selective treatment where affected hosts are identified and treated accordingly. In this article, we will focus our discussion on the challenges for the control of GIN in Latin America by 2020 imposed by reduced drug efficacy. We will evaluate phenotypic and molecular markers, methods for single-animal evaluation, and the implementation of schemes for anthelmintic treatment that address parasites in refugia. PMID- 21684691 TI - Efficacy of a combined oral formulation of derquantel-abamectin against the adult and larval stages of nematodes in sheep, including anthelmintic-resistant strains. AB - Derquantel (DQL), a semi-synthetic member of a novel anthelmintic class, the spiroindoles, in combination with abamectin (ABA) [as the combination product STARTECT((r))] is a new entry for the treatment and control of parasites in sheep. The 19 studies reported herein were conducted in Australia, New Zealand, South Africa and the United Kingdom to demonstrate the efficacy of derquantel abamectin (DQL-ABA) against a broad spectrum of gastrointestinal and respiratory nematodes of sheep, and to support registration of the combination product. Eleven studies were conducted using natural or experimental parasite infections with unknown or unconfirmed resistance, while eight studies utilised isolates/strains with confirmed or well characterised resistance to one or more currently available anthelmintics, including macrocyclic lactones. All studies included DQL-ABA and negative control groups, and in selected studies one or more reference anthelmintic groups were included. In all studies the commercial formulation of DQL-ABA was administered orally at 2mg/kg DQL and 0.2mg/kg ABA; placebo was administered in the same volume as DQL-ABA; and reference anthelmintics were administered as per label recommendations, except in one instance where levamisole was administered at twice the label dose. Infection, necropsy, worm collection and worm counting procedures were performed using standard techniques. Efficacy was calculated based on the percentage reduction in geometric mean worm count relative to negative control for each nematode species and lifecycle stage targeted. Twenty-two isolates/strains used in the eight studies targeting resistant worms had proven resistance: three to one anthelmintic class, eleven to two classes and eight to three or more classes; of these resistant strains, 16 demonstrated resistance to a macrocyclic lactone anthelmintic. Regardless of resistance status in the 19 studies, DQL-ABA controlled a broad range of economically important gastrointestinal and respiratory nematode parasites of sheep, as follows: >= 98.9% efficacy against Haemonchus contortus (adult and L4); Teladorsagia circumcincta (adult, L4 and hypobiotic L4); Teladorsagia trifurcata (L4); Trichostrongylus axei (adult and L4); Trichostrongylus colubriformis (adult and L4); Trichostrongylus falculatus (adult); Trichostrongylus rugatus (adult); Trichostrongylus vitrinus (adult and L4); Cooperia curticei (adult and L4); Cooperia oncophora (adult and L4); Nematodirus spathiger (adult); Nematodirus battus (adult); Nematodirus spp. (hypobiotic L4); Strongyloides papillosus (adult); Strongyloides spp. (L4); Chabertia ovina (adult); Oesophagostomum venulosum (adult); Dictyocaulus filaria (adult); and Protostrongylus rufescens (adult); >= 97.0% efficacy against Trichuris ovis (adult); and >= 95.9% efficacy against T. trifurcata (adult). Derquantel-abamectin is a highly effective combination anthelmintic, which will provide an important new tool for controlling helminths of sheep when used in conjunction with sustainable drenching practices. PMID- 21684692 TI - Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain. AB - Fibromyalgia (FM) is a condition of chronic generalized musculoskeletal pain that is thought to be a disorder of central pain sensitization. A number of neurotransmitters in the ascending and descending pain pathways have been implicated in FM including glutamate and GABA. Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the conversion of glutamate to GABA and decreased expression or activity of this enzyme could result in an imbalance of excitatory and inhibitory neurotransmission in the ascending and descending pain pathways. Specifically, the expression and activity of the predominant isoform of GAD (GAD65) is influenced by several factors that are associated with FM such as female sex, poor diet, obesity, sedentary lifestyle, and stress. We hypothesize that decreased GAD expression and/or activity plays a role in the development and exacerbation of FM leading to impairments in the three common domains of FM symptomatology: increased pain (hyperalgesia and allodynia), disrupted sleep, and disturbances in mood (anxiety and depression). There are several lines of evidence that appear to support a role of GAD in FM. First, the defining symptom of FM is pain and GAD65 knockout mice have been shown to exhibit supraspinal hyperalgesia. Second, GAD has been implicated in disorders of muscle stiffness and rigidity and morning stiffness is a common symptom of FM. Third, stress, depression, and anxiety, which are often comorbid with FM, decrease GAD activity. Fourth, FM is associated with poor sleep, specifically disrupted non-rapid eye movement (NREM) sleep, and the pharmacological induction of NREM sleep is associated with the activation of GAD-containing neurons in the preoptic hypothalamus. Fifth, FM is more commonly diagnosed in women than men and the activity of GAD is reduced by low levels of its cofactor pyroxidine, which is less well-absorbed by women and can be further lowered by diet, tobacco, and alcohol intake. Sixth, FM patients tend to be overweight or obese and caloric restriction and exercise have been shown to increase GAD expression and activity. These six general lines of evidence suggest that GAD expression and/or activity might underlie the pathophysiology of FM. If this hypothesis is supported by future empirical studies, our understanding of the etiology of FM could be greatly improved. Moreover, behavioral and pharmacological therapies that modulate or mimic the effects of GAD might hold promise for the treatment of this debilitating and poorly understood disorder. PMID- 21684693 TI - The short estrous cycle of mice may influence the effect of BRCA1 mutations. AB - Breast and ovarian cancer susceptibility gene 1 (BRCA1) was identified from the genomic analysis of breast cancer families. Women heterozygous for a germ line mutation in the BRCA1 gene have a high risk of developing breast or ovarian cancers. BRCA1-mutant mice were created to study the function of BRCA1, but the heterozygous mice were healthy. The reason for this difference in phenotype between mice and humans is unknown. Here, I emphasize that the estrous cycle of mice differs from the menstrual cycle of humans and that this difference may be responsible for the lack of tumorigenesis in the BRCA1-mutant mouse model. Even if this difference in the cycles is not responsible for the phenotype difference, researchers should note this estrous cycle variation in reports of mouse BRCA1 studies. A method for reducing the influence of the short estrous cycle in mouse studies is also discussed in this text. PMID- 21684694 TI - Ontological hypothesis of the cancer etiology: discord between cells' survival determinism and their disposition to biological altruism. AB - During the last decades, scientific community has implicitly viewed cancer as a number of different diseases with the same underlying phenotype. Such a view was justified for the fact that some of the genetic and phenotypic similarities, observed in different types of tumors, were perpetuated via some distinct mechanisms. Nevertheless, this manuscript aims to interpret all of these differences in a context of the same underlying cause. To do so, the epigenetic and genetic alterations observed in cancers are initially interpreted in the context of their advantage for the evolution of the early eukaryotic organisms. Subsequently, the proposed premises are further discussed with respect to their propagation in the subsequent generations of the new eukaryotic species, as well as their role in the development of the higher organisms. In the subsequent section, the role of the proposed mechanism is discussed in the context of cancer, which is proposed to originate due to the analogous underlying mechanisms. Finally, the proposed mechanism is briefly discussed in parallel with some other contemporary theories of carcinogenesis, aiming to further support its validity. Thereby, the model presents an alternative interpretation of multiple cancer-related biomedical phenomena from the aspect of a proposed evolutionary mechanism. PMID- 21684695 TI - Treatment of Asian flush with abacavir. PMID- 21684696 TI - Postweaning multisystemic wasting syndrome produced in gnotobiotic pigs following exposure to various amounts of porcine circovirus type 2a or type 2b. AB - In late 2005, a postweaning, high mortality syndrome spread rapidly through finishing barns in swine dense areas of the United States. Diagnostic investigations consistently detected porcine circovirus type 2 (PCV2) from diseased tissues. Subsequent genetic analysis revealed that the infectious agent was a PCV2 type termed "PCV2b". Prior to late 2004, only the PCV2a type, but not PCV2b, had been reported in North America. In this communication, we produce severe postweaning multisystemic wasting syndrome (PMWS) in gnotobiotic pigs using infectious PCV2a and PCV2b generated from DNA clones constructed from field isolates identified in the 2005 outbreak. Clinical signs exhibited by diseased pigs included anorexia, dyspnea and listlessness. Mortality was typically observed within 12h of onset of dyspnea. The most striking microscopic lesions in affected animals were severe hepatic necrosis and depletion of germinal centers in lymph nodes with associated abundant PCV2 viral antigen. Clinical signs and lesions observed in these studies were comparable to those reported in experiments with gnotobiotic pigs inoculated with a PCV2a isolate while concurrently receiving immune-stimulation or co-infection with porcine parvovirus or torque teno virus. The animals in these studies were confirmed to be free of detectable porcine parvovirus, porcine reproductive and respiratory syndrome virus, bovine viral diarrhea virus, swine hepatitis E virus, and aerobic and anaerobic bacteria. Seven out of 24 PCV2 inoculated pigs had a detectable congenital torque teno virus infection with no correlation to clinical disease. Thus, in these studies, both PCV2a and PCV2b isolates were singularly capable of inducing high mortality in the absence of any detectable infectious co-factor. PMID- 21684697 TI - Combined effect of menopause age and genotype on occurrence of breast cancer risk in Pakistani population. AB - Cancer incidences and mortality rates are rapidly increasing and breast cancer is among the most frequent malignancy experienced in women worldwide. The occurrence of breast cancer could be associated with various social, cultural, environmental, life-style, hormonal and genetic factors. OBJECTIVE: To establish if PvuII and XbaI polymorphisms of estrogen receptor alpha would make Pakistani women more susceptible to breast cancer. Furthermore, association between breast cancer and various factors was also explored to establish the contributing factors in breast cancer in Pakistani population. SUBJECTS AND METHODS: Two hundred samples, aged 15-65 years, consisting of 100 breast cancer patients and 100 control samples were ascertained for this case-control study in order to evaluate the factors related to disease incidence. 5-7 ml of blood sample of each participating women in the study was collected and analyzed for polymorphisms of PvuII and XbaI using PCR-RFLP method. RESULTS: The menopause had strong influence on incidences of cancer with ca 18-fold increase in risk of breast cancer in women with menopause compared with non-menopaused. Furthermore significant impact of menopause age (P<0.0001) was observed on the incidence of cancer, as high rate of cancer incidence was observed in patients with age between 36 and 45 years (P<0.0001). Similarly, the genotype XbaI had significant influence on the incidence of the disease with heterozygous genotype of XbaI was 45% higher than wild type in cancerous cases. The menopausal women having heterozygous and homozygous mutants of PvuII or XbaI genotypes were strongly correlated with breast cancer (P<0.01). CONCLUSION: The polymorphism of genes involving estrogen metabolizing pathway and estrogen receptor pathway may play an important role in the etiology of breast cancer in Pakistani women. PMID- 21684698 TI - The scent of emotion, sex, and evolution. PMID- 21684699 TI - Sudden death of an alcoholic elderly man with acute esophageal necrosis (black esophagus). AB - We report a fatal case of acute esophageal necrosis (black esophagus) in an elderly male with alcohol abuse who was found dead with coffee-ground vomiting. A postmortem examination revealed severe anemia and marked black coloring of the esophagus from the upper to the bottom end. This was accompanied by histologic evidence of extensive mucosal necrosis. Alcohol abuse and esophagitis-related vomiting were both considered to be factors that led to the acute fatal esophageal necrosis. The cause of death was undetermined. We discuss the possible role of acute esophageal necrosis in the cause of sudden death. PMID- 21684700 TI - Japanese contributions to child neurology - an international perspective. PMID- 21684701 TI - [Management of seat-belt aorta in severe polytrauma: a review]. AB - Blunt trauma of the abdominal aorta is rare. Secondary to high-energy trauma, it is observed mainly in association with complex lesions. Evaluation of injury to the aorta must be a priority due to the risk of life-threatening massive hemorrhage. The clinical presentation can be quite obvious but also variable and often misleading. If in doubt, a systematic injected whole body scan is essential to diagnose aortic lesions. Hemorrhage or ischemia dictates emergency laparotomy. Opening the retroperitoneum increases the risk of infection if there is an associated gastrointestinal tract injury and may contraindicate use of arterial prostheses. Endovascular treatment can be proposed for less symptomatic lesions, including intimal dissection. Stents can be inserted via a femoral approach. In the event of juxtarenal dissection, there is a risk of renal artery thrombosis. Endovascular treatment is currently not recommended. This treatment can be delayed for a few days if necessary. Morbidity is low and long-term results are good. PMID- 21684702 TI - [Candida albicans: a rare cause of emphymatous pyelonephritis]. PMID- 21684703 TI - Grading luminal Crohn's disease: which MRI features are considered as important? AB - OBJECTIVES: Magnetic resonance imaging (MRI) is increasingly used for disease activity grading in small bowel Crohn's disease. It is not known which imaging features are essential for grading. For further insight, we solicited the opinion of expert radiologists. METHODS: A questionnaire about the grading of Crohn's disease was sent to 36 radiologists who had published on MRI grading of Crohn's disease between January 2006 and January 2010. Radiologists were asked which MRI protocol they used, how they graded luminal Crohn's disease, which features they used, how important they considered those features for grading, and which reference standards they used. RESULTS: Twenty-four radiologists responded (66%). They used different protocols and features; most frequently T2-weighted sequences (79%) and contrast enhanced fat saturated T1-weighted sequences (83%). MR enterography was more often used than MR-enteroclysis (88% versus 33%). Features most frequently considered important for grading were bowel wall thickness (79% of radiologists), the presence of an abscess (75%), T1 enhancement (75%), and T1 stratification (46%). Reference standards differed; most commonly (ileo-) colonoscopy (88%) or surgery (75%) were used. CONCLUSIONS: Bowel wall thickness, abscess, T1 enhancement and T1 stratification are most often used for grading. Because of difference in grading, there is need for an international consensus on MRI grading of Crohn's disease. PMID- 21684704 TI - Loading of the knee during 3.0T MRI is associated with significantly increased medial meniscus extrusion in mild and moderate osteoarthritis. AB - PURPOSE: Standard knee MRI is performed under unloading (ULC) conditions and not much is known about changes of the meniscus, ligaments or cartilage under loading conditions (LC). The aim is to study the influence of loading of different knee structures at 3Tesla (T) in subjects with osteoarthritis (OA) and normal controls. MATERIALS AND METHODS: 30 subjects, 10 healthy and 20 with radiographic evidence of OA (10 mild and 10 moderate) underwent 3T MRI under ULC and LC at 50% body weight. All images were analyzed by two musculoskeletal radiologists identifying and grading cartilage, meniscal, ligamentous abnormalities. The changes between ULC and LC were assessed. For meniscus, cartilage and ligaments the changes of lesions, signal and shape were evaluated. In addition, for the meniscus changes in extrusion were examined. A multivariate regression model was used for correlations to correct the data for the impact of age, gender, BMI. A paired T-Test was performed to calculate the differences in meniscus extrusion. RESULTS: Subjects with degenerative knee abnormalities demonstrated significantly increased meniscus extrusion under LC when compared to normal subjects (p=0.0008 0.0027). Subjects with knee abnormalities and higher KL scores showed significantly more changes in lesion, signal and shape of the meniscus (80% (16/20) vs. 20% (2/10); p=0.0025), ligaments and cartilage during LC. CONCLUSION: The study demonstrates that axial loading has an effect on articular cartilage, ligament, and meniscus morphology, which is more significant in subjects with degenerative disease and may serve as an additional diagnostic tool for disease diagnosis and assessing progression in subjects with knee OA. PMID- 21684705 TI - Phenotypic and genetic characterization of rhizobia associated with alfalfa in the Hokkaido and Ishigaki regions of Japan. AB - Twenty five rhizobial isolates were obtained from root nodules of Medicago sativa inoculated with soil samples collected from the Sapporo region and Ishigaki Island in Japan. To study their diversity and characterize them in relation to the climatic conditions of their soils of origin, a polyphasic approach analyzing stress tolerance, symbiotic and genetic properties was used. Stress tolerance assays revealed marked variations in salinity, pH and temperature tolerance. Isolates originating from a sub-tropical climate in alkaline soil (Ishigaki Island) tolerated high temperature, salinity and pH levels. Moreover, isolates recovered from a temperate climate in acidic soil (Sapporo) were sensitive to high temperature and salinity, and tolerated acidic pH. Phylogenetic analysis of conserved 16S rRNA and recA genes, and symbiotic nodA and nifDK revealed 25 isolates to be closely related to Ensifer meliloti. Furthermore, the branch patterns of phylogenetic trees constructed from different genes revealed the existence of at least two E. meliloti types in the soils studied. These results may be relevant to programs directed towards improving crop productivity through biofertilization with locally adapted and genetically defined strains. PMID- 21684706 TI - Analytical strategy for the confirmatory analysis of the non-steroidal anti inflammatory drugs firocoxib, propyphenazone, ramifenazone and piroxicam in bovine plasma by liquid chromatography tandem mass spectrometry. AB - A sensitive and selective method for the simultaneous determination of non steroidal anti-inflammatory drugs in bovine plasma was developed. Confirmatory analysis was carried out by liquid chromatography coupled with an electrospray ionisation tandem mass spectrometer (LC-ESI-MS/MS). Target compounds were acidified in plasma and extracted with acetonitrile. Sodium chloride was added to assist separation of the plasma and acetonitrile mixture. The acetonitrile extract is then subjected to liquid-liquid purification by the addition of hexane. Accuracy of the methods in plasma was between 93 and 102%. The precision of the method for the basic NSAIDs in plasma expressed as % RSD, for the within laboratory reproducibility was less than 10%. Decision limit (CCalpha values) and detection capability (CCbeta) values were established. The methods were validated according to Commission Decision 2002/657/EC. PMID- 21684707 TI - Strong antioxidant phenolics from Acacia nilotica: profiling by ESI-MS and qualitative-quantitative determination by LC-ESI-MS. AB - Acacia nilotica (L.) Del. syn is a species rich in polyphenolic constituents, in which catechins are hypothesized to possess antioxidant properties and to play a role in the anti-inflammatory activity of several plants. Due to the complexity of catechin derivatives, the investigation of this class of natural compounds has been limited by difficulties in their separation. In this paper, rationalization of the phenolics occurring in the 80% EtOH extract of Acacia nilotica pods, on the basis of ESI-MS and ESI-MS/MS profiles, has been proposed. Additionally, an LC-ESI-MS qualitative study has been performed by using a C18 polar endcapped stationary phase. The fragmentation pattern obtained evidenced the presence in A. nilotica pods of galloylated catechin- and gallocatechin derivatives along with galloylated glucose derivatives. The structures were confirmed by NMR, after isolation of the pure compounds. In addition, the radical scavenging activities of extracts and pure compounds were investigated, by using the TEAC assay. Furthermore quantitative analyses were performed by LC-ESI-MS/MS, confirming the interest of this species as a rich source of very strong antioxidant principles. PMID- 21684708 TI - Exploring the short-term impact of DNA-testing in breast cancer patients: the counselees' perception matters, but the actual BRCA1/2 result does not. AB - OBJECTIVE: Previous studies suggest that learning a DNA-test-result has no direct impact on the medical-decisions and psychological well-being of counselees. Their perception, especially their recollections and interpretations of their cancer risks and heredity, predict and/or mediate this impact. These studies were criticized for their small range of predictors, mediators, outcomes and contextual factors. We studied the short-term impact of DNA-testing with an extended model. METHODS: Three months after disclosure of BRCA1/2-test-results, we sent counselees a questionnaire about their perception, medical and psychological outcomes, and medical, familial and psychological contexts. 248 affected women participated; 30 had received pathogenic-mutations, 16 unclassified-variants and 202 uninformative-results. RESULTS: The actually communicated genetic-information and the contextual variables predicted the counselees' perception, but did not directly predict any outcomes. The counselees' perception predicted and/or completely mediated the counselees' medical intentions and behavior, physical and psychological life-changes, stigma, mastery, negativity and cancer-worries. Short-term distress was related to the perception not only of their own risks, but also of their relatives' risks and heredity-likelihood. Effect sizes were medium to large. CONCLUSIONS AND IMPLICATIONS: The outcomes of DNA-testing were better predicted by the counselees' perception than by the actually given genetic-information. We recommend genetic-counselors to have tailored, interactive dialogues about the counselees' perception. PMID- 21684709 TI - A meta-analysis of combined endarterectomy and proximal balloon angioplasty for tandem disease of the arch vessels and carotid bifurcation. AB - OBJECTIVE: High grade stenoses of both the innominate (IA) or common carotid artery (CCA) and the carotid bifurcation are rare and represent a therapeutic dilemma for the treating physician. A hybrid procedure with concomitant carotid endarterectomy (CEA) and retrograde angioplasty has been proposed as a less invasive treatment option. The aim of this study is to review the existing literature on such hybrid procedures. METHODS: An electronic search of the pertinent English literature was undertaken. A meta-analysis of all studies reporting on simultaneous carotid endarterectomy and retrograde angioplasty for the treatment of tandem internal carotid and proximal common carotid or innominate artery lesions was performed. RESULTS: Thirteen studies, including 133 patients were identified. Sixty-eight percent of the patients were male, 83% symptomatic. Proximal lesions were located in ipsilateral CCA in 85 cases and in IA in 48 cases. Reported technical success of the procedure was 97%. In 79 of the 129 successful operations, a stent was implanted, while the remaining 50 patients underwent simple balloon angioplasty. Thirty-day mortality and stroke rate were 0.7% and 1.5%, respectively. Combined 30-day mortality and stroke rate was 1.5%. During a mean follow-up of 12 to 36 months, five patients presented symptoms of cerebral ischemia and 17 died. Ten patients developed restenosis of the proximal lesion, (4 symptomatic, 7 in cases without stent) and 2 restenoses of the endarterectomy (all asymptomatic). Restenosis was treated in 7 cases (4 repeat angioplasty, 3 bypass grafts). CONCLUSIONS: This meta-analysis reports the largest collection of patients having undergone hybrid treatment of tandem disease of the arch vessels and carotid bifurcation. Results from this study show that the combined stroke and death rate with this approach is equal to or better than that for isolated endarterectomy. When possible, balloon angioplasty with stenting of the proximal component of this disease should be pursued to avoid restenosis. PMID- 21684710 TI - Predictors of neck bleeding after eversion carotid endarterectomy. AB - OBJECTIVE: The aim of this study was to identify predictors for neck bleeding after eversion carotid endarterectomy (eCEA). METHODS: A prospectively compiled computerized database of all primary eCEAs performed at a tertiary referral center between September 1998 and December 2009 was analyzed. The end point was any neck bleeding after eCEA. End point predictors were identified by univariate analysis. RESULTS: Of 1458 eCEAs performed by the same surgeon on 1294 patients under general anesthesia with continuous electroencephalographic monitoring and selective shunting, there were five major and three minor perioperative strokes (0.5%), and no deaths. Neck bleeding after eCEA occurred in 120 cases (8.2%), of which 69 (4.7%) needed re-exploration. Univariate analysis (odds ratio [95% confidence interval]) identified preoperative antiplatelet treatment with clopidogrel (1.77 [1.20-2.62], P = .004), particularly when continued to the day before CEA (3.84 [2.01-7.33], P < .001), and postoperative hypertension (9.44 [6.34-14.06], P < .001) as risk factors for neck bleeding in general and for neck bleeding requiring re-exploration (4.50 [1.85-10.89], P = .001; 15.27 [2.08 104.43], P = .006, and 2.44 [1.12-5.30], P = .02, respectively). An increased risk of neck bleeding in general was associated with clopidogrel plus acetylsalicylic acid (12.00 [2.59-56.78], P = .005), acetylsalicylic acid alone (4.37 [1.99-9.57], P < .001), and ticlopidine (2.49 [1.10-5.63], P = .02) only when they were continued to the day before CEA. No neck bleeding was associated with preoperative treatment with dipyridamole or warfarin, or no medication. No further complications occurred in the patients who underwent re-exploration. CONCLUSIONS: The results of this single-center university hospital study show that neck bleeding after CEA is relatively common but is not associated with an increased risk of stroke or death. Preoperative treatment with clopidogrel, particularly when it is continued to the day before surgery, and postoperative arterial hypertension seem to be associated with a higher risk of neck bleeding after CEA, requiring re-exploration in most cases. Other antiplatelet agents appear to be associated with an increased risk of postoperative neck bleeding only if they are continued to the day before CEA. Larger studies are warranted to confirm our findings and prevent this feared surgical complication. PMID- 21684711 TI - Coagulation, fibrinolysis, and platelet activation in patients undergoing open and endovascular repair of abdominal aortic aneurysm. AB - BACKGROUND: Endovascular aneurysm repair (EVAR) is associated with an improved perioperative mortality compared to open surgical repair. This benefit may reflect reduced incidence of microvascular and macrovascular thrombotic complications after EVAR. PURPOSE: The purpose of this study was to review and compare the effects of abdominal aortic aneurysm (AAA), open surgical repair, and EVAR on coagulation, fibrinolysis, and platelet activation. METHODS: A MEDLINE (1966-2010) and Cochrane library search for articles relating to the effects of AAA, open surgical repair, and EVAR on hemostasis was performed utilizing and cross-linking terms such as clotting, fibrinolysis, AAA, EVAR, and open surgical repair. Studies with a small cohort of patients (less than 7) or in which values of assessed biomarkers were not included were rejected. RESULTS: AAA is associated with increased thrombin generation, activity, and fibrin turnover as evidenced by increased plasma levels of thrombin-antithrombin III-complex (TAT), activated protein C-protein C inhibitor (APC-PCI), fibrin-monomer-fibrinogen (FM F), F1+2, fibrinogen, and D-dimer. The extent of hemostatic derangement correlates with the volume of intraluminal thrombus. This procoagulant state is exaggerated in the immediate perioperative period after both open surgical repair and EVAR, but is attenuated at medium-term follow-up although not normalized. CONCLUSION: The resultant prothrombotic diathesis after open surgical repair and EVAR may account for the high level of perioperative thrombotic complications. PMID- 21684712 TI - Endovascular repair of a celiac trunk aneurysm with a new multilayer stent. AB - Operative treatment of celiac trunk aneurysms has traditionally involved open repair using simple ligation, interposition graft, resection, and direct repair or antegrade bypass from the aorta; recently, endovascular techniques have been proposed in selected cases. We report a 60-year-old man presenting with a celiac trunk aneurysm that we treated with a new multilayer stent with the aim of preserving the parent vessels arising from the aneurysm. Computed tomography angiography at the 12-month follow-up visit confirmed the patency of the stents, the complete thrombosis of the sac without impairment of the main branches, and the regular perfusion of the liver and spleen. PMID- 21684713 TI - A rare case of internal jugular vein aneurysmal degeneration in a type 1 neurofibromatosis complicated by potentially life-threatening thrombosis. AB - Type 1 neurofibromatosis (NF1) is an autosomal dominant disorder characterized by multiple forms of neural crest cell proliferation. Associated venous malformations are extremely rare. We present a case of a giant thrombosed internal jugular aneurysm with brachiocephalic vein thrombosis in an NF1 patient. Surgical correction required prophylactic left brachiocephalic vein ligation, aneurysm evacuation, and proximal jugular vein ligation. Extreme vein friability caused severe intraoperative bleeding. Vein wall histology confirmed neurofibromatosis infiltration. Jugular vein aneurysm and infiltration in NF1, although exceedingly rare, can pose a serious threat to the patient during surgical correction, with major vessel thrombosis enhancing morbidity and mortality. PMID- 21684714 TI - Alcohol consumption and outcome in stable outpatients with peripheral artery disease. AB - BACKGROUND: The influence of alcohol consumption on outcome in patients with peripheral artery disease (PAD) has not been thoroughly studied. METHODS: Factores de Riesgo y ENfermedad Arterial (FRENA) is an ongoing, multicenter, observational registry of consecutive stable outpatients with arterial disease. We compared the mortality rate and the incidence of subsequent ischemic events in patients with PAD, according to their alcohol habits. RESULTS: As of August 2010, 1073 patients with PAD were recruited, of whom 863 (80%) had intermittent claudication (Fontaine stage II), 102 (9.5%) had rest pain (Fontaine stage III), and 108 (10%) had ischemic skin lesions (Fontaine stage IV). In all, 422 patients (39%) consumed alcohol during the study period. Over a mean follow-up of 13 months, 150 patients (14%) developed subsequent ischemic events (myocardial infarction 28, stroke 30, disabling claudication/critical limb ischemia 100), and 70 patients (6.5%) died. The incidence of subsequent events was the same in both subgroups: 11.8 events per 100 patient-years (rate ratio: 1.00; 95% confidence interval [CI], 0.72-1.41), but the mortality rate was significantly lower in alcohol consumers than in non-consumers: 2.78 vs 6.58 deaths per 100 patient years (rate ratio: 0.42; 95% CI, 0.23-0.74; P = .002). This better outcome was consistently found in patients with Fontaine stages II and III or IV, and persisted after multivariate adjustment (relative risk: 0.49; 95% CI, 0.28-0.88). CONCLUSIONS: In patients with PAD, moderate alcohol consumption was associated with lower cardiovascular mortality and overall mortality than abstention. These patients should be informed that low to moderate alcohol consumption may not be harmful to their health. PMID- 21684716 TI - Long term follow-up and risk of breast cancer after a radial scar or complex sclerosing lesion has been identified in a benign open breast biopsy. AB - AIMS: Radial scars (RS)/complex sclerosing lesions (CSL) are rare, benign breast lesions of unknown aetiology. Associations with breast cancer have been suggested particularly with larger lesions. This study aims to identify the risk of developing subsequent breast cancer after excision of a benign RS/CSL with respect to lesion size and compared to expected rates in the normal UK population. METHODS: A prospective cohort analysis was performed on patients diagnosed with RS/CSL in benign, open breast biopsy specimens over a 20-year period. The rate of subsequent breast cancer development was compared to expected rates in the normal UK population. Subjects were divided into two groups according to lesion size and the rates of subsequent breast cancer compared. RESULTS: 149 women without proliferative breast disease were followed for an average of 68 months. Five women developed subsequent cancer, equating to a rate of 0.84% per year. This compares to 0.32% per year in the normal population (RR 2.6, 95% CI 0.86-6.0). There were two subsequent cancers in the RS group and three subsequent cancers in the CSL group, P = 0.64. CONCLUSIONS: The study finds no evidence to suggest that lesions greater than 10 mm (CSL) have any greater risk of developing cancer after excision than those below 10 mm (RS). Women treated for RS/CSL do not need any additional follow-up beyond routine mammographic breast screening. Additional surveillance should only be performed if there is associated pathology indicating an increased risk of subsequent malignancy. PMID- 21684715 TI - Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia. AB - OBJECTIVES: Cell therapy is a novel experimental treatment modality for patients with critical limb ischemia (CLI) of the lower extremities and no other established treatment options. This study was conducted to assess the safety and clinical efficacy of intramuscular injection of autologous tissue repair cells (TRCs). METHODS: A prospective, randomized double-blinded, placebo controlled, multicenter study (RESTORE-CLI) was conducted at 18 centers in the United States in patients with CLI and no option for revascularization. Enrollment of 86 patients began in April 2007 and ended in February 2010. For the prospectively planned interim analysis, conducted in February 2010, 33 patients had the opportunity to complete the trial (12 months of follow-up), and 46 patients had completed at least 6 months of follow-up. The interim analysis included analysis of both patient populations. An independent physician performed the bone marrow or sham control aspiration. The aspirate was processed in a closed, automated cell manufacturing system for approximately 12 days to generate the TRC population of stem and progenitor cells. An average of 136 +/- 41 * 10(6) total viable cells or electrolyte (control) solution were injected into 20 sites in the ischemic lower extremity. The primary end point was safety as evaluated by adverse events, and serious adverse events as assessed at multiple follow-up time points. Clinical efficacy end points included major amputation-free survival and time to first occurrence of treatment failure (defined as any of the following: major amputation, death, de novo gangrene, or doubling of wound size), as well as major amputation rate and measures of wound healing. RESULTS: There was no difference in adverse or serious adverse events between the two groups. Statistical analysis revealed a significant increase in time to treatment failure (log-rank test, P = .0053) and amputation-free survival in patients receiving TRC treatment, (log-rank test, P = .038). Major amputation occurred in 19% of TRC treated patients compared to 43% of controls (P = .14, Fisher exact test). There was evidence of improved wound healing in the TRC-treated patients when compared with controls at 12 months. CONCLUSIONS: Intramuscular injection of autologous bone marrow-derived TRCs is safe and decreases the occurrence of clinical events associated with disease progression when compared to placebo in patients with lower extremity CLI and no revascularization options. PMID- 21684717 TI - The challenges and benefits of cardiovascular risk assessment in clinical practice. AB - Current expert guidelines for the treatment of hypertension or dyslipidemia recommend the use of cardiovascular risk assessment to identify high-risk individuals most likely to benefit from risk factor management. The potential uses of risk assessment include reassuring low-risk individuals, motivating high risk individuals to modify their lifestyles or adhere to medical therapy, and track an individual's progress as risk factors come under better control. Despite the potential usefulness of cardiovascular risk assessment in clinical practice, the vast majority of patients have never had their cardiovascular risk assessed. This review describes the strengths and weaknesses of the currently available risk engines and suggests an approach, based on the currently available evidence, that can be used to maximize the clinical impact of risk assessment in daily clinical practice. PMID- 21684718 TI - Health behaviour advice from health professionals to Canadian adults with hypertension: results from a national survey. AB - BACKGROUND: Health professionals play an important role in providing health information to patients. The objectives of this study were to examine the type of advice that Canadians with hypertension recall receiving from health professionals to manage their condition, and to assess if there is an association between health behaviour advice provided by health professionals and self reported engagement in health behaviour modification. METHODS: Respondents of the 2009 Survey on Living with Chronic Diseases in Canada (N = 6142) were asked about sociodemographic characteristics, health care utilization, and health behaviour modification to control hypertension. Association between receipt of advice from health professional and ever engaging, continuing to engage, and not engaging in health behaviour modification was quantified by prevalence rate ratios. RESULTS: Most participants (90.9%; 95% confidence interval [CI], 89.6-92.2) reported that the health professional most responsible for treating their high blood pressure was their general practitioner. Approximately 9% reported that they had not received or do not recall receiving any advice for blood pressure control. The most commonly reported advice received from a health professional was to participate in physical activity or exercise (70.0%). Respondents who had received advice on health behaviour change to manage their high blood pressure were more likely to report engaging in the behaviour compared with those who did not receive such advice. CONCLUSIONS: Many Canadians with hypertension receive health behaviour change advice from their health professionals. Receiving this advice was associated with a greater likelihood of attempting health behaviour change and attempting to sustain that change. PMID- 21684719 TI - Determining the cost economic "tipping point" for the addition of a regional percutaneous coronary intervention facility. AB - BACKGROUND: The preferred reperfusion strategy for ST-segment elevation myocardial infarction (STEMI) is percutaneous coronary intervention (PCI) provided it can be performed in a timely fashion at an expert 24/7 facility. However, many Canadians reside in areas precluding timely transport to a specialized facility. A new regional PCI facility could be economically viable if implementation costs are at least comparable to urgent transportation and interventional team clinical competency is maintained. OBJECTIVES: Provide a cost economic model for assisting decisions regarding addition of a regional PCI facility. METHODS: We used the following in the model: (1) PCI laboratory construction costs, (2) ambulance transportation costs, (3) procedural costs, and (4) expected clinical volume. We compared expected per PCI cost of air transportation vs deploying a regional facility based on population and distance from an existing centre. RESULTS: Potential cost economic advantages exist for establishing new PCI centres with decreasing minimum populations of 208,100, 141,900, and 110,000 located at increasing distances of 150 km, 300 km, and 450 km, respectively, from the existing tertiary PCI centres. Sensitivity analyses suggest that regions with modest populations of approximately 200,000 located at these distances may be economically attractive. CONCLUSIONS: The derived algorithm can be used to assess the economics component of establishing regional PCI laboratories and identify opportunities for extending access for primary PCI. This model presents a means for evaluating the economic implications of constructing a new facility. Additional components such as staffing and patient preferences for location of care also require consideration. PMID- 21684720 TI - Ketogenic diet does not change NKCC1 and KCC2 expression in rat hippocampus. AB - In control rats, we examined the effects of ketogenic diet on NKCC1 and KCC2 expression levels in hippocampus. Neither the number of NKCC1 immunoreactive cells nor the intensity of labeling of KCC2 was found to modify in hippocampus of the rats after ketogenic diet treatment. These results indicate that ketogenic diet by itself does not modify the expression of these cation chloride cotransporters. PMID- 21684722 TI - Reduced activation of superior temporal gyrus during auditory comprehension in young offspring of patients with schizophrenia. AB - BACKGROUND: Smaller Superior Temporal Gyrus (STG) and reduced activation with language tasks have been found in schizophrenia emphasizing the involvement of parts of language network. Recently, we reported smaller STG in individuals at risk for psychosis. In this study, we examined the brain activation for auditory comprehension using fMRI in a group of young offspring of schizophrenia patients (HR) with a hypothesis that HR subjects will not activate STG as well as comparison subjects. METHODS: Fifteen HR (7M, 8F, mean age 15.9+/-3.1) and 17 comparison subjects (9M and 8F, mean age 14.5+/-3.5) participated. BOLD fMRI images were obtained using a 4 Tesla scanner with a multi echo-planar imaging sequence. The participants were asked to listen to 30 sec blocks of a story alternated with blocks of the same reading played backwards. The data were analyzed using Statistical Parametric Mapping (SPM5) and a BOLD activation exceeding a threshold of T>2.58 (p<0.01, uncorrected) was considered significant. RESULTS: The HR showed significantly lower BOLD activation at the STG bilaterally compared to normal controls (left STG; x=-64, y=-48, z=12, Z=2.95, right STG; x=62, y=-50, z=-16, Z=2.77). The effect was more pronounced in males and on left STG. CONCLUSIONS: These data suggest that adolescents at risk for schizophrenia show reduced activation of the STG compared to control subjects during a language related task (listening). This finding adds support to the idea that abnormal development of the language related cortex is a marker of increased susceptibility to schizophrenia and that such deviant development may be mediated by familial/genetic factors. PMID- 21684721 TI - Effects of antipsychotics on D3 receptors: a clinical PET study in first episode antipsychotic naive patients with schizophrenia using [11C]-(+)-PHNO. AB - Most antipsychotics are thought to have an effect on D(2) and D(3) receptors, although their D(3), versus D(2) binding has not been clearly established in vivo in humans. However, the development of [(11)C]-(+)-PHNO now permits the differentiation of antipsychotic activity on these two receptor subtypes. In this study we examined the effects of antipsychotics on D(2) and D(3) receptors by comparing [(11)C]-(+)-PHNO in D(2)-rich (caudate, CAU and putamen, PUT), mixed (ventral striatum) and D(3)-rich (globus-pallidus, GP and substantia nigra, SN) regions before and after the initiation of antipsychotic medication. The investigation therefore represents a longitudinal within-subject follow-up design wherein antipsychotic-naive patients with schizophrenia spectrum disorders were first scanned in a drug-naive state and then again after ~2.5 weeks of antipsychotic treatment (risperidone or olanzapine). Binding potential (non displaceable or BP(ND)) was obtained to derive estimates of drug occupancy in the identified brain regions. Antipsychotic treatment was associated with the expected occupancies in the D(2)-rich regions; unexpectedly though, patients showed a higher, rather than the expected lower, [(11)C]-(+)-PHNO BP(ND) in the GP and SN despite simultaneous evidence for ongoing D(2) blockade in the other regions (CAU and PUT). In conclusion, patients treated with atypical antipsychotics demonstrated no evidence of D(3) receptor occupancy, but instead possible D(3) up-regulation following short-term treatment. The present findings add to a very limited body of evidence related to D(3) binding in vivo. [(11)C] (+)-PHNO offer new opportunities for exploring the potential therapeutic significance of the D(3) receptor in schizophrenia and the action of antipsychotics. PMID- 21684723 TI - A protective genetic variant for adverse environments? The role of childhood traumas and serotonin transporter gene on resilience and depressive severity in a high-risk population. AB - Genetic aspects may influence the effect of early adverse events on psychological well being in adulthood. In particular, a common polymorphism within the serotonin transporter gene (5-HTTLPR short/long) has been associated to the risk for stress-induced psychopathology. In the present study we investigated the role of childhood traumas and 5-HTTLPR on measures of psychological resilience and depression in a sample of individuals at a high risk for psychological distress (763 male prisoners). The 5-HTTLPR genotype did not influence resilience and depressive severity. However, a significant interaction was observed between 5 HTTLPR and childhood traumas on both resilience and depressive severity. In particular, among subjects exposed to severe childhood trauma only, the long allele was associated to lower resilience scores and increased current depressive severity as compared to short/short homozygous. Sex specific effects, difference in type and duration of stressors and the specific composition of the sample may explain discrepancy with many studies reporting the short-allele as a vulnerability factor for reactivity to stress. We here speculated that in males the long-allele may confer lower resilience and therefore higher vulnerability for depressive symptoms in subjects exposed to early stress and currently living in stressful environments. PMID- 21684724 TI - Statistical adjustments for brain size in volumetric neuroimaging studies: some practical implications in methods. AB - Volumetric magnetic resonance imaging (MRI) brain data provide a valuable tool for detecting structural differences associated with various neurological and psychiatric disorders. Analysis of such data, however, is not always straightforward, and complications can arise when trying to determine which brain structures are "smaller" or "larger" in light of the high degree of individual variability across the population. Several statistical methods for adjusting for individual differences in overall cranial or brain size have been used in the literature, but critical differences exist between them. Using agreement among those methods as an indication of stronger support of a hypothesis is dangerous given that each requires a different set of assumptions be met. Here we examine the theoretical underpinnings of three of these adjustment methods (proportion, residual, and analysis of covariance) and apply them to a volumetric MRI data set. These three methods used for adjusting for brain size are specific cases of a generalized approach which we propose as a recommended modeling strategy. We assess the level of agreement among methods and provide graphical tools to assist researchers in determining how they differ in the types of relationships they can unmask, and provide a useful method by which researchers may tease out important relationships in volumetric MRI data. We conclude with the recommended procedure involving the use of graphical analyses to help uncover potential relationships the ROI volumes may have with head size and give a generalized modeling strategy by which researchers can make such adjustments that include as special cases the three commonly employed methods mentioned above. PMID- 21684725 TI - Niosomes vs microemulsions: new carriers for topical delivery of Capsaicin. AB - The development of advanced biomaterials and drug-delivery systems has had a significant impact on our ability to treat several diseases. A new study was performed on niosomal formulations obtained from a mixture of commercial surfactants (Tween 80 and Span 80) to be applied topically for the release of Capsaicin. Capsaicin is the pungent principle of red pepper and it has a variety of pharmacological actions on the cardiovascular, respiratory and nervous systems. Niosomal carriers were prepared using a particular ratio between surfactants, to obtain systems with a specific HLB (10,12,14) and characterized in terms of dimension, morphology and their drug entrapment efficiency. Niosomes were compared to microemulsions prepared from the same surfactants in the same ratio, to evaluate their possible use in transdermal drug delivery. As regards the in vitro percutaneous permeation of Capsaicin from both microemulsions and niosomal formulations, it was carried out using diffusion Franz cells. The results indicate that niosomes could better promote the transdermal delivery of Capsaicin, with respect to microemulsions, even if both carriers could be an effective vehicle for topical delivery of this drug. PMID- 21684726 TI - Photochemically triggered reaction of glucose oxidase in a fused vesicle containing Malachite Green leuconitrile derivative. AB - Glucose oxidase (GOD) was encapsulated in vesicles containing a photoionizable Malachite Green leuconitrile derivative (MGL). Subsequent UV irradiation of MGL afforded the fusion of GOD- and glucose-encapsulating vesicles and thus decreased the concentration of glucose in the vesicles. The time dependence of the vesicle fusion was studied using fluorescent probe molecules. This phototriggered fusion could be instrumental in the development of a system for the production of nanometer-sized bioreactors. PMID- 21684727 TI - Adsorption and separation of proteins by a synthetic hydrotalcite. AB - In this study, the potential use of a synthetic Mg/Al hydrotalcite (layered double hydroxide) as a novel chromatography material for protein purification was investigated. The hydrotalcite is present in its carbonate form and is characterized by an Al/Mg-ratio of 1.85. Zetapotential measurements confirm a positive surface potential up to pH 10 suggesting applicability as anion exchanger. The binding of model proteins covering a broad range of isoelectric points and molecular weights was performed at different pH-values under batch conditions to evaluate the binding behaviour of the hydrotalcite. Furthermore, static binding capacities were exemplarily determined for hemoglobin and human serum albumin. Additionally, the adsorption and elution of hemoglobin was studied under dynamic conditions. The binding behaviour of the hydrotalcite was compared to commercially available anion exchangers and was found to be a function of pH, depending on the model protein. Variant adsorption behaviour is explained by further interactions like hydrogen bonds and by an unequal charge distribution over the protein surfaces. The hydrotalcite reveals high adsorption capacities under static (260 mg/g) as well as under dynamic conditions (88 mg/g at 34 cm/h; 61 mg/g at 340 cm/h). With appropriate buffers like 500 mM carbonate (pH 10) the adsorbed proteins can be nearly completely desorbed making regeneration possible. Due to the binding and elution properties it is concluded, that the hydrotalcite can serve anion exchange material for chromatographic protein separations. PMID- 21684728 TI - Electrochemical oxidation and detection of paeonol on modified electrode with acetylene black nanoparticles. AB - With an aim to construct a sensing platform for the electrochemical detection of paeonol, we modified the glassy carbon electrode with acetylene black nanoparticle (AB). A sensitive oxidation peak of paeonol was observed with remarkably increased peak current on the modified electrode because the electrode has a big surface area due to three dimensional structure of AB nanoparticles. The optimization of detection conditions was performed, including pH value of the buffer, the amount of AB nanoparticles on the electrode surface, the accumulation potential and time of paeonol. Under the optimized conditions, the oxidation peak current of paeonol increased linearly with its concentration over the range from 5*10(-7) to 1*10(-4) M. The detection limit was calculated to be 1*10(-7) M. The modified electrode was successfully applied to detect the content of paeonol in cortex moutan, a common traditional Chinese medicine. The method is new, sensitive, rapid and convenient for the detection of paeonol. PMID- 21684729 TI - Etiopathogenesis of hyperostosis frontalis interna: a mystery still. AB - Hyperostosis frontalis interna is a morphological pattern characterized by single or multiple bony nodules situated on the inner lamina of the frontal bone. It is seldom found in males, but it is a common phenomenon among post-menopausal females in modern societies but relatively rare in antiquity. The etiopathogenesis of the trait is a matter of debate and ranges from genetic predisposition to epigenetic, while endocrine disturbances, aging, and dietary factors are also listed among the causes. We studied the frequency, characteristic features, and etiopathogenesis of the disease in recent cadaveric and dry skull specimens. The frequency of hyperostosis frontalis interna in cadavers and dry skull materials was almost identical, 12.5% and 12.3%, respectively. In cadavers, 87.5% of severe hyperostosis frontalis interna cases were found in females over 65 years-old. Interestingly, in two cadavers we found hyperostotic lesions spreading onto adjacent tissues such as the dura and falx cerebri. We provide some new aspects that may help in better understanding of the etiopathogenesis of hyperostosis frontalis interna. Thereby, we discuss the various etiopathogenesis models found in the literature. PMID- 21684730 TI - Clinical value of detection of metastasis of carina in patients with non-small cell lung cancer. AB - BACKGROUND: Although the utility of blind biopsy in the detection of metastasis in the carina has been reported, submucosal fine needle aspiration (SMFNA) has not been evaluated. We investigated how SMFNA of the main carina and upper-lobe carina in addition to blind biopsy affect management of patients with NSCLC. METHODS: Thirty-five patients were evaluated. During fiberoptic bronchoscopy (FOB), five blind biopsy and three SMFNA specimens were collected from normal appearing main carina (n = 35) and/or upper-lobe carina (n = 18). Subjects were staged for operability using traditional staging system, without knowing the blind biopsy or SMFNA results. Then, patients were staged again after results were made known. RESULTS: Thirty-five NSCLC patients were analyzed. The management of 12 patients (34%) was changed according to our results. Out of the patients, 8, 5 and one had microscopic metastasis in the main carina, ipsilateral upper-lobe carina and both, respectively. Although SMFNA were more diagnostic compared to blind forceps biopsy, there was no statistically difference between them. These procedures increased the success of detection of microscopic metastasis and the results changed management of those cases. CONCLUSION: SMFNA adds valuable information to blind biopsy, and their combination changed the management in one quarter of our NSCLC patients. PMID- 21684731 TI - Clinical and economic burden of patients diagnosed with COPD with comorbid cardiovascular disease. AB - BACKGROUND: Cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) commonly coexist, increasing the risk of hospitalization and mortality compared to either condition alone. The purpose of this study was to evaluate the impact of comorbid CVD on healthcare utilization and costs in a COPD population. METHODS: A retrospective cohort study of COPD patients CVD +/- >=40 years of age using administrative claims data was conducted. COPD-CVD patients were matched to COPD patients without CVD (COPD-Only cohort) using propensity scores. Multivariate analyses were conducted to assess the 1-year risk of COPD exacerbations (hospitalization and/or emergency room [ER] visits), along with differences in 1-year and 2-year all-cause and COPD-related utilization and costs (2008 USD) among COPD-CVD and COPD-Only cohorts. RESULTS: Each cohort included 4594 patients. Compared to COPD-Only cohort, the COPD-CVD cohort was almost 2 times more likely to require COPD-related hospitalization (odds ratio [OR], 1.95; p < 0.001), 47% more likely to have an ER visit (OR, 1.47; p < 0.001) and 62% more likely to require hospitalization and/or ER visit (OR, 1.62; p < 0.001). Average annual all-cause medical costs per patient were $22,755 for COPD-CVD vs $8036 for COPD-Only (p < 0.001), and total costs were $27,032 vs $11,506 (p < 0.001), respectively; corresponding average COPD-related annual medical costs were $1891 vs $1060 (p < 0.001) and total costs were $3295 vs $2379 (p < 0.001). CONCLUSIONS: COPD patients with CVD have significantly higher risk of COPD exacerbations and increased costs than COPD patients without CVD. This suggests a close association between COPD and CVD that warrants further exploration. PMID- 21684732 TI - Pulmonary-renal syndromes: an update for respiratory physicians. AB - Pulmonary-renal syndromes are a group of disorders characterised by necrotising glomerulonephritis and pulmonary haemorrhage. Small vessel systemic vasculitis is the most common cause of pulmonary-renal syndromes presenting to respiratory physicians. Rarer causes include systemic lupus erythematosus and connective tissue diseases though severe pneumonia or cardiac failure may mimic their presentation. Some forms of small vessel vasculitides have a predilection for the pulmonary and renal vascular beds and if left untreated can result in fulminant organ failure. Whilst the aetiology of these syndromes remains unclear, much is known about the disease mechanisms including the pathogenic role of autoantibodies, immune-complex mediated inflammation and microangiopathic in-situ thrombosis. Despite established treatments achieving successful remission induction, patient tolerability and side effect profiles have limited their use which has led to searches for more targeted treatments. Consequently newer biological therapies have gained wider acceptance despite little being known about their long term safety and efficacy. The European Vasculitis Study Group (EUVAS) have recently formulated guidelines to provide consensus on diagnosis and management in this area and work to define survival rates in these conditions with longer term follow-up studies is ongoing. This review summarises the current aetiopathogenesis thought to underlie these complex diseases, the diagnostic definitions and classification criteria currently in use and the evidence base for modern therapies. Though unusual for respiratory specialists to coordinate overall management of these patients, an update on their current management is regarded as important to their practice given the recently changing trends in treatments. PMID- 21684733 TI - Continuous high-solids anaerobic co-digestion of organic solid wastes under mesophilic conditions. AB - With increasing concerns over the limited capacity of landfills, conservation of resources, and reduction of CO(2) emissions, high-solids (dry) anaerobic digestion of organic solid waste (OSW) is attracting a great deal of attention these days. In the present work, two dry anaerobic co-digestion systems fed with different mixtures of OSW were continuously operated under mesophilic conditions. Dewatered sludge cake was used as a main seeding source. In reactor (I), which was fed with food waste (FW) and paper waste (PW), hydraulic retention time (HRT) and solid content were controlled to find the maximum treatability. At a fixed solid content of 30% total solids (TS), stable performance was maintained up to an HRT decrease to 40 d. However, the stable performance was not sustained at 30 d HRT, and hence, HRT was increased to 40 d again. In further operation, instead of decreasing HRT, solid content was increased to 40% TS, which was found to be a better option to increase the treatability. The biogas production rate (BPR), CH(4) production yield (MPY) and VS reduction achieved in this condition were 5.0m(3)/m(3)/d, 0.25 m(3) CH(4)/g COD(added), and 80%, respectively. Reactor (II) was fed with FW and livestock waste (LW), and LW content was increased during the operation. Until a 40% LW content increase, reactor (II) exhibited a stable performance. A BPR of 1.7 m(3)/m(3)/d, MPY of 0.26 m(3) CH(4)/g COD(added), and VS reduction of 72% was achieved at 40% LW content. However, when the LW content was increased to 60%, there was a significant performance drop, which was attributed to free ammonia inhibition. The performances in these two reactors were comparable to the ones achieved in the conventional wet digestion and thermophilic dry digestion processes. PMID- 21684734 TI - Highly sensitive chemiluminescent point mutation detection by circular strand displacement amplification reaction. AB - Single nucleotide polymorphism (SNP) genotyping is attracting extensive attentions owing to its direct connections with human diseases including cancers. Here, we have developed a highly sensitive chemiluminescence biosensor based on circular strand-displacement amplification and the separation by magnetic beads reducing the background signal for point mutation detection at room temperature. This method took advantage of both the T4 DNA ligase recognizing single-base mismatch with high selectivity and the strand-displacement reaction of polymerase to perform signal amplification. The detection limit of this method was 1.3 * 10( 16)M, which showed better sensitivity than that of most of those reported detection methods of SNP. Additionally, the magnetic beads as carrier of immobility was not only to reduce the background signal, but also may have potential apply in high through-put screening of SNP detection in human genome. PMID- 21684735 TI - Cellulose extraction from wood chip in an ionic liquid 1-allyl-3 methylimidazolium chloride (AmimCl). AB - In the present study, 1-allyl-3-methylimidazolium chloride (AmimCl), an ionic liquid (IL), was used to extract cellulose from pine, poplar, Chinese parasol, and catalpa wood chips. Results show that pine is the most suitable wood species for cellulose extraction with ILs. Its cellulose extraction rate can reach as high as 62% under optimized conditions and its cellulose content is as high as 85% when DMSO/water is used as the precipitant. The dissolution process can be clearly observed by hot stage optical microscopy, and the reaction time can be significantly reduced by microwave irradiation. (13)C CP/MAS NMR, FTIR, XRD, and SEM were used to analyze the cellulose-rich extracts of pine. Results show that IL dissolves pine wood by destroying inter and intramolecular hydrogen bonds between lignocelluloses. The major component of pine extract is cellulose with a homogeneous and dense structure. After extraction, AmimCl can be easily recycled and reused. PMID- 21684736 TI - Culture of Scenedesmus sp. LX1 in the modified effluent of a wastewater treatment plant of an electric factory by photo-membrane bioreactor. AB - To investigate the coupled technology for advanced wastewater treatment and microalgal biomass production, a photo-membrane bioreactor was constructed. The microalga Scenedesmus sp. LX1 was cultured in the bioreactor using liquor prepared from the effluent of an electronic device factory. The algal cell growth, nitrate nitrogen removal, orthophosphate phosphorus removal were investigated. When cultured with batch operation, the average specific growth rate was about 0.09 d(-1), and low nitrogen (N), phosphorus (P) concentrations in the liquor were achieved. However, under continuous operation with an inflow of 60 Lh(-1), the average specific growth rate was only 0.02 d(-1), and removal rates of 100% for orthophosphate P and 46% for nitrate N were achieved. With the inflow of 120 Lh(-1), the accumulated metal ions in the bioreactor adversely affected the algal cells. The algal cells were much easier to settle, and the removal efficiency for N and P decreased. PMID- 21684737 TI - Discovery of a novel class of 2-aminopyrimidines as CDK1 and CDK2 inhibitors. AB - A series of new 2-(2-aminopyrimidin-4-yl)phenol derivatives were synthesized as potential antitumor compounds. Substitution with pyrrolidine-3,4-diol at the 4 position of phenol provided potent inhibitory activity against CDK1 and CDK2. X ray crystal structural studies were performed to account for the effect of the substituent on both the enzymatic and cell growth inhibitory activities. PMID- 21684738 TI - Gold(III) chloride catalyzed regioselective synthesis of pyrano[3,4-b]indol-1(9H) ones and evaluation of anticancer potential towards human cervix adenocarcinoma. AB - A highly regioselective synthesis of pyrano[3,4-b]indol-1(9H)-ones via gold(III) chloride catalyzed cycloisomerization of 3-ethynyl-indole-2-carboxylic acid was achieved in good to excellent yields. These compounds were screened for their in vitro cytotoxicity against human cervical (HeLa) cell lines. Out of ten compounds, three compounds (7d, 7e and 7j) showed comparable proliferation inhibitory activity against the standard drug cisplatin. Compound 7d was found to be the most efficacious with IC(50) value of 0.22MUM. PMID- 21684739 TI - 2-Phenylimidazo[1,2-b]pyridazine derivatives highly active against Haemonchus contortus. AB - A series of 2-phenylimidazo[1,2-b]pyridazine derivatives were synthesized and evaluated for their in vitro anthelmintic activity against Haemonchus contortus. The most active compounds had in vitro LD(99) values of 30nM, which is comparable to that of the benchmark commercial nematocide, Ivermectin. PMID- 21684740 TI - Discovery of microsomal triglyceride transfer protein (MTP) inhibitors with potential for decreased active metabolite load compared to dirlotapide. AB - Analogues related to dirlotapide (1), a gut-selective inhibitor of microsomal triglyceride transfer protein (MTP) were prepared with the goal of further reducing the potential for unwanted liver MTP inhibition and associated side effects. Compounds were designed to decrease active metabolite load: reducing MTP activity of likely human metabolites and increasing metabolite clearance to reduce exposure. Introduction of 4'-alkyl and 4'-alkoxy substituents afforded compounds exhibiting improved therapeutic index in rats with respect to liver triglyceride accumulation and enzyme elevation. Likely human metabolites of select compounds were prepared and characterized for their potential to inhibit MTP in vivo. Based on preclinical efficacy and safety data and its potential for producing short-lived, weakly active metabolites, compound 13 (PF-02575799) advanced into phase 1 clinical studies. PMID- 21684741 TI - A reverse method for diversity introduction of benzimidazole to synthesize H(+)/K(+)-ATP enzyme inhibitors. AB - A series of 2-[(2-pyridylmethyl)sulfinyl]benzimidazole derivatives were synthesized via a solution phase synthetic route using a reversal method of diversity introduction. Using this synthetic strategy, we obtained two key intermediates (4-A and 4-B) simultaneously, which allows us to introduce diversity points onto the benzimidazole part of the final product under reliable reaction conditions to identify potent H(+)/K(+)-ATP enzyme inhibitors. Compound 14l (IC(50)=1.6*10(-5)M) was comparable with H(+)/K(+)-ATP enzyme inhibitor in vitro. PMID- 21684742 TI - Deciphering glycan linkages involved in Jurkat cell interactions with gold-coated nanofibers via sugar-displayed thiols. AB - Metabolic oligosaccharide engineering (MOE) provides a method to install novel chemical functional groups into the glycocalyx of living cells. In this Letter we use this technology to compare the impact of replacing natural sialic acid, GalNAc, and GlcNAc with their thiol-bearing counterparts in Jurkat and HL-60 cells. When incubated in the presence of gold-coated nanofibers, only Jurkat cells incubated with Ac(5)ManNTGc-an analogue that installs thiols into sialosides-experienced a distinctive 'spreading' morphology. The comparison of Ac(5)ManNTGc with Ac(5)GalNTGc and Ac(5)GlcNTGc in the two cell lines implicated sialosides of N-linked glycans as critical molecular mediators of the unusual responses evoked in the Jurkat line. PMID- 21684743 TI - MAO inhibitory activity modulation: 3-Phenylcoumarins versus 3-benzoylcoumarins. AB - With the aim of finding the structural features for the human MAO inhibitory activity and selectivity, in the present communication we report the synthesis, pharmacological evaluation and a comparative study of a new series of 3 phenylcoumarins (compounds 1-4) and 3-benzoylcoumarins (compounds 5-8). A bromo atom and a methoxy/hydroxy substituent were introduced in these scaffolds, at six and eight positions of the coumarin moiety, respectively. The synthesized compounds 1-8 were evaluated as MAO-A and B inhibitors using R-(-)-deprenyl and iproniazide as reference compounds. The presence or absence of a carbonyl group between the coumarin and the phenyl substituent in 3 position remarks, respectively, the MAO-A or MAO-B inhibitory activity. Some of the new compounds showed MAO-B inhibitory activities in the low nanomolar range. Compound 2 (IC(50)=1.35nM) showed higher inhibitory activity than the R-(-)-deprenyl (IC(50)=19.60nM) and higher MAO-B selectivity, with more than 74,074-fold inhibition level, respecting to the MAO-A isoform. PMID- 21684744 TI - A transcription factor hijacking to regulate RARalpha by using a chimeric molecule of retinoic acid and a DNA alkylator. AB - As a model compound for the transcription factor hijacking mechanism of action of DNA damaging agent that simultaneously bind to the nuclear receptor, we designed and synthesized a chimeric molecule, RA-mustard, which can bind with both retinoic acid receptor alpha (RARalpha) and DNA. The interaction between RA mustard with RARalpha was confirmed by binding assay using RARalpha overexpressing cell extract. RA-mustard-modified DNA diminished the RARalpha dependent luciferase expression in the RARalpha-abundant cells. PMID- 21684745 TI - Eudistomidins H-K, new beta-carboline alkaloids from the Okinawan marine tunicate Eudistoma glaucus. AB - Four new beta-carboline alkaloids, eudistomidins H-K (1-4), were isolated from an Okinawan marine tunicate Eudistoma glaucus and the structures of 1-4 were elucidated on the basis of spectroscopic data. Eudistomidins H (1) and I (2) were new beta-carboline alkaloids possessing a unique fused-tetracyclic ring system consisting of a tetrahydro beta-carboline ring and a hexahydropyrimidine ring. Eudistomidin J (3) showed relatively potent cytotoxicity against murine leukemia cells P388 and L1210, and human epidermoid carcinoma cells KB in vitro. PMID- 21684746 TI - 7-Alkyl-N(2)-substituted-3-deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity. AB - Several 2-anilino- and 2-benzylamino-3-deaza-6-oxopurines [3-deazaguanines] and selected 8-methyl and 8-aza analogs have been synthesized. 7-Substituted N(2)-(3 ethyl-4-methylphenyl)-3-deazaguanines were potent and selective inhibitors of Gram+ bacterial DNA polymerase (pol) IIIC, and 7-substituted N(2)-(3,4 dichlorobenzyl)-3-deazaguanines were potent inhibitors of both pol IIIC and pol IIIE from Gram+ bacteria, but weakly inhibited pol IIIE from Gram- bacteria. Potent enzyme inhibitors in both classes inhibited the growth of Gram+ bacteria (MICs 2.5-10MUg/ml), and were inactive against the Gram- organism Escherichia coli. Several derivatives had moderate protective activity in Staphylococcus aureus-infected mice. PMID- 21684747 TI - Distinct distal myopathy phenotype caused by VCP gene mutation in a Finnish family. AB - Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) is caused by mutations in the valosin-containing protein (VCP) gene. We report a new distal phenotype caused by VCP gene mutation in a Finnish family with nine affected members in three generations. Patients had onset of distal leg muscle weakness and atrophy in the anterior compartment muscles after age 35, which caused a foot drop at age 50. None of the siblings had scapular winging, proximal myopathy, cardiomyopathy or respiratory problems during long-term follow-up. Three distal myopathy patients developed rapidly progressive dementia, became bedridden and died of cachexia and pneumonia and VCP gene mutation P137L (c.410C>T) was then identified in the family. Late onset autosomal dominant distal myopathy with rimmed vacuolar muscle pathology was not sufficient for exact diagnosis in this family until late-occurring dementia provided the clue for molecular diagnosis. VCP needs to be considered in the differential diagnostic work-up in patients with distal myopathy phenotype. PMID- 21684748 TI - Settling down time following initial sitting and its relationship with comfort and discomfort. AB - This study examined the subjective rating of wheelchair comfort and discomfort (numerical rating scale questionnaire) and the duration of objective in-chair movement reduction "settling down time" following initial contact with the seating surface. Healthy young subjects (n = 22) sat for 5 min on contoured foam or wood cushion surfaces fitted to otherwise identical wheelchairs. Force sensing resistors attached to each quadrant of the sitting interface measured the relative movements of the subjects over time. A significant correlation was found between settling down time (SDT) and reported leg/feet discomfort (p = 0.003; correlation co-efficient = 0.44); and a significant negative correlation was found between SDT and overall comfort (p = 0.015; correlation co-efficient = 0.36). When comparing cushion surfaces: SDT was significantly longer (p < 0.0001) for subjects sitting on wood (5.8 s) compared to contoured foam (3.9 s); Leg/feet discomfort was significant higher (p = 0.007) for subjects sitting on wood (1.1 out of 10) compared to contoured foam (0.3 out of 10); Overall discomfort was significant higher (p = 0.009) for subjects sitting on wood (1.3 out of 10) compared to contoured foam (0.5 out of 10); Comfort was significantly lower (p = 0.001) for subjects sitting on wood (6.5 out of 10) compared to contoured foam (8.3 out of 10); Support was significantly lower (p = 0.001) for subjects sitting on wood (6.4 out of 10) compared to contoured foam (8 out of 10). The results of this study suggest that the shape and firmness of the surface at the buttock wheelchair interface can affect a subject's SDT following initial contact with the seat as well as their perception of comfort and discomfort. In addition, there appears to be a relationship between longer SDT's and increased discomfort ratings, and shorter SDT's and increased comfort ratings. Therefore, testing for SDT's may be useful in the indirect objective assessment of wheelchair cushions and possibly other types of seating surfaces with design differences that aim to improve comfort and minimize discomfort. PMID- 21684749 TI - Understanding the role of gut microbiome-host metabolic signal disruption in health and disease. AB - There is growing awareness of the importance of the gut microbiome in health and disease, and recognition that the microbe to host metabolic signalling is crucial to understanding the mechanistic basis of their interaction. This opens new avenues of research for advancing knowledge on the aetiopathologic consequences of dysbiosis with potential for identifying novel microbially-related drug targets. Advances in both sequencing technologies and metabolic profiling platforms, coupled with mathematical integration approaches, herald a new era in characterizing the role of the microbiome in metabolic signalling within the host and have far reaching implications in promoting health in both the developed and developing world. PMID- 21684750 TI - Gait analysis comparison of cruciate retaining and substituting TKA following PCL sacrifice. AB - The role of the posterior cruciate ligament (PCL) remains controversial in total knee arthroplasty (TKA), with some surgeons who believe in PCL sacrifice and substitution and others who believe in PCL preservation for stability. Manufacturers have developed both cruciate-substituting/posterior stabilized (PS) implants typically used when the ligament is sacrificed and cruciate retaining (CR) implants designed for ligament preservation. However, studies demonstrate excellent clinical results with CR implants despite PCL sacrifice. This study sought to determine functional stability differences between PS and CR TKAs following PCL sacrifice. Eighteen (9 matched pairs) subjects with either a PS or CR TKA and sacrificed PCL and a normal contralateral knee were subjected to physical exam and gait analysis (walking, stair ascent and descent) using a staircase model, passive reflective arrays and an optoelectric system. No differences were detected between the two groups among any of the measured parameters (knee flexion angle, knee flexion moment, knee power absorption, pelvic tilt). PCL sacrifice in a well-balanced cruciate retaining TKA did not result in instability during stair descent based on gait parameters. The decision to use a posterior stabilized design when faced with an incompetent PCL intraoperatively should be based on factors other than anticipated instability. PMID- 21684751 TI - Design, synthesis and antileishmanial in vitro activity of new series of chalcones-like compounds: a molecular hybridization approach. AB - The chalcone-like series 1a-1g was efficiently synthesized from Morita-Baylis Hillman reaction (52-74% yields). Compounds 1a-1g were designed by molecular hybridization based on the anti-inflammatory drug methyl salicylate (3) and the antileishmanial moiety of the Morita-Baylis-Hillman adducts 2a-2g. The 1a-1g compounds were much more actives than precursor series 2a-2g, for example, IC(50)=7.65 MUM on Leishmania amazonensis and 10.14 MUM on Leishmania chagasi (compound 1c) when compared to IC(50)=50.08 MUM on L. amazonensis and 82.29 MUM on L. chagasi (compound 2c). The IC(50) values of compound 3 (228.49 MUM on L. amazonensis and 261.45 MUM on L. chagasi) and acryloyl salicylate 4 (108.50 MUM on L. amazonensis and 118.83 MUM on L. chagasi) were determined here, by the first time, on Leishmania. PMID- 21684753 TI - Synthesis of novel inhibitors of beta-glucuronidase based on benzothiazole skeleton and study of their binding affinity by molecular docking. AB - Benzothiazole derivatives 1-26 have been synthesized and their in vitro beta glucuronidase potential has been evaluated. Compounds 4 (IC(50)=8.9 +/- 0.25 MUM), 5 (IC(50)=36.1 +/- 1.80 MUM), 8 (IC(50)=8.9 +/- 0.38 MUM), 13 (IC(50)=19.4 +/- 1.00 MUM), 16 (IC(50)=4.23 +/- 0.054 MUM), and 18 (IC(50)=2.26 +/- 0.06 MUM) showed beta-glucuronidase activity potent than the standard (d-saccharic acid 1,4 lactone, IC(50)=48.4 +/- 1.25 MUM). Compound 9 (IC(50)=94.0 +/- 4.16 MUM) is found to be the least active among the series. All active analogs were also evaluated for cytotoxicity and none of the compounds showed any cytotoxic effect. Furthermore, molecular docking studies were performed using the gold 3.0 program to investigate the binding mode of benzothiazole derivatives. This study identifies a novel class of beta-glucuronidase inhibitors. PMID- 21684752 TI - Probes for narcotic receptor mediated phenomena. 43. Synthesis of the ortho-a and para-a, and improved synthesis and optical resolution of the ortho-b and para-b oxide-bridged phenylmorphans: compounds with moderate to low opioid-receptor affinity. AB - N-Phenethyl-substituted ortho-a and para-a oxide-bridged phenylmorphans have been obtained through an improved synthesis and their binding affinity examined at the various opioid receptors. Although the N-phenethyl substituent showed much greater affinity for MU- and kappa-opioid receptors than their N-methyl relatives (e.g., K(i)=167 nM and 171 nM at MU- and kappa-receptors vs >2800 and 7500 nM for the N-methyl ortho-a oxide-bridged phenylmorphan), the a-isomers were not examined further because of their relatively low affinity. The N-phenethyl substituted ortho-b and para-b oxide-bridged phenylmorphans were also synthesized and their enantiomers were obtained using supercritical fluid chromatography. Of the four enantiomers, only the (+)-ortho-b isomer had moderate affinity for MU- and kappa-receptors (K(i)=49 and 42 nM, respectively, and it was found to also have moderate MU- and kappa-opioid antagonist activity in the [(35)S]GTP-gamma-S assay (K(e)=31 and 26 nM). PMID- 21684754 TI - Ecotypic variation in chloroplast small heat-shock proteins and related thermotolerance in Chenopodium album. AB - Production of chloroplast-localized small heat-shock proteins (Cp-sHSP) is correlated with increased thermotolerance in plants. Ecotypic variation in function and expression of Cp-sHSPs was analyzed in two Chenopodium album ecotypes from cool vs. warm-temperate USA habitats [New York (NY) and Mississippi (MS) respectively]. P(et) was more heat tolerant in the MS than the NY ecotype, and MS ecotype derived proportionally greater protection of P(et) by Cp-sHSP during high temperatures. Four genes encoding Cp-sHSPs were isolated and characterized: CaHSP25.99n (NY-1) and CaHSP26.23n (NY-2) from NY ecotype, and CaHSP26.04m (MS-1) and CaHSP26.26m (MS-2) from MS ecotype. The genes were nearly identical in predicted amino-acid sequence and hydrophobicity. Gene expression analysis indicated that MS-1 and MS-2 transcripts were constitutively expressed at low levels at 25 degrees C, while no NY-1 and NY-2 transcripts were detected at this temperature. Maximum accumulation of NY-1 and NY-2 transcripts occurred at 33 degrees C and 40 degrees C for MS-1 and MS-2. Immunoblot analysis revealed that (1) protein expression was highest at 37 degrees C in both ecotypes, but was greater in MS than NY ecotype at 40 degrees C; and (2) import of Cp-sHSP into chloroplasts was more heat-labile in NY ecotype. The higher expression of one isoform in MS ecotype may contribute to its enhanced thermotolerance. Absence of correlation between protein and transcript levels, suggests the post-transcriptional regulation is occurring. Promoter analysis of these genes revealed significant variations in heat-shock elements (HSE), core motifs required for heat-shock-factor binding. We propose a correlation between unique promoter architecture, Cp-sHSP expression and thermotolerance in both ecotypes. PMID- 21684755 TI - Functional regeneration of ischemic myocardium by transplanted cells overexpressing stromal cell-derived factor-1 (SDF-1): intramyocardial injection versus scaffold-based application. AB - OBJECTIVE: Stromal cell-derived factor-1 (SDF-1) is a potent chemotaxin. Increased SDF-1 levels can be found in ischemic myocardium and might protect against ischemia-reperfusion injury. We hypothesized that transplantation of stem cells overexpressing SDF-1 might improve cardiac function after myocardial infarction (MI). We compared intramyocardial injection with a scaffold-based application of SDF-1-transfected cells. METHODS: Skeletal myoblasts (SkMs) were isolated and expanded from newborn Lewis rats. Cells were transfected with pcDNA3 huSDF-1 and seeded on polyurethane (PU) scaffolds or diluted in medium for cell injection. Two weeks after myocardial infarction, seeded scaffolds were implanted epicardially into rats (group: PU-SDF-1-SkM) or the injection solution was applied intramyocardially (Inj-SDF-1-SkM). Additional groups were treated with non-transfected myoblasts either by injection (Inj-SkM) or by scaffold-based application (PU-SkM) or received a sham operation (Sham). Before this intervention and 6 weeks later, hemodynamic parameters were measured. Infarction size and neovascularization were assessed by histology at study end. RESULTS: In sham animals, we detected a clear decrease in systolic function from intervention to study end. In group Inj-SkM and PU-SkM, all hemodynamic parameters that were assessed remained unchanged during observation time. Systolic function as measured by dP/dt(max) and SB-Emax was significantly improved in groups Inj-SDF-1 SkM and PU-SDF-1-SkM at study end without a difference between the two SDF-1 groups. Diastolic function measured by post-interventional dP/dt(min) was also increased in group Inj-SDF-1-SkM but not in PU-SDF-1-SkM. Histological analysis revealed a reduced infarction size in all treatment groups at study end but enhanced neovascularization was not observable. CONCLUSIONS: Transplantation of myoblasts overexpressing SDF-1 improves cardiac function after MI. The restoration of hemodynamic parameters is accompanied by a reduction in infarction size. This reverse remodeling capacity is independent of a scaffold-based application of the SDF-1-transfected cells. PMID- 21684756 TI - Left atrial appendage occlusion by invagination and double suture technique. AB - Left atrial appendage (LAA) plays a crucial role as a source of atrial thrombus in patients with atrial fibrillation (AF). Thus, the need to close LAA becomes evident in patients with AF who undergo concomitant mitral valve surgery. Unfortunately, it has been reported a high rate of unsuccessful LAA occlusion, regardless of the technique employed.We propose a safe and simple method for LAA occlusion consisting in invagination of the appendage into the left atrium, followed by two sutures (purse string suture around the base of the LAA and a reinforce running suture). PMID- 21684757 TI - Complete intra-atrial implantation of a mitral-valve prosthesis in a severely calcified mitral annulus. PMID- 21684758 TI - Prognostic significance of IL-8-STAT-3 pathway in astrocytomas: correlation with IL-6, VEGF and microvessel morphometry. AB - Malignant astrocytomas are highly vascular neoplasms characterized by a potent angiogenic and immunosuppressive phenotype. Th2-cytokines (IL-6/IL-8) are implicated as major regulators of glioma cell growth and invasiveness. STAT-3, a downstream transducer of cytokine signaling is positively associated with tumor angiogenesis. The present study aimed to investigate the expression of IL-8 and p STAT-3 in 97 diffusely infiltrating astrocytomas of various grades, in relation to IL-6, VEGF, clinicopathological features, microvascular characteristics and patients' survival. IL-8 expression was localized in neoplastic cells, being associated with p-STAT-3 (p = 0.0013), IL-6 (p = 0.0004) and VEGF (p < 0.0001) around areas of necrosis as well as in perivascular inflammatory and endothelial cells. All the molecules under study correlated with tumor grade and degree of necrosis (p < 0.05, respectively). p-STAT-3, IL-8 and VEGF expression was positively associated with microvessel density (p = 0.0491, p < 0.0001 and p = 0.0118, respectively). Univariate analysis indicated that overexpression of IL-8 and IL-6 adversely affected survival in the entire cohort whereas increased p STAT-3 expression was predictive of improved survival in high grade (III/IV) astrocytomas (p = 0.0032). In multivariate analysis only IL-8 expression (p = 0.043) retained its significance. The prognostic significance of IL-8 expression and its correlation with p-STAT-3 and VEGF implicates this novel signaling pathway in astroglial tumors progression providing new targets for effective immunotherapy. PMID- 21684759 TI - Adjusted saddle position counteracts the modified muscle activation patterns during uphill cycling. AB - The main aim of this project was to study muscle activity patterns during steep uphill cycling (UC) (i.e., with a gradient of 20%) with (1) normal saddle geometry and (2) with adjusted saddle position ASP (i.e., moving the saddle forward and changing the tilt of the saddle by 20%). Based on our preliminary case study, we hypothesized that: (1) during 20% UC muscle activity patterns would be different from those of level cycling (LC) and (2) during 20% UC with ASP muscle activity patterns would resemble those of LC. Twelve trained male cyclists were tested on an electromagnetically braked cycle ergometer under three conditions with the same work rate (80% of maximal power output) and cadence (90 rpm): level (LC), 20% UC and 20% UC with ASP. Electromyographic signals were acquired from m. tibialis anterior (TA), m. soleus (SO), m. gastrocnemius (GC), m. vastus lateralis (VL), m. vastus medialis (VM), m. rectus femoris (RF), m. biceps femoris (BF) and m. gluteus maximus (GM). Compared to LC, 20% UC significantly modified both the timing and the intensity of activity of the selected muscles, while muscles that cross the hip joint were the most affected (RF later onset, earlier offset, shorter range of activity and decrease in peak amplitude of 34%; BF longer range of activity; GM increase in peak amplitude of 44%). These changes in EMG patterns during 20% UC were successfully counteracted by the use of ASP and it was interesting to observe that the use of ASP during 20% UC was perceived positively by all cyclists regarding both comfort and performance. These results could have a practical relevance in terms of improving performance during UC, together with reducing discomfort. PMID- 21684760 TI - Foot center of pressure manipulation and gait therapy influence lower limb muscle activation in patients with osteoarthritis of the knee. AB - BACKGROUND: Foot center of pressure (COP) manipulation has been associated with improved gait patterns. The purpose of this study was to determine lower limb muscle activation changes in knee osteoarthritis patients, both immediately after COP manipulation and when COP manipulation was combined with continuous gait therapy (AposTherapy). METHODS: Fourteen females with medial compartment knee osteoarthritis underwent EMG analyzes of key muscles of the leg. In the initial stage, trials were carried out at four COP positions. Following this, gait therapy was initiated for 3 months. The barefoot EMG was compared before and after therapy. RESULTS: The average EMG varied significantly with COP in at least one phase of stance in all examined muscles of the less symptomatic leg and in three muscles of the more symptomatic leg. After training, a significant increase in average EMG was observed in most muscles. Most muscles of the less symptomatic leg showed significantly increased peak EMG. Activity duration was shorter for all muscles of the less symptomatic leg (significant in the lateral gastrocnemius) and three muscles of the more symptomatic leg (significant in the biceps femoris). These results were associated with reduced pain, increased function and improved spatiotemporal parameters. CONCLUSIONS: COP manipulation influences the muscle activation patterns of the leg in patients with knee osteoarthritis. When combined with a therapy program, muscle activity increases and activity duration decreases. PMID- 21684761 TI - A comparison of cardiac output by thoracic impedance and direct fick in children with congenital heart disease undergoing diagnostic cardiac catheterization. AB - OBJECTIVE(S): To evaluate the measurement of cardiac output (CO) using continuous electrical bioimpedance cardiography (Physioflow; Neumedx, Philadelphia, PA) (CO(PF)) with a simultaneous direct Fick measurement (CO(FICK)) in children with congenital heart disease. DESIGN: A prospective cohort study comparing 2 methods of measurement of CO. SETTING: A quaternary university-affiliated pediatric hospital. PARTICIPANTS: Children undergoing cardiac catheterization for clinical care. INTERVENTIONS: The Physioflow measured continuous real time CO in 15-second epochs and simultaneous measurement of cardiac output by direct Fick (with mass spectrometry to assess VO(2)) were acquired. MEASUREMENTS AND MAIN RESULTS: Sixty five patients were recruited, and data from 56 (25 males) were adequate for analysis. The median age at study was 3.5 years (range, 0.4-16.6 years), and the median body surface area was 0.62 m(2) (range, 0.31-1.71). There were 25 of 56 (45%) with univentricular physiology. A total of 19,228 Physioflow data points were available for the analysis of which 14,569 (76%) were valid; 96% of the invalid measurements were identified as artifacts by the device. The average cardiac index of valid measurements was 3.09 +/- 0.72 L/min/m(2). Compared with the Fick CO, the mean bias was -0.09 L/min, but the 95% limits of agreement were 3.20 to +3.01 L/min/m(2). Consequently, only 20 of 56 (36%) of measurements were within 20%, and 31 of 56 (55%) of measurements were within 30% of each other. CONCLUSIONS: Compared with measurements made by direct Fick, CO measured using the Physioflow device was unreliable in anesthetized children with congenital heart disease. PMID- 21684762 TI - TEE for estimating pleural effusion volumes. PMID- 21684763 TI - Con: methylene blue should not be used routinely for vasoplegia perioperatively. PMID- 21684764 TI - Pro: methylene blue as a rescue therapy for vasoplegia after cardiac surgery. PMID- 21684765 TI - An unusual cause for an irregularly irregular pulse. PMID- 21684766 TI - The mysterious case of an absent true lumen in a patient with a type-A aortic dissection. PMID- 21684767 TI - Infectious disease or Hashimoto's encephalopathy flares: a case report. AB - Hashimoto's encephalopathy is an under-recognized and rare disease that presents a diagnostic conundrum since many features are suggestive of infectious etiologies and yet treatment is immunosuppressive medications. We describe a case of a male with a history of recurrent seizures who presented with a subacute onset of confusion, persistent leukocytosis and fever while on immunosuppressant therapy, whose response to high dose steroids was incomplete and who achieved a complete remission of all symptoms when plasmapheresis was initiated. A negative cerebrospinal fluid (CSF) and serum microbiological testing in a patient with an abnormal EEG, increased CSF protein, and elevated thyroid antibodies should prompt consideration of Hashimoto's encephalopathy. If after treating with high dose steroids, there is a sub-optimal clinical response, plasmapheresis should be considered. PMID- 21684768 TI - Endovascular repair of complicated acute type-B aortic dissection with stentgraft: early and mid-term results. AB - OBJECTIVES: To analyse the experience of a single centre and evaluate the early and mid-term results of endovascular repair of complicated acute type B aortic dissection with stentgrafts. METHOD: From July 2002 to January 2009, 45 patients (12 women, 33 men) with complicated acute type B aortic dissection (mean age, 42.6 years; range, 31-47 years) were treated with Thoracic Endovascular Aortic Repair (TEVAR). Indications for treatment included rupture in 6(13%), hemathorax with impending rupture in 27(60%), malperfusion syndrome in 11 (22%), and transient paraplegia in one patient (2.2%). Five kinds of commercially available thoracic stentgrafts were used. Follow up was 100% during a period of 13 months (range, 1-36 months). RESULTS: Technical success (coverage of the primary tear site) was achieved in all 45 patients(100%) including deliberate partial or total coverage of the LSA in 7 patients (15.6%). The 30-day and in-hospital mortality was 4.4% including one late rupture case. Overall survival was 95.6% at 1 and 3 years' follow-up. None of the patients with malperfusion required adjunct distal stents All hemothoces resolved within 3 months including 5 patient required thoracentesis and one had tube thoracostomy. And 7 patients required temporary dialysis In-hospital complications occurred in 26.7% of patients and re intervention was required in one patient and no patient had postoperative paraplegia Postoperative CT angiography showed 25 patients (58.1%) with complete thrombosis of the false lumen and re-expansion of the true lumen. CONCLUSIONS: Endovascular repair of complicated acute type B aortic dissection with stentgraft is proven to be a technically feasible and effective in this relatively difficult patient cohort, The short and mid-term efficacy are persuasive, however, the long term efficacy needs to be evaluated further. PMID- 21684769 TI - Long buccal nerve block: a previously unreported complication. AB - Although local anesthetic injections are commonly used in dental practice, the complex neurovascular anatomy of the face can present the practitioner with unexpected complications. Several reports document adverse events related to inferior dental blocks (IDBs), whereas long buccal nerve blocks are usually performed without incident. We describe a previously unreported complication of a long buccal nerve block involving blanching, pain, and paresthesia specifically within the infraorbital arterial territory of the face. We had previously reported an identical event resulting from an IDB. We discuss the facial vascular relationships that might explain this complication and how to manage it. PMID- 21684770 TI - A case-control study of burning mouth syndrome and sleep dysfunction. AB - OBJECTIVE: The objective of this study was to evaluate whether sleep dysfunction is a risk factor for burning mouth syndrome (BMS). STUDY DESIGN: An age- and sex matched case-control study of patients with BMS and controls with various oral conditions was conducted. A numerical rating scale for oral discomfort and the sleep scale from the medical outcomes study were used for measurements, and statistical analyses included use of logistic regression models. RESULTS: The odds ratios for lowest versus highest quartiles were sleep disturbance (OR = 9.7, P = .0095), sleep problems index (SLP)6 (OR = 7.5, P = .032), and SLP9 (OR = 27, P = .0058), which remained significant after controlling for age and number of sedating medications. CONCLUSIONS: Findings from this cross-sectional study, although unable to establish a causal relationship, demonstrate that patients with BMS report a greater degree of sleep problems as compared with controls, and suggest that sleep dysfunction may be a risk factor for BMS and a possible target for treatment. PMID- 21684771 TI - Orofacial granulomatosis associated with hypersensitivity to dental amalgam. AB - Orofacial granulomatosis is a clinicopathologic entity characterized by chronic swelling of the lip and possible soft tissues in the orofacial region owing to granulomatous inflammation of unknown cause. We present 3 cases of orofacial granulomatosis associated with allergic contact dermatitis to dental materials. Previous treatment with corticosteroids did not have any therapeutic effect. Patch testing revealed a positive reaction to several allergens, including dental amalgam and mercury in 2 cases. A lymphocyte transformation test modified for metals was used to evaluate lymphocyte reactivity. After the removal of the suspected allergens, all patients experienced recovery within 1 month, with the exception of the lip swelling, which gradually subsided over several months. PMID- 21684772 TI - Microcystic adnexal (sclerosing sweat duct) carcinoma of intraoral minor salivary gland origin: an extracutaneous adnexal neoplasm? PMID- 21684773 TI - Shortening the xerostomia inventory. AB - OBJECTIVES: The aim of this study was to determine the validity and properties of the Summated Xerostomia Inventory-Dutch Version in samples from Australia, The Netherlands, Japan, and New Zealand. STUDY DESIGN: Six cross-sectional samples of older people from The Netherlands (n = 50), Australia (n = 637; n = 245), Japan (n = 401), and New Zealand (n = 167; n = 86) were enrolled. Data were analyzed by using the Summated Xerostomia Inventory-Dutch Version. RESULTS: All datasets revealed a single extracted factor which explained about one-half of the variance, with Cronbach alpha values >=0.70. When mean scale scores were plotted against a "gold-standard" xerostomia question, statistically significant gradients were observed, with the highest score seen in those who always had dry mouth, and the lowest in those who never had it. CONCLUSIONS: The Summated Xerostomia Inventory-Dutch Version is valid for measuring xerostomia symptoms in clinical and epidemiologic research. PMID- 21684774 TI - Central odontogenic fibroma: new findings and report of a multicentric collaborative study. AB - OBJECTIVE: The aim of this study was to describe the clinicopathologic and immunohistochemical characteristics of 14 cases of central odontogenic fibroma (COF), and the ultrastructural features of 2 of them. STUDY DESIGN: Collaborative retrospective study based on the records of 4 oral pathology diagnostic services in Latin America based on the current World Health Organization classification. RESULTS: There were 7 male and 7 female patients (mean age 31.8 years). Eight tumors occurred in the maxilla and 6 in the mandible. Thirteen cases were epithelium-rich and 1 epithelium-poor COF. Three were classified as hybrid COF with giant cell lesion. Mean size of the hybrid lesions were larger than pure COF (3.8 vs. 2.4 cm). Odontogenic epithelial islands were immunoreactive for cytokeratin (CK) AE1/AE3, CK5, CK14, CK19, and 34BE12 and negative for CK1 and CK18. Langerhans cells positive for S-100 and CD1a were found within the epithelial islands in 6/6 tested cases. CD68 was expressed in the giant cells of the hybrid lesions and in a few mononuclear cells of 2 cases of COF. Ki-67 index was <1% in all cases. In 6 tumors (42.8%), there were small globular eosinophilic droplets within the epithelial islands, which were positive for collagen type IV, and 9/13 cases (69.2%) were focally positive for smooth muscle actin. In addition to fibroblasts, myofibroblastic differentiation was found in the 2 cases studied ultrastructurally. CONCLUSIONS: Immunohistochemistry was useful to confirm the presence of epithelium and to exclude other central fibrous tumors. COF also contains a variable number of mast cells, Langerhans cells, and myofibroblasts, and further studies are needed to better understand the participation of these cells in COF histogenesis. PMID- 21684776 TI - Full-arch fixed prosthesis supported by four implants in patients with recessive dystrophic epidermolysis bullosa. AB - OBJECTIVE: The aim of this study was to describe the rehabilitation of patients diagnosed with recessive dystrophic epidermolysis bullosa (RDEB), with edentulous maxillas and/or mandibles, by using fixed full-arch short-expand prostheses supported by 4 anterior implants. STUDY DESIGN: A retrospective study was carried out to study edentulous patients with RDEB rehabilitated with fixed full-arch prostheses supported by 4 anterior implants. RESULTS: In total, 32 anterior implants were placed and used to support 8 full-arch fixed prostheses; 20 implants were placed in the maxilla by using osteotomes and 12 in the mandible by using conventional drilling. Implant success rate was 100% after an average follow-up of 22.9 (range 12-48) months after prosthetic loading. Patient satisfaction with the implant therapy was very high (mean 9.0) for all the factors assessed. CONCLUSIONS: Fixed full-arch short-expand prostheses supported by 4 anterior implants can be successfully used to rehabilitate patients with recessive dystrophic epidermolysis bullosa, considerably improving these patients' quality of life. PMID- 21684777 TI - Scanning electron microscope and x-ray diffraction analysis assisting the diagnosis of a sialolith in the parotid duct. PMID- 21684779 TI - Focal dermal hypoplasia: a case report and literature review. AB - Focal dermal hypoplasia (FDH), also known as Goltz-Gorlin syndrome, is an autosomal dominant disease affecting tissues derived from the ectoderm and mesoderm. Knowledge and early diagnosis of the craniofacial alterations commonly found in patients with FDH provide oral health care professionals with effective preventive and therapeutic tools. This article aims to review the craniofacial characteristics present in FDH and the main systemic manifestations that have implications for dental management, while presenting a new case of the syndrome with novel oral findings. PMID- 21684780 TI - DNA damage in salivary gland tissue in patients with chronic kidney disease, measured by the comet assay. AB - OBJECTIVE: The aim of this observational study was to investigate the relationship between DNA damage in minor accessory salivary glands, hyposalivation, and inflammation in patients with chronic kidney disease (CKD). STUDY DESIGN: DNA strand breaks and oxidative DNA lesions in salivary glands, inflammatory markers, and uremic state were measured in 79 patients with CKD and matched controls. RESULTS: CKD patients not yet on dialysis had significantly more, and dialysis patients significantly less, DNA strand breaks in salivary tissue compared with controls. All measured inflammatory markers were higher in patients with CKD compared with controls. Salivary secretion rates were significantly lower in dialysis patients compared with controls. A high level of salivary secretion rate at rest significantly predicted a high level of DNA strand breaks in patients with CKD. CONCLUSIONS: Dialysis patients had fewer DNA strand breaks in minor accessory salivary glands than controls, suggesting that peripheral tissue is differently affected by CKD than leukocytes. PMID- 21684782 TI - Segmental odontomaxillary dysplasia: report of a series of 5 cases with long-term follow-up. AB - We report a series of 5 cases of segmental odontomaxillary dysplasia (SOMD) with follow-up periods ranging from 8 to 21 years, bringing the total number of reported cases to 45. SOMD is a sporadic, mesoectodermal dysplasia that presents early in life, possibly as early as in utero and exhibits male gender predominance (1.7:1.0). Its features include enlargement of the soft tissue and/or bone of 1 hemimaxilla that may produce mild facial asymmetry. Subsequent growth of the affected area is proportional to that of the unaffected hemimaxilla. Sclerotic radiographic bone changes and dental developmental abnormalities are also present. The dense bone, which often exhibits a radiographic vertical orientation of the trabecular bone pattern, is typically associated with delayed eruption of the teeth. Congenitally missing premolar teeth (either or both) is a common feature of this condition that is of significant diagnostic value. Although ipsilateral cutaneous findings have been reported in 23%, our cases exhibited none. Computed tomographic imaging demonstrated extensive involvement of the maxillary bone, including the lateral wall and floor of the maxillary sinus and the hard palate. The affected bone presents no impediment to either orthodontic tooth movement or to the successful osteointegration of dental implants. The cause of SOMD is unknown; the clues to the cause of this unusual phenotypic expression are buried in the intricacies of developmental biology within the first branchial arch. PMID- 21684786 TI - Is there an association between preterm birth or low birthweight and chronic widespread pain? Results from the 1958 Birth Cohort Study. AB - OBJECTIVE: The aim was to examine the relationship between gestational age and birthweight and adult chronic widespread pain (CWP). DESIGN AND PARTICIPANTS: A prospective cohort study of 18,558 participants recorded birthweight and gestation at birth. EXPOSURE: Participants were categorised by gestation (fullterm >=37 weeks; preterm <37 week) and birthweight (full birthweight (FBW) >=2.5 kg; low birthweight (LBW) 1.5-2.5 kg; and very low birthweight (VLBW) <1.5 kg). OUTCOME: The presence or absence of CWP was measured by self-completed questionnaire in 8572 participants at age 45 yrs. Risk ratios were calculated using Poisson regression. Adjustment was made for potential confounding factors. RESULTS: Premature birth was associated with a 26% increase in the risk of CWP compared to fullterm birth, although this was not statistically significant (risk ratio 1.26, 95% confidence interval 0.95-1.67). This increased risk was robust to adjustment for sex, social class at birth and age 42 yrs, or birthweight, but was completely attenuated when adjusted for childhood behavioural problems and adult psychiatric disorder. LBW was not associated with an increased risk of CWP (RR 1.01, 95%CI 0.78-1.32). VLBW was associated with a non-significant increased risk (RR 1.48, 0.42-5.22) although there was insufficient study power to examine this relationship in the context of other factors. CONCLUSIONS: Premature birth and VLBW are associated with increased risk of adult CWP although these effects are modest, and not statistically significant. Although not conclusive in itself, this study lends support to the theory that adult chronic pain may have its origins - at least in part - in very early life. PMID- 21684787 TI - Experimental neuropathy increases limbic forebrain CRF. AB - Neuropathic pain is often accompanied by stress, anxiety and depression. Although there is evidence for involvement of corticotropin-releasing factor (CRF), the detailed neuronal basis of these pain-related mood alterations is unknown. This study shows that peripheral mononeuropathy was accompanied by changes in limbic forebrain CRF, but did not lead to changes in the functioning of the hypothalamo pituitary-adrenal axis and the midbrain Edinger-Westphal centrally projecting (EWcp) neuron population, which play main roles in the organism's response to acute pain. Twenty-four days after chronic constriction injury (CCI) of the rat sciatic nerve, the oval bed nucleus of the stria terminalis (BSTov) contained substantially more Crf mRNA as did the central amygdala (CeA), which, in addition, possessed more CRF. In contrast, Crf mRNA and CRF contents of the hypothalamic paraventricular nucleus (PVN) were unaffected by CCI. Similarly, EWcp neurons, producing the CRF family member urocortin 1 (Ucn1) and constitutively activated by various stressors including acute pain, did not show an effect of CCI on Ucn1 mRNA or Ucn1. Also, the immediate early gene products cFos and deltaFosB in the EWcp were unaffected by CCI. These results indicate that neuropathic pain does not act via the HPA-axis or the EWcp, but includes a main role of Crf in the limbic system, which is in clear contrast to stressors like acute and chronic pain, which primarily act on the PVN and the EWcp. PMID- 21684788 TI - Large contiguous gene deletions in Sjogren-Larsson syndrome. AB - Sjogren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis. PMID- 21684789 TI - Fulminant type 1 diabetes mellitus-like presentation in a Hispanic woman in the United States. AB - AIM: To report the first case of fulminant-like type 1 diabetes mellitus in a Hispanic woman from the United States. METHOD: The clinical presentation and laboratory data is presented of a Hispanic woman that was diagnosed with fulminant type 1 diabetes mellitus with a review of the literature. RESULTS: An 18-year-old female presented with 1 week of polydyspea and polyuria. The patient was seen by her primary care doctor and found to have an elevated blood glucose. On presentation to the hospital, she was found to be in diabetic ketoacidosis. The laboratory analysis showed a C-peptide of 0.6 ng/mL and a glycohaemoglobin A(1c) of 6%. The patient had antibodies positive for glutamic acid decarboxylase. The patient was diagnosed with fulminant type 1 diabetes mellitus and was discharged in stable condition on basal/bolus subcutaneous insulin. CONCLUSION: Fulminant type 1 diabetes mellitus is a recently described presentation of diabetes mellitus that has been predominately reported in Japan and other Asian countries. The classical presentation includes rapid onset on ketosis within 1 week of symptoms of hyperglycaemia, with a near-normal glycohaemoglobin and absence of C-peptide. With the majority of case being reported from Asia, it has been hypothesized that there is a genetic determent that predisposes Asian individuals to develop fulminant type 1 diabetes mellitus. The addition of the case to the medical literature expands the focus of fulminant type 1 diabetes mellitus beyond the Asian population and supports the need that further research. PMID- 21684790 TI - [Pharmacological targeting of Mdm2: rationale and perspectives for radiosensitization]. AB - The central role of p53 after exposure to ionizing radiation has been widely demonstrated. Mdm2, the main cellular regulator of p53, is a promising target for radiosensitizing purposes. In this article, we review the most recent data on the pharmacological targeting of Mdm2, with focus on strategies of radiosensitization. Antitumor activity of Mdm2 inhibitors has been related with activation of p53-dependant apoptosis, action on DNA repair systems, and antiangiogenic activity. Preliminary data suggested a synergic interaction between Mdm2 inhibitors and ionizing radiations. However, no clinical data has been published yet on the pharmacological targeting of Mdm2. Given their new mechanisms of action, these new molecules should be subject to careful clinical assessment. Although promising, these strategies expose to unexpected toxicities. PMID- 21684791 TI - Graphene oxide based Pt-TiO2 photocatalyst: ultrasound assisted synthesis, characterization and catalytic efficiency. AB - An ultrasound-assisted method was used for synthesizing nanosized Pt-graphene oxide (GO)-TiO2 photocatalyst. The Pt-GO-TiO2 nanoparticles were characterized by diffused reflectance spectroscopy, X-ray diffraction, N2 BET adsorption desorption measurements, atomic force microscopy and transmission electron microscopy. The photocatalytic and sonophotocatalytic degradation of a commonly used anionic surfactant, dodecylbenzenesulfonate (DBS), in aqueous solution was carried out using Pt-GO-TiO2 nanoparticles in order to evaluate the photocatalytic efficiency. For comparison purpose, sonolytic degradation of DBS was carried out. The Pt-GO-TiO2 catalyst degraded DBS at a higher rate than P-25 (TiO2), prepared TiO2 or GO-TiO2 photocatalysts. The mineralization of DBS was enhanced by a factor of 3 using Pt-GO-TiO2 compared to the P-25 (TiO2). In the presence of GO, an enhanced rate of DBS oxidation was observed and, when doped with platinum, mineralization of DBS was further enhanced. The Pt-GO-TiO2 catalyst also showed a considerable amount of degradation of DBS under visible light irradiation. The initial solution pH had an effect on the rate of photocatalytic oxidation of DBS, whereas no such effect of initial pH was observed in the sonochemical or sonophotocatalytic oxidation of DBS. The intermediate products formed during the degradation of DBS were monitored using electrospray mass spectrometry. The ability of GO to serve as a solid support to anchor platinum particles on GO-TiO2 is useful in developing new photocatalysts. PMID- 21684792 TI - Dementia associated with Parkinson's disease: applying the Movement Disorder Society Task Force criteria. AB - BACKGROUND: Diagnostic criteria and procedures for dementia in Parkinson's disease (PDD) have been proposed by a Movement Disorders Society Task Force (MDS TF). The objective of this study was to explore the utility of the new MDS-TF criteria and procedures in clinical practice. METHODS: Two hundred ninety nine PD patients (36.5% with PDD as per MDFS-TF criteria; 33.1% according the DSM-IV) were included in the study. A variety of standardized motor, cognitive, psychiatric, and global severity measures were administered. A multivariate logistic regression model was built to determine the variables producing discrepancy between the MDS-TF and DSM-IV criteria for PDD and the clinical features that distinguished false negative cases. RESULTS: Agreement between MDS TF and DSM-IV criteria was substantial (87.3%; kappa = 0.72), but the DSM-IV criteria failed to identify 22% of patients fulfilling MDS-TF criteria. False negative cases were older and had more severe motor symptoms but less psychosis than those true non-demented PD. False positives had less severe motor symptoms than true PDD, although the difference did not reach statistical significance. CONCLUSIONS: Our findings suggest that the MDS-TF criteria are more sensitive than the DSM-IV for a diagnosis of PDD. Old age, absence of psychiatric symptoms, and severe motor impairment can hinder the diagnosis of PDD. PMID- 21684793 TI - The socio-spatial neighborhood estimation method: an approach to operationalizing the neighborhood concept. AB - The literature on neighborhoods and health highlights the difficulty of operationalizing "neighborhood" in a conceptually and empirically valid manner. Most studies, however, continue to define neighborhoods using less theoretically relevant boundaries, risking erroneous inferences from poor measurement. We review an innovative methodology to address this problem, called the socio spatial neighborhood estimation method (SNEM). To estimate neighborhood boundaries, researchers used a theoretically informed combination of qualitative GIS and on-the-ground observations in Texas City, Texas. Using data from a large sample, we assessed the SNEM-generated neighborhood units by comparing intra class correlation coefficients (ICCs) and multi-level model parameter estimates of SNEM-based measures against those for census block groups and regular grid cells. ICCs and criterion-related validity evidence using SF-36 outcome measures indicate that the SNEM approach to operationalization could improve inferences based on neighborhoods and health research. PMID- 21684794 TI - Root developmental adaptation to phosphate starvation: better safe than sorry. AB - Phosphorus is a crucial component of major organic molecules such as nucleic acids, ATP and membrane phospholipids. It is present in soils in the form of inorganic phosphate (Pi), which has low availability and poor mobility. To cope with Pi limitations, plants have evolved complex adaptive responses that include morphological and physiological modifications. This review describes how the model plant Arabidopsis thaliana adapts its root system architecture to phosphate deficiency through inhibition of primary root growth, increase in lateral root formation and growth and production of root hairs, which all promote topsoil foraging. A better understanding of plant adaptation to low phosphate will open the way to increased phosphorus use efficiency by crops. Such an improvement is needed in order to adjust how we manage limited phosphorus stocks and to reduce the disastrous environmental effects of phosphate fertilizers overuse. PMID- 21684795 TI - Protein degradation - an alternative respiratory substrate for stressed plants. AB - In cellular circumstances under which carbohydrates are scarce, plants can metabolize proteins and lipids as alternative respiratory substrates. Respiration of protein is less efficient than that of carbohydrate as assessed by the respiratory quotient; however, under certain adverse conditions, it represents an important alternative energy source for the cell. Significant effort has been invested in understanding the regulation of protein degradation in plants. This has included an investigation of how proteins are targeted to the proteosome, and the processes of senescence and autophagy. Here we review these events with particular reference to amino acid catabolism and its role in supporting the tricarboxylic acid cycle and direct electron supply to the ubiquinone pool of the mitochondrial electron transport chain in plants. PMID- 21684796 TI - An atlas-navigated optimal medial axis and deformable model algorithm (NOMAD) for the segmentation of the optic nerves and chiasm in MR and CT images. AB - In recent years, radiation therapy has become the preferred treatment for many types of head and neck tumors. To plan the procedure, vital structures, including the optic nerves and chiasm, must be identified using CT/MR imagery. In this work we present a novel method for automatically localizing the optic nerves and chiasm using a tubular structure localization algorithm in which a statistical model and image registration are used to incorporate a priori local intensity and shape information. The method results in mean Dice coefficients of 0.8 when compared to manual segmentations over ten test cases. This suggests that our method is more accurate than existing techniques developed for the segmentation of these structures. PMID- 21684797 TI - Free energy calculations of protein-ligand interactions. AB - In the calculation of free energies of binding for protein-ligand complexes, we distinguish endpoint methods, methods involving alchemical modifications and methods that physically displace the ligand from the protein. Most methodological advances seem to come from a clever combination of multiple existing methods to enhance the sampling or to utilize specific advantages of various approaches. The coupling parameters common in thermodynamic integration and in Hamiltonian replica exchange are for instance combined to yield replica exchange thermodynamic integration. As new methods mostly aim to improve efficiency or to attain more complete sampling, there are good prospects to understand and tackle the sampling problem better and to shift the focus towards the scoring problem in the context of more robust and accurate force fields. PMID- 21684798 TI - Natural product drug discovery: the successful optimization of ISP-1 and halichondrin B. AB - The concept that natural products provide excellent leads for drug discovery, ultimately producing viable drugs, is a widely accepted view. Natural products embody inherent structural complexity and biological activity which often leads to new targets, pathways, or modes of action. The challenge lies in identifying quality natural product scaffolds that can ultimately result in a drug. Two recently approved drugs originating from unlikely natural product leads, ISP-1 and halichondrin B, were examples of such high quality scaffolds. In initial testing, both compounds displayed excellent in vitro potency, but more importantly were amenable to chemical optimization. This combination of unique biological activity plus the generation of structural activity relationships (SAR) may be early indicators of a high quality natural product scaffold worthy of additional studies. PMID- 21684799 TI - Solution NMR study of integral membrane proteins. AB - Signals between a cell and its environment are often transmitted through membrane proteins; therefore, many membrane proteins, including G protein-coupled receptors (GPCRs) and ion channels, are important drug targets. Structural information about membrane proteins remains limited owing to challenges in protein expression, purification and the selection of membrane-mimicking systems that will retain protein structure and function. This review describes recent advances in solution NMR applied to the structural study of integral membrane proteins. The examples herein demonstrate that solution NMR spectroscopy will play a unique role not only in structural analysis, but also drug discovery of membrane proteins. PMID- 21684800 TI - Natural products as catalysts for innovation: a pharmaceutical industry perspective. AB - Natural products are evolutionarily designed and chemically distinct from most synthetic library molecules. In addition to their role as drugs, they are successfully used as molecular probes to identify disease relevant targets. Novel natural products are still routinely discovered from traditional sources through cultivation of microorganisms. Complementary approaches based on genome sequence information and subsequent annotation of biosynthetic pathways are emerging technologies. However, to be of practical use for drug discovery, these concepts must be advanced beyond their current state. PMID- 21684801 TI - Natural products from synthetic biology. AB - DNA sequencing has uncovered microbial secondary metabolic potential that never surfaced in fermentation based screens. Deep and cheap sequencing of a genus such as Streptomyces can rapidly expose hundreds of metabolic genes and operons. Meanwhile, synthetic biologists, in their quest to engineer advanced biofuels, are mastering metabolic engineering. Natural products, a reliable source of new therapeutic leads for many years, have fallen into disfavor with drug discoverers partly because these molecules are rarely available as pure compounds and sourcing is often problematic. The convergence of next generation sequencing and synthetic biology, along with less spectacular progress in analytic technologies such as mass spectroscopy, opens the door to the creation of large, reliable libraries of pure natural products for drug discovery. PMID- 21684802 TI - Chemical and structural lessons from recent successes in protein-protein interaction inhibition (2P2I). AB - Worldwide research efforts have driven recent pharmaceutical successes, and consequently, the emerging role of Protein-Protein Interactions (PPIs) as drug targets has finally been widely embraced by the scientific community. Inhibitors of these Protein-Protein Interactions (2P2Is or i-PPIs) are likely to represent the next generation of highly innovative drugs that will reach the market over the next decade. This review describes up-to-date knowledge on this particular chemical space, with a specific emphasis on a subset of this ensemble. We also address current structural knowledge regarding both protein-protein and protein inhibitor complexes, that is, the 2P2I database. Finally, ligand efficiency analyses permit us to relate potency to size and polarity and to discuss the need to co-develop nanoparticle drug delivery systems. PMID- 21684803 TI - High-content screening in infectious diseases. AB - The last decade has seen the development of automated microscopy and its adaptation for various areas of research, particularly infectious disease. Most of the high-content screening (HCS) platforms now integrate all of the following necessary steps: automated pipettes for assay miniaturization in 384-well plates, automated image acquisition and data storage and analysis. HCS was initially associated with RNA interference genetic screens for identifying host factors involved in host-pathogen interactions. More recently, both in academia and in industry, HCS has been adapted for drug discovery purposes. High-content analysis enables intracellular tracking of viral particles to profile the antiviral mechanisms of each compound. Adaptation to high-throughput screening in bacteriology and parasitology has already led to the discovery of new types of host-specific inhibitors that differ from those inhibitors that act directly on microbes. PMID- 21684804 TI - Natural product-like synthetic libraries. AB - There is a paucity of chemical matter suitably poised for effective drug development. Improving the quality and efficiency of research early on in the drug discovery process has been a long standing objective for the drug industry and improvements to the accessibility and quality of compound screening decks might have a significant and positive impact. In the absence of specific molecular information that can be modeled and used predicatively we are far from identifying which small molecules are most relevant to emerging biological targets such as protein-protein interactions. Natural products have been historically successful as an entry point for drug discovery and recently screening libraries are being synthesized to emulate natural product like features. PMID- 21684805 TI - Population attributable risk of tobacco and alcohol for upper aerodigestive tract cancer. AB - Tobacco and alcohol are major risk factors for upper aerodigestive tract (UADT) cancer and significant variation is observed in UADT cancer rates across Europe. We have estimated the proportion of UADT cancer burden explained by tobacco and alcohol and how this varies with the incidence rates across Europe, cancer sub site, gender and age. This should help estimate the minimum residual burden of other risk factors to UADT cancer, including human papillomavirus. We analysed 1981 UADT cancer cases and 1993 controls from the ARCAGE multicentre study. We estimated the population attributable risk (PAR) of tobacco alone, alcohol alone and their joint effect. Tobacco and alcohol together explained 73% of UADT cancer burden of which nearly 29% was explained by smoking alone, less than 1% due to alcohol on its own and 44% by the joint effect of tobacco and alcohol. Tobacco and alcohol together explained a larger proportion of hypopharyngeal/laryngeal cancer (PAR=85%) than oropharyngeal (PAR=74%), esophageal (PAR=67%) and oral cancer (PAR=61%). Tobacco and alcohol together explain only about half of the total UADT cancer burden among women. Geographically, tobacco and alcohol explained a larger proportion of UADT cancer in central (PAR=84%) than southern (PAR=72%) and western Europe (PAR=67%). While the majority of the UADT cancers in Europe are due to tobacco or the joint effect of tobacco and alcohol, our results support a significant role for other risk factors in particular, for oral and oropharyngeal cancers and also for UADT cancers in southern and western Europe. PMID- 21684806 TI - Development of a novel deltamethrin sensor based on molecularly imprinted silica nanospheres embedded CdTe quantum dots. AB - A novel procedure for the determination of deltmethrin (DM) is reported. The water-soluble CdTe quantum dots (QDs) and highly fluorescent silica molecularly imprinted nanospheres embedded CdTe QDs (CdTe-SiO2-MIPs) were prepared and characterized by fluorescence spectroscopy, UV-vis spectroscopy, TEM and IR. The fluorescence nanosensor based CdTe-SiO2-MIPs is developed. The possible quenching mechanism is discussed by DM. Under optimal conditions, the relative fluorescence intensity of CdTe-SiO2-MIPs decreased with increasing DM by a Stern-Volmer type equation in the concentration range of 0.5-35.0 MUg mL(-1), the corresponding detection limit is 0.16 MUg mL(-1). The developed sensor based on CdTe-SiO2-MIPs was applied to determine DM in fruit and vegetable samples. PMID- 21684807 TI - Electronic structures and absorption properties of three kinds of ruthenium dye sensitizers containing bipyridine-pyrazolate for solar cells. AB - The geometries, electronic structures and the electronic absorption spectra of three kinds of ruthenium complexes, which contain tridentate bipyridine pyrazolate ancillary ligands, were studied using density functional theory (DFT) and time-dependent DFT. The calculated results indicate that: (1) the strong conjugated effects are formed across the pyrazoalte-bipyridine groups; (2) the interfacial electron transfer between electrode and the dye sensitizers is an electron injection processes from the excited dyes to the conduction band of TiO2; (3) the absorption bands in visible region have a mixed character of metal to-ligand charge transfer and ligand-to-ligand charge transfer, but the main character of absorption bands near UV region ascribe to pi->pi* transitions; (4) introducing pyrazolate and -NCS groups are favorable for intra-molecular charge transfer, and they are main chromophores that contribute to the sensitization of photon-to-current conversion processes, but introducing -Cl and the terminal group -CF3 are unfavorable to improve the dye performance in dye sensitized solar cells. PMID- 21684808 TI - A community study of sleep bruxism in Hong Kong children: association with comorbid sleep disorders and neurobehavioral consequences. AB - BACKGROUND: The prevalence of childhood sleep bruxism (SB) varied from 5% to 46% among various studies. In addition to local facial and dental adverse consequences, accumulating evidence suggests that childhood SB could be associated with comorbid sleep and systemic neurobehavioral disturbances. This study attempted to investigate the prevalence and clinical correlates of SB in a large community sample. METHODS: This study was part of an ongoing epidemiologic study about sleep problems among Hong Kong Chinese children. A total of 9172 questionnaires were distributed to children of grades 1-6 from 13 randomly selected primary schools. Parents of the children were asked to complete and return the Hong Kong children sleep questionnaire, which aimed to explore the sleep problems and patterns of their children. RESULTS: Six thousand three hundred and eighty-nine questionnaires with valid answers to SB were received and the response rate was 69.7%. The mean age of the recruited children was 9.2+/ 1.8years (50.6%, boys). The prevalence of SB with teeth grinding frequency more than thrice weekly over the past year was 5.9%. SB was more prevalent among boys with decreasing prevalence across age. SB was associated with chronic medical diseases, sleep-related breathing problem, upper respiratory infection, and other parasomnia features, especially sleep talking (OR (95%CI)=4.07 (2.33-7.11)). Children with SB were more likely noticed by their parents to be hyperactive (OR (95%CI)=1.61 (1.25-2.07)) and bad-tempered (OR (95%CI)=1.69 (1.35-2.12)) and had deterioration in their academic performance (OR (95%CI)=1.22(1.03-1.43)). CONCLUSIONS: Almost 6% of Hong Kong primary schoolchildren suffered from frequent SB. The condition was most prevalent among young boys. SB was found to be associated with a variety of medical conditions, neuropsychiatric sequelae, and comorbid sleep conditions, especially sleep talking and sleep related breathing problems. Further prospective studies will need to clarify the longitudinal course of childhood SB and its response to treatment. PMID- 21684809 TI - Accelerometer-derived physical activity levels of preschoolers: a meta-analysis. AB - OBJECTIVES: This study synthesized the published estimates of daily moderate-to vigorous physical activity (MVPAd(-1)) of preschooler-age children (3-5 years). DESIGN: Meta-analysis of previously published studies reporting accelerometer derived estimates of daily MVPA of preschoolers. METHODS: A comprehensive literature review was conducted to identify studies published by March 2010 that reported daily minutes of accelerometer-derived MVPA in preschool-age children (3 5 years). Random effects point estimates and 95% confidence intervals (95% CIs) were calculated based on study weighted means and standard deviations of raw accelerometer counts per minute (cpm) and reported minutes of MVPA and/or percentage of time spent in MVPAd(-1). RESULTS: 29 articles representing 6309 preschoolers were included. Overall, preschoolers engaged in 42.8 min (95% CI 28.9-56.8) of MVPAd(-1), and 54.4 min (95% CI 29.9-78.9) and 45.4 min (95% CI 25.2-65.6) for boys and girls separately. This translated into approximately 5.5% (95% CI 3.7-7.2%) of time spent in MVPAd(-1), and 7.1% (95% CI 3.9-10.3%) for boys and 6.3% (95% CI 3.9-8.7%) for girls. Studies (76%) using ActiGraph accelerometers reported an average of 714 cpm (95% CI 678-751), with boys and girls having 783 cpm (95% CI 753-813) and 696 cpm (95% CI 665-727), respectively. CONCLUSIONS: Interpretation of accelerometer-derived MVPA is confounded by differences in cutpoints applied within a study. Great care, therefore, should be taken when interpreting the activity levels of preschoolers to inform policy decisions, such as the development of physical activity guidelines. Hence, considerable attention is required to unify accelerometer-derived MVPA so that unbiased comparisons across studies can be made. PMID- 21684810 TI - Proposals for uniform collection of biospecimens from neoadjuvant breast cancer clinical trials: timing and specimen types. AB - In this Personal View, we outline proposals for uniform collection of biospecimens obtained in neoadjuvant breast cancer trials undertaken by the Breast International Group (BIG) and the National Cancer Institute-sponsored North American Breast Cancer Group (NABCG). These proposals aim to standardise collection of high-quality specimens, with respect to both type and timing, to enhance and allow integration of results obtained from neoadjuvant trials done by several groups. They should be considered in parallel with recommendations for tissue-specimen collection and handling previously developed by BIG and NABCG. We propose that tumour tissue (formalin-fixed, paraffin-embedded and samples dedicated for molecular studies) should be taken at baseline, 1-3 weeks after the start of treatment, and at definitive surgery, with clear prioritisation in the study protocol of number, order, and preservation of samples to be gathered. This step should be accompanied by blood collection (plasma, serum, and whole blood) whenever possible. We advocate strongly a move towards one diagnostic and research biopsy procedure in all women with breast cancers potentially suitable for neoadjuvant treatment. If possible, patients should be referred at the outset to specialised centres to give them the opportunity to participate in neoadjuvant clinical trials, thereby avoiding several biopsy procedures. PMID- 21684811 TI - Human papillomavirus vaccination in the resourced and resource-constrained world. AB - Human papillomavirus has been established as the causal agent for cervical cancer. The identification of a clear cause presents an unparalleled opportunity for cancer control. As such, the development of prophylactic human papillomavirus vaccines has been rightly hailed as one of the significant scientific triumphs of the past 20 years. This story of scientific triumph over disease, however, is not yet complete. The fruit of scientific labour must be delivered to the people in order to fulfil the underlying intent of the research (i.e. to prevent cancer and save lives). The success of a vaccination programme, however, does not depend on the biological efficacy of the vaccine alone. Various other local factors, such as poverty, gender inequality, cultural traditions, or religious beliefs, can significantly constrain the success of any vaccination programme. In this chapter, we provide an overview of how the human papillomavirus vaccine works and its global uptake, as well as, how variations in local contexts can affect the successful implementation of a vaccination programme. Other factors besides vaccine costs also need serious attention. With better understanding of such factors, policy makers and medical health professionals will be better equipped to make informed decisions to maximise the potential benefits of the human papillomavirus vaccines for the most number of people in individual countries. PMID- 21684813 TI - Peripapillary vitreoretinal traction. AB - BACKGROUND: Vitreoretinal traction syndrome may occur in patients with incomplete posterior vitreous detachment. Although vitreoretinal traction of the macula is well-documented in the literature, the manifestations of peripapillary vitreoretinal traction are rarely discussed. CASE REPORT: A 62-year-old black woman presented for a comprehensive examination. She reported having uncontrolled diabetes and hypertension. Best-corrected visual acuities were 20/30 in the right eye (OD) and 20/25 in the left eye (OS). Dilated examination found a flame-shaped hemorrhage OD. The optic nerve margins OS were blurred, with the margins appearing elevated with peripapillary intraretinal hemorrhages. Cirrus spectral domain optical coherence tomography (OCT) found the presence of peripapillary vitreoretinal traction with concurrent vitreomacular traction OS. CONCLUSION: Although the effects of vitreoretinal traction are most commonly associated with the macula or peripheral retina, residual attachment can occur at the optic nerve head. Peripapillary vitreoretinal traction can cause optic nerve head elevation with the appearance of edema that must be distinguished from sight- or health threatening etiologies. OCT is a valuable diagnostic tool in confirming peripapillary vitreoretinal traction. PMID- 21684812 TI - Concurrent bevacizumab with a sequential regimen of doxorubicin and cyclophosphamide followed by docetaxel and capecitabine as neoadjuvant therapy for HER2- locally advanced breast cancer: a phase II trial of the NSABP Foundation Research Group. AB - BACKGROUND: Bevacizumab with chemotherapy improves outcomes in patients with metastatic breast cancer (MBC). The purpose of this trial was to determine the activity and safety profile of neoadjuvant bevacizumab with chemotherapy in women with locally advanced breast cancer (LABC). METHODS: Between November 2006 and August 2007, 45 women with HER2(-) LABC began preoperative standard AC (doxorubicin [Adriamycin], cyclophosphamide) * 4 cycles followed by docetaxel 75 mg/m(2) intravenously (I.V.) on day 1 and capecitabine 825 mg/m(2) twice daily on days 1-14 (TX, docetaxel [Taxotere] and capecitabine [Xeloda]) every 21 days for 4 cycles. Bevacizumab 15 mg/kg I.V. was given concurrently with chemotherapy every 21 days for a total of 6 preoperative doses. Postoperatively bevacizumab was resumed for a total of 10 doses. The primary endpoint was pathologic complete response (pCR) in the breast. RESULTS: Thirty patients (66.7%) had stage IIIA disease, 12 (26.7%) patients had stage IIIB, and 3 patients (6.7%) had stage IIIC. Of these, 10 (22%) had inflammatory breast cancer (IBC), and 27 (60%) had estrogen receptor (ER)(+) disease. A pCR in the breast with negative axillary nodes was documented in 4 (9%) of 45 patients. Toxicities that were seen with AC and bevacizumab included fatigue (grade 2/3; 31% and 9%, respectively), mucositis (grade 2/3; 29% and 2%, respectively), and headache (grade 2/3; 16% and 7%, respectively). Toxicities seen with TX and bevacizumab included mucositis (grade 2/3; 48% and 25%, respectively), fatigue (grade 2/3; 43% and 18%, respectively), and hand-foot syndrome (grade 2/3; 34% and 23%, respectively). CONCLUSIONS: This regimen demonstrated only modest activity with substantial toxicity and does not appear to warrant further evaluation. PMID- 21684814 TI - Toward the establishment of optimal computed tomographic parameters for the assessment of lumbar spinal fusion. AB - BACKGROUND CONTEXT: The accurate detection of the extent of bony fusion after attempted lumbar arthrodesis is important given that subsequent efforts-such as decisions regarding need for continued external bracing, use of enhancing modalities (electrical stimulation and pulsed ultrasound), recommended activity levels, return to employment, early surgical intervention, and others-may be needed to reduce the risk of late failure, especially in light of the fact that late revisions for failed fusions often result in poor outcomes and significant costs. Thin-cut computed tomography (CT) has emerged as the study of choice for this purpose. PURPOSE: To delineate the optimal CT parameters for determining fusion versus pseudarthosis after attempted lumbar fusion. STUDY DESIGN: Blinded CT assessment with cadaveric specimen as a gold standard. METHODS: A human cadaveric spine specimen with a T10 to S1 thoracolumbar posterolateral fusion augmented by instrumentation and anterior lumbar interbody fusions was used as a gold standard. Two experienced spine surgeons and one musculoskeletal radiologist all blinded to the pathology results-assessed a series of CT scans of the specimen, each CT using one of six predefined sets of parameters. RESULTS: Predictive values and sensitivity generally improved with decreasing slice thickness and slice spacing, but only modestly. All sets of parameters had higher negative predictive value (NPV) than positive predictive value (PPV). Computed tomographic parameters of 0.9-mm thick sections with 50% overlap showed the highest PPV and NPV, where NPV was 90, but PPV was only 59. CONCLUSIONS: In this study, using the best widely available CT technologies and the ideal gold standard, thin-cut CT remained less than ideal for the assessment of lumbar arthrodesis/pseudarthrosis. Tuning slice thickness and slice spacing down generally improves detail, but marginally. We have successfully defined "optimal" as "best available," but "optimal" as "nearly perfect" awaits further technological advances. PMID- 21684815 TI - Long-term results of 1-week intravaginal high-dose-rate brachytherapy alone for endometrial cancer. AB - OBJECTIVE: To compare the biologic equivalence in terms of local control and toxicity of a short course of high-dose-rate intravaginal brachytherapy alone (IVBa) delivered over five consecutive days (25 Gy/5 Rx/5 days) to other more protracted classical schemes 21 Gy/3 Rx/14-28 days (Postoperative Radiation Therapy in Endometrial Carcinoma [PORTEC]-2/Memorial Sloan-Kettering Cancer Center). METHODS AND MATERIALS: From February 2001 to May 2008, 122 patients with International Federation of Gynecology and Obstetrics Stage IaG3-IIIaG2 endometrial adenocarcinoma were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy followed by postoperative IVBa. Seventy-seven patients (63.1%) underwent surgical staging. Total IVBa dose was 25Gy in five consecutive daily fractions prescribed at 0.5-cm depth. RESULTS: After a median followup of 4.1 years, the rates of Radiation Therapy Oncology Group Grades 1, 2, and >=3 complications were 12.9%, 3.4%, and 0.8%, respectively. Five patients (4.1%) presented locoregional failures: two isolated nodal pelvic failures, one vaginal pelvic relapse (intra-abdominal lymph node metastases), one vaginal distant failure, and one combined locoregional and distant failure. The 8.5-year actuarial vaginal control rate was 97.5%, and the pelvic control rate was 94.3%. Six other patients developed distant metastases alone. The 8.5-year actuarial overall and disease-free survival rates were 90.3% and 87.2%, respectively. Univariate analysis revealed that histologic grade, deep myometrial invasion, advanced age, and categorization as high intermediate-risk patient according to the PORTEC-2 and the Gynecologic Oncology Group (GOG)-99 stratifications were statistically significant prognostic factors. After multivariate analysis, histologic grade (p=0.001) and high intermediate risk according to GOG-99 (p=0.004) and PORTEC-2 (p=0.001) remained significant. CONCLUSIONS: The proposed scheme reproduces the excellent results obtained with more protracted schemes and has the added advantage of shortened overall treatment time. PMID- 21684817 TI - Function and expression pattern of TRPM8 in bladder afferent neurons associated with bladder outlet obstruction in rats. AB - We investigated the function and expression pattern of the transient receptor potential melastatin-8 (TRPM8) in urinary bladder afferent neurons from control and bladder outlet obstruction (BOO) rats. BOO was produced and, after six weeks, the effects of intravesical infusion of menthol, the agonist of TRPM8, were investigated using unanesthetized cystometry. The intravesical infusion of menthol produced an increase in the micturition pressure in both sham surgery and BOO rats. In BOO rats, increased basal and threshold pressure and a decreased micturition interval were observed. Next, the population of TRPM8-positive and the co-expression proportion of TRPM8 with neurochemical markers (NF200 or TRPV1) in the bladder afferent neurons were each compared between the control and BOO rats using retrograde tracing and immunohistochemistry. The population of TRPM8 immunoreactive bladder afferent neurons was larger in BOO rats (3.28+/-0.43%) than in the control rats (1.33+/-0.18%). However, there were no statistical differences between the control and BOO rats in the co-expression proportion of neither TRPM8-NF200 (84.1+/-4.3% vs 79.7+/-2.7%, p=0.41) nor TRPM8-TRPV1 (33.3+/ 3.6% vs 40.8+/-2.6%, p=0.08) in the bladder afferent neurons. The present results suggest that the neuronal input through TRPM8-positive bladder afferent neurons are augmented after BOO, however, the neurochemical phenotype of the up-regulated TRPM8-positive bladder afferent neurons is not changed after BOO. PMID- 21684816 TI - Dosimetric effect of interfractional needle displacement in prostate high-dose rate brachytherapy. AB - PURPOSE: To quantify the dosimetric deviations that would arise from delivering subsequent prostate high-dose-rate fractions with only needle readjustment and no replanning after the first fraction. METHODS AND MATERIALS: Patients were treated with either two implant sessions (two 9.5-Gy fractions per session) separated by 2-4 weeks or with one implant session and external beam radiotherapy. After needle placement, needle positions were adjusted under CT guidance, after which dosimetric planning was performed before each fraction. To evaluate the consequence of not replanning before the second fraction, we analyzed the dosimetric parameters of 45 consecutive implants (26 patients). Needles with optimized dwell positions from the first fraction were transferred to the needle positions in the second fraction. Needle displacement between fractions was assessed as well as changes in plan metrics. RESULTS: After adjustment, the mean interfractional needle displacement was 3.5 mm. If replanned, the probability of planning target volume D90% >= 95% is 100%, prostate V100% >= 95% is 87%, and urethra V115% <=10% is 78%. If treated without replanning, the probability of planning target volume D90% >= 95% is 82%, prostate V100% >= 95% is 53%, and urethra V115% <= 10% is 69%. Even for implants with minimal needle displacement (<3 mm) and minimal prostate volume change (<3 cc), the dosimetric consequence of not replanning the second fraction would result in 46% of cases with a prostate V100% < 95%. CONCLUSION: The dosimetric consequences of not replanning the second fraction for prostate high-dose-rate implants results in significantly inferior plan metrics. PMID- 21684818 TI - The muscarinic-activated potassium channel always participates in vagal slowing of the guinea-pig sinoatrial pacemaker. AB - Controversy persists regarding participation of the muscarinic-activated potassium current (c(KACh)) in small and moderate vagal bradycardia. We investigated this by (i) critical examination of earlier experimental data for mechanisms proposed to operate in modest vagal bradycardia (modulation of I(f) and inhibition of a junctional Na(+) current) and (ii) experiments performed on isolated vagally-innervated guinea-pig atria. In 8 superperfused preparations, 10 s trains of vagal stimulation (1 to 20Hz) produced a bradycardia that ranged from 1 to 80%. Hyperpolarisation of sinoatrial cells accompanied bradycardia in 65/67 observations (linear correlation between bradycardia and increase in maximum diastolic potential (mV)=0.076x%; R(2)=0.57; P<0.001). In bath-mounted preparations single supramaximal stimuli to the vagus immediately and briefly increased pacemaker cycle length in 7 of 18 preparations. This response was eliminated by 300nM tertiapin-Q. Trains of 10 single supramaximal vagal stimuli applied at 1-s intervals caused progressive increase in overall cycle length during the train; immediate and brief increases in cycle length occurred following some stimuli. Immediate brief responses and part of the slower response to the stimulus train were removed by 300nM tertiapin-Q. SUMMARY: experimental data shows that small and modest vagal bradycardia is accompanied by hyperpolarisation of the pacemaker cell which is severely attenuated by tertiapin Q. These observations support the idea that activation of I(KACh) occurs at all levels of vagal bradycardia. Contradictory conclusions from earlier studies may be attributed to the nature of experimental models and experimental design. PMID- 21684819 TI - PCR and the detection of Pseudomonas aeruginosa in respiratory samples of CF patients. A literature review. AB - Previous studies proved the importance of rapid antibacterial intervention in case of Pseudomonas aeruginosa detection in respiratory samples of cystic fibrosis patients. To improve the early detection of P. aeruginosa, several culture, PCR and serology based approaches have been compared. Because an increasing number of routine microbiology laboratories have access to real-time PCR (qPCR), we reviewed the specificity and sensitivity of published PCR formats. The importance of choice of DNA-extraction methods and PCR formats and of the validation of their specificity and sensitivity with clinical samples is stressed. PMID- 21684820 TI - Determination of zoledronic acid in human urine and blood plasma using liquid chromatography/electrospray mass spectrometry. AB - A new method for the analysis of 1-hydroxy-2-imidazol-1-yl-phosphonoethyl phosphoric acid (zoledronic acid) in urine and blood samples has been developed. It consists of a derivatisation of the bisphosphonate with trimethylsilyl diazomethane under multiple methylester formation. The formed derivative can, in contrast to the non-derivatised analyte, easily be separated by reversed phase liquid chromatography due to its reduced polarity. Detection is performed by electrospray tandem mass spectrometry. For calibration purposes, a deuterated internal standard has been synthesised in a three-step synthesis starting with d(4)-imidazole. For human urine, the limit of detection (LOD) is 1.2x10(-7) mol/L, limit of quantification (LOQ) is 3.75*10(-7) mol/L in the MRM mode. For human blood plasma, a LOD of 1*10(-7) mol/L and a LOQ of 2.5*10(-7) mol/L were determined. The linear dynamic range comprised 3.5 decades starting at the limit of quantification. The method was successfully applied for the analysis of spiked urine and blood plasma samples as well as samples from two osteoporosis patients. PMID- 21684821 TI - Changing aetiological factors of hepatocellular carcinoma and their potential impact on the effectiveness of surveillance. AB - BACKGROUND: The aetiological factors of hepatocellular carcinoma may vary over time. AIMS: The study assessed the potential impact of the aetiological factors on the effectiveness of surveillance in real-world patients. METHODS: Multicentre, cross-sectional study enrolling consecutive hepatocellular carcinoma cases during a six month period. RESULTS: 1733 cases (1311 prevalent and 422 incident) were recruited (mean age 68.6 years; 46.1% cases over 70 years; 73.9% males; 95.3% with cirrhosis); 63.0% were hepatitis C virus positive and 23.7% were virus negative. Amongst incident HCCs, 34.5% were single <=3cm and 54.4% met the Milan criteria; 61.6% were diagnosed during surveillance; virus negative patients showed the lowest rate of surveillance (51.0%). Surveillance was an independent predictor of detecting single HCCs <=2cm (O.R.=5.4; 95% C.I.=2.4 12.4) or HCCs meeting the Milan criteria (O.R.=3.1; 95% C.I.=1.9-5.2). Compared with an earlier Italian survey, there was a higher proportion of elderly subjects (P<0.01), Child-Pugh class A cases (P<0.01), of virus-negative patients (P<0.01) and with single tumours <=3cm (P<0.01) and a lower prevalence of hepatitis C virus positive individuals (P<0.01). CONCLUSION: HCC is characterised by a growing prevalence of elderly patients and cases unrelated to hepatitis virus infections. The application of surveillance must be implemented, particularly amongst non-viral patients. PMID- 21684822 TI - Redistribution of regulatory T-cells across the evolving stages of chronic hepatitis C. AB - BACKGROUND: Hepatitis C virus infection frequently leads to chronic hepatitis, possibly evolving to end-stage liver disease and hepatocellular carcinoma. Regulatory T cells can affect antiviral immune response thus influencing the outcome of the disease. AIM: To determine numeric and functional distribution of regulatory T cells expressing CD4+CD25hiFoxp3+ (T-regs) during the different stages of hepatitis C virus-related liver disease. METHODS: 90 hepatitis C viraemic patients and 50 healthy controls were included. Surface and intracellular (Foxp3) T-reg markers were evaluated by flow cytometry. Target cell proliferation and interferon-gamma production were evaluated in 37 HCV patients. In 16 cases intrahepatic distribution of Foxp3 by immuno-histochemistry was assessed. RESULTS: T-regs were increased in hepatitis C virus infected patients and correlated inversely with aminotransferases and directly with MELD score and disease duration. A preserved inhibitory ability of interferon-gamma production was distinctive of patients with normal aminotransferases. Circulating T-regs did not correlate with intrahepatic distribution of Foxp3. CONCLUSIONS: In chronic hepatitis C, selective expansion of peripheral T-regs in patients with normal aminotransferases and advanced disease suggests that, though a continual low level inflammation does not prevent liver disease progression, once cirrhosis has developed it may represent an attempt to prevent immuno-mediated decompensation. PMID- 21684823 TI - [Unusual forms of mastoiditis: a presentation of two cases]. PMID- 21684824 TI - [Endobronchial tuberculosis as a cause of refractory pneumonia]. PMID- 21684825 TI - [Pulmonary function in children following community-acquired pneumonia contracted at pre-school age]. AB - AIM: Some studies relate pulmonary function (PF) during adult life to community acquired pneumonia (CAP) suffered during infancy. The aim of the present work was to evaluate PF in children following CAP, contracted at pre-school age, which required hospitalisation. The hypothesis was that, once resolved, CAP in pre school age children does not affect PF; further monitoring should therefore be unnecessary. METHODS AND MATERIALS: PF was studied in a cohort of children who had suffered CAP at pre-school age, for which they were hospitalised. Children aged over 4 years were selected to try to ensure adequate collaboration, and a forced spirometry test was attempted in all of them. RESULTS: Of the initial 49 patients, 42 (85.7%) correctly performed the forced spirometry test. All were asymptomatic at the time of examination. The mean age of these patients was 6,6 +/- 1,2 years; 25 were boys (54,3%). The mean time between CAP and the test was 19,5 +/- 7,6 months. The results (mean +/- SD) obtained with respect to theoretical values were: forced respiratory volume in the first second 107.73 +/- 14.56% and forced vital capacity 101,6 +/- 15,35%. CONCLUSIONS: The PF of children who have suffered CAP at pre-school age is normal following the resolution of the condition. No further PF studies are required after CAP resolves. PMID- 21684827 TI - The place of new haemostatic techniques in thyroid surgery. PMID- 21684826 TI - Does endoscopic release of the first extensor compartment have benefits over open release in de Quervain's disease? AB - Superficial radial nerve injury, incomplete release of the first extensor compartment, palmar subluxation of the tendons and painful scar are the main reasons for persistent pain and dysfunction after open release. We therefore asked whether the endoscopic release of the first extensor compartment is advantageous over the open release in terms of subjective pain and disability, complication and aesthetic appearance. METHODS: Fifty wrists treated with either open release (26 wrists) or endoscopic release (24 wrists) of the first extensor compartment in case of de Quervain's disease were included. All patients were evaluated at a minimum of 1-year follow-up using visual analogue scale (VAS) pain ratings and the Disabilities of Arm, Shoulder and Hand (DASH) score. RESULTS: The average operating time of endoscopic release was 4 min longer than that of open release. The mean VAS pain score was improved from an initial 6.4 to 0.5 in the open release group and from 6.7 to 0.1 in the endoscopic release group. The mean DASH score was improved from 60.1 to 6.8 in the open release group and from 64.4 to 1.5 in the endoscopic release group. No clinically significant difference was found between the two groups regarding subjective VAS pain and DASH scores at the last follow-up. In the open release group, superficial radial nerve injuries (five wrists), significant scar tenderness (three) and unsightly scar (six) were identified. CONCLUSIONS: Endoscopic release of the extensor compartment seems to be an effective and safe procedure in patients with de Quervain's disease who are unresponsive to non-operative treatments, despite a little increase in operation time. PMID- 21684828 TI - Ovarian squamous cell carcinoma arising from mature cystic teratoma. AB - Preoperative diagnosis of malignant transformation of an ovarian mature cystic teratoma to squamous cell carcinoma is difficult due to nonspecific tumor markers and imaging findings. This is an interesting case presentation that has prior imaging that demonstrates imaging characteristics of the transformation of a mature cystic teratoma to squamous cell carcinoma. PMID- 21684829 TI - Quantitative (177)Lu SPECT (QSPECT) imaging using a commercially available SPECT/CT system. AB - PURPOSE: The combination of single photon emission computed tomography (SPECT) and computer tomography (CT) that incorporates iterative reconstruction algorithms with attenuation and scatter correction should facilitate accurate non invasive quantitative imaging. Quantitative SPECT (QSPECT) may improve diagnostic ability and could be useful for many applications including dosimetry assessment. Using (177)Lu, we developed a QSPECT method using a commercially available SPECT/CT system. METHODS: Serial SPECT of (177)Lu sources (89-12,400 MBq) were acquired with multiple contiguous energy windows along with a co-registered CT, and were reconstructed using an iterative algorithm with attenuation and scatter correction. Camera sensitivity (based on reconstructed SPECT count rate) and dead time (based on wide-energy spectrum count rate) were resolved by non-linear curve fit. Utilizing these parameters, a SPECT dataset can be converted to a QSPECT dataset allowing quantitation in Becquerels per cubic centimetre or standardized uptake value (SUV). Validation QSPECT/CT studies were performed on a (177)Lu cylindrical phantom (7 studies) and on 5 patients (6 studies) who were administered a therapeutic dose of [(177)Lu]octreotate. RESULTS: The QSPECT sensitivity was 1.08 x 10(-5) +/- 0.02 x 10(-5) s(-1) Bq(-1). The paralyzing dead time constant was 0.78 +/- 0.03 us. The measured total activity with QSPECT deviated from the calibrated activity by 5.6 +/- 1.9% and 2.6 +/- 1.8%, respectively, in phantom and patients. Dead-time count loss up to 11.7% was observed in patient studies. CONCLUSION: QSPECT has high accuracy both in our phantom model and in clinical practice following [(177)Lu]octreotate therapy. This has the potential to yield more accurate dosimetry estimates than planar imaging and facilitate therapeutic response assessment. Validating this method with other radionuclides could open the way for many other research and clinical applications. PMID- 21684830 TI - Unicentric mixed variant Castleman disease associated with Hashimoto disease: the role of PET/CT in staging and evaluating response to the treatment. AB - Castleman disease (CD) is a rare atypical lymphoproliferative disease, pathologically classified as hyaline vascular, plasma cell type and mixed type variant. The underlying cause of CD is unknown, however several theories including autoimmunity have been proposed. We describe a patient diagnosed with unicentric mixed variant CD and Hashimoto thyroiditis, concurrently. She was staged with fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) and the disease was localized to the mediastinum. After 6 cycles of chemotherapy consisting of vincristine and prednisone, the mediastinal lymph nodes regressed, but did not disappear from the CT scan. However, FDG-PET/CT showed complete metabolic response. Although the role of FDG-PET/CT in staging and evaluation of treatment response is controversial, this case shows that PET/CT can be effective and even better for staging and response evaluation. This case is also unique as there no case of CD in association with Hashimoto thyroiditis has been reported previously. However, the possibility of a coincidental association must be raised, especially when the high prevalence of Hashimoto thyroiditis is considered. PMID- 21684834 TI - [Telomeres: a Nobel Prize at the beginning... of the end]. AB - The 2009 Nobel Prize for Physiology and Medicine was awarded to Elizabeth H. Blackburn, Carol W. Greider and Jack K. Szostak for their work on telomeres and telomerase. This prize acknowledges their pionneering discoveries on chromosomal extremities. Telomeres are the nucleoproteic complexes that may be found at the ends of linear chromosomes. They are essential for genomic stability and are involved in aging and tumorogenesis. PMID- 21684833 TI - The role of the extracellular matrix protein mindin in airway response to environmental airways injury. AB - BACKGROUND: Our previous work demonstrated that the extracellular matrix protein mindin contributes to allergic airways disease. However, the role of mindin in nonallergic airways disease has not previously been explored. OBJECTIVES: We hypothesized that mindin would contribute to airways disease after inhalation of either lipopolysaccharide (LPS) or ozone. METHODS: We exposed C57BL/6J and mindin deficient (-/-) mice to aerosolized LPS (0.9 MUg/m3 for 2.5 hr), saline, ozone (1 ppm for 3 hr), or filtered air (FA). All mice were evaluated 4 hr after LPS/saline exposure or 24 hr after ozone/FA exposure. We characterized the physiological and biological responses by analysis of airway hyperresponsiveness (AHR) with a computer-controlled small-animal ventilator (FlexiVent), inflammatory cellular recruitment, total protein in bronchoalveolar lavage fluid (BALF), proinflammatory cytokine profiling, and ex vivo bronchial ring studies. RESULTS: After inhalation of LPS, mindin-/- mice demonstrated significantly reduced total cell and neutrophil recruitment into the airspace compared with their wild-type counterparts. Mindin-/- mice also exhibited reduced proinflammatory cytokine production and lower AHR to methacholine challenge by FlexiVent. After inhalation of ozone, mice had no detectible differences in cellular inflammation or total BALF protein dependent on mindin. However, mindin /- mice were protected from increased proinflammatory cytokine production and AHR compared with their C57BL/6J counterparts. After ozone exposure, bronchial rings derived from mindin-/- mice demonstrated reduced constriction in response to carbachol. CONCLUSIONS: These data demonstrate that the extracellular matrix protein mindin modifies the airway response to both LPS and ozone. Our data support a conserved role of mindin in production of proinflammatory cytokines and the development of AHR in two divergent models of reactive airways disease, as well as a role of mindin in airway smooth muscle contractility after exposure to ozone. PMID- 21684831 TI - Arsenic toxicology: translating between experimental models and human pathology. AB - BACKGROUND: Chronic arsenic exposure is a worldwide health problem. How arsenic exposure promotes a variety of diseases is poorly understood, and specific relationships between experimental and human exposures are not established. We propose phenotypic anchoring as a means to unify experimental observations and disease outcomes. OBJECTIVES: We examined the use of phenotypic anchors to translate experimental data to human pathology and investigated research needs for which phenotypic anchors need to be developed. METHODS: During a workshop, we discussed experimental systems investigating arsenic dose/exposure and phenotypic expression relationships and human disease responses to chronic arsenic exposure and identified knowledge gaps. In a literature review, we identified areas where data exist to support phenotypic anchoring of experimental results to pathologies from specific human exposures. DISCUSSION: Disease outcome is likely dependent on cell-type-specific responses and interaction with individual genetics, other toxicants, and infectious agents. Potential phenotypic anchors include target tissue dosimetry, gene expression and epigenetic profiles, and tissue biomarkers. CONCLUSIONS: Translation to human populations requires more extensive profiling of human samples along with high-quality dosimetry. Anchoring results by gene expression and epigenetic profiling has great promise for data unification. Genetic predisposition of individuals affects disease outcome. Interactions with infectious agents, particularly viruses, may explain some species-specific differences between human pathologies and experimental animal pathologies. Invertebrate systems amenable to genetic manipulation offer potential for elaborating impacts of specific biochemical pathways. Anchoring experimental results to specific human exposures will accelerate understanding of mechanisms of arsenic-induced human disease. PMID- 21684835 TI - [EGFR/HER1: a target life]. AB - EGFR may be considered as an old target, which can be inhibited both by monoclonal antibodies and tyrosine kinase inhibitors. Those molecular targeted strategies are now approved in a wild range of tumors: colorectal cancer, lung cancer, pancreatic cancer and head and neck cancer. This paper proposes to describe the development of anti-EGFR drugs, highlighting several strategies points. Predicting biomarkers have been extensively studied for these agents, sustaining the hallmarks of the development of molecular targeting drugs. PMID- 21684836 TI - [Strategies for screening for pancreatic adenocarcinoma in high-risk patients]. AB - Screening high-risk individuals with imaging tests, such as endoscopic ultrasound and computed tomography, can lead to the detection and treatment of predominantly asymptomatic premalignant lesions. These pancreatic lesions consist of resectable, mostly branch-type non-invasive intraductal papillary mucinous neoplasms. Endoscopic ultrasound features of chronic pancreatitis are highly prevalent in high-risk individuals and these directly correlate with multifocal lobulocentric parenchymal atrophy due to pancreatic intraepithelial neoplasia. Long-term, multi-prospective studies are needed to determine if screening for early pancreatic adenocarcinoma and timely intervention will result in decreased pancreatic cancer incidence and mortality in high-risk individuals. PMID- 21684837 TI - Return to work after treatment for breast cancer: single center experience in a cohort of 273 patients. AB - BACKGROUND: An increasing number of patients is treated for breast cancer during their professional life. The aim of this study was to assess factors impacting return to work and time to return to work after treatment. PATIENTS AND METHODS: One thousand and sixty-seven patients less than 60 years of age, and surgically treated in our institution between January 1st, 2004 and December 31st, 2005 received a questionnaire with medical, sociodemographic and professional items. An answer was obtained in 586 cases. Two hundred and seventy-three patients were evaluable. All the clinical files of these patients were reviewed. RESULTS: Overall, 79.8% of the patients returned to work after a median delay of 11.5 months. In the multivariate analysis, the factors affecting the return to work were: age (P<0.0001), educational level (P<0.001), colleagues' support (P<0.001), chemotherapy (P<0.05), lymphedema (P<0.01), and the physical (P=0.01) and psychological (P<0.01) constraints of the job. The factors affecting the time until return to work were very quite similar. No significant difference was observed according to the type of surgery, radiation therapy or not, hormonotherapy or not. CONCLUSION: Eighty percent of the patients with a professional activity before treatment returned to work; the factors affecting return to work were medical, demographic and socio-professional. PMID- 21684838 TI - [Her2 a paradigm for targeted therapy]. AB - Fifteen percent of breast cancers overexpress Her2, a tyrosin-kinase receptor. Because of its prognosis and its incidence, several efforts have been done in the last years to better understand mechanisms of Her2 action. This led to the development of targeted therapies such as trastuzumab, monoclonal antibody directed against the Her2 extra-cellular domain. Trastuzumab provides significant clinical benefit in women with Her2-positive breast cancers. However, many women will either not respond or progress despite this treatment. The aim of this article is to summarize mechanisms of action of Her2 and of trastuzumab, and to better understand pathways activated in resistant tumors in order to identify ways to overcome them. PMID- 21684839 TI - Treatment of solar lentigines with trichloroacetic acid 40% vs. cryotherapy. PMID- 21684840 TI - Cutaneous polyarteritis nodosa: complete clearance of the leg ulcer after the amputation of the contralateral leg. PMID- 21684841 TI - DRESS-like syndrome induced by shiitake mushroom. PMID- 21684842 TI - The technologies used for developing orally disintegrating tablets: a review. AB - Orally disintegrating tablets (ODTs), also known as fast melts, quick melts, fast disintegrating and orodispersible systems, have the unique property of disintegrating in the mouth in seconds without chewing and the need of water and are thus assumed to improve patient compliance. Conventional methods like direct compression, wet granulation, moulding, spray-drying, freeze-drying and sublimation were used to prepare ODTs. New advanced technologies like Orasolv(r), Durasolv(r), Wowtab(r), Flashtab(r), Zydis(r), Flashdose(r), Oraquick(r), Lyoc(r), Advatab(r), Frosta(r), Quick-Disc(r) and Nanomelt(r) have been introduced by some pharmaceutical companies for the production of ODTs. The main objective of this review is to give a comprehensive insight into conventional and recent technologies used for the preparation of ODTs. PMID- 21684843 TI - Design and development of paclitaxel-loaded bovine serum albumin nanoparticles for brain targeting. AB - Bovine serum albumin (BSA) nanoparticles loaded with paclitaxel (PTX) were prepared using a desolvation technique. A 32 full factorial design (FFD) was employed to formulate nanoparticles. Nanoparticles were characterized for particle size by photon correlation spectroscopy and surface morphology by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Encapsulation efficiency, zeta potential and particle yield were also determined. Response surface linear modelling (RSLM) was used to predict the optimal formulation. Various models were applied to determine the release mechanism from PTX nanoparticles. The effect of drug-polymer ratio on the release profile of formulations was observed and was applied to determine the suitability of the predicted optimal formulation. A preliminary study to determine the feasibility of targeting the prepared nanoparticles to brain was also carried out using mice as in vivo models. PMID- 21684844 TI - Development and characterization of mucoadhesive patches of salbutamol sulfate for unidirectional buccal drug delivery. AB - Buccal patches of salbutamol sulfate were prepared using five different water soluble polymers in various proportions and combinations using PEG-400/PG as plasticizers. A 32 full factorial design was used to design the experiments for each polymer combination. Patches were laminated on one side with a water impermeable backing layer for unidirectional drug release. The thickness of medicated patches ranged between 0.2 and 0.4 mm and showed an increase in mass whenever PEG-400 was used as plasticizer. The surface pH of all patches approached neutral. Eight formulations which had shown high folding endurance (> 300) were selected for evaluation. Patches prepared with PEG-400 showed a high swelling index. The residence time of the tested patches ranged between 105 and 130 min. Formulations A10, A32, B10 and B32 fitted the Higuchi model best, whereas formulations A19 and B19 showed super case II transport drug release. Stability studies indicated that there was no change in the chemical and physical characteristics during the test period of 6 months. PMID- 21684845 TI - Synthesis and antimicrobial evaluation of some 6-aryl-5-cyano-2-thiouracil derivatives. AB - A series of 6-aryl-5-cyano-2-thiouracil derivatives (1a-d) was synthesized by the reaction of ethyl cyanoacetate with thiourea and aldehydes. These products were used as intermediate compounds for the synthesis of a number of thiouracil derivatives (2a-d to 10a-d). All compounds were screened for antibacterial and antifungal activities. Some of the prepared compounds, 6-(4-fluorophenyl)-4-oxo-2 thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (2a), 4-oxo-2-thioxo-6-(3,4,5 trimethoxyphenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (2d), 6-(4 fluorophenyl)-4-hydrazino-2-thioxo-1,2-dihydropyrimidine-5-cabonitrile (7a) and 4 hydrazino-2-thioxo-6-(3,4,5-trimethoxyphenyl)-1,2-dihydropyrimidine-5 carbonitrile (7d) revealed promising antimicrobial activity. PMID- 21684846 TI - Synthesis, antibacterial and potential anti-HIV activity of some novel imidazole analogs. AB - A series of 1-(2-methyl-4-nitro-imidazol-1-yl)-3-arylaminopropan-2-ones (2a-e), 2 methyl-5-nitro-1-{2-[arylmethoxy]ethyl}-1H-imidazoles (5a-d), and N-(3 hydroxyphenyl)-2-(substituted imidazol-1-yl)alkanamides (8a-e) were synthesized with the aim to develop novel imidazole analogs with broad-spectrum chemotherapeutic properties. Title compounds were evaluated for their anti-HIV and antibacterial activities. PMID- 21684847 TI - Formulation and evaluation of mucoadhesive glipizide films. AB - Glipizide is mainly absorbed in the proximal areas of the gastrointestinal tract. The purpose of this study was formulation and evaluation of mucoadhesive films to prolong the stay of drug in its absorption area. Glipizide was formulated in a mucoadhesive film that could be retained in the stomach for prolonged intervals. Polymeric films were designed with various compositions of hydroxypropyl cellulose and polyethylene glycol 400 (PEG 400). Properties of the mucoadhesive film such as tensile strength, percentage elongation, swelling index, moisture content, pH and viscosity of polymeric dispersion, film thickness, content uniformity and mucoadhesion in a simulated gastric environment were characterized. In addition, percentage drug retained in stomach mucosa was estimated using a simulated dynamic stomach system as a function of time. Increase in hydroxypropyl cellulose concentration resulted in a higher tensile strength and elongation at break, while increase in concentration of PEG 400 was reflected in a decrease in tensile strength and increase of elongation at break. Glipizide/hydroxypropyl cellulose/PEG 400 (2.5:1:0.5) (GF5) was found to be the optimal composition for a novel mucoadhesive stomach formulation that showed good peelability, relatively high swelling index, moderate tensile strength, and stayed on rat stomach mucosa up to 8 h. In vivo testing of the mucoadhesive films with glipizide demonstrated a potential hypoglycemic effect. PMID- 21684848 TI - Formulation and evaluation of effervescent floating tablets of tizanidine hydrochloride. AB - Tizanidine hydrochloride is an orally administered prokinetic agent that facilitates or restores motility through-out the length of the gastrointestinal tract. The objective of the present investigation was to develop effervescent floating matrix tablets of tizanidine hydrochloride for prolongation of gastric residence time in order to overcome its low bioavailability (34-40 %) and short biological half life (4.2 h). Tablets were prepared by the direct compression method, using different viscosity grades of hydroxypropyl methylcellulose (HPMC K4M, K15M and K100M). Tablets were evaluated for various physical parameters and floating properties. Further, tablets were studied for in vitro drug release characteristics in 12 hours. Drug release from effervescent floating matrix tablets was sustained over 12 h with buoyant properties. DSC study revealed that there is no drug excipient interaction. Based on the release kinetics, all formulations best fitted the Higuchi, first-order model and non-Fickian as the mechanism of drug release. Optimized formulation (F9) was selected based on the similarity factor (f2) (74.2), dissolution efficiency at 2, 6 and 8 h, and t50 (5.4 h) and was used in radiographic studies by incorporating BaSO4. In vivo X ray studies in human volunteers showed that the mean gastric residence time was 6.2 +/- 0.2 h. PMID- 21684849 TI - Synthesis, antispasmodic and antidiarrheal activities of some 1-substituted imidazole derivatives. AB - A series of 1-substituted imidazoles 1a-d and 2a-d were synthesized and screened for antispasmodic and antidiarrheal activities. Antispasmodic activity was tested at various concentrations on isolated tissue preparations; concentration-response curves were plotted and compared with atropine. All compounds were found to inhibit contraction of the guinea pig ileum. Castor oil-induced diarrhea model in rats was used for evaluation of antidiarrheal activity. Parameters such as intestinal transit and volume of intestinal fluid were measured for antidiarrheal activity at 40 mg kg-1 dose and compared with the standard drug loperamide at 6 mg kg-1 dose. Defecation frequency in the test group was found to be significantly lower (p < 0.01) compared to the control group and comparable with that of the standard. The present study reveals that the compounds exert antidiarrheal activity through possible inhibition of intestinal movement and reduction of capillary permeability in the abdominal cavity. PMID- 21684850 TI - Compatibility studies of nateglinide with excipients in immediate release tablets. AB - Experiments were done to assess the compatibility of nateglinide with selected excipients in the development of immediate release tablets of nateglinide by thermal and isothermal stress testing (IST) techniques. To evaluate the drug excipient compatibility, different techniques such as differential scanning calorimetric (DSC) study, infra-red (IR) spectrophotometric study and isothermal stress testing were adopted. The results of DSC study showed that magnesium stearate exhibited some interaction with nateglinide. However, the results of IR, and IST studies showed that all the excipients used in the formula were compatible with nateglinide. Optimized formulations developed using the compatible excipients were found to be stable over 3 months of accelerated stability studies (40 +/- 2 degrees C and 75 +/- 5% RH). Overall, compatibility of excipients with nateglinide was successfully evaluated using a combination of thermal and IST methods and the formulations developed using the compatible excipients were found to be stable. PMID- 21684851 TI - Application of artificial neural networks in optimizing the fatty alcohol concentration in the formulation of an O/W emulsion. AB - The purpose of this study was to optimize the concentration of a fatty alcohol, in addition to internal phase, for formulating a stable O/W emulsion, by using artificial neural networks (ANNs). Predictions from ANNs are accurate and allow quantification of the relative importance of the inputs. Furthermore, by varying the network topology and parameters it was possible to obtain output values that were close to experimental values. The ANN model's predictive results and the actual output values were compared. R(2) values depict the percentage of response variability for the model; R(2) value of 0.84 for the model suggested adequate modeling, which is supported by the correlation coefficient value of 0.9445. PMID- 21684852 TI - Potential strategies for an HIV infection cure. AB - Despite long-term viral suppression with antiretroviral therapy (ART), HIV persists in reservoirs and sanctuary sites. Lifelong therapy is therefore necessary, leading to problems of compliance, toxicity, and cost. Over the last few years, important advances have been made in our understanding of the composition and the maintenance mechanisms of the HIV reservoir. Although complete viral eradication is currently out of reach, a growing number of scientists think that a "functional" cure is achievable. This situation would combine no disease progression, no virus transmission, and a life expectancy close to uninfected individuals in the absence of ART. At acute HIV infection, ART increases the frequency of sustained viremia control after its discontinuation, compared with the natural history of untreated disease. For patients at the chronic stage of HIV infection, ART alone is insufficient to clear viral reservoirs and new molecules intended to purge this reservoir or gene therapy approaches are warranted. This search for a cure needs innovation, audaciousness, and coordination. It also needs political, institutional, and private commitments for funding, which by now are severely lacking. PMID- 21684853 TI - Similar efficacy of raltegravir when used with or without a protease inhibitor in treatment-experienced patients. AB - BACKGROUND: Patients with multiclass-resistant HIV-1 have limited treatment options. Raltegravir, an inhibitor of integrase, has shown excellent efficacy when used with protease inhibitors (Pis) in patients with drug-resistant HIV-1. Limited data are available however about the outcomes when using raltegravir without Pis in this population. METHODS: Medical records of subjects who received raltegravir as part of the Merck EAP study 0518 were reviewed and abstracted at participating sites. Eligibility criteria included HIV positivity, age >= 16 years, limited or no treatment options due to resistance or intolerance to multiple antiretroviral regimens, detectable viremia on current treatment regimen, and documented resistance to at least one drug in each antiretroviral class (PI, NNRTI, and nucleoside analogue). Demographic, clinical, and laboratory data were collected locally using a standardized collection form. Genotypic susceptibility scores (GSS) were determined from the most recent genotypic resistance test available prior to the initiation of raltegravir. The main objective was to compare virologic results in patients who received raltegravir with a PI versus those who received raltegravir without a PI. RESULTS: Four hundred forty-two subjects were evaluated from the respective sites in the EAP trial, of whom 340 were evaluable. The baseline mean HIV RNA was 4.6 log copies/ mL, and the mean CD4 cell count was 159 cells/MUL. The median number of total and new antiretroviral agents in the background regimen was 4 and 2, respectively. Among the 254 patients who received a PI, the most common PI used was darunavir (89%). Etravirine was commonly used in both groups: 39% of the PI group and 67% of the non-PI group. At week 12, 67% of PI patients and 64% of non-PI patients achieved HIV RNA <75 copies/mL and 85% and 86%, respectively, achieved HIV RNA <400 copies/mL GSS, which was similar in both groups at baseline, predicted achieving an HIV RNA of <400 and 75 copies/mL at week 12 (P < .05). CONCLUSIONS: In treatment-experienced patients, the combination of raltegravir with a regimen not containing a PI (used with etravirine in two-thirds of patients) had similar virologic activity when compared to more standard regimens using raltegravir with a PI. The main determinant of efficacy was the number of active drugs as measured by GSS. These data expand the potential utility of raltegravir in patients with multidrug-resistant HIV. PMID- 21684854 TI - Cardiovagal autonomic function in HIV-infected patients with unsuppressed HIV viremia. AB - PURPOSE: HIV infection has been implicated in dysregulation of the autonomic nervous system. METHOD: Cross-sectional study examining the relationship between the presence of persistent detectable HIV viral load with autonomic function, measured by heart rate variability (HRV). Non-virologic suppression (NVS) was defined as having a detectable viral load for at least 3 months prior to autonomic function testing. HRV was measured during the following 4 maneuvers: resting and paced respirations and sustained handgrip and tilt. Inferences on parasympathetic and sympathetic modulations were determined by analyzing time and frequency domains of HRV. RESULTS: 57 participants were enrolled in 3 groups: 22 were HIV-infected participants with HIV virologic suppression (VS; undetectable HIV viral load), 9 were HIV-infected participants who had NVS, and 26 were HIV seronegative controls. There were lower time domain parameters in the HIV infected group as a whole compared to controls. There were no significant differences in time domain parameters among HIV-infected participants. There were no differences in frequency domain parameters during any of the maneuvers between controls and all HIV-infected participants, nor between the NVS and VS groups. CONCLUSION: There were differences in autonomic function between HIV-infected individuals and HIV seronegative controls, but not between the NVS and VS groups. PMID- 21684855 TI - Treatment durability, effectiveness, and safety with atazanavir/ritonavir-based HAART regimen in treatment-naive HIV-infected patients. AB - PURPOSE: To describe the durability of treatment, virological and immunological response, and safety of an atazanavir/ritonavir (ATV/RTV)-based highly active antiretroviral therapy (HAART) regimen in treatment-naive HIV-infected patients. METHODS: This was a multicentre retrospective study. Medical charts of antiretroviral-na'i've HIV-infected adults who initiated ATV/RTV (300/100 mg) from January 2004 to December 2007 in 10 Canadian clinics were reviewed. Data were collected from time of ATV/RTV treatment initiation until discontinuation of ATV. Durability of treatment and time to virological response were estimated with Kaplan-Meier functions. Change in viral load, CD4 cell counts, and lipid parameters were assessed with linear regression analyses. RESULTS: 176 patients were enrolled, 153 (86.9%) were male, and the majority (52.3%) were 40 to 54 years old. Duration of observation ranged from 1.6 to 56 months. The mean (SE) durability of treatment was 33.5 (0.7) months. There were 37 (21.0%) patients who discontinued ATV/ RTV, among whom 18 (10.2%) discontinued due to toxicity, suboptimal virological response, loss to follow-up, or death. The mean (SE) time to HIV viral load of <50 and <400 copies/mL was 6.6 (0.4) and 4.3 (0.3) months, respectively. At 96 weeks of treatment, least squares mean (LSM) estimated change in log10(HIV copies/mL) was -2.94 (P < .001) and +245 cells/mL (P < .001) for CD4 cell count. A significant LSM increase in HDL-C of 0.24 mmol/L (P = .007 for trend over time) was also observed; total cholesterol, triglycerides, and LDL-C increased over time but their change did not reach statistical significance. The most frequently reported adverse event was increased bilirubin (16.5%). CONCLUSIONS: ATV/RTV-based first-line HAART regimen demonstrated durability and effectiveness and was well tolerated in treatment-naive HIV-infected patients. PMID- 21684856 TI - Self-reported symptoms among HIV-lnfected patients on highly active antiretroviral therapy in the ATHENA cohort in The Netherlands. AB - BACKGROUND: HIV-infected patients on combination antiretroviral therapy (cART) may experience symptoms because of HIV disease or treatment. Symptoms might negatively affect quality of life, adherence, virological response, and survival. We investigated to what extent HIV-infected patients receiving cART experience symptoms with a median follow-up of 5.1 years. Additionally, we studied whether self-reported symptoms were related to concurrent quality of life and virological failure. METHODS: Patients from the ATHENA cohort completed questionnaires on self-reported symptoms and quality of life every 6 months (January 1998 to June 2005). Quality of life was measured with the Medical Outcomes Study HIV Health Survey (MOS-HIV), resulting in a physical health summary (PHS) score and a mental health summary (MHS) score. Growth curve models were conducted to investigate the course of symptoms. Random effect models were carried out to study the association with concurrent quality of life and virological response. RESULTS: We included 391 patients, completing 2,851 questionnaires. Symptoms that increased significantly over time were numb feeling in fingers or toes (P < .01), pain in legs (P < .01), pain when urinating (P < .01), sore muscles (P = .02), tingling of hands or feet (P = .06), and difficulties with seeing (P < .01). All self reported symptoms were related to lower levels of PHS and MHS (P < .01). Trouble with sleeping (odds ratio [OR] 1.5; 95% Cl, 1.04-2.2), constipation (OR 2.8; 95% Cl, 1.7-1.8), pain in legs (OR 1.8; 95% Cl, 1.2-2.6), and numb feeling in fingers or toes (OR 1.7; 95% Cl, 1.1-2.7) were related to concurrent virological response. CONCLUSION: HIV-infected patients on cART report a large range of symptoms. Management of symptoms is relevant because a number of symptoms are related to poorer quality of life and virological failure. PMID- 21684857 TI - Use of non-nucleoside analogues together with rifampin in HIV patients with tuberculosis. AB - OBJECTIVE: The concomitant use of rifampin (RFP) with efavirenz (EFV) or nevirapine (NVP) is frequent in HIV patients with tuberculosis (TB). The necessity of increasing the dose of EFV remains controversial. The aim of the study was to evaluate the outcome of HIV infection in patients treated with non nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) and RFR. METHODS: Retrospective analysis of HIV patients who were simultaneously treated with RFP and NVP or EFV. The dose of EFV was considered to be adjusted in those patients receiving 600 mg when weighing <60 kg and 800 mg if >60 kg and was considered nonadjusted when the dose given was 600 mg in patients >60 kg. RESULTS: 63 patients were included: 13 received NVP and 50 received EFV based ART (30 adjusted and 20 nonadjusted). Treatment failure was observed in 7 (53.8%) of the NVP group; 11 (55%) of the nonadjusted EFV group, and 8 (26.7%) of the adjusted EFV group (P = .04). The relative risk (RR) of treatment failure comparing nonadjusted and adjusted EFV was 3.36 (95% Cl, 1.02-11.11). The proportion of treatment failure was 9/18 (50%) in the nonadjusted and 5/27(18.5%) in the adjusted EFV group. CONCLUSIONS: The effectiveness of NVP and nonadjusted EFV was lower than adjusted EFV-based ART. It may be advisable to increase the dose of EFV to 800 mg once daily when administered with rifampin in patients weighing >60 kg. PMID- 21684858 TI - [Recent advances in mutant p53 and novel personalized strategies for cancer therapy]. AB - Protein p53 is the most intensively studied tumor suppressor protein. Recent studies keep revealing its new function in metabolism and reproduction. At the same time, it is also found that varieties of p53 mutant gained new function in promoting tumorigenesis. These studies provide the basis for understanding the personalized gain of function of p53 mu-tants and help us searching for the new strategies for reactivation of wild-type p53 and correction of the function of p53 mutants. The personalized treatment targeting different p53 mutants will be the focus for cancer treatment. Here, we re-viewed the discovered gain of function of some p53 mutants and the molecular strategies for reactivating wild type p53 function: by use of small molecules or polypeptides to reactivate the wild type function of p53 mutants in tumor cells; by exogenous expression of wild type p53 carried by recombinant adenovirus in tumor cells; and by inhibition the interaction between p53 and mdm2 to stabilize wild type p53 proteins. Further study of variety of p53 point mutations farcilitates de-signing more effectively personalized strategies in the cancer therapy. PMID- 21684859 TI - [Advances in the molecular pathogenesis of hypertrophic cardiomyopathy]. AB - Hypertrophic Cardiomyopathy (HCM) is a primary cardiac disorder characterized by asymmetric thickening of the septum and left ventricular wall. HCM affects 1 in 500 individuals in the general population, and it is the most common cause of sudden death in the young and athletes. The clinic phenotype of HCM is highly variable with respect to age at onset, degree of symptoms, and risk of sudden death. HCM is usually inherited as a Mendelian autosomal dominant trait. To date, over 900 mutations have been reported in HCM, which were mainly located in 13 genes encoding cardiac sarcomere protein, e.g., MYH7, MYBPC3, and TnT. In addition, more and more mitochondrial DNA mutations were reported to be associated with the pathogenesis of HCM. Based on the description of the clinical phenotype and morphological characteristics, this review focuses on the research in the molecular pathogenic mechanism of HCM and its recent advances. PMID- 21684860 TI - [Advances in relationship between gastric disease and polymorphisms in both Helicobacter pylori virulence factors and host genetics]. AB - Helicobacter pylori infection may cause many gastric disease, such as peptic ulcers, chronic atrophic gastritis, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer. The different clinical outcomes of Helicobacter pylori infection are related to H. pylori virulence factors and host gene polymorphism. H.pylori had been confirmed to be the class I carcinogen by the World Health Organization and International Agency for Research on Cancer Consensus Group (IARC) in1994. Most severe diseases always occur in the background that certain microbial virulence markers (e.g. cagA, vacA) and susceptible host genetic polymorphisms harboured together. Herein, we reviewed the association with H. pylori-related gastric diseases in relation to diffirent H. pylori types and the host polymorphisms. PMID- 21684861 TI - [Progress of phiC31 integrase system in site-specific integration]. AB - Integrase of phage fC31 catalyses the homologous recombination between Streptomyces attachment site attB and the phage attachment site attP. Meanwhile, this integrase can mediate integration of attB-containing donor plasmids into the pseudo attP sites in eukaryotic genomes by a site-specific manner and resulting long-term and robust expression of integrated genes. Nowadays, fC31 integrase system is becoming a potential tool for genome modification, gene therapy and transgenic research. Recent progress of fC31 integrase system in integration mode in mammalian genomes, efficiency improvement and researches concerned on transgenic safety were summarized in this review. PMID- 21684862 TI - [Structure, localizations and functions of chromosomal passenger complex]. AB - Chromosomal passenger complex (CPC) is mainly composed of a protein kinase Aurora B, inner centromere protein, Survivin, and Borealin. As in different periods of cell division, CPC can localise correctly to relavent destinations in time and interact on its different substrates in the mitotic cell. CPC modulats phosphorylation of histone H3 in chromatin aggregation and controlls cohesion or segregation of sister chromatids. It is involved in assembly of a mitotic spindle and its chromosomes catched. Moreover, CPC corrects attachment errors between kinetochore and microtuble and gives faithfuly chromosomal segregation and promoting cytokinesis. Here, the structure compenants, localization on chromosomal arms, inner centromere and central spindle, and functions in defferent posisions of CPC were briefly descriped. PMID- 21684863 TI - [Progress in research on plant graft-induced genetic variation]. AB - Inheritable variation induced by plant grafting is a universal phenomenon; however, its mechanism has always been a controversial subject. In recent years, research on horizontal transfer of genetic materials between stock and scion has made great progress. The latest studies have found that genetic information in grafted plants is transported through plasmodesma and phloem to modulate the growth and development of the scion plants. Furthermore, non-coding RNAs could induce epigenetic modification, which facilitates plants to adapt to the grafting caused stress. This article focuses on the review of recent advances in the induction and maintenance of the graft-induced genetic variation and could be helpful in thoroughly understanding the mechanism. PMID- 21684864 TI - [Progress on avirulence genes of the rice blast fungus Magnaporthe grisea]. AB - Rice blast, caused by the fungal pathogen Magnaporthe grisea, is one of the most devastating diseases of rice. The specific interaction between rice and M. grisea is an important model system for studying the host-pathogen interaction mechanisms. In this article, we summarized recent research progresses on avirulence genes, which are the most important effectors in M. grisea with the focus on chromosome mapping, cloning method, functional analysis, and evolution study of avirulence genes, and the possible hotspot of the research on avirulence genes in the future was also been discussed. This knowledge may shed a light on the molecular mechanism underlying avirulence genes function and the possible interaction relationship between the host and the pathogen. PMID- 21684865 TI - [Mitochondrial tRNAMet mutation in Chinese Han essential hypertensive individuals]. AB - The objective of the present study was to explore the relationship between mitochondrial tRNAMet mutation and development of essential hypertension in Chinese Han individuals. A total of 990 patients with essential hypertension were involved. The general data (sex, age, body mass index, onset age, and family history) and information on routine blood test, blood biochemical examination, and color Doppler echocardiography of these patients were collected. All subjects under-went venous blood drawing for seperating white blood cells and DNA extraction. Then, mitochondrial tRNAMet was amplified and sequenced after purification. The patients who carried the tRNAMet mutation were taken as the indicative cases and the controls were the patients with essential hypertension who did not carry the mutation. We performed a comparative analysis on the routine blood test, blood biochemical examination, color Doppler echocardiography, and other data between the indicative cases and control cases. Among the 990 essential hypertensive patients, there were 8 who carried the tRNAMet mutation, and 6 mutation sites were confirmed, including A4401G, C4410A, U4418C, A4435G, U4454C, and C4456U. Compared with the control cases, the indicative cases developed essential hypertension at earlier ages. The average levels of high density of lipoprotein cholesterol, left ventricular end diastolic diameter, stroke volume, and cardiac index were higher in the indicative cases than in the controls. While the average levels of hemoglobin and left ventricular ejection fraction were lower in the indicative cases than in the control cases. Among the 8 indicative cases, 5 had maternally inherited hyper-tension; one had paternally inherited hypertension; and two denied any family history of hypertension. These results indicated that the mitochondrial tRNAMet mutations might induce the changes in structure and function, which was involved in the progress of the essential hypertension by disturbing the blood metabolism, the steady-state of the blood cells, and the cardiac structure and function. PMID- 21684866 TI - [Variation of plasma INH B, ACT A and FSH concentrations during an estrus cycle in Dazu black goat and Sannen dairy goat]. AB - To study the relationship between the concentrations of INH B (Inhibin B), ACT A (Activin A), and FSH (Follicle stimulating hormone) in blood plasma and fecundity, Dazu black goat with high productivity and Sannen dairy goat with low productivity were used as experiment objects in this research. The concentrations of INH B, ACT A, and FSH in blood plasma were measured by enzyme-linked immunosorbent assay (ELISA) in order to study the secretion rule of INH B, ACT A, and FSH during an estrus cycle of two goat breeds. The results indicated that the secretion of FSH showed a positive correlation with ACT A and a negative correlation with INH B. The mean concentration of FSH in Dazu black goat was higher than that in Sanen dairy goat during a estrous cycle. However, during the time from obviously estrus to ovulation, the mean concentration of FSH in Dazu black goat was significantly higher than that in Sannen dairy goat (0.0171% of seeds on some maternal plants, despite equal opportunity to father seeds. The rank ordering of donors was consistent across the four females and across treatments, indicating that there was concordant nonrandom mating, a requirement for sexual selection. The most successful donor in all treatments also had the greatest pollen production per flower, and this trait may therefore be an important cause of the observed patterns. We infer that pollinator behavior and postpollination processes both contribute to the nonrandom mating observed in the field, and discuss the advantages of this new experimental approach. PMID- 21684880 TI - Associations between leaf structure, orientation, and sunlight exposure in five Western Australian communities. AB - Five plant communities in Western Australia, as well as selected desert and Rocky Mountain species of the western USA, were surveyed to evaluate associations among leaf structure, orientational properties, and the sunlight exposure and precipitation characteristic of each community. Selected leaf structural features have been associated previously with photosynthetic function and included shape, thickness, the ratio of thickness to width, stomatal distribution, leaf surface coloration, and the number and distribution of palisade cell layers. Decreases in annual precipitation (<4 to over 15 cm/yr) and increases in total daily sunlight (4.2 to 29.2 mol photons/m1) corresponded strongly to an increase in the percentage of species in a given community with more inclined (more inclined than +/- 45 degrees from horizontal) or thicker leaf mesophyll (>0.4 mm) leaves. Also, the percentage of species with a leaf thickness to width ratio >0.1, which were amphistomatous, or which had palisade cell layers beneath both leaf surfaces, increased from >20% in the highest rainfall and lowest sunlight community to >80% in the community with least rainfall but greatest sunlight exposure. Over 70% of the species in the most mesic, shaded community had lighter abaxial than adaxial leaf surfaces (leaf bicoloration). All of the above structural features were positively associated with a more inclined leaf orientation (r1 = 0.79), except for leaf bicoloration, which was negatively associated (r1 = 0.75). The ratio of adaxial to abaxial light was more strongly associated with leaf bicoloration (r1 = 0.83) and the presence of multiple adaxial and isobilateral palisade cell layers(r1 = 0.80) than with total incident sunlight on just the adaxial leaf surface (r1 = 0.69 and 0.73, respectively). These results provide field evidence that leaf orientation and structure may have evolved in concert to produce a photosynthetic symmetry in leaf structure in response to the amount of sunlight and other limiting factors of the community. This structural symmetry may serve fundamentally to regulate the distribution of both light and CO2 levels inside the leaf and, thus, increase photosynthetic CO2 uptake per unit leaf biomass. PMID- 21684881 TI - Leaf domatia and foliar mite abundance in broadleaf deciduous forest of north Asia. AB - Plant morphology may be shaped, in part, by the third trophic level. Leaf domatia, minute enclosures usually in vein axils on the leaf underside, may provide the basis for protective mutualism between plants and mites. Domatia are particularly frequent among species of trees, shrubs, and vines in the temperate broadleaf deciduous forests in north Asia where they may be important in determining the distribution and abundance of mites in the forest canopy. In lowland and montane broadleaf deciduous forests at Kwangn;akung and Chumbongsan in Korea, we found that approximately half of all woody species in all forest strata, including many dominant trees, have leaf domatia. Pooling across 24 plant species at the two sites, mites occupied a mode of 60% (range 20-100%) of domatia and used them for shelter, egg-laying, and development. On average, 70% of all active mites and 85% of mite eggs on leaves were found in domatia; over three quarters of these were potentially beneficial to their hosts. Further, mite abundance and reproduction (expressed as the proportion of mites at the egg stage) were significantly greater on leaves of species with domatia than those without domatia in both forests. Effects of domatia on mite abundance were significant only for predaceous and fungivorous mite taxa; herbivore numbers did not differ significantly between leaves of species with and without domatia. Comparable patterns in broadleaf deciduous forest in North America and other biogeographic regions suggest that the effect of leaf domatia on foliar mite abundance is general. These results are consistent with several predictions of mutualism between plants and mites, and indicate that protective mutualisms may be frequent in the temperate zone. PMID- 21684882 TI - The effects of seed size, cotyledon reserves, and herbivory on seedling survival and growth in Quercus rugosa and Q. laurina (Fagaceae). AB - In a greenhouse experiment, seedling survival of two oak species (Quercus rugosa and Q. laurina) was greatly affected by the excision of cotyledons 1 mo after germination, with a greater impact on Q. laurina. The effect of seed size was also significant for both species, with a positive correlation between seed mass and survival and growth. The effect of cotyledon excision on seedling growth persisted throughout the first growing season in Q. rugosa and was not analyzed for Q. laurina due to the low number of seedlings that survived cotyledon excision. Seed size significantly affected seedling height, diameter, leaf area, and biomass at 6 mo. Seed size and cotyledon retention affected the ability of Q. rugosa to recover from herbivory, as both factors had a significant effect on relative growth rates after aerial biomass removal. The results show that seedlings originating from large seeds can better endure loss of cotyledons and aerial biomass and thus are better equipped to confront stress early in their lives. PMID- 21684883 TI - Efficiency of insect capture by Sarracenia purpurea (Sarraceniaceae), the northern pitcher plant. AB - Pitcher plants (Sarracenia purpurea L.) attract insects to pitchers and then capture them in fluid-filled, pitfall traps, but how efficient are pitcher plants at capturing prey in their natural environment? We monitored insect activity by videotaping pitchers and analyzing videotapes for several variables including identity of each visitor and outcome of each visit (e.g., departure or capture). Efficiency of capture (i.e., number of captures per number of visits) was low. Overall efficiency of capture was 0.83-0.93%, depending on whether potential prey were broadly or narrowly defined. Ants constituted 74% of the potential prey. Efficiency of capture of ants was even lower at 0.37%. Potential prey were more likely to visit pitchers with greater red venation and less water in the pitcher. There was no correlation between number of potential prey visiting a pitcher and pitcher age, length, or mouth width. Also, number of potential prey visits did not correlate with plant size, air temperature, time of day or date of videotaping. While the overall efficiency of prey capture was very low, pitcher plants may still benefit from the additional nutrients. However, the relationship between ants and S. purpurea remains an enigma, since it is unclear whether the plants capture enough ants to compensate for nectar lost to ants. PMID- 21684884 TI - Collapse of morphological species in the wild potato Solanum brevicaule complex (Solanaceae: sect. Petota). AB - The major cultivated potato, Solanum tuberosum, and six other related cultivated species, are hypothesized to have arisen from a group of weedy relatives indigenous to the central Andes of central Peru, Bolivia, and northern Argentina. A major problem hindering investigations of the origins of the cultivated species has been a continuing debate over the species boundaries of their putative progenitors. This study investigated the morphological phenetic species boundaries of these putative progenitors and five cultivated taxa, here collectively referred to as the Solanum brevicaule complex. Two hundred fifteen accessions of 30 taxa in the S. brevicaule complex and 42 accessions of six taxa outside of the complex were assessed for 53 morphological traits in replicate plots in a common garden, resulting in a total of over 81;t3000 data points. Phenetic analyses of these data are unable to support 30 taxa, suggesting instead a single variable complex at best only weakly divided into three widely intergrading sets of populations: (1) Peruvian and geographically adjacent Bolivian accessions (including wild species and all the cultigens), (2) Bolivian and Argentinian accessions and S. verrucosum from Mexico (including only wild species), and (3) the Bolivian and Argentinian wild species S. oplocense. These and other data suggest that Hawkes's 1990 treatment (The Potato: Evolution, Biodiversity, and Genetic Resources, Smithsonian Institute Press, Washington, DC.) of 232 morphological species is an overestimate for sect. Petota. PMID- 21684885 TI - Allopolyploid origin and population genetics of the rare orchid Spiranthes diluvialis. AB - The process of becoming and the attributes of being polyploid play a major role in the development and maintenance of genetic variation in allopolyploid species. A genetic survey employing protein electrophoresis on 12 populations of S. diluvialis, as well as on populations of eight congeneric species, was conducted to assess the putative allopolyploid origin of S. diluvialis and to determine the genetic variability within and among populations. Genetic identity values indicated S. diluvialis was more similar to S. magnicamporum (0.619) and S. romanzoffiana (0.727) than to any of the other congeneric species assayed. Similar to most allopolyploids, S. diluvialis showed high levels of fixed, or nearly fixed, heterozygosity and a high percentage of polymorphic loci (57.1 71.4%). The mean number of alleles per polymorphic locus in populations of S. diluvialis (2.6-3.3), however, was similar to mean values for both animal pollinated, outcrossing, diploid species, and geographically restricted, diploid species (2.6 and 2.5, respectively). Genetic divergence among populations (mean Fst = 0.083) was low, leading to relatively high estimates of interpopulational gene flow (mean Nm = 5.41). Thus, each population harbors most of the genetic variability found within the species. The genetic variation observed within S. diluvialis supports the occurrence of at least two separate hybridization events giving rise to S. diluvialis. PMID- 21684886 TI - Phylogenetic relationships in the Crassulaceae inferred from chloroplast DNA restriction-site variation. AB - A restriction-site analysis of chloroplast DNA from 44 species, representing 19 genera and all six subfamilies of the Crassulaceae was conducted using 12 restriction endonucleases. A total of 969 variable sites was detected, 608 of which were phylogenetically informative and used in parsimony analysis. Estimated values of nucleotide sequence divergence were used to construct a distance tree by the neighbor-joining method. Maximum sequence divergence in the family was ~7%. Different tree inference methods yielded only moderately different topologies. The amount of support for the monophyletic groups obtained in the Wagner parsimony analysis was evaluated by bootstrap and decay analysis. There is very strong support for a basal division of the family, which separates the monophyletic subfamily Crassuloideae from all other taxa. Four of the six traditionally recognized subfamilies are indicated to be polyphyletic. These include the Cotyledonoideae, Sempervivoideae, Sedoideae, and Echeverioideae. The Kalanchoideae and the genera Cotyledon and Adromischus exhibit low levels of cpDNA sequence divergence relative to one another, suggesting a relatively recent radiation. The genera Sedum and Rosularia are indicated to be polyphyletic. Sedum comprises sister taxa of most of the other genera of the family. PMID- 21684887 TI - Molecular evidence for polyploid origins in Saxifraga (Saxifragaceae): the narrow arctic endemic S. svalbardensis and its widespread allies. AB - The recently described polyploid Saxifraga svalbardensis is endemic to the arctic archipelago of Svalbard. We investigated relationships among four closely related species of Saxifraga in Svalbard and tested three previously proposed hypotheses for the origin of S. svalbardensis: (1) differentiation from the morphologically and chromosomally variable polyploid S. cernua; (2) hybridization between the diploid S. hyperborea and S. cernua; and (3) hybridization between the tetraploid S. rivularis and S. cernua. Fifteen populations were analyzed using random amplified polymorphic DNAs (RAPDs) and nucleotide sequences of the chloroplast gene matK and the internal transcribed spacers (ITS) of nuclear ribosomal DNA (rDNA). RAPD and matK data suggest that S. svalbardensis has originated from a hybrid with S. rivularis as the maternal parent and S. cernua as the paternal parent, possibly a single time, whereas ITS data could not be used to discriminate among the hypotheses. The data also suggest that the diploid S. hyperborea is a progenitor of the tetraploid S. rivularis. The four populations examined of S. svalbardensis were virtually identical for RAPD and ITS markers, whereas S. cernua showed high levels of variation, suggesting that the latter polyploid either has formed recurrently or has undergone considerable differentiation since its origin. PMID- 21684888 TI - The quantitative response to cytokinin in the moss Funaria hygrometrica does not reflect differential sensitivity of initial target cells. AB - Exposure to sufficient cytokinin induces the formation of buds from responsive cells in the protonema of Funaria hygrometrica. Initial perception of the phytohormone results in a Ca+2 cascade within minutes. A second cytokinin mediated event occurs some days later, and converts incipient buds into stably committed buds. The concentration of exogenous cytokinin also regulates the total number of buds produced from a protonemal colony. This concentration-dependent production of buds has been thought to reflect differential sensitivity of target cells. Under that hypothesis, the regulation of bud number occurs during initial perception of hormone. This paper presents direct experimental evidence to the contrary and supports the alternate hypothesis that bud formation involves the gating of large numbers of responding cells by later events. Experiments transferring protonema between media with different levels of cytokinin show that the cytokinin concentration during the initial perception of cytokinin is unimportant in controlling bud number. Instead, bud number is found to be regulated by the concentration of exogenous cytokinin as incipient buds or bud initials become stably committed buds. PMID- 21684889 TI - Hormone transport and action in the green shoot:long-term studies of a clonal stock of Coleus blumei(Labiatae). AB - A decades-long study of hormone production, transport, developmentalactions, and hormonal interactions in the green shoots of mature plantshas exploited a clone of Coleus blumei. To obtain data bothquantitative and reproducible, we greatly increased sample size over theclassical anatomical models, initiated round-the clock collections, andcountered that increased workload by clearing and staining organs ratherthan by embedding and serially sectioning them. Major developmentalevents occurred at night. The control of the normal differentiation andregeneration of tracheary cells and sieve-tube members byindole-3-acetic acid (IAA) and cytokinins and of fibers by IAA andgibberellic acid have been major findings from this approach. IAA fromthe leaf blade controls the timing of leaf abscission. As the leafages, the ability of the petiole to transport IAA from the blade to theabscission zone declines, with abscisic acid (ABA) decreasing IAAtransport down the petiole and concomitantly increasing the conjugationof IAA with aspartic acid. Evidence for transport barriers was found atnodes and abscission zones. PMID- 21684890 TI - Evolution of interspersed repetitive elements inGossypium (Malvaceae). AB - Very little is known regarding how repetitive elements evolve inpolyploid organisms. Here we address this subject by fluorescent insitu hybridization (FISH) of 20 interspersed repetitive elements tometaphase chromosomes of the cotton AD-genome tetraploid Gossypiumhirsutum and its putative A- and D-genome diploid ancestors. Theseelements collectively represent an estimated 18% of the G.hirsutum genome, and constitute the majority of high-copyinterspersed repetitive elements in G. hirsutum. Seventeen ofthe elements yielded FISH signals on chromosomes of both G.hirsutum subgenomes, while three were A-subgenome specific. Hybridization of eight selected elements, two of which were A subgenomespecific, to the A(2) genome of G. arboreum yielded asignal distribution that was similar to that of the G. hirsutumA-subgenome. However, when hybridized to the D(5) genome ofG. raimondii, the putative diploid ancestor of the G.hirsutum D-subgenome, none of the probes, including elements thatstrongly hybridized to both G. hirsutum subgenomes, yieldeddetectable signal. The results suggest that the majority, although notall, G. hirsutum interspersed repetitive elements haveundergone intergenomic concerted evolution following polyploidizationand that this has involved colonization of the D-subgenome byA subgenome elements and/or replacement of D-subgenome elements byelements of the A subgenometype. PMID- 21684891 TI - Dioecy and the evolution of pollination systems inSchiedea and Alsinidendron (Caryophyllaceae:Alsinoideae) in the Hawaiian Islands. AB - The transition from biotic to wind pollination and the consequencesof this transition for the evolution of dioecious breeding systems wereinvestigated in Schiedea and Alsinidendron(Caryophyllaceae: Alsinoideae), genera endemic to the Hawaiian Islands. The potential for wind pollination was studied for five species ofSchiedea using a wind tunnel. Morphological correlates of windpollination for these species were then used to infer the presence orabsence of wind pollination in the remaining Schiedea species. Hermaphroditic Alsinidendron and Schiedea species,which occur in mesic to wet forests, or less commonly in dry habitats,show little or no indication of wind pollination. These species had lowpollen:ovule ratios, large relative pollen size, diffuse inflorescences,substantial nectar production in several cases, and appear to bebiotically pollinated or autogamous. Sexually dimorphic species, whichall occur in dry habitats, are wind pollinated, based on wind tunnelresults or morphological adaptations indicating the potential for windpollination. These adaptations include high pollen:ovule ratios, smallpollen size, moderately to highly condensed inflorescences, and reducednectaries and nectar production. Shifts to wind pollination anddimorphism are strongly correlated in Schiedea, suggesting theclose functional relationship of the twophenomena. PMID- 21684892 TI - Pollen donor performance can be consistent acrossmaternal plants in wild radish (Raphanus sativus,Brassicaceae): a necessary condition for the action of sexualselection. AB - The possibility that sexual selection has played a role in theevolution of plant reproductive characters remains interesting, butcontroversial. One reason is that clear demonstration of the necessaryconditions for sexual selection is lacking. For sexual selection tooccur, differences in pollen donor performance must be consistent acrossmaternal plants and not be due to mechanisms such asself incompatibility that produce interactions between maternal plantsand pollen donors. Here, I performed two experiments with wild radish totest whether differences in pollen donor performance are consistentacross maternal plants and not due to subtle effects of theincompatibility system. In the first, all maternal and paternal lineageshad different S-alleles. There were 16 maternal plants, four in each offour lineages and four pollen donors, one in each of four lineages. Rankorder of pollen donor performance, in terms of number of seeds siredafter mixed pollination, was highly consistent across maternal plantsand maternal lineages. In addition, maternal stress treatment had aneffect on mating success of pollen donors, but the effect was subtle anddid not affect the rank order of seeds sired by the four pollen donors.In the second experiment, pollinations were performed on both mature andimmature stigmas. Immature stigmas allowed some self seed set, so theincompatibility system was compromised. There was some nonrandom seedpaternity on both mature and immature stigmas. However, the amount ofnonrandom mating was less on immature stigmas. Taken together, theseexperiments show that the kind of consistent nonrandom mating necessaryfor sexual selection occurs in wild radish, but that the incompatibilitysystem and the mechanisms for sorting among compatible mates may overlapin time of development or in somepathways. PMID- 21684893 TI - The chaparral vegetation in Mexico undernonmediterranean climate: the convergence and Madrean-Tethyan hypothesesreconsidered. AB - A comparative study between an unburned evergreen sclerophyllousvegetation located in south-central Mexico under a wet-summer climate,with mediterranean regions was conducted in order to re-analyzevegetation and plant characters claimed to converge under mediterraneanclimates. The comparison considered floristic composition,plant-community structure, and plant characters as adaptations tomediterranean climates and analyzed them by means of a correspondenceanalysis, considering a tropical spiny shrubland as the external group.We made a species register of the number of species that resproutedafter a fire occurred in 1995 and a distribution map of the evergreensclerophyllous vegetation in Mexico (mexical) under nonmediterraneanclimates.The Tehuacan mexical does not differ from the evergreensclerophyllous areas of Chile, California, Australia, and theMediterranean Basin, according to a correspondence analysis, whichordinated the Tehuacan mexical closer to the mediterranean areasthan to the external group.All the vegetation and floristic characteristics of the mexical, aswell as its distribution along the rain-shadowed mountain parts ofMexico, support its origin in the Madrean-Tethyan hypothesis of Axelrod.Therefore, these results allow to expand the convergence paradigm of thechaparral under an integrative view, in which a general trend to ariditymight explain floristic and adaptive patterns detected in theseenvironments. PMID- 21684894 TI - Studies in Neotropical paleobotany. XI. Late Tertiaryvegetation and environments of southeastern Guatemala: palynofloras fromthe Mio-Pliocene Padre Miguel Group and the Pliocene HerreriaFormation. AB - Plant microfossils are reported from the late Tertiary Padre MiguelGroup and the Pliocene Herreria Formation of southeasternGuatemala. The most abundant palynomorphs are cf. Acrostichum(maximum 45%), Cyperaceae (29%), cf. Antrophyum(27%), monolete fern spores (16%), and Pinus(11%). Pollen grains of Picea, Juglans,Quercus, and Ulmus, primarily from the Padre Miguelflora, reveal the presence of a northern cool-temperate element. Theyounger Herreria flora is more lowland and warm temperate. Inthe absence of evidence for substantially higher elevations, thedifferences between the Neogene and modern vegetation are attributedmostly to climate. MAT (mean annual temperature) is estimated2 degrees 3 degrees C cooler than at present for the Padre Miguel flora,and ~3.5 degrees C warmer for the Herreria flora. There islittle evidence for arid vegetation, and the tropical rain forest wasabsent or poorly represented. These data are consistent with those ofother fossil floras in the region and with trends suggested by isotopicpaleotemperature analysis and global sea-level changes. The Guatemalaassemblages further provide evidence that the current version of thetropical rain forest is recent in origin and has undergone considerablechange in its range and composition throughout the lateCenozoic. PMID- 21684895 TI - Studies in Neotropical paleobotany. XII. A palynoflorafrom the Pliocene Rio Banano Formation of Costa Rica and the Neogenevegetation of Mesoamerica. AB - An assemblage of 17 identified and four unknown pollen and sporetypes is reported from the Pliocene Rio Banano Formation of southeasternCosta Rica. The most abundant are monolete fern spores, Palmae, cf.Antrophyum, Symphonia, Pelliceria,Lacmella (previously unreported in the fossil record),Alchornea, and Sabicea. These arrange into twopaleocommunities-mangroves and lowland tropical rain forest. Annual precipitation is estimated at near the present ~3500 mm, butless seasonal, and the MAT (mean annual temperature) at ~27 degrees C. No pollen taxa representing distinctly arid or high-altitude vegetationwas being blown or washed into the coastal depositional basin, and nopollen grains were recovered of northern temperate elements that arepresent in Neogene floras to the north in Guatemala and southeasternMexico. These data are consistent with those from 12 other Miocene andPliocene palynofloras from northern Latin America, indicating the lateappearance of dry habitats and moderate paleoelevations and aprogressive southward introduction of northern temperate elements withlate Cenozoic cooling. PMID- 21684896 TI - Molecular tests of the proposed diploid hybrid originof Gilia achilleifolia (Polemoniaceae). AB - Gilia achilleifolia is a putative diploid hybrid species. Hybrid origin was hypothesized based on traditional biosystematicevidence (i.e., morphological, cytological, and crossability data),which may be insufficient to establish genealogical history. Here,phylogenetic analysis of sequence data from the internal transcribedspacer (ITS) regions is used to examine the relationship between theputative hybrid species and its proposed parents. Isozyme variation isassayed to test for genetic additivity in the putative hybrid taxon andmorphological data are analyzed cladistically to evaluate the charactersthat led to the original hypothesis of hybrid origin. The ITS-basedgene tree placed G. achilleifolia in two divergent clades, eachsister to one of the putative parental lineages. Little isozymeadditivity was observed and G. achilleifolia possessed sixunique alleles among 42 alleles observed. However, ITS and isozymetrees differed in their placement of the two lineages of G.achilleifolia; both lineages are closer to a third putative parentin the isozyme tree. Also, G. achilleifolia is intermediate orpolymorphic for all nine morphological characteristics differentiatingthe parental species. Sorting of ancestral polymorphisms cannot easilyaccount for expression patterns of seven of these characters. In ourview, these results fail to distinguish between alternative hypothesesof ancient hybrid origin and divergent evolution, belying the difficultyof detecting ancient hybrids. PMID- 21684897 TI - Phylogenetic relationships in Asarum(Aristolochiaceae) based on morphology and ITSsequences. AB - A cladistic analysis of Asarum was conducted using data frommorphology and nuclear ribosomal internal transcribed spacer sequences(ITS) to examine the relationships among several groups of taxa thathave often been treated as segregate genera. Morphological andmolecular data were analyzed simultaneously for a set of 36 terminalsrepresenting the taxonomic, morphological, and geographic diversity ofthe genus. The two data sources are generally congruent and togetherprovide more resolution than either by itself. The data support twomain clades in the genus: an Asarum sensu stricto clade and anAsiasarum + Hexastylis +Heterotropa clade. The former consists of ~17 species andis distributed through North America, Europe, and Asia. Within thisgroup, the North American species are monophyletic and derived fromwithin the paraphyletic Asiatic species group. The Asiasarum+ Hexastylis + Heterotropa clade consists oftwo Asiatic segregates and the North American segregate,Hexastylis. Resolution within this group supports both themonophyly of Heterotropa and a sister group relationship ofAsiasarum to Hexastylis + Heterotropa. Hexastylis is paraphyletic and occurs as two separate clades onthe tree; one of these is sister to Heterotropa and the otheris sister to the latter plus Heterotropa. The phylogeneticdata provide several clues about the biogeographic history ofAsarum and suggest that: (1) the genus likely originated inAsia and underwent substantial diversification prior to colonizing NorthAmerica; and (2) Asarum in North America represents at leasttwo historically distinct groups that likely achieved their NorthAmerican distributions at different times. The results of theseanalyses support recognition of two subgenera, Asarum andHeterotropa, each with two sections: Asarum andGeotaenium of the former, and Asiasarum andHeterotropa of the latter. Asarum sect.Ceratasarum (Hexastylis) is here treated as a synonymof Asarum sect. Heterotropa. A taxonomic conspectusof the genus is provided, and the combination Asarum sect.Geotaenium (F. Maek.) L. Kelly is made in accordance with therevised circumscription oftaxa. PMID- 21684898 TI - Evidence for the hybrid origin of Nuphar xrubrodisca (Nymphaeaceae). AB - Plants intermediate in appearance between Nuphar microphyllaand N. variegata (Nymphaeaceae) have long been assumed to bethe result of hybridization. The evidence for this is based primarilyon field observations of morphology, poor fruit production, closegeographical proximity of presumed parent species, and limited pollensterility data. Fertile populations of the same plants have also beendocumented. We employed multivariate analyses of morphology, pollenfertility studies, and random amplified polymorphic DNA (RAPD) markersto test the hypothesis that Nuphar * rubrodiscarepresents a natural interspecific hybrid between N.microphylla and N. variegata. Examination of 15morphological characters demonstrated the intermediacy of N.* rubrodisca between N. microphylla and N.variegata, and the pollen data revealed a markedly lower meanpollen viability in N. * rubrodisca (23%)compared to the other two species (91 and 86%, respectively). Eight 10-mer primers produced 13 species-specific RAPD markers forN. microphylla and nine for N. variegata, with all 22markers present in N. * rubrodisca. The datafrom RAPDs are concordant with morphology in implicating N.microphylla and N. variegata as parents of N.*rubrodisca. PMID- 21684899 TI - Pollination biology in a lowland dipterocarp forest inSarawak, Malaysia. I. Characteristics of the plant-pollinator communityin a lowland dipterocarp forest. AB - Flowerings and flower visitors were observed continuously in alowland dipterocarp forest in Sarawak, Malaysia, for 53 mo in1992-1996. Flower visitors of 270 plant species were observed orcollected, and pollinators were assessed by observing body contact tostigmas and anthers. We recognized 12 categories of pollination systems.Among them, plants pollinated by social bees included the largest numberof species (32%) and were followed by beetle-pollinated species(20%). Pollination systems were significantly related with somefloral characters (flowering time of day, reward, and floral shape), butnot with floral color. Based on the relationships between pollinatorsand floral characters, we described pollination syndromes found in alowland dipterocarp forest. The dominance of social bees and beetlesamong pollinators is discussed in relation to the general floweringobserved in dipterocarp forests of West Malesia. In spite of high plantspecies diversity and consequent low population densities of lowlanddipterocarp forests, long-distance-specific pollinators were uncommoncompared with theNeotropics. PMID- 21684900 TI - Analysis of the four cox2 genes found in turnip (Brassica campestris, Brassicaceae) mitochondria. AB - In turnip mitochondria the cox2 gene is partially contained within a 2-kb (kilobase) direct repeat that is the site of homologous recombination events that generate subgenomic molecules. Because of its partial presence within the direct repeat, the turnip cox2 gene exists in four genomic contexts, two on the master chromosome and one on each of the subgenomic circles. In order to gain information on the expression of plant mitochondrial genes that exist in multiple genomic contexts and on plant mitochondrial recombination repeats in general we have characterized all four copies of the turnip 2-kb repeat and the cox2 gene. DNA sequence analysis indicates that the turnip high-frequency recombination repeat is 2424 bp in length. All but the last 58 bp of the cox2 gene is contained within the repeat, resulting in the presence of two intact cox2 genes and two pseudogenes. An intact cox2 gene and a pseudogene are found on the master chromosome (218 kb). An intact cox2 gene is also found on the 135-kb subgenomic circle, while a pseudogene is found on the 83-kb subgenomic circle. The turnip cox2 gene is unique because it lacks the first or 5' intron and contains the second or 3' intron previously found only in the carrot. The turnip intron is a group II intron that has high similarity (94.7%) with the second intron in carrot; also it is in precisely the same position within the gene. Transcript mapping studies using locus-specific probes reveal stable transcripts from the intact genes but not from the pseudogenes. PMID- 21684901 TI - Male-specific DNA in the dioecious species Atriplex garrettii (Chenopodiaceae). AB - The mechanism of sex determination in dioecious species of the genus Atriplex (Chenopodiaceae) has not been determined. This paper reports the discovery of a male-specific DNA fragment in the diploid dioecious species A. garrettii. DNA samples extracted individually from ten male and ten female plants were bulked by sex. Random amplified polymorphic DNA (RAPD) fragments were generated in the two bulks in order to identify markers that were polymorphic between male and female plants. A total of 158 decamer primers were tested. A 2075 base-pair (bp) male specific DNA fragment generated with the OPAF-14 primer was identified. The fragment was cloned and partially sequenced and 24-mer primers that exclusively amplified this fragment were constructed. When 124 male plants, 126 female plants, and one hermaphroditic plant were tested individually, the male-specific 2075-bp DNA fragment was present in the hermaphrodite and all but one of the male plants, and was absent in all female plants. A smaller DNA fragment (~1800 bp) that was homologous to the 2075-bp fragment was amplified from the single male plant that lacked the 2075-bp fragment. Cytogenetic analysis revealed no apparent heteromorphic sex chromosomes. These observations suggest that sex determination in A. garrettii is genetic, with no evidence of heteromorphic sex chromosomes. PMID- 21684902 TI - Genome size and numerical polymorphism for the B chromosome in races of maize (Zea mays ssp. mays, Poaceae). AB - Twenty-one native populations (1120 individuals) of maize from Northern Argentina were studied. These populations, which belong to 13 native races, were cultivated at different altitudes (80-3620 m). Nineteen of the populations analyzed showed B chromosome (Bs) numerical polymorphism. The frequency of individuals with Bs varied from 0 to 94%. The number of Bs per plant varied from 0 to 8 Bs, with the predominant doses being 0, 1, 2, and 3. Those populations with varying number of Bs showed a positive and statistically significant correlation of mean number of Bs with altitude. The DNA content, in plants without Bs (A-DNA)(2n = 20), of 17 populations of the 21 studied was determined. A 36% variation (5.0-6.8 pg) in A DNA content was found. A significant negative correlation between A-DNA content and altitude of cultivation and between A-DNA content and mean number of Bs was found. This indicates that there is a close interrelationship between the DNA content of A chromosomes and doses of Bs. These results suggest that there is a maximum limit to the mass of nuclear DNA so that Bs are tolerated as long as this maximum limit is not exceeded. PMID- 21684903 TI - The methionine-rich low-molecular-weight chloroplast heat-shock protein: evolutionary conservation and accumulation in relation to thermotolerance. AB - The evolutionary conservation of the low-molecular-weight chloroplast-localized heat-shock protein (LMW chlpHsp) in vascular plants was examined using immunological methods. An antibody (Abmet) specific to the LMW chlpHsp was produced using a synthetic 28-residue peptide containing the most conserved elements of its unique "methionine-rich domain" as an antigen. This antibody detected a heat-inducible low-molecular-weight chloroplast protein in plants of six divergent Anthophyta species, including C3, C4, CAM, monocot, and dicot species. Abmet also detected a LMW chlpHsp in species from the Divisions Psilotophyta, Equisetophyta, Polypodiophyta, and Ginkgophyta. A preliminary examination of the relationship between accumulation of the LMW chlpHsp and habitat was also conducted. Seven Anthophyta species originating from both warm- and cool-temperature habitats were grown at 28C and then heat stressed at 40C. A positive qualitative relationship between the accumulation of the LMW chlpHsp and organismal thermotolerance in these species was observed; similar results were obtained separately with four nonAnthophyta species. The strong evolutionary conservation of this LMW Hsp and its localization to the chloroplast, and the correlation between production of this protein and plant thermotolerance, suggest that the LMW chlpHsp plays an important role in adaptation to heat stress. PMID- 21684904 TI - Floral ontogeny in legume genera Petalostylis, Labichea, and Dialium (Caesalpinioideae: Cassieae), a series in floral reduction. AB - Floral ontogeny of taxa of two subtribes (Labicheinae, Dialiinae) of caesalpinioid tribe Cassieae, characterized by reduced number of floral organs, was compared. All three taxa studied are distichous; Petalostylis labicheoides flowers are solitary in leaf axils, Labichea lanceolata has few-flowered racemes, and Dialium guineense has numerous-flowered cymes. The first sepal primordium in each is initiated abaxially and nonmedianly. Order of organogenesis in Petalostylis is: five sepals bidirectionally, five petals and carpel simultaneously, then five stamens bidirectionally, starting abaxially. The order in Labichea is: five sepals helically (one lagging in time), five petals unidirectionally starting abaxially, the carpel and petals concurrently, then two stamens successively, starting laterally. Order in Dialium is: five sepals bidirectionally, the single petal adaxially, and lastly the carpel and two stamens concurrently. Specializations include (1) reduction of the five sepals to four by fusion in Petalostylis and Labichea; (2) reduction of petal number to one in Dialium; (3) reduction of stamen number to two in Labichea and Dialium, and reduction of functional stamens to three in Petalostylis; and (4) an elaborate, late-developing style in Petalostylis. Floral asymmetry, another specialization, characterizes Labichea, expressed by dissimilar stamens, while the other genera have zygomorphic flowers. Floral ontogenies are compared with other taxa of Cassieae. PMID- 21684905 TI - Effects of variation in flower number on pollinator visits in Cirsium purpuratum (Asteraceae). AB - We examined the functional relationships between floral display and two types of bumble bee response, the visitation rate per plant and the number of flowers visited on a plant, in an artificially arranged field population of Cirsium purpuratum. To reduce the variance in data, we collected data for each day separately and adopted a Latin square design in selecting the focal plants within a day. We then tested several types of regressions to each set of data to find the best-fitting line accounting for the observed relationship between pollinator response and display size. We found that the visitation rate of bumble bees per plant was a decelerating function of floral display, and that the number of flowering heads visited on a plant increased linearly with display size. Predicted from the above two functions, the visitation rate per head was independent of floral display and nearly constant within each day. Our results suggest that conventional methods in collecting and analyzing data on pollinator visitation may yield large variance in data derived from temporal and spatial heterogeneity and that improved methods employed here are effective in reducing the variance and estimating patterns of pollinator response to floral display more accurately. PMID- 21684906 TI - Floral sex ratios and gynomonoecy in Aster (Asteraceae). AB - Gynomonoecy is the sexual system in which female and bisexual flowers occur on the same plant. This system has received little attention despite the considerable work on other plant sexual systems in the past few decades. Our study examines one hypothesized advantage of having two flower types on a plant, namely that this arrangement permits flexibility in allocation of resources to male and female reproductive functions. We examined 16 species of Aster (Asteraceae), a genus of gynomonoecious, perennial herbs. Plants in this genus produce heads consisting of a whorl of female flowers around a cluster of bisexual flowers. Among field-grown plants we found no evidence that plant size, date, position of heads, rainfall, or shade influenced the proportion of female flowers. A series of greenhouse experiments likewise revealed no large or consistent effects of light, nutrients, or position of heads on the proportion of ray flowers. While floral ratios proved very stable in the face of environmental and physiological variables, they exhibited significant variation among plants and among sibships in most species. We conclude that the presence of two flower types in gynomonoecious asters is not advantageous in permitting flexibility in allocation of resources to male and female functions. We believe that the advantage of the female flowers in aster heads lies either in reducing pollen pistil interference or in attracting pollinators. PMID- 21684907 TI - Sex differential nectar secretion in protandrous Alstroemeria aurea (Alstroemeriaceae): is production altered by pollen removal and receipt? AB - We examined diurnal and nocturnal nectar secretion across sexual stages in protandrous Alstroemeria aurea, a bumble bee-pollinated herb with long-lived flowers native to the southern Andes. We found the following patterns: (1) most nectar was produced diurnally and (2) three times more sugar was secreted during the male than female phase, not only because the male phase lasted longer but also because the rate of nectar production was higher. This 3:1 ratio in nectar production matched the ratio of the minimum number of bumble bee visits required on average to saturate male (pollen removal) vs. female (seed set) functions. Standing crop of nectar, on the other hand, did not differ greatly between male- and female- stage flowers left open to visitors, because the high-production male phase flowers were visited more frequently than female- phase flowers. In an experiment concurrent with the repeated nectar sampling of individual flowers over their life-span, we removed pollen from anthers or deposited pollen on stigmas by hand. Neither treatment, designed to mimic effects of visits by Alstroemeria's native bumble bee pollinator, affected nectar production. The absence of plasticity in nectar secretion in relation to pollination events may reflect a low cost of nectar production, or may result from developmental constraints related to the evolution of the synchronous protandry that characterizes A. aurea. PMID- 21684908 TI - Heritable variation in stomatal responses to elevated CO2 in wild radish, Raphanus raphanistrum (Brassicaceae). AB - Rising atmospheric carbon dioxide may affect plant populations in the short term through effects on photosynthesis and carbon allocation, and over the long term as an agent of natural selection. To test for heritable effects of elevated CO2 on stomatal responses and plant fecundity in Raphanus raphanistrum, we grew plants from 12 paternal families in outdoor open-top chambers at ambient (35 Pa) or elevated (67 Pa) CO2. Contrary to results from a previous study of this species, total flower and fruit production were marginally lower under elevated CO2. Across families, stomatal index and guard cell length showed little response to CO2 enrichment, but these characters varied significantly among paternal families in both the direction and magnitude of their response to changing CO2. Although these family-by-CO2 interactions suggest that natural selection might affect stomatal characters when ambient CO2 levels increase, we found no significant correlation between either character and flower or fruit production. Therefore, our data suggest that while heritable variation for stomatal index and guard cell length exists in this population, selection due to increasing CO2 is not likely to act on these traits because they had no detectable effect on lifetime fecundity. PMID- 21684909 TI - Nickel hyperaccumulation by Thlaspi montanum var. montanum (Brassicaceae): a constitutive trait. AB - Adaptations to particular stresses may occur only in populations experiencing those stresses or may be widespread within a species. Nickel hyperaccumulation is viewed as an adaptation to high-Ni (serpentine) soils, but few studies have determined if hyperaccumulation ability is restricted to populations from high-Ni soils or if it is a constitutive trait found in populations on both high- and low Ni soils. We compared mineral element concentrations of Thlaspi montanum var. montanum plants grown on normal and high-Ni greenhouse soils to address this question. Seed sources were from four populations (two serpentine, two non serpentine) in Oregon and northern California, USA. Plants from all populations were able to hyperaccumulate Ni, showing Ni hyperaccumulation to be a constitutive trait in this species. Populations differed in their ability to extract some elements (e.g., Ca, Mg, P) from greenhouse soils. We noted a negative correlation between tissue concentrations of Ni and Zn. We suggest that the ability to hyperaccumulate Ni has adaptive value to populations growing on non- serpentine soil. This adaptive value may be a consequence of metal-based plant defense against herbivores/pathogens, metal- based interference against neighboring plant species, or an efficient nutrient scavenging system. We suggest that the Ni hyperaccumulation ability of T. montanum var. montanum may be an inadvertent consequence of an efficient nutrient (possibly Zn or Ca) uptake system. PMID- 21684910 TI - Ontogenetic changes in size, allometry, and mechanical design of tropical rain forest trees. AB - Size, allometry, and mechanical design were measured for trees of three canopy species in a tropical rain forest in French Guiana. Mechanical design was expressed as the safety factor, using the elastic-stability model, and the wind resistance factor, using the constant-stress model. Changes with ontogeny were described as regressions using stem diameter as the independent variable, and they were compared between species. Height, crown size, and the wind resistance factor increased with ontogeny. The safety factor decreased to a minimum and then increased continuously in thicker trees. The crown width/height ratio did not change with ontogeny. Interspecific differences in allometry and mechanical design were related to the adult stature of the species, and not to shade tolerance. The short stature species (Vouacapoua americana) was less slender (height:DBH [stem diameter at 1.3 m] ratio) and had a higher crown width/height ratio than the tall stature species (Goupia glabra and Dicorynia guianensis). Vouacapoua had a higher safety factor, but a similar wind resistance factor. The safety factors of our study species were lower than those of two temperate tree species because of a higher slenderness. Differences in safety factors between tropical and temperate trees may result from unrealistic assumptions of the elastic-stability model, and may also be related to lower light levels and-or wind rates in the tropics. PMID- 21684911 TI - Degradation of the upper pulvinus in modern and fossil leaves of Cercis (Fabaceae). AB - Identification of fossil leaf impressions as Cercis has been questioned based upon the presence or absence of a pulvinus at the base of the lamina (upper pulvinus). In the present study, leaves of Cercis canadensis were examined before and after abscission to explore the degradation processes that could occur prior to fossilization, and the North American record for fossil foliage of Cercis was revised accordingly. Results for C. canadensis indicate that: (1) the pulvinus consists largely of tissues with nonlignified cells (a wide cortex, a nonlignified fiber sheath, phloem, and pith) that degrade rapidly after leaf abscission, (2) the lignified xylem tissue that remains in the pulvinus after degradation is in brittle strands, (3) the pulvinus degrades at a faster rate than the lamina or the petiole, and (4) the degraded pulvinus cushion leaves a semicircular pattern on the lamina. From examination of fossils as well as extant species, we: (1) demonstrated that in fossils, the upper pulvinus can show a greater degree of degradation than the adjoining petiole or lamina tissue, suggesting the degradation of upper pulvinus tissue is similar in modern vs. fossil specimens, (2) defined numerous other laminar characters that can be used in conjunction with, or in the absence of, an upper pulvinus to confirm the presence of Cercis in the fossil record, and (3) showed from those criteria that the earliest known North American fossil leaf record for Cercis, from a specimen newly reported in the present study, is from the middle Miocene Succor Creek flora of Oregon. PMID- 21684912 TI - Phylogenetic relationships of Cornaceae and close relatives inferred from matK and rbcL sequences. AB - Phylogenetic relationships were inferred using nucleotide sequences of the chloroplast gene matK for members of Cornales, a well-supported monophyletic group comprising Cornaceae and close relatives. The shortest trees resulting from this analysis were highly concordant with those based on previous phylogenetic analysis of rbcL sequences. Analysis of a combined matK and rbcL sequence data set (a total of 2652 bp [base pairs]) provided greater resolution of relationships and higher internal support for clades compared to the individual data sets. Four major clades (most inclusive monophyletic groups) of Cornales are indicated by both sets of genes: (1) Cornus-Alangium, (2) nyssoids (Nyssa-Davidia Camptotheca)- mastixioids (Mastixia, Diplopanax), (3) Curtisia, and (4) Hydrangeaceae-Loasaceae. The combined evidence indicates that clades 2 and 3 are sisters, with clade 4 sister to the remainder of Cornales. These relationships are also supported by other lines of evidence, including synapomorphies in fruit and pollen morphology and gynoecial vasculature. Comparisons of matK and rbcL sequences based on one of the most parsimonious rbcL-matK trees indicate that matK has a much higher A-T content (66.9% in matK vs. 55.8% in rbcL) and a lower transition:transversion ratio (1.23 in matK vs. 2.21 in rbcL). The total number of nucleotide substitutions per site for matK is 2.1 times that of rbcL in Cornales. These findings are similar to recent comparisons of matK and rbcL in other dicots. Variable sites of matK are almost evenly distributed among the three codon positions (1.0:1.0:1.3), whereas variable sites of rbcL are mostly at the third position (1.8:1.0 :7.5). Among- lineages rates of nucleotide substitutions in rbcL are basically homogeneous throughout Cornales, but are more heterogeneous in matK. PMID- 21684913 TI - Clonal analysis of leaf development in cotton. AB - Clonal analysis has been used to describe the cellular parameters of leaf development in American Pima cotton (Gossypium barbadense). Sectors (clones) induced before leaf initiation indicate that the leaf primordium arises from ~100 cells on the flank of the shoot meristem. An analysis of sector frequency during the period of leaf expansion suggests that the rate of cell division is fairly uniform throughout the length of the leaf, but is lower at the margin of the lamina than in intercalary regions. The shapes of marginal sectors indicate that the orientation of cell division (as defined by the orientation of the new cell wall) in this region is more often parallel to the margin than perpendicular to it, although the degree of polarization varies along the length of the margin. There is a slight gradient in the duration of cell division along the length of of the lamina late in development, with cell division ceasing progressively from the lamina tip to the base over two cell cycles. The parameters of cell division in cotton are therefore similar to those described for tobacco with the notable exception of the behavior of cells at the leaf margin. PMID- 21684914 TI - The OKRA leaf shape mutation in cotton is active in all cell layers of the leaf. AB - Okra (L2O) is a semidominant mutation of cotton (Gossypium barbadense) that alters leaf shape by increasing the length of lobes and decreasing lamina expansion. Chimeras containing L2O and wild-type tissue were generated using Semigamy (Se), a mutation that blocks syngamy during fertilization and produces haploid maternal/paternal chimeral progeny at low frequency. In sectorial chimeras, changes in leaf morphology coincide with the boundary between mutant and wild-type tissues, suggesting that L2O does not regulate a laterally diffusible factor within the leaf. However, in mericlinal or periclinal chimeras, the presence of L2O in tissue derived from any of the three histogenic layers (L1, L2, or L3) of the shoot apical meristem produced leaves with a partial mutant phenotype. The presence of L2O in the epidermis (an L1 derivative), or in the subepidermal mesophyll of the leaf (L2 derivatives) reduced the growth of the lamina and thus increased the depth of leaf lobes. The presence of L2O in the middle mesophyll of the lamina and the vasculature of major lateral veins (L3 derivatives) had no local effect on the expansion of the lamina, but significantly increased lobe length. These results demonstrate that L2O is active in every tissue layer of the leaf. PMID- 21684915 TI - Paternally biased cpDNA inheritance in Turnera ulmifolia (Turneraceae). AB - We end-labeled Hin fI restriction digests of a PCR-amplified plastid encoded gene, the large subunit of ribulose bisphosphate carboxylase, to investigate patterns of cpDNA inheritance in Turnera ulmifolia. A total of 70 progeny from crosses among plants taken from ten populations revealed varying patterns of inheritance. A majority of progeny inherited the paternal cpDNA (64%), while 19% exhibited maternal and 17% biparental inheritance. Eight variegated progeny showed biparental inheritance and were analyzed in greater detail. We extracted and analyzed the cpDNA content of light- vs. dark- green leaf sectors from these plants. The results showed that vegetative segregation of cpDNA had occurred for seven of the eight plants. PMID- 21684916 TI - Pollinator preferences and the persistence of crop genes in wild radish populations (Raphanus raphanistrum, Brassicaceae). AB - Crop-weed hybridization can potentially influence the evolutionary ecology of wild populations. Many crops are known to hybridize with wild relatives, but few studies have looked at the long-term persistence of crop genes in the wild. This study investigated one factor in the hybridization process in radish: differential pollinator visitation to wild radish (Raphanus raphanistrum) vs. crop-wild F1 hybrids (R. sativus x R. raphanistrum). Wild genotypes had yellow flowers, a recessive single-locus trait, whereas hybrids always had white or pale pink flowers. In experimental arrays in northern Michigan, total pollinator visitation was significantly biased toward wild plants when the frequencies of wild and hybrid plants were equal. Syrphid flies, the most frequent visitors, preferred wild plants while bumble bees showed no preference. This pattern was also observed when hybrid plants were overrepresented in the array (12 hybrid:2 wild). In contrast, when hybrid plants were rare (2 hybrid:12 wild), neither morph was preferred by any pollinator group. Later in the summer, pollinators were also observed in a large experimental garden with nearly equal frequencies of wild and hybrid plants. Cabbage butterflies (Pieris rapae) strongly overvisited wild plants, while bumble bees showed a slight preference for hybrids. Taken together, these studies suggest that F1 hybrids may not be at a disadvantage with regard to pollinator visits when they occur at low frequencies or when bumble bees are frequent flower visitors. Thus, variation in the proportion of white-flowered morphs among wild radish populations could be influenced by different histories of crop-to-wild hybridization, as well as by variation in the composition of local pollinator taxa. PMID- 21684917 TI - Genetic diversity and population structure of Yucca filamentosa (Agavaceae). AB - Using 19 allozyme loci we studied genetic diversity in 18 populations of Yucca filamentosa (Agavaceae) from the southeastern United States. Of the 19 loci surveyed, 17 (89.5%) were polymorphic in at least one of the populations sampled. There was considerable variation among populations in the percentage of polymorphic loci (range = 31.6-84.2%, mean = 67.6%). Similar heterogeneity among populations was observed for mean number of alleles per polymorphic locus (range = 2.0-3.0; mean = 2.48) and mean expected heterozygosity (range = 0.113-0.288; mean = 0.213). On average, 83% of the total genetic diversity was found within populations. Duplications of three allozyme loci were detected in several populations. The life-history characteristics of Y. filamentosa (a long-lived, semiwoody, predominantly outcrossing monocot with a large geographical range) may contribute to the maintenance of such high levels of genetic diversity. These results contradict expectations of the genetic structure of Y. filamentosa based on observations of the dispersal and pollination behavior of its sole pollinator, Tegeticula yuccasella, the yucca moth. PMID- 21684918 TI - Reproduction and development of the endangered Sedum integrifolium ssp. leedyi (Crassulaceae). AB - Information on reproduction and life history is important for the conservation of endangered plants. We investigated rates of flowering, seed set, and germination in populations of the endangered perennial plant Sedum integrifolium ssp. leedyi. Germination and flowering rates differed significantly among populations, but seed set rate did not. We assayed 26 plant clusters (81 stems) from four of the five known populations for evidence of clonal reproduction using 28 randomly amplified polymorphic DNA (RAPD) markers. Of the 81 stems, 75 had unique genotypes and three pairs had identical genotypes, suggesting that clonal reproduction is infrequent. Flowering, seed set, and germination rates were correlated with our estimates of ratios of effective to actual population sizes (Ne/N), but not with Ne. The single formally protected population may be experiencing inbreeding depression. We grew plants from seed to maturity in a greenhouse, with a germination rate of 77% and survival of 98% of the germinants at 6 mo, suggesting that this will be a viable means of ex situ propagation. Plants flowered 4-6 mo after germination and produced mature fruits 1-2 mo later, suggesting that they have the potential to sexually reproduce in their first or second season of growth. PMID- 21684919 TI - Patterns and consequences of self-pollen deposition on stigmas in heterostylous Persicaria japonica (Polygonaceae). AB - In order to test the "anti-interference" hypothesis for adaptive significance of reciprocal herkogamy, patterns of illegitimate pollination and effects of self pollen on the legitimate pollination and fertility were investigated in a naturally pollinated experimental population of distylous Persicaria japonica. Pollen deposition was compared among the emasculation treatments, i.e., emasculation of a single flower from individual inflorescences, emasculation of all the flowers of individual inflorescences, and no emasculation control. In both morphs, considerable illegitimate pollination was found to occur in all the treatments, and there was no significant difference in incompatible pollen load among the treatments. Therefore, it is suggested that herkogamy of P. japonica can sufficiently reduce both intraflower and intra-inflorescence self pollinations, but not interinflorescence geitonogamous and-or interclonal illegitimate pollination. Measurements of pollen load after the repetitive pollen addition showed that space on the stigma surface may not limit the legitimate pollination under natural pollination conditions. Seed sets after legitimate pollination following prior self-pollination did not differ from the controls without self-pollination. Therefore, there is little possibility that incompatible pollen load interferes with either pollination or fertilization by compatible pollen, suggesting that "anti-interference" is unimportant for adaptive significance of reciprocal herkogamy at least in P. japonica. PMID- 21684920 TI - Susceptibility of pollen to UV-B radiation: an assay of 34 taxa. AB - Much of the ultraviolet-B radiation (UV-B) research on plants has concentrated on vegetative plant parts, and only a small fraction has dealt with the reproductive system. The present study analyzed pollen grains of 34 taxa germinated and grown under two levels of UV-B radiation (187 and 460 mW/m2) or no UV-B (control group). Visible radiation at 260 mmol/m/s was present in all treatments. Taxa included those with binucleate and trinucleate pollen types. We detected differences among species. A significant reduction in pollen germination occurred in only five species. Pollen tubes of >50% of the species showed significant reduction in length. Trinucleate pollen types were more likely to exhibit tube length reduction than the binucleate types. Proportionately more monocotyledonous species were sensitive to UV-B treatment than dicotyledonous species, and proportionately more wild species were sensitive than cultivated species and pollen collected from plants growing in the field were somewhat more sensitive than pollen collected from plants grown in the greenhouse. Species in which pollination occurred earlier in the season were more likely to be susceptible to UV-B radiation than those for which anthesis took place later in the season, suggesting a possible adaptation to UV-B radiation. PMID- 21684921 TI - The role of mycorrhizal fungi and microsites in primary succession on Mount St. Helens. AB - This study was designed to examine the role of vesicular-arbuscular mycorrhizae (VAM) and microsites on the growth of pioneer species. Flat, rill, near-rock, and dead lupine microsites were created in plots in barren areas of the Pumice Plain of Mount St. Helens. VAM propagules were added to the soil in half of the plots. Six pioneer species were planted into both VAM and non-VAM inoculated microsites. Plants in dead lupine microsites were greater in biomass than those in flat, rill, and near-rock microsites. Significant effects of VAM on plant biomass did not occur. Microsites continue to be important to plant colonization on the Pumice Plain, but VAM do not yet appear to play an important role. This may be due to limited nutrient availability and the facultatively mycotrophic nature of the colonizing plant species. It is unlikely that VAM play an important role in successional processes in newly emplaced nutrient-poor surfaces. PMID- 21684922 TI - Tylerianthus crossmanensis gen. et sp. nov. (aff. Hydrangeaceae) from the Upper Cretaceous of New Jersey. AB - A fossil flower with affinities to the modern families of the saxifragalean complex is described. Fossils were collected at Old Crossman Pit, Raritan Formation, New Jersey, USA. These sediments are dated on the basis of palynology as Turonian (Upper Cretaceous, ~90 million years before present). Fossils are charcoalified and preserved with exceptional three- dimensional detail. The characters observed in these flowers, when compared with those of extant flowers of several families of the saxifragalean complex, suggest a close relationship with extant members of the Saxifragaceae and Hydrangeaceae. Hypotheses on the origin of petals and staminodes and a possible mechanism of pollination are discussed. This new taxon provides additional characters in the floral morphology of the fossil saxifragoids and extends their geographical distribution in the Cretaceous to North America. PMID- 21684923 TI - Chloroplast DNA characters, phylogeny, and classification of Lathyrus (Fabaceae). AB - Mapped cpDNA restriction site characters were analyzed cladistically and the resulting phylogenetic hypotheses were used to test monophyly and relationships of the infrageneric classification of Lathyrus (Fabaceae) proposed by Kupicha (1983, Notes from the Royal Botanic Garden Edinburgh 41: 209-244). The validity of previously proposed classification systems and questions presented by these classification schemes were explored. Two cpDNA regions, rpoC (rpoC1, its intron, part of rpoC2, and their intergenic spacer) and IR- (psbA, trnH-GUG, part of ndhF, and their intergenic spacers), were analyzed for 42 Lathyrus and two Vicia species. PCR (polymerase chain reaction) amplified rpoC and IR- products digested with 31 and 27 restriction endonucleases, respectively, resulted in 109 potentially informative characters. The strict consensus tree suggests that several of Kupicha's sections may be combined in order to constitute clades. The widespread section Orobus and the South American section Notolathyrus should be combined. Section Lathyrus, characterized by a twisted style, should either include sections Orobon and Orobastrum or be redefined as three sections, one of which is characterized by a 100 base pair deletion in the IR- region. Finally, a weighted parsimony analysis positions sections Clymenum (excluding L. gloeospermus) and Nissolia, both with phyllodic leaves, as sister sections. The affiliation of Lathyrus gloeospermus (section Clymenum) remains problematic. PMID- 21684924 TI - Phylogeny and radiation of pollination systems in DISA (Orchidaceae). AB - We studied the patterns of adaptive radiation in Disa, a large orchid genus in southern Africa. A cladogram for 27 species was constructed using 44 morphological characters. Pollination systems were then mapped onto the phylogeny in order to analyze pathways of floral evolution. Shifts from one pollination system to another have been a major feature of the evolutionary diversification of Disa. Unlike many plant genera that are pollinated mainly by a single group of insects, radiation in Disa has encompassed nearly all major groups of pollinating insects; in all, 19 different specialized pollination systems have been found in the 27 species included in this analysis. Another striking pattern is the repeated evolution of broadly similar pollination systems in unrelated clades. For example, butterfly-pollinated flowers have evolved twice; showy deceptive flowers pollinated by carpenter bees, twice; long-spurred flowers pollinated by long-tongued flies, four times; night-scented flowers pollinated by moths, three times; and self-pollination, three times. This suggests that a few dominant pollinator species in a region may be sufficient to generate diversification in plants through repeated floral shifts that never retrace the same pathways. PMID- 21684925 TI - Morphological, geographical, and ecological differentiation in the Carex willdenowii complex (Cyperaceae). AB - Field studies as well as principal components analysis and analyses of variance of specimen measurements revealed morphologic variation within Carex willdenowii correlated with differences in geographical distribution and habitat characteristics. C. willdenowii is actually a complex of three species, C. basiantha Steudel, C. willdenowii Willdenow, and C. superata Naczi, Reznicek, & B.A. Ford, sp. nov. Carex basiantha is a calciphile of moist forests in the southern United States. It has relatively long culms and terminal spikes with long staminate portions. Carex willdenowii is a calcifuge of dry forests in the northeastern United States and immediately adjacent Canada. It has relatively long culms and terminal spikes with short staminate portions. Carex superata is a facultative calciphile of moist to dry forests of the southeastern United States. It has relatively short culms and terminal spikes with long staminate portions. Synonymies, typifications, descriptions, and citations of representative specimens are provided for each species, along with an identification key. The recognition of previously unsuspected diversity in a species from a region with a relatively well-known flora suggests the systematics of other common, widespread, and morphologically divergent species should be investigated. PMID- 21684926 TI - Xylem feeding by spittlebug nymphs: some observations by optical and cryo scanning electron microscopy. AB - The feeding of spittlebug nymphs (Philaenus spumarius) from mature xylem vessels was studied by optical and cryo-analytical scanning electron microscopy. Feeding did not produce xylem embolisms and vessels remained liquid-filled during the day. Saliva secreted by the insect forms a hardened lining (salivary sheath) between the stylet bundle and the plant tissues. This sheath is continuous through the hole made by the stylets as they enter a vessel, and it extends into the vessel and along its periphery beyond the breach. The sheath is heterogeneous, with a thin outer layer adjoining the plant tissues and a thicker layer that contacts the stylet bundle. Both layers give positive histochemical reactions for proteins and, in fresh tissues, contain a red, strongly autofluorescent pigment, possibly condensed tannin derived from the plant (which is lost during tissue preparation), and other phenyl propanoid compounds, which are retained and which may produce the intense reaction of the periodic-acid Schiff's-positive inner layer. It is concluded that the salivary sheath allows the insects to feed from functioning vessels without embolizing them or losing xylem fluid to the surrounding tissues. These findings and others in the entomological literature indicate low daytime tensions in the xylem conduits of the host plants. PMID- 21684927 TI - Variation of silica bodies in leaf epidermal long cells within and among seventeen species of Oryza (Poaceae). AB - Morphometric procedures were used with scanning electron microscopy backscattered images to study silica bodies in epidermal long cells of four different leaf veins of 17 of the 20 species of Oryza. The veins studied were midrib, large vein, small vein, and marginal vein. Image analysis was used to study morphological variations among the silica bodies. Statistical analyses were based on 11 variables. Even within a single leaf, silica bodies were not uniform. However, the degree of morphological variation normally showed a distribution of morpholgical types around one modal shape. The most significant differences observed were between silica bodies of the midrib and those of other veins. Bodies varied with respect to both size and shape. Computer-assisted image analysis is an effective tool for categorizing basic data and for statistical analysis of variation among silica bodies. Morphological variation among silica bodies of a single leaf may be related to water-conducting systems and their influence on silica availability and phytolith formation. PMID- 21684928 TI - The colorless flavonoids of Arabidopsis thaliana (Brassicaceae). I. A model system to study the orthodihydroxy structure. AB - The orthodihydroxy structure may mediate flavonoid coloration or antioxidant activity, making it of interest to floral or health food industries, respectively. In the first of two companion papers, the authors demonstrate a model system to study the orthodihydroxy structure in colorless flavonoids of Arabidopsis, with tools similar to those used upon the colored flavonoids. The system includes a fluorescent staining procedure to visualize colorless orthodihydroxy flavonoids at a subcellular level and to screen seedlings for rare genetic recombinants. The system also includes mutant lines to study the synthesis of colorless orthodihydroxy flavonoids, their potential role as antioxidants, and their potential risk as oxidative mutagens. PMID- 21684929 TI - The colorless flavonoids of Arabidopsis thaliana (Brassicaceae). II. Flavonoid 3' hydroxylation and lipid peroxidation. AB - The 3' hydroxylation of kaempferol forms quercetin with an orthodihydroxy structure having two neighboring hydroxyl groups that could theoretically chelate with metal ions and mediate oxidative phenomena. Colorless flavonoids were purified by high pressure liquid chromatography (HPLC) and screened by diode array analysis. The accumulation of quercetin derivatives in Arabidopsis was coordinately regulated with flavonoid biosynthesis in a chalcone isomerase mutant having reduced flux through the biosynthetic pathway, but not within differing wild-type tissues, where seedling, floral, and leaf tissue have a reduced ratio of quercetin to kaempferol derivatives, respectively. The accumulation of lipid peroxidation products in kaempferol proficient mutant seedlings was indistinguishable from that in quercetin proficient wild-type seedlings, leaving no evidence for the role of quercetin antioxidants. However, laser scanning confocal microscopy revealed quercetin derivatives lining the tonoplast of diphenylboric acid 2-aminoethyl ester-stained Arabidopsis seedling tissue and floral papillae, and Norfluorazon induced oxidative stress decreased the most lipophilic of HPLC purified quercetin derivatives. Its potential involvement with lipophyllic oxidative phenomena may warrant further study. PMID- 21684930 TI - Lax midrib1-O, a systemic, heterochronic mutant of maize. AB - Lxm1-O, a dominant EMS (ethyl methanesulfonate) induced mutation in maize (Zea mays, Poaceae), was originally reported to affect the blade/sheath boundary over the midrib region of the leaf. Here we present a more extensive analysis of the Lxm phenotype in nine different inbred lines. Lxm leaves are longer and narrower, and can initiate ectopic leaves. Additionally, Lxm1-O affects all plant organs observed. Compared to wild-type siblings, Lxm plants have fewer nodes, basal displacement of reproductive structures, and advance more quickly to the reproductive phase. We address questions as to whether Lxm1-O abbreviates a specific developmental phase, using hair, wax, and ear node data. We found that each phase was affected, although to varying degrees, depending on the inbred line. We interpret Lxm1-O to be a heterochronic mutation, causing the developmental acceleration of each phase of the shoot. Lxm1-O is novel, since other systemic heterochronic maize mutants prolong the juvenile phase, thereby extending shoot development. We discuss the importance of heterochronic mutations in the context of morphological evolution. PMID- 21684931 TI - Development of protein bodies and accumulation of carbohydrates in a soybean (Leguminosae) shriveled seed mutant. AB - The soybean seed mutant T311, when grown under specific environmental conditions, produces shriveled seed. This research investigated changes in development of protein bodies and accumulation of carbohydrates during seed development by comparing the mutant with P2180 seeds. The shriveled seeds contained larger protein bodies but fewer protein bodies per cell than round seeds. Protein bodies in T311 seeds included more dispersed crystals and less globoid regions than P2180 seeds. The elemental compositions of the crystals and of whole seeds in T311 were different from that in P2180 seeds. Starch breakdown was reduced with concomitant lower soluble sugar content in T311 seeds after the D11 stage (10.0 11.9 mm long seeds). The reduced starch breakdown and lowered soluble sugar content were consistent with lower a-amylase activity and earlier and greater water loss in T311 seeds. Changes in development of protein bodies and accumulation of carbohydrates were associated with the development of the shriveled seeds. PMID- 21684932 TI - Pollination biology in hybridizing Baptisia (Fabaceae) populations. AB - In their classic study, Alston and Turner (American Journal of Botany, vol. 50, 159-173, 1963) documented extensive hybridization among four morphologically distinct Baptisia species native to East Texas. While Alston and Turner found putative F1 hybrids in great numbers, they found no evidence of backcrossing. In this study prezygotic and postzygotic reproductive barriers between two of these species, B. leucophaea and B. sphaerocarpa, were investigated and found to be quite weak. Flowering times overlap and bumble bees were observed visiting both species and intermediate hybrids. While pollinator constancy in flights between B. leucophaea and B. sphaerocarpa was moderately strong, significant levels of constancy were not observed in flights involving hybrids and either parental species. Thus, backcrossing was not impeded by pollinator behavior. Further, hybrid pollen was highly stainable (93.5%) and able to effectively set seed in crossing experiments with both parental species. Pollinator behavior was compared in experimental populations with and without hybrid ramets and found to differ between these two treatments. Hybrids were found to facilitate pollinator movement between species. In total, these results suggest that reproductive isolation is not responsible for the rarity of backcrossing in naturally hybridizing B. leucophaea and B. sphaerocarpa populations. PMID- 21684933 TI - Postpollination nectar reabsorption in the African epiphyte Aerangis verdickii (Orchidaceae). AB - Nectar reabsorption in flowering plants seems to be a rare phenomenon and to our knowledge it has not been reported previously in the Orchidaceae. In this study we present data that show statistically significant differences in nectar sugar concentrations before and after pollination. Virgin flowers of the African epiphytic orchid Aerangis verdickii showed mean sugar concentrations in the nectar of 14.4 and of 18.3% in 1994 and 1995, respectively (sucrose mass by mass equivalent). Sugar concentration in nectar from naturally pollinated flowers had a mean of 3.2 and of 8.7% for the same period. In an experiment in the wild 60 flowers were protected against nectar theft by the ants. Half of those flowers were hand-pollinated. Control (virgin) flowers had nectar with a mean value of 13.8%, while flowers measured 48 h after pollination had a mean sugar concentration of 4.3%. The mean volume of nectar based on measurements of 23 virgin flowers from nine different plants was 19 uL. We estimated an average energy value for the nectar produced of 684 J per plant per season. At the study site, over 60% of the unmanipulated flowers were robbed of all their nectar by arboreal ants, Polyrachis spp. (Formicinae). The adaptive significance of nectar reabsorption for A. verdickii is probably a function of the environmental stresses to which it has been exposed and the relative costs of nectar production. PMID- 21684934 TI - Subandrodioecy and male fitness in Sagittaria lancifolia subsp. lancifolia (Alismataceae). AB - Sagittaria lancifolia subsp. lancifolia is described as cosexual (monoecious), but the study population consisted of 84% cosexuals that typically had 35% pistillate buds and 16% predominant males that typically had 0-2% pistillate buds. Hand-pollinations showed that pistillate flowers required pollination to set seed, and pollen from both male and cosexual plants was potent. No gender switching was seen in the field or greenhouse. From 24 experimental crosses, 890 offspring were grown to maturity. Among these, all offspring of cosexual sires were cosexual, but approximately half the offspring of male sires were male, implying that maleness was inherited as a single, dominant allele. These results indicate that S. lancifolia is subandrodioecious, a very rare breeding system. It is rare, in part because its maintenance requires a large male-fitness differential between male and cosexual plants. In the study population, this condition was met by the differential survival of staminate buds on male racemes. Larvae of the weevil Listronotus appendiculatus killed many staminate buds. They did so in a vertical gradient, with buds lower on racemes safer. Male plants have replaced pistillate with staminate buds at these safer positions and thereby enjoy disproportionally higher male fitness. PMID- 21684935 TI - Sexual reproduction and clonal growth in Reinhardtia gracilis (Palmae), an understory tropical palm. AB - Patterns of sexual reproduction and clonal growth were investigated in the understory palm Reinhardtia gracilis var. gracilior over a 3-yr period. R. gracilis is a very abundant clonal palm in the tropical rain forest of Los Tuxtlas, Veracruz, Mexico. Because ramets form clumps, genets are easily identified in the field. Genets were monitored in a 0.5-ha area, and classified by size according to the number of ramets they possessed. In contrast to clonal growth, sexual reproduction was highly dependent on genet size. The probability of reproduction, the number of inflorescences, and the number of fruits produced were positively correlated with genet size. However, neither the probability of producing a ramet, nor the number of ramets produced per genet were correlated with genet size. Over the 3 yr of study, 55% of the genet population had at least one ramet with reproductive structures, while <1% (a single genet in one year) had six ramets with flowers. Thirty-two percent of the mature genets reproduced during each of three consecutive years. In contrast, 58% of the genets produced no new ramets during these 3 yr. No evidence was found of a trade-off between clonal growth and sexual reproduction. Ramet production increases genet size and this in turn increases genet reproductive performance. Clonal growth in this species may be viewed as a growth strategy that tends to maximize genet fitness. PMID- 21684936 TI - Conservation genetics of the endangered endemic Hawaiian genus Brighamia (Campanulaceae). AB - The endemic Hawaiian genus Brighamia (Campanulaceae) comprises two federally endangered, morphologically similar species, B. insignis from Kaua'i and Ni'ihau and B. rockii from Moloka'i. To assist the design of conservation management programs for these taxa, isozyme analyses were performed to assess the levels of genetic diversity at the population and species levels, including comparisons within and among seven natural populations and one ex situ collection each of B. insignis and B. rockii. Our sampling (N = 80) represents ~41% of all known individuals in the wild. Isozyme analyses revealed levels of genetic variation comparable to those reported for other Hawaiian flowering plant taxa but low levels of genetic variation at the population and species levels when compared to flowering plants in general. Ex situ individuals (N = 61) were genetically representative of natural populations and hence may appropriately serve as stock for population augmentations. The two morphologically similar Brighamia species were highly distinct genetically. The combination of morphological and ecological similarity with allozymic dissimilarity observed in Brighamia is unique among the Hawaiian taxa studied to date. PMID- 21684937 TI - Field tests of density-and frequency-dependent selection in Erigeron annuus (Compositae). AB - Selection may maintain genetic diversity in natural populations if the physical or biotic environment is variable over space and-or time. Because density and genotype frequencies can be heterogeneous, and because genotypes may differ in competitive ability, both density-and frequency-dependent selection have been considered to be potentially important evolutionary processes. To address the possibility that intraspecific interactions among plants are a source of fitness variation in Erigeron annuus, we conducted field experiments over 2 yr that were designed to examine the potential of population density, genotype frequency, and their interaction to act as selective agents. In both experiments, apomictic genotypes of Erigeron were paired. Seedlings were planted into plots that differed in density and the identity of minority and majority genotype. There was evidence for a differential effect of density among genotypes for only one year's experiment, suggesting that density-dependent selection is either weak or temporally variable. Genotype frequency had no effect on fitness in either year, and thus there was no evidence for frequency-dependent selection. In addition, the lack of a frequency ;ts density interaction demonstrates that resource partitioning, one mechanism for frequency dependence, is not strong among Erigeron genotypes. If frequency-dependent selection does occur in this species, it is either too weak to detect even in large field experiments, or occurs only in the presence of a selective agent (e.g., pathogens) that was lacking in our experiments. PMID- 21684938 TI - Allozyme variation and genetic relationships among species in the Carex willdenowii complex (Cyperaceae). AB - A taxonomic study by Naczi, Reznicek, and Ford (American Journal of Botany, 85, 434-447, 1998) has determined that three species (Carex willdenowii, C. basiantha, and C. superata) can be recognized within the C. willdenowii complex. To determine the amount of genetic divergence within and between these species, allozyme analyses were conducted on 14 populations distributed from Pennsylvania to eastern Texas. Seventeen loci were surveyed, 13 of which were polymorphic, with all populations being polymorphic at one or more loci. Interspecific genetic identities ranged from 0.560 (C. willdenowii and C. basiantha) to 0.807 (C. basiantha and C. superata). Alleles for the isozymes Aat-1, Dia-1, Idh-2, Mdh-2, Per-1, Pgm-1, and Pgm-2 served to distinguish C. willdenowii from C. basiantha and C. superata. Carex basiantha and C. superata were recognized by alleles of Mdh-2, Pgm-1, and Tpi-2. The genetic identities of populations within species were high and exceeded 0.957. A caespitose growth habit and perigynia in close proximity to the staminate flowers suggest adaptations for selfing and therefore low levels of heterozygosity. Paradoxically, the values for expected heterozygosities (Hexp) were always lower than those obtained by direct count (Hobs): F values were highly negative, indicating heterozygous excess. Disassortative mating and selection are discussed as possible mechanisms for maintaining heterozygous excess within populations. PMID- 21684939 TI - Epidermal anatomy of Barthelopteris germarii from the Upper Carboniferous and Lower Permian of France and Germany. AB - The epidermal anatomy of Barthelopteris germarii, a late Paleozoic seed fern, is described on the basis of material from the Upper Stephanian of Central France. A number of features are described for the first time for this species. Some have never been reported for late Paleozoic pteridosperms. Although our material is in most respects very similar to previously described material of B. germarii from Germany, there are also some striking differences, especially the peltate glandular trichomes that are very common in the French but completely absent in the German material. Their presence is most probably an ecological adaptation as in many modern plants. This and other epidermal and gross-morphological features (e.g., the presence of papillae on subsidiary cells of the stomata, anastomosing venation) indicate that B. germarii was well adapted to stressed conditions. Of more general interest is the preservation of the material. There appears to exist a clear relationship between the preservation of anticlinal walls and the thickness of the parenchymatic mesophyll; anticlinal walls are very well preserved where parenchyma was thin. Therefore, the absence of anticlinal walls in fossil cuticles, which has often been used as a taxonomic character, is not necessarily a primary feature. PMID- 21684940 TI - Molecular systematics of Apiaceae subfamily Apioideae: phylogenetic analyses of nuclear ribosomal DNA internal transcribed spacer and plastid RPO C1 intron sequences. AB - Evolutionary relationships among representatives of Apiaceae (Umbelliferae) subfamily Apioideae have been inferred from phylogenetic analyses of nuclear ribosomal DNA internal transcribed spacer (ITS 1 and ITS 2) and plastid rpoC1 intron sequences. High levels of nucleotide sequence variation preclude the use of the ITS region for examining relationships across subfamilial boundaries in Apiaceae, whereas the rpoC1 intron is more suitably conserved for family-wide phylogenetic study but is too conserved for examining relationships among closely related taxa. In total, 126 ITS sequences from subfamily Apioideae and 100 rpoC1 intron sequences from Apiaceae (all three subfamilies) and outgroups Araliaceae and Pittosporaceae were examined. Phylogenies estimated using parsimony, neighbor joining, and maximum likelihood methods reveal that: (1) Apiaceae subfamily Apioideae is monophyletic and is sister group to Apiaceae subfamily Saniculoideae; (2) Apiaceae subfamily Hydrocotyloideae is not monophyletic, with some members strongly allied to Araliaceae and others to Apioideae + Saniculoideae; and (3) Apiaceae subfamily Apioideae comprises several well supported subclades, but none of these coincide with previously recognized tribal divisions based largely on morphological and anatomical characters of the fruit. Four major clades in Apioideae are provisionally recognized and provide the framework for future lower level phylogenetic analyses. A putative secondary structure model of the Daucus carota (carrot) rpoC1 group II intron is presented. Of its six major structural domains, domains II and III are the most, and domains V and VI the least, variable. PMID- 21684941 TI - Diurnal patterns of CO2 and H2O exchange of the Arctic sedges Eriophorum angustifolium and E. vaginatum (Cyperaceae). AB - Eriophorum vaginatum and E. angustifolium are dominant arctic sedges of the well drained tussock tundra and the permanently flooded wet-sedge tundra, respectively. We determined diurnal courses of gas exchange and water relations of the two species in their natural habitat and compared their responses to changes in light, air temperature, and humidity. Mean photosynthetic response to light was similar between E. angustifolium and E. vaginatum and carbon gain in both species was light limited during most of the growing season. On sunny and dry days, both species closed stomata in response to high leaf-to-air vapor pressure deficits. Even though E. angustifolium was growing in standing water, it exhibited a tighter control of transpirational water loss and had lower hydraulic conductivity in the soil-root-shoot pathway than E. vaginatum. The different response pattern between the two species is discussed in the context of differences in habitat conditions. PMID- 21684942 TI - Specialized phloem parenchyma cells in Norway spruce (Pinaceae) bark are an important site of defense reactions. AB - The bark anatomy of Norway spruce clones that were resistant or susceptible to Ceratocystis polonica, a bark-beetle-vectored fungal pathogen, was compared. The major difference concerned the axial parenchyma cells, called polyphenolic parenchyma (PP cells) because of their vacuolar deposits. The phenolic nature of the deposits was indicated by autofluorescence under blue light, and immunocytochemical studies demonstrating PP cells are enriched in phenylalanine ammonia lyase (EC 4.3.1.5), a key enzyme in phenolic synthesis. Susceptible-clone PP cells occurred as single rows filled with dense deposits. The resistant clone had 40% more PP cells, which occurred in rows two cells thick plus as individual cells scattered among the sieve cells and had lighter deposits. Trees inoculated with fungus were analyzed but a distinct fungal response could not be separated from the general wound response. In the resistant clone, phenolic bodies were reduced in size and density or disappeared completely 12 d after wounding, and PP cell size increased. The susceptible-clone phenolics and cell size changed only slightly. These data show that PP cells are active in synthesis, storage, and modification of phenolics in response to wounding, providing an important site of constitutive and inducible defenses. PMID- 21684943 TI - Anatomy of shoots and tumors of in vitro habituated Rhododendron 'Montego' (Ericaceae) cultures with tissue proliferation. AB - Tissue proliferation (TP) is characterized primarily by the formation of galls or tumors at the crown of container-grown rhododendrons that were initially propagated in vitro. In the cultivar 'Montego', TP-like symptoms are first observed in vitro as shoot clusters with small leaves and nodal tumors. In addition, unlike the normal in vitro non-TP (TP-) shoots, in vitro TP (TP+) shoots proliferate rapidly without the presence of the plant growth regulator cytokinin in the tissue culture medium. Comparisons of the anatomy of TP+ and TP- shoot tips showed that TP+ shoots had a less developed vascular system, longer cells in the pith and cortex, and altered internodal elongation at the shoot apex. In addition, TP+ axillary buds were abnormal in that they were displaced onto the stem above the leaf axil, and a small group of proliferating cells replaced the shell zone at the base of the bud. Initiation of tumor formation began with the expansion of this region of cell proliferation (RCP) and shoot growth from the abnormal axillary bud (tumor bud). Organization of the tumor bud and extension of the RCP characterized the further development of two types of tumors. In polar shoot tumors, shoot growth continued from the persistent tumor bud and the tumor at the base of the shoot remained small in size. The RCP extends downward to the vascular junction of the subtending leaf and the stem of the TP+ shoot. In nonpolar tumors, continuous de novo meristem formation led to the development of large tumors with or without shoots. The RCP is present throughout the tumor and is associated with de novo meristem formation. Comparisons to the anatomy of other tumor-like structures showed that TP tumors of Rhododendron 'Montego' are most similar to tobacco genetic tumors. PMID- 21684944 TI - Intraspecific variation and phylogeographic patterns of Fagus crenata (Fagaceae) mitochondrial DNA. AB - Mitochondrial (mt) DNA variation in Japanese beech, Fagus crenata (Fagaceae), was studied in 17 populations distributed throughout the species' range. Total genomic DNA of samples from single trees representing each of 12 populations were digested with 18 restriction enzymes and hybridized with three probes containing coxI, coxIII, and atpA gene sequences. Thirty-four of the 54 enzyme/probe combinations showed polymorphisms and all the individuals were subsequently analyzed with six combinations of three probes and two enzymes. Restriction fragment length polymorphisms were evident around all three genes, allowing the identification of eight distinct haplotypes. Haplotype diversity within the populations was found to be very low (HS = 0.031), but population differentiation to be much higher (GST = 0.963). The mtDNA variation was strikingly different from allozyme variation (HS = 0.209; GST = 0.039). Gene flow for maternally inherited mtDNA should be restricted to seed dispersal while nuclear gene flow occurs by both seed and pollen dispersal. Therefore, the difference in the variation between mtDNA and allozymes may be largely a result of the much higher rate of gene flow associated with pollen dispersal than with seed dispersal. The mtDNA variation displayed strong geographic structure, which may reflect the species' distribution in the last glacial maximum and subsequent colonization, and probably also reflects intraspecific phylogeography of the species. PMID- 21684945 TI - Effect of cross proximity on progeny fitness in a rare and a common species of Eupatorium (Asteraceae). AB - Offspring from matings between near neighbors may exhibit lower fitness relative to offspring from more distant matings due to spatial structuring of populations resulting from limited dispersal of pollen and seed. This response, which can be interpreted as inbreeding depression, is studied in the rare species, Eupatorium resinosum, and a closely related congener, E. perfoliatum, through the use of hand pollinations representing three distance classes (near-within a population, far-within a population, and between populations) and an assay of the offspring in an experimental plot. Early traits such as seed mass and first-year stem length were not significantly affected by the cross type, although they were affected by maternal parentage. Size and reproduction in the second field season increased with increased pollen donor distance from the maternal plant. Cross type was significant for many traits in the second field season, indicating inbreeding depression in crosses of neighbors (for E. resinosum) and hybrid vigor between populations (both species). This suggests that the rare species, E. resinosum, had a more spatially structured population than E. perfoliatum. The implications of these results for conservation of rare species indicate that protection of habitats sufficient for large populations is necessary to maintain genetic diversity since each population likely consists of many smaller subpopulations. PMID- 21684946 TI - Artificial hybridization in the Hawaiian endemic genus Labordia (Loganiaceae). AB - Cross-pollinations were performed within and among eight species of Labordia from Oahu, Molokai, and Hawaii, and one species from Guam of the closely related genus Geniostoma. Detailed floral examination confirmed that the species are functionally dioecious, i.e., a given individual lacks either ovules or pollen grains. Female inflorescences bagged to prevent pollination never produced seed, but intraspecific crosses between male and female individuals nearly always yielded fruits with viable seed (>80%). Interspecific crosses between species from different islands and separate taxonomic sections of the genus also yielded good fruit set (>55%). Interspecific F1 hybrids were vigorous and appeared to be morphologically intermediate to their parents. Intergeneric crosses between Geniostoma and Labordia failed. Chromosome counts from Labordia species were found to be 2n = 80 or 2n =~80, twice the chromosome complement of two collections examined from its postulated ancestor, Geniostoma rupestre. Labordia species are distinct morphologically, ecologically, and geographically but apparently lack genetic barriers to interbreeding. This suggests that geographical and ecological isolation, recentness of colonization, and/or rapid speciation have been important factors in the origin of species of Labordia. PMID- 21684947 TI - Effects of inbreeding on traits that influence dispersal and progeny density in Cakile edentula var. lacustris (Brassicaceae). AB - Inbreeding may influence the intensity of sibling competition by altering the number of offspring produced or by changing plant morphology in ways that influence seed dispersion patterns. To test this possibility, effects of inbreeding on seed production and on traits that influence progeny density were measured using experimental pollinations of flowers of Cakile edentula var. lacustris. Different flowers on a plant were either hand pollinated with self pollen (with and without emasculation) or foreign pollen, or they were allowed to be pollinated naturally. Selfed flowers matured significantly fewer viable seeds than outcrossed flowers (10.3% less seed maturation with inbreeding depression of 19.2%), due in large part to a greater percentage of proximal seed abortions and lower germination success. Plants grown from selfed seeds tended to have lower seed production (37 fewer seeds on average, with inbreeding depression of 16.2%), caused in part by an increase in the percentage of fruits with proximal seed abortions, although this effect was not significant. Inbreeding depression in total fitness was 29.0%, which corresponds to a difference of 46 seeds per pollinated ovule. Selfing rate estimates were usually intermediate to high, indicating that inbreeding effects observed in this study would be present in naturally pollinated progeny. Although the influence of inbreeding directly on dispersal was negligible, the predicted reduction in sibling competition caused by reduced seed production resulted in an estimate of inbreeding depression of 17.5%, which is 11.5% lower than that measured under uniform conditions. Consequently, inbreeding depression estimated under natural dispersion patterns may be lower than that estimated under uniform conditions since seeds from self- and cross-pollination may not experience the same competitive environment in the field. Inbreeding in the maternal generation, therefore, could influence progeny fitness not only by determining the genetic composition of progeny, but also by influencing the competitive environment in which progeny grow. PMID- 21684948 TI - Interaction between ants and seeds of a nonmyrmecochorous neotropical tree, Cabralea canjerana (Meliaceae), in the Atlantic forest of southeast Brazil. AB - On the forest floor of two Atlantic forest sites in southeast Brazil, we recorded 26 ant species (12 genera) interacting with the seeds of Cabralea canjerana (Meliaceae), a typical ornithochorous tree whose seeds are covered by a lipid rich aril. The ants treat the arillate seeds in three different ways: (1) the large ponerine ants Pachycondyla striata and Odontomachus chelifer individually remove the seeds to their nests, (2) many species (Pheidole spp.) recruit workers to remove the aril on the spot, or (3) Solenopsis spp. recruit nestmates and cover the seeds with soil before removing the aril on the spot. The ants remove the aril exceptionally rapidly, and removal greatly facilitates seed germination. Seed predation by insects below fruiting trees is severe, and field experiments using vertebrate exclosures showed that rodents also prey heavily upon seeds found near parent trees. Ponerine ants actively remove seeds from this predation prone zone. By removing bird-manipulated and naturally fallen seeds, ants can play a key role in the fate of medium-sized seeds like those of C. canjerana. PMID- 21684949 TI - Seed dispersal characteristics of Brassavola nodosa (Orchidaceae). AB - We used mathematical models for wind-dispersed seeds and wind-tunnel experiments to predict modal seed dispersal distance of the Neotropical orchid Brassavola nodosa under conditions approximating those found in its natural habitat: mangrove islands in Belize, Central America. Key variables in a simple ballistic model for predicting modal dispersal distance (xm) of an individual seed include: height of release (h); free-stream velocity (Uc); and terminal velocity of the seed (Ut): xm = h Uc/Ut. Modal dispersal distance of dust-like orchid seeds were predicted adequately by this ballistic model at low wind velocities and low release heights, but it underestimated the increasing importance of turbulence at higher wind velocities and greater release heights. We estimated the magnitude and relative importance of one measure of turbulence, vertical mixing velocity (W*), on xm in wind tunnel experiments. Our estimates of W* were within the same order of magnitude as those found for other small dust-like seeds and pollen. In high turbulence conditions, incorporation of vertical mixing velocity effects into the ballistic model of seed dispersal overestimated modal seed dispersal distances. PMID- 21684950 TI - Genome size and karyotype evolution in the slipper orchids (Cypripedioideae: Orchidaceae). AB - Nuclear DNA contents (4C) were estimated by Feulgen microdensitometry in 27 species of slipper orchids. These data and recent information concerning the molecular systematics of Cypripedioideae allow an interesting re-evaluation of karyotype and genome size variation among slipper orchids in a phylogenetic context. DNA amounts differed 5.7-fold, from 24.4 pg in Phragmipedium longifolium to 138.1 pg in Paphiopedilum wardii. The most derived clades of the conduplicate leaved slipper orchids have undergone a radical process of genome fragmentation that is most parsimoniously explained by Robertsonian changes involving centric fission. This process seems to have occurred independently of genome size variation. However, it may reflect environmental or selective pressures favoring higher numbers of linkage groups in the karyotype. PMID- 21684951 TI - Phylogenetic relationships of conifers inferred from partial 28S rRNA gene sequences. AB - The conifers, which traditionally comprise seven families, are the largest and most diverse group of living gymnosperms. Efforts to systematize this diversity without a cladistic phylogenetic framework have often resulted in the segregation of certain genera and/or families from the conifers. In order to understand better the relationships between the families, we performed cladistic analyses using a new data set obtained from 28S rRNA gene sequences. These analyses strongly support the monophyly of conifers including Taxaceae. Within the conifers, the Pinaceae are the first to diverge, being the sister group of the rest of conifers. A recently discovered Australian genus Wollemia is confirmed to be a natural member of the Araucariaceae. The Taxaceae are nested within the conifer clade, being the most closely related to the Cephalotaxaceae. The Taxodiaceae and Cupressaceae together form a monophyletic group. Sciadopitys should be considered as constituting a separate family. These relationships are consistent with previous cladistic analyses of morphological and molecular (18S rRNA, rbcL) data. Furthermore, the well-supported clade linking the Araucariaceae and Podocarpaceae, which has not been previously reported, suggests that the common ancestor of these families, both having the greatest diversity in the Southern Hemisphere, inhabited Gondwanaland. PMID- 21684952 TI - Evolution in an autopolyploid group displaying predominantly bivalent pairing at meiosis: genomic similarity of diploid Vaccinium darrowi and autotetraploid V. corymbosum (Ericaceae). AB - The genomic relationship between V. darrowi Camp (2n = 2x = 24) and V. corymbosum L. (2n = 4x = 48) was examined using an interspecific tetraploid hybrid, US 75, and representatives of the parental species. Two features in the background of US 75 led to the prediction that it was an allopolyploid: (1) the parental species are quite distinct morphologically and geographically, and (2) the diploid genome was incorporated into US 75 via an unreduced gamete. However, US 75 recently was shown to display tetrasomic inheritance using molecular markers. In the present cytological study, US 75 was found to have a lower than expected number of multivalents for an autopolyploid, although it had a significantly higher number of quadrivalents than its autotetraploid parent, V. corymbosum. Normal chromosome distributions were observed at anaphase I and II, and pollen viability was high. Our findings suggest that little genomic divergence has developed between the Vaccinium species and that the polyploids may freely exchange genes with sympatric diploid species via unreduced gametes. This pattern of hybridization could be an important component of evolution in all autopolyploid groups, making them much more dynamic than traditionally assumed. PMID- 21684953 TI - Anatomically preserved leaves of the conifer Notophytum krauselii (Podocarpaceae) from the Triassic of Antarctica. AB - Permineralized leaves of the Triassic podocarpaceous conifer Notophytum krauselii are described from the Fremouw Formation of Antarctica. The leaves are elongate and apetiolate with 8-12 parallel veins. The adaxial epidermis consists of rows of rectangular to pentagonal cells; the abaxial epidermis is papillate. Longitudinally oriented stomata occur on both surfaces. An adaxial palisade layer is present and auxiliary sclereids are common in the mesophyll. The vascular bundles have a weakly defined sheath and are flanked by transfusion tracheids. Bundles in the basipetal area of the leaf are capped by sclerotic tissue and subtended by resin canals. These leaves are superficially similar to those of the extant podocarp genus Nageia, but probably represent a distinct acquisition of this leaf type within the Podocarpaceae. Notophytum leaves are similar to the common compression fossil Heidiphyllum elongatum and may be closely related or even conspecific. Evidence from Antarctica suggests that Heidiphyllum and the seed cone Telemachus were produced by the same plant, and may be closely related to several other early Mesozoic conifers with multiveined leaves. PMID- 21684954 TI - Sporophytes and gametophytes of Dicranaceae from the Santonian (Late Cretaceous) of Georgia, USA. AB - A new species (Campylopodium allonense) of the moss family Dicranaceae is described for fossil sporophyte capsules and associated gametophytes from the late Santonian (Late Cretaceous) Buffalo Creek Member of the Gaillard Formation in central Georgia, USA. The sporophyte capsules are most comparable to those of the living genus Campylopodium. Sporangia are curved, cylindrical, and strumose, with an obliquely rostrate operculum, cucullate calyptra, and compound annulus. The peristome is haplolepidous with 16 dicranoid, apically bifid teeth that are vertically striate on the outer surface and asymmetrically trabeculate on the inner surface. Spores are spherical, alete, and finely rugose, and thus differ from the finely papillose spores of extant Campylopodium. Associated fossil gametophytes are consistent with the morphology of extant Campylopodium and have leaves with a broad sheathing base and a narrow blade. Spores identical to those in the sporangium occur on the leaf surfaces of one of the gametophyte specimens, providing circumstantial evidence that both sporophyte and gametophyte belong to the same species. Inadequacies of the moss fossil record have led to contrasting interpretations of the timing of evolutionary change in this lineage since the Paleozoic. Campylopodium allonense unequivocally provides the earliest evidence of Dicranaceae in the fossil record. This material, along with other fossil mosses from this late Santonian locality, indicates the presence of modern families of mosses in the Cretaceous. In a phylogenetic context, these fossils from two different subclasses imply that mosses were already diverse by the Late Cretaceous. PMID- 21684955 TI - Ultrastructural interpretation of the Late Cretaceous megaspore Glomerisporites pupus and its associated microspores. AB - The ultrastructure of the Late Cretaceous (Santonian-?early Campanian) megaspore Glomerisporites pupus and its associated microspores has been examined in an attempt to resolve a number of problems concerning the interpretation of their morphology. The new observations presented are based on an analysis of entire, fragmentary, and thin-sectioned specimens under scanning and transmission electron microscopes. These add to, and partly correct, previous observations on this taxon. They include the following: (1) The exine of the megaspore consists of thin, homogeneous, outer undulating and inner electron dense layers, with a thicker zone of spongy structure in-between. (2) The perispore (or perine) of the megaspore comprises four layers, in order towards the exterior: loose filamentous, dense filamentous, vacuolate, and columnar. (3) This is completely enclosed by a thick mat of hairs, which appears to be attached to the underlying perisporal layers by means of connections with a few of the "spines" that originate from the dense filamentous zone, and with some elements of the columnar perine. (4) The tripartite neck (acrolamella) of the spore, which is hidden beneath the mat of hairs, is predominantly an extension of the dense filamentous and vacuolate layers, but also involves the columnar layer, especially in the lower part. (5) Some of the numerous small floats that are embedded in the mat have hairs originating from them. (6) Both long tangled and circinate hairs surround the perispore of the microspores. (7) The exine of the microspore was at least partly attached to the perispore when the organ was viable. (8) It comprises four zones that vary in structure and electron density. These facts and comparisons made with other megaspores and their associated microspores confirm evolutionary links between G. pupus and several taxa included within the Salviniaceae (Azolla, Parazolla, Salvinia) and possible ancestors of this group (the parent plants of Ariadnaesporites and Capulisporites). PMID- 21684956 TI - Ant protection of the nectaried fern Polypodium plebeium in central Mexico. AB - Nectaries on fronds of Polypodium spp. have been studied previously only in cultivated specimens. We conducted field observations in middle-elevation forests in Mexico and found five ant species associated with nectaries of Polypodium plebeium and P. lepidotrichum. To investigate whether nectaries promote protection against herbivores, we performed ant-exclusion experiments with nectary-bearing ferns (P. plebeium) and other ferns without nectaries (Polypodium plesiosorum, P. furfuraceum, and Phlebodium pseudoaureum). When ants were excluded from the developing fronds of Polypodium plebeium, damage from foliage feeding sawfly and lepidopteran caterpillars was significantly greater than in control fronds. Ferns without nectaries did not show a difference in damage between ant-excluded and control fronds. Our results demonstrate that fern nectaries can support ant defense of the plant body as do the extrafloral nectaries of many angiosperms. PMID- 21684957 TI - Primary classification and phylogeny of the Polemoniaceae, with comments on molecular cladistics. AB - The system of classification of the Polemoniaceae currently in use was published by Grant in 1959. Much new evidence concerning relationships in the family has been obtained by numerous workers since 1959, and the old system is in need of revision. A revised system down to the genus level, based on conventional and unconventional characters, including molecular evidence, is presented here. Nineteen genera are grouped into eight tribes and two subfamilies. Three new tribes are described: Acanthogilieae, Loeselieae, and Leptodactyloneae. Several genera are transferred to new groups. The phylogeny of the family is discussed in the light of both the older and new evidence. The approach used in constructing both the 1959 and new systems is that of evolutionary systematics. Two recent (1996, 1997) family-wide surveys of cpDNA and rDNA use cladistic methods of analysis to arrive at sets of major groups. Some of this molecular evidence has been adopted for the present revised system. However, much incongruence still exists between the new sets of clades, on the one hand, and the present revised system or the still-viable parts of the 1959 system on the other hand. The incongruences call for an examination and comparison of the contrasting methods of evolutionary systematics and molecular cladistics. A fundamental flaw in the 1996 and 1997 treatments is the attempt to classify plants on the basis of single gene gene trees. PMID- 21684958 TI - The features of cotyledon areoles in Leguminosae and their systematic utility. AB - The cotyledon areole, which is a spot with granular projections of epidermal cells, appears on the abaxial surface and on the midvein of some legume seed cotyledons. The distribution and systematic utility of cotyledon areoles were studied by observation of 132 legume species, which represent 100 genera and are classified into 34 tribes of three subfamilies, i.e., Caesalpinioideae, Mimosoideae, and Papilionoideae. The cotyledon areole is found in many species of Papilionoideae but not in the other two subfamilies. Presence of a cotyledon areole is presumed to be an apomorphic character state in Papilionoideae from the outgroup rule. PMID- 21684959 TI - Reductions in abscisic acid are linked with viviparous reproduction in mangroves. AB - We investigate physiological mechanisms behind the convergent evolutionary loss of seed dormancy in plant lineages, focusing on mangroves as a model system. More than 60 angiosperm families, including several mangrove taxa, contain species with seeds that are intolerant of drying and do not undergo dormancy. These desiccation-intolerant species occur with disproportionate frequency in wet or coastal tropical habitats. In plants, the hormone abscisic acid (ABA) coordinates both the development of desiccation tolerance during the onset of seed dormancy and whole-organism responses to flooding. Thus, changes in ABA levels and/or modes of action in different plant compartments are implicated in the repeated evolutionary loss of seed dormancy among species of wet habitats. We compare ontogenetic dynamics of ABA levels in embryonic, maternal, and mature vegetative tissue of four phylogenetically independent pairs of related viviparous mangroves and nonviviparous nonmangroves. We demonstrate that ABA levels are consistently lower in embryos of viviparous mangrove taxa than embryos of nonmangrove, nonviviparous sister taxa. In contrast, elevated tissue concentrations of ABA characterize leaves of all mangrove species tested, while ABA levels in maternal tissues vary among mangrove species. These commonalities suggest a functionally important trade-off between the maintenance of embryonic development and the adjustment of the parent tree to salinity stress. This study yields comparative data on seed physiology in naturally occurring desiccation-intolerant species, for which these data are currently scarce, and demonstrates a potentially significant role of phytohormones in the evolution of plant life histories. PMID- 21684960 TI - Mentor effects in wild species of Helianthus (Asteraceae). AB - Self-incompatibility (SI) is an effective method for limiting self-fertilization in flowering plant species, but there are circumstances in which an otherwise functional SI system may fail. One of the most intriguing of these is the induction of selfing by mixed loads of self and heterospecific pollen (the mentor effect) because it is likely to occur under natural conditions, such as in hybrid zones. Here we conducted a series of controlled crosses to determine whether mentor effects operate in two SI annual species, Helianthus annuus and H. petiolaris, and whether the failure of SI results in a decrease in the frequency of hybridization between these two species. Of the 1396 achenes examined from pollen mixtures that included varying ratios of self, intraspecific compatible, and interspecific pollen, 71 (5.1%) were selfed. Selfing frequencies were significantly less than expected based on pollen ratios, except when the proportion of intraspecific compatible pollen was low. Hybridization frequencies from these same pollen ratios averaged 41.8% with H. annuus as the maternal species and 13.3% with H. petiolaris as the mother. Analysis of 1404 achenes from pollen mixtures that excluded self pollen resulted in hybridization frequencies for H. annuus (42.2%) and H. petiolaris (18.2%) that do not differ significantly from those including self pollen. Thus, mentor effects do not appear to play an important role in reproductive isolation between these species. On the other hand, even a modest increase in self-fertilization in hybrid populations, such as that due to mentor effects, could enhance the probability of hybrid species establishment. PMID- 21684961 TI - Reproductive biology of two dominant prairie grasses (Andropogon gerardii and Sorghastrum nutans, Poaceae): male-biased sex allocation in wind-pollinated plants? AB - It has been proposed that some wind-pollinated plants have the necessary conditions for an optimal sex allocation that is male biased, though there are few data that address this prediction. We determined that two prairie grass species (Andropogon gerardii and Sorghastrum nutans) had reproductive characteristics that theoretically would result in a male-biased allocation: both species were self-incompatible and neither species had increased seed set after supplemental hand pollination. The relative allocation to pollen and seed production was measured in terms of biomass, energy, nitrogen, phosphorus, potassium, magnesium, and calcium. Sex allocation in A. gerardii was significantly male biased (from 60 to 89% male) when measured in currencies of biomass, energy, potassium, and calcium; there was no significant bias in the sex allocation (from 49 to 57% male) when measured in currencies of nitrogen, phosphorus, and magnesium. Sex allocation in S. nutans was significantly male biased (from 69 to 81% male) for all currencies except phosphorus (61% male). This is the first evidence for male-biased sex allocation in any plant or animal hermaphrodite. Though the necessary conditions may be uncommon, male-biased allocation may be found in other species with similar reproductive biology. PMID- 21684962 TI - Life history of the long-lived gynodioecious cushion plant Silene acaulis (Caryophyllaceae), inferred from size-based population projection matrices. AB - Alpine plants often appear to have long life-spans as an adaptation to harsh and unpredictable environmental conditions, yet many lack reliable indicators of age that would make it possible to determine their true longevity. Their extended life-spans also pose problems for measuring lifetime reproductive success, a key component of breeding system evolution in species such as the gynodioecious cushion plant Silene acaulis. For a population of S. acaulis in south-central Alaska, we applied a recently derived analytical approach using size-based population projection matrices that allowed us to estimate: (1) the relationship between cushion diameter and age; and (2) lifetime reproductive success through seed production by females relative to hermaphrodites. Because of a combination of slow growth, frequent shrinkage, and extremely high adult survival, we estimate that the largest cushions in our study population exceed 300 yr in age, and some may live substantially longer, despite the seemingly inhospitable alpine environment they inhabit. Females are estimated to produce 4.4 times as many offspring via seed production over the course of their lives as do hermaphrodites, a difference that is more than sufficient to assure the persistence of females despite their inability to transmit genes through pollen. These results highlight the utility of size-based projection matrices for studying the life histories of herbaceous perennials whose life-span and lifetime reproductive success cannot be determined easily by any other means. PMID- 21684963 TI - Fecundity, phenology, and seed dormancy of F1 wild-crop hybrids in Sunflower (Helianthus annuus, Asteraceae). AB - Crop-to-wild hybridization has the potential to introduce beneficial traits into wild populations. Gene flow from genetically engineered crops, in particular, can transfer genes coding for traits such as resistance to herbicides, insect herbivores, disease, and environmental stress into wild plants. Cultivated sunflower (Helianthus annuus) hybridizes spontaneously with wild/weedy populations (also H. annuus), but little is known about the relative fitness of F1 hybrids. In order to assess the ease with which crop-to-wild introgression can proceed, we compared characteristics of F1 wild-crop progeny with those of purely wild genotypes. Two nontransgenic, cultivated varieties were crossed with wild plants from three different regions-Texas, Kansas, and North Dakota. Seed burial experiments in the region of origin showed that wild-crop seeds had somewhat higher germination rates (less dormancy) than wild seeds from Kansas and North Dakota, while no differences were seen in seeds from Texas. Progeny from each type of cross were grown in outdoor pots in Ohio and in a weedy field in Kansas to quantify lifetime fecundity and flowering phenology. Flowering periods of hybrid and wild progeny overlapped considerably, especially in plants from North Dakota and Texas, suggesting that these hybrids are very likely to backcross with wild plants. In general, hybrid plants had fewer branches, flower heads, and seeds than wild plants, but in two crosses the fecundity of hybrids was not significantly different from that of purely wild plants. In Ohio, wild-crop hybrids from North Dakota appeared to be resistant to a rust that infected 53% of the purely wild progeny, indicating a possible benefit of "traditional" crop genes. In summary, our results suggest that F1 wild-crop hybrids had lower fitness than wild genotypes, especially when grown under favorable conditions, but the F1 barrier to the introgression of crop genes is quite permeable. PMID- 21684964 TI - Allozyme diversity in the endangered pitcher plant Sarracenia rubra ssp. Alabamensis (Sarraceniaceae) and its close relative S. rubra ssp. rubra. AB - Genetic variability in the federally endangered pitcher plant Sarracenia rubra ssp. alabamensis was assessed in eight Alabama populations using starch gel electrophoresis. Ten populations of the more widespread Sarracenia rubra ssp. rubra were sampled in the southeastern United States for comparison. Fifteen allozyme loci representing 13 enzyme systems were scored for each species. In contrast to S. oreophila and S. jonesii, two previously analyzed endangered pitcher plants, genetic diversity was high for both S. rubra subspecies. Within ssp. alabamensis the percentage polymorphic loci (Ps) was 80.0, the mean number of alleles per polymorphic locus was (APs) = 2.58, and expected heterozygosity (Hes) was 0.209. Genetic diversity was slightly lower for ssp. rubra (Ps = 73.3, APs = 2.91, and Hes = 0.177). The proportion of total genetic diversity found among populations was fairly low for both species (GST = 0.09 for ssp. alabamensis and 0.14 for ssp. rubra). Little genetic divergence has occurred between the two subspecies as indicated by the lack of diagnostic alleles, the proportion of total genetic diversity between taxa (GST = 0.09), and the genetic identity estimate (I = 0.90). The relatively high genetic diversity found for ssp. alabamensis indicates that the maintenance of its evolutionary potential is possible if population sizes are maintained or increased. Low levels of genetic diversity found within small Georgia ssp. rubra populations indicate that genetic erosion may increase extinction risks for these populations. PMID- 21684965 TI - RAPD variation in relation to population size and plant fitness in the rare Gentianella germanica (Gentianaceae). AB - We investigated the distribution of genetic variation and the relationship between population size and genetic variation in the rare plant Gentianella germanica using RAPD (random amplified polymorphic DNA) profiles. Plants for the analysis were grown from seeds sampled from 72 parent plants in 11 G. germanica populations of different size (40-5000 fruiting individuals). In large populations, seeds were sampled from parents in two spatially distinct subpopulations comparable in area to the total area covered by small populations. Analysis of molecular variance revealed significant genetic variation among populations (P <0.001), while genetic variation among subpopulations was marginally significant (P <0.06). Average molecular variance within subpopulations in large populations did not differ significantly from whole population values. There was a positive correlation between genetic variation and population size (P <0.01). Genetic variation was also positively correlated with the number of seeds per plant in the field (P <0.02) and the number of flowers per planted seed in a common garden experiment (P <0.051). We conclude that gene flow among natural populations is very limited and that reduced plant fitness in small populations of G. germanica most likely has genetic causes. Management should aim to increase the size of small populations to minimize further loss of genetic variation. Because a large proportion of genetic variation is among populations, even small populations are worth preserving. PMID- 21684966 TI - Early succession on lahars spawned by Mount St. Helens. AB - The effects of isolation on primary succession are poorly documented. I monitored vegetation recovery on two Mount St. Helens lahars (mud flows) with different degrees of isolation using contiguous plots. Seventeen years after the eruption, species richness was stable, but cover continued to increase. That isolation affects community structure was confirmed in several ways. The dominance hierarchies of the lahars differed sharply. Detrended correspondence analysis on Lahar I showed a trend related to distance from an adjacent woodland, whereas vegetation on Lahar II was relatively homogeneous. Spectra of growth forms and dispersal types also differed. Lahar I was dominated by species with modest dispersal ability, while Lahar II was dominated by species with better dispersal. Variation between plots should decline through time, a prediction confirmed on Lahar II. Lahar I remained heterogeneous despite having developed significantly higher cover. Here, the increasing distance from the forest has prevented plots from becoming more homogeneous. At this stage of early primary succession, neither lahar is converging towards the species composition of adjacent vegetation. This study shows that isolation and differential dispersal ability combine to determine initial vegetation structure. Stochastic effects resulting from dispersal limitations may resist the more deterministic effects of competition that could lead to floristic convergence. PMID- 21684967 TI - Importance of woody debris in seed germination of Tipularia discolor (Orchidaceae). AB - Concerns about declining populations of terrestrial orchids make it important to identify the environmental factors crucial to seedling recruitment. This study shows that seedlings of Tipularia discolor (cranefly orchid) primarily occur on decomposing wood. Extensive searches of decomposing logs and stumps in mature and successional forests revealed seedlings at 24 sites, of which 15 could be identified as originating from seven different deciduous trees and one conifer. Seeds were planted in natural habitats to test the hypothesis that germination requires decomposing wood. In one experiment, seeds were placed into soil at sites where adult plants were abundant; no germination resulted. In a second experiment, germination of seeds sown in ambient soil was compared with sowings in plots amended with decomposing wood collected from a stump where spontaneous seedlings grew. Germination was much more frequent in plots amended with decomposing wood. We conclude that germination of T. discolor is stimulated in substrates that contain decomposing wood; judging from the occurrence of spontaneous seedlings, wood from at variety of tree species offer a suitable substrate. PMID- 21684968 TI - The cashew nut, Anacardium occidentale (Anacardiaceae), and its perennial association with ants: extrafloral nectary location and the potential for ant defense. AB - Cashew nut trees are consistently ant-visited throughout the year, with the ants attracted to a large number of extrafloral nectaries on the leaves, inflorescences, flowers, and developing nuts. The commercial production of cashew nut, for example, in India, Brazil, and east Africa, consistently applies pesticides, especially insecticides, in large monoculture plantings. Each year prophylactic spraying begins with the first flush of new leaves, continues through flowering, ending at about mid-nut development. We surveyed for ant diversity in sprayed and unsprayed cashew monocultures of various sizes and ages in Sri Lanka, India, and Malaysia to document the ant-cashew relationship and to explore the potential of ants replacing chemical pesticides in insect control. Using for-profit, commercial-size plantations as examples, we present information that cashew has a strong potential for arthropod-dependent protection from pests and suggest important habitat considerations for encouraging ants within cashew plantings. PMID- 21684969 TI - Potential carbon gain of shingle leaves in juveniles of the vine Monstera tenuis (Araceae) in Costa Rica. AB - The amount of light intercepted by vertically oriented, shingle leaves of juvenile Monstera tenuis vines growing in forest understory was compared to the amount of light the leaves would intercept if they were horizontal. Light levels were monitored using quantum sensors and hemispherical photography. Shingle leaves absorb less light than they would if the leaves were horizontal at the same positions, and the difference increases with height in the forest. Modeling based on measured photosynthetic light responses and light interception suggests that at 1 m height, 75% more carbon could be gained if leaves were horizontal instead of vertical. Because the vertical leaf orientation reduces light interception, other selective factors are likely of greater importance in favoring the evolution of the shingle-leaved growth form. PMID- 21684970 TI - Phylogeny and biogeography of Aralia sect. Aralia (Araliaceae). AB - Aralia sect. Aralia (Araliaceae) consists of approximately eight species disjunctly distributed in Asia and North America. Phylogenetic and biogeographic analyses were conducted using sequences of the internal transcribed spacer regions of the nuclear ribosomal DNA. Aralia racemosa from eastern North America was sister to A. californica from western North America. Aralia cordata from eastern Asia did not form a species-pair relationship with the eastern North American A. racemosa. The two subspecies of A. racemosa formed a monophyletic group. Biogeographic analyses showed a close area relationship between eastern North America and western North America. The Himalayas were cladistically basal and eastern Asia was placed between the Himalayas and North America. The biogeographic analysis supported the origin of the eastern Asian and eastern North American disjunct pattern in Aralia sect. Aralia via the Bering land bridges. Comparisons with results of phylogenetic analyses of other genera suggested that (1) the floristic connection between eastern North America and western North America may be stronger than previously thought; and (2) the biogeographic patterns in the Northern Hemisphere are complex. Furthermore, a lack of correlation between sequence divergence values and phylogenetic positions was observed, suggesting the importance of a phylogenetic framework in biogeographic analyses. PMID- 21684971 TI - Circumscription of the Malvales and relationships to other Rosidae: evidence from rbcL sequence data. AB - The order Malvales remains poorly circumscribed, despite its seemingly indisputable core constituents: Bombacaceae, Malvaceae, Sterculiaceae, and Tiliaceae. We conducted a two-step parsimony analysis on 125 rbcL sequences to clarify the composition of Malvales, to determine the relationships of some controversial families, and to identify the placement of the Malvales within Rosidae. We sampled taxa that have been previously suggested to be within, or close to, Malvales (83 sequences), plus additional rosids (26 sequences) and nonrosid eudicots (16 sequences) to provide a broader framework for the analysis. The resulting trees strongly support the monophyly of the core malvalean families, listed above. In addition, these data serve to identify a broader group of taxa that are closely associated with the core families. This expanded malvalean clade is composed of four major subclades: (1) the core families (Bombacaceae, Malvaceae, Sterculiaceae, Tiliaceae); (2) Bixaceae, Cochlospermaceae, and Sphaerosepalaceae (Rhopalocarpaceae); (3) Thymelaeaceae sensu lato (s.l.); and (4) Cistaceae, Dipterocarpaceae s.l., Sarcolaenaceae (Chlaenaceae), and Muntingia. In addition, Neurada (Neuradaceae or Rosaceae) falls in the expanded malvalean clade but not clearly within any of the four major subclades. This expanded malvalean clade is sister to either the expanded capparalean clade of Rodman et al. or the sapindalean clade of Gadek et al. Members of Elaeocarpaceae, hypothesized by most authors as a sister group to the four core malvalean families, are shown to not fall close to these taxa. Also excluded as members of, or sister groups to, the expanded malvalean clade were the families Aextoxicaceae, Barbeyaceae, Cannabinaceae, Cecropiaceae, Dichapetalaceae, Elaeagnaceae, Euphorbiaceae s.l., Huaceae, Lecythidaceae, Moraceae s.l., Pandaceae, Plagiopteraceae, Rhamnaceae, Scytopetalaceae, Ulmaceae, and Urticaceae. PMID- 21684972 TI - Applications of the compensating pressure theory of water transport. AB - Some predictions of the recently proposed theory of long-distance water transport in plants (the Compensating Pressure Theory) have been verified experimentally in sunflower leaves. The xylem sap cavitates early in the day under quite small water stress, and the compensating pressure P (applied as the tissue pressure of turgid cells) pushes water into embolized vessels, refilling them during active transpiration. The water potential, as measured by the pressure chamber or psychrometer, is not a measure of the pressure in the xylem, but (as predicted by the theory) a measure of the compensating pressure P. As transpiration increases, P is increased to provide more rapid embolism repair. In many leaf petioles this increase in P is achieved by the hydrolysis of starch in the starch sheath to soluble sugars. At night P falls as starch is reformed. A hypothesis is proposed to explain these observations by pressure-driven reverse osmosis of water from the ground parenchyma of the petiole. Similar processes occur in roots and are manifested as root pressure. The theory requires a pump to transfer water from the soil into the root xylem. A mechanism is proposed by which this pump may function, in which the endodermis acts as a one-way valve and a pressure confining barrier. Rays and xylem parenchyma of wood act like the xylem parenchyma of petioles and roots to repair embolisms in trees. The postulated root pump permits a re-appraisal of the work done by evaporation during transpiration, leading to the proposal that in tall trees there is no hydrostatic gradient to be overcome in lifting water. Some published observations are re interpreted in terms of the theory: doubt is cast on the validity of measurements of hydraulic conductance of wood; vulnerability curves are found not to measure the cavitation threshold of water in the xylem, but the osmotic pressure of the xylem parenchyma; if measures of xylem pressure and of hydraulic conductance are both suspect, the accepted view of the hydraulic architecture of trees needs drastic revision; observations that xylem feeding insects feed faster as the water potential becomes more negative are in accord with the theory; tyloses, which have been shown to form in vessels especially vulnerable to cavitation, are seen as necessary for the maintenance of P, and to conserve the supplementary refilling water. Far from being a metastable system on the edge of disaster, the water transport system of the xylem is ultrastable: robust and self-sustaining in response to many kinds of stress. PMID- 21684973 TI - Factors limiting seed production of Taxus brevifolia (Taxaceae) in Western Oregon. AB - Seed production of Pacific yew (Taxus brevifolia), an understory conifer, was studied at four sites in western Oregon over 2 yr. The effects of pollen supplementation, overstory canopy, and predator exclusion on ovule attrition were examined. Supplemental hand-pollination of ten trees at two sites resulted in significantly increased rates of ovule development and a doubling of seed efficiency (ratio of seeds to ovules). However, seed efficiency still averaged <15% on branches receiving supplemental pollen, so pollination was not a primary factor limiting seed production. The number of developing ovules was positively associated with overstory openness, but seed production was not. Seed efficiency was negatively associated with overstory openness. Branches bagged to exclude vertebrate seed predators had higher seed production than unbagged branches at three of four sites for 2 yr. In contrast to unbagged branches, seed production on bagged branches was positively associated with overstory openness, as was the effectiveness of bagging. Therefore, both vertebrate predation and overstory were important in limiting seed production, and these factors interacted. Factors limiting seed production varied in importance among the four sites and between years, illustrating the importance of examining multiple limiting factors over several sites and years. PMID- 21684974 TI - Does self-pollination provide reproductive assurance in Aquilegia canadensis (Ranunculaceae)? AB - The ability to produce seeds when pollinators or potential mates are scarce is thought to be one of the main advantages of self-fertilization in flowering plants. However, whether autonomous selfing increases seed set in natural populations has seldom been tested, and even fewer studies have evaluated the advantage of selfing across a gradient of pollen availability. This study examines the fertility consequences of autonomous selfing in Aquilegia canadensis (Ranunculaceae), a short-lived, spring-flowering perennial typically found in small, patchy populations on rock outcrops. We used a pollinator exclusion experiment to confirm reports that A. canadensis has a well-developed capacity for autonomous selfing resulting from incomplete protogyny and close proximity of stigmas and anthers during dehiscence. Flowers excluded from pollinators set 87% as many seeds per carpel (X +/- 1 SE = 7.1 +/- 1.4 seeds) as hand-pollinated flowers (8.1 +/- 1.3 seeds), and seed production in unpollinated flowers correlated negatively with the distance between stigmas and anthers (r = -0.46). Autonomous selfing could be potentially valuable in providing reproductive assurance because only 2.7 +/- 0.5 pollen grains were deposited on each stigma before anther dehiscence, compared to 134.1 +/- 17.9 pollen grains by the end of anther dehiscence. However, prevention of autonomous selfing by anther removal before dehiscence did not decrease seed set, even for plants at low plant densities where outcross pollen may have been in short supply. Emasculated flowers set as many seeds per carpel (9.3 +/- 0.9) as intact flowers (8.4 +/- 1.1), indicating that sufficient cross pollen is deposited for full seed set. These results do not support the hypothesis that autonomous selfing by A. canadensis has been selected because it provides reproductive assurance. PMID- 21684975 TI - Combined effects of water, nutrient, and UV-B stress on female fitness in Brassica (Brassicaceae). AB - Our knowledge of the effects of increased levels of ultraviolet-B radiation (UV B) on plant fitness is limited mainly to yield studies in a few crop species. Previous greenhouse and garden studies of Brassica have found greater detrimental effects of UV-B on fitness in gardens than in the greenhouse, suggesting the possibility that additional stresses in the field decrease the ability of Brassica to cope with UV-B. Possible interactions between UV-B and water/nutrient stress in determining plant fitness have rarely, if ever, been studied experimentally. Here we report measurements of female fitness in two species of Brassica in an experiment in which both UV-B and levels of water and nutrients were varied in a 2 x 2 factorial design. Water and nutrient stress reduced female fitness in both species, while UV-B caused fitness reductions in only one of the species. There was evidence for interactions between UV-B and water/nutrient stress for only a few of the traits measured; most traits, including those closely related to fitness, showed no evidence of an interaction. PMID- 21684976 TI - Resource-based models of competitive interactions. I. Intraspecific competition in Ratibida columnifera ( Asteraceae). AB - We constructed and tested a series of regression models of intraspecific competition in Ratibida columnifera (Asteraceae), based on the growth and water use of individual plants. Models were constructed from a set of plants ("model") grown without competition under three watering regimes. Each model was then tested on another set of plants ("test") grown, singly or in pairs, under two watering regimes, one of them different than those of the "model" plants. Both sets of plants were grown simultaneously. Models that used only estimates of plant dry mass (ISON [interval by interval size only], and SON [size only]) were outperformed (i.e., the difference between predicted values of final dry mass and their true values were larger on average) by models that incorporated direct measures of water uptake and usage (ISAW [interval by interval size and water], WON [water only], SAW [size and water]). Harvest biomass predictions given by these three last models deviated from values of true biomass by an average of only 6.1%. PMID- 21684977 TI - Variability in leaf optical properties among 26 species from a broad range of habitats. AB - Leaves from 26 species with growth forms from annual herbs to trees were collected from open, intermediate, and shaded understory habitats in Mississippi and Kansas, USA. Leaf optical properties including reflectance, transmittance, and absorptance in visible and near infrared (NIR) wavelengths were measured along with leaf thickness and specific leaf mass (SLM). These leaf properties and internal light scattering have been reported to vary with light availability in studies that have focused on a limited number of species. Our objective was to determine whether these patterns in leaf optics and light availability were consistent when a greater number of species were evaluated. Leaf thickness and SLM varied by tenfold among species sampled, but within-habitat variance was high. Although there was a strong trend toward thicker leaves in open habitats, only SLM was significantly greater in open vs. understory habitats. In contrast, leaf optical properties were strikingly similar among habitats. Reflectance and reflectance/transmittance in the NIR were used to estimate internal light scattering and there were strong relationships (r1 > 0.65) between these optical properties and leaf thickness. We concluded that leaf thickness, which did not vary consistently among habitats, was the best predictor of NIR reflectance and internal light scattering. However, because carbon allocation to leaves was lower in understory species (low SLM) yet gross optical properties were similar among all habitats, the energy investment by shade leaves required to achieve optical equivalence with sun leaves was lower. Differences in leaf longevity and growth form within a habitat may help explain the lack of consistent patterns in leaf optics as the number of species sampled increases. PMID- 21684978 TI - Within-population genetic diversity of Taraxacum officinale (Asteraceae): differential genotype response and effect on interspecific competition. AB - Clonal offspring of five morphologically distinct individuals of Taraxacum officinale were planted in a greenhouse experiment with each of three competitors, Plantago major, Poa pratensis and Trifolium pratense. The competitors were chosen to represent a series of competitive environments experienced by a natural population of T. officinale through the year. Differences in size, morphology, and response to the competitive environments were found among clones and support classification of the five individuals as distinct genotypes. Both differential competitive responses (alteration in performance) and competitive effects (impediment by competitor performance) were exhibited among genotypes. The differential response by the T. officinale genotypes to the competitors indicates that the biotic environment may influence the genetic structure of a population. The biotic environment in this case is determined by the sequential appearance and dominance of competitors in a field rather than the spatial distribution of these competitors. Since competitors change in relative dominance across seasons, competition is likely to be a component of the genotype by season interaction that had been observed in the natural population. Thus, differential responses among genotypes to a temporally and spatially fluctuating biotic environment may contribute to the maintenance of within-population genetic diversity. PMID- 21684979 TI - Sapling biomass allocation and growth in the understory of a deciduous hardwood forest. AB - Above- and belowground tissues of co-occurring saplings (0.1-1 m height) of Acer saccharum Marsh. (very shade tolerant), Acer rubrum L. (shade tolerant), Fraxinus americana L. (intermediate shade tolerant), and Prunus serotina Ehrh. (shade intolerant) were harvested from a forest understory to test the hypothesis that the pattern of biomass allocation varied predictably with shade-tolerance rank. The placement and length of branches along the main axis were consistent with the formation of a monolayer of foliage for the tolerant and intermediate species. Other morphological characteristics did not vary predictably with shade-tolerance rank. The maintenance of high specific leaf area (SLA; leaf area/leaf mass) and leaf area ratio (LAR; leaf area/sapling mass) is considered important for growth under extreme shade, yet these traits were not clearly related to the shade tolerance rank of these species. Fraxinus americana, an intermediate species, had the highest LAR and growth rate in the understory, and with the exception of P. serotina, the very shade-tolerant A. saccharum had the lowest LAR. Prunus serotina maintained a large starch-rich tap root and shoot dieback was common, yielding the largest root/shoot ratio for these species. The observed allocation patterns were not similar to the long-standing expectation for the phenotypic response of juvenile trees to shade, but were consistent with three hypothetical "growth strategies" in the understory: (1) the low SLA and LAR of A. saccharum may provide a measure of defense against herbivores and pathogens and thus promote persistence in the understory, (2) the high SLA for F. americana and high LAR for F. americana and A. rubrum may enable these species to achieve high growth rates in shade, and (3) the large carbohydrate stores of P. serotina may poise this species for opportunistic growth following disturbance. The relative importance of resistance to herbivores and pathogens vs. the maintenance of high growth rates may be important in evaluating the patterns of biomass allocation in the understory. PMID- 21684980 TI - A new fossil flower from the Turonian of New Jersey: Dressiantha bicarpellata gen. et sp. nov. (Capparales). AB - Recent discoveries of fossil reproductive structures from deposits of the Raritan Formation in New Jersey (Turonian, Upper Cretaceous, ~90 million years BP) include a previously undescribed representative of the Order Capparales. The fossils are usually charcoalified with three-dimensional structure and excellent anatomical details. In the present contribution, we introduce a taxon represented by fossil flowers that have a combination of characters now found in the families of the Order Capparales sensu Cronquist. The fossil species is characterized by an unique suite of characters, such as the presence of a gynophore, arrangement of the sepals, unequal petal size, monothecal anthers, and a bicarpellate gynoecium, that are found in extant families of the Order Capparales. This new taxon constitutes an important addition to our understanding of Cretaceous angiosperm diversity and represents the oldest known fossil record for the Capparales. Heretofore, the oldest known capparalean was from the Late Tertiary sediments of North America. PMID- 21684981 TI - Origins of domestication and polyploidy in oca (Oxalis tuberosa : Oxalidaceae): nrDNA ITS data. AB - As part of a study aimed at elucidating the origins of the octoploid tuber crop "oca," Oxalis tuberosa, DNA sequences of the internal trancribed spacer of nuclear ribosomal DNA (nrDNA ITS) were determined for oca and several wild Oxalis species, mostly from Bolivia. Phylogenetic analysis of these data supports a group of these species as being close relatives of oca, in agreement with morphology and cytology, but at odds with traditional infrageneric taxonomy. Variation in ITS sequences within this group is quite low (0-7 substitutions in the entire ITS region), contrasting with the highly divergent (unalignable in some cases) sequences within the genus overall. Some groups of morphologically differentiated species were found to have identical sequences, notably a group that includes oca, wild populations of Oxalis that bear small tubers, and several other clearly distinct species. The presence of a second, minor sequence type in at least some oca accessions suggests a possible contribution from a second genome donor, also from within this same species group. ITS data lack sufficient variation to elucidate the origins of oca precisely, but have identified a pool of candidate species and so can be used as a tool to screen yet unsampled species for possible progenitors. PMID- 21684982 TI - Phylogeny of Podocarpaceae: comparison of evidence from morphology and 18S rDNA. AB - Maximum parsimony analyses of the genera of Podocarpaceae were conducted using sequence data from 18S ribosomal DNA. Trees from sequence, morphological, and combined data differ in taxon arrangement, but are similar in that Podocarpus sensu lato and Dacrydium s.l. are unnatural, while Podocarpaceae (including Phyllocladus) are monophyletic. The clade Microcachrys + Microstrobos is recognized in all analyses, but its placement differs, i.e., nested among other scale-leaved taxa in the morphological analysis, but associated with Nageia and other tropical genera in the sequence analyses. Trees from combined data reflect this ambiguity. Podocarpus sensu stricto is paraphyletic according to most trees. Inferences of plesiomorphic character states within the family are largely consistent between analyses and support the view that prototypical podocarps had bifacial leaves, cones with several fertile cone scales, and large epimatia (cone scales) that covered the inverted ovules. PMID- 21684983 TI - Parallel evolution of glucosinolate biosynthesis inferred from congruent nuclear and plastid gene phylogenies. AB - The phytochemical system of mustard-oil glucosides (glucosinolates) accompanied by the hydrolytic enzyme myrosinase (beta-thioglucosidase), the latter usually compartmented in special myrosin cells, characterizes plants in 16 families of angiosperms. Traditional classifications place these taxa in many separate orders and thus imply multiple convergences in the origin of this chemical defense system. DNA sequencing of the chloroplast rbcL gene for representatives of all 16 families and several putative relatives, with phylogenetic analyses by parsimony and maximum likelihood methods, demonstrated instead a single major clade of mustard-oil plants and one phylogenetic outlier. In a further independent test, DNA sequencing of the nuclear 18S ribosomal RNA gene for all these exemplars has yielded the same result, a major mustard-oil clade of 15 families (Akaniaceae, Bataceae, Brassicaceae, Bretschneideraceae, Capparaceae, Caricaceae, Gyrostemonaceae, Koeberliniaceae, Limnanthaceae, Moringaceae, Pentadiplandraceae, Resedaceae, Salvadoraceae, Tovariaceae, and Tropaeolaceae) and one outlier, the genus Drypetes, traditionally placed in Euphorbiaceae. Concatenating the two gene sequences (for a total of 3254 nucleotides) in a data set for 33 taxa, we obtain robust support for this finding of parallel origins of glucosinolate biosynthesis. From likely cyanogenic ancestors, the "mustard oil bomb" was invented twice. PMID- 21684984 TI - Polyphenol deposition in leaf hairs of Olea europaea (Oleaceae) and Quercus ilex (Fagaceae). AB - The subcellular localization (cytoplasm, vacuoles, cell walls) of polyphenol compounds during the development of the multicellular nonglandular leaf hairs of Olea europaea (scales) and Quercus ilex (stellates), was investigated. Hairs of all developmental stages were treated with specific inducers of polyphenol fluorescence, and the bright yellow-green fluorescence of individual hairs was monitored with epifluorescence microscopy. During the early ontogenetic stages, bright fluorescence was emitted from the cytoplasm of the cells composing the multicellular shield of the scales of O. europaea. Transmission electron micrographs of the same stages showed that these cells possessed poor vacuolation and thin cell walls. The nucleus of these cells may be protected against ultraviolet-B radiation damage. The progressive vacuolation that occurred during maturation was followed by a shifting of the bright green-yellow fluorescence from the perinuclear region and the cytoplasm to the cell walls. The same trends were observed during the development of the nonglandular stellate hairs of Quercus ilex, in which maturation was also accompanied by a considerable secondary thickening of the cell walls. Despite the differences in morphology, high concentrations of polyphenol compounds are initially located mainly in the cytoplasm of the developing nonglandular hairs, and their deposition on the cell walls takes place during the secondary cell wall thickening. These structural changes during the development of the leaf hairs make them a very effective barrier against abiotic (uv-B radiation) and probably biotic (pathogenic) stresses. PMID- 21684985 TI - Allozyme and RAPD analysis of the genetic diversity and geographic variation in wild populations of the American chestnut (Fagaceae). AB - Genetic variation among 12 populations of the American chestnut (Castanea dentata) was investigated. Population genetic parameters estimated from allozyme variation suggest that C. dentata at both the population and species level has narrow genetic diversity as compared to other species in the genus. Average expected heterozygosity was relatively low for the population collected in the Black Rock Mountain State Park, Georgia (He = 0.096 +/- 0.035), and high for the population in east central Alabama (He = 0.196 +/- 0.048). Partitioning of the genetic diversity based on 18 isozyme loci showed that ~10% of the allozyme diversity resided among populations. Cluster analysis using unweighted pair-group method using arithmetric averages of Rogers' genetic distance and principal components analysis based on allele frequencies of both isozyme and RAPD loci revealed four groups: the southernmost population, south-central Appalachian populations, north-central Appalachian populations, and northern Appalachian populations. Based on results presented in this study, a conservation strategy and several recommendations related to the backcross breeding aimed at restoring C. dentata are discussed. PMID- 21684986 TI - Multiple paternity in fruits of Ipomopsis aggregata (Polemoniaceae). AB - Two different mechanisms can result in multiple paternity within fruits: deposition of a mixed pollen load due to carryover of pollen from flower to flower and multiple pollinator visits in close succession. I investigated the extent of multiple paternity within fruits of Ipompsis aggregata containing from 2 to 14 seeds. A paternity analysis based on ten polymorphic isozyme markers revealed multiple paternity in a minimum of 68% (based on simple paternity exclusion) and up to 100% (based on identification of the most likely father) of the multiseeded fruits. The estimated number of fathers increased with the number of seeds in a fruit, with an average of four sires, and up to nine sires, represented in a single fruit. To explore whether this level of multiple paternity could be explained solely by simultaneous deposition of a mixed pollen load, I constructed a computer simulation model based on previous measurements of movement patterns and pollen carryover by the hummingbird pollinators. Model predictions provided a good match to observed values for number of sires per fruit. Thus, the extensive pollen carryover in this species and consequent mixed pollen loads can explain the high levels of multiple paternity in natural populations. PMID- 21684987 TI - SEM studies on vessels in ferns. 9. Dicranopteris (Gleicheniaceae) and vessel patterns in leptosporangiate ferns. AB - Ferns in which vessels have been demonstrated to date are phylogenetically relatively specialized and characteristic of habitats with marked extremes in temperature and water availability. These specifications do not apply to the Gleicheniaceae, which indicates that vessels may occur in a range of more primitive ferns, including those from more nearly mesic habitats. Vessels in Dicranopteris have perforation plates (both lateral and terminal) with morphology similar to that of lateral wall pitting as seen with light microscopy. Scanning electron microscopy (SEM) is therefore necessary to demonstrate presence of perforations. Vessel presence in Dicranopteris is important in forming a picture of vessel presence and specialization in ferns, the phylogenetic and ecological distribution of which may differ from the patterns found in monocotyledons and dicotyledons. We believe that presence of vessels may not be a reliable indicator of phylogenetic position among ferns. PMID- 21684988 TI - Characterization of 10 KDA prolamin genes in Phyllostachys aurea (Bambusoideae, Poaceae). AB - Prolamin is the dominant class of seed storage protein in grasses (Poaceae). Information on the 10 kDa multigene family coding for prolamins characteristic of the bambusoid-oryzoid grasses is limited. Two genes encoding 10 kDa prolamin were cloned and sequenced in the bambusoid species Phyllostachys aurea to assess the sequence diversity of this gene family in the oryzoid-bambusoid grasses. The genes, ~417 bp in length, were 96% similar at the DNA sequence level, differing in 12 base substitutions dispersed throughout the sequence. Eight of these mutations were nonsynonymous, leading to amino acid substitutions in the coding region, and one was nonsense, producing an amber stop codon. One gene had an open reading frame (ORF) of 139 amino acids, while the other gene had a shorter ORF (106 amino acids) due to the presence of a stop codon in the coding region and, thus, represents a pseudogene. Deduced proteins showed amino acid composition similar to that of rice. The study underscores the overall conserved nature of this multigene family and reflects considerable sequence divergence at the DNA and amino acid levels between the Oryza and the Phyllostachys genes. The systematic implication of the data is discussed in light of the inconsistent placement of Oryza in the Bambusoideae or Oryzoideae. PMID- 21684989 TI - Patterns of genetic variation detected by RAPDs suggest a single origin with subsequent mutations and long-distance dispersal in the apomictic fern Dryopteris remota (Dryopteridaceae). AB - Debates on speciation processes in pteridophytes have revived. In order to study the evolutionary origin of an apomictic fern species, we investigated the genetic variation in the strictly agamosporous Dryopteris remota. We determined the genotypes of 22 individuals from many different locations within the species' European distribution and of 20 individuals from a Swiss population. A previous study on isozyme variation showed no intraspecific genetic variation in a similar sample set (Schneller and Holderegger, 1994, American Fern Journal 84: 94-98). In contrast to this, four out of 12 random amplified polymorphic DNA (RAPD) primers tested revealed low genetic diversity among individuals of D. remota from different locations. Intrapopulational genetic variation was also very low, but in the single population studied, a unique multiband genotype could be detected. The geographic distribution of genetic variation found in D. remota was best explained by the assumption of a single origin, the accumulation of somatic mutations during spread, and occasional, but effective, events of dispersal over large distances. The present study thus stresses the importance of long-distance dispersal in evolutionary processes and biogeography of ferns. PMID- 21684990 TI - Evolution of novel morphological and reproductive traits in a clade containing Antirrhinum majus (Scrophulariaceae). AB - Phylogenetic analysis of DNA sequences of the chloroplast genes rcbL and ndhf revealed a highly supported clade composed of the families Plantaginaceae, Callitrichaceae, and Hippuridaceae in close association with the model organism Antirrhinum majus and other members of family Scrophulariaceae. Plantago has miniature actinomorphic wind-pollinated flowers that have evolved from zygomorphic animal-pollinated precursors. The aquatic Hippuridaceae have reduced windpollinated flowers with one reproductive organ per whorl, and three, rather than four, whorls. In monoecious aquatic Callitrichaceae, further reduction has occurred such that there is only one whorl per flower containing a single stamen or carpel. Optimization of character states showed that these families descended from an ancestor similar to Antirrhinum majus. Recent studies of plant developmental genetics have focused on distantly related species. Differences in the molecular mechanisms controlling floral development between model organisms are difficult to interpret due to phylogenetic distance. In order to understand evolutionary changes in floral morphology in terms of their underlying genetic processes, closely related species exhibiting morphological Variation should be examined. Studies of genes that regulate morphogenesis in the clade described here could aid in the elucidation of a general model tot such fundamental issues as how changes in floral symmetry, organ number, and whorl number are achieved, as well as providing insight on the evolution of dicliny and associated changes in pollination syndrome. PMID- 21684991 TI - Early development of androecia in polystemonous Hydrangeaceae. AB - Polystemonous androecia are diverse in both number and position of stamens. This investigation of polystemonous Hydrangeaceae uses developmental data to characterize (1) the range of developmental variations that account for the diverse androecial patterns and (2) how the expressions of polystemony among Hydrangeaceae compare to those found generally among other angiosperms and especially in their sister family, the Loasaceae, some of which have particularly complex androecia. All polystemonous Hydrangeaceae share the common element of stamen clusters in antesepalous positions. In each of these taxa, the first stamens are initiated opposite the medians of the sepals. Subsequently, stamens form laterally on the flanks of the initial antesepalous stamens, giving rise to the clusters designated as antesepalous triplets. The simplest elaborations based on those common initial developmental steps include (1) adding additional lateral flanking stamens and (2) adding a single stamen in each antepetalous position between adjacent antesepalous groups. More complex elaborations are characteristic of (1) Carpenteria and Philadelphus, which form common primordia at the beginning of androecial development and, subsequently, have stamen primordia form on them, and (2) Deinanthe, which has an elongate hypanthial region on which numerous whorls of stamens are initiated. Carpenteria is unique among Hydrangeaceae in having groups of stamens that are initiated centrifugally in antepetalous positions, and this is similar to complex elements found among some Loasaceae. Generally, the polystemony of Hydrangeaceae that is based in the formation of antesepalous triplets is very similar to that found to evolve in parallel among various clades of rosids and asterids. PMID- 21684992 TI - Preferential states of longitudinal tension in the outer tissues of Taraxcum officinale (Asteraceae) peduncles. AB - We tested Wilhelm Hofmeister's hypothesis that the outer layers of herbaceous stem tissues are held in a preferential state of longitudinal tension by more internal stem tissues that are held in a reciprocal state of compression. We measured (1) the biaxial stiffness of dandelion peduncles that were barometrically inflated with a Scholander pressure bomb, and (2) the stiffness and mechanical behavior of different layers of tissues that were surgically manipulated as longitudinal strips placed in uniaxial tension. Hofmeister's hypothesis predicts that stems will shorten and expand in girth as their volume transiently increases (due to barometric or hydrostatic inflation), that they will longitudinally rupture when excessively inflated, and that the principal stiffening agents in their outer tissues will be aligned in the longitudinal direction with respect to stem length. Our experiments confirmed these predictions: (1) the longitudinal strains observed for inflated peduncles were negative and smaller than the circumferential strains such that stems contracted in length and expanded in girth, (2) peduncles longitudinally ruptured when excessively inflated, (3) surgical experiments indicated that the epidermis was stiffer in longitudinal tension than any other immature peduncle tissue and was as stiff as any other tissue region in mature stems, and (4) microscopic analyses showed that the net orientation of cellulose microfibrils in the cell walls of the outer region of stem tissues was parallel to stem length. A strong positive correlation existed between the tensile stiffness of tissues and the net orientation of cell wall microfibrils. PMID- 21684993 TI - Stem biomechanics of three columnar cacti from the Sonoran Desert. AB - The allometric relationship of stem length L with respect to mean stem diameter D was determined for 80 shoots of each of three columnar cactus species (Stenocereus thurberi, Lophocereus schottii, and S. gummosus) to determine whether this relationship accords with that predicted by each of three contending models purporting to describe the mechanical architecture of vertical shoots (i.e., geometric, stress, and elastic similitude, which predict L proportional to D(alpha), with alpha = 1/1, 1/2, and 2/3, respectively). In addition, anatomical, physical, and biomechanical stem properties were measured to determine how the stems of these three species maintain their elastic stability as they increase in size. Reduced major axis regression of L with respect to D showed that alpha = 2.82 +/- 0.14 for S. thurberi, 2.32 +/- 0.19 for L. schottii, and 4.21 +/- 0.31 for S. gummosus. Thus, the scaling exponents for the allometry of L differed significantly from that predicted by each of the three biomechanical models. In contrast, these exponents were similar to that for the allometry previously reported for saguaro. Analyses of biomechanical data derived from bending tests performed on 30 stems selected from each of the three species indicated that the bulk stem tissue stiffness was roughly proportional to L2, while stem flexural rigidity (i.e., the ability to resist a bending force) scaled roughly as L3. Stem length was significantly and positively correlated with the volume fraction of wood, while regression analysis of the pooled data from the three species (i.e., 90 stems) indicated that bulk tissue stiffness scaled roughly as the 5/3-power of the volume fraction of wood in stems. These data were interpreted to indicate that wood served as the major stiffening agent in stems and that this tissue accumulates at a sufficient rate to afford unusually high scaling exponents tot stem length with respect to stem diameter (i.e., disproportionately large increments of stem length with respect to increments in stem diameter). Nevertheless, the safety factor against the elastic failure of stems (computed on the basis of the critical buckling height divided by actual stem length) decreased with increasing stem size tot each species, even though each species maintained an average safety factor equal to two. We speculate that the apparent upper limit to plant height calculated for each species may serve as a biomechanical mechanism for vegetative propagation and the establishment of dense plant colonies by means of extreme stem flexure and ultimate breakage, especially for S. gummosus. PMID- 21684994 TI - Postglacial migration and the loss of allozyme variation in northern populations of Asclepias exaltata (Asclepiadaceae). AB - The recent Wisconsin glaciation has provided opportunities for examining the effects of postglacial recolonization on the population genetics of plant and animal communities. In this study allozyme Variation was examined in 19 populations of the herbaceous perennial Asclepias exaltata occurring in previously glaciated regions of North America. These northern populations of A. exaltata possess significantly fewer polymorphic loci (46.31 +/- 2.7; mean +/- 1 SD), alleles per polymorphic locus (1.84 +/- 0.24), and expected heterozygosity (0.133 +/- 0.031) than populations found in the Pleistocene refugium in the southern Appalachians. Population-level allozyme diversity decreased linearly from south to north and from east to west. Nineteen uncommon alleles previously observed in southern Appalachian populations were undetected in the northern region. Seven common alleles exhibited a clinal change in allele frequency. Of these, only Pgd-1a and Mnr-1c were at low-frequency in the southern Appalachians and increased significantly with increasing latitude and longitude, respectively. Despite this loss of allozyme diversity following postglacial migration, northern populations of A. exaltata have higher allozyme diversity and lower population differentiation (G" = 0.1 17) than mean values for other long-lived herbaceous perennials. Increased habitat fragmentation in northern regions and potential habitat loss in the southern Appalachians are likely to reduce the historically rich gene pool that has provided the genetic stock for postglacial recoveries. PMID- 21684995 TI - Do surface plant and soil seed bank populations differ genetically? A multipopulation study of the desert mustard Lesquerella fendleri (Brassicaceae). AB - Seed banks are an important component of many plant populations, but few empirical studies have investigated the genetic relationship between soil seeds and surface plants. We compared the genetic structure of soil seeds and surface plants of the desert mustard Lesquerella fendleri within and among five ecologically diverse populations at the Sevilleta National Wildlife Refuge in Central New Mexico. At each site, 40 Lesquerella surface plants and 40 samples of soil seeds were mapped and genetically analyzed using starch gel electrophoresis. Overall allele frequencies of soil seeds and surface plants showed significant differences across the five populations and within three of the five individual populations. Surface plants had significantly greater amounts of single and multilocus heterozygosity, and mean surface plant heterozygosity was also greater at the total population level and in four of the five individual populations. Overall soil seed (bot not surface plant) homozygosity was significantly greater than predicted by Hardy-Weinberg expectations at the total and individual population levels. Although F-alpha estimates revealed similarly small but significant genetic divergence within each life-history stage, estimates of coancestry showed that fine-scale (0.5-2 m) genetic correlations among the surface plant genotypes were roughly twice those of soil seed genotypes. An unweighted pair group method with arithrnetic mean cluster analysis indicated that in the two geographically closest sites, the surface plants were slightly more genetically similar to each other than to their own respective seed banks. We also found weak and/or negative demographic associations between Lesquerella soil seed and surface plant densities within each of the five sites. We discuss the difficulties involved with sampling and genetically comparing these two life history stages. PMID- 21684996 TI - Latitudinal population differentiation in two species of Solidago (Asteraceae) introduced into Europe. AB - Solidago altissima and S. gigantea were introduced from North America to Europe ~250 yr ago and are now considered aggressive weeds in abandoned fields and conservation areas. We studied patterns of genetic differentiation in these two species along their present latitudinal range in Europe (44-61 degrees N). Two generations of clonally propagated ramets from randomly selected genets of 24 populations of each species were grown in a common-garden experiment at latitude 47 degrees N from 1991 to 1992. Both species showed significant variation among populations in morphological and life-history characters: at this southern location, plants from northern populations were smaller and flowered earlier than plants from southern populations. The gradient of clinal variation was more pronounced in the second year of cultivation than in the first and was steeper in S. altissima than in S. gigantea. Within-population variation among genotypes was significant tot most characters in the case of S. altissima. Phenological rate (reciprocal of days to flowering) and size at maturity showed a significant negative correlation among populations bot not among genotypes within populations, indicating that genetic trade-offs may occur at one but not another infraspecific level. We suggest that the pattern of among-population variation reflects rapid adaptive population differentiation after introduction of the species to Europe. PMID- 21684997 TI - Fossil Clusiaceae from the late Cretaceous (Turonian) of New Jersey and implications regarding the history of bee pollination. AB - The Turonian flora from Sayreville New Jersey includes one of the world's most diverse assemblages of Cretaceous angiosperm flowers. This flora is made even more interesting by its association with a large insect fauna that is preserved by charcoalification as well as in amber. Floral diversity includes numerous representatives of Magnoliidae, Hamamelididae, Rosidae, Dilleniidae, and Asteridae (Ericales sensu lato). Included are hypogynous, five-merous flowers with uniseriate hairs on the pedicels and stamens in bundles most frequently borne opposite the petals. There is considerable variation in filament length, and some filaments are branched. On some anthers, strands of residue, suggesting the former presence of a liquid of unknown nature, partially occlude the apparent zone of dehiscence. In other cases, open anthers are fully occluded by an amorphous substance. Pollen is rarely found associated with anthers, but is common on stigmatic surfaces. Pollen is prolate and tricolporate with reticulate micromorphology. The superior syncarpous ovary is five-carpellate with axile/intruded parietal placentation and numerous anatropous ovules/carpel. Ovary partitions have closely spaced, parallel ascending channels (secretory canals?), and there are apparent secretory canals/cavities in receptacles, sepals, and petals. Individual stigmas are cuneiform with a central groove and eccentrically peltate. Styles are short and fused. In aggregate, the stigmas form a secondarily peltate stigma. Seeds have a reticulate sculpture pattern, a pronounced raphe, and funicular arils with sculpture similar to the seeds. Phylogenetic analyses of several data matrices of extant taxa place this fossil in a monophyletic group with the modern genera Garcinia and Clusia within the Clusiaceae. As such, these fossils represent the earliest fossil evidence of the family Clusiaceae. Some modern Clusiaceae are notable, in particular, for their close relationship with meliponine and other highly derived bee pollinators; the fossil flowers share several characters that suggest a similar mode of pollination. This possibility is consistent with other floral and insect data from the same locality. PMID- 21684998 TI - Interspecific relationships in Fagopyrum (Polygonaceae) revealed by the nucleotide sequences of the rbcL and accD genes and their intergenic region. AB - DNA sequences of the rbcL and accD 5' coding regions and their intergenic region (IGR) were determined in 20 taxa of 12 species of Fagopyrum. By comparing the sequence data and constructing phylogenetic trees, phylogenetic relationships among Fagopyrum species were investigated. The accD 5' coding region and the IGR have evolved about five times faster than the rcbL coding region; hence the phylogenetic trees based on the data of the accD 5' coding region, the IGR, and these data combined, had higher resolution than the trees based on rcbL alone. The classification of Fagopyrum based on the DNA sequences was almost perfectly consistent with the classification by Ohnishi and Matsuoka (1996, Genes & Genetic Systems 71: 383-390). New facts and minor differences are (1) polyploidization in F. cymosum might have occurred more than once, (2) F. lineare may not be a sister species of F. leptopodum, and (3) F. pleioramosum rather than F. capillatum may be a sister species of F. gracilipes. PMID- 21684999 TI - Morphology and molecular data in phylogenetic fraternity: the tribe Wrightieae (Apocynaceae) revisited. AB - The monophyly and classification of the tribe Wrightieae of the subfarnily Apocynoideae (Apocynaceae) are cladistically investigated. Nine taxa from the Wrightieae sensu Leeuwenberg, nine from other Apocynoideae sensu lato (s.I., including two from the traditional Asclepiadaceae), and two outgroup taxa from the Plumerioideae (Apocynaceae) were scored for rcbL sequence data and morphological data, mainly floral characters, and analyzed using successive weighting parsimony analysis. The Wrightieae sensu Leeuwenberg are shown to be largely paraphyletic, the constituent taxa being dispersed among four monophyletic clades. Previously not suggested relationships indicated by the study are the association of Pachypodium with Funtumia, Holarrhena, and Mascarenhasia and the position of Beaumontia close to Trachelospermum. A reclassification of the Wrightieae is discussed, in which three of the identified clades are recognized as tribes, the Wrightieae sensu stricto (s.s.), the Nerieae, and the Malouetieae. The support for the Wrightieae s.s. is very strong, as evaluated with Bremer support and bootstrap analysis. The Malouetieae are also strongly supported, but the Nerieae less so. Using Potential morphological synapomorphies identified in the study, circumscription of the tribes is discussed. A potential pseudogene of rcbL is reported tot Beaumontia. PMID- 21685000 TI - Gall-inducing insects provide insights into plant systematic relationships. AB - Field surveys of cynipid gall-inducer occurrences on Quercus species were conducted in Florida, North Carolina, and Pennsylvania, USA. All cynipids demonstrated strong host species and organ fidelity. One result of this specialization is effective niche partitioning among cynipids. The host association patterns of these specialist herbivores should reflect similarities among oaks, thus we clustered oak species according to their cynipid distributions. Cynipids distinguished small differences among their hosts. A dendrogram of oak species based on cynipid distributions was largely congruent with botanical arrangernents. Cynipid occurrences offer information helpful to resolving some aspects of oak systematics. Collaborative efforts between taxonomic botanists and entomologists will be useful in resolving a variety of plant and insect systematic problems. PMID- 21685001 TI - Is relative pollen production or removal a good predictor of relative male fitness? An experimental exploration with a wild strawberry (Fragaria virginiana, Rosaceae). AB - Understanding plant reproduction requires knowledge of genetic contributions through pollen and seeds. Since direct genetic assessments of fitness through pollen are often intractable, reproductive ecologists use components of male fitness such as pollen production and pollen removal as surrogates tot paternity. However, we know little of the strength of the relationship between these components and actual paternity. Here, I report on a study undertaken to examine the relationship of pollen production and removal with paternity in Fragaria virginiana, a wild strawberry. A morphological marker was used to track paternity in experimental arrays exposed to native pollinators. Relative pellen production proved to be a poor predictor of relative paternity in most arrays, and over all arrays there was no significant correlation between relative paternity and relative pellen production. In contrast, relative pollen removed correlated significantly and positively with proportion of seeds sired, suggesting that a plant's contribution to the pool of removed pellen is a good predictor of its male reproductive success. Deviations from expected paternity based on relative pollen removal suggest a systematic overestimation of the siring success of plants with low pollen removal. And, in at least one specific case, low pellen removal may be explained by delayed anther dehiscence, which could lower the effectiveness of the removed pellen. PMID- 21685002 TI - Interspecific mating in the Piriqueta caroliniana (Turneraceae) complex: effects of pollen load size and composition. AB - Two taxa of Piriqueta (P. caroliniana and P. viridis) form a broad hybrid zone that extends over much of the central Florida peninsula. We used genetic markers to examine the strength of the isolation barriers between these taxa and the patterns of mating at the initial stages of hybridization. Regression models were employed to analyze the effects of pollen load size and the proportions of intra- and interspecific pollen on the frequency of first-generation (F1) hybrid formation. Overall, the postpollination mating barriers between these two taxa were relatively weak. However, there were significant effects of pollen load composition and size on the patterns of hybridization in both taxa with frequency dependent responses to composition in both taxa. The frequency of F1 hybrid formation was generally lower than expected based on the frequency of each pollen type on the stigma for P. caroliniana recipients. The lower frequencies of F1 seeds in this taxon were apparently due to a greater competitive ability for intraspecific pollen, since hybrid seed formation decreased with increasing pollen load size. Pollen from P. caroliniana donors was also competitively superior on P. viridis recipients, leading to higher than expected frequencies of hybrid seed formation. Pollen from P. caroliniana did suffer higher rates of pollen-tube attrition than intraspecific pollen on P. viridis recipients, so the frequency of hybrid seed formation would be lower when pellen load sizes were small. In general, reproductive isolation mechanisms were stronger in P. caroliniana, suggesting that introgression should occur into P. viridis when these taxa come into close contact. Comparison of these expected patterns of mating to the distribution of hybrid genotypes in Florida provides insights into the relative roles of mating and selection in the evolution of hybrid populations of Piriqueta. PMID- 21685003 TI - The evolution of beetle pollination in a South African orchid. AB - The pollination biology of the orchid Ceratandra grandiflora was investigated in order to determine whether the partial loss of a specialized floral reward (i.e., oil) was the result of an incomplete shift from one specialized pollinator to another. In the three-species clade of section Ceratandra, there has been a progressive loss of the oil-secreting callus. lt is always present in C atrata, sometimes present in C. grandiflora, and never present in C. globosa. Thirty-nine to 67% of individuals in populations of C. grandiflora bear the callus gland, but gland presence has no signifikant effect on the proportion of flowers pollinated. Pollinator observations show that the shift in pollinators is complete and that the oil-secreting callus is a vestige of the ancestral oil-bee pollination system that no longer plays a role in pollination. C grandiflora is pollinated almost exclusively by a single species of hopliine beetle (Scarabaeidae). Experiments with artificial flower traps indicate that color alone can explain the attraction of beetles to C. grandiflora, despite the absence of a floral reward. The proportion of C. grandiflora flowers pollinated (50.2 and 61.1%; N = 524 and 324 flowers, respectively) is unusually high for a plant that relies on generalized food deception and is probably due to the use of inflorescences as mating sites (i.e., rendezvous pollination). PMID- 21685004 TI - Allometry of axis length, diameter, and taper in the devil's walking stick (Aralia spinosa; Araliaceae). AB - The allometry of axis length, diameter, and taper is described for the trunk, rachis, and rachilla of nonbranching ramets of Aralia spinosa. Significant log linear relationships were found between length and diameter for all axis categories, and in all cases, scaling was negatively allometric. Linear models best described the relationship between length and diameter for the rachis and rachilla, while a quadratic model best described this relationship for the trunk. During the trunk-building stage, the safety factors for trunk height were size dependent, with larger trunks exceeding their predicted critical buckling height. Taper was described by a linear relationship between diameter and position along the axis for all axis categories. All rachises and rachillas sampled exhibited taper along the length of the axis, however, only 51% of the trunks showed continuous taper. The trunk was less tapered than the rachis, but no differences in taper were found between the trunk and the rachilla, or the rachis and the rachilla. In unbranched ramets the large bipinnately compound leaves occupy the space normally occupied by lateral branches. We suggest that the rachis and rachilla are functionally equivalent to branches, that is, acting as axes of exploration and exploitation of the environment. PMID- 21685005 TI - Resiliency and response to hurricane disturbance in atropical shrub, Ardisia escallonioides (Myrsinaceae), in southFlorida. AB - The resiliency to hurricane disturbance and the response toposthurricane environmental conditions were examined in the tropicalshrub Ardisia escallonioides (Myrsinaceae). Hurricane Andrewstruck three of four study sites in subtropical hardwood forests insouth Florida on 24 August 1992. Posthurricane understory light levelsin the disturbed sites ranged from 21 to 53% of full light in1993 and remained high in 1994; in contrast, light levels averaged only9% in the undisturbed forest. Significant differences inmortality, damage, and defoliation were observed among the threehurricane-damaged populations. Mortality was low, but adults sufferedhigh levels of damage and defoliation. Following the hurricane,populations in the most severely disturbed forests had more growth thanpopulations in lightly damaged or undamaged forests. Seed germinationand seedling growth were not associated with light availability. Nolong-term seed dormancy was observed. The observed response toposthurricane environmental conditions is consistent with understoryspecies that show release following canopy opening, but are able topersist under periods of canopy closure. The local dominance of thisspecies in many coastal forests in south Florida may be due to the highfrequency of hurricanedisturbance. PMID- 21685006 TI - Consequences of incongruency in diurnally varying resources for seedlings of Rumex crispus (Polygonaceae). AB - The incongruency of diurnally varying resources essential to plants may detrimentally affect plants early in their development as indicated by reduced water use efficiency and carbon gain. Typical diurnal patterns of light and CO(2) availability in a midsized temperate herbaceous or forest gap were simulated in specially designed growth chambers. A sinusoidally varying CO(2) treatment (400 ppm minimum, 800 ppm maximum) approximated the diurnal cycle of CO(2) at the soil surface, while a steady-state CO(2) treatment (600 ppm) with the same average CO(2 )concentration provided a control. Crossed with these two CO(2) treatments were two light regimes, one with 3 h of high light (850 MUmol.m.s) in the morning (west side of a gap), and the other with 3 h of high light in the afternoon (east side). All treatments received baseline low light (55 MUmol.m.s) for 14 h during the day. Rumex crispus was selected as a model species because of its rosette leaves, which grow close to the ground where diurnal CO(2 )variation is greatest. The relative timing of diurnal variations in light and CO(2) significantly affected seedling water use efficiency, carbon gain, and morphology. Total biomass, photosynthetic rates, daily integrated carbon, water use efficiency, and leaf area were enhanced by morning exposure to high light. Seedlings that were exposed to peak values of light and CO(2) incongruently, i.e., those plants receiving intense afternoon light with diurnally varying CO(2), were detrimentally affected relative to control plants receiving intense afternoon light with steady-state CO(2). The results of this experiment indicate that the incongruent availability of required resources-such as light and CO(2)-can detrimentally affect performance relative to when resources are congruent. These contrasting resource regimes can occur on the east and west side of gaps. PMID- 21685007 TI - Response of chaparral shrubs to below-freezing temperatures: acclimation, ecotypes, seedlings vs. adults. AB - Leaf death due to freezing was examined for four, co-occurring species of chaparral shrubs from the Santa Monica Mountains of southern California, Rhus laurina (= Malosma laurina), R. ovata, Ceanothus megacarpus, and C. spinosus. Measurements were made on seedlings vs. adults for all species, and for Rhus spp. in winter vs. summer, and at a warm vs. a cold site. We used four methods to determine the temperature for 50% change in activity or cell death (LT(50)) of leaves: (1) electrical conductivity (electrolyte leakage into a bathing solution), (2) photosynthetic fluorescent capacity (Fv/Fm), (3) percentage of palisade mesophyll cells stained by fluorescein diacetate vital stain, and (4) visual score of leaf color (Munsell color chart). In all four species seedlings were found to be more sensitive to freezing temperatures than were adults by 1 degrees -3 degrees C. For adults the LT(50) ranged from -5 degrees C for Rhus laurina in the summer to -16 degrees C for Rhus ovata in the winter. The LT(50) of R. ovata located at a colder inland site was 4C lower than R. ovata at the warmer coastal site just 4 km apart, suggesting ecotypic differences between R. ovata at the two sites. Both R. laurina and R. ovata underwent significant winter hardening. At the cold site, R. ovata acclimated by 6 degrees C on average, while R. laurina acclimated by only 3 degrees C. These results were consistent with species distributions and with field observations of differential shoot dieback between these two congeneric species after a natural freeze-thaw event in the Santa Monica Mountains. PMID- 21685008 TI - Female fertility per flower and trade-offs between size and number in Claytonia virginica (Portulacaceae). AB - A consistent and paradoxical feature in flowering plants is the production of many more flowers than appear required for female fertility through fruit and seed production. Many mechanistic hypotheses for this observation share key assumptions about (1) limited resources available for reproduction and (b) greater female fertility benefits from larger flowering-time investment. Here I investigate these assumptions in two populations of Claytonia virginica. I also test predictions from theoretical analyses, comparing patterns of flowering allocation and fertility per flower in 18 populations of C. virginica. Results support the assumption that larger benefits accrue from greater flowering-time investment. The between-population pattern of flowering allocation and fertility per flower is also consistent with theoretical expectation, although not statistically significant. Not supported is the assumption that reproduction occurs under strong resource constraint. Possible reasons for this discrepancy are discussed. PMID- 21685009 TI - Cytological and molecular evaluation of the reproductive behavior of Tripsacum andersonii and a female fertile derivative (Poaceae). AB - Research was conducted to characterize the reproductive behavior of the highly sterile Tripsacum andersonii Gray and its viable progeny through breeding, cytological, and molecular studies. Four progeny were obtained from open pollinated seeds of clones (M-34445, M-34450 and M-34455) of T. andersonii maintained at the USDA-ARS National Germplasm Repository, Miami, Florida. One of the progeny had 64 chromosomes, which is typical of T. andersonii, and probably resulted from apomictic reproduction. Karyotypes of the other three progeny indicated a tetraploid Tripsacum genomic constitution (2n = 4x = 72) plus a haploid set of Zea (1n = 1x = 10) chromosomes. Two of these progeny were completely sterile, whereas one (95-51) produced ~5% seed set when crossed with diploid (2n = 36) T. dactyloides (L.)L. The partially fertile 95-51 produced four progeny, one with 2n = 72 (elimination of 10 Zea chromosomes), two with 2n = 82 (apomictic reproduction) and one with 2n = 100 (sexual polyploidization). Polymerase Chain Reaction - Random Amplified Polymerase DNA analysis verified that T. andersonii accessions from seven countries were genetically uniform, and that its progeny were derived through apomixis and sexual polyploidization. This analysis also confirmed that chromosome elimination, apomixis, and sexual polyploidization reproductive behaviors occur in the T. andersonii derivative 95 51. PMID- 21685010 TI - Ecological and genetic factors contributing to the low frequency of male sterility in Chamaecrista Fasciculata (Fabaceae). AB - Bumble bee pollinated Chamaecrista fasciculata provides pollen as the sole reward to its pollinators. Male sterility, expressed as an absence or nearly complete absence of pollen production, occurs in low frequency in populations of C. fasciculata. Here we describe experiments, using C. fasciculata, to examine frequently cited determinants of the spread and maintenance of male sterility: compensation and the genetic basis of male sterility. In addition, we examine the role the pollination system plays in determining the reproductive success of the male steriles. Seventeen populations in Maryland, Illinois, and Kansas were surveyed and found to range from 0 to 6% male sterility per population. An artificial population of male-sterile simulants and hermaphrodites was created to examine how the local frequency of nonrewarding male steriles might affect male sterile female reproductive success. Male steriles performed equally poorly, with respect to seed production, whether surrounded by other male-sterile simulants or hermaphrodites. Compensation was examined by comparison of male steriles and hermaphrodites with respect to several reproductive and nonreproductive characters. Male steriles outperformed hermaphrodites in terms of nonreproductive biomass, but performed equally in terms of ovule number and produced many fewer flowers. The genetic basis of male sterility was examined by performing both intra- and interpopulational crosses of male steriles to hermaphrodites and indicate that male sterility is not purely cytoplasmic. The low frequency of male sterility in C. fasciculata populations may reflect reduced female reproductive success because of pollinator avoidance, lack of reproductive compensation, and a mode of inheritance that is not purely cytoplasmic. PMID- 21685011 TI - Genetic diversity and gene flow in the endangered dwarf bear poppy, Arctomecon humilis (Papaveraceae). AB - Arctomecon humilis is a critically endangered species endemic to the Moenkopi shale of Washington County, Utah. Recovery plans for the species would be improved by an understanding of genetic diversity and gene flow among its remaining populations. Ten variable isozyme loci were used to calculate genetic diversity statistics for study populations. Westerly populations possessed higher levels of genetic variability than other populations at the same isozyme loci. Three of the populations exhibited significant deviations from Hardy-Weinberg expectations. No correlation existed between genetic distance and geographic distance. Most of the genetic diversity was distributed among populations with little gene flow between populations, suggesting that observed genetic differences may arise from genetic drift. For the westerly populations, similar genotypes were observed in the seedling and old age classes, while intermediate age classes typically possessed an alternate set of genotypes at Pgi-2. Mean heterozygosity increased with age class across populations. Westerly populations of A. humilis shared more alleles with the nearest geographic population of A. californica than other populations. Since the westerly populations contained more genetic variability and more alleles in common with a near relative, they may be relictual. Other populations may contain less genetic diversity due to founder effects and/or genetic drift. PMID- 21685012 TI - Variation in allozymes and stomatal size in pinyon (Pinus edulis, Pinaceae), associated with soil moisture. AB - Microgeographic allozyme variation was examined in pinyon pine, Pinus edulis, among five collection sites in Owl Canyon, Colorado. Relatively dry and moist sites were identified by associated plant communities and the sizes and densities of trees. Three moist sites and two dry sites were compared, and because all sites were within 600 m of one another, isolation by distance was not considered as a viable explanation of genetic differentiation between sites. Allelic frequencies at glycerate dehydrogenase (Gly) differed by 14% between moist and dry areas, and the pattern of microgeographic variation found here-allele 3 higher in frequency on dry sites-was consistent with previous studies of microgeographic variation in contrasting moist and dry sites. Trees within one of the dry sites were examined to test the hypothesis that stomata sizes and densities are heterogeneous among Gly genotypes. Heterozygotes had the longest and widest stomata; the stomatal area of heterozygotes was 28% greater than the stomatal area of homozygotes. Whereas the stomatal areas of the two homozygotes were similar, their shapes did not overlap when projected on a bivariate plot of length and width. These results suggest that stomatal shape may play a role in adapting pinyon to heterogeneity in soil moisture. PMID- 21685013 TI - Variation in response to defoliation between populations of Bouteloua curtipendula var. caespitosa (Poaceae) with different livestock grazing histories. AB - Distinctive plant growth and development have been associated with resistance to defoliation by herbivores. Descriptions of resistance (tolerance/avoidance) strategies are common, although little is known about genetic variation affecting their expression in natural plant communities. This research compared response to three frequencies of defoliation in populations of Bouteloua curtipendula var. caespitosa from Arizona with different histories of exposure to domestic herbivores. One population occurs on a site that has likely been unaffected by large herbivores including cattle, while the other has been regularly grazed by cattle. Mixed-model analysis of variance was used to examine variation in traits associated with defoliation resistance. Data were collected in a 168-d greenhouse experiment using ramets of 15 genets from each population. Mortality was lower in the cattle-impacted population, suggesting improved defoliation resistance. This was associated with increased production of tillers with lower mass following defoliation. Plasticity was observed for all traits in response to different defoliation frequencies. The cattle-free population exhibited significant genetic variation for plasticity affecting leaf blade angle, while little variation was noted for this trait in the cattle-impacted population. Evidence of reduced genetic variation within the cattle-impacted population was noted for traits associated with defoliation resistance. In general, these observations are consistent with expectations following selection for resistance to defoliation. PMID- 21685014 TI - Two new fossil flowers of magnoliid affinity from the Late Cretaceous of New Jersey. AB - Two taxa of cupulate magnoliid fossil flowers, Cronquistiflora and Detrusandra, are described from the Late Cretaceous (Turonian, ~90 million years before present [MYBP]) Raritan (or lower Magothy) Formation of New Jersey. The fossil taxa are represented by flowers at various stages of development, associated fragments of cup-shaped floral receptacles with attached anthers, and isolated anthers. Both taxa have laminar stamens with adaxial thecae and valvate dehiscence. Pollen is boat-shaped and foveolate in anthers associated with Cronquistiflora and spherical with reticulate ornamentation in Detrusandra. Cup shaped receptacles are externally bracteose in both taxa. The receptacle of Cronquistiflora is broader than the campanulate one of Detrusandra. Cronquistiflora also has more carpels (~50 in a spiral vs. ~5 in a whorl or tight spiral). In Detrusandra the carpels are surrounded by dorsiventrally flattened structures (pistillodes?) that are remote from the attachment of the stamens near the distal rim of the receptacular cupule. Detrusandra stigmas are rounded and bilobed, while those of Cronquistiflora, although bilateral in symmetry, are somewhat peltate. The fossil taxa share prominent characters with extant cupulate magnoliids (e.g., Eupomatia, Calycanthus), but also share characters with other magnoliids including Winteraceae. These fossils represent taxa that are character mosaics relative to currently recognized families. Inclusion of these fossils in existing data matrices and ensuing phylogenetic analyses effect changes in tree topologies consistent with their mosaicism relative to modern taxa. But such analyses do not definitively demonstrate the affinities of the fossils other than illustrating that these fossils are generalized magnoliids. Additional analysis of modern and fossil magnoliids is necessary to fully appreciate the phylogenetic significance and positions of these fossil taxa. However, the results of the phylogenetic analyses do introduce the possibility that extinct taxa of Magnoliales with cupulate floral receptacles were transitional between basal angiosperms and those with tricolpate pollen. The fossils provide insights into the timing of evolution of character complexes now associated with coleopteran pollination. PMID- 21685015 TI - Reconstruction of the Jurassic conifer Sewardiodendron laxum (Taxodiaceae). AB - Compressed seed cones and pollen cones of Sewardiodendron laxum are described from the Middle Jurassic of Yima, Henan, central China. They are either organically attached to or associated with leafy shoots. Seed cones are terminally borne. Each cone is ovate to elongated, up to 6.5 cm long and 3.5 cm wide, and consists of a stout axis and numerous helically arranged bract-scale complexes. The bract protrudes beyond and is partially fused with the reduced ovuliferous scale. The ovuliferous scale bears approximately six inverted, small, and flattened seeds. Pollen cones are borne in terminal clusters. Microsporophylls are helically arranged, each bearing three abaxial, basally fused pollen sacs. Pollen is assaccate, rounded, and with an inconspicuous pore. Morphological, structural, and cuticular features of seed cones, pollen cones, and leafy shoots of S. laxum are compared with those of fossil and extant conifers. S. laxum is included in Taxodiaceae and believed to have its closest affinities with a Mesozoic conifer Elatides and a group of Cunninghamia-like conifers. It is reconstructed as a half-evergreen tree that lived in a humid, warm-temperate climate. PMID- 21685016 TI - The tortoise and the hare: choosing between noncoding plastome and nuclear Adh sequences for phylogeny reconstruction in a recently diverged plant group. AB - Phylogenetic resolution is often low within groups of recently diverged taxa due to a paucity of phylogenetically informative characters. We tested the relative utility of seven noncoding cpDNA regions and a pair of homoeologous nuclear genes for resolving recent divergences, using tetraploid cottons (Gossypium) as a model system. The five tetraploid species of Gossypium are a monophyletic assemblage derived from an allopolyploidization event that probably occurred within the last 0.5-2 million years. Previous analysis of cpDNA restriction site data provided only partial resolution within this clade despite a large number of enzymes employed. We sequenced three cpDNA introns (rpl16, rpoC1, ndhA) and four cpDNA spacers (accD-psaI, trnL-trnF, trnT-trnL, atpB-rbcL) for a total of over 7 kb of sequence per taxon, yet obtained only four informative nucleotide substitutions (0.05%) resulting in incomplete phylogenetic resolution. In addition, we sequenced a 1.65-kb region of a homoeologous pair of nuclear-encoded alcohol dehydrogenase (Adh) genes. In contrast with the cpDNA sequence data, the Adh homoeologues yielded 25 informative characters (0.76%) and provided a robust and completely resolved topology that is concordant with previous cladistic and phenetic analyses. The enhanced resolution obtained using the nuclear genes reflects an approximately three- to sixfold increase in nucleotide substitution rate relative to the plastome spacers and introns. PMID- 21685017 TI - A mating system conundrum: hybridization in Apocynum (Apocynaceae). AB - Based upon an intermediate morphology, Apocynum x-floribundum Greene has long been considered a hybrid involving A. androsaemifolium and A. cannabinum. The floral morphology in this genus, however, appears to prohibit both import and export of pollen, and observations of numerous insect visitors reveal that pollen is not routinely carried from flower to flower. Furthermore, reproductive success as measured by fruit set is very low in most populations. Hybridization was thus called into question, with allozyme evidence used to test the hypothesis of a hybrid origin for A. x-floribundum. Six diagnostic loci, as well as two loci exhibiting highly disparate allele frequencies, were resolved for each parent. All examined populations of A. x-floribundum were heterozygous at these loci, thus supporting the hypothesis of hybridization. Evidence from additional loci indicated that all populations tend to be strongly clonal. Observed heterozygosity was very low in the parental species, suggesting a history of inbreeding or a severe bottleneck. There was no support for earlier assumptions that some intermediates are derived from backcrosses or "secondary hybrids." Statistical analyses of plant height, leaf shape, petal length, sepal length, follicle length, seed length, and seed number per follicle supported these conclusions. The persistence and vegetative spread of hybrid clones may contribute to the illusion that hybridization is common. PMID- 21685018 TI - Circumscription and phylogeny of the Orthotrichales (Bryopsida) inferred from RBCL sequence analyses. AB - The affinities as well as the circumscription of the Orthotrichaceae (Bryopsida), one of the most diverse families of mosses, have been the focus of a controversy for much of the last century. We obtained rbcL sequences for 37 arthrodontous mosses, including 27 taxa of the Orthotrichales. The sequences were analyzed using maximum parsimony and neighbor joining in order to (1) test the monophyly of the Orthotrichales and the Orthotrichaceae; (2) determine their phylogenetic relationships; and (3) test the current subfamilial classification within the Orthotrichaceae. Both analyses suggest that the Orthotrichales are polyphyletic. The Erpodiaceae and the Rhachitheciaceae as well as Amphidium and Drummondia, two genera of the Orthotrichaceae, are shown to be of haplolepideous affinity. The Splachnales, the Bryales sensu lato, and the Orthotrichales form a monophyletic clade sister to the Haplolepideae. Both neighbor joining and maximum parsimony also suggest that the Orthotrichaceae are composed of two major lineages dominated either by acrocarpous or cladocarpous taxa. The monophyly of the family is, however, only well supported by Tamura's distances. The genera Macrocoma, Macromitrium, Orthotrichum, Ulota, and Zygodon all appear to be artificial assemblages. This study illustrates the contribution of rbcL sequence data to bryophyte systematics and, particularly, in determining the affinities of taxa lacking a peristome, whose characters are central to the classification of mosses. PMID- 21685019 TI - A chloroplast DNA phylogeny of lilacs (Syringa, Oleaceae): plastome groups show a strong correlation with crossing groups. AB - Phylogenetic relationships and genomic compatibility were compared for 60 accessions of Syringa using chloroplast DNA (cpDNA) and nuclear ribosomal DNA (rDNA) markers. A total of 669 cpDNA variants, 653 of which were potentially phylogenetically informative, was detected using 22 restriction enzymes. Phylogenetic analyses reveal four strongly supported plastome groups that correspond to four genetically incompatible crossing groups. Relationships of the four plastome groups (I(II(III,IV))) correlate well with the infrageneric classification except for ser. Syringa and Pinnatifoliae. Group I, which includes subg. Ligustrina, forms a basal lineage within Syringa. Group II includes ser. Syringa and Pinnatifoliae and the two series have high compatibility and low sequence divergence. Group III consists of three well-defined species groups of ser. Pubescentes. Group IV comprises all members of ser. Villosae and has the lowest interspecific cpDNA sequence divergences. Comparison of cpDNA sequence divergence with crossability data indicates that hybrids have not been successfully generated between species with divergence greater than 0.7%. Hybrid barriers are strong among the four major plastome groups, which have sequence divergence estimates ranging from 1.096 to 1.962%. In contrast, fully fertile hybrids occur between species pairs with sequence divergence below 0.4%. Three regions of the plastome have length variants of greater than 100 bp, and these indels identify 12 different plastome types that correlate with phylogenetic trees produced from cpDNA restriction site data. Biparentally inherited nuclear rDNA and maternally inherited cpDNA length variants enable the identification of the specific parentage of several lilac hybrids. PMID- 21685020 TI - Integrated transcriptional and proteomic analysis with in vitro biochemical assay reveal the important role of CYP3A46 in T-2 toxin hydroxylation in porcine primary hepatocytes. AB - Both T-2 toxin and its metabolites are highly potent mycotoxins that can cause severe human and animal diseases upon exposure. Understanding the toxic mechanism and biotransformation process of T-2 toxin at a cellular level is essential for the development of counter-measures. We investigated the effect of T-2 toxin in porcine primary hepatocytes using porcine genome array and two-dimensional difference gel electrophoresis with matrix-assisted laser desorption/ionization tandem time of flight mass spectrometry. Integrated transcriptional and proteomic analysis demonstrated that T-2 toxin adversely affected porcine hepatocytes by initiating lipid metabolism disorder, oxidative stress response, and apoptosis. In addition, xenobiotic metabolism genes, including cytochrome P450 3As (CYP3A46 and CYP3A39), carboxylesterase 1Cs (CES1C4 and CES1C5), and epoxide hydrolase (EPHX1), increased in T-2 toxin treatment cells. Using HepG2 cells to over express the recombinant xenobiotic metabolism genes above and rapid resolution liquid chromatography/tandem mass spectrometry to detect metabolites of T-2 toxin, we determined that porcine CYP3A46 mainly catalyzed T-2 to form 3'-hydroxy T-2, which was further confirmed by purified CYP3A46 protein. However, recombinant porcine CES1C5 and EPHX1 did not enhance hydrolysis and de epoxidation of T-2 implying that other esterases and epoxide hydrolases may play dominant roles in those reactions. PMID- 21685021 TI - Trajectories of illness in stage 5 chronic kidney disease: a longitudinal study of patient symptoms and concerns in the last year of life. AB - BACKGROUND AND OBJECTIVES: The illness trajectory in the last year of life in advanced (stage 5) chronic kidney disease is poorly understood. Mapping the trajectory of patient-centered outcomes could facilitate better care. The objectives of this study were to determine trajectories of symptoms and wider health-related concerns in the last year of life in stage 5 chronic kidney disease, managed without dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A longitudinal symptom survey in three UK renal units was used, using the Memorial Symptom Assessment Scale-Short Form and core Palliative Care Outcome Scale. Average (using mean scores over time) and individual (using individual scores over time, with visual graphical analysis) trajectories were mapped. RESULTS: Seventy-four patients (mean age, 81 +/- 6.8 years) were recruited; 49 died during follow-up. Average trajectories showed moderate symptom distress and health-related concerns, with marked increase in the last 2 months of life. Visual graphical analysis enabled stable, increasing, or fluctuant individual trajectories to be identified. The proportion following these trajectories varied between outcome measures; regarding symptoms, 50% followed a stable pattern, 24% increased, and 21% fluctuated compared with 26%, 57%, and 21%, respectively, for health-related concerns. Inter-rater agreement in grouping trajectories was high (kappa statistic, 0.80 and 0.86, respectively). CONCLUSIONS: In the 2 months before death, patients reported a sharp increase in symptom distress and health related concerns. Health care should anticipate and address this increase, which may indicate the patients is approaching death. Considerable individual variation and flexibility/responsiveness of care is important: one size of service does not fit all. PMID- 21685022 TI - GFR decline and mortality risk among patients with chronic kidney disease. AB - BACKGROUND AND OBJECTIVES: Estimates of the effect of estimated GFR (eGFR) decline on mortality have focused on populations with normal kidney function, or have included limited information on factors previously shown to influence the risk of death among patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We retrospectively assessed the effect of rate of eGFR decline on survival of patients with CKD receiving primary care through a large integrated health care system in central Pennsylvania between January 1, 2004, and December 31, 2009. RESULTS: A total of 15,465 patients were followed for a median of 3.4 years. Median rates of eGFR change by those in the lower, middle, and upper tertiles of eGFR slope were -4.8, -0.6, and 3.5 ml/min per 1.73 m(2)/yr, respectively. In Cox proportional hazard modeling for time to death, adjusted for baseline proteinuria, changes in nutritional parameters, and episodes of acute kidney injury during follow-up (among other covariates), the hazard ratio for those in the lower (declining) and upper (increasing) eGFR tertiles (relative to the middle, or stable, tertile) was 1.84 and 1.42, respectively. Longitudinal changes in nutritional status as well as episodes of acute kidney injury attenuated the risk only modestly. These findings were consistent across subgroups. CONCLUSIONS: eGFR change over time adds prognostic information to traditional mortality risk predictors among patients with CKD. The utility of incorporating eGFR trends into patient-risk assessment should be further investigated. PMID- 21685023 TI - Re-evaluating the Fistula First Initiative in Octogenarians on Hemodialysis. AB - BACKGROUND AND OBJECTIVES: Octogenarians frequently require maintenance hemodialysis (HD) for treatment of stage renal disease ESRD. Although the Fistula First Initiative recommends creating an arteriovenous fistula as the preferred dialysis access method, vascular access selection should be based on life expectancy and functional status at treatment initiation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a retrospective analysis of 4-year outpatient data (January 1, 2004 through December 31, 2007) of incident octogenarian dialysis population in an academic institution. Thirty-nine of 268 patients were octogenarians with a mean (+/- SD) age of 83.4 +/- 3.4 years, and 25 were men. Kaplan-Meier survival and Fisher's post hoc statistical analyses were performed. RESULTS: Thirty-seven octogenarian patients selected HD and two selected peritoneal dialysis. Among the 37 HD patients, 29 initiated dialysis with a tunneled cuffed catheter, 6 with an arteriovenous fistula, and 2 with an arteriovenous graft. Three patients regained renal function after an average 112 days and one was lost to follow-up. Of the 33 remaining on HD, 8 required nursing home admission and 25 were discharged home after initiating HD. Among these 33, 19 died and 14 remained on HD at the end of study period. Days on dialysis (mean +/- SEM) before death in those discharged to a nursing facility versus home were 52.6 +/- 14.7 versus 386.1 +/- 90.7 (P < 0.05), respectively. CONCLUSIONS: Vascular access planning should include assessment of functional status and life expectancy in octogenarian HD patients. PMID- 21685024 TI - Have we changed the outcome in membranous nephropathy? A propensity study on the role of immunosuppressive therapy. AB - BACKGROUND AND OBJECTIVES: The long-term effect of immunosuppressive therapy (IS) on kidney survival in idiopathic membranous nephropathy (MGN) is debated. The introduction of renin angiotensin blockade, rigorous BP control, and the increasing age at presentation of patients with MGN adds further uncertainty. Given these important changes, we sought to determine whether implementation of IS has altered outcome. DESIGN, SETTING, PARTICIPANTS, & METHODS: We prospectively evaluated 280 incident MGN patients from three distinct 10-year periods starting from 1975. RESULTS: We found expected changes in treatment regimens but also variations in age, renal function, severity of proteinuria, and BP at presentation over this time. Outcomes did not differ over time if these significant variations in clinical characteristics were not accounted for across the eras. The effect of IS in the 57 patients treated with currently recommended regimens was assessed using propensity adjustment to address selection bias and the effect of newer, conservative therapies. A propensity score estimating the probability of receiving IS permitted the pairing of 39 treated patients with controls with similar high risk of progression of clinical features. Using this approach, IS was associated not only with remissions in proteinuria but also with substantially improved renal survival. CONCLUSIONS: The study confirms that patient presenting characteristics and management regimens have changed significantly over time and the natural history of MGN has been altered. A study of propensity-matched patients confirms that current recommendations for IS have improved outcomes in MGN patients at high risk of progression. PMID- 21685025 TI - The knowns and the unknowns in HER2 testing in breast cancer. PMID- 21685026 TI - Pathology consultation on drug-induced hemolytic anemia. AB - Drug-induced immune hemolytic anemia is considered to be rare but is likely underrecognized. The consulting pathologist plays a critical role in integrating serologic findings with the clinical history, as drug-induced antibodies should be distinguished as either drug-dependent or drug-independent for appropriate clinical management. Drug-dependent antibodies (DDABs) are most commonly associated with cefotetan, ceftriaxone, and piperacillin, whereas fludarabine, methyldopa, beta-lactamase inhibitors, and platinum-based chemotherapeutics are frequent causes of drug-independent antibodies (DIABs). DDABs usually demonstrate a positive direct antiglobulin test and a negative elution, while DIABs are serologically indistinguishable from warm autoantibodies and are similarly steroid-responsive. Drug cessation is always recommended. PMID- 21685027 TI - Interference of hemoglobin Hope on beta-thalassemia diagnosis by the capillary electrophoresis Method. AB - The beta-chain hemoglobin (Hb) variants interfere with the diagnosis of beta thalassemia trait using high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE). We analyzed the effect of Hb Hope, a beta-chain Hb variant frequently found in the Thai population, on beta-thalassemia trait diagnosis. HPLC and CE were used to quantify the level of HbA(2) in 11 whole blood samples containing Hb Hope. The levels of Hb Hope detected by both methods were similar. An elevated HbA(2) level was found in all samples analyzed by the CE method, while 1 was increased when analyzed by HPLC, which was a compound heterozygous of Hb Hope and alpha-thalassemia-1 SEA-type deletion. Of 11 samples, 6 had mean corpuscular volumes within the reference range. All samples showed negative results for molecular analysis of beta(0)-thalassemia codon 17, 41/42, and 71/72 mutations and beta-thalassemia 3.5-kb deletion. Therefore, Hb Hope interfered with the diagnosis of beta-thalassemia trait analyzed by CE but not by HPLC. PMID- 21685028 TI - Estimation of plasma small dense LDL cholesterol from classic lipid measures. AB - Calculated low-density lipoprotein cholesterol (cLDL-C) may differ from direct measurement (dLDL-C), and this difference may depend on presence of small, dense LDL (sdLDL) particles in addition to variation in triglycerides (TG) and high density lipoprotein cholesterol (HDL-C) concentrations. The presence of such dependence would offer a simple means to estimate sdLDL. We studied dependence of sdLDL on cLDL-C, dLDL-C, and other variables. We measured the levels of glucose, creatinine, total cholesterol, TG, HDL-C, and dLDL-C using standardized methods in 297 samples. For sdLDL cholesterol (sdLDL-C), a novel homogeneous assay was used. The cLDL-C was calculated using the Friedewald formula for 220 subjects after excluding for liver or renal disease. Using stepwise regression analysis identified non-HDL-C, cLDL-C, and dLDL-C as significant variables (P < .001; R(2) = 0.88). The regression equation was as follows: sdLDL-C (mg/dL) = 0.580 (non-HDL C) + 0.407 (dLDL-C) - 0.719 (cLDL-C) - 12.05. The sdLDL-C concentration can be estimated from non-HDL-C, dLDL-C, and cLDL-C values. Identification of a simple, inexpensive marker for sdLDL particles provides a cost-effective method for screening cardiovascular disease risk. PMID- 21685029 TI - Meeting regulatory requirements by the use of cell phone text message notification with autoescalation and loop closure for reporting of critical laboratory results. AB - Critical laboratory results require timely and accurate transmission to the appropriate caregiver to provide intervention to prevent an adverse outcome. We report the use of text messages to notify critical laboratory results in a large teaching hospital to manage the documentation and audit requirements of critical result reporting by regulatory agencies. The text messaging system (critical reportable result health care messaging system [CRR-HMS]) allows a receiver to acknowledge or reject a critical result by short message service reply. Failure to obtain a confirmatory receipt within 10 minutes produces an automated escalation to an alternative physician according to a roster. The median time required for physician response decreased from 7.3 minutes to 2 minutes after implementation of the CRR-HMS. The CRR-HMS is a clinically useful tool to rapidly communicate critical results to targeted physicians to facilitate rapid and timely intervention. This feature seems to be an important laboratory process mediator, and recent Joint Commission reviews have placed this as a requirement. PMID- 21685030 TI - T-regulatory cells in lymph nodes: correlation with sex and HIV status. AB - Because T-regulatory cells (Tregs) can harmfully impair HIV-specific responses or beneficially limit immune activation, we compared the number of Tregs in lymph nodes from 48 HIV+ patients and 106 HIV- subjects. By using a microscope counting grid, we found that the mean +/- SD number of Tregs in lymph nodes was 3 times greater in HIV+ males than HIV+ females (23.5 +/- 20.7 vs 7.8 +/- 7.7; P = .0006) and almost twice as great in HIV+ males than HIV- males (23.5 +/- 20.7 vs 13.5 +/ 15.5; P = .04). There were fewer Tregs in HIV+ females than in HIV- females (mean +/- SD, 7.8 +/- 7.7 vs 13.4 +/- 13.3; P = .04). HIV+ males compared with HIV+ females had higher viral loads (VLs) and lower peripheral blood (PB) CD4 cell counts (mean +/- SD, 239,841 +/- 307,494 vs 73,038 +/- 146,763 copies/mL and 262 +/- 207 vs 466 +/- 278/mm(3); P = .02 and P = .01, respectively). Our data show that Tregs in lymph nodes from HIV+ patients are positively correlated with VL and negatively correlated with PB CD4 counts. These findings suggest that Tregs might impair an HIV-specific immune response, which could be modified by sex, or, alternatively, an increased VL causes increased Tregs. PMID- 21685031 TI - A systematic review and meta-analysis of the diagnostic accuracy of fine-needle aspiration cytology for parotid gland lesions. AB - The clinical usefulness of fine-needle aspiration cytology (FNAC) for the diagnosis of parotid gland lesions is controversial. Many accuracy studies have been published, but the literature has not been adequately summarized. We identified 64 studies on the diagnosis of malignancy (6,169 cases) and 7 studies on the diagnosis of neoplasia (795 cases). The diagnosis of neoplasia (area under the summary receiver operating characteristic [AUSROC] curve, 0.99; 95% confidence interval [CI], 0.97-1.00) had higher accuracy than the diagnosis of malignancy (AUSROC, 0.96; 95% CI, 0.94-0.97). Several sources of bias were identified that could affect study estimates. Studies on the diagnosis of malignancy showed significant heterogeneity (P < .001). The subgroups of American, French, and Turkish studies showed greater homogeneity, but the accuracy of these subgroups was not significantly different from that of the remaining subgroup. It is not possible to provide a general guideline on the clinical usefulness of FNAC for parotid gland lesions owing to the variability in study results. There is a need to improve the quality of reporting and to improve study designs to remove or assess the impact of bias. PMID- 21685032 TI - IkappaB Kinase epsilon expression in pancreatic ductal adenocarcinoma. AB - IkappaB kinase (IKKepsilon) is a serine/threonine protein kinase that belongs to the IKK kinase family. Recent studies have shown that IKKepsilon functions as a breast and ovarian cancer oncogene. We demonstrated frequent overexpression of IKKepsilon in pancreatic ductal adenocarcinoma (PDA). We immunohistochemically evaluated 78 PDAs using the avidin-biotin-peroxidase method and the anti IKKepsilon rabbit polyclonal antibody. Elevated IKKepsilon reactivity (immunohistochemical score, 4-9) was observed in 64% of PDAs (50/78), but in 0.0% of nonneoplastic pancreatic ductal epithelium (0/113; P < .001). Kaplan-Meier analysis of overall survival revealed that patients with high IKKepsilon immunohistochemical scores (4-9) had significantly shorter survival than did patients with low IKKepsilon immunohistochemical scores (0-3; P = .023; log-rank test) independent of tumor stage or grade. These data indicate that deregulation of IKKepsilon is a common event in PDA and might have an important role in the pathogenesis of this deadly disease. In addition, IKKepsilon could serve as a prognostic marker and potential therapeutic target for PDA intervention. PMID- 21685033 TI - The laboratory score/reference method score ratio (LSRSR) is a novel tool for monitoring laboratory performance in immunohistochemistry proficiency testing of hormone receptors in breast cancer: the CIQC experience. AB - Canadian Immunohistochemistry Quality Control (CIQC) operates an academic proficiency testing (PT) program using a traditional expert panel-based qualitative assessment system. The image analysis approach is increasingly considered for use in PT to follow demand for precision in immunohistochemical test calibration. CIQC introduces and explores the usefulness of a novel image analysis-based tool, the laboratory score/reference method score ratio (LSRSR) for PT. Two CIQC runs with 33 and 57 participants, respectively, were analyzed for interlaboratory concordance for estrogen receptor results using expert panel based and LSRSR systems. Samples included tissue microarrays with 40 tissue cores each. The LSRSR was calculated from participants' and reference laboratory H scores measured by image analysis. We found lower concordance with reference method results for participating laboratories by LSRSR than those reported by the expert panel; although the expert panel observed those differences, it was not able to measure them without LSRSR. LSRSR may be useful in monitoring laboratory performance for quantitative immunohistochemical testing. PMID- 21685034 TI - Gastrointestinal stromal tumor markers in cutaneous melanomas: relationship to prognostic factors and outcome. AB - Melanoma expresses c-kit, a gastrointestinal stromal tumor marker, but has not been extensively evaluated for protein kinase C theta (PKCtheta) or DOG1, and these stains have not been correlated with prognostic factors. We immunostained 62 primary cutaneous and 15 metastatic melanomas for polyclonal c-kit (pc-kit), monoclonal c-kit (mc-kit), PKCtheta, and DOG1 and correlated results with prognostic parameters and survival. Of the cutaneous melanomas, 34 (55%) stained for pc-kit, 30 (48%) for mc-kit, 11 (18%) for PKCtheta, and 2 (3%) for DOG1. The Breslow depth was 1.00 mm or less in 21 (68%) of 31 pc-kit+ cutaneous melanomas compared with 7 (27%) of 26 pc-kit- melanomas (P = .002). The pc-kit+ melanomas had less nodal disease (1/31 [3%] vs 9/25 [36%]; P = .001) and local recurrence (1/33 [3%] vs 6/27 [22%]; P = .021) but no statistically significant difference in the rate of distant metastases (13/32 [41%] vs 14/27 [52%]; P = .388) or survival (10/34 [29%] vs 16/39 [41%]; P = .301). We found that pc-kit correlates better with prognostic parameters than does mc-kit. PMID- 21685035 TI - Usefulness of immunohistochemical and histochemical studies in the classification of lung adenocarcinoma and squamous cell carcinoma in cytologic specimens. AB - Histologic subtyping of non-small cell lung carcinoma (NSCLC) is important because the efficacy of new treatments depends on tumor histologic features. We assessed the diagnostic accuracy of classification of lung adenocarcinoma and squamous cell carcinoma (SCC) on cytologic and biopsy specimens based on cytomorphologic studies alone or in combination with ancillary studies compared with resection specimens. Compared with adenocarcinoma, the diagnosis of SCC was based more often on cytomorphologic studies alone (139/185 [75.1%] vs 107/263 [40.7%]). Significantly increased use of immunohistochemical studies in cytology was noted after introduction of targeted lung carcinoma therapies (22/156 [14.1%] for adenocarcinoma and 5/46 [11%] for SCC from 2000-2004 vs 134/156 [85.9%] for adenocarcinoma and 41/46 [89%] for SCC from 2005-2010). Use of immunohistochemical studies resulted in increased diagnostic accuracy for adenocarcinoma (56% [44/78] from 2000-2004 vs 83.2% [154/185] after 2005) but not for SCC (77% [57/74] before 2004 vs 73.9% [82/111] from 2005-2010). Adenocarcinoma showed high expression of cytokeratin (CK)7 (146/146 [100%]), thyroid transcription factor-1 (131/152 [86.2%]), surfactant A (29/36 [81%]), and periodic acid-Schiff with diastase (69/86 [80%]). All SCCs were positive for CK5/6 and p63. Use of immunohistochemical studies on cytologic cell blocks may improve classification of NSCLC. PMID- 21685036 TI - Classical-type invasive lobular carcinoma with HER2 overexpression: clinical, histologic, and hormone receptor characteristics. AB - The majority of invasive lobular carcinomas (ILCs) express estrogen receptor (ER) and progesterone receptor (PR) but lack ERBB2 (HER2) amplification. HER2 overexpression is traditionally considered to occur in the pleomorphic variant of ILCs. We describe 12 cases of classical-type ILCs with HER2 overexpression in a 3 year period. All tumors displayed the characteristic morphologic features of classical ILC with uniform cells and discohesive growth patterns. The lobular phenotype was confirmed by the absence of E-cadherin staining. Multiple variables regarding clinical, histologic, and hormone receptor characteristics of tumors were evaluated and compared with a set of HER2- classical ILCs. The study identified 2 main pathologic features associated with HER2 overexpression in classical type ILC: histiocytoid morphologic features and absence of PR expression. ER is still expressed in HER2+ classical ILCs, although the level of expression is significantly reduced compared with the HER2- cases. The implications of the findings are discussed. PMID- 21685037 TI - Digital quantification of five high-grade prostate cancer patterns, including the cribriform pattern, and their association with adverse outcome. AB - Proper grading of the cribriform prostate cancer pattern has not previously been supported by outcome-based evidence. Among 153 men who underwent radical prostatectomy, 76 with prostate-specific antigen (PSA) failure (>=0.2 ng/mL [0.2 MUg/L]) were matched to 77 without failure. Frequencies of high-grade patterns included fused small acini, 83.7%; papillary, 52.3%; large cribriform, 37.9%; small (<=12 lumens) cribriform, 17.0%; and individual cells, 22.9%. A cribriform pattern was present in 61% (46/76) of failures but 16% (12/77) of nonfailures (P < .0001). Multivariate analysis showed the cribriform pattern had the highest odds ratio for PSA failure, 5.89 (95% confidence interval, 2.53-13.70; P < .0001). The presence of both large and small cribriform patterns was significantly linked to failure. The cumulative odds ratio of failure per added square millimeter of cribriform pattern was 1.173 (P = .008), higher than for any other pattern. All 8 men with a cribriform area sum of 25 mm(2) or more had failure (range, 33-930). Regrading cribriform cancer as Gleason 5 improved the grade association with failure, although half of all cases with individual cells also had a cribriform pattern, precluding a precise determination of the independent importance of the latter. The cribriform pattern has particularly adverse implications for outcome. PMID- 21685038 TI - Cytology workforce study: a report of current practices and trends in New York State. AB - A survey was conducted among 130 New York State (NYS) registered cytology laboratories to better understand current and future changes in the practice of cytology, changes in the cytotechnologist (CT) scope of practice, and the future need for CTs. A 51.5% (67/130) response rate was obtained. Trends for gynecologic case volume varied across facility types. Nongynecologic volume is growing primarily in hospitals and large medical center laboratories and private laboratories; the fine-needle aspiration volume is growing in hospital and large medical center laboratories. One third of responding laboratories anticipate a continued demand for CTs within the next 3 years owing to impending retirements. Few laboratories also report the gradual adoption of molecular testing with CTs directly involved. Because 60% (3/5) of NYS CT training programs have closed since 2008, the 2 remaining programs are a valuable key staffing resource for CTs. Continued viability of these programs is essential to provide the necessary training and staffing of NYS laboratories for cytopathology practice. PMID- 21685039 TI - Human papillomavirus (HPV) detection using in situ hybridization in histologic samples: correlations with cytologic changes and polymerase chain reaction HPV detection. AB - Although in situ hybridization (ISH) and polymerase chain reaction (PCR) have extensively been used on cytology specimens, there have been limited reports of the usefulness of these techniques in relation to confirmed histologic findings. In this study, we used PCR and ISH to detect human papillomavirus (HPV) in cytologic and histologic specimens, respectively. By using positive and negative likelihood ratios, we attempted to identify any predictive role of ISH testing alone or in combination with PCR for the development of high-grade histologic lesions (cervical intraepithelial neoplasia [CIN] 2+). In our study, ISH was a useful method for detection of HPV, even in a large fraction of samples with normal cytologic or biopsy findings. We suggest that when used together and evaluated in conjunction with histologic sections, ISH is a useful tool for ancillary molecular testing of HPV infection in cervical lesions, especially in CIN 2+ histological lesions where its analytic sensitivities and specificities were as good as those of PCR testing. PMID- 21685040 TI - The liver in celiac disease: clinical manifestations, histologic features, and response to gluten-free diet in 30 patients. AB - Descriptive reports of liver histologic features in celiac disease (CD) are sparse, and the effect of a gluten-free diet (GFD) on the course of liver injury is poorly understood. We reviewed liver biopsy specimens in 30 patients with CD and performed immunostains for IgG, IgG4, IgM, and IgA. Subsequent liver biochemical tests and compliance with the GFD were recorded. Of the patients, 19 had autoimmune-mediated liver disease (AILD; autoimmune hepatitis, 9; primary sclerosing cholangitis, 7; and primary biliary cirrhosis, 3). The remaining 11 patients had cryptogenic hepatitis (5), hepatitis C (2), steatohepatitis (2), sarcoidosis (1), and T-cell lymphoma (1). The liver disease diagnosis preceded the CD diagnosis in all groups except steatohepatitis. Although 82% of patients without AILD had symptomatic CD, only 26% of patients with AILD had such symptoms. The pathology of the specific liver disease was not atypical in histologic features or IgG/IgM ratios. While GFD improved cryptogenic hepatitis, it did not seem to affect AILD. We propose that AILD and cryptogenic hepatitis in patients with CD represent distinct clinical, histologic, and immunohistochemical entities rather than 2 ends of a spectrum of liver injury. PMID- 21685041 TI - Expression of l1 cell adhesion molecule and morphologic features at the invasive front of colorectal cancer. AB - To obtain the correlation between morphologic features in the invasive fronts of colorectal cancer (CRC) and L1 cell adhesion molecule (L1CAM) expression, 275 CRCs were assessed with L1CAM immunostaining and 29 CRCs were examined for L1CAM messenger RNA (mRNA) expression. Based on immunostaining, the positive rate of L1CAM expression increased according to the grade of tumor budding (P = .0002) and solid cancer nests (SCNs; P = .0046). L1CAM mRNA levels at the invasive front of the tumor were higher than those at the center of the tumor (median, 3.7 fold). The gap of L1CAM mRNA level between the invasive front and the central area was 7.3-fold in tumors having SCN lesions, whereas it was 1.9-fold in tumors having non-SCN lesions (P = .0004). L1CAM expression was correlated with nodal involvement in protein and mRNA levels (P = .0007 and P = .036, respectively). Tumor regulation of L1CAM expression is associated with morphologic features at the invasive front in CRC. PMID- 21685042 TI - High concordance between two companion diagnostics tests: a concordance study between the HercepTest and the HER2 FISH pharmDx kit. AB - The present study was done to investigate the concordance between the HER2 status measured by immunohistochemical analysis (HercepTest, DAKO, Carpinteria, CA) and fluorescence in situ hybridization (FISH; HER2 FISH pharmDx, DAKO) in a large study cohort (n = 681) of patients with high-risk breast cancer. A high agreement between immunohistochemical and FISH results was demonstrated. For the whole study population, the agreement between the 2 assays was 93.1% with a corresponding kappa coefficient of 0.85. When the equivocal immunohistochemical 2+ cases were excluded from the analysis (n = 79), the agreement increased to 95.0% with a kappa coefficient of 0.90. When the cutoff value for amplified/nonamplified cases in the HER2 FISH assay was increased from 2.0 to 2.2 as recommended in the American Society of Clinical Oncology/College of American Pathologists guidelines, the concordance between the 2 assays was 94.3% with a kappa coefficient of 0.87 in the whole study population. When the equivocal immunohistochemical 2+ cases were excluded from this analysis, the concordance is similar (95.7% with a kappa coefficient of 0.91). PMID- 21685043 TI - About the clinical performance of the Sysmex XE-500 for automated cerebrospinal fluid cell counts. PMID- 21685044 TI - Diagnostic usefulness of flow cytometry for immunophenotyping classical Hodgkin lymphoma. PMID- 21685045 TI - Immune system simulation online. AB - MOTIVATION: The recognition of antigenic peptides is a major event of an immune response. In current mesoscopic-scale simulators of the immune system, this crucial step has been modeled in a very approximated way. RESULTS: We have equipped an agent-based model of the immune system with immuno-informatics methods to allow the simulation of the cardinal events of the antigenic recognition, going from single peptides to whole proteomes. The recognition process accounts for B cell-epitopes prediction through Parker-scale affinity estimation, class I and II HLA peptide prediction and binding through position specific scoring matrices based on information from known HLA epitopes prediction tools, and TCR binding to HLA-peptide complex calculated as the averaged sum of a residue-residue contact potential. These steps are executed for all lymphocytes agents encountering the antigen in a wide-reaching Monte Carlo simulation. AVAILABILITY: http://www.cbs.dtu.dk/services/C-ImmSim-10.1/ PMID- 21685046 TI - Noise reduction in genome-wide perturbation screens using linear mixed-effect models. AB - MOTIVATION: High-throughput perturbation screens measure the phenotypes of thousands of biological samples under various conditions. The phenotypes measured in the screens are subject to substantial biological and technical variation. At the same time, in order to enable high throughput, it is often impossible to include a large number of replicates, and to randomize their order throughout the screens. Distinguishing true changes in the phenotype from stochastic variation in such experimental designs is extremely challenging, and requires adequate statistical methodology. RESULTS: We propose a statistical modeling framework that is based on experimental designs with at least two controls profiled throughout the experiment, and a normalization and variance estimation procedure with linear mixed-effects models. We evaluate the framework using three comprehensive screens of Saccharomyces cerevisiae, which involve 4940 single-gene knock-out haploid mutants, 1127 single-gene knock-out diploid mutants and 5798 single-gene overexpression haploid strains. We show that the proposed approach (i) can be used in conjunction with practical experimental designs; (ii) allows extensions to alternative experimental workflows; (iii) enables a sensitive discovery of biologically meaningful changes; and (iv) strongly outperforms the existing noise reduction procedures. AVAILABILITY: All experimental datasets are publicly available at www.ionomicshub.org. The R package HTSmix is available at http://www.stat.purdue.edu/~ovitek/HTSmix.html. CONTACT: ovitek@stat.purdue.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21685047 TI - AMIGO, a toolbox for advanced model identification in systems biology using global optimization. AB - MOTIVATION: Mathematical models of complex biological systems usually consist of sets of differential equations which depend on several parameters which are not accessible to experimentation. These parameters must be estimated by fitting the model to experimental data. This estimation problem is very challenging due to the non-linear character of the dynamics, the large number of parameters and the frequently poor information content of the experimental data (poor practical identifiability). The design of optimal (more informative) experiments is an associated problem of the highest interest. RESULTS: This work presents AMIGO, a toolbox which facilitates parametric identification by means of advanced numerical techniques which cover the full iterative identification procedure putting especial emphasis on robust methods for parameter estimation and practical identifiability analyses, plus flexible capabilities for optimal experimental design. AVAILABILITY: The toolbox and the corresponding documentation may be downloaded from: http://www.iim.csic.es/~amigo CONTACT: ebalsa@iim.csic.es. PMID- 21685048 TI - A tree-based approach for motif discovery and sequence classification. AB - MOTIVATION: Pattern discovery algorithms are widely used for the analysis of DNA and protein sequences. Most algorithms have been designed to find overrepresented motifs in sparse datasets of long sequences, and ignore most positional information. We introduce an algorithm optimized to exploit spatial information in sparse-but-populous datasets. RESULTS: Our algorithm Tree-based Weighted Position Pattern Discovery and Classification (T-WPPDC) supports both unsupervised pattern discovery and supervised sequence classification. It identifies positionally enriched patterns using the Kullback-Leibler distance between foreground and background sequences at each position. This spatial information is used to discover positionally important patterns. T-WPPDC then uses a scoring function to discriminate different biological classes. We validated T-WPPDC on an important biological problem: prediction of single nucleotide polymorphisms (SNPs) from flanking sequence. We evaluated 672 separate experiments on 120 datasets derived from multiple species. T-WPPDC outperformed other pattern discovery methods and was comparable to the supervised machine learning algorithms. The algorithm is computationally efficient and largely insensitive to dataset size. It allows arbitrary parameterization and is embarrassingly parallelizable. CONCLUSIONS: T-WPPDC is a minimally parameterized algorithm for both pattern discovery and sequence classification that directly incorporates positional information. We use it to confirm the predictability of SNPs from flanking sequence, and show that positional information is a key to this biological problem. AVAILABILITY: The algorithm, code and data are available at: http://www.cs.utoronto.ca/~juris/data/TWPPDC PMID- 21685049 TI - Enhancing the rate of scaffold discovery with diversity-oriented prioritization. AB - MOTIVATION: In high-throughput screens (HTS) of small molecules for activity in an in vitro assay, it is common to search for active scaffolds, with at least one example successfully confirmed as an active. The number of active scaffolds better reflects the success of the screen than the number of active molecules. Many existing algorithms for deciding which hits should be sent for confirmatory testing neglect this concern. RESULTS: We derived a new extension of a recently proposed economic framework, diversity-oriented prioritization (DOP), that aims by changing which hits are sent for confirmatory testing-to maximize the number of scaffolds with at least one confirmed active. In both retrospective and prospective experiments, DOP accurately predicted the number of scaffold discoveries in a batch of confirmatory experiments, improved the rate of scaffold discovery by 8-17%, and was surprisingly robust to the size of the confirmatory test batches. As an extension of our previously reported economic framework, DOP can be used to decide the optimal number of hits to send for confirmatory testing by iteratively computing the cost of discovering an additional scaffold, the marginal cost of discovery. CONTACT: swamidass@wustl.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21685050 TI - Genomic data integration using guided clustering. AB - MOTIVATION: In biomedical research transcriptomic, proteomic or metabolomic profiles of patient samples are often combined with genomic profiles from experiments in cell lines or animal models. Integrating experimental data with patient data is still a challenging task due to the lack of tailored statistical tools. RESULTS: Here we introduce guided clustering, a new data integration strategy that combines experimental and clinical high-throughput data. Guided clustering identifies sets of genes that stand out in experimental data while at the same time display coherent expression in clinical data. We report on two potential applications: The integration of clinical microarray data with (i) genome-wide chromatin immunoprecipitation assays and (ii) with cell perturbation assays. Unlike other analysis strategies, guided clustering does not analyze the two datasets sequentially but instead in a single joint analysis. In a simulation study and in several biological applications, guided clustering performs favorably when compared with sequential analysis approaches. AVAILABILITY: Guided clustering is available as a R-package from http://compdiag.uni regensburg.de/software/guidedClustering.shtml. Documented R code of all our analysis is included in the Supplementary Materials. All newly generated data are available at the GEO database (GSE29700). CONTACT: rainer.spang@klinik.uni regensburg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21685051 TI - Methyl-Analyzer--whole genome DNA methylation profiling. AB - SUMMARY: Methyl-Analyzer is a python package that analyzes genome-wide DNA methylation data produced by the Methyl-MAPS (methylation mapping analysis by paired-end sequencing) method. Methyl-MAPS is an enzymatic-based method that uses both methylation-sensitive and -dependent enzymes covering >80% of CpG dinucleotides within mammalian genomes. It combines enzymatic-based approaches with high-throughput next-generation sequencing technology to provide whole genome DNA methylation profiles. Methyl-Analyzer processes and integrates sequencing reads from methylated and unmethylated compartments and estimates CpG methylation probabilities at single base resolution. AVAILABILITY AND IMPLEMENTATION: Methyl-Analyzer is available at http://github.com/epigenomics/methylmaps. Sample dataset is available for download at http://epigenomicspub.columbia.edu/methylanalyzer_data.html. CONTACT: fgh3@columbia.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21685052 TI - Integration of gene normalization stages and co-reference resolution using a Markov logic network. AB - MOTIVATION: Gene normalization (GN) is the task of normalizing a textual gene mention to a unique gene database ID. Traditional top performing GN systems usually need to consider several constraints to make decisions in the normalization process, including filtering out false positives, or disambiguating an ambiguous gene mention, to improve system performance. However, these constraints are usually executed in several separate stages and cannot use each other's input/output interactively. In this article, we propose a novel approach that employs a Markov logic network (MLN) to model the constraints used in the GN task. Firstly, we show how various constraints can be formulated and combined in an MLN. Secondly, we are the first to apply the two main concepts of co-reference resolution-discourse salience in centering theory and transitivity-to GN models. Furthermore, to make our results more relevant to developers of information extraction applications, we adopt the instance-based precision/recall/F-measure (PRF) in addition to the article-wide PRF to assess system performance. RESULTS: Experimental results show that our system outperforms baseline and state-of-the art systems under two evaluation schemes. Through further analysis, we have found several unexplored challenges in the GN task. CONTACT: hongjie@iis.sinica.edu.tw SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21685053 TI - CHASM and SNVBox: toolkit for detecting biologically important single nucleotide mutations in cancer. AB - SUMMARY: Thousands of cancer exomes are currently being sequenced, yielding millions of non-synonymous single nucleotide variants (SNVs) of possible relevance to disease etiology. Here, we provide a software toolkit to prioritize SNVs based on their predicted contribution to tumorigenesis. It includes a database of precomputed, predictive features covering all positions in the annotated human exome and can be used either stand-alone or as part of a larger variant discovery pipeline. AVAILABILITY AND IMPLEMENTATION: MySQL database, source code and binaries freely available for academic/government use at http://wiki.chasmsoftware.org, Source in Python and C++. Requires 32 or 64-bit Linux system (tested on Fedora Core 8,10,11 and Ubuntu 10), 2.5*<= Python <3.0*, MySQL server >5.0, 60 GB available hard disk space (50 MB for software and data files, 40 GB for MySQL database dump when uncompressed), 2 GB of RAM. PMID- 21685054 TI - Decomposing flux distributions into elementary flux modes in genome-scale metabolic networks. AB - MOTIVATION: Elementary flux mode (EFM) is a fundamental concept as well as a useful tool in metabolic pathway analysis. One important role of EFMs is that every flux distribution can be decomposed into a set of EFMs and a number of methods to study flux distributions originated from it. Yet finding such decompositions requires the complete set of EFMs, which is intractable in genome scale metabolic networks due to combinatorial explosion. RESULTS: In this article, we proposed an algorithm to decompose flux distributions into EFMs in genome-scale networks. It is an iterative scheme of a mixed integer linear program. Unlike previous optimization models to find pathways, any feasible solutions can become EFMs in our algorithm. This advantage enables the algorithm to approximate the EFM of largest contribution to an objective reaction in a flux distribution. Our algorithm is able to find EFMs of flux distributions with complex structures, closer to the realistic case in which a cell is subject to various constraints. A case of Escherichia coli growth in the Lysogeny broth (LB) medium containing various carbon sources was studied. Essential metabolites and their syntheses were located. Information on the contribution of each carbon source not obvious from the apparent flux distribution was also revealed. Our work further confirms the utility of finding EFMs by optimization models in genome-scale metabolic networks. CONTACT: joshua.chan@connect.polyu.hk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21685055 TI - Menu-driven cloud computing and resource sharing for R and Bioconductor. AB - SUMMARY: We report CRdata.org, a cloud-based, free, open-source web server for running analyses and sharing data and R scripts with others. In addition to using the free, public service, CRdata users can launch their own private Amazon Elastic Computing Cloud (EC2) nodes and store private data and scripts on Amazon's Simple Storage Service (S3) with user-controlled access rights. All CRdata services are provided via point-and-click menus. AVAILABILITY AND IMPLEMENTATION: CRdata is open-source and free under the permissive MIT License (opensource.org/licenses/mit-license.php). The source code is in Ruby (ruby lang.org/en/) and available at: github.com/seerdata/crdata. CONTACT: hbolouri@fhcrc.org. PMID- 21685056 TI - KvSNP: accurately predicting the effect of genetic variants in voltage-gated potassium channels. AB - MOTIVATION: Non-synonymous single nucleotide polymorphisms (nsSNPs) in voltage gated potassium (Kv) channels cause diseases with potentially fatal consequences in seemingly healthy individuals. Identifying disease-causing genetic variation will aid presymptomatic diagnosis and treatment of such disorders. NsSNP-effect predictors are hypothesized to perform best when developed for specific gene families. We, thus, created KvSNP: a method that assigns a disease-causing probability to Kv-channel nsSNPs. RESULTS: KvSNP outperforms popular non gene family-specific methods (SNPs&GO, SIFT and Polyphen) in predicting the disease potential of Kv-channel variants, according to all tested metrics (accuracy, Matthews correlation coefficient and area under receiver operator characteristic curve). Most significantly, it increases the separation of the median predicted disease probabilities between benign and disease-causing SNPs by 26% on the next best competitor. KvSNP has ranked 172 uncharacterized Kv-channel nsSNPs by disease-causing probability. AVAILABILITY AND IMPLEMENTATION: KvSNP, a WEKA implementation is available at www.bioinformatics.leeds.ac.uk/KvDB/KvSNP.html. CONTACT: d.r.westhead@leeds.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21685057 TI - This special issue comprises the papers accepted for presentationat the 19th Annual International Conference on Intelligent Systemsfor Molecular Biology, joint with the 10th European Conference onComputational Biology, an official conference of the InternationalSociety for Computational Biology. PMID- 21685058 TI - A conditional random fields method for RNA sequence-structure relationship modeling and conformation sampling. AB - Accurate tertiary structures are very important for the functional study of non coding RNA molecules. However, predicting RNA tertiary structures is extremely challenging, because of a large conformation space to be explored and lack of an accurate scoring function differentiating the native structure from decoys. The fragment-based conformation sampling method (e.g. FARNA) bears shortcomings that the limited size of a fragment library makes it infeasible to represent all possible conformations well. A recent dynamic Bayesian network method, BARNACLE, overcomes the issue of fragment assembly. In addition, neither of these methods makes use of sequence information in sampling conformations. Here, we present a new probabilistic graphical model, conditional random fields (CRFs), to model RNA sequence-structure relationship, which enables us to accurately estimate the probability of an RNA conformation from sequence. Coupled with a novel tree guided sampling scheme, our CRF model is then applied to RNA conformation sampling. Experimental results show that our CRF method can model RNA sequence structure relationship well and sequence information is important for conformation sampling. Our method, named as TreeFolder, generates a much higher percentage of native-like decoys than FARNA and BARNACLE, although we use the same simple energy function as BARNACLE. CONTACT: zywang@ttic.edu; j3xu@ttic.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21685059 TI - Discovering and visualizing indirect associations between biomedical concepts. AB - MOTIVATION: Discovering useful associations between biomedical concepts has been one of the main goals in biomedical text-mining, and understanding their biomedical contexts is crucial in the discovery process. Hence, we need a text mining system that helps users explore various types of (possibly hidden) associations in an easy and comprehensible manner. RESULTS: This article describes FACTA+, a real-time text-mining system for finding and visualizing indirect associations between biomedical concepts from MEDLINE abstracts. The system can be used as a text search engine like PubMed with additional features to help users discover and visualize indirect associations between important biomedical concepts such as genes, diseases and chemical compounds. FACTA+ inherits all functionality from its predecessor, FACTA, and extends it by incorporating three new features: (i) detecting biomolecular events in text using a machine learning model, (ii) discovering hidden associations using co occurrence statistics between concepts, and (iii) visualizing associations to improve the interpretability of the output. To the best of our knowledge, FACTA+ is the first real-time web application that offers the functionality of finding concepts involving biomolecular events and visualizing indirect associations of concepts with both their categories and importance. AVAILABILITY: FACTA+ is available as a web application at http://refine1-nactem.mc.man.ac.uk/facta/, and its visualizer is available at http://refine1-nactem.mc.man.ac.uk/facta visualizer/. CONTACT: tsuruoka@jaist.ac.jp. PMID- 21685060 TI - MeSH: a window into full text for document summarization. AB - MOTIVATION: Previous research in the biomedical text-mining domain has historically been limited to titles, abstracts and metadata available in MEDLINE records. Recent research initiatives such as TREC Genomics and BioCreAtIvE strongly point to the merits of moving beyond abstracts and into the realm of full texts. Full texts are, however, more expensive to process not only in terms of resources needed but also in terms of accuracy. Since full texts contain embellishments that elaborate, contextualize, contrast, supplement, etc., there is greater risk for false positives. Motivated by this, we explore an approach that offers a compromise between the extremes of abstracts and full texts. Specifically, we create reduced versions of full text documents that contain only important portions. In the long-term, our goal is to explore the use of such summaries for functions such as document retrieval and information extraction. Here, we focus on designing summarization strategies. In particular, we explore the use of MeSH terms, manually assigned to documents by trained annotators, as clues to select important text segments from the full text documents. RESULTS: Our experiments confirm the ability of our approach to pick the important text portions. Using the ROUGE measures for evaluation, we were able to achieve maximum ROUGE-1, ROUGE-2 and ROUGE-SU4 F-scores of 0.4150, 0.1435 and 0.1782, respectively, for our MeSH term-based method versus the maximum baseline scores of 0.3815, 0.1353 and 0.1428, respectively. Using a MeSH profile-based strategy, we were able to achieve maximum ROUGE F-scores of 0.4320, 0.1497 and 0.1887, respectively. Human evaluation of the baselines and our proposed strategies further corroborates the ability of our method to select important sentences from the full texts. CONTACT: sanmitra-bhattacharya@uiowa.edu; padmini srinivasan@uiowa.edu. PMID- 21685061 TI - A folding algorithm for extended RNA secondary structures. AB - MOTIVATION: RNA secondary structure contains many non-canonical base pairs of different pair families. Successful prediction of these structural features leads to improved secondary structures with applications in tertiary structure prediction and simultaneous folding and alignment. RESULTS: We present a theoretical model capturing both RNA pair families and extended secondary structure motifs with shared nucleotides using 2-diagrams. We accompany this model with a number of programs for parameter optimization and structure prediction. AVAILABILITY: All sources (optimization routines, RNA folding, RNA evaluation, extended secondary structure visualization) are published under the GPLv3 and available at www.tbi.univie.ac.at/software/rnawolf/. PMID- 21685062 TI - Error correction of high-throughput sequencing datasets with non-uniform coverage. AB - MOTIVATION: The continuing improvements to high-throughput sequencing (HTS) platforms have begun to unfold a myriad of new applications. As a result, error correction of sequencing reads remains an important problem. Though several tools do an excellent job of correcting datasets where the reads are sampled close to uniformly, the problem of correcting reads coming from drastically non-uniform datasets, such as those from single-cell sequencing, remains open. RESULTS: In this article, we develop the method Hammer for error correction without any uniformity assumptions. Hammer is based on a combination of a Hamming graph and a simple probabilistic model for sequencing errors. It is a simple and adaptable algorithm that improves on other tools on non-uniform single-cell data, while achieving comparable results on normal multi-cell data. AVAILABILITY: http://www.cs.toronto.edu/~pashadag. CONTACT: pmedvedev@cs.ucsd.edu. PMID- 21685063 TI - Generative probabilistic models for protein-protein interaction networks--the biclique perspective. AB - MOTIVATION: Much of the large-scale molecular data from living cells can be represented in terms of networks. Such networks occupy a central position in cellular systems biology. In the protein-protein interaction (PPI) network, nodes represent proteins and edges represent connections between them, based on experimental evidence. As PPI networks are rich and complex, a mathematical model is sought to capture their properties and shed light on PPI evolution. The mathematical literature contains various generative models of random graphs. It is a major, still largely open question, which of these models (if any) can properly reproduce various biologically interesting networks. Here, we consider this problem where the graph at hand is the PPI network of Saccharomyces cerevisiae. We are trying to distinguishing between a model family which performs a process of copying neighbors, represented by the duplication-divergence (DD) model, and models which do not copy neighbors, with the Barabasi-Albert (BA) preferential attachment model as a leading example. RESULTS: The observed property of the network is the distribution of maximal bicliques in the graph. This is a novel criterion to distinguish between models in this area. It is particularly appropriate for this purpose, since it reflects the graph's growth pattern under either model. This test clearly favors the DD model. In particular, for the BA model, the vast majority (92.9%) of the bicliques with both sides >=4 must be already embedded in the model's seed graph, whereas the corresponding figure for the DD model is only 5.1%. Our results, based on the biclique perspective, conclusively show that a naive unmodified DD model can capture a key aspect of PPI networks. PMID- 21685064 TI - RINQ: Reference-based Indexing for Network Queries. AB - We consider the problem of similarity queries in biological network databases. Given a database of networks, similarity query returns all the database networks whose similarity (i.e. alignment score) to a given query network is at least a specified similarity cutoff value. Alignment of two networks is a very costly operation, which makes exhaustive comparison of all the database networks with a query impractical. To tackle this problem, we develop a novel indexing method, named RINQ (Reference-based Indexing for Biological Network Queries). Our method uses a set of reference networks to eliminate a large portion of the database quickly for each query. A reference network is a small biological network. We precompute and store the alignments of all the references with all the database networks. When our database is queried, we align the query network with all the reference networks. Using these alignments, we calculate a lower bound and an approximate upper bound to the alignment score of each database network with the query network. With the help of upper and lower bounds, we eliminate the majority of the database networks without aligning them to the query network. We also quickly identify a small portion of these as guaranteed to be similar to the query. We perform pairwise alignment only for the remaining networks. We also propose a supervised method to pick references that have a large chance of filtering the unpromising database networks. Extensive experimental evaluation suggests that (i) our method reduced the running time of a single query on a database of around 300 networks from over 2 days to only 8 h; (ii) our method outperformed the state of the art method Closure Tree and SAGA by a factor of three or more; and (iii) our method successfully identified statistically and biologically significant relationships across networks and organisms. PMID- 21685065 TI - Environment specific substitution tables improve membrane protein alignment. AB - MOTIVATION: Membrane proteins are both abundant and important in cells, but the small number of solved structures restricts our understanding of them. Here we consider whether membrane proteins undergo different substitutions from their soluble counterparts and whether these can be used to improve membrane protein alignments, and therefore improve prediction of their structure. RESULTS: We construct substitution tables for different environments within membrane proteins. As data is scarce, we develop a general metric to assess the quality of these asymmetric tables. Membrane proteins show markedly different substitution preferences from soluble proteins. For example, substitution preferences in lipid tail-contacting parts of membrane proteins are found to be distinct from all environments in soluble proteins, including buried residues. A principal component analysis of the tables identifies the greatest variation in substitution preferences to be due to changes in hydrophobicity; the second largest variation relates to secondary structure. We demonstrate the use of our tables in pairwise sequence-to-structure alignments (also known as 'threading') of membrane proteins using the FUGUE alignment program. On average, in the 10-25% sequence identity range, alignments are improved by 28 correctly aligned residues compared with alignments made using FUGUE's default substitution tables. Our alignments also lead to improved structural models. AVAILABILITY: Substitution tables are available at: http://www.stats.ox.ac.uk/proteins/resources. PMID- 21685066 TI - Construction of co-complex score matrix for protein complex prediction from AP-MS data. AB - MOTIVATION: Protein complexes are of great importance for unraveling the secrets of cellular organization and function. The AP-MS technique has provided an effective high-throughput screening to directly measure the co-complex relationship among multiple proteins, but its performance suffers from both false positives and false negatives. To computationally predict complexes from AP-MS data, most existing approaches either required the additional knowledge from known complexes (supervised learning), or had numerous parameters to tune. METHOD: In this article, we propose a novel unsupervised approach, without relying on the knowledge of existing complexes. Our method probabilistically calculates the affinity between two proteins, where the affinity score is evaluated by a co-complexed score or C2S in brief. In particular, our method measures the log-likelihood ratio of two proteins being co-complexed to being drawn randomly, and we then predict protein complexes by applying hierarchical clustering algorithm on the C2S score matrix. RESULTS: Compared with existing approaches, our approach is computationally efficient and easy to implement. It has just one parameter to set and its value has little effect on the results. It can be applied to different species as long as the AP-MS data are available. Despite its simplicity, it is competitive or superior in performance over many aspects when compared with the state-of-the-art predictions performed by supervised or unsupervised approaches. PMID- 21685067 TI - Uncover disease genes by maximizing information flow in the phenome-interactome network. AB - MOTIVATION: Pinpointing genes that underlie human inherited diseases among candidate genes in susceptibility genetic regions is the primary step towards the understanding of pathogenesis of diseases. Although several probabilistic models have been proposed to prioritize candidate genes using phenotype similarities and protein-protein interactions, no combinatorial approaches have been proposed in the literature. RESULTS: We propose the first combinatorial approach for prioritizing candidate genes. We first construct a phenome-interactome network by integrating the given phenotype similarity profile, protein-protein interaction network and associations between diseases and genes. Then, we introduce a computational method called MAXIF to maximize the information flow in this network for uncovering genes that underlie diseases. We demonstrate the effectiveness of this method in prioritizing candidate genes through a series of cross-validation experiments, and we show the possibility of using this method to identify diseases with which a query gene may be associated. We demonstrate the competitive performance of our method through a comparison with two existing state-of-the-art methods, and we analyze the robustness of our method with respect to the parameters involved. As an example application, we apply our method to predict driver genes in 50 copy number aberration regions of melanoma. Our method is not only able to identify several driver genes that have been reported in the literature, it also shed some new biological insights on the understanding of the modular property and transcriptional regulation scheme of these driver genes. CONTACT: ruijiang@tsinghua.edu.cn. PMID- 21685068 TI - Physical Module Networks: an integrative approach for reconstructing transcription regulation. AB - MOTIVATION: Deciphering the complex mechanisms by which regulatory networks control gene expression remains a major challenge. While some studies infer regulation from dependencies between the expression levels of putative regulators and their targets, others focus on measured physical interactions. RESULTS: Here, we present Physical Module Networks, a unified framework that combines a Bayesian model describing modules of co-expressed genes and their shared regulation programs, and a physical interaction graph, describing the protein-protein interactions and protein-DNA binding events that coherently underlie this regulation. Using synthetic data, we demonstrate that a Physical Module Network model has similar recall and improved precision compared to a simple Module Network, as it omits many false positive regulators. Finally, we show the power of Physical Module Networks to reconstruct meaningful regulatory pathways in the genetically perturbed yeast and during the yeast cell cycle, as well as during the response of primary epithelial human cells to infection with H1N1 influenza. AVAILABILITY: The PMN software is available, free for academic use at http://www.compbio.cs.huji.ac.il/PMN/. CONTACT: aregev@broad.mit.edu; nirf@cs.huji.ac.il. PMID- 21685069 TI - Identification of metabolic network models from incomplete high-throughput datasets. AB - MOTIVATION: High-throughput measurement techniques for metabolism and gene expression provide a wealth of information for the identification of metabolic network models. Yet, missing observations scattered over the dataset restrict the number of effectively available datapoints and make classical regression techniques inaccurate or inapplicable. Thorough exploitation of the data by identification techniques that explicitly cope with missing observations is therefore of major importance. RESULTS: We develop a maximum-likelihood approach for the estimation of unknown parameters of metabolic network models that relies on the integration of statistical priors to compensate for the missing data. In the context of the linlog metabolic modeling framework, we implement the identification method by an Expectation-Maximization (EM) algorithm and by a simpler direct numerical optimization method. We evaluate performance of our methods by comparison to existing approaches, and show that our EM method provides the best results over a variety of simulated scenarios. We then apply the EM algorithm to a real problem, the identification of a model for the Escherichia coli central carbon metabolism, based on challenging experimental data from the literature. This leads to promising results and allows us to highlight critical identification issues. PMID- 21685070 TI - TREEGL: reverse engineering tree-evolving gene networks underlying developing biological lineages. AB - MOTIVATION: Estimating gene regulatory networks over biological lineages is central to a deeper understanding of how cells evolve during development and differentiation. However, one challenge in estimating such evolving networks is that their host cells not only contiguously evolve, but also branch over time. For example, a stem cell evolves into two more specialized daughter cells at each division, forming a tree of networks. Another example is in a laboratory setting: a biologist may apply several different drugs individually to malignant cancer cells to analyze the effects of each drug on the cells; the cells treated by one drug may not be intrinsically similar to those treated by another, but rather to the malignant cancer cells they were derived from. RESULTS: We propose a novel algorithm, Treegl, an l(1) plus total variation penalized linear regression method, to effectively estimate multiple gene networks corresponding to cell types related by a tree-genealogy, based on only a few samples from each cell type. Treegl takes advantage of the similarity between related networks along the biological lineage, while at the same time exposing sharp differences between the networks. We demonstrate that our algorithm performs significantly better than existing methods via simulation. Furthermore we explore an application to a breast cancer dataset, and show that our algorithm is able to produce biologically valid results that provide insight into the progression and reversion of breast cancer cells. AVAILABILITY: Software will be available at http://www.sailing.cs.cmu.edu/. CONTACT: epxing@cs.cmu.edu. PMID- 21685072 TI - Optimally discriminative subnetwork markers predict response to chemotherapy. AB - MOTIVATION: Molecular profiles of tumour samples have been widely and successfully used for classification problems. A number of algorithms have been proposed to predict classes of tumor samples based on expression profiles with relatively high performance. However, prediction of response to cancer treatment has proved to be more challenging and novel approaches with improved generalizability are still highly needed. Recent studies have clearly demonstrated the advantages of integrating protein-protein interaction (PPI) data with gene expression profiles for the development of subnetwork markers in classification problems. RESULTS: We describe a novel network-based classification algorithm (OptDis) using color coding technique to identify optimally discriminative subnetwork markers. Focusing on PPI networks, we apply our algorithm to drug response studies: we evaluate our algorithm using published cohorts of breast cancer patients treated with combination chemotherapy. We show that our OptDis method improves over previously published subnetwork methods and provides better and more stable performance compared with other subnetwork and single gene methods. We also show that our subnetwork method produces predictive markers that are more reproducible across independent cohorts and offer valuable insight into biological processes underlying response to therapy. AVAILABILITY: The implementation is available at: http://www.cs.sfu.ca/~pdao/personal/OptDis.html CONTACT: cenk@cs.sfu.ca; alapuk@prostatecentre.com; ccollins@prostatecentre.com. PMID- 21685073 TI - Epistasis detection on quantitative phenotypes by exhaustive enumeration using GPUs. AB - MOTIVATION: In recent years, numerous genome-wide association studies have been conducted to identify genetic makeup that explains phenotypic differences observed in human population. Analytical tests on single loci are readily available and embedded in common genome analysis software toolset. The search for significant epistasis (gene-gene interactions) still poses as a computational challenge for modern day computing systems, due to the large number of hypotheses that have to be tested. RESULTS: In this article, we present an approach to epistasis detection by exhaustive testing of all possible SNP pairs. The search strategy based on the Hilbert-Schmidt Independence Criterion can help delineate various forms of statistical dependence between the genetic markers and the phenotype. The actual implementation of this search is done on the highly parallelized architecture available on graphics processing units rendering the completion of the full search feasible within a day. AVAILABILITY: The program is available at http://www.mpipsykl.mpg.de/epigpuhsic/. CONTACT: tony@mpipsykl.mpg.de. PMID- 21685074 TI - Detecting epistatic effects in association studies at a genomic level based on an ensemble approach. AB - MOTIVATION: Most complex diseases involve multiple genes and their interactions. Although genome-wide association studies (GWAS) have shown some success for identifying genetic variants underlying complex diseases, most existing studies are based on limited single-locus approaches, which detect single nucleotide polymorphisms (SNPs) essentially based on their marginal associations with phenotypes. RESULTS: In this article, we propose an ensemble approach based on boosting to study gene-gene interactions. We extend the basic AdaBoost algorithm by incorporating an intuitive importance score based on Gini impurity to select candidate SNPs. Permutation tests are used to control the statistical significance. We have performed extensive simulation studies using three interaction models to evaluate the efficacy of our approach at realistic GWAS sizes, and have compared it with existing epistatic detection algorithms. Our results indicate that our approach is valid, efficient for GWAS and on disease models with epistasis has more power than existing programs. CONTACT: jingli@case.edu. PMID- 21685075 TI - Efficient spatial segmentation of large imaging mass spectrometry datasets with spatially aware clustering. AB - MOTIVATION: Imaging mass spectrometry (IMS) is one of the few measurement technology s of biochemistry which, given a thin sample, is able to reveal its spatial chemical composition in the full molecular range. IMS produces a hyperspectral image, where for each pixel a high-dimensional mass spectrum is measured. Currently, the technology is mature enough and one of the major problems preventing its spreading is the under-development of computational methods for mining huge IMS datasets. This article proposes a novel approach for spatial segmentation of an IMS dataset, which is constructed considering the important issue of pixel-to-pixel variability. METHODS: We segment pixels by clustering their mass spectra. Importantly, we incorporate spatial relations between pixels into clustering, so that pixels are clustered together with their neighbors. We propose two methods. One is non-adaptive, where pixel neighborhoods are selected in the same manner for all pixels. The second one respects the structure observable in the data. For a pixel, its neighborhood is defined taking into account similarity of its spectrum to the spectra of adjacent pixels. Both methods have the linear complexity and require linear memory space (in the number of spectra). RESULTS: The proposed segmentation methods are evaluated on two IMS datasets: a rat brain section and a section of a neuroendocrine tumor. They discover anatomical structure, discriminate the tumor region and highlight functionally similar regions. Moreover, our methods provide segmentation maps of similar or better quality if compared to the other state-of-the-art methods, but outperform them in runtime and/or required memory. CONTACT: theodore@math.uni bremen.de. PMID- 21685076 TI - Automatic 3D neuron tracing using all-path pruning. AB - MOTIVATION: Digital reconstruction, or tracing, of 3D neuron structures is critical toward reverse engineering the wiring and functions of a brain. However, despite a number of existing studies, this task is still challenging, especially when a 3D microscopic image has low signal-to-noise ratio (SNR) and fragmented neuron segments. Published work can handle these hard situations only by introducing global prior information, such as where a neurite segment starts and terminates. However, manual incorporation of such global information can be very time consuming. Thus, a completely automatic approach for these hard situations is highly desirable. RESULTS: We have developed an automatic graph algorithm, called the all-path pruning (APP), to trace the 3D structure of a neuron. To avoid potential mis-tracing of some parts of a neuron, an APP first produces an initial over-reconstruction, by tracing the optimal geodesic shortest path from the seed location to every possible destination voxel/pixel location in the image. Since the initial reconstruction contains all the possible paths and thus could contain redundant structural components (SC), we simplify the entire reconstruction without compromising its connectedness by pruning the redundant structural elements, using a new maximal-covering minimal-redundant (MCMR) subgraph algorithm. We show that MCMR has a linear computational complexity and will converge. We examined the performance of our method using challenging 3D neuronal image datasets of model organisms (e.g. fruit fly). AVAILABILITY: The software is available upon request. We plan to eventually release the software as a plugin of the V3D-Neuron package at http://penglab.janelia.org/proj/v3d. CONTACT: pengh@janelia.hhmi.org. PMID- 21685077 TI - Sequence-based prediction of protein crystallization, purification and production propensity. AB - MOTIVATION: X-ray crystallography-based protein structure determination, which accounts for majority of solved structures, is characterized by relatively low success rates. One solution is to build tools which support selection of targets that are more likely to crystallize. Several in silico methods that predict propensity of diffraction-quality crystallization from protein chains were developed. We show that the quality of their predictions drops when applied to more recent crystallization trails, which calls for new solutions. We propose a novel approach that alleviates drawbacks of the existing methods by using a recent dataset and improved protocol to annotate progress along the crystallization process, by predicting the success of the entire process and steps which result in the failed attempts, and by utilizing a compact and comprehensive set of sequence-derived inputs to generate accurate predictions. RESULTS: The proposed PPCpred (predictor of protein Production, Purification and Crystallization) predict propensity for production of diffraction-quality crystals, production of crystals, purification and production of the protein material. PPCpred utilizes comprehensive set of inputs based on energy and hydrophobicity indices, composition of certain amino acid types, predicted disorder, secondary structure and solvent accessibility, and content of certain buried and exposed residues. Our method significantly outperforms alignment-based predictions and several modern crystallization propensity predictors. Receiver operating characteristic (ROC) curves show that PPCpred is particularly useful for users who desire high true positive (TP) rates, i.e. low rate of mispredictions for solvable chains. Our model reveals several intuitive factors that influence the success of individual steps and the entire crystallization process, including the content of Cys, buried His and Ser, hydrophobic/hydrophilic segments and the number of predicted disordered segments. AVAILABILITY: http://biomine.ece.ualberta.ca/PPCpred/. CONTACT: lkurgan@ece.ualberta.ca. PMID- 21685078 TI - Tanglegrams for rooted phylogenetic trees and networks. AB - MOTIVATION: In systematic biology, one is often faced with the task of comparing different phylogenetic trees, in particular in multi-gene analysis or cospeciation studies. One approach is to use a tanglegram in which two rooted phylogenetic trees are drawn opposite each other, using auxiliary lines to connect matching taxa. There is an increasing interest in using rooted phylogenetic networks to represent evolutionary history, so as to explicitly represent reticulate events, such as horizontal gene transfer, hybridization or reassortment. Thus, the question arises how to define and compute a tanglegram for such networks. RESULTS: In this article, we present the first formal definition of a tanglegram for rooted phylogenetic networks and present a heuristic approach for computing one, called the NN-tanglegram method. We compare the performance of our method with existing tree tanglegram algorithms and also show a typical application to real biological datasets. For maximum usability, the algorithm does not require that the trees or networks are bifurcating or bicombining, or that they are on identical taxon sets. AVAILABILITY: The algorithm is implemented in our program Dendroscope 3, which is freely available from www.dendroscope.org. CONTACT: scornava@informatik.uni-tuebingen.de; huson@informatik.uni-tuebingen.de. PMID- 21685079 TI - Mapping ancestral genomes with massive gene loss: a matrix sandwich problem. AB - MOTIVATION: Ancestral genomes provide a better way to understand the structural evolution of genomes than the simple comparison of extant genomes. Most ancestral genome reconstruction methods rely on universal markers, that is, homologous families of DNA segments present in exactly one exemplar in every considered species. Complex histories of genes or other markers, undergoing duplications and losses, are rarely taken into account. It follows that some ancestors are inaccessible by these methods, such as the proto-monocotyledon whose evolution involved massive gene loss following a whole genome duplication. RESULTS: We propose a mapping approach based on the combinatorial notion of 'sandwich consecutive ones matrix', which explicitly takes gene losses into account. We introduce combinatorial optimization problems related to this concept, and propose a heuristic solver and a lower bound on the optimal solution. We use these results to propose a configuration for the proto-chromosomes of the monocot ancestor, and study the accuracy of this configuration. We also use our method to reconstruct the ancestral boreoeutherian genomes, which illustrates that the framework we propose is not specific to plant paleogenomics but is adapted to reconstruct any ancestral genome from extant genomes with heterogeneous marker content. AVAILABILITY: Upon request to the authors. CONTACT: haris.gavranovic@gmail.com; eric.tannier@inria.fr. PMID- 21685080 TI - Predicting site-specific human selective pressure using evolutionary signatures. AB - MOTIVATION: The identification of non-coding functional regions of the human genome remains one of the main challenges of genomics. By observing how a given region evolved over time, one can detect signs of negative or positive selection hinting that the region may be functional. With the quickly increasing number of vertebrate genomes to compare with our own, this type of approach is set to become extremely powerful, provided the right analytical tools are available. RESULTS: A large number of approaches have been proposed to measure signs of past selective pressure, usually in the form of reduced mutation rate. Here, we propose a radically different approach to the detection of non-coding functional region: instead of measuring past evolutionary rates, we build a machine learning classifier to predict current substitution rates in human based on the inferred evolutionary events that affected the region during vertebrate evolution. We show that different types of evolutionary events, occurring along different branches of the phylogenetic tree, bring very different amounts of information. We propose a number of simple machine learning classifiers and show that a Support-Vector Machine (SVM) predictor clearly outperforms existing tools at predicting human non-coding functional sites. Comparison to external evidences of selection and regulatory function confirms that these SVM predictions are more accurate than those of other approaches. AVAILABILITY: The predictor and predictions made are available at http://www.mcb.mcgill.ca/~blanchem/sadri. CONTACT: blanchem@mcb.mcgill.ca. PMID- 21685081 TI - PhyloCSF: a comparative genomics method to distinguish protein coding and non coding regions. AB - MOTIVATION: As high-throughput transcriptome sequencing provides evidence for novel transcripts in many species, there is a renewed need for accurate methods to classify small genomic regions as protein coding or non-coding. We present PhyloCSF, a novel comparative genomics method that analyzes a multispecies nucleotide sequence alignment to determine whether it is likely to represent a conserved protein-coding region, based on a formal statistical comparison of phylogenetic codon models. RESULTS: We show that PhyloCSF's classification performance in 12-species Drosophila genome alignments exceeds all other methods we compared in a previous study. We anticipate that this method will be widely applicable as the transcriptomes of many additional species, tissues and subcellular compartments are sequenced, particularly in the context of ENCODE and modENCODE, and as interest grows in long non-coding RNAs, often initially recognized by their lack of protein coding potential rather than conserved RNA secondary structures. AVAILABILITY AND IMPLEMENTATION: The Objective Caml source code and executables for GNU/Linux and Mac OS X are freely available at http://compbio.mit.edu/PhyloCSF CONTACT: mlin@mit.edu; manoli@mit.edu. PMID- 21685082 TI - The role of proteosome-mediated proteolysis in modulating potentially harmful transcription factor activity in Saccharomyces cerevisiae. AB - MOTIVATION: The appropriate modulation of the stress response to variable environmental conditions is necessary to maintain sustained viability in Saccharomyces cerevisiae. Particularly, controlling the abundance of proteins that may have detrimental effects on cell growth is crucial for rapid recovery from stress-induced quiescence. RESULTS: Prompted by qualitative modeling of the nutrient starvation response in yeast, we investigated in vivo the effect of proteolysis after nutrient starvation showing that, for the Gis1 transcription factor at least, proteasome-mediated control is crucial for a rapid return to growth. Additional bioinformatics analyses show that potentially toxic transcriptional regulators have a significantly lower protein half-life, a higher fraction of unstructured regions and more potential PEST motifs than the non detrimental ones. Furthermore, inhibiting proteasome activity tends to increase the expression of genes induced during the Environmental Stress Response more than those in the rest of the genome. Our combined results suggest that proteasome-mediated proteolysis of potentially toxic transcription factors tightly modulates the stress response in yeast. CONTACT: jasmin.fisher@microsoft.com PMID- 21685083 TI - Mixed-model coexpression: calculating gene coexpression while accounting for expression heterogeneity. AB - MOTIVATION: The analysis of gene coexpression is at the core of many types of genetic analysis. The coexpression between two genes can be calculated by using a traditional Pearson's correlation coefficient. However, unobserved confounding effects may cause inflation of the Pearson's correlation so that uncorrelated genes appear correlated. Many general methods have been suggested, which aim to remove the effects of confounding from gene expression data. However, the residual confounding which is not accounted for by these generic correction procedures has the potential to induce correlation between genes. Therefore, a method that specifically aims to calculate gene coexpression between gene expression arrays, while accounting for confounding effects, is desirable. RESULTS: In this article, we present a statistical model for calculating gene coexpression called mixed model coexpression (MMC), which models coexpression within a mixed model framework. Confounding effects are expected to be encoded in the matrix representing the correlation between arrays, the inter-sample correlation matrix. By conditioning on the information in the inter-sample correlation matrix, MMC is able to produce gene coexpressions that are not influenced by global confounding effects and thus significantly reduce the number of spurious coexpressions observed. We applied MMC to both human and yeast datasets and show it is better able to effectively prioritize strong coexpressions when compared to a traditional Pearson's correlation and a Pearson's correlation applied to data corrected with surrogate variable analysis (SVA). AVAILABILITY: The method is implemented in the R programming language and may be found at http://genetics.cs.ucla.edu/mmc. CONTACT: nfurlott@cs.ucla.edu; eeskin@cs.ucla.edu. PMID- 21685085 TI - Systematic exploration of error sources in pyrosequencing flowgram data. AB - MOTIVATION: 454 pyrosequencing, by Roche Diagnostics, has emerged as an alternative to Sanger sequencing when it comes to read lengths, performance and cost, but shows higher per-base error rates. Although there are several tools available for noise removal, targeting different application fields, data interpretation would benefit from a better understanding of the different error types. RESULTS: By exploring 454 raw data, we quantify to what extent different factors account for sequencing errors. In addition to the well-known homopolymer length inaccuracies, we have identified errors likely to originate from other stages of the sequencing process. We use our findings to extend the flowsim pipeline with functionalities to simulate these errors, and thus enable a more realistic simulation of 454 pyrosequencing data with flowsim. AVAILABILITY: The flowsim pipeline is freely available under the General Public License from http://biohaskell.org/Applications/FlowSim. CONTACT: susanne.balzer@imr.no. PMID- 21685084 TI - A generalized model for multi-marker analysis of cell cycle progression in synchrony experiments. AB - MOTIVATION: To advance understanding of eukaryotic cell division, it is important to observe the process precisely. To this end, researchers monitor changes in dividing cells as they traverse the cell cycle, with the presence or absence of morphological or genetic markers indicating a cell's position in a particular interval of the cell cycle. A wide variety of marker data is available, including information-rich cellular imaging data. However, few formal statistical methods have been developed to use these valuable data sources in estimating how a population of cells progresses through the cell cycle. Furthermore, existing methods are designed to handle only a single binary marker of cell cycle progression at a time. Consequently, they cannot facilitate comparison of experiments involving different sets of markers. RESULTS: Here, we develop a new sampling model to accommodate an arbitrary number of different binary markers that characterize the progression of a population of dividing cells along a branching process. We engineer a strain of Saccharomyces cerevisiae with fluorescently labeled markers of cell cycle progression, and apply our new model to two image datasets we collected from the strain, as well as an independent dataset of different markers. We use our model to estimate the duration of post cytokinetic attachment between a S.cerevisiae mother and daughter cell. The Java implementation is fast and extensible, and includes a graphical user interface. Our model provides a powerful and flexible cell cycle analysis tool, suitable to any type or combination of binary markers. AVAILABILITY: The software is available from: http://www.cs.duke.edu/~amink/software/cloccs/. CONTACT: michael.mayhew@duke.edu; amink@cs.duke.edu. PMID- 21685086 TI - An enhanced Petri-net model to predict synergistic effects of pairwise drug combinations from gene microarray data. AB - MOTIVATION: Prediction of synergistic effects of drug combinations has traditionally been relied on phenotypic response data. However, such methods cannot be used to identify molecular signaling mechanisms of synergistic drug combinations. In this article, we propose an enhanced Petri-Net (EPN) model to recognize the synergistic effects of drug combinations from the molecular response profiles, i.e. drug-treated microarray data. METHODS: We addressed the downstream signaling network of the targets for the two individual drugs used in the pairwise combinations and applied EPN to the identified targeted signaling network. In EPN, drugs and signaling molecules are assigned to different types of places, while drug doses and molecular expressions are denoted by color tokens. The changes of molecular expressions caused by treatments of drugs are simulated by two actions of EPN: firing and blasting. Firing is to transit the drug and molecule tokens from one node or place to another, and blasting is to reduce the number of molecule tokens by drug tokens in a molecule node. The goal of EPN is to mediate the state characterized by control condition without any treatment to that of treatment and to depict the drug effects on molecules by the drug tokens. RESULTS: We applied EPN to our generated pairwise drug combination microarray data. The synergistic predictions using EPN are consistent with those predicted using phenotypic response data. The molecules responsible for the synergistic effects with their associated feedback loops display the mechanisms of synergism. AVAILABILITY: The software implemented in Python 2.7 programming language is available from request. CONTACT: stwong@tmhs.org. PMID- 21685087 TI - Accurate estimation of heritability in genome wide studies using random effects models. AB - MOTIVATION: Random effects models have recently been introduced as an approach for analyzing genome wide association studies (GWASs), which allows estimation of overall heritability of traits without explicitly identifying the genetic loci responsible. Using this approach, Yang et al. (2010) have demonstrated that the heritability of height is much higher than the ~10% associated with identified genetic factors. However, Yang et al. (2010) relied on a heuristic for performing estimation in this model. RESULTS: We adopt the model framework of Yang et al. (2010) and develop a method for maximum-likelihood (ML) estimation in this framework. Our method is based on Monte-Carlo expectation-maximization (MCEM; Wei et al., 1990), an expectation-maximization algorithm wherein a Markov chain Monte Carlo approach is used in the E-step. We demonstrate that this method leads to more stable and accurate heritability estimation compared to the approach of Yang et al. (2010), and it also allows us to find ML estimates of the portion of markers which are causal, indicating whether the heritability stems from a small number of powerful genetic factors or a large number of less powerful ones. CONTACT: saharon@post.tau.ac.il. PMID- 21685088 TI - StructHDP: automatic inference of number of clusters and population structure from admixed genotype data. AB - MOTIVATION: Clustering of genotype data is an important way of understanding similarities and differences between populations. A summary of populations through clustering allows us to make inferences about the evolutionary history of the populations. Many methods have been proposed to perform clustering on multilocus genotype data. However, most of these methods do not directly address the question of how many clusters the data should be divided into and leave that choice to the user. METHODS: We present StructHDP, which is a method for automatically inferring the number of clusters from genotype data in the presence of admixture. Our method is an extension of two existing methods, Structure and Structurama. Using a Hierarchical Dirichlet Process (HDP), we model the presence of admixture of an unknown number of ancestral populations in a given sample of genotype data. We use a Gibbs sampler to perform inference on the resulting model and infer the ancestry proportions and the number of clusters that best explain the data. RESULTS: To demonstrate our method, we simulated data from an island model using the neutral coalescent. Comparing the results of StructHDP with Structurama shows the utility of combining HDPs with the Structure model. We used StructHDP to analyze a dataset of 155 Taita thrush, Turdus helleri, which has been previously analyzed using Structure and Structurama. StructHDP correctly picks the optimal number of populations to cluster the data. The clustering based on the inferred ancestry proportions also agrees with that inferred using Structure for the optimal number of populations. We also analyzed data from 1048 individuals from the Human Genome Diversity project from 53 world populations. We found that the clusters obtained correspond with major geographical divisions of the world, which is in agreement with previous analyses of the dataset. AVAILABILITY: StructHDP is written in C++. The code will be available for download at http://www.sailing.cs.cmu.edu/structhdp. CONTACT: suyash@cs.cmu.edu; epxing@cs.cmu.edu. PMID- 21685089 TI - Reconstruction of genealogical relationships with applications to Phase III of HapMap. AB - MOTIVATION: Accurate inference of genealogical relationships between pairs of individuals is paramount in association studies, forensics and evolutionary analyses of wildlife populations. Current methods for relationship inference consider only a small set of close relationships and have limited to no power to distinguish between relationships with the same number of meioses separating the individuals under consideration (e.g. aunt-niece versus niece-aunt or first cousins versus great aunt-niece). RESULTS: We present CARROT (ClAssification of Relationships with ROTations), a novel framework for relationship inference that leverages linkage information to differentiate between rotated relationships, that is, between relationships with the same number of common ancestors and the same number of meioses separating the individuals under consideration. We demonstrate that CARROT clearly outperforms existing methods on simulated data. We also applied CARROT on four populations from Phase III of the HapMap Project and detected previously unreported pairs of third- and fourth-degree relatives. AVAILABILITY: Source code for CARROT is freely available at http://carrot.stanford.edu. CONTACT: sofiakp@stanford.edu. PMID- 21685090 TI - A method for probing the mutational landscape of amyloid structure. AB - MOTIVATION: Proteins of all kinds can self-assemble into highly ordered beta sheet aggregates known as amyloid fibrils, important both biologically and clinically. However, the specific molecular structure of a fibril can vary dramatically depending on sequence and environmental conditions, and mutations can drastically alter amyloid function and pathogenicity. Experimental structure determination has proven extremely difficult with only a handful of NMR-based models proposed, suggesting a need for computational methods. RESULTS: We present AmyloidMutants, a statistical mechanics approach for de novo prediction and analysis of wild-type and mutant amyloid structures. Based on the premise of protein mutational landscapes, AmyloidMutants energetically quantifies the effects of sequence mutation on fibril conformation and stability. Tested on non mutant, full-length amyloid structures with known chemical shift data, AmyloidMutants offers roughly 2-fold improvement in prediction accuracy over existing tools. Moreover, AmyloidMutants is the only method to predict complete super-secondary structures, enabling accurate discrimination of topologically dissimilar amyloid conformations that correspond to the same sequence locations. Applied to mutant prediction, AmyloidMutants identifies a global conformational switch between Abeta and its highly-toxic 'Iowa' mutant in agreement with a recent experimental model based on partial chemical shift data. Predictions on mutant, yeast-toxic strains of HET-s suggest similar alternate folds. When applied to HET-s and a HET-s mutant with core asparagines replaced by glutamines (both highly amyloidogenic chemically similar residues abundant in many amyloids), AmyloidMutants surprisingly predicts a greatly reduced capacity of the glutamine mutant to form amyloid. We confirm this finding by conducting mutagenesis experiments. AVAILABILITY: Our tool is publically available on the web at http://amyloid.csail.mit.edu/. CONTACT: lindquist_admin@wi.mit.edu; bab@csail.mit.edu. PMID- 21685091 TI - ccSVM: correcting Support Vector Machines for confounding factors in biological data classification. AB - MOTIVATION: Classifying biological data into different groups is a central task of bioinformatics: for instance, to predict the function of a gene or protein, the disease state of a patient or the phenotype of an individual based on its genotype. Support Vector Machines are a wide spread approach for classifying biological data, due to their high accuracy, their ability to deal with structured data such as strings, and the ease to integrate various types of data. However, it is unclear how to correct for confounding factors such as population structure, age or gender or experimental conditions in Support Vector Machine classification. RESULTS: In this article, we present a Support Vector Machine classifier that can correct the prediction for observed confounding factors. This is achieved by minimizing the statistical dependence between the classifier and the confounding factors. We prove that this formulation can be transformed into a standard Support Vector Machine with rescaled input data. In our experiments, our confounder correcting SVM (ccSVM) improves tumor diagnosis based on samples from different labs, tuberculosis diagnosis in patients of varying age, ethnicity and gender, and phenotype prediction in the presence of population structure and outperforms state-of-the-art methods in terms of prediction accuracy. AVAILABILITY: A ccSVM-implementation in MATLAB is available from http://webdav.tuebingen.mpg.de/u/karsten/Forschung/ISMB11_ccSVM/. CONTACT: limin.li@tuebingen.mpg.de; karsten.borgwardt@tuebingen.mpg.de. PMID- 21685092 TI - Ontology patterns for tabular representations of biomedical knowledge on neglected tropical diseases. AB - MOTIVATION: Ontology-like domain knowledge is frequently published in a tabular format embedded in scientific publications. We explore the re-use of such tabular content in the process of building NTDO, an ontology of neglected tropical diseases (NTDs), where the representation of the interdependencies between hosts, pathogens and vectors plays a crucial role. RESULTS: As a proof of concept we analyzed a tabular compilation of knowledge about pathogens, vectors and geographic locations involved in the transmission of NTDs. After a thorough ontological analysis of the domain of interest, we formulated a comprehensive design pattern, rooted in the biomedical domain upper level ontology BioTop. This pattern was implemented in a VBA script which takes cell contents of an Excel spreadsheet and transforms them into OWL-DL. After minor manual post-processing, the correctness and completeness of the ontology was tested using pre-formulated competence questions as description logics (DL) queries. The expected results could be reproduced by the ontology. The proposed approach is recommended for optimizing the acquisition of ontological domain knowledge from tabular representations. AVAILABILITY AND IMPLEMENTATION: Domain examples, source code and ontology are freely available on the web at http://www.cin.ufpe.br/~ntdo. CONTACT: fss3@cin.ufpe.br. PMID- 21685093 TI - Detection and interpretation of metabolite-transcript coresponses using combined profiling data. AB - MOTIVATION: Studying the interplay between gene expression and metabolite levels can yield important information on the physiology of stress responses and adaptation strategies. Performing transcriptomics and metabolomics in parallel during time-series experiments represents a systematic way to gain such information. Several combined profiling datasets have been added to the public domain and they form a valuable resource for hypothesis generating studies. Unfortunately, detecting coresponses between transcript levels and metabolite abundances is non-trivial: they cannot be assumed to overlap directly with underlying biochemical pathways and they may be subject to time delays and obscured by considerable noise. RESULTS: Our aim was to predict pathway comemberships between metabolites and genes based on their coresponses to applied stress. We found that in the presence of strong noise and time-shifted responses, a hidden Markov model-based similarity outperforms the simpler Pearson correlation but performs comparably or worse in their absence. Therefore, we propose a supervised method that applies pathway information to summarize similarity statistics to a consensus statistic that is more informative than any of the single measures. Using four combined profiling datasets, we show that comembership between metabolites and genes can be predicted for numerous KEGG pathways; this opens opportunities for the detection of transcriptionally regulated pathways and novel metabolically related genes. AVAILABILITY: A command line software tool is available at http://www.cin.ufpe.br/~igcf/Metabolites. CONTACT: henning@psc.riken.jp; igcf@cin.ufpe.br PMID- 21685094 TI - From sets to graphs: towards a realistic enrichment analysis of transcriptomic systems. AB - MOTIVATION: Current gene set enrichment approaches do not take interactions and associations between set members into account. Mutual activation and inhibition causing positive and negative correlation among set members are thus neglected. As a consequence, inconsistent regulations and contextless expression changes are reported and, thus, the biological interpretation of the result is impeded. RESULTS: We analyzed established gene set enrichment methods and their result sets in a large-scale investigation of 1000 expression datasets. The reported statistically significant gene sets exhibit only average consistency between the observed patterns of differential expression and known regulatory interactions. We present Gene Graph Enrichment Analysis (GGEA) to detect consistently and coherently enriched gene sets, based on prior knowledge derived from directed gene regulatory networks. Firstly, GGEA improves the concordance of pairwise regulation with individual expression changes in respective pairs of regulating and regulated genes, compared with set enrichment methods. Secondly, GGEA yields result sets where a large fraction of relevant expression changes can be explained by nearby regulators, such as transcription factors, again improving on set-based methods. Thirdly, we demonstrate in additional case studies that GGEA can be applied to human regulatory pathways, where it sensitively detects very specific regulation processes, which are altered in tumors of the central nervous system. GGEA significantly increases the detection of gene sets where measured positively or negatively correlated expression patterns coincide with directed inducing or repressing relationships, thus facilitating further interpretation of gene expression data. AVAILABILITY: The method and accompanying visualization capabilities have been bundled into an R package and tied to a grahical user interface, the Galaxy workflow environment, that is running as a web server. CONTACT: Ludwig.Geistlinger@bio.ifi.lmu.de; Ralf.Zimmer@bio.ifi.lmu.de. PMID- 21685095 TI - Small sets of interacting proteins suggest functional linkage mechanisms via Bayesian analogical reasoning. AB - MOTIVATION: Proteins and protein complexes coordinate their activity to execute cellular functions. In a number of experimental settings, including synthetic genetic arrays, genetic perturbations and RNAi screens, scientists identify a small set of protein interactions of interest. A working hypothesis is often that these interactions are the observable phenotypes of some functional process, which is not directly observable. Confirmatory analysis requires finding other pairs of proteins whose interaction may be additional phenotypical evidence about the same functional process. Extant methods for finding additional protein interactions rely heavily on the information in the newly identified set of interactions. For instance, these methods leverage the attributes of the individual proteins directly, in a supervised setting, in order to find relevant protein pairs. A small set of protein interactions provides a small sample to train parameters of prediction methods, thus leading to low confidence. RESULTS: We develop RBSets, a computational approach to ranking protein interactions rooted in analogical reasoning; that is, the ability to learn and generalize relations between objects. Our approach is tailored to situations where the training set of protein interactions is small, and leverages the attributes of the individual proteins indirectly, in a Bayesian ranking setting that is perhaps closest to propensity scoring in mathematical psychology. We find that RBSets leads to good performance in identifying additional interactions starting from a small evidence set of interacting proteins, for which an underlying biological logic in terms of functional processes and signaling pathways can be established with some confidence. Our approach is scalable and can be applied to large databases with minimal computational overhead. Our results suggest that analogical reasoning within a Bayesian ranking problem is a promising new approach for real-time biological discovery. AVAILABILITY: Java code is available at: www.gatsby.ucl.ac.uk/~rbas. CONTACT: airoldi@fas.harvard.edu; kheller@mit.edu; ricardo@stats.ucl.ac.uk. PMID- 21685096 TI - Characterization and improvement of RNA-Seq precision in quantitative transcript expression profiling. AB - MOTIVATION: Measurement precision determines the power of any analysis to reliably identify significant signals, such as in screens for differential expression, independent of whether the experimental design incorporates replicates or not. With the compilation of large-scale RNA-Seq datasets with technical replicate samples, however, we can now, for the first time, perform a systematic analysis of the precision of expression level estimates from massively parallel sequencing technology. This then allows considerations for its improvement by computational or experimental means. RESULTS: We report on a comprehensive study of target identification and measurement precision, including their dependence on transcript expression levels, read depth and other parameters. In particular, an impressive recall of 84% of the estimated true transcript population could be achieved with 331 million 50 bp reads, with diminishing returns from longer read lengths and even less gains from increased sequencing depths. Most of the measurement power (75%) is spent on only 7% of the known transcriptome, however, making less strongly expressed transcripts harder to measure. Consequently, <30% of all transcripts could be quantified reliably with a relative error<20%. Based on established tools, we then introduce a new approach for mapping and analysing sequencing reads that yields substantially improved performance in gene expression profiling, increasing the number of transcripts that can reliably be quantified to over 40%. Extrapolations to higher sequencing depths highlight the need for efficient complementary steps. In discussion we outline possible experimental and computational strategies for further improvements in quantification precision. CONTACT: rnaseq10@boku.ac.at PMID- 21685097 TI - An integrative clustering and modeling algorithm for dynamical gene expression data. AB - MOTIVATION: The precise dynamics of gene expression is often crucial for proper response to stimuli. Time-course gene-expression profiles can provide insights about the dynamics of many cellular responses, but are often noisy and measured at arbitrary intervals, posing a major analysis challenge. RESULTS: We developed an algorithm that interleaves clustering time-course gene-expression data with estimation of dynamic models of their response by biologically meaningful parameters. In combining these two tasks we overcome obstacles posed in each one. Moreover, our approach provides an easy way to compare between responses to different stimuli at the dynamical level. We use our approach to analyze the dynamical transcriptional responses to inflammation and anti-viral stimuli in mice primary dendritic cells, and extract a concise representation of the different dynamical response types. We analyze the similarities and differences between the two stimuli and identify potential regulators of this complex transcriptional response. AVAILABILITY: The code to our method is freely available http://www.compbio.cs.huji.ac.il/DynaMiteC. CONTACT: nir@cs.huji.ac.il. PMID- 21685100 TI - Piecewise linear approximation of protein structures using the principle of minimum message length. AB - Simple and concise representations of protein-folding patterns provide powerful abstractions for visualizations, comparisons, classifications, searching and aligning structural data. Structures are often abstracted by replacing standard secondary structural features-that is, helices and strands of sheet-by vectors or linear segments. Relying solely on standard secondary structure may result in a significant loss of structural information. Further, traditional methods of simplification crucially depend on the consistency and accuracy of external methods to assign secondary structures to protein coordinate data. Although many methods exist automatically to identify secondary structure, the impreciseness of definitions, along with errors and inconsistencies in experimental structure data, drastically limit their applicability to generate reliable simplified representations, especially for structural comparison. This article introduces a mathematically rigorous algorithm to delineate protein structure using the elegant statistical and inductive inference framework of minimum message length (MML). Our method generates consistent and statistically robust piecewise linear explanations of protein coordinate data, resulting in a powerful and concise representation of the structure. The delineation is completely independent of the approaches of using hydrogen-bonding patterns or inspecting local substructural geometry that the current methods use. Indeed, as is common with applications of the MML criterion, this method is free of parameters and thresholds, in striking contrast to the existing programs which are often beset by them. The analysis of results over a large number of proteins suggests that the method produces consistent delineation of structures that encompasses, among others, the segments corresponding to standard secondary structure. AVAILABILITY: http://www.csse.monash.edu.au/~karun/pmml. PMID- 21685098 TI - A novel computational framework for simultaneous integration of multiple types of genomic data to identify microRNA-gene regulatory modules. AB - MOTIVATION: It is well known that microRNAs (miRNAs) and genes work cooperatively to form the key part of gene regulatory networks. However, the specific functional roles of most miRNAs and their combinatorial effects in cellular processes are still unclear. The availability of multiple types of functional genomic data provides unprecedented opportunities to study the miRNA-gene regulation. A major challenge is how to integrate the diverse genomic data to identify the regulatory modules of miRNAs and genes. RESULTS: Here we propose an effective data integration framework to identify the miRNA-gene regulatory comodules. The miRNA and gene expression profiles are jointly analyzed in a multiple non-negative matrix factorization framework, and additional network data are simultaneously integrated in a regularized manner. Meanwhile, we employ the sparsity penalties to the variables to achieve modular solutions. The mathematical formulation can be effectively solved by an iterative multiplicative updating algorithm. We apply the proposed method to integrate a set of heterogeneous data sources including the expression profiles of miRNAs and genes on 385 human ovarian cancer samples, computationally predicted miRNA-gene interactions, and gene-gene interactions. We demonstrate that the miRNAs and genes in 69% of the regulatory comodules are significantly associated. Moreover, the comodules are significantly enriched in known functional sets such as miRNA clusters, GO biological processes and KEGG pathways, respectively. Furthermore, many miRNAs and genes in the comodules are related with various cancers including ovarian cancer. Finally, we show that comodules can stratify patients (samples) into groups with significant clinical characteristics. AVAILABILITY: The program and supplementary materials are available at http://zhoulab.usc.edu/SNMNMF/. CONTACT: xjzhou@usc.edu; zsh@amss.ac.cn PMID- 21685101 TI - QAARM: quasi-anharmonic autoregressive model reveals molecular recognition pathways in ubiquitin. AB - MOTIVATION: Molecular dynamics (MD) simulations have dramatically improved the atomistic understanding of protein motions, energetics and function. These growing datasets have necessitated a corresponding emphasis on trajectory analysis methods for characterizing simulation data, particularly since functional protein motions and transitions are often rare and/or intricate events. Observing that such events give rise to long-tailed spatial distributions, we recently developed a higher-order statistics based dimensionality reduction method, called quasi-anharmonic analysis (QAA), for identifying biophysically-relevant reaction coordinates and substates within MD simulations. Further characterization of conformation space should consider the temporal dynamics specific to each identified substate. RESULTS: Our model uses hierarchical clustering to learn energetically coherent substates and dynamic modes of motion from a 0.5 MUs ubiqutin simulation. Autoregressive (AR) modeling within and between states enables a compact and generative description of the conformational landscape as it relates to functional transitions between binding poses. Lacking a predictive component, QAA is extended here within a general AR model appreciative of the trajectory's temporal dependencies and the specific, local dynamics accessible to a protein within identified energy wells. These metastable states and their transition rates are extracted within a QAA-derived subspace using hierarchical Markov clustering to provide parameter sets for the second-order AR model. We show the learned model can be extrapolated to synthesize trajectories of arbitrary length. CONTACT: ramanathana@ornl.gov; chakracs@pitt.edu. PMID- 21685102 TI - Multi-view methods for protein structure comparison using latent dirichlet allocation. AB - MOTIVATION: With rapidly expanding protein structure databases, efficiently retrieving structures similar to a given protein is an important problem. It involves two major issues: (i) effective protein structure representation that captures inherent relationship between fragments and facilitates efficient comparison between the structures and (ii) effective framework to address different retrieval requirements. Recently, researchers proposed vector space model of proteins using bag of fragments representation (FragBag), which corresponds to the basic information retrieval model. RESULTS: In this article, we propose an improved representation of protein structures using latent dirichlet allocation topic model. Another important requirement is to retrieve proteins, whether they are either close or remote homologs. In order to meet diverse objectives, we propose multi-viewpoint based framework that combines multiple representations and retrieval techniques. We compare the proposed representation and retrieval framework on the benchmark dataset developed by Kolodny and co-workers. The results indicate that the proposed techniques outperform state-of-the-art methods. AVAILABILITY: http://www.cse.iitm.ac.in/~ashishvt/research/protein-lda/. CONTACT: ashishvt@cse.iitm.ac.in. PMID- 21685103 TI - Template-free detection of macromolecular complexes in cryo electron tomograms. AB - MOTIVATION: Cryo electron tomography (CryoET) produces 3D density maps of biological specimen in its near native states. Applied to small cells, cryoET produces 3D snapshots of the cellular distributions of large complexes. However, retrieving this information is non-trivial due to the low resolution and low signal-to-noise ratio in tomograms. Current pattern recognition methods identify complexes by matching known structures to the cryo electron tomogram. However, so far only a small fraction of all protein complexes have been structurally resolved. It is, therefore, of great importance to develop template-free methods for the discovery of previously unknown protein complexes in cryo electron tomograms. RESULTS: Here, we have developed an inference method for the template free discovery of frequently occurring protein complexes in cryo electron tomograms. We provide a first proof-of-principle of the approach and assess its applicability using realistically simulated tomograms, allowing for the inclusion of noise and distortions due to missing wedge and electron optical factors. Our method is a step toward the template-free discovery of the shapes, abundance and spatial distributions of previously unknown macromolecular complexes in whole cell tomograms. CONTACT: alber@usc.edu PMID- 21685104 TI - Sorting the nuclear proteome. AB - MOTIVATION: Quantitative experimental analyses of the nuclear interior reveal a morphologically structured yet dynamic mix of membraneless compartments. Major nuclear events depend on the functional integrity and timely assembly of these intra-nuclear compartments. Yet, unknown drivers of protein mobility ensure that they are in the right place at the time when they are needed. RESULTS: This study investigates determinants of associations between eight intra-nuclear compartments and their proteins in heterogeneous genome-wide data. We develop a model based on a range of candidate determinants, capable of mapping the intra nuclear organization of proteins. The model integrates protein interactions, protein domains, post-translational modification sites and protein sequence data. The predictions of our model are accurate with a mean AUC (over all compartments) of 0.71. We present a complete map of the association of 3567 mouse nuclear proteins with intra-nuclear compartments. Each decision is explained in terms of essential interactions and domains, and qualified with a false discovery assessment. Using this resource, we uncover the collective role of transcription factors in each of the compartments. We create diagrams illustrating the outcomes of a Gene Ontology enrichment analysis. Associated with an extensive range of transcription factors, the analysis suggests that PML bodies coordinate regulatory immune responses. PMID- 21685105 TI - vipR: variant identification in pooled DNA using R. AB - MOTIVATION: High-throughput-sequencing (HTS) technologies are the method of choice for screening the human genome for rare sequence variants causing susceptibility to complex diseases. Unfortunately, preparation of samples for a large number of individuals is still very cost- and labor intensive. Thus, recently, screens for rare sequence variants were carried out in samples of pooled DNA, in which equimolar amounts of DNA from multiple individuals are mixed prior to sequencing with HTS. The resulting sequence data, however, poses a bioinformatics challenge: the discrimination of sequencing errors from real sequence variants present at a low frequency in the DNA pool. RESULTS: Our method vipR uses data from multiple DNA pools in order to compensate for differences in sequencing error rates along the sequenced region. More precisely, instead of aiming at discriminating sequence variants from sequencing errors, vipR identifies sequence positions that exhibit significantly different minor allele frequencies in at least two DNA pools using the Skellam distribution. The performance of vipR was compared with three other models on data from a targeted resequencing study of the TMEM132D locus in 600 individuals distributed over four DNA pools. Performance of the methods was computed on SNPs that were also genotyped individually using a MALDI-TOF technique. On a set of 82 sequence variants, vipR achieved an average sensitivity of 0.80 at an average specificity of 0.92, thus outperforming the reference methods by at least 0.17 in specificity at comparable sensitivity. AVAILABILITY: The code of vipR is freely available via: http://sourceforge.net/projects/htsvipr/ CONTACT: altmann@mpipsykl.mpg.de. PMID- 21685107 TI - Meta-IDBA: a de Novo assembler for metagenomic data. AB - MOTIVATION: Next-generation sequencing techniques allow us to generate reads from a microbial environment in order to analyze the microbial community. However, assembling of a set of mixed reads from different species to form contigs is a bottleneck of metagenomic research. Although there are many assemblers for assembling reads from a single genome, there are no assemblers for assembling reads in metagenomic data without reference genome sequences. Moreover, the performances of these assemblers on metagenomic data are far from satisfactory, because of the existence of common regions in the genomes of subspecies and species, which make the assembly problem much more complicated. RESULTS: We introduce the Meta-IDBA algorithm for assembling reads in metagenomic data, which contain multiple genomes from different species. There are two core steps in Meta IDBA. It first tries to partition the de Bruijn graph into isolated components of different species based on an important observation. Then, for each component, it captures the slight variants of the genomes of subspecies from the same species by multiple alignments and represents the genome of one species, using a consensus sequence. Comparison of the performances of Meta-IDBA and existing assemblers, such as Velvet and Abyss for different metagenomic datasets shows that Meta-IDBA can reconstruct longer contigs with similar accuracy. AVAILABILITY: Meta-IDBA toolkit is available at our website http://www.cs.hku.hk/~alse/metaidba. CONTACT: chin@cs.hku.hk. PMID- 21685106 TI - IPknot: fast and accurate prediction of RNA secondary structures with pseudoknots using integer programming. AB - MOTIVATION: Pseudoknots found in secondary structures of a number of functional RNAs play various roles in biological processes. Recent methods for predicting RNA secondary structures cover certain classes of pseudoknotted structures, but only a few of them achieve satisfying predictions in terms of both speed and accuracy. RESULTS: We propose IPknot, a novel computational method for predicting RNA secondary structures with pseudoknots based on maximizing expected accuracy of a predicted structure. IPknot decomposes a pseudoknotted structure into a set of pseudoknot-free substructures and approximates a base-pairing probability distribution that considers pseudoknots, leading to the capability of modeling a wide class of pseudoknots and running quite fast. In addition, we propose a heuristic algorithm for refining base-paring probabilities to improve the prediction accuracy of IPknot. The problem of maximizing expected accuracy is solved by using integer programming with threshold cut. We also extend IPknot so that it can predict the consensus secondary structure with pseudoknots when a multiple sequence alignment is given. IPknot is validated through extensive experiments on various datasets, showing that IPknot achieves better prediction accuracy and faster running time as compared with several competitive prediction methods. AVAILABILITY: The program of IPknot is available at http://www.ncrna.org/software/ipknot/. IPknot is also available as a web server at http://rna.naist.jp/ipknot/. CONTACT: satoken@k.u-tokyo.ac.jp; ykato@is.naist.jp SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21685109 TI - Integration of rehabilitation and acupuncture in the treatment of a professional musician with temporomandibular joint dysfunction. AB - This case study describes the use of acupuncture in a professional musician with myogenic temporomandibular dysfunction. The 3-year history of symptoms was associated with persistent episodic tension-type headaches. Acupuncture was used for trigger point release, primarily of the masticatory muscles, in conjunction with exercise therapy. After 8 weekly acupuncture sessions, the patient's pain had completely resloved, headaches had resolved and the Patient-Specific Functional Scale showed significant improvements. PMID- 21685110 TI - Synovial membrane immunohistology in early untreated juvenile idiopathic arthritis: differences between clinical subgroups. AB - OBJECTIVE: Juvenile idiopathic arthritis (JIA) consists of a heterogeneous group of inflammatory disorders, within which there are a number of clinical subgroups. Diagnosis and assignment to a particular subgroup can be problematical and more concise methods of subgroup classification are required. This study of the synovial membrane characterises the immunohistochemical features in early untreated, newly diagnosed JIA and compares findings with disease subgroup at 2 years. METHODS: 42 patients with newly diagnosed untreated JIA underwent synovial biopsy before the administration of steroids or disease-modifying antirheumatic drugs. Patients were classified as either polyarticular, persistent oligoarticular or extended-to-be oligoarticular. The location and semiquantitative analysis of T-cell subsets, B cells, macrophages and blood vessels were determined using immunohistochemistry. RESULTS: Synovial hyperplasia varied significantly between the three groups (p<0.0001). There was a significant difference in the CD3 T-cell population between the three groups (p=0.004) and between the extended-to-be and persistent group (p=0.032). CD4 expression was significantly higher in the poly and extended-to-be oligo groups (p=0.002), again the extended-to-be group had more CD4 T cells than the persistent group (p=0.008). B-cell infiltrates were more marked in the polyarticular group and were significantly higher in the extended-to-be group compared with the persistent group (p=0.005). Vascularisation was more pronounced in the polyarticular and extended-to-be oligoarticular groups, the extended-to-be group had significantly more vascularisation than the persistent group (p=0.0002). CONCLUSIONS: There are significant differences in the histomorphometric features of synovial tissue between patient subgroups. Immunohistological examination of synovial membrane biopsies may provide further insight into early disease processes in JIA. PMID- 21685111 TI - Analgesic and sedative effects of intranasal dexmedetomidine in third molar surgery under local anaesthesia. AB - BACKGROUND: Dexmedetomidine (DEX) is an alpha 2-adrenoreceptor agonist, which induces sedation and analgesia. This study aimed to determine whether intranasal DEX offered perioperative sedation and better postoperative analgesia. METHODS: Patients having unilateral third molar surgery under local anaesthesia were recruited and allocated to receive either intranasal DEX 1 ug kg(-1) (Group D) or same volume of saline (Group P) 45 min before surgery. Patient-controlled sedation with propofol was offered as a rescue sedative. Perioperative sedation, postoperative pain relief and analgesic consumption, vital signs, adverse events, postoperative recovery, and satisfaction in sedation and analgesia were assessed. RESULTS: Thirty patients from each group were studied. Areas under curve (AUC) of postoperative numerical rating scale (NRS) pain scores 1-12 h at rest and during mouth opening were significantly lower in Group D (P=0.003 and 0.009, respectively). AUC BIS values and OAA/S sedation scores were significantly lower before surgery and at the recovery area (all P<0.01) with significantly less intra-operative propofol used in group D (P<0.01). In group D, heart rate was significantly lower at recovery period (P=0.005) while systolic blood pressure in different periods of the study (all P<0.01), but the decreases did not require treatment. More patients from placebo group experienced dizziness (P=0.026) but no serious adverse event was found. No difference was found in postoperative psychomotor recovery and satisfaction in pain relief and sedation. CONCLUSIONS: Patients receiving intranasal DEX for unilateral third molar surgery with local anaesthesia were more sedated perioperatively with better postoperative pain relief. No delay in psychomotor recovery was seen. PMID- 21685112 TI - Validation of a new non-invasive automatic monitor of respiratory rate for postoperative subjects. AB - BACKGROUND: Respiratory rate is an important measurement in patient care but frequently poorly assessed. We set out to develop a simple non-invasive device to reliably measure respiratory movements and estimate respiratory rate, in clinical circumstances. METHODS: Respiratory movement was detected with an encapsulated tri-axial accelerometer (Orient speck) and the data transmitted wirelessly to a computer for analysis. We studied subjects after gynaecological surgery who received opioid analgesia, and compared the derived signal with a signal from nasal cannula using directly matched breaths and within the same 5 min epoch. We analysed the signals for 5 min epochs over a 15 h recording period. RESULTS: For matched breath analysis, the instantaneous respiratory rates matched within 2 bpm on 86% of occasions. A similar match was found between epoch averages of the respiratory rate. The mean absolute difference between the respiratory rate measured by nasal cannula and Orient speck was 0.6 bpm. The Orient speck generated reliable measures of respiratory rate every 5 min in 95.4% of epochs. CONCLUSIONS: The Orient speck provides a reliable measure of respiratory rate at frequent intervals in subjects receiving patient-controlled morphine analgesia after surgery. PMID- 21685113 TI - Anaesthesia, critical care, and pain in the 21st century: the first decade. PMID- 21685114 TI - Medication errors: can we prevent them? PMID- 21685115 TI - Development of the faculty of intensive care medicine. PMID- 21685116 TI - Regional anaesthesia always works--provided you put the right dose of the right drug in the right place. PMID- 21685118 TI - Use of L'Abbe plot in meta-analysis. PMID- 21685119 TI - Smokeless tobacco and cardiovascular risk in non-Caucasian patients. PMID- 21685121 TI - Fluoroderma after exposure to sevoflurane. PMID- 21685122 TI - Emergency airway management in a patient with a Montgomery T-tube in situ. PMID- 21685123 TI - Perioperative cardiac arrest after thoracic epidural analgesia in a patient with increased pulmonary artery pressure. PMID- 21685124 TI - Decompensation of undiagnosed spinal dural arteriovenous fistulae after lumbar epidural injection and spinal anaesthesia. PMID- 21685125 TI - Caesarean section and brain tumour resection. PMID- 21685126 TI - Retraction. Notice of formal retraction of articles by Dr. Joachim Boldt. PMID- 21685127 TI - Gorilla genome structural variation reveals evolutionary parallelisms with chimpanzee. AB - Structural variation has played an important role in the evolutionary restructuring of human and great ape genomes. Recent analyses have suggested that the genomes of chimpanzee and human have been particularly enriched for this form of genetic variation. Here, we set out to assess the extent of structural variation in the gorilla lineage by generating 10-fold genomic sequence coverage from a western lowland gorilla and integrating these data into a physical and cytogenetic framework of structural variation. We discovered and validated over 7665 structural changes within the gorilla lineage, including sequence resolution of inversions, deletions, duplications, and mobile element insertions. A comparison with human and other ape genomes shows that the gorilla genome has been subjected to the highest rate of segmental duplication. We show that both the gorilla and chimpanzee genomes have experienced independent yet convergent patterns of structural mutation that have not occurred in humans, including the formation of subtelomeric heterochromatic caps, the hyperexpansion of segmental duplications, and bursts of retroviral integrations. Our analysis suggests that the chimpanzee and gorilla genomes are structurally more derived than either orangutan or human genomes. PMID- 21685130 TI - Presentation to the best candidate in the European diploma in hand surgery examination 2010. PMID- 21685129 TI - Unusually effective microRNA targeting within repeat-rich coding regions of mammalian mRNAs. AB - MicroRNAs (miRNAs) regulate numerous biological processes by base-pairing with target messenger RNAs (mRNAs), primarily through sites in 3' untranslated regions (UTRs), to direct the repression of these targets. Although miRNAs have sometimes been observed to target genes through sites in open reading frames (ORFs), large scale studies have shown such targeting to be generally less effective than 3' UTR targeting. Here, we show that several miRNAs each target significant groups of genes through multiple sites within their coding regions. This ORF targeting, which mediates both predictable and effective repression, arises from highly repeated sequences containing miRNA target sites. We show that such sequence repeats largely arise through evolutionary duplications and occur particularly frequently within families of paralogous C(2)H(2) zinc-finger genes, suggesting the potential for their coordinated regulation. Examples of ORFs targeted by miR 181 include both the well-known tumor suppressor RB1 and RBAK, encoding a C(2)H(2) zinc-finger protein and transcriptional binding partner of RB1. Our results indicate a function for repeat-rich coding sequences in mediating post transcriptional regulation and reveal circumstances in which miRNA-mediated repression through ORF sites can be reliably predicted. PMID- 21685131 TI - The treatment of finger glomus tumours by raising a full thickness nail bed flap or finger pulp flap. PMID- 21685132 TI - Re: Lindfors et al. Complications in the upper extremity following intra-arterial drug abuse. J Hand Surg Eur. 2010, 35: 499-504. PMID- 21685133 TI - Re: MM Al-Qattan. Wnt pathways and upper limb anomalies. J Hand Surg Eur. 2011, 36: 9-22. PMID- 21685134 TI - The clinicopathologic spectrum of benign mass lesions of the vocal fold due to vocal abuse. AB - Benign masses of the vocal fold related to phonotrauma are clinically classified into polyps, nodules, Reinke's edema, and cysts. Despite the apparent distinctiveness of the clinical nomenclature, low inter- and intraobserver diagnostic agreement has been reported. Excepting cysts, which are epithelial lined, histologic examination of the remaining lesions has shown a variety of overlapping features insufficiently specific for the clinical diagnoses. This study reviews the clinicopathologic characteristics among these benign lesions of the vocal fold. A total of 78 nonneoplastic lesions of the vocal fold were reviewed by 2 pathologists for the presence of epithelial hyperplasia, basement membrane thickening, edema, vascular proliferation, and extracellular "amyloid like" fibrin. In 46 cases with prebiopsy stroboscopic images, 2 otolaryngologists classified each lesion as polyp, nodule, Reinke's edema, cyst, or other. They agreed in 43% (n = 20, 13 polyps, 5 nodules, 1 Reinke's edema, 1 other) and disagreed in 57% (n = 26). There was no histologic feature that reliably distinguished among the lesions. In addition, reactive stromal cell atypia was present in 14 cases. Cysts were distinctive, as all were epithelial lined. The clinicopathologic classification of benign laryngeal lesions is neither clinically reproducible nor histologically unique. Treatment will continue to be individualized based on clinical judgment. PMID- 21685135 TI - A sperm's tail: the importance of getting it right. PMID- 21685128 TI - Deep small RNA sequencing from the nematode Ascaris reveals conservation, functional diversification, and novel developmental profiles. AB - Eukaryotic cells express several classes of small RNAs that regulate gene expression and ensure genome maintenance. Endogenous siRNAs (endo-siRNAs) and Piwi-interacting RNAs (piRNAs) mainly control gene and transposon expression in the germline, while microRNAs (miRNAs) generally function in post-transcriptional gene silencing in both somatic and germline cells. To provide an evolutionary and developmental perspective on small RNA pathways in nematodes, we identified and characterized known and novel small RNA classes through gametogenesis and embryo development in the parasitic nematode Ascaris suum and compared them with known small RNAs of Caenorhabditis elegans. piRNAs, Piwi-clade Argonautes, and other proteins associated with the piRNA pathway have been lost in Ascaris. miRNAs are synthesized immediately after fertilization in utero, before pronuclear fusion, and before the first cleavage of the zygote. This is the earliest expression of small RNAs ever described at a developmental stage long thought to be transcriptionally quiescent. A comparison of the two classes of Ascaris endo siRNAs, 22G-RNAs and 26G-RNAs, to those in C. elegans, suggests great diversification and plasticity in the use of small RNA pathways during spermatogenesis in different nematodes. Our data reveal conserved characteristics of nematode small RNAs as well as features unique to Ascaris that illustrate significant flexibility in the use of small RNAs pathways, some of which are likely an adaptation to Ascaris' life cycle and parasitism. The transcriptome assembly has been submitted to NCBI Transcriptome Shotgun Assembly Sequence Database(http://www.ncbi.nlm.nih.gov/genbank/TSA.html) under accession numbers JI163767-JI182837 and JI210738-JI257410. PMID- 21685136 TI - Genome-wide analysis identifies changes in histone retention and epigenetic modifications at developmental and imprinted gene loci in the sperm of infertile men. AB - BACKGROUND: The sperm chromatin of fertile men retains a small number of nucleosomes that are enriched at developmental gene promoters and imprinted gene loci. This unique chromatin packaging at certain gene promoters provides these genomic loci the ability to convey instructive epigenetic information to the zygote, potentially expanding the role and significance of the sperm epigenome in embryogenesis. We hypothesize that changes in chromatin packaging may be associated with poor reproductive outcome. METHODS: Seven patients with reproductive dysfunction were recruited: three had unexplained poor embryogenesis during IVF and four were diagnosed with male infertility and previously shown to have altered protamination. Genome-wide analysis of the location of histones and histone modifications was analyzed by isolation and purification of DNA bound to histones and protamines. The histone-bound fraction of DNA was analyzed using high-throughput sequencing, both initially and following chromatin immunoprecipitation. The protamine-bound fraction was hybridized to agilent arrays. DNA methylation was examined using bisulfite sequencing. RESULTS: Unlike fertile men, five of seven infertile men had non-programmatic (randomly distributed) histone retention genome-wide. Interestingly, in contrast to the total histone pool, the localization of H3 Lysine 4 methylation (H3K4me) or H3 Lysine 27 methylation (H3K27me) was highly similar in the gametes of infertile men compared with fertile men. However, there was a reduction in the amount of H3K4me or H3K27me retained at developmental transcription factors and certain imprinted genes. Finally, the methylation status of candidate developmental promoters and imprinted loci were altered in a subset of the infertile men. CONCLUSIONS: This initial genome-wide analysis of epigenetic markings in the sperm of infertile men demonstrates differences in composition and epigenetic markings compared with fertile men, especially at certain imprinted and developmental loci. Although no single locus displays a complete change in chromatin packaging or DNA modification, the data suggest that moderate changes throughout the genome exist and may have a cumulative detrimental effect on fecundity. PMID- 21685137 TI - Women's age at menarche and offspring sex ratio. PMID- 21685138 TI - The sex ratio of offspring is associated with the mothers' age at menarche. PMID- 21685139 TI - Interaction between uterine natural killer cells and extravillous trophoblast cells: effect on cytokine and angiogenic growth factor production. AB - BACKGROUND: Uterine natural killer (uNK) cells are a major source of cytokines and angiogenic growth factors (AGFs), with AGF levels decreasing and cytokine levels increasing with gestational age. The factors that regulate AGF and cytokine secretion are unclear but may involve interactions between uNK cells and extravillous trophoblast (EVT) cells. We hypothesize that uNK cell interaction with EVT cells alters their cytokine and AGF secretion. METHODS: Ex vivo co cultures of uNK cells with either EVT (irradiated or fresh) or villous cytotrophoblast (CTB; control cell type) cells isolated from the same patients at 8-10 or 12-14 weeks gestational age (n = 10 each group) were established. Co cultures were established with either direct contact between the different cell types or with the cells separated by a 0.4 um filter. AGFs and cytokines were measured in cell culture supernatants using multiplex analysis (FAST Quant) or ELISA. RESULTS: Secretion of angiopoietin-1 (P < 0.006) and vascular endothelial growth factor-C (P < 0.001) by uNK cells was lower when these cells were co cultured, either directly or indirectly, with both trophoblast cell types at both gestational ages tested compared with when cultured alone. In contrast, interleukin (IL)-6 (P < 0.0001), IL-8 (P < 0.0001) and transforming growth factor beta1 (P < 0.002) were decreased only in direct uNK/EVT and uNK/CTB co-culture conditions at 8-10 and 12-14 weeks gestational age. CONCLUSIONS: AGF and cytokine secretion was reduced after co-culture of uNK cells and both EVT and CTB cells. It remains unclear whether uNK cell AGF and cytokine production was reduced after co-culture with trophoblast cells (EVT or CTB) or whether trophoblast cell (EVT or CTB) AGF and cytokine production was reduced after co-culture with uNK cells. Local production of AGFs and cytokines in the placental bed may be lowered when uNK cells come in direct contact with EVT cells. PMID- 21685140 TI - Microarray assessment of methylation in individual mouse blastocyst stage embryos shows that in vitro culture may have widespread genomic effects. AB - BACKGROUND: Although assisted reproductive technology (ART) is reported to result in abnormal genomic imprinting and/or altered genomic methylation, few if any studies have used high-throughput methods to analyze genomic methylation in ART embryos. We hypothesized that a microarray-based assessment of genomic methylation could be used to reveal differences between ART and normal preimplantation embryos. METHODS: In this pilot study, we performed methylation sensitive amplification of genomic DNA from preimplantation mouse blastocysts, obtained by natural mating and either maintained in vivo until E3.5 (n = 4) or cultured in vitro (n = 4) from E0.5 until E3.5. An oligonucleotide microarray was then used to perform comparative hybridization of amplified DNA, allowing us to assess relative methylation at ~16,000 loci on mouse chromosome 7. RESULTS: We show that for in vivo derived embryos, the methylation/microarray results were strikingly consistent. In contrast, all four in vitro cultured embryos showed evidence of generalized hypermethylation as well as greater locus-to-locus variability, when compared with in vivo derived embryos. Genomic segments that overlapped exons and CpG islands were most likely to be hypomethylated in both normal and experimental blastocysts. Other sequence features, such as repetitive elements, were not associated with the presence of or the degree of methylation. CONCLUSIONS: We conclude that a general assessment of genomic methylation in blastocyst stage embryos is technically feasible. Data from this small sample suggest that in vitro embryo culture is associated with generalized hypermethylation as well as increased locus-to-locus variability in methylation. However, it is premature to conclude that this is a general property of in vitro cultured blastocysts. PMID- 21685141 TI - Catamenial pneumothorax and endometriosis-related pneumothorax: clinical features and risk factors. AB - BACKGROUND: Catamenial pneumothorax and thoracic endometriosis (TE) are still under diagnosed. The purpose of this study is to increase the diagnostic accuracy for these conditions in patients with spontaneous pneumothorax and to identify their risk factors. METHODS: We conducted a retrospective study on all consecutive women of reproductive age referred to our Centre for surgical treatment of spontaneous pneumothorax between July 2000 and January 2009. RESULTS: The study population comprised 156 premenopausal women of whom 49 (31.4%) had catamenial and/or TE-related pneumothorax. Over a quarter of these 49 patients had a previous history of recurrent thoracic or scapular catamenial pain. They experienced their first pneumothorax episode at an older age (mean +/- SD) (34.0 years +/- 6.7) than women with idiopathic pneumothorax (28.7 +/- 6.1 years, P < 0.001). Pelvic endometriosis was found in 51% of women with catamenial and/or TE-related pneumothorax. After adjustment for confounding factors by multiple logistic regression analysis, the results show that, infertility [odd ratio (OR) = 4.21, 95% confidence interval (CI) = 1.28-13.88] and a history of pelvic surgery with a uterine procedure and/or uterine scraping (OR = 2.85, 95% CI = 1.12-7.26) were the strongest predictors of catamenial and/or TE-related pneumothorax. CONCLUSIONS: Infertility and uterine procedures are significantly associated with catamenial and/or TE-related pneumothorax. Scapular or thoracic pain during menses often precedes the occurrence of pneumothorax and is highly specific for the diagnosis of TE. Our results suggest that in women with pelvic endometriosis, these symptoms should be systematically investigated for an earlier diagnosis of TE. PMID- 21685142 TI - Automation bias: a systematic review of frequency, effect mediators, and mitigators. AB - Automation bias (AB)--the tendency to over-rely on automation--has been studied in various academic fields. Clinical decision support systems (CDSS) aim to benefit the clinical decision-making process. Although most research shows overall improved performance with use, there is often a failure to recognize the new errors that CDSS can introduce. With a focus on healthcare, a systematic review of the literature from a variety of research fields has been carried out, assessing the frequency and severity of AB, the effect mediators, and interventions potentially mitigating this effect. This is discussed alongside automation-induced complacency, or insufficient monitoring of automation output. A mix of subject specific and freetext terms around the themes of automation, human-automation interaction, and task performance and error were used to search article databases. Of 13 821 retrieved papers, 74 met the inclusion criteria. User factors such as cognitive style, decision support systems (DSS), and task specific experience mediated AB, as did attitudinal driving factors such as trust and confidence. Environmental mediators included workload, task complexity, and time constraint, which pressurized cognitive resources. Mitigators of AB included implementation factors such as training and emphasizing user accountability, and DSS design factors such as the position of advice on the screen, updated confidence levels attached to DSS output, and the provision of information versus recommendation. By uncovering the mechanisms by which AB operates, this review aims to help optimize the clinical decision-making process for CDSS developers and healthcare practitioners. PMID- 21685143 TI - 2010 i2b2/VA challenge on concepts, assertions, and relations in clinical text. AB - The 2010 i2b2/VA Workshop on Natural Language Processing Challenges for Clinical Records presented three tasks: a concept extraction task focused on the extraction of medical concepts from patient reports; an assertion classification task focused on assigning assertion types for medical problem concepts; and a relation classification task focused on assigning relation types that hold between medical problems, tests, and treatments. i2b2 and the VA provided an annotated reference standard corpus for the three tasks. Using this reference standard, 22 systems were developed for concept extraction, 21 for assertion classification, and 16 for relation classification. These systems showed that machine learning approaches could be augmented with rule-based systems to determine concepts, assertions, and relations. Depending on the task, the rule based systems can either provide input for machine learning or post-process the output of machine learning. Ensembles of classifiers, information from unlabeled data, and external knowledge sources can help when the training data are inadequate. PMID- 21685145 TI - Non-cirrhotic portal fibrosis: one disease with many names? An analysis from morphological study of native explant livers with end stage chronic liver disease. AB - BACKGROUND: A group of non-cirrhotic chronic liver diseases, all with sustained portal hypertension and clinically mistaken as cirrhosis, have been described under various names, apparently because of differences in pathological features. The pathogenesis is uncertain and they were believed to have a good prognosis until it was recently shown, from study of explant livers, that they had progressed to end stage disease, needing liver transplantation. AIMS: To describe detailed morphological features of such end stage non-cirrhotic disease and examine whether the diseases bearing various names are different or represent variable morphological expressions of one entity. METHODS: Morphological features of 10 native explant livers from patients with pre-transplant diagnosis of end stage cirrhosis but finally categorised as non-cirrhotic portal fibrosis were analysed along with the relevant clinical information. RESULTS: Besides absence of criteria for cirrhosis, variable grades of obliterative changes in portal vein branches and portal fibrosis were consistently seen in all livers. Fibrous intimal thickening with luminal compromise in some medium and large sized portal veins was randomly distributed but appeared characteristic of this disease, very likely representing organised mural thrombi. Areas of closely placed nodular hyperplastic parenchyma separated by compressed hepatocytes, megasinusoids and peliotic changes were seen only in a proportion of cases. CONCLUSION: Non cirrhotic portal fibrosis is a justifiable name for this disease that can progress to end stage liver disease. It represents a single entity that has been considered as different diseases and given various names on the basis of the dominant element in its heterogeneous morphological manifestation. PMID- 21685144 TI - A regionalised strategy for improving motor vehicle-related highway driver deaths using a weighted averages method. AB - OBJECTIVE: The state of Florida has some of the most dangerous highways in the USA. In 2006, Florida averaged 1.65 fatalities per 100 million vehicle miles travelled (VMT) compared with the national average of 1.42. A study was undertaken to find a method of identifying counties that contributed to the most driver fatalities after a motor vehicle collision (MVC). By regionalising interventions unique to this subset of counties, the use of resources would have the greatest potential of improving statewide driver death. METHODS: The Florida Highway Safety Motor Vehicle database 2000-2006 was used to calculate driver VMT weighted deaths by county. A total of 3,468,326 motor vehicle crashes were evaluated. Counties that had driver death rates higher than the state average were sorted by a weighted averages method. Multivariate regression was used to calculate the likelihood of death for various risk factors. RESULTS: VMT-weighted death rates identified 12 out of 67 counties that contributed up to 50% of overall driver fatalities. These counties were primarily clustered in central and south Florida. The strongest independent risk factors for driver death attributable to MVC in these high-risk counties were alcohol/drug use, rural roads, speed limit >=45 mph, adverse weather conditions, divided highways, vehicle type, vehicle defects and roadway location. CONCLUSIONS: Using the weighted averages method, a small subset of counties contributing to the majority of statewide driver fatalities was identified. Regionalised interventions on specific risk factors in these counties may have the greatest impact on reducing driver-related MVC fatalities. PMID- 21685146 TI - Mario Monicelli's Grande guerra: the right of living and the choice of dying. AB - Monicelli's suicide has reawakened a political and legal dispute about the medical role in end-of-life decisions, allowing us to discuss medical, ethical, legal, religious and political debate in various paradigmatic conscious and unconscious cases of end-of-life decision. We analyse the uncertainty about the 'a priori' choice between different specific legislative systems, highlighting the need for a unifying model, dictated by the existing trust in the critical relationship between patient and doctor, whose primary mission should be not only 'to cure' but also 'to care'. PMID- 21685147 TI - Abortion decisions as inclusion and exclusion criteria in research involving pregnant women and fetuses. AB - From the perspective of investigators conducting research involving pregnant women and fetuses, a woman's decision about whether to have an abortion can sometimes be relevant to the suitability of the woman and fetus as research subjects. However, prominent ethicists disagree over whether it is permissible for a woman's decision about abortion to be an inclusion or exclusion criterion for participation in research. A widely held view is that fetuses to be aborted and fetuses to be carried to term should be treated equally as research subjects. Some hold that this principle implies that a woman's decision about whether to have an abortion should not be an inclusion or exclusion criterion. This paper identifies types of research in which investigators might want to have inclusion or exclusion criteria based on decisions about abortion. It examines the arguments for and against having the woman's decision about abortion included in such criteria. It is argued that there are types of research in which such criteria are ethically permissible. PMID- 21685148 TI - Informed consent for clinical trials of deep brain stimulation in psychiatric disease: challenges and implications for trial design. AB - Advances in neuromodulation and an improved understanding of the anatomy and circuitry of psychopathology have led to a resurgence of interest in surgery for psychiatric disease. Clinical trials exploring deep brain stimulation (DBS), a focally targeted, adjustable and reversible form of neurosurgery, are being developed to address the use of this technology in highly selected patient populations. Psychiatric patients deemed eligible for surgical intervention, such as DBS, typically meet stringent inclusion criteria, including demonstrated severity, chronicity and a failure of conventional therapy. Although a humanitarian device exemption by the US Food and Drug Administration exists for its use in obsessive-compulsive disorder, DBS remains a largely experimental treatment in the psychiatric context, with its use currently limited to clinical trials and investigative studies. The combination of a patient population at the limits of conventional therapy and a novel technology in a new indication poses interesting challenges to the informed consent process as it relates to clinical trial enrollment. These challenges can be divided into those that relate to the patient, their disease and the technology, with each illustrating how traditional conceptualisations of research consent may be inadequate in the surgical psychiatry context. With specific reference to risk analysis, patient autonomy, voluntariness and the duty of the clinician-researcher, this paper will discuss the unique challenges that clinical trials of surgery for refractory psychiatric disease present to the consent process. Recommendations are also made for an ethical approach to clinical trial consent acquisition in this unique patient population. PMID- 21685149 TI - What does 'respect for persons' require? Attitudes and reported practices of genetics researchers in informing research participants about research. AB - BACKGROUND: It has been suggested that researchers are obliged to offer summary findings to research participants to demonstrate respect for persons, and that this may increase public trust in, and awareness of, the research enterprise. Yet little research explores researchers' attitudes and practices regarding the range of initiatives that might serve these ends. METHODS: Results of an international survey of 785 eligible authors of genetics research studies in autism or cystic fibrosis are reported. RESULTS: Of 343 researchers who completed the survey (44% response rate), the majority agreed that their team should (i) inform participants of summary findings (90.7%) and (ii) ensure they gain an awareness of developments in the field (86.9%). Additionally, the majority reported that in practice, their team (i) informs participants of summary findings (69.4%) and (ii) provides other types of relevant non-results information (eg, state of science in the field, opportunities for research participation) (67.9%). CONCLUSION: Researchers endorsed the obligation of communicating with research participants by providing summary findings and other research-related information in equal measure. In light of these findings, it is suggested that while the provision of summary results may contribute to efforts to discharge the obligation of respect for persons, it may be neither a necessary nor a sufficient means to this end. PMID- 21685150 TI - Separate but interacting recognition memory systems for different senses: the role of the rat perirhinal cortex. AB - Two different models (convergent and parallel) potentially describe how recognition memory, the ability to detect the re-occurrence of a stimulus, is organized across different senses. To contrast these two models, rats with or without perirhinal cortex lesions were compared across various conditions that controlled available information from specific sensory modalities. Intact rats not only showed visual, tactile, and olfactory recognition, but also overcame changes in the types of sensory information available between object sampling and subsequent object recognition, e.g., between sampling in the light and recognition in the dark, or vice versa. Perirhinal lesions severely impaired object recognition whenever visual cues were available, but spared olfactory recognition and tactile-based object recognition when tested in the dark. The perirhinal lesions also blocked the ability to recognize an object sampled in the light and then tested for recognition in the dark, or vice versa. The findings reveal parallel recognition systems for different senses reliant on distinct brain areas, e.g., perirhinal cortex for vision, but also show that: (1) recognition memory for multisensory stimuli involves competition between sensory systems and (2) perirhinal cortex lesions produce a bias to rely on vision, despite the presence of intact recognition memory systems serving other senses. PMID- 21685151 TI - Contributions of dorsal striatal subregions to spatial alternation behavior. AB - Considerable evidence has shown a clear dissociation between the dorsomedial (DMS) and the dorsolateral (DLS) striatum in instrumental conditioning. In particular, DMS activity is necessary to form action-outcome associations, whereas the DLS is required for developing habitual behavior. However, few studies have investigated whether a similar dissociation exists in more complex goal-directed learning processes. The present study examined the role of the two structures in such complex learning by analyzing the effects of excitotoxic DMS and DLS lesions during the acquisition and extinction of spatial alternation behavior, in a continuous alternation T-maze task. We demonstrate that DMS and DLS lesions have opposite effects, the former impairing and the latter improving animal performance during learning and extinction. DMS lesions may impair the acquisition of spatial alternation behavior by disrupting the signal necessary to link a goal with a specific spatial sequence. In contrast, DLS lesions may accelerate goal-driven strategies by minimizing the influence of external stimuli on the response, thus increasing the impact of action-reward contingencies. Taken together, these results suggest that DMS- and DLS-mediated learning strategies develop in parallel and compete for the control of the behavioral response early in learning. PMID- 21685152 TI - On conceptualizing self-control as more than the effortful inhibition of impulses. AB - The notion that self-control entails effortful inhibition of impulses dominates prevailing psychological models of self-control. This article describes some of the conceptual and empirical limitations of defining self-control as the effortful inhibition of impulses. The present article instead advocates for a dual-motive conceptualization, which describes self-control as the process of advancing distal rather than proximal motivations when the two compete. Effortful impulse inhibition in this model represents only one of many means by which people promote their self-control efforts. Adopting a dual-motive approach offers new insight and proposes several new research directions. This article discusses these implications and calls for psychologists to reconsider the way self-control is currently understood. PMID- 21685153 TI - Type 2 deiodinase and host responses of sepsis and acute lung injury. AB - The role of thyroid hormone metabolism in clinical outcomes of the critically ill remains unclear. Using preclinical models of acute lung injury (ALI), we assessed the gene and protein expression of type 2 deiodinase (DIO2), a key driver for synthesis of biologically active triiodothyronine, and addressed potential association of DIO2 genetic variants with ALI in a multiethnic cohort. DIO2 gene and protein expression levels in murine lung were validated by microarrays and immunoblotting. Lung injury was assessed by levels of bronchoalveolar lavage protein and leukocytes. Single-nucleotide polymorphisms were genotyped and ALI susceptibility association assessed. Significant increases in both DIO2 gene and D2 protein expression were observed in lung tissues from murine ALI models (LPS- and ventilator-induced lung injury), with expression directly increasing with the extent of lung injury. Mice with reduced levels of DIO2 expression (by silencing RNA) demonstrated reduced thyroxine levels in plasma and increased lung injury (increased bronchoalveolar lavage protein and leukocytes), suggesting a protective role for DIO2 in ALI. The G (Ala) allele of the Thr92Ala coding single nucleotide polymorphism (rs225014) was protective in severe sepsis and severe sepsis-associated ALI after adjustments for age, sex, and genetic ancestry in a logistic regression model in European Americans. Our studies indicate that DIO2 is a novel ALI candidate gene, the nonsynonymous Thr92Ala coding variant of which confers ALI protection. Increased DIO2 expression may dampen the ALI inflammatory response, thereby strengthening the premise that thyroid hormone metabolism is intimately linked to the integrated response to inflammatory injury in critically ill patients. PMID- 21685154 TI - Up-regulation of receptors for advanced glycation end-products by alveolar epithelium influences cytodifferentiation and causes severe lung hypoplasia. AB - Receptors for advanced glycation end-products (RAGE) are cell-surface receptors expressed by pulmonary tissue that influence alveolar type (AT) II-ATI transition required for normal alveolar formation. However, the precise contribution of RAGE in interactions between pulmonary epithelium and splanchnic mesenchyme during lung organogenesis remains uncertain. To test the hypothesis that RAGE misexpression adversely affects lung morphogenesis, conditional transgenic mice were generated that overexpress RAGE. Mice that overexpress RAGE throughout embryogenesis experienced 100% mortality and significant lung hypoplasia coincident with large, vacuous areas in the periphery when compared with normal airway and alveolar architecture observed in control mouse lungs. Flow cytometry and immunohistochemistry employing cell-specific markers for distal (forkhead box protein A2) and respiratory (thyroid transcription factor-1) epithelium, ATII cells (pro-surfactant protein-C), and ATI cells (T1-alpha) demonstrated anomalies in key epithelial cell populations resulting from RAGE up-regulation. These results reveal that precise regulation of RAGE expression is required during lung formation. Furthermore, abundant RAGE results in profound alterations in epithelial cell differentiation that culminate in severe respiratory distress and perinatal lethality. PMID- 21685155 TI - Everything prevents emphysema: are animal models of cigarette smoke-induced chronic obstructive pulmonary disease any use? AB - There is a very large number of experimental approaches that prevent cigarette smoke-induced emphysema in laboratory animals, but the few similar treatments that have been tried in humans have had minimal effects, leading to questions of whether animal models of chronic obstructive pulmonary disease (COPD) are of any use in developing treatments for human disease. We review possible reasons for this problem. First, humans usually get treated when they have severe (Global Initiative for Chronic Obstructive Lung Disease III/IV) COPD, but animal models only produce mild (Global Initiative for Chronic Obstructive Lung Disease I/II) disease that never progresses after smoking cessation, and never develops spontaneous exacerbations (i.e., animal models are not models of severe human disease, and probably can't be used to model treatment of severe disease). Second, animal models have concentrated on emphysema and largely ignored small airway remodeling, but small airway remodeling is an equally important cause of airflow obstruction. In addition, small airway remodeling and emphysema are independent responses to smoke, and some experimental animal treatments prevent both lesions, but many do not. Third, animal models are typically Day 1 of smoke exposure "prevention" models, but humans are always treated well along in the course of their disease; thus, any human treatment will be an intervention, and not a prevention. We propose that animal models should examine both emphysema and small airway remodeling, and that experiments should include a relatively late intervention arm. This approach, combined with the realization that human COPD probably needs early rather than late treatment, may make development of treatments based on animal models more relevant. PMID- 21685156 TI - High stability of Stx2 phage in food and under food-processing conditions. AB - Bacteriophages (phages) carrying Shiga toxin genes constitute a major virulence attribute in enterohemorrhagic Escherichia coli (EHEC). Several EHEC outbreaks have been linked to food. The survival of such strains in different foods has received much attention, while the fate of the mobile Shiga toxin-converting phages (Stx phages) has been less studied. We have investigated the stability of an Stx phage in several food products and examined how storage, food processing, and disinfection influence the infectivity of phage particles. The study involved a recombinant Stx phage (Deltastx::cat) of an E. coli O103:H25 strain from a Norwegian outbreak in 2006. Temperature, matrix, and time were factors of major importance for the stability of phage particles. Phages stored at cooling temperatures (4 degrees C) showed a dramatic reduction in stability compared to those stored at room temperature. The importance of the matrix was evident at higher temperatures (60 degrees C). Phages in ground beef were below the detection level when heated to 60 degrees C for more than 10 min, while phages in broth exposed to the same heating conditions showed a 5-log-higher stability. The phages tolerated desiccation poorly but were infective for a substantial period of time in solutions. Under moist conditions, they also had a high ability to tolerate exposure to several disinfectants. In a dry-fermented sausage model, phages were shown to infect E. coli in situ. The results show that Stx phage particles can maintain their infectivity in foods and under food-processing conditions. PMID- 21685157 TI - Toxin-antitoxin systems influence biofilm and persister cell formation and the general stress response. AB - In many genomes, toxin-antitoxin (TA) systems have been identified; however, their role in cell physiology has been unclear. Here we examine the evidence that TA systems are involved in biofilm formation and persister cell formation and that these systems may be important regulators of the switch from the planktonic to the biofilm lifestyle as a stress response by their control of secondary messenger 3',5'-cyclic diguanylic acid. Specifically, upon stress, the sequence specific mRNA interferases MqsR and MazF mediate cell survival. In addition, we propose that TA systems are not redundant, as they may have developed to respond to specific stresses. PMID- 21685158 TI - Identification of biofilm matrix-associated proteins from an acid mine drainage microbial community. AB - In microbial communities, extracellular polymeric substances (EPS), also called the extracellular matrix, provide the spatial organization and structural stability during biofilm development. One of the major components of EPS is protein, but it is not clear what specific functions these proteins contribute to the extracellular matrix or to microbial physiology. To investigate this in biofilms from an extremely acidic environment, we used shotgun proteomics analyses to identify proteins associated with EPS in biofilms at two developmental stages, designated DS1 and DS2. The proteome composition of the EPS was significantly different from that of the cell fraction, with more than 80% of the cellular proteins underrepresented or undetectable in EPS. In contrast, predicted periplasmic, outer membrane, and extracellular proteins were overrepresented by 3- to 7-fold in EPS. Also, EPS proteins were more basic by ~2 pH units on average and about half the length. When categorized by predicted function, proteins involved in motility, defense, cell envelope, and unknown functions were enriched in EPS. Chaperones, such as histone-like DNA binding protein and cold shock protein, were overrepresented in EPS. Enzymes, such as protein peptidases, disulfide-isomerases, and those associated with cell wall and polysaccharide metabolism, were also detected. Two of these enzymes, identified as beta-N-acetylhexosaminidase and cellulase, were confirmed in the EPS fraction by enzymatic activity assays. Compared to the differences between EPS and cellular fractions, the relative differences in the EPS proteomes between DS1 and DS2 were smaller and consistent with expected physiological changes during biofilm development. PMID- 21685159 TI - Rapid detection and enumeration of Giardia lamblia cysts in water samples by immunomagnetic separation and flow cytometric analysis. AB - Giardia lamblia is an important waterborne pathogen and is among the most common intestinal parasites of humans worldwide. Its fecal-oral transmission leads to the presence of cysts of this pathogen in the environment, and so far, quantitative rapid screening methods are not available for various matrices, such as surface waters, wastewater, or food. Thus, it is necessary to establish methods that enable reliable rapid detection of a single cyst in 10 to 100 liters of drinking water. Conventional detection relies on cyst concentration, isolation, and confirmation by immunofluorescence microscopy (IFM), resulting in low recoveries and high detection limits. Many different immunomagnetic separation (IMS) procedures have been developed for separation and cyst purification, so far with variable but high losses of cysts. A method was developed that requires less than 100 min and consists of filtration, resuspension, IMS, and flow cytometric (FCM) detection. MACS MicroBeads were used for IMS, and a reliable flow cytometric detection approach was established employing 3 different parameters for discrimination from background signals, i.e., green and red fluorescence (resulting from the distinct pattern emitted by the fluorescein dye) and sideward scatter for size discrimination. With spiked samples, recoveries exceeding 90% were obtained, and false-positive results were never encountered for negative samples. Additionally, the method was applicable to naturally occurring cysts in wastewater and has the potential to be automated. PMID- 21685160 TI - High-temperature enzymatic breakdown of cellulose. AB - Cellulose is an abundant and renewable biopolymer that can be used for biofuel generation; however, structural entrapment with other cell wall components hinders enzyme-substrate interactions, a key bottleneck for ethanol production. Biomass is routinely subjected to treatments that facilitate cellulase-cellulose contacts. Cellulases and glucosidases act by hydrolyzing glycosidic bonds of linear glucose beta-1,4-linked polymers, producing glucose. Here we describe eight high-temperature-operating cellulases (TCel enzymes) identified from a survey of thermobacterial and archaeal genomes. Three TCel enzymes preferentially hydrolyzed soluble cellulose, while two preferred insoluble cellulose such as cotton linters and filter paper. TCel enzymes had temperature optima ranging from 85 degrees C to 102 degrees C. TCel enzymes were stable, retaining 80% of initial activity after 120 h at 85 degrees C. Two modes of cellulose breakdown, i.e., with endo- and exo-acting glucanases, were detected, and with two-enzyme combinations at 85 degrees C, synergistic cellulase activity was observed for some enzyme combinations. PMID- 21685161 TI - Pseudomonas fluorescens F113 mutant with enhanced competitive colonization ability and improved biocontrol activity against fungal root pathogens. AB - Motility is one of the most important traits for efficient rhizosphere colonization by Pseudomonas fluorescens F113rif (F113). In this bacterium, motility is a polygenic trait that is repressed by at least three independent pathways, including the Gac posttranscriptional system, the Wsp chemotaxis-like pathway, and the SadB pathway. Here we show that the kinB gene, which encodes a signal transduction protein that together with AlgB has been implicated in alginate production, participates in swimming motility repression through the Gac pathway, acting downstream of the GacAS two-component system. Gac mutants are impaired in secondary metabolite production and are unsuitable as biocontrol agents. However, the kinB mutant and a triple mutant affected in kinB, sadB, and wspR (KSW) possess a wild-type phenotype for secondary metabolism. The KSW strain is hypermotile and more competitive for rhizosphere colonization than the wild type strain. We have compared the biocontrol activity of KSW with those of the wild-type strain and a phenotypic variant (F113v35 [V35]) which is hypermotile and hypercompetitive but is affected in secondary metabolism since it harbors a gacS mutation. Biocontrol experiments in the Fusarium oxysporum f. sp. radicis lycopersici/Lycopersicum esculentum (tomato) and Phytophthora cactorum/Fragaria vesca (strawberry) pathosystems have shown that the three strains possess biocontrol activity. Biocontrol activity was consistently lower for V35, indicating that the production of secondary metabolites was the most important trait for biocontrol. Strain KSW showed improved biocontrol compared with the wild-type strain, indicating that an increase in competitive colonization ability resulted in improved biocontrol and that the rational design of biocontrol agents by mutation is feasible. PMID- 21685162 TI - Systematic search for cultivatable fungi that best deconstruct cell walls of Miscanthus and sugarcane in the field. AB - The goals of our project were to document the diversity and distributions of cultivable fungi associated with decaying Miscanthus and sugarcane plants in nature and to further assess biodegradation of host plant cell walls by these fungi in pure cultures. Late in 2008 and early in 2009 we collected decaying Miscanthus and Saccharum from 8 sites in Illinois and 11 sites in Louisiana, respectively. To recover fungi that truly decay plants and to recover slow growing fungi, we washed the plant material repeatedly to remove spores and cultivated fungi from plant fragments small enough to harbor at most one mycelium. We randomly selected 950 fungal colonies out of 4,560 microwell colonies and used molecular identification to discover that the most frequently recovered fungal species resided in Hypocreales (Sordariomycetes), Pleosporales (Dothideomycetes), and Chaetothryiales (Eurotiomycetes) and that only a few weedy species were recovered. We were particularly interested in Pleosporales and Chaetothyriales, groups that have not been mined for plant decay fungi. To confirm that we had truly recovered fungi that deconstruct plant cell walls, we assayed the capacity of the fungi to consume whole, alkali-pretreated, ground Miscanthus. Solid substrate cultures of the nine most commonly encountered Ascomycota resulted in Miscanthus weight loss of 8 to 13% over 4 weeks. This is the first systematic, high-throughput, isolation and biodegradation assessment of fungi isolated from decaying bioenergy grasses. PMID- 21685163 TI - Efficient inhibition of germination of coat-deficient bacterial spores by multivalent metal cations, including terbium (Tb3+). AB - Release of dipicolinic acid (DPA) and its fluorescence with terbium (Tb(3+)) allow rapid measurement of the germination and viability of spores of Bacillus and Clostridium species. However, germination of coat-deficient Bacillus spores was strongly inhibited by Tb(3+) and some other multivalent cations. Tb(3+) also inhibited germination of coat-deficient Clostridium perfringens spores. PMID- 21685164 TI - Beta-glucuronidase as a sensitive and versatile reporter in actinomycetes. AB - Here we describe a versatile and sensitive reporter system for actinomycetes that is based on gusA, which encodes the beta-glucuronidase enzyme. A series of gusA containing transcriptional and translational fusion vectors were constructed and utilized to study the regulatory cascade of the phenalinolactone biosynthetic gene cluster. Furthermore, these vectors were used to study the efficiency of translation initiation at the ATG, GTG, TTG, and CTG start codons. Surprisingly, constructs using a TTG start codon showed the best activity, whereas those using ATG or GTG were approximately one-half or one-third as active, respectively. The CTG fusion showed only 5% of the activity of the TTG fusion. A suicide vector, pKGLP2, carrying gusA in its backbone was used to visually detect merodiploid formation and resolution, making gene targeting in actinomycetes much faster and easier. Three regulatory genes, plaR1, plaR2, and plaR3, involved in phenalinolactone biosynthesis were efficiently replaced with an apramycin resistance marker using this system. Finally, we expanded the genetic code of actinomycetes by introducing the nonproteinogenic amino acid N-epsilon cyclopentyloxycarbonyl-l-lysine with the GusA protein as a reporter. PMID- 21685165 TI - Environmental, biogeographic, and biochemical patterns of archaea of the family Ferroplasmaceae. AB - About 10 years ago, a new family of cell wall-deficient, iron-oxidizing archaea, Ferroplasmaceae, within the large archaeal phylum Euryarchaeota, was described. In this minireview, I summarize the research progress achieved since then and report on the current status of taxonomy, biogeography, physiological diversity, biochemistry, and other research areas involving this exciting group of acidophilic archaea. PMID- 21685166 TI - Analysis of bla(CTX-M)-carrying plasmids from Escherichia coli isolates collected in the BfT-GermVet study. AB - In this study, 417 Escherichia coli isolates from defined disease conditions of companion and farm animals collected in the BfT-GermVet study were investigated for the presence of extended-spectrum beta-lactamase (ESBL) genes. Three ESBL producing E. coli isolates were identified among the 100 ampicillin-resistant isolates. The E. coli isolates 168 and 246, of canine and porcine origins, respectively, harbored bla(CTX-M-1), and the canine isolate 913 harbored bla(CTX M-15), as confirmed by PCR and sequence analysis. The isolates 168 and 246 belonged to the novel multilocus sequence typing (MLST) types ST1576 and ST1153, respectively, while isolate 913 had the MLST type ST410. The ESBL genes were located on structurally related IncN plasmids in isolates 168 and 246 and on an IncF plasmid in isolate 913. The bla(CTX-M-1) upstream regions of plasmids pCTX168 and pCTX246 were similar, whereas the downstream regions showed structural differences. The genetic environment of the bla(CTX-M-15) gene on plasmid pCTX913 differed distinctly from that of both bla(CTX-M-1) genes. Detailed sequence analysis showed that the integration of insertion sequences, as well as interplasmid recombination events, accounted for the structural variability in the bla(CTX-M) gene regions. PMID- 21685167 TI - Increased furfural tolerance due to overexpression of NADH-dependent oxidoreductase FucO in Escherichia coli strains engineered for the production of ethanol and lactate. AB - Furfural is an important fermentation inhibitor in hemicellulose sugar syrups derived from woody biomass. The metabolism of furfural by NADPH-dependent oxidoreductases, such as YqhD (low K(m) for NADPH), is proposed to inhibit the growth and fermentation of xylose in Escherichia coli by competing with biosynthesis for NADPH. The discovery that the NADH-dependent propanediol oxidoreductase (FucO) can reduce furfural provided a new approach to improve furfural tolerance. Strains that produced ethanol or lactate efficiently as primary products from xylose were developed. These strains included chromosomal mutations in yqhD expression that permitted the fermentation of xylose broths containing up to 10 mM furfural. Expression of fucO from plasmids was shown to increase furfural tolerance by 50% and to permit the fermentation of 15 mM furfural. Product yields with 15 mM furfural were equivalent to those of control strains without added furfural (85% to 90% of the theoretical maximum). These two defined genetic traits can be readily transferred to enteric biocatalysts designed to produce other products. A similar strategy that minimizes the depletion of NADPH pools by native detoxification enzymes may be generally useful for other inhibitory compounds in lignocellulosic sugar streams and with other organisms. PMID- 21685168 TI - 2,3-butanediol production by acetogenic bacteria, an alternative route to chemical synthesis, using industrial waste gas. AB - 2,3-Butanediol (23BD) is a high-value chemical usually produced petrochemically but which can also be synthesized by some bacteria. To date, the best microbial 23BD production rates have been observed using pathogenic bacteria in fermentation systems that depend on sugars as the carbon and energy sources for product synthesis. Here we present evidence of 23BD production by three nonpathogenic acetogenic Clostridium species-Clostridium autoethanogenum, C. ljungdahlii, and C. ragsdalei-using carbon monoxide-containing industrial waste gases or syngas as the sole source of carbon and energy. Through an analysis of the C. ljungdahlii genome, the complete pathway from carbon monoxide to 23BD has been proposed. Homologues of the genes involved in this pathway were also confirmed for the other two species investigated. A gene expression study demonstrates a correlation between mRNA accumulation from 23BD biosynthetic genes and the onset of 23BD production, while a broader expression study of Wood Ljungdahl pathway genes provides a transcription-level view of one of the oldest existing biochemical pathways. PMID- 21685169 TI - Rickettsia monteiroi sp. nov., infecting the tick Amblyomma incisum in Brazil. AB - Free-living adult Amblyomma incisum ticks were collected in an Atlantic rainforest area at Intervales State Park, State of Sao Paulo, Brazil. From an A. incisum specimen, rickettsiae were successfully isolated in Vero cell culture by the shell vial technique. Rickettsial isolation was confirmed by optical microscopy, transmission electron microscopy, and PCRs targeting portions of the rickettsial genes gltA, htrA, rrs, and sca1 on infected cells. Fragments of 1,089, 457, 1,362, and 443 nucleotides of the gltA, htrA, rrs, and sca1 genes, respectively, were sequenced. By BLAST analysis, the partial sequence of rrs of the A. incisum rickettsial isolate was closest to the corresponding sequence of Rickettsia bellii (99.1% similarity). The gltA partial sequence was closest to the corresponding sequences of "Candidatus Rickettsia tarasevichiae" (96.1% similarity) and Rickettsia canadensis (95.8% similarity). The htrA partial sequence was closest to the corresponding sequence of R. canadensis (89.8% similarity). The sca1 partial sequence was closest to the corresponding sequence of R. canadensis (95.2% similarity). Since our rickettsial isolate was genetically distinct from other Rickettsia species, we propose a new species designated Rickettsia monteiroi sp. nov. Phylogenetic analyses indicated that R. monteiroi belongs to the canadensis group within the genus Rickettsia, together with the species R. canadensis and "Candidatus R. tarasevichiae". Little or no antibody cross-reaction was observed between sera of R. monteiroi-inoculated guinea pigs and R. bellii-, Rickettsia rickettsii-, or R. canadensis-inoculated guinea pigs. PMID- 21685170 TI - Allelic diversity and population structure of Bacillus sphaericus as revealed by multilocus sequence typing. AB - The genetic diversity of 35 Bacillus sphaericus strains was analyzed by a newly developed multilocus sequence typing (MLST) scheme, toxin gene pool survey, and mosquito bioassay. The results demonstrated that strains assigned to the same sequence type (ST) had the same occurrence of toxin genes. Further sequence analysis revealed that toxic strains presented a nearly clonal population structure, whereas nontoxic strains had a high level of heterogeneity and were significantly distinct from toxic strains. PMID- 21685171 TI - Novel family of carbohydrate-binding modules revealed by the genome sequence of Spirochaeta thermophila DSM 6192. AB - Spirochaeta thermophila is a thermophilic, free-living, and cellulolytic anaerobe. The genome sequence data for this organism have revealed a high density of genes encoding enzymes from more than 30 glycoside hydrolase (GH) families and a noncellulosomal enzyme system for (hemi)cellulose degradation. Functional screening of a fosmid library whose inserts were mapped on the S. thermophila genome sequence allowed the functional annotation of numerous GH open reading frames (ORFs). Seven different GH ORFs from the S. thermophila DSM 6192 genome, all putative beta-glycanase ORFs according to sequence similarity analysis, contained a highly conserved novel GH-associated module of unknown function at their C terminus. Four of these GH enzymes were experimentally verified as xylanase, beta-glucanase, beta-glucanase/carboxymethylcellulase (CMCase), and CMCase. Binding experiments performed with the recombinantly expressed and purified GH-associated module showed that it represents a new carbohydrate binding module (CBM) that binds to microcrystalline cellulose and is highly specific for this substrate. In the course of this work, the new CBM type was only detected in Spirochaeta, but recently we found sequences with detectable similarity to the module in the draft genomes of Cytophaga fermentans and Mahella australiensis, both of which are phylogenetically very distant from S. thermophila and noncellulolytic, yet inhabit similar environments. This suggests a possibly broad distribution of the module in nature. PMID- 21685172 TI - Multi-analyte profiling reveals matrix metalloproteinase-9 and monocyte chemotactic protein-1 as plasma biomarkers of cardiac aging. AB - BACKGROUND: We have previously shown that cardiac sarcopenia occurs with age in C57/BL6J mice. However, underlying mechanisms and plasma biomarkers of cardiac aging have not been identified. Accordingly, the objective of this study was to identify and evaluate plasma biomarkers that reflect cardiac aging phenotypes. METHODS AND RESULTS: Plasma from adult (7.5+/-0.5 months old, n=27) and senescent (31.7+/-0.5 months old, n=25) C57/BL6J mice was collected, and levels of 69 markers were measured by multi-analyte profiling. Of these, 26 analytes were significantly increased and 3 were significantly decreased in the senescent group compared with the adult group. The majority of analytes that increased in the senescent group were inflammatory markers associated with macrophage functions, including matrix metalloproteinase-9 (MMP-9) and monocyte chemotactic protein-1 (MCP-1/CCL-2). Immunoblotting (n=12/group) showed higher MMP-9 and MCP-1 levels in the left ventricle (LV) of senescent mice (P<0.05), and their expression levels in the LV correlated with plasma levels (rho=0.50 for MMP-9 and rho =0.62 for MCP1, P<0.05). Further, increased plasma MCP-1 and MMP-9 levels correlated with the increase in end-diastolic dimensions that occurs with senescence. Immunohistochemistry (n=3/group) for Mac-3, a macrophage marker, showed increased macrophage densities in the senescent LV, and dual-labeling immunohistochemistry of Mac-3 and MMP-9 revealed robust colocalization of MMP-9 to the macrophages in the senescent LV sections, indicating that the macrophage is a major contributor of MMP-9 in the senescent LV. CONCLUSIONS: Our results suggest that MCP-1 and MMP 9 are potential plasma markers for cardiac aging and that augmented MCP-1 and MMP 9 levels and macrophage content in the LV could provide an underlying inflammatory mechanism of cardiac aging. PMID- 21685173 TI - Common variants in CASQ2, GPD1L, and NOS1AP are significantly associated with risk of sudden death in patients with coronary artery disease. AB - BACKGROUND: Recent evidence suggests a genetic component for sudden cardiac death (SCD) in subjects with coronary artery disease (CAD). We conducted a systematic candidate-gene approach using haplotype-tagging single nucleotide polymorphisms (htSNPs) to identify genes associated with SCD risk in the context of CAD. METHODS AND RESULTS: We investigated 1424 htSNPs representing 18 genes with mutations described in patients with ventricular arrhythmias in 291 subjects from the Oregon Sudden Unexpected Death Study (Ore-SUDS). The Ore-SUDS is an ongoing prospective investigation of SCD in the Portland, OR, metropolitan area (population, 1 000 000). SCD cases were ascertained from multiple sources and medical records were reviewed to determine the presence of CAD. A total of 36 SNPs were associated with risk of SCD (uncorrected probability values <0.01) in the initial study sample. These SNPs were subsequently tested for replication in an independent case-control study sample from the Ore-SUDS (n=688). The association analysis in the replication stage revealed 6 SNPs associated with SCD: CASQ2 region (rs17500488, P=0.04; rs3010396, P=0.007; rs7366407; P=0.04), NOS1AP (rs12084280, P=0.04; rs10918859, P=0.02), and 1 SNP located ~26 kb upstream of GPD1L (rs9862154, P=0.04). CONCLUSIONS: Common variations in or near CASQ2, GPD1L, and NOS1AP are associated with increased risk of SCD in patients with CAD. These findings provide further evidence for overlap between the genetic architecture of rare and common forms of SCD, and replication in additional populations is warranted. PMID- 21685174 TI - Paraoxonase-1 Q192R polymorphism and antiplatelet effects of clopidogrel in patients undergoing elective coronary stent placement. AB - BACKGROUND: Recently published data indicate that the paraoxonase-1 (PON1) Q192R genotype-and not as previously shown activity of cytochrome P450 (CYP) 2C19-is the major determinant of metabolic bioactivation of clopidogrel and thereby variability of antiplatelet effect of clopidogrel. We sought to investigate whether the PON1 Q192R gene polymorphism affects platelet reactivity in patients undergoing elective coronary stent placement. METHODS AND RESULTS: The study included 760 consecutive patients undergoing elective coronary stent placement after loading with clopidogrel 600 mg. Platelet function was assessed by adenosine diphosphate-induced (ADP 5 and 20 MUmol/L) platelet aggregation and by flow-cytometric analysis of platelet surface protein expression before clopidogrel, at the time of coronary stent placement, and before discharge after coronary stent placement. PON1 Q192R genotype [NM_000446.5:c.575A>G single nucleotide polymorphism (rs662)] was analyzed by TaqMan polymerase chain reaction. Residual platelet aggregation (ADP 5 MUmol/L) at predischarge was 8.0% (3.0% to 17.0%) [median (interquartile range)] in PON1 QQ192 patients (n=384), 8.0% (3.0% to 15.0%) in PON1 QR192 (n=304), and 11.0% (3.0% to 18.0%) in PON1 RR192 (n=72; P=0.603). By multivariable linear regression, residual platelet aggregation was not associated with PON1 QQ192/QR192 (partial eta(2)<0.001, P=0.728) but with CYP2C19*2 loss-of-function allele (partial eta(2)=0.045, P<0.001) as well as any CYP2C19*17 gain-of-function allele (partial eta(2)=0.012, P=0.004). All other platelet assays also showed no significant association between PON1 Q192R genotype and antiplatelet effect of clopidogrel. The 1-year incidence of death and myocardial infarction did not differ between PON1 Q192R genotypes. CONCLUSIONS: On-treatment platelet reactivity in patients undergoing coronary stent placement after loading with clopidogrel 600 mg was not associated with PON1 Q192R genotype. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00457236. PMID- 21685175 TI - New insights into the properties of pubescent surfaces: peach fruit as a model. AB - The surface of peach (Prunus persica 'Calrico') is covered by a dense indumentum, which may serve various protective purposes. With the aim of relating structure to function, the chemical composition, morphology, and hydrophobicity of the peach skin was assessed as a model for a pubescent plant surface. Distinct physicochemical features were observed for trichomes versus isolated cuticles. Peach cuticles were composed of 53% cutan, 27% waxes, 23% cutin, and 1% hydroxycinnamic acid derivatives (mainly ferulic and p-coumaric acids). Trichomes were covered by a thin cuticular layer containing 15% waxes and 19% cutin and were filled by polysaccharide material (63%) containing hydroxycinnamic acid derivatives and flavonoids. The surface free energy, polarity, and work of adhesion of intact and shaved peach surfaces were calculated from contact angle measurements of water, glycerol, and diiodomethane. The removal of the trichomes from the surface increased polarity from 3.8% (intact surface) to 23.6% and decreased the total surface free energy chiefly due to a decrease on its nonpolar component. The extraction of waxes and the removal of trichomes led to higher fruit dehydration rates. However, trichomes were found to have a higher water sorption capacity as compared with isolated cuticles. The results show that the peach surface is composed of two different materials that establish a polarity gradient: the trichome network, which has a higher surface free energy and a higher dispersive component, and the cuticle underneath, which has a lower surface free energy and higher surface polarity. The significance of the data concerning water-plant surface interactions is discussed within a physiological context. PMID- 21685176 TI - The Medicago FLOWERING LOCUS T homolog, MtFTa1, is a key regulator of flowering time. AB - FLOWERING LOCUS T (FT) genes encode proteins that function as the mobile floral signal, florigen. In this study, we characterized five FT-like genes from the model legume, Medicago (Medicago truncatula). The different FT genes showed distinct patterns of expression and responses to environmental cues. Three of the FT genes (MtFTa1, MtFTb1, and MtFTc) were able to complement the Arabidopsis (Arabidopsis thaliana) ft-1 mutant, suggesting that they are capable of functioning as florigen. MtFTa1 is the only one of the FT genes that is up regulated by both long days (LDs) and vernalization, conditions that promote Medicago flowering, and transgenic Medicago plants overexpressing the MtFTa1 gene flowered very rapidly. The key role MtFTa1 plays in regulating flowering was demonstrated by the identification of fta1 mutants that flowered significantly later in all conditions examined. fta1 mutants do not respond to vernalization but are still responsive to LDs, indicating that the induction of flowering by prolonged cold acts solely through MtFTa1, whereas photoperiodic induction of flowering involves other genes, possibly MtFTb1, which is only expressed in leaves under LD conditions and therefore might contribute to the photoperiodic regulation of flowering. The role of the MtFTc gene is unclear, as the ftc mutants did not have any obvious flowering-time or other phenotypes. Overall, this work reveals the diversity of the regulation and function of the Medicago FT family. PMID- 21685177 TI - Nuclear localization and interaction with COP1 are required for STO/BBX24 function during photomorphogenesis. AB - Arabidopsis (Arabidopsis thaliana) SALT TOLERANCE/B-BOX ZINC FINGER PROTEIN24 (STO/BBX24) is a negative regulator of the light signal transduction that localizes to the nucleus of plant cells and interacts with CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1) in the yeast (Saccharomyces cerevisiae) two-hybrid system. The protein contains two B-box zinc-finger motives at the N terminus and a conserved motif at the C-terminal part required for the interaction with COP1. BBX24 accumulates during deetiolation of young seedlings in the first hours of exposure to light. However, this accumulation is transient and decreases after prolonged light irradiation. Here, we identified the amino acidic residues necessary for the nuclear import of the protein. In addition, we created mutated forms of the protein, and analyzed them by overexpression in the bbx24-1 mutant background. Our results indicate that the degradation of BBX24 occurs, or at least is initiated in the nucleus, and this nuclear localization is a prerequisite to fulfill its function in light signaling. Moreover, mutations in the region responsible for the interaction with COP1 revealed that a physical interaction of the proteins is also required for degradation of BBX24 in the light and for normal photomorphogenesis. PMID- 21685178 TI - A mechanistic link between STM and CUC1 during Arabidopsis development. AB - The KNOXI transcription factor SHOOT MERISTEMLESS (STM) is required to establish and maintain the Arabidopsis (Arabidopsis thaliana) apical meristem, yet little is known about its direct targets. Using different approaches we demonstrate that the induction of STM causes a significant up-regulation of the organ boundary gene CUP SHAPED COTYLEDON1 (CUC1), which is specific and independent of other meristem regulators. We further show that the regulation of CUC1 by STM is direct and identify putative binding sites in its promoter. Continuous expression of STM in Arabidopsis leaf primordia also causes the activation of CUC2-3, as well as microRNA MIR164a, which provides a negative feedback loop by posttranscriptionally regulating CUC1 and CUC2. The results bring new insights into the mechanistic links between KNOXI and CUC transcription factors and contribute to the understanding of the regulatory network controlled by STM. PMID- 21685180 TI - GRACE risk recommendations in NICE CG94 are not appropriate. PMID- 21685179 TI - Phosphorylation of SOS3-like calcium-binding proteins by their interacting SOS2 like protein kinases is a common regulatory mechanism in Arabidopsis. AB - The Arabidopsis (Arabidopsis thaliana) genome encodes nine Salt Overly Sensitive3 (SOS3)-like calcium-binding proteins (SCaBPs; also named calcineurin B-like protein [CBL]) and 24 SOS2-like protein kinases (PKSs; also named as CBL interacting protein kinases [CIPKs]). A general regulatory mechanism between these two families is that SCaBP calcium sensors activate PKS kinases by interacting with their FISL motif. In this study, we demonstrated that phosphorylation of SCaBPs by their functional interacting PKSs is another common regulatory mechanism. The phosphorylation site serine-216 at the C terminus of SCaBP1 by PKS24 was identified by liquid chromatography-quadrupole mass spectrometry analysis. This serine residue is conserved within the PFPF motif at the C terminus of SCaBP proteins. Phosphorylation of this site of SCaBP8 by SOS2 has been determined previously. We further showed that CIPK23/PKS17 phosphorylated CBL1/SCaBP5 and CBL9/SCaBP7 and PKS5 phosphorylated SCaBP1 at the same site in vitro and in vivo. Furthermore, the phosphorylation stabilized the interaction between SCaBP and PKS proteins. This tight interaction neutralized the inhibitory effect of PKS5 on plasma membrane H(+)-ATPase activity. These data indicate that SCaBP phosphorylation by their interacting PKS kinases is a critical component of the SCaBP-PKS regulatory pathway in Arabidopsis. PMID- 21685181 TI - Sudden death and ion channel disease: pathophysiology and implications for management. AB - The underlying aetiology of sudden arrhythmic death syndrome is predominantly inherited cardiac disease, and 'channelopathies' (cardiac ion channel disease) are the most common detectable cause of death. This heterogeneous group includes Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia. Common features include variable penetrance, sudden death due to ventricular arrhythmias, and the absence of structural heart disease. The understanding of cardiac ion channel disease has been revolutionised by genetics. At present, genotype contributes to risk stratification in Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia, and the future promises management tailored to the genetic diagnosis. PMID- 21685182 TI - Overnight dehydration increases the risk of a morning infarct. PMID- 21685183 TI - Ablation of ventricular tachycardia arising from the left coronary cusp. PMID- 21685184 TI - Exercise training reverses adiponectin resistance in skeletal muscle of patients with chronic heart failure. AB - BACKGROUND: Resistance to the insulin-sensitising adipocytokine, adiponectin, has been described at the level of the skeletal muscle in patients with chronic heart failure (CHF). OBJECTIVE: To investigate whether exercise training (ET) would improve skeletal muscle energy metabolism and adiponectin signalling. METHODS: In a prospective cohort study, patients with CHF were recruited from the Cardiac Rehabilitation Centre, Antwerp University Hospital. They underwent 4 months' combined endurance-resistance ET. Skeletal muscle mRNA and protein expression of adiponectin, AdipoR1 and downstream metabolic genes were measured. RESULTS: Adiponectin mRNA expression in the nine CHF patients was higher than that in 10 matched healthy subjects (p=0.007), whereas AdipoR1 and downstream-located genes involved in lipid (PPAR-alpha, ACADM) and glucose metabolism (AMPK, hexokinase2) were down-regulated. Skeletal muscle AdipoR1 correlated with VO(2) peak (r=0.900; p=0.001), maximal workload (r=0.753; p=0.019) and steady state workload (r=0.928; p<0.001). ET increased maximal workload and muscle strength. In addition, ET lowered adiponectin mRNA expression (p=0.017), whereas the expression of AdipoR1 (p=0.011) and downstream metabolic genes was increased to levels comparable to those in healthy subjects. ELISA confirmed the normalisation of skeletal muscle adiponectin expression at the protein level (p=0.047). CONCLUSION: At the level of the skeletal muscle, CHF patients are characterised by increased adiponectin expression and decreased expression of AdipoR1 and downstream metabolic genes. ET normalises the mRNA expression of adiponectin and AdipoR1 and reverses disorders in lipid and glucose metabolism in skeletal muscle. These alterations in metabolic gene expression may help to understand the beneficial effects of ET in CHF. PMID- 21685185 TI - Characteristics of general practices associated with emergency-department attendance rates: a cross-sectional study. AB - BACKGROUND: Strategies are needed to contain emergency-department attendance. Quality of care in general practice might influence the use of emergency departments, including management of patients with chronic conditions and access to consultations. AIM: The aim was to determine whether emergency-department attendance rates are lower for practices with higher quality and outcomes framework performance and lower for practices with better patient reported access. DESIGN: A cross-sectional study. SETTING: Two English primary-care trusts, Leicester City and Leicestershire County and Rutland, with 145 general practices. METHOD: Using data on attendances at emergency departments in 2006/2007 and 2007/2008, a practice attendance rate was calculated for each practice. In a hierarchical negative binomial regression model, practice population characteristics (deprivation, proportion of patients aged 65 or over, ethnicity, gender) and practice characteristics (total list size, distance from the emergency department, quality and outcomes framework points, and variables measuring satisfaction with access) were included as potential explanatory variables. RESULTS: In both years, greater deprivation, shorter distance from the central emergency department, lower practice list size, white ethnicity and lower satisfaction with practice telephone access were associated with higher emergency department attendance rates. CONCLUSIONS: Performance as indicated by the quality and outcomes framework did not predict rates of attendance at emergency departments, but satisfaction with telephone access did. Consideration should be given to improving access to some general practices to contain the use of emergency departments. PMID- 21685186 TI - Rebound in ventilator-associated pneumonia rates during a prevention checklist washout period. AB - OBJECTIVE To describe the washout effect after stopping a prevention checklist for ventilator-associated pneumonia (VAP). METHODS VAP rates were prospectively monitored for special cause variation over 42 months in a paediatric intensive care unit. A VAP prevention bundle was implemented, consisting of head of bed elevation, oral care, suctioning device management, ventilator tubing care, and standard infection control precautions. Key practices of the bundle were implemented with a checklist and subsequently incorporated into the nursing and respiratory care bedside flow sheets to achieve long-term sustainability. Compliance with the VAP bundle was monitored throughout. The timeline for the project was retrospectively categorised into the benchmark phase, the checklist phase (implementation), the checklist washout phase, and the flowsheet phase (cues in the flowsheet). RESULTS During the checklist phase (12 months), VAP bundle compliance rose from <50% to >75% and the VAP rate fell from 4.2 to 0.7 infections per 1000 ventilator days (p<0.059). Unsolicited qualitative feedback from frontline staff described overburdensome documentation requirements, form fatigue, and checklist burnout. During the checklist washout phase (4 months), VAP rates rose to 4.8 infections per 1000 ventilator days (p<0.042). In the flowsheet phase, the VAP rate dropped to 0.8 infections per 1000 ventilator days (p<0.047). CONCLUSIONS Salient cues to drive provider behaviour towards best practice are helpful to sustain process improvement, and cessation of such cues should be approached warily. Initial education, year-long habit formation, and effective early implementation demonstrated no appreciable effect on the VAP rate during the checklist washout period. PMID- 21685188 TI - Does chlamydial infection increase the risk of cervical dysplasia? PMID- 21685190 TI - Determinants of HIV testing. AB - OBJECTIVE: To determine the characteristics of general practitioners (GPs) who test and patients who are tested for HIV in Australia. DESIGN AND SETTING: A secondary analysis of data from the Bettering the Evaluation and Care of Health programme; a cross-sectional, national survey of GP activity. METHODS: We identified GP, patient and encounter characteristics that were associated with HIV testing between April 2000 and March 2010. We looked at testing rates for patients with different characteristics, whether they had attended for screening and GP 'risk factor' identification. Multiple logistic regression was used to measure the independent effect of each GP, patient and encounter characteristic on testing for HIV. RESULTS: Data were available for 984,200 encounters from 9842 GPs. 1796 (18.2%) of GPs performed at least one HIV test. On logistic regression, independent predictors of HIV testing included the management of a 'risk factor' (OR 19.4, 95% CI 17.4 to 21.6), screening (OR 10.6, 95% CI 9.4 to 12.1), younger GP age, practice in a metropolitan area (OR 1.4, 95% CI 1.2 to 1.6), patient age, gender (male > female OR 3.0, 95% CI 2.7 to 3.3), being new to that practice (OR 2.1, 95% CI 1.8 to 2.3) and being Indigenous (OR 1.7, 95% CI 1.3 to 2.4). CONCLUSION: The most significant independent predictors of testing were identification of a risk factor and attendance for screening. Unless barriers to testing are addressed it is unlikely that altering guidelines alone will improve testing rates and reduce transmission. PMID- 21685191 TI - A review of mathematical models of HIV/AIDS interventions and their implications for policy. AB - OBJECTIVES: This review aims to summarise key messages emerging from mathematical models of HIV/AIDS interventions and identifies ways in which models can assist policy makers. METHODS: A search of the PubMed database was conducted and studies were included if they modelled the effects of HIV prevention or treatment programes. Conclusions of relevance to policy makers were summarised under a number of key themes. RESULTS: Mathematical models have evaluated a wide range of different HIV prevention and treatment programmes. Central themes include the positive effects of interventions beyond the groups in which they are introduced, the importance of intervening early, the potential for risk compensation to reverse gains made in HIV prevention and the emerging threat of drug resistance. Several freely available models have been developed to compare the impact and cost-effectiveness of different interventions. These and other models can be used to assess potential synergies between interventions as well as situations in which intervention impact may be mitigated by other interventions. CONCLUSIONS: Mathematical models can assist policy makers in comparing the relative impact and cost-effectiveness of different interventions, generalising the results of randomised controlled trials to the local setting, identifying threats to programme success, identifying opportunities for maximising intervention impact/efficiency and evaluating the extent to which observed trends in HIV prevalence are attributable to HIV/AIDS programme success. PMID- 21685192 TI - Early bioprosthetic valve failure due to carcinoid heart disease. PMID- 21685193 TI - N-terminal pro-b-type natriuretic peptide and left atrial function in patients with congestive heart failure and severely reduced ejection fraction. AB - AIMS: Amino-terminal portion of pro-B-type natriuretic peptide (NT-pro-BNP) is a valuable diagnostic and prognostic marker in congestive heart failure (CHF). In CHF patients, elevation of natriuretic peptide levels correlate with decreased left ventricular (LV) ejection fraction (EF) and increased left atrial (LA) volumes, but a correlation with LA function that is a determinant of haemodynamic and clinical status in CHF with independent prognostic value has never been investigated. Aim of this study was to evaluate the relationship between cardiac neurohormonal activation and LA function in patients with CHF due to dilated cardiomyopathy. METHODS AND RESULTS: One hundred and one patients (86% males; mean age, 64 +/- 11 years) with dilated ischaemic or non-ischaemic cardiomyopathy, LV EF <=45% (mean LV EF, 33 +/- 8%), and New York Heart Association class II-IV underwent transthoracic echocardiography to evaluate LA fractional active and total emptying from M- and B-Mode images, and, on the same day, venous blood sample collection to dose NT-pro-BNP. By univariate analyses, NT-pro-BNP significantly correlated to age, LA dimensions, LA function indexes, EF, and functional class. At multivariate analysis, LV EF and M- or B-Mode indexes of LA function were the only independent predictors of NT-pro-BNP values. A NT-pro-BNP cut-off of 1480 pg/mL identified LA dysfunction with 89% specificity and 54% sensitivity. CONCLUSION: In CHF patients with severely impaired systolic function, NT-pro-BNP levels reflect LA and LV dysfunction. These data should prompt studies to investigate the relationship between changes of LA function and NT-pro-BNP levels and their clinical value as prognostic and therapeutic targets in CHF. PMID- 21685194 TI - Atypical course of a persistent left superior vena cava through the left atrium. PMID- 21685187 TI - Genome-wide association study of smoking behaviours in patients with COPD. AB - Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2*10(-7). No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10(-6). Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (CHRNA3/CHRNA5; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6; eg, p=2.78*10(-5) for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in DBH was significantly (p=0.015) associated with smoking cessation. Conclusion The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD. PMID- 21685195 TI - Two-dimensional speckle-tracking strain imaging in the assessment of mechanical properties of carotid arteries: feasibility and comparison with conventional markers of subclinical atherosclerosis. AB - AIMS: The aim of our study was to assess the two-dimensional carotid strain as an index of arterial stiffness in a population of patients without carotid atherosclerotic plaques. METHODS AND RESULTS: Two-dimensional carotid strain, carotid intima-media thickness (CIMT), stiffness index (beta), Peterson's elastic modulus, and distensibility coefficient were evaluated in 47 patients. For all patients, cardiovascular risk scores were calculated. Peak systolic circumferential strain was significantly correlated with conventional indices of arterial stiffness and with the CIMT. Peak systolic circumferential strain adjusted for pulse pressure was the only parameter that showed a significant difference between the three cardiovascular risk groups in which patients were classified. Two-dimensional carotid strain showed an excellent reproducibility. CONCLUSION: The two-dimensional strain allows the assessment of carotid arterial mechanics. Probably the assessment of arterial stiffness allows a better risk stratification of patients. PMID- 21685196 TI - Functional assessment of the left atrium by real-time three-dimensional echocardiography using a novel dedicated analysis tool: initial validation studies in comparison with computed tomography. AB - AIMS: A novel real-time three-dimensional echocardiography (RT3DE) analysis tool specifically designed for evaluation of the left atrium enables comprehensive evaluation of left atrial (LA) size, global, and regional function using a dynamic 16-segment model. The aim of this study was the initial validation of this method using computed tomography (CT) as the method of reference. METHODS AND RESULTS: The study population consisted of 34 prospectively enrolled patients with clinical indication for pulmonary vein isolation. A dynamic polyhedron model of the left atrium was generated using RT3DE. LA maximum and minimum volumes (LA(max)/LA(min)) and emptying fraction (LAEF) were determined and compared with the results obtained by CT. High correlations between RT3DE and CT were found for LA(max) (r = 0.92, P < 0.001), LA(min) (r = 0.95, P < 0.001), and LAEF (r = 0.82, P < 0.001). LA(max) and LA(min) were lower by RT3DE than by CT (95.0 +/- 44.7 vs. 119.8 +/- 50.5 mL, P < 0.001 and 58.1 +/- 41.3 vs. 83.3 +/- 52.6 mL, P < 0.001, respectively), whereas LAEF was measured higher by RT3DE (42.8 +/- 15.2 vs. 34.2 +/- 15.4%, P < 0.001, respectively). RT3DE measurements closely correlated in terms of intra-observer (intra-class correlation r = 0.99, r = 0.99, r = 0.96, respectively) and inter-observer variability (r = 0.97, r = 0.98, r = 0.88, respectively). CONCLUSIONS: LA volumes and EF as assessed by RT3DE correlate highly with CT measurements, albeit there is some bias between the imaging modalities. Most importantly, RT3DE measurements using the novel dedicated LA analysis tool are robust in terms of observer variability and thus suitable for follow-up analyses. PMID- 21685197 TI - Real-time three-dimensional transoesophageal echocardiography during stereotactic needle biopsy of complex atrioventricular nodal tumour. PMID- 21685198 TI - The role of exercise echocardiography in the diagnostics of heart failure with normal left ventricular ejection fraction. AB - AIMS: Few data are available on the exercise-induced abnormalities of myocardial function in patients with exertional dyspnoea and normal left ventricular ejection fraction (LV EF). The main aims of this study were to determine the prevalence of isolated exercise-induced heart failure with normal ejection fraction (HFNEF) and to assess whether disturbances in LV or right ventricular longitudinal systolic function are associated with the diagnosis of HFNEF. METHODS AND RESULTS: Eighty-four patients with exertional dyspnoea and normal LV EF and 14 healthy controls underwent spirometry, NT-proBNP plasma analysis, and exercise echocardiography. Doppler LV inflow and tissue mitral and tricuspid annular velocities were analysed at rest and immediately after the termination of exercise. Of the 30 patients with the evidence of HFNEF, 6 (20%) patients had only isolated exercise-induced HFNEF. When compared with the remaining patients, those with HFNEF had a significantly lower resting and exercise peak mitral annular systolic velocity (Sa) and the mitral annular velocity during atrial contraction, lower exercise peak mitral annular velocity at early diastole, and lower exercise peak systolic velocity of tricuspid annular motion. The multivariate logistic regression analysis including both parameters standardly defining HFNEF and the new Doppler variables potentially associated with the diagnosis of HFNEF revealed that NT-proBNP, LV mass index, left atrial volume index, and Sa significantly and independently predict the diagnosis of HFNEF. CONCLUSION: A significant proportion of patients require exercise to diagnose HFNEF. Sa appears to be a significant independent predictor of HFNEF, which may increase the diagnostic value of models utilizing the variables recommended by the European Society of Cardiology guidelines. PMID- 21685199 TI - Role of echocardiography in the evaluation of patients with Staphylococcus aureus bacteraemia: time to look at the heart. PMID- 21685200 TI - Prevalence of infective endocarditis in patients with Staphylococcus aureus bacteraemia: the value of screening with echocardiography. AB - AIMS: Staphylococcus aureus infective endocarditis (IE) is a critical medical condition associated with a high morbidity and mortality. In the present study, we prospectively evaluated the importance of screening with echocardiography in an unselected S. aureus bacteraemia (SAB) population. METHODS AND RESULTS: From 1 January 2009 to 31 August 2010, a total of 244 patients with SAB at six Danish hospitals underwent screening echocardiography. The inclusion rate was 73% of all eligible patients (n= 336), and 53 of the 244 included patients (22%; 95% CI: 17 27%) were diagnosed with definite IE. In patients with native heart valves the prevalence was 19% (95% CI: 14-25%) compared with 38% (95% CI: 20-55%) in patients with prosthetic heart valves and/or cardiac rhythm management devices (P= 0.02). No difference was found between Main Regional Hospitals and Tertiary Cardiac Hospitals, 20 vs. 23%, respectively (NS). The prevalence of IE in high risk patients with one or more predisposing condition or clinical evidence of IE were significantly higher compared with low-risk patients with no additional risk factors (38 vs. 5%; P < 0.001). IE was associated with a higher 6 months mortality, 14(26%) vs. 28(15%) in SAB patients without IE, respectively (P < 0.05). CONCLUSION: SAB patients carry a high risk for development of IE, which is associated with a worse prognosis compared with uncomplicated SAB. The presenting symptoms and clinical findings associated with IE are often non-specific and echocardiography should always be considered as part of the initial evaluation of SAB patients. PMID- 21685201 TI - Extended-spectrum beta-lactamases and plasmid-mediated quinolone resistance in enterobacterial clinical isolates in the paediatric hospital of Uruguay. AB - OBJECTIVES: To analyse the prevalence of resistance to beta-lactams and plasmid mediated quinolone resistance in Enterobacteriaceae in the paediatric hospital of Uruguay. METHODS: A total of 368 enterobacterial isolates collected between 1 May and 30 November 2009 were studied for the presence of extended-spectrum beta lactamases (ESBLs), qnr alleles and aac(6')Ib by phenotypic and molecular methods. The genomic context and transferability of beta-lactamase and qnr genes were examined by PCR and conjugation, respectively. RESULTS: The proportion of inpatients having an infection caused by ESBL-producing enterobacteria was 0.23% (16/7073) in paediatrics wards, 0.640/00 (3/4696) in the neonatology department and 0.030/00 (1/32 557) in the emergency department. ESBL-carrying enterobacteria constituted a total of 21.6% (16/74), 13% (3/23) and 0.37% (1/271) when samples were obtained from paediatrics wards, the neonatology department and the emergency department, respectively. Overall, CTX-M-2 (n = 7), CTX-M-9 (n = 3), CTX-M-8 (n = 2), CTX-M-15 (n = 1), SHV-5 (n = 5) and SHV-2 (n = 2) beta lactamases were detected. Thirteen out of 20 ESBL-producing isolates also carried the aac(6')Ib gene, and the cr variant was detected in one of them. qnr alleles were detected in four isolates comprising two qnrA1 genes, a qnrB8-like variant and a new qnrB gene showing 26 amino acid differences from QnrB1. CONCLUSIONS: The proportion of ESBL-producing enterobacteria in Uruguay's paediatric hospital during the study period was 2.3 per 1000 hospitalized patients. The number of different microorganisms detected, as well as the various EBSLs, suggests the occurrence of sporadic episodes instead of nosocomial outbreaks. Nevertheless, the presence of new resistance genes reinforces the necessity for permanent surveillance programmes. PMID- 21685202 TI - Peripheral neuropathy in patients on long-term triazole antifungal therapy. AB - OBJECTIVES: Triazole antifungal drugs are the mainstay of treatment for patients with chronic pulmonary aspergillosis and are often used as steroid-sparing agents in patients with allergic aspergillosis. Peripheral neuropathy (PN) is a rare but reported side effect of triazole therapy in the acute management of invasive fungal infections, but its incidence during long-term triazole treatment for chronic aspergillosis is unknown. The goal of this study was to determine the incidence of PN in this context. PATIENTS AND METHODS: A retrospective cohort study was carried out to collect data on all patients with chronic aspergillosis commenced on long-term triazole therapy at the National Aspergillosis Centre in Manchester between 2007 and 2010. RESULTS: Two hundred and twenty-two patients were commenced on triazole therapy. Ten percent developed PN after an average of 4 months. Seventeen percent of patients taking itraconazole, 9% taking voriconazole and 3% taking posaconazole developed PN. This is the first report of posaconazole-induced PN. Twenty-two episodes of PN presented as numbness or tingling in the extremities, while four episodes presented as predominant leg weakness. The majority of cases were axonal, length-dependent neuropathies that recovered after triazole medication was discontinued. Two patients had non progressive but irreversible PN. Two patients were diagnosed with mononeuropathies. CONCLUSIONS: A 10% incidence of PN was observed for patients commenced on triazole therapy for chronic aspergillosis. Patients on long-term triazole therapy should be monitored for neurological symptoms. If PN is suspected, diagnosis should include nerve conduction studies, exclusion of other causes and consideration of dose reduction or cessation of therapy. PMID- 21685203 TI - Modeling neuronal defects associated with a lysosomal disorder using patient derived induced pluripotent stem cells. AB - By providing access to affected neurons, human induced pluripotent stem cells (iPSc) offer a unique opportunity to model human neurodegenerative diseases. We generated human iPSc from the skin fibroblasts of children with mucopolysaccharidosis type IIIB. In this fatal lysosomal storage disease, defective alpha-N-acetylglucosaminidase interrupts the degradation of heparan sulfate (HS) proteoglycans and induces cell disorders predominating in the central nervous system, causing relentless progression toward severe mental retardation. Partially digested proteoglycans, which affect fibroblast growth factor signaling, accumulated in patient cells. They impaired isolation of emerging iPSc unless exogenous supply of the missing enzyme cleared storage and restored cell proliferation. After several passages, patient iPSc starved of an exogenous enzyme continued to proliferate in the presence of fibroblast growth factor despite HS accumulation. Survival and neural differentiation of patient iPSc were comparable with unaffected controls. Whereas cell pathology was modest in floating neurosphere cultures, undifferentiated patient iPSc and their neuronal progeny expressed cell disorders consisting of storage vesicles and severe disorganization of Golgi ribbons associated with modified expression of the Golgi matrix protein GM130. Gene expression profiling in neural stem cells pointed to alterations of extracellular matrix constituents and cell-matrix interactions, whereas genes associated with lysosome or Golgi apparatus functions were downregulated. Taken together, these results suggest defective responses of patient undifferentiated stem cells and neurons to environmental cues, which possibly affect Golgi organization, cell migration and neuritogenesis. This could have potential consequences on post-natal neurological development, once HS proteoglycan accumulation becomes prominent in the affected child brain. PMID- 21685204 TI - The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase. AB - Recent studies have established ciliary dysfunction as the underlying cause of a broad range of multi-organ phenotypes, known as 'ciliopathies'. Ciliopathy associated proteins have a common site of action in the cilium, however, their overall importance for ciliary function differs, as implied by the extreme variability in ciliopathy phenotypes. The aim of this study was to gain more insight in the function of two ciliopathy-associated protein homologs, RPGR interacting protein 1 (RPGRIP1) and RPGRIP1-like protein (RPGRIP1L). Mutations in RPGRIP1 lead to the eye-restricted disease Leber congenital amaurosis, while mutations in RPGRIP1L are causative for Joubert and Meckel syndrome, which affect multiple organs and are at the severe end of the ciliopathy spectrum. Using tandem affinity purification in combination with mass spectrometry, we identified Nek4 serine/threonine kinase as a prominent component of both the RPGRIP1- as well as the RPGRIP1L-associated protein complex. In ciliated cells, this kinase localized to basal bodies, while in ciliated organs, the kinase was predominantly detected at the ciliary rootlet. Down-regulation of NEK4 in ciliated cells led to a significant decrease in cilium assembly, pointing to a role for Nek4 in cilium dynamics. We now hypothesize that RPGRIP1 and RPGRIP1L function as cilium specific scaffolds that recruit a Nek4 signaling network which regulates cilium stability. Our data are in line with previously established roles in the cilium of other members of the Nek protein family and define NEK4 as a ciliopathy candidate gene. PMID- 21685205 TI - Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients. AB - Amyotrophic lateral sclerosis (ALS) is an incurable neuromuscular disease that leads to a profound loss of life quality and premature death. Around 10% of the cases are inherited and ALS8 is an autosomal dominant form of familial ALS caused by mutations in the vamp-associated protein B/C (VAPB) gene. The VAPB protein is involved in many cellular processes and it likely contributes to the pathogenesis of other forms of ALS besides ALS8. A number of successful drug tests in ALS animal models could not be translated to humans underscoring the need for novel approaches. The induced pluripotent stem cells (iPSC) technology brings new hope, since it can be used to model and investigate diseases in vitro. Here we present an additional tool to study ALS based on ALS8-iPSC. Fibroblasts from ALS8 patients and their non-carrier siblings were successfully reprogrammed to a pluripotent state and differentiated into motor neurons. We show for the first time that VAPB protein levels are reduced in ALS8-derived motor neurons but, in contrast to over-expression systems, cytoplasmic aggregates could not be identified. Our results suggest that optimal levels of VAPB may play a central role in the pathogenesis of ALS8, in agreement with the observed reduction of VAPB in sporadic ALS. PMID- 21685206 TI - Rehabilitation of older patients: day hospital compared with rehabilitation at home. Clinical outcomes. AB - OBJECTIVES: to test the hypothesis that older people and their informal carers are not disadvantaged by home-based rehabilitation (HBR) relative to day hospital rehabilitation (DHR). DESIGN: pragmatic randomised controlled trial. SETTING: four geriatric day hospitals and four home rehabilitation teams in England. PARTICIPANTS: eighty-nine patients referred for multidisciplinary rehabilitation. The target sample size was 460. INTERVENTION: multidisciplinary rehabilitation either in the home or in the day hospital. MEASUREMENTS: the primary outcome measure was the Nottingham extended activities of daily living scale (NEADL). Secondary outcome measures included EQ-5D, hospital anxiety and depression scale, therapy outcome measures, hospital admissions and the General Health Questionnaire for carers. RESULTS: at the primary end point of 6 months NEADL scores were not significantly in favour of HBR cf. DHR; mean difference -2.139 (95% confidence interval -6.87 to 2.59, P = 0.37). A post hoc analysis suggested non-inferiority for HBR for NEADL but there was considerable statistical uncertainty. CONCLUSION: taken together the statistical analyses and lack of power of the trial outcomes do not provide sufficient evidence to conclude that patients in receipt of HBR are disadvantaged compared with those receiving DHR. PMID- 21685207 TI - Can T-type calcium channels make a change of heart after myocardial infarction? Fiction or fact, and for better or for worse? PMID- 21685208 TI - Is NOS uncoupling the missing link between atrial fibrillation and chronic non ischaemic cardiomyopathy? PMID- 21685211 TI - Cardiac involvement in falciparum malaria: a brief report. PMID- 21685210 TI - Time to stop blaming gastroesophageal reflux. AB - OBJECTIVES. Cough, pain, and desaturation episodes in infants are often ascribed to gastroesophageal reflux, and many are empirically treated with acid suppression medications. The authors hypothesize that most of these symptoms are not related to gastroesophageal reflux. METHODS. Retrospective review of 186 combined pH-multichannel intraluminal impedance studies performed in infants at Cincinnati Children's Hospital. RESULTS. Of 4159 symptoms reported 1504 (36%) were associated with reflux events (27% nonacid and 9% acid). When total number of symptoms and reflux events were taken into consideration, nonacid reflux events were as likely to be associated with a symptom as acid reflux events (P = .66). CONCLUSION. The extra-esophageal symptoms commonly attributed to gastroesophageal reflux in infants are most often not associated with a reflux event. Even though causality cannot be definitively proven, in the minority in whom a symptom association is observed, nonacid events are as likely as acid events to cause symptoms. PMID- 21685212 TI - Month-by-month age analysis of the risk for serious bacterial infections in febrile infants with bronchiolitis. AB - OBJECTIVE: This study's aim was to assess the risk of serious bacterial infections (SBI) in each of the first 3 months in hospitalizes febrile infants with bronchiolitis. PATIENTS AND METHODS: The risk of SBI was compared between hospitalized infant with or without bronchiolitis by age in months. RESULTS: A total of 1125 febrile infants aged <=3 months were admitted during the study period, 948 without and 177 with bronchiolitis. The incidence of SBI was significantly lower among infants with bronchiolitis compared with those without (4% vs 12.2%, P < .001). However, within the subgroup of neonates with bronchiolitis aged <=28 days, the incidence of SBI was 9.7% and was not significantly lower than in neonates without bronchiolitis. CONCLUSION: The risk of SBI among febrile infants with bronchiolitis is significantly lower compared with febrile infants without bronchiolitis, but only after the neonatal period in which the risk for urinary tract infection was relatively high (9.7%). PMID- 21685213 TI - Peanut allergy in children: relationships to health-related quality of life, anxiety, and parental stress. AB - Peanut allergy prevalence appears to be increasing in the pediatric population and pediatricians need to be aware how it may affect children's psychological functioning. This study examined relationships between health-related quality of life, child anxiety, and parental stress in children with peanut allergy. A total of 51 families completed questionnaires regarding child anxiety, parenting stress, and quality of life. Child anxiety and parenting stress were found to significantly predict parent proxy report of their child's health-related quality of life. Child anxiety, parenting stress, length of diagnosis, and experiencing an epinephrine shot predicted self-report of health-related quality of life. Although many children with peanut allergy function well, a certain subset of children and families appear to experience high levels of parenting stress and high levels of child anxiety that can affect health-related quality of life and these children may require referrals for mental health treatment. PMID- 21685215 TI - Acute onset of multi-organ system dysfunction. PMID- 21685214 TI - Impact of management and bacterial genomics on outcomes of Staphylococcus aureus bacteremia in children. AB - Children with Staphylococcus aureus bacteremia (SAB) generally presented with nonsevere signs and symptoms in sharp contrast to reports of adults with SAB. Despite incomplete adherence to current management guidelines, children with SAB did not experience mortality or relapse. Molecular characteristics of strains responsible for SAB in children were not significantly different than those described in adults. Improved outcomes in pediatric SAB compared with adults may most likely be attributed to less severe comorbidities in children. PMID- 21685216 TI - Role modeling at the bedside. PMID- 21685217 TI - Performance of the first Japanese large-scale facility for radon inhalation experiments with small animals. AB - A radon test facility for small animals was developed in order to increase the statistical validity of differences of the biological response in various radon environments. This paper illustrates the performances of that facility, the first large-scale facility of its kind in Japan. The facility has a capability to conduct approximately 150 mouse-scale tests at the same time. The apparatus for exposing small animals to radon has six animal chamber groups with five independent cages each. Different radon concentrations in each animal chamber group are available. Because the first target of this study is to examine the in vivo behaviour of radon and its effects, the major functions to control radon and to eliminate thoron were examined experimentally. Additionally, radon progeny concentrations and their particle size distributions in the cages were also examined experimentally to be considered in future projects. PMID- 21685218 TI - Natural radioactivity in granite stones used as building materials in Iran. AB - Due to increasing concern about environmental radiological protection, specific radioactivity concentrations of (226)Ra, (232)Th and (40)K in different types of commonly used granite stone samples collected from the Tehran city of Iran have been determined by means of a high-resolution HPGe gamma-spectroscopy system. The activity concentrations of (232)Th, (226)Ra and (40)K in the selected granite samples ranged from 18 to 178, 6 to 160 and 556 to 1539 Bq kg(-1), respectively. The radium equivalent activities (Ra(eq)) are lower than the limit of 370 Bq kg( 1) set by NEA-OECD [Nuclear Energy Agency. Exposure to radiation from natural radioactivity in building materials. Report by NEA Group of Experts. OECD (1979)], except in two samples. The internal hazard indexes have been found well below the acceptable limit in most of the samples. Five samples of investigated commercial granite stones do not satisfy the safety criterion illustrated by UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation. Exposure from natural sources of radiation. Report to the General Assembly (1993). Applying dose criteria recently recommended by the EC [European Commission Report on Radiological Protection Principles Concerning the Natural Radioactivity of Building Materials. Radiation Protection 112 (1999)] for superficial materials, all investigated samples meet the exemption dose limit of 0.3 mSv y(-1). PMID- 21685219 TI - Herpes simplex serious neurological disease in young children: incidence and long term outcome. AB - OBJECTIVE: To determine the contribution of herpes simplex virus (HSV) to serious neurological disease. SETTING AND PATIENTS: A 3-year prospective survey of children aged 2-23 months in Britain and Ireland. RESULTS: 19 children had HSV central nervous system (CNS) infection; 13 aged 2-11 months had focal neuroimaging abnormalities and 11 long-term neurological sequelae. Of six aged 12 35 months, one had abnormal neuroimaging and three long-term neurological sequelae. 17 of the 19 had serious neurological disease. HSV CNS infection accounted for 23% of serious neurological disease in children aged 2-11 months and 4.5% in older children. CONCLUSIONS: The incidence of HSV-induced serious neurological disease in the UK was estimated at 1 in 64 000/year in younger children and 1 in 230 000 in older children. HSV CNS infection has clinical effects ranging from frank encephalitis to severe illness with fever and convulsions to milder disease lacking encephalopathy. PMID- 21685220 TI - Is surgery indicated in patients with stage IIIa lung cancer and mediastinal nodal involvement? AB - The role of surgery in the treatment of patients with stage IIIa non-small cell lung cancer (NSCLC) and mediastinal node involvement is examined in this best evidence topic according to a structured protocol. A total of 579 papers were identified using the outlined search, 12 of which were deemed to represent the best available evidence. From the data summarized, we conclude that surgery, as part of a multimodality therapeutic approach, offers a survival benefit for patients with resectable N2 NSCLC. Overall five-year survival rates following primary resection ranged from 17% to 20% (four studies). Improved five-year survival was demonstrated with multimodality therapy (19-45%; 13 studies). Subgroup analysis demonstrates a five-year survival of 30.5% with postoperative chemo-radiotherapy, 22.2% with chemotherapy alone, and 27% with radiotherapy alone. In our review, we address three major issues regarding the management of stage IIIa NSCLC, the first of which is primary vs. postinduction surgery. The largest cohort series to date is the International Association for the Study of Lung Cancer Staging Committee paper on nodal disease, which reports that patients with single-zone N2 disease had the same survival outcome as patients with multizone N1 disease. The second issue is that of randomized vs. cohort studies: there have been five randomized trials reporting similar outcomes and hence equipoise. The third issue is postinduction staging. All studies evaluated reported a better outcome in patients with ypN0 (i.e. postinduction N0 disease). However, surgery should not be denied to patients with ypN1-N2, as there is evidence to demonstrate a significant improvement in survival time in all patients able to undergo surgery after induction chemo-radiotherapy. In conclusion, although some of the evidence available is equivocal regarding the survival benefit of resection for stage IIIa N2 disease, the authors believe surgery should be considered as part of a multimodality therapeutic strategy for patients with advanced nodal disease. PMID- 21685221 TI - Commentary: Non-communicable diseases in sub-Saharan Africa: a new global health priority and opportunity. PMID- 21685222 TI - Optimizing primary care telephone access and patient satisfaction. AB - Telephone medicine is often preferred by patients to meet primary care needs and may be associated with high patient satisfaction. This article presents findings about incoming patient calls to primary care for medically based reasons during office hours and reports factors independently associated with telephone encounter satisfaction, considering patient characteristics, call reasons, and staff responsiveness, for a national cohort of primary care users. Interviews were conducted with patients from 18 nationwide primary care clinics during the fall of 2009. Calling for an urgent medical issue was associated with dissatisfaction. Odds of call satisfaction were greater when patients thought staff was friendly (10*), call answer was timely (5*), and needed medical information was provided (7*). These findings can be used for interventions to optimize telephone access and patient satisfaction which is beneficial because satisfactory telephone encounters reduce primary care use and satisfied patients are more likely to be engaged in their health care. PMID- 21685224 TI - Chalk to iPod and local to global? Current trends in the education of professionals who work in child health settings. PMID- 21685223 TI - The links between religiosity, childhood sexual abuse, and subsequent marijuana use: an empirical inquiry of a sample of female college students. AB - A number of studies indicate that childhood sexual abuse (CSA) has a negative impact on later psychological well-being. It is well documented that experiences of CSA are associated with depression, self-destructiveness, and subsequent substance abuse or alcohol consumption. Compared with women who experienced no such sexual abuse in childhood, women who were victims of sexual abuse in childhood were more likely to be depressed and use drugs or consume alcohol in later life. Analyzing data of 1,569 females derived from the "Longitudinal Study of Violence Against Women," this study examines whether the strain caused by sexual victimization leads to a higher level of subsequent marijuana use and whether religiosity moderates the negative effects of CSA. It was found that CSA was associated with an increased level of marijuana use in high school. However, more proximate sexual victimization (victimization in college) seemed to override the impact of CSA on subsequent marijuana use. Religiosity was found to moderate the effect of CSA on marijuana use in high school. Religiosity was negatively associated with marijuana use in high school as well as the second and fourth collegiate years. Policy implications and promising directions for future research are discussed. PMID- 21685225 TI - The importance of including both a child perspective and the child's perspective within health care settings to provide truly child-centred care. AB - The UN Convention on the Rights of the Child (1989) asserts the right of every child to self-determination, dignity, respect, non-interference, and the right to make informed decisions. The provision of quality care in health services tailored to children's preferences means that health professionals have a responsibility to ensure children's rights, and that the child is encouraged and enabled to make his or her view known on issues that affect them. This paper will help illuminate and differentiate between a child perspective and the child's perspective in health care settings. The issues are supported with research which illustrates the different perspectives. Both perspectives are required to perceive and encounter children as equal human beings in child-centred health care settings. PMID- 21685226 TI - Behavioural treatments to encourage solo sleeping in pre-school children: an alternative to controlled crying. AB - Behavioural sleep treatments teach children to self soothe and sleep alone but often require a parent to ignore their child's cries for extended periods, a technique parents may find difficult. This paper presents a modified version of sleep training which aims to improve sleep but reduce crying in children and increase compliance in parents. Thirty-three children (Mean [SD] age = 27.01 [13.4] mths) from a clinical non-controlled population presenting with Behavioural Insomnia of Childhood, utilised a five-week sleep training method that teaches parents to gradually withdraw their assistance, allowing them to attend and calm their child whenever they choose and not to ignore their cries, components that differ from commonly utilised methods. Post treatment, all negative sleep associations, co-sleeping and family stress were reduced and all measures of sleep significantly improved: total night time sleep; time taken until sleep onset (SOL) and minutes awake during the night (WASO) (all p = < 0.002) with large treatment effects sizes (d = 0.94-1.85). Whilst the results are preliminary, this may offer an alternative method to explore in larger studies, given that many parents may have difficulty with ignoring the extended bouts of crying which often accompany commonly utilised sleep training methods. PMID- 21685227 TI - Sex differences in parental reaction to pediatric illness. AB - The 'Tend-and Befriend' hypothesis claims that whereas the response of males to stress is Fight-or-Flight, females respond with Tend-and-Befriend. We tested this hypothesis with a sample of 110 couples whose children had undergone neurosurgery. Both mothers and fathers answered questionnaires measuring levels of tending, befriending, stress, anxiety, and depression. As hypothesized, mothers scored higher than fathers did on all measures. However, according to the Tend-and Befriend hypothesis, the sex difference in tending and befriending should be more pronounced in couples suffering from high-stress in comparison to couples suffering from low-stress. This hypothesis was not supported by the data. We suggest that the heightened tending and befriending of women is not a reaction to stress, instead it is a persistent maternal characteristic. Moreover, we suggest that maternal anxiety and depression result from a heightened maternal sensitivity, selected for caregiving. The study results imply that support interventions should be aimed mostly at mothers, since they experience more distress, in comparison to fathers. PMID- 21685228 TI - Children with co-morbid recurrent abdominal pain and anxiety disorders: results from a multiple-baseline intervention study. AB - Recurrent Abdominal Pain (RAP), one of the most common complaints of childhood, is associated with many adverse outcomes. However, few treatment studies have been conducted, especially for children with co-morbid RAP and anxiety disorders. The primary aim of the present study was to explore the utility of a cognitive behavioral treatment (CBT) and a treatment that combined both CBT and family based approaches in a community sample of children with co-morbid anxiety and RAP. A multiple-baseline across participants design utilizing repeated measures of anxiety and pain was implemented (n = 8 families). An examination of the clinical significance of both treatment approaches is suggestive of their utility in the treatment of anxiety and pain symptoms in children with RAP. More research is warranted in RAP treatment outcome research, particularly with family-based approaches to treatment. PMID- 21685229 TI - Why is it not working? Identifying barriers to the therapy of paediatric obesity in an intercultural setting. AB - Given the high overweight prevalence among children with a migration background in Germany, this paper describes barriers to the treatment of paediatric obesity in a specialized clinic providing services to an ethnically diverse population. In a cross-sectional mixed-method design, a two-week participant observation was followed by a cultural competence survey among the healthcare professionals employed at the clinic. The present study revealed barriers related to all categories of social actors involved in the therapy process. A major difficulty encountered by providers when working with ethnically diverse patients was the lack of mutual understanding, often associated with language barriers. Language barriers were most prevalent between providers and ethnically diverse mothers. Targeted education programs for adults (particularly women) with a migration background and cultural competence training for healthcare providers are needed in Germany. Special attention should be paid to scheduling appointments and enhancing patients' engagement in the therapy process. PMID- 21685230 TI - Incorporation of an interferon-beta neutralizing antibody assay into routine clinical practice. AB - BACKGROUND: Incorporation of routine clinical testing for neutralizing antibodies (NAbs) to interferon (IFN)-beta has remained problematic. With increasing treatment choice for patients, routine NAb testing should be incorporated to aid therapeutic decisions. OBJECTIVE: We sought to improve interpretation of NAb results by combining the luciferase NAb assay (luciferase gene expression assay under control of interferon-stimulated response element) and in-vivo biomarker (myxovirus A protein, MxA) induction in patients with MS. METHODS: Blood samples (serum and PAXGene((r)) for RNA) were obtained pre-injection and 12 hours post injection of IFN-beta from 144 subjects. Sera were tested for NAbs using the luciferase assay. MxA expression was quantified by real-time polymerase chain reaction (PCR). RESULTS: 26% of samples were NAb positive (titre > 20 NU). There was no difference in NAb titres in the pre- or post-dose sera (p = 0.643). MxA expression was inhibited in a dose-dependent fashion in NAb positive samples. Mean MxA level post-IFN-beta: NAb negative 2330 (95% CI 1940-2719), NAb 20-99 NU 1533 (95% CI 741-2324), NAb 100-600 NU 832 (186-1478) and NAb > 600 NU 101 (95% CI 0-224). NAb titre and MxA level correlated strongly: MxA pre- (Spearman r = 0.72, p < 0.0001), MxA post- (Spearman r = -0.79, p < 0.0001) and MxA induction (Spearman r = -0.67, p = 0.0004). CONCLUSION: A single, 12-hour post-injection sample should be used to test for NAbs using the luciferase assay and IFN-beta bioactivity (MxA) in the clinical setting. PMID- 21685231 TI - Cognitive dysfunction and multiple sclerosis: developing a rationale for considering the efficacy of exercise training. AB - Cognitive impairment is a prevalent, disabling, and poorly managed consequence of multiple sclerosis (MS). This underscores the importance of considering alternative approaches, such as exercise training, for managing cognitive impairment in persons with MS. The consideration of exercise training is warranted based on evidence summarized in literature reviews and meta-analyses that (1) aerobic fitness, physical activity, and exercise training are associated with better cognitive function in older adults; and (2) exercise training has comparable effects on mobility and quality of life outcomes in older adults and persons with MS. To date, research examining aerobic fitness, physical activity, and exercise training effects on cognition in MS is nascent and mostly includes cross-sectional designs that provide preliminary evidence for a well-designed randomized controlled trial (RCT). We believe that a future RCT should adopt research methodologies and practices from gerontology when examining exercise training and cognition in MS. This will maximize the potential for successfully generating a body of knowledge on exercise training and cognition with the potential for impacting the lives of persons with MS. PMID- 21685232 TI - Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel. AB - BACKGROUND: Elevated Epstein-Barr virus (EBV) antibody titers are risk factors for multiple sclerosis (MS), but the strength and consistency of this association are not well characterized. OBJECTIVES: The objectives of this study were to determine whether this association is confounded by vitamin D or modified by gender or race, and the usefulness of EBV nuclear antigen (EBNA) antibodies as a marker for MS. METHODS: We conducted a prospective study among US military personnel. Antibody titers against EBV antigens were measured in serum samples from 222 individuals who developed MS and 444 age, sex, and race/ethnicity matched controls. Conditional logistic regression was used to estimate relative risks. RESULTS: MS risk increased with increasing titers of anti-EBNA complex (p < 10(-9)) and anti-EBNA-1 (p = 5.8 * 10(-9)) titers. MS risk was 36-fold higher among individuals with anti-EBNA complex IgG titers >=320 than among those with titers <20 (95% confidence interval [CI] 9.6-136), and 8-fold higher among those with anti-EBNA-1 >=320 than among those with anti-EBNA-1 <20 (95% CI 2.6-23). These associations were consistent across gender and race/ethnicity groups and independent from 25-hydroxyvitamin D levels. Areas under the receiver operating characteristic (ROC) curves were 0.67 for EBNA complex and 0.65 for EBNA-1. CONCLUSIONS: Serum titers of pre-onset anti-EBNA antibodies are strong, robust markers of MS risk and could be useful in an MS risk score. PMID- 21685233 TI - Leber's hereditary optic neuropathy associated with a multiple-sclerosis-like picture in a man. AB - A 35-year-old young man displayed Leber's optic neuropathy (LHON) due to T14484C and multiple sclerosis (MS) phenotype that was dominated by symptoms and signs of spinal cord impairment. Magnetic resonance imaging (MRI) revealed demyelinating lesions extending from D6 to D11 in the spinal cord with gadolinium enhancement, while only three linear demyelinating lesions were seen on brain MRI. In the literature, a major involvement of the spinal cord was already reported in three of four male patients with the 14484 LHON mutation who developed MS, but the reasons of this peculiar association remain unknown, and further research in this area is needed. PMID- 21685234 TI - Anthropometric measures, physical activity, and risk of glioma and meningioma in a large prospective cohort study. AB - Body fatness has been associated with increased risk of a number of hormone dependent cancers. Recent studies suggest that body mass index (BMI) may be related to meningiomas, which are more common in women than men, and for which estrogens are believed to play a role. Using data from a large European propective cohort, 203 incident cases of meningioma and 340 cases of glioma were included in the analysis for measures of body fat, height, and physical activity among 380,775 participants. All analyses were conducted using Cox proportional hazards model and controlling for age, sex, country, and education. A 71% increase in risk of meningioma was observed among men and women in the top quartile of waist circumference (HR = 1.71, 95% CI = 1.08-2.73, P(trend) = 0.01). A positive association was also observed for BMI and meningioma (HR = 1.48, 95% CI = 0.98-2.23, for BMI >=30 compared with a BMI of 20-24.9, P(trend) = 0.05). An association with height and meningioma was also suggestive (HR = 1.24, 95% 0.96 1.51, for each 10 cm increase). In contrast, no associations were observed for height and different measures of body fat and risk of glioma. Physical activity was not related to either type of brain tumors. Results from this study support an increase in risk of meningioma with higher body fatness among both men and women. No association was observed between anthropometric measures and risk of glioma. PMID- 21685235 TI - Lapatinib activity in premalignant lesions and HER-2-positive cancer of the breast in a randomized, placebo-controlled presurgical trial. AB - Dual epidermal growth factor receptor (EGFR) and HER2 targeting with the tyrosine kinase inhibitor lapatinib is approved for treating advanced HER2-positive breast cancer and can prevent estrogen receptor (ER)-negative mammary tumors in HER2 transgenic mouse models. Ki-67 labeling index (LI) has prognostic and predictive value and can be used to screen drugs' therapeutic and preventive potential in a clinical model of short-term presurgical therapy of breast cancer. We conducted a randomized, placebo-controlled trial of lapatinib (1500 mg/d) administered orally for three weeks between biopsy and surgery in 60 women with HER-2-positive breast cancer to assess lapatinib biomarker (including the primary endpoint, Ki-67 LI) and clinical activity in invasive breast cancer, adjacent ductal intraepithelial neoplasia (DIN, which comprises ductal carcinoma in situ and atypical ductal hyperplasia), and distant ductal hyperplasia without atypia (DH). Ki-67 LI increased progressively in association with disease stage, increasing in the placebo arm, for example, by medians of 3% in DH to 20% in DIN to 30% in invasive cancer. Ki-67 LI in cancer tissue decreased by a mean (+/-SD) of 9.3% (+/-34.2) in the lapatinib arm and increased by 15.1% (+/-30.9) in the placebo arm (P = 0.008). Compared with placebo, lapatinib reduced Ki-67 significantly more in ER negative tumors (by 34.8%; P = 0.01) but not significantly more in ER-positive tumors (by 12.3%; P = 0.2) and reduced Ki-67 more (nonsignificantly) in cytosol PTEN-overexpressing tumors (P = 0.057). The prevalence of DIN in post-treatment surgical specimens of both arms was similar (70%-76%), with a median Ki-67 of 15% (range, 5%-35%) on lapatinib versus 20% (5%-60%) on placebo (P = 0.067). The prevalence of DH also was similar in both arms (>90%), with a median Ki-67 of 1% (1%-7%) on lapatinib versus 3% (1%-5%) on placebo (P = 0.006). Other results of lapatinib versus placebo, respectively, were as follows: Median tumor diameter at surgery of 18 mm (11 mm-57 mm) versus 24 mm (10 mm-37 mm; P = 0.009); partial response of 13.6% versus 3.7%, stable disease of 59.1% versus 40.7%, and progression of 27.3% versus 55.6% (P-trend = 0.035). In conclusion, short-term lapatinib decreased cell proliferation in DIN, DH, and invasive HER-2-positive (especially ER-negative) breast cancer, thus providing the rationale for further clinical development of lapatinib for breast cancer prevention in high-risk patients, including those with HER-2-positive DIN. PMID- 21685236 TI - Iron homeostasis and distal colorectal adenoma risk in the prostate, lung, colorectal, and ovarian cancer screening trial. AB - Red meat consumption has been positively associated with colorectal cancer; however, the biological mechanism underlying this relationship is not understood. Red meat is a major source of iron, which may play a role in colorectal carcinogenesis via increased crypt cell proliferation, cytotoxicity, and endogenous N-nitrosation. In a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we prospectively evaluated multiple iron exposure parameters, including dietary intake and serum measures of iron, ferritin, transferrin, total iron binding capacity (TIBC), and unsaturated iron binding capacity (UIBC) in relation to incident colorectal adenoma in 356 cases and 396 matched polyp-free controls. We also investigated variation in eight key genes involved in iron homeostasis in relation to colorectal adenoma in an additional series totaling 1,126 cases and 1,173 matched controls. We observed a positive association between red meat intake and colorectal adenoma [OR comparing extreme quartiles (OR(q4-q1)) = 1.59, 95% CI = 1.02-2.49, P(trend) = 0.03]. Serum TIBC and UIBC were inversely associated with colorectal adenoma (OR(q4-q1) = 0.57, 95% CI = 0.37-0.88, P(trend) = 0.03; and OR(q4-q1) = 0.62, 95% CI = 0.40-0.95, P(trend) = 0.04, respectively). Colorectal adenoma was not associated with serum ferritin, iron, or transferrin saturation or with polymorphisms in genes involved in iron homeostasis. Serum TIBC and UIBC, parameters that have a reciprocal relationship with overall iron load, were inversely related to colorectal adenoma, suggesting that individuals with lower iron status have a reduced risk of developing colorectal adenoma. PMID- 21685237 TI - Biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomal cisplatin administered in Ehrlich tumor-bearing mice. AB - Cisplatin (CDDP) is one of the most active cytotoxic agents and has been widely used in the treatment of peritoneal carcinomatosis by the intraperitoneal (i.p.) route. However, CDDP, a low-molecular-weight compound, is rapidly absorbed by the capillaries in the i.p. serosa and transferred to the bloodstream, inducing the appearance of systemic side-effects, such as nephrotoxicity. Furthermore, the i.p. CDDP chemotherapy is limited to patients whose residual tumor nodules are less than 0.5 cm in diameter after surgical debulking. The failure of i.p. therapy is attributed to the poor penetration of CDDP into larger tumors. One strategy to improve drug delivery in the peritoneal region and reduce toxicity is the use of drug delivery systems. The objective of the present work was to evaluate the biodistribution and antitumoral effect of long-circulating and pH sensitive liposomes containing CDDP (SpHL-CDDP), as compared with free CDDP, after their i.p. administration in Ehrlich ascitic tumor-bearing mice. After administering a 6 mg/kg single i.p. bolus injection of either free CDDP or SpHL CDDP, ascitic fluid (AF), blood and organs (kidneys, liver, spleen and lungs) were collected and analyzed for CDDP content. The area under the CDDP concentration-time curve (AUC) obtained for AF and blood after SpHL-CDDP administration was 3.3-fold larger and 1.3-fold lower, respectively, when compared with free CDDP treatment, thus indicating its high retention within the peritoneal cavity. The determination of the ratio between AUC in each tissue and that in blood (Kp) showed a lower accumulation of CDDP in kidneys after SpHL-CDDP treatment. The SpHL-CDDP treatment demonstrated a significant uptake by the liver and spleen. SpHL-CDDP treatment led to a higher survival rate of mice with initial or disseminated peritoneal carcinomatosis than CDDP treatment. These results indicate that SpHL-CDDP may be useful for i.p. chemotherapy due to their greater concentration in the peritoneal cavity. PMID- 21685238 TI - New rat models of iron sucrose-induced iron overload. AB - The majority of murine models of iron sucrose-induced iron overload were carried out in adult subjects. This cannot reflect the high risk of iron overload in children who have an increased need for iron. In this study, we developed four experimental iron overload models in young rats using iron sucrose and evaluated different markers of iron overload, tissue oxidative stress and inflammation as its consequences. Iron overload was observed in all iron-treated rats, as evidenced by significant increases in serum iron indices, expression of liver hepcidin gene and total tissue iron content compared with control rats. We also showed that total tissue iron content was mainly associated with the dose of iron whereas serum iron indices depended essentially on the duration of iron administration. However, no differences in tissue inflammatory and antioxidant parameters from controls were observed. Furthermore, only rats exposed to daily iron injection at a dose of 75 mg/kg body weight for one week revealed a significant increase in lipid peroxidation in iron-treated rats compared with their controls. The present results suggest a correlation between iron overload levels and the dose of iron, as well as the duration and frequency of iron injection and confirm that iron sucrose may not play a crucial role in inflammation and oxidative stress. This study provides important information about iron sucrose-induced iron overload in rats and may be useful for iron sucrose therapy for iron deficiency anemia as well as for the prevention and diagnosis of iron sucrose-induced iron overload in pediatric patients. PMID- 21685239 TI - Bifidobacterium longum supplementation improved high-fat-fed-induced metabolic syndrome and promoted intestinal Reg I gene expression. AB - Recent evidence suggests that intestinal Bifidobacterium species (spp.) positively correlates with improved insulin resistance and obesity, and this might be linked to metabolic inflammation. The expression of intestinal REG (regenerating) family proteins which are widely involved in inflammatory bowel disease and diabetes are still unknown in metabolic syndrome. Hence, we investigated the effects of Bifidobacterium longum (BIF) supplementation on metabolic parameters, intestinal function and expression of Reg family genes in a rat model of metabolic syndrome induced by a high-fat (HF) diet. We specifically increased the gut bifidobacterial content of HF-fed rats through BIF supplementation. Compared with the normal chow-fed control rats, HF feeding significantly reduced intestinal Bifidobacterium. As expected, BIF supplementation fed rats had totally restored quantities of Bifidobacterium. HF diet-fed rats showed significant increase in body weight, fat deposits, systolic blood pressure, fasting glucose, fasting triglycerides and reduced insulin sensitivity, while increases of intestinal Bifidobacterium did improve HF-diet induced metabolic disorders. HF feeding led to significantly higher levels of the plasma lipopolysaccharide, interleukin-1beta and intestinal myeloperoxidase, as well as intestinal inflammatory activity index, while these parameters were normalized to the control levels in the HF + BIF-treated rats. The levels of RegI mRNA and protein in the HF + BIF group were significantly higher than the control and the HF groups. Increasing Bifidobacterium in the gut improved HF-fed-induced metabolic syndrome by reducing metabolic endotoxin concentrations and intestinal inflammation, as well as upgrading the expression of intestinal Reg I as a regulator of growth factor. PMID- 21685240 TI - Low-dose naltrexone suppresses ovarian cancer and exhibits enhanced inhibition in combination with cisplatin. AB - Ovarian cancer is the leading cause of death from gynecological malignancies. Although initial therapeutic modalities are successful, 65% of these women relapse with only palliative treatments available thereafter. Endogenous opioids repress the proliferation of human ovarian cancer cells in vitro, and do so in a receptor-mediated manner. The present study examined whether modulation of opioid systems by the opioid antagonist naltrexone (NTX), alone or in combination with standard of care therapies (taxol/paclitaxel, cisplatin), alters human ovarian cancer cell proliferation in tissue culture and tumor progression in mice. Administration of NTX for six hours every two days, but not continuously, reduced DNA synthesis and cell replication from vehicle-treated controls in tissue culture. Moreover, brief exposure to NTX in combination with taxol or cisplatin had an enhanced anticancer action. Mice with established ovarian tumors and treated with a low dosage of NTX (LDN), which invokes a short period of opioid receptor blockade, repressed tumor progression in a non-toxic fashion by reducing DNA synthesis and angiogenesis but not altering cell survival. The combination of LDN with cisplatin, but not taxol, resulted in an additive inhibitory effect on tumorigenesis with enhanced depression of DNA synthesis and angiogenesis. LDN combined with cisplatin alleviated the toxicity (e.g. weight loss) associated with cisplatin. LDN treatment upregulated the expression of the opioid growth factor (OGF, chemical term ([Met(5)]-enkephalin) and its receptor, OGFr. Previous tissue culture studies have reported that OGF is the only opioid peptide with antiproliferative activity on ovarian cancer cells, with OGF action mediated by OGFr. Thus, the common denominator of intermittent opioid receptor blockade by short-term NTX or LDN on ovarian cancer proliferation and tumorigenesis recorded herein appears to be related to the OGF-OGFr axis. These preclinical data may offer a non-toxic and efficacious pathway-related treatment that can benefit patients with ovarian cancer. PMID- 21685241 TI - Human immunodeficiency virus transgenic rats exhibit pulmonary hypertension. AB - Human immunodeficiency virus (HIV)-associated pulmonary arterial hypertension (PAH) is a serious noninfectious disease involving an aberrant increase in pressure in the blood vessels of the lung, which leads to right ventricular (RV) heart failure and can eventually result in death. A lack of viable animal models of HIV-PAH has limited the identification of signaling pathways involved in HIV mediated onset and progression of PAH. To determine whether the HIV-1 transgenic (HIV Tg) rat displays pathophysiological end points associated with PAH, we evaluated peak RV systolic pressure (RVSP), RV hypertrophy, pulmonary vessel remodeling, and alterations in gene expression by real-time PCR and microarray. RVSP was measured by RV catheterization via the right jugular vein in 3- and 9-mo old HIV Tg and age-matched Fischer 344 (control) male rats while under 2% isoflurane anesthesia. RVSP was elevated in the HIV Tg rats (34.2 +/- 2.5 mmHg) compared with the F344 controls (21.2 +/- 2.5 mmHg), with more significant elevations in the 9-mo-old HIV Tg rats (42.5 +/- 3.7 mmHg). We observed significant increases in RV wall thickness in HIV Tg rats compared with controls, both histologically and by echocardiograph measurement. HIV Tg rats also show increased thickening of the pulmonary artery and remodeling of small pulmonary arteries, as well as altered expression of gene pathways associated with PAH. These data represent the first analysis of PAH in HIV Tg rats and suggest that this model will be useful for investigating pathways and identifying potential therapies for HIV-PAH. PMID- 21685242 TI - TGF-beta2 reduces nitric oxide synthase mRNA through a ROCK-dependent pathway in airway epithelial cells. AB - Exhaled NO (eNO) is a potential noninvasive biomarker of inflammation in asthma. The significant intersubject variability of eNO within clinically similar patients has contributed to its limited clinical application. Arginase and NO synthase (NOS) utilize the same substrate (l-arginine) and contribute to the fibrotic and inflammatory features of asthma, respectively. Interestingly, TGF beta(2) can increase the expression of arginase, stimulates fibrosis, and is overexpressed in asthma. We hypothesized that TGF-beta(2)-enhanced arginase activity would decrease gas phase NO release from lung epithelial cells by limiting l-arginine availability for NOS. Our results show that TGF-beta(2) (5 ng/ml) significantly enhances total arginase activity up to two- to threefold in both primary small airway epithelial cells (SAECs) and the A549 cell line. Preincubation with TGF-beta(2) prior to cytokine (IL-1beta, TNF-alpha, and IFN gamma, 10 ng/ml each) stimulation decreases gas phase NO release to baseline levels (from 1.66 +/- 0.52 to 0.30 +/- 0.12 pl.s(-1).cm(-2) and from 0.27 +/- 0.03 pl.s(-1).cm(-2) to near zero in SAEC and A549 cells, respectively). Addition of arginase inhibitor (N(omega)-hydroxy-nor-l-arginine) or small interfering RNA only partly reverses the reduction. In contrast, Rho-kinase (ROCK) pathway inhibitor (Y-27632) completely recovers the cytokine-induced NO flux in the present of TGF-beta(2). Inducible NO synthase (iNOS) mRNA and protein levels change in a similar trend as NO release from the cells. We conclude that TGF beta(2) impacts cytokine-induced NO production in airway epithelial cells by reducing iNOS mRNA and protein levels through a ROCK-dependent pathway. PMID- 21685243 TI - The Janus-faced regulation of endothelial permeability by cyclic GMP. PMID- 21685244 TI - CD82 gene suppression in endometrial stromal cells leads to increase of the cell invasiveness in the endometriotic milieu. AB - Tetraspanin CD82 is a wide-spectrum tumor metastasis suppressor that inhibits motility and invasiveness of cancer cells. Endometriosis is a benign gynecological disorder, but appears malignant behaviors including invasion, ectopic implantation and recurrence. This study is to elucidate the role of CD82 expression regulation in the pathogenesis of endometriosis. The short interfering RNA silence was established to analyze the roles of CD82, chemokine CCL2, and its receptor CCR2 in the invasiveness of endometrial stromal cells (ESCs). We have found that the mRNA and protein levels of CD82 in the primary normal ESCs from endometrium without endometriosis are significantly higher than that of the primary ESCs from eutopic endometrium and ectopic tissue. CD82 inhibits the invasiveness of ESCs by downregulating CCL2 secretion and CCR2 expression via mitogen-activated protein kinase (MAPK) and integrinbeta1 signal pathway, and in turn upregulating the expression of TIMP1 and TIMP2 in an autocrine manner. The combination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with 17beta-estradiol can promote the invasion of ESCs via suppressing CD82 expression and stimulating CCL2 secretion and CCR2 expression, and the enhanced interaction of CCL2-CCR2 recruits more macrophages into the ectopic milieu in a paracrine manner, which further downregulates CD82 expression in the ectopic ESCs. Our study has demonstrated for the first time that the abnormal lower CD82 expression in ESCs induced by TCDD and estrogen may be an important molecular basis of endometriosis pathogenesis through enhancing the CCL2 secretion and CCR2 expression and the invasion of ESCs via MAPK and integrinbeta1 signal pathway. PMID- 21685245 TI - Preclinical disposition (in vitro) of novel MU-opioid receptor selective antagonists. AB - Recently, two novel N-heterocyclic derivatives of naltrexone [designated 17 cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6beta-[(4' pyridyl)acetamido]morphinan (NAP) and 17-cyclopropylmethyl-3,14beta-dihydroxy 4,5alpha-epoxy-6alpha-[(3'-isoquinolyl) acetamido]morphinan (NAQ)] have been proposed as MU-opioid receptor (MOR) selective antagonists. The goal of this study was to examine their absorption and metabolism. The bidirectional transport of NAP and NAQ was determined in Caco-2 and MDCKII-MDR1 cells, and the permeability directional ratio (PDR) was estimated (PDR = P(app, B-A)/P(app, A B), where P(app) is the apparent permeability, A is apical, and B is basolateral). Oxidative metabolism of NAQ (0.5-80 MUM) and NAP (0.5-30 MUM) was determined in pooled human liver microsomes. The reaction monitored the disappearance of NAQ/NAP. NAP and NAQ were quantitated by high-performance liquid chromatography-UV at 270 or 232 nm, respectively. The permeability of NAQ or NAP was similar to that of naltrexone or paracellular markers, respectively. NAP also exhibited a high PDR and was determined to be a P-glycoprotein (P-gp) substrate. Unbound fractions in human plasma for NAQ and NAP were 0.026 +/- 0.019 and 0.85 +/- 0.12, respectively. The metabolic oxidative reaction rates, fitted to a Michaelis-Menten model, yielded K(m) and V(max) values of 15.8 +/- 5.5 MUM and 192 +/- 24 pmol/min for NAQ and 1.8 +/- 1.5 MUM and 8.1 +/- 1.4 pmol/min for NAP. Intrinsic hepatic clearance was estimated to be 13 and 5 ml . min(-1) . kg(-1) for NAQ and NAP, respectively. Neither NAQ nor NAP underwent detectable glucuronidation. Thus, NAP was a P-gp substrate with low apparent permeability, whereas NAQ was not a P-gp substrate and showed better permeability. Therefore, in contrast to NAP, NAQ would be more suitable for oral absorption and penetration of the blood-brain barrier, yielding potential pharmacokinetic and pharmacodynamic advantages over naltrexone. PMID- 21685246 TI - SHIP-deficient, alternatively activated macrophages protect mice during DSS induced colitis. AB - mphi are heterogeneous in their functions, and although it is clear that inflammatory mphi contribute to inflammation in IBDs, multiple lines of evidence suggest that M2a mphi may offer protection during intestinal inflammation. In vivo SHIP-deficient mouse mphi are M2a so SHIP-deficient mice provide a unique genetic model of M2a mphi. Based on this, this study tested the hypothesis that SHIP-deficient, M2a mphi protect mice from intestinal inflammation. The objectives were to compare the susceptibility of SHIP+/+ and SHIP-/- littermates with DSS-induced intestinal inflammation and to determine whether protection was mphi-mediated and whether protection could be transferred to a susceptible host. We have found that SHIP-/- mice are protected during DSS-induced intestinal inflammation. SHIP-/- mice have delayed rectal bleeding and reduced weight loss, disruption of intestinal architecture, and immune cell infiltration during DSS induced colitis relative to their WT littermates. Using liposome depletion of mphi, we found that SHIP-/- mouse protection was indeed mphi-mediated. Finally, we determined that SHIP-/- mphi-mediated protection could be conferred to susceptible WT mice by adoptive transfer of M2a mphi derived ex vivo. This study supports our hypothesis by demonstrating that SHIP-deficient, M2a mphi are protective in this murine model of acute intestinal inflammation. Adoptive transfer of M2a mphi to patients with IBDs offers a promising, new strategy for treatment that may be particularly useful in patients who are otherwise refractory to conventional therapies. PMID- 21685247 TI - Lutzomyia longipalpis saliva drives apoptosis and enhances parasite burden in neutrophils. AB - Neutrophils are considered the host's first line of defense against infections and have been implicated in the immunopathogenesis of Leishmaniasis. Leishmania parasites are inoculated alongside vectors' saliva, which is a rich source of pharmacologically active substances that interfere with host immune response. In the present study, we tested the hypothesis that salivary components from Lutzomyia longipalpis, an important vector of visceral Leishmaniasis, enhance neutrophil apoptosis. Murine inflammatory peritoneal neutrophils cultured in the presence of SGS presented increased surface expression of FasL and underwent caspase-dependent and FasL-mediated apoptosis. This proapoptosis effect of SGS on neutrophils was abrogated by pretreatment with protease as well as preincubation with antisaliva antibodies. Furthermore, in the presence of Leishmania chagasi, SGS also increased apoptosis on neutrophils and increased PGE(2) release and decreased ROS production by neutrophils, while enhancing parasite viability inside these cells. The increased parasite burden was abrogated by treatment with z-VAD, a pan caspase inhibitor, and NS-398, a COX-2 inhibitor. In the presence of SGS, Leishmania-infected neutrophils produced higher levels of MCP-1 and attracted a high number of macrophages by chemotaxis in vitro assays. Both of these events were abrogated by pretreatment of neutrophils with bindarit, an inhibitor of CCL2/MCP-1 expression. Taken together, our data support the hypothesis that vector salivary proteins trigger caspase-dependent and FasL mediated apoptosis, thereby favoring Leishmania survival inside neutrophils, which may represent an important mechanism for the establishment of Leishmania infection. PMID- 21685249 TI - CXCR4 antagonism attenuates the cardiorenal consequences of mineralocorticoid excess. AB - BACKGROUND: Extensive evidence implicates aldosterone excess in the development and progression of cardiovascular disease states including hypertension, metabolic syndrome, cardiac hypertrophy, heart failure, and cardiorenal fibrosis. Recent studies show that activation of inflammatory cascade may play a specific role in the sequelae of mineralocorticoid activation, although the linking mechanism remains unclear. We tested the possibility that secondary stimulation of the stromal-derived factor 1/CXC chemokine receptor 4 (SDF-1/CXCR4) pathway plays a contributory role. METHODS AND RESULTS: We investigated the effect of the highly selective CXCR4 antagonist AMD3465 (6 mg/kg per day for 6 weeks through minipump) in dexoycorticosterone acetate (DOCA)-treated, uninephrectomized mice. CXCR4 antagonism significantly attenuated the induction of cardiac fibrosis, renal fibrosis, hypertension, and left ventricular hypertrophy by DOCA. Mineralocorticoid excess also stimulated the accumulation of T-lymphocytes in the heart and kidney and this was significantly blunted by CXCR4 inhibition. CONCLUSIONS: Taken together, these data strongly implicate the SDF-1/CXCR4 axis in the pathogenesis of mineralocorticoid excess induced hypertension, inflammation, and cardiorenal fibrosis. This insight provides a new potential therapeutic approach for the treatment of specific aspects of mineralocorticoid mediated cardiovascular disease. PMID- 21685248 TI - Toll-like receptor activation and hypoxia use distinct signaling pathways to stabilize hypoxia-inducible factor 1alpha (HIF1A) and result in differential HIF1A-dependent gene expression. AB - HIF1A is a transcription factor that plays a central role for the adaptation to tissue hypoxia and for the inflammatory response of myeloid cells, including DCs. HIF1A is stabilized by hypoxia but also by TLR ligands under normoxic conditions. The underlying signaling events leading to the accumulation of HIF1A in the presence of oxygen are still poorly understood. Here, we show that in contrast to hypoxic stabilization of HIF1A, normoxic, TLR-mediated HIF1A accumulation in DCs follows a different pathway that predominantly requires MYD88-dependent NF-kappaB activity. The TLR-induced HIF1A controls a subset of proinflammatory genes that are insufficiently induced following hypoxia-mediated HIF1A induction. Thus, TLR activation and hypoxia stabilize HIF1A via distinct signaling pathways, resulting in differential HIF1A-dependent gene expression. PMID- 21685250 TI - Tobacco smoking and cutaneous squamous cell carcinoma: a 16-year longitudinal population-based study. AB - BACKGROUND: Although tobacco smoking is commonly cited as a risk factor for cutaneous squamous cell carcinoma (SCC), the evidence from previous clinical and case-control studies is conflicting. We therefore aimed to prospectively examine the role of tobacco smoking in the development of SCC of the skin in a population based study. METHODS: Study participants were 1,287 adults aged 25 to 75 years in 1992, randomly selected from the Nambour community, with no previous history of SCC. Standard skin pigment and sun-sensitivity profiles were obtained at baseline. Detailed prospective information on sun exposure, smoking, and skin cancer occurrence (histologically confirmed) was collected over a 16-year period, 1992 to 2007. RESULTS: Of 1,287 participants, 43% were male and average age was 48 years. A total of 188 first cutaneous SCCs were identified during the study period. After adjustment for other known risk factors, neither former nor current smokers were at raised risk of SCC: relative risk (RR) = 1.1, 95% CI: 0.8-1.5 and RR = 1.1, 95% CI: 0.7-1.5, respectively, compared with lifelong nonsmokers, nor were there any dose-response relationships with amount smoked or duration of smoking and risk of SCC. CONCLUSIONS: In this Australian follow-up study, tobacco smoking did not increase the risk of SCC of the skin. IMPACT: These prospective adjusted data provide strong evidence which suggests that cutaneous SCC should not be on the list of tobacco-related cancers. PMID- 21685251 TI - Gulosibacter chungangensis sp. nov., an actinomycete isolated from a marine sediment, and emended description of the genus Gulosibacter. AB - A gram-positive, strictly aerobic, non-spore-forming, irregular short rod, strain CAU 9625(T), was isolated from a sediment of the Yellow Sea in the Republic of Korea. Strain CAU 9625(T) grew optimally at 37 degrees C, at pH 8.0 and in the presence of 1 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain CAU 9625(T) belonged to the genus Gulosibacter, which has one known member, Gulosibacter molinativorax. Strain CAU 9625(T) and G. molinativorax ON4(T) shared 97.8 % 16S rRNA gene sequence similarity and formed a distinct cluster (99 % bootstrap support) within the family Microbacteriaceae. DNA-DNA relatedness between strain CAU 9625(T) and G. molinativorax DSM 13485(T) was 35.4+/-0.9 %. The predominant menaquinone was MK-9. The major whole-cell sugars were ribose and glucose. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, an unidentified phospholipid and an unidentified lipid. The fatty acid composition was similar to that of G. molinativorax DSM 13485(T), with anteiso-C(15 : 0) as the predominant fatty acid. The DNA G+C content of strain CAU 9625(T) was 66.2 mol%. The phylogenetic and genetic distinctiveness and several differentiating phenotypic and chemotaxonomic properties revealed that strain CAU 9625(T) was distinguishable from G. molinativorax and other phylogenetic neighbours. On the basis of these data, strain CAU 9625(T) represents a novel species of the genus Gulosibacter, for which the name Gulosibacter chungangensis sp. nov. is proposed. The type strain is CAU 9625(T) ( = KCTC 13959(T) = CCUG 60841(T)). PMID- 21685252 TI - Inhella fonticola sp. nov., isolated from spring water, and emended description of the genus Inhella. AB - A yellow-pigmented bacterial strain designated TNR-25(T) was isolated from spring water in Taiwan and was characterized using a polyphasic taxonomic approach. Strain TNR-25(T) was gram-negative, obligately aerobic, rod-shaped, non-motile and non-spore-forming. Growth occurred at 15-40 degrees C (optimum, 25 degrees C), at pH 6.0-10.0 (optimum, pH 7.0) and with 0-0.5 % NaCl (optimum, 0 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain TNR 25(T) belonged to the genus Inhella and its closest neighbour was Inhella inkyongensis IMCC1713(T) with 98.1 % sequence similarity. The major fatty acids (>10 %) of strain TNR-25(T) were summed feature 3 (comprising C(16 : 1)omega7c and/or C(16 : 1)omega6c) and C(16 : 0). The major cellular hydroxy fatty acids were C(10 : 0) 3-OH and C(12 : 0) 3-OH. The isoprenoid quinone was Q-8 and the DNA G+C content was 69.6 mol%. The polar lipid profile consisted of a mixture of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, diphosphatidylglycerol and several uncharacterized phospholipids. The DNA-DNA relatedness between strain TNR-25(T) and I. inkyongensis IMCC1713(T) was about 30.6-35.5 %. On the basis of the genotypic and phenotypic data, strain TNR-25(T) represents a novel species in the genus Inhella, for which the name Inhella fonticola sp. nov. is proposed; the type strain is TNR-25(T) ( = BCRC 80211(T) = LMG 25721(T)). PMID- 21685253 TI - Lentibacter algarum gen. nov., sp. nov., isolated from coastal water during a massive green algae bloom. AB - Two novel Gram-stain-negative, aerobic strains (ZXM100(T) and ZXM098) were isolated from seawater in the coastal region of Qingdao (36.027 degrees N 120.184 degrees E), China, during a massive green algae bloom. Cells were ovoid to irregular short rods and lacked flagella. Poly-beta-hydroxybutyrate was accumulated. Cells did not contain bacteriochlorophyll a. The isolates grew at NaCl concentrations of 3-9 % and 22-28 degrees C. C(18 : 1)omega7c, C(18 : 0) and C(16 : 0) were the major fatty acid components. The polar lipids of ZXM100(T) were phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, a single lipid and an unidentified aminolipid. The predominant isoprenoid quinone of ZXM100(T) was Q-10. Phylogenetic analysis based on 16S rRNA gene sequences showed that strains belonged to the family Rhodobacteraceae. Based on the results obtained in this study, strain ZXM100(T) was considered to represent a novel species in a new genus, for which the name Lentibacter algarum gen. nov., sp. nov. is proposed. The type strain is ZXM100(T) ( = LMG 24861(T) = CGMCC 1.10234(T)); the DNA G+C content of the type strain is 54.6 mol%. PMID- 21685254 TI - Proposal of Intrasporangium mesophilum sp. nov., and reclassification of Humihabitans oryzae Kageyama et al. 2007 as Intrasporangium oryzae comb. nov. AB - A gram-positive and aerobic bacterium, designated strain YIM 49065(T), was isolated from rhizospheric soil of Jatropha curcas in Yunnan, China. This isolate formed branched and fragmented mycelia containing ll-diaminopimelic acid as the diagnostic diamino acid in the cell-wall peptidoglycan. The major cellular fatty acid profile was characterized by iso-C(14 : 0), iso-C(15 : 0) and iso-C(16 : 0), and the predominant menaquinone was MK-8(H(4)). The DNA G+C content was 69.6 mol%. A phylogenetic analysis based on 16S rRNA gene sequence demonstrated that strain YIM 49065(T) was closely associated with Intrasporangium calvum DSM 43043(T) and Humihabitans oryzae KV-657(T), exhibiting 98.8 % and 98.6 % 16S rRNA gene sequence similarities, respectively. Furthermore, DNA-DNA hybridizations among strains YIM 49065(T), I. calvum DSM 43043(T) and H. oryzae DSM 22331(T) indicated that this isolate represented a novel species in the genus Intrasporangium. On the basis of these data, we proposed one novel species, Intrasporangium mesophilum sp. nov., for strain YIM 49065(T) ( = DSM 23217(T) = CCTCC AA 209077(T)). Additionally, the comparison of biochemical and phylogenetic characters supported the reclassification of Humihabitans oryzae as a separate species within the genus Intrasporangium, Intrasporangium oryzae comb. nov. (type strain KV-657(T) = JCM 15924(T) = NBRC 101802(T) = NRRL B-24470(T)). PMID- 21685255 TI - Gracilibacillus kekensis sp. nov., a moderate halophile isolated from Keke Salt Lake. AB - A novel moderately halophilic bacterium, designated strain K170(T), was isolated from Keke Salt Lake in Qinghai, China. The strain grew with 0-22 % (w/v) NaCl, at 4-50 degrees C and at pH 6-11, with optimum growth in 3 % (w/v) NaCl, at 40 degrees C and at pH 8. The predominant respiratory quinone was menaquinone 7 (MK 7). The polar lipids included diphosphatidylglycerol, phosphatidylglycerol, unidentified phospholipids, aminolipids and glycolipids. The major cellular fatty acids were anteiso-C(15 : 0), iso-C(15 : 0) and anteiso-C(17 : 0). The DNA G+C content was 35.8 mol%. Phylogenetic analysis based on the full-length 16S rRNA gene sequence revealed that strain K170(T) was a member of the genus Gracilibacillus. High levels of 16S rRNA gene sequence similarity were found between strain K170(T) and Gracilibacillus boraciitolerans DSM 17256(T) (97.3 %) and Gracilibacillus thailandensis JCM 15569(T) (97.1 %). 16S rRNA gene sequence similarities between strain K170(T) and the type strains of other recognized members of the genus Gracilibacillus were below 97 %. The DNA-DNA hybridization values of strain K170(T) with G. boraciitolerans DSM 17256(T) and G. thailandensis JCM 15569(T) were 21.9 % and 34.3 %, respectively. On the basis of these results, strain K170(T) is considered to represent a novel species of the genus Gracilibacillus, for which the name Gracilibacillus kekensis sp. nov. is proposed; the type strain is K170(T) ( = CGMCC 1.10681(T) = DSM 23178(T)). PMID- 21685256 TI - Haloarchaeobius iranensis gen. nov., sp. nov., an extremely halophilic archaeon isolated from a saline lake. AB - Strain EB21(T) was isolated from a brine sample from Aran-Bidgol salt lake, a saline playa in Iran. Strain EB21(T) was an orange-red-pigmented, motile rod and required at least 2 M NaCl but not MgCl(2) for growth. Optimal growth was achieved at 3.5 M NaCl and 0.2 M MgCl(2). The optimum pH and temperature for growth were pH 7.5 and 40 degrees C, while it was able to grow at pH 6.0-8.0 and 25-55 degrees C. Analysis of the 16S rRNA gene sequence revealed that strain EB21(T) is a member of the family Halobacteriaceae, showing low levels of similarity to other members of the family. The highest sequence similarities, 91.8, 91.7 and 91.5 %, were obtained with the 16S rRNA gene sequences of the type strains of Halobiforma lacisalsi, Haloterrigena thermotolerans and Halalkalicoccus tibetensis, respectively. Polar lipid analyses revealed that strain EB21(T) contains phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester and phosphatidylglycerol sulfate. Three unidentified glycolipids and one minor phospholipid were also observed. The only quinone present was MK-8(II H(2)). The G+C content of its DNA was 67.7 mol%. On the basis of the data obtained, the new isolate could not be classified in any recognized genus. Strain EB21(T) is thus considered to represent a novel species in a new genus within the family Halobacteriaceae, order Halobacteriales, for which the name Haloarchaeobius iranensis gen. nov., sp. nov. is proposed. The type strain of Haloarchaeobius iranensis is EB21(T) ( = IBRC-M 10013(T) = KCTC 4048(T)). PMID- 21685257 TI - Salinimicrobium gaetbulicola sp. nov., isolated from tidal flat sediment. AB - A Gram-stain-negative, aerobic, non-flagellated, non-gliding and short rod- or rod-shaped bacterial strain, designated BB-My20(T), was isolated from tidal flat sediment taken from the southern coast of Korea. Strain BB-My20(T) grew optimally at 37 degrees C, at pH 7.0-7.5 and in the presence of 2 % (w/v) NaCl. A phylogenetic tree based on 16S rRNA gene sequences showed that strain BB-My20(T) fell within the clade comprising Salinimicrobium species, joining Salinimicrobium catena HY1(T), with which it had a 16S rRNA gene sequence similarity value of 97.4 %. It exhibited 95.4-96.9 % sequence similarity to the type strains of other members of the genus Salinimicrobium. Strain BB-My20(T) contained MK-6 as the predominant menaquinone and iso-C(15 : 0), anteiso-C(15 : 0) and iso-C(17 : 0) 3 OH as the major fatty acids. The major polar lipids detected in strain BB-My20(T) and S. catena JCM 14015(T) were phosphatidylethanolamine and one unidentified lipid. The DNA G+C content of strain BB-My20(T) was 45.1 mol% and its mean DNA DNA relatedness value with S. catena JCM 14015(T) was 4.5 %. Differential phenotypic properties, together with its phylogenetic and genetic distinctiveness, revealed that strain BB-My20(T) can be distinguished from the four recognized species of the genus Salinimicrobium. On the basis of the data presented, strain BB-My20(T) is considered to represent a novel species of the genus Salinimicrobium, for which the name Salinimicrobium gaetbulicola sp. nov. is proposed; the type strain is BB-My20(T) ( = KCTC 23579(T) = CCUG 60898(T)). PMID- 21685258 TI - Actinomadura rupiterrae sp. nov., isolated from cliff soil. AB - A novel actinomycete strain, designated CS5-AC15T, was isolated from a soil sample collected from a cliff on Mara Island, Jeju, Republic of Korea, and subjected to a polyphasic taxonomic analysis. The isolate produced well developed, yellow substrate mycelium and white aerial mycelium that differentiated into straight or flexuous chains of smooth-surfaced spores. 16S rRNA gene sequence analyses showed that the organism belonged to the family Thermomonosporaceae and formed a tight cluster with the type strain of Actinomadura oligospora (97.4 % sequence similarity). Chemotaxonomic characteristics were consistent with its assignment to the genus Actinomadura in that the isolate had meso-diaminopimelic acid as the diagnostic diamino acid in the cell wall, madurose as the characteristic sugar, N-acetyl type of murein in the peptidoglycan, MK-9(H6) and MK-9(H8) as major menaquinones and a polar lipid profile containing diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol and unknown phospholipids. Mycolic acids were not detected. The predominant fatty acids were C16:0, C18:1omega9c and iso-C16:0. The DNA G+C content was 70.9 mol%. DNA relatedness of strain CS5-AC15T and A. oligospora JCM 10648T was 37.9+/-0.7 %. On the basis of the phenotypic, phylogenetic and DNA-DNA hybridization data, strain CS5-AC15T is assigned to a novel species of the genus Actinomadura, for which the name Actinomadura rupiterrae sp. nov. is proposed (type strain CS5-AC15T=KCTC 19559T=DSM 45251T). PMID- 21685259 TI - A barley ROP GTPase ACTIVATING PROTEIN associates with microtubules and regulates entry of the barley powdery mildew fungus into leaf epidermal cells. AB - Little is known about the function of host factors involved in disease susceptibility. The barley (Hordeum vulgare) ROP (RHO of plants) G-protein RACB is required for full susceptibility of the leaf epidermis to invasion by the biotrophic fungus Blumeria graminis f. sp hordei. Stable transgenic knockdown of RACB reduced the ability of barley to accommodate haustoria of B. graminis in intact epidermal leaf cells and to form hairs on the root epidermis, suggesting that RACB is a common element of root hair outgrowth and ingrowth of haustoria in leaf epidermal cells. We further identified a barley MICROTUBULE-ASSOCIATED ROP GTPASE ACTIVATING PROTEIN (MAGAP1) interacting with RACB in yeast and in planta. Fluorescent MAGAP1 decorated cortical microtubules and was recruited by activated RACB to the cell periphery. Under fungal attack, MAGAP1-labeled microtubules built a polarized network at sites of successful defense. By contrast, microtubules loosened where the fungus succeeded in penetration. Genetic evidence suggests a function of MAGAP1 in limiting susceptibility to penetration by B. graminis. Additionally, MAGAP1 influenced the polar organization of cortical microtubules. These results add to our understanding of how intact plant cells accommodate fungal infection structures and suggest that RACB and MAGAP1 might be antagonistic players in cytoskeleton organization for fungal entry. PMID- 21685261 TI - Is arterial wall-strain stiffening an additional process responsible for atherosclerosis in coronary bifurcations?: an in vivo study based on dynamic CT and MRI. AB - Coronary bifurcations represent specific regions of the arterial tree that are susceptible to atherosclerotic lesions. While the effects of vessel compliance, curvature, pulsatile blood flow, and cardiac motion on coronary endothelial shear stress have been widely explored, the effects of myocardial contraction on arterial wall stress/strain (WS/S) and vessel stiffness distributions remain unclear. Local increase of vessel stiffness resulting from wall-strain stiffening phenomenon (a local process due to the nonlinear mechanical properties of the arterial wall) may be critical in the development of atherosclerotic lesions. Therefore, the aim of this study was to quantify WS/S and stiffness in coronary bifurcations and to investigate correlations with plaque sites. Anatomic coronary geometry and cardiac motion were generated based on both computed tomography and MRI examinations of eight patients with minimal coronary disease. Computational structural analyses using the finite element method were subsequently performed, and spatial luminal arterial wall stretch (LW(Stretch)) and stiffness (LW(Stiff)) distributions in the left main coronary bifurcations were calculated. Our results show that all plaque sites were concomitantly subject to high LW(Stretch) and high LW(Stiff), with mean amplitudes of 34.7 +/- 1.6% and 442.4 +/- 113.0 kPa, respectively. The mean LW(Stiff) amplitude was found slightly greater at the plaque sites on the left main coronary artery (mean value: 482.2 +/- 88.1 kPa) compared with those computed on the left anterior descending and left circumflex coronary arteries (416.3 +/- 61.5 and 428.7 +/- 181.8 kPa, respectively). These findings suggest that local wall stiffness plays a role in the initiation of atherosclerotic lesions. PMID- 21685260 TI - Maize opaque5 encodes monogalactosyldiacylglycerol synthase and specifically affects galactolipids necessary for amyloplast and chloroplast function. AB - The maize (Zea mays) opaque5 (o5) locus was shown to encode the monogalactosyldiacylglycerol synthase MGD1. Null and point mutations of o5 that affect the vitreous nature of mature endosperm engendered an allelic series of lines with stepwise reductions in gene function. C(18:3)/C(18:2) galactolipid abundance in seedling leaves was reduced proportionally, without significant effects on total galactolipid content. This alteration in polar lipid composition disrupted the organization of thylakoid membranes into granal stacks. Total galactolipid abundance in endosperm was strongly reduced in o5(-) mutants, causing developmental defects and changes in starch production such that the normal simple granules were replaced with compound granules separated by amyloplast membrane. Complete loss of MGD1 function in a null mutant caused kernel lethality owing to failure in both endosperm and embryo development. The data demonstrate that low-abundance galactolipids with five double bonds serve functions in plastid membranes that are not replaced by the predominant species with six double bonds. Furthermore, the data identify a function of amyloplast membranes in the development of starch granules. Finally, the specific changes in lipid composition suggest that MGD1 can distinguish the constituency of acyl groups on its diacylglycerol substrate based upon the degree of desaturation. PMID- 21685262 TI - Differential regulation of metabolism by nitric oxide and S-nitrosothiols in endothelial cells. AB - S-nitrosation of thiols in key proteins in cell signaling pathways is thought to be an important contributor to nitric oxide (NO)-dependent control of vascular (patho)physiology. Multiple metabolic enzymes are targets of both NO and S nitrosation, including those involved in glycolysis and oxidative phosphorylation. Thus it is important to understand how these metabolic pathways are integrated by NO-dependent mechanisms. Here, we compared the effects of NO and S-nitrosation on both glycolysis and oxidative phosphorylation in bovine aortic endothelial cells using extracellular flux technology to determine common and unique points of regulation. The compound S-nitroso-L-cysteine (L-CysNO) was used to initiate intracellular S-nitrosation since it is transported into cells and results in stable S-nitrosation in vitro. Its effects were compared with the NO donor DetaNONOate (DetaNO). DetaNO treatment caused only a decrease in the reserve respiratory capacity; however, L-CysNO impaired both this parameter and basal respiration in a concentration-dependent manner. In addition, DetaNO stimulated extracellular acidification rate (ECAR), a surrogate marker of glycolysis, whereas L-CysNO stimulated ECAR at low concentrations and inhibited it at higher concentrations. Moreover, a temporal relationship between NO- and S nitrosation-mediated effects on metabolism was identified, whereby NO caused a rapid impairment in mitochondrial function, which was eventually overwhelmed by S nitrosation-dependent processes. Taken together, these results suggest that severe pharmacological nitrosative stress may differentially regulate metabolic pathways through both intracellular S-nitrosation and NO-dependent mechanisms. Moreover, these data provide insight into the role of NO and related compounds in vascular (patho)physiology. PMID- 21685263 TI - P2X7 receptor agonists pre- and postcondition the heart against ischemia reperfusion injury by opening pannexin-1/P2X7 channels. AB - Protection of the heart from ischemia-reperfusion injury can be achieved by ischemic preconditioning and ischemic postconditioning. Previous studies revealed that a complex of pannexin-1 with the P2X(7) receptor forms a channel during ischemic preconditioning and ischemic postconditioning that results in the release of endogenous cardioprotectants. ATP binds to P2X(7) receptors, inducing the formation of a channel in association with pannexin-1. We hypothesized that this channel would provide a pathway for the release of these same cardioprotectants. Preconditioning-isolated perfused rat hearts with 0.4 MUM ATP preceding 40 min of ischemia minimized infarct size upon subsequent reperfusion (5% of risk area) and resulted in >80% recovery of left ventricular developed pressure. Postconditioning with ATP after ischemia during reperfusion was also protective (6% infarct and 72% recovery of left ventricular developed pressure). Antagonists of both pannexin-1 (carbenoxolone and mefloquine) and P2X(7) receptors (brilliant blue G and A438079) blocked ATP pre- and postconditioning, indicating that ATP protection was elicited via the opening of a pannexin 1/P2X(7) channel. An antagonist of binding of the endogenous cardioprotectant sphingosine 1-phosphate to its G protein-coupled receptor diminished protection by ATP, which is also consistent with an ATP-dependent release of cardioprotectants. Suramin, an antagonist of binding of ATP (and ADP) to P2Y receptors, was without effect on ATP protection. Benzoyl benzoyl-ATP, a more specific P2X(7) agonist, was also a potent pre- and postconditioning agent and sensitive to blockade by pannexin-1/P2X(7) channel antagonists. The data point out for the first time the potential of P2X(7) agonists as cardioprotectants. PMID- 21685265 TI - Prostanoids suppress the coronary vasoconstrictor influence of endothelin after myocardial infarction. AB - Myocardial infarction (MI) is associated with endothelial dysfunction resulting in an imbalance in endothelium-derived vasodilators and vasoconstrictors. We have previously shown that despite increased endothelin (ET) plasma levels, the coronary vasoconstrictor effect of endogenous ET is abolished after MI. In normal swine, nitric oxide (NO) and prostanoids modulate the vasoconstrictor effect of ET. In light of the interaction among NO, prostanoids, and ET combined with endothelial dysfunction present after MI, we investigated this interaction in control of coronary vasomotor tone in the remote noninfarcted myocardium after MI. Studies were performed in chronically instrumented swine (18 normal swine; 13 swine with MI) at rest and during treadmill exercise. Furthermore, endothelial nitric oxide synthase (eNOS) and cyclooxygenase protein levels were measured in the anterior (noninfarcted) wall of six normal and six swine with MI. eNOS inhibition with N(omega)-nitro-L-arginine (L-NNA) and cyclooxygenase inhibition with indomethacin each resulted in coronary vasoconstriction at rest and during exercise, as evidenced by a decrease in coronary venous oxygen levels. The effect of l-NNA was slightly decreased in swine with MI, although eNOS expression was not altered. Conversely, in accordance with the unaltered expression of cyclooxygenase-1 after MI, the effect of indomethacin was similar in normal and MI swine. L-NNA enhanced the vasodilator effect of the ET(A/B) receptor blocker tezosentan but exclusively during exercise in both normal and MI swine. Interestingly, this effect of L-NNA was blunted in MI compared with normal swine. In contrast, whereas indomethacin increased the vasodilator effect of tezosentan only during exercise in normal swine, indomethacin unmasked a coronary vasodilator effect of tezosentan in MI swine both at rest and during exercise. In conclusion, the present study shows that endothelial control of the coronary vasculature is altered in post-MI remodeled myocardium. Thus the overall vasodilator influences of NO as well as its inhibition of the vasoconstrictor influence of ET on the coronary resistance vessels were reduced after MI. In contrast, while the overall prostanoid vasodilator influence was maintained, its inhibition of ET vasoconstrictor influences was enhanced in post-MI remote myocardium. PMID- 21685264 TI - Prolonged QT interval and lipid alterations beyond beta-oxidation in very long chain acyl-CoA dehydrogenase null mouse hearts. AB - Patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency frequently present cardiomyopathy and heartbeat disorders. However, the underlying factors, which may be of cardiac or extra cardiac origins, remain to be elucidated. In this study, we tested for metabolic and functional alterations in the heart from 3- and 7-mo-old VLCAD null mice and their littermate counterparts, using validated experimental paradigms, namely, 1) ex vivo perfusion in working mode, with concomitant evaluation of myocardial contractility and metabolic fluxes using (13)C-labeled substrates under various conditions; as well as 2) in vivo targeted lipidomics, gene expression analysis as well as electrocardiogram monitoring by telemetry in mice fed various diets. Unexpectedly, when perfused ex vivo, working VLCAD null mouse hearts maintained values similar to those of the controls for functional parameters and for the contribution of exogenous palmitate to beta-oxidation (energy production), even at high palmitate concentration (1 mM) and increased energy demand (with 1 MUM epinephrine) or after fasting. However, in vivo, these hearts displayed a prolonged rate-corrected QT (QTc) interval under all conditions examined, as well as the following lipid alterations: 1) age- and condition-dependent accumulation of triglycerides, and 2) 20% lower docosahexaenoic acid (an omega-3 polyunsaturated fatty acid) in membrane phospholipids. The latter was independent of liver but affected by feeding a diet enriched in saturated fat (exacerbated) or fish oil (attenuated). Our finding of a longer QTc interval in VLCAD null mice appears to be most relevant given that such condition increases the risk of sudden cardiac death. PMID- 21685266 TI - ROS-induced ROS release in vascular biology: redox-redox signaling. AB - The involvement of reactive oxygen species (ROS) in regulating vascular function both in normal vessels and as part of an adaptive response during disease has been intensively studied. From the recognition that ROS serve as important signaling molecules has emerged multiple lines of evidence that there is a functional connectivity between intracellular sites of ROS production. This cross talk has been termed ROS-induced ROS release (RIRR) and is supported by a variety of observations showing that RIRR is a common mechanism for ROS amplification and regional ROS generation. The compartmentalization of ROS production within a cell is critical to its signaling function and is facilitated by microlocalization of specific scavengers. This review will provide descriptions and examples of important mechanisms of RIRR. PMID- 21685267 TI - Creation of myocardial fibrosis by transplantation of fibroblasts primed with survival factors. AB - One of the major obstacles in the creation of myocardial fibrosis using fibroblasts is massive cell death after cell injection. To overcome this problem, a method that delivers fibroblasts primed with survival factors was studied. Cardiac fibroblasts were isolated from wild-type male C57BL/6 mice. Female mice were randomly placed into the following three groups: 1) fibroblasts transfected with beta-galactosidase-containing adenovirus (control group), 2) fibroblasts treated with a necrosis inhibitor (NI group), and 3) fibroblasts transfected with Akt-containing adenovirus (Akt group). Pretreated cells were transplanted into the recipient heart by direct injection after a thoracotomy. Quantitative real time PCR and morphometric analysis were performed to investigate the effects of survival factor priming on the induction of cell engraftment and fibrosis. In addition, a canine model was used to investigate the development of fibrosis and conduction modification using autologous dermal fibroblasts. The NI and Akt groups showed a better engraftment rate: 13 (NI group) and 7 (Akt group) times greater at 21 days compared with the control group. Increased fibrosis and conduction delay were also observed in the NI and Akt groups compared with the control group. Survival factor priming increased cellular engraftment and enhanced the efficacy of cell transplantation. Delivery of fibroblasts primed with survival factors might be a promising approach to develop conduction modification as a novel strategy to treat arrhythmias. PMID- 21685268 TI - Sex differences and the effects of ovariectomy on the beta-adrenergic contractile response. AB - The presence of sex differences in myocardial beta-adrenergic responsiveness is controversial, and limited studies have addressed the mechanism underlying these differences. Studies were performed using isolated perfused hearts from male, intact female and ovariectomized female mice to investigate sex differences and the effects of ovarian hormone withdrawal on beta-adrenergic receptor function. Female hearts exhibited blunted contractile responses to the beta-adrenergic receptor agonist isoproterenol (ISO) compared with males but not ovariectomized females. There were no sex differences in beta(1)-adrenergic receptor gene or protein expression. To investigate the role of adenylyl cyclase, phosphodiesterase, and the cAMP-signaling cascade in generating sex differences in the beta-adrenergic contractile response, dose-response studies were performed in isolated perfused male and female hearts using forskolin, 3-isobutyl-1 methylxanthine (IBMX), and 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate (CPT-cAMP). Males showed a modestly enhanced contractile response to forskolin at 300 nM and 5 MUM compared with females, but there were no sex differences in the response to IBMX or CPT-cAMP. The role of the A(1) adenosine receptor (A(1)AR) in antagonizing the beta-adrenergic contractile response was investigated using both the A(1)AR agonist 2-chloro-N(6)-cyclopentyl-adenosine and A(1)AR knockout (KO) mice. Intact females showed an enhanced A(1)AR anti adrenergic effect compared with males and ovariectomized females. The beta adrenergic contractile response was potentiated in both male and female A(1)ARKO hearts, with sex differences no longer present above 1 nM ISO. The beta adrenergic contractile response is greater in male hearts than females, and minor differences in the action of adenylyl cyclase or the A(1)AR may contribute to these sex differences. PMID- 21685269 TI - The rate of O2 loss from mesenteric arterioles is not unusually high. AB - The O(2) disappearance curve (ODC) recorded in an arteriole after the rapid arrest of blood flow reflects the complex interaction among the dissociation of O(2) from hemoglobin, O(2) diffusivity, and rate of respiration in the vascular wall and surrounding tissue. In this study, the analysis of experimental ODCs allowed the estimation of parameters of O(2) transport and O(2) consumption in the microcirculation of the mesentery. We collected ODCs from rapidly arrested blood inside rat mesenteric arterioles using scanning phosphorescence quenching microscopy (PQM). The technique was used to prevent the artifact of accumulated O(2) photoconsumption in stationary media. The observed ODC signatures were close to linear, in contrast to the reported exponential decline of intra-arteriolar Po(2). The rate of Po(2) decrease was 0.43 mmHg/s in 20-MUm-diameter arterioles. The duration of the ODC was 290 s, much longer than the 12.8 s reported by other investigators. The arterioles associated with lymphatic microvessels had a higher O(2) disappearance rate of 0.73 mmHg/s. The O(2) flux from arterioles, calculated from the average O(2) disappearance rate, was 0.21 nl O(2).cm(-2).s(-1), two orders of magnitude lower than reported in the literature. The physical upper limit of the O(2) consumption rate by the arteriolar wall, calculated from the condition that all O(2) is consumed by the wall, was 452 nl O(2).cm(-3).s(-1). From consideration of the microvascular tissue volume fraction in the rat mesentery of 6%, the estimated respiration rate of the vessel wall was ~30 nl O(2).cm(-3).s(-1). This result was three orders of magnitude lower than the respiration rate in rat mesenteric arterioles reported by other investigators. Our results demonstrate that O(2) loss from mesenteric arterioles is small and that the O(2) consumption by the arteriolar wall is not unusually large. PMID- 21685270 TI - A new model of congestive heart failure in rats. AB - Current rodent models of ischemia/infarct or pressure-volume overload are not fully representative of human heart failure. We developed a new model of congestive heart failure (CHF) with both ischemic and stress injuries combined with fibrosis in the remote myocardium. Sprague-Dawley male rats were used. Ascending aortic banding (Ab) was performed to induce hypertrophy. Two months post-Ab, ischemia-reperfusion (I/R) injury was induced by ligating the left anterior descending (LAD) artery for 30 min. Permanent LAD ligation served as positive controls. A debanding (DeAb) procedure was performed after Ab or Ab + I/R to restore left ventricular (LV) loading properties. Cardiac function was assessed by echocardiography and in vivo hemodynamic analysis. Myocardial infarction (MI) size and myocardial fibrosis were assessed. LV hypertrophy was observed 4 mo post-Ab; however, systolic function was preserved. LV hypertrophy regressed within 1 mo after DeAb. I/R for 2 mo induced a small to moderate MI with mild impairment of LV function. Permanent LAD ligation for 2 mo induced large MI and significant cardiac dysfunction. Ab for 2 mo followed by I/R for 2 mo (Ab + I/R) resulted in moderate MI with significantly reduced ejection fraction (EF). DeAb post Ab + I/R to reduce afterload could not restore cardiac function. Perivascular fibrosis in remote myocardium after Ab + I/R + DeAb was associated with decreased cardiac function. We conclude that Ab plus I/R injury with aortic DeAb represents a novel model of CHF with increased fibrosis in remote myocardium. This model will allow the investigation of vascular and fibrotic mechanisms in CHF characterized by low EF, dilated LV, moderate infarction, near-normal aortic diameter, and reperfused coronary arteries. PMID- 21685271 TI - Extracellular proton depression of peak and late Na+ current in the canine left ventricle. AB - Cardiac ischemia reduces excitability in ventricular tissue. Acidosis (one component of ischemia) affects a number of ion currents. We examined the effects of extracellular acidosis (pH 6.6) on peak and late Na(+) current (I(Na)) in canine ventricular cells. Epicardial and endocardial myocytes were isolated, and patch-clamp techniques were used to record I(Na). Action potential recordings from left ventricular wedges exposed to acidic Tyrode solution showed a widening of the QRS complex, indicating slowing of transmural conduction. In myocytes, exposure to acidic conditions resulted in a 17.3 +/- 0.9% reduction in upstroke velocity. Analysis of fast I(Na) showed that current density was similar in epicardial and endocardial cells at normal pH (68.1 +/- 7.0 vs. 63.2 +/- 7.1 pA/pF, respectively). Extracellular acidosis reduced the fast I(Na) magnitude by 22.7% in epicardial cells and 23.1% in endocardial cells. In addition, a significant slowing of the decay (time constant) of fast I(Na) was observed at pH 6.6. Acidosis did not affect steady-state inactivation of I(Na) or recovery from inactivation. Analysis of late I(Na) during a 500-ms pulse showed that the acidosis significantly reduced late I(Na) at 250 and 500 ms into the pulse. Using action potential clamp techniques, application of an epicardial waveform resulted in a larger late I(Na) compared with when an endocardial waveform was applied to the same cell. Acidosis caused a greater decrease in late I(Na) when an epicardial waveform was applied. These results suggest acidosis reduces both peak and late I(Na) in both cell types and contributes to the depression in cardiac excitability observed under ischemic conditions. PMID- 21685272 TI - Endothelial C-reactive protein increases platelet adhesion under flow conditions. AB - While data regarding the pathogenetic role of C-reactive protein (CRP) in atherothrombosis are accumulating, it is still controversial whether local CRP secretion is of any pathobiological significance. The present study examined whether endothelial-derived CRP modulates autocrine prothrombotic activity. Endothelial cells were isolated from hearts of mice transgenic to human CRP and grown in primary cultures. Human CRP expression was confirmed in these cells compared with no expression in cultures derived from wild-type congenes. Adhesion of human platelets to endothelial cells was studied in the "cone and plate" flow system. Platelet adhesion to cells expressing CRP was significantly increased compared with that in controls (n = 6, P < 0.01). The proadhesive effect of CRP was significantly suppressed in mouse heart endothelial cells and in human umbilical vein endothelial cells following treatment with small interfering RNA for human CRP. Adhesion was modulated by an increase in P-selectin. P-selectin expression correlated with a proadhesive phenotype, and blocking P-selectin with neutralizing antibody significantly decreased the adhesion of platelets to CRP expressing cells (40.4 +/- 10.5 to 9.4 +/- 6.9 platelets/high-power field, n = 5 to 6, P < 0.01). In conclusion, human CRP that is locally produced in endothelial cells increases platelet adhesion to endothelial cells under normal shear flow conditions. These findings indicate that CRP exerts a local effect on endothelial cells via P-selectin expression, which promotes platelet adhesion and subsequent thrombus formation. PMID- 21685273 TI - Improved functional vasodilation in obese Zucker rats following exercise training. AB - Obese individuals exhibit impaired functional vasodilation and exercise performance. We have demonstrated in obese Zucker rats (OZ), a model of morbid obesity, that insulin resistance impairs functional vasodilation via an increased thromboxane receptor (TP)-mediated vasoconstriction. Chronic treadmill exercise training improves functional vasodilation in the spinotrapezius muscle of the OZ, but the mechanisms responsible for the improvement in functional vasodilation are not clear. Based on evidence that exercise training improves insulin resistance, we hypothesized that, in the OZ, exercise training increases functional vasodilation and exercise capability due to decreases TP-mediated vasoconstriction associated with improved insulin sensitivity. Six-week-old lean Zucker rats (LZ) and OZ were exercised on a treadmill (24 m/min, 30 min/day, 5 days/wk) for 6 wk. An oral glucose tolerance test was performed at the end of the training period. We measured functional vasodilation in both exercise trained (spinotrapezius) and nonexercise trained (cremaster) muscles to determine whether the improved functional vasodilation following exercise training in OZ is due to a systemic improved insulin resistance. Compared with LZ, the sedentary OZ exhibited impairments in glucose tolerance and functional vasodilation in both muscles. The TP antagonist SQ-29548 improved the vasodilator responses in the sedentary OZ with no effect in the LZ. Exercising training of the LZ increased the functional vasodilation in spinotrapezius muscle, with no effect in the cremaster muscle. Exercising training of the OZ improved glucose tolerance, along with increased functional vasodilation, in both the spinotrapezius and cremaster muscles. SQ-29548 treatment had no effect on the vasodilator responses in either cremaster or spinotrapezius muscles of the exercise-trained OZ. These results suggest that, in the OZ, there is a global effect of exercising training to improve insulin resistance and increase functional vasodilation via a decreased TP-mediated vasoconstriction. PMID- 21685274 TI - Complete genome sequence of a novel clinical isolate, the nontuberculous Mycobacterium strain JDM601. AB - Mycobacteriosis is on the increase. Nontuberculous mycobacteria (NTM) are resistant to most antituberculosis drugs naturally. We determined the complete genome sequence of a novel NTM strain, JDM601, of the Mycobacterium terrae complex, which was isolated from a patient with tuberculosis-like disease and with various antibiotic resistances. PMID- 21685275 TI - Genome sequence of the Chlamydophila abortus variant strain LLG. AB - Chlamydophila abortus is a common cause of ruminant abortion. Here we report the genome sequence of strain LLG, which differs genotypically and phenotypically from the wild-type strain S26/3. Genome sequencing revealed differences between LLG and S26/3 to occur in pseudogene content, in transmembrane head/inc family proteins, and in biotin biosynthesis genes. PMID- 21685276 TI - Cooperativity and interference of germination pathways in Bacillus anthracis spores. AB - Spore germination is the first step to Bacillus anthracis pathogenicity. Previous work has shown that B. anthracis spores use germination (Ger) receptors to recognize amino acids and nucleosides as germinants. Genetic analysis has putatively paired each individual Ger receptor with a specific germinant. However, Ger receptors seem to be able to partially compensate for each other and recognize alternative germinants. Using kinetic analysis of B. anthracis spores germinated with inosine and L-alanine, we previously determined kinetic parameters for this germination process and showed binding synergy between the cogerminants. In this work, we expanded our kinetic analysis to determine kinetic parameters and binding order for every B. anthracis spore germinant pair. Our results show that germinant binding can exhibit positive, neutral, or negative cooperativity. Furthermore, different germinants can bind spores by either a random or an ordered mechanism. Finally, simultaneous triggering of multiple germination pathways shows that germinants can either cooperate or interfere with each other during the spore germination process. We postulate that the complexity of germination responses may allow B. anthracis spores to respond to different environments by activating different germination pathways. PMID- 21685277 TI - Genome sequence of Listeria monocytogenes Scott A, a clinical isolate from a food borne listeriosis outbreak. AB - Listeria monocytogenes is an opportunistic food-borne pathogen and the causative agent of listeriosis in animals and humans. We present the genome sequence of Listeria monocytogenes Scott A, a widely distributed and frequently used serovar 4b clinical isolate from the 1983 listeriosis outbreak in Massachusetts. PMID- 21685278 TI - Genome sequence of Corynebacterium nuruki S6-4 T, isolated from alcohol fermentation starter. AB - Corynebacterium nuruki S6-4(T), isolated from Korean alcohol fermentation starter, is a strictly aerobic, nonmotile, Gram-positive, and rod-shaped bacterium belonging to the genus Corynebacterium and the actinomycete group. We report here the draft genome sequence of C. nuruki strain S6-4(T) (3,106,595 bp, with a G+C content of 69.5%). PMID- 21685279 TI - Complete genome sequence of the plant pathogen Ralstonia solanacearum strain Po82. AB - Ralstonia solanacearum strain Po82, a phylotype IIB/sequevar 4 strain, was found to be pathogenic to both solanaceous plants and banana. Here, we report the complete genome sequence of Po82 and its comparison with seven published R. solanacearum genomes. PMID- 21685280 TI - Genome sequence of Lactococcus garvieae 8831, isolated from rainbow trout lactococcosis outbreaks in Spain. AB - Lactococcus garvieae is the etiological agent of lactococcosis, one of the most important disease threats to the sustainability of the rainbow trout farming industry. Here, we present the draft genome sequence of Lactococcus garvieae strain 8831, isolated from diseased rainbow trout, which is composed of 2,087,276 bp with a G+C content of 38%. PMID- 21685281 TI - Draft genome sequence of Kocuria rhizophila P7-4. AB - We report the draft genome sequence of Kocuria rhizophila P7-4, which was isolated from the intestine of Siganus doliatus caught in the Pacific Ocean. The 2.83-Mb genome sequence consists of 75 large contigs (>100 bp in size) and contains 2,462 predicted protein-coding genes. PMID- 21685282 TI - Genome sequence of the 17beta-estradiol-utilizing bacterium Sphingomonas strain KC8. AB - Sphingomonas strain KC8 is known for its ability to utilize 17beta-estradiol, a natural estrogen and an environmental endocrine-disrupting compound, as the sole carbon and energy source. Here, we report the draft genome sequence of the strain KC8 (4,074,265 bp, with a GC content of 63.7%) and major findings from its annotation. PMID- 21685283 TI - Structure-based functional studies of the effects of amino acid substitutions in GerBC, the C subunit of the Bacillus subtilis GerB spore germinant receptor. AB - Highly conserved amino acid residues in the C subunits of the germinant receptors (GRs) of spores of Bacillus and Clostridium species have been identified by amino acid sequence comparisons, as well as structural predictions based on the high resolution structure recently determined for the C subunit of the Bacillus subtilis GerB GR (GerBC). Single and multiple alanine substitutions were made in these conserved residues in three regions of GerBC, and the effects of these changes on B. subtilis spore germination via the GerB GR alone or in concert with the GerK GR, as well as on germination via the GerA GR, were determined. In addition, levels of the GerBC variants in the spore inner membrane were measured, and a number of the GerBC proteins were expressed and purified and their solubility and aggregation status were assessed. This work has done the following: (i) identified a number of conserved amino acids that are crucial for GerBC function in spore germination via the GerB GR and that do not alter spores' levels of these GerBC variants; (ii) identified other conserved GerBC amino acid essential for the proper folding of the protein and/or for assembly of GerBC in the spore inner membrane; (iii) shown that some alanine substitutions in GerBC significantly decrease the GerA GR's responsiveness to its germinant l-valine, consistent with there being some type of interaction between GerA and GerB GR subunits in spores; and (iv) found no alanine substitutions that specifically affect interaction between the GerB and GerK GRs. PMID- 21685284 TI - Draft genome sequence of Methylophaga aminisulfidivorans MP T. AB - Methylophaga aminisulfidivorans MP(T) is a restricted facultatively marine methylotrophic bacterium that grows on methanol, methylated amines, dimethyl sulfide, and dimethyl sulfoxide. Here we present the high-quality draft genome sequence of M. aminisulfidivorans MP(T) (KCTC 12909(T) = JCM 14647(T)), consisting of a chromosome (3,092,085 bp) and a plasmid (16,875 bp). PMID- 21685285 TI - Draft genome sequence of Streptomyces strain S4, a symbiont of the leaf-cutting ant Acromyrmex octospinosus. AB - Streptomyces spp. are common symbionts of the leaf-cutting ant species Acromyrmex octospinosus, which feeds on basidiomycete fungus leaf matter and harvests the lipid- and carbohydrate-rich gongylidia as a food source. A. octospinosus and other ant genera use antifungal compounds produced by Streptomyces spp. and other actinomycetes in order to help defend their fungal gardens from parasitic fungi. Herein, we report the draft genome sequence of Streptomyces strain S4, an antifungal-producing symbiont of A. octospinosus. PMID- 21685286 TI - Genome sequence of Acinetobacter sp. strain P8-3-8, isolated from Fistularia commersonii in Vietnam. AB - Acinetobacter sp. strain P8-3-8 is an aerobic, Gram-negative marine bacterium isolated from the intestine of the bluespotted cornetfish (Fistularia commersonii). Here, we present the draft genome sequence of Acinetobacter sp. P8 3-8 (3,905,565 bp, with a G+C content of 37.6%) containing 3,621 putative coding sequences. The genome data reveal a high density of genes encoding transcriptional regulators involved in anaerobic respiration. PMID- 21685287 TI - Genome of Ochrobactrum anthropi ATCC 49188 T, a versatile opportunistic pathogen and symbiont of several eukaryotic hosts. AB - Ochrobactrum anthropi is a common soil alphaproteobacterium that colonizes a wide spectrum of organisms and is being increasingly recognized as an opportunistic human pathogen. Potentially life-threatening infections, such as endocarditis, are included in the list of reported O. anthropi infections. These reports, together with the scant number of studies and the organism's phylogenetic proximity to the highly pathogenic brucellae, make O. anthropi an attractive model of bacterial pathogenicity. Here we report the genome sequence of the type strain O. anthropi ATCC 49188, which revealed the presence of two chromosomes and four plasmids. PMID- 21685288 TI - Genome sequence of the curdlan-producing Agrobacterium sp. strain ATCC 31749. AB - Agrobacterium sp. ATCC 31749 is an industrial strain for the commercial production of curdlan, an important exopolysaccharide with food and medical applications. Here we report the genome sequence of the curdlan-producing strain ATCC 31749. Genome sequencing is the first step toward the understanding of regulation of curdlan biosynthesis. PMID- 21685289 TI - Complete genome sequence and updated annotation of Desulfovibrio alaskensis G20. AB - Desulfovibrio alaskensis G20 (formerly Desulfovibrio desulfuricans G20) is a Gram negative mesophilic sulfate-reducing bacterium (SRB), known to corrode ferrous metals and to reduce toxic radionuclides and metals such as uranium and chromium to sparingly soluble and less toxic forms. We present the 3.7-Mb genome sequence to provide insights into its physiology. PMID- 21685290 TI - The requirement for pneumococcal MreC and MreD is relieved by inactivation of the gene encoding PBP1a. AB - MreC and MreD, along with the actin homologue MreB, are required to maintain the shape of rod-shaped bacteria. The depletion of MreCD in rod-shaped bacteria leads to the formation of spherical cells and the accumulation of suppressor mutations. Ovococcus bacteria, such as Streptococcus pneumoniae, lack MreB homologues, and the functions of the S. pneumoniae MreCD (MreCD(Spn)) proteins are unknown. mreCD are located upstream from the pcsB cell division gene in most Streptococcus species, but we found that mreCD and pcsB are transcribed independently. Similarly to rod-shaped bacteria, we show that mreCD are essential in the virulent serotype 2 D39 strain of S. pneumoniae, and the depletion of MreCD results in cell rounding and lysis. In contrast, laboratory strain R6 contains suppressors that allow the growth of DeltamreCD mutants, and bypass suppressors accumulate in D39 DeltamreCD mutants. One class of suppressors eliminates the function of class A penicillin binding protein 1a (PBP1a). Unencapsulated Deltapbp1a D39 mutants have smaller diameters than their pbp1a(+) parent or Deltapbp2a and Deltapbp1b mutants, which lack other class A PBPs and do not show the suppression of DeltamreCD mutations. Suppressed DeltamreCD Deltapbp1a double mutants form aberrantly shaped cells, some with misplaced peptidoglycan (PG) biosynthesis compared to that of single Deltapbp1a mutants. Quantitative Western blotting showed that MreC(Spn) is abundant (~8,500 dimers per cell), and immunofluorescent microscopy (IFM) located MreCD(Spn) to the equators and septa of dividing cells, similarly to the PBPs and PG pentapeptides indicative of PG synthesis. These combined results are consistent with a model in which MreCD(Spn) direct peripheral PG synthesis and control PBP1a localization or activity. PMID- 21685291 TI - Genome of multidrug-resistant uropathogenic Escherichia coli strain NA114 from India. AB - Uropathogenic Escherichia coli (UPEC) causes serious infections in people at risk and has a significant environmental prevalence due to contamination by human and animal excreta. In developing countries, UPEC assumes importance in certain dwellings because of poor community/personal hygiene and exposure to contaminated water or soil. We report the complete genome sequence of E. coli strain NA114 from India, a UPEC strain with a multidrug resistance phenotype and the capacity to produce extended-spectrum beta-lactamase. The genome sequence and comparative genomics emanating from it will be significant in under-standing the genetic makeup of diverse UPEC strains and in boosting the development of new diagnostics/vaccines. PMID- 21685292 TI - De novo sequencing and assembly of the whole genome of Novosphingobium sp. strain PP1Y. AB - Novosphingobium sp. strain PP1Y is a marine bacterium specifically adapted to use fuels as an energy source. We sequenced and assembled its entire genome using the Roche 454 genome sequencer system, which led to the identification of two plasmids and one megaplasmid, besides a 3.9-Mb circular chromosome. PMID- 21685293 TI - Alterations in the beta flap and beta' dock domains of the RNA polymerase abolish NusA-mediated feedback regulation of the metY-nusA-infB operon. AB - The RimM protein in Escherichia coli is important for the in vivo maturation of 30S ribosomal subunits and a DeltarimM mutant grows poorly due to assembly and translational defects. These deficiencies are suppressed partially by mutations that increase the synthesis of another assembly protein, RbfA, encoded by the metY-nusA-infB operon. Among these suppressors are mutations in nusA that impair the NusA-mediated negative-feedback regulation at internal intrinsic transcriptional terminators of the metY-nusA-infB operon. We describe here the isolation of two new mutations, one in rpoB and one in rpoC (encoding the beta and beta' subunits of the RNA polymerase, respectively), that increase the synthesis of RbfA by preventing NusA from stimulating termination at the internal intrinsic transcriptional terminators of the metY-nusA-infB operon. The rpoB2063 mutation changed the isoleucine in position 905 of the beta flap-tip helix to a serine, while the rpoC2064 mutation duplicated positions 415 to 416 (valine isoleucine) at the base of the beta' dock domain. These findings support previously published in vitro results, which have suggested that the beta flap tip helix and beta' dock domain at either side of the RNA exit tunnel mediate the binding to NusA during transcriptional pausing and termination. PMID- 21685294 TI - Refining the binding of the Escherichia coli flagellar master regulator, FlhD4C2, on a base-specific level. AB - The Escherichia coli flagellar master regulator, FlhD(4)C(2), binds to the promoter regions of flagellar class II genes, yet, despite extensive analysis of the FlhD(4)C(2)-regulated promoter region, a detailed consensus sequence has not emerged. We used in vitro and in vivo experimental approaches to determine the nucleotides in the class II promoter, fliAp, required for the binding and function of FlhD(4)C(2). FlhD(4)C(2) protects 48 bp (positions -76 to -29 relative to the sigma(70)-dependent transcriptional start site) in the fliA promoter. We divided the 48-bp footprint region into 5 sections to determine the requirement of each DNA segment for the binding and function of FlhD(4)C(2). Results from an in vitro binding competition assay between the wild-type FlhD(4)C(2)-protected fragment and DNA fragments possessing mutations in one section of the 48-bp protected region showed that only one-third of the 48 bp protected by FlhD(4)C(2) is required for FlhD(4)C(2) binding and fliA promoter activity. This in vitro binding result was also seen in vivo with fliA promoter lacZ fusions carrying the same mutations. Only seven bases (A(12), A(15), T(34), A(36), T(37), A(44), and T(45)) are absolutely required for the promoter activity. Moreover, A(12), A(15), T(34), T(37), and T(45) within the 7 bases are highly specific to fliA promoter activity, and those bases form an asymmetric recognition site for FlhD(4)C(2). The implications of the asymmetry of the FlhD(4)C(2) binding site and its potential impact on FlhD(4)C(2) are discussed. PMID- 21685295 TI - Genetic and biochemical analysis of PadR-padC promoter interactions during the phenolic acid stress response in Bacillus subtilis 168. AB - Bacillus subtilis 168 is resistant to phenolic acids by expression of an inducible enzyme, the phenolic acid decarboxylase (PadC), that decarboxylates these acids into less toxic vinyl derivatives. In the phenolic acid stress response (PASR), the repressor of padC, PadR, is inactivated by these acids. Inactivation of PadR is followed by a strong expression of padC. To elucidate the functional interaction between PadR and the padC promoter, we performed (i) footprinting assays to identify the region protected by PadR, (ii) electrophoretic mobility shift assays (EMSAs) with a modified padC promoter protected region to determine the interacting sequences, and (iii) random mutagenesis of padR to identify amino acid residues essential for the function of PadR. We identified an important consensus dyad sequence called IR1-2 (ATGT-8N ACAT) overlapping a second dyad element (GTGT-8N-ACAT) that we named dIR1-2bis. The entire dIR1-2bis/IR1-2 sequence permits binding of two PadR dimers in EMSAs, which may be observed for bacteria grown under noninduced conditions where the padC promoter is completely repressed. Three groups of modified PadRs giving a PASR phenotype were characterized in vivo. The DNA sequences of certain mutant padR alleles indicate that important residues are all located in the region containing the coiled-coil leucine zipper domain that is involved in dimerization. These substitutions reduce the affinity of PadR binding to the padC promoter. Of particular interest are residue L128, located at the center of the putative coiled-coil leucine zipper domain, and residue E97, which is conserved among all PadRs. PMID- 21685296 TI - Crystal structure of Bacillus anthracis phosphoglucosamine mutase, an enzyme in the peptidoglycan biosynthetic pathway. AB - Phosphoglucosamine mutase (PNGM) is an evolutionarily conserved bacterial enzyme that participates in the cytoplasmic steps of peptidoglycan biosynthesis. As peptidoglycan is essential for bacterial survival and is absent in humans, enzymes in this pathway have been the focus of intensive inhibitor design efforts. Many aspects of the structural biology of the peptidoglycan pathway have been elucidated, with the exception of the PNGM structure. We present here the crystal structure of PNGM from the human pathogen and bioterrorism agent Bacillus anthracis. The structure reveals key residues in the large active site cleft of the enzyme which likely have roles in catalysis and specificity. A large conformational change of the C-terminal domain of PNGM is observed when comparing two independent molecules in the crystal, shedding light on both the apo- and ligand-bound conformers of the enzyme. Crystal packing analyses and dynamic light scattering studies suggest that the enzyme is a dimer in solution. Multiple sequence alignments show that residues in the dimer interface are conserved, suggesting that many PNGM enzymes adopt this oligomeric state. This work lays the foundation for the development of inhibitors for PNGM enzymes from human pathogens. PMID- 21685297 TI - Draft genome sequence of the thermoalkaliphilic Caldalkalibacillus thermarum strain TA2.A1. AB - The genes and molecular machines that allow for a thermoalkaliphilic lifestyle have not been defined. To address this goal, we report on the improved high quality draft genome sequence of Caldalkalibacillus thermarum strain TA2.A1, an obligately aerobic bacterium that grows optimally at pH 9.5 and 65 to 70 degrees C on a wide variety of carbon and energy sources. PMID- 21685298 TI - Acute and chronic effects of epicardial radiofrequency applications delivered on epicardial coronary arteries. AB - BACKGROUND: Epicardial coronary injury is by far the most feared complication of epicardial ablation. Little information is available regarding the chronic effects of delivering radiofrequency in the vicinity of large coronary vessels, and the long-term impact of this approach for mapping and ablation on epicardial vessel integrity is poorly understood. Therefore, the aim of this study was to characterize the acute and chronic histopathologic changes produced by in vivo epicardial pulses of radiofrequency ablation on coronary artery of porcine hearts. METHODS AND RESULTS: Seven pigs underwent a left thoracotomy. The catheter was sutured adjacent to the left anterior descending artery and left circumflex artery, and 20 pulses of radiofrequency energy were applied. Radiofrequency lesions located no more than 1 mm of the vessel were used for this analysis. Three animals were euthanized 20 days (acute phase) after the procedure and 4 animals after 70 days (chronic phase). The following parameters were obtained in each vessel analyzed: (1) internal and external perimeter; (2) vessel wall thickness; (3) tunica media thickness, and (4) tunica intima thickness. The presence of adipose tissue around the coronary arteries, the distance between the artery and the epicardium, and the anatomic relationship of the artery with the coronary vein was also documented for each section. Sixteen of 20 (80%) sections analyzed, showed intimal thickening with a mean of 0.18 +/- 0.14 mm compared with 0.13 +/- 0.16 mm in the acute phase (P = 0.331). The mean tunica media thickness was 0.25 +/- 0.10 mm in the chronic phase animals compared with 0.18 +/- 0.03 mm in the acute phase animals (P = 0.021). A clear protective effect of pericardial fat and coronary veins was also present. A positive correlation between depth of radiofrequency lesion and the degree of vessel injury expressed as intimal and media thickening (P = 0.001) was present. A negative correlation was identified (r = -0.83; P = 0.002) between intimal thickening and distance between epicardium and coronary artery. CONCLUSIONS: In this porcine model of in vivo epicardial radiofrequency ablation in proximity to coronary arteries leads to acute and chronic histopathologic changes characterized by tunica intima and media thickening, with replacement of smooth muscle cells with extracellular matrix, but no significant stenosis was observed up to 70 days after the ablation. The absence of acute coronary occlusion or injury does not preclude subsequent significant arterial damage, which frequently occurs when epicardial radiofrequency applications are delivered in close vicinity to the vessels. PMID- 21685299 TI - Late-age onset systemic sclerosis. AB - OBJECTIVE: Although patients who develop systemic sclerosis (SSc) later in life (>= 65 yrs) may express the entire clinical spectrum of disease, we hypothesize that patients with late-age onset SSc incur a different risk for specific organ manifestations of disease compared to those with early-age onset SSc. METHODS: In total, 2300 patients with SSc were evaluated between 1990 and 2009 and reviewed from a university-based scleroderma center cohort. Demographic profile, SSc subtype, autoantibody status, Medsger severity scores, pulmonary function tests, echocardiography, and right heart catheterization measures were compared between late-age onset vs younger-age onset patients with SSc. RESULTS: Overall, 2084 patients (91%) developed SSc prior to age 65, while 216 (9%) were >= 65 years. Late-age onset patients had a significantly higher proportion of anticentromere antibodies (42% vs 27%; p = 0.001) compared to early-age onset patients. Risk of pulmonary hypertension (OR 1.76, 95% CI 1.00, 3.12), muscle weakness (OR 1.85, 95% CI 1.30, 1.64), renal impairment (OR 2.83, 95% CI 1.98, 4.04), and cardiac disease (OR 2.69, 95% CI 1.92, 3.78) was greater among those with late-age onset SSc; although risk of digital ischemia (OR 0.64, 95% CI 0.47, 0.86) was reduced. The cumulative incidence of pulmonary hypertension at 5 years was greater among those with late-age onset SSc (9%) compared to those with early-age onset SSc (2.7%; log-rank, p < 0.001). CONCLUSION: These findings suggest that older patients with SSc are at greater risk for pulmonary hypertension, renal impairment, cardiac disease, and muscle weakness. Awareness of the distinct risk for specific organ manifestations in SSc, in particular pulmonary hypertension, should guide the care of patients with SSc whose disease begins after age 65. PMID- 21685300 TI - The tide keeps rising: the Great Flood of 2011. PMID- 21685301 TI - Strategies in disaster preparedness for the next generation of healthcare providers. PMID- 21685302 TI - Use of MSOFA for triage of disaster patients. PMID- 21685304 TI - A defining aspect of human resilience in the workplace: a structural modeling approach. AB - OBJECTIVES: It has been estimated that up to 90% of the US population is exposed to at least 1 traumatic event during their lifetime. Although there is growing evidence that most people are resilient, meaning that they have the ability to adapt to or rebound from adversity, between 5% and 10% of individuals exposed to traumatic events meet criteria for posttraumatic stress disorder. Therefore, identifying the elements of resilience could lead to interventions or training programs designed to enhance resilience. In this article, we test the hypothesis that the effects of stressor conditions on outcomes such as job-related variables may be mediated through the cognitive and affective registrations of those events, conceptualized as subjective stress arousal. METHODS: The subjects were 491 individuals employed in public accounting, who were sampled from a mailing list provided by the American Institute of Certified Public Accountants. The stressors used in this study were role ambiguity, role conflict, and role overload and the outcome measures were performance, turnover intentions, job satisfaction, and burnout. Stress arousal was measured using a previously developed stress arousal scale. We conducted a series of 2 EQS structural modeling analyses to assess the impact of stress arousal. The first model examined only the direct effects from the role stressors to the outcome constructs. The second model inserted stress arousal as a mediator in the relations between the role stressors and the outcomes. RESULTS: The results of our investigation supported the notion that subjective stress arousal provides greater explanatory clarity by mediating the effects of stressors upon job related outcome. Including stress arousal in the model provided a much more comprehensive understanding of the relation between stressor and outcomes, and the contribution of role ambiguity and role conflict were better explained. CONCLUSIONS: By understanding these relations, anticipatory guidance and crisis intervention programs can be designed and implemented to enhance human resilience. These data could serve to improve training programs for these "at risk" professional groups or even the population as a whole. PMID- 21685305 TI - Effects of the design and practice of points-of-dispensing on patient-reported satisfaction: municipal H1N1 clinics in Rhode Island. AB - OBJECTIVES: The primary objective of the study was to understand the public's perception of the effectiveness of Rhode Island's public health emergency response plans by using municipal H1N1 vaccination clinics conducted in Rhode Island in January and February 2010 as a basis for public reaction. The effect of previous exercises on public perception was also examined. METHOD: A survey of 926 H1N1 vaccination clinic attendees was conducted via mail during the period between March 18 and May 1, 2010. RESULTS: A total of 579 surveys were returned, rendering a response rate of 62.5%. The majority of clinic attendees traveled <=10 mi to the vaccination clinic (90.48%). The average self-reported wait time inside the clinic was 19.16 minutes, and 69.84% of respondents expected to have waited longer before attending the clinic. The self-reported wait time was negatively correlated with patient-reported overall clinic satisfaction. A total of 98.08% of respondents believed that the signage used at the clinics was easy to follow, 100% of respondents believed that the clinic staff was courteous and respectful, and 82.35% of respondents reported that they would rate the clinic they attended as excellent. CONCLUSIONS: Rhode Islanders prefer local public health service sites. There was a minor difference in the overall satisfaction of respondents who attended municipal clinics that had exercised emergency plans before activation for H1N1 vaccinations and those municipalities that had not previously exercised. The lack of difference between the practicing and nonpracticing points-of-dispensing may be caused by the standardization of municipal emergency plans, uniformity in the guidance and support of each clinic provided by the Rhode Island Department of Health, and municipalities that had not previously exercised had the opportunity to observe those that had exercised. Having thorough mass dispensing plans in place in advance of a public health emergency is as important as having exercised a point-of-dispensing before a real world activation. PMID- 21685306 TI - Developing-world disaster research: present evidence and future priorities. AB - OBJECTIVES: The technology and resource-rich solutions of the developed world may not be completely applicable to or replicable in disasters occurring in the developing world. With the current looming hazards of pandemics, climate change, global terrorism and conflicts around the world, policy makers and governments will need high-quality scientific data to make informed decisions for preparedness and mitigation. The evidence on disasters in peer-reviewed journals about the developing world was examined for quality and quantity in this systematic review. METHODS: PubMed was searched using the Medical Subject Heading (MeSH) terms disasters, disaster medicine, rescue work, relief work, and conflict and then refined using the MeSH term developing country. The final list of selected manuscripts were analyzed by type of article, level of evidence, theme of the manuscript and topic, author affiliation, and region of the study. RESULTS: After searching and refining, <1% of the citations in PubMed addressed disasters in developing countries. The majority was original research articles or reviews, and most of the original research articles were level IV or V evidence. Less than 25% of the authors were from the developing world. The predominant themes were missions, health care provision, and humanitarian aid during the acute phase of disasters in the developing world. CONCLUSIONS: Considering that 85% of disasters and 95% of disaster-related deaths occur in the developing world, the overwhelming number of casualties has contributed insignificantly to the world's peer-reviewed literature. Less than 1% of all disaster-related publications are about disasters in the developing world. This may be a publication bias, or it may be a genuine lack of submissions dealing with these disasters. Authors in this part of the world need to contribute to future disaster research through better-quality systematic research and better funding priorities. Aid for sustaining long-term disaster research may be a more useful investment in mitigating future disasters than short-term humanitarian aid missions to the developing world. PMID- 21685307 TI - Disaster metrics: quantitative benchmarking of hospital surge capacity in trauma related multiple casualty events. AB - OBJECTIVES: Hospital surge capacity in multiple casualty events (MCE) is the core of hospital medical response, and an integral part of the total medical capacity of the community affected. To date, however, there has been no consensus regarding the definition or quantification of hospital surge capacity. The first objective of this study was to quantitatively benchmark the various components of hospital surge capacity pertaining to the care of critically and moderately injured patients in trauma-related MCE. The second objective was to illustrate the applications of those quantitative parameters in local, regional, national, and international disaster planning; in the distribution of patients to various hospitals by prehospital medical services; and in the decision-making process for ambulance diversion. METHODS: A 2-step approach was adopted in the methodology of this study. First, an extensive literature search was performed, followed by mathematical modeling. Quantitative studies on hospital surge capacity for trauma injuries were used as the framework for our model. The North Atlantic Treaty Organization triage categories (T1-T4) were used in the modeling process for simplicity purposes. RESULTS: Hospital Acute Care Surge Capacity (HACSC) was defined as the maximum number of critical (T1) and moderate (T2) casualties a hospital can adequately care for per hour, after recruiting all possible additional medical assets. HACSC was modeled to be equal to the number of emergency department beds (#EDB), divided by the emergency department time (EDT); HACSC = #EDB/EDT. In trauma-related MCE, the EDT was quantitatively benchmarked to be 2.5 (hours). Because most of the critical and moderate casualties arrive at hospitals within a 6-hour period requiring admission (by definition), the hospital bed surge capacity must match the HACSC at 6 hours to ensure coordinated care, and it was mathematically benchmarked to be 18% of the staffed hospital bed capacity. CONCLUSIONS: Defining and quantitatively benchmarking the different components of hospital surge capacity is vital to hospital preparedness in MCE. Prospective studies of our mathematical model are needed to verify its applicability, generalizability, and validity. PMID- 21685308 TI - Model uniform core criteria for mass casualty triage. AB - There is a need for model uniform core criteria for mass casualty triage because disasters frequently cross jurisdictional lines and involve responders from multiple agencies who may be using different triage tools. These criteria (Tables 1-4) reflect the available science, but it is acknowledged that there are significant research gaps. When no science was available, decisions were formed by expert consensus derived from the available triage systems. The intent is to ensure that providers at a mass-casualty incident use triage methodologies that incorporate these core principles in an effort to promote interoperability and standardization. At a minimum, each triage system must incorporate the criteria that are listed below. Mass casualty triage systems in use can be modified using these criteria to ensure interoperability. The criteria include general considerations, global sorting, lifesaving interventions, and assignment of triage categories. The criteria apply only to providers who are organizing multiple victims in a discrete geographic location or locations, regardless of the size of the incident. They are classified by whether they were derived through available direct scientific evidence, indirect scientific evidence, expert consensus, and/or are used in multiple existing triage systems. These criteria address only primary triage and do not consider secondary triage. For the purposes of this document the term triage refers to mass-casualty triage and provider refers to any person who assigns primary triage categories to victims of a mass-casualty incident. PMID- 21685309 TI - Mass casualty triage: an evaluation of the science and refinement of a national guideline. AB - Mass casualty triage is the process of prioritizing multiple victims when resources are not sufficient to treat everyone immediately. No national guideline for mass casualty triage exists in the United States. The lack of a national guideline has resulted in variability in triage processes, tags, and nomenclature. This variability has the potential to inject confusion and miscommunication into the disaster incident, particularly when multiple jurisdictions are involved. The Model Uniform Core Criteria for Mass Casualty Triage were developed to be a national guideline for mass casualty triage to ensure interoperability and standardization when responding to a mass casualty incident. The Core Criteria consist of 4 categories: general considerations, global sorting, lifesaving interventions, and individual assessment of triage category. The criteria within each of these categories were developed by a workgroup of experts representing national stakeholder organizations who used the best available science and, when necessary, consensus opinion. This article describes how the Model Uniform Core Criteria for Mass Casualty Triage were developed. PMID- 21685310 TI - Working with interpreters during international health responses. AB - Health care providers face multiple difficulties in providing care to a disaster stricken community. Training, preparation, and a good attitude are important, as is adequate logistical support. An often-ignored issue is the difficulty encountered with language barriers during a response, and how using interpreters affects the quality and impact of the health care provided. This article reviews the use of interpreters and focuses on how they may affect an international health care response. PMID- 21685312 TI - Suicide notes among Native Americans, Hispanics, and Anglos. AB - Suicide is a significant health problem, yet many questions regarding suicide remain unanswered. One of the most frequently asked questions is related to motive: "Why did that person complete suicide?" We explored motivations for completing suicide, especially with regard to cultural differences, by analyzing suicide notes written by Native Americans, Hispanics, and Anglos in New Mexico. Five categories emerged describing motivation: feelings of (a) alienation, (b) failure or inadequacy, (c) being psychologically overwhelmed; (d) the desire to leave problems behind, and (e) reunification in an afterlife. The largest difference to emerge between ethnic groups was in the alienation category, which included more Hispanics and Native Americans than Anglos. The overall lack of differences in motivation among the ethnic groups suggests that commonalities in suicidal behavior outweigh the differences. Practical implications for research and practice are discussed, along with strengths and limitations of the study. PMID- 21685311 TI - Curing and caring: the work of primary care physicians with dementia patients. AB - The symbolic framework guiding primary care physicians' (PCPs) practice is crucial in shaping the quality of care for those with degenerative dementia. Examining the relationship between the cure and care models in primary care offers a unique opportunity for exploring change toward a more holistic approach to health care. The aims of this study were to (a) explore how PCPs approach the care of patients with Alzheimer's disease (AD), and (b) describe how this care unfolds from the physicians' perspectives. This was a cross-sectional study of 40 PCPs who completed semistructured interviews as part of a dementia caregiving study. Findings show that PCPs recognize the limits of the cure paradigm and articulate a caring, more holistic model that addresses the psychosocial needs of dementia patients. However, caring is difficult to uphold because of time constraints, emotional burden, and jurisdictional issues. Thus, the care model remains secondary and temporary. PMID- 21685313 TI - Toes that look like toes: Cambodian children's perspectives on prosthetic legs. AB - When designing assistive devices for people with disabilities in developing countries, product developers tend to prioritize economic and technical requirements, ignoring aesthetic and cultural issues. This can result in devices that create or reinforce social barriers, creating negative impacts on users' self-esteem and sense of well-being. To understand the social implications of using prosthetic legs for Cambodian children, a pilot research study was conducted in Phnom Penh and surrounding provinces. I used innovative research methods to help children share their perspectives. The objective was to help product designers develop improved assistive devices that not only increase mobility for child prosthesis users but also support the sociocultural integration of these children and their families. A philosophical hermeneutics research approach was used to seek the views of three children. The findings are useful for nongovernmental organizations and product developers that focus on the needs of impoverished children in rural, predominantly Buddhist communities. PMID- 21685314 TI - Reciprocal potentiation of the antitumoral activities of FK866, an inhibitor of nicotinamide phosphoribosyltransferase, and etoposide or cisplatin in neuroblastoma cells. AB - NAD is an essential coenzyme involved in numerous metabolic pathways. Its principal role is in redox reactions, and as such it is not heavily "consumed" by cells. Yet a number of signaling pathways that bring about its consumption have recently emerged. This has brought about the hypothesis that the enzymes that lead to its biosynthesis may be targets for anticancer therapy. In particular, inhibition of the enzyme nicotinamide phosphoribosyl transferase has been shown to be an effective treatment in a number of preclinical studies, and two lead molecules [N-[4-(1-benzoyl-4-piperidinyl)butyl]-3-(3-pyridinyl)-2E-propenamide (FK866) and (E)-1-[6-(4-chlorophenoxy)hexyl]-2-cyano-3-(pyridin-4-yl)guanidine (CHS 828)] have now entered preclinical trials. Yet, the full potential of these drugs is still unclear. In the present study we have investigated the role of FK866 in neuroblastoma cell lines. We now confirm that FK866 alone in neuroblastoma cells induces autophagy, and its effects are potentiated by chloroquine and antagonized by 3-methyladenine or by down-regulating autophagy related protein 7. Autophagy, in this model, seems to be crucial for FK866 induced cell death. On the other hand, a striking potentiation of the effects of cisplatin and etoposide is given by cotreatment of cells with ineffective concentrations of FK866 (1 nM). The effect of etoposide on DNA damage is potentiated by FK866 treatment, whereas the effect of FK866 on cytosolic NAD depletion is potentiated by etoposide. Even more strikingly, cotreatment with etoposide/cisplatin and FK866 unmasks an effect on mitochondrial NAD depletion. PMID- 21685315 TI - Foot clearance in walking and running in individuals with ankle instability. AB - BACKGROUND: Foot positioning before heel strike has been attributed to chronic ankle instability injury mechanics, and may play a role in developing and perpetuating chronic ankle instability. PURPOSE: This study was undertaken to determine if a group of individuals with mechanical instability (MI) or a group with functional instability (FI) of the ankle joint demonstrate less foot-floor clearance and a more inverted and plantar flexed position of the foot during the terminal swing phase of the running and walking cycles when compared with a group of ankle sprain copers who had an injury but no residual instability. STUDY DESIGN: Controlled laboratory study. METHODS: Three-dimensional motion analysis was performed on 3 groups (n = 11 male athletes each) differentiated based on ankle injury history and ligamentous laxity during walking and running on a raised platform. RESULTS: The MI group (14.8 degrees +/- 12.0 degrees ) demonstrated greater maximum foot external rotation than the FI (3.2 degrees +/- 6.0 degrees ) and coper groups (2.9 degrees +/- 11.0 degrees ) (P = .01; eta(p) (2) = .25) during running and greater rotation than the coper group during walking (3.3 degrees +/- 6.1 degrees vs -4.5 degrees +/- 4.1 degrees ; P = .03; eta(p) (2) = .21). The FI group (6.1 degrees +/- 3.2 degrees ) had greater plantar flexion at minimum than the MI group (0.1 degrees +/- 3.5 degrees ) during walking (P = .02; eta(p) (2) = .25). Other group differences demonstrated large effect sizes, but not statistical significance, including unstable groups having lower minimum metatarsal height than copers during running. CONCLUSION: Differences in foot and leg position during terminal swing were observed between MI and FI groups and copers. Greater plantar flexion and lower minimum metatarsal height may increase risk for inadvertent contact and thus episodes of instability. CLINICAL RELEVANCE: Rehabilitation programs may need to address terminal swing to improve mechanics and avoid potential episodes of giving way at the ankle. PMID- 21685316 TI - Shoulder range of motion measures as risk factors for shoulder and elbow injuries in high school softball and baseball players. AB - BACKGROUND: Range of motion deficits in shoulder external rotation (ER), internal rotation (IR), total rotation range of motion (ER + IR), and horizontal adduction (HA) have been retrospectively associated with overhand athletes' arm injuries. HYPOTHESIS: The authors expected the incidence of upper extremity injury in high school softball and baseball players with side-to-side shoulder range of motion deficits to be greater than the incidence of upper extremity injury in players with normal shoulder range of motion. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: High school softball and baseball players (N = 246) participated. Before the start of the season, passive shoulder ER, IR, and HA were assessed at 90 degrees of abduction with the scapula stabilized. Relative risk (RR) was calculated to examine range of motion measure, by categorical criteria, and risk of upper extremity injury. RESULTS: Twenty-seven shoulder and elbow injuries (9 softball, 18 baseball) were observed during the season. The dominant shoulder of all injured players and baseball players displayed a significant decrease in HA (P = .05) and IR (P = .04). The dominant shoulder total rotation of injured baseball players displayed a significant decrease (mean difference = 8.0 degrees +/- 0.1 degrees ; P = .05) as compared with the dominant shoulder of uninjured baseball players. Players who displayed a decrease of >=25 degrees of IR in the dominant shoulder were at 4 times greater risk of upper extremity injury compared with players with a <25 degrees decrease in IR, especially for baseball players. While we observed a 1.5 to 2 times increased risk of injury for the 10 degrees to 20 degrees loss in rotational range of motion for the overall sample and baseball, the risk estimates were not statistically significant (P > .05). CONCLUSION: There are large mean deficits in shoulder IR and HA between injured and noninjured players, but not in ER or total rotation. Passive shoulder IR loss >=25 degrees as compared bilaterally was predictive of arm injury. Shoulder range of motion deficits differed between sports and appeared more predictive of injury for baseball players. PMID- 21685317 TI - Arthroscopic-assisted reduction and percutaneous cannulated screw fixation for Ideberg type III glenoid fractures: a minimum 2-year follow-up of 18 cases. AB - BACKGROUND: Traditionally, open reduction and internal fixation is an acceptable choice for treating displaced glenoid articular fracture. Considering some major complications associated with open surgery, however, surgeons have explored a less invasive way to achieve fixation. PURPOSE: This investigation was undertaken to evaluate the clinical results of arthroscopic-assisted reduction and percutaneous cannulated screw fixation for the treatment of Ideberg type III glenoid fractures. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty-three consecutive patients with Ideberg type III glenoid fractures underwent arthroscopic-assisted reduction and percutaneous cannulated screw fixation. Eighteen patients (78.3%) were available for the final follow-up, at a mean of 37.6 months (range, 24-61 months). There were 12 men and 6 women, with an average age of 41.2 years (range, 22-62 years). Dominant sides were involved in 10 patients. The mean time from injury to surgery was 5.9 +/- 2.7 days. RESULTS: The average ranges of motion of the affected shoulders at the final follow-up were 162.8 degrees +/- 8.3 degrees in forward elevation, 67.2 degrees +/- 4.6 degrees in external rotation at the side, and T8 +/- 2 in internal rotation. The average visual analog scale pain score was 0.7 +/- 0.9 (range, 0-3), the average American Shoulder and Elbow Surgeons score was 96.0 +/- 5.4 (range, 80-100), the average Constant-Murley score was 96.8 +/- 2.9 (range, 90-100), and the average University of California, Los Angeles, score was 34.3 +/- 0.9 (range, 33-35). No hardware failure or redisplacement of the fracture occurred, and all fractures healed without any major complication associated with the surgery. CONCLUSION: Arthroscopic-assisted reduction and percutaneous cannulated screw fixation is a safe and effective method for the treatment of Ideberg type III glenoid fractures. PMID- 21685319 TI - Evidence for host cells as the major contributor of lipids in the intravacuolar network of Toxoplasma-infected cells. AB - The intracellular parasite Toxoplasma gondii develops inside a parasitophorous vacuole (PV) that derives from the host cell plasma membrane during invasion. Previous electron micrograph images have shown that the membrane of this vacuole undergoes an extraordinary remodeling with an extensive network of thin tubules and vesicles, the intravacuolar network (IVN), which fills the lumen of the PV. While dense granule proteins, secreted during and after invasion, are the main factors for the organization and tubulation of the network, little is known about the source of lipids used for this remodeling. By selectively labeling host cell or parasite membranes, we uncovered evidence that strongly supports the host cell as the primary, if not exclusive, source of lipids for parasite IVN remodeling. Fluorescence recovery after photobleaching (FRAP) microscopy experiments revealed that lipids are surprisingly dynamic within the parasitophorous vacuole and are continuously exchanged or replenished by the host cell. The results presented here suggest a new model for development of the parasitophorous vacuole whereby the host provides a continuous stream of lipids to support the growth and maturation of the PVM and IVN. PMID- 21685318 TI - Protein arginine methylation in parasitic protozoa. AB - Protozoa constitute the earliest branch of the eukaryotic lineage, and several groups of protozoans are serious parasites of humans and other animals. Better understanding of biochemical pathways that are either in common with or divergent from those of higher eukaryotes is integral in the defense against these parasites. In yeast and humans, the posttranslational methylation of arginine residues in proteins affects myriad cellular processes, including transcription, RNA processing, DNA replication and repair, and signal transduction. The protein arginine methyltransferases (PRMTs) that catalyze these reactions, which are unique to the eukaryotic kingdom of organisms, first become evident in protozoa. In this review, we focus on the current understanding of arginine methylation in multiple species of parasitic protozoa, including Trichomonas, Entamoeba, Toxoplasma, Plasmodium, and Trypanosoma spp., and discuss how arginine methylation may play important and unique roles in each type of parasite. We mine available genomic and transcriptomic data to inventory the families of PRMTs in different parasites and the changes in their abundance during the life cycle. We further review the limited functional studies on the roles of arginine methylation in parasites, including epigenetic regulation in Apicomplexa and RNA processing in trypanosomes. Interestingly, each of the parasites considered herein has significantly differing sets of PRMTs, and we speculate on the importance of this diversity in aspects of parasite biology, such as differentiation and antigenic variation. PMID- 21685320 TI - Functional dissection of a Candida albicans zinc cluster transcription factor, the multidrug resistance regulator Mrr1. AB - The overexpression of the MDR1 gene, which encodes a multidrug efflux pump of the major facilitator superfamily, is a frequent cause of resistance to the widely used antimycotic agent fluconazole and other toxic compounds in the pathogenic yeast Candida albicans. The zinc cluster transcription factor Mrr1 controls MDR1 expression in response to inducing chemicals, and gain-of-function mutations in MRR1 are responsible for the constitutive MDR1 upregulation in fluconazole resistant C. albicans strains. To understand how Mrr1 activity is regulated, we identified functional domains of this transcription factor. A hybrid protein consisting of the N-terminal 106 amino acids of Mrr1 and the transcriptional activation domain of Gal4 from Saccharomyces cerevisiae constitutively induced MDR1 expression, demonstrating that the DNA binding domain is sufficient to target Mrr1 to the MDR1 promoter. Using a series of C-terminal truncations and systematic internal deletions, we could show that Mrr1 contains multiple activation and inhibitory domains. One activation domain (AD1) is located in the C terminus of Mrr1. When fused to the tetracycline repressor TetR, this distal activation domain induced gene expression from a TetR-dependent promoter. The deletion of an inhibitory region (ID1) located near the distal activation domain resulted in constitutive activity of Mrr1. The additional removal of AD1 abolished the constitutive activity, but the truncated Mrr1 still could activate the MDR1 promoter in response to the inducer benomyl. These results demonstrate that the activity of Mrr1 is regulated in multiple ways and provide insights into the function of an important mediator of drug resistance in C. albicans. PMID- 21685321 TI - Variation among Plasmodium falciparum strains in their reliance on mitochondrial electron transport chain function. AB - Previous studies demonstrated that Plasmodium falciparum strain D10 became highly resistant to the mitochondrial electron transport chain (mtETC) inhibitor atovaquone when the mtETC was decoupled from the pyrimidine biosynthesis pathway by expressing the fumarate-dependent (ubiquinone-independent) yeast dihydroorotate dehydrogenase (yDHODH) in parasites. To investigate the requirement for decoupled mtETC activity in P. falciparum with different genetic backgrounds, we integrated a single copy of the yDHODH gene into the genomes of D10attB, 3D7attB, Dd2attB, and HB3attB strains of the parasite. The yDHODH gene was equally expressed in all of the transgenic lines. All four yDHODH transgenic lines showed strong resistance to atovaquone in standard short-term growth inhibition assays. During longer term growth with atovaquone, D10attB-yDHODH and 3D7attB-yDHODH parasites remained fully resistant, but Dd2attB-yDHODH and HB3attB yDHODH parasites lost their tolerance to the drug after 3 to 4 days of exposure. No differences were found, however, in growth responses among all of these strains to the Plasmodium-specific DHODH inhibitor DSM1 in either short- or long term exposures. Thus, DSM1 works well as a selective agent in all parasite lines transfected with the yDHODH gene, whereas atovaquone works for some lines. We found that the ubiquinone analog decylubiquinone substantially reversed the atovaquone inhibition of Dd2attB-yDHODH and HB3attB-yDHODH transgenic parasites during extended growth. Thus, we conclude that there are strain-specific differences in the requirement for mtETC activity among P. falciparum strains, suggesting that, in erythrocytic stages of the parasite, ubiquinone-dependent dehydrogenase activities other than those of DHODH are dispensable in some strains but are essential in others. PMID- 21685323 TI - Ethyl pyruvate rescues nigrostriatal dopaminergic neurons by regulating glial activation in a mouse model of Parkinson's disease. AB - This study examined whether ethyl pyruvate (EP) promotes the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) mouse model of Parkinson's disease. MPTP induced degeneration of nigrostriatal DA neurons and glial activation as visualized by tyrosine hydroxylase, macrophage Ag complex-1, and/or glial fibrillary acidic protein immunoreactivity. Western blotting and immunohistochemistry showed activation of microglial NADPH oxidase and astroglial myeloperoxidase (MPO) and subsequent reactive oxygen species/reactive nitrogen species production and oxidative DNA damage in the MPTP-treated substantia nigra. Treatment with EP prevented degeneration of nigrostriatal DA neurons, increased striatal dopamine levels, and improved motor function. This neuroprotection afforded by EP was associated with the suppression of astroglial MPO expression, NADPH oxidase-, and/or inducible NO synthase-derived reactive oxygen species/reactive nitrogen species production by activated microglia. Interestingly, EP was found to protect DA neurons from 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia but not in neuron-enriched mesencephalic cultures devoid of microglia. The present findings show that EP may inhibit glial mediated oxidative stress, suggesting that EP may have therapeutic value in the treatment of aspects of Parkinson's disease related to glia-derived oxidative damage. PMID- 21685324 TI - Cutting edge: JAM-C controls homeostatic chemokine secretion in lymph node fibroblastic reticular cells expressing thrombomodulin. AB - The development and maintenance of secondary lymphoid organs, such as lymph nodes, occur in a highly coordinated manner involving lymphoid chemokine production by stromal cells. Although developmental pathways inducing lymphoid chemokine production during organogenesis are known, signals maintaining cytokine production in adults are still elusive. In this study, we show that thrombomodulin and platelet-derived growth factor receptor alpha identify a population of fibroblastic reticular cells in which chemokine secretion is controlled by JAM-C. We demonstrate that Jam-C-deficient mice and mice treated with Ab against JAM-C present significant decreases in stromal cell-derived factor 1alpha (CXCL12), CCL21, and CCL19 intranodal content. This effect is correlated with reduced naive T cell egress from lymph nodes of anti-JAM-C treated mice. PMID- 21685322 TI - Impairment of immunological synapse formation in adaptively tolerant T cells. AB - Adaptive tolerance is a hyporesponsive state in which lymphocyte Ag receptor signaling becomes desensitized after prolonged in vivo encounter with Ag. The molecular mechanisms underlying this hyporesponsive state in T cells are not fully understood, although a major signaling block has been shown to be present at the level of ZAP70 phosphorylation of linker for activation of T cells (LAT). In this study, we investigated the ability of adaptively tolerant mouse T cells to form conjugates with Ag-bearing APCs and to translocate signaling molecules into the interface between the T cells and APCs. Compared with naive or preactivated T cells, adaptively tolerant T cells showed no dramatic impairment in their formation of conjugates with APCs. In contrast, there was a large impairment in immunological synapse formation. Adaptively tolerant T cells were defective in their translocation of signaling molecules, such as ZAP70, LAT, and phospholipase C gamma1, into the T cell-APC contact sites. Although Ag-induced activation of VAV1 was normal, VAV's recruitment into the synapse was also impaired. Interestingly, expressions of both IL-2-inducible T cell kinase and growth factor receptor-bound protein 2-related adaptor downstream of SHC were decreased by 60-80% in adaptively tolerant T cells. These decreases, in addition to the impairment in LAT phosphorylation by ZAP70, appear to be the major impediments to the phosphorylation of SLP76 (SRC homology 2 domain-containing leukocyte protein of 76 kDa) and the recruitment of VAV1, which are important for stable immunological synapse formation. PMID- 21685325 TI - Induction of mucin and MUC5AC expression by the protease activity of Aspergillus fumigatus in airway epithelial cells. AB - Allergic bronchopulmonary mycosis, characterized by excessive mucus secretion, airflow limitation, bronchiectasis, and peripheral blood eosinophilia, is predominantly caused by a fungal pathogen, Aspergillus fumigatus. Using DNA microarray analysis of NCI-H292 cells, a human bronchial epithelial cell line, stimulated with fungal extracts from A. fumigatus, Alternaria alternata, or Penicillium notatum, we identified a mucin-related MUC5AC as one of the genes, the expression of which was selectively induced by A. fumigatus. Quantitative RT PCR, ELISA, and histochemical analyses confirmed an induction of mucin and MUC5AC expression by A. fumigatus extracts or the culture supernatant of live microorganisms in NCI-H292 cells and primary cultures of airway epithelial cells. The expression of MUC5AC induced by A. fumigatus extracts diminished in the presence of neutralizing Abs or of inhibitors of the epidermal growth factor receptor or its ligand, TGF-alpha. We also found that A. fumigatus extracts activated the TNF-alpha-converting enzyme (TACE), critical for the cleavage of membrane-bound pro-TGF-alpha, and its inhibition with low-molecular weight inhibitors or small interfering RNA suppressed the expression of MUC5AC. The protease activity of A. fumigatus extracts was greater than that of other fungal extracts, and treatment with a serine protease inhibitor, but not with a cysteine protease inhibitor, eliminated its ability to activate TACE or induce the expression of MUC5AC mRNA in NCI-H292. In conclusion, the prominent serine protease activity of A. fumigatus, which caused the overproduction of mucus by the bronchial epithelium via the activation of the TACE/TGF-alpha/epidermal growth factor receptor pathway, may be a pathogenetic mechanism of allergic bronchopulmonary mycosis. PMID- 21685326 TI - A requirement for the p85 PI3K adapter protein BCAP in the protection of macrophages from apoptosis induced by endoplasmic reticulum stress. AB - Macrophages are innate immune cells that play key roles in regulation of the immune response and in tissue injury and repair. In response to specific innate immune stimuli, macrophages may exhibit signs of endoplasmic reticulum (ER) stress and progress to apoptosis. Factors that regulate macrophage survival under these conditions are poorly understood. In this study, we identified B cell adapter protein (BCAP), a p85 PI3K-binding adapter protein, in promoting survival in response to the combined challenge of LPS and ER stress. BCAP was unique among nine PI3K adapter proteins in being induced >10-fold in response to LPS. LPS stimulated macrophages incubated with thapsigargin, a sarcoplasmic/endoplasmic reticulum calcium ATPase inhibitor that induces ER stress, underwent caspase-3 activation and apoptosis. Macrophages from BCAP(-/-) mice exhibited increased apoptosis in response to these stimuli. BCAP-deficient macrophages demonstrated decreased activation of Akt, but not ERK, and, unlike BCAP-deficient B cells, expressed normal amounts of the NF-kappaB subunits, c-Rel and RelA. Retroviral transduction of BCAP-deficient macrophages with wild-type BCAP, but not a Y4F BCAP mutant defective in binding the SH2 domain of p85 PI3K, reversed the proapoptotic phenotype observed in BCAP-deficient macrophages. We conclude that BCAP is a nonredundant PI3K adapter protein in macrophages that is required for maximal cell survival in response to ER stress. We suggest that as macrophages engage their pathogenic targets, innate immune receptors trigger increased expression of BCAP, which endows them with the capacity to withstand further challenges from ongoing cellular insults, such as ER stress. PMID- 21685327 TI - Role for MyD88, TLR2 and TLR9 but not TLR1, TLR4 or TLR6 in experimental autoimmune encephalomyelitis. AB - The potential roles of TLRs in the cause and pathogenesis of autoimmune CNS inflammation remain contentious. In this study, we examined the effects of targeted deletions of TLR1, TLR2, TLR4, TLR6, TLR9, and MyD88 on the induction of myelin oligodendrocyte glycoprotein 35-55 (MOG(35-55)) peptide/CFA/pertussis toxin-induced autoimmune encephalomyelitis. Although C57BL/6.Tlr1(-/-), C57BL/6.Tlr4(-/-) and C57BL/6.Tlr6(-/-) mice showed normal susceptibility to disease, signs were alleviated in female C57BL/6.Tlr2(-/-) and C57BL/6.Tlr9(-/-) mice and C57BL/6.Tlr2/9(-/-) mice of both sexes. C57BL/6.Myd88(-/-) mice were completely protected. Lower clinical scores were associated with reduced leukocyte infiltrates. These results were confirmed by passive adoptive transfer of disease into female C57BL/6.Tlr2(-/-) and C57BL/6.Tlr9(-/-) mice, where protection in the absence of TLR2 was associated with fewer infiltrating CD4(+) cells in the CNS, reduced prevalence of detectable circulating IL-6, and increased proportions of central (CD62L(+)) CD4(+)CD25(+)Foxp3(+) regulatory T cells. These results provide a potential molecular mechanism for the observed effects of TLR signaling on the severity of autoimmune CNS inflammation. PMID- 21685329 TI - Experimental hypertension triggers varicosis-like maladaptive venous remodeling through activator protein-1. AB - An increase in circumferential wall tension (CWT) is an important determinant of vascular remodeling during hypertension or arteriosclerosis but also arteriogenesis. Although pivotal for such processes, the effect of this biomechanical force on venous remodeling has not yet been delineated. To this end, we raised the filling pressure in veins of the mouse auricle, which led to a 2.5-fold enlargement of these blood vessels within 4 d along with an increase in smooth muscle cell proliferation, matrix metalloproteinase 2 (MMP-2) expression and gelatinase activity. These changes were likewise observed in tissue samples of human varicose veins. Topical treatment of the auricles with a decoy oligonucleotide-neutralizing activator protein 1 (AP-1) inhibited these effects. Likewise, proliferation, MMP-2 expression, and gelatinase activity in both native and cultured venous smooth muscle cells exposed to enhanced stretch was decreased by up to 80% through inhibiting AP-1. In contrast, mutant control oligonucleotides had no effect on smooth muscle cell activation. These findings indicate that an increase in venous filling pressure and thus CWT is sufficient to activate AP-1, which, in turn, triggers varicose remodeling through fuelling MMP-2 activity and smooth muscle cell hyperplasia in the venous vessel wall. PMID- 21685328 TI - Notch signaling regulates mouse and human Th17 differentiation. AB - Th17 cells are known to play a critical role in adaptive immune responses to several important extracellular pathogens. Additionally, Th17 cells are implicated in the pathogenesis of several autoimmune and inflammatory disorders as well as in cancer. Therefore, it is essential to understand the mechanisms that regulate Th17 differentiation. Notch signaling is known to be important at several stages of T cell development and differentiation. In this study, we report that Notch1 is activated in both mouse and human in vitro-polarized Th17 cells and that blockade of Notch signaling significantly downregulates the production of Th17-associated cytokines, suggesting an intrinsic requirement for Notch during Th17 differentiation in both species. We also present evidence, using promoter reporter assays, knockdown studies, as well as chromatin immunoprecipitation, that IL-17 and retinoic acid-related orphan receptor gammat are direct transcriptional targets of Notch signaling in Th17 cells. Finally, in vivo inhibition of Notch signaling reduced IL-17 production and Th17-mediated disease progression in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Thus, this study highlights the importance of Notch signaling in Th17 differentiation and indicates that selective targeted therapy against Notch may be an important tool to treat autoimmune disorders, including multiple sclerosis. PMID- 21685330 TI - Angiopoietin-2 drives lymphatic metastasis of pancreatic cancer. AB - Lymphatic metastasis constitutes a critical route of disease dissemination, which limits the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). As lymphangiogenesis has been implicated in stimulation of lymphatic metastasis by vascular endothelial growth factor-C (VEGF-C) and VEGF-D, we studied the effect of the angioregulatory growth factor angiopoietin-2 (Ang-2) on PDAC progression. Ang-2 was found to be expressed in transformed cells of human PDAC specimens, with corresponding Tie-2 receptors present on blood and lymphatic endothelium. In vitro in PDAC cells, Ang-2 was subject to autocrine/paracrine TGF-beta stimulation (2-fold induction, P=0.0106) acting on the -61- to +476-bp element of the human Ang-2 promoter. In turn, Ang-2 regulated the expression of genes involved in cell motility and tumor suppression. Orthotopic PDAC xenografts with forced expression of Ang-2, but not Ang-1, displayed increased blood and lymphatic vessel density, and an enhanced rate of lymphatic metastasis (6.7- to 9.1-fold, P<0.01), which was prevented by sequestration of Ang-2 via coexpression of soluble Tie-2. Notably, elevated circulating Ang-2 in patients with PDAC correlated with the extent of lymphatic metastasis. Furthermore, median survival was reduced from 28.4 to 7.7 mo in patients with circulating Ang-2 >= 75th percentile (P=0.0005). These findings indicate that Ang-2 participates in the control of lymphatic metastasis, constitutes a noninvasive prognostic biomarker, and may provide an accessible therapeutic target in PDAC. PMID- 21685331 TI - Kruppel-like factor 4 (KLF4) directly regulates proliferation in thymocyte development and IL-17 expression during Th17 differentiation. AB - Kruppel-like factor 4 (KLF4), a transcription factor, plays a key role in the pluripotency of stem cells. We sought to determine the function of KLF4 in T-cell development and differentiation by using T-cell-specific Klf4-knockout (KO) mice. We found that KLF4 was highly expressed in thymocytes and mature T cells and was rapidly down-regulated in mature T cells after activation. In Klf4-KO mice, we observed a modest reduction of thymocytes (27%) due to the reduced proliferation of double-negative (DN) thymocytes. We demonstrated that a direct repression of Cdkn1b by KLF4 was a cause of decreased DN proliferation. During in vitro T-cell differentiation, we observed significant reduction of IL-17-expressing CD4(+) T cells (Th17; 24%) but not in other types of Th differentiation. The reduction of Th17 cells resulted in a significant attenuation of the severity (35%) of experimental autoimmune encephalomyelitis in vivo in Klf4-KO mice as compared with the Klf4 wild-type littermates. Finally, we demonstrated that KLF4 directly binds to the promoter of Il17a and positively regulates its expression. In summary, these findings identify KLF4 as a critical regulator in T-cell development and Th17 differentiation. PMID- 21685332 TI - Structure-based prediction reveals capping motifs that inhibit beta-helix aggregation. AB - The parallel beta-helix is a geometrically regular fold commonly found in the proteomes of bacteria, viruses, fungi, archaea, and some vertebrates. beta-helix structure has been observed in monomeric units of some aggregated amyloid fibers. In contrast, soluble beta-helices, both right- and left-handed, are usually "capped" on each end by one or more secondary structures. Here, an in-depth classification of the diverse range of beta-helix cap structures reveals subtle commonalities in structural components and in interactions with the beta-helix core. Based on these uncovered commonalities, a toolkit of automated predictors was developed for the two distinct types of cap structures. In vitro deletion of the toolkit-predicted C-terminal cap from the pertactin beta-helix resulted in increased aggregation and the formation of soluble oligomeric species. These results suggest that beta-helix cap motifs can prevent specific, beta-sheet mediated oligomeric interactions, similar to those observed in amyloid formation. PMID- 21685333 TI - Dynamic instability-driven centering/segregating mechanism in bacteria. AB - All cells require the ability to process spatial information to properly position intracellular molecules. Many protein complexes and DNA molecules are actively positioned either at the cell midpoint or cell poles, but the processes which drive intracellular positioning are still poorly understood. Using computational modeling we propose a bimodal centering/segregation mechanism in bacteria which is driven by the dynamic instability of polymerizing filaments, which grow and shrink with regularity. Modeled cell centering via dynamically unstable filaments is confirmed experimentally via in vivo time-lapse, colocalization measurements of a model system of clustered plasmid-DNA centered by the dynamically unstable actin-like protein filaments Alp7A in Bacillus subtilis. Generalizing to any cylindrical cell, we find strong cell-length dependence in the centering ability of dynamically unstable filaments, culminating in pole positioning when cell length decreases significantly below the theoretically predicted average filament length. Modeling dynamic instability-driven positioning mechanisms from multiple anisotropic in vivo systems demonstrates that dynamically unstable filaments are a general mechanism for both midcell and cell-pole (segregation) positioning, and that desired positioning is preferentially selected in vivo by intrinsic filament polymerization rates and number. PMID- 21685334 TI - Telomerase regulatory subunit Est3 in two Candida species physically interacts with the TEN domain of TERT and telomeric DNA. AB - The yeast telomerase regulatory protein Est3 is required for telomere maintenance in vivo, and shares intriguing structural and functional similarities with the mammalian telomeric protein TPP1. Here we report our physical and functional characterizations of Est3 homologues from Candida parapsilosis and Lodderomyces elongisporus, which bear unique N- and C-terminal tails in addition to a conserved central OB fold. We show that these Est3 homologues form stable complexes with the TEN domain of telomerase reverse transcriptase. Efficient complex formation requires both the N- and C-terminal tails, as well as conserved OB fold residues of Est3. Other Est3 homologues devoid of the tails failed to interact strongly with the cognate TEN domains. Remarkably, the C. parapsilosis Est3 alone exhibits no appreciable DNA-binding activity, but can be crosslinked to telomeric DNA in the presence of the TEN domain. A conserved basic residue on the putative DNA-binding surface of CpEst3 is required for efficient crosslinking. Mutating the equivalent residue in Candida albicans Est3 caused telomere attrition. We propose that interaction with the TEN domain unmasks a functionally important nucleic acid-binding activity in Est3. Our findings provide insights on the mechanisms and evolution of a widely conserved and functionally critical telomeric/telomerase component. PMID- 21685335 TI - Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes. AB - We present an intuitive strategy for predicting the effect of sequence variation on splicing. In contrast to transcriptional elements, splicing elements appear to be strongly position dependent. We demonstrated that exonic binding of the normally intronic splicing factor, U2AF65, inhibits splicing. Reasoning that the positional distribution of a splicing element is a signature of its function, we developed a method for organizing all possible sequence motifs into clusters based on the genomic profile of their positional distribution around splice sites. Binding sites for serine/arginine rich (SR) proteins tended to be exonic whereas heterogeneous ribonucleoprotein (hnRNP) recognition elements were mostly intronic. In addition to the known elements, novel motifs were returned and validated. This method was also predictive of splicing mutations. A mutation in a motif creates a new motif that sometimes has a similar distribution shape to the original motif and sometimes has a different distribution. We created an intraallelic distance measure to capture this property and found that mutations that created large intraallelic distances disrupted splicing in vivo whereas mutations with small distances did not alter splicing. Analyzing the dataset of human disease alleles revealed known splicing mutants to have high intraallelic distances and suggested that 22% of disease alleles that were originally classified as missense mutations may also affect splicing. This category together with mutations in the canonical splicing signals suggest that approximately one third of all disease-causing mutations alter pre-mRNA splicing. PMID- 21685337 TI - Relationship between outer retinal thickness substructures and visual acuity in eyes with dry age-related macular degeneration. AB - PURPOSE: To explore the correlation between outer retinal substructures and visual acuity in dry age-related macular degeneration (AMD). METHODS: Analysis of spectral domain optical coherence tomography datasets from 100 eyes of 100 consecutive patients with dry AMD was performed. The internal limiting membrane, outer nuclear layer (ONL), external limiting membrane (ELM), inner segment-outer segment (IS-OS) junction, outer photoreceptor border, inner and outer retinal pigment epithelium (RPE) borders, and Bruch's membrane, were manually segmented by Doheny Image Reading Center (DIRC) graders. Areas, thicknesses, and volumes of RPE, IS, OS, ONL, and the total retina in the foveal central subfield were correlated with the logarithm of minimal angle of resolution (logMAR) visual acuity using univariable and multivariable regression analysis. RESULTS: The visual acuity in this group ranged from logMAR 0 to 1.3 with a mean of 0.23. Areas, thicknesses, and volumes of ONL, IS and OS, thicknesses of total retinal and RPE, and intensities of IS, OS, and RPE, showed statistically significant association (P < 0.05) with logMAR best corrected visual acuity. The highest correlations were observed for the ONL (thickness: r = -0.49, volume: -0.47, area: -0.50) and photoreceptor IS (thickness: -0.59, area: -0.63, volume: -0.53). The model with the highest correlation in this study included thicknesses of ONL, IS, OS and RPE, as well as area of ONL, IS, OS, RPE, and intensity of RPE. CONCLUSIONS. Although integrity of outer retinal substructures in the foveal central subfield correlates with visual acuity in the eyes of patients with dry AMD, the correlation is only moderate and does not fully explain the variability in acuity in these cases. PMID- 21685338 TI - Effect and distribution of contrast medium after injection into the anterior suprachoroidal space in ex vivo eyes. AB - PURPOSE: To determine the effects and posterior distribution of injections made into the anterior suprachoroidal space (SCS). METHODS: The anterior SCS of adult porcine and canine ex vivo eyes was cannulated. Latex injections and high frequency ultrasound (50 MHz) was used to image the effect and distension of the SCS. Flow characteristics and percentage maximal distribution of microbubble contrast injection into the SCS were assessed by 2D and 3D ultrasound. RESULTS: Mean (SD) distension of the SCS with PBS increased from 1.57 (0.48) mm after injection of 250 MUL to 3.28 (0.57) mm with 1000 MUL PBS. Eyes injected at physiologic IOP had no significant difference in SCS distension. In real-time 2D ultrasound, the contrast agent flowed from the injection site to the opposite ventral anterior SCS and the posterior SCS. Contrast arrived at the opposite and posterior SCS 7.8 (4.6) and 7.7 (4.6) seconds after injection, respectively. In sagittal images, contrast was visible in 24.0%to 27.2% of the SCS; in 10 of 12 eyes, contrast reached the posterior pole of the eye. In 3D images, contrast medium occupied 39.0% to 52.1% of the entire SCS. CONCLUSIONS: These results suggest that the SCS can expand, in a dose-dependent manner, to accommodate various volumes of fluid and that it is possible to image the SCS with ultrasound contrast. The authors' hypothesis that a single anterior SCS injection can reach the ocular posterior segment was supported. Further development of SCS injections for treatment of the ocular posterior segment is warranted. PMID- 21685339 TI - The influence of corneoscleral topography on soft contact lens fit. AB - PURPOSE: To evaluate the influence of peripheral ocular topography, as evaluated by optical coherence tomography (OCT), compared with traditional measures of corneal profile using keratometry and videokeratoscopy, on soft contact lens fit. METHODS: Ocular surface topography was analyzed in 50 subjects aged 22.8 years (SD +/-5.0) using videokeratoscopy (central keratometry, corneal height, and shape factor) and OCT to give both full sagittal cross-sections of the cornea and cross-sections of the corneoscleral junctions. Corneoscleral junction angle, corneal diameter, corneal sagittal height, and scleral radius were analyzed from the images. Horizontal visible iris diameter and vertical palpebral aperture were analyzed from digital slit lamp images. Lens fit was graded after 30 minutes wear of a -2.50 D commercially available standard hydrogel (etafilcon A, modulus 0.30 MPa) and silicone hydrogel (galyfilcon A, 0.43 MPa) design of similar geometries (8.30-mm base curve, 14.0-mm diameter). RESULTS: The mean horizontal corneal diameter was 13.39 mm (SD +/-0.44). In many cases, there was a tangential transition at the corneoscleral junction. The corneoscleral shape profile analyzed from cross-sectional OCT images contributed significantly (P < 0.001) to the prediction of soft contact lens fit compared with keratometry and videokeratoscopy, accounting for up to 24% of the variance in lens movement. The fit of the stiffer material silicone hydrogel lens was better able to be predicted and was more varied than the hydrogel contact lens. CONCLUSIONS: The extra peripheral corneoscleral data gained from OCT characterization of ocular surface architecture provide valuable insight into soft contact lens fit dynamics. PMID- 21685340 TI - How reliable are tests for trachoma?--a latent class approach. AB - PURPOSE: Tests for ocular Chlamydia trachomatis have not been well characterized, because there is no gold standard test. Latent class analysis (LCA) was performed to estimate the sensitivity and specificity of laboratory and clinical tests for trachoma in the absence of a gold standard. METHODS: Individual data from pretreatment, hyperendemic areas in Ethiopia were used. A clustered LCA was performed for three diagnostic tests: PCR and WHO simplified criteria grades of follicular trachoma (TF) and intense trachomatous inflammation (TI). RESULTS: Data from 2111 subjects in 40 villages were available. TF was estimated to be 87.3% (95% CI, 83.3-90.1) sensitive and 36.6% (95% CI, 23.6-40.3) specific; TI was estimated to be 53.6% (95% CI, 46.1-88.0) sensitive and 88.3% (95% CI, 83.3 92.0) specific, and PCR was estimated to be 87.5% (95% CI, 79.9-97.2) sensitive and 100% (95% CI 69.3-100) specific. CONCLUSIONS: LCA allows for an estimate of test characteristics without prior assumption of their performance. TF and TI were found to act in a complementary manner: TF is a sensitive test and TI is a specific test. PCR is highly specific but lacks sensitivity. The performance of these tests may be due to the time course of ocular chlamydial infection, and for this reason, results may differ in areas of low prevalence or recent mass treatment (ClinicalTrials.gov number, NCT00221364). PMID- 21685341 TI - Interaction of alpha1D-adrenergic and P2X(7) receptors in the rat lacrimal gland and the effect on intracellular [Ca2+] and protein secretion. AB - PURPOSE: To determine whether alpha(1D)-adrenergic receptors (alpha(1D)-AR) and P2X(7) receptors interact by determining their effect on ATP release, intracellular [Ca(2+)] ([Ca(2+)](i)), and protein secretion in rat lacrimal gland acini. METHODS: Exorbital lacrimal glands from male Sprague-Dawley rats were divided into pieces or digested with collagenase to form acini. With the use of an imaging system, [Ca(2+)](i) was measured in acini loaded with fura-2. Adenosine triphosphate (ATP) release was determined using the luciferin luciferase reaction. Peroxidase secretion, our index for protein secretion, was measured spectrophotometrically. Acini were stimulated with the P2X(7) receptor agonist, (benzoylbenzoyl)adenosine 5' triphosphate (BzATP) or the alpha(1D)-AR agonist phenylephrine with or without antagonist preincubation. RESULTS: Phenylephrine increased ATP release from pieces in a time-dependent manner. The alpha(1D)-AR antagonist BMY7378 blocked the BzATP-stimulated increase in [Ca(2+)](i) but not in peroxidase secretion. The P2X(7) antagonist A438079 blocked the phenylephrine-stimulated increase in [Ca(2+)](i) but not peroxidase secretion. The increase in [Ca(2+)](i) caused by phenylephrine and BzATP used simultaneously or sequentially was additive, as was the increase in peroxidase secretion. The inhibition of protein kinase C isoforms or calcium calmodulin kinase II did not alter the BzATP-induced increase in [Ca(2+)](i). CONCLUSIONS: The authors conclude that activation of alpha(1D)-AR releases ATP, which induces P2X(7) receptors to increase [Ca(2+)](i) but not to stimulate protein secretion. P2X(7) receptors in turn activate alpha(1D)-AR to increase [Ca(2+)](i) but not to stimulate protein secretion. Furthermore, alpha(1D)-AR compared with P2X(7) receptors use different cellular mechanisms to increase [Ca(2+)](i) and cause protein secretion. PMID- 21685342 TI - Activation of MAPK signaling pathway and NF-kappaB activation in pterygium and ipsilateral pterygium-free conjunctival specimens. AB - PURPOSE: To evaluate mitogen-activated protein kinases (MAPKs) and nuclear factor kappaB (NF-kappaB) signaling pathways in pterygium and pterygium-free conjunctivas. METHODS: Primary pterygia (n = 21), ipsilateral superior-temporal bulbar conjunctivas (n = 8), and healthy conjunctival (n = 5) biopsy specimens were analyzed. Total and phosphorylated (phospho) levels of extracellular regulated 1/2 (ERK1/2), p38, and c-jun N-terminal (JNK) MAPKs and NF-kappaB inhibitor-alpha (IkappaBeta-alpha) were analyzed by immunobead-based assay. Tissue phospho-, total protein, and activation values determined by phospho/total ratios were compared. Correlation among those values and clinical parameters were determined. Average-linkage hierarchical cluster analysis identified patients with similar protein activation values. The k-nearest neighbor classifier predicted the origin of specimens based on protein levels. RESULTS: Pterygium samples had significantly lower total JNK and IkappaBeta-alpha levels than did healthy conjunctivas. Decreased total JNK and IkappaBeta-alpha and increased phospho-IkappaBeta-alpha levels and phospho/total ratio of JNK and IkappaBeta alpha were present in ipsilateral conjunctivas compared with healthy conjunctivas. Protein levels were correlated among them in pterygium, ipsilateral, and healthy conjunctivas and with sun exposure, pterygium grade, and pterygium measurements. Cluster analysis of activation values and ratios in pterygium and ipsilateral-conjunctiva revealed different groups of patients with similar values. Prediction accuracy was 70% to 80% for the classifiers phospho- and total protein levels and phospho/total ratio. CONCLUSIONS: Pterygium and pterygium-free ipsilateral conjunctivas had alterations in MAPK and NF-kappaB pathways not present in healthy conjunctivas. The high prediction accuracy based on phospho- and total protein levels and phospho/total ratio of ERK1/2, p38, JNK, and IkappaB-alpha suggests these molecules as potential biomarkers of inflammation in pterygia. PMID- 21685343 TI - PET/CT imaging of I-124-radiolabeled bevacizumab and ranibizumab after intravitreal injection in a rabbit model. AB - PURPOSE: To determine whether bevacizumab and ranibizumab remain confined within the vitreous cavity after intravitreal injection and to determine the pharmacokinetic properties of these agents within the vitreous cavity. METHODS: Radiolabeling with I-124 was completed using a modified Iodogen method. After testing for radiochemical purity, three anesthetized Dutch-belted rabbits underwent intravitreal injection with I-124 bevacizumab, and three underwent it with I-124 ranibizumab. All rabbits were imaged with a Micro PET-CT scanner on days 0, 2, 5, 7, 14, 21, 28, and 35. RESULTS: The intravitreally placed radiolabeled agents were found to be contained within the vitreous cavity for the duration of the study with no extravasation into the central nervous system or elsewhere. I-124 bevacizumab was detectable until day 28, whereas I-124 ranibizumab was detectable until day 21. The kinetic model appears to represent a two-compartment model, and the average retention times for bevacizumab and ranibizumab after correction for radioactive decay were found to be 4.2 days and 2.8 days, respectively. CONCLUSIONS: There was no significant escape of bevacizumab and ranibizumab from the vitreous cavity after intravitreal injection. After correction for radioactive decay, both agents remained detectable until 28 and 21 days, respectively, with retention properties that validated those methods reported in previous studies. PMID- 21685345 TI - Central processing energetic factors mediate impaired motor control in ADHD combined subtype but not in ADHD inattentive subtype. AB - Participants with attention-deficit/hyperactivity disorder (ADHD) are often impaired in visuomotor tasks. However, little is known about the contribution of modal impairment in motor function relative to central processing deficits or whether different processes underlie the impairment in ADHD combined (ADHD-C) versus ADHD inattentive (ADHD-I) subtype. The present study analyzes performance on the Visual Motor Integration Test relative to less effortful motor tests as well as on measures of energetics. Both ADHD groups showed evidence of impaired motor function on both visual-motor integration (VMI) and the less effortful motor tests. The ADHD-C group performed below the ADHD-I group on VMI, but their performance correlated highly with the measures of the energetic pools of arousal and effort. Different mechanisms may underlie impaired fine motor skills in ADHD. Central processing deficits contribute significantly to the deficit of ADHD-C but do not explain the motor impairment in ADHD-I. PMID- 21685344 TI - SSEA4 is a potential negative marker for the enrichment of human corneal epithelial stem/progenitor cells. AB - PURPOSE: To examine the expression of stage-specific embryonic antigen-4 (SSEA4) in the epithelium of the human ocular surface and characterize SSEA4(+) and SSEA4(-) limbal epithelial cells. METHODS: SSEA4 expression in the human cornea and limbus was examined by RT-PCR and immunohistochemistry. SSEA4(+) and SSEA4(-) cells were then separated by using magnetic beads. The phenotypes of these two cell populations were evaluated on the basis of cell size, clonogenic assay, and expression of putative limbal stem cell (LSC) and corneal epithelial differentiation markers. RESULTS: SSEA4 was expressed in all layers of the corneal and anterior limbal epithelia. Discrete clusters of SSEA4(+) cells were present in the central and posterior limbal epithelia. SSEA4(+) cells accounted for an average of 40% of the total limbal epithelial cells. The SSEA4(-) population contained five times more small cells (<=11 MUm in diameter) than did the SSEA4(+) population. The expression levels of the putative LSC markers ABCG2, DeltaNp63alpha, and cytokeratin (K)14 were significantly higher in the SSEA4(-) population than in the SSEA4(+) population. The SSEA4(-) cells also expressed a significantly higher level of N-cadherin, but a lower level of the differentiation marker K12. The colony-forming efficiency in the SSEA4(-) population was 25.2% (P = 0.04) and 1.6-fold (P < 0.05) higher than in the unsorted population and the SSEA4(+) population, respectively. CONCLUSIONS: SSEA4 is highly expressed in differentiated corneal epithelial cells, and SSEA4(-) limbal epithelial cells contain a higher proportion of limbal stem/progenitor cells. SSEA4 could be used as a negative marker to enrich the isolation of LSCs. PMID- 21685346 TI - A number sense intervention for low-income kindergartners at risk for mathematics difficulties. AB - Early number sense is a strong predictor of later success in school mathematics. A disproportionate number of children from low-income families come to first grade with weak number competencies, leaving them at risk for a cycle of failure. The present study examined the effects of an 8-week number sense intervention to develop number competencies of low-income kindergartners (N = 121). The intervention purposefully targeted whole number concepts related to counting, comparing, and manipulating sets. Children were randomly assigned to either a number sense intervention or a business as usual contrast group. The intervention was carried out in small-group, 30-min sessions, 3 days per week, for a total of 24 sessions. Controlling for number sense at pretest, the intervention group made meaningful gains relative to the control group at immediate as well delayed posttest on a measure of early numeracy. Intervention children also performed better than controls on a standardized test of mathematics calculation at immediate posttest. PMID- 21685347 TI - The construct and predictive validity of a dynamic assessment of young children learning to read: implications for RTI frameworks. AB - The purpose of this study was to examine the construct and predictive validity of a dynamic assessment (DA) of decoding learning. Students (N = 318) were assessed in the fall of first grade on an array of instruments that were given in hopes of forecasting responsiveness to reading instruction. These instruments included DA as well as one-point-in-time (static) measures of early alphabetic knowledge, rapid automatized naming (RAN), phonemic awareness, oral vocabulary, listening comprehension, attentive behavior, and hyperactive or impulsive behavior. An IQ test was administered in spring of second grade. Measures of reading outcomes administered in spring of first grade were accuracy and fluency of word identification skills and reading comprehension. Factor analysis using principal axis factor extraction indicated that DA loaded on a first factor that also included language abilities and IQ, which the authors refer to as the "language, IQ, and DA" factor. It was relatively distinct from two additional factors: (a) "speeded alphabetic knowledge and RAN" and (b) "task-oriented behavior." A three level (children nested within classroom; classrooms nested within school) random intercept model with fixed effects predictors suggested that DA differed from word attack in predicting future reading skill and that DA was a significant predictor of responsiveness to instruction, contributing unique variance to end of-first-grade word identification and reading comprehension beyond that explained by other well-established predictors of reading development. PMID- 21685348 TI - Creating a brief rating scale for the assessment of learning disabilities using reliability and true score estimates of the scale's items based on the Rasch model. AB - The purpose of the present studies was to provide the means to create brief versions of instruments that can aid the diagnosis and classification of students with learning disabilities and comorbid disorders (e.g., attention deficit/hyperactivity disorder). A sample of 1,108 students with and without a diagnosis of learning disabilities took part in study 1. Using information from modern theory methods (i.e., the Rasch model), a scale was created that included fewer than one third of the original battery items designed to assess reading skills. This best item synthesis was then evaluated for its predictive and criterion validity with a valid external reading battery (study 2). Using a sample of 232 students with and without learning disabilities, results indicated that the brief version of the scale was equally effective as the original scale in predicting reading achievement. Analysis of the content of the brief scale indicated that the best item synthesis involved items from cognition, motivation, strategy use, and advanced reading skills. It is suggested that multiple psychometric criteria be employed in evaluating the psychometric adequacy of scales used for the assessment and identification of learning disabilities and comorbid disorders. PMID- 21685349 TI - Implementing RTI in a high school: a case study. AB - This case study chronicles the efforts of a small high school over a 2-year period as it designed an implemented a response to intervention (RTI) program for students at the school. Their efforts were largely successful, with improved achievement, attendance, and grade point averages and a decrease in special education referrals. Major themes include the need to focus on quality core instruction as a means for preventing school failure, adopting a schoolwide approach, and developing curriculum-based assessments that make intervention meaningful. PMID- 21685350 TI - Comparing two forms of dynamic assessment and traditional assessment of preschool phonological awareness. AB - The goal of the current study was to compare two forms of dynamic assessment and standard assessment of preschool children's phonological awareness. The first form of dynamic assessment was a form of scaffolding in which item formats were modified in response to an error so as to make the task easier or more explicit. The second form of dynamic assessment was direct instruction of the phonological awareness tasks. The results indicate that preschool children's phonological awareness can be assessed using standard assessment procedures, provided the items require processing units larger than the individual phoneme. No advantage was found in reliability or validity for either dynamic assessment condition relative to the standard assessment condition. Dynamic assessment does not appear to improve reliability or validity of phonological awareness assessments when preschool children are given tasks that they can perform using standard administration procedures. PMID- 21685351 TI - Exploring dynamic assessment as a means of identifying children at risk of developing comprehension difficulties. AB - In this study, the authors explore a newly constructed dynamic assessment (DA) intended to tap inference-making skills that they hypothesize will be predictive of future comprehension performance. The authors administered the test to 100 second-grade children using a dynamic format to consider the concurrent validity of the measure. The dynamic portion of the assessment comprised teaching children to be "reading detectives" by using textual clues to solve what was happening in the story. During the DA children listened to short passages and answered three inferential questions (i.e., one setting, two causal). If children were unable to answer a question, they were reminded what a reading detective would do and given a set of increasingly concrete prompts and clues to orient them to the relevant portion of text until they could answer the question correctly. Results showed that the DA correlated significantly with a standardized measure of reading comprehension and explained a small but significant amount of unique variance in reading comprehension above and beyond vocabulary and word identification skills. In addition, results suggest that DA may be better than the standardized measure of reading comprehension at identifying intraindividual differences in young children's reading abilities. PMID- 21685352 TI - Two-stage screening for math problem-solving difficulty using dynamic assessment of algebraic learning. AB - The purpose of this study was to explore the utility of a dynamic assessment (DA) of algebraic learning in predicting third graders' development of mathematics word-problem difficulty. In the fall, 122 third-grade students were assessed on a test of math word-problem skill and DA of algebraic learning. In the spring, they were assessed on word-problem performance. Logistic regression was conducted to contrast two models. One relied exclusively on the fall test of math word-problem skill to predict word-problem difficulty on the spring outcome (less than the 25th percentile). The second model relied on a combination of the fall test of math word-problem skill and the fall DA to predict the same outcome. Holding sensitivity at 87.5%, the universal screener alone resulted in a high proportion of false positives, which was practically reduced when DA was included in the prediction model. Findings are discussed in terms of a two-stage process for screening students within a responsiveness-to-intervention prevention model. PMID- 21685353 TI - Clock reading: an underestimated topic in children with mathematics difficulties. AB - Recent studies have shown that children with mathematics difficulties (MD) have weaknesses in multiple areas of mathematics. Andersson, for example, recently found that children with MD perform significantly worse than other children on clock reading tasks. The present study builds on this recent finding and aims at a more profound understanding of the difficulties that children with MD experience with telling time. Therefore, clock reading abilities of 154 children with MD were compared to the abilities of 571 average achieving children, and a qualitative error analysis was performed. The results of this study confirm the earlier findings of Andersson that children with MD perform worse on clock reading than average achieving children and also show that children with MD especially struggle with the combination of procedural and retrieval strategies that are needed to read complex 5-min and 1-min clock times. Children with MD make more errors, which reflects immature counting strategies and deficits in memory retrieval. This finding is in line with Geary's theory of subtypes in MD, which argues that children with MD have problems with mathematical procedures and semantic memory retrieval. PMID- 21685354 TI - Emergent literacy intervention for prekindergartners at risk for reading failure: years 2 and 3 of a multiyear study. AB - This research examined the effectiveness of an emergent literacy intervention for prekindergarten children at risk for reading failure, to replicate and improve on significant findings from year 1 of the study. Data are reported for 266 children in 72 child care and preschool sites in year 2 of the study and for 374 children at 102 sites in year 3. The intervention consisted of eighteen 30-min lessons delivered twice weekly to small groups of children. Lessons targeted critical emergent literacy skills through explicit, developmentally appropriate activities for prekindergartners. Hierarchical linear models were used to nest children within center and measure treatment effects on phonological awareness, alphabet knowledge, and vocabulary skills. Results indicated significant treatment effects on multiple measures in years 2 and 3. This study replicated and strengthened findings from year 1 in demonstrating a positive impact of this intervention for prekindergarteners at risk for reading failure. PMID- 21685355 TI - Serological memory and long-term protection to novel H1N1 influenza virus after skin vaccination. AB - BACKGROUND: A major goal in influenza vaccine development is induction of serological memory and cellular responses to confer long-term protection and limit virus spread after infection. Here, we investigate induction of long-lived immunity against the 2009 H1N1 virus after skin vaccination. METHODS: BALB/c mice received a single dose of 5 MUg inactivated A/California/04/09 virus via coated metal microneedles (MN) applied to skin or via subcutaneous injection. RESULTS: MN or subcutaneous vaccination elicited similar serum IgG and hemagglutination inhibition titers and 100% protection against lethal viral challenge 6 weeks after vaccination. Six months after vaccination, the subcutaneous group exhibited a 60% decrease in functional antibody titers and extensive lung inflammation after challenge with 10 * LD(50) of homologous virus. In contrast, the MN group maintained high functional antibody titers and IFN-gamma levels, inhibition of viral replication, and no signs of lung inflammation after challenge. MN vaccination conferred complete protection against lethal challenge, whereas subcutaneous vaccination induced only partial protection. These findings were further supported by high numbers of bone marrow plasma cells and spleen antibody secreting cells detected in the MN group. CONCLUSIONS: A single skin vaccination with MN induced potent long-lived immunity and improved protection against the 2009 H1N1 influenza virus, compared with subcutaneous injection. PMID- 21685356 TI - Inconsistencies in findings from the early lung cancer action project studies of lung cancer screening. AB - Long-standing guidelines against screening high-risk individuals for lung cancer may change following the publication of the randomized National Lung Screening Trial (NLST), which shows a benefit of computed tomography compared with chest x ray screening. Guideline panels will likely also seek additional information from nonrandomized studies of computed tomography screening, such as the Early Lung Cancer Action Project (ELCAP). However, for the ELCAP findings to be incorporated into new guidelines, some inconsistencies in the published data should first be resolved. Specifically, some of the reports from ELCAP appear to contradict others in terms of important endpoints, and several findings from ELCAP appear to be statistically improbable or outliers when compared with analyses and studies by other research groups. Clarification of both internal and external inconsistencies is a prerequisite for evaluation of the body of work published by ELCAP investigators. PMID- 21685357 TI - Increased levels of circulating interleukin 6, interleukin 8, C-reactive protein, and risk of lung cancer. AB - BACKGROUND: Previous studies that were based primarily on small numbers of patients suggested that certain circulating proinflammatory cytokines may be associated with lung cancer; however, large independent studies are lacking. METHODS: Associations between serum interleukin 6 (IL-6) and interleukin 8 (IL-8) levels and lung cancer were analyzed among 270 case patients and 296 control subjects participating in the National Cancer Institute-Maryland (NCI-MD) case control study. Results were validated in 532 case patients and 595 control subjects in a nested case-control study within the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Association with C reactive protein (CRP), a systemic inflammation biomarker, was also analyzed. Associations between biomarkers and lung cancer were estimated using logistic regression models adjusted for smoking, stage, histology, age, and sex. The 10 year standardized absolute risks of lung cancer were estimated using a weighted Cox regression model. RESULTS: Serum IL-6 and IL-8 levels in the highest quartile were associated with lung cancer in the NCI-MD study (IL-6, odds ratio [OR] = 3.29, 95% confidence interval [CI] = 1.88 to 5.77; IL-8, OR = 2.06, 95% CI = 1.19 to 3.57) and with lung cancer risk in the PLCO study (IL-6, OR = 1.48, 95% CI = 1.04 to 2.10; IL-8, OR = 1.57, 95% CI = 1.10 to 2.24), compared with the lowest quartile. In the PLCO study, increased IL-6 levels were only associated with lung cancer diagnosed within 2 years of blood collection, whereas increased IL-8 levels were associated with lung cancer diagnosed more than 2 years after blood collection (OR = 1.57, 95% CI = 1.15 to 2.13). The 10-year standardized absolute risks of lung cancer in the PLCO study were highest among current smokers with high IL-8 and CRP levels (absolute risk = 8.01%, 95% CI = 5.77% to 11.05%). CONCLUSIONS: Although increased levels of both serum IL-6 and IL-8 are associated with lung cancer, only IL-8 levels are associated with lung cancer risk several years before diagnosis. Combination of IL-8 and CRP are more robust biomarkers than either marker alone in predicting subsequent lung cancer. PMID- 21685358 TI - Inflammatory biomarkers and risk of lung cancer. PMID- 21685359 TI - Novel effect of antihelminthic Niclosamide on S100A4-mediated metastatic progression in colon cancer. AB - BACKGROUND: Metastasis formation in colon cancer severely reduces the survival rate in patients. S100A4, a calcium-binding protein, is implicated in promoting metastasis formation in colon cancer. METHODS: To identify a transcription inhibitor of S100A4, high-throughput screening of 1280 pharmacologically active compounds was performed using a human colon cancer cell line expressing a S100A4 promoter-driven luciferase (LUC) reporter gene construct (HCT116-S1004p-LUC). Niclosamide, an antihelminthic agent, was identified as a potential candidate. Colon cancer cell lines (HCT116, SW620, LS174T, SW480, and DLD-1) were treated with 1 MUM niclosamide to analyze the effect on S100A4 mRNA and protein expression by quantitative reverse transcription-polymerase chain reaction and immunoblot assays, and effects on cell migration, invasion, proliferation, and colony formation were also assessed in vitro. The effect of niclosamide on liver metastasis was assessed in a xenograft mouse model of human colon cancer (n = 8 mice) by in vivo imaging. The long-term effect of niclosamide on metastasis formation after discontinued treatment was quantified by scoring, and overall survival (n = 12 mice) was analyzed by Kaplan-Meier method after discontinuation of treatment. All statistical tests were two-sided. RESULTS: Reduced S100A4 mRNA and protein expression, and inhibited cell migration, invasion, proliferation, and colony formation were observed in niclosamide-treated colon cancer cells in vitro. In vivo imaging of niclosamide-treated mice showed reduced liver metastasis compared with solvent-treated control mice (n = 4 mice per group). Compared with the control group, discontinuation of treatment for 26 days showed reduced liver metastasis formation in mice (n = 6 mice per group) (control vs discontinuous treatment, mean metastasis score = 100% vs 34.9%, mean difference = 65.1%; 95% confidence interval [CI] = 18.4% to 111.9%, P < .01) and increased overall survival (n = 6 mice per group; control vs discontinuous treatment, median survival = 24 vs 46.5 days, ratio = 0.52, 95% CI = 0.19 to 0.84, P = .001). CONCLUSION: Niclosamide inhibits S100A4-induced metastasis formation in a mouse model of colon cancer and has therapeutic potential. PMID- 21685360 TI - Niclosamide: an established antihelminthic drug as a potential therapy against S100A4-mediated metastatic colon tumors. PMID- 21685361 TI - Biological mechanisms, one molecule at a time. AB - The last 15 years have witnessed the development of tools that allow the observation and manipulation of single molecules. The rapidly expanding application of these technologies for investigating biological systems of ever increasing complexity is revolutionizing our ability to probe the mechanisms of biological reactions. Here, we compare the mechanistic information available from single-molecule experiments with the information typically obtained from ensemble studies and show how these two experimental approaches interface with each other. We next present a basic overview of the toolkit for observing and manipulating biology one molecule at a time. We close by presenting a case study demonstrating the impact that single-molecule approaches have had on our understanding of one of life's most fundamental biochemical reactions: the translation of a messenger RNA into its encoded protein by the ribosome. PMID- 21685362 TI - The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor. AB - We previously identified the E3 ubiquitin ligase IDOL as a sterol-dependent regulator of the LDL receptor (LDLR). The molecular pathway underlying IDOL action, however, remains to be determined. Here we report the identification and biochemical and structural characterization of an E2-E3 ubiquitin ligase complex for LDLR degradation. We identified the UBE2D family (UBE2D1-4) as E2 partners for IDOL that support both autoubiquitination and IDOL-dependent ubiquitination of the LDLR in a cell-free system. NMR chemical shift mapping and a 2.1 A crystal structure of the IDOL RING domain-UBE2D1 complex revealed key interactions between the dimeric IDOL protein and the E2 enzyme. Analysis of the IDOL-UBE2D1 interface also defined the stereochemical basis for the selectivity of IDOL for UBE2Ds over other E2 ligases. Structure-based mutations that inhibit IDOL dimerization or IDOL-UBE2D interaction block IDOL-dependent LDLR ubiquitination and degradation. Furthermore, expression of a dominant-negative UBE2D enzyme inhibits the ability of IDOL to degrade the LDLR in cells. These results identify the IDOL-UBE2D complex as an important determinant of LDLR activity, and provide insight into molecular mechanisms underlying the regulation of cholesterol uptake. PMID- 21685363 TI - A Smad action turnover switch operated by WW domain readers of a phosphoserine code. AB - When directed to the nucleus by TGF-beta or BMP signals, Smad proteins undergo cyclin-dependent kinase 8/9 (CDK8/9) and glycogen synthase kinase-3 (GSK3) phosphorylations that mediate the binding of YAP and Pin1 for transcriptional action, and of ubiquitin ligases Smurf1 and Nedd4L for Smad destruction. Here we demonstrate that there is an order of events-Smad activation first and destruction later-and that it is controlled by a switch in the recognition of Smad phosphoserines by WW domains in their binding partners. In the BMP pathway, Smad1 phosphorylation by CDK8/9 creates binding sites for the WW domains of YAP, and subsequent phosphorylation by GSK3 switches off YAP binding and adds binding sites for Smurf1 WW domains. Similarly, in the TGF-beta pathway, Smad3 phosphorylation by CDK8/9 creates binding sites for Pin1 and GSK3, then adds sites to enhance Nedd4L binding. Thus, a Smad phosphoserine code and a set of WW domain code readers provide an efficient solution to the problem of coupling TGF beta signal delivery to turnover of the Smad signal transducers. PMID- 21685364 TI - Biological significance of 5S rRNA import into human mitochondria: role of ribosomal protein MRP-L18. AB - 5S rRNA is an essential component of ribosomes of all living organisms, the only known exceptions being mitochondrial ribosomes of fungi, animals, and some protists. An intriguing situation distinguishes mammalian cells: Although the mitochondrial genome contains no 5S rRNA genes, abundant import of the nuclear DNA-encoded 5S rRNA into mitochondria was reported. Neither the detailed mechanism of this pathway nor its rationale was clarified to date. In this study, we describe an elegant molecular conveyor composed of a previously identified human 5S rRNA import factor, rhodanese, and mitochondrial ribosomal protein L18, thanks to which 5S rRNA molecules can be specifically withdrawn from the cytosolic pool and redirected to mitochondria, bypassing the classic nucleolar reimport pathway. Inside mitochondria, the cytosolic 5S rRNA is shown to be associated with mitochondrial ribosomes. PMID- 21685365 TI - An evolutionarily 'young' lysine residue in histone H3 attenuates transcriptional output in Saccharomyces cerevisiae. AB - The DNA entry and exit points on the nucleosome core regulate the initial invasion of the nucleosome by factors requiring access to the underlying DNA. Here we describe in vivo consequences of eliminating a single protein-DNA interaction at this position through mutagenesis of histone H3 Lys 42 to alanine. This substitution has a dramatic effect on the Saccharomyces cerevisiae transcriptome in both the transcriptional output and landscape of mRNA species produced. We attribute this in part to decreased histone H3 occupancy at transcriptionally active loci, leading to enhanced elongation. Additionally we show that this lysine is methylated in vivo, and genetic studies of methyl-lysine mimics suggest that this modification may be crucial in attenuating gene expression. Interestingly, this site of methylation is unique to Ascomycota, suggesting a recent evolutionary innovation that highlights the evolvability of post-translational modifications of chromatin. PMID- 21685366 TI - Analysis of protein dynamics at active, stalled, and collapsed replication forks. AB - Successful DNA replication and packaging of newly synthesized DNA into chromatin are essential to maintain genome integrity. Defects in the DNA template challenge genetic and epigenetic inheritance. Unfortunately, tracking DNA damage responses (DDRs), histone deposition, and chromatin maturation at replication forks is difficult in mammalian cells. Here we describe a technology called iPOND (isolation of proteins on nascent DNA) to analyze proteins at active and damaged replication forks at high resolution. Using this methodology, we define the timing of histone deposition and chromatin maturation. Class 1 histone deacetylases are enriched at replisomes and remove predeposition marks on histone H4. Chromatin maturation continues even when decoupled from replisome movement. Furthermore, fork stalling causes changes in the recruitment and phosphorylation of proteins at the damaged fork. Checkpoint kinases catalyze H2AX phosphorylation, which spreads from the stalled fork to include a large chromatin domain even prior to fork collapse and double-strand break formation. Finally, we demonstrate a switch in the DDR at persistently stalled forks that includes MRE11 dependent RAD51 assembly. These data reveal a dynamic recruitment of proteins and post-translational modifications at damaged forks and surrounding chromatin. Furthermore, our studies establish iPOND as a useful methodology to study DNA replication and chromatin maturation. PMID- 21685368 TI - Retraction. Alternative splicing produces high levels of noncoding isoforms of bHLH transcription factors during development. PMID- 21685367 TI - A DNA damage checkpoint in Caulobacter crescentus inhibits cell division through a direct interaction with FtsW. AB - Following DNA damage, cells typically delay cell cycle progression and inhibit cell division until their chromosomes have been repaired. The bacterial checkpoint systems responsible for these DNA damage responses are incompletely understood. Here, we show that Caulobacter crescentus responds to DNA damage by coordinately inducing an SOS regulon and inhibiting the master regulator CtrA. Included in the SOS regulon is sidA (SOS-induced inhibitor of cell division A), a membrane protein of only 29 amino acids that helps to delay cell division following DNA damage, but is dispensable in undamaged cells. SidA is sufficient, when overproduced, to block cell division. However, unlike many other regulators of bacterial cell division, SidA does not directly disrupt the assembly or stability of the cytokinetic ring protein FtsZ, nor does it affect the recruitment of other components of the cell division machinery. Instead, we provide evidence that SidA inhibits division by binding directly to FtsW to prevent the final constriction of the cytokinetic ring. PMID- 21685369 TI - Effectiveness of a multistimulant home-based program on cognitive function of older adults. AB - The purpose of this study was to test the effects of a multistimulant home-based program on cognitive function among older adults. This study was conducted in northeastern Turkey between March and June 2010. It was planned as an experimental versus control two-group design and carried out on 96 (intervention group = 48, control group = 48) participants. The intervention and control groups were similar regarding sex, education, partner status, and continuous drug use. Data were collected with a Standardized Mini Mental Test, the Geriatric Depression Scale (GDS), and the Beck Anxiety Scale. Each senior received a total of 10 home visits on a once-per-week basis. Results for the intervention group showed that the Mini Mental State Test scores of the participants had statistically increased, and the Beck Anxiety and the GDS scores showed a decrease. The study found an association between the multistimulant home-based intervention program and cognitive function. PMID- 21685371 TI - MicroRNA29a regulates the expression of the nuclear oncogene Ski. AB - MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate growth and differentiation. miRNAs are frequently located at cancer-specific fragile sites in the human genome, such as chromosome 7q. The nuclear oncogene SKI is up regulated in acute myeloid leukemia (AML) with -7/del7q. Here we asked whether loss of miRNAs on chromosome 7q may explain this up-regulation. miR-29a expression was found to be down-regulated in AML with -7/del7q. Forced expression of miR-29a down-regulated Ski and its target gene, Nr-CAM, whereas miR-29a inhibition induced Ski expression. Luciferase assays validated a functional binding site for miR-29a in the 3' untranslated region of SKI. Finally, in samples of AML patients, we observed an inverse correlation of Ski and miR-29a expression, respectively. In conclusion, up-regulation of Ski in AML with 7/del7q is caused by loss of miR-29a. miR-29a may therefore function as an important tumor suppressor in AML by restraining expression of the SKI oncogene. PMID- 21685370 TI - Fibrinogen beta-derived Bbeta(15-42) peptide protects against kidney ischemia/reperfusion injury. AB - Ischemia/reperfusion (I/R) injury in the kidney is a major cause of acute kidney injury (AKI) in humans and is associated with significantly high mortality. To identify genes that modulate kidney injury and repair, we conducted genome-wide expression analysis in the rat kidneys after I/R and found that the mRNA levels of fibrinogen (Fg)alpha, Fgbeta, and Fggamma chains significantly increase in the kidney and remain elevated throughout the regeneration process. Cellular characterization of Fgalpha and Fggamma chain immunoreactive proteins shows a predominant expression in renal tubular cells and the localization of immunoreactive Fgbeta chain protein is primarily in the renal interstitium in healthy and regenerating kidney. We also show that urinary excretion of Fg is massively increased after kidney damage and is capable of distinguishing human patients with acute or chronic kidney injury (n = 25) from healthy volunteers (n = 25) with high sensitivity and specificity (area under the receiver operating characteristic of 0.98). Furthermore, we demonstrate that Fgbeta-derived Bbeta(15 42) peptide administration protects mice from I/R-induced kidney injury by aiding in epithelial cell proliferation and tissue repair. Given that kidney regeneration is a major determinant of outcome for patients with kidney damage, these results provide new opportunities for the use of Fg in diagnosis, prevention, and therapeutic interventions in kidney disease. PMID- 21685372 TI - Plasmodium falciparum uses a key functional site in complement receptor type-1 for invasion of human erythrocytes. AB - The Plasmodium falciparum adhesin PfRh4 binds to complement receptor type-1 (CR1) on human erythrocytes and mediates a glycophorin-independent invasion pathway. CR1 is a complement regulator and immune-adherence receptor on erythrocytes required for shuttling of C3b/C4b-opsonized particles to liver and spleen for phagocytosis. Using recombinant CR1 constructs, we mapped the recognition site for PfRh4 to complement control protein modules 1 to 3 (CCP1-3) at the membrane distal amino terminus of CR1. This region of CR1 binds to C4b and C3b and accelerates decay of both classic pathway and alternative pathway C3 and C5 convertases. CCP1-3 competed for PfRh4 binding to erythroid CR1 and inhibited the PfRh4-CR1 invasion pathways across a wide range of P falciparum strains. PfRh4 did not bind significantly to other CR1 constructs, including CCP15-17, which is 85% identical to CCP1-3. PfRh4 binding to CR1 did not affect its C3b/C4b binding capability, and we show evidence for a ternary complex between CCP1-3, C4b, and PfRh4. PfRh4 binding specifically inhibited CR1's convertase decay-accelerating activity, whereas there was no effect on factor H-mediated decay-accelerating activity. These results increase our understanding of the functional implications of CR1 engagement with PfRh4 and highlight the interplay between complement regulation and infection. PMID- 21685373 TI - G-CSF supplementation with chemotherapy can promote revascularization and subsequent tumor regrowth: prevention by a CXCR4 antagonist. AB - Recombinant granulocyte colony-stimulating factor (G-CSF) is used to accelerate recovery from chemotherapy-induced myelosuppression. G-CSF has been recently shown to stimulate angiogenesis mediated by several types of bone marrow-derived cell populations. To investigate whether G-CSF may alter tumor response to therapy, we studied Lewis lung and EMT/6 breast carcinomas in mice treated with paclitaxel (PTX) chemotherapy in combination with G-CSF. We compared the results obtained to mice treated with PTX and AMD3100, a small-molecule drug antagonist of CXCR4 which, like G-CSF, can be used to mobilize hematopoietic cells. We show that PTX combined with G-CSF treatment facilitates revascularization, leading to an improvement in blood perfusion in LLC tumors, and a decrease in hypoxia in EMT/6 tumors, thus enhancing tumor growth in comparison to PTX or PTX and AMD3100 therapies. We found that hemangiocytes but not Gr-1(+) CD11b(+) cells colonize EMT/6 tumors after treatment with PTX and G-CSF, but not PTX and AMD3100, and therefore may contribute to angiogenesis. However, increases in hemangiocyte colonization were not observed in LLC PTX and G-CSF-treated tumors, suggesting distinct mechanisms of tumor revascularization after G-CSF. Overall, our observations suggest that despite its known considerable clinical benefits, G-CSF might contribute to tumor revascularization by various mechanisms, and diminish the antitumor activity of chemotherapy, an effect that can be prevented by AMD3100. PMID- 21685374 TI - Combination of pegylated IFN-alpha2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia. AB - Biologic and clinical observations suggest that combining imatinib with IFN-alpha may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-alpha2b (Peg-IFN-alpha2b) 50 MUg weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-alpha2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-alpha2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg IFN-alpha2b treatment (< 12-week MMR rate 67%, > 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-alpha2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg-IFN-alpha2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent. PMID- 21685376 TI - It's all in the name, or is it? The impact of labeling on health state values. AB - BACKGROUND: Many descriptions of health used in vignettes and condition-specific measures name the medical condition. This article assesses the impact of referring to the medical condition in the descriptions of health states valued by members of the general population. METHODS: A valuation study was conducted using face-to-face interviews involving the time trade-off valuation technique. All respondents valued essentially the same health states, but for each respondent, the descriptions featured an irritable bowel syndrome (IBS) label, a cancer label, or no label. Random effects generalized least squares regressions were used to estimate the impact of each label and experience of the condition on health state values. DATA: A sample of 241 members of the UK general population each valued 8 states, generating 1910 observations (response rate = 39%, completion rate = 99% for all states). RESULTS: The authors find no significant difference between health state values when the description contains no label or an IBS label. They find that the inclusion of a cancer label in health state descriptions affects health state values and that the impact is dependent on the severity of the state, with a significant reduction in values for more severe health states (up to -0.25 for the worst possible state) but no significant difference for mild states. CONCLUSIONS: A condition label can affect health state values, but this is dependent on the specific condition and severity. The authors recommend avoiding condition labels in health state descriptions (where possible) to ensure that values are not affected by prior knowledge or preconception of the condition that may distort the health state being valued. PMID- 21685375 TI - Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines. AB - Primary effusion lymphoma (PEL) is a diffuse-large B-cell lymphoma with poor prognosis. One hundred percent of PELs carry the genome of Kaposi sarcoma associated herpesvirus and a majority are coinfected with Epstein-Barr virus (EBV). We profiled genomic aberrations in PEL cells using the Affymetrix 6.0 SNP array. This identified for the first time individual genes that are altered in PEL cells. Eleven of 13 samples (85%) were deleted for the fragile site tumor suppressors WWOX and FHIT. Alterations were also observed in the DERL1, ETV1, RASA4, TPK1, TRIM56, and VPS41 genes, which are yet to be characterized for their roles in cancer. Coinfection with EBV was associated with significantly fewer gross genomic aberrations, and PEL could be segregated into EBV-positive and EBV negative clusters on the basis of host chromosome alterations. This suggests a model in which both host genetic aberrations and the 2 viruses contribute to the PEL phenotype. PMID- 21685377 TI - Measuring informed decision making about prostate cancer screening in primary care. AB - PURPOSE: To measure the extent of informed decision making (IDM) about prostate cancer screening in physician-patient encounters, describe the coding process, and assess the reliability of the IDM measure. METHODS: Audiorecoded encounters of 146 older adult men and their primary care physicians were obtained in a randomized controlled trial of mediated decision support related to prostate cancer screening. Each encounter was dual coded for the presence or absence of 9 elements that reflect several important dimensions of IDM, such as information sharing, patient empowerment, and engaging patients in preference clarification. An IDM-9 score (range = 0-9) was determined for each encounter by summing the number of elements that were coded as present. Estimates of coding reliability and internal consistency were calculated. RESULTS: Male patients tended to be white (59%), married (70%), and between the ages of 50 and 59 (70%). Physicians tended to be white (90%), male (74%), and have more than 10 years of practice experience (74%). IDM-9 scores ranged from 0 to 7.5 (mean [SD], 2.7 [2.1]). Reliability (0.90) and internal consistency (0.81) of the IDM-9 were both high. The IDM dimension observed most frequently was information sharing (74%), whereas the dimension least frequently observed was engagement in preference clarification (3.4%). CONCLUSIONS: In physician-patient encounters, the level of IDM concerning prostate cancer screening was low. The use of a dual-coding approach with audiorecorded encounters produced a measure of IDM that was reliable and internally consistent. PMID- 21685378 TI - Recommended levels of physical activity and insulin resistance in middle-aged women. AB - PURPOSE: The purpose of this study was to examine the relationship between recommended levels of physical activity (PA) and insulin resistance, as estimated by the homeostasis model assessment of insulin resistance (HOMA-IR) in middle aged women without diabetes. METHODS: This was a cross-sectional study of 264 women located in the Mountain West region of the United States. Sedentary time and moderate- and vigorous-intensity PA were determined objectively, via accelerometry, over 7 days. HOMA-IR was calculated from fasting insulin and glucose. Body mass index (kg/m2) was calculated from measured weight and height; body fat percentage was assessed using air displacement plethysmography; and abdominal circumference was measured at the umbilicus. Moderate- and vigorous intensity PA levels were based on recommendations for PA and health from the American College of Sports Medicine. RESULTS: Total time spent in sedentary activity was significantly related to insulin resistance. Time spent in moderate intensity or vigorous-intensity activity, at recommended levels, was also significantly and inversely related to insulin resistance. However, after statistically adjusting for body fat percentage or abdominal circumference individually, the relationship between sedentary activity, moderate-intensity, or vigorous-intensity activity and HOMA-IR was eliminated. CONCLUSIONS: Achieving recommended levels of PA is associated with lower HOMA-IR in healthy women without diabetes; however, adiposity accounts for part of this relationship. PMID- 21685379 TI - Greasing the palm: can collectivism promote bribery? AB - Why are there national differences in the propensity to bribe? To investigate this question, we conducted a correlational study with cross-national data and a laboratory experiment. We found a significant effect of the degree of collectivism versus individualism present in a national culture on the propensity to offer bribes to international business partners. Furthermore, the effect was mediated by individuals' sense of responsibility for their actions. Together, these results suggest that collectivism promotes bribery through lower perceived responsibility for one's actions. PMID- 21685380 TI - Getting a grip on drinking behavior: training working memory to reduce alcohol abuse. AB - Alcohol abuse disrupts core executive functions, including working memory (WM)- the ability to maintain and manipulate goal-relevant information. When executive functions like WM are weakened, drinking behavior gets out of control and is guided more strongly by automatic impulses. This study investigated whether training WM restores control over drinking behavior. Forty-eight problem drinkers performed WM training tasks or control tasks during 25 sessions over at least 25 days. Before and after training, we measured WM and drinking behavior. Training WM improved WM and reduced alcohol intake for more than 1 month after the training. Further, the indirect effect of training on alcohol use through improved WM was moderated by participants' levels of automatic impulses: Increased WM reduced alcohol consumption in participants with relatively strong automatic preferences for alcohol. These findings are consistent with the theoretical framework and demonstrate that training WM may be an effective strategy to reduce alcohol use by increasing control over automatic impulses to drink alcohol. PMID- 21685381 TI - Acyl-CoA:lysophosphatidylcholine acyltransferase I (Lpcat1) catalyzes histone protein O-palmitoylation to regulate mRNA synthesis. AB - The enzyme acyl-CoA:lysophosphatidylcholine acyltransferase (Lpcat1) is a critical cytosolic enzyme needed for lung surfactant synthesis that catalyzes an acyltransferase reaction by adding a palmitate to the sn-2 position of lysophospholipids. Here we report that histone H4 protein is subject to palmitoylation catalyzed by Lpcat1 in a calcium-regulated manner. Cytosolic Lpcat1 was observed to shift into the nucleus in lung epithelia in response to exogenous Ca(2+). Nuclear Lpcat1 colocalizes with and binds to histone H4, where it catalyzes histone H4 palmitoylation. Mutagenesis studies demonstrated that Ser(47) within histone H4 serves as a putative acceptor site, indicative of Lpcat1-mediated O-palmitoylation. Lpcat1 knockdown or expression of a histone H4 Ser(47A) mutant protein in cells decreased cellular mRNA synthesis. These findings provide the first evidence of a protein substrate for Lpcat1 and reveal that histone lipidation may occur through its O-palmitoylation as a novel post translational modification. This epigenetic modification regulates global gene transcriptional activity. PMID- 21685382 TI - Clostridium difficile has an original peptidoglycan structure with a high level of N-acetylglucosamine deacetylation and mainly 3-3 cross-links. AB - The structure of the vegetative cell wall peptidoglycan of Clostridium difficile was determined by analysis of its constituent muropeptides with a combination of reverse-phase high pressure liquid chromatography separation of muropeptides, amino acid analysis, mass spectrometry and tandem mass spectrometry. The structures assigned to 36 muropeptides evidenced several original features in C. difficile vegetative cell peptidoglycan. First, it is characterized by a strikingly high level of N-acetylglucosamine deacetylation. In addition, the majority of dimers (around 75%) contains A(2)pm(3) -> A(2)pm(3) (A(2)pm, 2,6 diaminopimelic acid) cross-links and only a minority of the more classical Ala(4) -> A(2)pm(3) cross-links. Moreover, a significant amount of muropeptides contains a modified tetrapeptide stem ending in Gly instead of D-Ala(4). Two L,D transpeptidases homologues encoding genes present in the genome of C. difficile 630 and named ldt(cd1) and ldt(cd2), were inactivated. The inactivation of either ldt(cd1) or ldt(cd2) significantly decreased the abundance of 3-3 cross-links, leading to a marked decrease of peptidoglycan reticulation and demonstrating that both ldt(cd1)-and ldt(cd2)-encoded proteins have a redundant L,D-transpeptidase activity. The contribution of 3-3 cross-links to peptidoglycan synthesis increased in the presence of ampicillin, indicating that this drug does not inhibit the L,D-transpeptidation pathway in C. difficile. PMID- 21685383 TI - Tissue-specific gene targeting by the multiprotein mammalian DREAM complex. AB - The mammalian DP, RB-like, E2F, and MuvB-like proteins (DREAM) complex, whose key components include p130 and E2F4, plays a fundamental role in repression of cell cycle-specific genes during growth arrest. Mammalian DREAM is well conserved with Drosophila and Caenorhabditis elegans complexes that repress pivotal developmental genes, but the mammalian complex has been thought to exist only in quiescent cells and not to be linked with development. However, new findings here identify tissue-specific promoters repressed by DREAM in proliferating precursors, revealing a new connection between control of growth arrest and terminal differentiation. Mechanistically, tissue-specific promoter occupation by DREAM is dependent on the integrity of a repressor form of the SWI/SNF chromatin remodeling complex. PMID- 21685384 TI - Caenorhabditis elegans evolves a new architecture for the multi-aminoacyl-tRNA synthetase complex. AB - MARS is an evolutionary conserved supramolecular assembly of aminoacyl-tRNA synthetases found in eukaryotes. This complex was thought to be ubiquitous in the deuterostome and protostome clades of bilaterians because similar complexes were isolated from arthropods and vertebrates. However, several features of the component enzymes suggested that in the nematode Caenorhabditis elegans, a species grouped with arthropods in modern phylogeny, this complex might not exist, or should display a significantly different structural organization. C. elegans was also taken as a model system to study in a multicellular organism amenable to experimental approaches, the reason for existence of these supramolecular entities. Here, using a proteomic approach, we have characterized the components of MARS in C. elegans. We show that this organism evolved a specific structural organization of this complex, which contains several bona fide components of the MARS complexes known so far, but also displays significant variations. These data highlight molecular evolution events that took place after radiation of bilaterians. Remarkably, it shows that expansion of MARS assembly in metazoans is not linear, but is the result of additions but also of subtractions along evolution. We then undertook an experimental approach, using inactivation of the endogenous copy of methionyl-tRNA synthetase by RNAi and expression of transgenic variants, to understand the role in complex assembly and the in vivo functionality, of the eukaryotic-specific domains appended to aminoacyl-tRNA synthetases. We show that rescue of the worms and assembly of transgenic variants into MARS rest on the presence of these appended domains. PMID- 21685385 TI - Structural basis of M3 muscarinic receptor dimer/oligomer formation. AB - Class A G protein-coupled receptors (GPCRs) are known to form dimers and/or oligomeric arrays in vitro and in vivo. These complexes are thought to play important roles in modulating class A GPCR function. Many studies suggest that residues located on the "outer" (lipid-facing) surface of the transmembrane (TM) receptor core are critically involved in the formation of class A receptor dimers (oligomers). However, no clear consensus has emerged regarding the identity of the TM helices or TM subsegments involved in this process. To shed light on this issue, we have used the M(3) muscarinic acetylcholine receptor (M3R), a prototypic class A GPCR, as a model system. Using a comprehensive and unbiased approach, we subjected all outward-facing residues (70 amino acids total) of the TM helical bundle (TM1-7) of the M3R to systematic alanine substitution mutagenesis. We then characterized the resulting mutant receptors in radioligand binding and functional studies and determined their ability to form dimers (oligomers) in bioluminescence resonance energy transfer saturation assays. We found that M3R/M3R interactions are not dependent on the presence of one specific structural motif but involve the outer surfaces of multiple TM subsegments (TM1-5 and -7) located within the central and endofacial portions of the TM receptor core. Moreover, we demonstrated that the outward-facing surfaces of most TM helices play critical roles in proper receptor folding and/or function. Guided by the bioluminescence resonance energy transfer data, molecular modeling studies suggested the existence of multiple dimeric/oligomeric M3R arrangements, which may exist in a dynamic equilibrium. Given the high structural homology found among all class A GPCRs, our results should be of considerable general relevance. PMID- 21685386 TI - SUMOylation-regulated protein phosphorylation, evidence from quantitative phosphoproteomics analyses. AB - Protein modification is critical for the regulation of protein functions. Cross talks among different types of protein modifications should yield concerted and coordinated regulatory networks for physiological functions. Here we have employed system-wide and quantitative phosphoproteomics analyses to reveal a global cross-talk for SUMOylation-modulated phosphorylation. Furthermore, as specific examples, we have shown that the alpha subunit of casein kinase II is SUMOylated and that this affects the phosphorylation of its substrates. SUMO regulated phosphorylation is involved in cell cycle control. Our data demonstrate an interplay between protein SUMOylation and phosphorylation and imply a regulatory role for this SUMOylation-modulated phosphorylation. PMID- 21685387 TI - Image-based screening identifies novel roles for IkappaB kinase and glycogen synthase kinase 3 in axonal degeneration. AB - Axon degeneration is an active, evolutionarily conserved self-destruction program by which compromised axons fragment in response to varied insults. Unlike programmed cell death, axon degeneration is poorly understood. We have combined robotic liquid handling with automated microscopy and image analysis to create a robust screening platform to measure axon degeneration in mammalian primary neuronal cultures. Using this assay, we performed an unbiased screen of 480 bioactive compounds, identifying 11 that reproducibly delay fragmentation of severed axons in vitro, including two inhibitors of glycogen synthase kinase 3 and two inhibitors of IkappaB kinase. Knockdown of each of these targets by shRNA lentivirus also delays axon degeneration in vitro, further supporting their role in the axon degeneration program. PMID- 21685388 TI - Hierarchical phosphorylation within the ankyrin repeat domain defines a phosphoregulatory loop that regulates Notch transcriptional activity. AB - The Notch signal transduction pathway mediates important cellular functions through direct cell-to-cell contact. Deregulation of Notch activity can lead to an altered cell proliferation and has been linked to many human cancers. Casein kinase 2 (CK2), a ubiquitous kinase, regulates several cellular processes by phosphorylating proteins involved in signal transduction, gene expression, and protein synthesis. In this report we identify Notch(ICD) as a novel target of phosphorylation by CK2. Using mapping and mutational studies, we identified serine 1901, located in the ankyrin domain of Notch, as the target amino acid. Interestingly, phosphorylation of serine 1901 by CK2 appears to generate a second phosphorylation site at threonine 1898. Furthermore, threonine 1898 phosphorylation only occurs when Notch forms a complex with Mastermind and CSL. Phosphorylation of both threonine 1898 and serine 1901 resulted in decreased binding of the Notch-Mastermind-CSL ternary complex to DNA and consequently lower transcriptional activity. These data indicate that the phosphorylation of serine 1901 and threonine 1898 negatively regulates Notch function by dissociating the complex from DNA. This study identifies a new component involved in regulation of Notch(ICD) transcriptional activity, reinforcing the notion that a precise and tight regulation is required for this essential signaling pathway. PMID- 21685389 TI - Molecular adaptation of the DegQ protease to exert protein quality control in the bacterial cell envelope. AB - To react to distinct stress situations and to prevent the accumulation of misfolded proteins, all cells employ a number of proteases and chaperones, which together set up an efficient protein quality control system. The functionality of proteins in the cell envelope of Escherichia coli is monitored by the HtrA proteases DegS, DegP, and DegQ. In contrast with DegP and DegS, the structure and function of DegQ has not been addressed in detail. Here, we show that substrate binding triggers the conversion of the resting DegQ hexamer into catalytically active 12- and 24-mers. Interestingly, substrate-induced oligomer reassembly and protease activation depends on the first PDZ domain but not on the second. Therefore, the regulatory mechanism originally identified in DegP should be a common feature of HtrA proteases, most of which encompass only a single PDZ domain. Using a DegQ mutant lacking the second PDZ domain, we determined the high resolution crystal structure of a dodecameric HtrA complex. The nearly identical domain orientation of protease and PDZ domains within 12- and 24-meric HtrA complexes reveals a conserved PDZ1 -> L3 -> LD/L1/L2 signaling cascade, in which loop L3 senses the repositioned PDZ1 domain of higher order, substrate-engaged particles and activates protease function. Furthermore, our in vitro and in vivo data imply a pH-related function of DegQ in the bacterial cell envelope. PMID- 21685390 TI - Structural model of ligand-G protein-coupled receptor (GPCR) complex based on experimental double mutant cycle data: MT7 snake toxin bound to dimeric hM1 muscarinic receptor. AB - The snake toxin MT7 is a potent and specific allosteric modulator of the human M1 muscarinic receptor (hM1). We previously characterized by mutagenesis experiments the functional determinants of the MT7-hM1 receptor interaction (Fruchart Gaillard, C., Mourier, G., Marquer, C., Stura, E., Birdsall, N. J., and Servent, D. (2008) Mol. Pharmacol. 74, 1554-1563) and more recently collected evidence indicating that MT7 may bind to a dimeric form of hM1 (Marquer, C., Fruchart Gaillard, C., Mourier, G., Grandjean, O., Girard, E., le Maire, M., Brown, S., and Servent, D. (2010) Biol. Cell 102, 409-420). To structurally characterize the MT7-hM1 complex, we adopted a strategy combining double mutant cycle experiments and molecular modeling calculations. First, thirty-three ligand-receptor proximities were identified from the analysis of sixty-one double mutant binding affinities. Several toxin residues that are more than 25 A apart still contact the same residues on the receptor. As a consequence, attempts to satisfy all the restraints by docking the toxin onto a single receptor failed. The toxin was then positioned onto two receptors during five independent flexible docking simulations. The different possible ligand and receptor extracellular loop conformations were described by performing simulations in explicit solvent. All the docking calculations converged to the same conformation of the MT7-hM1 dimer complex, satisfying the experimental restraints and in which (i) the toxin interacts with the extracellular side of the receptor, (ii) the tips of MT7 loops II and III contact one hM1 protomer, whereas the tip of loop I binds to the other protomer, and (iii) the hM1 dimeric interface involves the transmembrane helices TM6 and TM7. These results structurally support the high affinity and selectivity of the MT7-hM1 interaction and highlight the atypical mode of interaction of this allosteric ligand on its G protein-coupled receptor target. PMID- 21685391 TI - Timothy mutation disrupts the link between activation and inactivation in Ca(V)1.2 protein. AB - The Timothy syndrome mutations G402S and G406R abolish inactivation of Ca(V)1.2 and cause multiorgan dysfunction and lethal arrhythmias. To gain insights into the consequences of the G402S mutation on structure and function of the channel, we systematically mutated the corresponding Gly-432 of the rabbit channel and applied homology modeling. All mutations of Gly-432 (G432A/M/N/V/W) diminished channel inactivation. Homology modeling revealed that Gly-432 forms part of a highly conserved structure motif (G/A/G/A) of small residues in homologous positions of all four domains (Gly-432 (IS6), Ala-780 (IIS6), Gly-1193 (IIIS6), Ala-1503 (IVS6)). Corresponding mutations in domains II, III, and IV induced, in contrast, parallel shifts of activation and inactivation curves indicating a preserved coupling between both processes. Disruption between coupling of activation and inactivation was specific for mutations of Gly-432 in domain I. Mutations of Gly-432 removed inactivation irrespective of the changes in activation. In all four domains residues G/A/G/A are in close contact with larger bulky amino acids from neighboring S6 helices. These interactions apparently provide adhesion points, thereby tightly sealing the activation gate of Ca(V)1.2 in the closed state. Such a structural hypothesis is supported by changes in activation gating induced by mutations of the G/A/G/A residues. The structural implications for Ca(V)1.2 activation and inactivation gating are discussed. PMID- 21685392 TI - The miR-143/145 cluster is a novel transcriptional target of Jagged-1/Notch signaling in vascular smooth muscle cells. AB - Activation of Notch signaling by Jagged-1 (Jag-1) in vascular smooth muscle cells (VSMC) promotes a differentiated phenotype characterized by increased expression of contractile proteins. Recent studies show that microRNAs (miR)-143/145 regulates VSMC phenotype. The serum response factor (SRF)/myocardin complex binds to CArG sequences to activate miR-143/145 transcription, but no other regulators are known in VSMC. Using miR arrays, we found miR-143/145 induced following expression of a constitutively active Notch1 intracellular domain (N1ICD). We hypothesized that miR-143/145 is required for Jag-1/Notch-induced VSMC differentiation. Activation of Notch receptors by Jag-1 caused CBF1-dependent up regulation of miR-143/145, increased differentiation, and decreased proliferation. Conversely, inhibiting basal Notch signaling decreased steady state levels of miR-143/145. Using SRF knockdown, we found that Jag-1/Notch induction of miR-143/145 is SRF independent, although full acquisition of contractile markers requires SRF. Using miR-143/145 promoter reporter constructs we show Jag-1/Notch increases promoter activity, and this is dependent on intact CBF1 consensus sites within the promoter. Chromatin immunoprecipitation (ChIP) assays revealed that N1ICD-containing complexes bind to CBF1 sites in the miR 143/145 promoter. We also identified N1ICD complex binding to CBF1 sites within the endogenous human miR-143/145 promoter. Using miR-143/145-interfering oligonucleotides, we demonstrate that Jag-1/Notch signaling requires induction of both miR-143 and miR-145 to promote the VSMC contractile phenotype. Thus, miR 143/145 is a novel transcriptional target of Jag-1/Notch signaling in VSMC. We propose miR-143/145 as activated independently by Jag-1/Notch and SRF in parallel pathways. Multiple pathways converging on miR-143/145 provides potential for fine tuning or amplification of VSMC differentiation signals. PMID- 21685393 TI - Pheromone- and RSP5-dependent ubiquitination of the G protein beta subunit Ste4 in yeast. AB - Ste4 is the beta subunit of a heterotrimeric G protein that mediates mating responses in Saccharomyces cerevisiae. Here we show that Ste4 undergoes ubiquitination in response to pheromone stimulation. Ubiquitination of Ste4 is dependent on the E3 ligase Rsp5. Disrupting the activity of Rsp5 abolishes ubiquitination of Ste4 in vivo, and recombinant Rsp5 is capable of ubiquitinating Ste4 in vitro. We find also that Lys-340 is a major ubiquitination site on Ste4, as pheromone-induced ubiquitination of the protein is prevented when this residue is mutated to an arginine. Functionally, ubiquitination does not appear to regulate the stability of Ste4, as blocking ubiquitination has no apparent effect on either the abundance or the half-life of the protein. However, when presented with a concentration gradient of pheromone, Ste4(K340R) mutant cells polarize significantly faster than wild-type cells, indicating that ubiquitination limits pheromone-directed polarized growth. Together, these findings reveal a novel stimulus-dependent posttranslational modification of a Gbeta subunit, establish Ste4 as a new substrate of the E3 ligase Rsp5, and demonstrate a role for G protein ubiquitination in cell polarization. PMID- 21685395 TI - Dynamic changes in binding of immunoglobulin heavy chain 3' regulatory region to protein factors during class switching. AB - The 3' regulatory region (3' RR) of the Igh locus works at long distances on variable region (V(H)) and switch region (I) region promoters to initiate germ line (non-coding) transcription (GT) and promote class switch recombination (CSR). The 3' RR contains multiple elements, including enhancers (hs3a, hs1.2, hs3b, and hs4) and a proposed insulator region containing CTCF (CCCTC-binding factor) binding sites, i.e. hs5/6/7 and the downstream region ("38"). Notably, deletion of each individual enhancer (hs3a-hs4) has no significant phenotypic consequence, suggesting that the 3' RR has considerable structural flexibility in its function. To better understand how the 3' RR functions, we identified transcription factor binding sites and used chromatin immunoprecipitation (ChIP) assays to monitor their occupancy in splenic B cells that initiate GT and undergo CSR (LPS+/-IL4), are deficient in GT and CSR (p50(-/-)), or do not undergo CSR despite efficient GT (anti-IgM+IL4). Like 3' RR enhancers, hs5-7 and the 38 region were observed to contain multiple Pax5 binding sites (in addition to multiple CTCF sites). We found that the Pax5 binding profile to the 3' RR dynamically changed during CSR independent of the specific isotype to which switching was induced, and binding focused on hs1.2, hs4, and hs7. CTCF associated and CTCF-independent cohesin interactions were also identified. Our observations are consistent with a scaffold model in which a platform of active protein complexes capable of facilitating GT and CSR can be formed by varying constellations of 3' RR elements. PMID- 21685394 TI - Accumulation of the Raf-1 kinase inhibitory protein (Rkip) is associated with Cep290-mediated photoreceptor degeneration in ciliopathies. AB - Primary cilia regulate polarized protein trafficking in photoreceptors, which are dynamic and highly compartmentalized sensory neurons of retina. The ciliary protein Cep290 modulates cilia formation and is frequently mutated in syndromic and non-syndromic photoreceptor degeneration. However, the underlying mechanism of associated retinopathy is unclear. Using the Cep290 mutant mouse rd16 (retinal degeneration 16), we show that Cep290-mediated photoreceptor degeneration is associated with aberrant accumulation of its novel interacting partner Rkip (Raf 1 kinase inhibitory protein). This effect is phenocopied by morpholino-mediated depletion of cep290 in zebrafish. We further demonstrate that ectopic accumulation of Rkip leads to defective cilia formation in zebrafish and cultured cells, an effect mediated by its interaction with the ciliary GTPase Rab8A. Our data suggest that Rkip prevents cilia formation and is associated with Cep290 mediated photoreceptor degeneration. Furthermore, our results indicate that preventing accumulation of Rkip could potentially ameliorate such degeneration. PMID- 21685396 TI - Gamma-secretase-regulated proteolysis of the Notch receptor by mitochondrial intermediate peptidase. AB - Notch is a transmembrane receptor that controls a diverse array of cellular processes including cell proliferation, differentiation, survival, and migration. The cellular outcome of Notch signaling is dependent on extracellular and intracellular signals, but the complexities of its regulation are not well understood. Canonical Notch signaling involves ligand association that triggers sequential and regulated proteolysis of Notch at several sites. Ligand-dependent proteolysis at the S2 site removes the bulk of the extracellular domain of Notch. Subsequent gamma-secretase-mediated intramembrane proteolysis of the remaining membrane-tethered Notch fragment at the S3 site produces a nuclear-destined Notch intracellular domain (NICD). Here we show that following gamma-secretase cleavage, Notch is proteolyzed at a novel S5 site. We have identified this S5 site to be eight amino acids downstream of the S3 site. Biochemical fractionation and purification resulted in the identification of the S5 site protease as the mitochondrial intermediate peptidase (MIPEP). Expression of the MIPEP-cleaved NICD (DeltaNICD) results in a decrease in cell viability and mitochondria membrane potential. The sequential and regulated proteolysis by gamma-secretase and MIPEP suggests a new means by which Notch function can be modulated. PMID- 21685397 TI - Corticomuscular coherence reflects interindividual differences in the state of the corticomuscular network during low-level static and dynamic forces. AB - In the investigation of corticomuscular coherence (CMC), it remained unclear why some subjects do not present significant CMC. We predicted that such subjects will develop CMC as a result of learning as indexed by improved performance during a visuomotor task. We investigated CMC, cortical motor spectral power (SP), and performance in 14 subjects during isometric compensation of a static force or dynamic force (DF) with their right index finger. We compared data from the beginning of the experiment (Time-Period 1) and after learning (Time-Period 2). Eight subjects (Group CMC++) presented CMC during Period 1 which increased during Period 2. Six subjects (Group CMC-+) presented CMC only during Period 2. Group CMC-+ was "more desynchronized" (lower SP, and stronger task-related desynchronization) than Group CMC++. The performance was better in Group CMC++ than in Group CMC-+. Learning was associated with higher SP, higher CMC, and better performance in both groups. However, in the more complicated DF condition, Group CMC++ learned better than Group CMC-+. The present study demonstrates the presence of CMC in all subjects tested and evidence that this is due to the fact that individuals may fall into 2 different groups in terms of oscillatory motor control: Group CMC-+ presents CMC only after learning. PMID- 21685398 TI - Inhibition of matrix metalloproteinases prevents the potentiation of nondeprived eye responses after monocular deprivation in juvenile rats. AB - The ocular dominance (OD) shift induced by monocular deprivation (MD) during the critical period is mediated by an initial depression of deprived-eye responses followed by an increased responsiveness to the nondeprived eye. It is not fully clear to what extent these 2 events are correlated and which are their physiological and molecular mediators. The extracellular synaptic environment plays an important role in regulating visual cortical plasticity. Matrix metalloproteinases (MMPs) are a family of activity-dependent zinc-dependent extracellular endopeptidases mediating extracellular matrix remodeling. We investigated the effects of MMP inhibition on OD plasticity in juvenile monocularly deprived rats. By using electrophysiological recordings, we found that MMP inhibition selectively prevented the potentiation of neuronal responses to nondeprived-eye stimulation occurring after 7 days of MD and potentiation of deprived-eye responses occurring after eye reopening. Three days of MD only resulted in a depression of deprived-eye responses insensitive to MMP inhibition. MMP inhibition did not influence homeostatic plasticity tested in the monocular cortex but significantly prevented an increase in dendritic spine density present after 7 days MD in layer II-III pyramids. PMID- 21685399 TI - Speaking of which: dissecting the neurocognitive network of language production in picture naming. AB - The noninvasive methods of cognitive neuroscience offer new possibilities to study language. We used neuronavigated multisite transcranial magnetic stimulation (TMS) to determine the functional relevance of 1) the posterior part of left superior temporal gyrus (Wernicke's area), 2) a midportion of Broca's area (slightly posterior/superior to apex of vertical ascending ramus), and 3) the midsection of the left middle temporal gyrus (MTG), during overt picture naming. Our chronometric TMS design enabled us to chart the time points at which neural activity in each of these regions functionally contributes to overt speech production. Our findings demonstrate that the midsection of left MTG becomes functionally relevant at 225 ms after picture onset, followed by Broca's area at 300 ms and Wernicke's area at 400 ms. Interestingly, during this late time window, the left MTG shows a second peak of functional relevance. Each area thus contributed during the speech production process at different stages, suggesting distinct underlying functional roles within this complex multicomponential skill. These findings are discussed and framed in the context of psycholinguistic models of speech production according to which successful speaking relies on intact, spatiotemporally specific feed forward and recurrent feedback loops within a left hemispheric fronto-temporal brain connectivity network. PMID- 21685400 TI - Grasping with tools: corticospinal excitability reflects observed hand movements. AB - Although facilitation of the corticospinal system during action observation is widely accepted, it remains controversial whether this facilitation reflects a replica of the observed movements or the goal of the observed motor acts. In the present study, we asked whether, when an object is grasped by using a tool, corticospinal facilitation represents 1) the movements of the hand, 2) the movements of the tool, or 3) the distal goal of the action. To address this question, we recorded motor-evoked potentials (MEPs) to transcranial magnetic stimulation while participants observed a hand reaching and grasping a mothball by using 3 types of pliers, requiring different hand-tool movements to achieve the same goal (grasping the object). We found that MEPs recorded from the opponens pollicis and from the first dorsal interosseous reflected the observed hand movements rather than the movements of the tool or the distal goal of the action. These results suggest that during observation of tool actions, detailed motor matching recruits online the same muscles as those used in the observed action. PMID- 21685401 TI - Crowding is size and eccentricity dependent. AB - Crowding is a form of lateral interaction in which flanking items interfere with the detection or discrimination of a target stimulus. It is believed that crowding is a property of peripheral vision only and that no crowding occurs at fixation. If these two claims are true, then there must be a change in the nature of crowding interactions across the visual field. In three different tasks, we determined target size and flanker separation at threshold for eccentricities of 0 to 16 degrees in the lower visual field for 7 relative separations (1.25 to 8 times target size). In all three tasks, the magnitude of crowding increases with eccentricity; there was no crowding at fixation and extreme crowding at 16 degrees . Using a novel double-scaling procedure, we show that the non-foveal data in all three tasks can be characterized as shifted versions of the same psychometric function such that different sections of the function characterize data at each eccentricity. This pattern of results can be understood in terms of size-dependent responses to the target and distance-dependent interference from the flankers. The data suggest that the distance-dependent interference increases with eccentricity. PMID- 21685402 TI - A media advocacy intervention linking health disparities and food insecurity. AB - Media advocacy is a well-established strategy for transmitting health messages to the public. This paper discusses a media advocacy intervention that raised issues about how the public interprets messages about the negative effects of poverty on population health. In conjunction with the publication of a manuscript illustrating how income-related food insecurity leads to disparities related to the consumption of a popular food product across Canada (namely, Kraft Dinner(r)), we launched a media intervention intended to appeal to radio, television, print and Internet journalists. All the media coverage conveyed our intended message that food insecurity is a serious population health problem, confirming that message framing, personal narratives and visual imagery are important in persuading media outlets to carry stories about poverty as a determinant of population health. Among politicians and members of the public (through on-line discussions), the coverage provoked on-message as well as off message reactions. Population health researchers and health promotion practitioners should anticipate mixed reactions to media advocacy interventions, particularly in light of new Internet technologies. Opposition to media stories regarding the socio-economic determinants of population health can provide new insights into how we might overcome challenges in translating evidence into preventive interventions. PMID- 21685403 TI - Increased breakfast frequency and nutritional quality among schoolchildren after a national breakfast promotion campaign in Australia between 2000 and 2006. AB - This national study examined student breakfast consumption and nutritional quality of breakfast in 2000 and 2006 by gender, school grade, school socioeconomic status (SES) and weight status after the implementation of a national breakfast promotion campaign. Participants were 4237 schoolchildren in grades 2-12 from 32 schools in 2000 and 5645 schoolchildren from the same schools in 2006. Height and weight were measured. Missing breakfast decreased from 2000 to 2006 in primary school females (9.6-6.0%) and males (9.4-6.0%) and in secondary school females (27.7-18.7%) and males (19.9-12.1%). Breakfast skipping was greater and nutritional quality was poorer in students from low SES schools in both study years but significant improvement was seen from 2000 to 2006 among all SES groups. Overweight/obese participants were more likely than normal weight students to miss breakfast in 2000 (20.7% versus 16.0%) and in 2006 (14.3% versus 10.4%) but significant improvement was observed over the 6-year study period. Findings suggest that the consistent, significant and far-reaching improvements in breakfast consumption observed in this study were attributed to the breakfast promotion program conducted in each school community and disseminated nationally via a mass media campaign. PMID- 21685404 TI - Cholinesterase levels and morbidity in pesticide sprayers in North India. AB - BACKGROUND: Pesticide sprayers in North India use different application methods for different crops. AIMS: To compare cholinesterase activity and symptoms in knapsack and tractor-mounted pesticide sprayers. METHODS: Blood cholinesterase activity and symptoms were recorded for 42 knapsack and 66 tractor-mounted sprayers attending a health camp in North India in 2009 and for 30 controls. RESULTS: One hundred and eight of 197 (55%) eligible sprayers consented to participate. Mean acetylcholinesterase (AChE) and butyrylcholinesterase activity was 33 and 60% lower, respectively, in knapsack sprayers than in controls (P < 0.001) and 56 and 62% lower, respectively, in tractor-mounted sprayers than in controls (P < 0.001). AChE depletion was greater in tractor-mounted sprayers than in knapsack sprayers (P < 0.001). In knapsack sprayers compared to controls, odds ratios (OR) were significantly raised for musculoskeletal symptoms (OR 3.9, 95% CI 1.03-18) but not for other symptoms. In tractor-mounted sprayers compared to controls, ORs were significantly raised for neurological (OR 7, 95% CI 2-23), ocular (OR 8.7, 95% CI 2.7-32), respiratory (OR 5.14, 95% CI 1-29), cardiovascular (OR 7.5, 95% CI 2-42), gastrointestinal (OR 5.43, 95% CI 2-18) and musculoskeletal (OR 6.12, 95% CI 2-26) symptoms but not for dermal symptoms (OR 1.93, 95% CI 0.3-20). CONCLUSIONS: The risk of cholinesterase inhibition and symptoms is greater in tractor-mounted than in knapsack pesticide sprayers and in both groups compared to controls. Occupational exposure in pesticide sprayers in North India needs better control, perhaps through redesign of spraying equipment. PMID- 21685405 TI - Industry and job-specific mortality after occupational exposure to silica dust. AB - BACKGROUND: Occupational exposure to silica dust occurs in many workplaces and is well known to cause silicosis. However, the link between silica exposure, silicosis and other diseases is still disputed. AIMS: To evaluate cause-specific mortality in a cohort of Italian silicotics. METHODS: The cohort included 2034 male compensated for silicosis between 1943 and 1986, alive on 1 January 1987 and resident in the Latium region (Italy). Mortality follow-up was from 1987 to 2006. Vital status and death causes were ascertained from the regional mortality archive. Standardized mortality ratios (SMRs) were computed assuming a Poisson distribution of observed deaths. RESULTS: Significant excess mortality was observed from all causes (SMR: 1.17, 95% CI: 1.11-1.24), cancer of trachea, bronchus and lung (SMR: 1.39, 95% CI: 1.17-1.64), cancer of larynx (SMR: 2.18, 95% CI: 1.32-3.60) and tuberculosis (SMR: 5.85, 95% CI: 3.03-11.30). Higher risks were observed for masons (lung cancer, SMR: 2.46, 95% CI: 1.65-3.66) and miners (larynx cancer, SMR: 5.31, 95% CI: 1.88-15.03). In a Poisson regression analysis, the relative risk of death from lung cancer and silicosis increased with silicosis severity and decreased in more recent compensation periods. CONCLUSIONS: The excess mortality from respiratory tract cancers and other diseases detected among Italian workers compensated for silicosis confirms previous epidemiological findings. PMID- 21685406 TI - An X chromosome microRNA cluster in the marsupial species Monodelphis domestica. AB - MicroRNAs (miRNAs) are an important class of posttranscriptional gene expression regulators. In the course of mapping novel marsupial-specific miRNAs in the genome of the gray short-tailed opossum, Monodelphis domestica, we encountered a cluster of 39 actual and potential miRNAs spanning 102 kb of the X chromosome. Analysis of the cluster revealed that 37 of the 39 miRNAs are predicted to form thermodynamically stable hairpins, and at least 3 members have been directly cloned from M. domestica tissues. The sequence characteristics of these miRNAs suggest that they all descended from a single common ancestor. Further, 2 distinct families appear to have diversified from the ancestral sequence through different duplication mechanisms: one through a series of simple tandem duplications and the other through a recurrent transposon-mediated duplication process. PMID- 21685407 TI - Modality-specific neural effects of selective attention to taste and odor. AB - The insular cortex is implicated in general attention and in taste perception. The effect of selective attention to taste on insular responses may therefore reflect a general effect of attention or it may be (taste) modality specific. To distinguish between these 2 possibilities, we used functional magnetic resonance imaging to evaluate brain response to tastes and odors while subjects passively sampled the stimuli or performed a detection task. We found that trying to detect a taste (attention to taste) resulted in activation of the primary taste cortex (anterior and mid-dorsal insula) but not in the primary olfactory cortex (piriform). In contrast, trying to detect an odor (attention to odor) increased activity in primary olfactory but not primary gustatory cortex. However, we did identify a region of far anterior insular cortex that responded to both taste and odor "searches." These results demonstrate modality-specific activation of primary taste cortex by attention to taste and primary olfactory cortex by attention to odor and rule out the possibility that either response reflects a general effect of attentional deployment. The findings also support the existence of a multimodal region in far anterior insular cortex that is sensitive to directed attention to taste and smell. PMID- 21685408 TI - Respirable dust and quartz exposure from three South African farms with sandy, sandy loam, and clay soils. AB - OBJECTIVES: To quantify personal time-weighted average respirable dust and quartz exposure on a sandy, a sandy loam, and a clay soil farm in the Free State and North West provinces of South Africa and to ascertain whether soil type is a determinant of exposure to respirable quartz. METHODS: Three farms, located in the Free State and North West provinces of South Africa, had their soil type confirmed as sandy, sandy loam, and clay; and, from these, a total of 298 respirable dust and respirable quartz measurements were collected between July 2006-November 2009 during periods of major farming operations. Values below the limit of detection (LOD) (22 MUg . m(-3)) were estimated using multiple 'imputation'. Non-parametric tests were used to compare quartz exposure from the three different soil types. RESULTS: Exposure to respirable quartz occurred on all three farms with the highest individual concentration measured on the sandy soil farm (626 MUg . m(-3)). Fifty-seven, 59, and 81% of the measurements on the sandy soil, sandy loam soil, and clay soil farm, respectively, exceeded the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value (TLV) of 25 MUg . m(-3). Twelve and 13% of respirable quartz concentrations exceeded 100 MUg . m(-3) on the sandy soil and sandy loam soil farms, respectively, but none exceeded this level on the clay soil farm. The proportions of measurements >100 MUg . m(-3) were not significantly different between the sandy and sandy loam soil farms ('prop.test'; P = 0.65), but both were significantly larger than for the clay soil farm ('prop.test'; P = 0.0001). The percentage of quartz in respirable dust was determined for all three farms using measurements > the limit of detection. Percentages ranged from 0.5 to 94.4% with no significant difference in the median quartz percentages across the three farms (Kruskal-Wallis test; P = 0.91). CONCLUSION: This study demonstrates that there is significant potential for over-exposure to respirable quartz in farming and even clay soil farming may pose a risk. Soil type may determine whether exposure is >100 MUg . m(3), but the job type and the manner in which the task is performed (e.g. mechanical or manual) may be important determinants of exposure. Identifying quartz exposure determinants (e.g. type of job) and modifiers will be of value to focus implementation of controls of particular importance in developing countries. PMID- 21685409 TI - Sex differences in subclinical atherosclerosis by race/ethnicity in the multi ethnic study of atherosclerosis. AB - Sex differences in cardiovascular disease mortality are more pronounced among non Hispanic whites than other racial/ethnic groups, but it is unknown whether this variation is present in the earlier subclinical stages of disease. The authors examined racial/ethnic variation in sex differences in coronary artery calcification (CAC) and carotid intimal media thickness at baseline in 2000-2002 among participants (n = 6,726) in the Multi-Ethnic Study of Atherosclerosis using binomial and linear regression. Models adjusted for risk factors in several stages: age, traditional cardiovascular disease risk factors, behavioral risk factors, psychosocial factors, and adult socioeconomic position. Women had a lower prevalence of any CAC and smaller amounts of CAC when present than men in all racial/ethnic groups. Sex differences in the prevalence of CAC were more pronounced in non-Hispanic whites than in African Americans and Chinese Americans after adjustment for traditional cardiovascular disease risk factors, and further adjustment for behavioral factors, psychosocial factors, and socioeconomic position did not modify these results (for race/sex, P(interaction) = 0.047). Similar patterns were observed for amount of CAC among adults with CAC. Racial/ethnic variation in sex differences for carotid intimal media thickness was less pronounced. In conclusion, coronary artery calcification is differentially patterned by sex across racial/ethnic groups. PMID- 21685410 TI - Pancreatic cancer and exposure to dietary nitrate and nitrite in the NIH-AARP Diet and Health Study. AB - Nitrate and nitrite are precursors of N-nitroso compounds, which induce tumors of the pancreas in animals. The authors evaluated the relation of dietary nitrate and nitrite to pancreatic cancer risk in the NIH-AARP Diet and Health Study. Nitrate and nitrite intakes were assessed at baseline using a 124-item food frequency questionnaire. During approximately 10 years of follow-up between 1995 and 2006, 1,728 incident pancreatic cancer cases were identified. There was no association between total nitrate or nitrite intake and pancreatic cancer in men or women. However, men in the highest quintile of summed nitrate/nitrite intake from processed meat had a nonsignificantly elevated risk of pancreatic cancer (hazard ratio = 1.18, 95% confidence interval: 0.95, 1.47; P-trend = 0.11). The authors observed a stronger increase in risk among men for nitrate/nitrite intake from processed meat at ages 12-13 years (highest quintile vs. lowest: hazard ratio = 1.32, 95% confidence interval: 0.99, 1.76; P-trend = 0.11), though the relation did not achieve statistical significance. The authors found no associations between adult or adolescent nitrate or nitrite intake from processed meats and pancreatic cancer among women. These results provide modest evidence that processed meat sources of dietary nitrate and nitrite may be associated with pancreatic cancer among men and provide no support for the hypothesis in women. PMID- 21685411 TI - Inflammation biomarkers and risk of all-cause mortality in the Reasons for Geographic And Racial Differences in Stroke cohort. AB - Inflammation biomarkers, including higher high-sensitivity C-reactive protein (hsCRP) levels, higher white blood cell (WBC) counts, and lower serum albumin levels, are associated with an increased risk of all-cause mortality. Many studies have examined these biomarkers individually, but less is known about their joint association with mortality. hsCRP, WBC count, and serum albumin were measured at baseline in the Reasons for Geographic and Racial Differences in Stroke Study cohort members, who were enrolled in 2003-2007. Over 4.5 years, there were 1,062 deaths in 17,845 participants. High-risk categories were defined as hsCRP or WBC levels above the 75th percentile (5.1 mg/L and 6.9 * 10(9) cells/L, respectively) and albumin levels below the 25th percentile (4.00 g/dL). The authors derived 4 groups that corresponded to 0 (n = 8,341), 1 (n = 6,277), 2 (n = 2,635), or 3 (n = 592) biomarkers in the high-risk category. After adjustment for age, sex, waist circumference, race, region, smoking, alcohol use, income, educational level, physical activity frequency, and medical history and compared with those with no biomarkers in the high-risk category, the hazard ratios for all-cause mortality for 1, 2, and 3 biomarkers in the high-risk category were 1.56 (95% confidence interval: 1.33, 1.82), 2.19 (95% confidence interval: 1.84, 2.62), and 2.96 (95% confidence interval: 2.30, 3.80), respectively (P(trend) < 0.0001). Adding the 3 inflammation biomarkers to a fully adjusted model improved risk discrimination by 23.7% (95% confidence interval: 9.3, 39.9). Measurement of more than 1 biomarker is more useful in risk prediction than single biomarkers. PMID- 21685412 TI - Paralytic poliomyelitis associated with Sabin monovalent and bivalent oral polio vaccines in Hungary. AB - Historical records of patients with vaccine-associated paralytic poliomyelitis (VAPP) in Hungary during 1961-1981 were reviewed to assess the risk of VAPP after oral polio vaccine (OPV) administration. A confirmed VAPP case was defined as a diagnosis of paralytic poliomyelitis and residual paralysis at 60 days in a patient with an epidemiologic link to the vaccine. Archived poliovirus isolates were retested using polymerase chain reaction and sequencing of the viral protein 1 capsid region. This review confirmed 46 of 47 cases previously reported as VAPP. Three cases originally linked to monovalent OPV (mOPV) 3 and one case linked to mOPV1 presented after administration of bivalent OPV 1 + 3 (bOPV). The adjusted VAPP risk per million doses administered was 0.18 for mOPV1 (2 cases/11.13 million doses), 2.96 for mOPV3 (32 cases/10.81 million doses), and 12.82 for bOPV (5 cases/390,000 doses). Absence of protection from immunization with inactivated poliovirus vaccine or exposure to OPV virus from routine immunization and recent injections could explain the higher relative risk of VAPP in Hungarian children. In polio-endemic areas in which mOPV3 and bOPV are needed to achieve eradication, the higher risk of VAPP would be offset by the high risk of paralysis due to wild poliovirus and higher per-dose efficacy of mOPV3 and bOPV compared with trivalent OPV. PMID- 21685413 TI - Intraoperative hyperthermic versus postoperative normothermic intraperitoneal chemotherapy for colonic peritoneal carcinomatosis: a case-control study. AB - BACKGROUND: Cytoreductive surgery and intraperitoneal chemotherapy has improved prognosis in patients with peritoneal carcinomatosis. The main modes of intraperitoneal chemotherapy treatment are peroperative hyperthermic intraperitoneal chemotherapy (HIPEC) and normothermic sequential postoperative intraperitoneal chemotherapy (SPIC). The aim of this study was to compare HIPEC and SPIC with respect to overall survival, disease-free survival, morbidity, and mortality in patients with peritoneal carcinomatosis from colon cancer. PATIENTS AND METHODS: A matched case-control study was conducted in patients with surgical macroscopic complete removal of carcinomatosis; matching was according to the peritoneal cancer index score. Thirty-two patients were included, 16 in each group (HIPEC and SPIC). Overall survival, disease-free survival, morbidity, mortality, and clinicopathological parameters were compared. RESULTS: Median overall survival was 36.5 months in the HIPEC group and 23.9 months in the SPIC group (P = 0.01). Median disease-free survival for these groups was 22.8 (HIPEC) and 13.0 months (SPIC; P = 0.02). Morbidity was not statistically different, 19% in SPIC and 37% in HIPEC. Postoperative mortality was observed in one patient in each group. CONCLUSION: HIPEC was associated with improved overall survival and disease-free survival compared with SPIC at similar morbidity and mortality, suggesting that HIPEC is the treatment of choice in colonic peritoneal carcinomatosis. PMID- 21685414 TI - Significance analysis and statistical dissection of variably methylated regions. AB - It has recently been proposed that variation in DNA methylation at specific genomic locations may play an important role in the development of complex diseases such as cancer. Here, we develop 1- and 2-group multiple testing procedures for identifying and quantifying regions of DNA methylation variability. Our method is the first genome-wide statistical significance calculation for increased or differential variability, as opposed to the traditional approach of testing for mean changes. We apply these procedures to genome-wide methylation data obtained from biological and technical replicates and provide the first statistical proof that variably methylated regions exist and are due to interindividual variation. We also show that differentially variable regions in colon tumor and normal tissue show enrichment of genes regulating gene expression, cell morphogenesis, and development, supporting a biological role for DNA methylation variability in cancer. PMID- 21685415 TI - Nuclear factor-kappaB mediated lipopolysaccharide-induced mRNA expression of hepcidin in human peripheral blood leukocytes. AB - Hepcidin is a known key modulator of iron homeostasis and an innate immune molecule secreted by the liver. The transcriptional mechanism of hepcidin in hepatocytes during inflammation is mediated via the IL-6/STAT3 pathway. Recently, hepcidin demonstrated an anti-inflammatory function in endotoxic mice, and a TLR4 dependent inducible expression of hepcidin was detected in myeloid cells. In this study, we explored the expression and signaling mechanism regulating hepcidin mRNA expression in peripheral blood leukocytes. The mRNA levels of hepcidin in peripheral blood leukocytes from patients with severe sepsis (n = 14) was significantly higher than those in healthy controls (n = 16;0.286 +/- 0.065 vs 0.068 +/- 0.025; P < 0.05). Ex vivo studies found hepcidin mRNA can be highly induced by challenge of 100 ng/ml LPS or 20 ng/ml TNF-alpha in peripheral blood leukocytes rather than IL-6, IL-1 and IFN-gamma. Anti-TNF-alpha antibody significantly decreased the levels of hepcidin mRNA induced by LPS. Inhibitor of nuclear factor (NF)-kappaB rather than that of STAT3 completely abolished the inducibility of hepcidin mRNA in PBMCs and neutrophils. These results indicate that hepcidin mRNA expression in peripheral blood leukocytes induced by LPS depends on NF-kappaB, and TNF-alpha may be a key mediator in this procedure. PMID- 21685416 TI - VMD drops plans for POM-EA category. PMID- 21685417 TI - Great Britain to be declared free from bluetongue. PMID- 21685418 TI - Shedding light on bleeding calf syndrome. PMID- 21685419 TI - Celebrating 125 years of equine care. PMID- 21685421 TI - Botulism in cattle associated with poultry litter. PMID- 21685422 TI - Anthelmintic resistance: potential benefits of 'over-diagnosis'. PMID- 21685423 TI - A logo to reflect the profession? PMID- 21685424 TI - Gender balance in the veterinary profession. PMID- 21685425 TI - Gender balance in the veterinary profession. PMID- 21685426 TI - Recruitment of Temporary Veterinary Inspectors in FMD emergencies. PMID- 21685427 TI - Forensic veterinary science of bite wounds. PMID- 21685428 TI - Behavioral activation and therapeutic exposure for bereavement in older adults. AB - The development and clinical trial of a 5-session behavioral intervention for complicated bereavement (CB) is presented. We conceptualized CB in terms of Major Depression (MDD) and Post-traumatic Stress Disorder (PTSD) and consequently applied treatment components of Behavioral Activation and Therapeutic Exposure (BA-TE). In order to assure standardization of treatment, control costs, and engage patients, a multi-media, multi-context format was adopted to address avoidance and withdrawal behaviors conceptualized as central pathogenic responses in CB. Participants (N = 26) were assessed before and after BA-TE treatment via structured clinical interview and standardized questionnaires in terms of PTSD, MDD, CB, and health concerns. The number of days since the death of the loved one was widely variable and served as a covariate for all outcome analyses. ANCOVAS revealed statistically significant improvement, irrespective of how many days since death had elapsed prior to initiation of intervention, on structured interviews and self-report measures for most outcome variables. PMID- 21685430 TI - Insights into a hydration regulating system in Cupressus pollen grains. AB - BACKGROUND AND AIMS: Hydration, rupture and exine opening due to the sudden and large expansion of intine are typical of taxoid-type pollen grains. A hemispheric outgrowth external to the exine was observed on Cupressus and Juniperus pollen grains before the intine swelling and exine release. However, the actual existence of this permanent or temporary structure and its precise role in pollen hydration is still being debated. The aim of this paper is to collect information on the actual presence of this peculiar outgrowth on the surface of the Cupressus pollen grain, its structure, composition and function. METHODS: Pollen grains of several Cupressus species were observed using various techniques and methodologies, under light and fluorescence microscopy, phase-contrast microscopy, confocal microscopy, scanning electron microscopy, and an environmental scanning electron microscope. Observations were also performed on other species with taxoid-type pollen grains. KEY RESULTS: A temporary structure located just above the pore was observed on Cupressus pollen grains, as well as on other taxoid-type pollens. It is hemispheric, layered, and consists of polysaccharides and proteins. The latter are confined to its inner part. Its presence seems to regulate the entrance of water into the grains at the beginning of pollen hydration. CONCLUSIONS: The presence of a temporary structure over the pore of taxoid-type pollen grains was confirmed and its structure was resolved using several stains and observation techniques. This structure plays a role in the first phases of pollen hydration. PMID- 21685429 TI - NEMA, a functional-structural model of nitrogen economy within wheat culms after flowering. II. Evaluation and sensitivity analysis. AB - BACKGROUND AND AIMS: Simulating nitrogen economy in crop plants requires formalizing the interactions between soil nitrogen availability, root nitrogen acquisition, distribution between vegetative organs and remobilization towards grains. This study evaluates and analyses the functional-structural and mechanistic model of nitrogen economy, NEMA (Nitrogen Economy Model within plant Architecture), developed for winter wheat (Triticum aestivum) after flowering. METHODS: NEMA was calibrated for field plants under three nitrogen fertilization treatments at flowering. Model behaviour was investigated and sensitivity to parameter values was analysed. KEY RESULTS: Nitrogen content of all photosynthetic organs and in particular nitrogen vertical distribution along the stem and remobilization patterns in response to fertilization were simulated accurately by the model, from Rubisco turnover modulated by light intercepted by the organ and a mobile nitrogen pool. This pool proved to be a reliable indicator of plant nitrogen status, allowing efficient regulation of nitrogen acquisition by roots, remobilization from vegetative organs and accumulation in grains in response to nitrogen treatments. In our simulations, root capacity to import carbon, rather than carbon availability, limited nitrogen acquisition and ultimately nitrogen accumulation in grains, while Rubisco turnover intensity mostly affected dry matter accumulation in grains. CONCLUSIONS: NEMA enabled interpretation of several key patterns usually observed in field conditions and the identification of plausible processes limiting for grain yield, protein content and root nitrogen acquisition that could be targets for plant breeding; however, further understanding requires more mechanistic formalization of carbon metabolism. Its strong physiological basis and its realistic behaviour support its use to gain insights into nitrogen economy after flowering. PMID- 21685431 TI - NEMA, a functional-structural model of nitrogen economy within wheat culms after flowering. I. Model description. AB - BACKGROUND AND AIMS: Models simulating nitrogen use by plants are potentially efficient tools to optimize the use of fertilizers in agriculture. Most crop models assume that a target nitrogen concentration can be defined for plant tissues and formalize a demand for nitrogen, depending on the difference between the target and actual nitrogen concentrations. However, the teleonomic nature of the approach has been criticized. This paper proposes a mechanistic model of nitrogen economy, NEMA (Nitrogen Economy Model within plant Architecture), which links nitrogen fluxes to nitrogen concentration and physiological processes. METHODS: A functional-structural approach is used: plant aerial parts are described in a botanically realistic way and physiological processes are expressed at the scale of each aerial organ or root compartment as a function of local conditions (light and resources). KEY RESULTS: NEMA was developed for winter wheat (Triticum aestivum) after flowering. The model simulates the nitrogen (N) content of each photosynthetic organ as regulated by Rubisco turnover, which depends on intercepted light and a mobile N pool shared by all organs. This pool is enriched by N acquisition from the soil and N release from vegetative organs, and is depleted by grain uptake and protein synthesis in vegetative organs; NEMA accounts for the negative feedback from circulating N on N acquisition from the soil, which is supposed to follow the activities of nitrate transport systems. Organ N content and intercepted light determine dry matter production via photosynthesis, which is distributed between organs according to a demand-driven approach. CONCLUSIONS: NEMA integrates the main feedbacks known to regulate plant N economy. Other novel features are the simulation of N for all photosynthetic tissues and the use of an explicit description of the plant that allows how the local environment of tissues regulates their N content to be taken into account. We believe this represents an appropriate frame for modelling nitrogen in functional-structural plant models. A companion paper will present model evaluation and analysis. PMID- 21685432 TI - Polyamines, IAA and ABA during germination in two recalcitrant seeds: Araucaria angustifolia (Gymnosperm) and Ocotea odorifera (Angiosperm). AB - BACKGROUND AND AIMS: Plant growth regulators play an important role in seed germination. However, much of the current knowledge about their function during seed germination was obtained using orthodox seeds as model systems, and there is a paucity of information about the role of plant growth regulators during germination of recalcitrant seeds. In the present work, two endangered woody species with recalcitrant seeds, Araucaria angustifolia (Gymnosperm) and Ocotea odorifera (Angiosperm), native to the Atlantic Rain Forest, Brazil, were used to study the mobilization of polyamines (PAs), indole-acetic acid (IAA) and abscisic acid (ABA) during seed germination. METHODS: Data were sampled from embryos of O. odorifera and embryos and megagametophytes of A. angustifolia throughout the germination process. Biochemical analyses were carried out in HPLC. KEY RESULTS: During seed germination, an increase in the (Spd + Spm) : Put ratio was recorded in embryos in both species. An increase in IAA and PA levels was also observed during seed germination in both embryos, while ABA levels showed a decrease in O. odorifera and an increase in A. angustifolia embryos throughout the period studied. CONCLUSIONS: The (Spd + Spm) : Put ratio could be used as a marker for germination completion. The increase in IAA levels, prior to germination, could be associated with variations in PA content. The ABA mobilization observed in the embryos could represent a greater resistance to this hormone in recalcitrant seeds, in comparison to orthodox seeds, opening a new perspective for studies on the effects of this regulator in recalcitrant seeds. The gymnosperm seed, though without a connective tissue between megagametophyte and embryo, seems to be able to maintain communication between the tissues, based on the likely transport of plant growth regulators. PMID- 21685433 TI - Climbing plants in a temperate rainforest understorey: searching for high light or coping with deep shade? AB - BACKGROUND AND AIMS: While the climbing habit allows vines to reach well-lit canopy areas with a minimum investment in support biomass, many of them have to survive under the dim understorey light during certain stages of their life cycle. But, if the growth/survival trade-off widely reported for trees hold for climbing plants, they cannot maximize both light-interception efficiency and shade avoidance (i.e. escaping from the understorey). The seven most important woody climbers occurring in a Chilean temperate evergreen rainforest were studied with the hypothesis that light-capture efficiency of climbers would be positively associated with their abundance in the understorey. METHODS: Species abundance in the understorey was quantified from their relative frequency and density in field plots, the light environment was quantified by hemispherical photography, the photosynthetic response to light was measured with portable gas-exchange analyser, and the whole shoot light-interception efficiency and carbon gain was estimated with the 3-D computer model Y-plant. KEY RESULTS: Species differed in specific leaf area, leaf mass fraction, above ground leaf area ratio, light interception efficiency and potential carbon gain. Abundance of species in the understorey was related to whole shoot features but not to leaf level features such as specific leaf area. Potential carbon gain was inversely related to light interception efficiency. Mutual shading among leaves within a shoot was very low (<20 %). CONCLUSIONS: The abundance of climbing plants in this southern rainforest understorey was directly related to their capacity to intercept light efficiently but not to their potential carbon gain. The most abundant climbers in this ecosystem match well with a shade-tolerance syndrome in contrast to the pioneer-like nature of climbers observed in tropical studies. The climbers studied seem to sacrifice high-light searching for coping with the dim understorey light. PMID- 21685434 TI - Clarifying Baker's Law. AB - BACKGROUND: Baker's Law states that colonization by self-compatible organisms is more likely to be successful than colonization by self-incompatible organisms because of the ability for self-compatible organisms to produce offspring without pollination agents. This simple model has proved very successful in plant ecology and has been applied to various contexts, including colonizing or ruderal species, islands colonizers, invasive species or mating system variation across distribution ranges. Moreover, it is one of the only models in population biology linking two traits of major importance in ecology, namely dispersal and mating system. Although Baker's Law has stimulated a large number of empirical studies reporting the association of self-fertilization and colonizing ability in various contexts, the data have not established a general pattern for the association of traits. SCOPE: In this paper, a critical position is adopted to discuss and clarify Baker's Law. From the literature referring to Baker's Law, an analysis made regarding how mating success is considered in such studies and discrepancies with population genetics theory of mating systems are highlighted. The data reporting the association of self-fertilization and colonizing ability are also briefly reviewed and the potential bias in interpretation is discussed. Lastly, a recent theoretical model analysing the link between colonizing ability and self fertilization is considered. CONCLUSIONS: Evolutionary predictions are actually more complex than Baker's intuitive arguments. It appears that Baker's Law encompasses a variety of ecological scenarios, which cannot be considered a priori as equivalent. Questioning what has been considered as self-evident for more than 50 years seems a reasonable objective to analyse in-depth dispersal and mating system traits. PMID- 21685435 TI - Non-interventional management of acute coronary syndromes. PMID- 21685436 TI - Oral antiplatelet agents clopidogrel and prasugrel for the prevention of cardiovascular events. PMID- 21685437 TI - Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. AB - OBJECTIVE: To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy. DESIGN: Pre-specified analysis of pre randomisation defined subgroup of prospective randomised clinical trial. SETTING: 862 centres in 43 countries. PARTICIPANTS: 5216 (28%) of 18,624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non invasive management. INTERVENTIONS: Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615). MAIN OUTCOME MEASUREMENTS: Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year. RESULTS: 2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel. CONCLUSIONS: In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy. TRIAL REGISTRATION: Clinical trials NCT00391872. PMID- 21685438 TI - Management of nausea and vomiting in pregnancy. PMID- 21685439 TI - Women told that they must abstain from alcohol in pregnancy, in campaign financed by drinks industry. PMID- 21685440 TI - UK government is likely to give more prominence to scientific advice before emergencies occur. PMID- 21685441 TI - Chinese children with lead poisoning are denied treatment. PMID- 21685442 TI - US "Bad Ad" campaign leads to just five warning letters in its first year. PMID- 21685443 TI - The effects of induced state negative affect on performance monitoring processes. AB - Previous research suggests that performance-monitoring processes are related to personality traits; relationships with affective states, however, remain unclear. The purpose of this study was to replicate and extend previous findings that induced state negative affect alters electrophysiological reflections of performance monitoring. High-density event-related potentials (ERPs) were obtained from 69 healthy individuals (41 female, 28 male) who completed an Eriksen flanker task and received either encouraging or derogatory feedback based on mean reaction times (RTs) for 30-trial sub-blocks. Affective state, behavioral measures (i.e. error rates, RTs) and ERP measures [i.e. error-related negativity (ERN), post-error positivity (Pe) and N2] were assessed. Reaction times did not differ between feedback groups. Participants who received derogatory feedback committed more errors over time. Despite changes in affect, no significant group differences were demonstrated for behavioral or ERP measures of performance monitoring. Increases in vigilance were associated with more negative N2 amplitudes; no other changes in affective state were associated with changes in ERP measures. Results are consistent with findings suggesting performance monitoring processes are only slightly affected by changes in affective state and fail to replicate previous studies suggesting the ERN is related to state changes in affect-supporting the possibility of the ERN as an endophenotype. PMID- 21685444 TI - Human skeletal muscle feed arteries studied in vitro: the effect of temperature on alpha(1)-adrenergic responsiveness. AB - Heat and cold exposure can decrease and increase total peripheral resistance, respectively, in humans. With unique access to human skeletal muscle feed arteries, we sought both to characterize these vessels and to determine the interaction between temperature and alpha(1)-adrenergic receptor responsiveness. We hypothesized that alpha(1)-mediated vasocontraction of human feed arteries would be attenuated in response to 39 or 35 degrees C. Skeletal muscle feed arteries were harvested from thirty-two human volunteers and studied using isometric techniques. Vessel function was assessed using KCl, sodium nitroprusside (SNP), phenylephrine (PE) and ACh dose-response curves to characterize non-receptor- and receptor-mediated vasocontraction and vasorelaxation. Single doses of PE (1 mm) and KCl (100 mm) were administered at 37 degrees C and then, in a balanced design, repeated at both 35 and 39 degrees C. The KCl and PE dose-response curves elicited significant vasocontraction (2009 +/- 407 and 1974 +/- 508 mg developed tension, respectively), whereas SNP and ACh induced the expected vasorelaxation (102 +/- 6 and 73 +/- 10% relaxation, respectively). Altering the temperature had no effect on inherent smooth muscle function (KCl response), but both a reduction (35 degrees C) and an increase in temperature (39 degrees C) decreased the vasocontractile response to 1 mm PE (37 degrees C, 1478 +/- 338 mg; 35 degrees C, 546 +/- 104 mg; and 39 degrees C, 896 +/- 202 mg; P < 0.05) or across PE dose (P < 0.05, 35 and 39 versus 37 degrees C). Despite clear heterogeneity between both the human volunteers and the feed arteries themselves, this novel approach to the procurement of human vessels revealed a robust 'inverted U' response to altered temperature, such that alpha(1)-mediated vasocontraction was attenuated with either warming or cooling. PMID- 21685445 TI - Cerebroprotection by angiotensin-(1-7) in endothelin-1-induced ischaemic stroke. AB - Activation of angiotensin-converting enzyme 2 (ACE2), production of angiotensin (1-7) [Ang-(1-7)] and stimulation of the Ang-(1-7) receptor Mas exert beneficial actions in various peripheral cardiovascular diseases, largely through opposition of the deleterious effects of angiotensin II via its type 1 receptor. Here we considered the possibility that Ang-(1-7) may exert beneficial effects against CNS damage and neurological deficits produced by cerebral ischaemic stroke. We determined the effects of central administration of Ang-(1-7) or pharmacological activation of ACE2 on the cerebral damage and behavioural deficits elicited by endothelin-1 (ET-1)-induced middle cerebral artery occlusion (MCAO), a model of cerebral ischaemia. The results of the present study demonstrated that intracerebroventricular infusion of either Ang-(1-7) or an ACE2 activator, diminazine aceturate (DIZE), prior to and following ET-1-induced MCAO significantly attenuated the cerebral infarct size and neurological deficits measured 72 h after the insult. These beneficial actions of Ang-(1-7) and DIZE were reversed by co-intracerebroventricular administration of the Mas receptor inhibitor, A-779. Neither the Ang-(1-7) nor the DIZE treatments altered the reduction in cerebral blood flow elicited by ET-1. Lastly, intracerebroventricular administration of Ang-(1-7) significantly reduced the increase in inducible nitric oxide synthase mRNA expression within the cerebral infarct that occurs following ET-1-induced MCAO. This is the first demonstration of cerebroprotective properties of the ACE2-Ang-(1-7)-Mas axis during ischaemic stroke, and suggests that the mechanism of the Ang-(1-7) protective action includes blunting of inducible nitric oxide synthase expression. PMID- 21685446 TI - Effect of passive heat stress on arterial stiffness. AB - Arterial compliance, the inverse of arterial stiffness, is a prognostic indicator of arterial health. Central and peripheral arterial compliance decrease with acute cold stress and may increase postexercise when exercise-induced elevations in core temperature are likely still to be present. Increased blood flow through the conduit arteries associated with elevated core temperature increases shear stress, which in turn releases nitric oxide and other endothelium-derived factors. These changes, in conjunction with supportive in vitro data, suggest that elevated core temperature may indirectly increase central and peripheral arterial compliance (i.e. decrease arterial stiffness). The purpose of this study was to test the hypothesis that increased core temperature decreases central and peripheral arterial stiffness, as measured with pulse wave velocity (PWV). Using Doppler ultrasound, carotid-femoral (central) and carotid-radial (peripheral) arterial PWVs were measured from eight subjects (age 37 +/- 11 years; mass 68.8 +/- 11.1 kg; height 171 +/- 3 cm) before and during passive heat-stress-induced increases in core temperature of 0.47 +/- 0.05, 1.03 +/- 0.12 and 1.52 +/- 0.07 degrees C (i.e. baseline, 0.5, 1.0 and 1.5 degrees C, respectively). Changes in PWV were evaluated with one-way repeated-measures ANOVA. When analysed as group means, neither central (677 +/- 161, 617 +/- 72, 659 +/- 74 and 766 +/- 207 cm s( 1); P = 0.12) nor peripheral PWV (855 +/- 192, 772 +/- 95, 759 +/- 49 and 858 +/- 247 cm s(-1); P = 0.56) changed as core temperature increased from baseline to 0.5, 1.0 and 1.5 degrees C, respectively. However, individual changes in central (average r = -0.89, P < 0.05) and peripheral PWV (average r = -0.93, P < 0.05) with heat stress were significantly correlated with normothermic baseline PWV. In conclusion, these data suggest that the magnitude by which heat stress reduced PWV was predicated upon normothermic PWV, with the individuals having the highest normothermic PWV being most responsive to the heat-stress-induced reductions in PWV. PMID- 21685447 TI - Lentivirus-mediated overexpression of angiotensin-(1-7) attenuated ischaemia induced cardiac pathophysiology. AB - Myocardial infarction (MI) results in cell death, development of interstitial fibrosis, ventricular wall thinning and ultimately, heart failure. Angiotensin-(1 7) [Ang-(1-7)] has been shown to provide cardioprotective effects. We hypothesize that lentivirus-mediated overexpression of Ang-(1-7) would protect the myocardium from ischaemic injury. A single bolus of 3.5 * 10(8) transducing units of lenti Ang-(1-7) was injected into the left ventricle of 5-day-old male Sprague-Dawley rats. At 6 weeks of age, MI was induced by ligation of the left anterior descending coronary artery. Four weeks after the MI, echocardiography and haemodynamic parameters were measured to assess cardiac function. Postmyocardial infarction, rats showed significant decreases in fractional shortening and dP/dt (rate of rise of left ventricular pressure), increases in left ventricular end diastolic pressure, and ventricular hypertrophy. Also, considerable upregulation of cardiac angiotensin-converting enzyme (ACE) mRNA was observed in these rats. Lentivirus-mediated cardiac overexpression of Ang-(1-7) not only prevented all these MI-induced impairments but also resulted in decreased myocardial wall thinning and an increased cardiac gene expression of ACE2 and bradykinin B2 receptor (BKR2). Furthermore, in vitro experiments using rat neonatal cardiac myocytes demonstrated protective effects of Ang-(1-7) against hypoxia-induced cell death. This beneficial effect was associated with decreased expression of inflammatory cytokines (tumour necrosis factor-alpha and interleukin-6) and increased gene expression of ACE2, BKR2 and interleukin-10. Our findings indicate that overexpression of Ang-(1-7) improves cardiac function and attenuates left ventricular remodelling post-MI. The protective effects of Ang-(1-7) appear to be mediated, at least in part, through modulation of the cardiac renin-angiotensin system and cytokine production. PMID- 21685448 TI - Efficient recombinase-mediated cassette exchange at the AAVS1 locus in human embryonic stem cells using baculoviral vectors. AB - Insertion of a transgene into a defined genomic locus in human embryonic stem cells (hESCs) is crucial in preventing random integration-induced insertional mutagenesis, and can possibly enable persistent transgene expression during hESC expansion and in their differentiated progenies. Here, we employed homologous recombination in hESCs to introduce heterospecific loxP sites into the AAVS1 locus, a site with an open chromatin structure that allows averting transgene silencing phenomena. We then performed Cre recombinase mediated cassette exchange using baculoviral vectors to insert a transgene into the modified AAVS1 locus. Targeting efficiency in the master hESC line with the loxP-docking sites was up to 100%. Expression of the inserted transgene lasted for at least 20 passages during hESC expansion and was retained in differentiated cells derived from the genetically modified hESCs. Thus, this study demonstrates the feasibility of genetic manipulation at the AAVS1 locus with homologous recombination and using viral transduction in hESCs to facilitate recombinase-mediated cassette exchange. The method developed will be useful for repeated gene targeting at a defined locus of the hESC genome. PMID- 21685449 TI - Identification of a signature motif for the eIF4a3-SECIS interaction. AB - eIF4a3, a DEAD-box protein family member, is a component of the exon junction complex which assembles on spliced mRNAs. The protein also acts as a transcript selective translational repressor of selenoprotein synthesis during selenium deficiency. Selenocysteine (Sec) incorporation into selenoproteins requires a Sec Insertion Sequence (SECIS) element in the 3' untranslated region. During selenium deficiency, eIF4a3 binds SECIS elements from non-essential selenoproteins, preventing Sec insertion. We identified a molecular signature for the eIF4a3 SECIS interaction using RNA gel shifts, surface plasmon resonance and enzymatic foot printing. Our results support a two-site interaction model, where eIF4a3 binds the internal and apical loops of the SECIS. Additionally, the stability of the complex requires uridine in the SECIS core. In terms of protein requirements, the two globular domains of eIF4a3, which are connected by a linker, are both critical for SECIS binding. Compared to full-length eIF4a3, the two domains in trans bind with a lower association rate but notably, the uridine is no longer important for complex stability. These results provide insight into how eIF4a3 discriminates among SECIS elements and represses translation. PMID- 21685450 TI - Determinants of redox sensitivity in RsrA, a zinc-containing anti-sigma factor for regulating thiol oxidative stress response. AB - Various environmental oxidative stresses are sensed by redox-sensitive regulators through cysteine thiol oxidation or modification. A few zinc-containing anti sigma (ZAS) factors in actinomycetes have been reported to respond sensitively to thiol oxidation, among which RsrA from Streptomyces coelicolor is best characterized. It forms disulfide bonds upon oxidation and releases bound SigR to activate thiol oxidative stress response genes. Even though numerous ZAS proteins exist in bacteria, features that confer redox sensitivity to a subset of these have been uncharacterized. In this study, we identified seven additional redox sensitive ZAS factors from actinomycetes. Comparison with redox-insensitive ZAS revealed characteristic sequence patterns. Domain swapping demonstrated the significance of the region K(33)FEHH(37)FEEC(41)SPC(44)LEK(47) that encompass the conserved HX(3)CX(2)C (HCC) motif. Mutational effect of each residue on diamide responsive induction of SigR target genes in vivo demonstrated that several residues, especially those that flank two cysteines (E39, E40, L45, E46), contribute to redox sensitivity. These residues are well conserved among redox sensitive ZAS factors, and hence are proposed as redox-determinants in sensitive ZAS. H37A, C41A, C44A and F38A mutations, in contrast, compromised SigR-binding activity significantly, apparently affecting structural integrity of RsrA. The residue pattern around HCC motif could therefore serve as an indicator to predict redox-sensitive ZAS factors from sequence information. PMID- 21685451 TI - S1 ribosomal protein and the interplay between translation and mRNA decay. AB - S1 is an 'atypical' ribosomal protein weakly associated with the 30S subunit that has been implicated in translation, transcription and control of RNA stability. S1 is thought to participate in translation initiation complex formation by assisting 30S positioning in the translation initiation region, but little is known about its role in other RNA transactions. In this work, we have analysed in vivo the effects of different intracellular S1 concentrations, from depletion to overexpression, on translation, decay and intracellular distribution of leadered and leaderless messenger RNAs (mRNAs). We show that the cspE mRNA, like the rpsO transcript, may be cleaved by RNase E at multiple sites, whereas the leaderless cspE transcript may also be degraded via an alternative pathway by an unknown endonuclease. Upon S1 overexpression, RNase E-dependent decay of both cspE and rpsO mRNAs is suppressed and these transcripts are stabilized, whereas cleavage of leaderless cspE mRNA by the unidentified endonuclease is not affected. Overall, our data suggest that ribosome-unbound S1 may inhibit translation and that part of the Escherichia coli ribosomes may actually lack S1. PMID- 21685452 TI - A novel screening system improves genetic correction by internal exon replacement. AB - Trans-splicing is a powerful approach to reprogram the genome. It can be used to replace 5', 3' or internal exons. The latter approach has been characterized by low efficiency, as the requirements to promote internal trans-splicing are largely uncharacterized. The trans-splicing process is induced by engineered 'RNA trans-splicing molecules' (RTMs), which target a selected pre-mRNA to be reprogrammed via two complementary binding domains. To facilitate the development of more efficient RTMs for therapeutic applications we constructed a novel fluorescence based screening system. We incorporated exon 52 of the COL17A1 gene into a GFP-based cassette system as the target exon. This exon is mutated in many patients with the devastating skin blistering disease epidermolysis bullosa. In a double transfection assay we were able to rapidly identify optimal binding domains targeted to sequences in the surrounding introns 51 and 52. The ability to replace exon 52 was then evaluated in a more endogenous context using a target containing COL17A1 exon 51-intron 51-exon 52-intron 52-exon 53. Two selected RTMs produced significantly higher levels of GFP expression in up to 61% assayed cells. This novel approach allows for rapid identification of efficient RTMs for internal exon replacement. PMID- 21685453 TI - Molecular insights into miRNA processing by Arabidopsis thaliana SERRATE. AB - In plant, primary transcripts (pri-miRNAs) transcribed from miRNA genes by RNA polymerase II are first processed into stem-loop pre-miRNAs and further chopped into ~21 nt long miRNAs by RNase III-like enzyme DCL1. SERRATE (SE) protein is an essential component for miRNA processing by assisting DCL1 for accurate cleavage. Here we report the crystal structure of Arabidopsis SE core (residues 194-543) at 2.7 A. SE core adopts the 'walking man-like' topology with N-terminal alpha helices, C-terminal non-canonical zinc-finger domain and novel Middle domain resembling the leading leg, the lagging leg and the body, respectively. Pull-down assay shows that SE core provides the platform for HYL1 and DCL1 binding, whereas in vitro RNA binding and in vivo mutant rescue experiments suggest that the non canonical zinc-finger domain coupled with C-terminal tail binds miRNA precursors. SE presumably works as a scaffold-like protein capable of binding both protein and RNA to guide the positioning of miRNA precursor toward DCL1 catalytic site within miRNA processing machinery in plant. PMID- 21685454 TI - Enhancers in embryonic stem cells are enriched for transposable elements and genetic variations associated with cancers. AB - Using an enhancer-associated epigenetic signature, we made genome-wide predictions of transcriptional enhancers in human B and T lymphocytes and embryonic stem cells (ES cells). We validated and characterized the predicted enhancers using four types of information, including overlap with other genomic marks for enhancers; association with cell-type-specific genes; enrichment of cell-type-specific transcription factor binding sites; and genetic polymorphisms in predicted enhancers. We find that enhancers from ES cells, but not B or T cells, are significantly enriched for DNA sequences derived from transposable elements. This may be due to the generally relaxed repressive epigenetic state and increased activity of transposable elements in ES cells. We demonstrate that the wealth of new enhancer sequences discerned here provides an invaluable resource for the functional annotation of gene-distal single nucleotide polymorphisms identified through expression quantitative trait loci and genome wide association studies analyses. Notably, we find GWAS SNPs associated with various cancers are enriched in ES cell enhancers. In comparison, GWAS SNPs associated with diseases due to immune dysregulation are enriched in B and T cell enhancers. PMID- 21685455 TI - An investigation of the structural requirements for ATP hydrolysis and DNA cleavage by the EcoKI Type I DNA restriction and modification enzyme. AB - Type I DNA restriction/modification systems are oligomeric enzymes capable of switching between a methyltransferase function on hemimethylated host DNA and an endonuclease function on unmethylated foreign DNA. They have long been believed to not turnover as endonucleases with the enzyme becoming inactive after cleavage. Cleavage is preceded and followed by extensive ATP hydrolysis and DNA translocation. A role for dissociation of subunits to allow their reuse has been proposed for the EcoR124I enzyme. The EcoKI enzyme is a stable assembly in the absence of DNA, so recycling was thought impossible. Here, we demonstrate that EcoKI becomes unstable on long unmethylated DNA; reuse of the methyltransferase subunits is possible so that restriction proceeds until the restriction subunits have been depleted. We observed that RecBCD exonuclease halts restriction and does not assist recycling. We examined the DNA structure required to initiate ATP hydrolysis by EcoKI and find that a 21-bp duplex with single-stranded extensions of 12 bases on either side of the target sequence is sufficient to support hydrolysis. Lastly, we discuss whether turnover is an evolutionary requirement for restriction, show that the ATP hydrolysis is not deleterious to the host cell and discuss how foreign DNA occasionally becomes fully methylated by these systems. PMID- 21685456 TI - Genome-wide analysis of the relationships between DNaseI HS, histone modifications and gene expression reveals distinct modes of chromatin domains. AB - To understand the molecular mechanisms that underlie global transcriptional regulation, it is essential to first identify all the transcriptional regulatory elements in the human genome. The advent of next-generation sequencing has provided a powerful platform for genome-wide analysis of different species and specific cell types; when combined with traditional techniques to identify regions of open chromatin [DNaseI hypersensitivity (DHS)] or specific binding locations of transcription factors [chromatin immunoprecipitation (ChIP)], and expression data from microarrays, we become uniquely poised to uncover the mysteries of the genome and its regulation. To this end, we have performed global meta-analysis of the relationship among data from DNaseI-seq, ChIP-seq and expression arrays, and found that specific correlations exist among regulatory elements and gene expression across different cell types. These correlations revealed four distinct modes of chromatin domain structure reflecting different functions: repressive, active, primed and bivalent. Furthermore, CCCTC-binding factor (CTCF) binding sites were identified based on these integrative data. Our findings uncovered a complex regulatory process involving by DNaseI HS sites and histone modifications, and suggest that these dynamic elements may be responsible for maintaining chromatin structure and integrity of the human genome. Our integrative approach provides an example by which data from diverse technology platforms may be integrated to provide more meaningful insights into global transcriptional regulation. PMID- 21685457 TI - Cerebral microbleeds in familial Alzheimer's disease. PMID- 21685458 TI - The function of the left anterior temporal pole: evidence from acute stroke and infarct volume. AB - The role of the anterior temporal lobes in cognition and language has been much debated in the literature over the last few years. Most prevailing theories argue for an important role of the anterior temporal lobe as a semantic hub or a place for the representation of unique entities such as proper names of peoples and places. Lately, a few studies have investigated the role of the most anterior part of the left anterior temporal lobe, the left temporal pole in particular, and argued that the left anterior temporal pole is the area responsible for mapping meaning on to sound through evidence from tasks such as object naming. However, another recent study indicates that bilateral anterior temporal damage is required to cause a clinically significant semantic impairment. In the present study, we tested these hypotheses by evaluating patients with acute stroke before reorganization of structure-function relationships. We compared a group of 20 patients with acute stroke with anterior temporal pole damage to a group of 28 without anterior temporal pole damage matched for infarct volume. We calculated the average percent error in auditory comprehension and naming tasks as a function of infarct volume using a non-parametric regression method. We found that infarct volume was the only predictive variable in the production of semantic errors in both auditory comprehension and object naming tasks. This finding favours the hypothesis that left unilateral anterior temporal pole lesions, even acutely, are unlikely to cause significant deficits in mapping meaning to sound by themselves, although they contribute to networks underlying both naming and comprehension of objects. Therefore, the anterior temporal lobe may be a semantic hub for object meaning, but its role must be represented bilaterally and perhaps redundantly. PMID- 21685459 TI - Recruiting Latino and non-Latino families in pediatric research: considerations from a study on childhood disability. AB - OBJECTIVE: To improve representation of minorities in research, we examined recruitment methods from our study of Latino and non-Latino families of children with Intellectual Disability (ID). METHOD: We compared recruitment strategies that yielded the enrollment target of 200 matched Latino and nonLatino families of children with ID and controls. Active recruitment strategies involved direct contact with potential participants; passive strategies included disseminating study information. RESULTS: Effective outreach focused on community agencies where children had ongoing involvement and utilizing bilingual/bicultural staff. Latino families were significantly more likely to be recruited by an active strategy than non-Latino families. Active and passive strategies were both effective with non-Latino ID families. Asking research participants to inform other families about the study and sharing consent to contact lists with other investigators was productive with control families. CONCLUSIONS: Bilingual staff and active recruitment through familiar community services were successful in recruiting Latino families for research. PMID- 21685460 TI - Longitudinal associations among peer victimization and physical and mental health problems. AB - OBJECTIVE: This study examined how chronic experiences of peer victimization throughout childhood relate to mental and physical health outcomes in adolescence. METHODS: Children were tested in a laboratory playroom at the age of 5 years. They completed questionnaires at time 2, between the ages of 10 and 18 years, and a telephone interview at time 3, between the ages of 12 and 20 years. A total of 70 youth participated at all three time periods. Chronic victims were defined as having high levels of peer victimization at all three time points. RESULTS: Youth who were chronically victimized reported experiencing significantly more mental and physical health problems than youth categorized as desisters or nonvictims. Also, for girls only, chronic victims reported more specific health problems (headaches, sleep problems) than did nonchronic victims. CONCLUSIONS: The present findings may assist health professionals in assessing and treating physical and mental health problems that appear to be related to peer victimization. PMID- 21685461 TI - Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. AB - Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. A total of 1,596,670 new cancer cases and 571,950 deaths from cancer are projected to occur in the United States in 2011. Overall cancer incidence rates were stable in men in the most recent time period after decreasing by 1.9% per year from 2001 to 2005; in women, incidence rates have been declining by 0.6% annually since 1998. Overall cancer death rates decreased in all racial/ethnic groups in both men and women from 1998 through 2007, with the exception of American Indian/Alaska Native women, in whom rates were stable. African American and Hispanic men showed the largest annual decreases in cancer death rates during this time period (2.6% and 2.5%, respectively). Lung cancer death rates showed a significant decline in women after continuously increasing since the 1930s. The reduction in the overall cancer death rates since 1990 in men and 1991 in women translates to the avoidance of about 898,000 deaths from cancer. However, this progress has not benefitted all segments of the population equally; cancer death rates for individuals with the least education are more than twice those of the most educated. The elimination of educational and racial disparities could potentially have avoided about 37% (60,370) of the premature cancer deaths among individuals aged 25 to 64 years in 2007 alone. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population with an emphasis on those groups in the lowest socioeconomic bracket. CA Cancer J Clin 2011. (c) 2011 American Cancer Society. PMID- 21685462 TI - Physician characteristics associated with clinical trial enrollment. PMID- 21685463 TI - Dramatic increase in the use of implantable accelerated partial breast irradiation after breast-conserving surgery. PMID- 21685464 TI - Comment 2 on: Homeopathy has clinical benefits in rheumatoid arthritis patients that are attributable to the consultation process but not the homeopathic remedy: a randomized controlled clinical trial. PMID- 21685465 TI - Comment 1 on: Homeopathy has clinical benefits in rheumatoid arthritis patients that are attributable to the consultation process but not the homeopathic remedy: a randomized controlled trial. PMID- 21685466 TI - DNMT3A mutations are rare in childhood acute myeloid leukemia. PMID- 21685467 TI - Allogeneic hematopoietic stem cell transplantation for isolated and leukemic myeloid sarcoma in adults: a report from the Acute Leukemia Working Party of the European group for Blood and Marrow Transplantation. PMID- 21685468 TI - 18F-FDG-PET/CT for detection of extramedullary acute myeloid leukemia. AB - Myeloid sarcoma in acute myeloid leukemia has been clearly defined by the World Health Organization but studies regarding the prevalence and the prognostic impact of extramedullary acute myeloid leukemia have not been conducted. We performed (18)Fluoro-deoxy-Glucose Positron Emission Tomography/Computed Tomography scans in 10 patients with de novo and relapsed acute myeloid leukemia and histologically proven extramedullary disease. The scans were able to detect the known extramedullary lesions in 9 out of 10 patients (90%). Furthermore, additional extramedullary sites were detected in 6 patients (60%). Thus, it is possible to identify known and clinically undetectable extramedullary manifestations of acute myeloid leukemia. Since most of these patients relapsed within a short period of time after initiation of therapy or had refractory disease, the detection of extramedullary disease with (18)Fluoro-deoxy-Glucose Positron Emission Tomography/Computed Tomography might be helpful in the development of individual treatment algorithms for these high-risk patients. PMID- 21685469 TI - Multiple oligomerization domains of KANK1-PDGFRbeta are required for JAK2 independent hematopoietic cell proliferation and signaling via STAT5 and ERK. AB - BACKGROUND: KANK1-PDGFRB is a fusion gene generated by the t(5;9) translocation between KANK1 and the platelet-derived growth factor receptor beta gene PDGFRB. This hybrid was identified in a myeloproliferative neoplasm featuring severe thrombocythemia, in the absence of the JAK2 V617F mutation. DESIGN AND METHODS: KANK1-PDGFRB was transduced into Ba/F3 cells and CD34(+) human progenitor cells to gain insights into the mechanisms whereby this fusion gene transforms cells. RESULTS: Although platelet-derived growth factor receptors are capable of activating JAK2, KANK1-PDGFRbeta did not induce JAK2 phosphorylation in hematopoietic cells and a JAK inhibitor did not affect KANK1-PDGFRbeta-induced cell growth. Like JAK2 V617F, KANK1-PDGFRbeta constitutively activated STAT5 transcription factors, but this did not require JAK kinases. In addition KANK1 PDGFRbeta induced the phosphorylation of phospholipase C-gamma, ERK1 and ERK2, like wild-type PDGFRbeta and TEL-PDGFRbeta, another hybrid protein found in myeloid malignancies. We next tested various mutant forms of KANK1-PDGFRbeta in Ba/F3 cells and human CD34(+) hematopoietic progenitors. The three coiled-coil domains located in the N-terminus of KANK1 were required for KANK1-PDGFRbeta induced cell growth and signaling via STAT5 and ERK. However, the coiled-coils were not essential for KANK1-PDGFRbeta oligomerization, which could be mediated by another new oligomerization domain. KANK1-PDGFRbeta formed homotrimeric complexes and heavier oligomers. CONCLUSIONS: KANK1-PDGFRB is a unique example of a thrombocythemia-associated oncogene that does not signal via JAK2. The fusion protein is activated by multiple oligomerization domains, which are required for signaling and cell growth stimulation. PMID- 21685471 TI - Charlson comorbidity index and adult comorbidity evaluation-27 scores might predict treatment compliance and development of pleural effusions in elderly patients with chronic myeloid leukemia treated with second-line dasatinib. AB - BACKGROUND: Comorbidities may affect survival and choice of treatment among cancer patients. In fact, comorbidities have been identified as significant determinants of response to therapy in older patients with acute myeloid leukemia, breast cancer, head and neck cancer, and lung cancer. The Charlson comorbidity index and adult comorbidity evaluation-27 are lists of comorbidities with a weight assigned from 1 to 6 for the former and from 0 to 3 for the latter score, derived from relative risk estimates of a proportional hazard regression model using clinical data. DESIGN AND METHODS: We retrospectively evaluated the Charlson index and adult comorbidity evaluation-27 score in a cohort of 125 elderly (> 60 years) patients with chronic phase chronic myeloid leukemia who received dasatinib after showing resistance or intolerance to imatinib with the aim of establishing associations between comorbidities and the development of pleural effusions or compliance with the drug treatment. RESULTS: We found a significant association between the Charlson index as well as the adult comorbidity evaluation-27 score and the rate of drug reduction or suspension: with regards to the Charlson index, 49% of score 0 patients had a dose reduction compared to 63% of patients with score 1, 74% of those with score 2 and 100% of patients with score 3-5 (P=0.03); with regards to the adult comorbidity evaluation-27 score, 45% of patients had score 0-1 and 69% of patients with score 2-3 had a dose reduction. Of the 65 patients with Charlson score 0, 29% had at least one suspension of treatment (79% for hematologic and 21% for non hematologic toxicity), compared to 46% of patients with score 1 (37% for hematologic and 69% for non-hematologic toxicity), 58% of patients with score 2 (36% for hematologic and 64% for non-hematologic toxicity) and 100% of patients with score 3 or 4 (all patients for both types of toxicity). High adult comorbidity index-27 scores identified patients at high risk of grade 3/4 hematologic toxicity. Forty-one patients (32.8%) experienced pleural effusion during treatment: the highest scores for both indices were associated with an increased risk of pleural effusions. CONCLUSIONS: In elderly patients with chronic myeloid leukemia treated with dasatinib, the rate of drug reduction or suspension and the incidence of pleural effusions seem to be associated with the presence of comorbidities: stratification according to the Charlson index and adult comorbidity evaluation-27 score before dasatinib therapy may enable the identification of patients at risk of major toxicities. PMID- 21685470 TI - Prognostic value of FLT3 mutations in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy. AB - BACKGROUND: Fms-like tyrosine kinase-3 (FLT3) gene mutations are frequent in acute promyelocytic leukemia but their prognostic value is not well established. DESIGN AND METHODS: We evaluated FLT3-internal tandem duplication and FLT3-D835 mutations in patients treated with all-trans retinoic acid and anthracycline based chemotherapy enrolled in two subsequent trials of the Programa de Estudio y Tratamiento de las Hemopatias Malignas (PETHEMA) and Hemato-Oncologie voor Volwassenen Nederland (HOVON) groups between 1996 and 2005. RESULTS: FLT3 internal tandem duplication and FLT3-D835 mutation status was available for 306 (41%) and 213 (29%) patients, respectively. Sixty-eight (22%) and 20 (9%) patients had internal tandem duplication and D835 mutations, respectively. Internal tandem duplication was correlated with higher white blood cell and blast counts, lactate dehydrogenase, relapse-risk score, fever, hemorrhage, coagulopathy, BCR3 isoform, M3 variant subtype, and expression of CD2, CD34, human leukocyte antigen-DR, and CD11b surface antigens. The FLT3-D835 mutation was not significantly associated with any clinical or biological characteristic. Univariate analysis showed higher relapse and lower survival rates in patients with a FLT3-internal tandem duplication, while no impact was observed in relation to FLT3-D835. The prognostic value of the FLT3-internal tandem duplication was not retained in the multivariate analysis. CONCLUSIONS: FLT3-internal tandem duplication mutations are associated with several hematologic features in acute promyelocytic leukemia, in particular with high white blood cell counts, but we were unable to demonstrate an independent prognostic value in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline based regimens. PMID- 21685473 TI - Sensitivity of changes in chronic graft-versus-host disease activity to changes in patient-reported quality of life: results from the Chronic Graft-versus-Host Disease Consortium. AB - BACKGROUND: The 2005 National Institute of Health Chronic Graft-versus-Host Disease Consensus Conference recommended collection of patient-reported outcomes in clinical trials on chronic graft-versus-host disease. We assessed whether changes in chronic graft-versus-host disease severity, determined using National Institute of Health criteria, clinicians' assessment or patients' self evaluation, correlated with patient-reported quality of life as measured by the Short Form-36 and Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) instruments. DESIGN AND METHODS: Three-hundred and thirty-six adult patients (median age 52 years; range, 19-79) with chronic graft-versus-host disease from six transplant centers contributed baseline and follow-up data (from 936 visits overall). RESULTS: While the majority of the patients had stable chronic graft-versus-host disease, improvement or worsening was noted in approximately 40% of follow-up visits. Multivariable analysis demonstrated no association between change in chronic graft-versus-host disease severity evaluated by National Institute of Health criteria and change in quality of life, while clinician-reported changes in severity were associated with changes in some quality of life measures. Patient-reported changes in the severity of chronic graft-versus-host disease were associated with changes in all quality of life measures. Comparison of the Short Form-36 and the FACT-BMT suggested that the data collected in the Functional Assessment of Cancer Therapy-General (FACT-G) core survey are sufficient without the need for the Short Form-36 or the FACT-BMT subscale. CONCLUSIONS: We conclude that serial National Institute of Health and clinician-reported chronic graft-versus-host disease severity assessments cannot substitute for patient-reported outcomes in clinical trials. Collection of just the FACT-G instead of the Short Form-36 and the full FACT-BMT will decrease respondent burden without compromising quality of life assessment. PMID- 21685472 TI - Impact of genetic abnormalities after allogeneic stem cell transplantation in multiple myeloma: a report of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. AB - BACKGROUND: The impact of cytogenetic abnormalities in multiple myeloma after allogeneic stem cell transplantation has not been clearly defined. This study examines whether allogeneic stem cell transplantation could be of benefit for myeloma patients with high-risk cytogenetic abnormalities. DESIGN AND METHODS: This is a retrospective multicenter analysis of the registry of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire, including 143 myeloma patients transplanted between 1999 and 2008. RESULTS: The incidences of cytogenetic abnormalities were 59% for del(13q), 25% for t(4;14), 25% for del(17p) and 4% for t(14;16). When comparing the population carrying an abnormality to that without the same abnormality, no significant difference was found in progression-free survival, overall survival or progression rate. Patients were grouped according to the presence of any of the poor prognosis cytogenetic abnormalities t(4;14), del(17p) or t(14;16) (n=53) or their absence (n=32). No difference in outcomes was observed between these two groups: the 3 year progression-free survival, overall survival and progression rates were 30% versus 17% (P=0.9), 45% versus 39% (P=0.8) and 53% versus 75% (P=0.9), respectively. CONCLUSIONS: These data indicate that allogeneic stem cell transplantation could potentially be of benefit to high-risk myeloma patients. PMID- 21685474 TI - CYP2C8 gene polymorphism and bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma. AB - Osteonecrosis of the jaw is an uncommon but potentially serious complication of bisphosphonate therapy in multiple myeloma. Previous studies showed that the presence of one or two minor alleles of the cytochrome P450, subfamily 2C polypeptide 8 gene (CYP2C8) polymorphism rs1934951 was an independent prognostic marker associated with development of osteonecrosis of the jaw in multiple myeloma patients treated with bisphosphonates. The aim of this study was to validate the frequency of SNP rs193451 in 79 patients with multiple myeloma. In 9 (22%) patients developing osteonecrosis of the jaw, a heterozygous genotype was found, in contrast with those who did not develop osteonecrosis of the jaw (n=4, 11%) or healthy individuals (n=6, 13%). We found no differences in the cumulative risk of developing osteonecrosis of the jaw between patients homozygous and heterozygous for the major allele. We were unable to confirm a significant association between this polymorphism and the risk of developing osteonecrosis of the jaw. PMID- 21685475 TI - Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. AB - Epithelial-to-mesenchymal transition (EMT) is an important driver of tumor invasion and metastasis, which causes many cancer deaths. Cancer stem cells (CSC) that maintain and initiate tumors have also been implicated in invasion and metastasis, but whether EMT is an important contributor to CSC function is unclear. In this study, we investigated whether a population of CSCs that have undergone EMT (EMT CSCs) exists in squamous cell carcinoma (SCC). We also determined whether a separate population of CSCs that retain epithelial characteristics (non-EMT CSCs) is also present. Our studies revealed that self renewing CSCs in SCC include two biologically-distinct phenotypes. One phenotype, termed CD44(high)ESA(high), was proliferative and retained epithelial characteristics (non-EMT CSCs), whereas the other phenotype, termed CD44(high)ESA(low), was migratory and had mesenchymal traits characteristic of EMT CSCs. We found that non-EMT and EMT CSCs could switch their epithelial or mesenchymal traits to reconstitute the cellular heterogeneity which was characteristic of CSCs. However, the ability of EMT CSCs to switch to non-EMT character was restricted to cells that were also ALDH1(+), implying that only ALDH1(+) EMT cells had the ability to seed a new epithelial tumor. Taken together, our findings highlight the identification of two distinct CSC phenotypes and suggest a need to define therapeutic targets that can eradicate both of these variants to achieve effective SCC treatment. PMID- 21685476 TI - Retinoic acid enhances TRAIL-induced apoptosis in cancer cells by upregulating TRAIL receptor 1 expression. AB - Many human cancer cells are sensitive to killing by the proapoptotic ligand TNF related apoptosis-inducing ligand (TRAIL), which is under study for cancer treatment in clinical trials. The TRAIL receptor (TRAIL-R1; also known as death receptor 4) is a transmembrane receptor that mediates TRAIL-induced apoptosis in cancer cells. In this study, we show that retinoids sensitize cancer cells to TRAIL-induced apoptosis by upregulating expression of TRAIL-R1. All-trans retinoic acid (ATRA) upregulated TRAIL-R1 expression in human cancer cells at the transcriptional level. The ability of ATRA to activate TRAIL-R1 expression was inhibited by retinoic acid receptor (RAR) antagonists or siRNAs, but augmented by several RAR agonists. In analyzing how ATRA induces RAR-dependent transcriptional upregulation of TRAIL-R1, we identified 2 putative retinoic acid response elements termed Pal-17 (a palindrome separated by 17 bases) and DR-11 (a direct repeat separated by 11 bases) in the 5'-flanking region of TRAIL-R1 gene. Deletion of DR-11, but not Pal-17, abrogated the ability of ATRA to stimulate TRAIL-R1 promoter activity. Consistent with this observation, RAR binding to DR 11, but not to Pal-17, was detected by chromatin immunoprecipitation assay in ATRA-treated cells, arguing that DR-11 was responsible for ATRA-mediated activation of the TRAIL-R1 gene. ATRA augmented TRAIL-induced apoptosis of cancer cells, and this activity was attenuated by a blockade to upregulation of TRAIL-R1 expression. Taken together, our findings establish that ATRA accentuates TRAIL induced apoptosis, reveal a novel mechanism by which retinoids modulate apoptosis, and suggest a novel strategy to augment the anti-cancer activity of TRAIL. PMID- 21685477 TI - Prostate cancer diagnosis in a resource-poor setting: the changing role of digital rectal examination. AB - We undertook this study in order to determine the current role of digital rectal examination (DRE) in the diagnosis of prostate cancer in a resource-poor setting. The diagnosis of prostate cancer has been revolutionized by the introduction of prostate-specific antigen (PSA), transrectal ultrasound (TRUS) for biopsy guidance and more efficient biopsy equipment, but they are not readily available in most developing countries. This is a prospective study of 131 patients with suspected prostate cancer based on clinical presentation, DRE and elevated PSA. The presence or absence of cancer was confirmed by biopsy and histologic examination. Patients with screen- or incidentally-detected prostate cancer were excluded. The most common symptom was the development of lower urinary tract symptoms (LUTS). All patients had abnormal DRE and indurated prostate was the most frequent finding (50%). The mean PSA was 33.9 ng/mL: of the 131 patients, 80 (61.1%) had a malignant histology following biopsy, 47 (35.9%) were benign and four (3.0%) were prostate intraepithelial neoplasia (PIN). The low specificity of DRE in the diagnosis of prostate cancer requires that it should be combined with other diagnostic modalities such as PSA and TRUS-guided prostate biopsy. Thus government and health-care providers in resource-poor countries must strive to make these facilities available in order to improve prostate cancer diagnosis. PMID- 21685478 TI - Divergent RNA binding specificity of yeast Puf2p. AB - PUF proteins bind mRNAs and regulate their translation, stability, and localization. Each PUF protein binds a selective group of mRNAs, enabling their coordinate control. We focus here on the specificity of Puf2p and Puf1p of Saccharomyces cerevisiae, which copurify with overlapping groups of mRNAs. We applied an RNA-adapted version of the DRIM algorithm to identify putative binding sequences for both proteins. We first identified a novel motif in the 3' UTRs of mRNAs previously shown to associate with Puf2p. This motif consisted of two UAAU tetranucleotides separated by a 3-nt linker sequence, which we refer to as the dual UAAU motif. The dual UAAU motif was necessary for binding to Puf2p, as judged by gel shift, yeast three-hybrid, and coimmunoprecipitation from yeast lysates. The UAAU tetranucleotides are required for optimal binding, while the identity and length of the linker sequences are less critical. Puf1p also binds the dual UAAU sequence, consistent with the prior observation that it associates with similar populations of mRNAs. In contrast, three other canonical yeast PUF proteins fail to bind the Puf2p recognition site. The dual UAAU motif is distinct from previously known PUF protein binding sites, which invariably possess a UGU trinucleotide. This study expands the repertoire of cis elements bound by PUF proteins and suggests new modes by which PUF proteins recognize their mRNA targets. PMID- 21685479 TI - Regulation of cancer stem cells by cytokine networks: attacking cancer's inflammatory roots. AB - There is substantial evidence that many human cancers are driven by a subpopulation of cells that display stem cell properties. These cancer stem cells (CSC) may also contribute to metastasis and treatment resistance. Furthermore, just as normal stem cells are regulated by their microenvironment, or niche, CSCs interact with and in turn are regulated by cells in the tumor microenvironment. These interactions involve inflammatory cytokines, such as interleukin (IL)-1, IL 6, and IL-8, which in turn activate Stat3/NF-kappaB pathways in both tumor and stromal cells. Activation of these pathways stimulates further cytokine production, generating positive feedback loops that in turn drive CSC self renewal. These cytokine loops and the pathways they regulate resemble those activated during chronic inflammation and wound healing, and may contribute to the known link between inflammation and cancer. Inhibitors of these cytokines and their receptors have been developed as anti-inflammatory agents. By blocking signals from the tumor microenvironment, these agents have the potential to target CSCs. Future clinical trials using these compounds will be needed to determine whether targeting the CSC population has clinical benefit. PMID- 21685480 TI - Combined pre- and postnatal ethanol exposure in rats disturbs the myelination of optic axons. AB - AIMS: To analyse myelination and outgrowth of the optic axons in relation to the neuro-ophthalmological manifestations of ethanol (EtOH) abuse during pregnancy. METHODS: An experimental model of chronic EtOH exposure was developed in rats and their offspring by subjecting the dams to a liquid diet (35% of the daily total calories as either EtOH or maltose-dextrose nutritional controls (Con). Eyeballs and optic nerves were obtained at key developmental stages and processed for morphologic, immunocytochemical and immunoblotting procedures, using alternatively antibodies against myelin basic protein (MBP) or neurofilament (NF) protein, and image analysing. RESULTS: A significant delay in onset of optic axons myelination, as well as a significant reduction in optic nerve size (P < 0.001), optic axons number (P < 0.001), myelinated axons density (P < 0.001), number of myelin lamellae linked to axon diameter (P < 0.001) and optic axon cross-sectional area (P < 0.001) were detected in the global morphometric assessment of the EtOH nerves with respect to the Con. Expression of MBP and NF was noticeably reduced in the EtOH optic nerves when compared with the Con. CONCLUSION: Disturbed myelination of optic axons, caused by EtOH abuse, strongly disrupts the optic nerve development and the establishment of definitive retinal and optic nerve targets, and subsequently the visual patterns. PMID- 21685481 TI - Environmental impact of cardiac imaging tests for the diagnosis of coronary artery disease. AB - The use of cardiovascular imaging is growing inexorably and concerns have been expressed about its cost and radiation safety. In this study, the relative environmental impact of MRI, single photon emission tomography and cardiac ultrasound (echo) for the diagnosis of coronary artery disease were examined. The results emphasise that echo causes the least environmental impact at each stage of its life cycle. The effect of one echo on human health, ecosystem effects and resource use was of the order of 1-20% of those of the alternative methods. Although there are circumstances in which one imaging modality is preferred on clinical grounds, when everything else is equal, these results support the selection of echocardiography as the preferred test on environmental grounds. PMID- 21685482 TI - Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies. AB - OBJECTIVE: To estimate the probabilistic cost-effectiveness of cascade screening methods in familial hypercholesterolaemia (FH) from the UK NHS perspective. DESIGN: Economic evaluation (cost utility analysis) comparing four cascade screening strategies for FH: Using low-density lipoprotein (LDL) cholesterol measurements to diagnose affected relatives (cholesterol method); cascading only in patients with a causative mutation identified and using DNA tests to diagnose relatives (DNA method); DNA testing combined with LDL-cholesterol testing in families with no mutation identified, only in patients with clinically defined 'definite' FH (DNA+DFH method); DNA testing combined with LDL-cholesterol testing in no-mutation families of both 'definite' and 'probable' FH patients (DNA+DFH+PFH). A probabilistic model was constructed to estimate the treatment benefit from statins, with all diagnosed individuals receiving high-intensity statin treatment. POPULATION: A cohort of 1000 people suspected of having FH aged 50 years for index cases and 30 years for relatives, followed for a lifetime. MAIN OUTCOMES: Costs, quality-adjusted life-years (QALY) and incremental cost effectiveness ratios (ICER). RESULTS: The DNA+DFH+PFH method was the most cost effective cascade screening strategy. The ICER was estimated at L3666/QALY. Using this strategy, of the tested relatives 30.6% will be true positives, 6.3% false positives, 61.9% true negatives and 1.1% false negatives. Probabilistic sensitivity analysis showed that this approach is 100% cost-effective using the conventional benchmark for cost-effective treatments in the NHS of between L20,000 and L30,000 per QALY gained. CONCLUSION: Cascade testing of relatives of patients with DFH and PFH is cost-effective when using a combination of DNA testing for known family mutations and LDL-cholesterol levels in the remaining families. The approach is more cost-effective than current primary prevention screening strategies. PMID- 21685483 TI - Aortic valve surgery in children. PMID- 21685484 TI - Involving primary care and cardiac rehabilitation in a reorganised service could improve outcomes. PMID- 21685485 TI - Seven glorious years. PMID- 21685486 TI - Multislice computed tomography demonstrating anomalous left coronary artery from the pulmonary artery. PMID- 21685487 TI - Haemodynamic consequences of etomidate administration in elective cardiac surgery: a randomized double-blinded study. AB - BACKGROUND: The consequences of inhibition of cortisol synthesis by a single dose of etomidate on subsequent vasopressor drug usage and the duration of relative adrenal insufficiency (RAI) after cardiac surgery are not known. METHODS: This was a prospective, randomized, double-blinded controlled trial of 100 patients undergoing elective cardiac surgery and receiving either etomidate or propofol at induction of anaesthesia. A short corticotropin test was performed 12, 24, and 48 h after anaesthesia induction. RAI was defined as a response <250 nmol litre(-1). RESULTS: The mean (sd) norepinephrine infusion rate during the first 48 postoperative hours was 0.11 (0.01) and 0.11 (0.01) ug kg(-1) min(-1) in the etomidate and propofol groups, respectively (P=0.89). Time to norepinephrine withdrawal was similar between the groups. The incidence of RAI was higher in the etomidate group at 12 h (100% vs 41%, P<0.001) and 24 h (85% vs 25%, P<0.001). CONCLUSIONS: A single bolus of etomidate blunts the hypothalamic-pituitary adrenal axis response for more than 24 h in patients undergoing elective cardiac surgery, but this was not associated with an increase in vasopressor requirements. PMID- 21685488 TI - Efficacy and safety of tigecycline: a systematic review and meta-analysis. AB - BACKGROUND: Tigecycline is a novel glycylcycline that exhibits broad-spectrum antibacterial activity. Recently, the US FDA issued a warning concerning increased mortality with tigecycline in randomized controlled trials (RCTs). METHODS: We conducted a systematic review and meta-analysis of RCTs that compared tigecycline with any other antibiotic regimen for the treatment of any infection. A comprehensive search, without publication status or other restrictions, was conducted. The primary outcome was overall 30 day mortality. The secondary outcome included clinical and microbiological failure, superinfections and adverse events (AEs). The trials' risks of bias and their effects on results were assessed. Two reviewers independently extracted the data. Individual trials' relative risks (RRs) were pooled using a fixed effect meta-analysis. RESULTS: Fifteen trials (7654 patients) were included. Overall mortality was higher with tigecycline compared with other regimens [RR 1.29, 95% confidence interval (CI) 1.02-1.64, without heterogeneity]. The type of infection assessed and the trials' reported risks of bias did not affect this result. Clinical failure was significantly higher with tigecycline (RR 1.16, 95% CI 1.06-1.27) and non statistically significant higher rates of microbiological failure were demonstrated (RR 1.13, 95% CI 0.99-1.30). Development of septic shock was significantly more frequent with tigecycline (RR 7.01, 95% CI 1.27-38.66). Superinfections were significantly more common with tigecycline and so were AEs, including all AEs and AEs requiring discontinuation. CONCLUSIONS: In the light of the increased mortality, probably explained by decreased clinical and microbiological efficacy, clinicians should avoid tigecycline monotherapy in the treatment of severe infections and reserve it as a last-resort drug. PMID- 21685489 TI - Genome-wide survey and expression analysis of the plant-specific NAC transcription factor family in soybean during development and dehydration stress. AB - Plant-specific NAC transcription factors (TFs) play important roles in regulating diverse biological processes, including development, senescence, growth, cell division and responses to environmental stress stimuli. Within the soybean genome, we identified 152 full-length GmNAC TFs, including 11 membrane-bound members. In silico analysis of the GmNACs, together with their Arabidopsis and rice counterparts, revealed similar NAC architecture. Next, we explored the soybean Affymetrix array and Illumina transcriptome sequence data to analyse tissue-specific expression profiles of GmNAC genes. Phylogenetic analysis using stress-related NAC TFs from Arabidopsis and rice as seeding sequences identified 58 of the 152 GmNACs as putative stress-responsive genes, including eight previously reported dehydration-responsive GmNACs. We could design gene-specific primers for quantitative real-time PCR verification of 38 out of 50 newly predicted stress-related genes. Twenty-five and six GmNACs were found to be induced and repressed 2-fold or more, respectively, in soybean roots and/or shoots in response to dehydration. GmNAC085, whose amino acid sequence was 39%; identical to that of well-known SNAC1/ONAC2, was the most induced gene upon dehydration, showing 390-fold and 20-fold induction in shoots and roots, respectively. Our systematic analysis has identified excellent tissue-specific and/or dehydration-responsive candidate GmNAC genes for in-depth characterization and future development of improved drought-tolerant transgenic soybeans. PMID- 21685490 TI - Mass media campaigns within reach: effective efforts with limited resources in Russia's capital city. AB - Mass media campaigns, while often expensive, are proven, cost-effective interventions and should not be considered out-of-reach, especially where governments have some sway over media markets, where large media discounts are possible or where other novel strategies can be employed. PMID- 21685491 TI - Non-adherence in difficult asthma: time to take it seriously. AB - Recent studies have demonstrated a high prevalence of non-adherence with anti inflammatory medication in patients referred for specialist assessment with difficult-to-control asthma. As well as poor asthma outcome and increased healthcare cost, failure to detect non-adherence makes identification of true treatment-resistant/refractory asthma challenging. This is because guideline definitions of refractory asthma are all predicated on failure to respond to high dose anti-inflammatory therapy but do not state how adherence with this therapy should be assessed. With the advent of novel expensive biological therapies, the systematic identification of non-adherence becomes more essential to avoid targeting therapies at an inappropriate patient group. Novel biomarkers of steroid exposure, in combination with more traditional surrogate measures such as prescription filling assessment, may allow more objective assessments of non adherence to be developed in the future. When identified, non-adherence can potentially be targeted and improved, but the key challenge is to empower patients to make informed choices about medicines rather than decisions influenced by misplaced beliefs about benefit and harm. There is an urgent need for the systematic development of individualised interventions which allow non adherence to be effectively managed. Thus, non-adherence must become a priority in the clinical assessment of difficult-to-control asthma because addressing non adherence is likely to deliver greater benefits in this group than any novel treatment. It is essential that future research examines strategies and interventions to address non-adherence in subjects with difficult-to-control asthma. PMID- 21685492 TI - Oxygen and the airways. PMID- 21685493 TI - The cloud of pulmonary embolism during COPD exacerbation. PMID- 21685494 TI - A 76-year-old lady with chronic cough and a discharging chest wall sinus. PMID- 21685495 TI - Transfer coefficient of 137Cs from feed to cow milk in tropical region Kaiga, India. AB - In the transport model for the prediction of the concentration of (137)Cs in milk, the transfer coefficient from feed to milk, F(m), is an important parameter. Site-specific transfer coefficient from feed to cow's milk, for (137)Cs in the Kaiga environment, a nuclear power station site in India, determined over a period of 10 y is presented in this paper. The value is determined from (137)Cs concentration in milk and grass samples of the Kaiga region and the result ranged from 6.43E-03 to 1.09E-02 d l(-1) with a geometric mean value of 8.0E-03 d l(-1). The result is compared with that for (40)K, determined concurrently at the same region and ranged from 3.06E-03 to 3.48E-03 d l(-1) with a geometric mean value of 3.26E-03 d l(-1). This parameter is quite useful in decision-making for implementing countermeasures during a large area contamination with (137)Cs in tropical areas like Kaiga. PMID- 21685496 TI - Tell me about the context, and more. PMID- 21685497 TI - Mechanism of actin filament bundling by fascin. AB - Fascin is the main actin filament bundling protein in filopodia. Because of the important role filopodia play in cell migration, fascin is emerging as a major target for cancer drug discovery. However, an understanding of the mechanism of bundle formation by fascin is critically lacking. Fascin consists of four beta trefoil domains. Here, we show that fascin contains two major actin-binding sites, coinciding with regions of high sequence conservation in beta-trefoil domains 1 and 3. The site in beta-trefoil-1 is located near the binding site of the fascin inhibitor macroketone and comprises residue Ser-39, whose phosphorylation by protein kinase C down-regulates actin bundling and formation of filopodia. The site in beta-trefoil-3 is related by pseudo-2-fold symmetry to that in beta-trefoil-1. The two sites are ~5 nm apart, resulting in a distance between actin filaments in the bundle of ~8.1 nm. Residue mutations in both sites disrupt bundle formation in vitro as assessed by co-sedimentation with actin and electron microscopy and severely impair formation of filopodia in cells as determined by rescue experiments in fascin-depleted cells. Mutations of other areas of the fascin surface also affect actin bundling and formation of filopodia albeit to a lesser extent, suggesting that, in addition to the two major actin binding sites, fascin makes secondary contacts with other filaments in the bundle. In a high resolution crystal structure of fascin, molecules of glycerol and polyethylene glycol are bound in pockets located within the two major actin binding sites. These molecules could guide the rational design of new anticancer fascin inhibitors. PMID- 21685498 TI - A safety and efficacy pilot study of acupuncture for the treatment of chronic lymphoedema. AB - BACKGROUND: Lymphoedema is a distressing problem affecting many women after breast cancer surgery. There is no cure and existing treatments are marginally beneficial, rarely reducing arm swelling in any meaningful way. Needling and even lifting of objects using the affected arm has been prohibited, but our clinical experience and that of others suggested that acupuncture was safe and that it might be a useful treatment for lymphoedema. OBJECTIVE: We sought to conduct a pilot study of the safety and effectiveness of acupuncture in women diagnosed with chronic lymphoedema for at least 6 months and less than 5 years. METHODS: Women with chronic lymphoedema (affected arm with >2 cm circumference than unaffected arm) after breast cancer surgery received acupuncture twice a week for 4 weeks. Response was defined as at least a 30% reduction in the difference in size between the affected and unaffected arms. Monthly follow-up calls for 6 months following treatment were made to obtain information about side effects. RESULTS: Study goals were met after nine subjects were treated: four women showed at least a 30% reduction in the extent of lymphoedema at 4 weeks when compared with their respective baseline values. No serious adverse events occurred during or after 73 treatment sessions. Limitations This pilot study requires a larger, randomised follow-up investigation plus enquiries into possible mechanisms. Both are in development by our group. CONCLUSION: Acupuncture appears safe and may reduce lymphoedema associated with breast cancer surgery. PMID- 21685499 TI - Mass spectrometric identification of novel lysine acetylation sites in huntingtin. AB - Huntingtin (Htt) is a protein with a polyglutamine stretch in the N-terminus and expansion of the polyglutamine stretch causes Huntington's disease (HD). Htt is a multiple domain protein whose function has not been well characterized. Previous reports have shown, however, that post-translational modifications of Htt such as phosphorylation and acetylation modulate mutant Htt toxicity, localization, and vesicular trafficking. Lysine acetylation of Htt is of particular importance in HD as this modification regulates disease progression and toxicity. Treatment of mouse models with histone deacetylase inhibitors ameliorates HD-like symptoms and alterations in acetylation of Htt promotes clearance of the protein. Given the importance of acetylation in HD and other diseases, we focused on the systematic identification of lysine acetylation sites in Htt23Q (1-612) in a cell culture model using mass spectrometry. Myc-tagged Htt23Q (1-612) overexpressed in the HEK 293T cell line was immunoprecipitated, separated by SDS-PAGE, digested and subjected to high performance liquid chromatography tandem MS analysis. Five lysine acetylation sites were identified, including three novel sites Lys-178, Lys-236, Lys-345 and two previously described sites Lys-9 and Lys-444. Antibodies specific to three of the Htt acetylation sites were produced and confirmed the acetylation sites in Htt. A multiple reaction monitoring MS assay was developed to compare quantitatively the Lys-178 acetylation level between wild-type Htt23Q and mutant Htt148Q (1-612). This report represents the first comprehensive mapping of lysine acetylation sites in N-terminal region of Htt. PMID- 21685501 TI - Qualitative study: consultations between nurse prescribers and patients with diabetes in primary care: a qualitative study of patient views. PMID- 21685500 TI - Deficiency of PXR decreases atherosclerosis in apoE-deficient mice. AB - The pregnane X receptor (PXR, also known as SXR) is a nuclear hormone receptor activated by xenobiotics as well as diverse sterols and their metabolites. PXR functions as a xenobiotic sensor to coordinately regulate xenobiotic metabolism via transcriptional regulation of xenobiotic-detoxifying enzymes and transporters. Recent evidence indicates that PXR may also play an important role in lipid homeostasis and atherosclerosis. To define the role of PXR in atherosclerosis, we generated PXR and apoE double knockout (PXR(-/-)apoE(-/-)) mice. Here we show that deficiency of PXR did not alter plasma triglyceride and cholesterol levels in apoE(-/-) mice. However, PXR(-/-)apoE(-/-) mice had significantly decreased atherosclerotic cross-sectional lesion area in both the aortic root and brachiocephalic artery by 40% (P < 0.01) and 60% (P < 0.001), respectively. Interestingly, deficiency of PXR reduced the expression levels of CD36, lipid accumulation, and CD36-mediated oxidized LDL uptake in peritoneal macrophages of PXR(-/-)apoE(-/-) mice. Furthermore, immunofluorescence staining showed that PXR and CD36 were expressed in the atherosclerotic lesions of apoE(-/ ) mice, and the expression levels of PXR and CD36 were diminished in the lesions of PXR(-/-)apoE(-/-) mice. Our findings indicate that deficiency of PXR attenuates atherosclerosis development, which may result from decreased CD36 expression and reduced lipid uptake in macrophages. PMID- 21685502 TI - In older adults with chronic non-cancer pain, short-term use of opioids reduces pain and physical disability but does not benefit mental health, and 25% discontinue due to adverse effects. PMID- 21685503 TI - Economic burden of physical activity-related injuries in Dutch children aged 10 12. AB - BACKGROUND: Injuries in children occur most often in physical activity-related activities. A lot of these injuries result in direct and indirect costs. A detailed overview of the economic burden of those injuries in children is lacking. METHOD: A prospective study was conducted with 996 children in Dutch primary schools to describe the economic burden of injuries that occur during organised sports, leisure time and physical education (PE) class activities. Injuries were continuously monitored by PE teachers during the school year 2006 2007. An injury was recorded if it occurred during PE class, leisure time or organised sports activity and caused the child to at least stop the current activity. If an injury was recorded, parents received a cost diary to report the direct and indirect costs of the child's injury. Costs were collected from a societal perspective. RESULTS: During one school year, a total of 119 injuries were reported by 104 children. The mean total costs as a result of an injury were ?188 +/- 317. The mean direct costs as a result of an injury were much higher than the mean indirect costs (?131 +/- 213 and ?57 +/- 159, respectively). The highest costs were found for upper extremity and leisure time injuries. CONCLUSION: Physical activity-related injuries are common in children and result in medical costs. Injuries that lead to the highest costs are those that occur during leisure time activities and upper extremity injuries. Intervention programmes for children to prevent upper extremity injuries and leisure time activity injuries may reduce direct (ie, healthcare) and indirect costs. TRIAL REGISTRATION: ISRCTN78846684. PMID- 21685504 TI - The pros and cons of electronic prescribing for children. AB - The move from paper to electronic prescribing (EP) and medicine administration systems has long been advocated. Initial studies in the adult setting showed a significant reduction in medication errors. However, there are additional challenges to overcome to tailor these systems to paediatrics. Building on the basic elements of EP with the development of customised paediatric clinical decision support seems to offer the most benefit in terms of error reduction and increasing clinical effectiveness. Continued research is required to optimise these systems and minimise any unintended consequences at all stages of the medication use process. PMID- 21685505 TI - An analysis of successful litigation claims in children in England. AB - OBJECTIVE: To analyse the number of successful claims against the National Health Service (NHS) involving children, the nature and outcome of incidents leading to litigation and the costs of claims. METHOD: Under the Freedom of Information Act, details were sought of claims involving children made to the National Health Service Litigation Authority (NHSLA) from 1 April 2005 to 31 March 2010 together with the claim status on 30 September 2010. Closed cases involving financial compensation were analysed in relation to the nature of the incident, outcome and total cost of litigation. RESULTS: 195 closed cases were examined. The commonest causes of litigation were medication or vaccination errors (10), delayed septicaemia diagnosis (8), delayed meningitis diagnosis (7), delayed unspecified sepsis diagnosis (7), extravasation (7), delayed anorectal abnormality diagnosis (6), delayed cardiological diagnosis (6), delayed appendicitis diagnosis (6), epilepsy misdiagnosis (6), psychological/psychiatric effects on parent(s) following a medical error (4), delayed fracture diagnosis (4), gastrostomy related errors (3) and delayed testicular torsion diagnosis (3). The commonest outcomes were death (74), unnecessary pain (35), unnecessary operation (16), brain damage (12), scarring (12), psychiatric/psychological morbidity in parent(s) and/or child (10) and amputation (5). Total costs of litigation ranged from L600 to L3 044,943 (mean L127,975). CONCLUSION: Delayed diagnosis of severe sepsis is the commonest adverse incident leading to successful litigation and the commonest adverse outcome is death. The cost to the NHS is considerable. A better understanding of the causes of common errors in paediatrics should inform training and help to decrease these adverse events. PMID- 21685508 TI - The marvels of elite sports: how to get there? PMID- 21685506 TI - Independent analysis of the flagellum surface and matrix proteomes provides insight into flagellum signaling in mammalian-infectious Trypanosoma brucei. AB - The flagellum of African trypanosomes is an essential and multifunctional organelle that functions in motility, cell morphogenesis, and host-parasite interaction. Previous studies of the trypanosome flagellum have been limited by the inability to purify flagella without first removing the flagellar membrane. This limitation is particularly relevant in the context of studying flagellum signaling, as signaling requires surface-exposed proteins in the flagellar membrane and soluble signaling proteins in the flagellar matrix. Here we employ a combination of genetic and mechanical approaches to purify intact flagella from the African trypanosome, Trypanosoma brucei, in its mammalian-infectious stage. We combined flagellum purification with affinity-purification of surface-exposed proteins to conduct independent proteomic analyses of the flagellum surface and matrix fractions. The proteins identified encompass a broad range of molecular functionalities, including many predicted to function in signaling. Immunofluorescence and RNA interference studies demonstrate flagellum localization and function for proteins identified and provide insight into mechanisms of flagellum attachment and motility. The flagellum surface proteome includes many T. brucei-specific proteins and is enriched for proteins up regulated in the mammalian-infectious stage of the parasite life-cycle. The combined results indicate that the flagellum surface presents a diverse and dynamic host-parasite interface that is well-suited for host-parasite signaling. PMID- 21685509 TI - Injury resilience - let's control what can be controlled! PMID- 21685510 TI - Error-prone nonhomologous end joining repair operates in human pluripotent stem cells during late G2. AB - Genome stability of human embryonic stem cells (hESC) is an important issue because even minor genetic alterations can negatively impact cell functionality and safety. The incorrect repair of DNA double-stranded breaks (DSBs) is the ultimate cause of the formation of chromosomal aberrations. Using G2 radiosensitivity assay, we analyzed chromosomal aberrations in pluripotent stem cells and somatic cells. The chromatid exchange aberration rates in hESCs increased manifold 2 hours after irradiation as compared with their differentiated derivatives, but the frequency of radiation-induced chromatid breaks was similar. The rate of radiation-induced chromatid exchanges in hESCs and differentiated cells exhibited a quadratic dose response, revealing two-hit mechanism of exchange formation suggesting that a non-homologous end joining (NHEJ) repair may contribute to their formation. Inhibition of DNA-PK, a key NHEJ component, by NU7026 resulted in a significant decrease in radiation-induced chromatid exchanges in hESCs but not in somatic cells. In contrast, NU7026 treatment increased the frequency of radiation-induced breaks to a similar extent in pluripotent and somatic cells. Thus, DNA-PK dependent NHEJ efficiently participates in the elimination of radiation-induced chromatid breaks during the late G2 in both cell types and DNA-PK activity leads to a high level of misrejoining specifically in pluripotent cells. PMID- 21685511 TI - Human embryo stem cells and DNA repair. PMID- 21685512 TI - Besides Huntington's disease, does brain-type creatine kinase play a role in other forms of hearing impairment resulting from a common pathological cause? AB - Hearing impairment following cochlear damage due to noise trauma, ototoxicity caused by aminoglycoside antibiotics, or age-related cochlear degeneration was linked to a common pathogenesis involving the formation of reactive oxygen species (ROS). Cochleae are more vulnerable to oxidative stress than other organs because of the high metabolic demands of their mechanosensory hair cells in response to sound stimulation. We recently showed that patients and mice with Huntington's disease (HD) have hearing impairment and that the dysregulated phosphocreatine (PCr)-creatine kinase (CK) system may account for this auditory dysfunction. Given the importance of noninvasive biomarkers and the easy access of hearing tests, the symptom of hearing loss in HD patients may serve as a useful clinical indicator of disease onset and progression of HD. We also showed that dietary creatine supplementation rescued the impaired PCr-CK system and improved the expression of cochlear brain-type creatine kinase (CKB) in HD mice, thereby restoring their hearing. Because creatine is an antioxidant, we postulated that creatine might enhance expression of CKB by reducing oxidative stress. In addition to HD-related hearing impairment, inferior CKB expression and/or an impaired PCr-CK system may also play an important role in other hearing impairments caused by elevated levels of ROS. Most importantly, dietary supplements may be beneficial to patients with these hearing deficiencies. PMID- 21685514 TI - [Treatment of early postoperative adhesive small bowel obstruction]. AB - The results of treatment of 22 patients (12 men, 10 women) with acute early postoperative adhesive small bowel obstruction are presented. Obturation was detected in 16, strangulation - in 6 cases. In 12 patients obstruction was solved laparoscopically, in 8 patients laparotomy was performed, in two cases conversion was done. In 4 patients resection of the small intestine was done, in two instances terminal enterostomy was made. The average period passed from the previous operation till the intervention for bowel obstruction was 11,1 +/- 8,0 (2-30) days. In the laparotomy group the following complications were observed: enteric fistulas - 1 patient, subcutaneous eventration - 1 patient. There was no mortality. During the period of observation no recurrence of intestinal obstruction was observed. Laparoscopic adhesiolysis provides minimal trauma, which is especially important in the early postoperative period. PMID- 21685513 TI - Induction and persistence of radiation-induced DNA damage is more pronounced in young animals than in old animals. AB - Younger individuals are more prone to develop cancer upon ionizing radiation (IR) exposure. Radiation-induced tumors are associated with inefficient repair of IR induced DNA damage and genome instability. Phosphorylation of histone H2AX (gamma H2AX) is the initial event in repair of IR-induced DNA damage on the chromatin flanking the DNA strand breaks. This step is crucially important for the repair of DNA strand breaks and for the maintenance of genome stability. We studied the molecular underpinnings of the age-related IR effects using an animal model. By assaying for IR-induced gamma-H2AX foci we analyzed the induction and repair of the DNA strand breaks in spleen, thymus, liver, lung, kidney, cerebellum, hippocampus, frontal cortex and olfactory bulb of 7, 14, 24, 30 and 45 days old male and female mice as a function of age. We demonstrate that tissues of younger animals are much more susceptible to IR-induced DNA damage. Younger animals exhibited higher levels of gamma-H2AX formation which partially correlated with cellular proliferation and expression of DNA repair proteins. Induction and persistence of gamma-H2AX foci was the highest in lymphoid organs (thymus and spleen) of 7 and 14 day old mice. The lowest focal induction was seen in lung and brain of young animals. The mechanisms of cell and tissue-specificity of in vivo IR responses need to be further dissected. This study provides a roadmap for the future analyses of DNA damage and repair induction in young individuals. PMID- 21685515 TI - [The results of use of the antiadhesive seprafilm barrier in adhesive disease of abdomen]. AB - The results of treatment of 16 patients with abdominal adhesive disease are presented. In the surveyed group there were 7 women and 9 men. The average age of patients was 47,7 +/- 14,0 (23-71). Mean duration of history of intestinal obstruction were 48,9 +/- 31,5 (5-120) hours. 12 patients underwent surgery for acute adhesive small bowel obstruction. In 7 patients obturative and in 5 patients strangulated obstructions were revealed. In 9 patients laparoscopic resolution of obstruction was performed (no cases of conversion), in 3 patients open surgery is done. 4 patients were operated on for abdominal chronic pain, among them in three cases laparoscopy was performed, in one case open adhesiolysis was done. In order to prevent adhesions antiadhesive seprafilm membrane was applied in all patients. During laparoscopy the following technique was used - rolling of the film seprafilm with protective paper wrapper, the introduction into the abdominal cavity, the deployment of the roll, application of film to the anterior abdominal wall and the surfaces of omentum or intestines. No intra- and postoperative complications were observed. During observation no evidence of intestinal obstruction was observed in the operated patients. There was no mortality. The combination of laparoscopic adhesiolysis with antiadhesive barrier seprafilm is one of the best methods of treatment and prevention of adhesive disease of abdomen. PMID- 21685516 TI - [Oncotropic viruses and antitumor autovaccines (review)]. AB - Oncotropic viruses and antitumor autovaccines are reviewed. The progress of tumor process is associated with the invasive growth and the formation of metastases. Nowadays it is obvious that micrometastases are formed before any clinical symptoms are revealed, and, therefore, at the stage of clinical manifestation neoplastic process is in fact a systemic pathology and the surgical intervention is quite inefficient. This work deals with the main mechanisms of the progress of neoplastically transformed cells. Special account is given to the processes and methods which determine the antiblastomic effectiveness of the systemic influence of oncotropic viruses and antitumor autovaccines. The vaccine generated from the autologous tumor cells is actually quite individual. Technological procedure requires that the tissues should be removed from different places (primary base, metastases, lymph nodes), otherwise, the immune response to one or several determinants associated with tumor will not block the developing process, but it will promote the selective growth of subclones on the surface of which those determinants are not revealed. Hence, pharmacists face a difficult task - for the purpose of the advancement of the effectiveness of antitumor autovaccine therapy all the blastomic subclones should be infected with oncotropic viruses and additional viral antigens should be formed on their surface. Attenuated strains of natural viruses (flu, measles, herpes) and genetically engineered recombinanted viruses are generally used as oncotherapeutic agents. During the combined viro- and vaccinotherapy it is essentially important to keep the sequence of the following stages: 1) Evaluation of immune status and infection of the organism with oncotropic viruses; 2) Implementation of radical operation before the formation of antiviral immunoglobulins; 3) Removal of tumor tissues from different places ant preparation of autovaccine; 4) Starting the immunization. PMID- 21685517 TI - The psychological aspects of burning mouth syndrome. AB - It should be emphasized that at the present stage there is no consensus achieved regarding the etiopathogenesis of BMS. Almost all researchers point to lots of factors, simultaneously participating in genesis and development of BMS and at the same time most of them agreed on one - psychological factors play a crucial role in formation and maintenance of painful sensations. The aim of the study was the identification of psychological or psychiatric deviations (changes) among the patients with BMS to perform an adequate differentiated therapy. Clinico psychological examination (dentist, neurologist, psychiatrist) was carried out in 39 patients from 46 to 70 years of age. Among them women - 36 and men - 3. To identify clinical types of BMS a classification of P.J. Lamey (1996) was used and as a result, depression, insomnia, cancerophobia, severe neurologic disorders, phobic syndrome were revealed. Three main categories - a chronic somatoform dysfunction (23 cases), chronic vegetative disorders (8), and chronic pain phenomenon (12) were identified. Only in one case was revealed a paranoid syndrome. Alongside with the well-known scheme of treatment (antidepressants, anticonvulsants, or neuroleptics) Psychotherapy was conducted, while EEG-feed back (Biofeed back, Neurofeed back) method was used for the first time. A number of important decisions were made the most important of which are the following: BMS - must be regarded as a psychosomatic problem rather than a psychiatric disorder. In addition to psychotherapy, using of EEG - feedback method greatly improved patients' condition and in 4 cases BMS clinical manifestations were evened-out completely. PMID- 21685518 TI - Gemination or fusion? - challenge for dental practitioners (case study). AB - Gemination and fusion are anomalies in size, shape and structure of teeth. Gemination more frequently affects the primary teeth, but it may occur in permanent dentitions, usually in the incisor region. Geminated teeth are typically disfigured in appearance due to irregularities of the enamel. Fused teeth can have separated pulpal space, one pulp chamber and two canals or take the form of a large bifid crown with one pulpal space. It is hard to differentiate between fusion and gemination, especially if the supernumerary tooth bud is fused with the adjacent one. Usually, fusion may be differentiated from germination by a reduced number of teeth. An exception is in the unusual case in which the fusion is between a supernumerary tooth and normal tooth. A 20 year-old male referred to us at - "UniDent" - Dental Clinic, Training and Research Center. The patient complained about the large, unusual maxillary central incisors, lip irritation and aesthetic problems. According clinical examination and radiological findings, clinical diagnose was - bilateral germination of central incisors. Several treatment methods have been described in the literature with respect to the different types and morphological variations of fused and geminated teeth, including endodontic, direct?indirect restorative, surgical, periodontal and/or orthodontic treatment. Our patient has demanded for better aesthetics and he choose the treatment option to make two separate PFM crowns. In the beginning of treatment, the length of tooth 11 was 9.5mm, after prosthodontic treatment it has become 11.5mm. For tooth 21, it was 9.9 millimeter and became - 10.8 mm, while the primary width of right central incisor appeared 13.2 millimeter and was narrowed until 10.8 mm. 12.8 mm was the - width of left central incisor, which finally became - 10.4 mm. Despite the considerable number of cases reported in the literature, the differential diagnosis between these abnormalities is very difficult, as well as, to find guideline of proper outcome of treatment therapy of abovementioned abnormalities. That's why, the aesthetic rehabilitation of doubled teeth, has been suggested, to depend upon the patient's desires, but at the same time, avoid treatment plans with aggressive management. PMID- 21685519 TI - C-reactive protein level correlation with depression and anxiety among patients with coronary artery disease. AB - Some studies have reported that depression is associated with higher levels of C reactive protein (CRP) a marker of systemic inflammation that has been shown consistently to predict coronary heart disease risk. The aim of our study was to investigate the association between history of depressive episode and anxiety and presence of low-grade systemic inflammation as measured by serum CRP in postoperative period of coronary angioplasty and aorto-coronary bypass graft surgery. The research was performed in 80 patients (n = 80), mean age 60 +/- 15 years. These patients have no high cholesterol level, high body mass index and n = 64 (80%) of them are no smoker. To evaluate depression we used Beck depression scale. Anxiety was assessed by the Spilberger State-trait anxiety scale. CRP was measured in venous blood. Results show that increased level of C-reactive protein was found in aorto-coronary bypass graft surgery group n = 28 (70%), in angioplasty group C-reactive protein n = 12 (30%); chi2 = 6.40 p = 0.012. In angioplasty group patients who had increased level of CRP had high degree of depression p = 0.001. In these group was revealed high degree of trait anxiety p < 0.001 too. In aorto-coronary bypass surgery group elevated level of CRP was associated with high degree of depression p = 0.001. Our study demonstrated association between depression, anxiety and increased C-reactive protein level. Inflammation, the key regulator of CRP synthesis, plays a pivotal role in atherothrombotic cardiovascular disease. Our findings have important implications for explaining the pathophysiological mechanisms of cardiovascular disease. PMID- 21685520 TI - Rehabilitation results in patients with cervical spine problems. AB - The aim of the study is the effectiveness of a multi-week inpatient rehabilitation treatment with holistic complex conservative therapy for cervical present complaints using the Lawlis scores. A major part of the conservative treatment is represented by physical, physical therapy and sports therapy exercise programs. 77 patients with cervical spine disorders were treated 01-10 2006 to 30-09-2009 in rehabilitation clinic with a complex conservative treatment measures. The analysis was performed using a questionnaire, a clinical investigation, and a radiological examination of the cervical spine. At the beginning and end of the intervention subjective scores for symptoms complaints NRS scale and assessment of treatment results by the doctor after a 4-point rating scale were collected. The average age was 53.7 years at the time of treatment. Of these, 43 patients (56%) females and 34 (44%) were male. Of 77 patients 27 (35%) patients were the results excellent, 31 (40%) patients good, 8 (11%) patients satisfactory, 11 (14%) patients bad. Of 77 patients 66 (85.7%) patients were satisfied with rehabilitation treatment, 11 (14.3%) patients dissatisfied. The subjective assessment of the complaints numerical rating scale (NRS scale) improved significantly (p<0.001) from 8.5 to 2.4 points after treatment. An objective evaluation by the attending physician based on various clinical parameters was assessed in 75% of the cases as good or very good. Conservative treatment of cervical disorders included a variety of treatments available. A major part of the conservative treatment is represented by physical, physical therapy and sports therapy exercise programs. The primary goal of treatment is to eliminate pain or pain reduction. This can be achieved inter alia through Root detumescence and promotion of the venous flow. The success of each treatment varies from patient to patient. The study shows that the complex described here, conservative therapy, is a very good method for the treatment of cervical spine disorders in post-traumatic, degenerative and disc-related spinal disorders. The primary goal of treatment is to achieve freedom from pain was achieved as easily as the subjective assessment of the complaints proved using the NRS scale. Also the high patient satisfaction (86%) suggests that the complex conservative therapy can be a satisfactory choice as a treatment method. PMID- 21685521 TI - Valproic Acid related metabolic syndrome in patients with epilepsy. AB - Valproic acid (VPA) is an anticonvulsant and mood-stabilizing drug for the long term treatment. It is established that VPA has number of side effects affecting metabolic and endocrine system, like weight gain, hyperinsulinemia, changes in sex hormones, dyslipidemia, hyperleptinemia and etc. But the data are not sufficient to judge if VPA treatment can induce metabolic syndrome. Our aim was to investigate metabolic syndrome frequency in VPA-treated (n=11) and CBZ-treated (n=13) patients with epilepsy and in drug-free healthy subjects (n=11). We diagnosed metabolic syndrome according to Adult Treatment Panel III criteria (ATP III). We took blood samples for analysing triglyceride, HDL cholesterol and fasting glucose. Waist circumference and blood pressure was measured as well. Our data revealed that metabolic syndrome is relatively frequent in VPA-treated patients group (45,5%) compared with CBZ group and controls (15.4% and 27.3% respectively) (p<0,5). BMI did not differ between study groups. According to our preliminary data VPA monotherapy increases the risk of metabolic syndrome in patients with epilepsy, but BMI did not differ between VPA monotherapy study group, CBZ monotherapy study group and controls. PMID- 21685522 TI - [Effect of leptin on bone mineral dencity in premenopausal and postmenopausal women]. AB - Leptin raises considerable interest as a potential mediator of the protective effects of fat mass on bone tissue. The literature data support the hypothesis that leptin can act directly or indirectly on bone remodeling. However, such influence is not confirmed possibly because of the shifting balance between stimulatory direct action and suppressive indirect action of leptin on bones. The effects of oestrogen decline and deficiency during natural or artificially induced menopause and hormone replacement therapy on leptin production remains controversial. Various studies have shown differences in leptin values in pre-and postmenopausal women. Larger clinical studies are necessary to assess central and peripheral role of leptin in the overall maintenance of bone turnover. PMID- 21685523 TI - [The role of interleukin-1 and interleukin-1-receptor antagonist in development of familial mediterranean fever and other autoinflammatory diseases]. AB - Autoinflammatory diseases constitute a group of genetic disorders whose main clinical features are recurrent episodes of inflammatory lesions that can affect the skin, joints, bones, eyes, gastrointestinal tract and nervous system, in association with signs of systemic inflammation. Example of these disorders is familial Mediterranean fever (FMF). FMF is an autosomal recessive disease characterized by recurrent episodes of fever and inflammation affecting serosal surfaces, joints and skin. The gene of FMF is expressed in granulocytes, monocytes, dendritic cells and serosal and sinovial fibroblasts, which result in formation of pyrin. A large percentage of FMF-associated pyrin mutations reside in C-terminal B30.2 domain. Pyrin normally suppresses IL-1beta, but when mutated in case of FMF, it does not. Inhibition of the interaction between pyrin and caspase-1 leads to an increase in caspase-1 activity and subsequent increase in IL-1beta secretion. The interleukin-1-receptor antagonist binds to the interleukin-1 receptor, thereby blocking access of interleukin-1 to the receptor. The outcome of an inflammatory process is likely to be affected by the relative amounts of interleukin-1 and interleukin-1-receptor antagonist. PMID- 21685524 TI - Features and problems of nutrition among Georgian population. AB - The important role of food and nutrition in public health is being increasingly recognized as crucial for its potential impact on health-related quality of life. In developing countries, morbidity and mortality are directly related to protein and energy malnutrition, while in many Western countries, health officials have begun to actively promote the consumption of healthy food. The basic nutrition problems in Georgia are nutrition deficiency, deficiency of nutrients, nutrition monotonous, obesity, malnutrition. In the nutrition field is required not only adoption of appropriate laws, acts and decrees, but for practical implementation is also mandatory to set the objects, make necessary arrangements and carry out a monitoring of elaborated work. This article summarizes recent positive synergy between research in nutrition needs related. We illustrate several major examples, for which prospective synergy appears to be considerable. There have been extensive gains from such synergy in the past. Building upon research in the fields of nutrition and developing cross-sectional research are likely to have consequential payoffs in terms of understanding basic nutritional, economical and political issues. PMID- 21685525 TI - Disasters and their consequences for public health. AB - Humanitarian emergencies, including natural and human-made disasters, conflicts and complex emergencies, constitute what has traditionally been considered the main threat to health security worldwide. Each year millions of people are affected by natural and man-made disasters around the world. Tornados, hurricanes, heavy rains and earthquakes resulted in tens of thousands of deaths and many more affected. Indeed, disasters would not be disastrous if it were not for their effect on the human population. Links between the natural environment and human health have been suggested for centuries. Disasters throughout history have had significant impact on the numbers, health status and life style of populations. It induce: Deaths, Severe injuries, requiring extensive treatments, Increased risk of communicable diseases, Damage to the health facilities, Damage to the water systems, Food shortage, Population movements. The authors focused on the natural disasters, caused by natural forces rather than by acts associated with human behavior and that affect a large population in a widespread geographic region. Describing the general effects of disasters on health, it does not pretend to cover every contingency. Review of recent literature on humanitarian emergencies has shown that the public health consequences of natural disasters are complex. Disasters directly impact the health of the population resulting in physical trauma, acute disease and emotional trauma. In addition, disasters may increase the morbidity and mortality associated with chronic disease and infectious disease through the impact on the health care system. PMID- 21685526 TI - Influence of tetrapeptide on chromatin thermostability. AB - It is known that short peptides are capable to interact with DNA, as a result of changes in particular gene expression. In the given work, influence of Ala-Asp Glu-Leu peptide on thermostability of white rat liver chromatin, in which H1 histone and non-histone proteins are depleted, have been studied. It was shown that in 10 nm chromatin filaments, in which nucleosomas do not interact, the tetrapeptide unfolds the nucleosomal nucleus (core) and this causes release of about 15% of core DNA that melts in the melting temperature range of internucleosomal linker DNA. Thus, the studied tetrapeptide can increase accessibility of DNA for transcription. PMID- 21685527 TI - [Study of anxiety level and passive avoidance response in rats that in neonatal period undergo the prolonged dexamethasone treatment]. AB - The decrease in locomotor activity and the number of crossed sectors in open field, has been shown in the group of animals, which for four days in the neonatal period received dexamethasone treatment. Based on these data we decided in the same experimental conditions to study the animals' state of anxiety and the behavior in passive avoidance chamber. The newborn male pups were divided on four groups. The first group was left intact, the pups of the second group were injected by saline, the third group - by dexamethasone and the fourth group - with combination of dexamethasone and L-arginine. The received results show, that deficiency of nitric oxide in the early neonatal period caused by administration of dexamethasone led to statistically significant increase of anxiety level, but statisticaly significant changes in their behavior in a passive avoidance chamber was not observed. PMID- 21685528 TI - [Effect of exogenous calcitonin gene-related Peptide on systemic arterial blood pressure in pregnant and non-pregnant rats]. AB - It is known that in the process of gestation and delivery, jointly with well recognized regulatory factors such as sex steroids, catecholamines, oxytocin and prostaglandins the substances of peptidergic nature are also involved. One of these substances is a Calcitonin Gene-Related Peptide (CGRP). In experiments on groups of pregnant and non pregnant rats we have demonstrated that exogenous Calcitonin Gene-Related Peptide causes a decrease in mean systemic arterial pressure. Hypotensive effect of CGRP is due to dilation of blood vessels. CGRP exerts a dose-dependent hypotensive effect and this effect on pregnant rats significantly exceeds the effect, manifested in non-pregnant once. PMID- 21685529 TI - [Microbial spectrum of nosocomial pneumonia in traumatological patients]. AB - In this article there are given results of microbiological investigation of nosocomial pneumonia agents, microbial structure. Investigation was held in 727 cases of traumatological patients treated because of hip replacement or osteosinthesis of limbs. Complications with nosocomial pneumonia was found in 27 cases (3,7%). In 27 cases of diagnosed pneumonia, 66 microbial strains were isolated. In 4 cases (14,8%) was detected mono infection, different microbial association were isolated in 23 cases (85,2%) - 2 microbes in 7 and 3 microbes in 16 cases. Microbial structure was presented by: S.aureus (27,3%), Kl.pneumoniae (19.7%), S. pneumoniae (15,2%), A. baumanii (10,6%), E. coli (4,6%), enterobacter spp. (9,1%), P. aeruginosa (13,6%). Study of sensitiveness/resistance of separated stains to different groups of antibiotics showed, that micro organisms have high level of resistance to antibiotics and also pan-resistance. So, success of antimicrobial therapy depends on prompt and correct choice of antibiotics, based on aetiology of infection and sensitiveness to antibiotics. In cases of empirical administration, it is necessary to use antibiotics with high level of activity against pneumonia agents - carbapenems, and in case of high probability of MRSA - it is better to use linezolid or vancomicin. PMID- 21685530 TI - [Morphological criterion in the spleen organ-preserving experimental surgery]. AB - Thrombosis and inflammatory complications are concomitant to the post-surgery period of splenectomy due to the traumatic damage to the spleen. Therefore morphological analysis of the spleen residue after the partial spleen resection is of particular theoretical and practical interest. Total of 36 white rats, male, body mass 130-150 g., underwent partial resection of the spleen under the ether narcosis. Rats were withdrawn from the experiment on the first, 7-th, 15 th, 30-th, 90-th and 180-th day after the surgery. Spleen tissue samples were fixed in the 10% formaldehyde solution and stained with the use of routine methods. Homory method was used to reveal the argyrofilous fibers and ink injection was used to reveal blood vessels respectively. Spleen parameters were calculated morphometrically. Microsoft Excel program was used for statistical analysis of the data obtained. Partial disorder of blood microcirculation in the spleen after partial splenectomy was registered and in same time relative increase in the mass of the spleen and lymphatic follicles was shown concomitant to these disorders. The presence of the clusters of macrophages and lymphocytes capable of phagocytosis, as well as haemociderosis is considered as morphological criterion of the immune reaction. We can suppose that remainder spleen cells can induce immune response as regards autoantigens as response to the operational trauma and directed to restore the homeostasis. PMID- 21685531 TI - [The role of apoptosis in the development of virus hepatitis]. AB - In present review hepatocyte apoptosis is presented as universal defensive reaction of liver, to the damages. Hepatocyte apoptosis may be caused by hepatotropic virus's direct affection, or by the immune reactions initiated by viruses. Apoptosis development caused by virus direct affection varies and contains at lest two mechanisms: production of specific proteins: B virus - X protein and C virus - core-protein; expression of the receptors leading the induction of this process on the hepatocyte membrane, for example, increasing of Fas-receptor and cell sensation to apoptosis stimulus. In apoptosis induced by immune reaction T-lymphocytes could trigger off apoptosis in two principal ways: by releasing perporines that produce holes through hepatocyte membrane and according to this process granzyms are permetted inside the cells. By destroying of caspases by proteases that initiate apoptosis cascade. In this article molecular mechanisms of the processes mentioned above are also discussed. PMID- 21685532 TI - Polymorphisms of toll-like receptors and their pathways in viral hepatitis. AB - Toll-like receptors (TLRs) are an important part of the innate immune response to a variety of pathogens including hepatic viral infections. Activation of TLRs stimulates a complex intracellular signalling cascade that results in production of proinflammatory cytokines and interferons important for antiviral responses as well as induction of the adaptive arm of the immune system. There is substantial evidence for an important role for TLRs and TLR-mediated signalling in the pathogenesis and outcomes of hepatitis B and C in particular, but it might also influence responses to other viral hepatitis infections. Several single nucleotide polymorphisms (SNPs) of TLRs, relevant adaptor molecules and cytokines mediated by TLR signalling have been described that alter innate immune responses and have been implicated in a variety of human diseases including viral and other infections. There is now significant evidence that a number of TLR SNPs can affect various clinical outcomes in Caucasian patients with chronic HCV. However, the role of these polymorphisms in acute and other chronic hepatitis infections, including HBV as well as in non-Caucasian populations, has not been elucidated. In addition, results for SNPs downstream of TLR activation, such as in relevant cytokines, are inconsistent and their influence requires further investigation to determine the clinical significance of genetic variations in these mediators. PMID- 21685533 TI - Low-density lipoprotein size and lipoprotein-associated phospholipase A2 in HIV infected patients switching to abacavir or tenofovir. AB - BACKGROUND: The aim of this study was to assess changes in the size and cholesterol content of low-density lipoproteins (LDL) and changes in lipoprotein associated phospholipase A2 (Lp-PLA2) activity in HIV-infected patients switching to tenofovir + emtricitabine (TDF+FTC) or abacavir + lamivudine (ABC+3TC). METHODS: This was a substudy of a multicentre randomized trial comparing TDF+FTC with ABC+3TC-based regimens in patients with virological suppression. Fasting lipids and apolipoproteins (apo), LDL size and cholesterol content and Lp-PLA2 activity were measured at baseline and at week 48. RESULTS: A total of 62 patients, naive for the compared drugs, were included. At baseline, groups were comparable except for total Lp-PLA2 activity (P=0.047) and for a tendency towards the use of a major baseline thymidine analogue in the TDF+FTC arm (25 versus 18 patients; P=0.054). In the ABC+3TC arm a significant increase in total cholesterol (0.64 mmol/l; P=0.003), high-density lipoprotein cholesterol (HDL-c, 0.13 mmol/l; P=0.031), triglycerides (0.39 mmol/l; P=0.036), apo A-I (0.12 g/l; P=0.006), apo B (0.16 g/l; P=0.015) and non-HDL-c (0.50 mmol/l; P=0.009) concentrations was observed at week 48 compared with the TDF+FTC treatment arm. In addition, an increase in the cholesterol content of small, dense LDL subfractions (0.48 mmol/l; P=0.003) and a decrease in LDL size (-2.6 nm; P=0.011) was observed in the ABC arm without changes in the TDF patients. Total PLA2, LDL PLA2 and HDL-PLA2 activity decreased in the TDF arm, but multivariate analysis showed baseline PLA2 values and previous use of thymidine analogues as the factors associated with these changes. Estimated cardiovascular risk did not change in either arm. CONCLUSIONS: A more atherogenic LDL profile, including a decrease in LDL size, was found in the ABC group and not in TDF patients. PMID- 21685534 TI - Partial virological response to entecavir in treatment-naive patients with chronic hepatitis B. AB - BACKGROUND: The proposed definition of a partial virological response (PVR) to nucleos(t)ide analogue therapy in the 2009 European Association for the Study of the Liver (EASL) guidelines is based on limited evidence, especially in terms of the cutoff HBV DNA level and the time point at which to judge it. This study assessed optimal PVR criteria for predicting virological response (VR) at week 96 in treatment-naive patients with chronic hepatitis B (CHB) receiving entecavir (ETV). METHODS: A total of 175 patients (126 men, 49 women) who completed 96 weeks of first-line ETV therapy were prospectively recruited. For predicting VR at week 96, the area under the receiver operating characteristic curve (AUC) was used to find the optimal time point and the Youden index was used to calculate the optimal cutoff HBV DNA level. RESULTS: After 96 weeks of ETV therapy, 139 (79.4%) patients achieved VR. The AUC at week 48 was significantly better than that at week 24 for predicting VR at week 96 (P=0.023). The optimal cutoff HBV DNA level at week 48 was 35 IU/ml. Forty-one (23.4%) patients met this PVR criteria of ETV (HBV DNA level >35 IU/ml at week 48). CONCLUSIONS: An HBV DNA level >35 IU/ml at week 48 is the optimal PVR criteria for predicting non-VR at week 96 in treatment-naive patients with CHB who are receiving ETV. This study supports the proposed EASL PVR for ETV based on scientific evidence. PMID- 21685535 TI - De novo activation of HBV with escape mutations from hepatitis B surface antibody after living donor liver transplantation. AB - BACKGROUND: De novo activation of HBV occurs after liver transplantation from hepatitis B surface antigen (HBsAg)-negative and hepatitis B core antibody (anti HBc)-positive donors, even under hepatitis B immunoglobulin (HBIG) prophylaxis. One reason for the activation of HBV is the emergence of HBV with escape mutations from hepatitis B surface antibody (anti-HBs). The aim of this study is to clarify the clinical features for de novo activation of HBV with anti-HBs escape mutations after liver transplantation. METHODS: Clinical features of 75 patients who received HBIG prophylaxis >6 months after liver transplantation with liver grafts from anti-HBc-positive donors were retrospectively analysed. RESULTS: Among the 75 recipients, 19 (25%) developed de novo activation of HBV. Of the 19 recipients, the emergence of HBV with anti-HBs escape mutations was confirmed in 7 patients. The rate of de novo activation of HBV with anti-HBs escape mutations was 12% at 5 years. Sequence analysis revealed mutations in the common 'a' determinant region of the surface gene, including G145R, G145A and Q129P, in HBsAg. Administration of entecavir immediately after the occurrence of de novo HBV activation resolved hepatitis and induced clearance of serum HBsAg and HBV DNA in all four patients receiving entecavir. CONCLUSIONS: Escape mutations from anti-HBs caused de novo activation of HBV under HBIG prophylaxis after liver transplantation. Early administration of entecavir was effective on de novo activation of HBV with anti-HBs escape mutations. PMID- 21685536 TI - Interpretation of genotypic HIV-1 resistance to darunavir and virological response: validation of available systems and of a new score. AB - BACKGROUND: There is not yet consensus on interpretation of genotypic HIV-1 resistance to darunavir (DRV). We validated existing rules and a newly derived score. METHODS: Protease inhibitor (PI)-failing patients starting a DRV/ritonavir based regimen, with available baseline resistance genotypes, were extracted from three Italian databases. Virological response (VR) was analysed between 4 and 32 follow-up weeks, defined as a drop from baseline HIV RNA of >=2 log(10) or a value <50 copies/ml if the last measurement had been obtained at <=12 weeks and as HIV RNA<50 copies/ml if it had been obtained at >12 weeks of follow-up. DRV/ritonavir resistance was interpreted by seven algorithms. A new weighted score (DRV-2009) was derived and validated, analysing associations of protease mutations with VR. RESULTS: A total of 217 patients were analysed, with a mean (+/-sd) follow-up time of 17 (+/-9) weeks. At baseline, median HIV RNA was 4.26 log(10) copies/ml (IQR 3.11-5.03); VR was achieved in 135/217 (62%) patients. Adjusting for use of a new drug class, number of previous PIs experienced, CD4(+) T-cell count and HIV RNA, only the Rega DRV/ritonavir interpretation was significantly associated with VR (per increase in susceptibility category, OR 1.94, 95% CI 1.32-2.86; P<0.001). The DRV-2009 score V11I+L33F+R41K+I47V+2*I50V+2*I54M+K55R+D60E+L74P+L76V+N88D+2*L89V-L10I/V-I13V G16E-G48V-F53I/L-I62V-I66F-V77I (<0 indicating susceptibility, 0-1 intermediate resistance and >=2 resistance) correlated with VR in the derivation set (n=132, R=0.395; P<0.001). In the validation set (n=85), after adjusting for mutual interpretation and new use of enfuvirtide, DRV-2009 (P=0.017) and Rega (P=0.013) were both independently associated with VR. CONCLUSIONS: In contrast to the other algorithms, both the DRV-2009 score and Rega interpretation showed a robust predictive capacity of VR to DRV/ritonavir-containing regimens. PMID- 21685537 TI - Pharmacokinetics of switching unboosted atazanavir coadministered with tenofovir disoproxil fumarate from 400 mg once daily to 200 mg twice daily in HIV-positive patients. AB - BACKGROUND: Use of unboosted atazanavir (ATV) with tenofovir disoproxil fumarate (TDF), although attractive from a clinical view point, has not been tested in trials and is not currently recommended because of the risk of suboptimal ATV pharmacokinetics (PK). In order to improve ATV exposure, plasma and intracellular (IC) PK of ATV in patients administered with ATV 400 mg once daily and TDF/emtricitabine (FTC) and switched to ATV 200 mg twice daily were studied. METHODS: On day 0, 10 subjects on ATV 400 mg plus TDF/FTC once daily underwent intensive plasma and IC PK evaluation and bilirubin measurement. Patients were subsequently switched to ATV 200 mg twice daily for 10 days. On day 11, they once again underwent intensive PK and bilirubin evaluation. RESULTS: Switch to 200 mg twice daily led (in plasma) to a significant increase of the observed concentration at the end of dosing interval (C(trough); ratio twice daily/once daily 2.20; P=0.005), with a decrease from 60% to 20% of suboptimal values, a significant decrease of the maximum concentration (C(max); ratio twice daily/once daily 0.47; P=0.022), whereas no differences of other PK parameters or bilirubin were observed. IC ATV concentrations at 400 once daily showed higher C(trough) (ratio peripheral blood mononuclear cells [PBMCs]/plasma 2.86; P=0.005) and longer half-life (ratio PBMCs/plasma 1.44; P=0.007) as compared with plasma. After the switch, IC ATV accumulation showed changes similar to plasma. CONCLUSIONS: Switch to 200 mg twice daily appeared to optimize plasma and IC ATV PK, by increasing the determinant of efficacy (C(trough)) and decreasing C(max), without significant effect on total ATV plasma exposure and bilirubin. Dosage of 200 mg might provide an option to patients showing suboptimal ATV exposure with standard unboosted dosing. PMID- 21685538 TI - Changes of serum levels of keratin-18 fragments in hepatitis B e antigen-negative chronic hepatitis B patients under oral antiviral therapy. AB - BACKGROUND: The effect of chronic hepatitis B (CHB) treatment on hepatocyte apoptosis has not been evaluated. We investigated the changes in serum levels of the apoptotic caspase-generated fragments of keratin-18 (K-18) in hepatitis B e antigen (HBeAg)-negative CHB patients under nucleoside/nucleotide analogue(s). METHODS: We included 46 patients with HBeAg-negative CHB who had received lamivudine or adefovir monotherapy for >=12 months. Of the 42 lamivudine treated patients, 23 developed virological breakthroughs and received add-on adefovir therapy for >=12 months. Levels of K-18 fragments were measured blindly in stored serum samples using the M30-Apoptosense((r)) ELISA Kit (PEVIVA, Alexis, Grunwald, Germany). RESULTS: During initial therapy, the median serum K-18 fragment levels were significantly reduced from baseline (280 U/l [149-2,461]) to 6 months (164 U/l [110-454]; P<0.001) and from 6 to 12 months (145 U/l [113-280]; P=0.031). K 18 fragment levels increased at breakthroughs (187 U/l [137-1,063]) compared to last previous visits (145 U/l [118-389]; P=0.015) but remained lower than baseline (P=0.036). Changes of K-18 fragment levels correlated positively with changes of alanine aminotransferase (ALT) and HBV DNA from baseline to 6 or 12 months of initial therapy. In patients with breakthroughs, K-18 fragment levels had only a trend towards a decrease from adefovir addition (198 U/l [124-1,219]) to 6 months (170 U/l [122-1,576]; P=0.109) and mainly to 12 months (156 U/l [122 878]; P=0.055). CONCLUSIONS: Serum levels of K-18 fragments decrease significantly during oral antiviral therapy in HBeAg-negative CHB in parallel with the improvements in ALT and HBV DNA levels. They increased again during breakthroughs and improved after an effective rescue therapy, perhaps at a slower rate compared to the initial therapy. PMID- 21685539 TI - Lopinavir up-regulates expression of the antiviral protein ribonuclease L in human papillomavirus-positive cervical carcinoma cells. AB - BACKGROUND: We have previously shown that the HIV protease inhibitor lopinavir has selective toxicity against human papillomavirus (HPV)-positive cervical carcinoma cells via an unknown mechanism. METHODS: SiHa cervical carcinoma cells were stably transfected with the proteasome sensor vector pZsProSensor-1 to confirm lopinavir inhibits the proteasome in these cells. The Panorama Xpress profiler 725 antibody array was then used to analyse specific changes in protein expression in lopinavir-treated versus control untreated SiHa cells followed by PCR and western blotting. Colorimetric growth assays of lopinavir-treated E6/E7 immortalised versus control human keratinocytes were performed. Targeted small interfering RNA gene silencing followed by growth assay comparison of lopinavir treated/untreated SiHa cells was also used. RESULTS: Lopinavir induced an increase in the fluorescence of pZsProSensor-1 transfected SiHa cells, indicative of proteasomal inhibition. Ribonuclease L (RNASEL) protein was shown to be up regulated in lopinavir-treated SiHa cells, which was confirmed by PCR and western blot. Targeted silencing of RNASEL reduced the sensitivity of SiHa cells to lopinavir. Selective toxicity against E6/E7 immortalised keratinocytes versus control cells was also seen with lopinavir and was associated with up-regulated RNASEL expression. CONCLUSIONS: These data are consistent with the toxicity of lopinavir against HPV-positive cervical carcinoma cells being related to its ability to block viral proteasome activation and induce an up-regulation of the antiviral protein RNASEL. This is supported by the drug's selective toxicity and up-regulation of RNASEL in E6/E7 immortalised keratinocytes combined with the increased resistance to lopinavir observed in SiHa cells following silencing of RNASEL gene expression. PMID- 21685540 TI - Efavirenz and rifampicin in the South African context: is there a need to dose increase efavirenz with concurrent rifampicin therapy? AB - BACKGROUND: Increasing efavirenz (EFV) dose from 600 mg to 800 mg daily has been suggested with concomitant rifampicin (RFN), as induction of cytochrome P450 isoenzymes may reduce EFV plasma concentrations. METHODS: Individuals from the CIPRA-South Africa cohort taking EFV-based antiretroviral therapy with concomitant tuberculosis (TB) were dosed with either increased (800 mg) or standard (600 mg) dose EFV during TB treatment. After TB therapy, all individuals took 600 mg EFV. Two mid-dosing interval EFV concentrations were determined from each individual: after 4 weeks of concomitant EFV and RFN therapy, and >=4 weeks after TB therapy completion. Mid-dosing interval EFV concentrations were compared within individuals using the Wilcoxon signed-rank test. RESULTS: Paired samples were collected from 72 individuals. Overall, 45 (63%) were women and median weight was 59 kg (IQR 52-67). At antiretroviral therapy start, median CD4(+) T cell count was 114 cells/mm(3) (IQR 37-165), median viral load was 5.5 log (IQR 5.1-5.9). A total of 38 (53%) individuals took 800 mg EFV during TB treatment and 34 (47%) took 600 mg. EFV concentrations in the 800 mg group were higher with RFN (2.9 mg/l [IQR 1.8-5.6]) than without (2.1 mg/l [IQR 1.4-3.0]; P=0.0003). There was no significant difference in EFV concentrations with RFN (2.4 mg/l [IQR 1.2 5.1]) or without (2.2 mg/l [IQR 1.4-3.7]) in the 600 mg group. There was no increase in EFV-linked adverse effects in either group. The proportion of virologically suppressed individuals at 48 weeks was similar in both groups. CONCLUSIONS: EFV concentrations were significantly increased in the EFV 800 mg group on RFN. There was no significant decrease in EFV concentrations when on RFN in the 600 mg group. Dose escalation of EFV 600 mg to 800 mg is not required during concomitant TB therapy in South Africa. PMID- 21685541 TI - Effect of early antiretroviral therapy during primary HIV-1 infection on cell associated HIV-1 DNA and plasma HIV-1 RNA. AB - BACKGROUND: Early initiation of combination antiretroviral therapy (ART) during primary HIV-1 infection may prevent the establishment of large viral reservoirs, possibly resulting in improved control of plasma viraemia rebound after ART cessation. METHODS: Levels of cell-associated HIV-1 DNA and plasma HIV-1 RNA were measured longitudinally in 32 acutely and recently infected patients, who started ART <=120 days after the estimated date of infection, and interrupted ART after 18 months (median) of continuous therapy. Averages of HIV-1 DNA and RNA concentrations present in blood 30-365 days after therapy interruption (median duration 300 days, range 195-358) were compared between patients who started ART <=60 days after the estimated date of infection (early starters), those who started between 61 and 120 days (later starters), and, for HIV-1 RNA only, with 89 untreated participants of the Swiss HIV Cohort Study with documented seroconversion and longitudinal measurements collected 90-455 days after the first positive HIV test. RESULTS: In early ART starters, average levels of plasma HIV-1 RNA and cell-associated HIV-1 DNA after treatment interruption were 1 log(10) (P=0.008) and 0.4 log(10) (P=0.03) lower compared with later starters. Average post-treatment plasma HIV-1 RNA levels in early starters were significantly lower, respectively, compared with untreated controls (-1.2 log(10); P<0.0004). CONCLUSIONS: Early treatment initiation within 2 months after HIV infection compared with later therapy initiation resulted in reduced levels of plasma viraemia and proviral HIV-1 DNA for >=1 year after subsequent ART cessation. Plasma HIV-1 RNA levels in early starters were also significantly lower than in untreated controls. PMID- 21685542 TI - RNA interference and its potential applications to chronic HBV treatment: results of a Phase I safety and tolerability study. AB - BACKGROUND: RNA interference (RNAi) provides an attractive tool to modulate biological systems, and ultimately, to treat human diseases. We describe early results from a Phase Ib, first-in-human safety and tolerability study of an RNAi based therapy, NUC B1000, among patients with mild to moderate chronic HBV. METHODS: Three subjects received a single 5 mg DNA dose of NUC B1000 as part of a planned dose escalation study. RESULTS: All participants reported pharyngitis, chills, myalgia and fever approximately 4-7 h after dosing. All subjects were asymptomatic after a single antipyretic dose with no symptom recurrences. Measurements of interferon (IFN)-alpha and -gamma, interleukin (IL)-10, 12 18, 8 and 6, and tumour necrosis factor-alpha performed before and after dosing revealed cytokine increases before study drug administration. After drug administration, IFN-gamma and IL-10 increased in two patients; IL-8 increased in one. Most increases returned to pretreatment levels within 1 week. Two patients were subsequently successfully treated with entecavir indicating that NUC B1000 does not compromise subsequent antiviral therapy. CONCLUSIONS: Thus far, NUC B1000 appears safe and well-tolerated; safety and efficacy studies across a larger, more diverse patient spectrum using increasing doses are needed to determine its appropriate role in the antiviral armamentarium. PMID- 21685543 TI - Vitamin D is linked to carotid intima-media thickness and immune reconstitution in HIV-positive individuals. AB - BACKGROUND: Patients with HIV infection are at increased risk of cardiovascular disease (CVD). Vitamin D insufficiency has been associated with increased CVD risk in non-HIV populations. This study sought to determine the relationship between vitamin D status and markers of CVD and HIV-related factors in HIV positive patients. METHODS: Patients with HIV infection on antiretroviral therapy and healthy controls were prospectively enrolled. Fasting lipids, glucose, insulin, inflammatory markers (soluble tumour necrosis factor-alpha receptor I, interleukin-6 and high-sensitivity C-reactive protein) and endothelial markers (soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule-1) were measured. Fasting 25-hydroxyvitamin D (25(OH)D) was measured from stored serum samples. The internal carotid artery and common carotid artery (CCA) intima-media thickness (IMT) were measured in a subset of HIV-positive patients. Baseline cross-sectional data were analysed. RESULTS: A total of 149 HIV-positive patients (56 with carotid IMT) and 34 controls were included. Controls had higher adjusted mean 25(OH)D levels than HIV-positive patients (P=0.02). In multivariable linear regression among the HIV-positive patients, 25(OH)D was positively associated with CD4(+) T-cell restoration after antiretroviral therapy (DeltaCD4 = current - nadir CD4(+) T-cell; P<0.01), but was not associated with inflammatory or endothelial markers. In multivariable logistic regression, odds of having CCA IMT above the median were more than 10* higher in those with lower 25(OH)D levels (OR=10.62, 95% CI 1.37-82.34; P<0.01). CONCLUSIONS: Vitamin D status in HIV-positive patients was positively associated with improved immune restoration after antiretroviral therapy and negatively associated with CCA IMT. These findings suggest that vitamin D may play a role in HIV-related CVD and in immune reconstitution after antiretroviral therapy. PMID- 21685544 TI - Influence of HIV infection on cytomegalovirus-specific immunity: T-cell responses to pp65 and IE1 before and after HAART may reflect altered cytomegalovirus biology. AB - BACKGROUND: Data are inconclusive whether treatment with HAART induces functional recovery of HIV-specific T-cells. Since the introduction of HAART, a marked decrease of cytomegalovirus (CMV) disease - for which untreated HIV-infected individuals are at increased risk - is observed, suggesting that this treatment influences CMV-specific T-cell immunity. METHODS: To study potential functional recovery of HIV- and CMV-specific T-cells, CD4(+) and CD8(+) T-cell responses were measured longitudinally after in vitro expansion using gag, pp65 and IE1 peptide pools, during HIV infection and after long-term HAART. RESULTS: HIV specific T-cell function, measured by interferon (IFN)-gamma production, was low after initiation of HAART. Interestingly, the cytotoxic function - measured by CD107a expression - of these T-cells temporarily increased after start of treatment, suggesting some functional recovery. The pp65-specific CD8(+) T-cell responses tended to decrease during HIV infection, whereas pp65-specific CD4(+) T cell responses decreased upon treatment with HAART. Both pp65-specific CD4(+) and CD8(+) T-cell responses were low after initiation of HAART compared to healthy controls. By contrast, IE1-specific CD4(+) T-cell responses increased during the course of HIV infection. After initiation of HAART, IE1-specific T-cell responses decreased, but IE1-specific CD8(+) T-cells seemed increased compared to healthy controls. CONCLUSIONS: This study suggests that HIV-infection leads to an altered CMV biology, affecting pp65- and IE1-specific T-cell responses in a different way, which is not restored by treatment with long-term HAART. PMID- 21685545 TI - Antiviral effects of interferon-beta are enhanced in the absence of the translational suppressor 4E-BP1 in myocarditis induced by Coxsackievirus B3. AB - BACKGROUND: Viral myocarditis is most frequently associated with infection by Coxsackievirus B3 (CVB3). Interferon (IFN)-beta therapy has been studied and could reduce virally induced tissue damage and improve heart function. METHODS: In the present study we have investigated the role of translational suppression in the context of an IFN-alpha/beta-mediated antiviral immune response to CVB3 infection. Specifically, we examined the effects of IFN-alpha/beta treatment of CVB3-infected mouse embryonic fibroblast cells and splenocytes lacking eukaryotic initiation factor 4E binding protein-1 (4E-BP1), a suppressor of 5'-capped mRNA translation. Extending these in vitro studies, we examined the effects of CVB3 infection and IFN-beta treatment in 4E-BP1(-/-) mice. RESULTS: Our data show that 4E-BP1(-/-) cells are more -sensitive to the antiviral effects of IFN-alpha4 and IFN-beta treatment than 4E-BP1(+/+) cells when infected with CVB3. Similarly, 4E BP1(-/-) mice are more sensitive to treatment with IFN-beta, exhibiting lower viral titres in heart tissue than 4E-BP1(+/+) mice during the course of infection. Additionally, we demonstrate that treatment with IFN-beta reduces inflammatory infiltrates into the hearts of infected mice. CONCLUSIONS: These data identify 4E-BP1 as a novel drug target to augment responsiveness to IFN-beta therapy in CVB3-induced myocarditis. PMID- 21685546 TI - HBV primary drug resistance in newly diagnosed HIV-HBV-coinfected individuals in Spain. AB - BACKGROUND: The wide use of lamivudine (3TC) as oral therapy for chronic HBV infection has favoured the selection and circulation of 3TC-resistant HBV strains worldwide. Although transmission of 3TC-resistant HBV variants has been reported only sporadically, few studies have been conducted in the HIV population where exposure to 3TC has been greater forming part of antiretroviral therapy (ART) regimens. METHODS: All individuals positive for serum hepatitis B surface antigen (HBsAg), newly diagnosed with HIV-1 infection, naive to ART and enrolled in the Spanish HIV cohort (CoRIS) since 2004 were identified. The HBV polymerase gene was sequenced and drug resistance mutations were characterized retrospectively in stored frozen plasma specimens. RESULTS: From 4,419 ART-naive HIV-1-infected individuals, 223 (5.1%) were positive for serum HBsAg. Baseline stored sera were available for 84 patients, of whom 73 could be characterized virologically. This population was mainly represented by men who had sex with men (52.1%), native Spaniards (65.7%) and Latin Americans (16.4%). The mean age was 36 years, mean CD4(+) T-cell count 375 cells/mm(3) and mean plasma HIV RNA 4.5 log(10) copies/ml. The HBV genotype distribution was 64% A, 20% F, 12% D and 4% others. Drug-resistant mutations in the HBV polymerase were found in four (5.5%) patients: two harboured rtL180M, one rtL80V and one rtV173L. CONCLUSIONS: The rate of primary drug resistance in HBV among newly diagnosed HIV-HBV-coinfected patients in Spain is currently low (5.5%) and restricted to 3TC. Thus, HBV drug resistance testing before prescription of oral antiviral therapy is not warranted, although periodic surveillance might be recommended. PMID- 21685547 TI - Pre-existing albuminuria predicts AIDS and non-AIDS mortality in women initiating antiretroviral therapy. AB - BACKGROUND: We previously reported an increased risk of all-cause and AIDS mortality among HIV-infected women with albuminuria (proteinuria or microalbuminuria) enrolled in the Women's Interagency HIV Study (WIHS) prior to the introduction of HAART. METHODS: The current analysis includes 1,073 WIHS participants who subsequently initiated HAART. Urinalysis for proteinuria and semi-quantitative testing for microalbuminuria from two consecutive study visits prior to HAART initiation were categorized as follows: confirmed proteinuria (both specimens positive for protein), confirmed microalbuminuria (both specimens positive with at least one microalbuminuria), unconfirmed albuminuria (one specimen positive for proteinuria or microalbuminuria), or negative (both specimens negative). Time from HAART initiation to death was modelled using proportional hazards analysis. RESULTS: Compared with the reference group of women with two negative specimens, the hazard ratio (HR) for all-cause mortality was significantly increased for women with confirmed microalbuminuria (HR 1.9, 95% CI 1.2-2.9). Confirmed microalbuminuria was also independently associated with AIDS death (HR 2.3, 95% CI 1.3-4.3), whereas women with confirmed proteinuria were at increased risk for non-AIDS death (HR 2.4, 95% CI 1.2-4.6). CONCLUSIONS: In women initiating HAART, pre-existing microalbuminuria independently predicted increased AIDS mortality, whereas pre-existing proteinuria predicted increased risk of non-AIDS death. Urine testing may identify HIV-infected individuals at increased risk for mortality even after the initiation of HAART. Future studies should consider whether these widely available tests can identify individuals who would benefit from more aggressive management of HIV infection and comorbid conditions associated with mortality in this population. PMID- 21685548 TI - Neuraminidase of 2007-2008 influenza A(H1N1) viruses shows increased affinity for sialic acids due to the D344N substitution. AB - BACKGROUND: During the 2007-2008 season, A(H1N1) viruses naturally resistant to oseltamivir due to an H275Y substitution in the neuraminidase emerged and spread in the human population. The neuraminidase of 2007-2008 A(H1N1) viruses has an increased affinity for sialic acids as compared with the N1 of previously circulating viruses. METHODS: Using site-directed mutagenesis analysis and an enzymatic assay on cells transiently expressing the viral neuraminidase, the amino acid changes that could account for the particular enzymatic properties of the neuraminidase of 2007-2008 A(H1N1) viruses were explored. The affinity for the substrate (K(m)) and the inhibition constants for inhibitors (K(i)) were determined for wild-type and mutated neuraminidases. Reverse genetics was used to produce 6:2 reassortant viruses expressing haemagglutinin and neuraminidase derived from A(H1N1) viruses of the 2007-2008 season or from a previously circulating H1N1 virus, in an A/WSN/33 background. RESULTS: The D344N substitution characteristic of the N1 of 2007-2008 A(H1N1) viruses was identified as a major determinant of its increased affinity for sialic acids. According to the viral plaque phenotype of the 6:2 reassortant viruses, the H275Y mutation was deleterious when the surface glycoproteins were derived from the H1N1 virus isolated in 2004, but not when they were derived from A(H1N1) viruses of the 2007 2008 season. CONCLUSIONS: The D344N substitution, by modifying the enzymatic property of the N1, may have favoured the emergence and spread of viruses naturally resistant to oseltamivir. PMID- 21685549 TI - Lactic acidosis and symptomatic hyperlactataemia in a randomized trial of first line therapy in HIV-infected adults in South Africa. AB - BACKGROUND: Lactic acidosis (LA) is a potentially life-threatening complication of antiretroviral (ARV) therapy. Few randomized prospective studies have compared LA between different ARV regimens. METHODS: Characterization of cases of LA (serum lactate >5 mmol/l and arterial pH<7.35 or bicarbonate <20 mmol/l) and symptomatic hyperlactataemia (SH; serum lactate >2.2 mmol/l and symptoms) was made in a randomized open-label 2*2 factorial study of stavudine/lamivudine (d4T/3TC)-based versus didanosine/zidovudine-based therapy and lopinavir/ritonavir-based versus efavirenz (EFV)-based therapy in 1,771 HIV infected adults initiating therapy between 2004 and 2008. RESULTS: The LA incident rate was 3.5/1,000 person-years (95% CI 1.8-5.9), and for combined LA/SH was 11.0/1,000 person-years (95% CI 7.9-14.9). There were two deaths (15% mortality) among 13 LA cases; all 11 survivors experienced symptom resolution and started new ARV regimens. LA cases were more likely to be female (OR 7.19, 95% CI 1.84-40.75; P=0.001) and had a higher body mass index (BMI; P<0.0001) compared with non-cases. There was no increase in LA according to ARV regimen, age or CD4(+) T-cell count at randomization. When combined, LA/SH cases (n=41) were more often female (OR 4.76, 95% CI 2.36-10.08; P<0.0001), had increased BMI (P<0.0001), were more likely to be assigned d4T/3TC (OR 3.17, 95% CI 1.50-7.28; P=0.001) and were more likely to be assigned EFV (OR 2.18, 95% CI 1.08-4.61; P=0.026). CONCLUSIONS: Female sex and increased BMI were associated with severe LA in this large randomized trial of first-line ARV in South Africa. While female sex, increased BMI and d4T are previously described risk factors for the development of clinically significant lactate elevations, the independent risk associated with EFV is a novel observation warranting further investigation. PMID- 21685550 TI - Pleconaril-resistant chronic parechovirus-associated enteropathy in agammaglobulinaemia. AB - A 14 year old common variable immunodeficiency patient developed severe protein losing enteropathy. A chronic enteral infection with human parechovirus type 1 and norovirus was diagnosed. Treatment strategies aimed at virus eradication and providing supportive care were ineffective. The antipicornavirus agent pleconaril did not have any effect on viral replication. Symptoms improved on immunosuppressive therapy, suggesting infection-related immune dysregulation in an immunocompromised host. PMID- 21685551 TI - NS3 protease of genotype 3 subtype h HCV identified in southeastern France. AB - HCV displays considerable levels of nucleotide and amino acid diversity. Recently, the relevance of natural polymorphisms in worldwide isolates has been addressed in view of future protease inhibitor (PI)-based treatments; genotype- and subtype-specific natural polymorphisms within HCV NS3 protease were identified at amino acid sites associated either with resistance to PIs or with compensatory mutations. Here, we describe a case of chronic infection with HCV of genotype 3 subtype h (HCV-3h), formerly only described from three patients originating from Somalia, and we provide the first NS3 protease sequence for such strains. NS3 protease sequences of HCV-3h recovered in the present study harbour specific amino acid residues not encountered in other reference HCV genotypes and subtypes at nine of the 181 NS3 protease positions; none of these amino acids are known to confer resistance to PIs. Of note, 5' untranslated region sequence-based genotyping classifies them into genotype 1. PMID- 21685552 TI - Transport properties in ferromagnetic Josephson junctions between triplet superconductors. AB - Charge and spin Josephson currents in a ballistic superconductor-ferromagnet superconductor junction with spin-triplet pairing symmetry are studied using the quasiclassical Eilenberger equation. The gap vector of superconductors has an arbitrary relative angle with respect to magnetization of the ferromagnetic layer. We clarify the effects of the thickness of the ferromagnetic layer and the magnitude of the magnetization on the Josephson charge and spin currents. We find that the 0-pi transition can occur when the misorientation angle between the exchange field of the ferromagnetic layer and the d-vector is smaller than pi/4. We also show how spin current flows due to misorientation between the exchange field and the d-vector. PMID- 21685553 TI - Extended dynamic spin-fluctuation theory of metallic magnetism. AB - A dynamic spin-fluctuation theory that directly takes into account nonlocality of thermal spin fluctuations and their mode-mode interactions is developed. The Gaussian approximation in the theory is improved by a self-consistent renormalization of the mean field and spin susceptibility due to the third-and fourth-order terms of the free energy, respectively. This eliminates the fictitious first-order phase transition, which is typical for the Gaussian approximation, and yields a proper second-order phase transition. The effect of nonlocal spin correlations is enhanced by taking into account uniform fluctuations in the single-site mean Green function. Explicit computational formulae for basic magnetic characteristics are obtained. The extended theory is applied to the calculation of magnetic properties of Fe-Ni Invar. Almost full agreement with experiment is achieved for the magnetization, Curie temperature, and local and effective magnetic moments. PMID- 21685554 TI - Wavepacket scattering of Dirac and Schrodinger particles on potential and magnetic barriers. AB - We investigate the dynamics of a charged particle moving in a graphene layer and in a two-dimensional electron gas, where it obeys the Dirac and the Schrodinger equations, respectively. The charge carriers are described as Gaussian wavepackets. The dynamics of the wavepackets is studied numerically by solving both quantum-mechanical and relativistic equations of motion. The scattering of such wavepackets by step-like magnetic and potential barriers is analysed for different values of wavepacket energy and width. We find: (1) that the average position of the wavepacket does not coincide with the classical trajectory, and (2) that, for slanted incidence, the path of the centre of mass of the wavepacket does not have to penetrate the barrier during the scattering process. Trembling motion of the charged particle in graphene is observed in the absence of an external magnetic field and can be enhanced by a substrate-induced mass term. PMID- 21685555 TI - Compositional dependence of the thermoelectric properties of (Sr(x)Ba(x)Yb1 2x)(y)Co4Sb12 skutterudites. AB - High temperature thermoelectric (TE) properties for triple-filled skutterudites (Sr(x)Ba(x)Yb1-2x)(y)Co4Sb12 were investigated for alloy compositions in two sections of the system: (a) for x = 0.25 with a filling fraction y ranging from 0.1 to 0.25 and (b) for 0 < x < 0.5 and y = 0.11 + 0.259x. The representation of the figure of merit, ZT, as a function of skutterudite composition, defined the compositional range (0.25 < x < 0.4; 0.18 < y < 0.24) with ZT over 1.4 at 800 K. It was shown that an enhanced TE performance for these triple-filled skutterudites is caused by low electrical resistivities and low lattice thermal conductivities, as well as by a fine tuning of the chemical composition. Low temperature measurements for the samples with the highest ZT values showed that even a small change of the filler ratios changes the contribution of scattering effects, the carrier concentration and the mobility. PMID- 21685556 TI - High pressure ferroelastic phase transition in SrTiO3. AB - High pressure measurements of the ferroelastic phase transition of SrTiO3 (Guennou et al 2010 Phys. Rev. B 81 054115) showed a linear pressure dependence of the transition temperature between the cubic and tetragonal phase. Furthermore, the pressure induced transition becomes second order while the temperature dependent transition is near a tricritical point. The phase transition mechanism is characterized by the elongation and tilt of the TiO6 octahedra in the tetragonal phase, which leads to strongly nonlinear couplings between the structural order parameter, the volume strain and the applied pressure. The phase diagram is derived from the Clausius-Clapeyron relationship and is directly related to a pressure dependent Landau potential. The nonlinearities of the pressure dependent strains lead to an increase of the fourth order Landau coefficient with increasing pressure and, hence, to a tricritical-second order crossover. This behaviour is reminiscent of the doping related crossover in isostructural KMnF3. PMID- 21685557 TI - Probing near-surface nanoscale mechanical properties of low modulus materials using a quartz crystal resonator atomic force microscope. AB - We describe the development of a technique for making indentations on the top 5 20 nm of the surfaces of relatively low modulus materials using a high spatial and force sensitivity atomic force microscope (AFM) whose optical cantilever has been replaced by a quartz crystal resonator (QCR). Unlike conventional optical cantilever-based AFMs, the accuracy of this technique is not compromised by the compliance of the loading system due to the high stiffness of the QCR. To obtain material modulus values from the indentation results, we find the commonly used Oliver-Pharr model to be unsuitable because of our use of a sharp tip and relatively deep indentation. Instead, we develop a new analysis that may be more appropriate for the geometry we use as well as the non-linear constitutive behavior exhibited by the materials we examined. We calculated values for the moduli of several different materials, which we find to be consistent with the range of published data. PMID- 21685558 TI - Polymer-ultrathin graphite sheet-polymer composite structured flexible nonvolatile bistable organic memory devices. AB - We present data, which were obtained before bending and after bending, for the electrical bistabilities, memory stabilities, and memory mechanisms of three layer structured flexible bistable organic memory (BOM) devices, which were fabricated utilizing the ultrathin graphite sheets (UGS) sandwiched between insulating poly(methylmethacrylate) (PMMA) polymer layers. The UGS were formed by transferring UGS (about 30 layers) and using a simple spin-coating technique. Transmission electron microscopy (TEM) measurements were performed to investigate the microstructural properties of the PMMA/UGS/PMMA films. Current-voltage (I-V) measurements were carried out to investigate the electrical properties of the BOM devices containing the UGS embedded in the PMMA polymer. Current-time (I-t) and current-cycle measurements under flat and bent conditions were performed to investigate the memory stabilities of the BOM devices. The memory characteristics of the BOM maintained similar device efficiencies after bending and were stable during repeated bendings of the BOM devices. The mechanisms for these characteristics of the fabricated BOM are described on the basis of the I-V results. PMID- 21685559 TI - 'Sub-atomic' resolution of non-contact atomic force microscope images induced by a heterogeneous tip structure: a density functional theory study. AB - A Si adatom on a Si(111)-(7 * 7) reconstructed surface is a typical atomic feature that can rather easily be imaged by a non-contact atomic force microscope (nc-AFM) and can be thus used to test the atomic resolution of the microscope. Based on our first principles density functional theory (DFT) calculations, we demonstrate that the structure of the termination of the AFM tip plays a decisive role in determining the appearance of the adatom image. We show how the AFM image changes depending on the tip-surface distance and the composition of the atomic apex at the end of the tip. We also demonstrate that contaminated tips may give rise to image patterns displaying so-called 'sub-atomic' features even in the attractive force regime. PMID- 21685560 TI - Petri nets and the simulation of metabolic networks. PMID- 21685561 TI - Quantitative modeling of biochemical networks. AB - Today different database systems for molecular structures (genes and proteins) and metabolic pathways are available. All these systems are characterized by the static data representation. For progress in biotechnology, the dynamic representation of this data is important. The metabolism can be characterized as a complex biochemical network. Different models for the quantitative simulation of biochemical networks are discussed, but no useful formalization is available. This paper shows that the theory of Petrinets is useful for the quantitative modeling of biochemical networks. PMID- 21685562 TI - Topological analysis of metabolic networks based on petri net theory. AB - Petri net concepts provide additional tools for the modelling of metabolic networks. Here, the similarities between the counterparts in traditional biochemical modelling and Petri net theory are discussed. For example the stoichiometry matrix of a metabolic network corresponds to the incidence matrix of the Petri net. The flux modes and conservation relations have the T invariants, respectively, P-invariants as counterparts. We reveal the biological meaning of some notions specific to the Petri net framework (traps, siphons, deadlocks, liveness). We focus on the topological analysis rather than on the analysis of the dynamic behaviour. The treatment of external metabolites is discussed. Some simple theoretical examples are presented for illustration. Also the Petri nets corresponding to some biochemical networks are built to support our results. For example, the role of triose phosphate isomerase (TPI) in Trypanosoma brucei metabolism is evaluated by detecting siphons and traps. All Petri net properties treated in this contribution are exemplified on a system extracted from nucleotide metabolism. PMID- 21685563 TI - Quantitative petri net model of gene regulated metabolic networks in the cell. AB - A method to exploit hybrid Petri nets (HPN) for quantitatively modeling and simulating gene regulated metabolic networks is demonstrated. A global kinetic modeling strategy and Petri net modeling algorithm are applied to perform the bioprocess functioning and model analysis. With the model, the interrelations between pathway analysis and metabolic control mechanism are outlined. Diagrammatical results of the dynamics of metabolites are simulated and observed by implementing a HPN tool, Visual Object Net ++. An explanation of the observed behavior of the urea cycle is proposed to indicate possibilities for metabolic engineering and medical care. Finally, the perspective of Petri nets on modeling and simulation of metabolic networks is discussed. PMID- 21685564 TI - Petri nets for steady state analysis of metabolic systems. AB - Computer assisted analysis and simulation of biochemical pathways can improve the understanding of the structure and the dynamics of cell processes considerably. The construction and quantitative analysis of kinetic models is often impeded by the lack of reliable data. However, as the topological structure of biochemical systems can be regarded to remain constant in time, a qualitative analysis of a pathway model was shown to be quite promising as it can render a lot of useful knowledge, e. g., about its structural invariants. The topic of this paper are pathways whose substances have reached a dynamic concentration equilibrium (steady state). It is argued that appreciated tools from biochemistry and also low-level Petri nets can yield only part of the desired results, whereas executable high-level net models lead to a number of valuable additional insights by combining symbolic analysis and simulation. PMID- 21685565 TI - Biopathways representation and simulation on hybrid functional petri net. AB - The following two matters should be resolved in order for biosimulation tools to be accepted by users in biology/medicine: (1) remove issues which are irrelevant to biological importance, and (2) allow users to represent biopathways intuitively and understand/manage easily the details of representation and simulation mechanism. From these criteria, we firstly define a novel notion of Petri net called Hybrid Functional Petri Net (HFPN). Then, we introduce a software tool, Genomic Object Net, for representing and simulating biopathways, which we have developed by employing the architecture of HFPN. In order to show the usefulness of Genomic Object Net for representing and simulating biopathways, we show two HFPN representations of gene regulation mechanisms of Drosophila melanogaster (fruit fly) circadian rhythm and apoptosis induced by Fas ligand. The simulation results of these biopathways are also correlated with biological observations. The software is available to academic users from http://www.GenomicObject.Net/. PMID- 21685566 TI - Constructing biological pathway models with hybrid functional petri nets. AB - In many research projects on modeling and analyzing biological pathways, the Petri net has been recognized as a promising method for representing biological pathways. From the pioneering works by Reddy et al., 1993, and Hofestadt, 1994, that model metabolic pathways by traditional Petri net, several enhanced Petri nets such as colored Petri net, stochastic Petri net, and hybrid Petri net have been used for modeling biological phenomena. Recently, Matsuno et al., 2003b, introduced the hybrid functional Petri net (HFPN) in order to give a more intuitive and natural modeling method for biological pathways than these existing Petri nets. Although the paper demonstrates the effectiveness of HFPN with two examples of gene regulation mechanism for circadian rhythms and apoptosis signaling pathway, there has been no detailed explanation about the method of HFPN construction for these examples. The purpose of this paper is to describe method to construct biological pathways with the HFPN step-by-step. The method is demonstrated by the well-known glycolytic pathway controlled by the lac operon gene regulatory mechanism. PMID- 21685567 TI - STEPP - Search Tool for Exploration of Petri net Paths: A New Tool for Petri Net Based Path Analysis in Biochemical Networks. AB - To understand biochemical processes caused by, e.g., mutations or deletions in the genome, the knowledge of possible alternative paths between two arbitrary chemical compounds is of increasing interest for biotechnology, pharmacology, medicine, and drug design. With the steadily increasing amount of data from high throughput experiments new biochemical networks can be constructed and existing ones can be extended, which results in many large metabolic, signal transduction, and gene regulatory networks. The search for alternative paths within these complex and large networks can provide a huge amount of solutions, which can not be handled manually. Moreover, not all of the alternative paths are generally of interest. Therefore, we have developed and implemented a method, which allows us to define constraints to reduce the set of all structurally possible paths to the truly interesting path set. The paper describes the search algorithm and the constraints definition language. We give examples for path searches using this dedicated special language for a Petri net model of the sucrose-to-starch breakdown in the potato tuber. AVAILABILITY: http://sanaga.tfh-berlin.de/~stepp/ PMID- 21685568 TI - Ontology based standardization of petri net modeling for signaling pathways. AB - Taking account of the great availability of Petri nets in modeling and analyzing large complicated signaling networks, semantics of Petri nets is in need of systematization for the purpose of consistency and reusability of the models. This paper reports on standardization of units of Petri nets on the basis of an ontology that gives an intrinsic definition to the process of signaling in signaling pathways. PMID- 21685569 TI - Simulation-Based Validation of the p53 Transcriptional Activity with Hybrid Functional Petri Net. AB - MDM2 and p19ARF are essential proteins in cancer pathways forming a complex with protein p53 to control the transcriptional activity of protein p53. It is confirmed that protein p53 loses its transcriptional activity by forming the functional dimer with protein MDM2. However, it is still unclear that protein p53 keeps its transcriptional activity when it forms the trimer with proteins MDM2 and p19ARF. We have observed mutual behaviors among genes p53, MDM2, p19ARF and their products on a computational model with hybrid functional Petri net (HFPN) which is constructed based on information described in the literature. The simulation results suggested that protein p53 should have the transcriptional activity in the forms of the trimer of proteins p53, MDM2, and p19ARF. This paper also discusses the advantages of HFPN based modeling method in terms of pathway description for simulations. PMID- 21685570 TI - Analyzing stationary States of gene regulatory network using petri nets. AB - We introduce and formally define the notion of a stationary state for Petri nets. We also propose a fully automatic method for finding such states. The procedure makes use of the Presburger arithmetic to describe all the stationary states. Finally we apply this novel approach to find stationary states of a gene regulatory network describing the flower morphogenesis of A. thaliana. This shows that the proposed method can be successfully applied in the study of biological systems. PMID- 21685571 TI - Cell illustrator 4.0: a computational platform for systems biology. AB - Cell Illustrator is a software platform for Systems Biology that uses the concept of Petri net for modeling and simulating biopathways. It is intended for biological scientists working at bench. The latest version of Cell Illustrator 4.0 uses Java Web Start technology and is enhanced with new capabilities, including: automatic graph grid layout algorithms using ontology information; tools using Cell System Markup Language (CSML) 3.0 and Cell System Ontology 3.0; parameter search module; high-performance simulation module; CSML database management system; conversion from CSML model to programming languages (FORTRAN, C, C++, Java, Python and Perl); import from SBML, CellML, and BioPAX; and, export to SVG and HTML. Cell Illustrator employs an extension of hybrid Petri net in an object-oriented style so that biopathway models can include objects such as DNA sequence, molecular density, 3D localization information, transcription with frame-shift, translation with codon table, as well as biochemical reactions. PMID- 21685572 TI - Modeling of Cell-to-Cell Communication Processes with Petri Nets Using the Example of Quorum Sensing. AB - The understanding of the molecular mechanism of cell-to-cell communication is fundamental for system biology. Up to now, the main objectives of bioinformatics have been reconstruction, modeling and analysis of metabolic, regulatory and signaling processes, based on data generated from high-throughput technologies. Cell-to-cell communication or quorum sensing (QS), the use of small molecule signals to coordinate complex patterns of behavior in bacteria, has been the focus of many reports over the past decade. Based on the quorum sensing process of the organism Aliivibrio salmonicida, we aim at developing a functional Petri net, which will allow modeling and simulating cell-to-cell communication processes. Using a new editor-controlled information system called VANESA (http://vanesa.sf.net), we present how to combine different fields of studies such as life-science, database consulting, modeling, visualization and simulation for a semi-automatic reconstruction of the complex signaling quorum sensing network. We show how cell-to-cell communication processes and information-flow within a cell and across cell colonies can be modeled using VANESA and how those models can be simulated with Petri net network structures in a sophisticated way. PMID- 21685573 TI - On determining firing delay time of transitions for petri net based signaling pathways by introducing stochastic decision rules. AB - Parameter determination is important in modeling and simulating biological pathways including signaling pathways. Parameters are determined according to biological facts obtained from biological experiments and scientific publications. However, such reliable data describing detailed reactions are not reported in most cases. This prompted us to develop a general methodology of determining the parameters of a model in the case of that no information of the underlying biological facts is provided. In this study, we use the Petri net approach for modeling signaling pathways, and propose a method to determine firing delay times of transitions for Petri net models of signaling pathways by introducing stochastic decision rules. Petri net technology provides a powerful approach to modeling and simulating various concurrent systems, and recently have been widely accepted as a description method for biological pathways. Our method enables to determine the range of firing delay time which realizes smooth token flows in the Petri net model of a signaling pathway. The availability of this method has been confirmed by the results of an application to the interleukin-1 induced signaling pathway. PMID- 21685574 TI - Impact of delays and noise on dopamine signal transduction. AB - Dopamine is a critical neurotransmitter for the normal functioning of the central nervous system. Abnormal dopamine signal transmission in the brain has been implicated in diseases such as Parkinson's disease (PD) and schizophrenia, as well as in various types of drug addition. It is therefore important to understand the dopamine signaling dynamics in the presynaptic neuron of the striatum and the synaptic cleft, where dopamine synthesis, degradation, compartmentalization, release, reuptake, and numerous regulatory processes occur. The biochemical and biological processes governing this dynamics consist of interacting discrete and continuous components, operate at different time scales, and must function effectively in spite of intrinsic stochasticity and external perturbations. Not fitting into the realm of purely deterministic phenomena, the hybrid nature of the system requires special means of mathematical modeling, simulation and analysis. We show here how hybrid functional Petri-nets (HFPNs) and the software Cell Illustrator(r) facilitate computational analyses of systems that simultaneously contain deterministic, stochastic, and delay components. We evaluate the robustness of dopamine signaling in the presence of delays and noise and discuss implications for normal and abnormal states of the system. PMID- 21685575 TI - Role of mRNA Gestation and Senescence in Noise Reduction during the Cell Cycle. AB - Recent innovations in experimental techniques on single molecule detection resulted in advances in the quantification of molecular noise in several systems, and provide suitable data for defining stochastic computational models of biological processes. Some of the latest stochastic models of cell cycle regulation analyzed the effect of noise on cell cycle variability. In their study, Kar et al. (Proc. Natl. Acad. Sci. USA 106, 6471-6476, 2009) found that the observed variances of cell cycle time and cell division size distributions cannot be matched with the measured long half-lives of mRNAs. Here, we investigate through modeling and simulation how the noise created by the transcription and degradation processes of a key cell cycle controller mRNA affect the statistics of cell cycle time and cell size at division. Our model consists of an encoding of the model of Kar et al. into a stochastic Petri net, with the extensions necessary to represent multiple synthesis (gestation) and degradation (senescence) steps in the regulation of mRNAs. We found that few steps of gestation and senescence of mRNA are enough to give a good match for both the measured half-lives and variability of cell cycle-statistics. This result suggests that the complex process of transcription can be more accurately approximated by multi-step linear processes. PMID- 21685576 TI - Exhaustive analysis of the modular structure of the spliceosomal assembly network: a petri net approach. AB - Spliceosomes are macro-complexes involving hundreds of proteins with many functional interactions. Spliceosome assembly belongs to the key processes that enable splicing of mRNA and modulate alternative splicing. A detailed list of factors involved in spliceosomal reactions has been assorted over the past decade, but, their functional interplay is often unknown and most of the present biological models cover only parts of the complete assembly process. It is a challenging task to build a computational model that integrates dispersed knowledge and combines a multitude of reaction schemes proposed earlier. Because for most reactions involved in spliceosome assembly kinetic parameters are not available, we propose a discrete modeling using Petri nets, through which we are enabled to get insights into the system's behavior via computation of structural and dynamic properties. In this paper, we compile and examine reactions from experimental reports that contribute to a functional spliceosome. All these reactions form a network, which describes the inventory and conditions necessary to perform the splicing process. The analysis is mainly based on system invariants. Transition invariants (T-invariants) can be interpreted as signaling routes through the network. Due to the huge number of T-invariants that arise with increasing network size and complexity, maximal common transition sets (MCTS) and T-clusters were used for further analysis. Additionally, we introduce a false color map representation, which allows a quick survey of network modules and the visual detection of single reactions or reaction sequences, which participate in more than one signaling route. We designed a structured model of spliceosome assembly, which combines the demands on a platform that i) can display involved factors and concurrent processes, ii) offers the possibility to run computational methods for knowledge extraction, and iii) is successively extendable as new insights into spliceosome function are reported by experimental reports. The network consists of 161 transitions (reactions) and 140 places (reactants). All reactions are part of at least one of the 71 T-invariants. These T-invariants define pathways, which are in good agreement with the current knowledge and known hypotheses on reaction sequences during spliceosome assembly, hence contributing to a functional spliceosome. We demonstrate that present knowledge, in particular of the initial part of the assembly process, describes parallelism and interaction of signaling routes, which indicate functional redundancy and reflect the dependency of spliceosome assembly initiation on different cellular conditions. The complexity of the network is further increased by two switches, which introduce alternative routes during A-complex formation in early spliceosome assembly and upon transition from the B-complex to the C complex. By compiling known reactions into a complete network, the combinatorial nature of invariant computation leads to pathways that have previously not been described as connected routes, although their constituents were known. T-clusters divide the network into modules, which we interpret as building blocks in spliceosome maturation. We conclude that Petri net representations of large biological networks and system invariants, are well-suited as a means for validating the integration of experimental knowledge into a consistent model. Based on this network model, the design of further experiments is facilitated. PMID- 21685577 TI - Modelling the Molecular Interactions in the Flower Developmental Network of Arabidopsis thaliana. AB - We present a dynamical model of the gene network controlling flower development in Arabidopsis thaliana. The network is centered at the regulation of the floral organ identity genes (AP1, AP2, AP3, PI and AG) and ends with the transcription factor complexes responsible for differentiation of floral organs. We built and simulated the regulatory interactions that determine organ specificity using an extension of hybrid Petri nets as implemented in Cell Illustrator. The network topology is characterized by two main features: (1) the presence of multiple autoregulatory feedback loops requiring the formation of protein complexes, and (2) the role of spatial regulators determining floral patterning. The resulting network shows biologically coherent expression patterns for the involved genes, and simulated mutants produce experimentally validated changes in organ expression patterns. The requirement of heteromeric higher-order protein complex formation for positive autoregulatory feedback loops attenuates stochastic fluctuations in gene expression, enabling robust organ-specific gene expression patterns. If autoregulation is mediated by monomers or homodimers of proteins, small variations in initial protein levels can lead to biased production of homeotic proteins, ultimately resulting in homeosis. We also suggest regulatory feedback loops involving miRNA loci by which homeotic genes control the activity of their spatial regulators. PMID- 21685579 TI - "Initiate-build-operate-transfer" - a strategy for establishing sustainable telemedicine programs not only in the developing countries. AB - Establishing sustainable telemedicine has become a goal of many developing countries around the world. Yet, despite initiatives from a select few individuals and on occasion from various governments, often these initiatives never mature to become sustainable programs. The introduction of telemedicine and e-learning in the Balkans has been a pivotal step in advancing the quality and availability of medical services in a region whose infrastructure and resources have been decimated by wars, neglect, lack of funding, and poor management. The concept and establishment of the International Virtual e-Hospital (IVeH) has significantly impacted telemedicine and e-health services in Kosova. The success of the IVeH in Kosova has led to the development of similar programs in other Balkan countries and other developing countries in the hope of modernizing and improving their healthcare infrastructure. A comprehensive, four-pronged strategy developed by IVeH "Initiate-Build-Operate-Transfer" (IBOT), may be a useful approach in establishing telemedicine and e-health educational services not only in developing countries, but in developed countries. The development strategy, IBOT, used by the IVeH to establish and develop telemedicine programs is described. IBOT includes assessment of healthcare needs of each country, the development of a curriculum and education program, the establishment of a nationwide telemedicine network, and the integration of the telemedicine program into the very core of healthcare infrastructure. The end point is the transfer of a sustainable telehealth program to the nation involved. By applying IBOT, a sustainable telemedicine program of Kosova and Albania has been established as an effective prototype for telemedicine in the Balkans. Once fully matured, the program is transitioned to the Ministry of Health, which ensures the sustainability and ownership of the program. Similar programs are being established in Macedonia, Montenegro and other countries around the world. The IBOT model has been effective in creating sustainable telemedicine and e-health integrated programs in the Balkans and may be a good model for establishing such programs in developing countries. PMID- 21685580 TI - Ontologies, knowledge representation, artificial intelligence - hype or prerequisites for international pHealth Interoperability? AB - Nowadays, eHealth and pHealth solutions have to meet advanced interoperability challenges. Enabling pervasive computing and even autonomic computing, pHealth system architectures cover many domains, scientifically managed by specialized disciplines using their specific ontologies. Therefore, semantic interoperability has to advance from a communication protocol to an ontology coordination challenge including semantic integration, bringing knowledge representation and artificial intelligence on the table. The resulting solutions comprehensively support multi-lingual and multi-jurisdictional environments. PMID- 21685581 TI - E-health in graduate and postgraduate medical education: illusions, expectations and reality. AB - With the overall growth of informatics, the medical education system should also provide programs at both graduate and post-graduate levels. While there is a wide consensus as to the importance of this urgent need, several factors slow down the construction and operation of effective education programs in medical and nursing schools. The increasing need for better and more comprehensive training in informatics is strongly limited by several factors including undefined output skills, tight time frame etc. An efficient development of partnerships within the health care system assumes that all professionals involved must possess strong informatics and interpersonal knowledge, and skills reaching beyond their own individual fields. There is an emerging need to define the basic skills and knowledge for each level of the health care education. Trans-border cooperation offers a unique opportunity for the establishment of common criteria for basic skills and knowledge, via joint discussions, collaborative thinking and concerted action. PMID- 21685582 TI - A knowledge management system to study the quality of life in head and neck oncology patients. AB - The perception that an individual holds about his place in life, which depends upon his culture and values, defines this individual's Quality of Life (QoL). When applied in a health context this known as: Health-Related Quality of Life (HRQoL). The assessment of HRQoL is a Medical goal; it is used in clinical research, medical practice, health-related economic studies and in planning health management measures and strategies. Obtaining a patient self-assessment with QoL measuring instruments on the platform developed in this project, through user-friendly software, aids the study, promotes the creation of databases, and accelerates its statistical treatment. The possibility of graphically representing results that physician needs to analyze, immediately after the answer collection, makes this assessment a diagnosis instrument ready to be used routinely in clinical practice. Knowledge Management Systems (KMS) applied to this context enable knowledge creation and storage, and guide therapeutic decisions. PMID- 21685583 TI - Detection of nicotine content impact in tobacco manufacturing using computational intelligence. AB - A study is presented for the detection of nicotine impact in different cigarette type, using recorded data and Computational Intelligence techniques. Recorded puffs are processed using Continuous Wavelet Transform and used to extract time frequency features for normal and abnormal puffs conditions. The wavelet energy distributions are used as inputs to classifiers based on Adaptive Neuro-Fuzzy Inference Systems (ANFIS) and Genetic Algorithms (GAs). The number and the parameters of Membership Functions are used in ANFIS along with the features from wavelet energy distributionare selected using GAs, maximising the diagnosis success. GA with ANFIS (GANFIS) are trained with a subset of data with known nicotine conditions. The trained GANFIS are tested using the other set of data (testing data). A classical method by High-Performance Liquid Chromatography is also introduced to solve this problem, respectively. The results as well as the performances of these two approaches are compared. A combination of these two algorithms is also suggested to improve the efficiency of this solution procedure. Computational results show that this combined algorithm is promising. PMID- 21685585 TI - Extracting clinical information to support medical decision based on standards. AB - The paper presents a method connecting medical databases to a medical decision system, and describes a service created to extract the necessary information that is transferred based on standards. The medical decision can be improved based on many inputs from different medical locations. The developed solution is described for a concrete case concerning the management for chronic pelvic pain, based on the information retrieved from diverse healthcare databases. PMID- 21685584 TI - Creating ISO/EN 13606 archetypes based on clinical information needs. AB - Archetypes model individual EHR contents and build the basis of the dual-model approach used in the ISO/EN 13606 EHR architecture. We present an approach to create archetypes using an iterative development process. It includes automated generation of electronic case report forms from archetypes. We evaluated our approach by developing 128 archetypes which represent 446 clinical information items from the diabetes domain. PMID- 21685586 TI - eHealth in Switzerland - building consensus, awareness and architecture. AB - This paper reports on the process of the Swiss national strategy to define and implement eHealth. Switzerland is a federal political organization with 26 cantons that are autonomous for the health legal framework. Switzerland must also provide support for four national languages. Thus, this experience addresses many challenges that are experienced at the European level in a much larger scale. Also, Switzerland benefits from the major projects ongoing in Europe, such as epSOS, to define its own strategy. PMID- 21685587 TI - Patient empowerment by electronic health records: first results of a systematic review on the benefit of patient portals. AB - Patient portals provide patients with access to a provide-managed electronic health record (EHR). They may provide an interesting approach to increase patient empowerment. The objective of this paper is to provide a first overview of the state-of-the-art and the impact of patient portals. Based on a systematic literature search, we identified five evaluation studies on patient portals. These studies demonstrate only little effect of patient portals on patient empowerment. PMID- 21685588 TI - Empowerment of patients over their personal health record implies sharing responsibility with the physician. AB - Through this article, we point out the unavoidable empowerment of patients with regard to their personal health record and propose the mixed management of patients' medical records. This mixed management implies sharing responsibilities between the patient and the Medical Practitioner (MP) by making patients responsible for the validation of their administrative information, and MPs responsible for the validation of their patients' medical information. We propose a solution to gather and update patients' administrative and medical data in order to reconstitute patients' medical histories accurately. This method is based on two processes. The aim of the first process is to provide patients administrative data, in order to know where and when they received care (name of the health structure or health practitioner, type of care: outpatient or inpatient). The aim of the second process is to provide patients' medical information and to validate it under the responsibility of the MP with the help of patients if needed. During these two processes, the patients' privacy will be ensured through cryptographic hash functions like the Secure Hash Algorithm, which allows the pseudonymization of patients' identities. The Medical Record Search Engine we propose will be able to retrieve and to provide upon a request formulated by the MP all the available information concerning a patient who has received care in different health structures without divulging the patient's true identity. Associated with strong traceability of all access, modifications or deletions, our method can lead to improved efficiency of personal medical record management while reinforcing the empowerment of patients over their medical records. PMID- 21685589 TI - Personal information protection - exceptional challenges of integrated systems of eHealth. AB - Informatization has been bringing important, quick and extensive changes into the healthcare environment for years. Individual systems still represent isolated information islands; however, the need for interconnectivity and mutual accessibility has become more pronounced. On the one hand, integration of systems brings numerous, financially measurable advantages, and on the other hand, personal information in such systems becomes more vulnerable. Providing personal information protection is therefore the permanent task of informatisation and, with elimination of national borders and integration of national systems, it is becoming a challenge from the legal, organisational, technical and financial standpoints. PMID- 21685590 TI - XML as a cross-platform representation for medical imaging with fuzzy algorithms. AB - Machines that perform linguistic medical image interpretation are based on fuzzy algorithms. There are several frameworks that can edit and simulate fuzzy algorithms, but they are not compatible with most of the implemented applications. This paper suggests a representation for fuzzy algorithms in XML files, and using this XML as a cross-platform between the simulation framework and the software applications. The paper presents a parsing algorithm that can convert files created by simulation framework, and converts them dynamically into an XML file keeping the original logical structure of the files. PMID- 21685591 TI - Fully connected emergency intervention for the critical home care system. AB - The Critical Home Care System - CHCS, we propose, achieves permanent advising, frequent control appointments and quick reaction to critical conditions by constant remote monitoring of patient's vital signs from the hospital, while staying at his home. Physicians react properly to the developing condition, contacting the patient or a member of the household, or sending an ambulance in an emergency. The CHCS additionally provides constant inspection of the patient's condition to the ambulance doctor in emergency situations and to the urgent centre staff to prepare better for accepting the patient, enabling a fully connected emergency intervention. In this paper we will concentrate on the data flow during the emergency intervention in this highly collaborative system. PMID- 21685592 TI - How to ensure sustainable interoperability in heterogeneous distributed systems through architectural approach. AB - A major obstacle in ensuring ubiquitous information is the utilization of heterogeneous systems in eHealth. The objective in this paper is to illustrate how an architecture for distributed eHealth databases can be designed without lacking the characteristic features of traditional sustainable databases. The approach is firstly to explain traditional architecture in central and homogeneous distributed database computing, followed by a possible approach to use an architectural framework to obtain sustainability across disparate systems i.e. heterogeneous databases, concluded with a discussion. It is seen that through a method of using relaxed ACID properties on a service-oriented architecture it is possible to achieve data consistency which is essential when ensuring sustainable interoperability. PMID- 21685593 TI - A preliminary study on network traffic estimation in using EPR with thin-client computing over wide area network. AB - With the remarkable advantages of thin-client computing (TCC) on security enhancement and cost reduction, the TCC architecture seemed appropriate for EPR utilization in cross-border e-health systems. The advantage in less consumed network bandwidth, however, still remains quantitatively unidentified at present. This study aimed to estimate the network traffic required in using EPR on WAN environments through the comparison of TCC and server-client (SC) models The results indicated that one of representative TCC applications required much less network bandwidth than the conventional SC model. Further studies will be focused on the verification of the adopted scenarios and a combination of applications that would affect the estimation of the network bandwidth. PMID- 21685594 TI - Slovenian practice story: 10 years of e-counselling service for teenagers. AB - This is Me is the largest youth counseling web portal in Slovenia, providing teens with a friendly, simple, fast, free, anonymous and efficient public access to expert information and problem-solving assistance. Network of web counselors includes 38 experts (medical specialists, psychologists, social pedagogues, social workers, and teachers), who are volunteers from 12 different institutions. In the course of ten years, experts have answered almost 21,000 questions about dilemmas and problems faced by teens. The program was created by the Institute of Public Health Celje. This is Me supports adolescents in their problem-solving efforts. The program focuses on development of positive mental health, with emphasis on self-image, social and life skills. The program responds to the adolescents needs and makes efficient use of web technology. Youth web portal is a response to the current teen lifestyle. Most users are between ages of 13 and 18. PMID- 21685595 TI - E-learning for occupational physicians' CME: a study case. AB - The present study reports the results of the evaluation of an e-learning CME course in the field of Occupational Medicine. In particular the following aspects have been investigated: If and how the course contents have met the educational users' needs; The effectiveness of the course in terms of knowledge improvement; Users' behaviour. Attendance data and results of a sample of 1128 attendees have been analyzed via ad hoc developed tools for direct inspection of Moodle CMS database. The results document the effectiveness of the e-learning course, as regards meeting the educational needs of physicians and also the improvement in terms of knowledge and problem solving skill acquisition. Users' behaviour has revealed a certain tendency for passing the tests, more than for pursuing the best possible result. Interaction with the tutor is low. PMID- 21685596 TI - Regional medical data mining system. AB - This paper suggests a solution to acquire medical data from hospitals located in a region (addressing especially the DKMT Euroregion), and then perform data mining. The medical data from the hospital databases are exported in XML format, according to HL7 CDA standard. Afterwards, they are automatically centralized on a server in a database using web services calls. The data will be analyzed with the data mining tool WEKA. Data of interest are converted into ARFF format and loaded into WEKA. The next stage consists in preprocessing and analyzing the data based on the algorithms provided by WEKA, having as a goal several relevant medical conclusions. WEKA application interface has been improved to facilitate the process of performing predictions. PMID- 21685597 TI - Assessment of hospital information systems implementation: a case study. AB - The use of integrated Hospital Information Systems is related with many benefits for the healthcare system, increasing the effectiveness of the provided services and assuring quality of care. Aim of this study is to investigate the types of Information Systems, the level of integration and the problems identified during the implementation phase, in three public hospitals. The above are expected to contribute to the understanding of the organizational, human resource and technical factors related with the successful implementation of a hospital IS. In order to investigate those elements, an assessment questionnaire was developed and completed by nine hospitals IT employees of the three hospitals. In addition, open interviews were organized with the same employees to further formulate an overall aspect, while in one hospital case, observation and discussion with four different categories of involved staff was undertaken. It was found that the implementation problems are mainly related with the underfunding, inadequate use of standards, lack of skilled IT experts, insufficiently trained personnel and users' reserve. The problems may be tackled with a supportive hospital administration committed to the successful implementation. The external contracting company working on its own, without any participation of the hospital IT department seems to be a failure recipe. It is evident that an active management support and skillful hospital IT employees, are expected to result to success stories during the implementation of integrated hospital information systems. PMID- 21685598 TI - A methodology to assess experiences in implementing e-Health solutions in Croatian family medicine. AB - The central information system of primary health care of the Republic of Croatia is in an early stage of implementation which for now covers integration of all family doctors' offices into a single comprehensive eHealth network connecting their software solutions with the national payer institute and public health authority. Measuring the quality and efficiency of information systems at an early stage of development is a very difficult task. The main goal of this work is establishing the foundation for a formal methodology to measure and quantify the experience of family doctors in the current use of this system. A questionnaire has been created to support the work which, on one side carefully follows our assumptions for quality criteria, and on the other collects valuable input from the users of the technology and solutions implemented. Our work is closely aligned with worldwide accepted standards and recommendations carefully analyzed and localized to reflect the current environment and health policy. This paper presents some preliminary results based on the survey conducted with family doctors on the field. PMID- 21685599 TI - What are the barriers to conducting international research using routinely collected primary care data? AB - BACKGROUND: Primary care is computerized with routine data recorded at the point or care. Secondary use of these data includes: genetic study, epidemiology and clinical trials. However, there are relatively few international studies. OBJECTIVE: To identify the concepts that might predict readiness to collaborate in international research using routinely collected primary care data METHOD: Literature review and data gathering exercise, from international Primary Care Informatics working group workshops, and email modified Delphi exercise. RESULTS: To establish whether primary care data are fit for use in a collaborative study information is needed at the micro-, meso-, and macro-level. At the micro- or data level we need to use documented standards for interoperability, computerized records, to facilitate linkage of data. At the meso-level we need to understand the nature of the electronic patient record (EPR) and specific study requirements. At the macro-level: health system, social and cultural context constrain what data are available. The framework defines the information needed at the point of expression of interest, and joining a study. The initial assessment of readiness should be by self-assessment followed by an in depth appraisal more immediately prior to the start of the study. Finally, a sensitivity analysis should be conducted to test the robustness of the data model. CONCLUSIONS: The literature focuses on technical issues: interoperability, EPR and modeling; the workshops on socio-cultural and organizational. This framework will form the basis for developing a survey instrument of the initial assessment of readiness for collaboration in international research. PMID- 21685600 TI - Evaluation of possibilities in demographic data exchange support in Czech healthcare. AB - This paper summarizes the evaluation of two standardized approaches to implementation of messages for demographic data exchange between the preventive cardiology outpatient department located at the Institute of Computer Science AS CR, v.v.i. in Prague and the Outpatients Department of Cardiology of Municipal Hospital in Caslav. Our setting consists of four independent systems maintaining different clinical data (scheduling system, hospital information system, EHR system and a digital ECG). The aim is to avoid repetitive patient demographic data entry. We evaluate the suitability of IHE Patient Administration Management Profile (including HL7 v.2.5) and Czech national standard DASTA using Standard Evaluation Framework proposed and published in 2008 by J. Mykkanen et al. Besides the evaluation of standards, we also discuss some aspects of the framework. PMID- 21685601 TI - Character sets: an invisible pre-requisite towards cross-border interoperability? AB - Working interoperability not only requires harmonized system's architectures, but also the same interpretation of technical specifications in order to guide the development process. This paper analyzes the role individual characters play as the bearer of data in general and information in specific. This aspect of interoperability is especially important in the context of cross-border communication and collaboration. PMID- 21685602 TI - The role of basic data registers in cross-border interconnection of eHealth solutions. AB - The increasingly closer international business cooperation in the areas of production, trade, transport and activities such as tourism and education is promoting the mobility of people. This increases the need for the provision of health care services across borders. In order to provide increasingly safer and effective treatment that is of ever higher quality in these cases as well, it is necessary to ensure that data accompanies patients even when they travel to other regions, countries or continents. eHealth solutions are one of the key tools for achieving such objectives. When building these solutions, it is necessary to take into account the different aspects and limitations brought about by the differences in the environments where such a treatment of a patient takes place. In the debates on the various types of cross-border interoperability of eHealth solutions, it is necessary to bring to attention the necessity of suitable management and interconnection of data registers that form the basis of every information system: data on patients, health care service providers and basic code tables. It is necessary to promote well-arranged and quality data in the patient's domestic environment and the best possible options for transferring and using those data in the foreign environment where the patient is receiving medical care at a particular moment. Many of the discussions dealing with conditions for the interoperability of health care information systems actually start with questions of how to ensure the interconnectivity of basic data registers. PMID- 21685603 TI - Mapping the Finnish National EHR to the LOINC. AB - The unified content of EHRs promote shared understanding of patient data, information exchange between information systems and health care organizations, data retrieval from EHR and reuse of data for administrative purposes, statistical analysis or clinical research. The purpose of this study was to analyze to what extent Finnish national headings can be coded with the current version LOINC. Ten (37%) of national headings can be mapped to LOINC terms in clinical class. There were LOINC terms in other classes which correspond to headings. Furthermore, inconsistency exists in the names of headings. The need for mapping national headings to all terms in LOINC is needed. PMID- 21685604 TI - PSIP: an overview of the results and clinical implications. AB - Adverse Drug Events (ADEs) are injuries due to medication management rather than the underlying condition of the patient. They endanger the patients and most of them could be avoided and prevented. The detection of ADEs usually relies on spontaneous reporting or medical chart reviews. The first objective of the PSIP Project is to automatically detect cases of ADEs by means of Data Mining, and to provide these cases to healthcare professionals. The second objective is to prevent ADEs by means of contextualised Clinical Decision Support Systems (Cx CDSS) connected with Computerised Physician Order Entry (CPOE) or Electronic Health Record (EHR) systems. The detection of ADEs has been made possible through a set of rules able to identify relevant cases is a set of 92,000 medical cases. The results of this detection are provided through "ADE Scorecards". Contextualized Decision Support Systems have been developed by using the same set of rules and implemented in different software environments. The initial objectives of the PSIP project have been reached. The evaluation of the clinical impact has to be completed. PMID- 21685605 TI - The future of electronic prescribing. AB - Implementing electronic prescribing in health care has been a slow process. Health authorities are now requiring mandatory electronic prescribing because of patient safety concerns. Electronic prescribing is not yet a mature technology, and may therefore pose a risk if especially organizational conditions are not taken into account. The paper offers some thoughts on the future of electronic prescribing in practice. It is especially important to extend electronic prescribing to the continuum of care in order avoid that medication safety falls in the cracks of fragmented health care organizations. PMID- 21685606 TI - Accelerating patient safety through the innovative use of information technology. AB - Numerous studies have confirmed that the patient safety challenge remains tangible. Innovative use of healthcare IT (Information Technology) could play a part in the solution, if the costs of development and implementation are weighed against the major potential savings by improving quality and safety. It is suggested through the "Safe Seven"-checklist, that the design of supporting eHealth solutions lends principles from the patient safety and physical design domains. PMID- 21685607 TI - EU-ADR healthcare database network vs. spontaneous reporting system database: preliminary comparison of signal detection. AB - The EU-ADR project aims to exploit different European electronic healthcare records (EHR) databases for drug safety signal detection. In this paper we report the preliminary results concerning the comparison of signal detection between EU ADR network and two spontaneous reporting databases, the Food and Drug Administration and World Health Organization databases. EU-ADR data sources consist of eight databases in four countries (Denmark, Italy, Netherlands, and United Kingdom) that are virtually linked through distributed data network. A custom-built software (Jerboa(c)) elaborates harmonized input data that are produced locally and generates aggregated data which are then stored in a central repository. Those data are subsequently analyzed through different statistics (i.e. Longitudinal Gamma Poisson Shrinker). As potential signals, all the drugs that are associated to six events of interest (bullous eruptions - BE, acute renal failure - ARF, acute myocardial infarction - AMI, anaphylactic shock - AS, rhabdomyolysis - RHABD, and upper gastrointestinal bleeding - UGIB) have been detected via different data mining techniques in the two systems. Subsequently a comparison concerning the number of drugs that could be investigated and the potential signals detected for each event in the spontaneous reporting systems (SRSs) and EU-ADR network was made. SRSs could explore, as potential signals, a larger number of drugs for the six events, in comparison to EU-ADR (range: 630 3,393 vs. 87-856), particularly for those events commonly thought to be potentially drug-induced (i.e. BE: 3,393 vs. 228). The highest proportion of signals detected in SRSs was found for BE, ARF and AS, while for ARF, and UGIB in EU-ADR. In conclusion, it seems that EU-ADR longitudinal database network may complement traditional spontaneous reporting system for signal detection, especially for those adverse events that are frequent in general population and are not commonly thought to be drug-induced. The methodology for signal detection in EU-ADR is still under development and testing phase. PMID- 21685608 TI - 3,520 medication errors evaluated to assess the potential for IT-based decision support. AB - We have previously studied system failures involved in medication errors using a limited number of root cause analyses as source. The aim of this study was to describe a larger number of medication errors with respect to harm, involved medicines and involved system problems - thus providing information for the development of IT-based decision support. We evaluated 3,520 medication error reports derived from 12 months of consecutive reporting from 13 hospitals in the Capital Region of Denmark. We found 0.65% errors with serious harm and 16% with moderate harm. A small number of medicines were involved in the majority of the errors. The problems in the medication error process were heterogeneous. Some were related to specific medicines and others were related to the computerized order entry system. Accordingly decision support targeted at specific medicines and improved IT systems are part of the continuing work to reduce the frequency of medication errors. PMID- 21685609 TI - Drug knowledge expressed as computable semantic triples. AB - The majority of questions that arise in the practice of medicine relate to drug information. Additionally, adverse reactions account for as many as 98,000 deaths per year in the United States. Adverse drug reactions account for a significant portion of those errors. Many authors believe that clinical decision support associated with computerized physician order entry has the potential to decrease this adverse drug event rate. This decision support requires knowledge to drive the process. One important and rich source of drug knowledge is the DailyMed product labels. In this project we used computationally extracted SNOMED CTTM codified data associated with each section of each product label as input to a rules engine that created computable assertional knowledge in the form of semantic triples. These are expressed in the form of "Drug" HasIndication "SNOMED CTTM". The information density of drug labels is deep, broad and quite substantial. By providing a computable form of this information content from drug labels we make these important axioms (facts) more accessible to computer programs designed to support improved care. PMID- 21685610 TI - Exploring the relationship between usability and technology-induced error: unraveling a complex interaction. AB - The effective evaluation of the usability of health information systems is currently a major challenge. It is essential that the applications we develop are not only usable, but that they are also shown to be safe and do not inadvertently introduce errors. Furthermore, to provide appropriate feedback to designers of systems new methods for evaluation are needed as applications become more complex and distributed. To ensure system usability and safety a variety of methods have emerged from the area of usability engineering that have been adapted to healthcare. The authors have applied and adapted methods of usability engineering, working with hospitals and other healthcare organizations for designing and evaluating a range of health information systems over a number of years. We describe a methodological framework for considering some of these advances and show how a range of usability evaluations can be used to evaluate both the usability and safety of healthcare information systems both in artificial mocked up and real clinical settings using in-situ testing approaches. We conclude with a discussion of recent trends in the area of usability engineering in healthcare that have potential for improving the safety of healthcare information systems. PMID- 21685611 TI - ICT for quality and safety of care: beyond interoperability. AB - Risk Management in healthcare is a particularly challenging task. From a health system perspective a systemic and person centered approach is needed. From an ICT perspective, continuity of care and sharing information for clinical purposes, research and care improvement can be supported though interoperable systems and services and concurrent ability of proper interpretation of this knowledge by different users. Research provides solutions to specific patient safety challenges. Supporting the dynamics of change will furthermore necessitate strategies to shorten the innovation cycle from research to implementation, deployment, adoption and routine use. Transferring research results to deployable solutions requires in addition a high degree of co-ordination at EU level, with strong links to the national competent organisations and stakeholder communities. The breadth and complexity of the issues that need to be addressed require that an appropriate, EU Collaborative Governance is set up. PMID- 21685612 TI - Four principles for user interface design of computerised clinical decision support systems. AB - The paper presents results from a design research project of a user interface (UI) for a Computerised Clinical Decision Support System (CDSS). The ambition has been to design Human-Computer Interaction (HCI) that can minimise medication errors. Through an iterative design process a digital prototype for prescription of medicine has been developed. This paper presents results from the formative evaluation of the prototype conducted in a simulation laboratory with ten participating physicians. Data from the simulation is analysed by use of theory on how users perceive information. The conclusion is a model, which sum up four principles of interaction for design of CDSS. The four principles for design of user interfaces for CDSS are summarised as four A's: All in one, At a glance, At hand and Attention. The model emphasises integration of all four interaction principles in the design of user interfaces for CDSS, i.e. the model is an integrated model which we suggest as a guide for interaction design when working with preventing medication errors. PMID- 21685613 TI - Implementation of a taxonomy aiming to support the design of a contextualised clinical decision support system. AB - Clinical Decision Support Systems (CDSS) are recently implemented in hospital settings to improve the reliability of drug ordering. However, such systems have limited effects due to their tendency to overalert. To healthcare professionals consider alerts, it is necessary to adapt the CDSS to their activity. Thus, it is necessary to consider contextualisation aspects in the system design. In this article, we propose a taxonomy integrating contextualisation elements issued from an activity analysis to guide the design of a contextualised CDSS. This taxonomy has been developed within the framework of the European project PSIP (Patient Safety through Intelligent Procedures in medication) aiming to make easier the identification and the prevention of Adverse Drug Events. PMID- 21685614 TI - Medication related computerized decision support system (CDSS): make it a clinicians' partner! AB - Medication related Computerized Decision Support System (CDSS) are known to have a positive impact on Adverse Drug Events (ADE) prevention but they face acceptance problems due to over alerting and usability issues. We present here a Human factors approach to the design of these Clinical Decision Support (CDS) functions and to their integration into different Electronic Health Record (EHR) / Computerized Physicians Order Entry (CPOE) systems, so that the resulting CDSS corresponds to the users needs and fits clinical workflows and cognitive processes. We used ethnographic observations completed with semi-structured interviews to analyse existing work situations and work processes. These were then described in detail using the SHEL (Software, Hardware, Environment & Liveware) formalism, which enables a structured description of the work system and provides an appropriate classification of human errors potentially leading to ADEs. We then propose a Unified Modelling Language (UML) model supporting the characterization by the CDSS of the drug monitoring and clinical context of patients at risk of ADE. This model combines the status of the lab test orders on the one hand with the validity and normality of the lab results on the other hand. This makes the system able to catch the context of the monitoring of the drugs through their corresponding lab tests and lab results (e.g. kalemia for potassium) and also part of the context of the clinical status of the patient (actual lab values, but also diseases and other pathologies that are identified as potential causes of the ADE e.g. renal insufficiency and potassium). We show that making the system able to catch the monitoring and clinical contexts opens interesting opportunities for the design of the CDS information content and display mode. Implementing this model would allow the CDSS to take into account the actions already engaged by the healthcare team and to adapt the information delivered to the monitoring and clinical context, thus making the CDSS a partner to the clinicians, nurses and pharmacists. PMID- 21685615 TI - Information contextualization in decision support modules for adverse drug event prevention. AB - This paper presents an analysis of hospitals' organization and Hospital Information Systems' features which can contribute in contextualization of Clinical Decision Support Systems (CDSS) for Adverse Drug Event (ADE) prevention. We identified four categories of contextualization: ENVIRONMENT, TASKS, USERS and TEMPORAL ASPECTS. Based on this analysis, we studied the technical possibilities at the architectural level to determine which component(s) of a standalone knowledge platform could technically handle contextualization. The results impact three types of components of this platform: (1) a CDSS providing decision support based on ADE signals mined in large data repositories; (2) a Connectivity Platform providing transformation and routing services (enabling any application to connect to the CDSS); (3) three prototype applications for accessing the decision support services realized within an industrial Computerized Physician Order Entry, an industrial Electronic Health Record and in an independent Web prototype, respectively. In each of the above components we present the dimension(s) of contextualization that has/have been determined to cope with and the design followed in the implementation phase. PMID- 21685616 TI - Designing, implementing and evaluating e-prescription: a field study and comparison with PSIP results. AB - E-prescription is amongst the most widespread medical electronic support functions. However, several studies reported acceptance and utilisation rates not as high as expected. This paper performs firstly an analysis of the literature on e-prescription characteristics and functionalities especially with respect to their actual usage. Then a specific field study was conducted in an Internal Medicine ward, to investigate human factor issues associated to the introduction of an e-prescription system. Finally, the findings of the field study are framed within the actual implementation of various electronic support outputs resulting from the European Project "Patient safety through intelligent procedures in medication" (PSIP). The results show the importance of a systemic view when designing, implementing and evaluating medical support systems, as the pre existing structures and tools largely influence the impact of those systems and their effects. PMID- 21685617 TI - Shallow medication extraction from hospital patient records. AB - This paper presents methods for shallow Information Extraction (IE) from the free text zones of hospital Patient Records (PRs) in Bulgarian language in the Patient Safety through Intelligent Procedures in medication (PSIP) project. We extract automatically information about drug names, dosage, modes and frequency and assign the corresponding ATC code to each medication event. Using various modules for rule-based text analysis, our IE components in PSIP perform a significant amount of symbolic computations. We try to address negative statements, elliptical constructions, typical conjunctive phrases, and simple inferences concerning temporal constraints and finally aim at the assignment of the drug ACT code to the extracted medication events, which additionally complicates the extraction algorithm. The prototype of the system was used for experiments with a training corpus containing 1,300 PRs and the evaluation results are obtained using a test corpus containing 6,200 PRs. The extraction accuracy (f-score) for drug names is 98.42% and for dose 93.85%. PMID- 21685618 TI - Health multi-terminology portal: a semantic added-value for patient safety. AB - Since the mid-90s, several quality-controlled health gateways were developed. In France, CISMeF is the leading health gateway. It indexes Internet resources from the main institutions, using the MeSH thesaurus and the Dublin Core metadata element set. Since 2005, the CISMeF Information System (IS) includes 24 health terminologies, classifications and thesauri for indexing and information retrieval. This work aims at creating a Health Multi-Terminology Portal (HMTP) and connect it to the CISMeF Terminology Database mainly for searching concepts and terms among all the health controlled vocabularies available in French (or in English and translated in French) and browsing it dynamically. To integrate the terminologies in the CISMeF IS, three steps are necessary: (1) designing a meta model into which each terminology can be integrated, (2) developing a process to include terminologies into the HMTP, (3) building and integrating existing and new inter-terminology mappings into the HMTP. A total of 24 terminologies are included in the HMTP, with 575,300 concepts, 852,000 synonyms, 222,800 definitions and 1,180,000 relations. Heightteen of these terminologies are not included yet in the UMLS among them, some from the World Health Organization. Since January 2010, HMTP is daily used by CISMeF librarians to index in multi terminology mode. A health multiterminology portal is a valuable tool helping the indexing and the retrieval of resources from a quality-controlled patient safety gateway. It can also be very useful for teaching or performing audits in terminology management. PMID- 21685619 TI - Towards a standardised representation of a knowledge base for adverse drug event prevention. AB - Knowledge representation is an important part of knowledge engineering activities that is crucial for enabling knowledge sharing and reuse. In this regard, standardised formalisms and technologies play a significant role. Especially for the medical domain, where knowledge may be tacit, not articulated and highly diverse, the development and adoption of standardised knowledge representations is highly challenging and of outmost importance to achieve knowledge interoperability. To this end, this paper presents a research effort towards the standardised representation of a Knowledge Base (KB) encapsulating rule-based signals and procedures for Adverse Drug Event (ADE) prevention. The KB constitutes an integral part of Clinical Decision Support Systems (CDSSs) to be used at the point of care. The paper highlights the requirements at the domain of discourse with respect to knowledge representation, according to which GELLO (an HL7 and ANSI standard) has been adopted. Results of our prototype implementation are presented along with the advantages and the limitations introduced by the employed approach. PMID- 21685620 TI - Analysis of the medication-use process in North American hospital systems: underlining key points for adoption to improve patient safety in French hospitals. AB - This project was designed to underline any actions relative to medication error prevention and patient safety improvement setting up in North American hospitals which could be implemented in French Parisian hospitals. A literature research and analysis of medication-use process in the North American hospitals and a validation survey of hospital pharmacist managers in the San Diego area was performed to assess main points of hospital medication-use process. Literature analysis, survey analysis of respondents highlighted main differences between the two countries at three levels: nationwide, hospital level and pharmaceutical service level. According to this, proposal development to optimize medication-use process in the French system includes the following topics: implementation of an expanded use of information technology and robotics; increase pharmaceutical human resources allowing expansion of clinical pharmacy activities; focus on high risk medications and high-risk patient populations; develop a collective sense of responsibility for medication error prevention in hospital settings, involving medical, pharmaceutical and administrative teams. Along with a strong emphasis that should be put on the identified topics to improve the quality and safety of hospital care in France, consideration of patient safety as a priority at a nationwide level needs to be reinforced. PMID- 21685621 TI - An approach to 'dynamic--DDD (defined daily dose) monitoring' to reduce adverse clinical outcomes and increase patient safety: information repositories and event triggers in clinical practice. AB - The goal of every effort and actions/interventions in almost all healthcare settings throughout the world's health systems -primary care, inpatient, outpatient encounters, diagnostic and therapeutic interventions, peri-operative settings- is and has been to achieve a well defined outcome (a kind of improvement in health status of the patient under consideration, an observable and significant change(s) in selected set(s) of clinical parameters confirmed by laboratory results and pathology findings, improvements in clinical outcomes). Clinical inefficiencies, in this context, should be addressed very systematically and scientifically. This is achieved through a continuously monitoring approach to adverse drug events based on information repositories and evidence-based rule sets. For monitoring drug-related outcomes and clinical outcomes in general, the concept of DDD (Defined Daily Dose) compliance is explained in this article to eliminate and avoid adverse clinical outcomes. PMID- 21685622 TI - The ADE scorecards: a tool for adverse drug event detection in electronic health records. AB - Although several methods exist for Adverse Drug events (ADE) detection due to past hospitalizations, a tool that could display those ADEs to the physicians does not exist yet. This article presents the ADE Scorecards, a Web tool that enables to screen past hospitalizations extracted from Electronic Health Records (EHR), using a set of ADE detection rules, presently rules discovered by data mining. The tool enables the physicians to (1) get contextualized statistics about the ADEs that happen in their medical department, (2) see the rules that are useful in their department, i.e. the rules that could have enabled to prevent those ADEs and (3) review in detail the ADE cases, through a comprehensive interface displaying the diagnoses, procedures, lab results, administered drugs and anonymized records. The article shows a demonstration of the tool through a use case. PMID- 21685623 TI - Three different cases of exploiting decision support services for adverse drug event prevention. AB - Clinical Decision Support Systems (CDSSs) are implemented in clinical settings in order to improve patient outcomes and/or clinical practices. However, they are still not widely accepted by healthcare professionals due to over-alerting. The aim of the "Patient Safety through Intelligent Procedures in medication" (PSIP) project is to develop and demonstrate innovative tools so as to generate and provide relevant knowledge to healthcare professionals and patients for Adverse Drug Event (ADE) prevention by means of Information and Communication Technologies (ICT). PSIP employs a Knowledge Base (KB) as the core of its CDSS. This KB encapsulates signals capable of automatically detecting potential ADEs and contextualizing the CDSS output to the patient and healthcare professionals. To exploit the KB, a Global Knowledge Platform (GKP) has been created comprising of a KB system, a Connectivity Platform and appropriate user interface modules. The GKP has been tested to demonstrate integration of the KB in different work situations and it has been deployed in three different medical applications. The first is a Web application; the second involves a commercial French EHR (Electronic Health Record) and the third is a Danish CPOE (Computerised Physician Order Entry) system. This paper presents recent progress as regards the exploitation of the PSIP KB and the results obtained in the three different medical applications. PMID- 21685624 TI - Patient Summary and medicines reconciliation: application of the ISO/CEN EN 13606 standard in clinical practice. AB - The comparison of the patient's current medication list with the medication being ordered when admitted to Hospital, identifying omissions, duplications, dosing errors, and potential interactions, constitutes the core process of medicines reconciliation. Access to the medication the patient is taking at home could be unfeasible as this information is frequently stored in various locations and in diverse proprietary formats. The lack of interoperability between those information systems, namely the Primary Care and the Specialized Electronic Health Records (EHRs), facilitates medication errors and endangers patient safety. Thus, the development of a Patient Summary that includes clinical data from different electronic systems will allow doctors access to relevant information enabling a safer and more efficient assistance. Such a collection of data from heterogeneous and distributed systems has been achieved in this Project through the construction of a federated view based on the ISO/CEN EN13606 Standard for architecture and communication of EHRs. PMID- 21685625 TI - Engineering the electronic health record for safety: a multi-level video-based approach to diagnosing and preventing technology-induced error arising from usability problems. AB - Electronic health records (EHRs) promise to improve and streamline healthcare through electronic entry and retrieval of patient data. Furthermore, based on a number of studies showing their positive benefits, they promise to reduce medical error and make healthcare safer. However, a growing body of literature has clearly documented that if EHRS are not designed properly and with usability as an important goal in their design, rather than reducing error, EHR deployment has the potential to actually increase medical error. In this paper we describe our approach to engineering (and reengineering) EHRs in order to increase their beneficial potential while at the same time improving their safety. The approach described in this paper involves an integration of the methods of usability analysis with video analysis of end users interacting with EHR systems and extends the evaluation of the usability of EHRs to include the assessment of the impact of these systems on work practices. Using clinical simulations, we analyze human-computer interaction in real healthcare settings (in a portable, low-cost and high fidelity manner) and include both artificial and naturalistic data collection to identify potential usability problems and sources of technology induced error prior to widespread system release. Two case studies where the methods we have developed and refined have been applied at different levels of user-computer interaction are described. PMID- 21685626 TI - Mapping the ATC classification to the UMLS metathesaurus: some pragmatic applications. AB - ATC classification is a WHO international classification used to classify drugs. The aim of this paper is to evaluate two lexical methods in English and in French to map ATC to UMLS. Several applications have been impemented to illustrate the use of the ATC mapping in English and French: (a) MeSH translation in Norwegian, (b) Drug Information Portal, and (c) ATC to PubMed tool. Two lexical methods were used to map ATC to UMLS. The first approach used a French natural language processing tool to map French terms of ATC to the French terminologies of UMLS. The second approach used the MetaMap tool to map English terms of ATC to UMLS. The English MetaMap provides slightly more mappings than the French NLP tool (3,170 vs. 2,992). On the other hand, the French NLP tool provides a slightly better precision than MetaMap (88% vs. 86%). Using a manual mapping between ATC and MeSH, the union of the validated mappings between ATC and MeSH provides 2,824 mappings (68.7% of ATC codes of the fifth level). Lexical methods are powerful methods to map health terminologies to the UMLS Metathesaurus. Manual mapping is still necessary to complete the mapping. PMID- 21685627 TI - Lessons learnt from conducting a high fidelity simulation test in health IT. AB - Testing IT-systems by use of simulation requires a thorough planning and preparation in order to create a realistic clinical environment. For a successful test through simulation a dedicated test team to control the environment is needed, as well as people to play the role of patients and staff. Relevant artifacts and elaborate scenarios ensure the narrative. This paper explores the preliminary work and execution of an extensive test of a Computerized Order Entry System prototype. Central to the setup of the test is a script which outlines the method by guiding the preparation and execution. PMID- 21685628 TI - Impact evaluation of innovative technology: estimating the impact of the PSIP solutions. AB - Health informatics projects often develop innovative IT solutions for health care. Systematic evaluation of their impact and risks is an ethical imperative. However, field studies can often not be conducted because of immature solutions. On the other site, lab studies are not helpful when it comes to estimating the impact of an innovative IT solution. We faced this challenge within the PSIP projects where innovative tools for medication management are developed. In this paper, we present the approaches used within the PSIP project for estimating the impact of immature solutions, including surveys of future users, a Delphi study with experts, and a simulation study. The methodology and first results of those evaluations are presented, and lessons learnt for impact evaluation of immature solutions are discussed. PMID- 21685629 TI - Scorecards: a new method to prevent adverse drug events? Preliminary results from a clinical field study. AB - In the field of the detection and prevention of preventable ADEs, several methods have been explored to decrease the rate of ADEs due to monitoring errors. This paper describes an innovative method that aims at improving patient safety by increasing ADEs' awareness of healthcare professionals. To this end, ADE scorecards that provide healthcare professionals with retrospective data about ADEs' causes and rates have been developed. In order to evaluate the impact of this method on the ADE rate, in-field clinical tests have been set up. Data were collected by both qualitative (semi-structured interviews) and quantitative methods (log analysis and ADE rate calculation). Preliminary results reveal that ADE-scorecards are well-accepted by most of the healthcare professionals who intend to use them as discussion supports and/or learning tools. Thus, ADE scorecards seem to be a relevant method to improve patient safety by increasing ADE-awareness of healthcare professionals. PMID- 21685630 TI - Assessment of three systems to empower the patient and decrease the risk of adverse drug events. AB - One way to reduce adverse drug events (ADEs) is to empower the patient to participate in the control of medication. This empowerment can be supported in different ways by making knowledge and information available to the patient. This study examines the usefulness and safety of two different systems on the background of a paper-based medication list presenting prescribed medicine presently used in hospitals in Copenhagen. Each of the systems examined aims to reduce ADEs but presents information in different levels of detail, and anticipates different level of prior knowledge from the patient: a Web-based prototype presenting medication, lab-results and alerts, and a cell phone-based prototype presenting alerts. Six patients were introduced to each of the systems by performing small tasks and subsequently interviewed. The patients found the paper-based medication list useful and comprehensive for control of own prescribed medication. The Web-based prototype also proved to be useful, but drug and lab values were hard to correlate, and the alerts were hard to understand. The cell phone-based prototype proved less useful as the patients were challenged to vision the applicability of the system. Furthermore, it is a safety issue that the information the alert is based upon, stems from the patient alone. We conclude that, in order for the Web-based system as well as the cell phone system to empower patient and increase patient safety, further development of the systems is necessary. PMID- 21685631 TI - Validation of completeness, correctness, relevance and understandability of the PSIP CDSS for medication safety. AB - Medication errors and resulting Adverse Drug Events (ADEs) are an important issue of global healthcare. Within the European PSIP project that aims at developing solutions to improve medication safety, contextualized decision support modules aiming to prevent ADEs are being developed. The objective of this work was to thoroughly validate part of the CDSS (Clinical Decision Support System) and the underlying Knowledge Base, in order to detect incorrect or unclear alerts. We systematically developed a repository of test cases and used them for validation. The development of the test cases showed that there are differences among experts in interpreting the correctness of an alert, and that the clinical context is important when judging whether it is adequate. Overall, validation did not find major errors in the Knoweldge Base, but developed several recommendations for further improvement. PMID- 21685632 TI - Completion of structured patient descriptions by semantic mining. AB - This paper presents experiments in automatic Information Extraction of medication events, diagnoses, and laboratory tests form hospital patient records, in order to increase the completeness of the description of the episode of care. Each patient record in our hospital information system contains structured data and text descriptions, including full discharge letters. From these letters, we extract automatically information about the medication just before and in the time of hospitalization, especially for the drugs prescribed to the patient, but not delivered by the hospital pharmacy; we also extract values of lab tests not performed and not registered in our laboratory as well as all non-encoded diagnoses described only in the free text of discharge letters. Thus we increase the availability of suitable and accurate information about the hospital stay and the outpatient segment of care before the hospitalization. Information Extraction also helps to understand the clinical and organizational decisions concerning the patient without increasing the complexity of the structured health record. PMID- 21685633 TI - Effectiveness of cybertherapy in mental health: a critical appraisal. AB - Although Virtual Reality (VR) treatment and Internet-based cognitive behavior therapy (CBT) have been found to be effective in a large series of studies, dissemination of these therapies in the community at large is still in its infancy. A number of reasons for the lack of dissemination are discussed, including clinicians' resistance, lack of representation of samples studied, and lack of cost-effectiveness studies. Challenges for further studies are pointed out. PMID- 21685634 TI - Efficacy and effectiveness of online cognitive behavioral treatment: a decade of interapy research. AB - Since 1996, researchers of the Interapy research group of the University of Amsterdam have been examining the effects of online cognitive behavioral treatment (online CBT). Over the years, the group conducted nine controlled trials of online CBT for a variety of mental health disorders, among a total of 840 participants. These studies suggest that online CBT is a viable and effective alternative to face-to-face treatment. Treatment adherence was 82%, and reductions in psychopathology represented a large between-group effect size of SMD = 0.9 (95% CI: .7 to 1.1), which was maintained over long periods. The research culminated in the foundation of the Interapy clinic, which received Dutch health regulatory body approval in 2005. Since then, costs of online CBT are reimbursed through public health insurance. A large study of the treatment outcome of 1,500 patients of the Interapy clinic showed that effects in clinical practice are similar to those observed in the controlled trials, and comparable to selected benchmarks of naturalistic studies of face-to-face CBT. The accumulated evidence provides compelling support for the efficacy and effectiveness of online CBT. PMID- 21685635 TI - Between Cyberplace and Cyberspace: the researcher's role in virtual setting research. AB - Disciplines such as Internet Research, the Psychology of Cyberspace and the Social Psychology of Cyberplaces call for an epistemological reflection not merely on the universe of objects they deal with, but also, and perhaps especially, on the research settings used to investigate them. With this work, we intend to make a contribution to the debate on three issues: psychosocial interpretation of the new environments, the "mediated" nature of the researcher setting-study object relationship, and cyberplaces as settings for mediated interaction research. PMID- 21685636 TI - The similarity between the virtual and the real self--how the virtual self can help the real self. AB - In the exploration of a person's self-image in the Internet, it seems that there is one representing profile. But, is it coherent with the real self? Today we are able to perform counseling and therapeutic practices, and we can affect and change the human self and mindset in virtual spaces. Using the connection between neuroscience and philosophy, we show that there are different types of the self people adopt in cyberspace. By showing how their disposition changes many questions can be answered. What mind state provokes addictive impulses and enables therapy? How does the sense and concept of reality change? Can we transfer the experiences we gain in the virtual into real life? By investigating how the virtual affects us in a positive or negative way, support to successful treatment applications are possible. The goal of this study is to find answers for the virtual space usage as a treatment tool and to see what the future holds for such therapeutic tendencies. PMID- 21685637 TI - Use of robotics kits for the enhancement of metacognitive skills of mathematics: a possible approach. AB - The present study is aimed at analyzing the process of building and programming robots as a metacognitive tool of mathematics. Quantitative data from a study performed on a sample of students attending an Italian secondary school are described. Results showed that robotics activities may be used as a new metacognitive environment allowing students to improve their attitude towards mathematics, and to increase their attitude to reflect on themselves and on their own learning, and their higher-level control components, such as forecasting, planning, monitoring and evaluation exercises and problems related to implementation. PMID- 21685638 TI - Interpretations of virtual reality. AB - University students were surveyed to learn what they know about virtual realities. The two studies were administered with a half-year interval in which the students (N=90, specializing either in mathematics and science, or in social science and humanities) were asked to name particular examples of virtual realities. The second, but not the first study, was administered after the participants had the chance to see the movie "Avatar" (no investigation was held into whether they really saw it). While the students in both studies widely believed that activities such as social networking and online gaming represent virtual realities, some other examples provided by the students in the two studies differ: in the second study the participants expressed a better understanding of the items related to virtual realities. At the same time, not a single participant reported particular psychological states (either regular or altered) as examples of virtual realities. Profound popularization efforts need to be done to acquaint the public, including college students, with virtual realities and let the public adequately understand how such systems work. PMID- 21685639 TI - Towards immersive and adaptive augmented reality exposure treatment. AB - In this paper we introduce a novel augmented reality based exposure therapy system for phobia treatment. This allows patients to see virtual fear stimuli overlaid onto the real world and to fully interact with them in real time. Extending on previous work, we focus on creating a controllable and interactive system (through gesture recognition and physiological sensors) with a visually realistic context. Our goal is a very life-like system that allows full parameterization over stimulus intensity and other factors necessary for an effective exposure therapy system. PMID- 21685640 TI - Isolating the effect of Virtual Reality Based Exposure Therapy for agoraphobia: a comparative trial. AB - The isolated effect of Virtual Reality Based Exposure Therapy (VRBET) for agoraphobia was analyzed through a comparative trial involving the first 10 agoraphobic participants. The participants were randomly assigned to two groups: VREBT only and VREBT combined with cognitive therapy. All the required Virtual Environments (VE) were created with an inexpensive Game Level Editor (GLE). Outcome measures supported the immersive effect of the VEs. Questionnaires, behavioral tests and physiological measures indicated a positive effect of VRBET alone. The addition of cognitive therapy to VREBT did not appear to generate any significant differences. Consequences for future research and practice are discussed. PMID- 21685641 TI - Virtual reality exposure treatment of agoraphobia: a comparison of computer automatic virtual environment and head-mounted display. AB - In this study the effects of virtual reality exposure therapy (VRET) were investigated in patients with panic disorder and agoraphobia. The level of presence in VRET was compared between using either a head-mounted display (HMD) or a computer automatic virtual environment (CAVE). Results indicate that there was no relationship between the level of experienced presence and treatment outcome. Analyses indicate that VRET in general was more effective than no treatment. No differences in effectiveness were found between VRET using an HMD or CAVE. PMID- 21685642 TI - New technologies to manage exam anxiety. AB - A Stress Inoculation Training-based protocol tested if multimedia audio-video content induced emotional changes and reduced exam anxiety in university students. Seventy-five participants took part in six experimental sessions consisting of viewing multimedia content and performing relaxation exercises. Participants were randomly assigned to five experimental groups: 1) audio and video narrative on mobile phone (UMTS); 2) audio and video narrative on DVD (DVD), 3) audio narrative on MP3 player (M3), 4) audio narrative on CD (CD), 5) control group (CTRL). Results showed that audio/video content induced a significant reduction in exam anxiety and an increase of relaxation in students, compared to the audio-only contents. PMID- 21685643 TI - Virtual reality exposure on nicotine craving. AB - Several forms of treatment for nicotine dependence that combine the classical smoking cessation strategies with new Virtual Reality (VR) exposure techniques to smoking-related cues are in development. In this line, the main goal of our study was to develop a virtual platform in order to induce cravings in smokers. Sixty undergraduate students were randomly assigned to two different virtual environments (high-arousal cues and low-arousal cues). Both environments were based on a three-room apartment with commercial music playing and virtual characters interacting in a social event. The assessment was carried out before and after exposure through psychophysiological activation and self-report data for craving and nicotine dependence levels. No statistical differences were observed between smokers and non-smokers in psychophysiological activation. As far as self-report data is concerned, smokers revealed a significant increase in craving after the VR exposure to high arousal environments. Overall results were in line with previous studies suggesting the use of virtual environments as a tool for the existing smoking cessation programs. PMID- 21685644 TI - Interactive and passive virtual reality distraction: effects on presence and pain intensity. AB - The current study explores the effects of interactive versus passive Virtual Reality (VR) distraction on the sense of presence and pain intensity. Sixty-eight healthy students (mean age 21.8, SD = 4.3) underwent two consecutive cold-pressor trials (subject's hand immersed into 6 degrees C water as long as possible, with a time limit of five minutes), one without VR and another providing a VR distraction "Surreal World." Participants were randomly assigned to an interactive VR distraction condition, where a number of interactions with the environment were possible, or to a passive VR distraction condition, where they were also exposed to the surreal world, but instead of interacting with the virtual environment, they watched the navigation generated by another participant assigned to the interactive condition. After the VR cold-pressor trial, each subject provided ratings of pain intensity and rated the degree to which they had felt "present" in the virtual environment. Results showed that most of the participants who experienced the interactive VR distraction reported less pain intensity relative to the no-VR trial. However, in the passive VR condition, only 5.9% of participants showed a decreased level of pain intensity relative to the no-VR trial. Also, the amount of presence reported was significantly higher during the interactive VR distraction and correlated negatively with pain intensity scores. PMID- 21685645 TI - Evolution of smoking urge during exposure through virtual reality. AB - The use of Virtual Reality (VR) could be a useful tool for the improvement of Cue Exposure Therapy (CET) for smoking cessation. Nevertheless, it is necessary to know the appropriate parameters of exposure in order to develop efficacious treatment programs. This study was conducted to analyze the pattern of tobacco desire in a sample of smokers exposed to VR. Results showed that the environments were able to generate two different patterns of craving response. These results could contribute to determine exposure parameters when using VR technology in CET. PMID- 21685646 TI - Virtual reality exposure in patients with eating disorders: influence of symptom severity and presence. AB - The aim of this study was to examine the influence of several modulating variables on subjective discomfort experienced by patients with eating disorders while exposed to virtual environments that were emotionally significant for them. Severity of symptoms and sense of presence were analyzed. Both variables influenced the level of subjective discomfort during the exposure to virtual environments. PMID- 21685647 TI - Virtual reality to study responses to social environmental stressors in individuals with and without psychosis. AB - A Virtual Reality (VR) environment was created to study psychotic symptoms in patients and non-patients. Participants' task was to find five virtual characters that each had a small number label on his or her chest. The density and ethnic appearance of the virtual characters in the bar was controlled. For a non-patient group (N=24), results showed a significant main effect for density on participants' physiological responses, their behavior, reported level of discomfort, and their ability to remember place and location of the numbered avatars. The avatar's ethnicity had a significant effect on non-patients' physiological responses. Comparison between two patients and non-patient group showed differences in physiological responses, behavior and reported level of discomfort. PMID- 21685648 TI - Validation of a Neuro Virtual Reality-based version of the Multiple Errands Test for the assessment of executive functions. AB - The purpose of this study was to establish ecological validity and initial construct validity of the Virtual Reality (VR) version of the Multiple Errands Test (MET) (Shallice & Burgess, 1991; Fortin et al., 2003) based on the NeuroVR software as an assessment tool for executive functions. In particular, the MET is an assessment of executive functions in daily life, which consists of tasks that abide by certain rules and is performed in a shopping mall-like setting where items need to be bought and information needs to be obtained. The study population included three groups: post-stroke participants (n = 5), healthy, young participants (n = 5), and healthy, older participants (n = 5). Specific objectives were (1) to examine the relationships between the performance of three groups of participants in the Virtual Multiple Errands Test (VMET) and at the traditional neuropsychological tests employed to assess executive functions and (2) to compare the performance of post-stroke participants to those of healthy, young controls and older controls in the VMET and at the traditional neuropsychological tests employed to assess executive functions. PMID- 21685649 TI - A comparison of text and technology based training tools to improve cognitive skills in older adults. AB - Research has indicated that use of cognitive skills training tools can produce positive benefits with older adults. However, little research has compared the efficacy of technology-based interventions and more traditional, text-based interventions which are also available. This study aimed to investigate cognitive skills improvements experienced by 40 older adults using cognitive skills training tools. A Solomon 4 group design was employed to determine which intervention demonstrated the greatest improvement. Participants were asked to use the interventions for 5-10 minutes per day, over a period of 60 days. Pre and post-tests consisted of measures of numerical ability, self-reported memory and intelligence. Following training, older adults indicated significant improvements on numerical ability and intelligence regardless of intervention type. No improvement in selfreported memory was observed. This research provides a critical appraisal of brain training tools and can help point the way for future improvements in the area. Brain training improvements could lead to improved quality of life, and perhaps, have financial and independent living ramifications for older adults. PMID- 21685650 TI - The development of the SWEAT questionnaire: a scale measuring costs and efforts inherent to conducting exposure sessions. AB - For decades, empirical studies have shown the effectiveness of exposure techniques when used in cognitive-behavioral therapy (CBT) treatment for anxiety disorders. A few studies are now suggesting that using Virtual Reality (VR) may be an effective way to conduct exposure and overcome some of the limitations of in vivo exposure. The aim of this study is to validate the Specific Work for Exposure Applied in Therapy (SWEAT) questionnaire that measures costs and efforts required to conduct in vivo and in virtuo exposure. A total of 265 exposure sessions (in vivo = 140; in virtuo = 125) were rated by experienced psychologists. Reliability analysis revealed three main factors in the construct of the SWEAT questionnaire. Results also showed that conducting exposure in VR is less of a burden and more readily adapted to the patients' needs than in vivo. PMID- 21685651 TI - Control over the virtual environment influences the presence and efficacy of a virtual reality intervention on pain. AB - The main aim of this study is to investigate whether the control the user has over a virtual environment (VE) influences the sense of presence. A secondary purpose is to explore the relationship between Virtual Reality (VR) presence and pain tolerance during a cold-pressor experience. Ninety-four participants underwent two consecutive cold-pressor trials, one without VR exposure and the other providing a VR stereoscopic figure used as a symbolic representation of the sensation of pain. Participants were randomly assigned to an interactive condition in which they could actively manipulate the VR figure to achieve a pleasant, tranquil environment (analogous to no-pain situation) or to a passive intervention, in which they observed the changes in the VR figure. Results showed that the amount of VR presence reported was significantly higher in the interactive condition. Participants had a higher pain tolerance during both VR conditions than in the no-VR trial, with a greater increase in pain tolerance from the non-VR trial in the interactive condition. Presence scores correlated significantly and positively with pain tolerance scores. We discuss the importance of VR interaction and control over the VR environments used in VR pain interventions designed to increase cognitive control over pain. PMID- 21685652 TI - Affective reactions to visually masked stimuli within a virtual environment. AB - Within perceptual psychology, visual masking describes a process whereby the presentation of one image, the mask, affects the conscious perception of another, the target. Given the right conditions the target can effectively be rendered invisible. There is a dearth of research into the effects of visually masked stimuli within virtual environments, particularly with regard to affect psychology. Of the two studies presented here, the first study was used to establish the efficacy of visual masking using three dimensional, masked objects. Usually, mask and target stimuli are co-planar, with no internal depth disparity. This study found that visual masking is possible within a virtual space using target objects with internal depth disparity. The second study investigated affect driven, choice reactions to three dimensional, masked facial expressions. This study also found an effect, specifically an unconscious bias to navigate away from angry, masked faces and towards smiling, masked expressions. These two studies form a foundation for a wider project: using visual masking within a virtual environment for mood induction, primarily as a cybertherapeutic aid. PMID- 21685653 TI - Virtual reality and exercise: behavioral and psychological effects of visual feedback. AB - We herein report an experimental study examining the potential positive effects of Virtual Reality (VR) feedback during an indoor bicycling exercise. Using a regular bike coupled to a VR system, we compared conditions of no VR feedback, VR feedback and VR feedback with the presence of a virtual coach, acting as a pacer. In VR feedback conditions, we observed a decreased level of perceived exertion and an increased level of enjoyment of physical activity, when compared to a regular exercise situation (no VR feedback). We also observed a shift in the subjects' attentional focus, from association (in the absence of VR feedback) to dissociation (in VR feedback conditions). Moreover, the presence of a virtual coach in the VR environment triggered a systematic regulation of the (virtual) displacement speed, whose relationship with perceived enjoyment and exertion require further work. PMID- 21685654 TI - Telepresence experienced in videoconference varies according to emotions involved in videoconference sessions. AB - Previous studies have linked telepresence to the strength of the therapeutic relationship experienced during telepsychotherapy. This finding comes as a surprise for many people who have been involved in a teleconference meeting, where telepresence is often considered weak. The aim of this study is to (re)evaluate the impact of emotional engagement on telepresence. Participants were randomly assigned to one of the two conditions: (a) emotionally charged verbal exchange first (followed by a more neutral verbal exchange), or (b) emotionally neutral verbal exchange first (followed by an emotionally charged verbal exchange). A distraction task was performed between the two verbal exchanges in videoconference. Results showed that verbal exchanges involving stronger emotions increase telepresence. These results may explain why telepresence is so high in telepsychotherapy. PMID- 21685655 TI - Online social networking amongst teens: friend or foe? AB - The impact of Internet communication on adolescent social development is of considerable importance to health professionals, parents and teachers. Online social networking and instant messaging programs are popular utilities amongst a generation of techno-savvy youth. Although these utilities provide varied methods of communication, their social benefits are still in question. This study examined the relationship between online social interaction, perceived social support, self-esteem and psychological distress amongst teens. A total of 400 participants (M(age) = 14.31 years) completed an online survey consisting of parametric and non-parametric measures. No significant relationship was found between online interaction and social support. Time spent interacting online was negatively correlated with self-esteem and psychological distress. While previous research has focused on young adults, this study examines the impact of online social networking on emerging teens. It highlights the need for continued caution in the acceptance of these utilities. PMID- 21685656 TI - Perceived stress and life satisfaction: social network service use as a moderator. AB - Social Network Service (SNS) has become a buzzword in recent media coverage with the development of the second generation of Web-based communities. In China, SNS has played an increasingly important role in its users' daily lives, especially among students. With a sample of 471 college students, we tested the direct relationship between perceived stress and life satisfaction using a regression analysis. Moreover, we found SNS use could buffer the negative effect of perceived stress. This study has practical implications on Internet users' SNS use. PMID- 21685657 TI - People like virtual counselors that highly-disclose about themselves. AB - In this paper, we describe our findings from research designed to explore the effect of self-disclosure between virtual human counselors (interviewers) and human users (interviewees) on users' social responses in counseling sessions. To investigate this subject, we designed an experiment involving three conditions of self-disclosure: high-disclosure, low-disclosure, and non-disclosure. We measured users' sense of co-presence and social attraction to virtual counselors. The results demonstrated that users reported more co-presence and social attraction to virtual humans who disclosed highly intimate information about themselves than when compared to other virtual humans who disclosed less intimate or no information about themselves. In addition, a further analysis of users' verbal self-disclosure showed that users revealed a medium level of personal information more often when interacting with virtual humans that highly-disclosed about themselves, than when interacting with virtual humans disclosing less intimate or no information about themselves. PMID- 21685658 TI - A comparison of client characteristics in cyber and in-person counseling. AB - As cybertherapy diversifies into a wide variety of modalities, it is incumbent upon researchers and clinicians to determine the most suitable cybertherapy approach for clients. Suitability encompasses ethical considerations, client satisfaction, and treatment outcomes. The authors, working with an Employee and Family Assistance Program provider based in Canada, provided text-based e-mail counseling (cybercounseling) to clients across the country. Cybercounseling was accessible to clients through the same avenues as in-person counseling. Clients self-selected either cybercounseling or in-person counseling at intake. For the purposes of this study, data from 211 clients have been collected, including 105 online and 106 in-person clients. Client demographic data including age, gender, presenting problem, referral source and marital status were collected for each client. Comparing the cyber and in-person client data provides insights into the similarities and differences between cyber and in-person client groups. PMID- 21685659 TI - Towards a web 2.0 based software for the design and the facilitation of cognitive stimulation workshops. AB - Cognitive stimulation workshops (CSW) are recommended for elderly people with a decline in cognitive functions, for example, mild cognitive impairment. Information and Communication Technology (ICT) has the potential to enrich and facilitate preparation, facilitation and assessment of CSW interventions. We present the first steps of our co-design approach towards a Web 2.0 based software, called STIMULEE, for the design and the facilitation of CSW. Its achievement will provide novel therapeutic practices to our clinical partners. PMID- 21685660 TI - Active video gaming to improve balance in the elderly. AB - The combination of active video gaming and exercise (exergaming) is suggested to improve elderly people's balance, thereby decreasing fall risk. Exergaming has been shown to increase motivation during exercise therapy, due to the enjoyable and challenging nature, which could support long-term adherence for exercising balance. However, scarce evidence is available of the direct effects of exergaming on postural control. Therefore, the aim of the study was to assess the effect of a six-week videogame-based exercise program aimed at improving balance in elderly people. Task performance and postural control were examined using an interrupted time series design. Results of multilevel analyses showed that performance on the dot task improved within the first two weeks of training. Postural control improved during the intervention. After the intervention period task performance and balance were better than before the intervention. Results of this study show that healthy elderly can benefit from a videogame-based exercise program to improve balance and that all subjects were highly motivated to exercise balance because they found gaming challenging and enjoyable. PMID- 21685661 TI - Simulated interviews 3.0: virtual humans to train abilities of diagnosis- usability assessment. AB - Diagnostic interviews in Psychology require the mastery of several skills and abilities that are required and need to be trained. The purpose of this study was to develop a virtual environment that simulates a situation where trainees can interact with virtual patients. The usability of the application was assessed. Results suggested that simulated interviews are a friendly and motivating tool to train diagnostic abilities in psychology students. PMID- 21685662 TI - A lightweight augmented virtuality system for providing a faithful and spatially manipulable visual hand representation. AB - This paper introduces the technical foundations of a system designed to embed a lightweight, faithful and spatially manipulable representation of the user's hand into an otherwise virtual world - Augmented Virtuality (AV). A highly intuitive control during pointing-like near space interaction can be provided to the user, as well as a very flexible means to experimenters, in a variety of non-medical and medical contexts. Our approach essentially relies on stereoscopic video see through Augmented Reality (AR) technology and a generic, extendible framework for managing 3-D visual hand displacements. Research from human-computer interaction, perception and motor control has contributed to the elaboration of our proposal which combines a) acting in co-location, b) avoiding occlusion violations by assuring a correct scene depth ordering and c) providing a convincing visual feedback of the user's hand. We further present two cases in which this system has already successfully been used and then outline some other applications that we think are promising, for instance, in the fields of neuromotor rehabilitation and experimental neuroscience. PMID- 21685663 TI - An evidence-based toolset to capture, measure and assess emotional health. AB - We present: (1) an automated telephone check-in system to capture emotional health, based on automatic emotion classification, crowd-sourcing, and the experience sampling method; (2) a method that combines acoustic-based and perception-based emotion classifiers to maximize the likelihood of correctly identifying the emotion in a speech recording; (3) an evidence-based toolkit to measure and assess emotional health; and (4) the results of three experimental trials held in 2010 and 2011: (a) English speaking members of Alcoholics Anonymous, (b) English and French speaking general population, and (c) English speaking Opioid addicts undergoing Suboxone maintenance treatment. Emotional health can be defined as the ability to express emotions, identify one's own emotions, relate to other people's emotions, and to live life with predominantly positive emotions. Emotional health plays a major role in addiction treatment and Cognitive Behavioral Therapy (CBT). PMID- 21685664 TI - Accuracy of a Brain Computer Interface (P300 spelling device) used by people with motor impairments. AB - A Brain-Computer Interface (BCI) provides a completely new output pathway and so, an additional possible way a person can express himself if he/she suffers from disorders like amyotrophic lateral sclerosis (ALS), brainstem stroke, brain or spinal cord injury, or other diseases which impair the function of the common output pathways which are responsible for the control of muscles or impair the muscles. Although most BCIs are thought to help people with disabilities, they are mainly tested on healthy, young subjects who may achieve better results than people with impairments. In this study we compare measurements, performed on 10 physically disabled people, to the results of a previous study, taken using 100 healthy participants. We prove that, under certain constraints, most patients are able to control a P300-based spelling device with almost the same accuracy as the healthy ones. Tuning parameters are discussed, as well as criteria for people who are not able to use this device. PMID- 21685665 TI - Interweaving interactions in virtual worlds: a case study. AB - The aim of this study was to examine the effect of playing the online game World of Warcraft (WoW), both on adolescent's (effective) social interaction and on the competence they developed on it. Social interactions within the game environment have been investigated by integrating qualitative and quantitative methods: conversation analysis and social network analysis (SNA). From a psychosocial point of view, the in-game interactions, and in particular conversational exchanges, turn out to be a collaborative path of the joint definition of identities and social ties, with reflection on in-game processes and out-game relationship. PMID- 21685666 TI - Startle reactivity in acute stress disorder and posttraumatic stress disorder. AB - The aim of this study is to prospectively examine electromyographic (EMG) responses in patients diagnosed with acute stress disorder (ASD) after experiencing a traffic accident or violent attack, within one month after the traumatic event and six months later. Half of the participants met criteria for posttraumatic stress disorder (PTSD) after six months. Psychophysiological parameters can provide a better clarification between ASD and PTSD patients. Heightened startle magnitude in the immediate aftermath of trauma may be a good predictor of PTSD; moreover, a lack of startle habituation appears to be a more stable marker of PTSD, which persists for six months after trauma exposure. PMID- 21685667 TI - Immersive virtual environments for emotional engineering: description and preliminary results. AB - This work aims to identify the arousal and presence level during an emotional engineering study. During the experimental sessions, a high-immersion Virtual Reality (VR) system, a CAVE-like configuration, will be used. Thirty-six volunteers will navigate through virtual houses that can be customized and that have been designed for emotional induction. Emotional induction will be obtained by stimulating the senses of sight, hearing and smell. For this purpose, the ambient lighting, music and smell will be controlled by the researcher, who will create a comfortable environment for the subject. Several physiological variables - Electrocardiogram (ECG), Respiratory signal and Galvanic Skin Response (GSR) - will be recorded during the sessions. The obtained results will help furniture companies identify the senses that have more influence on emotions and will be the basis for new studies about user needs in the sector of furniture and interior decoration. PMID- 21685668 TI - Asynchronous sampling for ultrafast experiments with low momentum compaction at the ANKA ring. AB - A high-repetition-rate pump-probe experiment is presented, based on the asynchronous sampling approach. The low-alpha mode at the synchrotron ANKA can be used for a time resolution down to the picosecond limit for the time-domain sampling of the coherent THz emission as well as for hard X-ray pump-probe experiments, which probe structural dynamics in the condensed phase. It is shown that a synchronization of better than 1 ps is achieved, and examples of phonon dynamics of semiconductors are presented. PMID- 21685669 TI - A differential pumping system to deliver windowless VUV photons at atmospheric pressure. AB - In order to deliver VUV (vacuum ultraviolet) photons under atmospheric pressure conditions, a differential pumping system has been built on the DISCO beamline at the SOLEIL synchrotron radiation facility. The system is made of four stages and is 840 mm long. The conductance-limiting body has been designed to allow practicable optical alignment. VUV transmission of the system was tested under air, nitrogen, argon and neon, and photons could be delivered down to 60 nm (20 eV). PMID- 21685670 TI - Calculation of anisotropic properties of dental enamel from synchrotron data. AB - Obtaining information about the intrinsic structure of polycrystalline materials is of prime importance owing to the anisotropic behaviour of individual crystallites. Grain orientation and its statistical distribution, i.e. the texture, have an important influence on the material properties. Crystallographic orientations play an important role in all kinds of polycrystalline materials such as metallic, geological and biological. Using synchrotron diffraction techniques the texture can be measured with high local and angular resolving power. Here methods are presented which allow the spatial orientation of the crystallites to be determined and information about the anisotropy of mechanical properties, such as elastic modulus or thermal expansion, to obtained. The methods are adapted to all crystal and several sample symmetries as well as to different phases, for example with overlapping diffraction peaks. To demonstrate the abilities of the methods, human dental enamel has been chosen, showing even overlapping diffraction peaks. Likewise it is of special interest to learn more about the orientation and anisotropic properties of dental enamel, since only basic information is available up to now. The texture of enamel has been found to be a tilted fibre texture of high strength (up to 12.5*). The calculated elastic modulus is up to 155 GPa and the thermal expansion up to 22.3 * 10(-6) degrees C( 1). PMID- 21685671 TI - Atomic absorption background of Ba in EXAFS analysis of BaFe(12)O(19) nanoparticles. AB - The approximate barium X-ray atomic absorption in the energy region of L-edges is reconstructed from the absorption spectrum of an aqueous solution of BaCl(2). The result is corroborated by comparison with pure atomic absorption spectra of neighbour elements Xe and Cs. The application of the atomic absorption signal as a proper EXAFS background is demonstrated and discussed in the analysis of Ba hexaferrite nanoparticles with a very weak structural signal. The essential gain is found in the decrease of uncertainty intervals of structural parameters and their correlations. A simple analytical model of the absorption background for the practical EXAFS analysis is demonstrated. PMID- 21685672 TI - Hard X-ray Fourier transform holography from an array of oriented referenced objects. AB - Hard X-ray Fourier transform holography (HXFTH) is a promising method for imaging nanoscale objects, including biological molecules, with a spatial resolution of a nanometer or better. However, it suffers from low scattering intensities being available for imaging owing to smaller object size and the low scattering cross section inherent in hard X-rays. One technique to overcome the problem would be to use an array of oriented objects, each with its own reference. Here the feasibility of this approach was experimentally tested by recording diffraction patterns from nanofabricated test patterns arranged in a 5 * 5 matrix. At an X ray energy of 8 keV (lambda = 1.55 A), the image of the original test pattern was clearly restored with 60 s exposure on an imaging plate; the image was still recognizable with a 500 ms exposure on a CCD detector at the BL40XU beamline at SPring-8. The results demonstrate that the use of an array of referenced oriented objects for HXFTH is workable, and that it can be considered as a practical candidate for imaging biological molecules, identical particles of which are available but diffract even more weakly than artificially fabricated test patterns. PMID- 21685673 TI - Development of an X-ray real-time stereo imaging technique using synchrotron radiation. AB - An X-ray stereo imaging system with synchrotron radiation was developed at BL20B2, SPring-8. A portion of a wide X-ray beam was Bragg-reflected by a silicon crystal to produce an X-ray beam which intersects with the direct X-ray beam. Samples were placed at the intersection point of the two beam paths. X-ray stereo images were recorded simultaneously by a detector with a large field of view placed close to the sample. A three-dimensional wire-frame model of a sample was created from the depth information that was obtained from the lateral positions in the stereo image. X-ray stereo angiography of a mouse femoral region was performed as a demonstration of real-time stereo imaging. Three-dimensional arrangements of the femur and blood vessels were obtained. PMID- 21685674 TI - Achromatic nested Kirkpatrick-Baez mirror optics for hard X-ray nanofocusing. AB - The first test of nanoscale-focusing Kirkpatrick-Baez (KB) mirrors in the nested (or Montel) configuration used at a hard X-ray synchrotron beamline is reported. The two mirrors are both 40 mm long and coated with Pt to produce a focal length of 60 mm at 3 mrad incident angle, and collect up to a 120 um by 120 um incident X-ray beam with maximum angular acceptance of 2 mrad and a broad bandwidth of energies up to 30 keV. In an initial test a focal spot of about 150 nm in both horizontal and vertical directions was achieved with either polychromatic or monochromatic beam. The nested mirror geometry, with two mirrors mounted side-by side and perpendicular to each other, is significantly more compact and provides higher demagnification than the traditional sequential KB mirror arrangement. Ultimately, nested mirrors can focus larger divergence to improve the diffraction limit of achromatic optics. A major challenge with the fabrication of the required mirrors is the need for near-perfect mirror surfaces near the edge of at least one of the mirrors. Special polishing procedures and surface profile coating were used to preserve the mirror surface quality at the reflecting edge. Further developments aimed at achieving diffraction-limited focusing below 50 nm are underway. PMID- 21685676 TI - Automatic loop centring with a high-precision goniometer head at the SLS macromolecular crystallography beamlines. AB - Automatic loop centring has been developed as part of the automation process in crystallographic data collection at the Swiss Light Source. The procedure described here consists of an optional set-up part, in which the background images are taken, and the actual centring part. The algorithm uses boundary and centre-of-mass detection at two different microscope image magnifications. Micromounts can be handled as well. Centring of the loops can be achieved in 15 26s, depending on their initial position, and as fast as manual centring. The alignment of the sample is carried out by means of a new flexural-hinge-based compact goniometer head. The device features an electromagnet for robotic wet mounting of samples. The circle of confusion was measured to be smaller than 1 um (r.m.s.); its bidirectional backlash is below 2 um. PMID- 21685675 TI - Radiation-induced melting in coherent X-ray diffractive imaging at the nanoscale. AB - Coherent X-ray diffraction techniques play an increasingly significant role in the imaging of nanoscale structures, ranging from metallic and semiconductor to biological objects. In material science, X-rays are usually considered to be of a low-destructive nature, but under certain conditions they can cause significant radiation damage and heat loading on the samples. The qualitative literature data concerning the tolerance of nanostructured samples to synchrotron radiation in coherent diffraction imaging experiments are scarce. In this work the experimental evidence of a complete destruction of polymer and gold nanosamples by the synchrotron beam is reported in the case of imaging at 1-10 nm spatial resolution. Numerical simulations based on a heat-transfer model demonstrate the high sensitivity of temperature distribution in samples to macroscopic experimental parameters such as the conduction properties of materials, radiation heat transfer and convection. However, for realistic experimental conditions the calculated rates of temperature rise alone cannot explain the melting transitions observed in the nanosamples. Comparison of these results with the literature data allows a specific scenario of the sample destruction in each particular case to be presented, and a strategy for damage reduction to be proposed. PMID- 21685677 TI - Measurement of persistence in YAG:Ce(3+)scintillator with pulsed synchrotron X rays. AB - The decay time of YAG:Ce(3+) phosphor was studied using a CMOS camera with a frame rate of 1302000 s(-1) and pulsed X-rays from SPring-8. A high-resolution X ray detector with YAG:Ce(3+) was used with the camera to view the focused beam from the helical undulator. Mismatch between the ring circulation time and the frame time gave rise to a periodic variation of beam intensity in successive frames. Analysis of data obtained with two bunch modes showed that the decay time of YAG:Ce(3+) was 60 ns. The variation of the beam positions in isolated bunches was small enough to be neglected in experiments using the focused beam. The results also show the possibility of an X-ray diffraction study at high time and space resolution. PMID- 21685678 TI - Six-reflection meV-monochromator for synchrotron radiation. AB - An in-line monochromatization scheme suitable for 10-40 keV synchrotron radiation is presented based on the use of six crystal reflections that achieves meV and sub-meV bandwidths with high efficiency. The theoretical spectral efficiency surpasses all previous multicrystal designs and approaches that of single room temperature back-reflecting crystals. This article presents the designs of two such devices along with their theoretical and measured performances. PMID- 21685679 TI - SPIO-RGD nanoparticles as a molecular targeting probe for imaging tumor angiogenesis using synchrotron radiation. AB - Angiogenesis, new blood vessels sprouting from pre-existing vessels, is essential to tumor growth, invasion and metastasis. It can be used as a biomarker for early stage tumor diagnosis and targeted therapy. To visualize angiogenesis many molecular imaging modalities have been used. In this study a novel X-ray molecular targeting probe using superparamagnetic iron oxide (SPIO) conjugated with arginine-glycine-aspartic acid (SPIO-RGD) has been developed. Based on the extremely high sensitivity to the iron element of synchrotron radiation X-ray fluorescence and the superior spatial resolution of third-generation synchrotron radiation, the feasibility of SPIO-RGD as a promising molecular probe for imaging tumor angiogenesis has been demonstrated. PMID- 21685680 TI - ANKAphase: software for single-distance phase retrieval from inline X-ray phase contrast radiographs. AB - A computer program named ANKAphase is presented that processes X-ray inline phase contrast radiographs by reconstructing the projected thickness of the object(s) imaged. The program uses a single-distance non-iterative phase-retrieval algorithm described by David Paganin et al. [(2002), J. Microsc. 206, 33-40]. Allowing for non-negligible absorption in the sample, this method is strictly valid only for monochromatic illumination and single-material objects but tolerates deviations from these conditions, especially polychromaticity. ANKAphase is designed to be applied to tomography data (although it does not perform tomographic reconstruction itself). It can process series of images and perform flat-field and dark-field correction. Written in Java, ANKAphase has an intuitive graphical user interface and can be run either as a stand-alone application or as a plugin to ImageJ, a widely used scientific image-processing program. A description of ANKAphase is given and example applications are shown. PMID- 21685681 TI - DNA damage and repair kinetics after microbeam radiation therapy emulation in living cells using monoenergetic synchrotron X-ray microbeams. AB - A novel synchrotron-based approach, known as microbeam radiation therapy (MRT), currently shows considerable promise in increased tumour control and reduced normal tissue damage compared with conventional radiotherapy. Different microbeam widths and separations were investigated using a controlled cell culture system and monoenergetic (5.35 keV) synchrotron X-rays in order to gain further insight into the underlying cellular response to MRT. DNA damage and repair was measured using fluorescent antibodies against phosphorylated histone H2AX, which also allowed us to verify the exact location of the microbeam path. Beam dimensions that reproduced promising MRT strategies were used to identify useful methods to study the underpinnings of MRT. These studies include the investigation of different spatial configurations on bystander effects. gammaH2AX foci number were robustly induced in directly hit cells and considerable DNA double-strand break repair occurred by 12 h post-10 Gy irradiation; however, many cells had some gammaH2AX foci at the 12 h time point. gammaH2AX foci at later time points did not directly correspond with the targeted regions suggesting cell movement or bystander effects as a potential mechanism for MRT effectiveness. Partial irradiation of single nuclei was also investigated and in most cases gammaH2AX foci were not observed outside the field of irradiation within 1 h after irradiation indicating very little chromatin movement in this time frame. These studies contribute to the understanding of the fundamental radiation biology relating to the MRT response, a potential new therapy for cancer patients. PMID- 21685682 TI - Fast X-ray powder diffraction on I11 at Diamond. AB - The commissioning and performance characterization of a position-sensitive detector designed for fast X-ray powder diffraction experiments on beamline I11 at Diamond Light Source are described. The detecting elements comprise 18 detector-readout modules of MYTHEN-II silicon strip technology tiled to provide 90 degrees coverage in 2theta. The modules are located in a rigid housing custom designed at Diamond with control of the device fully integrated into the beamline data acquisition environment. The detector is mounted on the I11 three-circle powder diffractometer to provide an intrinsic resolution of Delta2theta approximately equal to 0.004 degrees . The results of commissioning and performance measurements using reference samples (Si and AgI) are presented, along with new results from scientific experiments selected to demonstrate the suitability of this facility for powder diffraction experiments where conventional angle scanning is too slow to capture rapid structural changes. The real-time dehydrogenation of MgH(2), a potential hydrogen storage compound, is investigated along with ultrafast high-throughput measurements to determine the crystallite quality of different samples of the metastable carbonate phase vaterite (CaCO(3)) precipitated and stabilized in the presence of amino acid molecules in a biomimetic synthesis process. PMID- 21685683 TI - Synchrotron scanning photoemission microscopy of homogeneous and heterogeneous metal sulfide minerals. AB - Scanning photoemission microscopy (SPEM) has been applied to the investigation of homogeneous and heterogeneous metal sulfide mineral surfaces. Three mineral samples were investigated: homogeneous chalcopyrite, heterogeneous chalcopyrite with bornite, and heterogeneous chalcopyrite with pyrite. Sulfur, copper and iron SPEM images, i.e. surface-selective elemental maps with high spatial resolution acquired using the signal from the S 2p and Cu and Fe 3p photoemission peaks, were obtained for the surfaces after exposure to different oxidation conditions (either exposed to air or oxidized in pH 9 solution), in addition to high resolution photoemission spectra from individual pixel areas of the images. Investigation of the homogeneous chalcopyrite sample allowed for the identification of step edges using the topography SPEM image, and high-resolution S 2p spectra acquired from the different parts of the sample image revealed a similar rate of surface oxidation from solution exposure for both step edge and a nearby terrace site. SPEM was able to successfully distinguish between chalcopyrite and bornite on the heterogeneous sample containing both minerals, based upon sulfur imaging. The high-resolution S 2p spectra acquired from the two regions highlighted the faster air oxidation of the bornite relative to the chalcopyrite. Differentiation between chalcopyrite and pyrite based upon contrast in SPEM images was not successful, owing to either the poor photoionization cross section of the Cu and Fe 3p electrons or issues with rough fracture of the composite surface. In spite of this, high-resolution S 2p spectra from each mineral phase were successfully obtained using a step-scan approach. PMID- 21685684 TI - BioCARS: a synchrotron resource for time-resolved X-ray science. AB - BioCARS, a NIH-supported national user facility for macromolecular time-resolved X-ray crystallography at the Advanced Photon Source (APS), has recently completed commissioning of an upgraded undulator-based beamline optimized for single-shot laser-pump X-ray-probe measurements with time resolution as short as 100 ps. The source consists of two in-line undulators with periods of 23 and 27 mm that together provide high-flux pink-beam capability at 12 keV as well as first harmonic coverage from 6.8 to 19 keV. A high-heat-load chopper reduces the average power load on downstream components, thereby preserving the surface figure of a Kirkpatrick-Baez mirror system capable of focusing the X-ray beam to a spot size of 90 um horizontal by 20 um vertical. A high-speed chopper isolates single X-ray pulses at 1 kHz in both hybrid and 24-bunch modes of the APS storage ring. In hybrid mode each isolated X-ray pulse delivers up to ~4 * 10(10) photons to the sample, thereby achieving a time-averaged flux approaching that of fourth generation X-FEL sources. A new high-power picosecond laser system delivers pulses tunable over the wavelength range 450-2000 nm. These pulses are synchronized to the storage-ring RF clock with long-term stability better than 10 ps RMS. Monochromatic experimental capability with Biosafety Level 3 certification has been retained. PMID- 21685685 TI - A narrow microbeam is more effective for tumor growth suppression than a wide microbeam: an in vivo study using implanted human glioma cells. AB - The tumoricidal mechanisms of microbeam radiation therapy, and the more recently proposed minibeam radiation therapy, for the treatment of brain tumors are as yet unclear. Moreover, from among the various parameters of beam geometry the impact of changing the beam width is unknown. In this study, suppression of tumor growth in human glioma cells implanted in mice was evaluated experimentally using microbeams of two different widths: a conventional narrow beam (20 um width, 100 um center-to-center distance) and a wide beam (100 um width, 500 um center-to center distance). The tumor growth ratio was compared and acute cell death was studied histologically. With cross-planar irradiation, tumor growth was significantly suppressed between days 4 and 28 after 20 um microbeam irradiation, whereas tumor growth was suppressed, and not significantly so, only between days 4 and 18 after 100 um microbeam irradiation. Immunohistochemistry using TUNEL staining showed no increase in TUNEL-positive cells with either microbeam at 24 and 72 h post-irradiation. The 20 um microbeam was found to be more tumoricidal than the 100 um microbeam, and the effect was not related to apoptotic cell death. The underlying mechanism may be functional tissue deterioration rather than direct cellular damage in the beam path. PMID- 21685686 TI - Background subtraction for fluorescence EXAFS data of a very dilute dopant Z in Z + 1 host. AB - When conducting EXAFS at the Cu K-edge for ZnS:Cu with very low Cu concentration (<0.04% Cu), a large background was present that increased with energy. This background arises from a Zn X-ray Raman peak, which moves through the Cu fluorescence window, plus the tail of the Zn fluorescence peak. This large background distorts the EXAFS and must be removed separately before reducing the data. A simple means to remove this background is described. PMID- 21685687 TI - Beamline 08ID-1, the prime beamline of the Canadian Macromolecular Crystallography Facility. AB - Beamline 08ID-1 is the prime macromolecular crystallography beamline at the Canadian Light Source. Based on a small-gap in-vacuum undulator, it is designed for challenging projects like small crystals and crystals with large cell dimensions. Beamline 08ID-1, together with a second bending-magnet beamline, constitute the Canadian Macromolecular Crystallography Facility (CMCF). This paper presents an overall description of the 08ID-1 beamline, including its specifications, beamline software and recent scientific highlights. The end station of the beamline is equipped with a CCD X-ray detector, on-axis crystal visualization system, a single-axis goniometer and a sample automounter allowing remote access to the beamline. The general user program is guaranteed up to 55% of the useful beam time and is run under a peer-review proposal system. The CMCF staff provide 'Mail-in' crystallography service to the users with the highest scored proposals. PMID- 21685690 TI - Hepatocyte-targeted gene transfection of galactosylated chitosan-graft low molecular polyethyleneimine/DNA complexes. AB - OBJECTIVE: To investigate the hepatocyte targeted specific property of galactosylated chitosan-graft-polyethyleneimine (GC-PEI)/DNA complexes in vitro and in vivo. METHODS: With the plasmid expressing enhanced green fluorescent protein (pEGFP-C1) as the reporter gene, the formation of GC-PEI/DNA complexes was induced to self-assemble in 0.01 mol/L phosphate buffered saline(PBS), 150 mmol/L NaCl, or 5% glucose solution (GS).The complexes were characterized by the particle size, Zeta potential, DNA binding and protection capacity, and further tested for cytotoxicity and hepatocyte targeted transfection activity. RESULTS: With the GC-PEI/DNA mass ratio from 1:1 to 2.5:1,the GC-PEI/DNA complexes effectively bound and protected the DNA from degradation of DNaseI and the serum, which presented as a well-formed sphere or compacted nucleocapsid structure at a diameter of 50-200 nm. The GC-PEI copolymer showed no obvious toxicity in the tested cell lines. Acute toxicity assay revealed that the mice grew well in 2 weeks with GC-PEI dosage from 50 to 300 MUg. The assay by flow cytometry and fluorescent microscope showed that the transfection efficiency in hepatocyte lines (L02, QSG7701/core) was higher than that in non-hepatocyte lines (SGC7901, HBE) in vitro. In vivo, the GFP was obviously expressed in the liver tissue and not expressed in other organs 48 h after the transfection. CONCLUSION: GC-PEI copolymer may carry the exogenous gene specifically to hepatocytes in vitro and in vivo,which has very good liver targeted specific property. PMID- 21685691 TI - MAGI1 inhibits cancer cell migration and invasion of hepatocellular carcinoma via regulating PTEN. AB - OBJECTIVE: To explore the biological function and molecular mechanism of membrane associated guanylate kinase, WW and PDZ domain containing 1 (MAGI1) in hepatocellular carcinoma. METHODS: HepG2(MAGI1) stable cell line was constructed by transfecting HepG2 cells with pcDNA3.1-MAGI1 plasmid. Wound healing and invasion assay were performed to compare the migration and invasion ability of HepG2(MAGI1) and HepG2 cells. Furthermore, the expression of MAGI1 and phosphatase and tensin homolog deleted on chromosome ten (PTEN) was also examined by Western blot and the relationship was analyzed. RESULTS: The wound healing assay showed that the closure of HepG2(MAGI1) cells was significantly slower than that of HepG2 cells [(90 +/- 10)% vs. (50 +/- 15)%, P<0.05], and the invasion assay showed that the number of HepG2(MAGI1) cells that passed through the matrigel was fewer than HepG2 cells (68 +/- 18 vs. 150 +/- 30, P<0.05). The protein expression level of PTEN was significantly elevated in HepG2(MAGI1) cells compared with HepG2 cells (1.40 +/- 0.32 vs. 0.28 +/- 0.15, P<0.05). MAGI1 and PTEN protein expression levels were positively correlated (r=0.913, P<0.01). CONCLUSION: MAGI1 may inhibit the cancer cell migration and invasion of hepatocellular carcinoma via regulating PTEN. PMID- 21685693 TI - IL-10 overexpression attenuated expression of TNF-alpha and IL-1beta activated by lipopolysaccharide in astrocytes. AB - OBJECTIVE: To investigate the intervention effect of lentivirus expressing human IL-10 (LV-hIL-10) on activated astrocytes. METHODS: DI TNC1 cell line was treated with different concentrations of lipopolysaccharide (LPS) and time points. The expression of proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukinb-1beta (IL-1beta) was detected by RT-PCR and ELISA. Moreover, the effect on the expression of proinflammatory cytokines TNF-alpha and IL-1beta was analyzed in DI TNC1 cell lines infected with and without LV-hIL-10. RESULTS: The expression of TNF-alpha and IL-1beta was increased in DI TNC1 induced by LPS. The expression of IL-10 was upregulated in DI TNC1 infected with LV-hIL-10. TNF-alpha and IL-1beta were inhibited by IL-10 overexpression in DI TNC1 actived by LPS. CONCLUSION: DI TNC1 is activated by LPS and secretes proinflammatory cytokines TNF-alpha and IL-1beta as immune-like cells, and these activation is inhibited by hIL-10 overexpression. PMID- 21685692 TI - Nerve growth factor induced expression of iNOS and substance P in dorsal root ganglion sensory neuron and interferon regulatory factor-1. AB - OBJECTIVE: To investigate the mechanism of airway neurogenic inflammation by studying the expression of inducible nitric oxide synthase (iNOS) and substance P in C(7)-T(5) dorsal root ganglion sensory neuron cells induced by nerve growth factor (NGF) and the role of interferon regulatory factor-1 (IRF-1). METHODS: The dorsal root ganglia neuron (DRGn) cells were primary cultured, and then stimulated with or without NGF or NGF+interferon (IFN)-gamma. Subsequently the DRGn cells were transinfected with or without green fluorescent protein (GFP)-IRF 1-vshRNA, and then stimulated with or without NGF. The expressions of iNOS and substance P were detected by real-time PCR. RESULTS: NGF induced the mRNA expression of iNOS and substance P in dorsal root ganglion sensory neuron cells, and IFN-gamma increased NGF-induced iNOS mRNA expression. The expressions of iNOS and substance P in sensory neuron cells were decreased significantly at the mRNA level after IRF-1 was blocked down by IRF-1-vshRNA transinfection. CONCLUSION: NGF is involved in the airway neurogenic inflammation by prompting the expression of iNOS and substance P through transcription factor IRF-1 in airway sensory neuron cells. IRF-1 may be a therapeutic target for airway neurogenic inflammation. PMID- 21685694 TI - Construction of Gadd45a expression plasmid and its expression in human T cells. AB - OBJECTIVE: To construct Gadd45a expression plasmid and induce its expression in human T cells. METHODS: Gadd45a was amplified by reverse transcription PCR from human embryonic stem cells, and cloned into the pcDNA3.1 vector.The recombinant plasmid or blank plasmid was transfected into Jurkat cells or normal human CD4(+)T cells using electroporation, and the expression of Gadd45a was detected by quantitative RT-PCR and Western blot. RESULTS: Human Gadd45a expression plasmid was constructed successfully. Gadd45a was overexpressed both in Jurkat cells and normal human CD4+T cells after these cells were transfected with pcDNA3.1-Gadd45a. CONCLUSION: The construction of Gadd45a expression plasmid and induction of Gadd45a overexpression in human T cells lay the foundation for further research on the role of Gadd45a in the epigenetic mechanism. PMID- 21685695 TI - Effect of human umbilical cord blood stem cells on flash visual evoked potential in traumatic optic neuropathy in rats. AB - OBJECTIVE: To investigate the effect of human umbilical cord blood stem cells on flash visual evoked potentials (F-VEP) of the traumatic optic neuropathy rats. METHODS: Forty-eight Sprague-Dawley rats were randomly divided into an injury group (Group A) and 3 treatment groups (Groups B, C, and D). A traumatic optic neuropathy model was built in Group A, and the rats in Groups B, C, and D were injected with the neurotrophic factor, human umbilical cord blood stem cells, and the mixture of the neurotrophic factor and human umbilical cord blood stem cells, respectively. F-VEP was recorded in both eyes of rats at the 1st h, 1st week, 2nd week, 3rd week, and 4th week after the optic nerve injury. RESULTS: At all time points, there were significant difference in the wave latency and amplitude between Group A and normal control eyes (P<0.01). The differences of the wave latency and amplitude between Group A and Groups B, C, and D were statistically significant at various time points after the injury except for the wave latency at the 1st h post-operation (P<0.05). The amplitude in Group D was higher while the latency was shorter than those of Group B at all time points since the 1st week (P<0.05). The comparisons at the same point in the remaining treatment groups were not significantly different (P<0.05). CONCLUSION: The mixture of human umbilical cord blood stem cells and neurotrophic factor has a promotion effect for the recovery of F-VEP of optic nerve in traumatic optic neuropathy in rats to some degrees. PMID- 21685696 TI - [Treatment of acute liver injury by intrasplenic transplantation of hepatic stem cells combined with heparin in rats]. AB - OBJECTIVE: To determine the treatment effects of transplanted hepatic progenitor cells (WB-F344 cells) combined with heparin on the acute liver injury in SD rats. METHODS: A total of 2*10(7) hepatic stem cells (WB-F344) infected with GFP lentivirus and 8 MUL heparin were transplanted through the spleen in SD rats with acute liver injury, which was induced by an intraperitoneal injection of CCl4. The liver and spleen tissues underwent fluorescence examination 1 day after the transplantation. The liver functions were tested, and the liver tissues were histopathologically examined on the 3rd, 7th, 14th, and 28th day of the cell transplantation. RESULTS: The transfected WB-F344 cells expressed GFP 3 days after the lentivirus infection and were found in the rat liver 1 day after the WB F344 transplantation. The liver function and histopathological recovery of the liver tissues in the group of WB-F344 transplantation were better than those of the control group (P<0.05). CONCLUSION: Transplantation of hepatic stem cells combined with heparin can promote the liver recovery in rats with acute liver injury induced by CCl4. PMID- 21685697 TI - [Experimental study of rabbit bone mesenchymal stem cells seeding onto xenogenic calf cortical bone with partial trabecular bone]. AB - OBJECTIVE: To explore the possibility of xenogenic calf cortical bone with partial trabecular bone as cell carriers in tissue engineering, and to provide direct evidence for clinical application of matrix scaffold. METHODS: Rabbit bone mesenchymal stem cells (BMSCs) were seperated and cultured on the surface of xenogenic calf cortical bone with partial trabecular bone. Relative growth rate was measured and cytotoxicity was graded. The growth, proliferation and matrix secretion of BMSCs in calf cortical strut were observed by scanning electron microscope. Sixty 3-month-old New Zealand rabbits were divided into 3 groups (20 in each group): a BMSCs/bone xenograft group, a simple bone xenograft group and an autogenous iliac bone group. Each group was implanted with the BMSCs induced osteogenic composite calf bone, simple bone xenograft and autogenous iliac bone into the ala of ilium. The expressions of bone morphogenetic protein-2 (BMP-2) mRNA were detected by reverse transcription polymerase chain reaction in 4, 8, 12, 24 weeks after the operation. RESULTS: The toxicity gradation was 0 to 1. BMSCs adhered the surface of calf cortical strut and extended in the cancellous bone, and extracellular matrices were found. The BMP-2 mRNA expression in the simple bone xenograft group was lower than that in the BMSCs/bone xenograft group and the autogenous iliac bone group at all time points (P<0.05),which was lower in the BMSCs/bone xenograft group than that in the autogenous iliac bone group (P<0.05). CONCLUSION: Rabbit BMSCs combined with calf cortical bonescaffold with partial cancellous bone have good osteogenic capacity in the New Zealand rabbits. PMID- 21685698 TI - [Role of LRRN3 in the cerebellum postnatal development in rats]. AB - OBJECTIVE: To explore the effect and possible mechanism of LRRN3 in the cerebellum postnatal development in rats. METHODS: New born rats were randomly divided into an experimental group and a control group, and each group included 3 sub-groups of different time points. Behavioral experiment, hematoxylin-eosin (HE) staining and immunohistochemistry were used to evaluate the effects of anti LRRN3 injection on the cerebellum development in new born rats. RESULTS: Compared with the control, the balance ability in the experiment group was weak, and there was significant difference in the static balance between the 2 groups (P<0.05). HE staining showed that molecular layer (ML) grew thicker from the 7th day to the 21st day after birth,and the structure changed dynamically. Vesicular glutamate transporter 1(VGluT1) expression was positive in the cerebellum of all groups, and the positive ML grew thicker from the 7th day to the 21st day after birth. Compared with the control, there was no obvious difference between the 2 groups on the 7th day after birth (P<0.05), while on the 14th day and the 21st day, there was significant difference (P<0.01). CONCLUSION: LRRN3 plays an important role in cerebellum postnatal development. Anti-LRRN3 antibody injection may down regulate the expression of VGluT1, reduce the synapse formation in the molecular layer,decrease the thickness of ML and inhibit the growth of cerebellum cortex and the functional neural circuit formation. PMID- 21685699 TI - [Retroperitoneoscopic dismembered pyeloplasty for pediatric ureteropelvic junction obstruction: a report of 85 cases]. AB - OBJECTIVE: To investigate the clinical application of retroperitoneoscopic dismembered pyeloplasty for pediatric ureteropelvic junction obstruction (UPJO). METHODS: Of the 85 pediatric patients with UPJO, 56 were boys and 29 were girls. The age of the patients ranged from 2.5 to 11 years (mean = 4.6 years).B ultrasonography showed hydronephrosis <15 mm (mild) in 15 patients,15-30 mm (moderate) in 59, <30 mm (severe) in the other 6. Intravenous urography (IVU) showed good imaging in 55 patients within 30 min, light imaging in 27 at 30-120 min, and no imaging in 3 after 120 min. The 85 patients underwent retroperitoneoscopic dismembered pyeloplasty. Conventional antegrade or modified antegrade double-J stenting was inserted in the 85 patients intraoperatively. RESULTS: The operation was successful in all, with no conversion to open surgery during the operation. The mean operation time was 146 min (125-240 min).The mean blood loss was 68 mL (55-112 mL).The mean postoperative hospitalization was 7 d (6-8 d ).Urine leakage occurred in 1 patient and with a good drainage, urine leakage disappeared in 1 week. Follow-up ranged 3-24 months (mean = 11 months).IVU showed on UPJ stricture, and good imaging in 75 patients within 30 min, light imaging in 10 at 30-120 min. Hydronephrosis was remitted:hydronephrosis resolution in 51 patients, mild in 6 and moderate in 3. CONCLUSION: Retroperitoneoscopic dismembered pyeloplasty is a safe, effective and mini-invasive procedure for pediatric ureteropelvic junction obstruction, with a rapid postoperative recovery. It will be the ideal treatment for UPJO in pediatric patients. PMID- 21685700 TI - [Reoperative valve surgery after open-heart valve surgery: a report of 155 cases]. AB - OBJECTIVE: To summarize the characteristics of reoperative valve surgery after previous open-heart valve surgery. METHODS: From 1996 to 2010, 155 patients who underwent reoperative valve surgery, either valve replacement or tricuspid annuloplasty or the repair of perivalvular leakage were included in the study. The reoperative interval was 1-266 (94.82 +/- 85.37) months. All surgeries were carried out with extracorporeal circulation under moderated hypothermia. The cardioplegic solution in cold crystal or blood was used if heart beating was stopped during the surgery. RESULTS: The total in-hospital mortality was 5.81%, while it was 2.75% from 2005 to 2010. The end-diastolic dimension, size of atrium and ventricles were reduced after the reoperation. Ventricular arrhythmia and low cardiac output were the most frequent complications. CONCLUSION: The success rate of reoperative valve surgery can be improved by the distinctive therapeutic strategies based on the clinical characteristics and therapy principles obtained from practice experiences. PMID- 21685701 TI - [Sperm-oocyte interaction and in vitro fertilization clinical outcomes in patients with unexplained infertility]. AB - OBJECTIVE: To determine the sperm-zona pellucida (ZP) binding and ZP-induced acrosome reaction in patients with unexplained infertility, and to discuss the relationship between ZP-induced acrosome reaction and fertilization rate. METHODS: We compared the fertilization rate and good embryo rate in patients with unexplained infertility after fertilization in 2 ways. Based on the causes of infertility, patients were divided into an unexplained infertility group (Group A) and a pure female tubal factor group (Group B). Oocytes which were obtained by super ovulation from 25 patients with unexplained infertility were randomly divided into 2 groups with conventional in vitro fertilization (IVF) (Group A1) and intracytoplasmic sperm injection (ICSI) fertilization (Group A2). The pure female tubal factor group (Group B) had conventional IVF. We conducted sperm-ZP binding and ZP-induced acrosome reaction experiments with 2 groups of men's sperms separately. We compared the number of sperm-egg binding and ZP-induced acrosome reaction rate and discussed the relationship between the ZP-induced acrosome reaction and fertilization rate, and also the fertilization rate, good embryo rate and pregnancy rate in patients with unexplained infertility after fertilization in 2 ways. RESULTS: The average number of sperm-egg binding (78.29 +/- 16.31) and the ZP-induced acrosome reaction rate (55.87 +/- 27.69) % in Group A were lower than those of Group B [94.63 +/- 6.72, (82.53 +/- 17.99)%]. The difference between the average number of sperm-egg binding and the ZP-induced acrosome reaction was significant (P <0.01). The fertilization rate of Group A1 was significantly lower than that of Group B and Group A2 (P <0.01). But there was no significant difference in the good embryo rate among the 3 groups. There was no significant difference between Group A2 and B in fertilization rate and good embryo rate (P <0.05). There was no significant difference in pregnancy rate between Group A and B (P <0.05). Fertilization rate and the rate of acrosome reaction had marked positive correlation with statistical significance (r =0.932, P <0.01). CONCLUSION: ZP binding and ZP-induced acrosome reaction are very important experiments in sperm function test for patients with unexplained infertility. It can not only effectively avoid no embryo transferring due to complete failure of fertilization but also get a desirable outcome of pregnancy using half-ICSI fertilization in patients with unexplained infertility. PMID- 21685702 TI - [Attitude of elementary and middle school students and their parents toward children affected by HIV/AIDS and its determinants]. AB - OBJECTIVE: To describe the attitude of elementary and middle school students and their parents toward children affected by HIV/AIDS and to analyze the determinants of such attitude. METHODS: A cross-sectional study with the stratified cluster sampling method was conducted to interview elementary and middle school students and their parents, and questionnaires were distributed to collect information about the basic characteristics, HIV/AIDS knowledge and attitude toward children affected by HIV/AIDS. Student's t-test, ANOVA and multilevel model were used to analyze the data. RESULTS: A total of 732 students and their parents finished the questionnaires. The students' and parents' awareness rates were 77.56% (95% CI: 63.08% - 92.05%)and 81.76% (95% CI: 72.33% - 91.20%), respectively. Questions with the lowest proportion of positive attitude included separating the children affected by HIV/AIDS and not studying with those children in the same class. Gender (b =-1.15, P =0.016) and knowledge (b =1.26, P <0.001) of students, as well as attitude (b =0.40, P <0.001) of parents were associated with the students' attitude, while parents' knowledge (b =0.93, P <0.001) was associated with parents' attitude. CONCLUSION: Discrimination towards children affected by HIV/AIDS exists among students and their parents. HIV/AIDS knowledge education helps to improve the students' and parents' caring and supporting attitude toward children affected by HIV/AIDS. PMID- 21685703 TI - [Jugular vein thrombosis, subclavian vein thrombosis and right brachiocephalic vein thrombosis after in vitro fertilization and embryo transfer: a case report]. AB - To discuss the diagnosis and treatment of jugular vein thrombosis, subclavian vein thrombosis and the right brachiocephalic vein thrombosis after in vitro fertilization and embryo transfer (IVF-ET)cycles in clinical practice. The clinical data regarding a case of jugular vein thrombosis, subclavian vein and the right brachiocephalic vein thrombosis in IVF-ET were reviewed. Clinical characteristics, prevention and treatment of jugular vein thrombosis, subclavian vein and the right brachiocephalic vein thrombosis in IVF-ET were discussed. A woman with secondary infertility underwent an IVF cycle with prolonged protocol controlled ovarian hyperstimulation. The oestradial concentration was 2 495 pg/mL on the day of human chorionic goeadotrophin (hCG). Fifteen occytes were retrieved and 2 embryos were transferred. Nine days after the embryos were transferred, the patient had ascites,hydrothorax and fluid of pelvic cavity accumulating, and was hospitalized. The patient underwent volume expansion and paracentesis, and left the hospital 30 days after the embryo transfer. Her right neck had pain 43 days after the embryo transfer. B ultrasound showed jugular vein thrombosis, subclavian vein and the right brachiocephalic vein thrombosis. The patient underwent low molecular weight heparin anticoagulation and low molecular weight dextran expansion, and left hospital with symptoms improved. She had Caesarean section and had a healthy baby girl. The thrombosis in the IVF-ET was a rare and serious complication. Prevention of ovarian hyperstimulation syndrome (OHSS) may reduce the incidence. The patients had local pain, swelling, skin temperature increased, headache, neck pain, and had to be checked to determine whether there were blood clots. The main treatment was low molecular weight heparin anticoagulation and low molecular weight dextran expansion. Timely Cesarean section is recommended to ensure the safety of perinatal mother and child. PMID- 21685704 TI - [Estimation of haplotypes based on DNA pooling]. AB - DNA pooling, a fast and economic study strategy, is widely used in areas of scientific research. In spite of various limits, researchers are making their efforts to improve DNA pooling toward a more perfect direction, including allele frequency detection and estimation of haplotypes. In haplotype estimation, more and more analyzing Methods originated from the expectation-maximization algorithm have appeared, with improved accuracy and practicality, such as HaploPool algorithm and PoooL algorithm. PMID- 21685705 TI - Defining the roles of alpha-catenin in cell adhesion and cytoskeleton organization: isolation of F9 cells completely lacking cadherin-catenin complex. AB - To define the roles of alpha-catenin in cell-cell adhesion, the E-cadherin, alpha catenin, beta-catenin, and/or plakoglobin genes were inactivated in F9 teratocarcinoma cells. An E-cadherin-alpha-catenin fusion protein (Ealpha) restored full cell-adhesion function and organized the actin-based cytoskeleton and ZO-1, an actin filament binding protein, in F9 cells lacking all endogenous cadherin-catenin complex components. There were two types of cadherin-based cell adhesion junctions in parental F9 cells, those with ZO-1 and those without ZO-1, and only junctions with ZO-1 were associated with thick actin bundles. Additionally, ZO-1 localized to most Ealpha-based cell-adhesion junctions. These data demonstrated that Ealpha supported cadherin-based cell adhesion and recruited actin bundles and ZO-1 to cell-cell contact sites in the absence of cytoplasmic alpha-catenin. Moreover, the C-terminal half of alpha-catenin was involved in the formation of cell-adhesion junctions with ZO-1. PMID- 21685706 TI - Acute effects of shortly pre- versus postprandial aerobic exercise on postprandial lipoprotein metabolism in healthy but sedentary young women. AB - AIM: To compare the acute effects of shortly pre- vs. postprandial exercise on postprandial lipid metabolism in healthy but sedentary young Japanese women. METHODS: Healthy young Japanese women with a sedentary lifestyle, normal weight (18.5 <= BMI < 25), normal ovarian cycle, and apolipoprotein E3/3 were selected as participants. A single bout of walking exercise was performed 20 min after (Exp. 1) or 50 min before (Exp. 2) the intake of oral fat tolerance test (OFTT) cream (1 g/kg body weight) at about 50% Vo(2)max for 30 min on a motorized treadmill. A control trial without exercise was also performed in each experiment. Each subject performed 2 trials in a randomized, cross-over design. Venous blood samples were drawn before the preprandial exercise (-1 h, Exp. 2 only) [corrected] and before (0 h) and 1, 2, 4 and 6 h after the fat intake for the determination of triglyceride (TG), apolipoprotein B-48 (apoB48), remnant like particle-TG (RLP-TG), lactate, free fatty acid (FFA), insulin, and glucose. RESULTS: In both experiments, postprandial serum TG concentrations in the exercise group were lower, but not significantly, than those in the control. In Exp. 1, incremental areas under the curve (IAUC) for TG and RLP-TG were slightly, but not significantly, smaller in the postprandial exercise group than the control. The values of apoB48, a marker of the chylomicron particle number, at 2, 4, and 6 h after the fat intake and IAUC for apoB48 were significantly lower in the postprandial exercise group than the control. In Exp. 2, IAUC for TG, RLP-TG, and apoB48 were not significantly different between the two groups. CONCLUSION: The present findings suggest that postprandial, but not preprandial, exercise may reduce the number of chylomicrons and chylomicron remnants and improve exogenous lipoprotein metabolism. Postprandial exercise is more effective for improving postprandial lipoprotein metabolism than preprandial exercise. PMID- 21685707 TI - Japanese dietary lifestyle and cardiovascular disease. AB - To demonstrate the reasons for low morbidity and mortality from coronary artery disease (CAD) and reconfirm the effectiveness of the Japanese dietary lifestyle for preventing CAD, we herein review the CAD risk transition, and post-war changes in Japanese food and nutrient intake. Large-scale cohort studies in Japan were selectively reviewed. Low serum total cholesterol contributed to preventing CAD, and decreased blood pressure was the major factor favoring stroke reduction. Japanese consumed more plant and marine origin foods, but fewer animal foods with saturated fatty acids (SFA) during the 1960-70s than in recent decades. Adequate control of total energy with restriction of saturated fatty acids from animal foods, increased intake of n-3 polyunsaturated fatty acids, including fish, soybean products, fruits and vegetables together with low salt intake are responsible for promoting CAD and stroke prevention. A diet with adequate total calories and increased intake of fish and plant foods, but decreased intake of refined carbohydrates and animal fat, a so-called Japan diet, appears to be quite effective for prevention of CAD risk factors and is recommended as dietary therapy for preventing CAD. PMID- 21685708 TI - Inhibitory effects of docetaxel on platelet-derived growth factor (PDGF)-BB induced proliferation of vascular smooth muscle cells through blocking PDGF receptor beta phosphorylation. AB - The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial wall is an important pathogenic factor for vascular disorders such as atherosclerosis and restenosis after angioplasty. The present study was designed to investigate the inhibitory effects of docetaxel on VSMC proliferation, as well as the molecular mechanism of this inhibition. Docetaxel at 10, 20 and 40 uM significantly inhibited both the proliferation and the DNA synthesis of fetal bovine serum (FBS)- and platelet-derived growth factor (PDGF)-BB-stimulated VSMCs in a concentration-dependent manner. In accordance with these findings, docetaxel blocked the FBS- and PDGF-BB-induced progression of synchronized cells through the G0/G1 phase of the cell cycle. Docetaxel also decreased the expressions of cell cycle-related proteins, including cyclin-dependent kinase (CDK) 2, cyclin E, CDK4, cyclin D1, retinoblastoma protein, and proliferative cell nuclear antigen in PDGF-BB-stimulated VSMCs. Docetaxel significantly inhibited the phosphorylation of extracellular signal-regulated kinase 1/2, Akt, and phospholipase C-gamma1, downstream molecule in the PDGF-BB signaling pathway. Docetaxel suppressed the phosphorylation of PDGF receptor (PDGF-R) beta, the upstream molecule in PDGF-BB signaling cascade, suggesting that the inhibitory effect of docetaxel on the proliferation of VSMCs may occur by blocking PDGF Rbeta phosphorylation. Thus, docetaxel may be a potential antiproliferative agent for the treatment of atherosclerosis and angioplasty restenosis.[Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.10276FP]. PMID- 21685709 TI - Improvement of porcine oocytes with low developmental ability after fusion of cytoplasmic fragments prepared by serial centrifugation. AB - We have shown in pigs that oocytes denuded of cumulus cells at 24 h of in vitro maturation culture and subsequently matured for a total of 46 h (DO24 oocytes) have lower cytoplasmic maturity than those matured with cumulus cells for 46 h and then denuded (DO46 oocytes). In the present study, DO24 zona-free oocytes were fused with one (1C) or two (2C) cytoplasmic fragments produced by serial centrifugation ("centri-fusion") of DO46 oocytes (DO24+1C and DO24+2C oocytes, respectively). Groups of (1) DO46 (a control), (2) DO24, (3) DO24+1C and (4) DO24+2C oocytes were partheno-activated by an electrical pulse or fertilized in vitro and subsequently cultured for 6 days. In the fused groups, female pronucleus (FPN) formation rates were higher than that in the DO24 group after parthenogenetic activation (PA); however, the blastocyst rates were intermediate between those of the control and DO24 groups. After in vitro fertilization, the male pronucleus (MPN) formation rates in the fused groups were similar to that in the control group and higher than that in the DO24 group; the normal fertilization rate in the DO24+2C group was higher than that in the DO24 group and similar to that in the control group, resulting in significantly higher blastocyst rates in the DO24+2C and control groups than that in the DO24 group. These results suggest that centri-fusion using ooplasm from fully matured DO46 oocytes can offer a potentially novel approach for restoration of cytoplasmic maturity to oocytes with low developmental ability and subsequent improvement of fertilization and developmental competence. PMID- 21685710 TI - Disease-dependent differently methylated regions (D-DMRs) of DNA are enriched on the X chromosome in uterine leiomyoma. AB - Uterine leiomyoma is the most common benign tumor in women. Although responsible gene mutations have not been found in leiomyomas, they represent a progressive disease with irreversible symptoms. To characterize epigenetic features of uterine leiomyomas, the DNA methylation status of a paired sample of leiomyoma and normal myometrium was subjected to a microarray-based DNA methylation analysis with restriction tag-mediated amplification (D-REAM). In the leiomyoma, we identified an aberrant DNA methylation status for 463 hypomethylated and 318 hypermethylated genes. Although these changes occurred on all chromosomes, aberrantly hypomethylated genes were preferentially located on the X chromosome. Using paired samples of normal myometrium and leiomyoma from 6 hysterectomy patients, methylation-sensitive quantitative real-time PCR revealed 14 shared X chromosome genes with an abnormal DNA hypomethylation status (FAM9A, CPXCR1, CXORF45, TAF1, NXF5, VBP1, GABRE, DDX53, FHL1, BRCC3, DMD, GJB1, AP1S2 and PCDH11X) and one hypermethylated locus (HDAC8). Expression of XIST, which is involved in X chromosome inactivation, was equivalent in the normal myometrium and leiomyoma, indicating that the epigenetic abnormality on the X chromosome did not result from aberration of XIST gene expression. Based on these data, a unique epigenetic signature for uterine leiomyomas has emerged. The 14 hypomethylated and one hypermethylated loci provide valuable biomarkers for understanding the molecular pathogenesis of leiomyoma. PMID- 21685711 TI - Analysis of marker expression in porcine cell lines derived from blastocysts produced in vitro and in vivo. AB - The present study was designed to extensively characterize cell lines derived from porcine blastocysts by several methodical approaches, including morphological observation, cytogenetic analysis, estimation of alkaline phosphatase activity and detection of specific marker expression at the mRNA/protein level. A comparison was made between the properties of cell lines isolated from in vivo- and in vitro-obtained blastocysts. Our results showed that 57.1% of the in vivo-obtained blastocysts attached to the feeder layer and that 33.3% of them started to grow in a monolayer. The percentage of attached in vitro produced blastocysts was lower (24.6%), and only 6.9% of them started to grow. Outgrowths from the in vitro-produced blastocysts formed mainly trophectoderm or epithelial-like monolayer, whereas the in vivo-obtained blastocysts formed heterogeneous outgrowths that also contained cells with embryonic stem (ES)-like morphology. Detailed analyses showed that the primary outgrowths with ES-like morphology expressed the pluripotency markers OCT-4 and NANOG and revealed intensive alkaline phosphatase staining, while they did not express markers of differentiation. The majority of passaged cells, including those with ES-like morphology, lacked OCT-4 protein and revealed expression of specific differentiation markers (cytokeratin 18, lamins A/C, transferrin, alpha fetoprotein and GATA-4), although they still expressed NANOG and exhibited weak alkaline phosphatase activity. Moreover, these cells spontaneously differentiated into neural, fibroblast or epithelial-like cells, even in the presence of leukaemia inhibitory factor. Our results show that complex analysis of markers of pluripotency as well as differentiation markers is necessary for proper interpretation of data in porcine embryonic stem cell studies. PMID- 21685712 TI - Effect of follicular aspiration at the onset of progesterone-based timed artificial insemination on the follicular dynamics and fertility of early postpartum Japanese black cows. AB - The effect of gonadotropin-releasing hormone analogue (GnRH-A) or follicular aspiration at the onset of progesterone-based timed artificial insemination (TAI) on subsequent follicular growth and synchronization of ovulation was examined in early postpartum Japanese Black cows. A total of 40 (22 in Exp. 1 and 18 in Exp. 2) Japanese Black cows at 20-30 days postpartum were fitted with a progesterone releasing internal device (PRID) for 7 days, injected with a prostaglandin F2alpha analogue upon removal of the PRID and GnRH-A 48 h later, and inseminated 18 h after GnRH-A injection. In Exp. 1, the animals were divided into three groups (untreated control, GnRH-A injection or follicular aspiration) of different treatments on the first day of PRID insertion (day 0), and the synchronized ovulation rate in the follicular aspiration group (100%; 8/8) tended to be higher (P = 0.077) than that in the control group (42.9%; 3/7). In Exp. 2, follicular growth in the GnRH (n = 9) and follicular aspiration (n = 9) groups was monitored by ultrasonography. Four out of the nine animals in the GnRH group had a corpus luteum on either day 4 or day 7 (OV group), and the other five animals had no induced ovulation (NOV group). The diameter of the ovulatory follicle on day 9 in the OV group (1.44 +/- 0.11 cm) tended to be greater (P = 0.078) than that in the NOV group (1.13 +/- 0.07 cm). Follicular aspiration at the onset of PRID-based TAI of early postpartum Japanese Black cows, regardless of the resumption of ovarian cyclicity, tended to result in a higher rate of synchronization of ovulation than that of the untreated controls. PMID- 21685713 TI - Expression of insulin-like growth factor (IGF) family members in porcine pregnancy. AB - Prenatal mortality is a prime concern for commercial swine industry in North America. Fetal losses occur throughout gestation but cluster in early (~day20) and mid (~day50) pregnancy. Adequate vascularization of the attachment site has emerged as a key factor contributing to fetal success. Since Insulin-Like Growth Factor (IGF) family members regulate angiogenesis in addition to promoting fetal development and growth, we hypothesized that conceptus success is governed by members of the IGF family. Using quantitative real time PCR, we analyzed expression of IGF family members (IGF-I, IGF-II, IGF-I Receptor (IGF-IR), IGF-IIR and their binding proteins, IGFBPs) in matched maternal and fetal tissues of healthy and arresting conceptuses at gestation days (gd) 20 and 50. IGF-II transcripts were 100 fold increased in both maternal and fetal tissues compared to IGF-I, but receptor transcripts were found in similar abundance irrespective of health status and gestation point. IGFBP3 was the most abundantly transcribed of the binding proteins. Using immunohistochemistry we confirmed the expression of IGF family members in maternal luminal and glandular epithelial cells, the endothelium of blood vessels and some scattered stromal cells. Our results suggest that IGF-I and II and their receptors are differentially expressed at the maternal and fetal components of the attachment site. PMID- 21685714 TI - A six-well plate method: less laborious and effective method for cultivation of obligate anaerobic microorganisms. AB - We developed a simple, less laborious method to cultivate and isolate obligate anaerobic microorganisms using a six-well plate together with the AnaeroPack System, designated as the six-well plate method. The cultivation efficiency of this method, based on colony-forming units, colony formation time, and colony size, was evaluated with four authentic obligate anaerobes (two methanogenic archaea and two sulfate-reducing bacteria). The method was found to be comparable to or even better than the roll tube method, a technique that is commonly used at present for the cultivation of obligate anaerobes. Further experiments using 21 representative obligate anaerobes demonstrated that all examined anaerobes (11 methanogens, 5 sulfate- or thiosulfate-reducing bacteria, and 5 syntrophs) could form visible colonies on the six-well plate and that these colonies could be successfully subcultured in fresh liquid media. Using this method, an unidentified sulfate-reducing bacterium was successfully isolated from an environmental sample. PMID- 21685715 TI - Microbial characterization of mercury-reducing mixed cultures enriched with different carbon sources. AB - The use of mixed microbial cultures enriched for biological mercury removal is explored in this paper, focusing on the ecological shifts occurring throughout acclimatization to mercury and on the long-term stability of four microbial enrichments. The 16S rRNA genetic profiles obtained by denaturing gradient gel electrophoresis (DGGE) revealed that the glucose and ethanol cultures had similar profiles, whereas the acetate cultures diverged into a totally dissimilar cluster. Quantification of the merA gene copies in each enrichment showed higher values for the glucose culture, followed by the ethanol and then the acetate cultures, which was consistent with the mercury removal performance throughout the study. Isolates were obtained from the four cultures and analyzed with respect to their genetic (16S rRNA) and functional (merA) phylogenies in order to identify mercury-resistant species enriched with different carbon sources. All mercury-resistant isolates obtained from the glucose and ethanol cultures belonged to the Gammaproteobacteria, whereas acetate cultures also contained members of other phyla, with differences in merA sequences. Higher phylogenetic than functional diversity of the isolates, together with increasing merA copies even after culture stabilisation, highlight the role of horizontal gene transfer in the acclimatization process. PMID- 21685716 TI - Clinical and MRI findings of lissencephaly in a mixed breed dog. AB - A 7-year-old castrated male mixed-breed dog was presented with a complaint of acute pain. The dog had suffered from isolated seizures for two years. Magnetic resonance imaging (MRI) of the brain revealed a smooth brain surface due to lack of gyri and sulci formation of the cerebrum and thick cortical grey matter. Additionally, ventriculomegaly and an arachnoid cyst were noted. Multiple spinal cord compressions induced by intervertebral disc protrusion were observed on a cervical MRI. Based on these findings, the dog was diagnosed as having lissencephaly concurrent with intervertebral cervical disease. After therapy for seizure and cervical pain, the clinical signs were completely resolved. To the author's knowledge, this is the case report to diagnose lissencephaly in a mixed breed dog. PMID- 21685717 TI - A case of Iriomote cat (Prionailurus bengalensis iriomotensis) with Hepatozoon felis parasitemia. AB - We herein present clinical findings of an Iriomote cat with Hepatozoon felis parasitemia. A male Iriomote cat was captured for ecological analyses three times from January 2010 to January 2011. Although this cat did not show any hematological abnormalities at the time of the first capture, H. felis parasitemia and increased serum creatine kinase levels were detected at the second and third captures. H. felis infection was confirmed by polymerase chain reaction, and amplified 18S ribosomal RNA gene fragments were 100% identical to those of H. felis in leopard cats in Korea. Although the virulence of H. felis in this cat was suggested to be low, this is the first report of an H. felis infected Iriomote cat with parasitemia. PMID- 21685718 TI - Protection against atypical Aeromonas salmonicida infection in common carp, Cyprinus carpio L., by oral administration of a mixed microbial culture of Lactobacillus paracasei, Pichia membranifaciens and Saccharomyces cereviciae. AB - A microbial culture was prepared by co-cultivation of Lactobacillus paracasei, Pichia membranifaciens and Saccharomyces cereviciae for 48 hr at 30 degrees C in rice bran extract medium, supplemented with dextrose. Oral administration of the resulting non-viable heat-inactivated microbial culture to common carp, Cyprinus carpio L., delivered in feed for four weeks, induced effective protection against experimental atypical Aeromonas salmonicida infection which causes "ulcer disease". After challenge of the carp by immersion, fish mortality and development of skin lesions such as hemorrhages and ulcers were significantly suppressed in carp treated with mixed microbial culture adsorbed on dry pellets relative to carp treated with medium or without extract. Atypical A. salmonicida was re-isolated from ulcerative lesions in parts of dead and surviving fish, but Aeromonas hydrophila and Flavobacterium sp. were also isolated from these fish, verifying microbial population changes during the progression of skin lesions. Among interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, as well as CXC alpha and CXC-beta chemokines, gene expression of IL-1beta was up regulated in the spleen and head kidney three weeks after administration of the mixed microbial culture. These results clearly show that this mixed microbial culture, delivered in feed, is effective in preventing A. salmonicida disease in carp. PMID- 21685719 TI - 1NM-PP1 treatment of mice infected with Toxoplasma gondii. AB - Bumped kinase inhibitors (BKIs) target analog-sensitive kinases, which the genomes of mammals rarely encode. Previously, we demonstrated that a BKI effectively suppressed the in vitro replication of Toxoplasma gondii, the causative pathogen of toxoplasmosis, by targeting T. gondii calcium-dependent protein kinase 1 (TgCDPK1) (Eukaryotic Cell, 9: 667-670). Here, we examined whether the BKI 1NM-PP1 reduced parasite replication in vivo. A high dose of 1NM PP1, by intraperitoneal injection, just before the parasite inoculation effectively reduced the parasite load in the brains, livers, and lungs of T. gondii-infected mice, however, a low dose of 1NM-PP1 with oral administration didn't change the survival rates of infected mice. PMID- 21685720 TI - Toxoplasma gondii seroprevalence in domestic animals and humans in Mymensingh District, Bangladesh. AB - The seroprevalence of Toxoplasma gondii was examined in adult women and domestic animals used for meat products from the Mymensingh District, Bangladesh. Cattle, goats and sheep showed a high seroprevalence (12, 32 and 40%, respectively), while the sera from all fifteen women examined in the same area were seronegative. Considering that primary infection in women during pregnancy can cause abortion and congenital defects, accidental ingestion of T. gondii infected meat products from domestic animals represents a risk factor for adult women living in the same area. PMID- 21685721 TI - Tryptase enzyme activity is correlated with severity of chronic obstructive pulmonary disease. AB - Tryptic enzymes, including tryptase, a signature enzyme in mast cells, are involved in the pathogenesis of chronic obstructive pulmonary disease (COPD), a chronic inflammatory airway disease. However, the relationship between tryptase enzyme activity and COPD remains to be investigated. We therefore measured the enzyme activity and immunoreactivity of tryptase in the sputum and plasma of COPD patients in the present study. The results showed that tryptase enzyme activity in the sputum of severe COPD patients (FEV(1)s being recorded at <= 30% prediction values) was 3.4 times greater than that in patients with mild COPD (FEV(1)s being recorded at >= 80% of predicted values), whereas tryptic activity was 2.0 times higher in the severe COPD patients than in mild COPD patients. Moreover, tryptase enzyme activity, but not tryptic enzyme activity, was significantly elevated in the plasma of severe COPD patients compared with that of mild COPD patients. The level of immunoreactive tryptase was 1.9 times higher in the sputum of the severe COPD patients at admission than that at remission stage. We also employed a rat model of cigarette smoke-induced COPD. After 36 weeks of daily challenges with cigarette smoke, a well-established risk factor of COPD, tryptic and tryptase activities in the bronchoalveolar lavage fluid were elevated 1.5 and 2.6 times, respectively. These results indicate that smoking induces tryptase enzyme activity in the airway. In conclusion, tryptase enzyme activity is markedly increased in sputum and plasma of severe COPD patients. Enhanced tryptase enzyme activity may contribute to the pathogenesis of COPD. PMID- 21685722 TI - Combined imaging with multi-detector row computed tomography and diffusion weighted imaging in the detection of pancreatic cancer. AB - Pancreatic cancer is one of the most aggressive malignant tumor types. Its prognosis is extremely poor without early detection, and an accurate diagnosis with imaging techniques is vital for any chance of long-term survival after treatment. Despite the great technical advances that have been made with various kinds of imaging equipment, detection of pancreatic cancer is unsatisfactory, and new modalities are required. Diffusion-weighted imaging (DWI) on magnetic resonance imaging (MRI) has high sensitivity and specificity for the detection of pancreatic cancer; however, it does not provide anatomic information. Quite often, the necessary spatial correlation of a high-intensity area with anatomic structures is constrained. If it becomes possible to combine the imaging technique of DWI with multi-detector row computed tomography (MDCT), such as is done with positron emission tomography (PET) and computed tomography (CT), it is expected that the early diagnostic capability will improve. The objective of this study was to introduce combined imaging with DWI and CT into clinical practice to improve the diagnosis of pancreatic cancer. In the current report, we demonstrate a clinical attempt to combine DWI on MRI with the anatomical accuracy of MDCT for two patients of pancreatic adenocarcinoma. Analysis of these two patients revealed that the combined images corresponded precisely to the operative findings. Thus, the combined imaging with DWI and MDCT is useful for the detection of the pancreatic cancer. PMID- 21685723 TI - JNK/stress-activated protein kinase associated protein 1 is required for early development of telencephalic commissures in embryonic brains. AB - We previously reported that mice lacking JSAP1 (jsap1-/-) were lethal and the brain of jsap1-/- at E18.5 exhibited multiple types of developmental defects, which included impaired axon projection of the corpus callosum and anterior commissures. In the current study, we examined whether the early telencephalic commissures were formed abnormally from the beginning of initial development or whether they arose normally, but have been progressively lost their maintenance in the absence of JSAP1. The early corpus callosum in the brain of jsap1+/+ at E15.5-E16.5 was found to cross the midline with forming a distinct U-shaped tract, whereas the early axonal tract in jsap1-/- appeared to cross the midline in a diffuse manner, but the lately arriving axons did not cross the midline. In the brain of jsap1-/- at E17.5, the axon terminals of lately arriving collaterals remained within each hemisphere, forming an early Probst's bundle-like shape. The early anterior commissure in the brain of jsap1+/+ at E14.5-E15.5 crossed the midline, whereas the anterior commissure in jsap1-/- developed, but was deviated from their normal path before approaching the midline. The axon tracts of the corpus callosum and anterior commissure in the brain of jsap1-/- at E16.5-E17.5 expressed phosphorylated forms of FAK and JNK, however, their expression levels in the axonal tracts were reduced compared to the respective controls in jsap1+/+. Considering the known scaffolding function of JSAP1 for the FAK and JNK pathways, these results suggest that JSAP1 is required for the pathfinding of the developing telencephalic commissures in the early brains. PMID- 21685724 TI - Beclin 1 deficiency is associated with increased hypoxia-induced angiogenesis. AB - Beclin 1, a tumor suppressor protein, acts as an initiator of autophagy in mammals. Heterozygous disruption of Beclin 1 accelerates tumor growth, but the underlying mechanisms remain unclear. We examined the role of Beclin 1 in tumor proliferation and angiogenesis, using a primary mouse melanoma tumor model. Beclin 1 (Becn1 (+/-) ) hemizygous mice displayed an aggressive tumor growth phenotype with increased angiogenesis under hypoxia, associated with enhanced levels of circulating erythropoietin but not vascular endothelial growth factor, relative to wild-type mice. Using in vivo and ex vivo assays, we demonstrated increased angiogenic activity in Becn1 (+/-) mice relative to wild-type mice. Endothelial cells from Becn1 (+/-) mice displayed increased proliferation, migration and tube formation in response to hypoxia relative to wild-type cells. Moreover, Becn1 (+/-) cells subjected to hypoxia displayed increased hypoxia inducible factor-2alpha (HIF-2alpha) expression relative to HIF-1alpha. Genetic interference of HIF-2alpha but not HIF-1alpha, dramatically reduced hypoxia inducible proliferation, migration and tube formation in Becn1 (+/-) endothelial cells. We demonstrated that mice deficient in the autophagic protein Beclin 1 display a pro-angiogenic phenotype associated with the upregulation of HIF-2alpha and increased erythropoietin production. These results suggest a relationship between Beclin 1 and the regulation of angiogenesis, with implications in tumor growth and development. PMID- 21685725 TI - Coordination of cell cycle, DNA repair and muscle gene expression in myoblasts exposed to genotoxic stress. AB - Upon exposure to genotoxic stress, skeletal muscle progenitors coordinate DNA repair and the activation of the differentiation program through the DNA damage activated differentiation checkpoint, which holds the transcription of differentiation genes while the DNA is repaired. A conceptual hurdle intrinsic to this process relates to the coordination of DNA repair and muscle-specific gene transcription within specific cell cycle boundaries (cell cycle checkpoints) activated by different types of genotoxins. Here, we show that, in proliferating myoblasts, the inhibition of muscle gene transcription occurs by either a G 1- or G 2-specific differentiation checkpoint. In response to genotoxins that induce G 1 arrest, MyoD binds target genes but is functionally inactivated by a c-Abl dependent phosphorylation. In contrast, DNA damage-activated G 2 checkpoint relies on the inability of MyoD to bind the chromatin at the G 2 phase of the cell cycle. These results indicate an intimate relationship between DNA damage activated cell cycle checkpoints and the control of tissue-specific gene expression to allow DNA repair in myoblasts prior to the activation of the differentiation program. PMID- 21685726 TI - Forkhead factors regulate epithelial plasticity: impact on cancer progression. AB - Fox-factors modulate epithelial and mesenchymal cell fates in different stages during embryonic development. In the context of cancer they have mainly been described by their impact on cell proliferation, apoptosis and angiogenesis. Several studies have now pointed out that distinct members of the Forkhead transcription factor family are critically involved in modulating epithelial plasticity of carcinoma cells and thereby putatively enhance their metastatic and malignant capacity. Here we highlight these recent findings about new aspects of Fox-factor biology, which suggest that Fox-factors have a central role in the regulation of epithelial cell fates and cancer progression. A comprehensive molecular understanding of Fox-factors in this regard may provide potential new targets for therapeutic intervention. PMID- 21685728 TI - Interprofessional education: the international journal for wound prevention and healing. PMID- 21685727 TI - AMP-activated protein kinase modulates cardiac autophagy in diabetic cardiomyopathy. AB - We have recently shown that in diabetic OVE26 mice (type I diabetes), the AMP activated protein kinase (AMPK) is reduced along with cardiac dysfunction and decreased cardiac autophagy. Genetic inhibition of AMPK in cardiomyocytes attenuates cardiac autophagy, exacerbates cardiac dysfunction and increases mortality in diabetic mice. More importantly, we have found chronic AMPK activation with metformin, one of the most used antidiabetes drugs and a well characterized AMPK activator, significantly enhances autophagic activity, preserves cardiac function and prevents most of the primary characteristics of diabetic cardiomyopathy in OVE26 mice, but not in dominant negative-AMPK diabetic mice. We conclude that AMPK activation protects cardiac structure and function by increasing cardiac autophagy in the diabetic heart. PMID- 21685729 TI - Technical points on wound photography. PMID- 21685732 TI - Why should wound care providers pay attention to Medicare payment indicators? PMID- 21685733 TI - Human fibroblast-derived dermal substitute: results from a treatment investigational device exemption (TIDE) study in diabetic foot ulcers. AB - OBJECTIVE: To gain experience in the use of Dermagraft (Advanced Biohealing Inc, La Jolla, California), a human fibroblast-derived dermal substitute (HFDS), for the treatment of nonhealing diabetic foot ulcers (DFUs). STUDY DESIGN: An open label, noncontrolled, multicenter clinical trial of HFDS in the treatment of DFU was conducted. Subjects with DFUs underwent sharp debridement of the study ulcer and were prescribed an off-loading device. All of the subjects enrolled received applications of HFDS, beginning at day 0 and applied weekly thereafter, along with saline gauze or polyurethane foam dressings from day 0 to week 20. A maximum of 8 HFDS applications was allowed. MAIN OUTCOME MEASURES: The primary and secondary end points of the study were complete wound closure by weeks 12 and 20, respectively. MAIN RESULTS: A total of 23 centers screened 91 subjects, and 18 centers enrolled an intent-to-treat (ITT) population of 62 subjects. For the ITT population, 27 (44%) subjects healed by week 12, and 32 (52%) healed by week 20. Fifty-one subjects (82%) completed the study to week 12, and 46 subjects (74%) completed the entire 20-week study; wound closure rates in these groups were 59% and 70%, respectively. Median time to healing was 13 weeks. The overall incidence of at least 1 adverse event (44%, 27/62) was typical for this subject population. No adverse events were attributable to HFDS. CONCLUSION: Data from this study support the safety and efficacy of HFDS in the treatment of nonhealing DFUs. PMID- 21685734 TI - The anatomy and physiology of a continuing medical education article: a resource guide for enhancing continuing education. AB - This article was designed to help healthcare professionals assess their roles and responsibilities as authors of articles certified for CME credit and to develop appropriate objectives to reflect the desired outcomes of education through CME articles. PMID- 21685736 TI - Beds: practical pressure management for surfaces/mattresses. AB - The prevention and management of pressure ulcers, including support surface selection, are a primary focus of healthcare providers. This article discusses the forces contributing to pressure ulcer formation and explores choosing therapeutic support surface features based on the patient's clinical needs and on using the evidence-informed support surface algorithm and decision trees. PMID- 21685738 TI - Social media collaboration checklist. PMID- 21685739 TI - The relation of near-infrared spectroscopy with changes in peripheral circulation in critically ill patients. AB - OBJECTIVE: We conducted this observational study to investigate tissue oxygen saturation during a vascular occlusion test in relationship with the condition of peripheral circulation and outcome in critically ill patients. DESIGN: Prospective observational study. SETTING: Multidisciplinary intensive care unit in a university hospital. PATIENTS: Seventy-three critically ill adult patients admitted to the intensive care unit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were followed every 24 hrs until day 3 after intensive care admission. Near-infrared spectroscopy was used to measure thenar tissue oxygen saturation, tissue oxygen saturation deoxygenation rate, and tissue oxygen saturation recovery rate after the vascular occlusion test. Measurements included heart rate, mean arterial pressure, forearm-to-fingertip skin-temperature gradient, and physical examination of peripheral perfusion with capillary refill time. Patients were stratified according to the condition of peripheral circulation (abnormal: forearm-to-fingertip skin-temperature gradient >=4 and capillary refill time >4.5 secs). The outcome was defined based on the daily Sequential Organ Failure Assessment score and blood lactate levels. Upon intensive care unit admission, 35 (47.9%) patients had abnormal peripheral perfusion (forearm-to-fingertip skin-temperature gradient >4 or capillary refill time >4.5 secs). With the exception of the tissue oxygen saturation deoxygenation rate, tissue oxygen saturation baseline and tissue oxygen saturation recovery rate were statistically lower in patients who exhibited abnormal peripheral perfusion than in those with normal peripheral perfusion: 72 +/- 9 vs. 81 +/- 9; p = .001 and 1.9 +/- 0.7 vs. 3.2 +/- 0.9; p = .001, respectively. When a mixed model analysis was performed over time for estimate (s) calculation, adjusted to the condition of disease, we did not find a significant clinical effect between vascular occlusion test-derived tissue oxygen saturation measurements (as response variables) and mean systemic hemodynamic variables (as independent variables): tissue oxygen saturation vs. heart rate: s (95% confidence interval) = 0.007 (-0.08; 0.09); tissue oxygen saturation vs. mean arterial pressure: s (95% confidence interval) = -0.02 (-0.12; 0.08); tissue oxygen saturation deoxygenation rate vs. heart rate: s (95% confidence interval) = 0.002 (-0.0004; 0.006); tissue oxygen saturation deoxygenation rate vs. mean arterial pressure: s (95% confidence interval) - 0.0007 (-0.003; 0.004); tissue oxygen saturation recovery rate vs. heart rate: s (95% confidence interval) = -0.009 (-0.02; 0.0015); tissue oxygen saturation recovery rate vs. mean arterial pressure: s (95% confidence interval) = 0.01 (0.002; 0.018). However, there was a strong association between tissue oxygen saturation baseline and tissue oxygen saturation recovery rate with abnormal peripheral perfusion: tissue oxygen saturation vs. abnormal peripheral perfusion: s (95% confidence interval) = -10.1 (-13.9; -6.2); tissue oxygen saturation recovery rate vs. abnormal peripheral perfusion: s (95% confidence interval) =-10.1 (-13.9; -6.2); tissue oxygen saturation recovery rate vs. abnormal peripheral perfusion: s (95% confidence interval) = -1.1 (-1.4; -0.81). Poor outcome was more closely related to abnormalities in peripheral perfusion than to tissue oxygen saturation-derived parameters. CONCLUSIONS: We found that the condition of peripheral circulation in critically ill patients strongly influences tissue oxygen saturation resting values and the tissue oxygen saturation reoxygenation rate but not the tissue oxygen saturation deoxygenation rate. In addition, changes in near-infrared spectroscopy-derived variables were independent of condition of disease and were not accompanied by any major differences in systemic hemodynamic variables. PMID- 21685740 TI - The epidemiology of sepsis in Colombia: a prospective multicenter cohort study in ten university hospitals. AB - OBJECTIVE: Our aim was to determine the frequency and the clinical and epidemiologic characteristics of sepsis in a hospital-based population in Colombia. DESIGN: Prospective cohort. SETTING: Ten general hospitals in the four main cities of Colombia. PATIENTS: Consecutive patients admitted in emergency rooms, intensive care units, and general wards from September 1, 2007, to February 29, 2008, with confirmation of infection according to the Centers for Disease Control and Prevention definitions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The following information was recorded: demographic, clinical, and microbiologic characteristics; Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores; requirement for intensive care unit; length of stay; and 28-day all-cause mortality. During a period of 6 months, 2,681 patients were recruited: 69% and 31% with community-acquired and hospital-acquired infections, respectively. The mean age was 55 yrs (SD = 21), 51% were female, and the median length of stay was 10 days (interquartile range, 5-19). The mean Acute Physiology and Chronic Health Evaluation score was 11.5 (SD = 7) and the mean Sequential Organ Failure Assessment score was 3.8 (SD = 3). A total of 422 patients with community-acquired infections (16%) were admitted to the intensive care unit as a consequence of their infection and the median length of stay was 4.5 days in the intensive care unit. At admission, 2516 patients (94%) met at least one sepsis criterion and 1,658 (62%) met at least one criterion for severe sepsis. Overall, the 28-day mortality rates of patients with infection without sepsis, sepsis without organ dysfunction, severe sepsis without shock, and septic shock were 3%, 7.3%, 21.9%, and 45.6%, respectively. In community-acquired infections, the most frequent diagnosis was urinary tract infection in 28.6% followed by pneumonia in 22.8% and soft tissue infections in 21.8%. Within hospital-acquired infections, pneumonia was the most frequent diagnosis in 26.6% followed by urinary tract infection in 20.4% and soft tissue infections in 17.4%. CONCLUSIONS: In a general inpatient population of Colombia, the rates of severe sepsis and septic shock are higher than those reported in the literature. The observed mortality is higher than the predicted by the Acute Physiology and Chronic Health Evaluation II score. PMID- 21685741 TI - Nursing considerations to complement the Surviving Sepsis Campaign guidelines. AB - OBJECTIVES: To provide a series of recommendations based on the best available evidence to guide clinicians providing nursing care to patients with severe sepsis. DESIGN: Modified Delphi method involving international experts and key individuals in subgroup work and electronic-based discussion among the entire group to achieve consensus. METHODS: We used the Surviving Sepsis Campaign guidelines as a framework to inform the structure and content of these guidelines. We used the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system to rate the quality of evidence from high (A) to very low (D) and to determine the strength of recommendations, with grade 1 indicating clear benefit in the septic population and grade 2 indicating less confidence in the benefits in the septic population. In areas without complete agreement between all authors, a process of electronic discussion of all evidence was undertaken until consensus was reached. This process was conducted independently of any funding. RESULTS: Sixty-three recommendations relating to the nursing care of severe sepsis patients are made. Prevention recommendations relate to education, accountability, surveillance of nosocomial infections, hand hygiene, and prevention of respiratory, central line-related, surgical site, and urinary tract infections, whereas infection management recommendations related to both control of the infection source and transmission-based precautions. Recommendations related to initial resuscitation include improved recognition of the deteriorating patient, diagnosis of severe sepsis, seeking further assistance, and initiating early resuscitation measures. Important elements of hemodynamic support relate to improving both tissue oxygenation and macrocirculation. Recommendations related to supportive nursing care incorporate aspects of nutrition, mouth and eye care, and pressure ulcer prevention and management. Pediatric recommendations relate to the use of antibiotics, steroids, vasopressors and inotropes, fluid resuscitation, sedation and analgesia, and the role of therapeutic end points. CONCLUSION: Consensus was reached regarding many aspects of nursing care of the severe sepsis patient. Despite this, there is an urgent need for further evidence to better inform this area of critical care. PMID- 21685742 TI - Ultrasound-guided subclavian vein catheterization: beyond just the jugular vein. PMID- 21685743 TI - So we use less pulmonary artery catheters--but why? PMID- 21685744 TI - Subdural hematoma: you can leave your hat on? PMID- 21685745 TI - Data"-omics" and intensive care unit patient care. PMID- 21685746 TI - Nicotine replacement therapy in critically ill patients and the long-range risks of comfortable inaction. PMID- 21685747 TI - Critical genetic variations in critical illness. PMID- 21685748 TI - Thenar tissue oxygen saturation monitoring: noninvasive does not mean simple or accurate! PMID- 21685749 TI - Fish oil is not the fix for acute lung injury. PMID- 21685750 TI - Innovative research on end-of-life decision making. PMID- 21685751 TI - Resuscitation from cardiac arrest: can we do better? PMID- 21685752 TI - Prognosis of sepsis: lessons from epidemiological studies. PMID- 21685753 TI - Leading an intensive care unit--we need more than medical knowledge! PMID- 21685754 TI - Salvaging the septic heart through targeting the interleukin-6/p38 mitogen activated protein kinase signaling network. PMID- 21685755 TI - Endothelial damage after resuscitation: reactive oxygen species as possible therapeutic targets? PMID- 21685756 TI - Recruitability, recruitment, and tidal volume interactions: is biologically variable ventilation a possible answer? PMID- 21685757 TI - Does positive end-expiratory pressure improve CO(2) exchange in controlled ventilation of acute airflow obstruction? PMID- 21685758 TI - Microparticles have macro effects in sepsis. PMID- 21685759 TI - Inactivity-induced diaphragm dysfunction and mitochondria-targeted antioxidants: new concepts in critical care medicine. PMID- 21685760 TI - Thromboprophylaxis in critically ill children: how should we define the "at risk" child? PMID- 21685761 TI - Steroids for respiratory syncytial virus: is it finally time to just say "no"? PMID- 21685762 TI - Antibiotics in intensive care: too little or too much? PMID- 21685763 TI - Psychiatric long-term complications of intensive care unit survivors. PMID- 21685764 TI - Albumin meta-analysis and epochs of care. PMID- 21685766 TI - Disinfection is not the same as cleaning. PMID- 21685767 TI - Emergency prehospital tracheal intubation. PMID- 21685768 TI - Fluids after cardiac surgery: do all cardiac surgical patients behave similarly? PMID- 21685771 TI - CT of the abdomen. PMID- 21685772 TI - A new use for Xifaxan. AB - Hepatic encephalopathy (HE) is responsible for an average of 50,000 hospitalizations of approximately 5.5 million individuals with liver cirrhosis every year. HE is a reversible complication of liver failure that causes neuropsychiatric problems. HE patients experience neurologic changes related to cognitive, psychiatric, and motor impairment. This impairment can be accompanied by a number of symptoms including decreased mental status, memory impairment, sensory changes, lack of concentration, disorientation, and coma. The exact cause of HE in patients with liver cirrhosis is unknown. However, the general consensus is that these individuals are unable to remove toxic substances, especially from ammonia-producing bacteria, from the gut via the liver. Therefore, treatment is focused on decreasing the production of these ammonia-producing bacteria, as episodes occur. PMID- 21685776 TI - Shedding light on testicular cancer. AB - Testicular cancer, though generally uncommon, is the most common cancer NPs will see in young men. Advances in surgery, radiation, and cisplatin-based chemotherapy, have made testicular cancer a "model" for a curable cancer. Survivors will likely live many years, but will require lifelong follow-up for possible recurrence and long-term treatment sequelae. PMID- 21685777 TI - Preoperative assessment of high-risk orthopedic surgery patients. AB - A review of guidelines and practice advisories provides the basis of recommendations for the NP to stratify high-risk patients prior to elective orthopedic surgery. A frame of reference for NPs performing preoperative assessment for patients with comorbidity, included cardiac risk and physiologic stratification tools are presented. PMID- 21685778 TI - Clinical issues in refugee healthcare: the Somali Bantu population. AB - With an estimated 803,500 refugees residing in the United States, many NPs will encounter patients who do not speak, read, or understand English. Many of these patients have challenging health issues such as parasitic diseases and chronic or acute diseases not commonly seen in the United States and NPs will need to be prepared for these challenges. PMID- 21685780 TI - Marital relationship quality in early-stage dementia: perspectives from people with dementia and their spouses. AB - Spouse caregivers of people with dementia (PwD) report relatively poor marital relationship quality (RQ), but few studies have obtained the perspective of the PwD, examined discrepancies between spouses, or considered changes in RQ over time. This study explored caregiver and PwD perceptions of RQ, identified associated factors, and examined changes over an 18-month period. Participants were 54 couples where one spouse had early-stage dementia and 54 were control couples. RQ was assessed with the Positive Affect Index. Measures of mood, stress, and quality of life (QoL) were also administered. The clinical couples were followed up after 9 and 18 months. Caregivers gave significantly lower RQ ratings than controls. PwD ratings did not differ significantly from those of caregivers or controls. Dyadic discrepancies were significantly greater in the clinical than in the control group. Caregiver ratings were associated with stress, whereas PwD ratings were associated with depression and QoL. Discrepancies were associated with caregiver stress and with PwD mood, QoL, and age. Caregiver ratings declined significantly over time; PwD ratings did not decline significantly, but showed different trends for men and women. It is important to consider RQ when considering how to support couples where one partner has early-stage dementia. PMID- 21685782 TI - Geriatric addictions. PMID- 21685783 TI - Platypnea-Orthodeoxia Syndrome: What Is the Driving Force? AB - A 69-year-old patient presented with episodic, acute hypoxia and an increasing oxygen requirement. His hemoglobin oxygenation reached its nadir in the 80% to 85% range as measured by pulse oximetry while he was sitting upright. Oxygenation would improve in this patient to percentages in the upper 90s when he was in the supine position. He was found to have a large secundum atrial septal defect with bidirectional intracardiac shunting, left hemidiaphragmatic dysfunction, a dilated ascending aorta and a prominent Eustachian valve. The patient was stabilized with oxygen therapy, and the cardiology service provided definitive treatment via percutaneous shunt closure with a septal occluder. PMID- 21685784 TI - Unilateral hyperhidrosis in malignant mesothelioma. PMID- 21685785 TI - Spinal hemangioblastoma. PMID- 21685786 TI - Treatment of proliferative and membranous lupus nephritis: review of key clinical trials. AB - Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE), which is associated with significant morbidity and mortality. Renal involvement in SLE is heterogeneous; therefore, the treatment of LN is determined by the pathological type of LN and ranges from nonspecific measures such as maintenance of adequate blood pressure control and blockade of renin-angiotensin aldosterone system to the use of immunosuppressive medications. Cyclophosphamide in combination with prednisone has been the standard of care for the treatment of proliferative forms of LN. However, the high rates of progression to end-stage renal disease coupled with adverse side effects from cyclophosphamide and prednisone administration have lead to an intensive search for more effective and less toxic therapies for LN. The authors review available treatment options for proliferative and membranous LN and summarize the results of recently published clinical trials that add new perspectives to the management of kidney disease in SLE. PMID- 21685781 TI - Apolipoprotein E epsilon2 and functional decline in amnestic mild cognitive impairment and Alzheimer disease. AB - BACKGROUND: Recent work has demonstrated the potentially protective effects of the apolipoprotein E (APOE) epsilon2 allele on cognitive functioning in individuals at risk for developing Alzheimer disease. However, little is known regarding the effect of epsilon2 genotype on rate of change in daily functioning over time. The aim of the current study was to examine the relationship between APOE genotype and change over time in ability to perform daily activities. METHODS: We examined the relationship between APOE genotype and change in the ability to perform activities of daily living at 12- and 24-month intervals in 225 healthy comparison subjects, 381 individuals with amnestic mild cognitive impairment, and 189 individuals with Alzheimer disease who were enrolled in the Alzheimer's Disease Neuroimaging Initiative study. Neuropsychological measures were also collected at each follow-up. RESULTS: Overall, individuals with at least one APOE-epsilon2 allele showed less functional decline over time and better performance on neuropsychological measures than those without an epsilon2 allele, even after controlling for potential confounders. When diagnostic groups were examined individually, presence of the epsilon2 allele continued to be associated with slower functional decline, although the relationship was no longer statistically significant in most cases, likely due to reduced statistical power. CONCLUSIONS: Our findings suggest that the APOE-epsilon2 allele provides a buffer against significant changes in daily functioning over time and is associated with better neuropsychological performance across a number of measures. PMID- 21685787 TI - Association of transforming growth factor-beta1 gene polymorphisms with genetic susceptibility to acute myocardial infarction. AB - INTRODUCTION: Transforming growth factor beta 1 (TGF-beta1) gene plays an important role in acute myocardial infarction (AMI); however, little is known about the relation of variations within the gene and risk of cardiovascular diseases. In this study, the authors evaluated the influence of TGF-beta1 polymorphisms on the onset and progression of AMI in Iranian patients comparing with healthy individuals. METHODS: Genomic DNA and peripheral blood mononuclear cells of 900 enrolled patients with AMI and 900 control subjects were extracted. The -509 C/T, 868T/C, 913G/C and 11929C/T TGF-beta1 polymorphisms were detected. The messenger RNA (mRNA) expression and serum levels of TGF-beta1 were analyzed by real-time reverse-transcriptase polymerase chain reaction and ELISA, respectively. RESULTS: The frequency of "T" allele in -509 C/T, "C" allele in 868T/C, "C" allele in 913G/C and "T" allele in 11929C/T polymorphisms were significantly higher in the patients than control subjects (P < 0.001). There were significant differences in circulating levels of TGF-beta1 in the patients than in control subjects (P < 0.001). These concentrations are associated with its gene polymorphism. The mRNA expression levels of TGF-beta1 were significantly higher in the patient serums compared with controls (P < 0.001). CONCLUSIONS: Our results confirmed the association between the TGF-beta1 polymorphisms and risk of AMI, which suggest that genetic polymorphisms in TGF-beta1 might be helpful for determining susceptibility to AMI in Iranian patients. There are also significant relationship between serum TGF-beta1 and occurrence of AMI. In addition, susceptibility to AMI might be related to TGF-beta1 gene expression, which affects its serum levels. PMID- 21685788 TI - Images in anesthesiology: Intermittent airway obstruction in a neonate. PMID- 21685789 TI - Anesthetic block of pain-related cortical activity in patients with peripheral nerve injury measured by magnetoencephalography. AB - BACKGROUND: This study examined whether chronic neuropathic pain, modulated by a local anesthetic block, is associated with cortical magnetic field changes. METHODS: In a group of 20 patients with pain caused by unilateral traumatic peripheral nerve injury, a local block with lidocaine 1% was administered and the cortical effects were measured and compared with a control group. The global field power (GFP), describing distribution of cortical activation after median and ulnar nerve stimulation, was plotted and calculated. The effects on the affected hemisphere and the unaffected hemisphere (UH) before and after a block of the injured nerve were statistically evaluated. RESULTS: Major differences based on the GFP curves, at a component between 50 ms - 90 ms (M70), were found in patients: in the affected hemisphere the M70 GFP peak values were statistically significantly larger in comparison with the UH, and the GFP curves differed morphologically. Interestingly, the mean UH responses were reduced in comparison with the control group, a finding suggesting that the UH is also part of the cortical changes. At M70, the GFP curves and values in the affected hemisphere were modulated by a local block of the median or the ulnar nerve. The most likely location of cortical adaptation is in the primary somatosensory cortex. CONCLUSIONS: Cortical activation is enhanced in the affected hemisphere compared with the UH and is modulated by a local block. The UH in neuropathic pain changes as well. Evoked fields may offer an opportunity to monitor the effectiveness of treatments of neuropathic pain in humans. PMID- 21685790 TI - Meta-analyses and randomized controlled trials in evaluating suture techniques and materials for elective midline abdominal closure. PMID- 21685791 TI - Utilization of laparoscopic colectomy in the United States before and after the clinical outcomes of surgical therapy study group trial. AB - OBJECTIVE: To evaluate the utilization of laparoscopic colectomy (LC) in the United States before and after prospective data supported its use for the treatment of colon cancer. METHODS: The Nationwide Inpatient Sample 2001-2003 [before Clinical Outcomes of Surgical Therapy (COST)] and 2005-2007 (after COST) was queried for elective colectomies for both benign and malignant disease. The COST trial was published in 2004; therefore, 2004 data were excluded. Univariate analyses including patient-specific, hospital-specific, and outcome variables were performed. Multivariate logistic regression models and subset analyses were used to evaluate these variables and operative approach by time frame. RESULTS: The query yielded 741,817 elective colectomies (684,969 open and 56,848 laparoscopic). The percentage of elective colectomies performed laparoscopically has increased over time. Laparoscopic colectomy for benign disease increased from 6.2% in 2001-2003 to 11.8% in 2005-2007, while those for colon cancer have increased by a larger percentage, 2.3% to 8.9%. In a multivariate model of patients with colon cancer, the odds ratio (OR) for having a laparoscopic approach after COST was 4.55 (confidence interval 3.81-5.44) compared with before COST. In contrast, for benign disease, the OR was 2.10 (confidence interval 1.79 2.46). Factors predictive of having a laparoscopic approach for cancer have changed very little over time: Patients are more likely to be male, insured, live in areas with the highest incomes, and undergo resection at urban teaching hospitals. CONCLUSIONS: Within 3 years after publication of the COST trial, the use of laparoscopic resection for colon cancer approached that of benign disease. However, almost 90% of cases are still performed open and utilization remains influenced by socioeconomic factors. PMID- 21685792 TI - Topical diltiazem cream versus botulinum toxin a for the treatment of chronic anal fissure: a double-blind randomized clinical trial. AB - OBJECTIVE: A double-blind randomized clinical trial to compare topical diltiazem with botulinum toxin A (BTA) in the treatment of chronic anal fissure. BACKGROUND: Chronic anal fissures remain a challenging condition. Topical diltiazem and BTA are promising agents in the treatment of anal fissure. As to date diltiazem and BTA were never compared in a solid randomized trial, which is the purpose of this study. METHODS: One hundred thirty-four patients were randomized to receive either diltiazem cream and placebo injection or BTA injection and placebo cream. The primary end point was fissure healing after 3 months. RESULTS: After 3 months healing of the fissure was noted in 32 of 74 (43%) patients in the diltiazem group and 26 of 60 (43%) patients in the BTA group. Reduction >50% in mean pain score was noted in 58 of 74 (78%) patients in the diltiazem group and 49 of 60 (82%) patients in the BTA group. Perianal itching was the only side effect reported and was noted in 15% of patients in the diltiazem group, and this difference was statistically significant (P = 0.012). CONCLUSIONS: BTA yields higher healing rates in the short term, though after 3 months diltiazem and BTA resulted in equal healing rates. Also no significant difference in pain reduction was observed for both treatments. This study shows no significant advantage of one treatment compared to the other. This randomized clinical trial is registered by the Dutch Trial Register as NTR1012. PMID- 21685793 TI - Disrupting incrementalism in health care innovation. AB - OBJECTIVE: To build enabling innovation frameworks for health care entrepreneurs to better identify, evaluate, and pursue entrepreneurial opportunities. BACKGROUND: Powerful frameworks have been developed to enable entrepreneurs and investors identify which opportunity areas are worth pursuing and which start-up ideas have the potential to succeed. These frameworks, however, have not been clearly defined and interpreted for innovations in health care. Having a better understanding of the process of innovation in health care allows physician entrepreneurs to innovate more successfully. METHODS: A review of academic literature was conducted. Concepts and frameworks related to technology innovation were analyzed. A new set of health care specific frameworks was developed. These frameworks were then applied to innovations in various health care subsectors. RESULTS: Health care entrepreneurs would greatly benefit from distinguishing between incremental and disruptive innovations. The US regulatory and reimbursement systems favor incrementalism with a greater chance of success for established players. Small companies and individual groups, however, are more likely to thrive if they adopt a disruptive strategy. Disruption in health care occurs through various mechanisms as detailed in this article. While the main mechanism of disruption might vary across different health care subsectors, it is shown that disruptive innovations consistently require a component of contrarian interpretation to guarantee considerable payoff. CONCLUSIONS: If health care entrepreneurs choose to adopt an incrementalist approach, they need to build the risk of disruption into their models and also ascertain that they have a very strong intellectual property (IP) position to weather competition from established players. On the contrary, if they choose to pursue disruption in the market, albeit the competition will be less severe, they need to recognize that the regulatory and reimbursement hurdles are going to be very high. Thus, they would benefit from seeking market opportunities that are large enough to warrant greater regulatory and reimbursement risks. PMID- 21685794 TI - Deskilling and adaptation among primary care physicians using two work innovations. AB - BACKGROUND: The U.S. health care system has innovated over the past decade in ways aimed at improving quality of care while increasing managerial control over how medicine is practiced. Two key issues in examining innovation implementation is the extent to which physicians may experience deskilling as part of innovation use and to what extent they actively participate in this deskilling through adaptations they make to accommodate and take advantage of the innovations in their everyday work. METHODOLOGY: Interviews with 78 U.S. primary care physicians were conducted. Data were transcribed and computer analyzed through an interactive process of open coding, theoretical sampling, vignette construction, and pattern recognition that proceeded in several stages. The two innovations examined were the use of electronic medical records and clinical guidelines. FINDINGS: Primary care physicians perceive and experience the use of electronic medical records and clinical guidelines in ways that indicate deskilling outcomes. The deskilling outcomes identified include decreased clinical knowledge, decreased patient trust, increased stereotyping of patients, and decreased confidence in making clinical decisions. Physicians are actively involved in the deskilling process through the adaptive choices made when incorporating the innovations into their everyday work. The existing primary care business model exacerbates the deskilling effects of the two innovations examined in the study. PRACTICE IMPLICATIONS: Primary care physicians perceive and experience deskilling as a tangible outcome of using particular health care innovations. However, such deskilling is, in part, a function of physicians' own actions as well as extant pressures in the surrounding work context. Health care organizations and managers have a productive role to play in attempting to mitigate these pressures and lessen the deskilling outcomes associated with them. This study supports closer examination of the total costs and benefits deriving from using different health care innovations while portraying innovation use as a negotiated set of outcomes. PMID- 21685795 TI - Inpatients' willingness to recommend: a multilevel analysis. AB - BACKGROUND: Satisfaction with health care is one of the most widely assessed measures of hospital care quality, yet studies that account for clustering effects are uncommon. We constructed a multilevel model to identify predictors of willingness to recommend while controlling for clustering effects due to hospital and care unit. We also examined differences in predictors by care unit. PURPOSE: The aim of this study was to identify factors that both influence patient perceptions of care and are potentially modifiable by the hospital delivering care. METHODOLOGY: Our sample includes Hospital Consumer Assessment of Healthcare Providers and Systems survey data collected between July 1, 2007, and June 30, 2008, for 131 hospitals and 33,445 patients. The primary outcome was willingness to recommend the hospital to family and friends. Variables were collected at three levels: patient (Hospital Consumer Assessment of Healthcare Providers and Systems survey item responses and demographics), care unit, and hospital. Data were analyzed using multilevel modeling. We also ran a series of two-level models to explore differences in predictors by care type. FINDINGS: The strongest predictors of willingness to recommend, controlling for clustering effects, were items that generally reflected interpersonal aspects of care such as nursing and physician behaviors. In the two-level models, predictors of willingness to recommend overlapped across care units, but important differences were noted. PRACTICE IMPLICATIONS: Our results suggest that hospitals that wish to improve their performance would benefit most from focusing on interpersonal aspects of care. Hospitals that focus resources on improving in these areas, that assess care units separately, and that investigate the meaning and context of survey responses will be most likely to see improvements in satisfaction scores. PMID- 21685796 TI - Preoperative differential diagnosis of minimal deviation adenocarcinoma and lobular endocervical glandular hyperplasia of the uterine cervix: a multicenter study of clinicopathology and magnetic resonance imaging findings. AB - OBJECTIVE: To clarify the preoperative differential diagnosis and management of minimal deviation adenocarcinoma (MDA) and lobular endocervical glandular hyperplasia (LEGH), a multicenter study was performed. METHODS: A total of 112 patients who underwent conization or a hysterectomy for suspected MDA were collected from 24 hospitals. The pathological diagnosis in each case was determined by a central pathological review board. The diagnostic significance of clinicopathologic findings including results of magnetic resonance imaging (MRI), Papanicolaou (Pap) smears, and testing for gastric mucin was analyzed. RESULTS: The central pathological review identified 37 cases of Nabothian cyst or tunnel cluster, 54 cases of LEGH, 6 cases of MDA, 11 cases of adenocarcinoma, and 4 cases of benign disease. Lobular endocervical glandular hyperplasia was often associated with adenocarcinoma in situ, MDA, and mucinous adenocarcinoma. Three MDA patients had a recurrence, whereas none of LEGH patients had a recurrence irrespective of the type of surgery. On MRI, LEGH appeared as a characteristic multicystic lesion with an inner solid component, whereas MDA showed a predominantly solid pattern. A Pap smear or gastric mucin alone had limited diagnostic power. However, a combination of these findings is useful; that is, a cystic structure with inner solid components on MRI associated with mild glandular atypia and gastric mucin strongly suggested LEGH (24/26, 92%). A solid structure with atypical glandular cells was indicative of MDA or adenocarcinoma (5/5, 100%). CONCLUSIONS: The combination of MRI, Pap smears, and gastric mucin will improve the accuracy of the preoperative diagnosis of MDA and LEGH. Patients suspected of having LEGH may need to be treated with less aggressive methods. PMID- 21685797 TI - Asymmetric bispectral index values in a patient with traumatic brain injury. PMID- 21685798 TI - Exploring the role of co-worker social support on health care utilization and sickness absence. AB - OBJECTIVES: To explore the association of baseline co-worker social support with follow-up measures of health care use and sickness absence. METHODS: Data were obtained on 1240 employees from 33 worksites, through Promoting Activity and Changes in Eating, a group randomized weight maintenance trial. Co-worker social support, health care utilization, and absenteeism were assessed via a self reported questionnaire. Generalized Estimating Equations were employed using STATA version 10. RESULTS: Higher baseline co-worker social support was significantly associated with a greater number of doctors' visits (P = 0.015). Co worker social support was unrelated to number of hospitalizations, emergency department visits, or absenteeism. CONCLUSIONS: The relationship between co worker social support and health care utilization and absenteeism is complex and uncertain. Future studies should measure more specific outcomes, incorporate important mediating variables, and distill how social networks influence these outcomes. PMID- 21685799 TI - Musculoskeletal pain in the workforce: the effects of back, arthritis, and fibromyalgia pain on quality of life and work productivity. AB - OBJECTIVE: To investigate the impact of musculoskeletal pain on health-related quality of life and work productivity losses among US workers. METHODS: Data from the 2008 US National Health and Wellness Survey were used. Among those currently employed aged 20 to 64 years (N = 30,868), workers with arthritis (n = 2,670), back (n = 4,920), and fibromyalgia (n = 439) pain were compared with workers without those respective musculoskeletal pain conditions. RESULTS: Arthritis, back, and fibromyalgia pain were all associated with significantly lower levels of health-related quality of life, often at clinically meaningful levels. All pain conditions were associated with higher levels of work productivity loss, even after adjusting for demographic and health characteristics. CONCLUSIONS: Musculoskeletal pain conditions were highly prevalent and associated with a significant burden. Improved management of these conditions may lead to improved productivity, benefiting both employers and workers alike. PMID- 21685800 TI - The effects of age and shiftwork on perceived sleep problems: results from the VISAT combined longitudinal and cross-sectional study. AB - OBJECTIVE: With workforces in industrialized countries getting older, the study examined how shiftworking affects sleep in later life. METHOD: Longitudinal data were collected in 1996, 2001, and 2006 from a large sample of employees who were 32, 42, 52, and 62 years old in 1996. RESULTS: Effects of shiftwork were most apparent in middle-aged participants, becoming less apparent in later years when people tended to leave shiftwork. Nevertheless, a group of younger former shiftworkers reported more sleep problems than those who had never worked shifts. Giving up shiftwork offset a trend for sleep problems to accumulate over time, with the net result of no change in sleep problems after cessation of shiftwork. CONCLUSIONS: Poor sleep quality is a temporary consequence of shiftwork for some, whereas for others it is a cause of shiftwork intolerance. PMID- 21685801 TI - Phosphatidylserine metabolism in human lymphoblastic cells exposed to chromium (VI). AB - OBJECTIVE: Hexavalent chromium (Cr(VI)) compounds are widely found in different working environments. These compounds can cause apoptosis in human cells, but the mechanisms underlying chromium-induced apoptosis are not clear. A marker of apoptosis is the exposure of phosphatidylserine on cell membrane and the modification of phosphatidylserine metabolism. The aim of this study was to verify whether chromium could cause phosphatidylserine exposure and modification of its metabolism in human lymphoblastic leukemia cell line (MOLT-4). METHODS: Phosphatidylserine exposure was evaluated by annexin V binding whereas phosphatidylserine metabolism was studied measuring the incorporation of [3H]serine. RESULTS: Cell treatment with Cr(VI) increases phosphatidylserine exposure and cell apoptosis, but decreases the incorporation of [3H]serine into phosphatidylserine in a dose- and time-dependent manner. CONCLUSIONS: The Cr(VI) induced apoptosis also through modification of phosphatidylserine exposure and metabolism. PMID- 21685802 TI - Chondroblastoma of the femoral neck as a cause of hip synovitis. AB - Chondroblastoma is a rare benign chondroid bone tumor, which typically arises from the epiphysis of a long tubular bone. We present a 13-year-old girl with persistent hip synovitis caused by a chondroblastoma that arose from the femoral neck (metaphysis) and uniquely extended extraosseously into the hip joint. Computed tomography scan clearly demonstrated a tumoral lesion of the left femoral neck and a periosteal reaction along the anterior cortex of the femur, distal to the legion. Magnetic resonance imaging showed reactive synovitis with marked joint effusion of the hip and an extensive edema in the proximal femur and the surrounding soft tissues. Aneurysmal bone cysts formation secondary to chondroblastoma was confirmed by histologic examinations of the excised specimens. Complete relief of pain and an improvement in the range of movement of the hip joint was obtained after surgical resection of the tumor. PMID- 21685803 TI - Surgical treatment of symptomatic discoid medial meniscus in childhood: a case report. AB - If the meniscus has a spherical shape and not a semilunary structure, it is called as discoid meniscus. This anomaly is generally seen in the lateral meniscus; however, it is rare in the medial meniscus. Although the discoid meniscus is usually asymptomatic in children and adolescents, it could present as a meniscal tear. An 11-year-old boy was admitted to our hospital with right knee pain and lack of extension of the knee joint. He was diagnosed as discoid medial meniscus. On physical examination, we observed tenderness at the knee joint line with an effusion of the knee and a restriction during the extension movement of the knee joint. McMurray test was positive. Conventional radiograms revealed widening of the medial joint line and cupping of the medial tibial plateau. Magnetic resonance imaging indicated a discoid meniscus image at sagittal slices. In this case, after the arthroscopic partial menisectomy, we obtained an excellent result at 2 years follow-up. PMID- 21685804 TI - Which is the preferred revision technique for loosened iliac screw? A novel technique of boring cement injection from the outer cortical shell. AB - STUDY DESIGN: An in vitro biomechanical cadaver study. OBJECTIVES: To evaluate the pull-out strength after 5000 cyclic loading among 4 revision techniques for the loosened iliac screw using corticocancellous bone, longer screw, traditional cement augmentation, and boring cement augmentation. SUMMARY OF BACKGROUND DATA: Iliac screw loosening is still a clinical problem for lumbo-iliac fusion. Although many revision techniques using corticocancellous bone, larger screw, and polymethylmethacrylate (PMMA) augmentation were applied in repairing pedicle screw loosening, their biomechanical effects on the loosened iliac screw remain undetermined. METHODS: Eight fresh human cadaver pelvises with the bone mineral density values ranging from 0.83 to 0.97 g/cm were adopted in this study. After testing the primary screw of 7.5 mm diameter and 70 mm length, 4 revision techniques were sequentially established and tested on the same pelvis as follows: corticocancellous bone, longer screw with 100 mm length, traditional PMMA augmentation, and boring PMMA augmentation. The difference of the boring technique from traditional PMMA augmentation is that PMMA was injected into the screw tract through 3 boring holes of outer cortical shell without removing the screw. On an MTS machine, after 5000 cyclic compressive loading of -200~-500 N to the screw head, axial maximum pull-out strengths of the 5 screws were measured and analyzed. RESULTS: The pull-out strengths of the primary screw and 4 revised screws with corticocancellous bone, longer screw and traditional and boring PMMA augmentation were 1167 N, 361 N, 854 N, 1954 N, and 1820 N, respectively. Although longer screw method obtained significantly higher pull-out strength than corticocancellous bone (P<0.05), the revised screws using these 2 techniques exhibited notably lower pull-out strength than the primary screw and 2 PMMA augmented screws (P<0.05). Either traditional or boring PMMA screw showed obviously higher pull-out strength than the primary screw (P<0.05); however, no significant difference of pull-out strength was detected between the 2 PMMA screws (P>0.05). CONCLUSIONS: Wadding corticocancellous bone and increasing screw length failed to provide sufficient anchoring strength for a loosened iliac screw; however, both traditional and boring PMMA-augmented techniques could effectively increase the fixation strength. On the basis of the viewpoint of minimal invasion, the boring PMMA augmentation may serve as a suitable salvage technique for iliac screw loosening. PMID- 21685805 TI - Surgical outcome of lumbar fusion surgery in patients with Parkinson disease. AB - STUDY DESIGN: Retrospective study. OBJECTIVES: To investigate the overall surgical outcome of lumbar fusion surgery in patients with Parkinson disease (PD). SUMMARY OF BACK GROUND DATA: Poor bone quality and muscular dysfunction are important clinical manifestations connected with musculoskeletal diseases in PD patients. These secondary changes caused by PD often result in spinal pathology, indicating spine operations for some patients with scoliosis, kyphosis, osteoporotic fracture, or degenerative spondylosis. However, little is known about the surgical outcome or prognosis of spine surgery in PD patients. METHODS: Lumbar fusion surgery was performed on 20 patients who had PD and degenerative spinal diseases. At the time of lumbar fusion surgery, the mean duration of PD, age, sex, the preoperative visual analog pain scale (VAS, 0 to 100 mm) for low back pain, Hoehn and Yahr staging, and other comorbidities were evaluated. Patients' postoperative clinical outcome was measured using the criteria of Kim and Kim and VAS for back pain. Radiographic assessment was made using plain films and a dynamogram. RESULTS: At the time of the spine surgery, Hoehn and Yahr staging of PD was from 1 to 2 in all patients. Only 1 patient had a satisfactory outcome; a good result according to Kim and Kim's criteria. The average postoperative VAS (mm) was 55.2, whereas the mean preoperative VAS (mm) was 53.9. Radiological assessment showed fusion status in 15 patients and probably no solid fusion mass in 5 patients. CONCLUSIONS: A poor surgical outcome would be inevitable because of the worsening of symptoms owing to the natural history of PD. Therefore, our current study suggested surgical indication should be exercised cautiously in the patients with PD and spinal stenosis. PMID- 21685806 TI - Acute hospital costs after minimally invasive versus open lumbar interbody fusion: data from a US national database with 6106 patients. AB - STUDY DESIGN: Retrospective multi-institutional database review. OBJECTIVE: To determine if minimally invasive interbody fusion is associated with cost savings when compared with open surgery. SUMMARY OF BACKGROUND DATA: Minimally invasive spine (MIS) surgeries are increasingly recognized as equivalent to open procedures. Although these techniques have been advocated for reducing pain, disability, and length of hospitalization, to date there has been little data demonstrating these benefits. METHODS: This study analyzed inpatient hospital records from the Premier Perspective database (2002 to 2009), including patients who underwent a posterior lumbar fusion with interbody cage placement by ICD-9 code, and had implant charge codes that allowed determination if MIS pedicle screws were utilized. Exclusion criteria included a refusion surgery, deformity, >2 levels, and anterior fusion. Total costs were adjusted for covariates (age, sex, race, hospital geography and setting, payor, and comorbidities) using an analysis of covariance model. RESULTS: A total of 6106 patients were identified (1667 MIS and 4439 open). Length of stay (LOS) for 1-level MIS surgery averaged of 3.35 days versus 3.6 days for open surgery (P<=0.006). For 2-level MIS surgery LOS averaged of 3.4 days versus 4.03 days for open surgery (P<=0.001). Total inflation-adjusted acute hospitalization cost averaged $29,187 for 1-level MIS procedures versus $29,947 for open surgery, a nonsignificant difference (P=0.55). Total inflation-adjusted acute hospitalization cost averaged $2106 lower for 2 level MIS surgery (total costs of $33,879 for MIS vs. $35,984 for open surgery, P=0.0023). Cost savings were attributable primarily to lower room and board ($857), operating room ($359), pharmacy ($304), and laboratory ($166) costs in the MIS group. High variances in the 2-level open surgery with prolonged hospital stay also accounted for overall cost differences. CONCLUSIONS: This data from a large nationwide sample of hospitalizations demonstrates that MIS lumbar interbody fusion results in a statistically significant reduction in hospital LOS and a reduction in total hospital costs with 2-level surgery after adjusting for significant covariates. The majority of cost savings from MIS surgery were due to more rapid mobilization and discharge, as well as a reduction in outliers with extended hospitalizations. PMID- 21685807 TI - Monocyte and T-cell responses to exercise training in elderly subjects. AB - The purpose of this study was to examine the effects of exercise training on age related impairment of immune parameters related to T-cell activation in elderly individuals. Twenty-four elderly subjects were assigned to an exercise training group (EXC: 3 men, 9 women; age 61-76 years) or a nonexercise control group (CON: 4 men, 8 women; age 62-79 years). Subjects in EXC participated in exercise sessions 2 d.wk(-1) for 12 weeks. The training session included stretching and endurance exercise (10 minutes), resistance training comprised leg extension, leg press, hip abduction, and hip adduction using exercise machine and each subject's body weight. Subjects in CON maintained their normal physical activity levels during the study period. Blood samples were collected before and after the training period. Samples were measured for the numbers of leukocytes, lymphocytes, and monocytes, and for CD3(+), CD4(+), CD8(+), CD28(+)CD4(+), CD28(+)CD8(+), TRL-4(+)CD14(+), and CD80(+)CD14(+) cells. The number of leukocytes, lymphocytes, monocytes, CD3(+), CD4(+), and CD8(+) cells did not change after 12 weeks in either EXC or CON. The number of CD28(+)CD8(+) cells increased significantly after training in EXC (p <= 0.05), although CON showed no significant change. In the EXC group, CD80(+)CD14(+) cell counts were significantly higher after training (p <= 0.05), but the TLR-4(+)CD14(+) cell counts were unchanged. In the CON group, no significant alteration existed in TLR 4(+)CD14(+) and CD80(+)CD14(+) cell numbers. In conclusion, exercise training in elderly people is associated with increased CD28-expressing Tc cells and CD80 expressing monocytes. Therefore, exercise training might upregulate monocyte and T-cell-mediated immunity in elderly people. PMID- 21685808 TI - Relation between total body load and session rating of perceived exertion in professional soccer players. AB - The aims of this study were to assess (a) the validity of total body load (TBL) obtained from the global position system (GPS) devices-to quantify soccer training load, assessing its relationship with session rating of perceived exertion (session-RPE) and (b) to analyze the differences in terms of TBL and session-RPE among defenders, midfielders, and forwards. Twenty-two professional soccer players (Spanish first division, season 2007-2008; 26.74 +/- 4.2 years; height 179.74 +/- 4.04 cm; weight 73.7 +/- 3.35 kg) participated in the study. During 13 training sessions composed predominantly of small-sided games, TBL and RPE multiplied by the minutes of session duration were determined using GPS and the 21-point scale, respectively. In each session, data from 10 players randomly selected and classified according to player position (defenders, midfielders, and forwards) were collected. Although session-RPE was a significant predictor of TBL (beta = 0.23, p < 0.05), this method only accounted for 5% of the variance in TBL. No significant differences in terms of TBL and session-RPE were found regarding player position. The results of this study suggest that TBL is not a valid measure to quantify training load because it is not strongly correlated with session-RPE. Furthermore, TBL and session-RPE in small-sided soccer games do not vary according to player positions. PMID- 21685809 TI - Intra and intersession reliability of balance measures during one-leg standing in young adults. AB - A study was designed to investigate the intra and intersession reliability during 1-leg standing recorded from a computerized balance platform. Thirty-nine healthy young men (n = 17, age range: 20-30 years) and women (n = 22, age range: 21-28 years) performed 3 testing sessions, with the second session 30 minutes (intrasession comparison) and the third session 1 week (intersession comparison) after the initial testing session. Within each testing session, participants completed 3 trials of 1-leg standing with their dominant leg. Reliability statistics were calculated using the mean of all 3 trials during each session for 6 balance measures (i.e., total displacements of the center of pressure [CoP], the CoP displacements in mediolateral and anterior-posterior directions, and the CoP speed and CoP area and their SD). Test-retest reliability was examined calculating both, intraclass correlation coefficient (ICC) with 95% confidence interval (95% CI) and Bland-Altman plots. In both sexes and irrespective of balance measure, ICC values were >=0.75 except for 1 parameter in men. This indicates an excellent intra and intersession reliability. Bland-Altman plots confirmed these findings by showing that only 1 or 2 (4.5-11.8%) of the data points were beyond the 95% CI. Practitioners and clinicians are provided with a posturographic test setup that proved to be reliable. Researchers can use these data to identify the range in which the true value of a subject's score lies and estimate a priori sample sizes. PMID- 21685810 TI - Reliance on Veterans Affairs outpatient care by Medicare-eligible veterans. AB - OBJECTIVE: To examine longitudinal changes in Medicare-eligible veterans' reliance on the Department of Veterans Affairs (VA) healthcare system for primary and specialty care over 4 years. METHODS: We merged VA administrative and Medicare claims data to examine outpatient use during fiscal years (FY) 2001 to 2004 by 15,520 Medicare-eligible veterans who used VA primary care in FY2000. Reliance on VA outpatient care was defined as the proportion of total (VA/Medicare) visits received in VA for primary or specialty care. RESULTS: Of 869,000 primary and specialty care visits in the study period, 39% occurred within VA and 77% were specialty care. Reliance on VA primary care was substantially higher than specialty care (66% vs. 50% in FY2001; P<0.001). Reliance on VA primary and specialty care decreased over time (57% vs. 31% in FY2004; P<0.001). Significant shifts occurred at both extremes of VA reliance. From FY2001 to FY2004, the proportion of patients in the top decile of reliance on VA primary care decreased from 39% to 31%, whereas the proportion in the bottom decile doubled from 8% to 18%. Similarly, the proportion of patients in the top decile of reliance on VA specialty care decreased from 24% to 13%, whereas the proportion in the bottom decile doubled from 22% to 47%. CONCLUSIONS: Reliance on VA primary and specialty care among VA primary care patients decreased substantially over time, particularly for specialty care. Increasing use of non-VA services may complicate VA's implementation of patient-centered medical home models and performance measurement. PMID- 21685811 TI - Quality of palliative care at US hospices: results of a national survey. AB - BACKGROUND: The National Quality Forum (NQF) identified hospice services as a national priority area for health care quality improvement and endorsed a set of preferred practices for quality palliative and hospice care. This study reports the first national data regarding hospices' self-reported implementation of the NQF preferred practices and identifies hospice characteristics associated with more comprehensive implementation. METHODS: We conducted a national cross sectional survey of a random sample of hospices (n=591; response rate, 84%) from September 2008 to November 2009. We evaluated the reported implementation of NQF preferred practices in the care of both patients and families. RESULTS: The range of reported implementation of individual NQF preferred practices among hospices was 45% to 97%. Twenty-one percent of hospices reported having implemented all patient-centered preferred practices, 26% all family-centered preferred practices, and 10% all patient and family-centered preferred practices. In adjusted analyses, large hospices (100 or more patients per day) were significantly more likely than small hospices (<20 patients per day) to report having implemented all patient-centered preferred practices [odds ratio (OR)=2.46; 95% CI, 1.24, 4.90] and all family-centered preferred practices (OR=1.88; 95% CI, 1.02, 3.45). Similarly, chain-affiliated hospices were significantly more likely than free-standing hospices to report having implemented all patient-centered preferred practices (OR=2.45; 95% CI, 1.23, 4.87) and all family-centered preferred practices (OR=1.85; 95% CI, 1.01, 3.41). CONCLUSIONS: Hospices' reported implementation of individual preferred practices for palliative and hospice care quality was high; however, reported comprehensive implementation of preferred practices was rare and may be difficult to achieve for small, free-standing hospices. PMID- 21685812 TI - Patterns of accelerometer-derived estimates of inactivity in middle-age women. AB - PURPOSE: The study's purpose was to characterize accelerometer-derived estimates of physical inactivity collected during five consecutive weeks in middle-age women. METHODS: Data were obtained from 63 participants (95.5%) enrolled in the Evaluation of Physical Activity Measures in Middle-Age Women Study. Inactive time (min . d(-1)) was estimated as the sum of activity counts <100, and inactive-to active transitions were defined as an interruption in which a period of inactivity was immediately followed by a minute or more above 100 counts. A repeated-measures ANOVA using PROC MIXED (SAS/STAT software, v. 9.2) was used to describe hourly, daily, and weekly variation in estimates of physical inactivity. RESULTS: Participants were 52.7 +/- 5.5 yr, 85.7% non-Hispanic white, and 63.5% postmenopausal, with a body mass index of 26.7 +/- 5.1 kg . m(-2). Inactive time gradually increased as the day continued, particularly on weekend days. When compared with weekdays, average inactive time was lower on Saturday and Sunday (all P < 0.01 except for Saturday vs Monday, P < 0.10); Saturdays were not significantly different from Sundays. Breaks in inactive time were significantly lower on Sunday when compared with weekdays and Saturday (all P < 0.05), and fewer breaks were noted on Saturday when compared with Wednesday and Friday (both P < 0.01). After adjustment for total wear time or inactive time, most day-to-day differences were attenuated. Week-by-week differences in physical inactivity estimates were also not statistically significant. CONCLUSIONS: The results of this study suggest that inactive time increases as the day continues and that daily physical inactivity estimates are more stable after 1) adjustment for wear time or 2) when averaged over the week. Researchers should carefully consider the intended application of physical inactivity estimates before data collection and processing, analysis, and final data reporting. PMID- 21685813 TI - A protein-leucine supplement increases branched-chain amino acid and nitrogen turnover but not performance. AB - PURPOSE: This study aimed to determine the effect of postexercise protein-leucine coingestion with CHO-lipid on subsequent high-intensity endurance performance and to investigate candidate mechanisms using stable isotope methods and metabolomics. METHODS: In this double-blind, randomized, crossover study, 12 male cyclists ingested a leucine/protein/CHO/fat supplement (LEUPRO 7.5/20/89/22 g . h(-1), respectively) or isocaloric CHO/fat control (119/22 g . h(-1)) 1-3 h after exercise during a 6-d training block (intense intervals, recovery, repeated sprint performance rides). Daily protein intake was clamped at 1.9 g . kg(-1) . d(-1) (LEUPRO) and 1.5 g . kg(-1) . d(-1) (control). Stable isotope infusions (1 (13)C-leucine and 6,6-(2)H2-glucose), mass spectrometry-based metabolomics, and nitrogen balance methods were used to determine the effects of LEUPRO on whole body branched-chain amino acid (BCAA) and glucose metabolism and protein turnover. RESULTS: After exercise, LEUPRO increased BCAA levels in plasma (2.6 fold; 90% confidence limits = *// 1.1) and urine (2.8-fold; *// 1.2) and increased products of BCAA metabolism plasma acylcarnitine C5 (3.0-fold; *// 0.9) and urinary leucine (3.6-fold; *// 1.3) and beta-aminoisobutyrate (3.4-fold; *// 1.4), indicating that ingesting ~10 g leucine per hour during recovery exceeds the capacity to metabolize BCAA. Furthermore, LEUPRO increased leucine oxidation (5.6-fold; *// 1.1) and nonoxidative disposal (4.8-fold; *// 1.1) and left leucine balance positive relative to control. With the exception of day 1 (LEUPRO = 17 +/- 20 mg N . kg(-1), control = -90 +/- 44 mg N . kg(-1)), subsequent (days 2-5) nitrogen balance was positive for both conditions (LEUPRO = 130 +/- 110 mg N . kg(-1), control = 111 +/- 86 mg N . kg(-1)). Compared with control feeding, LEUPRO lowered the serum creatine kinase concentration by 21%-25% (90% confidence limits = +/- 14%), but the effect on sprint power was trivial (day 4 = 0.4% +/- 1.0%, day 6 = -0.3% +/- 1.0%). CONCLUSIONS: Postexercise protein-leucine supplementation saturates BCAA metabolism and attenuates tissue damage, but effects on subsequent intense endurance performance may be inconsequential under conditions of positive daily nitrogen balance. PMID- 21685814 TI - Intrahospital weight and aerobic training in children with cystic fibrosis: a randomized controlled trial. AB - PURPOSE: The purpose of our study was to assess the effects of an 8-wk intrahospital combined circuit weight and aerobic training program performed by children with cystic fibrosis (of low-moderate severity and stable clinical condition) on the following outcomes: cardiorespiratory fitness (VO2peak) and muscle strength (five-repetition maximum (5RM) bench press, 5RM leg press, and 5RM seated row) (primary outcomes) and pulmonary function (forced vital capacity, forced expiratory volume in 1 s), weight, body composition, functional mobility (Timed Up and Down Stairs and 3-m Timed Up and Go tests), and quality of life (secondary outcomes). We also determined the effects of a detraining period (4 wk) on the aforementioned outcomes. METHODS: We performed a randomized controlled trial design. Eleven participants in each group (controls: 7 boys, age = 11 +/- 3 yr, body mass index = 17.2 +/- 0.8 kg . m(-2) (mean +/- SEM); intervention: 6 boys, age = 10 +/- 2 yr, body mass index = 18.4 +/- 1.0 kg . m(-2)) started the study. RESULTS: Adherence to training averaged 95.1% +/- 7.4%. We observed a significant group * time interaction effect (P = 0.036) for VO2peak. In the intervention group, VO2peak significantly increased with training by 3.9 mL . kg( 1) . min(-1) (95% confidence interval = 1.8-6.1 mL . kg(-1) . min(-1), P = 0.002), whereas it decreased during the detraining period (-3.4 mL . kg(-1) . min(-1), 95% confidence interval = -5.7 to -1.7 mL . kg(-1) . min(-1), P = 0.001). In contrast, no significant changes were observed during the study period within the control group. Although significant improvements were also observed after training for all 5RM strength tests (P < 0.001 for the interaction effect), the training improvements were not significantly decreased after the detraining period in the intervention group (all P > 0.1 for after training vs detraining). We found no significant training benefits in any of the secondary outcomes. CONCLUSIONS: A short-term combined circuit weight and aerobic training program performed in a hospital setting induces significant benefits in the cardiorespiratory fitness and muscle strength of children with cystic fibrosis. PMID- 21685815 TI - A 7-d exercise program increases high-molecular weight adiponectin in obese adults. AB - PURPOSE: High-molecular weight (HMW) adiponectin is the biologically active form of adiponectin and is related to enhanced insulin sensitivity and metabolic function. Previously, we found that 7 d of exercise improves insulin sensitivity in obese subjects; however, whether short-term exercise training affects HMW adiponectin in obese persons is unknown. METHODS: We examined the effect of seven consecutive days of supervised vigorous exercise (60 min . d(-1), 85% HRmax) on HMW adiponectin and leptin secretion in 17 obese individuals (age = 55 +/- 3 yr; body mass index = 33.7 +/- 0.9 kg . m(-2)). Insulin sensitivity was calculated from an oral glucose tolerance test (ISIOGTT) using the Matsuda Index. Fasting plasma HMW adiponectin and leptin were quantified from blood samples obtained before the ISIOGTT. Glucose and insulin measures were obtained before and every 30 min during the test. Dual-energy x-ray absorptiometry was used to determine body composition, and indirect calorimetry was used to assess fat oxidation. RESULTS: After the intervention, there was a significant increase in HMW adiponectin (3202 +/- 543 vs 3878 +/- 682 ng . mL(-1), P = 0.02) and a decrease in leptin (36.8 +/- 5.1 vs 31.1 +/- 4.2 MUg . mL(-1), P = 0.03). Further, we observed an increase in ISIOGTT (1.7 +/- 0.3 vs 2.1 +/- 0.3, P = 0.04) and a decrease in glucose area under the curve (30,871 +/- 2105 vs 28,469 +/- 1657 mg . dL(-1) for 3 h, P = 0.01). The increase in HMW adiponectin was positively associated with the increase in basal fat oxidation (r = 0.57, P = 0.03), consistent with an improvement in adipose tissue metabolic function. CONCLUSIONS: The data suggest that 7 d of exercise is sufficient not only to improve insulin sensitivity and fat oxidation but also to favorably alter adipokine secretion, independent of changes in body weight or composition. PMID- 21685818 TI - Augmentation index immediately after maximal exercise in patients with type 2 diabetes mellitus. AB - INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) have exaggerated brachial and central (ascending aortic) blood pressure (BP) during exercise, which is associated with adverse outcomes. Central systolic loading, represented by the augmentation index (AIx), may contribute to exaggerated exercise central BP. This study sought to compare the central AIx response to peak exercise in T2DM and control patients and to identify mechanisms of altered exercise central AIx. METHODS: Central BP and AIx were quantified by radial tonometry at rest and immediately after peak treadmill exercise in 106 patients with T2DM and 106 nondiabetic controls, pair-matched by age, gender, peak exercise brachial BP, and postexercise HR corresponding to tonometry acquisition. Cardiac volumes (by echocardiography) were assessed in a subgroup (22 T2DM and 22 controls) to derive rest and postexercise arterial-ventricular coupling parameters, including cardiac index (stroke volume index * HR), peripheral vascular resistance index (cardiac index / mean BP), and effective arterial elastance index (end-systolic pressure / stroke volume index). Reserve parameters (exercise--rest) were also defined. RESULTS: Patients with T2DM had lower postexercise central AIx (-1% +/- 13% vs 3% +/- 14%, P = 0.038) and greater central AIx reserve (-24% +/- 13% vs -20% +/- 11%, P = 0.002) compared with controls, despite raised postexercise peripheral vascular resistance index (P = 0.013) and effective arterial elastance index (P = 0.011); these parameters independently predicted higher central AIx at rest (P < 0.01) but not after exercise. Moreover, T2DM was independently associated with lower postexercise central AIx (beta = -0.21, P = 0.006). Cardiac index reserve, which was blunted in T2DM (P = 0.004), represented the only independent correlate of central AIx reserve (r = 0.39, P = 0.01). CONCLUSIONS: Patients with T2DM have significantly (and paradoxically) lower postexercise central AIx and greater central AIx reserve, which may be explained by an impaired cardiac functional reserve. PMID- 21685817 TI - Exercise does not attenuate early CAD progression in a pig model. AB - PURPOSE: This study was designed to examine the effects of high-fat (HF) diet and subsequent exercise training (Ex) on coronary arteries of an animal model of early stage CAD. We hypothesized that HF diet would induce early stage disease and promote a proatherogenic coronary phenotype, whereas Ex would blunt disease progression and induce a healthier anti-inflammatory environment reflected by the increased expression of antioxidant capacity and the decreased expression of inflammatory markers in both the macrovasculature and the microvasculature of the coronary circulation. METHODS: Immunohistochemistry in left anterior descending and right coronary arteries and immunoblots in left anterior descending and left ventricular arterioles were used to characterize the effects of HF diet and Ex on the progression of coronary atherosclerosis. RESULTS: Our results revealed that HF diet promoted a proatherogenic coronary endothelial cell phenotype as evidenced by the endothelial expression of inflammatory and oxidative stress markers. Ex did not significantly alter any of these immunohistochemical markers in conduit arteries; however, Ex did increase antioxidant protein content in left ventricular arterioles. CONCLUSIONS: We conclude that, at this early stage of CAD, Ex did not seem to modify vascular cell phenotypes of conduit coronary arteries from proatherogenic to a more favorable antiatherogenic status; however, Ex increased antioxidant protein content in coronary arterioles. These findings also support the idea that endothelial phenotype expression follows different patterns in the macrovasculature and microvasculature of the coronary circulation. PMID- 21685819 TI - Water ingestion improves performance compared with mouth rinse in dehydrated subjects. AB - It has been suggested that mouth rinse and/or ingestion of fluids during exercise may have a beneficial effect on performance. However, the existing results are controversial. PURPOSE: We hypothesized that pharyngeal receptor activation through ingestion of a small amount of water could enhance performance better than mouth rinse in dehydrated subjects. METHODS: Ten healthy trained male cyclists (weight = 78.2 +/- 2.2 kg, age = 25.9 +/- 1.0 yr, body fat = 15.6% +/- 1.6%, VO2max = 53.8 +/- 4.8 mL . kg(-1) . min(-1)) completed three time-to exhaustion cycling tests at 75% of their maximum power output after being dehydrated by 2% of their total body weight. Dehydration was induced by a 2-h moderate-intensity exercise (70% of maximum HR), which included 30-min intervals alternating between jogging and cycling in the heat (31 degrees C). All subjects repeated the protocol in random order on three separate occasions: a) mouth rinse with 25 mL of plain water before and every 5 min of the trial (MR), b) ingestion of 25 mL of plain water before and every 5 min (DR), and c) control (CON), where no fluids were provided. Blood and urine samples were collected at the beginning of the dehydration phase, before the performance test, and at the end of the experimental protocol. RESULTS: A significantly greater time to exhaustion was recorded in the DR trial compared with MR and CON trials (21.9 +/- 1.2 vs 18.7 +/ 1.3 and 17.7 +/- 1.1 min, respectively, P < 0.05). There were no differences in mean HR, maximum lactate concentration, or RPE between the three trials (P > 0.05). CONCLUSIONS: The results demonstrated that ingestion of even a small amount of water increased exercise time in dehydrated subjects possibly through activation of pharyngeal receptors. PMID- 21685821 TI - Focal fluorine-18 fluorodeoxyglucose-avid lesions without computed tomography correlate at whole-body positron emission tomography-computed tomography in oncology patients: how often are they malignant? AB - OBJECTIVE: To retrospectively evaluate the rate of malignancy of focal fluorine 18 fluorodeoxyglucose (18F-FDG)-avid lesions without computed tomography (CT) correlate at whole-body positron emission tomography (PET)-CT in oncology patients, because better defining these abnormalities could potentially lead to improved patient management algorithms that rely on PET-CT for detection, staging, and treatment monitoring of malignancies. METHODS: We performed a computer search of all PET-CT studies performed at our institution from 2006 to 2009, and identified 87 studies with findings of focal 18F-FDG-avid lesions without correlate at CT. The rate of malignancy of such lesions was determined by reviewing findings at follow-up imaging or by clinical or histopathological follow-up. Rates of malignancy were categorized and compared by lesion location and by the type of primary malignancy. RESULTS: The most common locations for focal 18F-FDG-avid lesions without CT correlate were: lymph node location (without visible lymph nodes; 27/87), bone (21/87), soft tissue (17/87), liver (9/87), and gastrointestinal tract (8/87). Forty-one percent (36/87) of the focal FDG-avid lesions without CT correlate were malignant (either metastatic disease or a second malignancy) at follow-up (mean follow-up: 5 months, range: 1-25 months). Focal FDG-avid lesions in lymph node location and in bone without CT correlate had higher rates of malignancy (56%, 15/27 and 52%, 11/21, respectively) than lesions in all other locations (26%, 10/39, P=0.028). In 15 of 87 cases, the only significant finding at PET-CT was an FDG-avid lesion without CT correlate. Of those, 53% (8/15) was positive for malignancy. There were no significant differences in the rates of malignancy for the focal FDG-avid lesions without CT correlate when stratified by the type of primary malignancy in this series. CONCLUSION: Focal FDG avid lesions without CT correlate were malignant in 41% of cases in our series of oncology patients. Lesions in lymph node location and in bones had the highest rates of malignancy. Knowledge of the patterns and risk of malignancy of focal FDG-avid lesions without CT correlate in oncology patients may facilitate the management of oncology patients with such lesions on PET-CT, and could lead to an improved interpretation of PET-CT scans by imaging specialists. PMID- 21685820 TI - The role of soy isoflavones in menopausal health: report of The North American Menopause Society/Wulf H. Utian Translational Science Symposium in Chicago, IL (October 2010). AB - OBJECTIVES: If and to what extent soy protein, soy isoflavones, and their metabolites, including S(--)-equol, have beneficial effects on women's health is currently unclear. The North American Menopause Society (NAMS)/Utian Translational Science Symposium on Soy and Soy Isoflavones convened October 9-10, 2010, to clarify basic and clinical research findings as they relate to the risk and benefits of soy products for peri- and postmenopausal women. METHODS: A working group of faculty and panelists composed of clinical and research experts in the fields of women's health and botanicals met during a 2-day translational symposium to cover the latest evidence-based science on isoflavones as they affect menopausal symptoms, breast and endometrial cancer, atherosclerosis, bone loss, and cognition. Full descriptions of the bioavailability and pharmacokinetics of isoflavones were also presented. Subspecialty groups then broke off with the goal of translating the information into a report for general medical practice and identifying further research areas. All faculty and panelists reviewed the final report, which was then approved by the NAMS Board of Trustees. RESULTS: From the hundreds of studies reviewed in this report, there are mixed results of the effects on midlife women. Soy-based isoflavones are modestly effective in relieving menopausal symptoms; supplements providing higher proportions of genistein or increased in S(--)-equol may provide more benefits. Soy food consumption is associated with lower risk of breast and endometrial cancer in observational studies. The efficacy of isoflavones on bone has not been proven, and the clinical picture of whether soy has cardiovascular benefits is still evolving. Preliminary findings on cognitive benefit from isoflavone therapy support a "critical window" hypothesis wherein younger postmenopausal women derive more than older women. CONCLUSIONS: Several areas for further research have been identified on soy and midlife women. More clinical studies are needed that compare outcomes among women whose intestinal bacteria have the ability to convert daidzein to equol (equol producers) with those that lack that ability (equol nonproducers) in order to determine if equol producers derive greater benefits from soy supplementation. Larger studies are needed in younger postmenopausal women, and more research is needed to understand the modes of use of soy isoflavone supplements in women. The interrelations of other dietary components on soy isoflavones consumed as a part of diet or by supplement on equol production also require further study, as do potential interactions with prescription and over-the-counter medications. And finally, greater standardization and documentation of clinical trial data of soy are needed. PMID- 21685822 TI - Quality assessment of fluorodeoxyglucose positron emission tomography imaging in clinical setting: definition of standard quality control parameters for patients treated for lymphoma. AB - PURPOSE: We designed standard parameters for quality controls (QCs) of F fluorodeoxyglucose positron emission tomography (FDG PET) images in the clinical setting, and validated them in both cross-sectional and longitudinal cohorts of patients with lymphoma under treatment. METHODS: The procedure is based on the measurement of mean standardized uptake value (SUV mean) in three specific regions of interest drawn within pulmonary, liver, and bone tissues [reference (Ref)]. Intraobserver and interobserver reproducibility [percentage of coefficient of variation (CV%)] were calculated using PET scans of healthy participants. Cross-sectional interpatient QCs were defined as the 95% ranges of normal values of Ref-SUV mean. Transversal QCs were applied on PET scans of patients treated for lymphoma (n=378) looking at Ref-SUV mean out of range. Longitudinal intrapatient QCs were defined as the 95% limits of the SUV mean variation between two consecutive scans (DeltaSUV limits). Longitudinal QCs were applied in a group of 94 pairs of consecutive PET scans under treatment for lymphoma looking at patients having Ref-DeltaSUV limits out of range. RESULTS: Intraobserver CV% remained below 3%, whereas interobserver CV% was a maximum of 5.3%. Both in transversal and longitudinal cohorts of patients treated for lymphoma, none of the PET scans simultaneously showed the three Ref-SUV mean out of range. Similar results were obtained with DeltaSUV limits. Situations in which these limits were exeeded were associated with a recent history of acute infectious pulmonary disease (lung tissues) and granulocytes colony-stimulating factors concomitant treatment and stimulation of bone marrow (bone tissues). CONCLUSION: A standardized and reproducible FDG PET QC protocol using SUV mean measurements using three tissues of Ref was validated, and may be applied in the clinical setting or in a clinical trial. PMID- 21685823 TI - Comparative study between a standard 25-gauge vitrectomy system and a new ultrahigh-speed 25-gauge system with duty cycle control in the treatment of various vitreoretinal diseases. AB - AIM: To compare a standard 25-gauge vitrectomy system with a new ultrahigh-speed (UHS) 25-gauge system with duty cycle control for pars plana vitrectomy. METHODS: In this prospective, controlled clinical trial, 120 patients (divided into 2 groups of 60 patients) underwent a 3-port pars plana vitrectomy for the treatment of epiretinal membranes, macular holes, retinal detachment, and complications of diabetic retinopathy. Evaluations were performed preoperatively, intraoperatively, on the first 3 postoperative days, and at 1 week, 1 month, and 3 months. Main outcome measures were vitrectomy time, induction of posterior vitreous detachment, and intra- and postoperative complications. Vitrectomy time included retinal manipulation, but did not include wound opening and closure. RESULTS: The duration of surgery was significantly different between the groups. Patients in the new UHS 25-gauge group had a significantly shorter duration of vitrectomy time (P < 0.0001). Mean overall vitrectomy time was 1,583.7 +/- 875.4 seconds (26 minutes) in the standard 25-gauge group and 1,106.3 +/- 575.9 seconds (18 minutes) in the UHS 25-gauge group. Twenty-nine patients (48.3%) in the standard group and 27 patients (45.0%) in the UHS group experienced induction of posterior vitreous detachment. Thirteen patients (21.7%) in the standard 25-gauge group and 1 patient (1.7%) in the new UHS group had intraoperative iatrogenic retinal breaks. CONCLUSION: The new-generation UHS 25-gauge system may provide a new paradigm of high-flow, smaller-diameter instrumentation, thus increasing the efficiency of the small-gauge technique and the safety of the surgery. PMID- 21685824 TI - A comparison of brilliant blue G, trypan blue, and indocyanine green dyes to assist internal limiting membrane peeling during macular hole surgery. AB - PURPOSE: To compare surgical outcomes with three dyes, brilliant blue G (BBG), trypan blue (TB) and indocyanine green (ICG), used to facilitate internal limiting membrane peeling during macular hole surgery. METHODS: This comparative, interventional cases series consisted of 50 eyes of 50 patients with senile idiopathic macular holes, who underwent vitrectomy with internal limiting membrane peeling using BBG (n = 15), TB (n = 20), or ICG (n = 15). The cases involving use of BBG and TB were enrolled prospectively and concurrently, and the cases using ICG were selected through chart reviews. We compared the intraoperative surgical facilitation with the 3 dyes and the surgical outcomes in terms of macular hole closure and visual improvement at 6 months. RESULTS: The 3 groups were similar in mean age, sex distribution, preoperative best-corrected visual acuity, and duration of follow-up (P = 0.957, 0.974, 0.939, and 0.5524, respectively). Of the 3 dyes, BBG appeared to provide greatest intraoperative facilitation: most convenient to use and remove, and similar to ICG in terms of internal limiting membrane staining. Six months postoperatively, macular hole closed in 100%, 95%, and 86% eyes (P = 0.48) and visual improvement occurred in 80%, 85%, and 33% eyes (P = 0.005) in BBG, TB, and ICG groups, respectively. The BBG and TB groups also had a better final best-corrected visual acuity than ICG group (P = 0.05) and smaller percentage of visual decline (5% and 6.7% vs. 40% respectively; P = 0.049). CONCLUSION: Brilliant blue G was comparable with TB in optimizing visual and functional outcomes, while it was similar to ICG in ease of internal limiting membrane peeling. PMID- 21685825 TI - GW0742, a high-affinity PPAR-delta agonist, mediates protection in an organotypic model of spinal cord damage. AB - STUDY DESIGN: Experimental study of spinal cord injury (SCI) using an organotypic slice culture. OBJECTIVE: To clarify the protective mechanism of PPAR-delta agonist GW0742 in the injured spinal cord using an in vitro model. SUMMARY OF BACKGROUND DATA: In vivo data suggest that ligands of the delta isoform have activity in a number of disease models that are partly driven by the inflammatory response. Moreover, reports from in vivo studies using models of ischemia reperfusion and Parkinson disease also have shown neuroprotection conferred by PPAR-delta. The biological role and function of PPAR-delta remains relatively unclear. METHODS: Spinal cord from 6-week-old mice was cut into transverse slices of 400-MUm thickness to generate the organotypic slice cultures. The slices were injured using a weight dropped onto the center of the slice. PPAR-delta agonist was applied at 10 MUM at 1 hour before injury. RESULTS: Our study shows that GW0742 incubation (10 MUM) at 1 hour before transverse lesion significantly reduced (1) p38 mitogen-activated protein kinase (MAPK), (2) c-Jun N-terminal kinase (JNK/SAP kinase), (3) NF-kappaB activation, (4) loss of neurotrophic factors (BDNF, GDNF), (5) COX-2 expression, and (6) cell death. CONCLUSION: GW0742 reduces the cellular and molecular changes occurring in SCI by targeting different downstream pathways modulating PPAR-delta receptors. PMID- 21685826 TI - Epstein-barr virus gene expression, human leukocyte antigen alleles and chronic high viral loads in pediatric renal transplant patients. AB - BACKGROUND: Studies have identified solid organ transplant recipients who remain asymptomatic despite maintaining chronic high Epstein-Barr virus (EBV) viral loads. We examined clinical manifestations, EBV gene expression, human leukocyte antigen (HLA) alleles, and specific T-cell responses to EBV infection in pediatric renal transplant patients. METHODS: Seventeen pediatric renal transplant patients were categorized according to EBV viral load into those with chronic high viral loads (CHL) and recipients who resolve EBV infection (REI). EBV gene expression was analyzed using real-time PCR assays and EBV-specific T cells were analyzed by flow cytometry. RESULTS: EBV gene, EBV-encoded small RNA 1, was expressed at significantly higher levels in CHL compared with EBV seropositive controls (P=0.005) and raised compared with REI. BamHI A right-ward transcripts were also expressed at higher levels in CHL patients (P=0.03) than in REI. Expression of latent genes, EBNA1, LMP1, LMP2, and lytic gene BZLF1 were restricted to the CHL group with viral gene expression varying over time. HLA A*02 allele expression was predominant in CHL patients (80%) and GLC lytic specific cytotoxic T-lymphocytes were absent. In contrast, HLA-B*08 allele expression was prevalent in REI patients (71%) and RAK lytic cytotoxic T lymphocytes were detected in all patients. CONCLUSION: EBV gene expression in CHL carriers differs from those that resolve infection and should be interpreted alongside HLA polymorphisms. PMID- 21685827 TI - When the law meets organ transplantation: the experience from the United kingdom. AB - Because the availability of organs falls short of the numbers of people who might benefit from transplantation, there has to be rationing of this resource. As organs donated from deceased donors are considered a national resource, there needs to be clear and transparent selection and allocation policies. There is the potential for a conflict between public and clinical priorities with legal requirements and this may lead to challenge in the courts. For example, both healthcare professionals and the general public may wish to give priority in allocation to children but this approach could be challenged on the basis of equity of access. We, therefore, recommend that selection and allocation policies should give clarity over the aims and assumptions, be evidence-based where possible or justify the assumptions where no evidence exists, have transparency of implementation and be supported by relevant stakeholders. PMID- 21685828 TI - Alcohol consumption, new onset of diabetes after transplantation, and all-cause mortality in renal transplant recipients. AB - BACKGROUND: Renal transplant recipients (RTR) are often advised to refrain from alcohol because of possible interaction with their immunosuppressive medication. Although moderate alcohol consumption is associated with reduced risk of diabetes and mortality in the general population, this is unknown for RTR. Therefore, we investigated the association of alcohol consumption with new onset of diabetes after transplantation (NODAT), mortality, and graft failure in RTR. METHOD: RTR were investigated between 2001 and 2003. Alcohol consumption was assessed by self report. Mortality and graft failure was recorded until May 2009. RESULTS: Six hundred RTR were studied (age 51 +/- 12 years, 55% men). Of these RTR, 48% were abstainers, 38% had light alcohol intake, 13% had moderate intake, and 1% were heavy consumers. Moderate alcohol consumption was associated with a lower risk of developing NODAT over the follow-up period than was abstention (OR = 0.36 [0.2 0.6], P = <0.001). During follow-up for 7.0 years [6.2-7.5 years], 133 recipients died. In Cox regression analyses, moderate alcohol consumption was associated with lower mortality period than was abstention (hazard ratio = 0.40 [0.2-0.8], P = 0.009). Adjustment for confounders, including age and smoking, did not materially change this association. No association was found between alcohol consumption and graft failure. CONCLUSIONS: Moderate alcohol consumption is associated with low prevalence of NODAT and reduced risk for mortality in RTR, in line with findings in the general population. These findings refute the common advice to refrain from alcohol in RTR. PMID- 21685829 TI - Incidence and outcomes of ganciclovir-resistant cytomegalovirus infections in 1244 kidney transplant recipients. AB - BACKGROUND: Cytomegalovirus (CMV) infections in kidney transplant recipients are in most cases successfully treated with oral valganciclovir (VGCV). However, in a few percent of patients, mutations in the UL 97 or UL 54 gene lead to drug resistance. METHODS: We investigated the incidence and outcomes of ganciclovir resistant CMV viremia in all 1244 kidney recipients transplanted at our center from 2004 through 2008. CMV DNAemia was monitored in all patients at least weekly, and patients who were positive were treated preemptively with VGCV (900 mg once daily). RESULTS: Ganciclovir-resistant mutations were detected in 27 patients (2.2%), of which 26 occurred in the 209 CMV IgG-negative recipients receiving a CMV-positive kidney (12.5%). All had UL97 gene mutations, and none had UL54 gene mutations. Mean DNAemia half-life for the first (nonresistance) episode of CMV viremia was 3.8 +/- 1.2 days. After established resistance, 25 of 27 patients had their mycophenolate mofetil dose reduced by approximately 50%, and 10 of these were also treated with intravenous foscarnet. The DNAemia half life was 3.7 +/- 1.4 days in the foscarnet-treated patients, significantly shorter than in the other 17 patients, 10.8 +/- 6.7 days (P = 0.001). Time to DNAemia eradication was 30 +/- 16 and 81 +/- 51 days in the two groups, respectively (P = 0.001). CONCLUSION: Use of 900 mg VGCV once daily for preemptive CMV treatment is associated with a high incidence of CMV UL97 resistance gene mutations in D+/R- patients. Foscarnet treatment rapidly and safely eradicated CMV DNAemia, and also patients who only reduced the immunosuppression and continued on VGCV treatment eventually cleared the virus. PMID- 21685832 TI - Automated clinical documentation: does it allow nurses more time for patient care? AB - When a west central Florida hospital prepared to move to an electronic health record with a clinical documentation system, the nursing staff and administration were concerned about the effects that the technology change would have on nursing work behavior. Specifically, would the move toward automation increase the time at the bedside, decrease the time nurses spent on documentation, and decrease time spent on administrative tasks? A time-in-motion study was conducted to specifically measure six categories of nurse work behavior on a progressive cardiac unit. The nurses were observed by data collectors prior to the implementation of the electronic health record and then again a year after the implementation. Results showed a significant increase (P=.000) in the amount of time nurses devoted to direct care. Furthermore, there was a significant increase (P=.000) in the time nurses spent documenting after the implementation of the electronic system. Much of the increased time available for direct care and documentation came from a 12% decrease in the time nurses spent on administrative tasks after implementing the automated documentation system. For this progressive cardiac unit, the move to automated documentation seems to be a positive step in developing a fully interactive computerized system. PMID- 21685833 TI - Using bibliometrics to support your selection of a nursing terminology set. AB - Nurses are being pressured to integrate standardized nursing terminology into the electronic health record to enable the representation and evaluation of nursing practice. Five terminology sets are recognized by the American Nurses Association that contain terms to represent nursing diagnoses, outcomes, and intervention: CCC, ICNP, NANDA/NOC/NIC, Omaha System, and PNDS. Key criteria for choosing the most suitable include demonstrated use and testing under real-time clinical conditions, scope of terms, cost, and the administrative infrastructure to sustain and evolve the terminology. Likelihood of survival is also critical and was evaluated here by examining the diffusion pattern of each terminology set through bibliometric analysis. Each of the five sets had a unique diffusion pattern, with NANDA/NOC/NIC demonstrating the most extensive penetration and author network in the CINAHL literature examined from 1982 to 2006. PMID- 21685836 TI - Development of a nasogastric tube insertion simulator: a collaborative interdisciplinary effort. AB - The nursing faculty shortage has created the need for more innovative and effective ways to better stimulate nursing students. Simulation technology is one way to increase the effectiveness of teaching faculty. In this article, a collaborative project between the College of Nursing and College of Engineering at the University of South Florida to develop and evaluate a PC-based software simulator based on videogame technologies for nursing skill acquisition is discussed. A software simulator for teaching and assessing mastery of the procedure for nasogastric tube insertion is described. The purpose of the simulator is to complement the standard training of nasogastric tube insertion that uses static mannequins and instruction/assessment by nursing instructors. The simulator was used in a fundamentals of nursing class at the University of South Florida, with 75 students enrolled. Evaluation showed that the simulator significantly increased the confidence of the students in their ability to perform nasogastric tube insertion. PMID- 21685835 TI - Electronic screening for mental health in rural primary care: feasibility and user testing. AB - Despite attention to prevention and screening for depression and alcohol use, Healthy People 2010 objectives continue to include goals to increase the detection of depression and decrease the rates of alcohol abuse. These problems remain significant. The overall goal of this study was to develop a computer based electronic screening (eScreening) tool and determine the feasibility of implementing computer-based eScreening technology for rural visitors to a primary care clinic. The study called specifically for an electronic touch screen with voice prompts. This tool, called the eScreening tool, screens for alcohol abuse and depression among rural patients in a primary care setting. The screening was offered to rural adults who are not in acute distress and not at end of life, regardless of their stated reason for seeking medical care. Phase 1 of the pilot was used to determine the perceptions of nurses, other providers, and consumers regarding the acceptability and perceived usefulness of an eScreening tool. Phase 2 involved user testing of the eScreening tool. The longer term goals of the research program are to work with rural nurses to improve patient outcomes and develop interventions and for educational, consultation, and/or direct clinical care. PMID- 21685837 TI - Attitudes of Australian nurses to information technology in the workplace: a national survey. AB - This article reports on the views of Australian nurses as to their use of computers in the workplace. Data were collected by questionnaires mailed to 10,000 members of the 150,000-member Australian Nursing Federation, which represents 60% of the Australian nursing workforce. The response rate was 43.3%. Computer use was 20% by assistants in nursing, rising to 75% by enrolled nurses and to more than 95% by RNs. Principal uses for the computers by the nurses were for access to patients' records and for internal communication. Most respondents (79%) agreed that the use of computers had improved information access. Only 9.4% considered that adoption of a national electronic health record would not be useful to healthcare. Fewer than 5% stated that they have no interest in computers, and 87% considered that their age was never or rarely a barrier to their use of the technology. However, not all aspects of computer introduction to nursing were positive. The proportions of respondents who considered that the use of computers had made their work easier, reduced duplication of data entry, and reduced errors in handing patient data were only 42%, 32%, and 31%, respectively. Results demonstrate a positive attitude toward information technology by Australian nurses but identify issues that must be addressed to support continued interest and engagement. PMID- 21685838 TI - Association of Women's Health, Obstetric, and Neonatal Nurses: uniting science with care for women and newborns. PMID- 21685839 TI - Leveraging standards to achieve interoperability: an update on the Healthcare Information Technology Standards Panel. PMID- 21685840 TI - The adult Fontan patient: update for 2011. AB - Congenital heart disease is the most common birth defect, with an estimated incidence of moderate to severe disease of 4-6 per 1,000 live births. Due to the dramatic advances in cardiac surgery and general pediatric cardiology care, approximately 85% of neonates with congenital heart disease (CHD) survive to adulthood. The most recent information, published in 2004, estimated 787,800 to 1.3 million adults with CHD living in the United States. This is expected to increase by 5% per year. It is estimated that within the next decade, 1 in every 150 young adults will have some form of CHD. DUe to the changing therapeutic options, a higher percentage of the adult CHD population will consist of more complicated cardiac disease during the coming years. It is estimated that 1-2% of children with CHD have single-ventricle physiology. Thus, as survival in this complex portion of the CHD population improves, the number of adult patients with previous Fontan palliation will dramatically increase. The goal of this article is to provide a brief background of the Fontan procedure and then discuss the late-term outcomes and complications in this unique patient type. The majority of the article will focus on information needed to adequately care for the adult Fontan patient. PMID- 21685841 TI - The pregnant patient with congenital heart disease. AB - Due to the advances in cardiovascular care of children born with congenital heart disease (CHD), the population of adults with congenital heart disease (ACHD) has increased substantially over the past 60 years. Similarly, the number of women with CHD who reach child-bearing age has also increased. With this reality comes the responsibility to educate these women on factors that would decrease the likelihood of an adverse outcome during pregnancy. It is well known that pregnancy may result in circulatory changes that could adversely affect the health status of a healthy patient. In a patient with CHD, with or without repair, the normal change in circulatory burden could increase adverse effects. Certain lesions are considered to be high risk (e.g., patients with Marfan syndrome and pulmonary hypertension), based on anecdotal evidence and small case study reports. Most advice given to patients with intermediate risk lesions (i.e., Fontan operation, transposition of great arteries, cyanotic heart disease without pulmonary hypertension) are based on theoretical determination of risk, and there are few studies done to validate these recommendations. This review serves to summarize the literature findings and make current recommendations on managing pregnancy in patients with CHD. PMID- 21685842 TI - Electrophysiology issues in adult congenital heart disease. AB - Improved surgical outcomes in children have led to a growing population of adults with congenital heart disease. Rhythm disturbances in the adult congenital heart disease (ACHD) patient can be intrinsic to the anomaly or acquired after palliation. Tachyarrhythmias, either supraventricular or ventricular, and bradyarrhythmias, either sinus node dysfunction or atrioventricular block, may occur frequently. Technological advances in intervention and surgical approaches have led to prophylactic and therapeutic reduction in arrhythmias. In order of escalation, this article addresses medical management, catheter ablation, device therapy for antitachycardia pacing and defibrillation, and surgical intervention. There are now an estimated one million-plus ACHD patients living in the United States. An estimated 45% of those have simple defects (e.g., atrial septal defects), 40% have moderately complex defects (e.g., tetralogy of Fallot, or ToF), and 15% have severely complex defects (e.g., single ventricle anatomy or surgical palliations for transposition of the great arteries [TGA]). The moderate and severe categories have a high incidence of arrhythmia. Of older repaired ToF patients, 34% develop symptomatic atrial or supraventricular tachycardias, 8.5% develop high-grade ventricular tachycardia (VT), and there are an increasing number of implantable defibrillators due to a sudden-death estimate of 2% per decade. Thus, an estimated 50,000 adults with repaired ToF will require electrophysiology follow-up with 100 sudden deaths per year nationally. Roughly 3% of all congenital heart surgeries requiring cardiopulmonary bypass have post operative AV block, and 1% will require permanent pacing. Older atriopulmonary Fontans have up to an estimated 50% incidence of atrial tachycardia within a decade of palliation due to suture lines and elevated atrial pressures. Patients who have undergone an atrial switch operation (e.g., Mustard or Senning operations) are rarely exclusively in sinus rhythm a decade after repair, thus posing problems for rhythm control and anticoagulation. Catheter ablation in congenital heart disease is often more challenging than structurally normal hearts because of abnormal anatomy (congenital and/or post-surgical) and thicker chamber walls due to unfavorable hemodynamics. In preparation, review of noninvasive imaging, previous catheterization angiography, and surgical palliation reports are paramount prior to a procedure. Fortunately, to meet the growing challenge, newer software with 3-D packages allow for improved mapping. In addition, advances with larger-tipped and irrigated-tip catheters allow for deeper, more effective lesions to be placed. Several advances in surgical approach have led to a reduction in arrhythmias. For example, the arterial switch operation for d-transposition of the great arteries instead of the aforementioned atrial switch operation eliminates the use of a systemic right ventricle that can later develop intra-atrial reentrant tachycardia and sinus node dysfunction. Other advances include paying careful attention to minimizing ventriculotomies in ToF and ventricular septal defect (VSD) repairs, earlier complete repairs, and valve sparing to reduce pulmonary insufficiency. Finally, completion of the extra cardiac Fontan procedure (e.g., total cavopulmonary connection) for single ventricles avoids extensive suture lines in the right atrium, thereby reducing scarring and higher pressures that lead to IART and sinus node dysfunction. Extracardiac (EC) conduits and lateral tunnel (LT) Fontans are preferred today, and the Fontan conversion procedure (converting prior atriopulmonary Fontans to the EC or LT type) can be performed to reduce arrhythmia and thromboembolic events. PMID- 21685843 TI - An approach to imaging adult congenital heart disease: pitfalls and pearls. AB - Noninvasive cardiovascular evaluation of an adult congenital heart disease (ACHD) patient is a multimodality endeavor that can include chest roentgenograms, electrocardiograms, echocardiography (including stress, three-dimensional, intravascular and intracardiac ultrasound, and transesophageal), cardiac magnetic resonance imaging (CMR), computed tomography angiography (CTA), single photon emission computed tomographic (SPECT) perfusion imaging, and positron emission tomography (PET). The cost-benefit ratio and limitations of each modality should always be considered (Table 1). Adults with ACHD often need repetitive imaging, making them vulnerable to radiation-induced cancer; hence, modalities using ionizing radiation should be minimized. A transthoracic echocardiogram remains the initial noninvasive modality of choice due to its real-time imaging capability with excellent temporal resolution and its ability to quickly assess hemodynamics along with anatomic delineation. A transesophageal echocardiogram is extremely helpful in further defining intracardiac anatomy and guiding surgical and interventional procedures. Cardiac magnetic resonance imaging is an adjunctive modality to an echocardiogram because ACHD patients frequently have intra-thoracic abnormalities (e.g., adhesions from multiple cardiac operations and lung disease) that can limit the resolution of the ultrasound beam. A CMR is especially helpful in periodic evaluation of the right ventricle, visceral situs, extracardiac anatomy, lesions of the pericardium, pulmonary veins, systemic veins, pulmonary arteries, and aorta. For real-time CMR, special techniques such as echo planar can be used; for hemodynamic evaluation by CMR, techniques like velocity-vector mapping, myocardial tagging, echo planar, and fast gradient echo can be used. Besides excellent spatial resolution, the advantage of CTA over other techniques is an extremely fast acquisition time. Furthermore, CTA can replace an invasive procedure such as catheterization and angiography for anatomical diagnosis where hemodynamics is not required, such as the diagnosis of arch or coronary artery anomalies. Nuclear scans such as lung perfusion scans and splenic scans are very helpful in determining differential pulmonary blood flow and splenic function, respectively. Both SPECT and PET are valuable in assessing tissue perfusion and metabolism and help to determine viable versus nonviable myocardium after surgery for hypoplastic left heart syndrome and coronary artery anomaly, after arterial switch operation for d-transposition of great arteries, and in acquired illness such as Kawasaki disease. When considering imaging a patient with ACHD, and overall evaluation strategy should include the aspects found in Table 2. PMID- 21685844 TI - A review of heart failure in adults with congenital heart disease. AB - The nearly one-million estimated adult congenital heart disease (ACHD) patients in the United States now outnumber children with congenital heart disease (CHD). With continued improvement in survival due to surgical and medical management of patients born with CHD, there is an overall shift in the burden of care from childhood to adulthood. Due to this transitioning population, the probability of heart failure continues to increase with age and represents nearly one-quarter of all mortality in ACHD. Despite these sobering figures adult cardiologist and fellows continue to have limited exposure in the care of patients with congenital heart disease. The syndrome of heart failure represents a complex derangement of neurohormones, natriuretic peptides, and cytokines leading to progressive symptoms of exercise intolerance, dyspnea, and fatigue. Congenital heart patients represent a unique challenge in both categorization and protocol management of heart failure (HF). It remains unclear if the current four-stage ACC/AHA guidelines for diagnosis and treatment of HF in adults can serve as a meaningful framework for congenital heart patients. Additionally, widely used conventional HF therapy of beta-blockers and angiotensin converting enzyme inhibitors (ACE-I) have not demonstrated clear survival benefit in this population. Unfortunately, adequately powered and controlled randomized studies are grossly lacking and remain challenging to conduct. Nonetheless, a review of heart failure associated with ACHD is provided. PMID- 21685845 TI - Caring for ACHD in a market-driven society. AB - Our cardiology community is responding to the growing number of emerging adults with often complex congenital heart disease. Collaborations are springing up between adult and pediatric cardiologists, advanced practice nurses, patients, and families to address the health care, research, and advocacy needs for this population. Workforce and institutional needs are being defined and research collaborations are being formed. Meanwhile, health care reform is evolving through fits and starts with little predictability regarding its medium and long term impact. Since ultimately finances trump philosophy, it is essential that we understand the financial underpinnings of healthcare delivery to patients with this unique model of chronic disease in order to carry out these plans. What is unique about this population with chronic disease? The most obvious feature is that they have the potential of contributing to the GDP for 40+ years. Another is that for the more complex lesions, society has already invested a considerable amount to achieve survival into adult life. Finally, the period of early adulthood is relatively uneventful in terms of complications and resource utilization compared with early childhood and later adult life. Thus, the basic needs to maintain cardiovascular status and prevent secondary disability may be modest in comparison with treating some of the severe consequences of their disease, such as poorly managed valve regurgitation or arrhythmia that eventually requires costly solutions such as transplantation. It is important, therefore, to define the resource requirements and potential health outcomes of a healthcare system that would be designed for this population. PMID- 21685846 TI - A cyanotic patient with prosthetic tricuspid valve thrombosis and primum atrial septal defect. PMID- 21685848 TI - Tissue characterization by cardiovascular magnetic resonance aids in the evaluation of a patient with ventricular tachycardia. PMID- 21685847 TI - Fungal mycotic vegetation in the ascending aorta. AB - In most clinical scenarios, the appropriate diagnostic methodology and treatment plan can be determined in a timely manner. However, complex clinical cases with obscure etiology can be deceptive, and a multidisciplinary approach can help to clarify things. At the Methodist DeBakey Heart & Vascular Center, we encountered a huge progressive mass in the ascending aorta in a 50-year-old chronic hemodialysis patient after mechanical aortic valve replacement. In addition to initial image diagnosis and consultation workups, a transcranial Doppler (TCD) study identified continuous generation of microemboli that suggested the need for urgent surgical resection instead of conservative heparin IV therapy. Histopathology showed the huge friable mass to be hyphenated fungal mycosis (Aspergillus or Fusarium) and necrotic tissue surrounded by fresh thrombus. The postoperative course was uneventful, and the patient was discharged home. PMID- 21685849 TI - Preventing healthcare-associated infections in cardiac surgical patients as a hallmark of excellence. AB - Healthcare-associated infections (HAI) are the tenth-leading cause of death in the United States. The Centers for Disease Control and Prevention (CDC) estimate that HAIs annually account for 1.7 million infections, 99,000 associated deaths, and a cost of approximately $30 billion. Nonreimbursement of some of these HAIs by the Centers for Medicare and Medicaid Services, public reporting of data (currently in 27 states), and the statistics listed above are driving quality initiatives to reduce or eliminate HAIs. However, a 2009 report from the Agency for Healthcare Research & Quality showed that little progress has been made towards eliminating HAIs. Reducing the risk of healthcare-associated infections is the Joint Commission's National Patient Safety Goal Number 7. Cardiac surgery has always been at the leading edge of innovation and quality care. Improvements in this field have been brought about by the needs of critically ill patients who are at high risk of death and by leaders such as Dr. Michael DeBakey who were driven to provide excellence in patient care. One of the prime examples of quality initiatives in cardiac surgery has been the development of the Society of Thoracic Surgeons (STS) National Database. This has helped to develop benchmarks by which different institutions are measured. The STS database will lead another initiative by providing public presentation of hospital- and surgeon-specific data in the near future. Even so, cardiac surgery patients are at especially high risk of developing HAIs. Use of invasive devices such as central lines, urinary catheters, ventilators, etc. - all of which are commonly utilized in the care of cardiac surgical patients - is one of the most significant risk factors for acquiring HAIs. Cardiac patients also have significant co-morbidities such as diabetes, obesity, increasing frailty, advanced age, and multiple redo operations. This combination makes our patients more vulnerable to HAIs. Accordingly, in 2010 the Society of Cardiovascular Anesthesiologists (SCA) Foundation launched the FOCUS (Flawless Operative Cardiovascular Unified Systems) Cardiac Surgery Patient Safety Initiative to help eliminate infections in cardiac surgery patients, especially catheter-related infections. This publication will briefly discuss the four most common infections and strategies to reduce HAIs and will touch on some of the infection-control experiences from the Methodist DeBakey Heart & vascular Center (MDHVC). PMID- 21685850 TI - Hubris syndrome and a new perspective on political psychiatry: need to protect prosocial behavior, public benefit and safety of our civilisation. PMID- 21685851 TI - Attention deficit hyperactivity disorder in imprisoned individuals--a review. AB - Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders with lifelong impact of the affected individuals. It is usually co-morbid with other psychiatric disorders. This paper aims to review current knowledge about ADHD in imprisoned individuals. The rate of ADHD in prisoners ranges from 10% to 70% and it has been suggested that ADHD, even without co-morbidity with conduct disorder, is a risk factor for imprisonment. Based on these findings, it may be wise to include the assessment of ADHD symptoms in all adult and adolescent prisoners. This is while available psychiatric resources for the adequate management of ADHD in prisoners are limited. Most of current knowledge on the topic comes from western countries. There is an urgent need for studies that will explore the effect of other cultures on the interactions between ADHD and imprisonment, especially in developing countries worldwide. At this point, ADHD seems to be an ignored research area in developing countries. PMID- 21685852 TI - Problems with 'Internet addiction' diagnosis and classification. AB - Owing to the fact that the Internet is spreading rapidly and influencing all aspects of everyday life, a task is assigned to the academic and clinical circles to establish a diagnosis and provide treatment for disorders brought about by its dysfunctional use. This paper presents a review of the most frequent problems and difficulties in dealing with individuals complaining of the symptoms of Internet use disorder, as well as some suggestions for overcoming and alleviating these problems. For the diagnostic criteria problem, a solution can be provided in the form of behavioural addictions category in order to solve the problem of the classification of not only this disorder but also other forms, such as pathological gambling, compulsive shopping etc. However, since there are obvious similarities with the compulsive behaviour, we suggest the term Internet Use Disorder, which appears most acceptable in terms of avoiding beforehand the indecisiveness of this disorder nature. Certainly, in the practical work with each client, by means of a precise and complex clinical interview, it would be further determined which subtype is under question and whether the mechanism of its realisation is more that of a compulsive or addictive nature. We also suggest an approach of defining a set of minimal key symptoms and manifestations of this problem, rather than singling out the personality profiles of individuals who constitute the population at risk. By prevention, the attentiveness of the public would be in that way directed towards the critical aspects of behaviour, and not towards a vague picture which causes panic and doubt, rather than reasonable ways of the problem solution. PMID- 21685853 TI - Psychiatric aspects of basal ganglia diseases. AB - This review clarifies the fact that basal ganglia diseases are psychiatric as much as neurological diseases. It illustrates psychiatric aspects in Parkinson's disease and other hereditary basal ganglia diseases such as Wilson's disease, Huntington's chorea and others. In these diseases, psychological disorders can be difficult to diagnose, whether they are concomitant with the primary (neurological) disease, they are its consequence, or they are the result of a specific pharmacotherapy prescribed for these disease, etc. Thus, the choice of appropriate psychopharmacotherapy for these disorders represents a very subtle problem. PMID- 21685854 TI - Ethnic differences in the knowledge, attitude and beliefs towards mental illness in a traditional fast developing country. AB - BACKGROUND: The aim of the study was to examine the ethnic differences in knowledge, attitude and practice towards mental illness in a sample of Qatari and non-Qatari Arabs. SUBJECTS AND METHODS: This is a cross sectional survey conducted in Primary Health Care centers, Qatar from October to June 2009. A representative sample of 3000 Qatari and non-Qatari Arabs above 20 years of age were approached and 2514 subjects (83.8%) gave consent to participate in this study. RESULTS: More than non-Qatari Arabs, a significant proportion of Qataris thought that mental illness can be a punishment from God (44.5% vs 50.6%; p=0.002) and that people with mental illness are mentally retarded (35.1% vs 45.1%; p<0.001). Qatari nationals had a poor knowledge about causes of mental illness compared to non-Qatari Arabs such as a belief that mental illness is due to possession of evil spirits (40.5% vs 37.6%) and psychiatric medication will cause addiction (61% vs 57.3%). CONCLUSION: The study revealed that there is an ethnic diversity within Arab societies in their knowledge, attitude and practice towards mental illness. PMID- 21685855 TI - Correlation of pre-morbid alcoholism and changes in the level of biogenic amine metabolites in cerebrospinal fluid of accute brain infarction patients. AB - BACKGROUND: The disorder of biogenic amine metabolism (serotonin - 5-HT and dopamine - DA) is expected in the brain (neuron) damage caused by acute ischemia. It is known that long-term abuse of ethyl-alcohol damages the quality of neurons diffusely in the brain. Cerebrospinal fluid (CSF) and its biochemical content, 5 HT and DA, are reliable indicators of the vitality of neurons. The main objective of this research was to demonstrate that the elevated content of metabolites 5-HT and DA in the CSF in patients with acute brain infarction, who were pre-morbid alcohol-dependent patients, is additionally emphasized by diffusive damage of neuron vitality caused by alcoholism. SUBJECTS AND METHODS: Study sample consists of two groups - 50 alcohol-dependent patients with acute brain infarction under the age of 65 (group A) and 50 patients with acute brain infarction who were not alcohol-dependent (group B). All subjects underwent the same procedure - CSF was taken during admission to the hospital and history was obtained through anamnesis, heteroanamnesis and clinical examinations. RESULTS: Metabolism of DA and metabolic turnover of DA (3, 4 dihydroxyphenylacetic acid + homovanilic acid; DOPAC + HVA) was elevated in the liquor of both patient groups. The statistically significant difference between the groups was found in metabolic turnover of 5-HT (p<0.05), and metabolic turnover of DA (p<0.001). CONCLUSIONS: The metabolic neuron disbalance, i.e. their pathophysiological-biochemical dysfunction as a result of acute brain infarction, is present in a higher degree in patients with pre-morbid long-term alcohol abuse. PMID- 21685856 TI - Croatian war veterans in print media in 1996 and in 2006. AB - INTRODUCTION: The media have an important role in maintaining and creating social relations and social environment. This especially refers to the war and post-war period in which the media can form a part of the prevention context, i.e., the media can facilitate the process of recovery from war trauma, but they can also contribute to stigmatization and retraumatization. Our aim was to analyze Croatian newspaper reports about Croatian war veterans and to determine the differences in ways of dealing with the subject during 1996 and 2006. METHODS: The data were gathered by reviewing two daily papers, Novi list and Ve?ernji list and Globus weekly. The analysis included newspaper reports related to the subject of Croatian war veterans, published in the first six months of 1996 and 2006. Quantitative and qualitative methods were used to analyze both the form and the content of the reports. RESULTS: A total of 538 newspaper reports were published in the above-stated periods. In the first half of 2006 the number of reports related to the subject of Croatian war veterans dropped 6.5 percent compared to the first half of 1996. Topics prevalent at the end of the war were different from those ten years later. The 1996 articles mostly reported on activities organized by various associations, medal-awarding ceremonies, military operations etc. Ten years later the topics focused on war crimes, trials of Croatian war generals and dissatisfaction with veterans' rights and legislation. Moreover, articles relating to crime and reports about suicides and attempts of suicide increased significantly in 2006. CONCLUSION: During the ten-year period, the media image of Croatian war veterans significantly changed, which was expected owing to different social circumstances immediately after the war and ten years later. The prevalence of topics negative in tone and a lack of proactive stories reflect, but also create, a social context which can affect the process of recovery from traumatization. PMID- 21685857 TI - Prescribing changes in anxiolytics and antidepressants in Slovenia. AB - BACKGROUND: The ratio of anxiolytics to antidepressants is an indicator of the quality of treatment of depression and anxiety in primary care. The objective of the study was to investigate the prescription of anxiolytics and antidepressants among Slovenian family physicians, including patient demographics and possible time-trends. SUBJECTS AND METHODS: An exploratory survey and register-based analysis of anxiolytic and antidepressant prescriptions in 2005 and 2008 was performed. Drugs included in the study were classified according to an Anatomical Therapeutic-Chemical (ATC) drug classification system, and ATC data were used to calculate defined daily doses (DDD) per 1,000 practice population per day. Descriptive analysis of anxiolytic/antidepressant ratio by patients' age, gender and region of residency was performed. RESULTS: Total amount of prescribed antidepressant drugs increased by 45% during the observed 3-year period, while total prescribing of anxiolytics decreased by 14%, leading to the anxiolytics/antidepressants ratio diminishing from 1 to about 0.5. The highest reduction in the ratio was observed in the northeast region, characterised by high social deprivation and one of the highest suicide rates in Europe. The highest prescribing of anxiolytics and antidepressants was observed in the central region around the capital Ljubljana. CONCLUSIONS: The reduction of anxiolytic prescribing and increase in antidepressant prescribing indicates improvement in prescribing practice of Slovenian family physicians. There are big variations in prescribing among different Slovenian regions, which are attributable to the number of psychiatrists and access to psychiatric treatment. PMID- 21685858 TI - Comparison of depression treatment among different age groups in primary care setting. AB - BACKGROUND: The aim of this study was to explore the association between age and care of patients with depression in primary care setting. A comparison was made among the groups of elderly patients, middle aged patients and younger patients with diagnosis of depressive episode (F32). SUBJECTS AND METHODS: Patients (17.290) from ten GP offices in the city of Zagreb formed the representative sample for this study according to the estimated depression prevalence in Europe of 5%. A group of 231 (60%) patients with diagnosis Depressive episode (F32), out of 383 patients with Depression diagnosis according to ICD-10, were reviewed and extracted from GPs' standardized medical files. They were divided in three age groups: <45 years (n=58), 45-65 years (n=97) and >65 years (n=76). Data were tracked longitudinally and obtained retrospectively for one-year period from 1st January to 31th December 2009. Pharmacotherapy was classified according to the Anatomical Therapeutic Chemical (ATC) classification index. RESULTS: The youngest and the oldest age group mainly used only one drug in their therapy (47% vs 64%), but middle age group almost equally used one or two drugs (42 vs 45%). About 50% of all patients used SSRIs. Benzodiazepines were used most frequently in middle and in the oldest age group (71% vs 60%). The most frequent combinations of antidepressants in the youngest age group were SSRIs and combination of SSRIs and benzodiazepines; in middle age group it was combination of SSRIs and benzodiazepines and benzodiazepines; and in the oldest benzodiazepines, and SSRIs. Benzodiazepines were used mainly discontinuously in oppose to significant continuous usage in middle age group (P 0.043). In the oldest age groupe, depression diagnose was mostly given by GP and the most frequent therapy was combination of pharmacotherapy and GP's support. Unaided clinical assessment of depression outcome by GP did not differ significantly between age groups although some differences existed. CONCLUSION: Number and sort of antidepressants as well as sort of physician: GP or psychiatrist differed between age groups of depressed patients. Further investigation of specifical depression treatment compared with outcome measures should give answer whether those differences are justified. PMID- 21685859 TI - Adherence to Turkish psychiatric association guideline for bipolar depression treatment in a specialized mood disorders outpatient unit. AB - BACKGROUND: Bipolar patients spend up to one third of their lives in depression however, acute treatment guidelines mainly focused on the manic phase of illness. With recent attention to the importance of evidence-based medicine in psychiatry, a number of treatment guidelines have emerged to aid clinicians in clinical decision making. Here, we aim to measure concordance with the Turkish Psychiatric Association Treatment Guideline for Bipolar Disorders (TPATGBD) for the depressive phase of illness. SUBJECTS AND METHODS: Bipolar patients attending the Rasit Tahsin Mood Disorders Outpatient Unit of Istanbul Bakirkoy Research and Training Hospital for Psychiatry, Neurolgy & Neurosurgery, were assessed using standardized forms based on a nation-wide mood disorders follow-up program. Concordance of implementations with the TPATGBD were evaluated step by step for each level of depression severity. RESULTS: Concordance rates with the first step recommendations of the guideline were 29.4%, 27.4% and 87.5% for mild-moderate, moderate-severe (without psychosis) and severe depression (with psychosis), respectively. Concordance rates with the second step recommendations of the guideline were lower for bipolar depressions without psychosis. Overall, adherence to the guideline did not impact on time to remission (p=0.19). CONCLUSIONS: Despite considerable efforts to develop and disseminate evidence based guidelines, they are not widely followed by clinicians and important opportunities clearly exist to educate clinicians about the feasibility and utility of clinical guidelines for bipolar disorder. Systematic studies in the future are required to clarify our understanding of clinicians' attitudes to the use of guidelines and to explain the discrepancy between guidelines and clinical practice. PMID- 21685861 TI - Promazine in the treatment of delusional parasitosis. AB - Delusional parasitosis (DP) is an uncommon and complex to treat form of delusional disorder, somatic type. The syndrome may occur in association with a number of psychotic disorders, such as schizophrenia, organic mental disorder, or even in dementia with behavioral and psychological symptoms. Evidence of efficacy of treatment options is weak and there is little known about the specific use of typical and atypical antipsychotics. We report on a case of primary DP in a 75 year-old Caucasian woman with a 3-year-long history of dermatological consultations due to unspecified complains who responded to the typical antipsychotic promazine. This case is unique in pharmacological respect as it presents the first reported DP treatment with promazine. It also raises the issue of efficacy and safety of low-potency typical antipsychotics in the elderly population. PMID- 21685860 TI - Exanthema medicamentosum as a side effect of promazine. AB - Dermatological side effects of psychopharmacological drugs are fortunately not so often. They are mostly presented in the group of mood stabilizers and antiepileptic drugs, particularly the carbamazepine and lamotrigine, and can be manifested through the Stevens Johnson syndrome, Toxic Epidermal Necrolysis (TEN)/Lyell's syndrome with about 30% lethality. According to the literature the group of phenothiazines is the category of drugs with rare appearances of skin reactions. Promazine, aliphatic phenothiazines antipsychotic, including less frequent side effects in the leaflet states increased skin sensitivity to sun, skin rash-associated with contact dermatitis, allergic reactions, cholestatic icterus. The only reported dermatological side effect of promazine is its metabolites deposition in the cornea. Analyzing the e-data basis we have not found references connecting the Exanthema medicamentosum as a side effect of promazine. A forty-two years old female patient was admitted to the Dermatological Clinic because of suspected exanthema, undoubtedly caused by promazine as a medication for Sy. Borderline. PMID- 21685862 TI - Integrative sulpiride with a homeopathic therapy for treating depressive syndrome -an observational study. PMID- 21685863 TI - Acute liver failure due to acute fatty liver of pregnancy. AB - Acute fatty liver of pregnancy (AFLP) is a rare but serious liver disease and typically occurs during the third trimester. It carries the risk for significant perinatal and maternal mortality. Therefore an early diagnosis and delivery, followed by close monitoring and optimized management of the impaired liver function with all associated problems are necessary to prevent maternal and foetal death. This case report focuses on the management of acute liver failure due to AFLP in a 31 year old women treated in our intensive care unit (ICU) after an emergency C-section. PMID- 21685864 TI - Acute kidney injury: the Italian perspective. PMID- 21685865 TI - Alemtuzumab: what is the secret to safe therapy? AB - Over the past decade, the use of the monoclonal antibody alemtuzumab in chronic lymphocytic leukemia has expanded from administration as a single-agent therapy, into use in combination with fludarabine or rituximab, and further to use as a consolidation agent with the goal of eradicating minimal residual disease. Numerous clinical studies have shown that alemtuzumab is effective as first-line treatment and in patients who have relapsed disease or who are refractory to fludarabine. Despite improvements in response rates and survival compared with combination chemotherapy, there remains some hesitation to incorporate alemtuzumab into management because of known toxicities. Adverse events in patients treated with standard-dose, single-agent alemtuzumab occur at generally predictable time points during treatment and can be managed effectively; this outcome is less established when alemtuzumab is incorporated into combination regimens. Variability in alemtuzumab dosing, route of administration, and duration of therapy has led to inconsistent and sometimes adverse safety consequences. This article presents an overview of clinical studies with alemtuzumab as a single agent, in combination, or in consolidation, with discussion of toxicity and suggestions for ensuring that the efficacious outcomes following alemtuzumab therapy are not outweighed by safety concerns. PMID- 21685866 TI - Non-small cell lung cancer therapy in the elderly. AB - To date, lung cancer is still the leading cause of cancer-related mortality worldwide, with the majority of lung cancers arising in the elderly. As a consequence, we can expect an increase in the number of older lung cancer patients considered suitable for chemotherapy in the near future. Elderly patients often have comorbid conditions and progressive physiologic reduction of organ function, which can make the selection of proper treatment daunting. Some patients will be able to tolerate chemotherapy as well as their younger counterparts, whereas others will experience severe toxicity and require treatment modifications. Thus, a major issue is effectively selecting patients suitable for standard or attenuated therapy. A comprehensive geriatric assessment performed at baseline is a useful tool that can help select the best treatment regimen to be administered to elderly patients. Until now, few trials have specifically focused on elderly patients affected by non-small cell lung cancer (NSCLC), particularly those with advanced disease; prospective elderly-specific studies in early stages are still lacking. High priority should be given to evaluating the role of new targeted therapies. Unfortunately, to date, clinical trials that include functional status and comorbidity as part of the geriatric assessment are rare. Future trials, specifically in the elderly population, should include these kinds of evaluations. The most recent therapies for the treatment of elderly patients with NSCLC will be discussed here. PMID- 21685867 TI - Estrogen and progesterone receptors in breast cancer. PMID- 21685868 TI - Updates in the management of medullary thyroid cancer. PMID- 21685869 TI - JAK2 inhibitors in polycythemia vera. PMID- 21685870 TI - Idiopathic thrombocytopenic purpura: advances in management. PMID- 21685871 TI - Cauda equina lymphoma: a case report including postmortem examination. PMID- 21685872 TI - Lymphomatous meningitis as a presentation of non-Hodgkin lymphoma. PMID- 21685873 TI - Identity, regulation and in vivo function of gut NKp46+RORgammat+ and NKp46+RORgammat- lymphoid cells. AB - The gut is a major barrier against microbes and encloses various innate lymphoid cells (ILCs), including two subsets expressing the natural cytotoxicity receptor NKp46. A subset of NKp46(+) cells expresses retinoic acid receptor-related orphan receptor gammat (RORgammat) and produces IL-22, like lymphoid tissue inducer (LTi) cells. Other NKp46(+) cells lack RORgammat and produce IFN-gamma, like conventional Natural Killer (cNK) cells. The identity, the regulation and the in vivo functions of gut NKp46(+) ILCs largely remain to be unravelled. Using pan genomic profiling, we showed here that small intestine (SI) NKp46(+)RORgammat(-) ILCs correspond to SI NK cells. Conversely, we identified a transcriptional programme conserved in fetal LTi cells and adult SI NKp46(+)RORgammat(+) and NKp46(-)RORgammat(+) ILCs. We also demonstrated that the IL-1beta/IL-1R1/MyD88 pathway, but not the commensal flora, drove IL-22 production by NKp46(+)RORgammat(+) ILCs. Finally, oral Listeria monocytogenes infection induced IFN-gamma production in SI NK and IL-22 production in NKp46(+)RORgammat(+) ILCs, but only IFN-gamma contributed to control bacteria dissemination. NKp46(+) ILC heterogeneity is thus associated with subset-specific transcriptional programmes and effector functions that govern their implication in gut innate immunity. PMID- 21685874 TI - Sgf29 binds histone H3K4me2/3 and is required for SAGA complex recruitment and histone H3 acetylation. AB - The SAGA (Spt-Ada-Gcn5 acetyltransferase) complex is an important chromatin modifying complex that can both acetylate and deubiquitinate histones. Sgf29 is a novel component of the SAGA complex. Here, we report the crystal structures of the tandem Tudor domains of Saccharomyces cerevisiae and human Sgf29 and their complexes with H3K4me2 and H3K4me3 peptides, respectively, and show that Sgf29 selectively binds H3K4me2/3 marks. Our crystal structures reveal that Sgf29 harbours unique tandem Tudor domains in its C-terminus. The tandem Tudor domains in Sgf29 tightly pack against each other face-to-face with each Tudor domain harbouring a negatively charged pocket accommodating the first residue alanine and methylated K4 residue of histone H3, respectively. The H3A1 and K4me3 binding pockets and the limited binding cleft length between these two binding pockets are the structural determinants in conferring the ability of Sgf29 to selectively recognize H3K4me2/3. Our in vitro and in vivo functional assays show that Sgf29 recognizes methylated H3K4 to recruit the SAGA complex to its targets sites and mediates histone H3 acetylation, underscoring the importance of Sgf29 in gene regulation. PMID- 21685875 TI - Molecular basis of positive allosteric modulation of GluN2B NMDA receptors by polyamines. AB - NMDA receptors (NMDARs) form glutamate-gated ion channels that have central roles in neuronal communication and plasticity throughout the brain. Dysfunctions of NMDARs are involved in several central nervous system disorders, including stroke, chronic pain and schizophrenia. One hallmark of NMDARs is that their activity can be allosterically regulated by a variety of extracellular small ligands. While much has been learned recently regarding allosteric inhibition of NMDARs, the structural determinants underlying positive allosteric modulation of these receptors remain poorly defined. Here, we show that polyamines, naturally occurring polycations that selectively enhance NMDARs containing the GluN2B subunit, bind at a dimer interface between GluN1 and GluN2B subunit N-terminal domains (NTDs). Polyamines act by shielding negative charges present on GluN1 and GluN2B NTD lower lobes, allowing their close apposition, an effect that in turn prevents NTD clamshell closure. Our work reveals the mechanistic basis for positive allosteric modulation of NMDARs. It provides the first example of an intersubunit binding site in this class of receptors, a discovery that holds promise for future drug interventions. PMID- 21685879 TI - Antibiotics as probes of biological complexity. PMID- 21685880 TI - Behind the folding funnel diagram. AB - This Commentary clarifies the meaning of the funnel diagram, which has been widely cited in papers on protein folding. To aid in the analysis of the funnel diagram, this Commentary reviews historical approaches to understanding the mechanism of protein folding. The primary role of free energy in protein folding is discussed, and it is pointed out that the decrease [corrected] in the configurational entropy as the native state is approached hinders folding, rather than guiding it. Diagrams are introduced that provide a less ambiguous representation of the factors governing the protein folding reaction than the funnel diagram. PMID- 21685882 TI - Metabolic engineering: from retrofitting to green field. PMID- 21685883 TI - Biosynthesis: a twist in the tail. PMID- 21685884 TI - Protein regulation: the statistical theory of allostery. PMID- 21685885 TI - Huntington's disease: flipping a switch on huntingtin. PMID- 21685886 TI - Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. AB - Mitochondria from diverse organisms are capable of transporting large amounts of Ca(2+) via a ruthenium-red-sensitive, membrane-potential-dependent mechanism called the uniporter. Although the uniporter's biophysical properties have been studied extensively, its molecular composition remains elusive. We recently used comparative proteomics to identify MICU1 (also known as CBARA1), an EF-hand containing protein that serves as a putative regulator of the uniporter. Here, we use whole-genome phylogenetic profiling, genome-wide RNA co-expression analysis and organelle-wide protein coexpression analysis to predict proteins functionally related to MICU1. All three methods converge on a novel predicted transmembrane protein, CCDC109A, that we now call 'mitochondrial calcium uniporter' (MCU). MCU forms oligomers in the mitochondrial inner membrane, physically interacts with MICU1, and resides within a large molecular weight complex. Silencing MCU in cultured cells or in vivo in mouse liver severely abrogates mitochondrial Ca(2+) uptake, whereas mitochondrial respiration and membrane potential remain fully intact. MCU has two predicted transmembrane helices, which are separated by a highly conserved linker facing the intermembrane space. Acidic residues in this linker are required for its full activity. However, an S259A point mutation retains function but confers resistance to Ru360, the most potent inhibitor of the uniporter. Our genomic, physiological, biochemical and pharmacological data firmly establish MCU as an essential component of the mitochondrial Ca(2+) uniporter. PMID- 21685887 TI - Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway. AB - High-dose intravenous immunoglobulin is a widely used therapeutic preparation of highly purified immunoglobulin G (IgG) antibodies. It is administered at high doses (1-2 grams per kilogram) for the suppression of autoantibody-triggered inflammation in a variety of clinical settings. This anti-inflammatory activity of intravenous immunoglobulin is triggered by a minor population of IgG crystallizable fragments (Fcs), with glycans terminating in alpha2,6 sialic acids (sFc) that target myeloid regulatory cells expressing the lectin dendritic-cell specific ICAM-3 grabbing non-integrin (DC-SIGN; also known as CD209). Here, to characterize this response in detail, we generated humanized DC-SIGN mice (hDC SIGN), and demonstrate that the anti-inflammatory activity of intravenous immunoglobulin can be recapitulated by the transfer of bone-marrow-derived sFc treated hDC-SIGN(+) macrophages or dendritic cells into naive recipients. Furthermore, sFc administration results in the production of IL-33, which, in turn, induces expansion of IL-4-producing basophils that promote increased expression of the inhibitory Fc receptor FcgammaRIIB on effector macrophages. Systemic administration of the T(H)2 cytokines IL-33 or IL-4 upregulates FcgammaRIIB on macrophages, and suppresses serum-induced arthritis. Consistent with these results, transfer of IL-33-treated basophils suppressed induced arthritic inflammation. This novel DC-SIGN-T(H)2 pathway initiated by an endogenous ligand, sFc, provides an intrinsic mechanism for maintaining immune homeostasis that could be manipulated to provide therapeutic benefit in autoimmune diseases. PMID- 21685888 TI - A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. AB - Mitochondrial Ca(2+) homeostasis has a key role in the regulation of aerobic metabolism and cell survival, but the molecular identity of the Ca(2+) channel, the mitochondrial calcium uniporter, is still unknown. Here we have identified in silico a protein (named MCU) that shares tissue distribution with MICU1 (also known as CBARA1), a recently characterized uniporter regulator, is present in organisms in which mitochondrial Ca(2+) uptake was demonstrated and whose sequence includes two transmembrane domains. Short interfering RNA (siRNA) silencing of MCU in HeLa cells markedly reduced mitochondrial Ca(2+) uptake. MCU overexpression doubled the matrix Ca(2+) concentration increase evoked by inositol 1,4,5-trisphosphate-generating agonists, thus significantly buffering the cytosolic elevation. The purified MCU protein showed channel activity in planar lipid bilayers, with electrophysiological properties and inhibitor sensitivity of the uniporter. A mutant MCU, in which two negatively charged residues of the putative pore-forming region were replaced, had no channel activity and reduced agonist-dependent matrix Ca(2+) concentration transients when overexpressed in HeLa cells. Overall, these data demonstrate that the 40-kDa protein identified is the channel responsible for ruthenium-red-sensitive mitochondrial Ca(2+) uptake, thus providing a molecular basis for this process of utmost physiological and pathological relevance. PMID- 21685889 TI - Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation. AB - Self-renewal of rodent embryonic stem cells is enhanced by partial inhibition of glycogen synthase kinase-3 (Gsk3; refs 1, 2). This effect has variously been attributed to stimulation of Wnt signalling by beta-catenin, stabilization of Myc protein and global de-inhibition of anabolic processes. Here we demonstrate that beta-catenin is not necessary for embryonic stem cell identity or expansion, but its absence eliminates the self-renewal response to Gsk3 inhibition. Responsiveness is fully restored by truncated beta-catenin lacking the carboxy terminal transactivation domain. However, requirement for Gsk3 inhibition is dictated by expression of T-cell factor 3 (Tcf3) and mediated by direct interaction with beta-catenin. Tcf3 localizes to many pluripotency genes in embryonic stem cells. Our findings confirm that Tcf3 acts as a transcriptional repressor and reveal that beta-catenin directly abrogates Tcf3 function. We conclude that Gsk3 inhibition stabilizes the embryonic stem cell state primarily by reducing repressive influence on the core pluripotency network. PMID- 21685891 TI - RasGRF suppresses Cdc42-mediated tumour cell movement, cytoskeletal dynamics and transformation. AB - Individual tumour cells move in three-dimensional environments with either a rounded or an elongated 'mesenchymal' morphology. These two modes of movement are tightly regulated by Rho family GTPases: elongated movement requires activation of Rac1, whereas rounded/amoeboid movement engages specific Cdc42 and Rho signalling pathways. In siRNA screens targeting the genes encoding guanine nucleotide exchange factors (GEFs), we found that the Ras GEF RasGRF2 regulates conversion between elongated- and rounded-type movement. RasGRF2 suppresses rounded movement by inhibiting the activation of Cdc42 independently of its capacity to activate Ras. RasGRF2 and RasGRF1 directly bind to Cdc42, outcompeting Cdc42 GEFs, thereby preventing Cdc42 activation. By this mechanism, RasGRFs regulate other Cdc42-mediated cellular processes such as the formation of actin spikes, transformation and invasion in vitro and in vivo. These results demonstrate a role for RasGRF GEFs as negative regulators of Cdc42 activation. PMID- 21685890 TI - Differential requirement for the dual functions of beta-catenin in embryonic stem cell self-renewal and germ layer formation. AB - Canonical Wnt signalling has been implicated in mouse and human embryonic stem cell (ESC) maintenance; however, its requirement is controversial. beta-catenin is the key component in this highly conserved Wnt pathway, acting as a transcriptional transactivator. However, beta-catenin has additional roles at the plasma membrane regulating cell-cell adhesion, complicating the analyses of cells/tissues lacking beta-catenin. We report here the generation of a Ctnnb1 (beta-catenin)-deficient mouse ESC (mESC) line and show that self-renewal is maintained in the absence of beta-catenin. Cell adhesion is partially rescued by plakoglobin upregulation, but fails to be maintained during differentiation. When differentiated as aggregates, wild-type mESCs form descendants of all three germ layers, whereas mesendodermal germ layer formation and neuronal differentiation are defective in Ctnnb1-deficient mESCs. A Tcf/Lef-signalling-defective beta catenin variant, which re-establishes cadherin-mediated cell adhesion, rescues definitive endoderm and neuroepithelial formation, indicating that the beta catenin cell-adhesion function is more important than its signalling function for these processes. PMID- 21685892 TI - Heterochromatin boundaries are hotspots for de novo kinetochore formation. AB - The centromere-specific histone H3 variant CENH3 (also known as CENP-A) is considered to be an epigenetic mark for establishment and propagation of centromere identity. Pulse induction of CENH3 (Drosophila CID) in Schneider S2 cells leads to its incorporation into non-centromeric regions and generates CID islands that resist clearing from chromosome arms for multiple cell generations. We demonstrate that CID islands represent functional ectopic kinetochores, which are non-randomly distributed on the chromosome and show a preferential localization near telomeres and pericentric heterochromatin in transcriptionally silent, intergenic chromatin domains. Although overexpression of heterochromatin protein 1 (HP1) or increasing histone acetylation interferes with CID island formation on a global scale, induction of a locally defined region of synthetic heterochromatin by targeting HP1-LacI fusions to stably integrated Lac operator arrays produces a proximal hotspot for CID deposition. These data indicate that the characteristics of regions bordering heterochromatin promote de novo kinetochore assembly and thereby contribute to centromere identity. PMID- 21685893 TI - Willin and Par3 cooperatively regulate epithelial apical constriction through aPKC-mediated ROCK phosphorylation. AB - Apical-domain constriction is important for regulating epithelial morphogenesis. Epithelial cells are connected by apical junctional complexes (AJCs) that are lined with circumferential actomyosin cables. The contractility of these cables is regulated by Rho-associated kinases (ROCKs). Here, we report that Willin (a FERM-domain protein) and Par3 (a polarity-regulating protein) cooperatively regulate ROCK-dependent apical constriction. We found that Willin recruits aPKC and Par6 to the AJCs, independently of Par3. Simultaneous depletion of Willin and Par3 completely removed aPKC and Par6 from the AJCs and induced apical constriction. Induced constriction was through upregulation of the level of AJC associated ROCKs, which was due to loss of aPKC. Our results indicate that aPKC phosphorylates ROCK and suppresses its junctional localization, thereby allowing cells to retain normally shaped apical domains. Thus, we have uncovered a Willin/Par3-aPKC-ROCK pathway that controls epithelial apical morphology. PMID- 21685894 TI - Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal. AB - The co-occupancy of Tcf3 with Oct4, Sox2 and Nanog on embryonic stem cell (ESC) chromatin indicated that Tcf3 has been suggested to play an integral role in a poorly understood mechanism underlying Wnt-dependent stimulation of mouse ESC self-renewal of mouse ESCs. Although the conventional view of Tcf proteins as the beta-catenin-binding effectors of Wnt signalling suggested Tcf3-beta-catenin activation of target genes would stimulate self-renewal, here we show that an antagonistic relationship between Wnt3a and Tcf3 on gene expression regulates ESC self-renewal. Genetic ablation of Tcf3 replaced the requirement for exogenous Wnt3a or GSK3 inhibition for ESC self-renewal, demonstrating that inhibition of Tcf3 repressor is the necessary downstream effect of Wnt signalling. Interestingly, both Tcf3-beta-catenin and Tcf1-beta-catenin interactions contributed to Wnt stimulation of self-renewal and gene expression, and the combination of Tcf3 and Tcf1 recruited Wnt-stabilized beta-catenin to Oct4 binding sites on ESC chromatin. This work elucidates the molecular link between the effects of Wnt and the regulation of the Oct4/Sox2/Nanog network. PMID- 21685895 TI - A screen for regulators of survival of motor neuron protein levels. AB - The motor neuron disease spinal muscular atrophy (SMA) results from mutations that lead to low levels of the ubiquitously expressed protein survival of motor neuron (SMN). An ever-increasing collection of data suggests that therapeutics that elevate SMN may be effective in treating SMA. We executed an image-based screen of annotated chemical libraries and discovered several classes of compounds that were able to increase cellular SMN. Among the most important was the RTK-PI3K-AKT-GSK-3 signaling cascade. Chemical inhibitors of glycogen synthase kinase 3 (GSK-3) and short hairpin RNAs (shRNAs) directed against this target elevated SMN levels primarily by stabilizing the protein. It was particularly notable that GSK-3 chemical inhibitors were also effective in motor neurons, not only in elevating SMN levels, but also in blocking the death that was produced when SMN was acutely reduced by an SMN-specific shRNA. Thus, we have established a screen capable of detecting drug-like compounds that correct the main phenotypic change underlying SMA. PMID- 21685896 TI - Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. AB - Acetylcholine is a neurotransmitter that has a major role in the function of the insulin-secreting pancreatic beta cell. Parasympathetic innervation of the endocrine pancreas, the islets of Langerhans, has been shown to provide cholinergic input to the beta cell in several species, but the role of autonomic innervation in human beta cell function is at present unclear. Here we show that, in contrast to the case in mouse islets, cholinergic innervation of human islets is sparse. Instead, we find that the alpha cells of human islets provide paracrine cholinergic input to surrounding endocrine cells. Human alpha cells express the vesicular acetylcholine transporter and release acetylcholine when stimulated with kainate or a lowering in glucose concentration. Acetylcholine secretion by alpha cells in turn sensitizes the beta cell response to increases in glucose concentration. Our results demonstrate that in human islets acetylcholine is a paracrine signal that primes the beta cell to respond optimally to subsequent increases in glucose concentration. Cholinergic signaling within islets represents a potential therapeutic target in diabetes, highlighting the relevance of this advance to future drug development. PMID- 21685897 TI - Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia. AB - Chuvash polycythemia is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the VHL (von Hippel-Lindau) gene, whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark abnormalities of Chuvash polycythemia, such as hypersensitivity to erythropoietin, are unclear. Here we show that VHL directly binds suppressor of cytokine signaling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction. In contrast, Chuvash polycythemia-associated VHL mutants have altered affinity for SOCS1 and do not engage with and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reversed the disease phenotype in Vhl(R200W/R200W) knock-in mice, an experimental model that recapitulates human Chuvash polycythemia. These results show that VHL is a SOCS1-cooperative negative regulator of JAK2 and provide biochemical and preclinical support for JAK2-targeted therapy in individuals with Chuvash polycythemia. PMID- 21685898 TI - Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors. AB - Effective cancer immunotherapy requires the release of a broad spectrum of tumor antigens in the context of potent immune activation. We show here that a cDNA library of normal tissue, expressed from a highly immunogenic viral platform, cures established tumors of the same histological type from which the cDNA library was derived. Immune escape occurred with suboptimal vaccination, but tumor cells that escaped the immune pressure were readily treated by second-line virus-based immunotherapy. This approach has several major advantages. Use of the cDNA library leads to presentation of a broad repertoire of (undefined) tumor associated antigens, which reduces emergence of treatment-resistant variants and also permits rational, combined-modality approaches in the clinic. Finally, the viral vectors can be delivered systemically, without the need for tumor targeting, and are amenable to clinical-grade production. Therefore, virus expressed cDNA libraries represent a novel paradigm for cancer treatment addressing many of the key issues that have undermined the efficacy of immuno- and virotherapy to date. PMID- 21685899 TI - Nanomedicine: swarming towards the target. PMID- 21685900 TI - Giant Rashba-type spin splitting in bulk BiTeI. AB - There has been increasing interest in phenomena emerging from relativistic electrons in a solid, which have a potential impact on spintronics and magnetoelectrics. One example is the Rashba effect, which lifts the electron-spin degeneracy as a consequence of spin-orbit interaction under broken inversion symmetry. A high-energy-scale Rashba spin splitting is highly desirable for enhancing the coupling between electron spins and electricity relevant for spintronic functions. Here we describe the finding of a huge spin-orbit interaction effect in a polar semiconductor composed of heavy elements, BiTeI, where the bulk carriers are ruled by large Rashba-like spin splitting. The band splitting and its spin polarization obtained by spin- and angle-resolved photoemission spectroscopy are well in accord with relativistic first-principles calculations, confirming that the spin splitting is indeed derived from bulk atomic configurations. Together with the feasibility of carrier-doping control, the giant-Rashba semiconductor BiTeI possesses excellent potential for application to various spin-dependent electronic functions. PMID- 21685901 TI - Linear coupling of alignment with transport in a polymer electrolyte membrane. AB - Polymer electrolyte membranes (PEMs) selectively transport ions and polar molecules in a robust yet formable solid support. Tailored PEMs allow for devices such as solid-state batteries,'artificial muscle' actuators and reverse-osmosis water purifiers. Understanding how PEM structure and morphology relate to mobile species transport presents a challenge for designing next-generation materials. Material length scales from subnanometre to 1 MUm influence bulk properties such as ion conductivity and water transport. Here we employ multi-axis pulsed-field gradient NMR to measure diffusion anisotropy, and (2)H NMR spectroscopy and synchrotron small-angle X-ray scattering to probe orientational order as a function of water content and of membrane stretching. Strikingly, transport anisotropy linearly depends on the degree of alignment, signifying that membrane stretching affects neither the nanometre-scale channel dimensions nor the defect structure,causing only domain reorientation. The observed reorientation of anisotropic domains without perturbation of the inherent nematic-like domain character parallels the behaviour of nematic elastomers, promises tailored membrane conduction and potentially allows understanding of tunable shape-memory effects in PEM materials. This quantitative understanding will drive PEM design efforts towards optimal membrane transport, thus enabling more efficient polymeric batteries, fuel cells, mechanical actuators and water purification. PMID- 21685902 TI - Supramolecular spin valves. AB - Magnetic molecules are potential building blocks for the design of spintronic devices. Moreover, molecular materials enable the combination of bottom-up processing techniques, for example with conventional top-down nanofabrication. The development of solid-state spintronic devices based on the giant magnetoresistance, tunnel magnetoresistance and spin-valve effects has revolutionized magnetic memory applications. Recently, a significant improvement of the spin-relaxation time has been observed in organic semiconductor tunnel junctions, single non-magnetic molecules coupled to magnetic electrodes have shown giant magnetoresistance and hybrid devices exploiting the quantum tunnelling properties of single-molecule magnets have been proposed. Herein, we present an original spin-valve device in which a non-magnetic molecular quantum dot, made of a single-walled carbon nanotube contacted with non-magnetic electrodes, is laterally coupled through supramolecular interactions to TbPc(2) single-molecule magnets (Pc=phthalocyanine). Their localized magnetic moments lead to a magnetic field dependence of the electrical transport through the single-walled carbon nanotube, resulting in magnetoresistance ratios up to 300% at temperatures less than 1 K. We thus demonstrate the functionality of a supramolecular spin valve without magnetic leads. Our results open up prospects of new spintronic devices with quantum properties. PMID- 21685903 TI - Nanoparticles that communicate in vivo to amplify tumour targeting. AB - Nanomedicines have enormous potential to improve the precision of cancer therapy, yet our ability to efficiently home these materials to regions of disease in vivo remains very limited. Inspired by the ability of communication to improve targeting in biological systems, such as inflammatory-cell recruitment to sites of disease, we construct systems where synthetic biological and nanotechnological components communicate to amplify disease targeting in vivo. These systems are composed of 'signalling' modules (nanoparticles or engineered proteins) that target tumours and then locally activate the coagulation cascade to broadcast tumour location to clot-targeted 'receiving' nanoparticles in circulation that carry a diagnostic or therapeutic cargo, thereby amplifying their delivery. We show that communicating nanoparticle systems can be composed of multiple types of signalling and receiving modules, can transmit information through multiple molecular pathways in coagulation, can operate autonomously and can target over 40 times higher doses of chemotherapeutics to tumours than non-communicating controls. PMID- 21685904 TI - Atomic layer-deposited tunnel oxide stabilizes silicon photoanodes for water oxidation. AB - A leading approach for large-scale electrochemical energy production with minimal global-warming gas emission is to use a renewable source of electricity, such as solar energy, to oxidize water, providing the abundant source of electrons needed in fuel synthesis. We report corrosion-resistant, nanocomposite anodes for the oxidation of water required to produce renewable fuels. Silicon, an earth abundant element and an efficient photovoltaic material, is protected by atomic layer deposition (ALD) of a highly uniform, 2 nm thick layer of titanium dioxide (TiO(2)) and then coated with an optically transmitting layer of a known catalyst (3 nm iridium). Photoelectrochemical water oxidation was observed to occur below the reversible potential whereas dark electrochemical water oxidation was found to have low-to-moderate overpotentials at all pH values, resulting in an inferred photovoltage of ~550 mV. Water oxidation is sustained at these anodes for many hours in harsh pH and oxidative environments whereas comparable silicon anodes without the TiO(2) coating quickly fail. The desirable electrochemical efficiency and corrosion resistance of these anodes is made possible by the low electron tunnelling resistance (<0.006 Omega cm(2) for p(+)-Si) and uniform thickness of atomic-layer deposited TiO(2). PMID- 21685905 TI - A pipeline that integrates the discovery and verification of plasma protein biomarkers reveals candidate markers for cardiovascular disease. AB - We developed a pipeline to integrate the proteomic technologies used from the discovery to the verification stages of plasma biomarker identification and applied it to identify early biomarkers of cardiac injury from the blood of patients undergoing a therapeutic, planned myocardial infarction (PMI) for treatment of hypertrophic cardiomyopathy. Sampling of blood directly from patient hearts before, during and after controlled myocardial injury ensured enrichment for candidate biomarkers and allowed patients to serve as their own biological controls. LC-MS/MS analyses detected 121 highly differentially expressed proteins, including previously credentialed markers of cardiovascular disease and >100 novel candidate biomarkers for myocardial infarction (MI). Accurate inclusion mass screening (AIMS) qualified a subset of the candidates based on highly specific, targeted detection in peripheral plasma, including some markers unlikely to have been identified without this step. Analyses of peripheral plasma from controls and patients with PMI or spontaneous MI by quantitative multiple reaction monitoring mass spectrometry or immunoassays suggest that the candidate biomarkers may be specific to MI. This study demonstrates that modern proteomic technologies, when coherently integrated, can yield novel cardiovascular biomarkers meriting further evaluation in large, heterogeneous cohorts. PMID- 21685906 TI - A targeted proteomics-based pipeline for verification of biomarkers in plasma. AB - High-throughput technologies can now identify hundreds of candidate protein biomarkers for any disease with relative ease. However, because there are no assays for the majority of proteins and de novo immunoassay development is prohibitively expensive, few candidate biomarkers are tested in clinical studies. We tested whether the analytical performance of a biomarker identification pipeline based on targeted mass spectrometry would be sufficient for data dependent prioritization of candidate biomarkers, de novo development of assays and multiplexed biomarker verification. We used a data-dependent triage process to prioritize a subset of putative plasma biomarkers from >1,000 candidates previously identified using a mouse model of breast cancer. Eighty-eight novel quantitative assays based on selected reaction monitoring mass spectrometry were developed, multiplexed and evaluated in 80 plasma samples. Thirty-six proteins were verified as being elevated in the plasma of tumor-bearing animals. The analytical performance of this pipeline suggests that it should support the use of an analogous approach with human samples. PMID- 21685907 TI - Inositol hexakisphosphate kinase 1 regulates neutrophil function in innate immunity by inhibiting phosphatidylinositol-(3,4,5)-trisphosphate signaling. AB - Inositol phosphates are widely produced throughout animal and plant tissues. Diphosphoinositol pentakisphosphate (InsP7) contains an energetic pyrophosphate bond. Here we demonstrate that disruption of inositol hexakisphosphate kinase 1 (InsP6K1), one of the three mammalian inositol hexakisphosphate kinases (InsP6Ks) that convert inositol hexakisphosphate (InsP6) to InsP7, conferred enhanced phosphatidylinositol-(3,4,5)-trisphosphate (PtdIns(3,4,5)P3)-mediated membrane translocation of the pleckstrin homology domain of the kinase Akt and thus augmented downstream PtdIns(3,4,5)P3 signaling in mouse neutrophils. Consequently, these neutrophils had greater phagocytic and bactericidal ability and amplified NADPH oxidase-mediated production of superoxide. These phenotypes were replicated in human primary neutrophils with pharmacologically inhibited InsP6Ks. In contrast, an increase in intracellular InsP7 blocked chemoattractant elicited translocation of the pleckstrin homology domain to the membrane and substantially suppressed PtdIns(3,4,5)P3-mediated cellular events in neutrophils. Our findings establish a role for InsP7 in signal transduction and provide a mechanism for modulating PtdIns(3,4,5)P3 signaling in neutrophils. PMID- 21685908 TI - Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells. AB - How the pore-forming protein perforin delivers apoptosis-inducing granzymes to the cytosol of target cells is uncertain. Perforin induces a transient Ca2+ flux in the target cell, which triggers a process to repair the damaged cell membrane. As a consequence, both perforin and granzymes are endocytosed into enlarged endosomes called 'gigantosomes'. Here we show that perforin formed pores in the gigantosome membrane, allowing endosomal cargo, including granzymes, to be gradually released. After about 15 min, gigantosomes ruptured, releasing their remaining content. Thus, perforin delivers granzymes by a two-step process that involves first transient pores in the cell membrane that trigger the endocytosis of granzyme and perforin and then pore formation in endosomes to trigger cytosolic release. PMID- 21685909 TI - Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas. AB - Lymphoid-enhancer-binding factor 1 (LEF1), coupling with beta-catenin, functions as a key nuclear mediator of WNT/beta-catenin signaling, which regulates cell proliferation and survival. LEF1 has an important role in lymphopoiesis, and is normally expressed in T and pro-B cells but not mature B cells. However, gene expression profiling demonstrates overexpression of LEF1 in chronic lymphocytic leukemia, and knockdown of LEF1 decreases the survival of the leukemic cells. So far, the data on LEF1 expression in B-cell lymphomas are limited. This study represents the first attempt to assess LEF1 by immunohistochemistry in a large series (290 cases) of B-cell lymphomas. Strong nuclear staining of LEF1 was observed in virtually all neoplastic cells in 92 of 92 (100%) chronic lymphocytic leukemia/small lymphocytic lymphomas including two CD5- cases, with strongest staining in cells with Richter's transformation. LEF1 also highlighted the morphologically inconspicuous small lymphocytic lymphoma component in three composite lymphomas. All 53 mantle cell lymphomas, 31 low-grade follicular lymphomas and 31 marginal zone lymphomas, including 3 CD5+ cases, were negative. In 12 grade 3 follicular lymphomas, LEF1 was positive in a small subset (5-15%) of cells. Diffuse large B-cell lymphoma, however, demonstrated significant variability in LEF1 expression with overall positivity in 27 of 71 (38%) cases. Our results demonstrate that nuclear overexpression of LEF1 is highly associated with chronic lymphocytic leukemia/small lymphocytic lymphoma, and may serve as a convenient marker for differential diagnosis of small B-cell lymphomas. The expression of beta-catenin, the coactivator of LEF1 in WNT signaling, was examined in 50 chronic lymphocytic leukemia/small lymphocytic lymphomas, of which 44 (88%) showed negative nuclear staining. The findings of universal nuclear overexpression of LEF1 but lack of nuclear beta-catenin in the majority of chronic lymphocytic leukemia/small lymphocytic lymphoma suggest that the pro survival function of LEF1 in this disease may be independent of WNT/beta-catenin signaling. PMID- 21685910 TI - Reduced numbers of Sertoli, germ, and spermatogonial stem cells in impaired spermatogenesis. AB - A key step in the investigation of male infertility is the appropriate classification of impaired spermatogenesis. In this study, we precisely identified Sertoli and distinct germ-cell types in the rat, the mouse, and in the human testis. As a proof of principle, we studied testis biopsy samples from azoospermic patients with defined spermatogenic defects. Remarkably, we found that already the numbers of Sertoli cells, spermatogonia and a subset of spermatogonia including stem cells are significantly reduced in patients with maturation arrest at the level of primary spermatocytes (n=33) compared with patients with histologically normal spermatogenesis (n=33). In patients with hypospermatogenesis (n=44) a significant reduction of spermatogonial cell numbers was observed. The numbers of primary and diplotene spermatocytes were reduced by 84%. However, the strongest reduction (96%) was revealed in the numbers of spermatids in patients with maturation arrest. In contrast, patients with hypospermatogenesis showed only modestly reduced numbers of spermatocytes and spermatids compared with normal spermatogenesis. No correlation was found with age or obstruction. For a detailed analysis of the patients, we distinguished between 'pool of founder cells'-related deficiencies (reduced numbers of Sertoli cells, spermatogonia, and spermatogonial stem cells) and 'meiotic' deficiencies (reduced numbers of spermatocytes, meiotic divisions, and spermatids). Interestingly, patients with maturation arrest showed meiotic deficiencies (36%), while the majority additionally demonstrated deficiencies in the founder pool (58%). In contrast, patients with normal spermatogenesis most often had no deficiencies at all (45%) or founder pool-related deficiencies (33%) but an apparently normal meiosis. This is the first report showing that many infertile patients face besides meiotic defects the problem of reduced numbers of Sertoli cells, spermatogonia, and spermatogonial stem cells. PMID- 21685911 TI - Single-molecule transport across an individual biomimetic nuclear pore complex. AB - Nuclear pore complexes regulate the selective exchange of RNA and proteins across the nuclear envelope in eukaryotic cells. Biomimetic strategies offer new opportunities to investigate this remarkable transport phenomenon. Here, we show selective transport of proteins across individual biomimetic nuclear pore complexes at the single-molecule level. Each biomimetic complex is constructed by covalently tethering either Nup98 or Nup153 (phenylalanine-glycine (FG) nucleoporins) to a solid-state nanopore. Individual translocation events are monitored using ionic current measurements with sub-millisecond temporal resolution. Transport receptors (Impbeta) proceed with a dwell time of ~2.5 ms for both Nup98- and Nup153-coated pores, whereas the passage of non-specific proteins is strongly inhibited with different degrees of selectivity. For pores up to ~25 nm in diameter, Nups form a dense and low-conducting barrier, whereas they adopt a more open structure in larger pores. Our biomimetic nuclear pore complex provides a quantitative platform for studying nucleocytoplasmic transport phenomena at the single-molecule level in vitro. PMID- 21685913 TI - CTCF-mediated functional chromatin interactome in pluripotent cells. AB - Mammalian genomes are viewed as functional organizations that orchestrate spatial and temporal gene regulation. CTCF, the most characterized insulator-binding protein, has been implicated as a key genome organizer. However, little is known about CTCF-associated higher-order chromatin structures at a global scale. Here we applied chromatin interaction analysis by paired-end tag (ChIA-PET) sequencing to elucidate the CTCF-chromatin interactome in pluripotent cells. From this analysis, we identified 1,480 cis- and 336 trans-interacting loci with high reproducibility and precision. Associating these chromatin interaction loci with their underlying epigenetic states, promoter activities, enhancer binding and nuclear lamina occupancy, we uncovered five distinct chromatin domains that suggest potential new models of CTCF function in chromatin organization and transcriptional control. Specifically, CTCF interactions demarcate chromatin nuclear membrane attachments and influence proper gene expression through extensive cross-talk between promoters and regulatory elements. This highly complex nuclear organization offers insights toward the unifying principles that govern genome plasticity and function. PMID- 21685912 TI - Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. AB - Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P <= 10(-3). We found significant previously unidentified signals (P < 5 * 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. PMID- 21685915 TI - Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. AB - Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential. PMID- 21685914 TI - A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. AB - Autosomal dominant polycystic liver disease results from mutations in PRKCSH or SEC63. The respective gene products, glucosidase IIbeta and SEC63p, function in protein translocation and quality control pathways in the endoplasmic reticulum. Here we show that glucosidase IIbeta and Sec63p are required in mice for adequate expression of a functional complex of the polycystic kidney disease gene products, polycystin-1 and polycystin-2. We find that polycystin-1 is the rate limiting component of this complex and that there is a dose-response relationship between cystic dilation and levels of functional polycystin-1 following mutation of Prkcsh or Sec63. Reduced expression of polycystin-1 also serves to sensitize the kidney to cyst formation resulting from mutations in Pkhd1, the recessive polycystic kidney disease gene. Finally, we show that proteasome inhibition increases steady-state levels of polycystin-1 in cells lacking glucosidase IIbeta and that treatment with a proteasome inhibitor reduces cystic disease in orthologous gene models of human autosomal dominant polycystic liver disease. PMID- 21685916 TI - Social regulation of aggression by pheromonal activation of Or65a olfactory neurons in Drosophila. AB - When two socially naive Drosophila males meet, they will fight. However, prior social grouping of males reduces their aggression. We found olfactory communication to be important for modulating Drosophila aggression. Although acute exposure to the male-specific pheromone 11-cis-vaccenyl acetate (cVA) elicited aggression through Or67d olfactory receptor neurons (ORNs), chronic cVA exposure reduced aggression through Or65a ORNs. Or65a ORNs were not acutely involved in aggression, but blockade of synaptic transmission of Or65a ORNs during social grouping or prior chronic cVA exposure eliminated social modulation of aggression. Artificial activation of Or65a ORNs by ectopic expression of the Drosophila gene TrpA1 was sufficient to reduce aggression. Social suppression of aggression requires subsets of local interneurons in the antennal lobe. Our results indicate that activation of Or65a ORNs is important for social modulation of male aggression, demonstrate that the acute and chronic effects of a single pheromone are mediated by two distinct types of ORNs, reveal a behaviorally important role for interneurons and suggest a chemical method to reduce aggression in animals. PMID- 21685917 TI - Mushroom body efferent neurons responsible for aversive olfactory memory retrieval in Drosophila. AB - Aversive olfactory memory is formed in the mushroom bodies in Drosophila melanogaster. Memory retrieval requires mushroom body output, but the manner in which a memory trace in the mushroom body drives conditioned avoidance of a learned odor remains unknown. To identify neurons that are involved in olfactory memory retrieval, we performed an anatomical and functional screen of defined sets of mushroom body output neurons. We found that MB-V2 neurons were essential for retrieval of both short- and long-lasting memory, but not for memory formation or memory consolidation. MB-V2 neurons are cholinergic efferent neurons that project from the mushroom body vertical lobes to the middle superiormedial protocerebrum and the lateral horn. Notably, the odor response of MB-V2 neurons was modified after conditioning. As the lateral horn has been implicated in innate responses to repellent odorants, we propose that MB-V2 neurons recruit the olfactory pathway involved in innate odor avoidance during memory retrieval. PMID- 21685918 TI - Imaging analysis of clock neurons reveals light buffers the wake-promoting effect of dopamine. AB - How animals maintain proper amounts of sleep yet remain flexible to changes in environmental conditions remains unknown. We found that environmental light suppressed the wake-promoting effects of dopamine in fly brains. The ten large lateral-ventral neurons (l-LNvs), a subset of clock neurons, are wake-promoting and respond to dopamine, octopamine and light. Behavioral and imaging analyses suggested that dopamine is a stronger arousal signal than octopamine. Notably, light exposure not only suppressed l-LNv responses, but also synchronized responses of neighboring l-LNvs. This regulation occurred by distinct mechanisms: light-mediated suppression of octopamine responses was regulated by the circadian clock, whereas light regulation of dopamine responses occurred by upregulation of inhibitory dopamine receptors. Plasticity therefore alters the relative importance of diverse cues on the basis of the environmental mix of stimuli. The regulatory mechanisms described here may contribute to the control of sleep stability while still allowing behavioral flexibility. PMID- 21685919 TI - Glia instruct developmental neuronal remodeling through TGF-beta signaling. AB - We found that glia secrete myoglianin, a TGF-beta ligand, to instruct developmental neural remodeling in Drosophila. Glial myoglianin upregulated neuronal expression of an ecdysone nuclear receptor that triggered neurite remodeling following the late-larval ecdysone peak. Thus glia orchestrate developmental neural remodeling not only by engulfment of unwanted neurites but also by enabling neuron remodeling. PMID- 21685920 TI - Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy. AB - Myotonic dystrophy is an RNA gain-of-function disease caused by expanded CUG or CCUG repeats, which sequester the RNA binding protein MBNL1. Here we describe a newly discovered function for MBNL1 as a regulator of pre-miR-1 biogenesis and find that miR-1 processing is altered in heart samples from people with myotonic dystrophy. MBNL1 binds to a UGC motif located within the loop of pre-miR-1 and competes for the binding of LIN28, which promotes pre-miR-1 uridylation by ZCCHC11 (TUT4) and blocks Dicer processing. As a consequence of miR-1 loss, expression of GJA1 (connexin 43) and CACNA1C (Cav1.2), which are targets of miR 1, is increased in both DM1- and DM2-affected hearts. CACNA1C and GJA1 encode the main calcium- and gap-junction channels in heart, respectively, and we propose that their misregulation may contribute to the cardiac dysfunctions observed in affected persons. PMID- 21685921 TI - Integrating energy calculations with functional assays to decipher the specificity of G protein-RGS protein interactions. AB - The diverse Regulator of G protein Signaling (RGS) family sets the timing of G protein signaling. To understand how the structure of RGS proteins determines their common ability to inactivate G proteins and their selective G protein recognition, we combined structure-based energy calculations with biochemical measurements of RGS activity. We found a previously unidentified group of variable 'Modulatory' residues that reside at the periphery of the RGS domain-G protein interface and fine-tune G protein recognition. Mutations of Modulatory residues in high-activity RGS proteins impaired RGS function, whereas redesign of low-activity RGS proteins in critical Modulatory positions yielded complete gain of function. Therefore, RGS proteins combine a conserved core interface with peripheral Modulatory residues to selectively optimize G protein recognition and inactivation. Finally, we show that our approach can be extended to analyze interaction specificity across other large protein families. PMID- 21685922 TI - Eisosome-driven plasma membrane organization is mediated by BAR domains. AB - Plasma membranes are organized into domains of different protein and lipid composition. Eisosomes are key complexes for yeast plasma membrane organization, containing primarily Pil1 and Lsp1. Here we show that both proteins consist mostly of a banana-shaped BAR domain common to membrane sculpting proteins, most similar to the ones of amphiphysin, arfaptin 2 and endophilin 2. Our data reveal a previously unrecognized family of BAR-domain proteins involved in plasma membrane organization. PMID- 21685923 TI - Testosterone level and mortality in elderly men with systolic chronic heart failure. AB - Previous studies on the prognostic significance of serum levels of androgens in patients with chronic heart failure (CHF) have yielded conflicting results. The aim of this study was to examine the relationship between serum concentration of testosterone and mortality in men with systolic CHF. A total of 175 elderly men (age >= 60 years) with CHF were recruited. Total testosterone (TT) and sex hormone-binding globulin (SHBG) were measured, and estimated free testosterone (eFT) was calculated. The median follow-up time was 3.46 years. Of these patients, 17 had a TT level below 8 nmol l-1 (230 ng dl-1), 27 had an eFT level below 0.225 nmol l-1 (65 pg ml-1) and 12 had both. Using the age-specific tenth percentiles of TT and eFT in healthy men in our laboratory as cutoff points, the prevalences of TT and eFT deficiency was 21.7% (38/175) and 27.4% (48/175), respectively. Both TT and eFT were inversely associated with left ventricular ejection fraction (LVEF) and N-terminal pro-brain natriuretic peptide (NT-pro BNP) (all P<0.01). Kaplan-Meier curves for patients in low, medium and high tertiles according to TT and eFT level showed significantly different cumulative survival rate (both P<0.01 by log-rank test). However, after adjustment for clinical variables, there were no significant associations of either TT or eFT levels with survival time (OR=0.97, 95% CI: 0.84-1.12, P=0.28 and OR=0.92, 95% CI: 0.82-1.06, P=0.14, respectively). Our study showed that levels of TT and eFT are commonly decreased in elderly patients with systolic CHF and related to disease severity, but they are not independent predictors for mortality. PMID- 21685924 TI - Highlights on FOXO3 and tumor-associated dendritic cells in prostate cancer. PMID- 21685925 TI - The role of antioxidant therapy in the treatment of male infertility: an overview. AB - In recent years, many studies have focused on the effect of oxidative stress, reactive oxygen species (ROS) and antioxidants on the male eproductive system. Under physiological conditions, sperm produces small amounts of ROS, which are needed for fertilisation, acrosome reaction and capacitation. However, if an increased production of ROS is not associated with a similar increase in scavenging systems, peroxidative damage of the sperm plasma membrane and loss of DNA integrity typically occur, which leads to cell death and reduced fertility. Furthermore, since there is no linear correlation between sperm quality and pregnancy rates, an improvement in semen parameters should not be the sole outcome considered in studies of antioxidant therapies. A definitive conclusion regarding the benefit of these therapies is difficult to obtain, as most of the previous studies lacked control groups, considered different antioxidants in different combinations and doses, or did not evaluate pregnancy rates in previously infertile couples. Even if beneficial effects were reported in a few cases of male infertility, more multicentre, double-blind studies performed with the same criteria are necessary for an increased understanding of the effects of various antioxidants on fertility. PMID- 21685926 TI - Proteomic alterations in mouse kidney induced by andrographolide sodium bisulfite. AB - AIM: To identify the key proteins involved in the nephrotoxicity induced by andrographolide sodium bisulfite (ASB). METHODS: Male ICR mice were intravenously administrated with ASB (1000 or 150 mg.kg-1.d-1) for 7 d. The level of malondialdehyde (MDA) and the specific activity of superoxide dismutase (SOD) in kidneys were measured. The renal homogenates were separated by two-dimensional electrophoresis, and the differential protein spots were identified using a matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF)/TOF mass spectrometry. RESULTS: The high dose (1000 mg/kg) of ASB significantly increased the MDA content, but decreased the SOD activity as compared to the control mice. The proteomic analysis revealed that 6 proteins were differentially expressed in the high-dose group. Two stress-responsive proteins, ie heat shock cognate 71 kDa protein (HSC70) and peroxiredoxin-6 (PRDX6), were regulated at the expression level. The remaining 4 proteins involving in cellular energy metabolism, including isoforms of methylmalonyl-coenzyme A mutase (MUT), nucleoside diphosphate-linked moiety X motif 19 (Nudix motif19), mitochondrial NADH dehydrogenase 1 alpha subcomplex subunit 10 (NDUFA10) and nucleoside diphosphate kinase B (NDK B), were modified at the post-translational levels. CONCLUSION: Our findings suggest that the mitochondrion is the primary target of ASB and that ASB induced nephrotoxicity results from oxidative stress mediated by superoxide produced by complex I. PMID- 21685927 TI - Multiple signaling pathways involved in stimulation of osteoblast differentiation by N-methyl-D-aspartate receptors activation in vitro. AB - AIM: Glutamate receptors are expressed in osteoblastic cells. The present study was undertaken to investigate the mechanisms underlying the stimulation of osteoblast differentiation by N-methyl-D-aspartate (NMDA) receptor activation in vitro. METHODS: Primary culture of osteoblasts was prepared from SD rats. Microarray was used to detect the changes of gene expression. The effect of NMDA receptor agonist or antagonist on individual gene was examined using RT-PCR. The activity of alkaloid phosphotase (ALP) was assessed using a commercial ALP staining kit. RESULTS: Microarray analyses revealed that 10 genes were up regulated by NMDA (0.5 mmol/L) and down-regulated by MK801 (100 MUmol/L), while 13 genes down-regulated by NMDA (0.5 mmol/L) and up-regulated by MK801 (100 MUmol/L). Pretreatment of osteoblasts with the specific PKC inhibitor Calphostin C (0.05 MUmol/L), the PKA inhibitor H-89 (20 nmol/L), or the PI3K inhibitor wortmannin (100 nmol/L) blocked the ALP activity increase caused by NMDA (0.5 mmol/L). Furthermore, NMDA (0.5 mmol/L) rapidly increased PI3K phosphorylation, which could be blocked by pretreatment of wortmannin (100 nmol/L). CONCLUSION: The results suggest that activation of NMDA receptors stimulates osteoblasts differentiation through PKA, PKC, and PI3K signaling pathways, which is a new role for glutamate in regulating bone remodeling. PMID- 21685928 TI - Tissue-specific alterations in expression and function of P-glycoprotein in streptozotocin-induced diabetic rats. AB - AIM: To investigate the changes of expression and function of P-glycoprotein (P GP) in cerebral cortex, hippocampus, liver, intestinal mucosa and kidney of streptozocin-induced diabetic rats. METHODS: Diabetic rats were prepared via a single dose of streptozocin (65 mg/kg, ip). Abcb1/P-GP mRNA and protein expression levels in tissues were evaluated using quantitative real time polymerase chain reaction (QRT-PCR) analysis and Western blot, respectively. P-GP function was investigated via measuring tissue-to-plasma concentration ratios and body fluid excretion percentages of rhodamine 123. RESULTS: In 5- and 8-week diabetic rats, Abcb1a mRNA levels were significantly decreased in cerebral cortices and intestinal mucosa, but dramatically increased in hippocampus and kidney. In liver, the level was increased in 5-week diabetic rats, and decreased in 8-week diabetic rats. Abcb1b mRNA levels were increased in cerebral cortex, hippocampus and kidney, but reduced in liver and intestinal mucosa in the diabetic rats. Western blot results were in accordance with the alterations of Abcb1a mRNA levels in most tissues examined. P-GP activity was markedly decreased in most tissues of diabetic rats, except kidney tissues. CONCLUSION: Alterations in the expression and function of Abcb1/P-GP under diabetic conditions are tissue specific, Abcb1 specific and diabetic duration-dependent. PMID- 21685929 TI - CaMKII in cerebral ischemia. AB - Ischemic insults on neurons trigger excessive, pathological glutamate release that causes Ca2+ overload resulting in neuronal cell death (excitotoxicity). The Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) is a major mediator of physiological excitatory glutamate signals underlying neuronal plasticity and learning. Glutamate stimuli trigger autophosphorylation of CaMKII at T286, a process that makes the kinase "autonomous" (partially active independent from Ca2+ stimulation) and that is required for forms of synaptic plasticity. Recent studies suggested autonomous CaMKII activity also as potential drug target for post-insult neuroprotection, both after glutamate insults in neuronal cultures and after focal cerebral ischemia in vivo. However, CaMKII and other members of the CaM kinase family have been implicated in regulation of both neuronal death and survival. Here, we discuss past findings and possible mechanisms of CaM kinase functions in excitotoxicity and cerebral ischemia, with a focus on CaMKII and its regulation. PMID- 21685933 TI - Disruption of Tacc3 function leads to in vivo tumor regression. AB - The formation of the bipolar spindle is responsible for accurate chromosomal segregation during mitosis. The dynamic instability of microtubules has an important role in this process, and has been shown to be an effective target for cancer chemotherapy. Several agents that target non-microtubule mitotic proteins, including the motor protein Eg5, Aurora kinases and Polo-like kinases, are currently being developed as chemotherapeutic drugs. However, because the efficacies of these drugs remain elusive, new molecular targets that have essential roles in tumor cells are desired. Here, we provide in vivo evidence that transforming acidic coiled-coil-3 (Tacc3) is a potential target for cancer chemotherapy. Using MRI, we showed that Tacc3 loss led to the regression of mouse thymic lymphoma in vivo, which was accompanied by massive apoptosis. By contrast, normal tissues, including the thymus, showed no overt abnormalities, despite high Tacc3 expression. in vitro analysis indicated that Tacc3 depletion induced multi polar spindle formation, which led to mitotic arrest, followed by apoptosis. Similar responses have been observed in Burkitt's lymphoma and T-ALL. These results show that Tacc3 is a vulnerable component of the spindle assembly in lymphoma cells and is a promising cancer chemotherapy target. PMID- 21685932 TI - The benefits of noise in neural systems: bridging theory and experiment. AB - Although typically assumed to degrade performance, random fluctuations, or noise, can sometimes improve information processing in non-linear systems. One such form of 'stochastic facilitation', stochastic resonance, has been observed to enhance processing both in theoretical models of neural systems and in experimental neuroscience. However, the two approaches have yet to be fully reconciled. Understanding the diverse roles of noise in neural computation will require the design of experiments based on new theory and models, into which biologically appropriate experimental detail feeds back at various levels of abstraction. PMID- 21685931 TI - From the stochasticity of molecular processes to the variability of synaptic transmission. AB - The variability of the postsynaptic response following a single action potential arises from two sources: the neurotransmitter release is probabilistic, and the postsynaptic response to neurotransmitter release has variable timing and amplitude. At individual synapses, the number of molecules of a given type that are involved in these processes is small enough that the stochastic (random) properties of molecular events cannot be neglected. How the stochasticity of molecular processes contributes to the variability of synaptic transmission, its sensitivity and its robustness to molecular fluctuations has important implications for our understanding of the mechanistic basis of synaptic transmission and of synaptic plasticity. PMID- 21685935 TI - EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin. AB - The enhancer of zeste homolog 2 (EZH2) is upregulated and has an oncogenic role in several types of human cancer. However, the abnormalities of EZH2 and its underlying mechanisms in the pathogenesis of nasopharyngeal carcinoma (NPC) remain unknown. In this study, we found that high expression of EZH2 in NPC was associated closely with an aggressive and/or poor prognostic phenotype (P<0.05). In NPC cell lines, knockdown of EZH2 by short hairpin RNA was sufficient to inhibit cell invasiveness/metastasis both in vitro and in vivo, whereas ectopic overexpression of EZH2 supported NPC cell invasive capacity with a decreased expression of E-cadherin. In addition, ablation of endogenous Snail in NPC cells virtually totally prevented the repressive activity of EZH2 to E-cadherin, indicating that Snail might be a predominant mediator of EZH2 to suppress E cadherin. Furthermore, co-immunoprecipitation (IP), chromatin IP and luciferase reporter assays demonstrated that in NPC cells, (1) EZH2 interacted with HDAC1/HDAC2 and Snail to form a repressive complex; (2) these components interact in a linear fashion, not in a triangular fashion, that is, HDAC1 or HDAC2 bridge the interaction between EZH2 and Snail; and (3) the EZH2/HDAC1/2/Snail complex could closely bind to the E-cadherin promoter by Snail, but not YY1, to repress E cadherin. The data provided in this report suggest a critical role of EZH2 in the control of cell invasion and/or metastasis by forming a co-repressor complex with HDAC1/HDAC2/Snail to repress E-cadherin, an activity that might be responsible, at least in part, for the development and/or progression of human NPCs. PMID- 21685934 TI - TRPV4 mediates tumor-derived endothelial cell migration via arachidonic acid activated actin remodeling. AB - Changes in intracellular calcium [Ca(2+)](i) levels control critical cytosolic and nuclear events that are involved in the initiation and progression of tumor angiogenesis in endothelial cells (ECs). Therefore, the mechanism(s) involved in agonist-induced Ca(2+)(i) signaling is a potentially important molecular target for controlling angiogenesis and tumor growth. Several studies have shown that blood vessels in tumors differ from normal vessels in their morphology, blood flow and permeability. We had previously reported a key role for arachidonic acid (AA)-mediated Ca(2+) entry in the initial stages of tumor angiogenesis in vitro. In this study we assessed the mechanism involved in AA-induced EC migration. We report that TRPV4, an AA-activated channel, is differentially expressed in EC derived from human breast carcinomas (BTEC) as compared with 'normal' EC (HMVEC). BTEC display a significant increase in TRPV4 expression, which was correlated with greater Ca(2+) entry, induced by AA or 4alphaPDD (a selective TRPV4 agonist) in the tumor-derived ECs. Wound-healing assays revealed a key role of TRPV4 in regulating cell migration of BTEC but not HMVEC. Knockdown of TRPV4 expression completely abolished AA-induced BTEC migration, suggesting that TRPV4 mediates the pro-angiogenic effects promoted by AA. Furthermore, pre-incubation of BTEC with AA induced actin remodeling and a subsequent increase in the surface expression of TRPV4. This was consistent with the increased plasma membrane localization of TRPV4 and higher AA-stimulated Ca(2+) entry in the migrating cells. Together, the data presented herein demonstrate that: (1) TRPV4 is differentially expressed in tumor-derived versus 'normal' EC; (2) TRPV4 has a critical role in the migration of tumor-derived but not 'normal' EC migration; and (3) AA induces actin remodeling in BTEC, resulting in a corresponding increase of TRPV4 expression in the plasma membrane. We suggest that the latter is critical for migration of EC and thus in promoting angiogenesis and tumor growth. PMID- 21685936 TI - Regulation of the activation of the Fanconi anemia pathway by the p21 cyclin dependent kinase inhibitor. AB - Fanconi anemia (FA) is a rare disease characterized by congenital defects, progressive bone marrow failure and heightened cancer susceptibility. The FA proteins, BRCA1 and FANCD1/BRCA2 function cooperatively in the FA-BRCA pathway to repair damaged DNA. Activation of the FA-BRCA pathway occurs via the monoubiquitination of the FANCD2 and FANCI proteins, targeting these proteins to discrete nuclear foci where they function in DNA repair. The cellular regulation of FANCD2/I monoubiquitination, however, remains poorly understood. In this study, we have examined the roles of the p53 tumor suppressor protein, as well as its downstream target, the p21(Cip1/Waf1) cyclin-dependent kinase inhibitor, in the regulation of the activation of the FA-BRCA pathway. We demonstrate that, in contrast to p53, p21 has a major role in the regulation of the activation of the FA-BRCA pathway: p21 promotes S-phase and DNA damage-inducible FANCD2/I monoubiquitination and nuclear foci formation. Several lines of evidence establish that this effect is not a consequence of a defective G1-S checkpoint or altered cell-cycle progression in the absence of p21. Instead, we demonstrate that p21 is required for the transcriptional repression of the USP1 deubiquitinating enzyme upon exposure to DNA-damaging agents. In the absence of p21, persistent USP1 expression precludes the DNA damage-inducible accumulation of monoubiquitinated FANCD2 and FANCI. Consequently, p21(-/-) cells exhibit increased levels of mitomycin C-inducible complex chromosomal aberrations and elevated gammaH2AX nuclear foci formation. Our results demonstrate that p21 has a critical role in the regulation of the activation of the FA-BRCA pathway and suggest a broader role for p21 in the orchestration of DNA repair processes following exposure to DNA crosslinking agents. PMID- 21685937 TI - SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival. AB - Aberrant expression of Secreted Protein Acidic and Rich in Cysteine (SPARC)/osteonectin has been associated with an invasive tumor cell phenotype and poor outcome in human melanomas. Although it is known that SPARC controls melanoma tumorigenesis, the precise role of SPARC in melanoma cell survival is still unclear. Here, we show that SPARC has a cell-autonomous survival activity, which requires Akt-dependent regulation of p53. Suppression of SPARC by RNA interference in several human melanoma cells and xenografted A375 tumors triggers apoptotic cell death through the mitochondrial intrinsic pathway and activation of caspase-3. Cell death induced by depletion of SPARC is dependent on p53 and induction of Bax, and results in the generation of ROS. Stabilization of p53 in SPARC-depleted cells is associated with a decrease in Akt-mediated activating phosphorylation of MDM2. Inhibition of Akt signaling pathway is important for the observed changes as overexpression of constitutively active Akt protects cells against apoptosis induced by SPARC depletion. Conversely, increased expression of SPARC stimulates Akt and MDM2 phosphorylation, thus facilitating p53 degradation. Finally, we show that overexpression of SPARC renders cells more resistant to the p53-mediated cytotoxic effects of the DNA-damaging drug actinomycin-D. Our study indicates that SPARC functions through activation of Akt and MDM2 to limit p53 levels and that acquired expression of SPARC during melanoma development would confer survival advantages through suppression of p53-dependent apoptotic pathways. PMID- 21685938 TI - Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. AB - MicroRNAs are often associated with the pathogenesis of many cancers, including head and neck squamous cell carcinoma (HNSCC). In particular, microRNA-21 (miR 21) appears to have a critical role in tumor cell survival, chemoresistance and HNSCC progression. In this study, we investigated matrix hyaluronan (HA)-induced CD44 (a primary HA receptor) interaction with the stem cell markers, Nanog and Stat-3, in HNSCC cells (HSC-3 cells). Our results indicate that HA binding to CD44 promotes Nanog-Stat-3 (also tyrosine phosphorylated Stat-3) complex formation, nuclear translocation and transcriptional activation. Further analyses reveal that miR-21 is controlled by an upstream promoter containing Stat-3 binding site(s), while chromatin immunoprecipitation assays demonstrate that stimulation of miR-21 expression by HA/CD44 signaling is Nanog/Stat-3-dependent in HNSCC cells. This process results in a decrease of a tumor suppressor protein (PDCD4), and an upregulation of i nhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in HSC-3 cells. Treatment of HSC-3 cells with Nanog- and/or Stat-3-specific small interfering RNAs effectively blocks HA mediated Nanog-Stat-3 signaling events, abrogates miR-21 production and increases PDCD4 expression. Subsequently, this Nanog-Stat-3 signaling inhibition causes downregulation of survival protein (IAP) expression and enhancement of chemosensitivity. To further evaluate the role of miR-21 in tumor cell-specific functions, HSC-3 cells were also transfected with a specific anti-miR-21 inhibitor in order to silence miR-21 expression and block its target functions. Our results demonstrate that anti-miR-21 inhibitor not only upregulates PDCD4 expression but also decreases IAP expression and enhances chemosensitivity in HA treated HNSCC cells. Together, these findings indicate that the HA-induced CD44 interaction with Nanog and Stat-3 has a pivotal role in miR-21 production leading to PDCD4 reduction, IAP upregulation and chemoresistance in HNSCC cells. This novel Nanog/Stat-3 signaling pathway-specific mechanism involved in miR-21 production is significant for the formation of future intervention strategies in the treatment of HA/CD44-activated HNSCC. PMID- 21685940 TI - Opposing roles of angiomotin-like-1 and zona occludens-2 on pro-apoptotic function of YAP. AB - YAP (Yes-associated protein) oncogene has been found to form a stable complex with members of the Angiomotin (Amot) family of proteins, which bind WW domains of YAP and sequester the protein in the cytoplasm and junctional complexes. The Amot-mediated retention of YAP in the cytoplasm results in the inhibition of its proliferative function. Using apoptotic 'read-out' of YAP in HEK293 cells, we confirmed the molecular mode by which Amot regulates YAP. We showed that a representative member of the Amot family, AmotL1 (Angiomotin-like-1), uses its PPxY motifs to bind WW domains of YAP and inhibit YAP's nuclear translocation and pro-apoptotic function. Recently we also showed that YAP uses its PDZ-binding motif to interact with zona occludens-2 (ZO-2) protein, which promotes YAP's translocation to the nucleus. We also asked if AmotL1, YAP and ZO-2 signal together. We report here that AmotL1 and ZO-2 form a tripartite complex with YAP and regulate its function in HEK293 cells in opposite directions. AmotL1 inhibits pro-apoptotic function of YAP, whereas ZO-2 enhances it. As YAP is a potent oncogene, the identification and characterization of its regulators is important. AmotL1 and ZO-2 are two candidates that could be harnessed to control the oncogenic function of YAP. PMID- 21685939 TI - Identification of the cathelicidin peptide LL-37 as agonist for the type I insulin-like growth factor receptor. AB - The human cathelicidin antimicrobial protein-18 and its C terminal peptide, LL 37, displays broad antimicrobial activity that is mediated through direct contact with the microbial cell membrane. In addition, recent studies reveal that LL-37 is involved in diverse biological processes such as immunomodulation, apoptosis, angiogenesis and wound healing. An intriguing role for LL-37 in carcinogenesis is also beginning to emerge and the aim of this paper was to explore if and how LL 37 contributes to the signaling involved in tumor development. To this end, we investigated the putative interaction between LL-37 and growth factor receptors known to be involved in tumor growth and progression. Among several receptors tested, LL-37 bound with the highest affinity to insulin-like growth factor 1 receptor (IGF-1R), a receptor that is strongly linked to malignant cellular transformation. Furthermore, this interaction resulted in a dose-dependent phosphorylation and ubiquitination of IGF-1R, with downstream signaling confined to the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)-pathway but not affecting phosphatidylinositol 3 kinase/Akt signaling. We found that signaling induced by LL-37 was dependent on the recruitment of beta arrestin to the fully functional IGF-1R and by using mutant receptors we demonstrated that LL-37 signaling is dependent on beta-arrestin-1 binding to the C-terminus of IGF-1R. When analyzing the biological consequences of increased ERK activation induced by LL-37, we found that it resulted in enhanced migration and invasion of malignant cells in an IGF-1R/beta-arrestin manner, but did not affect cell proliferation. These results indicate that LL-37 may act as a partial agonist for IGF-1R, with subsequent intra-cellular signaling activation driven by the binding of beta-arrestin-1 to the IGF-1R. Functional experiments show that LL 37-dependent activation of the IGF-1R signaling resulted in increased migratory and invasive potential of malignant cells. PMID- 21685941 TI - Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells. AB - Bmi1 is a key stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including medulloblastoma. Overexpression of Bmi1 promotes cell proliferation and is required for hedgehog (Hh) pathway-driven tumorigenesis. This study aimed to determine if Sonic hedgehog (Shh) modulates the key stem cell regulatory gene Bmi1 in childhood medulloblastoma brain tumor initiating cells (BTICs). Although current literature suggests that there is a correlation between Shh pathway genes and Bmi1 expression, it is unclear whether there is indeed a direct regulatory mechanism. To address whether Shh induces expression of Bmi1, stem cell-enriched populations from medulloblastoma cell lines and primary samples were treated with Shh ligand and KAAD-cyclopamine (Shh antagonist). Our data indicate that Bmi1 expression positively correlates with increasing Shh ligand concentrations. Chromatin immunoprecipitation reveals that Gli1 preferentially binds to the Bmi1 promoter, and Bmi1 transcript levels are increased and decreased by Gli1 overexpression and downregulation, respectively. Knockdown experiments of Bmi1 in vitro and in vivo demonstrate that Hh signaling not only drives Bmi1 expression, but a feedback mechanism exists wherein downstream effectors of Bmi1 may, in turn, activate Hh pathway genes. These findings implicate Bmi1 and Hh as mutually indispensable pathways in medulloblastoma BTIC maintenance. Recent molecular characterization of medulloblastoma also reveals that Bmi1 is overexpressed across all subgroups of medulloblastoma, particularly in the most aggressive subtypes. Lastly, despite recent identification of BTIC markers, the molecular characterization of these cell populations remains unclear. In this work, we propose that the BTIC marker CD133 may segregate a cell population with a Hh-receptor phenotype, thus demonstrating a cell-cell interaction between the CD133+ Hh receptor cells and the CD133- Hh-secreting cells. PMID- 21685942 TI - Early-stage formation of an epigenetic field defect in a mouse colitis model, and non-essential roles of T- and B-cells in DNA methylation induction. AB - Epigenetic fields for cancerization are involved in development of human cancers, especially those associated with inflammation and multiple occurrences. However, it is still unclear when such field defects are formed and what component of inflammation is involved in induction of aberrant DNA methylation. Here, in a mouse colitis model induced by dextran sulfate sodium (DSS), we identified three CpG islands specifically methylated in colonic epithelial cells exposed to colitis. Their methylation levels started to increase as early as 8 weeks after DSS treatment and continued to increase until colon cancers developed at 15 weeks. In contrast to the temporal profile of DNA methylation levels, infiltration of inflammatory cells spiked immediately after the DSS treatment and then gradually decreased. Exposure of cultured colonic epithelial cells to DSS did not induce DNA methylation and it was indicated that inflammation triggered by the DSS treatment was responsible for methylation induction. To clarify components of inflammation involved, severe combined immunodeficiency (SCID) mice that lack functional T- and B-cells were similarly treated. Even in SCID mice, DNA methylation, along with colon tumors, were induced at the same levels as in their background strain of mice (C.B17). Comparative analysis of inflammation related genes showed that Ifng, Il1b and Nos2 had expression concordant with methylation induction whereas Il2, Il6, Il10, Tnf did not. These results showed that an epigenetic field defect is formed at early stages of colitis-associated carcinogenesis and that functional T and B cells are non-essential for the formation. PMID- 21685943 TI - A mouse model of heterogeneous, c-MYC-initiated prostate cancer with loss of Pten and p53. AB - Human tumors are heterogeneous and evolve through a dynamic process of genetic mutation and selection. During this process, the effects of a specific mutation on the incipient cancer cell may dictate the nature of subsequent mutations that can be tolerated or selected for, affecting the rate at which subsequent mutations occur. Here we have used a new mouse model of prostate cancer that recapitulates several salient features of the human disease to examine the relative rates in which the remaining wild-type alleles of Pten and p53 tumor suppressor genes are lost. In this model, focal overexpression of c-MYC in a few prostate luminal epithelial cells provokes a mild proliferative response. In the context of compound Pten/p53 heterozygosity, c-MYC-initiated cells progress to prostatic intraepithelial neoplasia (mPIN) and adenocarcinoma lesions with marked heterogeneity within the same prostate glands. Using laser capture microdissection and gene copy number analyses, we found that the frequency of Pten loss was significantly higher than that of p53 loss in mPIN but not invasive carcinoma lesions. c-MYC overexpression, unlike Pten loss, did not activate the p53 pathway in transgenic mouse prostate cells, explaining the lack of selective pressure to lose p53 in the c-MYC-overexpressing cells. This model of heterogeneous prostate cancer based on alterations in genes relevant to the human disease may be useful for understanding pathogenesis of the disease and testing new therapeutic agents. PMID- 21685945 TI - Rack1 promotes epithelial cell-cell adhesion by regulating E-cadherin endocytosis. AB - E-cadherin and its cytoplasmic partners, catenins, mediate epithelial cell-cell adhesion. Disruption of this adhesion allows cancer cells to invade and metastasize. Aberrant activation of the Src tyrosine kinase disrupts cell-cell contacts through an E-cadherin/catenin-dependent mechanism. Previously we showed that Rack1 regulates the growth of colon cells by suppressing Src activity at G(1) and mitotic checkpoints, and in the intrinsic apoptotic and Akt cell survival pathways. Here we show that Rack1, partly by inhibiting Src, promotes cell-cell adhesion and reduces the invasive potential of colon cancer cells. Rack1 stabilizes E-cadherin and catenins at cell-cell contacts by inhibiting the Src phosphorylation of E-cadherin, the ubiquitination of E-cadherin by the E3 ligase Hakai and the endocytosis of E-cadherin. Upon depletion and restoration of extracellular calcium, Rack1 facilitates the re-assembly of E-cadherin-containing cell-cell contacts. Rack1 also blocks HGF-induced endocytosis of E-cadherin, disruption of cell-cell contacts and cell scatter. Our results uncover a novel function of Rack1 in maintaining the junctional homeostasis of intestinal epithelial cells by regulation of the Src- and growth factor-induced endocytosis of E-cadherin. PMID- 21685944 TI - beta-arrestin1 mediates metastatic growth of breast cancer cells by facilitating HIF-1-dependent VEGF expression. AB - beta-Arrestins 1 and 2 are multifunctional adaptor proteins originally discovered for their role in desensitizing seven-transmembrane receptor signaling via the heterotrimeric guanine nucleotide-binding proteins. Recently identified roles of beta-arrestins include regulation of cancer cell chemotaxis and proliferation. Herein, we report that beta-arrestin1 expression regulates breast tumor colonization in nude mice and cancer cell viability during hypoxia. beta Arrestin1 robustly interacts with nuclear hypoxia-induced factor-1alpha (HIF 1alpha) that is stabilized during hypoxia and potentiates HIF-1-dependent transcription of the angiogenic factor vascular endothelial growth factor-A (VEGF A). Increased expression of beta-arrestin1 in human breast cancer (infiltrating ductal carcinoma or IDC and metastatic IDC) correlates with increased levels of VEGF-A. While the anti-angiogenic drug thalidomide inhibits HIF-1-dependent VEGF transcription in breast carcinoma cells, it does not prevent HIF-1alpha stabilization, but leads to aberrant localization of HIF-1alpha to the perinuclear compartments and surprisingly stimulates nuclear export of beta arrestin1. Additionally, imatinib mesylate that inhibits release of VEGF induces nuclear export of beta-arrestin1-HIF-1alpha complexes. Our findings suggest that beta-arrestin1 regulates nuclear signaling during hypoxia to promote survival of breast cancer cells via VEGF signaling and that drugs that induce its translocation from the nucleus to the cytoplasm could be useful in anti angiogenic and breast cancer therapies. PMID- 21685947 TI - Detecting oxysterols in the human circulation. PMID- 21685948 TI - Sculpting the immune response to infection. PMID- 21685949 TI - The 50th Midwinter Conference of Immunologists at Asilomar. PMID- 21685950 TI - Innate IL-13 in virus-induced asthma? PMID- 21685951 TI - Where, in antiviral defense, does IFIT1 fit? PMID- 21685952 TI - An unexpected role for IL-17 in lymphoid organogenesis. PMID- 21685953 TI - La(s)t but not least. PMID- 21685956 TI - Toxicology and carcinogenesis studies of tetralin (CAS No. 119-64-2) in F344/N rats and B6C3F1 mice (inhalation studies). AB - Tetralin is used as an industrial solvent primarily for naphthalene, fats, resins, oils, and waxes; as a solvent and stabilizer for shoe polishes and floor waxes; as a solvent for pesticides, rubber, asphalt, and aromatic hydrocarbons (e.g., anthracene); as a dye solvent carrier in the textile industry; as a substitute for turpentine in lacquers, paints, and varnishes; in paint thinners and as a paint remover; in alkali-resistant lacquers for cleaning printing ink from rollers and type; as a constituent of motor fuels and lubricants; for the removal of naphthalene in gas distribution systems; and as an insecticide for clothes moths. Tetralin was nominated by the National Cancer Institute for carcinogenicity and disposition studies because of its structure, high production volume, and high potential for worker and consumer exposure. Male and female F344/N rats and B6C3F1 mice were exposed to tetralin (at least 97% pure) by inhalation for 2 weeks, 3 months, or 2 years; male NCI Black Reiter (NBR) rats were exposed to tetralin by inhalation for 2 weeks. Male NBR rats do not produce 2u-globulin; the NBR rats were included to study the relationship of 2u-globulin and renal lesion induction. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male (F344/N and NBR) and five female (F344/N) rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 12 exposures. All rats survived to the end of the studies. The final mean body weight of female rats exposed to 120 ppm and mean body weight gains of female rats exposed to 30 ppm or greater were significantly less than those of the chamber controls. Final mean body weights of exposed groups of male NBR rats and mean body weight gains of all exposed groups of male rats were significantly less than those of the chamber controls. Dark-stained urine was observed in all 120 ppm rats. Squinting, weeping, or matted fur around the eyes were noted in the majority of F344/N rats exposed to 120 ppm. The 2u-globulin concentrations in the kidney of male F344/N rats were significantly greater in all exposed groups than in the chamber control group. The absolute kidney weight of 60 ppm females and the relative kidney weights of male F344/N rats exposed to 30 ppm or greater and female rats exposed to 15 ppm or greater were significantly increased. The absolute liver weight of 120 ppm NBR male rats and the relative liver weights of male and female rats exposed to 60 or 120 ppm were significantly increased. In the nose, the incidences of mononuclear cell cellular infiltration were generally significantly increased in all exposed groups of rats, and incidences of olfactory epithelium degeneration and glandular hypertrophy occurred in all male F344/N rats exposed to 120 ppm. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 13 exposures. All mice survived to the end of the study. Mean body weights of male and female mice were similar to those of the chamber controls. Dark-stained urine was observed in most of the exposed mice. The absolute and relative liver weights of 60 and 120 ppm males and 30 and 120 ppm females and the relative liver weights of 60 ppm females were significantly greater than those of the chamber controls. In the nose, the incidences of olfactory epithelium atrophy were significantly increased in 60 and 120 ppm males and females. Glandular dilatation occurred in all 120 ppm females, and glandular hyperplasia occurred in all 120 ppm males and females. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. The same exposure concentrations were given to additional groups of 10 male and 10 female clinical pathology study rats for up to 6 weeks and five male renal toxicity rats for 2 weeks. All rats survived to the end of the study. During the first 4 weeks of exposure, dark-stained urine was observed in the catch pans of rats exposed to 30, 60, or 120 ppm. Tetralin induced a minimal decrease in the erythron in both sexes that resulted in a hematopoietic response. Tetralin increased urine aspartate aminotransferase and urine lactate dehydrogenase activities (males and females) and glucose/creatinine ratio (males), suggestive of renal injury. The absolute kidney weights of 60 and 120 ppm females and the relative kidney weights of males and females exposed to 15 ppm or greater were significantly greater than those of the chamber controls. Concentrations of 2u-globulin in the kidney of exposed male rats were generally greater than those of the chamber controls at all time points and greater at 6 and 14 weeks than at 2 weeks. There were significantly increased incidences of olfactory epithelium necrosis in rats exposed to 30 ppm or greater and of olfactory epithelium regeneration in 60 and 120 ppm rats. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of 120 ppm males were significantly less than those of the chamber controls. Dark-stained urine was observed in the catch pans of mice exposed to 30, 60, or 120 ppm during the first month of the study. Tetralin induced a minimal decrease in the erythron in both sexes that resulted in a hematopoietic response. The relative liver weights of 120 ppm males and 30 ppm or greater females were significantly greater than those of the chamber controls. Incidences of olfactory epithelium metaplasia in 60 and 120 ppm males and females, respiratory epithelium hyaline droplet accumulation in 120 ppm males and 60 and 120 ppm females, cytoplasmic eosinophilic granules within the transitional epithelium lining the urinary bladder in all exposed groups of males and females, and ovarian atrophy and uterine atrophy in 60 and 120 ppm females were significantly increased. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to tetralin at air concentrations of 0, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Additional groups of five male and five female rats were exposed to the same concentrations for 12 months. Survival of all exposed groups of rats was similar to that of the chamber controls. Mean body weights of 120 ppm females were 6% less than those of the chamber controls after week 29. Dark-stained urine was observed in all exposed groups of rats. Creatinine-adjusted levels of all urinary metabolites increased with increasing exposure concentration in males and females. In the standard evaluation of the kidney, there were slightly increased incidences of cortical renal tubule adenoma in male rats. In the combined analysis of single and step sections, the incidence of cortical renal tubule adenoma was significantly increased in the 120 ppm group. In the combined analysis, there was also a significantly increased incidence of renal tubule hyperplasia in the 120 ppm group. In 120 ppm males in the standard evaluation, the severity of chronic nephropathy was increased and the incidence of transitional epithelial hyperplasia in the renal pelvis was significantly increased. Three hepatocellular adenomas occurred in 120 ppm females, and one hepatocellular carcinoma each was observed in the 60 and 120 ppm groups. The incidences of uterine stromal polyp and endometrium hyperplasia were significantly increased in 120 ppm females. Incidences of interstitial cell adenoma and germinal epithelium atrophy of the testis in 30 and 120 ppm males were significantly greater than those in the chamber controls. The incidences of olfactory epithelium degeneration, metaplasia, basal cell hyperplasia, suppurative inflammation, and mineralization (except 30 ppm females) in the nose were significantly increased in all exposed groups of rats. The incidences of glandular dilatation were significantly increased in 120 ppm males and all exposed groups of females. The incidences of respiratory epithelium chronic inflammation were significantly increased in males exposed to 60 or 120 ppm and all exposed groups of females. The incidences of lens cataract in 120 ppm females were significantly increased. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to tetralin at air concentrations of 0, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Additional groups of five male and five female mice were exposed to the same concentrations for 12 months. Survival of 60 and 120 ppm female mice was significantly greater than that of the chamber controls. The mean body weights of all exposed groups of male and female mice were similar to those of the chamber controls by the end of the study. Dark-stained urine was observed in all exposed groups of male mice and in females exposed to 60 or 120 ppm. Creatinine-adjusted levels of all urinary metabolites increased with increasing exposure concentration in males and females. The incidence of hemangiosarcoma of the spleen was increased in 120 ppm females and exceeded the historical control range for inhalation studies. The incidences of olfactory epithelium atrophy, respiratory metaplasia, glandular hyperplasia, and suppurative inflammation in exposed groups of mice were significantly greater than those in the chamber controls. Transitional epithelium cytoplasmic eosinophilic granules were present in the urinary bladder of all exposed mice. (ABSTRACT TRUNCATED) PMID- 21685958 TI - General quasi-nonspreading linear three-dimensional wave packets. AB - We introduce a general approach for generation of sets of three-dimensional quasi nonspreading wave packets propagating in linear media, also referred to as linear light bullets. The spectrum of rigorously nonspreading wave packets in media with anomalous group velocity dispersion is localized on the surface of a sphere, thus drastically restricting the possible wave packet shapes. However, broadening slightly the spectrum affords the generation of a large variety of quasi nonspreading distributions featuring complex topologies and shapes in space and time that are of interest in different areas, such as biophysics or nanosurgery. Here we discuss the method and show several illustrative examples of its potential. PMID- 21685959 TI - Focal plane tuning in wide-field-of-view microscope with Talbot pattern illumination. AB - We have developed a focal plane tuning technique for use in focus-grid-based wide field-of-view microscopy (WFM). In WFM, the incidence of a collimated beam on a mask with a two-dimensional grid of aperture produced the Talbot images of the aperture grid. The Talbot pattern functioned as a focus grid and was used to illuminate the sample. By scanning the sample across the focus grid and collecting the transmission, we can generate a microscopy image of the sample. By tuning the wavelength of the laser, we can tune the focal plane of the WFM and acquire images of different depth into the sample. Images of a green algae microscope slide were acquired at different focal planes for demonstration. PMID- 21685957 TI - Toxicology and carcinogenesis studies of milk thistle extract (CAS No. 84604-20 6) in F344/N rats and B6C3F1 mice (Feed Studies). AB - Milk thistle extracts have been used as medicinal herbs in the treatment of liver cirrhosis, chronic hepatitis (liver inflammation), and gallbladder disorders. Treatment claims also include lowering cholesterol levels; reducing insulin resistance; reducing the growth of cancer cells in breast, cervical, and prostate gland cancers; and antiviral activity. Other reported uses of milk thistle in folk medicine include as a treatment for malarial fever, bronchitis, gallstones, jaundice, peritonitis, uterine congestion, varicose veins, and as a milk production stimulant for nursing mothers. The roots soaked in water overnight are used in food, and the despined leaves are added to salads. Roasted milk thistle fruit has been used as a coffee substitute. Milk thistle extract was nominated for study by the National Institute of Environmental Health Sciences because it is one of the most widely used herbs in the United States. Male and female F344/N rats and B6C3F1 mice were exposed to an ethanol/water extract of milk thistle fruit (milk thistle extract) containing approximately 65% silymarin in feed for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 3,125, 6,250, 12,500, 25,000, or 50,000 ppm milk thistle extract (equivalent to average daily doses of approximately 260, 525, 1,050, 2,180, or 4,500 mg milk thistle extract/kilogram body weight to males and 260, 510, 1,050, 2,150, or 4,550 mg/kg to females) for 14 weeks. All rats survived to the end of the study. Mean body weights of exposed groups were within 10% of those of the controls. Feed consumption by exposed and control groups was similar. The sperm motility in 12,500, 25,000, and 50,000 ppm males was decreased by 5%, 11%, and 9%, respectively, relative to that of the controls; the total number of spermatid heads per testis decreased by 11%, 21%, and 9% in 12,500, 25,000, and 50,000 ppm males. No significant differences in estrous cyclicity were observed between exposed and control groups of female rats. No exposure-related histopathologic lesions were observed. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 3,125, 6,250, 12,500, 25,000, or 50,000 ppm milk thistle extract (equivalent to average daily doses of approximately 640, 1,340, 2,500, 5,280, or 11,620 mg/kg to males and 580, 1,180, 2,335, 4,800, or 9,680 mg/kg to females) for 14 weeks. All mice survived to the end of the study. Mean body weights and feed consumption of all exposed groups were similar to those of the controls. Absolute and relative thymus weights were significantly decreased in 25,000 and 50,000 ppm males. No significant differences were observed between exposed and control groups, for sperm parameters of male mice, for estrous cyclicity of female mice, or for reproductive organ weights of male or female mice, when mice were administered milk thistle extract in feed at 12,500, 25,000, or 50,000 ppm. No exposure-related histopathologic lesions were observed. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 0, 12,500, 25,000, or 50,000 ppm milk thistle extract (equivalent to average daily doses of approximately 570, 1,180, or 2,520 mg/kg to males and 630, 1,300, or 2,750 mg/kg to females) for 105 to 106 weeks. Exposure to milk thistle extract had no effect on survival of male or female rats. Mean body weights of all exposed groups were similar to those of the controls throughout the study. Feed consumption by exposed groups of males and females was generally similar to that by the controls throughout the study. Significantly decreased incidences of mammary gland fibroadenoma, adenoma, or carcinoma (combined) occurred in females exposed to 25,000 or 50,000 ppm. Significantly increased incidences of clear cell and mixed cell focus of the liver occurred in 25,000 and 50,000 ppm females. The incidences of bile duct hyperplasia were significantly decreased in 50,000 ppm males and in all exposed groups of females, and the incidence of mixed inflammatory cell infiltration was significantly decreased in 50,000 ppm males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were fed diets containing 0, 12,500, 25,000, or 50,000 ppm milk thistle extract (equivalent to average daily doses of approximately 1,610, 3,530, or 7,770 mg/kg to males and 1,500, 3,175, or 7,180 mg/kg to females) for 105 to 106 weeks. Exposure to milk thistle extract had no effect on survival of male or female mice. The mean body weights of the 25,000 ppm groups were less than those of controls after week 25; mean body weights of 50,000 ppm groups were less than those of controls after week 12. Feed consumption by exposed groups of males and females was generally similar to that by the controls throughout the study. Significantly decreased incidences of hepatocellular adenoma and hepatocellular carcinoma occurred in 50,000 ppm males, and decreased incidences of hepatocellular adenoma or carcinoma (combined) occurred in 25,000 and 50,000 ppm males. GENETIC TOXICOLOGY: Five milk thistle extracts were tested independently in bacterial mutagenicity studies using a variety of S. typhimurium tester strains and one E. coli strain. Results were negative in three of the five studies, with and without exogenous metabolic activation. In two studies, milk thistle extract was mutagenic in S. typhimurium strain TA98 in the presence of exogenous metabolic activation enzymes. Silymarin, a major constituent of milk thistle extract, was positive in S. typhimurium strains TA98 and TA100, when testing occurred in the presence of exogenous metabolic activation enzymes. Silybin, another component of milk thistle extract, was negative in a S. typhimurium gene mutation assay, with and without liver S9 activation enzymes. Administration of milk thistle extract in feed for 3 months did not increase the frequencies of micronucleated normochromatic erythrocytes, an indication of chromosomal abnormalities, in the peripheral blood of male or female B6C3F1 mice. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of milk thistle extract in male or female F344/N rats or B6C3F1 mice exposed to 12,500, 25,000, or 50,000 ppm. Exposure to milk thistle extract resulted in increased incidences of clear cell and mixed cell foci in the liver of female rats and decreases in body weights of exposed groups of male and female mice. Decreased incidences of mammary gland neoplasms occurred in exposed groups of female rats, and decreased incidences of hepatocellular neoplasms occurred in exposed groups of male mice. PMID- 21685955 TI - T-bet in disease. AB - The activation of immune-defense mechanisms in response to a microbial attack must be robust and appropriately tailored to fight particular types of pathogens. Infection with intracellular microorganisms elicits a type 1 inflammatory response characterized by mobilization of T helper type 1 (T(H)1) cells to the site of infection, where they are responsible for the recruitment and activation of macrophages. At the center of the type 1 inflammatory response is the transcription factor T-bet, a critical regulator of the T(H)1 differentiation program. T-bet induces the production of interferon-gamma (IFN-gamma) and orchestrates the T(H)1 cell-migratory program by regulating the expression of chemokines and chemokine receptors. However, tight regulation of the type 1 inflammatory response is essential for the prevention of immunopathology and the development of organ-specific autoimmunity. In this review, we discuss how T-bet expression drives autoaggressive and inflammatory processes and how its function in vivo must be delicately balanced to avoid disease. PMID- 21685960 TI - High-concentration Er:YAG single-crystal fibers grown by laser-heated pedestal growth technique. AB - High-concentration Er:YAG single-crystal fibers have been grown using the laser heated pedestal growth technique. Instability in the melt and concomitant opacity of fibers were observed at source concentrations higher than 15 mol.%. Spectroscopic examination shows that broadening of the linewidth of the 4I(13/2) > 4I(15/2) transition is strongly dependent on Er3+ concentration. PMID- 21685961 TI - Group velocity manipulation in active fibers using mutually modulated cross-gain modulation: from ultraslow to superluminal propagation. AB - We propose and experimentally demonstrate the propagation of slow/fast light in an erbium-doped fiber (EDF) using mutually modulated cross-gain modulation. The group velocity of the light signal can be manipulated by the effect of gain cross saturation modulation by a saturating light at an arbitrary wavelength in the gain bandwidth of the EDF. The ultraslow propagation with a small group velocity of 5.6 * 10-3c (c is the light speed in free space) and superluminal propagation with a negative group velocity of -1.1 * 10-3c has been observed under different modulation phases. PMID- 21685962 TI - Modulation-free optical locking of an external-cavity diode laser to a filter cavity. AB - Optical locking to a filter cavity is an effective method to eliminate the limitations of an external-cavity diode laser, such as broad spontaneous emission backgrounds and frequency jitters. Stable operation of the optical locking requires simultaneous control of the feedback phase and the diode-laser frequency. Frequency dither is usually used to extract the two error signals, but this causes extra frequency modulation in the output beam. A modulation-free method for deriving the error signals by modulating the laser-cavity coupling strength is demonstrated with a violet diode laser. A modulation-free linewidth upper limit of about 7 kHz for a 1 s measurement is realized by the method. PMID- 21685963 TI - Actively mode-locked fiber laser using a deformable micromirror. AB - We present what we believe to be the first fiber laser system that is actively mode-locked by a deformable micromirror. The micromirror device is placed within the laser cavity and performs a dual function of modulator and end-cavity mirror. The mode-locked laser provides ~1-ns-long pulses with 20 nJ/pulse energy at 5 MHz repetition rates. PMID- 21685964 TI - Depth from structured defocus that is independent of the object reflectivity function. AB - Depth from defocus using structured light is a useful optical metrology technique since the camera and projector can be placed on the same optical axis and it can cope with depth discontinuities. However, the technique can suffer from large errors when used on surfaces with differing reflective properties. This paper demonstrates a method for overcoming this problem. PMID- 21685965 TI - Fiber refractometer based on a fiber Bragg grating and single-mode-multimode single-mode fiber structure. AB - A refractive index (RI) sensor based on a novel fiber structure that consists of a single-mode-multimode-single-mode (SMS) fiber structure followed by a fiber Bragg grating was demonstrated. The multimode fiber in the SMS structure excites cladding modes within output single-mode fiber (SMF) and recouple the reflected cladding Bragg wavelength to the input SMF core. By measuring the relative Bragg wavelength shift between core and cladding Bragg wavelengths, the RI can be determined. Experimentally we have achieved a maximum sensitivity of 7.33 nm/RIU (RI unit) at RI range from 1.324 to 1.439. PMID- 21685966 TI - Multifocus with small size, uniform intensity, and nearly circular symmetry. AB - We investigate in detail the focusing properties of the composite vector beam (CVB) composed of two orthogonally linearly polarized beams with inhomogeneous polarization modulation. By optimizing the modulation factor, a multifocus with excellent quality is obtained, where the sizes of each focus are fairly smaller than that of the focusing spot of a radially polarized beam, the uniformity in the intensity of the focal spots is as high as 1, and the distributions of each focal spot have nearly circular symmetry. In order to decrease the power loss of the incident beam, the CVB formed by an annular beam is demonstrated as the substitute for the optimized CVB formed by a Gaussian beam. This work is important for high-resolution and high-speed imaging in biology and micro nanofabrication. PMID- 21685967 TI - High quality factor nitride-based optical cavities: microdisks with embedded GaN/Al(Ga)N quantum dots. AB - We compare the quality factor values of the whispering gallery modes of microdisks (MU-disks) incorporating GaN quantum dots (QDs) grown on AlN and AlGaN barriers by performing room temperature photoluminescence (PL) spectroscopy. The PL measurements show a large number of high Q factor resonant modes on the whole spectrum, which allows us to identify the different radial mode families and to compare them with simulations. We report a considerable improvement of the Q factor, which reflects the etching quality and the relatively low cavity loss by inserting QDs into the cavity. GaN/AlN QDs-based MU-disks show very high Q values (Q>7000) whereas the Q factor is only up to 2000 in MU-disks embedding QDs grown on the AlGaN barrier layer. We attribute this difference to the lower absorption below bandgap for AlN barrier layers at the energies of our experimental investigation. PMID- 21685968 TI - Analytical properties of the plasmon decay profile in a periodic metal nanoparticle chain. AB - We show that the spatial decay of plasmons in a periodic metal-nanoparticle chain is composed of exponential and power-law decays. Our results show a high level of similarity between the absorptive and radiative decay channels. By analyzing the poles (and the corresponding residues) of the generating function for the lattice Green's function, we explain the details of the spatial decay profile. We also present an analytical formula for the decay profile. PMID- 21685969 TI - X-ray spatial harmonic imaging of phase objects. AB - Refractive index gradients in materials or at material interfaces lead to x-ray diffraction. Interference of this radiation with adjacent x-ray waves causes phase contrast that can be used for imaging purposes if an x-ray source with sufficient spatial coherence is used. The imaging modality presented here uses hard x radiation diffracted at interfaces, but requires only little spatial coherence. We report experiments showing, first, that image contrast is not diminished by motional blurring, and second, that contrast can be increased by orders of magnitude relative to in-line x-ray phase-contrast imaging. These properties substantially broaden the applicability of phase-sensitive imaging to moving samples and very weak density gradients. PMID- 21685970 TI - Distinguishing fingerprints of hyperchaotic and stochastic dynamics in optical chaos from a delayed opto-electronic oscillator. AB - In the dynamics of optical systems, one commonly needs to cope with the problem of coexisting deterministic and stochastic components. The separation of these components is an important, although difficult, task. Often the time scales at which determinism and noise dominate the system's dynamics differ. In this Letter we propose to use information-theory-derived quantifiers, more precisely, permutation entropy and statistical complexity, to distinguish between the two behaviors. Based on experiments of a paradigmatic opto-electronic oscillator, we demonstrate that the time scales at which deterministic or noisy behavior dominate can be identified. Supporting numerical simulations prove the accuracy of this identification. PMID- 21685971 TI - Analysis of the principal component algorithm in phase-shifting interferometry. AB - We recently presented a new asynchronous demodulation method for phase-sampling interferometry. The method is based in the principal component analysis (PCA) technique. In the former work, the PCA method was derived heuristically. In this work, we present an in-depth analysis of the PCA demodulation method. PMID- 21685972 TI - Strong coupling of localized and surface plasmons to microcavity modes. AB - We strongly couple surface plasmon modes on a thin metal layer via localized plasmons of nanowires to photonic microcavity modes. In particular, we place an array of nanowires close to a mirror and position a second mirror at Bragg distance. The coupling becomes evident from an anticrossing of the resonances in the dispersion diagram. We experimentally determine the dispersion by applying external pressure to the microcavity and find excellent agreement with simulations. PMID- 21685974 TI - Energy transport in a metamaterial subwavelength open-cavity resonator. AB - We present a theoretical and experimental investigation into the energy transport in a conjugate matched bilayer consisting of epsilon-negative (ENG) and MU negative (MNG) slabs. It is proved that the conjugated matched ENG/MNG bilayer is a subwavelength open-cavity resonator, in which the resonance frequency is determined by the complete tunneling condition, and the Q factor increases exponentially with the slab thickness. It is revealed that the wave is not evanescent inside the bilayer, but it is a hybrid of a traveling wave and a reactive standing wave. It is also manifested during the transient wave propagation that the reactive field energy stored inside the bilayer is provided by the incident wave. PMID- 21685973 TI - Cellular resolution optical coherence microscopy with high acquisition speed for in-vivo human skin volumetric imaging. AB - In this Letter, we report for the first time (to our knowledge) in-vivo volumetric optical coherence microscopy images of skin epidermal cells. We achieved micrometer-class resolution, 2 MUm laterally and axially, with an acquisition speed of 23 K A-scans/s and over 90 dB sensitivity to a depth of 1 mm by employing a custom, liquid-lens-based, dynamic-focusing objective, a broadband light source, and a custom, astigmatism-corrected Czerny-Turner spectrometer with a high-speed complementary metal-oxide-semiconductor camera. PMID- 21685975 TI - Framework for three-dimensional coherent diffraction imaging by focused beam x ray Bragg ptychography. AB - We present the framework for convergent beam Bragg ptychography, and, using simulations, we demonstrate that nanocrystals can be ptychographically reconstructed from highly convergent x-ray Bragg diffraction. The ptychographic iterative engine is extended to three dimensions and shown to successfully reconstruct a simulated nanocrystal using overlapping raster scans with a defocused curved beam, the diameter of which matches the crystal size. This object reconstruction strategy can serve as the basis for coherent diffraction imaging experiments at coherent scanning nanoprobe x-ray sources. PMID- 21685976 TI - Demonstration of a mode-conversion cavity add-drop filter. AB - We experimentally demonstrate a new type of add-drop filter incorporating an asymmetric Y-branch waveguide coupler and a shifted-grating mode-conversion cavity. The device relies on mode separation in the asymmetric Y-branch and wavelength-selective mode conversion upon reflection from the shifted-grating cavity. Add-drop functionality is demonstrated in a three-port integrated silicon on-insulator device. PMID- 21685977 TI - High-sensitivity, evanescent field refractometric sensor based on a tapered, multimode fiber interference. AB - We propose and experimentally demonstrate an enhanced evanescent field fiber refractometer based on a tapered multimode fiber sandwiched between two single mode fibers. Experiments show that this fiber sensor offers ultrahigh sensitivity [better than 1900 nm/RIU at a refractive index (RI) of 1.44] for RI measurements within the range of 1.33-1.44, in agreement with the theoretical predictions. This is the highest value reported to date (to our knowledge) in the literature. PMID- 21685978 TI - Quantitative imaging of mixing dynamics in microfluidic droplets using two-photon fluorescence lifetime imaging. AB - Droplet-based microfluidic systems enable miniaturization of chemical reactions in femtoliter to picoliter volume compartments. Quantifying mixing dynamics of the reagents in droplets is critical to determine the system performance. In this Letter, we developed a two-photon excitation fluorescence lifetime imaging technique to quantitatively image the mixing dynamics in microfluidic droplets. A cross/autocorrelation method was used to reconstruct a high-quality fluorescence lifetime image of the droplet. The fluorescence decay was analyzed for accurate determination of the mixing ratio at each pixel of the image. PMID- 21685979 TI - Effect of multiphoton absorption and free carriers in slow-light photonic crystal waveguides. AB - We examine the effects of multiphoton absorption, free carriers, and disorder induced linear scattering in slow-light photonic crystal waveguides. We derive an analytic formulation for self-phase modulation including the group velocity scaling of the nonlinear phase shift in materials limited by three-photon absorption as a representative nonlinear process. We investigate the role of free carriers and derive an approximate critical intensity at which these effects begin to strongly modify the optical field. This critical intensity is employed to determine an optimal group index for the self-phase modulation in the slow light devices. These observations are confirmed with numerical modeling. PMID- 21685980 TI - Highly efficient downconversion white light in Tm3+/Tb3+/Mn2+ tridoped P2O5-Li2O Sb2O3 glass. AB - Tm3+/Tb3+/Mn2+ tridoped phosphate glasses containing different Mn2+ ion concentrations were synthesized to explore new white-light-emitting material. Under 355 nm excitation, the CIE coordinates (x=0.328, y=0.337) of the Mn0.10 sample doped with 0.10 wt. % Mn2+ are close to the standard equal energy white light illumination (x=0.333, y=0.333). The quantum efficiency of the Mn0.01 sample is very high (~72.32%). The concentration of Mn2+ ions has a great effect on the emission color, and the energy transitions from Tm3+, Tb3+ to Mn2+ become more intense with an increase in Mn2+ ion concentrations. The phenomenon is reasonably interpreted based on the analysis of the luminescence lifetime. PMID- 21685981 TI - Contrast enhancement in widefield CARS microscopy by tailored phase matching using a spatial light modulator. AB - We introduce a widefield CARS microscope implementation that uses a spatial light modulator to obtain extremely precise control over the pump/probe-beam incidence geometry, which provides the possibility to enhance the image contrast at specific target resonances by fine-tuning the incidence angles. We show how this technique can be used to optimize the image contrast between objects of different size and to practically eliminate the undesired signal from the solvent that embeds small target specimens. Changing the numerical aperture of the illumination from 1.27 to 1.24 improved the ratio of the signals of 500 nm polystyrene beads and the agarose solvent by about 20 dB. PMID- 21685982 TI - Planar defects in three-dimensional chalcogenide glass photonic crystals. AB - Here we report on the direct laser writing fabrication of Fabry-Perot-type planar microcavities in a three-dimensional (3D) photonic crystal (PhC) embedded within a high-refractive nonlinear chalcogenide glass (ChG) film. The fabricated planar microcavities in a nonlinear ChG 3D PhC facilitate the observation of resonant modes inside the stop gap. The experimental results show that the length of the planar cavity can be well controlled by the fabrication power and thus be used to tune the defect modes. The tunability of the observed defect modes is confirmed by the theoretical prediction. PMID- 21685983 TI - Trapping two types of particles using a focused partially coherent elegant Laguerre-Gaussian beam. AB - The radiation forces on a Rayleigh dielectric sphere induced by a focused partially coherent elegant Laguerre-Gaussian (ELG) beam are investigated by using the Rayleigh scattering theory. It is found that a focused partially coherent ELG beam with suitable mode orders can be used to trap a Rayleigh particle whose refractive index is larger or smaller than that of the ambient by varying its initial spatial coherence width. Therefore, one can use one optical-trap system to trap two types of particles with different refractive indices. PMID- 21685984 TI - Fourier optics analysis of grating sensors with tilt errors. AB - Dynamic diffraction gratings can be microfabricated with precision and offer extremely sensitive displacement measurements and light intensity modulation. The effect of pure translation of the moving part of the grating on diffracted order intensities is well known. This study focuses on the parameters that limit the intensity and the contrast of the interference. The effects of grating duty cycle, mirror reflectivities, sensor tilt and detector size are investigated using Fourier optics theory and Gaussian beam optics. Analytical findings reveal that fringe visibility becomes <0.3 when the optical path variation exceeds half the wavelength within the grating interferometer. The fringe visibility can be compensated by monitoring the interfering portion of the diffracted order light only through detector size reduction in the expense of optical power. Experiments were conducted with a grating interferometer that resulted in an eightfold increase in fringe visibility with reduced detector size, which is in agreement with theory. Findings show that diffraction grating readout principle is not limited to translating sensors but also can be used for sensors with tilt or other deflection modes. PMID- 21685985 TI - Continuous-wave diode-pumped laser action of Nd3+-doped photo-thermo-refractive glass. AB - Laser action of the photo-thermo-refractive (PTR) glass, which is the photosensitive material for holographic recording of volume Bragg gratings (VBGs), was demonstrated for the first time by introducing Nd3+. Nd:PTR glass has a bandwidth of 27.8 nm and 16.0 nm for luminescence and absorption, respectively. An uncoated 2 mm thick Nd:PTR element generated cw laser output of 124 mW, with a slope efficiency of 25%, by laser diode pumping. This Nd:PTR glass also performed wide bandwidth laser action at 1053.9-1063.3 nm, where the decrease of the pump absorption efficiency was held off below 30%, even under a 3.5 nm shift of pump wavelength from its absorption center. PMID- 21685986 TI - Three-dimensional coordinate measurements using a multiple-pinhole interferometer. AB - We propose a method for noncontact measurements of three-dimensional (3D) coordinates based on a Y-typed multiple-pinhole (MP) interferometer and demonstrate its feasibility in experiments. In this method, a Y-typed MP plate is inserted between the target and an image sensor to form a common-path interferometer. The 3D coordinates of the target are found by an effective algorithm using the discrete phase values on the measurement pinholes of the MP plate. These phase values can be directly extracted from a Fourier transform of the recorded intensity pattern without need of any iterative or phase-shifting algorithm. The method could be significant in real-time coordinate measurements and position tracking applications. PMID- 21685987 TI - Enhanced bandgap in annular photonic-crystal silicon-on-insulator asymmetric slabs. AB - Photonic band structures of annular photonic-crystal (APC) silicon-on-insulator (SOI) asymmetric slabs with finite thickness were investigated by the three dimensional plane-wave expansion method. The results show that for a broad range of air-volume filling factors, APC slabs can exhibit a significantly larger bandgap than conventional circular-hole photonic-crystal (PC) slabs. Bandgap enhancements over conventional air hole PC SOI slabs as large as twofold are predicted for low air-volume filling factors below 15%. This desirable behavior suggests a potential for APC SOI slabs to serve as the basis of various optical cavities, waveguides, and mirrors. PMID- 21685988 TI - Optical surface Bloch modes of complete photonic bandgap materials as a basis of optical sensing. AB - Surface Bloch modes induced on three-dimensional dielectric photonic crystals with a complete photonic bandgap are evanescently decaying states at surfaces and have large field overlap with low-index media, resulting in narrow spectrum linewidth and simultaneously a large resonance shift due to a perturbation of the refractive index in the background media. Surface Bloch resonance states are analyzed for (001), (100), and (110) woodpile surface planes. Low-loss, high sensitivity surface Bloch modes are also analyzed on a flat-top (001) woodpile planar surface. These analyzed surface Bloch modes are confined in a subwavelength scale and are expected to form a basis set used for optical resonance sensing. PMID- 21685989 TI - Accurate and efficient Monte Carlo solutions to the radiative transport equation in the spatial frequency domain. AB - We present an approach to solving the radiative transport equation (RTE) for layered media in the spatial frequency domain (SFD) using Monte Carlo (MC) simulations. This is done by obtaining a complex photon weight from analysis of the Fourier transform of the RTE. We also develop a modified shortcut method that enables a single MC simulation to efficiently provide RTE solutions in the SFD for any number of spatial frequencies. We provide comparisons between the modified shortcut method and conventional discrete transform methods for SFD reflectance. Further results for oblique illumination illustrate the potential diagnostic utility of the SFD phase-shifts for analysis of layered media. PMID- 21685990 TI - Examining surface and bulk structures using combined nonlinear vibrational spectroscopies. AB - We combined sum-frequency generation (SFG) vibrational spectroscopy with coherent anti-Stokes Raman scattering (CARS) spectroscopy in one system to examine both surface and bulk structures of materials with the same geometry and without the need to move the sample. Poly(methyl methacrylate) (PMMA) and polystyrene (PS) thin films were tested before and after plasma treatment. The sensitivities of SFG and CARS were tested by varying polymer film thickness and using a lipid monolayer. PMID- 21685991 TI - Mid-IR frequency comb source spanning 4.4-5.4 MUm based on subharmonic GaAs optical parametric oscillator. AB - Broadband mid-IR output suitable for producing 1000-nm-wide frequency combs centered at 4.9 MUm was achieved in a degenerate subharmonic optical parametric oscillator (OPO) based on 500-MUm-long Brewster-angled orientation-patterned GaAs crystal. The OPO was synchronously pumped at 182 MHz repetition rate by 100 fs pulses from a Cr2+:ZnSe laser with the central wavelength of 2.45 MUm and the average power of 100 mW. PMID- 21685992 TI - Plasmonic rod dimers as elementary planar chiral meta-atoms. AB - We theoretically calculate the electromagnetic response of metallic rod dimers for the arbitrary planar arrangement of rods in the dimer. It is shown that dimers without an in-plane symmetry axis exhibit elliptical dichroism and act as "atoms" in planar chiral metamaterials. Because of a very simple geometry of the rod dimer, such planar metamaterials are much easier to fabricate than conventional split-ring or gammadion-type structures and lend themselves to a simple analytical treatment based on a coupled dipole model. Dependencies of the metamaterial's directional asymmetry on the dimer's geometry are established analytically and confirmed in numerical simulations. PMID- 21685993 TI - Measuring the scattering parameters of tissues from quantitative phase imaging of thin slices. AB - We employed the scattering-phase theorem recently derived in our laboratory to extract tissue scattering properties from quantitative phase images. Using tissue path-length maps that contain nanoscale information about the tissue, the scattering mean free path l(s) and anisotropy factor g were measured in a spatially resolved manner. PMID- 21685994 TI - Experimental verification of coherent diffractive imaging by a direct phase retrieval method with an aperture-array filter. AB - Recently, we have proposed a coherent diffractive imaging using a noniterative phase retrieval method with the filter of an aperture array. The first (to our knowledge) experimental demonstration of this coherent imaging is presented here, in which a complex-valued object illuminated by a diode laser is reconstructed from the isolated diffraction intensities of the object's wave field, transmitted through an array filter of square apertures by using the phase retrieval method. This imaging method requires only a single measurement of the diffraction intensity and does not need a tight object's support constraint utilized in iterative phase retrieval algorithms or a reference wave used in holographic techniques. PMID- 21685995 TI - Generation of orthogonal codes with chaotic optical systems. AB - We propose to use an electro-optic oscillator based on two Mach-Zehnder modulators in two different delayed feedback loops to generate two orthogonal chaotic spreading sequences (codes). We numerically demonstrate, for such codes, spectrally efficient multiplexing and demultiplexing of two digital data streams at multi-Gb/s rates using chaos synchronization and covariance-based detection. PMID- 21685996 TI - Generation of near-infrared frequency combs from a MgF2 whispering gallery mode resonator. AB - We report on generation of a 20 nm wide, 35 GHz repetition rate optical frequency comb in a magnesium fluoride whispering gallery mode resonator pumped with 2 mW of 1543 nm light. The high efficiency of comb generation is associated with the small anomalous group velocity dispersion of the resonator. Growth dynamics of the comb is studied and compared with earlier theoretical predictions. PMID- 21685997 TI - Kilowatt-peak-power, single-frequency, pulsed fiber laser near 2 MUm. AB - We generated single-frequency pulses at kilowatt peak power from an all-fiber Tm doped master oscillator power amplifier system, which is the first report of this kind (to the best of our knowledge) of a laser in the 2 MUm region. Compared with the laser linewidth of seed pulses, spectral broadening by a factor of 3 was observed with the amplified pulses. This was attributed to self-phase modulation in passive pigtail fibers of the components (isolator and wavelength division multiplexing) that were placed after the fiber amplifier. The short pulse width (~7 ns) of the kilowatt-level pulses prevents an onset of stimulated Brillouin scattering in the long fiber. When launching the pulses into several-meter single mode fiber, significant nonlinear spectral broadening occurs due to modulation instability in the fiber. This reaction is beneficial for generation of a mid- and long-wavelength IR supercontinuum in nonlinear IR fibers. PMID- 21685998 TI - Few-cycle attosecond pulses via periodic resonance interaction with hydrogenlike atoms. AB - We show that it is possible to produce nearly bandwidth-limited few-cycle attosecond pulses based on periodic resonance interaction of a quasi monochromatic radiation with the bound states of hydrogenlike atoms. A periodic resonance is provided by a far-off-resonant laser field with intensity much below the atomic ionization threshold via periodic tunnel ionization from the excited states and adiabatic Stark splitting of the excited energy levels. Without external synchronization of the spectral components, it is possible to produce 135 as pulses at 13.5 nm in Li2+-plasma controlled by radiation of a mode-locked Nd:YAG laser, as well as 1.25 fs pulses at 122 nm in atomic hydrogen controlled by radiation of a CO2 laser. PMID- 21685999 TI - 1.6-W self-referenced frequency comb at 2.06 MUm using a Ho:YLF multipass amplifier. AB - A high-power optical frequency comb at 2.06 MUm has been generated using a Ho:YLF multipass amplifier seeded by the long wavelength supercontinuum tail of an octave-spanning Er:fiber comb source. The Ho:YLF amplifier showed a net gain larger than 30 dB from 2048 to 2068 nm, allowing the generation of a 20 nm bandwidth comb with a mode spacing of 100 MHz and a power per mode ranging from 20 to 370 MUW. In the time domain, the amplified comb corresponds to a pulse train with 1.6 W total power and 508 fs transform-limited pulse duration. Using a self-referencing f-2f interferometer and a phase-locking loop, spectral narrowing of the offset frequency down to less than 17 Hz has been achieved. PMID- 21686000 TI - Addressable microlens array for parallel laser microfabrication. AB - Parallel processing in femtosecond-laser-based microfabrication is demonstrated using a microlens array in conjunction with a liquid-crystal spatial light modulator (SLM). A portion of the SLM is mapped onto each individual lenslet in the array and can be used to effectively switch foci on and off for fabrication. In addition, the technique allows for homogenizing the intensity of the array of foci and translating spots relative to their natural focus. The technique demonstrates the potential for high efficiency processing of aperiodic structures. PMID- 21686001 TI - Comb filter with independently tunable wavelength spacing and bandwidth using cascaded variable differential group delay elements. AB - An all-optical comb filter with independently tunable wavelength spacing and bandwidth (BW) is proposed. Using three cascaded variable differential-group delay elements, we demonstrate theoretically and experimentally the tunability of the comb filter with >10 dB sidelobe reduction by adjusting three elements. The wavelength spacing is determined by the first filter module, while the sidelobe suppression ratio and the BW are defined by the middle and the last one, respectively. PMID- 21686003 TI - Label-free flow cytometry using multiplex coherent anti-Stokes Raman scattering (MCARS) for the analysis of biological specimens. AB - We present the first demonstration, to our knowledge, of a label-free flow cytometer for the analysis of biological specimens using multiplex coherent anti Stokes Raman scattering (MCARS) and elastic scatter measurements. The MCARS system probes the Raman vibrational energy levels and the elastic scatter provides morphological information. We demonstrate these capabilities by probing a culture of Saccharomyces cerevisiae at 100 spectra/s and constructing a background-free Raman reconstruction using a Kramers-Kronig relation. A theoretical analysis shows that this system could operate at speeds of 10 kHz with appropriate hardware; thus facilitating integration into commercial flow cytometers or use as a high-speed, stand-alone device. PMID- 21686004 TI - Hybrid plasmonic waveguide with gain medium for lossless propagation with nanoscale confinement. AB - In this Letter, we propose a hybrid plasmonic nanosystem consisting of a silver cladding layer with a semicylinder bump on top of InGaAsP nanowire. Because of the coupling between the dielectric waveguide mode and surface plasmon polariton mode, the hybrid plasmonic mode can exhibit low loss with strong field localization. The finite element method numerical simulations are employed to evaluate the performances of the hybrid mode. In order to achieve the lossless propagation of the hybrid mode with the mode area of 0.0058(lambda2/4) at 1.55 MUm, the material gain of 200 nm * 300 nm InGaAsP nanowire should reach 1223 cm 1. PMID- 21686005 TI - Compression of fiber supercontinuum pulses to the Fourier-limit in a high numerical-aperture focus. AB - A multiphoton intrapulse interference phase scan (MIIPS) adaptively and automatically compensates the combined phase distortion from a fiber supercontinuum source, a spatial light modulator pulse shaper, and a high-NA microscope objective, allowing Fourier-transform-limited compression of the supercontinuum pulses at the focus of the objective. A second-harmonic-generation based method is employed to independently validate the transform-limited compression. The compressed pulses at the focus of the objective have a tunable duration of 10.8-38.9 fs (FWHM), a central wavelength of ~1020 nm, an average power of 18-70 mW, and a repetition rate of 76 MHz, permitting the application of this source to nonlinear optical microscopy and coherently controlled microspectroscopy. PMID- 21686006 TI - Demodulation of a single-image interferogram using a Zernike-polynomial-based phase-fitting technique with a differential evolution algorithm. AB - We propose a simple and robust polynomial-based phase-fitting (PPF) technique for single interferogram demodulation. Based on the smoothness assumption, the method employs a set of Zernike polynomials (ZPs) to fit the phase and estimates the expansion coefficients using a global optimization algorithm, i.e., differential evolution. The fitting order of the ZPs and the bounds of the coefficients can be intuitively determined according to the shape and number of fringes of the interferogram. Different from classical methods that need predefined scanning paths to guide the phase estimator, the PPF demodulates an interferogram globally and is insensitive to local defects, which allows it to deal with very noisy interferograms. Moreover, as the PPF gives the reconstructed phase by use of the ZPs, no further phase-unwrapping or wavefront-fitting procedures are needed. Experimental results have demonstrated the robustness and effectiveness of the method. PMID- 21686007 TI - Generalized fiber Fourier optics. AB - A twofold generalization of the optical schemes that perform the discrete Fourier transform (DFT) is given: new passive planar architectures are presented where the 2 * 2 3 dB couplers are replaced by M * M hybrids, reducing the number of required connections and phase shifters. Furthermore, the planar implementation of the discrete fractional Fourier transform (DFrFT) is also described, with a waveguide grating router (WGR) configuration and a properly modified slab coupler. PMID- 21686008 TI - Imprinted bidirectional waveguide platform for large-core optical transceiver. AB - We introduce a new configuration for large-core optical transceiver platforms based on asymmetric three-dimensional multimode Y junctions. We developed a simply structured bidirectional waveguide platform without using a wavelength division multiplexing filter or angled mirror. This structure was designed with two different size waveguides by using the three-dimensional ray-tracing method. This structure transmitted nearly 100% power in each direction, upstream and downstream. This simple and cost-effective structure was fabricated by the imprint process using a metallic master fabricated by an ultraprecision machining method. The experimental results show that this structure is suitable for bidirectional communications in large-core optical transceivers at 155 Mbits/s. PMID- 21686009 TI - Nonunity permeability in metamaterial-based GaInAsP/InP multimode interferometers. AB - We demonstrated an InP-based optical multimode interferometer (MMI) combined with metamaterials consisting of minute split-ring resonators (SRRs) arrayed on the MMI. The MMI could operate at an optical fiber communication wavelength of 1.5 MUm. Magnetic resonance occurred between the SRR metamaterial and light at 1.5 MUm, and the relative permeability of the metamaterial increased to 2.4 around this wavelength. This result shows that it is possible to use new materials with nonunity permeability to construct semiconductor-based photonic devices. PMID- 21686010 TI - Differential matrix formalism for depolarizing anisotropic media. AB - Azzam's differential matrix formalism [J. Opt. Soc. Am. 68, 1756 (1978)], originally developed for longitudinally inhomogeneous anisotropic nondepolarizing media, is extended to include depolarizing media. The generalization is physically interpreted in terms of means and uncertainties of the elementary optical properties of the medium, as well as of three anisotropy absorption parameters introduced to describe the depolarization. The formalism results in a particularly simple mathematical procedure for the retrieval of the elementary properties of a generally depolarizing anisotropic medium, assumed to be globally homogeneous, from its experimental Mueller matrix. The approach is illustrated on literature data and the conditions of its validity are identified and discussed. PMID- 21686011 TI - Angularly separated harmonic generation from intense laser interaction with blazed diffraction gratings. AB - We made numerical simulations of the generation of narrowband beams of extreme ultraviolet radiation from intense laser interaction with a blazed grating surface. Strong fifth harmonic emission into its blazed diffraction order was observed as well as heavy suppression of the fundamental frequency with comparison to a typical harmonic spectrum from a flat target. The results demonstrate a new highly efficient method of generating near-monochromatic harmonics from the fundamental with minimal effect on the pulse duration. PMID- 21686012 TI - Femtosecond filamentation in argon and higher-order nonlinearities. AB - We numerically investigate the femtosecond filamentation dynamics in argon by considering the higher-order nonlinearities measured by a recent experiment. Our result indicates that, instead of plasma, these higher-order nonlinearities can provide main defocusing effect as shown by a recent theoretical work. However, when the higher-order nonlinearity is so strong to provide a main defocusing effect, some phenomena inconsistent with previous experiments such as pulse splitting and pulse self-compression can appear. Therefore, we infer that the values of higher-order nonlinear coefficients are overestimated, and the plasma should be the defocusing mechanism at least in the argon filament. PMID- 21686013 TI - Subwavelength localization of near fields in coupled metallic spheres for single emitter polarization analysis. AB - We numerically demonstrate selective near-field localization determined by the polarization state of a single emitter coupled to a plasmonic nanocluster. Seven gold nanospheres are carefully arranged such that up to 10 polarization states of the single emitter, including linear, circular, and elliptical polarizations, can be distinguished via the distinct field localization in four gaps. The ability to transform polarization states into field spatial localizations may find application in single emitter polarization analysis. PMID- 21686014 TI - Characterization of vector diffraction-free beams. AB - It is observed that a constant unit vector denoted by I is needed to characterize a complete orthonormal set of vector diffraction-free beams. The previously found diffraction-free beams are shown to be included as special cases. The I dependence of the longitudinal component of diffraction-free beams is also discussed. PMID- 21686015 TI - Spectral narrowing and manipulation in an optical parametric oscillator using periodically poled lithium niobate electro-optic polarization-mode converters. AB - We report a unique spectral narrowing and manipulation technique in an optical parametric oscillator (OPO) realized by an integrated periodically poled lithium niobate comprising an optical parametric gain medium sandwiched by two electro optic polarization-mode converters (EO PMCs). We achieved a manipulation of the gain spectrum of the OPO via EO and/or temperature control of the EO PMCs, in which we obtained single to multiple signal spectral peaks from the OPO with a spectral width reduced by up to 10 times and peak intensity increased by up to 6 times in comparison with the original signal. Fast EO tuning of the narrowed signal spectral peak has also been demonstrated. PMID- 21686016 TI - Surface-mediated four-wave mixing of nanostructures with counterpropagating surface plasmon polaritons. AB - We demonstrate that four-wave mixing (FWM) signals from individual Si nanoparticles can be generated by the surface fields of traveling surface plasmon polariton modes. We have chosen a counterpropagating excitation scheme in which the nanoparticle is exposed only to surface excitation fields and not to direct laser illumination. We show that background-free, surface-mediated FWM of nanoparticles can be acquired, and that the resulting nonlinear radiation is coherent. PMID- 21686017 TI - Cascaded Raman shifting of high-peak-power nanosecond pulses in As2S3 and As2Se3 optical fibers. AB - We report efficient cascaded Raman scattering of near-IR nanosecond pulses in large-core (65 MUm diameter) As2S3 and As2Se3 optical fibers. Raman scattering dominates other spectral broadening mechanisms, such as four-wave mixing, modulation instability, and soliton dynamics, because the fibers have large normal group-velocity dispersion in the spectral range of interest. With ~2 ns pump pulses at a wavelength of 1.9 MUm, four Stokes peaks, all with peak powers greater than 1 kW, have been measured. PMID- 21686018 TI - Nanostructured gradient-index antireflection diffractive optics. AB - We describe the fabrication and characterization of a nanostructured diffractive element with near-zero reflection losses. In this element, subwavelength nanostructures emulating adiabatic index matching are integrated on the surface of a diffractive microstructure to suppress reflected diffraction orders. The fabricated silicon grating exhibits reflected efficiencies that are suppressed by 2 orders of magnitude over broad wavelength bands and wide incident angles. Theoretical models of the fabricated structure based on rigorous coupled-wave analysis and effective medium theory are in agreement with the experimental data. The proposed principles can be applied to improve the performance of any diffractive structures, potentially leading to more efficient Fresnel lenses, holographic elements, and integrated optical systems. PMID- 21686019 TI - Interferometry using binary holograms without high order diffraction effects. AB - We describe a technique for a phase-stepping interferometer based on programmable binary phase holograms, particularly useful for optical testing of aspheric or free-form surfaces. It is well-known that binary holograms can be used to generate reference surfaces for interferometry, but a major problem is that cross talk from higher diffraction orders and aliasing can reduce the fidelity of the system. Here, we propose a new encoding technique which improves the accuracy of the technique and demonstrate its implementation using a binary liquid crystal spatial light modulator. PMID- 21686020 TI - Suspended-core fiber Bragg grating sensor for directional-dependent transverse stress monitoring. AB - This Letter presents simulation and experimental results of orientation-dependent transverse stress fiber sensors using fiber Bragg gratings (FBGs) inscribed in four-hole suspended-core fibers. Resonant peak shifts and splitting of FBGs were studied as functions of the applied transverse load and fiber orientation. Both simulation and experimental results revealed that the response of FBGs in suspended-core fibers is sensitive to both the orientation and magnitude of an applied transverse stress. PMID- 21686021 TI - Power-efficient impulse radio ultrawideband pulse generator based on the linear sum of modified doublet pulses. AB - We propose a new and power-efficient impulse radio ultawideband (IR-UWB) pulse design concept. The proposed concept is based on a linear sum of modified doublet pulses. The proposed concept is both simulated and experimentally demonstrated. The experimental demonstration employs a photonic scheme that generates the designed pulse using two main steps, mainly optical shaping and differential detection. The optical shaping is performed using a single electro-optic modulator biased in the nonlinear portion of its transfer function, and the differential detection is performed using a balanced photodetector. The generated IR-UWB pulse is fully Federal Communications Commission compliant, even in the highly power-restricted global positioning system band. The proposed optical scheme has potential to be integrated on a compact optical chip and thus suitable for reliable, low-cost, high-speed, short-range UWB wireless access, such as in building networks. PMID- 21686022 TI - Investigation and suppression of the pump-to-Stokes relative intensity noise transfer in chalcogenide waveguide Raman laser. AB - The characteristic of pump-to-Stokes relative intensity noise (RIN) transfer is comprehensively investigated for integrated As2Se3 waveguide Raman laser (As2Se3 WRL). It is found that, compared to its silicon counterpart, the RIN transfer is 5 dB lower across all frequencies for As2Se3-WRL, mainly due to its relatively smaller Raman gain coefficient. A bidirectional pumping scheme is proposed and verified as an effective configuration to suppress RIN transfer because doubling of the inverse round trip time eliminates the RIN transfer peak at the odd multiples of the resonance frequency. The optimization of waveguide length on RIN transfer is also performed, in which two distinct regions are identified due to different dominant physical processes. In addition, we show that RIN transfer in As2Se3-WRL can be further reduced by using a high cavity for both pump and Stokes waves. PMID- 21686023 TI - Controlling magnetic dipole transition with magnetic plasmonic structures. AB - A plasmonic structure with double gold patches is proposed for enhancing the spontaneous emission of a magnetic dipole transition through a magnetic hot area. A Purcell factor of nearly 2000 can be obtained at optical frequencies together with a low sensitivity in spatial and spectral mismatches between the light emitter and the resonance mode. The associated resonance can be tuned from the visible to the IR frequencies, enabling efficient control of forbidden transitions using plasmonic structures. PMID- 21686024 TI - High sensitivity third-order autocorrelation measurement by intensity modulation and third harmonic detection. AB - We demonstrate a novel (to our knowledge) method for high sensitivity measurement of pulsed light at the telecommunication wavelength of 1558 nm using a GaAsP photomultiplier tube. By modulating the input power and analyzing the harmonic components, high sensitivity third-order autocorrelation is obtained in the wavelength and power regimes where a mixture of two-photon absorption and three photon absorption in the photomultiplier tube is present. PMID- 21686025 TI - Spectral control in anisotropic resonance-domain metamaterials. AB - We introduce a concept to control the spectral and dichroic properties of metamaterials. The approach is based on anisotropic metal nanoparticles and on varying their mutual orientation in a periodic lattice. Even seemingly inconsequential changes in particle ordering strongly modify the dichroic properties of the arrays and result in either very narrow resonances or ultrabroad extinction ranges. The results arise from long-range diffractive coupling between the particles, as determined by the dependence of the array unit cell size on particle ordering. PMID- 21686026 TI - Observation of stimulated Brillouin scattering in polymer optical fiber with pump probe technique. AB - Stimulated Brillouin scattering (SBS) in a perfluorinated graded-index polymer optical fiber (POF) with 120 MUm core diameter was experimentally observed for the first time, to the best of our knowledge, at 1.55 MUm wavelength with the pump-probe technique. Compared to spontaneous Brillouin scattering previously reported, the Brillouin gain spectrum (BGS) was detected with an extremely high signal-to-noise ratio, even with a short POF (1 m) and scrambled polarization state. We also investigated the BGS dependences on probe power and temperature, which indicate that SBS in a POF measured with this technique can be utilized to develop high-accuracy temperature sensing systems. PMID- 21686027 TI - Subwavelength terahertz spin-flip laser based on a magnetic point-contact array. AB - We present a theoretical design for a single-mode, truly subwavelength terahertz disk laser based on a nanocomposite gain medium comprising an array of normal metal/ferromagnetic (FM) point contacts embedded in a thin dielectric layer. Stimulated emission of light occurs due to spin-flip relaxation of spin-polarized electrons injected from the FM side of the contacts. Ultrahigh electrical current densities in the contacts and a dielectric material with a large refractive index, neither condition being achievable in conventional semiconductor media, enables the thresholds of lasing to be overcome for the lowest-order modes of the disk, making single-mode operation possible. PMID- 21686028 TI - Polychlorinated Biphenyl (PCB) carcinogenicity with special emphasis on airborne PCBs. AB - Polychlorinated biphenyls (PCBs) are industrial chemicals used in various applications requiring chemical stabilityand have now become widely dispersed. Their characteristics of persistence, low water/higher lipid solubility, contribute to their ability to bioconcentrate and bioaccumulate. Traditionally PCBs have been regulated as food contaminants and the general population is primarily exposed by that route. PCBs in foodstuffs are generally higher chlorinated, resistant to metabolic breakdown, and elicit toxic changes that are thought to be predominantly receptor/parent PCB-driven. But for certain occupational exposures, and for those persons residing or working in contaminated buildings, and in large cities, an inhalation route of exposure may predominate. Airborne PCBs are, in contrast to foodborne PCBs, lower chlorinated, more volatile, and subject to metabolic attack. In this review, we have explored (geno ) toxic manifestations of PCBs typical of those found in air. Here metabolic conversion of the parent PCB to hydroxylated and other metabolic progeny appear to play a dominant role, especially in genotoxicity. We should be cognizant of the impact of exposures to airborne PCBs for those individuals who are occupationally exposed, for persons living near contaminated sites, for those who work or go to school in contaminated buildings, and especially cognizant of the young, the socio-economically disadvantaged and medically-underserved or nutritionally-deficient populations. PMID- 21686029 TI - Majority Rules? The Effects of School Ethnic Composition on Substance Use by Mexican Heritage Adolescents. AB - This article examines key aspects of the school environment - its composition by ethnicity and acculturation - as important social contexts for understanding Mexican immigrant and Mexican American adolescents' drug use norms and behaviors. Results are presented based on surveys completed by Mexican-background students from 35 Phoenix. Arizona middle schools, whose enrollment ranged from a numerical minority to an overwhelming majority. Multivariate mixed models tested for the influence of school ethnic composition measures on substance use outcomes, while accounting for individual level predictors and for the nesting of data at the school level. The proportional representation of Latinos in the school was not a factor in an individual's drug use norms or drug use for the sample overall. Once students were broken down by acculturation status, however, ethnic composition had an effect. Less acculturated Mexican heritage students in schools with higher proportions of Latino students reported less substance use and less adherence to pro-drug norms. Further investigation using other measures of ethnic composition suggested that these effects were attributable to the larger presence of less acculturated Latinos in the school rather than more acculturated Latino students. These school-level effects support the individual-level results indicating that less acculturated Mexican American students face less daunting substance use risks. The results suggest that ethnic group size, but not necessarily numerical predominance, matters and that within-group differences influence the effect of a particular ethnic group's presence in the school. In other words, the majority does not always rule. These findings are interpreted using the concepts of segmented assimilation and school level social capital. PMID- 21686030 TI - Survey of modular ontology techniques and their applications in the biomedical domain. AB - In the past several years, various ontologies and terminologies such as the Gene Ontology have been developed to enable interoperability across multiple diverse medical information systems. They provide a standard way of representing terms and concepts thereby supporting easy transmission and interpretation of data for various applications. However, with their growing utilization, not only has the number of available ontologies increased considerably, but they are also becoming larger and more complex to manage. Toward this end, a growing body of work is emerging in the area of modular ontologies where the emphasis is on either extracting and managing "modules" of an ontology relevant to a particular application scenario (ontology decomposition) or developing them independently and integrating into a larger ontology (ontology composition). In this paper, we investigate state-of-the-art approaches in modular ontologies focusing on techniques that are based on rigorous logical formalisms as well as well-studied graph theories. We analyze and compare how such approaches can be leveraged in developing tools and applications in the biomedical domain. We conclude by highlighting some of the limitations of the modular ontology formalisms and put forward additional requirements to steer their future development. PMID- 21686031 TI - Pharmacokinetic Modeling of the Glucoregulatory System. AB - A pharmacokinetic model is proposed to describe the glucoregulatory process. The model describes the dynamics of glucose, amino acids, and fatty acids, as well as both the hormonal actions and dynamics of insulin, glucagon, epinephrine, and glucagon-like peptide-one. The model was developed assuming that the dynamics of each species occurrs in only one compartment. Several forms of the metabolic absorption and elimination rates, along with possibilities for increasing the complexity of each compartmental model are discussed. Once properly identified and validated, the novel model has the potential to be more descriptive than other models describing glucose dynamics in the body. PMID- 21686032 TI - Recent Studies Assessing the Proliferative Capability of a Novel Adult Stem Cell Identified in Menstrual Blood. AB - We are in the beginning of the era of regenerative medicine and many researchers are testing adult stem cells to be used for tissue repair and regeneration in the human body. Many adult stem cells have been discovered since the late 1990's with more recently a novel adult stem cell described in menstrual blood. The menstrual blood is derived from shedding of the endometrial lining, specifically the functionalis layer, which contains highly proliferative cells used to prepare the female body for implementation of a fertilized egg. Cell characterization experiments of stromal stem cells discovered in menstrual blood have demonstrated cells to be multipotent which can successfully differentiate in vitro into cell lineages derived from the mesoderm and the ectoderm.When menstrual blood cells were seeded in culture the average number of adherent cells was 8.50 % with a range of 0.48% to 47.76%. Demonstrating longevity one cell line allowed to grow was subcultured 47 times before complete senescence and death. The menstrual blood stromal stem cell phenotypic analysis incorporates mesenchymal cell markers such as CD13, CD29, CD44, CD49f, CD73, CD90, CD105, CD166, MHC Class I and pluripotent embryonic stem cell markers SSEA-4, Nanog and Oct-4. Karyotypic analysis demonstrated the maintenance of diploid cells without chromosomal abnormalities.In conclusion preliminary studies have demonstrated menstrual stem cells are easily expandable to clinical relevance. Pivotal pre-clinical studies are now underway to test the safety and efficacy of menstrual stem cells in several different animal models including one for neuroprotection following transplantation into an experimental stroke model. The study demonstrates menstrual stem cells are a novel cell population that may be routinely and safely isolated to provide a renewable source of stem cells from child-bearing women. PMID- 21686033 TI - Confirmatory factor analysis of brief pain inventory (BPI) functional interference clusters in patients with bone metastases. AB - To determine which of the previously proposed functional interference cluster models is most appropriate in patients with bone metastases and to determine if the cluster structures identified at baseline differed between responders and non responders following palliative radiotherapy. METHODS: The confirmatory test data set consists of breast and prostate cancer patients treated with palliative radiotherapy between May 2003 to January 2007. Worst pain and functional interference scores were assessed using Brief Pain Inventory at baseline, 4, 8 and 12 weeks post radiation treatment. The baseline cluster structure of the confirmatory dataset was compared to each of the previously proposed baseline cluster models. Maximum likelihood CFA was used to account for possible correlation amongst the factor components. A MIMIC model was used to determine the invariance of the cluster models between responders and non-responders during follow-up. RESULTS: A total of 169 eligible patients were analysed. There were 91 male and 78 female patients with a median age of 68 years. The median KPS was 70. A single 8 Gy and 20 Gy in 5 fractions were used in 97% of all analysed patients. The RTOG model, in which relationships with others and sleep comprised the mood related interference cluster and walking ability and normal work comprised the physical-interference cluster, provides the best fit for the sample data. The follow-up cluster structure is not similar across the responder groups indicating that cluster structures shift following radiation treatment, as evidenced by pain response. CONCLUSION: Although differing slightly this analysis confirms pretreatment symptom clusters exist for patients with bone metastases from breast or prostate cancer based on the RTOG 9714 data. This could help formulate symptom management interventions at initial diagnosis. Symptom clusters dissolve or change after treatment which may be a function of the treatment or population and requires further study. PMID- 21686034 TI - The Preventing Relational Aggression in Schools Everyday Program: A Preliminary Evaluation of Acceptability and Impact. AB - Despite recent research suggesting that relationally aggressive behaviors occur frequently and may lead to physically aggressive actions within urban school settings, there has been little prior research to develop and evaluate relational aggression prevention efforts within the urban schools. The current article describes the development and preliminary evaluation of the Preventing Relational Aggression in Schools Everyday (PRAISE) Program. PRAISE is a 20-session classroom based universal prevention program, designed to be appropriate and responsive to the needs of youth within the urban school context. Results suggest strong acceptability for the program and feasibility of implementation. Further, the program was especially beneficial for girls. For instance, girls in classrooms randomly assigned to the PRAISE Program demonstrated higher levels of knowledge for social information processing and anger management techniques and lower levels of relational aggression following treatment as compared to similar girls randomly assigned to a no-treatment control condition. Further, relationally aggressive girls exhibited similar benefits from the program (greater knowledge and lower levels of relational aggression) plus lower levels of overt aggression following treatment as compared to relationally aggressive girls within the control classrooms. In contrast, the program was not associated with improvements for boys across most measures. The significance and implications of the findings for research and practice are discussed. PMID- 21686035 TI - Church-Based Emotional Support And Self-Forgiveness in Late Life. AB - The purpose of this study is to see whether emotional support from fellow church members is associated with self-forgiveness in late life. The data come from a longitudinal nationwide survey of older adults. An effort is made to contribute to the literature by comparing and contrasting the effects of two church-based support measures: the amount of emotional support that is provided by fellow church members and satisfaction with emotional support from co-religionists. The findings suggest that older study participants who are more satisfied with the emotional support they have received from the members of their church are more likely to forgive themselves than older people who are not satisfied with the emotional support they have received in church. In contrast, significant effects failed to emerge with the measure of the amount of received emotional support. PMID- 21686036 TI - The Effects of 24-hour Sleep Deprivation on the Exploration-Exploitation Trade off. AB - Sleep deprivation has a complex set of neurological effects that go beyond a mere slowing of mental processes. While cognitive and perceptual impairments in sleep deprived individuals are widespread, some abilities remain intact. In an effort to characterize these effects, some have suggested an impairment of complex decision making ability despite intact ability to follow simple rules. To examine this trade-off, 24-hour total sleep deprived individuals performed two versions of a resource acquisition foraging task, one in which exploration is optimal (to succeed, abandon low value, high saliency options) and another in which exploitation is optimal (to succeed, refrain from switching between options). Sleep deprived subjects exhibited decreased performance on the exploitation task compared to non-sleep deprived controls, yet both groups exhibited increased performance on the exploratory task. These results speak to previous neuropsychological work on cognitive control. PMID- 21686037 TI - The Role of Suggestions in Hypnosis for Chronic Pain: A Review of the Literature. AB - Several controlled trials have demonstrated that hypnosis is an efficacious treatment for chronic pain. However, less attention has been given to the specific procedures and suggestions used in hypnotic treatments in research. The goal of this review was to address the issue of differences in the content of hypnotic suggestions, including pain management suggestions, non-pain related suggestions, and posthypnotic suggestions, in the context of published clinical trials of hypnosis for chronic pain management. This review focused on the types of suggestions used in twenty five studies comparing hypnosis to active treatments (e.g., relaxation, biofeedback), non-treatment control groups (e.g., standard care/wait-list control, supportive attention), or both in adult populations with various chronic pain conditions. Overall, these studies found hypnosis to be more effective than non-treatment control groups and similarly effective when compared to active treatments on pain-related outcomes when either pain-related suggestions or non-pain related suggestions were used. However, for studies that included both pain-specific and non-pain related suggestions, hypnosis was found to be superior to active treatments on a variety of pain related outcomes. PMID- 21686038 TI - Pneumatically Operated MRI-Compatible Needle Placement Robot for Prostate Interventions. AB - Magnetic Resonance Imaging (MRI) has potential to be a superior medical imaging modality for guiding and monitoring prostatic interventions. The strong magnetic field prevents the use of conventional mechatronics and the confined physical space makes it extremely challenging to access the patient. We have designed a robotic assistant system that overcomes these difficulties and promises safe and reliable intra-prostatic needle placement inside closed high-field MRI scanners. The robot performs needle insertion under real-time 3T MR image guidance; workspace requirements, MR compatibility, and workflow have been evaluated on phantoms. The paper explains the robot mechanism and controller design and presents results of preliminary evaluation of the system. PMID- 21686039 TI - HSP20 phosphorylation and airway smooth muscle relaxation. AB - HSP20 (HSPB6) is a small heat shock protein expressed in smooth muscles that is hypothesized to inhibit contraction when phosphorylated by cAMP-dependent protein kinase. To investigate this hypothesis in airway smooth muscle (ASM) we showed that HSP20 was constitutively expressed as well as being inducible in cultured hASM cells by treatment with 1 MUM isoproterenol or 10 MUM salmeterol. In contrast, a mixture of proinflammatory mediators (interleukin-1beta, tumor necrosis factor alpha, and interferon gamma) inhibited expression of HSP20 by about 50% in 48 hours. To determine whether phosphorylation of HSP20 is sufficient to induce relaxation, canine tracheal smooth muscle was treated with a cell permeant phosphopeptide that mimics the phosphorylation of HSP20. The HSP20 phosphopeptide antagonized carbachol-induced contraction by 60% with no change in myosin light chain phosphorylation. Recombinant full length HSP20 inhibited skeletal actin binding to smooth muscle myosin subfragment 1 (S1), and recombinant cell permeant TAT-HSP20 S16D mutant reduced F-actin filaments in cultured hASM cells. Carbachol stimulation of canine tracheal smooth muscle tissue caused redistribution of HSP20 from large macromolecular complexes (200 500 kDa) to smaller complexes (<60 kDa). The results are consistent with HSP20 expression and macromolecular structure being dynamically regulated in airway smooth muscle. HSP20 is upregulated by beta agonists and downregulated by proinflammatory cytokines. HSP20 is phosphorylated in vivo in a cAMP-dependent manner and the phosphorylated form promotes airway smooth muscle relaxation, possibly through depolymerization of F-actin as well as inhibition of myosin binding to actin. PMID- 21686040 TI - Gout disease-specific quality of life and the association with gout characteristics. AB - PURPOSE: Assess the association of gout characteristics with health-related quality of life (HRQoL) using a new gout-specific HRQoL instrument, the Gout Impact Scale (GIS). PATIENTS AND METHODS: Gout patients completed the GIS (five scales [0-100 score each] representing impact of gout overall [three scales] and during an attack [two scales]) and other questions describing recent gout attacks, treatment, gout history, comorbidities, and demographics. Physicians confirmed gout diagnosis, presence of tophi, and most recent serum uric acid (sUA) level. Relationships between gout characteristics and GIS scores were examined using analysis of variance and correlation analyses. RESULTS: The majority of patients were male (90.2%) with a mean age of 62.2 (+/-11.8) years. Approximately one-half (49.7%) reported >=3 gout attacks in the past year and the majority (57.9%) reported experiencing gout-related pain between attacks. Patients had appreciable concern about their gout ("gout concern overall" scale, 63.1 +/- 28.0) but believed their treatment was adequate ("unmet gout treatment need" scale (38.2 +/- 21.4) below scale mid-point). Significantly worse GIS scores were associated with increasing attack frequency and greater amount of time with pain between attacks (most scales, P < 0.001). Common objective measures such as sUA level, presence of tophi and the number of joints involved in a typical attack did not appear to be good indicators of the impact of gout on the patients' HRQoL. CONCLUSION: Attack frequency and gout pain between attacks were important correlates of patients' ratings of gout impact on their HRQoL. Further studies are needed to determine the minimal important difference for each GIS scale and interpret our results relative to other patient populations with gout. PMID- 21686041 TI - Frictional Behavior of Individual Vascular Smooth Muscle Cells Assessed By Lateral Force Microscopy. AB - With the advancement of the field of biotribology, considerable interest has arisen in the study of cell and tissue frictional properties. From the perspective of medical device development, the frictional properties between a rigid surface and underlying cells and tissues are of a particular clinical interest. As with many bearing surfaces, it is likely that contact asperities exist at the size scale of single cells and below. Thus, a technique to measure cellular frictional properties directly would be beneficial from both a clinical and a basic science perspective. In the current study, an atomic force microscope (AFM) with a 5 MUm diameter borosilicate spherical probe simulating endovascular metallic stent asperities was used to characterize the surface frictional properties of vascular smooth muscle cells (VSMCs) in contact with a metallic endovascular stent. Various treatments were used to alter cell structure, in order to better understand the cellular components and mechanisms responsible for governing frictional properties. The frictional coefficient of the probe on VSMCs was found to be approximately 0.06. This frictional coefficient was significantly affected by cellular crosslinking and cytoskeletal depolymerization agents. These results demonstrate that AFM-based lateral force microscopy is a valuable technique to assess the friction properties of individual single cells on the micro-scale. PMID- 21686042 TI - Trauma of Pregnancy Loss and Infertility for Mothers and Involuntarily Childless Women in the Contemporary United States. AB - Recent studies have repeatedly associated posttraumatic symptoms with women's experience of pregnancy loss. Using a nationally representative sample of American women (N = 2,894) from the National Survey of Fertility Barriers, the current study examines long-term psychological outcomes and reactions to pregnancy loss and infertility among mothers and involuntary childless women. In general, childless women who have experienced pregnancy loss or failure to conceive report the lowest life satisfaction and highest levels of depression despite a considerable period of time (seven years) since the loss or first year without a conception. However, women with the dual experience of pregnancy loss and involuntary childlessness report the most fertility-related distress. Results of the current study suggest that the "non-event" of involuntary childlessness may serve as an additional stressor in the traumatic experience of pregnancy loss. PMID- 21686043 TI - Attributions of Agency and the Construction of Moral Order: Dementia, Death, and Dignity in Nursing-home Care. AB - Using evidence gathered during 18 months of participant-observation in 2 nursing homes and 65 interviews with staff, this article examines how nursing-home staff use agency as a rhetorical resource to construct a dignified workplace. Staff attribute agency to dying residents, saying they choose the timing and conditions of their death. Staff equally insist that aggressive residents do not have agency. These two sets of attributions are used as counterpoints. Both go well beyond the available facts of the situation and reflect unspoken assumptions and interests of nursing-care workers. Through these attributions, the staff achieves a situated moral order in which compassionate care is provided to deserving residents in caring nursing homes. Staff attributions of agency are collectively shaped by professional philosophies, training and education, and regulatory guidelines. Finally, this article shows how it is analytically and theoretically productive to recast agency as a cultural object, whose use is subject to empirical investigation, rather than as a theoretical construct. PMID- 21686044 TI - PROTEIN N-GLYCOSYLATION OF GASTROPODS. AB - Glycosylation plays an important role in several types of recognition processes associated with fertilisation and development, allergies, pathological events and cell death. Whereas the amino acid sequence of a protein is fixed by the DNA, the glycosylation abilities depend on enzymes and substrates currently present in the cell.During the last decades our knowledge on glycosylation - the structure of glycans as well as the corresponding biochemical pathways including the responsible enzymes - especially on glycans of mammalian origin increased enormously. The glycosylation capabilities of other species were under investigation only if their glycans were for any reason connected to human life (e.g. some recognition processes of pathogens or allergy on food or plant glycans) or if they were potent candidates for cell culture systems for the expression of therapeutic agents (some insect, yeast and plant cells). However, in the meantime there is an increasing interest also in invertebrate glycosylation.Snails in particular show a broad spectrum of glycosylation abilities within their N-glycosylation pattern. In one case this has been shown to be involved in an intermediate host - parasite recognition process. For other snail species, it was found that they share many structural elements of N-glycans with mammals, plants, insects or nematodes. Sometimes several of these elements are present within one single structure.Here we present an overview of the current knowledge of N-glycosylation of snails, the glycan structures and the corresponding enzymes involved in the biosynthetic glycosylation pathway. PMID- 21686045 TI - Differences in onset and abuse/dependence episodes between prescription opioids and heroin: results from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - OBJECTIVES: To examine patterns of onset and abuse/dependence episodes of prescription opioid (PO) and heroin use disorders in a national sample of adults, and to explore differences by gender and substance abuse treatment status. METHODS: Analyses of data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (N = 43,093). RESULTS: Of all respondents, 5% (n = 1815) reported a history of nonmedical PO use (NMPOU) and 0.3% (n = 150) a history of heroin use. Abuse was more prevalent than dependence among NMPOUs (PO abuse, 29%; dependence, 7%) and heroin users (heroin abuse, 63%; dependence, 28%). Heroin users reported a short mean interval from first use to onset of abuse (1.5 years) or dependence (2.0 years), and a lengthy mean duration for the longest episode of abuse (66 months) or dependence (59 months); the corresponding mean estimates for PO abuse and dependence among NMPOUs were 2.6 and 2.9 years, respectively, and 31 and 49 months, respectively. The mean number of years from first use to remission from the most recent episode was 6.9 years for PO abuse and 8.1 years for dependence; the mean number of years from first heroin use to remission from the most recent episode was 8.5 years for heroin abuse and 9.7 years for dependence. Most individuals with PO or heroin use disorders were remitted from the most recent episode. Treated individuals, whether their problem was heroin or POs, tended to have a longer mean duration of an episode than untreated individuals. CONCLUSION: Periodic remissions from opioid or heroin abuse or dependence episodes occur commonly but take a long time. Timely and effective use of treatment services are needed to mitigate the many adverse consequences from opioid/heroin abuse and dependence. PMID- 21686046 TI - Cross-Regulation Between Wnt and NF-kappaB Signaling Pathways. AB - Cross-regulation between the Wnt and nuclear factor (NF)-kappaB signaling pathways has emerged as an important area for the regulation of a diverse array of genes and pathways active in chronic inflammation, immunity, development, and tumorigenesis. The ligands, kinases, transcription factors, and products of their target gene expression are involved in cross-regulation of these two signaling pathways. Both beta-catenin and NF-kappaB activate inducible nitric oxide synthase (iNOS) gene expression; however, beta-catenin also exerts an inhibitory effect on NF-kappaB-mediated transcriptional activation, including iNOS. The recent discovery of functional cross-regulation between these two pathways has shown complex roles for Wnt/beta-catenin and NF-kappaB signaling in the pathogenesis of certain cancers and other diseases. This review focuses on the molecular mechanisms of cross-regulation between Wnt/beta-catenin and NF-kappaB signaling pathways in cancer cells. PMID- 21686047 TI - The Limits of Self-Management: Community and Health Care System Barriers Among Latinos With Diabetes. AB - Although numerous studies examine diabetes self-care, few regard ecological framework correlates such as community and institutional level factors as fundamental for understanding diabetes management for Latinos. This article addresses the dearth of research that exists regarding social contextual forces and diabetes management for Latinos. Given the scarcity of research on this topic, studies of non-Latino groups were reviewed to illustrate the importance of community and institutional influences on diabetes care. Consideration of fundamental correlates within the ecological framework may better discern the underlying rationale for inadequate diabetes self-management for individuals who live in impoverished communities. PMID- 21686048 TI - ASSOCIATIONS BETWEEN MOTHERS' EXPERIENCE WITH THE TROUBLES IN NORTHERN IRELAND AND MOTHERS' AND CHILDREN'S PSYCHOLOGICAL FUNCTIONING: THE MODERATING ROLE OF SOCIAL IDENTITY. AB - Relatively little research has examined the relations between growing up in a community with a history of protracted violent political conflict and subsequent generations' well-being. The current article examines relations between mothers' self-report of the impact that the historical political violence in Northern Ireland (known as the Troubles) has on her and her child's current mental health. These relations are framed within the social identity model of stress, which provides a framework for understanding coping responses within societies that have experienced intergroup conflict. Mother-child dyads (N = 695) living in Belfast completed interviews. Results suggest that the mother-reported impact of the Troubles continue to be associated with mothers' mental health, which, in turn, is associated with her child's adjustment. The strength of mothers' social identity moderated pathways between the impact of the Troubles and her mental health, consistent with the social identity model of stress. PMID- 21686049 TI - Cell interactions with hierarchically structured nano-patterned adhesive surfaces. AB - The activation of well-defined numbers of integrin molecules in predefined areas by adhesion of tissue cells to biofunctionalized micro-nanopatterned surfaces was used to determine the minimum number of activated integrins necessary to stimulate focal adhesion formation. This was realized by combining micellar and conventional e-beam lithography, which enabled deposition of 6 nm large gold nanoparticles on predefined geometries. Patterns with a lateral spacing of 58 nm and a number of gold nanoparticles, ranging from 6 to 3000 per adhesive patch, were used. For alpha(v) beta(3)-integrin activation, gold nanoparticles were coated with c(-RGDfK-)-thiol peptides, and the remaining glass surface was passivated to prevent non-specific protein adsorption and cell adhesion. Results show that focal adhesion formation is dictated by the underlying hierarchical nanopattern. Adhesive patches with side lengths of 3000 nm and separated by 3000 nm, or with side lengths of 1000 nm and separated by 1000 nm, containing approximately 3007 +/- 193 or 335 +/- 65 adhesive gold nanoparticles, respectively, induced the formation of actin-associated, paxillin-rich focal adhesions, comparable in size and shape to classical focal adhesions. In contrast, adhesive patches with side lengths of 500, 250 or 100 nm, and separated from adjacent adhesive patches by their respective side lengths, containing 83 +/ 11, 30 +/- 4, or 6 +/- 1 adhesive gold nanoparticles, respectively, showed a significant increase in paxillin domain length, caused by bridging the pattern gap through an actin bundle in order to mechanically, synergistically strengthen each single adhesion site. Neither paxillin accumulation nor adhesion formation was induced if less than 6 c(-RGDfK-)-thiol functionalised gold nanoparticles per adhesion site were presented to cells. PMID- 21686050 TI - Scaling of Linking and Writhing Numbers for Spherically Confined and Topologically Equilibrated Flexible Polymers. AB - Scaling laws for Gauss linking number Ca and writhing number Wr for spherically confined flexible polymers with thermally fluctuating topology are analyzed. For ideal (phantom) polymers each of N segments of length unity confined to a spherical pore of radius R there are two scaling regimes: for sufficiently weak confinement (R ? N(1/3)) each chain has |Wr| ~ N(1/2), and each pair of chains has average |Ca| ~ N/R(3/2); alternately for sufficiently tight confinement (N(1/3) ? R), |Wr| ~ |CA| ~ N/R(3/2). Adding segment-segment avoidance modifies this result: for n chains with excluded volume interactions |Ca| ~ (N/n)(1/2)f(phi) where f is a scaling function that depends approximately linearly on the segment concentration phi = nN/R(3). Scaling results for writhe are used to estimate the maximum writhe of a polymer; this is demonstrated to be realizable through a writhing instability that occurs for a polymer which is able to change knotting topology and which is subject to an applied torque. Finally, scaling results for linking are used to estimate bounds on the entanglement complexity of long chromosomal DNA molecules inside cells, and to show how "lengthwise" chromosome condensation can suppress DNA entanglement. PMID- 21686051 TI - Quantifying Tight Junction Disruption Caused by Biomimetic pH-Sensitive Hydrogel Drug Carriers. AB - Facilitation of protein transport across biomimetic polymers and carriers used in drug delivery is a subject of major importance in the field of oral delivery. Quantitative immunofluorescence of epithelial tight junctions can be a valuable tool in the evaluation of paracellular permeation enhancement and macromolecular drug absorption. The tight junctional space is composed of transmembrane protein networks that provide both mechanical support and a transport barrier. Both of these may be affected by drug delivery agents that enhance paracytosis. Imaging is the only tool that can tease apart these processes. A confocal microscopy imaging method was developed to determine the effect of microparticulate poly(methacrylic acid) grafted poly(ethylene glycol) (P(MAA-g-EG)) hydrogel drug carriers on the integrity of claudin-1 and E-cadherin networks in Caco-2 monolayers. Z-stack projection images showed the lateral disruption of tight junctions in the presence of drug carriers. Tight junction image fraction measurements showed more significant differences between membranes exposed to microparticles and a control group. Mechanical disruption was much more pronounced in the presence of P(MAA-g-EG) microparticles as compared to the effect of EDTA. PMID- 21686052 TI - Use of Partial Stimulus Information by Cochlear Implant Users and Listeners with Normal Hearing in Identifying Spoken Words: Some Preliminary Analyses. AB - An error analysis of the word recognition responses of cochlear implant users and listeners with normal hearing was conducted to determine the types of partial information used by these two populations when they identified spoken words under auditory-alone and audiovisual conditions. The results revealed that the two groups used different types of partial information in identifying spoken words under auditory-alone or audiovisual presentation. Different types of partial information were also used in identifying words with different lexical properties. In our study, however, there were no significant interactions with hearing status, indicating that cochlear implant users and listeners with normal hearing identify spoken words in a similar manner. The information available to users with cochlear implants preserves much of the partial information necessary for accurate spoken word recognition. PMID- 21686053 TI - A Versatile Monomer for Preparing Well-Defined Functional Polycarbonates and Poly(ester-carbonates). AB - Despite the increasing demands for functional degradable biomaterials, strategies for generating materials with modular compositions and well-defined functionalities from common building blocks are still lacking. Here we report an azido-functionalized cyclic carbonate monomer, AzDXO, that exhibited controlled/"living" ring-opening polymerization kinetics under the catalysis of 1,8-diazabicyclo[5.4.0]-undec-7-ene. Homopolymerization of AzDXO and copolymerization of AzDXO with lactide resulted in polycarbonate and poly(ester carbonates) with well-defined composition and narrow polydispersity. Further side chain functionalizations of these polymers were accomplished under facile conditions via copper-catalyzed or copper-free strain-promoted azido-alkyne cyclcoaddition. This versatile monomer building block, obtainable in two steps without tedious purifications, provides a practical solution to the preparation of well-defined functional polycarbonates and poly(ester-carbonates). PMID- 21686054 TI - Emotion facilitation and passive avoidance learning in psychopathic female offenders. AB - Research on psychopathy among incarcerated, Caucasian males has consistently demonstrated deficits in emotion processing and response inhibition. Using the PCL-R to classify participants as psychopathic or non-psychopathic, this study examined the performance of incarcerated, Caucasian females on two laboratory tasks: A lexical decision task used to assess emotion processing and a passive avoidance task used to assess response inhibition. Contrary to prediction, deficits in performance typically exhibited by psychopathic males were not exhibited by psychopathic females in this sample. Implications of these findings are discussed and an interpretation of the results in the context of the Response Modulation Hypothesis is presented. PMID- 21686055 TI - Detecting anticipatory effects in speech articulation by means of spectral coefficient analyses. AB - Few acoustic studies have attempted to examine anticipatory effects in the earliest part of the release of stop consonants. We investigated the ability of spectral coefficients to reveal anticipatory coarticulation in the burst and early aspiration of stops in monosyllables. Twenty American English speakers produced stop (/k,t,p/) - vowel (/ae,i,o/) - stop (/k,t,p/) sequences in two phrase positions. The first four spectral coefficients (mean, standard deviation, skewness, kurtosis) were calculated for one window centered on the burst of the onset consonant and two subsequent, non-overlapping windows. All coefficients showed an influence of vowel-to-consonant anticipatory coarticulation. Which onset consonant showed the strongest vowel effect depended on the specific coefficient under consideration. A context-dependent consonant-to-consonant anticipatory effect was observed for onset /p/. Findings demonstrate that spectral coefficients can reveal subtle anticipatory adjustments as early as the burst of stop consonants. Different results for the four coefficients suggest that comprehensive spectral analyses offer advantages over other approaches. Studies using these techniques may expose previously unobserved articulatory adjustments among phonetic contexts or speaker populations. PMID- 21686056 TI - A Simple Marcus-Theory Type Model for Hydrogen Atom Transfer/Proton-Coupled Electron Transfer. AB - Hydrogen atom transfer reactions are the simplest class of proton-coupled electron transfer (PCET) processes. These reactions involve transfer of one electron and one proton from one reagent to another, in the same kinetic step: XH + Y -> X + HY. A predictive model for these reactions based on the Marcus cross relation is described. The model predicts rate constants within one or two orders of magnitude in most cases, over a very wide range of reactants and solvents. This remarkable result implies a surprising generality of the additivity postulate for the reaction intrinsic barriers, and a smaller role for the quantum mechanical details of the proton and electron transfers. PMID- 21686057 TI - Chemoenzymatic synthesis of alpha2-3-sialylated carbohydrate epitopes. AB - Sialic acids are common terminal carbohydrates on cell surface. Together with internal carbohydrate structures, they play important roles in many physiological and pathological processes. In order to obtain alpha2-3-sialylated oligosaccharides, a highly efficient one-pot three-enzyme synthetic approach was applied. The P. multocida alpha2-3-sialyltransferase (PmST1) involved in the synthesis was a multifunctional enzyme with extremely flexible donor and acceptor substrate specificities. Sialyltransferase acceptors, including type 1 structure (Galbeta1-3GlcNAcbetaProN(3)), type 2 structures (Galbeta1-4GlcNAcbetaProN(3) and 6-sulfo-Galbeta1-4GlcNAcbetaProN(3)), type 4 structure (Galbeta1 3GalNAcbetaProN(3)), type 3 or core 1 structure (Galbeta1-3GalNAcalphaProN(3)) and human milk oligosaccharide or lipooligosaccharide lacto-N-tetraose (LNT) (Galbeta1-3GlcNAcbeta1-3Galbeta1-4GlcbetaProN(3)), were chemically synthesized. They were then used in one-pot three-enzyme reactions with sialic acid precursor ManNAc or ManNGc, to synthesize a library of natural occurring alpha2-3-linked sialosides with different internal sugar units. The sialylated oligosaccharides obtained are valuable probes for their biological studies. PMID- 21686059 TI - Marijuana But Not Alcohol Use During Adolescence Mediates the Association Between Transmissible Risk for Substance Use Disorder and Number of Lifetime Violent Offenses. AB - AIM: This study determined the extent to which alcohol and marijuana use during adolescence mediates the relation between transmissible risk for substance use disorder (SUD) and lifetime number of different types of violent offenses. METHODS: The transmissible liability index was administered to 359 10-12 year old youths who were tracked to 22 years of age. Past year frequency of alcohol and marijuana consumption was longitudinally tracked to age 22 at which time lifetime violent offenses was recorded. RESULTS: Rate of increase in marijuana use mediated the association between transmissible risk and lifetime number of different types of violent offenses. No association was found between past year frequency of alcohol use and violent offenses. CONCLUSIONS: Prevention directed at lowering the psychological characteristics associated with transmissible risk for SUD may also reduce violent offending. PMID- 21686058 TI - Perivascular adipose tissue and vascular disease. AB - Perivascular adipose tissue is a local deposit of adipose tissue surrounding the vasculature. Perivascular adipose tissue is present throughout the body and has been shown to have a local effect on blood vessels. The influence of perivascular adipose tissue on the vasculature changes with increasing adiposity. This article describes the anatomy and pathophysiology of perivascular adipose tissue and the experimental evidence supporting its local adverse effect on the vasculature. Methods for quantifying perivascular adipose tissue in free-living populations will be described. Finally, the epidemiological literature demonstrating an association between perivascular adipose tissue and cardiometabolic disease will be explored. PMID- 21686060 TI - New Paradigms in Hypertrophic Cardiomyopathy: Insights from Genetics. AB - Understanding the genetic basis of hypertrophic cardiomyopathy (HCM) provides a remarkable opportunity to predict and prevent disease. HCM is caused by mutations in sarcomere genes and is the most common monogenic cardiovascular disorder. Although unexplained left ventricular hypertrophy (LVH) is considered diagnostic, LVH is not always present. LV wall thickness is often normal until adolescence or later, even in individuals known to carry pathogenic sarcomere mutations. In contrast, genetic testing can identify both individuals who carry pathogenic sarcomere mutations and have a clinical diagnosis of HCM, as well as mutation carriers who have not yet manifest LVH but are at very likely to develop disease. Studying this important new patient subset, designated early or preclinical HCM, allows characterization of the initial consequences of sarcomere mutations, prior to the onset of overt hypertrophic remodeling. Such study has defined novel early phenotypes, including impaired left ventricular relaxation, myocardial energetic deficiencies, and altered collagen metabolism, in mutation carriers with apparently normal cardiac morphology. These results indicate that sarcomere mutations have substantial impact on myocardial function and biochemistry before the onset of frank hypertrophy. Furthermore, animal models of preclinical HCM have identified promising new treatment strategies that may diminish the emergence of overt disease. We can now begin to reshape the paradigm for treating genetic disorders. With improved mechanistic insight and the capability for early diagnosis, genetic advances can lead to new approaches for disease modification and prevention. PMID- 21686061 TI - Arterial Pressure Monitoring in Mice. AB - The use of mice for the evaluation and study of cardiovascular pathophysiology is growing rapidly, primarily due to the relative ease for developing genetically engineered mouse models. Arterial pressure monitoring is central to the evaluation of the phenotypic changes associated with cardiovascular pathology and interventions in these transgenic and knockout models. There are four major techniques for measuring arterial pressure in the mouse: tail cuff system, implanted fluid filled catheters, Millar catheters and implanted telemetry systems. Here we provide protocols for their use and discuss the advantages and limitations for each of these techniques . PMID- 21686062 TI - Nidicolous ticks of small mammals in Anaplasma phagocytophilum-enzootic sites in northern California. AB - Ixodes spp. tick-borne zoonotic diseases are present across the Holarctic in humans, domestic animals, and wildlife. Small mammals are reservoirs for the rickettsial pathogen Anaplasma phagocytophilum and tick vectors may include catholic-feeding bridge vectors as well as host-specialist or nidicolous ticks. Far western North American communities in which A. phagocytophilum is maintained are complex ecologically, with multiple reservoir host and tick species, multiple strains of the bacterial pathogen A. phagocytophilum and differences in dynamics of hosts and vectors across heterogeneous landscapes. We evaluated sites in northern California in order to identify primarily nidicolous ticks and the hosts they infest. A total of 667 ticks was found in 11 study sites, including 288 on flags and 379 attached to small mammals. Larvae were over-represented among attached ticks and adults on flags. The most abundant species was I. pacificus. Two-hundred fourteen nidicolous ticks were found, most abundantly I. angustus and I. spinipalpis. All adult I. ochotonae, I. auritulus, I. angustus, I. jellisoni, and I. woodi were female, while the male:female ratio of I. spinipalpis was 1.2:1 and 1:1 for I. pacificus. The greatest number of ticks was obtained from Tamias ochrogenys, Peromyscus spp., and Neotoma fuscipes. Of 234 small mammal individuals that were infested with Ixodes spp., only 81 (34.6%) were infested with I. pacificus. The remaining infested small mammals hosted nidicolous tick species. Eight ticks were PCR-positive, including 6 I. pacificus (one adult, one larva, and 6 nymphs), and 2 adult I. ochotonae and high PCR prevalences of 18% and 9% were detected in woodrats and chipmunks, respectively. Nymphal I. angustus ticks were active year-long with a possible increase in August while larval activity was only observed in December and spring months and adults only during spring and fall. Overall, we show high tick species richness and year-round high levels of infestation on rodents by several different nidicolous ticks in areas where A. phagocytophilum is enzootic, including on reported reservoir species. PMID- 21686063 TI - Implementation of Accelerated Molecular Dynamics in NAMD. AB - Accelerated molecular dynamics (aMD) is an enhanced-sampling method that improves the conformational space sampling by reducing energy barriers separating different states of a system. Here we present the implementation of aMD in the parallel simulation program NAMD. We show that aMD simulations performed with NAMD have only a small overhead compared with classical MD simulations. Through example applications to the alanine dipeptide, we discuss the choice of acceleration parameters, the interpretation of aMD results, as well as the advantages and limitations of the aMD method. PMID- 21686064 TI - Intergenerational Ambivalence: Aging Mothers Whose Adult Daughters are Mentally Ill. AB - Research on families dealing with mental illness has considered either positive or negative aspects of intergenerational family relationships. The current study extends this work by using intergenerational ambivalence theory to examine aging mothers' contradictory expectations toward adult daughters who are mentally ill. This study focuses on interviews obtained from a sample of 22 mothers aged 52-90 who expressed considerable sociological ambivalence in relation to their grown daughters. Four strategies of managing ambivalence are identified: excusing behaviors, reducing expectations, adjusting help-giving, and confronting. The implications are that practitioners should be aware of intergenerational ambivalence, help aging parents identify their ambivalence management strategies, and assess the extent to which these strategies are adaptive. Future research directions in this area are also discussed. PMID- 21686065 TI - One world, one woman: a transformational leader's approach to primary ovarian insufficiency. AB - Lectureship endowment funds are created to honor major contributions that have clearly advanced a field. In some select cases they recognize the contributions of a transformational leader. Such was the case in the creation of the Wulf H. Utian Endowed Lectureship Fund. The express purpose of the fund is to provide travel to the annual meeting by a lecturer selected by the North American Menopause Society Scientific Program Committee. Wulf H. Utian changed the paradigm for menopause by creating an organization whose major purpose was to employ an integrated approach to the condition. Such an approach would benefit many areas of healthcare. This report summarizes my thoughts on how such an integrated approach might advance the field of primary ovarian insufficiency. PMID- 21686066 TI - Immune System as a Sensory System. AB - As suggested by the well-known gestalt concept the immune system can be regarded as an integrated complex system, the functioning of which cannot be fully characterized by the behavior of its constituent elements. Similar approaches to the immune system in particular and sensory systems in general allows one to discern similarities and differences in the process of distinguishing informative patterns in an otherwise random background, thus initiating an appropriate and adequate response. This may lead to a new interpretation of difficulties in the comprehension of some immunological phenomena. PMID- 21686067 TI - Developmental Foundations and Clinical Applications of Social Information Processing: A Review. AB - Social information processing has emerged as an important construct in understanding children's interpersonal functioning. This article reviews (a) the theoretical models guiding research, (b) the development of normative and atypical social problem solving, and (c) the connection between social information processing and individual differences in functioning. Finally, this review ends with a summary of efficacy of programs aimed at preventing social information processing biases or intervening with youth who display dysfunctional social information processing skills. PMID- 21686068 TI - Relational Uncertainty and Cortisol Responses to Hurtful and Supportive Messages from a Dating Partner. AB - This paper evaluates theoretical claims linking relational uncertainty about a relationship partner to experiences of stress during interactions with that partner. Two observational studies were conducted to evaluate the association between relational uncertainty and salivary cortisol in the context of hurtful and supportive interactions. In Study 1, participants (N = 89) engaged in a conversation about core traits or values with a partner, who was trained to be hurtful. In Study 2, participants (N = 89) received supportive messages after completing a series of stressful tasks and receiving negative performance feedback. As predicted, partner uncertainty was associated with greater cortisol reactivity to the hurtful interaction in Study 1. Contrary to expectations, Study 1 results also indicated that self uncertainty was associated with less cortisol reactivity, when self, partner, and relationship uncertainty were tested in the same model. Study 2 revealed that relational uncertainty dampened cortisol reactions to performing poorly on tasks while the partner observed. As predicted, Study 2 also found that partner uncertainty was associated with less cortisol recovery after the supportive interaction, but neither self nor relationship uncertainty was associated with rate of cortisol change during the recovery period. PMID- 21686069 TI - Use of Professional and Informal Support by Black Men with Mental Disorders. AB - This study utilized data from the National Survey of American Life to investigate the use of professional services and informal support among African American and Caribbean black men with a lifetime mood, anxiety, or substance use disorder. Thirty-three percent used both professional services and informal support, 14% relied on professional services only, 24% used informal support only, and 29% did not seek help. African American men were more likely than to rely on informal support alone. Having co-occurring mental and substance disorders, experiencing an episode in the past 12 months, and having more people in the informal network increased the likelihood of using professional services and informal supports. Marital status, age, and socioeconomic status were also significantly related to help-seeking. The results suggests potential unmet need. However, the reliance on informal support also suggests a strong protective role that informal networks play in the lives of black men. PMID- 21686070 TI - Nanostructure of Solid Precipitates Obtained by Expansion of Polystyrene-block Polybutadiene Solutions in Near Critical Propane: Block Ratio and Micellar Solution Effects. AB - In contrast to incompressible liquid solutions, compressible near-critical solutions of block copolymers allow for controlling rapid structure transformations with pressure alone. For example, when dissolved in near-critical propane, polystyrene-block-polybutadiene can form a random molecular solution at high pressures, a micellar solution at moderate pressures, and a solvent-free precipitate at low pressures. In contrast to the unstructured virgin copolymer, such a propane-treated precipitate rapidly self assembles toward structures characteristic of equilibrated block copolymers, such as lamellae, spheres or cylinders, which depend on the block ratio rather than on the decompression rate or temperature, at least within the rate and temperature ranges investigated in this work. At lower temperatures, however, say below 40 degrees C, glass transition of the styrene-butadiene diblocks can inhibit independent structure formation while crystallization of their hydrogenated-butadiene analogs can preserve the micellar-solution structure. PMID- 21686072 TI - Embracing the Open-Source Movement for the Management of Spatial Data: A Case Study of African Trypanosomiasis in Kenya. AB - The past decade has seen an explosion in the availability of spatial data not only for researchers, but the public alike. As the quantity of data increases, the ability to effectively navigate and understand the data becomes more challenging. Here we detail a conceptual model for a spatially explicit database management system that addresses the issues raised with the growing data management problem. We demonstrate utility with a case study in disease ecology: to develop a multi-scale predictive model of African Trypanosomiasis in Kenya. International collaborations and varying technical expertise necessitate a modular open-source software solution. Finally, we address three recurring problems with data management: scalability, reliability, and security. PMID- 21686071 TI - How grossed out are you? The neural bases of emotion regulation from childhood to adolescence. AB - The ability to regulate one's emotions is critical to mental health and well being, and is impaired in a wide range of psychopathologies, some of which initially manifest in childhood or adolescence. Cognitive reappraisal is a particular approach to emotion regulation frequently utilized in behavioral psychotherapies. Despite a wealth of research on cognitive reappraisal in adults, little is known about the developmental trajectory of brain mechanisms subserving this form of emotion regulation in children. In this functional magnetic resonance imaging study, we asked children and adolescents to up-and down regulate their response to disgusting images, as the experience of disgust has been linked to anxiety disorders. We demonstrate distinct patterns of brain activation during successful up- and down-regulation of emotion, as well as an inverse correlation between activity in ventromedial prefrontal cortex (vmPFC) and limbic structures during down-regulation, suggestive of a potential regulatory role for vmPFC. Further, we show age-related effects on activity in PFC and amygdala. These findings have important clinical implications for the understanding of cognitive-based therapies in anxiety disorders in childhood and adolescence. PMID- 21686073 TI - Sociodemographic factors in a pediatric chronic pain clinic: The roles of age, sex and minority status in pain and health characteristics. AB - Little is known about how sociodemographic factors relate to children's chronic pain. This paper describes the pain, health, and sociodemographic characteristics of a cohort of children presenting to an urban tertiary chronic pain clinic and documents the role of age, sex and minority status on pain-related characteristics. A multidisciplinary, tertiary clinic specializing in pediatric chronic pain. Two hundred and nineteen patients and their parents were given questionnaire packets to fill out prior to their intake appointment which included demographic information, clinical information, Child Health Questionnaire - Parent Report, Functional Disability Index - Parent Report, Child Somatization Index - Parent Report, and a Pain Intensity Scale. Additional clinical information was obtained from patients' medical records via chart review. This clinical sample exhibited compromised functioning in a number of domains, including school attendance, bodily pain, and health compared to normative data. Patients also exhibited high levels of functional disability. Minority children evidenced decreased sleep, increased somatization, higher levels of functional disability, and increased pain intensity compared to Caucasians. Caucasians were more likely to endorse headaches than minorities, and girls were more likely than boys to present with fibromyalgia. Younger children reported better functioning than did teens. The results indicate that sociodemographic factors are significantly associated with several pain-related characteristics in children with chronic pain. Further research must address potential mechanisms of these relationships and applications for treatment. PMID- 21686075 TI - The Role of Genetics in Nicotine Dependence: Mapping the Pathways from Genome to Syndrome. AB - Nicotine dependence continues to be a major public health problem worldwide and there is unequivocal evidence that genetics play a substantial role in its etiology. This review provides an overview of the evidence for genetic influences and recent advances in the field. Traditional quantitative genetics studies have revealed nicotine dependence is heritable and molecular genetics studies are providing increasing evidence that the genes responsible for nicotine's pharmacokinetics and pharmacodynamics are particularly important. Despite considerable progress, a number of significant complexities and challenges remain. These include determining the specificity of genetic influences and clarifying the role of interactive contributions. One promising strategy for addressing these issues is an intermediate phenotype approach that attempts to identify the intervening proximal mechanisms that confer differential genetic risk. Understanding these mechanisms may permit more precision in understanding genetic influences and may also identify novel targets for intervention or prevention. PMID- 21686076 TI - Therapeutic immune clearance of rabies virus from the CNS. AB - The long-held concept that rabies infection is lethal in humans once the causative rabies virus has reached the CNS has been called into question by the recent survival of a number of patients with clinical rabies. Studies in animal models provide insight into why survival from a rabies virus infection that has spread to the CNS is possible and the immune mechanisms involved. In the CNS, both innate mechanisms capable of inhibiting virus replication and the activity of infiltrating rabies virus-specific T and B cells with the capacity to clear the virus are required. Deficiencies in the induction of either aspect of rabies immunity can lead to lethal consequences but may be overcome by novel approaches to active and passive immunization. PMID- 21686074 TI - Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain. AB - Neuropathic pain remains a major clinical problem and a therapeutic challenge because existing analgesics are often ineffective and can cause serious side effects. Increased N-methyl-d-aspartate receptor (NMDAR) activity contributes to central sensitization in certain types of neuropathic pain. NMDAR antagonists can reduce hyperalgesia and allodynia in animal models of neuropathic pain induced by nerve injury and diabetic neuropathy. Clinically used NMDAR antagonists, such as ketamine and dextromethorphan, are generally effective in patients with neuropathic pain, such as complex regional pain syndrome and painful diabetic neuropathy. However, patients with postherpetic neuralgia respond poorly to NMDAR antagonists. Recent studies on identifying NMDAR-interacting proteins and molecular mechanisms of increased NMDAR activity in neuropathic pain could facilitate the development of new drugs to attenuate abnormal NMDAR activity with minimal impairment of the physiological function of NMDARs. Combining NMDAR antagonists with other analgesics could also lead to better management of neuropathic pain without causing serious side effects. PMID- 21686077 TI - Inhibitory effects of calcitriol on the growth of MCF-7 breast cancer xenografts in nude mice: selective modulation of aromatase expression in vivo. AB - Calcitriol (1,25-dihydroxyvitamin D(3)), the hormonally active metabolite of vitamin D, exerts many anticancer effects in breast cancer (BCa) cells. We have previously shown using cell culture models that calcitriol acts as a selective aromatase modulator (SAM) and inhibits estrogen synthesis and signaling in BCa cells. We have now examined calcitriol effects in vivo on aromatase expression, estrogen signaling, and tumor growth when used alone and in combination with aromatase inhibitors (AIs). In immunocompromised mice bearing MCF-7 xenografts, increasing doses of calcitriol exhibited significant tumor inhibitory effects (~50% to 70% decrease in tumor volume). At the suboptimal doses tested, anastrozole and letrozole also caused significant tumor shrinkage when used individually. Although the combinations of calcitriol and the AIs caused a statistically significant increase in tumor inhibition in comparison to the single agents, the cooperative interaction between these agents appeared to be minimal at the doses tested. Calcitriol decreased aromatase expression in the xenograft tumors. Importantly, calcitriol also acted as a SAM in the mouse, decreasing aromatase expression in the mammary adipose tissue, while increasing it in bone marrow cells and not altering it in the ovaries and uteri. As a result, calcitriol significantly reduced estrogen levels in the xenograft tumors and surrounding breast adipose tissue. In addition, calcitriol inhibited estrogen signaling by decreasing tumor ERalpha levels. Changes in tumor gene expression revealed the suppressive effects of calcitriol on inflammatory and growth signaling pathways and demonstrated cooperative interactions between calcitriol and AIs to modulate gene expression. We hypothesize that cumulatively these calcitriol actions would contribute to a beneficial effect when calcitriol is combined with an AI in the treatment of BCa. PMID- 21686078 TI - Newkome-type dendron stabilized gold nanoparticles: Synthesis, reactivity, and stability. AB - We report the synthesis and evaluation of four Newkome-type dendrons, G1-COOH, G2 COOH, SH-G1-COOH, and TA-G1-COOH, and their respective gold-dendron conjugates, where GX represents the generation number. G1- and G2-COOH are 2-directional symmetric dendrons that have cystamine cores containing a disulfide group. SH-G1 COOH was prepared by treatment of G1-COOH with dithioerythritol to yield a free thiol group to replace the disulfide linkage. TA-G1-COOH has a thioctic acid moiety, which is a 5-member ring containing a disulfide group that cleaves to produce two anchoring thiols to bond with the gold surface. All dendrons have peripheral carboxylate groups to afford hydrophilicity and functionality. Gold nanoparticle conjugates were prepared by reaction of each dendron solution with a suspension of gold colloid (nominally 10 nm diameter) and purified by stirred cell ultrafiltration. Chemical structures were confirmed by (1)H and (13)C nuclear magnetic resonance spectroscopy and matrix assisted laser desorption/ionization time-of-flight mass spectrometry. Particle size and surface plasmon resonance of the conjugates were characterized by dynamic light scattering (DLS) and UV-Vis spectroscopy, respectively. X-ray photoelectron spectroscopy (XPS) was utilized to confirm covalent bonding between the thiols on the dendron and the gold surface. XPS also revealed changes in the S/Au intensity ratio as a function of the dendron chemical structure, suggesting steric effects play a role in the reaction and/or conformation of dendrons on the gold surface. The colloidal and chemical stability of the conjugates as a function of temperature, pH, and suspending medium, and with respect to chemical resistance toward KCN, was investigated using DLS and UV-Vis absorption. PMID- 21686079 TI - Stem cell therapy for glaucoma: possibilities and practicalities. AB - Glaucoma is a progressive, neurodegenerative, optic neuropathy in which currently available therapies cannot always prevent, and do not reverse, vision loss. Stem cell transplantation may provide a promising new avenue for treating many presently incurable degenerative conditions, including glaucoma. This article will explore the various ways in which transplantation of stem or progenitor cells may be applied for the treatment of glaucoma. We will critically discuss the translational prospects of two cell transplantation-based treatment modalities: neuroprotection and retinal ganglion cell replacement. In addition, we will identify specific questions that need to be addressed and obstacles to overcome on the path to clinical translation, and offer insight into potential strategies for approaching this goal. PMID- 21686080 TI - Sign Perception and Recognition in Non-Native Signers of ASL. AB - Past research has established that delayed first language exposure is associated with comprehension difficulties in non-native signers of American Sign Language (ASL) relative to native signers. The goal of the current study was to investigate potential explanations of this disparity: do non-native signers have difficulty with all aspects of comprehension, or are their comprehension difficulties restricted to some aspects of processing? We compared the performance of deaf non-native, hearing L2, and deaf native signers on a handshape and location monitoring and a sign recognition task. The results indicate that deaf non-native signers are as rapid and accurate on the monitoring task as native signers, with differences in the pattern of relative performance across handshape and location parameters. By contrast, non-native signers differ significantly from native signers during sign recognition. Hearing L2 signers, who performed almost as well as the two groups of deaf signers on the monitoring task, resembled the deaf native signers more than the deaf non-native signers on the sign recognition task. The combined results indicate that delayed exposure to a signed language leads to an overreliance on handshape during sign recognition. PMID- 21686081 TI - Who Spanks Infants and Toddlers? Evidence from the Fragile Families and Child Well-Being Study. AB - We use data from the Fragile Families and Child Well-Being Study (FFCW), a birth cohort study of children in 18 medium to large U.S. cities, to examine the prevalence and determinants of spanking among infants and toddlers (at mean age 14 months). Taking advantage of the large and diverse sample in FFCW, we conduct separate analyses for children of African American (N=1,710), Hispanic (N=853), and white non-Hispanic (N=812) mothers. Overall, about 15% of children are spanked at 12 months, with this share rising to 40% by 18 months and nearly 50% for children age 20 months or older. We find that there are marked differences in the use of spanking across the three racial/ethnic groups, with children of African American mothers more likely to be spanked and at a younger age. Moreover, while some predictors of spanking are seen across all three groups, others vary. Mothers who are young, who report more parental stress, or report their child has a more difficult temperament are more likely to spank across all three groups. However, being a boy increases the risk of spanking only within African American families. First-born children are at elevated risk of spanking to at least some extent in all groups, but much more so within Hispanic families. In addition, maternal employment is associated with a greater likelihood of spanking in Hispanic families.Although spanking at these young ages is not necessarily indicative of maltreatment, it may be a marker for families who are at elevated risk of maltreatment. As such, our findings, by highlighting some risk factors that are common across groups as well as some that are more important for particular groups, may have implications for child abuse prevention. PMID- 21686082 TI - Bioanalytical Screening of Riboflavin Antagonists for Targeted Drug Delivery - A Thermodynamic and Kinetic Study. AB - The present study screened riboflavin mimicking small molecules to determine their binding activity for the riboflavin binding protein. We performed thermodynamic and kinetic binding studies of these molecules using a combination of two analytical approaches; isothermal titration calorimetry and surface plasmon resonance spectroscopy. Screening of a biased set of non-riboflavin based small molecules by microcalorimetry led to the discovery of two known drug molecules, quinacrine and chloroquine, as favorable ligands for the riboflavin receptor with K(D) value of 264, and 2100 nM, respectively. We further demonstrated that quinacrine is a competitive ligand for the receptor as measured by surface plasmon resonance. Thus this study describes the identification of a novel class of dual acting riboflavin antagonists that target riboflavin receptor for cellular uptake and display multifunctional activities upon cellular entry. PMID- 21686083 TI - Random walk with barriers. AB - Restrictions to molecular motion by barriers (membranes) are ubiquitous in porous media, composite materials and biological tissues. A major challenge is to characterize the microstructure of a material or an organism nondestructively using a bulk transport measurement. Here we demonstrate how the long-range structural correlations introduced by permeable membranes give rise to distinct features of transport. We consider Brownian motion restricted by randomly placed and oriented membranes (d - 1 dimensional planes in d dimensions) and focus on the disorder-averaged diffusion propagator using a scattering approach. The renormalization group solution reveals a scaling behavior of the diffusion coefficient for large times, with a characteristically slow inverse square root time dependence for any d. Its origin lies in the strong structural fluctuations introduced by the spatially extended random restrictions, representing a novel universality class of the structural disorder. Our results agree well with Monte Carlo simulations in two dimensions. They can be used to identify permeable barriers as restrictions to transport, and to quantify their permeability and surface area. PMID- 21686084 TI - Response to Pearl's comments on principal stratification. AB - Dr. Pearl invites researchers to justify their use of principal stratification. This comment explains how the use of principal stratification simplified a complex mediational problem encountered when evaluating a smoking cessation intervention's effect on reducing smoking withdrawal symptoms. PMID- 21686085 TI - Clarifying the role of principal stratification in the paired availability design. AB - The paired availability design for historical controls postulated four classes corresponding to the treatment (old or new) a participant would receive if arrival occurred during either of two time periods associated with different availabilities of treatment. These classes were later extended to other settings and called principal strata. Judea Pearl asks if principal stratification is a goal or a tool and lists four interpretations of principal stratification. In the case of the paired availability design, principal stratification is a tool that falls squarely into Pearl's interpretation of principal stratification as "an approximation to research questions concerning population averages." We describe the paired availability design and the important role played by principal stratification in estimating the effect of receipt of treatment in a population using data on changes in availability of treatment. We discuss the assumptions and their plausibility. We also introduce the extrapolated estimate to make the generalizability assumption more plausible. By showing why the assumptions are plausible we show why the paired availability design, which includes principal stratification as a key component, is useful for estimating the effect of receipt of treatment in a population. Thus, for our application, we answer Pearl's challenge to clearly demonstrate the value of principal stratification. PMID- 21686086 TI - ON THE GRENANDER ESTIMATOR AT ZERO. AB - We establish limit theory for the Grenander estimator of a monotone density near zero. In particular we consider the situation when the true density f(0) is unbounded at zero, with different rates of growth to infinity. In the course of our study we develop new switching relations using tools from convex analysis. The theory is applied to a problem involving mixtures. PMID- 21686087 TI - The Effect of Productive Activities on Depressive Symptoms Among Older Adults With Dual Sensory Loss. AB - The purpose of this study was to evaluate the ability of three productive activities (paid employment, volunteer work, and informal helping) to mitigate the negative effects of dual sensory loss (DSL) on depressive symptoms among older adults. Multilevel modeling was used to analyze longitudinal data from the nationally representative Health and Retirement Study. The sample consisted of 2,688 persons: 1,380 who developed DSL during the study and 1,308 who did not. Although participation in each of the productive activities was associated with fewer depressive symptoms for older adults with DSL, volunteering was also the only variable that moderated the relationship between DSL and depressive symptoms. Persons with a DSL who volunteered exhibited a larger decrease in depressive symptoms compared to persons without sensory loss who volunteered. A volunteer intervention for older adults with DSL may be a viable option to help reduce depression in this population. PMID- 21686088 TI - Lithography of Polymer Nanostructures on Glass for Teaching Polymer Chemistry and Physics. AB - As nanolithography becomes increasingly important in technology and daily life, a variety of inexpensive and creative methods toward communicating the concepts underpinning these processes in the classroom are necessary. An experiment is described that uses simple CD-Rs, C-clamps, an oven, and a freezer to provide concrete examples and insights into the chemistry and principles of nanolithography. The experiment also has flexibility, making it suitable for a range of classroom levels from high school to more advanced labs in college. Because CD-Rs are composed of grooves of polycarbonate, the experiment provides a basis for discussions and exploration into the chemistry and physics of polymers on the nanoscale. PMID- 21686089 TI - Room Temperature Z-Selective Homocoupling of alpha Olefins by Tungsten Catalysts. PMID- 21686090 TI - High Performance IT-MS Sequencing of Glycans (Spatial Resolution of Ovalbumin Isomers). AB - This report outlines and applies a high performance sequencing technology to evaluate the glycome of a common model glycoprotein, ovalbumin. The targets were the N-linked glycans enzymatically released from the protein, the N glycoproteome. These product glycans were reduced, methylated and directly infused into the MS using a chip-based nanoelectrospray with the ions structurally characterized by sequential disassembly. Ten major ions were selected for detailed analysis. Isomer topologies (glycan connectivity) were determined from ion pathways of disassembly. Linkage information was revealed by specific cross-ring cleavage fragments within smaller oligomers. Both connectivity and linkage features were assisted with described bioinformatic tools and details confirmed with a standards library of fragments. The number of isomeric structures found within these 10 parent ions were 37, more than double earlier reports, and setting a new goal for developing technology. In this non chromatographic, high performance spatial approach, the focus has been patterned to be comprehensive, and stay within the bounds of a plausible high throughput strategy consistent with automation. Selective structures are described in the text to appraise readers of the general approach; a more comprehensive coverage has been included in supplemental material. PMID- 21686091 TI - Criminality Among Rural Stimulant Users in the United States. AB - Despite the increase in media attention on "meth cooking" in rural areas of the United States, little is known about rural stimulant use, particularly the criminality associated with stimulant use. Data were collected from community stimulant users in rural Ohio, Arkansas, and Kentucky (N=709). Findings from three logistic regression models indicate that younger stimulant users (x =32.55, SD = 10.35), those with more convictions, and those who used crack frequently were significantly more likely to have been arrested for committing a substance related crime, a property crime, or another crime in the 6-months before entering the study. Implications include the need for longitudinal studies to further understand rural stimulant use as well as increasing community and corrections based drug abuse prevention and treatment interventions for stimulant users who live in rural areas. PMID- 21686092 TI - Using C. elegans for antimicrobial drug discovery. AB - INTRODUCTION: The number of microorganism strains with resistance to known antimicrobials is increasing. Therefore, there is a high demand for new, non toxic and efficient antimicrobial agents. Research with the microscopic nematode Caenorhabditis elegans can address this high demand for the discovery of new antimicrobial compounds. In particular, C. elegans can be used as a model host for in vivo drug discovery through high-throughput screens of chemical libraries. AREAS COVERED: This review introduces the use of substitute model hosts and especially C. elegans in the study of microbial pathogenesis. The authors also highlight recently published literature on the role of C. elegans in drug discovery and outline its use as a promising host with unique advantages in the discovery of new antimicrobial drugs. EXPERT OPINION: C. elegans can be used, as a model host, to research many diseases, including fungal infections and Alzheimer's disease. In addition, high-throughput techniques, for screening chemical libraries, can also be facilitated. Nevertheless, C. elegans and mammals have significant differences that both limit the use of the nematode in research and the degree by which results can be interpreted. That being said, the use of C. elegans in drug discovery still holds promise and the field continues to grow, with attempts to improve the methodology already underway. PMID- 21686093 TI - Use of a Parent Management Training Intervention with Urban Foster Parents: A Pilot Study. AB - The development of effective interventions for foster children with behavior problems is essential given the consequences of behavior problems for children's placement stability and permanency outcomes. This article presents findings from a pilot study of an intervention providing parent management training (PMT) and support to foster parents in groups and home visits. The intervention was an adaptation of the KEEP (Keeping Foster Parents Trained and Supported) group intervention, provided in a large urban child welfare agency serving predominantly African American foster parents. The study used an intent-to-treat design, with 25 foster parents of 31 children (age 4-12) in specialized foster care assigned to either an intervention or treatment as usual control group. Longitudinal outcomes were analyzed using random effect regression models. Over time, children's behavior problems were significantly lower in the intervention group relative to the control group, and the effect of the intervention was partially mediated by parents' understanding of how to appropriately use the intervention parenting skills. These results provide support for the effectiveness of KEEP with urban foster children with significant behavior problems. PMID- 21686094 TI - The privileged status of locality in consonant harmony. AB - While the vast majority of linguistic processes apply locally, consonant harmony appears to be an exception. In this phonological process, consonants share the same value of a phonological feature, such as secondary place of articulation. In sibilant harmony, [s] and [?] ('sh') alternate such that if a word contains the sound [?], all [s] sounds become [?]. This can apply locally as a first-order or non-locally as a second-order pattern. In the first-order case, no consonants intervene between the two sibilants (e.g., [pisasu], [pi?a?u]). In second-order case, a consonant may intervene (e.g., [sipasu], [?ipa?u]). The fact that there are languages that allow second-order non-local agreement of consonant features has led some to question whether locality constraints apply to consonant harmony. This paper presents the results from two artificial grammar learning experiments that demonstrate the privileged role of locality constraints, even in patterns that allow second-order non-local interactions. In Experiment 1, we show that learners do not extend first-order non-local relationships in consonant harmony to second-order nonlocal relationships. In Experiment 2, we show that learners will extend a consonant harmony pattern with second-order long distance relationships to a consonant harmony with first-order long distance relationships. Because second-order non-local application implies first-order non local application, but first-order non-local application does not imply second order non-local application, we establish that local constraints are privileged even in consonant harmony. PMID- 21686096 TI - Launching Cellular Logistics. PMID- 21686095 TI - One Pot Spiropyrazoline Synthesis via Intramolecular Cyclization/Methylation. AB - Regioisomeric spiropyrazolines were synthesized through a tandem intramolecular cyclization/methylation reaction of a functionalized 5,5-disubstituted pyrazoline in one reaction vessel. The 5,5-pyrazolines were constructed through a 1,3 dipolar cycloaddition reaction of aromatic ring containing nitrile imines and a disubstituted geminal alkene. An evaluation of the relative location of the nucleophilic and electrophilic functional groups on the pyrazoline was performed in order to ascertain the best pyrazoline system for the intramolecular cyclization/methylation reaction. Higher spiropyrazoline isolated yields were realized from pyrazolines with the electrophilic ester located further away from the pyrazoline when compared to pyrazolines with a directly bonded ester. PMID- 21686097 TI - The Cellular Logistics Blog (CellLogBlog): A place for reviews and reasoned debate. PMID- 21686098 TI - This article contains supplemental information... or not. PMID- 21686099 TI - A brief history of the cisternal progression-maturation model. PMID- 21686100 TI - Involvement of pigment globules containing multiple melanosomes in the transfer of melanosomes from melanocytes to keratinocytes. AB - The mechanism of melanosome transfer from melanocytes to keratinocytes has not been fully clarified. We now show a route of melanosome transfer using co cultures of normal human melanocytes and keratinocytes. Substantial levels of melanosome transfer were elicited in co-cultures of melanocytes and keratinocytes separated by a microporous membrane filter. The melanocyte dendrites penetrated into the keratinocyte layer through the filter and many pigment globules were observed in keratinocytes. Electron microscopic observations revealed that melanosomes incorporated in keratinocytes were packed in clusters enclosed by a double membrane. Numerous pigment globules budded off from melanocyte dendrites and were released into the culture medium. Those pigment globules were filled with multiple melanosomes and a few mitochondria but no nuclei. When those globules were added to the culture medium of keratinocytes, they were incorporated and showed double membrane-enclosed melano-phagolysosomes consistent with the structures obtained from the co-culture system. In contrast, when individual naked melanosomes isolated from melanocytes were added to keratinocytes, they were also phagocytosed by keratinocytes but were enclosed by a single membrane in a manner distinct from the co-culture system. These results suggest a novel mechanism of melanosome transfer, wherein melanosomes are packed in membrane globules that bud off from melanocyte dendrites, where they are released into the extracellular space and then phagocytosed by keratinocytes. PMID- 21686101 TI - Ypt31/32 GTPases and their F-Box effector Rcy1 regulate ubiquitination of recycling proteins. AB - Ypt/Rab GTPases are conserved molecular switches that regulate the different steps of intracellular trafficking pathways. In yeast, the Ypt31/32 GTPases are required for exit from the trans-Golgi and for recycling from the plasma membrane (PM), through early endosomes, to the Golgi. We have previously shown that the recycling function of Ypt31/32 is mediated by an effector called Rcy1. Specifically, both Ypt31/32 and Rcy1 are required for recycling the vSNARE Snc1. Rcy1 contains an F-box domain shared by proteins that act in substrate recognition of ubiquitin ligases. Here, we show that both Ypt31/32 and Rcy1 are important for Snc1 ubiquitination and that such ubiquitination plays a role in Snc1 recycling. Direct interaction between Rcy1 and Snc1 was demonstrated using two independent approaches. In vitro interaction was observed using co precipitation of recombinant proteins, whereas interaction in yeast cells was observed using bimolecular fluorescence complementation. Ubiquitination of Snc1 in vivo at the K63 position was previously shown in a proteomic study. We show that the Snc1-K63R mutant protein is less ubquitinated than wild-type Snc1 and is defective in endosome-to-Golgi transport. Additionally, wild-type Snc1 is ubiquitinated to a lesser extent in ypt31/32ts and rcy1Delta mutant cells and Snc1 recycling is also blocked in endosomes in these mutants. Therefore, ubiquitination plays a role in the recycling of Snc1 from the PM to the Golgi, and Ypt31/32 and Rcy1 regulate this ubiquitination. Together, these results suggest a new role for ubiquitination in cargo recycling. Moreover, we propose that Ypt/Rabs integrate intra-cellular trafficking with ubiquitination. PMID- 21686102 TI - Circadian genes and insulin exocytosis. AB - The molecular clock controls 24-hour cycles of behavioral and physiological processes across the day-night cycle. Disruption of circadian rhythmicity has been implicated in the pathogenesis of several diseases, including the metabolic syndrome, although the role of clock genes in these disorders is still not well understood. Studies of the etiology of diabetes in circadian mutant mice have revealed a novel role for the clock in pancreatic beta-cell insulin secretion, suggesting that a major cellular function of the circadian network involves control of protein exocytosis. PMID- 21686103 TI - mRNA imprinting: Additional level in the regulation of gene expression. AB - Following its synthesis in the nucleus, mRNA undergoes various stages that are critical for the proper synthesis, localization and possibly functionality of its encoded protein. Recently, we have shown that two RNA polymerase II (Pol II) subunits, Rpb4p and Rpb7p, associate with the nascent transcript co transcriptionally. This "mRNA imprinting" lasts throughout the mRNA lifetime and is required for proper regulation of all major stages that the mRNA undergoes. Other possible cases of co-transcriptional imprinting are discussed. Since mRNAs can be transported from the synthesizing cell to other cells, we propose that mRNA imprinting can also affect the phenotype of the recipient cells. This can be viewed as "mRNA-based epigenetics." PMID- 21686104 TI - Editorial Introduction: Welcome to Journal of Interventional Gastroenterology (JIG). PMID- 21686105 TI - Retrospective analysis showing the water method increased adenoma detection rate a hypothesis generating observation. AB - BACKGROUND: A water method developed to attenuate discomfort during colonoscopy enhanced cecal intubation in unsedated patients. Serendipitously a numerically increased adenoma detection rate (ADR) was noted. OBJECTIVE: To explore databases of sedated patients examined by the air and water methods to identify hypothesis generating findings. DESIGN: Retrospective analysis. SETTING: VA endoscopy center. PATIENTS: creening colonoscopy. INTERVENTIONS: From 1/2000-6/2006 the air method was used - judicious air insufflation to permit visualization of the lumen to aid colonoscope insertion and water spray for washing mucosal surfaces. From 6/2006-11/2009 the water method was adopted - warm water infusion in lieu of air insufflation and suction removal of residual air to aid colonoscope insertion. During colonoscope withdrawal adequate air was insufflated to distend the colonic lumen for inspection, biopsy and polypectomy in a similar fashion in both periods. Main outcome measurements: ADR. RESULTS: The air (n=683) vs. water (n=495) method comparisons revealed significant differences in overall ADR 26.8% (183 of 683) vs. 34.9% (173 of 495) and ADR of adenomas >9 mm, 7.2% vs. 13.7%, respectively (both P<0.05, Fisher's exact test). LIMITATIONS: Non-randomized data susceptible to bias by unmeasured parameters unrelated to the methods. CONCLUSION: Confirmation of the serendipitous observation of an impact of the water method on ADR provides impetus to call for randomized controlled trials to test hypotheses related to the water method as an approach to improving adenoma detection. Because of recent concerns over missed lesions during colonoscopy, the provocative hypothesis-generating observations warrant presentation. PMID- 21686106 TI - The water method significantly enhances proximal diminutive adenoma detection rate in unsedated patients. AB - BACKGROUND: Colonoscopy has been reported to fail to prevent some post screening colonoscopy incident cancers or minimize cancer mortality in the proximal colon. These reports question the effectiveness of colonoscopy in detecting all proximal adenomas. Diminutive ones which can be obscured by residual feces are particularly at risk. The water method provides salvage cleansing of sub-optimal preparations. OBJECTIVE: To test the hypothesis that the water method enhances proximal diminutive adenoma detection rate (ADR). DESIGN: The data bases of two parallel RCT were combined and analyzed. SETTING: Two Veterans Affairs endoscopy units. PATIENT AND METHODS: The water and air methods were compared in these two parallel RCT examining unsedated patients. MAIN OUTCOME MEASUREMENTS: The combined data on diminutive and overall ADR in the proximal colon, overall ADR, cecal intubation rate, withdrawal time and global bowel cleanliness score. RESULTS: Data in the water (n=92) and the air (n=90) groups were assessed. The water method yielded a significantly higher proximal diminutive ADR, 28.3% vs. 14.4% (p=0.0298); cecal intubation rate, 99% vs. 90% (p=0.0091); mean withdrawal time 19 (10) vs. 15 (8) min (p=0.0065) and mean global bowel cleanliness score during withdrawal, 2.6 (0.7) vs. 2.3 (0.6) (p=0.0032). Increase in proximal overall ADR in the water group approached significance, 29.3% vs. 16.7% (p=0.0592). LIMITATION: Small number of predominantly male veterans. CONCLUSION: The significantly higher cecal intubation rate, longer mean withdrawal time and better mean global bowel cleanliness score favor the outcome of significantly enhanced proximal diminutive ADR in the water group. PMID- 21686107 TI - ERCP training - the potential role of simulation practice. AB - Clinical ERCP training is limited by the availability of patients. Different ERCP simulators are available to supplement the basic training of novice trainees. An IDEAL simulation practice should provide trainees with the opportunity to Improve basic skills, Demonstrates realism, with Ease of incorporating into a training program and Application in teaching therapeutic techniques, and allows Learning with real scope and accessories including the use of simulation fluoroscopy. Whether simulation practice will impact trainee performance and clinical outcome of ERCP procedures will require prospective evaluation with randomized controlled studies. PMID- 21686108 TI - Is there a place for sedationless colonoscopy? AB - Usedated colonoscopy is routinely available in many parts of the world. In the US, only educated professionals appear to be knowledgeable enough to request the unsedated option. Colonoscopists have also been willing to perform unsedated colonoscopy when a patient presents without an escort after undergoing bowel purge preparation. While the actual side-effects of sedation are minimal, the escort requirement and time burden of sedation are barriers to the uptake of screening colonoscopy in the US. The recent trend of deep sedation with propofol for screening colonoscopy increases the efficiency of the colonoscopists at significant costs (e.g. anesthetist reimbursement). The options of as needed and on demand sedation permit patients to complete colonoscopy without sedation. The latter appears to be potentially less coercive. Nurses with experience in the unsedated options recognize the benefit of the quick turn-around of the examination room and shortened occupancy of the recovery area. Discharge planning can be optimized due to absence of amnesia. Patients completing unsedated colonoscopy have given their endorsement of the options. Pain and discomfort continue to limit the success rate of cecal intubation to about 80%. A recently described water method (warm water infusion in lieu of air insufflation combined with removal of all residual colonic air by suction and residual feces by water exchange) has the potential of decreasing procedural discomfort and enhancing cecal intubation in unsedated colonoscopy. The availability of the novel water method assures colonoscopists that high success rate of cecal intubation can be achieved in the unsedated patients. PMID- 21686109 TI - Endoscope-assisted brachytherapy for pancreatic cancer: From tumor killing to pain relief and drainage. AB - Locally advanced or metastatic pancreatic cancer has been a long-term challenge to clinicians, due to the poor overall survival rate compared with that of other gastrointestinal malignancies. Recently, with the emerging applications of therapeutic endoscopic ultrasonography (EUS), EUS- guided fine needle injection with antitumor agents is considered a promising modality. In this review, we summarize recently published data on the efficacy of endoscope guided interventional procedures with radioactive seeds. Firstly, EUS-guided iodine-125 seed implantation was reported to have a short-term efficacy on pancreatic cancer, with a three-month partial remission rate of 13.6% to 27%. Thereafter, feasibility of celiac ganglion radiation was tested in animal models to achieve pain relief. Recently, a seed-based stent has been introduced in the endoscopic retrograde cholangio-pancreatography (ERCP) drainage of biliary obstruction caused by pancreatic cancer, with a response rate of 72.7%. In addition, we discuss the potential of radioactive seed-based, endoscope-assisted interventional treatment of patients with locally advanced pancreatic cancer. Further studies should focus on the precise amount and distribution of seeds with the aim to improve the survival rate as well as the quality of life. PMID- 21686110 TI - Unusual locations of pseudo aneurysms as a sequel of chronic pancreatitis. AB - In patients with chronic pancreatitis, an actively bleeding pseudo aneurysm can be life threatening. Common sites of pseudoaneurysms are splenic, gastro duodenal, superior & inferior pancreaticoduodenal arterial branches. Angioembolisation is an effective alternative to a complex and morbid operative management. Here we report 4 cases of unusual sites of pseudoaneurysms as a complication of pancreatitis, involving superior mesenteric and inferior phrenic arteries. Successful angioembolisation using glue and coil was achieved in 3 patients where as one underwent surgery. Technical success was 100% with the combination approach, though one patient died from multiorgan failure. This short case series reiterates the importance of vascular complications in pancreatitis at rare sites and also timely combined radiological and surgical approach for ensuring favorable outcome. PMID- 21686111 TI - Porto-gastric fistula from penetration of coil from gastric varix after TIPS procedure for bleeding gastric varices. PMID- 21686112 TI - Anomalous biliary duct mistaken as hilar stricture. A case report. AB - Anomalous biliary anatomy is frequently encountered by surgeons during cholecystectomy. Importance of its recognition lies in avoiding serious biliary injuries. One such anomaly is cholecystohepatic duct. We describe rare clinical situation wherein agenesis of CHD along with cholecystohepatic duct was mistaken for hilar stricture. PMID- 21686114 TI - The patient's perspective - patients should be made aware of the options of sedation or no sedation and have a choice in screening colonoscopy. PMID- 21686113 TI - Options of sedation or no sedation for colonoscopy - the perspective of the GI nurses and technicians. AB - OBJECTIVE: Nurses (patient-advocates) and technicians (member of colonoscopy team) collected data on patient discomfort and evaluated various options of sedation or no sedation associated with the air and water methods for performing colonoscopy. METHOD: Veterans participated in studies comparing air and water method colonoscopy. Options using minimal or on demand sedation were evaluated. RESULTS: Compared with the air method, the water method was associated with significantly lower pain scores, higher patient satisfaction ratings and shorter recovery times. On demand sedation was comparable to routine sedation when the water method was used. Patients prefer to be in control of when their medications would be administered during colonoscopy. CONCLUSION: Evaluations by nurses (patient advocates) and technicians (member of colonoscopy team) with experience in assisting patients undergoing colonoscopy using the various options indicate the following. In settings without access to sedation, the water method is ideal for unsedated colonoscopy or extended flexible sigmoidoscopy for screening. Otherwise, the water method and on demand sedation is the most credible combination of options for patient care. PMID- 21686115 TI - Patients' perspective - written testimonials from physician-patients and oral accounts presented by patients in person. PMID- 21686116 TI - Introduction to Small GTPases. PMID- 21686119 TI - Distinct roles of Rac GTPases and the UNC-73/Trio and PIX-1 Rac GTP exchange factors in neuroblast protrusion and migration in C. elegans. AB - The Rac and Cdc42 GTPases as well as the multiple GTP exchange factors that regulate their activity have been implicated in the pathways that drive actin cytoskeleton reorganization, but the individual contributions of these molecules to cell migration remain unknown. Studies shown here examine the roles of CED 10/Rac, MIG-2/RhoG and CDC-42 in the migration of the QL and QR neuroblasts in C. elegans. CED-10/Rac was found to normally limit protrusion and migration, whereas MIG-2/RhoG was required for protrusion and migration. CED-10/Rac and MIG-2/RhoG also had redundant roles in Q protrusion and migration. Surprisingly, CDC-42 was found to have only weak effects on the protrusion and the migration. We found that a mutation of unc-73/Trio, which encodes a GEF for CED-10/Rac and MIG 2/RhoG, caused protrusions that were thin and filopodia-like, suggesting that UNC 73/Trio is required for robust lamellipodia-like protrusion. A screen of the 19 C. elegans Dbl homology Rho GEF genes revealed that PIX-1 was required for proper Q neuroblast protrusion and migration. Genetic analysis indicated that PIX-1 might act in the CED-10/Rac pathway in parallel to MIG-2/RhoG and that PIX-1 has redundant function with UNC-73/Trio in Q neuroblast protrusion and migration. These results indicate that Rho GTPases and GEFs have both unique and overlapping roles in neuronal migration. PMID- 21686120 TI - Structure of the MxA stalk elucidates the assembly of ring-like units of an antiviral module. AB - The dynamin-like MxA GTP ase (Myxovirus resistance protein 1) mediates cellular resistance against a wide range of viruses. MxA is composed of an amino-terminal G domain, a middle domain and a carboxy-terminal GTPase effector domain. We recently determined the structure of the middle domain and GTPase effector domain of MxA constituting an elongated helical stalk, and elucidated the mechanism how the stalk mediates formation of ring-like MxA oligomers. Here, we shortly review our work and discuss the MxA rings as functional units of a cellular module orchestrating and executing the antiviral response. PMID- 21686121 TI - RhoGDI: A rheostat for the Rho switch. AB - Regulation of the Rho switch has been typically centered on their main regulators, RhoGEFs and RhoGAPs. On the side, RhoGDI proteins have been considered mostly as passive regulators devoid of catalytic activity simply holding Rho proteins in the cytosol. In the May issue of Nature Cell Biology,1 we describe a novel evolutionary conserved function for RhoGDI1 as a chaperoning protein which prevents degradation of prenylated Rho GTPases. The limited amount of RhoGDI1 in cells generates a competitive balance between GTPases in order to prevent their degradation. Therefore, this creates a crosstalk regulatory mechanism of Rho proteins, whereby the level of one Rho protein can affect both the level and activity of the others. For example, overexpression of a single GTPase will promote the degradation and inactivation of all endogenous Rho proteins bound to GDI. These results suggest that some of the conclusions drawn from studies that manipulate Rho protein levels may need to be reevaluated. Here, we discuss some of the consequences of this mechanism on the regulation of Rho proteins, the dissociation of Rho-RhoGDI complexes by GDF and whether this regulation might be extended to other GTPases of the Ras superfamily. PMID- 21686118 TI - Rho-guanine nucleotide exchange factors during development: Force is nothing without control. AB - The development of multicellular organisms is associated with extensive rearrangements of tissues and cell sheets. The driving force for these rearrangements is generated mostly by the actin cytoskeleton. In order to permit the reproducible development of a specific body plan, dynamic reorganization of the actin cytoskeleton must be precisely coordinated in space and time. GTP exchange factors that activate small GTPases of the Rho family play an important role in this process. Here we review the role of this class of cytoskeletal regulators during important developmental processes such as epithelial morphogenesis, cytokinesis, cell migration, cell polarity, neuronal growth cone extension and phagocytosis in different model systems. PMID- 21686117 TI - Ras history: The saga continues. AB - Although the roots of Ras sprouted from the rich history of retrovirus research, it was the discovery of mutationally activated RAS genes in human cancer in 1982 that stimulated an intensive research effort to understand Ras protein structure, biochemistry and biology. While the ultimate goal has been developing anti-Ras drugs for cancer treatment, discoveries from Ras have laid the foundation for three broad areas of science. First, they focused studies on the origins of cancer to the molecular level, with the subsequent discovery of genes mutated in cancer that now number in the thousands. Second, elucidation of the biochemical mechanisms by which Ras facilitates signal transduction established many of our fundamental concepts of how a normal cell orchestrates responses to extracellular cues. Third, Ras proteins are also founding members of a large superfamily of small GTPases that regulate all key cellular processes and established the versatile role of small GTP-binding proteins in biology. We highlight some of the key findings of the last 28 years. PMID- 21686122 TI - A transcriptional cross-talk between RhoA and c-Myc inhibits the RhoA/Rock dependent cytoskeleton. AB - The GTPase RhoA and the transcriptional factor c-Myc are closely intertwined in cancer cells. Although this cross-talk results in potent synergistic effects that favor the transformed phenotype of cancer cells, recent results from our laboratory indicate that c-Myc also participates in a negative feed-back loop that blocks specific RhoA signaling branches connected to the induction of stress fibers, focal adhesions and actomyosin contractility. Using microarray analysis, we have unveiled a RhoA/c-Myc-dependent gene signature in charge of this negative cross-talk. This signature is composed of upregulated and repressed transcripts encoding cytoskeletal modulators located downstream of both RhoA and Rock. Our results also indicate that this negative feed-back loop modifies the invasion and adhesion properties of RhoA-transformed cells, suggesting that it may be important to ensure fluid cytoskeletal dynamics of cancer cells. Preliminary data indicate that c-Myc may also use a different transcriptional program to interfere with the RhoA/Rock-dependent cytoskeletal branch in non-transformed cells. PMID- 21686124 TI - Design and validity of a clinic-based case-control study on the molecular epidemiology of lymphoma. AB - We present the design features and implementation of a clinic-based case-control study on the molecular epidemiology of lymphoma conducted at the Mayo Clinic (Rochester, Minnesota, USA), and then assess the internal and external validity of the study. Cases were newly diagnosed lymphoma patients from Minnesota, Iowa and Wisconsin seen at Mayo and controls were patients from the same region without lymphoma who had a pre-scheduled general medical examination, frequency matched on age, sex and residence. Overall response rates were 67% for cases and 70% for controls; response rates were lower for cases and controls over age 70 years, cases with more aggressive disease, and controls from the local area, although absolute differences were modest. Cases and controls were well-balanced on age, sex, and residence characteristics. Demographic and disease characteristics of NHL cases were similar to population-based cancer registry data. Control distributions were similar to population-based data on lifestyle factors and minor allele frequencies of over 500 SNPs, although smoking rates were slightly lower. Associations with NHL in the Mayo study for smoking, alcohol use, family history of lymphoma, autoimmune disease, asthma, eczema, body mass index, and single nucleotide polymorphisms in TNF (rs1800629), LTA (rs909253), and IL10 (rs1800896) were at a magnitude consistent with estimates from pooled studies in InterLymph, with history of any allergy the only directly discordant result in the Mayo study. These data suggest that this study should have strong internal and external validity. This framework may be useful to others who are designing a similar study. PMID- 21686123 TI - Francisella Subverts Innate Immune Signaling: Focus On PI3K/Akt. AB - Intracellular bacterial pathogens exploit host cells as a part of their lifecycle, and they do so by manipulating host cell signaling events. Many such bacteria are known to produce effector proteins that promote cell invasion, alter membrane trafficking, and disrupt signaling cascades. This review highlights recent advances in our understanding of signaling pathways involved in host cell responses to Francisella tularensis, a facultative Gram-negative intracellular pathogen that causes tularemia. We highlight several key pathways that are targeted by Francisella, with a focus on the phosphatidylinositol 3-kinase/Akt pathway. Lastly, we discuss the emerging role of microRNAs (miRs), specifically miR-155, as a key regulator of host signaling and defense. PMID- 21686125 TI - Plasma alkaline phosphatase is elevated in Alzheimer's disease and inversely correlates with cognitive function. AB - Alkaline phosphatase is present on neuronal membranes and plasma alkaline phosphatase activity increases in brain injury and cerebrovascular disease, suggesting that plasma alkaline phosphatase may partly reflect neuronal loss. As neuronal loss occurs in Alzheimer's disease (AD), we hypothesised that alterations in plasma alkaline phosphatase activity may correlate with cognitive impairment. Plasma alkaline phosphatase activity was measured in the longitudinal Oxford Project to Investigate Memory and Aging (OPTIMA) cohort (121 AD patients, 89 mild cognitive impairment (MCI) patients and 180 control subjects). Plasma alkaline phosphatase activity was significantly higher in the AD patients relative to the controls (p<0.001). In the MCI patients, plasma alkaline phosphatase was at a level in between that seen in control and AD subjects, consistent with the clinical status of this group. Furthermore, plasma alkaline phosphatase activity inversely correlated with cognitive function (assessed by the Cambridge Examination for Mental Disorders (CAMC0G)) in controls (z= -2.21 p=0.027), MCI (z= -2.49, p=0.013) and AD patients (z= -3.61, p=0.0003). These data indicate that plasma alkaline phosphatase activity is increased in AD and inversely correlates with cognitive function regardless of diagnostic status. PMID- 21686126 TI - An assessment of CETP sequence variation in relation to cognitive decline and dementia risk. AB - The gene encoding the cholesteryl ester transfer protein (CETP) plays an integral role in lipid metabolism. We evaluated common genetic variation spanning CETP for association with cognitive decline as well as incident and prevalent dementia and Alzheimer disease risk. Data from four population-based twin studies and a case control sample were included, encompassing an analysis sample of 1513 dementia cases and 2137 controls with available CETP genotypes and covariates. Memory and perceptual speed performance was assessed over 16 years in up to 1540 participants. Only sporadic associations were observed across 26 markers and were largely consistent with statistical noise. Polymorphism in CETP is unlikely to contribute to cognitive change or dementia risk. PMID- 21686127 TI - Emergence of novel Norovirus recombinants with NVGII.1/NVGII.5 RdRp gene and NVGII.13 capsid gene among children and adults in Kolkata, India. AB - Norovirus (NoV) is a leading cause of non bacterial acute gastroenteritis in human beings. Molecular characterization of NoVs following continuous, stringent surveillance had earlier shown that novel strains representing an intergenogroup as well as GII NoV intergenotype recombinants were in circulation among acute watery diarrhoea cases in Kolkata, India. The present study documents characterization of two recombinant NoV strains (Hu/NoV/ IDH1501/2009/IND and Hu/NoV/IDH1873/2009/IND) along with other interesting GII NoV strains. Similarity plot and phylogenetic analysis confirmed the strain Hu/NoV/IDH1501/2009/IND as a NoV recombinant strain with genes for RNA dependent RNA polymerase (RdRp) GII.1 like and capsid GII.13-like; the strain Hu/NoV/IDH1873/2009/IND was a NoV recombinant strain with its RdRp gene GII.5-like and capsid gene being GII.13 like. Clinical symptoms chiefly associated with the cases that had NoV infection was varying duration of diarrohea and vomiting with some dehydration. PMID- 21686128 TI - Novel abdominal adiposity genes and the risk of type 2 diabetes: findings from two prospective cohorts. AB - Three loci were recently identified for central adiposity from a genome wide association study (MSRA [rs545854; G/C], LYPLAL1 [rs2605100; G/A], TFAP2B [rs987237; A/G]). Central obesity is a strong risk factor for type 2 diabetes (T2D). Therefore, we hypothesized that these single nucleotide polymorphisms (SNPs) would be associated with increased risk of T2D and may influence circulating adipokine concentrations. Participants from two large case control studies nested in the Nurses' Health Study (3394 women, 1245 cases) and the Health Professionals Follow-up Study (2154 men, 862 cases) were genotyped for these SNPs. The association of these SNPs with plasma adipokine concentrations was determined among a subgroup of women without diabetes (n=987). After adjustment for age and other risk factors of diabetes, the MSRA variant was associated with an increased T2D risk in men only, with an adjusted OR of 1.30 (95% CI: 1.09-1.56) associated with each copy of the variant allele. In pooled analyses of men and women, each additional copy of the LYPLAL1 allele (G) was associated with 9% increased T2D risk (adjusted OR 1.09; 95%CI: 0.99-1.19). No significant associations were seen with the TFAP2B SNP with a pooled adjusted OR of 1.05 (95% CI: 0.95-1.17) per allele copy. In addition, carriers of the MSRA risk variant had lower percent high molecular weight adiponectin (-2.1%, p=0.04). Carriers of the TFAP2B risk variant, however, had lower leptin levels (-2.7 ng/ml, p=0.005). These findings suggest potential associations of novel central obesity genes with T2D risk and adipokine regulation. PMID- 21686129 TI - Discovery of common SNPs in the miR-205/200 family-regulated epithelial to mesenchymal transition pathway and their association with risk for non-small cell lung cancer. AB - The activation of the epithelial-to-mesenchymal transition (EMT) program is an important step for tumor initiation, invasion, and metastasis in solid tumors, including lung cancer. The purpose of this study was to identify the sequence variants in the miR-205/200 family-regulated EMT pathway and test their association with risk for lung cancer. Fifty samples were resequenced to identify sequence variants in the miR-205/200 family-regulated EMT pathway. The association between tagSNPs and risk for non-small cell lung cancer was discovered and validated in New Mexico (386 cases and 514 controls) and Massachusetts (2453 cases and 1555 controls) case-control studies, respectively. The function of SNPs on miR-200b-a-429 promoter activity was tested using luciferase reporter and expression assays. Forty-one sequence variants with minor allele frequency >= 0.03 were identified, and 16 variants were selected as tagSNPs. Genetic association analysis identified that the G allele of rs61768479 was associated with a 50% reduced risk for lung cancer (OR=0.50, 95%CI=0.30-0.85, uncorr-P=0.01); however, this association was not validated (OR=0.90, 95%CI=0.72 1.13, uncorr-P=0.35). The G allele of rs61768479 was associated with lower promoter activity and miR expression by disrupting the binding of NKX2.5. In summary, no association was identified between sequence variants in the miR 205/200 family-regulated EMT pathway and risk for lung cancer. However, this study identified a comprehensive panel of tagSNPs (n=16) in the miR-205/200 family-regulated EMT pathway that can be applied to other EMT-related phenotypes such as cancer chemoresistence and prognosis. PMID- 21686130 TI - Tumour necrosis factor-alpha (TNF-alpha) and miRNA expression in frontal and temporal neocortex in Alzheimer's disease and the effect of TNF-alpha on miRNA expression in vitro. AB - Micro-RNAs (miRNAs) are short non-coding RNAs capable of regulating gene expression at the translational level. A number of studies have suggested that the expression of several miRNAs is changed in AD. The pro-inflammatory cytokine tumour necrosis factor-a (TNF-alpha) is increased in serum and CSF in AD. We measured the expression of TNFA and several AD candidate gene-associated miRNAs (let7a/b, miR-128a/b, miR-27a/b, miR-155) in frontal and temporal neocortex from AD and control brains. The expression of these miRNAs was also measured after incubating non-differentiated (NDC) and retinoic acid -differentiated (DC) SH SY5Y neuroblastoma cells with TNF-alpha. TNFA expression was similar in AD and control brains but miR-128a/b levels were significantly reduced in the temporal cortex and miR-128b in the frontal cortex in AD. MiRNA levels did not correlate with TNFA expression in brain tissue but exposure of NDC and DC SH-SY5Y cells to TNF-alpha caused a variable dose-dependent response in the level of some of the miRNAs studied. Our brain tissue findings argue against a role for TNF-alpha in influencing the expression of these miRNAs in AD. PMID- 21686131 TI - Effect of genome-wide simultaneous hypotheses tests on the discovery rate. AB - An increasing number of genome-wide association studies are being performed in hundreds of thousands of single nucleotide polymorphisms (SNPs). Many of such studies carry on a second stage in which a selected number of SNPs are genotyped in new individuals in order to validate genome-wide findings. Unfortunately, a large proportion of such studies have been unable to validate the genome-wide findings. In this study we aim to better understand how to distinguish the truly associated features from the false positives in genome-wide scans. In order to achieve this goal we use empirical data to look at three aspects that may play a key role in determining which features are called to be associated with the phenotype. First, we examine the usual assumption of a uniform distribution on null p-values and assess whether or not it affects which features are called significant and the number of significant features. Second, we compare the global behavior of the p-value distribution genome-wide with the local behavior at regions such as chromosomes. Third, we look at the effect of minor allele frequency in the p-value distribution. We show empirically that the uniform distribution is not a generally valid assumption and we find that as a consequence strikingly different conclusions can be drawn regarding what we call significant associations and the number of significant findings. We propose that in order to better assign significance to potential associations one needs to estimate the true distribution of null and non-null p-values. PMID- 21686132 TI - Comparison of PCR with other diagnostic techniques for the detection of H. pylori infection in patients presenting with gastroduodenal symptons in Nigeria. AB - The study was aimed at comparing PCR methods of direct detection from biopsy using the boiling method and one other method with two known gold standards (histology and CLO test) for the diagnosis of H. pylori in Nigeria. A total of 168 biopsies (three from antrum and one from corpus each) were taken from 42 patients presenting with various gastroduodenal symptons after informed consent was obtained from them.The biopsies were analysed using the CLO test kit and histology, while the boiling method as described by Holmes and Quigley (1981) was used to obtain DNA and then PCR using the 16S rRNA gene, glmM gene and cagA gene. With CLO test 15/42 (35.71%) were positive, histology 13/42 (30.95%) were positive, 16S rRNA 22/42 (52.38%) were positive, glmM 19/42 (45.24%) were positive, cagA 19/42 (45.24%) were positive. The sensitivity and specificity of the PCR tests with CLO as the gold standard showed that the tests were 100% sensitive and varied between 74.1% to 84.1% in specificity. The PPV and NPV showed that the NPV was almost 100%, while the PPV was between 68.2% and 75%. Using the histology as the gold standard, the sensitivity was almost 100% while the specificity, the PPV were reduced in comparison to the CLO test. The PCR test using the glmM gene appears to be the most reliable test for diagnosis of H. pylori in Nigeria most especially where culture is difficult due to the power outages. PMID- 21686133 TI - Polymorphisms in ABCB1 and ERCC2 associated with ovarian cancer outcome. AB - Using the most comprehensive approach to selecting polymorphisms to date, we sought to examine whether time to recurrence in ovarian cancer was associated with common inherited variation in eight genes involved in drug metabolism, multi drug resistance, or DNA repair, namely ABCB1, CYP2C8, CYP3A4, ERCC1, ERCC2, GSTM1, XPC, and XRCC1. Invasive epithelial ovarian cancer patients (N=445) seen at the Mayo Clinic from 1999 to 2009 with 275 observed recurrences or deaths were analyzed at 94 SNPs in these candidate genes. Cox regression was used to estimate hazard ratios and 95% confidence intervals for each single nucleotide polymorphism (SNP) and outcome (defined as time to recurrence or death). Analyses were conducted at the gene level and on case subsets defined by histopathology and chemotherapeutic agent. At ABCB1, minor alleles at several SNPs were associated with outcome, with the most significant being the intronic SNP rs12334183 (HR=0.65, 95% Cl 0.51-0.83; p=0.0005). Overall variation in ABCB1 was predictive of outcome as well (p=0.003). At ERCC2, minor alleles at several SNPs were associated with outcome among women with high-grade serous disease (e.g., rs238417, HR 0.74, 95% Cl 0.59-0.92; p=0.006). No associations with outcome were observed in GSTM1, CYP2C8, CYP3A4, ERCC1, XPC, or XRCC1. In summary, inherited variation in ABCB1 and ERCC2 was associated with outcome in patients with ovarian cancer seen at the Mayo Clinic. As the associated SNPs have not been studied previously in ovarian cancer, these findings suggest novel sites of variation which may, in part, explain the range of treatment responses seen in this disease. PMID- 21686134 TI - Development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of IGF2-P3 and IGF2-P4 regulatory sequences. AB - BACKGROUND: The human IGF2-P3 and IGF2-P4 promoters are highly active in bladder carcinoma, while existing at a nearly undetectable level in the surrounding normal tissue. A double promoter DTA-expressing vector was created, carrying on a single construct two separate genes expressing diphtheria toxin A-fragment (DTA), from two different regulatory sequences, selected from the cancer-specific promoters IGF2-P3 and IGF2-P4. METHODS: IGF2-P3 and IGF2-P4 expression was tested in samples of urothelial carcinoma (UC) of the bladder (n=67) by RT-PCR or by ISH. The therapeutic potential of single promoter expression vectors (P3-DTA and P4-DTA) was tested and compared to the double promoter toxin vector P4-DTA-P3-DTA in UC cell lines and in heterotopic and orthotopic animal models for bladder cancer. RESULTS: Nearly 86% of UC patients highly expressed IGF2-P4 and IGF2-P3, as determined by ISH. The double promoter vector (P4-DTA-P3-DTA) exhibited superior ability to inhibit tumor development by 68% (P=0.004) compared to the single promoter expression vectors, in heterotopic bladder tumors. The average size of the P4-DTA-P3-DTA bladder tumors (in orthotopically treated mice) was 83% smaller (P<0.001) than that of the control group. CONCLUSIONS: Overall, the double promoter vector exhibited enhanced anti-cancer activity relative to single promoter expression vectors carrying either gene alone. Our findings show that bladder tumors may be successfully treated by intravesical instillation of the double promoter vector P4-DTA-P3-DTA. PMID- 21686135 TI - Mg deficiency results in modulation of serum lipids, glutathione, and NO synthase isozyme activation in cardiovascular tissues: relevance to de novo synthesis of ceramide, serum Mg and atherogenesis. AB - The present work tested the hypothesis that short-term (S-T) dietary deficiency of magnesium (Mg) (21 days) in rats would: 1) result in reduction in serum(s) sphingomyelin (SM) and changes in several blood lipids, HDL-cholesterol (HDL-C) and phosphatidylcholine (PC) concomitant with elevations in s cholesterol (chol), s LDL+VLDL and trigycerides (TG), as well as reduction in the PC/cholesterol ratio; 2) lead to oxidative stress, characterized by reductions in glutathione (glut) content in the various chambers of the heart and activation of e-NOS and n NOS in the atria, ventricles and aortic smooth muscle (ASM); 3) produce early cardiac damage characterized by leakage of creatine kinase (CK) and lactic dehydrogenase (LDH); and 4) demonstrate that these pathophysiological changes are a result of profound reductions in s ionized Mg (Mg(2+)) and activation of the SM ceramide pathway. In addition, we hypothesized that: 1) exposure of primary cultured vascular smooth muscle cells (VSMCs) to low extracellular Mg(2+) would lead to de novo synthesis of ceramide and activation of NO synthase with reduction in glut, both of which would be attenuated by inhibition of sphingomyelinase (SMase) and serine palmitoyl CoA transferase (SPT); and 2) low levels of Mg(2+)added to the drinking water would either prevent or ameliorate these manifestations. Our data indicate that S-T Mg deficiency resulted in reductions in s Mg(2+), SM, PC, HDL-C and the PC/chol ratio concomitant with decreases in tissue levels of glut, leakage of cardiac CK and LDH, as well as activation of e-NOS and n-NOS in all chambers of the heart and ASM. The greater the reduction in s Mg(2+), the greater the effects on all parameters analyzed; very significant correlations to levels of s SM and Mg(2+) were found with all of the serum and tissue biochemical -molecular analytes measured. Our experiments also showed that VSMCs exposed to low Mg(2+)resulted in activation of NO synthase, loss of glut and de novo synthesis of ceramide which were attenuated by inhibitors of SMase and SPT. Low levels of drinking water Mg(2+)(e.g., 15 ppm) were cardio- and vascular protective. We believe these new findings support our concept of an important role for the SM-ceramide pathway in the manifestations of Mg deficiency and atherogenesis. PMID- 21686136 TI - Studies of the pharmacology of 17alpha-ethynyl-androst-5-ene-3beta,7beta,17beta triol, a synthetic anti-inflammatory androstene. AB - 17alpha-Ethynyl-androst-5ene-3beta, 7beta, 17beta-triol (HE3286) is an orally bioavailable analogue of androst-5-ene-3beta,7beta,17beta-triol, a non glucocorticoid anti-inflammatory metabolite of the adrenal steroid, dehydroepiandrosterone. The pharmacology of HE3286 was characterized in preparation for clinical trials in type 2 diabetes mellitus and other diseases of inflammation. Interactions with nuclear hormone receptors and P450 enzymes were measured in vitro. Drug metabolism was studied preclinically in mice, rats, dogs, and monkeys. Neurological and cardiopulmonary safety and dose-ranging and chronic toxicity studies were conducted in rats and dogs in accordance with FDA guidelines. Pharmacokinetics and metabolites were measured in Phase I clinical trials. HE3286 was differentially metabolized between species. HE3286 and metabolites did not bind or transactivate steroid binding nuclear hormone receptors or inhibit P450 enzymes. There were no adverse effects in safety pharmacology and canine toxicology studies. Although HE3286 did not elicit systemic toxicity in rats, mild estrogenic effects were observed, but without apparent association to hormonal changes. Safety margins were greater than 20 fold in rats and dogs with respect to the most commonly used clinical dose of 10 mg/day. The terminal half-life in humans was 8 hours in males and 5.5 hours in females. HE3286 is the first derivative of the DHEA metabolome to undergo a comprehensive pharmacological and safety evaluation. The results of these investigations have shown that HE3286 has a low potential for toxicity and possesses pharmacological properties generally suitable for use in human medicine. The favorable profile of HE3286 warrants further exploration of this new class of anti-inflammatory agents. PMID- 21686137 TI - Effects of panax quinquefolium on streptozotocin-induced diabetic rats: role of C peptide, nitric oxide and oxidative stress. AB - BACKGROUND: Insulin-dependent diabetes mellitus are at high risk for vascular disorders as hypertension and nephropathy. Ginseng is one of the most widely used herbal medicines and is reported to have a wide range of therapeutic and pharmacological applications for antioxidant and vasorelaxation although the mechanism is not clear. This study, aimed to evaluate hypoglycemic, antioxidant and vasodilator effects of Panax quinquefolium aqueous ginseng extract (AGE) against streptozotocin (STZ)-induced diabetes in male rats. Furthermore explore the role of AGE in C-peptide and nitric oxide (NO) and their relation in STZ induced diabetic rats. METHODS: Thirty White male Sprague daw-ley rats weighing 150-200 gm, about 4 month old were equally divided into the following: a control group (normal, nondiabetic), a diabetic group induced by intraperitoneal (I/P) injection of STZ (non-AGE-treated) and an AGE-treated diabetic group (STZ+AGE) (for 8 days). Serum level of urea, creatinine, glucose, insulin, C-peptide and NO were analyzed. Activities of hepatic glucose-6-phosphatase (G6Pase), hepatic glycogen phosphorylase and the renal antioxidant enzyme, catalase were analyzed. Also renal oxidative stress marker malondialdehyde (MDA) was measured. RESULTS: Data showed that STZ treated rats produced a significant increased level of serum urea, creatinine, glucose, NO and renal MDA. Also, induced significantly higher activities of hepatic G6Pase and glycogen phosphorylase compared with controls, while give significant lowered serum insulin, C-peptide level and renal catalase activity. Whereas treatment with AGE led to a significant amelioration in the hyperglycemia (lower the activity of G6Pase and glycogen phosphorylase), hyperinsulinemia and oxidative stress markers. Besides declining the higher level of renal function test and NO. CONCLUSIONS: STZ induced-diabetes (DM) associated with renal function disturbances, hypoinsulinemia, defective antioxidant stability and increased (NO) this may have implications for the progress of DM and its related problems. Treatment with AGE improved DM and its associated metabolic problems in different degrees. Furthermore it has insulin sensitizing, hypoglycemic, antioxidant and vasodilator effects. Communally AGE is a potential way to surmount the diabetic state and it has vasodilator effects. PMID- 21686138 TI - Application of hazard models for patients with breast cancer in Cuba. AB - There has been a rapid development in hazard models and survival analysis in the last decade. This article aims to assess the overall survival time of breast cancer in Cuba, as well as to determine plausible factors that may have a significant impact in the survival time. The data are obtained from the National Cancer Register of Cuba. The data set used in this study relates to 6381 patients diagnosed with breast cancer between January 2000 and December 2002. Follow-up data are available until the end of December 2007, by which time 2167 (33.9%) had died and 4214 (66.1%) were still alive. The adequacy of six parametric models is assessed by using their Akaike information criterion values. Five of the six parametric models (Exponential, Weibull, Log-logistic, Lognormal, and Generalized Gamma) are parameterized by using the accelerated failure-time metric, and the Gompertz model is parameterized by using the proportional hazard metric. The main result in terms of survival is found for the different categories of the clinical stage covariate. The survival time among patients who have been diagnosed at early stage of breast cancer is about 60% higher than the one among patients diagnosed at more advanced stage of the disease. Differences among provinces have not been found. The age is another significant factor, but there is no important difference between patient ages. PMID- 21686139 TI - The prevalence and risk factors of decreased bone mineral density in firstly diagnosed ulcerative colitis patients in the eastern region of Turkey. AB - The prevalance of osteoporosis or osteopenia in Turkish population with ulcerative colitis (UC) at the diagnosis time has not been evaluated so far. Therefore we aimed to determine the prevelance and risk factors of decreased bone mineral density (BMD) in UC patients at the diagnosis time in Turkey. We retrospectively evaluated dexa results, demographic and clinical characteristics, and some biochemical markers of bone turnover of the UC patients at the diagnosis time between June 2005 and February 2010 from the gastroenterology clinic records of the university hospital. The study population consisted of firstly diagnosed 63 UC patients (male: female = 27: 36; mean age 41.8 years). 38.1% at lumbar spine and 44.4% at femoral neck of the Turkish UC patients patients had low BMD at the diagnosis time. The occurrence of osteoporosis among Turkish UC patients at the diagnosis time were 8% at lumbar spine and 11% at femoral neck. 30.1% at lumbar spine and 33.3% at femoral neck of the patients had osteopenia at the diagnosis time. Pearson's coefficient of correlation showed significant correlations between low BMD and pancolitis (p<0.01), age, menopause, and symptom duration before the diagnosis (p<0.05).In conclusion, the prevelance of low bone density at the diagnosis time in Turkish UC patients is in accordance with Western and Eastern societies. Pancolitis, age, duration of symptoms, and menopause are predictive factors for low bone density in these patients. PMID- 21686140 TI - Cytokine-mediated inflammation is independently associated with insulin sensitivity measured by the euglycemic insulin clamp in a community-based cohort of elderly men. AB - Both clinical and experimental studies suggest a close relation between an inflammatory state and insulin resistance. We investigated the association between cytokine-mediated inflammation (high sensitivity C reactive protein [hsCRP] and interleukin [IL] 6) and insulin sensitivity (insulin-mediated glucose disposal rate, assessed by the euglycemic insulin clamp) in a community-based cohort, with subgroup analyses of normal weight individuals without diabetes mellitus and metabolic syndrome (NCEP). hsCRP and IL-6 were inversely associated with insulin sensitivity (multivariable-adjusted regression coefficient for 1-SD increase of hsCRP -0.12 (-0.21-(-0.03), p=0.01) and of IL-6 -0.11 (-0.21-(-0.02), p=0.01) in models adjusting for age and components of the metabolic syndrome (systolic and diastolic blood pressure, antihypertensive drugs, HDL-cholesterol, triglycerides, fasting plasma glucose, waist circumference). The multivariable adjusted association between hsCRP, IL-6 and insulin sensitivity were of a similar magnitude in normal weight individuals without diabetes and without the metabolic syndrome. Our data show that cytokine -mediated subclinical inflammation is independently associated with decreased insulin sensitivity also in apparently metabolically healthy normal weight individuals, indicating that the interplay between inflammatory processes and insulin resistance is present already in the early stages of the development of glucometabolic disease. PMID- 21686141 TI - Oseltamivir use in psychiatric inpatients taking clozapine: effect on neuropsychiatric events. PMID- 21686142 TI - Partial disclosure of a co-diagnosis of bipolar disorder in a woman with borderline personality disorder. PMID- 21686143 TI - Gender patterns in borderline personality disorder. AB - Gender differences in patients with borderline personality disorder are potentially relevant because they may guide clinicians in assessment and treatment. To date, a number of clinical features in borderline personality disorder have been examined for gender differences. As for prevalence, earlier research concluded that a higher proportion of women than men suffer from borderline personality disorder, although more recent research has determined no differences in prevalence by gender. In addition, there may not be gender differences in borderline personality disorder with respect to specific types of self-harm behavior, such as self-cutting or levels of psychological distress at clinical presentation. However, current evidence indicates that there are notable gender differences in borderline personality disorder with regard to personality traits, Axis I and II comorbidity, and treatment utilization. With regard to personality traits, men with borderline personality disorder are more likely to demonstrate an explosive temperament and higher levels of novelty seeking than women with borderline personality disorder. As for Axis I comorbidity, men with borderline personality disorder are more likely to evidence substance use disorders whereas women with borderline personality disorder are more likely to evidence eating, mood, anxiety, and posttraumatic stress disorders. With regard to Axis II comorbidity, men with borderline personality disorder are more likely than women to evidence antisocial personality disorder. Finally, in terms of treatment utilization, men with borderline personality disorder are more likely to have treatment histories relating to substance abuse whereas women are more likely to have treatment histories characterized by more pharmacotherapy and psychotherapy. PMID- 21686144 TI - Assessment of everyday functioning in schizophrenia. AB - Patients with schizophrenia manifest substantial cognitive and functional impairments. Assessment of these impairments is complicated by impairments in the accuracy of self-assessment of functioning on the part of both people with schizophrenia and certain classes of informants. Many of these reports correlate close to zero with performance measured objectively by performance-based tests. Much like the phenomenon of lack of insight, unawareness of functional impairments is predicted by cognitive impairments. In addition, like other neuropsychiatric conditions and healthy individuals, mild depression is associated with increased accuracy of self-assessment. High-contact clinicians may provide reports of functioning that are more convergent with patients' ability as measured by performance-based assessments. Clinicians who are assessing deficits in cognition and everyday functioning may need to carefully consider the source of the information obtained before making treatment and placement decisions. PMID- 21686145 TI - Can tactile sensory processing differentiate between children with autistic disorder and asperger's disorder? AB - OBJECTIVE: There are debates whether autistic disorder (autism) and Asperger's disorder are two distinct disorders. Moreover, interventional sensory occupational therapy should consider the clinical characteristics of patients. Already, commonalities and differences between Asperger's disorder and autistic disorder are not well studied. The aim of this study is to compare tactile sensory function of children with autistic disorder and children with Asperger's disorder. METHODS: Tactile sensory function was compared between 36 children with autism and 19 children with Asperger's disorder. The two disorders were diagnosed based on Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision. The parent-reported Tactile Dysfunction Checklist was used to assess the three aspects of hypersensitivity, hyposensitivity, and poor tactile perception and discrimination. Developmental coordination was also assessed. RESULTS: Developmental coordination problems total score was not associated with group. The mean (standard deviation) score of tactile hyper-responsivity was not different between the groups. Tactile hyporesponsivity and poor tactile perception and discrimination scores were statistically higher in autistic disorder than Asperger's disorder group. CONCLUSION: These results for the first time indicated that at least some aspects of tactile perception can differentiate these two disorders. Children with autistic disorder have more tactile sensory seeking behaviors than children with Asperger's disorder. Moreover, the ability of children with autistic disorder for tactile discrimination and sensory perception is less than those with Asperger's disorder. Interventional sensory therapy in children with autistic disorder should have some characteristics that can be different and specific for children with Asperger's disorder. Formal intelligence quotient testing was not performed on all of the children evaluated, which is a limitation to this study. In some cases, a clinical estimation of intelligence quotient was given, which limits the conclusions that can be drawn from the data. Additional research using formal intelligence quotient testing on all of the subjects should be performed in order to draw more concrete conclusions. PMID- 21686146 TI - Visual hallucinations following a left-sided unilateral tuberothalamic artery infarction. AB - A 20-year-old man presented with realistic visual hallucinations and no motor or sensory neurological findings. The absence of motor or sensory deficits on physical examination made for a diagnostic challenge, but an altered mental status with dysnomic word-finding difficulty was the clue to the existence of an encephalopathy that resulted in evaluation for structural pathology. Brain imaging revealed an infarction in the territory of the left tuberothalamic artery. A head magnetic resonance imaging scan identified the neuropathology that led to immediately starting treatment for stroke. PMID- 21686147 TI - Examining the therapeutic relationship and confronting resistances in psychodynamic psychotherapy: a certified public accountant case. AB - Psychodynamic psychotherapy is effective for a variety of mental health symptoms. This form of psychotherapy uses patient self reflection and self examination, as well as the therapeutic relationship between the patient and psychiatrist, to explore maladaptive coping strategies and relationship patterns of the patient. A thorough understanding of resistance and the core conflictual relationship theme afford the psychiatrist the ability to facilitate this work. In this article, the composite case illustrates some of the psychodynamic psychotherapy techniques that can be employed in a psychotherapy case. In this example, the case is about a certified public accountant that came to treatment because of an acute stressor that put her career goals at risk. An acute episode or event can bring to light chronic and ongoing symptoms, which have had a remitting and relapsing course, and leave the patient unable to compensate on his or her own. PMID- 21686148 TI - Abraham's Wife, Katurah. PMID- 21686149 TI - Phenols in leaves and bark of Fagus sylvatica as determinants of insect occurrences. AB - Beech forests play an important role in temperate and north Mediterranean ecosystems in Greece since they occupy infertile montane soils. In the last glacial maximum, Fagus sylvatica (beech) was confined to Southern Europe where it was dominant and in the last thousand years has expanded its range to dominate central Europe. We sampled four different beech forest types. We found 298 insect species associated with beech trees and dead beech wood. While F. sylvatica and Quercus (oak) are confamilial, there are great differences in richness of the associated entomofauna. Insect species that inhabit beech forests are less than one fifth of those species living in oak dominated forests despite the fact that beech is the most abundant central and north European tree. There is a distinct paucity of monophagous species on beech trees and most insect species are shared between co-occurring deciduous tree species and beech. This lack of species is attributed to the vegetation history and secondary plant chemistry. Bark and leaf biophenols from beech indicate that differences in plant secondary metabolites may be responsible for the differences in the richness of entomofauna in communities dominated by beech and other deciduous trees. PMID- 21686150 TI - Mechanistic investigation of ROS-induced DNA damage by oestrogenic compounds in lymphocytes and sperm using the comet assay. AB - Past research has demonstrated that oestrogenic compounds produce strand breaks in the DNA of sperm and lymphocytes via reactive oxygen species (ROS). In the current investigation, sperm and lymphocytes were treated in vitro with oestrogenic compounds (diethylstilboestrol, progesterone, 17beta-oestradiol, noradrenaline and triiodotyronine) and several aspects of DNA damage were investigated. Firstly, mediation of DNA damage by lipid peroxidation was investigated in the presence of BHA (a lipid peroxidation blocker). BHA reduced the DNA damage generated by 17beta-oestradiol and diethylstilboestrol in a statistically significant manner. No effects were observed for sperm. Secondly, the presence of oxidized bases employing FPG and EndoIII were detected for lymphocytes and sperm in the negative control and after 24 h recovery in lymphocytes but not immediately after treatment for both cell types. The successful detection of oxidized bases in the negative control (untreated) of sperm provides an opportunity for its application in biomonitoring studies. DNA repair at 24 h after exposure was also studied. A nearly complete recovery to negative control levels was shown in lymphocytes 24 h recovery after oestrogenic exposure and this was statistically significant in all cases. Rapid rejoining of DNA, in a matter of hours, is a characteristic of DNA damaged by ROS. PMID- 21686151 TI - Impact of the 237th residue on the folding of human carbonic anhydrase II. AB - The deficiency of human carbonic anhydrase II (HCAII) has been recognized to be associated with a disease called CAII deficiency syndrome (CADS). Among the many mutations, the P237H mutation has been characterized to lead to a significant decrease in the activity of the enzyme and in the Gibbs free energy of folding. However, sequence alignment indicated that the 237th residue of CAII is not fully conserved across all species. The FoldX theoretical calculations suggested that this residue did not significantly contribute to the overall folding of HCAII, since all mutants had small DeltaDeltaG values (around 1 kcal/mol). The experimental determination indicated that at least three mutations affect HCAII folding significantly and the P237H mutation was the most deleterious one, suggesting that Pro237 was important to HCAII folding. The discrepancy between theoretical and experimental results suggested that caution should be taken when using the prediction methods to evaluate the details of disease-related mutations. PMID- 21686152 TI - Membrane-based inverse transition cycling: an improved means for purifying plant derived recombinant protein-elastin-like polypeptide fusions. AB - Elastin-like peptide (ELP) was fused to two different avian flu H5N1 antigens and expressed in transgenic tobacco plants. The presence of the ELP tag enhanced the accumulation of the heterologous proteins in the tobacco leaves. An effective membrane-based Inverse Transition Cycling was developed to recover the ELPylated antigens and antibodies from plant material. The functionality of both the ELPylated neuraminidase and an ELPylated nanobody was demonstrated. PMID- 21686153 TI - In vitro antioxidant activity of selected 4-hydroxy-chromene-2-one derivatives SAR, QSAR and DFT studies. AB - The series of fifteen synthesized 4-hydroxycoumarin derivatives was subjected to antioxidant activity evaluation in vitro, through total antioxidant capacity, 1,1 diphenyl-2-picryl-hydrazyl (DPPH), hydroxyl radical, lipid peroxide scavenging and chelating activity. The highest activity was detected during the radicals scavenging, with 2b, 6b, 2c, and 4c noticed as the most active. The antioxidant activity was further quantified by the quantitative structure-activity relationships (QSAR) studies. For this purpose, the structures were optimized using Paramethric Method 6 (PM6) semi-empirical and Density Functional Theory (DFT) B3LYP methods. Bond dissociation enthalpies of coumarin 4-OH, Natural Bond Orbital (NBO) gained hybridization of the oxygen, acidity of the hydrogen atom and various molecular descriptors obtained, were correlated with biological activity, after which we designed 20 new antioxidant structures, using the most favorable structural motifs, with much improved predicted activity in vitro. PMID- 21686154 TI - Serine proteases-like genes in the asian rice gall midge show differential expression in compatible and incompatible interactions with rice. AB - The Asian rice gall midge, Orseolia oryzae (Wood-Mason), is a serious pest of rice. Investigations into the gall midge-rice interaction will unveil the underlying molecular mechanisms which, in turn, can be used as a tool to assist in developing suitable integrated pest management strategies. The insect gut is known to be involved in various physiological and biological processes including digestion, detoxification and interaction with the host. We have cloned and identified two genes, OoprotI and OoprotII, homologous to serine proteases with the conserved His(87), Asp(136) and Ser(241) residues. OoProtI shared 52.26% identity with mosquito-type trypsin from Hessian fly whereas OoProtII showed 52.49% identity to complement component activated C1s from the Hessian fly. Quantitative real time PCR analysis revealed that both the genes were significantly upregulated in larvae feeding on resistant cultivar than in those feeding on susceptible cultivar. These results provide an opportunity to understand the gut physiology of the insect under compatible or incompatible interactions with the host. Phylogenetic analysis grouped these genes in the clade containing proteases of phytophagous insects away from hematophagous insects. PMID- 21686155 TI - Conformationally constrained histidines in the design of peptidomimetics: strategies for the chi-space control. AB - A successful design of peptidomimetics must come to terms with chi-space control. The incorporation of chi-space constrained amino acids into bioactive peptides renders the chi(1) and chi(2) torsional angles of pharmacophore amino acids critical for activity and selectivity as with other relevant structural features of the template. This review describes histidine analogues characterized by replacement of native alpha and/or beta-hydrogen atoms with alkyl substituents as well as analogues with alpha, beta-didehydro unsaturation or C(alpha)-C(beta) cyclopropane insertion (ACC derivatives). Attention is also dedicated to the relevant field of beta-aminoacid chemistry by describing the synthesis of beta(2) and beta(3)-models (beta-hHis). Structural modifications leading to cyclic imino derivatives such as spinacine, aza-histidine and analogues with shortening or elongation of the native side chain (nor-histidine and homo-histidine, respectively) are also described. Examples of the use of the described analogues to replace native histidine in bioactive peptides are also given. PMID- 21686156 TI - The different muscle-energetics during shortening and stretch. AB - The helical shape of the thin filaments causes their passive counterclockwise rotation during muscle stretch that increases tensile stress and torque at first by unwinding and then by winding up the four anchoring Z-filaments. This means storage of energy in the series elastic Z-filaments and a considerable decrease of the liberated energy of heat and work to (h-w(ap)), where h is the heat energy and w(ap) the stretch energy induced from outside by an apparatus. The steep thin filament helix with an inclination angle of 70 degrees promotes the passive rotation during stretch, but impedes the smooth sliding of shortening by increased friction and production of frictional heat. The frictional heat may be produced by the contact with the myosin cross-bridges: (1) when they passively snap on drilling thin filaments from cleft to cleft over a distance 2 * 2.7 nm = 5.4 nm between the globular actin monomers in one groove, causing stepwise motion; or (2) when they passively cycle from one helical groove to the next (distance 36 nm). The latter causes more heat and may take place on rotating thin filaments without an effective forward drilling ("idle rotation"), e.g., when they produce "unexplained heat" at the beginning of an isometric tetanus. In an Appendix to this paper the different states of muscle are defined. The function of its most important components is described and rotation model and power-stroke model of muscular contraction is compared. PMID- 21686158 TI - A newly isolated thermostable lipase from Bacillus sp. AB - A thermophilic lipolytic bacterium identified as Bacillus sp. L2 via 16S rDNA was previously isolated from a hot spring in Perak, Malaysia. Bacillus sp. L2 was confirmed to be in Group 5 of bacterial classification, a phylogenically and phenotypically coherent group of thermophilic bacilli displaying very high similarity among their 16S rRNA sequences (98.5-99.2%). Polymerase chain reaction (PCR) cloning of L2 lipase gene was conducted by using five different primers. Sequence analysis of the L2 lipase gene revealed an open reading frame (ORF) of 1251 bp that codes for 417 amino acids. The signal peptides consist of 28 amino acids. The mature protein is made of 388 amino acid residues. Recombinant lipase was successfully overexpressed with a 178-fold increase in activity compared to crude native L2 lipase. The recombinant L2 lipase (43.2 kDa) was purified to homogeneity in a single chromatography step. The purified lipase was found to be reactive at a temperature range of 55-80 degrees C and at a pH of 6-10. The L2 lipase had a melting temperature (Tm) of 59.04 degrees C when analyzed by circular dichroism (CD) spectroscopy studies. The optimum activity was found to be at 70 degrees C and pH 9. Lipase L2 was strongly inhibited by ethylenediaminetetraacetic acid (EDTA) (100%), whereas phenylmethylsulfonyl fluoride (PMSF), pepstatin-A, 2-mercaptoethanol and dithiothreitol (DTT) inhibited the enzyme by over 40%. The CD spectra of secondary structure analysis showed that the L2 lipase structure contained 38.6% alpha-helices, 2.2% beta strands, 23.6% turns and 35.6% random conformations. PMID- 21686157 TI - Dissimilar roles of the four conserved acidic residues in the thermal stability of poly(A)-specific ribonuclease. AB - Divalent metal ions are essential for the efficient catalysis and structural stability of many nucleotidyl-transfer enzymes. Poly(A)-specific ribonuclease (PARN) belongs to the DEDD superfamily of 3'-exonucleases, and the active site of PARN contains four conserved acidic amino acid residues that coordinate two Mg(2+) ions. In this research, we studied the roles of these four acidic residues in PARN thermal stability by mutational analysis. It was found that Mg(2+) significantly decreased the rate but increased the aggregate size of the 54 kDa wild-type PARN in a concentration-dependent manner. All of the four mutants decreased PARN thermal aggregation, while the aggregation kinetics of the mutants exhibited dissimilar Mg(2+)-dependent behavior. A comparison of the kinetic parameters indicated that Asp28 was the most crucial one to the binding of the two Mg(2+) ions, while metal B might be more important in PARN structural stability. The spectroscopic and aggregation results also suggested that the alterations in the active site structure by metal binding or mutations might lead to a global conformational change of the PARN molecule. PMID- 21686159 TI - Flavonoids, phenolics, and antioxidant capacity in the flower of Eriobotrya japonica Lindl. AB - Flavonoids and phenolics are abundant in loquat flowers. Methanol had the highest extraction efficiency among five solvents, followed by ethanol. Considering the safety and residue, ethanol is better as extraction solvent. The average content of flavonoids and phenolics of loquat flower of five cultivars were 1.59 +/- 0.24 and 7.86 +/- 0.87 mg/g DW, respectively, when using ethanol as extraction solvent. The contents of both bioactive components in flowers at different developmental stages and in the various flower tissues clearly differed, with the highest flavonoids and phenolics content in flowers of stage 3 (flower fully open) and petal, respectively. The antioxidant capacity was measured using FRAP, DPPH, and ABTS methods. The values of ABTS method was highest, followed by DPPH, the lowest was FRAP, when using vitamin C equivalent antioxidant capacity (VCEAC) as unit. Correlation analysis showed that the ABTS method showed the highest correlation coefficients with flavonoids and phenolics, i.e., 0.886 and 0.973, respectively. PMID- 21686160 TI - D-(+)-galactose-conjugated single-walled carbon nanotubes as new chemical probes for electrochemical biosensors for the cancer marker galectin-3. AB - D-(+)-Galactose-conjugated single-walled carbon nanotubes (SWCNTs) were synthesized for use as biosensors to detect the cancer marker galectin-3. To investigate the binding of galectin-3 to the d-(+)-galactose-conjugated SWCNTs, an electrochemical biosensor was fabricated by using molybdenum electrodes. The binding affinities of the conjugated SWCNTs to galectin-3 were quantified using electrochemical sensitivity measurements based on the differences in resistance together with typical I-V characterization. The electrochemical sensitivity measurements of the d-(+)-galactose-conjugated SWCNTs differed significantly between the samples with and without galectin-3. This indicates that d-(+) galactose-conjugated SWCNTs are potentially useful electrochemical biosensors for the detection of cancer marker galectin-3. PMID- 21686161 TI - Polyphenolic contents and antioxidant potential of stem bark extracts from Jatropha curcas (Linn). AB - We assessed the polyphenolic contents and antioxidant potential of the aqueous, ethanol and methanol stem bark extracts of Jatropha curcas. The total phenol, flavonoids, flavonols and proanthocyanidin contents of the extracts were evaluated to determine their effect on the antioxidant property of this plant, using standard phytochemical methods. The antioxidant and free radical scavenging activity of ethanol, methanol and aqueous extracts of the plant were also assessed against 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis-(3 ethylbenzothiazoline-6-sulphonic acid) (ABTS), ferric reducing, nitric oxide (NO), superoxide anion, (O(2) (-)) and hydrogen peroxide (H(2)O(2)) using spectroscopic methods and results were compared with that of butylated hydroxyl toluene (BHT) and ascorbic acid as standards. The concentrations of different classes of phenolic compounds were higher in methanol and ethanol extracts compared to aqueous extracts. There was correlation between total phenol, total flavonoids, total flavonol and total proanthocyanidins (r = 0.996, 0.978, 0.908, and 0.985) respectively. There was correlations between the amount of phenolic compounds and percentage inhibition of DPPH radicals scavenging activity of the extract (r = 0.98). Findings from the present study indicated that J. curcas is a potential source of natural antioxidants and may be a good candidate for pharmaceutical plant based products. PMID- 21686162 TI - First-principles investigation of Ag-doped gold nanoclusters. AB - Gold nanoclusters have the tunable optical absorption property, and are promising for cancer cell imaging, photothermal therapy and radiotherapy. First-principle is a very powerful tool for design of novel materials. In the present work, structural properties, band gap engineering and tunable optical properties of Ag doped gold clusters have been calculated using density functional theory. The electronic structure of a stable Au(20) cluster can be modulated by incorporating Ag, and the HOMO-LUMO gap of Au(20-) (n)Ag(n) clusters is modulated due to the incorporation of Ag electronic states in the HOMO and LUMO. Furthermore, the results of the imaginary part of the dielectric function indicate that the optical transition of gold clusters is concentration-dependent and the optical transition between HOMO and LUMO shifts to the low energy range as the Ag atom increases. These calculated results are helpful for the design of gold cluster based biomaterials, and will be of interest in the fields of radiation medicine, biophysics and nanoscience. PMID- 21686163 TI - 3D-QSAR studies on a series of dihydroorotate dehydrogenase inhibitors: analogues of the active metabolite of leflunomide. AB - The active metabolite of the novel immunosuppressive agent leflunomide has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. Self-organizing molecular field analysis (SOMFA), a simple three-dimensional quantitative structure-activity relationship (3D-QSAR) method is used to study the correlation between the molecular properties and the biological activities of a series of analogues of the active metabolite. The statistical results, cross-validated r(CV) (2) (0.664) and non cross-validated r(2) (0.687), show a good predictive ability. The final SOMFA model provides a better understanding of DHODH inhibitor enzyme interactions, and may be useful for further modification and improvement of inhibitors of this important enzyme. PMID- 21686164 TI - Knockdown of Akt sensitizes osteosarcoma cells to apoptosis induced by cisplatin treatment. AB - Akt plays an important role in the inhibition of apoptosis induced by chemotherapy and other stimuli. We therefore investigated if knockdown of Akt2 promoted drug-induced apoptosis in cultured osteosarcoma cells in vitro. SAOS-2 cells were transfected with Akt2 siRNA. The sensitivity of the transformed cell line to the chemotherapeutic drug cisplatin was assessed. Reduced expression of Akt2 did not directly inhibit the growth rate of the transfected cells; however, it significantly increased their sensitivity to cisplatin. Knockdown of Akt2, together with cisplatin treatment, promoted the expression of p53 up-regulated modulator of apoptosis (PUMA). It is possible that the augmentation of cisplatin cytotoxicity may be mediated by PUMA activation. The results of this study suggest that knockdown of Akt2 expression may have therapeutic applications in enhancing the efficacy of chemotherapy in patients with osteosarcoma. PMID- 21686165 TI - Optimization of ultrasound-assisted extraction of anthocyanins from mulberry, using response surface methodology. AB - Mulberry is one of the most widely used traditional Chinese medicines. Anthocyanins are the main bioactive components of mulberry, and possess important biological activities, such as antimicrobial, anti-inflammatory and antioxidant activities. This study investigated the ultrasound-assisted extraction (UAE) of anthocyanins from mulberry by using response surface methodology (RSM). The extraction conditions associated with anthocyanin yield, including extraction solvent, liquid-to-solid rate, temperature and extraction time, are discussed. The optimal conditions obtained by RSM for UAE from mulberry include 63.8% methanol contains 1% (v/v) trifluoroacetic acid (TFA), 43.2 degrees C temperature, 23.8 (v/w) liquid-to-solid ratio, and 40 min time for the maximum yield (64.70 +/- 0.45 mg/g). The results indicated that the UAE can be an effective method for the extraction of some active components from plant materials. PMID- 21686166 TI - Investigations on inhibitors of hedgehog signal pathway: a quantitative structure activity relationship study. AB - The hedgehog signal pathway is an essential agent in developmental patterning, wherein the local concentration of the Hedgehog morphogens directs cellular differentiation and expansion. Furthermore, the Hedgehog pathway has been implicated in tumor/stromal interaction and cancer stem cell. Nowadays searching novel inhibitors for Hedgehog Signal Pathway is drawing much more attention by biological, chemical and pharmological scientists. In our study, a solid computational model is proposed which incorporates various statistical analysis methods to perform a Quantitative Structure-Activity Relationship (QSAR) study on the inhibitors of Hedgehog signaling. The whole QSAR data contain 93 cyclopamine derivatives as well as their activities against four different cell lines (NCI H446, BxPC-3, SW1990 and NCI-H157). Our extensive testing indicated that the binary classification model is a better choice for building the QSAR model of inhibitors of Hedgehog signaling compared with other statistical methods and the corresponding in silico analysis provides three possible ways to improve the activity of inhibitors by demethylation, methylation and hydroxylation at specific positions of the compound scaffold respectively. From these, demethylation is the best choice for inhibitor structure modifications. Our investigation also revealed that NCI-H466 served as the best cell line for testing the activities of inhibitors of Hedgehog signal pathway among others. PMID- 21686167 TI - Effect of combined high pressure and thermal treatment on myofibrillar proteins solubilization of beef muscle. AB - The effects of high pressure (to 600 MPa) at different temperatures (20 to 60 degrees C) for 20 min on protein solubilization and electrophoretic pattern in beef post-rigor longissimus dorsi muscle were studied. The results showed that protein solubilization increased with increasing temperature, especially from 40 degrees C to 60 degrees C. A regular trend of protein solubilization was found when isolated myofibrils were subjected to high pressure at different temperatures, an increase was observed with increasing pressure up to about 400 MPa, solubility then decreasing to 600 MPa. Electrophoretic profiles showed that myosin light chains and actin thin filaments were sensitive to pressure, and were released from myofibrils subjected to 100 MPa and higher pressures at the different temperatures. PMID- 21686168 TI - Immobilization of glucose oxidase in alginate-chitosan microcapsules. AB - In order to improve its stability and catalytic rate in flour, the immobilization of glucose oxidase (GOX) was investigated in this work. The enzyme was encapsulated in calcium alginate-chitosan microspheres (CACM) using an emulsification-internal gelation-GOX adsorption-chitosan coating method. The interaction between alginate and chitosan was confirmed by infrared spectroscopy (IR). The resultant CACM in wet state, whose morphology was investigated by scanning electron microscopy (SEM), was spherical with a mean diameter of about 26 MUm. The GOX load, encapsulation efficiency and activity of the CACM-GOX were influenced by concentration of chitosan, encapsulation time and encapsulation pH. The highest total enzymatic activity and encapsulation efficiency was achieved when the pH of the adsorption medium was near the isoelectric point (pI) of GOX, approximately pH 4.0. In addition, the molecular weight of chitosan also evidently influenced the encapsulation efficiency. Storage stabilities of GOX samples were investigated continuously over two months and the retained activity of CACM-GOX was 70.4%, markedly higher than the 7.5% of free enzyme. The results reveal the great potential of CACM-GOX as a flour improver. PMID- 21686169 TI - Genetic diversity and phylogeny of antagonistic bacteria against Phytophthora nicotianae isolated from tobacco rhizosphere. AB - The genetic diversity of antagonistic bacteria from the tobacco rhizosphere was examined by BOXAIR-PCR, 16S-RFLP, 16S rRNA sequence homology and phylogenetic analysis methods. These studies revealed that 4.01% of the 6652 tested had some inhibitory activity against Phytophthora nicotianae. BOXAIR-PCR analysis revealed 35 distinct amplimers aligning at a 91% similarity level, reflecting a high degree of genotypic diversity among the antagonistic bacteria. A total of 25 16S RFLP patterns were identified representing over 33 species from 17 different genera. Our results also found a significant amount of bacterial diversity among the antagonistic bacteria compared to other published reports. For the first time; Delftia tsuruhatensis, Stenotrophomonas maltophilia, Advenella incenata, Bacillus altitudinis, Kocuria palustris, Bacillus licheniformis, Agrobacterium tumefaciens and Myroides odoratimimus are reported to display antagonistic activity towards Phytophthora nicotianae. Furthermore, the majority (75%) of the isolates assayed for antagonistic activity were Gram-positives compared to only 25% that were Gram-negative bacteria. PMID- 21686170 TI - Antioxidant properties of aminoethylcysteine ketimine decarboxylated dimer: a review. AB - Aminoethylcysteine ketimine decarboxylated dimer is a natural sulfur-containing compound detected in human plasma and urine, in mammalian brain and in many common edible vegetables. Over the past decade many studies have been undertaken to identify its metabolic role. Attention has been focused on its antioxidant properties and on its reactivity against oxygen and nitrogen reactive species. These properties have been studied in different model systems starting from plasma lipoproteins to specific cellular lines. All these studies report that aminoethylcysteine ketimine decarboxylated dimer is able to interact both with reactive oxygen and nitrogen species (hydrogen peroxide, superoxide anion, hydroxyl radical, peroxynitrite and its derivatives). Its antioxidant activity is similar to that of Vitamin E while higher than other hydrophilic antioxidants, such as trolox and N-acetylcysteine. PMID- 21686171 TI - Required levels of catalysis for emergence of autocatalytic sets in models of chemical reaction systems. AB - The formation of a self-sustaining autocatalytic chemical network is a necessary but not sufficient condition for the origin of life. The question of whether such a network could form "by chance" within a sufficiently complex suite of molecules and reactions is one that we have investigated for a simple chemical reaction model based on polymer ligation and cleavage. In this paper, we extend this work in several further directions. In particular, we investigate in more detail the levels of catalysis required for a self-sustaining autocatalytic network to form. We study the size of chemical networks within which we might expect to find such an autocatalytic subset, and we extend the theoretical and computational analyses to models in which catalysis requires template matching. PMID- 21686172 TI - Nitrogen substituted phenothiazine derivatives: modelling of molecular self assembling. AB - The study aims to present a detailed theoretical investigation of noncovalent intermolecular interactions between different pi-pi stacking nitrogen substituted phenothiazine derivatives by applying second-order Moller-Plesset perturbation (MP2), density functional (DFT) and semiempirical theories. The conformational stability of these molecular systems is mainly given by the dispersion-type electron correlation effects. The density functional tight-binding (DFTB) method applied for dimer structures are compared with the results obtained by the higher level theoretical methods. Additionally, the optimal configuration of the investigated supramolecular systems and their self-assembling properties are discussed. PMID- 21686173 TI - Inflammation, oxidative stress, and obesity. AB - Obesity is a chronic disease of multifactorial origin and can be defined as an increase in the accumulation of body fat. Adipose tissue is not only a triglyceride storage organ, but studies have shown the role of white adipose tissue as a producer of certain bioactive substances called adipokines. Among adipokines, we find some inflammatory functions, such as Interleukin-6 (IL-6); other adipokines entail the functions of regulating food intake, therefore exerting a direct effect on weight control. This is the case of leptin, which acts on the limbic system by stimulating dopamine uptake, creating a feeling of fullness. However, these adipokines induce the production of reactive oxygen species (ROS), generating a process known as oxidative stress (OS). Because adipose tissue is the organ that secretes adipokines and these in turn generate ROS, adipose tissue is considered an independent factor for the generation of systemic OS. There are several mechanisms by which obesity produces OS. The first of these is the mitochondrial and peroxisomal oxidation of fatty acids, which can produce ROS in oxidation reactions, while another mechanism is over-consumption of oxygen, which generates free radicals in the mitochondrial respiratory chain that is found coupled with oxidative phosphorylation in mitochondria. Lipid-rich diets are also capable of generating ROS because they can alter oxygen metabolism. Upon the increase of adipose tissue, the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), was found to be significantly diminished. Finally, high ROS production and the decrease in antioxidant capacity leads to various abnormalities, among which we find endothelial dysfunction, which is characterized by a reduction in the bioavailability of vasodilators, particularly nitric oxide (NO), and an increase in endothelium-derived contractile factors, favoring atherosclerotic disease. PMID- 21686174 TI - Impaired mitochondrial respiratory functions and oxidative stress in streptozotocin-induced diabetic rats. AB - We have previously shown a tissue-specific increase in oxidative stress in the early stages of streptozotocin (STZ)-induced diabetic rats. In this study, we investigated oxidative stress-related long-term complications and mitochondrial dysfunctions in the different tissues of STZ-induced diabetic rats (>15 mM blood glucose for 8 weeks). These animals showed a persistent increase in reactive oxygen and nitrogen species (ROS and RNS, respectively) production. Oxidative protein carbonylation was also increased with the maximum effect observed in the pancreas of diabetic rats. The activities of mitochondrial respiratory enzymes ubiquinol: cytochrome c oxidoreductase (Complex III) and cytochrome c oxidase (Complex IV) were significantly decreased while that of NADH:ubiquinone oxidoreductase (Complex I) and succinate:ubiquinone oxidoreductase (Complex II) were moderately increased in diabetic rats, which was confirmed by the increased expression of the 70 kDa Complex II sub-unit. Mitochondrial matrix aconitase, a ROS sensitive enzyme, was markedly inhibited in the diabetic rat tissues. Increased expression of oxidative stress marker proteins Hsp-70 and HO-1 was also observed along with increased expression of nitric oxide synthase. These results suggest that mitochondrial respiratory complexes may play a critical role in ROS/RNS homeostasis and oxidative stress related changes in type 1 diabetes and may have implications in the etiology of diabetes and its complications. PMID- 21686175 TI - Chemometric analysis of the amino acid requirements of antioxidant food protein hydrolysates. AB - The contributions of individual amino acid residues or groups of amino acids to antioxidant activities of some food protein hydrolysates were investigated using partial least squares (PLS) regression method. PLS models were computed with amino acid composition and 3-z scale descriptors in the X-matrix and antioxidant activities of the samples in the Y-matrix; models were validated by cross validation and permutation tests. Based on coefficients of the resulting models, it was observed that sulfur-containing (SCAA), acidic and hydrophobic amino acids had strong positive effects on scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and H(2)O(2) radicals in addition to ferric reducing antioxidant power. For superoxide radicals, only lysine and leucine showed strong positive contributions while SCAA had strong negative contributions to scavenging by the protein hydrolysates. In contrast, positively-charged amino acids strongly contributed negatively to ferric reducing antioxidant power and scavenging of DPPH and H(2)O(2) radicals. Therefore, food protein hydrolysates containing appropriate amounts of amino acids with strong contribution properties could be potential candidates for use as potent antioxidant agents. We conclude that information presented in this work could support the development of low cost methods that will efficiently generate potent antioxidant peptide mixtures from food proteins without the need for costly peptide purification. PMID- 21686176 TI - First principles study on the electronic properties of Zn(64)Sb(64-x)Te(x) solid solution (x = 0, 2, 3, 4). AB - The electronic properties of Te doped-ZnSb systems are investigated by first principles calculations. We focus on the Zn(64)Sb(64-) (x)Te(x) systems (x = 0, 2, 3, 4), which respond to the 0, 1.56at%, 2.34at% and 3.12at% of Te doping concentration. We confirm that the amount of Te doping will change the conductivity type of ZnSb. In the cases of x = 2 and 3, we find that the Te element in ZnSb introduces some bands originating from Te s and p orbits and a donor energy level in the bottom of the conduction band, which induce the n-type conductivity of ZnSb. From these findings for the electronic structure and the conductivity mechanism, we predict that Te doping amounts such as 1.56at% and 2.34at% can be considered as suitable candidates for use as donor dopant. PMID- 21686177 TI - Enhancing effect of glycerol on the tensile properties of Bombyx mori cocoon sericin films. AB - An environmental physical method described herein was developed to improve the tensile properties of Bombyx mori cocoon sericin films, by using the plasticizer of glycerol, which has a nontoxic effect compared with other chemical crosslinkers. The changes in the tensile characteristics and the structure of glycerolated (0-40 wt% of glycerol) sericin films were investigated. Sericin films, both in dry and wet states, showed enhanced tensile properties, which might be regulated by the addition of different concentrations of glycerol. The introduction of glycerol results in the higher amorphous structure in sericin films as evidenced by analysis of attenuated total reflection Fourier transform infrared (ATR-FTIR) spectra, thermogravimetry (TGA) and differential scanning calorimetry (DSC) curves. Scanning Electron Microscopy (SEM) observation revealed that glycerol was homogeneously blended with sericin molecules when its content was 10 wt%, while a small amount of redundant glycerol emerged on the surface of sericin films when its content was increased to 20 wt% or higher. Our results suggest that the introduction of glycerol is a novel nontoxic strategy which can improve the mechanical features of sericin-based materials and subsequently promote the feasibility of its application in tissue engineering. PMID- 21686178 TI - Mesomorphic properties of an homologous series of thioalkyl-terminated azomesogens. AB - A new homologous series (ten compounds) of 2-hydroxy azo compounds SR(n) (where n:1-10) were synthesized. Their structures were elucidated using spectroscopic techniques such as IR (Infrared), (1)H-NMR as well as elemental analysis. Mesomorphic properties and phase transitions were studied using polarized hot stage optical microscopy and differential scanning calorimetry (DSC), and are discussed as a function of the number of carbon atoms in the thioalkyl chain. It has been found that all compounds in the series are pure nematogens. PMID- 21686179 TI - KRAS mutation detection in paired frozen and Formalin-Fixed Paraffin-Embedded (FFPE) colorectal cancer tissues. AB - KRAS mutation has been unambiguously identified as a marker of resistance to cetuximab-based treatment in metastatic colorectal cancer (mCRC) patients. However, most studies of KRAS mutation analysis have been performed using homogenously archived CRC specimens, and studies that compare freshly frozen specimens and formalin-fixed paraffin-embedded (FFPE) specimens of CRC are lacking. The aim of the present study was to evaluate the impact of tissue preservation on the determination of KRAS mutational status. A series of 131 mCRC fresh-frozen tissues were first analyzed using both high-resolution melting (HRM) and direct sequencing. KRAS mutations were found in 47/131 (35.8%) using both approaches. Out of the 47 samples that were positive for KRAS mutations, 33 had available matched FFPE specimens. Using HRM, 2/33 (6%) demonstrated suboptimal template amplification, and 2/33 (6%) expressed an erroneous wild-type KRAS profile. Using direct sequencing, 6/33 (18.1%) displayed a wild-type KRAS status, and 3/33 (9.1%) showed discordant mutations. Finally, the detection of KRAS mutations was lower among the FFPE samples compared with the freshly frozen samples, demonstrating that tissue processing clearly impacts the accuracy of KRAS genotyping. PMID- 21686180 TI - Novel strategies for drug discovery based on Intrinsically Disordered Proteins (IDPs). AB - Intrinsically disordered proteins (IDPs) are proteins that usually do not adopt well-defined native structures when isolated in solution under physiological conditions. Numerous IDPs have close relationships with human diseases such as tumor, Parkinson disease, Alzheimer disease, diabetes, and so on. These disease associated IDPs commonly play principal roles in the disease-associated protein protein interaction networks. Most of them in the disease datasets have more interactants and hence the size of the disease-associated IDPs interaction network is simultaneously increased. For example, the tumor suppressor protein p53 is an intrinsically disordered protein and also a hub protein in the p53 interaction network; alpha-synuclein, an intrinsically disordered protein involved in Parkinson diseases, is also a hub of the protein network. The disease associated IDPs may provide potential targets for drugs modulating protein protein interaction networks. Therefore, novel strategies for drug discovery based on IDPs are in the ascendant. It is dependent on the features of IDPs to develop the novel strategies. It is found out that IDPs have unique structural features such as high flexibility and random coil-like conformations which enable them to participate in both the "one to many" and "many to one" interaction. Accordingly, in order to promote novel strategies for drug discovery, it is essential that more and more features of IDPs are revealed by experimental and computing methods. PMID- 21686181 TI - Evolution of plant-made pharmaceuticals. AB - The science and policy of pharmaceuticals produced and/or delivered by plants has evolved over the past twenty-one years from a backyard remedy to regulated, purified products. After seemingly frozen at Phase I human clinical trials with six orally delivered plant-made vaccines not progressing past this stage over seven years, plant-made pharmaceuticals have made a breakthrough with several purified plant-based products advancing to Phase II trials and beyond. Though fraught with the usual difficulties of pharmaceutical development, pharmaceuticals made by plants have achieved pertinent milestones albeit slowly compared to other pharmaceutical production systems and are now at the cusp of reaching the consumer. Though the current economic climate begs for cautious investment as opposed to trail blazing, it is perhaps a good time to look to the future of plant-made pharmaceutical technology to assist in planning for future developments in order not to slow this technology's momentum. To encourage continued progress, we highlight the advances made so far by this technology, particularly the change in paradigms, comparing developmental timelines, and summarizing the current status and future possibilities of plant-made pharmaceuticals. PMID- 21686182 TI - Mechanism of sphingosine 1-phosphate- and lysophosphatidic acid-induced up regulation of adhesion molecules and eosinophil chemoattractant in nerve cells. AB - The lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) act via G-protein coupled receptors S1P(1-5) and LPA(1-3) respectively, and are implicated in allergy. Eosinophils accumulate at innervating cholinergic nerves in asthma and adhere to nerve cells via intercellular adhesion molecule-1 (ICAM-1). IMR-32 neuroblastoma cells were used as an in vitro cholinergic nerve cell model. The G(i) coupled receptors S1P(1), S1P(3), LPA(1), LPA(2) and LPA(3) were expressed on IMR-32 cells. Both S1P and LPA induced ERK phosphorylation and ERK- and G(i)-dependent up-regulation of ICAM-1 expression, with differing time courses. LPA also induced ERK- and G(i)-dependent up-regulation of the eosinophil chemoattractant, CCL-26. The eosinophil granule protein eosinophil peroxidase (EPO) induced ERK-dependent up-regulation of transcription of S1P(1), LPA(1), LPA(2) and LPA(3), providing the situation whereby eosinophil granule proteins may enhance S1P- and/or LPA- induced eosinophil accumulation at nerve cells in allergic conditions. PMID- 21686183 TI - Novel natural inhibitors of CYP1A2 identified by in silico and in vitro screening. AB - Inhibition of cytochrome P450 (CYP) is a major cause of herb-drug interactions. The CYP1A2 enzyme plays a major role in the metabolism of drugs in humans. Its broad substrate specificity, as well as its inhibition by a vast array of structurally diverse herbal active ingredients, has indicated the possibility of metabolic herb-drug interactions. Therefore nowadays searching inhibitors for CYP1A2 from herbal medicines are drawing much more attention by biological, chemical and pharmological scientists. In our work, a pharmacophore model as well as the docking technology is proposed to screen inhibitors from herbal ingredients data. Firstly different pharmaphore models were constructed and then validated and modified by 202 herbal ingredients. Secondly the best pharmaphore model was chosen to virtually screen the herbal data (a curated database of 989 herbal compounds). Then the hits (147 herbal compounds) were continued to be filtered by a docking process, and were tested in vitro successively. Finally, five of eighteen candidate compounds (272, 284, 300, 616 and 817) were found to have inhibition of CYP1A2 activity. The model developed in our study is efficient for in silico screening of large herbal databases in the identification of CYP1A2 inhibitors. It will play an important role to prevent the risk of herb-drug interactions at an early stage of the drug development process. PMID- 21686184 TI - Microfluidic mixing: a review. AB - The aim of microfluidic mixing is to achieve a thorough and rapid mixing of multiple samples in microscale devices. In such devices, sample mixing is essentially achieved by enhancing the diffusion effect between the different species flows. Broadly speaking, microfluidic mixing schemes can be categorized as either "active", where an external energy force is applied to perturb the sample species, or "passive", where the contact area and contact time of the species samples are increased through specially-designed microchannel configurations. Many mixers have been proposed to facilitate this task over the past 10 years. Accordingly, this paper commences by providing a high level overview of the field of microfluidic mixing devices before describing some of the more significant proposals for active and passive mixers. PMID- 21686185 TI - In vitro antioxidant activities of sulfated derivatives of polysaccharides extracted from Auricularia auricular. AB - In this research, two types of sulfated polysaccharide derivatives were successfully synthesized. Their antioxidant activities were investigated by employing various established in vitro systems. In addition, the degree of sulfation was evaluated using ion-chromatography and IR spectra. The results verify that, when employing scavenging superoxide radical tests, both the sulfation of acid Auricularia auricular polysaccharides (SAAAP) and the sulfation of neutral Auricularia auricular polysaccharides (SNAAP) derivatives possessed considerable antioxidant activity and had a more powerful antioxidant competence than that of the native non-sulfated polysaccharides (AAAP and NAAP). On the other hand, AAAP and NAAP exhibited stronger activity on scavenging both the hydroxyl radical and lipid peroxidation. Available data obtained with in vitro measurements indicates that the sulfated groups of AAAP and NAAP played an important role on antioxidant activity. In sum, the research demonstrates that the antioxidant activity of sulfated polysaccharide derivatives in vitro has a potential significance for seeking new natural antioxidant protective agents. PMID- 21686186 TI - Nanomedicine: application areas and development prospects. AB - Nanotechnology, along with related concepts such as nanomaterials, nanostructures and nanoparticles, has become a priority area for scientific research and technological development. Nanotechnology, i.e., the creation and utilization of materials and devices at nanometer scale, already has multiple applications in electronics and other fields. However, the greatest expectations are for its application in biotechnology and health, with the direct impact these could have on the quality of health in future societies. The emerging discipline of nanomedicine brings nanotechnology and medicine together in order to develop novel therapies and improve existing treatments. In nanomedicine, atoms and molecules are manipulated to produce nanostructures of the same size as biomolecules for interaction with human cells. This procedure offers a range of new solutions for diagnoses and "smart" treatments by stimulating the body's own repair mechanisms. It will enhance the early diagnosis and treatment of diseases such as cancer, diabetes, Alzheimer's, Parkinson's and cardiovascular diseases. Preventive medicine may then become a reality. PMID- 21686187 TI - Behavior of phenols and phenoxyacids on a bisphenol-A imprinted polymer. Application for selective solid-phase extraction from water and urine samples. AB - A molecularly imprinted polymer (MIP), obtained by precipitation polymerisation with 4-vinylpyridine as the functional monomer, ethylene glycol dimethacrylate as cross-linker, and bisphenol-A (BPA) as template, was prepared. The binding site configuration of the BPA-MIP was examined using Scatchard analysis. Moreover, the behaviour of the BPA-MIP for the extraction of several phenolic compounds (bisphenol-A, bisphenol-F, 4-nitrophenol, 3-methyl-4-nitrophenol) and phenoxyacid herbicides such as 2,4-D, 2,4,5-T and 2,4,5-TP has been studied in organic and aqueous media in the presence of other pesticides in common use. It was possible to carry out the selective preconcentration of the target analytes from the organic medium with recoveries of higher than 70%. In an aqueous medium, hydrophobic interactions were found to exert a remarkably non-specific contribution to the overall binding process. Several parameters affecting the extraction efficiency of the BPA-MIP were evaluated to achieve the selective preconcentration of phenols and phenoxyacids from aqueous samples. The possibility of using the BPA-MIP as a selective sorbent to preconcentrate these compounds from other samples such as urine and river water was also explored. PMID- 21686188 TI - Lycopene enhances antioxidant enzyme activities and immunity function in N-methyl N'-nitro-N-nitrosoguanidine-enduced gastric cancer rats. AB - To investigate anticancer effect of lycopene, we examined the effects of lycopene on the oxidative injury and immunity activities of N-methyl-N'-nitro-N nitrosoguanidine (MNNG)-induced gastric cancer rats. The animals were divided into five groups. Group I served as the normal control and was given corn oil orally for 20 weeks. Group II were induced with MNNG 200 mg/kg body weight by oral gavage at days 0 and 14, and saturated NaCl (1 mL per rats) was given once every three days for four weeks until the end of the experimental period. Group III, IV and V were posttreated with lycopene (50, 100 and 150 mg/kg body weight, dissolved in corn oil) from the sixth week of MNNG (as in group II) induction up to the end of the experimental period. In the presence of MNNG, MDA and immunity levels were significantly increased, whereas enzymatic (SOD, CAT, and GPx) antioxidant activities were decreased in the treated rats compared with normal control rats. Administration of lycopene to gastric carcinoma-induced rats largely up-regulated the redox status and immunity activities to decrease the risk of cancer compared to group II. We conclude that up-regulation of antioxidants and immunity by lycopene treatment might be responsible for the anticancer effect in gastric carcinoma. PMID- 21686189 TI - Anticoagulant, antioxidant and antitumor activities of heterofucans from the seaweed Dictyopteris delicatula. AB - In the present study, six families of sulfated polysaccharides were obtained from seaweed Dictyopteris delicatula by proteolytic digestion, followed by acetone fractionation and molecular sieving on Sephadex G-100. Chemical analyses demonstrated that all polysaccharides contain heterofucans composed mainly of fucose, xylose, glucose, galactose, uronic acid, and sulfate. The fucans F0.5v and F0.7v at 1.0 mg/mL showed high ferric chelating activity (~45%), whereas fucans F1.3v (0.5 mg/mL) showed considerable reducing power, about 53.2% of the activity of vitamin C. The fucan F1.5v presented the most prominent anticoagulant activity. The best antiproliferative activity was found with fucans F1.3v and F0.7v. However, F1.3v activity was much higher than F0.7v inhibiting almost 100% of HeLa cell proliferation. These fucans have been selected for further studies on structural characterization as well as in vivo experiments, which are already in progress. PMID- 21686191 TI - How does the preparation of rye porridge affect molecular weight distribution of extractable dietary fibers? AB - Extractable dietary fiber (DF) plays an important role in nutrition. This study on porridge making with whole grain rye investigated the effect of rest time of flour slurries at room temperature before cooking and amount of flour and salt in the recipe on the content of DF components and molecular weight distribution of extractable fructan, mixed linkage (1->3)(1->4)-beta-d-glucan (beta-glucan) and arabinoxylan (AX) in the porridge. The content of total DF was increased (from about 20% to 23% of dry matter) during porridge making due to formation of insoluble resistant starch. A small but significant increase in the extractability of beta-glucan (P = 0.016) and AX (P = 0.002) due to rest time was also noted. The molecular weight of extractable fructan and AX remained stable during porridge making. However, incubation of the rye flour slurries at increased temperature resulted in a significant decrease in extractable AX molecular weight. The molecular weight of extractable beta-glucan decreased greatly during a rest time before cooking, most likely by the action of endogenous enzymes. The amount of salt and flour used in the recipe had small but significant effects on the molecular weight of beta-glucan. These results show that whole grain rye porridge made without a rest time before cooking contains extractable DF components maintaining high molecular weights. High molecular weight is most likely of nutritional importance. PMID- 21686204 TI - President's address: thinking about the unthinkable. PMID- 21686190 TI - Expression of an endo-beta-1,4-glucanase gene from orpinomyces PC-2 in Pichia pastoris. AB - The endo-beta-1,4-glucanase gene celE from the anaerobic fungus Orpinomyces PC-2 was placed under the control of an alcohol oxidase promoter (AOX1) in the plasmid pPIC9K, and integrated into the genome of a methylotrophic yeast P. pastoris GS115 by electroporation. The strain with highest endo-beta-1,4-glucanase activity was selected and designed as P. pastoris egE, and cultivated in shaking flasks. The culture supernatant was assayed by SDS-polyacrylamide gel electrophoresis and showed a single band at about 52 kDa. Furthermore, the recombinant P. pastoris egE was proved to possess the ability to utilize sodium carboxymethyl cellulose as a carbon source. The recombinant endoglucanase produced by P. pastoris showed maximum activity at pH 6.0 and temperature 45 degrees C, indicating it was a mesophilic neutral endo-beta-1,4-glucanase, suitable for denim biofinishing/washing. Further research was carried out in suitable fermentation medium in shaking flasks. The most favorable methanol addition concentration was discussed and given as 1.0%. After methanol induction for 96 h, the endo-beta-1,4-glucanase activity reached 72.5 IU mL(-1). This is the first report on expression and characterization of endo-beta-1,4-glucanase from Orpinomyces in P. pastoris. The endo-beta-1,4-glucanase secreted by recombinant P. pastoris represents an attractive potential for both academic research and textile industry application. PMID- 21686205 TI - Rational therapeutic options for patients with myeloproliferative neoplasms. AB - Patients with advanced forms of primary myelofibrosis (PMF) have an average survival of 4 to 5 years. At present, the standard of care for these patients is largely palliative, including supportive measures and the use of a variety of therapeutic agents, each of which's directed toward reducing transfusion requirements or decreasing the degree of splenomegaly. Currently, allogeneic stem cell transplantation remains the only potentially curative approach for PMF. Although the administration of Janus Kinase 2 (JAK2) inhibitors to patients with PMF often dramatically reduces the degree of splenomegaly and improves in systemic symptoms, these drugs do not correct the cytopenias associated with PMF, nor do they reverse abnormalities of BM architecture or substantially influence the JAK2V617F allele burden. Furthermore, the effects of such small-molecule therapy on the natural history of PMF and the rate of its evolution to acute myeloid leukemia (AML) remain uncertain. Recently, additional genetic alterations that precede or accompany JAK2V617F in PMF have been documented. These findings indicate that therapies directed against a single genetic lesion such as JAK2V617F are unlikely to be curative of PMF. These observations have led us to consider alternative therapeutic targets for drug development. The dysregulation of the hematopoietic microenvironment in PMF provides an attractive therapeutic target. Novel agents capable of correcting the abnormalities seen in PMF would probably be used in combination with the currently available therapeutic armamentarium, including the JAK2 inhibitors, to treat patients with PMF, which would represent a paradigm shift in the management of such patients. PMID- 21686206 TI - The role of CD23 in IgE dependent signaling: implications from pharmacogenetics. AB - The association of immunoglobulin E (IgE) with allergic diseases and asthma is well established. IgE binds to two receptors on various immune and inflammatory cells. The lower-affinity IgE Fc receptor, CD23, has multiple functions in enhancing the regulation of IgE production itself, and that of various pro inflammatory activities and mediators. The data in this report are derived from an analysis of variation in the CD23 gene that leads to a coding exchange and to a single nucleotide polymorphism (SNP) associated with the substitution of an arginine residue for a tryptophan residue in the protein structure of CD23. This genetic variation is associated with three findings identified in this report. First, the tryptophan exchange is associated with greater expression of RNA for the interleukin (IL)-4 receptor alpha chain and greater expression of RNA for egr 1 transcription factor, both of which are proinflammatory gene products that influence allergy-related immune functions. Second, the exchange is associated with cell surface expression of IL-4R. Third, an analysis of potential arginine to-tryptophan exchanges in the entire human genome has identified a number of interesting exchanges in immunologic genes of interest for their role in allergic responses. A discussion of these three findings is presented. PMID- 21686208 TI - Challenges and opportunities facing medical education. AB - Medical education is at a crossroads. Although unique features exist at the undergraduate, graduate, and continuing education levels, shared aspects of all three levels are especially revealing, and form the basis for informed decision making about the future of medical education.This paper describes some of the internal and external challenges confronting undergraduate medical education. Key internal challenges include the focus on disease to the relative exclusion of behavior, inpatient versus outpatient education, and implications of a faculty whose research is highly focused at the molecular or submolecular level. External factors include the exponential growth in knowledge, associated technologic ("disruptive") innovations, and societal changes. Addressing these challenges requires decisive institutional leadership with an eye to 2020 and beyond--the period in which current matriculants will begin their careers. This paper presents a spiral-model format for a curriculum of medical education, based on disease mechanisms, that addresses many of these challenges and incorporates sound educational principles. PMID- 21686207 TI - Fever, hyperthermia, and the lung: it's all about context and timing. AB - Although body temperature is tightly regulated in humans, elevated temperatures are frequently encountered during febrile illnesses and exertional and environmental hyperthermia. Such temperature increases exert profound effects on cell signaling and gene expression patterns, which have important consequences for innate immune function and cell injury, apoptosis, and recovery. The lung offers a framework for understanding how these effects can either benefit or harm the host. We present data demonstrating that exposure to febrile-range hyperthermia (~39.5 degrees C) exerts multiple biologic effects that converge on enhanced neutrophil recruitment to the lung, and describe the consequences of these effects for pathogen clearance and collateral tissue injury. We also discuss the influence of temperature on apoptosis in lung epithelium. Collectively, the data presented identify body temperature as a modifiable factor that exerts profound influence on the outcome of infection and injury. PMID- 21686209 TI - Therapeutic Hypothermia: What's Hot about Cold. AB - Reducing body temperature to 33 degrees C in patients who have been resuscitated from cardiac arrest but who remain comatose can ameliorate anoxic encephalopathy and improve recovery. Experimental animal studies have suggested that cooling to 33 degrees C also aids the resuscitative process itself, facilitating the resumption of spontaneous circulation (ROSC). The mechanism of cooling benefit is probably the reduction of metabolic demand of most organs, and reduced production of toxic metabolites and reactive oxygen species. External cooling by application of ice or pads through which cold water circulates is effective but requires up to 8 hours to achieve the target temperature of 33 degrees C. Our goal was to develop a faster method of cooling that could be initiated during cardiopulmonary resuscitation. In anesthetized swine, we induced ventricular fibrillation by passing alternating current down an electrode catheter in the right ventricle. We then ventilated the animals' lungs with liquid perfluorocarbons (PFCs), a technique known as total liquid ventilation (TLV). Perfluorocarbons are oxygen carrying modules; we pre-oxygenated the PFCs by bubbling 100% O(2) through the solution for 2 minutes before use, and pre-cooled the PFCs to -15 degrees C. The cold oxygenated PFCs reduced pulmonary artery temperature (a surrogate for myocardial temperature) to 33 degrees C in about 6 minutes. Using this technique we achieved ROSC in 8 of 11 (82%) animals given TLV versus 3 of 11 (27%) control animals receiving conventional CPR without PFCs (P<0.05). We also compared the cold TLV technique with the administration of intravenous iced saline to achieve hypothermia. Both the cold TLV and cold saline techniques produced rapid hypothermia, but we could achieve ROSC in only 2 of 8 (25%) animals given cold saline versus 7 of 8 (88%) given cold TLV. This result is likely due to the rise in right atrial pressure and corresponding reduction in coronary perfusion pressure caused by volume loading with IV saline, in addition to the higher pO(2) associated with pre-oxygenated PFCs. Cold TLV is a promising technique for achieving rapid intra-arrest and post-resuscitation hypothermia in patients experiencing cardiac arrest. PMID- 21686210 TI - Rise above: muscle ring-finger-1 (MURF1) regulation of cardiomyocyte size and energy metabolism. AB - Cardiac hypertrophy develops in response to increases in afterload, most commonly as the result of hypertension. When left untreated, cardiac hypertrophy commonly progresses to heart failure, one of the leading causes of death in the US. A number of studies have shown that reversing cardiac hypertrophy can decrease the progression to heart failure. However, the treatments now used to decrease cardiac hypertrophy have had limited success. Our laboratory has found that the novel muscle-specific ubiquitin ligase named muscle ring-finger-1 (MuRF1) inhibits cardiac hypertrophy and is necessary for its experimental reversal. We have developed transgenic mouse models that have been instrumental in unraveling some of the mechanisms by which MuRF1 inhibits cardiac hypertrophy. We have also identified specific ways in which MuRF1 regulates metabolism at the level of the phosphocreatine shuttle and fatty-acid and glucose metabolism. The knowledge gained from these studies has helped us to understand the processes regulating cardiac hypertrophy, and to identify specific pathways against which to target new therapies that can halt the progression and even possibly reverse the damage associated with cardiac hypertrophy. PMID- 21686211 TI - Regulation of renal urea transport by vasopressin. AB - Terrestrial life would be miserable without the ability to concentrate urine. Production of concentrated urine requires complex interactions among the nephron segments and vasculature in the kidney medulla. In addition to water channels (aquaporins) and sodium transporters, urea transporters are critically important to the theories proposed to explain the physiologic processes occurring when urine is concentrated. Vasopressin (anti-diuretic hormone) is the key hormone regulating the production of concentrated urine. Vasopressin rapidly increases water and urea transport in the terminal inner medullary collecting duct (IMCD). Vasopressin rapidly increases urea permeability in the IMCD through increases in phosphorylation and apical plasma-membrane accumulation of the urea transporter A1 (UT-A1). Vasopressin acts through two cAMP-dependent signaling pathways in the IMCD: protein kinase A and exchange protein activated by cAMP Epac. Protein kinase A phosphorylates UT-A1 at serines 486 and 499. In summary, vasopressin regulates urea transport acutely by increasing UT-A1 phosphorylation and the apical plasma-membrane accumulation of UT-A1 through two cAMP-dependent pathways. PMID- 21686212 TI - Extending closed-loop control to the management of chronic disease. AB - A closed-loop control process assures that a system performs within control limits by direct feedback of the system's output to change the system's inputs. We developed methods for the closed-loop control of system-based practice, using ventilator management as a model or test bed. The control system has three components: 1) an explicit end-to-end plan; 2) a record of what is done as it is done; and 3) an instant display of the status of each patient against the plan for that patient. The status display provides process control by showing the clinical team where corrections are needed while the team still has the time needed to act prospectively. We are extending these methods to the management of chronic disease. Their extension requires engagement of the patient as a member of the team, a coordinated plan across the care continuum, informatics algorithms to stratify individual patients according to co-morbidities and their current level of control, and a means of detecting the presence or absence of a reaction to each action taken by the team. PMID- 21686213 TI - Eliminating hospital acquired infections: is it possible? Is it sustainable? Is it worth it? AB - An estimated 2 million hospital-acquired infections (HAI) are now reported annually in the US, and are associated with an estimated $5 billion in additional health care costs. With this, the growing incidence of HAI has become "ground zero" in the campaign to improve patient safety and eliminate waste in health care.We studied the characteristics of high-performing organizations and their leaders outside of health care to determine how such organizations become "best in class." We then sought to apply the principles that led to this status to eliminating HAI associated with central venous catheters.Observations of the current condition of health care revealed multiple defects in various processes, that were breeding grounds for error. Redesign of these processes by the people involved in them under the guidance of a leader resulted in an 86% reduction in infections in the blood. Overall, financial performance improved by $5.1 million over a 2-year period. Mortality in intensive care units declined by 29%.Using methods borrowed from highly reliable industries and engaging workers at the point of care can have profound and sustainable effects in nearly eliminating HAI, with significant clinical and financial benefits. PMID- 21686214 TI - Protecting the herd: the remarkable effectiveness of the bacterial meningitis polysaccharide-protein conjugate vaccines in altering transmission dynamics. AB - Interrupting human-to-human transmission of the agents (Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae) of bacterial meningitis by new capsular polysaccharide-protein conjugate vaccines (PPCVs) has proven to be a remarkable (and unanticipated) contributor to vaccine effectiveness. Herd immunity accounts for ~50% of the protection by meningococcal serogroup C PPCVs, pneumococcal PPCV7, and H. influenzae b PPCVs. Nasopharyngeal carriage can be reduced >=75% for vaccine serotypes; the decrease in carriage is correlated with disease reduction in unvaccinated individuals, and the impact of herd immunity lasts for years. Based on these data, models for using herd immunity in vaccine based prevention strategies are underway for control of meningitis in sub-Saharan Africa. Although the immunologic basis of herd immunity and impact on microbial biology need more study, protecting the unvaccinated by altering pathogen transmission dynamics is a powerful effect of PPCVs and increasingly important in vaccine introduction, implementation, and evaluation strategies. PMID- 21686215 TI - Consequences of frequent hemodialysis: comparison to conventional hemodialysis and transplantation. AB - The average life expectancy of a person on hemodialysis is less than 3 years and hasn't changed in 20 years. The Hemodialysis (HEMO) trial, a randomized trial to determine whether increasing urea removal to the maximum practical degree through a 3-times-a-week schedule, showed no difference in mortality in the treatment and control groups. Investigators speculated that the increment in functional waste removal in the HEMO study was too small to produce improvements in mortality. To test this hypothesis, the NIDDK funded the Frequent Hemodialysis Network, a consortium of centers testing whether patients randomized to intensive dialysis would demonstrate improved (reduced) left ventricular LV mass and quality of life. The trial has two arms: the daily (in-center) and the home (nocturnal) arms. Each arm has patients randomized to conventional dialysis or 6 days (or nights) of dialysis. The results of the HEMO trial will be reported in the fall of 2010. PMID- 21686217 TI - Mary Allen Engle Award: The glue of life--a career retrospective. AB - The author was privileged to be an early contributor to the concept that cell adhesion molecules, the leukocyte (beta2) integrins, play a pivotal role in the acute inflammatory process. For the author, this began with the development of a monoclonal antibody (anti-Mo1) that identified a differentiation antigen on the surface of human myeloid cells (including neutrophils, monocytes, and natural killer (NK) cells). Serendipitously, it was discovered that the Mo1 antigen was the heterodimeric glycoprotein (gp155,95) absent from the surface of neutrophils isolated from patients with adhesion defects in vitro and a syndrome characterized by chronic, life-threatening infections in vivo (a syndrome now termed leukocyte adhesion deficiency, type 1) (LAD-1). Collaborative efforts with other investigators (including members of the ACCA) revealed that patients with LAD-1 exhibited genetic mutations on chromosome 21 resulting in absent or diminished expression of a class of 4 surface adhesion molecules (now termed CD11a/CD18, CD11b/CD18, CD11c/CD18, and CD11d/CD18) known as the leukocyte or beta2 family of integrins. Knowledge of the role of the beta2 integrins in the acute inflammatory response led to the development of effective gene therapy strategies to treat LAD-1 in preclinical animal models and to the comprehensive testing of anti-integrin antibodies as anti-inflammatory agents to prevent organ damage as a complication of acute inflammation. This retrospective provides one illustration of the potential of bench-to-bedside research to generate new knowledge of clinical significance. PMID- 21686221 TI - Theodore E. Woodward Award: lactase persistence SNPs in African populations regulate promoter activity in intestinal cell culture. AB - Lactase-phlorizin hydrolase, lactase, is the intestinal enzyme responsible for the digestion of the milk sugar lactose. The majority of the world's human population experiences a decline in expression of the lactase gene by late childhood (lactase non-persistence). Individuals with lactase persistence, however, continue to express high levels of the lactase gene throughout adulthood. Lactase persistence is a heritable autosomal dominant condition and has been strongly correlated with several single nucleotide polymorphisms (SNPs) located ~14 kb upstream of the lactase gene in different ethnic populations: 13910*T in Europeans and -13907*G, -13915*G, and -14010*C in several African populations. The coincidence of the four SNPs clustering within 100 bp strongly suggests that this region mediates the lactase non-persistence/persistence phenotype. Having previously characterized the European SNP, we aimed to determine whether the African SNPs similarly mediate a functional role in regulating the lactase promoter. Human intestinal Caco-2 cells were transfected with lactase SNP/promoter-reporter constructs and assayed for promoter activity. The -13907*G and -13915*G SNPs result in a significant enhancement of lactase promoter activity relative to the ancestral lactase non-persistence genotype. Such differential regulation by the SNPs is consistent with a causative role in the mechanism specifying the lactase persistence phenotype. PMID- 21686222 TI - Improving health care workers for seasonal influenza vaccination at university health system: a paradigm for closing the quality chasm. AB - Significant gaps in quality and patient safety in the US health-care system have been identified and were reported in the past decade by the Institute of Medicine. Despite recognition of these gaps in "knowing versus doing," change in health care is slow and difficult. The quality improvement and clinical safety movement is increasing among US medical centers. Our health science center implemented the UT System Clinical Safety and Effectiveness course, providing project-based teaching of quality-improvement tools and principles of patient safety. A quality-improvement project that increased healthcare workers' influenza vaccination rate by 17.8% from that in 2008 to a rate of 76.6% in 2009 serves as a paradigm of how physicians can lead quality-improvement project teams to narrow the quality chasm (1). Local efforts to narrow the chasm are discussed in the present paper, including inter-professional education in quality improvement and clinical safety. PMID- 21686223 TI - Clinical utility and development of biomarkers in invasive aspergillosis. AB - The diagnosis of invasive aspergillosis remains very difficult, and there are limited treatment options for the disease. Pre-clinical models have been used to evaluate the diagnosis and treatment of Aspergillus infection and to assess the pathogenicity and virulence of the organism. Extensive efforts in Aspergillus research have significantly expanded the genomic information about this microorganism. The standardization of animal models of invasive aspergillosis can be used to enhance the evaluation of genomic information about the organism to improve the diagnosis and treatment of invasive aspergillosis. One approach to this process has been the award of a contract by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health to establish and standardize animal models of invasive aspergillosis for the development of new diagnostic technologies for both pulmonary and disseminated Aspergillus infection. This work utilizes molecular approaches for the genetic manipulation of Aspergillus strains that can be tested in animal-model systems to establish new diagnostic targets and tools. Studies have evaluated the performance characteristics of assays for cell-wall antigens of Aspergillus including galactomannan and beta-D-glucan, as well as for DNA targets in the organism, through PCR. New targets, such as proteomic and genomic approaches, and novel detection methods, such as point-of-care lateral-flow devices, have also been evaluated. The goal of this paper is to provide a framework for evaluating genomic targets in animal models to improve the diagnosis and treatment of invasive aspergillosis toward ultimately improving the outcomes for patients with this frequently fatal infection. PMID- 21686224 TI - Out on a LIM: chronic kidney disease, podocyte phenotype and the Wilm's tumor interacting protein (WTIP). AB - Normal function of the glomerular filtration barrier requires wild-type differentiation of the highly specialized glomerular epithelial cell, the podocyte. Podocytes express three distinct domains, consisting of a cell body, primary processes, and secondary foot processes (FP). These FP express slit diaphragms, which are highly specialized cell-cell contacts critical for filtration-barrier function. Foot processes are dynamic structures that reorganize within minutes through actin cytoskeletal rearrangement. Glomerular diseases are characterized by a persistent simplification in podocyte domain structure with loss of FP, a phenotype described as FP effacement. The generation of such phenotypic plasticity requires that signaling pathways in subcellular compartments be integrated dynamically for a cell to respond appropriately to information flow from its microenvironment. We have identified a LIM-domain containing protein, Wilm's tumor interacting protein (WTIP), that regulates podocyte actin dynamics to maintain stable cell contacts. After glomerular injury, the WTIP molecule shuttles to the podocyte nucleus in response to changes in slit-diaphragm assembly, and changes gene transcription to permit podocyte remodeling. Defining regulatory pathways of podocyte differentiation identifies novel, druggable targets for chronic kidney diseases characterized by glomerular scarring. PMID- 21686225 TI - Adenosine receptor subtypes and the heart failure phenotype: translating lessons from mice to man. AB - Adenosine plays an important role in the pathophysiology of heart failure and in myocardial protection during ischemia and reperfusion. The action of adenosine in the heart is mediated by four G-protein-coupled receptors: A(1)-AR and A(3)-AR, which act via Galpha(1), and A(2A)-AR and A(2B)-AR, which act via Galpha(s). Understanding of cellular signaling pathways triggered by adenosine has been complicated by the availability of only partially specific adenosine agonists/antagonists. Adenosine signaling appears to be at times redundant in receptor function, and cellular signaling pathways for adenosine are multiple, parallel, and interrelated. Data obtained about the specific role of individual adenosine receptors, through the genetic modulation of receptors in murine hearts have provided important information about the role of adenosine receptors in the heart. Here we review existing data and present new results that clarify the function of individual adenosine receptors in the heart and their role in the development of left ventricular dysfunction, and about the downstream signaling systems that are modified by adenosine receptor activation. PMID- 21686228 TI - H1 and PAR2 receptors enhance delivery of immune-competent cells and molecules by interrupting E-cadherin adhesion in epithelia. AB - The lung's epithelial surface is at the same time vitally exchanging gas with the environment and acting as a barrier that protects the organism from the environment. We hypothesized that activation of epithelial-cell G-protein-coupled receptors for immune-defense molecules would temporarily interrupt cadherin dependent cell-cell adhesion of epithelial cells and thereby focally and temporarily compromise the epithelial barrier to facilitate delivery of other immune molecules and cells to challenged sites. Activation of type 1 histamine or type 2 PAR receptors on the basolateral surface of primary airway epithelial cells or L-cells expressing E-cadherin interrupted cadherin adhesion and caused approximately a 50% decrease in the epithelial barrier for 2-3 minutes. Given basic biochemical observations of others, we further hypothesized that activation of the receptors altered the barrier by phosphorylating tyrosines on an essential cadherin-complex component, beta-catenin. Y-F mutations in beta-catenin completely blocked the effects of activating the same receptors on cadherin dependent adhesion and on the epithelial barrier. Hence, G-protein-coupled receptors responding to immune-defense molecules temporarily and focally interrupt the lung epithelial barrier by compromising cadherin-based adhesion. PMID- 21686230 TI - Alcohol and HIV Infection. AB - Alcohol abuse and human immunodeficiency virus (HIV) infection are major public health problems and frequently coexist in the same individual. Although several studies have shown a significant association between alcohol consumption and the risk of being infected with HIV, it is unclear whether this association is due to behavioral and/or biomedical mechanisms. Studies of HIV-infected patients are inherently limited in their ability to control for variables such as timing and dose of HIV exposure, nutrition, concurrent use of drugs of abuse, use of anti retroviral therapy, and the frequency of alcohol consumption and amount of alcohol consumed. In order to study the impact of alcohol on HIV infection, we developed a model of chronic alcohol consumption in rhesus macaques monkeys (Macaca mulatta) infected with simian immunodeficiency virus (SIV), a lentivirus closely related to HIV that infects and destroys CD4+ cells and produces a progressive immunodeficiency representative of HIV disease. Using this model, our studies have shown that plasma viral loads are significantly higher in alcohol consuming macaques at 60-120 days after SIV infection (viral set point) than in control animals. The viral set point has been shown to be predictive of disease progression, and in our studies, alcohol consumption was associated with accelerated disease progression to end-stage disease. The rhesus macaque SIV model should be useful in identifying the mechanisms by which alcohol increases the viral load of HIV, affects HIV-associated comorbidities, and influences the efficacy of anti-retroviral therapy. PMID- 21686229 TI - This is not Dr. Conn's aldosterone anymore. AB - In 1955, Dr. Jerome Conn described a patient with severe hypertension and hypokalemia and an aldosterone-secreting adenoma. The prevalence of hyperaldosteronism is increased among patients with obesity or resistant hypertension. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers reduce the secretion of aldosterone, but with chronic treatment aldosterone concentrations "escape" back to baseline values. Mineralocorticoid receptor (MR) antagonism reduces mortality in patients with heart disease who are already taking an ACE inhibitor and diuretic. In addition to affecting sodium and potassium homeostasis via classical MR-dependent pathways, aldosterone induces inflammation and causes cardiovascular remodeling and renal injury. Some of these effects involve MR-independent pathways. At the same time, ligands other than aldosterone can activate the MR. This paper reviews mechanism(s) for the proinflammatory and profibrotic effects of aldosterone and presents data indicating that endogenous aldosterone, acting at the MR, contributes to many of the pro-inflammatory and pro-fibrotic effects of angiotensin II in vivo. PMID- 21686233 TI - A history of physical examination texts and the conception of bedside diagnosis. PMID- 21686232 TI - Jeremiah Metzger Lecture: cholesterol, inflammation and atherosclerotic cardiovascular disease: is it all LDL? AB - Scientific investigation of the relationship between atherosclerosis, inflammation, and lipoprotein metabolism originated in the mid-19(th) century and has increased exponentially over the past 50 years. Basic research that characterized the lipoproteins and their metabolism was followed by clinical and epidemiologic studies that began to link elevated levels of cholesterol in the blood to the development of atherosclerosis and increased risk for cardiovascular disease. The link between elevated serum cholesterol levels and cardiovascular disease, known as the "lipid hypothesis," was confirmed with the discoveries of the low-density lipoprotein (LDL) receptor and of the statins. Subsequent results of multiple clinical trials, particularly with statins, have established that reductions in LDL cholesterol are associated with reduced risk for coronary heart disease (CHD). A growing body of evidence suggests that measures of inflammation, such as C-reactive protein (CRP), may enhance cardiovascular risk assessment and help guide clinical decision-making. Reductions in CRP in individuals with low serum levels of LDL cholesterol have been shown to reduce cardiovascular events. A variety of agents designed to further reduce LDL cholesterol, increase high density lipoprotein (HDL) cholesterol, and target inflammation are currently in development. Future research can help clarify the roles of emerging biomarkers and lipid fractions other than LDL cholesterol in the prevention, diagnosis, and treatment of cardiovascular disease. PMID- 21686234 TI - PAI-1 antagonists: the promise and the peril. AB - The plasminogen activator (i.e., fibrinolytic) system is one of the key endogenous defense mechanisms against intravascular thrombosis. Thrombolytic agents represent the only direct way of augmenting fibrinolytic activity in humans, and have proven to be of value in the treatment of acute myocardial infarction and stroke. Although these agents are efficacious in the acute setting, they are not a viable option for long-term use. Net fibrinolytic activity is plasma is largely determined by the balance between tissue-type plasminogen activator (t-PA) and its natural, fast-acting inhibitor, plasminogen activator inhibitor-1 (PAI-1). The recent development of specific PAI-1 antagonists promises to expand the limits of understanding of the role of the fibrinolytic system in human disease, and to break through the current confines of therapeutic options that can effectively restore and augment the activity of the fibrinolytic system. PMID- 21686235 TI - The role of biliary epithelial cells in the immunopathogenesis of non-suppurative destructive cholangitis in murine hepatic graft-versus-host disease. AB - Non-suppurative destructive cholangitis (NSDC) is characterized by T-cell infiltration of the biliary epithelia of small-to medium-caliber bile ducts, causing apoptosis of biliary epithelial cells (BEC) and, ultimately, ductopenia. NSDC is the primary histopathologic process in the autoimmune disease known as primary biliary cirrhosis (PBC) and in alloimmune graft-versus-host disease (GVHD) and hepatic allograft rejection. The onset of NSDC in the B10.D2->BALB/c murine model of hepatic GVHD is preceded by hepatic production of pro inflammatory cytokines, accumulation of lipopolysaccharide (LPS), and expression of chemokine genes. To explain the curious restriction of NSDC to small- and medium-caliber intrahepatic bile ducts, we hypothesized that BEC lining these bile ducts secrete chemokines and cytokines that chemoattract, activate, and polarize the effector T cells mediating NSDC. To test this hypothesis we stimulated BALB/c immortalized BEC (IBEC) in vitro with pro-inflammatory mouse recombinant cytokines with and without LPS and determined the expression of chemokines and cytokines by IBEC using a polymerase chain reaction (PCR), quantitative protein enzyme-linked immunosorbent assays (ELISAs), and microarrays. The capacity of stimulated IBEC to chemoattract activated T cells was assessed in the presence and absence of inhibitors of specific chemokine receptors. We found that pro-inflammatory cytokines, especially the combination of IFNgamma and TNFalpha, induced IBEC gene expression and the secretion of chemokine ligands for the chemokine receptors CCR1, CCR3, CCR5, and CXCR3. Chemokines secreted by IBEC stimulated with IFNgamma plus TNFalpha chemoattracted activated T cells. Inhibition of CCR1, CCR3, CCR5, or CXCR3 significantly reduced the chemoattraction of activated T cells. We conclude that BEC probably play an active role in the immunopathogenesis of NSDC by mediating the chemoattraction and terminal activation of effector T cells responsible for apoptosis of BECs and ductopenia. Selective chemokine expression by BEC lining small- and medium caliber bile ducts could explain the restriction of NSDC to ducts of this caliber. Inhibition of CCR1, CCR3, CCR5, and CXCR3 to block the chemoattraction and terminal activation of alloreactive T cells represents a potential therapeutic strategy for preventing NSDC after hematopoietic stem-cell transplantation or orthotopic liver transplantation. PMID- 21686236 TI - Neuroethics, neuroimaging, and disorders of consciousness: promise or peril? AB - The advent of powerful neuroimaging tools such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) has begun to redefine how we diagnose, define, and understand disorders of consciousness such as the vegetative and minimally conscious states. In my paper, I review how research using these methods is both elucidating these brain states and creating diagnostic dilemmas related to their classification as the specificity and sensitivity of traditional behavior-based assessments are weighed against sensitive but not yet fully validated neuroimaging data. I also consider how these methods are being studied as potential communication vectors for therapeutic use in subjects who heretofore have been thought to be unresponsive or minimally conscious. I conclude by considering the ethical challenges posed by novel diagnostic and therapeutic neuroimaging applications and contextualize these scientific developments against the broader needs of patients and families touched by severe brain injury. PMID- 21686237 TI - The AED in resuscitation: it's not just about the shock. AB - The automated external defibrillator (AED), in combination with effective cardiopulmonary resuscitation (CPR), is a critical part of the American Heart Association's "Chain of survival." Newer guidelines have simplified resuscitation and emphasized the importance of CPR in providing rapid and deep compressions with minimal interruptions; in fact, CPR should resume immediately after the shock given by the AED, without the delay entailed in checking for pulse or rhythm conversion. Our experience with the AED aboard aircraft, showing 40% long term survival with the AED in ventricular fibrillation, demonstrated the safety and efficacy of the device. Despite this and other reports of successful AED deployment, AEDs are not yet available at all public locations. Prospective research, as undertaken by the Resuscitation Outcomes Consortium, will be the key to future refinements of the guidelines and enhanced survival with use of the AED in sudden cardiac arrest. PMID- 21686238 TI - Evolution of synthetic polymers. AB - A strategy for the enrichment of a DNA template that encodes a functionalized PNA oligomer is discussed. The method relies on iterated cycles of chemical translation (of the template into PNA), selection (for function), and amplification (of the survivors). Potential restrictions and future perspectives are considered. PMID- 21686239 TI - Small RNAs hit a new target: Modulation of gene expression by targeting the non coding sequences downstream from a gene. AB - The University of Texas researchers have recently discovered that small synthetic RNAs (sRNAs) that are complementary to sequences located 3'-outside of genes can efficiently modulate gene expression. These new findings significantly expand the transcription-regulatory potential of sRNAs, and they also may provide useful leads for other artificial nucleobase oligomers to target sequences beyond the 3' termini of mRNA. PMID- 21686240 TI - Adding mRNA to the list of spatially organized components in bacteria. AB - Using LNA in situ hybridization, select mRNAs have been shown to be spatially confined to their chromosomal loci in two distantly related bacterial organisms. Translating ribosomes are diffusion limited by mRNA association. PMID- 21686241 TI - 1,4-linked 1,2,3-Triazole des-peptidic analogues of PNA (TzNA): Synthesis of TzNA oligomers by "click" reaction on solid phase and stabilization of derived triplexes with DNA. AB - 1,2,3-triazole analogues of PNA (TzNA) in which the amide link in backbone is replaced by triazole ring is synthesized on solid phase by 'click' chemistry and such triazolothymine PNA chimeric oligomers are shown to significantly stabilize the derived PNA(2):DNA triplexes. With increasing number of triazole units in the backbone, single stranded PNA oligomers exhibit enhanced self-ordering. PMID- 21686242 TI - PNA-based microbial pathogen identification and resistance marker detection: An accurate, isothermal rapid assay based on genome-specific features. AB - With the rapidly growing availability of the entire genome sequences of microbial pathogens, there is unmet need for increasingly sensitive systems to monitor the gene-specific markers for diagnosis of bacteremia that enables an earlier detection of causative agent and determination of drug resistance. To address these challenges, a novel FISH-type genomic sequence-based molecular technique is proposed that can identify bacteria and simultaneously detect antibiotic resistance markers for rapid and accurate testing of pathogens. The approach is based on a synergistic combination of advanced Peptide Nucleic Acid (PNA)-based technology and signal-enhancing Rolling Circle Amplification (RCA) reaction to achieve a highly specific and sensitive assay. A specific PNA-DNA construct serves as an exceedingly selective and very effective biomarker, while RCA enhances detection sensitivity and provide with a highly multiplexed assay system. Distinct-color fluorescent decorator probes are used to identify about 20 nucleotide-long signature sequences in bacterial genomic DNA and/or key genetic markers of drug resistance in order to identify and characterize various pathogens. The technique's potential and its utility for clinical diagnostics are illustrated by identification of S. aureus with simultaneous discrimination of methicillin-sensitive (MSSA) versus methicillin-resistant (MRSA) strains. Overall these promising results hint to the adoption of PNA-based rapid sensitive detection for diagnosis of other clinically relevant organisms. Thereby, new assay enables significantly earlier administration of appropriate antimicrobial therapy and may, thus have a positive impact on the outcome of the patient. PMID- 21686243 TI - A pyrenyl-PNA probe for DNA and RNA recognition: Fluorescence and UV absorption studies. AB - The design and the synthesis of a PNA oligomer containing a pyrenyl residue in the backbone were performed. PNA sequence was chosen complementary to a "G rich" target sequence involved in G-quadruplex formation. The pyrenyl unit replaced a nucleobase in the middle of the PNA through covalent linkage to the backbone by a carboxymethyl unit. A systematic study on the binding properties of this probe towards DNA and RNA complementary strands was carried out by UV and fluorescence spectroscopy. UV melting curves indicated that the PNA probe binds more tightly to RNA rather than to DNA. Thermodynamic data obtained by Van't Hoff fitting of the melting curves indicated that, in the case of RNA, a more favorable interaction occurs between the pyrenyl unit and the RNA nucleobases, leading to a very favorable enthalpic contribution.The fluorescence analysis showed specific quenching of the pyrene emission associated to the formation of the full-match PNA-DNA or PNA-RNA duplexes. Again, this behavior was more evident in the case of RNA, consistently with the stronger interaction of the pyrenyl unit with the complementary strand. In order to study the sequence specificity of the pyrenyl PNA probe (pyr-PNA), recognition experiments on mismatched DNA and RNA sequences were also performed. PMID- 21686244 TI - Hydrogelation abilities of nucleobase-modified cytidines possessing substituted triazoles. AB - Nucleoside-derived hydrogelators have been sought for their potential biomedical applications, such as are found in tissue engineering and drug delivery. By judiciously adding a degree of hydrophobicity certain analogues are able to form micelles, bi-layers and gels in water. Research in this area has yet to lay down solid ground rules for the rational design of novel nucleoside gelators making further studies necessary. The synthesis and examination of a series of aryl substituted 5-triazolylcytidines yielded an analogue that gelates water. 5-(1 (2,2'-bithiophen-3-yl)-1H-1,2,3-triazol-4-yl)-2'-deoxycytidine was found to form gels in water down to 0.3 wt%. The ribocytidine analogue failed to form gel in aqueous solution; but was able to form a hydrogel in the presence of guanosine. Images obtained by SEM show the different architectures of the gel; varying from cribriform to fibrous to lamellar. The present gelating compound studied may have potential as a component of a controlled-release drug delivery system. PMID- 21686245 TI - DNA breathes Hoogsteen. AB - A recent claim is discussed that Watson-Crick pairs in the naked duplex DNA spontaneously flip into Hoogsteen pairs under ordinary conditions. The claim is considered within the historical retrospective and is put into the broader context of DNA biophysics. PMID- 21686246 TI - Natural Arsenate DNA? AB - The recent paper by Wolfe-Simon et al.1 reporting a bacterial strain, which is able to grow in high concentrations of arsenate, apparently in the absence of phosphate, and claims that in this strain arsenate is substituting for phosphate, e.g. in nucleic acids (Figure 1), was highly profiled, attracted broad attention, and almost immediately resulted in heavy scientific criticism (see e.g. 2-7). PMID- 21686247 TI - Antisense mediated exon skipping therapy for duchenne muscular dystrophy (DMD). AB - Duchenne Muscular Dystrophy (DMD) is a lethal disease caused by mutations in the dystrophin gene (DMD) that result in the absence of essential muscle protein dystrophin. Among many different approaches for DMD treatment, exon skipping, mediated by antisense oligonucleotides, is one of the most promising methods for restoration of dystrophin expression. This approach has been tested extensively targeting different exons in numerous models both in vitro and in vivo. During the past 10 years, there has been a considerable progress by using DMD animal models involving three types of antisense oligonucleotides (2'-O-methyl phosphorothioate (2OME-PS), phosphorodiamidate morpholino oligomer (PMO)) and peptide nucleic acid (PNA). PMID- 21686248 TI - Molecular computing by PNA:PNA duplex formation. AB - Molecular computing is potentially one of the most powerful tools for the development of massive parallel computing protocols. In the present paper, a first example of the use of PNA:PNA interactions in molecular computing is described. A series of short PNA sequences have been designed with a four base stretch coding for variables and solutions. Hybridization of the components in different combinations was tested both in solution and in a microarray format. A series of PNA representing the solutions were spotted on a microarray surface in order to simulate the hardware. A series of PNA representing the variables, labeled with TAMRA, were used to interrogate the device enabling to solve non deterministic logic operations. The system was shown to be able to solve a two variable equation with a high signal to noise ratio. This paper intends to provide a proof of principle that PNA, on account of their stability and specificity of binding, are most suitable for constructing organic-type computers. PMID- 21686250 TI - A novel pseudo-complementary PNA G-C base pair. AB - Pseudo-complementary oligonucleotide analogues and mimics provide novel opportunities for targeting duplex structures in RNA and DNA. Previously, a pseudo-complementary A-T base pair has been introduced. Towards sequence unrestricted targeting, a pseudo-complementary G-C base pair consisting of the unnatural nucleobases n6-methoxy-2,6-diaminopurine (previously described in a DNA context) and N4-benzoylcytosine is now presented for design of pseudo complementary PNA oligomers (pcPNAs). PMID- 21686249 TI - Targeted gene correction using psoralen, chlorambucil and camptothecin conjugates of triplex forming peptide nucleic acid (PNA). AB - Gene correction activation effects of a small series of triplex forming peptide nucleic acid (PNA) covalently conjugated to the DNA interacting ligands psoralen, chlorambucil and camptothecin targeted proximal to a stop codon mutation in an EGFP reporter gene were studied. A 15-mer homopyrimidine PNA conjugated to the topoisomerase I inhibitor camptothecin was found to increase the frequency of repair domain mediated gene correctional events of the EGFP reporter in an in vitro HeLa cell nuclear extract assay, whereas PNA psoralen or chlorambucil conjugates both of which form covalent and also interstrand crosslinked adducts with dsDNA dramatically decreased the frequency of targeted repair/correction. The PNA conjugates were also studied in mammalian cell lines upon transfection of PNA bound EGFP reporter vector and scoring repair of the EGFP gene by FACS analysis of functional EGFP expression. Consistent with the extract experiments, treatment with adduct forming PNA conjugates (psoralen and chlorambucil) resulted in a decrease in background correction frequencies in transiently transfected cells, whereas unmodified PNA or the PNA-camptothecin conjugate had little or no effect. These results suggest that simple triplex forming PNAs have little effect on proximal gene correctional events whereas PNA conjugates capable of forming DNA adducts and interstrand crosslinks are strong inhibitors. Most interestingly the PNA conjugated to the topoisomerase inhibitor, camptothecin enhanced repair in nuclear extract. Thus the effects and use of camptothecin conjugates in gene targeted repair merit further studies. PMID- 21686251 TI - Focusing on Arf GAPs. PMID- 21686252 TI - GAPs: Terminator versus effector functions and the role(s) of ArfGAP1 in vesicle biogenesis. AB - Whether your passion is to understand and reverse disease processes or "simply" a better understanding of how cells work, anyone wishing to understand cell regulation today must have a detailed and accurate understanding of regulatory GTPase mechanisms and their application to specific pathways. This is becoming increasingly difficult as the details of signaling by members of different families of GTPases and their regulators expand. But this is all the more reason to continually ask, which aspects of GTPase signaling are distinct to a GTPase or its subfamily and which are conserved throughout the superfamily? We each have slightly different views of the key aspects of GTPase signaling that are derived from the main GTPases studied in our own labs; e.g., translocation onto a membrane is an essential and integral aspect of Arf activation but not of other GTPases. However, one aspect of GTPase signaling that I had come to believe to be widespread and of general importance is not universally accepted. In fact, through my conversations at the recent FASEB summer research conference on "Arf Family GTPases" and reading of the literature in a graduate tutorial class, I realized that it is not known or accepted by the majority of researchers. The question is the role of GTPase activating proteins (GAPs) in signaling. Are they "pure" terminators of signaling or do they serve effector functions? PMID- 21686253 TI - GAPs in the context of COPI: Enzymes, coat components or both? AB - TRAFFICKING IN THE EARLY SECRETORY PATHWAY AT FIRST GLANCE IS WELL UNDERSTOOD ACCORDING TO TEXTBOOK KNOWLEDGE: To achieve secretion and to maintain organelle homeostasis, protein and lipid cargo need to be transported constitutively from their origins of biosynthesis to their respective destinations. Thus, secretory cargo exits the ER and is shuttled to the Golgi via vesicular COPII carriers. Lipid and protein cargo is enzymatically modified in the Golgi, transported from cis- to trans- (by mechanisms that are still debated today), and from there travel to their final destinations. The best established roles for COPI vesicles, simply spoken, is to mediate retrograde trafficking of cargo molecules that were transported forward, but need to be transported back. PMID- 21686254 TI - Role of ArfGAP1 in COPI vesicle biogenesis. AB - Studies from our group suggest that ArfGAP1 acts not only as an Arf regulator but also as an Arf effector, with both roles promoting COPI vesicle formation. However, others have concluded differently, specifically that ArfGAP1 only acts as an Arf regulator, which involves inhibition of COPI vesicle formation by preventing components of the COPI complex from binding to target membrane. Here, we propose plausible reconciling explanations for this apparent contradiction. PMID- 21686255 TI - Rab11-FIP2 influences multiple components of the endosomal system in polarized MDCK cells. AB - The Rab11 Family Interacting Proteins (Rab11-FIPs) are hypothesized to regulate sequential steps in the apical recycling and transcytotic pathways of polarized epithelial cells. Previous studies have suggested that Rab11-FIP proteins assemble into multi-protein complexes regulating plasma membrane recycling. Rab11 FIP2 interacts with both myosin Vb and Rab11. Recent investigations have noted that that Rab11-FIP2 mutants [Rab11-FIP2(129-512), also designated Rab11 FIP2(DeltaC2) and Rab11-FIP2(S229A, R413G), also designated Rab11-FIP2(SARG)], are potent inhibitors of transcytosis in polarized MDCK cells. Interestingly, Rab11-FIP2(DeltaC2), but not Rab11-FIP2(SARG), also altered the morphology of the EEA-1 positive early endosomal compartment. These findings suggested that Rab11 FIP2 mutants could differentiate different points along the recycling pathway. We therefore sought to investigate whether Rab11-FIP2 is a general regulator of the early endosomal system. Both Rab11-FIP2 mutants altered the localization and co localized with dynein heavy chain. In contrast, both clathrin heavy chain and AP 1 accumulated with membranes containing Rab11-FIP2(SARG), but not with Rab11 FIP2(DeltaC2). Expression of Rab11-FIP2(DeltaC2), but not Rab11-FIP2(SARG), caused clustering of early endosomal markers Rab5b, Epsin 4 and IQGAP1, around a collapsed Rab11-FIP2 containing membranous cisternum. Interestingly, neither Rab11-FIP2 mutant had any effect on the distribution of Rab5a, a classical early endosome marker. The results support the view that Rab11-FIP2 may influence microtubule-dependent centripetal movement of subsets of early endosomes as well as processing through the common and recycling endosomal systems. PMID- 21686256 TI - The Garz Sec7 domain guanine nucleotide exchange factor for Arf regulates salivary gland development in Drosophila. AB - Surface delivery of proteins involved in cell-cell and cell-matrix interactions in cultured mammalian cells requires the GBF1 guanine nucleotide exchange factor. However, the role of GBF1 in delivery of adhesion proteins during organogenesis in intact animals has not been characterized. Here, we report the function of the fly GBF1 homolog, Gartenzwerg (Garz) in the development of the salivary gland in Drosophila melanogaster. We used the GAL4/UAS system to selectively deplete Garz from salivary gland cells. We show that depletion of Garz disrupts the secretory pathway as evidenced by the collapse of Golgi-localized Lava lamp (Lva) and the TGN-localized gamma subunit of the clathrin-adaptor protein complex (AP-1). Additionally, Garz depletion inhibits trafficking of cell-cell adhesion proteins cadherin (DE-cad) and Flamingo to the cell surface. Disregulation of trafficking correlates with mistargeting of the tumor suppressor protein Discs large involved in epithelial polarity determination. Garz-depleted salivary cells are smaller and lack well-defined plasma membrane domains. Garz depletion also inhibits normal elongation and positioning of epithelial cells, resulting in a disorganized salivary gland that lacks a well defined luminal duct. Our findings suggest that Garz is essential for establishment of epithelial structures and demonstrate an absolute requirement for Garz during Drosophila development. PMID- 21686257 TI - The compartmentalized vessel: The bacterial cell as a model for subcellular organization (a tale of two studies). AB - The traditional view of bacterial cells as non-compartmentalized, which is based on the lack of membrane-engulfed organelles, is currently being reassessed. Many studies in recent years led to the realization that bacteria have an intricate internal organization that is vital for various cellular processes. Specifically, various machineries were shown to localize to the poles of rod-shaped bacteria. We have recently shown that the control center of the PTS system, which governs carbon uptake and metabolism, localizes to the poles of E. coli cells. Notably, the machinery that controls bacterial taxis along chemical gradients (chemotaxis) has a similar localization pattern. The fact that the two systems need to communicate in order to generate an optimal metabolic response suggests that their similar spatial organization is not a coincidence. Rather, due to their special characteristics, the poles may function as hubs for signaling systems to allow for efficient crosstalk between different pathways in order to improve coordination of their actions.The regulatory mechanisms that underlie the spatial and temporal organization of microbial cells are largely unknown. Thus far, these mechanisms were believed to rely on embedded features of the localized proteins. In another study, we have recently shown that mRNAs are capable of migrating to particular domains in the bacterial cell where their protein products are required. In contrast to the view that transcription and translation are coupled in bacteria, localization of bacterial transcripts may occur in a translation independent manner. Hence, it seems that the mechanistic basis for separating transcription and translation is more primitive than assumed up until now. We propose that bacteria synthesize proteins either by a transcription-translation coupled mechanism or by transporting mRNAs away from the transcription apparatus. Obviously, eukaryotic cells rely on the latter mechanism. Hence, the capacity of prokaryotic cells to adopt the division between transcription and translation was a crucial step in the evolution of nucleus-containing cells from the prokaryotic origin. Summarily, the line that separates cells with nucleus and cells without is fading, leading to the realization that bacteria are suitable model organisms for studying universal mechanisms that underlie spatial regulation of cellular processes. PMID- 21686258 TI - The peer review process from an editor's point of view. PMID- 21686259 TI - RHO GTPase in plants: Conservation and invention of regulators and effectors. AB - Plants possess a single subfamily of Rho GTPases, ROP, which does usual things as do Rho-family GTPases in animal and fungal systems, namely participating in the spatial control of cellular processes by signaling to the cytoskeleton and vesicular trafficking. As one would expect, ROPs are modulated by conserved regulators such as DHR2-type GEFs, RhoGAPs and Rho GDIs. What is surprising is that plants have invented new regulators such as PRONE-type GEFs (known as RopGEFs) and effectors such as RICs and ICRs/RIPs in the regulation of the cytoskeleton and vesicular trafficking. This review will discuss recent work on characterizing ROP regulators and effectors as well as addressing why and how a mixture of conserved and novel Rho signaling mechanisms is utilized to modulate fundamental cellular processes such as cytoskeletal dynamics/reorganization and vesicular trafficking. PMID- 21686260 TI - Perturbation of cytoskeleton dynamics by the opposing effects of Rac1 and Rac1b. AB - Rac1, a ubiquitously expressed member of the Rho GTPase family, plays a pivotal role in the regulation of multiple cellular processes including cytoskeleton reorganization, cell growth, differentiation and motility. Here we show that the tumor-specific splice variant of Rac1, Rac1b, negatively regulates Rac1 activity. The expression of Rac1b in HeLa cells interferes with Rac1 activation by PDGF, leads to a reduction in membrane-bound Rac1 and promotes an increase in Rho activity. The antagonistic relationship between Rac1 and Rac1b perturbs the regulatory circuitry that controls actin cytoskeleton dynamics thereby leading to tumor-linked alterations in cell morphology and motility. PMID- 21686261 TI - Subtle functional defects in the Arf-specific guanine nucleotide exchange factor IQSEC2 cause non-syndromic X-linked intellectual disability. AB - Mutations in IQSEC2, a guanine nucleotide exchange factor for the ADP ribosylation factor (Arf) family of small GTPases have recently been shown to cause non-syndromic X-linked intellectual disability (ID), characterised by substantial limitations in intellectual functioning and adaptive behaviour. This discovery was revealed by a combination of large-scale resequencing of the X chromosome, and key functional assays that revealed a reduction, but not elimination, of IQSEC2 GEF activity for mutations affecting conserved amino acids in the IQ-like and Sec7 domains. Compromised GTP binding activity of IQSEC2 leading to reduced activation of selected Arf substrates (Arf1, Arf6) is expected to impact on cytoskeletal organization, dendritic spine morphology and synaptic organisation. This study highlights the need for further investigation of the IQSEC gene family and Arf GTPases in neuronal morphology and synaptic function, and suggests that the genes encoding the ArfGEFs IQSEC1 and IQSEC3 should be considered as candidates for screening in autosomal ID. PMID- 21686262 TI - Grhl3 and GEF19 in the front rho. AB - Directional migration is a critical component of cell motility is observed in many diverse processes including embryogenesis, immune surveillance and wound repair. A central aspect of directional migration is cellular polarity, which is established through several signaling pathways that converge on the small GTPases. These factors orchestrate precise spatial and temporal organization of the actin cytoskeleton at the leading edge of the cell, and induce polarized capture and stabilization of microtubules and their associated microtubule organizing center (MTOC). Studies of the regulation of the GTPases have predominantly focused on post-translational mechanisms involving guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs). In this commentary, we examine the transcriptional regulation of these factors, focusing on the recently described regulation of RhoGEF19, an activator of RhoA, by the epidermal-specific transcription factor GRHL3, and the importance of this regulatory mechanism in wound repair. Our findings establish novel links between epidermal cell migration in wound healing and the planar cell polarity (PCP) signaling pathway, and establish a paradigm for tissue-specific regulation of Rho GTPase activity. PMID- 21686263 TI - The mechanism and implications of hScrib regulation of ERK. AB - Scribble is a potential tumor suppressor protein, whose loss is a frequent event in late stage cancer development. In both Drosophila and mammalian model systems, Scribble has been shown capable of regulating cell polarity, cell proliferation and apoptosis. Although several interacting partners, including betaPiX, have been identified that help to explain how Scribble can regulate cell polarity and migration, little is known about how Scribble can control cell proliferation. Recent work from our laboratory has shown that Scribble can directly regulate the ERK signaling pathway. This is mediated by a direct protein-protein interaction between Scribble and ERK, which has two components. In the first, Scribble appears to anchor ERK at membrane-bound sites, with the loss of Scribble enhancing ERK nuclear translocation. In the second, Scribble can decrease the levels of active phosphorylated ERK, a function that is dependent upon the ability of Scribble to bind ERK directly. One of the consequences of this activity of Scribble is the inhibition of EJ-ras induced cell transformation. These results provide some of the first direct mechanistic information on how Scribble can regulate cell proliferation and, furthermore, they provide indications as to the identity of other signaling intermediates that may be recruited by Scribble to directly regulate mitogenic signaling pathways. PMID- 21686264 TI - Integrating chemotaxis and contact-inhibition during collective cell migration: Small GTPases at work. AB - For directional cell migration to occur cells must interpret guiding cues present in their environment. Chemotaxis based on negative or positive signals has been long thought as the main driving force of guided cell migration. However during collective cell migration cells do receive information from external signals but also upon interactions with their direct neighbours. These multiple inputs must be translated into intracellular reorganisation in order to promote efficient directional migration. Small GTPases, being involved in establishing cell polarity and regulating protrusive activity, are likely to play a central role in signal integration. Indeed, recent findings from our laboratory indicate that Contact-Inhibition of Locomotion controlled by N-Cadherin and chemotaxis dependent on Sdf1/Cxcr4 signaling converge towards regulation of the localized activity of RhoA and Rac1. All together they establish cell polarity and select well-oriented cell protrusions to ensure directional cell migration. PMID- 21686265 TI - eIF5 is a dual function GAP and GDI for eukaryotic translational control. AB - We recently showed in a publication in Nature that the eukaryotic translation initiation factor eIF5 has a second regulatory function and is a GDI (GDP dissociation inhibitor) in addition to its previously characterized role as a GAP (GTPase accelerating protein). These findings provide new insight into the mechanism of translation initiation in eukaryotic cells. Additional findings show that the GDI function is critical for the normal regulation of protein synthesis by phosphorylation of eIF2alpha at ser51. Because eIF2 phosphorylation is a ubiquitous mode of translational control these results are of broad interest. Here we review these and related studies and suggest they offer further evidence of parallels between the functions of regulators of the translation factor eIF 2 and both heterotrimeric and small GTPases. PMID- 21686267 TI - GTPase activity of Di-Ras proteins is stimulated by Rap1GAP proteins. AB - The Ras family is the largest and most diverse sub-group of Ras-like G proteins. This complexity is further increased by the high number of regulatory Guanine nucleotide Exchange Factors (GEFs) and GTPase Activating Proteins (GAPs) that target specific members of this subfamily. Di-Ras1 and Di-Ras2 are little characterized members of the Ras-like sub-group with still unidentified regulatory and effector proteins. Here we determined the nucleotide binding properties of Di-Ras1/Di-Ras2. The above nanomolar affinity and the inability to react with members of the Cdc25 RasGEF family might suggest that activation does not require a GEF. We identified Rap1GAP1 and Rap1GAP2 as specific GTPase activating proteins of the Di-Ras family. Dual-specificity GAPs of the GAP1(m) family could not activate Di-Ras proteins, despite the presence of the required catalytic residue. Although Di-Ras proteins share GAPs with Rap G proteins, no common effectors could be identified in vitro. PMID- 21686266 TI - p21-activated kinases in Erbb2-positive breast cancer: A new therapeutic target? AB - The activation of receptor tyrosine kinases, particularly ErbB2, has been linked to the genesis and progression of breast cancer. Two of the central signaling pathways activated by ErbB2 are the Ras/Raf-1/Mek/Erk pathway, which plays an important role in tumor cell growth and migration, and the PI3K/Akt pathway, which plays an important role in cell survival. Recently, we and others have shown that signaling through the Ras-Erk pathway can be influenced by p21 activated kinase 1 (Pak1), an effector of the Rho family GTP ases Rac and Cdc42. Expression of activated forms of Rac promotes activation of Erk through mechanisms involving Pak1 phosphorylation of Raf-1 and Mek1. In addition, Pak1 has also been implicated in the activation of Akt. However, our understanding regarding the degree to which Rho GTPases, and their effectors such as Pak1, contribute to ErbB2-mediated signaling is very limited.Recent results from our laboratory indicate that ErbB2 expression correlates with Pak activation in estrogen receptor negative human breast tumor samples. Using a three-dimensional (3D) culture of human MCF-10A mammary epithelial cells, we found that activation of Rac-Pak pathway by ErbB2 induces growth factor independent proliferation and promotes disruption of acini-like structures through the activation of the Erk and Akt pathways. We also observed that blocking Pak1 activity by small molecule inhibitors impeded the ability of activated ErbB2 to transform these cells and to activate its associated downstream signaling targets. In addition, we found that suppressing Pak activity in ErbB2-amplified breast cancer cells delayed tumor formation and downregulated Erk and Akt signaling in vivo. These results support a model in which Pak, by activating Erk and Akt, cooperates with ErbB2 in transforming mammary epithelial cells. PMID- 21686268 TI - RhoGDI3 and RhoG: Vesicular trafficking and interactions with the Sec3 Exocyst subunit. AB - RhoGDIs are negative regulators of small GTP-binding proteins of the Rho family, which have essential cellular functions in most aspects of actin-based morphology and motility processes. They extract Rho proteins from membranes, keep them in inactive rhoGDI/Rho complexes and eventually deliver them again to specific membranes in response to cellular signals. RhoGDI3, the most divergent member of the rhoGDI family, is well suited to document the underlying molecular mechanisms, since the active and inactive forms of its cellular target, RhoG, have well-separated subcellular localizations. In this study, we investigate trafficking structures and molecular interactions involved in rhoGDI3-mediated shuttling of RhoG between the Golgi and the plasma membrane.Bimolecular fluorescence complementation and acceptor-photobleaching FRET experiments suggest that rhoGDI3 and RhoG form complexes on Golgi and vesicular structures in mammalian cells. 4D-videomicroscopy confirms this localization, and show that RhoG/rhoGDI3-labelled structures are less dynamic than RhoG and rhoGDI3-labeled vesicles, consistent with the inhibitory function of rhoGDI3. Next, we identify the Exocyst subunit Sec3 as a candidate rhoGDI3 partner in cells. RhoGDI3 relocates a subcomplex of the Exocyst (Sec3 and Sec8) from the cytoplasm to the Golgi, while Sec6 is unaffected. Remarkably, Sec3 increases the level of GTP bound endogenous RhoG, the RhoG-dependent induction of membrane ruffles, and the formation of intercellular tunneling nanotube-like protrusions.Altogether, our study identifies a novel link between vesicular traffic and the regulation of Rho proteins by rhoGDIs. It also suggests that components of the Exocyst machinery may be involved in RhoG functions, possibly regulated by rhoGDI3. PMID- 21686269 TI - RLIP76 (RalBP1): The first piece of the structural puzzle. AB - RLIP76 (RalBP1) is a multidomain protein that is a downstream effector of the small GTP ases RalA and RalB. As well as the Ral binding domain it contains a RhoGAP domain active against Cdc42 and Rac1. RLIP76 also binds to proteins involved in endocytosis and to R-Ras. We recently solved the structure of the Ral binding domain of RLIP76 and the structure of the complex that it forms with RalB. The structure shows that, unlike the other Ral effectors characterized so far, RLIP76 forms a coiled-coil that interacts with RalB. The RLIP76 Ral binding domain binds to both the switch regions of RalB, which are the parts of the G protein that chance conformation upon nucleotide exchange. Here, we review our structure and discuss how it sheds light on the other functions of RLIP76. PMID- 21686270 TI - Cooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis. AB - Melanoma displays frequent activation of RAS/RAF/MAPK and PI3K/AKT signaling pathways as well as inactivation of CDKN2A (INK4a/ARF) and PTEN tumor suppressors via genetic and epigenetic alterations. Pathogenetic roles of these melanoma prone mutations and their genetic interactions have been established in genetically engineered mouse models. Here, we catalog frequent genetic alterations observed in human melanomas and describe mouse models of melanoma initiation and progression, including our recent study that investigated the genetic interactions of RAS activation and PTEN loss in a CDKN2A (INK4a/ARF) null melanoma prone genetic background. We showed that loss of PTEN cooperates with HRAS activation, leading to increased development of melanoma and emergence of metastasis. Moreover, we observed that RNA i-mediated PTEN inactivation in RAS driven melanomas enhanced migration and invasion with concomitant downregulation of E-cadherin, the major regulator of epithelial and mesenchymal transition, and enhanced AKT2 phosphorylation, which has been previously linked to invasion and metastasis of several cancer types, including breast and ovary. These data show that activated RAS cooperates with PTEN loss in melanoma genesis and progression. PMID- 21686271 TI - 14-3-3, an integrator of cell mechanics and cytokinesis. AB - One of the goals of understanding cytokinesis is to uncover the molecular regulation of the cellular mechanical properties that drive cell shape change. Such regulatory pathways are likely to be used at multiple stages of a cell's life, but are highly featured during cell division. Recently, we demonstrated that 14-3-3 (encoded by a single gene in the social amoeba Dictyostelium discoideum) serves to integrate key cytoskeletal components-microtubules, Rac and myosin II-to control cell mechanics and cytokinesis. As 14-3-3 proteins are frequently altered in a variety of human tumors, we extend these observations to suggest possible additional roles for how 14-3-3 proteins may contribute to tumorigenesis. PMID- 21686272 TI - Rab GTPases act in sequential steps to regulate phagolysosome formation. AB - During apoptosis, apoptotic cells are recognized and quickly engulfed by phagocytes. The internalized cell corpses are enclosed within membrane-bound vesicles called phagosomes. Cell corpse degradation depends on the phagosomes undergoing a maturation process, but regulation of phagosomal maturation is not well understood. Recently, we identified C. elegans Rab GTPase 14 as a novel regulator of apoptotic cell degradation. Loss of rab-14 function affects several steps of phagosome maturation, causing accumulation of persistent cell corpses. RAB-14 and UNC-108 (Rab GTPase 2) function redundantly to regulate phagosome maturation. Three Rabs, RAB-14, UNC-108/RAB2 and RAB-7, act cooperatively to control phagolysosome formation. RAB-14 and UNC-108 recruit lysosomes, while RAB 7 mediates fusion of lysosomes to phagosomes. Our data thus reveal the sequential action of Rab GTPases in regulating tethering, docking and fusion of lysosomes to phagosomes. PMID- 21686273 TI - Multiple roles for RhoA during T cell transendothelial migration. AB - T cells need to cross endothelial barriers during immune surveillance and inflammation. This involves T-cell adhesion to the endothelium followed by polarization and crawling with a lamellipodium at the front and contractile uropod at the back. T cells subsequently extend lamellipodia and filopodia under the endothelium in order to transmigrate. Rho GTPases play key roles in cell migration by regulating cytoskeletal dynamics and cell adhesion. We have found that the Rho GTPase RhoA is required for efficient T-cell polarization and migration on endothelial cells as well as transendothelial migration. RhoA depleted cells lack both lamellipodia and uropods, and instead have narrow protrusions extending from a rounded cell body. Using a RhoA activity biosensor, we have shown that RhoA is active at the leading edge in lamellipodia and filopodia of crawling and transmigrating T cells, as well as in the uropod. In lamellipodia, its activity correlates with both protrusion and retraction. We predict that RhoA signals via the formin mDIA 1 during lamellipodial protrusion whereas it induces lamellipodial retraction via the kinase ROCK and actomyosin contractility. We propose that different guanine-nucleotide exchange factors (GEFs) are responsible for coordinating RhoA activation and signaling in different regions of transmigrating T cells. PMID- 21686274 TI - Inhibition of Cdc42-mediated activation of mixed lineage kinase 3 by the tumor suppressor protein merlin. AB - Mammalian mitogen-activated protein kinase (MAPK) signaling pathways respond to diverse extracellular signals and coordinate a range of cellular responses. Mixed lineage kinase 3 (MLK3) is a member of the mixed lineage kinase family of MAPK kinase kinases (MAP3Ks) that functions to regulate multiple MAPK signaling pathways. Activated forms of the Rho GTP ases, Rac and Cdc42, interact with MLK3 through the Cdc42/Rac-interactive binding (CRIB) motif and promote MLK3 catalytic activity. Our recent findings demonstrate that merlin, the product of the neurofibromatosis type 2 (NF2) tumor suppressor gene, is a physiological inhibitor of MLK3. Our results suggest that merlin inhibits MLK3 activity by blocking the Cdc42-MLK3 interaction. In this commentary, the effect of merlin on Cdc42-mediated activation of MLK3 and MAPK signaling will be discussed. PMID- 21686275 TI - Scientific dialogue in the electronic age. PMID- 21686276 TI - Evolution of the Ras-like small GTPases and their regulators. AB - Small GTPases are molecular switches at the hub of many signaling pathways and the expansion of this protein family is interwoven with the origin of unique eukaryotic cell features. We have previously reported on the evolution of CDC25 Homology Domain containing proteins, which act as guanine nucleotide exchange factors (GEFs) for Ras-like proteins. We now report on the evolution of both the Ras-like small GTPases as well as the GTPase activating proteins (GAPs) for Ras like small GTPases. We performed an in depth phylogenetic analysis in 64 genomes of diverse eukaryotic species. These analyses revealed that multiple ancestral Ras-like GTPases and GAPs were already present in the Last Eukaryotic Common Ancestor (LECA), compatible with the presence of RasGEFs in LECA . Furthermore, we endeavor to reconstruct in which order the different Ras-like GTPases diverged from each other. We identified striking differences between the expansion of the various types of Ras-like GTPases and their respective GAPs and GEFs. Altogether, our analysis forms an extensive evolutionary framework for Ras-like signaling pathways and provides specific predictions for molecular biologists and biochemists. PMID- 21686277 TI - Rho family GTPase Chp/RhoV induces PC12 apoptotic cell death via JNK activation. AB - Rho GTPases regulate numerous cellular processes including apoptosis. Chp/RhoV is an atypical Rho GTPase which functions are poorly understood. Here we investigated the role of Chp in regulation of cell viability using PC12 cells with inducible expression of Chp as a model. We found that expression of Chp results in apoptosis in PC12 cells. Chp-induced apoptosis was accompanied by activation of JNK signaling and both death receptor-mediated and mitochondrial apoptotic pathways as justified by caspase-8 and caspase-9 activation, respectively. Moreover, inhibition of JNK by SP600125 rescued PC12 cells from Chp triggered cell death and attenuated activation of caspases-9 and -3/7 suggesting that activation of JNK mediates pro-apoptotic effect of Chp. Expression of Chp resulted in increased phosphorylation of c-Jun in PC12 cells, and Chp expression in HE K293 cells upregulated AP-1-dependent transcription in a JNK-dependent manner. Together results of our study reveal the role of Chp GTPase as a putative regulator of JNK-dependent apoptotic death in PC12 cells, similarly to previously described pro-apoptotic activity of the related Cdc42 and Rac1 GTPases. PMID- 21686278 TI - GTP-dependent scaffold formation in the GTPase of Immunity Associated Protein family. AB - GTP ases of Immunity-Associated Proteins (GIMAPs) are a family of guanine nucleotide binding (G) proteins which are implicated in the regulation of apoptosis in lymphocytes. GIMAPs are composed of an amino-terminal G domain and carboxy-terminal extensions of varying size. Our recent biochemical and structural analysis of a representative GIMAP family member, GIMAP2, revealed the molecular basis of GTP-dependent oligomerization which involves two interfaces in the G domain. Whereas the amphipathic helix alpha7 in the C-terminal extension closely folds against the G domain in the GDP-bound state, it might be released in the GTP-bound state to assemble interaction partners. We also showed that the GIMAP2 oligomer functions at the surface of lipid droplets in a Jurkat T cell line. Here, we review our recent work and discuss the GIMAP2 oligomer as a GTP dependent protein scaffold at the surface of lipid droplets controlling apoptosis. PMID- 21686279 TI - Gimap3: A foot-in-the-door to tissue-specific regulation of mitochondrial DNA genetics. AB - Mitochondrial DNA (mtDNA) is a multi-copy genome encoding for proteins essential for aerobic energy metabolism. Mutations in mtDNA can lead to a variety of human diseases, from mild metabolic syndromes to severe fatal encephalomyopathies. Most mtDNA mutations co-exist with wild type genomes in a state known as heteroplasmy. The segregation of these pathogenic mutants is tissue and mutation specific, and a key determinant in the onset and severity of human mitochondrial disorders. We used a forward genetic approach in mice to identify and demonstrate that Gimap3 (GTP ase of immunity associated protein) is a key regulator of mtDNA segregation in leukocytes. The Gimap gene cluster is found only in vertebrates and appear to be a class of nucleotide-dependent dimerization GTP ases. Gimap3 is a membrane anchored GTP ase with a critical role in T cell development. Here, we summarize our genetic findings and postulate how Gimap3 might regulate mtDNA genetics. PMID- 21686280 TI - Regulation of cell adhesion and migration in cortical neurons: Not only Rho but also Rab family small GTPases. AB - Accumulating evidence indicate that Rho family small GTPases, including RhoA, Rac1 and Cdc42, control cytoskeletal organization and cell adhesion, and thereby cell migration in vitro and in vivo. Recently, the involvement of other small GTPases, such as Rab and Arf family proteins in cell migration has also been evaluated. Rab5, Rab11 and Rab7, which regulate endocytosis, recycling and lysosomal degradation pathways, respectively, are shown to have essential roles in the migration of immature neurons during the development of cerebral cortex in vivo. These Rab proteins control distinct steps of neuronal migration through the regulation of N-cadherin-mediated cell adhesion. In this extra view paper, I will discuss the functions of Rho and Rab family small GTP ases in cell migration with particular focus on the migrating neurons in the developing cerebral cortex. PMID- 21686281 TI - C/EBPbeta's role in determining Ras-induced senescence or transformation. AB - Introduction of activated Ras into normal cells leads to senescence, a tumor suppressive mechanism, whereas expression of this oncogene in many immortalized cell lines leads to transformation. Studying the signaling differences in cells that undergo Ras-induced senescence versus Ras transformation may shed light on potential therapeutic targets in the treatment of cancer. C/EBPbeta is a transcription factor necessary for both Ras-induced senescence and Ras transformation. Three isoforms of this transcription factor exist due to alternative translation initation at three in frame ATGs. C/EBPbeta1 is the isoform responsible for oncogene-induced senescence, and this isoform is degraded by the proteosome during Ras transformation. Phosphorylation of C/EBPbeta1 on Thr235 by Cdk2 is necessary, but not sufficient, for degradation of C/EBPbeta1. Proteasomal degradation of C/EBPbeta1 may represent a mechanism to evade senescence. In contrast, C/EBPbeta2 is expressed in breast cancer cells and is involved in proliferation, supporting a role for this isoform in Ras transformation. We propose here that one potential signaling difference in Ras induced senescence versus Ras transformation is that Ras signals through different C/EBPbeta isoforms (C/EBPbeta1 versus C/EBPbeta2) during these processes. PMID- 21686282 TI - "RACK"-ing up the effectors: Receptor for activated C kinase acts downstream of Rac GTPase signaling in growth cone outgrowth. PMID- 21686283 TI - Vimentin: Central hub in EMT induction? AB - Epithelial-to-mesenchymal transition (EMT) is a critical event in the induction of cell motility and increased survival both under physiological situations like wound healing and during development as well as in malignant cells undergoing invasion and metastasis. Vimentin is an intermediate filament protein which is characteristically upregulated in cells undergoing EMT. For decades vimentin has been considered as a marker for EMT but its functional contribution to the process has remained unclear. Our data demonstrate that vimentin contributes to EMT via upregulating the gene expression of several EMT-linked genes. Especially, we find that vimentin regulates EMT associated induced migration via upregulation of the expression of receptor tyrosine kinase Axl. In addition to our data, several other exciting recent studies support the notion that vimentin in fact functions as a positive regulator of EMT and upregulation of vimentin appears to be a prerequisite for EMT induction. PMID- 21686284 TI - Signaling of the direction-sensing FAK/RACK1/PDE4D5 complex to the small GTPase Rap1. AB - We recently reported that a complex between focal adhesion kianse (FAK) and the molecular scaffold RACK1 controlled nascent integrin adhesion formation and cell polarization, via peripheral recruitment of the cAMP - degrading PDE4D5 isoform. Here we review and extend these studies by demonstrating that the FAK/RACK1/PDE4D5 'direction-sensing' complex likely functions by signaling, via the guanine nucleotide exchange factor EPAC , to its small GTPase target Rap1. Specifically, activating EPAC suppresses polarization of squamous cancer cells, while, in contrast, modulating PKA, the other major cAMP effector, has no effect. Moreover, FAK-deficient malignant keratinocytes re-expressing a FAK mutant that cannot bind to RACK1, namely FAK-E139A,D140A, display elevated Rap1 that is linked to impaired polarization. Thus, it is likely that the FAK/RACK1/PDE4D5 complex signals to keep Rap1 low at appropriate times and in a spatially regulated manner as cells first sense their environment and make decisions about nascent adhesion stabilization and polarization. RACK1 is abundantly expressed in both normal and malignant keratinocytes, while FAK and PDE4D5 are both elevated in the cancer cells, suggesting that the FAK/RACK1/PDE4D5/Rap1 signaling axis may contribute to FAK's well documented role in tumor progression. PMID- 21686285 TI - Open Medicine is indexed in PubMed. PMID- 21686286 TI - Open Medicine's ghost and guest authorship policy. PMID- 21686287 TI - Access to primary percutaneous coronary intervention for ST-segment elevation myocardial infarction in Canada: a geographic analysis. AB - BACKGROUND: Primary percutaneous coronary intervention (PCI) is preferred over fibrinolysis for the treatment of ST-segment elevation myocardial infarction (STEMI). In the United States, nearly 80% of people aged 18 years and older have access to a PCI facility within 60 minutes. We conducted this study to evaluate the areas in Canada and the proportion of the population aged 40 years and older with access to a PCI facility within 60, 90 and 120 minutes. METHODS: We used geographic information systems to estimate travel times by ground transport to PCI facilities across Canada. Time to dispatch, time to patient and time at the scene were considered in the overall access times. Using 2006 Canadian census data, we extracted the number of adults aged 40 years and older who lived in areas with access to a PCI facility within 60, 90 and 120 minutes. We also examined the effect on these estimates of the hypothetical addition of new PCI facilities in underserved areas. RESULTS: Only a small proportion of the country's geographic area was within 60 minutes of a PCI facility. Despite this, 63.9% of Canadians aged 40 and older had such access. This proportion varied widely across provinces, from a low of 15.8% in New Brunswick to a high of 72.6% in Ontario. The hypothetical addition of a single facility to each of 4 selected provinces could increase the proportion by 3.2% to 4.3%, depending on the province. About 470 000 adults would gain access in such a scenario of new facilities. INTERPRETATION: We found that nearly two-thirds of Canada's population aged 40 years and older had timely access to PCI facilities. The proportion varied widely across the country. Such information can inform the development of regionalized STEMI care models. PMID- 21686288 TI - Should geographic analyses guide the creation of regionalized care models for ST segment elevation myocardial infarction? PMID- 21686289 TI - Pharmaceutical industry representation on CIHR's governing council. PMID- 21686290 TI - Neoliberalism, conflict of interest, and the governance of health research in Canada. PMID- 21686291 TI - Determinants of knowledge gain in evidence-based medicine short courses: an international assessment. AB - BACKGROUND: Health care professionals worldwide attend courses and workshops to learn evidence-based medicine (EBM), but evidence regarding the impact of these educational interventions is conflicting and of low methodologic quality and lacks generalizability. Furthermore, little is known about determinants of success. We sought to measure the effect of EBM short courses and workshops on knowledge and to identify course and learner characteristics associated with knowledge acquisition. METHODS: Health care professionals with varying expertise in EBM participated in an international, multicentre before-after study. The intervention consisted of short courses and workshops on EBM offered in diverse settings, formats and intensities. The primary outcome measure was the score on the Berlin Questionnaire, a validated instrument measuring EBM knowledge that the participants completed before and after the course. RESULTS: A total of 15 centres participated in the study and 420 learners from North America and Europe completed the study. The baseline score across courses was 7.49 points (range 3.97-10.42 points) out of a possible 15 points. The average increase in score was 1.40 points (95% confidence interval 0.48-2.31 points), which corresponded with an effect size of 0.44 standard deviation units. Greater improvement in scores was associated (in order of greatest to least magnitude) with active participation required of the learners, a separate statistics session, fewer topics, less teaching time, fewer learners per tutor, larger overall course size and smaller group size. Clinicians and learners involved in medical publishing improved their score more than other types of learners; administrators and public health professionals improved their score less. Learners who perceived themselves to have an advanced knowledge of EBM and had prior experience as an EBM tutor also showed greater improvement than those who did not. INTERPRETATION: EBM course organizers who wish to optimize knowledge gain should require learners to actively participate in the course and should consider focusing on a small number of topics, giving particular attention to statistical concepts. PMID- 21686292 TI - Extracts from the meeting of the Standing Committee on Health on the appointment of Dr. Prigent to the governing council of the Canadian Institutes of Health Research. PMID- 21686294 TI - Guest authorship: the practice of author pooling. PMID- 21686293 TI - Analyzing composite outcomes in cardiovascular studies: traditional Cox proportional hazards versus quality-of-life-adjusted survival approaches. AB - BACKGROUND: Composite outcomes that weight each component equally are commonly used to study treatment effects. We hypothesized that each component of a composite outcome would differentially affect patients' overall health-related quality of life (HRQL). METHODS: We tested our hypothesis using data from 2 published clinical studies of treatment for heart failure, one comparing metformin and sulfonylurea and the other comparing digoxin and placebo. We applied the quality-adjusted survival (QAS) approach, which incorporates HRQL data to accommodate differential weights for 2 components (in this analysis, death or admission to hospital) of a commonly used composite end point. For each of the 2 studies, the composite outcome was partitioned into its components, to which utility weights derived from the literature were assigned. Total QAS time determined for each treatment by the QAS analysis was compared with the results from traditional survival analyses based on Cox proportional hazards regression. RESULTS: In the observational study of metformin in heart failure, the risk of the composite outcome of death or admission to hospital was lower for those receiving metformin therapy than for those who received sulfonylurea (event rate 160 [77%] v. 658 [85%]; hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.70 0.99). With traditional survival analysis, the net gain was 0.82 years (95% CI 0.26-1.37), whereas the difference in QAS time was less, at 0.54 years (95% CI 0.20-0.89). In the randomized trial of digoxin therapy, the risk of the composite outcome was lower for those receiving the intervention than for those receiving placebo (event rate 1291 [38%] v. 1041 [31%]; HR 0.75, 95% CI 0.69-0.82). With traditional survival analysis, the net gain was 0.06 years (95% CI 0.02-0.16), whereas the difference in QAS time was greater, at 0.11 years (95% CI 0.06-0.16). INTERPRETATION: Studies that assume equal weights for the components of composite outcomes may overestimate or underestimate treatment effects. By incorporating HRQL into survival analyses, the impact of the various components of the outcome can be assessed more directly. PMID- 21686295 TI - Impact of rosiglitazone meta-analysis on use of glucose-lowering medications. AB - BACKGROUND: In May 2007 Nissen and Wolski reported the results of a meta-analysis showing an association between use of rosiglitazone and increased risk of myocardial infarction (N Engl J Med 2007;356(24):2457-2471). Rosiglitazone is an insulin-sensitizing agent used to control blood glucose levels in patients with type 2 diabetes. Subsequent analyses provided evidence that the meta-analysis led to a decline in new and prevalent use of rosiglitazone. We sought to evaluate the impact of the meta-analysis on patterns of use of glucose-lowering drugs and patterns of initiation, cessation and switching of drug therapy, and to estimate these effects in relation to other predictors of initiation and cessation of rosiglitazone. METHODS: We used an interrupted time series analysis to test the impact of the meta-analysis on monthly utilization of glucose-lowering drugs for the 4.3 million residents of the province of British Columbia. We used multivariate logistic regression with generalized estimating equations to test predictors of initiation and cessation of rosiglitazone, including the influence of microvascular and macrovascular comorbidities, before and after the meta analysis. RESULTS: A comparison of predicted and observed utilization for November 2007 showed that use of rosiglitazone declined by 40% (95% confidence interval 39%-42%), whereas use of pioglitazone, insulin and sulfonylureas increased. The presence of macrovascular comorbidities strengthened both the negative impact of the meta-analysis on initiation of rosiglitazone therapy and the positive impact of the meta-analysis on cessation of this drug. INTERPRETATION: The shift in utilization from rosiglitazone to insulin and sulfonylureas and the modest increase in use of pioglitazone suggest that the latter drug was not embraced as a less harmful alternative to rosiglitazone. Macrovascular comorbidities played a greater role in decisions to start or stop rosiglitazone therapy after the meta-analysis was published. PMID- 21686296 TI - CONSORT 2010 Statement: updated guidelines for reporting parallel group randomized trials. PMID- 21686298 TI - Opening Pandora's box: the public declaration of competing interests. PMID- 21686297 TI - Financial Conflicts of Interest Checklist 2010 for clinical research studies. AB - A conflict of interest is defined as "a set of conditions in which professional judgment concerning a primary interest (such as a patient's welfare or the validity of research) tends to be unduly influenced by a secondary interest (such as financial gain)" [Thompson DF. Understanding financial conflicts of interest. N Engl J Med 1993;329(8):573-576]. Because financial conflict of interest (fCOI) can occur at different stages of a study, and because it can be difficult for investigators to detect their own bias, particularly retrospectively, we sought to provide funders, journal editors and other stakeholders with a standardized tool that initiates detailed reporting of different aspects of fCOI when the study begins and continues that reporting throughout the study process to publication. We developed a checklist using a 3-phase process of pre-meeting item generation, a stakeholder meeting and post-meeting consolidation. External experts (n = 18), research team members (n = 12) and research staff members (n = 4) rated or reviewed items for some or all of the 7 major iterations. The resulting Financial Conflicts of Interest Checklist 2010 consists of 4 sections covering administrative, study, personal financial, and authorship information, which are divided into 6 modules and contain a total of 15 items and their related sub-items; it also includes a glossary of terms. The modules are designed to be completed by all investigators at different points over the course of the study, and updated information can be appended to the checklist when it is submitted to stakeholder groups for review. We invite comments and suggestions for improvement at http://www.openmedicine.ca/fcoichecklist and ask stakeholder groups to endorse the use of the checklist. PMID- 21686300 TI - To test or not to test? Self-monitoring of blood glucose in patients with type 2 diabetes managed without insulin. PMID- 21686299 TI - Efficacy of self-monitoring of blood glucose in patients with type 2 diabetes mellitus managed without insulin: a systematic review and meta-analysis. AB - BACKGROUND: Self-monitoring of blood glucose levels is commonly performed by patients with diabetes mellitus. However, there is debate surrounding the clinical utility and cost-effectiveness of this practice among patients with type 2 diabetes managed without insulin. We conducted a systematic review and meta analysis to determine the effect of self-monitoring versus no self-monitoring, and the optimal frequency of self-monitoring, in this population. METHODS: MEDLINE, EMBASE, BIOSIS Previews, CINAHL and PsycINFO were searched for randomized controlled trials (RCTs) and observational studies published in English from January 1990 to March 2009. Additional citations were obtained through searches of the Internet and conference proceedings, and from stakeholder feedback. Two reviewers independently selected studies, extracted data and performed an assessment of the methodologic quality of the studies. Key outcomes of interest were hemoglobin A1c (HbA(1c)) concentration, hypoglycemia, quality of life, long-term complications of diabetes and death. Where appropriate, we pooled data using random-effects meta-analysis. RESULTS: We identified 1624 citations through the literature search and selected 25 articles for inclusion. We observed a statistically significant improvement in the HbA(1c) concentration across RCTs that compared self-monitoring of blood glucose levels with no self-monitoring among patients taking oral antidiabetes drug therapy (weighted mean difference - 0.25%, 95% confidence interval -0.36% to -0.15%). Subgroup analysis indicated that results from RCTs that provided patients with education on how to interpret and apply self-monitoring test results were similar to those from RCTs that did not. On the basis of limited evidence, self-monitoring of blood glucose levels did not demonstrate consistent benefits in terms of quality of life, patient satisfaction, prevention of hypoglycemia or long-term complications of diabetes, or reduction of mortality. There was insufficient evidence pertaining to the optimal frequency of self-monitoring. INTERPRETATION: Self-monitoring of blood glucose levels was associated with a modest, statistically significant reduction in hemoglobin A1c concentrations, regardless of whether patients were provided with education on how to interpret and use the test results. Further studies are required to determine whether self-monitoring reduces the risk of long-term complications of diabetes and to identify patients most likely to benefit from self-monitoring. PMID- 21686301 TI - Governance of conflicts of interest in postmarketing surveillance research and the Canadian Drug Safety and Effectiveness Network. PMID- 21686302 TI - The ethics of organ donation after cardiocirculatory death: Do the guidelines of the Canadian Council for Donation and Transplantation measure up? PMID- 21686303 TI - Keeping the GINA in the bottle: assessing the current need for genetic non discrimination legislation in Canada. PMID- 21686304 TI - Tobacco control and the collateral damage of conflict of interest. PMID- 21686305 TI - Ezogabine: a new angle on potassium gates. AB - Ezogabine is a new drug for adjunctive therapy of partial-onset seizures with a novel mechanism of action. As a potassium-channel facilitator, it promotes membrane repolarization and thus opposes rapid repetitive discharges. Side effects are typical for antiepileptic drugs and the safety profile is good. Occasional instances of urinary difficulty may require surveillance. PMID- 21686306 TI - Explaining the unexplained; expecting the unexpected: where are we with sudden unexpected death in epilepsy? AB - Sudden death is over 20 times more frequent in people with epilepsy than the general population. The literature on clinical risk factors is now able to define individuals at the highest risk. Despite these advances in our understanding of risk, the mechanism of sudden unexpected death in epilepsy remains elusive. While it is unlikely that a single mechanism will be found to explain all deaths, there have been recent advances that identify factors that play a critical role. This review provides an update on new advances in the understanding of sudden unexpected death in epilepsy. PMID- 21686307 TI - Revisiting AMPA receptors as an antiepileptic drug target. AB - In the 1990s there was intense interest in ionotropic glutamate receptors as therapeutic targets for diverse neurological disorders, including epilepsy. NMDA receptors were thought to play a key role in the generation of seizures, leading to clinical studies of NMDA receptor blocking drugs in epilepsy. Disappointing results dampened enthusiasm for ionotropic glutamate receptors as a therapeutic target. Eventually it became appreciated that another type of ionotropic glutamate receptor, the AMPA receptor, is actually the predominant mediator of excitatory neurotransmission in the central nervous system and moreover that AMPA receptors are critical to the generation and spread of epileptic activity. As drugs became available that selectively target AMPA receptors, it was possible to demonstrate that AMPA receptor antagonists have powerful antiseizure activity in in vitro and in vivo models. A decade later, promising clinical studies with AMPA receptor antagonists, including the potent noncompetitive antagonist perampanel, are once again focusing attention on AMPA receptors as a drug target for epilepsy therapy. PMID- 21686308 TI - Overcoming the effects of rogue taxa: Evolutionary relationships of the bee flies. AB - Bombyliidae (5000 sp.), or bee flies, are a lower brachyceran family of flower visiting flies that, as larvae, act as parasitoids of other insects. The evolutionary relationships are known from a morphological analysis that yielded minimal support for higher-level groupings. We use the protein-coding gene CAD and 28S rDNA to determine phylogeny and to test the monophyly of existing subfamilies, the divisions Tomophtalmae, and 'the sand chamber subfamilies'. Additionally, we demonstrate that consensus networks can be used to identify rogue taxa in a Bayesian framework. Pruning rogue taxa post-analysis from the final tree distribution results in increased posterior probabilities. We find 8 subfamilies to be monophyletic and the subfamilies Heterotropinae and Mythicomyiinae to be the earliest diverging lineages. The large subfamily Bombyliinae is found to be polyphyletic and our data does not provide evidence for the monophyly of Tomophthalmae or the 'sand chamber subfamilies'. PMID- 21686309 TI - Weekly influenza-like-Illness rates were significantly lower in areas where schools were not in session in the United States during the 2009 H1N1 pandemic. AB - This study investigated the relationship between school session status and H1N1 influenza prevalence. Weekly means of Influenza-like-Illness (ILI) rates over the period May 1 to October 31,2009 were compared between areas where schools were and were not in session in the United States. Rates were substantially and significantly higher in areas where schools were in session. This result held separately in spring and fall and was robust to various controls. PMID- 21686310 TI - Resolving the phylogenetic and taxonomic relationship of Xanthomonas and Stenotrophomonas strains using complete rpoB gene sequence. PMID- 21686311 TI - Cocos: Constructing multi-domain protein phylogenies. AB - Phylogenies of multi-domain proteins have to incorporate macro-evolutionary events, which dramatically increases the complexity of their construction.We present an application to infer ancestral multi-domain proteins given a species tree and domain phylogenies. As the individual domain phylogenies are often incongruent, we provide diagnostics for the identification and reconciliation of implausible topologies. We implement and extend a suggested algorithmic approach by Behzadi and Vingron (2006). PMID- 21686312 TI - Stability of white matter changes related to Huntington's disease in the presence of imaging noise: a DTI study. AB - Movement artifacts and other sources of noise are a matter of concern particularly in the neuroimaging research of movement disorders such as Huntington's disease (HD). Using diffusion weighted imaging (DWI) and fractional anisotropy (FA) as a compound marker of white matter integrity, we investigated the effect of movement on HD specific changes in magnetic resonance imaging (MRI) data and how post hoc compensation for it affects the MRI results. To this end, we studied by 3T MRI: 18 early affected, 22 premanifest gene-positive subjects, 23 healthy controls (50 slices of 2.3 mm thickness per volume, 64 diffusion weighted directions (b = 1000 s/mm2), 8 minimal diffusion-weighting (b = 100 s/mm2)); and by 1.5 T imaging: 29 premanifest HD, 30 controls (40 axial slices of 2.3 mm thickness per volume, 61 diffusion-weighted directions (b = 1000 s/mm2), minimal diffusion-weighting (b = 100 s/mm2)). An outlier based method was developed to identify movement and other sources of noise by comparing the index DWI direction against a weighted average computed from all other directions of the same subject. No significant differences were observed when separately comparing each group of patients with and without removal of DWI volumes that contained artifacts. In line with previous DWI-based studies, decreased FA in the corpus callosum and increased FA around the basal ganglia were observed when premanifest mutation carriers and early affected patients were compared with healthy controls. These findings demonstrate the robustness of the FA value in the presence of movement and thus encourage multi-center imaging studies in HD. PMID- 21686313 TI - Multivariate Comparison of Male and Female Adolescent Substance Abusers with Accompanying Legal Problems. AB - PURPOSE: The factors that distinguish adolescent male and female substance abusers with and without legal problems were investigated. METHOD: Youths (N = 4,071) admitted for substance abuse treatment were administered the revised Drug Use Screening Inventory (DUSI-R) to measure severity of health, behavior, and social adjustment problems. RESULTS: Legal problems were more frequent among boys; however, severity of disturbance was greater in girls on 9 of 10 scales. Substance abusing girls and boys with legal problems reported more severe behavior, substance abuse, family adjustment, and peer relationship problems than substance abusing peers without legal problems. Quality of peer relationship mediated the association of family dysfunction, substance abuse and behavior problems with legal problems in boys only. CONCLUSIONS: Gender and legal status both need to be taken into account to potentiate treatment prognosis of substance abusing youths. PMID- 21686314 TI - Quality Mesh Smoothing via Local Surface Fitting and Optimum Projection. AB - The smoothness and angle quality of a surface mesh are two important indicators of the "goodness" of the mesh for downstream applications such as visualization and numerical simulation. We present in this paper a novel surface mesh processing method not only to reduce mesh noise but to improve angle quality as well. Our approach is based on the local surface fitting around each vertex using the least square minimization technique. The new position of the vertex is obtained by finding the maximum inscribed circle (MIC) of the surrounding polygon and projecting the circle's center onto the analytically fitted surface. The procedure above repeats until the maximal vertex displacement is less than a pre defined threshold. The mesh smoothness is improved by a combined idea of surface fitting and projection, while the angle quality is achieved by utilizing the MIC based projection scheme. Results on a variety of geometric mesh models have demonstrated the effectiveness of our method. PMID- 21686315 TI - An Efficient Stochastic Search for Bayesian Variable Selection with High Dimensional Correlated Predictors. AB - We present a Bayesian variable selection method for the setting in which the number of independent variables or predictors in a particular dataset is much larger than the available sample size. While most existing methods allow some degree of correlations among predictors but do not consider these correlations for variable selection, our method accounts for correlations among the predictors in variable selection. Our correlation-based stochastic search (CBS) method, the hybrid-CBS algorithm, extends a popular search algorithm for high-dimensional data, the stochastic search variable selection (SSVS) method. Similar to SSVS, we search the space of all possible models using variable addition, deletion or swap moves. However, our moves through the model space are designed to accommodate correlations among the variables. We describe our approach for continuous, binary, ordinal, and count outcome data. The impact of choices of prior distributions and hyper-parameters is assessed in simulation studies. We also examined performance of variable selection and prediction as the correlation structure of the predictors varies. We found that the hybrid-CBS resulted in lower prediction errors and better identified the true outcome associated predictors than SSVS when predictors were moderately to highly correlated. We illustrate the method on data from a proteomic profiling study of melanoma, a skin cancer. PMID- 21686316 TI - Factor structure and sex differences on the Wechsler Preschool and Primary Scale of Intelligence in China, Japan and United States. AB - This study presents data on the factor structure of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) and sex and cultural differences in WPPSI test scores among 5- and 6-year-olds from China, Japan, and the United States. Results show the presence of a verbal and nonverbal factor structure across all three countries. Sex differences on the 10 subtests were generally consistent, with a male advantage on a subtest of spatial abilities (Mazes). Males in the Chinese sample obtained significantly higher Full Scale IQ scores than females and had lower variability in their test scores. These observations were not present in the Japan and United States samples. Mean Full Scale IQ score in the Chinese sample was 104.1, representing a 4-point increase from 1988 to 2004. PMID- 21686317 TI - Effects of gender and regional dialect on prosodic patterns in American English. AB - While cross-dialect prosodic variation has been well established for many languages, most variationist research on regional dialects of American English has focused on the vowel system. The current study was designed to explore prosodic variation in read speech in two regional varieties of American English: Southern and Midland. Prosodic dialect variation was analyzed in two domains: speaking rate and the phonetic expression of pitch movements associated with accented and phrase-final syllables. The results revealed significant effects of regional dialect on the distributions of pauses, pitch accents, and phrasal boundary tone combinations. Significant effects of talker gender were also observed on the distributions of pitch accents and phrasal-boundary tone combinations. The findings from this study demonstrate that regional and gender identity features are encoded in part through prosody, and provide further motivation for the close examination of prosodic patterns across regional and social varieties of American English. PMID- 21686318 TI - That's nice, but what does IT do? Evaluating the impact of bar coded medication administration by measuring changes in the process of care. AB - Health information technology (IT) is widely endorsed as a way to improve key health care outcomes, particularly patient safety. Applying a human factors approach, this paper models more explicitly how health IT might improve or worsen outcomes. The human factors model specifies that health IT transforms the work system, which transforms the process of care, which in turn transforms the outcome of care. This study reports on transformations of the medication administration process that resulted from the implementation of one type of IT: bar coded medication administration (BCMA). Registered nurses at two large pediatric hospitals in the US participated in a survey administered before and after one of the hospitals implemented BCMA. Nurses' perceptions of the administration process changed at the hospital that implemented BCMA, whereas perceptions of nurses at the control hospital did not. BCMA appeared to improve the safety of the processes of matching medications to the medication administration record and checking patient identification. The accuracy, usefulness, and consistency of checking patient identification improved as well. In contrast, nurses' perceptions of the usefulness, time efficiency, and ease of the documentation process decreased post-BCMA. Discussion of survey findings is supplemented by observations and interviews at the hospital that implemented BCMA. By considering the way that IT transforms the work system and the work process a practitioner can better predict the kind of outcomes that the IT might produce. More importantly, the practitioner can achieve or prevent outcomes of interest by using design and redesign aimed at controlling work system and process transformations. PMID- 21686319 TI - Simultaneous TMS-fMRI of the Visual Cortex Reveals Functional Network, Even in Absence of Phosphene Sensation. AB - Phosphene sensation is commonly used to measure cortical excitability during transcranial magnetic stimulation (TMS) of the occipital cortex. However, some individuals lack this perception, and the reason for it is still unknown. In this work, we used functional magnetic resonance imaging (fMRI) to detect brain activation during local TMS of the occipital cortex in twelve healthy subjects. We found that TMS modulated brain activity in areas connected to the stimulation site, even in people unable to see phosphene. However, we observed a trend for a lower blood-oxygenation-level dependent (BOLD) signal, and smaller brain activation clusters near the stimulated site than in the interconnected brain areas, suggesting that TMS pulse is more effective downstream than at its application site. Furthermore, we noted prominent differences in brain activation/deactivation patterns between subjects who perceived phosphene and those who did not, implying a functional distinction in their neuronal networks that might explain the origin of differences in phosphene generation. PMID- 21686320 TI - Monteggia Type IV Equivalent Injury. AB - Equivalent lesions of Monteggia type IV injury have not appeared so far in the literature. Two Monteggia type IV equivalent lesions, which included a fracture of the radial head associated with midshaft fractures of the radius and ulna in a 3- and in a 12-year-old girl, are reported. The lesion presented in this report could be considered as a missing piece in the puzzle of Monteggia and equivalent injuries, and it could also add towards considering type IV injury as a primary lesion and not as a variant of type I injury. PMID- 21686321 TI - The aseptic femoral and tibial shaft non-union in healthy patients - an analysis of the health-related quality of life and the socioeconomic outcome. AB - Long bone non-unions may lead to recurrent surgical procedures and in-hospital stays. Thus, restrictions of the health-related quality of life and of socioeconomic parameters might be expected. Knowledge of the impact on several parameters of professional life is sparse. Therefore, we analyzed the outcome in patients following non-unions of the tibial and femoral shaft after fracture compared to patients with uneventful healing. MATERIAL AND METHODOLOGY: 51 patients following non-unions of the the femoral (FNU) or tibial shaft (TNU) were compared to 51 patients (groups FH and TH) with uneventful fracture healing. Physical and mental health was assessed using the Short-Form Health Survey (SF 12), Hospital Anxiety and Depression Scale (HADS) and the Impact of Event Scale (IES). We also analyzed employment status and the usage of medical aids. RESULTS: Scores of the SF-12 physical and psychological were lower in group TNU compared to group TH, the score of SF-12 physical but not psychological was significantly lower in group FNU compared to FH. Compared to uneventful healing, a significantly more frequent usage of medical aids was found in both non-union groups. A higher incidence of early retirement and unemployment was found in group FNU but not in group TNU. CONCLUSIONS: There is a profound influence on the quality of life following femoral or tibial non-unions after trauma. Compared to patients with uneventful fracture healing, patients with tibial and even more so femoral non-union show worse scores of the SF-12. Medical aids are frequently used following both, femoral and tibial non-unions. Not tibial, but femoral non unions frequently lead to severe restrictions in professional life such as early retirement and unemployment. PMID- 21686322 TI - Aripiprazole augmentation in patients with resistant obsessive compulsive disorder: a pilot study. AB - BACKGROUND: Antipsychotic augmentation is an effective treatment intervention for Obsessive Compulsive Disorder (OCD) patients resistant to Selective Serotonin Reuptake Inhibitors (SSRI) agents. This pilot study was conducted to evaluate the effectiveness and tolerability of Aripiprazole for the augmentation of standard treatments in patients with resistant OCD. METHODS: Twenty patients diagnosed with OCD according to DSM-IV TR criteria and having a history of resistance to standard pharmacological treatment were included in the study. Aripiprazole was added to ongoing SSRI or clomipramine treatment with a starting dose of 5 mg/day and titrated up to a maximum of 20 mg/day (mean dose 12.62 mg +/- 4.25). Efficacy was assessed with the Yale-Brown obsessive compulsive scale (Y-BOCS) and the Clinical Global Improvement-severity scale (CGI-S) at baseline and at week 12 of Aripiprazole augmentation. Side effects were monitored by the Udvalg for Kliniske Undersogelser (UKU) side effect rating scale. RESULTS: All 20 subjects enrolled in our study completed the full 12-week course of treatment. A significant improvement over the 12-week study period was observed (paired t-test for mean Y BOCS total score at week 12 as compared with baseline - all patients: t = 13.146, d.f. = 19, p= 0.0001). Aripiprazole was generally well tolerated and no changes were observed in vital signs. The most commonly observed side effects after the introduction of the augmenting agent included: akathysia, nausea/vomiting, hyperkinesia, tension/inner unrest, tremors, asthenia/lassitude/increased fatiguability. CONCLUSIONS: Although results of this pilot study are preliminary and require confirmation in randomized controlled trials, our experience suggested that Aripiprazole is effective and well-tolerated as an augmenting agent in patients with treatment resistant OCD. PMID- 21686323 TI - Compartment syndrome following lower limb arthroplasty: a review. AB - Compartment syndrome is an urgent clinical entity characterised by an increase in the interstitial pressure within a closed osseofascial compartment. Although well recognised as a potential complication after orthopaedic trauma, it is very rarely presented after elective orthopaedic surgery and especially joint arthroplasty. In these rare cases a number of variables are associated with it (positioning, coagulopathy, extensive soft tissue dissection, previous scarring, and epidural analgesia). In this study we present the current evidence with regard to incidence and causation of compartment syndrome after lower limb joint arthroplasty and make recommendations on how to avoid the development of this devastating complication. PMID- 21686324 TI - Evaluation of Corneal Epithelial Healing Under Contact Lens with Spectral-Domain Anterior Segment Optical Coherence Tomography (SD-OCT). AB - PURPOSE: To describe a novel technique of using Spectral-domain (SD) anterior segment optical coherence tomography (SD-OCT) in the evaluation of corneal epithelial healing under a therapeutic contact lens (TCL) after lamellar keratoplasty and Epi-LASIK procedures. DESIGN: Prospective, non-comparative, observational case series. METHODS: Ten eyes of eight patients undergoing lamellar corneal transplantation and Epi-LASIK procedures at the Singapore National Eye Centre were included in the study. Ultra-high resolution SD-OCT scans of the cornea with a TCL in-situ were performed sequentially on the first, third and fifth day after procedure, with the RTVue (Optovue, Inc, Fremont, CA, USA), and the image findings were correlated with the clinical picture. Complete epithelial healing was verified with removal of TCL and fluorescein staining. RESULTS: 5 eyes underwent Descemet's stripping automated endothelial keratoplasty (DSAEK), 1 eye underwent deep anterior lamellar keratoplasty (DALK) and 4 eyes underwent Epi-LASIK. All eyes had complete epithelial healing with TCL in-situ by the third post-operative day. SD-OCT images were able to demonstrate the epithelial layer distinctly under the TCL in all cases. CONCLUSIONS: SD-OCT is a valuable imaging tool for monitoring the progression of epithelial healing with TCL in situ in patients following corneal surgical procedures. PMID- 21686325 TI - Coordinated gene expression of Th17- and Treg-associated molecules correlated with resolution of the monophasic experimental autoimmune uveitis. AB - PURPOSE: To investigate the role of T-cell-mediated immune response in a monophasic experimental autoimmune uveitis (EAU). METHODS: A monophasic EAU was induced in Lewis rats by immunization with interphotoreceptor retinoid-binding protein peptide. Optimized quantitative real-time RT-PCR was used for consecutive measurement of the relative expression of Th17-associated molecules, including interleukin 6 (IL-6), transforming growth factor-beta (TGF-beta), interleukin 23p19 (IL-23p19), interleukin 23p40 (IL-23p40), CD4, CD8, major histocompatibility complex I (MHC I), major histocompatibility complex II (MHC II), interleukin 17 (IL-17), interleukin 17F (IL-17F), interleukin 17 receptor A (IL-17RA), retinoic acid-related orphan receptor gammat (RORgammat) and Chemokine receptor 6 (CCR6), in addition to Treg-related forkhead box P3 (Foxp3), C-X-C chemokine receptor type 5 (CXCR5), and cluster of differentiation 25 (CD25) at the initiation, effector, and resolution phases of EAU and compared with those at 14 days post-immunization of control animals. Immunohistochemisty was used to examine IL-17 expression in retinas. Glial fibrillary acidic protein retinal astrocytes, Neuronal class III beta-Tubulin(Tuj1(+))retinal ganglion cells, and infiltrating CD11b(+) microglia were analyzed by fluorescent microscopy in a kinetic manner. RESULTS: Our results indicated well organized T-cell activity, measured by relative expression of multiple T-cell-related factors at the mRNA level, synchronized with the initiation of autoimmune inflammation, and thereafter resolution of the monophasic EAU. Immune balance was achieved several times through coordinated expression of Th17- and Treg-related factors. The expression pattern of these factors and results from immunochemistry with an IL 17 antibody indicated that there may be intensive crosstalk between infiltrating immune cells and the resident neural cells, which were significantly activated during the course of disease. CONCLUSIONS: T-cell-mediated immune response played a positive role in resolution of the monophasic EAU. PMID- 21686326 TI - Association of EPHA2 polymorphisms and age-related cortical cataract in a Han Chinese population. AB - PURPOSE: The gene for Eph-receptor tyrosinekinase-type A2 (EPHA2) has been shown to be involved in the pathogenesis of age-related cataract (ARC). The aim of this study was to examine whether EPHA2 polymorphisms were associated with the susceptibility to age-related cortical cataract in a Han Chinese population. METHODS: Five single-nucleotide polymorphisms (SNPs)-rs3768293, rs3754334, rs7548209, rs707455, and rs477558-in the EPHA2 gene were genotyped in 422 Han Chinese patients with age-related cortical cataract and 317 age-, sex-, and ethnically matched healthy controls using a PCR restriction fragment length polymorphism (PCR-RFLP) assay. Data were analyzed by chi(2) analysis. RESULTS: The results showed that the five analyzed polymorphisms in EPHA2 were in Hardy Weinberg equilibrium both in the patients and in the controls. The frequency of the rs477558 AA genotype was significantly increased in ARC patients compared with controls (chi(2)=8.649, pc=0.045, odds ratio [OR] 1.555, 95% CI 1.158 to 2.089). The frequency of the rs477558 AG genotype was significantly decreased in ARC patients compared with controls (chi(2)=9.281, pc=0.030, OR 0.626, 95% CI 0.463 to 0.847). Significantly higher frequencies of the GG genotype and the G allele of rs7548209 were observed in ARC patients compared with controls (chi(2)=10.430, pc=0.015, OR 1.660, 95% CI 1.219 to 2.261 and chi(2)=8.537, pc=0.015, OR 1.486, 95% CI 1.138 to 1.940, respectively). On the other hand, significantly decreased frequencies of the rs7548209 CG genotype and the C allele were observed in ARC patients compared with controls (chi(2)=9.999, pc=0.030, OR 0.603, 95% CI 0.440 to 0.826 and chi(2)=8.537, pc=0.015, OR 0.673, 95% CI 0.515 to 0.879, respectively). There was no difference in the frequencies of the genotype and allele of the rs3768293, rs3754334, and rs707455 SNPs between the patients with ARC and the controls. CONCLUSIONS: Our study suggests that both SNP rs477558 and SNP rs7548209 of EPHA2 are associated with age-related cortical cataract in a Han Chinese population. PMID- 21686327 TI - The role of SLIT-ROBO signaling in proliferative diabetic retinopathy and retinal pigment epithelial cells. AB - PURPOSE: SLIT-ROBO signaling acts as a cue in neuronal guidance and plays a role in vasculogenesis and angiogenesis. The aim of this study is to explore the effects of robo1 and slit2 on the formation of fibrovascular membranes (FVMs) in samples from patients with proliferative diabetic retinopathy. The effects of advanced glycation end products (AGEs) on robo1 and slit2 expression in human retinal pigment epithelium (RPE) cells and the role of recombinant N-SLIT2 protein in human RPE cell regulation were investigated. METHODS: Immunohistochemistry was performed to determine the presence and distribution of robo1 and slit2 in FVMs, and to confirm the effects of SLIT-ROBO signaling on FVM formation. The expression levels of robo1 and slit2 in RPE cells under basal and differential concentrations of AGEs were measured using real-time reverse transcription-polymerase chain reaction (RT-PCR), immunoblotting, or enzyme linked immunosorbent assay. LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), was used to help determine the AGE signaling mechanism. Recombinant N SLIT2 protein was used to study the effects of slit2 on RPE cells in vitro. Cell proliferation, migration, and cell cycling were assessed using an 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay assay (MTT) assay, a Boyden chamber assay, and flow cytometry. Real-time RT-PCR and enzyme-linked immunosorbent assay were used to study vascular endothelial growth factor (VEGF) mRNA expression in and VEGF protein secretion from RPE cells. RESULTS: Robo1 and Slit2 were expressed in FVMs in RPE cells coimmunostained for pancytokeratin. AGEs resulted in an increase in robo1 and slit2 levels in RPE cells, and inhibition of PI3K-blocked robo1 and slit2 expression. Recombinant N-SLIT2 protein increased proliferation, attachment, and migration of the RPE cells, and these cells demonstrated significant accumulation in the S phase compared to control cells. Furthermore, RPE cells treated with exogenous N-SLIT2 protein had higher levels of VEGF mRNA expression and VEGF protein secretion (p<0.05). CONCLUSIONS: Robo1 and slit2 may play a role in the formation of FVMs. The presence of AGEs increased levels of robo1 and slit2 in human RPE cells via signaling through the PI3K/Akt pathway. Recombinant N-SLIT2 protein increased the biologic activity of RPE cells, as well as the expression of VEGF. From these results, we may conclude that SLIT-ROBO signaling potentially contributes to the development of diabetic retinopathy. PMID- 21686328 TI - Mutational screening of six genes in Chinese patients with congenital cataract and microcornea. AB - PURPOSE: To identify mutations in 6 genes of 9 Chinese families with congenital cataract and microcornea. METHODS: Nine unrelated families with congenital cataract and microcornea were collected. Cycle sequencing was used to detect variants in the coding and adjacent regions of the crystallin alpha A (CRYAA), crystallin beta B1 (CRYBB1), crystallin beta A4 (CRYBA4), crystallin gamma C (CRYGC), crystallin gamma D (CRYGD), and gap junction protein alpha 8 (GJA8) genes. RESULTS: Upon complete analysis of the 6 genes, three mutations in 2 genes were detected in 3 families, respectively. These mutations were not present in 96 normal controls. Of the three mutations, two novel heterozygous mutations in GJA8, c.136G>A (p.Gly46Arg) and c.116C>G (p.Thr39Arg), were found in two families with congenital cataract and microcornea. The rest one, a heterozygous c.34C>T (p.Arg12Cys) mutation in CRYAA, was identified in three patients from a family with nuclear cataract, microcornea with axial elongation. No mutation in the 6 genes was detected in the remaining 6 families. CONCLUSIONS: Mutations in GJA8 and CRYAA were identified in three families with cataract and microcornea. Elongation of axial length accompanied with myopia was a novel phenotype in the family with the c.34C>T mutation in CRYAA. Our results expand the spectrum of GJA8 mutations as well as their associated phenotypes. PMID- 21686329 TI - Seven novel mutations in the long isoform of the USH2A gene in Chinese families with nonsyndromic retinitis pigmentosa and Usher syndrome Type II. AB - PURPOSE: To describe the clinical and genetic findings in one Chinese family with autosomal recessive retinitis pigmentosa (arRP) and in three unrelated Chinese families with Usher syndrome type II (USH2). METHODS: One family (FR1) with arRP and three unrelated families (F6, F7, and F8) with Usher syndrome (USH), including eight affected members and seven unaffected family individuals were examined clinically. The study included 100 normal Chinese individuals as normal controls. After obtaining informed consent, peripheral blood samples from all participants were collected and genomic DNA was extracted. Genotyping and haplotyping analyses were performed on the known genetic loci for arRP with a panel of polymorphic markers in family FR1. In all four families, the coding region (exons 2-72), including the intron-exon boundary of the USH2A (Usher syndrome type -2A protein) gene, was screened by PCR and direct DNA sequencing. Whenever substitutions were identified in a patient, a restriction fragment length polymorphism (RFLP) analysis, single strand conformation polymorphism (SSCP) analysis, or high resolution melt curve analysis (HRM) was performed on all available family members and on the 100 normal controls. RESULTS: The affected individuals presented with typical fundus features of retinitis pigmentosa (RP), including narrowing of the vessels, bone-spicule pigmentation, and waxy optic discs. The electroretinogram (ERG) wave amplitudes of the available probands were undetectable. Audiometric tests in the affected individuals in family FR1 were normal, while indicating moderate to severe sensorineural hearing impairment in the affected individuals in families F6, F7, and F8. Vestibular function was normal in all patients from all four families. The disease-causing gene in family FR1 was mapped to the USH2A locus on chromosome 1q41. Seven novel mutations (two missenses, one 7-bp deletion, two small deletions, and two nonsenses) were detected in the four families after sequencing analysis of USH2A. CONCLUSIONS: The results further support that mutations of USH2A are also responsible for non-syndromic RP. The mutation spectrum among Chinese patients might differ from that among European Caucasians. PMID- 21686330 TI - A recurrent mutation in CRYBA1 is associated with an autosomal dominant congenital nuclear cataract disease in a Chinese family. AB - PURPOSE: Congenital cataracts are a clinically and genetically heterogeneous lens disorder. The purpose of this study was to identify the genetic mutation and the molecular phenotype responsible for the presence of an autosomal dominant congenital nuclear cataract disease in a Chinese family. METHODS: Patients were given a physical examination and their blood samples were collected for DNA extraction. Genotyping was performed by microsatellite markers, and a logarithm of odds (LOD) score was calculated using the LINKAGE programs. Mutation detection was performed by direct sequencing. RESULTS: Linkage to the crystallin beta A1 (CRYBA1) locus was identified. DNA sequencing of the gene revealed a c.279 281delGAG mutation in exon 4, which resulted in a glycine residue deletion at position 91 (DeltaG91). This mutation was identified in all of the affected individuals but was not found in the 100 control chromosomes. CONCLUSIONS: Our results identify that the c.279-281delGAG mutation in CRYBA1 is responsible for the autosomal dominant congenital nuclear cataract disease in this Chinese family. PMID- 21686331 TI - Challenging urban health: towards an improved local government response to migration, informal settlements, and HIV in Johannesburg, South Africa. AB - This article is a review of the PhD thesis undertaken by Joanna Vearey that explores local government responses to the urban health challenges of migration, informal settlements, and HIV in Johannesburg, South Africa. Urbanisation in South Africa is a result of natural urban growth and (to a lesser extent) in migration from within the country and across borders. This has led to the development of informal settlements within and on the periphery of urban areas. The highest HIV prevalence nationally is found within urban informal settlements. South African local government has a 'developmental mandate' that calls for government to work with citizens to develop sustainable interventions to address their social, economic, and material needs. Through a mixed-methods approach, four studies were undertaken within inner-city Johannesburg and a peripheral urban informal settlement. Two cross-sectional surveys - one at a household level and one with migrant antiretroviral clients - were supplemented with semi structured interviews with multiple stakeholders involved with urban health and HIV in Johannesburg, and participatory photography and film projects undertaken with urban migrant communities. The findings show that local government requires support in developing and implementing appropriate intersectoral responses to address urban health. Existing urban health frameworks do not deal adequately with the complex health and development challenges identified; it is essential that urban public health practitioners and other development professionals in South Africa engage with the complexities of the urban environment. A revised, participatory approach to urban health - 'concept mapping' - is suggested which requires a recommitment to intersectoral action, 'healthy urban governance' and public health advocacy. PMID- 21686333 TI - Acute vomiting and mental status changes: a case of acute intraventricular haemorrhage from an optic chiasm tumour. AB - In this article, we describe a 5- year-old girl who presented to an emergency department with 1 day of vomiting, mental status changes and decreased activity. Imaging studies revealed a mass in the optic chiasm which had haemorrhaged into her ventricles causing acute hydrocephalus. This case highlights the diligence and broad differential one must have when evaluating a child presenting with a sole complaint of vomiting. PMID- 21686334 TI - Efficacy of low-dose topical mitomycin C treatment for primary acquired melanosis. AB - Primary acquired melanosis (PAM) with atypical cytological features has nearly a 50% chance of progressing to malignant melanoma. Surgical excision with cryotherapy has been the mainstay of treatment, but topical treatment with mitomycin C (MMC) is an increasingly common alternative treatment. Since PAM is relatively rare and MMC is a new treatment option, publications are limited to case reports and a few small series. Optimum doses, duration and timing of treatment cycles have not been established. Two patients were diagnosed with PAM with atypia and were treated with either primary or adjuvant treatment of 0.02% MMC for approximately 10 days for three cycles, which is the lowest dose protocol published to date for the treatment of PAM. Both patients showed stable partial response and only experienced temporary ocular drug toxicity. PMID- 21686335 TI - Incidental adrenocortical oncocytoma. AB - A 66-year-old man with a history of hypertension and poor compliance with therapeutic regimens for the past 10 years presented with right renal colic. Sonographic evaluation of the kidneys revealed an incidental left renal upper pole mass. There were no palpitations, headache, weakness or fatigue, and the physical examination was unremarkable. Further evaluation including laboratory tests, abdominal computed tomography scan and magnetic resonance imaging revealed a non-functioning left adrenal mass with no malignant characteristic. Laparascopic left adrenalectomy and subsequent pathologic examination demonstrated a 8*6.5*4 cm oncocytoma. Follow-up of the patient for 1 year has revealed no complication or recurrence. Adrenocortical oncocytoma is an exceptionally rare tumour, mainly non-functional and benign, that should be considered in the differential diagnosis of adrenal "incidentalomas". PMID- 21686336 TI - Can Salmonella enteritidis cause fatal necrotising fasciitis? A case report. AB - This is a presentation of a case of mono microbial necrotising fasciitis due to the unusual organism Salmonella enteritidis. The patient presented with swelling and blistering of the right calf. There are only five other such cases reported in the literature. This was the only case that had positive blood cultures for the organism. Prompt and appropriate treatment was intuited but the patient died because of multi-organ failure. PMID- 21686337 TI - Fatality from minor cervical trauma in ankylosing spondylitis. AB - Cervical injury is a serious and often fatal complication of ankylosing spondylitis in the setting of minor trauma. This case report describes a 51-year old woman with ankylosing spondylitis and a minor trauma who developed severe bradycardia during positioning for x ray. Further diagnostic revealed a hyperextensive fracture of C4 with fragments compressing the cervical medulla. The woman subsequently died from hypoxic brain damage. Reviewing the literature, a high alertness in ankylosing spondylitis and minor trauma with neck immobilisation is emphasised, early diagnosis using cervical spine computed tomography is essential to a favourable outcome, and the mechanism of bradycardia in cervical trauma is discussed. PMID- 21686332 TI - Quantitative proteomics: assessing the spectrum of in-gel protein detection methods. AB - Proteomics research relies heavily on visualization methods for detection of proteins separated by polyacrylamide gel electrophoresis. Commonly used staining approaches involve colorimetric dyes such as Coomassie Brilliant Blue, fluorescent dyes including Sypro Ruby, newly developed reactive fluorophores, as well as a plethora of others. The most desired characteristic in selecting one stain over another is sensitivity, but this is far from the only important parameter. This review evaluates protein detection methods in terms of their quantitative attributes, including limit of detection (i.e., sensitivity), linear dynamic range, inter-protein variability, capacity for spot detection after 2D gel electrophoresis, and compatibility with subsequent mass spectrometric analyses. Unfortunately, many of these quantitative criteria are not routinely or consistently addressed by most of the studies published to date. We would urge more rigorous routine characterization of stains and detection methodologies as a critical approach to systematically improving these critically important tools for quantitative proteomics. In addition, substantial improvements in detection technology, particularly over the last decade or so, emphasize the need to consider renewed characterization of existing stains; the quantitative stains we need, or at least the chemistries required for their future development, may well already exist. PMID- 21686338 TI - Synchronous occurrence of adenocarcinoma of the rectum with squamous cell carcinoma of a retrorectal cyst: report of a case and review of the literature. AB - Retrorectal cysts are rare congenital anomalies which are more common in females. Rarely, malignant transformation can occur in these cysts. We report here the case of a middle-aged man who had synchronous presentation of adenocarcinoma of the rectum and squamous cell carcinoma in a retrorectal cyst. The patient presented with rectal bleeding and constipation, and underwent abdominoperineal resection and complete excision of the cyst. Postoperative histopathological examination showed adenocarcinoma of the rectum and squamous cell carcinoma of the cyst. The patient received adjuvant chemotherapy and after 18 months of follow-up is free of any local or metastatic disease. Synchronous occurrence of rectal cancer with carcinoma in a retrorectal cyst has not been previously reported in the literature in English. PMID- 21686339 TI - Acute myeloid leukaemia presenting as faecal incontinence. AB - Epidural sacral nerve compression as an initial feature of leukaemia is a rare complication. The findings in a 16-year-old boy who presented to an emergency department with symptoms of faecal incontinence are reported herein. Radiological imaging demonstrated soft tissue masses in the sacral epidural space. The diagnosis of acute myeloid leukaemia was confirmed on bone marrow aspirate. The characteristics and management of extramedullary leukaemia are discussed. PMID- 21686340 TI - Lemierre syndrome: a needle in a haystack. AB - A young woman with no significant past medical history presented with worsening cough, swinging fevers, persistent chest pain and neck tenderness. On examination she was tachycardic, hypotensive, pyrexial and became increasingly confused. Inflammatory markers in her blood were raised, but the chest film showed clear lung fields and urinalysis was negative. The impression was sepsis query source and broad-spectrum intravenous antibiotics were commenced. The patient deteriorated into respiratory failure and was transferred to intensive care. Some days after admission, an anaerobic bacillus, known to cause Lemierre syndrome, was cultured from her blood sample. The patient was treated with organism sensitive antibiotics and improved over the next few days. She was discharged after further radiological investigations returned normal. PMID- 21686341 TI - Thyroid swelling in a 32-year-old male. AB - Patients with intrathyroidal metastasis may present with previous history of malignancy or they may present with a secondary neoplasm prompting us to search for the primary site. A 32-year-old male presented with a 4-month history of thyroid swelling and abdomen pain. Fine-needle aspiration cytology from the thyroid swelling revealed deposits from the mucinous adenocarcinoma. The further diagnostic and metastatic work-up identified a diffuse carcinoma of the stomach as the primary site with liver as secondary and retroperitoneal lymph nodes having mucinous deposits with associated Peutz-Jeghers polyposis. This is the first report in the English literature of intrathyroidal metastasis from carcinoma of the stomach with Peutz-Jeghers polyposis presenting primarily as a thyroid swelling. Preoperative diagnosis, proper evaluation and high degree of suspicion may avoid unnecessary thyroidectomy and effective palliation can be achieved with chemotherapy in view of disseminated disease. PMID- 21686342 TI - Propafenone induced Brugada-like ECG changes mistaken as acute myocardial infarction. AB - Brugada syndrome is one of the important causes of sudden cardiac death in young adults. The condition is associated with typical electrocardiogram (ECG) changes in anteroseptal leads V1 and V2 that can be unmasked by various medications, electrolyte disturbances, and even by the febrile state in susceptible individuals. The case history is reported of a patient with atrial flutter and atrial fibrillation who developed Brugada-like ECG changes when treated with propafenone. He was mistakenly diagnosed as having acute myocardial infarction when he presented to the emergency room with acute precordial chest pain. Cardiac catheterisation revealed normal coronary arteries and normal left ventricular systolic function. A review of previous ECGs showed the temporal relationship of ECG changes to initiation of propafenone a few years earlier. The ECG changes resolved with discontinuation of propafenone and re-emerged when he was rechallenged with oral propafenone. This case highlights the importance of recognising the characteristic ECG changes of Brugada syndrome and being able to differentiate them from those of acute myocardial infarction and other conditions manifesting with similar changes. PMID- 21686343 TI - Low molecular weight heparin (enoxaparin) reverses pregangrene in a preterm neonate. AB - A 34-week-old, 1.6 kg preterm boy was admitted for management of mild respiratory distress syndrome. On the third day of life 1 min after an intravenous cannulation attempt at the right cubital fossa, he developed pregangrene bluish discoloration of all fingertips up to the distal interphalangial joint and pallor of right palm. Pulsations on right forearm were reduced. There was no evidence of sepsis.Enoxaparin, a low molecular weight heparin (1.5 mg/kg (standard dose)) was injected subcutaneously in the abdomen in two doses 12 h apart within 2 h of the event. At 6 h after the first dose, brachial artery pulsation was bilaterally symmetrical. After the second dose, bilateral radial artery pulsation became symmetrical. The pregangrene changes returned to normal within 20 h as the distal phalanges became pink and warm. He was discharged on the eighth day of life. Enoxaparin was safe and effective in this preterm infant for reversal of pregangrene. PMID- 21686344 TI - Achalasia: a rare cause of failure to thrive in children. PMID- 21686345 TI - Spontaneous cerebrospinal fluid rhinorrhoea as the presenting feature of an invasive macroprolactinoma. AB - A 29-year-old male university student, with no prior history of trauma, presented with a 1 year history of clear fluid leaking intermittently from his left nostril. His past medical history included bilateral gynaecomastia since age 12, and recent low libido. beta2-transferrin analysis of the nasal fluid confirmed a diagnosis of cerebrospinal fluid (CSF) rhinorrhoea. The serum prolactin was grossly elevated at 42 700 mU/l and brain magnetic resonance imaging (MRI) revealed a large parasellar/sellar mass. A diagnosis of invasive macroprolactinoma complicated by spontaneous CSF rhinorrhoea was made. The patient was commenced on treatment with cabergoline, but while awaiting surgery to repair the CSF leak he developed streptococcus mitis and sanguis meningitis. He made an uncomplicated recovery with antibiotic treatment. Immediately following this episode, the CSF rhinorrhoea resolved spontaneously. Subsequently, a repeat MRI scan revealed dramatic involution of the pituitary mass and the serum prolactin had fallen to 604 mU/l. PMID- 21686346 TI - Autopsy report on pseudo-Bartter syndrome with renal calcification induced by diuretics and diet pills. AB - A woman in her mid-forties had repeated vomiting and diarrhoea accompanied by muscle weakness soon after she started taking seven different diet pills imported from Thailand. After she had taken the pills for 8 days, respiratory depression progressed rapidly to arrest. Blood tests at the Emergency Department showed severe hypokalaemia with metabolic alkalosis. We diagnosed that she had developed pseudo-Bartter syndrome from the findings based on ionic abnormalities and high renin and aldosterone levels, and hyperplasia of the juxtaglomerular apparatus. A postmortem blood analysis indicated subtherapeutic levels of furosemide. We concluded that the patient died from pseudo-Bartter syndrome, which was triggered by chronic self-administration of furosemide and aggravated by the diet pills. This is the first pseudo-Bartter syndrome autopsy report to show histological localisation of calcification in the kidneys. PMID- 21686347 TI - Non-invasive antenatal diagnosis of fetal rhesus status in an alloimmunised patient. AB - Alloimmunisation against the RhD red cell surface antigen was the most common cause of haemolytic disease of the fetus and newborn until recently. Maternal plasma has now almost replaced fetal cells obtained by amniocentesis or chorionic villous sampling, as the source of fetal DNA, hence eliminating the need for invasive sampling procedures. The fetal rhesus typing was done from maternal plasma in a woman in her fourth pregnancy, though she was isoimmunised in her previous pregnancies and needed invasive tests like cordocentesis in the past. The fetus was diagnosed to be rhesus negative from maternal plasma and that avoided the need for amniocentesis or cordocentesis. PMID- 21686348 TI - Intravenous radiocontrast induced anaphylactoid reaction: a rare cause of death. AB - Anaphylactoid reaction after the injection of iodinated contrast media can be life threatening. A 23-year-old woman presented to the emergency room with abdominal pain and fever, for couple of days duration. After completion of a computed tomography (CT) scan of the abdomen and pelvis with intravenous contrast, the patient complained of feeling hot and shortness of breath. She became unresponsive, cyanotic, and developed asystole. The patient was successfully intubated without any laryngeal oedema or bronchial spasm. Despite all resuscitation efforts the patient died. The patient had undergone CT scans with contrast three times in the past. An autopsy could not reveal any obvious cause and the serum tryptase concentration was 211 ng/ml (normal <9 ng/ml). PMID- 21686349 TI - Acute prostatitis as an uncommon presentation of brucellosis. AB - The present report concerns a 46-year-old man who presented with acute prostatitis due to Brucella melitensis infection. He was first treated with doxycycline and ciprofloxacin, but after 3 months he was admitted again with the same diagnosis. The relapse was probably related to ciprofloxacin use, or the length of treatment not being sufficient. The patient was successfully treated with a combination of doxycycline and rifampin for 3 months. In conclusion, prostatitis due to Brucella, such as spondylitis, meningoencephalitis and endocarditis, should be treated for longer courses. PMID- 21686350 TI - Wired bladder in a cordless era. PMID- 21686351 TI - Post pericardiocentesis low cardiac output syndrome in a patient with malignant thymoma. AB - We describe a case of transient biventricular failure after pericardiocentesis in a patient with malignant thymoma. Within 1 week the cardiac function returned to normal. The epidemiology and pathophysiology of the post pericardiocentesis low cardiac output syndrome is discussed. PMID- 21686352 TI - Recurrent enterovirus encephalitis: chance or something else? AB - A 22-month-old boy presented with repeated enterovirus infections including two episodes of encephalitis at the age of 8 months and 16 months and two episodes of febrile illnesses at 14 and 19 months old. These episodes were associated with at least two different serotypes of enterovirus. There were no residual neurological deficits and he underwent complete recovery in between. Immunology workup showed normal circulating leucocyte differential counts and lymphocyte subsets. His serum IgG concentration was persistently low but could mount satisfactory specific antibody responses to booster vaccines. The clinical picture was compatible with transient hypogammaglobulinaemia of infancy (THI) which was traditionally believed not to be associated with serious viral infections. This is the first case report to alert physicians that repeated serious enterovirus infections can happen in a relatively benign immunodeficiency disease. PMID- 21686353 TI - Worsening of bone disease after curative surgery in primary hyperparathyroidism. AB - We describe the case of a 33-year-old woman who underwent surgery successfully 3 years earlier for primary hyperparathyroidism, and subsequently presented with severe bone disease due to secondary hyperparathyroidism associated with chronic kidney disease and vitamin D deficiency. PMID- 21686354 TI - Acute abdomen and hypothyroidism. AB - Acute abdomen with multicystic ovaries as a presenting manifestation of juvenile primary hypothyroidism is rare. Appropriate diagnosis and levothyroxine treatment is rewarding and avoids inadvertent surgery. We present three such cases. PMID- 21686355 TI - Hashimoto's encephalopathy: an under diagnosed entity. AB - We describe a 60-year-old woman with Hashimoto's thyroiditis who presented with neuropsychiatric manifestations even on optimal and stable doses of levothyroxine replacement therapy. She had high anti-thyroid peroxidase antibody and responded to glucocorticoid treatment. PMID- 21686357 TI - Primary neuroendocrine neoplasm of the gallbladder. AB - Carcinoid tumours are distinct neuroendocrine tumours with characteristic clinical and histological behavioural properties which arise mainly in the gastrointestinal tract (73.7%) or bronchopulmonary system (25.1%). Neuroendocrine tumours of the gallbladder are rare-to date there have been only 42 cases reported in the literature. This case was an incidental finding which was recognised during routine histopathological examination after laparoscopic cholecystectomy for symptomatic cholelithiasis. The patient recovered well from the operation. There were no concurrent lesions or metastases noted on further investigations, and the final diagnosis was a primary neuroendocrine tumour of the gallbladder. PMID- 21686356 TI - Management of multiple foreign body ingestion in a prisoner. PMID- 21686358 TI - Malignant transformation of an intracranial germinoma into a choriocarcinoma. AB - The recurrence or metastasis of intracranial pure germinomas as germ cell tumours of different histological types has rarely been reported. The present report concerns the first case in the literature of intracranial recurrence of a germinoma transformed into a choriocarcinoma. A 17-year-old man presented with a 1 month history of headache. MRI revealed a homogeneously enhanced mass within the pineal and suprasellar regions. The tumour was resected, and histological examination identified it as a pure germinoma. After resection, the patient underwent chemotherapy and radiotherapy and the mass disappeared. At 5 years and 5 months later, the patient presented with nausea and headache, and recurrence of the tumour was revealed in the left lateral ventricle. The tumour was resected and histological diagnosis identified it as a choriocarcinoma. The patient was treated with chemotherapy and radiotherapy, but died due to dissemination 1 month later. An autopsy was not performed. PMID- 21686359 TI - Diagnostic delay in a case of herpes simplex encephalitis. AB - Herpes simplex encephalitis (HSE) is the most frequent cause of sporadic fatal encephalitis in the Western world. Definitive diagnosis by viral PCR of cerebrospinal fluid (CSF) and treatment with aciclovir have improved the prognosis significantly. Nevertheless, the condition is rare and presents with non-specific symptoms that can easily be mistaken for systemic infection or non infective encephalopathy. We report a case of HSE which was not recognised by four separate doctors, leading to substantial delay in diagnosis and treatment. Our patient presented with fever, headaches, altered behaviour and generalised bradykinesia. This was initially diagnosed as otitis interna (labyrinthitis) and, subsequently, an ischaemic stroke. There was a delay of 10 days in the initiation of aciclovir from symptom onset. MRI and CSF PCR confirmed herpes simplex virus type-1 (HSV-1) infection. The patient improved on aciclovir, but is disabled with word-finding difficulties and cognitive slowing. PMID- 21686360 TI - Catecholamine-induced transient myocardial dysfunction. AB - This report presents an interesting case of acute myocardial stunning secondary to catecholamine surge from a phaeochromocytoma. A 39-year-old British Asian man was admitted with chest pain, labile blood pressure, dynamic ECG changes and positive troponin I level. Echocardiogram showed severe global impairment of his left ventricular systolic function but sparing of the basal segments. Portable renal ultrasonography revealed a 6 cm mass in the left adrenal gland. The clinical suspicion was of catecholamine-induced acute myocardial dysfunction secondary to underlying phaeochromocytoma. Intravenous alpha blockade resulted in a dramatic clinical improvement and near resolution of the echocardiographic abnormalities. Subsequent coronary angiography confirmed normal coronary arteries. He was discharged, well, on oral alpha-adrenergic and beta-adrenergic blockade. Outpatient metaiodobenzylguanidine scanning was consistent with the diagnosis and a left phaeochromocytoma was successfully removed laparoscopically. PMID- 21686361 TI - Multiple steno-obstructive vascular lesions and femoral superficial artery dissection in a young Caucasian male with antiphospholipid syndrome. AB - A young Caucasian male was admitted for claudication intermittens, hyposphygmia on the right lower limb, high blood pressure and deterioration of renal function. Instrumental investigations documented right renal artery stenosis, multiple steno-obstructive manifestations of the splanchnic artery system, occlusion of the right external iliac artery and dissection of the left superficial femoral artery. The patient had not been previously diagnosed with antiphospholipid syndrome. Subsequently, the vascular lesions, because of his thrombophilic state, needed endovascular treatment and anticoagulant therapy. PMID- 21686362 TI - Prolonged fever, dyspnoea and diffuse pleural thickening in a 20-year-old man. AB - A 20-year-old man was referred for intermittent fever associated with weight loss and progressive dyspnoea that were unresponsive to empirical antibiotics and anti tuberculous chemotherapy. A diagnosis of pleuropulmonary sarcoidosis was eventually made histologically via a thoracotomy and the patient improved with corticosteroid therapy. PMID- 21686363 TI - An unusual presentation of obstructive sleep apnoeas. AB - We report the case of a 69-year-old married man who presented with features of irritability, characterised by outbursts of anger, short-term memory deficits and clumsiness, which progressed over a period of some 20 years. A detailed review elicited motor and verbal agitation during sleep, a history that was only available from his wife. He had excessive daytime sleepiness. A parasomnia in association with his possible neurological disorder was suspected and a referral made to the sleep disorders clinic. Further investigation with polysomnography determined that the abnormal behaviours during the night were secondary to arousals caused by obstructive sleep apnoea. Treatment with continuous positive airways pressure therapy prevented the abnormal behaviours at night, improved his daytime sleepiness but also led to improvements in his clumsiness, short-term memory and temper, all corroborated by his wife. PMID- 21686364 TI - An unusual case of infective endocarditis presenting as acute myocardial infarction. AB - A 39-year-old Zimbabwean man presented with a 1 week history of fever, general malaise and acute onset chest pain. He had a urethral stricture, which had been managed with an indwelling supra-pubic catheter. The electrocardiography on admission showed inferior ST-T segments elevation. His chest pain and electrocardiography changes resolved subsequent to thrombolysis, and he remained haemodynamically stable. The 12 h troponin I was increased at 10.5 ug/l (NR <0.04 ug/l). Echocardiography confirmed severe mitral regurgitation and a flail anterior mitral valve leaflet with an independently oscillating mobile vegetation. Enterococci faecalis were grown on blood cultures. A diagnosis of enterococci infective endocarditis with concomitant acute myocardial infarction due to possible septic emboli was made. Despite the successful outcome from thrombolysis in the setting of acute myocardial infarction with infective endocarditis, the case highlights the current lack of definitive data on the optimal acute management of such an unusual clinical scenario. Although there is serious concern that thrombolytic treatment for myocardial infarction in the setting of infective endocarditis may be associated with higher risk of cerebral haemorrhage, there is little documented evidence supporting the safety of primary percutaneous coronary intervention with these patients. PMID- 21686365 TI - Ruptured intraspinal dermoid. PMID- 21686366 TI - An unusual "hernia": losing a stone is not always a good thing! AB - A 42-year-old woman presented to the surgical outpatient department with what appeared to be a strangulated recurrent paraumbilical hernia. She was taken to theatre, where exploration revealed an unexpected diagnosis: an abdominal wall abscess that had formed around what appeared to be a gallstone dropped at the umbilical port site of a laparoscopic cholecystectomy performed 10 years previously. The abscess was incised and drained and a connection with the abdominal cavity excluded. The patient made a full recovery. Complications relating to spilled gallstones are rare, but can present in a variety of ways and sometimes many years after the original surgery. They should always be considered in a patient with a history of cholecystectomy presenting with an abdominal wall mass. There is no clear evidence of the best imaging modalities to be used for investigation. Methods for reducing the risk of such complications and the principles of different treatments are discussed. PMID- 21686367 TI - Using non-steroidal anti-inflammatory drugs (NSAIDs) in volume depleted children can precipitate acute renal failure. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are increasingly popular in hospital medicine and general practice and are readily available over the counter. The vast majority of healthy children who ingest therapeutic doses of NSAIDs for a limited duration tolerate them without any significant adverse effects. However, the risk of renal toxicity is potentially increased in situations where there is stimulation of the renin-angiotensin system such as with volume depletion or in pre-existing chronic renal disease. We describe four cases which illustrate this complication occurring in a children's hospital. We have not proven cause and effect, but further research is needed to define the true risk of the potential renal complications of NSAIDs in patients at risk of dehydration. PMID- 21686368 TI - Can posterior hip fracture-dislocation occur in indoor football (futsal)? A report of two cases. AB - Hip fracture-dislocation is extremely rare in sports and is most frequently seen after road traffic accidents. This injury is associated with considerable long term disability and rapidly progressive joint degeneration. This case report illustrates two cases of hip fracture dislocation that occurred while playing recreational indoor football (futsal). Futsal is a fast-emerging recreational sport in Malaysia and we are now beginning to see high-impact injuries rarely encountered in recreational sports. Therefore, futsal cannot be taken lightly and it is important to take adequate precautions to prevent serious injuries when participating in such sports. PMID- 21686369 TI - Stabbing? Cause. PMID- 21686370 TI - Human syngamosis: an unusual cause of chronic cough in travellers. AB - We describe a case of syngamosis in a 43-year-old Italian tourist presenting with chronic cough and episodes of haemoptysis upon return from the Caribbean. The patient underwent many diagnostic procedures and was repeatedly, yet unsuccessfully, treated (for asthma, bronchitis and gastro-oesophageal reflux disease) before the correct diagnosis was reached. During a fibre optic bronchoscopy a Y-shaped red object was extracted from the airways and identified as a pair of Mammomonogamus laryngeus. After this procedure the patient improved, although a dry cough persisted and two other minor episodes of haemoptysis occurred. The patient was treated with anti-helmintic drugs and recovered after 3 months. PMID- 21686371 TI - Reversible valproate hepatotoxicity due to mutations in mitochondrial DNA polymerase gamma (POLG1). AB - We report the case of a 2-year-old boy with seizures who developed hepatic failure shortly after commencing sodium valproate. Unexpectedly, liver function returned to normal on stopping the drug. Sequencing of the mitochondrial polymerase gamma gene (POLG1) revealed four heterozygous substitutions, two of which have been identified in cases of Alpers-Huttenlocher disease. PMID- 21686372 TI - Trumpet tension. AB - The case of a 78-year-old man with progressive glaucoma despite seemingly adequate control of his intraocular eye pressure is presented. On further questioning he was discovered to have played the trumpet for up to 4 h per day for 60 years. Significant increases in intraocular pressure were subsequently recorded during trumpet playing. PMID- 21686373 TI - Unexpected finding on staging bone marrow aspirate for Hodgkin's lymphoma. PMID- 21686374 TI - Intravascular large B cell lymphoma with neurological symptoms diagnosed on the basis of a senile angioma-like eruption. AB - Intravascular large B cell lymphoma (IVLBCL) presents various neurological symptoms, and the prognosis frequently deteriorates with a delay in diagnosis. In addition, for the diagnosis of IVLBCL, invasive biopsies are generally performed in main organs, such as the brain. We report a case of IVLBCL in which an early diagnosis was enabled by skin biopsy. The patient in this case had cauda equine syndrome and had developed multiple brain infarctions. She received six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) treatment and is currently in complete remission. At the macroscopic level, her lesions resembled senile angioma, commonly observed in normal elderly persons. Eruptions of this type are not currently recognised as IVLBCL lesions and might easily be overlooked. In cases in which IVLBCL could be suspected, an active search and biopsy of skin lesions, including an eruption of this type, are useful for early diagnosis and treatment. PMID- 21686375 TI - Bilateral carpal tunnel syndrome and ulnar neuropathy at the elbow in a pizza chef. AB - A case of bilateral carpal tunnel syndrome and ulnar neuropathy at the elbow in a 22-year-old pizza chef is described. An on-site analysis revealed that job tasks performed by the worker exposed him to a combination of biomechanical risk factors. Patient history and workplace observations suggest that occupational physical exposure may have caused the bilateral entrapment neuropathies. The present report underlines the advisability of a detailed occupational history in the case of entrapment neuropathies of the upper limbs commonly regarded as being related to biomechanical occupational exposure. PMID- 21686376 TI - Obstructive jaundice due to autoimmune cholangiopathy. AB - A 59-year-old man presented with upper abdominal pain, cholestasis and radiological evidence of common hepatic duct hilar stricture which was suggestive of cholangiocarcinoma. The patient initially underwent percutaneous drainage and a laparotomy. No evidence of malignancy was identified. He was noted to have retroperitoneal fibrosis, which was confirmed on histology. The combination of cholangiopathy and retroperitoneal fibrosis suggested an underlying autoimmune process. Although the investigations did not show any evidence of IgG4 related disease, the combination of a cholangiopathy and retroperitoneal fibrosis is in keeping with autoimmune cholangiopathy and a steroid regimen was commenced. Our patient is now symptom-free with no further episodes of cholangitis. He has commenced azathioprine to maintain long term remission. PMID- 21686377 TI - A cyst in the sacrum. PMID- 21686378 TI - Arachnoid cyst masquerading as Alzheimer's disease. PMID- 21686379 TI - A deadly cargo. PMID- 21686380 TI - Topiramate induced agranulocytosis. AB - A man in his 40s with a past history of neutropenia during zonisamide administration developed agranulocytosis 1 month after adding on topiramate to treat intractable partial epilepsy. His concurrent medication included phenytoin and acetazolamide. His white blood cell count recovered 5 days after discontinuation of topiramate. Topiramate is a sulfamate whose mechanism of antiepileptic activity is considered to include inhibition of carbonic anhydrase. Topiramate has a potential risk for haematopoietic adverse events; such events are rare and are related to immuno-allergic reaction or toxic effect of sulfonamides and sulfamates, including carbonic anhydrase inhibitors. Because this class of drugs is commonly used as an anti-glaucoma or diuretic agent, particular attention should be paid when initiating topiramate to a patient with a history of sulfonamide or sulfamate induced agranulocytosis, or when co administrating topiramate with sulfonamides and sulfamates including carbonic anhydrase inhibitors. PMID- 21686381 TI - Acute dysphagia: an unusual treatable cause. AB - Bariatric surgery is a rapidly expanding surgical sub-speciality, with a large proportion of the relevant surgical procedures being performed in the private sector. Acute complications of newer surgical procedures can lead to emergency department presentation, with which the staff may be unfamiliar. A 34-year-old woman was seen in the emergency department with acute total dysphagia following laparoscopic adjustable gastric banding, which was treated successfully by a simple bedside procedure. PMID- 21686382 TI - Gabapentin toxicity: an important cause of altered consciousness in patients with uraemia. AB - Gabapentin toxicity should be considered one of the differential diagnoses of altered consciousness in patients with compromised renal function, even after a single dose. We report a 57-year-old woman with diabetes mellitus and uraemia on regular haemodialysis who developed severe dizziness and lethargy after a single recommended dose of gabapentin for bilateral leg dysthesia. Because of progressive drowsiness and decreasing level of consciousness, one session of haemodialysis was performed and clinical recovery was dramatic. The adverse effects of gabapentin seem to vary from person to person and should be viewed with a high degree of suspicion, especially in patients taking this drug at the beginning. PMID- 21686383 TI - Small bowel volvulus in a patient with chronic idiopathic intestinal pseudo obstruction. AB - Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a rare syndrome of ineffectual gut motility associated with clinical, endoscopic and radiological exclusion of mechanical causes, as well as evidence of air-fluid levels in distended bowel loops. A case of small bowel volvulus in a patient with an established diagnosis of CIIP is presented. The case is illustrated by images of operative findings and computed tomography scan reconstruction, showing the classical appearances of small bowel volvulus. The patient recovered well after surgery and is maintained on parenteral nutrition. CIIP is a heterogeneous disorder in which the primary aims of management are nutrition, pain control and the avoidance of unnecessary repeated laparotomies. However, even in the presence of an established diagnosis of CIIP, surgeons should be vigilant to the possibility that an operable mechanical obstruction may still occur. PMID- 21686384 TI - Pulmonary actinomycosis complicating infliximab therapy for Crohn disease. AB - The use of anti-tumour necrosis factor (TNF) agents has expanded significantly over the past few years, particularly for rheumatological diseases and Crohn disease. A number of associated opportunistic infections have been observed as a result of suppression of T-cell-mediated immunity, the most frequent being tuberculosis. This report describes a case of pulmonary actinomycosis in a 52 year-old patient receiving regular infusions of infliximab, an anti-TNF agent, for Crohn disease. He presented with a 12-day history of fever, night sweats and a non-productive cough on a background of a 9-year history of Crohn terminal ileitis. There was radiological evidence of a left upper lobe non-cavitatory pneumonia and bronchoscopic lavage fluid eventually grew Actinomyces graevenitzii. The patient was hospitalised and improved with antibiotic therapy. Within 4 weeks there was almost complete radiological resolution and infliximab was restarted after 4 months without further complication. PMID- 21686385 TI - Glioblastoma in a boy with fragile X: an unusual case of neuroprotection. AB - Glioblastomas in children usually occur in the brainstem and are often untreatable and associated with an extremely poor prognosis. Such tumours may however occur in supratentorial locations more typically associated with adult gliomas, where the outcome is more variable, but still poor. This report describes the case of a boy with fragile X who also developed an inoperable midbrain glioblastoma, but who has survived 8 years after diagnosis. PMID- 21686386 TI - Persistent unilateral mydriasis and headache. AB - A 50-year-old white Caucasian woman with previously diagnosed migraine was admitted with unilateral headache and anisocoria. An initial assessment revealed no cause for this abnormality and she was thought to have mydriasis in the context of migraine. However, failure of her symptoms and signs to resolve prompted further investigation and demonstrated the diagnosis of intermittent angle-closure glaucoma. PMID- 21686387 TI - Bilateral atraumatic medial meniscal tears in a 17-year-old rower. AB - Meniscal injury produces disability in a large portion of the population, and sports injuries are a common cause. Atraumatic meniscal tears may occur after repetitive low-energy loading. Rowing is a highly technical sport and very demanding on an athlete's body. There are numerous reports on patellofemoral and iliotibial band friction syndrome in rowers but there is an extremely low incidence of meniscal tears reported in these athletes. This is a unique case report of a young adolescent athlete who suffered bilateral medical meniscal tears during sporting activity. Rowing is a low impact sport making this an unusual occurrence, especially in a young individual. This case report highlights the importance of considering all training activities when trying to isolate the mechanism of injury in an athlete. PMID- 21686388 TI - Paradoxical embolism: a rare complication of thrombolysis. AB - Paradoxical embolus is a rare complication of thrombolysis. With a high prevalence of clinically silent septal defects and widespread use of thrombolysis, recognition of the risks, clinical signs and symptoms is important. A case is reported of paradoxical embolus following thrombolysis in a woman with a previously undiagnosed patent foramen ovale. PMID- 21686389 TI - Heeding clues to metformin-associated lactic acidosis: prompt response can save life. AB - The case history is presented of a patient who developed metformin-associated lactic acidosis. The patient made a complete recovery with supportive care. Recognition of metformin-associated lactic acidosis requires a high index of suspicion, as presentation can be very subtle. PMID- 21686390 TI - Rosai-Dorfman disease: sinus histiocytosis with massive lymphadenopathy. AB - A 25-year-old man presented with a 3 month history of a painless mass on the right side of his neck. Physical examination revealed a smooth surfaced, bilobed, 4*3 cm, semimobile mass at the right and 3*2 cm at the left jugulodigastric region. Endoscopic examination of the patient showed a granular tumour in both nasal cavities. After biopsies were taken from the mass from the nasal cavity, a diagnosis of Rosai-Dorfman disease was made. A conservative approach was taken to treatment and after the 6 month follow-up period, the patient was in a stable condition. PMID- 21686391 TI - Indolent form of mediastinitis caused by oesophageal perforation from fish bone ingestion. AB - Mediastinitis caused by oesophageal perforation usually presents as a severe disease that can quickly progress to sepsis and death. We report a case with an indolent form of mediastinitis, caused by fish bone ingestion, which was successfully and exclusively treated with antibiotics. The patient had only one symptom, intense thoracic pain, with no signs of infection except for elevated C reactive protein. The diagnosis was difficult to obtain because of this atypical clinical presentation. The chest computed tomography scan combined with the thoracic pain and the history of fish bone ingestion allowed us to confirm the diagnosis and initiate treatment. PMID- 21686392 TI - Giant popliteal aneurysm with deep vein thrombosis, foot drop and arteriomegali. AB - Popliteal artery aneurysms are the most common peripheral arterial aneurysms and are the second most common aneurysm after abdominal aortic aneurysms. Popliteal artery aneurysm affects mostly elderly men and atherosclerosis plays the major role in the aetiology of the disease. The management of popliteal artery aneurysms requires great care. Popliteal aneurysms are asymptomatic or otherwise present with intermittent claudication, compression symptoms in the popliteal fossa, distal embolisation and, rarely, rupture. We present a patient with a remarkably large popliteal aneurysm of 8*11 cm presenting as a popliteal swelling with foot drop and deep vein thrombosis and limb ischaemia. According to our thorough search of literature printed in English, it is one of the largest reported popliteal aneurysms with arteriomegaly, and its co-existing symptoms are unusual. The diagnostic investigations and treatment are presented. PMID- 21686393 TI - Pyridoxal phosphate-dependent neonatal epileptic encephalopathy. AB - Pyridox(am)ine-5'-phosphate oxidase converts pyridoxine phosphate and pyridoxamine phosphate to pyridoxal phosphate, a cofactor in many metabolic reactions, including neurotransmitter synthesis. A family with a mutation in the pyridox(am)ine-5'-phosphate oxidase gene presenting with neonatal seizures unresponsive to pyridoxine and anticonvulsant treatment but responsive to pyridoxal phosphate is described. Pyridoxal phosphate should be considered in neonatal epileptic encephalopathy unresponsive to pyridoxine. PMID- 21686394 TI - Life-threatening episode after ingestion of toad eggs: a case report with literature review. AB - It is known that the toad possesses several toxic substances in the skin and parotid glands. In the past, toad-venom poisoning has been reported from ingestion of toad soup, Kyushin and aphrodisiac pills, but poisoning from toad eggs is observed for the first time. The case of a healthy female who had previously eaten toad soup twice without any discomfort is reported. She developed gastrointestinal symptoms and life-threatening cardiac rhythm after ingestion of toad eggs. A transvenous temporary pacemaker was used promptly to prevent from lethal bradyarrhythmia. Hyperkalaemia was managed with insulin, glucose water and sodium bicarbonate. A digoxin-specific Fab fragment was administered to this young woman 4 h subsequent to her admission. PMID- 21686395 TI - Essential thrombocythaemia presenting with subclavian artery thrombosis and multiple embolic events. AB - The present report describes a case of in situ thrombosis of the left subclavian artery complicated by posterior circulation stroke, left arm ischaemia and possibly ischaemic pancreatitis. Essential thrombocythaemia was found to be the underlying cause. PMID- 21686396 TI - Cultivated autologous limbal epithelial transplantation for symptomatic bullous keratopathy. AB - We report the clinical outcome of cultivated autologous limbal epithelial transplantation for symptomatic bullous keratopathy in an 87-year-old female patient presenting with recurrent corneal erosion and intractable ocular pain. The patient refused corneal transplantation, and transplantation of a cultivated autologous limbal epithelial sheet was carried out to free her of the symptoms associated with chronic pseudophakic bullous keratopathy. Both integrity of transplanted epithelium and relief from intolerable ocular pain were achieved and maintained immediately after surgery. No complications were noted in either the transplanted eye or donor eye during the 43-month follow-up period. Our findings support that patients with bullous keratopathy not consenting to procedures to improve visual acuity in whom the primary aim is relief of symptoms may benefit from cultivated autologous limbal epithelial transplantation. PMID- 21686397 TI - Vertebral artery dissection presenting as isolated vertigo. AB - In this report a central cause of isolated vertigo in a 24-year-old woman is presented: brainstem infarct secondary to vertebral artery dissection. PMID- 21686398 TI - A case of haemangioblastoma of the fourth ventricle presenting with depression. AB - Haemangioblastoma (Hab) is a rare, benign and slow-growing tumour of uncertain histiogenesis. It constitutes roughly 1% to 2% of all intracranial tumours and most commonly arises in the posterior cranial fossa: more than 80% of Habs are located in the cerebellar hemispheres, the remaining cases lie in the vermis, brainstem and spinal cord. In about 20% of the cases Habs are associated with the hereditary disorder known as von Hippel-Lindau disease (VHL). Usually, Hab presents with symptoms of increased intracranial pressure and focal neurological symptoms, which depend on the tumour location. Here, a case of Hab localised in the fourth ventricle that manifested with an unusual clinical picture featuring predominant psychiatric symptoms is described; the condition went unrecognised until the patient's death. PMID- 21686399 TI - Successful thrombolysis of mechanical mitral valve prosthesis in a patient with cardiogenic shock. AB - A 48-year-old woman with cardiogenic shock was admitted to a nearby hospital. Her medical history included mechanical replacement of her mitral valve 4 years previously in Russia because of rheumatic stenosis. On admission, her international normalised ratio (INR) was significantly reduced below the therapeutic limit. A severe stenosis of the valve prosthesis was identified by transthoracic and transoesophageal echocardiography and the patient was transferred to our university hospital for discussion of an immediate therapeutic procedure and to ensure cardiac surgical backup. Here, the patient's poor clinical status led to the decision for a non-routine treatment: a successful series of intravenous thrombolysis with alteplase. Clinical symptoms and echocardiographic parameters improved significantly. PMID- 21686400 TI - Subpubic cartilaginous cyst: an unusual cause of a vulval mass. AB - We present a case of a postmenopausal female who visited her doctor for a slowly growing mass in the vulval region. The mass did not show typical clinical features of a vulval neoplasm. Magnetic resonance imaging (MRI) revealed a mass arising from the undersurface of the symphysis pubis. A literature review revealed characteristics of this lesion compatible with a subpubic cartilaginous cyst-a rare benign degenerative condition of the symphysis pubis. As a result the mass was managed non-operatively and the patient remains well 2 years later. This article highlights the role of MRI in the diagnosis of this unusual vulval mass. PMID- 21686401 TI - Exotic snakes are not always found in exotic places: how poison centres can assist emergency departments. AB - Emergency departments throughout the USA may have some familiarity with the management of envenomation from indigenous snake species such as Crotalinae (rattlesnakes) and Micrurus (coral snakes). However, venomous species may include exotic reptiles whose bites pose substantial treatment challenges due to both a lack of experience and the difficulty in obtaining antivenoms. Two pet cobra envenomation incidents illustrate the challenges that face emergency departments, especially in urban settings, that are confronted with these exposures. It is important for emergency departments to be aware of the large underground presence of exotic venomous reptile pets and to utilise the expertise of regional poison centres that will also assist in the procurement of exotic antivenoms. PMID- 21686402 TI - Laryngeal tuberculosis: a diagnosis not to be missed. AB - A 66-year-old Caucasian female was referred to the ear, nose and throat outpatient by her general practitioner with complaints of worsening sore throat, hoarseness of voice and productive cough for 3 months. The patient also had a history of rigors and evening temperature. She was using long-term steroids for nephrotic syndrome. The patient was treated for pulmonary tuberculosis as a child. An exophytic left supraglottic mass involving the left aryepiglottic fold, epiglottis and left vocal cord was revealed on fibre-optic laryngoscopy. The diagnosis of laryngeal tuberculosis was confirmed on repeat biopsy. The sputum smear was also positive for acid-fast bacilli. Chest x ray reported fibrosis of the right upper lobe indicating tuberculosis. The patient was started on anti tuberculous treatment and made a steady recovery. There is reactivation of pulmonary tuberculosis in our case report with secondary involvement of larynx probably due to long-term use of steroids for nephrotic syndrome. PMID- 21686403 TI - Non-Langerhans cell histiocytosis in a child with Kawasaki disease. AB - Polymorphous skin rashes are one of the major presentations in children with Kawasaki disease. This report describes an unusual presentation of a skin rash (non-Langerhans cell histiocytosis) in a 4-month-old baby with resistance to intravenous immunoglobulin (IVIG) treatment and coronary artery dilatation. Though refractory to repeat dosages of IVIG treatment, the patient had a favourable response to methylprednisolone pulse therapy. PMID- 21686404 TI - A "growing cause" of diabetic ketoacidosis. AB - The progress of a young woman presenting with diabetic ketoacidosis is described. She was managed as for a new presentation of type 1 diabetes, but was subsequently diagnosed with acromegaly due to a large pituitary tumour. Following treatment for this, and relative normalisation of growth hormone levels, she was able to stop insulin completely. Subsequently, an oral glucose tolerance test showed no evidence of abnormal glucose tolerance and she remains non-diabetic. PMID- 21686405 TI - Iatrogenic Cushing syndrome caused by ocular glucocorticoids in a child. AB - A boy aged 7.6 years presented to our Unit of Paediatric Endocrinology for evaluation of obesity. Progressive weight gain (10 kg) started 6 months earlier after an accidental penetrating orbital injury on the right eye. During this period the child has been treated with oral betamethasone (0.5 mg/day) for 1 month and dexamethasone 2% ocular drops (2 hourly by day) for 6 months. Physical examination showed he was 113.5 cm in height (-1.5 SD), weight 36.0 kg, blood pressure 110/90 mmHg (90th centile), body mass index 28 (+5 SD), truncal obesity, buffalo hump, "moon-face", increased lanugo hair and supraclavicular fullness. Endocrinological work-up revealed undetectable levels of basal adrenocorticotropic hormone (ACTH), basal and ACTH-stimulated cortisol and 24 h urine excretion cortisol, confirming the diagnosis of iatrogenic Cushing syndrome. The abrupt withdrawal of ocular glucocorticoids by the parents evoked two adrenal crises; 4 months later the patient recovered. In conclusion, we would alert doctors that every formulation of glucocorticoids, no ocular drops excluded, can determine severe systemic side effects and iatrogenic Cushing syndrome. PMID- 21686406 TI - Right aortic cusp aneurysm causing aortic valve regurgitation with complete heart block. AB - The present report describes a rare case of aortic valve aneurysm without any vegetation with complete heart block. A 26-year-old man with severe acute aortic regurgitation was admitted to our admitted to our hospital. Transthoracic echocardiography showed right cusp aneurysm without any vegetations. Transoesophageal echocardiography confirmed these findings. Colour Doppler echocardiography revealed severe aortic regurgitation. For complete heart block, a transvenous permanent pacemaker was inserted as a first stage of treatment. Successful aortic valve replacement was performed as a second stage. The possible aetiology of this case is endocarditis. PMID- 21686407 TI - Congenital candidiasis presenting as septic shock without rash. AB - Congenital candidiasis is rare and often benign. This report describes the case of twins born at 32 weeks of gestation with different manifestations of congenital candidiasis. One twin was born well though neutropenic, and died from overwhelming sepsis with septic shock at 22 h. The other twin presented with a delayed onset of rash at 2 days, remained well and survived. PMID- 21686408 TI - Cutaneous mycobacterial spindle cell pseudotumour. AB - Mycobacterial spindle cell pseudotumour (MSCP) has been reported in various sites, including skin, lymph nodes, bone marrow, lung and spleen. Cutaneous lesions are extremely rare and the differential diagnoses include various spindle cell lesions. Literature review shows that this lesion has preponderance for upper limb involvement and occurs largely in immunosuppressed individuals. We report a case of MSCP of the skin due to atypical mycobacterium and discuss the risk of misdiagnosis as a sarcoma. PMID- 21686409 TI - Markedly elevated CA19-9 associated with benign ovarian cyst and ascites. AB - A 60-year-old woman presented after a fall and was noted to have ascites. She had a history of ulcerative colitis. History and physical examination did not reveal the likely aetiology of the ascites, but a sample showed it to be a blood-stained exudate. A malignant cause appeared likely, cross-sectional imaging was arranged and tumour markers sent. CA125 was 34 IU/ml (0-30); alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) were normal. However, CA19-9 was 2880 U/ml (0-31). Pancreatic carcinoma or cholangiocarcinoma were of prime concern, but a CT scan and MRI imaging were normal. At laparoscopy a benign ruptured ovarian cyst was detected, and ascites drained. CA19-9 returned to normal and the patient remains well 9 months later. This case demonstrates how tumour markers may be misleading in the context of diagnostics, and is the highest reported example of CA19-9 rise in the context of benign ascites and benign ovarian pathology. PMID- 21686410 TI - Pseudomembranous colitis in four patients with cystic fibrosis following lung transplantation. AB - In the present study, 4 patients with cystic fibrosis undergoing lung transplantation (from a total of 137) who developed fulminant pseudomembranous colitis are described. Initial presentation was variable and the mortality rate was 50% despite urgent colectomy. In one case the presenting abdominal distension was thought to be due to meconium ileus equivalent. It is concluded that Clostridium difficile colitis may be a difficult diagnosis in patients with cystic fibrosis and follows a fulminant course after lung transplantation. PMID- 21686411 TI - Linezolid for treatment of catheter-related cerebrospinal fluid infections in preterm infants. AB - Ventriculostomy-related cerebrospinal fluid (CSF) infection remains a major problem in neonatal intensive care. The spectrum of pathogens causing these infections is dominated by coagulase-negative staphylococci, and vancomycin is the antibiotic of choice for treatment. However, vancomycin is known to have only poor penetration into the CSF when applied intravenously and is therefore being applied intraventricularly. The oxazolidinone linezolid has antibacterial activity against most drug-resistant Gram-positive bacteria and has been shown to have excellent penetration into the CSF in adults. Here, its successful use in five neonates with infected ventriculostomies is described. PMID- 21686412 TI - Treating subglottic haemangioma with methylprednisolone and interferonalpha-2a. AB - Subglottic haemangiomas are benign vascular malformations presenting in early infancy with respiratory distress due to progressive airway obstruction. The lesion, after undergoing proliferation during the first few months, naturally involutes by an age of 2-3 years. Due to high incidence of mortality, therapy should be initiated immediately. Multiple therapeutic options, such as steroids, interferon, surgery and laser ablation, are available but the best treatment is controversial. This report describes an infant presenting with respiratory distress and cutaneous haemangioma who was detected to have airway obstructive haemangioma from the subglottis to the carina. Due to the massive size, surgical and laser ablation could not be exercised. Also, the infant showed no response to dexamethasone, prednisolone or interferon. Following failure of these modalities, the infant was successfully managed with concurrent administration of daily interferon and pulse methylprednisolone. The regime resulted in rapid shrinkage of the haemangioma and resolution of symptoms, with no recurrence up to 24 months of age. PMID- 21686413 TI - Salmonella meningitis in an adult with type B viral hepatitis and an incidental schwannoma. AB - Salmonella meningitis is an unusual complication of Salmonella sepsis that occurs almost exclusively in infants and young children. Cases that do occur in adults are associated with a high morbidity and mortality. The present study concerns a rare case of Salmonella meningitis, the first to be reported in Qatar, in a previously healthy young adult man who was admitted with fever, headache and nuchal rigidity. Cerebrospinal fluid (CSF) culture produced Salmonella paratyphi A, although cultures of blood were negative. The patient was admitted to the medical intensive care unit (MICU) and assisted with mechanical ventilation for 1 week, then transferred to the medical ward where he exhibited progressive improvement on treatment with meropenam for 3 weeks. The patient was found to have an incidental schwannoma causing right-sided hydronephrosis, and hydroureter, treated with double J stent insertion. He was discharged in good condition without any neurological sequelae. PMID- 21686414 TI - Duodenal stenosis associated with weakness of sphincter of Oddi. PMID- 21686415 TI - Spontaneous intracranial hypotension: a cause of severe acute headache. AB - Severe acute headache is a common presenting symptom to an accident and emergency department. Spontaneous intracranial hypotension (SIH) is an increasingly recognised cause of these symptoms and has characteristic clinical and imaging findings. SIH is characterised by headache worse on standing, low opening cerebrospinal fluid pressures at lumbar puncture and uniform pachymeningeal enhancement with gadolinium enhanced magnetic resonance imaging of the brain, all in the absence of dural trauma. Atypical presentations occur and severe neurological decline can rarely be associated with this condition. A review of five patients presenting recently to our institution with classical imaging findings together with a review of the literature is presented. PMID- 21686416 TI - Histopathological findings after retinal endovascular lysis in central retinal vein occlusion. AB - This case study explores the histopathological findings 9 months after retinal endovascular lysis (REVL) in a 62-year-old woman having a 7-week-old, highly ischaemic central retinal vein occlusion (CRVO) with hand movement vision. Angiographic examination 3 days postoperatively did not show improved arteriovenous passage time. In addition, the patient's postoperative vision did not change, and despite intensive photocoagulation and cryotherapy in the early postoperative period, the globe had to be removed 9 months later because of painful phthisis. Histological findings at the site of puncture were epiretinal membrane, interrupted internal limiting membrane and thickened venous wall. This is the first case to show the histological changes after surgical REVL in a human eye. In this case, REVL did not prevent neovascular glaucoma despite successful recombinant tissue plasminogen activator (rt-PA) injection in a venous branch close to the papilla. It was concluded that rt-PA injection after 7 weeks of CRVO is too late. PMID- 21686417 TI - Fulminant myocarditis: a rare but life-threatening association of Crohn disease. AB - Myocarditis is an uncommon association of Crohn disease. It has been reported to occur independently of inflammatory bowel disease activity. The case history is presented of a young woman admitted to hospital with acute small bowel obstruction as a presentation of active Crohn disease, which was further complicated by fulminant myocarditis leading to cardiogenic shock. This could have proved fatal if not recognised and managed appropriately. Myocarditis is rare, but it can be a life-threatening association of inflammatory bowel disease that needs early recognition and prompt treatment. PMID- 21686418 TI - Keratoconus associated with congenital stationary night blindness type 1. AB - A 35-year-old man presented with keratoconus; his best corrected visual acuities were -18.00/+10.00 *180 (6/60) oculus dexter and -10.00/+8.00 *5 (6/36) oculus sinister. Bilateral steep central corneal thinning, paracentral ectasia and Vogts striae were present. Normal fundi. Corneal topography disclosed 7.4 dioptres of irregular astigmatism in the central 3 mm with thinning (335 MUm). Electroretinography (ERG) showed no response. There were no medical or environmental influences for his keratoconus. Occurrence of keratoconus and congenital stationary night blindness (CSNB) in the patient may represent a chance association, but keratoconus has not been previously linked with CSNB1 either as a chance or true association though both show genetic predisposition. PMID- 21686419 TI - An intrasellar mixed gangliocytoma-adenoma including ependymal component, and review of the literature. AB - A rare case of intrasellar mixed gangliocytoma-adenoma including ependymal component, which presented clinically with acromegaly and menstrual disorder, is described here. The tumour was totally removed via trans-sphenoidal surgery. A histological examination of the resected specimen showed that the tumour was composed of ganglion cells, adenomatous cells and ependymal cells. Most intrasellar gangliocytomas are composed of two components: adenomatous cells and ganglion cells. In this case, in addition to mixed adenomatous and ganglion cells, focal ependymal cells forming small cysts were found. Based on these histopathological findings, it was inferred that stem cells existed in the pituitary gland during embryonic development. The stem cells were able to differentiate into three directions: ganglion cells, adenomatous cells and ependymal cells, and as a result an intrasellar mixed gangliocyto-adenoma including ependymal component developed. PMID- 21686420 TI - A colonic submucosal lipoma presenting with recurrent intestinal obstruction attacks. AB - Colonic submucosal lipomas are rare benign tumours of the colon, which may be discovered incidentally at colonoscopy, through imaging such as CT or at autopsy. These tumours can cause complications such as bleeding, intussusception and bowel obstruction. We describe the case of a patient in whom a small submucosal lipoma was identified at the time of colonoscopy and who did not receive follow-up treatment. The patient presented 1 year later with intussusception and obstruction resulting from this polyp and required urgent surgery. With the increasing use of colonoscopy and CT, such lesions are likely to be discovered more often. As complications can ensue, guidelines should be developed to advise on the management of such polyps in order to prevent consequent complications. PMID- 21686421 TI - Neuroimaging in subclavian steal syndrome. PMID- 21686422 TI - A unique case of systemic lupus erythematosus. AB - An 18-year-old Asian girl was referred to the nephrology unit with rapidly progressive renal failure. At the age of 15 she was diagnosed as having systemic lupus erythematosus but had defaulted treatment. Her renal functions improved with cyclophosphamide pulse treatment but she continued to have central nervous system vasculitis, gastrointestinal vasculitis and opportunistic infections making her a unique and challenging case of systemic lupus erythematosus. PMID- 21686423 TI - The importance of pre-contouring a cricket-pad splint to avoid complications. PMID- 21686424 TI - Wii knee revisited: meniscal injury from 10-pin bowling. AB - The present report concerns a 23-year-old woman who sustained an injury to her right knee while playing 10-pin bowling on a Nintendo Wii video game console. She presented to our orthopaedic outpatients clinic 3 months later with history and examination findings suggestive of a medial meniscal tear, which was confirmed by MRI scan. She underwent arthroscopic partial medial meniscectomy and made an uneventful recovery. PMID- 21686425 TI - Neurosarcoidosis with necrotising sarcoid granulomatosis mimicking meningiomatosis cerebri: case report and literature search. AB - A 52-year-old woman presented with headaches, difficulty with word finding and left eye blindness. MRI showed enhancing frontal dural-based masses suggestive of meningiomatosis. Biopsy and debulking revealed necrotising granulomas, without discernible micro-organisms or neoplasia; a thorough clinical work-up was negative for infection and vasculitis. A CT scan showed mild bilateral hilar lymphadenopathy, a tiny pulmonary nodule and cirrhotic liver. Her subsequent alteration of mental status was attributed to hepatic encephalopathy based upon elevated aminotransferase and ammonia levels, biopsy evidence of hepatoportal sclerosis with rare granulomas and response to lactulose. A diagnosis of neurosarcoidosis of the necrotising sarcoid granulomatosis variant (NS-NSG) with atypical systemic involvement was made. This is the fifth case report of NS-NSG clinically mimicking a neoplasm and histologically mimicking a mycobacterial infection. NS-NSG can have an atypical clinical picture including intracranial masses; a thorough work-up to exclude infectious and other non-infectious aetiologies is a prerequisite to its diagnosis. PMID- 21686426 TI - Spinal meningioma containing bone: a case report and review of literature. AB - Meningiomas constitute about 25% of primary spinal tumours and 1% to 5% of them are calcified. Ossification is a rare event and is rarely reported. Here, the case of a 40-year-old woman who had dorsal spinal cord meningioma (globular variety) at the T(6) vertebral level is reported; the meningioma showed a nidus of T2 weighting hypointensity on MRI as well as a bony chip inside the tumour intraoperatively. The tumour was successfully resected. Though the aetiology of ossification in the meningioma is not well known, metaplasia of arachnoid cells/dystrophic calcification may be the cause. Ossified meningiomas are more difficult to resect than the usual variety. Hypointensity inside tumour in T2 weighted images of MRI should make the surgeon suspicious of this condition, which may in some cases complicate tumour resection. PMID- 21686427 TI - Transient neonatal diabetes mellitus in an extremely preterm infant. AB - The present report concerns transient neonatal diabetes mellitus in an extremely preterm infant (gestational age 27 weeks, birth weight 718 g). The patient had intrauterine growth retardation and developed hyperglycaemia on the first day of life. Insulin administration was discontinued on the 89th day of life, which was 1 day before the original due date. This case suggests that (a) insufficient insulin secretion started at least from the second trimester of the pregnancy, and (b) the duration needed for recovery of insulin secretion was not dependent on the maturity. PMID- 21686428 TI - Intraventricular haemorrhage without subarachnoid haemorrhage due to a ruptured aneurysm. AB - The incidence of aneurysmal subarachnoid haemorrhage (SAH) in the UK is about 10 per 100 000 of the population per year and it is a potentially fatal condition. Prompt recognition and referral to a neurosurgical unit is crucial for a better outcome. A typical history of sudden severe headache, CT scan and sometimes a lumbar puncture would help clinch the diagnosis. Though intracerebral haemorrhage (ICH) and intraventricular haemorrhage (IVH) are not uncommon after an aneurysmal rupture, ICH and/or IVH without SAH are rare (<2%). In such cases, a high index of suspicion is needed to deliver the correct management. This report describes a case of posterior communicating artery aneurysm presenting with pure IVH on CT. The aneurysm was diagnosed by performing a CT angiogram and the patient underwent a successful coil embolisation. PMID- 21686429 TI - Osteoradionecrosis of the cervical spine complicated by pneumocephalus and meningitis in a nasopharyngeal cancer patient radically treated with radiotherapy 11 years ago. AB - Superimposed infection of osteoradionecrotic cervical spine with cranial extension is difficult to treat and potentially fatal. This report describes the case of a middle-aged Chinese man 11 years post radical radiotherapy for nasopharyngeal cancer with no evidence of disease presenting initially with neck pain secondary to cervical osteoradionecrosis. He was re-admitted a month later with aspiration pneumonia associated with Streptococcus milleri bacteraemia, complicated by septic shock. The last re-admission was 2 months later with fever, expressive dysphasia and right upper motor neuron signs. There was interval increase of dental and peridental soft tissue mass, interval widening of atlantodental distance on MRI cervical spine associated with pneumocephalus, meningeal enhancement and pre-pontine soft tissue mass on CT brain consistent with infected osteoradionecrotic cervical spine complicated by cranial extension. The patient also had concomitant bilateral pneumonia and subsequently passed away from fulminant sepsis. PMID- 21686430 TI - Gestational gigantomastia. AB - A case of massive hypertrophy of the breasts in pregnancy was seen in our institution, which is a tertiary referral centre for the United Arab Emirates region with a delivery rate of 7000/year. It is a very rare condition (1 in 100000) and the only case seen in our hospital over the past 20 years. No similar case has been reported from the United Arab Emirates or Gulf regions, to our knowledge. The patient presented at a gestational age of 18 weeks on account of progressive swelling of the breasts which started at 14 weeks' gestation. In pregnancy she was managed conservatively with analgesics, bromocriptine and breast support. She had bilateral reduction mammoplasty 1 year after delivery. The outcome was satisfactory, and the patient was pleased with the cosmetic result. PMID- 21686431 TI - Bleomycin lung: a case report. AB - A 69-year-old gentleman with non-Hodgkin's lymphoma (stage I), with baseline fibrotic lung changes on CT, received six cycles of R-PMitCebo chemotherapy containing bleomycin. Three months later he presented to the Accident and Emergency Department with progressive dyspnoea, dry cough, pyrexia and generalised lethargy. Chest radiographs showed bilateral lower zone opacities. Clinically, all signs initially pointed to community-acquired penumonia, but he failed to respond to standard treatment for this. Repeat high-resolution CT (HRCT) subsequently showed widespread peripheral interstitial changes consistent with marked fibrotic lung changes. It became apparent that this was in fact bleomycin-induced pulmonary toxicity. The patient rapidly deteriorated and developed type I respiratory failure. Despite intensive steroid treatment, the patient progressively got worse and died in the Intensive Therapy Unit 10 days after admission. Death was directly attributed to pulmonary fibrosis secondary to bleomycin treatment. PMID- 21686432 TI - Postprandial hyperinsulinaemic hypoglycaemia and type 1 diabetes mellitus. AB - A patient with severe postprandial hyperinsulinaemic hypoglycaemia (PPHH) for 4 years developed type 1 diabetes mellitus. She had no insulin or insulin receptor antibodies but was positive for islet cell and glutamic acid decarboxylase (GAD) antibodies. PPHH prior to the onset of type 1 diabetes mellitus has not been previously described and may be a prodrome of type 1 diabetes mellitus. PMID- 21686433 TI - Ping-pong champion with adrenal insufficiency. AB - A 62-year-old Japanese man, a bronze medal winner in the World Championship of table tennis when in his 20s, was diagnosed with secondary adrenocortical insufficiency due to isolated adrenocorticotropic hormone (ACTH) deficiency, and steroid administration was started. About 1 year after the diagnosis, he took part in a table tennis championship which was open to those 40 years or older. He took 10 mg hydrocortisone after breakfast as usual, played 10 matches, each of which took 20-30 min, and won the championship in about 8 h. Since the man could not always win the gruelling competition even when in his 50s, it is suggested that extra steroid hormone is not necessary for patients with adrenocortical insufficiency due to ACTH deficiency in order to successfully engage in sports requiring such intensity and endurance. PMID- 21686434 TI - Traumatic abdominal wall hernia. PMID- 21686435 TI - Mucormycosis complicating lower limb crash injury in a multiple traumatised patient: an unusual case. AB - Necrotising skin and soft tissues infections are most commonly bacterial in origin. However, saprophytic fungi of the class Zygomycetes, family Mucoraceae, can cause highly aggressive infections (mucormycoses) mainly in immunocompromised patients. Severe trauma is one of the major risk factors for mucormycosis. Fungal traumatic wound infection is an unusual complication associated with crash limb injury. This report describes a case of serious necrotising soft tissue infection caused by Mucor sp following primary fungal environmental wound contamination in a multiply injured patient. Despite undelayed diagnosis and proper treatment (surgical debridement and limb amputation, amphotericin B therapy) the patient presented a fatal outcome. PMID- 21686436 TI - Polymorphic ventricular tachycardia during a stress test. PMID- 21686437 TI - Gastric mucosal metastasis from primary colorectal carcinoma. AB - A 44-year-old man with a background of metastatic colorectal cancer presented with haematemesis. An oesophago-gastroduodenoscopy was performed and revealed five focally haemorrhagic grey mucosal lesions in the body and fundus regions of the stomach between 5 mm and 4 mm in diameter. The biopsies of the gastric mucosal lesions showed invasive poorly differentiated adenocarcinoma in which signet ring cells were a prominent component, thus related to the primary cancer. The background mucosa showed no dysplasia. PMID- 21686438 TI - Clostridium difficile enteritis in a patient after total proctocolectomy. AB - Clostridium difficile infection is associated with antibiotic therapy and usually limited to the colonic mucosa. However, it is also a rare cause of enteritis, with only a few cases reported in the literature. In the present report, the case of a 30-year-old woman with Clostridium difficile enteritis who previously had a panproctocolectomy with end ileostomy for severe ulcerative colitis is described. Previously reported cases of Clostridium difficile enteritis are also reviewed. Previous antibiotic therapy had been present in all cases and appears causative, major colonic resection is a precipitating factor. Small bowel Clostridium difficile infection should be considered in any patient with ileostomy flux/diarrhoea after major colonic surgery. If recognised early and treated aggressively the high mortality associated with Clostridium difficile enteritis may be avoided. PMID- 21686439 TI - The enhanced S-cone syndrome in children. AB - The enhanced S-cone syndrome (ESCS), a rare retinal degenerative disease often associated with NR2E3 mutation, is due to increased numbers of S-cones at the expense of other photoreceptors or miswiring distal to the photoreceptors. Paediatric ESCS and its differing clinical features (as opposed to adult ESCS) is the subject of this report. PMID- 21686440 TI - Splenohepatic lesions: unusual presentation of gastric lymphoma. PMID- 21686441 TI - Diabetes mellitus type I associated with dermatomyositis: an extraordinary rare case with a brief literature review. AB - Insulin dependent diabetes mellitus (IDDM) is considered to be an autoimmune disease. IDDM is associated with other autoimmune diseases such as rheumatoid arthritis, autoimmune thyroid disease, multiple sclerosis, ankylosing spondylitis, psoriasis and systemic lupus erythematosus. Dermatomyositis (DM) is a disease of autoimmune aetiology involving skin and skeletal muscles damaged by an inflammatory process dominated by lymphatic infiltration. The association of IDDM with DM is extraordinarily rare. To our best knowledge, to date only two reports-one of them referring to a patient in childhood-have been published worldwide. DM and IDDM affect children and young adults. Herein, a case of DM in association with IDDM in a 28-year-old man is presented. PMID- 21686442 TI - An interesting case of paraganglioma. PMID- 21686443 TI - Herpetic neonatal pustular rash. AB - Pustular rash in a neonate is very common and is usually associated with staphylococcal infection. The present report describes the case of a 12-day-old neonate with a pustular rash, secondary to herpes simplex infection. A high index of suspicion is necessary in neonates presenting with suggestive signs, especially with negative bacterial cultures. Prompt initiation of aciclovir treatment after obtaining diagnostic samples may be life-saving. PMID- 21686444 TI - Splenic artery aneurysm rupture: case report of this uncommon presentation. AB - Rupture of a splenic artery aneurysm remains an uncommon cause of hypovolaemic shock in the emergency department. This case report highlights that rapid resuscitation, diagnostic imaging, surgical consultation and subsequent laparotomy remain the priorities in patient management. PMID- 21686445 TI - Ischaemic infarction masking aortic dissection: a pitfall to be avoided before thrombolysis. AB - Acute aortic dissection complicated by stroke is not uncommon but may be difficult to evaluate, especially in patients with impaired mental status. This report describes a patient who had evidence of an ischaemic stroke but was fortuitously not given thrombolytic treatment. She was subsequently found to have an extensive aortic dissection involving both carotid arteries. The decision of whether to give thrombolytic treatment is understandably an urgent one, but careful attention should be paid to subtle signs and symptoms such as atypical chest pain and carotid bruits that might suggest aortic dissection, especially involving the carotid arteries. There should be a high index of suspicion for acute aortic dissection in such cases and a low threshold for performing carotid ultrasound. PMID- 21686446 TI - Response to infliximab in SAPHO syndrome. AB - Infliximab has become increasingly important in the treatment of SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome. There is, however, little experience with this biological agent, and treatment protocols usually follow the regimens for spondylarthropathies. We report a patient with a highly unusual and severe clinical presentation of SAPHO syndrome including widespread bone and skin disease, and collagenous colitis. Infliximab treatment (5 mg/kg) given at weeks 0, 2 and 6 and every 8 weeks thereafter, induced rapid remission of the osteoarticular symptoms, although the skin lesions improved only partially, and after 10 months continuous therapy with infliximab a bone scan even uncovered new active bone lesions. Collagenous colitis is unresponsive to tumour necrosis factor alpha (TNFalpha) blocking agents. This moderate response to infliximab may indicate that a more aggressive treatment protocol is mandatory. We further believe that remission of osteoarticular complaints should be routinely confirmed by scintigraphic findings to verify treatment response. PMID- 21686447 TI - Three-dimensional CT images of high aortic occlusion associated with small aorta syndrome. PMID- 21686448 TI - Osborn waves in hypothermia induced by baclofen overdose. PMID- 21686449 TI - Basal ganglion stroke presenting as subtle behavioural change. AB - Cerebral infarctions can have many presentations ranging from hemiparesis to subtle behavioural changes. A case is presented in which the only sign of a left basal ganglion infarct was isolated abulia. This case highlights the importance of a thorough evaluation in cases of acute unexplained changes in behaviour. PMID- 21686450 TI - A case of primary thyroid squamous cell cancer: transformation from benign tumour associated with chronic thyroiditis? AB - Primary squamous cell cancer of the thyroid gland (SCT) is a rare malignant tumour and is associated with a high mortality. A female patient who suffered from primary SCT is described in this report. The cancer was identified with acute painful swelling of the thyroid gland, when the patient was under periodical observation for her chronic thyroiditis at our outpatient's clinic. In spite of the highly malignant potential of the cancer as indicated by histological examinations, including p53 and MIB-1 index analyses, the patient has been successfully treated so far with surgery and radiation therapy, surviving for more than 34 months with no sign of recurrence or metastasis. Early diagnosis and prompt treatment might have been essential for the successful management of this patient. Further observations and investigations are necessary to clarify the mechanisms of the long survival and to find a better treatment for the disease. PMID- 21686451 TI - A rare cause of partial intestinal obstruction in a child: colonic lithobezoar. AB - The accumulation of undigested foreign bodies or nutrients in the gastrointestinal tract forming a conglomeration is called a bezoar. Bezoars are referred to according to the foreign bodies that constitute their core: phytobezoar (fibres or seeds of vegetables and fruits), trichobezoar (hair), lactobezoar (remnants of milk) and lithobezoar (rock or similar substances). PMID- 21686452 TI - Postural orthostatic tachycardia syndrome. AB - Postural orthostatic tachycardia syndrome (POTS) is characterised by the development of excessive tachycardia on standing with maintained blood pressure. We report a case of POTS in a 20-year-old girl with type 1 diabetes who presented with a 3-week history of lethargy, fatigue and orthostatic intolerance. Examination revealed a postural rise in heart rate of over 50 bpm with maintained blood pressure. This was associated with symptoms of light-headedness. Cardiac structure and function as assessed by ECG and ECHO were normal as was thyroid and adrenal function. POTS was confirmed with tilt table testing. Treatment was initiated with increased fluid intake, fludrocortisone and bisoprolol with improvement. POTS is a disabling condition which can significantly limit a patient's activities and working capacity and should be considered in a young, otherwise well patient who presents with orthostatic intolerance and a postural rise in heart rate. PMID- 21686453 TI - Bilateral temporomandibular joint dislocation following pulmonary function testing: a case report and review of closed reduction techniques. AB - Temporomandibular joint dislocation is not a common presentation to the emergency department but it is one that requires prompt diagnosis and reduction. This is thought to be the first reported case of spontaneous bilateral temporomandibular joint dislocation after routine pulmonary function testing. The management of the case is discussed and a review of closed reduction techniques commonly used in the emergency department is presented. PMID- 21686454 TI - A sticky situation. AB - We present a complicated case of extensive intra-abdominal venous thrombosis manifesting with severe central abdominal discomfort following trivial blunt local trauma and discuss the therapeutic interventions that can be used in these cases. PMID- 21686455 TI - Crohn disease in Nepal: true rarity or gross underdiagnosis? AB - Gross and histopathological examination of a resected segment of ileum in a 72 year-old man with the preoperative diagnosis of small intestinal perforation peritonitis revealed the first-ever diagnosed case of Crohn Disease (CD) at the B P Koirala Institute of Health Sciences, Dharan, Nepal. In view of the recent reports on rising incidence of CD in neighbouring Asian countries, it was decided to perform an exhaustive literature search to find out the documented prevalence of CD in Nepal. It was surprising to find only a single case of CD from Nepal, occurring in the year 1980, to be documented in English literature. Further, the index case of CD presenting with acute abdomen is of interest since only about 100 cases of CD with small intestinal perforation have been so far reported worldwide. PMID- 21686457 TI - Marked coronary artery dilation in a young adult requiring extracorporeal membrane oxygenation support for adult respiratory distress syndrome due to Kawasaki disease. PMID- 21686456 TI - Malignant hypertension complicated by acute renal failure. AB - Malignant hypertension is closely associated with impairment of multiple organs, and renal dysfunction remains an important cause of morbidity and mortality in patients with malignant hypertension. The renal histopathological changes usually indicate malignant arteriolar nephrosclerosis (MANS) that is characterised by fibrinoid necrosis in small arteries. However, renal biopsies were not taken routinely in previous reports. We report an educational case of malignant hypertension caused by MANS leading to thrombotic microangiopathy (TMA). PMID- 21686458 TI - Anatomic variations of the non-recurrent inferior laryngeal nerve. PMID- 21686459 TI - A child with abdominal mass and severe anaemia. PMID- 21686460 TI - Double superior vena cavae. PMID- 21686461 TI - Acute delirium in a critically ill patient may be a wolf in sheep's clothing. AB - Acute delirium is a commonly encountered problem in the intensive care unit (ICU), which has a myriad of causes and contributes to poor outcomes. We present the case of an alcoholic critically ill patient who developed prolonged acute ICU delirium wrongly diagnosed as sedation and alcohol withdrawal. Protracted vomiting, swallowing disorders and continuous aspirations prevented him from enteral feeding and discontinuation of mechanical ventilation. After several days, it became clear that the patient had been misdiagnosed. Fortunately, nystagmus and ophthalmoplegia then allowed the recognition of Wernicke's encephalopathy, confirmed by cerebral MRIs. After thiamine supplementation, his state improved but he was discharged only on day 32. Wernicke's encephalopathy is an acute reversible neuropsychiatric emergency, which is falsely considered as uncommon, and is largely misdiagnosed, especially in critically ill patients. Thiamine should be systematically given to all critically ill alcoholic patients, especially those with protracted vomiting. PMID- 21686462 TI - Spontaneous pneumomediastinum: rare complication of diabetic ketoacidosis. PMID- 21686463 TI - A primary adenocarcinoma of the transverse colon mimicking Crohn's disease: a case report and literature review. AB - Diarrhoea and weight loss are presenting features of both Crohn's disease and colorectal cancer; however, the two conditions can usually be distinguished on the basis of characteristic patterns of abnormalities observed at the time of initial blood testing and imaging. In patients with suspected Crohn's disease these are often considered sufficient grounds to commence empirical treatment before the results of histology are available. This case report describes a 45 year-old man whose initial clinical, endoscopic and radiological investigations were strongly suggestive of a diagnosis of Crohn's disease, but who subsequently was found to have an adenocarcinoma of the mid-transverse colon. He went on to have an emergency extended right hemi-colectomy. PMID- 21686464 TI - Ketonuria and HELLP syndrome. AB - We recently managed a patient with the HELLP syndrome (Haemolysis, Elevated Liver enzymes and Low Platelet count) where there was a delay in diagnosis due to gastroenteritis. This case also reiterates the varied or lack of symptomatology in patients developing HELLP and obscuring the initial diagnosis. Patients with HELLP syndrome have significant maternal morbidity and mortality, hence clinical vigilance and high suspicion play a key role in the diagnosis and subsequent management. PMID- 21686465 TI - Repeated phlebotomies improve and stabilise renal function in cyanotic nephropathy. AB - Patients over 10 years of age with cyanotic congenital heart disease (CCHD) risk developing significant glomerular proteinuria, a condition called cyanotic nephropathy. Even though the pathogenesis of glomerulopathy associated with CCHD is still unclear, a potential mechanism is hyperviscosity-induced decrease in peritubular capillary blood flow leading to an increase in glomerular capillary pressure, in turn resulting in proteinuria. Although angiotensin-converting enzyme (ACE) inhibitors have been traditionally used in the treatment of these patients with cyanotic nephropathy, they may, however, not be well tolerated. Here we present a case of an adult patient with CCHD who could not tolerate an ACE inhibitor but showed improvement and stabilisation of her renal function following treatment with repeated phlebotomies. PMID- 21686466 TI - Infectious mononucleosis complicated by acute hepatitis and myocarditis: a response to corticosteroids. AB - Infectious mononucleosis, or glandular fever, is a viral illness which commonly affects young adults. Symptoms can vary from sore throat, enlarged lymph glands, lethargy and weight loss to more serious clinical manifestations such as myocarditis or hepatitis. Treatment is usually conservative although there has been significant debate over the role of oral corticosteroids, especially in more serious cases. Evidence based medicine suggests that there is little to no role for steroids, but there are enough published case reports where steroid therapy has been potentially life saving that the debate continues. We present a case of a fit and well man who had significant multi-organ involvement secondary to infectious mononucleosis, and our experience of oral corticosteroid treatment. PMID- 21686467 TI - Anticonvulsant hypersensitivity syndrome closely mimicking Kawasaki disease. AB - Anticonvulsant hypersensitivity syndrome (AHS) is an acute, life-threatening, idiosyncratic drug reaction seen within 1-8 weeks after administration of an aromatic antiepileptic drug. The authors present the case of a 16-month-old boy who developed prolonged fever, a generalised pruritic rash and eosinophilia within 4 weeks after starting treatment with phenobarbital for complicated febrile seizures. He gradually fulfilled the diagnostic criteria for classical Kawasaki disease (KD), although the rash and the subsequent desquamation were atypical, he did not defervesce quickly with administration of corticosteroids and intravenous gamma-globulin, and he had only two suggestive cardiac features of KD-that is, perivascular echogenicity of the coronary arteries and a small pericardial effusion. Other conditions considered in the differential diagnosis were excluded by appropriate extensive serological and microbiological studies. He recovered fully. This report shows that drugs such as phenobarbital may be responsible for febrile exanthematous illnesses that closely mimic KD. PMID- 21686468 TI - Atypical femoral diaphyseal and subtrochanteric fractures and their association with bisphosphonates. AB - Antiresorptive bisphosphonate agents are the mainstay of treatment for osteoporosis in both men and postmenopausal women. However, recent studies have raised concerns about the oversuppression of bone turnover related to the long term use of bisphosphonates. Cases of atypical femoral diaphyseal and subtrochanteric fracture were reported recently in patients on long-term alendronate, and oversuppression of bone turnover was postulated to be the cause. We retrospectively reviewed all patients with femoral diaphyseal and subtrochanteric fracture presented between July 2003 and June 2008, and identified 10 patients who reported prior bisphosphonate use. Bone formation markers of all these patients were in the low range. Although the incidence of bisphosphonate-related atypical fracture accounts for an extremely low percentage of the total number of femoral diaphyseal and subtrochanteric fractures, we observed a steady increase from 0% in 2003 to 2004 to 25% in 2007 to 2008. PMID- 21686469 TI - Canalicular adenoma: a case report of an unusual parotid lesion. AB - The present report describes a case of an 85-year-old woman who underwent an excisional biopsy of a preauricular lesion centred over the zygoma and subsequently developed an immediate iatrogenic facial palsy. Histopathological diagnosis revealed a canalicular adenoma of the parotid gland. PMID- 21686470 TI - Factitious hyperamylasuria by a nurse: a symptom of Munchausen syndrome. AB - A 30-year-old nurse presented with abdominal pain and tenderness. Her blood tests, including amylase, were normal. Urinary amylase was extremely high. The source of the increased urinary amylase was found to be the patient's saliva-she had spat into her urine sample. Subsequent investigation showed that she had Munchausen syndrome. PMID- 21686471 TI - Successful IVF pregnancy after radical trachelectomy using transabdominal cervico isthmic cerclage. AB - A 34-year-old woman was referred to the in vitro fertilisation (IVF) clinic following failure to conceive after ovulation induction with antioestrogens and intrauterine insemination. She had a long history of hypothalamic amenorrhoea secondary to weight loss and stress and received hormone replacement to maintain her bone density. She also underwent radical trachelectomy and bilateral laparoscopic pelvic node dissection as fertility sparing surgery for cancer of the cervix stage 1B. She remained under our care for 4 years during which she had two successful IVF pregnancies with elective single embryo transfers on both occasions. She delivered preterm by caesarean section at 31 weeks and 35 weeks, respectively, for premature rupture of membranes with good outcomes. There was no evidence of local or distant recurrence of her early cervical cancer at 10-year follow-up at the combined gynaecology oncology clinic and she was discharged to primary care for follow-up. PMID- 21686472 TI - Supplemental vitamin K improves the stability of anticoagulation in a patient with low tissue stores of vitamin K secondary to coeliac disease. AB - Maintenance of a patient's international normalised ratio (INR) within the appropriate target range remains a challenge in clinical practice. The effects of concurrent medication, alcohol and compliance on stable control are well documented. Recent evidence also shows that supplemental vitamin K in patients with low body stores improves the stability of INR in these patients. Here, the case of a 57-year-old with coeliac disease requiring warfarin for a metallic mitral valve, who had poor INR stability resulting in thrombotic and bleeding complications, is described. Her vitamin K body stores were extremely low. Supplementation of vitamin K (100 MUg daily) resulted in improvement in anticoagulation stability (mean (SD) 3.41 (1.68) vs 4.68 (3.34)). The percentage time spent within target INR range doubled following vitamin K supplementation. This case illustrates a relatively new approach to managing patients with highly unstable INR levels and provides extra understanding of factors influencing INR stability. PMID- 21686473 TI - A case report: an unsuspected case of acute mesenteric ischaemia. AB - Acute mesenteric ischaemia is a severe surgical condition with significant mortality, and it requires prompt recognition and surgical intervention. This report describes a case of a middle-aged gentleman with no previous risk factors who presented with an acute abdomen secondary to mesenteric ischaemia and made a full recovery. This case illustrates that mesenteric ischaemia can occur without the presence of any obvious risk factors and if treated early can result in successful outcomes. PMID- 21686474 TI - Elevated CA125 in primary peritoneal serous psammocarcinoma: a case report and review of the literature. AB - Psammocarcinoma is a rare form of serous carcinoma of the ovary or peritoneum, and it is characterised by extensive psammoma body formation and invasion of surrounding structures. This report describes the case of a 42-year-old woman who presented with large ascites and raised CA125 level. Following a full staging laparotomy, she was made stable in stage IIIC. Despite the limited number of cases reported, the clinical prognosis of carcinomas resembling the serous borderline lesions seems much more favourable than the common serous carcinomas. A summary of all the reported cases is provided to highlight the clinical and prognostic features of this scarce tumour. PMID- 21686475 TI - Exacerbation of asthma secondary to fentanyl transdermal patch. AB - Asthma is a common chronic inflammatory disorder of the airways associated with hyperresponsiveness, reversible airflow limitation and respiratory symptoms.1 All patients with asthma are at risk for exacerbations that may range from mild to life threatening. Different triggers cause asthma exacerbation by inducing airway inflammation and/or provoking bronchospasm. Allergen-induced bronchospasm results from IgE-dependent release of mediators including histamine, prostaglandins and leukotrienes.2 Opiates are commonly used to treat chronic pain.3 Although hypersensitivity to opiates or accumulation of opiates can cause respiratory depression, opiates are also used in the management of cough and dyspnoea associated with advanced COPD and heart failure.4(,)5 Here, a report is presented on a patient who developed persistent exacerbation of underlying stable asthma after initiating fentanyl transdermal therapy for chronic low back pain. He underwent extensive investigations and a detailed reassessment of history, especially medication history, led to the possible causative factor; once recognised, removal of the offending agent (fenatnyl) resulted in complete improvement in his symptoms within 72 h. PMID- 21686476 TI - An atypical presentation of breast cancer metastasis. AB - A 78-year-old woman heard a crack in her left mandible while eating a biscuit and reported to her dentist, who urgently referred her to the oral and maxillofacial surgery department. On examination she had a lesion in the body of her left mandible, which had eroded through the lower border and caused a pathological fracture. Her past medical history included a left mastectomy and level II axillary lymph node dissection for a 27 mm grade III invasive ductal carcinoma of the left breast 9 months prior to her mandibular fracture. A transoral incisional biopsy was performed which confirmed the mandibular lesion to be an osteolytic metastasis from the breast. The metastasis was subsequently surgically removed and the remaining mandible repaired with a reconstruction plate followed by postoperative radiotherapy. The patient regained full function of her mandible and is now eating normally. She is being closely followed-up in the oncology outpatient department. PMID- 21686477 TI - Silent rupture of aneurysm of arch of aorta mimicking malignancy. PMID- 21686478 TI - Gastrointestinal lesions in parvovirus B19 infection. AB - A 13-year-old girl with persistent fever, pharyngitis, acute anaemia, peripheral blood and bone marrow positive for parvovirus B19 DNA.Microscopic findings of gastrointestinal biopsy showed diffuse vacuolar alteration of the cytoplasma of duodenal enterocytes and virological analysis demonstrated the presence of parvovirus in lymphocytes of the duodenal wall's epithelial layer.In unexplained gastrointestinal pathologies, the role of parvovirus B19 infection should be investigated. PMID- 21686479 TI - A piece of hammer in the right ventricle of the heart. PMID- 21686480 TI - Pulmonary infarction from central venous air embolism mimicking round pneumonia. AB - A 49-year-old man with an 11 year history of dilated cardiomyopathy presented with a worsening of symptoms associated with an upper respiratory tract infection. During his hospitalisation, a central venous catheter (CVC) was inserted and this was complicated by pulmonary infarct from an air embolism. The infarct had the appearance of a round pneumonia on radiography. The patient died one week after the CVC insertion from cardiogenic shock and multi-organ failure. PMID- 21686481 TI - Walk like an Egyptian. PMID- 21686482 TI - Prenatal findings and neonatal immature gastric teratoma. AB - Immature teratoma of the stomach in the neonate is extremely rare.1(,)2 This report outlines a case of giant immature teratoma of the stomach, which was detected by prenatal ultrasonography in the third trimester as an echogenic mass contiguous with the stomach bubble. It increased from 4.5 cm in diameter to 7 cm between 34 and 37 weeks gestation. The baby was delivered by elective caesarean section at 37 weeks gestation. Neonatal imaging highlighted a differential diagnosis of nephroblastoma, neuroblastoma, pancreatoblastoma and teratoma. The infant underwent surgical excision of the abdominal mass on the 10th day of life. Histology revealed grade III immature gastric teratoma arising from the posterior wall of stomach, outlining the unknown implications of such a designation in an extraovarian site. The infant made a good postoperative recovery and is currently well 9 months later, without adjuvant therapy, and with no evidence of recurrent disease. PMID- 21686483 TI - Ileosigmoid knot complicated by gastric and splenic mucormycosis: a lethal combination. AB - Two very rare conditions, ileosigmoid knot and intra-abdominal mucormycosis, occurred sequentially in a middle-aged HIV positive male.At laparotomy for peritonitis, a gangrenous sigmoid volvulus with ileosigmoid knot was resected; 2 days later, colo-rectal continuity was restored, the distal ileum stapled and an end jejunostomy fashioned.At re-laparotomy on day 15, necrotic stomach and spleen required a total gastrectomy and splenectomy. At reoperation 2 days later, a bile leak at the oesophago-jejunostomy site was repaired. Despite this intervention he continued to deteriorate and died of multiple organ failure 4 days later. PMID- 21686484 TI - Symptomatic hypertrophic obstructive cardiomyopathy: semi-supine bicycle ergometry as a useful provocative manoeuvre to elicit latent gradient. AB - We report the case of a 58-year-old Caucasian woman with severe symptoms attributable to hypertrophic obstructive cardiomyopathy (HOCM). When supine there was no significant left ventricular outflow tract (LVOT) gradient on echocardiography or cardiac catheter measurements-despite provocation with supine leg exercise and right ventricular pacing. However, semi-supine bicycle exercise induced a marked increase in the LVOT gradient, which helped guide successful percutaneous alcohol septal ablation. This case report demonstrates the usefulness of bicycle exercise echocardiography in diagnosing HOCM with latent LVOT obstruction. PMID- 21686485 TI - Clinical importance of delayed MRI contrast enhancement of primary central nervous system lymphoma in AIDS. AB - Accurately distinguishing between cerebral toxoplasmosis and primary central nervous system lymphoma (PCNSL), still the most common secondary CNS mass lesion complications of AIDS, has long represented a diagnostic challenge in those with HIV. A young adult male with AIDS presented with evolving ophthalmoplegias, Parinaud's syndrome and gait dysfunction. MRI with gadolinium contrast revealed a brainstem lesion failing to enhance on initially obtained post-contrast images yet prominently enhancing on images acquired endmost within the same scanning session. Biopsy ultimately confirmed lesion aetiology as PCNSL. While the definitive diagnosis of PCNSL generally requires brain biopsy, different MRI contrast-enhancement time courses of PCNSL versus toxoplasmosis (PCNSL tends to peak-enhance sooner than toxoplasmosis) can provide differential diagnostic insight. These images underscore the delayed nature of PCNSL contrast enhancement and demonstrate the diagnostic importance of attending to post-gadolinium image acquisition timing to help inform utilisation of MRI for PCNSL identification. PMID- 21686486 TI - Acute respiratory distress following the inhalation of an aerosol upholstery cleaner: the importance of reporting from the Emergency Department. AB - Aerosols are commonplace in the home and in industry as they provide a quick and controlled way of distributing chemicals or perfumes. It is well known that deliberating concentrating and inhaling vapours may result in dizziness, euphoria, blackouts, respiratory distress, cardiac and renal failure. However, in the most part, warnings and guidance on use are sparse. Here, a proven case of acute respiratory distress is presented and a reporting mechanism via the UK National Poisons Information Service (NPIS) directly from the Emergency Department (ED) is highlighted. In this case, as a result of our reporting, the aerosol was redesigned and redeployed as a trigger spray with better consumer guidance. Clinicians are reminded of the central role of the ED in the reporting of such hazards. PMID- 21686487 TI - Lemierre syndrome: once seen it can never be mistaken. AB - Lemierre syndrome is a rare but severe septicaemia due most frequently to Fusobacterium necrophorum, with primary foci in the head, internal jugular vein thrombosis and metastatic infections, mainly in the lungs. We report two cases of Lemierre syndrome admitted to the paediatric unit of our hospital at 2-month intervals. The first was 10 years old and the second one was a 3-month-old infant. They were diagnosed on the 25th hospital day and at the time of admission, respectively. In the first case, diagnosis was delayed due to unfamiliarity with this disease. In the second patient the diagnosis was established on the first day because of the recent experience with patient 1. In both cases, bacteriological investigations were not helpful. Both patients had a favourable outcome after prolonged antibiotic treatment, anticoagulation and surgical drainage. PMID- 21686488 TI - An unusual case of acute on chronic renal failure following percutaneous coronary intervention. AB - Contrast nephrotoxicity is a common and well-documented complication of procedures utilising x ray contrast medium. It should be looked for whenever patients are exposed to contrast medium as it carries a good prognosis if managed appropriately, with only a minority of cases requiring dialysis. It is essential, however, that other causes of renal dysfunction are excluded before making a firm diagnosis of contrast nephropathy. Any delay in administering the appropriate treatment depending on the underlying pathology can result in devastating consequences. The differential diagnosis of acute renal failure is extensive and a systematic diagnostic approach should always be observed. PMID- 21686489 TI - An interesting case of cerebral abscess. AB - An immigrant from Romania was referred to the neurosurgical unit with a cerebral abscess. On examination she was cyanosed and had clubbing of her fingers. A cardiovascular system examination revealed a systolic murmur heard all over the precordium. However, the diagnosis was not congenital cyanotic heart disease. The patient had a history of frequent nosebleeds and had multiple telangiectases on her body, leading to the diagnosis of hereditary haemorrhagic telangiectasia (HHT). A search was carried out for the presence of arteriovenous malformations in internal organs. Large arteriovenous malformations were found in the lungs, causing her cyanosis due to right-to-left shunting of blood and cerebral abscess due to paradoxical septic embolisation into cerebral circulation. PMID- 21686490 TI - Sudden appearance and spontaneous regression of diffuse large B cell lymphoma in a man with a broken arm. AB - An elderly, demented man with stable kappa bi-clonal gammopathy of unknown significance suffered a severe displaced right humeral fracture in a fall. One week later a rapidly enlarging head, neck and axillary adenopathy first appeared, including a 2 cm tonsillar node that partially obstructed the oropharynx. A left cervical node biopsy demonstrated diffuse large B cell lymphoma with CD20+, bcl 2+, kappa+, CD3-, Epstein-Barr virus negative malignant cells. During the next month lymphadenopathy regressed more than 90% in the absence of treatment with chemotherapeutic agents, radiation or glucocorticoids. Following 2 months of clinical improvement, he died of pneumonia 95 days after the injury. An autopsy demonstrated residual right hilar and mediastinal malignant lymphadenopathy. These unusual events may be related to immunosuppressive and other systemic effects of acute injury on tumour behaviour. PMID- 21686491 TI - Spontaneous descending retropharyngeal abscess. AB - Retropharyngeal abscesses are rare but can occur spontaneously in adults and are potentially life threatening. Such a diagnosis should be considered so that aggressive treatment can be initiated as soon as possible to avoid life threatening mediastinal complications. PMID- 21686492 TI - Leiomyosarcoma arising from the inferior mesenteric vein. AB - Leyomiosarcomas arising from the portal/mesenteric venous system are very rare tumours, and only a few cases have been reported in the global literature. As the other leyomiosarcomas of vascular origin, they are associated with a poor prognosis. The present report describes the case of a 66-year-old woman with a leyomiosarcoma of the inferior mesenteric vein, unexpectedly found during a CT scan performed for another indication. A brief review of the literature is also given. The patient underwent radical surgical excision and enjoys a good health, without radiological signs of recurrence, 24 months after surgery. In this case, an early incidental diagnosis determined an early treatment and, probably, a favourable prognosis. This is the second case of leyomiosarcoma of the inferior mesenteric vein reported in the literature. PMID- 21686493 TI - Right atrial mass in the context of recurrent non-Hodgkin's lymphoma: atrial myxoma presenting with atrial flutter. AB - A case is described of a 57-year-old man with a background of low-grade bronchus associated lymphoid tissue (BALT) non-Hodgkin's lymphoma presenting with dyspnoea and palpitations. Diagnostic work-up revealed paroxysmal atrial flutter and the presence of a mass in the right lower lobe at bronchoscopy, with histology confirming recurrent BALTOMA. Transthoracic echocardiography (TTE) revealed a mass in the right atrium. Transoesophageal echocardiography (TOE) confirmed the presence of a fleshy, mobile pedunculated right atrial mass adherent to the interatrial septum, with features more in keeping with an atrial myxoma rather than intracardiac lymphoma. He proceeded to cardiotomy and excision of the mass with histology confirming an atrial myxoma. The clinical and echocardiographic features of atrial myxomas and intracardiac lymphomas are briefly discussed. PMID- 21686494 TI - Beware of the malformed nasogastric tube. AB - Untoward events with faulty instruments and apparatus are well known and if not recognised can be disastrous. We present a case of a faulty nasogastric tube having both ends sharp-edged and closed with a detachable blocker. In our case, had we inserted the faulty nasogastric tube, the impact of the blocker, although small, in the tract could have eroded the nasal/oesophageal/gastric mucosa causing its sequalae. Thus, we would like to emphasise the need to check all instruments before using them to prevent any catastrophic complication. PMID- 21686495 TI - Report on a patient with pre-existing venous thrombosis and incidental malignancy undergoing urgent laparotomy: preoperative concerns. AB - The management of a patient with pre-existing deep venous thrombosis (DVT) who was subsequently found to have a malignancy planned for urgent laparotomy is reported.A 30-year-old woman presented to the emergency room and was diagnosed to have a DVT. During work-up, she was found to have a malignanacy and was scheduled for urgent laparotomy. The patient was put on enoxaprin (injection) and warfarin (tablets). The patient was started on heparin (injection) 1000 IU/h at 72 h prior to operation, stopped 6 h prior to surgery. Anaesthesia and surgery were uneventful.A number of issues related to pre-existing DVTs prior to gynaecological surgery require further clarification; the optimal duration of pharmacological treatment, and the optimal duration/modality of prophylaxis to prevent thromboembolism in high-risk patients with cancer.Patients presenting for DVT must be evaluated for its causative factor(s), and malignancy in particular, based on clinical findings and investigations. Before planning surgical procedures, adequate anticoagulation must be achieved to prevent further complications of DVT, thromboembolism and pulmonary embolism in particular. PMID- 21686496 TI - Asymptomatic pneumocephalus after head trauma: case report. AB - A 66-year-old man was brought in to our emergency department (ED) with head trauma and was diagnosed with frontal located pneumocephalus based on a cranial computed tomography (CT) scan. At the time of arrival, he was alert and his Glasgow Coma Score (GCS) was 15. A neurological examination revealed no deficit and during follow-up in the ED his GCS did not deteriorate. Cranial CT scan demonstrated nasal fracture. On maxillofacial CT examination, we detected a nasal bone fracture, air loss and fluid was seen in the maxillary and ethmoid sinuses. In our case, pneumocephalus is assumed to be the result of ethmoid bone fracture. Despite the large amount of air in the subdural area, our patient had no symptoms. He was admitted to the intensive care unit for close monitoring and was discharged from hospital without neurological deficit on the fifth day of follow up. PMID- 21686497 TI - Disseminated intravascular coagulation complicating HELLP syndrome: perioperative management. AB - HELLP syndrome may lead to disseminated intravascular coagulation (DIC) which can make emergency surgery a serious challenge. A 29-year-old female presented with haematuria, epistaxis and hypertension in the emergency ward and a diagnosis of DIC complicating HELLP in preeclampsia was made. She had continuous epistaxis and elective tracheal intubation was carried out. During emergency caesarean section the patient was managed with blood products, antihypertensive drugs and general anaesthesia together with invasive monitoring. She required postoperative ventilatory support. HELLP syndrome may progress to DIC in 15-38% of patients. The prothrombin time, activated partial thromboplastin time and serum fibrinogen levels are normal in HELLP syndrome but are prolonged in DIC. Evaluation of more sensitive markers of DIC, such as antithrombin III, alpha-2 antiplasmin, plasminogens, fibrin monomer and D-dimers, differentiates DIC from HELLP syndrome. Aggressive treatment is indicated and delivery should be expedited, by caesarean section if necessary although vaginal delivery is not contraindicated, along with control of blood pressure and coagulation abnormality. We conclude that patients with DIC complicating HELLP syndrome and preeclampsia require great vigilance and multimodal management in the perioperative period for uneventful outcome. PMID- 21686498 TI - Pulmonary arteriolar muscle thickening in sudden infant death syndrome. AB - Pulmonary arteriolar thickening in sudden infant death syndrome has been repeatedly reported but this finding has been challenged. We report a case of a previously healthy 23-day-old infant girl who was witnessed by her parents to die suddenly and unexpectedly. During a routine bottle-feeding, she suddenly began to cry loudly and her face became deep-red and then pale. She became limp and began to gasp. Resuscitation efforts were to no avail. The post-mortem examination, including toxicological studies, screening for inborn errors of metabolism and genetic studies for prolonged Qt syndrome, failed to reveal the cause of death. A more focused study of the lungs showed extensive pulmonary arteriolar thickening. The events in the sudden death of this infant are remarkably similar to deaths in infants with various disorders associated with pulmonary arteriolar thickening. We suggest that this vascular abnormality and associated pulmonary hypertension played a critical role in this infant's death. PMID- 21686499 TI - Seizure or syncope? A channelopathy with cardiac and cerebral manifestation. AB - A 24-year-old woman was diagnosed with long QT syndrome (LQTS) because of recurring losses of consciousness. She was implanted with a cardioverter defibrillator, but losses of consciousness reoccurred. Genetic analysis proved LQTS. An electroencephalogram showed spontaneous generalised spikes and polyspike waves with a 3-4/s frequency. Losses of consciousness ceased only after antiepileptic treatment. We conclude that it may by worthwhile scrutinising patients with LQTS for subtle epileptic activity to find evidence for a cerebral manifestation of a disease thought to be confined to the heart. PMID- 21686500 TI - Osteogenesis imperfecta with partial trisomy 15. AB - Osteogenesis imperfecta (OI) is the most common genetic cause of osteoporosis, which presents as multiple fractures of bone. Mutations in the loci COL1A1 on band 17q21 and COL1A2 on band 7q22 have been reported as the cause in most cases of OI, but partial trisomy 15 has not been reported previously as a possible cause. A 3-month-old child with OI with an unusual association of partial trisomy 15 is reported. PMID- 21686501 TI - A large chest wall tumour in an asymptomatic 15-year-old girl. AB - A 15-year-old asymptomatic girl was found to have a large left lower chest wall mass associated with chest wall invasion on an opportunistic chest radiograph. The tumour was excised and shown to be a clear cell sarcoma. Adjuvant chemotherapy was administered and she was disease free at her 10 month follow up. PMID- 21686502 TI - A unique case of merkel cell carcinoma and chronic lymphocytic leukaemia presenting in a single cutaneous lesion (collision tumour). AB - A 58-year-old man with 10 year history of chronic lymphocytic leukaemia (CLL) presented with a bulging mass (3.2*1.6*1.5 cm) in the right anterior abdominal wall. On microscopic examination the mass was found to be an epithelial neoplasm in the background of lymphoid proliferation. The epithelial cells were of moderate size, with scant cytoplasm and round nuclei, forming glandular, alveolar or sheet-like structures. These cells were immunoreactive for cytokeratin 20, chromogranin and synaptophysin. The above findings supported a diagnosis of Merkel cell carcinoma (MCC). The background small lymphocytes expressed phenotypic markers of B cells (CD20) and CD5, consistent with his known diagnosis of CLL. The incidence of a patient with a known history of CLL who develops a secondary MCC is rare. This is believed to be the second case report of a single lesion containing CLL and MCC. PMID- 21686503 TI - Sentinel node biopsy in floor of mouth cancers: the need to clear level I. AB - Tumour lymphatic spread in head and neck squamous cell carcinomas is the single most important prognostic indicator. With advances in histological examination, sentinel node biopsy is proving to be an accurate method for staging the clinically N0 neck. We have previously highlighted the difficulties in locating sentinel nodes in the neck from floor of mouth primaries. We also raised the question whether level I nodes should be cleared as part of sentinel node procedures in floor of mouth tumours. We describe a case which illustrates the difficulties encountered when performing sentinel node biopsies in patients with floor of mouth cancers and the rationale behind asking such a question. PMID- 21686504 TI - Keeping a high index of suspicion: lessons learned in the management of methanol ingestion. AB - Methanol ingestion is an uncommon form of poisoning that can cause severe metabolic disturbances and potentially fatal and often irreversible organ/tissue damage. The diagnosis is sometimes elusive and requires a high index of suspicion. Because extent and irreversibility of the damage caused by formic acid is time sensitive, methanol poisoning should be recognised promptly so that it can be treated. Metabolic acidosis associated with an increased anion gap and osmolar gap is an important laboratory finding but is not always present. A case of severe methanol poisoning is presented that demonstrates the unique challenges in the diagnosis and management, and the lack of readiness of the health care system for such cases. We highlight some of the diagnostic difficulties associated with treating a patient with a reduced level of consciousness and severe metabolic acidosis. We also review the pitfalls of using laboratory tests to rule out alcohol ingestion and discuss the definitive management of methanol poisoning. PMID- 21686505 TI - Bilateral stony lung: pulmonary alveolar microlithiasis. AB - A 40-year-old male paddy field worker was referred for exertional shortness of breath and non-productive cough for 4 years. He had been treated for pulmonary tuberculosis twice. Chest radiograph showed extensive bilateral nodular opacities ("sandstorm-like") in the middle and lower lobe. Pulmonary function tests revealed a restrictive ventilatory defect. High resolution CT showed widespread nodular infiltration with "crazy paving" appearance and interrupted black pleura sign. This was confirmed as pulmonary alveolar microlithiasis (PAM) by trans bronchial lung biopsy, which showed normal respiratory lining epithelium with dilated alveolar spaces containing many calcific bodies, some of which showed concentric calcification. The possibilities of silicosis (due to exposure to husk) and tuberculosis, both of which can mimic PAM clinically and radiologically, made this case a diagnostic challenge. PMID- 21686506 TI - Severe metabolic alkalosis due to the combination of unmeasured cations and hypochloraemia in a patient with gastroparesia and frequent emesis. AB - This report describes a patient with gastroparesia and frequent emesis admitted with severe metabolic alkalaemia, hyperlactataemia and acute renal failure. Metabolic alkalaemia was not only due to hypochloraemia but also due to unmeasured cations. These cations were found to be present by calculating anion gap and strong ion gap (both were negative, which is rare). After massive gastric bleeding the patient had a cardiac arrest; following cardiopulmonary resuscitation and infusion of a large volume of normal saline, new blood tests revealed improvement in chloraemia but also a significant increase in the anion gap, suggesting that unmeasured anions rapidly overcame unmeasured cations. The patient died after sequential episodes of cardiac arrest. Anion gap and strong ion gap were useful in the diagnosis of this "hidden" unusual cause of metabolic alkalosis and also in the diagnosis of metabolic acidosis after cardiac arrest, even with normal/high values of base excess and bicarbonate. PMID- 21686507 TI - Diabetic muscle infarction. AB - Diabetic muscle infarction (DMI) is a rare complication of longstanding, poorly controlled diabetes. Only a few cases have been reported in the literature. The case of a 34-year-old man with a 7-year history of type 2 diabetes mellitus, with sudden onset of left thigh pain, is described here. A final diagnosis of DMI was made, the pathophysiology of which remains unclear. MRI findings were diagnostic and characteristic. The management of this condition is usually symptomatic. Short-term prognosis is very good; however, the recurrence rate is high. Long term prognosis is poor, with most patients dying from cardiovascular complications of diabetes within 5 years of diagnosis. This case supports the need for a high index of suspicion, when a poorly controlled patient with diabetes presents with non-traumatic limb pain. PMID- 21686508 TI - Syphilis presenting with headache and papilloedema. AB - A 41-year-old homosexual man presented with a 10-week history of headache without pressure features commencing 10 weeks after a new sexual contact. Three days after the headache onset he noticed intermittent, bilateral visual blurring, worse in the right eye. The visual disturbance persisted intermittently and led to his referral to a local ophthalmology department where he was found to have bilateral papilloedema. There were no other abnormal signs on full examination of other systems and no other abnormal ocular findings. Cerebral imaging studies were normal. A lumbar puncture revealed a raised opening pressure of 35 mm cerebrospinal fluid (CSF) with a white cell count of 58 cells/mcl (mainly lymphocytes). Venereal disease research laboratory (VDRL), Treponema pallidum haemagglutination (TPHA) and Inno-LIA tests confirmed the presence of neurosyphilis. HIV testing was negative. He was treated with CSF pressure reduction via repeat lumbar puncture and acetozolamide and procaine penicillin intramuscularly. He recovered and remains symptom free at 1 year. PMID- 21686509 TI - Foreign body reaction to a bioabsorbable interference screw after anterior cruciate ligament reconstruction. AB - Bioabsorbable interference screws have been effective for graft fixation in anterior cruciate ligament (ACL) reconstruction. The overall complication rate associated with the use of these screws is low but some unique problems have been reported in the literature. We present a case of unusual tissue reaction to a bioabsorbable interference screw following ACL reconstruction.A young male underwent ACL reconstruction, during which a bioabsorbable interference screw was used for graft fixation at the tibial end. The patient presented with a pretibial swelling at 30 months after the operation. Exploration revealed chalky white remnants of the bioabsorbable screw with no evidence of infection. Histological studies confirmed a foreign body reaction against screw remnants with the presence of multinucleated giant cells.The patient had a full recovery with no compromise to graft stability. Bioabsorbable interference screws are usually inert but can initiate a tissue reaction. The presentation can be as late as 2-3 years postoperatively and may mimic an infection. Satisfactory results can be achieved by proper exploration and debridement. PMID- 21686510 TI - Ectopic mediastinal thyroid tissue: cervical or mediastinum originated? AB - A 22-year-old female patient was admitted to our clinic after both clinical and laboratory findings suggested hyperthyroidism. At pre-operative magnetic resonance imaging (MRI), we detected a substernal goitre with lobulated outlines at the inferior of the right lobe that extended 5 cm inferior to the carina. The thyroid mass extended to the mediastinum and was totally extracted by cervical incision. Postoperatively, a residual thyroid mass of 8.5*9*10 cm in size, was detected on MRI at the median part of the anterior mediastinum. The isolated mediastinal thyroid mass was then extracted by sternotomy. We believe that, because of the close anatomical relationship between the thyroid tissue extending cervically and the mass detected in the mediastinum, the mediastinal mass might have developed from the cervical thyroid tissue residues by pushing the cervical thyroid or it might have mechanically entered the mediastinum. PMID- 21686511 TI - Overdrinking-induced hyponatraemia in the 2007 London Marathon. AB - We report a case of overdrinking-induced hyponatraemia from the 2007 London Marathon. The patient was a 37-year-old experienced female marathon runner. She was brought to the emergency room more than 6 h after completing the marathon suffering from diarrhoea, vomiting and confusion, and was unable to recall any detail of the race. An arterial blood sample confirmed hyponatraemia ([Na(+)] 117 mmol.l(-1)) associated with hypokalaemia (serum potassium concentration 3.4 mmol.l(-1)) and respiratory alkalosis (pH 7.62, bicarbonate 16.1 mmol.l(-1) and Pco(2) 2.14 kPa). A diagnosis of uncomplicated exercise-associated hyponatraemia due to voluntary overdrinking was made and the patient was catherised and treated with a slow (1 h) intra-venous infusion of 500 ml of 1.8% sodium chloride (NaCl) solution. The following morning her serum [Na(+)] had normalised at 135 mmol.l( 1) and she was discharged in the afternoon. She has recovered fully without sequelae. PMID- 21686512 TI - Papilloedema and hypertrichosis: the varied and harried manifestations of POEMS syndrome. PMID- 21686513 TI - A pleural mass with pulmonary infiltrates. AB - This case study describes a 34-year-old woman presenting with a subacute history of dyspnoea associated with pleural based masses and pulmonary infiltrates. A computed tomography guided biopsy confirmed the presence of a pleural based thymoma, and a video assisted thoracoscopic lung biopsy revealed the pulmonary infiltrates to be a lymphocytic interstitial pneumonitis (LIP). The thymomas responded successfully to chemotherapy and the LIP improved following corticosteroid therapy. PMID- 21686514 TI - Acute pancreatitis during interferon-alpha and ribavirin treatment for hepatitis C. AB - A patient treated with interferon-alpha and ribavirin for hepatitis C, who developed acute pancreatitis, is presented here along with a literature review. A 45-year-old Caucasian man was admitted to the intensive care unit because of an acute pancreatitis. According to the adverse drug reaction probability scale, it is probable that pancreatitis was induced by treatment (interferon and ribavirin) for chronic hepatitis C (CHC) commenced 2 months ago. We performed a literature search of all available English-language articles published on MEDLINE between January 1966 and July 2008 using the key terms "acute pancreatitis", "interferon" and "ribavirin"; only four papers were found with a total of 13 reported cases demonstrating acute pancreatitis developed during treatment for CHC. Looking out for the minimal clinical signs and symptoms of acute pancreatitis in patients with CHC using interferon and ribavirin can help to detect this relevant and rare adverse drug reaction early. PMID- 21686515 TI - Fatal giant cell myocarditis in a patient with multiple autoimmune disorders. AB - A case of circulatory collapse due to severe heart failure is reported in a 52 year old male with autoimmune disorders in the form of type-1 diabetes, Graves' disease and total alopecia.Upon admission, the patient had severe heart failure with a cardiac index of 0.9 l/min/m(2), a mixed venous saturation of 29% and left ventricular ejection fraction of 5%. The condition was refractory to treatment with inotropic agents and required mechanical cardiopulmonary support. Endomyocardial biopsies revealed extensive giant cell myocarditis (GCM). Immunosuppressant treatment did not alter the condition and urgent orthotopic heart transplantation was performed.Histopathological examination of the explanted heart confirmed the diagnosis and showed widespread vascular deposition of complement C4d suggesting a pathogenic role for the innate immune system in GCM.At 1-year follow-up the patient was in New York Heart Association (NYHA) class I, had episodes of sustained ventricular tachycardia but showed no evidence of GCM recurrence in endomyocardial biopsies. PMID- 21686516 TI - Keratoacanthoma. PMID- 21686517 TI - The impact of tuberculosis treatment on glycaemic control and the significant response to rosiglitazone. AB - This case involves a 43-year-old female patient with highly uncontrolled type 2 diabetes for the past 14 years. Her weekly mean (SD) glycaemia (WMG) concentration at week 1 was 20.9 (4.8) mmol/l (377 (87) mg/dl). Four weeks after reaching full control at week 3 with insulin glargine plus regular insulin and metformin (WMG 7.0 (1.9) mmol/l (127 (34) mg/dl)) she was diagnosed with acute pulmonary tuberculosis and treated with rifampicin, isoniazid and pyrazinamide, which caused her to lose glycaemic control (WMG 21.0 (7.1) mmol/l (378 (128) mg/dl)). No other potentially hyperglycaemic drug such as corticosteroid was used. During this entire period she was intensively treated with NPH (neutral protamine Hagedorn) and regular insulins, reaching a total daily dose of 170 IU, but with no clinical response. Together with insulin therapy, rosiglitazone was started at week 12 and glycaemic control returned to normal within just 3 weeks (WMG 6.6 (2.9) mmol/l (120 (53) mg/dl)). PMID- 21686518 TI - Cytological vitreous findings in a patient with infantile neurological cutaneous and articular (CINCA) syndrome. AB - The CINCA syndrome is an inflammatory disease characterised by persistent rash and chronic aseptic meningitis, with extensive infiltration of polymorphonuclear and macrophage cells at the sites of inflammation. The CINCA syndrome belongs to the group of systemic autoinflammatory diseases characterised by episodic or fluctuating degrees of inflammation, without evidence of high-titre autoantibodies or antigen-specific T cells. The disease is caused by mutations in the CIAS1 gene that encodes a protein cryopyrin, NALP3 or PYPAF1. Mutations in cryopyrin have a profound pro-inflammatory effect. Cryopyrin is a caspase 1 activator, which in turn causes the activation of interleukin (IL)1beta. The activating mutations of cryopyrin induce an excessive activation of IL1beta, which causes an influx of macrophages and polymorphonuclear cells to the site of inflammation, in our patient, in his eye. PMID- 21686519 TI - Retrovesical hydatic cyst with spontaneous fistulisation in the bladder. PMID- 21686520 TI - "Popcorn worker's lung" in Britain in a man making potato crisp flavouring. AB - This case involves a 36 year old non-smoker who worked in a factory producing food flavourings for potato crisps. He developed exertional breathlessness associated with fixed airway obstruction shortly after an uncharacteristically high exposure to the food flavouring chemical diacetyl. Unfortunately, even though he was removed from further exposure to this agent, his symptoms and spirometry did not improve. PMID- 21686521 TI - Call-Fleming syndrome associated with subarachnoid haemorrhage: three new cases. AB - The Call-Fleming syndrome (CFS) comprises acute severe recurrent (thunderclap) headaches, occasional transient or fluctuating neurological abnormalities and reversible segmental cerebral vasoconstriction. It is a benign condition with an excellent prognosis, yet because it is often clinically and radiologically similar to a number of commonly encountered conditions, diagnostic difficulties may arise, leading to inappropriate, and even potentially harmful, investigative and therapeutic approaches. Three personal cases are presented to highlight the occurrence of subarachnoid haemorrhage (SAH) as part of CFS. In two patients with a positive CT head, SAH involved the sulci in the upper cerebral convexity, an unusual location in aneurysmal SAH. SAH is not an uncommon feature of CFS, occurring in approximately 25% of reported cases, and may pose a diagnostic challenge. CFS has a relatively characteristic spectrum of features, allowing a confident diagnosis in most cases, even when atypical features such as SAH are present. Recognising the spectrum of abnormalities seen in CFS, including particularly SAH, allows a sound approach to a safe diagnosis. PMID- 21686522 TI - Immunotherapy responsive startle with antibodies to voltage gated potassium channels. AB - Antibodies to potassium channels (VGKC-Ab) were first associated with acquired neuromyotonia and its variant with CNS involvement, Morvan's syndrome. Recently, VGKC-Ab were found in patients with non-paraneoplastic limbic encephalitis (LE), characterised by personality changes, seizures and memory impairment. These patients may respond to immunotherapies. Thus the association of VGKC-Ab and non paraneoplastic LE established the concept of a potentially reversible autoimmune encephalopathy. We describe a patient with startle syndrome and VGKC-Ab, without neuromyotonia or LE, who responded dramatically to plasma exchange (PE) and immunosuppression, adding to the spectrum of disorders associated with VGKC-Ab. PMID- 21686523 TI - Haemolytic disease of the newborn due to anti-c. AB - Anti-D isoimmunisation remains the most common cause of erythroblastosis fetalis. Whereas most clinically significant blood group sensitisations noted during pregnancy are still secondary to anti-D incompatibility, sensitisation to antigens other than D in the CDE system is not uncommon and can cause severe disease. The widespread use of Rh-D immune globulin has led to a relative increase in the importance of non-Rh-D isoimmunisation as a cause of haemolytic disease of the newborn. We report the case of a baby with severe hyperbilirubinaemia and persistent anaemia due to anti-c isoimmunisation with a high-titre maternal c antibody. The baby required emergency transfusion and intensive phototherapy. The medical literature relating to maternal c isoimmunisation and neonatal outcome is also reviewed. Because of its ability to cause clinically significant haemolytic disease of the newborn, practitioners must manage anti-c isoimmunisation in a manner similar to that for anti-D. PMID- 21686524 TI - Triple A syndrome: two novel mutations in the AAAS gene. AB - Triple A syndrome is a rare disease of autosomal recessive inheritance. It was first described in 1978. The typical triad includes adrenocorticotrophic-hormone resistant glucocorticoid insufficiency, reduced or absent tearing (alacrima) and achalasia. But clinical symptoms can be extremely heterogeneous and of variable clinically expression. This report describes a 7-year-old boy with a 1 year history of fatigue and muscle weakness. Physical examination showed skin and mucosal hyperpigmentation, and hormonal analysis revealed isolated glucocorticoid function. Medical history was marked by megaoesophagus and achalasia. The absence of tears when crying had been noted since birth. In the presence of the classical triad, triple A syndrome was diagnosed. Clinical diagnosis was confirmed by molecular analysis of the AAAS gene on chromosome 12q13. The novel compound heterozygous mutation c.1304delA and c.1292-1294delTTCinsA was found. PMID- 21686525 TI - Coronary thrombosis: In vivo, ex vivo and in vitro. AB - Acute stent thrombosis remains one of the most important concerns in clinical cardiology. The mechanism is not fully understood but a prothrombotic state is a key component. We describe a case of acute stent thrombosis, within an hour of rescue angioplasty, despite use of full dose fibrinolytic (reteplase) and antiplatelet therapy (aspirin and clopidogrel). Risk of acute stent thrombosis was predicted an hour earlier, when the patient was clinically well, by a novel near-patient test of thrombotic and thrombolytic status (in vitro). Subsequent stent thrombosis was visualised angiographically (in vivo) and confirmed by extraction of the thrombus (ex vivo). The near-patient test sensitively detected reversal of the prothrombotic state after abciximab treatment. We believe this is the first description of the clinical use of a near-patient test within the cardiac catheterisation laboratory to predict risk of imminent stent thrombosis. PMID- 21686526 TI - Rapidly lethal metastatic melanoma arising from a large congenital melanocytic naevus. AB - A case of fatal metastatic melanoma arising from a very large congenital melanocytic naevus (VLCMN) is reported. Large congenital naevi (LCMN) are naevi >20 cm in diameter. VLCMN is used in this report to mean an extensive LCMN involving a large percentage of the body, including smaller so-called satellite naevi. A 19-year-old man with a large congenital melanocytic naevus (LCMN) presented with a new nodule on the left chest wall, which was diagnosed as a thick melanoma with synchronous axillary lymph-node metastasis. The patient developed widespread distant metastasis within weeks after surgical resection of the primary site and lymph-node basin, which was unresponsive to systemic chemotherapy and whole brain radiation therapy, and he died 7 months after diagnosis of the primary melanoma. PMID- 21686527 TI - Combination treatment of intravenous immunoglobulin and cultivated oral mucosal epithelial transplantation for ocular cicatricial pemphigoid. AB - Ocular cicatricial pemphigoid (OCP) is a progressive cicatrising autoimmune disease affecting the skin and mucous membranes, including ocular surface epithelia. Although systemic immunosuppression is advocated, both progression of ocular surface inflammation and systemic side effects remain a problem. For the treatment of an active OCP, both control of autoimmune reaction and ocular surface reconstruction are necessary. We believe that the combination of intravenous immunoglobulin (IVIg) and cultivated oral mucosal epithelial transplantation (COMET) is a powerful treatment modality while minimising the risk of postoperative consequences inevitably associated with immunosuppression. A patient with OCP successfully treated by a combination of IVIg and COMET is described here. PMID- 21686528 TI - Epilepsy and cerebellar ataxia associated with anti-glutamic acid decarboxylase antibodies. AB - Anti-glutamic acid decarboxylase (GAD) antibodies are described in stiff-person syndrome and also in other neurological syndromes, including cerebellar ataxia and epilepsy. This paper reports the case of a patient who had chronic focal epilepsy, upbeat nystagmus and cerebellar ataxia, associated with a polyautoimmune response including anti-GAD antibodies. Both gait and nystagmus improved markedly after immunosuppressive treatment with corticosteroids and azathioprine. After the introduction of benzodiazepines, previously refractory seizures were completely controlled. Anti-GAD antibodies should be actively sought out in pharmacoresistant epilepsy, particularly if other neurological abnormalities are present. Combined treatment with immunosuppressants and gammahydroxybutyric acidergic agents may be highly effective. PMID- 21686529 TI - Rapidly progressive cryptogenic organising pneumonia presenting as a lung mass. AB - A very rare case of a rapidly progressive variant of cryptogenic organising pneumonia (COP) presenting as a focal mass-like lesion with compression of the large airways leading to respiratory failure is described. A 60-year-old lady presented to the Aga Khan University Hospital Emergency Department in hypoxaemic respiratory failure with a 6-day history of dyspnoea, productive cough and fever. Chest x ray showed a right upper lobe mass-like lesion compressing the large airways and right pleural effusion. She deteriorated in the Emergency Department and was intubated due to worsening hypoxaemic respiratory failure. The pleural fluid and bronchoscopic specimens were negative on microbiological and cytological examination. CT-guided right lung biopsy revealed chronic non specific inflammation without granuloma and malignancy. COP was diagnosed on video-assisted thoracoscopic (VATS) lung biopsy. She was successfully treated with high dose steroids and discharged in a stable condition; her 3-month follow up chest x rays showed complete resolution of the lung lesion with some residual fibrosis. PMID- 21686530 TI - Pleural effusion: what lies underneath? AB - Malignant mesothelioma is a tumour of serous surfaces mainly arising at the pleura or the peritoneum. The diagnosis encompasses multiple problems as there is no pathognomonic hallmark for the disease, there are multiple histological types and the differentiation from other tumours, such as adenocarcinoma or metastatic pleural disease, can represent quite a challenge. Usually a diagnosis of malignant mesothelioma carries a dismal prognosis with scarce therapeutical options.The present report concerns a patient with a diagnosis of malignant pleural mesothelioma with endobronchial extension. Biopsy specimens were obtained through fibreoptic bronchoscopy and blind needle pleural biopsy. The final diagnosis was only possible after careful histological evaluation with a combination of immunohistochemical markers. PMID- 21686531 TI - The management of metastatic hepatic germ cell tumour in a young woman: case report and literature review. AB - Germ cell tumours (GCTs) have an excellent prognosis but rarely arise from the liver. Our case describes a young woman referred for urgent radiotherapy for a bone metastasis. There was also a large lesion in the liver and marked elevation of the serum alpha-fetoprotein (AFP) level. Liver biopsy indicated a germ cell tumour. Reduced intensity chemotherapy was commenced using the combination of etoposide, cisplatin and paclitaxel. After four cycles the AFP values had fallen, the liver function tests had normalised and the previous bone lesions had healed. The predominant lesion in the liver had also regressed. Hepatocellular carcinoma (HCC) is the main differential diagnosis. Hepatic germ cell tumours predominantly occur in young, healthy women whereas hepatocellular carcinoma occurs in cirrhotic male livers. These two malignancies are very different and accurate diagnosis is essential. Diagnosing this rare condition early allows the delivery of effective therapy and a better outcome. PMID- 21686532 TI - Not the typical winter cough. AB - We report on a young adult with a foreign body lodged in the right main bronchus for at least 5 days, with no alleged recollection of aspiration despite the size and shape of the object, which was removed successfully by rigid bronchoscopy. PMID- 21686533 TI - Spinal claudication due to myxopapillary ependymoma. AB - Spinal, also called neurogenic, claudication is common, and in the elderly it is almost invariably caused by degenerative disease of the lumbar spine. There are, however, a few rare but important other causes that should be considered, as in this case. PMID- 21686534 TI - Fatal pulmonary Mycobacterium xenopi in a patient with rheumatoid arthritis receiving etanercept. AB - In this case study, a 71 year old man with emphysema and severe rheumatoid arthritis, previously treated with a TNFalpha receptor antagonist, presented with progressive dyspnoea and weight loss. Thoracic imaging revealed extensive destruction of the left lung and this was associated with positive Mycobacterium xenopi cultures from respiratory samples. Anti-mycobacterial chemoptherapy was poorly tolerated and the patient subsequently died from respiratory failure and generalised wasting. PMID- 21686536 TI - Capecitabine induced acute coronary syndrome. AB - Capecitabine is an oral chemotherapeutic agent recommended by the National Institute for Clinical Excellence as first line treatment for metastatic bowel cancer and second line for breast cancer. With the increasing prevalence and diagnosis of these common malignancies, it is essential that physicians are made aware of the rare, but potentially fatal, cardiac effects of capecitabine. This case report demonstrates a typical presentation of suspected acute coronary syndrome with associated ECG changes in a patient who had started capecitabine 2 days before admission. His troponin was mildly elevated and his ECGs resolved on discontinuation of the drug, but a positive exercise tolerance test precipitated coronary angiography; which was essentially normal, as was his echocardiogram and computed tomography scan. Previous literature has highlighted potential cardiac complications of a similar chemotherapeutic agent 5-fluorouracil, which is the active metabolite present in capecitabine. The possible presentations, complications and clinical management are discussed in this case report. PMID- 21686535 TI - Tennis ranking related to exercise capacity. AB - This is the first 7-year prospective case report on the relationship between VO(2)max during preparation and the following year's entry ranking for a top athlete. The strong relationship between VO(2)max and the following year's ATP entry ranking over time underlines the importance of the preseason training period to optimise cardiorespiratory capacity. The current findings emphasise the relevance and predictive value of continuous performance tests and the need for more elaborate and longitudinal tracking study designs, as well as regression models that include playing style as a covariate. PMID- 21686537 TI - Use of transoesophageal echocardiography in the diagnosis of pulmonary arterio venous malformations. PMID- 21686538 TI - An unusual cause of obstructive jaundice. AB - An 80-year-old Caucasian woman presented with a 3-week history of painless jaundice, pruritis, dark urine and weight loss. Blood analysis demonstrated an obstructive jaundice pattern. A CT scan demonstrated a gas-filled duodenal diverticulum arising from the second part of the duodenum. Once food material was cleared from the diverticulum endoscopically, there was clinical and biochemical improvement. This case demonstrates an unusual cause of obstructive jaundice that has seldom been reported in the literature; once impacted food material was removed from the diverticulum, there was radiological improvement of the patient's condition. PMID- 21686539 TI - Antipsychotic-drug-induced dilated cardiomyopathy. AB - A man in his 30s presented with symptoms of shortness of breath (SOB). He was on clozapine for schizophrenic symptoms. From the initial two presentations it was thought to be and managed as a chest infection, and a perfusion ventilation scan was done to rule out pulmonary embolism. However, with worsening SOB on exertion, he presented for a third time, and was referred and seen in the Department of Medicine on this occasion. The ECG showed evidence of left atrial and ventricular enlargement. The chest x ray showed an increased cardiothoracic ratio. An urgent echocardiogram showed the presence of dilated cardiomyopathy with severe left ventricular systolic function impairment. The patient had a coronary angiogram and other relevant investigations to look for the cause of the dilated cardiomyopathy. These investigations did not reveal any significant abnormality. The cause appeared to be related to the drug clozapine. The patient was treated for heart failure, and clozapine was stopped. He improved and repeat echocardiogram at follow-up showed a definite improvement in the symptoms and the echocardiogram. PMID- 21686540 TI - Iatrogenic gastric tear. PMID- 21686541 TI - Consumption of cannabis and cocaine: correct mix for arterial occlusions. AB - We present a case of a young Afro-Caribbean man who presented with sudden unilateral loss of vision due to central retinal artery occlusion. He was a cocaine and cannabis abuser for 6 years. Acute central retinal artery occlusion at such a young age is unusual. We discuss the possible pathogenesis and treatment options for acute retinal artery occlusion, due to suspected cocaine and cannabis abuse, and present our experience of its management. PMID- 21686542 TI - Cardiac tamponade caused by epithelioid haemangioendothelioma. AB - Epithelioid haemangioendothelioma (EHE) is a tumour of vascular endothelial origin. The rarity of EHE has limited the complete understanding of the disease. Here, a unique case of EHE complicated with cardiac tamponade with an unusual initial presentation, scoliosis, is reported. The discordant findings between a Tc99m bone scan and 2-fluoro-2-deoxy-d-glucose positron emission tomography (FDP PET) also serve to impart another lesson about investigating bone metastasis in EHE. PMID- 21686543 TI - Gastric lipoma: a rare cause of iron-deficiency anaemia. AB - A 60-year-old man presented with asymptomatic iron deficiency anaemia. Gastroscopy revealed a large submucosal mass involving the antrum and duodenal bulb with a deep ulcer in the gastric component. Computed tomography scan showed the lesion to be a rare gastric lipoma. PMID- 21686544 TI - Moebius-Poland syndrome and drug associations. PMID- 21686545 TI - Severe varicella infection occurring after herpes zoster reactivation in a patient with AIDS. AB - Herpes zoster reactivation occurs in patients who had primary varicella infection, afflicting mainly the elderly and the immunocompromised. However, it is rare that varicella infection develop after zoster reactivation. We report on a patient with underlying HIV/AIDS who had two previous episodes of herpes zoster and still developed varicella infection, complicated by pneumonitis and polyradiculitis. We also review the relevant literature. PMID- 21686546 TI - Recurrent sterile abscesses following aluminium adjuvant-containing vaccines. AB - Abscess formation following immunisation is a previously reported complication, generally associated with microbial contamination of the vaccine. Less commonly, such abscesses have been sterile. Here we describe two children evaluated in the Center for Disease Control and Prevention (CDC)-funded Clinical Immunization Safety Assessment (CISA) network who developed recurrent sterile abscesses after administration of vaccines containing aluminium adjuvant, either individually or in combination. Although the abscesses healed without sequelae, these occurrences support an association between receipt of aluminium adjuvant and sterile abscesses in susceptible patients. For patients with similar symptoms, clinicians may wish to choose a vaccine formulation containing the least amount of aluminium adjuvant. PMID- 21686547 TI - Cardiopulmonary arrest caused by acute abdominal aortic thrombosis: a case report. AB - Acute abdominal aortic thrombosis is a rare but potentially fatal condition. The patient was a 56-year-old man who developed lower back pain and arrived at our emergency room in a state of shock. He was alert, but could not move his legs. Cardiac echo revealed abnormal movement of the heart, and acute myocardial ischaemia was suspected as a differential diagnosis. Emergency coronary angiography and aortography together with percutaneous cardiopulmonary support were attempted. Both femoral arteries were punctured, but the guide wire could not be advanced from the bifurcation to the aorta. Heart stoppage occurred and lifesaving treatment was ineffective. A large thrombus from the abdominal aorta to both common iliac arteries was observed by aortography. To reduce mortality in acute abdominal aortic thrombosis, the disease must be recognised early based on clinical symptoms, followed by immediate contrast CT and surgical management by thrombectomy or re-establishment of the blood circulation. PMID- 21686548 TI - Central hypoventilation with PHOX2B expansion mutation presenting in adulthood. AB - The case history is described of a 41 year old male who presented with acute-on chronic respiratory failure due to PHOX2B mutation-associated central hypoventilation with a quantified impaired response to hypercapnia. He was successfully treated with non-invasive ventilation, which has been continued nocturnally at home. PMID- 21686549 TI - A novel phenotype of sporadic Creutzfeldt-Jakob disease. AB - An atypical case of sporadic Creutzfeldt-Jakob disease (CJD) is described in a 78 year-old woman homozygous for methionine at codon 129 of the prion protein (PrP) gene. The neuropathological signature was the presence of PrP immunoreactive plaque-like deposits in the cerebral cortex, striatum and thalamus. Western blot analysis showed a profile of the pathological form of PrP (PrP(Sc)) previously unrecognised in sporadic CJD, marked by the absence of diglycosylated protease resistant species. These features define a novel neuropathological and molecular CJD phenotype. PMID- 21686550 TI - Atypical erythema nodosum in atypical tuberculosis presentation. AB - Erythema nodosum (EN) is an inflammatory disease of the skin and subcutaneous tissue that may be found in association with many systemic diseases such as infectious diseases, sarcoidosis, Behcet disease, inflammatory bowel diseases and tumours, in particular lymphoma. EN may be also induced by some drugs, including mainly estroprogestinics, salicylic acid, minocycline and sulfamidic acid. Due to the numerous possible causes, sometimes it may be very difficult to achieve a correct diagnostic interpretation, especially when an isolated EN represents the revealing feature, as in the following case. We describe the case of a patient, of young age and good clinical condition, who developed EN during the course of abdominal tuberculosis. The diagnosis was obtained by histologic examination of the abdominal formation since positron emission tomography and total body axial tomography were not useful in discriminating EN from malignancies. PMID- 21686551 TI - Skin reactions after intramuscular injection of Botulinum toxin A: a rare side effect. AB - The use of Botulinum toxin as a treatment for dystonia and other neurological conditions has been rapidly increasing over the past decade. In general, idiosyncratic adverse reactions to repeated injections of Botulinum toxin seem to be rare and were described in only a few recent reports. We present two cases of substantial skin reactions, one with systemic involvement, after intramuscular application of Botulinum toxin A. The possible role of immunologic factors and other mechanisms such as intolerance and pseudoallergic reaction are discussed. We would like to alert the clinician to this rare, but occasionally serious side effect that may be underestimated. PMID- 21686552 TI - Immediate post-parathyroidectomy stridor resolved with intravenous calcium. AB - A 73-year-old woman underwent an uncomplicated focused parathyroidectomy for an adenoma. Immediately after extubation she developed respiratory distress and her airway became compromised. No obvious cause could be found for the stridor and no response was obtained from nebulised adrenaline (norepinephrine). An intravenous bolus of calcium provided immediate but temporary relief. Lasting relief was obtained following the administration of an intravenous calcium infusion. Serology later confirmed a small decrease in calcium concentrations but at the time of the respiratory compromise the values were still within normal range. PMID- 21686554 TI - Accidental mobile phone card ingestion. AB - Accidental overdose, poisoning and foreign-body ingestion are common presentations to the emergency department. Usually, the ingested material is a common drug or household product. We present an unusual case of accidental ingestion where the foreign body was a mobile phone simulation (SIM) card. PMID- 21686553 TI - Transient global amnesia caused by painless aortic dissection. AB - Neurological syndromes secondary to acute aortic dissection (AAD) are uncommon and usually consist of focal deficits after an embolic cerebral infarction. This article reports the observation of an AAD with the chief complaint of transient acute memory impairment-that is, a non-usual stroke-like symptom. PMID- 21686555 TI - Successful repeated treatment with high dose cyclophosphamide and autologous blood stem cell transplantation in CIDP. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterised by the occurrence of symmetrical weakness and sensory impairment in arms and legs. The course is relapsing or chronic and progressing. CIDP is considered to be an autoimmune disease, which is supported by the beneficial response to immunomodulating therapies in most patients. We report on a patient with CIDP who has been in remission for more than 3 years after treatment with high dose cyclophosphamide and autologous blood stem cell transplantation in CIDP on two occasions. PMID- 21686556 TI - Herb-related aneuploidy in breast fibroadenoma. AB - There is consensus that attitudes toward seeking complementary and alternative medicine (CAM) are different between oriental and western patients. A 16-year-old girl who presented with enlarged breast tumours also had a 3-year history of "Si Wu-Tang" (SWT) intake. Pathology of the resected breast tumour disclosed a giant fibroadenoma with aneuploid status. A cohort study was conducted between two groups of patients with fibroadenomas: SWT intake (+) group and SWT intake (-) group. Patients were told to discontinue SWT intake for 3 months, and this was followed by breast ultrasonographic examination in both groups. The tumour sizes before and after discontinued SWT intake were 2.3+/-0.11 cm and 1.5+/-0.12 cm in the SWT (+) group, and 1.7+/-0.15 cm and 1.6+/-0.14 cm in SWT (-) group, respectively (p<0.05). It is concluded that this report provides important information for patients with breast tissue diseases and that continuous intake of medicinal herbs is recommended only under the guidance of trained CAM providers. PMID- 21686557 TI - Idiopathic necrotising fasciitis. PMID- 21686558 TI - Thrombotic thrombocytopenic purpura following zoledronic acid infusion with a fatal outcome. AB - A 56-year-old woman presented with generalised bone pain with bone mineral density showing severe osteoporosis for which she received a single 4 mg infusion of zoledronic acid (ZA). On the second day following the infusion, she developed fever with altered sensorium. A complete blood count showed anaemia and thrombocytopenia with peripheral blood smear repeatedly showing schistocytes, anisopoikilocytes and target cells. Serum biochemistry revealed elevation of serum creatinine at 1.5 mg/dl. In view of microangiopathic haemolytic anaemia, fever, renal insufficiency, neurological abnormality and thrombocytopenia, the patient was presumed to have developed thrombotic thrombocytopenic purpura (TTP). Accordingly, a combination therapy with glucocorticoids and fresh frozen plasma transfusion was begun pending plasmapharesis. She manifested a fluctuating level of mental status with progressive purpuric and ecchymotic lesions and she sustained cardiorespiratory arrest from which she could not be revived. The temporal sequence of events following ZA infusion with typical manifestations of TTP strongly suggests ZA as the most probable cause of her fatal TTP. PMID- 21686559 TI - Fulminant adult-onset subacute sclerosing panencephalitis: a case report. AB - We present the case of a young adult who developed acute encephalopathy with severe status epilepticus and rapid deterioration to vegetative state and death within 6 weeks. Although the clinical picture, MRI and EEG findings were atypical, the hypothesis of subacute sclerosing panencephalitis (SSPE) was suggested by markedly increased intrathecal IgG synthesis in the cerebrospinal fluid, and diagnosis was confirmed by the presence of high antimeasles antibodies in cerebrospinal fluid and brain biopsy findings. Acute SSPE is an exceptionally rare and little-known form of SSPE with protean symptomatology, and this case is to our knowledge the first observation of SSPE presenting with status epilepticus in adults. Our case reinforces the need to include, even in developed countries, SSPE as a diagnostic possibility in unexplained acute encephalopathies. PMID- 21686560 TI - A dilemma solved. AB - A 63-year-old woman with severe symptomatic postural hypotension was treated unsuccessfully, and no underlying cause was found for 3 years until she was noted to have hypoalbuminaemia and proteinuria. A renal biopsy led to the diagnosis of amyloidosis. Despite being an established cause for autonomic neuropathy, amyloidosis was not suspected early enough. Although a diagnosis was reached and treatment started, the patient died as a complication of chemotherapy. PMID- 21686561 TI - Pulmonary alveolar microlithiasis. PMID- 21686562 TI - Internet diagnosis of digitalis toxicity. AB - A 65-year-old male with an ischaemic cardiomyopathy and an implantable cardioverter defibrillator got a shock at home. A web-based monitoring system was used to check his device, and the interrogation showed that he had had several episodes of ventricular fibrillation and new onset of complete heart block that required back-up pacing by his defibrillator. The combination of enhanced automaticity (frequent premature ventricular complexes and ventricular arrhythmias) and impaired conduction (heart block) are the hallmarks of digitalis toxicity. Paramedics were called and the patient was brought to the emergency room where he was confirmed to have digitalis toxicity and was quickly treated with digoxin-specific Fab antibody fragments. Web-based monitoring systems helped in the diagnosis of this potentially lethal drug toxicity. PMID- 21686563 TI - Syndrome of pleural and retrosternal "bridging" fibrosis and retroperitoneal fibrosis in patients with asbestos exposure. AB - Two case histories are described of pleural and anterior mediastinal fibrosis presenting as a continuous fibrotic process with thick parietal pleural plaques extending from one pleura to the contralateral pleura through the retrosternal area, and with retroperitoneal fibrosis. Follow-up over 4 years in one case demonstrated rapid progression of disease, with pleural fibrosis preceding retrosternal and retroperitoneal fibrosis. Histopathological analysis in both cases showed non-tumoral fibrosis with broad fibrous bundles surrounding fibroblasts (and lymphocytes in one case). Possible causes such as infections and exposure to ergot derivatives were excluded. Both patients had been slightly or moderately exposed to asbestos. PMID- 21686564 TI - Lambert-Eaton myasthenic syndrome. AB - Lambert-Eaton myasthenic syndrome is a disorder of neuromuscular transmission in which an autoantibody is directed against the pre-synaptic calcium channel. It presents with proximal limb weakness, greater in the legs, with or without peripheral and autonomic neuropathy. Bulbar involvement is rare and fatigueability is not a feature. PMID- 21686565 TI - Acute hepatitis induced by glatiramer acetate. AB - Glatiramer acetate, a mixture of synthetic polypeptides able to prevent autoimmune encephalomyelitis in experimental models, is used as a treatment for patients with active relapsing-remitting multiple sclerosis. We report one case of glatiramer acetate induced hepatitis. Liver biopsy was consistent with a diagnosis of drug induced hepatitis and alanine aminotransferase returned to normal values after treatment discontinuation. The present case should serve as a warning that glatiramer acetate may cause acute liver disease. PMID- 21686566 TI - Goltz syndrome: report of two severe cases. AB - Goltz syndrome is a rare, X-linked dominant congenital disorder with abnormalities in derivatives of each of the three embryonic germ layers. Its clinical phenotype varies widely, ranging from isolated skin defects to absence of limbs and/or organs. The rarity and wide range of presentation contribute to delayed or missed diagnosis. PMID- 21686567 TI - Asymptomatic presentation of mesalamine-induced lung injury in an adolescent with Crohn disease. AB - The present report describes the case of a 14-year-old boy receiving mesalamine for Crohn disease who was discovered to have incidental pulmonary infiltrates on chest radiograph and CT scan shortly after increasing the dose of this medication. Despite the significant radiographic abnormalities, he had no respiratory symptoms. He had normal oxygenation and normal pulmonary function tests including spirometry, lung volumes and diffusion capacity. Transbronchial biopsies showed patchy interstitial fibrosis with ill-defined non-necrotising granulomas and lymphoid aggregates. Pulmonary infiltrates resolved within 6 weeks of discontinuation of mesalamine and the addition of low-dose daily corticosteroids. This case likely represents an asymptomatic "early stage" of mesalamine-induced lung injury preceding the onset of symptoms. Alternatively, mesalamine may induce asymptomatic lung injury more commonly than is presently suspected. To the best of our knowledge this is the first time this complication has been reported without respiratory symptoms. PMID- 21686568 TI - Secondary bronchiolitis obliterans organising pneumonia in a patient with carbamazepine-induced hypogammaglobulinaemia. AB - Here we describe a case of a secondary bronchiolitis obliterans organizing pneumonia (BOOP), which was associated with repeated respiratory infections caused by carbamazepine (CBZ)- induced hypogammaglobulinaemia. A 49-year-old woman had been treated with CBZ (400 mg/day). Two and a half years later, she developed of dyspnea with productive cough and high-grade fever. Chest roentgenogram and computed tomography showed bilateral infiltrates in lower lung fields. Her laboratory findings revealed severe hypogammaglobulinaemia, suggesting that an immune system disorder caused pulmonary infection. Histological examination by trans-bronchial lung biopsy (TBLB) demonstrated that many foamed alveolar macrophages were obstructing the alveolar ducts and adjacent alveoli, suggesting BOOP. After cessation of CBZ, the hypogammaglobulinaemia and chest roentgenogram findings markedly improved. The present case suggests that CBZ may have some adverse effects on the immune system and cause frequent airway infections, and that secondary BOOP could be induced by repeated infections caused by CBZ-induced hypogammaglobulinaemia. PMID- 21686569 TI - Localised retinal vasculitis in cat scratch disease. AB - We report an atypical presentation of ocular cat scratch disease (CSD) in an 8 year-old Caucasian male who presented with localised retinal arterial vasculitis and associated retinal oedema. His history of headaches, frequent contact with a kitten and a high Bartonella henslelae titre confirmed the diagnosis of CSD. Over an 18-month follow-up period, his best corrected visual acuity in the affected eye improved from 20/30-2 to 20/25+3 without treatment; however, the affected retinal artery remained sheathed. PMID- 21686570 TI - MRI features of pleural endometriosis after catamenial haemothorax. AB - A 43-year-old multiparous woman with a history of pelvic endometriosis and myocardial infarction presented with acute onset of right hemithorax pain and dyspnoea coinciding with dysmenorrhoeic menstruation. A chest CT confirmed the presence of a right hydropneumothorax which was drained. A video-assisted thoracoscopy was unremarkable but at a subsequent menses, an MRI chest demonstrated a lesion in the right costophrenic angle. The patient underwent a hysterectomy and oophorectomy for treatment of endometriosis. Six months later, she was free of thoracic symptoms and a repeat MRI scan showed resolution of the right pleural abnormality. PMID- 21686571 TI - Pituitary apoplexy can mimic subarachnoid haemorrhage clinically and radiologically. AB - Pituitary apoplexy is when there is acute haemorrhage into a pituitary adenoma. It presents with headache and altered consciousness with loss of pituitary function. Many cases have bitemporal hemianopia. Subarachnoid haemorrhage is in the differential diagnosis, but does not cause a similar visual field defect. Magnetic resonance imaging is required to diagnose the pituitary tumour. An elderly man who presented with acute headache, and who was initially diagnosed with subarachnoid haemorrhage but re-presented with features of pituitary apoplexy, is described. PMID- 21686572 TI - Hereditary multiple exostosis in two Nigerian siblings. AB - Two siblings of an achondroplastic father with radiological features of hereditary multiple exostoses are presented. This condition is rarely reported and there are few reports among black Africans. These two cases are reported to heighten the index of suspicion in diagnosis. PMID- 21686573 TI - The "fish-vertebra" sign. AB - The "fish-vertebra" sign appears as biconcave lumbar vertebrae with bone softening in lateral and posterior-anterior radiographs of the spine as an exaggeration of the normal concavity of the superior and inferior surfaces of one or more vertebral bodies. This is due to ischaemia of the central growth plate of the spine, and is typically seen in sickle cell disease. PMID- 21686574 TI - Primary leiomyoma of the liver: accurate preoperative diagnosis on liver biopsy. AB - Primary leiomyoma of the liver is an exceptionally rare tumour in non immunocompromised patients. Preoperative diagnosis of the lesion is difficult as complete imaging of this type of lesion is scarcely defined and preoperative biopsy was not the practice in previously reported cases. We report a voluminous primary leiomyoma of the liver occurring in a healthy middle-aged woman where a preoperative diagnosis was accurately achieved on biopsy. Because of its size, surgery was undertaken for exclusion of malignancy. A 16-month uneventful follow up has been completed. We discuss the advantage of a preoperative diagnosis and propose that an imaging-guided liver biopsy should be undertaken, provided malignancy features are absent. This could prevent liver surgery merely for diagnostic purposes. Finally, we report imaging features that have not been previously described, namely on magnetic resonance imaging, which may provide an insight about the nature of this particular lesion and, advantageously, contribute toward a non-invasive diagnosis. PMID- 21686575 TI - An elderly woman with Prevotella bacteraemia secondary to pyometra. AB - An 87-year-old woman was admitted to our hospital with sepsis and foetid vaginal discharge. She presented an abdominal mass that had been present for the last 20 years, refused diagnostic or therapeutic procedures. A computed tomography scan detected a uterine body with multiple calcifications and an internal collection of 10 cm. No other infectious sources were apparent. A tentative diagnostic of pyometra was made and empiric antibiotic treatment was initiated. A hysteroscopy was performed with incomplete drainage of purulent material, due to important vaginal atrophy. In both blood and vaginal fluid cultures Prevotella spp. was isolated. Clinical evolution was favourable with metronidazole. The patient refused a hysterectomy or other surgical drainages, and she was discharged from hospital with oral antibiotics. The patient underwent antibiotic therapy during 1 month; 1 week after finishing this treatment, the patient died. The characteristics of clinical evolution in these last days were not known. PMID- 21686576 TI - Trichotillomania: a cry for help. PMID- 21686577 TI - Benign endoscopic biopsies may be a red herring. AB - A 64-year-old man presented with haematemesis and melena. Repeated endoscopies showed extensive candidiasis with an exophytic mass like a shelf of tumour. Biopsies showed chronic inflammatory changes with candidiasis without evidence of malignancy. His only complaint was feeling tired and loss of energy. There was no dysphagia but slight retrostenal discomfort on swallowing. Computed tomography scan reported an opacification in the right upper lobe adjacent to the mediastinum. This contained air bronchograms and several irregular air filled cavities. There was significant mediastinal adenopathy. Two endoscopies were done after that and both of them demonstrated a fistulous connection with the bronchial tree. Biopsies failed to show any neoplasm. The patient underwent a three stage oesophagectomy with removal of the adjacent lung lobe and a reconstructive procedure. The resected mass was sent for histopathology which showed a well differentiated squamous cell carcinoma of the oesophagus which locally invaded the lung. PMID- 21686578 TI - A patient with Legionnaires' disease transferred after a traffic accident. AB - Legionnaires' disease (LD) ranks among the three most common causes of severe pneumonia, but is often not specifically diagnosed. Among patients with LD, 40% to 50% of the patients develop neuromuscular signs and symptoms. A patient with LD transferred to our department after a traffic accident. When the patient arrived at our hospital, his respiratory rate was 27 breaths per min. His pulse was 148 beats per min and blood pressure was 116/57 mm Hg. Temperature was 39.6 degrees C. He had copious watery diarrhoea and had been diagnosed as having acute gastroenteritis. The patient had urinary incontinence, gait disturbance, mild headache, fatigue and excessive decrease in spontaneous speech. A urinary antigen test for Legionella pneumophila turned out to be positive. LD commonly involves the neuromuscular system. Although this may be an atypical case of LD, it implies the need for awareness of LD. PMID- 21686579 TI - Isochromosome 9q as a sole anomaly in an Omani boy with acute lymphoblastic leukaemia. AB - This report describes a case of acute lymphoblastic leukaemia in which isochromosome 9q (i(9q)) was the sole acquired cytogenetic abnormality. The Immunophenotype showed positivity for CD3, CD4, CD5, CD7, CD8, CD10, CD71, CD117 and TdT, consistent with T cell acute lymphoblastic leukaemia (ALL). The chromosomal analysis of bone marrow showed 46,XY,i(9)(q10) in all the metaphases analysed. The bone marrow morphology was ALL-L2 as per the French-American British criteria. Isochromosomes are rare chromosomal abnormalities in childhood ALL and the effect of i(9q) is not well established. The patient's good response to therapy with normal cytogenetics within a month of induction, and disease-free survival after bone marrow transplant are indicative of a good prognosis in such cases. PMID- 21686580 TI - Severe upper airway obstruction in a preterm infant with nasal continuous positive airway pressure. PMID- 21686581 TI - Bilateral pulmonary alveolar infiltrate and prostate tumour in a 54-year-old man. AB - THIS CASE STUDY DESCRIBES THE ASSOCIATION BETWEEN TWO RARE ENTITIES: pulmonary alveolar proteinosis (PAP) and embryonic rhabdomyosarcoma of the prostate in a 54 year old male presenting with pulmonary symptoms and obstructive urinary symptoms. The prostate tumour was treated with a radical cystectomy and adjuvant chemotherapy and radiotherapy. The patient did not wish to have treatment for his pulmonary disease and died 1 year after surgery as a result of intra-abdominal spread of the neoplasm. PMID- 21686582 TI - Drug extravasation: a dreaded complication. AB - A 62-year-old man diagnosed with a stage I lung adenocarcinoma was treated by an upper right lobectomy. Eighteen months later an elevation of carcinoembryoinc antigen (CEA) was detected, and CT tomography revealed a stage IV disease. Chemotherapy including cisplatin (Platinol) and docetaxel (Taxotere) was administered. He presented 12 days after receiving an intravenous infusion because he noticed a burning sensation, erythema and blisters at the site of the last infusion and proximal to that area. On physical examination he had a 9*4.5 cm swollen area of erythema and multiple blisters. The diagnosis of delayed and distant docetaxel extravasation was made. The treatment consisted of normal saline washes, topical hydrocortisone and antibiotic-based ointment which produced relief of the symptoms. This reaction resolved over the next 6 weeks, leaving two areas of brownish pigmentation of the skin as the only sequelae. PMID- 21686583 TI - Broken bioabsorbable femoral cross-pin as a cause of a chondral lesion after anterior cruciate ligament reconstruction. AB - We present a case of a chondral lesion after anterior cruciate ligament (ACL) reconstruction caused by femoral cross-pin breakage and intra-articular migration of the fragment. A 20-year-old man initially underwent ACL reconstruction using a hamstring autograft. The RigidFix bioabsorbable cross-pin (DePuy Mitek) was used for the femoral fixation. The patient returned to a pre-injury level of activity (professional soccer player) 6 months postoperatively. However, 20 months postoperatively, the patient presented with effusion and lateral joint-line pain after practice, without signs of instability in clinical examination. Conservative treatment failed and at re-arthroscopy a chondral lesion of the lateral femoral and tibial condyle was found, which had been caused by the broken femoral cross-pin. The fragment was removed and the symptoms resolved. Orthopaedic surgeons should be aware of this complication when using a bioabsorbable cross-pin for femoral fixation in ACL reconstruction. PMID- 21686584 TI - Persistent diffuse pulmonary interstitial emphysema mimicking pulmonary emphysema. AB - A 69-year-old male non-smoker with a history of atopic asthma presented with symptoms suggestive of chronic obstructive pulmonary disease and this appeared to be corroborated by lung function testing and a chest radiograph. However, a chest CT showed no evidence of pulmonary emphysema and instead demonstrated free air along the bronchovascular sheaths indicative of pulmonary interstistial emphysema, possibly caused by repeated prior exacerbations of asthma. His lung function tests and symptoms improved within months of being treated for his airways disease but the CT findings were unchanged after 2 years. PMID- 21686585 TI - Calciphylaxis associated with widespread pulmonary calcification. AB - We report a patient with Crohn's disease and end-stage renal failure, which resulted in severe vitamin D deficiency and hyperparathyroidism. This resulted in the development of calciphylaxis, which initially manifested as pulmonary vasculature calcification; however, the diagnosis was not clear until the classic skin lesions had developed. Calciphylaxis is a rare condition, which is increasing in incidence, and a high index of suspicion is essential for early diagnosis and treatment. This condition is associated with a high degree of morbidity and mortality and, indeed, our patient died within 7 days of diagnosis. PMID- 21686586 TI - Doxylamine toxicity: seizure, rhabdomyolysis and false positive urine drug screen for methadone. AB - The present report highlights the possible adverse effects of doxylamine, a common over the counter sleep aid. Doxylamine is an antihistamine that at toxic doses can cause anticholinergic effects, including seizures, rhabdomyolysis and death. The following case describes a patient with doxylamine toxicity who presented with seizure and confusion. Our patient was managed symptomatically, and remained otherwise stable throughout his hospitalisation. This case is atypical in terms of a delayed rhabdomyolysis and a false positive urine drug screen test for methadone. There is evidence that doxylamine at toxic levels can lead to false positives for methadone and phencyclidine testing using immunoassay based urine drug screen kits. Urine drug screen testing on patients who are hospitalised is typically performed using immunoassays. However, in certain cases confirmatory secondary testing may be required. Doxylamine is prone to abuse and knowledge of the clinical presentation of its toxicity and the management of acute overdose can be life-saving. PMID- 21686587 TI - Gefitinib-induced hair alterations. AB - Human epidermal growth factor receptor (EGFR) is an attractive target for anticancer therapy. EGFR tyrosine kinase inhibitors are generally well tolerated and do not have the severe systemic side-effects usually seen with cytotoxic drugs. A specific adverse effect common to this class of agent is a papulopustular rash, usually on the face and upper torso. During prolonged treatment with EGFR inhibitors, changes of the hairs can be noticed. This report describes a rare case of a non-small-cell lung cancer with hair changes after several months of treatment with the EGFR inhibitor gefitinib. The patient's scalp hair grew more slowly and adopted a finer, more brittle and curly aspect. However, the eyelashes, eyebrows and hair of other parts of the face did not display similar changes. Little is known about the aetiology of this kind of hair alteration, and there are no clear evidence-based management recommendations. Histological data indicate that the hair alteration may be caused by EGFR inhibition in skin, although this has not been confirmed. Further studies are needed to investigate the reason for this phenomenon. PMID- 21686588 TI - Keratoconus associated with CSNB1. AB - A 35-year-old man with best corrected visual acuities of -18.00/+10.00*180 (6/60) OD and -10.00/+8.00*5 (6/36) OS. Bilateral steep central corneal thinning, paracentral ectasia and Vogts striae were present; normal fundi. Corneal topography disclosed 7.4 dioptres of irregular astigmatism in the central 3 mm with thinning (335 MUm). Electroretinography (ERG) showed no response. There were no medical or environmental influences for his keratoconus. Occurrence of keratoconus and CSNB in the patient may represent a chance association, but keratoconus has not been previously linked with CSNB1 either as a chance or true association though both show genetic predisposition. PMID- 21686589 TI - Stroke due to a cardiac myxoma. AB - Cardioembolic stroke is an important cause of stroke in young people. Cardioembolism classically causes infarcts in multiple vascular territories. In the case described here a young woman developed cardioembolic stroke secondary to atrial myxoma. The presentation was atypical in that the woman had no systemic manifestations of her myxoma. PMID- 21686590 TI - Deterioration of the liver biochemistry due to reactivation of chronic hepatitis B during etanercept treatment for rheumatoid arthritis. AB - To report a hepatitis B virus (HBV) reactivation during the treatment of etanercept for rheumatoid arthritis (RA).The chronological course of a patient with RA who developed HBV reactivation associated with etanercept treatment was recorded.A Taiwanese woman with RA was treated by etanercept. A severe deterioration of liver biochemistry occurred soon after the start of the biologicals because of the previously unrecognised HBV carrier status. The condition was successfully alleviated by oral lamivudine administration.In the prevalent area of HBV, viral titre monitoring and pre-emptive antiviral treatment may be fundamentally important to avoid serious complications of HBV reactivation whenever a new treatment modality such as biologicals is started for patients with RA. PMID- 21686591 TI - Prolonged use of atosiban and grade IV intraventricular haemorrhage in an infant born at 29 weeks and 4 days. AB - A woman in her second pregnancy (G2P1), with a prior history of preterm birth at 21 weeks, had been using vaginal progesterone suppositories as prophylaxis and presented with cervical shortening and funnelling. At 24 weeks, betamethasone and nifedipine was started because of contractions. At 26 weeks, a new period of preterm contractions emerged and atosiban was added. Attempts were made to stop administration of atosiban, but every time the contractions returned. At 27 weeks the decision was made to continue atosiban and nifedipine until a gestational age of 30 weeks. At 29 weeks and 4 days she went into labour and delivered vaginally after a very short second stage. The baby weighed 1340 g with a 5-minute Apgar score of 8. The infant was admitted to the neonatal intensive care ward. On day 3, a diagnosis was made of grade IV intraventricular haemorrhage. PMID- 21686592 TI - Anomalous origin and aneurysm of the suprascapular artery: the first case observed. AB - A 45-year-old woman was referred to our department having suddenly developed, 9 months earlier, a pulsating mass on the right supraclavicular fossa and torticollis. Colour Doppler sonography and computed tomographic angiography showed the presence of an aneurysm (21 mm in diameter) of the suprascapular artery that had an anomalous origin from the subclavian artery. Thoracic outlet syndrome was excluded. After selective arteriography, the aneurysm of the suprascapular artery was successfully treated with ethylene-vinyl alcohol polymer (Onyx, MicroTherapeutics, Irvine, California, USA), a liquid embolic agent. The patient was discharged on the first postoperative day in good condition. Control colour Doppler sonography at 1 year confirmed the complete thrombosis of the aneurysm sac. PMID- 21686593 TI - Bad gut feeling: ACE inhibitor induced intestinal angioedema. AB - Angiotensin-converting enzyme (ACE) inhibitor treatment was started in a 67-year old woman with arterial hypertension. Two days later she complained of a hoarse, raspy voice and progressive abdominal pain. The laboratory investigation was within normal limits. However, CT scans of the abdomen revealed marked thickening of the proximal jejunum together with substantial fluid accumulation in the abdomen and pelvis. Due to the severity of the symptoms diagnostic laparatomy was considered as a surgical option. Several hours later the patient started to complain about a progressive inspiratory stridor, which resolved after treatment with epinephrine, antihistamines and corticosteroids. ACE inhibitor induced angioedema was suspected and ACE inhibitor treatment was stopped, after which the severe abdominal symptoms also resolved completely. ACE inhibitor induced angioedema is a rare and often unrecognised side effect of ACE inhibitor treatment that physicians need to be aware of in order to avoid unnecessary invasive procedures, including explorative laparatomy. PMID- 21686594 TI - Polydipsia and psychosis in subdural haemorrhage. AB - This report describes the unusual case of a man with chronic mental illness, presenting with polydipsia and psychotic symptoms atypical of his usual episodes of illness. This report is a reminder to all doctors to beware of organic causes of mental illness, not only in new presentations but also in patients well known to services. In particular this is important when unusual symptoms are present. The report includes some discussion of why finding an organic cause in patients with psychiatric illness can pose challenges and demonstrates the need for good communication between professionals in order to best serve patients. It also highlights the importance of appropriate and timely investigations. PMID- 21686595 TI - Tracheo-oesophageal fistula in a patient with oesophageal squamous cell carcinoma. PMID- 21686596 TI - Visual recovery after impalement injury of the orbit by reinforced steel bar. AB - Impalement injuries to the head and neck are quite rare, commonly lethal, and vision threatening when involving the orbit. Here, a case of impalement injury involving a steel bar to the neck and left orbit with full visual recovery is presented. The bar was removed, leaving non-displaced fractures of the floor of the left orbit and ethmoid bone. The disinserted left medial rectus was resutured. The perforated upper eyelid was sutured. The patient ended with mild ptosis. PMID- 21686597 TI - Good outcome after rituximab treatment for a mixed warm and cold autoimmune haemolytic anaemia. AB - Mixed warm and cold autoimmune anaemia is a rare haemolytic anaemia that is commonly associated with lymphoproliferative disorders and autoimmune diseases. Although steroid therapy is the first-line treatment, rituximab represents a good alternative. The present study reports on a successful treatment with rituximab in a young woman suffering from a mixed warm and cold autoimmune haemolytic anaemia associated with a mixed connective tissue disease. PMID- 21686598 TI - Linear scleroderma in a child with diabetes. PMID- 21686599 TI - Disappearance of "phantom limb" and amputated arm usage during dreaming in REM sleep behaviour disorder. AB - Limb amputation is followed, in approximately 90% of patients, by "phantom limb" sensations during wakefulness. When amputated patients dream, however, the phantom limb may be present all the time, part of the time, intermittently or not at all. Such dreaming experiences in amputees have usually been obtained only retrospectively in the morning and, moreover, dreaming is normally associated with muscular atonia so the motor counterpart of the phantom limb experience cannot be observed directly. REM sleep behaviour disorder (RBD), in which muscle atonia is absent during REM sleep and patients act out their dreams, allows a more direct analysis of the "phantom limb" phenomena and their modifications during sleep. PMID- 21686600 TI - A case of lymphoma presenting as splenic infarction. PMID- 21686601 TI - Impaired estimated glomerular filtration rate associated with hypothyroidism. Does it really mean an acute renal failure? AB - A case of a young man with myopathy, elevated serum aminotransferase and serum creatinine levels is presented. He had a polymyositis-like-syndrome caused by hashimoto thyroiditis with hypothyroidism. Thyroid hormone replacement therapy led to improvement in both the clinical and laboratory abnormalities. With the established tests for estimating the glomerular filtration rate we cannot determine if there was really a reversible acute renal failure or not. PMID- 21686602 TI - Can a chronic expanding haematoma mimic a soft tissue sarcoma? AB - A 68-year-old woman presented with a gradually increasing left gluteal swelling that she had first noted 2 years previously. The results of both clinical and radiological examinations were consistent with soft tissue sarcoma, but the final diagnosis after resection was haematoma. PMID- 21686603 TI - New onset psoriasis in a patient receiving abatacept for rheumatoid arthritis. AB - Administration of abatacept is a new treatment modality for rheumatoid arthritis (RA). We describe a patient in whom psoriasiform skin lesions developed 4 months after the initiation of abatacept therapy for longstanding, rheumatoid factor positive RA. Histological findings were consistent with psoriasis. The skin lesions subsided after discontinuation of abatacept and reappeared after re exposure to the drug, suggesting a causal connection between abatacept and the development of psoriasis. PMID- 21686604 TI - Fetal splenic cyst: antenatal diagnosis and outcome. PMID- 21686605 TI - Corneal rupture in a child with Down syndrome and hyperthyroidism. AB - The present report describes the clinical findings in a rare case of a child with trisomy 21 and hyperthyroidism, who developed severe acute hydrops with corneal perforation secondary to underlying keratoconus. There is a known association between trisomy 21 and keratoconus (a conic protrusion of the cornea),1 and children with trisomy 21 are also at increased risk of developing thyroid disease, including thyrotoxicosis with exophthalmos.2(,)3 However, a paediatric case with dual underlying diagnoses of trisomy 21 and hyperthyroidism, who subsequently developed severe hydrops, has not to our knowledge been previously described. PMID- 21686606 TI - An acute abdomen pain. PMID- 21686607 TI - Mediastinal abscess and suppurative thrombophlebitis possibly because of an accidental inhalation of paraquat. PMID- 21686608 TI - Eosinophilic vasculitis in an isolated central nervous system distribution. AB - Eosinophilic vasculitis has been described as part of the Churg-Strauss syndrome, but affects the central nervous system (CNS) in <10% of cases. A 39-year-old woman with a history of migraine without aura presented to an institution in an acute confusional state with concurrent headache and left-sided weakness. Laboratory evaluation showed an increased cerebrospinal fluid (CSF) protein level, but otherwise unremarkable serologies. Magnetic resonance imaging showed bifrontal polar gyral-enhancing brain lesions. Her symptoms resolved over two weeks without residual deficits. Eighteen months later the patient presented with similar symptoms and neuroradiological findings showed involvement of territories different from those in her first episode. Brain biopsy showed transmural, predominantly eosinophilic, inflammatory infiltrates and fibrinoid necrosis without granulomas. She improved when treated with corticosteroids. To our knowledge, this is the first case of non-granulomatous eosinophilic vasculitis isolated to the CNS. No aetiology for this patient's primary CNS eosinophilic vasculitis has yet been identified. PMID- 21686609 TI - Age indications for carotid sinus massage: a case for maintaining the status quo? AB - A 43-year-old man was referred with a history of unexplained falls associated with transient loss of consciousness. He had evidence of cardioinhibitory carotid sinus hypersensitivity (CSH) on carotid sinus massage and subsequently confirmed to have periods of symptomatic asystole on an implantable loop recorder, consistent with a diagnosis of cardioinhibitory CSH. PMID- 21686610 TI - Shrinking lung syndrome. PMID- 21686611 TI - Delayed therapeutic hypothermia following cardiac arrest secondary to chloroquine toxicity. AB - We describe a case of severe chloroquine intoxication resulting in a cardiac arrest requiring prolonged cardiopulmonary resuscitation. An excellent neurological outcome was achieved because the cardiac arrest occurred in a young patient lacking comorbidities in an environment where advanced life support was provided rapidly and effectively. Therapeutic hypothermia was instigated once profound shock and arrhythmias had resolved, and this may have contributed to her recovery. If a patient's immediate clinical condition post-cardiac arrest precludes therapeutic hypothermia, the use of this therapy should be reconsidered as their condition changes. PMID- 21686612 TI - Sacral neuromodulation enabling simultaneous pancreas and kidney transplantation: a first case. AB - We report a case where simultaneous pancreas and kidney transplantation was precluded because of recurrent urinary tract infections due to non-obstructive chronic urinary retention requiring clean intermittent self catheterisation in a diabetic woman with end stage renal disease. Sacral neuromodulation restored voiding and cured recurrent urinary tract infections, enabling her to undergo simultaneous pancreas and kidney transplantation. PMID- 21686613 TI - Corticobasal syndrome due to a thalamic tuberculoma and focal cortical atrophy. AB - Corticobasal syndrome (CBS) is characterised by asymmetric apraxia, cortical sensory loss, extrapyramidal features and cognitive decline. Although CBS is classically described as a taupathy, heterogeneity of its aetiology is increasingly recognised. Clinical presentation of CBS appears to reflect areas of the brain involved and not necessarily the nature of the underlying pathology. We report a patient in whom resolution of a thalamic tuberculoma was associated with progressive atrophy of the parietotemporal cortex, resulting in an unusual presentation of CBS. PMID- 21686614 TI - Chronic fatigue syndrome and complement activation. AB - This report describes a case of chronic fatigue syndrome (CFS) that followed a well-documented episode of acute Epstein-Barr virus (EBV) mononucleosis. All aetiological tests for chronic fatigue were found to be negative or normal, as were immunological tests. After 2 years of chronic fatigue following the acute illness, measurements of complement split products were performed to test for complement activation. These were positive and remained positive for 14 months, after which the patient then recovered from CFS. PMID- 21686615 TI - Diffuse intestinal angiomatosis as a possible paraneoplastic manifestation of small cell lung cancer: a case of small bowel angiomatosis. AB - Vascular malformations are rare, incompletely understood and heterogeneous in presentation and clinical course. They are known to be associated with a number of benign syndromes, commonly presenting in childhood. Angiomatosis is a form of vascular malformation, hardly documented in the English literature, and has only rarely been described in the small bowel. We present a case of a middle-aged female who developed small bowel obstruction secondary to diffuse small bowel angiomatosis and subsequently developed aggressive multifocal small cell lung cancer 2 months later. Her condition rapidly deteriorated with multiple metastases and she passed away 4 months later secondary to brain metastases and diffuse disease. Small cell lung cancer is well known for its association with paraneoplastic syndromes and has been reported to cause a rise in vascular endothelial growth factor. We postulate that in this case angiomatosis presented as a paraneoplastic syndrome associated with small cell lung cancer. PMID- 21686616 TI - "Metallic taste": search for the needle in a haystack (exemplary diagnostic measures and successful minimal invasive endoscopic treatment of a needle-like copper-containing foreign body in the gastric wall). AB - Chronic complaints and non-specific symptoms are always challenging for the selection of adequate diagnostic management and therapeutic decision making (eg, in uncharacteristic metallic taste). In this extraordinary, but exemplary case, the successful outcome for a 51-year-old woman with a chronic complaint of metallic taste (believed to be the first report in the literature as a cause of copper overload) is described. The patient underwent, after appropriate diagnostic measures, including MRI (detection), laboratory analysis of serum copper level (increased) and endoscopic ultrasound scan (localising the site), a minimal invasive treatment using endoscopic mucosectomy to remove a detected needle-like copper-containing foreign body from the intramural site of the gastric wall. PMID- 21686617 TI - Relapsing encephalopathy in a patient with alpha-methylacyl-CoA racemase deficiency. AB - alpha-Methylacyl-CoA racemase (AMACR) deficiency is a rare disorder of fatty acid metabolism which has recently been described in three adult cases. We have identified a further patient with clinical features of a relapsing encephalopathy, seizures and cognitive decline over a 40 year period. Biochemical studies revealed grossly elevated plasma pristanic acid levels, and a deficiency of AMACR in skin fibroblasts. Sequence analysis of AMACR cDNA identified a homozygous point mutation (c154T>C). This case adds to the phenotypic variation seen in this peroxisomal disorder and highlights the importance of screening for plasma pristanic acid levels in patients with unexplained relapsing encephalopathies. PMID- 21686618 TI - Applying salve in complex regional pain syndrome. PMID- 21686619 TI - Unexpected myocarditis in thalassaemia major patient screened for iron load cardiomyopathy. PMID- 21686620 TI - Ventricular tachycardia as the first manifestation of cardiac sarcoidosis. AB - The case of a 32-year-old man with sustained ventricular tachycardia and hypotension is described. Following pharmacological treatment the patient switched to a sinus rhythm and was transferred to a university hospital for further diagnostic procedures and treatment. Cardiac catherisation ruled out underlying coronary artery disease, and cardiac MRI as well as echocardiography demonstrated a moderately reduced left ventricular ejection fraction, marked thickening of the interventricular septum and extensive intramural and epicardial infiltration of both ventricles. Endomyocardial biopsies were inconclusive; an implantable cardioverter defibrillator (ICD) was implanted in order to prevent a fatal arrhythmic event. Only repeated lymph node biopsies revealed typical findings of granulomatous disease, which together with the clinical course and the cardiac MRI findings strongly supported cardiac sarcoidosis. A few days after initiation of therapy with corticosteroids, the patient experienced the first of a number of ICD discharges, demanding aggressive anti-arrhythmic treatment regimen for the future. PMID- 21686621 TI - Torsional deviations with voluntary saccades caused by a unilateral midbrain lesion. AB - Three dimensional eye rotations were measured using the magnetic search coil technique in a patient with a lesion of the right rostral interstitial nucleus of the medial longitudinal fasciculus (RIMLF) and in four control subjects. Up to 10 degrees contralesional torsional deviations with each voluntary saccade were revealed, which also could be seen during bedside examination. There was no spontaneous nystagmus. Based on MRI criteria, the lesion involved the RIMLF but spared the interstitial nucleus of Cajal. To date, this deficit has not been described in patients. Our results support the hypothesis that the vertical torsional saccade generator in humans is organised similarly as in monkeys: each RIMLF encodes torsional saccades in one direction, while both participate in vertical saccades. PMID- 21686622 TI - Extramedullary plasmacytoma masquerading as Tolosa-Hunt syndrome: a case report. AB - Painful ophthalmoplegia due to extramedullary plasmacytoma is a rare initial manifestation of multiple myeloma. The present report describes a 48-year-old man who suffered an acute onset of retro-orbital pain, left abducens palsy and left facial hypoesthesia. In addition, he exhibited an elevated erythrocyte sedimentation rate and partial responsiveness to corticosteroid treatment, all of which resemble the features of Tolosa-Hunt syndrome. Imaging studies revealed a multilobulated tumour invading the left sphenoid bone and sphenoid sinus, later confirmed as a plasmacytoma at pathology. Multiple myeloma was also diagnosed by bone marrow examination. After completion of chemotherapy and radiotherapy, the patient has been free of symptoms for 10 months. Although cranial neuropathies with any combination of oculomotor, abducens, trochlear, ophthalmic and maxillary nerves may indicate a cavernous sinus lesion, neuropathies exclusive to the abducens and maxillary nerves may raise the possibility of extracavernous sinus origin. Cranial imaging is crucial in diagnosing painful ophthalmoplegia with additional minimal cranial nerve signs. PMID- 21686623 TI - Varicella-zoster virus reactivation during acute enterovirus infection is associated with CD8 lymphocytopenia. AB - The trigger or triggers for reactivation of varicella-zoster virus have not been well defined in the medical literature. We investigated the role of enterovirus infections in triggering herpes zoster in five patients and correlated the reactivation with transient CD8 T lymphocyte depletion during the acute enterovirus infection. PMID- 21686624 TI - Follow-up in patients with disseminated peritoneal leiomyomatosis: a report of an unusual, high-risk case. AB - Leiomyomatosis peritonei disseminata is a condition seen uncommonly in states of oestrogen hypersecretion in women of childbearing age. There are no clear guidelines for the primary management and follow-up of these patients. Here, a rare case in a postmenopausal woman with a normal hormonal state who may be considered higher risk is presented, with a review suggesting a management pathway in these patients. PMID- 21686625 TI - An unusual clinical case of haemoptysis in spontaneous pneumothorax: blood clots within emphysematous bulla. AB - We report an unusual case of spontaneous haemopneumothorax associated with haemoptysis due to blood clots within emphysematous bulla in a 42-year-old man. Haemoptysis disappeared after surgery. PMID- 21686626 TI - Ocular phenylephrine 2.5% continues to be dangerous. AB - Phenylephrine 10% is used for pupillary dilatation and capillary decongestion. It had been advised to use a 2.5% concentration instead of 10% to guard against systemic reactions. Here, a case of severe systemic manifestation following conjuctival application of 2.5% phenylephrine is described.A healthy adult was admitted for pterygium excision under ophthalmic blockade. Vital signs remained normal until a sponge soaked with phenylephrine 2.5% was applied over the excised pterygium to control bleeding. The patient developed bradycardia (heart rate of 30 bpm) and hypotension (pressure 80/40 mmHg), so intravenous atropine was given. This was followed by tachycardia (heart rate of 150 bpm) and hypertension (pressure 240/130 mmHg) and ECG showed ischaemic changes. Treatment included propofol, labetalol, frusamide, morphine and dexamethasone. The next day, a 12 lead ECG showed no ischaemic changes and the myocardial infarction screen was negative. Fundus examination showed no sign of papilloedema. This report emphasises that phenylephrine 2.5% is still dangerous, with unpredictable response. PMID- 21686627 TI - Non-traumatic splenic rupture in a patient with Kasabach-Merritt syndrome. AB - This report presents a case illustrating the complications of Kasabach-Merritt syndrome in a 22-year-old man. The patient presented with acute abdominal pain and profound anaemia; a CT scan revealed intraperitoneal bleeding from spontaneous splenic rupture. The patient underwent initial emergency laparotomy and splenectomy, with a subsequent further laparotomy to control haemorrhage. Blood products requirements were extensive: 28 units red blood cells, 14 units fresh frozen plasma, 10 units platelets, 10 units cryoprecipitate and 2* Novo VII. He was then transferred to a nearby tertiary care unit for further management to control his coagulaopathy and he made a full recovery after 4 weeks. PMID- 21686628 TI - A supernumerary extensor tendon to the thumb with an accessory tendon to extensor indicis. AB - We present a report of an anatomical variation, the function of which is unclear. An anomalous, independent tendon to the thumb was accompanied by an accessory supernumerary tendon to the extensor indicis. This particular variation has not previously been described and was discovered during routine dissection of a male cadaveric upper limb. It is important to revisit these variations of anatomy as they may be relevant to explain clinical signs or during surgical procedures as detailed in this report. PMID- 21686629 TI - Hydrocephalus induced chorea. AB - Chorea can result from many causes, and the diagnostic workup can be challenging. Although often accompanied by other extrapyramidal symptoms, hydrocephalus has not been mentioned as a possible cause of chorea to date. Here we report an unusual case of chorea secondary to normal pressure hydrocephalus, which clearly improved after shunt placement. PMID- 21686630 TI - Pan-urothelial verrucous carcinoma unrelated to schistosomiasis. AB - Verrucous carcinoma is a well differentiated squamous cell carcinoma with a well known histological appearance and clinical behaviour. We present a case of verrucous carcinoma extensively affecting the urothelium of the right renal pelvis, right ureter and urinary bladder over a 3-year period. This pan urothelial involvement of a verrucous carcinoma has not been previously reported. The potential for regional spread with subsequent urinary tract obstruction by this tumour calls for aggressive local surgical treatment as the main modality of therapy. PMID- 21686631 TI - An unusual pacemaker related swelling. PMID- 21686632 TI - Putaminal petechial haemorrhage as the cause of non-ketotic hyperglycaemic chorea: a neuropathological case correlated with MRI findings. AB - Acute generalised chorea can be attributed to multiple causes, including non ketotic hyperglycaemia. This cause has been associated with characteristic image signs of striatal hyperdensity on CT scan and hyperintensity on T1 weighted (T1W) MRI. We report a patient presenting with this syndrome in which a postmortem study was conducted. The findings of striatum petechial hemorrhages gives a significant contribution towards explaining the nature of the imaging signs observed in the syndrome of acute chorea associated with non-ketotic hypergycaemia. PMID- 21686633 TI - Adult intussusception: diagnostic imagery. PMID- 21686634 TI - Diagnostic value of anti-GQ1b antibodies in a patient with relapsing dysarthria and ataxia. AB - Serum antibodies to the ganglioside GQ1b are associated with immune-mediated ophthalmoplegia and ataxia in patients with Miller-Fisher syndrome (MFS) and Guillain-Barre syndrome. A patient with two clinically similar episodes of progressive bulbar signs, ophthalmoplegia and ataxia is reported here. During both episodes the patient required artificial ventilation. Serum anti-GQ1b antibodies were detected during the first episode compatible with MFS, but were absent during the second. Neuroradiological investigations during the second episode showed brain stem ischaemia and obstruction of the left posterior inferior cerebral artery. These findings illustrate that anti-GQ1b serology is a reliable and robust method that helped to distinguish between different causes of relapsing dysarthria and ataxia. PMID- 21686636 TI - Heterotopic pregnancy: a growing diagnostic challenge. AB - This report describes a 26-year-old female who presented at 5 weeks of gestation with intrauterine pregnancy after gonadotrophin stimulation and intrauterine insemination. The patient complained of abdominal pain, abdominal distension and nausea diagnosed as moderate ovarian hyper-stimulation syndrome (OHSS) with early pregnancy and was treated accordingly. The patient was readmitted at 7 and 9 weeks of gestation with persistent left lower abdominal pain. At 9 weeks' gestation she also had a low grade fever and since the pelvic ultrasound showed a left tubo-ovarian mass she was treated for pelvic infection. The follow-up ultrasounds in the 5th, 9th and 12th weeks showed a normal intrauterine pregnancy in addition to a persistent left adnexal mass without any suspicion of a heterotopic pregnancy. The diagnosis of heterotopic pregnancy became possible only at 13 weeks of gestation during laparotomy when the right fallopian tube showed a leaking ectopic pregnancy. A right-sided salpingostomy was carried out. The intrauterine pregnancy is still ongoing without complications. PMID- 21686635 TI - Paediatric unilateral giant hydroureteronephrosis from idiopathic ureterovesical stricture: a case report. AB - A congenital type of ureterovesical junction obstruction may be present in the fetus or at any stage during childhood, more commonly associated with urinary tract infections and other secondary causes. We present the case of a 6-year-old boy who suffered from colic and side pain, which was worsening monthly. He suffered from a giant hydroureteronephrosis resulting from idiopathic ureterovesical junction obstruction, with no clinical or laboratory signs of urinary tract infection or other secondary causes of obstruction. Indications for surgery were a decrease in kidney function (<40%) at scintigraphy, severe hydronephrosis (>30 mm), and the coexistence of symptoms (colic pain). After surgery, kidney function returned to almost completely normal. Unexpectedly an obstruction may become symptomatic late in infancy, especially in patients with normal prenatal ultrasound screening and postnatal life, as was the case for our patient in whom the only clinical sign was pain at flank. PMID- 21686637 TI - Parkinson's disease with Onuf's nucleus involvement mimicking multiple system atrophy. AB - Urinary frequency, urgency and nocturia are common complaints in Parkinson's disease (PD). The hypothesis most widely proposed to explain neurogenic bladder symptoms in PD is that cell loss in the substantia nigra may cause detrusor hyperactivity due to a loss in the D1 receptor-mediated tonic inhibition of the micturition reflex, although other causes including anti-parkinsonian medication cortical effects have been considered.1 We present the clinical and pathological findings of a patient with parkinsonism who presented with prominent dysautonomia and a poor response to dopaminergic medications and was considered to have possible multiple system atrophy parkinsonism (MSA-P). Pathological examination revealed that the patient had PD with alpha-synuclein pathology in the Onuf's nucleus (ON). PMID- 21686638 TI - Congenital absence of left circumflex artery with a dominant right coronary artery. AB - Case 1: a 40-year-old man was admitted to our hospital with progressively worsening post myocardial infarction angina. Cardiac catheterisation was performed, which showed total occlusion of the left anterior descending artery (LAD) and the left circumflex artery (LCX) was not visualised. The right coronary artery (RCA) was a large artery supplying the left ventricular inferior and posterolateral walls and filling the LAD artery in retrograde. The patient was referred for coronary artery bypass grafting. Peroperative findings confirmed the angiographic evidence of congenitally absent LCX artery.Case 2: a 39-year-old man with a family history of premature coronary artery disease underwent coronary angiography for the work-up of chest pain. A coronary angiogram showed normal LAD artery and absence of left circumflex system. The RCA was superdominant. An aortogram confirmed no anomalous origin and true absence of LCX artery. PMID- 21686639 TI - Poliomyelitis-like syndrome with matching magnetic resonance features in a case of Lyme neuroborreliosis. AB - Lyme disease is a multisystemic disorder caused by an epizootic organism of the spirochete group, called Borrelia burgdorferi, which is transmitted to humans by ticks of the genus Ixodes. Lyme neuroborreliosis may occur during the early dissemination phase, most often as a painful meningo-radiculitis and very rarely as a radiculo-myelitis, whereas encephalomyelitis is observed in the late phase. We report the case of a patient with an early subacute poliomyelitis-like syndrome closely matching the selective involvement of the anterior horns and roots of the cervical spinal cord seen on magnetic resonance imaging. This condition improved with appropriate antibiotics. PMID- 21686640 TI - Concurrent primary biliary cirrhosis and autoimmune hepatitis presenting as subfulminant hepatic failure. AB - Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) overlap syndrome may be found in a significant percentage of patients with either PBC or AIH. However, it is conceivable that most cases of PBC-AIH overlap syndrome are a concurrent manifestation of both diseases which therefore requires treatment of both disease entities. While most cases are found in asymptomatic patients or in patients who have been previously diagnosed with PBC, our patient presented with concurrent PBC and AIH resulting in subfulminant liver failure that responded to treatment with prednisone and ursodeoxycholic acid (UDCA). Extended 4-year follow up and treatment with UDCA confirmed the diagnosis of PBC and demonstrated serological resolution of AIH. PMID- 21686641 TI - Bilateral mesial temporal polymicrogyria: a case report. AB - Polymicrogyria is a malformation of cortical organisation morphologically marked by an irregular brain surface with multiple excessively folded small gyri. Cortical thickness is reduced but appears increased in some areas as a result of the fusion of small gyri. On magnetic resonance imaging polymicrogyria is delineated by an abnormal gyral pattern, increased cortical thickness and irregularity of the cortical-white matter junction. PMID- 21686642 TI - The surgical management of pancreaticoduodenal tumours in multiple endocrine neoplasia type 1. AB - A 48-year-old man was admitted under the care of urologists with acute renal failure and septicaemia secondary to pyelonephritis. Upon investigation, he was found to have renal stone disease secondary to a parathyroid adenoma. Further tests revealed high pituitary hormone and gastrin values, confirming the diagnosis of multiple endocrine neoplasia type 1 (MEN 1) and Zollinger-Ellison syndrome. Soon after this he experienced a series of renal complications due to his renal stone disease and multiple complications of his gastrinoma, including two gastrointestinal perforations and three episodes of significant upper gastrointestinal bleeds (two of which required laparotomies), and a full length oesophageal stricture-all within the span of 9 months. His complications were managed appropriately and the oesophageal stricture was treated with a full length metallic stent. He was discharged home in a reasonably good condition with normal swallowing, but unfortunately died of aspiration pneumonia 3 weeks later. PMID- 21686643 TI - Severe drug induced acute hepatitis associated with use of St John's wort (Hypericum perforatum) during treatment with pegylated interferon alpha. AB - A 61-year-old woman with chronic hepatitis C received peginterferon alpha 180 MUg/week, and obtained undetectable qualitative hepatitis C virus (HCV) RNA (lower limit of detection 50 IU/ml) after 8 weeks of treatment. Shortly thereafter aminotransferase values greatly increased (>20 * upper limit of normal) and did not decline after treatment suspension. The patient admitted taking St John's wort (Hypericum perforatum) for depressed mood, recommended by a friend, during the preceding 6 weeks. Liver function tests continued to worsen and international normalised ratio (INR) prolongation developed; the patient was hospitalised. Test for antinuclear antibody was positive (1:320) and treatment with methylprednisolone was started; bilirubin and aminotransferase levels slowly declined, though a new flare occurred when steroids were tapered. After 6 months of prednisone treatment, the liver function tests returned to baseline levels. The combination of peginterferon alpha and St John's wort resulted in a severe acute hepatitis in this patient. Patients should be advised of this potential toxic effect of this herbal remedy. PMID- 21686644 TI - Post-mortem evidence of idiopathic left ventricular hypertrophy and idiopathic interstitial myocardial fibrosis: is exercise the cause? AB - We report the case of an experienced, highly trained marathon runner who died suddenly while running. On post-mortem examination, left ventricle hypertrophy and idiopathic interstitial myocardial fibrosis was found. We believe that life long, repetitive bouts of arduous physical activity resulted in fibrous replacement of the myocardium, causing a pathological substrate for the propagation of fatal arrhythmias. PMID- 21686645 TI - Diffuse alveolar haemorrhage secondary to warfarin therapy for atrial fibrillation: a case report and literature review. AB - Alveolar haemorrhage is a rare and serious medical emergency with many causes. Diffuse alveolar haemorrhage due to warfarin therapy has been rarely reported in the literature. In this paper, we describe the case of 62-year-old woman with a history of chronic atrial fibrillation treated with warfarin, who was admitted to our institution with haemoptysis and dyspnoea. Alveolar haemorrhage was suspected clinically and subsequently confirmed by bronchoscopy. The patient required aggressive treatment with fresh frozen plasma, vitamin K and mechanical ventilation with a successful outcome. We emphasise the need for early diagnosis and fast therapeutic intervention, especially with over-anticoagulation (INR >9), in patients with this rare and potentially lethal condition. PMID- 21686646 TI - Treat the patient not the blood test: the implications of an increase in cardiac troponin after prolonged endurance exercise. AB - Collapse after prolonged endurance exercise is common and usually benign. This case study reports a triathlete who suffered a vaso-vagal associated collapsed after exercise. Misdiagnosis of myocardial injury in the presence of elevated cardiac troponins and ECG anomalies led to inappropriate management and highlights the difficulty in treating the collapsed athlete following arduous exercise. PMID- 21686647 TI - Bariatric surgery does not cure all type 2 diabetes. AB - Bariatric surgery is a treatment increasingly used for morbid obesity and a significant number of patients undergoing this procedure will have diabetes. While bariatric surgery has been shown to be one of the most effective treatments for long term weight control, it has also been shown that it leads to improvements in comorbidities associated with obesity including type 2 diabetes. In fact one large series showed that over 80% of patients treated with gastric bypass procedures no longer required treatment for their diabetes. We report the case of a patient with insulin-treated type 2 diabetes who underwent gastric banding and 2 days post-operatively presented with severe diabetic ketoacidosis. PMID- 21686648 TI - Dementia and leukoencephalopathy due to lymphomatosis cerebri. AB - Lymphomatosis cerebri (LC) is a rare variant of primary central nervous system lymphoma (PCNSL). Clinically, the disease typically presents with a rapidly progressive dementia and unsteadiness of gait. Its presentation on cerebral MRI, which is characterised by diffuse leukoencephalopathy without contrast enhancement, often causes diagnostic confusion1 with suspected diagnoses ranging from Binswanger's disease to leukoencephalopathy or encephalomyelitis. Here we report a patient with subacute dementia and diffuse bilateral white matter changes in the cerebral hemispheres and additional involvement of the brainstem, basal ganglia and thalamus on MRI. Initially, she was considered to suffer from an autoimmune encephalitis, transiently responded to immunosuppression but then developed multiple solid appearing cerebral lymphomas. PMID- 21686649 TI - Extensive bruising secondary to vitamin C deficiency. AB - An otherwise fit and well 56-year-old man presented with extensive ecchymosis and soft-tissue haematomas affecting his legs. Coagulation studies were normal. Further questioning revealed a severely restricted diet. The bruising improved rapidly after commencing oral vitamin C supplementation. Serum vitamin C level was low, supporting the clinical diagnosis of scurvy. PMID- 21686650 TI - Developmental regression caused by complex multiloculated cystic hydrocephalus. PMID- 21686651 TI - Diagnosis and treatment difficulties of psychiatric symptoms in Klinefelter syndrome: a case report. AB - Klinefelter syndrome (KS) can involve various psychiatric symptoms that are often heterogeneous and atypical. To illustrate the diagnosis and treatment difficulties of psychiatric non-specific symptoms occurring in KS, we report a 17 year-old man presenting with gynaecomastia and marfanoid features. Investigations showed high concentrations of gonadotrophins and a 47,XXY karyotype. Although his serum testosterone was normal, the patient had clinical hypogonadism and suffered from recent headache. Magnetic resonance imaging revealed pituitary non-invasive macroadenoma. Treatment with Cabergolin resulted in a normalisation of prolactin levels and a decrease in tumour size. During follow-up, the patient presented a permanent state of passivity and disinterest in imaginative experiences, without any obvious specific diagnoses, according to psychiatric examination. Further investigations showed major depression, schizotypical personality and patterns of psychotic functioning. Initial treatment with selective serotonin re-uptake inhibitors was not effective and he was switched to an atypical antipsychotic drug that was not tolerated and rapidly stopped by the patient. PMID- 21686652 TI - Relapsing polychondritis: an uncommon cause of dementia. AB - Relapsing polychondritis Is a rare disorder that is characterised by recurrent and progressive inflammation of cartilaginous structures. Nervous system involvement in relapsing polychondritis has been described. We describe two cases of relapsing polychondritis with subacute dementia. PMID- 21686653 TI - Effect of long term intermittent nocturnal non-invasive positive pressure ventilation on patient with severe kyphoscoliosis and hypoxaemia. AB - Kyphoscoliosis is one of the causes of restrictive lung disease. It can lead to chronic hypercapnic respiratory failure and hypoxaemia. The benefits of long term intermittent nocturnal non-invasive positive pressure ventilation (NIPPV) to these patients have been shown in regard to improved vital capacity, total lung capacity, muscle strength and daytime oxygenation. In our case, we found long term intermittent nocturnal NIPPV also had a beneficial effect on exercise capacity and pulmonary hypertension. This is good for patients with kyphoscoliosis not only in terms of their survival but also for their quality of life. We recommend long term intermittent nocturnal NIPPV as a routine intervention for severe kyphoscoliosis with hypoxaemia, and transthoracic echocardiography as a routine evaluation tool for determining the response of pulmonary hypertension to management. PMID- 21686654 TI - Acute stridor caused by tracheal compression from a thoracic aortic aneurysm. PMID- 21686655 TI - A report of succinate dehydrogenase B deficiency associated with metastatic papillary renal cell carcinoma: successful treatment with the multi-targeted tyrosine kinase inhibitor sunitinib. AB - We report a patient who initially presented with an abdominal paraganglioma and subsequently metastatic papillary cell renal cancer. Genetic analysis revealed a 141 G>A (exon 2) Trp47X mutation within the succinate dehydrogenase B gene. Treatment with the novel multi-targeted tyrosine kinase inhibitor sunitinib resulted in a sustained partial response and reduced the level of the angiogenic marker PIGF. TRIAL REGISTRATION NUMBER: a6181037. PMID- 21686656 TI - Dementia presenting with visual complaints. AB - A 78-year-old female developed memory problems after a 2-year history of persistent visual complaints. Ocular pathology did not explain the extent of her perceived visual impairment. Cognitive screening tests found prominent visuo constructive deficits and a comprehensive dementia assessment revealed the diagnosis of Alzheimer's disease. This case describes visual complaints as the initial symptom of dementia, pre-dating memory impairment by several years. We discuss clinical signs of cerebral visual impairment and suggest a simple screening measure. PMID- 21686657 TI - A rare cause of reversible complete heart block. AB - Lyme disease is a recognised cause of atrioventricular heart block. In the majority of cases conduction disturbances are reversed with antibiotic treatment. The diagnosis of Lyme disease is not always obvious and its recognition is important if unnecessary implantation of a permanent pacemaker is to be avoided. A 34-year-old man presented to our hospital with complete heart block due to Lyme carditis. This resolved completely within a few days after treatment with appropriate antibiotics. PMID- 21686658 TI - The most common complication of coronary angiography. AB - An 82-year-old woman re-presented with severe angina many years after coronary artery bypass surgery. Myocardial perfusion imaging suggested reversible ischaemia in the inferior territory. Diagnostic angiography demonstrated no vein grafts, an occluded right internal mammary artery graft (RIMA), and a patent left internal mammary graft. The native right coronary was stenosed in several sections and she was referred for angioplasty to this artery. After initial balloon inflation in the native right coronary, to our surprise a large arterial graft was revealed-the apparently blocked RIMA. In fact the RIMA was not occluded; the graft was assumed to be pedicle whereas in fact it had been grafted to the ascending aorta. The interventional strategy was revised and both the RIMA and native right coronary artery were successfully treated. PMID- 21686659 TI - Bilateral symptomatic hypertrophic ligamentum teres of the hip in a young athlete. AB - We report the case of a 14-year-old female gymnast who presents with bilateral hip pain and mechanical symptoms with extremes of range of motion. The patient failed conservative management and had worsening symptoms, including pain at rest. Diagnostic imaging failed to provide any definitive diagnosis and the patient underwent staged bilateral hip arthroscopies with debridement of inflamed, hypertrophic ligamentum teres. The patient did well postoperatively and has returned to athletic activities. PMID- 21686660 TI - Imperforate hymen: a cause of abdominal pain in female adolescents. AB - A 16-year-old girl presented with primary amenorrhea and had had cyclical abdominal pain for almost a year. At examination we observed a painful mass in the lower abdomen and normal secondary sex characteristics. Perineal examination showed a bluish bulging hymen. Transabdominal ultrasonography revealed a dense mass in the pelvis measuring about 12*11 cm. We diagnosed an imperforate hymen with haematocolpos and haematometra. The hymen was opened surgically and a large quantity of menstrual blood was drained from the vagina and uterus. Postoperative recovery was normal without any pain. The patient now menstruates regularly. An imperforate hymen occurs in 0.05% of women. It is important to be aware of this while examining a female adolescent presenting with cyclical abdominal pain and primary amenorrhea. Late discovery of an imperforate hymen may lead to pain, infections, hydronephrosis and endometriosis with subfertility as a possible consequence. PMID- 21686661 TI - Secondary aorto-enteric fistula: a case report and review of literature. AB - Aorto-enteric fistula (AEF) is an uncommon but potentially fatal condition that is important to identify early because early diagnosis and aggressive management can reduce mortality. We report the case of a 73-year-old man with a history of aorto-bifemoral bypass grafting who was admitted for investigation of tiredness and lethargy. He passed melaena on the day of admission with an associated drop in haemoglobin. Initial upper gastrointestinal endoscopy revealed no significant abnormality. Later in the admission he again passed melaena, this time in large amounts. A repeat endoscopy identified a defect in the duodenal mucosa with visible Dacron graft. The patient went on to suffer another large bleed from which he could not be resuscitated. Our report highlights a fatal manifestation of aorto-enteric fistula, and reviews the associated literature. PMID- 21686662 TI - Cerebral haemorrhage as the presenting feature of myeloproliferative disorder. AB - Myeloproliferative disorders predispose individuals to bleeding and thrombosis, often with devastating consequences. We report a 41-year-old man who presented with headache, amnesia and dysphagia due to cerebral haemorrhage. Extensive investigation revealed the cause of the neurological syndrome as an underlying essential thrombocytosis. The patient made a full recovery following extensive inpatient and community rehabilitation, returning to work after 6 months. We discuss the diagnosis and management of stroke due to myeloproliferative conditions. This case report illustrates the importance of multidisciplinary teamwork in fully investigating and treating all patients with acute onset of stroke. PMID- 21686663 TI - Deletion of C2orf34, PREPL and SLC3A1 causes atypical hypotonia-cystinuria syndrome. AB - Hypotonia-cystinuria syndrome (HCS) and 2p21 deletion syndrome are two recessive contiguous gene deletion syndromes associated with cystinuria type I. In HCS patients, only SLC3A1 and PREPL are disrupted. In the 2p21 deletion syndrome, two additional genes (C2orf34 and PPM1B) are lost. Molecular analysis of the SLC3A1/PREPL locus was performed in the patients using quantitative polymerase chain reaction (PCR) methods. HCS in both siblings was confirmed with the deletion screen of the SLC3A1/PREPL locus. Fine mapping of the breakpoint revealed a deletion of 77.4 kb, including three genes: SLC3A1, PREPL and C2orf34. Features not present in classical HCS were a mild/moderate mental retardation and a respiratory chain complex IV deficiency. We report the first patients with a deletion of SLC3A1, PREPL and C2orf34. They present with a phenotype intermediate between HCS and 2p21 deletion syndrome. PMID- 21686664 TI - Hypophosphataemic neuropathy during total parenteral nutrition. AB - Intravenous glucose administration is the most common cause of hypophosphataemia in hospitalised patients. While most of these cases are asymptomatic, severe hypophosphataemia, when combined with phosphorus depletion, can cause acute neuropathy that mimics Guillain-Barre syndrome. A malnourished patient who received intravenous hyperalimentation (IVH) without intravenous phosphate (IP) developed hypophosphataemia and acute sensorimotor neuropathy. F waves in the peripheral nerve trunk were absent or diminished, while nerve conduction velocities were nearly normal. The sural nerve biopsy revealed the presence of some subperineurial oedema and mild axonal atrophy. Prompt IP administration reversed the patients' neurological symptoms and normalised F waves. Our data suggest that hypophosphataemia plays a role in the pathogenesis of neuropathy that develops in patients following IVH without IP. PMID- 21686665 TI - Clostridium difficile-associated colitis following the use of Chinese medicine. AB - Chinese medicine is becoming widely used in the UK to treat many medical conditions, including acne. We report a case in which Chinese medicine, Lian Qiao Bai Du Wan, was used to treat acne in a teenage boy. The patient then suffered severe diarrhoea with blood and mucus per rectum. Examination of the stool revealed Clostridium difficile infection. Treatment with oral metronidazole improved his symptoms. PMID- 21686666 TI - Neovascularisation in flexor carpi ulnaris tendinopathy: novel combined sclerosing therapy and eccentric training of the forearms in athletics' wrist pain. AB - Tendinopathy of the flexor carpi ulnaris tendon is a rare entity. We present a 35 year old tennis player suffering tremendous pain (visual analogue scale (VAS) rating of 9/10) at the flexor carpi ulnaris tendon with adjacent calcification in close proximity to the pisiform bone. Sclerosing therapy using polidocanol under power and laser Doppler guidance was initiated, with immediate decrease of capillary blood flow by 25% with resolution of the neovascularisation in power Doppler. Immediately following sclerosing, the patient's reported pain level on the VAS was reduced from 9/10 to 4/10. Following a short period of rest, eccentric training of the forearm muscle was initiated over 12 weeks with functional complete recovery and complete resolution of wrist pain. PMID- 21686667 TI - Non-convulsive status epilepticus causing focal neurological deficits in CADASIL. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by mutations of the Notch3 gene. Clinical manifestations include migraine with or without aura, psychiatric disorders, recurrent ischaemic strokes and cognitive decline. Brain MRI shows confluent hyperintense signal alterations involving characteristically the anterior part of the temporal lobes and widespread areas of the deep and periventricular white matter. Focal or generalised seizures represent a rare neurological manifestation in CADASIL with a frequency of 6-10% in two large series. Status epilepticus, however, has not been reported so far. Herein we describe a patient with CADASIL with an acute focal neurological deficit following a prolonged migraine attack. The symptoms were first interpreted as an ischaemic stroke but subsequently diagnosed to be due to a non convulsive status epilepticus. PMID- 21686668 TI - De novo seven extra repeat expanded mutation in the PRNP gene in an Italian patient with early onset dementia. AB - Point and octapeptide repeat (24 bp) insertional mutations in the prion protein gene (PRNP) cause a dominantly transmitted dementia, associated with spongiform degeneration of the brain, astrocytic gliosis and neuronal loss due to cell accumulation of mutated protease resistant prion protein. The octapeptide repeat region lies between codon 51 and 91, and comprises a nonapeptide followed by a tandem repeat containing four copies of an octapeptide. The normal tandem length in healthy individuals is five repeats R1-R2-R2-R3-R4, but mutations can contain up to nine additional extra repeats. Some insight into this genetic mechanism comes from the de novo meiotic insertional extra repeat mutation in PRNP we detected in a patient whose parents had a normal phenotype and a wild-type sequence in the same gene. To our knowledge, this is the first time this condition has been described. PMID- 21686669 TI - Possible case of peripheral osmotic demyelination syndrome. AB - Central pontine myelinolysis (CPM) is an uncommon neurological syndrome that is usually related to the rapid restoration of a previous hyponatraemia. Although the most frequent location of CPM injury is the pons, it is now designated osmotic demyelination syndrome (ODS) because, as well as in the brainstem, these injuries can be observed in other parts of the central nervous system (CNS)-for example, the thalamus, subthalamic nucleus, external geniculate body, putamen, globus pallidum, internal capsule, white matter of cerebellum and the deep layers of the brain cortex. However, an exhaustive search of the literature (MEDLINE 1967-2007) has revealed no case report of peripheral nervous system (PNS) demyelination secondary to severe hyponatraemia. PMID- 21686670 TI - Hypocretinergic dysfunction in neuromyelitis optica with coma-like episodes. AB - Devic's neuromyelitis optica (NMO) is a severe demyelinating disease of the central nervous system, often misdiagnosed as multiple sclerosis, and involving mainly optic nerves and the spinal cord. We report on a peculiar case of relapsing NMO with severe recurrent dysautonomia and hypersomnia, in which we had the opportunity to observe a dramatic decrease in hypocretin/orexin cerebrospinal fluid level. PMID- 21686671 TI - Strong diabetes. AB - The case of a 36-year-old male professional bodybuilder is reported. He presented to the accident and emergency department with right upper quadrant pain. This was on the background of a 15-year history of anabolic steroid and growth hormone misuse. Examination revealed mild hepatomegaly and a random blood sugar of 30.2 mmol/l. There was no evidence of ketonuria or acidosis. Biochemical evidence of hepatitis was found, and the patient was in acute renal failure. He was given a sliding scale of insulin and an intravenous infusion of crystalloid. The hepatitis and hyperglycaemia settled with conservative treatment. It is believed that this is the first reported case of frank diabetes precipitated by supraphysiological recreational growth hormone misuse. PMID- 21686672 TI - Peripheral neuropathy in chromosome16q22.1 linked autosomal dominant cerebellar ataxia. AB - Autosomal dominant cerebellar ataxia (ADCA) includes heterogeneous neurodegenerative diseases with or without various neurological signs and symptoms. Ishikawa et al reported a new type of ADCA, named chromosome16q22.1 linked ADCA (16q-ADCA), attributed to a heterozygous C->T substitution in the 5' non-coding region of puratrophin-1 gene. We searched for this mutation in168 patients from 129 families with ADCA and found it in six patients. The patients generally showed late onset pure cerebellar ataxia similar to previous reports but two had mild axonal neuropathy and orthostatic hypotension (OH). Our results suggest that 16q-ADCA shows a broader clinical presentation than previously thought. PMID- 21686673 TI - Subthalamic nucleus stimulation in Parkinson's disease is associated with a risk of fixed epiglottis. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates motor disability of patients with Parkinson's disease (PD). Mental changes and other adverse events are common, but typically transient. Severe complications such as intracerebral haemorrhage or infection are rare, but 6 of 73 patients who underwent STN-DBS died of pneumonia, cardiac failure or pulmonary embolism. We describe a patient with PD who had sudden respiratory difficulty due to a fixed epiglottis after STN-DBS. This symptom was confirmed to be related to STN stimulation on fibre-optic examination of the larynx. PMID- 21686674 TI - Fatal small bowel ischaemia following laparoscopic cholecystectomy: report of a case. AB - Veress needle, trocar insertion, pneumoperitoneum-related complications, biliary injuries apart from haemorrhage, intestinal injuries and lateral thermal injuries are all well described entities following laparoscopic cholecystectomy. The development of intestinal ischaemia following laparoscopic cholecystectomy is rare; this report describes a case of fatal small bowel ischaemia following laparoscopic cholecystectomy and discusses the various possibilities that led to this event. PMID- 21686676 TI - Sealed rupture of aortic aneurysm in an elderly patient with non-specific abdominal pain. PMID- 21686675 TI - Painful neuropathy with skin denervation after prolonged use of linezolid. AB - The prolonged use of linezolid, a new antibiotic against drug-resistant Gram positive pathogens, might cause painful neuropathy. This finding raises the possibility that small-diameter sensory nerves in the skin, which are responsible for transmitting nociceptive information, might be affected. We report a 53-year old female who developed pure small-fibre painful neuropathy (visual analogue scale, VAS =82 on 0-100 scale) with marked skin denervation in the leg (epidermal nerve density, END =2.32 fibres/mm, norm <5.88 fibres/mm) and significant elevation of the warm threshold in the foot (40.0 degrees C, norm <39.4 degrees C) after the use of linezolid for 6 months. Eight months after the discontinuation of linezolid, the skin became fully reinnervated (END =9.04 fibres/mm), with disappearance of neuropathic pain (VAS =0) and normalisation of the warm threshold (36.3 degrees C). Nerve conduction studies for large-diameter motor and sensory nerves were normal. This report documents a pure small-fibre sensory neuropathy after prolonged use of linezolid, and the relationship between skin innervation and corresponding neuropathic pain. PMID- 21686677 TI - Heat stress disorders and headache: a case of new daily persistent headache secondary to heat stroke. AB - Headache is considered as a common symptom of heat stress disorders (HSD), but no forms of secondary headache from heat exposure are reported in the International Classification of Headache Disorders-2 Edition (ICHD-II). Heat-stroke (HS) is the HSD most severe condition, it may be divided into two forms: classic (due to a long period environmental heat exposure) and exertional (a severe condition caused by strenuous physical exercises in heat environmental conditions). Here we report the case of a patient who developed a headache clinical picture fulfilling the diagnostic criteria for new daily persistent headache (NDPH), after an exertional HS, and discuss about possible pathophysiological mechanisms and classification aspects of headache induced by heat conditions. PMID- 21686678 TI - A rare case of ciprofloxacin-induced bilateral rupture of the Achilles tendon. AB - Fluoroquinolone antibiotics have been widely used for over 25 years. Their key adverse effect is tendinopathy. A 76-year-old woman developed bilateral Achilles tendinopathy on the fourth day of fluoroquinolone use. Her doctor advised her to complete the course; however, she went on to sustain bilateral tendoachilles rupture. The patient undertook self-referral to a Primary Care Musculoskeletal Assessment Service, where bilateral Achilles tendon rupture was confirmed by ultrasonography. Surgical repair of both tendons was undertaken. Several months postoperatively the patient was discharged. Fluoroquinolone-related tendinopathy can occur within hours of commencing the medication or up to 6 months post cessation. The incidence of Achilles tendon disorders significantly outweighs pathology in other tendons. Men are up to four times more susceptible than women, hence bilateral rupture in a 76-year-old woman is rare. Patients prescribed fluoroquinolones presenting with tendinopathy require consideration of dose reduction or cessation of fluoroquinolone therapy. PMID- 21686679 TI - Contribution of the 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography to the diagnosis of primary osseous Hodgkin lymphoma. AB - Hodgkin lymphoma typically presents as a nodal lesion and infrequently involves extra nodal sites. Although cases of primary extra-nodal Hodgkin lymphoma have been reported previously, the reality of the primitive nature of the disease was difficult to authenticate with traditional high resolution imaging techniques, such as computed tomography or magnetic resonance imaging, because they cannot evaluate the spread of the disease throughout the whole body. We report here a case of primary osseous Hodgkin lymphoma, regarded as stage I extranodal IE thanks to the important contribution of a new imaging technique, the 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography/ computed tomography (18F FDG-PET/CT). PET enables systemic Hodgkin lymphoma with secondary bone invasion to be distinguished from primitive osseous Hodgkin lymphoma. This technique is highly specific in demonstrating the isolated osseous localisation of the tumour and should be recommended in all patients with putative osseous lymphoma. PMID- 21686680 TI - Varus instability of the hallux interphalangeal joint in a taekwondo athlete. AB - The hallux interphalangeal joint is stable in the transverse plane and there have been only a few reports of varus instability of this joint. A case is described of varus subluxation of the hallux interphalangeal joint in a taekwondo athlete and the surgical outcome after reconstruction of the collateral ligament. Taekwondo athletes, who require fast powerful kicks, should be warned about this type of forefoot injury. PMID- 21686681 TI - Treatment of Buerger disease (thromboangiitis obliterans) with bosentan: a case report. AB - Buerger disease (thromboangiitis obliterans) is a non-atherosclerotic segmental inflammatory disease strongly associated with tobacco use, and it affects small and medium-sized blood vessels in the upper and lower extremities. The only known treatment for this disease is complete discontinuation of tobacco use. This report describes the case history of a woman with Buerger disease treated with the oral dual endothelin receptor antagonist bosentan. It is believed that this is the first description in the literature of this use for bosentan. PMID- 21686682 TI - Paraneoplastic (non-metastatic) adrenal insufficiency preceded the onset of primary lung cancer by 12 weeks. AB - Clinically evident adrenal insufficiency associated with lung cancer is a rare entity. Among reported cases, adrenal insufficiency has occurred with or succeeded the primary lung cancer. Adrenal insufficiency has also been secondary to metastasis to the adrenal gland. The present report concerns a 61-year-old man, a chronic smoker, who presented to us with symptomatic adrenal insufficiency. He had no evidence of lung cancer during this visit. The primary lung cancer was only identified 12 weeks later. Additionally, his adrenals showed no evidence of metastasis. Hence his adrenal insufficiency had been a paraneoplastic manifestation of the lung cancer, and it had also preceded the primary by 12 weeks. PMID- 21686683 TI - Complete deletion of the aprataxin gene: ataxia with oculomotor apraxia type 1 with severe phenotype and cognitive deficit. AB - Ataxia with oculomotor apraxia type 1 (AOA1) is a recently described autosomal recessive neurodegenerative condition of childhood onset. It is caused by mutations in the APTX gene, which encodes the protein aprataxin. Clinical features include gait and limb ataxia, dysarthria, oculomotor apraxia, mild peripheral neuropathy and progression of neurological deficits.1 Some patients manifest parkinsonian symptoms or mental retardation, although the latter has been reported predominantly in Japanese patients.2 We report a patient with homozygous deletion of APTX, who presented with behavioural changes (social withdrawal), and subsequent rapid progression of neurological symptoms associated with severe cognitive decline. We suggest that complete deletion of APTX is associated with a more severe phenotype than that associated with point mutations. PMID- 21686684 TI - Loss of exploratory vertical saccades after unilateral frontal eye field damage. AB - Despite their relevance for locomotion and social interaction in everyday situations, little is known about the cortical control of vertical saccades in humans. Results from microstimulation studies indicate that both frontal eye fields (FEFs) contribute to these eye movements. Here, we present a patient with a damaged right FEF, who hardly made vertical saccades during visual exploration. This finding suggests that, for the cortical control of exploratory vertical saccades, integrity of both FEFs is indeed important. PMID- 21686685 TI - Intramuscular myxoma of the deltoid muscle: report of a case. AB - Intramuscular myxoma is a rare, benign lesion of mesenchymal origin, affecting the skeletal muscles. We report the case of a 75-year-old woman presenting with a mass of the right deltoid region. On the MRI examination it was interpreted as a lipomatous lesion. She underwent marginal excision. The pathological examination revealed the diagnosis of intramuscular myxoma. PMID- 21686686 TI - Acute psychotic episode in a patient with thyrotoxicosis factitia. AB - Psychotic syndromes in the context of hyperthyroidism are seldom mentioned in medical textbooks and only a few cases have been published. Typically, such cases present as an affective psychosis. Schizophrenia-like psychosis is a rare occurrence in hyperthyroidism and the link between these two conditions is still poorly understood.We report the case of a female patient with a known history of chronic lymphocytic thyroiditis. The patient presented to our emergency department with an acute schizophrenia-like psychosis. Elevated levels of T4 and free T4 were found. These resulted from the patient's voluntary intake of excess levothyroxine as an attempt to lose weight (thyrotoxicosis factitia). Normalisation of thyroid hormone levels and antipsychotic treatment led to prompt remission of the psychosis. Even though the patient stopped the antipsychotics, she remained free of symptoms during the follow-up. Similar cases are briefly reviewed and some of the data from basic research is also considered. PMID- 21686687 TI - Working effectively with patients with comorbid mental illness and substance abuse: a case study using a structured motivational behavioural approach. AB - This case describes the use of innovative person-centred motivational behaviour change tools to enhance chronic condition self-management with a person with chronic paranoid schizophrenia, significant drug abuse and multiple psychosocial issues. In standard care, the complexity of this patient's presentation, their cognitive impairment level and history of violence would likely exclude them from many therapies and treatment programs as unsuitable or in the "too hard" basket. In fact, using a motivational and highly person-centred approach proved to be extremely necessary and rewarding for the person and their mental health worker. This approach provided a clear structure, actual tools and a clear rationale for what many would argue, yet is often ill-defined, was "just good clinical practice". However, it also facilitated the development of "something special" in the relationship between the person and their worker that is central to person centred care. Through a semistructured, motivational, sequential process that encouraged gradual disclosure and greater self-awareness by the client and active listening by the worker, greater collaboration and shared responsibility was enhanced. PMID- 21686688 TI - Corticosteroid-associated osteonecrosis of the femoral head: complete resolution on MRI with conservative treatment. PMID- 21686689 TI - Merkel cell carcinoma; a rare, aggressive, cutaneous malignancy. PMID- 21686690 TI - Raynaud phenomenon that rapidly progressed to digital gangrene: a challenging diagnosis. PMID- 21686691 TI - Acute myelopathy selectively involving lumbar anterior horns following intranasal insufflation of ecstasy and heroin. AB - We report a patient who developed acute myelopathy after intranasal insufflation of amphetamines and heroin. The functional prognosis was very poor; after 4 months, she remained paraplegic. MRI imaging showed selective T2 hyperintensity and intense enhancement confined to the spinal anterior horns and lumbar nerve roots and plexus. This unique MRI pattern, together with neurophysiological data, suggests that the pathological process at the first primary affected spinal anterior horns (SAH), conditioning motoneuron cell death, and then nerve roots and lumbar plexus as a consequence of wallerian degeneration. PMID- 21686692 TI - Isolated cytochrome c oxidase deficiency as a cause of MELAS. AB - Deletion of a single nucleotide (7630delT) within MT-CO2, the gene of subunit II of cytochrome c oxidase (COX), was identified in a clinically typical MELAS case. The deletion-induced frameshift results in a stop codon close to the 5' end of the reading frame. The lack of subunit II (COII) precludes the assembly of COX and leads to the degradation of unassembled subunits, even those not directly affected by the mutation. Despite mitochondrial proliferation and transcriptional upregulation of nuclear and mtDNA-encoded COX genes (including MT-CO2), a severe COX deficiency was found with all investigations of the muscle biopsy (histochemistry, biochemistry, immunoblotting). The 7630delT mutation in MT-CO2 leads to a lack of COII with subsequent misassembly and degradation of respiratory complex IV despite transcriptional upregulation of its subunits. The genetic and pathobiochemical heterogeneity of MELAS appears to be greater than previously appreciated. PMID- 21686693 TI - Duplication of the Williams-Beuren critical region: case report and further delineation of the phenotypic spectrum. AB - Only 12 patients with a duplication of the Williams-Beuren critical region (WBCR) have been reported to date, with variable developmental, psychomotor and language delay, in the absence of marked dysmorphic features. In this paper we present a new WBCR microduplication case, which supports the wide variability displayed by this duplication in the phenotype. The WBCR microduplication may be associated with autistic spectrum disorder, but most reported cases do not show this behavioral disorder, or may even show a hypersociable personality, as with our patient. From the present case and a review of the 12 previously described,1(-)6 we conclude that the phenotype associated with duplication of WBCR can affect the same domains as WBCR deletion, but that they cluster near the polar ends of social relationship (autism-like v hypersociability), language (expressive language impairment v "cocktail party" speech), visuospatial (severe v normal), mental retardation (severe v mild) and dysmorphic (severe v mild) features. PMID- 21686695 TI - Acute abdomen due to retroperitoneal haematoma: a surgical dilemma. AB - A 73-year-old man presented with features of acute abdomen 2 days following evacuation of a subdural haematoma. CT scan demonstrated significant free fluid in the peritoneal cavity as well as an extensive abnormal area in the upper retroperitoneum. There was no obvious free gas or leak of contrast. As there was persistent metabolic acidosis and significant peritonism, the patient proceeded to an exploratory laparotomy. This revealed a large non-expanding retroperitoneal haematoma and free blood in the peritoneal cavity. There was no evidence of active bleeding and the bowel was found to be viable. As the patient was haemodynamically stable, a laparostomy was fashioned and the patient subsequently underwent angiography. This revealed a 1.5 cm pseudoaneurysm arising from the superior mesenteric artery which was treated with coil embolisation. The patient made an uneventful recovery and the laparostomy was closed. PMID- 21686694 TI - Treatment of chronic bleeding of the small intestine in Rendu-Osler-Weber disease with argon plasma coagulation under double-balloon enteroscopy. AB - A 39-year-old man with chronic bleeding from Rendu-Osler-Weber disease in the small intestine was treated with argon plasma coagulation using a custom-made probe under double-balloon enteroscopy. A 10 month follow-up showed no evidence of bleeding. PMID- 21686696 TI - Intravenous immunoglobulin therapy in proximal diabetic neuropathy. AB - A 57-year-old man with type 2 diabetes mellitus for 10 years showed progressive loss of muscle strength in both legs, pain and muscle atrophy in the femoral region and significant weight loss. On admission, he could not stand alone and used a wheelchair. He also complained of severe pain in the lower extremities. He was diagnosed with proximal diabetic neuropathy (PDN) by characteristic clinical and electrophysiological features. Intravenous immunoglobulin therapy (IVIg 0.4 g/kg*5 days) markedly reduced the severe pain and muscle weakness in the legs. Eventually, pain assessed by the Visual Analogue Scale was relieved by 80% and muscle strength was also well recovered, thereby enabling the patient to walk with a cane. The present case suggests that IVIg therapy may be effective for the relief of pain in PDN. PMID- 21686697 TI - Hydroxychloroquine: a diabetic drug in disguise? AB - Hydroxychloroquine (HCQ) is an antimalarial agent that is commonly used to treat rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The present report documents a case of hypoglycaemia due to HCQ in a patient with SLE and diabetes mellitus type 2, in which the HCQ completely replaced the need for daily subcutaneous insulin. PMID- 21686699 TI - "Goalkeeper's hip": acute haematogenous osteomyelitis secondary to apophyseal fractures. AB - We report two cases of acute haematogenous osteomyelitis in the anterior superior iliac spine (ASIS) in adolescent goalkeepers following trauma of the iliac crest apophysis. Both patients complained of pain over their right ASIS and were pyrexial. They were given antibiotics and were discharged from follow up without complication 64 and 90 days after starting treatment. PMID- 21686698 TI - A novel founder mutation in the MFN2 gene associated with variable Charcot-Marie Tooth type 2 phenotype in two families from Southern Italy. AB - Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy. CMT falls into two main forms: the demyelinating CMT type 1 with decreased nerve conduction velocities and the axonal CMT type 2. CMT2 is further subtyped by linkage analysis into >10 loci, with eight genes identified.Recently, mutations in the mitochondrial fusion protein 2 (MFN2) gene were reported in families with CMT2A1 and additional mutations have been detected in other studies, bringing to 42 the total number of different MFN2 mutations described thus far.2(-)4In the current study, we report a novel MFN2 mutation shared by two apparently unrelated CMT2 families originating from the same area in Southern Italy. PMID- 21686700 TI - Vacuolar leucoencephalopathy and pulvinar sign in association with coeliac disease. AB - Several neurological disorders have been associated with coeliac disease, including epilepsy, ataxia and neuropathy. Here we report a rare case of white matter disease in a 55-year-old man with coeliac disease. He presented with anxiety, headache and left upper limb jerking. He subsequently developed epilepsy and brain MRI revealed diffuse white matter abnormality. He died 6 months after presentation due to status epilepticus and sepsis. Brain biopsy demonstrated vacuolar leucoencephalopathy with no evidence of vCJD. An extensive clinical screen excluded infectious, inflammatory and para-neoplastic causes for this condition. Coeliac disease may be causally associated with vacuolar leucoencephalopathy in this case. PMID- 21686701 TI - Mild clinical expression of Lambert-Eaton myasthenic syndrome in a patient with HIV infection. AB - Neuromuscular complications of HIV are related to immunodeficiency, direct cytotoxicity of the virus or side effect of the treatments. Autoimmune disorders involving the nervous system, including Guillain-Barre syndrome, myositis and vasculitis, have been described in association with HIV. Neuromuscular junction autoimmune diseases such as myasthenia gravis have been occasionally reported in patients with HIV, whereas the Lambert-Eaton myasthenic syndrome (LEMS) has never been described. We report an unusual case of paucisymptomatic LEMS in a patient with HIV infection. PMID- 21686702 TI - Rasmussen encephalitis with ipsilateral brain stem involvement in an adult patient. AB - Rasmussen encephalitis is a rare unihemispheric inflammatory disease of the brain that leads to intractable seizures, cognitive decline and progressive neurological deficits associated with the affected hemisphere. It predominantly affects children, with the onset in adults having a milder course. Here the case of an adult woman with Rasmussen encephalitis responsive to immunosupression is reported. PMID- 21686703 TI - An unusual presentation of optic neuritis and the Pulfrich phenomenon. AB - The Pulfrich effect (named after Carl Pulfrich) is a well described visual stereoillusion observed when a swinging pendulum bob is viewed through a neutral density filter in front of one eye. The Pulfrich effect can be demonstrated spontaneously (ie, without a neutral density filter) in patients with multiple sclerosis because of the delayed optic nerve conduction seen after unilateral optic neuritis in multiple sclerosis. Here, a Pulfrich effect is described in a man with subclinical multiple sclerosis who only became symptomatic when playing squash. PMID- 21686704 TI - Relapse of chronic inflammatory demyelinating polyneuropathy 5 years after autologous stem cell transplantation. AB - We describe relapse of chronic inflammatory demyelinating polyneuropathy in a patient who had been in remission for 5 years after treatment with autologous stem cell transplantation. Before the transplant, he needed higher doses of immunosuppressive treatment than are now necessary to maintain his improved condition. He now receives intravenous immunoglobulins at monthly intervals. PMID- 21686705 TI - Sensorineural deafness and male infertility: a contiguous gene deletion syndrome. AB - Syndromic hearing loss that results from contiguous gene deletions is uncommon.Three families with a novel syndrome characterised by deafness and infertility are described. Linkage was established by completing a genome-wide scan and candidate genes in the linked region were screened by direct sequencing. The deleted region is about 100 kb long and involves four genes (KIAA0377, CKMT1B, STRC and CATSPER2), each of which has a telomeric duplicate. This genomic architecture underlies the mechanism by which these deletions occur. CATSPER2 and STRC are expressed in the sperm and inner ear, respectively, consistent with the phenotype in persons homozygous for this deletion. A deletion of this region has been reported in one other family segregating male infertility and sensorineural deafness. We have identified three families segregating an autosomal recessive contiguous gene deletion syndrome characterised by deafness and sperm dysmotility. This new syndrome is caused by the deletion of contiguous genes at 15q15.3. PMID- 21686706 TI - Retroperitoneal and pleural fibrosis in an insulator working in power plants. AB - We describe a case history of a former insulator who developed concomitant retroperitoneal and pleural fibrosis. In his work, the patient had been exposed on a daily basis to asbestos dust while demolishing and installing pipeline insulations. The heavy asbestos exposure was confirmed by a high level of asbestos content in his autopsy lung sample. We propose that both retroperitoneal fibrosis and diffuse pleural thickening were induced in our patient by an abundant amount of amphibole asbestos fibres found in his lung and retroperitoneal tissues. PMID- 21686707 TI - Dramatic response to levetiracetam in post-ischaemic Holmes' tremor. AB - Holmes' tremor refers to an unusual combination of rest, postural and kinetic tremor of extremities. Common causes of Holmes' tremor include stroke, trauma, vascular malformations and multiple sclerosis, with lesions involving the thalamus, brain stem or cerebellum. Although some drugs (eg, levodopa and dopaminergic drugs, clonazepam and propranolol) have been occasionally reported to give some benefit, medical treatment of Holmes' tremor is unsatisfactory, and many patients require thalamic surgery to achieve satisfactory control. We report a patient in whom post-ischaemic Holmes' tremor dramatically responded to levetiracetam treatment. PMID- 21686708 TI - Unusual case of methicillin resistant staphylococcus aureus and acanthamoeba keratitis in a non-contact lens wearer from Kashmir, India. AB - Acanthamoeba species can cause a chronic, progressive, ulcerative keratitis of the eye, which is not responsive to the usual antimicrobial treatment and is frequently mistaken for stromal herpes keratitis. Acanthamoeba keratitis continues to be a burgeoning and unsolved problem. Although soft contact lens wear is reported as the major risk factor in other parts of the world, reports from India suggest that acanthamoeba keratitis is more common among non-contact lens wearers. An unusual case of coinfection with Acanthamoeba and methicillin resistant staphylococcus aureus (MRSA) as causes of corneal keratitis in a contact lens wearer from Kashmir, India, is reported. Recent findings have shown that MRSA uses amoebae to spread, sidestepping hospital and other protection measures. Cysts of the isolated Acanthamoeba tolerated an incubation temperature of 40 degrees C, indicating a pathogenic species. This case highlights the importance of culture methods in the diagnosis of corneal infection and the choice of treatment regimen. PMID- 21686709 TI - A case report of a salivary amylase secreting plasmacytoma in a patient with multiple myeloma. AB - A 70-year-old lady with a past medical history of light chain myeloma, chronic renal failure and a left breast plasmacytoma treated with radiotherapy was admitted for drainage of a subsequent left pleural effusion. She was given high dose steroids for her myeloma, following which she developed abdominal pain suspicious of pancreatitis. Results revealed a raised serum amylase of 5117, a modified Glasgow score of 3 and normal calcium levels. The working diagnosis was drug-induced pancreatitis and steroids were stopped. She remained well and her abdominal pain settled, but amylase remained markedly raised despite no findings of pancreatic pathology. A subsequent isoenzyme test on the amylase found it to be salivary amylase secreted from the plasmacytoma. The patient had her steroid therapy restarted and was allowed to be discharged from hospital. PMID- 21686710 TI - Gas forming liver abscess caused by Klebsiella pneumoniae. PMID- 21686711 TI - Occipital condyle syndrome: self diagnosed. AB - We present the case of a 71-year-old man who presented to us with unilateral lower motor neuron hypoglossal palsy along with the characteristic occipital headache. He himself forwarded a paper on occipital condyle syndrome to the clinician who initially reviewed him. Later the patient underwent a series of investigations that confirmed the diagnosis of underlying prostatic carcinoma with widespread metastasis to bones including the base of the skull. Seven months after the diagnosis he is doing well, his headache is much better and the tongue deviation is stable. He was initially treated with tapering doses of dexamethasone and is currently receiving the depo gonadorelin analogue leuprorelin. PMID- 21686712 TI - Acute small bowel obstruction due to impacted bone: a case report. AB - A 71-year-old man was admitted with features of intestinal obstruction. His past surgical history included an appendicectomy as a child and three laparotomies. A CT scan of the abdomen revealed a high attenuation foreign body impacted in the distal ileum, associated with small bowel obstruction. At laparotomy, a bone was removed from the terminal ileum. PMID- 21686713 TI - G2019S LRRK2 mutation causing Parkinson's disease without Lewy bodies. AB - The G2019S leucine-rich repeat kinase 2 gene (LRRK2) mutation has been identified in a significant proportion of familial and sporadic cases of Parkinson's disease (PD). Until now, information on the neuropathological changes associated with the G2019S LRRK2 mutation has been sparse. We report a 77-year-old patient who presented with a 14 year history of PD but, unexpectedly, histopathological examination disclosed mild neuronal loss in the substantia nigra without alpha synuclein, tau or ubiquitin cytoplasmic inclusions. A G2019S LRRK2 mutation was eventually detected. The present case confirms that clinical PD caused by G2019S mutations can be associated with non-specific nigral degeneration without Lewy. PMID- 21686714 TI - Atypical midgut malrotation presenting as chronic bowel obstruction in the eighth decade. AB - An elderly patient was referred urgently to our rapid access suspected colorectal cancer clinic with symptoms suspicious for malignancy. Despite exhaustive investigations, no cause for his symptomatology could be identified. However, his condition deteriorated and we elected to undertake exploratory surgery, at which time a congenital midgut malrotation, causing chronic small bowel obstruction, was identified. The malrotation was surgical corrected and the patient has made a full recovery. PMID- 21686715 TI - Successful management of intussusception with total polyp clearance in Peutz Jeghers syndrome using a combined endoscopic and surgical approach. AB - Intussusception due to small intestinal polyps in Peutz-Jeghers syndrome represents a significant clinical challenge. Neither pure surgical nor endoscopic approaches alone are effective in the long-term management of this problem. We describe a combined approach using both surgery and small bowel endoscopy in the management of this condition, which resulted in both immediate and long-term success. Although not new, we believe this approach remains relevant despite recent technological advancements in this area. PMID- 21686716 TI - Total removal of cervicothoracic intramedullary 160-mm-long spinal cord ependymoma: a rare case report. AB - Ependymomas are neuroectodermal tumours arising from ependymal cells of the ventricular system, choroid plexus, filum terminale, or central canal of the spinal cord. We report on a 160-mm-long cervicothoracic intramedullary spinal cord ependymoma. The tumour was totally removed; no radiotherapy was used as an adjunctive therapy. Postoperative magnetic resonance imaging confirmed that the tumour had been totally removed. PMID- 21686717 TI - Scleromyexdema? PMID- 21686718 TI - Milky ascites after loss to follow-up. PMID- 21686719 TI - Human herpesvirus type 6 hepatitis or familiar intrahepatic cholestasis: the importance of follow-up. AB - A 1-month-old child presented to our unit with jaundice and raised aminotransferases, gamma-glutamyltranspeptidase and bilirubin. Metabolic diseases were ruled out and ultrasound found no alterations. Human herpesvirus type 6 (HHV 6) DNA was found in blood and saliva and IgG anti-HHV-6 in serum, and a diagnosis of HHV-6 hepatitis was made. In the following weeks, aminotransferase values remained raised while gamma-glutamyltranspeptidase levels returned to normal in 45 days. At the age of 5 months symptoms and elevated aminotransferases persisted and immunohistochemistry performed on liver tissue allowed a diagnosis of progressive familiar intrahepatic cholestasis type 2 to be made. The patient is now 7 months old, and cholestatic jaundice and pruritus continue to be present. PMID- 21686720 TI - Brain metastases from pancreatic adenocarcinoma. AB - Brain metastases from pancreatic adenocarcinoma (PA) are extremely rare. We report the case of a patient with PA treated by chemotherapy for liver and lung metastases. In spite of efficient control of the disease and an overall survival of more than 4 years with chemotherapy, the patient developed brain metastases. Brain metastases were revealed by headaches with mental confusion, and diagnosed by cerebral computed tomography scan. Treatment by radiotherapy could not be started because of the rapid fatal outcome of the disease. TRIAL REGISTRATION NUMBER: REFERENCE PUBMED (PMID): 17158774. PMID- 21686721 TI - Travoprost and latanoprost, but not bimatoprost, induced nausea, vomiting and diarrhoea. AB - A 46-year-old woman with glaucoma secondary to chronic iridocyclitis complained of nausea, vomiting and diarrhoea upon topical application of travoprost and latanoprost. Unmasked dechallenge and rechallenge with both travoprost and latanoprost were carried out. Challenge with bimatoprost on both eyes was also performed. Travoprost and latanoprost, but not bimatoprost, induced nausea, vomiting and diarrhoea. Based on the findings of unmasked dechallenge and rechallenge, nausea, vomiting and sometimes diarrhoea should be considered as adverse effects of travoprost and latanoprost. In this report, bimatoprost did not induce the same gastrointestinal adverse effects, probably due to its different chemical structure and receptors. PMID- 21686722 TI - Ruptured abdominal aortic aneurysm presenting as testicular pain. AB - A 70-year-old man presented with severe right testicular pain radiating to the groin, and was admitted under the urologist. A kidney, ureter and bladder CT scan showed a leaking abdominal aortic aneurysm (AAA). The presentation, nature and management of a leaking AAA are reviewed. PMID- 21686723 TI - New formulation of Botox: complete antibody-induced treatment failure in cervical dystonia. AB - Botulinum toxin is used with remarkable success to treat various muscle and exocrine gland hyperactivity syndromes. Rarely, treatment failure due to formation of botulinum toxin antibodies (ABF) occurs. To reduce the risk of ABF, a new formulation of Botox (in the following "current Botox"; Allergan, Irvine, California, USA) with increased specific biological potency was introduced. Here we report the case of a 50-year-old woman who developed ABF despite receiving current Botox. PMID- 21686724 TI - Steal phenomenon in the lower limb: presentation of a case with osseous metastases secondary to renal cell carcinoma and review of the literature. AB - Renal cell carcinoma is reported to have potent angiogenic activity with a high microvascular density in both primary and metastatic sites compared with other adenocarcinomas. Angiogenesis can lead to the formation of abnormal arteriovenous shunts that can, in patients with peripheral vascular disease, result in worsening of the degree of ischaemia by producing a vascular steal-like phenomena. Nevertheless, steal phenomena secondary to malignancies are extremely rare. We report a case of distal critical limb ischaemia in a patient with peripheral vascular disease exacerbated by massive arteriovenous shunting due to tibial metastases from renal cell carcinoma. PMID- 21686725 TI - Left renal pseudocyst associated with alcoholic chronic pancreatitis. PMID- 21686726 TI - A black femoral head. PMID- 21686727 TI - Argyria: permanent skin discoloration following protracted colloid silver ingestion. PMID- 21686728 TI - Late fracture of a Burch-Schneider acetabular cage: rare occurrence following polyethylene cup wear. AB - We report a case of a 46-year-old male patient who sustained a fracture of the Burch-Schneider anti-protrusio cage (APC) that was implanted 13 years before. The fracture occurred in the transitional area to the proximal flange and was caused by direct and recurrent contact between the prosthetic metal head and the acetabular device. Late failure was related to increased wear of the polyethylene cup further aggravated by vertical orientation of the cage. Revision surgery included acetabular reconstruction using a new APC and cross-linked polyethylene cup, and replacement of the 36 mm diameter ball head. At 18 months follow-up the patient showed a complete functional recovery. When a reconstruction device is used, particularly in a young patient, special attention should be paid to the correct positioning of the cage in order to prevent accelerated polyethylene wear. Furthermore, cross-linked polyethylene cups that have become available in recent years must be used. PMID- 21686729 TI - Cerebral atypical teratoid rhabdoid tumour arising in a child treated for acute lymphoblastic leukaemia. AB - Atypical teratoid rhabdoid tumours (ATRT) are rare, arising typically in childhood. ATRT arising as a secondary tumour in children treated for acute lymphoblastic leukaemia have not been reported so far. We report a case of ATRT in a 17-year-old boy, 11 years after he was treatment for acute lymphoblastic leukaemia with cranial radiation. PMID- 21686730 TI - Congenital laryngomucocoele: a rare cause for CHAOS. AB - Congenital high airway obstruction syndrome (CHAOS) is a rare but life threatening condition that results from the obstruction of the upper airways.We describe a female newborn, from a Gravida II, Para 0, 36-year-old woman, with a routine ultrasound at 30 weeks' gestation that showed polyhydramnios. She delivered a live-born female baby at 36 weeks without any dismorphic features but with respiratory distress. Attempts at endotracheal intubation were unsuccessful due to the presence of a mass obstructing the larynx. The reanimation process was stopped after 20 minutes. Post-mortem examination demonstrated the presence of a total occlusion of the larynx by a laryngomucocoele. Laryngocele, a congenital cyst of the larynx, occurs rarely and hardly ever as a cause of CHAOS. What is more, laryngomucocoele has not been previously reported as a cause of CHAOS. These conditions represent a neonatal emergency with reserved prognosis unless diagnosed antenatally allowing for a programmed ex utero intrapartum treatment (EXIT) by performing tracheostomy while maintaining the placental circulation. PMID- 21686731 TI - Right hemisphere dominance for understanding the intentions of others: evidence from a split-brain patient. AB - Understanding the actions performed by other people is a key aspect of social interaction, including in clinical settings where patients are learning from therapists and caregivers. While lesions of the left cerebral hemisphere induce praxic disorders, the hemispheric specialisation of intention understanding remains unclear. Do patients with a right hemispheric lesion understand the intentions of other people properly? The present study investigates how a split brain patient understands the means (what) and intentions (why) of the actions of other people. Results show a significant left hemispheric dominance for understanding what is done, and a significant right hemispheric dominance for understanding why an action is carried out. This discovery might have important clinical implications in neurological patients, especially when those with right hemisphere lesions are faced with important decisions related to the interpretation of other's intentions. PMID- 21686732 TI - Septic pulmonary embolism associated with a peri-proctal abscess in an immunocompetent host. AB - Septic pulmonary embolism is an uncommon disease in which septic thrombi are mobilised from an infectious nidus and transported in the vascular system of the lungs. It is usually associated with tricuspid valve vegetation, septic thrombophlebitis or infected venous catheters. We report an immunocompetent young man who presented with fever and pleuritic chest pain. Chest roentgenography and CT showed multiple ill-defined nodules, with central cavitation and feeding vessels. He was found to have a clinically infectious source of methicillin resistant staphylococcus aureus (MRSA) cultured from the peri-proctal abscess with the same bacteraemia. Pulmonary septic embolism from peri-proctal abscess was diagnosed by image study and bacterial culture correlation. All of the clinical presentations improved after the incision of the peri-proctal abscess and anti-MRSA antibiotics treatment. PMID- 21686733 TI - Deliberate overdose with Epsom salts. AB - Epsom salts contains the active compound magnesium sulfate and is used most commonly as a laxative. There are potential serious toxic effects, including cardiac arrest, when the serum concentration rises above therapeutic values. We present a case of deliberate self poisoning with a large quantity of Epsom salts, resulting in a toxic serum magnesium concentration of 9.7 mmol/l (0.70-1.0 mmol/l). Clinical features included limb weakness, vomiting and confusion, with a subsequent rapid deterioration in level of consciousness and bradydysrhythmia. There was no significant response to calcium gluconate, so haemodialysis was urgently arranged. The patient made a full recovery. Hypermagnesaemia is unusual in patients with normal renal function. Although clinical severity does not always correlate with serum magnesium values, risk of cardiac arrest occurs with concentrations >6 mmol/l. Initial treatment is supportive. Dialysis should be considered when life threatening features or renal impairment are present. PMID- 21686734 TI - Multiple fractures due to osteogenesis imperfecta mistaken as child abuse. AB - A 15-month-old African-American boy receiving chemotherapy for Wilms tumour was diagnosed to have a fracture of left femur at the emergency department (ED) of our hospital. A month earlier, the patient had been seen at the same ED for a fracture of right femur. The skeletal survey this time also showed an old posterior rib fracture. Child abuse was suspected. The child's custody was transferred to the maternal grandparents. However, 2 months later while with the grandparents, he sustained a fracture of the left distal tibia. This led to an investigation for osteogenesis imperfecta (OI). The child was found to have a collagen mutation, COL1A1, strongly suggesting that the child's multiple fractures were most likely due to OI.The child had no physical stigmata of classical OI except for blue sclera. Multiple bone fractures alone without other physical signs of abuse should always raise a possibility of OI. TRIAL REGISTRATION NUMBER: POG9440. PMID- 21686735 TI - Lymphatic system anomalies in Crouzon syndrome. AB - Crouzon syndrome is a rare genetic disorder characterised mainly by distinctive malformations of the skull and facial region and caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. No study reported on oedemas related to lymphatic system abnormalities in these patients. A case of Crouzon syndrome displaying classic facial anomalies but also with bilateral lower limb oedema is reported in whom lymphoscintigraphic investigation of the limbs clearly delineated the presence of lymphatic system anomalies. PMID- 21686736 TI - Fistula on the upper back revealing extensive pulmonary actinomycosis with epidural abscess and spondylitis. PMID- 21686737 TI - Spontaneous rupture of hepatocellular carcinoma presented as low back pain to an emergency department: a case report. AB - INTRODUCTION: Spontaneous haemoperitoneum due to rupture of hepatocellular carcinoma (HCC) is a surgical emergency and may have catastrophic outcomes. CLINICAL PICTURE: A 62-year-old male presented with nausea, dizziness and low back pain. There was no history of malignancy. Physical examination revealed a surgical abdominal emergency, but there was no physical finding that pointed towards a specific diagnosis. Laboratory studies revealed decreased haematocrit (27.6%) and increased INR (2.8) levels. A computed tomography scan showed a tumoral lesion within the fourth segment of the liver and fluid collection (haemoperitoneum) with normal vascular and intra-abdominal structures. TREATMENT: Exploratory laparotomy was performed; the appearance of the liver was cirrhotic and nodular. Actively bleeding tumoral lesion was confirmed in fourth segment of the liver, "packing" applied with sponges to stop bleeding. On the post-operative day 22, the patient was discharged. CONCLUSIONS: Spontaneous rupture of HCC is rare and should be considered in the differential diagnosis of non-traumatic spontaneous haemoperitoneum. PMID- 21686738 TI - Concomitant cystic fibrosis and coeliac disease: reminder of an important clinical lesson. AB - A 31/2-year-old apparently healthy girl with normal development presented with steatorrhoea. Both positive serum anti-tissue transglutaminase antibody levels and an intestinal biopsy were consistent with coeliac disease. A positive sweat test and genetic analysis confirmed cystic fibrosis. PMID- 21686739 TI - Recurring paralysis. AB - A 22-year-old Chinese man presented with sudden onset of generalised muscular weakness and paralysis upon awakening in the morning, due to sporadic periodic paralysis (SPP), a type of hypokalaemic periodic paralysis (HPP) without hyperthyroidism or familial history of paralysis. Laboratory studies showed marked hypokalaemia (K(+) 1.6 mmol/litre). He received intravenous KCl supplementation at a rate of 0.14 mmol/kg/h and developed a paradoxical fall in serum K(+) concentration from 1.6 to 1.4 mmol/litre during KCl therapy. After 160 mmol KCl supplementation his muscular strength recovered, but muscular paralysis recurred 2 h later. Acute recurrent hypokalaemia was the presumptive initial diagnosis and intravenous KCl supplementation was briefly reinitiated. Despite no obvious abnormalities on ECG monitoring, a 12-lead ECG clearly demonstrated tented T waves in the precordial leads suggestive of hyperkalaemia, later found to be 6.9 mmol/litre. After treatment with intravenous calcium gluconate, insulin and loop diuretics, his serum K(+) concentration fell to 4.7 mmol/litre and muscular paralysis resolved in 3 h. PMID- 21686740 TI - Fugue associated with migraine. AB - Fugue states are characterised by a complete loss of memory for all personal details. Although often witnessed on stage and screen, real-life fugue states are rare. They are often psychogenic and rarely organic in origin. Here a case of fugue in a patient with migraines is reported. It is possible that cerebral vasoconstriction in this case caused the memory impairment; this is supported by cerebral hypo-perfusion demonstrated on SPECT scanning. The patient's fugue resolved after treatment for migraine. PMID- 21686741 TI - A case of an 18-year-old male rugby union forward with a C5/C6 central disc herniation. AB - The patient was an 18-year-old front row forward rugby player who had a history of episodic neck pain for over 2 years following playing games of rugby. The initial event of April 2005 for which the symptoms manifested was a scrum collapse; he continued playing until a front-on tackle occurred when the symptoms dictated that he leave the field and be taken to the local hospital. A diagnosis of a cervical sprain was made and conservative management ensued. During the selections held on January 2008, a medical assessment was made and an MRI found that he had a central disc herniation at C5/C6. He was referred to a spinal orthopaedic surgeon for further treatment. The risks to cervical spinal injuries are illustrated in this case, in a scrum and in the tackle. The prevention of such an injury is discussed. PMID- 21686742 TI - Acute pericarditis with transient constriction: surgical impetus must be contained. AB - Constrictive pericarditis is typically a chronic and progressive condition characterised by debilitating chronic right heart failure and surgical pericardiectomy remains the treatment of choice. Although most cases of acute pericarditis are self-limiting, an uncommon but known complication is a transient form of constrictive pericarditis that shares the same clinical features with the chronic form but resolves without surgical intervention.We report a case of a 29 year-old man with acute idiopathic pericarditis complicated with overt signs of constriction with complete recovery after medical treatment. The knowledge of this transient pattern of cardiac constriction complicating acute pericarditis may avoid unnecessary morbidity and mortality related to surgical procedure in a pericardium with acute inflammatory reaction. PMID- 21686743 TI - Sarcoidosis with basal ganglial infiltration presenting as Parkinsonism. AB - The present report describes the case of a woman with symptoms of Parkinsonism (slow and monotonous speech, left foot dragging and micrographia) that gradually developed over a period of 12 months. She had a 10-month history of untreated, asymptomatic sarcoidosis diagnosed by routine biopsy of an enlarged left supraclavicular lymph node. After her condition deteriorated, a brain MRI showed right basal ganglial areas of haemorrhage with perilesional fast fluid-attenuated inversion-recovery (FLAIR) abnormalities. Right stereotactic frame-based brain parenchymal biopsy of the lesion site revealed reactive central nervous system (CNS) tissue with perivascular chronic inflammation and non-caseating granulomas consistent with definite neurosarcoidosis. The patient was started on a high dose of prednisone with good initial response. When mild progression was noted within the next 12 months azathioprine was added to her treatment. The patient's neurological status has been stable without progression of her Parkinsonian symptomatology. PMID- 21686744 TI - Unable to weight-bear: a common presentation in emergency department that always needs thorough assessment: a case report. AB - Femoral neck fracture in young individuals with an unusual mechanism of injury is uncommon. We report a case of grade 3 fracture in young adults without significant trauma. This case reinforces the need for a thorough assessment of the hip joint even after an apparently trivial mechanism of injury. PMID- 21686745 TI - Extra-adrenal paravertebral myelolipoma mimicking a thoracic schwannoma. AB - Myelolipoma of the adrenal gland is composed of both adipose tissue and normal haematopoietic elements. Extra-adrenal myelolipomas are rare. We present the case of a 63-year-old female patient with adenoma of the adrenal gland and an additional paravertebral lesion in the thoracic spine. Previous computed tomography of the lesion covering the nerve roots in the right T8-T9 foramina was compatible with a schwannoma. Post-mortem histopathology showed the incidental finding of a paravertebral myelolipoma. PMID- 21686746 TI - Dandy-Walker malformation. PMID- 21686747 TI - Parkinson's disease misdiagnosed as stroke. AB - Parkinson's disease (PD) is a neurodegenerative disease, the clinical features of which are usually asymmetrical at presentation. This can lead to difficulty in differentiating it from other asymmetric neurological disorders. We present two cases where idiopathic PD was initially misdiagnosed as stroke, leading to a delay in appropriate symptomatic therapy. Physicians involved in diagnosis and treatment of people with strokes should consider PD when formulating their differential diagnosis. PMID- 21686748 TI - Nd-YAG laser treatment in a patient with complicated pilonidal cysts. AB - A 38-year-old woman with a recurrent suppurative pilonidal cyst was successfully treated causally with an Nd-YAG (neodymium-doped yttrium aluminium garnet) laser, and with no recurrence at 3-month follow-up. A similar success was observed for another 15 consecutively treated patients, including suppurative cases. The effect could be attributable to the ability of the YAG laser to operate at a wavelength of 1064 nm and to penetrate the skin to levels deeper than that of most other lasers before the energy is absorbed in melanin and oxyhaemoglobin. Consequently, the contents of the cyst can be reached and destroyed. The treatment could be a very attractive alternative to open surgery. PMID- 21686749 TI - A rare association of B cell lymphoma and ectodermal dysplasia presenting with protein-losing enteropathy. AB - This patient, known to have ectodermal dysplasia, was referred to the hospital to investigate the cause for his significant pedal oedema and hypoproteinaemia. Investigations ruled out protein loss from the kidney and there was no evidence of chronic liver disease. Protein-losing enteropathy became a diagnosis of exclusion. To investigate it further, he underwent an oral gastroduodenoscopy and a computed tomography scan of the abdomen, which showed an abnormal duodenal mucosa and extensive retroperitoneal lymphadenopathy. Biopsies confirmed this to be grade II follicular non-Hodgkin lymphoma. The lymphadenopathy was causing obstructive hydronephrosis, which required a nephrostomy. He received a course of steroids and chemotherapy. His condition, however, deteriorated and he died. PMID- 21686751 TI - High output heart failure caused by extensive arteriovenous malformation: problems and pregnancy. AB - ARTERIOVENOUS MALFORMATION (AVM) OCCURRING IN ASSOCIATION WITH SOFT TISSUE AND SKELETAL HYPERTROPHY FORMS THE BASIS OF THE PARKES WEBER SYNDROME: a rare congenital angio-osteohypertrophy condition with no obvious racial, gender or geographic preference. Usually in the lower limbs, the AVM can result in a dilated cardiomyopathy due to a high output cardiac state. We describe the case of a 21-year-old woman with an extensive AVM affecting one leg, which included the pelvic vasculature. The case concerns assessment of the current high output "heart failure" and her cardiovascular risk from future pregnancy. PMID- 21686750 TI - De novo HRAS and KRAS mutations in two siblings with short stature and neuro cardio-facio-cutaneous features. AB - Mutations in genes involved in Ras signalling cause Noonan syndrome and other disorders characterised by growth disturbances and variable neuro-cardio-facio cutaneous features. We describe two sisters, who presented with dysmorphic features, hypotonia, retarded growth and psychomotor retardation. The patients were initially diagnosed with Costello syndrome, an autosomal recessive inheritance was assumed. Remarkably, however, we identified a germline HRAS mutation (G12A) in one sister and a germline KRAS mutation (F156L) in her sibling. Both mutations had arisen de novo. The F156L mutant K-Ras protein accumulated in the active, guanosine triphosphate-bound conformation and affected downstream signalling. The patient harbouring this mutation was followed for three decades, and her cardiac hypertrophy gradually normalised. However, she developed severe epilepsy with hippocampal sclerosis and atrophy. The occurrence of distinct de novo mutations adds to variable expressivity and gonadal mosaicism as possible explanations of how an autosomal dominant disease may manifest as an apparently recessive condition. PMID- 21686752 TI - Ocular blunt trauma: loss of sight from an ice hockey injury. AB - A case of ocular blunt trauma is described where a 17 year old male collided with an opponent during a game of ice hockey. The opponent's stick travelled under his half-face visor and struck his left eye causing hyphema, angle recession, lens subluxation and choroidal rupture over the macula, reducing his vision to counting fingers permanently. Sequelae of ocular blunt trauma are discussed along with methods of injury prevention by addressing players' behaviour and safety equipment. This injury is unlikely to have occurred with properly used full-face protection. PMID- 21686753 TI - Small bowel angiodysplasia in a patient on haemodialysis: difficulties in diagnosis and management. AB - Angiodysplasia is a common cause of gastrointestinal blood loss in patients with end stage renal disease. Diagnosis is especially difficult when the angiodysplastic lesions are concentrated in the small bowel. This report describes a case of a patient on haemodialysis who had transfusion-dependent anaemia from small bowel angiodysplasia. Endoscopic treatment was unsuccessful, tranexamic acid caused complications with thrombosis, and thalidomide showed no benefit. This case report highlights the problems in the diagnosis and management of this condition in patients on haemodialysis. Early diagnosis and optimisation of the patient for treatment is key to the successful outcomes of such patients. PMID- 21686754 TI - Ablative thyroid treatment for thyrotoxicosis due to thyrotropin-producing pituitary tumours. AB - Thyrotropin (TSH)-secreting pituitary adenomas (TSHomas) are rare tumours. It has been suggested that thyroid surgery or radioiodine treatment should not be considered in patients with such tumours as these treatments may facilitate rapid tumour expansion. We studied the effects of thyroid ablative treatment on tumour size and thyroid status in two patients with TSHomas. Patients studied were: (1) a female with a TSHoma who declined to undergo pituitary surgery and underwent a total thyroidectomy instead and (2) a male patient who opted for radioiodine treatment for his recurrent TSHoma. Changes in tumour size on serial magnetic resonance imaging scans, and restoration of euthyroidism were studied. No marked changes in tumour size or features of aggressiveness occurred in these patients over periods of 8 and 12 years. Euthyroidism was restored and maintained in both patients. Ablative thyroid treatment can be a safe and successful option to treat TSHomas. PMID- 21686755 TI - Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications? AB - Chronic consumption of alcohol represents one of the greatest health and socioeconomic problems worldwide. We report on a 54-year-old patient with a severe anxiety disorder and secondary depressive disorder in whom bilateral deep brain stimulation (DBS) of the nucleus accumbens was carried out. Despite the absence of desired improvement in his primary disorder, we observed a remarkable although not primarily intended alleviation of the patient's comorbid alcohol dependency. Our case report demonstrates the extremely effective treatment of alcohol dependency by means of DBS of the nucleus accumbens and may reveal new prospects in overcoming therapy resistance in dependencies in general. PMID- 21686756 TI - Metastatic osteosarcoma to the liver and the kidney: a case report and review of the literature. AB - Improvements in multimodal treatment for osteosarcoma, especially in the use of adjuvant chemotherapy, have increased event-free and overall survival. Meanwhile, the prolonged survival of patients has permitted the appearance of new, significant, extrapulmonary targets for metastasis. Here we report a middle-aged adult with osteosarcoma who developed hepatic and renal metastases 4 months after the diagnosis of osteosarcoma. Chemotherapy and radiofrequency ablation were performed. CT scan has shown that the metastatic lesion has stabilised in the liver and kidney in the latest follow-up. This suggests that early multimodal treatment may improve both the survival rate and the quality of life of osteosarcoma patients with extrapulmonary metastases. PMID- 21686757 TI - C34T mutation of the AMPD1 gene in an elite white runner. AB - The case is reported of an elite, male, white endurance runner (28 years of age), who is one of the best non-African runners in the world despite carrying the C34T mutation in the gene (AMPD1) that encodes the skeletal muscle specific isoform of AMP deaminase, an enzyme important in muscle metabolism. The frequency of the mutant allele in sedentary white people is 8-11%. Previous research has shown that this mutation, at least in homozygotes, can impair the exercise capacity of untrained people and their trainability. The maximum oxygen uptake (VO(2MAX)) of the study subject was exceptionally high (83.6 mlO(2)/kg/min), whereas his ammonia and lactate concentrations at high submaximal running speeds were lower than those of other world class runners who are not carriers of the mutation. The partial metabolic deficiency of the study subject is possibly compensated for by his exceptionally favourable anthropometric characteristics (body mass index 18.2 kg/m(2)). PMID- 21686758 TI - Neuro-Sweet disease: report of the first autopsy case. AB - BACKGROUND: Neuro-Sweet disease is a rare condition of central nervous involvement accompanied by cutaneous Sweet lesions. Neuropathological changes in neuro-Sweet disease are unknown. OBJECTIVE: To describe post-mortem findings of the first case of neuro-Sweet disease. RESULTS: A 44-year-old Japanese man developed recurrent episodes of cerebral and brainstem encephalitis with cutaneous Sweet lesions from the age of 34 years. His HLA typing was B54 and Cw1, and the symptoms and MRI abnormalities markedly subsided following corticosteroid therapy. Histologically, there were multiple lesions of perivascular cuffing of small venules by macrophages without vasculitis in the thalamus, temporal lobe, basal ganglia, pons, leptomeninges or ventricular ependym. CONCLUSIONS: THE CORE NEUROPATHOLOGICAL FINDINGS WERE: perivascular cuffing around particularly small veins; absence of granulomatous or necrotic angitis; mainly macrophage infiltration; and the thalamus being most affected. In the present case, the diagnosis of neuro-Sweet disease was made by skin biopsy 5 years after the onset of the central neuron system symptoms. We should pay more attention to skin lesions in steroid responsive recurrent encephalitis in patients who are HLA-B54 or Cw1 positive. PMID- 21686759 TI - Severe herpes zoster in an immunocompromised patient. PMID- 21686760 TI - Isolated shoulder palsy due to cortical infarction: localisation and electrophysiological correlates of recovery. AB - The corticospinal tract influences the distal musculature more than the proximal, and the mechanisms involved in recovery of proximal muscle strength after stroke are unclear. A 65 year old man developed right shoulder weakness due to infarction in the left precentral gyrus. MRI showed a 3 mm cortical-subcortical ischaemic lesion in the superior genu of the left precentral gyrus medially to the knob-like structure corresponding to the motor area of the hand. Two months after stroke, when the patient was able to abduct the right arm against gravity and seven months after stroke when the patient had almost completely recovered, maximal TMS of the contralateral and ipsilateral motor cortex during voluntary contraction did not evoke a MEP in the right deltoid either with a focal or a non focal coil. Recovery of proximal muscles in these cases may be mediated by elements other than the fast corticospinal neurones responsible for MEP generation. PMID- 21686761 TI - Non-convulsive status epilepticus causing focal neurological deficits in CADASIL. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by mutations of the Notch3 gene. Clinical manifestations include migraine with or without aura, psychiatric disorders, recurrent ischaemic strokes and cognitive decline. Brain MRI shows confluent hyperintense signal alterations involving characteristically the anterior part of the temporal lobes and widespread areas of the deep and periventricular white matter. Focal or generalised seizures represent a rare neurological manifestation in CADASIL with a frequency of 6-10% in two large series.1(,)2 Status epilepticus, however, has not been reported so far. Herein we describe a patient with CADASIL with an acute focal neurological deficit following a prolonged migraine attack. The symptoms were first interpreted as an ischaemic stroke but subsequently diagnosed to be due to a non convulsive status epilepticus. PMID- 21686762 TI - Poliomyelitis-like syndrome with matching magnetic resonance features in a case of Lyme neuroborreliosis. AB - Lyme disease is a multisystemic disorder caused by an epizootic organism of the spirochete group, called Borrelia burgdorferi (Bb), which is transmitted to humans by ticks of the genus Ixodes. Lyme neuroborreliosis may occur during the early dissemination phase, most often as a painful meningo-radiculitis and very rarely as a radiculo-myelitis, whereas encephalomyelitis is observed in the late phase. We report the case of a patient with an early subacute poliomyelitis-like syndrome closely matching the selective involvement of the anterior horns and roots of the cervical spinal cord seen on magnetic resonance (MR) imaging. This condition improved with appropriate antibiotics. PMID- 21686763 TI - Reactivation of herpes zoster along the trigeminal nerve with intractable pain after facial trauma: a case report and literature review. AB - We report the rare occurrence of herpes zoster reactivation after facial trauma. Herpes zoster appeared in painful groups of distended vesicles containing clear fluid on an erythematous base within the secondary division of the trigeminal nerve. The patient was treated with acyclovir (intravenous, 250 mg, every 8 hours) combined with topical steroids and anti-neuropathic pain medication. The zoster-associated neuralgia subsided gradually 1.5 months after diagnosis. We illustrate this unique case to highlight the fact that reactivation of the varicella zoster virus from childhood chicken pox can reappear at a traumatic site in late adulthood. PMID- 21686764 TI - Refeeding syndrome, an undiagnosed and forgotten potentially fatal condition. AB - Refeeding syndrome (RFS) has been well described but is also a frequently forgotten and undiagnosed complication in clinical practice, which, if untreated, may lead to death. Patients who are more prone to developing RFS are those with at least one of the following conditions: BMI <16 kg/m(2), a recent unintentional weight loss >15%, very little nutritional intake for >10 days, and/or low plasma concentrations of potassium, phosphate or magnesium before feeding; and those with at least two of the following conditions: BMI <18.5 kg/m(2), a recent weight loss >10%, very little nutritional intake for >5 day, and/or a history of alcohol abuse or drug use, including insulin, chemotherapy or diuretics. We report here a patient who, after undergoing intestinal resection (short gut syndrome), presented diarrhoea, weight loss and protein-energy malnutrition. After nutritional assessment, the nutritional support team decided to feed the patient by the parenteral route. After 16 h of parenteral nutrition, the patient developed supraventricular tachycardia, hypomagnesaemia and hypocalcaemia, and RFS was diagnosed and managed. After intestinal adaptation, the patient is currently able to maintain his nutritional status with nutrition therapy by the oral route. PMID- 21686765 TI - Lymphoedema: a paradoxical effect of tumour necrosis factor inhibitors - case report and review of literature. AB - This report describes the development of lymphoedema in a patient with rheumatoid arthritis (RA) who was treated with tumour necrosis factor alpha (TNFalpha) inhibitors.The patient was a 62-year-old woman with a long-standing history of RA that had been uncontrolled with steroids and methotrexate. Eight months after initiation of treatment with TNFalpha inhibitors she developed progressive symmetrical ascending non-pitting oedema of both legs with extensive keratinisation. A diagnosis of lymphoedema was made based on the clinical presentation and exclusion of alternative diagnoses. Skin biopsy showed dermatosclerosis consistent with lymphoedema. The temporal relationship suggested a link between the initiation of TNFalpha inhibitors and the development of lymphoedema. TNFalpha inhibitors are widely used to treat inflammatory diseases including lymphoedema. Paradoxically, there are reports suggesting the appearance of psoriasis, vasculitis and other inflammatory cutaneous conditions after the use of TNFalpha inhibitors. A review of literature is also presented. PMID- 21686766 TI - Retained surgical swab following breast augmentation: a rare cause of a breast mass. AB - Retained surgical swab or sponge following surgery is an uncommon finding seen most commonly following abdominal and pelvic procedures. Reports of such lesions in the breast are particularly rare with only two previously published cases. We report here the first case of a retained swab following breast augmentation where unique diagnostic problems are encountered because of the presence of implants. This case shows that a retained swab should be considered in the differential diagnosis of any postoperative breast mass and highlights that ignoring the fundamental principles of any surgical procedure can cause serious complications. PMID- 21686767 TI - One man, one disease? AB - We report the case of a 12-year-old girl with a strong family history of malignancy who presented with immature teratoma and gliomatosis peritonei. Despite first and second line chemotherapy, the disease ran an unusually refractory course. Although the presentation was not the typical tumour presentation of Li-Fraumeni syndrome (LFS), we proceeded to undertake tumour genetic testing of the patient and her parents. LFS was diagnosed in this patient and her father with a sequence variation of CGG>TGG, R248W, which is one of the most common transcriptionally inactive mutations detected in LFS. Genetic counselling was offered to the father. A tumour screening programme and genetic screening for the p53 gene mutation for the surviving family members can be offered once consent is obtained from the father. This case illustrates the importance of cancer genetic study, even if the tumour presentation is not typical for any familial cancer syndrome. PMID- 21686768 TI - Acute methaemoglobinaemia after massive nitrobenzene ingestion. AB - Flower-N is a flowering stimulant composition with 22% nitrobenzene. The main systemic effect associated with human exposure to nitrobenzene is methaemoglobinaemia. A 25-year-old female presented after 3 hours following ingestion of 100 ml of 22% Nitrobenzene (Flower-N). Her initial methaemoglobin (MetHb) was 81%; this responded to methylene blue. However, she developed recurrent methaemoglobinaemia on days 3 and 5 with haemolytic anaemia. The treatments that were provided were repeated methylene blue treatment and exchange transfusion. Nitrobenzene ingestion is a known cause of methaemoglobinaemia and haemolytic anaemia. The recurrence suggests a long half-life. The recurrent MetHb has clinical implications as patients may require repeated treatment. Massive nitrobenzene ingestion can cause haemolysis and recurrent methaemoglobinaemia. PMID- 21686769 TI - Rapid improvement of diffusion-weighted imaging abnormalities after glucose infusion in hypoglycaemic coma. AB - Diffusion-weighted imaging (DWI) may detect hyperintense lesions in patients with transient hypoglycaemia-induced hemiparesis or coma, which are completely reversible after glucose infusion.1(-)3 In vivo animal studies have documented the visualisation of such hypoglycaemia-induced changes of signal intensity and the reversal by glucose intake in detail.4 However, the time necessary for hyperintense lesions on DWI to disappear after glucose infusion in humans is still unclear. A 54 year old woman presented comatose with brain stem signs and severe hypoglycaemia. DWI demonstrated hyperintense lesions in the corpus callosum and internal capsules. She was treated with IV glucose. These lesions had resolved significantly on imaging 2 hours later and completely resolved on repeat imaging 2 days later. This report documents the time course of recovery of neurological lesions induced by hypoglycaemia after treatment with IV glucose. PMID- 21686770 TI - Myeloma induced osteolysis and nephromegaly. PMID- 21686771 TI - Reversible limbic encephalitis with antibodies against the membranes of neurones of the hippocampus. AB - The authors report a patient with limbic encephalitis associated with an ovarian teratoma. An antibody against the membranes of neurones of the hippocampus was identified in both serum and CSF. Immunosuppressive treatments such as plasmapheresis and high-dose intravenous immunoglobulin administration resulted in a rapid clinical recovery. PMID- 21686772 TI - Megarectum in goitrous hypothyroidism. PMID- 21686773 TI - Hydrocephalus induced chorea. AB - Chorea can result from many causes, and the diagnostic workup can be challenging. Although often accompanied by other extrapyramidal symptoms, hydrocephalus has not been mentioned as a possible cause of chorea to date. Here we report an unusual case of chorea secondary to normal pressure hydrocephalus, which clearly improved after shunt placement. PMID- 21686774 TI - A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy. AB - To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder.Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing.A homoplasmic nonsense mutation m.8529G->A (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue. Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNAWe describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme. PMID- 21686775 TI - Identification of a novel PEX14 mutation in Zellweger syndrome. AB - Here we report a patient with Zellweger syndrome, who presented at the age of 3 months with icterus, dystrophy, axial hypotonia, and hepatomegaly. Abnormal findings of metabolic screening tests included hyperbilirubinaemia, hypoketotic dicarboxylic aciduria, increased C(26:0) and decreased C(22:0) plasma levels, and strongly reduced plasmalogen concentrations. In fibroblasts, both peroxisomal alpha- and beta-oxidation were impaired. Liver histology revealed bile duct paucity, cholestasis, arterial hyperplasia, very small branches of the vena portae, and parenchymatic destruction. Immunocytochemical analysis of cultured fibroblasts demonstrated that the cells contain peroxisomal remnants lacking apparent matrix protein content and PEX14, a central membrane component of the peroxisomal matrix protein import machinery. Transfection of fibroblasts with a plasmid coding for wild-type PEX14 restored peroxisomal matrix protein import. Mutational analysis of this gene revealed a genomic deletion leading to the deletion of exon 3 from the coding DNA (c.85-?_170+?del) and a concomitant change of the reading frame (p.[Ile29_Lys56del;Gly57GlyfsX2]). PMID- 21686776 TI - Diarrhoea caused by a stenosis of the coeliac artery: suggestive for mesenteric steal. AB - The classical triad of postprandial pain, weight loss and an abdominal bruit is thought to be the most common presentation of chronic gastrointestinal ischaemia. We describe a patient with severe diarrhoea as an uncommon presenting symptom of small bowel ischaemia, suggesting a mesenteric steal phenomenon due to a significant atherosclerotic coeliac artery stenosis. The stenosis and concomitant steal effect was successfully treated by stent placement. The latter is supported by the patient's uneventful course after stent placement. This case illustrates that chronic gastrointestinal ischaemia has to be considered in patients with otherwise unexplained diarrhoea. PMID- 21686777 TI - Arrival and survival of a 3-week-old boy from Pakistan with an arterial oxygen saturation of 17%. AB - In newborn infants, acute perinatal hypoxic/ischaemic events and associated hyperoxia/reperfusion injury frequently lead to devastating neonatal brain damage. The present report concerns a 3-week-old boy from Pakistan with d transposition of the great arteries (d-TGA), prolonged and severe hypoxaemia, and multiresistant bacterial sepsis. The term newborn infant underwent public airline transportation to Europe and presented on the airport's runway with severe hypoxaemia (pulsoximetric oxygen saturations (SpO2) 17%) and systemic hypotension. The patient eventually underwent late balloon atrial septostomy, followed by a successful two-stage arterial switch operation. A clinical follow up 3-5 years later revealed lack of cerebral dysfunction, adequate neurodevelopment, good biventricular function, regular coronary flow, as well as normal ECG, blood pressure and SpO(2). The findings may indicate the neonatal brain adjusts better to chronic, slowly worsening hypoxia than to acute hypoxia (eg, "birth asphyxia"), and also suggests a greater tolerance for chronic hypoxia in neonates vs adults. PMID- 21686778 TI - A young man with bowel obstruction and cachexia. AB - A young man from Jamaica was admitted with cachexia, postprandial epigastric pain and vomiting. His abdominal examination revealed a soft abdomen with hyperactive bowel sounds, the laboratory investigations showed mild anaemia and hypoalbuminaemia, and abdominal x ray showed dilated and oedematous bowel loops. A duodenal biopsy revealed larvae and eggs in the epithelium consisted with Strongyloides infection. In retrospect the patient was found to be HTLV-1 positive. Helminthic infections can present with bowel obstruction even in the absence of eosinophilia or diarrhoea, and should be considered in patients with the appropriate epidemiological background. PMID- 21686779 TI - Infective endocarditis from injecting heroin into a leg ulcer. PMID- 21686780 TI - Inflammatory sciatica due to spinal tophaceous gout. AB - A 73-year-old woman with chronic tophaceous gout presented with acute right-sided sciatica. Conventional radiology and CT scan of the lumbar spine revealed severe degenerative changes at the level of L3/4 and L4/5 disc and tophaceous deposits around the facet joints bilaterally. Investigations revealed a raised acute phase response (C reactive protein 97 mg/l, erythrocyte sedimentation rate >100 mm/h), leucocytosis and thrombocytosis. Because of non-steroidal anti-inflammatory drug induced gastrointestinal toxicity and intolerance to colchicine, a local steroid infiltration of the L4-5 facet joint was administered with a partial response. The patient was treated with anakinra 100 mg daily administered for 3 days. The treatment led to rapid clinical improvement of sciatica as well as normalisation of the acute phase response. She was subsequently maintained on anakinra 100 mg three times weekly with total resolution of sciatic pain. PMID- 21686781 TI - Takayasu's arteritis associated with Crohn's disease: a case report and literature review. AB - Takayasu's arteritis and inflammatory bowel disease are rarely found together, although the number of cases reported in the literature is increasing. Takayasu's arteritis has been studied in 31 patients from the Arab world but in none of them was it associated with Crohn's disease. We report the case of a Saudi woman previously diagnosed with Crohn's disease who subsequently developed Takayasu's arteritis, which may represent one of many extra-intestinal manifestations of inflammatory bowel disease. The possible aetiological factors, diagnostic methods, differential diagnoses and common pathophysiological mechanisms of the two diseases are discussed. This is the first case report of these two diseases in an Arab patient. PMID- 21686782 TI - Lamotrigine overdose associated with generalised seizures. AB - This report describes the occurrence of generalised seizures in a 42-year-old woman who presented to hospital after deliberate lamotrigine overdose. Seizure activity was promptly terminated after intravenous benzodiazepine administration, and the patient subsequently made a complete recovery. Serum lamotrigine concentration was 30 mg/l at 1.3 h post-ingestion, which is substantially higher than the therapeutic reference range; the estimated elimination half life was 18.3 h. This case reminds us that lamotrigine toxicity may provoke generalised seizures in susceptible individuals. PMID- 21686783 TI - Skin lesions with scanning speech and memory loss. PMID- 21686784 TI - Ultrasound findings of bilateral hypoplasia of the vertebral arteries associated with a persistent carotid-hypoglossal artery. AB - We present a 31-year-old female who was admitted to our neurology department for vertigo, partial left-sided hemihypesthesia and nuchal headache of subacute onset. Colour-duplex ultrasound disclosed bilateral low flow with a high resistance flow pattern in both vertebral arteries in the V2 segments, while the basilar artery had normal flow. CT angiography and MRI ruled out any ischaemic cerebral infarct and disclosed a persistent hypoglossal artery (PHA) originating from the left internal carotid artery (ICA). The patient was eventually treated for cervicobrachialgia. Persistent carotid-basilar anastomosis such as PHA may account for an atypical stroke pattern in carotid disease, aneurysms and arterovenous malformations. In retrospect, PHA is amendable to colour-Duplex investigation due to an abnormal ICA flow and a discrepancy between the vertebral and basilar flow patterns. Ultrasound investigation of the vertebrobasilar system remains a challenge as variants appear frequently; hypoplasia of the vertebral arteries should thus be confirmed using CT or MR angiography. PMID- 21686785 TI - 46 XX pure gonadal dysgenesis: an infrequent cause of primary amenorrhoea. AB - Amenorrhoea can be primary or secondary. Primary amenorrhoea is a relatively common problem among teenage girls. They usually consult their paediatrician or family doctor. This condition is present in patients with normal secondary sexual characteristics but no menarche by 16 years of age, or patients who have not had menstrual flow by age 14 and are lacking normal secondary sexual characteristics. Gonadal dysgenesis is an infrequent cause for primary amenorrhoea. In this paper, the case of a 16-year-old girl whose mother consulted their family doctor because of worries about her daughter's lack of menarche is presented. A blood test showed elevated levels of follicle stimulating hormone (FSH) and luteinising hormone (LH) and low levels of oestradiol. An abdominal ultrasound was abnormal. A diagnostic laparoscopy with biopsy of both gonads was performed. Replacement hormonal therapy was applied resulting in normal menstruations after few months. An early diagnosis is extremely important. PMID- 21686786 TI - Osteoporosis in a young woman after 6 years of levonorgestrel administration from intrauterine devices? AB - This report describes a young woman who developed dysmenorrhoea at the age of 12. She received a levonorgestrel (LNg)-releasing intrauterine device at the age of 21, and this was replaced twice within 8 years. At the age of 28, she started to have multiple bone and joint pain (predominantly low back pain), which, after intensive diagnostic of blood parameters and bone CT, turned out to result - from a manifest (mild) osteoporosis. Since the woman developed very low (postmenopausal) oestradiol levels during the presence of the gestagen-releasing device and encountered normalisation of oestradiol production after removal, suppression of the hypophysial-ovarian axis is proposed as the cause of both lack of oestradiol and osteoporosis. This poses the question of whether long-term use of such devices in young women may result in reduced bone density in the early phases of life, paving the way to serious osteoporosis at menopause. PMID- 21686787 TI - Non-arteritic anterior ischaemic optic neuropathy associated with neovascular glaucoma. AB - We report a case of non-arteritic anterior ischaemic optic neuropathy (NAION) associated with neovascular glaucoma (NVG). A 63-year-old man who had undergone cataract surgery 3 months previously presented with sudden visual loss in his right eye. Ocular examination revealed a relative afferent pupillary defect, intraocular pressure (IOP) of 27 mm Hg, and 360 degrees neovascularisation. Fundus examination revealed a pale and swollen optic disc with diabetic retinopathy. NAION associated with NVG was diagnosed. NVG, leading to reduced optic nerve perfusion pressure, concurrent with ischaemic processes of diabetic retinopathy, resulted in NAION. PMID- 21686788 TI - Abdominal wall pain in obese women: frequently missed and easily treated. AB - Chronic abdominal pain is a common symptom with an extensive differential diagnosis. The work-up is frequently costly, yet many patients elude definitive diagnosis. We describe 12 obese women with long-standing abdominal pain, many of whom eluded diagnosis but who met criteria for abdominal wall pain. Each patient underwent a focused history and physical examination which included checking for Carnett's sign and performing a "pinch test". All patients had positive Carnett's sign and pinch tests. An injection of local anaesthetic, with or without corticosteroid, completely relieved the pain within 10 min. Of the six patients seen in follow-up, four remained pain free and two responded to a second injection of local anaesthetic. Abdominal wall pain is an under-appreciated cause of chronic abdominal pain. Diagnosis is often straightforward and treatment with a local injection of anaesthetic is both diagnostic and curative. PMID- 21686789 TI - Psychopharmacological treatment of behavioural problems in Sanfilippo syndrome. AB - The present report illustrates successful use of psychotropic medication targeted at symptom clusters of behavioural disturbance in a 7-year-old girl with Sanfilippo syndrome, a mucopolysaccharidosis. By identifying and targeting symptom clusters, psychotropic medication was prescribed with significant results. This approach to treatment of behavioural disturbance in Sanfilippo syndrome has not been previously described to our knowledge. Caution with regards side effects and interaction of medication is advised. PMID- 21686790 TI - Acute diarrhoea: an unusual presentation. AB - An obese diabetic male presented with self limiting diarrhoea of 1 day duration, which had started after he ate sausages. Examination was unrevealing except for persistent low blood pressure. Computed tomographic (CT) scan, done to rule out retroperitoneal bleed, incidentally showed air in the gall bladder. He underwent emergent cholecystectomy, and a gangrenous gall bladder that grew Clostridium perfringens was removed. Emphysematous cholecystitis is not so infrequent, although only rarely does it present as diarrhoea alone. A high index of clinical suspicion is necessary as even advanced presentation can be subtle and appropriate radio imaging essential. Although abdominal radiograph and ultrasound could be useful, a CT scan is diagnostic. The CT scan and its classical finding confirmed the diagnosis, and it reiterates the importance of timely identification and urgent action, as emphysematous cholecystitis is associated with high mortality. PMID- 21686791 TI - Persistent high nevirapine blood level with DRESS syndrome 12 days after interruption of antiretroviral therapy. AB - Nevirapine is an antiretroviral agent associated with drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Such a case in an immunocompetent woman recently treated with nevirapine for postexposure HIV prophylaxis is reported here. Despite a period of 12 days after interruption of treatment, a high blood level of nevirapine was still observed. PMID- 21686792 TI - Acute hypophosphataemia and hypokalaemia in a patient starting antiretroviral therapy in Zambia-a new context for refeeding syndrome? AB - High mortality rates have been reported in the first 90 days of antiretroviral therapy in Zambia and other low-income countries. We report a case of acute hypophosphataemia and hypokalaemia in the first week of antiretroviral therapy in a patient with extreme AIDS wasting. Given its occurrence in an extremely wasted patient, it may be physiologically similar to refeeding syndrome but other causes could be relevant as well. Acute hypophosphataemia may contribute to early antiretroviral therapy associated mortality in low-income countries. PMID- 21686793 TI - Double gastrointestinal stromal tumour (GIST) of the stomach. AB - Gastrointestinal stromal tumour (GIST), within its definition, is a gastrointestinal (GI) mesenchymal tumour containing spindle cells and showing CD 117 immunopositivity. The incidence of GISTs is estimated at 10-20/million. GISTs occur typically in people over 50 years of age. Over 95% of primary GISTs are solitary. Rarely, GISTs are multifocal and occur in young adults and children. A case of a 60-year-old women with double GIST of the stomach is reported here. The patient approached her general practitioner because of stomach ache, chronic diarrhoea and weight loss. Ultrasonography showed an abdominal tumour. During gastroscopy a submucosal tumour in the antral part of the stomach was found. Computed tomography revealed a pathological lesion between the stomach and the liver and an intramural tumour of the stomach. Two stomach tumours were found, and a Bilroth I gastrectomy was performed. Histopathological examination showed GIST in both tumours. This case shows that multifocal GISTs of the stomach can arise in older patients. PMID- 21686794 TI - Cyclophosphamide-induced reversible posterior leukoencephalopathy syndrome. AB - Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical radiological syndrome, characterised by acute headache, altered consciousness, seizures and hypertension. The most frequent causes are hypertensive encephalopathy, eclampsia and some immunosuppressive therapies. The pathogenesis remains unclear, but it appears to be related to altered cerebral circulation, producing oedema that can be seen on MRI, and it resolves in 2 or 3 weeks. In the present report, a possible first reported case of cyclophosphamide-induced RPLS in a 27-year-old man with high blood pressure (HBP) and glomerulonephritis caused by Goodpasture syndrome, treated with cyclophosphamide during the last month and prednisone for glomerulonephritis resulting from Goodpasture syndrome without other immunosuppressive drugs, is described.Symptoms appeared during a hypertensive crisis, but when cyclophosphamide was replaced by rituximab and hypertension was controlled, the patient did not have neurological symptoms. Almost all reported cases induced by immunosuppressive therapy or other causes were associated with hypertension as well. PMID- 21686795 TI - Doctor, I hear hissing sounds coming from my chest!? PMID- 21686796 TI - A complication of sclerotherapy for oesophageal varices. PMID- 21686797 TI - Factitious disorder presenting as type 1 diabetes mellitus. AB - Factitious disorder (FD) is a condition characterised by the intentional production of illness to assume the sick role in the absence of external incentive. It is an illness that can be challenging, frustrating and troublesome for busy clinicians, and is easily misdiagnosed. Nonetheless, an accurate diagnosis is essential given that FD can lead to irreversible health consequences and unnecessary cost to society. This report describes the case of a middle-aged man with FD presenting as type 1 diabetes mellitus with recurrent hypoglycaemic episodes. PMID- 21686798 TI - Scurvy induced by obsessive-compulsive disorder. AB - Historically, scurvy has been associated with sailors of great navigational epochs. This disease has been known since ancient Egypt, but nowadays it is almost forgotten. Although its prevalence has decreased over the centuries, scurvy is still present in developed countries. A 61-year-old man was referred to hospital with a 30-day history of anorexia, fatigue, gingival bleeding and ecchymosis of the arms and legs. On physical examination he presented gingival hypertrophic lesions, signs of chronic periodontitis and petechial rash, and several bruises on his arms and legs. A food frequency questionnaire revealed a long history of poor diet, with no vegetables or fruit. The patient had ingested only chocolate milk and cookies for the last 10 years due to fear of pesticides being present in foods of vegetable origin. A diagnosis of scurvy induced by obsessive-compulsive disorder was suspected, and after vitamin C supplementation there was a marked improvement of symptoms. PMID- 21686799 TI - A case for varicella vaccination in the immunosuppressed. AB - A middle-aged man with long-standing Crohn disease maintained in remission on low dose immunosuppression presented with abdominal pain. Over the following few days he developed a vesicular rash, became dyspnoeic, confused and had two seizures. Despite high-dose intravenous aciclovir, he died. Disseminated varicella zoster virus, the cause of his death, could potentially have been prevented had he received varicella vaccination at an earlier stage. PMID- 21686800 TI - Sleep disruption following paramedian pontine stroke. AB - Pontine structures are critical for the generation of rapid eye movement sleep but there are only a few reports of the effects of focal pontine lesions on sleep patterns in humans. We report the case of an 81-year-old man admitted for the acute onset of disordered speech and motor deficit in the upper right arm who developed hypersomnia within a week. A 24-hour polysomnographic study revealed a very severe disruption of both circadian rhythm and sleep organisation, and a brain MRI documented an ischaemic lesion of the anterior left paramedian portion of the pons. Our observation suggests that even small, paramedian pontine ischaemic lesions can acutely induce a very severe sleep disorder. PMID- 21686801 TI - Saphenous vein graft aneurysm: an incidental finding. AB - Saphenous vein graft aneurysm (SVGA) is an uncommon complication of coronary artery bypass graft surgery (CABG). An 82-year-old man underwent contrast enhanced computed tomography to investigate aorto-iliac disease. He was coincidentally noted to have an aneurysm of the saphenous vein graft to his right coronary artery. This was visualised on transthoracic echocardiography, computed tomography and coronary angiography. In the absence of symptoms and in view of high surgical risk, conservative management with anticoagulation was chosen. The patient was commenced on warfarin and remains asymptomatic. PMID- 21686802 TI - Early gastric cancer in Menetrier's disease. AB - Uncommon conditions such as pernicious anaemia and hypertrophic gastropathies have been considered as risk factors for gastric cancer; however, the exact increase in risk is unknown. Menetrier's disease is a rare hyperproliferative disorder of the stomach caused by an overexpression of tumour growth factor alpha, a ligand for the tyrokinase epidermal growth factor receptor, resulting in a selective expansion of surface mucous cells in the body and fundus of the stomach. There have been nearly 200 cases of Menetrier's disease reported in the literature yet less than 15 have been associated with gastric adenocarcinoma. Here, we report an early stage gastric adenocarcinoma detected incidentally in a patient recently diagnosed with Menetrier's disease. PMID- 21686803 TI - Herpes zoster induced acute urinary retention in the immunocompetent female. AB - We present a rare case of acute urinary retention complicated by constipation secondary to a unilateral herpes zoster reactivation in the S2-4 dermatomes of an immunocompetent female. Diagnosis was confirmed by clinical examination, negative cystoscopy and positive viral polymerase chain reaction (PCR) for herpes zoster virus. The patient was commenced on a course of oral acyclovir, the bowel symptoms resolved, and the patient was discharged with a urinary catheter in situ for an outpatient trial without catheter for 2 weeks to be followed by a course of intermittent self catheterisation pending resolution of symptoms. PMID- 21686804 TI - The definition and management of Barrett's oesophagus: a case report, review of the literature and a suggestion for the future. AB - The definition of Barrett's oesophagus continues to evolve and there has been divergence in the diagnostic criteria internationally, which has implications for surveillance practices and research inclusion criteria. Here we describe the case of a 69-year-old female with 10 cm of gastric-type columnar-lined oesophagus confirmed on histochemical staining. Surveillance biopsies, performed according to protocol, revealed an intramucosal adenocarcinoma. The patient was successfully treated with a transhiatal oesophagectomy and a detailed examination of the entire surgical specimen confirmed that the columnar oesophagus was lined by gastric villiform mucosa complicated by intramucosal carcinoma, on the background of dysplasia with no intestinal metaplasia. This highlights the spectrum of metaplastic epithelia that can harbour malignant potential. There is a need for an international consensus on the classification of Barrett's oesophagus to aid research progress. Therefore, we propose a new classification for Barrett's oesophagus based on a combination of endoscopic and histopathological features. PMID- 21686805 TI - Capecitabine (oral 5-fluorouracil pro-drug) treatment for colorectal carcinoma causing ischaemic chest pain. AB - We present a case of cardiac ischaemia associated with capecitabine chemotherapy. An elderly female receiving capecitabine chemotherapy developed acute onset severe anterior chest pain associated with ischaemic changes on ECG. The pain and ECG changes failed to respond to thrombolysis and she proceeded to coronary angiogram and stenting of a thrombosed right coronary vessel. She inadvertently recommenced her capecitabine with a further episode of chest pain. On cessation of capecitabine she had no further episodes of chest pain. PMID- 21686806 TI - Hypoglycaemia and fits in a thyrotoxic man. AB - We report prolonged severe hypoglycaemia with raised serum insulin levels in a Sri Lankan man with recently diagnosed Graves disease being treated with carbimazole. We diagnosed insulin autoimmune syndrome on the basis of raised anti insulin antibody levels, and this diagnosis was supported by the subsequent course of the illness. The patient recovered completely after carbimazole was replaced with propylthiouracil and he was treated with dextrose infusions, frequent high-carbohydrate meals and a course of prednisolone. PMID- 21686807 TI - Management of ovarian cysts during infancy: autoamputation presenting as a possible pitfall. AB - The widespread use of routine antenatal ultrasound has relatively increased the frequency of intrauterine diagnosis of ovarian cysts. In utero adnexal torsion may present with subsequent autoamputation in some of these lesions. Prenatal and postnatal ultrasonographic findings, however, may not always be relevant in making the correct diagnosis. The authors report on two cases with prenatally diagnosed hypoechogenic cystic masses. The cysts failed to resolve after a period of conservative management. A laparoscopic approach revealed ovarian autoamputation presenting as cystic mass. Preoperative ultrasound, abdominal CT and MRI failed to detect the presence of autoamputation. The present report discusses the possibility of an otherwise silent ovarian autoamputation, which may necessitate laparoscopic intervention for correct diagnosis, in neonates presenting with persistent ovarian cysts. PMID- 21686808 TI - Multiple mononeuropathy following cocaine abuse. AB - A 31-year-old man with acute-onset of left-sided weakness following the sniffing of cocaine was admitted with rhabdomyolysis. Neurophysiological studies showed axonal degeneration in 4/10 sensory and 3/8 motor nerves, and conduction block outside the typical compression-sites in 3/8 motor nerves. The findings are consistent with a diagnosis of multiple mononeuropathy. Ischaemia due to vasoconstriction is currently believed to be the cause of muscle necrosis following cocaine abuse and we hypothesise that it also explains the neuropathy in this case. PMID- 21686809 TI - Fatal acute disseminated encephalomyelitis associated with cytomegalovirus infection. AB - We present the case of a young man with recent cytomegalovirus (CMV) infection who was admitted with generalised seizure and coma. Computed tomography scan and magnetic resonance imaging (MRI) on admission were normal. Despite transient initial improvement he rapidly deteriorated leading to repeated MRI that revealed findings highly suggestive of acute haemorrhagic leucoencephalitis (AHLE). The patient died despite treatment with pulse methylprednisolone and intravenous immunoglobulin. Acute disseminated encephalomyelitis (ADEM)/AHLE should be considered in the differential diagnosis of rapid neurological deterioration even when initial imaging is normal. This case report underscores the importance of early diagnosis as early aggressive treatment may improve outcome. PMID- 21686810 TI - Recurrent thyroid storm induced by heretofore unrecognised causes in a patient with thyroid cancer. AB - An unusual encounter of a thyroid storm, on two separate occasions, is reported in a patient with metastatic differentiated thyroid cancer following initially direct trauma to, and later tumour embolisation of, a metastatic skeletal lesion. Shortly after a fall, our patient presented with pain and swelling in the right shoulder, high fever, change in mental status, anorexia, nausea and vomiting, tachycardia and dehydration. The laboratory tests were consistent with hyperthyroidism. As the patient improved, arterial embolisation of the large right humerus metastasis was performed to decrease the tumour burden. The patient, however, developed a similar clinical and biochemical picture to that at her presentation, with a very high free thyroxine (T(4)) level, a few days after successful embolisation. Treatment of the thyroid storm was initiated and the patient eventually improved. Awareness of such occurrences is helpful in early diagnosis and effective management of this potentially fatal complication. PMID- 21686811 TI - Whipple's disease: misdiagnosed as sarcoidosis with further tricuspid valve endocarditis and pulmonary embolism - a case report. AB - GH Whipple described a 36-year-old physician in 1907 with gradual loss of weight and strength, stools consisting chiefly of neutral fat and fatty acids, indefinite abdominal signs and a peculiar multiple arthritis. The patient died of this progressive illness. Whipple called it intestinal lipodystrophy since he observed accumulation of large masses of neutral fats and fatty acids in the lymph spaces. It was renamed Whipple's disease in 1949. An infectious aetiology was suspected as early as Whipple's initial report. However, successful treatment with antibiotics was not reported until 1952, which resulted in dramatic clinical responses. The cause is now known to be Tropheryma whipplei. Light and electron microscopy of infected tissue identified a gram-positive, non-acid-fast, periodic acid-Schiff (PAS) positive bacillus with a characteristic trilamellar plasma membrane resembling that of gram-negative bacteria. Whipple's disease is extremely rare. It is a systemic infectious disorder affecting mostly middle-aged white men. The clinical presentation is often non-specific, which may make its diagnosis difficult. The four cardinal clinical manifestations are arthralgias, weight loss, diarrhoea and abdominal pain. The frequently vague articular symptoms can precede the diagnosis of Whipple's disease by an average of 6-8 years. Lymph nodes and other tissues may present diagnostic problems, since the changes in routinely stained sections may mimic those of sarcoidosis. The detection of PAS-positive histiocytes in the small intestine remains the mainstay of the diagnosis, although Whipple's disease without gastrointestinal involvement is described. We illustrate a case in which, retrospectively, the clinical presentation would have been typical for Whipple's disease. However, the clinical presentation and the histological examinations of lymph nodes, liver biopsies and ascites initially were misinterpreted as sarcoidosis with consecutive immunosuppressive therapy and progressive worsening of the patient's health presenting at least as sepsis with endocarditis. PMID- 21686812 TI - Ruptured intracranial aneurysm in pregnancy: a case report. AB - Rupture of intracranial aneurysm in pregnancy is rare and the presentation is easily confused with eclampsia. A high index of suspicion could lead to early diagnosis and prompt management. A multidisciplinary team approach is essential for best outcome. PMID- 21686813 TI - Non-alcoholic fatty liver disease in a patient with maturity onset diabetes in the young. AB - We present the case of a 34-year-old man who was first seen in our clinic in 2003. His alpha-glutamyl transferase (GGT) was raised but the rest of the liver function tests (LFTs) and liver screen were normal. He was diagnosed with maturity onset diabetes of the young (MODY) when he was 21 years old. Abdominal ultrasound showed fatty liver disease. Liver biopsy in 2006 showed non-alcoholic fatty liver disease (NAFLD). This combination has rarely been described in the medical literature. Metformin and gliclizide was started and weight reduction advised. Despite this there is no change in his LFTs, and in 2008, his GGT concentration was even higher. This condition is challenging because of the limited treatment options. Globally, NAFLD is rising and complications such as liver cirrhosis can be seen commonly. NAFLD in a patient with MODY needs thorough attention. PMID- 21686814 TI - In-transit metastasis of the breast region from malignant melanoma of the trunk. AB - Extramammarian cancer metastases to the breast are rare. Melanoma is one of the malignancies that can metastasise to the breast. The distinction between a primary breast carcinoma and a metastatic neoplasm is crucial because surgical and therapeutic treatment options will vary accordingly. The present report concerns a case of breast metastasis from melanoma of the trunk. A 50-year-old man with a self-detected left breast lump who had previously undergone wide local excision and axillary dissection for melanoma was admitted to our department. Ultrasonography showed an 0.8 cm hypoechoic nodule with silent margins. The palpable mass was excised. Surgical pathology revealed metastatic melanoma. PMID- 21686815 TI - Therapeutic immobilisation for small guitar player's dystonia: a case report. AB - The development of focal hand dystonia through repetitive tasks is a result of degradation of cortical somatosensory representation due to repetitive fast stimuli sufficient to alter the sensory-motor stimulus, harming the motor control. A sensory-motor training program can modify this disorder. A behavioural intervention focusing on movement could help reduce or eliminate these conditions. PMID- 21686816 TI - Chest pain in Marfan syndrome. PMID- 21686817 TI - Pathological extracardiac uptake of Tc-99m sestamibi (MIBI) leading to a false impression of reduced wall thickening in a region of apparent hyperperfusion on gated myocardial perfusion single photon emission computed tomography (G-SPECT). PMID- 21686818 TI - A case report of neuroleptic malignant syndrome. AB - A 32-year-old male patient with a history of treatment resistant paranoid schizophrenia developed neuroleptic malignant syndrome (NMS) during changeover of his antipsychotic medication from zuclopenthixol depot to clozapine. This case highlights the difficulties of cross-tapering two antipsychotics-that is, converting from a typical depot medication to an oral atypical antipsychotic. PMID- 21686819 TI - Mandibular neurofibromatosis type 1 misdiagnosed and treated as odontogenic abscess. PMID- 21686820 TI - Chrysiasis: a gold "curse"! PMID- 21686821 TI - Severe unrecognised hypoglycaemia presenting as pseudonormoglycaemia and unexplained coma in two patients with renal failure. AB - We describe the occurrence of pseudonormoglycaemia and the consequences of severe prolonged hypoglycaemia observed in two patients with renal failure requiring renal replacement therapy. There was a persistent discrepancy, in both cases, between glucose levels measured by the hospital laboratory and those measured by the bedside glucometer, resulting in a significantly false high glucose measurement (pseudonormoglycaemia). This inaccurate glucose determination led to a delayed diagnosis of their truly severe and prolonged hypoglycaemia ultimately leading to prolonged coma and death. Icodextrin, a polysaccharide commonly used in continuous ambulatory peritoneal dialysis solutes, and maltose-containing solutions such as immunoglobulins for intravenous administration, can cause a dangerous overestimation of glucose levels determined by capillary blood glucose analysers utilising glucose dehydrogenase. A high level of awareness is required in order to avoid incidents related to misinterpretation of glucose levels. PMID- 21686822 TI - Arteriovenous malformation of brain with stroke in Down syndrome: a case report. AB - Down syndrome is a common chromosomal aberration in children. A variety of associated malformations have been reported in the literature, including vascular malformations of pelvic organs. The vascular malformations of brain with Down syndrome have not been reported in the literature. Therefore, we report a child with Down syndrome, with associated arteriovenous malformation in the brain, who developed stroke and was treated successfully. PMID- 21686823 TI - Hepatitis, rhabdomyolysis and multi-organ failure resulting from statin use. AB - OBJECTIVE: To report a case of hepatitis, rhabdomyolysis and multi-organ failure resulting from the use of statins. CASE SUMMARY: A 70 year old Caucasian woman was admitted with general malaise, myalgia and jaundice. She was being treated with a statin for aortic stenosis, the dose of which had been increased approximately 6 months earlier. Investigations showed evidence of hepatitis and rhabdomyolysis resulting in multi-organ failure, eventually leading to her death. DISCUSSION: Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and are commonly used for treatment of hypercholesterolaemia. The use of high dose statin is becoming increasingly common with emerging evidence suggesting improved outcomes in various conditions. Statins have transformed the care of patients with vascular disease. Statins generally have an excellent safety profile and low risk of adverse reactions, but cases of rhabdomyolysis and hepatitis resulting from their use have been reported. CONCLUSION: While there is good evidence suggesting improved outcomes with use of high dose statins, the potential drug interactions and adverse effects need close attention. All patients started on statin therapy should be counselled regarding the signs and symptoms of muscle injury, particularly those who are on drugs that may have an interaction. In this patient the Naranjo probability scale revealed a probable adverse reaction associated with atorvastatin therapy. PMID- 21686824 TI - Malignant pilomatricoma in the upper eyelid. AB - Pilomatrix carcinoma is a rare, low grade malignant neoplasm arising from the hair matrix. This neoplasm can exhibit local aggressive behaviour and occasionally distant metastasis. In this report, we present a case of malignant pilomatricoma in the eyelid. Differential diagnosis and treatment are discussed. PMID- 21686825 TI - Spinal supports and physical therapy in patients with low back pain: a case series. AB - The association of low back pain with physical workload in seated workstation related jobs has been debated and remains controversial. Clinical studies eliciting the natural history of the disease in this emerging population are insufficient to make definitive conclusions. We report four consecutive cases of patients suffering from low back pain presenting to a tertiary spine clinic with severe non-specific low back pain. Two patients as age-matched controls with persistent low back pain were followed for 6 months after receiving conventional treatment. In comparison, two test patients received parallel conventional treatment along with orthopaedic full spinal supports as an additional treatment modality. Outcomes analysed demonstrate the efficacy of orthopaedic full spinal supports for treating low back pain. TRIAL REGISTRATION NUMBER: NCT00553540. PMID- 21686826 TI - A case of vertebral osteomyelitis due to quinolone-resistant Salmonella paratyphi A. AB - This is a case of a 63-year-old Asian female patient who presented to accident and emergency with a febrile illness 3 weeks after her return from the Indian subcontinent. She was given empirical treatment with ciprofloxacin. Blood cultures grew a quinolone-resistant resistant Salmonella paratyphi A so she was re-called, admitted to hospital and treated with intravenous cefotaxime. She did not have known risk factors for invasive salmonellosis. On day 8 she complained of back pain, but since her fever was settling an MRI of the spine was not performed at that point.On day 19 her fever relapsed so the MRI was done and showed images consistent with vertebral osteomyelitis at T7-T8 level. She completed 8 weeks of intravenous antibiotic therapy with good clinical response and normalisation of inflammatory markers, and was discharged on an 8 week course of oral azithromycin. On follow-up after 7 months, her back pain had settled and an MRI showed improvement. PMID- 21686827 TI - Case report of vasculitic rash induced by Ginkgo biloba and/or Horny Goat Weed. AB - A case of a vasculitic rash induced by the herbal remedy Ginkgo biloba and/or Horny Goat Weed is described. PMID- 21686828 TI - 71-year-old woman with dizziness and lipomatous hypertrophy of the left atrium. AB - Lipomatous hypertrophy, an unencapsulated atrial mass of adipose tissue, occurs in 1% of the population; the clinical significance of this is uncertain. Diagnosis is by echocardiography, computed tomography or magnetic resonance imaging scan. Surgical intervention is thought to be indicated in patients with obstruction, thromboembolism, uncontrollable arrhythmia or when liposarcoma cannot be excluded. We describe a case in which a 71-year-old woman was diagnosed with lipomatous hypertrophy of the left atrium. The finding of a large atrial mass was unexpected in this case. The clinical implications of the finding are unclear, since the aetiology and prognostic consequences are unknown. As the finding is not that uncommon others may find similar cases. It is therefore important that echocardiographers are aware of this entity and the aspects one needs to consider when deciding upon the best evaluation and treatment strategy. PMID- 21686829 TI - Diffuse mesangial IgA glomerulonephritis in a patient with rheumatoid arthritis: a possible extra-articular manifestation in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an inflammatory joint disease, in which, unlike systemic lupus erythematosus (SLE), renal involvement is uncommon. The major causes of renal disease in RA are usually linked to amyloid or secondary effects of drugs. Nevertheless the relation between IgA, IgA-rheumatoid factor (RF) and renal disease in patients with RA is not clear, but the affinity of IgA for mesangium, skin and synovium might explain clinical presentation of RA with mesangial IgA glomerulonephritis. The case of a 42-year-old Caucasian man with RA and diffuse mesangial IgA glomerulonephritis proven by renal biopsy is presented. The patient was treated with boluses of methylprednisolone 1000 mg and cyclophosphamide 1000 mg monthly for 13 months. Between boluses there was a supported therapy with methylprednisolone 8 mg/day. After a year of treatment full clinical and laboratory remission of RA and IgA glomerulonephritis was achieved. Pathogenic therapy will be stopped and the patient followed-up. PMID- 21686830 TI - Improvement of glycaemic control and elevation of C-peptide following a diet free of dairy products in an insulin-treated, patient with type 2 diabetes with ulcerative colitis. AB - An insulin-treated patient with type 2 diabetes mellitus started a diet free of dairy products. Unexpectedly, she developed episodes of hypoglycaemia, without any change in her usual medication (insulin NPH at bedtime and Metformin). Laboratory tests showed an improvement of endogenous insulin secretion as demonstrated by the induction of hypoglycaemia and the elevation to normalisation of C-peptide levels. The patient was rechallenged with dairy products, leading to the lowering of the C-peptide levels back to abnormal levels, and an increase in HBA1C levels. The findings in our patient contrast with the insulinotropic effect of milk in healthy subjects described in the literature. The two main "milk debates" on the relation between milk (or its components) and diabetes are presented. Further observations will be needed to clarify the question of whether a diet free of dairy products can improve glycaemic control in other insulin treated patients with type 2 diabetes. PMID- 21686831 TI - Late diagnosis of a rare disease. AB - Rare diseases may be misdiagnosed if laboratory investigations show a common diagnosis instead. This is the story of 24-year-old male patient misdiagnosed as a case of hereditary spherocytosis at the age of 10 years. He received regular blood transfusions. Thorough investigations revealed microcytic anaemia, with results for all hereditary and acquired causes of haemolytic anemia negative, iron overload in the liver, stunted growth, insulin-dependent diabetes mellitis, hypercellular bone marrow and marked depletion of its iron stores. The transferrin level was very low when repeatedly measured, making congenital atransferrinaemia the most acceptable diagnosis for this case with haemochromatosis. Congenital atransferrinaemia is a very rare disease, with few cases recorded worldwide. Most cases died at a young age if not treated properly. Our patient is still alive although only recently diagnosed. He is now undergoing treatment with plasma transfusion, iron-chelating therapy and antituberculous treatment for pulmonary and osteoarthritic tuberculosis. PMID- 21686832 TI - Acute myocardial infarction in the presence of normal coronaries and the absence of risk factors in a young, lifelong regular exerciser. AB - Around 6% of patients suffering an acute myocardial infarction (AMI) have normal coronary arteries. The mechanisms responsible are not fully known, but include hypercoagulable state, coronary endothelial dysfunction, aortic dissection, inflammation, coronary thrombosis, aortic wall stiffening, cocaine abuse, carbon monoxide poisoning and paradoxical embolism. Here, the case of a lifelong regular exerciser without risk factors for cardiovascular disease who suffered an AMI with normal coronaries is reported. Despite normal cardiac function on left ventriculography and echocardiography, late gadolinium enhancement by cardiac magnetic resonance (CMR) revealed significant cardiac necrosis. The long-term prognosis is favourable with low rates of coronary morbidity and mortality. Acute chest pain should not be considered as benign and warrants medical investigation. PMID- 21686833 TI - Omalizumab for exacerbations of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. AB - Anti-IgE therapy was proposed to two teenagers with cystic fibrosis (CF) with allergic bronchopulmonary aspergillosis (ABPA) exacerbation, reluctant to a further course of oral steroids. Both patients experienced ABPA exacerbations within the past 3 years, requiring oral steroid bursts. Clinical, laboratory and radiographic features were consistent with ABPA exacerbations (representing at the time of evaluation the fourth and third episodes for patient 1 and 2, respectively). Total serum IgE was very high, >1000 kU/litre in both cases. Treatment consisting of subcutaneous injections of 375 mg anti-IgE (omalizumab) twice monthly was successful in rapidly improving respiratory symptoms and lung function. Based on clinical and functional improvement, interval between injections was progressively increased and treatment could be withdrawn after 11 injections, without recurrence at 20 weeks of follow-up after withdrawal. PMID- 21686834 TI - Dermatofibrosarcoma protuberans of the vulva: a case report. AB - Dermatofibrosarcoma protuberans (DFSP) is a low-grade to intermediate-grade well differentiated sarcoma of dermal origin. Local recurrence rates are high but distant metastases are rare. This report describes a case of vulvar DFSP requiring four resections for primary clearance. A 56-year-old woman referred after excision of a vulvar tumour and histology had DFSP extending to the resection margins. Two more extended excisions again yielded a specimen with positive margins. The last excision was performed with intraoperative frozen section analysis of the margins. Frozen section analysis of the resected specimen revealed clear margins and this was confirmed by final pathology. The postoperative course was uneventful. The patient has been without recurrence for 15 months. A wide and deep local excision is recommended for both primary and recurrent lesions. The patient had three resections before clear surgical margins were achieved. Intraoperative frozen section analysis is helpful in assessing resection margins. PMID- 21686835 TI - Boerhaave syndrome: a diagnostic conundrum. AB - A 79-year-old man presented to the Emergency Department with abdominal pain 1 day after an elective total knee replacement. The patient was confused and drowsy, with a high fever, hypotension and uncontrolled atrial fibrillation. He subsequently developed respiratory failure, requiring admission to intensive care. It was then noted that a large pleural effusion had developed between two chest radiographs performed only 4 h apart. A pigtail catheter inserted into the pleural space revealed a transudate of pH 7.0 with an amylase of 17 220 U (serum amylase 54 U), and thus a diagnosis of spontaneous oesophageal rupture or Boerhaave syndrome was made. Despite drainage of the pleural space, the patient developed shock and multiorgan failure requiring mechanical ventilation, renal replacement therapy and cardiovascular support. The oesophageal leak was treated conservatively with intercostal tube drainage; the patient made a full recovery and was discharged from hospital 75 days later. PMID- 21686836 TI - Pulmonary actinomycosis: the great masquerader. AB - Actinomycosis is a rare but treatable disease. Thoracic manifestations are varied and can mimic malignancy or tuberculosis. We report the case of a 54-year-old man who presented with a persistent cough and radiological evidence of right upper lobe lung mass. Conventional computed tomography guided biopsy and bronchoscopy proved to be non-diagnostic. Thoracotomy and histopathologic examination of the tissue confirmed actinomycosis infection. Excellent clinical and radiologic responses were noted following treatment with penicillin V. Despite a high clinical suspicion, the diagnosis can prove to be challenging. PMID- 21686837 TI - The association of HTLV-1 infection, persistent intestinal infection with Strongyloides stercoralis and gastrointestinal lymphoma. AB - Human T cell lymphotropic virus type 1 (HTLV-1) infection is a risk factor for Strongyloides stercoralis infection. HTLV-1 also predisposes to the development of T cell malignancies. We report a case of a patient with severe, treatment resistant Strongyloides infection and HTLV-1 infection who progressed to develop an advanced high grade T cell lymphoma of the intestine. PMID- 21686838 TI - Gallstone ileus with air in the gallbladder. PMID- 21686839 TI - Posterior reversible encephalopathy syndrome (PRES). PMID- 21686840 TI - Temporary allergy to Neocate: possible association with immunisation. AB - A 5-month-old baby exhibited an allergic reaction to Nutramigen 1 day after his third set of immunisations. The following day he had a similar reaction to Neocate, which was being used as an alternative to Nutramigen. One month later Neocate was slowly reintroduced back into the diet with no ill effects. PMID- 21686841 TI - Night sweat and fever with liver mass on the CT scan. PMID- 21686842 TI - A rare case of a carotid loop anomaly. PMID- 21686843 TI - Evolution of chest radiograph. PMID- 21686844 TI - A rare cause of dysphagia and gastroparesis. AB - An 82-year-old woman was admitted with severe vomiting and progressive dysphagia mainly to solids. She gave a 3-month history of increasing heartburn, vomiting, tiredness, lethargy, anorexia and 13 kg weight loss. Her past medical history was unremarkable and she was a non-smoker. Physical examination revealed evidence of significant weight loss and dehydration only. Gastroscopy revealed mild oesophagitis, tongues of Barrett oesophagus and mild antral gastritis. CT scan of the thorax and abdomen was normal. Unfortunately her condition deteriorated rapidly and she died from aspiration pneumonia. Postmortem examination revealed thickening of the muscular wall of lower oesophagus and pylorus, but without any malignancy. The histological assessment of the oesophageal as well as gastric biopsies confirmed the diagnosis of gastrointestinal amyloidosis accounting for her symptoms of dysphagia and vomiting respectively. PMID- 21686845 TI - Endoscopic removal of retained T- tube fragment. AB - T-tube usage is common following common bile duct exploration for calculi and other complex biliary surgeries to ensure proper biliary diversion and healing. A 25-year-old woman was referred from a surgical unit with a history of open cholecystectomy and common bile duct exploration for cholelithiasis and choledocholithiasis with T-tube placement in the common bile duct for postoperative biliary diversion. While retrieving the T-tube, it got fractured and the fragment remained in the bile duct. We report a rare case of retained T tube fragment after T-tube removal that was retrieved endoscopically. PMID- 21686846 TI - Acute fulminant carditis presenting with sustained ventricular tachycardia, and recovery after extracorporeal cardiopulmonary resuscitation. AB - A 12-year-old boy consulted a local physician with complaints of cough, abdominal pain, shortness of breath and general malaise. Medications for symptomatic relief and bed rest were suggested. The flu-like symptoms were relieved on the 2nd day, and the general malaise with repeated vomiting, chest pain and chest tightness attenuated on the 3rd day. A chest x ray showed multiple pneumonic patches with borderline cardiomegaly. Poor left ventricular function was noted, and the left ventricular ejection fraction was reduced to 21%. Although multiple episodes of sustained ventricular tachycardia were converted by six repeated cardiac defibrillations and a xylocaine (intravenous) bolus infusion, his general condition went downhill to shock and proceeded to several episodes of heart standstill that necessitated cardiopulmonary resuscitation. Extracorporeal cardiopulmonary resuscitation was installed via femoral cannulation. Cardiac function progressively recovered to normal, and extracorporeal membrane oxygenation was removed on the 7th day. The patient completely recovered and was discharged on the 15th day with no neurological sequelae. PMID- 21686847 TI - Behcet's disease, painful genital ulcerations and steroid pulse therapy. AB - Behcet's disease (BD) is a rare cause of painful genital ulcerations. It is a chronic condition in which the acute phases come and go with varying intensity. Mouth ulcers are the most common and earliest sign of BD. Other manifestations include genital ulcers, skin lesions and uveitis. The disease may also affect blood vessels, gastrointestinal tract, respiratory tract and the central nervous system. PMID- 21686848 TI - Iron deficiency masquerading as idiopathic intracranial hypertension. AB - A 13-year-old female presented with complaints of headache, vomiting, diplopia and progressive blurring of vision developing sequentially over 1 month. Examination revealed marked pallor and bilateral lateral rectus palsy with a visual acuity of 6/12 and 6/36 in the left and the right eye, respectively. Fundus examination showed late stage papilloedema in both eyes. Investigation for anaemia revealed severe iron deficiency. MRI of the brain was normal. The cerebrospinal fluid opening pressure was markedly raised at 320 mm of water but fluid analysis did not reveal any abnormality. Thus, a diagnosis of iron deficiency anaemia with idiopathic intracranial hypertension was made. The patient responded dramatically to intravenous iron treatment. Physicians must be aware of this rare presentation of the common problem of iron deficiency, the rapid correction of which plays an instrumental role in salvaging the patient's vision and preventing a recurrence of disease. PMID- 21686849 TI - Presumed fungal retinitis associated with pseudomyxoma peritonei. AB - Pseudomyxoma peritonei is a rare malignant growth characterised by the progressive accumulation of mucus-secreting (mucinous) tumour cells within the abdomen and pelvis.1 No previous ophthalmic associations have been reported with this condition. We present a case involving this rare cancer and fungal retinitis. Our patient developed a florid retinitis, which was thought to have a fungal aetiology, most likely because he was immunocompromised. Numerous factors are thought to have contributed to the development of ocular symptoms. He was treated appropriately and recovered his vision well. A holistic, multidisciplinary approach should be adopted when managing these patients. PMID- 21686850 TI - Acute generalised exanthematous pustulosis (AGEP) after cefotaxime use. AB - A case of acute generalised exanthematous pustulosis (AGEP) after cefotaxime use confirmed by a positive patch test is reported. A 30-year-old woman received cefotaxime, fosfomycin and ciprofloxacin for sinusitis. At 12 days after drug initiation, she developed an extending pustular erythaema associated with fever. Laboratory investigations showed marked leukocytosis. Her blood chemistry was normal. The histological examination showed parakeratosis, spongiosis and non follicular intra epidermal pustules consistent with AGEP. All medications were withdrawn. The symptoms resolved within 11 days after cefotaxime discontinuation. Patch tests were positive to cefotaxime after 48 h, while ciprofloxacin and fosfomycin yielded negative findings. Based on the Naranjo algorithm, it is probable that the AGEP reaction was due to cefotaxime. To our knowledge, this is the first reported case of AGEP associated to positive cefotaxime patch testing. PMID- 21686851 TI - Rare case of internal pancreatic fistula in a young adult presenting with massive bilateral pleural effusion. AB - Pancreatic pleural fistula is a rare sequel of acute or chronic pancreatitis. The diagnosis is usually delayed due to low index of suspicion and the need for advanced diagnostic tools. The clinical presentation is often misleading because respiratory rather than abdominal symptoms predominate. The majority of reported cases of pancreatic pleural fistula present as unilateral pleural effusion; presentation as bilateral pleural effusion is extremely rare. We report a case of a 16-year-old boy with traumatic acute pancreatitis who presented with a massive bilateral pleural effusion caused by pancreatico-pleural fistula. PMID- 21686852 TI - Testicular metastasis found in a patient with previous large bowel tumour. AB - Epididymo-testicular metastasis arising from a colonic primary neoplasm is exceptionally rare. We present two cases, one where the ipsilateral intrascrotal metastasis was evidence of recurrence 3 years after colonic surgery, and the other where the contralateral epididymo-testicular metastasis was the initial presentation. PMID- 21686853 TI - Extracorporeal elimination in acute valproate intoxication. AB - Severe poisoning with valproate may result in coma and death. The management of valproate intoxication is principally supportive. Valproate is scarcely excreted renally and is mainly protein bound and, therefore, not considered to be amenable for extracorporeal elimination. Despite these unfavourable pharmacokinetic properties, several case reports showed successful treatment of valproate intoxication with haemodialysis and/or haemoperfusion. We describe a male patient (57 years) after ingestion of 64 g of valproate. The patient was successfully treated with haemodialysis for 6 h. Haemodialysis was followed by continuous venovenous haemodiafiltration (CVVH-D) for 18 h to prevent a rebound phenomenon. This report confirms the benefit of haemodialysis in serious valproate overdose. A review of the literature shows that haemodialysis followed by CVVH-D is the treatment of choice in severe valproate intoxication. PMID- 21686854 TI - Oxaliplatin-induced coronary artery spasm: first report of an important side effect. AB - A 67-year-old woman with metastatic colorectal cancer was given her first oxaliplatin infusion as part of the XELOX protocol. She developed chest pain with ECG changes leading subsequently to a diagnosis of coronary artery spasm. To our knowledge, this is the first report of oxaliplatin-induced coronary artery spasm. PMID- 21686855 TI - Bilateral ophthalmic artery occlusion. AB - We describe an unusual case of an elderly patient with all the symptoms of ocular ischaemic syndrome and stenosis of both ophthalmic arteries alone. PMID- 21686856 TI - Outbreak of fatal mushroom poisoning with Amanita franchetii and Ramaria rufescens. AB - Mushroom poisoning continues to occur worldwide. We report a cluster of sudden death in two villages of the Gan County, Jiangxi Province, People's Republic of China in September 2005. Extensive investigations on the clinical presentation, epidemiological features, food and water sources have led to the identification of mushroom poisoning. Each of the 10 patients ate wild mushrooms, identified as Amanita franchetii and Ramaria rufescens, and suffered gastrointestinal symptoms prior to sudden deaths. PMID- 21686857 TI - Miliary lung metastasis due to papillary thyroid carcinoma. PMID- 21686858 TI - The use of infliximab in a patient with idiopathic granulomatous hepatitis. AB - We report a therapeutic response to infliximab in a patient with idiopathic granulomatous hepatitis resistant to treatment with methotrexate and corticosteroids. A 41-year-old woman presented with a 12-month history of fever, night sweat, gross hepatomegaly and 13 kg weight loss. Infection and malignancy were carefully excluded and a liver biopsy showed changes consistent with idiopathic granulomatous hepatitis. The patient was treated with high dose steroids and methotrexate, but her clinical symptoms and biochemical and radiological signs did not settle. Introduction of infliximab led to rapid and sustained resolution of symptoms, hepatomegaly and liver function tests (LFTs) after 1 year of follow-up. To our knowledge this is the first successful use of infliximab in idiopathic granulomatous hepatitis. PMID- 21686859 TI - Stendhal syndrome: a case of cultural overload. AB - An elderly artist developed a transient paranoid psychosis when on a cultural tour of Florence, a city of particular emotional significance to him. He has since had several milder relapses that quickly settle. PMID- 21686860 TI - Hydroxychloroqine induced dilated cardiomyopathy and lupus mastitis. PMID- 21686861 TI - Epiphrenic diverticulum and oesophageal fungal bezoar. PMID- 21686862 TI - Mucinous cystadenocarcinoma of the renal pelvis: a case report and clues to histogenesis. AB - We present a case of mucinous cystadenocarcinoma of the renal pelvis associated with a collecting duct carcinoma in a 58-year-old woman with diabetes. Even though several theories about the aetiology of mucinous cystadenocarcinoma of the renal pelvis have been proposed, its origin remains unknown. The present case shows a distinct morphology and immunohistochemical profile that may suggest a clue to its histogenesis. PMID- 21686863 TI - Complication of a dorsal penile block: needle breakage and migration. AB - We present a case where the hypodermic needle used to administer the local anaesthetic broke off from the plastic hub during the administration of a penile block in an adult and migrated 15 cm to the left groin. This prompted a review of the manufacturer's technical data and biomechanical studies. On the basis of these, we recommend that utmost care be taken to maintain control of the needle during injection, particularly to prevent buckling forces that might lead to breakage. PMID- 21686864 TI - Ocular tuberculosis misdiagnosed as retinoblastoma: an interesting case. AB - Tuberculosis is a ubiquitous disease and a public health problem of major importance in almost all developing and underdeveloped countries. It can involve any part of the body, including the eye. We report a case of a young child presenting with a painful blind eye with leucocoria, where a misdiagnosis of retinoblastoma was made clinically. The eye was enucleated, and subsequent pathological examination led to a final diagnosis of ocular tuberculosis. The patient was put on anti-tubercular treatment, and responded well. PMID- 21686865 TI - Type IV para-oesophageal hiatal hernia: it's a gut feeling. PMID- 21686866 TI - Ureterocolic fistula in the presence of a solitary kidney. AB - Among the entero-urinary fistulae, those between the ureter and colon are rare. Most spontaneous ureterocolic fistulae are caused by urinary calculi. We report a case of a spontaneous ureterocolic fistula which occurred as a consequence of diverticular disease. This rare presentation was further complicated as it occurred in the presence of a solitary kidney. The patient underwent a laparoscopic defunctioning loop ileostomy and after 6 weeks underwent definitive surgical treatment of the ureterocolic fistula. We describe the presentation and management of this fistula and review the current literature. PMID- 21686867 TI - Rieger syndrome with multiple chromosomal breaks and chromosome 4 deletion. AB - Rieger syndrome (RS) is a rare autosomal dominant disorder with variable expressivity and complete penetrance. Axenfeld-Rieger syndrome (ARS) shows genetic heterogeneity with mutations in several chromosomal loci being implicated including PITX2, FOXC1 and PAX6. Cytogenetic analysis was done in this case. Patient had de novo 46,XY,del(4q25-q27) karyotype with a high percentage (>35%) of chromosomal breaks. The breaks were on different chromosomes and not related to disease phenotype of RS. Such chromosomal breaks are diagnostic of chromosomal instability syndromes. Available literature does not report chromosomal breaks in RS or due to culture condition. Such a high percentage of chromosomal breaks are associated with development of certain cancers. In the present case we did not find any features consistent with any of the chromosomal instability syndromes like Fanconi's anaemia and Blooms syndrome, but such cases need to be under regular follow-up. Thus RS cases with multiple chromosomal breaks need regular follow-up and genetic counselling. PMID- 21686868 TI - Childhood mucoepidermoid carcinoma-an interesting case. PMID- 21686869 TI - Extensively drug resistant tuberculosis in a 7-year-old child with interferon gamma and interleukin-12 deficiency. AB - Defects in interferon-gamma axis have been shown to be associated with disseminated mycobacterial disease. A case of a previously healthy HIV seronegative child with disseminated extensively drug resistant Mycobacterium tuberculosis infection presenting as splenic abscesses with lymphadenopathy and progressing to disseminated tuberculosis with absent interferon-gamma and interleukin-12 production is reported here. PMID- 21686870 TI - A rare cause of a scrotal mass: primary leiomyosarcoma of epididymis. AB - Most masses encountered within the scrotal sac are neoplastic and occur within the testis; however a subset (2-3%) of these tumours is extra-testicular and usually arises from paratesticular tissue. Although uncommon, these tumours have a high incidence of malignancy reaching 30%, mainly represented by sarcomas (90%). Tumours occurring in the paratesticular region may be clinically indistinguishable from testicular tumours, thus resulting in initial misdiagnosis. In addition, the clinical findings are by no means specific to a tumour type and cannot distinguish between a benign and a malignant tumour, which results in difficulty in diagnosis and management. All paratesticular tumours are amenable to adequate surgical resection. Definite diagnosis is determined by histological evaluation.Leiomyosarcoma, the second most common paratesticular sarcoma after liposarcoma, is represented in the literature primarily as case reports. We report a case of LMS arising from the epididymis and focus on clinical presentation and differential diagnosis of such tumours. PMID- 21686871 TI - Morning pseudoneutropenia during risperidone treatment. AB - Risperidone, an atypical antipsychotic drug, is associated with neutropenia in some individuals. When the absolute neutrophil count falls below 1.8*10(9)/l clinicians may consider switching the drug. We report the case of a young man who developed neutropenia while on risperidone and also showed a pronounced diurnal variation, with normal neutrophil counts later in the day. Hence neutrophil counts should be measured in the afternoon sample before making modifications to the therapeutic agent based only on a early morning sample. PMID- 21686872 TI - Polymorphism rtQ215H in primary resistance to adefovir dipivoxil in hepatitis B virus infection: a case report. AB - The benefit of lamivudine (LAM) in hepatitis B virus (HBV) infection is compromised by the progressively increasing emergence of drug-resistant mutant strains. Although the addition of adefovir dipivoxil (ADV) usually induces complete suppression of viral replication, primary non-response to ADV in LAM resistant patients has been reported in a variable percentage of cases. Here we report a case of a patient with HBV infection and hepatocellular carcinoma who started LAM therapy and subsequently developed virological breakthrough. The patient was given ADV, but HBV-DNA negativisation was not reached. However, HBV clearance was obtained when the patient was switched from ADV to tenofovir. Virological evaluations showed two well-known LAM-related mutations (rtL180M and rtM204I) in addition to reverse-transcriptase rtQ215H. This is the first case suggesting that this mutation may have an impact on viral replication. Finally, we also report that rtQ215H is responsive to tenofovir. PMID- 21686873 TI - Transient loss of consciousness with convulsions in two young adults with potentially fatal underlying heart disease: syncope versus seizures. AB - The differential diagnosis of syncope versus seizures represents a daily challenge for cardiologists and neurologists. Long Q-T syndrome and hypertrophic cardiomyopathy (HCM) are two hereditary arrhythmogenic heart conditions causing syncope in early adulthood. We report the cases of two patients who were reassessed for transient loss of consciousness (TLOC) with convulsions despite treatment. The first patient, a 40-year-old woman, had been diagnosed with epilepsy and was given phenytoin. Her episodes took place while swimming or when in emotional distress and were not followed by post-ictal confusion. An electrocardiogram showed a very prolonged Q-Tc interval. The second patient, a 30 year-old man with HCM in whom a defibrillator had been implanted on the assumption that he was having cardiogenic syncopes, was actually found to have epilepsy. Adequate treatment rendered both patients asymptomatic. In conclusion, the clinical history and 12-lead electrocardiography remain crucial in the management of TLOC, ideally involving both cardiologists and neurologists. PMID- 21686874 TI - Variability and diversity of the electrical cardiac systole. AB - The electrical cardiac systole originates from the beginning of the P wave (atrial depolarisation) until the end of the downward branch of the T wave (ventricular repolarisation). It includes, therefore, succession P-QRS-T and its corresponding intervals and segments: PQ, ST, and QT. The mathematical possibilities of variability in the length of the electrical systole of the heart may be diverse. It is well documented and established that such changes in length may make the myocardial cells more vulnerable and unstable, and may also cause serious cardiac arrhythmias and even sudden death. The current presentation illustrates these electrocardiographic entities with significant variations in the length of its waves and intervals: short PQ and QT intervals, short PQ and long QT, long PQ and long QT. All parameters appeared in young adult males. PMID- 21686875 TI - A patient with refractory testicular adrenal rest tumour in the setting of cyp11b1 deficiency congenital adrenal hyperplasia. AB - Testicular adrenal rest tumour (TART) due to CYP11B1 deficiency is a very rare clinical finding. Only seven cases have been reported previously. Here, the case of a 19-year-old boy with classic CYP11B1 deficiency and large testicles refractory to medical treatment that led to orchidectomy is reported. The clinical and laboratory manifestations of this patient are discussed and compared with that of the previously reported cases. The patient presented with rapid body growth, precocious puberty, hypertension, recurrent hypokalaemic paralysis and testicular enlargement. The most important differential diagnosis of his latter presentation is Leydig cell tumour (LCT). It was found that positive family history of congenital adrenal hyperplasia (CAH), hypertension, bilaterality, hypokalaemia and multiple hypoechoic masses on ultrasonography of the testes are in favour of a diagnosis of TART. Conversely, high titres of tumour markers and presence of Reinke crystalloids are supportive of a diagnosis of LCT. PMID- 21686876 TI - Diagnosis of scabies by dermoscopy. PMID- 21686877 TI - Metal in stomach: a rare cause of gastric bezoar. AB - Bezoars are conglomerates of undigested organic matter, which forms a mass in the gastrointestinal tract. This report describes a patient who developed a gastric bezoar from ingesting a large number of metal objects in order to "treat" his pulmonary tuberculosis. PMID- 21686878 TI - A diagnostic dilemma of syncope: a patient with chronic pulmonary embolism. AB - In the present report, the case of a 60-year-old man who presented with syncope secondary to chronic thromboemboli of the main pulmonary arteries and pulmonary arterioles is described. PMID- 21686879 TI - Dysphagia caused by ptosis. AB - A 64-year-old-man visited our clinic because of dysphagia and hoarseness. Fibreoptic laryngoscopic examination revealed pooling of saliva around his pharynx and larynx. However, the glottal closure was perfect without laryngeal paralysis in phonation, and the hoarseness was caused by the vibration of aspirated saliva. We also noted severe ptosis in both eyes. According to the patient and his family, the ptosis and dysphagia had been recognised 5 years previously. The ptosis forced him to extend his neck upward when swallowing since it prevented the head down or ordinary position, and thus satisfactory laryngeal elevation could not be achieved while swallowing. We consulted the reconstructive surgical department concerning the patient's ptosis. After reconstructive surgery, the ptosis resolved and the patient was able to swallow without difficulty. Postoperative fibreoptic laryngoscopic examination showed that the saliva pooling sign had disappeared in both pyriform recesses. The patient's hoarseness had also disappeared. PMID- 21686880 TI - Enteropathy associated T cell lymphoma: common in coeliac disease. AB - A 56-year-old male admitted with haematemesis and epigastric pain and severe weight loss on a background of coeliac disease. Computed tomography (CT) abdomen revealed a thickening of the mucosal folds of a short segment of jejunum. He deteriorated and had an exploratory laparotomy and bowel resection with side-side jejojejunal stapled anastomosis and extended right hemicolectomy and ileocolic anastomosis. Histology demonstrated multifocal high-grade malignant T cell lymphoma. Coeliac disease is a very common lifelong disorder. It is associated with osteoporosis, infertility, autoimmune disorders and increased risk of malignancy including an increased risk of non-Hodgkin's lymphoma (NHL) especially of the T cell type. Enteropathy-type T cell lymphoma is associated with a very poor prognosis. There is significant evidence that adherence to a gluten-free diet decreases the risk of developing enteropathy-type T cell lymphoma and helps to prevent development of autoimmune diseases, diabetes mellitus and osteoporosis in patients with coeliac disease. PMID- 21686881 TI - Thrombolysis for ischaemic stroke and glioblastoma multiforme: a case report. AB - OBJECTIVE: To report the uncomplicated use of systemic thrombolysis for stroke in a patient with a misdiagnosed glioblastoma multiforme mimicking brain ischaemia and to suggest that new clinical situations question the stated exclusion criteria for intravenous thrombolysis. PATIENT: A 57-year-old male presented at the emergency room with a sudden aphasia. MEASUREMENT AND MAIN RESULTS: After Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) exclusion criteria were ruled out, intravenous alteplase was administered. The patient presented with tonic-clonic seizures 17 min after perfusion completion, requiring phenytoine administration. Additional computed tomography scan did not show haemorrhagic transformation or brain oedema. A left temporal lobe glioblastoma multiforme was diagnosed after magnetic resonance imaging and neurosurgery. The patient became asymptomatic on the seventh day. CONCLUSION: Any history of central nervous system neoplasm is considered a contraindication to thrombolysis, but the true risk of systemic thrombolysis-precipitated intracranial bleeding is unknown. Further data are needed to establish real haemorrhage risk in this clinical condition. PMID- 21686882 TI - Nasopharyngeal teratoma causing airway obstruction in the neonate. AB - Teratomas are the most common congenital tumours, but teratomas of the nasopharynx are rare in neonates. The present report concerns a premature 30-week old infant girl with an extensive nasopharyngeal teratoma protruding from the oral cavity. The tumour completely obstructed the airway and necessitated immediate intubation. The tumour was successfully resected directly via the transoral route without needing external incisions. Histological examination of the specimen revealed it to be a mature teratoma. The management and differential diagnosis is discussed, accompanied by a review of the literature. PMID- 21686883 TI - A bleeding gastric myeloma. PMID- 21686884 TI - Traumatic diaphragmatic hernia resulting in intestinal obstruction. AB - Traumatic ruptures of the diaphragm occur after blunt or penetrating thoracoabdominal injuries and are one of the most overlooked conditions. Although the risk of death due to rupture per se is low, when left undiagnosed this condition may cause serious complications and death due to gastrointestinal herniation. In this report, a patient with traumatic rupture of the diaphragm who presented with signs of intestinal obstruction is reported. The rupture occurred as a result of an abdominal penetrating injury sustained 3 years ago, and was not diagnosed during the acute phase of injury. PMID- 21686885 TI - Diffuse pleural thickening and diaphragmatic paralysis causing combined intrathoracic and extrathoracic pulmonary restriction. PMID- 21686886 TI - Metachronous Abrikossoff's tumour of the breast and tongue. PMID- 21686887 TI - Unusual dyspnoea in a patient with liver cirrhosis. AB - A 66-year-old woman with hepatitis C related liver cirrhosis presented to our hospital for dyspnoea and cyanosis. Tachypnoea, low grade fever, clubbed fingers, palmar erythaema, spider angioma, wheezing and severe hypoxaemia were found. Chronic obstructive pulmonary disease (COPD) with acute exacerbation was diagnosed and she recovered after bronchodilator and antibiotic treatment. However, dyspnoea and hypoxaemia recurred with widened alveolar-arterial gradient, which was unusual in COPD. A pulmonary function test showed moderate obstructive ventilatory defect and chest high resolution CT scan disclosed some dilated vessels over the left lower lung. Interestingly, platypnoea and orthodeoxia were observed, therefore hepatopulmonary syndrome was suspected and was confirmed by contrast echocardiography, lung perfusion scan and 100% oxygen administration. Her dyspnoea improved gradually after oxygen use. She was followed in our clinic for 3 years and her respiratory condition on home oxygen remained stable, as did the liver cirrhosis. PMID- 21686888 TI - Mixed hydroblast and missile injury with abdominal eventeration: case report. AB - Gunshot injuries are quite common nowadays. Increasing numbers of high-pressure injection injuries are also being observed with a good correlation with industrial progress. High-pressure devices produce pressures and velocities of fluid streams similar to those generated in firearms. However, no missile plays a part in high-pressure injection injuries. We present the unusual case of mixed missile and hydroblast injury, which has not yet been reported. Physical characteristics, typical patterns of injury and the possibility of infectious complications are shown. The importance of educating workers about safety precautions is emphasised. PMID- 21686889 TI - Multiple abscesses in brucellosis with Wright's test negativity. AB - We report a case of metastatic abscesses caused by a chronic form of brucellosis in a shepherd. When she was admitted the patient was cachectic with haematological signs of phlogosis. An abdominal computed tomography scan revealed the presence of multiple hepatic and renal abscesses with a fluid mass in the abdominal wall. The blood cultures, tuberculin skin test, and Wright reaction all gave negative results, but the brucellosis Coombs test for Brucella species was highly positive. Diagnosis was confirmed by a high titre of anti-Brucella IgM antibodies. The patient started antibiotic treatment with a progressive clinical improvement, but after discharge she was lost to follow-up and died 7 months later. PMID- 21686890 TI - Myeloid sarcoma of the prostate revealed by urinary retention: a case report. AB - Myeloid sarcoma (MS) of the prostate is very uncommon with only 17 reported cases in the literature. Here, a singular case of a MS of the prostate discovered through investigations for urinary retention and revealing an acute leukaemia classified as an acute myeloid leukaemia (AML) with inversion 16 (inv16) according to the World Health Organization (WHO) classification (AML-M4 with inv16 in the French-American-British (FAB) classification) in a 65-year-old man is presented. None of the previously reported and reviewed cases of prostatic MS were of AML-M4 type. Moreover, a translocation t(3;7) was identified in our case. Such a translocation was recently described in some acute myeloid processes. MS treatment consists of combining surgical intervention and chemotherapy. Radiation therapy could be beneficial for the localised disease of the prostate. Allogenic haematopoietic stem cell transplantation is also a promising therapy for MS. PMID- 21686891 TI - Neuro-regression in vitamin B12 deficiency. AB - Neuroregression in infants has varied aetiology and vitamin B12 deficiency is one of the uncommon causes. Infantile vitamin B12 deficiency is encountered in malnourished infants or in offspring of strict vegan mothers. We present two cases, both infants of 10 and 8 months of age, whose mothers had vitamin B12 deficiency. On admission, the patients were apathic, hypotonic and lethargic. Serum vitamin B12 levels were below normal limits. On cranial MRI, T2-weighted images revealed frontoparietal cortical atrophy. Both the infants responded to vitamin B12 treatment. PMID- 21686892 TI - Pulmonary nocardiosis mimicking relapse of tuberculosis. AB - The present report concerns a case of pulmonary nocardiosis in an immunocompetent host. This patient was diagnosed as having smear positive pulmonary tuberculosis and received supervised antitubercular treatment for 6 months from a government run tuberculosis centre (Directly Observed Therapy, Short-Course (DOTS) centre). At 3 months after completion of treatment, she presented with fever and cough with posterior-anterior (PA) view chest x ray showing a cavitary lesion on left upper zone. She was subsequently diagnosed as having a case of pulmonary nocardiosis and responded to oral cotrimoxazole. PMID- 21686893 TI - The A, B, C, D of hypercalcaemia in Down syndrome. AB - Hypercalcaemia in infants with Down syndrome is an uncommon condition with only five previous case reports. The patients often present in the toddler years with the classical triad of Down syndrome, biochemical hypercalcaemia, and nephrocalcinosis. We present the sixth case and second male with this condition and further review the clinical details of this under-recognised condition and stratify the diagnostic criteria. The management mandates a reduction in calcium intake as a first step. The natural history of the various aspects of this condition is also considered. PMID- 21686894 TI - Amiodarone induced acute interstitial pneumonitis. AB - Amiodarone has several potentially fatal toxicities, the most important of which is amiodarone pulmonary toxicity (APT). We report a rare case where a patient developed acute interstitial pneumonitis 2 days after starting amiodarone. This report reveals the potential for rapid onset of APT and will help to increase awareness among health care professionals who very often underestimate the incidence of the toxic effects of amiodarone. A simple, cost effective screening tool to detect APT in its early stage is recommended. PMID- 21686895 TI - A case of anti-myelin-associated glycoprotein polyneuropathy and multiple sclerosis: one disease instead of two? AB - A male patient diagnosed elsewhere as having multiple sclerosis (MS) was recently referred to our MS centre. Despite the presence of scattered T2-hyperintense MS like lesions on MRI and cerebrospinal fluid (CSF) oligoclonal bands, his MS diagnosis was unpersuasive. Distal symmetric hypotonia, tendon areflexia and distal muscle weakness were present. A mostly demyelinating sensory polyneuropathy was disclosed at electroneurography. Serum IgM band, free monoclonal light chains and increased anti-myelin-associated glycoprotein IgM were detected. At 18 months later, and after three intravenous Ig treatments, a clinical electroneurographic improvement was evident along with the disappearance of some brain MRI lesions, reduction of serum anti-myelin-associated glycoprotein (MAG) IgM level and of the number of CSF oligoclonal bands. Although the cause/effect relation cannot be proven, we hypothesise that not only peripheral but also central demyelination may be related to the presence of anti-MAG antibodies with central nervous system (CNS) patterns on MRI resembling those seen in MS. PMID- 21686896 TI - Ventilator related barotrauma: an interesting chest x ray. PMID- 21686897 TI - Motor worsening and tardive dyskinesia with aripiprazole in Lewy body dementia. AB - Aripiprazole (APZ) is a novel antipsychotic agent which does not block dopamine (DA) receptors but is rather a partial DA agonist. Thus, it has been proposed that APZ may not induce tardive dyskinesia (TD), a disfiguring and sometimes disabling and irreversible side effect of neuroleptics. Our patient had Lewy body dementia (LBD) and developed severe worsening of parkinsonism over 1 month of APZ treatment. Within days of discontinuation of APZ dramatic orobuccal dyskinesias emerged. Treatment emergent worsening of parkinsonism improved but orobuccal dyskinesias persisted unchanged until his death 8 months later. Others have reported severe extrapyramidal reactions including neuroleptic malignant syndrome and TD with APZ. APZ has been suggested as a treatment for TD but treatment benefit may reflect "masked" dyskinesia. We conclude that, despite an attractive in vitro profile and promising animal data, APZ can induce serious extrapyramidal side effects, including TD. PMID- 21686898 TI - Laparoscopic sleeve gastrectomy in the treatment of gastrointestinal stroma tumours in morbid obese patients. AB - We saw two cases of gastrointestinal stroma tumour (GIST) in morbid obese patients 6 months ago. They were diagnosed with endoscopic ultrasonography. We used laparoscopic sleeve gastrectomy (LSG), a new bariatric surgery, in order to treat morbid obesity and GISTs at the same time. After the operation, the GISTs were removed successfully. The body weights and fasting glucose levels decreased significantly. As a result, LSG is a good and simple method in treating GISTs in morbid obese patients. PMID- 21686899 TI - Russell-Silver syndrome: twin presentation. PMID- 21686900 TI - Multiple giant saccular aneurysms in coronary circulation. PMID- 21686901 TI - An important clinical lesson from a patient infected with HIV with diabetic nephropathy and retinopathy. AB - In resource-rich settings, advances in antiretroviral therapy have reduced the morbidity and increased the life expectancy of patients infected with HIV and consequently increased the likelihood of observing other non-HIV-related diseases in this group of patients. We report a high-risk pregnancy in a 26-year-old woman infected with HIV with complicated insulin-dependent diabetes mellitus. Because of maternal concomitant disease and concerns regarding potential antiretroviral toxicity on maternal disease, an abbreviated regimen of zidovudine prophylaxis was offered to prevent neonatal infection. After the iatrogenic preterm delivery of a healthy and uninfected baby, the patient experienced vulvar oedema and she is now waiting for renal transplantation.In conclusion, our case is one of a range of possible scenarios that may develop in pregnant women who are infected with HIV, reflecting the highly active antiretroviral therapy (HAART)-associated improvements in survival and health. PMID- 21686903 TI - Mediastinal mayhem. PMID- 21686902 TI - A case report of hepatic and renal dysfunction complicating midgut malrotation in an adult. AB - A 39-year-old man had an unusual presentation of jaundice and acute renal dysfunction complicating midgut malrotation. Diagnosis by computed tomography scan enabled prompt surgery and functional correction of the malrotation, with a full return to normal life. PMID- 21686904 TI - Yin and yang of Pott's disease. PMID- 21686905 TI - Massive haemorrhagic adrenal metastases leading to sudden death: a case report. AB - Although adrenal glands are a common site of metastatic cancer, clinically significant haemorrhage into these is very uncommon with only a few cases having been previously published in the English literature. Here, a case of massive adrenal haemorrhage secondary to metastasis of lung cancer that led to the death of the patient is reported. To the best of our knowledge, such an acute death, without any prior medical attention or intervention, as a consequence of haemorrhagic adrenal metastasis has not been described before and is an important consideration in a person with lung cancer who dies unexpectedly. PMID- 21686906 TI - Congestive heart failure and acute renal failure due to lumbar arteriovenous malformations in a young adult. PMID- 21686907 TI - Tako-tsubo cardiomyopathy in a patient with myasthenia gravis crisis: a rare clinical association. AB - Tako-tsubo cardiomyopathy (TTC) is increasingly being recognised as transient left ventricular dysfunction following various hyperadrenergic states such as emotional or physical stressors. The association of this rare clinical entity with myasthenia gravis (MG) has been reported only twice in the literature, both following plasmapheresis for MG crisis. Here we describe a unique case of TTC in a 40-year-old woman with MG admitted with MG crisis managed conservatively. This case suggests that plasmapheresis is unlikely to have a causative role in the development of TTC in these patients. Patients with MG crisis may be at potential risk of developing TTC and careful clinical and electrocardiographic monitoring is necessary while treating them. The possible role of stress as the common precipitating factor in both conditions is also discussed. PMID- 21686908 TI - Alports syndrome: a cause of Horner's syndrome due to internal carotid dissection? AB - This case illustrates the importance of prompt investigation and management in a patient with localising physical signs. The significance of having the gene for Alports syndrome is unknown, but is of interest as this may have bearing on the aetiology of this patient's diagnosis. PMID- 21686909 TI - Is an atypical presentation becoming typical of coeliac disease? AB - A 38-year-old woman was referred to a gastroenterology clinic for investigation of abnormal liver function test (LFT). She had no history of pre-existing liver disease, diabetes mellitus, hypertension, excess alcohol consumption or use of any hepatotoxic drugs. She was being investigated and treated by oral surgeons for recurrent mouth ulcers which she had for about 18 months. She had been seen by the rheumatology team for pain and early morning stiffness affecting the peripheral small joints. Clinical examination was unremarkable apart from the presence of an increased body mass index of 36 kg/m(2). Her haematological and biochemical profile including liver screen did not reveal any abnormalities. Her anti-endomyseal antibody and duodenal biopsies were consistent with the diagnosis of coeliac disease. Her LFT returned to normal within 3 months of starting on a gluten-free diet and remained normal over the next 12 months. She also remained free of mouth ulcers during this period. PMID- 21686910 TI - Embolisation of a bleeding iatrogenic arteriovenous fistula after paracentesis. AB - A 48-year-old Caucasian male developed an iatrogenic arteriovenous fistula involving a branch of the circumflex iliac artery and an abdominal wall vein after undergoing paracentesis 3 months prior to his presentation. He presented to our emergency room with a large abdominal wall haematoma. The fistula that caused the haematoma was embolised with no further complication. PMID- 21686911 TI - Memory loss with enlarged brain ventricles. PMID- 21686912 TI - Multiple lesions on CT brain scan: tuberculosis or neurocysticercosis? AB - An 8-year-old girl with miliary tuberculosis, receiving appropriate treatment, presented with clinical features suggestive of increased intracranial pressure. She tested positive with the highly sensitive and specific1 enzyme-linked immunoelectrotransfer blot assay for cysticercosis. PMID- 21686913 TI - Paediatric sports-related mild traumatic brain injury. AB - Mild traumatic brain injury (mTBI) is a common but relatively understudied childhood injury that can impact cognitive functioning and development. The present report describes a case study of a 14-year-old boy who sustained two consecutive sports-related mTBIs within a 24 h period. Neurocognitive functioning at 2, 6, 8, 55 and 225 days after injury is compared to baseline prior to injury assessment on the same measures. Results from Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), Conner Continuous Performance Test 2 (CPT-II) and the Attention Network Test (ANT) revealed decreased performance in attention, visual memory functioning and impulsivity, with some measures still not returning to baseline at 225 days post injury. The results are discussed with respect to return to normal activities at 4 days post injury. This case study highlights the need for increased research regarding the clinical management of mTBI in the paediatric population, particularly the potential deleterious effects of cumulative injuries. PMID- 21686914 TI - When clinical course contradicts images: necrotising enterocolitis. PMID- 21686915 TI - An example of the healing powers of a human being. AB - A 60-year-old man was referred as an emergency with a 3 month history of left sided abdominal pain and weight loss. He had no other medical problems and took no medications. An endoscopy was performed. This demonstrated a normal oesophagus and stomach and a fleshy mass in the first part of the duodenum with surrounding slough. As this was presumed to be malignant, biopsies were taken. Computed tomography (CT) scan of the abdomen was performed which showed a large, complex, loculated intra-abdominal collection containing air. Results from duodenal biology showed the presence of ulcer slough and liver tissue. The patient was diagnosed with a perforated duodenal ulcer, which had occurred some months previously, and which had eroded into the liver. He was observed and treated with intravenous antibiotics. The patient was discharged on day 14. Follow-up CT scan at 6 weeks showed complete resolution of the collection. PMID- 21686916 TI - A spiked arrowhead in severe hypothermia: the Osborn wave. PMID- 21686917 TI - A patient carrying HIV. AB - A 52-year-old Caucasian man presented to hospital with confusion and was treated for a urinary tract infection. He developed new and unexpected signs and symptoms during his stay in hospital. On further questioning, the story of his social background unfolded and, following further investigation, he was diagnosed with human immunodeficiency virus (HIV). This case reminds all clinicians to think about HIV in the older patient and it also gives direction for investigation and management of similar cases in the future. Identifying HIV early is imperative because it allows effective treatment to be initiated and this will impact upon the patient's quality and longevity of life. PMID- 21686918 TI - Fragile X mosaic male full mutation/normal allele detected by PCR/MS-MLPA. AB - We report on a fragile X mosaic male full mutation/normal allele detected by PCR and methylation-specific multiplex ligation-dependent probe amplification (MS MLPA). This combined analysis provides a diagnostic approach for fragile X syndrome (FXS). The method assesses the presence of expansion (full mutation), the CpG methylation status and could determine copy number changes (large deletions/duplications) along the FMR1 and FMR2 (fragile X mental retardation) genes. The method avoids detection of premutations, which makes it applicable for newborn screening. It can also be used in clarification of mosaic cases. The PCR results in our patient showed one normal allele; three repeats larger than his mother's one. The MS-MLPA showed hypermethylated full mutation pattern in the proband. Both results are compatible with FXS mosaic case full mutation/normal allele. The patient demonstrates atypical mild clinical manifestation of the disease, which correlates to the presence of a normal size allele in the patient's cells. PMID- 21686919 TI - Cerebral salt wasting syndrome following atlantoaxial fracture dislocation in Down syndrome. AB - We describe cerebral salt wasting syndrome (CSWS) in a 5-year-old female child with Down syndrome who had acute myelopathy secondary to chronic atlantoaxial subluxation and fracture dislocation of the odontoid process. The patient developed hyponatraemia associated with excessive urine output and elevated urine sodium concentration following her injury. An administered volume-for-volume replacement of urine loss with 0.9% sodium chloride resulted in an excellent outcome. This patient illustrates the importance of ascertaining CSWS in children with spinal cord disorders, in addition to the syndrome of inappropriate antidiuretic hormone (SIADH) secretion and diabetes insipidus (DI) commonly encountered following a central nervous system (CNS) injury, as the specific treatment approaches is clearly associated with an excellent outcome. PMID- 21686920 TI - Wild lettuce (Lactuca virosa) toxicity. AB - Wild lettuce (Lactuca virosa) can cause toxic effects when eaten. Wild lettuce grows in the north of Iran and some natives consume it unaware of its adverse side effects. We describe eight patients with manifestations of wild lettuce toxicity, admitted to a general hospital affiliated to the Golestan University of Medical Sciences. All the patients recovered (although one had to spend 48 h in the intensive care unit) and no chronic complications were reported. A clinical suspicion of toxicity caused by wild lettuce intake and an accurate history formed the basis of the diagnosis. Conservative treatment, vital sign monitoring, control of patient intake and output, and reducing patient agitation provided the basis for treatment. PMID- 21686922 TI - Gait disorder and cognitive impairment in an elderly patient. PMID- 21686921 TI - Scrotal carcinoma: a reminder of a disappearing occupational disease. AB - A 55-year-old man presented with a 12 month history of a gradually enlarging eroded lesion on his right scrotum. The patient was a 15-20 cigarettes a day lifelong smoker. Initial histological examination showed a benign squamous lesion. Repeat biopsy at 3 months now showed a poorly differentiated squamous cell carcinoma. Occupational enquiry revealed a long history of exposure to mineral oils. The carcinogenic properties of mineral oils is well recognised and is strongly linked with squamous cell carcinoma (SCC) of the skin, including scrotal carcinoma. This case report highlights the importance of reviewing histology with a second biopsy if clinical manifestations change, and secondly to obtain a thorough occupational history in oddly- presenting lesions. PMID- 21686923 TI - Malignant neurilemoma with xeroderma pigmentosum. AB - Xeroderma pigmentosum is a rare autosomal recessive disease characterised by hypersensitivity to sunlight, and is associated with a high incidence of skin cancer. We report a case of xeroderma pigmentosum with malignant neurilemoma in a 46-year-old woman which is unique due to its presentation, which was confirmed histopathologically. TRIAL REGISTRATION NUMBER: 31095. PMID- 21686924 TI - Basic life-support kit in an out-of-hospital emergency. AB - An 8-year-old boy suffered a skull fracture and severe brain injury while attending a skiing event. A physician, equipped with his private emergency kit accomplished placement of a venous access line enabling administration of analgesic and sedating medication with ketamine and midazolam. When the helicopter emergency medical service arrived on the scene the patient's peripheral circulation had decreased to such an extent that further attempts to place a second peripheral venous line were impossible. Securing the airways by tracheal intubation was not considered necessary; the spine was stabilised with a cervical collar and a vacuum mattress. Transport to the trauma centre and intensive care were uneventful. The importance of a specially adjusted emergency kit for first aid by experienced medical personnel is discussed. PMID- 21686925 TI - Tick-borne relapsing fever: conjunctival haemorrhages. PMID- 21686926 TI - The net which made her wet: two unusual cases of stress incontinence. AB - This report describes two cases of urinary stress incontinence secondary to mesh repair of large abdominal hernias. Both patients had never experienced urinary incontinence before their hernia repair. In both cases, polypropylene nets were inserted to stabilise the abdominal wall. Immediately after the intervention, both patients became stress incontinent. Probably pressure transmission to the pelvic floor was increased due to stabilisation of the abdominal wall, which worked as a "windpipe" before surgery. After the insertion of suburethral tapes the incontinence resolved. PMID- 21686927 TI - Possible manic switch induced by combination of bupropion and electroconvulsive therapy in recurrent unipolar depression: a case series. AB - Although there is sufficient evidence of manic switch induced by bupropion or electroconvulsive therapy (ECT) in bipolar depression, the evidence is not robust for unipolar recurrent depression. We present two patients with unipolar recurrent depression, with no family history of bipolarity or relevant personal medical history, who switched states while on a possible combination of bupropion and ECT. We believe that a hypersensitive state caused by ECT may have been aggravated by the dopamine synergistic action of bupropion, causing the switch. As current guidelines (American Psychiatric Association versus the National Institute for Health and Clinical Excellence) give contradictory advice regarding the treatment of patients with severe depression especially about combining pharmacotherapy and ECT, such patients need to be carefully evaluated before being treated with ECT. PMID- 21686928 TI - Incidental huge abdominal aortic aneurysm. PMID- 21686929 TI - Progressive acute kidney injury following myocardial infarction: cholesterol embolisation. AB - Acute kidney injury following acute coronary event can occur from multiple factors, including secondary to volume depletion, poor perfusion because of cardiac dysfunction, secondary to medications such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers or because of aggressive diuretics or use of contrast agents. Atheroembolism (cholesterol embolisation) often occurs following an intervention, such as angiography or revascularisation procedure. An uncommon presentation of atheroembolic renal disease that likely was precipitated by the use of thrombolytics and/or anticoagulation is discussed. PMID- 21686930 TI - Pseudocyst of the spleen caused by tuberculosis: a rare entity. AB - Splenic cysts can be primary or secondary, depending upon the aetiology and pathology. Secondary cysts can be of inflammatory, infective, degenerative or traumatic aetiology. Splenic cysts can be true (lined by epithelium) or secondary (pseudocyst, not lined by epithelium). True splenic cysts are mainly congenital and pseudocysts are mainly traumatic in origin. Pseudocyst of the spleen due to tuberculosis is extremely rare .We report one such case of pseudocyst of the spleen caused by tuberculosis together with a relevant review of literature. Our case probably represents the first reported case of tubercular pseudocyst of the spleen. PMID- 21686931 TI - Amelanotic melanoma presenting with cervical lymphadenopathy. AB - We present a rare case of an amelanotic melanoma of unknown primary presenting with cervical lymphadenopathy. A 20-year-old man presented with large left sided neck lump, associated dysphagia and weight loss. Examination revealed a hard mass in the left posterior triangle of neck and sacral sensory loss. Fine needle aspiration cytology of the mass suggested a poorly differentiated carcinoma. Computed tomography showed a left sided, 8*13 cm cervical mass with liver, lung and bony metastases. Histological examination of the lymph nodal mass confirmed the diagnosis of a metastatic amelanotic melanoma. The patient was treated with glucocorticoids, radiation therapy for the sacral bony deposit, and chemotherapy. Despite an initial reduction of his target lesions, his condition subsequently deteriorated and he died 4 months after diagnosis. PMID- 21686932 TI - A case of periodic fever and persistent splenomegaly in a 2-year-old boy. AB - We report an unusual case of periodic fever associated with persistent splenomegaly in a 2-year-old boy. Febrile episodes occurred at regular 2 weekly intervals and each lasted for 1-2 days. Following resolution of the fever on each occasion, the patient developed neck stiffness of 1-2 days duration. The periodic febrile episodes, as well as the splenomegaly, spontaneously resolved 9 months after the onset of disease. Infectious and malignant causes were ruled out as far as possible. This patient's clinical features are unusual and do not match any known category of periodic fevers in childhood. We believe this case highlights the diagnostic challenges periodic fevers commonly represent. PMID- 21686933 TI - A misdiagnosed scalp rash with a devastating outcome. PMID- 21686934 TI - Reversible pulmonary hypertension in Whipple disease: a case report with clinicopathological implications, and literature review. AB - Whipple disease is a rare multisystemic disorder of infectious aetiology caused by Tropheryma whipplei. Pulmonary hypertension is a rare association for which the underlying pathophysiological mechanism is unclear. Our patient was a 54-year old man with a 1-year history of progressive polyarticular arthritis, and worsening respiratory and gastrointestinal symptoms. Pulmonary artery catheterisation demonstrated moderate-to-severe pulmonary hypertension. Duodenal biopsies, with electron microscopy, were diagnostic of Whipple disease. Involvement by Whipple disease was also evident in the stomach, bone marrow and pulmonary pleura. A 2-week course of intravenous ceftriaxone was initiated and this was followed by a 1-year course of trimethoprim/sulfamethoxazole (160/800), once daily. Nine months into antibiotic treatment, a repeat echocardiogram showed normalisation of the size and function of the cardiac chambers, including the right atrium and right ventricle. There was complete resolution of the severe tricuspid insufficiency and pulmonary hypertension. Whipple disease is not generally considered as a possible cause of pulmonary hypertension but such awareness is important given that it may be potentially reversible with antibiotic therapy. PMID- 21686935 TI - Headache, personality changes and fine motor disturbances. PMID- 21686936 TI - Bartonella endocarditis complicating congenital heart disease. AB - The present report describes a case of Bartonella henselae endocarditis affecting an adolescent with congenital heart disease. A teenager from Eastern Europe was referred to for surgical treatment of aortic endocarditis. She admitted close contact with cats. Blood culture was negative. Diagnosis of B henselae was established on direct PCR amplification and 16SrRNA gene sequencing of the aortic valve tissue and confirmed after 4 weeks by valve culture isolate. The patient underwent extended root replacement (the Ross-Konno operation) with a favourable outcome. PMID- 21686937 TI - Osteochondritis dessicans of the talus in a 26-year-old woman. PMID- 21686938 TI - Rapidly progressive bronchiolitis obliterans organising pneumonia (BOOP). PMID- 21686939 TI - The feto-amnio-placental complex. PMID- 21686940 TI - Ruptured pseudoaneurysm of the radial artery. AB - A 40-year-old man presented with a progressively increasing swelling over the ventral aspect of the right wrist of 23 days duration following a laceration. The swelling was soft, pulsatile and was intermittently bleeding, with poor distal capillary filling and cold distal extremity. Clinically it was diagnosed as pseudoaneurysm of the radial artery and was sent for a duplex scan for confirmation. The lesion ruptured in the radiology department before the scan was done, and the patient went into hypovolaemia. In view of this, the patient underwent exploration of the pseudoaneurysm under brachial block, and the radial artery was found to be transected just proximal to the dorsal branch. It was decided to repair the artery as there was no evidence of adequate circulation supply or the patency of the ulnar artery preoperatively. Doppler study at 15 and 45 days postoperatively showed good flow through, with no evidence of thrombus. PMID- 21686941 TI - Mesodiverticular band simulating acute appendicitis? PMID- 21686942 TI - Rare combination of cervical spine tumours. AB - Osteoid osteoma, osteoblastoma, and haemangioma should be included in the differential diagnosis of any young patient with pain in the back or the neck, painful scoliosis, or radicular or referred-type pain into the lower limb or the shoulder. Osteoid osteoma and haemangioma may occur in the same cervical spine and both have a significant importance in the prognosis, management and possible complications. Early diagnosis with a bone scan and computed tomography scan, leading to prompt treatment, decreases the average duration of symptoms by two thirds. Early diagnosis and treatment of symptomatic vertebral haemangiomas is essential to prevent permanent and irreversible neurologic deficit. PMID- 21686943 TI - Cardiogenic shock secondary to spontaneous mitral rupture. PMID- 21686944 TI - A boy with enlarging hands and feet. PMID- 21686945 TI - Acute liver impairment after sodium valproate overdose. AB - Liver impairment is a recognised adverse effect of long-term sodium valproate treatment, but there are few reports concerning its occurrence after acute overdose. This report describes a 36-year-old woman who deliberately ingested 32 g of sodium valproate (Epilim). Serum valproate concentration was 4370 MUmol/l (630 mg/l) at 4.3 h post-ingestion (therapeutic reference range: 300-600 MUmol/l), and the elimination half-life was 14.1 h. Liver biochemistry tests were initially normal but gradually became impaired, and highest alanine aminotransferase (761 U/l) occurred 2.3 days after ingestion. Supportive measures alone were sufficient to allow recovery of liver function. This case indicates that sodium valproate overdose may cause acute hepatocellular injury, even in the absence of pre-existing liver disease. PMID- 21686946 TI - Use of an inelastic bandage as an adaptation of the lymphatic drainage technique in lower limbs. AB - The inelastic bandage is an adaptation of the manual lymphatic drainage, which substitutes the circular movements of the fingers. A patient with lymphoedema underwent 20 sessions using the modified lymphatic drainage technique. Perimetric measurements were taken before and after each session, and volumetric measurements at the first, 10th, and 20th sessions. Limb circumference was significantly reduced at three points on the perimeter (10, 15 and 25 cm): 2.5 cm (7.3%), 2.5 cm (6.5%) and 1.5 cm (5%), respectively. Volumetry decrease of 26.4% from initial limb volume was observed. The use of the inelastic bandage proved to be an effective adaptation when compared with the results using other techniques described. PMID- 21686947 TI - Peritonitis caused by hepatic pyocyst rupture. PMID- 21686948 TI - A patient with a large pericardial cyst. PMID- 21686949 TI - Whole lung lavage in alveolar proteinosis: manual clapping versus mechanical chest percussion. AB - Alveolar proteinosis is an uncommon lung disease presenting in primary or secondary forms, characterised by surfactant derived proteinous material accumulation within the lungs. The most effective treatment remains whole lung lavage under general anaesthesia. We have recently performed whole lung lavage in a 46-year-old patient with alveolar proteinosis who presented with severe dyspnoea and hypoxia. During the left lung lavage, outwards flow was enhanced at random either by manual clapping or by mechanical chest percussion with a vest airway clearance system. The protein and surfactant protein A concentrations in the 13 successive samples of the left lavage solution showed an exponential decline, not different between manual clapping and chest mechanical percussion. The average concentration of surfactant protein was not different between manual clapping and chest percussion. We conclude that in alveolar proteinosis, manual clapping replacement by mechanical chest percussion during whole lung lavage merits further evaluation. PMID- 21686950 TI - Lymphoproliferative disorder due to sulphasalazine. AB - We present the case of a 57-year-old man who had been on sulphasalazine for 20 years for seropositive non-erosive rheumatoid arthritis and developed a lymphoproliferative disorder, which resolved completely on cessation of sulphasalazine. This is the first report of lymphoproliferative disorder secondary to sulphasalazine. Lymphoproliferative disorders are well recognised with methotrexate and cyclosporine, and recognition of this disorder is critical due to the fact that a number of patients' symptoms will resolve completely with discontinuation of the drug and will not need further treatment. This case report discusses the literature on lymphoproliferative disorders as well as differential diagnoses like drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. PMID- 21686951 TI - Transient global amnesia associated with statin intake. AB - A 57-year-old man treated with statins developed a range of amnestic features that led to concerns he might be suicidal; however, he did not appear to have depression. His problems began after starting rosuvastatin and cleared on discontinuation. PMID- 21686952 TI - Spontaneous haematoma of the pinna. PMID- 21686953 TI - First reported cluster of overwhelming group A streptococcal septicaemia and associated chickenpox infection in the UK. AB - We report the first reported cases of epidemiologically linked invasive group A streptococcal septicaemia, with one fatality, following primary chickenpox infection in previously fit and well children who attended the same preschool. Invasive group A streptococcal sepsis is a well documented complication of chickenpox, which requires prompt and aggressive treatment. Following the cluster, public health measures were put in place to prevent further disease. Varicella vaccination has been shown to significantly reduce hospital admissions as well as deaths related to chickenpox infection. This is the first reported cluster of two epidemiologically linked patients in the UK. PMID- 21686954 TI - A rare complication of a therapeutic manoeuvre. AB - A 20-year-old asthmatic woman presented with palpitations and shortness of breath. She had not had similar episodes previously. There was no history of fever or trauma and she denied drug abuse. On examination she had a regular tachycardia of 165 beats/min and electrocardiogram (ECG) showed a regular narrow complex tachycardia. The admission chest x ray showed increased bronchovascular markings. The Valsalva manoeuvre was performed twice in an attempt to control the heart rate and establish the underlying rhythm. The patient became more short of breath and a repeat chest x ray showed pneumopericardium, pneumomediastinum and surgical emphysema. She was treated conservatively and improved with spontaneous resolution of the pneumopericardium, pneumomediastinum and surgical emphysema. PMID- 21686955 TI - Keep an eye on the lung. AB - The case of a 42-year-old man, originally seen in the Ophthalmology clinic after his wife noticed his pupil sizes were different, is presented. He had been feeling tired with lack of energy for 6 months, during which time he had lost about 6.4 kg in weight. Then he started to have night sweats and a non-productive cough. His appetite was good. A chest x ray showed right midzone and some left lung opacities. Thoracic high-resolution CT showed patchy consolidation involving both midzones with widespread nodular shadowing. Transbronchial biopsies showed non-caseating epitheloid cell granulomata consistent with sarcoidosis. PMID- 21686956 TI - Musical hallucinations in normal children and adult non-psychiatric population. AB - A descriptive account of musical hallucinations of a series of 19 people is presented. Five people reported the onset of hallucination before adulthood. In this paper we demonstrate that musical hallucinations are not necessarily pathological and can occur as a normal experience in people (children and adults) who have no contact with mental health services and no concurrent mental disorder. This is also the first paper to recognise that children can experience musical hallucinations. Also, we show that musical hallucinations are more common than previously thought, but people do not report their occurrence. It seems plausible that in musical hallucinations there is an insult to the ear or brain that produces a change in quality of these images, converting them to a psychotic experience. Musical hallucinations should be regarded as a continuum with normal experiences and clinical syndromes. PMID- 21686957 TI - "The cry of a trapped heart". AB - We present a case referred for endoscopy because of symptoms of dyspepsia and abnormal liver function tests. These more obvious symptoms masked an underlying history of shortness of breath on exertion and mild bipedal oedema. Physical examination revealed a raised jugular venous pulse with pulsus parodoxus, hepatomegaly, mild ascites and slight bipedal oedema. Investigations confirmed the presence of idiopathic calcific constrictive pericarditis. An early surgical pericardiectomy led to resolution of symptoms and signs, and a normalisation of liver biochemistry. PMID- 21686958 TI - An unexpected cause of deep venous thrombosis. PMID- 21686959 TI - Difficulties diagnosing psychiatric paraneoplastic syndromes in patients with a psychiatric history: a patient with secondary mania and renal cell carcinoma. AB - Renal cell carcinoma (RCC) is characterised by lack of early warning signs. The classic triad (palpable mass, haematuria and flank pain) occurs in less than 15% of cases and paraneoplastic syndromes develop in 10-40%, often preceding the detection of the neoplasm. This report describes a 51-year-old woman who displayed manic symptomatology and was investigated due to anaemia. RCC was diagnosed and her psychiatric symptomatology remitted after the nephrectomy. PMID- 21686960 TI - Traumatic transection of the pancreatic duct. AB - A young man presented after a mountain biking accident having received a sharp blow from his handlebars to just below his right costal margin. Although initially he was clinically well and his primary investigations were normal, he was admitted for observation. After becoming peritonitic, his amylase increased to 502 U/ml, and an axial CT scan showed transection of the pancreas. An endoscopic retrograde cholangio-pancreatography (ERCP) was arranged in the operating department, confirming ductal damage. A stent was placed to bridge the pancreatic duct preoperatively, and a laparotomy lavage was carried out and an external drain placed. The patient recovered well and 12 weeks later, after the stent was removed, there was no evidence of pancreatic stricture. Pancreatic injuries must be suspected in blunt abdominal trauma, and preoperative endoscopic stenting may provide the definitive procedure for ductal injuries. PMID- 21686961 TI - Familial 4.3 Mb duplication of 21q22 sheds new light on the Down syndrome critical region. AB - A 4.3 Mb duplication of chromosome 21 bands q22.13-q22.2 was diagnosed by interphase fluorescent in situ hybridisation (FISH) in a 31 week gestational age baby with cystic hygroma and hydrops; the duplication was later found in the mother and in her 8-year-old daughter. All had the facial gestalt of Down syndrome (DS). This is the smallest accurately defined duplication of chromosome 21 reported with a DS phenotype. The duplication encompasses the gene DYRK1 but not DSCR1 or DSCAM. Previous karyotype analysis and telomere screening of the mother, and karyotype analysis and metaphase FISH of a chorionic villus sample, had all failed to reveal the duplication. The findings in this family add to the identification and delineation of a "critical region" for the DS phenotype on chromosome 21. PMID- 21686962 TI - Autism, language delay and mental retardation in a patient with 7q11 duplication. AB - Chromosomal rearrangements are found in a subset of patients with autism. Duplications involving loci associated with behavioural disturbances constitute an especially good candidate mechanism. The Williams-Beuren critical region (WBCR), located at 7q11.23, is commonly deleted in Williams-Beuren microdeletion syndrome (WBS). However, only four patients with a duplication of the WBCR have been reported to date. Here, 206 patients with autism spectrum disorders were screened for the WBCR duplication by quantitative microsatellite analysis and multiple ligation-dependent probe amplification. One male patient with a de novo interstitial duplication of the entire WBCR of paternal origin was identified. The patient had autistic disorder, severe language delay and mental retardation, with mild dysmorphism. The present report concerns the first patient with autistic disorder and a WBCR duplication. This observation indicates that the 7q11.23 duplication could be involved in complex clinical phenotypes, ranging from developmental or language delay to mental retardation and autism. PMID- 21686963 TI - Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA). AB - Myopathy, lactic acidosis and sideroblastic anaemia (MLASA) is a rare condition that combines early-onset myopathy with lactic acidosis and sideroblastic anaemia. MLASA has been associated with a missense mutation in pseudouridylate synthase 1 (PUS1), an enzyme located in both nucleus and mitochondria, which converts uridine into pseudouridine in several cytosolic and mitochondrial tRNA positions and increases the efficiency of protein synthesis in both compartments. We examined two Italian brothers with MLSA and sequenced the PUS1 gene. We found combined defects in mitochondrial respiratory chain complexes in muscle and fibroblast homogenates of both patients, and low levels of mtDNA translation products in fibroblast mitochondria. A novel, homozygous stop mutation was present in PUS1 (E220X). The stop mutation in PUS1 is likely to determine the loss of function of the protein, since it predicts the synthesis of a protein missing 208/427 amino acid residues on the C terminus, and was associated with low mtDNA translation. PMID- 21686964 TI - Abdominal pain and milky plasma. PMID- 21686965 TI - Post-transplant lymphoproliferative disorder in an adolescent masquerading as a complicated primary EBV infection. AB - This report describes an adolescent girl with primary Epstein-Barr virus (EBV) infection in the setting of intensive immunosuppression for a cardiac transplant. She went on to develop progressive pain, weight loss and night sweats with necrosis of the tonsils over 8 weeks. The clinical impression was initially that of a complicated tonsillitis secondary to immune dysfunction. Biopsy 2 months after first presentation demonstrated diffuse B cell lymphoma consistent with post-transplant lymphoproliferative disorder (PTLD). We present this case to highlight the need for a high degree of clinical suspicion for PTLD in a population of patients who commonly experience primary exposure to EBV. PMID- 21686966 TI - Performance-related workload in alpine skiing with congenital heart disease. AB - The present case report assesses the individual performance-related workload in three male children with left ventricular outflow tract (LVOT) obstruction during alpine skiing. Spirometric data (VO(2)) and heart rate (HR) were monitored during alpine skiing in various terrains according to the subject's performance level. A portable spirometric device was used for on-slope data sampling. Relative workload was calculated in relation to peak cardiorespiratory values, obtained during an incremental laboratory cycle test. On the slope the subjects reached 78% to 103% of their peak ergometric HR and a VO(2peak) of 65% to 100%. Young beginners and intermediates with LVOT obstruction seem to face a high cardiorespiratory stress during alpine skiing. For the beginner, an additional load is seen during uphill sidestepping with skis. In children suffering from congenital heart disease, physiological aspects of sports activities such as skiing should not be viewed separately from the possibilities of sports participation and social interactions. PMID- 21686967 TI - Cerebral infarction in idiopathic thrombocytopenic purpura: a case report. AB - Cerebral infarction is a rare but recognised complication of idiopathic thrombocytopenic purpura. With traditional therapies including antiplatelets precluded in such patients and little guidance in the literature, the optimal treatment strategy is unknown. This report describes a case of ischaemic stroke in a patient with idiopathic thrombocytopenic purpura and deteriorating neurology. A successful outcome was made possible using a sequential approach initially improving platelet levels with steroids and intravenous immunoglobulin and then commencing antiplatelet agents. A possible mechanism for thrombosis in idiopathic thrombocytopenic purpura is considered. PMID- 21686968 TI - Hypercalcaemia in breast cancer patients: not always bony metastases. AB - An 80-year-old woman with a history of bilateral breast cancer was referred for investigation of hypercalcaemia, initially suspected to be bone metastasis. Sestamibi scan revealed the cause to be a large parathyroid adenoma which was then removed. Hypercalcaemia is the most frequent metabolic complication of breast cancer. Primary hyperparathyroidism is one of the most frequent causes of benign hypercalcaemia, but is often not considered in oncology patients. This case illustrates the importance of considering two primary pathologies. PMID- 21686969 TI - Phaeohyphomycosis masquerading as a palatal neoplasm in a patient who is immunocompetent. AB - A female patient presented with facial pain, discharge and headache. She had undergone excision of a palatal swelling 2 weeks previously, following which she had developed an oroantral fistula with necrosis of the palate. Imaging studies were suggestive of chronic sinusitis. A biopsy from the maxillary antrum revealed phaeohyphomycosis, a group of fungal infections caused by saprophytic fungi. The patient was treated with antifungal treatment and had a complete response. Phaeohyphomycosis is of rare occurrence in the paranasal sinus and in patients who are immunocompetant. There are only eight previous reports of this occurrence in the literature worldwide. PMID- 21686970 TI - Management of immune thrombocytopoenia in a patient with newly-diagnosed smouldering myeloma and colorectal cancer. AB - Immune thrombocytopoenia (ITP) is one of the most common autoimmune manifestations of B cell lymphoproliferative diseases. The association with multiple myeloma (MM) and solid tumours is rare. Here, a case of ITP associated with asymptomatic multiple myeloma and colon carcinoma, refractory to standard therapy and responsive to rituximab, is described. ITP should be considered in the differential diagnosis of thrombocytopoenia in MM and colon cancer. Understanding of the potential risk and reversibility of ITP should aid in the management of these patients. PMID- 21686971 TI - Axillary lymphadenopathy as a first symptom of diabetic mastopathy. AB - Diabetic mastopathy is an unusual fibroinflammatory breast lesion that characteristically presents in premenopausal women with long-standing type 1 diabetes mellitus.Patients present with clinically suspicious breast masses or axillary lymph nodes with imaging characteristics indistinguishable from malignancy. Fine needle aspiration is often inadequate and a core biopsy should be performed. Excisional biopsy is not necessary, and annual follow-up is recommended. Recognition of diabetic mastopathy should lead to better care of patients with breast nodules or axillary masses who are diabetic, avoiding surgery for this benign condition. PMID- 21686972 TI - The 'pulsatile' sebaceous cyst: beware of a superficial temporal artery aneurysm. AB - True aneurysms of the superficial temporal artery (STA) are quite uncommon. Only 14 such cases are described in the literature. Ultrasound scan (USS) is an appropriate and easily accessible non-invasive diagnostic modality, as it can show both the anatomical and flow characteristics of the aneurysmal vessel. Other conditions to be included in the differential diagnosis are haematoma, angiofibroma, eroding middle meningeal artery aneurysm, abscess or a parotid mass. Operative intervention is indicated to relieve symptoms as in this case, and to prevent rupture. PMID- 21686973 TI - Giant true cyst of the spleen with elevated serum markers, carbohydrate antigen 19-9 and cancer antigen 125. AB - A 19-year-old woman presented with a left upper abdominal mass. Computed tomography of the abdomen showed a solitary cystic lesion in the splenic hilum, approximately 20*16 cm in size, demonstrating almost total displacement of the remaining splenic parenchyma. She had high serum concentrations of carbohydrate antigen 19-9 and cancer antigen 125. A splenectomy was performed. Immunohistochemical study confirmed the existence of an epithelial cyst. Following surgery, the serum concentrations of the tumour markers decreased gradually. True splenic cysts are rare and their origin is controversial. In splenic cysts with high serum concentrations of tumour markers, such as occurred in our patient, cystectomy or splenectomy were preferred to remove tumour marker producing epithelium and to prevent recurrence after treatment. If the epithelial lining of the cyst cannot be detected under light microscopy, immunohistochemical study should be performed. PMID- 21686974 TI - Superficial siderosis: a rare complication of brain surgery. PMID- 21686975 TI - Generalised chronic tophaceous gout. PMID- 21686976 TI - A case of rare anomalies. PMID- 21686977 TI - Unstable angina following intracavernous injection of alprostadil: a case study. AB - Intracavernous injection of alprostadil is the gold standard treatment for erectile dysfunction following radical prostatectomy. After surgery, low doses of alprostadil can be delivered for the sole purpose of penile rehabilitation. The only reported systemic side effects of such injections are arterial hypotension and headache. In the current report, a case of unstable angina immediately following an intracavernous injection of alprostadil is described. PMID- 21686978 TI - Osseous metaplasia in a juvenile retention polyp: a case report. AB - We report a unique case of juvenile rectal polyp occurring in a 15-year-old male which showed osseous (bony) metaplasia on histological examination. The phenomenon is striking on histological examination but it appears to have no clinical significance. PMID- 21686979 TI - Pre-emptive treatment for Clostridium tetani: importance of early recognition and treatment in the community. AB - The case of a 79-year-old woman with neurotoxin producing Clostridium tetani identified in a lower limb laceration that was promptly treated is presented; the patient developed no symptoms of tetanus. Her antibody levels were measured as 0.01 U/ml (protective levels >0.01 U/ml) and were therefore not protective. The isolate of C tetani was identified by 16S sequencing. The potential to produce tetanus toxin was determined by detection of a fragment of the C tetani neurotoxin gene. She was given a week long course of oral flucloxacillin, 500 mg four times a day and metronidazole, 400 mg three times a day, for 5 days. The patient was subsequently given prophylactic immunoglobulin (500 IU) as per guidelines. The fact that the patient did not manifest any symptoms of localised or generalised tetanus could be attributed to prompt management when she presented to her primary care site. PMID- 21686980 TI - Takotsubo cardiomyopathy following lightning strike. AB - Lightning strike is the most common environmental cause of sudden cardiac death, but it may also be associated with a myriad of injuries to various organ systems. Direct myocardial injury may be manifest as electrocardiographic alterations or elevation in cardiac-specific isoenzymes; however, significant electrical cardiac trauma appears uncommon. A case is presented of severe acute cardiomyopathy in a "Takotsubo" distribution causing cardiogenic shock following lightning strike in a previously healthy 37-year-old woman. Although rarely identified in this context, Takotsubo cardiomyopathy (also known as "transient left ventricular apical ballooning syndrome") is characterised by transient cardiac dysfunction, electrocardiographic changes that may mimic acute myocardial infarction and minimal release of cardiac-specific enzymes in the absence of obstructive coronary artery disease. The condition is associated with a substantial female bias (up to 90% of cases) in reported series, and despite occasionally dramatic presentations recovery of left ventricular function is almost universal over days to weeks. In rare instances, however, the syndrome has been associated with more catastrophic complications such as papillary muscle or cardiac free wall rupture, necessitating emergency surgical intervention to preserve life. In clinical practice, non-lethal lightning strike-induced cardiac injury is frequently associated with small elevations of cardiac isoenzymes without overt clinical sequelae; however, the incidence of silent myocardial mechanical dysfunction remains unknown. Cases such as the one presented highlight the potential for serious, albeit usually transient, cardiac sequelae from lightning strike injury and remind us that our mothers' advice to remain indoors during thunderstorms is probably worth heeding. PMID- 21686981 TI - Atropine-like poisoning caused by topical use of undiluted topical robinul. AB - A case is described in which a patient inadvertently applied undiluted Robinul to a sweat rash in the groin and experienced two episodes of atropine-like poisoning. We highlight important diagnostic issues and identify concerns with prescribing unfamiliar medications. PMID- 21686982 TI - Atypical uterine leiomyoma: a rare variant of a common problem. AB - A myomectomy was performed in a 35-year-old woman, and microscopic examination of the resulting specimen revealed an atypical myoma. Due to the rarity of this diagnosis, it is difficult to give clinical guidance for these patients, especially when they are considering pregnancy in the future. We advised 6 monthly vaginal ultrasound and did not advise against pregnancy. At 18 months there are no signs of recurrence, although the patient is not yet pregnant. PMID- 21686983 TI - NSAIDs-induced diaphragm-like colonic strictures: a case report. AB - A 48-year-old woman presented with a 2-week history of diarrhoea and abdominal pain. No overt gastrointestinal bleeding was reported and there was no history of loss of weight or loss of appetite. General and abdominal examination was unremarkable except for subconjunctival pallor. The haemoglobin was 7.1 g/dl at presentation with the peripheral blood film indicating iron deficiency anaemia. An urgent colonoscopy revealed two strictures within a 5 cm segment of transverse colon. The distal stricture showed significant ulceration and inflammation, while the proximal one showed an impassable "diaphragm-like" stricture. Biopsies from both of the strictures showed chronic inflammatory infiltrate with numerous eosinophils and no evidence of malignancy. The patient had been taking enteric coated diclofenac tablets 50 mg three times daily over the past 10 years for chronic backache. Her bowel symptoms resolved significantly within 4 weeks of stopping diclofenac and she continued to remain relatively asymptomatic at 3 months follow-up. PMID- 21686984 TI - A case of IgG4-related sclerosing disease complicated by sclerosing cholangitis, retroperitoneal fibrosis and orbital pseudotumour. AB - We present a case of IgG4-related sclerosing disease complicated by sclerosing cholangitis (SC), idiopathic retroperitoneal fibrosis (IRF) and orbital pseudotumour (OPT). Clinical, radiographic and pathological findings later suggested that the patient had SC complicated by IRF. The patient's SC and IRF were well controlled for the first 10 years of the follow-up period; OPT developed in the tenth year. During investigation of the OPT, serum IgG4 level was found to be significantly elevated. The patient was then diagnosed with IgG4 related sclerosing disease complicated by SC, IRF and OPT. This is a rare manifestation of IgG4-related sclerosing disease, which was diagnosed incidentally during OPT work-up. We suggest that this is a variation of the so called IgG4-related sclerosing disease or hyper-IgG4 disease. PMID- 21686985 TI - Giant right atrial cystic hamartoma: a case report and literature review. AB - An 11-year-old boy presenting with palpitation and chest distress was found to have gross cardiomegaly on chest radiography. Subsequent echocardiography revealed an intramural giant cystic mass in the right atrium. An operative measure was planned to prevent acute cardiac tamponade and right coronary artery obstruction. The patient successfully underwent open cystectomy to remove the mass, which was located on the front wall of the right atrium and extended to the atrioventricular appendage. Histopathological examination confirmed a cystic hamartoma. To the best of our knowledge, this is the first reported case of a giant cystic hamartoma located on the right atrium. TRIAL REGISTRATION NUMBER: 704640. PMID- 21686986 TI - A case of leiomyoadenomatoid tumour of uterine serosa: speculations about differential diagnosis. AB - Adenomatoid tumour is a benign rare lesion of the female genital tract, localised in the wall of fallopian tubes or beneath the uterine serosa. It is often accompanied by smooth muscle proliferation, obscuring the presence of adenomatoid tumour, resulting in misdiagnosis of cellular leiomyoma.Here, a case of uterine serosal adenomatoid tumour associated with multiple leiomyomas and pelvic endometriosis in a 44-year-old woman who underwent surgical removal for uterine bleeding and abdominal pain is presented. PMID- 21686987 TI - Skull metastases from thyroid carcinoma. PMID- 21686988 TI - Bleeding stomal varices: a marker of chronic liver disease. AB - A 44-year-old man presented with acute onset painless haemorrhage from his ileostomy. He had undergone panproctocolectomy for ulcerative colitis 17 years previously. Immediately following admission, he experienced further massive haemorrhage, developing hypovolaemic shock. Active resuscitation including suturing of a bleeding stomal varix was successful. An ultrasound scan of the liver was reported to be normal and the patient was discharged for further outpatient investigation. However he reattended 8 days later with further significant haemorrhage. Investigation with CT revealed portal hypertension and cirrhosis. The patient is currently awaiting a transjugular intrahepatic portosystemic shunt (TIPS) procedure and transjugular biopsy to alleviate his portal hypertension and yield a tissue sample for histological diagnosis. The case highlights the need for clinicians to have a high index of suspicion when presented with bleeding stomas. Further investigation is warranted and may reveal significant underlying hepatic disease. Additionally, further procedures may be necessitated to prevent recurrence of haemorrhage. PMID- 21686989 TI - Dysgeusia in symptomatic syndrome of inappropriate antidiuretic hormone secretion: think of lung cancer. AB - The case of a 60-year-old woman who presented with marked dysgeusia to all food and symptomatic syndrome of inappropriate antidiuretic hormone secretion (SIADH) is described. She eventually turned out to have metastatic small cell lung cancer. The case study explores the interesting constellation of dysgeusia, SIADH and lung cancer. PMID- 21686990 TI - Abdominal wall haematoma in cardioembolic stroke due to enoxaparine therapy: a report of two cases. AB - Abdominal wall haematomas are uncommon and often misdiagnosed entities. Most of the time the haematoma is produced by rupture of the epigastric vessels, deep circumflex iliac artery or tear in the rectus or lateral oblique muscle. Predisposing factors such as arteriosclerosis of vessels, old age, straining while urinating and coughing and use of anticoagulant agents make bleeding more likely. Here, two uncommon cases who experienced cardioembolic stroke are described. The patients were given enoxaparin sodium urgently, administered to the stomach area subcutaneously. They presented with abdominal masses, periumbilical and inguinal ecchymosis. Their haemoglobin levels dropped. Abdominal CT scan and ultrasonography revealed rectus sheath and internal abdominal oblique muscle haematomas. The patients were treated conservatively. This report concerns this rare condition, often misdiagnosed in unconscious patients, that has not been reported as being due to cardiogenic brain embolism in the literature to date. PMID- 21686991 TI - Organising pneumonia after near-drowning. AB - A 38 year-old female with no significant medical history was transferred to a medical centre in Hawaii after near-drowning at the beach. She was noted to have increasing shortness of breath. Subsequently she was placed on non-invasive ventilation and then intubated for respiratory support. She was thought to have early stage acute respiratory distress syndrome after sea water aspiration. By multidisciplinary treatment, she was able to be extubated successfully on hospital day 5, and then flew back to Japan. When visiting our hospital in Japan, further examinations were conducted for prolonged respiratory symptoms and pulmonary infiltrates by CT. A specimen obtained by transbronchial lung biopsy revealed organising pneumonia which was thought to be related to sea water aspiration. Methylprednisolone treatment resolved her respiratory symptoms and pulmonary infiltrates. PMID- 21686992 TI - Relapsing-remitting type multiple sclerosis with olfactory hallucinosis and secondary delusions. AB - Multiple sclerosis is frequently associated with psychiatric symptoms. In more than 50% of the patients symptoms of affective disorder or cognitive decline are observed. A significantly smaller proportion of these individuals develop psychotic symptoms usually during the course of the disease. In this report the rare clinical case of a woman who developed olfactory hallucinations and delusional disorder after 13 years of relapsing-remitting type multiple sclerosis is described. PMID- 21686993 TI - Dyspnoea in a patient with chronic heart failure: surprise, surpise! AB - Dyspnoea is one of the typical symptoms of congestive heart failure. The cause of dyspnoea in this patient with chronic heart failure, 8 months after coronary artery bypass grafting, was a great surprise for the heart failure physician, showing that a more broad view of dyspnoea is warranted in this common symptom. PMID- 21686994 TI - Antipsychotic-induced urinary dysfunction: anticholinergic effect or otherwise? AB - Although urinary difficulties such as incontinence (UI) and retention (UR), reported with both typical and atypical antipsychotics, have been hypothesised as being a form of extrapyramidal side effects or due to anticholinergic side effects, we believe this may not be the case. We report here a male patient with bipolar disorder who developed urinary difficulties with antipsychotics, both typical and atypical, and in whom only aripiprazole seemed to work. We also hypothesise on the possible mechanisms of adverse urinary effects of antipsychotics. PMID- 21686995 TI - Pituitary tumour apoplexy following acute coronary syndrome management. PMID- 21686996 TI - Generating hand dysaesthesiae: the "GHD phenomenon" - straight to the diagnosis. AB - Two Irish women presented with difficulty in completion of hair straightening, limited by upper limb dysaesthesiae due to claudication or brachial plexus entrapment induced by sustained shoulder abduction beyond 90 degrees. The first described arm pain precipitated by elevation and sustained abduction above shoulder level, particularly while using her GHD hair-straightener. Elevated arm stress test was positive and a left cervical rib was seen on chest x ray. Neurogenic thoracic outlet syndrome (TOS) was diagnosed and the cervical rib was resected. The second described arm tingling and weakness when performing tasks involving shoulder abduction and elevation, limiting GHD use to 10 min before having to rest. Upper limb blood pressure and pulses were undetectable. Erythrocyte sedimentation rate was elevated and flow on radial Doppler disappeared on abduction and elevation of each arm. A CT pulmonary angiography demonstrated features of Takayasu's arteritis. Vascular TOS was diagnosed. Symptoms resolved with corticosteroids, followed by long-term immunosuppression and anti-coagulation. PMID- 21686997 TI - Colonic MALToma: a case report and review of the literature. AB - Gastric mucosa associated lymphoid tissue lymphomas (MALTomas) are well documented and their management effectively established, but colonic MALTomas are extremely rare and not many know it could occur. We report the first colonic MALToma in the UK. The patient was managed in accordance with gastric MALToma management modalities in accordance with the evidence in the literature. After failure of medical management, a surgical resection was the last and successful option for treatment.Though gastric MALToma management is well-established, the colonic form of the disease does not act the same and requires a more aggressive approach. PMID- 21686998 TI - "Scoping-around" a sigmoidorectal intussusception: a pitfall of flexible sigmoidoscopy. AB - A 66-year-old woman presented with 3-month history of progressive constipation and occasional bright red per-rectal bleeding. An urgent flexible sigmoidoscopy (FS) showed an abnormal lesion within the anal canal and biopsy showed tubulovillous adenoma with low-grade dysplasia. She mentioned "no" response to a preparatory enema given before FS. The patient presented 4 days after FS with absolute constipation and passing a "jelly-like" substance since the procedure. A large soft tissue lump with "currant jelly" mucus discharge was noted on per rectal examination. An abdominal x ray was suggestive of distal large bowel obstruction and a water-soluble contrast enema suggested sigmoidorectal intussusception. The intussusception was irreducible with rigid sigmoidocopy and therefore the patient underwent sigmoid resection and Hartmann's procedure, which showed a distal sigmoid polyp as a lead point for the intussusception. Retrospectively looking into the case, the intussusception was present during FS, but was scoped-around and therefore lesion was considered to be in the anal canal. PMID- 21686999 TI - A case of recurrent gastrinoma in the liver with a review of "primary" hepatic gastrinomas. AB - The present report concerns a patient with a malignant gastrin-producing neuroendocrine tumour (ie, Zollinger-Ellison syndrome) with recurrent hepatic gastrinomas, in whom no gastrinoma in the duodenum, pancreas or other extrahepatic sites could be identified despite the use of multiple, repeatedly performed imaging and exploration techniques over the past 20 years. A short review on primary liver gastrinomas published since 1981 is also given. Interestingly, our patient is the only case with documented recurrent gastrinoma in the liver. None of the cases in the literature had liver gastrinomas as part of the multiple endocrine neoplasia type I syndrome. The interpretation of hepatic gastrinomas as primary lesions is questionable unless comprehensive investigation and well documented long-term follow-up is performed. PMID- 21687000 TI - Thunderclap headache after take off of a commercial jet airplane. PMID- 21687001 TI - Torticollis with tonsillitis. Is imaging necessary? PMID- 21687002 TI - Massaging the outcome: an unusual presentation of pulmonary embolism. AB - A 56-year-old man with a previous deep venous thrombus presented with dyspnoea after a leg massage. A transthoracic echocardiogram demonstrated a "worm-shaped" right atrial embolus, most probably a femoral cast. A pulmonary artery angiogram confirmed a large wedge-shaped perfusion defect caused by a pulmonary embolus. There are previous case reports about leg massage causing pulmonary emboli but this is the first reported event where the thrombus has been visualised directly. Also, it demonstrates the important role that echocardiography plays in pulmonary embolus. PMID- 21687003 TI - Pneumothorax: a common complication of CT-guided transthoracic needle lung biopsy. PMID- 21687004 TI - Pasteurella multocida septicaemia in a patient on haemodialysis. AB - This case report details the presentation of a 76-year-old man on haemodialysis who rapidly developed overwhelming sepsis over a 24 h period with isolation of the pathogen Pasteurella multocida in blood cultures. Despite treatment with antibiotics shown to have good activity against this pathogen, the patient died. During further questioning, it transpired that the patient had allowed his dog to lick him, including the neck haemodialysis cannula, though no direct trauma in the form of bites or scratches were evident. The authors postulate that the dog licking may have been a possible route of transmission. To date, there is very little information on P multocida septicaemia in a haemodialysis patient and this report calls attention to the need for greater awareness as to the potential dangers of exposure to oral flora of pet animals in haemodialysis patients. PMID- 21687005 TI - Dual life-threatening pathologies presenting simultaneously. AB - A 70-year-old male presented to hospital with both anterior ST elevation myocardial infarction and spontaneous oesophageal rupture (Boerhaave's syndrome). He underwent primary angioplasty and stenting for a lesion of the left anterior descending in addition to cardiothoracic surgery for the oesophageal rupture. This combination of pathologies is a rare entity and often difficult to diagnose. To date, only a few cases have been reported. PMID- 21687006 TI - Diagnostic difficulty of pulmonary embolus in a bariatric patient and complication of therapeutic dose low-molecular weight heparin to the surgical anastomosis. AB - Bariatric surgery is a rapidly expanding surgical speciality. A patient developed new onset shortness of breath and pleuritic chest pain post-laparoscopic gastric bypass surgery. Investigations were consistent with type 1 respiratory failure. Such patients are at high risk of venous thromboembolism. A clinical diagnosis of a pulmonary embolus was made. Treatment was initiated with therapeutic dose low molecular weight heparin (LMWH)-enoxaparin. Subsequently she developed bleeding from the anastomotic sites. Subsequent investigations, including a CT pulmonary angiogram, diagnosed hospital-acquired pneumonia to which she has responded to antibiotic treatment. There is little in the published literature as to the successful treatment of pulmonary embolus in bariatric patients, and little about the potentially devastating bleeding from the anastomotic sites by treatment with LMWH. PMID- 21687007 TI - Pramipexole as a possible cause of the syndrome of inappropriate antidiuresis. AB - A 60-year-old man with Parkinson's disease developed hyponatraemia with low plasma osmolarity, urine hyperosmolarity and an elevated urine sodium concentration. Plasma vasopressin (AVP) level was five times the upper normal limit and a diagnosis of the syndrome of inappropriate antidiuresis (SIAD) was made. Although the patient was treated with levodopa/carbidopa 500 mg/50 mg, entacapone 400 mg, seregiline 5 mg, cabergoline 1 mg, pergolide 250 MUg and pramipexole 3 mg, SIAD resolved after the dose reduction of pramipexole. Dopamine is reported to facilitate AVP secretion through activation of D4 receptors. The hD4:hD2L pKi ratio calculated from published data is 0.017 for cabergoline, 0.44 for pergolide, 1.1 for ropinirole and 13 for pramipexole. The hD4:hD2 pKi ratio of dopamine is reported to be 1. Accordingly, pramipexole has a higher selectivity for D4 receptor than other dopamine agonists. Pramipexole is likely to increase AVP secretion, which is a prerequisite for developing SIAD. PMID- 21687008 TI - Giant somatotropinoma. PMID- 21687009 TI - A 14-year-old girl with a sudden arm swelling after axillary depilatory wax. AB - Takayasu's arteritis is a systemic vasculitis predominantly affecting the aorta and its major branches. We report a 14-year-old girl in whom incidentally a deep upper limb vein thrombosis was found. She was referred to the emergency unit due to swelling and intermittent cyanosis of the right arm following an axillary depilatory wax. High-resolution echo colour Doppler ultrasonography showed a deep vein thrombosis with thickening of the proximal common carotids. A diagnosis of type IIb Takayasu's arteritis was made. The patient's history revealed fatigue, myalgia and headache. Immunosuppressive treatment and anticoagulation were introduced with a rapid and sustained improvement. PMID- 21687010 TI - Acute retinal arterial occlusion after intravenous administration of bevacizumab. AB - Retinal artery occlusions are usually the result of emboli, although non-embolic causes such as vasculitides, coagulopathies, and vasospasms resulting from migraines and inflammatory conditions do occur. Bevacizumab, a humanised monoclonal antibody, is designed to bind to and inhibit vascular endothelial growth factor (VEGF). VEGF is a protein that plays a critical role in tumour angiogenesis, the formation of new blood vessels to the tumour. The use of bevacizumab has spread worldwide, but the drug related adverse events associated with its use have been reported in a few retrospective reviews. We report on a previously unpublished case of retinal artery occlusion following the use of systemic bevacizumab. PMID- 21687011 TI - Unexplained high thyroid stimulating hormone: a "BIG" problem. AB - Macro-hormones and macro-enzymes are high molecular weight conjugates of hormones or enzymes, respectively, often with immunoglobulins. These are referred to as macromolecular complexes, and may cause artefactually elevated biochemical tests results. Macro enzymes of the most commonly measured serum enzymes have been identified and are recognised as a source of elevated measurements that may cause diagnostic confusion; macro-creatine kinase and macro-amylase are the two better known macro-enzymes in clinical practice. Literature on macro-hormones is largely restricted to macro-prolactin. We present a case of a clinically euthyroid patient, who had persistently elevated thyroid stimulating hormone (TSH) but free thyroxine within the reference limits. She underwent repeated thyroid investigations and thyroid hormone interference studies, until macro-TSH was identified as the most likely cause of unexplained elevated TSH. Following the identification and characterisation of this biochemical abnormality, she is no longer subject to repeated blood tests for assessment of thyroid function; the patient currently remains clinically euthyroid. PMID- 21687012 TI - A case of acquired trichomegaly following treatment with erlotinib. AB - A woman on erlotinib treatment for lung cancer presented with a corneal ulcer from aberrant eyelash touch. She developed coarse, hyperpigmented and irregular eyelash and eyebrow growth a few months following treatment. She was treated successfully with epilation, eyelash trimming, lid hygiene and intensive topical lubrication. This is the first case report in the UK of trichomegaly with associated corneal ulceration. Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has recently been approved for use as a chemotherapeutic agent by the National Institute for Health and Clinical Excellence. Ophthalmologists and oncologists should be aware of the adnexal and ocular surface changes that can occur, and that simple interventions may be used to manage them. PMID- 21687013 TI - Isolated tear of the tendon to the medial head of gastrocnemius presenting as a painless lump in the calf. AB - We report on a case of isolated tear of the medial head of gastrocnemius tendon. The patient presented with a painless lump in the right calf and denied any prior history of trauma or strain to the leg. A longitudinal split of the tendon was demonstrated at ultrasound and magnetic resonance imaging (MRI). There were no other abnormalities and the gastrocnemius muscle was normal. There are no reports in the literature of isolated gastrocnemius tendon tear. To date the calf muscle complex injury described in this area is tearing of the medial head of gastrocnemius muscle, sometimes referred to as "tennis leg". We conclude that an isolated tear of the tendon to the medial head of gastrocnemius should be considered in the differential diagnosis of a lump or swelling in the upper medial area of the calf and we recommend ultrasound or MRI as the investigations of choice. PMID- 21687014 TI - Diverticular disease presenting as subcutaneous emphysema of the thigh. AB - A normally fit and well 79-year-old lady presented acutely confused and shocked after a few months history of atypical left-sided back and thigh pain. She was unable to tolerate movement of her left leg and soft tissue crepitus was palpable over her thigh. Emergency incision and drainage of the leg was performed with intraoperative swabs growing Streptococcusmilleri and coliforms. Postoperatively, in the Intensive Care Unit (ICU) deep faecal contamination of the wound was noted. Contrast imaging revealed severe diverticular disease and colocutaneous fistula. Abdominal examination was unremarkable throughout her admission and initial CT scan had not revealed the underlying pathology. A defunctioning colostomy was fashioned and after a prolonged period of rehabilitation the patient returned to being functionally independent. PMID- 21687015 TI - Immature embryoid teratoma of the gall bladder: case of a primary primitive neoplasm. AB - This study presents diagnostic histopathological features of a primary embryoid teratomatous neoplasm in the gall bladder of a 60-year-old woman, and also discusses its pathogenesis. Sections revealed immature and typical embryoid bodies and dispersed syncytial trophoblasts along with mature and immature neuroectodermal and mesodermal elements. The residual endothelial lining of the gall bladder showed in situ and proliferative changes characteristic of an endodermal tumour. Ultrasonographic and magnetic resonance imaging findings of the rest of the abdominal and pelvic organs appeared normal. Results show that the mature adult gall bladder is susceptible to primary neoplasms of a primitive nature ranging from immature embryoma and teratoma to neuroectodermal tumour. Such primitive neoplasms in adult organs where benign neuroectodermal elements are present may evolve from a constituent cell of an adult organ acquired during embryogenesis from a morula that differentiated into trophoblastic (outer) and embryoblastic (inner) cells, and existing dormant cells at rest until reactivation during oncogenesis. PMID- 21687016 TI - Port wine stain, soft tissue bone hypertrophy and leg ulcer. PMID- 21687017 TI - Cough's postulates. PMID- 21687018 TI - Conversion (dissociative) symptoms as a presenting feature in early onset bipolar disorder: a case series. AB - We present three cases of early onset bipolar disorder where dissociative (conversion) symptoms preceded the onset of mania. This case series underscores the significance of dissociative/conversion symptoms as an early atypical presentation in juvenile bipolar disorder. PMID- 21687019 TI - Severe iron intoxication treated with exchange transfusion. AB - An 18-month-old previous healthy girl who had ingested 442 mg elemental iron/kg was admitted to a paediatric intensive care unit. The child was treated with gastric lavage, whole bowel irrigation and intravenous deferoxamine. After 2 h of standard therapy serum iron had risen threefold to 1362 ug/dl (244 umol/l). The child was treated with exchange transfusion (ET; 52 ml/kg) and serum iron fell to 134 ug/dl (24 umol/l). The patient made an uncomplicated recovery. ET should be considered in severe iron poisoning when standard therapy is inadequate. PMID- 21687020 TI - Malignant adenomyoepithelioma of the breast: a case report with review of literature. AB - Adenomyoepitheliomas are uncommon breast tumours. By definition they have a prominent component of myoepithelial cells, in addition to glandular elements lined by epithelial cells. Malignant adenomyoepithelioma of the breast is even more rare, characterised by malignant proliferation of epithelial and myoepithelial cells that show characteristic histological and immunohistochemical features. Only 11 cases have been reported to date. A case of malignant adenomyoepithelioma of the breast is reported. PMID- 21687021 TI - Sweet's syndrome in Crohn's colitis. AB - We would like to report a case involving a 38-year-old woman who presented with knee and ankle swellings 2 weeks prior to admission. There were also multiple painful oral ulcers and a few skin sores on the wrist. She also had associated diarrhoea for 2 weeks. There was also marked loss of weight (6 kg in 2 weeks). Colonoscopy examination showed macroscopic and histopathological findings of Crohn's disease; however, skin histology showed extensive neutrophilic infiltration in the dermis, predominantly in the perivascular region. Her final diagnosis was Sweet's syndrome with Crohn's disease. PMID- 21687022 TI - The farmer who didn't need a wheel barrow. AB - We report the difficulties encountered in diagnosing leptospirosis in an 85-year old man who presented with non-specific signs and symptoms. Initially, a wide haematologic and oncologic work-up without significant results was performed, as symptoms of several organ dysfunctions emerged and the clinical course showed a rapid deterioration. After several days without a definite diagnosis, the infection was finally detected after reviewing all results and considering the patient's profession as a farmer. After receiving appropriate antibiotic treatment the patient recovered fully. PMID- 21687023 TI - An unusual differential diagnosis of a left iliac fossa mass. AB - We present a case of decompensated alcoholic liver cirrhosis with widespread porto-systemic anastamoses that resulted in varices within the rectus muscle. A literature review reveals only two similar cases previously. Intramuscular varices may predispose to local haemorrhage, especially in those with underlying coagulopathy as a result of liver cirrhosis. Management options include optimising medical management of the underlying condition, simple analgesics, and for those at high risk of bleeding, decompression by transjugular intrahepatic porto-systemic shunting. Interim monitoring by ultrasonography is also helpful in detecting rapid increases in vascular size. In our case the patient continued to drink heavily and developed hepatic encephalopathy. Her prognosis remains poor and is currently a poor candidate for any surgical intervention. PMID- 21687024 TI - Acute aortic dissection mimicking an acute coronary syndrome through occlusion of the right coronary artery. AB - Occlusion of the right coronary artery (RCA) is an uncommon complication of type A aortic dissection. Aortic dissection and acute coronary syndrome (ACS) share a similar pathogenesis in atherosclerosis and hypertension. Consequently a patient with ischaemic risk factors presenting with chest pain and dynamic ECG change may well be incorrectly treated for ACS if careful attention is not paid to the presenting symptoms and signs. This case report describes a 59-year-old man who presented with chest pain, confusion and an ischaemic ECG and was initially treated for ACS. He subsequently deteriorated clinically and imaging confirmed type A aortic dissection complicated by RCA occlusion. Following emergent surgery with aortic root replacement and coronary artery bypass grafting he later made a good recovery. PMID- 21687025 TI - Sotalol induced QT prolongation and torsades de pointes. PMID- 21687026 TI - Segmental absence of intestinal musculature (SAIM): a case report in an adult. AB - Segmental absence of intestinal musculature (SAIM) is a rare entity of uncertain aetiology. A case of SAIM in an adult is presented, and three other adult cases of SAIM are reviewed. Our case concerns a middle-aged man who underwent a Whipple's procedure for a suspected neoplasm in the head of the pancreas. At surgery, a redundant segment of proximal jejunum with multiple large diverticula was incidentally noted and resected. On histological examination, the small bowel segment showed focal extreme thinning of the muscularis propria, focally amounting to complete absence. A peritoneal biopsy was also submitted which showed changes consistent with an old thrombosed vessel. PMID- 21687027 TI - A mimicry of an acute coronary syndrome. AB - BACKGROUND: A 79-year-old woman was out in the garden having lunch on a hot summer day. She developed stabbing chest pains, more severe on her left side, associated with radiation down her left arm. Severity was 7 out of 10. There was no relief of pain with glyceryl trinitrate spray. Risk factors for ischaemic heart disease include hyperlipidaemia, being an ex-smoker (40 years), no history of diabetes or hypertension. There was a family history of her father having a myocardial infarction at the age of 54. Echocardiogram (ECG) revealed widespread deep symmetrical T-wave inversion in the chest leads and lateral limb leads. INVESTIGATIONS: The patient's serum creatine kinase level was 180 IU/litre (normal range 30-135), troponin I level was 6.56 g/litre (normal range 0-0.10), D dimer was negative and random serum cholesterol level was 5.3 mmol/litre (3.8 5.2). Significant coronary stenoses were excluded. A left ventriculogram revealed a hyperkinetic base and a dyskinetic apical region of the left ventricle. Echocardiography showed normal valves, basal septal hypertrophy and a dilated akinetic apex, with the region of akinesia spanning more than the arterial territory. DIAGNOSIS: Takotsubo cardiomyopathy. MANAGEMENT: Treatment with aspirin, angiotensin-converting enzyme (ACE) inhibitor, beta blocker and a statin. PMID- 21687028 TI - Rickets and tracheobronchomalacia. AB - Rickets is increasingly encountered in practice, even in the Western world. One recent publication reports an overall incidence of 7.5 per 100 000 children. Respiratory infections are well known to be associated with rickets. We present a case of rickets with severe respiratory complications. Tracheobronchomalacia was detected on bronchoscopy. We believe that tracheobronchomalacia may be a hitherto unrecognised finding in rickets and may need to be investigated further. PMID- 21687029 TI - Chylothorax. AB - During a high speed road traffic accident, a 26-year-old man suffered multiple fractures of his thoracic vertebrae and bilateral pneumothoraces. The day after admission and commencement of nasogastric feeding, milky fluid was noted in his right chest drain. Feeding was stopped and a contrast oesophogram and oesophagoscopy were performed, which were normal. The chylothorax quickly resolved and both drains were removed on day 6. Initial treatment of chylothorax aims to decompress the pleural space and minimise chyle production by stopping enteral feeding. Most authors recommend conservative management for 2 weeks or more unless certain parameters are met: average daily chyle loss of >1.5 litres for a 5 day period, or imminent nutritional complications. In this case, surgical management of the chylothorax and spinal fractures was planned. However, conservative management was successful, highlighting the fact that early aggressive surgical intervention for chyle leaks in blunt trauma is not necessary. PMID- 21687030 TI - Recurrent episodes of upper airway blockage associated with Ascaris lumbricoides causing cardiopulmonary arrest in a young patient. AB - Ascaris lumbricoides (AL) is one of the most common helminthic infections of humans, affecting mainly children and malnourished individuals residing in developing countries. It is estimated the 25% of the world's population is infected with this nematode. Infection occurs via ingestion of water and food contaminated by Ascaris eggs, causing asymptomatic infection to disease with abdominal pain, vomiting, constipation and faecal passage of worms. The present report concerns an unusual case in which AL travelled retrograde and lodged in the vocal cords causing upper airway obstruction leading to asystolic cardiac arrest. PMID- 21687031 TI - Cerebellar haemangioblastoma: temporising treatment in a high risk pregnancy. AB - We describe the case of a young woman who was 29 weeks pregnant and presented with preterm labour along with hydrocephalus and brain stem symptoms from a large cytic lesion associated with a precariously sited haemangioblastoma. Cyst drainage was initially employed, with an Ommaya reservoir and periodic percutaneous drainage until the patient could undergo a full-term delivery. Following delivery, the tumour was embolised and resected surgically in the following week. The patient had no new deficits following surgery. We believe this temporising approach for symptomatic haemangioblastomas discovered in high risk pregnancies can lead to a better outcome for the mother and child. PMID- 21687032 TI - Severe myositis on commencement of efavirenz, abacavir and lamivudine, in the absence of lactic acidosis or classical abacavir hypersensitivity. AB - Myositis in HIV may be due to HIV itself, or to opportunistic infection, malignancy or drug treatment. Severe myositis or rhabdomyolysis have never been reported with the commonly used nucleoside reverse transcriptase inhibitor abacavir, although creatine phosphokinase may rise modestly, particularly if abacavir hypersensitivity occurs. We report an unusual case of abacavir use associated with a thousand-fold rise in creatine phosphokinase in the absence of features of hypersensitivity. The case was also notable firstly in that there was an absence of the HLA-B5701 allele, the most common human leucocyte antigen (HLA) allele associated with hypersensitivity, and, secondly, as the case occurred in an African patient, African people not being prone to abacavir hypersensitivity. PMID- 21687033 TI - An unusual "internal" penetrating liver injury. PMID- 21687034 TI - Response of facial haemangioma to oral propranolol. AB - Haemangioma is the most common vascular tumour of childhood. Most cases require no therapeutic intervention, with spontaneous involution by 5-9 years of age. Some haemangiomas may become large in size impinging on vital structures such as eyes, mouth, nose or larynx, and require certain therapeutic interventions to prevent major morbidities. The usual treatments include oral/intralesional steroids, alpha interferon, cytotoxins, remobilisation, pulsed dye laser and cosmetic surgery resection; these treatments are not free of multiple complications and toxic side effects. This report describes the case of a 4-month old female baby with progressively increasing haemangioma of the right upper eyelid impinging over the upper outer visual field. The haemangioma responded promptly to low-dose oral propranolol. A clinical response was noticed few days after the start of the treatment and was free of any major side effects. PMID- 21687036 TI - Potter syndrome with an unusual cardiac anomaly. AB - Potter syndrome is a congenital anomaly characterised by bilateral renal agenesis, pulmonary hypoplasia, cardiac, skeletal abnormalities and maternal oligohydramnios. Here we report a case of Potter syndrome with bilateral renal agenesis, pulmonary hypoplasia and complete transposition of the great vessels, which had been identified during a post-mortem examination. Although cardiac anomalies are known to exist with Potter syndrome, complete transposition of the great vessels has not been reported in the literature. PMID- 21687037 TI - When a nephrectomy cures hypoglycaemia. AB - A 40-year-old woman presented with a 10 day history of episodic vagueness, speech disturbance and blurred vision. Episodes typically occurred in the morning after awaking from sleep and resolved with food ingestion. She had no past medical history, did not drink alcohol and was not on any medication. Physical examination was normal with no evidence of endocrinopathy. After 10 h of fasting, she became hypoglycaemic with evidence of neuroglycopenia, which resolved with intravenous dextrose. Biochemical investigations revealed decreased glucose, insulin and C-peptide values with an increased excess insulin-like growth factor II: excess insulin-like growth factor I (IGF-II: IGF-I) ratio. Radiological examinations of the abdomen and pelvis revealed a heterogenous 10.5 cm left renal mass. The patient underwent a radical left nephrectomy. She had complete resolution of hypoglycaemic events. Histology revealed a renal sarcoma, grade 2/3. This is the first report in the literature involving a renal sarcoma causing non-islet cell tumour hypoglycaemia via excess IGF-II secretion. PMID- 21687043 TI - Prolonged gastric stasis of enteric-coated granules. AB - A 90-year-old woman with reflux oesophagitis had been receiving a regimen of a generic brand of lansoprazole (15 mg/day), an aspirin tablet (81 mg), and anti hypertensive medicines. In 2008 she underwent a gastroduodenoscopic examination more than 3 hours after ingesting these medicines. The endoscopy revealed white substances in the antrum and an oval-shaped agglomeration of granules in the stomach body. No specific findings such as pylorus stenosis were confirmed. Because the lansoprazole capsule was designed to dissolve in the intestine, the therapeutic concentration could not be obtained in the blood until 3 hours after the ingestion. When prescribing medication for elderly people with gastrointestinal hypomotility, physicians should note the bioavailability of the drugs, especially when using delayed-release capsules with enteric-coated granules inside. PMID- 21687045 TI - Differential diagnosis of non-atherosclerotic left main coronary artery stenosis. AB - A left main coronary artery (LMCA) stenosis without any atherosclerotic changes elsewhere in the coronary artery tree is a rare finding, and some uncommon reasons for luminal narrowing should be considered. An unusual case of non atherosclerotic LMCA stenosis is reported.A middle-aged patient presented with acute myocardial infarction. An immediate coronary angiography was ordered and revealed a subtotal mid LMCA stenosis. A drug-eluting stent was successfully implanted in the LMCA.Operative revascularisation was recommended. Routine surgery was performed and surprisingly revealed an extended mass of a mediastinal tumour surrounding the aortic root. Histopathological examination of the tumour revealed a poorly differentiated squamous cell carcinoma.Postoperatively, the patient was treated with chemotherapy (carboplatin and docetaxel). Five years after the first admission to our hospital, the patient died as a result of ventricular fibrillation.The differential diagnosis of non-atherosclerotic LMCA stenoses is discussed. PMID- 21687046 TI - Improved parameters of metabolic glycaemic and immune function and arterial stiffness with naltrexone implant therapy. AB - Here the dramatic and rapid response of a 54-year-old obese hypertensive man with poorly controlled insulin-dependent diabetes with a 33 year history of high dose heroin use, a 1 year history of refractory ulceration of his hands, ankles and feet, treated coronary artery disease, and the metabolic syndrome, to implantation with long-acting naltrexone implants is presented. In particular his hyperlipidaemia, hyperglycaemia, proinflammatory state, evidence of hepatic and renal insufficiency, arterial stiffness, and extensive and chronic cutaneous ulceration all improved dramatically over just 13 weeks, in association with complete control of his heroin, benzodiazepine, tobacco and cannabis use. The metabolic and vascular benefits were all highly statistically significant. The case is the first to document dramatic and rapid metabolic, immune and vascular improvements in association with clinical naltrexone therapy and are consistent with its likely effects in restoring addiction-related stem cell and immunological deficits. PMID- 21687047 TI - Reminder of an important clinical lesson in the presentation of an inguinoscrotal bladder hernia and its CT findings. AB - Inguinoscrotal bladder hernias are still a rare finding in clinical practice. The present report describes the case of a patient who presented with minimal symptoms and was found to have an inguinoscrotal bladder hernia that was confirmed on CT. The CT findings include very clear and interesting images, and the case is discussed further. PMID- 21687048 TI - Cold comfort pharm. AB - In Wilson's disease copper accumulates within the basal ganglia resulting in a movement disorder. Treatment is with copper chelation. In the case described here treatment with trientene failed because the medication was stored at the incorrect temperature. PMID- 21687049 TI - Rapid improvement of massive bloody pleural effusion after splenectomy for splenic marginal zone lymphoma. AB - Splenic marginal zone lymphoma (SMZL) is a rare malignant lymphoma involving marginal zone B cells, accounting for only 1% of non-Hodgkin lymphomas. No previous reports have documented SMZL accompanied by massive bloody pleural effusion. Herein, the case of a patient with SMZL that was only diagnosed after splenectomy and thoracoscopic pleural biopsy is presented. SMZL in this patient was accompanied by massive bloody pleural effusion. The characteristics of the patient's pleural effusion changed from bloody to transudative after splenectomy, and rapid improvement was observed. It was considered that the splenectomy was valid for treatment of unidentified pleural effusion with enlarged spleen. PMID- 21687050 TI - Intravitreal voriconazole as primary treatment for endogenous Aspergillus endophthalmitis. AB - This report describes the first case of Aspergillus endophthalmitis after heart transplantation which was successfully treated with intravitreal voriconazole. A 62-year-old man receiving immunosuppressive agents after a heart transplant presented with pain, reduced visual acuity and redness of the left eye. The patient had been diagnosed with invasive pulmonary aspergillosis and was being treated with intravenous voriconazole. Endogenous endophthalmitis was diagnosed. Aspergillus fumigatus was isolated in a vitreous sample. After five intravitreal voriconazole injections (50 MUg/0.1 ml), pars plana vitrectomy, intravenous and topical voriconazole treatment, there was no ocular inflammation and the visual acuity improved from counting fingers at 50 cm to 20/20. This case report shows that intravitreal voriconazole, in addition to topical and systemic treatment, was safe and very effective in treating Aspergillus endophthalmitis. More clinical studies are needed to determine the optimal treatment for this condition. PMID- 21687052 TI - Left-ventricle leiomyosarcoma: imaging by multislices computed tomography with retrospective electrocardiogram-gated reconstruction. PMID- 21687053 TI - Calcified left ventricular aneurysm with delayed thrombus formation. PMID- 21687054 TI - Persistent flank pain without active urinary sediments. PMID- 21687055 TI - Lamotrigine rash-a potentially life-threatening complication. PMID- 21687056 TI - An unusual symptom of cystic teratoma cases. PMID- 21687057 TI - Intrathoracic lipoma in a child. PMID- 21687058 TI - Jaw fracture as a result of dog bite in a 9-month-old infant. PMID- 21687059 TI - Descent of a bullet in the spinal canal. PMID- 21687060 TI - Double wall sign. PMID- 21687061 TI - Haemoptysis from the pulmonary artery. PMID- 21687062 TI - Colonic phytobezoar. PMID- 21687063 TI - Venous gangrene secondary to an aorto-caval fistula. PMID- 21687064 TI - Penetrating cardiac nail gun injury. PMID- 21687065 TI - Rupture of pectoralis major: an occupational injury. PMID- 21687066 TI - Transurethral catheter in the distal ureter as a cause for acute abdominal pain. PMID- 21687067 TI - Traumatic diaphragmatic rupture: a diagnostic challenge in the emergency department. PMID- 21687068 TI - Bleeding from a gastric Dieulafoy lesion. PMID- 21687069 TI - Wood tick. PMID- 21687070 TI - Ring enhancing lesion on CT scan: metastases or a brain abscess? PMID- 21687071 TI - A case of paraquat burns following an industrial accident. PMID- 21687072 TI - Outlined psoas muscle shadow. PMID- 21687073 TI - Omental infarction: a rare cause of acute abdominal pain. PMID- 21687074 TI - Fracture of an unnamed bone. PMID- 21687075 TI - An unusual cause of dyspnoea. PMID- 21687076 TI - When neurological deficit is not a stroke. PMID- 21687077 TI - Ping-pong fracture. PMID- 21687078 TI - Vacuum phenomenon in a dislocated joint. PMID- 21687079 TI - Open dislocation of the elbow with ipsilateral fracture of the radial head and distal radius: a rare combination without vascular injury. PMID- 21687080 TI - Intercostal aneurysm causing massive haemothorax. PMID- 21687081 TI - Pneumocephalus after epidural injections. PMID- 21687082 TI - Atrial thromboembolism. PMID- 21687083 TI - Calcaneal fracture with ipsilateral bi-malleolar and fourth and fifth metatarsal fractures. PMID- 21687084 TI - A rare penetrating neck trauma to zone III. PMID- 21687085 TI - Faecal mediastinitis following decompression of suspected tension pneumothorax. PMID- 21687086 TI - Large prepubertal ovarian cyst. PMID- 21687087 TI - Fracture of the posterior process of the talus: an unusual injury. PMID- 21687088 TI - Gas-forming Ludwig's angina. PMID- 21687089 TI - Oesophageal dilatation due to a paraoesophageal hernia and gastric volvulus as a cause of stridor. PMID- 21687090 TI - Secondary bronchiolitis obliterans organising pneumonia in a patient with carbamazepine-induced hypogammaglobulinemia. PMID- 21687091 TI - Multiple thoracic osteophytes presenting as mediastinal mass. PMID- 21687092 TI - Pulmonary infarction from central venous air embolism mimicking round pneumonia. PMID- 21687093 TI - A "fat chance" it's malignant: lipoid pneumonia simulating lung cancer on PET scan. PMID- 21687094 TI - F-FDG PET scan as follow-up tool for sarcoidosis with symptomatic cardiac conduction disturbances requiring a pacemaker. PMID- 21687095 TI - Tracheal bronchus in a 6-month-old infant identified by CT with three-dimensional airway reconstruction. PMID- 21687096 TI - MRI features of pleural endometriosis after catamenial haemothorax. PMID- 21687097 TI - Massive pulmonary arteriovenous malformation presenting with tamponading haemothorax. PMID- 21687098 TI - Spontaneous rupture of an intercostal artery aneurysm during air flight. PMID- 21687099 TI - Persistent diffuse pulmonary interstitial emphysema mimicking pulmonary emphysema. PMID- 21687101 TI - Left atrial tachycardia and inferior vena cava thrombotic occlusion complicating atrial fibrillation ablation successfully treated from the right subclavian vein. PMID- 21687100 TI - Multifocal pneumocyte hyperplasia in tuberous sclerosis. PMID- 21687102 TI - Extrinsic compression of an anomalous right coronary artery causing cardiac arrest. PMID- 21687103 TI - Successful stenting of stenotic lesion and spontaneous dissection of left internal mammary artery graft. PMID- 21687104 TI - Massive intrapericardial fibroma presenting with palpitations. PMID- 21687105 TI - Non-invasive diagnosis of an intramyocardial dissecting haematoma of the left ventricular free wall by cardiac magnetic resonance. PMID- 21687106 TI - Non-coronary sinus of Valsalva aneurysm rupture. PMID- 21687107 TI - Effective thrombus extraction strategies in acute saphenous vein graft intervention. PMID- 21687108 TI - Interrupted aortic arch and aortopulmonary window demonstrated on 64-slice multidetector computed tomography angiography. PMID- 21687109 TI - Percutaneous patent foramen ovale closure in a patient with platypnoea orthodeoxia syndrome. PMID- 21687110 TI - Blockage of bileaflet mitral valve prosthesis imaged by computed tomography virtual endoscopy. PMID- 21687111 TI - Wegener's granulomatosis with progressive conduction disturbances and atrial fibrillation. PMID- 21687112 TI - Coronary artery-left atrial fistula caused by feeding artery rupture in cardiac myxoma. PMID- 21687113 TI - Dynamic left main coronary artery stenosis caused by an aortic aneurysm after aortic valve replacement. PMID- 21687114 TI - Free-floating left atrial thrombus formed in a few weeks in a patient with a normal mitral prosthesis. PMID- 21687115 TI - Retrograde coronary interventions of chronic total occlusions. PMID- 21687116 TI - Asynchronic and hypokinetic movement of the left ventricular posterior wall due to preexcitation syndrome. PMID- 21687117 TI - Metastatic squamous cell carcinoma causing right ventricular outflow tract obstruction. PMID- 21687118 TI - Giant left atrium and a right sided heart. PMID- 21687119 TI - Do unapposed stent struts endothelialise? In vivo demonstration with optical coherence tomography. PMID- 21687120 TI - Severe intimal hyperplasia after sirolimus eluting stent deployment: evaluation by optical coherence tomography. PMID- 21687121 TI - True isolated right ventricular infarction with tombstone anterior ST elevation. PMID- 21687122 TI - Spontaneous coronary vasospasm in the catheterisation laboratory: prompt resolution after atropine injection. PMID- 21687123 TI - Visualisation of a St Jude prosthetic mitral valve using electron beam tomography. PMID- 21687124 TI - Brain abscess associated with an unusual cause of right to left shunt. PMID- 21687125 TI - Atrial myxoma. PMID- 21687126 TI - Left ventricular pressure-volume loops during mechanical alternans in a patient with dilated cardiomyopathy. PMID- 21687127 TI - Aberrant origin of the left coronary artery from the right-facing sinus of Valsalva with intramural course: preoperative and postoperative imaging. PMID- 21687128 TI - Post myocardial infarction left ventricular free wall rupture diagnosed by multidetector computed tomography. PMID- 21687129 TI - Loeffler endocarditis: findings on magnetic resonance imaging. PMID- 21687131 TI - Multidetector computed tomography image of apical left ventricular descending aorta conduit. PMID- 21687130 TI - Right ventricular pacing-induced hypotension. PMID- 21687132 TI - Isolated ventricular non-compaction in a patient initially diagnosed with arrhythmogenic right ventricular cardiomyopathy. PMID- 21687133 TI - Endocarditis of left ventricular apical patch with cavity formation. PMID- 21687134 TI - Left ventricular thrombus associated with left ventricular apical ballooning. PMID- 21687135 TI - Acute liver failure in a patient with lung cancer. PMID- 21687136 TI - Importance of preserving coronary branches during angioplasty, assessed by cardiac resonance. PMID- 21687137 TI - The "winking" coronary sinus. PMID- 21687138 TI - Pseudoaneurysm of the left ventricle after repairing a ventricular septal defect complicating acute myocardial infarction. PMID- 21687139 TI - Evolving pneumopericardium. PMID- 21687140 TI - Hydatid cyst of the heart. PMID- 21687142 TI - A post-infarction myocardium sinus. PMID- 21687141 TI - A rare single coronary artery with an anomalous origin of the left coronary artery from the posterior atrioventricular right coronary artery. PMID- 21687143 TI - My heart is popping out of my chest: left ventricular pseudoaneurysm with systemic arterial embolism. PMID- 21687144 TI - Angina during upper limb exercise: pathognomonic clinical feature of coronary subclavian steal syndrome? PMID- 21687146 TI - Dynamic collateral coronary circulation: angiographic evidence. PMID- 21687145 TI - Spontaneous intracranial hypotension in adolescence. PMID- 21687147 TI - Vascular tumour blush of cardiac angiosarcoma on coronary angiography. PMID- 21687148 TI - Diagnosing chest pain: characteristic ECG changes in acute pericarditis. PMID- 21687149 TI - Artefactual limitations of magnetic resonance imaging in the diagnosis of recoarctation of the aorta. PMID- 21687150 TI - Extensive aortic dissection presenting as acute inferior myocardial infarction. PMID- 21687151 TI - Rescue saphenous vein graft, 19 years on. PMID- 21687152 TI - Congenital absence of the pulmonary valve. PMID- 21687153 TI - Isolated "superdominant" single coronary artery: a particularly rare coronary anomaly. PMID- 21687154 TI - Small-bowel ulcerations at wireless capsule endoscopy: go the whole way. PMID- 21687155 TI - 64 multidetector CT in patent foramen ovale. PMID- 21687156 TI - Cardiomyopathy associated with Wegener's granulomatosis. PMID- 21687157 TI - Spontaneous intraoperative ventricular haematoma in a neonate. PMID- 21687158 TI - A case of brain embolism during catheter embolisation of head arteriovenous malformation. What is the mechanism of stroke? PMID- 21687159 TI - A hypothyroid neonate with a lingual tumour. PMID- 21687160 TI - An internuclear ophthalmoplegia with ipsilateral abduction deficit: half and half syndrome. PMID- 21687161 TI - Lung cancer in natural history crossing the pericardium: a rare echocardiographic view. PMID- 21687162 TI - Chiari I malformation with holocord syrinx. AB - We present the magnetic resonance imaging findings of a classical case of Chiari I malformation with holocord syringohydromyelia. The clinical presentation, imaging findings and treatment options are discussed. PMID- 21687163 TI - Four-valve endocarditis caused by group G Streptoccocci. PMID- 21687164 TI - Mid-brain molar tooth sign: expanding the clinical spectrum. PMID- 21687165 TI - Three-dimensional whole heart magnetic resonance imaging of anomalous origin of the right coronary artery from the left sinus of Valsalva. PMID- 21687166 TI - Parallel stenting using two sirolimus-eluting stents in an ectatic coronary artery stenosis. PMID- 21687167 TI - Type A aortic dissection: a hidden and lethal cause for failed thrombolytic treatment in acute myocardial infarction. PMID- 21687168 TI - Horner's syndrome and ipsilateral tongue paresis due to carotid artery dissection. PMID- 21687169 TI - Dengue haemorrhagic fever: an unusual cause of intracranial haemorrhage. PMID- 21687170 TI - Partial anomalous pulmonary venous connection of left pulmonary veins to innominate vein evaluated by multislice CT. PMID- 21687171 TI - Apical thrombus in tako-tsubo cardiomyopathy. PMID- 21687172 TI - Exertional dyspnoea due to spontaneous coronary artery dissection in a 55-year old man. PMID- 21687173 TI - WolffParkinsonWhite syndrome and persistent azygous drainage of the inferior vena cava. PMID- 21687174 TI - Multiple coronary artery fistulae or Thebesian veins? PMID- 21687175 TI - "Dynamic imaging" (systolic compression) of myocardial bridge visualised by electronic beam computed tomography. PMID- 21687176 TI - Iron-deficiency anaemia. PMID- 21687177 TI - Bridge to recovery in a patient with ChurgStrauss myocarditis by long-term percutaneous support with microaxial blood pump. PMID- 21687178 TI - Involvement of the recurrent artery of Heubner with contralateral middle cerebral artery infarction. PMID- 21687179 TI - Late adverse ventricular remodelling as a consequence of acute left main coronary artery occlusion. PMID- 21687180 TI - Intra-coronary alteplase for extensive coronary artery thrombus. PMID- 21687181 TI - A huge intra-abdominal mass in a young man. PMID- 21687182 TI - Cerebral air emboli on T2-weighted gradient-echo magnetic resonance imaging. PMID- 21687183 TI - Incidental patent foramen ovale detected by 64-detector row CT before radiofrequency ablation therapy. PMID- 21687184 TI - Meningococcal septicaemia and dental changes. PMID- 21687185 TI - Delayed passage of metallic foreign bodies. PMID- 21687186 TI - Intracardiac echocardiography in the diagnosis of prosthetic valve endocarditis. PMID- 21687187 TI - Additional coronary sinus shocking lead improved defibrillation threshold. PMID- 21687188 TI - Severe plaque prolapse after stenting a lesion with large areas of necrotic core. PMID- 21687189 TI - Severe coronary luminal narrowing ascribed to aortic intramural haematoma after valve surgery. PMID- 21687190 TI - The changing faces of aortic dissection: an unusual presentation mimicking pulmonary embolism. PMID- 21687191 TI - Severe haemodynamic compromise due to left atrial compression by oesophageal haematoma. PMID- 21687192 TI - An unusual origin of the left coronary system. PMID- 21687193 TI - Giant coronary artery aneurysm in Behets disease. PMID- 21687194 TI - Giant coronary artery aneurysm in Behets disease. PMID- 21687196 TI - Stenting of a stenosed modified Blalock-Taussig shunt after Norwood-I palliation for hypoplastic left heart. PMID- 21687195 TI - Percutaneous coronary intervention for chronic total occlusions: value of preprocedural multislice CT guidance. PMID- 21687197 TI - A rare complication of peptic ulcer disease. PMID- 21687198 TI - Oesophagogastric fistula: a post-operative complication. PMID- 21687199 TI - Carotid embolism. PMID- 21687200 TI - An unexpected finding during planned primary percutaneous coronary angioplasty. PMID- 21687201 TI - Inappropriate ICD shocks. PMID- 21687202 TI - Upper gastrointestinal bleeding with a difficult endoscopy. PMID- 21687203 TI - Haemorrhagic gastritis in a neurologically impaired boy. PMID- 21687204 TI - Sigmoid stricture in a 39-year-old female. PMID- 21687205 TI - Incidental finding of endocarditis in a preterm neonate. PMID- 21687206 TI - Late adaptive coronary artery remodelling after implantation of a biodegradable stent. PMID- 21687207 TI - A cause of cholestatic jaundice. PMID- 21687208 TI - Cardiac amyloid by cardiovascular magnetic resonance. PMID- 21687209 TI - Dynamic changing mass behind the left atrium. PMID- 21687210 TI - Pneumopericardium in a term infant on nasal continuous positive airway pressure. PMID- 21687211 TI - Obstructive jaundice with fever and eosinophilia. PMID- 21687212 TI - Stent strut fracture-induced restenosis in the right coronary artery: detection by MDCT. PMID- 21687213 TI - Glagov remodelling in the atherosclerotic carotid artery by cardiovascular magnetic resonance. PMID- 21687214 TI - Multiple ring enhancing lesions in brain MRI of a patient with AIDS. PMID- 21687215 TI - Haematemesis with mediastinal lymphadenopathy. PMID- 21687216 TI - ECG findings in fatal flecainide intoxication. PMID- 21687217 TI - Facial submandibular cellulitis-adenitis in a preterm infant. PMID- 21687218 TI - A case of asymptomatic high-grade aortic coarctation. PMID- 21687219 TI - Suspected coronary artery dissection post-stenting, confirmed by optical coherence tomography. PMID- 21687220 TI - Strut fracture of a sirolimus-eluting stent at the ostium of the right coronary artery. PMID- 21687221 TI - Transcatheter closure of the aortopulmonary window in a symptomatic infant using the Amplatzer ductal occluder. PMID- 21687222 TI - Follow-up in Tako-tsubo cardiomyopathy by real-time three-dimensional echocardiography. PMID- 21687223 TI - Intraoperative assessment of coronary grafts with fluorescent angiography. PMID- 21687224 TI - Bubbles in the left cardiac cavities after diving. PMID- 21687225 TI - Left ventricular non-compaction in an infant. PMID- 21687226 TI - A case of Tako-tsubo cardiomyopathy. PMID- 21687227 TI - An unusual cause of ascites. PMID- 21687229 TI - Use of percutaneous angioplasty to facilitate implantation of the left ventricular pacemaker lead for CRT. PMID- 21687228 TI - Ruptured intracranial dermoid. PMID- 21687230 TI - Multiple sessile polypoid lesions in the stomach. PMID- 21687231 TI - Massive transcalvarial lymphoma. PMID- 21687232 TI - A child with upper abdominal pain and pancreatitis. PMID- 21687233 TI - Giant coronary-pulmonary artery fistula with multiple saccular aneurysms: multidetector CT evaluation. PMID- 21687234 TI - An unusual complication of phototherapy. PMID- 21687235 TI - Acute strokes in the setting of a persistent primitive trigeminal artery. PMID- 21687236 TI - A heartless patient. PMID- 21687237 TI - Asymptomatic spontaneous resolution of a giant fusiform M2-M3 dissecting aneurysm in a teenager. PMID- 21687238 TI - Bilateral caudate nucleus infarction associated with variant in circle of Willis. PMID- 21687239 TI - A peculiar gallbladder content. PMID- 21687240 TI - Herpes zoster duplex bilateralis. PMID- 21687241 TI - Ultrasound guided percutaneous relief of tension pneumomediastinum in a 1-day-old newborn. PMID- 21687242 TI - Forgotten needles. PMID- 21687243 TI - "Reflections" on an interesting case: an oropharyngeal foreign body presenting as cleft palate. PMID- 21687244 TI - Chilaiditi's sign or Chilaiditi's syndrome in the emergency department. PMID- 21687245 TI - An unusual presentation of diaphragmatic hernia. PMID- 21687246 TI - Lateral skull radiograph in a patient with post-traumatic tension pneumocephalus complicated by late epilepsy. PMID- 21687247 TI - Primary aortoenteric fistula. PMID- 21687248 TI - Laparotomy for treatment of seizures. PMID- 21687249 TI - Case review of an old disease: empyema necessitates. PMID- 21687250 TI - Circumferential aortic dissection. PMID- 21687251 TI - Tumoral calcinosis of bilateral hip. PMID- 21687252 TI - "All that wheezes is not asthma". PMID- 21687253 TI - Spontaneous globe luxation. PMID- 21687254 TI - Congenital diaphragmatic hernia. PMID- 21687256 TI - Air below the right diaphragm: Chilaiditi sign. PMID- 21687255 TI - Painful Horner's syndrome. PMID- 21687257 TI - Beware the pulsatile proptosis. PMID- 21687258 TI - Lingual haematoma: a rare complication of usual warfarin dose. PMID- 21687259 TI - Phlegmasia cerulea dolens, a rare complication of deep vein thrombosis. PMID- 21687260 TI - Acute widening of mediastinum in a patient with oesophageal cancer after surgery. PMID- 21687261 TI - Bedside echogram in ischaemic bowel. PMID- 21687262 TI - Keep an eye on the heart. PMID- 21687263 TI - The "Mickey Mouse" sign. PMID- 21687264 TI - Coital paraphimosis causing penile necrosis. PMID- 21687265 TI - Unexpected left upper quadrant abdominal pain in a 30-year-old man. PMID- 21687266 TI - Coma from cerebral venous thrombosis: an overlooked cause. PMID- 21687267 TI - Bronchogenic cyst treated by endobronchial ultrasound drainage. PMID- 21687268 TI - Pulmonary cryptococcosis mimicking solitary lung cancer in an immunocompetent patient. PMID- 21687269 TI - Right-sided aortic arch with Kommerell's diverticulum: 64-DCTA with 3D reconstructions. PMID- 21687270 TI - Conus medullaris lesion causing bilateral lower limb myokymia. PMID- 21687271 TI - Acute renal artery embolism treated with a cardiac thrombectomy catheter. PMID- 21687272 TI - Puppy sign indicating bilateral dissection of internal carotid artery. PMID- 21687273 TI - Dorsal intramedullary tuberculoma. PMID- 21687274 TI - FDG-PET in meningeal lymphomatosis. PMID- 21687275 TI - Glossoplegia in a small cortical infarction. PMID- 21687276 TI - Primary pericardial malignant fibrosarcoma presenting as sudden onset of substernal pain. PMID- 21687277 TI - The sonographic pitfall of carotid collateralisation via the vasa vasorum. PMID- 21687278 TI - Complications from cervical intra-arterial heroin injection. PMID- 21687279 TI - Emergence of Scedosporium apiospermum in patients with cystic fibrosis. PMID- 21687280 TI - In vivo visualisation of coronary artery development by high-resolution optical coherence tomography. PMID- 21687281 TI - Varicella zoster virus and intracranial dolichoectasia in a late adult cancer survivor. PMID- 21687282 TI - Multidetector-row computed tomography in the diagnosis of Collet-Sicard syndrome. PMID- 21687283 TI - Elongated styloid process (Eagle's syndrome) as a cause of atypical craniocervical pain. PMID- 21687284 TI - Congenital hyperinsulinism: [F]DOPA PET/CT scan of a focal lesion in the head of the pancreas. PMID- 21687285 TI - An interesting presentation of antiphospholipid syndrome. PMID- 21687286 TI - Rapidly growing basilar dissecting aneurysm. PMID- 21687287 TI - Portal-systemic encephalopathy in a non-cirrhotic patient. PMID- 21687288 TI - Eosinophilic meningitis and an ocular worm in a patient from Kerala, south India. PMID- 21687289 TI - Embolic spread of tuberculomas in the brain in multidrug resistant tubercular meningitis. PMID- 21687290 TI - Identifying aortic plaque inflammation as a potential cause of stroke. PMID- 21687291 TI - Coronary thrombectomy by retrieval of an open emboli-protection filter device. PMID- 21687292 TI - Images in paediatrics: Sinovenous thrombosis due to mastoiditis. PMID- 21687293 TI - Images in paediatrics: Ironing board impalement. PMID- 21687294 TI - Medulla compression caused by vertebral artery dolichoectasia. PMID- 21687295 TI - Identification of multiple plaque ruptures by optical coherence tomography in a patient with acute myocardial infarction: a three-vessel study. PMID- 21687296 TI - Unilateral pulmonary vein stenosis secondary to idiopathic fibrosing mediastinitis. PMID- 21687297 TI - Horner syndrome due to jugular vein thrombosis (Lemierre syndrome). PMID- 21687298 TI - Extensive cerebral calcification in a patient with systemic lupus erythematosus. PMID- 21687299 TI - Aplasia cutis in association with a triplet pregnancy and fetus papyraceus. PMID- 21687300 TI - Acute brainstem displacement without uncal herniation and posterior cerebral artery injury. PMID- 21687301 TI - "Bubbling brain". PMID- 21687302 TI - An unusual cause of cord compression: synovial cyst of the thoracic spine. PMID- 21687303 TI - "Hand Knob" infarction. PMID- 21687304 TI - Recurrent asystolia in right middle cerebral artery infarct with predominant insular involvement. PMID- 21687305 TI - Breach rhythm related to a solitary skull lesion caused by multiple myeloma. PMID- 21687307 TI - Coil embolisation for diffuse pulmonary arteriovenous malformations. PMID- 21687306 TI - Radiological findings in cyclical administration of intravenous pamidronate in children with osteoporosis. PMID- 21687308 TI - Two- and three-dimensional imaging of coarctation shelf in the human fetus. PMID- 21687309 TI - Familial Sneddon's syndrome with microbleeds in MRI. PMID- 21687310 TI - Spontaneous intracranial hypotension, hygromata and haematomata. PMID- 21687311 TI - Normal x rays in Perthes disease. PMID- 21687312 TI - The midline nasal lesion. PMID- 21687313 TI - Kneeling delivery in America 2000 years ago. PMID- 21687314 TI - Nicorandil-induced colonic ulceration. PMID- 21687315 TI - "Glue lung": pulmonary micro-embolism caused by the glue used during interventional radiology. PMID- 21687316 TI - Failed endothelialisation of a percutaneous atrial septal defect closure device. PMID- 21687317 TI - Purulent pericarditis secondary to septic arthritis: a rare life threatening association. PMID- 21687318 TI - Rapid diagnosis of cerebral sinovenous thrombosis complicating group B streptococcus meningitis by multidetector CT venography. PMID- 21687319 TI - Live three-dimensional echocardiography of cor triatriatum in a child. PMID- 21687320 TI - Unexpected supraglottic injury following a frontal impact motor-vehicle accident. PMID- 21687321 TI - An infant with yellow skin. PMID- 21687322 TI - Circumferential aortic dissection. PMID- 21687323 TI - Necrotising fasciitis complicating varicella. PMID- 21687324 TI - Acute discrete dissection of the ascending aorta. PMID- 21687325 TI - Persistent left superior vena cava: diagnosis with saline contrast echocardiography. PMID- 21687326 TI - Quadricuspid aortic valve; a rare cause of aortic insufficiency. PMID- 21687327 TI - Percutaneous closure of a large peri-prosthetic left ventricular pseudoaneurysm in a high-risk surgical candidate. PMID- 21687328 TI - Inverted left atrial appendage. PMID- 21687329 TI - Single coronary artery: circumflex/right coronary circle. PMID- 21687330 TI - "A close shave": use of a disposable razor blade in the management of rhinophyma. PMID- 21687331 TI - Iatrogenic vitamin K deficiency and life threatening coagulopathy. AB - A man was admitted with abdominal pain. Treatment for acute diverticulitis was instituted with intravenous antibiotics and oral limitation. Imaging demonstrated a complex inflammatory mass. Prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen were within normal limits. However, repeat preoperative clotting studies demonstrated a severe unexpected coagulopathy to have developed since admission that could have caused fatal intraoperative exsanguination. Direct assays showed severe, isolated deficiency of vitamin K dependent clotting factors, and mixing studies normalised both the PT and APTT, ruling out a coagulation inhibitor. The coagulopathy responded to intravenous vitamin K administration. Dietary insufficiency underlies vitamin K deficiency in the presence of normal biliary and enteral function. A significant coagulopathy can result with additional eradication of intestinal microflora. Hypoprothombinaemia is recognised as a consequence of protracted treatment with broad spectrum antibiotics, and vigilance is required for those at risk. The development of such a rapid and unexpected coagulopathy posed a complex preoperative management issue delaying operative intervention; although avoided by fortuitous preoperative screening, it could have caused significant intraoperative bleeding. The remarkably specific lack of vitamin K dependent clotting factors strongly suggested a vitamin K deficiency and administration of coumarins was ruled out. PMID- 21687333 TI - Marketing before patenting: implications for price controls in Canada. AB - The Patented Medicine Prices Review Board (PMPRB) regulates the introductory price of new patented medications in Canada. Some drugs are marketed before they are patented and are therefore outside the authority of the PMPRB. This study was undertaken to determine how many drugs fall into this category, the time period between marketing and patenting, and the excess revenue, if any, earned before prices are subject to regulation. Between 2000 and 2008 a total of 42 drugs were marketed before being patented. Complete data were not available for 9 of these, leaving 33 of the 42 for analysis. Drugs were potentially being marketed between 54 and 2707 days before they came under PMPRB jurisdiction. Three products were eventually deemed to have exceeded the maximum introductory price, and the total excess revenue for these 3 was $9,289,688. Although only 3 of 33 drugs were found to be overpriced, the fact that prices can go unregulated for up to 7.4 years is troublesome. If companies are charging excessive prices, then the additional payments they receive may limit the ability of provincial formularies to list additional drugs. Controlling prices on the basis of patent status has significant limitations, and a new system that deals with prices of all medications should be developed. PMID- 21687332 TI - Institutional financial conflicts of interest policies at Canadian academic health science centres: a national survey. PMID- 21687334 TI - Cardiovascular risk factors in ethnic populations within Canada: results from national cross-sectional surveys. AB - BACKGROUND: Differences in the prevalence of cardiovascular disease and associated risk factors have been noted across ethnic groups both within and between countries. The Canadian population is becoming increasingly diverse because of immigration. Understanding ethnic differences in cardiovascular risk factors is critically important in planning appropriate prevention strategies for the country's rapidly changing population. We sought to examine the prevalence of cardiovascular risk factors in various Canadian ethnic groups. METHODS: We analyzed 3 cross-sectional cycles (for 2000, 2003 and 2005) of the Canadian Community Health Survey of people aged 12 years and older. The surveys were conducted by means of self-reported questionnaires. We used stratified analysis to evaluate the relation between risk factors and ethnicity. The effect of participants' ethnicity on the prevalence of risk factors was estimated by means of logistic regression, with adjustment for differences in age, sex, marital status, education, household income, language spoken, immigration status, residency type (urban or rural), household size, region (province or territory) and chronic diseases (heart disease, stroke, cancer, bronchitis, chronic obstructive pulmonary disease, bowel disease, arthritis, epilepsy, ulcers, thyroid disease and diabetes mellitus). RESULTS: We included 371 154 individuals in the analysis. Compared with white people, people from visible minorities (i.e., neither white nor Aboriginal) had a lower prevalence of diabetes mellitus (4.5% v. 4.0%), hypertension (14.7% v. 10.8%), smoking (20.4% v. 9.7%) and obesity (defined as body mass index >= 30; 14.8% v. 9.7%) but a higher prevalence of physical inactivity (50.3% v. 58.1%). More specifically, after adjustment for sociodemographic characteristics, people from most visible minorities, in comparison with the white population, were less likely to smoke; were more likely to be physically inactive, with the exception of people of Korean, Japanese and Latin ethnicity; and were less likely to be obese, with the exception of people of black, Latin, Arab or West Asian ethnicity. However, relative to white people, hypertension was more prevalent among those of Filipino or South East Asian background (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.23-1.93) and those of black ancestry (OR 1.69, 95% CI 1.43-2.00). INTERPRETATION: Cardiovascular risk factors vary dramatically by ethnic group. Health professionals should increase their promotion of physical activity among visible minorities and should prioritize the detection and control of diabetes and hypertension during routine contact with patients of visible minorities, particularly those of South Asian, Filipino and black ethnicity. PMID- 21687335 TI - Intravenous immunoglobulin for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy: a systematic review and meta-analysis. AB - BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired immune-mediated inflammatory disorder that targets the myelin sheaths of the peripheral nervous system. Intravenous immunoglobulin (IVIg) is a blood product containing immunoglobulin G pooled from many human donors. In fall 2008, CIDP became an approved indication for IVIg in the United States and Canada. OBJECTIVE: To evaluate the clinical effectiveness and safety of IVIg for the treatment of CIDP through a systematic review of published randomized controlled trials. METHODS: We searched the MEDLINE (1996-2009, including in-process and other non-indexed citations), Embase (1996-2009) and other databases through the Ovid interface. We applied a methodological filter to limit retrieval to controlled clinical trials, meta-analyses and systematic reviews, and health technology assessments. Retrieval was limited to studies involving humans, and no language restrictions were employed. We pooled extracted data to estimate the effect size of IVIg treatment based on the random-effects model. RESULTS: We identified 9 unique randomized controlled trials. Of these, 3 compared IVIg therapy with an active comparator (plasma exchange, plasma exchange using extracorporeal immunoadsorption, oral prednisolone, respectively); the other 6 trials had placebo controls. No incremental benefit was seen in terms of primary outcomes for comparisons of IVIg therapy and an active comparator. Data from 4 of the 6 placebo-controlled trials were included in a meta-analysis. A significant improvement in disability (i.e., reduction in disability score) was found, with a standardized mean difference of 0.65 (95% confidence interval [CI] 0.23 to 1.08) in favour of IVIg. A pooled analysis of the proportion of patients with a response to treatment, as defined by the investigators of each of the trials, resulted in a risk ratio of 2.74 (95% CI 1.80 to 4.15) favouring IVIg. INTERPRETATION: IVIg therapy was statistically superior to placebo in reducing disability and impairment among patients with CIDP. The effectiveness of IVIg was similar to that of the alternative treatment strategies of plasma exchange and oral prednisolone. PMID- 21687336 TI - The use of knowledge translation and legal proceedings to support evidence-based drug policy in Canada: opportunities and ongoing challenges. AB - There is growing recognition, particularly in the areas of illicit drug policy and HIV prevention, that policy-makers are in many instances implementing suboptimal programs and services because they are not basing their decisions on the best available scientific evidence. One notable example where a policy-making body has failed to use scientific evidence to inform policy is the Canadian federal government's opposition to Vancouver's supervised injection facility despite a large body of scientific evidence indicating that the program is associated with a range of health and social benefits. Two of the key strategies that have been used to try to shift drug policy toward an evidence-based approach and maintain the operation of this evidence-based health facility are knowledge translation and legal actions. We provide an overview of these two strategies and hope it will offer lessons for the implementation of evidence-based approaches in other controversial areas of public policy. PMID- 21687338 TI - Surveying the medical literature: five notable articles in general internal medicine from 2008 and 2009. AB - Given the vast and growing volume of medical literature, it is essential to develop reliable strategies for identifying articles of importance and relevance. Here, we summarize 5 notable articles for general internal medicine published in 2008 and 2009. Clinical vignettes are presented to illustrate situations in which each study might apply, and each summary ends with a description of how a physician might use the study findings to resolve the vignette case. Finally, we describe a surveillance strategy that physicians can use to identify articles important to their own practices. PMID- 21687337 TI - Analyzing the effects of place on injury: Does the choice of geographic scale and zone matter? AB - BACKGROUND: Recent studies have shown that the morbidity and mortality associated with injury of pedestrians are inversely related to socio-economic status (SES). However, in drawing inferences from this association, investigators have paid little attention to the modifiable artifacts related to scale and how the data are partitioned. The purpose of this population-based study was to identify the relation between SES and incidence patterns of pedestrian injury at 4 different geographic scales. METHODS: We used a Poisson generalized linear model, stratified by age and sex, to analyze the relation between each of 4 area measures of SES and incidence patterns of pedestrian injuries occurring in metropolitan Vancouver between 1 January 2001 and 31 March 2006. The 4 area measures of SES were based on boundaries of dissemination areas, census tracts, custom-defined census tracts (generated by reassignment of dissemination area boundaries by means of a geographic information system) and census subdivisions of the Canadian census. We measured the SES of the location where the injury occurred with the Vancouver Area Neighbourhood Deprivation Index. RESULTS: A total of 262 injuries in adults (18 years of age or older) were analyzed. Among adult men, the odds ratio (OR) for injury of pedestrians at the scale of dissemination area was 4.93 (95% confidence interval [CI] 2.89-8.42) for areas having the lowest SES relative to those with the highest SES. For the same population, the OR for injury was lower with increasing aggregation of data: 2.33 (95% CI 1.45-3.74) when census tracts were used, 3.26 (95% CI 2.06-5.16) when modified census tracts were used and 1.27 (95% CI 0.47-3.45) when census subdivisions were used. Among adult women, the OR for pedestrian injury by SES was highest at the scale of census subdivision within medium-low SES areas (4.33, 95% CI 1.23-15.22). At the census subdivision scale, the relation between SES and incidence pattern of injury was not consistent with findings at smaller geographic scales, and the OR for injury decreased with each increase in SES. INTERPRETATION: In this analysis, there was significant variability when different administrative boundaries were applied as proxy measures of the effects of place on incidence patterns of injury. The hypothesized influence of SES on prevalence of pedestrian injury followed a statistically significant socio economic gradient when analyzed using small-area boundaries of the census. However, researchers should be aware of the inherent variability that remains even among the more homogenous population units. PMID- 21687339 TI - A patient with shortness of breath and bilateral pulmonary infiltrates. AB - Eosinophilic disorders are rare and clinically challenging diagnoses. In part, the challenge comes from the fact that some classifications of eosinophilic diseases have been based on the site of eosinophilic infiltration whereas others have been based on the actual number of blood eosinophils present. We describe a 54-year-old woman who had a history of asthma and presented with shortness of breath and eosinophilia. The differential diagnosis is broad and includes infectious diseases, inflammatory conditions such as Churg-Strauss syndrome, and hematologic conditions such as hypereosinophilic syndrome. We describe the diagnostic challenges inherent in such a presentation and also the changing landscape of disease labels in light of our evolving ability to diagnose genetic abnormalities. PMID- 21687340 TI - Denaturalizing "natural" disasters: Haiti's earthquake and the humanitarian impulse. PMID- 21687341 TI - Endovascular treatment for multiple sclerosis: The intersection of science, policy and the public. AB - The Canadian Institutes of Health Research and the Multiple Sclerosis (MS) Society of Canada recently convened an Invitational Panel to consider the scientific evidence linking chronic cerebrospinal venous insufficiency (CCSVI) and MS. The panel supported studies to determine whether CCSVI causes MS, but felt that there is currently so much uncertainty about the relationship between CCSVI and MS that a clinical trial is not indicated at this time. This commentary argues that the decision about whether a clinical trial is warranted must be informed by science, but should be addressed from a broader societal perspective. We suggest that members of the public should be more actively involved in scientifically based, but patient-relevant and emotionally charged issues considered by organizations that fund health research. PMID- 21687342 TI - Is PiSS Alpha-1 Antitrypsin Deficiency Associated with Disease? AB - Background. Alpha-1 antitrypsin deficiency (AAT) is an inherited condition that predisposes to lung and/or liver disease. Objective. The current study examined the clinical features of the PiSS genotype. Methods. Nineteen study participants (PiSS) and 29 matched control participants (PiMM) were telephone interviewed using a standardized questionnaire. Demographic features, cigarette smoking, vocation, medication history, and clinical diagnoses were compared. Statistical analysis was performed. Finally, a comprehensive literature review was performed by two investigators. Results. 12/19 (63.2%) study participants reported the presence of lung and/or liver disease compared to 12/29 (41.4%) control participants. There trended toward having a higher frequency of medication allergies in the study population (42.11% versus 20.69%). Conclusions. The PiSS genotype was associated with a similar incidence of obstructive lung disease to controls. Selective bias intrinsic in testing for AAT deficiency and the rarity of the PiSS genotype will make future study of this association dependent on population-based tests. PMID- 21687343 TI - Mechanisms of cellular uptake of cell-penetrating peptides. AB - Recently, much attention has been given to the problem of drug delivery through the cell-membrane in order to treat and manage several diseases. The discovery of cell penetrating peptides (CPPs) represents a major breakthrough for the transport of large-cargo molecules that may be useful in clinical applications. CPPs are rich in basic amino acids such as arginine and lysine and are able to translocate over membranes and gain access to the cell interior. They can deliver large-cargo molecules, such as oligonucleotides, into cells. Endocytosis and direct penetration have been suggested as the two major uptake mechanisms, a subject still under debate. Unresolved questions include the detailed molecular uptake mechanism(s), reasons for cell toxicity, and the delivery efficiency of CPPs for different cargoes. Here, we give a review focused on uptake mechanisms used by CPPs for membrane translocation and certain experimental factors that affect the mechanism(s). PMID- 21687344 TI - The era of nanomedicine. PMID- 21687345 TI - Myocardial infarction and stem cells. AB - Permanent loss of cardiomyocytes and scar tissue formation after myocardial infarction (MI) results in an irreversible damage to the cardiac function. Cardiac repair (replacement, restoration, and regeneration) is, therefore, essential to restore function of the heart following MI. Existing therapies lower early mortality rates, prevent additional damage to the heart muscle, and reduce the risk of further heart attacks. However, there is need for treatment to improve the infarcted area by replacing the damaged cells after MI. Thus, the cardiac tissue regeneration with the application of stem cells may be an effective therapeutic option. Recently, interest is more inclined toward myocardial regeneration with the application of stem cells. However, the potential benefits and the ability to improve cardiac function with the stem cell based therapy need to be further addressed. In this review, we focus on the clinical applications of stem cells in the cardiac repair. PMID- 21687346 TI - Aliskiren: An orally active renin inhibitor. AB - Renin inhibitors are antihypertensive drugs that block the first step in the renin-angiotensin system. Their mechanism of action differs from that of the angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists, but like these drugs, renin inhibitors interrupt the negative feedback effects of angiotensin II on renin secretion. The renin-angiotensin-aldosterone system (RAAS) has long been recognized to play a significant role in hypertension pathophysiology. Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes. Optimization of this compound by Novartis led to the development of aliskiren - the only direct renin inhibitor which is clinically used as an antihypertensive drug. Aliskiren is the first of a new class of antihypertensive agents. Aliskiren is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once-daily oral dosing. In short-term studies, it was effective in lowering blood pressure either alone or in combination with valsartan and hydrochlorothiazide, and had a low incidence of serious adverse effects. It was approved by the Food and Drug Administration in 2007 for the use as a monotherapy or in combination with other antihypertensives. Greater reductions in blood pressure have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin-receptor blocker. The most common adverse effects reported in clinical trials were headache, fatigue, dizziness, diarrhea, and nasopharyngitis. Aliskiren has not been studied in patients with moderate renal dysfunction; as an RAAS-acting drug, it should be prescribed for such patients only with caution. PMID- 21687348 TI - Evaluation of roll compaction as a preparation method for hydroxypropyl cellulose based matrix tablets. AB - Roll compaction was applied for the preparation of hydroxypropyl cellulose (HPC) based sustained-release matrix tablets. Matrix tablets made via roll compaction exhibited higher dosage uniformity and faster drug release than direct-compacted tablets. HPC viscosity grade, roll pressure, and milling speed affected tablet properties significantly. Roll compaction seems to be an adequate granulation method for the preparation of HPC-based matrix tablets due to the simplicity of the process, less handling difficulty from HPC tackiness as well as easier particle size targeting. Selecting the optimum ratio of plastic excipients and the particle size of starting materials can however be critical issues in this method. PMID- 21687347 TI - Antidepressant potential of nitrogen-containing heterocyclic moieties: An updated review. AB - Depression is currently the fourth leading cause of disease or disability worldwide. Antidepressant is approved for the treatment of major depression (including paediatric depression), obsessive-compulsive disorder (in both adult and paediatric populations), bulimia nervosa, panic disorder and premenstrual dysphoric disorder. Antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription a risk, despite claims of superior efficacy. Our current understanding of its pathogenesis is limited and existing treatments are inadequate, providing relief to only a subset of people suffering from depression. Reviews of literature suggest that heterocyclic moieties and their derivatives has proven success in treating depression. PMID- 21687349 TI - Peptide IC-20, encoded by skin kininogen-1 of the European yellow-bellied toad, Bombina variegata, antagonizes bradykinin-induced arterial smooth muscle relaxation. AB - OBJECTIVES: The objectives were to determine if the skin secretion of the European yellow-bellied toad (Bombina variegata), in common with other related species, contains a bradykinin inhibitor peptide and to isolate and structurally characterize this peptide. MATERIALS AND METHODS: Lyophilized skin secretion obtained from this toad was subjected to reverse phase HPLC fractionation with subsequent bioassay of fractions for antagonism of the bradykinin activity using an isolated rat tail artery smooth muscle preparation. Subsequently, the primary structure of the peptide was established by a combination of microsequencing, mass spectroscopy, and molecular cloning, following which a synthetic replicate was chemically synthesised for bioassay. RESULTS: A single peptide of molecular mass 2300.92 Da was resolved in HPLC fractions of skin secretion and its primary structure determined as IYNAIWP-KH-NK-KPGLL-. Database interrogation with this sequence indicated that this peptide was encoded by skin kininogen-1 previously cloned from B. variegata. The blank cycles were occupied by cysteinyl (C) residues and the peptide was located toward the C-terminus of the skin kininogen, and flanked N-terminally by a classical -KR- propeptide convertase processing site. The peptide was named IC-20 in accordance (I = N-terminal isoleucine, C = C terminal cysteine, 20 = number of residues). Like the natural peptide, its synthetic replicate displayed an antagonism of bradykinin-induced arterial smooth muscle relaxation. CONCLUSION: IC-20 represents a novel bradykinin antagonizing peptide from amphibian skin secretions and is the third such peptide found to be co-encoded with bradykinins within skin kininogens. PMID- 21687350 TI - In vitro antimicrobial activity of methanolic leaf extract of Psidium guajava L. AB - AIM: This study was designed to examine the chemical composition and in vitro antimicrobial potential of methanolic extract of Psidium guajava Linn (Myrtaceae). MATERIALS AND METHODS: The inhibitory effect of methanolic extract of P. guajava was tested against three bacterial and two fungal strains by using the paper disc diffusion method. RESULTS: The methanolic extract exhibited antibacterial activity against E. coli with minimum inhibitory concentration, 0.78 MUg/ml, minimum bactericidal concentration of 50 MUg/ml, and appreciable antifungal activity with minimum inhibitory concentration of 12.5 MUg/ml. Preliminary phytochemical analysis of methanolic extract revealed the presence of antimicrobial compounds such as flavonoids, steroids, and tannins, which may contribute for the antimicrobial action of P. guajava. CONCLUSION: The extract was found to be bacteriostatic and fungistatic in action. PMID- 21687351 TI - Antihyperlipidemic effect of Trichilia connaroides in hypercholesterolemic rats and its possible mechanism. AB - OBJECTIVES: The primary objective of this study was to investigate the antihyperlipidemic effect of the chloroform (CETC) and methanol (METC) extracts of leaves of Trichilia connaroides in hypercholesterolemic rats and, subsequently, to evaluate the possible mechanism of its antihyperlipidemic effect. MATERIALS AND METHODS: The antihyperlipidemic activity of CETC and METC (100 mg/kg) in hypercholesterolemic rats was investigated by recording the serum lipid profile after a month-long oral treatment of these extracts. Further, hypercholesterolemic regression test and hypercholesterolemic progression test were carried out to understand the possible mechanism of its antihypercholesterolemic effect. The data were analyzed for statistical significance by one-way ANOVA, followed by Dunnet's test. RESULTS AND CONCLUSION: Hypercholesterolemic rats treated with CETC and METC produced a significant fall (P<0.05) in plasma triglyceride, total cholesterol, very low density lipoprotein (VLDL )-cholesterol and low density lipoprotein (LDL)-cholesterol and rise (P < 0.05) in high density lipoprotein (HDL) -cholesterol. A significant reduction (P < 0.01) in atherogenic index, increase (P < 0.05) in body weight and an insignificant influence on food intake were also observed at the end of the study. A hypercholesterolemic regression test revealed a significant reduction (P < 0.05) in the serum cholesterol level in both CETC and METC extract-treated animals. During the hypercholesterolemic progression test, a similar reduction in the serum cholesterol level was observed only in the METC extract-treated animals. The antihyperlipidemic effect was similar to fenofibrate and ezitimibe. Significant changes in the lipid profile in hypercholesterolemic animals confirm a potential antihyperlipidemic activity of the extracts. The CETC and METC extracts influenced the absorption and metabolism of dietary cholesterol to elicit the antihyperlipidemic effect. PMID- 21687352 TI - Antiulcer effect of the methanolic extract of Tamarindus indica seeds in different experimental models. AB - BACKGROUND: Peptic ulcer is a global health problem of the gastrointestinal tract characterized by mucosal damage secondary to pepsin and gastric acid secretion which occurs due to due to an imbalance between offensive and defensive factors. OBJECTIVE: The present study was carried out with methanolic extract of the seed coat of Tamarindus indica Linn. to evaluate its antiulcer potential on ibuprofen, alcohol and pyloric ligation induced gastric lesions. MATERIALS AND METHODS: Doses of 100 mg/kg & 200 mg/kg of methanolic extract wre administered orally to rats of different groups. Ranitidine at a dose of 50 mg/kg was used as a standard drug for these gastric ulcer models. The gastric content was collected and the volume was measured. The ulceration index was determined by examining the inner lining of each stomach. Furthermore, the effect was assessed by free acidity, pepsin activity, total carbohydrate (TC), protein content (PK). RESULT: The result showed that the methanolic extract of seed coats of Tamarindus indica significantly reduce the total volume of gastric juice, free and total acidity of gastric secretion (P < 0.01) in pylorus ligation induced ulcer model as is comparable with the standard drug ranitidine. There was also a significant reduction in ulcer index (P < 0.01) as compared to control group. CONCLUSION: The methanolic extracts of seed coat of Tamarindus indica can be used as a new source of antiulcer agent in animals. PMID- 21687353 TI - Antidiabetic activity of medium-polar extract from the leaves of Stevia rebaudiana Bert. (Bertoni) on alloxan-induced diabetic rats. AB - OBJECTIVE: To investigate the medicative effects of medium-polar (benzene:acetone, 1:1, v/v) extract of leaves from Stevia rebaudiana (family Asteraceae) on alloxan-induced diabetic rats. MATERIALS AND METHODS: Diabetes was induced in adult albino Wistar rats by intraperitoneal (i.p.) injection of alloxan (180 mg/kg). Medium-polar extract was administered orally at daily dose of 200 and 400 mg/kg body wt. basis for 10 days. The control group received normal saline (0.9%) for the same duration. Glibenclamide was used as positive control reference drug against Stevia extract. RESULTS: Medium-polar leaf extract of S. rebaudiana (200 and 400 mg/kg) produced a delayed but significant (P < 0.01) decrease in the blood glucose level, without producing condition of hypoglycemia after treatment, together with lesser loss in the body weight as compared with standard positive control drug glibenclamide. CONCLUSIONS: Treatment of diabetes with sulfonylurea drugs (glibenclamide) causes hypoglycemia followed by greater reduction in body weight, which are the most worrisome effects of these drugs. Stevia extract was found to antagonize the necrotic action of alloxan and thus had a re-vitalizing effect on beta-cells of pancreas. PMID- 21687354 TI - Trichosanthes dioica Roxb.: Pharmacognostic standardization of the female leaves with special emphasis on the microscopic technique. AB - OBJECTIVES: Standardization is essentially a measure for ensuring the quality control of herbal drugs. But the gender of the plant affecting the quality of crude drugs does not appear to have been taken care of so far. Today, sophisticated modern research tools for the evaluation of the plant drugs are available but the microscopic method is one of the simplest and cheapest methods. METHODS AND MATERIALS: The pharmacognostic investigation of the fresh, powdered, and anatomical sections of the female leaves of Trichosanthes dioica Roxb. was carried out to determine its bioprospective constants. RESULTS AND DISCUSSION: Externally, the leaves possess a cordate base, a sinuate and dentate margin, an acute to acuminate apex, and both surfaces are very rough with rigid hair surface. Internally, it shows the presence of anomocytic stomata, unicellular, and both glandular and simple covering trichomes scattered as such throughout or attached with the cells of the epidermis. Majority of the glandular trichomes are with a four-to-five-celled uniseriate stalk and unicellular head; very few are short and with uni- to bicellular stalk and uni- to multicellular head especially from that of the petiole region. Simple covering, multicellular, uniseriate thick walled trichomes are of various sizes. Usually cells of both simple and glandular trichomes are often embedded with cystolith. Phytochemical studies of the powdered leaves revealed the presence of alkaloids, resins, glycosides, flavonoids and some carbohydrates. The pharmacognostic profile of the leaves will assist in the standardization for quality, purity, and sample identification. PMID- 21687355 TI - Experimental re-evaluation of flunarizine as add-on antiepileptic therapy. AB - BACKGROUND: Experimental studies have found several calcium channel blockers with anticonvulsant property. Flunarizine is one of the most potent calcium channel blockers, which has shown anticonvulsant effect against pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures. However, further experimental and clinical trials have shown varied results. We conducted a PTZ model experimental study to re-evaluate the potential of flunarizine for add-on therapy in the management of refractory epilepsy. MATERIALS AND METHODS: Experiments were conducted in PTZ model involving Swiss strain mice. Doses producing seizures in 50% and 99% mice, i.e. CD(50) and CD(99) values of PTZ were obtained from the dose-response study. Animals received graded, single dose of sodium valproate (100-300 mg/kg), lamotrigine (3-12 mg/kg) and flunarizine (5-20 mg/kg), and then each group of mice was injected with CD(99) dose of PTZ (65mg/kg i.p.). Another group of mice received single ED(50) dose (dose producing seizure protection in 50% mice) of sodium valproate and flunarizine separately in left and right side of abdomen. Results were analysed by Kruskal-Wallis ANOVA on Ranks test. RESULTS: As compared to control, sodium valproate at 250 mg/kg and 300 mg/kg produced statistical significant seizure protection. At none of the pre-treatment dose levels of lamotrigine, the seizure score with PTZ differed significantly from that observed in the vehicle-treated group. Pre-treatment with flunarizine demonstrated dose-dependent decrease in the seizure score to PTZ administration. As compared to control group, flunarizine at 20 mg/kg produced statistical significant seizure protection. CONCLUSION: As combined use of sodium valproate and flunarizine has shown significant seizure protection in PTZ model, flunarizine has a potential for add-on therapy in refractory cases of partial seizures. It is therefore, we conclude that further experimental studies and multicenter clinical trials involving large sample size are needed to establish flunarizine as add-on therapy in refractory epilepsy. PMID- 21687356 TI - Anti-inflammatory and antinociceptive evaluation of newly synthesized 4 (substituted ethanoyl) amino-3-mercapto-5-(4-methoxy) phenyl-1,2,4-triazoles. AB - INTRODUCTION: 1,2,4-triazoles and its derivatives have been reported to possess anti-inflammatory, analgesic, antimicrobial, anticancer, antitumor, antitubercular, anticonvulsant, openers of Ca-activated potassium (Maxi-K) channels, antiviral properties, hypoglycemic, anxiolytic and antidepressant activity. Therefore, 1,2,4-triazole seems to be an important pharmacophore. MATERIALS AND METHODS: The synthesis of 4-(substituted ethanoyl) amino-3-mercapto 5-(4-methoxy) phenyl-1,2,4-triazoles (6a-o) were prepared following six step starting 4-methoxy benzoic acid and using different secondary amines and were characterized with the help of FT-IR,(1)H,(13)C NMR, FAB Mass and nitrogen analysis. These synthesized compounds (6a-o) were then evaluated for anti inflammatory activity by carrageenan induced paw edema method.Out of these synthesized compounds, some (6f, i and k) were evaluated for antinociceptive activity by Hot plate method and Tail immersion method. RESULTS AND DISCUSSION: The synthesis of 4-(substituted amino)-3-mercapto-5-(4-methoxy) phenyl-1,2,4 triazoles (6a-o) was accomplished. The IR spectra exhibited characteristic bands for C-N, C=N, SH and C=O at 1350-1360, 1511-1548, 2520-2594.3 and 1650-1719 cm( 1). The C-O-C asymmetric and symmetric str. was at 1250-1254 and 1027-1079.3 cm( 1) respectively. In(1)H-NMR spectra, a singlet of CONH was found in the range of delta 9.92-10.18 ppm and another singlet of thiol group was observed in the range of delta 8.63-9.92 ppm. A singlet of Ar-OCH(3) was also found between delta 3.57 3.91 ppm. In(13) C- NMR spectra, C-3 and C-5 of the 1,2,4 - triazole nucleus were observed in the range of delta 147-166.9 ppm. Carbonyl carbon and methylene carbon of -NHCOCH(2) N< were found between delta 166.5-177.5 and delta 47.1-62 ppm respectively. Acute toxicity study was donr following OECD-423 and cut-off dose was found to be between 1000-1500 mg/kg body weight. At the dose level of 100 mg/kg, 6f, 6i and 6k exhibited appreciable inhibition of oedema especially 6k exhibiting a percentage of oedema inhibition of 40.28%, which was comparable to that of the standard drug indomethacin (62.50% at 10mg/kg dose). Among the compounds tested, compound 6k exhibited good anti-nociceptive activity in both methods used. Pethidine (20mg/kg body weight s.c) is used as the standard drug. CONCLUSION: SAR of these synthesized compounds shows that substitution with heterocyclic moiety at C-2 of the acetamido group at position 4 of the 1,2,4 triazole produces appreciable activity as compared to substitution with aliphatic moieties since among all the synthesized compounds, the most active ones are 6f, 6i and 6k that have piperdine, 1-benzyl piperazine and morpholine group, respectively at C-2 of the acetamido group at position 4 of the 1,2,4-triazole. PMID- 21687357 TI - Artificial semi-rigid tissue sensitized with natural pigments: Effect of photon radiations. AB - BACKGROUND: A new approach for evaluating the optical penetration depth and testing its validity with Monte Carlo simulations and Kubelka-Munk theory is used for artificial semi-rigid tissue sensitized with natural pigments. Photodynamic therapy is a promising cancer treatment in which a photosensitizing drug concentrates in malignant cells and is activated by visible light at certain wavelength. MATERIALS AND METHODS: Cheap artificial semi-rigid tissue incorporated with scattering and absorbing materials along with some other composites comparable to normal human tissue has been performed. The optical parameters as measured with different conditions and calculated with various techniques are investigated. RESULTS: The probability of interaction of light with tissue is very high when exposed to light in presence of Cichorium pumilum and RBCs followed by photohemolysis or/and photodegradation. The optical penetration depth calculated by linear absorption coefficient ranges from 0.63 to 2.85 mm is found to be comparable to those calculated using Kubelka-Munk theory or Monte Carlo simulation (range from 0.78 to 2.42 mm). The ratio of absorption to the scattering is independent of thickness and decreases with increasing irradiation time. Moreover, the optical parameters as well as their ratios are in very good agreement in the two approaches of calculation. The values of absorption and scattering coefficients are independent of thickness. Furthermore, the average photon ranges in the samples containing no scattering and absorbing materials are about three times greater than those samples containing scattering materials. CONCLUSION: Our results suggest that light propagation with optical properties presented in this work could be applicable in diagnostic and therapeutic of the human biological tissue for photodynamic therapy. PMID- 21687358 TI - Evaluation of nutraceutical properties of selected small millets. AB - OBJECTIVE: The aim of this study was to evaluate the nutraceutical properties and nutritional value of grains of four selected small millets viz. finger millet, foxtail millet, prosomillet and khodomillet. MATERIALS AND METHODS: The qualitative analysis of phytochemicals viz. phenolics, flavonoids, alkaloids and saponins present in the four small millets was done. The water-soluble proteins, crude fiber content and the reducing power of the grains of these four millets were analyzed. RESULTS AND CONCLUSIONS: The khodomillet showed maximum phenolic content (10.3%) and foxtail millet showed minimum phenolics (2.5%). As far as reducing capacity was concerned, finger millet was highest (5.7%). The prosomillet showed least reducing property (2.6%). The finger millet (391.3 mg/g each) showed maximum reducing sugar content. The prosomillet showed minimum reducing sugar (195 mg/g). The foxtail millet showed maximum protein content (305.76 mg/g) and prosomillet showed minimum protein content (144.23 mg/g). The khodomillet showed maximum crude fiber content (14.3%).The finger millet showed maximum reducing sugar content (391.3 mg/g) whereas, the khodomillet showed minimum reducing sugar (130.43 mg/g). PMID- 21687359 TI - Polymeric ocular hydrogels and ophthalmic inserts for controlled release of timolol maleate. AB - BACKGROUND: Ophthalmic drug delivery systems are the challenging subject for the researchers because of delicate nature of ocular membrane and preventive barriers leading to less than 1 % of Bioavailability. Reasons for reduced bioavailability are due to rapid pre corneal elimination, tear turnover, lacrimal drainage, blinking and degradation by enzymes. Less bioavailability causes short duration of action and increased frequency of administration. MATERIALS AND METHODS: Timolol maleate was used as model drug. Dynamic drug release studies were used to study the polymeric hydrogels and ophthalmic inserts. Rheological studies were carried out by Brookfield Viscometer LVDV- II+. RESULT AND DISCUSSION: Viscosity value lies in the range of 4.08 to 31.8 cps. Drug release data was fitted to various kinetic equations such as First order plots, Higuchi plots, Peppa's exponential plots. The results shows fairly linear curve and the slope value of the Peppa's equation is less than 0.5 and hence follows the fickian diffusion. CONCLUSION: The developed hydrogels and inserts were therapeutically effacious, stable, non irritant and provide a sustained release of drug over 8 hours time period. PMID- 21687360 TI - Anticancer studies of drug encapsulated polyethylene terephthalate-Co-polylactic acid nanocapsules. AB - OBJECTIVES: The purpose of this study was to investigate the anticancer activity of anticancer drugs (5-fluorouracil and 6-thioguanine) in polymeric nanocapsules in the presence and in the absence of gold and iron oxide nanoparticles toward Hep2 cancer cells. MATERIALS AND METHODS: MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide) assay was used for quantitative measurements for the anticancer cell activity. Encapsulated drug in polyethylene terephthalate polylactic acid copolymer (PET-co-PLA) nanocapsules in the presence and absence of gold and iron oxide nanoparticles were prepared via the W/O/W emulsification solvent-evaporation method. Morphology of the nanoparticles was characterized by transmission electron microscopy and scanning electron microscopy. CONCLUSION: The average size of the polymeric nanocapsules, gold nanoparticles, and iron oxide nanoparticles were found to be in range of 230-260, 18 -20 nm, 5-10 nm, respectively. The findings in this study inferred that incorporated drug in polymeric nanocapsules with gold nanoparticles and iron oxide nanoparticles show better anticancer activity when compared with encapsulated drug in polymeric nanocapsules. PMID- 21687361 TI - Photosensitizers for photodynamic therapy: One-pot heterogeneous catalytic transfer reduction of porphyrins. AB - A number of new porphyrin-based photosensitizers have been developed for Photodynamic Therapy (PDT) in recent years. Chlorins, which are a reduced form of porphyrins, show better potential of application since they have a stronger absorption band on the red region of the visible spectrum and, hence, a deeper penetration into tissues. We found that by using heterogeneous catalytic transfer reduction (CTR), meso-tetraphenylporphyrin (TPP) could be hydrogenated, although in modest yields, to meso-tetraphenylchlorin (TPC) in a single reaction step. Best reaction conditions were attained using formic acid or sodium phosphinate/water as hydrogen donors, tetrahydrofuran (THF) or toluene as solvent and 10% palladium on charcoal as catalyst. PMID- 21687362 TI - Prospective encounter study of the degree of adherence to patient care indicators related to drug dispensing in Health Care facilities: A Sri Lankan perspective. AB - The World Health Organization-recommended patient care indicators in Government Hospitals were assessed in 422 patients attending the Outpatient Department in selected hospitals of the Galle district in Southern Province. The average dispensing time (ADT), percentage of drugs actually dispensed (PDAD), percentage of drugs adequately labeled (PDAL) and patient's knowledge on correct dosage (PKCD) were compared in these selected teaching hospitals (TH), general hospitals (GHs) and district hospitals (DHs) in Galle. ADT in DH (1.16 min) and GH (1.07 min) were high when compared with ADT in TH (0.81 min). PDAD was 100% in DH, 97.79% in GH and lowest in TH (94.64%). PDAL was highest (22.66%) in TH, 17.57% in GH and lowest in DH (1.57%). PKCD was 100% in GH and lowest in DH (0%) and only 50% in TH in Galle district. We noted that there was a significant difference in ADT in all three categories (P < 0.05). We noted that dispensers spend only a short dispensing time and showed a tendency for dispensing errors. We found that PDAL was very low in all hospitals but PDAD was significantly high. Even though the ADT was high in DH, PKCD was 0% due to negligence in dispensing practices. We also noted a 100% PKCD only in GH due to the practice of a well prepared correct labeling system in GH. We noticed that these patients were provided drugs with inadequate labeling and that patients had only a poor knowledge about the drug administration schedule. We conclude that there was a low dispenser-patient ratio in all three hospitals and that there was a need for an implementation plan for proper dispensing techniques by introducing a well prepared drug labeling system in a printed format. PMID- 21687363 TI - Studies on aerial parts of Artemisia pallens wall for phenol, flavonoid and evaluation of antioxidant activity. AB - Herbs have been used for medicinal purposes for centuries. According to recent investigations, they may help reduce the risk of chronic diseases, cardiovascular disease, and cancer due to antioxidant properties, which in turn can be attributed to the various phytoconstituents. With this intention, evaluation of antioxidant activity was performed. Methanol extract of aerial parts of Artemisia pallens Wall was screened for its antioxidant activity due to phenolic and flavonoid contents, by employing radical scavenging assays; 2,2 -diphenyl, 1 picryl hydrazyl (DPPH) and nitric oxide. Ascorbic acid was used as a standard. Quantitative determination of phenols and flavonoids were carried out using spectrophotometric method. Total flavonoid content was determined as quercetin equivalent and total phenolic content was determined as pyrocatechol equivalent using Folin-Ciocalteu reagent. Plant produces more phenolic compounds than flavonoids. IC(50) value of methanol extract for DPPH free radical scavenging activity was found to be 292.7 MUg, whereas for nitric oxide it was 204.61 MUg. The result obtained in the present study indicates that the aerial parts of this plant are a rich source of natural antioxidants. PMID- 21687364 TI - Does atorvastatin work more effectively than biguanides in reducing cardiovascular risk factors? AB - Increased risk of coronary artery disease in diabetic persons is associated with increased level of lipoproteins. Usually, such risks are reverted with glycemic control by antidiabetic medicines in Type I diabetes millitus. However, in Type II diabetes mellitus lipid values can be improved using antidiabetics but still the risk of coronary artery disease remains. The initial approach for reducing lipid contents in diabetic patients should include glycemic control, diet, weight loss, and exercise. But if it fails then lipid-lowering agents like fibrate and HMG CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase) inhibitors should work effectively. In the present study results of atorvastatin compared with biguanides proved atorvastatin as a more effective lipid-lowering agent along with antidiabetic activity so it can effectively help in reducing the risk of cardiovascular disease (CVD). PMID- 21687365 TI - Development and validation of a stability indicating method for the enantioselective estimation of omeprazole enantiomers in the enteric-coated formulations by high-performance liquid chromatography. AB - Omeprazole is widely prescribed in the form of enteric-coated formulations, due to the rapid degradation of the drug in the acidic condition of the stomach. In the current article, we are reporting the development and complete validation of a stability indicating chiral high-performance liquid chromatography (HPLC) method for the enantioselective analysis of omeprazole in the enteric-coated formulations. A precise and sensitive enantiomeric separation of omeprazole was obtained on Chiralcel OD-H analytical column (250mm * 4.6 mm, 5MUm particle size) using normal phase chromatography. The analysis was performed under UV detection at 301nm wavelength. During method development, the addition of methanol to the mobile phase helped in getting the sharp peaks. The developed method showed linear response over a wide concentration range of 0.39-800MUg/ml and the regression coefficients value (r(2)) was obtained more than 0.999 for (S)- and (R)-omeprazole. The lower limit of detection (LLOD) and lower limit of quantification (LLOQ) for (R)-omeprazole were found to be 0.39 and 0.78 MUg/ml, respectively for 5 MUl injection volume. The percentage recovery of (R) omeprazole ranged from 93.5 to 104 in spiked formulation samples and omeprazole sample solution and mobile phase were found to be stable for at least 24 h at room temperature. The proposed method was found to be suitable and accurate for the quantitative determination of undesired enantiomer in the enteric-coated omeprazole formulations. PMID- 21687366 TI - Fukushima, Japan: An apocalypse in the making? PMID- 21687367 TI - Assessment of asthma and chronic obstructive pulmonary disorder. PMID- 21687368 TI - Fighting microbes the 'Nano' way. PMID- 21687369 TI - An in vitro evaluation of anthelmintic activity of Zingiber zerumbet rhizomes and Cucurbita maxima seeds on Pheretima posthuma model: A comparative study. PMID- 21687370 TI - EPR as a tool for the evaluation of novel lyophilized blood products as absorbents for chemical gas masks. PMID- 21687371 TI - Tesamorelin: A hope for ART-induced lipodystrophy. PMID- 21687372 TI - Tensions Between Community-based and Community-owned. PMID- 21687373 TI - Urbanization and health challenges: need to fast track launch of the national urban health mission. PMID- 21687374 TI - Nutritional anemia in young children with focus on Asia and India. PMID- 21687375 TI - A Descriptive Study on the Users and Utility of HIV/AIDS Helpline in Karnataka, India. AB - BACKGROUND: Globally, Telephone help-lines have proved their utility in several crisis situations. They were introduced in India for helping persons in need of counseling or emergency care such as victims of suicide, cardiac arrests, etc. The utility of such help-lines in HIV/AIDS has not been established .Hence this study done in ASHA Foundation, Bangalore. OBJECTIVES: To determine the characteristics of persons who access the HIV/AIDS helpline. To determine the reasons for calling the helpline. To identify the gaps in the provision of this service. MATERIALS AND METHODS: Details on all calls received on ASHA Foundation's HIV/AIDS help line during the period January 2007 to December 2008, were entered on MS excel worksheet and analyzed using the SPSS software. RESULTS: Majority of callers are male, are in the age group of 20-39 years and educated. The most common reasons for calling the helpline were for HIV testing, information about HIV/AIDS, care and support services and referrals to other services not linked to HIV/AIDS. Reasons for calling were linked to risk ( HIV testing, condom use etc) in younger persons, and to avail of care and support services in the older age-group. CONCLUSIONS: The main users of the HIV/AIDS helpline are urban ,young, educated males. PMID- 21687376 TI - Public private partnerships for emergency obstetric care: lessons from maharashtra. AB - BACKGROUND: The National Rural Health Mission of India advocates public private partnerships (PPPs) to meet its "service guarantee" of Emergency obstetric care (EmOC) provision. The Janani Suraksha Yojana (JSY) has a provision of Rs. 1500 for contracting in obstetric specialists. OBJECTIVES: The study aimed to understand the issues in the design and implementation of the PPPs for EmOC under the JSY in Maharashtra and how they affect the availability of EmOC services to women. MATERIALS AND METHODS: A cross-sectional study using the rapid assessment approach was conducted in Ahmednagar district of Maharashtra spanning 1-year duration ending in June 2009. Primary data were obtained through interviews with women, providers, and administrators at various levels. Data were analyzed thematically. RESULTS: The PPP scheme for EmOC is restricted to deliveries by Caesarean section.The administrators prefer subsidization of costs for services in private facilities to contracting in. There are no PPPs executed in the study district. This study identifies barriers to women in accessing the benefit and the difficulties faced by administrators in implementing the scheme. CONCLUSION: The PPPs for EmOC under the JSY have minimally influenced the out-of-pocket payments for EmOC. Infrastructural inadequacies and passive support of the implementers are major barriers to the implementation of contracting-in model of PPPs. Capacities in the public health system are inadequate to design and manage PPPs. PMID- 21687377 TI - Noncompliance to DOTS: How it can be Decreased. AB - BACKGROUND: Tuberculosis is a communicable disease requiring prolonged treatment.The therapeutic regimens as recommended by WHO have been shown to be highly effective for both preventing and treating tuberculosis but poor adherence to medication is a major barrier to its global control. AIM: The aim was to elicit reasons of treatment default from a cohort of tuberculosis patients treated under Directly Observed Treatment Short course chemotherapy. SETTINGS AND DESIGN: Thiscross-sectional study was conducted in Agra city using the multistage simple random sampling. MATERIALS AND METHODS: A total of 900 patients attending DOTS centres of the selected designated microscopy centers (DMCs) were included in the study from January 2007 onward. The information was obtained from treatment cards of patients and those who defaulted were further interviewed in community. STATISTICAL ANALYSIS: Chi-square test was applied to observe the significance of association using the Epi Info software (version 6). RESULTS: More default was observed among the age group of >45 years (22.8%), male (18.7%), business men (30.6%), and retired and unemployed patients. Other factors associated with higher default were pulmonary disease (18.2%), retreatment cases (30.6%) and category II patients (26.4%). Important reasons of default were side effects following medication (43.2%), improvement in symptoms (14.4%), and lack of time (13.5%). No relief in symptoms and lack of awareness were other important reasons. CONCLUSIONS: Noncompliance was found to be mainly due to side effects of medicines, lack of time, and unawareness. So educating the patient about various aspects of tuberculosis and some measures to decrease side effects are of utmost importance. PMID- 21687378 TI - Study of Sexual Behaviour of Bar-girls Residing in an Urban Slum Area of Mumbai. AB - BACKGROUND: Bar girls are unorganized, difficult to reach high-risk group, and an urban phenomenon. OBJECTIVES: To study the demographic profile and sexual behavior of bar girls. MATERIALS AND METHODS: Study setting is an urban slum area situated in the northwest part of Mumbai. Study design is a community-based cross sectional study. Study duration was from January 2003 to January 2005. Phase I: Identification of key informants was done. Phase II: Mapping of bar girls in the study area was done with the help of key informants. SAMPLING: Out of the estimated 800-1200 bar girls, 120 bar girls who were willing to participate in the study were included in the study after obtaining informed consent. Confidentiality of names and locations was assured to both key informants and study subjects. Information was gathered about demographic profile, educational status, and their sexual behavior by conducting one to one interview with the use of predesigned, pre-tested semi-structured questionnaire. RESULTS: Most of the bar girls were in the age group of 21-25 years 52 (43.3%). None of them were educated above secondary level. Most of the subjects belong to West Bengal state 58 (48.4%). Majority of the subjects 88 (73.3%) reported that they have ever practiced commercial sex, and money was the criteria of selection of customers 53 (60.22%). Condom usage was reported less with regular customer as compared with that of nonregular customers (chi(2) = 6.02, P < 0.02). CONCLUSIONS: Need to emphasize condom use with each and every sexual act irrespective of type of customers. PMID- 21687379 TI - Modeling of H1N1 Outbreak in Rajasthan: Methods and Approaches. AB - BACKGROUND: Mathematical models could provide critical insights for informing preparedness and planning to deal with future epidemics of infectious disease. OBJECTIVE: The study modeled the H1N1 epidemic in the city of Jaipur, Rajasthan using mathematical model for prediction of progression of epidemic and its duration. MATERIALS AND METHODS: We iterated the model for various values of R(0) to determine the effect of variations in R(0) onthe potential size and time course of the epidemic, while keeping value of 1/gamma constant. Further simulation using varying values of 1/gamma were done, keeping value of R(0) constant. We attempted to fit the actual reported data and compared with prediction models. RESULTS: As R(0) increases,incidence of H1N1 rises and reaches peak early. The duration of epidemic may be prolonged if R(0) is reduced. Using the parameters R(0) as 1.4 and 1/gamma as 3, it estimated that there would have been 656 actually infected individuals for each reported case. CONCLUSION: The mathematical modeling can be used for predicting epidemic progression and impact of control measures. Decreasing the value of R(0) would decrease the proportion of total population infected by H1N1; however, the duration of the outbreak may be prolonged. PMID- 21687380 TI - Evaluation of work place stress in health university workers: a study from rural India. AB - BACKGROUND: Healthcare providers being over-worked and under staffed are prone to poor mental health. Unhealthy work place compounds it further. AIMS: This study was aimed at to assess the mental health status of a medical university employee with special reference to work place stressors. SETTINGS AND DESIGN: A cross sectional study was designed and carried out at a Rural Health University. MATERIALS AND METHODS: Both the General Health Questionnaire (GHQ)-12 and Holmes Rahe Scale were used to evaluate 406 participants. STATISTICAL ANALYSIS: Multivariate analysis, correlation, and ANOVA by SPSS 11.0. RESULTS: The minimum age of the participant was 19 years and the maximum 64 years, with an average age at 35.09 years. On the GHQ scale 239(58.9%) recorded psychiatric morbidity out of which 201(49.5%) had moderate and 38(9.3%) severe morbidity. Doctors were the highest stressed group (P <= 0.04). Prominent work environmental stressors were poor departmental reorganization, lack of cohesiveness in department, difficult superiors and juniors (P <= 0.001, Pearson correlation). Stressors associated with work organization and work nature were: noninvolvement in departmental decision making and lack of proper feedback; along with; work load, lack of clarity in job, and a erratic work schedule (P <= 0.001 on Pearson correlation). Harassment, favoritism, discrimination, and lack of self-expression (P <= 0.003) were other factors responsible for work dissatisfaction. CONCLUSIONS: A high stress level was detected in the study population. The principal stressors were work environment related. Poor work culture was found to lead to job dissatisfaction among majority. PMID- 21687381 TI - Study of childhood obesity among school children aged 6 to 12 years in union territory of puducherry. AB - OBJECTIVE: To study the prevalence of obesity and overweight among school children in Puducherry. To identify any variation as per age, gender, place of residence and type of school. SETTING AND DESIGN: Secondary data analysis of a school-based cross sectional study in all the four regions of Puducherry. MATERIALS AND METHODS: Children between 6 and 12 yrs were sampled using multistage random sampling with population proportionate to size from 30 clusters. Anthropometric data (BMI) was analyzed using CDC growth charts. Data was analyzed using SPSS, BMI (CDC) calculator, CI calculator and OR calculator. RESULTS: The prevalence of overweight (>=85(th) percentile) among children was 4.41% and prevalence of obesity (>95(th) percentile) was 2.12%. Mahe region had the highest prevalence of overweight (8.66%) and obesity (4.69%). Female children from private schools and urban areas were at greater risk of being overweight and obese. CONCLUSIONS: Childhood obesity is a problem in Puducherry and requires timely intervention for its control. PMID- 21687382 TI - Cardiovascular Risk Behavior among Students of a Medical College in Delhi. AB - BACKGROUND: Life style related behavioural risk factors are mainly implicated for increased burden of cardio- vascular diseases. Research related to these risk behaviours especially among medical students is essential, considering their role as future physicians and role models in public health intervention programmes. OBJECTIVE: To evaluate the burden of cardiovascular risk behaviours among students of a medical college of Delhi, India. MATERIALS AND METHODS: A cross sectional study was carried out among undergraduate medical students of a medical college in Delhi. Self administered questionnaire was used to collect information on identification data and risk behaviours in relation to cardiovascular diseases. Binary logistic regression analysis was done to calculate adjusted odds ratio to assess association between risk behaviours and covariates. RESULTS: The minimum recommendation of taking at least five servings per day of fruits and vegetables was complied only by 12% of students. Consumption of carbonated soft drinks either once or more on daily basis was present in 23.7% students and 32.0% reported frequent consumption of fast foods in past week. Consumption of alcohol was present in 28.8% students but only small proportion of students (7%) was current tobacco users. Large proportions of students (42.6%) were either not carrying out or were involved in only occasional physical activity in past week. CONCLUSIONS: Unhealthy behavioural practises are present and may progress as student advance through medical college. Developing strategies targeting at these risk behaviours and determining factors is necessary to promote healthy life style among medical students. PMID- 21687383 TI - Study of cu T utilization status and some of the factors associated with discontinuation of cu T in rural part of yavatmal district. PMID- 21687384 TI - Reading Down of Section 377 of Indian Penal code is a Welcome Move for HIV Prevention and Control Among Men Having Sex with Men in India. PMID- 21687385 TI - Primary report on the risk factors affecting female infertility in South Indian districts of Tamil Nadu and kerala. PMID- 21687386 TI - A Study on Stroke and its Outcome in Young adults (15-45 Years) from coastal South India. PMID- 21687387 TI - Vibrio Cholerae O1 Ogawa Serotype outbreak in a village of Ambala district in Haryana, India. PMID- 21687388 TI - Current status of partial nephrectomy for renal mass. AB - The standard treatment for a small mass has shifted from radical nephrectomy to partial nephrectomy. The benefits of partial nephrectomy, including preserving renal function, prolonging overall survival, preventing postoperative chronic kidney disease, and reducing cardiovascular events, have been discussed in many studies. With the accumulation of surgeons' experience and simplification of the operative procedures, the warm ischemic time has become shorter despite the indication of tumor size becoming larger. With the help of intraoperative ultrasound, partial nephrectomy can be performed for an endophytic renal mass. Recently, laparoscopic partial nephrectomy has become well indicated for most renal tumors in many centers with advanced laparoscopic expertise. Open partial nephrectomy remains indicated for complex tumors. With technical innovation, robotic partial nephrectomy shows at least comparable perioperative outcomes with a benefit for challenging cases. Laparoendoscopic single-site partial nephrectomy has recently been tried in limited indications and seems to be feasible. PMID- 21687389 TI - Prognostic factors in transitional cell carcinoma of the upper urinary tract after radical nephroureterectomy. AB - PURPOSE: The aim of this study was to evaluate the prognostic factors for survival in patients treated surgically for transitional cell carcinoma of the upper urinary tract (UUT-TCC). MATERIALS AND METHODS: We retrospectively reviewed the medical records of 87 patients (64 men and 23 women, mean age of 62.2 years) with UUT-TCC who had undergone radical nephroureterectomy at our institution between June 1994 and June 2009. The median follow-up period was 32 months. The prognostic significance of various clinicopathological variables for recurrence free and cancer-specific survival was analyzed by using univariate and multivariate analysis. RESULTS: Of the total 87 patients, 21 patients (24.1%) developed local recurrence or distant metastasis and 16 patients (18.4%) died of disease during the follow-up period. The 5-year recurrence-free and cancer specific survival rates were 74.6% and 75.2%, respectively. In the univariate analysis, hydronephrosis, T stage, N stage, and lymphovascular invasion (LVI) were significant prognostic factors for recurrence-free and cancer-specific survival. In the multivariate analysis, T stage and LVI were independent prognostic factors for recurrence-free and cancer-specific survival. CONCLUSIONS: The T stage and LVI are independent prognostic factors for recurrence-free and cancer-specific survival in patients with UUT-TCC treated by radical nephroureterectomy. These findings would be helpful for guiding decisions about adjuvant therapies and the surveillance interval. PMID- 21687390 TI - Expression of claudin-1 and -7 in clear cell renal cell carcinoma and its clinical significance. AB - PURPOSE: We investigated the correlations between the expression of claudin-1 and claudin-7 in clear cell renal cell carcinoma (clear cell RCC) and clinical parameters. MATERIALS AND METHODS: The subjects of this study were 119 patients with confirmed clear cell RCC between January 2000 and December 2007. Their RCC tissues were immunohistochemically stained for claudin-1 and claudin-7. The correlations between the expression of claudin and parameters such as sex, age, body mass index (BMI), tumor size, TNM stage, Furhman nuclear grade, postoperative distant metastasis, and cancer-specific survival were analyzed. RESULTS: Among the total 119 subjects, claudin-1 was expressed in 18 (15.1%) and claudin- 7 in 31 (26.1%). Claudin-1 was expressed in patients who were older (p=0.007), who had a greater tumor size (p=0.001), who had a higher pathologic T stage (p=0.009), who had preoperative distant metastasis (p=0.035), and who had a higher Furhman nuclear grade (p=0.004). Claudin-7 was expressed only in patients who had a higher Furhman nuclear grade (p=0.031). The risk of postoperative distant metastasis was associated with the expression of claudin-1 (p<0.001) but not with the expression of claudin-7 (p=0.668). The expression of claudin-1 and 7 was not associated with cancer-specific survival (p>0.05). CONCLUSIONS: In clear cell RCC, claudin-1 was expressed in patients who were older and who had a greater tumor size, who had higher T or M stages, and who had a higher Furhman nuclear grade. The expression of claudin-1 was associated with a higher risk of postoperative distant metastasis. PMID- 21687391 TI - Effectiveness of an immediate mitomycin C instillation in patients with superficial bladder cancer receiving periodic mitomycin C instillation. AB - PURPOSE: We analyzed the impact of immediate intravesical mitomycin C instillation after transurethral resection of the bladder (TURB) on tumor recurrence and progression in patients with periodic mitomycin C instillation. MATERIALS AND METHODS: Between June 2000 and June 2006, a retrospective study was performed in a total of 115 patients with primary bladder tumors receiving a 6 week course of mitomycin C instillation after TURB. The patients were assigned to two groups: 53 patients in the immediate mitomycin C (I-MMC) group were treated by immediate instillation of mitomycin C after TURB and periodic instillation (6 times, 1 time per week), and 62 patients in the MMC group received only periodic instillation. Tumor recurrence and progression were compared in the two groups. RESULTS: During the mean follow-up period of 46.5 months in the I-MMC group and 47.2 months in the MMC group, early recurrence (within 1 year) occurred in 6 of 53 patients (11.3%) in the I-MMC group and in 18 of 62 patients (29.0%) in the MMC group (p<0.02). Although a significantly lower early recurrence rate was observed in the I-MMC group, this difference was not significant for recurrence within 2 or 3 years or for total recurrence. Progression was not significantly different between the two groups regarding the early and total period. CONCLUSIONS: Our study confirmed the positive effect of a single, immediate mitomycin C instillation in patients with non-muscle-invasive bladder tumors who received periodic mitomycin C instillation. This benefit was limited to early recurrence and was not maintained with long-term follow-up. This approach can be an alternative to periodic mitomycin C instillation without immediate instillation. PMID- 21687392 TI - Combined treatment with anticancer vaccine using genetically modified endothelial cells and imatinib in bladder cancer. AB - PURPOSE: We sought to maximize the antitumor effect of an anticancer vaccine based on genetically modified endothelial cells by combining it with the platelet derived growth factor receptor inhibitor imatinib. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were infected with 10 MOI of Ad-CMV mGMCSF to make anticancer vaccines. One million mouse bladder cancer cells (MBT 2) were subcutaneously inoculated in C3H mice. The experimental groups included the following: Group 1 (phosphate-buffered saline), Group 2 (anticancer vaccine and GM-CSF), Group 3 (imatinib), and Group 4 (anticancer vaccine, GM-CSF, and imatinib). Tumor growth and body weight were measured weekly. At 4 weeks, the tumors were immunostained with anti-CD31, and microvessel density (MVD) was measured. To evaluate the immunological mechanism of each treatment, flow cytometry analysis of activated CD4 and CD8 cells was performed. RESULTS: At 4 weeks, the mean body weight of each group, excluding the extracted tumor weight, was not significantly different. Since week 3, the mean tumor volume in Group 4 was the smallest among the treatment groups (p<0.05), and a synergistic suppressive effect on tumor volume was observed in Group 4. The MVD in Group 4 was the most suppressed among the treatment groups (p<0.05), and a synergistic anti-angiogenic effect was observed. Flow cytometry analysis revealed that activated CD4+ and CD8+ cells increased in Group 2 and decreased in Group 3 compared with the other groups. CONCLUSIONS: The combination of genetically modified endothelial cell vaccines and imatinib showed a synergistic antiangiogenic effect in bladder cancer. PMID- 21687393 TI - Efficacy and safety of the TVT-SECUR(r) and impact on quality of life in women with stress urinary incontinence: a 2-year follow-up. AB - PURPOSE: As recently reported, the short-term results of the tension-free vaginal tape SECUR(r) (TVT-S) procedure seem to be similar to those of the conventional transobturator tape (TOT) procedure. However, results of efficacy and satisfaction with TVT-S are insufficient in patients with more than 1 year of follow-up. Therefore, we evaluated the results of the TVT-S procedure in women with stress urinary incontinence (SUI) during 2 years. MATERIALS AND METHODS: We evaluated 51 patients with clinical and urodynamic diagnoses of SUI who underwent the TVT-S procedure from March 2008 to February 2009. Preoperative evaluation included a history, cough stress test with full bladder, urodynamic study, and incontinence quality of life (I-QoL) questionnaire. Following the postoperative period, urinary incontinence status was examined through a physical examination and the I-QoL questionnaire was completed in an outpatient setting or by telephone. RESULTS: Data from 2 years of follow-up were available for 46 of 51 patients. The cure rate was 80.4% at 1 month after TVT-S and 76.0% at 2 years after TVT-S. The cure or improvement rate was 93.5% at 1 month after TVT-S and 86.8% at 2 years after TVT-S. The mean total I-QoL score increased by 42 points at 1 month after TVT-S (p<0.026) and by 32 points at 2 years after TVT-S (p<0.013). Most patients reported significant improvements in quality of life. At the 2-year follow-up, there were no significant complications related to TVT-S. CONCLUSIONS: The results of this study suggest that TVT-S is an efficient and safe procedure for the improvement of both the quality of life of the patients and the SUI itself. PMID- 21687394 TI - Interleukin-1beta, calcium-sensing receptor, and urokinase gene polymorphisms in korean patients with urolithiasis. AB - PURPOSE: There are various causes of ureter calculi, and genetic factors are known to play a role. Interleukin-1beta (IL-1beta) and calcium-sensing receptor (CaSR) genes are related to hypercalciuria, and urokinase is related to the formation of calcium oxalate stones. This study investigated polymorphisms in IL 1beta, CaSR, and urokinase in patients with urolithiasis and healthy controls. MATERIALS AND METHODS: Urolithiasis patients treated at Chung-Ang University Hospital were enrolled from January 2007 to December 2008. The control group of volunteers displayed normal urinalysis findings in the health screening, no stones identified by ultrasonography, and no history of urolithiasis. DNA extracted from peripheral blood was analyzed by the polymerase chain reaction. Patients were genetically screened for mutations in IL-1beta (484 urolithiasis patients, 208 controls), CaSR (433 urolithiasis patients, 197 controls), and urokinase (370 urolithiasis patients, 167 controls). Stone metabolic study was done to see the differences between the metabolic factors and to discern normal genes from polymorphic genes. RESULTS: According to the genotype frequency and allele frequency analysis, there were no statistically significant differences between IL-1beta, CaSR, and urokinase genes. Also, the analysis between genotypes and metabolic factors did not show statistically significant differences between the three genes. CONCLUSIONS: In Korean urolithiasis patients, IL-1beta, CaSR, and urokinase gene polymorphisms do not differ from those of healthy individuals. A larger-scale study is needed to confirm the need for other genetic markers of urolithiasis. PMID- 21687395 TI - Results of urine culture and antimicrobial sensitivity tests according to the voiding method over 10 years in patients with spinal cord injury. AB - PURPOSE: We studied the results of urine cultures and antimicrobial sensitivity tests according to the voiding method used by spinal cord injury (SCI) patients over a recent 10-year period. MATERIALS AND METHODS: We retrospectively analyzed 1,236 urine samples and their antimicrobial sensitivity tests for 112 patients who had used only one voiding method between January 2000 and December 2009. The voiding methods were classified into four groups: clean intermittent catheterization (CIC), suprapubic catheterization, urethral Foley catheter, and spontaneous voiding. RESULTS: Of the 1,236 urine samples, 925 (74.8%) were positive and 279 (30.2%) had more than one bacteria. The CIC group showed the lowest rate of bacteriuria, colony counts, and polymicrobial infection (p<0.001). Causative organisms were mostly Gram-negative bacteria (84%), including Pseudomonas aeruginosa (22.9%), Escherichia coli (21.1%), Klebsiella species (6.7%), and Citrobacter species (6.3%). The rate of Gram-positive bacterial infection was 13.6%, and major pathogenic organisms were Streptococcus species (8.6%) and Staphylococcus species (2.6%). Major pathogenic organisms and the results of antimicrobial sensitivity tests differed according to the voiding method. CONCLUSIONS: Although the patient's condition and preferences are important when choosing the method of bladder management, CIC is the best voiding method for reducing urinary tract infections in SCI patients. When immediate use of antibiotics is needed for treatment of urinary tract infections, an appropriate antibiotic can be chosen according to the voiding method on the basis of our study and can be administered before the results of an antimicrobial sensitivity test are available. PMID- 21687396 TI - Does bicycle riding impact the development of lower urinary tract symptoms and sexual dysfunction in men? AB - PURPOSE: This study was designed to determine whether men who engaged in recreational bicycle riding are more likely to be affected by lower urinary tract symptoms (LUTS) and sexual dysfunction than are man who exercised by amateur marathon running with less perineal impact. MATERIALS AND METHODS: A total of 22 healthy male amateur bicyclists and 17 healthy male amateur marathoners were enrolled in the study. We evaluated questionnaires including the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF), serum prostate-specific antigen (PSA), uroflowmetric values, postvoid residual (PVR) urine volume, and transrectal ultrasound of the prostate in all subjects. We also compared the prevalence of urination disorders (UD) and erectile dysfunction (ED). RESULTS: There were no significant differences between the two groups in age, body mass index, comorbidities, or exercise habits (p>0.05). Mean total and subscale scores of the IPSS and IIEF and the prevalence of UD (8/22 vs. 4/17, p=0.494) and ED (11/22 vs. 10/17, p=0.748) were not significantly different between the two groups. Also, there were no significant differences between the two groups in uroflowmetric parameters such as peak urinary flow rates, voided urine volume, PVR urine volume, prostate volume, or serum PSA level. CONCLUSIONS: Bicycle riding seems to have no measurable hazardous effect on voiding function or sexual function in men who cycled recreationally. PMID- 21687397 TI - Diagnostic laparoscopy for the management of impalpable testes. AB - PURPOSE: Controversy exists regarding the best approach to impalpable testes. We determined the usefulness of diagnostic laparoscopy for the management of impalpable testes. MATERIALS AND METHODS: Between 2000 and 2008, 86 patients with a mean age of 34 months underwent diagnostic laparoscopy. An inguinal canal exploration was performed in all cases, except in patients in whom the internal spermatic vessels terminated intraperitoneally with a blind end. RESULTS: The undescended testis was right-sided in 24 patients (27.9%), left-sided in 47 patients (54.7%), and bilateral in 15 patients (17.4%). Three patients (3.5%) had bilateral impalpable testes. The vas and vessels traversed the internal ring in 51 of 89 impalpable testes (57.3%); 20 (22.5%) were localized intraperitoneally, and 18 (20.2%) were diagnosed as vanishing testes. Open orchiopexies were performed on 24 testes (27.0%) and orchiectomies were performed on 43 nubbin testes (48.3%). After a mean follow-up period of 30 months, 12 of the 14 testes (85.7%) were viable following open conventional orchiopexy, compared with 6 of the 10 testes (60%) following a 1-stage Fowler-Stephens orchiopexy. CONCLUSIONS: Diagnostic laparoscopy is a very helpful and minimally invasive technique in the diagnosis of impalpable testes, especially when preoperative ultrasonography is not sufficiently informative. PMID- 21687398 TI - Transplantation of muscle-derived stem cells into the corpus cavernosum restores erectile function in a rat model of cavernous nerve injury. AB - PURPOSE: Muscle-derived stem cells (MDSCs) harvested from skeletal muscles have the advantage of providing easier access and do not pose the immunogenic risks of embryonic stem cells. We investigated the effect of intracavernosal transplantation of MDSCs on erectile function in rats with bilateral cavernous nerve injury. MATERIALS AND METHODS: Adult male white rats underwent experimentation in 3 groups: group I, sham operation; group II, bilateral cavernous nerve injury; group III, bilateral cavernous nerve injury with MDSC injection. MDSCs were harvested from the femoral muscle of rats and were then injected into the cavernosum. Survival of MDSCs and measurement of erectile function was studied after 4 weeks. We checked the intracavernosal pressure (ICP) and obtained penile tissue. The expression of cyclic guanosine monophosphate (cGMP) was analyzed. RESULTS: Four weeks after transplantation, PKH-26-labeled MDSCs were identified in the cavernosal tissues of group III. Peak ICP and the drop rate of group II were 52+/-8.7 mmHg and 34+/-6.5 mmHg/min, respectively, whereas peak ICP and the drop rate of group III were 97+/-15.6 mmHg and 17+/-4.9 mmHg/min, respectively, showing that erectile function improved after MDSC transplantation (p<0.05). The expression of cGMP was significantly lower in group II (21.9+/-5.8 fmol/well) than in group I and group III (70.2+/-10.3 and 58.9+/ 10.5 fmol/well, respectively). CONCLUSIONS: In a cavernous nerve injury rat model, intracavernosal transplantation of MDSCs showed acceptable survival of MDSCs as well as improvement of erectile function. PMID- 21687399 TI - Polyarteritis nodosa presenting with bilateral testicular swelling and complicated by unilateral facial nerve palsy. AB - Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that is generally restricted to medium-sized vessels. Here we describe the first case of a patient in which a bilateral testicular mass was a presenting symptom and the diagnosis was made on the basis of testicular histopathology. A 53-year-old Asian man presented with a history of constitutional symptoms and testicular swelling. Scrotal ultrasound revealed two avascular, bilateral, intratesticular lesions. The bilateral testicular abscess was treated without improvement. The patient developed left seventh cranial nerve palsy during his admission. The clinical changes made vasculitis or a related disorder more likely and the patient underwent a right testicular biopsy. Histopathology demonstrated features of transmural inflammation and fibrinoid necrosis of medium-sized vessel walls, consistent with PAN. This case illustrates the difficulty in diagnosing polyarteritis nodosa with isolated bilateral testicular swelling and the delay in the diagnosis. After 9 months of follow-up, no relapse had occurred and the patient's testosterone level was on the lower side of normal. PMID- 21687400 TI - Isolated congenital urethrocutaneous fistula of the anterior urethra. AB - Isolated congenital urethrocutaneous fistula of the anterior urethra is an extremely rare anomaly in which, along with a normal urethra and meatus, a fistula is present. These cases usually present in the pediatric age group. To date, only one such case has been described in the adult population. We describe one such case in an adult and discuss the management of this uncommon anomaly. PMID- 21687402 TI - Inflammasomes: caspase-1-activating platforms with critical roles in host defense. AB - Activation of the inflammatory cysteine protease caspase-1 in inflammasome complexes plays a critical role in the host response to microbial infections. Inflammasome activation induces inflammation through secretion of the pro inflammatory cytokines interleukin (IL)-1beta and IL-18 and through extracellular release of the alarmin high mobility group box 1. Moreover, caspase-1 activation by inflammasomes counters bacterial replication and induces pyroptosis, a specialized cell death program that removes infected immune cells as part of the host defense system. It is thus not surprising that bacterial and viral pathogens evolved virulence factors targeting inflammasome activation and activity. Here, we provide an overview of the distinct inflammasome complexes that are activated in a pathogen-specific manner and discuss the diverse strategies employed by viruses and bacteria to modulate inflammasome function. PMID- 21687401 TI - Mycobacterium Tuberculosis Infection and Inflammation: what is Beneficial for the Host and for the Bacterium? AB - Tuberculosis is still a major health problem in the world. Initial interactions between Mycobacterium tuberculosis and the host mark the pathway of infection and the subsequent host inflammatory response. This inflammatory response is tightly regulated by both the host and the bacterium during different stages of infection. As infection progresses, the initial intense pro-inflammatory response observed is regulated by suppressive mediators balancing inflammation. In this environment, M. tuberculosis battles to survive interfering with the host inflammatory response. In this review we discuss the major effector molecules involved in inflammation in relation to the different stages of M. tuberculosis infection. PMID- 21687403 TI - Epstein-barr virus, the immune system, and associated diseases. AB - Host immune system is designed (or evolved) to fight against different pathogens. Many viruses infect the immune cells for the propagation of new progenies, thus the infection may modulate the host immune homeostasis. It has been more than 45 years since the discovery of Epstein-Barr virus (EBV) from a Burkitt's lymphoma derived cell line. The ability of EBV to transform primary B cells in vitro leads to the suggestion for its oncogenic potential. However, except the clear understanding of the role of EBV in post-transplantation lymphoproliferative disease, it remains ambiguous why such a ubiquitous virus causes malignant diseases only in a very small subset of individuals. Possible explanation is that EBV may cooperate with other environmental and host genetic factors and lead to the development of EBV associated neoplastic diseases. In addition to infecting B cells, recent studies revealed that EBV may impact host immune system more broadly than previously thought, for example the development of regulatory NKT subsets. Instead of an intensive review, this article aims to provide a linkage to recent advances on the interplay between EBV and host immune system and to inspire further studies on EBV related diseases, especially autoimmune diseases. PMID- 21687404 TI - Taking Out TB-Lysosomal Trafficking and Mycobactericidal Ubiquitin-Derived Peptides. AB - Tuberculosis remains a significant global health concern. The hallmark of Mycobacterium tuberculosis pathogenicity is its ability to infect resting macrophages and establish an intracellular niche. Activated and autophagic macrophages control mycobacterial infections through bactericidal mechanisms ranging from reactive oxygen and nitrogen intermediates to the delivery of the bacterium to the acidified, hydrolytically active lysosome. The mycobactericidal activity of the lysosome is due in part to the action of ubiquitin-derived peptides (Ub-peptides). In this review we discuss the trafficking events that result in delivery M. tuberculosis to the lysosome, the source and lysosomal generation of Ub-peptides and their role in macrophage control of M. tuberculosis infection. PMID- 21687405 TI - Role of inflammasomes in salmonella infection. AB - Pattern recognition receptors (PRRs) play a crucial role in both the detection of pathogens and the activation of the innate immune system. Nod-like receptors (NLR) family members are cytosolic PRRs that sense bacterial products or endogenous danger signals. Recent evidence suggests that NLRs contribute to the detection of Salmonella through the activation of inflammasomes, molecular platforms that promotes the maturation of the proinflammatory cytokines IL-1beta and IL-18. During enteric Salmonella infection the activation of caspase-1 and the production of IL-1beta and IL-18 result in a protective host response. In macrophages, the activation of caspase-1 induced by Salmonella is mainly mediated by the NLR family member NLRC4 that senses cytosolic flagellin. Recent data suggest that an effective innate immune response against Salmonella requires the engagement of multiple inflammasomes in both hematopoietic and non-hematopoietic cell lineages. Further understanding of the innate immune response mediated by inflammasomes should provide new insights into the mechanisms of host defense and the pathogenesis of inflammatory diseases. PMID- 21687406 TI - The subversion of the immune system by francisella tularensis. AB - Francisella tularensis is a highly virulent bacterial pathogen and the causative agent of tularemia. Perhaps the most impressive feature of this bacterium is its ability to cause lethal disease following inoculation of as few as 15 organisms. This remarkable virulence is, in part, attributed to the ability of this microorganism to evade, disrupt, and modulate host immune responses. The objective of this review is to discuss the mechanisms utilized by F. tularensis to evade and inhibit innate and adaptive immune responses. The capability of F. tularensis to interfere with developing immunity in the host was appreciated decades ago. Early studies in humans were the first to demonstrate the ability of F. tularensis to suppress innate immunity. This work noted that humans suffering from tularemia failed to respond to a secondary challenge of endotoxin isolated from unrelated bacteria. Further, anecdotal observations of individuals becoming repeatedly infected with virulent strains of F. tularensis suggests that this bacterium also interferes with the generation of adequate adaptive immunity. Recent advances utilizing the mouse model for in vivo studies and human cells for in vitro work have identified specific bacterial and host compounds that play a role in mediating ubiquitous suppression of the host immune response. Compilation of this work will undoubtedly aid in enhancing our understanding of the myriad of mechanisms utilized by virulent F. tularensis for successful infection, colonization, and pathogenesis in the mammalian host. PMID- 21687407 TI - Francisella Recognition by Inflammasomes: Differences between Mice and Men. AB - Pathogen recognition by intracellular sensors involves the assembly of a caspase 1 activation machine termed the inflammasome. Intracellular pathogens like Francisella that gain access to the cytosolic detection systems are useful tools to uncover the details of caspase-1 activation events. This review overviews Francisella function in the mononuclear phagocyte with particular attention to inflammasome versus pyroptosome roles and outlines differences between mouse and human caspase-1 activation pathways. Specific attention is placed on functional differences between human and murine pyrin as an intracellular recognition molecule for Francisella. PMID- 21687408 TI - Role of the nlrp3 inflammasome in microbial infection. AB - The intracellular Nod-like receptor Nlrp3 has emerged as the most versatile innate immune receptor because of its broad specificity in mediating immune response to a wide range of microbial or danger signals. Nlrp3 mediates assembly of the inflammasome complex in the presence of microbial components leading to the activation of caspase-1 and the processing and release of the pro inflammatory cytokines IL-1beta and IL-18. In this review, we give an update on the recent literature examining the role of Nlrp3 inflammasome in response to fungal, bacterial, and viral infections. PMID- 21687409 TI - Chlamydia trachomatis secretion of proteases for manipulating host signaling pathways. AB - The human pathogen Chlamydia trachomatis secretes numerous effectors into host cells in order to successfully establish and complete the intracellular growth cycle. Three C. trachomatis proteases [chlamydial proteasome/protease-like activity factor (CPAF), tail-specific protease (Tsp), and chlamydial high temperature requirement protein A (cHtrA)] have been localized in the cytosol of the infected cells either by direct immunofluorescence visualization or functional implication. Both CPAF and Tsp have been found to play important roles in C. trachomatis interactions with host cells although the cellular targets of cHtrA have not been identified. All three proteases contain a putative N-terminal signal sequence, suggesting that they may be secreted via a sec-dependent pathway. However, these proteases are also found in chlamydial organism-free vesicles in the lumen of the chlamydial inclusions before they are secreted into host cell cytosol, suggesting that these proteases may first be translocated into the periplasmic region via a sec-dependent pathway and then exported outside of the organisms via an outer membrane vesicles (OMVs) budding mechanism. The vesiculized proteases in the inclusion lumen can finally enter host cell cytosol via vesicle fusing with or passing through the inclusion membrane. Continuing identification and characterization of the C. trachomatis-secreted proteins (CtSPs) will not only promote our understanding of C. trachomatis pathogenic mechanisms but also allow us to gain novel insights into the OMV pathway, a well known mechanism used by bacteria to export virulence factors although its mechanism remains elusive. PMID- 21687410 TI - Innate immune recognition of francisella tularensis: activation of type-I interferons and the inflammasome. AB - Francisella tularensis is an intracellular pathogen that can cause severe disease in a wide range of mammalian hosts. Primarily residing in host macrophages, F. tularensis escapes phagosomal degradation, and replicates in the macrophage cytosol. The macrophage uses a series of pattern recognition receptors to detect conserved microbial molecules from invading pathogens, and initiates an appropriate host response. In the cytosol, F. tularensis is recognized by the inflammasome, a multiprotein complex responsible for the activation of the cysteine protease caspase-1. Caspase-1 activation leads to processing and release of proinflammatory cytokines and host cell death. Here we review recent work on the molecular mechanisms of inflammasome activation by F. tularensis, and its consequences both in vitro and in vivo. Finally, we discuss the coordination between the inflammasome and other cytosolic host responses, and the evidence for F. tularensis virulence factors that suppress inflammasome activation. PMID- 21687411 TI - Sulfur metabolism in the extreme acidophile acidithiobacillus caldus. AB - Given the challenges to life at low pH, an analysis of inorganic sulfur compound (ISC) oxidation was initiated in the chemolithoautotrophic extremophile Acidithiobacillus caldus. A. caldus is able to metabolize elemental sulfur and a broad range of ISCs. It has been implicated in the production of environmentally damaging acidic solutions as well as participating in industrial bioleaching operations where it forms part of microbial consortia used for the recovery of metal ions. Based upon the recently published A. caldus type strain genome sequence, a bioinformatic reconstruction of elemental sulfur and ISC metabolism predicted genes included: sulfide-quinone reductase (sqr), tetrathionate hydrolase (tth), two sox gene clusters potentially involved in thiosulfate oxidation (soxABXYZ), sulfur oxygenase reductase (sor), and various electron transport components. RNA transcript profiles by semi quantitative reverse transcription PCR suggested up-regulation of sox genes in the presence of tetrathionate. Extensive gel based proteomic comparisons of total soluble and membrane enriched protein fractions during growth on elemental sulfur and tetrathionate identified differential protein levels from the two Sox clusters as well as several chaperone and stress proteins up-regulated in the presence of elemental sulfur. Proteomics results also suggested the involvement of heterodisulfide reductase (HdrABC) in A. caldus ISC metabolism. A putative new function of Hdr in acidophiles is discussed. Additional proteomic analysis evaluated protein expression differences between cells grown attached to solid, elemental sulfur versus planktonic cells. This study has provided insights into sulfur metabolism of this acidophilic chemolithotroph and gene expression during attachment to solid elemental sulfur. PMID- 21687412 TI - An optimal method of iron starvation of the obligate intracellular pathogen, Chlamydia trachomatis. AB - Iron is an essential cofactor in a number of critical biochemical reactions, and as such, its acquisition, storage, and metabolism is highly regulated in most organisms. The obligate intracellular bacterium, Chlamydia trachomatis experiences a developmental arrest when iron within the host is depleted. The nature of the iron starvation response in Chlamydia is relatively uncharacterized because of the likely inefficient method of iron depletion, which currently relies on the compound deferoxamine mesylate (DFO). Inefficient induction of the iron starvation response precludes the identification of iron-regulated genes. This report evaluated DFO with another iron chelator, 2,2'-bipyridyl (Bpdl) and presented a systematic comparison of the two across a range of criteria. We demonstrate that the membrane permeable Bpdl was superior to DFO in the inhibition of chlamydia development, the induction of aberrant morphology, and the induction of an iron starvation transcriptional response in both host and bacteria. Furthermore, iron starvation using Bpdl identified the periplasmic iron binding protein-encoding ytgA gene as iron-responsive. Overall, the data present a compelling argument for the use of Bpdl, rather than DFO, in future iron starvation studies of chlamydia and other intracellular bacteria. PMID- 21687413 TI - Chlamydia Pneumoniae CdsL Regulates CdsN ATPase Activity, and Disruption with a Peptide Mimetic Prevents Bacterial Invasion. AB - Chlamydiae are obligate intracellular pathogens that likely require type III secretion (T3S) to invade cells and replicate intracellularly within a cytoplasmic vacuole called an inclusion body. Chlamydia pneumoniae possess a YscL ortholog, CdsL, that has been shown to interact with the T3S ATPase (CdsN). In this report we demonstrate that CdsL down-regulates CdsN enzymatic activity in a dose-dependent manner. Using Pepscan epitope mapping we identified two separate binding domains to which CdsL binds viz. CdsN(221-229) and CdsN(265-270). We confirmed the binding domains using a pull-down assay and showed that GST CdsN(221-270), which encompasses these peptides, co-purified with His-CdsL. Next, we used orthology modeling based on the crystal structure of a T3S ATPase ortholog from Escherichia coli, EscN, to map the binding domains on the predicted 3D structure of CdsN. The CdsL binding domains mapped to the catalytic domain of the ATPase, one in the central channel of the ATPase hexamer and one on the outer face. Since peptide mimetics have been used to disrupt essential protein interactions of the chlamydial T3S system and inhibit T3S-mediated invasion of HeLa cells, we hypothesized that if CdsL-CdsN binding is essential for regulating T3S then a CdsN peptide mimetic could be used to potentially block T3S and chlamydial invasion. Treatment of elementary body with a CdsN peptide mimetic inhibited C. pneumoniae invasion into HeLa cells in a dose-dependent fashion. This report represents the first use of Pepscan technology to identify binding domains for specific T3S proteins viz. CdsL on the ATPase, CdsN, and demonstrates that peptide mimetics can be used as anti-virulence factors to block bacterial invasion. PMID- 21687415 TI - Molecular Characterization of Exploitation of the Polyubiquitination and Farnesylation Machineries of Dictyostelium Discoideum by the AnkB F-Box Effector of Legionella Pneumophila. AB - The Dot/Icm-translocated Ankyrin B (AnkB) F-box effector of Legionella pneumophila is essential for intra-vacuolar proliferation and functions as a platform for the docking of polyubiquitinated proteins to the Legionella containing vacuole (LCV) within macrophages and ameba. Here we show that ectopically expressed AnkB in Dictyostelium discoideum is targeted to the plasma membrane where it recruits polyubiquitinated proteins and it trans-rescues the intracellular growth defect of the ankB null mutant, which has never been demonstrated for any effector in ameba. Using co-immunoprecipitation and bimolecular fluorescence complementation we show specific interaction of Skp1 of D. discoideum with the F-box domain of AnkB, which has never been demonstrated in ameba. We show that anchoring of AnkB to the cytosolic face of the LCV membrane in D. discoideum is mediated by the host farnesylation of the C-terminal eukaryotic CaaX motif of AnkB and is independent of the F-box and the two ANK domains, which has never been demonstrated in ameba. Importantly, the three host farnesylation enzymes farnesyl transferase, RCE-1, and isoprenyl cysteine carboxyl methyl transferase of D. discoideum are recruited to the LCV in a Dot/Icm-dependent manner, which has never been demonstrated in ameba. We conclude that the polyubiquitination and farnesylation enzymatic machineries of D. discoideum are recruited to the LCV in a Dot/Icm-dependent manner and the AnkB effector exploits the two evolutionarily conserved eukaryotic machineries to proliferate within ameba, similar to mammalian cells. We propose that L. pneumophila has acquired ankB through inter-kingdom horizontal gene transfer from primitive eukaryotes, which facilitated proliferation of L. pneumophila within human cells and the emergence of Legionnaires' disease. PMID- 21687414 TI - Quinolone resistance: much more than predicted. AB - Since quinolones are synthetic antibiotics, it was predicted that mutations in target genes would be the only mechanism through which resistance could be acquired, because there will not be quinolone-resistance genes in nature. Contrary to this prediction, a variety of elements ranging from efflux pumps, target-protecting proteins, and even quinolone-modifying enzymes have been shown to contribute to quinolone resistance. The finding of some of these elements in plasmids indicates that quinolone resistance can be transferable. As a result, there has been a developing interest on the reservoirs for quinolone-resistance genes and on the potential risks associated with the use of these antibiotics in non-clinical environments. As a matter of fact, plasmid-encoded, quinolone resistance qnr genes originated in the chromosome of aquatic bacteria. Thus the use of quinolones in fish-farming might constitute a risk for the emergence of resistance. Failure to predict the development of quinolone resistance reinforces the need of taking into consideration the wide plasticity of biological systems for future predictions. This plasticity allows pathogens to deal with toxic compounds, including those with a synthetic origin as quinolones. PMID- 21687417 TI - Molecular, epidemiological, and clinical complexities of predicting patterns of infectious diseases. PMID- 21687416 TI - Global proteomic analysis of two tick-borne emerging zoonotic agents: anaplasma phagocytophilum and ehrlichia chaffeensis. AB - Anaplasma phagocytophilum and Ehrlichia chaffeensis are obligatory intracellular alpha-proteobacteria that infect human leukocytes and cause potentially fatal emerging zoonoses. In the present study, we determined global protein expression profiles of these bacteria cultured in the human promyelocytic leukemia cell line, HL-60. Mass spectrometric (MS) analyses identified a total of 1,212 A. phagocytophilum and 1,021 E. chaffeensis proteins, representing 89.3 and 92.3% of the predicted bacterial proteomes, respectively. Nearly all bacterial proteins (>=99%) with known functions were expressed, whereas only approximately 80% of "hypothetical" proteins were detected in infected human cells. Quantitative MS/MS analyses indicated that highly expressed proteins in both bacteria included chaperones, enzymes involved in biosynthesis and metabolism, and outer membrane proteins, such as A. phagocytophilum P44 and E. chaffeensis P28/OMP-1. Among 113 A. phagocytophilum p44 paralogous genes, 110 of them were expressed and 88 of them were encoded by pseudogenes. In addition, bacterial infection of HL-60 cells up-regulated the expression of human proteins involved mostly in cytoskeleton components, vesicular trafficking, cell signaling, and energy metabolism, but down-regulated some pattern recognition receptors involved in innate immunity. Our proteomics data represent a comprehensive analysis of A. phagocytophilum and E. chaffeensis proteomes, and provide a quantitative view of human host protein expression profiles regulated by bacterial infection. The availability of these proteomic data will provide new insights into biology and pathogenesis of these obligatory intracellular pathogens. PMID- 21687419 TI - Vaccination with Human Induced Pluripotent Stem Cells Creates an Antigen-Specific Immune Response Against HIV-1 gp160. AB - Induced pluripotent stem cells (iPSCs) are artificially derived from somatic cells that have been transduced with defined reprogramming factors. A previous report has indicated the possibility of using iPSCs as an immune stimulator to generate antigen-specific immunity. In our current study, we have investigated whether human iPSCs (hiPSCs) have the ability to enhance specific immune response against a human immunodeficiency virus type 1 (HIV-1) antigen in a xenogenic mouse model. Our results show that BALB/c mice immunized with hiPSCs transduced with an adenoviral vector encoding HIV-1 gp160 exhibited prominent antigen specific cellular immune responses. We further found that pre-treatment of hiPSCs with ionizing radiation promotes the secretion of pro-inflammatory cytokines such as interleukin-1 alpha (IL-1alpha), IL-12, and IL-18. These cytokines might promote the activation of antigen-presenting cells and the effective induction of cellular immunity. Our present findings thus demonstrate that a hiPSCs-based vaccine has the potential to generate cellular immunity against viral antigens such as HIV-1 gp160 in a xenogenic condition. PMID- 21687420 TI - Commentary on Immune System Associated Diseases Caused by Viruses: The Role of EBV. PMID- 21687418 TI - Immunity to Francisella. AB - In recent years, studies on the intracellular pathogen Francisella tularensis have greatly intensified, generating a wealth of new information on the interaction of this organism with the immune system. Here we review the basic elements of the innate and adaptive immune responses that contribute to protective immunity against Francisella species, with special emphasis on new data that has emerged in the last 5 years. Most studies have utilized the mouse model of infection, although there has been an expansion of work on human cells and other new animal models. In mice, basic immune parameters that operate in defense against other intracellular pathogen infections, such as interferon gamma, TNF-alpha, and reactive nitrogen intermediates, are central for control of Francisella infection. However, new important immune mediators have been revealed, including IL-17A, Toll-like receptor 2, and the inflammasome. Further, a variety of cell types in addition to macrophages are now recognized to support Francisella growth, including epithelial cells and dendritic cells. CD4(+) and CD8(+) T cells are clearly important for control of primary infection and vaccine induced protection, but new T cell subpopulations and the mechanisms employed by T cells are only beginning to be defined. A significant role for B cells and specific antibodies has been established, although their contribution varies greatly between bacterial strains of lower and higher virulence. Overall, recent data profile a pathogen that is adept at subverting host immune responses, but susceptible to many elements of the immune system's antimicrobial arsenal. PMID- 21687422 TI - Targeting One of its Own: Expanding Roles of Substrates of the Legionella Pneumophila Dot/Icm Type IV Secretion System. PMID- 21687421 TI - Type IV Pili in Francisella - A Virulence Trait in an Intracellular Pathogen. AB - Francisella tularensis is a highly virulent intracellular human pathogen that is capable of rapid proliferation in the infected host. Mutants affected in intracellular survival and growth are highly attenuated which highlights the importance of the intracellular phase of the infection. Genomic analysis has revealed that Francisella encodes all genes required for expression of functional type IV pili (Tfp), and in this focused review we summarize recent findings regarding this system in the pathogenesis of tularemia. Tfp are dynamic adhesive structures that have been identified as major virulence determinants in several human pathogens, but it is not obvious what role these structures could have in an intracellular pathogen like Francisella. In the human pathogenic strains, genes required for secretion and assembly of Tfp and one pilin, PilA, have shown to be required for full virulence. Importantly, specific genetic differences have been identified between the different Francisella subspecies where in the most pathogenic type A variants all genes are intact while several Tfp genes are pseudogenes in the less pathogenic type B strains. This suggests that there has been a selection for expression of Tfp with different properties in the different subspecies. There is also a possibility that the genetic differences reflect adaptation to different environmental niches of the subspecies and plays a role in transmission of tularemia. This is also in line with recent findings where Tfp pilins are found to be glycosylated which could reflect a role for Tfp in the environment to promote survival and transmission. We are still far from understanding the role of Tfp in virulence and transmission of tularemia, but with the genomic information and genetic tools available we are in a good position to address these issues in the future. PMID- 21687424 TI - The Nlrc4 Inflammasome Contributes to Restriction of Pulmonary Infection by Flagellated Legionella spp. that Trigger Pyroptosis. AB - The Nlrc4 inflammasome is triggered in response to contamination of the host cell cytoplasm with bacterial flagellin, which induces pyroptosis, a form of cell death that accounts for restriction of bacterial infections. Although induction of pyroptosis has been extensively investigated in response to Salmonella typhimurium and Legionella pneumophila, little is known regarding the role of the inflammasome for restriction of non-pneumophila Legionella species. Here, we used five species of the Legionella genus to investigate the importance of the inflammasome for restriction of bacterial infection in vivo. By infecting mice deficient for inflammasome components, we demonstrated that caspase-1 and Nlrc4, but not Asc, contribute to restriction of pulmonary infection with L. micdadei, L. bozemanii, L. gratiana, and L. rubrilucens. L. longbeachae, a non-flagellated bacterium that fails to trigger pyroptosis, was not restricted by the inflammasome and induced death in the infected mice. In contrast to L. longbeachae, flagellin mutants of L. pneumophila did not induce mice death; therefore, besides bypassing the Nlrc4 inflammasome, L. longbeachae may employ additional virulence strategies to replicate in mammalian hosts. Collectively, our data indicate that the Nlrc4 inflammasome plays an important role in host protection against opportunistic pathogenic bacteria that express flagellin. PMID- 21687423 TI - Internalization of Escherichia coli o157:h7 by bovine rectal epithelial cells. AB - Escherichia coli O157:H7 (O157) causes human diarrheal disease and healthy cattle are its primary reservoir. O157 colonize the bovine epithelial mucosa at the recto-anal junction (RAJ). Previous studies show that O157 at this site are not eliminated by aggressive interventions including applications of O157-specific lytic bacteriophages and other bactericidal agents. We hypothesize that some O157 at the RAJ mucosa are protected from these killing agents by host cell internalization. To test this hypothesis, rectal biopsies from O157 culture positive and negative cattle were analyzed by fluorescent microscopy and subjected to gentamicin protection assays. GFP-labeled bacteria were found located deep within the tissue crypts and a small number of O157 were recovered from rectal biopsies after gentamicin treatment. Primary bovine rectal epithelial (PBRE) cell cultures were incubated with O157 and subjected to gentamicin protection assays. Strains ATCC 43895, 43894, Sakai, and WSU180 entered the PBRE cells with different levels of efficiency ranging from 0.18 to 19.38% of the inocula. Intracellular bacteria were confirmed to be within membrane-bounded vacuoles by electron microscopy. Cytochalasin D curtailed internalization of O157 indicating internalization was dependent on eukaryotic microfilament assembly. Strain ATCC 43895 exhibited the highest efficiency of internalization and survived for at least 24 h within PBRE cells. Deletion mutation of intimin or its receptor in ATCC 43895 did not reduce bacterial internalization. This strain produced more biofilm than the others tested. Retrospective analysis of cattle challenged with two O157 strains, showed ATCC 43895, the most efficient at host cell internalization, was most persistent. PMID- 21687425 TI - Francisella-arthropod vector interaction and its role in patho-adaptation to infect mammals. AB - Francisella tularensis is a Gram-negative, intracellular, zoonotic bacterium, and is the causative agent of tularemia with a broad host range. Arthropods such as ticks, mosquitoes, and flies maintain F. tularensis in nature by transmitting the bacteria among small mammals. While the tick is largely believed to be a biological vector of F. tularensis, transmission by mosquitoes and flies is largely believed to be mechanical on the mouthpart through interrupted feedings. However, the mechanism of infection of the vectors by F. tularensis is not well understood. Since F. tularensis has not been localized in the salivary gland of the primary human biting ticks, it is thought that bacterial transmission by ticks is through mechanical inoculation of tick feces containing F. tularensis into the skin wound. Drosophila melanogaster is an established good arthropod model for arthropod vectors of tularemia, where F. tularensis infects hemocytes, and is found in hemolymph, as seen in ticks. In addition, phagosome biogenesis and robust intracellular proliferation of F. tularensis in arthropod-derived cells are similar to that in mammalian macrophages. Furthermore, bacterial factors required for infectivity of mammals are often required for infectivity of the fly by F. tularensis. Several host factors that contribute to F. tularensis intracellular pathogenesis in D. melanogaster have been identified, and F. tularensis targets some of the evolutionarily conserved eukaryotic processes to enable intracellular survival and proliferation in evolutionarily distant hosts. PMID- 21687426 TI - Identification of Residues in the BST-2 TM Domain Important for Antagonism by HIV 1 Vpu Using a Gain-of-Function Approach. AB - The HIV-1 Vpu protein enhances the release of viral particles from the cell surface in a cell-type specific manner. In the absence of Vpu, nascent virions remain tethered to the cell-surface in restricted cell-types. Recently, the human host factor BST-2/CD317/tetherin was found to be responsible for the inhibition of virus release. It was also reported that HIV-1 Vpu can target human BST-2 but is unable to interfere with the function of murine or simian BST-2. We performed a gain-of-function study to determine which of the differences between human and rhesus BST-2 account for the differential sensitivity to Vpu. We transferred human BST-2 sequences into rhesus BST-2 and assessed the resulting chimeras for inhibition of HIV-1 virus release and sensitivity to Vpu. We found that rhesus BST-2 carrying the transmembrane (TM) domain of human BST-2 is susceptible to HIV 1 Vpu. Finally, a single-amino-acid change in the rhesus BST-2 TM domain was sufficient to confer Vpu sensitivity. PMID- 21687427 TI - Striking a balance: modulation of host cell death pathways by legionella pneumophila. AB - Programmed cell death is considered the ultimate solution for the host to eliminate infected cells, leading to the abolishment of the niche for microbial replication and the ablation of infection. Thus, it is not surprising that successful pathogens have evolved diverse strategies to reprogram the cell death pathways for their proliferation. Using effector proteins translocated by the Dot/Icm type IV secretion system, the facultative intracellular pathogen Legionella pneumophila manipulates multiple host cellular processes to create a niche within host cells to support its replication. Investigation in the past decade has established that in mammalian cells this bacterium actively modulates two host cell death pathways, namely the canonical apoptotic pathway controlled by the mitochondrion and the pyroptotic pathway controlled by the Nod-like receptor Naip5 and the Ipaf inflammasome. In this review, I will discuss the recent progress in understanding the mechanisms the bacterium employs to interfere with these host cell death pathways and how such modulation contribute to the intracellular life cycle of the pathogen. PMID- 21687429 TI - Characterization of EhaJ, a New Autotransporter Protein from Enterohemorrhagic and Enteropathogenic Escherichia coli. AB - Enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) are diarrheagenic pathotypes of E. coli that cause gastrointestinal disease with the potential for life-threatening sequelae. While certain EHEC and EPEC virulence mechanisms have been extensively studied, the factors that mediate host colonization remain to be properly defined. Previously, we identified four genes (ehaA, ehaB, ehaC, and ehaD) from the prototypic EHEC strain EDL933 that encode for proteins that belong to the autotransporter (AT) family. Here we have examined the prevalence of these genes, as well as several other AT-encoding genes, in a collection of EHEC and EPEC strains. We show that the complement of AT-encoding genes in EHEC and EPEC strains is variable, with some AT-encoding genes being highly prevalent. One previously uncharacterized AT-encoding gene, which we have termed ehaJ, was identified in 12/44 (27%) of EHEC and 2/20 (10%) of EPEC strains. The ehaJ gene lies immediately adjacent to a gene encoding a putative glycosyltransferase (referred to as egtA). Western blot analysis using an EhaJ-specific antibody indicated that EhaJ is glycosylated by EgtA. Expression of EhaJ in a recombinant E. coli strain, revealed EhaJ is located at the cell surface and in the presence of the egtA glycosyltransferase gene mediates strong biofilm formation in microtiter plate and flow cell assays. EhaJ also mediated adherence to a range of extracellular matrix proteins, however this occurred independent of glycosylation. We also demonstrate that EhaJ is expressed in a wild-type EPEC strain following in vitro growth. However, deletion of ehaJ did not significantly alter its adherence or biofilm properties. In summary, EhaJ is a new glycosylated AT protein from EPEC and EHEC. Further studies are required to elucidate the function of EhaJ in colonization and virulence. PMID- 21687428 TI - Genetic and Functional Diversity of Pseudomonas aeruginosa Lipopolysaccharide. AB - Lipopolysccharide (LPS) is an integral component of the Pseudomonas aeruginosa cell envelope, occupying the outer leaflet of the outer membrane in this Gram negative opportunistic pathogen. It is important for bacterium-host interactions and has been shown to be a major virulence factor for this organism. Structurally, P. aeruginosa LPS is composed of three domains, namely, lipid A, core oligosaccharide, and the distal O antigen (O-Ag). Most P. aeruginosa strains produce two distinct forms of O-Ag, one a homopolymer of D-rhamnose that is a common polysaccharide antigen (CPA, formerly termed A band), and the other a heteropolymer of three to five distinct (and often unique dideoxy) sugars in its repeat units, known as O-specific antigen (OSA, formerly termed B band). Compositional differences in the O units among the OSA from different strains form the basis of the International Antigenic Typing Scheme for classification via serotyping of different strains of P. aeruginosa. The focus of this review is to provide state-of-the-art knowledge on the genetic and resultant functional diversity of LPS produced by P. aeruginosa. The underlying factors contributing to this diversity will be thoroughly discussed and presented in the context of its contributions to host-pathogen interactions and the control/prevention of infection. PMID- 21687430 TI - Technologies and approaches to elucidate and model the virulence program of salmonella. AB - Salmonella is a primary cause of enteric diseases in a variety of animals. During its evolution into a pathogenic bacterium, Salmonella acquired an elaborate regulatory network that responds to multiple environmental stimuli within host animals and integrates them resulting in fine regulation of the virulence program. The coordinated action by this regulatory network involves numerous virulence regulators, necessitating genome-wide profiling analysis to assess and combine efforts from multiple regulons. In this review we discuss recent high throughput analytic approaches used to understand the regulatory network of Salmonella that controls virulence processes. Application of high-throughput analyses have generated large amounts of data and necessitated the development of computational approaches for data integration. Therefore, we also cover computer aided network analyses to infer regulatory networks, and demonstrate how genome scale data can be used to construct regulatory and metabolic systems models of Salmonella pathogenesis. Genes that are coordinately controlled by multiple virulence regulators under infectious conditions are more likely to be important for pathogenesis. Thus, reconstructing the global regulatory network during infection or, at the very least, under conditions that mimic the host cellular environment not only provides a bird's eye view of Salmonella survival strategy in response to hostile host environments but also serves as an efficient means to identify novel virulence factors that are essential for Salmonella to accomplish systemic infection in the host. PMID- 21687431 TI - Vaccines for gonorrhea: can we rise to the challenge? AB - Immune responses to the gonococcus after natural infection ordinarily result in little immunity to reinfection, due to antigenic variation of the gonococcus, and redirection or suppression of immune responses. Brinton and colleagues demonstrated that parenteral immunization of male human volunteers with a purified pilus vaccine gave partial protection against infection by the homologous strain. However, the vaccine failed in a clinical trial. Recent vaccine development efforts have focused on the female mouse model of genital gonococcal infection. Here we discuss the state of the field, including our unpublished data regarding efficacy in the mouse model of either viral replicon particle (VRP) vaccines, or outer membrane vesicle (OMV) vaccines. The OMV vaccines failed, despite excellent serum and mucosal antibody responses. Protection after a regimen consisting of a PorB-VRP prime plus recombinant PorB boost was correlated with apparent Th1, but not with antibody, responses. Protection probably was due to powerful adjuvant effects of the VRP vector. New tools including novel transgenic mice expressing human genes required for gonococcal infection should enable future research. Surrogates for immunity are needed. Increasing antimicrobial resistance trends among gonococci makes development of a vaccine more urgent. PMID- 21687432 TI - Salmonella - at home in the host cell. AB - The Gram-negative bacterium Salmonella enterica has developed an array of sophisticated tools to manipulate the host cell and establish an intracellular niche, for successful propagation as a facultative intracellular pathogen. While Salmonella exerts diverse effects on its host cell, only the cell biology of the classic "trigger"-mediated invasion process and the subsequent development of the Salmonella-containing vacuole have been investigated extensively. These processes are dependent on cohorts of effector proteins translocated into host cells by two type III secretion systems (T3SS), although T3SS-independent mechanisms of entry may be important for invasion of certain host cell types. Recent studies into the intracellular lifestyle of Salmonella have provided new insights into the mechanisms used by this pathogen to modulate its intracellular environment. Here we discuss current knowledge of Salmonella-host interactions including invasion and establishment of an intracellular niche within the host. PMID- 21687433 TI - Immune Control of Legionella Infection: An in vivo Perspective. AB - Legionella pneumophila is an intracellular pathogen that replicates within alveolar macrophages. Through its ability to activate multiple host innate immune components, L. pneumophila has emerged as a useful tool to dissect inflammatory signaling pathways in macrophages. However the resolution of L. pneumophila infection in the lung requires multiple cell types and abundant cross talk between immune cells. Few studies have examined the coordination of events that lead to effective immune control of the pathogen. Here we discuss L. pneumophila interactions with macrophages and dendritic cell subsets and highlight the paucity of knowledge around how these interactions recruit and activate other immune effector cells in the lung. PMID- 21687434 TI - Soil Bacteria and Fungi Respond on Different Spatial Scales to Invasion by the Legume Lespedeza cuneata. AB - The spatial scale on which microbial communities respond to plant invasions may provide important clues as to the nature of potential invader-microbe interactions. Lespedeza cuneata (Dum. Cours.) G. Don is an invasive legume that may benefit from associations with mycorrhizal fungi; however, it has also been suggested that the plant is allelopathic and may alter the soil chemistry of invaded sites through secondary metabolites in its root exudates or litter. Thus, L. cuneata invasion may interact with soil microorganisms on a variety of scales. We investigated L. cuneata-related changes to soil bacterial and fungal communities at two spatial scales using multiple sites from across its invaded N. American range. Using whole-community DNA fingerprinting, we characterized microbial community variation at the scale of entire invaded sites and at the scale of individual plants. Based on permutational multivariate analysis of variance, soil bacterial communities in heavily invaded sites were significantly different from those of uninvaded sites, but bacteria did not show any evidence of responding at very local scales around individual plants. In contrast, soil fungi did not change significantly at the scale of entire sites, but there were significant differences between fungal communities of native versus exotic plants within particular sites. The differential scaling of bacterial and fungal responses indicates that L. cuneata interacts differently with soil bacteria and soil fungi, and these microorganisms may play very different roles in the invasion process of this plant. PMID- 21687435 TI - Consciousness, plasticity, and connectomics: the role of intersubjectivity in human cognition. AB - Consciousness is typically construed as being explainable purely in terms of either private, raw feels or higher-order, reflective representations. In contrast to this false dichotomy, we propose a new view of consciousness as an interactive, plastic phenomenon open to sociocultural influence. We take up our account of consciousness from the observation of radical cortical neuroplasticity in human development. Accordingly, we draw upon recent research on macroscopic neural networks, including the "default mode," to illustrate cases in which an individual's particular "connectome" is shaped by encultured social practices that depend upon and influence phenomenal and reflective consciousness. On our account, the dynamically interacting connectivity of these networks bring about important individual differences in conscious experience and determine what is "present" in consciousness. Further, we argue that the organization of the brain into discrete anti-correlated networks supports the phenomenological distinction of prereflective and reflective consciousness, but we emphasize that this finding must be interpreted in light of the dynamic, category-resistant nature of consciousness. Our account motivates philosophical and empirical hypotheses regarding the appropriate time-scale and function of neuroplastic adaptation, the relation of high and low-frequency neural activity to consciousness and cognitive plasticity, and the role of ritual social practices in neural development and cognitive function. PMID- 21687436 TI - The perspective matters! Multisensory integration in ego-centric reference frames determines full-body ownership. AB - Recent advances in experimental science have made it possible to investigate the perceptual processes involved in generating a sense of owning an entire body. This is achieved by full-body ownership illusions which make use of specific patterns of visual and somatic stimuli integration. Here we investigate the fundamental question of the reference frames used in the process of attributing an entire body to the self. We quantified the strength of the body-swap illusion in conditions where the participants were observing this artificial body from the perspective of the first or third person. Consistent results from subjective reports and physiological recordings show that the first person visual perspective is critical for the induction of this full-body ownership illusion. This demonstrates that the multisensory integration processes producing the sense of corporeal self operates in an ego-centric reference frame. PMID- 21687438 TI - Mind as music. AB - Cognitive neuroscience typically develops hypotheses to explain phenomena that are localized in space and time. Specific regions of the brain execute characteristic functions, whose causes and effects are prompt; determining these functions in spatial and temporal isolation is generally regarded as the first step toward understanding the coherent operation of the whole brain over time. In other words, if the task of cognitive neuroscience is to interpret the neural code, then the first step has been semantic, searching for the meanings (functions) of localized elements, prior to exploring neural syntax, the mutual constraints among elements synchronically and diachronically. While neuroscience has made great strides in discovering the functions of regions of the brain, less is known about the dynamic patterns of brain activity over time, in particular, whether regions activate in sequences that could be characterized syntactically. Researchers generally assume that neural semantics is a precondition for determining neural syntax. Furthermore, it is often assumed that the syntax of the brain is too complex for our present technology and understanding. A corollary of this view holds that functional MRI (fMRI) lacks the spatial and temporal resolution needed to identify the dynamic syntax of neural computation. This paper examines these assumptions with a novel analysis of fMRI image series, resting on the conjecture that any computational code will exhibit aggregate features that can be detected even if the meaning of the code is unknown. Specifically, computational codes will be sparse or dense in different degrees. A sparse code is one that uses only a few of the many possible patterns of activity (in the brain) or symbols (in a human-made code). Considering sparseness at different scales and as measured by different techniques, this approach clearly distinguishes two conventional coding systems, namely, language and music. Based on an analysis of 99 subjects in three different fMRI protocols, in comparison with 194 musical examples and 700 language passages, it is observed that fMRI activity is more similar to music than it is to language, as measured over single symbols, as well as symbol combinations in pairs and triples. Tools from cognitive musicology may therefore be useful in characterizing the brain as a dynamical system. PMID- 21687437 TI - Hand in motion reveals mind in motion. AB - Recently, researchers have measured hand movements en route to choices on a screen to understand the dynamics of a broad range of psychological processes. We review this growing body of research and explain how manual action exposes the real-time unfolding of underlying cognitive processing. We describe how simple hand motions may be used to continuously index participants' tentative commitments to different choice alternatives during the evolution of a behavioral response. As such, hand-tracking can provide unusually high-fidelity, real-time motor traces of the mind. These motor traces cast novel theoretical and empirical light onto a wide range of phenomena and serve as a potential bridge between far reaching areas of psychological science - from language, to high-level cognition and learning, to social cognitive processes. PMID- 21687439 TI - Studying neonates' language and memory capacities with functional near-infrared spectroscopy. AB - The measurement of newborns' brain hemodynamic activity has improved our understanding of early cognitive processes, in particular of language acquisition. In this paper, we describe two experimental protocols adapted to study neonates' speech-processing capacities using functional near-infrared spectroscopy (fNIRS): the block design and the familiarization-recognition design. We review some of their benefits and disadvantages, and refer to research issues that can be explored by means of these protocols. We also illustrate the use of the two experimental designs through representative fNIRS studies that reveal specific patterns of activation of the newborn brain during speech perception, learning of repetition structures, and word recognition. PMID- 21687440 TI - Attending to One of Many: When Infants are Surprisingly Poor at Discriminating an Item's Size. AB - Despite a prevailing assumption in the developmental literature that changes in continuous quantities (i.e., surface area, duration) are easier to detect than changes in number, very little research has focused on the verity of this assumption. The few studies that have directly examined infants' discriminations of continuous extent have revealed that infants discriminate the duration of a single event and the area of a single item with similar levels of precision (Brannon et al., 2006; vanMarle and Wynn, 2006). But what about when items are presented in arrays? Infants appear to be much worse at representing the cumulative surface area compared to the numerosity of an array (Cordes and Brannon, 2008a), however this may be due to a noisy accumulation process and not a general finding pertaining to representations of the extent within an array. The current study investigates how well infants detect changes in the size of individual elements when they are presented within an array. Our results indicate that infants are less sensitive to continuous properties of items when they are presented within a set than when presented in isolation. Specifically we demonstrate that infants required a fourfold change in item size to detect a change when items were presented within a set of homogeneous elements. Rather than providing redundant cues that aided discrimination, presenting a set of identical elements appeared to hamper an infant's ability to detect changes in a single element's size. In addition to providing some of the first evidence to suggest that the presence of multiple items may hinder extent representations, these results provide converging lines of evidence to support the claim that, contrary to popular belief, infants are better at tracking number than continuous properties of a set. PMID- 21687441 TI - The other half of the embodied mind. AB - Embodied theories of mind tend to be theories of the cognitive half of the mind and to ignore its emotional half while a complete theory of the mind should account for both halves. Robots are a new way of expressing theories of the mind which are less ambiguous and more capable to generate specific and non controversial predictions than verbally expressed theories. We outline a simple robotic model of emotional states as states of a sub-part of the neural network controlling the robot's behavior which has specific properties and which allows the robot to make faster and more correct motivational decisions, and we describe possible extensions of the model to account for social emotional states and for the expression of emotions that, unlike those of current "emotional" robots, are really "felt" by the robot in that they play a well-identified functional role in the robot's behavior. PMID- 21687442 TI - Functional lateralization of speech processing in adults and children who stutter. AB - Developmental stuttering is a speech disorder in fluency characterized by repetitions, prolongations, and silent blocks, especially in the initial parts of utterances. Although their symptoms are motor related, people who stutter show abnormal patterns of cerebral hemispheric dominance in both anterior and posterior language areas. It is unknown whether the abnormal functional lateralization in the posterior language area starts during childhood or emerges as a consequence of many years of stuttering. In order to address this issue, we measured the lateralization of hemodynamic responses in the auditory cortex during auditory speech processing in adults and children who stutter, including preschoolers, with near-infrared spectroscopy. We used the analysis-resynthesis technique to prepare two types of stimuli: (i) a phonemic contrast embedded in Japanese spoken words (/itta/ vs. /itte/) and (ii) a prosodic contrast (/itta/ vs. /itta?/). In the baseline blocks, only /itta/ tokens were presented. In phonemic contrast blocks, /itta/ and /itte/ tokens were presented pseudo randomly, and /itta/ and /itta?/ tokens in prosodic contrast blocks. In adults and children who do not stutter, there was a clear left-hemispheric advantage for the phonemic contrast compared to the prosodic contrast. Adults and children who stutter, however, showed no significant difference between the two stimulus conditions. A subject-by-subject analysis revealed that not a single subject who stutters showed a left advantage in the phonemic contrast over the prosodic contrast condition. These results indicate that the functional lateralization for auditory speech processing is in disarray among those who stutter, even at preschool age. These results shed light on the neural pathophysiology of developmental stuttering. PMID- 21687443 TI - Decision-making under risk in children, adolescents, and young adults. AB - Adolescents often make risky and impulsive decisions. Such behavior has led to the common assumption that a dysfunction in risk-related decision-making peaks during this age. Differences in how risk has been defined across studies, however, make it difficult to draw conclusions about developmental changes in risky decision-making. Here, we developed a non-symbolic economic decision-making task that can be used across a wide age span and that uses coefficient of variation (CV) in reward as an index of risk. We found that young children showed the strongest preference for risky compared to sure bet options of equal expected value, adolescents were intermediate in their risk preference, and young adults showed the strongest risk aversion. Furthermore, children's preference for the risky option increased for larger CVs, while adolescents and young adults showed the opposite pattern, favoring the sure bet more often as CV increased. Finally, when faced with two gambles in a risk-return tradeoff, all three age groups exhibited a greater preference for the option with the lower risk and return as the disparity in risk between the two options increased. These findings demonstrate clear age-related differences in economic risk preferences that vary with choice set and risk. Importantly, adolescence appears to represent an intermediate decision-making phenotype along the transition from childhood to adulthood, rather than an age of heightened preference for economic risk. PMID- 21687445 TI - Data with hierarchical structure: impact of intraclass correlation and sample size on type-I error. AB - Least squares analyses (e.g., ANOVAs, linear regressions) of hierarchical data leads to Type-I error rates that depart severely from the nominal Type-I error rate assumed. Thus, when least squares methods are used to analyze hierarchical data coming from designs in which some groups are assigned to the treatment condition, and others to the control condition (i.e., the widely used "groups nested under treatment" experimental design), the Type-I error rate is seriously inflated, leading too often to the incorrect rejection of the null hypothesis (i.e., the incorrect conclusion of an effect of the treatment). To highlight the severity of the problem, we present simulations showing how the Type-I error rate is affected under different conditions of intraclass correlation and sample size. For all simulations the Type-I error rate after application of the popular Kish (1965) correction is also considered, and the limitations of this correction technique discussed. We conclude with suggestions on how one should collect and analyze data bearing a hierarchical structure. PMID- 21687444 TI - Alpha rhythms in audition: cognitive and clinical perspectives. AB - Like the visual and the sensorimotor systems, the auditory system exhibits pronounced alpha-like resting oscillatory activity. Due to the relatively small spatial extent of auditory cortical areas, this rhythmic activity is less obvious and frequently masked by non-auditory alpha-generators when recording non invasively using magnetoencephalography (MEG) or electroencephalography (EEG). Following stimulation with sounds, marked desynchronizations can be observed between 6 and 12 Hz, which can be localized to the auditory cortex. However knowledge about the functional relevance of the auditory alpha rhythm has remained scarce so far. Results from the visual and sensorimotor system have fuelled the hypothesis of alpha activity reflecting a state of functional inhibition. The current article pursues several intentions: (1) Firstly we review and present own evidence (MEG, EEG, sEEG) for the existence of an auditory alpha like rhythm independent of visual or motor generators, something that is occasionally met with skepticism. (2) In a second part we will discuss tinnitus and how this audiological symptom may relate to reduced background alpha. The clinical part will give an introduction into a method which aims to modulate neurophysiological activity hypothesized to underlie this distressing disorder. Using neurofeedback, one is able to directly target relevant oscillatory activity. Preliminary data point to a high potential of this approach for treating tinnitus. (3) Finally, in a cognitive neuroscientific part we will show that auditory alpha is modulated by anticipation/expectations with and without auditory stimulation. We will also introduce ideas and initial evidence that alpha oscillations are involved in the most complex capability of the auditory system, namely speech perception. The evidence presented in this article corroborates findings from other modalities, indicating that alpha-like activity functionally has an universal inhibitory role across sensory modalities. PMID- 21687446 TI - Sharing One Biographical Detail Elicits Priming between Famous Names: Empirical and Computational Approaches. AB - In this paper three experiments and corresponding model simulations are reported that investigate the priming of famous name recognition in order to explore the structure of the part of the semantic system dealing with people. Consistent with empirical findings, novel computational simulations using Burton et al.'s interactive activation and competition model point to a conceptual distinction between how priming is initiated in single- and double-familiarity tasks, indicating that priming should be weaker or non-existent for the single familiarity task. Experiment 1 demonstrates that, within a double-familiarity framework using famous names, categorical, and associative priming are reliable effects. Pushing the model to the limit, it predicts that pairs of celebrities who are neither associatively nor categorically related but who share single biographical features, both died in a car crash for example, should prime each other. Experiment 2 investigated this in a double-familiarity task but the effect was not observed. We therefore simulated and realized a pairwise learning task that was conceptually similar to the double-familiarity-decision task but allowed to strengthen the underlying connections. Priming based on a single biographical feature could be found both in simulations and the experiment. The effect was not due to visual or name similarity which were controlled for and participants did not report using the biographical links between the people to learn the pairs. The results are interpreted to lend further support to structural models of the memory for persons. Furthermore, the results are consistent with the idea that episodic features known about people are stored in semantic memory and are automatically activated when encountering that person. PMID- 21687447 TI - Out-group mating threat and disease threat increase implicit negative attitudes toward the out-group among men. AB - We investigated if perceiving an out-group as a threat to one's mating opportunities enhanced the implicit negative attitudes toward that out-group. In addition, we examined the moderating effect of disease threat on the relationship between an out-group mating threat and implicit negative attitudes toward that out-group. In Experiment 1, an out-group mating threat led to stronger implicit negative out-group attitudes as measured by the Implicit Association Test, but only for men with high chronic perceived vulnerability to disease. No such effects were found among women. In Experiment 2, men in the out-group mating threat condition who were primed with disease prevalence showed significantly stronger implicit negative attitudes toward the out-group than controls. Findings are discussed with reference to the functional approach to prejudice and sex specific motivational reactions to different out-group threats. PMID- 21687448 TI - Organization, maturation, and plasticity of multisensory integration: insights from computational modeling studies. AB - In this paper, we present two neural network models - devoted to two specific and widely investigated aspects of multisensory integration - in order to evidence the potentialities of computational models to gain insight into the neural mechanisms underlying organization, development, and plasticity of multisensory integration in the brain. The first model considers visual-auditory interaction in a midbrain structure named superior colliculus (SC). The model is able to reproduce and explain the main physiological features of multisensory integration in SC neurons and to describe how SC integrative capability - not present at birth - develops gradually during postnatal life depending on sensory experience with cross-modal stimuli. The second model tackles the problem of how tactile stimuli on a body part and visual (or auditory) stimuli close to the same body part are integrated in multimodal parietal neurons to form the perception of peripersonal (i.e., near) space. The model investigates how the extension of peripersonal space - where multimodal integration occurs - may be modified by experience such as use of a tool to interact with the far space. The utility of the modeling approach relies on several aspects: (i) The two models, although devoted to different problems and simulating different brain regions, share some common mechanisms (lateral inhibition and excitation, non-linear neuron characteristics, recurrent connections, competition, Hebbian rules of potentiation and depression) that may govern more generally the fusion of senses in the brain, and the learning and plasticity of multisensory integration. (ii) The models may help interpretation of behavioral and psychophysical responses in terms of neural activity and synaptic connections. (iii) The models can make testable predictions that can help guiding future experiments in order to validate, reject, or modify the main assumptions. PMID- 21687449 TI - Impaired executive functioning in subclinical compulsive checking with ecologically valid stimuli in a working memory task. AB - We previously showed that working memory (WM) performance of subclinical checkers can be affected if they are presented with irrelevant but misleading information during the retention period (Harkin and Kessler, 2009, 2011). The present study differed from our previous research in the three crucial aspects. Firstly, we employed ecologically valid stimuli in form of electrical kitchen appliances on a kitchen countertop in order to address previous criticism of our research with letters in locations as these may not have tapped into the primary concerns of checkers. Secondly, we tested whether these ecological stimuli would allow us to employ a simpler (un-blocked) design while obtaining similarly robust results. Thirdly, in Experiment 2 we improved the measure of confidence as a metacognitive variable by using a quantitative scale (0-100), which indeed revealed more robust effects that were quantitatively related to accuracy of performance. The task in the present study was to memorize four appliances, including their states (on/off), and their locations on the kitchen countertop. Memory accuracy was tested for the states of appliances in Experiment 1, and for their locations in Experiment 2. Intermediate probes were identical in both experiments and were administered during retention on 66.7% of the trials with 50% resolvable and 50% irresolvable/misleading probes. Experiment 1 revealed the efficacy of the employed stimuli by revealing a general impairment of high- compared to low checkers, which confirmed the ecological validity of our stimuli. In Experiment 2 we observed the expected, more differentiated pattern: High checkers were not generally affected in their WM performance (i.e., no general capacity issue); instead they showed a particular impairment in the misleading distractor-probe condition. Also, high checkers' confidence ratings were indicative of a general impairment in metacognitive functioning. We discuss how specific executive dysfunction and general metacognitive impairment may affect memory traces in the short- and in the long-term. PMID- 21687451 TI - Lexical selection in multi-word production. AB - In multi-word utterances, target words need to be selected in the context of other target words. In the present study, three hypotheses were tested that differed in their assumptions about whether the lexical selection mechanism considers the activation levels of the other target lexical representations, and whether it takes into account their grammatical class properties. Participants produced adjective + noun and noun + noun utterances in response to colored word and picture + word stimulus displays. In both types of utterances, the frequency of the first and second response was manipulated. The results revealed an effect of the frequency of the second response that did not depend on the utterance type, and additive effects for the frequency of the first and the second response in both utterance types. These results are interpreted in terms of a model of lexical selection that assumes that selection is non-competitive. PMID- 21687450 TI - The role of orbitofrontal cortex in processing empathy stories in 4- to 8-year old children. AB - This study investigates the neuronal correlates of empathic processing in children aged 4-8 years, an age range discussed to be crucial for the development of empathy. Empathy, defined as the ability to understand and share another person's inner life, consists of two components: affective (emotion-sharing) and cognitive empathy (Theory of Mind). We examined the hemodynamic responses of preschool and school children (N = 48), while they processed verbal (auditory) and non-verbal (cartoons) empathy stories in a passive following paradigm, using functional Near-Infrared Spectroscopy. To control for the two types of empathy, children were presented blocks of stories eliciting either affective or cognitive empathy, or neutral scenes which relied on the understanding of physical causalities. By contrasting the activations of the younger and older children, we expected to observe developmental changes in brain activations when children process stories eliciting empathy in either stimulus modality toward a greater involvement of anterior frontal brain regions. Our results indicate that children's processing of stories eliciting affective and cognitive empathy is associated with medial and bilateral orbitofrontal cortex (OFC) activation. In contrast to what is known from studies using adult participants, no additional recruitment of posterior brain regions was observed, often associated with the processing of stories eliciting empathy. Developmental changes were found only for stories eliciting affective empathy with increased activation, in older children, in medial OFC, left inferior frontal gyrus, and the left dorsolateral prefrontal cortex. Activations for the two modalities differ only little, with non-verbal presentation of the stimuli having a greater impact on empathy processing in children, showing more similarities to adult processing than the verbal one. This might be caused by the fact that non-verbal processing develops earlier in life and is more familiar. PMID- 21687452 TI - Trial-by-Trial Variations in Subjective Attentional State are Reflected in Ongoing Prestimulus EEG Alpha Oscillations. AB - Parieto-occipital electroencephalogram (EEG) alpha power and subjective reports of attentional state are both associated with visual attention and awareness, but little is currently known about the relationship between these two measures. Here, we bring together these two literatures to explore the relationship between alpha activity and participants' introspective judgments of attentional state as each varied from trial-to-trial during performance of a visual detection task. We collected participants' subjective ratings of perceptual decision confidence and attentional state on continuous scales on each trial of a rapid serial visual presentation detection task while recording EEG. We found that confidence and attentional state ratings were largely uncorrelated with each other, but both were strongly associated with task performance and post-stimulus decision-related EEG activity. Crucially, attentional state ratings were also negatively associated with prestimulus EEG alpha power. Attesting to the robustness of this association, we were able to classify attentional state ratings via prestimulus alpha power on a single-trial basis. Moreover, when we repeated these analyses after smoothing the time series of attentional state ratings and alpha power with increasingly large sliding windows, both the correlations and classification performance improved considerably, with the peaks occurring at a sliding window size of approximately 7 min worth of trials. Our results therefore suggest that slow fluctuations in attentional state in the order of minutes are reflected in spontaneous alpha power. Since these subjective attentional state ratings were associated with objective measures of both behavior and neural activity, we suggest that they provide a simple and effective estimate of task engagement that could prove useful in operational settings that require human operators to maintain a sustained focus of visual attention. PMID- 21687453 TI - How "social" is the social Simon effect? AB - In the standard Simon task, participants carry out spatially defined responses to non-spatial stimulus attributes. Responses are typically faster when stimulus location and response location correspond. This effect disappears when a participant responds to only one of the two stimuli and reappears when another person carries out the other response. This social Simon effect (SSE) has been considered as providing an index for action co-representation. Here, we investigated whether joint-action effects in a social Simon task involve mechanisms of action co-representation, as measured by the amount of incorporation of another person's action. We combined an auditory social Simon task with a manipulation of the sense of ownership of another person's hand (rubber hand illusion). If the SSE is established by action co-representation, then the incorporation of the other person's hand into one's own body representation should increase the SSE (synchronous > asynchronous stroking). However, we found the SSE to be smaller in the synchronous as compared to the asynchronous stroking condition (Experiment 1), suggesting that the SSE reflects the separation of spatial action events rather than the integration of the other person's action. This effect is independent of the active involvement (Experiment 2) and the presence of another person (Experiment 3). These findings suggest that the "social" Simon effect is not really social in nature but is established when an interaction partner produces events that serve as a spatial reference for one's own actions. PMID- 21687455 TI - The Radical Plasticity Thesis: How the Brain Learns to be Conscious. AB - In this paper, I explore the idea that consciousness is something that the brain learns to do rather than an intrinsic property of certain neural states and not others. Starting from the idea that neural activity is inherently unconscious, the question thus becomes: How does the brain learn to be conscious? I suggest that consciousness arises as a result of the brain's continuous attempts at predicting not only the consequences of its actions on the world and on other agents, but also the consequences of activity in one cerebral region on activity in other regions. By this account, the brain continuously and unconsciously learns to redescribe its own activity to itself, so developing systems of meta representations that characterize and qualify the target first-order representations. Such learned redescriptions, enriched by the emotional value associated with them, form the basis of conscious experience. Learning and plasticity are thus central to consciousness, to the extent that experiences only occur in experiencers that have learned to know they possess certain first-order states and that have learned to care more about certain states than about others. This is what I call the "Radical Plasticity Thesis." In a sense thus, this is the enactive perspective, but turned both inwards and (further) outwards. Consciousness involves "signal detection on the mind"; the conscious mind is the brain's (non-conceptual, implicit) theory about itself. I illustrate these ideas through neural network models that simulate the relationships between performance and awareness in different tasks. PMID- 21687454 TI - Task-specific modulation of human auditory evoked response in a delayed-match-to sample task. AB - In this study, we focus our investigation on task-specific cognitive modulation of early cortical auditory processing in human cerebral cortex. During the experiments, we acquired whole-head magnetoencephalography data while participants were performing an auditory delayed-match-to-sample (DMS) task and associated control tasks. Using a spatial filtering beamformer technique to simultaneously estimate multiple source activities inside the human brain, we observed a significant DMS-specific suppression of the auditory evoked response to the second stimulus in a sound pair, with the center of the effect being located in the vicinity of the left auditory cortex. For the right auditory cortex, a non-invariant suppression effect was observed in both DMS and control tasks. Furthermore, analysis of coherence revealed a beta band (12~20 Hz) DMS specific enhanced functional interaction between the sources in left auditory cortex and those in left inferior frontal gyrus, which has been shown to be involved in short-term memory processing during the delay period of DMS task. Our findings support the view that early evoked cortical responses to incoming acoustic stimuli can be modulated by task-specific cognitive functions by means of frontal-temporal functional interactions. PMID- 21687456 TI - What brain plasticity reveals about the nature of consciousness: commentary. PMID- 21687457 TI - Early ERP Modulation for Task-Irrelevant Subliminal Faces. AB - A number of investigations have reported that emotional faces can be processed subliminally, and that they give rise to specific patterns of brain activation in the absence of awareness. Recent event-related potential (ERP) studies have suggested that electrophysiological differences occur early in time (<200 ms) in response to backward-masked emotional faces. These findings have been taken as evidence of a rapid non-conscious pathway, which would allow threatening stimuli to be processed rapidly and subsequently allow appropriate avoidance action to be taken. However, for this to be the case, subliminal processing should arise even if the threatening stimulus is not attended. This point has in fact not yet been clearly established. In this ERP study, we investigated whether subliminal processing of fearful faces occurs outside the focus of attention. Fourteen healthy participants performed a line judgment task while fearful and non-fearful (happy or neutral) faces were presented both subliminally and supraliminally. ERPs were compared across the four experimental conditions (i.e., subliminal and supraliminal; fearful and non-fearful). The earliest differences between fearful and non-fearful faces appeared as an enhanced posterior negativity for the former at 170 ms (the N170 component) over right temporo-occipital electrodes. This difference was observed for both subliminal (p < 0.05) and supraliminal presentations (p < 0.01). Our results confirm that subliminal processing of fearful faces occurs early in the course of visual processing, and more importantly, that this arises even when the subject's attention is engaged in an incidental task. PMID- 21687458 TI - Studying Multisensory Processing and Its Role in the Representation of Space through Pathological and Physiological Crossmodal Extinction. AB - The study of crossmodal extinction has brought a considerable contribution to our understanding of how the integration of stimuli perceived in multiple sensory modalities is used by the nervous system to build coherent representations of the space that directly surrounds us. Indeed, by revealing interferences between stimuli in a disturbed system, extinction provides an invaluable opportunity to investigate the interactions that normally exist between those stimuli in an intact system. Here, we first review studies on pathological crossmodal extinction, from the original demonstration of its existence, to its role in the exploration of the multisensory neural representation of space and the current theoretical accounts proposed to explain the mechanisms involved in extinction and multisensory competition. Then, in the second part of this paper, we report recent findings showing that physiological multisensory competition phenomena resembling clinical crossmodal extinction exist in the healthy brain. We propose that the development of a physiological model of sensory competition is fundamental to deepen our understanding of the cerebral mechanisms of multisensory perception and integration. In addition, a similar approach to develop a model of physiological sensory competition in non-human primates should allow combining functional neuroimaging with more invasive techniques, such as transient focal lesions, in order to bridge the gap between works done in the two species and at different levels of analysis. PMID- 21687459 TI - Metaphors are Embodied, and so are Their Literal Counterparts. AB - This study investigates whether understanding up/down metaphors as well as semantically homologous literal sentences activates embodied representations online. Participants read orientational literal sentences (e.g., she climbed up the hill), metaphors (e.g., she climbed up in the company), and abstract sentences with similar meaning to the metaphors (e.g., she succeeded in the company). In Experiments 1 and 2, participants were asked to perform a speeded upward or downward hand motion while they were reading the sentence verb. The hand motion either matched or mismatched the direction connoted by the sentence. The results showed a meaning-action effect for metaphors and literals, that is, faster hand motion responses in the matching conditions. Notably, the matching advantage was also found for homologous abstract sentences, indicating that some abstract ideas are conceptually organized in the vertical dimension, even when they are expressed by means of literal sentences. In Experiment 3, participants responded to an upward or downward visual motion associated with the sentence verb by pressing a single key. In this case, the facilitation effect for matching visual motion-sentence meaning faded, indicating that the visual motion component is less important than the action component in conceptual metaphors. Most up and down metaphors convey emotionally positive and negative information, respectively. We suggest that metaphorical meaning elicits upward/downward movements because they are grounded on the bodily expression of the corresponding emotions. PMID- 21687460 TI - Can changes in eye movement scanning alter the age-related deficit in recognition memory? AB - Older adults typically exhibit poorer face recognition compared to younger adults. These recognition differences may be due to underlying age-related changes in eye movement scanning. We examined whether older adults' recognition could be improved by yoking their eye movements to those of younger adults. Participants studied younger and older faces, under free viewing conditions (bases), through a gaze-contingent moving window (own), or a moving window which replayed the eye movements of a base participant (yoked). During the recognition test, participants freely viewed the faces with no viewing restrictions. Own-age recognition biases were observed for older adults in all viewing conditions, suggesting that this effect occurs independently of scanning. Participants in the bases condition had the highest recognition accuracy, and participants in the yoked condition were more accurate than participants in the own condition. Among yoked participants, recognition did not depend on age of the base participant. These results suggest that successful encoding for all participants requires the bottom-up contribution of peripheral information, regardless of the locus of control of the viewer. Although altering the pattern of eye movements did not increase recognition, the amount of sampling of the face during encoding predicted subsequent recognition accuracy for all participants. Increased sampling may confer some advantages for subsequent recognition, particularly for people who have declining memory abilities. PMID- 21687461 TI - Large-scale brain networks underlying language acquisition in early infancy. AB - A critical issue in human development is that of whether the language-related areas in the left frontal and temporal regions work as a functional network in preverbal infants. Here, we used 94-channel near-infrared spectroscopy to reveal the functional networks in the brains of sleeping 3-month-old infants with and without presenting speech sounds. During the first 3 min, we measured spontaneous brain activation (period 1). After period 1, we provided stimuli by playing Japanese sentences for 3 min (period 2). Finally, we measured brain activation for 3 min without providing the stimulus (period 3), as in period 1. We found that not only the bilateral temporal and temporoparietal regions but also the prefrontal and occipital regions showed oxygenated hemoglobin signal increases and deoxygenated hemoglobin signal decreases when speech sounds were presented to infants. By calculating time-lagged cross-correlations and coherences of oxy-Hb signals between channels, we tested the functional connectivity for the three periods. The oxy-Hb signals in neighboring channels, as well as their homologous channels in the contralateral hemisphere, showed high correlation coefficients in period 1. Similar correlations were observed in period 2; however, the number of channels showing high correlations was higher in the ipsilateral hemisphere, especially in the anterior-posterior direction. The functional connectivity in period 3 showed a close relationship between the frontal and temporal regions, which was less prominent in period 1, indicating that these regions form the functional networks and work as a hysteresis system that has memory of the previous inputs. We propose a hypothesis that the spatiotemporally large-scale brain networks, including the frontal and temporal regions, underlie speech processing in infants and they might play important roles in language acquisition during infancy. PMID- 21687462 TI - Improving the estimation of psychometric functions in 2AFC discrimination tasks. AB - Ulrich and Vorberg (2009) presented a method that fits distinct functions for each order of presentation of standard and test stimuli in a two-alternative forced-choice (2AFC) discrimination task, which removes the contaminating influence of order effects from estimates of the difference limen. The two functions are fitted simultaneously under the constraint that their average evaluates to 0.5 when test and standard have the same magnitude, which was regarded as a general property of 2AFC tasks. This constraint implies that physical identity produces indistinguishability, which is valid when test and standard are identical except for magnitude along the dimension of comparison. However, indistinguishability does not occur at physical identity when test and standard differ on dimensions other than that along which they are compared (e.g., vertical and horizontal lines of the same length are not perceived to have the same length). In these cases, the method of Ulrich and Vorberg cannot be used. We propose a generalization of their method for use in such cases and illustrate it with data from a 2AFC experiment involving length discrimination of horizontal and vertical lines. The resultant data could be fitted with our generalization but not with the method of Ulrich and Vorberg. Further extensions of this method are discussed. PMID- 21687464 TI - Perisylvian Functional Connectivity during Processing of Sentential Negation. AB - Every language has the means to reverse the truth value of a sentence by using specific linguistic markers of negation. In the present study we investigated the neural processing costs afforded by the construction of meaning in German sentences containing negation in different clause types. We studied negations within and across clause boundaries as well as single and double negations. Participants read German sentences comprising of affirmations, single negations in the main or in the subordinate clause, or double negations. As a result, we found a network including the left inferior frontal gyrus (pars triangularis, BA 45), and the left inferior parietal gyrus (BA 40) to be activated whenever negations in the main clause had to be processed. Additionally, we found increased functional coupling between the left pars triangularis (BA 45), left pars opercularis (BA 44), left SMA (BA 6), and left superior temporal gyrus (BA 42) during the processing of main clause negations. The study shows that in order to process negations that require semantic integration across clause boundaries left BA 45 interplays with other areas that have been related to language processing and/or the processing of cognitive demands and logical/conditional reasoning. Thus, the results indicate that the left perisylvian language network synchronizes in order to resolve negations, in particular, whenever requirements on meaning integration are enhanced. PMID- 21687465 TI - Introspecting on the Timing of One's Actions in a Visuo-Motor Synchronization Task. AB - By means of a new visuo-motor synchronization paradigm we test the frequently made proposition that one's feeling of having voluntarily made a decision to act is in fact postdictively established contingent on the outcome of his action rather than on its aim. Subjects had to (1) synchronize a key-press with the end of a random synchronization interval (SI) shorter or longer than their reaction time (RT) and (2) judge thereafter whether (Q1) SI had been long enough to allow synchronization, (Q2) their motor response had been "reactive" (i.e., close to their RT) or delayed, or (Q3) whether SI was short or long. SI was denoted by the filling-up time of an annular "gauge." In principle, the "synchronization" key press should be reactive for SI <= RT and delayed in proportion with SI for SI > RT. Instead, response time distributions were bimodal for the shortest (0 ms) and longest (500 ms) SIs and widely spread for intermediate SIs. To all three questions asked, subjects' responses strongly correlated with SI itself (r = 0.62 0.76) and barely with their actual response times (r = 0.03-0.42). Hence subjects' introspective judgments on their trial-by-trial potential capability to synchronize their motor response (Q1) and on their reactive vs. delayed response mode reflected the objective cause of their action rather than being "corrupted" by its outcome (namely their actual response time). That subjects could not reliably decide whether their motor response was reactive or delayed implies that they did not have retrospective access to (or did not remember) their motor decisions which amounts to say that they could not decide on the intentionality of their actions. PMID- 21687463 TI - Using brain-computer interfaces and brain-state dependent stimulation as tools in cognitive neuroscience. AB - Large efforts are currently being made to develop and improve online analysis of brain activity which can be used, e.g., for brain-computer interfacing (BCI). A BCI allows a subject to control a device by willfully changing his/her own brain activity. BCI therefore holds the promise as a tool for aiding the disabled and for augmenting human performance. While technical developments obviously are important, we will here argue that new insight gained from cognitive neuroscience can be used to identify signatures of neural activation which reliably can be modulated by the subject at will. This review will focus mainly on oscillatory activity in the alpha band which is strongly modulated by changes in covert attention. Besides developing BCIs for their traditional purpose, they might also be used as a research tool for cognitive neuroscience. There is currently a strong interest in how brain-state fluctuations impact cognition. These state fluctuations are partly reflected by ongoing oscillatory activity. The functional role of the brain state can be investigated by introducing stimuli in real-time to subjects depending on the actual state of the brain. This principle of brain state dependent stimulation may also be used as a practical tool for augmenting human behavior. In conclusion, new approaches based on online analysis of ongoing brain activity are currently in rapid development. These approaches are amongst others informed by new insight gained from electroencephalography/magnetoencephalography studies in cognitive neuroscience and hold the promise of providing new ways for investigating the brain at work. PMID- 21687466 TI - Racism and the empathy for pain on our skin. AB - Empathy is a critical function regulating human social life. In particular, empathy for pain is a source of deep emotional feelings and a strong trigger of pro-social behavior. We investigated the existence of a racial bias in the emotional reaction to other people's pain and its link with implicit racist biases. Measuring participants' physiological arousal, we found that Caucasian observers reacted to pain suffered by African people significantly less than to pain of Caucasian people. The reduced reaction to the pain of African individuals was also correlated with the observers' individual implicit race bias. The role of others' race in moderating empathic reactions is a crucial clue for understanding to what extent social interactions, and possibly integration, may be influenced by deeply rooted automatic and uncontrollable responses. PMID- 21687467 TI - Relating pitch awareness to phonemic awareness in children: implications for tone deafness and dyslexia. AB - Language and music are complex cognitive and neural functions that rely on awareness of one's own sound productions. Information on the awareness of vocal pitch, and its relation to phonemic awareness which is crucial for learning to read, will be important for understanding the relationship between tone-deafness and developmental language disorders such as dyslexia. Here we show that phonemic awareness skills are positively correlated with pitch perception-production skills in children. Children between the ages of seven and nine were tested on pitch perception and production, phonemic awareness, and IQ. Results showed a significant positive correlation between pitch perception-production and phonemic awareness, suggesting that the relationship between musical and linguistic sound processing is intimately linked to awareness at the level of pitch and phonemes. Since tone-deafness is a pitch-related impairment and dyslexia is a deficit of phonemic awareness, we suggest that dyslexia and tone-deafness may have a shared and/or common neural basis. PMID- 21687468 TI - Event-related brain potential investigation of preparation for speech production in late bilinguals. AB - It has been debated how bilinguals select the intended language and prevent interference from the unintended language when speaking. Here, we studied the nature of the mental representations accessed by late fluent bilinguals during a rhyming judgment task relying on covert speech production. We recorded event related brain potentials in Chinese-English bilinguals and monolingual speakers of English while they indicated whether the names of pictures presented on a screen rhymed. Whether bilingual participants focussed on rhyming selectively in English or Chinese, we found a significant priming effect of language-specific sound repetition. Surprisingly, however, sound repetitions in Chinese elicited significant priming effects even when the rhyming task was performed in English. This cross-language priming effect was delayed by ~200 ms as compared to the within-language effect and was asymmetric, since there was no priming effect of sound repetitions in English when participants were asked to make rhyming judgments in Chinese. These results demonstrate that second language production hinders, but does not seal off, activation of the first language, whereas native language production appears immune to competition from the second language. PMID- 21687469 TI - Testing a simplified method for measuring velocity integration in saccades using a manipulation of target contrast. AB - A growing number of studies in vision research employ analyses of how perturbations in visual stimuli influence behavior on single trials. Recently, we have developed a method along such lines to assess the time course over which object velocity information is extracted on a trial-by-trial basis in order to produce an accurate intercepting saccade to a moving target. Here, we present a simplified version of this methodology, and use it to investigate how changes in stimulus contrast affect the temporal velocity integration window used when generating saccades to moving targets. Observers generated saccades to one of two moving targets which were presented at high (80%) or low (7.5%) contrast. In 50% of trials, target velocity stepped up or down after a variable interval after the saccadic go signal. The extent to which the saccade endpoint can be accounted for as a weighted combination of the pre- or post-step velocities allows for identification of the temporal velocity integration window. Our results show that the temporal integration window takes longer to peak in the low when compared to high contrast condition. By enabling the assessment of how information such as changes in velocity can be used in the programming of a saccadic eye movement on single trials, this study describes and tests a novel methodology with which to look at the internal processing mechanisms that transform sensory visual inputs into oculomotor outputs. PMID- 21687471 TI - Women's Health Kaiser Permanente-Improving Women's Lives through Health Care Research, Innovation, and Education. PMID- 21687472 TI - Why Research at KP? PMID- 21687470 TI - Alpha oscillations and early stages of visual encoding. AB - For a long time alpha oscillations have been functionally linked to the processing of visual information. Here we propose an new theory about the functional meaning of alpha. The central idea is that synchronized alpha reflects a basic processing mode that controls access to information stored in a complex long-term memory system, which we term knowledge system in order to emphasize that it comprises not only declarative memories but any kind of knowledge comprising also procedural information. Based on this theoretical background, we assume that during early stages of perception, alpha "directs the flow of information" to those neural structures which represent information that is relevant for encoding. The physiological function of alpha is interpreted in terms of inhibition. We assume that alpha enables access to stored information by inhibiting task-irrelevant neuronal structures and by timing cortical activity in task relevant neuronal structures. We discuss a variety findings showing that evoked alpha and phase locking reflect successful encoding of global stimulus features in an early post-stimulus interval of about 0-150 ms. PMID- 21687473 TI - The Women's Health Research Institute: Mission Overview with Featured Research Projects. PMID- 21687474 TI - Fragile fracture care management program. PMID- 21687475 TI - Intrauterine contraception: study to evaluate clinical practice and to increase utilization. PMID- 21687476 TI - Management of menopause and midlife health issues: what do midlife women want from primary care clinicians? PMID- 21687477 TI - The perinatal patient safety project: new can be great! PMID- 21687479 TI - Translating research into innovative practices. PMID- 21687478 TI - Four decades of research on hormonal contraception. PMID- 21687480 TI - Managing High-Risk Obstetric Cases and Analyzing Neonatal Outcome: The KP Northern California Regional Perinatal Service Center. PMID- 21687481 TI - Minilaparotomy: a minimally invasive alternative for major gynecologic abdominal surgery. PMID- 21687482 TI - Laparoscopically assisted vaginal extraction of the kidney after laparoscopic radical nephrectomy. AB - BACKGROUND: Gynecologists have long used a vaginal incision for surgical treatment of pelvic pathology. More recently, however, laparoscopy has allowed gynecologists and other specialists to replace laparotomy with minimally invasive surgical techniques. The combination of laparoscopic and vaginal approaches has increased the surgical armamentarium of both the gynecologist and the urologist. CASE: A gynecologist found a renal cell carcinoma in a 52-year-old woman. The Urology and Gynecol-ogy Departments of the Kaiser Permanente (KP) Hawaii Region (KP Hawaii) planned a combined minimally invasive surgical procedure that became Hawaii's first reported retroperitoneal radical nephrectomy followed by laparoscopically assisted vaginal extraction of an intact kidney. CONCLUSION: Collaboration between laparoscopic surgeons in the Departments of Urology and Gynecology has allowed us to share surgical techniques and approaches to perform minimally invasive surgery instead of using more morbid large incisions of the abdomen or flank as required previously. PMID- 21687483 TI - Women at Risk for Coronary Heart Disease: How Research is Translated Into Innovation and Quality Outcomes at Kaiser Permanente. PMID- 21687484 TI - Mammography screening: addressing myths and other reasons for noncompliance. AB - In the Kaiser Permanente (KP) Georgia Region, a program of extensive mailings, call center contacts, and other avenues of patient education has been designed to increase the number of women having mammograms and to decrease the mortality rate from breast cancer. Citing statistics from various studies nationwide and in the Atlanta area, the authors outline some reasons for patient resistance to mammography and describe the resulting development of a "patient fact sheet" and other interventions intended to increase the rate of screening mammograms conducted in our target population of KP members. PMID- 21687485 TI - The kaiser permanente interregional breast care leaders. PMID- 21687486 TI - Vision, Research, Innovation and Influence: Early Start's 15-Year Journey from Pilot Project to Regional Program. PMID- 21687487 TI - Family violence prevention program: another way to save a life. PMID- 21687488 TI - Preventing Unintended Pregnancy: Eight Years of Effort at KP San Diego. PMID- 21687489 TI - Fighting breast cancer: a call for a new paradigm. PMID- 21687490 TI - Sentinel lymph node biopsy for patients with breast cancer: five-year experience. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) is rapidly gaining acceptance as a diagnostic tool for staging breast cancer. OBJECTIVE: Analyze trends among surgeons and facilities in Kaiser Permanente Northern California (KPNC) in adopting SLNB to stage cases of breast cancer and assess success in locating the sentinel node. METHODS: Retrospective review of data for patients whose breast cancer was staged using SLNB and axillary lymph node dissection between July 1997 through December 2002 at KPNC. Rates of false-negative results were calculated and stratified by surgeons' experience with SLNB. RESULTS: The number of SLNB procedures performed each month increased steadily from fewer than ten (in late 1998) to about 80 per month (in mid-2002) and were done at 17 facilities. Of the 132 surgeons who performed SLNB, most had done fewer than 15 procedures. The false-negative result rate overall was 6.53% (95% CI 4.75%, 8.73%); for surgeons who performed <30 procedures the rate was 8.58% (95% CI 5.52%, 12.60%); for surgeons who performed 20 to 30 procedures the rate was 13.08% (95% CI 7.34%, 20.98%); and for surgeons who performed more than 30 procedures the rate was 5.05% (95% CI 3.07%, 7.78%). CONCLUSIONS: SLNB is rapidly being adopted at KPNC to stage cases of breast cancer and surgeons achieve an acceptable 6.53% false negative result rate overall. The higher false-negative rate for surgeons who performed 20 to 30 procedures suggests that departments should expand efforts to monitor and proctor these surgeons. PMID- 21687491 TI - Kaiser Permanente Women's Health Center of Excellence in Culturally Competent Care. PMID- 21687492 TI - Can patients and physicians thrive in the 21st century? PMID- 21687493 TI - The Women's Health Track of the Kaiser Permanente National Primary Care Conference. PMID- 21687494 TI - The emergency contraception online learning module. PMID- 21687495 TI - Teen challenges. PMID- 21687496 TI - Doctor, should I take hormones? PMID- 21687498 TI - Disaster relief-"what can I do to help?". PMID- 21687497 TI - Normal birth. PMID- 21687499 TI - The Voltage-Sensing Domain of K(v)7.2 Channels as a Molecular Target for Epilepsy Causing Mutations and Anticonvulsants. AB - Understanding the molecular mechanisms underlying voltage-dependent gating in voltage-gated ion channels (VGICs) has been a major effort over the last decades. In recent years, changes in the gating process have emerged as common denominators for several genetically determined channelopathies affecting heart rhythm (arrhythmias), neuronal excitability (epilepsy, pain), or skeletal muscle contraction (periodic paralysis). Moreover, gating changes appear as the main molecular mechanism by which several natural toxins from a variety of species affect ion channel function. In this work, we describe the pathophysiological and pharmacological relevance of the gating process in voltage-gated K(+) channels encoded by the K(v)7 gene family. After reviewing the current knowledge on the molecular mechanisms and on the structural models of voltage-dependent gating in VGICs, we describe the physiological relevance of these channels, with particular emphasis on those formed by K(v)7.2-K(v)7.5 subunits having a well-established role in controlling neuronal excitability in humans. In fact, genetically determined alterations in K(v)7.2 and K(v)7.3 genes are responsible for benign familial neonatal convulsions, a rare seizure disorder affecting newborns, and the pharmacological activation of K(v)7.2/3 channels can exert antiepileptic activity in humans. Both mutation-triggered channel dysfunction and drug-induced channel activation can occur by impeding or facilitating, respectively, channel sensitivity to membrane voltage and can affect overlapping molecular sites within the voltage-sensing domain of these channels. Thus, understanding the molecular steps involved in voltage-sensing in K(v)7 channels will allow to better define the pathogenesis of rare human epilepsy, and to design innovative pharmacological strategies for the treatment of epilepsies and, possibly, other human diseases characterized by neuronal hyperexcitability. PMID- 21687500 TI - The grand challenge for integrative and regenerative pharmacology. PMID- 21687502 TI - Hyperforin, an Anti-Inflammatory Constituent from St. John's Wort, Inhibits Microsomal Prostaglandin E(2) Synthase-1 and Suppresses Prostaglandin E(2) Formation in vivo. AB - The acylphloroglucinol hyperforin (Hyp) from St. John's wort possesses anti inflammatory and anti-carcinogenic properties which were ascribed among others to the inhibition of 5-lipoxygenase. Here, we investigated whether Hyp also interferes with prostanoid generation in biological systems, particularly with key enzymes participating in prostaglandin (PG)E(2) biosynthesis, i.e., cyclooxygenases (COX)-1/2 and microsomal PGE(2) synthase (mPGES)-1 which play key roles in inflammation and tumorigenesis. Similar to the mPGES-1 inhibitors MK-886 and MD-52, Hyp significantly suppressed PGE(2) formation in whole blood assays starting at 0.03-1 MUM, whereas the concomitant generation of COX-derived 12(S) hydroxy-5-cis-8,10-trans-heptadecatrienoic acid, thromboxane B(2), and 6-keto PGF(1alpha) was not significantly suppressed up to 30 MUM. In cell-free assays, Hyp efficiently blocked the conversion of PGH(2) to PGE(2) mediated by mPGES-1 (IC(50) = 1 MUM), and isolated COX enzymes were not (COX-2) or hardly (COX-1) suppressed. Intraperitoneal (i.p.) administration of Hyp (4 mg kg(-1)) to rats impaired exudate volume and leukocyte numbers in carrageenan-induced pleurisy associated with reduced PGE(2) levels, and Hyp (given i.p.) inhibited carrageenan induced mouse paw edema formation (ED(50) = 1 mg kg(-1)) being superior over indomethacin (ED(50) = 5 mg kg(-1)). We conclude that the suppression of PGE(2) biosynthesis in vitro and in vivo by acting on mPGES-1 critically contributes to the anti-inflammatory efficiency of Hyp. PMID- 21687503 TI - Recent advances in the pathogenesis and drug action in periodic paralyses and related channelopathies. AB - The periodic paralysis (PP) are rare autosomal-dominant disorders associated to mutations in the skeletal muscle sodium, calcium, and potassium channel genes characterized by muscle fiber depolarization with un-excitability, episodes of weakness with variations in serum potassium concentrations. Recent advances in thyrotoxic PP and hypokalemic PP (hypoPP) confirm the involvement of the muscle potassium channels in the pathogenesis of the diseases and their role as target of action for drugs of therapeutic interest. The novelty in the gating pore currents theory help to explain the disease symptoms, and open the possibility to more specifically target the disease. It is now known that the fiber depolarization in the hypoPP is due to an unbalance between the novel identified depolarizing gating pore currents (I(gp)) carried by protons or Na(+) ions flowing through aberrant alternative pathways of the mutant subunits and repolarizing inwardly rectifying potassium channel (Kir) currents which also includes the ATP-sensitive subtype. Abnormal activation of the I(gp) or deficiency in the Kir channels predispose to fiber depolarization. One pharmacological strategy is based on blocking the I(gp) without affecting normal channel gating. It remains safe and effective the proposal of targeting the K(ATP), Kir channels, or BK channels by drugs capable to specifically open at nanomolar concentrations the skeletal muscle subtypes with less side effects. PMID- 21687505 TI - Anti-inflammatory and immunomodulatory effects of paeonia lactiflora pall., a traditional chinese herbal medicine. AB - In China, Korea, and Japan, a decoction of the dried root without bark of Paeonia lactiflora Pall. has been used in the treatment of rheumatoid arthritis, systemic lupus erythematosus, hepatitis, dysmenorrhea, muscle cramping and spasms, and fever for more than 1200 years. A water/ethanol extract of the root is now known as total glucosides of peony (TGP), which contains more than 15 components. Paeoniflorin is the most abundant ingredient and accounts for the pharmacological effects observed with TGP in both in vitro and in vivo studies. The analgesic effect of TGP was confirmed in various animal models of pain, which may be mediated partly by adenosine A1 receptor. The direct anti-inflammatory effects of TGP were observed in animal models of both acute and subacute inflammation, by inhibiting the production of prostaglandin E2, leukotriene B4, and nitric oxide, and by suppressing the increase of intracellular calcium ion concentration. TGP was also reported to have protective effects of cells against oxidative stress. In vitro, dual effects of TGP were noted on the proliferation of lymphocytes, differentiation of Th/Ts lymphocytes, and the production of proinflammatory cytokines and antibodies. In vivo, TGP inhibited the delayed-type hypersensitivity in immuno-activated mice, and enhanced the delayed-type hypersensitivity in immuno-suppressed mice. In adjuvant arthritis rats, paeoniflorin exerted immunosuppressive effects. The beneficial effects of TGP in treating rheumatoid arthritis were verified by randomized controlled trials. The adverse events of TGP were mainly gastrointestinal tract disturbances, mostly mild diarrhea. PMID- 21687504 TI - Selectivity and specificity of sphingosine-1-phosphate receptor ligands: caveats and critical thinking in characterizing receptor-mediated effects. AB - Receptors for sphingosine-1-phosphate (S1P) have been identified only recently. Their medicinal chemistry is therefore still in its infancy, and few selective agonists or antagonists are available. Furthermore, the selectivity of S1P receptor agonists or antagonists is not well established. JTE-013 and BML-241 (also known as CAY10444), used extensively as specific S1P(2) and S1P(3) receptors antagonists respectively, are cases in point. When analyzing S1P induced vasoconstriction in mouse basilar artery, we observed that JTE-013 inhibited not only the effect of S1P, but also the effect of U46619, endothelin-1 or high KCl; JTE-013 strongly inhibited responses to S1P in S1P(2) receptor knockout mice. Similarly, BML-241 has been shown to inhibit increases in intracellular Ca(2+) concentration via P(2) receptor or alpha(1A)-adrenoceptor stimulation and alpha(1A)-adrenoceptor-mediated contraction of rat mesenteric artery, while it did not affect S1P(3)-mediated decrease of forskolin-induced cyclic AMP accumulation. Another putative S1P(1/3) receptor antagonist, VPC23019, does not inhibit S1P(3)-mediated vasoconstriction. With these examples in mind, we discuss caveats about relying on available pharmacological tools to characterize receptor subtypes. PMID- 21687506 TI - Human Urinary Bladder Strip Relaxation by the beta-Adrenoceptor Agonist Isoprenaline: Methodological Considerations and Effects of Gender and Age. AB - The present study was primarily designed to explore various methodological aspects related to organ bath experiments evaluating human detrusor relaxation by the beta-adrenoceptor agonist isoprenaline. Data are based upon a series of 30 consecutive patients, and this cohort was also used to explore possible effects of gender and age. KCl-induced contraction was related to strip length but not weight or cross-sectional area, indicating that the former is most suitable for data normalization. Storage of detrusor strips in cold buffer for up to 2 days did not affect contractile responses to KCl or efficacy of isoprenaline to cause relaxation but significantly affected the isoprenaline potency. No such alterations were observed with up to 1 day of cold storage. The type (KCl vs. passive tension) or strength of contractile stimulus had only minor effects on isoprenaline responses although these differences reached statistical significance in some cases. Similarly, gender and age had only minor if any effects on KCl-induced contraction or isoprenaline-induced relaxation, but the current data are too limited for robust conclusions. In summary we have evaluated experimental conditions for the testing of human detrusor strip contraction and relaxation which should be useful for future larger studies. PMID- 21687501 TI - Pharmacogenetics of antidepressants. AB - Up to 60% of depressed patients do not respond completely to antidepressants (ADs) and up to 30% do not respond at all. Genetic factors contribute for about 50% of the AD response. During the recent years the possible influence of a set of candidate genes as genetic predictors of AD response efficacy was investigated by us and others. They include the cytochrome P450 superfamily, the P glycoprotein (ABCB1), the tryptophan hydroxylase, the catechol-O methyltransferase, the monoamine oxidase A, the serotonin transporter (5-HTTLPR), the norepinephrine transporter, the dopamine transporter, variants in the 5 hydroxytryptamine receptors (5-HT1A, 5-HT2A, 5-HT3A, 5-HT3B, and 5-HT6), adrenoreceptor beta-1 and alpha-2, the dopamine receptors (D2), the G protein beta 3 subunit, the corticotropin releasing hormone receptors (CRHR1 and CRHR2), the glucocorticoid receptors, the c-AMP response-element binding, and the brain derived neurotrophic factor. Marginal associations were reported for angiotensin I converting enzyme, circadian locomotor output cycles kaput protein, glutamatergic system, nitric oxide synthase, and interleukin 1-beta gene. In conclusion, gene variants seem to influence human behavior, liability to disorders and treatment response. Nonetheless, gene * environment interactions have been hypothesized to modulate several of these effects. PMID- 21687507 TI - Caenorhabditis Elegans Mutants Predict Regulation of Fatty Acids and Endocannabinoids by the CYP-35A Gene Family. AB - BACKGROUND: Cytochrome P450s (CYPs) are mono-oxygenases that metabolize endogenous compounds, such as fatty acids and lipid signaling molecules, and furthermore have a role in metabolism of xenobiotics. In order to investigate the role of CYP genes in fat metabolism at the molecular level, four Caenorhabditis elegans mutants lacking functional CYP-35A1, CYP-35A2, CYP-35A4, and CYP-35A5 were characterized. Relative amounts of fatty acids, as well as endocannabinoids, which regulate weight gain and accumulation of fats in mammals, were measured while fat contents in worms were visualized using Oil-Red-O staining. RESULTS: The cyp-35A1 and cyp-35A5 mutants had a significantly lower intestinal fat content than wild-type animals, whereas cyp-35A2 and cyp-35A4 mutants appeared normal. The overall fatty acid compositions of CYP mutants did not alter dramatically, although modest but significant changes were observed. cyp-35A1 and cyp-35A5 mutants had significantly higher levels of C18:1n7 and lower C18:2n6c. All four mutants had higher relative amounts of C18:1n7 than the wild-type. In the cyp-35A5 mutant, the levels of the endocannabinoid anandamide were found to be 4.6-fold higher than in wild-type. Several fatty acid synthesis genes were over-expressed in cyp-35A1 including fat-2. Feeding oleic or elaidic triglycerides to wild-type animals demonstrated that cyp-35A1 transcriptional levels are insensitive to environmental exposure of these fats, while cyp-35A2, cyp-35A4, and cyp-35A5 were significantly down regulated. CONCLUSION: These results demonstrate a dynamic role for CYP-35A subfamily members in maintaining the diversity of fatty acid profiles in C. elegans, and more generally highlight the importance of CYPs in generating both structural and signaling fatty acid functions in other organisms. PMID- 21687508 TI - Chewing-stick practices using plants with anti-streptococcal activity in a ugandan rural community. AB - BACKGROUND: The high dental disease burden in developing countries has created a need to explore and develop cheap and accessible methods of dental disease prevention. Traditional toothbrushes (chewing-sticks) prepared from specific plants have been used for dental hygiene for generations. When properly used, chewing-sticks may be as effective as synthetic toothbrushes. This study set out to describe traditional chewing-stick practices in a Ugandan rural community, and evaluate the antibacterial activity of two most commonly used plants. METHODS: Interviews were done to identify chewing-stick plants and obtain socio-cultural information relating to the practice in two villages in rural Uganda. Field walks were done to pick and voucher the plants, for taxonomical identification and storage. For the two most reported plants, aqueous extracts were prepared and tested for antibacterial activity against Streptococcus mutans using the agar well diffusion method. RESULTS: Of the 21 key informants interviewed, all were using or had used chewing-sticks in the past. A total of eight plants were identified as sources of chewing-sticks, with Rhus vulgaris and Lantana trifolia most commonly mentioned. Chewing-sticks were preferred over synthetic tooth brushes because they were less likely to traumatize the gums. Their use has been limited of recent due to scarcity of some plants. R. vulgaris and L. trifolia aqueous extracts showed antibacterial activity against S. mutans with mean diameters of inhibition of 24.33 +/- 0.58 and 14.17 +/- 0.29 mm on Blood agar respectively, compared to benzyl penicillin control 30.67 +/- 0.29 mm. CONCLUSION: R. vulgaris and L. trifolia are the most common sources of chewing sticks for cleaning teeth in this community. The plants contain compounds that are active against S. mutans. These plants merit further studies as they are possible sources of cheap dental health care for the rural poor. PMID- 21687509 TI - Pleiotropic effects of glitazones: a double edge sword? AB - Glitazones (thiazolidinediones) are drugs used for diabetes mellitus type 2. By binding to peroxisome proliferator-activated receptor gamma (PPARgamma) they modulate transcription of genes of carbohydrate and lipid metabolism. Through PPARgamma stimulation, however, glitazones also affect other genes, encompassing inflammation, cell growth and differentiation, angiogenesis, which broads their therapeutic potential. The gene expression profile induced by each glitazone shows peculiarities, which may affect its benefit/risk balance; indeed, troglitazone and rosiglitazone have been associated with liver failure and coronary disease, respectively; whether or not these severe adverse effects are solely related to PPARgamma remains yet unclear, since glitazones exert also PPARgamma-independent effects. Glitazone chemistry serves as scaffold for synthesizing new compounds with PPARgamma-independent pharmacological properties and we report here a preliminary observation of inhibition of vasoconstriction by troglitazone in isolated vessels, an effect that appears fast, reversible, and PPARgamma-independent. Pleiotropic effects of glitazones need specific attention in terms of drug safety, but also provide basis for drug development and novel experimental therapeutics. PMID- 21687510 TI - Baicalin induced dendritic cell apoptosis in vitro. AB - This study was aimed to investigate the effects of baicalin (BA), a major flavonoid constituent found in the herb Baikal skullcap, on dendritic cells (DCs). DCs were generated by culturing murine bone marrow (BM) cells for 6 days with granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4, and lipopolysaccharide (LPS) was added on day 5 to stimulate DCs maturation. The expression levels of DC maturity markers (CD80/CD86) were assessed by flow cytometry using direct immunofluorescence method. IL-12 levels in the culture supernatants were assayed by ELISA. Apoptosis of DCs was analyzed by flow cytometry after annexin V/propidium iodide staining. The mitochondrial membrane potential (Deltapsi(m)) changes were measured by using the J-aggregate forming lipophilic cation 5,5',6,6'-tetrachloro-1,1',3,3' tetraethylbenzimidazolcarbocyanine iodide (JC-1). Exposure of DCs to BA (2-50 MUM) during BM cell differentiation showed no effects on the up-regulation of CD80/CD86 expression on DCs in response to LPS stimulation, but reduced DCs recovery by inducing apoptosis, and significantly inhibited the release of IL-12 to culture supernatants. BA-induced DC apoptosis in a time- and dose-dependent way, and immature DCs were more sensitive for BA-induced apoptosis than mature DC. BA also induced Deltapsi(m) changes in DCs. These results demonstrate that BA induces selective apoptosis in immature DCs possibly through mitochondria mediated pathway. PMID- 21687511 TI - Concordance between Sources of Morbidity Reports: Self-Reports and Medical Records. AB - As part of a 10-year follow-up study of morbidity following spouse bereavement, concordance between subject reports of their illness experience and that given by their doctors' and other medical records has been assessed. Enumeration from medical records involved extensive and careful perusal of general practitioner, specialist, and hospital records while subject reports were aided by a structured questionnaire which helped to prompt subjects' memories. The findings showed generally poor concordance between these two sources of morbidity data. Overall only 22% of disease events were found in both sources: of the diseases that did not match 65% were from the record source and 35% were from the self-report source. Despite finding that concordance rates varied with some subject and disease factors, concordance was always less than might be expected to occur by random chance (the throw of a coin). These findings have serious implications for epidemiological and pharmacoeconomic research involving morbidity history as they suggest that neither the subject nor their medical record can generally be assumed to provide a complete enumeration of morbidity burden. Indeed, irrespective of the significant factors under consideration, the maximum concordance reached in this study was 45.7%. PMID- 21687512 TI - Hydrogen Therapy may be a Novel and Effective Treatment for COPD. AB - The protective effect of hydrogen (H(2)) on ROS-induced diseases has been proved by many researches, which demonstrated that through eliminating *OH and *ONOO-, H(2) could effectively attenuate lipid and DNA peroxidation, improve cellular antioxidant capacity, and then protect cells against oxidant damage. Most of free radicals in human body are ROS, including O(2)*-,*OH, H(2)O(2), NO*,*ONOO-, and so on. Under normal circumstances cells are able to maintain an adequate homeostasis between the formation and removal of ROS through particular enzymatic pathways or antioxidants. But under some pathological conditions, the balance is disturbed, leading to oxidative stress and various diseases, such as chronic obstructive pulmonary disease (COPD). Studies have shown that ROS played a pivotal role in the development of COPD and some antioxidants were effective in the protection against the damaging effects of oxidative stress. Therefore, we hypothesize that owing to its peculiarity to eliminate toxic ROS, hydrogen therapy may be a novel and effective treatment for COPD. PMID- 21687513 TI - Therapeutic strategies in pulmonary hypertension. AB - Pulmonary hypertension (PH) is a life-threatening condition characterized by elevated pulmonary arterial pressure. It is clinically classified into five groups: patients in the first group are considered to have pulmonary arterial hypertension (PAH) whereas patients of the other groups have PH that is due to cardiopulmonary or other systemic diseases. The management of patients with PH has advanced rapidly over the last decade and the introduction of specific treatments especially for PAH has lead to an improved outcome. However, despite the progress in the treatment, the functional limitation and the survival of these patients remain unsatisfactory and there is no cure for PAH. Therefore the search for an "ideal" therapy still goes on. At present, two levels of treatment can be identified: primary and specific therapy. Primary therapy is directed at the underlying cause of the PH. It also includes a supportive therapy consisting in oxygen supplementation, diuretics, and anticoagulation which should be considered in all patients with PH. Specific therapy is directed at the PH itself and includes treatment with vasodilatators such as calcium channel blockers and with vasodilatator and pathogenetic drugs such as prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors. These drugs act in several pathogenetic mechanisms of the PH and are specific for PAH although they might be used also in the other groups of PH. Finally, atrial septostomy and lung transplantation are reserved for patients refractory to medical therapy. Different therapeutic approaches can be considered in the management of patients with PH. Therapy can be established on the basis of both the clinical classification and the functional class. It is also possible to adopt a goal oriented therapy in which the timing of treatment escalation is determined by inadequate response to known prognostic indicators. PMID- 21687514 TI - Stroke, high blood pressure and the Renin-Angiotensin-aldosterone system - new developments. AB - This review considers whether a case can be made for a protective effect of inhibitors and blockers of the renin-angiotensin-aldosterone system (RAAS) on the cerebral circulation. It first looks at whether there exists a preferential effect on the cerebral circulation during a drug-induced lowering of high arterial blood pressure and cardiovascular morbi-mortality. It then goes on to consider background studies on the relationship between inhibition of the RAAS and stroke. This is followed by exploration of possible new directions in the inhibition of the RAAS and its effect on stroke. PMID- 21687515 TI - Beneficial effects of anisodamine in shock involved cholinergic anti-inflammatory pathway. AB - Anisodamine, an antagonist of muscarinic receptor, has been used therapeutically to improve blood flow in circulatory disorders such as septic shock in China since 1965. The main mechanism of anisodamine for anti-shock proposed in Pharmacology for Chinese medical students is to improve blood flow in the microcirculation. Here, we suggest a new mechanism for its anti-shock effect. That is, anisodamine, by blocking muscarinic receptor, results in rerouting of acetylcholine to alpha7 nicotinic acetylcholine receptor (alpha7nAChR) bringing about increased acetylcholine-mediated activation of alpha7nAChR and the cholinergic anti-inflammatory pathway. PMID- 21687516 TI - Prostacyclin: an inflammatory paradox. AB - Prostacyclin (PGI(2)) is a member of the prostaglandin family of bioactive lipids. Its best-characterized role is in the cardiovascular system, where it is released by vascular endothelial cells, serving as a potent vasodilator and inhibitor of platelet aggregation. In recent years, prostacyclin (PGI(2)) has also been shown to promote differentiation and inhibit proliferation in vascular smooth muscle cells. In addition to these well-described homeostatic roles within the cardiovascular system, prostacyclin (PGI(2)) also plays an important role as an inflammatory mediator. In this review, we focus on the contribution of prostacyclin (PGI(2)) as both a pathophysiological mediator and therapeutic agent in three major inflammatory-mediated disease processes, namely rheumatoid arthritis, where it promotes disease progression ("pro-inflammatory"), along with pulmonary vascular disease and atherosclerosis, where it inhibits disease progression ("anti-inflammatory"). The emerging role of prostacyclin (PGI(2)) in this context provides new opportunities for understanding the complex molecular basis for inflammatory-related diseases, and insights into the development of current and future anti-inflammatory treatments. PMID- 21687518 TI - Selectivity and specificity of sphingosine 1-phosphate receptor ligands: "off targets" or complex pharmacology? AB - A recent perspective published in Frontiers of Pharmacology by Salomone and Waeber (2011) discussed the selectivity and specificity of sphingosine 1 phosphate (S1P) receptor ligands. This perspective surveyed the use of various S1P receptor ligands and attempted to reconcile a number of inconsistencies in the predicted biological outcomes: these were interpreted as "off-target" effects. Therefore the perspective cautioned against the use of these S1P receptor ligands. Here we highlight the complex pharmacology of S1P receptors, which along with "inside-out" signaling might provide an alternative explanation for "off-target" effects. PMID- 21687517 TI - The Pharmacology of TD-8954, a Potent and Selective 5-HT(4) Receptor Agonist with Gastrointestinal Prokinetic Properties. AB - This study evaluated the in vitro and in vivo pharmacological properties of TD 8954, a potent and selective 5-HT(4) receptor agonist. TD-8954 had high affinity (pK(i) = 9.4) for human recombinant 5-HT(4(c)) (h5-HT(4(c))) receptors, and selectivity (>2,000-fold) over all other 5-hydroxytryptamine (5-HT) receptors and non-5-HT receptors, ion channels, enzymes and transporters tested (n = 78). TD 8954 produced an elevation of cAMP in HEK-293 cells expressing the h5-HT(4(c)) receptor (pEC(50) = 9.3), and contracted the guinea pig colonic longitudinal muscle/myenteric plexus preparation (pEC(50) = 8.6). TD-8954 had moderate intrinsic activity in the in vitro assays. In conscious guinea pigs, subcutaneous administration of TD-8954 (0.03-3 mg/kg) increased the colonic transit of carmine red dye, reducing the time taken for its excretion. Following intraduodenal dosing to anesthetized rats, TD-8954 (0.03-10 mg/kg) evoked a dose-dependent relaxation of the esophagus. Following oral administration to conscious dogs, TD 8954 (10 and 30 MUg/kg) produced an increase in contractility of the antrum, duodenum, and jejunum. In a single ascending oral dose study in healthy human subjects, TD-8954 (0.1-20 mg) increased bowel movement frequency and reduced the time to first stool. It is concluded that TD-8954 is a potent and selective 5 HT(4) receptor agonist in vitro, with robust in vivo stimulatory activity in the gastrointestinal (GI) tract of guinea pigs, rats, dogs, and humans. TD-8954 may have clinical utility in patients with disorders of reduced GI motility. PMID- 21687520 TI - Introducing Artificial DNA: PNA & XNA. PMID- 21687521 TI - Direct observation of two cyclohexenyl (CeNA) ring conformations in duplex DNA. AB - Cyclohexene Nucleic Acids (CeNA), in which the 2'-deoxyribofuranose ring of the DNA building blocks is substituted by a cyclohexenyl ring, were designed as potential mimics of natural nucleic acids for antisense and, later, for siRNA applications. CeNA units, in contrast to HNA (hexitol nucleic acid) building blocks, show more flexibility at the level of the C2'-C3' bond due to the possibility of the cyclohexenyl moiety to adopt different conformations. In order to analyze the influence of CeNA residues onto the helix conformation and hydration of natural nucleic acid structures and to verify the cyclohexenyl ring conformation, a cyclohexenyl-thymine building block was incorporated into the non self-complementary sequence d(GCG(xT)GCG)/d(CGCACGC) with (xT) a cyclohexene residue. The crystal structure of this sequence has been determined to a resolution of 1.17 A and contains two duplexes in the asymmetric unit. The global helices belong to the B-type family and the conformations of the cyclohexenyl rings in both duplexes are different. The cyclohexene ring adopts as well the (2)H(3)-conformation (similar to C2'-endo) as the (3)H(2)-conformation (similar to C3'-endo). The crystal packing is stabilized by cobalt hexamine residues and triplet formation. PMID- 21687519 TI - MT-MMPS as Regulators of Vessel Stability Associated with Angiogenesis. AB - The development of vascular system depends on the coordinated activity of a number of distinct families of molecules including growth factors and their receptors, cell adhesion molecules, extracellular matrix (ECM) molecules, and proteolytic enzymes. Matrix metalloproteases (MMPs) are a family of ECM degrading enzymes required for both physiological and pathological angiogenesis. Increasing evidence, point to a direct role of membrane type-MMPs (MT-MMPs) in vascular system stabilization, maturation, and leakage. Our understanding of the nature of MT-MMP interaction with extracellular and cell surface molecules and their multiple roles in vessel walls and perivascular stroma may provide new insights into mechanisms underlying vascular cell-ECM interactions and cell fate decisions in pathological conditions. Regulation of vascular leakage by MT-MMP interactions with the ECM could also lead to novel targeting opportunities for drug delivery in tumor. This review will shed lights on the emerging roles of MT1-MMP and MT4 MMP in vascular system alterations associated with cancer progression. PMID- 21687522 TI - Improving gene silencing of siRNAs via tricyclo-DNA modification. AB - Small interfering RNAs (siRNAs) can be exploited for the selective silencing of disease-related genes via the RNA interference (RNAi) machinery and therefore raise hope for future therapeutic applications. Especially chemically modified siRNAs are of interest as they are expected to convert lead siRNA sequences into effective drugs. To study the potential of tricyclo-DNA (tc-DNA) in this context we systematically incorporated tc-DNA units at various positions in a siRNA duplex targeted to the EGFP gene that was expressed in HeLa cells. Silencing activity was measured by FACS, mRNA levels were determined by RT-PCR and the biostability of the modifed siRNAs was determined in human serum. We found that modifications in the 3'-overhangs in both the sense and antisense strands were compatible with the RNAi machinery leading to similar activities compared to wild type (wt) siRNA. Additional modifications at the 3'-end, the 5'-end and in the center of the sense (passenger) strand were also well tolerated and did not compromise activity. Extensive modifications of the 3'- and the 5'-end in the antisense (guide) strand, however, abolished RNAi activity. Interestingly, modifications in the center of the duplex on both strands, corresponding to the position of the cleavage site by AGO2, increased efficacy relative to wt by a factor of 4 at the lowest concentrations (2 nM) investigated. In all cases, reduction of EGFP fluorescence was accompanied with a reduction of the EGFP mRNA level. Serum stability analysis further showed that 3'-overhang modifications only moderately increased stability while more extensive substitution by tc-DNA residues significantly enhanced biostability. PMID- 21687523 TI - Inhibition of hepatitis B virus replication in vivo using lipoplexes containing altritol-modified antiviral siRNAs. AB - Chronic infection with the hepatitis B virus (HBV) occurs in approximately 6% of the world's population and carriers of the virus are at risk for complicating hepatocellular carcinoma. Current treatment options have limited efficacy and chronic HBV infection is likely to remain a significant global medical problem for many years to come. Silencing HBV gene expression by harnessing RNA interference (RNAi) presents an attractive option for development of novel and effective anti HBV agents. However, despite significant and rapid progress, further refinement of existing technologies is necessary before clinical application of RNAi-based HBV therapies is realized. Limiting off target effects, improvement of delivery efficiency, dose regulation and preventing reactivation of viral replication are some of the hurdles that need to be overcome. To address this, we assessed the usefulness of the recently described class of altritol containing synthetic siRNAs (ANA siRNAs), which were administered as lipoplexes and tested in vivo in a stringent HBV transgenic mouse model. Our observations show that ANA siRNAs are capable of silencing of HBV replication in vivo. Importantly, non specific immunostimulation was observed with unmodified siRNAs and this undesirable effect was significantly attenuated by ANA modification. Inhibition of HBV replication of approximately 50% was achieved without evidence for induction of toxicity. These results augur well for future application of ANA siRNA therapeutic lipoplexes. PMID- 21687524 TI - Peptide nucleic acid probes with charged photocleavable mass markers: Towards PNA based MALDI-TOF MS genetic analysis. AB - Halogen-labelled peptide organic acid (HPOA) monomers have been synthesised and incorporated into sequence-specific peptide nucleic acid (PNA) probes. Three different types of probe have been prepared; the unmodified PNA probe, the PNA probe with a mass marker, and the PNA probe with photocleavable mass marker. All three types of probe have been used in model studies to develop a mass spectrometry-based hybridisation assay for detection of point mutations in DNA. PMID- 21687525 TI - In vivo efficacy and off-target effects of locked nucleic acid (LNA) and unlocked nucleic acid (UNA) modified siRNA and small internally segmented interfering RNA (sisiRNA) in mice bearing human tumor xenografts. AB - The clinical use of small interfering RNA (siRNA) is hampered by poor uptake by tissues and instability in circulation. In addition, off-target effects pose a significant additional problem for therapeutic use of siRNA. Chemical modifications of siRNA have been reported to increase stability and reduce off target effects enabling possible therapeutic use of siRNA. Recently a large scale direct comparison of the impact of 21 different types of novel chemical modifications on siRNA efficiency and cell viability was published.1 It was found that several types of chemical modifications could enhance siRNA activity beyond that of an unmodified siRNA in vitro. In addition, a novel siRNA design, termed small internally segmented interfering RNA (sisiRNA), composed of an intact antisense strand and segmented guide strand stabilized using LNA was shown to be effective in cell based assays. In the present study we examined the in vivo efficacy of the LNA and UNA modified siRNA and sisiRNA in a mouse model bearing human tumor xenografts. We studied the biodistribution and efficacy of target knockdown in the mouse model. In addition we used whole genome profiling to assess the off-target effects in the liver of the mouse and the tumor xenografts. We report that LNA and UNA modified siRNA and sisiRNA improve the efficacy in target knockdown as compared with unmodified siRNA in the tumor xenografts without formulation. However, the level of off-target gene regulation in both the tumor and the liver correlated with the increase in efficacy in target knockdown, unless the seed region of the siRNA was modified. PMID- 21687526 TI - Sequence specificity at targeting double-stranded DNA with a gamma-PNA oligomer modified with guanidinium G-clamp nucleobases. AB - gamma-PNA, a new class of peptide nucleic acids, promises to overcome previous sequence limitations of double-stranded DNA (dsDNA) targeting with PNA. To check the potential of gamma-PNA, we have synthesized a biotinylated, pentadecameric gamma-PNA of mixed sequence carrying three guanidinium G-clamp nucleobases. We have found that strand invasion reactions of the gamma-PNA oligomer to its fully complementary target within dsDNA occurs with significantly higher binding rates than to targets containing single mismatches. Association of the PNA oligomer to mismatched targets does not go to completion but instead reaches a stationary level at or below 60%, even at conditions of very low ionic strength. Initial binding rates to both matched and mismatched targets experience a steep decrease with increasing salt concentration. We demonstrate that a linear DNA target fragment with the correct target sequence can be purified from DNA mixtures containing mismatched target or unrelated genomic DNA by affinity capture with streptavidin-coated magnetic beads. Similarly, supercoiled plasmid DNA is obtained with high purity from an initial sample mixture that included a linear DNA fragment with the fully complementary sequence. Based on the results obtained in this study we believe that gamma-PNA has a great potential for specific targeting of chosen duplex DNA sites in a sequence-unrestricted fashion. PMID- 21687527 TI - Mega-cloning and the advent of synthetic genomes. AB - Molecular biology owes its prominent role in the biological sciences to the tools of recombinant DNA. While the foundations of recombinant DNA were laid in the 1970s with the discovery of type II restriction endonucleases,1,2 development of robust sequencing technology3 and pioneering work on gene synthesis,4,5 it was not until the turn of the new millennium before the first complete synthetic viral genomes saw the light of day including that of hepatitis C,6 poliovirus,7 and bacteriophage PhiX174.8 Recombinant DNA has come of age as entire cellular genomes are sequenced and stored as digitized information. So what's next? One novel branch of recombinant DNA, referred to as synthetic genomics,9 is occupied with (re)construction of entire cellular genomes from virtual sequence information and using chemical components. Here we look at the most recent developments in such de novo construction. For a broader and more extensive review on genome engineering, the reader is referred to the excellent paper by Carr and Church.10. PMID- 21687528 TI - Natural - synthetic - artificial! AB - The terms "natural," "synthetic" and "artificial" are discussed in relation to synthetic and artificial chromosomes and genomes, synthetic and artificial cells and artificial life. PMID- 21687529 TI - Bacteriophage: A new journal for the most ubiquitous organisms on Earth. PMID- 21687530 TI - Genomic and molecular analysis of phage CMP1 from Clavibacter michiganensis subspecies michiganensis. AB - Bacteriophage CMP1 is a member of the Siphoviridae family that infects specifically the plant-pathogen Clavibacter michiganensis subsp. michiganensis. The linear double- stranded DNA is terminally redundant and not circularly permuted. The complete nucleotide sequence of the bacteriophage CMP1 genome consists of 58,652 bp including the terminal redundant ends of 791 bp. The G+C content of the phage (57%) is significantly lower than that of its host (72.66%). 74 potential open reading frames were identified and annotated by different bioinformatic tools. Two large clusters which encode the early and the late functions could be identified which are divergently transcribed. There are only a few hypothetical gene products with conserved domains and significant similarity to sequences from the databases. Functional analyses confirmed the activity of four gene products, an endonuclease, an exonuclease, a single-stranded DNA binding protein and a thymidylate synthase. Partial genomic sequences of CN77, a phage of Clavibacter michiganensis subsp. nebraskensis, revealed a similar genome structure and significant similarities on the level of deduced amino acid sequences. An endolysin with peptidase activity has been identified for both phages, which may be good tools for disease control of tomato plants against Clavibacter infections. PMID- 21687531 TI - Naturally resident and exogenously applied T4-like and T5-like bacteriophages can reduce Escherichia coli O157:H7 levels in sheep guts. AB - In preparing sheep for an in vivo Escherichia coli O157:H7 eradication trial, we found that 20/39 members of a single flock were naturally colonized by O157:H7 infecting phages. Characterization showed these were all one phage type (subsequently named CEV2) infecting 15/16 O157:H7, 7/72 ECOR and common lab strains. Further characterization by PFGE (genome~120 kb), restriction enzyme digest (DNA appears unmodified), receptor studies (FhuA but not TonB is required for infection) and sequencing (>95% nucleotide identity) showed it is a close relative of the classically studied coliphage T5. Unlike T5, CEV2 infects O157:H7 in vitro, both aerobically and anaerobically, rapidly adsorbing and killing, but resistant mutants regrew within 24 h. When used together with T4-like CEV1 (MOI ~2 per phage), bacterial killing was longer lasting. CEV2 did not reproduce when co-infecting the same cell as CEV1, presumably succumbing to CEV1's ability to shut off transcription of cytosine-containing DNA. In vivo sheep trials to remove resident O157:H7 showed that a cocktail of CEV2 and CEV1 (~10(11) total PFU) applied once orally was more effective (>99.9% reduction) than CEV1 alone (~99%) compared to the untreated phage-free control. Those sheep naturally carrying CEV2, receiving no additional phage treatment, had the lowest O157:H7 levels (~99.99% reduction). These data suggest that phage cocktails are more effective than individual phage in removing O157:H7 that have taken residence if the phage work in concert with one another and that naturally resident O157:H7-infecting phages may prevent O157:H7 gut colonization and be one explanation for the transient O157:H7 colonization in ruminants. PMID- 21687532 TI - The lysis cassette of bacteriophage phiKMV encodes a signal-arrest-release endolysin and a pinholin. AB - The lysis cassette of Pseudomonas aeruginosa phage phiKMV encodes a holin, endolysin, Rz and Rz1 in the canonical order. It has a tight organization with a high degree of overlapping genes and is highly conserved (between 96 and 100% identity at the protein level) among several other members of the "phiKMV-like viruses." The endolysin KMV45 exhibits characteristics as expected for a signal arrest-release (SAR) endolysin, whereas the holin KMV44 is a typical pinholin. KMV45 is initially secreted as an inactive, membrane-anchored endolysin, which is subsequently released by membrane depolarization driven by the pinholin KMV44. The SAR domain of KMV45 is necessary for its full enzymatic activity, suggesting a refolding of the catalytic cleft upon release from the membrane. The physical proximity of the catalytic glutamic acid residue close to SAR domain suggests an alternative activation mechanism compared to the SAR endolysin of phages P1, ERA103 and 21. Expression of KMV44 leads to a quick cell lysis when paired with SAR endolysin KMV45, but not with the cytoplasmic phage lambda endolysin, indicating the membrane depolarizing function of KMV44 rather than the large hole making function characteristic of classical holins. PMID- 21687534 TI - Lysis from without. AB - In this commentary I consider use of the term "lysis from without" (LO) along with the phenomenon's biological relevance. LO originally described an early bacterial lysis induced by high-multiplicity virion adsorption and that occurs without phage production (here indicated as LO(V)). Notably, this is more than just high phage multiplicities of adsorption leading to bacterial killing. The action on bacteria of exogenously supplied phage lysin, too, has been described as a form of LO (here, LO(L)). LO(V) has been somewhat worked out mechanistically for T4 phages, has been used to elucidate various phage-associated phenomena including discovery of the phage eclipse, may be relevant to phage ecology, and, with resistance to LO (LO(R)), is blocked by certain phage gene products. Speculation as to the impact of LO(V) on phage therapy also is fairly common. Since LO(V) assays are relatively easily performed and not all phages are able to induce LO(V), a phage's potential to lyse bacteria without first infecting should be subject to at least in vitro experimental confirmation before the LO(V) label is applied. The term "abortive infection" may be used more generally to describe non-productive phage infections that kill bacteria. PMID- 21687533 TI - Phages in nature. AB - Bacteriophages or phages are the most abundant organisms in the biosphere and they are a ubiquitous feature of prokaryotic existence. A bacteriophage is a virus which infects a bacterium. Archaea are also infected by viruses, whether these should be referred to as 'phages' is debatable, but they are included as such in the scope this article. Phages have been of interest to scientists as tools to understand fundamental molecular biology, as vectors of horizontal gene transfer and drivers of bacterial evolution, as sources of diagnostic and genetic tools and as novel therapeutic agents. Unraveling the biology of phages and their relationship with their hosts is key to understanding microbial systems and their exploitation. In this article we describe the roles of phages in different host systems and show how modeling, microscopy, isolation, genomic and metagenomic based approaches have come together to provide unparalleled insights into these small but vital constituents of the microbial world. PMID- 21687535 TI - In the beginning... PMID- 21687536 TI - Phage or Phages. PMID- 21687537 TI - Bilateral burkitt lymphoma of the ovaries: a report of a case in a child with williams syndrome. AB - A 10-year-old female with Williams Syndrome (WS) presented with a two-month history of fatigue, weight loss, and bilateral ovarian masses. Histologic, immunophenotypic, and cytogenetic studies confirmed the diagnosis of Burkitt lymphoma (BL). While there is no established association between the two disorders, this is the third case in the literature of Burkitt lymphoma in a patient with Williams Syndrome. PMID- 21687538 TI - Laparoendoscopic Single-Site (LESS) Retroperitoneal Radical Nephrectomy in a Patient with Renal Cell Carcinoma Receiving Hemodialysis. AB - We present here the patient undergoing laparoendoscopic single-site (LESS) retroperitoneal radical nephrectomy while receiving hemodialysis. An 81-year-old man under hemodialysis for 6 years was incidentally discovered to have two left renal masses with acquired cystic disease of the kidney (ACDK). A 4-cm flank incision for GelPort was made. Three trocars were inserted into the retroperitoneum through GelPort. After division of the renal vessels and ureter, the kidney was placed into the extraction bag and was retrieved through flank incision without any extra skin incision. There were no intraoperative and postoperative complications. This procedure offers an effective, minimally invasive therapeutic alternative to the standard laparoscopic technique in high risk end-stage renal disease patients. PMID- 21687539 TI - Direct determination of ECD in ECD Kit: a solid sample quantitation method for active pharmaceutical ingredient in drug product. AB - Technetium-99m ethyl cysteinate dimer (Tc-99m-ECD) is an essential imaging agent used in evaluating the regional cerebral blood flow in patients with cerebrovascular diseases. Determination of active pharmaceutical ingredient, that is, L-Cysteine, N, N'-1,2-ethanediylbis-, diethyl ester, dihydrochloride (ECD) in ECD Kit is a relevant requirement for the pharmaceutical quality control in processes of mass fabrication. We here presented a direct solid sample determination method of ECD in ECD Kit without sample dissolution to avoid the rapid degradation of ECD. An elemental analyzer equipped with a nondispersive infrared detector and a calibration curve of coal standard was used for the quantitation of sulfur in ECD Kit. No significant matrix effect was found. The peak area of coal standard against the amount of sulfur was linear over the range of 0.03-0.10 mg, with a correlation coefficient (r) of 0.9993. Method validation parameters were achieved to demonstrate the potential of this method. PMID- 21687540 TI - Breast fistula repair after autologous fat graft: a case report. AB - We report the case of a 55-year-old female patient who attended our clinic for the presence of a scar retraction in the upper pole of the left breast as a complication of breast augmentation. In the scar area, we observed an orifice that probing revealed to be a fistula. The patient was referred to surgical intervention under general anesthesia to obtain scar contracture release using autologous fat graft; one month after autologous fat injection, following healing of the fistula, the patient underwent a second surgical procedure to replace the left breast implant. Unexpectedly, two weeks after the surgical procedure, complete healing of the breast fistula within the scar area was observed; this observation was confirmed during the second surgical step for left breast implant repositioning, when we observed the absence of the fistula orifice in the breast implant cavity. Upon clinical examination at 1-year followup, tissue integrity was preserved. The patient's satisfaction was excellent. We have observed a possible additional effect of fat graft. PMID- 21687542 TI - A case of brucellosis presenting with multiple hypodense splenic lesions and bilateral pleural effusions. AB - Brucellosis is a zoonotic infectious disease, which mainly present with lymphoreticular system invovement. However any organ system can be attacked by the microorganism. In this paper we present a 52-year-old female patient who was admitted to the Infectious Diseases Department with complaints of fatigue, arthralgias, fever, and weight loss. In the medical examination and radiological analysis bilateral pleural effusions and hepatosplenomegaly were detected. Serum transaminase levels were two times higher than the upper limits of normal. Abdominal ultrasound revealed sludge in the gallbladder and multiple hypodense splenic lesions (the largest was 1 cm in diameter). Brucella melitensis was isolated from the blood culture of the patient. Rifampicin (600 mg/day) and doxycycline (200 mg/day) therapy was started. Follow-up chest radiography and ultrasonography revealed the absence of pleural effusion. Splenic lesions and hepatosplenomegaly were totally regressed. The patient has been followed for 3 months after 6 week antibiotic regimen without recurrence. Brucellosis was expected to be the cause of all pathological signs. PMID- 21687541 TI - The application of SELDI-TOF-MS in clinical diagnosis of cancers. AB - Cancer diagnosis is important, and the early diagnosis of cancers could predict a more successful treatment. The proteomic studies emerged to be useful in combined analyses of samples from patients and provide more accurate diagnosis when compared to the single-factor-based diagnosis. In recent years, cancer detection with surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS) is flourishing and brought significant progress in this area. This paper summarizes some recent results with this technique for cancer diagnosis. PMID- 21687544 TI - Acute interstitial pneumonia (hamman-rich syndrome) as a cause of idiopathic acute respiratory distress syndrome. AB - Hamman-Rich syndrome, also known as acute interstitial pneumonia, is a rare and fulminant form of idiopathic interstitial lung disease. It should be considered as a cause of idiopathic acute respiratory distress syndrome. Confirmatory diagnosis requires demonstration of diffuse alveolar damage on lung histopathology. The main treatment is supportive care. It is not clear if glucocorticoid therapy is effective in acute interstitial pneumonia. We report the case of a 77-year-old woman without pre-existing lung disease who initially presented with mild upper respiratory tract infection and then progressed to rapid onset of hypoxic respiratory failure similar to acute respiratory distress syndrome with unknown etiology. Despite glucocorticoid therapy, she did not achieve remission and expired after 35 days of hospitalization. The diagnosis of acute interstitial pneumonia was supported by the histopathologic findings on her lung biopsy. PMID- 21687543 TI - NK cells and psoriasis. AB - Psoriasis is a chronic condition of the skin characterised by distinctive scaly plaques. The immune system is now thought to play a major role in the development and pathogenesis of psoriasis with immune cells and cytokines influencing keratinocyte function. Keratinocytes in turn, can activate and recruit immune cells leading to a positive feedback loop in disease. Natural Killer (NK) cells are lymphocytes that are best known for killing virally infected and cancer cells. However, evidence is emerging to support a role for NK cells in psoriasis. NK cells are found in the inflammatory infiltrate in psoriatic skin lesions. They can produce a range of inflammatory cytokines, many of which are important in the pathogenesis of psoriasis. Recent genetic studies have identified a range of potential molecules relating to NK cell biology that are known to be important in psoriasis. This paper will discuss the evidence, both cellular and genetic, for NK cell involvement in psoriasis. PMID- 21687545 TI - Preoperative assessment of anomalous right coronary artery arising from the main pulmonary artery. AB - Anomalous origin of the right coronary artery from the pulmonary artery is a rare condition. Two cases are presented in this paper. One case was treated by ligation and coronary artery bypass. The other was treated by direct reimplantation of the anomalous coronary artery into the aorta. PMID- 21687546 TI - Histamine blood concentration in ischemic heart disease patients. AB - The aim of this study was to investigate histamine blood concentration in subjects suffering from different types of ischemic heart diseases during the period of eight days. Our results showed that the histamine blood level was associated with different types of ischemic heart diseases. The blood histamine level in all investigated patients was significantly higher when compared to control subjects (44.87 +/- 1.09 ng mL(-1)), indicating the increase of histamine release in patients suffering from coronary diseases. In patients suffering from ACS-UA and ACS-STEMI, the second day peak of histamine level occurs (90.85 +/- 6.34 ng mL(-1) and 121.7 +/- 6.34 ng mL(-1), resp.) probably as the reperfusion event. Furthermore, our data suggest that histamine can be additional parameter of myocardial ischemia along with cardiac specific enzymes and may prove to be an excellent single prognostic marker for multitude of ischemic heart diseases. PMID- 21687547 TI - Potential role of NK cells in the pathogenesis of inflammatory bowel disease. AB - NK cells are a major component of the innate immune system and play an important role in the tissue inflammation associated with autoimmune diseases such as inflammatory bowel disease (IBD). NK cells are unique in bearing both stimulatory and inhibitory receptors specific for MHC class I molecules, and their function is regulated by a series of inhibiting or activating signals. The delicate balance between activation and inhibition that decides NK cell final action provides an opportunity for their possible modulatory effect on specific therapeutic settings. Intestinal NK cells are phenotypically distinct from their counterparts in the blood and resemble "helper" NK cells, which have potentially important functions both in promoting antipathogen responses and in the maintenance of intestinal epithelial homeostasis. NK cell activities have been found to be significantly below normal levels in both remissive and active stages of IBD patients. However, some proinflammatory cytokines (e.g., IL-15, IL-21, and IL-23) could potently induce NK cell activation to secret high levels of proinflammatory cytokines (e.g., IFN-gamma and TNF) and promote the cytolytic activities against the target cells. This paper provides the characteristics of intestinal NK cells and their potential role in the pathogenesis of IBD. PMID- 21687548 TI - Flow cytometry as a diagnostic tool in the early diagnosis of aggressive lymphomas mimicking life-threatening infection. AB - Aggressive lymphomas can present with symptoms mimicking life-threatening infection. Flow cytometry (FC) is usually recommended for the classification and staging of lymphomas in patients with organomegaly and atypical cells in effusions and blood, after the exclusion of other possible diagnoses. FC may also have a place in the initial diagnostic investigation of aggressive lymphoma. Three cases are presented here of highly aggressive lymphomas in young adults, which presented with the clinical picture of fever of unknown origin (FUO) in patients severely ill. All followed a life-threatening clinical course, and two developed the hemophagocytic syndrome (HPS), but microbiological, immunological, and morphological evaluation and immunohistochemistry (IHC) failed to substantiate an early diagnosis. FC was the technique that provided conclusive diagnostic evidence of lymphoma, subsequently verified by IHC. Our experience with these three cases highlights the potential role of FC as an adjunct methodology in the initial assessment of possible highly aggressive lymphoma presenting with the signs and symptoms of life-threatening infection, although the definitive diagnosis should be established by biopsy. In such cases, FC can contribute to the diagnosis of lymphoma, independently of the presence of HPS. PMID- 21687550 TI - Low molecular weight heparin-induced skin necrosis: a case report. AB - Low molecular weight heparins (LMWHs) are the standard agents used for antithrombotic therapy and prophylaxis. Despite their widespread use, reports about adverse effects from LMWHs are very scarce. Heparin-induced skin necrosis at the injection site is a rare adverse effect, more commonly associated with unfractionated heparin (UFH) rather than with LMWH, while its mechanism remains unclear. This paper deals with the enoxaparin induced skin necrosis. PMID- 21687549 TI - Chronic heat stress weakened the innate immunity and increased the virulence of highly pathogenic avian influenza virus H5N1 in mice. AB - Chronic heat stress (CHS) can negatively affect immune response in animals. In this study we assessed the effects of CHS on host innate immunity and avian influenza virus H5N1 infection in mice. Mice were divided into two groups: CHS and thermally neutral (TN). The CHS treatment group exhibited reduced local immunity in the respiratory tract, including the number of pulmonary alveolar macrophages and lesions in the nasal mucosa, trachea, and lungs. Meanwhile, CHS retarded dendritic cells (DCs) maturation and reduced the mRNA levels of IL-6 and IFN-beta significantly (P < .05). After the CHS treatment, mice were infected with H5N1 virus. The mortality rate and viral load in the lungs of CHS group were higher than those of TN group. The results suggest that the CHS treatment could suppress local immunity in the respiratory tract and innate host immunity in mice significantly and moderately increased the virulence in H5N1-infected mice. PMID- 21687551 TI - Immunologic monitoring of cellular immune responses in cancer vaccine therapy. PMID- 21687552 TI - Prolonged Dyspnea after Interscalene Block: Attributed to Undiagnosed Addison's Disease and Myasthenia Gravis. AB - This report describes a patient who had a series of daily interscalene nerve blocks to treat pain following a shoulder manipulation for postsurgical stiffness. She experienced acute respiratory compromise that persisted for many weeks. All typical and unusual causes of these symptoms were ruled out. Her treating pulmonologist theorized that the ipsilateral carotid body had been injured. However, it was subsequently determined that the constellation of symptoms and their prolonged duration were best explained by a poor stress response from Addison's disease coupled with exacerbation of early onset myasthenia gravis. This patient's case is not a typical reaction to interscalene nerve blocks, and thus preoperative testing would not be recommended for myasthenia gravis or Addison's disease without underlying suspicion. We describe this report to inform physicians to consider a workup for these diagnoses if a typical workup rules out all usual causes of complications from an interscalene block. PMID- 21687553 TI - Minimizing the dysfunctional interplay between activity and recovery: A grounded theory on living with fibromyalgia. AB - The aim of this study was to generate a substantive theory, based on interviews with women with fibromyalgia, explaining how they manage their main concerns in daily life. The study has an inductive approach in line with classic grounded theory (Glaser, 1992). Twenty-three women living in the southwest region of Sweden were interviewed in-depth about their daily living with fibromyalgia and problems related to this. Probing and follow-up questions were asked by the interviewers when relevant. The interviews were transcribed verbatim and consecutively analysed in line with guidelines for grounded theory. The results showed that the main concern for women with fibromyalgia was to reach a balance in daily life. This concern was resolved by them using different strategies aimed at minimizing the dysfunctional interplay between activity and recovery (core category). This imbalance includes that the women are forcing themselves to live a fast-paced life and thereby tax or exceed their physical and psychological abilities and limits. Generally, the fibromyalgia symptoms vary and are most often unpredictable to the women. Pain and fatigue are the most prominent symptoms. However, pain-free periods occur, often related to intense engagement in some activity, relaxation or joy, but mainly the "pain gaps" are unpredictable. To reach a balance in daily life and manage the dysfunctional interplay between activity and recovery the women use several strategies. They are avoiding unnecessary stress, utilizing good days, paying the price for allowing oneself too much activity, planning activities in advance, distracting oneself from the pain, engaging in alleviating physical activities, and ignoring pain sensations. Distracting from the pain seems to be an especially helpful strategy as it may lead to "pain gaps". This strategy, meaning to divert attention from the pain, is possible to learn, or improve, in health promoting courses based on principles of cognitive behavioural therapy (CBT). We suggest that such courses are offered in primary care for patients with fibromyalgia or other types of longstanding pain. The courses should be led by registered nurses or psychologists, who are experienced in CBT and have extensive knowledge about theories on longstanding pain, stress and coping. Such courses would increase well-being and quality of life in women suffering from fibromyalgia. PMID- 21687554 TI - Reframing urban health, reconnecting public health and contextualizing HIV. Lessons from South Africa. PMID- 21687555 TI - Repertoire of SSRs in the Castor Bean Genome and Their Utilization in Genetic Diversity Analysis in Jatropha curcas. AB - Castor bean and Jatropha contain seed oil of industrial importance, share taxonomical and biochemical similarities, which can be explored for identifying SSRs in the whole genome sequence of castor bean and utilized in Jatropha curcas. Whole genome analysis of castor bean identified 5,80,986 SSRs with a frequency of 1 per 680 bp. Genomic distribution of SSRs revealed that 27% were present in the non-genic region whereas 73% were also present in the putative genic regions with 26% in 5'UTRs, 25% in introns, 16% in 3'UTRs and 6% in the exons. Dinucleotide repeats were more frequent in introns, 5'UTRs and 3'UTRs whereas trinucleotide repeats were predominant in the exons. The transferability of randomly selected 302 SSRs, from castor bean to 49 J. curcas genotypes and 8 Jatropha species other than J. curcas, showed that 211 (~70%) amplified on Jatropha out of which 7.58% showed polymorphisms in J. curcas genotypes and 12.32% in Jatropha species. The higher rate of transferability of SSR markers from castor bean to Jatropha coupled with a good level of PIC (polymorphic information content) value (0.2 in J. curcas genotypes and 0.6 in Jatropha species) suggested that SSRs would be useful in germplasm analysis, linkage mapping, diversity studies and phylogenetic relationships, and so forth, in J. curcas as well as other Jatropha species. PMID- 21687556 TI - Proteomic Analysis of Larval Midgut from the Silkworm (Bombyx mori). AB - The midgut is the major organ for food digestion, nutrient absorption and also a barrier for foreign substance. The 5th-instar larval stage of silkworm is very important for larval growth, development, and silk production. In the present study, we used 2-DE and matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF-MS) to analyze the midgut proteins from the 5th-instar larvae as well as the midgut proteins under starvation condition. A total of 96 proteins were identified in this study; and among them, 69 proteins were observed in midgut for the first time. We also found that the silkworm larval midgut responded to starvation by producing a 10 kDa heat shock protein and a diapause hormone precursor. PMID- 21687557 TI - Medical cost trajectories and onsets of cancer and noncancer diseases in US elderly population. AB - Time trajectories of medical costs-associated with onset of twelve aging-related cancer and chronic noncancer diseases were analyzed using the National Long-Term Care Survey data linked to Medicare Service Use files. A special procedure for selecting individuals with onset of each disease was developed and used for identification of the date at disease onset. Medical cost trajectories were found to be represented by a parametric model with four easily interpretable parameters reflecting: (i) prediagnosis cost (associated with initial comorbidity), (ii) cost of the disease onset, (iii) population recovery representing reduction of the medical expenses associated with a disease since diagnosis was made, and (iv) acquired comorbidity representing the difference between post- and pre diagnosis medical cost levels. These parameters were evaluated for the entire US population as well as for the subpopulation conditional on age, disability and comorbidity states, and survival (2.5 years after the date of onset). The developed approach results in a family of new forecasting models with covariates. PMID- 21687558 TI - Spinal Manipulation is Not an Emerging Risk Factor for Stroke Nor is it Major Head/Neck Trauma. Don't Just Read the Abstract! PMID- 21687560 TI - Improved dual-luciferase reporter assays for nuclear receptors. AB - Nuclear receptors play important roles in many cellular functions through control of gene transcription. It is also a large target class for drug discovery. Luciferase reporter assays are frequently used to study nuclear receptor function because of their wide dynamic range, low endogenous activity, and ease of use. Recent improvements of luciferase genes and vectors have further enhanced their utilities. Here we applied these improvements to two reporter formats for studying nuclear receptors. The first assay contains a Murine Mammary Tumor Virus promoter upstream of a destabilized luciferase. The presence of response elements for nuclear hormone receptor in this promoter allows the studies of endogenous and/or exogenous full length receptors. The second assay contains a ligand binding domain (LBD) of a nuclear receptor fused to the GAL4 DNA binding domain (DBD) on one vector and multiple Gal4 Upstream Activator Sequences (UAS) upstream of luciferase reporter on another vector. We showed that codon optimization of luciferase reporter genes increased expression levels in conjunction with the incorporation of protein destabilizing sequences into luciferase led to a larger assay dynamic range in both formats. The optimum number of UAS to generate the best response was determined. The expression vector for nuclear receptor LBD/GAL4 DBD fusion also constitutively expresses a Renilla luciferase-neo(R) fusion protein, which provides selection capability (G418 resistance, neo(R)) as well as an internal control (Renilla luciferase). This dual-luciferase format allowed detecting compound cytotoxicity or off-target change in expression during drug screening, therefore improved data quality. These luciferase reporter assays provided better research and drug discovery tools for studying the functions of full length nuclear receptors and ligand binding domains. PMID- 21687561 TI - Predictor model of root caries in older adults: reporting of evidence to the translational evidence mechanism. AB - Compared to younger adults, older adults are at greater risk for root caries. A model of root caries may assist dentists in predicting disease outcomes. OBJECTIVES: Using the Iowa 65+ Oral Health Survey, analysis was done to model the patterns of the root caries development in older adults. METHODS: The statistical analysis included Markov chain modeling, model estimation and validation. RESULTS: The model effectively predicts root caries using an 18-month predictive cycle and is validated up to 36 months (two cycles), with no significant differences (Chi-square test p-values >0.1) between predicted and observed distributions. However, we do not have observed data for validation beyond 36 months since the model was designed to perform only at single or multiple 18 month cycles. As expected, the predicted distribution at 54-month (3 cycles) and the observed distribution at 60-month differed significantly (p<0.0001). CONCLUSIONS: The model demonstrated a high probability that a sound surface will remain caries free. However, one and multiple-surface lesions aggressively infect adjoining surfaces. Maturing of the carious lesion occurs with the 4-surface lesion, decreasing the probability of tooth loss. Thus, maintaining a sound root surface and early treatment intervention reduces the risk of tooth dysfunction (morphological destruction) and loss. DATABASE FILTERS: P: Tooth/Subject characteristics-Older adults, 65 years of age or more, male and female participants, regional rural Iowa residents, race unspecified, functional status non-institutionalized level unspecified, risk level unspecified I: Root caries P (C-not applicable): Probability/Statistical significance for decision data only/Clinical significance-dataset over 20 years old/Utility data not included/Cost data not included/Meaning in practice undetermined. O: Each year through a three year cycle, caries progression from a sound root surface A: Data attached: ? Published manuscript ? Unpublished manuscript ? Raw data R: Primary author contact information present. PMID- 21687562 TI - E-health for individualized prevention of eating disorders. AB - In the field of illness prevention, it is becoming increasingly important that effective treatments be broadly disseminated and easily accessible to large populations located over wide geographical areas. The internet offers many opportunities to improve illness prevention and has become an important tool for both providers and users. An increasing number of users are looking for help on web-pages, in forums and chat rooms, to access information and exchange experiences with other users or counselors. Appetite for Life is an Internet based program for the prevention of eating disorders (ED) in college students. It provides individualized support to students at-risk of developing an ED. Depending on initial screening results, specific program modules are recommended to the user, matching their individual needs. The program contains a web-page with psychoeducational information on ED, an anonymous forum to receive and provide peer support, a supportive monitoring and feedback program and a chat platform, which can be used to communicate with professional counselors and other users. If needed, users can be referred to face-to-face counseling.In this paper we report experience in practical use of the program at the Trinity College Dublin. Participants could anonymously register and individually choose the length of participation in the prevention program. Two months after registration and at the time of deregistration, participants were asked to evaluate the program. Data of Nscreened=457 and Nregistered=100 students are presented. Experiences with the program indicate that support can be matched to individual requirements by providing Internet-delivered stepped-care modules that encourage the user to seek support according to their personal preferences and needs. PMID- 21687563 TI - One year after navigated total knee replacement, no clinically relevant difference found between fixed bearing and mobile bearing knee replacement in a double-blind randomized controlled trial. AB - BACKGROUND: The mobile bearing designs have not yet been shown to improve clinical outcome of total knee arthroplasty (TKA). In this prospective randomized study, we compared the short-term clinical results of a mobile bearing implant with those of the fixed bearing version of the same implant. METHODS: We randomized 100 knees into two double-blind groups who received either the fixed (FB, 52 knees) or the mobile bearing (MB, 48 knees) version of the same implant. We used navigation to standardize the surgical technique. For up to one year, we recorded the Knee Society (KSS) and Oxford (OXF) scores. We performed an exploratory analysis of variance (ANOVA) to determine the influence of baseline scores as covariate and the extent of improvement in clinical outcome over time. RESULTS: After one year, we did not detect any statistically significant difference between the two groups. The KSS scores differed by 2 points, the OXF scores by 1.1 points. CONCLUSION: Even with identical geometry of implant surfaces and a navigated surgical technique, first-year results do not support a preference for either a fixed or a mobile design. PMID- 21687564 TI - EDX-Element Analysis of the In Vitro Effect of Fluoride Oral Hygiene Tablets on Artificial Caries Lesion Formation and Remineralization in Human Enamel. AB - Aim of this in-vitro-study was to assess the remineralization potential of a tooth cleaning tablet with different fluoride content quantitatively using EDX analysis.Twenty three caries free impacted third molars were examined; enamel surfaces were wax coated leaving two 3x4mm windows for exposure to demineralization/remineralization cycles. The teeth were randomly assigned to 4 groups of 5 control and 6 experimental teeth each. Demineralization by standardized HEC-gel, pH 4.7 at 37 degrees C for 72h, was alternated by rinsing in remineralization solution, pH 7.0 at 37 degrees C for 72h, total challenge time 432h. The negative control group N was treated during remineralization cycles with saline; positive control group P was treated with remineralization solution; experimental group D1 was exposed to remineralization solution containing Denttabs((r))-tablets with 1450 ppm F; experimental group D2 was exposed to remineralization solution and Denttabs((r))-tablets with 4350 ppm F. Each tooth was cut into serial sections and analyzed by scanning electron microscopy with EDX element analysis for assessment of the different zones of the lesions in 3 representative sections. Statistical analysis was based on the AVOVA test for repeated measurements and post hoc Bonferroni adjustment. The results showed a significantly higher Ca and P content in the body of the lesion in both fluoride treated groups compared to the controls. It can be concluded that higher concentrations of NaF may be more effective in remineralization of early advanced caries lesions. PMID- 21687566 TI - Corneal microstructural analysis in weill-marchesani syndrome by in vivo confocal microscopy. AB - A thick cornea is a constant ocular finding in the mesodermal dysmorphodystrophy (Weill-Marchesani Syndrome). In this study we investigated with confocal microscopy, the corneal structure in vivo in the patient affected by Weill Marchesani Syndrome (WMS) in an attempt to explain the thickness increment. The corneal study showed in both eyes a highly increased central thickness with normal topography and sensitivity. The confocal examination revealed an increased evidence of keratocytes in the anterior stroma with abnormal and activated appearance. The mid and deep stroma and endothelial layer were normal. These confocal findings are a newly described feature of corneal involvement in WMS. The increase of the corneal thickness in the affected patient maybe associated with connective tissue alterations, such as abnormal collagen synthesis, that characterizes the disease. PMID- 21687565 TI - Functional remediation for bipolar disorder. AB - Neurocognitive impairment constitutes a core feature of bipolar illness. The main domains affected are verbal memory, attention, and executive functions. Deficits in these areas as well as difficulties to get functional remission seem to be increased associated with illness progression. Several studies have found a strong relationship between neurocognitive impairment and low functioning in bipolar disorder, as previously reported in other illnesses such as schizophrenia. Cognitive remediation strategies, adapted from work conducted with traumatic brain injury patients and applied to patients with schizophrenia, also need to be adapted to individuals with bipolar disorders. Early intervention using functional remediation, involves neurocognitive techniques and training, but also psychoeducation on cognition-related issues and problem-solving within an ecological framework. PMID- 21687567 TI - Effect of Growth Regulators on In Vitro Morphogenic Response of Boscia senegalensis (Pers.) Lam. Poir. Using Mature Zygotic Embryos Explants. AB - The percent study describes the in vitro responses of mature zygotic embryos of Boscia senegalensis to different concentrations (0.0-5.0 mg/L) of 6-benzyladnine (BA), Thidiazuron (TDZ), alpha-Naphthalene acetic acid (NAA), and 2, 4 Dichlorophenoxyacetic acid (2, 4-D) supplemented on Murashige and Skoog medium (MS). The plant growth regulators (PGRs) were considerably affected the morphogenetic responses. BA produced adventitious shoots through two ways: direct organogenesis and auxiliary shoot formation. Both 2, 4-D and TDZ tend to produce callus, whereas NAA improve the development of embryos to seedlings. Maximum number of shoots/explant (14.8 +/- 0.6) was obtained on MS medium supplemented with 3.0 mg/L BA. 67.0% of excised shoots were rooted either on 1/2 MS medium augmented with or without 0.25 mg/L IBA. The highest number of roots (1.2 +/- 0.4) and root length (0.5 +/- 0.2 cm) was produced on 0.25 mg/L IBA-containing medium. Regenerated plants were successfully acclimatized and transferred to the green house with 70% survival rate. All the plants appeared morphologically uniform with normal growth pattern. A rapid (30 days), efficient and without subculturing protocol for in vitro regeneration of B. senegalensis was developed. PMID- 21687568 TI - ELAN: a software package for analysis and visualization of MEG, EEG, and LFP signals. AB - The recent surge in computational power has led to extensive methodological developments and advanced signal processing techniques that play a pivotal role in neuroscience. In particular, the field of brain signal analysis has witnessed a strong trend towards multidimensional analysis of large data sets, for example, single-trial time-frequency analysis of high spatiotemporal resolution recordings. Here, we describe the freely available ELAN software package which provides a wide range of signal analysis tools for electrophysiological data including scalp electroencephalography (EEG), magnetoencephalography (MEG), intracranial EEG, and local field potentials (LFPs). The ELAN toolbox is based on 25 years of methodological developments at the Brain Dynamics and Cognition Laboratory in Lyon and was used in many papers including the very first studies of time-frequency analysis of EEG data exploring evoked and induced oscillatory activities in humans. This paper provides an overview of the concepts and functionalities of ELAN, highlights its specificities, and describes its complementarity and interoperability with other toolboxes. PMID- 21687569 TI - In Critically Ill Patients, Serum Procalcitonin Is More Useful in Differentiating between Sepsis and SIRS than CRP, Il-6, or LBP. AB - We studied the usefulness of serum procalcitonin (PCT), interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP) levels and C-reactive protein (CRP) levels, in differentiating between systemic inflammatory response syndrome (SIRS) and sepsis in critically ill patients. Methods. In this single centre prospective observational study we included all consecutive patients admitted with SIRS or sepsis to the ICU. Blood samples for measuring CRP, PCT, IL-6 and LBP were taken every day until ICU discharge. Results. A total of 76 patients were included, 32 with sepsis and 44 with SIRS. Patients with sepsis were sicker on admission and had a higher mortality. CRP, PCT, IL-6 and LBP levels were significantly higher in patients with sepsis as compared to SIRS. With PCT levels in the first 24 hours after ICU admission <2 ng/mL, sepsis was virtually excluded (negative predictive value 97%). With PCT >10 ng/mL, sepsis with bacterial infection was very likely (positive predictive value 88%). PCT was best at discriminating between SIRS and sepsis with the highest area under the ROC curve (0.95, 95% CI 0.90-0.99). Discussion. This study showed that PCT is more useful than LBP, CRP and IL-6 in differentiating sepsis from SIRS. PMID- 21687570 TI - Iatrogenic hepatic pneumovenogram. AB - Accidental air entry during central venous catheterization is a preventable iatrogenic complication that can cause venous air embolism (VAE). Many cases of VAE are subclinical with no adverse outcome and thus go unreported. Usually, when symptoms are present, they are nonspecific, and a high index of clinical suspicion of possible VAE is required to prompt investigations and initiate appropriate therapy. Occasionally large embolism can lead to life-threatening acute cor pulmonale, asystole, sudden death, and arterial air embolism in the presence of shunt or patent foramen ovale. This paper discusses VAE during emergency central line placement and the diagnostic dilemma that it can be created in critically ill patients. All necessary precautions have to be strictly followed to prevent this iatrogenic complication. PMID- 21687571 TI - Pelvic electrical neuromodulation for the treatment of overactive bladder symptoms. AB - Overactive bladder syndrome negatively affects the daily life of many people. First-line conservative treatments, such as antimuscarinics, do not always lead to sufficient improvement of the complaints and/or are often associated with disabling adverse effects leading to treatment failure. Electrical stimulation of the sacral nerves has emerged as an alternative and attractive treatment for refractory cases of bladder overactivity. Few theories attempted to explain its mechanism of action which remains elusive. It involves percutaneous posterior tibial nerve stimulation and more commonly sacral neuromodulation. For the latter, temporary sacral nerve stimulation is the first step. If the test stimulation is successful, a permanent device is implanted. The procedure is safe and reversible. It carries a durable success rate. The technique should be combined with careful followup and attentive adjustments of the stimulation parameters in order to optimize the clinical outcomes. This paper provides a review on the indications, possible mechanisms of action, surgical aspects and possible complications, and safety issues of this technique. The efficacy of the technique is also addressed. PMID- 21687573 TI - rtMEG: a real-time software interface for magnetoencephalography. AB - To date, the majority of studies using magnetoencephalography (MEG) rely on off line analysis of the spatiotemporal properties of brain activity. Real-time MEG feedback could potentially benefit multiple areas of basic and clinical research: brain-machine interfaces, neurofeedback rehabilitation of stroke and spinal cord injury, and new adaptive paradigm designs, among others. We have developed a software interface to stream MEG signals in real time from the 306-channel Elekta Neuromag MEG system to an external workstation. The signals can be accessed with a minimal delay (<=45 ms) when data are sampled at 1000 Hz, which is sufficient for most real-time studies. We also show here that real-time source imaging is possible by demonstrating real-time monitoring and feedback of alpha-band power fluctuations over parieto-occipital and frontal areas. The interface is made available to the academic community as an open-source resource. PMID- 21687574 TI - Current and future strategies in the diagnosis and management of penile cancer. AB - Penile cancer is an uncommon malignancy that has a devastating effect on the patient while also being challenging to diagnose and treat. By implementing preventive measures, we can decrease the incidence of this disease and improve the quality of life of our patients. Early detection plays an important role in disease control and proper diagnostic modalities must be used in order to accurately identify the cancer and its progression. Primary penile lesions should be initially approached when surgically feasible and clinically appropriate with penile preserving surgical techniques. Advances in inguinal lymph node detection and management, has improved the clinical outcome of penile cancer. Advanced penile cancer still portends a poor prognosis and should be approached via a multimodal treatment regimen. In this review, we address the importance of prevention, early detection, and the contemporary management of primary penile lesions, as well as the advances in inguinal lymph node disease detection and surgical treatment, for both localized and advanced disease. PMID- 21687572 TI - The Strong Protective Effect of Circumcision against Cancer of the Penis. AB - Male circumcision protects against cancer of the penis, the invasive form of which is a devastating disease confined almost exclusively to uncircumcised men. Major etiological factors are phimosis, balanitis, and high-risk types of human papillomavirus (HPV), which are more prevalent in the glans penis and coronal sulcus covered by the foreskin, as well as on the penile shaft, of uncircumcised men. Circumcised men clear HPV infections more quickly. Phimosis (a constricted foreskin opening impeding the passage of urine) is confined to uncircumcised men, in whom balanitis (affecting 10%) is more common than in circumcised men. Each is strongly associated with risk of penile cancer. These findings have led to calls for promotion of male circumcision, especially in infancy, to help reduce the global burden of penile cancer. Even more relevant globally is protection from cervical cancer, which is 10-times more common, being much higher in women with uncircumcised male partners. Male circumcision also provides indirect protection against various other infections in women, along with direct protection for men from a number of genital tract infections, including HIV. Given that adverse consequences of medical male circumcision, especially when performed in infancy, are rare, this simple prophylactic procedure should be promoted. PMID- 21687575 TI - Craniux: a LabVIEW-based modular software framework for brain-machine interface research. AB - This paper presents "Craniux," an open-access, open-source software framework for brain-machine interface (BMI) research. Developed in LabVIEW, a high-level graphical programming environment, Craniux offers both out-of-the-box functionality and a modular BMI software framework that is easily extendable. Specifically, it allows researchers to take advantage of multiple features inherent to the LabVIEW environment for on-the-fly data visualization, parallel processing, multithreading, and data saving. This paper introduces the basic features and system architecture of Craniux and describes the validation of the system under real-time BMI operation using simulated and real electrocorticographic (ECoG) signals. Our results indicate that Craniux is able to operate consistently in real time, enabling a seamless work flow to achieve brain control of cursor movement. The Craniux software framework is made available to the scientific research community to provide a LabVIEW-based BMI software platform for future BMI research and development. PMID- 21687576 TI - Metabolic changes after urinary diversion. AB - Urinary diversion is performed on a regular basis in urological practice. Surgeons tend to underestimate the metabolic effects of any type of diversion. From the patient's perspective, diarrhea is the most bothersome complaint after urinary diversion. This might be accompanied by malabsorption syndromes, such as vitamin B12 deficiency. Electrolyte abnormalities can occur frequently such as hyperchloremic metabolic acidosis, or less frequently such as hypokalemia, hypocalcaemia, and hypomagnesaemia. Bone health is at risk in patients with urinary diversion. Some patients might benefit from vitamin D and calcium supplementation. Many patients are also subject to urinary calculus formation, both at the level of the upper urinary tract as in intestinal reservoirs. Urinary diversion can affect hepatic metabolism, certainly in the presence of urea splitting bacteria. The kidney function has to be monitored prior to and lifelong after urinary diversion. Screening for reversible causes of renal deterioration is an integral part of the followup. PMID- 21687577 TI - A Statistical Approach for Optimization of Simultaneous Production of beta Glucosidase and Endoglucanase by Rhizopus oryzae from Solid-State Fermentation of Water Hyacinth Using Central Composite Design. AB - The production cost of beta-glucosidase and endoglucanase could be reduced by using water hyacinth, an aquatic weed, as the sole carbon source and using cost efficient fermentation strategies like solid-state fermentation (SSF). In the present study, the effect of different production conditions on the yield of beta glucosidase and endoglucanase by Rhizopus oryzae MTCC 9642 from water hyacinth was investigated systematically using response surface methodology. A Central composite experimental design was applied to optimize the impact of three variables, namely, substrate concentration, pH, and temperature, on enzyme production. The optimal level of each parameter for maximum enzyme production by the fungus was determined. Highest activity of endoglucanase of 495 U/mL was achieved at a substrate concentration of 1.23%, pH 7.29, and temperature 29.93 degrees C whereas maximum beta-glucosidase activity of 137.32 U/ml was achieved at a substrate concentration of 1.25%, pH 6.66, and temperature 32.09 degrees C. There was a direct correlation between the levels of enzymatic activities and the substrate concentration of water hyacinth as carbon source. PMID- 21687578 TI - Positive fluid balance is associated with higher mortality and prolonged mechanical ventilation in pediatric patients with acute lung injury. AB - Introduction. We analyzed a database of 320 pediatric patients with acute lung injury (ALI), to test the hypothesis that positive fluid balance is associated with worse clinical outcomes in children with ALI. Methods. This is a post-hoc analysis of previously collected data. Cumulative fluid balance was analyzed in ml per kilogram per day for the first 72 hours after ALI while in the PICU. The primary outcome was mortality; the secondary outcome was ventilator-free days. Results. Positive fluid balance (in increments of 10 mL/kg/24 h) was associated with a significant increase in both mortality and prolonged duration of mechanical ventilation, independent of the presence of multiple organ system failure and the extent of oxygenation defect. These relationships remained unchanged when the subgroup of patients with septic shock (n = 39) were excluded. Conclusions. Persistently positive fluid balance may be deleterious to pediatric patients with ALI. A confirmatory, prospective randomized controlled trial of fluid management in pediatric patients with ALI is warranted. PMID- 21687580 TI - Acute respiratory distress syndrome after onyx embolization of arteriovenous malformation. AB - Purpose. We report a case of a 60-year-old male who underwent sequential Onyx embolizations of a cerebral arteriovenous malformation (AVM) which we implicate as the most likely etiology of subsequent acute respiratory distress syndrome (ARDS). Methods. Case report and literature review. Results. Shortly after the second Onyx embolization procedure, the patient declined from respiratory failure secondary to pulmonary edema. Clinical entities typically responsible for pulmonary edema including cardiac failure, renal failure, iatrogenic volume overload, negative-pressure pulmonary edema, and infectious etiologies were evaluated and excluded. The patient required mechanical ventilatory support for several days, delaying operative resection. The patient met clinical and radiographic criteria for ARDS. After excluding other etiologies of ARDS, we postulate that ARDS developed as a result of Onyx administration. The Onyx copolymer is dissolved in dimethyl sulfoxide (DMSO), a solvent excreted through the lungs and has been implicated in transient pulmonary side effects. Additionally, a direct toxic effect of the Onyx copolymer is postulated. Conclusion. Onyx embolization and DMSO toxicity are implicated as the etiology of ARDS given the lack of other inciting factors and the close temporal relationship. A strong physiologic rationale provides further support. Clinicians should consider this uncommon but important complication. PMID- 21687581 TI - Solifenacin in multiple sclerosis patients with overactive bladder: a prospective study. AB - Objective. To assess the efficacy and the effect on Qol of solifenacin for the treatment of OAB in MS patients. Patients and Methods. Thirty MS patients suffering from OAB were treated with solifenacin 5/10 mg for 8 weeks. The first 4 weeks patients received solifenacin 5 mg. At week 4 patients could request a dose increase to 10 mg. The efficacy was evaluated at 8 weeks. Results. After 4 weeks of treatment, 28 patients reported acceptable or no side effects. 17 continued the study with the 10 mg dosage, and 11 stayed on 5 mg solifenacin. Two patients withdrew from the study due to side effects. Solifenacin 5/10 mg for 8 weeks resulted in a significant decrease in number of micturitions and number of pads used per day compared to baseline. Also the severity of urgency prior to voiding decreased significantly, and an increase was seen in the volume per void. Twenty out of 30 patients chose to continue solifenacin therapy after termination of the study. The majority of patients reported global QoL improvement. Conclusions. Solifenacin is effective in the treatment of MS patients with OAB symptoms. This is the first study with solifenacin in a specific neurogenic patient group with a neurogenic disease-specific QoL outcome measure (MS-QoL 54). PMID- 21687579 TI - An overview of the clinical use of antimuscarinics in the treatment of overactive bladder. AB - Overactive bladder is a common and bothersome condition. Antimuscarinic agents, as a class, are the cornerstone of medical treatment of overactive bladder. They offer significant improvements in symptoms and patients' quality of life. Antimuscarinics are generally well tolerated with mild and predictable side effects. Available antimuscarinics have small, yet statistically significant, differences in their efficacy and tolerability profiles. In clinical practice, finding the agent that offers the optimum balance of efficacy and side effects for an individual patient remains the major challenge. PMID- 21687582 TI - Prevalence of metabolic syndrome in urban India. AB - Background. Metabolic syndrome (MS) is characterised by a constellation of individual risk factors of cardiovascular disease. Materials and Methods. The current study was a population-based survey of cohort of subjects in the metropolitan city of Mumbai. A total of 548 subjects, who attended the CARDIAC evaluation camp, were recruited in the study. Participants with complete fasting lipid profiles, blood glucose, and known cardiac risk markers were evaluated. Results. On applying modified NCEP ATP III, we found out that nearly 95% of the subjects had at least one abnormal parameter. We found the prevalence of MS in our study population to be 19.52%. The prevalence of MS in males was almost double than females (P = .008). The overall prevalence of BMI (>23 kg/m(2)) was 79.01%. Increased hypertriglyceridemia and decreased levels of HDL-C were found to be more in males (P < .0001). Conclusion. The low percentage of subjects with normal and controlled parameters suggests that there is a need for awareness programs and lifestyle interventions for the prevention and control of MS. PMID- 21687583 TI - The rare malignancy of the hepatobiliary system: ampullary carcinoid tumor. AB - Introduction. Carcinoid tumors are low-grade tumors originating from endoderm and mostly involving the gastrointestinal system. However; they may be seen in any site within the gastrointestinal system. Case Presentation. A 69-year-old female patient. The results of blood tests were observed to be consistent with obstructive jaundice. A mass appearance was not encountered on tomographic examination. Papilla that was tumor-like macroscopically was seen in the second part of the duodenum in diagnostic endoscopy. Pylorus-preserving pancreaticoduodenectomy surgical procedure was applied. On pathological examination of the mass, a tumoral mass was detected in ampulla vateri localization, 1.5 * 1 * 0.8 cm in size, which, in immunohistochemical staining, was evaluated as a neuroendocrine tumor. Also, Metastasis was observed. Conclusion. The rarest type of carcinoid tumor is ampullary located carcinoid tumor, and tumor size is not a reliable indicator for tumor aggressivity in ampullary carcinoid tumors. PMID- 21687584 TI - Optimal control of HIV dynamic using embedding method. AB - This present study proposes an optimal control problem, with the final goal of implementing an optimal treatment protocol which could maximize the survival time of patients and minimize the cost of drug utilizing a system of ordinary differential equations which describes the interaction of the immune system with the human immunodeficiency virus (HIV). Optimal control problem transfers into a modified problem in measure space using an embedding method in which the existence of optimal solution is guaranteed by compactness of the space. Then the metamorphosed problem is approximated by a linear programming (LP) problem, and by solving this LP problem a suboptimal piecewise constant control function, which is more practical from the clinical viewpoint, is achieved. The comparison between the immune system dynamics in treated and untreated patients is introduced. Finally, the relationships between the healthy cells and virus are shown. PMID- 21687585 TI - Traditional Japanese Kampo Medicine: Clinical Research between Modernity and Traditional Medicine-The State of Research and Methodological Suggestions for the Future. AB - The Japanese traditional herbal medicine, Kampo, has gradually reemerged and 148 different formulations (mainly herbal extracts) can be prescribed within the national health insurance system. The objective of this article is to introduce Kampo and to present information from previous clinical studies that tested Kampo formulae. In addition, suggestions on the design of future research will be stated. The literature search was based on a summary, up until January 2009, by the Japanese Society of Oriental Medicine and included only those trials which were also available in either Pubmed or ICHUSHI (Japan Medical Abstracts Society). We included 135 studies, half of these studies (n = 68) used a standard control and 28 a placebo control. Thirty-seven trials were published in English [all randomized controlled trials (RCTs)] and the remaining articles were in Japanese only. The sample size for most studies was small (two-third of the studies included less than 100 patients) and the overall methodological quality appeared to be low. None of the studies used Kampo diagnosis as the basis for the treatment. In order to evaluate Kampo as a whole treatment system, certain aspects should be taken into account while designing studies. RCTs are the appropriate study design to test efficacy or effectiveness; however, within the trial the treatment could be individualized according to the Kampo diagnosis. Kampo is a complex and individualized treatment with a long tradition, and it would be appropriate for further research on Kampo medicine to take this into account. PMID- 21687586 TI - Primary lymphangioma of the tonsil: a case report. AB - Benign tumors of the tonsils occur infrequently. Lymphangiomas are rare congenital tumors of the lymphatic system, and tonsillar lymphangioma is an extremely rare occurrence. Its pathogenesis is uncertain, but history, clinical examination, and histological examination should establish the diagnosis. We present a 17-year-old white male with lymphangioma of the right tonsil. The tonsils were excised and biopsy confirmed the diagnosis. Tonsillar lymphangioma is a rare clinical entity, which should be known to the otolaryngologist, in order to diagnose and treat it appropriately and avoid confusion with tonsillar malignancies. PMID- 21687587 TI - The effects of old age on hepatic stellate cells. AB - Aging is associated with marked changes in the hepatic sinusoid, yet the effect of old age on hepatic stellate cells (HSC) has not been well described. Transmission electron microscopy and immunohistochemistry were used to study the effects of aging on HSC in livers from rats (3-4 mths versus 24-27 mths) and mice (2-3 mths versus 20-22 mths). Desmin-positive HSC doubled in old age in both mice and rats. Alpha-smooth muscle actin- (alphaSMA-) positive cells did not increase significantly and remained only a small percentage of desmin-positive cells. Electron microscopy revealed that old age is associated with HSC that have a substantial increase in the number of lipid droplets which are larger in diameter. There was also a marked increase of HSC that protruded into the sinusoidal lumen in old mice. In conclusion, old age is associated with hyperplasia of HSC that are not activated and are engorged with lipid droplets. PMID- 21687588 TI - Applications of different weighting schemes to improve pathway-based analysis. AB - Conventionally, pathway-based analysis assumes that genes in a pathway equally contribute to a biological function, thus assigning uniform weight to genes. However, this assumption has been proved incorrect, and applying uniform weight in the pathway analysis may not be an appropriate approach for the tasks like molecular classification of diseases, as genes in a functional group may have different predicting power. Hence, we propose to use different weights to genes in pathway-based analysis and devise four weighting schemes. We applied them in two existing pathway analysis methods using both real and simulated gene expression data for pathways. Among all schemes, random weighting scheme, which generates random weights and selects optimal weights minimizing an objective function, performs best in terms of P value or error rate reduction. Weighting changes pathway scoring and brings up some new significant pathways, leading to the detection of disease-related genes that are missed under uniform weight. PMID- 21687590 TI - EEGLAB, SIFT, NFT, BCILAB, and ERICA: new tools for advanced EEG processing. AB - We describe a set of complementary EEG data collection and processing tools recently developed at the Swartz Center for Computational Neuroscience (SCCN) that connect to and extend the EEGLAB software environment, a freely available and readily extensible processing environment running under Matlab. The new tools include (1) a new and flexible EEGLAB STUDY design facility for framing and performing statistical analyses on data from multiple subjects; (2) a neuroelectromagnetic forward head modeling toolbox (NFT) for building realistic electrical head models from available data; (3) a source information flow toolbox (SIFT) for modeling ongoing or event-related effective connectivity between cortical areas; (4) a BCILAB toolbox for building online brain-computer interface (BCI) models from available data, and (5) an experimental real-time interactive control and analysis (ERICA) environment for real-time production and coordination of interactive, multimodal experiments. PMID- 21687589 TI - The blood-brain barrier and microvascular water exchange in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia in the elderly. Although traditionally considered a disease of neurofibrillary tangles and amyloid plaques, structural and functional changes in the microvessels may contribute directly to the pathogenesis of the disease. Since vascular dysfunction often precedes cognitive impairment, understanding the role of the blood-brain barrier (BBB) in AD may be key to rational treatment of the disease. We propose that water regulation, a critical function of the BBB, is disturbed in AD and results in abnormal permeability and rates of water exchange across the vessel walls. In this paper, we describe some of the pathological events that may disturb microvascular water exchange in AD and examine the potential of a relatively new imaging technique, dynamic contrast-enhanced MRI, to quantify water exchange on a cellular level and thus serve as a probe of BBB integrity in AD. PMID- 21687591 TI - Gastric trichobezoar causing intermittent small bowel obstruction: report of a case and review of the literature. AB - We report the unusual case of a 45-year-old woman who presented with multiple episodes of small bowel obstruction. Initial exploratory lap-roscopy did not reveal an etiology of the obstruction. Subsequent upper endoscopy identified a non-obstructing gastric trichobezoar which could not be removed endoscopically but was not thought to be responsible for the small bowel obstruction given its location. One week postoperatively, the patient experienced recurrence of small bowel obstruction. Repeat endoscopy disclosed that the trichobezoar was no longer located in the stomach and upon repeat laparotomy was extracted from the mid jejunum. In the following 8 months, the patient had no further episodes of small bowel obstruction. Consequently, gastric bezoars should be included in the differential diagnosis of recurrent small bowel obstruction. PMID- 21687592 TI - Prediction and Characterization of Missing Proteomic Data in Desulfovibrio vulgaris. AB - Proteomic datasets are often incomplete due to identification range and sensitivity issues. It becomes important to develop methodologies to estimate missing proteomic data, allowing better interpretation of proteomic datasets and metabolic mechanisms underlying complex biological systems. In this study, we applied an artificial neural network to approximate the relationships between cognate transcriptomic and proteomic datasets of Desulfovibrio vulgaris, and to predict protein abundance for the proteins not experimentally detected, based on several relevant predictors, such as mRNA abundance, cellular role and triple codon counts. The results showed that the coefficients of determination for the trained neural network models ranged from 0.47 to 0.68, providing better modeling than several previous regression models. The validity of the trained neural network model was evaluated using biological information (i.e. operons). To seek understanding of mechanisms causing missing proteomic data, we used a multivariate logistic regression analysis and the result suggested that some key factors, such as protein instability index, aliphatic index, mRNA abundance, effective number of codons (N(c)) and codon adaptation index (CAI) values may be ascribed to whether a given expressed protein can be detected. In addition, we demonstrated that biological interpretation can be improved by use of imputed proteomic datasets. PMID- 21687594 TI - Olfactory delusional syndrome and intracranial meningioma. AB - We report the case of a 37-year-old female in which the removal of a suprasellar neoplasm was accompanied by the disappearance of a longstanding olfactory delusion syndrome. In primary care the patient condition was exclusively thought to be psychic in origin, neglecting the possible, not infrequent, organic contribution. The delayed diagnosis produced neurological impairment, only partially recovered after surgical therapy. This case might help to improve the patient management via multi-specialist cooperation and to broaden the knowledge about somatic mechanisms of psychic disturbances, are not often taken into account. PMID- 21687593 TI - Total Splenectomy due to an Unexpected "Complication" after Successful Extended Laparoscopic Partial Decapsulation of a Giant Epidermoid Splenic Cyst: A Case Report. AB - Splenic cysts are rare entities and are classified as true cysts or pseudocysts based on the presence of an epithelial lining. Congenital nonparasitic true cysts can be epidermoid, dermoid, or endodermoid, present at a young age, and are commonly located in the upper pole of the spleen. Surgical treatment is recommended for symptomatic, large (more than 5 cm), or complicated cysts. Depending on cyst number, location, relation to hilus, and the major splenic vessels, the surgical options include aspiration, marsupialization, cystectomy, partial cystectomy (decapsulation), and partial or complete splenectomy. Laparoscopic techniques have now become the standard approach for many conditions, including the splenic cysts, with emphasis on the spleen-preserving minimally invasive operations. We present the successful extended partial laparoscopic decapsulation of a giant epidermoid splenic cyst in a young female patient that, although asymptomatic, was unfortunately followed by complete splenectomy five days later due to a misinterpreted abdominal CT suggesting splenic postoperative ischemia. PMID- 21687595 TI - Giant cell tumor of the pes anserine bursa (extra-articular pigmented villonodular bursitis): a case report and review of the literature. AB - Pigmented villonodular synovitis (PVNS) is a rare, benign, proliferating disease affecting the synovium of joints, bursae, and tendon sheaths. Involvement of bursa (PVNB, pigmented villonodular bursitis) is the least common, and only few cases of exclusively extra-articular PVNB of the pes anserinus bursa have been reported so far. We report a case of extra-articular pes anserine PVNB along with a review of the literature. The lesion presented as a painful soft tissue mass in the medial part of the proximal leg. A magnetic resonance imaging showed areas of low to intermediate signals in all sequences and the lesion enhanced heterogeneously with contrast. Diagnosis was confirmed by an incisional biopsy, and an intralesional resection was performed. The postoperative course was uneventful, and the patient is free of disease with no functional deficit at 2 years followup. As with other rare lesions, clinical and radiographic findings in addition to histological examination are essential for correct diagnosis. PMID- 21687597 TI - Management of differentiated thyroid cancer in pregnancy. AB - In young women, differentiated thyroid cancer is the second most common malignancy diagnosed around the time of pregnancy. Management of thyroid cancer during pregnancy poses distinct challenges due to concerns regarding maternal and fetal well-being. In most cases surgery can be safely delayed until after delivery and with adequate management and outcome of pregnancy in women with thyroid cancer is excellent. Ideally these patients should be managed by a multidisciplinary team, and management plan should be determined by a consensus between the patient and the healthcare team. PMID- 21687598 TI - In Vitro and In Vivo Antimalarial Activity Assays of Seeds from Balanites aegyptiaca: Compounds of the Extract Show Growth Inhibition and Activity against Plasmodial Aminopeptidase. AB - Balanites aegyptiaca (Balanitaceae) is a widely grown desert plant with multiuse potential. In the present paper, a crude extract from B. aegyptiaca seeds equivalent to a ratio of 1 : 2000 seeds to the extract was screened for antiplasmodial activity. The determined IC(50) value for the chloroquine susceptible Plasmodium falciparum NF54 strain was 68.26 MUg/MUL +/- 3.5. Analysis of the extract by gas chromatography-mass spectrometry detected 6-phenyl-2(H) 1,2,4-triazin-5-one oxime, an inhibitor of the parasitic M18 Aspartyl Aminopeptidase as one of the compounds which is responsible for the in vitro antiplasmodial activity. The crude plant extract had a K(i) of 2.35 MUg/MUL and showed a dose-dependent response. After depletion of the compound, a significantly lower inhibition was determined with a K(i) of 4.8 MUg/MUL. Moreover, two phenolic compounds, that is, 2,6-di-tert-butyl-phenol and 2,4-di tert-butyl-phenol, with determined IC(50) values of 50.29 MUM +/- 3 and 47.82 MUM +/- 2.5, respectively, were detected. These compounds may contribute to the in vitro antimalarial activity due to their antioxidative properties. In an in vivo experiment, treatment of BALB/c mice with the aqueous Balanite extract did not lead to eradication of the parasites, although a reduced parasitemia at day 12 p.i. was observed. PMID- 21687596 TI - Mechanisms of resistance to EGFR TKIs and development of a new generation of drugs in non-small-cell lung cancer. AB - Gefitinib and erlotinib, which are epidermal growth factor receptor- (EGFR-) specific tyrosine kinase inhibitors (TKIs), are widely used as molecularly targeted drugs for non-small-cell lung cancer (NSCLC). Currently, the search for EGFR gene mutations is becoming essential for the treatment of NSCLC since these have been identified as predictive factors for drug sensitivity. On the other hand, in almost all patients responsive to EGFR-TKIs, acquired resistance is a major clinical problem. Mechanisms of acquired resistance reported in the past few years include secondary mutation of the EGFR gene, amplification of the MET gene, and overexpression of HGF; novel pharmaceutical agents are currently being developed to overcome resistance. This review focuses on these mechanisms of acquired resistance to EGFR-TKIs and discusses how they can be overcome. PMID- 21687599 TI - Formate formation and formate conversion in biological fuels production. AB - Biomethanation is a mature technology for fuel production. Fourth generation biofuels research will focus on sequestering CO(2) and providing carbon-neutral or carbon-negative strategies to cope with dwindling fossil fuel supplies and environmental impact. Formate is an important intermediate in the methanogenic breakdown of complex organic material and serves as an important precursor for biological fuels production in the form of methane, hydrogen, and potentially methanol. Formate is produced by either CoA-dependent cleavage of pyruvate or enzymatic reduction of CO(2) in an NADH- or ferredoxin-dependent manner. Formate is consumed through oxidation to CO(2) and H(2) or can be further reduced via the Wood-Ljungdahl pathway for carbon fixation or industrially for the production of methanol. Here, we review the enzymes involved in the interconversion of formate and discuss potential applications for biofuels production. PMID- 21687600 TI - Impaired deoxyribonuclease I activity in patients with inflammatory bowel diseases. AB - Background and Aims. Deoxyribonuclease I (DNaseI) is an endonuclease that facilitates chromatin breakdown and promotes susceptibility to autoimmune disorders. The aim of current study was to investigate serum DNase I activity in patients with inflammatory bowel diseases (IBD). Patients and Methods. A cohort of 110 IBD patients was evaluated, aged 35 +/- 12 years, 77 with Crohn's disease (CD) and 33 with ulcerative colitis (UC). 50 SLE patients and 50 healthy blood donors were examined as control groups. Results. DNase I activity in IBD patients was significantly lower than in healthy individuals, but higher than in SLE patients (P < .0001). Patients with UC showed higher DNase I activity than CD patients, P = .21. DNase I activity in female patients with IBD was significantly lower than in males, P = .024; however, no differences in DNase I activity were found in relation to gender in healthy individuals. DNase I activity has shown a strong negative correlation with the serum concentration of anti-nucleosomal antibodies in the autoimmune (SLE + IBD) cohort, as well as in the separate IBD cohort. Conclusions. Reduced serum DNase I activity probably has pathogenetic consequences in IBD. Induction of autoantibodies towards nucleosomes could be a reflection of impaired DNase I activity. PMID- 21687601 TI - Lymph node thyroglobulin measurement in diagnosis of neck metastases of differentiated thyroid carcinoma. AB - Aim. Enlarged cervical lymph nodes (LNs) in patients with thyroid cancer are usually assessed by fine-needle aspiration cytology (FNAC). Thyroglobulin (Tg) is frequently elevated in malignant FNAC needle wash specimens (FNAC-Tg). The objectives of the study were to (1) determine an appropriate diagnostic cut-off for FNAC-Tg levels (2) compare FNAC and FNAC-Tg results in a group of 108 patients affected by differentiated thyroid carcinoma (DTC). Methods. A total of 126 consecutive FNACs were performed on enlarged LNs and the final diagnosis was confirmed by surgical pathology examination or clinical follow-up. The best FNAC Tg cut-off level was selected by receiver operating curve analysis, and diagnostic performances of FNAC and FNAC-Tg were compared. Results. The rate of FNAC samples adequate for cytological examination was 77% in contrast FNAC-Tg available in 100% of aspirates (P < .01). The sensitivity, specificity, and accuracy of FNAC were 71%, 80%, 74%, 100%, 80%, and 94%, respectively. The most appropriate cut-off value for the diagnosis of thyroid cancer metastatic LN was 1.1 ng/mL (sensitivity 100%, specificity 100%). Conclusions. The diagnostic performance of needle washout FNAC-Tg measurement with a cut-off of 1.1 ng/mL compared favorably with cytology in detecting DTC node metastases. PMID- 21687602 TI - Acute Disruption of Bone Marrow B Lymphopoiesis and Apoptosis of Transitional and Marginal Zone B Cells in the Spleen following a Blood-Stage Plasmodium chabaudi Infection in Mice. AB - B cells and antibodies are essential for the protective immune response against a blood-stage Plasmodium infection. Although extensive research has focused on memory as well as plasma B-cell responses during infection, little is known about how malaria affects B-cell development and splenic maturation into marginal zone B (MZB) and follicular B (FoB) cells. In this study, we show that acute Plasmodium chabaudi AS infection in C57Bl/6 mice causes severe disruption of B lymphopoiesis in the bone marrow, affecting in particular pro-, pre-, and immature B cells as well as the expression of the bone marrow B-cell retention chemokine CXCL12. In addition, elevated apoptosis of transitional T2 and marginal zone (MZ) B cells was observed during and subsequent to the control of the first wave of parasitemia. In contrast, Folllicular (Fo) B cells levels were retained in the spleen throughout the infection, suggesting that these are essential for parasite clearance and proper infection control. PMID- 21687603 TI - Interaction between Calcineurin and Ca/Calmodulin Kinase-II in Modulating Cellular Functions. AB - Roles of calcineurin (CaN), a Ca(2+)/calmodulin- (CaM-) dependent protein phosphatase, and Ca(2+)/CaM-dependent protein kinase-II (CaMKII) in modulating K(+) channel activity and the intracellular Ca(2+) concentration ([Ca(2+)](i)) have been investigated in renal tubule epithelial cells. The channel current through the cell membrane was recorded with the patch-clamp technique, and [Ca(2+)](i) was monitored using fura-2 imaging. We found that a CaN-inhibitor, cyclosporin A (CyA), lowered the K(+) channel activity and elevated [Ca(2+)](i), suggesting that CyA closes K(+) channels and opens Ca(2+)-release channels of the cytosolic Ca(2+)-store. Moreover, both of these responses were blocked by KN-62, an inhibitor of CaMKII. It is suggested that the CyA-mediated response results from the activation of CaMKII. Indeed, Western blot analysis revealed that CyA increased phospho-CaMKII, an active form of CaMKII. These findings suggest that CaN-dependent dephosphorylation inhibits CaMKII-mediated phosphorylation, and the inhibition of CaN increases phospho-CaMKII, which results in the stimulation of CaMKII-dependent cellular actions. PMID- 21687605 TI - Diagnostic value of the C methacetin breath test in various stages of chronic liver disease. AB - The accuracy of the (13)C-methacetin breath test ((13)C-MBT) in differentiating between various stages of liver disease is not clear. A cross-sectional study of Asian patients was conducted to examine the predictive value of the (13)C-MBT in various stages of chronic liver diseases. Diagnostic accuracy of the breath test was determined by sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve analysis. Seventy-seven patients (47 men/30 women, mean age 50 +/- 16 years) were recruited. Forty-seven patients had liver cirrhosis (Child Pugh A = 11, Child Pugh B = 15, and Child Pugh C = 21), 21 had fibrosis, and 9 had chronic inflammation. The sensitivity and positive predictive value for liver fibrosis, cirrhosis (all stages), Child-Pugh A, Child Pugh B, and Child-Pugh C were 65% and 56%, 89% and 89%, 67% and 42%, 40% and 40%, and 50% and 77%, respectively. Area under curve values for fibrosis was 0.62 (0.39-0.86), whilst that for cirrhosis (all stages) was 0.95 (0.91-0.99). The (13)C-methacetin breath test has a poor predictive value for liver fibrosis but accurately determines advanced cirrhosis. PMID- 21687604 TI - Thyroid-specific transcription factors and their roles in thyroid cancer. AB - Homeodomain, forkhead domain, and paired domain-containing transcription factors play a major role in development, tissue-specific gene expression, and tissue homeostasis in organs where they are expressed. Recently, their roles in stem cell and cancer biology are emerging. In the thyroid, NKX2-1, FOXE1, and PAX8 transcription factors are responsible for thyroid organogenesis and expression of thyroid-specific genes critical for thyroid hormone synthesis. In contrast to their known roles in gene regulation, thyroid development and homeostasis, their involvement in stem cell, and/or cancer biology are still elusive. In order to further understand the nature of thyroid cancer, it is critical to determine their roles in thyroid cancer. PMID- 21687606 TI - Trypanosoma cruzi Coexpressing Ornithine Decarboxylase and Green Fluorescence Proteins as a Tool to Study the Role of Polyamines in Chagas Disease Pathology. AB - Polyamines are essential for Trypanosoma cruzi, the causative agent of Chagas disease. As T. cruzi behaves as a natural auxotrophic organism, it relies on host polyamines biosynthesis. In this paper we obtained a double-transfected T. cruzi parasite that expresses the green fluorescent protein (GFP) and a heterologous ornithine decarboxylase (ODC), used itself as a novel selectable marker. These autotrophic and fluorescent parasites were characterized; the ODC presented an apparent Km for ornithine of 0.51 +/- 0.16 mM and an estimated V(max) value of 476.2 nmoles/h/mg of protein. These expressing ODC parasites showed higher metacyclogenesis capacity than the auxotrophic counterpart, supporting the idea that polyamines are engaged in this process. This double-transfected T. cruzi parasite results in a powerful tool-easy to follow by its fluorescence-to study the role of polyamines in Chagas disease pathology and in related processes such as parasite survival, invasion, proliferation, metacyclogenesis, and tissue spreading. PMID- 21687608 TI - An early presenting esophageal schwannoma. AB - Esophageal schwannoma is a rare diagnosis and historically has been a tumor of middle-aged females. We report a case of a 22-year-old male presenting initially with dyspnea secondary to tracheal compression from an 8 * 6 * 3.0 cm esophageal schwannoma. The tumor was surgically resected, and diagnosis was confirmed with immunohistochemical and pathological studies. We report the youngest case of esophageal schwannoma in an otherwise healthy individual. PMID- 21687607 TI - Medullary thyroid carcinoma: molecular signaling pathways and emerging therapies. AB - Research on medullary thyroid carcinoma (MTC) over the last 55 years has led to a good understanding of the genetic defects and altered molecular pathways associated with its development. Currently, with the use of genetic testing, patients at high risk for MTC can be identified before the disease develops and offered prophylactic treatment. In cases of localized neck disease, surgery can be curative. However, once MTC has spread beyond the neck, systemic therapy may be necessary. Conventional chemotherapy has been shown to be ineffective; however, multikinase inhibitors have shown promise in stabilizing disease, and this year will probably see the approval of a drug (Vandetanib) for advanced unresectable or metastatic disease, which represents a new chapter in the history of MTC. In this paper, we explore newly understood molecular pathways and the most promising emerging therapies that may change the management of MTC. PMID- 21687609 TI - Chemical and physicochemical pretreatment of lignocellulosic biomass: a review. AB - Overcoming the recalcitrance (resistance of plant cell walls to deconstruction) of lignocellulosic biomass is a key step in the production of fuels and chemicals. The recalcitrance is due to the highly crystalline structure of cellulose which is embedded in a matrix of polymers-lignin and hemicellulose. The main goal of pretreatment is to overcome this recalcitrance, to separate the cellulose from the matrix polymers, and to make it more accessible for enzymatic hydrolysis. Reports have shown that pretreatment can improve sugar yields to higher than 90% theoretical yield for biomass such as wood, grasses, and corn. This paper reviews different leading pretreatment technologies along with their latest developments and highlights their advantages and disadvantages with respect to subsequent hydrolysis and fermentation. The effects of different technologies on the components of biomass (cellulose, hemicellulose, and lignin) are also reviewed with a focus on how the treatment greatly enhances enzymatic cellulose digestibility. PMID- 21687610 TI - Thyroid antibodies and miscarriage: where are we at a generation later? AB - In 1990, an association between thyroid antibody positivity and spontaneous miscarriage was first reported. A generation has passed since the initial observation. Over that time a robust literature has developed which has confirmed the initial finding and expanded upon it. The present paper reviews the literature that has been generated over the last twenty years on the following topics: (1) thyroid antibodies and spontaneous miscarriage, (2) thyroid antibodies and recurrent abortion, (3) etiology of pregnancy loss in thyroid antibody positive women, and (4) discussion of future research directions. PMID- 21687611 TI - Prevalence of malnutrition in orally and tube-fed elderly nursing home residents in Germany and its relation to health complaints and dietary intake. AB - Objective. To investigate the prevalence of malnutrition in orally and tube-fed nursing home (NH) residents in Germany and its relation to common health complaints and dietary intake. Methods. In 350 NH residents, subjects' characteristics, Mini Nutritional Assessment (MNA), and several health problems were inquired with the nursing staff using standardised interviews. In a subset of 122 residents, dietary intake was assessed by 3-day weighing records. Results. 7.7% of the participants were tube fed. 24.1% of orally nourished and 57.7% of tube-fed residents were malnourished (MNA < 17 p.). Malnutrition was significantly related to nausea/vomiting, constipation, pressure ulcers, dehydration, infections, antibiotic use, and hospitalisation. Mean daily energy intake was 1535 +/- 413 kcal and mean protein intake was 54.2 +/- 0.9 g/d irrespective of the nutritional state. Conclusion. In Germany, malnutrition is widespread among NH residents and is related to common health problems. The MNA rather reflects health condition than currently reduced dietary intake. PMID- 21687612 TI - Gastroesophageal Reflux and Body Movement in Infants: Investigations with Combined Impedance-pH and Synchronized Video Recording. AB - The aim of this paper was to investigate the temporal association of gastroesophageal reflux (GER) and body movement in infants. GER were registered by combined impedance-pH, documentation of body movement was done by video. Videorecording time (Vt) was divided into "resting time" and "movement time" and analyzed for occurrence of GER. Association was defined as movement 1 minute before/after the beginning of a GER. Statistical evaluation was by Fisher's exact test. In 15 infants, 341 GER were documented during Vt (86 hours). 336 GER (99%) were associated with movement, only 5 episodes (1%) occured during resting time. Movement was significantly associated with the occurrence of GER (P < .0001). There is a strong temporal association between GER and body movement in infants. However, a clear distinction between cause and effect could not be made with the chosen study design. Combined impedance-pH has proven to be the ideal technique for this approach. PMID- 21687613 TI - Chiral Pharmaceutical Intermediaries Obtained by Reduction of 2-Halo-1-(4 substituted phenyl)-ethanones Mediated by Geotrichum candidum CCT 1205 and Rhodotorula glutinis CCT 2182. AB - Enantioselective reductions of p-R(1)-C(6)H(4)C(O)CH(2)R(2) (R(1) = Cl, Br, CH(3), OCH(3), NO(2) and R(2) = Br, Cl) mediated by Geotrichum candidum CCT 1205 and Rhodotorula glutinis CCT 2182 afforded the corresponding halohydrins with complementary R and S configurations, respectively, in excellent yield and enantiomeric excesses. The obtained (R)- or (S)-halohydrins are important building blocks in chemical and pharmaceutical industries. PMID- 21687615 TI - Aberrant right hepatic duct draining into the cystic duct: clinical outcomes and management. AB - Background. Aberrant right hepatic duct (ARHD) draining into cystic duct (CD) is relatively rare but clinically important because of its susceptibility to injuries during cholecystectomy. These injuries are often-times missed or diagnosed late and as a result can develop serious complications. Methods. Four consecutive patients diagnosed with ARHD draining into CD were identified for inclusion. Results. The mean age of patients was 42.5 years. The diagnosis in one of the patient was incidental during a routine endoscopic retrograde cholangiopancreatography (ERCP). Other three patients were diagnosed post cholecystectomy- one presented with suspected intra-operative biliary injury, one with persistent bile leak and another with recurrent cholangitis. Inadequate filling of the segment of liver on ERCP with dilation of intrahepatic ducts in the corresponding segment on imaging was present in two patients with complete obstruction of ARHD which was managed surgically. In another patient, the partially obstructed ARHD was managed by endoscopic therapy. Conclusion. ARHD draining into the CD can have varied clinical manifestations. In appropriate clinical settings, it should be suspected in patients with persistence of bile leak early after cholecystectomy, segmental dilation of intrahepatic-bile ducts on imaging and paucity of intrahepatic filling in a segment of liver on ERCP. PMID- 21687614 TI - Role of estrogen in thyroid function and growth regulation. AB - Thyroid diseases are more prevalent in women, particularly between puberty and menopause. It is wellknown that estrogen (E) has indirect effects on the thyroid economy. Direct effects of this steroid hormone on thyroid cells have been described more recently; so, the aim of the present paper was to review the evidences of these effects on thyroid function and growth regulation, and its mechanisms. The expression and ratios of the two E receptors, alpha and beta, that mediate the genomic effects of E on normal and abnormal thyroid tissue were also reviewed, as well as nongenomic, distinct molecular pathways. Several evidences support the hypothesis that E has a direct role in thyroid follicular cells; understanding its influence on the growth and function of the thyroid in normal and abnormal conditions can potentially provide new targets for the treatment of thyroid diseases. PMID- 21687616 TI - A new technique in primary repair of congenital esophageal atresia preventing anastomotic stricture formation and describing the opening condition of blind pouch: plus ("+") incision. AB - Anastomotic strictures are common and important problems following repair procedures of esophageal atresia. We hereby defined an anastomosis technique that could efficiently prevent this complication in 11 patients with esophageal atresia (EA) and tracheoesophageal fistula (TEF). The proximal end of the atretic esophagus was opened with a plus ("+")-shaped incision providing sufficient anastomosis width. Longitudinal incisions of 2 mm length were made on the anterior and posterior parts of the distal end according to the patients. The two ends were anastomosed with a primary suture at a single plain. We performed this technique on 11 patients, and in the 4-year follow-up period no dilatation proved necessary in any of our patients due to anastomotic strictures or symptomatic dysphagia. This technique that we have described provides a large zigzag anastomosis line and in this way minimizes the incidence of stricture formation. Furthermore, this technique, which we believe to have provided a new opinion on the topic of how to open the proximal end of an atretic esophagus, is quite easy and effective. PMID- 21687617 TI - Unusual noncommunicating isolated enteric duplication cyst in adults. AB - Duplication cysts are rare gastrointestinal congenital abnormalities and can occur anywhere within the gastrointestinal tract. Duplication cysts are firmly attached to or share the wall of the alimentary tract and have a common blood supply with the adjacent segment of the bowel. Completely isolated duplication cysts are an extremely rare variety of gastrointestinal duplications with their own exclusive blood supply, and they do not communicate with the intestine. These cysts are usually diagnosed during early childhood, and very rarely detected in adults, mostly incidentally, due to a lack of symptoms. A 28-year-old male was admitted to our hospital with a chief complaint of lower abdominal pain and distention and a palpable mass for 1 month. Based upon computed tomography and sonographic findings, a small bowel duplication cyst was tentatively diagnosed. The cyst had no connection to the gastrointestinal tract. Herein we report the case of a noncommunicating isolated ileal duplication cyst in an adult. Resection of the cyst was performed safely without requiring bowel resection. PMID- 21687618 TI - Lafutidine 10 mg versus Rabeprazole 20 mg in the Treatment of Patients with Heartburn-Dominant Uninvestigated Dyspepsia: A Randomized, Multicentric Trial. AB - Background. Empirical therapy with antisecretory agents like PPIs and H2RAs has long been the traditional approach in the initial management of uninvestigated dyspepsia. Aim. The objective of the study was to examine relief of dyspepsia with lafutidine, a second-generation H(2)-RA, and rabeprazole and to compare their efficacy. Methods. This was a randomized, open, comparative trial in adult uninvestigated dyspeptic patients, who had at least moderate severity of symptoms, defined as a score of >=4 on a 7-point global overall symptom (GOS) scale, and were randomized to receive once daily either lafutidine 10 mg or rabeprazole 20 mg for 4 weeks. Results. A total of 236 patients were enrolled, out of which 194 patients were included in the analysis. At the end of week 4, a significant difference was observed for symptom relief (lafutidine 89.90% versus rabeprazole 65.26%, P < .01) and symptom resolution (lafutidine 70.71% versus rabeprazole 25.26%, P < .01). Both the drugs were well tolerated. Conclusion. Both lafutidine and rabeprazole provide symptom relief in patients with heartburn dominant uninvestigated dyspepsia. The present study confirms the appropriateness of lafutidine as an empiric treatment and superior efficacy for primary care practice patients with dyspepsia. PMID- 21687619 TI - A meta-analysis of enteral nutrition and total parenteral nutrition in patients with acute pancreatitis. AB - Objective. To analyze the effect of total parenteral nutrition (TPN) and enteral nutrition (EN) in patients with acute pancreatitis. Methods. Randomized controlled trials of TPN and EN in patients with acute pancreatitis were searched in NCBI and CBM databases and The Cochrane Controlled Trials Register. Six studies were enrolled into the analysis, and the details about the trial designs, characters of the subjects, results of the studies were reviewed by two independent authors and analyzed by STATA 11.0 software. Results. Compared with TPN, EN was associated with a significantly lower incidence of pancreatic infection complications (RR = 0.556, 95% CI 0.436~0.709, P = .000), MOF (RR = 0.395, 95% CI 0.272~0.573, P = .003), surgical interventions (RR = 0.556, 95% CI 0.436~0.709, P = .000), and mortality (RR = 0.426, 95% CI 0.238~0.764, P = .167). There was no statistic significance in non-pancreatitis-related complications (RR = 0.853, 95% CI 0.490~1.483, P = .017). However, EN had a significantly higher incidence of non-infection-related complications (RR = 2.697, 95% CI 1.947~3.735, P = .994). Conclusion. EN could be the preferred nutrition feeding method in patients with acute pancreatitis. PMID- 21687620 TI - Perioperative nutrition in abdominal surgery: recommendations and reality. AB - Introduction. Preoperative malnutrition is a major risk factor for increased postoperative morbidity and mortality. Definition and diagnosis of malnutrition and its treatment is still subject for controversy. Furthermore, practical implementation of nutrition-related guidelines is unknown. Methods. A review of the available literature and of current guidelines on perioperative nutrition was conducted. We focused on nutritional screening and perioperative nutrition in patients undergoing digestive surgery, and we assessed translation of recent guidelines in clinical practice. Results and Conclusions. Malnutrition is a well recognized risk factor for poor postoperative outcome. The prevalence of malnutrition depends largely on its definition; about 40% of patients undergoing major surgery fulfil current diagnostic criteria of being at nutritional risk. The Nutritional Risk Score is a pragmatic and validated tool to identify patients who should benefit from nutritional support. Adequate nutritional intervention entails reduced (infectious) complications, hospital stay, and costs. Preoperative oral supplementation of a minimum of five days is preferable; depending on the patient and the type of surgery, immune-enhancing formulas are recommended. However, surgeons' compliance with evidence-based guidelines remains poor and efforts are necessary to implement routine nutritional screening and nutritional support. PMID- 21687621 TI - Cerebrovascular accidents associated with sorafenib in hepatocellular carcinoma. AB - Sorafenib is an oral angiogenetic multikinase inhibitor approved in the treatment of renal and hepatocellular carcinoma. Bleeding and venous thrombotic events have been described with angiogenetic agents but cerebrovascular accidents are rarely reported. We report two cases of patients with hepatocellular carcinoma who developed a cerebrovascular accident while on sorafenib. Neither patient had any risk factors for the cerebrovascular events apart from gender and age in the second patient. Laboratory data were noncontributory. The head CT scan did not reveal acute abnormalities. No hemodynamically significant stenosis was visible in the carotid ultrasound, and the echocardiogram showed normal size of the heart chambers and normal systolic function of the left ventricle. Sorafenib was discontinued in both cases. Physicians should monitor patients receiving sorafenib for neurologic symptoms, and in the absence of other etiology, prompt discontinuation of this drug should be considered. PMID- 21687622 TI - Enzymatic biodiesel synthesis using a byproduct obtained from palm oil refining. AB - An alternative route to produce biodiesel is based on esterification of free fatty acids present in byproducts obtained from vegetable oil refining, such as palm oil fatty acid distillate (PFAD). PFAD is a byproduct of the production of edible palm oil, which contains 96 wt.% of free fatty acids. The purpose of this work was to study biodiesel synthesis via esterification of PFAD with methanol and ethanol, catalyzed by commercial immobilized lipases (Novozym 435, Lipozyme RM-IM, and Lipozyme TL-IM), in a solvent-free system. The effects of reaction parameters such as type of lipase, enzyme amount, type of alcohol, alcohol amount, and enzyme reuse were studied. Fatty acid conversion of 93% was obtained after 2.5 h of esterification reaction between PFAD and ethanol using 1.0 wt.% of Novozym 435 at 60 degrees C. PMID- 21687623 TI - Acute intermittent porphyria associated with respiratory failure: a multidisciplinary approach. AB - Despite being challenging, delivery of effective nursing care to patients with acute intermittent porphyria is a matter of utmost importance. In this paper, the diversity of symptoms and the difficult diagnosis of this condition are emphasized, and details concerning the treatment of this disorder in the intensive care unit are presented. We believe that acute intermittent porphyria should be borne in mind during performance of differential diagnosis of neurological, psychiatric, and gastroenterological disorders on patients whose routine investigation tests are normal, especially when precipitating factors exist. Intensive care measures and a multidisciplinary team approach are essential. PMID- 21687624 TI - A very long foreign body in the bladder. AB - In the urinary tract, foreign body is most commonly found in the urinary bladder. But it is anatomically very difficult for a man to self-insert a long object into the urinary bladder. Here we report a case of a 49-year-old Japanese man who has inserted a 140-cm vinyl tube in the bladder for masturbation. He could not retrieve it, and the bladder foreign body remained in this position for about two years. He was referred to our hospital and open surgery was performed. PMID- 21687625 TI - Biomarkers in overactive bladder: a new objective and noninvasive tool? AB - Overactive bladder syndrome (OAB) is a highly prevalent urinary dysfunction, with considerable economic and human costs. Clinical diagnosis of OAB is still based on subjective symptoms. A new accurate, objective and noninvasive test to diagnose OAB and assess therapeutic outcome is lacking. Recent studies in lower urinary tract (LUT) dysfunctions, particularly in OAB patients, indicate that urinary proteins (neurotrophins, prostaglandins, and cytokines), serum C reactive protein, and detrusor wall thickness are altered, and such changes could be used as biomarkers of the disease. Nowadays, increasing emphasis has been given to the role of urinary neurotrophins, namely nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), as key players in some urinary dysfunctions. Although recently considered to be a bladder dysfunction biomarker, urinary NGF presents low sensitivity and specificity. Preliminary results suggest that BDNF may serve as a more efficient biomarker. Even though we have to wait for future studies to confirm the potential role of NGF and BDNF as OAB biomarkers, it is already clear that neurotrophins will contribute to elucidate the physiopathological basis of OAB. Herein are reviewed the latest advances in this new and exciting field, the detection and clinical application of emerging OAB biomarkers. PMID- 21687626 TI - Impact of a Multimodal Antimicrobial Stewardship Program on Pseudomonas aeruginosa Susceptibility and Antimicrobial Use in the Intensive Care Unit Setting. AB - Objective. To study the impact of our multimodal antibiotic stewardship program on Pseudomonas aeruginosa susceptibility and antibiotic use in the intensive care unit (ICU) setting. Methods. Our stewardship program employed the key tenants of published antimicrobial stewardship guidelines. These included prospective audits with intervention and feedback, formulary restriction with preauthorization, educational conferences, guidelines for use, antimicrobial cycling, and de escalation of therapy. ICU antibiotic use was measured and expressed as defined daily doses (DDD) per 1,000 patient-days. Results. Certain temporal relationships between antibiotic use and ICU resistance patterns appeared to be affected by our antibiotic stewardship program. In particular, the ICU use of intravenous ciprofloxacin and ceftazidime declined from 148 and 62.5 DDD/1,000 patient-days to 40.0 and 24.5, respectively, during 2004 to 2007. An increase in the use of these agents and resistance to these agents was witnessed during 2008-2010. Despite variability in antibiotic usage from the stewardship efforts, we were overall unable to show statistical relationships with P. aeruginosa resistance rate. Conclusion. Antibiotic resistance in the ICU setting is complex. Multimodal stewardship efforts attempt to prevent resistance, but such programs clearly have their limits. PMID- 21687628 TI - Predicting housekeeping genes based on Fourier analysis. AB - Housekeeping genes (HKGs) generally have fundamental functions in basic biochemical processes in organisms, and usually have relatively steady expression levels across various tissues. They play an important role in the normalization of microarray technology. Using Fourier analysis we transformed gene expression time-series from a Hela cell cycle gene expression dataset into Fourier spectra, and designed an effective computational method for discriminating between HKGs and non-HKGs using the support vector machine (SVM) supervised learning algorithm which can extract significant features of the spectra, providing a basis for identifying specific gene expression patterns. Using our method we identified 510 human HKGs, and then validated them by comparison with two independent sets of tissue expression profiles. Results showed that our predicted HKG set is more reliable than three previously identified sets of HKGs. PMID- 21687627 TI - Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders. AB - BACKGROUND: Structural variation in the neurexin-1 (NRXN1) gene increases risk for both autism spectrum disorders (ASD) and schizophrenia. However, the manner in which NRXN1 gene variation may be related to brain morphology to confer risk for ASD or schizophrenia is unknown. METHOD/PRINCIPAL FINDINGS: 53 healthy individuals between 18-59 years of age were genotyped at 11 single nucleotide polymorphisms of the NRXN1 gene. All subjects received structural MRI scans, which were processed to determine cortical gray and white matter lobar volumes, and volumes of striatal and thalamic structures. Each subject's sensorimotor function was also assessed. The general linear model was used to calculate the influence of genetic variation on neural and cognitive phenotypes. Finally, in silico analysis was conducted to assess potential functional relevance of any polymorphisms associated with brain measures. A polymorphism located in the 3' untranslated region of NRXN1 significantly influenced white matter volumes in whole brain and frontal lobes after correcting for total brain volume, age and multiple comparisons. Follow-up in silico analysis revealed that this SNP is a putative microRNA binding site that may be of functional significance in regulating NRXN1 expression. This variant also influenced sensorimotor performance, a neurocognitive function impaired in both ASD and schizophrenia. CONCLUSIONS: Our findings demonstrate that the NRXN1 gene, a vulnerability gene for SCZ and ASD, influences brain structure and cognitive function susceptible in both disorders. In conjunction with our in silico results, our findings provide evidence for a neural and cognitive susceptibility mechanism by which the NRXN1 gene confers risk for both schizophrenia and ASD. PMID- 21687629 TI - Evidence for a higher number of species of Odontotermes (Isoptera) than currently known from Peninsular Malaysia from mitochondrial DNA phylogenies. AB - Termites of the genus Odontotermes are important decomposers in the Old World tropics and are sometimes important pests of crops, timber and trees. The species within the genus often have overlapping size ranges and are difficult to differentiate based on morphology. As a result, the taxonomy of Odontotermes in Peninsular Malaysia has not been adequately worked out. In this study, we examined the phylogeny of 40 samples of Odontotermes from Peninsular Malaysia using two mitochondrial DNA regions, that is, the 16S ribosomal RNA and cytochrome oxidase subunit I genes, to aid in elucidating the number of species in the peninsula. Phylogenies were reconstructed from the individual gene and combined gene data sets using parsimony and likelihood criteria. The phylogenies supported the presence of up to eleven species in Peninsular Malaysia, which were identified as O. escherichi, O. hainanensis, O. javanicus, O. longignathus, O. malaccensis, O. oblongatus, O. paraoblongatus, O. sarawakensis, and three possibly new species. Additionally, some of our taxa are thought to comprise a complex of two or more species. The number of species found in this study using DNA methods was more than the initial nine species thought to occur in Peninsular Malaysia. The support values for the clades and morphology of the soldiers provided further evidence for the existence of eleven or more species. Higher resolution genetic markers such as microsatellites would be required to confirm the presence of cryptic species in some taxa. PMID- 21687630 TI - Zebrafish kruppel-like factor 4a represses intestinal cell proliferation and promotes differentiation of intestinal cell lineages. AB - BACKGROUND: Mouse kruppel-like factor 4 (Klf4) is a zinc finger-containing transcription factor required for terminal differentiation of goblet cells in the colon. However, studies using either Klf4(-/-) mice or mice with conditionally deleted Klf4 in their gastric epithelia showed different results in the role of Klf4 in epithelial cell proliferation. We used zebrafish as a model organism to gain further understanding of the role of Klf4 in the intestinal cell proliferation and differentiation. METHODOLOGY/PRINCIPAL FINDINGS: We characterized the function of klf4a, a mammalian klf4 homologue by antisense morpholino oligomer knockdown. Zebrafish Klf4a shared high amino acid similarities with human and mouse Klf4. Phylogenetic analysis grouped zebrafish Klf4a together with both human and mouse Klf4 in a branch with high bootstrap value. In zebrafish, we demonstrate that Klf4a represses intestinal cell proliferation based on results of BrdU incorporation, p-Histone 3 immunostaining, and transmission electron microscopy analyses. Decreased PepT1 expression was detected in intestinal bulbs of 80- and 102-hours post fertilization (hpf) klf4a morphants. Significant reduction of alcian blue-stained goblet cell number was identified in intestines of 102- and 120-hpf klf4a morphants. Embryos treated with gamma-secretase inhibitor showed increased klf4a expression in the intestine, while decreased klf4a expression and reduction in goblet cell number were observed in embryos injected with Notch intracellular domain (NICD) mRNA. We were able to detect recovery of goblet cell number in 102-hpf embryos that had been co-injected with both klf4a and Notch 1a NICD mRNA. CONCLUSIONS/SIGNIFICANCE: This study provides in vivo evidence showing that zebrafih Klf4a is essential for the repression of intestinal cell proliferation. Zebrafish Klf4a is required for the differentiation of goblet cells and the terminal differentiation of enterocytes. Moreover, the regulation of differentiation of goblet cells in zebrafish intestine by Notch signaling at least partially mediated through Klf4a. PMID- 21687631 TI - Mycobacterium tuberculosis acg gene is required for growth and virulence in vivo. AB - Mycobacterium tuberculosis dosRS two-component regulatory system controls transcription of approximately 50 genes including hspX, acg and Rv2030c, in response to hypoxia and nitric oxide conditions and within macrophages and mice. The hspX lies between acg and Rv2030c. However, the functions of the dosR regulated genes in vitro and in vivo are largely unknown. Previously, we demonstrated that deletion of hspX gene produced a mutant which grew faster in macrophages and in mice. In this study, we attempted to determine the functions of acg and Rv2030c by gene inactivation. We demonstrate that Rv2030c is dispensable for virulence and growth. However, deletion of acg produced a mutant which is attenuated in both resting and activated macrophages and in acute and persistent murine infection models. Surprisingly, deletion of acg did not compromise the viability of the mutant to nitrosative and oxidative stresses in vitro and in vivo. In addition, when the WT and the acg mutants were treated with antibiotics such as the prodrugs nitrofurantoin and nitrofuran, the acg mutant became more sensitive than the WT strain to these drugs. This suggests that Acg may not function as a nitroreductase. These data indicate that acg encodes an essential virulence factor for M. tuberculosis and enables it to grow and survive in macrophages and in mouse organs. PMID- 21687632 TI - Adeno-associated viral vector-mediated transgene expression is independent of DNA methylation in primate liver and skeletal muscle. AB - Recombinant adeno-associated viral (rAAV) vectors can support long-term transgene expression in quiescent tissues. Intramuscular (i.m.) administration of a single stranded AAV vector (ssAAV) in the nonhuman primate (NHP) results in a peak protein level at 2-3 months, followed by a decrease over several months before reaching a steady-state. To investigate transgene expression and vector genome persistence, we previously demonstrated that rAAV vector genomes associate with histones and form a chromatin structure in NHP skeletal muscle more than one year after injection. In the mammalian nucleus, chromatin remodeling via epigenetic modifications plays key role in transcriptional regulation. Among those, CpG hyper-methylation of promoters is a known hallmark of gene silencing. To assess the involvement of DNA methylation on the transgene expression, we injected NHP via the i.m. or the intravenous (i.v.) route with a recombinant ssAAV2/1 vector. The expression cassette contains the transgene under the transcriptional control of the constitutive Rous Sarcoma Virus promoter (RSVp). Total DNA isolated from NHP muscle and liver biopsies from 1 to 37 months post-injection was treated with sodium bisulfite and subsequently analyzed by pyrosequencing. No significant CpG methylation of the RSVp was found in rAAV virions or in vector DNA isolated from NHP transduced tissues. Direct de novo DNA methylation appears not to be involved in repressing transgene expression in NHP after gene transfer mediated by ssAAV vectors. The study presented here examines host/vector interactions and the impact on transgene expression in a clinically relevant model. PMID- 21687633 TI - Knockdown of MTDH sensitizes endometrial cancer cells to cell death induction by death receptor ligand TRAIL and HDAC inhibitor LBH589 co-treatment. AB - Understanding the molecular underpinnings of chemoresistance is vital to design therapies to restore chemosensitivity. In particular, metadherin (MTDH) has been demonstrated to have a critical role in chemoresistance. Over-expression of MTDH correlates with poor clinical outcome in breast cancer, neuroblastoma, hepatocellular carcinoma and prostate cancer. MTDH is also highly expressed in advanced endometrial cancers, a disease for which new therapies are urgently needed. In this present study, we focused on the therapeutic benefit of MTDH depletion in endometrial cancer cells to restore sensitivity to cell death. Cells were treated with a combination of tumor necrosis factor-alpha-related apoptosis inducing ligand (TRAIL), which promotes death of malignant cells of the human reproductive tract, and histone deacetylase (HDAC) inhibitors, which have been shown to increase the sensitivity of cancer cells to TRAIL-induced apoptosis. Our data indicate that depletion of MTDH in endometrial cancer cells resulted in sensitization of cells that were previously resistant in response to combinatorial treatment with TRAIL and the HDAC inhibitor LBH589. MTDH knockdown reduced the proportion of cells in S and increased cell arrest in G2/M in cells treated with LBH589 alone or LBH589 in combination with TRAIL, suggesting that MTDH functions at the cell cycle checkpoint to accomplish resistance. Using microarray technology, we identified 57 downstream target genes of MTDH, including calbindin 1 and galectin-1, which may contribute to MTDH-mediated therapeutic resistance. On the other hand, in MTDH depleted cells, inhibition of PDK1 and AKT phosphorylation along with increased Bim expression and XIAP degradation correlated with enhanced sensitivity to cell death in response to TRAIL and LBH589. These findings indicate that targeting or depleting MTDH is a potentially novel avenue for reversing therapeutic resistance in patients with endometrial cancer. PMID- 21687634 TI - Preconditioning involves selective mitophagy mediated by Parkin and p62/SQSTM1. AB - Autophagy-dependent mitochondrial turnover in response to cellular stress is necessary for maintaining cellular homeostasis. However, the mechanisms that govern the selective targeting of damaged mitochondria are poorly understood. Parkin, an E3 ubiquitin ligase, has been shown to be essential for the selective clearance of damaged mitochondria. Parkin is expressed in the heart, yet its function has not been investigated in the context of cardioprotection. We previously reported that autophagy is required for cardioprotection by ischemic preconditioning (IPC). In the present study, we used simulated ischemia (sI) in vitro and IPC of hearts to investigate the role of Parkin in mediating cardioprotection ex vivo and in vivo. In HL-1 cells, sI induced Parkin translocation to mitochondria and mitochondrial elimination. IPC induced Parkin translocation to mitochondria in Langendorff-perfused rat hearts and in vivo in mice subjected to regional IPC. Mitochondrial depolarization with an uncoupling agent similarly induced Parkin translocation to mitochondria in cells and Langendorff-perfused rat hearts. Mitochondrial loss was blunted in Atg5-deficient cells, revealing the requirement for autophagy in mitochondrial elimination. Consistent with previous reports indicating a role for p62/SQSTM1 in mitophagy, we found that depletion of p62 attenuated mitophagy and exacerbated cell death in HL-1 cardiomyocytes subjected to sI. While wild type mice showed p62 translocation to mitochondria and an increase in ubiquitination, Parkin knockout mice exhibited attenuated IPC-induced p62 translocation to the mitochondria. Importantly, ablation of Parkin in mice abolished the cardioprotective effects of IPC. These results reveal for the first time the crucial role of Parkin and mitophagy in cardioprotection. PMID- 21687635 TI - Genetic diversity and antimicrobial resistance of Escherichia coli from human and animal sources uncovers multiple resistances from human sources. AB - Escherichia coli are widely used as indicators of fecal contamination, and in some cases to identify host sources of fecal contamination in surface water. Prevalence, genetic diversity and antimicrobial susceptibility were determined for 600 generic E. coli isolates obtained from surface water and sediment from creeks and channels along the middle Santa Ana River (MSAR) watershed of southern California, USA, after a 12 month study. Evaluation of E. coli populations along the creeks and channels showed that E. coli were more prevalent in sediment compared to surface water. E. coli populations were not significantly different (P = 0.05) between urban runoff sources and agricultural sources, however, E. coli genotypes determined by pulsed-field gel electrophoresis (PFGE) were less diverse in the agricultural sources than in urban runoff sources. PFGE also showed that E. coli populations in surface water were more diverse than in the sediment, suggesting isolates in sediment may be dominated by clonal populations.Twenty four percent (144 isolates) of the 600 isolates exhibited resistance to more than one antimicrobial agent. Most multiple resistances were associated with inputs from urban runoff and involved the antimicrobials rifampicin, tetracycline, and erythromycin. The occurrence of a greater number of E. coli with multiple antibiotic resistances from urban runoff sources than agricultural sources in this watershed provides useful evidence in planning strategies for water quality management and public health protection. PMID- 21687636 TI - The shift from local to global visual processing in 6-year-old children is associated with grey matter loss. AB - BACKGROUND: A real-world visual scene consists of local elements (e.g. trees) that are arranged coherently into a global configuration (e.g. a forest). Children show psychological evolution from a preference for local visual information to an adult-like preference for global visual information, with the transition in visual preference occurring around 6 years of age. The brain regions involved in this shift in visual preference have not been described. METHODS AND RESULTS: We used voxel-based morphometry (VBM) to study children during this developmental window to investigate changes in gray matter that underlie the shift from a bias for local to global visual information. Six-year old children were assigned to groups according to their judgment on a global/local task. The first group included children who still presented with local visual processing biases, and the second group included children who showed global visual processing biases. VBM results indicated that compared to children with local visual processing biases, children with global visual processing biases had a loss of gray matter in the right occipital and parietal visuospatial areas. CONCLUSIONS: These anatomical findings are in agreement with previous findings in children with neurodevelopmental disorders and represent the first structural identification of brain regions that allow healthy children to develop a global perception of the visual world. PMID- 21687637 TI - Role and mechanism of arsenic in regulating angiogenesis. AB - Arsenic is a wide spread carcinogen associated with several kinds of cancers including skin, lung, bladder, and liver cancers. Lung is one of the major targets of arsenic exposure. Angiogenesis is the pivotal process during carcinogenesis and chronic pulmonary diseases, but the role and mechanism of arsenic in regulating angiogenesis remain to be elucidated. In this study we show that short time exposure of arsenic induces angiogenesis in both human immortalized lung epithelial cells BEAS-2B and adenocarcinoma cells A549. To study the molecular mechanism of arsenic-inducing angiogenesis, we find that arsenic induces reactive oxygen species (ROS) generation, which activates AKT and ERK1/2 signaling pathways and increases the expression of hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF). Inhibition of ROS production suppresses angiogenesis by decreasing AKT and ERK activation and HIF-1 expression. Inhibition of ROS, AKT and ERK1/2 signaling pathways is sufficient to attenuate arsenic-inducing angiogenesis. HIF-1 and VEGF are downstream effectors of AKT and ERK1/2 that are required for arsenic-inducing angiogenesis. These results shed light on the mechanism of arsenic in regulating angiogenesis, and are helpful to develop mechanism-based intervention to prevent arsenic-induced carcinogenesis and angiogenesis in the future. PMID- 21687639 TI - E-manuscript article summaries. PMID- 21687638 TI - Rapid turnover of 2-LTR HIV-1 DNA during early stage of highly active antiretroviral therapy. AB - BACKGROUND: Despite prolonged treatment with highly active antiretroviral therapy (HAART), the infectious HIV-1 continues to replicate and resides latently in the resting memory CD4+ T lymphocytes, which blocks the eradication of HIV-1. The viral persistence of HIV-1 is mainly caused by its proviral DNA being either linear nonintegrated, circular nonintegrated, or integrated. Previous reports have largely focused on the dynamics of HIV-1 DNA from the samples collected with relatively long time intervals during the process of disease and HAART treatment, which may have missed the intricate changes during the intervals in early treatment. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the dynamics of HIV-1 DNA in patients during the early phase of HARRT treatment. Using optimized real time PCR, we observed significant changes in 2-LTR during the first 12-week of treatment, while total and integrated HIV-1 DNA remained stable. The doubling time and half-life of 2-LTR were not correlated with the baseline and the rate of changes in plasma viral load and various CD4+ T-cell populations. Longitudinal analyses on 2-LTR sequences and plasma lipopolysaccharide (LPS) levels did not reveal any significant changes in the same treatment period. CONCLUSIONS/SIGNIFICANCE: Our study revealed the rapid changes in 2-LTR concentration in a relatively large number of patients during the early HAART treatment. The rapid changes indicate the rapid infusion and clearance of cells bearing 2-LTR in the peripheral blood. Those changes are not expected to be caused by the blocking of viral integration, as our study did not include the integrase inhibitor raltegravir. Our study helps better understand the dynamics of HIV-DNA and its potential role as a biomarker for the diseases and for the treatment efficacy of HAART. PMID- 21687640 TI - Towards Al-induced manganese-containing superoxide dismutase inactivation and conformational changes: an integrating study with docking simulations. AB - Superoxide dismutase (SOD, EC 1.15.1.1) plays an important antioxidant defense role in skins exposed to oxygen. We studied the inhibitory effects of Al(3+) on the activity and conformation of manganese-containing SOD (Mn-SOD). Mn-SOD was significantly inactivated by Al(3+) in a dose-dependent manner. The kinetic studies showed that Al(3+) inactivated Mn-SOD follows the first-order reaction. Al(3+) increased the degree of secondary structure of Mn-SOD and also disrupted the tertiary structure of Mn-SOD, which directly resulted in enzyme inactivation. We further simulated the docking between Mn-SOD and Al(3+) (binding energy for Dock 6.3: -14.07 kcal/mol) and suggested that ASP152 and GLU157 residues were predicted to interact with Al(3+), which are not located in the Mn-contained active site. Our results provide insight into the inactivation of Mn-SOD during unfolding in the presence of Al(3+) and allow us to describe a ligand binding via inhibition kinetics combined with the computational prediction. PMID- 21687642 TI - Angiostrongylus vasorum: Experimental Infection and Larval Development in Omalonyx matheroni. AB - The susceptibility and suitability of Omalonyx matheroni as an intermediate host of Angiostrongylus vasorum and the characteristics of larval recovery and development were investigated. Mollusks were infected, and from the 3rd to the 25th day after infection, larvae were recovered from groups of 50 individuals. The first observation of L2 was on the 5th day, and the first observation of L3 was on the 10th day. From the 22nd day on, all larvae were at the L3 stadium. Larval recovery varied from 78.2% to 95.2%. We found larval development to be faster in O. matheroni than in Biomphalaria glabrata. Our findings indicate that this mollusk is highly susceptible to A. vasorum. Infective L3 were orally inoculated into a dog, and the prepatent period was 39 days. This is the first study to focus on O. matheroni as an intermediate host of A. vasorum. PMID- 21687641 TI - Primary biliary cirrhosis: family stories. AB - Primary biliary cirrhosis (PBC) is a chronic immune-mediated cholestatic liver disease of unknown aetiology which affects mostly women in middle age. Familial PBC is when PBC affects more than one member of the same family, and data suggest that first-degree relatives of PBC patients have an increased risk of developing the disease. Most often, these familial clusters involve mother-daughter pairs, which is consistent with the female preponderance of the disease. These clusters provide evidence towards a genetic basis underlying PBC. However, clusters of nonrelated individuals have also been reported, giving strength to an environmental component. Twin studies have demonstrated a high concordance for PBC in monozygotic twins and a low concordance among dizygotic twins. In conclusion, studies of PBC in families clearly demonstrate that genetic, epigenetic, and environmental factors play a role in the development of the disease. PMID- 21687643 TI - Cotranslational protein folding and terminus hydrophobicity. AB - Peptides fold on a time scale that is much smaller than the time required for synthesis, whence all proteins potentially fold cotranslationally to some degree (followed by additional folding events after release from the ribosome). In this paper, in three different ways, we find that cotranslational folding success is associated with higher hydrophobicity at the N-terminus than at the C-terminus. First, we fold simple HP models on a square lattice and observe that HP sequences that fold better cotranslationally than from a fully extended state exhibit a positive difference (N-C) in terminus hydrophobicity. Second, we examine real proteins using a previously established measure of potential cotranslationality known as ALR (Average Logarithmic Ratio of the extent of previous contacts) and again find a correlation with the difference in terminus hydrophobicity. Finally, we use the cotranslational protein structure prediction program SAINT and again find that such an approach to folding is more successful for proteins with higher N-terminus than C-terminus hydrophobicity. All results indicate that cotranslational folding is promoted in part by a hydrophobic start and a less hydrophobic finish to the sequence. PMID- 21687644 TI - Ameliorative effect of vitamin C on alterations in thyroid hormones concentrations induced by subchronic coadministration of chlorpyrifos and lead in wistar rats. AB - The present study evaluated the ameliorative effect of vitamin C on alteration in thyroid hormones induced by low-dose subchronic coadministration of chlorpyrifos (CPF) and lead (Pb). Forty Wistar rats were divided into 4 groups of 10 animals each. Groups I and II were administered soya oil (2 mL/kg) and vitamin C (100 mg/kg), respectively. Group III was coadministered CPF (4.25 mg/kg ~1/20th LD(50)) and Pb (250 mg/kg ~1/20th LD(50)), respectively. Group IV was pretreated with vitamin C (100 mg/kg) and then coadministered with CPF (4.25 mg/kg) and Pb (250 mg/kg), 30 min later. The regimens were administered by gavage for a period of 9 weeks. The marginal decrease in serum triiodothyronine and thyroxine and the significant increase in the concentrations of thyroid stimulating hormone and malonaldehyde in the group coadministered with CPF and Pb were ameliorated by vitamin C partly due to its antioxidant properties. PMID- 21687645 TI - Highly Elevated Serum Hepcidin in Patients with Acute Myeloid Leukemia prior to and after Allogeneic Hematopoietic Cell Transplantation: Does This Protect from Excessive Parenchymal Iron Loading? AB - Hepcidin is upregulated by inflammation and iron. Inherited (HFE genotype) and treatment-related factors (blood units (BU), Iron overload) affecting hepcidin (measured by C-ELISA) were studied in 42 consecutive patients with AML prior to and after allogeneic hematopoietic cell transplantation (HCT). Results. Elevated serum ferritin pre- and post-HCT was present in all patients. Median hepcidin pre and post-HCT of 358 and 398 ng/mL, respectively, were elevated compared to controls (median 52 ng/mL) (P < .0001). Liver and renal function, prior chemotherapies, and conditioning had no impact on hepcidin. Despite higher total BU after HCT compared to pretransplantation (P < .0005), pre- and posttransplant ferritin and hepcidin were similar. BU influenced ferritin (P = .001) and hepcidin (P = .001). No correlation of pre- or posttransplant hepcidin with pretransplant ferritin was found. HFE genotype did not influence hepcidin. Conclusions. Hepcidin is elevated in AML patients pre- and post-HCT due to transfusional iron-loading suggesting that hepcidin synthesis remains intact despite chemotherapy and HCT. PMID- 21687646 TI - Macrofilaricidal Activity in Wuchereria bancrofti after 2 Weeks Treatment with a Combination of Rifampicin plus Doxycycline. AB - Infection with the filarial nematode Wuchereria bancrofti can lead to lymphedema, hydrocele, and elephantiasis. Since adult worms cause pathology in lymphatic filariasis (LF), it is imperative to discover macrofilaricidal drugs for the treatment of the infection. Endosymbiotic Wolbachia in filariae have emerged as a new target for antibiotics which can lead to macrofilaricidal effects. In Ghana, a pilot study was carried out with 39 LF-infected men; 12 were treated with 200 mg doxycycline/day for 4 weeks, 16 were treated with a combination of 200 mg doxycycline/day + 10 mg/kg/day rifampicin for 2 weeks, and 11 patients received placebo. Patients were monitored for Wolbachia and microfilaria loads, antigenaemia, and filarial dance sign (FDS). Both 4-week doxycycline and the 2 week combination treatment reduced Wolbachia load significantly. At 18 months posttreatment, four-week doxycycline resulted in 100% adult worm loss, and the 2 week combination treatment resulted in a 50% adult worm loss. In conclusion, this pilot study with a combination of 2-week doxycycline and rifampicin demonstrates moderate macrofilaricidal activity against W. bancrofti. PMID- 21687647 TI - Antineutrophil cytoplasmic antibodies testing in a large cohort of unselected greek patients. AB - Objective. To retrospectively evaluate ANCA testing in a cohort of unselected Greek in- and outpatients. Methods. In 10803 consecutive serum samples, ANCA were tested by indirect immunofluorescence (IIF) and ELISA. ELISA in inpatients was performed only on IIF positive sera. Results. Low prevalence (6.0%) of IIF positive samples was observed. Among these samples, 63.5% presented perinuclear (p-ANCA), 9.3% cytoplasmic (c-ANCA) and 27.2% atypical (x-ANCA) pattern. 16.1% of p-ANCA were antimyeloperoxidase (anti-MPO) positive, whereas 68.3% of c-ANCA were antiproteinase-3 (anti-PR3) positive. Only 17 IIF negative outpatients' samples were ELISA positive. ANCA-associated vasculitides (AAV), connective tissue disorders and gastrointestinal disorders represented 20.5%, 23.9%, and 21.2% of positive results, respectively. AAV patients exhibited higher rates of MPO/PR3 specificity compared to non-AAV (93.8% versus 8%). Conclusions. This first paper on Greek patients supports that screening for ANCA by IIF and confirming positive results by ELISA minimize laboratory charges without sacrificing diagnostic accuracy. PMID- 21687648 TI - The central effects of thyroid hormones on appetite. AB - Obesity is a major public health issue worldwide. Current pharmacological treatments are largely unsuccessful. Determining the complex pathways that regulate food intake may aid the development of new treatments. The hypothalamic pituitary-thyroid (HPT) axis has well-known effects on energy expenditure, but its role in the regulation of food intake is less well characterised. Evidence suggests that the HPT axis can directly influence food intake. Thyroid dysfunction can have clinically significant consequences on appetite and body weight. Classically, these effects were thought to be mediated by the peripheral effects of thyroid hormone. However, more recently, local regulation of thyroid hormone in the central nervous system (CNS) is thought to play an important role in physiologically regulating appetite. This paper focuses on the role of the HPT and thyroid hormone in appetite and provides evidence for potential new targets for anti-obesity agents. PMID- 21687649 TI - Neutropenia and Neutropenic Complications in ABVD Chemotherapy for Hodgkin Lymphoma. AB - A combination of Adriamycin (a.k.a. Doxorubicin), Bleomycin, Vinblastine, and Dacarbazine (ABVD) is the most commonly used chemotherapy regime for Hodgkin lymphoma. This highly effective treatment is associated with a significant risk of neutropenia. Various strategies are adopted to counter this commonly encountered problem, including dose modification, use of colony stimulating factors, and prophylactic or therapeutic use of antibiotics. Data to support these approaches is somewhat controversial, and in keeping with the paucity of definitive evidence, there is a wide disparity in the management of neutropenia in patients receiving ABVD chemotherapy. This paper summarizes the evidence for managing ABVD-related neutropenia during the treatment of Hodgkin lymphoma. PMID- 21687650 TI - CD8 T Cells and Toxoplasma gondii: A New Paradigm. AB - CD8 T cells are essential for control of Toxoplasma gondii infection. Once activated they undergo differentiation into short-lived effector and memory precursor effector cells. As effector cells, CD8 T cells exert immune pressure on the parasite via production of inflammatory cytokines and through their cytolytic activity. Once immune control has been established, the parasite encysts and develops into chronic infection regulated by the memory CD8 T-cell population. Several signals are needed for this process to be initiated and for development of fully differentiated memory CD8 T cells. With newly developed tools including CD8 T-cell tetramers and TCR transgenic mice, dissecting the biology behind T. gondii-specific CD8 T-cell responses can now be more effectively addressed. In this paper, we discuss what is known about the signals required for effective T. gondii-specific CD8 T-cell development, their differentiation, and effector function. PMID- 21687651 TI - Multiple autoimmune propensity and B-non-hodgkin lymphoma: cause or effect? AB - We report a case of multiple autoimmunity consisting of the presence of autoimmune haemolytic anaemia (AIHA), antimitochondrial antibodies (AMAs), and antiphospholipid antibodies (APLAbs) as the presenting manifestations of an extrahepatic B-non-Hodgkin lymphoma (B-NHL) in a 63-year-old woman. The patient presented with fatigue attributed to severe AIHA. Due to increased serum IgM and gamma-GT levels, an investigation for AMA was performed, which proved positive with anti-M2 specificity. A prolongation of activated partial thromboplastin time (aPTT) led to the determination of APLAbs (lupus anticoagulant and other APLAbs) which were also positive. Bone marrow biopsy in combination with immmunohistochemical studies established the diagnosis of lymphoplasmacytic B NHL. Ten months later, B-NHL was in remission while AMA and APLAbs were still positive. In conclusion, we documented the coexistence of multiple autoimmune reactions together with B-NHL highlighting the possible common pathogenetic pathways of the two entities. PMID- 21687652 TI - MicroRNA Role in Thyroid Cancer Development. AB - MicroRNAs (miRNAs) are endogenous noncoding RNAs that negatively regulate gene expression by binding the 3' noncoding region of the messenger RNA targets inducing their cleavage or blocking the protein translation. They play important roles in multiple biological and metabolic processes, including developmental timing, signal transduction, and cell maintenance and differentiation. Their deregulation can predispose to diseases and cancer. miRNA expression has been demonstrated to be deregulated in many types of human tumors, including thyroid cancers, and could be responsible for tumor initiation and progression. In this paper we reviewed the available data on miRNA deregulation in different thyroid tumors and describe the putative role of miRNA in thyroid cancer development. PMID- 21687653 TI - The Management of Classical Hodgkin's Lymphoma: Past, Present, and Future. AB - The management of classical Hodgkin's lymphoma (CHL) is a success story of modern multi-agent haemato-oncology. Prior to the middle of the twentieth century CHL was fatal in the majority of cases. Introduction of single agent radiotherapy (RT) demonstrated for the first time that these patients could be cured. Developments in chemotherapy including the mechlorethamine, vincristine, procarbazine and prednisolone (MOPP) and Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) regimens have resulted in cure rates of over 80%. Even in relapse, CHL patients can be salvaged with high dose chemotherapy and autologous haematopoietic stem cell transplantation (ASCT). Challenges remain, however, in finding new strategies to manage the small number of patients who continue to relapse or progress. In addition, the young age of many Hodgkin's patients forces difficult decisions in balancing the benefit of early disease control against the survival disadvantage of late toxicity. In this article we aim to summarise past trials, define the current standard of care and appraise future developments in the management of CHL. PMID- 21687655 TI - An ELISA to Detect Serum Antibodies to the Salivary Gland Toxin of Ixodes holocyclus Neumann in Dogs and Rodents. AB - The Ixodes holocyclus tick causes paralysis in up to 10,000 companion and domestic animals each year in Australia. Treatment requires the removal of the parasite and the administration of a commercial tick antiserum that is prepared from hyperimmune dogs. Each batch of this serum is initially tested for toxin neutralising potency in a mouse bioassay that is expensive, time consuming, and subjective. With the aim of developing a rapid in vitro assay to replace the bioassay, we used a partially purified antigen prepared from I. holocyclus salivary glands to develop an ELISA to detect toxin-reactive antibodies in hyperimmune dog sera. The optimised ELISA reliably detected antibodies reactive to I. holocyclus salivary gland antigens. Parallel testing of sera with a negative control antigen prepared from the salivary glands of the nontoxic tick Rhipicephalus (Boophilus) microplus provided further evidence that we were detecting toxin-specific antibodies in the assay. Using the ELISA, we could also detect antibodies induced in rats after experimental infestation with I. holocyclus. This assay shows promise as an alternative means of assessing the potency of batches of hyperimmune dog serum and to screen for toxin-reactive monoclonal antibodies produced from immunised rodents. PMID- 21687654 TI - Biosynthesis of galactofuranose in kinetoplastids: novel therapeutic targets for treating leishmaniasis and chagas' disease. AB - Cell surface proteins of parasites play a role in pathogenesis by modulating mammalian cell recognition and cell adhesion during infection. beta Galactofuranose (Galf) is an important component of glycoproteins and glycolipids found on the cell surface of Leishmania spp. and Trypanosoma cruzi. beta-Galf containing glycans have been shown to be important in parasite-cell interaction and protection against oxidative stress. Here, we discuss the role of beta-Galf in pathogenesis and recent studies on the Galf-biosynthetic enzymes: UDP galactose 4' epimerase (GalE), UDP-galactopyranose mutase (UGM), and UDP galactofuranosyl transferase (GalfT). The central role in Galf formation, its unique chemical mechanism, and the absence of a homologous enzyme in humans identify UGM as the most attractive drug target in the beta-Galf-biosynthetic pathway in protozoan parasites. PMID- 21687656 TI - Insights into the changing perspectives of multiple sclerosis in India. AB - Multiple Sclerosis (MS) is being diagnosed in increasing numbers in metropolitan cities of India for which the availability of specialist neurologists and magnetic resonance imaging (MRI) facilities are primarily responsible. Epidemiological data are unavailable. Existing data have been obtained from small often retrospective studies from different parts of the country. These earlier studies suggested that optic nerve and spinal cord involvement are considerably high, and that perhaps optic spinal MS was the most prevalent form in India. On this basis it was also speculated that neuromyelitis optica (NMO) may be overrepresented in Indians. However in recent times, prospective studies backed by MRI data have shown no distinct differences between MS seen in the west and India. Sero positivity for NMO IgG is low though NMO phenotype disorders constitute nearly 20% of demyelinating disorders in India. Genetic susceptibility for MS among Indians may be similar to that for white populations. In the major histocompatibility complex (MHC), HLA DR1*1501 has been strongly associated with MS in Indians. A recent study that evaluated the established non-MHC multiple sclerosis loci in a small data set of Indian patients suggested a strong similarity with white populations. This review highlights some of the background information available on MS from India and so also some recent studies that unveiled the disease characteristics in Indian patients. PMID- 21687657 TI - Anti-inflammatory cytokines predominate in acute human Plasmodium knowlesi infections. AB - Plasmodium knowlesi has entered the human population of Southeast Asia. Naturally acquired knowlesi malaria is newly described with relatively little available data, including data on the host response to infection. Therefore pre-treatment cytokine and chemokine profiles were determined for 94 P. knowlesi, and for comparison, 20, P. vivax and 22 P. falciparum, patients recruited in Malaysian Borneo. Nine, five and one patient with P. knowlesi, P. falciparum and P. vivax respectively had complicated malaria as defined by World Health Organisation. Patients with uncomplicated P. knowlesi had lower levels of the pro-inflammatory cytokines IL-8 and TNFalpha than those with complicated disease (both p<0.05, Dunn's post test, DPT). The anti-inflammatory cytokines IL-1ra and IL-10 were detected in all patients in the study. IL-1ra, the most abundant cytokine measured, correlated with parasitaemia in P. knowlesi (r(s) = 0.47, p = <0.0001), P. vivax (r(s) = 0.61, p = 0.0042) and P. falciparum (r(s) = 0.57,p = 0.0054) malaria. IL-10 correlated with parasitaemia in both P. knowlesi (r(s) = 0.54, p = <0.0001) and P. vivax (r(s) = 0.78, p = <0.0001) infections. There were between group differences in soluble markers of macrophage activation (MIP 1beta and MCP-1). P. knowlesi patients had significantly lower levels of MIP 1beta than P. falciparum (DPT, p = <0.01). Uncomplicated P. knowlesi patients had significantly lower levels of MCP-1 than uncomplicated P. falciparum patients (DPT, p = <0.001). There was no significant difference between complicated and uncomplicated P. knowlesi infections. MCP-1, MIP-1beta, IL-8 and TNFalpha increased in complicated P. knowlesi but decreased in complicated P. falciparum infections. Descriptions of human knowlesi malaria provide a comparative means to discover mediators of pathophysiology in severe P. knowlesi as well as P. falciparum malaria. Crucially, P. knowlesi may be the disease and experimental primate model for severe malaria. PMID- 21687658 TI - Searching for speciation genes: molecular evidence for selection associated with colour morphotypes in the Caribbean reef fish genus Hypoplectrus. AB - Closely related species that show clear phenotypic divergence, but without obvious geographic barriers, can provide opportunities to study how diversification can occur when opportunities for allopatric speciation are limited. We examined genetic divergence in the coral reef fish genus Hypoplectrus (family: Serranidae), which comprises of 10-14 morphotypes that are distinguished solely by their distinct colour patterns, but which show little genetic differentiation. Our goal was to detect loci that show clear disequilibrium between morphotypes and across geographical locations. We conducted Amplified Fragment Length Polymorphism molecular analysis to quantify genetic differentiation among, and selection between, morphotypes. Three loci were consistently divergent beyond neutral expectations in repeated pair-wise morphotype comparisons using two different methods. These loci provide the first evidence for genes that may be associated with colour morphotype in the genus Hypoplectrus. PMID- 21687659 TI - Accumulation of long-chain glycosphingolipids during aging is prevented by caloric restriction. AB - BACKGROUND: Chronic kidney disease and end-stage renal disease are major causes of morbidity and mortality that are seen far more commonly in the aged population. Interestingly, kidney function declines during aging even in the absence of underlying renal disease. Declining renal function has been associated with age-related cellular damage and dysfunction with reports of increased levels of apoptosis, necrosis, and inflammation in the aged kidney. Bioactive sphingolipids have been shown to regulate these same cellular processes, and have also been suggested to play a role in aging and cellular senescence. METHODOLOGY/PRINCIPAL FINDINGS: We hypothesized that alterations in kidney sphingolipids play a role in the declining kidney function that occurs during aging. To begin to address this, the sphingolipid profile was measured in young (3 mo), middle aged (9 mo) and old (17 mo) C57BL/6 male mice. Interestingly, while modest changes in ceramides and sphingoid bases were evident in kidneys from older mice, the most dramatic elevations were seen in long-chain hexosylceramides (HexCer) and lactosylceramides (LacCer), with C14- and C16 lactosylceramides elevated as much as 8 and 12-fold, respectively. Increases in long-chain LacCers during aging are not exclusive to the kidney, as they also occur in the liver and brain. Importantly, caloric restriction, previously shown to prevent the declining kidney function seen in aging, inhibits accumulation of long-chain HexCer/LacCers and prevents the age-associated elevation of enzymes involved in their synthesis. Additionally, long-chain LacCers are also significantly elevated in human fibroblasts isolated from elderly individuals. CONCLUSION/SIGNIFICANCE: This study demonstrates accumulation of the glycosphingolipids HexCer and LacCer in several different organs in rodents and humans during aging. In addition, data demonstrate that HexCer and LacCer metabolism is regulated by caloric restriction. Taken together, data suggest that HexCer/LacCers are important mediators of cellular processes fundamental to mammalian aging. PMID- 21687660 TI - MRI study of minor physical anomaly in childhood autism implicates aberrant neurodevelopment in infancy. AB - BACKGROUND: MPAs (minor physical anomalies) frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm in the first trimester. Conventionally, MPAs are measured by evaluation of external appearance. Using MRI can help overcome inherent observer bias, facilitate multi-centre data acquisition, and explore how MPAs relate to brain dysmorphology in the same individual. Optical MPAs exhibit a tightly synchronized trajectory through fetal, postnatal and adult life. As head size enlarges with age, inter-orbital distance increases, and is mostly completed before age 3 years. We hypothesized that optical MPAs might afford a retrospective 'window' to early neurodevelopment; specifically, inter-orbital distance increase may represent a biomarker for early brain dysmaturation in autism. METHODS: We recruited 91 children aged 7-16; 36 with an autism spectrum disorder and 55 age- and gender-matched typically developing controls. All children had normal IQ. Inter-orbital distance was measured on T1-weighted MRI scans. This value was entered into a voxel-by-voxel linear regression analysis with grey matter segmented from a bimodal MRI data-set. Age and total brain tissue volume were entered as covariates. RESULTS: Intra-class coefficient for measurement of the inter-orbital distance was 0.95. Inter-orbital distance was significantly increased in the autism group (p = 0.03, 2-tailed). The autism group showed a significant relationship between inter-orbital distance grey matter volume of bilateral amygdalae extending to the unci and inferior temporal poles. CONCLUSIONS: Greater inter-orbital distance in the autism group compared with healthy controls is consistent with infant head size expansion in autism. Inter-orbital distance positively correlated with volume of medial temporal lobe structures, suggesting a link to "social brain" dysmorphology in the autism group. We suggest these data support the role of optical MPAs as a "fossil record" of early aberrant neurodevelopment, and potential biomarker for brain dysmaturation in autism. PMID- 21687661 TI - Sero-prevalence and incidence of A/H1N1 2009 influenza infection in Scotland in winter 2009-2010. AB - BACKGROUND: Sero-prevalence is a valuable indicator of prevalence and incidence of A/H1N1 2009 infection. However, raw sero-prevalence data must be corrected for background levels of cross-reactivity (i.e. imperfect test specificity) and the effects of immunisation programmes. METHODS AND FINDINGS: We obtained serum samples from a representative sample of 1563 adults resident in Scotland between late October 2009 and April 2010. Based on a microneutralisation assay, we estimate that 44% (95% confidence intervals (CIs): 40-47%) of the adult population of Scotland were sero-positive for A/H1N1 2009 influenza by 1 March 2010. Correcting for background cross-reactivity and for recorded vaccination rates by time and age group, we estimated that 34% (27-42%) were naturally infected with A/H1N1 2009 by 1 March 2010. The central estimate increases to >40% if we allow for imperfect test sensitivity. Over half of these infections are estimated to have occurred during the study period and the incidence of infection in late October 2009 was estimated at 4.3 new infections per 1000 people per day (1.2 to 7.2), falling close to zero by April 2010. The central estimate increases to over 5.0 per 1000 if we allow for imperfect test specificity. The rate of infection was higher for younger adults than older adults. Raw sero-prevalences were significantly higher in more deprived areas (likelihood ratio trend statistic = 4.92,1 df, P = 0.03) but there was no evidence of any difference in vaccination rates. CONCLUSIONS: We estimate that almost half the adult population of Scotland were sero-positive for A/H1N1 2009 influenza by early 2010 and that the majority of these individuals (except in the oldest age classes) sero converted as a result of natural infection with A/H1N1 2009. Public health planning should consider the possibility of higher rates of infection with A/H1N1 2009 influenza in more deprived areas. PMID- 21687662 TI - Genetic and physiological analysis of iron biofortification in maize kernels. AB - BACKGROUND: Maize is a major cereal crop widely consumed in developing countries, which have a high prevalence of iron (Fe) deficiency anemia. The major cause of Fe deficiency in these countries is inadequate intake of bioavailable Fe, where poverty is a major factor. Therefore, biofortification of maize by increasing Fe concentration and or bioavailability has great potential to alleviate this deficiency. Maize is also a model system for genomic research and thus allows the opportunity for gene discovery. Here we describe an integrated genetic and physiological analysis of Fe nutrition in maize kernels, to identify loci that influence grain Fe concentration and bioavailability. METHODOLOGY: Quantitative trait locus (QTL) analysis was used to dissect grain Fe concentration (FeGC) and Fe bioavailability (FeGB) from the Intermated B73 * Mo17 (IBM) recombinant inbred (RI) population. FeGC was determined by ion coupled argon plasma emission spectroscopy (ICP). FeGB was determined by an in vitro digestion/Caco-2 cell line bioassay. CONCLUSIONS: Three modest QTL for FeGC were detected, in spite of high heritability. This suggests that FeGC is controlled by many small QTL, which may make it a challenging trait to improve by marker assisted breeding. Ten QTL for FeGB were identified and explained 54% of the variance observed in samples from a single year/location. Three of the largest FeGB QTL were isolated in sister derived lines and their effect was observed in three subsequent seasons in New York. Single season evaluations were also made at six other sites around North America, suggesting the enhancement of FeGB was not specific to our farm site. FeGB was not correlated with FeGC or phytic acid, suggesting that novel regulators of Fe nutrition are responsible for the differences observed. Our results indicate that iron biofortification of maize grain is achievable using specialized phenotyping tools and conventional plant breeding techniques. PMID- 21687663 TI - Inhibition of cell proliferation by an anti-EGFR aptamer. AB - Aptamers continue to receive interest as potential therapeutic agents for the treatment of diseases, including cancer. In order to determine whether aptamers might eventually prove to be as useful as other clinical biopolymers, such as antibodies, we selected aptamers against an important clinical target, human epidermal growth factor receptor (hEGFR). The initial selection yielded only a single clone that could bind to hEGFR, but further mutation and optimization yielded a family of tight-binding aptamers. One of the selected aptamers, E07, bound tightly to the wild-type receptor (K(d) = 2.4 nM). This aptamer can compete with EGF for binding, binds to a novel epitope on EGFR, and also binds a deletion mutant, EGFRvIII, that is commonly found in breast and lung cancers, and especially in grade IV glioblastoma multiforme, a cancer which has for the most part proved unresponsive to current therapies. The aptamer binds to cells expressing EGFR, blocks receptor autophosphorylation, and prevents proliferation of tumor cells in three-dimensional matrices. In short, the aptamer is a promising candidate for further development as an anti-tumor therapeutic. In addition, Aptamer E07 is readily internalized into EGFR-expressing cells, raising the possibility that it might be used to escort other anti-tumor or contrast agents. PMID- 21687664 TI - Extending the aerolysin family: from bacteria to vertebrates. AB - A number of bacterial virulence factors have been observed to adopt structures similar to that of aerolysin, the principal toxin of Aeromonas species. However, a comprehensive description of architecture and structure of the aerolysin-like superfamily has not been determined. In this study, we define a more compact aerolysin-like domain--or aerolysin fold--and show that this domain is far more widely spread than anticipated since it can be found throughout kingdoms. The aerolysin-fold could be found in very diverse domain and functional contexts, although a toxic function could often be assigned. Due to this diversity, the borders of the superfamily could not be set on a sequence level. As a border defining member, we therefore chose pXO2-60--a protein from the pathogenic pXO2 plasmid of Bacillus anthracis. This fascinating protein, which harbors a unique ubiquitin-like fold domain at the C-terminus of the aerolysin-domain, nicely illustrates the diversity of the superfamily. Its putative role in the virulence of B. anthracis and its three dimensional model are discussed. PMID- 21687665 TI - Twin Town in South Brazil: a Nazi's experiment or a genetic founder effect? AB - Candido Godoi (CG) is a small municipality in South Brazil with approximately 6,000 inhabitants. It is known as the "Twins' Town" due to its high rate of twin births. Recently it was claimed that such high frequency of twinning would be connected to experiments performed by the German Nazi doctor Joseph Mengele. It is known, however, that this town was founded by a small number of families and therefore a genetic founder effect may represent an alternatively explanation for the high twinning prevalence in CG. In this study, we tested specific predictions of the "Nazi's experiment" and of the "founder effect" hypotheses. We surveyed a total of 6,262 baptism records from 1959-2008 in CG catholic churches, and identified 91 twin pairs and one triplet. Contrary to the "Nazi's experiment hypothesis", there is no spurt in twinning between the years (1964-1968) when Mengele allegedly was in CG (P = 0.482). Moreover, there is no temporal trend for a declining rate of twinning since the 1960s (P = 0.351), and no difference in twinning among CG districts considering two different periods: 1927-1958 and 1959 2008 (P = 0.638). On the other hand, the "founder effect hypothesis" is supported by an isonymy analysis that shows that women who gave birth to twins have a higher inbreeding coefficient when compared to women who never had twins (0.0148, 0.0081, respectively, P = 0.019). In summary, our results show no evidence for the "Nazi's experiment hypothesis" and strongly suggest that the "founder effect hypothesis" is a much more likely alternative for explaining the high prevalence of twinning in CG. If this hypothesis is correct, then this community represents a valuable population where genetic factors linked to twinning may be identified. PMID- 21687666 TI - Flexibility in problem solving and tool use of kea and New Caledonian crows in a multi access box paradigm. AB - Parrots and corvids show outstanding innovative and flexible behaviour. In particular, kea and New Caledonian crows are often singled out as being exceptionally sophisticated in physical cognition, so that comparing them in this respect is particularly interesting. However, comparing cognitive mechanisms among species requires consideration of non-cognitive behavioural propensities and morphological characteristics evolved from different ancestry and adapted to fit different ecological niches. We used a novel experimental approach based on a Multi-Access-Box (MAB). Food could be extracted by four different techniques, two of them involving tools. Initially all four options were available to the subjects. Once they reached criterion for mastering one option, this task was blocked, until the subjects became proficient in another solution. The exploratory behaviour differed considerably. Only one (of six) kea and one (of five) NCC mastered all four options, including a first report of innovative stick tool use in kea. The crows were more efficient in using the stick tool, the kea the ball tool. The kea were haptically more explorative than the NCC, discovered two or three solutions within the first ten trials (against a mean of 0.75 discoveries by the crows) and switched more quickly to new solutions when the previous one was blocked. Differences in exploration technique, neophobia and object manipulation are likely to explain differential performance across the set of tasks. Our study further underlines the need to use a diversity of tasks when comparing cognitive traits between members of different species. Extension of a similar method to other taxa could help developing a comparative cognition research program. PMID- 21687667 TI - Dinosaur peptides suggest mechanisms of protein survival. AB - Eleven collagen peptide sequences recovered from chemical extracts of dinosaur bones were mapped onto molecular models of the vertebrate collagen fibril derived from extant taxa. The dinosaur peptides localized to fibril regions protected by the close packing of collagen molecules, and contained few acidic amino acids. Four peptides mapped to collagen regions crucial for cell-collagen interactions and tissue development. Dinosaur peptides were not represented in more exposed parts of the collagen fibril or regions mediating intermolecular cross-linking. Thus functionally significant regions of collagen fibrils that are physically shielded within the fibril may be preferentially preserved in fossils. These results show empirically that structure-function relationships at the molecular level could contribute to selective preservation in fossilized vertebrate remains across geological time, suggest a 'preservation motif', and bolster current concepts linking collagen structure to biological function. This non-random distribution supports the hypothesis that the peptides are produced by the extinct organisms and suggests a chemical mechanism for survival. PMID- 21687668 TI - Evidence that aberrant expression of tissue transglutaminase promotes stem cell characteristics in mammary epithelial cells. AB - Cancer stem cells (CSCs) or tumor initiating cells (TICs) make up only a small fraction of total tumor cell population, but recent evidence suggests that they are responsible for tumor initiation and the maintenance of tumor growth. Whether CSCs/TICs originate from normal stem cells or result from the dedifferentiation of terminally differentiated cells remains unknown. Here we provide evidence that sustained expression of the proinflammatory protein tissue transglutaminase (TG2) confers stem cell like properties in non-transformed and transformed mammary epithelial cells. Sustained expression of TG2 was associated with increase in CD44(high)/CD24(low/-) subpopulation, increased ability of cells to form mammospheres, and acquisition of self-renewal ability. Mammospheres derived from TG2-transfected mammary epithelial cells (MCF10A) differentiated into complex secondary structures when grown in Matrigel cultures. Cells in these secondary structures differentiated into Muc1-positive (luminal marker) and integrin alpha6 positive (basal marker) cells in response to prolactin treatment. Highly aggressive MDA-231 and drug-resistant MCF-7/RT breast cancer cells, which express high basal levels of TG2, shared many traits with TG2-transfected MCF10A stem cells but unlike MCF10A-derived stem cells they failed to form the secondary structures and to differentiate into Muc1-positive luminal cells when grown in Matrigel culture. Downregulation of TG2 attenuated stem cell properties in both non-transformed and transformed mammary epithelial cells. Taken together, these results suggested a new function for TG2 and revealed a novel mechanism responsible for promoting the stem cell characteristics in adult mammary epithelial cells. PMID- 21687669 TI - Aerosolized BC-819 inhibits primary but not secondary lung cancer growth. AB - Despite numerous efforts, drug based treatments for patients suffering from lung cancer remains poor. As a promising alternative, we investigated the therapeutic potential of BC-819 for the treatment of lung cancer in mouse tumor models. BC 819 is a novel plasmid DNA which encodes for the A-fragment of Diphtheria toxin and has previously been shown to successfully inhibit tumor growth in human clinical study of bladder carcinoma. In a first set of experiments, we examined in vitro efficacy of BC-819 in human lung cancer cell-lines NCI-H460, NCI-H358 and A549, which revealed >90% reduction of cell growth. In vivo efficacy was examined in an orthotopic mouse xenograft lung cancer model and in a lung metastasis model using luminescent A549-C8-luc adenocarcinoma cells. These cells resulted in peri- and intra-bronchiolar tumors upon intrabronchial application and parenchymal tumors upon intravenous injection, respectively. Mice suffering from these lung tumors were treated with BC-819, complexed to branched polyethylenimine (PEI) and aerosolized to the mice once per week for a period of 10 weeks. Using this regimen, growth of intrabronchially induced lung tumors was significantly inhibited (p = 0.01), whereas no effect could be observed in mice suffering from lung metastasis. In summary, we suggest that aerosolized PEI/BC 819 is capable of reducing growth only in tumors arising from the luminal part of the airways and are therefore directly accessible for inhaled BC-819. PMID- 21687670 TI - Does intraspecific size variation in a predator affect its diet diversity and top down control of prey? AB - It has long been known that intraspecific variation impacts evolutionary processes, but only recently have its potential ecological effects received much attention. Theoretical models predict that genetic or phenotypic variance within species can alter interspecific interactions, and experiments have shown that genotypic diversity in clonal species can impact a wide range of ecological processes. To extend these studies to quantitative trait variation within populations, we experimentally manipulated the variance in body size of threespine stickleback in enclosures in a natural lake environment. We found that body size of stickleback in the lake is correlated with prey size and (to a lesser extent) composition, and that stickleback can exert top-down control on their benthic prey in enclosures. However, a six-fold contrast in body size variance had no effect on the degree of diet variation among individuals, or on the abundance or composition of benthic or pelagic prey. Interestingly, post-hoc analyses revealed suggestive correlations between the degree of diet variation and the strength of top-down control by stickleback. Our negative results indicate that, unless the correlation between morphology and diet is very strong, ecological variation among individuals may be largely decoupled from morphological variance. Consequently we should be cautious in our interpretation both of theoretical models that assume perfect correlations between morphology and diet, and of empirical studies that use morphological variation as a proxy for resource use diversity. PMID- 21687671 TI - Social status affects the degree of sex difference in the songbird brain. AB - It is thought that neural sex differences are functionally related to sex differences in the behaviour of vertebrates. A prominent example is the song control system of songbirds. Inter-specific comparisons have led to the hypothesis that sex differences in song nuclei size correlate with sex differences in song behaviour. However, only few species with similar song behaviour in both sexes have been investigated and not all data fit the hypothesis. We investigated the proposed structure-function relationship in a cooperatively breeding and duetting songbird, the white-browed sparrow weaver (Plocepasser mahali). This species lives in groups of 2-10 individuals, with a dominant breeding pair and male and female subordinates. While all male and female group members sing duet and chorus song, a male, once it has reached the dominant position in the group, sings an additional type of song that comprises a distinct and large syllable repertoire. Here we show for both types of male female comparisons a male-biased sex difference in neuroanatomy of areas of the song production pathway (HVC and RA) that does not correlate with the observed polymorphism in song behaviour. In contrast, in situ hybridisation of mRNA of selected genes expressed in the song nucleus HVC reveals a gene expression pattern that is either similar between sexes in female-subordinate male comparisons or female-biased in female-dominant male comparisons. Thus, the polymorphic gene expression pattern would fit the sex- and status-related song behaviour. However, this implies that once a male has become dominant it produces the duetting song with a different neural phenotype than subordinate males. PMID- 21687673 TI - Imaging mass spectrometry detection of gangliosides species in the mouse brain following transient focal cerebral ischemia and long-term recovery. AB - Gangliosides, a member of the glycosphingolipid family, are heterogeneously expressed in biological membranes and are particularly enriched within the central nervous system. Gangliosides consist of mono- or poly-sialylated oligosaccharide chains of variable lengths attached to a ceramide unit and are found to be intimately involved in brain disease development. The purpose of this study is to examine the spatial profile of ganglioside species using matrix assisted laser desorption/ionization (MALDI) imaging (IMS) following middle cerebral artery occlusion (MCAO) reperfusion injury in the mouse. IMS is a powerful method to not only discriminate gangliosides by their oligosaccharide components, but also by their carbon length within their sphingosine base. Mice were subjected to a 30 min unilateral MCAO followed by long-term survival (up to 28 days of reperfusion). Brain sections were sprayed with the matrix 5-Chloro-2 mercaptobenzothiazole, scanned and analyzed for a series of ganglioside molecules using an Applied Biosystems 4800 MALDI TOF/TOF. Traditional histological and immunofluorescence techniques were performed to assess brain tissue damage and verification of the expression of gangliosides of interest. Results revealed a unique anatomical profile of GM1, GD1 and GT1b (d18:1, d20:1 as well as other members of the glycosphingolipid family). There was marked variability in the ratio of expression between ipsilateral and contralateral cortices for the various detected ganglioside species following MCAO-reperfusion injury. Most interestingly, MCAO resulted in the transient induction of both GM2 and GM3 signals within the ipsilateral hemisphere; at the border of the infarcted tissue. Taken together, the data suggest that brain region specific expression of gangliosides, particularly with respect to hydrocarbon length, may play a role in neuronal responses to injury. PMID- 21687674 TI - Pop up satellite tags impair swimming performance and energetics of the European eel (Anguilla anguilla). AB - Pop-up satellite archival tags (PSATs) have recently been applied in attempts to follow the oceanic spawning migration of the European eel. PSATs are quite large, and in all likelihood their hydraulic drag constitutes an additional cost during swimming, which remains to be quantified, as does the potential implication for successful migration. Silver eels (L(T) = 598.6+/-29 mm SD, N = 9) were subjected to swimming trials in a Steffensen-type swim tunnel at increasing speeds of 0.3 0.9 body lengths s(-1), first without and subsequently with, a scaled down PSAT dummy attached. The tag significantly increased oxygen consumption (MO(2)) during swimming and elevated minimum cost of transport (COT(min)) by 26%. Standard (SMR) and active metabolic rate (AMR) as well as metabolic scope remained unaffected, suggesting that the observed effects were caused by increased drag. Optimal swimming speed (U(opt)) was unchanged, whereas critical swimming speed (U(crit)) decreased significantly. Swimming with a PSAT altered swimming kinematics as verified by significant changes to tail beat frequency (f), body wave speed (v) and Strouhal number (St). The results demonstrate that energy expenditure, swimming performance and efficiency all are significantly affected in migrating eels with external tags. PMID- 21687672 TI - An essential nuclear protein in trypanosomes is a component of mRNA transcription/export pathway. AB - In eukaryotic cells, different RNA species are exported from the nucleus via specialized pathways. The mRNA export machinery is highly integrated with mRNA processing, and includes a different set of nuclear transport adaptors as well as other mRNA binding proteins, RNA helicases, and NPC-associated proteins. The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, a widespread and neglected human disease which is endemic to Latin America. Gene expression in Trypanosoma has unique characteristics, such as constitutive polycistronic transcription of protein-encoding genes and mRNA processing by trans-splicing. In general, post-transcriptional events are the major points for regulation of gene expression in these parasites. However, the export pathway of mRNA from the nucleus is poorly understood. The present study investigated the function of TcSub2, which is a highly conserved protein ortholog to Sub2/ UAP56, a component of the Transcription/Export (TREX) multiprotein complex connecting transcription with mRNA export in yeast/human. Similar to its orthologs, TcSub2 is a nuclear protein, localized in dispersed foci all over the nuclei -except the fibrillar center of nucleolus- and at the interface between dense and non-dense chromatin areas, proposing the association of TcSub2 with transcription/processing sites. These findings were analyzed further by BrUTP incorporation assays and confirmed that TcSub2 is physically associated with active RNA polymerase II (RNA pol II), but not RNA polymerase I (RNA pol I) or Spliced Leader (SL) transcription, demonstrating participation particularly in nuclear mRNA metabolism in T. cruzi. The double knockout of the TcSub2 gene is lethal in T. cruzi, suggesting it has an essential function. Alternatively, RNA interference assays were performed in Trypanosoma brucei. It allowed demonstrating that besides being an essential protein, its knockdown causes mRNA accumulation in the nucleus and decrease of translation levels, reinforcing that Trypanosoma-Sub2 (Tryp-Sub2) is a component of mRNA transcription/export pathway in trypanosomes. PMID- 21687675 TI - How close do we live to water? A global analysis of population distance to freshwater bodies. AB - Traditionally, people have inhabited places with ready access to fresh water. Today, over 50% of the global population lives in urban areas, and water can be directed via tens of kilometres of pipelines. Still, however, a large part of the world's population is directly dependent on access to natural freshwater sources. So how are inhabited places related to the location of freshwater bodies today? We present a high-resolution global analysis of how close present-day populations live to surface freshwater. We aim to increase the understanding of the relationship between inhabited places, distance to surface freshwater bodies, and climatic characteristics in different climate zones and administrative regions. Our results show that over 50% of the world's population lives closer than 3 km to a surface freshwater body, and only 10% of the population lives further than 10 km away. There are, however, remarkable differences between administrative regions and climatic zones. Populations in Australia, Asia, and Europe live closest to water. Although populations in arid zones live furthest away from freshwater bodies in absolute terms, relatively speaking they live closest to water considering the limited number of freshwater bodies in those areas. Population distributions in arid zones show statistically significant relationships with a combination of climatic factors and distance to water, whilst in other zones there is no statistically significant relationship with distance to water. Global studies on development and climate adaptation can benefit from an improved understanding of these relationships between human populations and the distance to fresh water. PMID- 21687677 TI - Do male desert gobies compromise offspring care to attract additional mating opportunities? AB - Males often play a critical role in offspring care but the time and energy invested in looking after young can potentially limit their ability to seek out additional mating opportunities. Recent studies, however, suggest that a conflict between male parental effort and mating effort may not always be inevitable, especially if breeding occurs near the nest, or if parental behaviours are under sexual selection. Accordingly, we set out to experimentally investigate male care and courtship in the desert goby Chlamydogobius eremius, a nest-guarding fish with exclusive paternal care. Despite courtship occurring near the nest, we found that when egg-tending males were given the opportunity to attract additional females, they fanned their eggs less often, engaged in shorter fanning bouts, and spent more of their time outside their nests courting. Our findings highlight the importance of understanding the circumstances under which reproductive tradeoffs are expected to occur and how these, in turn, operate to influence male reproductive decisions. PMID- 21687676 TI - Antibody against extracellular vaccinia virus (EV) protects mice through complement and Fc receptors. AB - Protein-based subunit smallpox vaccines have shown their potential as effective alternatives to live virus vaccines in animal model challenge studies. We vaccinated mice with combinations of three different vaccinia virus (VACV) proteins (A33, B5, L1) and examined how the combined antibody responses to these proteins cooperate to effectively neutralize the extracellular virus (EV) infectious form of VACV. Antibodies against these targets were generated in the presence or absence of CpG adjuvant so that Th1-biased antibody responses could be compared to Th2-biased responses to the proteins with aluminum hydroxide alone, specifically with interest in looking at the ability of anti-B5 and anti A33 polyclonal antibodies (pAb) to utilize complement-mediated neutralization in vitro. We found that neutralization of EV by anti-A33 or anti-B5 pAb can be enhanced in the presence of complement if Th1-biased antibody (IgG2a) is generated. Mechanistic differences found for complement-mediated neutralization showed that anti-A33 antibodies likely result in virolysis, while anti-B5 antibodies with complement can neutralize by opsonization (coating). In vivo studies found that mice lacking the C3 protein of complement were less protected than wild-type mice after passive transfer of anti-B5 pAb or vaccination with B5. Passive transfer of anti-B5 pAb or monoclonal antibody into mice lacking Fc receptors (FcRs) found that FcRs were also important in mediating protection. These results demonstrate that both complement and FcRs are important effector mechanisms for antibody-mediated protection from VACV challenge in mice. PMID- 21687678 TI - Conserved CDC20 cell cycle functions are carried out by two of the five isoforms in Arabidopsis thaliana. AB - BACKGROUND: The CDC20 and Cdh1/CCS52 proteins are substrate determinants and activators of the Anaphase Promoting Complex/Cyclosome (APC/C) E3 ubiquitin ligase and as such they control the mitotic cell cycle by targeting the degradation of various cell cycle regulators. In yeasts and animals the main CDC20 function is the destruction of securin and mitotic cyclins. Plants have multiple CDC20 gene copies whose functions have not been explored yet. In Arabidopsis thaliana there are five CDC20 isoforms and here we aimed at defining their contribution to cell cycle regulation, substrate selectivity and plant development. METHODOLOGY/PRINCIPAL FINDINGS: Studying the gene structure and phylogeny of plant CDC20s, the expression of the five AtCDC20 gene copies and their interactions with the APC/C subunit APC10, the CCS52 proteins, components of the mitotic checkpoint complex (MCC) and mitotic cyclin substrates, conserved CDC20 functions could be assigned for AtCDC20.1 and AtCDC20.2. The other three intron-less genes were silent and specific for Arabidopsis. We show that AtCDC20.1 and AtCDC20.2 are components of the MCC and interact with mitotic cyclins with unexpected specificity. AtCDC20.1 and AtCDC20.2 are expressed in meristems, organ primordia and AtCDC20.1 also in pollen grains and developing seeds. Knocking down both genes simultaneously by RNAi resulted in severe delay in plant development and male sterility. In these lines, the meristem size was reduced while the cell size and ploidy levels were unaffected indicating that the lower cell number and likely slowdown of the cell cycle are the cause of reduced plant growth. CONCLUSIONS/SIGNIFICANCE: The intron-containing CDC20 gene copies provide conserved and redundant functions for cell cycle progression in plants and are required for meristem maintenance, plant growth and male gametophyte formation. The Arabidopsis-specific intron-less genes are possibly "retrogenes" and have hitherto undefined functions or are pseudogenes. PMID- 21687680 TI - Imperfect vaccine aggravates the long-standing dilemma of voluntary vaccination. AB - Achieving widespread population immunity by voluntary vaccination poses a major challenge for public health administration and practice. The situation is complicated even more by imperfect vaccines. How the vaccine efficacy affects individuals' vaccination behavior has yet to be fully answered. To address this issue, we combine a simple yet effective game theoretic model of vaccination behavior with an epidemiological process. Our analysis shows that, in a population of self-interested individuals, there exists an overshooting of vaccine uptake levels as the effectiveness of vaccination increases. Moreover, when the basic reproductive number, R0, exceeds a certain threshold, all individuals opt for vaccination for an intermediate region of vaccine efficacy. We further show that increasing effectiveness of vaccination always increases the number of effectively vaccinated individuals and therefore attenuates the epidemic strain. The results suggest that 'number is traded for efficiency': although increases in vaccination effectiveness lead to uptake drops due to free riding effects, the impact of the epidemic can be better mitigated. PMID- 21687679 TI - Clinical efficacy of blue light full body irradiation as treatment option for severe atopic dermatitis. AB - BACKGROUND: Therapy of atopic dermatitis (AD) relies on immunosuppression and/or UV irradiation. Here, we assessed clinical efficacy and histopathological alterations induced by blue light-treatment of AD within an observational, non interventional study. METHODOLOGY/PRINCIPAL FINDINGS: 36 patients with severe, chronic AD resisting long term disease control with local corticosteroids were included. Treatment consisted of one cycle of 5 consecutive blue light irradiations (28.9 J/cm(2)). Patients were instructed to ask for treatment upon disease exacerbation despite interval therapy with topical corticosteroids. The majority of patients noted first improvements after 2-3 cycles. The EASI score was improved by 41% and 54% after 3 and 6 months, respectively (p<=0.005, and p<=0.002). Significant improvement of pruritus, sleep and life quality was noted especially after 6 months. Also, frequency and intensity of disease exacerbations and the usage of topical corticosteroids was reduced. Finally, immunohistochemistry of skin biopsies obtained at baseline and after 5 and 15 days revealed that, unlike UV light, blue light-treatment did not induce Langerhans cell or T cell depletion from skin. CONCLUSIONS/SIGNIFICANCE: Blue light-irradiation may represent a suitable treatment option for AD providing long term control of disease. Future studies with larger patient cohorts within a randomized, placebo-controlled clinical trial are required to confirm this observation. PMID- 21687681 TI - Antidepressant response in major depressive disorder: a meta-regression comparison of randomized controlled trials and observational studies. AB - BACKGROUND: To compare response to antidepressants between randomized controlled trials (RCTs) and observational trials. METHODS AND FINDINGS: Published and unpublished studies (from 1989 to 2009) were searched for by 2 reviewers on Medline, the Cochrane library, Embase, clinicaltrials.gov, Current Controlled Trial, bibliographies and by mailing key organisations and researchers. RCTs and observational studies on fluoxetine or venlafaxine in first-line treatment for major depressive disorder reported in English, French or Spanish language were included in the main analysis. Studies including patients from a wider spectrum of depressive disorders (anxious depression, minor depressive episode, dysthymia) were added in a second analysis. The main outcome was the pre-/post-treatment difference on depression scales standardised to 100 (17-item or 21-item Hamilton Rating Scale for Depression or Montgomery and Asberg Rating Scale) in each study arm. A meta-regression was conducted to adjust the comparison between observational studies and RCTs on treatment type, study characteristics and average patient characteristics. 12 observational studies and 109 RCTs involving 6757 and 11035 patients in 12 and 149 arms were included in the main analysis. Meta-regression showed that the standardised treatment response in RCTs is greater by a magnitude of 4.59 (2.61 to 6.56). Study characteristics were related to standardised treatment response, positively (study duration, number of follow up assessments, outpatients versus inpatients, per protocol analysis versus intention to treat analysis) or negatively (blinded design, placebo design). At patient level, response increased with baseline severity and decreased with age. Results of the second analysis were consistent with this. CONCLUSIONS: Response to antidepressants is greater in RCTs than in observational studies. Observational studies should be considered as a necessary complement to RCTs. PMID- 21687684 TI - Migratory pathways and connectivity in Asian houbara bustards: evidence from 15 years of satellite tracking. AB - Information on migratory pathways and connectivity is essential to understanding population dynamics and structure of migrant species. Our manuscript uses a unique dataset, the fruit of 103 individual Asian houbara bustards captured on their breeding grounds in Central Asia over 15 years and equipped with satellite transmitters, to provide a better understanding of migratory pathways and connectivity; such information is critical to the implementation of biologically sound conservation measures in migrant species. At the scale of the distribution range we find substantial migratory connectivity, with a clear separation of migration pathways and wintering areas between western and eastern migrants. Within eastern migrants, we also describe a pattern of segregation on the wintering grounds. But at the local level connectivity is weak: birds breeding within the limits of our study areas were often found several hundreds of kilometres apart during winter. Although houbara wintering in Arabia are known to originate from Central Asia, out of all the birds captured and tracked here not one wintered on the Arabian Peninsula. This is very likely the result of decades of unregulated off-take and severe habitat degradation in this area. At a time when conservation measures are being implemented to safeguard the long-term future of this species, this study provides critical data on the spatial structuring of populations. PMID- 21687683 TI - Down regulation of a matrix degrading cysteine protease cathepsin L, by acetaldehyde: role of C/EBPalpha. AB - BACKGROUND: The imbalance between extra cellular matrix (ECM) synthesis and degradation is critical aspect of various hepatic pathologies including alcohol induced liver fibrosis. This study was carried out to investigate the effect of acetaldehyde on expression of an extra cellular matrix degrading protease cathepsin L (CTSL) in HepG2 cells. METHODOLOGY AND RESULTS: We measured the enzymatic activity, protein and, mRNA levels of CTSL in acetaldehyde treated and untreated cells. The binding of CAAT enhancer binding protein alpha (C/EBP alpha) to CTSL promoter and its key role in the transcription from this promoter and conferring responsiveness to acetaldehyde was established by site directed mutagenesis, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) assays and siRNA technology. Acetaldehyde treatment significantly decreased CTSL activity and protein levels in HepG2 cells. A similar decrease in the mRNA levels and promoter activity was also observed. This decrease by acetaldehyde was attributed to the fall in the liver enriched transcription factor C/EBP alpha levels and it's binding to the CTSL promoter. Mutagenesis of C/EBP alpha binding motifs revealed the key role of this factor in CTSL transcription as well as conferring responsiveness to acetaldehyde. The siRNA mediated silencing of the C/EBP alpha expression mimicked the effect of acetaldehyde on CTSL levels and its promoter activity. It also abolished the responsiveness of this promoter to acetaldehyde. CONCLUSION: Acetaldehyde down regulates the C/EBP alpha mediated CTSL expression in hepatic cell lines. The decreased expression of CTSL may at least in part contribute to ECM deposition in liver which is a hallmark of alcoholic liver fibrosis. PMID- 21687682 TI - Aberrant expression of functional BAFF-system receptors by malignant B-cell precursors impacts leukemia cell survival. AB - Despite exhibiting oncogenic events, patient's leukemia cells are responsive and dependent on signals from their malignant bone marrow (BM) microenvironment, which modulate their survival, cell cycle progression, trafficking and resistance to chemotherapy. Identification of the signaling pathways mediating this leukemia/microenvironment interplay is critical for the development of novel molecular targeted therapies.We observed that primary leukemia B-cell precursors aberrantly express receptors of the BAFF-system, BAFF-R, BCMA, and TACI. These receptors are functional as their ligation triggers activation of NF-kappaB, MAPK/JNK, and Akt signaling. Leukemia cells express surface BAFF and APRIL ligands, and soluble BAFF is significantly higher in leukemia patients in comparison to age-matched controls. Interestingly, leukemia cells also express surface APRIL, which seems to be encoded by APRIL-delta, a novel isoform that lacks the furin convertase domain. Importantly, we observed BM microenvironmental cells express the ligands BAFF and APRIL, including surface and secreted BAFF by BM endothelial cells. Functional studies showed that signals through BAFF-system receptors impact the survival and basal proliferation of leukemia B-cell precursors, and support the involvement of both homotypic and heterotypic mechanisms.This study shows an unforeseen role for the BAFF-system in the biology of precursor B-cell leukemia, and suggests that the target disruption of BAFF signals may constitute a valid strategy for the treatment of this cancer. PMID- 21687685 TI - A latent model for prioritization of SNPs for functional studies. AB - One difficult question facing researchers is how to prioritize SNPs detected from genetic association studies for functional studies. Often a list of the top M SNPs is determined based on solely the p-value from an association analysis, where M is determined by financial/time constraints. For many studies of complex diseases, multiple analyses have been completed and integrating these multiple sets of results may be difficult. One may also wish to incorporate biological knowledge, such as whether the SNP is in the exon of a gene or a regulatory region, into the selection of markers to follow-up. In this manuscript, we propose a Bayesian latent variable model (BLVM) for incorporating "features" about a SNP to estimate a latent "quality score", with SNPs prioritized based on the posterior probability distribution of the rankings of these quality scores. We illustrate the method using data from an ovarian cancer genome-wide association study (GWAS). In addition to the application of the BLVM to the ovarian GWAS, we applied the BLVM to simulated data which mimics the setting involving the prioritization of markers across multiple GWAS for related diseases/traits. The top ranked SNP by BLVM for the ovarian GWAS, ranked 2(nd) and 7(th) based on p-values from analyses of all invasive and invasive serous cases. The top SNP based on serous case analysis p-value (which ranked 197(th) for invasive case analysis), was ranked 8(th) based on the posterior probability of being in the top 5 markers (0.13). In summary, the application of the BLVM allows for the systematic integration of multiple SNP "features" for the prioritization of loci for fine-mapping or functional studies, taking into account the uncertainty in ranking. PMID- 21687687 TI - The first model-based geostatistical map of anaemia. PMID- 21687686 TI - One universal common endpoint in mouse models of amyotrophic lateral sclerosis. AB - There is no consensus among research laboratories around the world on the criteria that define endpoint in studies involving rodent models of amyotrophic lateral sclerosis (ALS). Data from 4 nutrition intervention studies using 162 G93A mice, a model of ALS, were analyzed to determine if differences exist between the following endpoint criteria: CS 4 (functional paralysis of both hindlimbs), CS 4+ (CS 4 in addition to the earliest age of body weight loss, body condition deterioration or righting reflex), and CS 5 (CS 4 plus righting reflex >20 s). The age (d; mean +/- SD) at which mice reached endpoint was recorded as the unit of measurement. Mice reached CS 4 at 123.9+/-10.3 d, CS 4+ at 126.6+/ 9.8 d and CS 5 at 127.6+/-9.8 d, all significantly different from each other (P<0.001). There was a significant positive correlation between CS 4 and CS 5 (r = 0.95, P<0.001), CS 4 and CS 4+ (r = 0.96, P<0.001), and CS 4+ and CS 5 (r = 0.98, P<0.001), with the Bland-Altman plot showing an acceptable bias between all endpoints. Logrank tests showed that mice reached CS 4 24% and 34% faster than CS 4+ (P = 0.046) and CS 5 (P = 0.006), respectively. Adopting CS 4 as endpoint would spare a mouse an average of 4 days (P<0.001) from further neuromuscular disability and poor quality of life compared to CS 5. Alternatively, CS 5 provides information regarding proprioception and severe motor neuron death, both could be important parameters in establishing the efficacy of specific treatments. Converging ethics and discovery, would adopting CS 4 as endpoint compromise the acquisition of insight about the effects of interventions in animal models of ALS? PMID- 21687688 TI - Mapping the risk of anaemia in preschool-age children: the contribution of malnutrition, malaria, and helminth infections in West Africa. AB - BACKGROUND: Childhood anaemia is considered a severe public health problem in most countries of sub-Saharan Africa. We investigated the geographical distribution of prevalence of anaemia and mean haemoglobin concentration (Hb) in children aged 1-4 y (preschool children) in West Africa. The aim was to estimate the geographical risk profile of anaemia accounting for malnutrition, malaria, and helminth infections, the risk of anaemia attributable to these factors, and the number of anaemia cases in preschool children for 2011. METHODS AND FINDINGS: National cross-sectional household-based demographic health surveys were conducted in 7,147 children aged 1-4 y in Burkina Faso, Ghana, and Mali in 2003 2006. Bayesian geostatistical models were developed to predict the geographical distribution of mean Hb and anaemia risk, adjusting for the nutritional status of preschool children, the location of their residence, predicted Plasmodium falciparum parasite rate in the 2- to 10-y age group (Pf PR(2-10)), and predicted prevalence of Schistosoma haematobium and hookworm infections. In the four countries, prevalence of mild, moderate, and severe anaemia was 21%, 66%, and 13% in Burkina Faso; 28%, 65%, and 7% in Ghana, and 26%, 62%, and 12% in Mali. The mean Hb was lowest in Burkina Faso (89 g/l), in males (93 g/l), and for children 1-2 y (88 g/l). In West Africa, severe malnutrition, Pf PR(2-10), and biological synergisms between S. haematobium and hookworm infections were significantly associated with anaemia risk; an estimated 36.8%, 14.9%, 3.7%, 4.2%, and 0.9% of anaemia cases could be averted by treating malnutrition, malaria, S. haematobium infections, hookworm infections, and S. haematobium/hookworm coinfections, respectively. A large spatial cluster of low mean Hb (<80 g/l) and maximal risk of anaemia (>95%) was predicted for an area shared by Burkina Faso and Mali. We estimate that in 2011, approximately 6.7 million children aged 1-4 y are anaemic in the three study countries. CONCLUSIONS: By mapping the distribution of anaemia risk in preschool children adjusted for malnutrition and parasitic infections, we provide a means to identify the geographical limits of anaemia burden and the contribution that malnutrition and parasites make to anaemia. Spatial targeting of ancillary micronutrient supplementation and control of other anaemia causes, such as malaria and helminth infection, can contribute to efficiently reducing the burden of anaemia in preschool children in Africa. PMID- 21687689 TI - Depot-dependent effects of adipose tissue explants on co-cultured hepatocytes. AB - We have developed an in vitro hepatocyte-adipose tissue explant (ATE) co-culture model enabling examination of the effect of visceral and subcutaneous adipose tissues on primary rat hepatocytes. Initial analyses of inflammatory marker genes were performed in fractionated epididymal or inguinal adipose tissues. Expressions of inflammation related genes (IL-6, TNF-alpha, COX-2) were higher in the inguinal than the epididymal ATE. Similarly, expressions of marker genes of macrophage and monocyte (MPEG-1, CD68, F4/80, CD64) were higher in the stromal vascular fraction (SVF) isolated from inguinal ATE than that from epididymal ATE. However, expressions of lipolysis related genes (ATGL, HSL, perilipin-1) were higher in the epididymal adipocytes than inguinal adipocytes. Moreover, secretion of IL-6 and PGE(2) was higher from inguinal ATEs than from epididymal ATEs. There was a trend that the total levels of IL-6, TNF-alpha and PGE(2) in the media from inguinal ATEs co-cultured with primary rat hepatocytes were higher than that in the media from epididymal ATEs co-cultured with hepatocytes, although the significant difference was only seen in PGE(2). Lipolysis, measured as glycerol release, was similar in the ATEs isolated from inguinal and epididymal adipose tissues when cultured alone, but the glycerol release was higher in the ATEs isolated from epididymal than from inguinal adipose tissue when co-cultured with hepatocytes. Compared to epididymal ATEs, the ATEs from inguinal adipose tissue elicited a stronger cytotoxic response and higher level of insulin resistance in the co-cultured hepatocytes. In conclusion, our results reveal depot-dependent effects of ATEs on co-cultured primary hepatocytes, which in part may be related to a more pronounced infiltration of stromal vascular cells (SVCs), particularly macrophages, in inguinal adipose tissue resulting in stronger responses in terms of hepatotoxicity and insulin-resistance. PMID- 21687690 TI - Monoclonal antibodies against accumulation-associated protein affect EPS biosynthesis and enhance bacterial accumulation of Staphylococcus epidermidis. AB - Because there is no effective antibiotic to eradicate Staphylococcus epidermidis biofilm infections that lead to the failure of medical device implantations, the development of anti-biofilm vaccines is necessary. Biofilm formation by S. epidermidis requires accumulation-associated protein (Aap) that contains sequence repeats known as G5 domains, which are responsible for the Zn(2+)-dependent dimerization of Aap to mediate intercellular adhesion. Antibodies against Aap have been reported to inhibit biofilm accumulation. In the present study, three monoclonal antibodies (MAbs) against the Aap C-terminal single B-repeat construct followed by the 79-aa half repeat (AapBrpt1.5) were generated. MAb(18B6) inhibited biofilm formation by S. epidermidis RP62A to 60% of the maximum, while MAb(25C11) and MAb(20B9) enhanced biofilm accumulation. All three MAbs aggregated the planktonic bacteria to form visible cell clusters. Epitope mapping revealed that the epitope of MAb(18B6), which recognizes an identical area within AapBrpt constructs from S. epidermidis RP62A, was not shared by MAb(25C11) and MAb(20B9). Furthermore, all three MAbs were found to affect both Aap expression and extracellular polymeric substance (EPS, including extracellular DNA and PIA) biosynthesis in S. epidermidis and enhance the cell accumulation. These findings contribute to a better understanding of staphylococcal biofilm formation and will help to develop epitope-peptide vaccines against staphylococcal infections. PMID- 21687691 TI - A fast and accessible methodology for micro-patterning cells on standard culture substrates using ParafilmTM inserts. AB - Micropatterning techniques provide direct control over the spatial organization of cells at the sub-mm scale. Regulation of these spatial parameters is important for controlling cell fate and cell function. While micropatterning has proved a powerful technique for understanding the impact of cell organization on cell behaviour, current methods for micropatterning cells require complex, specialized equipment that is not readily accessible in most biological and bioengineering laboratories. In addition, currently available methods require significant protocol optimization to ensure reliable and reproducible patterning. The inaccessibility of current methods has severely limited the widespread use of micropatterning as a tool in both biology and tissue engineering laboratories. Here we present a simple, cheap, and fast method to micropattern mammalian cells into stripes and circular patterns using ParafilmTM, a common material found in most biology and bioengineering laboratories. Our method does not require any specialized equipment and does not require significant method optimization to ensure reproducible patterning. Although our method is limited to simple patterns, these geometries are sufficient for addressing a wide range of biological problems. Specifically, we demonstrate i) that using our ParafilmTM insert method we can pattern and co-pattern ARPE-19 and MDCK epithelial cells into circular and stripe micropatterns in tissue culture polystyrene (TCPS) wells and on glass slides, ii) that we can contain cells in the desired patterns for more than one month and iii) that upon removal of the ParafilmTM insert we can release the cells from the containment pattern and allow cell migration outward from the original pattern. We also demonstrate that we can exploit this confinement release feature to conduct an epithelial cell wound healing assay. This novel micropatterning method provides a reliable and accessible tool with the flexibility to address a wide range of biological and engineering problems that require control over the spatial and temporal organization of cells. PMID- 21687692 TI - Secretory leukocyte protease inhibitor (SLPI) is, like its homologue trappin-2 (pre-elafin), a transglutaminase substrate. AB - Human lungs contain secretory leukocyte protease inhibitor (SLPI), elafin and its biologically active precursor trappin-2 (pre-elafin). These important low molecular weight inhibitors are involved in controlling the potentially deleterious proteolytic activities of neutrophil serine proteases including elastase, proteinase 3 and cathepsin G. We have shown previously that trappin-2, and to a lesser extent, elafin can be linked covalently to various extracellular matrix proteins by tissue transglutaminases and remain potent protease inhibitors. SLPI is composed of two distinct domains, each of which is about 40% identical to elafin, but it lacks consensus transglutaminase sequence(s), unlike trappin-2 and elafin. We investigated the actions of type 2 tissue transglutaminase and plasma transglutaminase activated factor XIII on SLPI. It was readily covalently bound to fibronectin or elastin by both transglutaminases but did not compete with trappin-2 cross-linking. Cross-linked SLPI still inhibited its target proteases, elastase and cathepsin G. We have also identified the transglutamination sites within SLPI, elafin and trappin-2 by mass spectrometry analysis of tryptic digests of inhibitors cross-linked to mono dansyl cadaverin or to a fibronectin-derived glutamine-rich peptide. Most of the reactive lysine and glutamine residues in SLPI are located in its first N terminal elafin-like domain, while in trappin-2, they are located in both the N terminal cementoin domain and the elafin moiety. We have also demonstrated that the transglutamination substrate status of the cementoin domain of trappin-2 can be transferred from one protein to another, suggesting that it may provide transglutaminase-dependent attachment properties for engineered proteins. We have thus added to the corpus of knowledge on the biology of these potential therapeutic inhibitors of airway proteases. PMID- 21687693 TI - Evaluation of coseasonality of influenza and invasive pneumococcal disease: results from prospective surveillance. AB - BACKGROUND: The wintertime co-occurrence of peaks in influenza and invasive pneumococcal disease (IPD) is well documented, but how and whether wintertime peaks caused by these two pathogens are causally related is still uncertain. We aimed to investigate the relationship between influenza infection and IPD in Ontario, Canada, using several complementary methodological tools. METHODS AND FINDINGS: We evaluated a total number of 38,501 positive influenza tests in Central Ontario and 6,191 episodes of IPD in the Toronto/Peel area, Ontario, Canada, between 1 January 1995 and 3 October 2009, reported through population based surveillance. We assessed the relationship between the seasonal wave forms for influenza and IPD using fast Fourier transforms in order to examine the relationship between these two pathogens over yearly timescales. We also used three complementary statistical methods (time-series methods, negative binomial regression, and case-crossover methods) to evaluate the short-term effect of influenza dynamics on pneumococcal risk. Annual periodicity with wintertime peaks could be demonstrated for IPD, whereas periodicity for influenza was less regular. As for long-term effects, phase and amplitude terms of pneumococcal and influenza seasonal sine waves were not correlated and meta-analysis confirmed significant heterogeneity of influenza, but not pneumococcal phase terms. In contrast, influenza was shown to Granger-cause pneumococcal disease. A short-term association between IPD and influenza could be demonstrated for 1-week lags in both case-crossover (odds ratio [95% confidence interval] for one case of IPD per 100 influenza cases = 1.10 [1.02-1.18]) and negative binomial regression analysis (incidence rate ratio [95% confidence interval] for one case of IPD per 100 influenza cases = 1.09 [1.05-1.14]). CONCLUSIONS: Our data support the hypothesis that influenza influences bacterial disease incidence by enhancing short-term risk of invasion in colonized individuals. The absence of correlation between seasonal waveforms, on the other hand, suggests that bacterial disease transmission is affected to a lesser extent. Please see later in the article for the Editors' Summary. PMID- 21687694 TI - MiRNA expression in psoriatic skin: reciprocal regulation of hsa-miR-99a and IGF 1R. AB - BACKGROUND: Psoriasis is a complex disease at the cellular, genomic and genetic levels. The role of microRNAs in skin development was shown in a keratinocyte specific Dicer knockout mouse model. Considering that two main characteristics of psoriasis are keratinocytes hyperproliferation and abnormal skin differentiation, we hypothesized that aberrant microRNA expression contributes to the psoriatic phenotype. Here, we describe the differential expression of miRNAs in psoriatic involved and uninvolved skin as compared to normal skin, revealing an additional aspect of this complex disorder. METHODOLOGY/PRINCIPAL FINDINGS: Expression arrays were used to compare microRNA expression in normal skin versus psoriatic involved and uninvolved skin. Fourteen differentially expressed microRNAs were identified, including hsa-miR-99a, hsa-miR-150, hsa-miR-423 and hsa-miR-197. The expression of these microRNAs was reevaluated by qPCR. IGF-1R, which is involved in skin development and the pathogenesis of psoriasis, is a predicted target of hsa-miR-99a. In an in situ hybridization assay, we found that IGF-1R and miR-99a are reciprocally expressed in the epidermis. Using a reporter assay, we found that IGF-1R is targeted by hsa-miR-99a. Moreover, over expression of miR-99a in primary keratinocytes down-regulates the expression of the endogenous IGF-1R protein. Over expression of miR-99a also inhibits keratinocyte proliferation and increases Keratin 10 expression. These findings suggest that overexpression of hsa-miR-99a in keratinocytes drives them towards differentiation. In primary keratinocytes grown in high Ca(++), miR-99a expression increases over time. Finally, we found that IGF1 increases the expression of miR-99a. CONCLUSIONS/SIGNIFICANCE: We identified several microRNAs that are expressed differentially in normal and psoriatic skin. One of these miRNAs is miR-99a that regulates the expression of IGF-1R. Moreover, miR-99a seems to play a role in the differentiation of keratinocytes. We suggest that miR-99a is one of the regulators of the IGF-1R signaling pathway in keratinocytes. Activation of IGF1 signaling results in elevation of miR-99a which represses the expression of IGF 1R. PMID- 21687701 TI - Confusion and slurred speech in a 34-year-old woman from India. AB - A 34-year-old woman from India, presented with episodes of confusion and progressive speech deterioration. She also had a painless neck "lump", which persisted despite antibiotics. She was diagnosed to have a space occupying lesion in the left parietal lobe, which was subsequently biopsied. PMID- 21687702 TI - Unusual interferon gamma measurements with QuantiFERON-TB Gold and QuantiFERON-TB Gold In-Tube tests. AB - INTRODUCTION: Interferon gamma (IFN-gamma) release assays, such as QuantiFERON(r) TB Gold test (QFT-G) and QuantiFERON(r)-TB Gold In-Tube test (QFT-GIT) are designed to detect M. tuberculosis (Mtb) infection. Recognition of unusual IFN gamma measurements may help indicate inaccurate results. METHODS: We examined QFT G and QFT-GIT results from subjects who had two or more tests completed. We classified unusual IFN-gamma measurements as: 1) High Nil Concentration (HNC) when IFN-gamma concentration in plasma from unstimulated blood exceeded 0.7 IU/mL; 2) Low Mitogen Response (LMR) when Mitogen Response was <0.5 IU/mL; 3) Very Low Mitogen Response (VLMR) when Mitogen Response was <=-0.5 IU/mL; and 4) Very Low Antigen Response (VLAR) when the response to a Mtb antigen was <=-0.35 IU/mL and <=-0.5 times the IFN-gamma concentration in plasma from unstimulated blood. RESULTS: Among 5,309 results from 1,728 subjects, HNC occurred in 234 (4.4%) tests for 162 subjects, LMR in 108 (2.0%) tests for 85 subjects, VLMR in 22 (0.4%) tests for 21 subjects, and VLAR in 41 (0.8%) tests for 39 subjects. QFT GIT had fewer HNC, VLMR, and VLAR (p = 0.042, 0.004, and 0.067 respectively); QFT G had fewer LMR (p = 0.005). Twenty-four (51.6%) of 47 subjects with positive results and HNC were negative or indeterminate by all other tests. Thirteen (61.9%) of 21 subjects with positive results and LMR were negative or indeterminate by all other tests. CONCLUSION: Unusual IFN-gamma measurements including HNC, LMR, VLMR, and VLAR were encountered in small numbers, and in most instances were not seen on simultaneously or subsequently performed tests. To avoid erroneous diagnosis of Mtb infection, IGRAs with unusual IFN-gamma measurements should be repeated with another blood sample and interpreted with caution if they recur. PMID- 21687703 TI - SLC5A8 gene, a transporter of butyrate: a gut flora metabolite, is frequently methylated in African American colon adenomas. AB - BACKGROUND: Colon cancer is one of the leading causes of cancer related deaths. Its impact on African Americans (AAs) is higher than in the general population both in the incidence and mortality from the disease. Colon cancer aggressiveness in AAs as well as non-frequent check-ups and follow up in this population have been proposed as ways to explain the observed discrepancies. These facts made the detection of early carcinogenesis markers in this population a priority. MATERIALS AND METHODS: Here, we analyzed 50 colon adenomas from AA patients for both microsatellite instability (MSI) and the methylation status of SLC5A8 gene. This gene's product is involved in the transport of butyrate that has anti proliferative properties through its effects on histone acetylation and gene expression. A proteomic analysis to check the expressed histones in adenoma and normal tissues was also performed. RESULTS: The analyzed samples displayed 82% (n = 41) methylation level of SLC5A8 gene in adenomas. The MSI-H (high) adenoma were about 18% (n = 9) while the rest were mostly MSS (microsatellite stable) with few MSI-L (Low). No association was found between SLC5A8 methylation and the MSI status. Also, there was no association between SLC5A8 methylation and the sex and age of the patients. However, there were more right sided adenomas with SLC5A8 methylation than the left sided ones. The proteomic analysis revealed distinct histone expression profiles between normal and adenoma tissues. CONCLUSION: SLC5A8 is highly methylated in AA colon adenomas which points to its potential use as a marker for early detection. The MSI rate is similar to that found in colon cancer tumors in AAs. These findings suggest that both processes stem from the same epigenetic and genetic events occurring at an early stage in colon carcinogenesis in AAs. PMID- 21687704 TI - Independent evolution of leaf and root traits within and among temperate grassland plant communities. AB - In this study, we used data from temperate grassland plant communities in Alberta, Canada to test two longstanding hypotheses in ecology: 1) that there has been correlated evolution of the leaves and roots of plants due to selection for an integrated whole-plant resource uptake strategy, and 2) that trait diversity in ecological communities is generated by adaptations to the conditions in different habitats. We tested the first hypothesis using phylogenetic comparative methods to test for evidence of correlated evolution of suites of leaf and root functional traits in these grasslands. There were consistent evolutionary correlations among traits related to plant resource uptake strategies within leaf tissues, and within root tissues. In contrast, there were inconsistent correlations between the traits of leaves and the traits of roots, suggesting different evolutionary pressures on the above and belowground components of plant morphology. To test the second hypothesis, we evaluated the relative importance of two components of trait diversity: within-community variation (species trait values relative to co-occurring species; alpha traits) and among-community variation (the average trait value in communities where species occur; beta traits). Trait diversity was mostly explained by variation among co-occurring species, not among-communities. Additionally, there was a phylogenetic signal in the within-community trait values of species relative to co-occurring taxa, but not in their habitat associations or among-community trait variation. These results suggest that sorting of pre-existing trait variation into local communities can explain the leaf and root trait diversity in these grasslands. PMID- 21687705 TI - A new crocodylian from the late Maastrichtian of Spain: implications for the initial radiation of crocodyloids. AB - BACKGROUND: The earliest crocodylians are known primarily from the Late Cretaceous of North America and Europe. The representatives of Gavialoidea and Alligatoroidea are known in the Late Cretaceous of both continents, yet the biogeographic origins of Crocodyloidea are poorly understood. Up to now, only one representative of this clade has been known from the Late Cretaceous, the basal crocodyloid Prodiplocynodon from the Maastrichtian of North America. METHODOLOGY/PRINCIPAL FINDINGS: The fossil studied is a skull collected from sandstones in the lower part of the Tremp Formation, in Chron C30n, dated at 67.6 to 65.5 Ma (late Maastrichtian), in Aren (Huesca, Spain). It is located in a continuous section that contains the K/P boundary, in which the dinosaur faunas closest to the K/P boundary in Europe have been described, including Arenysaurus ardevoli and Blasisaurus canudoi. Phylogenetic analysis places the new taxon, Arenysuchus gascabadiolorum, at the base of Crocodyloidea. CONCLUSIONS/SIGNIFICANCE: The new taxon is the oldest crocodyloid representative in Eurasia. Crocodyloidea had previously only been known from the Palaeogene onwards in this part of Laurasia. Phylogenetically, Arenysuchus gascabadiolorum is situated at the base of the first radiation of crocodyloids that occurred in the late Maastrichtian, shedding light on this part of the cladogram. The presence of basal crocodyloids at the end of the Cretaceous both in North America and Europe provides new evidence of the faunal exchange via the Thulean Land Bridge during the Maastrichtian. PMID- 21687706 TI - Defining reference sequences for Nocardia species by similarity and clustering analyses of 16S rRNA gene sequence data. AB - BACKGROUND: The intra- and inter-species genetic diversity of bacteria and the absence of 'reference', or the most representative, sequences of individual species present a significant challenge for sequence-based identification. The aims of this study were to determine the utility, and compare the performance of several clustering and classification algorithms to identify the species of 364 sequences of 16S rRNA gene with a defined species in GenBank, and 110 sequences of 16S rRNA gene with no defined species, all within the genus Nocardia. METHODS: A total of 364 16S rRNA gene sequences of Nocardia species were studied. In addition, 110 16S rRNA gene sequences assigned only to the Nocardia genus level at the time of submission to GenBank were used for machine learning classification experiments. Different clustering algorithms were compared with a novel algorithm or the linear mapping (LM) of the distance matrix. Principal Components Analysis was used for the dimensionality reduction and visualization. RESULTS: The LM algorithm achieved the highest performance and classified the set of 364 16S rRNA sequences into 80 clusters, the majority of which (83.52%) corresponded with the original species. The most representative 16S rRNA sequences for individual Nocardia species have been identified as 'centroids' in respective clusters from which the distances to all other sequences were minimized; 110 16S rRNA gene sequences with identifications recorded only at the genus level were classified using machine learning methods. Simple kNN machine learning demonstrated the highest performance and classified Nocardia species sequences with an accuracy of 92.7% and a mean frequency of 0.578. CONCLUSION: The identification of centroids of 16S rRNA gene sequence clusters using novel distance matrix clustering enables the identification of the most representative sequences for each individual species of Nocardia and allows the quantitation of inter- and intra-species variability. PMID- 21687707 TI - Impact of metabolic regulators on the expression of the obesity associated genes FTO and NAMPT in human preadipocytes and adipocytes. AB - BACKGROUND: FTO and NAMPT/PBEF/visfatin are thought to play a role in obesity but their transcriptional regulation in adipocytes is not fully understood. In this study, we evaluated the transcriptional regulation of FTO and NAMPT in preadipocytes and adipocytes by metabolic regulators. METHODOLOGY AND PRINCIPAL FINDINGS: We assessed FTO mRNA expression during human adipocyte differentiation of Simpson-Golabi-Behmel syndrome (SGBS) cells and primary subcutaneous preadipocytes in vitro and evaluated the effect of the metabolic regulators glucose, insulin, dexamethasone, IGF-1 and isoproterenol on FTO and NAMPT mRNA expression in SGBS preadipocytes and adipocytes. FTO mRNA levels were not significantly modulated during adipocyte differentiation. Also, metabolic regulators had no impact on FTO expression in preadipocytes or adipocytes. In SGBS preadipocytes NAMPT expression was more than 3fold induced by dexamethasone and isoproterenol and 1.6fold by dexamethasone in adipocytes. Complete glucose restriction caused an increase in NAMPT mRNA expression by more than 5fold and 1.4fold in SGBS preadipocytes and adipocytes, respectively. CONCLUSION: FTO mRNA expression is not significantly affected by differentiation or metabolic regulators in human adipocytes. The stimulation of NAMPT expression by dexamethasone, isoproterenol and complete glucose restriction may indicate a regulation of NAMPT by metabolic stress, which was more pronounced in preadipocytes compared to mature adipocytes. PMID- 21687708 TI - Global change could amplify fire effects on soil greenhouse gas emissions. AB - BACKGROUND: Little is known about the combined impacts of global environmental changes and ecological disturbances on ecosystem functioning, even though such combined impacts might play critical roles in shaping ecosystem processes that can in turn feed back to climate change, such as soil emissions of greenhouse gases. METHODOLOGY/PRINCIPAL FINDINGS: We took advantage of an accidental, low severity wildfire that burned part of a long-term global change experiment to investigate the interactive effects of a fire disturbance and increases in CO(2) concentration, precipitation and nitrogen supply on soil nitrous oxide (N(2)O) emissions in a grassland ecosystem. We examined the responses of soil N(2)O emissions, as well as the responses of the two main microbial processes contributing to soil N(2)O production--nitrification and denitrification--and of their main drivers. We show that the fire disturbance greatly increased soil N(2)O emissions over a three-year period, and that elevated CO(2) and enhanced nitrogen supply amplified fire effects on soil N(2)O emissions: emissions increased by a factor of two with fire alone and by a factor of six under the combined influence of fire, elevated CO(2) and nitrogen. We also provide evidence that this response was caused by increased microbial denitrification, resulting from increased soil moisture and soil carbon and nitrogen availability in the burned and fertilized plots. CONCLUSIONS/SIGNIFICANCE: Our results indicate that the combined effects of fire and global environmental changes can exceed their effects in isolation, thereby creating unexpected feedbacks to soil greenhouse gas emissions. These findings highlight the need to further explore the impacts of ecological disturbances on ecosystem functioning in the context of global change if we wish to be able to model future soil greenhouse gas emissions with greater confidence. PMID- 21687709 TI - Extreme conservation leads to recovery of the Virunga mountain gorillas. AB - As wildlife populations are declining, conservationists are under increasing pressure to measure the effectiveness of different management strategies. Conventional conservation measures such as law enforcement and community development projects are typically designed to minimize negative human influences upon a species and its ecosystem. In contrast, we define "extreme" conservation as efforts targeted to deliberately increase positive human influences, including veterinary care and close monitoring of individual animals. Here we compare the impact of both conservation approaches upon the population growth rate of the critically endangered Virunga mountain gorillas (Gorilla beringei beringei), which increased by 50% since their nadir in 1981, from approximately 250 to nearly 400 gorillas. Using demographic data from 1967-2008, we show an annual decline of 0.7%+/-0.059% for unhabituated gorillas that received intensive levels of conventional conservation approaches, versus an increase 4.1%+/-0.088% for habituated gorillas that also received extreme conservation measures. Each group of habituated gorillas is now continuously guarded by a separate team of field staff during daylight hours and receives veterinary treatment for snares, respiratory disease, and other life-threatening conditions. These results suggest that conventional conservation efforts prevented a severe decline of the overall population, but additional extreme measures were needed to achieve positive growth. Demographic stochasticity and socioecological factors had minimal impact on variability in the growth rates. Veterinary interventions could account for up to 40% of the difference in growth rates between habituated versus unhabituated gorillas, with the remaining difference likely arising from greater protection against poachers. Thus, by increasing protection and facilitating veterinary treatment, the daily monitoring of each habituated group contributed to most of the difference in growth rates. Our results argue for wider consideration of extreme measures and offer a startling view of the enormous resources that may be needed to conserve some endangered species. PMID- 21687710 TI - Comparing the performances of apes (Gorilla gorilla, Pan troglodytes, Pongo pygmaeus) and human children (Homo sapiens) in the floating peanut task. AB - Recently, Mendes et al. [1] described the use of a liquid tool (water) in captive orangutans. Here, we tested chimpanzees and gorillas for the first time with the same "floating peanut task." None of the subjects solved the task. In order to better understand the cognitive demands of the task, we further tested other populations of chimpanzees and orangutans with the variation of the peanut initially floating or not. Twenty percent of the chimpanzees but none of the orangutans were successful. Additional controls revealed that successful subjects added water only if it was necessary to obtain the nut. Another experiment was conducted to investigate the reason for the differences in performance between the unsuccessful (Experiment 1) and the successful (Experiment 2) chimpanzee populations. We found suggestive evidence for the view that functional fixedness might have impaired the chimpanzees' strategies in the first experiment. Finally, we tested how human children of different age classes perform in an analogous experimental setting. Within the oldest group (8 years), 58 percent of the children solved the problem, whereas in the youngest group (4 years), only 8 percent were able to find the solution. PMID- 21687711 TI - Analyzing media coverage of the global fund diseases compared with lower funded diseases (childhood pneumonia, diarrhea and measles). AB - BACKGROUND: Pneumonia, diarrhea and measles are the leading causes of death in children worldwide, but have a disproportionately low share of international funding and media attention. In comparison, AIDS, tuberculosis and malaria- diseases that also significantly affect children--receive considerably more funding and have relatively high media coverage. This study investigates the potential relationship between media agenda setting and funding levels in the context of the actual burden of disease. METHODS: The news databases Lexis Nexis, Factiva, and Google News Archive were searched for the diseases AIDS, TB and Malaria and for lower funded pediatric diseases: childhood pneumonia, diarrhea, and measles. A sample of news articles across geographic regions was also analyzed using a qualitative narrative frame analysis of how the media stories were told. RESULTS: There were significantly more articles addressing the Global Fund diseases compared to the lower funded pediatric diseases between 1981 and 2008 (1,344,150 versus 291,865 articles). There were also notable differences in the framing of media narratives: 1) There was a high proportion of articles with the primary purpose of raising awareness for AIDS, TB and malaria (46.2%) compared with only 17.9% of the pediatric disease articles. 2) Nearly two-thirds (61.5%) of the AIDS, tuberculosis and malaria articles used a human rights, legal or social justice frame, compared with 46.2% for the lower funded pediatric disease articles, which primarily used an ethical or moral frame. CONCLUSION: This study demonstrates that lower funded pediatric diseases are presented differently in the media, both quantitatively and qualitatively, than higher funded, higher profile diseases. PMID- 21687712 TI - The nucleosome (histone-DNA complex) is the TLR9-specific immunostimulatory component of Plasmodium falciparum that activates DCs. AB - The systemic clinical symptoms of Plasmodium falciparum infection such as fever and chills correspond to the proinflammatory cytokines produced in response to the parasite components released during the synchronized rupture of schizonts. We recently demonstrated that, among the schizont-released products, merozoites are the predominant components that activate dendritic cells (DCs) by TLR9-specific recognition to induce the maturation of cells and to produce proinflammatory cytokines. We also demonstrated that DNA is the active constituent and that formation of a DNA-protein complex is essential for the entry of parasite DNA into cells for recognition by TLR9. However, the nature of endogenous protein-DNA complex in the parasite is not known. In this study, we show that parasite nucleosome constitute the major protein-DNA complex involved in the activation of DCs by parasite nuclear material. The parasite components were fractionated into the nuclear and non-nuclear materials. The nuclear material was further fractionated into chromatin and the proteins loosely bound to chromatin. Polynucleosomes and oligonucleosomes were prepared from the chromatin. These were tested for their ability to activate DCs obtained by the FLT3 ligand differentiation of bone marrow cells from the wild type, and TLR2(-/-), TLR9(-/-) and MyD88(-/-) mice. DCs stimulated with the nuclear material and polynucleosomes as well as mono- and oligonucleosomes efficiently induced the production of proinflammatory cytokines in a TLR9-dependent manner, demonstrating that nucleosomes (histone-DNA complex) represent the major TLR9-specific DC immunostimulatory component of the malaria parasite nuclear material. Thus, our data provide a significant insight into the activation of DCs by malaria parasites and have important implications for malaria vaccine development. PMID- 21687714 TI - The Sea Peoples, from cuneiform tablets to carbon dating. AB - The 13(th) century BC witnessed the zenith of the Aegean and Eastern Mediterranean civilizations which declined at the end of the Bronze Age, ~3200 years ago. Weakening of this ancient flourishing Mediterranean world shifted the political and economic centres of gravity away from the Levant towards Classical Greece and Rome, and led, in the long term, to the emergence of the modern western civilizations. Textual evidence from cuneiform tablets and Egyptian reliefs from the New Kingdom relate that seafaring tribes, the Sea Peoples, were the final catalyst that put the fall of cities and states in motion. However, the lack of a stratified radiocarbon-based archaeology for the Sea People event has led to a floating historical chronology derived from a variety of sources spanning dispersed areas. Here, we report a stratified radiocarbon-based archaeology with anchor points in ancient epigraphic-literary sources, Hittite Levantine-Egyptian kings and astronomical observations to precisely date the Sea People event. By confronting historical and science-based archaeology, we establish an absolute age range of 1192-1190 BC for terminal destructions and cultural collapse in the northern Levant. This radiocarbon-based archaeology has far-reaching implications for the wider Mediterranean, where an elaborate network of international relations and commercial activities are intertwined with the history of civilizations. PMID- 21687715 TI - Effects of individual pre-fledging traits and environmental conditions on return patterns in juvenile king penguins. AB - Despite the importance of early life stages in individuals' life history and population dynamics, very few studies have focused on the constraints to which these juvenile traits are subjected. Based on 10 years of automatic monitoring of over 2500 individuals, we present the first study on the effects of environmental conditions and individual pre-fledging traits on the post-fledging return of non banded king penguins to their natal colony. Juvenile king penguins returned exclusively within one of the three austral summers following their departure. A key finding is that return rates (range 68-87%) were much higher than previously assumed for this species, importantly meaning that juvenile survival is very close to that of adults. Such high figures suggest little juvenile dispersal, and selection occurring mostly prior to fledging in king penguins. Pre-fledging conditions had a strong quadratic impact on juvenile return rates. As expected, cohorts reared under very unfavourable years (as inferred by the breeding success of the colony) exhibited low return rates but surprisingly, so did those fledged under very favourable conditions. Juvenile sojourns away from the colony were shorter under warm conditions and subsequent return rates higher, suggesting a positive effect of climate warming. The longer the post-fledging trip (1, 2 or 3 years), the earlier in the summer birds returned to their natal colony and the longer they stayed before leaving for the winter journey. The presence of juveniles in the colony was more than twice the duration required for moulting purposes, yet none attempted breeding in the year of their first return. Juvenile presence in the colony may be important for acquiring knowledge on the social and physical colonial environment and may play an important part in the learning process of mating behaviour. Further studies are required to investigate its potential implications on other life-history traits such as recruitment age. PMID- 21687713 TI - Yes-associated protein 65 (YAP) expands neural progenitors and regulates Pax3 expression in the neural plate border zone. AB - Yes-associated protein 65 (YAP) contains multiple protein-protein interaction domains and functions as both a transcriptional co-activator and as a scaffolding protein. Mouse embryos lacking YAP did not survive past embryonic day 8.5 and showed signs of defective yolk sac vasculogenesis, chorioallantoic fusion, and anterior-posterior (A-P) axis elongation. Given that the YAP knockout mouse defects might be due in part to nutritional deficiencies, we sought to better characterize a role for YAP during early development using embryos that develop externally. YAP morpholino (MO)-mediated loss-of-function in both frog and fish resulted in incomplete epiboly at gastrulation and impaired axis formation, similar to the mouse phenotype. In frog, germ layer specific genes were expressed, but they were temporally delayed. YAP MO-mediated partial knockdown in frog allowed a shortened axis to form. YAP gain-of-function in Xenopus expanded the progenitor populations in the neural plate (sox2(+)) and neural plate border zone (pax3(+)), while inhibiting the expression of later markers of tissues derived from the neural plate border zone (neural crest, pre-placodal ectoderm, hatching gland), as well as epidermis and somitic muscle. YAP directly regulates pax3 expression via association with TEAD1 (N-TEF) at a highly conserved, previously undescribed, TEAD-binding site within the 5' regulatory region of pax3. Structure/function analyses revealed that the PDZ-binding motif of YAP contributes to the inhibition of epidermal and somitic muscle differentiation, but a complete, intact YAP protein is required for expansion of the neural plate and neural plate border zone progenitor pools. These results provide a thorough analysis of YAP mediated gene expression changes in loss- and gain-of-function experiments. Furthermore, this is the first report to use YAP structure-function analyzes to determine which portion of YAP is involved in specific gene expression changes and the first to show direct in vivo evidence of YAP's role in regulating pax3 neural crest expression. PMID- 21687716 TI - Prokineticin 2 regulates the electrical activity of rat suprachiasmatic nuclei neurons. AB - Neuropeptide signaling plays roles in coordinating cellular activities and maintaining robust oscillations within the mammalian suprachiasmatic nucleus (SCN). Prokineticin2 (PK2) is a signaling molecule from the SCN and involves in the generation of circadian locomotor activity. Prokineticin receptor 2 (PKR2), a receptor for PK2, has been shown to be expressed in the SCN. However, very little is known about the cellular action of PK2 within the SCN. In the present study, we investigated the effect of PK2 on spontaneous firing and miniature inhibitory postsynaptic currents (mIPSCs) using whole cell patch-clamp recording in the SCN slices. PK2 dose-dependently increased spontaneous firing rates in most neurons from the dorsal SCN. PK2 acted postsynaptically to reduce gamma-aminobutyric acid (GABA)-ergic function within the SCN, and PK2 reduced the amplitude but not frequency of mIPSCs. Furthermore, PK2 also suppressed exogenous GABA-induced currents. And the inhibitory effect of PK2 required PKC activation in the postsynaptic cells. Our data suggest that PK2 could alter cellular activities within the SCN and may influence behavioral and physiological rhythms. PMID- 21687717 TI - Seasonal Expression of the Picocyanobacterial Phosphonate Transporter Gene phnD in the Sargasso Sea. AB - In phosphorus-limited marine environments, picocyanobacteria (Synechococcus and Prochlorococcus spp.) can hydrolyze naturally occurring phosphonates as a P source. Utilization of 2-aminoethylphosphonate (2-AEP) is dependent on expression of the phn genes, encoding functions required for uptake, and C-P bond cleavage. Prior work has indicated that expression of picocyanobacterial phnD, encoding the phosphonate binding protein of the phosphonate ABC transporter, is a proxy for the assimilation of phosphonates in natural assemblages of Synechococcus spp. and Prochlorococcus spp (Ilikchyan et al., 2009). In this study, we expand this work to assess seasonal phnD expression in the Sargasso Sea. By RT-PCR, our data confirm that phnD expression is constitutive for the Prochlorococcus spp. detected, but in Synechococcus spp. phnD transcription follows patterns of phosphorus availability in the mixed layer. Specifically, our data suggest that phnD is repressed in the spring when P is bioavailable following deep winter mixing. In the fall, phnD expression follows a depth-dependent pattern reflecting depleted P at the surface following summertime drawdown, and elevated P at depth. PMID- 21687718 TI - The dawning era of comprehensive transcriptome analysis in cellular microbiology. AB - Bacteria rapidly change their transcriptional patterns during infection in order to adapt to the host environment. To investigate host-bacteria interactions, various strategies including the use of animal infection models, in vitro assay systems and microscopic observations have been used. However, these studies primarily focused on a few specific genes and molecules in bacteria. High-density tiling arrays and massively parallel sequencing analyses are rapidly improving our understanding of the complex host-bacterial interactions through identification and characterization of bacterial transcriptomes. Information resulting from these high-throughput techniques will continue to provide novel information on the complexity, plasticity, and regulation of bacterial transcriptomes as well as their adaptive responses relative to pathogenecity. Here we summarize recent studies using these new technologies and discuss the utility of transcriptome analysis. PMID- 21687719 TI - Fungi are Not All "Fun-Guys" after All. PMID- 21687720 TI - Model systems to study plague pathogenesis and develop new therapeutics. AB - The Gram negative bacterium Yersinia pestis can infect humans by multiple routes to cause plague. Three plague pandemics have occurred and Y. pestis has been linked to biowarfare in the past. The continued risk of plague as a bioweapon has prompted increased research to understand Y. pestis pathogenesis and develop new plague therapeutics. Several in vivo models have been developed for this research and are reviewed here. PMID- 21687721 TI - Hypertonic Saline Therapy in Cystic Fibrosis: Do Population Shifts Caused by the Osmotic Sensitivity of Infecting Bacteria Explain the Effectiveness of this Treatment? AB - Cystic fibrosis (CF) is caused by a defect in the CF transmembrane regulator that leads to depletion and dehydration of the airway surface liquid (ASL) of the lung epithelium, providing an environment that can be infected by bacteria leading to increased morbidity and mortality. Pseudomonas aeruginosa chronically infects more than 80% of CF patients and one hallmark of infection is the emergence of a mucoid phenotype associated with a worsening prognosis and more rapid decline in lung function. Hypertonic saline (HS) is a clinically proven treatment that improves mucociliary clearance through partial rehydration of the ASL of the lung. Strikingly, while HS therapy does not alter the prevalence of P. aeruginosa in the CF lung it does decrease the frequency of episodes of acute, severe illness known as infective exacerbations among CF patients. In this article, we propose a hypothesis whereby the positive clinical effects of HS treatment are explained by the osmotic sensitivity of the mucoid sub-population of P. aeruginosa in the CF lung leading to selection against this group in favor of the osmotically resistant non-mucoid variants. PMID- 21687722 TI - The grand challenge of microbiology: to know better, protect, utilize and celebrate the unseen majority on our planet. PMID- 21687724 TI - Group-ICA Model Order Highlights Patterns of Functional Brain Connectivity. AB - Resting-state networks (RSNs) can be reliably and reproducibly detected using independent component analysis (ICA) at both individual subject and group levels. Altering ICA dimensionality (model order) estimation can have a significant impact on the spatial characteristics of the RSNs as well as their parcellation into sub-networks. Recent evidence from several neuroimaging studies suggests that the human brain has a modular hierarchical organization which resembles the hierarchy depicted by different ICA model orders. We hypothesized that functional connectivity between-group differences measured with ICA might be affected by model order selection. We investigated differences in functional connectivity using so-called dual regression as a function of ICA model order in a group of unmedicated seasonal affective disorder (SAD) patients compared to normal healthy controls. The results showed that the detected disease-related differences in functional connectivity alter as a function of ICA model order. The volume of between-group differences altered significantly as a function of ICA model order reaching maximum at model order 70 (which seems to be an optimal point that conveys the largest between-group difference) then stabilized afterwards. Our results show that fine-grained RSNs enable better detection of detailed disease related functional connectivity changes. However, high model orders show an increased risk of false positives that needs to be overcome. Our findings suggest that multilevel ICA exploration of functional connectivity enables optimization of sensitivity to brain disorders. PMID- 21687725 TI - Grand challenges in extreme microbiology. PMID- 21687723 TI - A Tale of Two Toxins: Helicobacter Pylori CagA and VacA Modulate Host Pathways that Impact Disease. AB - Helicobacter pylori is a pathogenic bacterium that colonizes more than 50% of the world's population, which leads to a tremendous medical burden. H. pylori infection is associated with such varied diseases as gastritis, peptic ulcers, and two forms of gastric cancer: gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. This association represents a novel paradigm for cancer development; H. pylori is currently the only bacterium to be recognized as a carcinogen. Therefore, a significant amount of research has been conducted to identify the bacterial factors and the deregulated host cell pathways that are responsible for the progression to more severe disease states. Two of the virulence factors that have been implicated in this process are cytotoxin associated gene A (CagA) and vacuolating cytotoxin A (VacA), which are cytotoxins that are injected and secreted by H. pylori, respectively. Both of these virulence factors are polymorphic and affect a multitude of host cellular pathways. These combined facts could easily contribute to differences in disease severity across the population as various CagA and VacA alleles differentially target some pathways. Herein we highlight the diverse types of cellular pathways and processes targeted by these important toxins. PMID- 21687727 TI - Denoising two-photon calcium imaging data. AB - Two-photon calcium imaging is now an important tool for in vivo imaging of biological systems. By enabling neuronal population imaging with subcellular resolution, this modality offers an approach for gaining a fundamental understanding of brain anatomy and physiology. Proper analysis of calcium imaging data requires denoising, that is separating the signal from complex physiological noise. To analyze two-photon brain imaging data, we present a signal plus colored noise model in which the signal is represented as harmonic regression and the correlated noise is represented as an order autoregressive process. We provide an efficient cyclic descent algorithm to compute approximate maximum likelihood parameter estimates by combing a weighted least-squares procedure with the Burg algorithm. We use Akaike information criterion to guide selection of the harmonic regression and the autoregressive model orders. Our flexible yet parsimonious modeling approach reliably separates stimulus-evoked fluorescence response from background activity and noise, assesses goodness of fit, and estimates confidence intervals and signal-to-noise ratio. This refined separation leads to appreciably enhanced image contrast for individual cells including clear delineation of subcellular details and network activity. The application of our approach to in vivo imaging data recorded in the ferret primary visual cortex demonstrates that our method yields substantially denoised signal estimates. We also provide a general Volterra series framework for deriving this and other signal plus correlated noise models for imaging. This approach to analyzing two-photon calcium imaging data may be readily adapted to other computational biology problems which apply correlated noise models. PMID- 21687726 TI - Nitrogen fixation in denitrified marine waters. AB - Nitrogen fixation is an essential process that biologically transforms atmospheric dinitrogen gas to ammonia, therefore compensating for nitrogen losses occurring via denitrification and anammox. Currently, inputs and losses of nitrogen to the ocean resulting from these processes are thought to be spatially separated: nitrogen fixation takes place primarily in open ocean environments (mainly through diazotrophic cyanobacteria), whereas nitrogen losses occur in oxygen-depleted intermediate waters and sediments (mostly via denitrifying and anammox bacteria). Here we report on rates of nitrogen fixation obtained during two oceanographic cruises in 2005 and 2007 in the eastern tropical South Pacific (ETSP), a region characterized by the presence of coastal upwelling and a major permanent oxygen minimum zone (OMZ). Our results show significant rates of nitrogen fixation in the water column; however, integrated rates from the surface down to 120 m varied by ~30 fold between cruises (7.5+/-4.6 versus 190+/-82.3 umol m(-2) d(-1)). Moreover, rates were measured down to 400 m depth in 2007, indicating that the contribution to the integrated rates of the subsurface oxygen deficient layer was ~5 times higher (574+/-294 umol m(-2) d(-1)) than the oxic euphotic layer (48+/-68 umol m(-2) d(-1)). Concurrent molecular measurements detected the dinitrogenase reductase gene nifH in surface and subsurface waters. Phylogenetic analysis of the nifH sequences showed the presence of a diverse diazotrophic community at the time of the highest measured nitrogen fixation rates. Our results thus demonstrate the occurrence of nitrogen fixation in nutrient-rich coastal upwelling systems and, importantly, within the underlying OMZ. They also suggest that nitrogen fixation is a widespread process that can sporadically provide a supplementary source of fixed nitrogen in these regions. PMID- 21687728 TI - 5-HT(2C) receptors localize to dopamine and GABA neurons in the rat mesoaccumbens pathway. AB - The serotonin 5-HT(2C) receptor (5-HT(2C)R) is localized to the limbic corticostriatal circuit, which plays an integral role in mediating attention, motivation, cognition, and reward processes. The 5-HT(2C)R is linked to modulation of mesoaccumbens dopamine neurotransmission via an activation of gamma aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA). However, we recently demonstrated the expression of the 5-HT(2C)R within dopamine VTA neurons suggesting the possibility of a direct influence of the 5-HT(2C)R upon mesoaccumbens dopamine output. Here, we employed double-label fluorescence immunochemistry with the synthetic enzymes for dopamine (tyrosine hydroxylase; TH) and GABA (glutamic acid decarboxylase isoform 67; GAD-67) and retrograde tract tracing with FluoroGold (FG) to uncover whether dopamine and GABA VTA neurons that possess 5-HT(2C)R innervate the nucleus accumbens (NAc). The highest numbers of FG-labeled cells were detected in the middle versus rostral and caudal levels of the VTA, and included a subset of TH- and GAD-67 immunoreactive cells, of which >50% also contained 5-HT(2C)R immunoreactivity. Thus, we demonstrate for the first time that the 5-HT(2C)R colocalizes in DA and GABA VTA neurons which project to the NAc, describe in detail the distribution of NAc-projecting GABA VTA neurons, and identify the colocalization of TH and GAD-67 in the same NAc projecting VTA neurons. These data suggest that the 5-HT(2C)R may exert direct influence upon both dopamine and GABA VTA output to the NAc. Further, the indication that a proportion of NAc-projecting VTA neurons synthesize and potentially release both dopamine and GABA adds intriguing complexity to the framework of the VTA and its postulated neuroanatomical roles. PMID- 21687729 TI - Zigzag turning preference of freely crawling cells. AB - The coordinated motion of a cell is fundamental to many important biological processes such as development, wound healing, and phagocytosis. For eukaryotic cells, such as amoebae or animal cells, the cell motility is based on crawling and involves a complex set of internal biochemical events. A recent study reported very interesting crawling behavior of single cell amoeba: in the absence of an external cue, free amoebae move randomly with a noisy, yet, discernible sequence of 'run-and-turns' analogous to the 'run-and-tumbles' of swimming bacteria. Interestingly, amoeboid trajectories favor zigzag turns. In other words, the cells bias their crawling by making a turn in the opposite direction to a previous turn. This property enhances the long range directional persistence of the moving trajectories. This study proposes that such a zigzag crawling behavior can be a general property of any crawling cells by demonstrating that 1) microglia, which are the immune cells of the brain, and 2) a simple rule-based model cell, which incorporates the actual biochemistry and mechanics behind cell crawling, both exhibit similar type of crawling behavior. Almost all legged animals walk by alternating their feet. Similarly, all crawling cells appear to move forward by alternating the direction of their movement, even though the regularity and degree of zigzag preference vary from one type to the other. PMID- 21687730 TI - Polymorphic structures of Alzheimer's beta-amyloid globulomers. AB - BACKGROUND: Misfolding and self-assembly of Amyloid-beta (Abeta) peptides into amyloid fibrils is pathologically linked to the development of Alzheimer's disease. Polymorphic Abeta structures derived from monomers to intermediate oligomers, protofilaments, and mature fibrils have been often observed in solution. Some aggregates are on-pathway species to amyloid fibrils, while the others are off-pathway species that do not evolve into amyloid fibrils. Both on pathway and off-pathway species could be biologically relevant species. But, the lack of atomic-level structural information for these Abeta species leads to the difficulty in the understanding of their biological roles in amyloid toxicity and amyloid formation. METHODS AND FINDINGS: Here, we model a series of molecular structures of Abeta globulomers assembled by monomer and dimer building blocks using our peptide-packing program and explicit-solvent molecular dynamics (MD) simulations. Structural and energetic analysis shows that although Abeta globulomers could adopt different energetically favorable but structurally heterogeneous conformations in a rugged energy landscape, they are still preferentially organized by dynamic dimeric subunits with a hydrophobic core formed by the C-terminal residues independence of initial peptide packing and organization. Such structural organizations offer high structural stability by maximizing peptide-peptide association and optimizing peptide-water solvation. Moreover, curved surface, compact size, and less populated beta-structure in Abeta globulomers make them difficult to convert into other high-order Abeta aggregates and fibrils with dominant beta-structure, suggesting that they are likely to be off-pathway species to amyloid fibrils. These Abeta globulomers are compatible with experimental data in overall size, subunit organization, and molecular weight from AFM images and H/D amide exchange NMR. CONCLUSIONS: Our computationally modeled Abeta globulomers provide useful insights into structure, dynamics, and polymorphic nature of Abeta globulomers which are completely different from Abeta fibrils, suggesting that these globulomers are likely off pathway species and explaining the independence of the aggregation kinetics between Abeta globulomers and fibrils. PMID- 21687731 TI - Islet-like cell aggregates generated from human adipose tissue derived stem cells ameliorate experimental diabetes in mice. AB - BACKGROUND: Type 1 Diabetes Mellitus is caused by auto immune destruction of insulin producing beta cells in the pancreas. Currently available treatments include transplantation of isolated islets from donor pancreas to the patient. However, this method is limited by inadequate means of immuno-suppression to prevent islet rejection and importantly, limited supply of islets for transplantation. Autologous adult stem cells are now considered for cell replacement therapy in diabetes as it has the potential to generate neo-islets which are genetically part of the treated individual. Adopting methods of islet encapsulation in immuno-isolatory devices would eliminate the need for immuno suppressants. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we explore the potential of human adipose tissue derived adult stem cells (h-ASCs) to differentiate into functional islet like cell aggregates (ICAs). Our stage specific differentiation protocol permit the conversion of mesodermic h-ASCs to definitive endoderm (Hnf3beta, TCF2 and Sox17) and to PDX1, Ngn3, NeuroD, Pax4 positive pancreatic endoderm which further matures in vitro to secrete insulin. These ICAs are shown to produce human C-peptide in a glucose dependent manner exhibiting in-vitro functionality. Transplantation of mature ICAs, packed in immuno-isolatory biocompatible capsules to STZ induced diabetic mice restored near normoglycemia within 3-4 weeks. The detection of human C-peptide, 1155+/-165 pM in blood serum of experimental mice demonstrate the efficacy of our differentiation approach. CONCLUSIONS: h-ASC is an ideal population of personal stem cells for cell replacement therapy, given that they are abundant, easily available and autologous in origin. Our findings present evidence that h-ASCs could be induced to differentiate into physiologically competent functional islet like cell aggregates, which may provide as a source of alternative islets for cell replacement therapy in type 1 diabetes. PMID- 21687732 TI - Nanopods: a new bacterial structure and mechanism for deployment of outer membrane vesicles. AB - BACKGROUND: Bacterial outer membrane vesicles (OMV) are packets of periplasmic material that, via the proteins and other molecules they contain, project metabolic function into the environment. While OMV production is widespread in proteobacteria, they have been extensively studied only in pathogens, which inhabit fully hydrated environments. However, many (arguably most) bacterial habitats, such as soil, are only partially hydrated. In the latter, water is characteristically distributed as films on soil particles that are, on average thinner, than are typical OMV (ca. <=10 nm water film vs. 20 to >200 nm OMV;). METHODOLOGY/PRINCIPAL FINDINGS: We have identified a new bacterial surface structure, termed a "nanopod", that is a conduit for projecting OMV significant distances (e.g., >=6 um) from the cell. Electron cryotomography was used to determine nanopod three-dimensional structure, which revealed chains of vesicles within an undulating, tubular element. By using immunoelectron microscopy, proteomics, heterologous expression and mutagenesis, the tubes were determined to be an assembly of a surface layer protein (NpdA), and the interior structures identified as OMV. Specific metabolic function(s) for nanopods produced by Delftia sp. Cs1-4 are not yet known. However, a connection with phenanthrene degradation is a possibility since nanopod formation was induced by growth on phenanthrene. Orthologs of NpdA were identified in three other genera of the Comamonadaceae family, and all were experimentally verified to form nanopods. CONCLUSIONS/SIGNIFICANCE: Nanopods are new bacterial organelles, and establish a new paradigm in the mechanisms by which bacteria effect long-distance interactions with their environment. Specifically, they create a pathway through which cells can effectively deploy OMV, and the biological activity these transmit, in a diffusion-independent manner. Nanopods would thus allow environmental bacteria to expand their metabolic sphere of influence in a manner previously unknown for these organisms. PMID- 21687733 TI - Unexpected accumulation of ncm(5)U and ncm(5)S(2) (U) in a trm9 mutant suggests an additional step in the synthesis of mcm(5)U and mcm(5)S(2)U. AB - BACKGROUND: Transfer RNAs are synthesized as a primary transcript that is processed to produce a mature tRNA. As part of the maturation process, a subset of the nucleosides are modified. Modifications in the anticodon region often modulate the decoding ability of the tRNA. At position 34, the majority of yeast cytosolic tRNA species that have a uridine are modified to 5 carbamoylmethyluridine (ncm(5)U), 5-carbamoylmethyl-2'-O-methyluridine (ncm(5)Um), 5-methoxycarbonylmethyl-uridine (mcm(5)U) or 5-methoxycarbonylmethyl 2-thiouridine (mcm(5)s(2)U). The formation of mcm(5) and ncm(5) side chains involves a complex pathway, where the last step in formation of mcm(5) is a methyl esterification of cm(5) dependent on the Trm9 and Trm112 proteins. METHODOLOGY AND PRINCIPAL FINDINGS: Both Trm9 and Trm112 are required for the last step in formation of mcm(5) side chains at wobble uridines. By co-expressing a histidine-tagged Trm9p together with a native Trm112p in E. coli, these two proteins purified as a complex. The presence of Trm112p dramatically improves the methyltransferase activity of Trm9p in vitro. Single tRNA species that normally contain mcm(5)U or mcm(5)s(2)U nucleosides were isolated from trm9Delta or trm112Delta mutants and the presence of modified nucleosides was analyzed by HPLC. In both mutants, mcm(5)U and mcm(5)s(2)U nucleosides are absent in tRNAs and the major intermediates accumulating were ncm(5)U and ncm(5)s(2)U, not the expected cm(5)U and cm(5)s(2)U. CONCLUSIONS: Trm9p and Trm112p function together at the final step in formation of mcm(5)U in tRNA by using the intermediate cm(5)U as a substrate. In tRNA isolated from trm9Delta and trm112Delta strains, ncm(5)U and ncm(5)s(2)U nucleosides accumulate, questioning the order of nucleoside intermediate formation of the mcm(5) side chain. We propose two alternative explanations for this observation. One is that the intermediate cm(5)U is generated from ncm(5)U by a yet unknown mechanism and the other is that cm(5)U is formed before ncm(5)U and mcm(5)U. PMID- 21687735 TI - Cloning and characterization of a putative TAC1 ortholog associated with leaf angle in maize (Zea mays L.). AB - BACKGROUND: Modifying plant architecture to increase photosynthesis efficiency and reduce shade avoidance response is very important for further yield improvement when crops are grown in high density. Identification of alleles controlling leaf angle in maize is needed to provide insight into molecular mechanism of leaf development and achieving ideal plant architecture to improve grain yield. METHODOLOGY/PRINCIPAL FINDINGS: The gene cloning was done by using comparative genomics, and then performing real-time polymerase chain reaction (RT PCR) analysis to assay gene expression. The gene function was validated by sequence dissimilarity analysis and QTL mapping using a functional cleaved amplified polymorphism (CAP). CONCLUSIONS: The leaf angle is controlled by a major quantitative trait locus, ZmTAC1 (Zea mays L. Leaf Angle Control 1). ZmTAC1 has 4 exons encoding a protein with 263 amino acids, and its domains are the same as those of the rice OsTAC1 protein. ZmTAC1 was found to be located in the region of qLA2 by using the CAP marker and the F(2:3) families from the cross between Yu82 and Shen137. Real-time PCR analysis revealed ZmTAC1 expression was the highest in the leaf-sheath pulvinus, less in the leaf and shoot apical meristem, and the lowest in the root. A nucleotide difference in the 5'-untranslated region (UTR) between the compact inbred line Yu82 ("CTCC") and the expanded inbred line Shen137 ("CCCC") influences the expression level of ZmTAC1, further controlling the size of the leaf angle. Sequence verification of the change in the 5'-UTR revealed ZmTAC1 with "CTCC" was present in 13 compact inbred lines and ZmTAC1 with "CCCC" was present in 18 expanded inbred lines, indicating ZmTAC1 had been extensively utilized in breeding with regard to the improvement of the maize plant architecture. PMID- 21687734 TI - Association between urinary excretion of cortisol and markers of oxidatively damaged DNA and RNA in humans. AB - Chronic psychological stress is associated with accelerated aging, but the underlying biological mechanisms are not known. Prolonged elevations of the stress hormone cortisol is suspected to play a critical role. Through its actions, cortisol may potentially induce oxidatively generated damage to cellular constituents such as DNA and RNA, a phenomenon which has been implicated in aging processes. We investigated the relationship between 24 h excretion of urinary cortisol and markers of oxidatively generated DNA and RNA damage, 8-oxo-7,8 dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydroguanosine, in a sample of 220 elderly men and women (age 65-83 years). We found a robust association between the excretion of cortisol and the oxidation markers (R(2) = 0.15, P<0.001 for both markers). Individuals in the highest quartile of cortisol excretion had a 57% and 61% higher median excretion of the DNA and RNA oxidation marker, respectively, than individuals in the lowest quartile. The finding adds support to the hypothesis that cortisol-induced damage to DNA/RNA is an explanatory factor in the complex relation between stress, aging and disease. PMID- 21687736 TI - Enhanced immunogenicity, mortality protection, and reduced viral brain invasion by alum adjuvant with an H5N1 split-virion vaccine in the ferret. AB - BACKGROUND: Pre-pandemic development of an inactivated, split-virion avian influenza vaccine is challenged by the lack of pre-existing immunity and the reduced immunogenicity of some H5 hemagglutinins compared to that of seasonal influenza vaccines. Identification of an acceptable effective adjuvant is needed to improve immunogenicity of a split-virion avian influenza vaccine. METHODS AND FINDINGS: Ferrets (N = 118) were vaccinated twice with a split-virion vaccine preparation of A/Vietnam/1203/2004 or saline either 21 days apart (unadjuvanted: 1.9 ug, 7.5 ug, 30 ug, or saline), or 28 days apart (unadjuvanted: 22.5 ug, or alum-adjuvanted: 22.5 or 7.5 ug). Vaccinated animals were challenged intranasally 21 or 28 days later with 10(6) EID(50) of the homologous strain. Immunogenicity was measured by hemagglutination inhibition and neutralization assays. Morbidity was assessed by observed behavior, weight loss, temperature, cytopenias, histopathology, and viral load. No serum antibodies were detected after vaccination with unadjuvanted vaccine, whereas alum-adjuvanted vaccination induced a robust antibody response. Survival after unadjuvanted dose regimens of 30 ug, 7.5 ug and 1.9 ug (21-day intervals) was 64%, 43%, and 43%, respectively, yet survivors experienced weight loss, fever and thrombocytopenia. Survival after unadjuvanted dose regimen of 22.5 ug (28-day intervals) was 0%, suggesting important differences in intervals in this model. In contrast to unadjuvanted survivors, either dose of alum-adjuvanted vaccine resulted in 93% survival with minimal morbidity and without fever or weight loss. The rarity of brain inflammation in alum-adjuvanted survivors, compared to high levels in unadjuvanted vaccine survivors, suggested that improved protection associated with the alum adjuvant was due to markedly reduced early viral invasion of the ferret brain. CONCLUSION: Alum adjuvant significantly improves efficacy of an H5N1 split-virion vaccine in the ferret model as measured by immunogenicity, mortality, morbidity, and brain invasion. PMID- 21687737 TI - 3, 3'5 Triiodo L thyronine induces apoptosis in human breast cancer MCF-7 cells, repressing SMP30 expression through negative thyroid response elements. AB - BACKGROUND: Thyroid hormones regulate cell proliferation, differentiation as well as apoptosis. However molecular mechanism underlying apoptosis as a result of thyroid hormone signaling is poorly understood. The antiapoptotic role of Senescence Marker Protein-30 (SMP30) has been characterized in response to varieties of stimuli as well as in knock out model. Our earlier data suggest that thyroid hormone 3, 3'5 Triiodo L Thyronine (T(3)), represses SMP30 in rat liver. METHODOLOGY/PRINCIPAL FINDINGS: In highly metastatic MCF-7, human breast cancer cell line T3 treatment repressed SMP30 expression leading to enhanced apoptosis. Analysis by flow cytometry and other techniques revealed that overexpression and silencing of SMP30 in MCF-7 resulted in decelerated and accelerated apoptosis respectively. In order to identify the cis-acting elements involved in this regulation, we have analyzed hormone responsiveness of transiently transfected hSMP30 promoter deletion reporter vectors in MCF-7 cells. As opposed to the expected epigenetic outcome, thyroid hormone down regulated hSMP30 promoter activity despite enhanced recruitment of acetylated H3 on thyroid response elements (TREs). From the stand point of established epigenetic concept we have categorised these two TREs as negative response elements. Our attempt of siRNA mediated silencing of TRbeta, reduced the fold of repression of SMP30 gene expression. In presence of thyroid hormone, Trichostatin- A (TSA), which is a Histone deacetylase (HDAC) inhibitor further inhibited SMP30 promoter activity. The above findings are in support of categorisation of both the thyroid response element as negative response elements as usually TSA should have reversed the repressions. CONCLUSION: This is the first report of novel mechanistic insights into the remarkable downregulation of SMP30 gene expression by thyroid hormone which in turn induces apoptosis in MCF-7 human breast cancer cells. We believe that our study represents a good ground for future effort to develop new therapeutic approaches to challenge the progression of breast cancer. PMID- 21687738 TI - Differential expression of PGC-1alpha and metabolic sensors suggest age-dependent induction of mitochondrial biogenesis in Friedreich ataxia fibroblasts. AB - BACKGROUND: Friedreich's ataxia (FRDA) is a mitochondrial rare disease, which molecular origin is associated with defect in the expression of frataxin. The pathological consequences are degeneration of nervous system structures and cardiomyopathy with necrosis and fibrosis, among others. PRINCIPAL FINDINGS: Using FRDA fibroblasts we have characterized the oxidative stress status and mitochondrial biogenesis. We observed deficiency of MnSOD, increased ROS levels and low levels of ATP. Expression of PGC-1alpha and mtTFA was increased and the active form of the upstream signals p38 MAPK and AMPK in fibroblasts from two patients. Interestingly, the expression of energetic factors correlated with the natural history of disease of the patients, the age when skin biopsy was performed and the size of the GAA expanded alleles. Furthermore, idebenone inhibit mitochondriogenic responses in FRDA cells. CONCLUSIONS: The induction of mitochondrial biogenesis in FRDA may be a consequence of the mitochondrial impairment associated with disease evolution. The increase of ROS and the involvement of the oxidative phosphorylation may be an early event in the cell pathophysiology of frataxin deficiency, whereas increase of mitochondriogenic response might be a later phenomenon associated to the individual age and natural history of the disease, being more evident as the patient age increases and disease evolves. This is a possible explanation of heart disease in FRDA. PMID- 21687739 TI - Temporal analysis of the honey bee microbiome reveals four novel viruses and seasonal prevalence of known viruses, Nosema, and Crithidia. AB - Honey bees (Apis mellifera) play a critical role in global food production as pollinators of numerous crops. Recently, honey bee populations in the United States, Canada, and Europe have suffered an unexplained increase in annual losses due to a phenomenon known as Colony Collapse Disorder (CCD). Epidemiological analysis of CCD is confounded by a relative dearth of bee pathogen field studies. To identify what constitutes an abnormal pathophysiological condition in a honey bee colony, it is critical to have characterized the spectrum of exogenous infectious agents in healthy hives over time. We conducted a prospective study of a large scale migratory bee keeping operation using high-frequency sampling paired with comprehensive molecular detection methods, including a custom microarray, qPCR, and ultra deep sequencing. We established seasonal incidence and abundance of known viruses, Nosema sp., Crithidia mellificae, and bacteria. Ultra deep sequence analysis further identified four novel RNA viruses, two of which were the most abundant observed components of the honey bee microbiome (~10(11) viruses per honey bee). Our results demonstrate episodic viral incidence and distinct pathogen patterns between summer and winter time-points. Peak infection of common honey bee viruses and Nosema occurred in the summer, whereas levels of the trypanosomatid Crithidia mellificae and Lake Sinai virus 2, a novel virus, peaked in January. PMID- 21687740 TI - A novel network profiling analysis reveals system changes in epithelial mesenchymal transition. AB - Patient-specific analysis of molecular networks is a promising strategy for making individual risk predictions and treatment decisions in cancer therapy. Although systems biology allows the gene network of a cell to be reconstructed from clinical gene expression data, traditional methods, such as bayesian networks, only provide an averaged network for all samples. Therefore, these methods cannot reveal patient-specific differences in molecular networks during cancer progression. In this study, we developed a novel statistical method called NetworkProfiler, which infers patient-specific gene regulatory networks for a specific clinical characteristic, such as cancer progression, from gene expression data of cancer patients. We applied NetworkProfiler to microarray gene expression data from 762 cancer cell lines and extracted the system changes that were related to the epithelial-mesenchymal transition (EMT). Out of 1732 possible regulators of E-cadherin, a cell adhesion molecule that modulates the EMT, NetworkProfiler, identified 25 candidate regulators, of which about half have been experimentally verified in the literature. In addition, we used NetworkProfiler to predict EMT-dependent master regulators that enhanced cell adhesion, migration, invasion, and metastasis. In order to further evaluate the performance of NetworkProfiler, we selected Krueppel-like factor 5 (KLF5) from a list of the remaining candidate regulators of E-cadherin and conducted in vitro validation experiments. As a result, we found that knockdown of KLF5 by siRNA significantly decreased E-cadherin expression and induced morphological changes characteristic of EMT. In addition, in vitro experiments of a novel candidate EMT related microRNA, miR-100, confirmed the involvement of miR-100 in several EMT related aspects, which was consistent with the predictions obtained by NetworkProfiler. PMID- 21687741 TI - Surface hardness impairment of quorum sensing and swarming for Pseudomonas aeruginosa. AB - The importance of rhamnolipid to swarming of the bacterium Pseudomonas aeruginosa is well established. It is frequently, but not exclusively, observed that P. aeruginosa swarms in tendril patterns--formation of these tendrils requires rhamnolipid. We were interested to explain the impact of surface changes on P. aeruginosa swarm tendril development. Here we report that P. aeruginosa quorum sensing and rhamnolipid production is impaired when growing on harder semi-solid surfaces. P. aeruginosa wild-type swarms showed huge variation in tendril formation with small deviations to the "standard" swarm agar concentration of 0.5%. These macroscopic differences correlated with microscopic investigation of cells close to the advancing swarm edge using fluorescent gene reporters. Tendril swarms showed significant rhlA-gfp reporter expression right up to the advancing edge of swarming cells while swarms without tendrils (grown on harder agar) showed no rhlA-gfp reporter expression near the advancing edge. This difference in rhamnolipid gene expression can be explained by the necessity of quorum sensing for rhamnolipid production. We provide evidence that harder surfaces seem to limit induction of quorum sensing genes near the advancing swarm edge and these localized effects were sufficient to explain the lack of tendril formation on hard agar. We were unable to artificially stimulate rhamnolipid tendril formation with added acyl-homoserine lactone signals or increasing the carbon nutrients. This suggests that quorum sensing on surfaces is controlled in a manner that is not solely population dependent. PMID- 21687742 TI - Green crab (Carcinus maenas) foraging efficiency reduced by fast flows. AB - Predators can strongly influence prey populations and the structure and function of ecosystems, but these effects can be modified by environmental stress. For example, fluid velocity and turbulence can alter the impact of predators by limiting their environmental range and altering their foraging ability. We investigated how hydrodynamics affected the foraging behavior of the green crab (Carcinus maenas), which is invading marine habitats throughout the world. High flow velocities are known to reduce green crab predation rates and our study sought to identify the mechanisms by which flow affects green crabs. We performed a series of experiments with green crabs to determine: 1) if their ability to find prey was altered by flow in the field, 2) how flow velocity influenced their foraging efficiency, and 3) how flow velocity affected their handling time of prey. In a field study, we caught significantly fewer crabs in baited traps at sites with fast versus slow flows even though crabs were more abundant in high flow areas. This finding suggests that higher velocity flows impair the ability of green crabs to locate prey. In laboratory flume assays, green crabs foraged less efficiently when flow velocity was increased. Moreover, green crabs required significantly more time to consume prey in high velocity flows. Our data indicate that flow can impose significant chemosensory and physical constraints on green crabs. Hence, hydrodynamics may strongly influence the role that green crabs and other predators play in rocky intertidal communities. PMID- 21687743 TI - Immunogenicity and efficacy of flagellin-fused vaccine candidates targeting 2009 pandemic H1N1 influenza in mice. AB - We have previously demonstrated that the globular head of the hemagglutinin (HA) antigen fused to flagellin of Salmonella typhimurium fljB (STF2, a TLR5 ligand) elicits protective immunity to H1N1 and H5N1 lethal influenza infections in mice (Song et al., 2008, PLoS ONE 3, e2257; Song et al., 2009, Vaccine 27, 5875-5888). These fusion proteins can be efficiently and economically manufactured in E. coli fermentation systems as next generation pandemic and seasonal influenza vaccines. Here we report immunogenicity and efficacy results of three vaccine candidates in which the HA globular head of A/California/07/2009 (H1N1) was fused to STF2 at the C-terminus (STF2.HA1), in replace of domain 3 (STF2R3.HA1), or in both positions (STF2R3.2xHA1). For all three vaccines, two subcutaneous immunizations of BALB/c mice with doses of either 0.3 or 3 ug elicit robust neutralizing (HAI) antibodies, that lead to > = 2 Log(10) unit reduction in day 4 lung virus titer and full protection against a lethal A/California/04/2009 challenge. Vaccination with doses as low as 0.03 ug results in partial to full protection. Each candidate, particularly the STF2R3.HA1 and STF2R3.2xHA1 candidates, elicits robust neutralizing antibody responses that last for at least 8 months. The STF2R3.HA1 candidate, which was intermediately protective in the challenge models, is more immunogenic than the H1N1 components of two commercially available trivalent inactivated influenza vaccines (TIVs) in mice. Taken together, the results demonstrate that all three vaccine candidates are highly immunogenic and efficacious in mice, and that the STF2R3.2xHA1 format is the most effective candidate vaccine format. PMID- 21687744 TI - Interaction of beta-sheet folds with a gold surface. AB - The adsorption of proteins on inorganic surfaces is of fundamental biological importance. Further, biomedical and nanotechnological applications increasingly use interfaces between inorganic material and polypeptides. Yet, the underlying adsorption mechanism of polypeptides on surfaces is not well understood and experimentally difficult to analyze. Therefore, we investigate here the interactions of polypeptides with a gold(111) surface using computational molecular dynamics (MD) simulations with a polarizable gold model in explicit water. Our focus in this paper is the investigation of the interaction of polypeptides with beta-sheet folds. First, we concentrate on a beta-sheet forming model peptide. Second, we investigate the interactions of two domains with high beta-sheet content of the biologically important extracellular matrix protein fibronectin (FN). We find that adsorption occurs in a stepwise mechanism both for the model peptide and the protein. The positively charged amino acid Arg facilitates the initial contact formation between protein and gold surface. Our results suggest that an effective gold-binding surface patch is overall uncharged, but contains Arg for contact initiation. The polypeptides do not unfold on the gold surface within the simulation time. However, for the two FN domains, the relative domain-domain orientation changes. The observation of a very fast and strong adsorption indicates that in a biological matrix, no bare gold surfaces will be present. Hence, the bioactivity of gold surfaces (like bare gold nanoparticles) will critically depend on the history of particle administration and the proteins present during initial contact between gold and biological material. Further, gold particles may act as seeds for protein aggregation. Structural re-organization and protein aggregation are potentially of immunological importance. PMID- 21687745 TI - Controlling attention to nociceptive stimuli with working memory. AB - BACKGROUND: Because pain often signals the occurrence of potential tissue damage, a nociceptive stimulus has the capacity to involuntarily capture attention and take priority over other sensory inputs. Whether distraction by nociception actually occurs may depend upon the cognitive characteristics of the ongoing activities. The present study tested the role of working memory in controlling the attentional capture by nociception. METHODOLOGY AND PRINCIPAL FINDINGS: Participants performed visual discrimination and matching tasks in which visual targets were shortly preceded by a tactile distracter. The two tasks were chosen because of the different effects the involvement of working memory produces on performance, in order to dissociate the specific role of working memory in the control of attention from the effect of general resource demands. Occasionally (i.e. 17% of the trials), tactile distracters were replaced by a novel nociceptive stimulus in order to distract participants from the visual tasks. Indeed, in the control conditions (no working memory), reaction times to visual targets were increased when the target was preceded by a novel nociceptive distracter as compared to the target preceded by a frequent tactile distracter, suggesting attentional capture by the novel nociceptive stimulus. However, when the task required an active rehearsal of the visual target in working memory, the novel nociceptive stimulus no longer induced a lengthening of reaction times to visual targets, indicating a reduction of the distraction produced by the novel nociceptive stimulus. This effect was independent of the overall task demands. CONCLUSION AND SIGNIFICANCE: Loading working memory with pain-unrelated information may reduce the ability of nociceptive input to involuntarily capture attention, and shields cognitive processing from nociceptive distraction. An efficient control of attention over pain is best guaranteed by the ability to maintain active goal priorities during achievement of cognitive activities and to keep pain-related information out of task settings. PMID- 21687746 TI - Continuous non-invasive monitoring of tidal volumes by measurement of tidal impedance in neonatal piglets. AB - BACKGROUND: Electrical Impedance measurements can be used to estimate the content of intra-thoracic air and thereby give information on pulmonary ventilation. Conventional Impedance measurements mainly indicate relative changes, but no information concerning air-volume is given. The study was performed to test whether a 3-point-calibration with known tidal volumes (VT) during conventional mechanical ventilation (CMV) allows subsequent calculation of VT from total Tidal Impedance (tTI) measurements using Quadrant Impedance Measurement (QIM). In addition the distribution of TI in different regions of the thorax was examined. METHODOLOGY AND PRINCIPAL FINDINGS: QIM was performed in five neonatal piglets during volume-controlled CMV. tTI values at three different VT (4, 6, 8 ml/kg) were used to establish individual calibration curves. Subsequently, each animal was ventilated with different patterns of varying VT (2-10 ml/kg) at different PEEP levels (0, 3, 6, 9, 12 cmH(2)O). VT variation was repeated after surfactant depletion by bronchoalveolar lavage. VT was calculated from tTI values (VT(calc)) and compared to the VT delivered by the ventilator (VT(PNT)). Bland-Altman analysis revealed good agreement between VT(calc) and VT(PNT) before (bias -0.08 ml; limits of agreement -1.18 to 1.02 ml at PEEP = 3 cmH(2)O) and after surfactant depletion (bias -0.17 ml; limits of agreement -1.57 to 1.22 ml at PEEP = 3 cmH(2)O). At higher PEEP levels VT(calc) was lower than VT(PNT), when only one fixed calibration curve (at PEEP 3 cmH(2)O) was used. With a new calibration curve at each PEEP level the method showed similar accuracy at each PEEP level. TI showed a homogeneous distribution over the four assessed quadrants with a shift toward caudal regions of the thorax with increasing VT. CONCLUSION: Tidal Impedance values could be used for precise and accurate calculation of VT during CMV in this animal study, when calibrated at each PEEP level. PMID- 21687748 TI - Profiles of Microbial Fatty Acids in the Human Metabolome are Disease-Specific. AB - The human gastrointestinal tract is inhabited by a diverse and dense symbiotic microbiota, the composition of which is the result of host-microbe co-evolution and co-adaptation. This tight integration creates intense cross-talk and signaling between the host and microbiota at the cellular and metabolic levels. In many genetic or infectious diseases the balance between host and microbiota may be compromised resulting in erroneous communication. Consequently, the composition of the human metabolome, which includes the gut metabolome, may be different in health and disease states in terms of microbial products and metabolites entering systemic circulation. To test this hypothesis, we measured the level of hydroxy, branched, cyclopropyl and unsaturated fatty acids, aldehydes, and phenyl derivatives in blood of patients with a hereditary autoinflammatory disorder, familial Mediterranean fever (FMF), and in patients with peptic ulceration (PU) resulting from Helicobacter pylori infection. Discriminant function analysis of a data matrix consisting of 94 cases as statistical units (37 FMF patients, 14 PU patients, and 43 healthy controls) and the concentration of 35 microbial products in the blood as statistical variables revealed a high accuracy of the proposed model (all cases were correctly classified). This suggests that the profile of microbial products and metabolites in the human metabolome is specific for a given disease and may potentially serve as a biomarker for disease. PMID- 21687747 TI - Exploitation of host cell biology and evasion of immunity by francisella tularensis. AB - Francisella tularensis is an intracellular bacterium that infects humans and many small mammals. During infection, F. tularensis replicates predominantly in macrophages but also proliferate in other cell types. Entry into host cells is mediate by various receptors. Complement-opsonized F. tularensis enters into macrophages by looping phagocytosis. Uptake is mediated in part by Syk, which may activate actin rearrangement in the phagocytic cup resulting in the engulfment of F. tularensis in a lipid raft rich phagosome. Inside the host cells, F. tularensis resides transiently in an acidified late endosome-like compartment before disruption of the phagosomal membrane and escape into the cytosol, where bacterial proliferation occurs. Modulation of phagosome biogenesis and escape into the cytosol is mediated by the Francisella pathogenicity island-encoded type VI-like secretion system. Whilst inside the phagosome, F. tularensis temporarily induce proinflammatory cytokines in PI3K/Akt-dependent manner, which is counteracted by the induction of SHIP that negatively regulates PI3K/Akt activation and promotes bacterial escape into the cytosol. Interestingly, F. tularensis subverts CD4 T cells-mediated killing by inhibiting antigen presentation by activated macrophages through ubiquitin-dependent degradation of MHC II molecules on activated macrophages. In the cytosol, F. tularensis is recognized by the host cell inflammasome, which is down-regulated by F. tularensis that also inhibits caspase-1 and ASC activity. During late stages of intracellular proliferation, caspase-3 is activated but apoptosis is delayed through activation of NF-kappaB and Ras, which ensures cell viability. PMID- 21687749 TI - Therapeutic effects of hydrogen in animal models of Parkinson's disease. AB - Since the first description of Parkinson's disease (PD) nearly two centuries ago, a number of studies have revealed the clinical symptoms, pathology, and therapeutic approaches to overcome this intractable neurodegenerative disease. 1 methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are neurotoxins which produce Parkinsonian pathology. From the animal studies using these neurotoxins, it has become well established that oxidative stress is a primary cause of, and essential for, cellular apoptosis in dopaminergic neurons. Here, we describe the mechanism whereby oxidative stress evokes irreversible cell death, and propose a novel therapeutic strategy for PD using molecular hydrogen. Hydrogen has an ability to reduce oxidative damage and ameliorate the loss of nigrostriatal dopaminergic neuronal pathway in two experimental animal models. Thus, it is strongly suggested that hydrogen might provide a great advantage to prevent or minimize the onset and progression of PD. PMID- 21687750 TI - Sleep Duration and "on" Time during Different Periods of the Day and Night in Patients with Advanced Parkinson's Disease Receiving Adjunctive Ropinirole Prolonged Release. AB - Patients undergoing long-term therapy for PD often experience motor fluctuations and nocturnal disturbances. In a post-hoc analysis, we explored effects of ropinirole prolonged release on sleep, night-time awakenings, and "on" time over 24 hours. Patients with advanced PD suboptimally controlled with L-dopa were randomized to adjunctive ropinirole prolonged release (2-24 mg/day) or placebo for 24 weeks. Awake/asleep and, if awake, "on"/"off" status was recorded via diary cards. At week 24 last observation carried forward, changes in nighttime or daytime sleep duration were not significantly different between treatments. Of patients with baseline awakenings, a significantly higher proportion in the ropinirole prolonged release group had a reduction in awakenings versus placebo. Patients receiving ropinirole prolonged release had a significantly greater increase in amount/percentage of awake time "on"/"on" without troublesome dyskinesia during all periods assessed (including night-time and early morning), versus placebo, and higher odds for being "on" on waking. Adjunctive once-daily ropinirole prolonged release may help provide 24-hour symptom control in patients with advanced PD not optimally controlled with L-dopa. PMID- 21687751 TI - Adherence to and invasion of host cells by spotted Fever group rickettsia species. AB - The pathogenic lifecycle of obligate intracellular bacteria presents a superb opportunity to develop understanding of the interaction between the bacteria and host under the pretext that disruption of these processes will likely lead to death of the pathogen and prevention of associated disease. Species of the genus Rickettsia contain some of the most hazardous of the obligate intracellular bacteria, including Rickettsia rickettsii and R. conorii the causative agents of Rocky Mountain and Mediterranean spotted fevers, respectively. Spotted fever group Rickettsia species commonly invade and thrive within cells of the host circulatory system whereby the endothelial cells are severely perturbed. The subsequent disruption of circulatory continuity results in much of the severe morbidity and mortality associated with these diseases, including macropapular dermal rash, interstitial pneumonia, acute renal failure, pulmonary edema, and other multisystem manifestations. This review describes current knowledge of the essential pathogenic processes of adherence to and invasion of host cells, efforts to disrupt these processes, and potential for disease prevention through vaccination with recently identified bacterial adherence and invasion proteins. A more complete understanding of these bacterial proteins will provide an opportunity for prevention and treatment of spotted fever group Rickettsia infections. PMID- 21687752 TI - Olfactory loss in Parkinson's disease. AB - Impairment of olfaction is a characteristic and early feature of Parkinson's disease. Recent data indicate that >95% of patients with Parkinson's disease present with significant olfactory loss. Deficits in the sense of smell may precede clinical motor symptoms by years and can be used to assess the risk for developing Parkinson's disease in otherwise asymptomatic individuals. This paper summarizes the available information about olfactory function in Parkinson's disease, indicating the advantageous use of olfactory probes in early and differential diagnosis. PMID- 21687754 TI - Nonmotor symptoms groups in Parkinson's disease patients: results of a pilot, exploratory study. AB - Nonmotor symptoms (NMS) like neuropsychiatric symptoms, sleep disturbances or autonomic symptoms are a common feature of Parkinson's disease (PD). To explore the existence of groups of NMS and to relate them to PD characteristics, 71 idiopathic non-demented PD out-patients were recruited. Sleep was evaluated by the PD Sleep Scale (PDSS). Several neuropsychiatric, gastrointestinal and urogenital symptoms were obtained from the NMSQuest. Sialorrhea or dysphagia severity was obtained from the Unified PD Rating Scale activities of daily living section. MADRS depression scale was also administered. Exploratory factor analysis revealed the presence of 5 factors, explaining 70% of variance. The first factor included PDSS measurement of sleep quality, nocturnal restlessness, off-related problems and daytime somnolence; the second factor included nocturia (PDSS) and nocturnal activity; the third one included gastrointestinal and genitourinary symptoms; the forth one included nocturnal psychosis (PDSS), sialorrhea and dysphagia (UPDRS); and the last one included the MADRS score as well as neuropsychiatric symptoms. Sleep disorders correlated with presence of wearing-off, nocturia with age >69 years, and nocturnal psychosis with levodopa equivalent dose or UPDRS II score. Neuropsychiatric symptoms correlated with UPDRS II+III score and non-tricyclic antidepressants. These results support the occurrence of significant NMS grouping in PD patients. PMID- 21687755 TI - Host-mediated post-translational prenylation of novel dot/icm-translocated effectors of legionella pneumophila. AB - The Dot/Icm type IV translocated Ankyrin B (AnkB) effector of Legionella pneumophila is modified by the host prenylation machinery that anchors it into the outer leaflet of the Legionella-containing vacuole (LCV), which is essential for biological function of the effector in vitro and in vivo. Prenylation involves the covalent linkage of an isoprenoid lipid moiety to a C-terminal CaaX motif in eukaryotic proteins enabling their anchoring into membranes. We show here that the LCV harboring an ankB null mutant is decorated with prenylated proteins in a Dot/Icm-dependent manner, indicating that other LCV membrane anchored proteins are prenylated. In silico analyses of four sequenced L. pneumophila genomes revealed the presence of eleven other genes that encode proteins with a C-terminal eukaryotic CaaX prenylation motif. Of these eleven designated Prenylated effectors of Legionella (Pel), seven are also found in L. pneumophila AA100. We show that six L. pneumophila AA100 Pel proteins exhibit distinct cellular localization when ectopically expressed in mammalian cells and this is dependent on action of the host prenylation machinery and the conserved cysteine residue of the CaaX motif. Although inhibition of the host prenylation machinery completely blocks intra-vacuolar proliferation of L. pneumophila, it only had a modest effect on intracellular trafficking of the LCV. Five of the Pel proteins are injected into human macrophages by the Dot/Icm type IV translocation system of L. pneumophila. Taken together, the Pel proteins are novel Dot/Icm translocated effectors of L. pneumophila that are post-translationally modified by the host prenylation machinery, which enables their anchoring into cellular membranes, and the prenylated effectors contribute to evasion of lysosomal fusion by the LCV. PMID- 21687753 TI - The Role of the Francisella Tularensis Pathogenicity Island in Type VI Secretion, Intracellular Survival, and Modulation of Host Cell Signaling. AB - Francisella tularensis is a highly virulent gram-negative intracellular bacterium that causes the zoonotic disease tularemia. Essential for its virulence is the ability to multiply within host cells, in particular monocytic cells. The bacterium has developed intricate means to subvert host immune mechanisms and thereby facilitate its intracellular survival by preventing phagolysosomal fusion followed by escape into the cytosol, where it multiplies. Moreover, it targets and manipulates numerous host cell signaling pathways, thereby ameliorating the otherwise bactericidal capacity. Many of the underlying molecular mechanisms still remain unknown but key elements, directly or indirectly responsible for many of the aforementioned mechanisms, rely on the expression of proteins encoded by the Francisella pathogenicity island (FPI), suggested to constitute a type VI secretion system. We here describe the current knowledge regarding the components of the FPI and the roles that have been ascribed to them. PMID- 21687756 TI - Circadian clock proteins in prokaryotes: hidden rhythms? AB - Circadian clock genes are vital features of eukaryotes that have evolved such that organisms can adapt to our planet's rotation in order to anticipate the coming day or night as well as unfavorable seasons. This circadian clock uses oscillation as a timekeeping element. However, circadian clock mechanisms exist also in prokaryotes. The circadian clock of Cyanobacteria is well studied. It is regulated by a cluster of three genes: kaiA, kaiB, and kaiC. In this review, we will discuss the circadian system in cyanobacteria, and provide an overview and updated phylogenetic analysis of prokaryotic organisms that contain the main circadian genes. It is evident that the evolution of the kai genes has been influenced by lateral transfers but further and deeper studies are needed to get an in depth understanding of the exact evolutionary history of these genes. Interestingly, Legionella pneumophila an environmental bacterium and opportunistic human pathogen that parasitizes protozoa in fresh water environments also contains kaiB and kaiC, but their functions are not known. All of the residues described for the biochemical functions of the main pacemaker KaiC in Synechococcus elongatus are also conserved in the L. pneumophila KaiC protein. PMID- 21687757 TI - Influence of different cut-off values on the diagnosis of mild cognitive impairment in Parkinson's disease. AB - Comparable to Alzheimer's disease, mild cognitive impairment in Parkinson's disease (PD-MCI) is associated with an increased risk for dementia. However different definitions of PD-MCI may have varying predictive accuracy for dementia. In a cohort of 101 nondemented Parkinson patients who underwent neuropsychological testing, the frequency of PD-MCI subjects and PD-MCI subtypes (i.e., amnestic/nonamnestic) was determined by use of varying healthy population based cut-off values. We also investigated the association between defined PD-MCI groups and ADL scales. Varying cut-off values for the definition of PD-MCI were found to affect frequency of PD-MCI subjects (9.9%-92.1%) and, maybe more important, lead to a "shift" of proportion of detected PD-MCI subtypes especially within the amnestic single-domain subtype. Models using a strict cut-off value were significantly associated with lower ADL scores. Thus, the use of defined cut off values for the definition of PD-MCI is highly relevant for comparison purposes. Strict cut-off values may have a higher predictive value for dementia. PMID- 21687758 TI - Exploitation of Host Polyubiquitination Machinery through Molecular Mimicry by Eukaryotic-Like Bacterial F-Box Effectors. AB - Microbial pathogens have evolved exquisite mechanisms to interfere and intercept host biological processes, often through molecular mimicry of specific host proteins. Ubiquitination is a highly conserved eukaryotic post-translational modification essential in determining protein fate, and is often hijacked by pathogenic bacteria. The conserved SKP1/CUL1/F-box (SCF) E3 ubiquitin ligase complex plays a key role in ubiquitination of proteins in eukaryotic cells. The F box protein component of the SCF complex provides specificity to ubiquitination by binding to specific cellular proteins, targeting them to be ubiquitinated by the SCF complex. The bacterial pathogens. Legionella pneumophila, Agrobacterium tumefaciens, and Ralstonia solanacearum utilize type III or IV translocation systems to inject into the host cell eukaryotic-like F-box effectors that interact with the host SKP1 component of the SCF complex to trigger ubiquitination of specific host cells targets, which is essential to promote proliferation of these pathogens. Our bioinformatic analyses have identified at least 74 genes encoding putative F-box proteins belonging to 22 other bacterial species, including human pathogens, plant pathogens, and amebal endosymbionts. Therefore, subversion of the host ubiquitination machinery by bacterial F-box proteins may be a widespread strategy amongst pathogenic bacteria. The findings that bacterial F-box proteins harbor Ankyrin repeats as protein-protein interaction domains, which are present in F-box proteins of primitive but not higher eukaryotes, suggest acquisition of many bacterial F-box proteins from primitive eukaryotic hosts rather than the mammalian host. PMID- 21687759 TI - A brief history of the antibiotic era: lessons learned and challenges for the future. AB - This article gives a very brief overview of the antibiotic era, beginning from the discovery of first antibiotics until the present day situation, which is marred by the emergence of hard-to-treat multiple antibiotic-resistant infections. The ways of responding to the antibiotic resistance challenges such as the development of novel strategies in the search for new antimicrobials, designing more effective preventive measures and, importantly, better understanding the ecology of antibiotics and antibiotic resistance are discussed. The expansion of conceptual frameworks based on recent developments in the field of antimicrobials, antibiotic resistance, and chemotherapy is also discussed. PMID- 21687760 TI - Relationships between Cytokine Profiles and Signaling Pathways (IkappaB Kinase and p38 MAPK) in Parainfluenza Virus-Infected Lung Fibroblasts. AB - Respiratory viruses such as parainfluenza virus (PIV) in individuals with certain genetic predispositions in early life are associated with the induction of wheezing, which can progress to the development of asthma. It has been suggested that aberrant production of various cytokines due to viral infection are associated with virus-induced asthma. However, the mechanisms of how respiratory viruses induce and exacerbate asthma have yet to be clarified. To examine cytokine responses to PIV infection, we assessed 27 cytokine levels released from PIV-infected human fetal lung fibroblasts. In addition, we examined relationships between these cytokine responses and signaling pathways (IkappaB kinase and p38 MAPK) in PIV-infected cells. At 24 h after infection, PIV-infected cells significantly released a number of cytokines, namely, proinflammatory cytokines [interleukins (IL)-1beta, IL-6, and tumor necrosis factor-alpha], anti inflammatory cytokine (IL-1ra), Th1 cytokines (interferon-gamma, and IL-2), Th2 cytokines (IL-4, IL-5, and IL-10), granulopoiesis-inducing cytokines (granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor), neutrophil recruitment-inducing cytokines (IL-8 and interferon-inducible protein 10), and eosinophil recruitment-inducing cytokines (eotaxin and regulated on activation normal T-cell expressed and secreted). PIV infection enhanced phosphorylation of both IkappaB and p38 MAPK, but not Akt, in the cells. Signaling pathway inhibitors, BMS-345541 (a specific IkappaB kinase inhibitor) and SB203580 (a specific p38 MAPK inhibitor), significantly suppressed release of these cytokines from PIV-infected cells. The results indicate that PIV infection induces aberrant production and release of various cytokines through IkappaB kinase and p38 MAPK pathways in human lung fibroblasts. Overproduction and imbalance of these cytokines may be partially associated with the pathophysiology of virus-induced asthma. PMID- 21687762 TI - Two phosphodiesterases from ustilago maydis share structural and biochemical properties with non-fungal phosphodiesterases. AB - The dependence of Protein Kinase A (PKA) activity on cAMP levels is an important facet of the dimorphic switch between budding and filamentous growth as well as for pathogenicity in some fungi. To better understand these processes in the pathogenic fungus Ustilago maydis, we characterized the structure and biochemical functions of two phosphodiesterase (PDE) genes. Phosphodiesterases are enzymes involved in cAMP turnover and thus, contribute to the regulation of the cAMP-PKA signaling pathway. Two predicted homologs of PDEs were identified in the genome of U. maydis and hypothesized to be involved in cAMP turnover, thus regulating activity of the PKA catalytic subunit. Both umpde1 and umpde2 genes contain domains associated with phosphodiesterase activity predicted by InterPro analysis. Biochemical characterization of recombinantly produced UmPde1 (U. maydis Phosphodiesterase I) and UmPde2 demonstrated that both enzymes have phosphodiesterase activity in vitro, yet neither was inhibited by the phosphodiesterase inhibitor IBMX. Moreover, UmPde1 is specific for cAMP, while UmPde2 has broader substrate specificity, utilizing cAMP and cGMP as substrates. In addition, UmPde2 was also found to have nucleotide phosphatase activity that was higher with GMP compared to AMP. These results demonstrate that UmPde1 is a bona fide phosphodiesterase, while UmPde2 has more general activity as a cyclic nucleotide phosphodiesterase and/or GMP/AMP phosphatase. Thus, UmPde1 and UmPde2 likely have important roles in cell morphology and development and share some characteristics with a variety of non-fungal phosphodiesterases. PMID- 21687761 TI - The involvement of neuroinflammation and kynurenine pathway in Parkinson's disease. AB - Parkinson's disease (PD) is a common neurodegenerative disorder characterised by loss of dopaminergic neurons and localized neuroinflammation occurring in the midbrain several years before the actual onset of symptoms. Activated microglia themselves release a large number of inflammatory mediators thus perpetuating neuroinflammation and neurotoxicity. The Kynurenine pathway (KP), the main catabolic pathway for tryptophan, is one of the major regulators of the immune response and may also be implicated in the inflammatory response in parkinsonism. The KP generates several neuroactive compounds and therefore has either a neurotoxic or neuroprotective effect. Several of these molecules produced by microglia can activate the N-methyl-D-aspartate (NMDA) receptor-signalling pathway, leading to an excitotoxic response. Previous studies have shown that NMDA antagonists can ease symptoms and exert a neuroprotective effect in PD both in vivo and in vitro. There are to date several lines of evidence linking some of the KP intermediates and the neuropathogenesis of PD. Moreover, it is likely that pharmacological modulation of the KP will represent a new therapeutic strategy for PD. PMID- 21687763 TI - Francisella tularensis metabolism and its relation to virulence. AB - Francisella tularensis is a Gram-negative bacterium capable of causing the zoonotic disease tularaemia in a large number of mammalian species and in arthropods. F. tularensis is a facultative intracellular bacterium that infects and replicates in vivo mainly inside macrophages. During its systemic dissemination, F. tularensis must cope with very different life conditions (such as survival in different target organs or tissues and/or survival in the blood stream...) and may thus encounter a broad variety of carbon substrates, nitrogen, phosphor, and sulfur sources, as well as very low concentrations of essential ions. The development of recent genome-wide genetic screens have led to the identification of hundreds of genes participating to variable extents to Francisella virulence. Remarkably, an important proportion of the genes identified are related to metabolic and nutritional functions. However, the relationship between nutrition and the in vivo life cycle of F. tularensis is yet poorly understood. In this review, we will address the importance of metabolism and nutrition for F. tularensis pathogenesis, focusing specifically on amino acid and carbohydrate requirements. PMID- 21687764 TI - Traditional chinese medicine improves activities of daily living in Parkinson's disease. AB - We evaluated the effects of a traditional Chinese medicine (TCM), named Zeng-xiao An-shen Zhi-chan 2 (ZAZ2), on patients with Parkinson's disease (PD). Among 115 patients with idiopathic PD enrolled (mean age, 64.7 +/- 10.2 years old), 110 patients (M = 65, F = 45; mean age, 64.9 +/- 10.7 years old) completed the study. Patients took either ZAZ2 (n = 59) or placebo granule (n = 56) in a blind manner for 13 weeks while maintaining other anti-Parkinson medications unchanged. All participants wore a motion logger, and we analyzed the power-law temporal autocorrelation of the motion logger records taken on 3 occasions (before, one week, and 13 weeks after the drug administration). Drug efficacy was evaluated with the conventional Unified Parkinson Disease Rating Scale (UPDRS), as well as the power-law exponent alpha, which corresponds to the level of physical activity of the patients. ZAZ2 but not placebo granule improved the awake-sleep rhythm, the UPDRS Part II, Part II + III, and Part IV scores, and the alpha values. The results indicate that ZAZ2 improved activities of daily living (ADL) of parkinsonism and, thus, is a potentially suitable drug for long-term use. PMID- 21687765 TI - Defining pathogenic bacterial species in the genomic era. AB - Actual definitions of bacterial species are limited due to the current criteria of definition and the use of restrictive genetic tools. The 16S ribosomal RNA sequence, for example, has been widely used as a marker for phylogenetic analyses; however, its use often leads to misleading species definitions. According to the first genetic studies, removing a certain number of genes from pathogenic bacteria removes their capacity to infect hosts. However, more recent studies have demonstrated that the specialization of bacteria in eukaryotic cells is associated with massive gene loss, especially for allopatric endosymbionts that have been isolated for a long time in an intracellular niche. Indeed, sympatric free-living bacteria often have bigger genomes and exhibit greater resistance and plasticity and constitute species complexes rather than true species. Specialists, such as pathogenic bacteria, escape these bacterial complexes and colonize a niche, thereby gaining a species name. Their specialization allows them to become allopatric, and their gene losses eventually favor reductive genome evolution. A pathogenic species is characterized by a gene repertoire that is defined not only by genes that are present but also by those that are lacking. It is likely that current bacterial pathogens will disappear soon and be replaced by new ones that will emerge from bacterial complexes that are already in contact with humans. PMID- 21687766 TI - Molecular Detection of Legionella: Moving on From mip. AB - The detection of Legionella pneumophila in environmental and clinical samples is frequently performed by PCR amplification of the mip and/or 16S rRNA genes. Combined with DNA sequencing, these two genetic loci can be used to distinguish different species of Legionella and identify L. pneumophila. However, the recent Legionella genome sequences have opened up hundreds of possibilities for the development of new molecular targets for detection and diagnosis. Ongoing comparative genomics has the potential to fine tune the identification of Legionella species and serogroups by combining specific and general genetic targets. For example, the coincident detection of LPS biosynthesis genes and virulence genes may allow the differentiation of both pathogen and serogroup without the need for nucleotide sequencing. We tested this idea using data derived from a previous genomic subtractive hybridization we performed between L. pneumophila serogroup 1 and L. micdadei. Although not yet formally tested, these targets serve as an example of how comparative genomics has the potential to improve the scope and accuracy of Legionella molecular detection if embraced by laboratories undertaking Legionella surveillance. PMID- 21687767 TI - Freshwater Bacteria are Stoichiometrically Flexible with a Nutrient Composition Similar to Seston. AB - Although aquatic bacteria are assumed to be nutrient-rich, they out-compete other foodweb osmotrophs for nitrogen (N) and phosphorus (P) an apparent contradiction to resource ratio theory. This paradox could be resolved if aquatic bacteria were demonstrated to be nutrient-poor relative other portions of the planktonic food web. In a survey of >120 lakes in the upper Midwest of the USA, the nutrient content of bacteria was lower than previously reported and very similar to the Redfield ratio, with a mean biomass composition of 102:12:1 (C:N:P). Individual freshwater bacterial isolates grown under P-limiting and P-replete conditions had even higher C:P and N:P ratios with a mean community biomass composition ratio of 875C:179N:1P suggesting that individual strains can be extremely nutrient-poor, especially with respect to P. Cell-specific measurements of individual cells from one lake confirmed that low P content could be observed at the community level in natural systems with a mean biomass composition of 259C:69N:1P. Variability in bacterial stoichiometry is typically not recognized in the literature as most studies assume constant and nutrient-rich bacterial biomass composition. We present evidence that bacteria can be extremely P-poor in individual systems and in culture, suggesting that bacteria in freshwater ecosystems can either play a role as regenerators or consumers of inorganic nutrients and that this role could switch depending on the relationship between bacterial biomass stoichiometry and resource stoichiometry. This ability to switch roles between nutrient retention and regeneration likely facilitates processing of terrestrial organic matter in lakes and rivers and has important implications for a wide range of bacterially mediated biogeochemical processes. PMID- 21687768 TI - Of Mice and Men: On the Origin of XMRV. AB - The novel human retrovirus xenotropic murine leukemia virus-related virus (XMRV) is arguably the most controversial virus of this moment. After its original discovery in prostate cancer tissue from North American patients, it was subsequently detected in individuals with chronic fatigue syndrome from the same continent. However, most other research groups, mainly from Europe, reported negative results. The positive results could possibly be attributed to contamination with mouse products in a number of cases, as XMRV is nearly identical in nucleotide sequence to endogenous retroviruses in the mouse genome. But the detection of integrated XMRV proviruses in prostate cancer tissue proves it to be a genuine virus that replicates in human cells, leaving the question: how did XMRV enter the human population? We will discuss two possible routes: either via direct virus transmission from mouse to human, as repeatedly seen for, e.g., Hantaviruses, or via the use of mouse-related products by humans, including vaccines. We hypothesize that mouse cells or human cell lines used for vaccine production could have been contaminated with a replicating variant of the XMRV precursors encoded by the mouse genome. PMID- 21687769 TI - Use of a rabbit soft tissue chamber model to investigate campylobacter jejuni host interactions. AB - Despite the prevalence of Campylobacter jejuni as an important food borne pathogen, the microbial factors governing its infection process are poorly characterized. In this study, we developed a novel rabbit soft tissue chamber model to investigate C. jejuni interactions with its host. The in vivo transcriptome profile of C. jejuni was monitored as a function of time post infection by competitive microarray hybridization with cDNA obtained from C. jejuni grown in vitro. Genome-wide expression analysis identified 449 genes expressed at significantly different levels in vivo. Genes implicated to play important roles in early colonization of C. jejuni within the tissue chamber include up-regulation of genes involved in ribosomal protein synthesis and modification, heat shock response, and primary adaptation to the host environment (DccSR regulon). Genes encoding proteins involved in the TCA cycle and flagella related components were found to be significantly down-regulated during early colonization. Oxidative stress defense and stringent response genes were found to be maximally induced during the acute infectious phase. Overall, these findings reveal possible mechanisms involved in adaptation of Campylobacter to the host. PMID- 21687770 TI - The francisella tularensis proteome and its recognition by antibodies. AB - Francisella tularensis is the causative agent of a spectrum of diseases collectively known as tularemia. The extreme virulence of the pathogen in humans, combined with the low infectious dose and the ease of dissemination by aerosol have led to concerns about its abuse as a bioweapon. Until recently, nothing was known about the virulence mechanisms and even now, there is still a relatively poor understanding of pathogen virulence. Completion of increasing numbers of Francisella genome sequences, combined with comparative genomics and proteomics studies, are contributing to the knowledge in this area. Tularemia may be treated with antibiotics, but there is currently no licensed vaccine. An attenuated strain, the Live Vaccine Strain (LVS) has been used to vaccinate military and at risk laboratory personnel, but safety concerns mean that it is unlikely to be licensed by the FDA for general use. Little is known about the protective immunity induced by vaccination with LVS, in humans or animal models. Immunoproteomics studies with sera from infected humans or vaccinated mouse strains, are being used in gel-based or proteome microarray approaches to give insight into the humoral immune response. In addition, these data have the potential to be exploited in the identification of new diagnostic or protective antigens, the design of next generation live vaccine strains, and the development of subunit vaccines. Herein, we briefly review the current knowledge from Francisella comparative proteomics studies and then focus upon the findings from immunoproteomics approaches. PMID- 21687771 TI - Both high and low doses of cocaine derail normal maternal caregiving - lessons from the laboratory rat. PMID- 21687772 TI - Role of phospholipases in fungal fitness, pathogenicity, and drug development - lessons from cryptococcus neoformans. AB - Many pathogenic microbes, including many fungi, produce phospholipases which facilitate survival of the pathogen in vivo, invasion and dissemination throughout the host, expression of virulence traits and evasion of host immune defense mechanisms. These phospholipases are either secreted or produced intracellularly and act by physically disrupting host membranes, and/or by affecting fungal cell signaling and production of immunomodulatory effectors. Many of the secreted phospholipases acquire a glycosylphosphatidylinositol sorting motif to facilitate membrane and/or cell wall association and secretion. This review focuses primarily on the role of two members of the phospholipase enzyme family, phospholipase B (Plb) and phosphatidylinositol (PI)-specific phospholipase C (PI-C/Plc), in fungal pathogenesis and in particular, what has been learnt about their function from studies performed in the model pathogenic yeast, Cryptococcus neoformans. These studies have revealed how Plb has adapted to become an important part of the virulence repertoire of pathogenic fungi and how its secretion is regulated. They have also provided valuable insight into how the intracellular enzyme, Plc1, contributes to fungal fitness and pathogenicity - via a putative role in signal transduction pathways that regulate the production of stress-protecting pigments, polysaccharide capsule, cell wall integrity, and adaptation to growth at host temperature. Finally, this review will address the role fungal phospholipases have played in the development of a new class of antifungal drugs, which mimic their phospholipid substrates. PMID- 21687773 TI - Visual symptoms in Parkinson's disease. AB - Parkinson's disease (PD) is a common disorder of middle-aged and elderly people in which degeneration of the extrapyramidal motor system causes significant movement problems. In some patients, however, there are additional disturbances in sensory systems including loss of the sense of smell and auditory and/or visual problems. This paper is a general overview of the visual problems likely to be encountered in PD. Changes in vision in PD may result from alterations in visual acuity, contrast sensitivity, colour discrimination, pupil reactivity, eye movements, motion perception, visual field sensitivity, and visual processing speeds. Slower visual processing speeds can also lead to a decline in visual perception especially for rapidly changing visual stimuli. In addition, there may be disturbances of visuospatial orientation, facial recognition problems, and chronic visual hallucinations. Some of the treatments used in PD may also have adverse ocular reactions. The pattern electroretinogram (PERG) is useful in evaluating retinal dopamine mechanisms and in monitoring dopamine therapies in PD. If visual problems are present, they can have an important effect on the quality of life of the patient, which can be improved by accurate diagnosis and where possible, correction of such defects. PMID- 21687774 TI - The degenerating substantia nigra as a susceptible region for gene transfer mediated inflammation. AB - Parkinson's disease (PD) is characterized by the progressive degeneration of neurons in the substantia nigra pars compacta (SN). The naive SN is highly susceptible to inflammation. In addition, microglial activation in the degenerating SN displays distinct characteristics that increase the reactivity of the region towards inflammatory stimuli. On the other hand, gene therapy for PD has recently move forward into clinical settings, with PD being the neurodegenerative disorder with the highest number of Phase I/II gene therapy clinical trials approved and completed. These clinical trials are not targeting the SN, but this region is a certain candidate for future gene therapy interventions. Here, the unique immune-related properties of the degenerating SN in the context of a putative gene therapy intervention are reviewed. Several variables affecting the host response to gene delivery such as vector type and dosage, age and stage of disease of patients, and method of gene delivery and transgene used are discussed. Finally, approaches to diminish the risk of immune mediated toxicity by gene transfer in the SN are presented. PMID- 21687775 TI - Replication of Legionella Pneumophila in Human Cells: Why are We Susceptible? AB - Legionella pneumophila is the causative agent of Legionnaires' disease, a serious and often fatal form of pneumonia. The susceptibility to L. pneumophila arises from the ability of this intracellular pathogen to multiply in human alveolar macrophages and monocytes. L. pneumophila also replicates in several professional and non-professional phagocytic human-derived cell lines. With the exception of the A/J mouse strain, most mice strains are restrictive, thus they do not support L. pneumophila replication. Mice lacking the NOD-like receptor Nlrc4 or caspase-1 are also susceptible to L. pneumophila. On the other hand, in the susceptible human hosts, L. pneumophila utilizes several strategies to ensure intracellular replication and protect itself against the host immune system. Most of these strategies converge to prevent the fusion of the L. pneumophila phagosome with the lysosome, inhibiting host cell apoptosis, activating survival pathways, and sequestering essential nutrients for replication and pathogenesis. In this review, we summarize survival mechanisms employed by L. pneumophila to maintain its replication in human cells. In addition, we highlight different human-derived cell lines that support the multiplication of this intracellular bacterium. Therefore, these in vitro models can be applicable and are reproducible when investigating L. pneumophila/phagocyte interactions at the molecular and cellular levels in the human host. PMID- 21687776 TI - Francisella tularensis blue-gray phase variation involves structural modifications of lipopolysaccharide o-antigen, core and lipid a and affects intramacrophage survival and vaccine efficacy. AB - Francisella tularensis is a CDC Category A biological agent and a potential bioterrorist threat. There is no licensed vaccine against tularemia in the United States. A long-standing issue with potential Francisella vaccines is strain phase variation to a gray form that lacks protective capability in animal models. Comparisons of the parental strain (LVS) and a gray variant (LVSG) have identified lipopolysaccharide (LPS) alterations as a primary change. The LPS of the F. tularensis variant strain gains reactivity to F. novicida anti-LPS antibodies, suggesting structural alterations to the O-antigen. However, biochemical and structural analysis of the F. tularensis LVSG and LVS LPS demonstrated that LVSG has less O-antigen but no major O-antigen structural alterations. Additionally, LVSG possesses structural differences in both the core and lipid A regions, the latter being decreased galactosamine modification. Recent work has identified two genes important in adding galactosamine (flmF2 and flmK) to the lipid A. Quantitative real-time PCR showed reduced transcripts of both of these genes in the gray variant when compared to LVS. Loss of flmF2 or flmK caused less frequent phase conversion but did not alter intramacrophage survival or colony morphology. The LVSG strain demonstrated an intramacrophage survival defect in human and rat but not mouse macrophages. Consistent with this result, the LVSG variant demonstrated little change in LD(50) in the mouse model of infection. Furthermore, the LVSG strain lacks the protective capacity of F. tularensis LVS against virulent Type A challenge. These data suggest that the LPS of the F. tularensis LVSG phase variant is dramatically altered. Understanding the mechanism of blue to gray phase variation may lead to a way to inhibit this variation, thus making future F. tularensis vaccines more stable and efficacious. PMID- 21687777 TI - A Modified Kendall Rank-Order Association Test For Evaluating The Repeatability Of Two Studies With A Large Number Of Objects. AB - Assessing the reproducibility of research studies can be difficult, especially when the number of objects involved is large. In such situations, there is only a small set of those objects that are truly relevant to the scientific questions. For example, in microarray analysis, despite data sets containing expression levels for tens of thousands of genes, it is expected that only a small fraction of these genes are regulated by the treatment in a single experiment. In such cases, it is acknowledged that reproducibility of two studies is high only for objects with real signals. One way to assess reproducibility is to measure the associations between the two sets of data. The traditional association methods suffered from the lack of adequate power to detect the real signals, however. We propose in this article the use of a modified Kendall rank-order test of association, based on truncated ranks. Simulation results show that the proposed procedure increases the capacity to detect the real signals considerably. PMID- 21687778 TI - Bayesian Nonparametric Hidden Markov Models with application to the analysis of copy-number-variation in mammalian genomes. AB - We consider the development of Bayesian Nonparametric methods for product partition models such as Hidden Markov Models and change point models. Our approach uses a Mixture of Dirichlet Process (MDP) model for the unknown sampling distribution (likelihood) for the observations arising in each state and a computationally efficient data augmentation scheme to aid inference. The method uses novel MCMC methodology which combines recent retrospective sampling methods with the use of slice sampler variables. The methodology is computationally efficient, both in terms of MCMC mixing properties, and robustness to the length of the time series being investigated. Moreover, the method is easy to implement requiring little or no user-interaction. We apply our methodology to the analysis of genomic copy number variation. PMID- 21687780 TI - Sharing Research Models: Using Software Engineering Practices for Facilitation. AB - Increasingly, researchers are turning to computational models to understand the interplay of important variables on systems' behaviors. Although researchers may develop models that meet the needs of their investigation, application limitations-such as nonintuitive user interface features and data input specifications-may limit the sharing of these tools with other research groups. By removing these barriers, other research groups that perform related work can leverage these work products to expedite their own investigations. The use of software engineering practices can enable managed application production and shared research artifacts among multiple research groups by promoting consistent models, reducing redundant effort, encouraging rigorous peer review, and facilitating research collaborations that are supported by a common toolset. This report discusses three established software engineering practices- the iterative software development process, object-oriented methodology, and Unified Modeling Language-and the applicability of these practices to computational model development. Our efforts to modify the MIDAS TranStat application to make it more user-friendly are presented as an example of how computational models that are based on research and developed using software engineering practices can benefit a broader audience of researchers. PMID- 21687781 TI - Evidence-Based School Behavior Assessment of Externalizing Behavior in Young Children. AB - This study examined the psychometric properties of the Revised Edition of the School Observation Coding System (REDSOCS). Participants were 68 children ages 3 to 6 who completed parent-child interaction therapy for Oppositional Defiant Disorder as part of a larger efficacy trial. Interobserver reliability on REDSOCS categories was moderate to high, with percent agreement ranging from 47% to 90% (M = 67%) and Cohen's kappa coefficients ranging from .69 to .95 (M = .82). Convergent validity of the REDSOCS categories was supported by significant correlations with the Intensity Scale of the Sutter-Eyberg Student Behavior Inventory-Revised and related subscales of the Conners' Teacher Rating Scale Revised: Long Version (CTRS-R: L). Divergent validity was indicated by nonsignificant correlations between REDSOCS categories and scales on the CTRS-R: L expected not to relate to disruptive classroom behavior. Treatment sensitivity was demonstrated for two of the three primary REDSOCS categories by significant pre to posttreatment changes. This study provides psychometric support for the designation of REDSOCS as an evidence-based assessment procedure for young children. PMID- 21687779 TI - Computational Models for Neuromuscular Function. AB - Computational models of the neuromuscular system hold the potential to allow us to reach a deeper understanding of neuromuscular function and clinical rehabilitation by complementing experimentation. By serving as a means to distill and explore specific hypotheses, computational models emerge from prior experimental data and motivate future experimental work. Here we review computational tools used to understand neuromuscular function including musculoskeletal modeling, machine learning, control theory, and statistical model analysis. We conclude that these tools, when used in combination, have the potential to further our understanding of neuromuscular function by serving as a rigorous means to test scientific hypotheses in ways that complement and leverage experimental data. PMID- 21687782 TI - RACE/ETHNICITY AND U.S. ADULT MORTALITY: Progress, Prospects, and New Analyses. AB - Although there have been significant decreases in U.S. mortality rates, racial/ethnic disparities persist. The goals of this study are to: (1) elucidate a conceptual framework for the study of racial/ethnic differences in U.S. adult mortality, (2) estimate current racial/ethnic differences in adult mortality, (3) examine empirically the extent to which measures of socioeconomic status and other risk factors impact the mortality differences across groups, and (4) utilize findings to inform the policy community with regard to eliminating racial/ethnic disparities in mortality. Relative Black-White differences are modestly narrower when compared to a decade or so ago, but remain very wide. The majority of the Black-White adult mortality gap can be accounted for by measures of socioeconomic resources that reflect the historical and continuing significance of racial socioeconomic stratification. Further, when controlling for socioeconomic resources, MexicanAmericans and Mexican immigrants exhibit significantly lower mortality risk than non-Hispanic Whites. Without aggressive efforts to create equality in socioeconomic and social resources, Black-White disparities in mortality will remain wide, and mortality among the Mexican-origin population will remain higher than what would be the case if that population achieved socioeconomic equality with Whites. PMID- 21687783 TI - Mining metabolites: extracting the yeast metabolome from the literature. AB - Text mining methods have added considerably to our capacity to extract biological knowledge from the literature. Recently the field of systems biology has begun to model and simulate metabolic networks, requiring knowledge of the set of molecules involved. While genomics and proteomics technologies are able to supply the macromolecular parts list, the metabolites are less easily assembled. Most metabolites are known and reported through the scientific literature, rather than through large-scale experimental surveys. Thus it is important to recover them from the literature. Here we present a novel tool to automatically identify metabolite names in the literature, and associate structures where possible, to define the reported yeast metabolome. With ten-fold cross validation on a manually annotated corpus, our recognition tool generates an f-score of 78.49 (precision of 83.02) and demonstrates greater suitability in identifying metabolite names than other existing recognition tools for general chemical molecules. The metabolite recognition tool has been applied to the literature covering an important model organism, the yeast Saccharomyces cerevisiae, to define its reported metabolome. By coupling to ChemSpider, a major chemical database, we have identified structures for much of the reported metabolome and, where structure identification fails, been able to suggest extensions to ChemSpider. Our manually annotated gold-standard data on 296 abstracts are available as supplementary materials. Metabolite names and, where appropriate, structures are also available as supplementary materials. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306 010-0251-6) contains supplementary material, which is available to authorized users. PMID- 21687784 TI - Excited-State Electronic Structure with Configuration Interaction Singles and Tamm-Dancoff Time-Dependent Density Functional Theory on Graphical Processing Units. AB - Excited-state calculations are implemented in a development version of the GPU based TeraChem software package using the configuration interaction singles (CIS) and adiabatic linear response Tamm-Dancoff time-dependent density functional theory (TDA-TDDFT) methods. The speedup of the CIS and TDDFT methods using GPU based electron repulsion integrals and density functional quadrature integration allows full ab initio excited-state calculations on molecules of unprecedented size. CIS/6-31G and TD-BLYP/6-31G benchmark timings are presented for a range of systems, including four generations of oligothiophene dendrimers, photoactive yellow protein (PYP), and the PYP chromophore solvated with 900 quantum mechanical water molecules. The effects of double and single precision integration are discussed, and mixed precision GPU integration is shown to give extremely good numerical accuracy for both CIS and TDDFT excitation energies (excitation energies within 0.0005 eV of extended double precision CPU results). PMID- 21687785 TI - Constant pH Molecular Dynamics in Explicit Solvent with lambda-Dynamics. AB - pH is an important parameter in condensed-phase systems, because it determines the protonation state of titratable groups and thus influences the structure, dynamics, and function of molecules in solution. In most force field simulation protocols, however, the protonation state of a system (rather than its pH) is kept fixed and cannot adapt to changes of the local environment. Here, we present a method, implemented within the MD package GROMACS, for constant pH molecular dynamics simulations in explicit solvent that is based on the lambda-dynamics approach. In the latter, the dynamics of the titration coordinate lambda, which interpolates between the protonated and deprotonated states, is driven by generalized forces between the protonated and deprotonated states. The hydration free energy, as a function of pH, is included to facilitate constant pH simulations. The protonation states of titratable groups are allowed to change dynamically during a simulation, thus reproducing average protonation probabilities at a certain pH. The accuracy of the method is tested against titration curves of single amino acids and a dipeptide in explicit solvent. PMID- 21687786 TI - The two-mutant problem: clonal interference in evolutionary graph theory. AB - In large asexual populations, clonal interference, whereby different beneficial mutations compete to fix in the population simultaneously, may be the norm. Results extrapolated from the spread of individual mutations in homogeneous backgrounds are found to be misleading in such situations: clonal interference severely inhibits the spread of beneficial mutations. In contrast with results gained in systems with just one mutation striving for fixation at any one time, the spatial structure of the population is found to be an important factor in determining the fixation probability when there are two beneficial mutations. PMID- 21687787 TI - The effects of pooling on spike train correlations. AB - Neurons integrate inputs from thousands of afferents. Similarly, some experimental techniques record the pooled activity of large populations of cells. When cells in these populations are correlated, the correlation coefficient between the collective activity of two subpopulations is typically much larger than the correlation coefficient between individual cells: The act of pooling individual cell signals amplifies correlations. We give an overview of this phenomenon and present several implications. In particular, we show that pooling leads to synchronization in feedforward networks and that it can amplify and otherwise distort correlations between recorded signals. PMID- 21687788 TI - Combining Computational Fluid Dynamics and Agent-Based Modeling: a new approach to evacuation planning. AB - We introduce a novel hybrid of two fields-Computational Fluid Dynamics (CFD) and Agent-Based Modeling (ABM)-as a powerful new technique for urban evacuation planning. CFD is a predominant technique for modeling airborne transport of contaminants, while ABM is a powerful approach for modeling social dynamics in populations of adaptive individuals. The hybrid CFD-ABM method is capable of simulating how large, spatially-distributed populations might respond to a physically realistic contaminant plume. We demonstrate the overall feasibility of CFD-ABM evacuation design, using the case of a hypothetical aerosol release in Los Angeles to explore potential effectiveness of various policy regimes. We conclude by arguing that this new approach can be powerfully applied to arbitrary population centers, offering an unprecedented preparedness and catastrophic event response tool. PMID- 21687789 TI - Dietary salt levels affect salt preference and learning in larval Drosophila. AB - Drosophila larvae change from exhibiting attraction to aversion as the concentration of salt in a substrate is increased. However, some aversive concentrations appear to act as positive reinforcers, increasing attraction to an odour with which they have been paired. We test whether this surprising dissociation between the unconditioned and conditioned response depends on the larvae's experience of salt concentration in their food. We find that although the point at which a NaCl concentration becomes aversive shifts with different rearing experience, the dissociation remains evident. Testing larvae using a substrate 0.025 M above the NaCl concentration on which the larvae were reared consistently results in aversive choice behaviour but appetitive reinforcement effects. PMID- 21687791 TI - Effects of vitamin d plus calcium supplements on pharmacokinetics of isoflavones in thai postmenopausal women. AB - The objective of this study was to determine the effects of vitamin D(3) plus calcium supplements (D(3)-calcium) on pharmacokinetics of isoflavones in Thai postmenopausal women. This study was an open-labeled, randomized three-phase crossover study. Twelve healthy subjects were randomized to receive one of the following regimens: (a) a single dose of isoflavones, (b) a single dose of isoflavones, and D(3)-calcium, or (c) continuous D(3)-calcium for 7 days followed by a single dose of isoflavones on the 8th day. After a washout period, subjects were switched to receive the 2 remaining regimens according to their randomized sequences. Blood samples were collected before dose and at specific time points until 32 hours after isoflavone administration. Plasma was treated with beta glucuronidase/sulfatase to hydrolyze glucuronide and sulfate conjugates of daidzein and genistein. Plasma concentrations of daidzein and genistein were determined by high performance liquid chromatography. The estimated pharmacokinetic parameters of isoflavones were time to maximal plasma concentration (T(max)), maximal plasma concentration (C(max)), half-life (t(1/2)) and area under the plasma concentration-time curve (AUC). T(max) of daidzein and genistein after regimen B was significantly longer than that of regimen A. Other pharmacokinetic parameters of daidzein and genistein obtained following the three regimens were not significantly different. PMID- 21687790 TI - Complementary spiritist therapy: systematic review of scientific evidence. AB - Spiritism is the third most common religion in Brazil, and its therapies have been used by millions worldwide. These therapies are based on therapeutic resources including prayer, laying on of hands, fluidotherapy (magnetized water), charity/volunteering, spirit education/moral values, and disobsession (spirit release therapy). This paper presents a systematic review of the current literature on the relationship among health outcomes and 6 predictors: prayer, laying on of hands, magnetized/fluidic water, charity/volunteering, spirit education (virtuous life and positive affect), and spirit release therapy. All articles were analyzed according to inclusion/exclusion criteria, Newcastle Ottawa and Jadad score. At present, there is moderate to strong evidence that volunteering and positive affect are linked to better health outcomes. Furthermore, laying on of hands, virtuous life, and praying for oneself also seem to be associated to positive findings. Nevertheless, there is a lack of studies on magnetized water and spirit release therapy. In summary, science is indirectly demonstrating that some of these therapies can be associated to better health outcomes and that other therapies have been overlooked or poorly investigated. Further studies in this field could contribute to the disciplines of Complementary and Alternative Medicine by investigating the relationship between body, mind, and soul/spirit. PMID- 21687792 TI - Species identification of marine fishes in china with DNA barcoding. AB - DNA barcoding is a molecular method that uses a short standardized DNA sequence as a species identification tool. In this study, the standard 652 base-pair region of the mitochondrial cytochrome oxidase subunit I gene (COI) was sequenced in marine fish specimens captured in China. The average genetic distance was 50 fold higher between species than within species, as Kimura two parameter (K2P) genetic distances averaged 15.742% among congeners and only 0.319% for intraspecific individuals. There are no overlaps of pairwise genetic variations between conspecific and interspecific comparisons apart from the genera Pampus in which the introgressive hybridization was detected. High efficiency of species identification was demonstrated in the present study by DNA barcoding. Due to the incidence of cryptic species, an assumed threshold is suggested to expedite discovering of new species and biodiversity, especially involving biotas of few studies. PMID- 21687794 TI - Music and the brain, literally. PMID- 21687793 TI - Differential contribution of right and left temporo-occipital and anterior temporal lesions to face recognition disorders. AB - In the study of prosopagnosia, several issues (such as the specific or non specific manifestations of prosopagnosia, the unitary or non-unitary nature of this syndrome and the mechanisms underlying face recognition disorders) are still controversial. Two main sources of variance partially accounting for these controversies could be the qualitative differences between the face recognition disorders observed in patients with prevalent lesions of the right or left hemisphere and in those with lesions encroaching upon the temporo-occipital (TO) or the (right) anterior temporal cortex. Results of our review seem to confirm these suggestions. Indeed, they show that (a) the most specific forms of prosopagnosia are due to lesions of a right posterior network including the occipital face area and the fusiform face area, whereas (b) the face identification defects observed in patients with left TO lesions seem due to a semantic defect impeding access to person-specific semantic information from the visual modality. Furthermore, face recognition defects resulting from right anterior temporal lesions can usually be considered as part of a multimodal people recognition disorder. The implications of our review are, therefore, the following: (1) to consider the components of visual agnosia often observed in prosopagnosic patients with bilateral TO lesions as part of a semantic defect, resulting from left-sided lesions (and not from prosopagnosia proper); (2) to systematically investigate voice recognition disorders in patients with right anterior temporal lesions to determine whether the face recognition defect should be considered a form of "associative prosopagnosia" or a form of the "multimodal people recognition disorder." PMID- 21687795 TI - Lactate fuels the neonatal brain. PMID- 21687796 TI - Faces and eyes in human lateral prefrontal cortex. AB - Much of the work on face-selective neural activity has focused on posterior, ventral areas of the human and non-human primate brain. However, electrophysiological and fMRI studies have identified face responses in the prefrontal cortex. Here we used fMRI to characterize these responses in the human prefrontal cortex compared with face selectivity in posterior ventral region. We examined a region at the junction of the right inferior frontal sulcus and the precentral sulcus (right inferior frontal junction or rIFJ) that responds more to faces than to several other object categories. We find that the rIFJ and the right fusiform face area (rFFA) are broadly similar in their responses to whole faces, headless bodies, tools, and scenes. Strikingly, however, while the rFFA preferentially responds to the whole face, the rIFJ response to faces appears to be driven primarily by the eyes. This dissociation provides clues to the functional role of the rIFJ face response. We speculate on this role with reference to emotion perception, gaze perception, and to behavioral relevance more generally. PMID- 21687798 TI - Dual roles for spike signaling in cortical neural populations. AB - A prominent feature of signaling in cortical neurons is that of randomness in the action potential. The output of a typical pyramidal cell can be well fit with a Poisson model, and variations in the Poisson rate repeatedly have been shown to be correlated with stimuli. However while the rate provides a very useful characterization of neural spike data, it may not be the most fundamental description of the signaling code. Recent data showing gamma frequency range multi-cell action potential correlations, together with spike timing dependent plasticity, are spurring a re-examination of the classical model, since precise timing codes imply that the generation of spikes is essentially deterministic. Could the observed Poisson randomness and timing determinism reflect two separate modes of communication, or do they somehow derive from a single process? We investigate in a timing-based model whether the apparent incompatibility between these probabilistic and deterministic observations may be resolved by examining how spikes could be used in the underlying neural circuits. The crucial component of this model draws on dual roles for spike signaling. In learning receptive fields from ensembles of inputs, spikes need to behave probabilistically, whereas for fast signaling of individual stimuli, the spikes need to behave deterministically. Our simulations show that this combination is possible if deterministic signals using gamma latency coding are probabilistically routed through different members of a cortical cell population at different times. This model exhibits standard features characteristic of Poisson models such as orientation tuning and exponential interval histograms. In addition, it makes testable predictions that follow from the gamma latency coding. PMID- 21687797 TI - Loss of specificity in Basal Ganglia related movement disorders. AB - The basal ganglia (BG) are a group of interconnected nuclei which play a pivotal part in limbic, associative, and motor functions. This role is mirrored by the wide range of motor and behavioral abnormalities directly resulting from dysfunction of the BG. Studies of normal behavior have found that BG neurons tend to phasically modulate their activity in relation to different behavioral events. In the normal BG, this modulation is highly specific, with each neuron related only to a small subset of behavioral events depending on specific combinations of movement parameters and context. In many pathological conditions involving BG dysfunction and motor abnormalities, this neuronal specificity is lost. Loss of specificity (LOS) manifests in neuronal activity related to a larger spectrum of events and consequently a large overlap of movement-related activation patterns between different neurons. We review the existing evidence for LOS in BG-related movement disorders, the possible neural mechanisms underlying LOS, its effects on frequently used measures of neuronal activity and its relation to theoretical models of the BG. The prevalence of LOS in a many BG-related disorders suggests that neuronal specificity may represent a key feature of normal information processing in the BG system. Thus, the concept of neuronal specificity may underlie a unifying conceptual framework for the BG role in normal and abnormal motor control. PMID- 21687799 TI - Investigating the role of the ventromedial prefrontal cortex in the assessment of brands. AB - The ventromedial prefrontal cortex (vmPFC) is believed to be important in everyday preference judgments, processing emotions during decision-making. However, there is still controversy in the literature regarding the participation of the vmPFC. To further elucidate the contribution of the vmPFC in brand preference, we designed a functional magnetic resonance imaging (fMRI) study where 18 subjects assessed positive, indifferent, and fictitious brands. Also, both the period during and after the decision process were analyzed, hoping to unravel temporally the role of the vmPFC, using modeled and model-free fMRI analysis. Considering together the period before and after decision-making, there was activation of the vmPFC when comparing positive with indifferent or fictitious brands. However, when the decision-making period was separated from the moment after the response, and especially for positive brands, the vmPFC was more active after the choice than during the decision process itself, challenging some of the existing literature. The results of the present study support the notion that the vmPFC may be unimportant in the decision stage of brand preference, questioning theories that postulate that the vmPFC is in the origin of such a choice. Further studies are needed to investigate in detail why the vmPFC seems to be involved in brand preference only after the decision process. PMID- 21687800 TI - Purification of immature neuronal cells from neural stem cell progeny. AB - Large-scale proliferation and multi-lineage differentiation capabilities make neural stem cells (NSCs) a promising renewable source of cells for therapeutic applications. However, the practical application for neuronal cell replacement is limited by heterogeneity of NSC progeny, relatively low yield of neurons, predominance of astrocytes, poor survival of donor cells following transplantation and the potential for uncontrolled proliferation of precursor cells. To address these impediments, we have developed a method for the generation of highly enriched immature neurons from murine NSC progeny. Adaptation of the standard differentiation procedure in concert with flow cytometry selection, using scattered light and positive fluorescent light selection based on cell surface antibody binding, provided a near pure (97%) immature neuron population. Using the purified neurons, we screened a panel of growth factors and found that bone morphogenetic protein-4 (BMP-4) demonstrated a strong survival effect on the cells in vitro, and enhanced their functional maturity. This effect was maintained following transplantation into the adult mouse striatum where we observed a 2-fold increase in the survival of the implanted cells and a 3-fold increase in NeuN expression. Additionally, based on the neural-colony forming cell assay (N-CFCA), we noted a 64 fold reduction of the bona fide NSC frequency in neuronal cell population and that implanted donor cells showed no signs of excessive or uncontrolled proliferation. The ability to provide defined neural cell populations from renewable sources such as NSC may find application for cell replacement therapies in the central nervous system. PMID- 21687801 TI - Regulation of francisella tularensis virulence. AB - Francisella tularensis is one of the most virulent bacteria known and a Centers for Disease Control and Prevention Category A select agent. It is able to infect a variety of animals and insects and can persist in the environment, thus Francisella spp. must be able to survive in diverse environmental niches. However, F. tularensis has a surprising dearth of sensory and regulatory factors. Recent advancements in the field have identified new functions of encoded transcription factors and greatly expanded our understanding of virulence gene regulation. Here we review the current knowledge of environmental adaptation by F. tularensis, its transcriptional regulators and their relationship to animal virulence. PMID- 21687802 TI - Harnessing the power of microbial genomics for exploring exceptions and shifting perceptions. PMID- 21687803 TI - Toward an understanding of the perpetuation of the agent of tularemia. AB - The epidemiology of tularemia has influenced, perhaps incorrectly skewed, our views on the ecology of the agent of tularemia. In particular, the central role of lagomorphs needs to be reexamined. Diverse observations, some incidental, and some that are more generally reproducible, have not been synthesized so that the critical elements of the perpetuation of Francisella tularensis can be identified. Developing a quantitative model of the basic reproduction number of F. tularensis may require separate treatments for Type A and Type B given the fundamental differences in their ecology. PMID- 21687804 TI - Neurobiology of depression and anxiety in Parkinson's disease. AB - Depression and anxiety are common in Parkinson's disease (PD) and have important consequences on quality of life. These have long been recognized as frequent accompanying syndromes of PD, and several reports suggest that these are the causative process or risk factors that are present many years before the appearance of motor symptoms. The neurochemical changes in PD involving dopamine, norepinephrine, and serotonin might be related to the pathophysiology of depression and anxiety, but this is still not clear. Several studies showed that anxiety in PD patients occurs earlier than depression, during premotor phase, suggesting that there may be a link between the mechanisms that cause anxiety and PD. Whereas a recent study reported that PD patients with depression and anxiety were associated with different demographic and clinical features. PMID- 21687805 TI - Mitochondrial contribution to Parkinson's disease pathogenesis. AB - The identification of the etiologies and pathogenesis of Parkinson's disease (PD) should play an important role in enabling the development of novel treatment strategies to prevent or slow the progression of the disease. The last few years have seen enormous progress in this respect. Abnormalities of mitochondrial function and increased free radical mediated damage were described in post mortem PD brain before the first gene mutations causing familial PD were published. Several genetic causes are now known to induce loss of dopaminergic cells and parkinsonism, and study of the mechanisms by which these mutations produce this effect has provided important insights into the pathogenesis of PD and confirmed mitochondrial dysfunction and oxidative stress pathways as central to PD pathogenesis. Abnormalities of protein metabolism including protein mis-folding and aggregation are also crucial to the pathology of PD. Genetic causes of PD have specifically highlighted the importance of mitochondrial dysfunction to PD: PINK1, parkin, DJ-1 and most recently alpha-synuclein proteins have been shown to localise to mitochondria and influence function. The turnover of mitochondria by autophagy (mitophagy) has also become a focus of attention. This review summarises recent discoveries in the contribution of mitochondrial abnormalities to PD etiology and pathogenesis. PMID- 21687807 TI - Word Identification in Noise. AB - Speech intelligibility has traditionally been measured by presenting words mixed in noise to listeners for identification at several different signal-to-noise ratios. The words are produced in isolation or in sentence contexts where the predictability of specific items can be varied. Psychometric functions are typically obtained relating signal-to-noise ratio to percent correct recognition. Error analyses are often carried out by examining response confusions to construct similarity spaces for words which reflect their perceptual organisation and acoustic-phonetic similarity. When using these techniques to measure speech discrimination or speech intelligibility in an open-set format, the recognition score obtained reflects the combined influence of both the sensory information encoded in the speech signal as well as the listener's decision process and response biases. Despite this limitation, the procedure has strong face validity as a measure of word recognition performance in normal-hearing listeners as well as other clinical populations which routinely use speech audiometry techniques to diagnose and assess both peripheral and central hearing impairments. All of the major findings and phenomena in the spoken word recognition literature can be demonstrated and explored with this experimental method. This technique continues to provide extremely valuable information about the organisation of words in the mental lexicon and how these sound patterns are accessed from acoustic-phonetic information in the speech signal. PMID- 21687806 TI - The francisella intracellular life cycle: toward molecular mechanisms of intracellular survival and proliferation. AB - The tularemia-causing bacterium Francisella tularensis is a facultative intracellular organism with a complex intracellular lifecycle that ensures its survival and proliferation in a variety of mammalian cell types, including professional phagocytes. Because this cycle is essential to Francisella pathogenesis and virulence, much research has focused on deciphering the mechanisms of its intracellular survival and replication and characterizing both bacterial and host determinants of the bacterium's intracellular cycle. Studies of various strains and host cell models have led to the consensual paradigm of Francisella as a cytosolic pathogen, but also to some controversy about its intracellular cycle. In this review, we will detail major findings that have advanced our knowledge of Francisella intracellular survival strategies and also attempt to reconcile discrepancies that exist in our molecular understanding of the Francisella-phagocyte interactions. PMID- 21687808 TI - Church-based social relationships, belonging, and health among older Mexican Americans. AB - The purpose of this study is to explain how church-based emotional support influences the health of older Mexican Americans. This issue is evaluated with a theoretical model that contains the following core linkages: (1) older Mexican Americans who go to church more often will be more likely to receive emotional support from fellow church members; (2) older Mexican Americans who receive more support from their fellow church members will be more likely to feel they belong in their congregation; (3) older Mexican Americans who feel they belong in their congregation are likely to have a stronger sense of personal control; and (4) older Mexican Americans who have a stronger sense of personal control are likely to enjoy better health. Data from a recent nationwide survey of older Mexican Americans provide support for each of these relationships. PMID- 21687809 TI - Testing and Estimating Shape-Constrained Nonparametric Density and Regression in the Presence of Measurement Error. AB - In many applications we can expect that, or are interested to know if, a density function or a regression curve satisfies some specific shape constraints. For example, when the explanatory variable, X, represents the value taken by a treatment or dosage, the conditional mean of the response, Y , is often anticipated to be a monotone function of X. Indeed, if this regression mean is not monotone (in the appropriate direction) then the medical or commercial value of the treatment is likely to be significantly curtailed, at least for values of X that lie beyond the point at which monotonicity fails. In the case of a density, common shape constraints include log-concavity and unimodality. If we can correctly guess the shape of a curve, then nonparametric estimators can be improved by taking this information into account. Addressing such problems requires a method for testing the hypothesis that the curve of interest satisfies a shape constraint, and, if the conclusion of the test is positive, a technique for estimating the curve subject to the constraint. Nonparametric methodology for solving these problems already exists, but only in cases where the covariates are observed precisely. However in many problems, data can only be observed with measurement errors, and the methods employed in the error-free case typically do not carry over to this error context. In this paper we develop a novel approach to hypothesis testing and function estimation under shape constraints, which is valid in the context of measurement errors. Our method is based on tilting an estimator of the density or the regression mean until it satisfies the shape constraint, and we take as our test statistic the distance through which it is tilted. Bootstrap methods are used to calibrate the test. The constrained curve estimators that we develop are also based on tilting, and in that context our work has points of contact with methodology in the error-free case. PMID- 21687810 TI - A Nature-Inspired Diels-Alder Reaction Facilitates Construction of the Bicyclo[2.2.2]octane Core of Andibenin B. AB - A rapid synthesis of the bicyclo[2.2.2]octane core of andibenin B via a nature inspired intramolecular [4+2] cycloaddition is described. This cycloaddition permits the construction of a sterically congested bicycle and simultaneously establishes three new all-carbon quaternary stereogenic centers in a highly efficient fashion. PMID- 21687813 TI - Enticing the New Lad: Masculinity as a Product of Consumption in Tobacco Industry Developed Lifestyle Magazines. AB - We demonstrate how an industry promoted and defined masculinity as a product of consumption. We analyze previously-secret tobacco industry documents and the content of two tobacco industry-produced magazines, Unlimited (from Philip Morris, makers of Marlboro) and Real Edge (from Brown & Williamson, makers of Lucky Strike), which were distributed to millions of young adult men from the late 1990s and early 2000s to promote their tobacco brands. We find that Unlimited and Real Edge exhibited similar themes previously reported to typify "new lad" magazines, but with risky behaviors in the forefront. We build upon the existing masculinity literature by providing insight into how corporations study and interpret cultural constructions of masculinity, and then use masculinity as both a vehicle and a product of consumption. PMID- 21687811 TI - A Brief History of Pancreatic Reg: Implications as to its Clinical Importance. AB - Although the pancreatic regenerating (reg) gene, was first isolated from a rat regenerating islets in 1988, its protein product was originally described in the 1970s. Reg proteins arise from a multigene family with three subtypes, and have a protein structure similar to calcium dependent lectins. Reg I and II have been implicated in control of pancreatic development and may play a role in maintenance of the beta-cell mass in the mature pancreas. Administration of reg I protein has been used in experimental animals as a therapy for surgically-induced diabetes mellitus. Reg I protein is also an inhibitor of calcium carbonate crystalization, important in maintaining the fluidity of pancreatic juice. The reg III gene, whose protein product is pancreatitis associated protein, is induced during pancreatic inflammation. Serum levels of reg III protein are a sensitive marker of severity of pancreatitis. It is an endogenous pancreatic factor that prevents the bacteria infection and scavenges oxygen-derived free radicals. Reg mRNA has been detected in non-pancreatic tissue such as the enterochromaffin-like cells of the stomach, neoplastic tissues of the colon, the small intestine, nervous system, liver tumors, and pituitary. Reg proteins are mitogens to intestinal epithelial cells, pancreatic ductal, beta cells, and Schwann cells, and are likely important to the overall integrity of the pancreas and gastrointestinal tract. PMID- 21687814 TI - Implementation of Walking Exercise Programs for Nursing Home Residents with AD. AB - Traditional exercise programs for older adults may not be suitable for frail, deconditioned nursing home residents with AD. Adaptations for this population include self-paced walking, use of assistive devices, rest as indicated, redirection when distracted, and engagement in conversation to increase willingness to participate. Appropriate footwear, monitoring response to the exercise, removal of fall hazards and use of a gait belt are suggested. Two studies of the effect of a program of regularly scheduled assisted walking on mobility and function of nursing home residents with AD are reported. Results of the first study suggest that participation in a walking exercise program can contribute to maintenance of mobility and that willingness to participate is significantly enhanced by development of a relationship with the intervenor. Preliminary results from the second study suggest that ability to perform the basic activities of daily living may also be supported by this type of exercise. PMID- 21687815 TI - Management decisions for nodal metastasis from an unknown primary melanoma. PMID- 21687816 TI - Exposure to the Endocrine Disruptor Bisphenol A Alters Susceptibility for Mammary Cancer. AB - Bisphenol A (BPA) is a synthetically made chemical used in the production of polycarbonate plastics and epoxy resins. Recent studies have shown over ninety percent of humans investigated have detectable BPA concentrations. Yet, the biggest concern for BPA is exposure during early development because BPA has been shown to bind to the estrogen receptors (ER) and cause developmental and reproductive toxicity. We have investigated the potential of perinatal BPA to alter susceptibility for chemically-induced mammary cancer in rats. We demonstrate that prepubertal exposure to low concentrations of orally administered BPA given to lactating dams resulted in a significantly decreased tumor latency and increased tumor multiplicity in the dimethylbenz[a]anthracene (DMBA) model of rodent mammary carcinogenesis. Our data suggested that the mechanism of action behind this carcinogenic response was mediated through increased cell proliferation, decreased apoptosis, and centered on an up regulation of steroid receptor coactivators (SRCs) 1-3, erbB3, and increased Akt signaling in the mammary gland.Also, we demonstrate that prenatal exposure to BPA shifts the time of susceptibility from 50 days to 100 days for chemically-induced mammary carcinogenesis. Proteomic data suggest that prenatal BPA exposure alters the expression of several proteins involved in regulating protein metabolism, signal transduction, developmental processes, and cell cycle and proliferation. Increases in ER-alpha, SRCs 1-3, Bcl-2, epidermal growth factor-receptor (EGFR), phospho-IGF-1R, phospho-c-Raf, phospho-ERKs 1/2, phospho-ErbB2 and phospho-Akt are accompanied by increase in cell proliferation. We conclude that exposure to low concentrations of BPA during the prenatal and early postnatal periods of life can predispose for chemically-induced mammary cancer. PMID- 21687817 TI - ? AB - El Programa CITI (Collaborative Institutional Training Initiative) es un curso basado en Internet y desarrollado por voluntarios, que brinda material educacional sobre proteccion de sujetos humanos en investigaciones biomedicas y de conducta, buenas practicas clinicas, conducta responsable de la investigacion y trato humanitario a animales de laboratorio. Es un esfuerzo conjunto del Fred Hutchinson Cancer Research Center y la Universidad de Miami.Con la colaboracion de expertos locales, gran parte del contenido se ha adaptado para America Latina, se ha traducido al espanol y portugues y se han establecido acuerdos de colaboracion con instituciones especializadas en bioetica en Chile, Brasil, Costa Rica y Peru. Los autores presentan una metodologia accesible para la capacitacion en etica de la investigacion y una justificacion de su uso y difusion en America Latina. PMID- 21687818 TI - Fabrication of Density Gradients of Biodegradable Polymer Microparticles and Their Use in Guiding Neurite Outgrowth. AB - We report a new method for generating both continuous and discrete density gradients in microparticles of biodegradable polymers via an electrospray technique. The gradients were generated by spatially varying the deposition time of electrosprayed microparticles. The substrate coated with a density gradient of microparticles has varying surface roughness, offering a unique system for studying the effect of physical cues on neurite outgrowth from dorsal root ganglia. We obtained an optimal surface roughness for promoting neuron adhesion and neurite extension in vitro. Furthermore, this capability of approach was extended to generate a gradient of fluorescein isothiocyanate-labeled bovine serum albumin by encapsulating it in the polymer microparticles in situ during electrospray. Taken together, this new class of substrates with gradients of microparticle density can potentially be used in various biomedical applications such as neural tissue engineering. PMID- 21687819 TI - Protein structural dynamics revealed by site-directed spin labeling and multifrequency EPR. AB - Multifrequency electron paramagnetic resonance (EPR), combined with site-directed spin labeling, is a powerful spectroscopic tool to characterize protein dynamics. The lineshape of an EPR spectrum reflects combined rotational dynamics of the spin probe's local motion within a protein, reorientations of protein domains, and overall protein tumbling. All these motions can be restricted and anisotropic, and separation of these motions is important for thorough characterization of protein dynamics. Multifrequency EPR distinguishes between different motions of a spin-labeled protein, due to the frequency dependence of EPR resolution to fast and slow motion of a spin probe. This gives multifrequency EPR its unique capability to characterize protein dynamics in great detail. In this review, we analyze what makes multifrequency EPR sensitive to different rates of spin probe motion and discuss several examples of its usage to separate spin probe dynamics and overall protein dynamics, to characterize protein backbone dynamics, and to resolve protein conformational states. PMID- 21687821 TI - Robust neural network with applications to credit portfolio data analysis. AB - In this article, we study nonparametric conditional quantile estimation via neural network structure. We proposed an estimation method that combines quantile regression and neural network (robust neural network, RNN). It provides good smoothing performance in the presence of outliers and can be used to construct prediction bands. A Majorization-Minimization (MM) algorithm was developed for optimization. Monte Carlo simulation study is conducted to assess the performance of RNN. Comparison with other nonparametric regression methods (e.g., local linear regression and regression splines) in real data application demonstrate the advantage of the newly proposed procedure. PMID- 21687820 TI - Signal Transduction Pathways Leading to Heat Shock Transcription. AB - Heat shock proteins (HSP) are essential for intracellular protein folding during stress and protect cells from denaturation and aggregation cascades that can lead to cell death. HSP genes are regulated at the transcriptional level by heat shock transcription factor 1 (HSF1) that is activated by stress and binds to heat shock elements in HSP genes. The activation of HSF1 during heat shock involves conversion from an inert monomer to a DNA binding trimer through a series of intramolecular folding rearrangements. However, the trigger for HSF1 at the molecular level is unclear and hypotheses for this process include reversal of feedback inhibition of HSF1 by molecular chaperones and heat-induced binding to large non-coding RNAs. Heat shock also causes a profound modulation in cell signaling pathways that lead to protein kinase activation and phosphorylation of HSF1 at a number of regulatory serine residues. HSP genes themselves exist in an accessible chromatin conformation already bound to RNA polymerase II. The RNA polymerase II is paused on HSP promoters after transcribing a short RNA sequence proximal to the promoter. Activation by heat shock involves HSF1 binding to the promoter and release of the paused RNA polymerase II followed by further rounds of transcriptional initiation and elongation. HSF1 is thus involved in both initiation and elongation of HSP RNA transcripts. Recent studies indicate important roles for histone modifications on HSP genes during heat shock. Histone modification occurs rapidly after stress and may be involved in promoting nucleosome remodeling on HSP promoters and in the open reading frames of HSP genes. Understanding these processes may be key to evaluating mechanisms of deregulated HSP expression that plays a key role in neurodegeneration and cancer. PMID- 21687822 TI - Perception of 3-D Layout in Stereo Displays. AB - As stereoscopic displays become more commonplace, it is more important than ever for those displays to create a faithful impression of the 3-D structure of the object or scene being portrayed. This article reviews current research on the ability of a viewer to perceive the 3-D layout specified by a stereo display. PMID- 21687823 TI - Comparison of Antinociceptive Effects Induced by Kappa Opioid Agonists in Male and Female Mice. AB - A recent clinical report suggested that kappa opioids such as nalbuphine and butorphanol produced greater pain relief in women than in men. However, both compounds have been characterized as partial agonists with mixed mu/kappa opioid actions in animal studies. The aim of this study was to evaluate whether there is a sex difference in antinociception caused by nalbuphine and butorphanol as well as more selective kappa opioid agonists including U50,488 and Cl-977 in mice. In the acid-induced writhing assay, all compounds (U50,488: 1-10 mg/kg; Cl-977: 0.01 0.1 mg/kg; nalbuphine: 1-320 mg/kg; butorphanol: 0.032-0.32 mg/kg) dose dependently inhibited writhing, but there were no sex-related differences found when comparing ED(50) values in male and female mice. In the warm water (48 degrees C) tail withdrawal assay, U50,488 (10-100 mg/kg) and Cl-977 (0.1-3.2 mg/kg) also dose-dependently produced antinociception, although there were no sex related differences observed. Nalbuphine (10-320 mg/kg) did not have antinociceptive effects under this condition. On the other hand, butorphanol (0.32-32 mg/kg) produced greater antinociception in male (50% MPE) than female mice (20% MPE). Further antagonist studies revealed that butorphanol is a mixed mu/kappa opioid with low efficacy. In summary, there were no sex-related differences in response to more selective kappa opioid agonists on antinociception in mice under these conditions. PMID- 21687824 TI - Stigma Related to HIV among Community Health Workers in Chile. AB - PURPOSE: When healthcare workers have stigmatizing attitudes toward people living with HIV it may lead to discriminatory behavior that interferes with prevention, treatment, and care. This research examined the HIV-related stigmatizing attitudes reported by health workers in Santiago, Chile. METHODS: The study used focus group data from the first phase of a larger study to develop and test a HIV prevention intervention for Chilean health workers. Ten focus groups were conducted with Health workers in two communities in Santiago, Chile. Content analysis was used to analyze the data. RESULTS: Two central themes emerged: Societal stigma and discrimination towards people living with HIV and healthcare system's policies related to HIV. Both inaccurate fears of transmission among the general public and Chilean Health workers and societal prejudices against homosexuals contributed to stigmatization and discrimination. CONCLUSIONS: Health workers did not recognize their own stigmatizing attitudes or discriminatory behaviors, but their discussion indicated that these behaviors and attitudes did exist. Healthcare system issues identified included problems with confidentiality due to the desire to inform other health workers about client HIV status. Health workers must be sensitized to the current stigmatization and misinformation associated with HIV and its negative impacts on persons living with HIV and the general community. IMPLICATIONS: All clinical and non-clinical workers at community clinics need mandatory education for HIV prevention that focuses on changing attitudes as well as sharing knowledge. Also, the Chilean law protecting people living with HIV and the confidentiality of their medical care needs to be publicized, along with guidelines for its enactment in clinics and other health facilities. PMID- 21687825 TI - Contextual risk and parenting as predictors of effortful control and social competence in preschool children. AB - Using a short-term longitudinal design (6 months), this study examined cumulative contextual risk as a predictor of effortful control (EC) and social competence in a community sample of children (N = 80, ages 33-40 months at time 1). Maternal parenting was examined as a mediator of contextual risk. EC was assessed using laboratory tasks, and parenting was assessed using observational ratings. Time 1 contextual risk was negatively related to time 2 EC after controlling for time 1 EC. Mothers' limit setting and scaffolding predicted higher time 2 EC and accounted for the effect of contextual risk. Time 1 EC, contextual risk, and parenting predicted time 2 social competence, and contextual risk had an indirect effect on social competence through parenting. Results suggest that contextual risk predicts smaller relative increases in EC and that parenting accounts for this effect. Knowledge of the factors that divert or promote effortful control can provide targets for intervention to enhance effortful control abilities and better adjustment. PMID- 21687826 TI - Overcoming Barriers to Cervical Cancer Screening Among Asian American Women. AB - Significant disparities in cervical cancer incidence and mortality exist among ethnic minority women, and in particular, among Asian American women. These disparities have been attributed primarily to differences in screening rates across ethnic/racial groups. Asian American women have one of the lowest rates of screening compared to other ethnic/racial groups. Yet Asian Americans, who comprise one of the fastest growing populations in the United States, have received the least attention in cancer control research. Studies suggest that various factors, including lack of knowledge, psychosocial and cultural beliefs, and access barriers, are associated with cervical cancer screening behaviors among Asian American women. Indeed, the few interventions that have been developed for Asian American women demonstrate that targeting these factors can yield significant increases in screening rates. It is important to note, however, that the effectiveness of educational interventions is often attenuated if access barriers are not adequately addressed. Hence, interventions that include key essential components, such as the use of community individuals as lay health workers, culturally-tailored and linguistically-appropriate educational materials, and navigation assistance to overcome access barriers, are more likely to be successful in enhancing screening rates. As the benefits of community-based cervical cancer prevention programs become more apparent, it will be essential to identify effective approaches for disseminating such programs more broadly. In conclusion, community-based cervical cancer screening programs have demonstrated promise in addressing existing cervical cancer disparities by increasing awareness and knowledge and promoting recommended screening behaviors. These findings will be instrumental in guiding future community-based programs to reduce cervical cancer health disparities among Asian American women. PMID- 21687827 TI - A Purification Method for Enrichment of the Toxoplasma gondii Cyst Wall. AB - The tissue cyst wall of Toxoplasma gondii is a stage-specific structure that is produced by modification of the bradyzoite-containing parasitophorous vacuole. It is a limiting membrane structure and is critically important for cyst survival and transmission of infection. Studies on the structure and function of the cyst wall should provide new therapeutic strategies for the elimination or prevention of latency during T. gondii infection. The membrane proteins of the T. gondii cyst are an important target for studies of the biochemical and immunological function(s) of the cyst. However, the components of the cyst membrane have been poorly characterized due to the difficulty of purification of these membrane proteins. We developed a lectin DBA (Dolichos biflorus) coated magnetic bead isolation method to isolate T. gondii cyst wall proteins. Our data suggests that this method can isolate cyst wall proteins from both in vitro cell culture or in vivo mouse brain derived tissue cysts. Antibodies to these isolated protein preparations were shown to localize to the cyst wall. PMID- 21687828 TI - Compound adaptive GPU design for clinical trials. AB - In clinical trials, several competing treatments are often carried out in the same trial period. The goal is to assess the performances of these different treatments according to some optimality criterion and minimize risks to the patients in the entire process of the study. For this, each coming patient is allocated sequentially to one of the treatments according to a mechanism defined by the optimality criterion. In practice, sometimes different optimality criteria, or the same criterion with different regimes, need to be considered to assess the treatments in the same study, so that each mechanism is also evaluated through the trail study. In this case, the question is how to allocate the treatments to the incoming patients so that the criteria/mechanisms of interest are assessed during the trail process, and the overall performance of the trial is optimized under the combined criteria or regimes. In this paper, we consider this problem by investigating a compound adaptive generalized Polya urn design. Basic asymptotic properties of this design are also studied. PMID- 21687829 TI - GREEN TEA POLYPHENOLS MEDIATED APOPTOSIS IN INTESTINAL EPITHELIAL CELLS BY A FADD DEPENDENT PATHWAY. AB - Colorectal cancer is the most common malignant complication in patients with chronic inflammatory bowel disease (IBD). In addition, these patients are at risk for developing painful complications during chemotherapy due to cytotoxic effects of drugs currently in use. Past studies have suggested a protective effect of tea consumption on gastrointestinal (GI) malignancies. Green tea polyphenols (GrTP) inhibited carcinogen-induced GI tumors in rodents and induced apoptosis in various carcinoma cell lines. We hypothesized that GrTP and its polyphenolic compounds regulate apoptosis in the intestinal epithelia. In this study, the effects of GrTP and its polyphenolics on apoptosis was evaluated in intestinal epithelial, IEC-6, cells grown to 85% confluency. GrTP (400-800 mg/ml) induced DNA fragmentation in a dose dependent fashion. Higher concentrations (>800 mg/ml) induced a mixed apoptosis and cytolysis. Epithelial cells exposed to GrTP and a major polyphenol, EGCG, but not EGC or EC, increased caspase activities in a time and dose dependent manner. The caspase inhibitors rescued cells from GrTP and EGCG-induced cell death. Concomitantly, GrTP resulted in activation of fatty acid synthase (Fas)-associated protein with death domain (FADD) and recruitment to Fas/CD95 domain 30 minutes following treatment. While GrTP also blocked NF-kappaB activation, an NFkappa-B inhibitor (MG132) only promoted cytolysis. In conclusion, these data demonstrated GrTP and EGCG induced apoptosis in intestinal epithelia mediated by caspase-8 through a FADD dependent pathway. Future investigation may warrant preventive as well as therapeutic strategies for GrTP in GI malignancy. PMID- 21687830 TI - Magnetic Iron Oxide Nanoworms for Tumor Targeting and Imaging. PMID- 21687831 TI - The Demand for, and Impact of, Learning HIV Status. AB - This paper evaluates an experiment in which individuals in rural Malawi were randomly assigned monetary incentives to learn their HIV results after being tested. Distance to the HIV results centers was also randomly assigned. Without any incentive, 34 percent of the participants learned their HIV results. However, even the smallest incentive doubled that share. Using the randomly assigned incentives and distance from results centers as instruments for the knowledge of HIV status, sexually active HIV-positive individuals who learned their results are three times more likely to purchase condoms two months later than sexually active HIV-positive individuals who did not learn their results; however, HIV positive individuals who learned their results purchase only two additional condoms than those who did not. There is no significant effect of learning HIV negative status on the purchase of condoms. PMID- 21687832 TI - DESCRIBING DISABILITY THROUGH INDIVIDUAL-LEVEL MIXTURE MODELS FOR MULTIVARIATE BINARY DATA. AB - Data on functional disability are of widespread policy interest in the United States, especially with respect to planning for Medicare and Social Security for a growing population of elderly adults. We consider an extract of functional disability data from the National Long Term Care Survey (NLTCS) and attempt to develop disability profiles using variations of the Grade of Membership (GoM) model. We first describe GoM as an individual-level mixture model that allows individuals to have partial membership in several mixture components simultaneously. We then prove the equivalence between individual-level and population-level mixture models, and use this property to develop a Markov Chain Monte Carlo algorithm for Bayesian estimation of the model. We use our approach to analyze functional disability data from the NLTCS. PMID- 21687834 TI - Selective Intrabronchial Air Insufflation for Acute Lobar Collapse in the Surgical Intensive Care Unit. AB - OVERVIEW: The horseshoe kidney is more prone to blunt abdominal trauma because of its low position and the presence of the isthmus across the midline. This is a rare case of complete transection of a horseshoe kidney at the isthmus due to blunt abdominal trauma with two sites of active extravasation on initial CT imaging. This extravasation was successfully treated by embolization with coils. Superselective embolization may be used for effective, minimally invasive control of active extravasation due to blunt renal trauma, even in kidneys with congenital malformations such as the horseshoe kidney. PMID- 21687833 TI - Nanotechnology of emerging targeting systems. AB - Recent developments in the design and testing of complex nanoscale payload carrying systems (i.e. systems with payloads that do not exceed 100 nm in size) are the focus of this brief review. Emerging systems include targeted single walled nanotubes, viral capsids, dendrimers, gold nanoparticles, milled boron carbide nanoparticles, and protein nucleic acid assemblies. Significant advances are emerging with each of these bionanotechnological approaches to cellular targeting. PMID- 21687835 TI - Destruction and reconstruction of the robust [Cu2(OOCR)4] unit during crystal structure transformations between two coordination polymers. AB - This work first demonstrates that the robust [Cu(2)(OOCR)(4)] unit can be destroyed and reconstructed in the solid state, as observed in water-induced structural interconversion of two distinct coordination polymers with 5 bromonicotinate. PMID- 21687836 TI - On-demand preparation of quantum dot-encoded microparticles using a droplet microfluidic system. AB - Optical barcoding technology based on quantum dot (QD)-encoded microparticles has attracted increasing attention in high-throughput multiplexed biological assays, which is realized by embedding different-sized QDs into polymeric matrixes at precisely controlled ratios. Considering the advantage of droplet-based microfluidics, producing monodisperse particles with precise control over the size, shape and composition, we present a proof-of-concept approach for on-demand preparation of QD-encoded microparticles based on this versatile new strategy. Combining a flow-focusing microchannel with a double T-junction in a microfluidic chip, biocompatible QD-doped microparticles were constructed by shearing sodium alginate solution into microdroplets and on-chip gelating these droplets into a hydrogel matrix to encapsulate CdSe/ZnS QDs. Size-controllable QD-doped hydrogel microparticles were produced under the optimum flow conditions, and their fluorescent properties were investigated. A novel multiplex optical encoding strategy was realized by loading different sized QDs into a single droplet (and thus a hydrogel microparticle) with different concentrations, which was triggered by tuning the flow rates of the sodium alginate solutions entrapped with different-colored QDs. A series of QD-encoded microparticles were controllably, and continuously, produced in a single step with the present approach. Their application in a model immunoassay demonstrated the potential practicability of QD-encoded hydrogel microparticles in multiplexed biomolecular detection. This simple and robust strategy should be further improved and practically used in making barcode microparticles with various polymer matrixes. PMID- 21687837 TI - High performance electrocatalyst: Pt-Cu hollow nanocrystals. AB - Pt-Cu hollow nanocrystals with excellent electrocatalytic activities were produced by a one-pot synthesis method. The catalytic activities of these nanocrystals toward methanol electro-oxidation were studied by cyclic voltammetry (CV). The Pt-Cu hollow nanocrystals exhibited higher catalytic activity for methanol oxidation than commercial Pt black and Pt/C. PMID- 21687838 TI - Solution processing of transparent conductors: from flask to film. AB - This critical review focuses on the solution deposition of transparent conductors with a particular focus on transparent conducting oxide (TCO) thin-films. TCOs play a critical role in many current and emerging opto-electronic devices due to their unique combination of electronic conductivity and transparency in the visible region of the spectrum. Atmospheric-pressure solution processing is an attractive alternative to conventional vacuum-based deposition methods due to its ease of fabrication, scalability, and potential to lower device manufacturing costs. An introduction into the applications of and material criteria for TCOs will be presented first, followed by a discussion of solution routes to these systems. Recent studies in the field will be reviewed according to their materials system. Finally, the challenges and opportunities for further enabling research will be discussed in terms of emerging oxide systems and non-oxide based transparent conductors (341 references). PMID- 21687840 TI - Evaluation of a tape-stripping technique for measuring dermal exposure to pyrene and benzo(a)pyrene. AB - Epidemiological studies have shown an increased incidence of cancer among workers occupationally exposed to polycyclic aromatic hydrocarbons (PAHs). As the dermal route is considered important for exposure to PAHs in the workplace, the aim of this study was to develop and evaluate a tape-stripping technique for monitoring dermal exposure to pyrene and benzo(a)pyrene. The tape-stripping method was evaluated by applying different concentrations of pyrene and benzo(a)pyrene directly onto tape strips (spiked tapes), clean glass plates, and on the skin of five volunteers. The glass plates were stripped using a single strip of tape and the skin of the volunteers was stripped with five consecutive strips of tape after 0 and 30 minutes. The method was also tested on five chimney sweeps at three exposure sites. High-performance liquid chromatography with fluorescence detection was employed for the quantification of pyrene and benzo(a)pyrene. The mean recovery from the spiked tapes was 97% for pyrene and 93% for benzo(a)pyrene. The mean overall recovery from the glass plates was 88% and 76% for pyrene and 88 and 85% for benzo(a)pyrene. The recovery from human skin was 70% and 63% for pyrene and 60 and 54% for benzo(a)pyrene, after 0 and 30 minutes, respectively. A concentration gradient was clearly detected between the five consecutive strips. Detectable amounts of pyrene and benzo(a)pyrene were found on all chimney sweeps at all exposure sites. This method can thus be used to detect and quantify dermal exposure to pyrene and benzo(a)pyrene. The results also show that pyrene and benzo(a)pyrene may be taken up by the skin. PMID- 21687839 TI - Spatial and temporal trends of selected trace elements in liver tissue from polar bears (Ursus maritimus) from Alaska, Canada and Greenland. AB - Spatial trends and comparative changes in time of selected trace elements were studied in liver tissue from polar bears from ten different subpopulation locations in Alaska, Canadian Arctic and East Greenland. For nine of the trace elements (As, Cd, Cu, Hg, Mn, Pb, Rb, Se and Zn) spatial trends were investigated in 136 specimens sampled during 2005-2008 from bears from these ten subpopulations. Concentrations of Hg, Se and As were highest in the (northern and southern) Beaufort Sea area and lowest in (western and southern) Hudson Bay area and Chukchi/Bering Sea. In contrast, concentrations of Cd showed an increasing trend from east to west. Minor or no spatial trends were observed for Cu, Mn, Rb and Zn. Spatial trends were in agreement with previous studies, possibly explained by natural phenomena. To assess temporal changes of Cd, Hg, Se and Zn concentrations during the last decades, we compared our results to previously published data. These time comparisons suggested recent Hg increase in East Greenland polar bears. This may be related to Hg emissions and/or climate-induced changes in Hg cycles or changes in the polar bear food web related to global warming. Also, Hg:Se molar ratio has increased in East Greenland polar bears, which suggests there may be an increased risk for Hg(2+)-mediated toxicity. Since the underlying reasons for spatial trends or changes in time of trace elements in the Arctic are still largely unknown, future studies should focus on the role of changing climate and trace metal emissions on geographical and temporal trends of trace elements. PMID- 21687841 TI - A novel NHC-catalyzed transformation of 2H-chromene-3-carboxaldehydes to 3-methyl 2H-chromen-2-ones. AB - An unexpected transformation of 2H-chromene-3-carboxaldehydes to coumarin derivatives, mediated by NHC, is reported. PMID- 21687842 TI - Bent bonds, the antiperiplanar hypothesis and the theory of resonance. A simple model to understand reactivity in organic chemistry. AB - By taking into consideration bent bonds (tau-bonds, tau-bonds), the antiperiplanar hypothesis, the classic theory of resonance, and the preference for staggered bonds over eclipsed bonds in tetrahedral systems, a simple qualitative model is presented to rationalize the conformation and reactivity for a wide range of compounds containing double bonds and/or carbonyl groups. Alkenes, carbonyl and carboxyl derivatives, conjugated systems as well as other functional groups are revisited. This also leads to a simple model to understand aromaticity, and electrocyclic reactions. The bent bond model and the antiperiplanar hypothesis provide a qualitative model for better understanding the electron delocalization and the reactivity inherent to unsaturated organic systems by an alternative view of the classic resonance theory. PMID- 21687843 TI - Addition of TMSCN to chiral ketimines derived from isatin. Synthesis of an oxindole-based peptidomimetic and a bioactive spirohydantoin. AB - We investigated the Strecker-type reaction of isatin derived chiral ketimines with TMSCN in the presence of a Lewis acid. The desired alpha-amino nitriles have been obtained in good yields with moderate diastereoselectivity. Further elaboration of the cyanide group allowed the preparation of a new oxindole-based peptidomimetic and a pharmaceutically relevant spirohydantoin. PMID- 21687844 TI - Bioconjugation via azide-Staudinger ligation: an overview. AB - Bioconjugation techniques using organic azides are compared in this critical review. A particular focus is on chemical ligation reactions and their application to chemical biology (179 references). PMID- 21687845 TI - Size-dependent endocytosis of single gold nanoparticles. AB - Herein we investigate the size-dependent force of endocytosing single gold nanoparticles by HeLa cells. The results reveal that both the uptake and unbinding force values are dependent upon the size of gold nanoparticles. PMID- 21687846 TI - Monitoring cellular stress responses to nanoparticles using a lab-on-a-chip. AB - As nanotechnology moves towards widespread commercialization, new technologies are needed to adequately address the potential health impact of nanoparticles (NPs). Assessing the safety of over 30,000 NPs through animal testing would not only be expensive, but it would also raise a number of ethical considerations. Furthermore, existing in vitro cell-based assays are not sufficient in scope to adequately address the complexity of cell-nanoparticle interactions including NP translocation, accumulation and co-transport of e.g. allergens. In particular, classical optical/fluorescent endpoint detection methods are known to provide irreproducible, inaccurate and unreliable results since these labels can directly react with the highly catalytic surfaces of NP. To bridge this technological gap we have developed a lab-on-a-chip capable of continuously and non-invasively monitoring the collagen production of primary human fibroblast cells (NHDF) using contactless dielectric microsensors. Human dermal fibroblast cells are responsible for the maintenance of soft tissue integrity, are found throughout the human body and their primary function is collagen expression. We show that cellular collagen production can be readily detected and used to assess cellular stress responses to a variety of external stimuli, including exposure to nanoparticles. Results of the study showed a 20% and 95% reduction of collagen production following 4 hour exposure to 10 MUg mL(-1) gold and silver nanoparticles (dia.10 nm), respectively. Furthermore a prolonged perfusion of sub toxic concentrations (0.1 MUg mL(-1)) of silver NP reduced NHDF collagen production by 40% after 10 h indicating increased NP take up and accumulation. We demonstrate that the application of microfluidics for the tailored administration of different NP treatments constitutes a powerful new tool to study cell nanoparticle interactions and nanoparticle accumulation effects in small cell populations. PMID- 21687847 TI - Zn(II) and Cd(II)-based complexes for probing the enzymatic hydrolysis of Na4P2O7 by alkaline phosphatase in physiological conditions. AB - Newly synthesized Zn(II) and Cd(II)-based complexes show unique selectivity towards inorganic pyrophosphate (PPi) in 100% aqueous medium at pH = 7.4 and act as a "turn-on" and "turn-off" real-time assay, respectively, for the evaluation of the enzymatic activity of alkaline phosphatase. PMID- 21687848 TI - Single electron transfer (SET) activity of the dialkyl-amido sodium zincate [(TMEDA).Na(MU-TMP)(MU-tBu)Zn(tBu)] towards TEMPO and chalcone. AB - More usually thought of as a base, the sodium zincate [(TMEDA).Na(MU-TMP)(MU (t)Bu)Zn((t)Bu)] 1 can undergo single electron transfer with TEMPO to give [(TMEDA).Na(MU-TMP)(MU-TEMPO(-))Zn((t)Bu)] 2 and [(TMEDA).Na(MU-TEMPO( ))(2)Zn((t)Bu)] 3; and with chalcone [PhCOCH=CHPh] gives [{(TMEDA).Na(MU TMP)Zn((t)Bu)}(2)(MU-OCPhCH=CHPhCHPhCH=CPh-MU-O)] which contains two chalcone units C-C coupled though their benzylic C atoms. PMID- 21687849 TI - A theoretical investigation of the low energy conformers of the isomers glycine and methylcarbamic acid and their role in the interstellar medium. AB - We have theoretically investigated the low energy conformers of neutral glycine (NH(2)CH(2)COOH) and its isomer methylcarbamic acid (CH(3)NHCOOH) in the gas phase. A total of 16 different levels of the theory, including CCSD(T), MP2 and B3LYP methods with various Pople and Dunning type basis sets with and without polarization and diffuse functions were used. We found eight low energy glycine conformers, where the heavy atoms in three have a planar backbone, and four low energy methylcarbamic acid conformers all with non-planar backbones. Interestingly at all levels of theory, we found that the most stable methylcarbamic acid conformer is significantly lower in energy than the lowest energy glycine conformer. The MP2 level and single point CCSD(T) calculations show the lowest energy methylcarbamic acid conformer to be between 31 to 37 kJ mol(-1) lower in energy than the lowest energy glycine conformer. These calculations suggest that methylcarbamic acid might serve as a precursor to glycine formation in the Interstellar Medium (ISM). We also report the theoretical harmonic vibrational frequencies, infrared intensities, moment of inertia, rotational constants and dipole moments for all of the conformers. In order to understand how glycine or methylcarbamic acid might be formed in the ISM, larger calculations which model glycine or its isomer interacting with several surrounding molecules, such as water, are needed. We demonstrate that B3LYP method should provide a reliable and computationally practical approach to modeling these larger systems. PMID- 21687850 TI - Polymer-nanoparticle interfacial behavior revisited: a molecular dynamics study. AB - By tuning the polymer-filler interaction, filler size and filler loading, we use a coarse-grained model-based molecular dynamics simulation to study the polymer filler interfacial structural (the orientations at the bond, segment and chain length scales, chain size and conformation), dynamic and stress-strain properties. Simulated results indicate that the interfacial region is composed of partial segments of different polymer chains, which is consistent with the experimental results presented by Chen et al. (Macromolecules, 2010, 43, 1076). Moreover, it is found that the interfacial region is within one single chain size (R(g)) range, irrespective of the polymer-filler interaction and the filler size, beyond which the bulk behavior appears. In the interfacial region, the orientation and dynamic behaviors are induced by the interfacial enthalpy, while the size and conformation of polymer chains near the filler are controlled by the configurational entropy. In the case of strong polymer-filler interaction (equivalent to the hydrogen bond), the innerest adsorbed polymer segments still undergo adsorption-desorption process, the transport of chain mass center in the interfacial region exhibits away from the glassy behavior, and no plastic-like yielding point appears in the stress-strain curve, which indicates that although the mobility of interfacial polymer chains is restricted, there exist no "polymer glassy layers" surrounding the filler. In addition, it is evidenced that the filler particle prefers selectively adsorbing the long polymer chains for attractive polymer-filler interaction, validating the experimental explanation of the change of the bound rubber (BR). In short, this work provides important information for further experimental and simulation studies of polymer nanoparticle interfacial behavior. PMID- 21687851 TI - Quantitative feature extraction reveals the status quo of protein fibrillation in the cell nucleus. AB - Stepwise fibrillation of otherwise soluble proteins to insoluble amyloid-like protein aggregates is a hallmark of neurodegenerative protein-misfolding diseases including Alzheimer's, polyglutamine diseases, and the prion encephalopathies. Investigation of protein aggregation mechanisms has considerably advanced in vitro due to recent technical innovation, whereas the development of analyses tools for intracellular protein fibrillation remains a major challenge. Here, we introduce a method that enables monitoring of the protein fibrillation status in the cell nucleus. We show that the amyloid indicator Congo red can be induced to bind to distinct nucleoplasmic microdomains that are describable by application of discrete mathematics on the image information. Since formation of Congo red binding nuclear microdomains (CRBDs) correlates with increased amyloid formation and decreased solubility of endogenous proteins with homopolymeric polyglutamine (polyQ) stretches we introduce the idea that different protein fibrillation steps can be characterized intracellularly by graph theory-aided pattern recognition. PMID- 21687852 TI - Influence of thermal vibrations on aromaticity of benzene. AB - The values of twenty-eight aromaticity indices were estimated for distorted benzene geometries coming from normal modes of thermal vibrations at room temperature. The applied Principal Component Analysis (PCA) revealed that four orthogonal principal components are sufficient for the description of 80% of the population variance. The importance of different aromaticity criteria was confirmed by values of variable loadings. The first principal component has a quite complex composition. Although the highest contribution to PC1 comes from ATI the roles of magnetic susceptibility, REC, EN and A(j) are also non negligible. The second orthogonal set of variables constituting PC2 comprises PDI and to a lesser extent REC. The importance of theta and EN is emphasized by contributions to PC3. The fourth PC is defined mostly by DeltaE. This suggests that geometry alterations encountered during thermal vibrations are associated with changes in electron delocalization and chemical shift. Additionally, electron density changes along normal vibration modes affect also the resonance energy of the ring. Although thermal vibrations of benzene at room temperature do not exceed +/-25% and most of analyzed parameters fluctuate within +/-10%, the very different molecular properties must be taken into account for proper description of consequences of molecular vibrations on pi-electron delocalization in a benzene ring. PMID- 21687853 TI - Jet-cooled hydrates of chiral (S) 1,2,3,4-tetrahydro-3-isoquinoline methanol (THIQM): structure and mechanism of formation. AB - The mechanism of formation of hydrates of chiral (S) 1,2,3,4-tetrahydro-3 isoquinoline (THIQM) with two water molecules has been investigated in jet-cooled condition by means of resonance-enhanced two-photon ionization and IR-UV double resonance experiments. Quantum chemical calculations reveal that only one isomer of the THIQM is involved in the THIQM-(H(2)O)(2) complex formation, in contrast with what was observed for THIQM-(H(2)O). Anharmonic vibration calculations allowed unambiguous assignment of THIQM-(H(2)O)(2) to a complex resulting from the addition of a water molecule on the most stable THIQM-(H(2)O) complex. A sequential mechanism for complex formation has been deduced from these results. PMID- 21687854 TI - Constructing simple yet accurate potentials for describing the solvation of HCl/water clusters in bulk helium and nanodroplets. AB - The infrared spectroscopy of molecules, complexes, and molecular aggregates dissolved in superfluid helium clusters, commonly called HElium NanoDroplet Isolation (HENDI) spectroscopy, is an established, powerful experimental technique for extracting high resolution ro-vibrational spectra at ultra-low temperatures. Realistic quantum simulations of such systems, in particular in cases where the solute is undergoing a chemical reaction, require accurate solute helium potentials which are also simple enough to be efficiently evaluated over the vast number of steps required in typical Monte Carlo or molecular dynamics sampling. This precludes using global potential energy surfaces as often parameterized for small complexes in the realm of high-resolution spectroscopic investigations that, in view of the computational effort imposed, are focused on the intermolecular interaction of rigid molecules with helium. Simple Lennard Jones-like pair potentials, on the other hand, fall short in providing the required flexibility and accuracy in order to account for chemical reactions of the solute molecule. Here, a general scheme of constructing sufficiently accurate site-site potentials for use in typical quantum simulations is presented. This scheme employs atom-based grids, accounts for local and global minima, and is applied to the special case of a HCl(H(2)O)(4) cluster solvated by helium. As a first step, accurate interaction energies of a helium atom with a set of representative configurations sampled from a trajectory following the dissociation of the HCl(H(2)O)(4) cluster were computed using an efficient combination of density functional theory and symmetry-adapted perturbation theory, i.e. the DFT-SAPT approach. For each of the sampled cluster configurations, a helium atom was placed at several hundred positions distributed in space, leading to an overall number of about 400,000 such quantum chemical calculations. The resulting total interaction energies, decomposed into several energetic contributions, served to fit a site-site potential, where the sites are located at the atomic positions and, additionally, pseudo-sites are distributed along the lines joining pairs of atom sites within the molecular cluster. This approach ensures that this solute-helium potential is able to describe both undissociated molecular and dissociated (zwitter-) ionic configurations, as well as the interconnecting reaction pathway without re-adjusting partial charges or other parameters depending on the particular configuration. Test calculations of the larger HCl(H(2)O)(5) cluster interacting with helium demonstrate the transferability of the derived site-site potential. This specific potential can be readily used in quantum simulations of such HCl/water clusters in bulk helium or helium nanodroplets, whereas the underlying construction procedure can be generalized to other molecular solutes in other atomic solvents such as those encountered in rare gas matrix isolation spectroscopy. PMID- 21687855 TI - Dissociative photoionization mechanism of methanol isotopologues (CH3OH, CD3OH, CH3OD and CD3OD) by iPEPICO: energetics, statistical and non-statistical kinetics and isotope effects. AB - The dissociative photoionization of energy selected methanol isotopologue (CH(3)OH, CD(3)OH, CH(3)OD and CD(3)OD) cations was investigated using imaging Photoelectron Photoion Coincidence (iPEPICO) spectroscopy. The first dissociation is an H/D-atom loss from the carbon, also confirmed by partial deuteration. Somewhat above 12 eV, a parallel H(2)-loss channel weakly asserts itself. At photon energies above 15 eV, in a consecutive hydrogen molecule loss to the first H-atom loss, the formation of CHO(+)/CDO(+) dominates as opposed to COH(+)/COD(+) formation. We see little evidence for H-atom scrambling in these processes. In the photon energy range corresponding to the B[combining tilde] and C[combining tilde] ion states, a hydroxyl radical loss appears yielding CH(3)(+)/CD(3)(+). Based on the branching ratios, statistical considerations and ab initio calculations, this process is confirmed to take place on the first electronically excited A(2)A' ion state. Uncharacteristically, internal conversion is outcompeted by unimolecular dissociation due to the apparently weak Renner-Teller like coupling between the X[combining tilde] and the A ion states. The experimental 0 K appearance energies of the ions CH(2)OH(+), CD(2)OH(+), CH(2)OD(+) and CD(2)OD(+) are measured to be 11.646 +/- 0.003 eV, 11.739 +/- 0.003 eV, 11.642 +/- 0.003 eV and 11.737 +/- 0.003 eV, respectively. The E(0)(CH(2)OH(+)) = 11.6454 +/- 0.0017 eV was obtained based on the independently measured isotopologue results and calculated zero point effects. The 0 K heat of formation of CH(2)OH(+), protonated formaldehyde, was determined to be 717.7 +/- 0.7 kJ mol(-1). This yields a 0 K heat of formation of CH(2)OH of -11.1 +/- 0.9 kJ mol(-1) and an experimental 298 K proton affinity of formaldehyde of 711.6 +/- 0.8 kJ mol(-1). The reverse barrier to homonuclear H(2)-loss from CH(3)OH(+) is determined to be 36 kJ mol(-1), whereas for heteronuclear H(2)-loss from CH(2)OH(+) it is found to be 210 kJ mol(-1). PMID- 21687856 TI - Non-invasive measurement of carbon monoxide burden in Guatemalan children and adults following wood-fired temazcal (sauna-bath) use. AB - The use of wood-fired steam baths, or temazcales, is a potentially dangerous source of CO exposure in Guatemalan Highland communities where adults and children use them regularly for bathing, relaxation, and healing purposes. Physical characteristics of children predispose them to absorb CO faster than adults, placing them at greater exposure and health risks. Efforts to quantify temazcal exposures across all age groups, however, have been hampered by the limitations in exposure measurement methods. In this pilot study we measured COHb levels in children and adults following use of the temazcal using three field based, non-invasive CO measurement methods: CO-oximetry, exhaled breath, and by estimation of COHb using micro-environmental concentrations and time diaries. We then performed a brief comparison of methods. Average CO concentrations measured during temazcal use were 661 +/- 503 ppm, approximately 10 times the 15 min WHO guideline. Average COHb levels for all participants ranged from 12-14% (max of 30%, min 2%), depending on the method. COHb levels measured in children were not significantly different from adults despite the fact that they spent 66% less time exposed. COHb measured by CO-oximetry and exhaled breath had good agreement, but precision of the former was affected substantially by random instrument error. The version of the field CO-oximeter device used in this pilot could be useful in screening for acute CO exposure events in children but may lack the precision for monitoring the burden from less extreme, but more day-to-day CO exposures (e.g. indoor solid fuel use). In urban settings, health effects in children and adults have been associated with chronic exposure to ambient CO concentrations much lower than measured in this study. Future research should focus on reducing exposure from temazcales through culturally appropriate modifications to their design and practices, and targeted efforts to educate communities on the health risks they pose and actions they can take to reduce this risk. PMID- 21687857 TI - Sources and fate of Salmonella and fecal indicator bacteria in an urban creek. AB - This research aimed to understand the sources and fate of Salmonella and fecal bacteria in urban surface waters. An urban creek (San Pedro Creek, California, USA) that had unusually high levels of Salmonella and fecal bacteria relative to other nearby waterbodies was chosen as a model field site. State of the art microbiological methods were used in concert with modeling to investigate Salmonella and fecal bacteria sources, and determine field-relevant dark inactivation and photoinactivation rates. Three along-creek surveys that spanned reaches adjacent to both urban and forested land covers were conducted to measure Salmonella, enterococci, Escherichia coli, and horse- and human-specific Bacteroidales. Salmonella were detected adjacent to and downstream of urban land cover, but not adjacent to forested land cover. No human or horse-specific Bacteroidales fecal markers were detected implicating other urban animal sources of bacteria. Two locations along the creek where Salmonella was consistently detected were sampled hourly for 25 hours and a mass-balance model was applied to determine field-relevant light and dark inactivation rates for Salmonella, enterococci, and E. coli. Sunlight inactivation did not appear to be important in modulating concentrations of Salmonella, but was important in modulating both enterococci and E. coli concentrations. Dark inactivation was important for all three organisms. This is the first study to quantitatively examine the fate of Salmonella within an urban surface water. Although the work is carried out at a single site, the methodologies are extendable to source tracking in other waterbodies. Additionally, the rate constants determined through the modeling will be useful for modeling these organisms in other surface waters, and represent useful benchmarks for comparison to laboratory-derived inactivation rates. PMID- 21687858 TI - Analysis of transient migration behavior of natural killer cells imaged in situ and in vitro. AB - We present a simple method for rapid and automatic characterization of lymphocyte migration from time-lapse fluorescence microscopy data. Time-lapse imaging of natural killer (NK) cells in vitro and in situ, both showed that individual cells transiently alter their migration behavior. Typically, NK cells showed periods of high motility, interrupted by transient periods of slow migration or almost complete arrests. Analysis of in vitro data showed that these periods frequently coincided with contacts with target cells, sometimes leading to target cell lysis. However, NK cells were also commonly observed to stop independently of contact with other cells. In order to objectively characterize the migration of NK cells, we implemented a simple method to discriminate when NK cells stop or have low motilities, have periods of directed migration or undergo random movement. This was achieved using a sliding window approach and evaluating the mean squared displacement (MSD) to assess the migration coefficient and MSD curvature along trajectories from individual NK cells over time. The method presented here can be used to quickly and quantitatively assess the dynamics of individual cells as well as heterogeneity within ensembles. Furthermore, it may also be used as a tool to automatically detect transient stops due to the formation of immune synapses, cell division or cell death. We show that this could be particularly useful for analysis of in situ time-lapse fluorescence imaging data where most cells, as well as the extracellular matrix, are usually unlabelled and thus invisible. PMID- 21687860 TI - Field nanoemitter: one-dimension Al4C3 ceramics. AB - As a kind of ionic (or salt-like) carbide, Al(4)C(3) hardly any active functions have been found except for structure material purposes. However, considering the unique characteristic features of its crystal structure, we think Al(4)C(3) in fact might have huge potential for exhibiting active functionality on field emission application. Herein, we report for the first time the catalyst-free synthesis and excellent field emission properties of Al(4)C(3) one-dimension (1 D) nanostructures. The 1-D nanostructures acting as cold electron emitters display excellent field emission performance with the turn-on field as low as 1.4 2.0 V MUm(-1) and the threshold field down to 4.2-4.4 V MUm(-1). Such emitters are technologically useful, because they can be easily fabricated on large substrates, and the synthesis process is simple and broadly applicable. The findings conceptually provide new opportunities for the application of Al(4)C(3) ceramic material in vacuum microelectronic devices. PMID- 21687859 TI - From cysteine to longer chain thiols: thermodynamic analysis of cadmium binding by phytochelatins and their fragments. AB - Isothermal Titration Calorimetry (ITC) was used to study the binding of Cd(2+) by phytochelatins ((gammaGlu-Cys)(n)-Gly, PC(n); n = 1-5) and their selected fragments (Cys, Cys-Gly and gammaGlu-Cys) in order to understand the influence of the chain length on the complex stabilities and the origin of the enhanced affinities in Tris buffer at pH 7.5 and 8.5 and at 25 degrees C. Different complexes are formed with glutathione (GSH) and its fragments, Cys, Cys-Gly and gammaGlu-Cys, and their stabilities depend on the corresponding pK(a) value of the thiol group in the ligands. The stability of Cd-PC(n) complexes increases moving towards higher PC(2-5), as well as the complexing capacity expressed as the number of metal ions that can be bound by one ligand molecule. The affinity of Cd(2+) for the PC(n) can be described by the following GSH < PC(2) < PC(3)<= PC(4)<= PC(5) sequence. On the basis of these thermodynamic data it is possible to explain the abundance of certain Cd-PC(n) complexes found in nature. The comprehension of the thermodynamic rules that govern the interactions of Cd(2+) with PC(n) and their constituents is of great service in the research with real plant samples subjected to metal stress and in the development of new strategies of bio/phytoremediation. PMID- 21687861 TI - A pillared-bilayer porous coordination polymer with a 1D channel and a 2D interlayer space, showing unique gas and vapor sorption. AB - A new 2D pillared-bilayer porous coordination polymer (PCP) has been synthesized and structurally characterized that shows selective adsorption of CO(2) over other gases (N(2), O(2), Ar, H(2), CH(4)) and guest selective single/double-step adsorption of vapor correlated to the successive confinement of adsorbates in a 1D channel and a 2D interlayer space. PMID- 21687862 TI - Morpholine catalyzed direct C3 alkenylation of indoles with alpha,beta unsaturated aldehydes. AB - Organocatalytic direct C3 alkenylation of indoles has been developed. Simple and readily available morpholine trifluoroacetic acid salt is employed as an efficient catalyst in this oxidative dehydrogenative reaction. Simplicity and practicality constitute the most attractive advantages of this reaction. PMID- 21687863 TI - Enthalpy and entropy of nanoparticle association from temperature-dependent cryo TEM. AB - Quantum dots form equilibrium structures in liquid dispersions, due to thermodynamic forces that are often hard to quantify. Analysis of these structures, visualized using cryogenic electron microscopy, yields their formation free energy. Here we show that the nanoparticle interaction free energy can be further separated into the enthalpic and entropic contributions, using the temperature dependence of the assembled structures. Monodisperse oleic acid capped PbSe nanoparticles dispersed in decalin were used as a model system, and the temperature-dependent equilibrium structures were imaged by cryo-TEM, after quenching from different initial temperatures. The interaction enthalpy and entropy follow from van 't Hoff's exact equation for the temperature dependence of thermodynamic equilibria, now applied to associating nanoparticles. The enthalpic component gives the magnitude of the contact interaction, which is crucial information in understanding the energetics of the self-assembly of nanoparticles into ordered structures. PMID- 21687864 TI - Phospholamban generates cation selective ion channels. AB - Phosholamban (PLN) is involved in the contractility of cardiac muscles by regulating the intracellular calcium concentration (Ca(2+)(cyt)) of cardiac myocytes. This occurs via a modulation of the sarco-/endoplasmic CaATPase (SERCA). In spite of high-resolution structures the molecular mode of PLN action is yet not known. In the present paper we readdress the question whether PLN proteins can generate ion channel activity. Reconstitution of PLN in planar lipid bilayers reveals single channel fluctuations, which are characterized by two conductance levels, long open/closed dwell times, moderate selectivity between monovalent cations and no perceivable Ca(2+) permeability. The PLN generated channel activity could be inhibited by a PLN antibody (abPLN) implying that the channel activity is indeed due to the inherent channel function of the PLN protein. PMID- 21687865 TI - Monitoring selected hydrogen bonds in crystal hydrates of amino acid salts: combining variable-temperature single-crystal X-ray diffraction and polarized Raman spectroscopy. AB - Predicting behaviour of hydrogen bonds with varying temperature, in particular correlating donor-acceptor distances in the O-H...O hydrogen bonds with the frequencies of O-H stretching vibrations is important for understanding dynamics of biomolecules and phase transitions in crystals. A commonly used correlation suggested earlier in the literature is based on statistical analysis of different compounds [A. Novak, Structure and Bonding, 1974, 18, 177; K. Nakamoto, M. Margoshes, R. E. Rundle, J. Am. Chem. Soc., 1955, 77, 6480]. The present study is a rare example when correlations between geometry and energy parameters have been found for selected individual hydrogen bonds in the same crystalline compound at multiple temperatures. The properties of several types of O-H...O hydrogen bonds in bis(DL-serinium) oxalate dihydrate and DL-alaninium semi-oxalate monohydrate have been studied by a combination of variable-temperature single-crystal X-ray diffraction and polarized Raman spectroscopy. The changes in the hydrogen bonds geometry could be compared with the changes of the corresponding spectral modes. The correlation suggested by Novak is roughly followed, better for medium and weak, than for short hydrogen bonds. Fine details of spectral changes differ for individual bonds. The way how H-bonds are affected by cooling depends on their environment in the crystal structure. Short O-H...O hydrogen bonds in bis(DL serinium) oxalate dihydrate expand or remain almost unchanged on cooling, whereas in DL-alaninium semi-oxalate monohydrate all strong H-bonds are compressed under these conditions. The distortion of individual hydrogen bonds on temperature variations is correlated with the anisotropy of lattice strain. PMID- 21687866 TI - Template-free synthesis and characterization of mesoporous tungsten nitride nanoplates. AB - We report well-defined mesoporous beta-W(2)N nanoplates prepared by using layered WO(3).H(2)O without templates. The tungsten nitride nanoplates exhibit typical mesoporous structures with size-controlled monomodal pore distributions. PMID- 21687867 TI - Catalytic activity of platinum nanoparticles on highly boron-doped and 100 oriented epitaxial diamond towards HER and HOR. AB - Platinum nanoparticles supported on boron-doped single-crystalline diamond surfaces were used as a model system to investigate the catalytic activity with respect to the influence of particle morphology, particle density and surface preparation of the diamond substrates. We report on the preparation, characterization and activity regarding hydrogen evolution reaction (HER) and hydrogen oxidation reaction (HOR) of these Pt/diamond electrodes. Two kinds of diamond layers with boron doping above 10(20) cm(-3) were grown epitaxially on (100)-oriented diamond substrates; post-treatments of wet chemical oxidation and radio frequency (rf) oxygen plasma treatments were applied. Electrochemical deposition of Pt was performed using a potentiostatic double-pulse technique, which allowed variation of the particle size in the range between 1 nm and 15 nm in height and 5 nm and 50 nm in apparent radius, while keeping the particle density constant. Higher nucleation densities on the plasma processed surface at equal deposition parameters could be related to the plasma-induced surface defects. Electrochemical characterization shows that the platinum particles act as nanoelectrodes and form an ohmic contact with the diamond substrate. The catalytic activity regarding HER and HOR of the platinum nanoparticles exhibits no dependence on the particle size down to particle heights of ~1 nm. The prepared Pt on diamond(100) samples show a similar platinum-specific activity as bulk platinum. Therefore, while keeping the activity constant, the well-dispersed particles on diamond offer an optimized surface-to-material ratio. PMID- 21687868 TI - Ru-TAP complexes with btz and pytz ligands: novel candidates as photooxidizing agents. AB - Two ligands containing 1,2,3-triazole moieties 1 and 3 were easily prepared by a Cu(I)-catalysed "click reaction" between commercially available (trimethylsilyl)alkynes and benzyl azide. These ligands were used in the synthesis of Ru(II) complexes with TAP ligands, i.e. [Ru(TAP)(2)btz](2+)2 and [Ru(TAP)(2)pytz](2+)4. The electrochemical and photophysical properties of these complexes were investigated. The data show that both complexes should behave as highly oxidizing agents under illumination. However, complex 4 displays more attractive photophysical properties than complex 2 and constitutes thus a Ru-TAP compound that can be easily derivatized for photodamaging biomolecules. PMID- 21687869 TI - From insertion of rhodium acetate paddlewheels into functionalized 7-azaindole hydrogen-bonded dimers to infinite architectures. AB - In order to take advantage of the peculiar mode of interaction consisting in the combination of hydrogen and coordination bonding displayed by the 7-azaindole core towards tetraacetate paddlewheel type complexes, a series of new derivatives, bearing peripheral interacting sites at the position 3, have been prepared and their self-assembly into dimeric H-bonded species was established in the solid state. Furthermore, the heterochelate mode of binding was exploited both in the solid state and in solution using [Rh(2)(OAc)(4)] paddlewheel to generate discrete capped complexes resulting from the coordination of the pyridyl nitrogen atom to the axial position of the Rh(ii) cations and hydrogen bonding between the pyrrolic NH and an oxygen atom of one of the equatorial acetate groups. The extension to infinite hybrid networks was achieved using derivatives bearing self complementary H-bond donor and acceptor groups such as a carboxylic moiety. PMID- 21687870 TI - A fully automated iterative moving averaging (AIMA) technique for baseline correction. AB - Baseline correction is one of the pre-processing steps in the analysis of metabolite signals from chemometric analytical instruments. Fully automated baseline correction techniques, although more convenient to use, tend to be less accurate than semi-automated baseline correction. A fully automated baseline correction algorithm, the automated iterative moving averaging algorithm (AIMA), is presented and compared with three recently introduced semi-automated algorithms, namely the adaptive iteratively reweighted penalized least squares (airPLS), Asymmetric Least Squares baseline correction (ALS) and a parametric method, using NMR, Raman and HPLC chromatograms. AIMA's potential in increasing the accuracy of multivariate analysis via SELTI-TOF and LCMS chromatograms was also assessed. The results show that the AIMA's accuracy is comparable to these semi-automated algorithms and has the advantage of ease of use. An AIMA plug-in for an open source metabolomics analysis tool, MZmine, was also developed. The AIMA plug-in is available at http://padel.nus.edu.sg/software/padelaima. PMID- 21687871 TI - Ion chromatography on carbon clad zirconia modified by diazonium chemistry and functionalized latex particles. AB - This work explores the potential of 3 MUm carbon coated zirconia particles as a stationary phase for ion chromatography for the separation of organic acids and inorganic ions. A 4-phenylsulfonic acid functionality is introduced onto the carbon surface by reducing 4-phenylsulfonic acid diazonium chloride with borohydride in the presence of carbon clad zirconia particles. The elemental sulfur analysis gave 132 MUeq-SO(3)H/g carbon clad zirconia and 2% S atomic concentration by XPS analysis. The -SO(3)(-) groups serve as electrostatic anchors for latex nanoparticles bearing quaternary triethylamine functional groups. The agglomeration step in 5 * 0.4 cm i.d. columns converts the packed particles into an anion exchanger. The breakthrough curves with nitrate indicate a capacity of 3 MUeq/column. Separation of common organic acids and inorganic ions using carbonate eluent and suppressed conductivity detection yield plate heights (H) of 0.023-0.05 mm. PMID- 21687872 TI - Large-scaled star-shaped alpha-MnS nanocrystals with novel magnetic properties. AB - A cooperative thermal decomposition route to large-scaled star-shaped alpha-MnS nanocrystals, which show novel magnetic properties, i.e., a high blocking temperature (275 K) and a large coercive field (1573 Oe), is reported. PMID- 21687873 TI - Hydrothermal synthesis and magnetic properties of single-crystalline BiFeO3 nanowires. AB - One-dimensional, single-crystalline BiFeO(3) nanowires presenting a diameter of 45-200 nm and a length from hundreds of nanometres to several microns have been prepared using an improved hydrothermal method. The characterization results of ZFC and FC magnetizations at different temperatures indicate that single crystalline BiFeO(3) nanowires show a spin-glass transition below the freezing temperature of 55 K. PMID- 21687874 TI - Ion pair receptors based on anion-pi interaction. AB - A novel type of ditopic ion pair receptors based on anion-pi interaction is reported. Oxacalix[2]arene[2]triazine azacrowns were synthesized efficiently from a one-pot reaction between 2,4-dichloro-4-methoxytriazine and 3,5 dihydroxybenzaldehyde followed by condensation with a diamine and reduction of bisimine; they acted as selective ditopic receptors to recognize ion pairs. PMID- 21687875 TI - Sulfonyl: a new application of electron-withdrawing substituent in highly efficient photovoltaic polymer. AB - A strong electron-withdrawing group, sulfonyl, was firstly introduced to a semiconducting polymer, PBDTTT-S. The PCE of the PBDTTT-S device reached 6.22% with a high open-circuit voltage of 0.76 V. The sulfonyl group is thus a promising candidate as a strong electron-withdrawing group applied to high efficiency PSCs. PMID- 21687876 TI - Facile fabrication of recyclable and active nanobiocatalyst: purification and immobilization of enzyme in one pot with Ni-NTA functionalized magnetic nanoparticle. AB - Ni-NTA functionalized iron oxide magnetic nanoparticle was synthesized and used to selectively immobilize a his-tagged enzyme from cell free extract as an active and recyclable nanobiocatalyst, where purification and immobilization of the target enzyme were accomplished in one pot. PMID- 21687877 TI - Synthesis and chiroptical properties of ferrocene-[4]-helicenequinones: kinetic resolution of a planar-chiral diene. AB - Both enantiomers of ferrocene [4]-helicenequinone 6, showing planar and helical chiralities, have been synthesized with very high optical purities using, as the key step, a kinetic resolution process between planar-chiral racemic ferrocene diene 2 and enantiopure sulfinyl benzoquinone (S)-3. PMID- 21687878 TI - Evaluation of methods to predict reactivity of gold nanoparticles. AB - Several methods have appeared in the literature for predicting reactivity on metallic surfaces and on the surface of metallic nanoparticles. All of these methods have some relationship to the concept of frontier molecular orbital theory. The d-band theory of Hammer and Norskov is perhaps the most widely used predictor of reactivity on metallic surfaces, and it has been successfully applied in many cases. Use of the Fukui function and the condensed Fukui function is well established in organic chemistry, but has not been so widely applied in predicting the reactivity of metallic nanoparticles. In this article, we will evaluate the usefulness of the condensed Fukui function in predicting the reactivity of a family of cubo-octahedral gold nanoparticles and make comparison with the d-band method. PMID- 21687879 TI - Superexchange mediated energy transfer in zinc(II) porphyrin-free base porphyrin dimers: comparison of m- and p-bis(phenylethynyl) phenylene linked dimers. AB - The singlet-singlet energy transfer rate in a new zinc(II) porphyrin-free base porphyrin dimer, having a m-bis(phenylethynyl)phenylene bridge, was found to be slower than that in the corresponding p-bis(phenylethynyl)phenylene-bridged dimer, despite the shorter donor-acceptor distance and pathway. The slower rate is interpreted as evidence for a major contribution of the superexchange mechanism. PMID- 21687880 TI - Molecular mass dependence of adsorbed amount and hydrodynamic thickness of polyelectrolyte layers. AB - Highly charged polyelectrolytes adsorbed on oppositely charged colloidal particles are investigated by electrophoresis and dynamic light scattering. The dependence of the adsorbed amount and of the hydrodynamic layer thickness on the molecular mass and the salt level is analyzed. The adsorbed amount increases with increasing salt level and decreases with increasing molecular mass. The hydrodynamic layer thickness is independent of the molecular mass at low salt levels, but increases with the molecular mass as a power law with an exponent 0.10 +/- 0.01 at high salt. The same behavior was observed for different polyelectrolytes and substrates and therefore is suspected to be generic. Due to semi-quantitative agreement with computer simulations carried out by Kong and Muthukumar in 1998, the observed behavior is interpreted with conformational changes of single adsorbed polyelectrolyte chains. PMID- 21687881 TI - Laboratory simulation of Kuiper belt object volatile ices under ionizing radiation: CO-N2 ices as a case study. AB - The exposure of icy Kuiper belt objects (KBOs) by ionizing radiation was simulated in this case of exposing carbon monoxide-nitrogen (CO-N(2)) ices by energetic electrons. The radiation-induced chemical processing was monitored on line and in situ via FTIR spectroscopy and quadrupole mass spectrometry. Besides the array of carbon oxides being reproduced as in neat irradiated carbon monoxide (CO) ices studied previously, the radiation exposure at 10 K resulted in the formation of nitrogen-bearing species of isocyanato radical (OCN), linear (l NCN), nitric oxide (NO), nitrogen dioxide (NO(2)), plus diazirinone (N(2)CO). The infrared assignments of these species were further confirmed by isotopic shifts. The temporal evolution of individual species was found to fit in first-order reaction schemes, prepping up the underlying non-equilibrium chemistry on the formation of OCN, l-NCN, and NO radicals in particular. Also unique to the binary KBO model ices and viable for the future remote detection is diazirinone (N(2)CO) at 1860 cm(-1) (2nu(5)) formed at lower radiation exposure. PMID- 21687882 TI - Bias-stress effects in organic field-effect transistors based on self-assembled monolayer nanodielectrics. AB - The electrical stability of low-voltage organic transistors based on phosphonic acid self-assembled monolayer (SAM) dielectrics is investigated using four different semiconductors. The threshold voltage shift in these devices shows a stretched-exponential time dependence under continuous gate bias with a relaxation time in the range of 10(3)-10(5) s, at room temperature. Differences in the bias instability of transistors based on different self-assembled monolayers and organic semiconductors suggest that charge trapping into localized states in the semiconductor is not the only mechanism responsible for the observed instability. By applying 1-5 s long programming voltage pulses of 2-3 V in amplitude, a large reversible threshold voltage shift can be produced. The retention time of the programmed state was measured to be on the order of 30 h. The combination of low voltage operation and relatively long retention times makes these devices interesting for ultra-low power memory applications. PMID- 21687883 TI - Actinide sulfides in the gas phase: experimental and theoretical studies of the thermochemistry of AnS (An = Ac, Th, Pa, U, Np, Pu, Am and Cm). AB - The gas-phase thermochemistry of actinide monosulfides, AnS, was investigated experimentally and theoretically. Fourier transform ion cyclotron resonance mass spectrometry was employed to study the reactivity of An(+) and AnO(+) (An = Th, Pa, U, Np, Pu, Am and Cm) with CS(2) and COS, as well as the reactivity of the produced AnS(+) with oxidants (COS, CO(2), CH(2)O and NO). From these experiments, An(+)-S bond dissociation energies could be bracketed. Density functional theory studies of the energetics of neutral and monocationic AnS (An = Ac, Th, Pa, U, Np, Pu, Am and Cm) provided values for bond dissociation energies and ionization energies; the computed energetics of neutral and monocationic AnO were also obtained for comparison. The theoretical data, together with comparisons with known An(+)-O bond dissociation energies and M(+)-S and M(+)-O dissociation energies for the early transition metals, allowed for the refining of the An(+)-S bond dissociation energy ranges obtained from experiment. Examination of the reactivity of AnS(+) with dienes, coupled to comparisons with reactivities of the AnO(+) analogues, systematic considerations and the theoretical results, allowed for the estimation of the ionization energies of the AnS; the bond dissociation energies of neutral AnS were consequently derived. Estimates for the case of AcS were also made, based on correlations of the data for the other An and the electronic energetics of neutral and ionic An. The nature of the bonding in the elementary molecular actinide chalcogenides (oxides and sulfides) is discussed, based on both the experimental data and the computed electronic structures. DFT calculations of ionization energies for the actinide atoms and the diatomic sulfides and oxides are relatively reliable, but the calculation of bond dissociation energies is not uniformly satisfactory, either with DFT or CCSD(T). A key conclusion from both the experimental and theoretical results is that the 5f electrons do not substantially participate in actinide sulfur bonding. We emphasize that actinides form strikingly strong bonds with both oxygen and sulfur. PMID- 21687884 TI - Stabilizing carbon-lithium stars. AB - We have explored in silico the potential energy surfaces of the C(5)Li(n)(n-6) (n = 5, 6, and 7) clusters using the Gradient Embedded Genetic Algorithm (GEGA) and other computational strategies. The most stable forms of C(5)Li(5)(-) and C(5)Li(6) are two carbon chains linked by two lithium atoms in a persistent seven membered ring capped by two Li atoms. The other Li atoms are arrayed on the edge of the seven membered ring. In contrast, the global minimum structure for C(5)Li(7)(+) is a bicapped star of D(5h) symmetry. The molecular orbital analysis and computed magnetic field data suggest that electron delocalization, as well as the saturation of the apical positions of the five-membered carbon ring with lithium atoms in C(5)Li(7)(+) plays a key role in the stabilization of the carbon lithium star. In fact, the planar star sub-structure for the carbon ring are unstable without the apical caps. This is also what has been found for the Si analogues. The split of the B(ind)(z) in its sigma- and pi-contribution indicates that C(5)Li(7)(+) is a pi-aromatic and sigma-nonaromatic system. PMID- 21687885 TI - Dimer formation of organic fluorophores reports on biomolecular dynamics under denaturing conditions. AB - Stacking interactions between organic fluorophores can cause formation of non fluorescent H-dimers. Dimer formation and dissociation of two fluorophores site specifically incorporated in a biomolecule result in fluorescence intermittency that can report on conformational dynamics. We characterize intramolecular dimerization of two oxazine fluorophores MR121 attached to an unstructured polypeptide. Formation of stable non-fluorescent complexes with nano- to microsecond lifetimes is a prerequisite for analysing the intermittent fluorescence emission by fluorescence correlation spectroscopy and extracting relaxation time constants on nano- to millisecond time scales. Destabilization of the generally very stable homodimers by chemical denaturation reduces the lifetime of H-dimers. We demonstrate that H-dimer formation of an oxazine fluorophore reports on end-to-end contact rates in unstructured glycine-serine polypeptides under denaturing conditions. PMID- 21687886 TI - Electronic structure of sub-10 nm colloidal silica nanoparticles measured by in situ photoelectron spectroscopy at the aqueous-solid interface. AB - X-Ray photoelectron spectroscopy has been extended to colloidal nanoparticles in aqueous solution using a liquid microjet in combination with synchrotron radiation, which allowed for depth-dependent measurements. Two distinct electronic structures are evident in the Si 2p photoelectron spectrum of 7 nm SiO(2)-nanoparticles at pH 10. A core-shell model is proposed where only the outermost layer of SiO(2) nanoparticles, which is mainly composed of deprotonated silanol groups, >Si-O(-), interacts with the solution. The core of the nanoparticles is not affected by the solvation process and retains the same electronic structure as measured in vacuum. Future opportunities of this new experiment are also highlighted. PMID- 21687887 TI - Chiral induction by helical neighbour: spectroscopic visualization of macroscopic interaction among self-sorted donor and acceptor pi-stacks. AB - Supramolecular induction of chirality to a pi-stacked dialkoxynaphthalene (DAN) fiber (made of achiral building blocks) from a neighbouring helical naphthalenediimide (NDI)-fiber is reported. CD-studies helped in understanding the nature of co-assembly in the donor-acceptor chromophore mixture from molecular to macroscopic scale. PMID- 21687888 TI - Ytterbium stabilized ordered mesoporous titania for near-infrared photocatalysis. AB - An effective synthetic strategy is demonstrated for preparing highly ordered crystallized mesoporous TiO(2) by introducing rare earth in the synthesis process; the obtained product exhibits near-infrared photocatalytic activity. PMID- 21687889 TI - Ordered mesoporous carbon catalyst for dehydrogenation of propane to propylene. AB - Metal-free ordered mesoporous carbons were demonstrated to be robust catalysts for direct dehydrogenation of propane to propylene, in the absence of any auxiliary steam, exhibiting high activity and selectivity, as well as long catalytic stability, in comparison with nanostructured carbons. PMID- 21687890 TI - Tandem indole C-H alkenylation/arylation for tetra-substituted alkene synthesis. AB - Alkynyl indoles undergo a novel sequence of Pd-catalysed indole C-H activation/alkyne carbopalladation/arylation, with diaryliodonium salts providing the aryl components. An array of functionalised indole alkenes have been prepared in good to excellent yield, with the reaction being selective for the Z-alkene. PMID- 21687891 TI - A Wulff-type boronate for boronate affinity capture of cis-diol compounds at medium acidic pH condition. AB - A new Wulff-type boronate was designed and synthesized. Upon immobilization on a polymeric monolith and acidified as boronic acid, the ligand exhibited specific boronate affinity to cis-diol compounds at medium acidic pH condition. PMID- 21687892 TI - Surface immobilizable chelator for label-free electrical detection of pyrophosphate. AB - A new pyrophosphate (PPi) chelator was designed for surface-sensitive electrical detection of biomolecular reactions. This article describes the synthesis of the PPi-selective receptor, its surface immobilization and application to label-free electrical detection on a silicon-based field-effect transistor (FET) sensor. PMID- 21687893 TI - TAP studies of ammonia decomposition over Ru and Ir catalysts. AB - The Temporal Analysis of Products (TAP) technique has been used to investigate the mechanism involved in the catalytic decomposition of NH(3) over a series of catalysts consisting of activated carbon supported Ru (promoted and non-promoted with Na) and over an activated carbon supported Ir. An extensive study of the role played by both the support and the promoter in the "side reactions" and in the stability and surface lifetime of the NH(x) species has been performed. It was suggested that the N(2) produced during the first steps of the reaction over the activated carbon supported Ru catalysts promoted with Na forms a Na-N-Ru complex at the promoter-transition metal crystallite interface. This study also suggests that the Na promoter prevents the diffusion of hydrogen from the metal to the support via spill-over. A similar effect was observed after the thermal treatment at high temperature of the carbon catalyst support. Finally large differences in multi-pulse TAP results have been detected between Ru and Ir catalysts implying that the NH(3) decomposition reaction mechanism must be different on both metals. PMID- 21687894 TI - Modification of the ZnO(0001)-Zn surface under reducing conditions. AB - The ZnO(0001)-Zn terminated crystal face was studied after reduction at high temperatures by combination of STM, STS, XPS and TDS. The clean ZnO(0001)-Zn surface exhibits triangular reconstruction in UHV, while after exposure to 10(-5) mbar H(2) at RT this reconstruction is lifted and a rough surface has formed. The roughness as well as the metallic character of the surface increased with the applied low-pressure reduction temperature up to 800 K. XPS revealed that exposure to 1 bar H(2) at RT led to the formation of OH groups; at higher temperatures progressive metallization of the ZnO surface was found to occur. Analysis of the thermal desorption results showed that huge amounts of H(2) dissolved into the ZnO crystal. The results obtained under these conditions were in good accordance with thermodynamic calculations. The experimental ratio between the absorbed amount of H(2) at RT and 800 K amounts to 1000. The ratio calculated from increasing diffusion coefficients with temperature only amounts to 6. This emphasizes the importance of ZnO as a H supplier by spillover, and proves that metallic Zn boosts dissociative adsorption of H(2). This surface modification of the ZnO structure during the reduction promotes an enhanced activity of the Cu/ZnO catalyst at elevated temperatures. PMID- 21687895 TI - Edge effects, electronic arrangement, and aromaticity patterns on finite-length carbon nanotubes. AB - Previous investigations have revealed that even long carbon nanotubes (CNTs) retain bond patterns that are characterized by the localization of Clar rings. Even for CNTs with 10 nm length, an alternated, oscillating structure of Clar and Kekule patterning was also found, indicating that these arrangements may possibly persist for even longer nanotubes, given that they are finite. In the present work, we perform a detailed and comprehensive theoretical study of this phenomenon, in order to find the causes that give rise to these patterns. A complete set of CNTs with different chiralities, diameters (up to 2 nm), lengths (up to 10 nm) and endings (capped, uncapped, and tailored endings) was considered for such purposes. The results indicate that the Clar patterning appears not only on armchair CNTs, but also on those with chiral angle values close to 30 degrees , and this results in a stabilization of the structure, when compared with the uniform, zigzag CNTs. This stabilizing effect points to the causes that underlie the three Nakamura CNT types, resulting as the superposition of structures with a maximal number of Clar rings. Although there is a strict dependence on the border shape, the main cause of the bond patterning in long tubes is to be found in the intrinsic wrapping of each CNT, because the type and number of oscillations present in the longest structures do not depend on the particular length. Nevertheless, the three Nakamura types of armchair tubes appear to subsist beyond the appearance of oscillations, because each of these sets evolves in a different manner, and energy properties that link them together. Apart from the geometry, Clar patterning was investigated through NICS (Nucleus Independent Chemical Shifts) measures, which reveal a connection between the Clar rings and a local concentration of aromaticity. PMID- 21687896 TI - Effects of the substituents on the reactivity of carbonyl oxides. A theoretical study on the reaction of substituted carbonyl oxides with water. AB - The reactions between fifteen carbonyl oxides and water have been investigated with the aim of contributing to a better understanding of the effects of the substituents in the reactivity of carbonyl oxides. We have employed density functional theory and large scale ab initio methods (CCSD(T), CASSCF, and CASPT2), combined with transition state theory, to investigate the addition of water to carbonyl oxide and, for those carbonyl oxides having a methyl substituent in syn, the hydrogen transfer from the methyl group to the terminal oxygen of carbonyl oxide. In this case, the water acts as a catalyst and this reaction can contribute to the atmospheric formation of a hydroxyl radical. Carbonyl oxides with electron withdrawing substituents and zwitterionic character have low energy barriers and react fast, whereas carbonyl oxides with electron releasing substituents have high energy barriers and react slowly. The position of the substituents plays also an important role and carbonyl oxides having a hydrogen atom substituent in syn react faster than carbonyl oxides having a hydrogen atom substituent in anti. The differences in the reactivity of different substituted carbonyl oxides raise up to ten orders of magnitude and the branching ratios for the two different reactions investigated are also reported. PMID- 21687897 TI - Novel halogen-free chelated orthoborate-phosphonium ionic liquids: synthesis and tribophysical properties. AB - We report on the synthesis, characterisation, and physical and tribological properties of halogen-free ionic liquids based on various chelated orthoborate anions with different phosphonium cations, both without halogen atoms in their structure. Important physical properties of the ILs including glass transition temperatures, density, viscosity and ionic conductivity were measured and are reported here. All of these new halogen-free orthoborate ionic liquids (hf-BILs) are hydrophobic and hydrolytically stable liquids at room temperature. As lubricants, these hf-BILs exhibit considerably better antiwear and friction reducing properties under boundary lubrication conditions for steel-aluminium contacts as compared with fully formulated (15W-50 grade) engine oil. Being halogen free these hf-BILs offer a more environmentally benign alternative to ILs being currently developed for lubricant applications. PMID- 21687898 TI - Discrete half-sandwich Ir, Rh-based organometallic molecular boxes: synthesis, characterization, and their properties. AB - The treatment of binuclear complexes [Cp*(2)M(2)(MU-QA)Cl(2)] (M = Ir, 2a; M = Rh, 2b) (H(2)QA = 1,4-dihydroxyanthraquinone) with pyrazine or bifuncational pyridyl-based ligands (4,4'-dipyridine (bpy), E-1,2-bis(4-pyridyl)ethene (bpe), 2,5-bis(4-pyridyl)-1,3,4-oxadiazole (bpo), and 2,5-bis(4-pyridyl)-1,3,4 thiadiazol (bpt)) in the presence of AgOTf (OTf = CF(3)SO(3)) in CH(3)OH, gave the corresponding tetra-nuclear complexes, with a general formula of [Cp*(4)M(4)(MU-QA)(2)(MU-L)(2)](OTf)(4) (M = Ir, 3a-7a; M = Rh, 3b-7b), respectively. The molecular structure of [Cp*(4)Ir(4)(MU-QA)(2)(MU pyrazine)(2)](OTf)(4) (3a) has been determined by single-crystal X-ray analysis, revealing that the metal centers were connected by pyrazine and bis-bidentate QA(2-) ligands to construct a rectangular cavity with the dimension of 7.30 * 8.41 * 6.92 A. Complexes 3a and 3b were found to exhibit selective trapping of halocarbons properties. PMID- 21687899 TI - Rhodium and iridium complexes of an asymmetric bicyclic NHC bearing secondary pyridyl donors. AB - A tridentate N^C^N ligand, 1, containing a bicyclic central NHC ring and two flanking pyridyl groups has been coordinated to Rh(I) and Ir(I) to give complexes of the type [M(kappa(3)-1)(1,5-COD)]PF(6) (2 M = Rh; 3 M = Ir). In contrast to our earlier study with this ligand, the complexes have been shown to approximate to a trigonal bipyramidal geometry in the solid state and exist as an isomeric mixture in solution as determined by (1)H and (13)C NMR spectroscopy. Electrochemical studies revealed that both complexes undergo a 1-electron oxidation with the potential of the Rh complex 0.1 V less than that of the Ir complex in CH(2)Cl(2). Preliminary DFT studies confirm the lowest energy conformations as those seen in the solid state and show the location and energy of the HOMOs to be identical in 2 and 3. Partial charge analysis shows a greater positive charge on the Ir in 3 compared to the Rh in 2. Some preliminary studies of hydrogenation reactivity have shown the complexes to be efficient for both transfer and direct hydrogenation of prochiral ketones and alkenes at moderate temperatures but without any discernible enantioselectivity. PMID- 21687900 TI - Bis(2-pyridylimino)isoindolato iron(II) and cobalt(II) complexes: structural chemistry and paramagnetic NMR spectroscopy. AB - Condensation of phthalodinitrile and 2-amino-5,6,7,8-tetrahydroquinoline gave the bis(2-pyridylimino)isoindole protioligand 1 (thqbpiH) in high yield. Deprotonation of thqbpiH (1) using LDA in THF at -78 degrees C yields the corresponding lithium complex [Li(THF)(thqbpi)] (2) in which the lithium atom enforces almost planar arrangement of the tridentate ligand, with an additional molecule of THF coordinated to Li. Reaction of cobalt(II) chloride or iron(II) chloride with one equivalent of the lithium complex 2 in THF led to formation of the metal complexes [CoCl(THF)(thqbpi)] (3a) and [FeCl(THF)(thqbpi)] (3b). The paramagnetic susceptibility of 3a,b in solution was measured by the Evans method (3a: MU(eff) = 4.17 MU(B); 3b: MU(eff) = 5.57 MU(B)). Stirring a solution of 1 and cobalt(II) acetate tetrahydrate in methanol yielded the cobalt(II) complex 4 which was also accessible by treatment of 3a with one equivalent of silver or thallium acetate in DMSO. Whereas 3a,b were found to be mononuclear in the solid state, the acetate complex 4 was found to be dinuclear, the two metal centres being linked by an almost symmetrically bridging acetate. For all transition metal complexes paramagnetic (1)H as well as (13)C NMR spectra were recorded at variable temperatures. The complete assignment of the paramagnetic NMR spectra was achieved by computation of the spin densities within the complexes using DFT. The proton NMR spectra of 3a and 3b displayed dynamic behaviour. This was attributed to the exchange of coordinating solvent molecules by an associative mechanism which was analysed using lineshape analysis (DeltaS(?)= -154 +/- 25 J mol(-1) K(-1) for 3a and DeltaS(?) = -168 +/- 15 J mol(-1) K(-1) for 3b). PMID- 21687901 TI - Tris(pyrazolyl)borate amidoborane complexes of the group 4 metals. AB - Treatment of the tris(pyrazolyl)borate metal triamides Tp'M(NMe(2))(3), where Tp' = (C(3)H(3)N(2))(3)BH (Tp) or (3,5-Me(2)C(3)HN(2))(3)BH (Tp*) and M = Ti, Zr and Hf, with the Bronsted acidic Lewis adduct (C(6)F(5))(3)B.NH(3) in toluene solution leads to the formation of Tp'M(NMe(2))(2){NH(2)B(C(6)F(5))(3)} complexes. The exception to this was the attempted preparation of Tp*Ti(NMe(2))(2){NH(2)B(C(6)F(5))(3)} which was unsuccessful. Where Tp' = Tp and M = Ti and Zr and where Tp' = Tp* and M = Zr the complexes have been characterized by single crystal X-ray diffraction methods, revealing the first examples of octahedral amidoborane complexes of the group 4 metals. Attempts to drive the reactions to completion resulted in competing preferential hydrolysis of the amidoborane group, regenerating (C(6)F(5))(3)B.NH(3). PMID- 21687902 TI - Individually color-coded plasmonic nanoparticles for RGB analysis. AB - Colors of scattering light of single gold nanoparticles (AuNPs) were coded with the tricolor (RGB) system by assigning digital values to R, G and B and then this was applied to binding studies of thiols to AuNPs through RGB analysis. PMID- 21687903 TI - Pickering emulsion templated soft capsules by self-assembling cross-linkable ferritin-polymer conjugates. AB - Oil-in-water (o/w) and water-in-oil (w/o) Pickering emulsions were prepared using ferritin-polymer conjugates. UV cross-linking stabilised the particle assembly around the fluid droplets. The resulting soft protein-polymer capsules were transferred to a medium of equal polarity as the inside of the capsule, creating water-in-water (w/w) and oil-in-oil (o/o) capsules. PMID- 21687904 TI - Inhibiting CO formation by adjusting surface composition in PtAu alloys for methanol electrooxidation. AB - CO poisoning during methanol electrooxidation was investigated on PtAu alloys with different surface compositions. Results show that the CO formation can be reduced gradually with increasing surface Au fractions in PtAu alloys and CO poisoning can be almost eliminated by adjusting to a proper surface Au fraction. PMID- 21687905 TI - Vitamin B12-derivatives-enzyme cofactors and ligands of proteins and nucleic acids. AB - B(12)-cofactors play important roles in the metabolism of microorganisms, animals and humans. Microorganisms are the only natural sources of B(12)-derivatives, and the latter are "vitamins" for other B(12)-requiring organisms. Some B(12) dependent enzymes catalyze complex isomerisation reactions, such as methylmalonyl CoA mutase. They need coenzyme B(12), an organometallic B(12)-derivative, to induce enzymatic radical reactions. Another group of widely relevant enzymes catalyzes the transfer of methyl groups, such as methionine synthase, which uses methylcobalamin as cofactor. This tutorial review covers structure and reactivity of B(12)-derivatives and structural aspects of their interactions with proteins and nucleotides, which are crucial for the efficient catalysis by the important B(12)-dependent enzymes, and for achieving and regulating uptake and transport of B(12)-derivatives. PMID- 21687906 TI - Psychiatry research in South Africa: reason for cautious celebration? PMID- 21687907 TI - Public and community health psychiatry in Africa: from humble beginnings to a promising future. PMID- 21687908 TI - Genetics of schizophrenia: communicating scientific findings in the clinical setting. AB - The expected identification of susceptibility genes for psychiatric disorders may bring new opportunities and expectations from patients and families for the clinical translation of research findings in psychiatric genetics. In this article information is provided about familial risk of schizophrenia with the theory behind individualizing risk of recurrence highlighted. Recent new findings regarding the new genetic frontier, Copy Number Variations (CNV), are summarized and the genetic architecture of familial and sporadic schizophrenia applicable to the clinical situation is reviewed. A scenario in which genetic testing could be applied in velocardiofacial syndrome (VCFS) type schizophrenia is debated. Referring to genetic discrimination in mental disorders, reference is made to the implementation of the Federal Genetic Information non-discrimination Act (GINA) of 2008 in the USA and the Mental Health Care Act of 2002 in SA. PMID- 21687909 TI - Acute mental health care according to recent mental health legislation. Part III. Structuring space for acute mental health care. AB - OBJECTIVE: This is the third of three reports on the follow-up review of mental health care at Helen Joseph Hospital (HJH). The study reviewed existing South African standards for mental health care facilities. Architectural principles and implications for the use of space were deducted from recent legislation. Objectives were to evaluate the use of space in the existing physical facilities, to identify appropriate architectural solutions considering identified human rights requirements and to provide provisional cost estimates to align the unit towards its designated functions. METHOD: Personal interviews were conducted. An on-site assessment and survey was made of existing and potential new spaces. RESULTS: Spatial requirements for implementing the Mental Health Act, No. 17 of 2002 (MHCA) were explored. Principles for spatial design of acute facilities include that: - spaces should communicate clear individual identity; - space should be segregated into zones according to user functionality and privacy; - communal leisure spaces should open into safe contained outdoor spaces; - circulation routes should preferably be circular; - sufficient visual connection should exist between circulation space and group activities; and - open lines of sight should be provided to all access points. The potential options for extension included: - an extensive unused single storey structural shell for a potential office wing on the same floor; - a huge vacant double volume space which could be accessed across the existing flat roof for potential occupational therapy activities; and - the existing roof area could be altered and secured to become an adequate outside leisure and garden area. A proposed concept design in two phases - based on these principles - was submitted to hospital and provincial management. CONCLUSION: To implement the MHCA without violating the human rights of mental health care users at HJH will require specific adjustment and extension of the current use of space at HJH. PMID- 21687910 TI - Patient and social work factors related to successful placement of long-term psychiatric in-patients from a specialist psychiatric hospital in South Africa. AB - OBJECTIVE: The slow discharge of long-term psychiatry patients from Weskoppies Hospital into the community has not matched the national and international drive towards deinstitutionalisation. This article investigates patient and social work factors related to successful community placement, in the context of limited community care facilities. METHOD: Thirty-six long-term patients who were successfully placed outside of the hospital during a seven month period were compared to 235 unplaced long-term patients in terms of demographic and clinical variables. Social work services were analysed in terms of which patients received the most interventions, and the most common type of interventions. RESULTS: The most significant patient factors associated with successful placement were: female patients; medium-to-high level of functioning; having involved relatives living far away; a low frequency of behavioural problems (especially of cannabis abuse, verbal or physical aggression, uncontrolled sexual activity), and agitation or restlessness. These patient factors were mirrored in the social work services rendered to the long-term patients during the study period: The recipients were mostly female, in open wards (higher-functioning); and the social services utilised were mostly related to planning for placement and patient support. CONCLUSION: The lack of community care facilities in the Pretoria area that are able to care for the more difficult long-term psychiatry patients, limits successful placement and increases the burden of hospital based social workers. The problem cannot be resolved at a hospital level and needs to be addressed in the context of provincial and national health departments. PMID- 21687911 TI - Patient aggression in psychiatric services: the experience of a sample of nurses at two psychiatric facilities in Nigeria. AB - OBJECTIVE: Aggression is a common feature in psychiatric in-patient units in Africa. The attitudes of psychiatric nurses and their perceptions of the frequency of in-patient aggression have not been explored in the Nigerian context. METHOD: Using a crosssectional study design, two self-report questionnaires (the Attitudes toward Aggression Scale (ATAS) and the Perception of the Prevalence of Aggression Scale (POPAS)) were administered to nursing staff (n=73) at two psychiatric facilities in Benin City, Nigeria. RESULTS: Overall, nurses viewed aggression as offensive, destructive and intrusive. They were less likely to view it as a means of communication or serving protective functions. Verbal aggression was the commonest type of aggression experienced while sexual intimidation and suicide attempts were least common. Male nurses were more likely to experience physical violence and aggressive 'splitting' behaviours, while nurses with over a decade of professional experience were more likely to experience verbal and humiliating aggressive behaviours. In contrast to previous studies, fewer nurses required days off work due to aggressive behaviour. CONCLUSION: Aggression is commonly experienced by nurses in in-patient units in Nigeria. Their views were predominantly negative. Training programmes are required to change staff attitudes as well as research on the cultural factors mediating these attitude dispositions. PMID- 21687912 TI - Lifetime mental disorders and suicidal behaviour in South Africa. AB - OBJECTIVE: There is relatively little data on the relationship between lifetime mental disorders and suicidal behaviour in low and middle income countries. This study examines the relationship between lifetime mental disorders, and subsequent suicide ideation, plans, and suicide attempts in South Africa. METHOD: A national survey of 4185 South African adults was conducted using the World Health Organization Composite International Diagnostic Interview (CIDI) to generate psychiatric diagnoses and suicidal behaviour. Bivariate, multivariate and discrete-time survival analyses were employed to investigate the associations between mental disorders and subsequent suicide ideation, plans, and attempts. RESULTS: Sixty-one percent of people who seriously considered killing themselves at some point in their lifetime reported having a prior DSM-IV disorder. Mental disorders predict the onset of suicidal ideation, but have weaker effects in predicting suicide plans or attempts. After controlling for comorbid mental disorders, PTSD was the strongest predictor of suicidal ideation and attempts. There is a relationship between number of mental disorders and suicidal behaviour, with comorbidity having significantly sub-additive effects. CONCLUSION: Consistent with data from the developed world, mental disorders are strong predictors of suicidal behaviour, and these associations are more often explained by the prediction of ideation, rather than the prediction of attempts amongst ideators. This suggests some universality of the relevant mechanisms underlying the genesis of suicidal thoughts, and the progression to suicide attempts. PMID- 21687913 TI - Prevalence of common phobias and their socio-demographic correlates in children and adolescents in a traditional developing society. AB - OBJECTIVE: The aim of this study was to identify the most common phobias in children and adolescents and to determine the prevalence, age distribution, and socio-demographic correlates of phobias. METHOD: This was a prospective cross sectional study conducted at public and private schools from July 2009 to February 2009. The questionnaire included socio-demographic information, extra curricular activities and hobbies, behaviour at home and various phobic fears and it was distributed among children aged 6 to 18 years. Psychiatrists determined the definitive diagnosis for various phobias by checking and screening their symptoms. RESULTS: Of the studied subjects, 44% were males and 56% were females. The overall prevalence of phobia in children and adolescents was 19.7%. Among children with phobia, females had higher rates of phobias (62.4% vs 37.6%) than males. Nearly half of total sufferers were in the 12-15 year age group (46.3%). Social phobia (12.7%) was the commonest phobia found followed by agoraphobia (8.6%). Secondary school children were highly afflicted with social phobia (14.9%), agoraphobia (11.7%) and specific phobia (9.6%), while preparatory students (8.3%) were more likely to have 'medical' phobia (fear of physical illness, medical tests and procedures). A significant difference was observed between the age groups in children with agoraphobia (p=0.002). CONCLUSION: The overall prevalence of phobia in children and adolescents in Qatar was higher than rates found in other epidemiologic studies, with the most common phobias observed being social phobia, agoraphobia and specific phobia. PMID- 21687914 TI - Gender differences in barriers to alcohol and other drug treatment in Cape Town, South Africa. AB - OBJECTIVE: The study aimed to identify gender differences in barriers to alcohol and other drug (AOD) treatment use among disadvantaged communities in Cape Town, South Africa. The Behavioral Model of Health Services Utilization was used as an analytic framework. METHOD: A case-control design was used to compare 434 individuals with AOD problems from disadvantaged communities who had accessed treatment with 555 controls who had not accessed treatment on a range of variables. Logistic regression procedures were employed to examine the unique profile of variables associated with treatment utilization for male and female participants. RESULTS: Few gender differences emerged in terms of the pattern of variables associated with AOD treatment use. Greater awareness of treatment options and fewer geographic access and affordability barriers were strongly associated with an increased likelihood of AOD treatment use for both men and women from disadvantaged communities. However, while similar types of barriers to treatment were reported by men and women, these barriers had a greater impact on treatment utilization for women compared to men. CONCLUSION: Compared to men, women from disadvantaged communities in South Africa do not have equal access to AOD treatment. Recommendations on how to reduce these barriers and ways to improve AOD treatment use among women from disadvantaged communities in South Africa are provided. PMID- 21687915 TI - Phaeochromocytoma -- a classic (but easily forgotten) cause of anxiety. PMID- 21687916 TI - Anticoagulants. Old and new. AB - Anticoagulants are effective in the prevention and treatment of a variety of arterial and venous thrombotic disorders but are associated with an increased risk of serious bleeding complications. Based on well documented studies of patients using vitamin K antagonists the incidence of major bleeding is 0.5%/year and the incidence of intracranial bleeding is 0.2%/year, however, in real life practice this incidence may be even higher. Risk factors for bleeding are the intensity of anticoagulation, the management strategy to keep the anticoagulant effect in the desired range, and patient characteristics. Recently, a new generation of anticoagulants have been developed and is currently evaluated in clinical trials. Initial results show a similar or superior efficacy over conventional anticoagulant agents with a good safety profile. In case of serious bleeding complications in a patient who uses vitamin K antagonists, this anticoagulant treatment can be quickly reversed by administration of vitamin K or coagulation factor concentrates. For the newer anticoagulants, quick reversal strategies are more cumbersome, although some interventions, including prothrombin complex concentrates, show promising results in initial experimental studies. PMID- 21687917 TI - Adipocyte enhancer-binding protein 1 (AEBP1) (a novel macrophage proinflammatory mediator) overexpression promotes and ablation attenuates atherosclerosis in ApoE (-/-) and LDLR (-/-) mice. AB - Atherogenesis is a long-term process that involves inflammatory response coupled with metabolic dysfunction. Foam cell formation and macrophage inflammatory response are two key events in atherogenesis. Adipocyte enhancer-binding protein 1 (AEBP1) has been shown to impede macrophage cholesterol efflux, promoting foam cell formation, via peroxisome proliferator-activated receptor (PPAR)-gamma1 and liver X receptor alpha (LXRalpha) downregulation. Moreover, AEBP1 has been shown to promote macrophage inflammatory responsiveness by inducing nuclear factor (NF) kappaB activity via IkappaBalpha downregulation. Lipopolysaccharide (LPS)-induced suppression of pivotal macrophage cholesterol efflux mediators, leading to foam cell formation, has been shown to be mediated by AEBP1. Herein, we showed that AEBP1-transgenic mice (AEBP1(TG)) with macrophage-specific AEBP1 overexpression exhibit hyperlipidemia and develop atherosclerotic lesions in their proximal aortas. Consistently, ablation of AEBP1 results in significant attenuation of atherosclerosis (males: 3.2-fold, P = 0.001 [en face]), 2.7-fold, P = 0.0004 [aortic roots]; females: 2.1-fold, P = 0.0026 [en face], 1.7-fold, P = 0.0126 [aortic roots]) in the AEBP1(-/-)/low-density lipoprotein receptor (LDLR )(-/-) double-knockout (KO) mice. Bone marrow (BM) transplantation experiments further revealed that LDLR (-/-) mice reconstituted with AEBP1(-/-)/LDLR (-/-) BM cells (LDLR (-/-)/KO-BM chimera) display significant reduction of atherosclerosis lesions (en face: 2.0-fold, P = 0.0268; aortic roots: 1.7-fold, P = 0.05) compared with control mice reconstituted with AEBP1(+/+)/LDLR (-/-) BM cells (LDLR (-/-)/WT-BM chimera). Furthermore, transplantation of AEBP1(TG) BM cells with the normal apolipoprotein E (ApoE) gene into ApoE (-/-) mice (ApoE (-/-)/TG BM chimera) leads to significant development of atherosclerosis (males: 2.5-fold, P = 0.0001 [en face], 4.7-fold, P = 0.0001 [aortic roots]; females: 1.8-fold, P = 0.0001 [en face], 3.0-fold, P = 0.0001 [aortic roots]) despite the restoration of ApoE expression. Macrophages from ApoE (-/-)/TG-BM chimeric mice express reduced levels of PPARgamma1, LXRalpha, ATP-binding cassette A1 (ABCA1) and ATP-binding cassette G1 (ABCG1) and increased levels of the inflammatory mediators interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha compared with macrophages of control chimeric mice (ApoE (-/-)/NT-BM ) that received AEBP1 nontransgenic (AEBP1(NT) ) BM cells. Our in vivo experimental data strongly suggest that macrophage AEBP1 plays critical regulatory roles in atherogenesis, and it may serve as a potential therapeutic target for the prevention or treatment of atherosclerosis. PMID- 21687918 TI - Factors associated with misdiagnosis of COPD in primary care. AB - AIMS: To assess the misclassification of chronic obstructive pulmonary disease (COPD) in Australian primary care. METHODS: A cross-sectional study was performed in 31 (19%) practices in one Australian state. 341 patients with COPD (database diagnosis or current use of tiotropium plus GP confirmation) completed spirometry and questionnaires. Predictors of misclassification were investigated with multi level mixed-effects logistic regression allowing for clustering by practice. RESULTS: Spirometric confirmation of COPD (forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio <0.7) was not present in 107 (31%) patients; 60 (56%) had normal lung function, seven (7%) had scalloped flow-volume curves and FEV1 <80% predicted, 40 (37%) had restriction (FVC <80% predicted). Among 107 misclassified patients the bronchodilators used were tiotropium in 26% and long acting beta2-agonists in 22%. The likelihood of misclassification increased with overweight/obesity (odds ratio (OR) 2.66; 95% CI 1.50 to 4.70) and self-reported allergic rhinitis/hay fever (OR 1.72; 95% CI 1.13 to 2.64) after adjustment for age, gender, and smoking. CONCLUSIONS: Symptom-based diagnosis of COPD in primary care is unreliable, especially if patients are overweight, so diagnostic spirometry is essential to avoid inappropriate management. PMID- 21687919 TI - A randomised controlled trial of the effect of automated interactive calling combined with a health risk forecast on frequency and severity of exacerbations of COPD assessed clinically and using EXACT PRO. AB - BACKGROUND: We have developed a winter forecasting service to predict when patients with COPD are at higher risk of an exacerbation and alert them via an automated telephone call. AIMS: To assess the effect of the service and its ability to predict periods of increased risk. METHODS: A 4-month prospective randomised controlled trial using clinical criteria and the EXACT PRO questionnaire to identify exacerbations. Patients were randomly allocated to receive alert calls. All patients completed a diary including the EXACT PRO questionnaire on a BlackBerry Smartphone each day. They were contacted and assessed if they appeared to be exacerbating. RESULTS: 79 patients participated, 40 received alert calls. The exacerbation frequency per patient per week was significantly greater during periods of predicted high risk (0.086 +/- 0.010 v 0.055 +/- 0.010). The exacerbation frequency (+/- standard error of the mean, SEM) in patients receiving alert calls was lower (0.95 +/- 0.27 v 1.17 +/- 0.29) but this was not statistically significant. Fewer patients receiving alert calls had one or more EXACT event compared to the controls (34% v 53%, p=0.11), their duration was shorter (8.2 +/- 2.0 v10.1 +/- 1.9 days, p=0.481) and they were less severe (AUC 65 +/- 21 v 115 +/- 22, p=0.118). There were no significant differences in the mean change (+/- SEM) in SGRQ scores between the groups. CONCLUSIONS: The ability of the forecast to predict high risk periods was confirmed unequivocally. Alert calls appeared to reduce the frequency and severity of exacerbations but these effects did not reach statistical significance, perhaps because of the number of participants, lower than expected exacerbation rates, and the fact that there was contact with patients in both groups whenever they appeared to be exacerbating. PMID- 21687920 TI - Nurse-led multidisciplinary programme for patients with COPD in primary health care: a controlled trial. AB - AIM: To investigate the effects of a nurse-led multidisciplinary programme (NMP) of pulmonary rehabilitation in primary health care with regard to functional capacity, quality of life (QoL), and exacerbations among patients with chronic obstructive pulmonary disease (COPD). METHOD: A 1-year longitudinal study with a quasi-experimental design was undertaken in patients with COPD, 49 in the intervention group and 54 in the control group. Functional capacity was assessed using the 6-minute walking test, and quality of life (QoL) was assessed using the Clinical COPD Questionnaire. Exacerbations were calculated by examination of patient records. RESULTS: No significant differences were found between the groups in functional capacity and QoL after 1 year. The exacerbations decreased in the intervention group (n = -0.2) and increased in the control group (n = 0.3) during the year after NMP. The mean difference of change in exacerbation frequency between the groups was statistically significant after one year (p=0.009). CONCLUSIONS: The NMP in primary care produced a significant reduction in exacerbation frequency, but functional capacity and QoL were unchanged. More and larger studies are needed to evaluate potential benefits in functional capacity and QoL. PMID- 21687921 TI - Parkinson's disease among gardeners exposed to pesticides--a Danish cohort study. AB - OBJECTIVE: Several studies have found positive associations between exposure to pesticides and Parkinson's disease. As Danish gardeners have had frequent, intensive exposure to pesticides, the aim of this study was to investigate their risk for Parkinson's disease. METHODS: The cohort was comprised of 3124 male members of the Danish Union of Gardeners on 1 April 1975. Hospital register data were used to follow them for a primary diagnosis of Parkinson's disease during 1977-2008 and to calculate standardized hospitalization rate ratios (SHR) for this disease among gardeners and the general Danish population for comparison. Data from the Danish Cancer Registry were used to calculate standardized incidence rate ratios (SIR) for smoking-related cancers among gardeners and the general population. RESULTS: The SHR for Parkinson's disease among gardeners was close to that of the general population [1.14, 95% confidence interval (95% CI) 0.76-1.65]. In a birth cohort analysis, a downward trend was observed, with the highest risk among gardeners born before 1915 (SHR 1.55, 95% CI 0.77-2.77). The SIR for smoking-related cancers did not differ from that of the general population. CONCLUSION: The results indicate a weak but dose-related association between exposure to pesticides and risk for Parkinson's disease; however, the results were based on 28 cases and the possibility of no association cannot be ruled out. PMID- 21687922 TI - Strategies for assessment and outcome measurement in physical and rehabilitation medicine: an educational review. AB - The aim of this educational review, which is based upon expert opinion, is to describe to clinicians training in Physical and Rehabilitation Medicine and research students training to work in the field, the appropriate attributes and standards required for assessment and outcome measurement. "What to assess" is discussed in the context of the conceptual framework provided by the International Classification of Functioning, Disability and Health, supplemented with quality of life as an additional construct. The reasons for making the assessment, and the context in which the assessment will be used, are then considered. Examples of recommendations of some international organizations regarding what and how to assess are presented. Suggestions are made about the selection of assessment tools, including examples from two diagnostic groups: stroke and rheumatoid arthritis. Finally, the basic psychometric standards required for any assessment tool, and additional requirements for outcome assessment, are explained. PMID- 21687923 TI - Effects of whole body vibration therapy on main outcome measures for chronic non specific low back pain: a single-blind randomized controlled trial. AB - OBJECTIVE: The aim of this study was to determine whether a 12-week course of low frequency vibrating board therapy is a feasible therapy for non-specific chronic low back pain, and whether it improves the main outcome measures. DESIGN: Randomized controlled trial. PATIENTS: A total of 50 patients with non-specific low back pain were included. They were randomly assigned to either a vibrating plate via reciprocation therapy group (n = 25) or a control group (n = 25). METHODS: The 12-week vibration therapy programme consisted of a total of 24 training sessions (2 times/week, with 1 day of rest between sessions). Assessments of the main outcome measures for non-specific low back pain were performed at baseline and at 12 weeks. RESULTS: In the vibration therapy group there was a statistically significant improvement, of 20.37% (p = 0.031) in the Postural Stability Index (anterior-posterior); 25.15% (p = 0.013) in the Oswestry Index; 9.31% in the Roland Morris Index (p = 0.001); 8.57% (p = 0.042) in EuroQol 5D-3L; 20.29% (p = 0.002) in the Sens test; 24.13% (p = 0.006) in visual analogue scale back; and 16.58% (p = 0.008) in the Progressive Isoinertial Lifting Evaluation test. CONCLUSION: A 12-week course of low-frequency vibrating board therapy is feasible and may represent a novel physical therapy for patients with non-specific low back pain. PMID- 21687924 TI - Perceived disadvantages caused by low back pain. AB - OBJECTIVE: To evaluate the perceived disadvantages caused by low back pain in work, household chores and leisure-time activities, as expressed by patients themselves. DESIGN AND SUBJECTS: Structured telephone interviews, carried out among a sample of 39 physician referrals (29 women and 10 men) for non-specific chronic low back pain to University Hospital, Turku, covered how low back pain affected their daily living, with separate sections for work, household chores and leisure time. Disadvantages in daily activities were measured using numeric rating scales (0-100). The differences between scores for ability to perform with low back pain and for expected performance if the subject did not have low back pain were used to depict the disadvantage in each activity. RESULTS: Men reported a greater disadvantage than women in work, household chores and leisure-time activities. The ability to perform in any of the 3 daily activities was associated with an ability to perform in the others. Good performance at work was reported by 81.0% of the women and 42.9% of the men. Because of low back pain, leisure-time activities had been reduced by 82.1% of the patients and, out of them, 64.1% had completely given up at least one leisure-time activity. CONCLUSION: When estimating the overall burden of low back pain, the measure of work-related loss of productivity should be complemented by measures of performance in household chores and limitations to leisure-time activities. To depict extensively the burden to the patients, such measures should be based on the activities the patients consider important. These are best determined by using the phrasings and expressions the patients themselves use. PMID- 21687925 TI - EURO-MUSCULUS-I and -II behind and EURO-MUSCULUS-III ahead. PMID- 21687926 TI - Post-polio syndrome, spinal cord injury and statin myopathy: double trouble or incorrect diagnosis? Two case reports. AB - OBJECTIVE: To discuss the importance of a thorough clinical examination and evaluation of symptoms in upper and lower motor neurone lesions. DESIGN: Case report. METHODS: Post-polio outpatient clinic, Danderyds University Hospital, Stockholm, Sweden. We describe here two patients with a past history of poliomyelitis, who were experiencing increasing muscular weakness. Clinical evaluation led to diagnoses of spinal cord injury and statin myopathy, respectively. CONCLUSION: In order to make a correct diagnosis it is essential to distinguish between lower and upper motor neurone lesions. In the case of a lower motor neurone disorder a neurophysiological examination is necessary for a correct diagnosis, and is a prerequisite for adequate treatment and rehabilitation. PMID- 21687927 TI - miRNA expression profiling identifies DSPP regulators in cultured dental pulp cells. AB - Dentin sialophosphoprotein (DSPP), an important marker of odontoblast differentiation, is a prerequisite for tooth development and mineralization; however, the molecular mechanisms of both temporal and spatial regulation remain unknown. MicroRNAs (miRNAs) provide an additional level of control beyond that of transcription factors, which regulate post-transcriptional control of gene expression. The present study was designed to provide a first attempt at an in depth analysis of dental pulp cells at various odontoblastic differentiation stages to obtain miRNA differential expression patterns, and to determine the contribution of miRNAs in the expression of DSPP during odontoblast differentiation. Dual luciferase reporter assays and qRT-PCR were used to validate miRNAs identified from bioinformatic analyses to determine whether they were able to regulate the DSPP gene in dental pulp cells cultured in a mineralizing medium. The results presented here suggest that DSPP is regulated post-transcriptionally by mir32, mir885-5p and mir586 during odontoblast differentiation. PMID- 21687928 TI - Bezafibrate prevents palmitate-induced apoptosis in osteoblastic MC3T3-E1 cells through the NF-kappaB signaling pathway. AB - Osteoporosis is a bone condition defined by low bone mass and increase of fracture risk due to imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Low bone mass is likely to be due to the alteration of the osteoclast and osteoblast lifespan through regulated apoptosis. Saturated fatty acid (SFA) intake is negatively associated with bone mineral density (BMD). Furthermore, SFA induces apoptosis in osteoblastic cell lines. Bezafibrate could increase bone mass in intact male rats principally through increasing periosteal bone formation. At present, it is unknown whether bezafibrate attenuates palmitate-induced apoptosis in MC3T3-E1 cells. In the present study, we found that palmitate stimulated the degradation of IkappaBalpha and NF-kappaB translocation, as well as up-regulation of NF-kappaB-mediated Fas expression in obsteoblastic MC3T3-E1 cells. Furthermore, the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) could restore palmitate-induced caspase-3 decrease and inhibit palmitate-induced cleaved caspase-3 increase. We observed that bezafibrate, a dual ligand for the peroxisome proliferator-activated receptors alpha (PPARalpha) and PPARdelta, significantly attenuated the palmitate-induced cytotoxicity as determined by the MTT assay and inhibited the palmitate-induced apoptosis as determined by a flow cytometry assay using Annexin V-FITC/PI and assessment of the activity of caspase-3. Pre-treatment of bezafibrate prevented palmitate-induced NF-kappaB activation. Therefore, these findings indicate that bezafibrate inbibits palmitate-induced apoptosis via the NF-kappaB signaling pathway. Our results point to bezafibrate as a new strategy to attenuate bone loss associated with high fat diet beyond its lipid-lowering actions. PMID- 21687929 TI - Expression, purification, refolding, and characterization of octreotide interleukin-2: a chimeric tumor-targeting protein. AB - The targeting of tumor cells by peptides for drug delivery is a promising strategy for cancer therapy. Interleukin-2 (IL-2), which mediates anti-tumor cellular immune responses, has been approved as a therapy for cancer. However, the serious side effects and short half-life of recombinant IL-2 (rIL-2) has limited its use clinically. Somatostatin receptors (SSTRs), which are expressed in a large number of human tumors, are the targets for in vivo tumor targeting. In this study, we have constructed and expressed a novel chimeric recombinant protein containing octreotide analogs and IL-2 in order to target the SSTR binding with tumor cells. The fusion protein somatostatin receptor targeted interleukin-2 (SIL), which was purified from bacterial inclusion bodies and refolded with high purity, was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and reverse-phase high-performance liquid chromatography. Tryptophan emission fluorescence was used to measure the structural changes in SIL after renaturation. Cell proliferation experiments showed that this chimeric protein retained the biological activities of hIL-2. Furthermore, the tumor binding capacity of SIL acting through SSTRs was shown through co immunoprecipitation. Competition binding with octreotide of tumor cells also confirmed that SIL binds to tumor cells through the target peptide octreotide. Moreover, the performance of SIL in stimulating the proliferation of lymphocyte cell lines after binding to tumor cells showed that the immunocytokine, SIL, retained its bioactivity at the tumor site. These results suggest that SIL is a recombinant fusion protein that may be used for tumor-targeted drug delivery. PMID- 21687930 TI - The sap of Acer okamotoanum decreases serum alcohol levels after acute ethanol ingestion in rats. AB - In the present study, we examined whether Acer okamotoanum (A. okamotoanum) sap decreased the serum alcohol and acetaldehyde levels after acute ethanol treatment in a rat model. Male rats were orally administered 25, 50 or 100% A. okamotoanum sap 30 min prior to oral challenge with 3 ml of ethanol (15 ml/kg of a 20% ethanol solution in water), and the blood concentrations of alcohol and acetaldehyde were analyzed up to 7 h after the treatment. Pre-treatment with the sap significantly decreased the blood ethanol and acetaldehyde concentrations after 5 h when compared with ethanol treatment alone (a negative control). The expression levels of liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) mRNA were increased significantly in animals pre-treated with A. okamotoanum sap when compared with negative and positive controls. The data suggest that sap pre-treatment enhanced the alcohol metabolism rate in the rat liver. To investigate the involvement of mitochondrial regulation in the ethanol induced hepatocyte apoptosis, we carried out an immunohistochemical analysis of Bax and Bcl-2. Pre-treatment with sap significantly decreased Bax expression and increased Bcl-2 expression 7 h after ethanol administration when compared with the negative control. The data suggest that A. okamotoanum sap pre-treatment may reduce the alcohol-induced oxidative stress in the rat liver. PMID- 21687931 TI - Transplantation of adipose-derived stem cells for peripheral nerve repair. AB - Mesenchymal stem cells have become a very attractive source of cell implantation for neural tissue engineering. The ideal stem cells for transplantation should be easily obtained, and should rapidly proliferate in vitro and have low immunogenicity. The purpose of this study was to investigate the regenerative potential of adipose-derived stem cells (ADSC) on peripheral nerve repair. ADSCs were isolated from rat adipose tissue and cultured until adherent cells became morphologically homogeneous with a fibroblast-like shape, and transplanted with acellular nerve allografts (ANAs) into rat models with a 10 mm gap of transected sciatic nerve defect. After cell transplantation, we found that ADSC implantation improved functional recovery of exercise behavior and increased wet weight ratio of the anterior tibial muscle. In the electrophysiological testing, we found that the percentage of activated fibers was higher in the ADSC-implanted animals as evidenced by the increase of nerve conduction velocity and amplitude. Histological examination revealed that the number of nerve fibers, axonal diameter and myelin thickness were significantly higher in the ADSC-implanted animals compared to the control. In addition, we demonstrated that the progression of the regenerative process after ADSC implantation was accompanied by elevated expression of neurotrophic factors at both the early and later phase. Taken together, these results suggest that ADSCs can promote the repair of peripheral nerve injury, and the combination of ADSC and ANA transplantation is a new therapeutic method for long distant peripheral nerve defects. Our data also provide evidence indicating the strong association of neurotrophic factor production to the regenerative potential of implanted ADSCs. PMID- 21687932 TI - Secretory leukocyte protease inhibitor is associated with MMP-2 and MMP-9 to promote migration and invasion in SNU638 gastric cancer cells. AB - Secretory leukocyte protease inhibitor (SLPI) protects tissue from proteases, and promotes cell proliferation and healing during inflammatory response. SLPI is also overexpressed in gastric, lung and ovarian cancers, which accelerates the metastasis of cancer cells. Matrix metalloproteinases-2, -9 (MMP-2 and MMP-9) are overexpressed in high metastatic cancers, and promote the migration of cancer cells through collagen degradation. SLPI and MMP-2, -9 are critical factors in stimulating the metastatic processes but there are no reports of a direct correlation between these molecules. Therefore, this study examined the role of SLPI related to MMP-2 and MMP-9 using two gastric cancer cell lines, such as characterized non-metastatic SNU484 and highly metastatic SNU638 cells. SLPI, MMP 2 and MMP-9 mRNA and protein expression were higher in SNU638 cells than in SNU484 cells. In addition, the rate of cell migration and invasion was higher in the SNU638 cells than in SNU484 cells. Interestingly, after treatment with SLPI, the rate of migration and invasion was higher in the SNU484 cells than in the positive control (PC) SNU484 cells. The rate of migration was also higher in the SNU638 cells after SLPI treatment than in the SNU638 cells (PC) but the invasion rate was not changed. The expression and secretion of MMP-2 and MMP-9 as well the rate of cell migration and invasion were significantly lower in SLPI-siRNA transfected SNU638 cells (si-SLPI/SNU638) but higher in SLPI-treated SNU484 cells (SNU484 + SLPI). Strong Elk-1 phosphorylation was detected in SNU484 + SLPI and SNU638 cells but was barely detectable in SNU484 and si-SLPI/SNU638 cells. These results show that SLPI promotes the metastasis of SNU638 gastric cancer cells by increasing MMP-2 and MMP-9 expression through Elk-1 signaling, indicating its role as a signaling molecule not a protease inhibitor. PMID- 21687933 TI - Cytotoxicity of tubeimoside I in human choriocarcinoma JEG-3 cells by induction of cytochrome c release and apoptosis via the mitochondrial-related signaling pathway. AB - Mitochondria play important roles in the intrinsic pathways that trigger apoptosis. Anticancer chemotherapies eliminate cancer cells mainly through the induction of apoptosis. In the present study, we investigated the mechanism of the cytotoxic effects of tubeimoside I (TBMS1) on the human choriocarcinoma cell line (JEG-3). Choriocarcinoma is one of the most common malignant tumors in the reproductive system. TBMS1, a triterpenoid saponin, isolated from the tubers of Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), showed potent antitumor effects. However, the potential roles of TBMS1 in the treatment of choriocarcinoma remain unknown. In the present study, we examined the effects of TBMS1 on JEG-3 cells. TBMS1 displayed strong growth inhibitory effects on JEG-3 cell growth. In addition, TBMS1 treatment with TBMS1 led to marked cell apoptosis, significant cell cycle arrest at G2 phase and decrease in mitochondrial transmembrane potential (DeltaPsim). Cytochrome c was released from the mitochondria and caspase-3 expression was enhanced. Furthermore, TBMS1 induced the up-regulation of Bcl-2 associated X protein (Bax) expression, down regulation of Bcl-2 expression, inhibition of nuclear factor-kappa-B (NF-kappaB) function and impacted the phosphorylation of p38 mitogen-activated protein kinase (p38/MAPK), extracellular signal-regulated kinases (ERK)1/2 and protein kinase B (Akt). Taken together, our findings suggest that TBMS1 is an efficient apoptosis inducing agent for choriocarcinoma cells, which exerts its effects, at least partially, by the induction of mitochondrial dysfunction and regulation of the p38/MAPK, ERK1/2 and PI3K/Akt signaling pathways. PMID- 21687934 TI - Synergistic antinociceptive effects of N-methyl-D-aspartate receptor antagonist and electroacupuncture in the complete Freund's adjuvant-induced pain model. AB - This study examined the synergistic antinociceptive effects associated with signaling pathway proteins of the spinal cord in a complete Freund's adjuvant (CFA)-induced pain model when electroacupuncture (EA) and a N-methyl-D-aspartate receptor (NMDAR) antagonist were administered in combination. EA stimulation (2 Hz, 1 mA) was needle-delivered for 20 min once daily at acupoints corresponding to Zusanli and Sanyinjiao with intrathecal injection of the NMDAR antagonist dizocilpine (MK801). Thermal sensitivity of the hindpaw induced by CFA was strongly inhibited by dizocilpine injection and EA stimulation. Co-treatment with EA and dizocilpine showed a synergistic antinociceptive effect against inflammatory pain. On day two of the experiment, we examined the phosphorylation of the NMDAR NR2B subunit, of the extracellular signal-regulated kinase (ERK), p38 and of the cAMP response element-binding protein (CREB) in the ipsilateral dorsal horn of L4-5 segments by Western blot analysis. Phosphorylation of the NMDAR NR2B subunit induced by CFA was markedly inhibited by co-treatment with dizocilpine and EA, but not by dizocilpine or EA treatment alone. CFA-induced phosphorylation of the ERK was inhibited by both dizocilpine and EA, but that of p38 was inhibited by EA only. CFA-induced phosphorylation of CREB was inhibited by dizocilpine, but did not show marked changes. Immunohistochemical analyses confirmed that there was a significant difference in the NMDAR NR2B subunit and ERK phosphorylation. It is possible that the combined treatment with EA and the NMDAR antagonist dizocilpine resulted in synergistic antinociceptive effects in an inflammatory pain model via the inactivation of both the NMDAR NR2B subunit and ERK of the spinal cord. PMID- 21687935 TI - Integrated analysis of copy number and loss of heterozygosity in primary breast carcinomas using high-density SNP array. AB - Breast cancer is a heterogeneous disease, marked by extensive chromosomal aberrations. In this study, we aimed to explicate the underlying chromosomal copy number (CN) alterations and loss of heterozygosity (LOH) implicated in a cohort of Malaysian hospital-based primary breast carcinoma samples using a single nucleotide polymorphism (SNP) array platform. The analysis was conducted by hybridizing the extracted DNA of 70 primary breast carcinomas and 37 normal peripheral blood samples to the Affymetrix 250K Sty SNP arrays. Locus-specific CN aberrations and LOH were statistically summarized using the binary segmentation algorithm and hidden Markov model. Selected genes from the SNP array analysis were also validated using quantitative real-time PCR. The merging of CN and LOH data fabricated distinctive integrated alteration profiles, which were comprised of finely demarcated minimal sites of aberrations. The most prevalent gains (>= 30%) were detected at the 8q arm: 8q23.1, 8q23.3, 8q24.11, 8q24.13, 8q24.21, 8q24.22, 8q24.23 and 8q24.3, whilst the most ubiquitous losses (>= 20%) were noted at the 8p12, 8p21.1, 8p21.2, 8p21.1-p21.2, 8p21.3, 8p22, 8p23.1, 8p23.1 p23.2, 8p23.3, 17p11.2, 17p12, 17p11.2-p12, 17p13.1 and 17p13.2 regions. Copy neutral LOH was characterized as the most prevailing LOH event, in which the most frequent distributions (>= 30%) were revealed at 3p21.31, 5q33.2, 12q24.12, 12q24.12-q24.13 and 14q23.1. These findings offer compre-hensive genome-wide views on breast cancer genomic changes, where the most recurrent gain, loss and copy-neutral LOH events were harboured within the 8q24.21, 8p21.1 and 14q23.1 loci, respectively. This will facilitate the uncovering of true driver genes pertinent to breast cancer biology and the develop-ment of prospective therapeutics. PMID- 21687936 TI - Pharmacological induction of leukotriene B4-12-hydroxydehydrogenase suppresses the oncogenic transformation of human hepatoma HepG2 cells. AB - Leukotriene B4-12-hydroxydehydrogenase (LTB4DH) is characterized as a chemopreventive and tumor suppressor gene. The aim of this study was to investigate the pharmaco-logical induction of LTB4DH and potential anticancer activity. Using HepG2 cells as a cellular detector, we successfully isolated the active compounds from the herbs Radix Astragali and Radix Paeoniae Rubra through a bioactivity-guided fractionation procedure. Using various analytical techniques including electronic spray ionization-mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR), gallic acid (GA) was identified as the active compound from Radix Paeoniae Rubra whereas the active compound from Radix Astragali, designated as RA-C, was also purified to the extent that it is now suitable for further identifi-cation. We found that the active compounds from these two different herbs synergistically induced LTB4DH expression in a dose- and time dependent manner. A key finding was that commercial GA in combination with purified RA-C attenuated the focus formation and anchorage-independent growth, two indexes of in vitro oncogenic transformation, of HepG2 cells via the induction of LTB4DH expression. Moreover, the combination of GA and purified RA-C significantly induced G2/M cell cycle arrest in HepG2 cells. Our results demon strated for the first time that GA and purified RA-C suppress the in vitro oncogenic transformation of HepG2 cells via the induction of LTB4DH expression. Importantly, pharmaco-logical induction of LTB4DH represents a potential alternative strategy for the therapy of hepatocellular carcinoma. PMID- 21687937 TI - The cell death response to the ROS inducer, cobalt chloride, in neuroblastoma cell lines according to p53 status. AB - Cobalt chloride (CoCl2), a hypoxia-mimetic agent, induces reactive oxygen species (ROS) generation, leading to cell death. Divergent data have been reported concerning p53 implication in this apoptotic mechanism. In this study, we studied cobalt-induced cell death in neuroblastoma cell lines carrying wild-type (WT) p53 ( SHSY5Y) and a mutated DNA-binding domain p53 [SKNBE(2c)]. CoCl2 induced an upregulation of p53, p21 and PUMA expression in WT cells but not in SKNBE(2c). In SHSY5Y cells, p53 serine-15 phosphorylation appeared early (6 h) in the mitochondria, and also in the nucleus after 12 h. In contrast, in SKNBE(2c) cells, the slight nuclear signal disappeared with CoCl2 treatment. In SHSY5Y cells, a mitochondrial pathway dependent on caspases [collapse of mitochondrial transmembrane potential (?Psimt), caspase 3 and 9 activation], was activated in a time-dependent manner. SKNBE(2c) cells exhibited a delay in the cell death executive phase linked to a caspase-independent pathway, involving apoptosis inducing factor nuclear translocation, but also an autophagic process attested by LC3-II expression and cathepsin-B activation. The downregulation of p53 in SHSY5Y cells by siRNA induced a cell death pathway related to the one observed in SKNBE(2c) cells. Finally, CoCl2 induced time-dependent canonical p53 mitochondrial apoptosis in the WT p53 cell line, and caspase-independent cell death in cells with a mutated or KO p53. PMID- 21687938 TI - Downregulation of microRNA-211 is involved in expression of preferentially expressed antigen of melanoma in melanoma cells. AB - MicroRNAs (miRNAs) are small non-coding RNAs whose aberrations are involved in the initiation and progression of human cancers. To seek unique miRNAs contributing to melanoma tumorigenesis, we investigated the global miRNA expression profile of 7 melanoma cell lines and 3 primary cultures of neonatal human epidermal melanocytes (NHEMs) using the stem-loop real-time PCR method. We found 7 miRNAs that were commonly downregulated and 18 that were upregulated in all of the melanoma cell lines in comparison with the 3 primary cultures of NHEMs. We focused on one commonly downregulated miRNA (miR-211), and analyzed its relationship to the expression of preferentially expressed antigen of melanoma (PRAME) protein, which is a potential target of miR-211. We found that all melanoma cell lines exhibited marked down--regulation of miR-211 and upregulation of PRAME mRNA/protein expression in comparison with NHEMs (P<0.05). A significant inverse correlation between miR-211 and PRAME protein expression was found in melanoma cell lines and primary cultures of NHEMs (correlation coefficient of 0.733, P<0.05). We demonstrated that overexpression of miR-211 induced a reduction of PRAME protein levels, and confirmed the target specificity between miR-211 and PRAME by luciferase reporter assay. These results suggest that downregulation of miR-211 may be partly involved in aberrant expression of the PRAME protein in melanoma cells. PMID- 21687940 TI - Icariin induces apoptosis in mouse MLTC-10 Leydig tumor cells through activation of the mitochondrial pathway and down-regulation of the expression of piwil4. AB - The Leydig cell tumor, derived from interstitial cells, is a rare neoplasm. In most cases, Leydig cell tumors are benign, however, if the tumor is malignant, no effective treatments are currently available. In this study, we aimed to evaluate the effects of icariin on the growth of the mouse Leydig tumor cell line MLTC-1 and to examine its underlying mechanism. Icariin caused a dose-dependent decrease in the viability of MLTC-1 cells, which coincided with an increase in cell apoptosis through regulation of the expression of Bcl-2/Bax and cytochrome c, activation of caspase-9 and -3. Moreover, the pro-apoptotic effect of icariin on MLTC-1 cells is related to piwil4, since icariin induced a decrease in piwil4 protein expression and piwil4 silencing significantly enhanced the cytotoxic effects of icariin in MLTC-1 cells. These findings suggest a novel anticancer effect of icariin in Leydig cell tumor through activation of the mitochondrial pathway and down-regulation of the expression of piwil4. PMID- 21687939 TI - Cisplatin and TRAIL enhance breast cancer stem cell death. AB - Triple negative breast cancer (TNBC) has increased recurrence and poor survival, despite a high response rate to neoadjuvant chemotherapy. The aim of this study was to determine whether current drug treatment(s) eliminates bulk of tumor cells, but it has a minimal effect on cancer stem cells (CSCs) leading to tumor recurrence. We studied the effects of PARP inhibitors (AZD2281 and BSI-201), paclitaxel, docetaxel, cisplatin and cisplatin plus TRAIL on CSCs derived from CRL-2335 and MDA-MB-468 TNBC cells in vitro. The in vitro data indicate that cisplatin plus TRIAL treatment was most effective in eliminating CSCs compared to PARP inhibitors, cisplatin, paclitaxel and docetaxel. Treatment with cisplatin plus TRAIL also inhibits Wnt-1 signaling and its downstream target, beta-catenin, phospho beta-catenin, cyclin D1, increased apoptosis, reduced proliferation and mammosphere formation. Inhibition of Wnt-1 by siRNA significantly reduced the ability of CSCs to form mammospheres compared to control. However, maximum effect was seen in cisplatin plus TRAIL-treated cells. Taken together the data suggest that cisplatin plus TRAIL treatment has the potential of providing a new strategy for improving the therapeutic outcome in TNBC patients. PMID- 21687941 TI - Statins induce apoptosis and inhibit proliferation in cholangiocarcinoma cells. AB - Given the poor prognosis for cholangiocarcinoma, new and effective treatments are urgently needed. HMG-CoA reductase inhibitors (statins) reportedly exert anticancer effects in a variety of diseases, but there have been no reports of these effects in cholangiocarcinoma. In this study, we investigated the utility of statins for cholangiocarcinoma treatment. Proliferation suppression by pitavastatin and atorvastatin was investigated in the human cholangiocarcinoma cell lines HuCCT1 and YSCCC while changes in the cell cycle and intracellular signals were examined by FACS and Western blotting, respectively. Additive proliferation suppression by statins and pre-existing anticancer drugs was also investigated. HuCCT1 and YSCCC cell proliferation was dramatically suppressed by incubation with statins for 72 h or longer. Cell cycle analysis revealed a reduction in the G2M fraction and an increase in the sub-G1 fraction in statin treated cells, while Western blotting showed increased levels of cleaved caspase 3 and a reduction in p-ERK. Furthermore, statins in combination with gemcitabine, cisplatin and 5-FU showed additive proliferation suppression. In this study, treatment of human cholangiocarcinoma cells with statins induced apoptosis via suppression of the classical MAPK pathway. Together, these results suggest that statins may be a new cholangiocarcinoma treatment option that could potentially enhance the anticancer effect of pre-existing anticancer drugs. PMID- 21687942 TI - Expression of CD24 in cholangiocarcinoma cells is associated with disease progression and reduced patient survival. AB - Cholangiocarcinoma is frequently found to invade local tissues and metastasize to distal organs. We investigated the expression of CD24 in cholangiocarcinoma samples and its prognostic significance. In addition, the cellular function of CD24 was studied in the RMCCA1 cholangiocarcinoma cell line. High CD24 expression significantly correlated with lymph node metastasis and positive surgical margins in cholangiocarcinoma patients. Univariate and multivariate analyses further demonstrated that CD24 expression was significantly associated with the overall survival of these patients (p=0.007 and p=0.040, respectively). For in vitro studies, the magnetic-activated cell sorting (MACS) system was used to isolate CD24+ and CD24- cell populations from RMCCA1 cells. CD24+ RMCCA1 cells had increased chemoresistance, adhesion (p=0.004), motility (p<0.001), migration (p<0.001) and invasion (p<0.001) capabilities when compared to CD24- cells. The matrix metalloproteinase (MMP)-7 was significantly elevated in CD24+ RMCCA1 cells (p=0.01). We found that inhibition of CD24 using siRNA silencing significantly decreased the invasive capacity of RMCCA1 cells. Both clinical and in vitro studies suggest that expression of CD24 is associated with cholangiocarcinoma disease progression. CD24 may thus serve as a new target for directed molecular therapy of cholangiocarcinoma. PMID- 21687943 TI - Identification of an HLA-A*0201-restricted cytotoxic T lymphocyte epitope from the lung carcinoma antigen, Lengsin. AB - Lengsin is an eye lens protein with a glutamine synthetase domain. We previously identified this protein as a lung carcinoma antigen through cDNA microarray analysis. Lengsin protein is overexpressed irrespective of the histological type of lung carcinoma, but not in normal tissues other than the lens. Therefore, to significantly extend the use of Lengsin-based T-cell immunotherapies for the treatment of patients with lung carcinoma, we searched for HLA-A*0201-restricted epitopes from this protein by screening predicted Lengsin-derived candidate peptides for the induction of tumor-reactive CTLs. Four Lengsin-derived peptides were selected by computerized algorithm based on a permissive HLA-A*0201 binding motif, and were used to immunize HLA-A*0201 transgenic (HHD) mice. Two of the immunizing peptides, Lengsin(206-215)(FIYDFCIFGV) and Lengsin(270 279)(FLPEFGISSA), induced peptide-specific cytotoxic T lymphocytes (CTLs) in HHD mice, and thus were used to stimulate human peripheral blood lymphocytes in vitro. Lengsin(206-215) and Lengsin (270-279) also induced human peptide-specific CTLs, and we were able to generate Lengsin(206-215)- and Lengsin(270-279) specific CTL clones. The Lengsin(270-279)-specific CTL clone specifically recognized peptide-pulsed T2 cells, COS-7 cells expressing HLA-A*0201 and Lengsin, and HLA-A*0201+/Lengsin+ lung carcinoma cells in an HLA-A*0201 restricted manner. On the other hand, the Lengsin(206-215)-specific CTL clone failed to recognize HLA-A*0201+/Lengsin+ target cells in the absence of cognate peptide. These results suggest that Lengsin(270-279) is naturally processed and presented by HLA-A*0201 molecules on the surface of lung carcinoma cells and may be a new target for antigen-specific T-cell immunotherapy against lung cancer. PMID- 21687944 TI - Nuclear localization of phosphorylated ERK1 and ERK2 as markers for the progression of ovarian cancer. AB - We examined the possibility that the localization of phosphorylated ERK1 and ERK2 (pERK1/2) can serve as a marker for the development of benign and borderline tumors as well as carcinoma of the ovary by an immunohistochemical method on ovarian paraffin sections, obtained from women aged 41-83 years. In normal tissue, 28.3% of nuclei were labeled, mainly confined to the epithelial cells at the surface of the ovary. In benign serous tumors, the label rose to 55.0%, while the intensity of the staining was weak. In contrast, in borderline serous tumors and in ovarian serous carcinoma (stage II) 52.1% and 70.3% of nuclei, respectively, were labeled with a high intensity. In mucinous benign tumors, the number of labeled nuclei was as in the control, but in addition, 49.4% of the cells demonstrated high concentration of pERK1/2 in aggregated form that was evident in the cytoplasm of the cells. In the mucinous and endometrioid ovarian carcinomas (stage II) very intensive labeling was found in 60% and 77.3% of cells, respectively. It is, therefore, suggested that since nuclear pERK1/2 can be mitogenic, it can serve as a reliable marker for the progression of ovarian cancer. Interestingly, the intense labeling of pERK1/2 was mainly confined to the peripheral areas of ovarian endometrioid carcinoma (stage II). In addition, all tumor cells in this class of cancer were positively stained with mutated p53. It seems, therefore, that immunohistochemical staining of normal and ovarian tumor cells with anti-pERK1/2 is a reliable marker for early detection of the cancer, which may assist in the early diagnosis and prognosis of this lethal disease. PMID- 21687945 TI - Connexin 32 and its derived homotypic gap junctional intercellular communication inhibit the migration and invasion of transfected HeLa cells via enhancement of intercellular adhesion. AB - The effects of connexin (Cx) and its derived homotypic gap junctional intercellular communication (GJIC) between tumor cells on the invasion of metastatic cancers and the underlying mechanisms remain unclear. In this study, we investigated the influence of Cx32 and the homotypic GJIC mediated by this Cx on the migration, invasion and intercellular adhesion of transfected HeLa cells. The expression of Cx32 significantly increased cell adhesion and inhibited migration and invasion. The inhibition of GJIC by oleamide, a widely used GJIC inhibitor, reduced the enhanced adhesion and partly reversed the decreased migration and invasion that had been induced by Cx32 expression. Blockage of the p38 and extracellular signal-regulated kinase 1 and 2 mitogen-activated protein kinase (ERK1/2 MAPKs) pathways using their specific inhibitors attenuated the effects of Cx32, but not those of GJIC, on cell adhesion, migration and invasion. These results indicate that the homotypic GJIC mediated by Cx32, as well as the Cx itself, inhibit cell migration and invasion, most likely through the elevation of intercellular adhesion. The suppressive effect of Cx32 on the migration and invasion of cancer cells, but not that of its derived homotypic GJIC, partly depends on the activation of the p38 and the ERK1/2 MAPKs pathways. PMID- 21687946 TI - Transplantation of neural stem cells enhances expression of synaptic protein and promotes functional recovery in a rat model of traumatic brain injury. AB - Transplantion of neural stem cells (NSCs) has shown promise for the treatment of traumatic brain injury (TBI). Although the functional mechanisms underlying transplant-mediated recovery following TBI have yet to be determined, previous studies demonstrated that transplanted NSCs may respond to the release of specific neurotransmitters, and/or the production of factors that promote neuronal growth. Therefore, we hypothesize that the direct transplantation of NSCs into the injured brain enhanced the expression of synaptic protein and regeneration-associated protein, which may be responsible for promoting functional recovery in a rat model of TBI. Our results showed that NSC transplant significantly improved neurological motor function in selected behavioral tests compared to saline control rats. Our data showed that the number of surviving cells engrafted into the rats was 4.1+/-0.9% of engrafted cells at 8 weeks post transplantation, with 11.4+/-1.6% betaIII-tubulin-immunopositive cells of these cells. RT-PCR and Western blot analysis demonstrated that the expression of synaptophysin (SYP) and regeneration-associated protein (GAP43) in the injured brain of NSC-transplanted rats was significantly increased compared to the saline control rats during the experimental period. These data suggest that NSCs transplanted directly into the injured brain are capable of surviving, differentiating into neurons and promoting functional recovery in a rat model of TBI. Engrafted NSCs increase the expression of SYP and GAP43 in the injured brain of NSC-transplanted rats, which is suggested as one of the mechanisms underlying the improved functional recovery on motor behavior due to the transplantation of NSCs following TBI. PMID- 21687947 TI - Inhibitory effect of resveratrol on the expression of the VEGF gene and proliferation in renal cancer cells. AB - Resveratrol (Res) is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. In this study, we investigated the effects of Res on the expression of the vascular endothelial growth factor (VEGF) gene and on cell proliferation in human renal cancer (786-0) cells. The 786-0 cells were treated with various concentrations of Res (0, 10, 20 and 40 umol/l) for different time periods (24, 48 and 72 h). Cell proliferation was examined by MTT analysis and the expression of the VEGF gene was analyzed RT-PCR and Western blot analysis. Res inhibited the expression of the VEGF gene, and its inhibitory effect increased according to the concentration and treatment time. These results indicate that Res significantly inhibits the proliferation of 786-0 cells and exerts an antitumor effect by suppressing the expression of the VEGF gene. PMID- 21687948 TI - 'Genetic profiling' and ovarian cancer therapy (review). AB - High variability observed among ovarian cancer patients in response to the same therapy and the related toxicity may be correlated to gene polymorphisms and genetic alterations affecting the metabolism of drugs commonly used to treat this tumor. Recent studies have shown a correlation between the polymorphisms characterizing GSTM1-T1 detoxifying enzymes and poor outcome in advanced ovarian cancer patients treated with platinum/paclitaxel-based chemotherapy. Multidrug resistance 1 (mdr-1) polymorphisms were found to be associated with resistance to paclitaxel treatment. Polymorphisms of MRP2, a protein involved in methotrexate, cisplatin and irinotecan active metabolite glucuronide transport, negatively affect platinum-based chemotherapy response. A similar occurrence has been observed with CYP1A1 Ile462Val and ercc1 C118T polymorphisms while patients who were carriers of MTHFR C677T polymorphism had a better response to methotrexate therapy, but an elevated risk of toxicity. Biological therapy with Bevacizumab, the anti-vascular endothelial growth factor has been shown to be less efficient in ovarian cancer patients carrying the polymorphism of the Interleukin-8 gene. Instead, polymorphisms in the XPD gene (Lys751Gln and Asp312Asn), a member of the nucleotide excision repair pathway, positively affects the response to therapy with carboplatin/paclitaxel. Therefore, the study of 'genetic profiling' is crucial to improving the clinician's ability to tailor effective therapy to the molecular profile of the patient while minimizing toxicities. This review describes clinical applications of the above genetic polymorphisms in ovarian cancer patients treated with platinum/paclitaxel-based chemotherapy. PMID- 21687950 TI - Involvement of CD147 isoform-4 in the proliferation of SiHa cells: a possible molecular mechanism of cervical cancer. AB - CD147, a multifunction glycoprotein of the immuno-globulin family, is associated with many types of tumors, and the overexpression of CD147 can enhance malignancy. However, the role of CD147 in cervical cancer remains unclear. In the present study, cervical cancer cells were found to express much more CD147 protein and isoform-4 than normal cervical cells (P<0.05), suggesting that CD147 and isoform-4 are involved in cervical cancers. Furthermore, we overexpressed the CD147 isoform-4 (CD147-4) in the cervical cancer cell line SiHa by transfection and found that CD147-4 promoted the proliferation of SiHa cells with a considerable proportion of cells in the S phase in which the expression of CIP2A, Plk and cyclin D1 was up-regulated while the expression of P27 was down regulated. This may be one of the molecular mechanisms involved in cervical cancer progression by CD147. PMID- 21687949 TI - Tubeimoside I sensitizes cisplatin in cisplatin-resistant human ovarian cancer cells (A2780/DDP) through down-regulation of ERK and up-regulation of p38 signaling pathways. AB - Cisplatin (CDDP) is a major chemotherapeutic drug used in the treatment of human ovarian cancer. Tubeimoside I (TBMS1) has also shown potent antitumor and antitumor-promoting effects, and may offer a promising new approach in the effective treatment of CDDP-resistant human ovarian cancers. This study aimed to investigate the effect of TBMS1 in sensitizing CDDP in CDDP-resistant human ovarian cancer cells (A2780/DDP). A variety of methods were employed to measure cell apoptosis, p38, ERK1/2 and glutathione S-transferase (GST)-pi expressions. It was found that TBMS1 combined with CDDP promoted cell apoptosis, decreased proliferation activity and increased cytosolic Ca2+ levels. Bcl-2 protein expression was down-regulated but Bax was up-regulated. Moreover, GST-pi mRNA and protein expression were decreased. TBMS1 reduced the resistance of the cells to CDDP-induced cytotoxicity. Both the p38 inhibitor (SB203580) and the ERK1/2 inhibitor (PD98059) effectively blocked this effect. These results suggest that TBMS1 can effectively sensitize CDDP in CDDP-resistant human ovarian cancer cells through the down-regulation of the ERK1/2 and the up-regulation of the p38 signaling pathways. PMID- 21687952 TI - Multidrug resistance and rhabdomyosarcoma (Review). AB - Classical cytotoxic treatment of rhabdomyosarcoma (RMS) is often accompanied by significant morbidity and poor response. This cytotoxic therapy may induce a multidrug resistance (MDR) phenotype in RMS which is associated with decreased effectiveness of chemotherapy. The majority of MDR molecules belong to a family of ABC (ATP binding cassette) transporters. Studies of drug resistance in RMS suggest that there are various mechanisms acting simultaneously, which might explain the low percentage of long-term survival in this malignancy. Moreover, although cells exposed to cytotoxic agents increase expression of muscle differentiation markers indicating myogenic differentiation, multidrug resistance may be a major obstacle in differentiation therapy for RMS. This review briefly discusses the current knowledge of resistance in RMS and emphasizes the importance of understanding the different aspects of MDR status in these patients. PMID- 21687951 TI - Gastric cancer and concomitant renal cancer: a systematic immunohistochemical and molecular analysis. AB - The frequency of gastric cancer in patients with renal cell carcinoma (RCC) is exceptionally high in our region suggesting a common molecular basis. Our study aimed to characterize tumors and to analyze possible underlying molecular features in 12 patients with gastric cancer and concomitant RCC. We performed an immunohistochemical analysis including p53 protein expression, proliferative activity (MIB-1), mismatch repair status (hMLH1, hMSH2, hMSH6, PMS2) and E cadherin expression in gastric cancers, which were additionally analyzed for Epstein-Barr-Encoded-RNA (EBER) by in situ hybridization. Microsatellite instability was analyzed with a PCR multiplex system and capillary electrophoresis. KRAS mutations in codons 12 and 13 were tested by pyrosequencing. All patients had clear cell RCCs, 10 of which were well differentiated and diagnosed in an early stage, while the gastric cancers of these patients were generally poorly or undifferentiated and diagnosed in an advanced stage. Gastric cancers showed reduced E-cadherin staining in 10 out of 12 cases. Two gastric cancers demonstrated loss of hMLH1 and PMS2, which was confirmed by molecular analysis showing a high degree of microsatellite instability. All RCCs were microsatellite stable. KRAS mutation was detected in one of the two instable gastric cancers, while none of the RCCs had KRAS mutations. Another gastric cancer was positive for EBV. In conclusion, a coherent cause for gastric cancer and concomitant RCC, such as Lynch syndrome, a prominent role of KRAS mutation or EBV infection, was not found in our series. Other factors leading to a higher susceptibility for cancer must be explored to explain why individuals with RCC have a higher risk of developing gastric cancer in our region. PMID- 21687953 TI - Signaling pathway involved in cyclooxygenase-2 up-regulation by hepatocyte growth factor in endometrial cancer cells. AB - Hepatocyte growth factor (HGF) is up-regulated in tissue repair and has been implicated in playing a role in this process through its anti-apoptotic and proliferative activities. Cyclooxygenase-2 (COX-2) is an inducible enzyme in the biosynthetic pathway of prostaglandins, and its activation has been shown to play an important role in cell growth. We previously reported that HGF significantly inhibited anoikis, possibly through the up-regulation of COX-2 expression in the endometrial RL95-2 cancer cell line. Here, we report that i) treatment of RL95-2 cells with HGF resulted in phosphorylation of the HGF receptor c-Met, activation of Akt and IkappaB, translocation of NF-kappaB into the nucleus, and up regulation of COX-2 mRNA; ii) the IkappaB-alpha phosphorylation inhibitor BAY11 7082 and the selective COX-2 inhibitor CAY10452 blocked HGF-mediated anoikis resistance in RL95-2 cells; and iii) HGF induced migration and invasion in RL95-2 cells, while the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and CAY10452 blocked these effects of HGF stimulation. Our data suggest that HGF possesses chemotactic ability, has anti-apoptosis action, and induces cellular infiltration via the PI3K/Akt pathway; it also triggers NF-kappaB activation and up-regulates COX-2 gene expression in endometrial cancer cells. PMID- 21687954 TI - Expression of MET and SOX2 genes in non-small cell lung carcinoma with EGFR mutation. AB - Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer-related deaths. Aberrance of the two oncogenes MET and SOX2 are frequently encountered in NSCLC. Exons 18 through 21 of the EGFR gene were screened and MET and SOX2 immunostaining was conducted to analyze the immunohistological staining of MET and SOX2 and the EGFR mutation status. One hundred and fifty tissue samples were examined including 57 squamous cell carcinomas (SCCs), 80 adenocarcinomas (ADCs), 9 adenosquamous carcinomas (ADSCs) and 4 large cell carcinomas (LCCs). The 32 NSCLCs harboring an EGFR mutation included 28 ADCs, 3 SCCs and 1 ADSC. A higher level of SOX2 expression appeared in NSCLCs without the EGFR mutation compared to those with EGFR mutation (chi2=9.02, P=0.0027). Of the 28 ADCs, 24 (85.7%) with an EGFR mutation showed low level of SOX2 expression. ADCs with deletion in exon 19 overexpressed MET and showed low levels of SOX2. SOX2 expression was inversely correlated to the expression of MET in NSCLC and mainly present in non-mutated NSCLC (r=-0.42, P<0.0001). There was a tendency for SOX2 to be expressed in SCCs and particularly in the part of SCC among ADSCs, whereas MET was mainly expressed in the part of ADC among ADSCs and ADCs. High level of MET and SOX2 expression were respectively demonstrated in ADCs and SCCs; MET activation was accompanied with exon 19 deletion in ADCs. EGFR and MET coordinate to drive tumorigenesis. Detection of the activation of MET and EGFR may be used for targeted drug therapy. PMID- 21687955 TI - Plasmacytoid dendritic cell subpopulations in head and neck squamous cell carcinoma. AB - Human plasmacytoid dendritic cells (PDCs) are present in solid tumor tissue and metastatic cervical lymph nodes (CLN) in head and neck squamous cell carcinoma (HNSCC). We recently showed that classical PDC functions are heavily disturbed in the tumor microenvironment. In this study we present a new approach to the subject by introducing 3 PDC subsets in HNSCC, characterized by the surface markers CD25, CD56 and CD203c. The first subset, positive for CD25, is significantly induced by HNSCC in vitro and present in metastatic lymph nodes in vivo. This subset can be phenotypically subdivided into matured cells and into a group expressing early T cell markers. Functionally this subgroup is associated with the secretion of IL-8. The second subset, positive for CD56, constitutes 4 5% of all PDCs and is significantly down-regulated by HNSCC. Furthermore, this population sporadically expresses perforin/granzyme B and is absent in metastatic lymph nodes. The third subset, positive for the basophile marker CD203c, is inducible by crosslinking BDCA-2 in the presence of HNSCC and IL-4. Future studies will have to clarify the in vivo relevance of the different PDC subsets in HNSCC. PMID- 21687956 TI - Modulation of biomarkers related to tumor initiation and promotion in mouse skin by a natural beta-glucuronidase inhibitor and its precursors. AB - Carcinogen-mediated labilization of lysosomal enzymes such as beta-glucuronidase (betaG) is often associated with the general process of inflammation. Therefore, the primary goal of this study was to demonstrate that exposing the skin of SENCAR mice to the natural betaG inhibitor D-glucaro-1,4-lactone (1,4-GL) and its precursor D-glucuronic acid-gamma-lactone (GUL), prior to and during 7,12 dimethylbenz[alpha]anthracene (DMBA) treatment inhibits not only epidermal hyperplasia but also inflammation in the mouse skin complete carcinogenesis model, i.e., the 4-week inflammatory-hyperplasia assay. Topical administration of 1,4-GL or GUL prior to repetitive, high-dose DMBA treatment markedly and in a dose-related manner inhibited DMBA-induced epidermal hyperplasia (i.e., up to 57%). DMBA-mediated Ha-ras mutations in codon 61 were reduced by up to 78% by 1,4 GL. DMBA-induced inflammation, as measured by dermal leukocyte counts and immunologically, was inhibited by up to 37% by topical 1,4-GL but not by GUL. The inhibition of cellular proliferation and inflammation coincided with the inhibition of betaG expression. Thus, the present study suggests that in the DMBA induced complete skin carcinogenesis model, 1,4-GL when applied topically had both anti-proliferative properties as well as anti-inflammatory properties, whereas GUL had only anti-proliferative when applied topically. However, the number of inflammatory cells in the dermal portion of the skin of mice was significantly reduced by dietary treatment of GUL, whereas both topical and dietary treatments with 1,4-GL were very effective. PMID- 21687957 TI - Arsenic trioxide re-sensitizes ERalpha-negative breast cancer cells to endocrine therapy by restoring ERalpha expression in vitro and in vivo. AB - Approximately one-third of breast cancers lack estrogen receptor alpha (ERalpha) because of the hypermethylation of the CpG island in the receptor's promoter. These tumors are associated with poorer histological differentiation, a higher growth fraction, are rarely responsive to endocrine therapy and have a worse clinical outcome. Thus, re-expression of ERalpha in ERalpha-negative breast cancers may restore the sensitivity of antiestrogen therapy. The ERalpha-negative breast cancer cell line MDA-MB-435s was treated with different concentrations of arsenic trioxide (As2O3). MS-PCR was used to detect the change in the methylation status of ERalpha. RT-PCR, immunohistochemistry and Western blot analyses were used to detect changes in the mRNA and protein expression of DNA methyl transferase-1 (DNMT1) and ERalpha. Cell proliferation was examined using the MTT assay. A xenograft model in nude mice was used to further examine the results we observed in vitro. The ERalpha gene was demethylated after As2O3 treatment of MDA MB-435s cells. RT-PCR, immunohistochemistry and Western blot analyses revealed that DNMT1 expression was inhibited and ERalpha was re-expressed in a concentration-dependent manner after As2O3 treatment. The MTT assay showed that cell proliferation was significantly suppressed after exposure to different concentrations of As2O3. Addition of tamoxifen (TAM) further suppressed levels of cell proliferation. In vivo, the xenograft tumor volumes of As2O3-treated mice were smaller than those observed in untreated and TAM-treated mice. Treatment with a combination of As2O3+TAM resulted in further suppression. As2O3 can act as a demethylation agent to restore ERalpha expression in ERalpha-negative breast cancer cells and re-sensitize these cells to endocrine therapy in vitro and in vivo. PMID- 21687958 TI - Proteomic-based analysis for identification of potential serum biomarkers in gallbladder cancer. AB - Gallbladder cancer is the most common malignant tumor of the biliary tract. Early diagnosis of gallbladder cancer is difficult because of the latent onset and lack of good biomarkers. To identify new biomarkers that improve the early diagnosis and/or serve as possible therapeutic targets in gallbladder cancer is essential. In the present study, serum proteins were separated by two-dimensional gel electrophoresis (2-DE) in 3 patients with gallbladder cancer and 3 healthy volunteers. The differentially expressed spots were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Western blotting and immunohistochemistry were performed to verify the expression of certain candidate proteins. Protein expression and clinical correlation was evaluated. We found that 64 protein spots were significantly changed in gallbladder cancer. Twenty-four proteins including S100A10, haptoglobin, cystatin B, profilin-1 and superoxide dismutase were successfully identified. Among these proteins, S100A10 and haptoglobin were validated using Western blotting. Immunohistochemically, the expression of S100A10 and haptoglobin proteins was found to be higher in gallbladder cancer tissues compared to that in gallbladder adenoma, liver cholangiocarcinoma and cholecystitis tissue. Patients with high expression of S100A10 and haptoglobin were linked to late stage disease and poor clinical prognosis. Our data suggest that combined comparative proteomic analysis by 2-DE and MALDI-TOF-MS is an effective method for identifying differentially expressed proteins in serum samples. These proteomic approaches could be used for identifying new serum biomarkers in gallbladder cancer. S100A10, haptoglobin and other identified proteins may be potential molecular targets for early gallbladder cancer diagnostics and therapeutic applications. PMID- 21687959 TI - Complete acetabular cup revision versus isolated liner exchange for polyethylene wear and osteolysis without loosening in cementless total hip arthroplasty. AB - INTRODUCTION: Revision surgery in patients showing polyethylene wear and acetabular osteolysis without visible acetabular cup loosening involves the difficult decision of whether to revise only the liner or both the cup and the liner. The purpose of this study is to compare the outcomes of complete acetabular revision and isolated liner exchange in patients showing wear and osteolysis without loosening. MATERIALS AND METHODS: We evaluated 80 cases of revision surgery for polyethylene wear and osteolysis without cup loosening performed between October 1997 and December 2008. The cup revision group consisted of 45 patients who underwent a complete acetabular cup replacement, and the cup retention group consisted of 35 patients who underwent either an isolated liner exchange or a liner cementing procedure. Comparisons between the two groups were performed. RESULTS: There were differences in femoral stem revision, estimated blood loss, and hospital stay. Other variables including complications, osteolysis progression, re-revision rate, clinical score, and satisfaction showed no differences between the two groups. There was one case of early loosening and subsequent re-revision surgery in the cup revision group, as well as one case of wear progression and liner dislodgement leading to complete re-revision of the acetabular component and femoral stem in the cup retention group. CONCLUSION: We found no differences in acetabular osteolysis progression, fixation failure, or complication between the cup revision and retention groups. Therefore, isolated liner exchange without cup extraction in cases of osteolysis that includes a well fixed and well-positioned shell could be considered as a viable treatment option. PMID- 21687960 TI - Subarachnoid hemorrhage-associated arachnoiditis and syringomyelia. PMID- 21687961 TI - Aneurysm of the superficial temporal artery: case report and review. PMID- 21687962 TI - Identification of potential cell wall component that allows Taka-amylase A adsorption in submerged cultures of Aspergillus oryzae. AB - We observed that alpha-amylase (Taka-amylase A; TAA) activity in the culture broth disappeared in the later stage of submerged cultivation of Aspergillus oryzae. This disappearance was caused by adsorption of TAA onto the cell wall of A. oryzae and not due to protein degradation by extracellular proteolytic enzymes. To determine the cell wall component(s) that allows TAA adsorption efficiently, the cell wall was fractionated by stepwise alkali treatment and enzymatic digestion. Consequently, alkali-insoluble cell wall fractions exhibited high levels of TAA adsorption. In addition, this adsorption capacity was significantly enhanced by treatment of the alkali-insoluble fraction with beta glucanase, which resulted in the concomitant increase in the amount of chitin in the resulting fraction. In contrast, the adsorption capacity was diminished by treating the cell wall fraction with chitinase. These results suggest that the major component that allows TAA adsorption is chitin. However, both the mycelium and the cell wall demonstrated the inability to allow TAA adsorption in the early stage of cultivation, despite chitin content in the cell wall being identical in both early and late stages of cultivation. These results suggest the existence of unidentified factor(s) that could prevent the adsorption of TAA onto the cell wall. Such factor(s) is most likely removed or diminished from the cell wall following longer cultivation periods. PMID- 21687963 TI - Red mold fermented products and Alzheimer's disease: a review. AB - Alzheimer's disease is seen mainly in individuals over the age of 65, and the morbidity rate increases with age. Regarding the health function of Monascus fermented red mold rice (RMR), besides hypolipidemic and hypotensive effects, other health functions of RMR such as anti-oxidation, cancer prevention, anti fatigue, and anti-obesity have also been reported. Many published studies have shown the efficacy of RMR in the prevention of Alzheimer's disease. The current article discusses and provides evidence to support the beneficial potential of RMR in the prevention of Alzheimer's disease by discussing the pathogenic factors of Alzheimer's disease and the secondary metabolites of Monascus. PMID- 21687964 TI - Efficient accumulation of oleic acid in Saccharomyces cerevisiae caused by expression of rat elongase 2 gene (rELO2) and its contribution to tolerance to alcohols. AB - When the cells of Saccharomyces cerevisiae are exposed to high concentration of ethanol, the content of oleic acid (C18:1n-9) increased as the initial concentration of ethanol increased. Based on this observation, we attempted to confer ethanol tolerance to S. cerevisiae by manipulating fatty acid composition of the cells. Rather than altering OLE1 expression [the desaturase making both C16:1n-7 (palmitoleic acid) and C18:1n-9], we introduced elongase genes. Introduction of rat elongase 1 gene (rELO1) into S. cerevisiae gave cis-vaccenic acid (cis-C18:1n-7) by conversion from C16:1n-7, and the increase in this C18:1 fatty acid did not confer ethanol tolerance to the cells. On the other hand, the introduction of rat elongase 2 gene (rELO2), which elongates C16:0 to C18:0, drastically increased C18:1n-9 content, and the cells acquired ethanol tolerance, emphasizing the specific role of C18:1n-9. Furthermore, the transformant of rELO2 also conferred tolerance to n-butanol, n-propanol, and 2-propanol. PMID- 21687965 TI - Cloning and expression of a tyrosinase from Aspergillus oryzae in Yarrowia lipolytica: application in L-DOPA biotransformation. AB - Amplification of the tyrosinase gene (melO) from the genomic DNA of Aspergillus oryzae NCIM 1212 yielded a 1.6-kb product. This gene was cloned into pYLEX1, and the resulting pTyro-YLEX1 vector was transformed in Yarrowia lipolytica strain Po 1 g. A clone displaying the highest specific activity for tyrosinase (10.94 U/mg) was used for obtaining the complementary DNA (cDNA) and for protein expression studies. cDNA sequence analysis indicated the splicing of an intron present in the melO gene by Po 1 g. Native polyacrylamide gel electrophoresis, acidification at pH 3.0 followed by activity staining with L-DOPA indicated the expression of an active tyrosinase. The clone over-expressing the tyrosinase transformed L tyrosine to L-DOPA. On optimization of conditions for the biotransformation (pH 4.0, temperature 60 degrees C and with 3.5 mg of biomass), 0.4 mg/ml of L-DOPA was obtained. PMID- 21687967 TI - The role of age of acquisition in bilingual word translation: evidence from Spanish-English bilinguals. AB - The present research tested the hypothesis that the age at which one's first language (L1) words are learned influences language processing in bilinguals. Prior research on bilingual language processing by Kroll and colleagues has suggested that memory links between L1 words and conceptual representations are stronger than memory links between one's second language (L2) word and conceptual representations. We hypothesized that the strengths of memory links between L1 words and conceptual representations are stronger for words learned early in life than for words learned later in life. Support for the hypothesis was obtained in bilingual translation experiment with 36 Spanish-English bilinguals. Participants translated L1 words into L2 and L2 words into L1. Half of the L1 words were learned early in childhood (early AoA words), and half were learned later in life (late AoA words). The L2 words were translation equivalents of the L1 words tested; the average age at which L2 words were learned was age 7. Target words were presented either in random order or blocked by semantic category. Translation times were longer when trials were blocked by semantic category (i.e., categorical interference) occurred only when early AoA L1 words were translated into L2. Implications for current models of bilingual memory are discussed. PMID- 21687966 TI - Heme biosynthesis and its regulation: towards understanding and improvement of heme biosynthesis in filamentous fungi. AB - Heme biosynthesis in fungal host strains has acquired considerable interest in relation to the production of secreted heme-containing peroxidases. Class II peroxidase enzymes have been suggested as eco-friendly replacements of polluting chemical processes in industry. These peroxidases are naturally produced in small amounts by basidiomycetes. Filamentous fungi like Aspergillus sp. are considered as suitable hosts for protein production due to their high capacity of protein secretion. For the purpose of peroxidase production, heme is considered a putative limiting factor. However, heme addition is not appropriate in large scale production processes due to its high hydrophobicity and cost price. The preferred situation in order to overcome the limiting effect of heme would be to increase intracellular heme levels. This requires a thorough insight into the biosynthetic pathway and its regulation. In this review, the heme biosynthetic pathway is discussed with regards to synthesis, regulation, and transport. Although the heme biosynthetic pathway is a highly conserved and tightly regulated pathway, the mode of regulation does not appear to be conserved among eukaryotes. However, common factors like feedback inhibition and regulation by heme, iron, and oxygen appear to be involved in regulation of the heme biosynthesis pathway in most organisms. Therefore, they are the initial targets to be investigated in Aspergillus niger. PMID- 21687968 TI - Urine analysis of glucose tetrasaccharide by HPLC; a useful marker for the investigation of patients with Pompe and other glycogen storage diseases. AB - A high performance liquid chromatography method, adapted from an established urinary sugars method, has been developed for the analysis of a tetraglucose oligomer (Glc(4)) in urine. Pompe disease results from defects in the activity of lysosomal acid alpha-glucosidase (GAA) with patients typically excreting increased amounts of Glc(4). Rapid determination of GAA in dried blood spots is now possible. However, enzymatic analysis is unable to discriminate between patients with Pompe disease and those individuals harbouring pseudo deficiency mutations. This method was able to quantify Glc(4) levels in all patients analysed with an established diagnosis of Pompe disease, and all controls analysed had Glc(4) levels below the limit of detection for this method. Importantly the method was able to discriminate between an individual known to harbour a pseudo Pompe mutation and patients with Pompe disease, providing a useful supporting test to enzymatic analysis. Sequential measurement of urinary Glc(4) has been proposed to monitor the effects of enzyme replacement therapy (ERT). We observed a clear decrease in Glc(4) levels following commencement of treatment in three patients studied. Additionally, raised levels of Glc(4) were observed in patients with glycogen storage disease (GSD) type Ia and type III suggesting that this method may have applications in other GSDs. PMID- 21687969 TI - Two and a half clavicles--a case report. PMID- 21687970 TI - The efficacy of intraoperative atrial radiofrequency ablation for atrial fibrillation during concomitant cardiac surgery-the Surgical Atrial Fibrillation Suppression (SAFS) Study. AB - INTRODUCTION: Studies assessing radiofrequency ablation (RFA) for atrial fibrillation (AF) performed at the time of concomitant cardiac surgery have reported high success rates. The efficacy of this treatment has primarily been determined by a single electrocardiogram (ECG) or 24-h Holter monitor at follow up. We sought to assess the true efficacy of this procedure using prolonged cardiac rhythm monitoring. METHODS: One hundred patients with paroxysmal (n = 47) and persistent AF (n = 53) requiring cardiac surgery were enrolled. Patients were clinically reviewed 6 weeks post-operatively and were monitored with 7-day Holter with full disclosure, 6 months post-surgery. A cohort of 50 patients also underwent 7 day Holter monitoring preoperatively. AF recurrence was defined as >30 s of AF. RESULTS: At 6 months, 75% of patients were in sinus rhythm according to a single ECG. However, only 62% of patients were free from AF on 7-day Holter; all AF episodes in these patients were asymptomatic. The procedure resulted in a significant decrease in AF burden from 56.2% at baseline to 27.5% at 6 months follow-up, (p < 0.001). Predictors of AF recurrence were (1) pre-operative AF duration; (2) persistent compared with paroxysmal AF; (3) increasing left atrial diameter and (4) requirement for mitral valve surgery. CONCLUSIONS: Surgical RFA for the treatment of AF, during concomitant cardiac surgery, is a successful procedure and significantly reduces AF burden. However, 13% of patients have asymptomatic AF episodes only identified with continuous monitoring. This has important implications for post-operative anti-arrhythmic and anticoagulant management and for the definition of surgical AF ablation success. PMID- 21687971 TI - Exploring polymorphisms of the bovine RARRES2 gene and their associations with growth traits. AB - Retinoic acid receptor responder 2 gene (RARRES2) encodes a novel adipokine protein that plays a crucial role in regulating several biological processes, including immune responses, adipocyte differentiation, type 2 diabetes and metabolic syndrome. In this paper, polymorphisms of the bovine RARRES2 gene were detected in 1300 individuals from six breeds by DNA pooling, CRS-PCR-RFLP and DNA sequencing methods. The results showed that NC_007302:g.117035859A>G, 117035706G>A and 117034290A>G were in the coding region, which resulted in three synonymous mutations and only 117033779C>G was in the 3' UTR. Additionally, associations of the four novel SNPs with growth traits were analyzed in Nanyang cattle up to 2 years of age. In P1-PvuII locus, individuals with genotype BC had greater body height and hucklebone width than those with genotype AA, AC and AB at the age of 24 months. In P3-BamHI locus, individuals with genotype AG had higher hucklebone width than those with genotype GG at the age of 24 months. However, no statistically significant differences were observed in P5-SmaI locus. These results indicated that RARRES2 gene might be a potential candidate gene for marker-assisted selection (MAS). PMID- 21687972 TI - Polymorphism analysis of csd gene in six Apis mellifera subspecies. AB - The complementary sex determination (csd) gene is the primary gene determining the gender of honey bees (Apis spp). In this study we analyzed the polymorphism of csd gene in six Apis mellifera subspecies. The genomic region 3 of csd gene in these six A. mellifera was cloned, and identified. A total of 79 haplotypes were obtained from these six subspecies. Analysis showed that region 3 of csd gene has a high level of polymorphism in all the six A. mellifera subspecies. The A. m. anatolica subspecies has a slightly higher nucleotide diversity (pi) than other subspecies, while the pi values showed no significant difference among the other five subspecies. The phylogenetic tree showed that all the csd haplotypes from different A. mellifera subspecies are scattered throughout the tree, without forming six different clades. Population differentiation analysis showed that there are significant genetic differentiations among some of the subspecies. The NJ phylogenetic tree showed that the A. m. caucasica and A. m. carnica have the closest relationship, followed by A. m. ssp, A. m. ligustica, A. m. carpatica and A. m. anatolica that were gathered in the tree in turn. PMID- 21687973 TI - Proteomics of rat hypothalamus, hippocampus and pre-frontal/frontal cortex after central administration of the neuropeptide PACAP. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that exerts pleiotropic functions, acting as a hypophysiotropic factor, a neurotrophic and a neuroprotective agent. The molecular pathways activated by PACAP to exert its physiological roles in brain are incompletely understood. In this study, adrenocorticotropic hormone (ACTH), prolactin, luteinising hormone (LH), follicle stimulating hormone (FSH), thyroid-stimulating hormone (TSH), brain-derived neurotrophic factor and corticosterone blood levels were determined before and 20, 40, 60, and 120 min after PACAP intracerebroventricular administration. PACAP treatment increased ACTH, corticosterone, LH and FSH blood concentrations, while it decreased TSH levels. A proteomics investigation was carried out in hypothalamus, hippocampus and pre-frontal/frontal cortex (P/FC) using 2 dimensional gel electrophoresis at 120 min, the end-point suggested by studies on PACAP hypophysiotropic activities. Spots showing statistically significant alterations after PACAP treatment were identified by Matrix-assisted laser desorption/ionization-Time of flight mass spectrometry. Identified proteins were consistent with PACAP involvement in different molecular processes in brain. Altered expression levels were observed for proteins involved in cytoskeleton modulation and synaptic plasticity: actin in the hypothalamus; stathmin, dynamin, profilin and cofilin in hippocampus; synapsin in P/FC. Proteins involved in cellular differentiation were also modulated: glutathione-S-transferase alpha and peroxiredoxin in hippocampus; nucleoside diphosphate kinase in P/FC. Alterations were detected in proteins involved in neuroprotection, neurodegeneration and apoptosis: ubiquitin carboxyl-terminal hydrolase isozyme L1 and heat shock protein 90-beta in hypothalamus; alpha-synuclein in hippocampus; glyceraldehyde-3 phosphate dehydrogenase and prohibitin in P/FC. This proteomics study identified new proteins involved in molecular mechanisms mediating PACAP functions in the central nervous system. PMID- 21687974 TI - Polymorphism of exon 2 of BoLA-DRB3 gene and its relationship with somatic cell score in Beijing Holstein cows. AB - In the present study, the exon 2 and 3' end sequence of intron 1 of BoLA-DRB3 gene of 211 Beijing Holstein cows was amplified and a uniform fragment of 284 bp was obtained. The genetic polymorphism was investigated by PCR-RFLP using two restriction endonucleases HaeIII and BstYI. Seven genotypes were detected by digesting the PCR products with HaeIII. The frequency of AA, AB, AC, AD, BB, BC and BF genotypes was 0.4638, 0.0193, 0.0193, 0.3478, 0.0290, 0.0386 and 0.0822, respectively. Three genotypes were found by digesting the PCR products with BstYI. The frequency of AA, AB and BB genotypes was 0.0569, 0.2844 and 0.6587, respectively. The relationship between the polymorphisms in exon 2 of BoLA-DRB3 gene and somatic cell score (SCS) in Beijing Holstein cows was analyzed by least squares linear model. No significant difference was detected among least squares means of SCS for seven HaeIII-RFLP genotypes (P > 0.05). As for BstYI-RFLP analysis, least squares mean of SCS for AA was significantly lower than that for AB (P < 0.05) or BB (P < 0.05), and no significant difference was detected between AB and BB genotypes (P > 0.05). BstYI AA was the most favorable genotype and BstYI BB was the most unfavorable genotype for mastitis resistance. The information found in the present study is very important for improving mastitis resistance in dairy cattle by marker assisted selection. PMID- 21687975 TI - Molecular cloning of a stress-responsive aldehyde dehydrogenase gene ScALDH21 from the desiccation-tolerant moss Syntrichia caninervis and its responses to different stresses. AB - Aldehyde dehydrogenases (ALDHs) are key enzymes of abiotic stress-tolerance in a variety of organisms. The ALDH gene superfamily in eukaryotes has identified 22 protein families based upon sequence identity. ALDH21 is unique to mosses and represented by a single transcript gene in the desiccation-tolerant moss Tortula ruralis. We describe the cloning and characterization of an ALDH21 homologue from Syntrichia caninervis (ScALDH21), an extremely desiccation-tolerant moss found in deserts of Central Asia. The ScALDH21 cDNA is 1,452 bp and encodes a deduced polypeptide of 483 amino acids (53 kDa), approximately 97% identical to T. ruralis ALDH21 (TrALDH21A). The ScALDH21 gene was subcloned into pET26b(+) and expressed in Escherichia coli (Rosetta) to determine the peptides function in response to desiccation and salinity. Quantitative RT-PCR was used to analyze steady-state mRNA amounts in response to Abscisic acid (ABA) and desiccation. ScALDH21 transcript levels increased significantly in response to both desiccation and ABA. In the transgenic E. coli, ScALDH21 protein could be induced under the salinity and desiccation stress and was more abundant within salt treated gametophores relative to control tissue. The data suggest that ScALDH21 participates in the stress-resistant pathways and plays an important role in response to desiccation and salinity stresses. PMID- 21687977 TI - [Wound healing. Practical aspects for dermatologists]. PMID- 21687976 TI - Polymorphism C1420T of Serine hydroxymethyltransferase gene on maternal risk for Down syndrome. AB - Recent researches have investigated the factors that determine the maternal risk for Down syndrome (DS) in young woman. In this context, some studies have demonstrated the association between polymorphisms in genes involved on folate metabolism and the maternal risk for DS. These polymorphisms may result in abnormal folate metabolism and methyl deficiency, which is associated with aberrant chromosome segregation leading to trisomy 21. In this study, we analyzed the influence of the polymorphism C1420T in Serine hydroxymethyltransferase (SHMT) gene on maternal risk for DS and on metabolites concentrations of the folate pathway (serum folate and plasma homocysteine and methylmalonic acid). The study group was composed by 105 mothers with DS children (case group) and 185 mothers who had no children with DS (control group). The genotype distribution did not show significant statistical difference between case and control mothers (P = 0.24) however a protective effect between genotypes CC (P = 0.0002) and CT (P < 0.0001) and maternal risk for DS was observed. Furthermore, the SHMT C1420T polymorphism (rs1979277) does not affect the concentration of metabolites of folate pathway in our DS mothers. In conclusion, our data showed a protective role for the genotypes SHMT CC and CT on maternal risk for DS. The concentrations of metabolites of folate pathway did not differ significantly between the genotypes SHMT. PMID- 21687978 TI - Na,K-ATPase activity in mouse muscle is regulated by AMPK and PGC-1alpha. AB - Na,K-ATPase activity, which is crucial for skeletal muscle function, undergoes acute and long-term regulation in response to muscle activity. The aim of the present study was to test the hypothesis that AMP kinase (AMPK) and the transcriptional coactivator PGC-1alpha are underlying factors in long-term regulation of Na,K-ATPase isoform (alpha,beta and PLM) abundance and Na(+) affinity. Repeated treatment of mice with the AMPK activator AICAR decreased total PLM protein content but increased PLM phosphorylation, whereas the number of alpha- and beta-subunits remained unchanged. The K(m) for Na(+) stimulation of Na,K-ATPase was reduced (higher affinity) after AICAR treatment. PLM abundance was increased in AMPK kinase-dead mice compared with control mice, but PLM phosphorylation and Na,K-ATPase Na(+) affinity remained unchanged. Na,K-ATPase activity and subunit distribution were also measured in mice with different degrees of PGC-1alpha expression. Protein abundances of alpha1 and alpha2 were reduced in PGC-1alpha +/- and -/- mice, and the beta(1)/beta(2) ratio was increased with PGC-1alpha overexpression (TG mice). PLM protein abundance was decreased in TG mice, but phosphorylation status was unchanged. Na,K-ATPase V (max) was decreased in PCG-1alpha TG and KO mice. Experimentally in vitro induced phosphorylation of PLM increased Na,K-ATPase Na(+) affinity, confirming that PLM phosphorylation is important for Na,K-ATPase function. In conclusion, both AMPK and PGC-1alpha regulate PLM abundance, AMPK regulates PLM phosphorylation and PGC 1alpha expression influences Na,K-ATPase alpha(1) and alpha(2) content and beta(1)/beta(2) isoform ratio. Phosphorylation of the Na,K-ATPase subunit PLM is an important regulatory mechanism. PMID- 21687979 TI - Clinical and microbiological effects of photodynamic therapy associated with nonsurgical periodontal treatment. A 6-month follow-up. AB - Experimental studies in animals and in vitro have shown the usefulness of photodynamic therapy (PDT) as an adjunct to periodontal treatment. The aim of this study was to evaluate the long-term clinical and microbiological effects of PDT associated with nonsurgical periodontal treatment. Three sites in each of 33 patients with chronic periodontitis were randomly allocated in a split-mouth design to a treatment group: (1) scaling and root planing (SRP group); (2) SRP and irrigation with toluidine blue O (TBO group); and (3) SRP, irrigation with TBO and low-level laser irradiation (PDT group). Clinical parameters including visible plaque index, bleeding gingival index, bleeding on probing, probing depth, gingival recession and clinical attachment level were measured at baseline, and after 60, 90 and 180 days. Additionally, subgingival plaque samples were collected for microbiological analysis by PCR. Intergroup and intragroup statistical analyses were performed. All treatment groups showed an improvement in all clinical parameters, and a significant reduction in the proportion of sites positive for periodontopathogens at 60, 90 and 180 days compared to baseline (p < 0.05). None of the periodontal parameters showed a significant difference among the groups (p > 0.05). At 180 days, PDT treatment led to a significant reduction in the percentage of sites positive for all bacteria compared to SRP alone (p < 0.05). Within the limits of this study it may be concluded that PDT as an adjunct to periodontal treatment produced statistically significant reductions in some of the key periodontal pathogens but produced no statistically significant benefit in terms of clinical outcome. PMID- 21687980 TI - Histological and immunohistochemical evaluation of new epithelium after removal of oral leukoplakia with Nd:YAG laser treatment. AB - Laser excision has been used with increasing success to treat oral leukoplakia. The aim of the present study was to evaluate whether clinical healing of a leukoplakia after laser surgery is associated with a normal functional status of the new epithelium and whether pathological alterations in these parameters are related to the risk of local recurrence. The study population consisted of 13 consecutive patients with oral leukoplakia in which clinical healing was achieved after laser therapy using an Nd:YAG laser (Model 6000, Laser Sonics, Cooper Laser Sonics). At the end of the therapy, all patients underwent a second biopsy of the clinically healthy tissue. Epithelial cell turnover was evaluated before and after laser surgery by Ki67 protein expression, and positive staining of more than 20% was considered abnormal. All patients were followed on a monthly basis. Eight patients had abnormally high Ki67 values before laser therapy (mean 27.4 +/ 6.2%), but the levels decreased significantly after treatment (17.6 +/- 8.5%; t = 2.6, p < 0.05). High Ki67 values persisted in three patients, and local recurrences in the new epithelium was observed in two of these patients. Kaplan Meier statistics showed that the between-group difference was statistically significant (Chi square 7.3; p < 0.01). In conclusion, this is the first prospective study to show that clinical healing of leukoplakia treated by laser surgery may be accompanied by altered cell turnover in 20% of the cases. Ki67, as a marker of proliferative status, may be a prognostic indicator in the mucosa replacing the lesion. PMID- 21687982 TI - The feasibility of adapted group-based interpersonal therapy (IPT) for the treatment of depression by community health workers within the context of task shifting in South Africa. AB - Within the context of a large treatment gap for depression and a scarcity of specialist resources, there is a need for task shifting to scale up mental health services to address this gap in South Africa. This study assessed the feasibility of an adapted manualized version of grouped based Interpersonal Therapy (IPT) for use by supervised community health workers through a pilot study on 60 primary health care clinic users screened as having moderate to severe depression. Retention was good and participants in the group-based IPT intervention showed significant reduction in depressive symptoms on completion of the 12-week intervention as well as 24 weeks post baseline compared to the control group. Qualitative process evaluation suggests that improved social support, individual coping skills and improved personal agency assisted in the reduction of depressive symptoms. PMID- 21687981 TI - Comparison of treated and untreated major depressive disorder in a nationwide sample of Korean adults. AB - We examined factors associated with lifetime treatment of major depressive disorder (MDD) in a nationwide sample of Korean adults. Of the 6,510 subjects aged 18-64 years who participated in the Korean Epidemiologic Catchment Area study, 362 (5.6%) with a lifetime diagnosis of MDD were analyzed. Diagnostic assessments were based on the Korean version of the Composite International Diagnostic Interview administered by lay interviewers. Of the 362 respondents with a lifetime diagnosis of MDD, 117 (32.3%) had been treated for psychiatric problems. Treated individuals with MDD were more likely to have chronic episode(s), more symptoms of depression, insomnia, and suicidal ideation, and were less likely to have feelings of guilt. In addition, treated individuals were more likely to have comorbid anxiety disorders, especially obsessive-compulsive disorder, post-traumatic stress disorder, and generalized anxiety disorder. Treatment-seeking by individuals with MDD is affected by socio-cultural factors such as misconception and stigma of mental illness, as well as severity of depression and comorbid conditions. PMID- 21687983 TI - Recovery centers for people with severe mental illness: a survey of programs. AB - Recovery centers are physical entities offering various services and resources for people living with severe mental illness. In this study we identified and surveyed 24 recovery centers recruited through snowball sampling. The goal was to understand the range, common features and nature of current incarnations of recovery centers, assessing commonalities and differences with regards to: (1) overarching philosophies; (2) organizational and operational factors; (3) clientele; (4) service offerings; (5) staffing and financing; and (6) governance and oversight. We discuss some of the advantages and disadvantages of recovery centers, especially important given wider policy commitment to recovery, detailing the importance of future research and evaluation. PMID- 21687984 TI - The impact of fetal alcohol spectrum disorders on families: evaluation of a family intervention program. AB - The main purpose of the present study was to conduct a preliminary evaluation of the coaching families (CF) program, which aids families and caregivers raising children with fetal alcohol spectrum disorders (FASD). Mentors in the program work with families to educate them about FASD, access resources, and advocate on their behalf. Retrospective data from 186 families were analyzed from pre- to post-program. As expected, among caregivers there was a significant decrease in needs and increase in goal attainment from pre- to post-program. Further, there was a significant decrease in caregiver stress from pre- to post-program. Families reported high overall satisfaction with the CF program. The limitations, directions for future research, and implications for service providers were also discussed. PMID- 21687985 TI - Colour-induced relationship between affect and reaching kinematics during a goal directed aiming task. AB - A link between affect and action has been supported by the discovery that threat information is prioritized through an action-centred pathway--the dorsal visual stream. Magnocellular afferents, which originate from the retina and project to dorsal stream structures, are suppressed by exposure to diffuse red light, which diminishes humans' perception of threat-based images. In order to explore the role of colour in the relationship between affect and action, participants donned different pairs of coloured glasses (red, yellow, green, blue and clear) and completed Positive and Negative Affect Scale questionnaires as well as a series of target-directed aiming movements. Analyses of affect scores revealed a significant main effect for affect valence and a significant interaction between colour and valence: perceived positive affect was significantly smaller for the red condition. Kinematic analyses of variable error in the primary movement direction and Pearson correlation analyses between the displacements travelled prior to and following peak velocity indicated reduced accuracy and application of online control processes while wearing red glasses. Variable error of aiming was also positively and significantly correlated with negative affect scores under the red condition. These results suggest that only red light modulates the affect-action link by suppressing magnocellular activity, which disrupts visual processing for movement control. Furthermore, previous research examining the effect of the colour red on psychomotor tasks and perceptual acceleration of threat-based imagery suggest that stimulus-driven motor performance tasks requiring online control may be particularly susceptible to this effect. PMID- 21687986 TI - Bimanual reaches with symbolic cues exhibit errors in target selection. AB - We examined the movement trajectories of symmetric and asymmetric bimanual reaches to targets specified by direct spatial cues and by indirect symbolic cues. Symbolically cued asymmetric reaches have been shown to exhibit longer reaction times compared with symmetric reaches, whereas no such reaction time cost is observed when targets are spatially cued--a pattern thought to implicate increased demands on response selection (Diedrichsen et al. in Psychol Sci 12(6):493-498, 2001). As symbolically cued reaches impose greater demands on cognitive visuomotor translation than spatially cued reaches (Diedrichsen et al. in Cereb Cortex 16(12):1729-1738, 2006), we asked whether bimanual movements exhibit more spatial coupling with symbolic cues than with spatial cues. Participants made bimanual symmetric and asymmetric reaches to short- and long distance targets cued either symbolically or spatially. We replicated the reaction time cost for symbolically cued asymmetric movements. A subset of these asymmetric reaches also showed large trajectory modulations. It appeared that this subset had been incorrectly prepared and the movements required of the left and right arms had been switched. No such errors in target selection were observed when targets were spatially cued. In contrast to the reaction time cost and errors in selection for symbolically cued movements, we observed little evidence of increased spatial coupling with symbolic cues when movements were initiated towards the correct targets. We conclude that cognitive visuomotor translation demands during response selection increases bimanual coupling at the level of response selection (reaction time cost, errors in target selection) but not at the level of movement execution (spatial coupling). PMID- 21687987 TI - Human locomotion through a multiple obstacle environment: strategy changes as a result of visual field limitation. AB - This study investigated how human locomotion through an obstacle environment is influenced by visual field limitation. Participants were asked to walk at a comfortable pace to a target location while avoiding multiple vertical objects. During this task, they wore goggles restricting their visual field to small (S: 40 degrees *25 degrees ), medium (M: 80 degrees *60 degrees ), large (L: 115 degrees *90 degrees ), or unlimited (U) visual field sizes. Full-body motion capture was used to extract for each trial the mean speed, pathlength, mean step width, magnitude of head rotation and head mean angular speed. The results show that compared with the U condition, the M and L conditions caused participants to select a wider path around the obstacles without slowing down or altering step width. However, the S condition did slow down the participants, and increased both their step width and path length. We conclude that only for the S condition, balancing problems were substantial enough to spend more energy associated with increased step width. In all cases, participants choose to optimize safety (collision avoidance) at the cost of spending more energy. PMID- 21687988 TI - Functional characterization of the human myosin-7a motor domain. AB - Myosin-7a participates in auditory and visual processes. Defects in MYO7A, the gene encoding the myosin-7a heavy chain, are causative for Usher syndrome 1B, the most frequent cause of deaf-blindness in humans. In the present study, we performed a detailed kinetic and functional characterization of the isolated human myosin-7a motor domain to elucidate the details of chemomechanical coupling and the regulation of motor function. A rate-limiting, slow ADP release step causes long lifetimes of strong actin-binding intermediates and results in a high duty ratio. Moreover, our results reveal a Mg(2+)-sensitive regulatory mechanism tuning the kinetic and mechanical properties of the myosin-7a motor domain. We obtained direct evidence that changes in the concentration of free Mg(2+) ions affect the motor properties of human myosin-7a using an in vitro motility assay system. Our results suggest that in a cellular environment, compartment-specific fluctuations in free Mg(2+) ions can mediate the conditional switching of myosin 7a between cargo moving and tension bearing modes. PMID- 21687989 TI - Involvement of members of the Rab family and related small GTPases in autophagosome formation and maturation. AB - Macroautophagy, the process by which cytosolic components and organelles are engulfed and degraded by a double-membrane structure, could be viewed as a specialized, multistep membrane transport process. As such, it intersects with the exocytic and endocytic membrane trafficking pathways. A number of Rab GTPases which regulate secretory and endocytic membrane traffic have been shown to play either critical or accessory roles in autophagy. The biogenesis of the pre autophagosomal isolation membrane (or phagophore) is dependent on the functionality of Rab1. A non-canonical, Atg5/Atg7-independent mode of autophagosome generation from the trans-Golgi or endosome requires Rab9. Other Rabs, such as Rab5, Rab24, Rab33, and Rab7 have all been shown to be required, or involved at various stages of autophagosomal genesis and maturation. Another small GTPase, RalB, was very recently demonstrated to induce isolation membrane formation and maturation via its engagement of the exocyst complex, a known Rab effector. We summarize here what is now known about the involvement of Rabs in autophagy, and discuss plausible mechanisms with future perspectives. PMID- 21687990 TI - NFE2L3 (NRF3): the Cinderella of the Cap'n'Collar transcription factors. AB - NFE2L3 [Nuclear factor (erythroid-derived 2)-like 3] or NRF3, a member of the Cap'n'Collar (CNC) family, is a basic-region leucine zipper (bZIP) transcription factor that was first identified over 10 years ago. Contrary to its extensively studied homolog NFE2L2 (NRF2), the regulation and function of the NFE2L3 protein have not yet attracted as much attention. Nevertheless, several recent reports have now shed light on the possible roles of NFE2L3. Structural and biochemical studies revealed a series of domains and modifications that are critical for its cellular regulation. The control of the subcellular localization of NFE2L3 appears to be essential for understanding its role in various cellular processes. Importantly, newer studies provide fascinating insights linking NFE2L3 to differentiation, inflammation, and carcinogenesis. Here, we present an overview of the current level of knowledge of NFE2L3 transcription factor biology in humans and mice. From being the Cinderella of the CNC transcription factors for many years, NFE2L3 may now rapidly come into its own. PMID- 21687992 TI - Mollusc communities in Bulgarian fens: predictive power of the environment, vegetation, and spatial structure in an isolated habitat. AB - Mollusc communities of previously unexplored Bulgarian fens were studied in order to determine and generalise the patterns of species richness and composition along the mineral richness gradient. The aim was also to compare predictive values of the environment, vegetation and spatial structure. Altogether, 44 mollusc species were recorded at 40 treeless fen sites. Species richness varied from 0 to 18 species per site, and it was positively associated with the mineral gradient and negatively with altitude. However, the best predictor was obtained using plant species composition. All explanatory variables had higher effect on land snails than on the entire mollusc assemblage (including aquatic species). Species richness and abundance were significantly and positively correlated with the species composition turnover; the communities were highly nested, with poor sites having subsets of the fauna found in the richest. The main direction of mollusc species turnover was highly associated with that observed for vegetation, and the main gradient of plant species composition was able to explain nearly 20% of total variation in mollusc data. We found that spatial structure explained by far the highest proportion of independent variation, which reflected the high level of geographical isolation of Bulgarian fens and regional differences independent of any environmental variation. Our results demonstrate (1) the general role of mineral richness gradient for structuring mollusc communities in fens, (2) the pivotal indicator role of plant species composition in predicting species composition of mollusc communities, despite being trophically independent and (3) the effect of isolation and origins of the habitat on species composition: most species have wide geographical distributions within the habitat type, and geographical patterns within Bulgaria may have a stochastic element. PMID- 21687991 TI - Functional interplay between tetraspanins and proteases. AB - Several recent publications have described examples of physical and functional interations between tetraspanins and specific membrane proteases belonging to the TM-MMP and alpha-(ADAMs) and gamma-secretases families. Collectively, these examples constitute an emerging body of evidence supporting the notion that tetraspanin-enriched microdomains (TEMs) represent functional platforms for the regulation of key cellular processes including the release of surface protein ectodomains ("shedding"), regulated intramembrane proteolysis ("RIPing") and matrix degradation and assembly. These cellular processes in turn play a crucial role in an array of physiological and pathological phenomena. Thus, TEMs may represent new therapeutical targets that may simultaneously affect the proteolytic activity of different enzymes and their substrates. Agonistic or antagonistic antibodies and blocking soluble peptides corresponding to tetraspanin functional regions may offer new opportunities in the treatment of pathologies such as chronic inflammation, cancer, or Alzheimer's disease. In this review article, we will discuss all these aspects of functional regulation of protease activities by tetraspanins. PMID- 21687994 TI - Reply to: reply to: the parabolic power-velocity relationship does apply to fatigued states. PMID- 21687995 TI - The 894G>T endothelial nitric oxide synthase genetic polymorphism affects hemodynamic responses to mental stress performed before and after exercise. AB - Nitric oxide is the primary mediator of vasodilation during mental stress. Since genetic polymorphisms in the nitric oxide synthase (eNOS) gene seem to impair the production of NO, this study aimed to evaluate the effect of an exercise bout on hemodynamic responses to mental stress in subjects with the 894G>T polymorphism of eNOS. Subjects without (wild-type group; n = 16) or with (polymorphic-type group; n = 19) the 894G>T polymorphism underwent a mental stress challenge before and after a maximal cardiopulmonary exercise test. Blood pressure was measured by auscultation and forearm blood flow by venous occlusion plethysmography. The groups were similar regarding anthropometric, metabolic, resting blood pressure and exercise variables. Before exercise, systolic blood pressure response during mental stress was higher in the polymorphic-type group (?wild-type: 8.0 +/- 2.0% vs. ?polymorphic-type: 12.5 +/- 1.8%, P = 0.01), while the increase in forearm vascular conductance was similar between the groups (?wild-type 90.8 +/- 26.4% vs. ?polymorphic-type: 86.3 +/- 24.1%, P = 0.44). After exercise, the systolic blood pressure at baseline and during mental stress was lower than before exercise in the whole group (P < 0.05), but the pressure response during mental stress was still higher in the polymorphic-type group (?wild-type: 5.8 +/- 1.5% vs. ?polymorphic-type: 10.2 +/- 1.4%, P = 0.01). The increase in forearm vascular conductance was inhibited only in the polymorphic-type group (?before exercise 86.3 +/- 24.1% vs. ?after exercise: 41.5 +/- 12.6%, P = 0.04). In conclusion, these results suggest the 894G>T eNOS polymorphism is associated with altered hemodynamic responses to mental stress both before and after a single bout of dynamic exercise with potential clinical implications. PMID- 21687996 TI - Aerobic fitness testing in 6- to 9-year-old children: reliability and validity of a modified Yo-Yo IR1 test and the Andersen test. AB - This study analysed the reliability and validity of two intermittent running tests (the Yo-Yo IR1 test and the Andersen test) as tools for estimating VO(2max) in children under the age of 10. Two groups, aged 6-7 years (grade 0, n = 18) and 8-9 years (grade 2, n = 16), carried out two repetitions of a modified Yo-Yo IR1 test (2 * 16 m) and the Andersen test, as well as an incremental treadmill test, to directly determine the VO(2max). No significant differences were observed in test-retest performance of the Yo-Yo IR1 test [693 +/- 418 (+/-SD) and 670 +/- 328 m, r (2) = 0.79, CV = 19%, p > 0.05, n = 32) and the Andersen test (988 +/- 77 and 989 +/- 87 m, r (2) = 0.86, CV = 3%, p > 0.05, n = 31). The Yo-Yo IR1 (r (2) = 0.47, n = 31, p < 0.002) and Andersen test performance (r (2) = 0.53, n = 32, p < 0.001) correlated with the VO(2max). Yo-Yo IR1 performance correlated with Andersen test performance (r (2) = 0.74, n = 32, p < 0.0001). In conclusion, the Yo-Yo IR1 and the Andersen tests are reproducible and can be used as an indicator of aerobic fitness for 6- to 9-year-old children. PMID- 21687997 TI - Fascicle-tendon behavior of the gastrocnemius and soleus muscles during ankle bending exercise at different movement frequencies. AB - The present study investigated the effect of movement frequencies on the behavior of fascicles and tendons of synergistic muscles. Seven male subjects performed ankle bending (calf-raise) exercises at four movement frequencies (1.33, 1.67, 1.84, and 2.00 Hz), performed with an identical range of ankle joint motion. The fascicle and tendon behavior of medial gastrocnemius (MG) and soleus (SOL) was measured by ultrasonography while kinematic and kinetic parameters of the ankle were recorded. The torque of ankle joint was larger at higher exercise frequencies. The length change of muscle decreased and that of tendon increased at higher frequencies both for MG and for SOL, with no significant inter-muscle differences in the relative changes of muscle or tendon lengths to that of MTU. Changes of pennation angles and electromyographic activities as a function of movement frequency were also comparable for MG and SOL. These results suggest that under a stretch-shortening cycle action, the muscle-tendon interaction is altered by the movement frequency toward greater use of tendon elastic energy to provide greater MTU power at a higher frequency. Results also suggest that the movement frequency dependence of fascicle and tendon behavior is comparable between MG and SOL. PMID- 21687993 TI - Evolutionary diversity and developmental regulation of X-chromosome inactivation. AB - X-chromosome inactivation (XCI) results in the transcriptional silencing of one X chromosome in females to attain gene dosage parity between XX female and XY male mammals. Mammals appear to have developed rather diverse strategies to initiate XCI in early development. In placental mammals XCI depends on the regulatory noncoding RNA X-inactive specific transcript (Xist), which is absent in marsupials and monotremes. Surprisingly, even placental mammals show differences in the initiation of XCI in terms of Xist regulation and the timing to acquire dosage compensation. Despite this, all placental mammals achieve chromosome-wide gene silencing at some point in development, and this is maintained by epigenetic marks such as chromatin modifications and DNA methylation. In this review, we will summarise recent findings concerning the events that occur downstream of Xist RNA coating of the inactive X-chromosome (Xi) to ensure its heterochromatinization and the maintenance of the inactive state in the mouse and highlight similarities and differences between mammals. PMID- 21687999 TI - Cavum velum interpositum, cavum septum pellucidum, and cavum vergae: a review. AB - INTRODUCTION: Anterior midline intracranial cysts may be found most often in three forms: cavum septum pellucidum, cavum vergae, and cavum velum interpositum. A single offering that reviews these entities is difficult to find in the extant literature. Therefore, the present review was performed. MATERIALS AND METHODS: Various search engines and germane texts were reviewed for the terms cavum septum pellucidum, cavum vergae, and cavum velum interpositum. RESULTS: We report the findings of our search of the literature regarding these midline cystic structures. CONCLUSIONS: A better understanding of the associated anatomy, embryology, and pathology of these cysts will assist the clinician who treats such patients. PMID- 21687998 TI - Blood-derived anti-inflammatory protein solution blocks the effect of IL-1beta on human macrophages in vitro. AB - OBJECTIVE: The purpose of this research was to determine if an autologous protein solution (APS), prepared from platelet-rich plasma (PRP), could reduce the deleterious effects of inflammatory cytokines in vitro. METHODS: APS was prepared by processing human blood in a tuned density buoy separation device (Platelet Separation System, Biomet Biologics, LLC) to produce platelet-rich plasma (PRP) and processing the PRP in a concentration device containing polyacrylimide beads to produce a highly concentrated anti-inflammatory solution. A functional assay was designed using recombinant interleukin (IL)-1beta to upregulate IL-8 production by human monocytes. Either recombinant human interleukin-1 receptor antagonist (rhIL-1ra) or APS was added to some samples to determine if a reduced inflammatory response could be identified in vitro. The enzyme-linked immunosorbent assay (ELISA) method was employed to perform cytokine analyses, and Student's t test (alpha = 0.05) was used for all statistical analyses. RESULTS: Both the rhIL-1ra and the APS reduced the effect of IL-1beta on human macrophages in vitro. This was measured by the reduced production of IL-8 and tumor necrosis factor (TNF)-alpha. Further analysis of the supernatants confirmed the presence of high concentrations of IL-1ra and soluble TNF receptor I (sTNF-RI) with the APS treatment. CONCLUSION: The ability of the APS to reduce the effect of IL 1beta and limit the expression of other inflammatory cytokines in vitro validates its potential use as an autologous treatment for osteoarthritis. PMID- 21688000 TI - Thoracolumbar burst fractures with a neurological deficit treated with posterior decompression and interlaminar fusion. AB - INTRODUCTION: To our knowledge, thoracolumbar burst fractures with a neurological deficit treated with posterior decompression and interlaminar fusion have never been reported. Our study was to assess the outcome of posterior decompression and interlaminar fusion in treating thoracolumbar burst fractures with a neurological deficit. MATERIALS AND METHODS: Forty-one patients suffering from thoracolumbar burst fractures with a neurological deficit were included this study. All patients were treated with posterior decompression, interlaminar fusion and short segment fixation of the vertebrae above and below the fracture level and the fractured vertebrae. RESULTS: All patients were followed up for at least 24 months after surgery. Operative time and blood loss averaged 72 min and 325 ml, respectively. Thirty-eight patients with incomplete neurological lesions improved, by at least one American Spine Injury Association grade, whereas no neurological deterioration was observed in any case. Overall sagittal alignment improved from an average preoperative 22.4 degrees -4.6 degrees kyphosis at the final follow-up observation. The anterior vertebral body height ratio improved from 0.61 before surgery to 0.90 after surgery, whereas posterior vertebral body height ratio improved from 0.90 to 0.95. Spinal canal encroachment was reduced from an average 61.5% before surgery to 8.7% after surgery. Interlaminar radiological fusion was achieved within 6-8 months after surgery. No instrumentation failure was found in any patients. CONCLUSION: Posterior decompression, interlaminar fusion with posterior short-segment fixation provided excellent immediate reduction for traumatic segmental kyphosis and significant spinal canal clearance, and restored vertebral body height in the fracture level in patients with a thoracolumbar burst fracture and associated neurological deficit. PMID- 21688002 TI - Exploring within- and between-gender differences in burnout: 8 different occupational groups. AB - OBJECTIVES: The aim of this study was to examine gender differences in burnout within and between occupations using latent mean analysis. METHODS: Burnout was measured using the Oldenburg Burnout Inventory (OLBI), designed to assess the two sub-dimension exhaustion and disengagement. Men and women from eight different occupational groups in Norway were investigated: lawyers, physicians, nurses, teachers, church ministers, bus drivers and people working in advertising and information technology (n = 4,965). The average age was 42 years (SD 10.8), and 50.5% of the respondents were female. Within- and between-gender differences were examined by multi-group latent mean analysis by means of LISREL. RESULTS: Significant latent mean differences in the two dimensions of burnout between men and women were demonstrated. In general, the analyses indicate that overall, women report more exhaustion, but not more disengagement, than men. However, separate analyses indicate that the gender differences vary across occupational groups, especially for the disengagement dimension. Within-gender analyses suggest an approximately similar burnout profile across occupational groups for men and women. CONCLUSIONS: Despite gender equality in society in general, and inconclusive findings in previous studies on gender differences in burnout, women in this study seem to experience slightly higher burnout levels than men. Occupational differences found in the burnout profiles indicate that some professions may be more prone to burnout than others. For the occupational groups most at risk, more research is needed to disclose potential organizational factors that may make these workers more prone to burnout than others. PMID- 21688001 TI - In vivo three-dimensional segmental analysis of adolescent idiopathic scoliosis. AB - INTRODUCTION: An accurate assessment of three-dimensional (3D) intervertebral deviation is crucial to the better surgical correction of adolescent idiopathic scoliosis (AIS). However, a precise 3D study of intervertebral deviation has not been previously reported. OBJECTIVE: The purpose of the present study is to evaluate the intervertebral coronal inclination, axial rotation and sagittal angulation of AIS using 3D bone models and a local coordinate system. MATERIALS AND METHODS: 3D bone models of the thoracic and lumbar spine of ten AIS patients were constructed using computed tomography. The local coordinate axis was determined semi-automatically for each vertebra. By using these local coordinates, the intervertebral deviation angles were calculated in the coronal, axial and sagittal planes and projected to subjacent local coordinates. RESULT: The intervertebral deformity in the coronal plane was larger near the apical region and smaller near the junctional region. Conversely, the intervertebral rotation in the axial plane was smaller near the apical region, and larger near the junctional region. Concerning the sagittal plane deformity, the constant tendency was not recognized. CONCLUSION: Using a local coordinate system for the vertebra of AIS, we measured the 3D intervertebral coronal, axial and sagittal deviation of the thoracolumbar spine and found that the change in the intervertebral inclination angle in the coronal plane increased toward the apical region and decreased toward the junctional region, and that the converse tendency was noted for the axial intervertebral rotational angle. This analysis provides an improved 3D guide for the surgical correction of AIS. PMID- 21688003 TI - Adaptive statistical iterative reconstruction versus filtered back projection in the same patient: 64 channel liver CT image quality and patient radiation dose. AB - OBJECTIVES: To compare routine dose liver CT reconstructed with filtered back projection (FBP) versus low dose images reconstructed with FBP and adaptive statistical iterative reconstruction (ASIR). METHODS: In this retrospective study, patients had a routine dose protocol reconstructed with FBP, and again within 17 months (median 6.1 months), had a low dose protocol reconstructed twice, with FBP and ASIR. These reconstructions were compared for noise, image quality, and radiation dose. RESULTS: Nineteen patients were included. (12 male, mean age 58). Noise was significantly lower in low dose images reconstructed with ASIR compared to routine dose images reconstructed with FBP (liver: p < .05, aorta: p < 0.001). Low dose FBP images were scored significantly lower for subjective image quality than low dose ASIR (2.1 +/- 0.5, 3.2 +/- 0.8, p < 0.001). There was no difference in subjective image quality scores between routine dose FBP images and low dose ASIR images (3.6 +/- 0.5, 3.2 +/- 0.8, NS).Radiation dose was 41% less for the low dose protocol (4.4 +/- 2.4 mSv versus 7.5 +/- 5.5 mSv, p < 0.05). CONCLUSIONS: Our initial results suggest low dose CT images reconstructed with ASIR may have lower measured noise, similar image quality, yet significantly less radiation dose compared with higher dose images reconstructed with FBP. PMID- 21688004 TI - Extra-mammary findings in breast MRI. AB - OBJECTIVES: Incidental extra-mammary findings in breast Magnetic Resonance Imaging (MRI) may be benign in nature, but may also represent a metastasis or another important lesion. We aimed to analyse the prevalence and clinical relevance of these unexpected findings. METHODS: A retrospective review of 1535 breast MRIs was conducted. Only axial sequences were reassessed. Confirmation examinations were obtained in all cases. RESULTS: 285 patients had a confirmed incidental finding, which were located in the liver (51.9%), lung (11.2%), bone (7%), mediastinal lymph nodes (4.2%) or consisted of pleural/pericardial effusion (15.4%). 20.4% of incidental findings were confirmed to be malignant. Positive predictive value for MRI to detect a metastatic lesion was high if located within the bone (89%), lymph nodes (83%) and lung (59%), while it was low if located within the liver (9%) or if it consisted of pleural/pericardial effusion (6%). The axial enhanced sequence showed superior sensitivity to unenhanced images in detecting metastatic lesions, especially if only smaller (<=10 mm.) lesions were considered. CONCLUSIONS: The prevalence of metastatic incidental extra-mammary findings is not negligible. Particular attention should be to incidental findings located within the lung, bone and mediastinal lymph nodes. PMID- 21688005 TI - Identification and further differentiation of subendocardial and transmural myocardial infarction by fast strain-encoded (SENC) magnetic resonance imaging at 3.0 Tesla. AB - OBJECTIVES: To investigate whether subendocardial and transmural myocardial infarction can be identified and differentiated using the peak circumferential and longitudinal strains measured by fast strain-encoded (SENC). METHODS: Nineteen patients with ischemic heart diseases underwent imaging with fast SENC and late gadolinium enhancement (LGE) MRI at 3 T. Fast SENC measurements were performed in three short-axis slices (basal, mid-ventricular and apical levels) and one long-axis view (four-chamber) to assess peak longitudinal and circumferential systolic strains. RESULTS: All patients showed myocardial infarction with an average of 7 positive LGE segments. A total of 304 segments for longitudinal strains (LS) and 114 segments for circumferential strains (CS) could be analysed. Positive LGE segments showed lower peak CS and LS compared with the no LGE segments (P < 0.0001 for both). Segments with subendocardial infarction showed reduced CS and LS compared with the no LGE segments (P < 0.0001 for both). There was a significant difference in CS between subendocardial and transmural infarct segments (P = 0.03), but no significant difference in LS between them (P = 0.64). CONCLUSIONS: Fast SENC can identify old myocardial infarction and differentiate subendocardial from transmural infarction. PMID- 21688006 TI - Does the degree of background enhancement in breast MRI affect the detection and staging of breast cancer? AB - OBJECTIVE: The purpose of this study was to assess the influence of background enhancement on the detection and staging of breast cancer using MRI as an adjunct to mammography or ultrasound. METHODS: One hundred forty-six bilateral breast MRI examinations were evaluated to assess the extent of a known primary tumour and to problem solve after mammography or ultrasound without adjusting for the phase in the patients' menstrual cycle. The background enhancement was classified into four categories by visual evaluation: minimal, mild, moderate and marked. RESULTS: In total, 131 histologically confirmed abnormal cases (104 malignant and 27 benign) and 15 normal cases were included in the analysis. There was no tumour size-related bias between the groups (p = 0.522). For the primary index tumour, the sensitivities of MRI with minimal/mild and moderate/marked background enhancement were 100% and 76% (p = 0.001), respectively. Thus, the degree of background enhancement did not affect the specificity. For evaluating tumour extent (n = 104), the accuracy of MRI with moderate/marked background enhancement (52%) was significantly lower than that with minimal/mild background enhancement (84%; p = 0.002). CONCLUSION: The degree of background enhancement affected the detection and staging of breast cancer using MRI. PMID- 21688007 TI - Diagnostic performance of diffusion-weighted magnetic resonance imaging in bladder cancer: potential utility of apparent diffusion coefficient values as a biomarker to predict clinical aggressiveness. AB - OBJECTIVES: The diagnostic performance of diffusion-weighted magnetic resonance imaging (DW-MRI) in bladder cancer and the potential role of apparent diffusion coefficient (ADC) values in predicting pathological bladder cancer phenotypes associated with clinical aggressiveness were investigated. METHODS: One hundred and four bladder cancer patients underwent DW-MRI and T2-weighted magnetic resonance imaging (T2W-MRI) before transurethral resection. The image sets were reviewed by two independent radiologists. ADC values were measured in 121 eligible tumours. RESULTS: In detecting patients with bladder cancer, DW-MRI exhibited high sensitivity equivalent to that of T2W-MRI (>90%). Interobserver agreement was excellent for DW-MRI (kappa score, 0.88) though moderate for T2W MRI (0.67). ADC values were significantly lower in high-grade (vs. low-grade, P < 0.0001) and high-stage (T2 vs. T1 vs. Ta, P < 0.0001) tumours. At a cut-off ADC value determined by partition analysis, clinically aggressive phenotypes including muscle-invasive bladder cancer (MIBC) and high-grade T1 disease were differentiated from less aggressive phenotypes with a sensitivity of 88%, a specificity of 85% and an accuracy of 87%. CONCLUSION: DW-MRI exhibits high diagnostic performance in bladder cancer with excellent objectivity. The ADC value could potentially serve as a biomarker to predict clinical aggressiveness in bladder cancer. PMID- 21688008 TI - The association between fluid balance and outcomes after subarachnoid hemorrhage. AB - BACKGROUND: We sought to determine the association between early fluid balance and neurological/vital outcome of patients with subarachnoid hemorrhage. METHODS: Hospital admission, imaging, ICU and outcome data were retrospectively collected from the medical records of adult patients with aneurysmal SAH admitted to a level-1 trauma and stroke referral center during a 5-year period. Two groups were identified based on cumulative fluid balance by ICU day 3: (i) patients with a positive fluid balance (n = 221) and (ii) patients with even or negative fluid balance (n = 135). Multivariable logistic regression was used to adjust for age, Hunt-Hess and Fisher scores, mechanical ventilation and troponin elevation (>0.40 ng/ml) at ICU admission. The primary outcome was a composite of hospital mortality or new stroke. RESULTS: Patients with positive fluid balance had worse admission GCS and Hunt-Hess score, and by ICU day 3 had cumulatively received more IV fluids, but had less urine output when compared with the negative fluid balance group. There was no difference in the odds of hospital death or new stroke (adjusted OR: 1.47, 95%CI: 0.85, 2.54) between patients with positive and negative fluid balance. However, positive fluid balance was associated with increased odds of TCD vasospasm (adjusted OR 2.25, 95%CI: 1.37, 3.71) and prolonged hospital length of stay. CONCLUSIONS: Although handling of IV fluid administration was not an independent predictor of mortality or new stroke, patients with early positive fluid balance had worse clinical presentation and had greater resource use during the hospital course. PMID- 21688009 TI - Lemon verbena infusion consumption attenuates oxidative stress in dextran sulfate sodium-induced colitis in the rat. AB - BACKGROUND: Inflammatory bowel diseases (IBD) consist of an uncontrolled intestinal inflammation leading to mucosal disruption. This inflammation is accompanied by an excessive production of reactive oxygen species (ROS). Polyphenols are micronutrients with antioxidative and anti-inflammatory properties, and may play an interesting role in the prevention of intestinal inflammation. Lemon verbena (Aloysia triphylla) infusion is a popular herbal infusion rich in polyphenols (flavones and verbascoside). AIMS: This study evaluated the preventive effects of lemon verbena infusion consumption against mild-to-moderate dextran sulfate sodium (DSS)-induced colitis in rats. METHODS: Wistar rats drank water or lemon verbena infusion for 14 days. On day 15, half of the rats received DSS (4%) in their drink for 7 days. At the end of the experimental period, the colon was taken for histopathological examination and determination of myeloperoxidase (MPO) activity, antioxidant enzyme activities (superoxide dismutase [SOD], glutathione peroxidase [GPx], glutathione reductase [GR], catalase [CAT]), glutathione and lipid peroxidation. Lymphocyte populations were determined in blood, mesenteric nodes and Peyer's patches. RESULTS: Rats ingested daily 5.6 MUmol of polyphenols. DSS reduced food intake and induced colitis, as reflected by histological lesions and increased MPO activity. Although these alterations were not significantly counteracted by lemon verbena consumption, the herbal infusion increased colonic SOD activity and decreased lipid peroxidation (malondialdehyde). Other oxidative stress markers (GPx, GR, CAT, glutathione) were not significantly modified. CONCLUSION: Our study shows that the preventive consumption of lemon verbena infusion offered some antioxidative protection during experimental colitis by stimulating SOD activity and decreasing lipid peroxidation. PMID- 21688010 TI - Telephone reminder call in addition to mailing notification improved the acceptance rate of colonoscopy in patients with a positive fecal immunochemical test. AB - BACKGROUND AND AIMS: Colorectal cancer (CRC) screening with a fecal immunochemical test (FIT) reduces CRC mortality; however, the acceptance rate of a colonoscopy in patients with a positive FIT was not high. The aim of this study was therefore to determine whether a telephone reminder call could increase the acceptance rate of colonoscopy in patients with a positive FIT. METHODS: We performed FITs for asymptomatic participants aged 50 years or older. For patients with a positive FIT, a colonoscopy was recommended via mailing notification only (control group) or via a telephone reminder call after mailing notification (intervention group). The calls informed patients about the significance of a positive FIT and encouraged a colonoscopy following positive FITs. RESULTS: The FIT results were positive in 90 of 8,318 patients who received FITs. Fifty patients were advised to receive colonoscopy via mailing notification only, and 40 patients were advised via both a telephone reminder call and a mailing notification. The acceptance rate of colonoscopy was significantly higher in the intervention group than in the control group (p = 0.038). The lesion-detection rate for an advanced neoplasia was also significantly higher in the intervention group than in the control group (p = 0.046). According to multivariate logistic regression analysis, a telephone reminder was a significant determinant of colonoscopy acceptance in patients with a positive FIT (OR 4.33; 95% CI, 1.19 15.75; p = 0.026). CONCLUSIONS: Telephone reminder calls in addition to mailing notification improved the acceptance rate of colonoscopy in patients with a positive FIT. PMID- 21688011 TI - Assessment of radon equilibrium factor from distribution parameters of simultaneous radon and radon progeny measurements. AB - In Canada, a radon and radon progeny survey was carried out in the 1970s in 19 cities. To the authors' knowledge, this is the only large survey of simultaneous radon and radon progeny measurements up to the present time. However, the survey was carried out for the purpose of establishing geographic variation of radon and radon progeny; therefore, radon equilibrium factors, F, were not assessed at that time. From the summary results of this large simultaneous radon and radon progeny survey, the characteristics of radon equilibrium factor were assessed. The average F factor assessed from this survey in 12,576 houses is 0.54. The current assessment may indicate that the typical F value of 0.4 recommended by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), and the International Commission on Radiological Protection (ICRP) could lead to a downward bias in the estimation of radon doses to the lung. PMID- 21688012 TI - Biokinetics of 90Sr after chronic ingestion in a juvenile and adult mouse model. AB - The aim of our study was to define the biokinetics of (90)Sr after chronic contamination by ingestion using a juvenile and adult murine model. Animals ingested (90)Sr by drinking water containing 20 kBq l(-1) of (90)Sr. For the juvenile model, parents received (90)Sr before mating and their offspring were killed between birth and 20 weeks of ingestion. For the adult model, (90)Sr ingestion started at 9 weeks of age and they were killed after different ingestion periods up to 20 weeks. The body weight, food and water consumption of the animals were monitored on a weekly basis. Before killing and sampling of organs, animals were put in metabolic cages. (90)Sr in organs and excreta was determined by liquid scintillation beta counting. Highest (90)Sr contents were found in bones and were generally higher in females than in males, and (90)Sr retention varied according to the skeletal sites. An accumulation of (90)Sr in the bones was observed over time for both models, with a plateau level at adult age for the juvenile model. The highest rate of (90)Sr accumulation in bones was observed in early life of offspring, i.e. before the age of 6 weeks. With the exception of the digestive tract, (90)Sr was below the detection limit in all other organs sampled. Overall, our results confirm that (90)Sr mainly accumulates in bones. Furthermore, our results indicate that there are gender- and age dependent differences in the distribution of (90)Sr after low-dose chronic ingestion in the mouse model. These results provide the basis for future studies on possible non-cancerous effects during chronic, long-term exposure to (90)Sr through ingestion in a mouse model, especially on the immune and hematopoietic systems. PMID- 21688013 TI - A novel method of augmenting gene expression and angiogenesis in the normal and ischemic canine myocardium. AB - This study presents a novel method that direct intramyocardial injection of low dose plasmid DNA and microbubbles combined with insonation could further augment gene expression in normal and ischemic canine myocardium. Plasmids encoding enhanced green fluorescent protein (pEGFP) and hepatocyte growth factor (pHGF) (500 MUg) were individually mixed with 0.5 ml of microbubble solution (MB) and injected into the normal or acute ischemic canine myocardium. The dogs in the plasmid + MB/US group underwent insonation (US). Other dogs were randomly divided into three treatment groups: plasmid and insonation, plasmid and MB injection, and plasmid injection only. The EGFP and HGF mRNA expressions were assessed in the myocardium at the injection site and at sites 0.5 and 1 cm remote from the injection site. Compared to plasmid transfer alone, a mean 13.4-fold enhancement of gene expression was achieved in the EGFP + MB/US group at 48 h (p < 0.01). HGF mRNA expression in ischemic zones was markedly elevated after 28 days, with a mean 9.0-fold enhancement in the HGF + MB/US group (p < 0.01). EGFP protein expression was detected in the normal myocardium at 1 cm remote from the injection site in the EGFP + MB/US group. Similarly, HGF protein expression was detected in the ischemic myocardium at 0.5 cm remote from the injection site in the HGF + MB/US group. These findings indicate that the radius of gene expression was partly extended in the two plasmid + MB/US groups. The capillary density increased from 20.9 +/- 5.3/mm(2) in control myocardial infarction dogs without treatment to 126.7 +/- 38.2/mm(2) in the HGF + MB/US group (p < 0.01). Taken together, the present data demonstrate that direct intramyocardial injection of an angiogenic gene and microbubbles combined with insonation can augment gene expression and angiogenesis. Consequently, this strategy may be a useful tool for gene therapy of ischemic heart disease. PMID- 21688014 TI - Simultaneous post-transcriptional gene silencing of two different chalcone synthase genes resulting in pure white flowers in the octoploid dahlia. AB - Garden dahlias (Dahlia variabilis) are autoallooctoploids with redundant genes producing wide color variations in flowers. There are no pure white dahlia cultivars, despite its long breeding history. However, the white areas of bicolor flower petals appear to be pure white. The objective of this experiment was to elucidate the mechanism by which the pure white color is expressed in the petals of some bicolor cultivars. A pigment analysis showed that no flavonoid derivatives were detected in the white areas of petals in a star-type cultivar 'Yuino' and the two seedling cultivars 'OriW1' and 'OriW2' borne from a red-white bicolor cultivar, 'Orihime', indicating that their white areas are pure white. Semi-quantitative RT-PCR showed that in the pure white areas, transcripts of two chalcone synthases (CHS), DvCHS1 and DvCHS2 which share 69% nucleotide similarity with each other, were barely detected. Premature mRNA of DvCHS1 and DvCHS2 were detected, indicating that these two CHS genes are silenced post transcriptionally. RNA gel blot analysis revealed that small interfering RNAs (siRNAs) derived from CHSs were produced in these pure white areas. By high throughput sequence analysis of small RNAs in the pure white areas with no mismatch acceptance, small RNAs were mapped to two alleles of DvCHS1 and two alleles of DvCHS2 expressed in 'Yuino' petals. Therefore, we concluded that simultaneous siRNA-mediated post-transcriptional gene silencing of redundant CHS genes results in the appearance of pure white color in dahlias. PMID- 21688015 TI - EST analysis of functional genes associated with cell wall biosynthesis and modification in the secondary xylem of the yellow poplar (Liriodendron tulipifera) stem during early stage of tension wood formation. AB - A cDNA library was constructed from secondary xylem in the stem of a 2-year-old yellow poplar after being bent for 6 h with a 45 degrees configuration to isolate genes related to cell wall modification during the early stages of tension wood formation. A total of 6,141 ESTs were sequenced to generate a database of 5,982 high-quality expressed sequence tags (ESTs). These sequences were clustered into 1,733 unigenes, including 822 contigs and 911 singletons. Homologs of the genes regulate many aspects of secondary xylem development, including those for primary and secondary metabolism, plant growth hormones, transcription factors, cell wall biosynthesis and modification, and stress responses. Although there were only 1,733 annotated ESTs (28.9%), the annotated ESTs obtained in this study provided sequences for a broad array of transcripts expressed in the stem upon mechanical bending, and the majority of them were the first representatives of their respective gene families in Liriodendron tulipifera. In the case of lignin, xylem-specific COMTs were identified and their expressions were significantly downregulated in the tension wood-forming tissues. Additionally, the majority of the auxin- and BR-related genes were downregulated significantly in response to mechanical bending treatment. Despite the small number of ESTs sequenced in this study, many genes that are relevant to cell wall biosynthesis and modification have been isolated. Expression analysis of selected genes allow us to identify the regulatory genes that may perform essential functions during the early stages of tension wood formation and associated cell wall modification. PMID- 21688016 TI - Proliferative retinopathy predicts nephropathy: a 25-year follow-up study of type 1 diabetic patients. AB - We wanted to examine proliferative retinopathy as a marker of incident nephropathy in a 25-year follow-up study of a population-based cohort of Danish type 1 diabetic patients and to examine cross-sectional associations between nephropathy and retinopathy in long-term surviving patients of the same cohort. All type 1 diabetic patients from Fyn County, Denmark, were identified as of 1 July 1973. One hundred and eighty four patients were examined in 1981-1982 (baseline) and in 2007-2008 (follow-up). The level of retinopathy was graded by ophthalmoscopy at baseline and nine-field digital colour fundus photographs at follow-up. Single spot urine was used to evaluate nephropathy at both examinations. Proliferative retinopathy was present in 29 patients (15.8%) at baseline. At follow-up, these patients were more likely to macroalbuminuria (20.7% vs. 6.5%) than patients without proliferative retinopathy at baseline. In a multivariate logistic regression adjusted for baseline age, sex, duration of diabetes, smoking, HbA(1,) systolic and diastolic blood pressure, odds ratio of nephropathy (micro- and macroalbuminuria combined) was 2.98 (95% confidence interval 1.18-7.51, p = 0.02) for patients with proliferative retinopathy at baseline as compared to those without. At follow-up, there was a close relation between retinopathy and nephropathy. The level of macroalbuminuria was 4.3, 4.6 and 13.0% for patients with no or mild non-proliferative retinopathy, moderate non-proliferative retinopathy and proliferative retinopathy, respectively. In conclusion, proliferative retinopathy is an independent marker of long-term nephropathy in type 1 diabetes. Upcoming studies should examine whether these microvascular complications are also causally linked in type 1 diabetes. PMID- 21688017 TI - Kidney function and retinol status in type 2 diabetes mellitus patients. AB - Kidneys play an important role in retinol turnover. We postulated that retinol homeostasis is disturbed in diabetic nephropathy. The aim of this research was to study the effect of kidney impairment on urinary excretion and on serum concentrations of retinol in type 2 diabetes mellitus patients. For this purpose, 41 type 2 diabetes patients and 9 sex -and age-matched healthy subjects were enrolled. Serum and urinary retinol and retinol-binding protein (RBP) were assessed by high-pressure liquid chromatography and enzyme-linked immunosorbent assay, respectively. The study showed that 17 out of 41 diabetic patients (41.5%) and none of the controls excreted retinol in urine (P < 0.02). Retinol excretion in the urine in these patients was 1.5-fold more prevalent than hypercreatininemia. Urinary retinol significantly correlated with clinically diagnosed nephropathy (P = 0.02). All but one of the patients with hypercreatininemia excreted retinol in the urine. Serum retinol and RBP in patients with hypercreatininemia were higher than in controls (P < 0.002). Values of urinary retinol, unlike urinary RBP, albumin and total protein, did not overlap between patients and controls. Our results indicate that (i) urinary retinol is a specific sign of tubular damage in type 2 diabetic patients and (ii) urinary retinol enables a more clear-cut identification of proximal tubule dysfunction in type 2 diabetes patients than urinary RBP or albumin. PMID- 21688018 TI - Evaluation of 1,5-anhydroglucitol as a marker for glycemic variability in patients with type 2 diabetes mellitus. AB - 1,5-anhydroglucitol (1,5-AG) has been suggested as a marker for short-term glycemic control and postprandial hyperglycemia. However, the role of 1,5-AG in glycemic variability has not been established. The aim of this study was to demonstrate the usefulness of 1,5-AG as a marker for glycemic variability in patients with type 2 diabetes. Sixty patients with type 2 diabetes were enrolled, and a continuous glucose monitoring system (CGMS) was applied for 72 h. Continuous overlapping net glycemic action (CONGA), mean amplitude of glycemic excursion (MAGE), and mean of the daily differences (MODD) were calculated for the assessment of glycemic variability and compared with 1,5-AG. Urinary 8-iso prostaglandin F2alpha (8-isoPGF2alpha) was measured to assess oxidative stress. 1,5-AG was correlated with fasting blood glucose, HbA1c, postprandial area under the curve for glucose above 180 mg/dL (AUC-180), and mean post-meal maximum glucose (MPMG). However, 1,5-AG did not show significant correlation with CONGA 1, MAGE, and MODD (R = -0.053, P = 0.689; R = -0.148, P = 0.259; R = -0.123, P = 0.350). In patients with HbA1c <= 8.0% (n = 35), 1,5-AG was significantly correlated with HbA1c, mean glucose, postprandial AUC-180, and MPMG. However, in patients with HbA1c > 8.0% (n = 25), 1,5-AG did not show correlation with any glycemic markers. Oxidative stress measured as urine 8-isoPGF2alpha showed positive correlations with CONGA-1, MAGE, AUC-180, postprandial AUC-180, and MPMG only in men. However, 1,5-AG did not correlate with oxidative stress. Our data suggested a limited usefulness of 1,5-AG in estimating glycemic variability and oxidative stress. 1,5-AG was able to represent mean glucose and postprandial hyperglycemia only in well-controlled diabetic patients. PMID- 21688019 TI - The coexistence of type 1 diabetes, MODY2 and metabolic syndrome in a young girl. AB - Even though autoantibodies to pancreatic islet cells are normally found in type 1 diabetes and insulin-resistance due to overweight is more reminiscent of type 2 diabetes, some studies have described beta-cell antibodies also in maturity-onset diabetes of the young (MODY) and in type 2 diabetes. A 7-year-old girl was referred to our Unit for incidental hyperglycemia and family history of MODY2 and type 2 diabetes. Genetic evaluation confirmed mutation L134P in exon 4 of the glucokinase gene and a high HLA-risk of type 1 diabetes. During follow-up, she developed type 1 diabetes and overweight-induced metabolic syndrome. The coexistence of MODY, type 1 diabetes and overweight-induced metabolic syndrome confirms that diabetes subtype probably represents a continuum of immune and metabolic dysfunction modified by genetic factors. PMID- 21688021 TI - A systematic review on the outcomes of correction of diastasis of the recti. AB - PURPOSE: Diastasis or divarication of the rectus abdominus muscles describes the separation of the recti, usually as a result of the linea alba thinning and stretching. This review examines whether divaricated recti should be repaired and tries to establish if the inherent co-morbidity associated with surgical correction outweighs the benefits derived. METHODS: EMBASE, MEDLINE and the Cochrane library were searched for ('divarication' OR 'diastasis') AND ('recti' OR 'rectus'). A standard data extraction form was used to extract data from each text. Due to the lack of randomised control trials, meta-analysis was not possible. RESULTS: Seven studies report that patient satisfaction was high following surgery. The most common complication seen was the development of a seroma. Other common complications included haematomas, minor skin necrosis, wound infections, dehiscence, post-operative pain, nerve damage and recurrence, the rate of which may be as high as 40%. CONCLUSIONS: Further studies are required to compare laparoscopic and open abdominoplasty techniques. Patients and physicians should be advised that correction is largely cosmetic, and although divarications may be unsightly they do not carry the same risks of actual herniation. Progressive techniques have resulted in risk reduction with no associated surgical mortality. However, the outcomes may be imperfect, with unsightly scarring, local sepsis and the possibility of recurrence. PMID- 21688020 TI - [Colorectal polyposis syndrome: a guide to diagnosis]. AB - Biopsies and resection specimens of the gastrointestinal tract are a major part of the routine workload in many histopathology departments, whereby polypoid lesions are generally the main focus. In addition to distinguishing non neoplastic from neoplastic polyps and evaluating the grade of dysplasia of the latter, the pathologist should always consider the possibility of an underlying polyposis syndrome. Not only have additional hereditary polyposis syndromes been identified in recent years due to a better understanding of their genetic and epigenetic alterations but also knowledge on well known polyposes has improved, leading to subtyping of various forms according to their different genotype. It is essential for the histopathologist to understand that the conventional histomorphology of individual polyps combined with information on the number and distribution of these lesions and clinical data can provide clues regarding a possible hereditary background. Therefore, the correct histological assessment of polyps is not just about getting the diagnosis right, it might also lead to genetic screening of family members and spouses. PMID- 21688023 TI - Acquired equivalence of cues by presentation in a common context in rats. AB - It is well established that humans and other animals may treat two perceptually different cues alike, if the cues have been individually paired with a common antecedent or a common consequence. Recently, Molet et al. (Psychon Bull Rev 18:618-623, 2011) reported evidence for a new form of acquired equivalence in human conditional discrimination, namely context-mediated equivalence. In the present research, using a flavor conditioning procedure, we asked whether rats would show similar context-mediated equivalence to demonstrate that this new form of acquired equivalence is a general phenomenon. Rats experienced two flavor cues A and B each presented either in the same context, X, or each in its own distinctive context, X or Y. Subsequently, the rats experienced B with sucrose in a third context, Z, and then the generalization of conditioning to A was assessed. When tested in Context Z, consumption of A was more marked when A and B had both been presented in the same context than when they had been presented in two different contexts. Thus, importantly, in the absence of the training context, cues that shared a common context at different times came to be treated as equivalent. This represents the first evidence of context-mediated equivalence in a nonhuman species. PMID- 21688022 TI - Gastric tuft cells express DCLK1 and are expanded in hyperplasia. AB - Epithelial tuft cells are named after their characteristic microtubule bundles located at the cell apex where these are exposed to the luminal environment. As such, tuft cells are found in multiple organs, including the gastrointestinal (GI) tract where the apical "tuft" is hypothesized to detect and transmit environmental signals. Thus, the goal of our study was to characterize gastric tuft cells during GI tract development, then subsequently in the normal and metaplastic adult stomach. GI tracts from mouse embryos, and newborn and postnatal mice were analyzed. Tuft cells were identified by immunohistochemistry using acetylated-alpha-tubulin (acTub) antibody to detect the microtubule bundle. Additional tuft cell markers, e.g., doublecortin-like kinase 1 (DCLK1), were used to co-localize with acTub. Tuft cells were quantified in human gastric tissue arrays and in mouse stomachs with or without inflammation. In the developing intestine, tuft cells in both the crypts and villi expressed all markers by E18.5. In the stomach, acTub co-localized with DCLK1 and other established tuft cell markers by E18.5 in the antrum, but not until postnatal day 7 in the corpus, with the highest density of tuft cells clustered at the forestomach ridge. Tuft cell numbers increased in hyperplastic human and mouse stomachs. In the adult GI tract, the tuft cell marker acTub co-expressed with DCKL1 and chemosensory markers, e.g.,TRPM5. In summary, tuft cells appear in the gastric antrum and intestine at E18.5, but their maximal numbers in the corpus are not achieved until after weaning. Tuft cell numbers increase with inflammation, hyperplasia, and metaplasia. PMID- 21688025 TI - [Imaging of tumors of the female pelvis - an interdisciplinary task]. PMID- 21688024 TI - Abscisic acid in soil facilitates community succession in three forests in China. AB - Plants release secondary metabolites into the soil that change the chemical environment around them. Exogenous abscisic acid (ABA) is an important allelochemical whose role in successional trajectories has not been examined. We hypothesized that ABA can accumulate in the soil through successional processes and have an influence on forest dynamics. To this end, we investigated the distribution of ABA in forest communities from early to late successional stages and the response of dominant species to the gradient of ABA concentrations in three types of forests from northern to southern China. Concentrations of ABA in the soils of three forest types increased from early to late successional stages. Pioneer species' litters had the lowest ABA content, and their seed germination and seedling early growth were the most sensitive to the inhibitory effect of ABA. Mid- and late-successional species had a much higher ABA content in fallen leaves than pioneer species, and their seed germination and seedling early growth were inhibited by higher concentrations of ABA than pioneers. Late-successional species showed little response to the highest ABA concentration, possibly due to their large seed size. The results suggest that ABA accumulates in the soil as community succession proceeds. Sensitivity to ABA in the early stages, associated with other characteristics, may result in pioneer species losing their advantage in competition with late-successional species in an increasingly high ABA concentration environment, and being replaced by ABA-tolerant, late-successional species. PMID- 21688026 TI - [Uterine cervical cancer : preoperative staging with magnetic resonance imaging]. AB - The treatment of uterine cervical carcinoma is largely dependent on the tumor stage. Despite significant inaccuracies in the clinical examination, uterine cervical cancer remains the only gynecological form of cancer still largely staged according to clinical findings. Although imaging is still not included in the staging the recently published revised FIGO (Federation International de Gynecologie et d'Obstetrique) system encourages the use of modern cross-sectional imaging (magnetic resonance imaging MRI and computed tomography CT). Due to its high soft tissue contrast MRI allows excellent non-invasive assessment of the cervix with direct tumor delineation as well as assessment of the prognosis based on morphological factors. Studies in the literature report an accuracy of 93% for MRI in the preoperative assessment of tumor size and in the differentiation of operable from advanced cervical cancer. Therefore MRI is considered to be the optimal modality for diagnostic evaluation starting from FIGO stage IB1, for radiation therapy planning, and for exclusion of recurrence in follow-up. In this paper we give an overview of the role of magnetic resonance imaging in preoperative staging of uterine cervical cancer. PMID- 21688027 TI - Painful fingertip swelling of the middle finger. Osteoid osteoma of the distal phalanx of the middle finger. PMID- 21688029 TI - Characterization of the autophosphorylating kinase, PkaF, in Streptomyces coelicolor A3(2) M130. AB - Streptomyces coelicolor, the model species for morphologically complex actinomycete bacteria, has unique characteristics such as morphological and physiological differentiation, which are controlled by various factors and several protein kinases. From the whole genomic sequence of S. coelicolor A3(2), 44 putative serine/threonine (Ser/Thr) protein kinases were identified, and the pkaF gene was chosen as the best-conserved protein for typical Ser/Thr protein kinases. pkaF encodes a 667-amino acid protein with a predicted N-terminal Ser/Thr kinase domain and four repeated C-terminal penicillin-binding domains and Ser/Thr kinase-associated (PASTA) domains. Based on PCR, a pkaF gene was cloned and heterologously expressed. PkaF expressed in Escherichia coli had the bigger molecular size than the expected value (75 kDa) and was further purified by Ni2+ NTA agarose affinity column chromatography to homogeneity. The purified PkaF was autophosphorylated through the transfer of the gamma-phosphate group of ATP. The extent of phosphorylation was proportional to the amount of PkaF, and the phospho PkaF was dephosphorylated by the addition of the cell lysate of S. coelicolor A3(2). Although no change was observed in the pkaF disruptant, overexpression of pkaF induced severe repression of morphogenesis and actinorhodin production, but not undecylprodigiosin production, implying that PkaF specifically regulates morphogenesis and actinorhodin production in S. coelicolor. PMID- 21688030 TI - Pharmacokinetics of propofol in patients undergoing total hip replacement : effect of acute hypervolemic hemodilution. AB - OBJECTIVE: The aim of the study was to investigate the effects of acute hypervolemic hemodilution (HHD) on the pharmacokinetics of propofol in patients undergoing total hip replacement. METHODS: A total of 16 patients undergoing elective surgery for total hip replacement under general anesthesia in combination with epidural analgesia were randomly assigned to 2 groups: the control group (n = 8) or the HHD group (n = 8). All patients in both groups received lactated Ringer's solution before induction of general anesthesia. In the control group the conventional fluid replacement protocol was used. In the HHD group 4% succinylated gelatin was infused at the rate of 20 ml*kg(-1)BW*h(-1 )with a targeted hematocrit of 30. Anesthesia was induced with midazolam 0.04 mg*kg(-1), fentanyl 4 ug*kg(-1) and propofol 1.5 mg*kg(-1). Tracheal intubation was facilitated by infusion of succinylcholine 2 mg*kg(-1). Anesthesia was maintained with isoflurane, fentanyl, vecuronium and epidural analgesia. Electrocardiogram (ECG), blood pressure (BP), blood oxygen saturation (SpO(2)), partial pressure of end-tidal carbon dioxide (P(ET)CO(2)) and central venous pressure (CVP) were monitored continuously. Blood samples were taken at 1, 2, 4, 6, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, 300 and 360 min after propofol administration to determine plasma concentrations of propofol by high performance liquid chromatography (HPLC). RESULTS: Plasma propofol concentrations were significantly lower in the HHD group than in the control group at 1, 2, 4, 6 and 10 min after propofol administration (p < 0.01) while there were no significant differences in plasma propofol levels 15-360 min after administration of propofol (p > 0.05). In the HHD group the volume of distribution of the central compartment (V(C)) increased significantly, elimination half-life (T(1/2) (gamma)) was significantly prolonged, the elimination rate constant (K(10)) and the whole-body clearance (CL) were significantly decreased compared with the control group (p < 0.01 or 0.05). There were no significant differences of the half-life of the fast distribution phase (T(1/2) (alpha)), half-life of the slower distribution phase (T(1/2) (beta)), K(12), K(21), K(13), K(31) and the area under the curve (AUC) (p > 0.05). The pharmacokinetic profile of propofol is best described by a three-compartment model in both groups using minimal Akaike information criteria (AIC). CONCLUSION: Acute HHD increases V(C), prolongs the T(1/2) (gamma), and decreases K(10) and CL, which suggests that care must be taken when propofol is used in patients undergoing HHD. The induction dose should be increased, but the maintenance dose should be decreased. The time to emergency from anesthesia will likely be prolonged, especially in patients receiving prolonged continuous infusions. PMID- 21688032 TI - Monitoring the sedimentary carbon in an artificially disturbed deep-sea sedimentary environment. AB - An area of 0.6 km(2) in the manganese nodule field of the Central Indian Basin was physically disturbed and sediments discharged in the near bottom waters to simulate seabed mining and study its impact on benthic ecosystem. An estimated 2 to 3 tonnes of sedimentary organic carbon (C(org)) was resuspended into the water column during a 9-day experiment. The majority of the sediment cores from within the disturbed area and areas towards the south showed a ~30% increase in C(org) content as well as an increase in carbon burial rates after disturbance, though with a reduction in carbon/phosphorus ratios. High specific surface area (SSA~25 m(2) g(-1)) and low C(org)/SSA ratios (mostly <0.5) are typical of deep-sea sediments. The increased C(org) values were probably due to the organic matter from dead biota and the migration and redeposition of fine-grained, organic-rich particles. Spatial distribution patterns of C(org) contents of cores taken before and after disturbance were used to infer the direction of plume migration and re sedimentation. A positive relationship was observed between total and labile C(org) and macrobenthos density and total bacterial numbers prior to disturbance, whereas a negative relationship was seen after disturbance owing to drastic reduction in the density of macrofauna and bacteria. Overall decrease in labile organic matter, benthic biota and redistribution of organic matter suggest that the commercial mining of manganese nodules may have a significant immediate negative effect on the benthic ecosystem inducing changes in benthic community structure. PMID- 21688031 TI - HS-SPME/GC-MS analysis of volatile and semi-volatile organic compounds emitted from municipal sewage sludge. AB - The aim of the research involved identification and semi-quantitative determination of unknown volatile and semi-volatile organic compounds emitted to air by sewage sludge formed in the process of municipal wastewater treatment in a sewage treatment plant. Samples taken directly after completion of the technological process as well as the sludge stored on the premise of the sewage treatment plant were analyzed. A simple method using off-line headspace solid phase microextraction combined with gas chromatography-mass spectrometry has been proposed for extraction and detection of organic pollutants. For reliable identification of compounds, combination of two independent parameters: mass spectra and linear temperature programmed retention indices were employed. Over 170 compounds of different structure were identified including aliphatic and aromatic hydrocarbons, alcohols, esters, carbonyls, as well as sulfur, nitrogen, and chlorine containing compounds. The prevailing substances included: ethyl ether, n-hexane, p-xylene, o-xylene, mesitylene, m-ethylbenzene, limonene, n decane, n-undecane, and n-dodecane. A few compounds such as methanetiol, dimethyl polisulfide, octaatomic sulfur, phthalic anhydride, and indoles were identified in the sludge for the first time. PMID- 21688033 TI - HPLC-FLD determination of 4-nonylphenol and 4-tert-octylphenol in surface water samples. AB - A simple, sensitive and reliable HPLC-FLD method for the routine determination of 4-nonylphenol, 4-NP and 4-tert-octylphenol, 4-t-OP content in water samples was developed. The method consists in a liquid-liquid extraction of the target analytes with dichloromethane at pH 3.0-3.5 followed by the HPLC-FLD analysis of the organic extract using a Zorbax Eclipse XDB C8 column, isocratic elution with a mixed solvent acetonitrile/water 65:35, at a flow rate of 1.0 mL/min and applying a column temperature of 40 degrees C. The method was validated and then applied with good results for the determination of 4-NP and 4-t-OP in Ialomita River water samples collected each month during 2006. The concentration levels of 4-NP and 4-t-OP vary between 0.08-0.17 MUg/L with higher values of 0.24-0.37 MUg/L in the summer months for 4-NP, and frequently <0.05 MUg/L but also between 0.06-0.09 MUg/L with higher values of 0.12-0.16 MUg/L in July and August for 4-t OP and were strongly influenced by sesonial and anthropic factors. The method was also applied on samples collected over 2 years 2007 and 2008 from urban wastewaters discharged into sewage or directly into the rivers by economic agents located in 30 Romanian towns. Good results were obtained when the method was used for analysis of effluents discharged into surface waters by 16 municipal wastewater treatment plants, during the year 2008. PMID- 21688034 TI - Erlotinib inhibits osteolytic bone invasion of human non-small-cell lung cancer cell line NCI-H292. AB - Previous preclinical and clinical findings have suggested a potential role of epidermal growth factor receptor (EGFR) in osteoclast differentiation and the pathogenesis of bone metastasis in cancer. In this study, we investigated the effect of erlotinib, an orally active EGFR tyrosine kinase inhibitor (TKI), on the bone invasion of human non-small-cell lung cancer (NSCLC) cell line NCI-H292. First, we established a novel osteolytic bone invasion model of NCI-H292 cells which was made by inoculating cancer cells into the tibia of scid mice. In this model, NCI-H292 cells markedly activated osteoclasts in tibia, which resulted in osteolytic bone destruction. Erlotinib treatment suppressed osteoclast activation to the basal level through suppressing receptor activator of NF-kappaB ligand (RANKL) expression in osteoblast/stromal cell at the bone metastatic sites, which leads to inhibition of osteolytic bone destruction caused by NCI-H292 cells. Erlotinib inhibited the proliferation of NCI-H292 cells in in vitro. Erlotinib suppressed the production of osteolytic factors, such as parathyroid hormone related protein (PTHrP), IL-8, IL-11 and vascular endothelial growth factor (VEGF) in NCI-H292 cells. Furthermore, erlotinib also inhibited osteoblast/stromal cell proliferation in vitro and the development of osteoclasts induced by RANKL in vitro. In conclusion, erlotinib inhibits tumor-induced osteolytic invasion in bone metastasis by suppressing osteoclast activation through inhibiting tumor growth at the bone metastatic sites, osteolytic factor production in tumor cells, osteoblast/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells. PMID- 21688035 TI - Individualised therapy of angiotensin converting enzyme (ACE) inhibitors in stable coronary artery disease: overview of the primary results of the PERindopril GENEtic association (PERGENE) study. AB - In patients with stable coronary artery disease (CAD) without overt heart failure, ACE inhibitors are among the most commonly used drugs as these agents have been proven effective in reducing the risk of cardiovascular events. Considerable individual variations in the blood pressure response to ACE inhibitors are observed and as such heterogeneity in clinical treatment effect would be likely as well. Assessing the consistency of treatment benefit is essential for the rational and cost-effective prescription of ACE inhibitors. Information on heterogeneities in treatment effect between subgroups of patients could be used to develop an evidence-based guidance for the installation of ACE inhibitor therapy. Obviously, therapy should only be applied in those patients who most likely will benefit. Attempts to develop such treatment guidance by using clinical characteristics have been unsuccessful. No heterogeneity in risk reduction by ACE inhibitors has been observed in relation to relevant clinical characteristics. A new approach to such 'guided-therapy' could be to integrate more patient-specific characteristics such as the patients' genetic information. If proven feasible, pharmacogenetic profiling could optimise patients' benefit of treatment and reduce unnecessary treatment of patients. Cardiovascular pharmacogenetic research of ACE inhibitors in coronary artery disease patients is in a formative stage and studies are limited. The PERGENE study is a large pharmacogenetic substudy of the EUROPA trial, aimed to assess the achievability of pharmacogenetic profiling. We provide an overview of the main results of the PERGENE study in terms of the genetic determinants of treatment benefit and blood pressure response. The main results of the PERGENE study show a pharmacogenetic profile related to the treatment benefit of perindopril identifying responders and non-responders to treatment. PMID- 21688036 TI - A young man with near-syncope. PMID- 21688037 TI - Multiple laparotomic myomectomy during pregnancy: a case report. AB - The presence of uterine myomas during pregnancy is considered a risk factor for gestation and delivery. In literature, myomas are related to spontaneous abortion, bleeding, PPROM, preterm delivery, placenta previa, placental abruption, fetal malpresentations, mechanical dystocia and high incidence of cesarean section. Laparotomic myomectomy done during pregnancy is indicated when symptoms related to uterine myomas, as acute pelvic pain or gastroenteric or urinary symptoms, persist despite the pharmacological therapy. The purpose of this study is to show a successful surgical management of uterine myomas at 15.5 weeks of pregnancy, which allowed the continuation of gestation and a delivery without major complications. PMID- 21688038 TI - The high-level expression of human tissue plasminogen activator in the milk of transgenic mice with hybrid gene locus strategy. AB - Transgene expression for the mammary gland bioreactor aimed at producing recombinant proteins requires optimized expression vector construction. Previously we presented a hybrid gene locus strategy, which was originally tested with human lactoferrin (hLF) as target transgene, and an extremely high-level expression of rhLF ever been achieved as to 29.8 g/l in mice milk. Here to demonstrate the broad application of this strategy, another 38.4 kb mWAP-htPA hybrid gene locus was constructed, in which the 3-kb genomic coding sequence in the 24-kb mouse whey acidic protein (mWAP) gene locus was substituted by the 17.4 kb genomic coding sequence of human tissue plasminogen activator (htPA), exactly from the start codon to the end codon. Corresponding five transgenic mice lines were generated and the highest expression level of rhtPA in the milk attained as to 3.3 g/l. Our strategy will provide a universal way for the large-scale production of pharmaceutical proteins in the mammary gland of transgenic animals. PMID- 21688039 TI - Over expression of rice chitinase gene in transgenic peanut (Arachis hypogaea L.) improves resistance against leaf spot. AB - A Rice chitinase-3 under enhance version of CaMV 35S was introduced into peanut (Arachis hypogaea L.) through Agrobacterium mediation. Agrobacterium tumefaciens strain LB4404 was used harboring the binary vector (pB1333-EN4-RCG3) containing the chitinase (chit) and hygromycin resistance (hpt) gene as selectable marker. Putative transgenic shoots were regenerated and grown on MS medium supplemented with 5 mg/l BAP, 1 mg/l kinetin, and 30 mg/l hygromycin. Elongated shoots were examined for the presence of the integrated rice chitinase gene along with hygromycin gene as selectable. The integration pattern of transgene in the nuclear genome of the putative transformed plants (T(0)) was confirmed through Southern hybridization analysis of the genomic DNA. Survival rate of the in vitro regenerated plantlets was over 60% while healthy putatively transgenic (T(0)) plants with over 42% transformation frequency were produced through Agrobacterium mediated gene transfer of the rice chitinase gene and all the plants flowered and set seed normally. T1 plants were tested for resistance against Cercospora arachidicola by infection with the microspores. Transgenic strains exhibited a higher resistance than the control (non-transgenic plants). chitinase gene expression in highly resistant transgenic strains was compared to that of a susceptible control. A good correlation was observed between chitinase activity and fungal pathogen resistance. PMID- 21688040 TI - Inter- and intra-varietal genetic variability in Malvasia cultivars. AB - The DNA molecular analyses together with ampelography, ampelometry, and biochemistry are essential for grapevine identification and investigation of genetic differences among the Vitis vinifera L. cultivars and clones. Ten Malvasia cultivars (i.e., Istrian Malvasia; M. delle Lipari; M. bianca di Candia; M. di Candia Aromatica; M. del Lazio; M. bianca lunga, also known as Malvasia del Chianti; M. nera di Brindisi/Lecce; M. di Casorzo; M. di Schierano, and M. nera di Bolzano) were analyzed using molecular approaches to study the genetic inter varietal variability. Thirty Istrian Malvasia genotypes (i.e., 8 Italian clones, such as ISV 1, ISV F6, VCR 4, VCR 113, VCR 114, VCR 115, ERSA 120, ERSA 121, and 22 autochthonous grapevine accessions grown in Istrian Peninsula, Croatia) were investigated to evaluate the morphological and genetic intra-varietal variability. DNA analysis allowed discrimination of all Malvasia genotypes at molecular level using AFLP, SAMPL, and M-AFLP markers. Italian clones and autochthonous Croatian accessions of Istrian Malvasia were grouped according to their different geographic origins. These results showed the great genetic variability of Malvasia genotypes suggesting the need for the preservation of autochthonous grapevine biotypes found on different areas to approve the correct choice and selection of the grape multiplication materials. PMID- 21688041 TI - Thought problems from adolescence to adulthood: measurement invariance and longitudinal heritability. AB - This study investigates the longitudinal heritability in Thought Problems (TP) as measured with ten items from the Adult Self Report (ASR). There were ~9,000 twins, ~2,000 siblings and ~3,000 additional family members who participated in the study and who are registered at the Netherlands Twin Register. First an exploratory factor analysis was conducted to examine the underlying factor structure of the TP-scale. Then the TP-scale was tested for measurement invariance (MI) across age and sex. Next, genetic and environmental influences were modeled on the longitudinal development of TP across three age groups (12 18, 19-27 and 28-59 year olds) based on the twin and sibling relationships in the data. An exploratory factor analysis yielded a one-factor solution, and MI analyses indicated that the same TP-construct is assessed across age and sex. Two additive genetic components influenced TP across age: the first influencing TP throughout all age groups, while the second arises during young adulthood and stays significant throughout adulthood. The additive genetic components explained 37% of the variation across all age groups. The remaining variance (63%) was explained by unique environmental influences. The longitudinal phenotypic correlation between these age groups was entirely explained by the additive genetic components. We conclude that the TP-scale measures a single underlying construct across sex and different ages. These symptoms are significantly influenced by additive genetic factors from adolescence to late adulthood. PMID- 21688042 TI - Expression of myeloperoxidase in swine influenza virus (SIV)-infected neutrophils in lungs from pigs experimentally infected with SIV subtype H1N2. AB - The expression of myeloperoxidase (MPO) was examined in the swine influenza virus (SIV)-infected neutrophils in the lungs of pigs experimentally infected with swine influenza virus (SIV) subtype H1N2 by immunohistochemistry. Five pigs each from the infected and non-infected group were euthanized 1, 3, 5, 7, and 10 days post-inoculation (dpi). Immunohistochemical reactivity was mainly seen in neutrophils. The score for pulmonary histopathological lesions correlated with the score for MPO immunohistochemical reactivity (r ( s ) = 0.962, P < 0.01). In addition, the score for in situ hybridization of SIV nucleic acid correlated with the score for MPO immunohistochemical reactivity (r ( s ) = 0.976, P < 0.01). These results suggest neutrophils are one of the primary effector cells in the early phase of SIV infection in pigs. PMID- 21688043 TI - Expression of nuclear factor -kappaBp65 in mononuclear cells in Kawasaki disease and its relation to coronary artery lesions. AB - OBJECTIVE: To assess the association of nuclear factor-kappa B (NF-kappaB) and complications of Kawasaki disease (KD) in Chinese children. METHODS: Based on color Doppler examination results, 86 affected children in the KD group were divided into two groups: 39 cases in coronary artery lesion group (CALs subgroup) and 47 cases in non-coronary artery lesion group (Non-CALs subgroup). Infection control group consisted of 65 cases of hospitalized infected children with fever, having same age as the affected children. Healthy control group consisted of 102 cases of healthy children of the same age, visiting the hospital for physical examination. Western blot was used to detect the expression of NF-kBp65 and IkBalpha proteins in periphery blood mononuclear cells (PBMC); reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression of TNF-alpha and MCP-1 mRNA. RESULTS: The value of NF-kBp65 (optical density) in the PBMC cell nuclei in the KD group was significantly higher than that in the two control groups (p < 0.01). The value of NF-kappaBp65 in the CALs subgroup was significantly higher than that in the Non-CALs subgroup (p < 0.05). The value of NF-kappaBp65 inhibitor IkappaBalpha in the KD group was significantly lower than that in the infection control group and the healthy control group (p < 0.01). There was a positive correlation between the ratio nucleus NF-kappaBP65/ IkappaBalpha and the severity degree of CALs(r = 0.536, p < 0.05). The value of TNF-alpha mRNA (O.D ratio) in the KD group was significantly higher than that in the two control groups (P < 0.01), and the value of TNF-alpha mRNA in the CALs subgroup was significantly higher than that in the Non-CALs subgroup (P < 0.05). The value of MCP-1 mRNA in the KD group was significantly higher than that in the two control groups (P < 0.01), and the value of MCP-1 mRNA in the CALs subgroup was significantly higher than that in the Non-CALs subgroup (P < 0.05). CONCLUSIONS: NF-kappaBp65 participates in the pathogenesis of vasculitis of KD in acute stage, and may aggravate the vasculitis in KD and plays a part in the formation of CALs. PMID- 21688044 TI - Statin pretreatment may increase the risk of symptomatic intracranial haemorrhage in thrombolysis for ischemic stroke: results from a case-control study and a meta analysis. AB - The influence of statins on the results of intravenous thrombolysis for ischemic stroke is controversial. We studied the risks and benefits of statin pretreatment (SP) in patients treated with intravenous alteplase (t-PA) at our institution, and included our data to a meta-analysis of previous related studies. We reviewed prospectively collected data from consecutive patients with acute ischemic stroke treated with IV rt-PA at our institution over the past 9 years. We compared symptomatic intracranial haemorrhage (SICH), favourable short-term outcome (decrease of >=4 points on the NIHSS score after 24 h from baseline assessment), favourable long-term outcome (mRS score <=2 at 3 months) and mortality rates between statin-pretreated (SPP) and nonstatin-pretreated patients (NSPP). We performed a systematic search through MEDLINE/PubMed and Embase datasets to identify similar English language studies. A total of 182 patients were included (mean age 68.3 +/- 11.4 years, 54.3% men). There were no significant differences between SPP and NSPP regarding SICH (3.3 vs. 1.7%, p = 0.47), favourable short term outcome (44.8 vs 56%, p = 0.31) and favourable long-term outcome rates (40 vs 44.1%, p = 0.84). In a meta-analysis of 1,055 patients, SP was neither related to long-term functional outcome nor mortality, but it was a risk factor for SICH (OR 1.99, 95% CI 1.03-3.84, p = 0.04). Statin pretreatment may increase the risk of SICH in patients receiving IV t-PA for ischemic stroke, though it does not influence the 3 months outcome. Prospective studies are needed to confirm this safety concern. PMID- 21688045 TI - Long-term outcome after conservative and surgical treatment of acute sigmoid diverticulitis. AB - PURPOSE: This study was designed to compare the long-term outcome of patients treated with conservative versus surgical treatment for acute sigmoid diverticulitis (SD). PATIENTS AND METHODS: Consecutive admissions of all patients with acute SD were prospectively recruited from January 2004 to June 2007. In June 2008, all patients were contacted using a standardized questionnaire. Outcomes were compared based on initial therapy (conservative vs. surgical). Furthermore, multiple logistic regression was used to identify risk factors for recurrence of SD. RESULTS: A total of 210 patients were included in the study. One hundred fifty-three patients were reached for follow-up: 70 (45.8%) presented with their first episode, and 83 (54.2%) had a prior history of SD. The median follow-up was 32 months (range 12-52). Thirteen (32.5%) of 40 conservatively treated patients and four (3.5%) of 113 surgically treated patients had a recurrence of SD (p < 0.001) during follow-up. One patient (2.5%) required emergency surgery after conservative treatment due to free perforation (p = 0.567). Treatment groups did not differ in age, gender, and inflammatory parameters, but conservatively treated patients had a significantly higher comorbidity (>2 disorders; p = 0.038) and less frequently a severe SD (p = 0.022) at the index admission. Recurrent episode of SD, covered perforated SD, and conservative treatment were identified as risk factors for recurrence of SD on multiple logistic regression. CONCLUSIONS: Surgical treatment of acute SD is more effective in preventing an eventual relapse of SD than conservative treatment, particularly in patients with recurrent and severe diverticulitis. The necessity for an emergency operation during follow-up is low and did not differ between the two treatment groups. The initial clinical presentation of SD is not a strong predictor of recurrence. PMID- 21688046 TI - S-15176 and its methylated derivative suppress the CsA-insensitive mitochondrial permeability transition and subsequent cytochrome c release induced by silver ion, and show weak protonophoric activity. AB - A recent report has described that S-15176 (N-[(3,5-di-tert-butyl-4-hydroxy-1 thiophenyl)]-3-propyl-N'-(2,3,4-trimethoxybenzyl) piperazine), an anti-ischemic agent, inhibits the mitochondrial permeability transition (PT) induced by not only Ca(2+) and inorganic phosphate, but also by tert-butylhydroperoxide or phenylarsine oxide [Morin et al. (Biochem Pharmacol 72:911-918, 2006)]. In the present study, we tested the effects of S-15176 on the PT induced by Ag(+), PT of which is not suppressed by cyclosporin A or oligomycin. S-15176 was effective in suppressing the PT and the subsequent cytochrome c release induced by Ag(+), and hence, it was concluded to be a more universal PT inhibitor than cyclosporin A or oligomycin. In addition to the PT-suppression activity, S-15176 also showed weak protonophoric activity. Thus, we further tested to investigate whether the hydroxyl group of S-15176 was involved in its PT-suppression or weak protonophoric activities. The methylated derivative of S-15176 also showed both PT suppression and weak protonophoric activities; hence, the hydroxyl group of S 15176 was concluded not to be involved in these activities. PMID- 21688047 TI - Neuroprotective effects of 3alpha-acetoxyeudesma-1,4(15),11(13)-trien-12,6alpha olide against dopamine-induced apoptosis in the human neuroblastoma SH-SY5Y cell line. AB - Dopamine (DA), as a neurotoxin, can elicit severe Parkinson's disease-like syndrome by elevating intracellular reactive oxygen species (ROS) levels and apoptotic activity. We examined the inhibitory effects of 3alpha-acetoxyeudesma 1,4(15),11(13)-trien-12,6alpha-olide (AETO), purified from the leaves of Laurus nobilis L., on DA-induced apoptosis and alpha-synuclein (alpha-syn) formation in dopaminergic SH-SY5Y cells. AETO decreased the active form of caspase-3 and the levels of p53, which were accompanied by increased levels of Bcl-2 in a dose dependent manner. Flow cytometric and Western blot analysis showed that AETO significantly inhibited DA-induced apoptosis along with suppression of intracellular tyrosinase activity, ROS generation, quinoprotein, and alpha-syn formation (P < 0.01). These results indicate that AETO inhibited DA-induced apoptosis, which is closely related to the suppression of intracellular tyrosinase activity and the formation of alpha-syn, ROS, and quinoprotein in SH SY5Y cells. PMID- 21688048 TI - Distribution and time-course of 4-hydroxynonenal, heat shock protein 110/105 family members and cyclooxygenase-2 expression in the hippocampus of rat during trimethyltin-induced neurodegeneration. AB - Trimethyltin (TMT), an organotin compound considered a useful tool to obtain an experimental model of neurodegeneration, exhibits neurotoxicant effects selectively localised in the limbic system and especially in the hippocampus, which are different in the rat and in mice. In the rat hippocampus, we investigated the expression of aldehyde 4-hydroxynonenal, a major bioactive marker of membrane lipid peroxidation, heat shock protein (HSP) 110/105 family members, markers of oxidative stress, and the neuroinflammatory marker cyclooxygenase-2 after TMT-intoxication at various time points after treatment. Our data show that TMT-induced neurodegeneration in the rat hippocampus is associated specifically with oxidative stress and lipid peroxidation, but not with HSP expression, indicating species-specific differences in the neurotoxicity of TMT between rats and mice. PMID- 21688049 TI - Integrated SPECT/CT for assessment of haemodynamically significant coronary artery lesions in patients with acute coronary syndrome. AB - PURPOSE: Early risk stratification in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) is important since the benefit from more aggressive and costly treatment strategies is proportional to the risk of adverse clinical events. In the present study we assessed whether hybrid single photon emission computed tomography (SPECT)/coronary computed tomography angiography (CCTA) technology could be an appropriate tool in stratifying patients with NSTE-ACS. METHODS: SPECT/CCTA was performed in 90 consecutive patients with NSTE-ACS. The Thrombolysis in Myocardial Infarction risk score (TIMI-RS) was used to classify patients as low- or high-risk. Imaging was performed using SPECT/CCTA to identify haemodynamically significant lesions defined as >50% stenosis on CCTA with a reversible perfusion defect on SPECT in the corresponding territory. RESULTS: CCTA demonstrated at least one lesion with >50% stenosis in 35 of 40 high-risk patients (87%) as compared to 14 of 50 low-risk patients (35%; TIMI-RS<3; p<.0001). Of the 40 high-risk and 50 (16%) low-risk TIMI-RS patients, 16 (40%) and 8 (16%), respectively, had haemodynamically significant lesions (p=0.01). Patients defined as high-risk by a high TIMI-RS, a positive CCTA scan or both (n=45) resulted in a sensitivity of 95%, specificity of 49%, PPV of 35% and NPV of 97% for having haemodynamically significant coronary lesions. Those with normal perfusion were spared revascularization procedures, regardless of their TIMI-RS. CONCLUSION: Noninvasive assessment of coronary artery disease by SPECT/CCTA may play an important role in risk stratification of patients with NSTE-ACS by better identifying the subgroup requiring intervention. PMID- 21688051 TI - Microstructure of polyelectrolyte nanoaggregates studied by fluorescence probe method. AB - The microstructure of water soluble nanoaggregates based on polyelectrolyte complex formed by the cationic comb-type copolymer poly(acrylamide -co-[3- (methacryloyl-amino)propyl] trimethylammonium chloride)-graft- polyacrylamide [P(AM-co-MAPTAC)-g-PAM] and the anionic linear polyelectrolyte sodium polyacrylate (NaPA) was investigated using the fluorescence probe technique. The fluorescence probe were 1-anilinonaphthalene-8-sulfonic acid (ANS), pyrene (Py) and 1,10-bis(1-pyrene) decane (PD). The fluorescence properties in polyelectrolyte complex solutions, which are sensitive to either micropolarity (ANS, Py) or microviscosity (PD), were related to the quantities obtained in different pure or mixed solvents. Micropolarities were quantified utilizing the polarity common index (Reichardt) E(T)(30). ANS and Py showed a variation of the micropolarity with the charge ratio of the two polymers, with the lowest polarity reached at the complex neutralization. The PD probe, by its excimer-to-monomer fluorescence intensities ratio, enabled us to evidence the effect of the composition and the comb-type copolymer grafting density on the microviscosity of the interpolyelectrolytes aggregates. It has been found that the microviscosity increased with the density of the grafting PAM chains. PMID- 21688050 TI - Value of a Dixon-based MR/PET attenuation correction sequence for the localization and evaluation of PET-positive lesions. AB - PURPOSE: In this study, the potential contribution of Dixon-based MR imaging with a rapid low-resolution breath-hold sequence, which is a technique used for MR based attenuation correction (AC) for MR/positron emission tomography (PET), was evaluated for anatomical correlation of PET-positive lesions on a 3T clinical scanner compared to low-dose CT. This technique is also used in a recently installed fully integrated whole-body MR/PET system. METHODS: Thirty-five patients routinely scheduled for oncological staging underwent (18)F fluorodeoxyglucose (FDG) PET/CT and a 2-point Dixon 3-D volumetric interpolated breath-hold examination (VIBE) T1-weighted MR sequence on the same day. Two PET data sets reconstructed using attenuation maps from low-dose CT (PET(AC_CT)) or simulated MR-based segmentation (PET(AC_MR)) were evaluated for focal PET positive lesions. The certainty for the correlation with anatomical structures was judged in the low-dose CT and Dixon-based MRI on a 4-point scale (0-3). In addition, the standardized uptake values (SUVs) for PET(AC_CT) and PET(AC_MR) were compared. RESULTS: Statistically, no significant difference could be found concerning anatomical localization for all 81 PET-positive lesions in low-dose CT compared to Dixon-based MR (mean 2.51 +/- 0.85 and 2.37 +/- 0.87, respectively; p = 0.1909). CT tended to be superior for small lymph nodes, bone metastases and pulmonary nodules, while Dixon-based MR proved advantageous for soft tissue pathologies like head/neck tumours and liver metastases. For the PET(AC_CT)- and PET(AC_MR)-based SUVs (mean 6.36 +/- 4.47 and 6.31 +/- 4.52, respectively) a nearly complete concordance with a highly significant correlation was found (r = 0.9975, p < 0.0001). CONCLUSION: Dixon-based MR imaging for MR AC allows for anatomical allocation of PET-positive lesions similar to low-dose CT in conventional PET/CT. Thus, this approach appears to be useful for future MR/PET for body regions not fully covered by diagnostic MRI due to potential time constraints. PMID- 21688053 TI - [Acute myopia]. AB - This paper presents a case of ocular involvement during acute renal failure caused by hantavirus. A 34-year-old man suffered from sudden visual loss during acute onset fever with nausea and renal failure. The ophthalmologic examination showed myopia in both eyes and no signs of infection but virological studies revealed an infection with hantavirus. During treatment of the renal failure the myopia improved spontaneously. Transient myopia is a typical ocular involvement during infections with hantavirus which leads to renal failure. PMID- 21688052 TI - Albumin-binding domain conjugate for near-infrared fluorescence lymphatic imaging. AB - PURPOSE: The aim of this study was to develop and characterize a novel peptide imaging agent for noninvasive near-infrared fluorescence imaging of protein transport by the lymphatics. An imaging agent consisting of a cyclic albumin binding domain (cABD) peptide, with sequence, Arg-Leu-Ile-Glu-Asp-Ile-Cys-Leu-Pro Arg-Trp-Gly-Cys-Leu-Trp-Glu-Asp-Asp-Lys, was conjugated to a near-infrared fluorophore, IRDye800CW, allowing for enhanced vascular uptake, retention, and fluorescence imaging. PROCEDURE: Characterization of the cABD-IRDye800 peptide conjugate was performed using fluorescence spectroscopy to assess optical properties and SDS-PAGE and Biacore binding assays to determine binding affinity and specificity. Fluorescence imaging of normal C57BL/6 mice was conducted to monitor lymphatic uptake and retention. RESULTS: cABD-IRDye800 exhibited approximately six times greater fluorescent yield and greater stability than indocyanine green, an agent previously used in humans to image lymphatic vasculature. The agent exhibited affinity for albumin with IC(50) and Kd in the nanomolar range and demonstrated superior retention characteristics within mouse lymphatics when compared with IRDye800CW. CONCLUSIONS: cABD-IRDye800 has utility for assessing lymphatic function in mouse models of human lymphatic disease and the potential for use in clinical diagnostic imaging of the lymphatic vasculature. PMID- 21688054 TI - Noninvasive cardiac output monitoring during general anesthesia for Cesarean delivery in a patient with severe aortic stenosis. AB - PURPOSE: The anesthetic management of women with severe aortic stenosis (AS) undergoing Cesarean delivery (CD) remains controversial. We used a relatively new bioreactance technology to highlight the continuous hemodynamic changes related to anesthesia, delivery, and recovery in a parturient with severe AS. CLINICAL FEATURES: A 29-yr-old woman, New York Heart Association Class II, with a congenital bicuspid aortic valve and AS presented for CD at 36.5 weeks of gestation. The estimated aortic valve area on echocardiogram was 0.75 cm(2), and the maximal transvalvular gradient was 64 mmHg. Cesarean delivery was performed under general anesthesia with an epidural catheter placed prior to induction for postoperative analgesia. Noninvasive cardiac output (CO) monitoring based on bioreactance was used throughout the procedure. Cardiac output increased from 7 12 L.min(-1) following delivery primarily due to an increase in stroke volume. Both stroke volume variation and total peripheral resistance decreased, while the patient's heart rate did not change. Increased stroke volume, likely associated with decreased afterload and increased preload, contributed to an increase in CO from 7-12 L.min(-1). CONCLUSION: Continuous CO data obtained from bioreactance based monitoring suggests that pregnant women with severe AS may experience an increase in CO under certain circumstances. This result is in keeping with data obtained from non-pregnant individuals and is an interesting finding that warrants further study. Noninvasive CO monitoring may improve our understanding of the peripartum changes in women with heart disease. PMID- 21688055 TI - [The relevance of the sagittal profile in cervical artificial discs]. AB - We report on the results of 246 Bryan cervical discs, which were implanted between June 2002 and September 2010 in 146 patients. Of the patients 74 (128 prostheses) could be followed up for more than 1 year and the average follow-up period was 2.6 years. Of the patients 18 were operated on at one level (group 1), 77 prostheses were multilevel surgery (group 2) and with 33 patients arthroplasty was combined with fusion (hybrid, group 3). The global lordosis remained unchanged during follow-up and a recurrence of kyphosis was evident in group 3. The overall mobility improved in all 3 subgroups and 2 cases (group 3) fused. With 5 patients the prosthesis had to be removed and the segment had to be fused in the postoperative course. As a conclusion a meticulous preoperative planning as well as a subtle surgical technique is the main prerequisite for long-lasting mobility of the Bryan prosthesis. PMID- 21688056 TI - [Spine fractures in patients with ankylosing spondylitis: an analysis of 129 fractures after surgical treatment]. AB - INTRODUCTION: The ankylosing spondylitis (AS) is a systemic rheumatic disease, which affects the skeleton, joints and internal organs. Attributed to the augmented rigidity of the spine and the concomitant impairment of compensatory mechanism minor force might cause spine fractures. Multilevel stabilization and dorsoventral instrumentation is a well - established procedure. This study was to evaluate the surgical outcome of 119 patients with AS associated spine fractures. METHODS: From 07/96 to 01/10, 119 patients with 129 spine fractures due to AS were treated in our department. Data were collected retrospectively. In all patients the operative treatment of the fracture was either performed by ventral and/or dorsal spondylodesis. RESULTS: The median age was 67 years (37-95). There were 51 cervical, 55 thoracic and 23 lumbar spine fractures. On initial presentation no fractures in 18 patients (15%) and stable fractures in 15 patients (13%) were detected, which further secondarily dislocated. Thus, in 28% of the patients the injury was assessed falsely. 47% of the fractures were preceded by a trivial trauma in domestic surrounding. 61 patients (51%) developed either an incomplete or a complete paraplegia. In 32 patients ventral instrumentation, in 82 patients dorsal and in 15 patients dorsoventral instrumentation were performed. 14% developed postoperative wound infection an in 15% revision surgery due to implant loosening or insufficient stabilization was required. CONCLUSION: Early diagnostic of AS associated spine fractures using conventional radiographs and computed tomography scans is important for the detection and adequate treatment. A great amount of spine fractures are obviously either under diagnosed or underestimated, initially. A secondary dislocation of the fracture might result in severe neurological complications up to paraplegia. PMID- 21688057 TI - 3D characterization of bone strains in the rat tibia loading model. AB - Bone strain is considered one of the factors inducing bone tissue response to loading. Nevertheless, where animal studies can provide detailed data on bone response, they only offer limited information on experimental bone strains. Including micro-CT-based finite element (micro FE) models in the analysis represents a potent methodology for quantifying strains in bone. Therefore, the main objective of this study was to develop and validate specimen-specific micro FE models for the assessment of bone strains in the rat tibia compression model. Eight rat limbs were subjected to axial compression loading; strain at the medio proximal site of the tibiae was measured by means of strain gauges. Specimen specific micro FE models were created and analyzed. Repeated measurements on each limb indicated that the effect of limb positioning was small (COV = 6.45 +/- 2.27 %). Instead, the difference in the measured strains between the animals was high (54.2%). The computational strains calculated at the strain gauge site highly correlated to the measured strains (R (2) = 0.95). Maximum peak strains calculated at exactly 25% of the tibia length for all specimens were equal to 435.11 +/- 77.88 microstrains (COV = 17.19%). In conclusion, we showed that strain gauge measurements are very sensitive to the exact strain gauge location on the bone; hence, the use of strain gauge data only is not recommended for studies that address at identifying reliable relationships between tissue response and local strains. Instead, specimen-specific micro FE models of rat tibiae provide accurate estimates of tissue-level strains. PMID- 21688058 TI - Metal accumulation and evaluation of effects in a freshwater turtle. AB - A variety of contaminants have been detected in aquatic and terrestrial environments around the Paducah Gaseous Diffusion Plant (PGDP), Kentucky. The presence of these contaminants at the PGDP may pose a risk to biota, yet little is known about the bioaccumulation of contaminants and associated effects in wildlife, especially in aquatic turtles. The current study was initiated to evaluate: (1) the accumulation of heavy metals (Cd, Cr, Cu, Pb, and Hg) in aquatic ecosystems associated with the PGDP using red-eared slider turtle (Trachemys scripta elegans) as biomonitors; (2) maternal transfer of heavy metals; and (3) potential hematological and immunological effects resulting from metal accumulation. A total of 26 turtles were collected from 7 ponds located south, adjacent, and north of the PGDP. Liver Cu concentrations were significantly different among ponds and Cu concentrations in eggs were positively correlated with female Cu concentrations in kidney. The concentrations of heavy metals measured in turtle tissues and eggs were low and, based on previous studies of reptiles and established avian threshold levels of heavy metals, did not appear to have adverse effects on aquatic turtles inhabiting ponds near the PGDP. However, total white blood cell counts, heterophil to lymphocyte ratio, and phytohemagglutinin stimulation index were correlated with metal concentrations. Because other factors may affect the hematological and immunological indices, further investigation is needed to determine if these effects are associated with metal exposure, other contaminants, or disease. PMID- 21688060 TI - Primary neural degeneration in the Guinea pig cochlea after reversible noise induced threshold shift. AB - Recent work in mouse showed that acoustic overexposure can produce a rapid and irreversible loss of cochlear nerve peripheral terminals on inner hair cells (IHCs) and a slow degeneration of spiral ganglion cells, despite full recovery of cochlear thresholds and no loss of inner or outer hair cells (Kujawa and Liberman, J Neurosci 29:14077-14085, 2009). This contrasts with earlier ultrastructural work in guinea pig suggesting that acute noise-induced neural degeneration is followed by full regeneration of cochlear nerve terminals in the IHC area (Puel et al., Neuroreport 9:2109-2114, 1998; Pujol and Puel, Ann N Y Acad Sci 884:249-254, 1999). Here, we show that the same patterns of primary neural degeneration reported for mouse are also seen in the noise-exposed guinea pig, when IHC synapses and cochlear nerve terminals are counted 1 week post exposure in confocal images from immunostained whole mounts and that the same slow degeneration of spiral ganglion cells occurs despite no loss of IHCs and apparent recovery of cochlear thresholds. The data cast doubt on prior claims that there is significant neural regeneration and synaptogenesis in the adult cochlea and suggest that denervation of the inner hair cell is an important sequela of "reversible" noise-induced hearing loss, which likely applies to the human ear as well. PMID- 21688059 TI - Effects of pesticide compounds (chlorothalonil and mancozeb) and benzo[a]pyrene mixture on aryl hydrocarbon receptor, p53 and ubiquitin gene expression levels in haemocytes of soft-shell clams (Mya arenaria). AB - The aim of this study is to investigate the effects of the pesticides/polycyclic aromatic hydrocarbon mixture on aryl hydrocarbon receptor (AhR), p53 and ubiquitin mRNA level in haemocytes of Mya arenaria exposed to a mixture of chlorothalonil, mancozeb and benzo[a]pyrene (BaP) for 48 and 72 h. AhR, p53 and ubiquitin gene expression levels were quantified using quantitative Real-time PCR. For robust and accurate quantification of transcripts, suitable housekeeping genes were selected from four sets of ribosomal and elongation factors transcripts previously sequenced from Mya arenaria using geNorm open source software. Quantitative Real-time PCR data exhibited a significantly high expression of AhR after 72 h of exposure (P <= 0.05). p53 gene expression seems to be up-regulated by the mixture after 48 h, however not significantly; but the level of p53 mRNA is down-regulated by the xenobiotics between 48 and 72 h after exposure. This study postulates that AhR mRNA levels could be used as an indicator of the exposure of clams' haemocytes to a mixture of xenobiotics such as chlorothalonil, mancozeb and BaP. However, further studies have to be pursued in order to unravel the molecular mechanisms involved in the p53 signaling pathway. PMID- 21688061 TI - Evolutionary genetics of MHC class II beta genes in the brown hare, Lepus europaeus. AB - The genes of the major histocompatibility complex (MHC) are attractive candidates for investigating the link between adaptive variation and individual fitness. High levels of diversity at the MHC are thought to be the result of parasite mediated selection and there is growing evidence to support this theory. Most studies, however, target just a single gene within the MHC and infer any evidence of selection to be representative of the entire gene region. Here we present data from three MHC class II beta genes (DPB, DQB, and DRB) for brown hares in two geographic regions and compare them against previous results from a class II alpha-chain gene (DQA). We report moderate levels of diversity and high levels of population differentiation in the DQB and DRB genes (Na = 11, D (est) = 0.071 and Na = 15, D (est) = 0.409, respectively), but not for the DPB gene (Na = 4, D (est) = 0.00). We also detected evidence of positive selection within the peptide binding region of the DQB and DRB genes (95% CI, omega > 1.0) but found no signature of selection for DPB. Mutation and recombination were both found to be important processes shaping the evolution of the class II genes. Our findings suggest that while diversifying selection is a significant contributor to the generally high levels of MHC diversity, it does not act in a uniform manner across the entire MHC class II region. The beta-chain genes that we have characterized provide a valuable set of MHC class II markers for future studies of the evolution of adaptive variation in Leporids. PMID- 21688063 TI - FIP/AAPS joint workshop report: dissolution/in vitro release testing of novel/special dosage forms. PMID- 21688064 TI - Anesthesia risks associated with pediatric imaging. PMID- 21688066 TI - Main pulmonary artery diameter from attenuation correction CT scans in cardiac SPECT accurately predicts pulmonary hypertension. AB - OBJECTIVES: To establish the value of the main pulmonary artery (MPA) diameter assessed from unenhanced computer tomography (CT) scans used for attenuation correction (AC) of single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) to predict pulmonary hypertension (PHT). BACKGROUND: In contrast-enhanced chest CT scans an MPA diameter of 29 mm or greater is an established predictor of PHT. However, it is unknown, whether measurements from an unenhanced CT scan for AC may be used as predictor of PHT. METHODS: 100 patients underwent SPECT MPI for assessment of coronary artery disease. PHT was defined as a right ventriculo-atrial gradient of 30 mm Hg or greater by Doppler echocardiography. We compared MPA diameter from CT to SPECT findings (right ventricular hypertrophy/enlargement, septal wall motion abnormality/perfusion defect, and D-shape) to determine the best predictor of PHT. RESULTS: PHT was found in 37 patients. An MPA diameter of 30 mm or greater yielded a sensitivity, specificity, accuracy, positive, and negative predictive value of 78%, 91%, 86%, 83%, and 88%, respectively. This yielded an area under the ROC curve of 0.85. CONCLUSIONS: MPA diameter from low-dose unenhanced multi-slice CT reliably predicts PHT, providing an important added clinical value from AC for SPECT MPI. PMID- 21688067 TI - Parasite fauna of farmed Nile tilapia (Oreochromis niloticus) and African catfish (Clarias gariepinus) in Uganda. AB - An intensive parasite survey was conducted in 2008 to better understand the parasite fauna occurrence, distribution and diversity in the commercial aquaculture fish species in Uganda. A total of 265 fish collected from hatcheries and grow-out systems were examined for parasites using routine parasitological techniques. The survey yielded 17 parasite species: 11 from Oreochromis niloticus and ten from Clarias gariepinus. Four parasites-Amirthalingamia macracantha, Monobothrioides sp., Zoogonoides sp. and a member of the family Amphilinidae-were recorded for the first time in the country. The parasite diversity was similar between hosts; however, O. niloticus was dominated by free-living stage transmitted parasites in lower numbers, whereas both trophically and free-living stage-transmitted parasites were equally represented in C. gariepinus in relatively high intensities. The patterns in parasite numbers and composition in the two hosts reflect differences in fish habitat use and diet. A shift in parasite composition from monoxenous species-dominated communities in small-sized fish to heteroxenous in large fishes was recorded in both hosts. This was linked to ontogenetic feeding changes and prolonged exposure to parasites. Polyculture systems showed no effect on parasite intensity and composition. The gills were highly parasitized, mainly by protozoans and monogeneans. Generally, the occurrence and diversity of parasites in these fish species highlight the likelihood of disease outbreak in the proposed intensive aquaculture systems. This calls for raising awareness in fish health management among potential farmers, service providers and researchers. PMID- 21688068 TI - Bounded outcome score modeling: application to treating psoriasis with ustekinumab. AB - Disease status is often measured with bounded outcome scores (BOS) which report a discrete set of values on a finite range. The distribution of BOS data is often non-standard, e.g., J- or U-shaped, thus making standard analysis methods that assume normality inappropriate. Data transformations aiming to achieve normality with BOS can be much more difficult than with many other types of skewed distributions, and application of methodologies explicitly dealing with this problem has not been previously published in pharmacokinetic/pharmacodynamic modeling literature. In this analysis, a coarsened latent variable (CO) approach is augmented with flexible transformations and applied for the purpose of demonstrating ustekinumab effects on four clinical components (involved body surface area, induration, erythema, and scaling) in patients with moderate to severe psoriasis from two Phase 3 studies. Patients were randomized to receive placebo or ustekinumab 45 or 90 mg, followed by randomized withdrawal and long term extension periods. The approach was used together with a previously established novel semi-mechanistic, mixed-effect exposure-response model integrated with placebo effect and disease progression, and with potential influence of dropout investigated. An additional transformation further modifying both tails of the standard logit transformation in the original CO approach was shown to be necessary in this application. PMID- 21688069 TI - Volatile organic compounds and bioaerosols in the vicinity of a municipal waste organic fraction treatment plant. Human health risks. AB - PURPOSE: The aim of this study was to analyze air concentrations of chemical and microbiological pollutants in the vicinity of an organic waste treatment plant, Ecoparc-2, located in Montcada i Reixac (Catalonia, Spain), as well as to determine the seasonal trends. The human health risks due to the presence of those agents were also assessed. METHODS: Air samples were collected at different distances and wind directions from the Ecoparc-2 in two campaigns (winter and summer of 2010). The levels of 19 volatile organic compounds (VOCs) were analyzed by GC-MS or HPLC-UV. In turn, the airborne amount of total bacteria, gram negative bacteria, and fungi (including Aspergillus fumigatus) was also determined. RESULTS: Mean VOC concentrations were found to be 32.4 and 15.7 MUg/m(3) in winter and summer, respectively. Fungi at 25 degrees C presented the highest geometric mean (1,126 and 863 cfu/m(3) in winter and summer, respectively), while the concentrations of fungi at 37 degrees C and total bacteria were also important in the hot season (332 and 250 cfu/m(3), respectively). These results are in agreement with data obtained from the scientific literature. Anyhow, no significant differences were observed between both campaigns including those related to distances and wind directions. The current pollutant levels in the surrounding environment were also various orders of magnitude lower than those recently observed inside the facility. CONCLUSIONS: The human exposure to VOCs near the Ecoparc-2 was estimated to be low. Furthermore, the current environmental concentrations of those chemical and microbiological agents were clearly below threshold values recommended by regulatory organizations. PMID- 21688070 TI - Suitability of Scirpus maritimus for petroleum hydrocarbons remediation in a refinery environment. AB - PURPOSE: In the ambit of a project searching for appropriate biological approaches for recovering a refinery soil contaminated with petroleum hydrocarbons (PHC), we compared results obtained in the absence and in the presence of the salt marsh plant Scirpus maritimus or Juncus maritimus or an association of these two plants, which were tested in the refinery environment. Synergistic effects caused by addition of a non-ionic surfactant and/or a bioaugmentation product were also investigated. Major challenges of this study were: field conditions and weathered contamination. METHODS: Transplants of the plants were carried out in individual containers filled with a weathered contaminated soil, which was recontaminated with turbine oil with two purposes: for increasing PHC level and allowing a comparison of the potential of plants for remediation of ancient and recent contamination. RESULTS: Analysis of total PHC led to the conclusion that, after 24-month exposure, neither J. maritimus nor the association caused any improvement in remediation. In contrast, S. maritimus revealed potential for PHC remediation, favoring degradation of both recent and older contamination (which was refractory to natural attenuation). About 15% of remediation improvement was found in the soil layer with higher root density (5 10 cm). A more marked improvement in that layer (28%) was observed when non-ionic surfactant amendment and bioaugmentation were used jointly. CONCLUSIONS: The fact that S. maritimus has demonstrated capability for PHC remediation, leads to admit that it has potential to be also used for recovering sediments that have suffered accidental oil spills. PMID- 21688071 TI - Induction of root colonization by Piriformospora indica leads to enhanced asiaticoside production in Centella asiatica. AB - Centella asiatica (Indian pennywort) has wide application in Indian and Chinese traditional medicines with documented evidence for wound healing and neuroprotective and anti-aging potential. Asiaticoside, a trisaccharide triterpene, is the most medicinally active compound in the plant. beta-Amyrin synthase and squalene synthase have been identified as the two key genes in the triterpenoid pathway which regulate the production of asiaticoside in C. asiatica. The paper reports salient findings of our study utilizing the growth promoting endophytic fungus Piriformospora indica to successfully colonize roots of C. asiatica in vitro cultures for investigating the effect of the mutualistic association on asiaticoside production. Co-cultivation of P. indica resulted in the rapid enhancement of root and shoot biomass of host plant, which was visible after 7 days of culture and continued up to 45 days. P. indica co-cultivation also favored the synthesis of asiaticosides, as evidenced by HPLC analysis which indicated about twofold increase (0.53% (w/w) in leaves and 0.23% (w/w) in whole plant) over control (0.33% (w/w) in leaves and 0.14% (w/w) in whole plant). Real time PCR results confirmed the strong upregulation of squalene synthase and beta amyrin synthase transcripts in P. indica-challenged plants compared with the control. Our data demonstrate the potential use of P. indica as a means to enhance plant secondary metabolite production in planta with scope for further field evaluation. PMID- 21688072 TI - Lightness constancy and illumination discounting. AB - Contrary to the implication of the term "lightness constancy", asymmetric lightness matching has never been found to be perfect unless the scene is highly articulated (i.e., contains a number of different reflectances). Also, lightness constancy has been found to vary for different observers, and an effect of instruction (lightness vs. brightness) has been reported. The elusiveness of lightness constancy presents a great challenge to visual science; we revisit these issues in the following experiment, which involved 44 observers in total. The stimuli consisted of a large sheet of black paper with a rectangular spotlight projected onto the lower half and 40 squares of various shades of grey printed on the upper half. The luminance ratio at the edge of the spotlight was 25, while that of the squares varied from 2 to 16. Three different instructions were given to observers: They were asked to find a square in the upper half that (i) looked as if it was made of the same paper as that on which the spotlight fell (lightness match), (ii) had the same luminance contrast as the spotlight edge (contrast match), or (iii) had the same brightness as the spotlight (brightness match). Observers made 10 matches of each of the three types. Great interindividual variability was found for all three types of matches. In particular, the individual Brunswik ratios were found to vary over a broad range (from .47 to .85). That is, lightness matches were found to be far from veridical. Contrast matches were also found to be inaccurate, being on average, underestimated by a factor of 3.4. Articulation was found to essentially affect not only lightness, but contrast and brightness matches as well. No difference was found between the lightness and luminance contrast matches. While the brightness matches significantly differed from the other matches, the difference was small. Furthermore, the brightness matches were found to be subject to the same interindividual variability and the same effect of articulation. This leads to the conclusion that inexperienced observers are unable to estimate both the brightness and the luminance contrast of the light reflected from real objects lit by real lights. None of our observers perceived illumination edges purely as illumination edges: A partial Gelb effect ("partial illumination discounting") always took place. The lightness inconstancy in our experiment resulted from this partial illumination discounting. We propose an account of our results based on the two-dimensionality of achromatic colour. We argue that large interindividual variations and the effect of articulation are caused by the large ambiguity of luminance ratios in the stimulus displays used in laboratory conditions. PMID- 21688075 TI - Abstracts of the Winter Scientific Meeting of the Faculty of Public Health Medicine of the Royal College of Physicians of Ireland. December 8, 2010. Dublin, Ireland. PMID- 21688074 TI - Endovascular repair of acute symptomatic pararenal aortic aneurysm with three chimney and one periscope graft for complete visceral artery revascularization. AB - PURPOSE: To describe a modified endovascular technique for complete revascularization of visceral and renal arteries in symptomatic pararenal aortic aneurysm (PRAA). TECHNIQUE: Arterial access was surgically established in both common femoral arteries (CFAs) and the left subclavian artery (LSA). Revascularization of the left renal artery, the celiac trunk, and the superior mesenteric artery was performed through one single sheath via the LSA. Suitable covered stents were put in the aortic branches but not deployed. The right renal artery was accessed over the left CFA. Due to the longitudinal extension of the presented aneurysm two stent-grafts were introduced via the right CFA. After deploying the aortic stent-grafts, all covered stents in the side branches were deployed consecutively with a minimum overlap of 5 mm over the cranial and caudal stent-graft edges. Simultaneous ballooning was performed to fully expand all stent-grafts and warranty patency. CONCLUSION: This is the first report in the literature of chimney grafting in PRAA for complete revascularization of visceral and renal branches by using more than two covered stents introduced from one side through one single sheath. However this technique is modified, it should be used only in bailout situations when branched stent-grafts are not available and/or surgery is not suitable. PMID- 21688073 TI - Correction of endothelial dysfunction after selective homocysteine lowering gene therapy reduces arterial thrombogenicity but has no effect on atherogenesis. AB - Hyperhomocysteinemia is an independent risk factor for ischemic cardiovascular diseases, but its causal role in atherothrombosis remains controversial. Proatherogenic and/or prothrombotic effects may underlie the potential causal relation between hyperhomocysteinemia and cardiovascular events. Here, the effects of selective lowering of plasma homocysteine, plasma cholesterol, or both on endothelial function and on atherogenesis in male hyperlipidemic and hyperhomocysteinemic C57BL/6 low-density lipoprotein receptor (LDLr)(-/ )/cystathionine-beta-synthase (CBS)(+/-)-deficient mice were investigated. Second, we evaluated whether selective homocysteine lowering has anti-thrombotic effects in a model of arterial thrombosis. A hyperhomocysteinemic and atherogenic diet was started at the age of 12 weeks. Three weeks later, gene transfer was performed with E1E3E4-deleted adenoviral vectors for hepatocyte-restricted overexpression of CBS (AdCBS) or of the LDLr (AdLDLr), or with the control vector Adnull. In a fourth group, AdCBS and AdLDLr were co-administered. Selective homocysteine lowering but not selective cholesterol lowering restored endothelial function at 6 weeks after gene transfer. Intimal area in the aortic root and in the brachiocephalic artery at 13 weeks was more than 100-fold (p < 0.001) smaller in AdLDLr and AdCBS/AdLDLr mice than in control mice and AdCBS mice. No differences in intimal area were observed between control mice and AdCBS mice. In a model of carotid artery thrombosis, the average time to first occlusion and to stable occlusion were 1.9-fold (p < 0.01) and 2.1-fold longer (p < 0.01), respectively, in AdCBS-treated mice than in control mice. Taken together, these data show that correction of endothelial dysfunction following selective homocysteine lowering has anti-thrombotic but no anti-atherogenic effects. PMID- 21688076 TI - Direct assessment of the antioxidant properties of midazolam by electron spin resonance spectroscopy. AB - Some antioxidant anesthetics directly inhibit lipid peroxidation mediated via the generation of reactive oxygen species (ROS). To date, the scavenging effects of midazolam on ROS have not been directly assessed. We investigated the inhibitory effect of midazolam on ROS [hydroxyl radical (HO(.)) and superoxide (O (2) (.-) )] by in vitro X-band electron spin resonance with the spin-trapping agent 5,5 dimethyl-1-pyrroline-N-oxide. Our results indicated that HO(.) and O (2) (.-) were not affected by midazolam at clinically relevant concentrations, but were directly scavenged by midazolam at high concentrations (i.e., >4.6 and >1.5 mM, respectively). PMID- 21688077 TI - The distribution of vascular endothelial growth factor-producing cells in clinical radiation necrosis of the brain: pathological consideration of their potential roles. AB - The cell type and localization of vascular endothelial growth factor (VEGF) producing cells in human radiation necrosis (RN) are investigated from a histopathological and immunohistochemical standpoint using clinical specimens. Eighteen surgical specimens of symptomatic RN in the brain were retrospectively reviewed. These cases included different original histological tumor types and were treated with different radiation modalities. Histological analyses were performed using hematoxylin and eosin (H&E) staining, and anti-VEGF and anti hypoxia-inducible factor (HIF)-1alpha immunohistochemistry. H&E staining showed marked angiogenesis and reactive astrocytosis at the perinecrotic area. The most prominent vasculature in this area was identified as telangiectasis. Immunohistochemistry indicated that HIF-1alpha was expressed predominantly in the perinecrotic area and that a large majority of VEGF-expressing cells were reactive astrocytes intensively distributed in this area. VEGF produced by the reactive astrocytes localized mainly in the perinecrotic area might be a major cause of both angiogenesis and the subsequent perilesional edema typically found in RN of the brain. The benefits of anti-VEGF antibody (bevacizumab) treatment in RN may be that VEGF secretion from the perinecrotic tissue is inhibited and that surgery would remove this tissue; both of these benefits result in effective reduction of edema associated with RN. PMID- 21688078 TI - Pain characteristics after laparoscopic inguinal hernia repair. AB - BACKGROUND: Previous studies have shown different pain characteristics in different types of laparoscopic operations, but pain pattern has not been studied in detail after laparoscopic inguinal hernia repair. To optimise preoperative patient information and postoperative analgesic treatment the present study investigated postoperative pain in terms of time course, pain intensity and individual pain components during the first 4 days after transabdominal preperitoneal hernia repair (TAPP). METHODS: The study was a single-centre prospective trial including 50 consecutive male patients with primary or recurrent inguinal and/or femoral hernia undergoing elective repair. Several pain components (visceral pain, incisional pain and shoulder pain) were studied as well as pain at the three different trocar incisions. Pain was recorded before operation and on a daily basis during the first four postoperative days using a visual analogue and a verbal rating scale. We used 1 * 12 and 2 * 5 mm trocars for TAPP. RESULTS: A total of 46 patients were available for analyses (age median 58 years, range 27-69 years). Visceral pain dominated significantly compared with incisional pain (P < 0.01), which again dominated over shoulder pain intensity and incidence (P < 0.01). Pain intensity did not significantly differ between different trocar incisions (5 and 12 mm) (P > 0.05). The overall pain intensity (a conglomerate of the different pain components) was most intense 3 h after TAPP and declined to preoperative levels on day 3 (P > 0.5). CONCLUSION: Pain was most intense 3 h after the operation and declined to low levels within the first 3 days. Visceral pain was by far the dominating pain component compared with incisional and shoulder pain. PMID- 21688079 TI - Visceral fat area is superior to body mass index as a predictive factor for risk with laparoscopy-assisted gastrectomy for gastric cancer. AB - INTRODUCTION: After adopting preoperative assessment of the perigastric vessels using 3D-CT and standardization of the procedures, obesity still influences smooth laparoscopy assisted gastrectomy (LAG). We evaluated the impact of body mass index (BMI) and area of visceral fat tissue on the risks of LAG. METHODS: Sixty-six patients who underwent LAG for gastric cancer were included. The patients were divided into two groups by BMI (<25 BMI-L group: n = 53; >=25 BMI-H group: n = 13) and area of intraperitoneal fat tissue (<100 cm(2) AF-L group: n = 35; >=100 cm(2) AF-H group: n = 31), respectively. Fat scan((r)), which was computer software operating on abdominal CT, was used to measure the visceral fat areas (VFA). The incidence of postoperative complications, operation time, intraoperative blood loss, and number of dissected lymph nodes were compared between each two groups. RESULTS: The incidence of postoperative complications of BMI-L and BMI-H groups was 11.3% and 30%, respectively (p = 0.18). The mean blood loss was 85 and 134 g, respectively (p = 0.21). There were no significant differences in operation time and the number of retrieved LNs. The incidence postoperative complications (29%) and mean blood loss (148 g) of then VFA-H group were significantly higher than those of the VFA-L group (5.7%, 48 g). The number of retrieved LNs of the VFA-H group (n = 25) was significantly lower than that of the VFA-L group (n = 34). There was no significant difference in operation time. CONCLUSIONS: In the VFA-H group, the incidence of postoperative complications and intraoperative blood loss increased, and the dissected number of LNs decreased. The area of visceral fat tissue was useful to predict risks of LAG and postoperative complications with higher precision compared with BMI. PMID- 21688080 TI - Laparoscopic resection vs. open liver resection for peripheral hepatocellular carcinoma in patients with chronic liver disease: a case-matched study. AB - BACKGROUND: Studies that compare laparoscopic to open liver resection for hepatocellular carcinoma (HCC) in cirrhotic patients are rare and may have suffered from low patient numbers. This work was designed to determine the impact of laparoscopic resection on postoperative and long-term outcomes in a large series of cirrhotic patients with hepatocellular carcinoma (HCC) compared with open resection. METHODS: From 2002 to 2009, 36 patients with chronic liver disease with complicating HCC were selected for laparoscopic resection (laparoscopic group, LG). The outcomes were compared with those of 53 patients who underwent open hepatectomy (open group, OG) during the same period in a matched-pair analysis. The two groups were similar in terms of tumor number and size and number of resected segments. RESULTS: Morbidity and mortality rates were similar in the two groups (respectively 25 and 0% in LG vs. 35.8 and 7.5% in OG; p = 0.3). Severe complications were more frequent in OG (13.2%) than in LG (2.8%; p = 0.09). Despite similar portal hypertension levels, complications related to ascites (namely evisceration or variceal bleeding) were fatal in 4 of 12 affected patients in OG but 0 of 5 cases in LG (p = 0.2). The mean hospitalization durations were 6.5 +/- 2.7 days and 9.5 +/- 4.8 days in LG and OG, respectively (p = 0.003). The surgical margins were similar in the two groups. Although there was a trend toward better 5-year overall survival in LG (70 vs. 46% in OG; p = 0.073), 5-year disease-free survival was similar (35.5 vs. 33.6%). CONCLUSIONS: Laparoscopic resection of HCC in patients with chronic liver disease has similar results to open resection in terms of postoperative outcomes, surgical margins, and long-term survival. PMID- 21688082 TI - Age is not a contraindication for orthotopic liver transplantation: a single institution experience with recipients older than 75 years. AB - INTRODUCTION: Transplant community has arbitrary age limit for liver transplantation based on the increased comorbidities in aging population. There has been an increased demand to consider older patients to have access to liver transplantation as the US population continues to live longer with better health. METHODS: This is a single institution, retrospective review of patients, who were age 75 or over underwent liver transplantation. RESULTS: There were 13 patients, who were 75 years or older at the time of orthotopic liver transplantation. There were no intraoperative or perioperative deaths. Seven of 13 patients are still alive (53.8%) with a mean survival of 65 months. CONCLUSION: Our study demonstrates that a with proper evaluation and careful consideration of risk factors, individuals older than 75 years of age can undergo this life-saving procedure with acceptable long-term survival. PMID- 21688081 TI - Single cell viability and impact of heating by laser absorption. AB - Optical traps such as tweezers and stretchers are widely used to probe the mechanical properties of cells. Beyond their large range of applications, the use of infrared laser light in optical traps causes significant heating effects in the cell. This study investigated the effect of laser-induced heating on cell viability. Common viability assays are not very sensitive to damages caused in short periods of time or are not practicable for single cell analysis. We used cell spreading, a vital ability of cells, as a new sensitive viability marker. The optical stretcher, a two beam laser trap, was used to simulate heat shocks that cells typically experience during measurements in optical traps. The results show that about 60% of the cells survived heat shocks without vital damage at temperatures of up to 58 +/- 2 degrees C for 0.5 s. By varying the duration of the heat shocks, it was shown that 60% of the cells stayed viable when exposed to 48 +/- 2 degrees C for 5 s. PMID- 21688083 TI - Long-term cultivation of in vitro Apis mellifera cells by gene transfer of human c-myc proto-oncogene. AB - Establishment of cell lines representative of honeybee character would greatly assist in their analysis. Here, we show that immortalized cell line, designated as MYN9, has been generated from honeybee embryo by the gene transfer of human c myc proto-oncogene. The morphology of the cell is characteristic of embryonic stem cell, although the cell is stable and does not spontaneously differentiate. Polymerase chain reaction analyses show that the cell is originated from authentic honeybee cell. It is proposed that the integration of human c-myc gene into honeybee precursor populations results in the establishment of stable cell line suitable for cellular and molecular studies. PMID- 21688084 TI - Muscle sympathetic responses during orthostasis in heat-stressed individuals. AB - PURPOSE: Whole-body heat stress compromises the control of blood pressure during an orthostatic challenge, although the extent to which this occurs can vary greatly between individuals. The mechanism(s) responsible for these varying responses remain unclear. This study tested the hypothesis that the individuals who are best able to tolerate an orthostatic challenge while heat stressed are the ones with the largest increase in sympathetic activity during orthostasis, indexed from recordings of muscle sympathetic nerve activity (MSNA). METHODS: MSNA, arterial blood pressure, and heart rate were recorded from 11 healthy volunteers throughout passive whole-body heating and during 15 min of 60 degrees head-up tilt (HUT) or until the onset of pre-syncopal symptoms. RESULTS: Whole body heating significantly increased core temperature (~0.9 degrees C), supine heart rate and MSNA. Eight of 11 subjects developed pre-syncopal symptoms resulting in early termination of HUT. The HUT tolerance time was positively correlated (R = 0.82, P = 0.01) with the increase in MSNA by HUT. CONCLUSION: These data suggest that the individuals with the largest increase in MSNA during upright tilt have the greatest capacity to withstand the orthostatic challenge while heat stressed. PMID- 21688085 TI - High serum potassium levels after using losartan can reflect more severe renal disease. PMID- 21688086 TI - Effect of shRNA mediated down-regulation of Annexin A2 on biological behavior of human lung adencarcinoma cells A549. AB - In the previous study, we found that Annexin A2 was significantly up-regulated in lung cancer and could induce related-antigen in lung cancer patients' serum. To further study the function of Annexin A2, the short hairpin RNA plasmid targeting Annexin A2 was constructed in vitro and transfected into human lung adencarcinoma A549 cells. Knocking down Annexin A2 expression by shRNA, the mRNA level of Annexin A2 was investigated by semi-quantitative RT-PCR. The expression of Annexin A2 protein was examined by Western Blotting and Immuocytochemistry. MTT assay and Transwell chamber model were used to evaluate proliferation and invasion of A549 cells in vitro. The concentration of matrix metalloproteinase-2 (MMP-2) and cathepsin B (CB) in the supernatant was evaluated by ELISA. At 48 h after transfection, the expression of Annexin A2 mRNA and protein was down regulated significantly, respectively (p < 0.05).The proliferation and invasion capability of A549 cells also decreased significantly (p < 0.05). The concentration of MMP-2 and CB was down-regulated obviously, respectively (p < 0.05). This study implies that Annexin A2 might play an important role in the progression and invasion of human lung cancer cells, and could promote progression of lung cancer by regulating the expression of MMP-2 and CB. PMID- 21688088 TI - Prevalence and biology of goat warble fly infestation by Przhevalskiana silenus in Jammu province, India. AB - Examination of 3,960 goats brought from six districts of Jammu province and slaughtered at Jammu abattoir from July 2005 to June 2006 revealed 47.22% prevalence of larval stages of warble fly (Przhevalskiana silenus Brauer, 1858) in goats. Highest prevalence was recorded in Udhampur (56.44%) and lowest in Doda district (13.49%). Classification of the study area into four zones based on height (meters above sea level), viz., zone I (300-325 m asl), zone II (325-800 m asl), zone III (800-1,500 m asl), and zone IV (>1,500 m asl), revealed significant (p < 0.01) difference in infestation among animals of zone II (71.68%), zone III (40.12%), and zone IV (22.41%). However, animals of zone I did not reveal any infestation. Statistical analysis in relation to age showed significant (p < 0.01) difference among different age groups, i.e., <1 year (2.81%), 1-3 years (51.17%), and >3 years (43.16%). Breed-wise analysis also showed significantly (p < 0.01) higher infestation rate among Bakerwali (51.51%) goats as compared to Beetal (42.59%). But no significant difference was recorded among male (47.81%) and female (46.82%) animals. The overall mean larva count (L1, L2, and L3) was observed to be 14.72 +/- 0.34, ranging from 4 to 72. It was significantly (p < 0.05) higher in animals of zone II (22.20 +/- 0.21) as compared to goats of zones III (14.21 +/- 0.41) and IV (7.73 +/- 0.90). Age-wise analysis of mean larva count also showed significant (P < 0.05) difference between animals of 1-3 years (16.25 +/- 0.37) and >3 years of age (13.18 +/- 0.40). Mean larvae count in relation to sex and breed did not reveal any significant difference. First-instar larvae (L(1)) were recorded from May to mid September, second larval stage (L(2)) from mid-September to mid-December, and third-stage larvae (L(3)) from mid-December to February. However, No larvae were recorded from March to April, which is suggestive of pupation period in this region. Thus, it is concluded that adult fly is active in April to June. The results further confirmed that internal life cycle of P. silenus is subcutaneous and no migration of larvae occurs. This is the first report from India, based on slaughter house study on the prevalence and biology of goat warble fly infestation. It will help in devising suitable prophylactic and eradication program to check the economic losses rendered by adult fly. PMID- 21688087 TI - Indeterminate cell histiocytosis in a pediatric patient: successful treatment with thalidomide. AB - The 15-year-old male patient presented several 2-6 mm large livid reddish yellowish, shiny, compact papules on the head, trunk and extremities, which had developed within the last 4 months. Histology showed normal epidermis with dense dermal infiltrate of histiocytes accompanied by few eosinophils, Touton or foamy giant cells. The histiocytes were S100 positive, CD1a negative and did not contain Birbeck granules ultrastructurally. Chest X ray, EEG, skull MRI did not show pathology. Opthalmology, neurology, oto-rhino-laryngology did not reveal alterations. Based upon the clinical symptoms and the histopathology, the diagnosis of indeterminate cell histiocytosis was confirmed. Cryotherapy and cauterization did not stop the progression of the disease, however, under thalidomide treatment no new symptoms developed and the lesions healed with pigmentation. PMID- 21688091 TI - [Pertrochanteric fractures]. PMID- 21688089 TI - Assessment of the Short Acculturation Scale for Hispanics (SASH) among low income, immigrant Hispanics. AB - The present analysis sought to determine the usefulness and validity of the Short Acculturation Scale for Hispanics (SASH) in assessment of acculturation among Hispanics participating in a colorectal cancer screening study. Primary data was collected from 2008 to 2009 through surveys in East Harlem community-based sites and health clinics among Hispanics. Bivariate correlations and independent samples t tests assessed SASH correlation with acculturation proxies and relationships between proxies, SASH, and sociodemographics. SASH was highly correlated with commonly used acculturation proxies; inter-scale correlations and alpha scores were high. Sociodemographics associated with proxy variables were associated with SASH. In conclusion, SASH is useful and valid for assessing acculturation among Hispanics; however, a shortened version or acculturation proxy variables could also be utilized. PMID- 21688092 TI - [Systemic lupus erythematosus]. AB - Systemic lupus erythematosus (SLE) is the classical systemic autoimmune disease. Its prevalence is slightly below 1:1,000 in women and 10-fold lower in men. Typically, the disease manifests in women of childbearing age. While severe untreated SLE used to be a fatal disease, prognosis has improved stepwise with corticosteroids, cyclophosphamide and novel therapies. Deaths directly related to SLE are uncommon nowadays but infections, thromboses and accelerated atherosclerosis cause significant problems. The current review presents the state of the art in managing SLE patients. PMID- 21688096 TI - Genetic and epigenetic regulation of Tcrb gene assembly. AB - Vertebrate development requires the formation of multiple cell types from a single genetic blueprint, an extraordinary feat that is guided by the dynamic and finely tuned reprogramming of gene expression. The sophisticated orchestration of gene expression programs is driven primarily by changes in the patterns of covalent chromatin modifications. These epigenetic changes are directed by cis elements, positioned across the genome, which provide docking sites for transcription factors and associated chromatin modifiers. Epigenetic changes impact all aspects of gene regulation, governing association with the machinery that drives transcription, replication, repair and recombination, a regulatory relationship that is dramatically illustrated in developing lymphocytes. The program of somatic rearrangements that assemble antigen receptor genes in precursor B and T cells has proven to be a fertile system for elucidating relationships between the genetic and epigenetic components of gene regulation. This chapter describes our current understanding of the cross-talk between key genetic elements and epigenetic programs during recombination of the Tcrb locus in developing T cells, how each contributes to the regulation of chromatin accessibility at individual DNA targets for recombination, and potential mechanisms that coordinate their actions. PMID- 21688099 TI - Unusual misplacement of a femoral central venous catheter. PMID- 21688100 TI - Bispectral index and suppression ratio during hypothermia after cardiac arrest. PMID- 21688101 TI - A UK approach to urgent endotracheal intubation. PMID- 21688102 TI - Corticosteroid treatment in severe community-acquired pneumonia: duration of treatment affects control of systemic inflammation and clinical improvement. PMID- 21688103 TI - Neuroleptic malignant syndrome with metoclopramide overdose coexisting with Clostridium difficile diarrhea. PMID- 21688104 TI - Primary ileus after total hip arthroplasty: rare complication or sentinel event? AB - The incidence of hip dislocation after primary total hip arthroplasty (THA) has been reported to range from 1 to 25% in THA revision. Here, we explore the hypothesis that there is a correlation between postoperative ileus (POI) and THA dislocation, with POI after THA possibly representing a sentinel event. We retrospectively identified a cohort of 529 consecutive patients who underwent hip arthroplasty from 2008 to 2010. Of them, 251 were male and 278 were female, and a mean average for age of 71.5 (range 65-76). In particular, 19 THA patients showed signs of gastrointestinal complications, and therapeutic consultation was performed with the onset of the first intestinal symptom. Of these 19 patients, 3 THA patients developed POI within 1 week after surgical treatment. A conservative treatment was practised and it seemed to improve the condition: canalization returned and all patients were discharged from the hospital. Unfortunately, two of these patients were readmitted after 2 weeks due to THA dislocation and they underwent THA revision and were discharged from the hospital 7 days later. Follow up revealed no further problems at 6 months. Our clinical experience with these post-THA primary ileus patients raises the possibility that intra-abdominal symptoms represent a sentinel event in THA dislocation. THA dislocation using neuronal pathway of immunomodulation may modulate POI. Since the risk of THA dislocation is the greatest in the first 3 months after hip arthroplasty, the surgeon should be familiar with the relationship between THA and various pelvic and visceral complications to ensure that POI remains only a rare complication. PMID- 21688105 TI - Molecular characterization of a porcine astrovirus strain in China. AB - Pigs are increasingly recognized to harbor a wide range of viruses that apparently establish long-term persistence in these animals. They serve as reservoirs for a number of human zoonotic diseases. In this study, a porcine astrovirus (PAstV) strain, designated as PAstV JWH-1, is identified from a diarrheal pig in China, and it is partially characterized genetically. Sequence analysis shows that the PAstV JWH-1 strain contains divergent nucleotide sequences in both the open reading frame (ORF)1b/ORF2 consensus and the 3'-UTR regions (s2m motif), which are usually highly conserved among members of the family Astroviridae. Phylogenetic analysis indicates that the JWH-1 strain clusters closely with newly identified strains PAstV 12-4 and 14-4 and forms a group of mamastroviruses with the proposed novel deer astrovirus. Further recombination analysis shows that two possible interspecies recombination events between porcine and deer astroviruses occurred in the genome of the JWH-1 strain. This study further confirms that multiple lineages are present among PAstVs, and each lineage likely represents an independent origin. Additionally, the possibility of interspecies transmission among PAstVs is also suggested. PMID- 21688106 TI - Immunoglobulin G subclasses in antibody responses to St. Louis encephalitis virus infections. AB - The aim of this study was to recognize the specific antiviral response patterns of IgG1, IgG2, IgG3 and IgG4 subclasses, elicited during St. Louis encephalitis virus (SLEV) infection in humans. Eighty-five samples of human sera from 44 patients with SLEV infection were obtained between days 1 and 365 or later, after onset of the disease. These samples were processed by immunofluorescence assay for detection of IgG1-, IgG2-, IgG3- and IgG4-specific antibodies. We demonstrate the presence of all isotypes of IgG for more than a year in patients infected with SLEV. However; isotype IgG1 was present at the highest titers, with a peak between days 8 and 30 after onset of the disease. PMID- 21688107 TI - Enhanced visualisation for minimally invasive surgery. AB - PURPOSE: Endoscopes used in minimally invasive surgery provide a limited field of view, thus requiring a high degree of spatial awareness and orientation. Attempts at expanding this small, restricted view with previously observed imagery have been made by researchers and is generally known as image mosaicing or dynamic view expansion. For minimally invasive endoscopy, SLAM-based methods have been shown to have potential values but have yet to address effective visualisation techniques. METHODS: The live endoscopic video feed is expanded with previously observed footage. To this end, a method that highlights the difference between actual camera image and historic data observed earlier is proposed. Old video data is faded out to grey scale to mimic human peripheral vision. Specular highlights are removed with the help of texture synthesis to avoid distracting visual cues. The method is further evaluated on in vivo and phantom sequences by a detailed user study to examine the ability of the user in discerning temporal motion trajectories while visualising the expanded field of view, a feature that is of practical value for enhancing spatial awareness and orientation. RESULTS: The difference between historic data and live video is integrated effectively. The use of a single texture domain generated by planar parameterisation is demonstrated for view expansion. Specular highlights can be removed through texture synthesis without introducing noticeable artefacts. The implicit encoding of motion trajectory of the endoscopic camera visualised by the proposed method facilitates both global awareness and temporal evolution of the scene. CONCLUSIONS: Dynamic view expansion provides more context for navigation and orientation by establishing reference points beyond the camera's field of view. Effective integration of visual cues is paramount for concise visualisation. PMID- 21688108 TI - Percutaneous foot joint needle placement using a C-arm flat-panel detector CT. AB - PURPOSE: Image guidance is valuable for diagnostic injections in foot orthopaedics. Flat-detector computed tomography (FD-CT) was implemented using a C arm, and the system was tested for needle guidance in foot joint injections. METHODS: FD-CT-guided joint infiltration was performed in 6 patients referred from the orthopaedic department for diagnostic foot injections. All interventions were performed utilising a flat-panel fluoroscopy system utilising specialised image guidance and planning software. Successful infiltration was defined by localisation of contrast media depot in the targeted joint. The pre- and post interventional numeric analogue scale (NAS) pain score was assessed. RESULTS: All injections were technically successful. Contrast media deposit was documented in all targeted joints. Significant relief of symptoms was noted by all 6 participants. CONCLUSIONS: FD-CT-guided joint infiltration is a feasible method for diagnostic infiltration of midfoot and hindfoot joints. The FD-CT approach may become an alternative to commonly used 2D-fluoroscopically guidance. PMID- 21688109 TI - Inhibition of adherence of multi-drug resistant E. coli by proanthocyanidin. AB - Proanthocyanidin is commonly used for inhibiting urinary tract infection (UTI) of sensitive strains of Escherichia coli. The aim of this study was to investigate the effect of proanthocyanidin on adherence of uropathogenic multi-drug resistant E. coli to uroepithelial cells, which has not yet been investigated so far. Extracts of the purified proanthocyanidin were prepared from dried cranberry juice. Purity and structural assignment of proanthocyanidin was assessed using high performance liquid chromatography and (13)C nuclear magnetic resonance spectroscopy, respectively. Subsequently, its affect on multi-drug resistant bacteria as well as quantification of anti-adherence bioactivity on human vaginal and bladder epithelial cells was appraised. Inhibition of adherence to an extent of about 70% with multi-drug resistant E. coli strains was observed on uroepithelial cell. The anti-adherence bioactivity of the proanthocyanidin was detected at concentrations of 10-50 ug/ml with significant bacteriuria. Probable proanthocyanidin through A-type linkages either combines to P-fimbriae of bacterial cells or modifies the structural entity of P-fimbriae and inhibits bacterial adherence to uroepithelial cells. The proanthocyanidin exhibited anti adherence property with multi-drug resistant strains of uropathogenic P fimbriated E. coli with in vitro study. Hence proanthocyanidin may be considered as an inhibitory agent for multi-drug resistant strains of E. coli adherence to uroepithelial cells. PMID- 21688110 TI - Intimate partner violence affects skilled attendance at most recent delivery among women in Kenya. AB - Delivery assistance by skilled health personnel is a key progress indicator for Millennium Development Goal 5, which aims to reduce the worldwide maternal mortality ratio by 75% between 1990 and 2015. The role of socio-demographic factors in determining skilled attendance at delivery has been widely explored, but relatively little attention has been paid to the effect of gender power relations on delivery care. This analysis investigated whether women's status in the household, as measured by their experience of intimate partner violence (IPV), affected skilled attendance at most recent delivery among women in Kenya. Cross-sectional data were obtained from the 2003 Kenya Demographic and Health Surveys (KDHS). 975 ever-married women who had given birth in the past year and completed the KDHS domestic violence module were included in the analysis. Logistic regression was used to assess the association between skilled attendance and IPV. In this sample, 46% reported having experienced any type of IPV, with 39% reporting physical violence, 21% emotional violence, and 13% sexual violence. After adjusting for demographic characteristics and number of antenatal visits, lifetime experience of emotional violence was found to decrease the odds of skilled attendance at most recent delivery by 40%, while lifetime experience of physical violence reduced the odds by 29%. Women's experience of IPV may influence receipt of skilled attendance during parturition, and should be addressed as national programs and their international partners align efforts to contribute to the achievement of Millennium Development Goal 5. PMID- 21688111 TI - Special delivery: an analysis of mHealth in maternal and newborn health programs and their outcomes around the world. AB - Mobile health (mHealth) encompasses the use of mobile telecommunication and multimedia into increasingly mobile and wireless health care delivery systems and has the potential to improve tens of thousands of lives each year. The ubiquity and penetration of mobile phones presents the opportunity to leverage mHealth for maternal and newborn care, particularly in under-resourced health ecosystems. Moreover, the slow progress and funding constraints in attaining the Millennium Development Goals for child and maternal health encourage harnessing innovative measures, such as mHealth, to address these public health priorities. This literature review provides a schematic overview of the outcomes, barriers, and strategies of integrating mHealth to improve prenatal and neonatal health outcomes. Six electronic databases were methodically searched using predetermined search terms. Retrieved articles were then categorized according to themes identified in previous studies. A total of 34 articles and reports contributed to the findings with information about the use and limitations of mHealth for prenatal and neonatal healthcare access and delivery. Health systems have implemented mHealth programs to facilitate emergency medical responses, point-of care support, health promotion and data collection. However, the policy infrastructure for funding, coordinating and guiding the sustainable adoption of prenatal and neonatal mHealth services remains under-developed. The integration of mobile health for prenatal and newborn health services has demonstrated positive outcomes, but the sustainability and scalability of operations requires further feedback from and evaluation of ongoing programs. PMID- 21688112 TI - Mild cognitive impairment exists in Parkinson's disease. AB - Cognitive impairment exists in Parkinson's disease (PD) as a transitional state between cognitively intact and demented PD patients. It seems to be a risk factor for the development of dementia in PD, but the precise criteria and unfavorable cognitive profile of mild cognitive impairment in PD (MCI-PD) have not yet been established. The concept may turn to be different from that in Alzheimer's disease since we search for those already diagnosed PD patients who are at risk of developing dementia. In addition, clinical variables specific for PD also play role. Importantly, MCI possesses a metabolic basis in PD. Various biomarkers particularly including neuropsychological testing and the brain imaging hold promise in identification of MCI-PD patients with unfavorable prognoses. Well designed longitudinal studies in MCI-PD cohorts are needed to assess the sensitivity and specificity of the PD-MCI designation as far as dementia development is concerned. PMID- 21688114 TI - Is there a beneficial role for a flexible bronchoscopic approach to oesophageal tumour-related tracheobronchial stenosis? AB - BACKGROUND: Interventional pulmonology, in particular, tracheobronchial stent insertion, has been well described in the treatment of tracheobronchial malignant disease. Its benefits are particularly obvious in patients with inoperable malignancy or in those unfit for surgery and have been extensively described. Fewer data exist on the benefits of using self-expanding metal stents (SEMS) inserted via flexible bronchoscopy in the treatment of tracheobronchial stenosis due to extrinsic compression or infiltration from primary oesophageal malignancy. METHODS: We retrospectively reviewed all patients who had stent insertion via flexible bronchoscopy from 2002 to 2010 at our institution. RESULTS: We found 14 patients who had UltraflexTM self-expanding metal stent insertion for this condition. We analysed this group of patients with respect to their presentation; indications for stent insertion over surgery; size, location, and number of stents inserted; sedative dose; complications of therapy; and survival time. CONCLUSION: We conclude that insertion of SEMS via flexible bronchoscopy is a safe and effective therapy for those individuals who require palliation or are too unfit for the general anaesthesia required for surgery. Moreover, this form of stent insertion may be performed by respiratory physicians in the bronchoscopy suite, rather than by their cardiothoracic counterparts in theatre. PMID- 21688113 TI - Neurocognitive-genetic and neuroimaging-genetic research paradigms in schizophrenia and bipolar disorder. AB - Studies examining intermediate phenotypes such as neurocognitive and neuroanatomical measures along with susceptibility genes are important for improving our understanding of the neural basis of schizophrenia (SZ) and bipolar disorder (BD). In this paper, we review extant studies involving neurocognitive genetic and neuroimaging-genetic perspectives and particularly related to catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin-1 (NRG1) genes in SZ and BD. In terms of neurocognitive-genetic investigations, COMT and BDNF are the two most studied candidate genes especially in patients with SZ. Whereas BDNF Met carriers perform worse on verbal working memory, problem solving and visuo-spatial abilities, COMT Met carriers perform better in working memory, attention, executive functioning with evidence of genotype by diagnosis interactions including high-risk individuals. In terms of genetic-structural MRI studies, patients with SZ are found to have reductions in the frontal, temporal, parietal cortices, and limbic regions, which are associated with BDNF, COMT, and NRGI genes. Genetic-functional MRI studies in psychotic disorders are sparse, especially with regard to BD. These neurocognitive and neuroimaging findings are associated with genes which are implicated in functional pathways related to neuronal signaling, inter-neuronal communication and neuroplasticity. PMID- 21688115 TI - 3D airway tree reconstruction in healthy subjects and emphysema. AB - Several algorithms for the segmentation of the 3D human airway tree from computed tomography (CT) images have recently been proposed, but the effects of lung volume and the presence of emphysema on segmentation accuracy has not been investigated. Two different sets of CT images taken on nine healthy subjects and nine patients with severe emphysema (FEV(1) = 19 +/- 4.1 SD % pred) were used to reconstruct the trachea-bronchial tree by a region-growing algorithm at two different lung volumes: total lung capacity (TLC) and residual volume (RV). The sixth generation was reached in 67% of the healthy subjects and 22% of the emphysematous patients at TLC. At RV, fifth generation was reached in 33 and 11% of healthy subjects and emphysematous patients. At TLC, 67 +/- 2 and 39 +/- 2% of airways belonging to the fourth generation were successfully reconstructed, respectively in healthy and emphysematous subjects. At RV, the percentage of successful reconstruction was 33 +/- 2 and 16 +/- 2%, respectively. Segmentation was significantly influenced by the presence of disease (P < 0.001) and lung volume (P < 0.001) at which the CT scans were acquired. Airway tree reconstruction performed by means of a region-growing algorithm depends on lung volume and presence of emphysema, both of which have significant effect, even at the level of lobar and segmental bronchi. PMID- 21688116 TI - The importance of methylmalonic acid dosage on the assessment of patients with neurological manifestations following bariatric surgery. AB - Vitamin B12 or cyanocobalamin is an important substance that is included in several metabolic pathways. Its deficiency is a common event after bariatric surgery, decreasing the vitamin B12 absorption after almost all of the stomach and duodenum are eliminated from the digestion process. Neurological manifestations of cyanocobalamin deficiency are not uncommon. We report a case of a young woman who developed ataxia, weakness and peripheral neuropathy after bariatric surgery, but with normal value of vitamin B12 dosage. For the diagnosis, it was necessary to dose methylmalonic acid. We discuss the importance of methylmalonic acid dosage after bariatric surgery in patients who present suspect of cyanocobalamin deficiency with normal values of this vitamin and the role of proton pump inhibitor use and vitamin supplementation in patients with early neurological presentation. PMID- 21688118 TI - Gastric by-pass with fixed 230-cm-long common limb and variable alimentary and biliopancreatic limbs in morbid obesity. AB - BACKGROUND: Morbid obesity is a disease of increasing prevalence. Diet and exercise are not effective for excess weight loss (EWL) in most patients; therefore, different bariatric surgery procedures based in restriction or malabsorption, or a combination of both, i.e., the Roux-en-Y gastric by-pass (RYGBP) hybrid operation, have been established. Here, we report the outcome of a modified RYGBP operation in 565 obese patients. METHODS: Our modified RYGBP operation consisted of a pouch smaller than 25 cc, a fixed common limb of 230 cm, and the rest of the small bowel redistributed among the alimentary channel (60%) and the biliopancreatic channel (40%). RESULTS: A large variation in the whole length of small bowel was observed (380-820 cm). EWL was gradually increasing from month 1 after surgery (20.1%) to month 12 (70.1%); this value was maintained in the 2-8-year follow-up period. No differences in fecal protein and carbohydrate loss, before and after surgery, were seen; in contrast, three- to tenfold-higher lipid loss was produced after surgery. Long-term complications were scarce (28 patients with chronic anemia, 3 patients with flatulence, and 8 patients with mild diarrhea). CONCLUSIONS: Gastric pouch smaller than 25 cc and measurement of the entire small bowel length during RYGBP surgery, leaving a 230 cm length of common limb and redistributing the remaining 60% in the alimentary channel and 40% in the biliopancreatic channel produced sustained EWL with few secondary nutrient deficits along an 8-year follow-up period. PMID- 21688119 TI - Natural resistance to apoptosis correlates with resistance to chemotherapy in colorectal cancer cells. AB - Defects in apoptotic machinery vary among individual cancer cells, and the efficacy of chemotherapy in killing cancer cells depends on the successful induction of apoptosis. This study tested the hypothesis that the intrinsic ability of a cancer cell's natural resistance to apoptosis would indicate its ability in resistance to chemotherapy. Four widely studied human colorectal cancer cell lines, SW480, HT-29, LoVo and Caco-2, were examined for their apoptotic fates in spontaneous cultures for up to 6 days using flowcytometry. Chemoresponse of these cells was tested against anti-colorectal cancer drugs 5 fluorouracil (5-FU) and oxaliplatin (OXP) at different peak plasma concentrations (PPCs) using MTT assay. Apoptosis analyses demonstrated that, from Day 2 to Day 6 in spontaneous cultures, SW480 and HT-29 lines showed resistance to apoptosis by having much less average early and late apoptotic cells than LoVo and Caco-2 lines with differences of 3.2- to 5.2-fold. Interestingly, apoptosis-resistant SW480 and HT-29 exhibited higher chemoresistance to both 5-FU (P < 0.01 at 5*, 10*, and 50* PPC) and OXP (P < 0.01 at 5* and 10* PPC, and P < 0.05 at 50* PPC) than LoVo and Caco-2. Colorectal cancer cells' natural resistance to apoptosis is an intrinsic ability that correlates with resistance to chemotherapeutic drugs 5 FU and OXP. Cancer cells' natural apoptotic phenotypes may help predict the outcome of chemotherapy in colorectal cancers. PMID- 21688120 TI - The expression of cyclin G in nasopharyngeal carcinoma and its significance. AB - To investigate the expression of cyclin G1, cyclin G2 in nasopharyngeal carcinoma (NPC) cell lines and its significance. The protein expression of cyclin G1, cyclin G2 in NPC cell lines of different differentiation degree (HNE2, CNE1) was detected by indirect immunofluorescence. The mRNA expression of cyclin G1, cyclin G2 in HNE2 and CNE1 was measured with RT-PCR. The cyclin G1 expression in HNE2 and CNE1 was weak, and cyclin G2 expression in the cytoplasm near cell membrane was strong, continuous, and homogeneous. The expression level of cyclin G1-mRNA in HNE2 was 2.097 +/- 0.262, which was significantly higher than CNE1 (0.997 +/- 0.286, P < 0.05); the expression level of cyclin G2-mRNA in HNE2 was 0.708 +/- 0.107, which was significantly lower than CNE1 (1.216 +/- 0.037, P < 0.05). Abnormal expression of cyclin G was closely related to tumor differentiation, the origin, and progression of NPC. PMID- 21688121 TI - Differential acute toxicity of tetrachlorobenzene isomers to oligochaetes in soil and water: application of the critical body residue concept. AB - The acute, lethal potency of the 1,2,3,4-, 1,2,4,5- and 1,2,3,5 tetrachlorobenzene isomers was compared in the terrestrial and aquatic oligochaetes Eisenia andrei and Tubifex tubifex. 1,2,4,5-TeCB was neither lethal, nor produced any perceptible adverse effects, at lipid normalized concentrations predicted to be lethal according to the well-established critical body residue concept. If a narcotic is defined as a substance capable of inducing narcosis, rather than a substance displaying certain physical or chemical properties (e.g., log K(ow)), then we do not believe these findings challenge the critical body residue because by the former definition, 1,2,4,5-tetrachlorobenzene is not a narcotic. PMID- 21688122 TI - The immunomodulatory properties of viable Lactobacillus salivarius ssp. salivarius CECT5713 are not restricted to the large intestine. AB - PURPOSE: The aim of this study was to better characterise the biological effects of Lactobacillus salivarius ssp. salivarius CECT5713, a probiotic with immunomodulatory properties. METHODS: Live or dead probiotic was assayed in the TNBS model of rat colitis to determine whether viability was a requisite to exert the beneficial effects. In vitro studies were also performed in Caco-2 cells to evaluate its effects on epithelial cell recovery and IL-8 production. Finally, the probiotic was assayed in the LPS model of septic shock in mice to establish its effects when there is an altered systemic immune response. RESULTS: The viability of the probiotic was required for its anti-inflammatory activity. The probiotic inhibited IL-8 production in stimulated Caco-2 cells and facilitated the recovery of damaged intestinal epithelium. In LPS-treated mice, the probiotic inhibited the production of TNFalpha in plasma and lungs and increased the hepatic glutathione content. These effects were associated with an improvement in the altered production of the T-cell cytokines in splenocytes, by reducing IL-2 and IL-5 and by increasing IL-10. Finally, it reduced the increased plasma IgG production in LPS-treated mice. CONCLUSION: The anti-inflammatory effects of viable L. salivarius ssp. salivarius CECT5713 are not restricted to the gastrointestinal tract. PMID- 21688123 TI - Bovine lactoferrin induces interleukin-11 production in a hepatitis mouse model and human intestinal myofibroblasts. AB - PURPOSE: Orally administered bovine lactoferrin (bLF) exerts an anti-inflammatory effect on hepatitis and colitis animal models. To investigate the mechanism underlying the action of bLF, we explored the expression of inflammation-related factors in the intestine of a hepatitis mouse model after the oral administration of bLF and in several human intestinal cell lines treated with bLF. METHODS: The effects of bLF on the expression of interleukin-11 (IL-11) and bone morphogenetic protein 2 (BMP2) in the intestinal mucosa of a hepatitis mouse model as well as in cell cultures of human intestinal epithelial cells, myofibroblasts, and monocytes were examined using the real-time reverse transcription polymerase chain reaction. Epithelial cells and myofibroblasts were also cocultured using transwells. bLF transport, and IL-11 and BMP2 induction, as well as the interactions between the two cell types, were then analyzed after bLF treatment. RESULTS: In vivo, oral bLF administration increased the production of IL-11 and BMP2 in intestinal specimens. In vitro, bLF only stimulated the production of IL 11 in human intestinal myofibroblasts; i.e., it had no effect on BMP2 production in any cell type. In the transwell cocultures, bLF passed through the epithelium and directly stimulated IL-11 production in the myofibroblasts on the basolateral side. The IL-11 produced in the myofibroblasts subsequently acted protectively on the epithelial cells of the coculture. CONCLUSIONS: bLF upregulated the activity of anti-inflammatory factors, such as IL-11, in the intestine of a hepatitis mouse model and human intestinal myofibroblasts. PMID- 21688124 TI - The protective mechanism for the blood-brain barrier induced by aminoguanidine in surgical brain injury in rats. AB - This study was performed to investigate the mechanism of blood-brain barrier (BBB) permeability change, which was induced by aminoguanidine (AG) after surgical brain injury (SBI) in rats. Compared to control group, AG (150 mg/kg, i.p.) significantly reduced Evans blue extravasation into brain tissue at 24 h after surgical resection, it also induced a 32% decrease of malondialdehyde (MDA) values and a 1.1-fold increase of the glutathione (GSH) levels at 12 h after injury. The expression of inducible nitric oxide synthase (iNOS) reached the peak value at 24 h after SBI, which was significantly attenuated after AG treatment. In addition, ZO-1 protein was up-regulated by AG (150 mg/kg) treatment at 24 h after SBI. Our results indicated that AG could protect the BBB after SBI, which could be correlated with antioxidative property, the down-regulation of iNOS and up-regulation of tight junction protein expression. PMID- 21688125 TI - Hydroxysafflor yellow A protects PC12 cells against the apoptosis induced by oxygen and glucose deprivation. AB - Hydroxysafflor yellow A (HSYA) was reported neuroprotective under several ischemic models in vivo. In this study, the direct effect of HSYA against oxygen glucose deprivation (OGD) inducing acute neuronal injury and the underling mechanisms in vitro were investigated. Four-hour oxygen and glucose deprivation (OGD) followed by 20 h reperfusion (adding back oxygen and glucose, OGD-R) was used to induce in vitro ischemia reperfusion injury in differentiated rat pheochromocytoma PC12 cells. HSYA (1, 10, and 100 MUmol/l) was added to the cultures 30 min prior to the ischemic insult and was present during OGD and reoxygenation phases. The survival rate of PC12 cells was detected by MTT assay. The contents of malondialdehyde (MDA), superoxide dismutase (SOD) activity were elevated by biochemical method. Hoechst 33258 staining and flow cytometric analysis were used to detect apoptosis; western blotting was used to detect the expression of Bcl-2, Bax, and Cytochrome C protein. The activity of caspase-3 was assessed by colorimetry. HSYA concentration-dependently attenuated neuronal damage with characteristics of increasing injured neuronal absorbance of MTT, decreasing cell apoptosis, and antagonizing decreases in SOD activity and increase in MDA level induced by OGD-R. Moreover, the down-regulation of Bcl-2, up-regulation of Bax and the release of mitochondrial cytochrome c to cytosol and the consequent activation of caspase-3 were reversed by HSYA in a dose-dependent manner. These results suggest that apoptosis is an important characteristic of OGD-R-induced PC 12 death and that treatment of PC12 cells with HSYA can block OGD-R-induced apoptosis through suppression of intracellular oxidative stress and mitochondria dependent caspase cascade. PMID- 21688126 TI - Variants in COMT and DBH influence on response inhibition ability in Chinese Han females. AB - Catechol-O-methyltransferase (COMT) and dopamine-beta hydroxylase (DBH) are key enzymes to breakdown dopamine. Some previous studies have indicated that val158met in COMT and 19 bp insertion/deletion in 5' flank of DBH are related to the performance of executive function. To further investigate the associations of the two genes with executive function, we performed a population-based study in a Chinese Han population. The results indicated that val158met in COMT and the 19 bp insertion/deletion of DBH were associated with the average reaction time of response inhibition in female group (P = 0.01, P = 0.03), respectively. Furthermore, there was a significant interaction of the two genes on the reaction time (P = 0.006). This present study suggests that not only do COMT and DBH influence independently on response inhibition in females, but also exert a significant interaction on response inhibition. PMID- 21688127 TI - Relationship of pancreatic mass size and diagnostic yield of endoscopic ultrasound-guided fine needle aspiration. AB - BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is central to discerning the diagnosis of solid pancreatic tumors through tissue acquisition. Test performance is affected by a number of factors including location of mass within the pancreas, presence of onsite cytology technologist, and number of passes with the needle. The influence of tumor size has not been well studied. AIM: The objective of the current study was to determine whether the size of mass affects the diagnostic accuracy for solid pancreatic lesions aspirated under EUS guidance. METHODS: Data were collected retrospectively on all patients with solid pancreatic masses undergoing EUS-FNA from June 2003 to August 2010. The cytology samples were reported as positive, suspicious for malignancy, atypical, negative, or nondiagnostic. The gold standard for a cytological diagnosis was histological confirmation or clinical follow-up of more than 6 months with repeat imaging. Patients were divided into five groups based upon lesion size as follows: (a) less than 1 cm, (b) 1-2 cm, (c) 2-3 cm, (d) 3-4 cm, and (e) greater than 4 cm. Performance characteristics of EUS-FNA including sensitivity, specificity, and accuracy were compared for each group. Accuracy was defined as the ratio of the sum of true-positive and true-negative values divided by the number of lesions. RESULTS: We identified 583 patients with solid pancreatic lesions in which EUS-FNA was performed and adequate cellularity was obtained (47% men, mean age 65 +/- 1.4 (SE) years). Overall, 486 (83%) of lesions were pancreatic adenocarcinoma, 18 (3%) were neuroendocrine tumors, 12 (2%) were lymphomas, and 67 (12%) were benign lesions. The median size of the mass was 3 cm (range, 0.5-7 cm). A mean of 4.9 passes (range, 1-9 passes) was needed to obtain adequate samples from lesions. The overall yield of obtaining adequate samples for diagnosis was 85%. When stratified by size, the EUS-FNA sensitivity for lesions with size <1, 1-2, 2-3, 3-4, and >4 cm was 40, 75.9, 86.9, 93.2, and 91.6%, respectively; EUS-FNA sensitivity strongly correlate with tumor size (p < 0.001). Similarly, the accuracy of EUS-FNA increased as lesion size increased, ranging from 47% for tumors less than 1 cm to 88% for tumors greater than 4 cm (p < 0.05). Location of tumor and number of needle passes did not significantly influence EUS-FNA performance characteristics. CONCLUSIONS: The sensitivity and diagnostic accuracy of EUS-FNA for solid pancreatic lesions is strongly correlated with tumor size. Sensitivity and accuracy decrease significantly for tumors that are smaller than 1 cm. PMID- 21688128 TI - Magnetic resonance enterography: safe and effective imaging for stricturing Crohn's disease. AB - BACKGROUND: Symptomatic Crohn's disease (CD) patients often undergo diagnostic imaging studies for evaluation of disease activity or complications including bowel strictures and obstruction. Magnetic resonance enterography (MRE) provides information regarding disease activity, chronicity, and stricture formation without using ionizing radiation. AIM: Examine the use of MRE among CD patients presenting with symptoms suggesting obstruction in a tertiary care practice setting. METHODS: We performed a retrospective study of all CD patients undergoing MRE at a tertiary IBD referral center over a 3-year study period including a subgroup analysis of patients presenting obstructive symptoms. Positive and negative findings from MRE were correlated with medical and surgical decision outcomes over the subsequent 90-day period. RESULTS: In the study, 119 CD patients underwent 133 MRE scans, including 40 scans on individuals presenting with obstructive symptoms. Positive findings of CD including active inflammation, stricturing, and penetrating disease were more frequent in MREs ordered to evaluate obstructive symptoms (87.5%) compared other indications (58.1%, p = 0.001). In patients presenting with obstructive symptoms, MRE findings assisted in directing a change of clinical management towards escalation of medical therapy in 55% and surgery in 32.5%. Review of surgical resection specimens corroborated MRE findings of disease activity and fibrosis in 92% of cases going to surgery. CONCLUSIONS: In practice-based use at a tertiary IBD referral center, MRE provided an effective, radiation-free alternative to computed tomography by providing valuable diagnostic information for evaluating and directing care in Crohn's disease, particularly for patients presenting with obstructive symptoms. PMID- 21688129 TI - The impact of time elapsed between endoscopic ultrasound and esophagectomy on concordance of ultrasonographic and pathologic staging of esophageal malignancy. AB - BACKGROUND: Endoscopic ultrasound (EUS) is frequently used for staging of esophageal malignancies prior to esophagectomy. AIMS: The purpose of this study was to evaluate the effect of elapsed time between endoscopic ultrasound (EUS) staging and esophagectomy on the accuracy of EUS T- and N-staging. METHODS: This was a retrospective case series of 45 patients with esophageal malignancy who underwent staging EUS and subsequent esophagectomy at our center without neoadjuvant therapy between 2000 and 2009. The main outcome measurements were accuracy of EUS T- and N-staging when compared with surgical pathology. RESULTS: EUS staging was accurate in 55.6% of patients for tumor stage, and in 75.6% of patients for nodal stage. The median time between EUS and esophagectomy was 26 days (range 3-64). Among patients with surgery performed 3-15, 16-30, and 31-64 days after EUS, EUS tumor staging was accurate in 90.9, 47.4, and 40.0%, respectively (P = 0.02). EUS nodal staging among patients with surgery performed 3-15, 16-30, or 31-64 days after EUS was accurate in 63.6, 84.2, and 73.3% of cases, respectively (P = 0.44). Among the 20 patients for whom T-stage was discordant, 45% were understaged and 55% were overstaged by EUS. There were 11 patients in whom N-stage was discordant; 45.5% were understaged and 54.5% were overstaged. CONCLUSIONS: Pathologic T-staging is concordant with EUS T-staging when esophagectomy is performed within 15 days of endoscopic evaluation. Correlation between EUS and pathologic N-staging is unlikely to be affected by length of time between EUS and esophagectomy. PMID- 21688130 TI - Temporal trends in geographic disparities in small-area-level colorectal cancer incidence and mortality in the United States. AB - OBJECTIVE: We examined the extent of changes in absolute and relative geographic disparities in six colorectal cancer (CRC) indicators using data about persons aged 50 and older from 195 counties in the 1988-2006 Surveillance, Epidemiology, and End Results Program database. METHODS: County-level trends in six colorectal cancer indicators (overall CRC incidence, descending colon cancer incidence, proximal colon cancer incidence, late-stage CRC incidence, CRC mortality, and 5 year probability of CRC death) were summarized using the estimated annual percentage change. Observed county rates were smoothed using Bayesian hierarchical spatiotemporal methods to calculate measures of absolute and relative geographic disparity and their changes over time. RESULTS: During the study period, absolute disparity for all six indicators decreased (CRC incidence: 43.2%; proximal colon cancer: 31.9%; descending colon cancer: 52.8%; late-stage CRC: 50.0%; CRC mortality: 57.8%; 5-year CRC-specific probability of death: 12.2%). Relative disparity remained stable for all six indicators over the entire study period. CONCLUSION: Important progress has been made toward achieving the Healthy People 2010 and NCI strategic objectives for reducing geographic disparities, although absolute and relative disparities remain in CRC. PMID- 21688131 TI - Impaired glucose metabolism and diabetes and the risk of breast, endometrial, and ovarian cancer. AB - BACKGROUND: Epidemiological evidence indicates that individuals with type 2 diabetes are at an increased risk of cancer. Elevated glucose levels, below the diagnostic threshold for diabetes, have also been suggested to be associated with increased cancer risks. METHODS: We investigated possible associations between glucose levels and the risk of breast, endometrial, and ovarian cancer in a cohort of more than 230,000 women, for which information on outcome and potential confounders was obtained by record linkage to population-based registers. RESULTS: Diabetes was associated with an increased risk of postmenopausal breast cancer (HR = 1.22, 95% CI 1.04-1.43). An indication of a slightly elevated breast cancer risk was also found in postmenopausal women with impaired glucose metabolism (HR = 1.11, 95% CI 0.96-1.28). Diabetes (HR = 1.46, 95% CI 1.09-1.96) and impaired glucose metabolism (HR = 1.41, 95% CI 1.08-1.85) were associated with an increased risk of endometrial cancer. No associations were found between glucose levels and ovarian cancer risk. Following adjustment for BMI, estimates were attenuated for endometrial cancer, while point estimates for breast and ovarian cancer remained essentially unchanged. CONCLUSIONS: Our results indicate that glucose levels below the diagnostic threshold for diabetes modify the risk not only of endometrial cancer but possibly also of postmenopausal breast cancer. PMID- 21688132 TI - Preparing for a public sector mental health reform in New Mexico: the experience of agencies serving adults with serious mental illness. AB - In 2005, New Mexico began a comprehensive reform of state-funded mental health care. This paper reports on differences in characteristics, infrastructure, financial status, and services across mental health agencies. We administered a telephone survey to senior leadership to assess agency status prior to and during the first year of reform. Non-profit/public agencies were more likely than others to report reductions or no changes in administrative staff. CMHCs were more likely to report a decline in their financial situation. Findings demonstrated that CMHCs, non-profit/public agencies and rural agencies were more likely to offer critical services to adults with serious mental illness. PMID- 21688133 TI - Regional wall motion abnormality in apical ballooning syndrome (Takotsubo/stress cardiomyopathy): importance of biplane left ventriculography for differentiating from spontaneously aborted anterior myocardial infarction. AB - Understanding the precise distribution of the regional wall motion abnormality (RWMA) in apical ballooning syndrome (ABS) is important because the cardiomyopathy can mimic an acute anterior ST-elevation myocardial infarction (STEMI). The aim of the study was to quantify the severity and distribution of RWMA in ABS, compare it to anterior STEMI, and correlate with clinical features. RWMA (normal = 1, hypokinetic = 2, akinetic = 3) was quantified from the biplane left ventriculogram using a nine-segment model in 95 ABS and 17 anterior STEMI patients at the time of their presentation. Regional wall motion score index (RWMSI) was higher in ABS [2.1 (1.9, 2.1)] compared to anterior STEMI [2.0 (1.8, 2.0)], P = 0.024]. The region that most clearly differentiated ABS from anterior STEMI was the posterolateral segment (sensitivity 81% and specificity 100%) which was hypocontractile in 81% of ABS, but none of the STEMI patients (P < 0.001). RWMSI in ABS had a modest positive correlation with the troponin T levels (r = 0.23, P = 0.029). Patients with ABS with ST-segment elevation had the highest RWMSI [2.1(2.0, 2.2)], while those with non specific changes had the lowest [1.9 (1.8, 2.1)] (P = 0.007). In conclusion, patients with ABS have greater and more diffuse RWMA compared to anterior STEMI. The presence of systolic dysfunction in the posterolateral segment in the left anterior oblique projection of the left ventriculogram most accurately distinguishes ABS from an anterior STEMI highlighting the utility of biplane angiography for this purpose. The severity of RWMA correlates with the extent of troponin release and ECG abnormality. PMID- 21688134 TI - Beneficial effect of anti-platelet therapies on atherosclerotic lesion formation assessed by phase-contrast X-ray CT imaging. AB - We have applied an imaging system of phase-contrast X-ray CT to the detection of atherosclerotic plaque components by means of the differences of tissue mass densities. In this study, we investigated the effect of the anti-platelet therapies, widely used for secondly prevention of cardiovascular events, on plaque stability and examined whether this novel technique could detect the changes of plaque components under the therapy. Apolipoprotein E-deficient mice were fed on high-cholesterol diet alone and either with 0.1% cilostazol or clopidogrel for 10 weeks. We assessed atherosclerotic lesion volumes and components at brachiocephalic artery by the phase-contrast X-ray CT imaging and histochemistry. The phase-contrast X-ray CT imaging could reveal that cilostazol and clopidogrel significantly decreased atherosclerotic lesion volumes at brachiocephalic artery (31.2% reduction in cilostazol group and 37.4% reduction in clopidogrel group), compared with control group. In addition, the mass densities calculated by this method revealed the anti-platelet treatment increased stable plaque areas including high collagen content, but decreased unstable plaque areas including lipid and macrophage content. These findings were confirmed by histological analyses. Real-time PCR analyses indicated that anti platelets inhibited gene expressions of cytokines and adhesion molecules, such as IFNgamma and ICAM-1. Anti-platelet therapies had a beneficial effect on plaque stability maybe due to anti-inflammatory actions. Phase-contrast X-ray CT imaging could quantify the plaque volume and qualify the plaque components affected by anti-platelet therapies. This novel phase-contrast X-ray CT imaging system could be a plausible method to detect the unstable plaque non-invasively in the future. PMID- 21688135 TI - Baseline asynchrony, assessed circumferentially using temporal uniformity of strain, besides coincidence between site of latest mechanical activation and presumed left ventricular lead position, predicts favourable prognosis after resynchronization therapy. AB - Traditional indexes of LV dyssynchrony (DYS) in pts to be resynchronized are sensitive to noise, while the concordance between LV lead position and site of latest mechanical activation is suggested to be, in these patients, clinically relevant. Both aspects, asynchrony and lead position have been addressed separately but unclear is their potential synergistic role in the clinical evolution of CRT patients. We assessed clinical and echocardiographic outcome, as well as mid-term prognosis, in a population of CHF patients submitted to CRT, stratified according to a novel asynchrony quantitation (temporal uniformity of strain: TUS) method and concordance or not between presumed LV lead position and site of latest mechanical activation. TUS was computed in 85 pts (QRS > 120 ms, EF < 0.35) in whom we measured circumferential and longitudinal strains using speckle-tracking 2D-echocardiography before and 3-6 months after CRT, together with triplane apical LV volumes. Optimal LV lead position in short axis view was defined as concordance of the segment with latest systolic circumferential strain prior-CRT and segment with assumed LV lead position. Assumed LV lead position was defined from a chest X-ray obtained 1 day after implantation and scored as anterior, lateral, posterior or inferior using 2 orthogonal views (antero posterior and lateral). Following CRT, LV volume decreased (diastolic -8 +/- 20%) and EF improved (+6 +/- 9%, P < 0.001 for both). Two-way ANOVA revealed TUS improvement post-CRT (+22 +/- 68%, P = 0.025), with a clear evidence for more marked asynchrony detectable at circumferential (from 0.53 +/- 0.20 to 0.55 +/- 0.19) as compared with longitudinal level (from 0.56 +/- 0.14 to 0.62 +/- 0.14) (P = 0.017). Multivariate analysis revealed that greater baseline asynchrony, as assessed circumferentially (P = 0.079), together with concordance between LV lead position and site of activation (P = 0.012), besides younger age (P = 0.051), longer QRS duration (P = 0.021) and higher baseline EF (P = 0.04),), but not longitudinal TUS (P = 0.231) did predict death from any cause or new episodes of pulmonary or systemic congestion requiring i.v. diuretics during a 529 +/- 357 days clinical follow-up. We conclude that DYS indexed by circumferential TUS yields CRT benefits, supporting the idea of targeting TUS-measured DYS as the informative asynchrony quantitative measurement in CRT pts. Significant predictability in medium-term clinical follow-up of patients to be resynchronized is also associated with concordance between site of latest mechanical activation and presumed LV lead position in the present study. PMID- 21688136 TI - Accuracy of dual-source CT to identify significant coronary artery disease in patients with uncontrolled hypertension presenting with chest pain: comparison with coronary angiography. AB - It has been previously reported that the sensitivity and specificity of multislice CT for detecting significant CAD (coronary artery disease) is high. Chest pain is a common presentation in patients with uncontrolled hypertension. We investigated the sensitivity and specificity of dual-source CT to detect and rule out significant CAD in patients presenting with uncontrolled hypertension accompanied by chest pain. 260 consecutive patients presenting with acute chest pain in the context of stage 2 hypertension (systolic pressure >=160 and/or diastolic pressure >=100) were enrolled in the study. After admission, control of blood pressure and risk stratification, 82 patients were excluded due to renal insufficiency, prior coronary revascularisation or refused participation in the study. 90 further patients with low pre-test probability of CAD were also excluded. 88 remaining patients were subjected to CT coronary angiography using dual-source CT (Definition, Siemens Medical Solutions, Forchheim, Germany) within 24 h before invasive coronary angiography. A contrast-enhanced volume dataset was acquired (120 kV, 400 mAs/rot, collimation 2 * 64 * 0.6 mm, retrospective ECG gating). Data sets were evaluated concerning the presence or absence of significant coronary stenoses and validated against invasive coronary angiography. A significant stenosis was assumed if the diameter reduction was >=50%. 88 patients (mean age 66 +/- 11 years, mean heart rate 61 +/- 9 bpm) were evaluated regarding the presence or absence of significant CAD (at least one stenosis >=50% diameter reduction). Mean systolic blood pressure on presentation was 203 +/- 20 mmHg and mean diastolic blood pressure was 103 +/- 13 mmHg. On a per patient basis, the sensitivity and specificity for dual-source CT to detect significant CAD in vessels >1.5 mm diameter was 100% (36/36, 95% CI 90-100) and 90% (47/52, 95% CI 79-97), respectively with a negative predictive value (NPV) of 100% (47/47, 95% CI 92-100) and a positive predictive value (PPV) of 88% (36/41, 95% CI 74-96). On a per artery basis, 352 vessels were evaluated (left main, left anterior descending, left circumflex and right coronary artery in 88 patients, 12 vessels could not be assessed due to either motion artefacts or heavy calcification and were considered positive for stenoses) with a sensitivity of 84% (54/64, 95% CI 72-95) and specificity of 94% (272/288, 95% CI 88-100); NPV was 96% (272/282, 95% CI 90-100) and PPV was 77% (54/70, 95% CI 62-91). Our study demonstrates high sensitivity, specificity and negative predictive value of dual source CT to detect significant CAD in patients presenting with uncontrolled hypertension accompanied by chest pain. Dual-source CT angiography may be useful to safely rule out coronary artery stenoses and avoid invasive angiograms in these patients. PMID- 21688137 TI - Fiber components of the shoulder superior labrum. AB - PURPOSE: The purpose of this study was to investigate the anatomy of the superior glenoid labrum focusing on the fiber arrangement of its components. METHODS: Forty-nine embalmed shoulder girdles were removed and each posterior capsule was incised. After recording the macroscopic findings 12 superior-half glenoids were histologically examined. In nine serially sectioned glenoids, four were cut parallel to and five were cut vertical to the glenoid surface. The remaining three glenoids were radially sectioned at the clock position for each hour between 10:00 and 14:00. RESULTS: The superior labrum had a semi-circular fiber component along the outer margin of the glenoid. In addition, a so-called 'sheet like structure' which branched off the rotator interval and contained many elastic fibers, attached to its anterosuperior portion. The fibers of the sheet like structure mixes with fibers of the semi-circular component and ran posteriorward. The fibers of the long head of the biceps tendon extended posteriorward from its origin along the glenoid edge. These fibers communicated with other labrum fibers and became a major element of the posterior portion. CONCLUSION: The superior labrum is not homogenous. The posterior portion mainly consists of the robust fiber component of the long head of the biceps tendon. The anterosuperior portion includes fibers of the sheet-like structure which contains numerous elastic fibers. Tensile stress from the rotator interval might be conveyed to the anterosuperior labrum. PMID- 21688138 TI - Type 2 proatlantal intersegmental artery associated with persistent trigeminal artery diagnosed by MR angiography. AB - PURPOSE: The type 2 proatlantal intersegmental artery (PIA) is a rare anastomosis between the external carotid artery (ECA) and vertebral artery (VA) that passes through the foramen magnum. The persistent trigeminal artery (TA) is the most common anastomosis between the internal carotid artery (ICA) and basilar artery. The purpose of this paper is to present the first case of a type 2 PIA associated with an ipsilateral persistent TA diagnosed using magnetic resonance (MR) angiography, and we briefly discuss the embryology of this rare anomaly. METHODS: An 83-year-old man with cerebral infarctions underwent cerebral MR imaging, and head and neck MR angiography using a 1.5 T imager. MR angiography was obtained using the standard non-contrast three-dimensional time-of-flight technique. RESULTS: MR angiography showed aplasia of the proximal left VA and a large anastomotic artery between the left ECA and distal left VA that passed through the foramen magnum, indicative of a type 2 PIA. This patient also had an anastomosis between the precavernous segment of the left ICA and midbasilar artery via a lateral course, indicative of a lateral-type persistent TA. CONCLUSION: We present the first case of type 2 PIA associated with ipsilateral lateral-type persistent TA diagnosed by MR angiography. MR angiography should be performed including the carotid bifurcation to find more frequently extracranial arterial variations, including type 2 PIAs. PMID- 21688139 TI - Bladder agenesis and bilateral ectopic ureters draining into the vagina in a female infant: demonstrated by MR imaging. AB - Complete agenesis of the bladder and urethra is an extremely rare congenital anomaly and most of these patients are stillborn or die during infancy. We report the case of a 1-month-old female infant with bladder and urethral agenesis who presented with bilateral dilated and tortuous ectopic ureters draining into the vagina diagnosed using MR imaging. Our patient was maintained on antibiotic prophylaxis and she remained well during the 3-year follow-up. MR imaging can be used as a valuable modality for genitourinary abnormalities, particularly in cases of inconclusive ultrasound or retrograde pyelography findings. PMID- 21688140 TI - The effects of social rearing on preferences formed during filial imprinting and their neural correlates. AB - Filial imprinting was originally proposed to be an irreversible process by which a young animal forms a preference for an object experienced early in life. The present study examined the effects of experience after imprinting on the stability of preferences of domestic chicks (Gallus gallus domesticus) for an imprinting stimulus by rearing imprinted chicks socially or in isolation. Chicks reared socially or in isolation retained preferences for the imprinting stimulus; however, social rearing weakened the strength of preferences. The responses of neurons within the intermediate and medial mesopallium--a forebrain region necessary for imprinting were also recorded in socially reared and isolated chicks when presented with the visual component of the imprinting stimulus and novel object. Consistent with existing findings, neurons recorded from isolated chicks responded more strongly to the imprinting stimulus than novel object. However, social rearing diminished the disparity between responses to stimuli such that neurons recorded from socially reared chicks responded similarly to the imprinting stimulus and novel object. These findings suggest that social rearing may impair the retention of preferences formed during imprinting through mechanisms involving the IMM. PMID- 21688141 TI - Hard and fast rules about the body: contributions of the action stream to judging body space. AB - Analogously to the visual system, somatosensory processing may be segregated into two streams, with the body constituting either part of the action system or a perceptual object. Experimental studies with participants free from neurological disease which test this hypothesis are rare, however. The present study explored the contributions of the two putative streams to a task that requires participants to estimate the spatial properties of their own body. Two manipulations from the visuospatial literature were included. First, participants were required to point either backward towards pre-defined landmarks on their own body (egocentric reference frame) or to a forward projection of their own body (allocentric representation). Second, a manipulation of movement mode was included, requiring participants to perform pointing movements either immediately, or after a fixed delay, following instruction. Results show that accessing an allocentric representation of one's own body results in performance changes. Specifically, the spatial bias shown to exist for body space when pointing backward at one's own body disappears when participants are requested to mentally project their body to a pre-defined location in front space. Conversely, delayed execution of pointing movements does not result in performance changes. Altogether, these findings provide support for a constrained dual stream hypothesis of somatosensory processing and are the first to show similarities in the processing of body space and peripersonal space. PMID- 21688142 TI - The time course of breaking mental sets and forming novel associations in insight like problem solving: an ERP investigation. AB - In the present study, high-density event-related potentials were recorded to examine the electrophysiological correlates of logogriph problem solving in using a new experimental paradigm (learning-testing model) that was adopted in order to enable subjects to find a solution on their own initiative. For each trial, subjects were given a target logogriph followed by three types of base logogriphs: surface similarity logogriphs (SUSL, the base logogriph and target logogriph share some same words), structural similarity logogriphs (STSL, the base and target logogriphs do not have any words in common), and baseline logogriphs (BSL, the base and target logogriphs are all simple character generation tasks). The results demonstrated a more negative event-related potential deflection during STSL than during SUSL in both the 300-500 and 1,100 1,300 ms time windows, most likely reflecting the breaking of mental sets during insight-like problem solving. Moreover, SUSL and STSL demonstrated greater positivity than BSL in a time window between 900 and 1,700 ms, possibly reflecting processes such as forming novel associations. PMID- 21688143 TI - The effect of ageing on multisensory integration for the control of movement timing. AB - Previously, it has been shown that synchronising actions with periodic pacing stimuli are unaffected by ageing. However, synchronisation often requires combining evidence across multiple sources of timing information. We have previously shown the brain integrates multisensory cues to achieve a best estimate of the events in time and subsequently reduces variability in synchronised movements (Elliott et al. in Eur J Neurosci 31(10):1828-1835, 2010). Yet, it is unclear if sensory integration of temporal cues in older adults is degraded and whether this leads to reduced synchronisation performance. Here, we test for age-related changes when synchronising actions to multisensory temporal cues. We compared synchronisation performance between young (N = 15, aged 18-37 years) and older adults (N = 15, aged 63-80 years) using a finger-tapping task to auditory and tactile metronomes presented unimodally and bimodally. We added temporal jitter to the auditory metronome to determine whether participants would integrate auditory and tactile signals, with reduced weighting of the auditory metronome as its reliability decreased under bimodal conditions. We found that older adults matched the performance of young adults when synchronising to an isochronous auditory or tactile metronome. When the temporal regularity of the auditory metronome was reduced, older adults' performance was degraded to a greater extent than the young adults in both unimodal and bimodal conditions. However, proportionally both groups showed similar improvements in synchronisation performance in bimodal conditions compared with the equivalent, auditory-only conditions. We conclude that while older adults become more variable in synchronising to less regular beats, they do not show any deficit in the integration of multisensory temporal cues, suggesting that using multisensory information may help mitigate any deficits in coordinating actions to complex timing cues. PMID- 21688144 TI - Clinical outcome of rearthrodesis in cases of non-union following four-corner fusion. AB - PURPOSE: Four-corner fusion is a proven treatment option for degenerative arthritis of the wrist (SLAC/SNAC); however, in some cases, non-union occurs. The purpose of this study was to evaluate the clinical outcome of rearthrodesis in cases of non-union following four-corner fusion. Furthermore, the goal was to identify the cause of non-union and the location of pseudarthrosis within the fusion. METHODS: Seven patients (5 males, 2 females) who experienced pseudarthrosis following a four-corner fusion procedure and subsequently elected a rearthrodesis procedure were clinically and radiologically examined. The average age was 58 years (range 48-71 years). Average follow-up after rearthrodesis was 27 months (range 4-60 months). All patients experienced persistent wrist pain and non-union was diagnosed via radiography or CT scan. Range of motion, grip strength, the Modified Mayo Wrist score, and the DASH score were evaluated. The level of pain was determined by using a visual analogue scale. Patients were also asked whether they were satisfied with the procedure and if they would elect it again. RESULTS: In all patients, the rearthrodesis procedure led to proper bone consolidation, which was verified by radiological examination. Due to persistent wrist pain, one patient required additional procedures (denervation, wrist arthroscopy). In four cases, the location of pseudarthrosis occurred between the triquetrum and hamate. In three cases, the location of pseudoarthrosis was between the capitate and lunate and, additionally, between the triquetrum and hamate. The average DASH score value was 38 and the average Modified Mayo Wrist score was 66. Grip strength was reduced to 85 percent of the contralateral, unaffected side. Three patients indicated that they are dissatisfied with the results and would not elect the procedure again. CONCLUSIONS: The most frequent location of pseudarthrosis was between the triquetrum and the hamate, which was caused by incomplete cartilage debridement. Proper bone consolidation could be attained by means of rearthrodesis in cases of non-union following four-corner fusion. However, clinical results remain only moderate. PMID- 21688145 TI - Nacre-driven water-soluble factors promote wound healing of the deep burn porcine skin by recovering angiogenesis and fibroblast function. AB - To assess the recovery effect of water-soluble components of nacre on wound healing of burns, water-soluble nacre (WSN) was obtained from powdered nacre. Alterations to WSN-mediated wound healing characteristics were examined in porcine skin with deep second-degree burns; porcine skin was used as a proxy for human. When WSN was applied to a burned area, the burn-induced granulation sites were rapidly filled with collagen, and the damaged dermis and epidermis were restored to the appearance of normal skin. WSN enhanced wound healing recovery properties for burn-induced apoptotic and necrotic cellular damage and spurred angiogenesis. Additionally, WSN-treated murine fibroblast NIH3T3 cells showed increased proliferation and collagen synthesis. Collectively, the findings indicate that WSN improves the process of wound healing in burns by expeditiously restoring angiogenesis and fibroblast activity. WSN may be useful as a therapeutic agent, with superior biocompatibility to powdered nacre, and evoking less discomfort when applied to a wounded area. PMID- 21688147 TI - Characterization, expression profile, polymorphism and association of porcine NAT9 gene. AB - The N-acetyltransferase 9 (NAT9) is an important reproduction related gene. In this study, we cloned the full-length cDNA sequence of porcine NAT9 gene through the rapid amplification of cDNA ends method. The porcine NAT9 gene encodes a protein of 206 amino acids which shares high homology with the NAT9 of seven species: rhesus monkey (87%), chimpanzee (87%), human (87%), horse (86%), rat (80%), mouse (79%) and gray short-tailed opossum (79%). This gene is structured in six exons and five introns as revealed by computer-assisted analysis. Tissue transcription profile analysis indicated that the porcine NAT9 gene is generally but differentially expressed in the detected tissues including spleen, large intestine, lung, fat, muscle, heart, liver, kidney and ovary. PCR-Alu I-RFLP was established to detect an A/G mutation on the position of 699-bp of mRNA and eight pig breeds display obvious genotype and allele frequency differences at this mutation locus. Association of this SNP with litter size traits was assessed in Large White (n = 100) and Landrace (n = 100) pig populations, and results demonstrated that this polymorphic locus is significantly associated with the litter size of first parity (P < 0.05). This suggests that the NAT9 gene can be an useful candidate gene in selection for increasing litter size in pigs. PMID- 21688146 TI - The mouse B cell-specific mb-1 gene encodes an immunoreceptor tyrosine-based activation motif (ITAM) protein that may be evolutionarily conserved in diverse species by purifying selection. AB - The B-lymphocyte accessory molecule Ig-alpha (Ig-alpha) is encoded by the mouse B cell-specific gene (mb-1), and along with the Ig-beta (Ig-beta) molecule and a membrane bound immunoglobulin (mIg) makes up the B-cell receptor (BCR). Ig-alpha and Ig-beta form a heterodimer structure that upon antigen binding and receptor clustering primarily initiates and controls BCR intracellular signaling via a phosphorylation cascade, ultimately triggering an effector response. The signaling capacity of Ig-alpha is contained within its immunoreceptor tyrosine based activation motif (ITAM), which is also a key component for intracellular signaling initiation in other immune cell-specific receptors. Although numerous studies have been devoted to the mb-1 gene product, Ig-alpha, and its signaling mechanism, an evolutionary analysis of the mb-1 gene has been lacking until now. In this study, mb-1 coding sequences from 19 species were compared using Bayesian inference. Analysis revealed a gene phylogeny consistent with an expected species divergence pattern, clustering species from the primate order separate from lower mammals and other species. In addition, an overall comparison of non-synonymous and synonymous nucleotide mutational changes suggests that the mb-1 gene has undergone purifying selection throughout its evolution. PMID- 21688149 TI - The association between the PTPN22 C1858T polymorphism and systemic sclerosis: a meta-analysis. AB - The aim of this study was to determine whether the functional protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism (rs2476601) confers susceptibility to systemic sclerosis (SSc) in different ethnic populations. A meta-analysis was conducted on the PTPN22 C1858T polymorphism across twelve comparative studies containing 4,367 SSc patients and 4,771 normal control subjects. The analysis showed an association between the PTPN22 1858T allele and SSc in all study subjects (OR [odds ratio] 1.169, 95% confidence interval [CI] 1.051, 1.300, P = 0.004). Analysis after stratification by ethnicity indicated that the PTPN22 1858T allele was significantly associated with SSc in Europeans (OR 1.147, 95% CI 1.029, 1.278, P = 0.013), and analysis showed an association between the T allele and SSc in anti-centromere antibody (ACA)-positive European subjects (OR 1.220, 95% CI 1.051, 1.417, P = 0.009). However, no association was found between the allele and anti-topoisomerase antibody (ATA)-positive SSc European patients (OR 1.1786, 95% CI 0.979, 1.417, P = 0.083). In addition, African Americans were found to have a much lower prevalence of the T allele (1.5%) than any other population studied, and Europeans had the highest prevalence (8.2%). This meta-analysis confirms that the PTPN22 C1858T polymorphism is associated with SSc susceptibility and ACA status in Europeans, and that its prevalence is dependent on ethnicity. PMID- 21688148 TI - Polymorphic variants of genes involved in homocysteine metabolism in celiac disease. AB - Celiac disease (CD) is a polygenic chronic enteropathy conferring an increased risk for various nutrient deficiency states. Hyperhomocysteinemia is a frequent finding in CD and may be related to the development of venous thrombosis, cardiovascular disease, and stroke in untreated CD patients. Recently, a possible excess in the frequency of the MTHFR c.677C>T (rs1801133) gene variant in CD patients was reported. The purpose of this study was to determine if there exist differences in the distribution of polymorphic variants of genes involved in homocysteine/methyl group metabolism between CD patients and the general population. A set of 10 gene polymorphisms (MTHFR rs1801133, MTR rs1805087, MTHFD1 rs2236225, MTRR rs1801394, CBS 844ins68, BHMT1 rs7356530 and rs3733890, BHMT2 rs526264 and rs625879, and TCN2 rs1801198) was tested in 134 patients with CD and 160 matched healthy controls. The frequency of the MTR rs1805087 GG genotype in CD patients was lower than in controls (0.01 and 0.06, respectively), although statistical significance was not achieved (P = 0.06). For the other analyzed polymorphisms, there was no evidence of difference in both allelic and genotypic distribution between cases and controls. The exhaustive Multifactor Dimensionality Reduction analysis revealed no combination of interactive polymorphisms predicting the incidence of CD. In contrast to the well-documented clinical observations of increased risks of vascular disease in patients with longstanding untreated CD, in our group of patients no significant association with CD was found for all tested polymorphic variants of genes involved in homocysteine metabolism. These findings should be replicated in studies with a larger sample size. PMID- 21688150 TI - Study of planarian stem cell proliferation by means of flow cytometry. AB - The stem cells in freshwater flatworms (planarian) are called neoblasts. Neoblasts are capable of proliferation and differentiation into every cell type, including the gametes. For the investigation of the mechanisms of stem cells proliferation and differentiation the proper evaluation of changes in the cell cycle of neoblasts in different physiological conditions of planarian is necessary. In the present study the possibility of qualitative and quantitative characteristics of the neoblasts population were investigated using flow cytometry. In the cell suspension prepared from planarian tissue proliferating neoblasts have been observed in heterogenic cell population. Quantitative estimation of the cell cycle related changes of planarian stem cells system have been performed in various physiological conditions (intact and regenerating animals) and under the influence of physical (ionizing radiation) and chemical (melatonin and colchicine) factors. The modified protocol for planarian stem cells isolation proved to be effective and reproducible and can be recommended for flow cytometry analyses of human and animal proliferating cells. PMID- 21688151 TI - Inhibitor of DNA-binding-1/inhibitor of differentiation-1 (ID-1) is implicated in various aspects of gastric cancer cell biology. AB - In order to determine the biological roles of the inhibitor of DNA-binding 1/inhibitor of differentiation-1 (ID-1) protein in MGC803 and AGS cell lines, we ectopically expressed or downregulated ID-1 in the both gastric cell lines and measured various parameters of tumor cell development, including cell proliferation, cell cycle progression, apoptosis and cell migration. The ectopic expression of ID-1 significantly enhanced cell proliferation, cell cycle progression and cell migration, and protected MGC803 and AGS cell lines from cisplatin-induced apoptosis. The opposite effects were observed after downregulation of ID-1, which in combination with cisplatin treatment enhanced apoptosis in a synergistic fashion. Collectively, these findings demonstrate that ID-1 plays pivotal and diverse roles in the biology of certain gastric cancer cells, further suggesting that ID-1 is implicated in the pathogenesis and progression of gastric cancer. PMID- 21688152 TI - Influence of genomic variation in FTO at 16q12.2, MC4R at 18q22 and NRXN3 at 14q31 genes on breast cancer risk. AB - Breast cancer is a major cause of cancer-related deaths in women. It is known that obesity is one of the risk factors of breast cancer. The subject of our interest was genes: FTO, MC4R and NRXN3-associated with obesity. In this study we have analyzed frequencies of genomic variants in FTO, MC4R and NRXN3 in the group of 134 breast cancer patients. We genotyped two polymorphic sites located in FTO gene (rs993909 and rs9930506), one polymorphic site of MC4R gene (rs17782313) and one polymorphic site of NRXN3 gene (rs10146997). Our hypothesis was that above mentioned SNPs could participate in carcinogenesis. Our research has showed that only rs10146997 was significantly (P = 0.0445) associated with higher risk of breast cancer development (OR = 0.66 (95% CI 0.44-0.99)). Moreover, G allele carriers in rs10146997 of the NRXN3 gene were the youngest patients at onset of breast cancer. On the basis of our research we suggest that further functional may elucidate the role of genomic variation in breast cancer development. PMID- 21688153 TI - Association of EphA4 polymorphism with swine reproductive traits and mRNA expression of EphA4 during embryo implantation. AB - The swine erythropoietin-producing hepatocellular A4 (EphA4) gene, which was detected in the endometrium during embryo implantation in pigs, was one of the potential candidate genes for reproductive traits. In the study, two single nucleotide polymorphism (SNP) loci (EphA4_1 and EphA4_2) in exon 3 of EphA4 gene were analyzed to determine whether EphA4 influenced total number born (TNB) and number born alive (NBA). Association of two diallelic polymorphisms with reproductive traits was assessed in Landrace, Yorkshire and Duroc populations with 2,014 litter records of 765 sows. The results showed that G allele at EphA4_1 locus or C allele at EphA4_2 locus seemed to have advantageous effects on litter size. And the combined analyzed results demonstrated that genotype AGTC, AGCC and GGCC are better than genotype AATT, AATC and AGTT for TNB and NBA in either single parity or all parities. The results in this study demonstrated that EphA4 gene was significantly associated with litter size in pigs. In addition, a high mRNA expression of EphA4 was found in small intestine, large intestine, stomach and endometrium, and the expression decreased during implantation in pigs. Further studies were needed to confirm these preliminary researches. PMID- 21688154 TI - Eicosadienoic acid differentially modulates production of pro-inflammatory modulators in murine macrophages. AB - Eicosadienoic acid (Delta11,14-20:2; EDA) is a rare, naturally occurring n-6 polyunsaturated fatty acid (PUFA) found mainly in animal tissues. EDA is elongated from linoleic acid (LA), and can also be metabolized to dihomo-gamma linolenic acid (DGLA), arachidonic acid (AA), and sciadonic acid (Delta5,11,14 20:3; SCA). Although, the metabolism of EDA has been extensively studied, there are few reports regarding how EDA might affect inflammatory processes. The objective of this study was to determine the effect of EDA on the n-6 PUFA composition and inflammatory response of murine RAW264.7 macrophages to lipopolysaccharide (LPS). EDA was taken up rapidly by macrophages and metabolized to SCA, and the percentages of both fatty acids increased in cellular phospholipids in a dose-dependent manner. The incorporation of EDA into macrophage lipids increased the proportions of LA, DGLA, and AA as well, and reduced the proportion of total monounsaturated fatty acids. When LPS were applied to the macrophages, EDA decreased the production of nitric oxide (NO), and increased that of prostaglandin E(2) (PGE(2)) and tumor necrotic factor alpha. The modulation of NO and PGE(2) was due, in part, to the modified expression of inducible nitric oxide synthase and type II cyclooxygenase. The differential effects of EDA on pro-inflammatory mediators might attribute to the negative feedback mechanism associated with prolonged inflammation. Furthermore, EDA was a weaker pro-inflammatory agent than LA, and not as anti-inflammatory as SCA. This study shows that EDA can modulate the metabolism of PUFA and alter the responsiveness of macrophages to inflammatory stimulation. PMID- 21688155 TI - IKKbeta downregulation is critical for triggering JNKs-dependent cell apoptotic response in the human hepatoma cells under arsenite exposure. AB - Arsenite has a long history in treating leukemia, which might be also effective in the therapy of other cancers. Our previous published data have demonstrated that arsenite exposure induces apoptosis in the HepG2 human hepatoma cells via activating JNKs/AP-1 pathway, but the upstream signaling events responsible for JNKs (c-Jun N-terminal kinase) cascade activation have not been fully discovered. Since cross-talk between IKK/NF-kappaB and JNKs pathways under stress conditions is a hot topic, in this article, we investigate the potential roles of IKKalpha and IKKbeta, the catalytic subunits of IKK complexes, in the arsenite-induced JNKs pathway activation in the HepG2 cells. We found that arsenite exposure induced JNKs and AP-1 activation accompanying with a significant reduction of both IKKalpha and IKKbeta expressions. Overexpression of IKKbeta, but not of IKKalpha, inhibited arsenite-induced MKK7/JNKs/AP-1 pathway activation as well as the apoptotic response. Therefore, we conclude that the downregulation of IKKbeta expression is the prerequisite signaling event for mediating JNKs pathway activation and the cellular apoptotic response in the HepG2 cells under arsenite exposure. Targeting IKKbeta might be helpful to enhance the tumor therapeutic effect of arsenite. PMID- 21688156 TI - Global effect on multi-segment physiological tremors due to localized fatiguing contraction. AB - Physiological tremors within a limb are coupled, whereas between-limb tremors are thought to oscillate independently for a healthy subject. This study was undertaken to reinvestigate bilateral tremor relations and intra-limb tremor dynamics for a two-limb task after exhausting a single joint. Fifteen volunteers conducted prolonged tracking with the left (target) shoulder. Neuromuscular functions were monitored before and after the exercise-fatiguing intervention, including tracking displacement, muscle activity of the deltoid, and physiological tremors in the bilateral upper limbs. Localized fatiguing contraction degraded tracking accuracy and movement smoothness, accompanied by an increase in deltoid activation. Segment tremors in the bilateral limbs and inter limb tremor coherences in 8-12 Hz increased, though coherence peaks in 5-8 Hz waned with fatigue response. Intra-limb tremor relations in the target and non target limbs were also reorganized with unilateral fatiguing contraction. Tremor coupling in the arm-C7 complexes was enhanced, associated with tremor uncoupling in the forearm-arm and hand-forearm complexes. Tracking error in the pre- fatigue and post-fatigue conditions was predicted by different principal components that had high communalities with tremors of distal and proximal segments of the target limb, respectively. The adaptive changes in tremor dynamics were attributable to fatigue-induced enhancement of common central drive and decline in neural inputs of long-looped reflexes that diverge to contralateral segments. PMID- 21688157 TI - Electrostatically-driven fast association and perdeuteration allow detection of transferred cross-relaxation for G protein-coupled receptor ligands with equilibrium dissociation constants in the high-to-low nanomolar range. AB - The mechanism of signal transduction mediated by G protein-coupled receptors is a subject of intense research in pharmacological and structural biology. Ligand association to the receptor constitutes a critical event in the activation process. Solution-state NMR can be amenable to high-resolution structure determination of agonist molecules in their receptor-bound state by detecting dipolar interactions in a transferred mode, even with equilibrium dissociation constants below the micromolar range. This is possible in the case of an inherent ultra-fast diffusive association of charged ligands onto a highly charged extracellular surface, and by slowing down the (1)H-(1)H cross-relaxation by perdeuterating the receptor. Here, we demonstrate this for two fatty acid molecules in interaction with the leukotriene BLT2 receptor, for which both ligands display a submicromolar affinity. PMID- 21688158 TI - Stigma and discrimination toward mental illness: translation and validation of the Italian version of the Attribution Questionnaire-27 (AQ-27-I). AB - PURPOSE: The aim of this study was to translate the Attribution Questionnaire-27 (AQ-27) to the Italian language (AQ-27-I), and to examine the reliability and validity of this new Italian version. METHODS: The questionnaire was translated using the standard translation/back-translation method. Cronbach's alpha and intraclass coefficients were used to estimate instrument reliability. Confirmatory factor analysis was conducted to corroborate the original English version factor structure in the new measure, and to establish validity. Path analyses were meant to validate relationships found in the English version among Italian-speaking participants. RESULTS: The AQ-27-I demonstrated acceptable internal consistency, with a Cronbach's alpha of 0.82 for the total scale and ranging between 0.52 and 0.91 for the subscales. The test-retest reliability was also satisfactory, with intraclass correlation coefficients of 0.72 for the total scale and ranging between 0.51 and 0.89 for the subscales. Fit indices of the model supported the factor structure and paths. CONCLUSIONS: The AQ-27-I is a reliable measure to assess stigmatizing attitudes in Italian. PMID- 21688159 TI - Single dietary amino acids control resting egg production and affect population growth of a key freshwater herbivore. AB - The enormous success of the genus Daphnia in freshwater ecosystems is at least partially due to their cyclical parthenogenetic life cycle, in which asexual and sexual reproduction alternate periodically. This temporal change between reproductive strategies allows for (1) rapid population growth via subitaneously developing eggs when environmental conditions are appropriate and (2) the maintenance of genetic diversity via sexual reproduction and the production of resting eggs when environmental conditions deteriorate. We show here that dietary amino acids are involved in triggering the switch between reproductive modes in Daphnia pulex. Supplementation experiments demonstrate that specific dietary amino acids, in particular arginine and histidine, avert crowding-induced resting egg production, enhance subitaneous reproduction by increasing algal food quality and, as a combined effect of both processes, increase population growth rates. These findings suggest that the availability of single dietary amino acids potentially affects the seasonal dynamics and long-term persistence of Daphnia populations in the field, which may have consequences for the efficiency of carbon transfer and thus the trophic structure of freshwater food webs. PMID- 21688160 TI - Species replacement by a nonnative salmonid alters ecosystem function by reducing prey subsidies that support riparian spiders. AB - Replacement of a native species by a nonnative can have strong effects on ecosystem function, such as altering nutrient cycling or disturbance frequency. Replacements may cause shifts in ecosystem function because nonnatives establish at different biomass, or because they differ from native species in traits like foraging behavior. However, no studies have compared effects of wholesale replacement of a native by a nonnative species on subsidies that support consumers in adjacent habitats, nor quantified the magnitude of these effects. We examined whether streams invaded by nonnative brook trout (Salvelinus fontinalis) in two regions of the Rocky Mountains, USA, produced fewer emerging adult aquatic insects compared to paired streams with native cutthroat trout (Oncorhynchus clarkii), and whether riparian spiders that depend on these prey were less abundant along streams with lower total insect emergence. As predicted, emergence density was 36% lower from streams with the nonnative fish. Biomass of brook trout was higher than the cutthroat trout they replaced, but even after accounting for this difference, emergence was 24% lower from brook trout streams. More riparian spiders were counted along streams with greater total emergence across the water surface. Based on these results, we predicted that brook trout replacement would result in 6-20% fewer spiders in the two regions. When brook trout replace cutthroat trout, they reduce cross-habitat resource subsidies and alter ecosystem function in stream-riparian food webs, not only owing to increased biomass but also because traits apparently differ from native cutthroat trout. PMID- 21688161 TI - Audio recordings of mindfulness-based stress reduction training to improve cancer patients' mood and quality of life--a pilot feasibility study. AB - PURPOSE: Mindfulness-based stress reduction (MBSR), typically taught in eight weekly classes, helps patients cope with illness, including cancer. Current research is almost exclusively based on post-treatment class attendance. Research suggests that short courses and alternative delivery techniques may also be beneficial. This pilot study assessed whether it would be feasible for cancer patients receiving chemotherapy to listen to MBSR audio recordings individually during treatment and at home and evaluate whether the intervention shows preliminary evidence of efficacy to improve patients' mood and quality of life (QoL). METHODS: Patients were recruited from two oncology clinics. Inclusion criteria included a score >= 8 on the Hospital Anxiety and Depression Scale (HADS). Participants were asked to listen to study CDs containing MBSR instructions at least 5 days/week for 3 months and to maintain study diaries of their meditation practices. RESULTS: Twenty-three patients enrolled in the study, and 20 (87%; 95% confidence interval (CI), 66% to 97%) completed the study protocol. Analysis showed that participants listened to study CDs an average of 39 times during the study; mean HADS scores declined from 18.3 to 12.2 (change = 6.1 points; 95% CI, -2.9 to -9.4). Participants reported subjectively that participation improved their mood and QoL. CONCLUSIONS: This pilot study demonstrates the feasibility of investigating an individual audio MBSR intervention for patients with cancer and provides preliminary evidence that MBSR may benefit chemotherapy patients' mood and QoL. Fully powered comparative clinical trials to asses this MBSR modality to help improve mood and QoL for patients receiving chemotherapy are feasible and needed. PMID- 21688162 TI - Gastrointestinal symptoms, electrogastrography, inflammatory markers, and PG-SGA in patients with advanced cancer. AB - OBJECTIVES: Electrogastrography (EGG) is a technique used to record gastric myoelectrical activity (GMA). Our aim is to investigate the (1) prevalent patterns of GMA, (2) most frequent gastrointestinal (GI) symptoms reported on the Dyspepsia Symptom Severity Index (DSSI), and (3) EGG diagnosis and correlations with GI symptoms, ghrelin, and inflammatory markers. METHODS: An EGG was performed 10 min preprandial and 30 min postprandial after ingestion of 500 ml water. EGG measurements were recorded by electrodes positioned externally on the abdominal wall. C-reactive protein (CRP), ghrelin, and albumin were included at baseline. RESULT: There were 53 patients enrolled, with a median age of 60 years (range, 18-82 years) and EGG diagnoses of mixed dysrhythmia (n = 25), tachygastria (n = 15), bradygastria (n = 6), gastric outlet obstruction (n = 1), and normal (n = 6). Forty-seven patients with an abnormal EGG had high median CRP, low median albumin, and high median ghrelin levels when compared to 6 patients with a normal EGG, with CRP [12 (8-22) vs. 6 (5-8)]; albumin [35 (26-40) vs. 38.5 (34-42)]; ghrelin [4 (2-10) vs. 2.5 (2-9)]. According to the DSSI, the most frequent dysmotility-like symptoms were (1) frequent burping and belching [73.6%], (2) bloating [60.4%], (3) feeling full after meals [69.8%], (4) inability to finish normal-sized meal [66%], (5) abdominal distention [51%], and (6) nausea after meals [50.9%]. The most frequent reflux- and ulcer-like symptoms were (1) regurgitation of bitter fluid [43.4%] and abdominal pain before meals [39.6%]. The most frequent nutrition impact symptoms as recorded on the Patient Generated Subjective Global Assessment in patients with an abnormal EGG diagnosis were no appetite or did not feel like eating, nausea, vomiting, and feeling full quickly. CONCLUSIONS: Abnormal EGG diagnosis, ghrelin, albumin, and CRP levels are found in the majority of patients with advanced cancer. Further studies are needed to better understand the correlation of these abnormal serum levels and their interaction with the pathogenesis of abnormal electrogastrographic rhythms. PMID- 21688163 TI - Effect of medical Qigong on cognitive function, quality of life, and a biomarker of inflammation in cancer patients: a randomized controlled trial. AB - PURPOSE: Cancer patients often experience diminished cognitive function (CF) and quality of life (QOL) due to the side effects of treatment and the disease symptoms. This study evaluates the effects of medical Qigong (MQ; combination of gentle exercise and meditation) on CF, QOL, and inflammation in cancer patients. METHODS: Eighty-one cancer patients recruited between October 2007 and May 2008 were randomly assigned to two groups: a control group (n = 44) who received the usual health care and an intervention group (n = 37) who participated in a 10 week MQ program. Self-reported CF was measured by the European Organization for Research and Treatment of Cancer (EORTC-CF) and the Functional Assessment of Cancer Therapy-Cognitive (FACT-Cog). The Functional Assessment of Cancer Therapy General (FACT-G) was used to measure QOL. C-reactive protein (CRP) was assessed as a biomarker of inflammation. RESULTS: The MQ group self-reported significantly improved CF (mean difference (MD) = 7.78, t (51) = -2.532, p = 0.014) in the EORTC-CF and all the FACT-Cog subscales [perceived cognitive impairment (MD = 4.70, t (43) = -2.254, p = 0.029), impact of perceived cognitive impairment on QOL (MD = 1.64, t (45) = -2.377, p = 0.024), and perceived cognitive abilities (MD = 3.61, t (45) = -2.229, p = 0.031)] compared to controls. The MQ group also reported significantly improved QOL (MD = 12.66, t (45) = -5.715, p < 0.001) and had reduced CRP levels (MD = -0.72, t (45) = 2.092, p = 0.042) compared to controls. CONCLUSIONS: Results suggest that MQ benefits cancer patients' self reported CF, QOL, and inflammation. A larger randomized controlled trial including an objective assessment of CF is planned. PMID- 21688164 TI - Awareness of dying: it needs words. AB - PURPOSE: The purpose of this research is to study to what extent dying patients are aware of the imminence of death, whether such awareness is associated with patient characteristics, symptoms and acceptance of dying, and whether medical records and nurses' and family caregivers' views on patients' awareness of dying agree. METHODS: Nurses and family caregivers of 475 deceased patients from three different care settings in the southwest Netherlands were requested to fill out questionnaires. The two groups were asked whether a patient had been aware of the imminence of death. Also, medical records were screened for statements indicating that the patient had been informed of the imminence of death. RESULTS: Nurses completed questionnaires about 472 patients, family caregivers about 280 patients (response 59%). According to the medical records, 51% of patients had been aware of the imminence of death; according to nurses, 58%; according to family caregivers, 62%. Patients who, according to their family caregiver, had been aware of the imminence of death were significantly more often in peace with dying and felt more often that life had been worth living. Inter-rater agreement on patients' awareness of dying was fair (Cohen's kappa = 0.23-0.31). CONCLUSIONS: Being aware of dying is associated with acceptance of dying, which supports the idea that open communication in the dying phase can contribute to the quality of the dying process. However, views on whether or not patients are aware of the imminence of death diverge between different caregivers. This suggests that communication in the dying phase of patients is open for improvement. PMID- 21688165 TI - Symptom improvement as prognostic factor for survival in cancer patients undergoing palliative care: a pilot study. AB - BACKGROUND: The Edmonton Symptom Assessment Scale (ESAS) is a validated tool for physical symptom assessment in palliative care practice which evaluates symptoms through a numeric scale from 0 to 10. The use of symptom improvement as a prognostic factor is controversial. To this purpose, a pilot study in advanced cancer patients now undergoing only palliative care was conducted. METHODS: Patients were considered eligible if no longer able to receive any anticancer treatment; they were scheduled to undergo ESAS assessment at the hospitalization and hospital discharge time points. Symptoms' scores were divided into three severity classes: mild, moderate and severe. Differences across symptoms' classes between hospitalization and hospital discharge time points were analysed with the paired-data McNemar test, according to tumour types. RESULTS: ESAS assessment was administered to 68 patients with gastrointestinal (39 patients) and non-small cell lung cancer (29 patients); median age was 69 years; Karnofsky Performance Status was 50 in 27 (39.7%) patients and >50 in 41 (60.3%) patients. Palliative Prognostic Score was A for 26 (38.2%) patients, B for 37 (54.4%) patients and C for 5 (7.4%) patients. A statistically significant reduction of severe severity class rates was observed. Symptom improvement correlates with survival improvement: Palliative Prognostic Score (hazard ratio (HR) 2.95, 95% CI 1.35 6.41, p = 0.006) and anorexia (HR 3.21, 95% 1.33-7.72, p = 0.009) appear to be prognostic factors for survival at the multivariate analysis for gastrointestinal cancer patients; asthenia is the only significant variable (HR 5.11, 95% CI 1.86 14.03, p = 0.002) for non-small cell lung cancer patients. CONCLUSIONS: Symptom improvement according to ESAS after palliative care treatment represents an important prognostic for survival in patients no longer suitable to receive any anticancer active therapies. PMID- 21688166 TI - Bt rice expressing Cry1Ab does not stimulate an outbreak of its non-target herbivore, Nilaparvata lugens. AB - In this study, the non-target effects of Bt rice "KMD2" expressing a Cry1Ab protein on the performance of the brown planthopper (BPH), Nilaparvata lugens, over multiple generations were evaluated under laboratory and field conditions. In the laboratory, BPH was reared to observe the impact of the Bt rice as compared to its parental non-Bt cultivar Xiushui 11, while the population dynamics and oviposition performance of BPH were investigated in the field. The survival of BPH nymphs fed Bt and non-Bt rice did not differ significantly. The nymph developmental duration of BPH was significantly delayed by the Bt rice by comparison with the non-Bt rice for the 1st and 2nd but not the 4th generation. Most importantly, the fecundity of BPH on the Bt rice was significantly decreased in every generation when compared with the non-Bt rice. In the field investigations, the population density of BPH nymphs was significantly lower in the Bt rice field. However, the temporal pattern of population dynamics of BPH adults was similar between the Bt and non-Bt rice, presumably due to migratory interference of the adults. In the Bt rice field, the percentage of tillers with eggs and the number of eggs per tiller were also significantly lower from tillering to mature stage. Additionally, Cry1Ab protein could not be detected in guts from single BPH adults. In general, our results suggest that the Bt rice "KMD2" could not stimulate an outbreak of BPH. PMID- 21688167 TI - Neuraminidase inhibitor susceptibility of swine influenza A viruses isolated in Germany between 1981 and 2008. AB - European swine influenza A viruses donated the matrix protein 2 as well as the neuraminidase (NA) gene to pandemic influenza A (H1N1) viruses that emerged in 2009. As a result, the latter became amantadine resistant and neuraminidase inhibitor (NAI) susceptible. These recent developments reflecting the close connection between influenza A virus infection chains in humans and pigs urge an antiviral surveillance within swine influenza A viruses. Here, NAI susceptibility of 204 serologically typed swine influenza A viruses of subtypes H1N1, H1N2, and H3N2 circulating in Germany between 1981 and 2008 was analyzed in chemiluminescence-based NA inhibition assays. Mean 50% inhibitory concentrations of oseltamivir and zanamivir indicate a good drug susceptibility of tested viruses. As found for human isolates, the oseltamivir and zanamivir susceptibility was subtype-specific. So, swine influenza A (H1N1) viruses were just as susceptible to oseltamivir as to zanamivir. In contrast, swine H1N2 and H3N2 influenza A viruses were more sensitive to oseltamivir than to zanamivir. Furthermore, reduction in plaque size and virus spread by both drugs was tested with selected H1N1 and H1N2 isolates in MDCK cells expressing similar amounts of alpha2.3- and alpha2.6-linked sialic acid receptors. Data obtained in cell culture-based assays for H1N1 isolates correlated with that from enzyme inhibition assays. But, H1N2 isolates that are additionally glycosylated at Asn158 and Asn163 near the receptor-binding site of hemagglutinin (HA) were resistant to both NAI in MDCK cells. Possibly, these additional HA glycosylations cause a misbalance between HA and NA function that hampers or abolishes NAI activity in cells. PMID- 21688168 TI - An alternative to treat palmar hyperhidrosis: use of oxybutynin. AB - PURPOSE: To evaluate the effectiveness and patient satisfaction with the use of oxybutynin at low doses for treating palmar hyperhidrosis in a large series of patients. METHODS: From January 2007 to June 2009, 180 consecutive patients with palmar hyperhidrosis were treated with oxybutynin. Data were collected from 139 patients (41 patients were lost to follow-up). During the first week, patients received 2.5 mg of oxybutynin once per day; from the 8th to the 42nd day, 2.5 mg twice per day; and from the 43rd day to the end of the 12th week, 5 mg, twice per day. All of the patients underwent three evaluations before and after the oxybutynin treatment (at 6 and 12 weeks), using a clinical questionnaire and a clinical protocol for quality of life (QOL). RESULTS: More than 80% of the patients experienced an improvement in palmar hyperhidrosis. Most of the patients showed improvements in their QOL (74.6%). The side effects were minor, with dry mouth being the most frequent (70.5%). CONCLUSION: The use of oxybutynin is an alternative as the first step in the treatment of palmar hyperhidrosis, given that it presents good results and improves QOL. PMID- 21688169 TI - Co-involvement of psychological and neurological abnormalities in infertility with polycystic ovarian syndrome. AB - OBJECTIVE: To investigate psychological distress, serum levels of monoamine neurotransmitters and their metabolites, as well as their correlation with polycystic ovarian syndrome (PCOS). METHODS: Thirty infertility patients with PCOS were assigned as the experimental group and 30 infertility patients without PCOS were assigned as the control group. Psychological distress was self evaluated in all patients with Symptom Checklist 90 (SCL-90). Serum concentrations of norepinephrine (NE) and its metabolite 3-methoxy-4 hydroxyphenylglycol (MHPG), 5-hydroxytryptamine (5-HT) and its metabolite 5 hydroxyindoleacetic acid (5-HIAA), dopamine (DA) and its metabolites homovanillic acid (HVA) and dihydroxy-phenyl acetic acid (DOPAC) were measured by high performance liquid chromatography. RESULTS: The anxious and depressive subscales of SCL-90 were significantly higher in infertility patients with PCOS than those without PCOS (p < 0.05). The serum concentrations of 5-HT, 5-HIAA and HVA were significantly lower in infertility patients with PCOS than those without PCOS (p < 0.05). Importantly, the phobia subscale scores of SCL-90 positively correlated with serum MHPG level (p < 0.05), while the hostility subscale's scores negatively correlated with serum DOPAC level (p < 0.05). CONCLUSION: Psychological and neurological factors play a crucial role in PCOS. PMID- 21688170 TI - The synthetic strigolactone GR24 influences the growth pattern of phytopathogenic fungi. AB - Strigolactones that are released by plant roots to the rhizosphere are involved in both plant symbiosis with arbuscular mycorrhizal fungi and in plant infection by root parasitic plants. In this paper, we describe the response of various phytopathogenic fungi to the synthetic strigolactone GR24. When GR24 was embedded in the growth medium, it inhibited the growth of the root pathogens Fusarium oxysporum f. sp. melonis, Fusarium solani f. sp. mango, Sclerotinia sclerotiorum and Macrophomina phaseolina, and of the foliar pathogens Alternaria alternata, Colletotrichum acutatum and Botrytis cinerea. In the presence of this synthetic strigolactone, intense branching activity was exhibited by S. sclerotiorum, C. acutatum and F. oxysporum f. sp. melonis. Slightly increased hyphal branching was observed for A. alternata, F. solani f. sp. mango and B. cinerea, whereas suppression of hyphal branching by GR24 was observed in M. phaseolina. These results suggest that strigolactones not only affect mycorrhizal fungi and parasitic plants, but they also have a more general effect on phytopathogenic fungi. PMID- 21688171 TI - Determinants of pharmacodynamic trajectory of the therapeutic response to paroxetine in Japanese patients with panic disorder. AB - PURPOSE: The objective of this study was to evaluate genetic and pharmacokinetic factors to establish the pharmacotherapeutic effect of paroxetine (PAX) in patients with panic disorder (PD). METHOD: Subjects were 65 drug-naive patients who fulfilled the DSM-IV-TR criteria for PD diagnosis. All subjects were administered PAX (10 mg/day) for 4 weeks, and PD severity was assessed using the Panic and Agoraphobia Scale (PAS) at baseline and at 2 and 4 weeks after initiation of treatment. Plasma PAX concentration was determined by high performance liquid chromatography. Serotonin transporter gene-linked polymorphic region (5-HTTLPR) variants and the -1019C/G promoter polymorphism of the serotonin 1A receptor (5-HT(1A)) gene were determined by PCR analysis. RESULTS: Multiple regression analysis revealed that the plasma concentrations of PAX, 5 HTTLPR genotype, and -1019C/G 5-HT(1A) gene polymorphism were significant factors affecting clinical response to PAX (reduction ratio of PAS score) at 2 weeks after the initiation of pharmacotherapy. The -1019C/G 5-HT(1A) gene promoter polymorphism, PAS score at baseline, and adverse effects were found to be the significant factors affecting clinical response to PAX at 4 weeks after initiation of pharmacotherapy. CONCLUSION: The present study revealed that plasma concentration of PAX, 5-HTTLPR genotype, -1019C/G 5-HT(1A) genotype, PAS score at baseline, and adverse effects may influence the therapeutic response to PAX in patients with PD. PMID- 21688172 TI - Detection of dichloromethane with a bioluminescent (lux) bacterial bioreporter. AB - The focus of this research effort was to develop an autonomous, inducible, lux based bioluminescent bioreporter for the real-time detection of dichloromethane. Dichloromethane (DCM), also known as methylene chloride, is a volatile organic compound and one of the most commonly used halogenated solvents in the U.S., with applications ranging from grease and paint stripping to aerosol propellants and pharmaceutical tablet coatings. Predictably, it is released into the environment where it contaminates air and water resources. Due to its classification as a probable human carcinogen, hepatic toxin, and central nervous system effector, DCM must be carefully monitored and controlled. Methods for DCM detection usually rely on analytical techniques such as solid-phase microextraction (SPME) and capillary gas chromatography or photoacoustic environmental monitors, all of which require trained personnel and/or expensive equipment. To complement conventional monitoring practices, we have created a bioreporter for the self directed detection of DCM by taking advantage of the evolutionary adaptation of bacteria to recognize and metabolize chemical agents. This bioreporter, Methylobacterium extorquens DCM( lux ), was engineered to contain a bioluminescent luxCDABE gene cassette derived from Photorhabdus luminescens fused downstream to the dcm dehalogenase operon, which causes the organism to generate visible light when exposed to DCM. We have demonstrated detection limits down to 1.0 ppm under vapor phase exposures and 0.1 ppm under liquid phase exposures with response times of 2.3 and 1.3 h, respectively, and with specificity towards DCM under relevant industrial environmental monitoring conditions. PMID- 21688173 TI - Sex-specific effect of the TP53 PIN3 polymorphism on cancer risk in a cohort study of TP53 germline mutation carriers. AB - Germline mutations in the tumor suppressor gene TP53 occur in the majority of families with Li-Fraumeni syndrome, who are at an increased risk for a wide spectrum of early onset cancers. Several genetic polymorphisms in TP53 modify its effect on cancer risk. While some studies indicate that the TP53 PIN3 deletion allele (D) accelerate tumor onset in carriers with TP53 germline mutations, other studies have shown that the TP53 PIN3 insertion allele (I) confers a significantly higher risk of developing cancer than D allele. To further determine the effects of the TP53 PIN3 polymorphism on cancer development among TP53 germline mutations and to evaluate if those are differenence between male and female carriers, we studied a total of 152 germline mutation carriers with available DNA samples that can be used for genotyping. Our results indicate that the TP53 PIN3 polymorphism has a sex-specific effect on the risk of cancer in TP53 mutation carriers, conferring cancer risk in men (P = 0.0041) but not women with DI or II genotypes. PMID- 21688174 TI - The allometry of parrot BMR: seasonal data for the Greater Vasa Parrot, Coracopsis vasa, from Madagascar. AB - In this study we examined the allometry of basal metabolic rate (BMR) of 31 parrot species. Unlike previous reports, we show that parrots per se do not display BMRs that are any different to other captive-raised birds of their body size. An ordinary least squares regression fitted the data best and body mass explained 95% of the variation in BMR. There was no phylogenetic signal in the BMR data. We also provide new data for the Greater Vasa Parrot (Coracopsis vasa) of Madagascar. We tested the hypotheses that C. vasa may, because of its insular existence, display conservative energetic traits (low BMR, use of adaptive heterothermy) similar to those observed in several Malagasy mammals. However, this was not the case. C. vasa had a higher BMR than other parrots, especially during summer, when BMR was up-regulated by 50.5% and was 95.7% higher than predicted from an ordinary least squares (OLS) allometry of parrots (BMR = 0.042M (b) (0.649) , BMR in Watts, M (b) in grammes). Compared with BMR data for 94 captive-raised bird species, the winter and summer BMRs were, respectively, 45.5 and 117.8% higher than predicted by a phylogenetic generalised least squares (PGLS) allometry (BMR = 0.030M (b) (0.687) , BMR in Watts, M (b) in grammes). The summer up-regulation of BMR is the highest recorded for a bird of any size to date. We suggest that the costs of a high summer BMR may be met by the unusual cooperative breeding system of C. vasa in which groups of males feed the female and share paternity. The potential breeding benefits of a high summer BMR are unknown. PMID- 21688175 TI - Leptospirosis is associated with markedly increased triglycerides and small dense low-density lipoprotein and decreased high-density lipoprotein. AB - The objective of the present study was to evaluate the effects of acute infection with Leptospira interrogans on lipids, lipoproteins and associated enzymes. Fasting serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoproteins (apo) A-Iota, B, E, C-II, C-III and lipoprotein (a) [Lp(a)] were determined in patients with Leptospirosis on diagnosis and 4 months after recovery as well as in age- and sex-matched controls. Activities of cholesteryl ester transfer protein (CETP) and lipoprotein-associated phospholipase A(2) (Lp PLA(2)) as well as paraoxonase 1 (PON1) hydrolysing activity and levels of cytokines were determined. LDL subclass analysis was performed with Lipoprint LDL System. Eleven patients (10 men, mean age 49.5 +/- 8.4 years) and 11 controls were included. TC, HDL-C, LDL-C, apoA-I, apoB and Lp(a) levels were lower at baseline, whereas TG and apoE levels were elevated compared with 4 months later. At baseline, higher levels of cytokines and cholesterol concentration of small dense LDL particles (sdLDL-C) were noticed, whereas LDL particle size was lower compared with follow-up. Activities of plasma Lp-PLA(2) and HDL-associated Lp PLA(2) were lower at baseline compared with post treatment values, whereas PON1 activity was similar at baseline and 4 months later. 4 months after recovery, the levels of all lipid parameters evaluated did not differ compared with controls, except for HDL-C which remained lower. PON1 activity both at baseline and 4 months later was lower in patients compared with controls. Leptospirosis is associated with atherogenic changes of lipids, lipoproteins and associated enzymes. PMID- 21688177 TI - Structural features specific to plant metallothioneins. AB - The metallothionein (MT) superfamily combines a large variety of small cysteine rich proteins from nearly all phyla of life that have the ability to coordinate various transition metal ions, including Zn(II), Cd(II), and Cu(I). The members of the plant MT family are characterized by great sequence diversity, requiring further subdivision into four subfamilies. Very peculiar and not well understood is the presence of rather long cysteine-free amino acid linkers between the cysteine-rich regions. In light of the distinct differences in sequence to MTs from other families, it seems obvious to assume that these differences will also be manifested on the structural level. This was already impressively demonstrated with the elucidation of the three-dimensional structure of the wheat E(c)-1 MT, which revealed two metal cluster arrangements previously unprecedented for any MT. However, as this structure is so far the only one available for the plant MT family, other sources of information are in high demand. In this review the focus is thus set on any structural features known, deduced, or assumed for the plant MT proteins. This includes the determination of secondary structural elements by circular dichroism, IR, and Raman spectroscopy, the analysis of the influence of the long linker regions, and the evaluation of the spatial arrangement of the sequence separated cysteine-rich regions with the aid of, e.g., limited proteolytic digestion. In addition, special attention is paid to the contents of divalent metal ions as the metal ion to cysteine ratios are important for predicting and understanding possible metal-thiolate cluster structures. PMID- 21688178 TI - Immunotherapy of prostate cancer: should we be targeting stem cells and EMT? AB - Cancer stem cells have been implicated in a number of solid malignancies including prostate cancer. In the case of localised prostate cancer, patients are often treated with surgery (radical prostatectomy) and/or radiotherapy. However, disease recurrence is an issue in about 30% of patients, who will then go on to receive hormone ablation therapy. Hormone ablation therapy is often palliative in a vast proportion of individuals, and for hormone-refractory patients, there are several immunotherapies targeting a number of prostate tumour antigens which are currently in development. However, clinical responses in this setting are inconsistent, and it is believed that the failure to achieve full and permanent tumour eradication is due to a small, resistant population of cells known as 'cancer stem cells' (CSCs). The stochastic and clonal evolution models are among several models used to describe cancer development. The general consensus is that cancer may arise in any cell as a result of genetic mutations in oncogenes and tumour suppressor genes, which consequently result in uncontrolled cell growth. The cancer stem cell theory, however, challenges previous opinion and proposes that like normal tissues, tumours are hierarchical and only the rare subpopulation of cells at the top of the hierarchy possess the biological properties required to initiate tumourigenesis. Furthermore, where most cancer models infer that every cell within a tumour is equally malignant, i.e. equally capable of reconstituting new tumours, the cancer stem cell theory suggests that only the rare cancer stem cell component possess tumour-initiating capabilities. Hence, according to this model, cancer stem cells are implicated in both tumour initiation and progression. In recent years, the role of epithelial--mesenchymal transition (EMT) in the advancement of prostate cancer has become apparent. Therefore, CSCs and EMT are both likely to play critical roles in prostate cancer tumourigenesis. This review summarises the current immunotherapeutic strategies targeting prostate tumour antigens taking into account the need to consider treatments that target cancer stem cells and cells involved in epithelial- mesenchymal transition. PMID- 21688176 TI - Vascular beta-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAbeta mice. AB - Cerebrovascular lesions related to congophilic amyloid angiopathy (CAA) often accompany deposition of beta-amyloid (Abeta) in Alzheimer's disease (AD), leading to disturbed cerebral blood flow and cognitive dysfunction, posing the question how cerebrovascular pathology contributes to the pathology of AD. To address this question, we characterised the morphology, biochemistry and functionality of brain blood vessels in transgenic arctic beta-amyloid (arcAbeta) mice expressing human amyloid precursor protein (APP) with both the familial AD-causing Swedish and Arctic mutations; these mice are characterised by strong CAA pathology. Mice were analysed at early, mid and late-stage pathology. Expression of the glucose transporter GLUT1 at the blood-brain barrier (BBB) was significantly decreased and paralleled by impaired in vivo blood-to-brain glucose transport and reduced cerebral lactate release during neuronal activation from mid-stage pathology onwards. Reductions in astrocytic GLUT1 and lactate transporters, as well as retraction of astrocyte endfeet and swelling consistent with neurovascular uncoupling, preceded wide-spread beta-amyloid plaque pathology. We show that CAA at later disease stages is accompanied by severe morphological alterations of brain blood vessels including stenoses, BBB leakages and the loss of vascular smooth muscle cells (SMCs). Together, our data establish that cerebrovascular and astrocytic pathology are paralleled by impaired cerebral metabolism in arcAbeta mice, and that astrocyte alterations occur already at premature stages of pathology, suggesting that astrocyte dysfunction can contribute to early behavioural and cognitive impairments seen in these mice. PMID- 21688180 TI - Epidemiology of insulinoma in Tunisia. PMID- 21688179 TI - Intraoperative multiple-staged resection and tumor tissue identification using frozen sections provide the best result for the accurate localization and complete resection of tumors in Cushing's disease. AB - The treatment of choice in Cushing's disease (CD) is surgical removal; however, most tumors are too small to be detected. The objective was to establish a method to achieve the complete removal of tumors on the basis of the results of high resolution magnetic resonance imaging (MRI), inferior petrosal sinus sampling (IPSS), and a surgical resection technique using frozen biopsy. Eighteen patients who underwent transsphenoidal surgery from 2004 to 2010 were included. High resolution MRI and IPSS, multiple-staged resection, and tumor tissue identification in frozen sections (surgical and histological identification, SHI) were performed. All patients achieved surgical remission, as confirmed by 24 h urinary free cortisol excretion tests. Visible microlesions were identified on the initial MRI in 11 patients (61%). The SHI findings agreed with the MRI findings in 10 of the 11 patients (90.9%) and with IPSS lateralization in 6 of the 11 patients (54.5%). In the 7 patients whose lesions were not visible on the initial MRI, only 1 (14.3%) showed an agreement between IPSS and SHI. In 3 of the 7 patients, the microlesions were identified by additional MRI. The rate of concordance with SHI was 77.8% for the overall MRI and 38.9% for IPSS. High resolution MRI is better than IPSS for localizing corticotroph adenomas. In patients with lesions not visible on the initial MRI, additional MRI should be performed using a different protocol. Although high-resolution MRI is better for localizing tumors, SHI remains an important approach for removing the tumors completely. PMID- 21688181 TI - Medulloblastoma with myogenic differentiation: long-term survival in a patient treated with aggressive combination therapy and autologous stem cell transplantation. AB - Medulloblastoma with myogenic differentiation (MMD) is a rare and aggressive variant of medulloblastoma, occurring predominantly in children. There have been only two case reports of long-term survival previously published. We report a case of long-term disease-free survival in a 21-year-old diagnosed with MMD. PMID- 21688183 TI - Knowledge about genomic recurrence risk testing among breast cancer survivors. AB - Genomic expression profiling of tumors is used to individualize early-stage breast cancer treatment. However, very little is known about patients' understanding of and desired information about these tests, such as Oncotype DX. We addressed these issues via a survey mailed to 130 early-stage breast cancer patients who received an Oncotype DX test result. The survey assessed understanding (14 items), information desired about genomic expression profiling tests, and if and where they sought information about Oncotype DX. Sixty-four surveys were returned. Overall, 54% of the knowledge items were answered correctly. Patients wanted education about genomic tests in many areas. Overall, 62% sought information about the test, primarily from the Internet (48%) and doctor or health care provider (31%). In sum, patients' misunderstanding of genomic tests abound, necessitating better educational efforts on behalf of health care systems to meet their needs for varied information through different communication channels. PMID- 21688182 TI - Tenofovir disoproxil fumarate for the treatment of chronic hepatitis B monoinfection. AB - INTRODUCTION: Resistance in nucleoside/nucleotide analog (NA) therapy has always been a challenge in the management of chronic hepatitis B (CHB). CLINICAL STUDIES: Initially developed for the treatment of HIV infection, early in vitro and clinical observational studies had shown tenofovir disoproxil fumarate (TDF) to be also active against CHB. Recent data from various multicenter phase 3 and 4 clinical trials have confirmed TDF being able to achieve a high viral suppression in both NA-naive and -experienced CHB patients. There are also emerging data on the efficacy of TDF in decompensated CHB. Although there are in vitro studies identifying certain mutation loci associated with a reduced susceptibility to TDF, there have so far been no reports of virologic resistance to TDF in clinical studies. TDF has a favorable safety profile, although more long-term data would be needed. CONCLUSIONS: TDF has the makings of an "ideal" first-line drug for the treatment of CHB. PMID- 21688184 TI - Illness representations of lung cancer, lung cancer worry, and perceptions of risk by smoking status. AB - We examined perceived risk, worry, and illness representations of lung cancer by smoking status using data from the 2005 Health Information National Trends Survey (n = 1,765). Perceived lung cancer risk was rated "very high" more frequently by current (15.2%) than former (1.9%) and never (1.6%) smokers. Current smokers more frequently reported worry about lung cancer (18.4%) than former (3.1%) and never smokers (1.8%). Confusion about lung cancer prevention was higher among current (55.2%) than former (41.3%) or never smokers (38.2%). Agreement that lung cancer is caused by a person's behavior was higher among never (86.1%) and former (82.6%) than current smokers (75.4%). In multivariable models, never (OR = .07) and former smokers (OR = .16) were less likely than current smokers to perceive their lung cancer risk as high. Never smokers (OR = .21) were significantly less likely than current smokers to report worrying about lung cancer, while former and current smokers did not differ. PMID- 21688185 TI - Pharmacotherapy of heart failure in the elderly: adverse events. AB - Aging is associated with numerous alterations in body composition and organ function that result in substantial changes in the absorption, distribution, metabolism, and elimination of virtually all drugs. In addition, older patients with heart failure (HF) almost invariably have multiple coexisting medical conditions for which they are receiving medications. This article reviews common adverse drug effects and drug interactions associated with HF therapy in older patients and discusses strategies for reducing the risk of adverse drug events. In order to minimize these risks, it is essential that clinicians avoid prescribing unnecessary medications, adjust medication dosages to optimally balance benefits and side effects, and remain ever vigilant to the potential for medications to cause or contribute to clinically important adverse events and impaired quality of life. In treating older HF patients, the oft-cited dictum "start low, go slow" clearly applies. Despite the inherent challenges, with careful management and close follow-up, most older HF patients can be successfully treated through the judicious use of guideline-recommended HF therapies. PMID- 21688186 TI - Inflammatory activation: cardiac, renal, and cardio-renal interactions in patients with the cardiorenal syndrome. AB - Although inflammation is a physiologic response designed to protect us from infection, when unchecked and ongoing it may cause substantial harm. Both chronic heart failure (CHF) and chronic kidney disease (CKD) are known to cause elaboration of several pro-inflammatory mediators that can be detected at high concentrations in the tissues and blood stream. The biologic sources driving this chronic inflammatory state in CHF and CKD are not fully established. Traditional sources of inflammation include the heart and the kidneys which produce a wide range of pro-inflammatory cytokines in response to neurohormones and sympathetic activation. However, growing evidence suggests that non-traditional biomechanical mechanisms such as venous and tissue congestion due to volume overload are also important as they stimulate endotoxin absorption from the bowel and peripheral synthesis and release of pro-inflammatory mediators. Both during the chronic phase and, more rapidly, during acute exacerbations of CHF and CKD, inflammation and congestion appear to amplify each other resulting in a downward spiral of worsening cardiac, vascular, and renal functions that may negatively impact patients' outcome. Anti-inflammatory treatment strategies aimed at attenuating end organ damage and improving clinical prognosis in the cardiorenal syndrome have been disappointing to date. A new therapeutic paradigm may be needed, which involves different anti-inflammatory strategies for individual etiologies and stages of CHF and CKD. It may also include specific (short-term) anti inflammatory treatments that counteract inflammation during the unsettled phases of clinical decompensation. Finally, it will require greater focus on volume overload as an increasingly significant source of systemic inflammation in the cardiorenal syndrome. PMID- 21688188 TI - Association between osteoporosis and sleep duration in healthy middle-aged and elderly adults: a large-scale, cross-sectional study in Japan. AB - STUDY OBJECTIVES: This study aims to explore the association between osteoporosis and nightly sleep duration among adult outpatients. DESIGN: This is a large scale, retrospective cross-sectional study. SETTING: The setting was in a preventive medicine health center at a general community hospital in Tokyo, Japan. PARTICIPANTS: There were 19,321 healthy individuals (>=50 years old) who underwent annual general health checkup between January and December 2008. MEASUREMENTS: The participants were divided into four groups according to their self-reported average nightly sleep duration (<6, 6-6.9, 7-7.9, and >8 h). Radial bone mineral density was measured using dual-energy X-ray absorptiometry, and T score was compared to young adult mean to diagnose osteoporosis. Multivariate logistic regression was used to explore the association between sleep duration and osteoporosis. RESULTS: The mean age of the participants was 60.9 years (standard deviation [SD], 7.9) and 48.0% were female. The prevalence of osteoporosis was 8.0% (95% confidence interval [CI] = 7.6-8.4%). Those with sleep duration of >8 h were more likely to have osteoporosis (odds ratio [OR] = 1.35; 95% CI = 1.06-1.73) than those with short sleep duration (<6 h). CONCLUSION: Those individuals with self-reported sleep duration of more than 8 h (long sleepers) appear to have higher odds of osteoporosis compared to the progressively shorter sleepers. PMID- 21688187 TI - Resveratrol in cardiovascular disease: what is known from current research? AB - Resveratrol is a well-known antioxidant that exists in grape skin/seed, red wine, and the root of Polygonum cuspidatum, a traditional Chinese and Japanese medicinal material. Studies have found that resveratrol has many interesting properties, including anti-carcinogenic properties, anti-microbial and antiviral effects, the ability to reverse dyslipidemia and obesity, the ability to attenuate hyperglycemia and hyperinsulinemia, and the ability to protect endothelial function. Heart failure is the final consequence of the majority of cardiovascular diseases, and resveratrol has been shown to directly attenuate heart contraction. The cardiovascular protective capacities of resveratrol are associated with multiple molecular targets and may lead to the development of novel therapeutic strategies for atherosclerosis, ischemia/reperfusion, metabolic syndrome, and heart failure. This article will mainly review recently published basic researches about the protective cardiovascular effects of resveratrol because these results may lead to the development of new clinical therapeutics in patients. PMID- 21688189 TI - Ciliogenesis in normal human kidney development and post-natal life. AB - Ciliogenesis in developing and post-natal human kidneys appears to influence cell proliferation and differentiation, apico-basal cell polarity, and tubular lumen formation. We have analyzed the appearance of primary cilia and differentiation of kidney cells in ten human conceptuses aged 6-22 weeks and in one 5-year-old kidney, using a double immunofluorescence labeling technique for alpha-tubulin, gamma-tubulin, Oct-4, and Ki-67 and by electron microscopy. Immature forms of nephrons and ampullae were characterized by intense cell proliferation, which subsequently decreased during development. Primary cilia appeared on the surfaces of non-proliferating cells in developing nephrons, gradually increasing in length from 0.59 MUm in renal vesicles to 0.81 MUm in the S-forms of nephrons, ultimately reaching 3.04 MUm in length in mature fetal and post-natal nephrons. Ciliary length increased from 0.59 MUm in ampullae to 1.28 MUm in post-natal collecting tubules. Mesenchymal to epithelial transformation of kidney cells coincided with the appearance of apico-basal polarity, both gap and tight junctions, and lumen formation. Up-regulation of Oct-4 expression correlated with the onset of kidney cell differentiation. Our results demonstrate the importance of proper primary cilia lengthening and Oct-4 expression for the normal development of fetal and post-natal kidneys and of apico-basal polarity for normal tubular lumen formation. Disturbances in these processes are associated with ciliopathies. PMID- 21688190 TI - Clinical presentation and metabolic features of overt and occult urolithiasis. AB - Although pediatricians are frequently confronted with patients presenting urolithiasis symptoms without obvious stones, the syndrome of occult urolithiasis may be still viewed with some skepticism. We have compared the clinical and metabolic features of 197 children with obvious calculi, 189 with microcalculi (diameter <= 3 mm based on renal sonography), and 114 with symptoms of urolithiasis and normal renal sonography findings. Only microcalculi and normal sonography subjects with a urinary abnormality potentially leading to urolithiasis were included in the study. Age at presentation increased significantly (p = 0.0001) in the groups in the order normal sonography to microcalculi to calculi groups. There was no significant difference among the three groups in terms of family history of urolithiasis, gender distribution, and degree of hypercalciuria, hyperuricosuria, hyperoxaluria, or hypocitraturia. The average frequency of pain attacks of patients with recurrent abdominal pain (RAP) ranged from 3.6 to 4.6 days of pain per month among the three groups, which is four to ninefold lower than that reported for children with functional or organic gastrointestinal RAP. The consistency of many clinical and urinary metabolic characteristics indicates a common underlying disorder in overt and occult urolithiasis. The increase of age at presentation from the normal sonography to microcalculi and calculi groups may reflect progressive crystal accretion leading ultimately to overt stone formation. PMID- 21688191 TI - The role of molecular genetics in diagnosing familial hematuria(s). AB - Familial microscopic hematuria (MH) of glomerular origin represents a heterogeneous group of monogenic conditions involving several genes, some of which remain unknown. Recent advances have increased our understanding and our ability to use molecular genetics for diagnosing such patients, enabling us to study their clinical characteristics over time. Three collagen IV genes, COL4A3, COL4A4, and COL4A5 explain the autosomal and X-linked forms of Alport syndrome (AS), and a subset of thin basement membrane nephropathy (TBMN). A number of X linked AS patients follow a milder course reminiscent of that of patients with heterozygous COL4A3/COL4A4 mutations and TBMN, while at the same time a significant subset of patients with TBMN and familial MH progress to chronic kidney disease (CKD) or end-stage kidney disease (ESKD). A mutation in CFHR5, a member of the complement factor H family of genes that regulate complement activation, was recently shown to cause isolated C3 glomerulopathy, presenting with MH in childhood and demonstrating a significant risk for CKD/ESKD after 40 years old. Through these results molecular genetics emerges as a powerful tool for a definite diagnosis when all the above conditions enter the differential diagnosis, while in many at-risk related family members, a molecular diagnosis may obviate the need for another renal biopsy. PMID- 21688193 TI - Untreated hypertension decreases heritability of cognition in late middle age. AB - Hypertension is a risk factor for cognitive decline, but the mechanisms underlying the effects of hypertension on cognition, particularly in midlife, are unclear. We examined whether hypertension modifies genetic influences on individual differences in cognition. Nine cognitive domains and general cognitive ability were assessed in a sample of 1,237 male twins aged 51-60 who were divided into three blood pressure groups: non-hypertensive; medicated hypertensive; and unmedicated hypertensive. Heritability was significantly lower among unmedicated hypertensives compared to medicated hypertensives and non-hypertensives for visual-spatial ability (p = 0.013) and episodic memory (p = 0.004). There were no heritability differences between non-hypertensives and medicated hypertensives. In addition, there were no significant differences in mean level cognition across the three blood pressure groups. These results suggest that in middle-aged men, untreated hypertension suppresses normal genetic influences on individual differences in certain domains of cognition prior to the emergence of hypertension-related effects on cognitive performance. These results further suggest that antihypertensive medication may protect against or reverse this effect. PMID- 21688194 TI - Mercury concentrations in snapping turtles (Chelydra serpentina) correlate with environmental and landscape characteristics. AB - Mercury (Hg) deposited onto the landscape can be transformed into methylmercury (MeHg), a neurotoxin that bioaccumulates up the aquatic food chain. Here, we report on Hg concentrations in snapping turtles (Chelydra serpentina) across New York State, USA. The objectives of this study were to: (1) test which landscape, water, and biometric characteristics correlate with total Hg (THg) concentrations in snapping turtles; and (2) determine whether soft tissue THg concentrations correlate with scute (shell) concentrations. Forty-eight turtles were sampled non lethally from ten lakes and wetlands across New York to observe patterns under a range of ecosystem variables and water chemistry conditions. THg concentrations ranged from 0.041 to 1.50 MUg/g and 0.47 to 7.43 MUg/g wet weight of muscle tissue and shell, respectively. The vast majority of mercury (~94%) was in the MeHg form. Sixty-one percent of turtle muscle samples exceeded U.S. Environmental Protection Agency (U.S. EPA) consumption advisory limit of 0.3 MUg Hg/g for fish. Muscle THg concentrations were significantly correlated with sulfate in water and the maximum elevation of the watershed. Shell THg concentrations were significantly correlated with the acid neutralizing capacity (ANC) of water, the maximum elevation of the watershed, the percent open water in the watershed, the lake to watershed size, and various forms of atmospheric Hg deposition. Thus, our results demonstrate that THg concentrations in snapping turtles are spatially variable, frequently exceed advisory limits, and are significantly correlated with several landscape and water characteristics. PMID- 21688192 TI - Autoimmunity and inflammation: murine models and translational studies. AB - Autoimmune and inflammatory diseases, including type 1 diabetes, multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis, constitute an important and growing public health burden. However, in many cases our understanding of disease biology is limited and available therapies vary greatly in their efficacy and safety. Animal models of autoimmune and inflammatory diseases have provided valuable tools to researchers investigating their aetiology, pathology, and novel therapeutic strategies. Although such models vary in the degree to which they reflect human autoimmune and inflammatory diseases and caution is required in the extrapolation of animal data to the clinical setting, therapeutic approaches first evaluated in established animal models, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and the nonobese diabetic mouse, have successfully progressed to clinical investigation and practice. Similarly, these models have proven useful in providing support for basic hypotheses regarding the underlying causes and pathology of autoimmune and inflammatory diseases. Here we review selected murine models of autoimmunity and inflammation and efforts to translate findings from these models into both basic insights into disease biology and novel therapeutic strategies. PMID- 21688195 TI - Randomized trial of bioelectrical impedance analysis versus clinical criteria for guiding ultrafiltration in hemodialysis patients: effects on blood pressure, hydration status, and arterial stiffness. AB - BACKGROUND: Chronic fluid overload is common in maintenance hemodialysis (HD) patients and is associated with severe cardiovascular complications, such as arterial hypertension, left ventricular hypertrophy, congestive heart failure, and arrhythmia. Therefore, a crucial target of HD is to achieve the so-called dry weight; however, the best way to assess fluid status and dry weight is still unclear. Dry weight is currently determined in most dialysis units on a clinical basis, and it is commonly defined as the lowest body weight a patient can tolerate without developing intra-dialytic or inter-dialytic hypotension or other symptoms of dehydration. One of the most promising methods that have emerged in recent years is bioelectrical impedance analysis (BIA), which estimates body composition, including hydration status, by measuring the body's resistance and reactance to electrical current. Our objective was to study the effect BIA-guided versus clinical-guided ultrafiltration on various cardiovascular disease risk factors and markers in HD patients. MATERIALS AND METHODS: We included 135 HD patients from a single center in a prospective study, aiming to compare the long term (12 months) effect of BIA-based versus clinical-based assessment of dry weight on blood pressure (BP), pulse wave velocity (PWV), and serum N-terminal fragment of B-type natriuretic peptide (NT-proBNP). The body composition was measured using the portable whole-body multifrequency BIA device, Body Composition Monitor-BCM((r)) (Fresenius Medical Care, Bad Homburg, Germany). RESULTS: In the "clinical" group there were no changes in BP, body mass index (BMI), and body fluids. The PWV increased from 7.9 +/- 2.5 to 9.2 +/- 3.6 m/s (P = 0.002), whereas serum NT-proBNP decreased from 5,238 to 3,883 pg/ml (P = 0.05). In the "BIA" group, BMI and body volumes also did not change; however, there was a significant decrease in both systolic BP, from 144.6 +/- 14.7 to 135.3 +/- 17.8 mmHg (P < 0.001), and diastolic BP, from 79.5 +/- 9.7 to 73.2 +/- 11.1 mmHg (P < 0.001). In this group, PWV also decreased from 8.2 +/- 2.3 to 6.9 +/- 2.3 m/s (P = 0.001) and NT-proBNP decreased from 7,552 to 4,561 pg/ml (P = 0.001). CONCLUSION: BIA is not inferior and possibly even better than clinical criteria for assessing dry weight and guiding ultrafiltration in HD patients. PMID- 21688196 TI - Sympatho-renal axis in chronic disease. AB - Essential hypertension, insulin resistance, heart failure, congestion, diuretic resistance, and functional renal disease are all characterized by excessive central sympathetic drive. The contribution of the kidney's somatic afferent nerves, as an underlying cause of elevated central sympathetic drive, and the consequences of excessive efferent sympathetic signals to the kidney itself, as well as other organs, identify the renal sympathetic nerves as a uniquely logical therapeutic target for diseases linked by excessive central sympathetic drive. Clinical studies of renal denervation in patients with resistant hypertension using an endovascular radiofrequency ablation methodology have exposed the sympathetic link between these conditions. Renal denervation could be expected to simultaneously affect blood pressure, insulin resistance, sleep disorders, congestion in heart failure, cardiorenal syndrome and diuretic resistance. The striking epidemiologic evidence for coexistence of these disorders suggests common causal pathways. Chronic activation of the sympathetic nervous system has been associated with components of the metabolic syndrome, such as blood pressure elevation, obesity, dyslipidemia, and impaired fasting glucose with hyperinsulinemia. Over 50% of patients with essential hypertension are hyperinsulinemic, regardless of whether they are untreated or in a stable program of treatment. Insulin resistance is related to sympathetic drive via a bidirectional mechanism. In this manuscript, we review the data that suggests that selective impairment of renal somatic afferent and sympathetic efferent nerves in patients with resistant hypertension both reduces markers of central sympathetic drive and favorably impacts diseases linked through central sympathetics-insulin resistance, heart failure, congestion, diuretic resistance, and cardiorenal disorders. PMID- 21688198 TI - Novel hormone-regulated genes in visceral adipose tissue: cloning and identification of proinflammatory cytokine-like mouse and human MEDA-7: implications for obesity, insulin resistance and the metabolic syndrome. AB - AIMS/HYPOTHESIS: We sought to characterise novel genes dysregulated by sex hormonal imbalances that induce obesity and metabolic disorder in a setting of oestrogen deficiency and androgen dominance in follicle-stimulating hormone receptor (For [also known as Fshr]) knockout female mice. METHODS: Transcriptome analysis of mesenteric adipose tissue (MAT) of mutants revealed novel genes. One novel gene named Meda-7 was selected for study. Meda-7 was cloned from mouse and human adipose tissue; its expression, hormonal regulation and function were characterised. RESULTS: Mouse Meda-7 is richly expressed in deep visceral adipose tissue and encodes a 22 kDa secreted protein with 71% homology to human mesenteric oestrogen-dependent adipose gene- 7 (MEDA-7) protein. Both have six conserved cysteines like many cytokines. In obese patients, MEDA-7 is more abundant in omental than subcutaneous fat. Meda-7 is downregulated in For knockout female MAT at 5 months (obese state) followed by steep upregulation at 9 months (prediabetic condition) when mutants progress towards the metabolic syndrome. Meda-7 is expressed predominantly in the stromal-vascular cell fraction. In this fraction,M1-proinflammatorymacrophages are rich in Meda-7. Meda 7 dysregulation in 5-month-old For-knockout MAT is restored by oestrogen, but treatment has no effect in older mutants. Overabundance of MEDA-7 in HEK-293 cells enhances cell proliferation via p42/44 mitogen-activated protein kinases. Secreted MEDA-7 attenuates insulin-stimulated glucose uptake in 3T3-L1 adipocytes, while downregulating glucose transporter-4 and upregulating both monocyte chemotactic protein-1 and suppressor of cytokine signalling-3. Downstream activity of the insulin signalling mediator, phospho-AKT, is also downregulated. CONCLUSIONS/INTERPRETATION: MEDA-7 is a hormone-regulated adipokine/proinflammatory cytokine that is implicated in causing chronic inflammation, affecting cellular expansion and blunting insulin response in adipocytes. PMID- 21688197 TI - Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments. AB - Cancer cells, both in vivo and in vitro, have been demonstrated to release membranous structures, defined as microvesicles or exosomes, consisting of an array of macromolecules derived from the originating cells, including proteins, lipids, and nucleic acids. While only recently have the roles of these vesicular components in intercellular communication become elucidated, significant evidence has demonstrated that tumor exosomes can exert a broad array of detrimental effects on the immune system-ranging from apoptosis of activated cytotoxic T cells to impairment of monocyte differentiation into dendritic cells, to induction of myeloid-suppressive cells and T regulatory cells. Immunosuppressive exosomes of tumor origin can be found within neoplastic lesions and in biologic fluids from cancer patients, implying a potential role of these pathways in in vivo tumor progression and systemic paraneoplastic syndromes. Through the expression of molecules involved in angiogenesis promotion, stromal remodeling, signaling pathway activation through growth factor/receptor transfer, chemoresistance, and genetic intercellular exchange, tumor exosomes could represent a central mediator of the tumor microenvironment. By understanding the nature of these tumor-derived exosomes/microvesicles and their roles in mediating cancer progression and modulating the host immune response will significantly impact therapeutic approaches targeting exosomes. PMID- 21688199 TI - Biological reactivity of TiO2 nanoparticles assessed by ex vivo testing. AB - Isolated digestive gland epithelium from a model invertebrate organism was used in an ex vivo system to assess the potential of nanoparticulate TiO(2) to disrupt cell membranes. Primary particle size, surface area, concentration of particles in a suspension, and duration of exposure to TiO(2) particles were all found to have effects, which are observed at concentrations of nano-TiO(2) as low as 1 MUg mL(-1). The test system employed here can be used as a fast screening tool to assess biological potential of nanoparticles with similar chemical composition but different size, concentration, or duration of exposure. We discuss the potential of ex vivo tests to avoid some of the limitations of conventional in vitro tests. PMID- 21688200 TI - Down-regulated miRNA-214 induces a cell cycle G1 arrest in gastric cancer cells by up-regulating the PTEN protein. AB - To detect the expression of miRNA-214 in human gastric cancer cell lines of BGC823, MKN45 and SGC7901, and to identify the effect of miRNA-214 on cell cycle and apoptosis of these cells. Expression of miRNA-214 in human normal gastric mucosal cell line GES-1 and human gastric cancer cell lines was detected by real time reverse-transcription polymerase chain reaction. Antisense-miRNA-214 oligonucleotides were transfected transiently into gastric cancer cell lines to down-regulate the expression of miRNA-214. The cell cycle and apoptosis were studied by flow cytometry assay. PTEN, one of the target genes of miRNA-214 was detected by using of immunocytochemistry and Western blotting. MiRNA-214 was overexpressed in gastric cancer cell lines of BGC823, MKN45 and SGC7901 compared with normal gastric mucosal cell line GES-1. Antisense-miRNA-214 oligonucleotides significantly down-regulated the expression of miRNA-214, and increased the portion of G1-phase and decreased the portion of S-phase in BGC823 and MKN45 cells. The immunocytochemistry test and Western blotting analysis showed that the down-regulation of miRNA-214 could significantly up-regulate the expression of PTEN in BGC823 and MKN45 cells. MiRNA-214 is overexpressed in human gastric cancer cell lines of BGC823, MKN45 and SGC7901. The down-regulation of miRNA-214 could induce a G1 cell cycle arrest in them, the up-regulation of PTEN maybe one of the mechanism. PMID- 21688201 TI - How I do it: cervical lateral mass screw fixation. AB - BACKGROUND: Cervical lateral mass screw fixation is indicated for the treatment of cervical subaxial C3-C7 lesions associated with instability. METHOD: The authors first describe the surgical anatomy of the subaxial cervical posterior approach. Then the Magerl technique is detailed. In particular, tricks to avoid complications are presented. The ideal screw entry point, direction, size and exit point are mentioned. A surgical video, artist's drawings and a radiological case report are included. CONCLUSION: The Magerl technique is a safe and effective lateral mass fixation technique. Respecting anatomical landmarks is crucial to avoid nerve root, vertebral artery and facet joint injury. PMID- 21688202 TI - Plant phenology networks of citizen scientists: recommendations from two decades of experience in Canada. AB - Plant phenology networks of citizen scientists have a long history and have recently contributed to our understanding of climate change effects on ecosystems. This paper describes the development of the Alberta and Canada PlantWatch programs, which coordinate networks of citizen scientists who track spring development timing for common plants. Tracking spring phenology is highly suited to volunteers and, with effective volunteer management, observers will stay loyal to a phenology program for many years. Over two decades beginning in 1987, Alberta PlantWatch volunteers reported 47,000 records, the majority contributed by observers who participated for more than 9 years. We present a quantitative analysis of factors that determine the quality of this phenological data and explore sources of variation. Our goal is to help those who wish to initiate new observer networks with an analysis of the effectiveness of program protocols including selected plant species and bloom stages. PMID- 21688203 TI - Natural resins and balsams from an eighteenth-century pharmaceutical collection analysed by gas chromatography/mass spectrometry. AB - Historical nomenclature has not always been unequivocally associated with the botanical origin of natural resins. The availability of natural resins has changed throughout the centuries and so have their trade names. Furthermore, adulterations and lack of knowledge have led to variations in the composition of the products traded under the same name. This investigation aims at a new understanding of the interrelation between the historical and modern terms for natural resins. Different Pinaceae and Pistacia resins, mastic, sandarac, copaiba balm and burgundy pitch from Vigani's Cabinet, a 300-year-old pharmaceutical collection owned by Queens' College, Cambridge (UK) were investigated. Related reference materials from modern collections were analysed together with natural resins derived from reliable botanical sources. The analytical method was gas chromatography/mass spectrometry (GC-MS) with and without derivatisation with trimethylsulfonium hydroxide. This technique provided detailed molecular compositions of the studied materials, which in turn led to particular data profiles of the materials. Marker molecules of Copaifera, Pinaceae, Cupressaceae and Pistacia resins were identified. By comparing the GC-MS data profiles to the reference samples, a clearer picture of the connection between nomenclature and botanical origin was obtained. With the aid of the marker molecules and data profiles, it was then possible to clarify the nomenclature of the aged resins sampled from Vigani's Cabinet. PMID- 21688204 TI - Differential physiological roles of ESCRT complexes in Caenorhabditis elegans. AB - Endosomal sorting complex required for transport (ESCRT) complexes are involved in endosomal trafficking to the lysosome, cytokinesis, and viral budding. Extensive genetic, biochemical, and structural studies on the ESCRT system have been carried out in yeast and mammalian systems. However, the question of how the ESCRT system functions at the whole organism level has not been fully explored. In C. elegans, we performed RNAi experiments to knock-down gene expression of components of the ESCRT system and profiled their effects on protein degradation and endocytosis of YP170, a yolk protein. Targeted RNAi knock-down of ESCRT-I (tsg-101 and vps-28) and ESCRT-III (vps-24, and vps-32.2) components interfered with protein degradation while knock-down of ESCRT-II (vps-25 and vps-36) and ESCRT-III (vps-20 and vps-24) components hampered endocytosis. In contrast, the knockdown of vps-37, another ESCRT-I component, showed no defect in either YP170 uptake or degradation. Depletion of at least one component from each complex - ESCRT-0 (hgrs-1), ESCRT-I (tsg-101, vps-28, and vps-37), ESCRT-II (vps-36), ESCRT III (vps-24), and Vps4 (vps-4) - resulted in abnormal distribution of embryos in the uterus of worms, possibly due to abnormal ovulation, fertilization, and egglaying. These results suggest differential physiological roles of ESCRT-0, -I, -II, and -III complexes in the context of the whole organism, C. elegans. PMID- 21688206 TI - Adverse effects of azacitidine: onset, duration, and treatment. AB - High-risk myelodysplastic syndromes present a poor prognosis, with survivals of close to only 1 year. The use of azacitidine, a DNA methyltransferase inhibitor, in this group of patients has transformed this grey image, with a demonstrated improvement in survival. Responses to survival are attained in a progressive manner, providing that the drug is used continually. This requires a good control of the adverse effects of the drug, which are primarily in the first cycles of treatment. The hematological adverse effects can be handled with transfusions and growth factors. The nonhematological adverse effects can be prevented with the use of antiemetics and a good technique of drug administration. PMID- 21688205 TI - Arabidopsis cell death in compatible and incompatible interactions with Alternaria brassicicola. AB - Two strains of necrotrophic Alternaria brassicicola, Ab40857 and Ab42464, are virulent on Korean cabbage and several wild types of Arabidopsis thaliana. Interaction between Ab42464 and Col-0 was compatible, whereas interaction between Ab40857 and Col-0 was incompatible. The loss of defense, no death (dnd) 1 function abrogated the compatibility between Ab42464 and Col-0, and the accelerated cell death (acd) 2 mutation attenuated the Col-0's resistance against Ab40857. These two fungal strains induced PR1 transcription in Col-0. Ab40857 accelerated transcription of PDF1.2, THI2.1, CAT, and POX by 12 h compared to those challenged with Ab42464. More abundant cell death was observed in Col-0 infected with Ab42464, however, callose deposition was evident in the incompatible interaction. Remarkably, Ab40857-infected areas of acd2-2 underwent rampant cell death and Ab42464 triggered callose production in dnd1-1. Furthermore, the incompatibility between Ab40857 and Col-0 was nullified by the coronatine-insensitive 1 (coi1) and phytoalexin-deficient 3 (pad3) mutations but not by nonexpresser of PR genes (npr1) and pad4. Ab40857 induced abundant cell death in pad3. Taken together, cell death during the early infection stage is a key determinant that discriminates between a compatible interaction and an incompatible one, and the resistance within Col-0 against Ab40857 is dependent on a defense-signaling pathway mediated by jasmonic acid and PAD3. PMID- 21688207 TI - Azacitidine adverse effects in patients with myelodysplastic syndromes. AB - Azacitidine is now considered one of the standard-of-care agents for patients with high-risk myelodysplastic syndromes who are not candidates for high-dose chemotherapy. Considering the mechanism of action of the agent, it is critical to maintain adequate dose intensities for prolonged periods of time in order for treatment to be effective. Therefore, aggressive prevention as well as treatment of side effects is critical. The drug mainly causes hematological toxicity that is managed with growth factor support, blood transfusions, and dose and schedule adjustment. Nonhematological side effects are mainly gastrointestinal and cutaneous in nature, and can be easily managed with symptomatic treatment and correct administration techniques. PMID- 21688208 TI - Chronic alcohol consumption, abstinence and relapse: brain proton magnetic resonance spectroscopy studies in animals and humans. AB - This chapter summarizes the peer-reviewed literature of proton magnetic resonance spectroscopy ((1)H MRS) studies on the effects of chronic and excessive alcohol consumption in both the animal and human brain. After a brief summary of the neuropathology of alcohol use disorders (AUD), we describe the primary brain metabolites measured by in vivo (1)H MRS. We then focus on published MRS studies of animal models of alcohol dependence and of treatment-seeking humans with AUD. We also summarize the scant MRS research on the much larger fraction of treatment naive individuals with AUD and the similarities and discrepancies relative to treatment-seekers. It is exceedingly apparent that premorbid and/or comorbid disorders/conditions, especially chronic smoking, among individuals with AUD contribute to the considerable variability in the pattern and magnitude of neurobiological and neurocognitive abnormalities in AUD. Therefore, we also review studies on the neurobiological consequences of the combined effects of chronic drinking and smoking in AUD. Finally, as AUD is characterized by a chronically relapsing/remitting course over lifetime and identification of those at greatest risk for relapse is important, we review (1)H MRS studies on brain spectroscopic measures that contribute to the prediction of relapse in AUD. We conclude with an overall assessment of the MRS research literature on brain alcohol effects, the role of animal and human studies in understanding the disease, and discuss the need of widely integrative MRS studies of cohorts that include individuals with comorbidies that are reflective of the general population with AUD. PMID- 21688209 TI - M cell-targeted mucosal vaccine strategies. AB - Immune responses in the aerodigestive tract are characterized by production and transport of specific IgA antibodies across the epithelium to act as a first line of defense against pathogens in the external environment. To sample antigens on mucosal surfaces in the intestine and upper respiratory tract, the immune system relies on a close collaboration between specialized antigen-sampling epithelial M cells and lymphoid cells. Depending on various factors, local antigen presentation in the mucosal tissue leads to tolerance or initiation of an active immune response. Recently, molecules that could be used to target vaccine antigens to apical M cell surfaces have been identified. Here we review the M cell-targeted vaccine strategy, an approach that could be used to enhance uptake and efficacy of vaccines delivered in the nasal cavity or intestine. PMID- 21688210 TI - Compliance to continuous positive airway pressure therapy in a group of Portuguese patients with obstructive sleep apnea syndrome. AB - INTRODUCTION: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is an emerging public health concern. Although different treatments for OSAHS had been proposed, continuous positive airway pressure (CPAP) is the first-line treatment in moderate to serious OSAHS in which success can be achieved by increasing compliance to CPAP. MATERIALS AND METHODS: This study analyzes long-term CPAP compliance in patients with OSAHS on CPAP therapy for at least 1 month, who began CPAP therapy between January 2004 and December 2006, followed up at a Portuguese Sleep Outpatient Clinic in Santo Antonio Hospital. Only effective data of CPAP use had been considered. During the first year of CPAP therapy, 96 patients were enrolled and followed up, but 15 patients had discontinued CPAP treatment. CPAP was used on average 5.1 h per day and in 80.1% of the total follow-up days. When compliance is defined as the use of CPAP for a minimum of 4 h per day in at least 70% of the follow-up days, only 54% of patients were classified as compliants during the first year. RESULTS AND CONCLUSION: No statistically significant differences were found throughout the first year (p > 0.05) in terms of the percentage of compliants, controlling for demographic and clinic variables. None of the demographic and clinical baseline variables studied were found to be significant predictor of CPAP compliance (p > 0.05). This study diagnosed a low compliance to CPAP therapy in the studied sample, warning to the need of developing further studies in this area and to the need of implementing strategies to increase CPAP compliance. PMID- 21688211 TI - Factors affecting summer maize yield under climate change in Shandong Province in the Huanghuaihai region of China. AB - Clarification of influencing factors (cultivar planted, cultivation management, climatic conditions) affecting yields of summer maize (Zea mays L.) would provide valuable information for increasing yields further under variable climatic conditions. Here, we report actual maize yields in the Huanghuaihai region over the past 50 years (1957-2007), simulated yields of major varieties in different years (Baimaya in the 1950s, Zhengdan-2 in the 1970s, Yedan-13 in the 1990s, and Zhengdan-958 in the 2000s), and factors that influence yield. The results show that, although each variety change has played a critical role in increasing maize yields, the contribution of variety to yield increase has decreased steadily over the past 50 years (42.6%-44.3% from the 1950s to the 1970s, 34.4%-47.2% from the 1970s to the 1990s, and 21.0%-37.6% from the 1990s to the 2000s). The impact of climatic conditions on maize yield has exhibited an increasing trend (0.67%-22.5% from the 1950s to the 1970s, 2.6%-27.0% from the 1970s to the 1990s, and 9.1% 51.1% from the 1990s to the 2000s); however, interannual differences can be large, especially if there were large changes in temperature and rainfall. Among climatic factors, rainfall had a greater positive influence than light and temperature on yield increase. Cultivation measures could change the contribution rates of variety and climatic conditions. Overall, unless there is a major breakthrough in variety, improving cultivation measures will remain important for increasing future summer maize yields in the Huanghuaihai region. PMID- 21688214 TI - Stent selection and tips on placement technique of EUS-guided biliary drainage: transduodenal and transgastric stenting. AB - Endoscopic ultrasonography-guided biliary drainage (EUS-BD) has been carried out as an alternative to the percutaneous or surgical approach when endoscopic retrograde cholangiopancreatography fails. However, there is no standard technique or device for EUS-BD. In this review, we focus on how we choose the stents and described our tips on this EUS-BD technique. The plastic stent (PS) and the self-expandable metallic stent (SEMS) are used for EUS-BD. The latter is further divided into the fully covered SEMS (FCSEMS), partially covered SEMS (PCSEMS), and uncovered SEMS (UCSEMS) types. Although PS is not expensive, the duration of stent patency is short. SEMS is expensive but the duration of stent patency is long. With UCSEMS, basically there is no stent malpositioning; however, if the gap between the bile duct and the GI tract becomes displaced, bile leakage from the mesh of the stent is likely to occur. Though there is no bile leakage with FCSEMS, the side branch of the bile duct may become occluded, and migration and dislocation sometimes occur. PCSEMS is basically similar to FCSEMS. When EUS-BD was first developed, drainage by PS was common, although reports on drainage by SEMS have increased recently. PMID- 21688213 TI - Osteonecrosis of the femoral head and glaucoma caused by topical corticosteroid application. AB - A 37-year-old man was diagnosed with bilateral osteonecrosis of the femoral head (ONFH) and glaucoma. He had no risk factors for either ONFH or glaucoma, except for 24 years' continuous use of topical corticosteroid ointments for treating atopic dermatitis. We determined that the topical steroid had caused both the pathological conditions. It is necessary to recognize that continuous topical corticosteroid therapy may cause the same pathological conditions as those caused by the systemic administration of these agents. PMID- 21688215 TI - [Annual meeting - appeal for a renaissance of conservative methods]. PMID- 21688212 TI - Enriched environment and physical activity reduce microglia and influence the fate of NG2 cells in the amygdala of adult mice. AB - Proliferative cells expressing proteoglycan neuron-glia 2 (NG2) are considered to represent parenchymal precursor cells in the adult brain and are thought to differentiate primarily into oligodendrocytes. We have studied cell genesis in the adult amygdala and found that, up to 1 year after the labeling of proliferating cells with bromodeoxyuridine, most proliferating NG2 cells remain NG2 cells, and only a few slowly differentiate into mature oligodendrocytes, as assessed by the expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase. We have detected no signs of neurogenesis but have confirmed the expression of "neuronal" markers such as Doublecortin in NG2 cells. Nestin-expressing NG2 cells in the amygdala show electrophysiological properties known for oligodendrocyte precursor cells in the corpus callosum. Application of the glutamate agonist kainate elicits a "complex" response consisting of a rapid and long-lasting blockade of the resting K(+) conductance, a transient cationic current, and a transient increase of an outwardly directed K(+) conductance, suggesting the responsiveness of NG2 cells to excitation. Proliferation of NG2 cells increases in response to behavioral stimuli of activity, voluntary wheel running, and environmental enrichment. In addition to reducing the number of newborn microglia, behavioral activity results in a decrease in S100beta-expressing newborn NG2 cells in the amygdala. Because S100beta expression in NG2 cells ceases with oligodendrocyte maturation, this finding suggests that NG2 cells in the amygdala undergo activity-dependent functional alterations, without resulting in a measurable increase in new mature oligodendrocytes over the time period covered by the present study. The adult amygdala thus shows signs of mixed activity-dependent plasticity: reduced numbers of microglia and, presumably, an altered fate of NG2 cells. PMID- 21688216 TI - [New generation physicians - physician shortage - also a moderate problem ]. PMID- 21688217 TI - [Research in surgery: "Soon the cart will run into the wall" (interview by B. E.)]. PMID- 21688219 TI - [Total joint replacement - postoperative fever and leukocytosis]. PMID- 21688220 TI - [Not Available]. PMID- 21688221 TI - [Not Available]. PMID- 21688222 TI - [Not Available]. PMID- 21688223 TI - [110th Anniversary of DGOOC and 60th Anniversary of DGU - 120th Anniversary of "Zeitschrift fur Orthopadie, Orthopadische Chirurgie und Unfallchirurgie"]. PMID- 21688224 TI - [Letter to the Article of D. Goebel and W. Schultz: Physiotherapeutic interventions on an outpatient basis for orthopaedic and trauma surgery: can success be recorded?]. PMID- 21688225 TI - [Letter to the Article of D. Goebel and W. Schultz: Physiotherapeutic interventions on an outpatient basis for orthopaedic and trauma surgery: can success be recorded?]. PMID- 21688226 TI - [Awake craniotomy for brain tumor resection - what does the anaesthesist do?]. AB - The numbers of awake craniotomies performed worldwide are rising. The technique allows a maximum of brain tumor resection with a minimal risk of functional damage in patients, where the tumor is growing close to functional relevant brain areas. The maximal resection improves the long-term outcome of these patients. For the anaesthetist awake craniotomy can be challenging, because he misses the advantages of general anaesthesia (safe airway, suppressed reflexes), but has to deal with the added risks of brain mapping and cortical stimulation (induction of epileptic insults). After adequate patient selection and intense (psychological) preparation a careful anaesthesiologist will be able to accompany the patient throughout this procedure safe and comfortable. This article describes the anaesthesiological management at Erasmus MC, University Medical Centre Rotterdam, The Netherlands, in detail. PMID- 21688227 TI - [Anaesthesia in noma-patients - facts and management of a forgotten disease]. AB - Noma (cancrum oris) is an unspecific bacterial infection in the oro-facial area. In the industrial countries noma is generally unknown, but in the 3rd world - especially in West Africa - it is widespread and one of the main causes of mortalitiy and reason for disability in children. Pathogenesis, clinical course, management and treatment of noma are described with the consequences for anaesthesia. PMID- 21688228 TI - [Patient blood management (part 1) - patient-specific concept to reduce and avoid anemia, blood loss and transfusion]. AB - Patient blood management (PBM) is a patient-specific multidisciplinary, multimodal, evidence-based concept to appropriately conserve and manage a patient's own blood as a vital resource. PBM is based on 3 pillars: the first is the optimization of the patient's endogenous red cell mass, the second is the minimization of bleeding and blood loss and the third involves harnessing and optimizing the patient-specific physiological tolerance of anemia, including adopting more restrictive transfusion thresholds. PBM primarily identifies patients at risk of transfusion and provides a management plan aimed at reducing or eliminating the need for allogeneic transfusion, thus reducing the inherent risks, inventory pressures and the escalating costs associated with transfusion. PBM is applicable to surgical and medical patients. The application of PBM systematically reduces the impact of 3 major contributors to negative outcome: anemia, blood loss and transfusion. PMID- 21688229 TI - [Transport with ongoing cardiopulmonary resuscitation - when does is it make sense?]. AB - The currently valid guidelines for resuscitation of the European Resuscitation Council (ERC) do not give any unambiguous recommendations for "transport with ongoing cardiopulmonary resuscitation". Furthermore, up to now there are no generally accepted criteria for terminating cardiopulmonary resuscitation, apart from certain signs of death. In spite of the generally poor outcome of patients being transported with ongoing cardiopulmonary resuscitation, there are a number of positive case reports and undisputable indications (e.g., in cases with a potentially reversible cause of cardiac arrest). The increase observed over the past few years in the number of patients being transported under cardiopulmonary resuscitation has as yet not been reflected in an improved prognosis for these patients. The use of mechanical chest compression devices with a better quality of chest compression, also under transport conditions, may have an influence on the number transports but this has not yet been evaluated sufficiently with regard to patient outcome. However, the decision to transport a patient resides with the responsible emergency physician who has to evaluate the prognosis for the patient on an individual basis. PMID- 21688230 TI - [Heart failure - therapy with mechanical circulatory support: status quo and perspectives]. PMID- 21688231 TI - [Technical possibilities and limitations of mechanical circulatory support]. AB - Ventricular assist devices (VAD) to support the left (LVAD), the right (RVAD) or both ventricles (BVAD) have emerged as one standard of care for advanced heart failure patients. Initially used to bridge patients to transplantation (BTT) they are now more frequently implanted as permanent support (destination therapy, DT). Bridge to recovery (BTR) is a valid option for only a small number of patients. Although there are different devices available, patient selection, preoperative and intraoperative management, and the timing of VAD implantation are the elements critical to successful circulatory support. PMID- 21688232 TI - [Postoperative management of patients undergoing left ventricular assist device implantation]. AB - Left ventricular assist devices (LVAD) have become an important option for the treatment of patients with advanced heart failure. Unfortunately, patients undergoing LVAD-implantation still experience considerable perioperative morbidity and mortality. Right ventricular failure, bleeding, infections and device-associated problems represent the major postoperative complications. The present overview summarizes current strategies for preoperative risk estimation and for the prevention and treatment of frequently occurring perioperative complications. PMID- 21688233 TI - [Current success and risks of mechanichal circulatory support]. AB - The growing number of patients suffering from severe congestive heart failure (HF) worldwide still means a challenge for the therapeutic options, mainly in the older population. According to the rapid development in the possibilities for mechanical circulatory support (MCS), the increasing use of left ventricular assist devices (LVADs) as bridge to transplantation (BTT) or destination therapy (DT) reflects a change in the up-to-date therapy of HF. This article gives a broad overview concerning indications, patient selection, choice of the device and mainly a study update. It is clearly shown, that VAD therapy has become an effective tool in the treatment of HF, and that the modern continuous flow pumps have replaced the older, bulky, pulsatile devices, especially in the LVAD sector. PMID- 21688234 TI - [The Scientific Working Group, "Young Scientists" of the German Society for Anesthesiology and Intensive Care Medicine]. PMID- 21688235 TI - Concomitant intramedullary pilocytic astrocytoma and conus medullaris myxopapillary ependymoma: a case report. PMID- 21688236 TI - Endoscopic hyaluronic acid/dextranomer gel implantation is effective as first line treatment of vesicoureteral reflux (VUR) in children: a single centre experience. AB - PURPOSE: Aim of the study was to analyse the success rate of endoscopic treatment (ET) using Dx/HA for primary vesicoureteral reflux (VUR) in children and to assess the incidence of postoperative urinary tract infections (UTIs). METHODS: We retrospectively reviewed the charts of 103 children with VUR grade II-V who underwent ET, including children with additional urogenital malformations. Outcomes were verified with voiding cystourethrography (VCUG) and periodical urinalysis. RESULTS: 103 children with a total of 174 ureters underwent ET. 71 patients presented with bilateral VUR. Additional malformations were: duplex ureters (19 patients), posterior urethral valves (PUV) (12 patients), diverticulum (4 patients), neurogenic bladder and ectopic orifice. VUR grade was II in 52, III in 74, IV in 41 and V in 7 ureters, respectively. Postoperative VCUG demonstrated no VUR in 140 ureters (80%) and diminished VUR grade in an additional 18 ureters (total 91%). After a second ET, VCUG was negative in 28 ureters. The overall success rate was 98%. 30 patients had had more than 3 febrile and 67 patients had had 1-3 febrile UTIs before ET. 4 out of 103 patients (3.9%) had 1 febrile UTI within the first year of follow-up. Serious complications after ET were not noted. CONCLUSION: ET is effective at eliminating VUR in children, even in patients with high-grade reflux, as well as in patients with VUR and additional malformations. Early intervention may reduce the incidence of UTIs and prevent long-term renal damage. PMID- 21688237 TI - [Development of diagnosis-related groups in different surgical disciplines]. AB - BACKGROUND: Since the introduction of Diagnosis-Re-lat-ed Groups (DRGs) in Germany, the variables of remuneration have continuously changed. Subjectively, reimbursement by DRG has a negative connotation among all specialities. We analysed the development of reimbursement and length of stay in different surgical specialties. MATERIAL AND METHODS: By grouping the top-10-diagnoses and therapies in hand surgery, trauma surgery, general surgery as well as cardiothoracic and vascular surgery between 2004 and 2010, DRGs were obtained, compared and the data deduced. RESULTS: While the lower threshold of length of stay remained almost the same, mean value and upper threshold became shorter in most of the top-10-diagnoses. During the observation period, total reimbursement increased by 30 % in hand surgery, 20 % in general surgery and 17 % in cardiothoracic and vascular surgery, while in trauma surgery it decreased by 1 %. This corresponds to mean annual growth rates of 4.47 %, 3.08 %, 2.68 % and - 0.15 %, respectively. No correlation was found between the 4 disciplines and macro economic parameters. CONCLUSION: Reductions of mean and upper thresholds of length of stay are present in all surgical disciplines. Total reimbursements developed partially in a contradictory manner. Negative growth involves the danger that hospital investments cannot be realised, especially in the presence of high personnel costs. PMID- 21688238 TI - The language of discovery. AB - Discovery, as a public attribution, and discovering, the act of conducting research, are experiences that entail "languaging" the unknown. This distinguishing property of language - its ability to bring forth, out of the unspoken realm, new knowledge, original ideas, and novel thinking - is essential to the discovery process. In sharing their ideas and views, scientists create co negotiated linguistic distinctions that prompt the revision of established mental maps and the adoption of new ones. While scientific mastery entails command of the conversational domain unique to a specific discipline, there is an emerging conversational domain that must be mastered that goes beyond the language unique to any particular specialty. Mastery of this new conversational domain gives researchers access to their hidden mental maps that limit their ways of thinking about and doing science. The most effective scientists use language to recontextualize their approach to problem-solving, which triggers new insights (previously unavailable) that result in new discoveries. While language is not a replacement for intuition and other means of knowing, when we try to understand what's outside of language we have to use language to do so. PMID- 21688239 TI - Vascular access cannulation in hemodialysis patients - a survey of current practice and its relation to dialysis dose. AB - PURPOSE: The appropriate use of vascular access is of fundamental importance in the treatment of hemodialysis (HD) patients. This survey entailed collecting data on current practice of vascular access cannulation to assess its relation to dialysis dose. METHODS: This international, multicenter, observational, cross sectional survey was performed in 171 dialysis centers of the European dialysis network of Fresenius Medical Care in Europe and South Africa during April 2009. Practice patterns of vascular access cannulations were documented by means of a 24-item questionnaire. Dialysis dose from the documented hemodialysis treatments was derived from the clinical database EuCliD(r). RESULTS: In total, 10,807 cannulations in hemodialysis patients with either arteriovenous fistula (91%) or arteriovenous graft (9%) were documented. For the puncture, the area technique was applied most frequently using 15G and 16G needles. Blood flow rates were mostly between 300 and 400 mL/min and adjusted to the needle size used. In two thirds of cases the arterial needle was placed first, mostly in an antegrade direction, with an average distance to the venous needle of 7.0+/-3.7 cm. More than two-thirds of the cannulations were performed by nurses with more than 5 years of experience in dialysis. A logistic regression model revealed a significantly higher odds ratio to attain Kt/V = 1.2 for retrograde placement of the arterial needle, and for using needles with bigger diameter. CONCLUSIONS: This survey covered a broad number of countries and centers and provides information on current practice of vascular access cannulation, their effect on dialysis dose, and serves as feedback to the dialysis centers for their quality management process. PMID- 21688240 TI - A breakthrough technique for the removal of a hemodialysis catheter stuck in the central vein: endoluminal balloon dilatation of the stuck catheter. AB - BACKGROUND: Hemodialysis (HD) catheters can get stuck in the central vein after long-term use and their removal might become difficult especially in patients with fibrosed or occluded central veins. Herein, a breakthrough technique is reported for the easy removal of a stuck HD catheter from the central vein. CASE REPORT: Attempts were made to remove a tunneled double-lumen HD catheter from the central vein of a 74-year-old woman, only to find that the catheter was stuck. The patient was transferred to the operating room and a skin incision was made in the neck and the subcutaneous portion of the HD catheter was retrieved from the tunnel. Under fluoroscopy, a guide wire was inserted into one lumen of the HD catheter and advanced into the right atrium beyond the catheter tip. A 5 mm * 4 cm balloon angioplasty catheter was then inserted into the HD catheter lumen over the guide wire and advanced into the jugular vein junction of the HD catheter around the thoracic inlet. The balloon was inflated to its maximum dimension and pressure. This endoluminal dilatation of the HD catheter was continued by deflating the balloon and then pushing the angioplasty catheter 4 cm at a time towards the tip of the HD catheter in the right atrium. After a second balloon angioplasty catheter of 6 mm * 4 cm was used to expand the entire segment of the other lumen, the HD catheter was pulled out easily from the central vein without any resistance. COMMENTS: The endoluminal balloon dilatation of the HD catheter not only separates the stuck HD catheter from the adherent vein by breaking the adhesions between them, but also expands the vein simultaneously, thus enabling easy removal of the HD catheter. PMID- 21688241 TI - Sharp needle recanalization for salvaging hemodialysis accesses with chronically occluded peripheral outflow. AB - PURPOSE: To assess the effectiveness of sharp needle recanalization (SNR) for treatment of chronically occluded venous outflow in hemodialysis access. METHODS: A retrospective analysis of patient records from January 2006 to March 2010 was conducted. Forty-four hemodialysis patients (31 fistulas, 13 grafts) were referred for arm swelling (18%), excessive bleeding after dialysis (29%), and thrombosis (53%). All patients had chronic occlusion of the outflow vein which failed conventional recanalization techniques. A new outflow pathway was established by advancing a 21g needle and dilating the subcutaneous tract to bridge the fistula body to a juxtaposed patent vein. If necessary, uncovered or covered stents were utilized to maintain patency of the newly formed subcutaneous tract. RESULTS: Forty-four patients underwent 45 SNR procedures, with restoration of normal function and complete relief of symptoms in 40 (91%) patients. The average tract length was 15 mm (range, 1 to 32) and the average dilatation diameter was 8 mm. During the initial SNR procedure, bare metal (n=21) or covered (n=5) stents were inserted in 26 patients. The average follow-up was 18.4 months (range, 0.2 to 48 months). No major complications were observed with the procedure. At 12 months, the primary access, primary tract, and secondary access patencies were 10%, 51%, and 92%, respectively. Percutaneous thrombectomy procedures were performed at a rate of 1.16 per access-year and the number of interventions within the tract was 0.94 per access-year. CONCLUSIONS: Sharp needle recanalization is an effective percutaneous treatment for restoring function to hemodialysis accesses with chronically occluded venous outflow pathways. PMID- 21688242 TI - Time to move away from damage control strategy in hemodialysis vascular access management: a view from Saudi Arabia. AB - For the last 40 years, most of the research and publications on hemodialysis access, has focused on the management of its complications e.g. thrombosis, infection, aneurysms. In other words, a damage control strategy. While this is undoubtedly an important part of access management, it is a deficient reactive strategy that does not enhance a better quality of life for patients or help reduce the burden on health care resources. To achieve these objectives, efforts should be directed at ways which provide a longer access life with fewer complications. Such an approach would save costs and reduce the suffering of the patient. In this paper we will focus on hemodialysis management in Saudi Arabia, describe the reasons for the current unsatisfactory situation, and highlight possible remedies. PMID- 21688243 TI - Independent prediction factors for primary patency loss in arteriovenous grafts within six months. AB - PURPOSE: The objective of this study was to explore the association between loss of primary functional patency within 6 months of first use and demographic and clinical characteristics in patients with arteriovenous grafts (AVGs) receiving chronic hemodialysis. The knowledge and management of these characteristics will minimize the proportion of catheterdependent dialysis patients for whom AVGs are the best choice. METHODS: This was a retrospective study of all chronic hemodialysis patients with AVGs followed by the Southern Alberta Renal Program from January 2005 to June 2008. Demographic and clinical variables and initial intra-access blood flow (IABF) were compared between those with and without loss of primary functional patency. To determine the contribution of independent variables to the dependant variable of loss of primary functional patency, a multivariable analysis using logistic regression was performed. RESULTS: The incidence of primary failure was 30% (107/359). Multivariable analysis found that low initial IABF (<650 mL/ min, odds ratio [OR] 31, P < 0.001), presence of diabetes (OR 3.5, P = 0.001), older age (>65 years OR 3.2, P< 0.001), and presence of peripheral vascular disease (OR 2.5, P< 0.005) were independently associated with loss of primary patency. CONCLUSIONS: AVGs are sometimes a better choice for those patients in which the time to and probability of successful fistula maturation may be a concern. Close monitoring of AVGs in patients with the identified risk factors associated with loss of primary patency may improve the life expectancy of the access. PMID- 21688244 TI - Malign epithelioid tumor at the site of an arteriovenous fistula in a dialysis patient. PMID- 21688245 TI - Vascular access for hemodialysis via the iliac vessels. PMID- 21688246 TI - Spontaneous delayed expansion of Bard G2 X filter upper struts. PMID- 21688247 TI - Nephrology around Europe: organization models and management strategies: Spain. AB - The main aim of this report is to present a picture of the current organization of nephrology in Spain. The Spanish health system offers almost universal coverage, a wide variety of services and a high-quality network of hospitals and primary care centers. Spain has a specialized health care training system that is highly developed, highly regulated, with the capacity to provide high-quality training in 54 different specialties. Nephrology is basically a hospital-based specialty. There are no private dialysis patients in Spain. Hemodialysis centers are 40% public, 15% private and 45% run by companies. The National Health System covers 95% of the population, and there is no cost to patients for treatment of renal disease (dialysis and transplant). We observed a clear decrease of nephrology in residents' election rankings, with position 29 out of 47 specialties in 2007. Some of the reasons for this are the complexity of the subject, no clear information at the university, reduction of professional posts and a very good public service with minimal private practice. In Spain, a model of organization for transplantation was adopted based on a decentralized transplant coordinating network. For cadaveric donors, it compares favorably with rates in other Western countries. Living donor transplantation is very low in Spain--just 10% of total renal transplantation activity. New programs due to financial constraints need to include reduced dialysis costs, greater cost effectiveness of prescriptions, better handling of ethical issues related to the need for using a clinical score of chronic kidney disease patients to make decisions about conservative or renal replacement therapy and an action plan for improvement of organ donation and transplantation. Recovery of skills (acute kidney injury, biopsies, vascular access, etc.), research and advances in autonomous activities (imaging, surgical and medical vascular training, etc.) are some of the future educational paths needed in nephrology. Adequate decisions in the context of economic restrictions need to be discussed for the sustainability of nephrological care. PMID- 21688248 TI - Incident isolated 1,25(OH)(2)D(3) deficiency is more common than 25(OH)D deficiency in CKD. AB - INTRODUCTION: Vitamin D deficiencies are well described in general populations and in those with chronic kidney disease (CKD). Although serum 25(OH)D may be a good indicator of vitamin D status in healthy individuals, the hydroxylated product, 1,25(OH)(2)D, essential for important biological functions such as mineral metabolism, bone turnover, regulation of protein synthesis, cell differentiation and proliferation may be a more suitable indicator for individuals with CKD. METHODS: We report an observational prospective cohort study of the incidence after 12 months of new isolated 1,25(OH)(2)D and new 25(OH)D deficiency in CKD patients (estimated glomerular filtration rate [eGFR] <60 ml/min), who were vitamin D replete at baseline. All analyses were run in a central laboratory. RESULTS: Of 1,256 patients who completed the study at 12 months, 631 were replete in both 25(OH)D and 1,25(OH)(2)D at baseline; at 12 months, 65% remained replete, 25% developed an isolated 1,25(OH)(2)D deficiency, whereas only 6% developed an isolated 25(OH)D deficiency. Based on the multinomial logistic regression model, factors that were associated with 12-month changes in vitamin D status were diabetes, baseline values of eGFR, albumin and both 25(OH)D and 1,25(OH)(2)D (all p values <0.03). Patients with diabetes, lower albumin, lower eGFR, lower levels of 25(OH)D and 1,25(OH)(2)D at baseline were at increased risk of developing isolated 1,25(OH)(2)D deficiency. CONCLUSIONS: The high incidence of new isolated 1,25(OH)(2)D deficiency as compared with new 25(OH)D deficiency, in the presence of 25(OH)D sufficiency, brings into question the value of measuring 25(OH)D levels in CKD. The significance of these findings and implications for replacement strategies require further study. PMID- 21688249 TI - Inhibitors of vascular calcification as potential therapeutic targets. AB - Vascular calcification is frequent in the general population. Its incidence increases with age. It contributes to cardiovascular morbidity and mortality in patients with advanced atherosclerosis, in the presence or absence of diabetes mellitus and chronic kidney disease (CKD). Both diabetes and CKD aggravate its degree of severity and accelerate its progression. Vascular calcification is the result of both passive and active processes of calcium phosphate deposition in the arterial wall. These processes are more or less successfully opposed by inhibitory proteins and nonpeptidic factors. In the present overview we discuss the roles of several among these vascular calcification inhibitors which represent potential therapeutic targets. PMID- 21688250 TI - The impact of short daily and nocturnal hemodialysis on quality of life, cardiovascular risk and survival. AB - End-stage renal disease (ESRD) is a significant global health problem that places a considerable burden on health care resources. The leading cause of death in ESRD patients is cardiovascular disease, which is often preceded by changes in cardiac geometry, including left ventricular hypertrophy (LVH). Treatments that result in regression of LVH have been shown to lead to better clinical outcomes. Globally, most ESRD patients receive conventional hemodialysis (CHD) 3 times per week, but mortality rates remain high and quality of life (QoL) is poor. Increasing the frequency of HD to 5 or 6 times per week, either as short daily HD (SDHD) or nocturnal HD (NHD), can improve QoL, reduce cardiovascular risk and prolong survival, compared with CHD. Improvements in these end points are likely driven by enhancements in fluid management, blood pressure control, mineral metabolism and left ventricular mass regression. From a practical standpoint, SDHD and NHD are best delivered at home. Barriers to adoption of home HD are chiefly modifiable, and may include lack of a care partner or family support, fear of cannulation and access disconnection, and uncertainty in one's ability to learn the procedures required to perform self-HD. On a positive note, substantial progress has been made to overcome these and other perceived barriers. PMID- 21688252 TI - Long-term close follow-up of chorioretinal lesions in presumed ocular tuberculosis. AB - PURPOSE: To evaluate the long-term outcome (up to 7 years) of presumed ocular tuberculosis (TB) when the therapeutic decision was based on WHO guidelines. METHODS: Twelve out of 654 new uveitic patients (1998-2004) presented with choroiditis and positive tuberculosis skin test (TST) (skin lesion diameter >15 mm). Therapy was administered according to WHO recommendations after ophthalmic and systemic investigation. The area size of ocular lesions at presentation and after therapy, measured on fluorescein and indocyanine green angiographies, was considered the primary outcome. Relapse of choroiditis was considered a secondary outcome. The T-SPOT TB test was performed when it became available. RESULTS: Visual acuity significantly improved after therapy (p=0.0357). The mean total surface of fluorescein lesions at entry was 44.8 +/- 20.9 (arbitrary units) and decreased to 32.5 +/- 16.9 after therapy (p=0.0165). The mean total surface of indocyanine green lesions at entry was 24.5 +/- 13.3 and decreased to 10.8 +/- 5.4 after therapy (p=0.0631). The T-SPOT TB revealed 2 false TST-positive results. The mean follow-up was 4.5 +/- 1.5 years. Two relapses out of 10 confirmed ocular TB was observed after complete lesion healing, 2.5 years and 4.5 years after therapy, respectively. CONCLUSIONS: A decrease of ocular lesion mean size and a mean improvement of VA were observed after antituberculous therapy. Our long-term follow-up of chorioretinal lesions demonstrated relapse of ocular tuberculosis in 10% of patients with confirmed ocular TB, despite complete initial retinal scarring. PMID- 21688253 TI - Bilateral symmetric autosomal dominant sector chorioretinopathy with late maculopathy: a review based on a case with 48 years follow-up. AB - PURPOSE: To describe the long-term course of bilateral symmetric autosomal dominant sector chorioretinopathy in a 79-year-old man who was diagnosed at age 31. METHODS: Ophthalmic examinations including fundus photography, fluorescein and indocyanine angiography, adaptometry, and ocular electrophysiology were performed at intervals from 1962 to 2010. RESULTS AND CONCLUSIONS: The patient experienced no visual symptoms during his entire working life, but acquired an exudative maculopathy in his left eye at age 67. Two years later, a central subretinal neovascular membrane affected the right eye. The latter responded only temporarily to photodynamic therapy (Visudyne), and from age 71 he had best corrected visual acuities <0.1 in both eyes, with eccentric fixation. We are not aware of any report on late macular involvement in this disorder. Whether the maculopathy should be considered a late manifestation of the sector chorioretinopathy or a coincidental occurrence of age-related macular degeneration remains unsettled. PMID- 21688254 TI - Use of in vivo biotinylation for chromatin immunoprecipitation. AB - This unit describes a system for expression of biotinylated proteins in mammalian cells in vivo, and its application to chromatin immunoprecipitation (ChIP). The system is based on co-expression of the target protein fused to a short biotin acceptor domain, together with the biotinylating enzyme BirA from Escherichia coli. The superior strength of the biotin-avidin interaction in the modified ChIP protocol presented here allows one to employ more stringent washing conditions, resulting in a better signal/noise ratio. Methods for interpreting the data obtained from ChIP samples analyzed by qPCR, and methods for testing the efficiency of biotinylation using a streptavidin gel-shift are also presented. In addition, a complementary method, based on isothermal multiple strand displacement amplification (IMDA) of circular concatemers generated from the DNA fragments obtained after ChIP, is described. This method helps to decrease bias in DNA amplification and is useful for the analysis of complex mixtures of DNA fragments typically generated in miniscale ChIP experiments. PMID- 21688255 TI - Evaluation of antiseptic antiviral activity of chemical agents. AB - Antiviral antisepsis and disinfection are crucial for preventing the environmental spread of viral infections. Emerging viruses and associated diseases, as well as nosocomial viral infections, have become a real issue in medical fields, and there are very few efficient and specific treatments available to fight most of these infections. Another issue is the potential environmental resistance and spread of viral particles. Therefore, it is essential to properly evaluate the efficacy of antiseptics-disinfectants (ATS-D) on viruses. ATS-D antiviral activity is evaluated by (1) combining viruses and test product for an appropriately defined and precise contact time, (2) neutralizing product activity, and (3) estimating the loss of viral infectivity. A germicide can be considered to have an efficient ATS-D antiviral activity if it induces a >3 or >4 log(10) reduction (American and European regulatory agency requirements, respectively) in viral titers in a defined contact time. This unit describes a global methodology for evaluating chemical ATS-D antiviral activity. PMID- 21688256 TI - Rapid titration of viruses by flow cytometry. AB - Traditionally, the most common methods used to titrate virus stocks are the plaque assay and the hemagglutination assay. The protocol presented here is based on the detection of viral-expressed proteins in infected cells by flow cytometry. It is simpler and more rapid than the traditional plaque-forming assay and it enables high-throughput analyses. PMID- 21688257 TI - An enzymatic assay for detection of viral entry. AB - This unit describes a viral entry assay where a beta-lactamase reporter protein fused to the matrix protein of either influenza (BlaM1) or ebola virus (BlaVP40) is packaged as a structural component into virus-like particles (VLPs). The Bla reporter is released upon fusion with target cells and can be detected in live cells by flow cytometry, microscopy, or a fluorometric plate reader for utility in high-throughput screening approaches. The transfer of Bla to a target cell by BlaM1 or BlaVP40 VLPs requires the presence of influenza hemagglutinin (HA) and neuraminidase (NA) or EboV glycoprotein (GP), respectively. This straightforward assay has broad application for studying the entry steps of enveloped viruses, especially those that require high levels of biosafety containment. PMID- 21688258 TI - Neurodevelopmental MRI brain templates for children from 2 weeks to 4 years of age. AB - Spatial normalization and segmentation of pediatric brain magnetic resonance images (MRI) data with adult templates may impose biases and limitations in pediatric neuroimaging work. To remedy this issue, we created a single database made up of a series of pediatric, age-specific MRI average brain templates. These average, age-specific templates were constructed from brain scans of individual children obtained from two sources: (1) the NIH MRI Study of Normal Brain Development and (2) MRIs from University of South Carolina's McCausland Brain Imaging Center. Participants included young children enrolled at ages ranging from 8 days through 4.3 years of age. A total of 13 age group cohorts spanning the developmental progression from birth through 4.3 years of age were used to construct age-specific MRI brain templates (2 weeks, 3, 4.5, 6, 7.5, 9, 12, 15, 18 months, 2, 2.5, 3, 4 years). Widely used processing programs (FSL, SPM, and ANTS) extracted the brain and constructed average templates separately for 1.5T and 3T MRI volumes. The resulting age-specific, average templates showed clear changes in head and brain size across ages and between males and females, as well as changes in regional brain structural characteristics (e.g., myelin development). This average brain template database is available via our website (http://jerlab.psych.sc.edu/neurodevelopmentalmridatabase) for use by other researchers. Use of these age-specific, average pediatric brain templates by the research community will enhance our ability to gain a clearer understanding of the early postnatal development of the human brain in health and in disease. PMID- 21688259 TI - Multiparameter grouping delineates heterogeneous populations of human IL-17 and/or IL-22 T-cell producers that share antigen specificities with other T-cell subsets. AB - The ontogenic relationship between pro-inflammatory populations of interleukin-17 (IL-17A)- and/or IL-22-producing T cells and other T-cell subsets is currently unclear in humans. To appreciate T helper cell-lineage commitment, we combined cytokine production profiles of in vitro expanded T-cell clones with T-cell receptor (TCR) clonotypic signatures. Moreover, ex vivo cytokine production profiles at the single-cell level were analyzed using an original approach based on the hierarchical cluster analysis of multiparametric flow cytometry data. These combined approaches enabled the delineation of distinct functional T-cell subsets, including Th1, Th2, Tr1, Th17 cells and a highly polyfunctional IL-22 producing T-cell population. Cluster analysis highlighted that the IL-22 producing T-cell population should be considered independently from the Th17 and Th1 subsets, although it was more closely related to the former. In parallel, we observed extensive TCRalphabeta sharing across all five subsets defined. The strategy described here allows the objective definition of cellular subsets and an unbiased insight into their similarities. Together, our results underscore the ontogenic plasticity of CD4(+) T-cell progenitors, which can adopt a differentiation profile irrespective of antigen specificity. PMID- 21688260 TI - Sympathetic and parasympathetic responses to social stress across adolescence. AB - Many transformations that occur in adolescence are related to emotion and emotion regulation, yet very little is known about the autonomic underpinnings of these changes. The aim of the study was to document age-related differences in autonomic responses to social stress and relations to emotion regulation. Ninety nine female adolescents engaged in a paced breathing and a spontaneous speech task while electrocardiography measurements were taken. Spectral decomposition of the heart period data was used to create measures of sympathetic and parasympathetic activity. Results revealed a positive correlation between age and sympathetic activity and a negative correlation between age and parasympathetic activity. These findings contribute to a better understanding of the age-related norms of cardiac variability across adolescence. PMID- 21688261 TI - Triggering of TNFRSF25 promotes CD8+ T-cell responses and anti-tumor immunity. AB - TNFRSF25 is a member of the TNF receptor superfamily (TNFRSF) that binds to the TNF-like protein TL1A. Although recent studies have demonstrated a role for TNFRSF25 in regulating CD4(+) T-cell responses, it remains to be determined if TNFRSF25 functions as a costimulatory receptor for CD8(+) T cells. Here, we demonstrate that ectopic expression of TL1A on mouse plasmacytomas promotes elimination of tumor cells in a CD8(+) T-cell-dependent manner and renders mice immune to a subsequent challenge with tumor cells. To gain further insight into the role of TNFRSF25 in CD8(+) T-cell responses, we analyzed the effect of TNFRSF25 triggering on OT-I TCR transgenic T cells. We demonstrate that TNFRSF25 triggering in vivo with soluble TL1A promotes the proliferation and accumulation of antigen-specific CD8(+) T cells as well as their differentiation into CTLs. Furthermore, we show that TNFRSF25 also functions as a costimulatory receptor for memory CD8(+) T cells. Thus, TNFRSF25 triggering enhances the secondary expansion of endogenous antigen-specific memory CD8(+) T cells. Our data suggest that TNFRSF25 agonists, such as soluble TL1A, could potentially be used to enhance the immunogenicity of vaccines that aim to elicit human anti-tumor CD8(+) T cells. PMID- 21688262 TI - Vaccination with filamentous bacteriophages targeting DEC-205 induces DC maturation and potent anti-tumor T-cell responses in the absence of adjuvants. AB - The efficacy of a new vaccine-delivery vector, based on the filamentous bacteriophage fd displaying a single-chain antibody fragment known to bind the mouse DC surface molecule DEC-205, is reported. We demonstrate both in vitro and in vivo an enhanced receptor-mediated uptake of phage particles expressing the anti-DEC-205 fragment by DCs. We also report that DCs targeted by fd virions in the absence of other stimuli produce IFN-alpha and IL-6, and acquire a mature phenotype. Moreover, DC-targeting with fd particles double-displaying the anti DEC-205 fragment on the pIII protein and the OVA(257-264) antigenic determinant on the pVIII protein induced potent inhibition of the growth of the B16-OVA tumor in vivo. This protection was much stronger than other immunization strategies and similar to that induced by adoptively transferred DCs. Since targeting DEC-205 in the absence of DC activation/maturation agents has previously been described to result in tolerance, the ability of fd bacteriophages to induce a strong tumor specific immune response by targeting DCs through DEC-205 is unexpected, and further validates the potential employment of this safe, versatile and inexpensive delivery system for vaccine formulation. PMID- 21688263 TI - Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways. AB - ATP citrate lyase (ACL) catalyzes the conversion of cytosolic citrate to acetyl CoA and oxaloacetate. A definitive role for ACL in tumorigenesis has emerged from ACL RNAi and chemical inhibitor studies, showing that ACL inhibition limits tumor cell proliferation and survival and induces differentiation in vitro. In vivo, it reduces tumor growth leading to a cytostatic effect and induces differentiation. However, the underlying molecular mechanisms are poorly understood and agents that could enhance the efficacy of ACL inhibition have not been identified. Our studies focus on non-small cell lung cancer (NSCLC) lines, which show phosphatidylinositol 3-kinase (PI3K)/AKT activation secondary to a mutation in the K-Ras gene or the EGFR gene. Here we show that ACL knockdown promotes apoptosis and differentiation, leading to the inhibition of tumor growth in vivo. Moreover, in contrast to most studies, which elucidate how activation/suppression of signaling pathways can modify metabolism, we show that inhibition of a metabolic pathway "reverse signals" and attenuates PI3K/AKT signaling. Additionally, we find that statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which act downstream of ACL in the cholesterol synthesis pathway, dramatically enhance the anti-tumor effects of ACL inhibition, even regressing established tumors. With statin treatment, both PI3K/AKT and the MAPK pathways are affected. Moreover, this combined treatment is able to reduce the growth of EGF receptor resistant tumor cell types. Given the essential role of lipid synthesis in numerous cancers, this work may impact therapy in a broad range of tumors. PMID- 21688264 TI - Glucocorticoid alternative effects on proliferating and differentiated mammary epithelium are associated to opposite regulation of cell-cycle inhibitor expression. AB - Glucocorticoids influence post-natal mammary gland development by sequentially controlling cell proliferation, differentiation, and apoptosis. In the mammary gland, it has been demonstrated that glucocorticoid treatment inhibits epithelial apoptosis in post-lactating glands. In this study, our first goal was to identify new glucocorticoid target genes that could be involved in generating this effect. Expression profiling, by microarray analysis, revealed that expression of several cell-cycle control genes was altered by dexamethasone (DEX) treatment after lactation. Importantly, it was determined that not only the exogenous synthetic hormone, but also the endogenous glucocorticoids regulated the expression of these genes. Particularly, we found that the expression of cell cycle inhibitors p21CIP1, p18INK4c, and Atm was differentially regulated by glucocorticoids through the successive stages of mammary gland development. In undifferentiated cells, DEX treatment induced their expression and reduced cell proliferation, while in differentiated cells this hormone repressed expression of those cell cycle inhibitors and promoted survival. Therefore, differentiation status determined the effect of glucocorticoids on mammary cell fate. Particularly, we have determined that p21CIP1 inhibition would mediate the activity of these hormones in differentiated mammary cells because over-expression of this protein blocked DEX-induced apoptosis protection. Together, our data suggest that the multiple roles played by glucocorticoids in mammary gland development and function might be at least partially due to the alternative roles that these hormones play on the expression of cell cycle regulators. PMID- 21688265 TI - Midkine prevented hypoxic injury of mouse embryonic stem cells through activation of Akt and HIF-1alpha via low-density lipoprotein receptor-related protein-1. AB - Stem cell functions are dramatically altered by oxygen in tissue culture, which means the antioxidant/oxidant balance is critical for protection as well as toxicity. This study examined the effect of the heparin-binding growth factor midkine (MK) on hypoxia-induced apoptosis and related signal pathways in mouse embryonic stem cells (mESCs). Hypoxia (60 h) increased lactate dehydrogenase release and apoptosis, and reduced cell viability and proliferation. These effects were reversed by MK (100 ng/ml). MK also reversed hypoxia-induced increases of intracellular reactive oxygen species, c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) phosphorylation. Blockage of JNK and p38 MAPK using small interference (si)RNAs produced a decrease in apoptosis. A loss of mitochondrial membrane potential, increases of cytochrome c release from mitochondria to cytosol, and cleaved caspase-3 expression, as well as decreases in cIAP-2 and Bcl-2 were also reversed by MK. Hypoxia alone and hypoxia with MK increased low-density lipoprotein receptor-related protein-1 (LRP 1) mRNA and protein expression. Hypoxia with MK rapidly increased serine/threonine protein kinase (Akt) phosphorylation which reversed by LRP-1 Ab (0.1 ug/ml) and prolonged heme oxygenase-1 (HO-1) expression. In addition, hypoxia with MK increased the expression of hypoxia-inducible factor-1alpha (HIF 1alpha). Moreover, inhibition of Akt, HO-1, and HIF-1alpha signaling pathways abolished the MK-induced blockage of apoptosis. In conclusion, MK partially prevented hypoxic injury of mESCs through activation of Akt, HO-1, and HIF-1alpha via LRP-1. PMID- 21688267 TI - Post-transcriptional regulation of the Ras-ERK/MAPK signaling pathway. AB - The Ras-ERK/MAP (Mitogen-Activated Protein) kinase signaling pathway governs many cellular processes such as proliferation, differentiation, cell fate, homeostasis, and survival in all eukaryotes. Constitutive activation of the Ras ERK/MAPK signaling pathway often leads to promotion of abnormal cell growth and tumorigenesis. Although the regulation of the Ras-ERK/MAPK signaling pathway by post-translational modification has been well elucidated, post-transcriptional regulations of this pathway are beginning to emerge in invertebrates and this work is extended to humans. In this review, we describe the conserved regulation of Ras-ERK/MAPK signaling by RNA-binding proteins (PUF, KH-domain, HuR, and LARP) and microRNAs (let-7 family miRNAs) and important implications for human diseases including cancers. PMID- 21688266 TI - Neurosteroid allopregnanolone regulates EAAC1-mediated glutamate uptake and triggers actin changes in Schwann cells. AB - Recent evidence shows that neurotransmitters (e.g., GABA, Ach, adenosine, glutamate) are active on Schwann cells, which form myelin sheaths in the peripheral nervous system under different pathophysiologic conditions. Glutamate, the most important excitatory neurotransmitter, has been recently involved in peripheral neuropathies, thus prevention of its toxic effect is desirable to preserve the integrity of peripheral nervous system and Schwann cells physiology. Removal of glutamate from the extracellular space is accomplished by the high affinity glutamate transporters, so we address our studies to analyze their functional presence in Schwann cells. We first demonstrate that Schwann cells express the EAAC1 transporter in the plasma membrane and in intracellular vesicular compartments of the endocytic recycling pathways. Uptake experiments confirm its presence and functional activity in Schwann cells. Secondly, we demonstrate that the EAAC1 activity can be modulated by exposure to the neurosteroid allopregnanolone 10 nM (a progesterone metabolite proved to support Schwann cells). Transporter up-regulation by allopregnanolone is rapid, does not involve protein neo-synthesis and is prevented by actin depolymerization. Allopregnanolone modulation involves GABA-A receptor and PKC activation, promotes the exocytosis of the EAAC1 transporter from intracellular stores to the Schwann cell membrane, in actin-rich cell tips, and modifies the morphology of cell processes. Finally, we provide evidence that glutamate transporters control the allopregnanolone-mediated effects on cell proliferation. Our findings are the first to demonstrate the presence of a functional glutamate uptake system, which can be dynamically modulated by allopregnanolone in Schwann cells. Glutamate transporters may represent a potential therapeutic target to control Schwann cell physiology. PMID- 21688268 TI - Let's talk: a narrative of mental illness, recovery, and the psychotherapist's personal treatment. AB - This article describes the author's experience in psychotherapy, beginning as a suicidal teenager with a dismal prognosis, through 5 years of hospitalization, including shock treatment that erased most memory before age 20, through an Ivy League education, and successful professional career. Retraumatization triggered by reading her hospital records 40 years later adds a unique perspective, as the author watched, but could not control, a process within herself that she regularly addressed as therapist with her own patients. Healing aspects of relationships with three psychodynamic psychotherapists (two psychiatrists and a social worker), credited with her survival and success, are examined. A dramatic interview with Harold Searles, her psychiatrist's supervisor, and its role in her recovery is considered. Lasting lessons concerning the healing aspects of psychotherapy, the effects of repressed early trauma encountered late in life, the need to counter stigma, and the value of personal psychotherapy are discussed. PMID- 21688269 TI - Classical complement activation as a footprint for murine and human antiphospholipid antibody-induced fetal loss. AB - Recurrent miscarriage, fetal growth restriction and intrauterine fetal death are frequently occurring complications of pregnancy in patients with systemic lupus erythaematosus (SLE) and antiphospholipid syndrome (APS). Murine models show that complement activation plays a pivotal role in antiphospholipid antibody-mediated pregnancy morbidity, but the exact pathways of complement activation and their potential role in human pregnancy are insufficiently understood. We hypothesized that the classical pathway would play a major role in inducing fetal loss. Pregnant C57BL/6 mice and mice deficient in C1q and factor D were injected with antiphospholipid antibodies or normal human IgG. Mouse placentas were subsequently stained with an anti-C4 antibody and anti-normal human IgG to determine the presence of classical complement activation and IgG binding. Findings in mice were validated in 88 human placentae from 83 women (SLE and APS cases versus controls), which were immunohistochemically stained for C4d, C1q, properdin and MBL. Staining patterns were compared to pregnancy outcome. In murine placentae of mice pretreated with antiphospholipid antibodies, increased C4 deposition was observed, which was associated with adverse fetal outcome but not with IgG binding. In humans, diffuse C4d staining at the feto-maternal interface was present almost exclusively in patients with SLE and/or APS (p < 0.001) and was related to intrauterine fetal death (p = 0.03). Our data show that presence of C4d in murine and human placentae is strongly related to adverse fetal outcome in the setting of SLE and APS. The excessive deposition of C4d supports the concept of severe autoantibody-mediated injury at the fetal-maternal interface. We suggest C4d as a potential biomarker of autoantibody-mediated fetal loss in SLE and APS. PMID- 21688271 TI - Three-dimensional sonograph of a monochorionic diamniotic triplet pregnancy. AB - A monochorionic diamniotic triplet pregnancy was diagnosed by sonographic scan at 9 weeks of gestation. The three embryos appeared to share the same trophoblast, with two of them sharing the same amniotic sac. The two amniotic sacs were divided by a thin membrane, with no chorionic projection within it, and each amniotic sac presented a single yolk sac. Only few cases of nontrichorionic triamniotic triplets have been reported in the literature. Although the diagnosis was reached using the two-dimensional ultrasound, the complementary use of three dimensional ultrasound helped in confirming the diagnosis, and in offering the couple an adequate counseling. PMID- 21688270 TI - Contrast-enhanced sonography of postbiopsy arteriovenous fistulas in kidney grafts. AB - PURPOSE: To assess the usefulness of contrast-enhanced ultrasonography (CE-US) in the visualization of a kidney graft following a biopsy that was complicated by an arteriovenous fistula (AVF). METHODS: Four postrenal transplant patients who had developed AVFs following graft biopsy were examined using standard US and CE-US. Additionally, follow-up examinations were conducted using CE-US, at 4-6 weeks and 10-12 weeks following fistula closure. RESULTS: The fistulas were detected using color Doppler US, Power Doppler US, and B-flow technique. Reduced parenchymal flow was only detected in one case using standard flow visualization techniques. CE-US allowed for the visualization of regions of disturbed parenchymal perfusion that were not visible in the standard examinations. At follow-up, B-mode ultrasound and standard flow examinations appeared normal. However, all contrast enhanced images showed clearly demarcated residual regions of reduced parenchymal perfusion, in areas where the fistulas had been previously present. CONCLUSIONS: A posttraumatic AVF reduces parenchymal perfusion in the affected region. CE-US examination may help in monitoring fistulas during the active phase and following spontaneous closure. PMID- 21688272 TI - Unusual fetal abdominal wall presentation mimicking an abdominal wall defect. PMID- 21688273 TI - Prenatal diagnosis of choledochal cyst: a case report. AB - Choledochal cyst is one of the intra-abdominal abnormalities of the biliary ducts that present as a cystic mass in the right upper quadrant abdomen. Prenatal diagnosis has been achieved by the demonstration of a connection between a dilated common bile duct and a cystic lesion. In this report, we describe a pregnant woman in whom routine fetal anomaly scan strongly suggested a choledochal cyst at 29 weeks of gestation by demonstrating a round cystic mass in the right upper quadrant of the abdomen, completely separated from the stomach, bowel loops, and gall bladder, and which showed a connection with the dilated common bile duct. PMID- 21688274 TI - Prenatal sonographic diagnosis of tuberous sclerosis complex. AB - We report the case of a male fetus with tuberous sclerosis complex (TSC), in whom multiple cardiac rhabdomyomas and renal angiomyolipomas were detected at 33 weeks by ultrasound with additional brain lesions detected on MRI, all confirmed after birth. DNA analysis of the TSC2 gene detected a de novo mutation in the TSC2 gene. Postnatal follow-up and neurological examination were normal, as were the results of Holter monitoring. PMID- 21688275 TI - Do physical and relational aggression explain adolescents' friendship selection? The competing roles of network characteristics, gender, and social status. AB - The role of physical and relational aggression in adolescents' friendship selection was examined in a longitudinal sample of 274 Chilean students from 5th and 6th grade followed over 1 year. Longitudinal social network modeling (SIENA) was used to study selection processes for aggression while influence processes were controlled for. Furthermore, the effects of network characteristics (i.e., reciprocity and transitivity), gender, and social status on friendship selection were examined. The starting assumption of this study was that selection effects based on aggression might have been overestimated in previous research as a result of failing to consider influence processes and alternative characteristics that steer friendship formation. The results show that selection effects of both physical and relational aggression disappeared when network effects, gender, and social status were taken into account. Particularly gender and perceived popularity appeared to be far more important determinants of friendship selection over time than aggression. Moreover, a peer influence effect was only found for relational aggression, and not for physical aggression. These findings suggest that similarity in aggression among befriended adolescents can be considered to be mainly a by-product rather than a leading dimension in friendship selection. PMID- 21688276 TI - Heart failure after myocardial infarction: clinical implications and treatment. AB - Heart failure is a frequent complication of myocardial infarction. Several factors, such as recurrent myocardial ischemia, infarct size, ventricular remodeling, stunned myocardium, mechanical complications, and hibernating myocardium influence the appearance of left ventricular systolic dysfunction after myocardial infarction. Importantly, its presence increases the risk of death by at least 3- to 4-fold. The knowledge of the mechanisms and clinical features are essential for the diagnosis and treatment of left ventricular dysfunction and heart failure after myocardial infarction. Therefore, this review will focus on the clinical implications and treatment of heart failure after myocardial infarction. (c) 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose. PMID- 21688277 TI - Field-amplified online sample stacking capillary electrophoresis UV detection for plasma malondialdehyde measurement. AB - Malondialdehyde (MDA) determination is the most widely used method for monitoring lipid peroxidation. Here, we describe an easy field-amplified sample injection (FASI) CE method with UV detection for the detection of free plasma MDA. MDA was detected within 8 min by using 200 mmol/L Tris phosphate pH 5.0 as running buffer. Plasma samples treated with ACN for protein elimination were directly injected on capillary without complex cleanup and/or sample derivatization procedures. Using electrokinetic injection, the detection limit in real sample was 3 nmol/L, thus improving of about 100-fold the LOD of the previous described methods based on CE. Precision tests indicate a good repeatability of our method both for migration times (CV = 1.11%) and for areas (CV = 2.05%). Moreover, a good reproducibility of intra- and inter-assay tests was obtained (CV = 2.55% and CV = 5.14%, respectively). Suitability of the method was tested by measuring MDA levels in 44 healthy volunteers. PMID- 21688278 TI - Strategy for high-fidelity multiplex DNA copy number assay system using capillary electrophoresis devices. AB - Structural variation of human genome such as duplications and deletions, collectively termed copy number variation (CNV), is one of the major genetic variations. Reliable and efficient measurement of CNV will be essential to develop diagnostic tools for CNV-related diseases. We established a strategy based on multiplex PCR and capillary electrophoresis (CE) for reliable CNV assay. Multiplex-PCR was performed using five primer sets for target loci and a diploid control (DC). We designed primers satisfying three conditions: different size of each PCR product for CE separation, unified annealing temperature for multiplex PCR, and suitability for quantitative PCR (qPCR). We defined the accurate PCR cycles for quantification of copy numbers at which the amplifications for all targets were supposed to be exponential, named maximum doubling cycle. CE was carried out with PCR product and the ratio of the peak areas (target/diploid control) was calculated. Our multiplex PCR-CE analysis reliably determined copy numbers of X chromosome with variable copies ranging from 1 to 5 and showed higher reliability than qPCR (correlation coefficient 0.996 versus 0.898). When measuring the six randomly selected autosomal CNV targets using our multiplex PCR CE, the results agreed with those from qPCR. In addition, our strategy was validated for the broad application to commonly used CE devices. Taken together, this assay will be useful for accurate analysis of multiple disease-associated CNVs in a clinical setting. PMID- 21688279 TI - Protocol for high-resolution electrophoresis separation of myosin heavy chain isoforms in bovine skeletal muscle. AB - In this short communication we describe a specific protocol for SDS-PAGE separation of adult bovine myosin heavy-chain (MyHC) isoforms. The conditions defined in this protocol allow a good separation with a good reproducibility of the four MyHC isoforms (MyHC I, IIa, IIx, IIb) identified in adult skeletal muscle of this species. This procedure uses mini-gel electrophoresis system and does not involve preparation of gradient separating gels. In addition, this protocol can also be applied to the electrophoretic separation of ovine and camel MyHC isoforms. PMID- 21688280 TI - Testosterone and prolactin increase carboxypeptidase-D and nitric oxide levels to promote survival of prostate cancer cells. AB - BACKGROUND: Plasma-membrane carboxypeptidase-D (CPD) releases arginine from extracellular substrates. Arginine is converted intracellularly to nitric oxide (NO). This study determined the effects of testosterone (T) and prolactin (PRL) on CPD expression, and the role(s) of CPD in NO production and survival of prostate cancer (PCa) cells. METHODS: LNCaP cells were treated with T and/or PRL. CPD expression was measured. Regulation by T (low doses) was determined using transfected cells overexpressing 5alpha-reductase type-1 (5alphaR1), which converts T to the more potent dihydrotestosterone. The effects of siRNAs targeting CPD (siCPDs) on NO production, cell viability, and apoptosis were determined using DAF2-DA, MTS, and Annexin-V assays. The effects of PRL/T on CPD/NO levels in PC-3, MDA-PCa-2b, and 22Rv1 cells were also evaluated. RESULTS: In LNCaP cells, 10 nM T and 10 ng/ml PRL-upregulated CPD mRNA/protein levels. In pTRE-transfectants, 1 nM T-upregulated CPD mRNA levels by ~2-fold over controls, whereas 0.1 nM T caused similar upregulation in pTRE-5alphaR1-transfectants. In LNCaP cells cultured in arginine-free medium, addition of furylacryloyl-Ala-Arg (FAR; CPD substrate) increased NO levels. NO production, with FAR, was enhanced by PRL and/or T. siCPDs decreased NO production and cell viability, but increased apoptosis. QPCR analysis showed T/PRL-upregulation of CPD in 22Rv1, MDA-PCa-2b, and PC-3 cells. NO production was doubled by T/PRL in 22Rv1 cells, tripled by T in MDA-PCa-2b cells, and marginally increased by PRL in MDA-PCa-2b and PC-3 cells. CONCLUSIONS: T and PRL upregulate CPD and NO levels in PCa cells. CPD increases NO production to promote PCa cell survival. PMID- 21688281 TI - Contemporary experience with ketoconazole in patients with metastatic castration resistant prostate cancer: clinical factors associated with PSA response and disease progression. AB - BACKGROUND: Adrenal/intratumoral androgen biosynthesis contributes to ligand dependent androgen receptor activation in metastatic castration-resistant prostate cancer (mCRCP). Compounds targeting CYP-17 hydroxylase and lyase, as ketoconazole and abiraterone, block adrenal/intratumoral androgen biosynthesis, and are used as sequential endocrine approaches in mCRCP. We aimed to describe contemporary experience and association of clinical factors with Prostate specific antigen (PSA) response and disease progression, in mCRPC progressing on GnRH-agonist, antiandrogen, antiandrogen withdrawal, and treated with ketoconazole. METHODS: Data were retrospectively analyzed in all mCRPC patients treated with ketoconazole. Patients continued GnRH-agonist, and treated with ketoconazole 200-400 mg 3* a day until dose-limiting toxicity or disease progression. A multivariate cox regression model was used to identify clinical factors associated with PSA response and disease progression. RESULTS: From 1999 to 2010, 114 mCRPC patients were treated with ketoconazole. With a median follow up time of 31 months (range 5-129), 25 patients (22%) had grade 3/4 toxicity, most commonly fatigue, abdominal discomfort, nausea, and dizziness. Sixty-one patients (54%) had >=50% PSA decline. Median time to progression was 8 months (range 1-129). Factors associated with PSA response and disease progression were response to prior antiandrogen (>=6 vs. <6 months), pre-treatment PSADT (>=3 vs. <3 months) and extent of disease (limited-axial skeleton and/or nodal vs. extensive-appendicular skeleton and/or visceral). CONCLUSIONS: Ketoconazole is effective and safe in mCRPC. Prior response to antiandrogen, pre-treatment PSADT, and disease extent are associated with PSA response and disease progression, and further supports a therapeutic role in suppressing adrenal androgens in mCRPC. PMID- 21688282 TI - The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. AB - Information on the long-term prognosis of nonalcoholic fatty liver disease (NAFLD) is limited. We sought to describe the long-term morbidity and mortality of patients with NAFLD with advanced fibrosis or cirrhosis by prospectively studying 247 such patients from four international centers (in Australia, USA, UK and Italy). Their natural history was then compared with 264 patients with HCV infection who were either naive or non-responders to treatment. Both cohorts were Child-Pugh class A and had advanced fibrosis (stage 3) or cirrhosis (stage 4) confirmed by liver biopsy at enrollment. In the NAFLD cohort, followed up for a mean of 85.6 months (range, 6-297), there were 48 (19.4%) liver-related complications and 33 (13.4%) deaths or liver transplants. In the HCV cohort, followed up for 74.9 months (mean; range, 6-238), there were 47 (16.7%) liver related complications and 25 (9.4%) deaths or liver transplants. When adjusting for baseline differences in age and gender, the cumulative incidence of liver related complications was lower in the NAFLD than the HCV cohort (P = 0.03), including incident hepatocellular cancer (6 versus 18; P = 0.03), but that of cardiovascular events (P = 0.17) and overall mortality (P = 0.6) were similar in both groups. In the NAFLD cohort, platelet count, stage 4 fibrosis, lowered platelet count, and lowered serum cholesterol and alanine aminotransferase (ALT) levels were associated with liver-related complications; an aspartate aminotransferase/ALT ratio >1 and older age were associated with overall mortality, and higher serum bilirubin levels and stage 4 fibrosis were associated with liver-related mortality. CONCLUSIONS: Patients with NAFLD with advanced fibrosis or cirrhosis have lower rates of liver-related complications and hepatocellular cancer than corresponding patients with HCV infection, but similar overall mortality. Some clinical and laboratory features predict liver-related complications and other outcomes in patients with NAFLD. PMID- 21688283 TI - Aldo-keto reductase-7A protects liver cells and tissues from acetaminophen induced oxidative stress and hepatotoxicity. AB - Aldo-keto reductase-7A (AKR7A) is an enzyme important for bioactivation and biodetoxification. Previous studies suggested that Akr7a might be transcriptionally regulated by oxidative stress-responsive transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a protein highly responsive to acetaminophen (APAP) or its intermediate metabolite, N-acetyl-p benzoquinoneimine (NAPQI). This study was, therefore, carried out to investigate whether Akr7a is involved in the protection against APAP-induced oxidative stress and hepatotoxicity. We found that in response to APAP or NAPQI exposure, Akr7a3 mRNA and protein were significantly up-regulated in vitro in human HepG2 and LO2 cells. Similarly, strong induction was observed for Akr7a5 in mouse AML12 hepatocytes exposed to APAP. In vivo in wild-type rats, significant up-regulation of hepatic AKR7A1 protein was observed after administration of APAP. On the other hand, depletion of Nrf2 reduced the expression of Akr7a3, suggesting that Nrf2, indeed, contributes significantly to the induction of Akr7a. Moreover, loss of cell viability in Nrf2-depleted cells was significantly rescued by coexpression of AKR7A3. Furthermore, increased AKR7A3 in HepG2 cells was associated with the up-regulation of oxidative stress-related enzymes to enhance cellular antioxidant defense, which appeared to contribute significantly to protection against APAP induced toxicity. In a line of transgenic rats overexpressing AKR7A1, increased AKR7A1 stimulated the expression of Nrf2 and other Nrf2-regulated genes, but did not better protect rats from APAP insults. In contrast, depletion of Akr7a5 in vitro in cultured AML12 cells or depletion of Akr7a1 in vivo in rat liver greatly increased APAP-induced hepatotoxicity. CONCLUSION: AKR7A proteins are significantly up-regulated in response to APAP/NAPQI exposure to contribute significantly to protection against APAP-induced hepatotoxicity. AKR7A mediates this protection, in part, through enhancing hepatocellular antioxidant defense. PMID- 21688284 TI - Liver transplant recipient survival benefit with living donation in the model for endstage liver disease allocation era. AB - Receipt of a living donor liver transplant (LDLT) has been associated with improved survival compared with waiting for a deceased donor liver transplant (DDLT). However, the survival benefit of liver transplant has been questioned for candidates with Model for Endstage Liver Disease (MELD) scores <15, and the survival advantage of LDLT has not been demonstrated during the MELD allocation era, especially for low MELD patients. Transplant candidates enrolled in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study after February 28, 2002 were followed for a median of 4.6 years. Starting at the time of presentation of the first potential living donor, mortality for LDLT recipients was compared to mortality for patients who remained on the waiting list or received DDLT (no LDLT group) according to categories of MELD score (<15 or >= 15) and diagnosis of hepatocellular carcinoma (HCC). Of 868 potential LDLT recipients (453 with MELD <15; 415 with MELD >= 15 at entry), 712 underwent transplantation (406 LDLT; 306 DDLT), 83 died without transplant, and 73 were alive without transplant at last follow-up. Overall, LDLT recipients had 56% lower mortality (hazard ratio [HR] = 0.44, 95% confidence interval [CI] 0.32 0.60; P < 0.0001). Among candidates without HCC, mortality benefit was seen both with MELD <15 (HR = 0.39; P = 0.0003) and MELD >= 15 (HR = 0.42; P = 0.0006). Among candidates with HCC, a benefit of LDLT was not seen for MELD <15 (HR = 0.82, P = 0.65) but was seen for MELD >= 15 (HR = 0.29, P = 0.043). CONCLUSION: Across the range of MELD scores, patients without HCC derived a significant survival benefit when undergoing LDLT rather than waiting for DDLT in the MELD liver allocation era. Low MELD candidates with HCC may not benefit from LDLT. PMID- 21688285 TI - Genome-wide copy number analyses identified novel cancer genes in hepatocellular carcinoma. AB - A powerful way to identify driver genes with causal roles in carcinogenesis is to detect genomic regions that undergo frequent alterations in cancers. Here we identified 1,241 regions of somatic copy number alterations in 58 paired hepatocellular carcinoma (HCC) tumors and adjacent nontumor tissues using genome wide single nucleotide polymorphism (SNP) 6.0 arrays. Subsequently, by integrating copy number profiles with gene expression signatures derived from the same HCC patients, we identified 362 differentially expressed genes within the aberrant regions. Among these, 20 candidate genes were chosen for further functional assessments. One novel tumor suppressor (tripartite motif-containing 35 [TRIM35]) and two putative oncogenes (hairy/enhancer-of-split related with YRPW motif 1 [HEY1] and small nuclear ribonucleoprotein polypeptide E [SNRPE]) were discovered by various in vitro and in vivo tumorigenicity experiments. Importantly, it was demonstrated that decreases of TRIM35 expression are a frequent event in HCC and the expression level of TRIM35 was negatively correlated with tumor size, histological grade, and serum alpha-fetoprotein concentration. CONCLUSION: These results showed that integration of genomic and transcriptional data offers powerful potential for identifying novel cancer genes in HCC pathogenesis. PMID- 21688287 TI - Publications in Hepatology: is there a pro-United States bias? PMID- 21688286 TI - Hu antigen R and tristetraprolin: counter-regulators of rat apical sodium dependent bile acid transporter by way of effects on messenger RNA stability. AB - The apical sodium-dependent bile acid transporter (ASBT, SLC10A2) mediates intestinal, renal, and cholangiocyte bile acid reclamation. Transcriptional regulation of ASBT is well described, whereas information on posttranscriptional regulation is limited. Prior studies suggested that ontogeny of ASBT is controlled in part by changes in messenger RNA (mRNA) stability. We studied the role that Hu antigen R (HuR) and tristetraprolin (TTP) play in regulating the expression of mRNA that contains the 3' untranslated region (UTR) of rat ASBT. The 3'UTR was incorporated into an SV-40 driven luciferase reporter (rASBT3 luciferase) for rapid screening of regulatory effects. Silencing HuR reduced luciferase reporter activity, whereas silencing TTP enhanced luciferase activity. Conversely, overexpression of HuR enhanced rASBT3-luciferase reporter activity. The same 3'UTR fragments of rat ASBT were incorporated into a beta-globin coding mRNA construct for analysis of mRNA stability (rASBT3-betaglobin). mRNA half-life was progressively shortened by the incorporation of increasing sized fragments of the 3'UTR. Silencing HuR shortened the half-life of rASBT3-betaglobin containing 0.3 kb of the rat ASBT 3'UTR. Gel shift assays revealed binding of HuR and TTP to rat ASBT 3'UTR. Endogenously expressed human ASBT mRNA half-lives and steady state protein levels in Caco-2 cells were repressed when HuR was silenced but was enhanced when TTP was silenced. Developmental changes in HuR and TTP protein abundance correlated with previously characterized ontogenic changes in rat ileal and renal ASBT expression. CONCLUSION: These studies not only show that ASBT expression is controlled at the level of mRNA stability by way of its 3'UTR, but also identify HuR and TTP as two key transacting factors that are involved in exerting counterregulatory effects on ASBT mRNA stability. PMID- 21688288 TI - Slit-Robo signals regulate pioneer axon pathfinding of the tract of the postoptic commissure in the mammalian forebrain. AB - During early vertebrate forebrain development, pioneer axons establish a symmetrical scaffold descending longitudinally through the rostral forebrain, thus forming the tract of the postoptic commissure (TPOC). In mouse embryos, this tract begins to appear at embryonic day 9.5 (E9.5) as a bundle of axons tightly constrained at a specific dorsoventral level. We have characterized the participation of the Slit chemorepellants and their Robo receptors in the control of TPOC axon projection. In E9.5-E11.5 mouse embryos, Robo1 and Robo2 are expressed in the nucleus origin of the TPOC (nTPOC), and Slit expression domains flank the TPOC trajectory. These findings suggested that these proteins are important factors in the dorsoventral positioning of the TPOC axons. Consistently with this role, Slit2 inhibited TPOC axon growth in collagen gel cultures, and interfering with Robo function in cultured embryos induced projection errors in TPOC axons. Moreover, absence of both Slit1 and Slit2 or Robo1 and Robo2 in mutant mouse embryos revealed aberrant TPOC trajectories, resulting in abnormal spreading of the tract and misprojections into both ventral and dorsal tissues. These results reveal that Slit-Robo signaling regulates the dorsoventral position of this pioneer tract in the developing forebrain. PMID- 21688289 TI - A deregulated integrated stress response promotes interferon-gamma-induced medulloblastoma. AB - Endoplasmic reticulum (ER) stress activates pancreatic ER kinase (PERK), which coordinates an adaptive program known as the integrated stress response (ISR) by phosphorylating translation initiation factor 2alpha (eIF2alpha). There is evidence that the ISR is involved in tumor development. Recent studies also show that the ISR stimulates the expression of vascular endothelial growth factor A (VEGF-A), a master regulator of angiogenesis. Our previous studies have demonstrated that enforced expression of interferon-gamma (IFNgamma) in the central nervous system during development induces sonic hedgehog expression and leads to cerebellar dysplasia or medulloblastoma. Here we report that PERK was activated in cerebellar dysplasia and medulloblastoma in IFNgamma-expressing mice. We found that inactivation of the growth arrest and DNA damage 34 (GADD34) gene, encoding the stress-inducible regulatory subunit of a phosphatase complex that dephosphorylates eIF2alpha, enhanced ISR signaling and facilitated medulloblastoma formation in IFNgamma-expressing mice. Moreover, we found that the induction of VEGF-A and enhanced angiogenesis were associated with medulloblastoma formation in IFNgamma-expressing mice on the GADD34 mutation background. Thus, our data provide genetic evidence that the ISR facilitates medulloblastoma development. PMID- 21688290 TI - Modulation of dopamine-dependent behaviors by the Caenorhabditis elegans Olig homolog HLH-17. AB - In vertebrates and invertebrates, dopamine signaling modulates a wide variety of physical and behavioral functions and exerts these effects through heterotrimeric G proteins. The soil nematode Caenorhabditis elegans has been used to model dopamine signaling and reacts reproducibly to alterations in dopamine levels through eight well-characterized dopaminergic neurons located in the head. In C. elegans, the basic helix-loop-helix transcription factor HLH-17 is strongly and constitutively expressed in the glia cells that ensheath four of the dopaminergic neurons, yet it is not required for specification or development of either the glia or the neurons. In this study, we sought to determine whether HLH-17 functions in dopamine signaling. We found that, unlike wild-type animals, hlh-17 animals are resistant to the effects of exogenous dopamine on egg laying and mobility. hlh-17 animals are also defective in the basal slowing and gustatory plasticity behaviors that require functional dopamine signaling. We also found that the expression of the dopamine receptor genes dop-1, dop-2, and dop-3 and the RGS protein gene egl-10 is significantly reduced in hlh-17 animals. Together these results point to a role for HLH-17 in dopamine signaling in C. elegans. PMID- 21688291 TI - Human L1CAM carrying the missense mutations of the fibronectin-like type III domains is localized in the endoplasmic reticulum and degraded by polyubiquitylation. AB - Any mutations in the human neural cell adhesion molecule L1 (hL1CAM) gene might cause various types of serious neurological syndromes in humans, characterized by increased mortality, mental retardation, and various malformations of the nervous system. Such missense mutations often cause severe abnormalities or even fatalities, and the reason for this may be a disruption of the adhesive function of L1CAM resulting from a misdirection of the degradative pathway. Transfection studies using neuroblastoma N2a cells demonstrated that hL1CAM carrying the missense mutations in the fibronectin-like type III (FnIII) domains most likely is located within the endoplasmic reticulum (ER), but it is less well expressed on the cell surface. One mutant, L935P, in the fourth FnIII domain, was chosen from six mutants (K655 and G698 at Fn1, L935P and P941 at Fn4, W1036 and Y1070 at Fn5) in the FnIII domains to study in detail the functions of hL1CAM(200 kDa) , such as the intracellular traffic and degradation, because only a single band at 200 kDa was detected in the hL1CAM(L935P) -transfected cells. hL1CAM(200 kDa) is expressed predominantly in the ER but not on the cell surface. In addition, this missense mutated hL1CAM(200 kDa) is polyubiquitylated at some sites in the extracellular domain and thus becomes degraded by proteasomes via the ER associated degradation pathway. These observations demonstrate that the missense mutations of hL1CAM in the FnIII domain may cause the resultant pathogenesis because of a loss of expression on the cell surface resulting from misrouting to the degradative pathway. PMID- 21688292 TI - Chronic stress and antidepressant agomelatine induce region-specific changes in synapsin I expression in the rat brain. AB - The antidepressant agomelatine acts as a melatonergic receptor (MT(1)/MT(2)) agonist and 5-HT(2C) receptor antagonist. Agomelatine has demonstrated efficacy in treating depression, but its neurobiological effects merit further investigation. Preclinical studies reported that agomelatine enhances adult hippocampal neurogenesis and increases expression of several neuroplasticity associated molecules. Recently, we showed that agomelatine normalizes hippocampal neuronal activity and promotes neurogenesis in the stress-compromised brain. To characterize further the effects of this antidepressant in the stressed brain, here we investigated whether it induces changes in the expression of synapsin I (SynI), a regulator of synaptic transmission and plasticity. Adult male rats were subjected to daily footshock stress and agomelatine treatment for 3 weeks. Their brains were subsequently stained for total and phosphorylated SynI. Chronic footshock and agomelatine induced region-specific changes in SynI expression. Whereas chronic stress increased total SynI expression in all layers of the medial prefrontal cortex, agomelatine treatment abolished some of these effects. Furthermore, chronic agomelatine administration decreased total SynI expression in the hippocampal subregions of both stressed and nonstressed rats. Importantly, chronic stress decreased the fraction of phosphorylated SynI in all layers of the medial prefrontal cortex as well as selectively in the outer and middle molecular layers of the hippocampal dentate gyrus. These stress effects were at least partially abolished by agomelatine. Altogether, our data show that chronic stress and agomelatine treatment induce region-specific changes in SynI expression and its phosphorylation. Moreover, agomelatine partially counteracts the stress effects on SynI, suggesting a modulation of synaptic function by this antidepressant. PMID- 21688293 TI - Differential polymorphism in cutaneous glands of archaic Leiopelma species. AB - Endemic New Zealand frogs of the genus Leiopelma are from a basal lineage of extant anurans that release defensive secretions onto their skin when disturbed. Here, we characterize the gross anatomy and microscopic structure of the skin of L. archeyi, L. hochstetteri, and L. pakeka using stereoscopic, light and transmission electron microscopy. The terrestrial L. archeyi and L. pakeka possess dimorphic granular glands, categorized as type I and II, based on their frequency and morphological traits, whereas the semi-aquatic L. hochstetteri lacks type I glands. This is the first report of differential dimorphism in anurans of the same genus. This dimorphism could be interpreted as an adaptation to different physiological or ecological needs of these species. However, species within this ancient genus share similar general gland morphology with other anurans, namely, a secretory unit containing storage granules ensheathed by myoepithelial cells. Type I glands are ellipsoid, large and contain a homogeneous mass of electron-dense granules (1.8 +/- 0.08 MUm in diameter). Type II glands are round and contain larger heterogeneous granules (4.06 +/- 0.16 MUm) of varying densities. Exposure to noradrenaline causes the contraction of myoepithelial cells, resulting in bulk discharge of type I glands through the epidermal duct onto the skin surface. Differential release of secretions from dimorphic glands may be indicative of their functional specialisation in antipredatory or regulative roles. Mass spectrometric techniques were used to de novo sequence peptides present in the skin secretions of Leiopelma species. A total of 30 previously undescribed peptides from Leiopelma species were fully or partially sequenced. These peptides exhibited no similarity to any known compounds. PMID- 21688294 TI - Functional morphology of mouthparts and digestive system during larval development of the cleaner shrimp Lysmata amboinensis (de Man, 1888). AB - Mouthpart and alimentary canal development was examined in Lysmata amboinensis larvae using scanning electron microscopy and histology. The gross morphological features of external mouthparts and internal digestive tract structures of larvae at different developmental stages indicate that ingestive and digestive capabilities are well developed from early on. With increasing age of the larvae the mouthpart appendages increased in size, the hepatopancreas in tubular density and the midgut in length. The density of setae and robustness of teeth and spines of individual structures increased. The most pronounced changes from early to late stage larvae involved formation of pores on the paragnaths and labrum, transformation of the mandibular spine-like teeth to molar cusps, development of the filter press in the proventriculus and of infoldings in the previously straight hindgut. The results suggest that early stage L. amboinensis larvae may benefit from soft, perhaps gelatinous prey, whereas later stages are better equipped to handle larger, muscular or more fibrous foods. PMID- 21688295 TI - Characterization of the adhesive areas in Sepia tuberculata (Mollusca, Cephalopoda). AB - Adhesion in cephalopods is either mechanical, involving a reduced-pressure system of the arm and tentacle suckers, or is chemically mediated by special adhesive gland structures (as proposed for Euprymna, Idiosepius, and Nautilus). Four species of Sepia (S. typica, S. papillata, S. pulchra, and S. tuberculata) possess grooved structures on the ventral mantle surface and on the fourth arm pair, which are used to attach mechanically to the substratum. Because these areas are often partly covered with sand or debris, it has been hypothesized that chemical substances were involved in this attachment process. This study provides a histochemical and ultrastructural description of the glandular epithelium in the adhesive area of Sepia tuberculata. Two specific glandular cells (Type 1 and Type 2) are present in the epithelium, which differ clearly in their granule size and cellular structure. The aggregation of both cell types and their simultaneous secretion suggest that the secretions of both cell types work synergistically providing a two-component adhesive system which supports the primarily mechanical sucker adhesion by making the arm surface sticky. PMID- 21688296 TI - Ultrastructure of the spermatozoon of the American Alligator, Alligator mississippiensis (Reptilia: Alligatoridae). AB - This study details the ultrastructure of the spermatozoa of the American Alligator, Alligator mississippiensis. American Alligator spermatozoa are filiform and slightly curved. The acrosome is tapered at its anterior end and surrounded by the acrosome vesicle and an underlying subacrosomal cone, which rests just cephalic to the nuclear rostrum. One endonuclear canal extends from the subacrosomal cone through the rostral nucleus and deep into the nuclear body. The neck region separates the nucleus and midpiece and houses the proximal centriole and pericentriolar material. The distal centriole extends through the midpiece and has 9 * 3 sets of peripheral microtubules with a central doublet pair within the axoneme that is surrounded by a dense sheath. The midpiece is composed of seven to nine rings of mitochondria, which have combinations of concentrically and septate cristae. The principal piece has a dense fibrous sheath that surrounds an axoneme with a 9 + 2 microtubule arrangement. The sheath becomes significantly reduced in size caudally within the principal piece and is completely missing from the endpiece. Dense peripheral fibers, especially those associated with microtubule doublets 3 and 8, penetrate into the anterior portion of the principal piece axoneme. The data reported here hypothesize that sperm morphology is highly conserved in Crocodylia; however, specific morphological differences can exist between species. PMID- 21688297 TI - Adapting to cope with eucalypt oils: mandibular extensions in pergid sawfly larvae and potential preadaptations in its sister family Argidae (Insecta, Hymenoptera, Symphyta). AB - Each of the interior mandibular surfaces of Australian sawfly larvae in the subfamily Perginae is equipped with a soft, brush-like scopa mandibularis. These insects are associated with oil-rich Myrtaceae, including Eucalyptus, and the scopa is involved in separating leaf oils from nutritive plant matter. The oil is stored internally in a diverticulum and is emitted during defense reactions. However, this is known only from mature larvae and the mandibular structure has been investigated and partially illustrated in only one genus of pergines, Pergagrapta. Here, we provide a full description, extend this to a second genus, Perga, and include first instar larvae of Perga and Pseudoperga genera to confirm the presence of the scopa and diverticula through the entire larval life, and thus infer their developmental trajectory. Superficial descriptions of mandibular projections in some Nearctic species in the family Argidae, which is phylogenetically sister to the Pergidae, have been published. Modifications of the inner mandibular surface of representatives of the argid genera Sericoceros, Sphacophilus, and Zynzus are therefore fully illustrated and compared with those of the Pergidae, so this phylogenetic relationship can be assessed. PMID- 21688298 TI - Skeleto-musculature of the mandible and its function in podocopid ostracodes exemplified by Loxoconcha pulchra (Cytheroidea: Loxoconchidae) and Fabaeformiscandona tyrolensis (Cypridoidea: Candonidae). AB - A new anatomical interpretation of the skeleto-musculature of the mandible in podocopid ostracodes is proposed based on ultrastructural observations of Loxoconcha pulchra Ishizaki, 1968 and Fabaeformiscandona tyrolensis (Loffler, 1963). Attachment cells with their numerous microfibers anchor the sclerotized lamella cuticle (chitinous rod) to the outer lamella cuticle via intracuticular fibers. A pan-shaped structure develops at the attachment area in the outer lamella cuticle and is responsible for the mandibular scar. The sclerotized lamella cuticle is continuous with the dorsal apex of the mandibular coxa, which touches the fulcral point directly without intermediate epidermis. The calcification of the fulcral point starts immediately after ecdysis and this rapid calcification suggests that the fulcral point must play a significant role in functional morphology of podocopid ostracodes. After 3D-reconstruction of the set of mandibular extrinsic muscles in a podocopid ostracode, we suggest that the fulcral point is a key character for carapace opening by transmitting the force from the mandibular coxa to the valve and at the same time functions as the stable fulcrum for mandibular movement during mastication. PMID- 21688299 TI - The vascular morphology and in vivo muscle temperatures of thresher sharks (Alopiidae). AB - The thresher sharks comprise a single family (Alopiidae) of pelagic sharks most easily recognized by the elongate dorsal lobe of their caudal fin. Despite morphological similarities among the alopiids, the common thresher (Alopias vulpinus) is unique in that its red, aerobic myotomal muscle (RM) is medially positioned (i.e., closer to the vertebrae), its systemic blood is supplied through a lateral circulation which give rise to counter-current heat exchanging retia, and it is capable of regional RM endothermy. Despite this information, it remains unknown if the other two alopiid species (bigeye thresher, Alopias superciliosus and pelagic thresher, Alopias pelagicus) also possess some or all of the characteristics related to regional RM endothermy. Thus, this study aimed to 1) document the presence of vascular specializations necessary for heat retention and RM endothermy and 2) measure the in vivo muscle temperatures of all three alopiid species. Laboratory dissections of the thresher species showed that only A. vulpinus possesses the lateral branching of the dorsal aorta giving rise to a lateral subcutaneous circulation and retial system, and that RM temperatures are elevated relative to ambient temperature. By contrast, both A. pelagicus and A. superciliosus have a similar systemic blood circulation pathway, in which the dorsal aorta and postcardinal vein form the basis for the central circulation and in vivo RM temperature measurements closely matched those of the ambient temperature at which the sharks were captured. Collectively, the vascular anatomy and in vivo temperature data suggest that only one species of thresher shark (A. vulpinus) possesses the requisite vascular specializations (i.e., lateral subcutaneous vessels and retia mirabilia) that facilitate RM endothermy. PMID- 21688300 TI - Sexual, habitat-constrained and parasite-induced dimorphism in the shell of a freshwater mussel (Anodonta anatina, Unionidae). AB - Intraspecific trends in freshwater mussel (unionoid) shells that are consistently associated with differences in the mussels' sex and/or parasitic infestation can potentially be used to reconstruct sex ratios or parasitic levels of modern and ancient unionoid populations. In contrast to morphological patterns within mammal species, such dimorphic trends within unionoid species are, however, poorly understood. This study investigates, for the first time, to what extent sex, trematode infection and indirect habitat effects determine shell morphology in the freshwater mussel Anodonta anatina. Three of the five study populations displayed significant sexual shell width dimorphism. Here, shells of females were significantly wider than males, probably as a result of altered shell growth to accommodate marsupial gills. In two of these populations, female shells were additionally significantly thinner than those of males, which could be a result of resource depletion by offspring production. Two other A. anatina populations showed no significant dimorphic patterns, and our results indicate that this interpopulational difference in the degree of sexual dimorphism may reflect the overarching effect of habitat on morphology. Thus, populations in the most favourable habitats exhibit faster growth rates, attain larger maximum sizes and produce more offspring, which results in more swollen gills and consequently more inflated shells of gravid females compared to less fecund populations. None of the populations showed any evidence for sexual dimorphism in overall size, growth rate, sagittal shape and density of shells. In addition to sexual dimorphisms, infestation by bucephalid trematode parasites (Rhipidocotyle sp.) significantly altered sagittal and lateral shell shape of A. anatina in one of the populations, with infected specimens growing wider and more elongated. PMID- 21688302 TI - Proteolysis of the matricellular protein hevin by matrix metalloproteinase-3 produces a SPARC-like fragment (SLF) associated with neovasculature in a murine glioma model. AB - The matricellular SPARC-family member hevin (Sparc-like 1/SPARCL-1/SC1/Mast9) contributes to neural development and alters tumor progression in a range of mammalian models. Based on sequence similarity, we hypothesized that proteolytic digestion of hevin would result in SPARC-like fragments (SLF) that affect the activity and/or location of these proteins. Incubation of hevin with matrix metalloproteinase-3 (MMP-3), a protease known to cleave SPARC, produced a limited number of peptides. Sequencing revealed the major proteolytic products to be SPARC-like in primary structure. In gliomas implanted into murine brain, a SLF was associated with SPARC in the neovasculature but not with hevin, the latter prominent in the astrocytes encompassed by infiltrating tumor. In this model of invasive glioma that involves MMP-3 activity, host-derived SLF was not observed in the extracellular matrix adjacent to tumor cells. In contrast, it occurred with its homolog SPARC in the angiogenic response to the tumor. We conclude that MMP-3-derived SLF is a marker of neovessels in glioma, where it could influence the activity of SPARC. PMID- 21688303 TI - Gene modification with integrin-linked kinase improves function of endothelial progenitor cells in pre-eclampsia in vitro. AB - Integrin-linked kinase (ILK), a multifunctional serine-threonine protein kinase, has been shown to have implications for the treatment of ischemia vascular diseases by promoting angiogenesis in various tissues. However, whether this kinase has therapeutic potential in pre-eclampsia is not well studied. In this report, we determined the changes in the production and action of ILK on endothelial progenitor cells (EPCs) isolated from patients with pre-eclampsia. The effects of ILK transfection on proliferation, migration, and angiogenesis of EPCs were investigated. We showed that EPCs transfected with the ILK gene expressed high levels of ILK protein and mRNA. Transfection with ILK also enhanced the proliferative, migratory, and angiogenic capabilities of EPCs, and promoted the production of VEGF. These results suggest that ILK gene transfection is an effective approach to augment angiogenic properties of EPCs in vitro and providing basis for clinical cell-based gene therapy in patients with pre eclampsia. PMID- 21688304 TI - Thymoquinone-induced platelet apoptosis. AB - Thymoquinone (TQ) is a nutrient with anticarcinogenic activity that stimulates suicidal death of tumor cells. Moreover, TQ triggers suicidal death of erythrocytes or eryptosis, an effect at least partially due to increase in cytosolic Ca(2+) activity and ceramide formation. The present experiments explored whether TQ influences apoptosis of blood platelets. Cell membrane scrambling was determined utilizing Annexin V binding to phosphatidylserine exposing platelets, cytosolic Ca(2+) activity utilizing Fluo 3-AM fluorescence, caspase activity utilizing immunofluorescence and Western blotting of active caspase-3 and inactive procaspase-3, mitochondrial potential utilizing DiOC(6) fluorescence and ceramide by FACS analysis of ceramide-binding antibodies. A 30 min exposure to TQ (>=5 uM) was followed by Annexin V binding, paralleled by caspase activation, increase of cytosolic Ca(2+) activity, mitochondrial depolarization, and ceramide formation. P-selectin exposure and integrin alpha(IIb) beta(3) activation did not increase in response to TQ. Nominal absence of extracellular Ca(2+) blunted but did not fully abolish the TQ-induced activation of caspase-3. The effects of TQ on platelets are significantly abolished with phosphoinositide-3 kinase (PI3K) inhibitor wortmannin and G protein coupled receptor (GPCR) inhibitor pertussis toxin treatment prior to TQ stimulation. In conclusion, TQ triggers suicidal death of blood platelets in a PI3K-dependent manner, possibly through a GPCR family receptor; an effect paralleled by increase of cytosolic Ca(2+) activity, ceramide formation, mitochondrial depolarization, and caspase-3 activation. PMID- 21688301 TI - A randomized, pilot trial of etanercept in dermatomyositis. AB - OBJECTIVE: The aims of this pilot study were to assess (1) the safety and tolerability of etanercept in dermatomyositis (DM); (2) the feasibility and safety of a forced prednisone taper; and (3) outcome measures, including those recommended by the International Myositis Assessment Clinical Study (IMACS) group. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of etanercept (50mg subcutaneously weekly) for 52 weeks in DM subjects. Subjects were tapered off prednisone in a standardized schedule as tolerated over the initial 24 weeks of the study. Principal outcomes included adverse events, time from randomization to treatment failure (inability to wean off prednisone on schedule), and average prednisone dosage after week 24. RESULTS: Sixteen subjects were randomized, 11 to etanercept and 5 to placebo. There were no significant differences in adverse event rates between the treatment groups, although 5 etanercept-treated and 1 placebo-treated subjects developed worsening rash. All 5 subjects receiving placebo were treatment failures (median time to treatment failure 148 days). In contrast, 5 of 11 subjects in the etanercept arm were successfully weaned off prednisone; the median time to treatment failure in this group was 358 days (p = 0.0002). The median of the average prednisone dosage after week 24 was 29.2mg/day in the placebo group and 1.2mg/day in the etanercept group (p = 0.02). IMACS and other outcome measures demonstrated excellent test retest reliability (intraclass correlation coefficients 0.79-0.99). There was no significant treatment effect on functional outcome. INTERPRETATION: The findings of no major safety concerns and a steroid-sparing effect in our study suggest that further investigation of etanercept as a treatment for DM is warranted. PMID- 21688305 TI - Simulation of branched serial first-order decay of atrazine and metabolites in adapted and nonadapted soils. AB - In the present study a branched serial first-order decay (BSFOD) model is presented and used to derive transformation rates describing the decay of a common herbicide, atrazine, and its metabolites observed in unsaturated soils adapted to previous atrazine applications and in soils with no history of atrazine applications. Calibration of BSFOD models for soils throughout the country can reduce the uncertainty, relative to that of traditional models, in predicting the fate and transport of pesticides and their metabolites and thus support improved agricultural management schemes for reducing threats to the environment. Results from application of the BSFOD model to better understand the degradation of atrazine supports two previously reported conclusions: atrazine (6 chloro-N-ethyl-N'-(1-methylethyl)-1,3,5-triazine-2,4-diamine) and its primary metabolites are less persistent in adapted soils than in nonadapted soils; and hydroxyatrazine was the dominant primary metabolite in most of the soils tested. In addition, a method to simulate BSFOD in a one-dimensional solute-transport unsaturated zone model is also presented. PMID- 21688306 TI - Dissipation of six acid herbicides in water and sediment of two Canadian prairie wetlands. AB - In the present study, an ephemeral (E) and a semipermanent (SP) wetland were divided into halves using a polyvinyl curtain and one-half of each wetland was treated with dicamba (3,6-dichloro-o-anisic acid), bromoxynil (3,5-dibromo-4 hydroxy-benzonitrile), MCPA [(4-chloro-2-methylphenoxy)acetic acid], 2,4-D [(2,4 dichlorophenoxy)acetic acid], mecoprop-P (R)-2-(4-chloro-o-tolyloxy)propionic acid], and dichlorprop [(RS)-2-(2,4-dichlorophenoxy)propionic acid] such that concentrations in the water simulated an overspraying event, thus representing a worst-case scenario for wetland contamination. Water and sediment samples were taken over the 77-d study period to monitor herbicide concentrations. The dissipation of all six herbicides could be described by first-order reaction kinetics. In water, the field half-life (DT50) values ranged from 2.3 d (bromoxynil) to 31 d (dichlorprop). All six herbicides were detected in sediment samples from both wetlands. Overall, the phenoxypropionic acids (mecoprop-P and dichlorprop) were more persistent than the phenoxyacetic acids (2,4-D and MCPA) in both sediment and water. Use of bromide ion as a conservative tracer indicated that infiltration through sediment was an important route of water loss in both wetlands, especially in wetland E. Because strong correlations were found between the mass of each herbicide and bromide ion mass in wetland SP (r(2) = 0.59-0.76) and wetland E (r(2) = 0.80-0.95), it is likely that herbicide dissipation was due, in part, to mass lost by way of infiltration through sediment. PMID- 21688307 TI - Diclofenac in fish: blood plasma levels similar to human therapeutic levels affect global hepatic gene expression. AB - Diclofenac is a nonsteroidal anti-inflammatory drug frequently found in the aquatic environment. Previous studies have reported histological changes in the liver, kidney, and gills of fish at concentrations similar to those measured in treated sewage effluents (approximately 1 ug/L). Analyses or predictions of blood plasma levels in fish allow a direct comparison with human therapeutic plasma levels and may therefore be used to indicate a risk for pharmacological effects in fish. To relate internal exposure to a pharmacological interaction, we investigated global hepatic gene expression together with bioconcentration in blood plasma and liver of rainbow trout (Oncorhynchus mykiss) exposed to waterborne diclofenac. At the highest exposure concentration (81.5 ug/L), the fish plasma concentration reached approximately 88% of the human therapeutic levels (C(max) ) after two weeks. Using an oligonucleotide microarray followed by quantitative PCR, we found extensive effects on hepatic gene expression at this concentration, and some genes were found to be regulated down to the lowest exposure concentration tested (1.6 ug/L), corresponding to a plasma concentration approximately 1.5% of the human C(max) . Thus, at concentrations detected in European surface waters, diclofenac can affect the expression of multiple genes in exposed fish. Functional analysis of differentially expressed genes revealed effects on biological processes such as inflammation and the immune response, in agreement with the mode of action of diclofenac in mammals. In contrast to some previously reported results, the bioconcentration factor was found to be stable (4.02 +/- 0.75 for blood plasma and 2.54 +/- 0.36 for liver) regardless of the water concentration. PMID- 21688308 TI - Salinity effects on the bioavailability of aqueous metals for the estuarine killifish Fundulus heteroclitus. AB - Estuarine organisms experience varying salinity conditions on a daily and seasonal basis, and these fluctuations could influence the amount of metal accumulated from the aqueous phase. The present study experimentally assessed the role of salinity (0, 2, 6, 12, and 25 ppt) on the uptake of As, Cd, Cr, inorganic Hg [Hg(II)], and methylmercury (MeHg) into the euryhaline killifish (Fundulus heteroclitus) from the aqueous phase using gamma-emitting radioisotopes. Patterns of metal uptake as a function of salinity varied by metal. Chromium showed no relationship with salinity; Cd, which was most affected by salinity, showed an inverse relationship; and As, Hg(II), and MeHg uptake increased as salinity increased from 0 ppt to 25 ppt. Arsenic (salinities <= 6 ppt) and Cr were regulated by the fish, whereas Cd, Hg(II), and MeHg were not. Cadmium, Hg(II), and MeHg are chloro-complexed, increasing bioavailability for Hg(II) and MeHg, and reducing bioavailability for Cd. Concentration factors (CFs) were >1 at all salinities for Cd, Hg(II), and MeHg, indicating that the fish were more enriched in the metal than the surrounding water, whereas As and Cr CFs were <1 at all salinities. Uptake rate constants (k(u)s) were highest for MeHg (0.79-2.29 L g( 1) d(-1)), followed by Hg(II), Cd, Cr, and lowest for As (0.0004-0.0008 L g(-1) d(-1)). Tissue distribution of each metal was determined by dissections. Data for Cd showed that as salinity increased, the concentration of this metal increased in the viscera, whereas it decreased in the head and gills, suggesting that drinking to osmoregulate may account for a portion of Cd uptake from the aqueous phase in marine fish. PMID- 21688309 TI - Do naturalistic enclosures provide suitable environments for zoo animals? AB - Zoo visitors perceive naturalistic enclosures (i.e. those attempting to replicate identifiable parts of the landscape of the species' habitat) as those that best satisfy the biological needs of the animals, and ensure therefore their welfare. However, the provision of a suitable environment with the resources that will allow the animals to satisfy their main biological needs in naturalistic enclosures has never been systematically explored; instead, it has been assumed. In this study we provide evidence that supports the general idea that naturalistic designs provide suitable environments for the animals. For that purpose, we analyzed 1,381 naturalistic and non-naturalistic enclosures in 63 Spanish zoological parks. In order to assess the suitability of the environment provided within each enclosure, a number of aspects related to the animals' main biological requirements were analyzed. We found a relationship between naturalistic designs and the suitability of the environment for the species housed. Most naturalistic enclosures (77.8%) provided suitable environments for their inhabitants. Non-naturalistic ones also had suitable environments, but in a lower percentage (39.7%). These results should be taken into account during zoo inspection and accreditation appointments, where enclosure suitability must be assessed in an accurate and fast manner. In this regard, a naturalistic design can be used as an adjunct indicator of enclosure suitability, but not exclusively, as not every naturalistic enclosure was suitable for the animals, neither as an indispensable one, given that near 40% of non-naturalistic ones were appropriate for the species housed. PMID- 21688310 TI - Zoo and aquarium webcams: an informed view. AB - Providing webcams for public viewing is a relatively new but growing phenomenon among zoos and aquariums. Reasons for incorporating this programmatic feature are varied, and no guidelines exist to aid institutions considering webcam installations. Decision makers need to know how much effort the cameras require as well as how successful other zoos have found them to be. We evaluated existing webcams and provide an overview of their characteristics, including reliability. Quantitative evaluations provided by zoo/aquarium staff and by zoo members indicate generally positive perceptions of webcams, whereas staff acknowledge a notable level of effort required. Here, we strive to offer guidelines that will help institutions considering this venture. PMID- 21688311 TI - Alterations of overused supraspinatus tendon: a possible role of glycosaminoglycans and HARP/pleiotrophin in early tendon pathology. AB - Supraspinatus tendon overuse injuries lead to significant pain and disability in athletes and workers. Despite the prevalence and high social cost of these injuries, the early pathological events are not well known. We analyzed the potential relation between glycosaminoglycan (GAG) composition and phenotypic cellular alteration using a rat model of rotator cuff overuse. Total sulfated GAGs increased after 4 weeks of overuse and remained elevated up to 16 weeks. GAG accumulation was preceded by up-regulation of decorin, versican, and aggrecan proteoglycans (PGs) mRNAs and proteins and biglycan PG mRNA after 2 weeks. At 2 weeks, collagen 1 transcript decreased whereas mRNAs for collagen 2, collagen 3, collagen 6, and the transcription factor Sox9 were increased. Protein levels of heparin affine regulatory peptide (HARP)/pleiotrophin, a cytokine known to regulate developmental chondrocyte formation, were enhanced especially at 4 weeks, without up-regulation of HARP/pleiotrophin mRNA. Further results suggest that the increased GAGs present in early lesions may sequester HARP/pleiotrophin, which could contribute to a loss of tenocyte's phenotype. All these modifications are characteristic of a shift towards the chondrocyte phenotype. Identification of these early changes in the extra-cellular matrix may help to prevent the progression of the pathology to more disabling, degenerative alterations. PMID- 21688312 TI - BMP-2 mediates PGE(2) -induced reduction of proliferation and osteogenic differentiation of human tendon stem cells. AB - Tendon stem cells (TSCs) have been proposed to play a major role in the development of tendinopathy, which refers to pathological changes, such as calcification, in affected tendons. Using a human TSC (hTSC) culture model, this study investigated the effects of PGE(2) , an inflammatory mediator present in injured tendons, on hTSC proliferation and differentiation as well as the molecular mediator for such PGE(2) -induced effects. We found that PGE(2) treatment of hTSCs decreased cell proliferation and caused osteogenic differentiation of hTSCs in a dose-dependent manner. Also, PGE(2) treatment of hTSCs induced dose-dependent BMP-2 production in culture, and moreover, addition of BMP-2 to hTSC culture decreased cell proliferation and induced hTSC differentiation into osteoblasts. Finally, addition of BMP-2 antibodies to hTSC culture treated with PGE(2) nearly abolished PGE(2) effects on both cell proliferation and osteogenic differentiation. Taken together, the findings of this study showed that BMP-2 mediates PGE(2) -induced reduction of proliferation and osteogenic differentiation of hTSCs. We suggest that such a mechanism may be partially responsible for the formation of calcified tissues in tendinopathic tendons seen in clinical settings. PMID- 21688313 TI - Low intensity pulsed ultrasound enhances fracture healing in both ovariectomy induced osteoporotic and age-matched normal bones. AB - Low intensity pulsed ultrasound (LIPUS) was proven to enhance fracture healing effectively. Similar effect of LIPUS on accelerating the osteoporotic fracture healing was therefore hypothesized. The normal and osteoporotic fracture healings under this non-invasive biophysical intervention of LIPUS were compared and investigated. Closed femoral fracture procedures were performed on 120 Sprague Dawley rats, in which 60 of them were ovariectomized (OVX). The rats were randomly assigned into four groups: sham OVX with treatment (Sham-T), sham OVX control (Sham-C), OVX with treatment (OVX-T) and OXV control (OVX-C). LIPUS treatment was 20 min a day, 5 days a week for durations of 2, 4, or 8 weeks. Results from weekly radiography, histomorphometry, micro-computed tomography and mechanical test showed both the treatment groups were with better healing responses than their control groups. Moreover, between the normal and the osteoporotic treatment groups, a significantly higher (p = 0.015) callus width (week 4), higher ratio of increment in bone volume to tissue volume ratio value (7.4% more), faster response of endochondral ossification and a higher stiffness measurement were observed in the osteoporotic treatment group. These comparable results on healing responses imply that LIPUS can be applied clinically to enhance both normal and osteoporotic fracture healing. PMID- 21688314 TI - Fast radiofrequency flip angle calibration by Bloch-Siegert shift. AB - In a recent work, we presented a novel method for B 1+ field mapping based on the Bloch-Siegert shift. Here, we apply this method to automated fast radiofrequency transmit gain calibration. Two off-resonance radiofrequency pulses were added to a slice-selective spin echo sequence. The off-resonance pulses induce a Bloch Siegert phase shift in the acquired signal that is proportional to the square of the radiofrequency field magnitude B(1) (2) . The signal is further spatially localized by a readout gradient, and the signal-weighted average B(1) field is calculated. This calibration from starting system transmit gain to average flip angle is used to calculate the transmit gain setting needed to produce a desired imaging sequence flip angle. A robust implementation is demonstrated with a scan time of 3 s. The Bloch-Siegert-based calibration was used to predict the transmit gain for a 90 degrees radiofrequency pulse and gave a flip angle of 88.6 +/- 3.42 degrees when tested in vivo in 32 volunteers. PMID- 21688316 TI - A quantitative comparison of the influence of individual versus population derived vascular input functions on dynamic contrast enhanced-MRI in small animals. AB - For quantitative analysis of dynamic contrast enhanced magnetic resonance imaging data, the time course of the concentration of the contrast agent in the blood plasma, or vascular input function (VIF), is required. We compared pharmacokinetic parameters derived using individual and population-based VIFs in mice for two different contrast agents, gadopentetate dimeglumine and P846. Eleven mice with subcutaneous 4T(1) breast cancer xenografts were imaged at 7 T. A precontrast T(1) map was acquired along with dynamic T(1) -weighted gradient echo images before, during, and after a bolus injection of contrast agent delivered via a syringe pump. Each animal's individual VIF and derived population averaged VIF were used to extract parameters from the signal-time curves of tumor tissue at both the region of interest and voxel level. The results indicate that for both contrast agents, K(trans) values estimated using population-averaged VIF have a high correlation (concordance correlation coefficient > 0.85) with K(trans) values estimated using individual VIF on both a region of interest and voxel level. This work supports the validity of using of a population-based VIF with a stringent injection protocol in preclinical dynamic contrast enhanced magnetic resonance imaging studies. PMID- 21688317 TI - Fast CPMG-based Bloch-Siegert B(1)+ mapping. AB - A novel method for B(1)+ mapping based on the Bloch-Siegert (BS) shift was recently presented. This method applies off-resonant pulses before signal acquisition to encode B(1) information into the signal phase. BS-based methods possess significant advantages in measurement time and accuracy compared to magnitude-based B(1)+ methods. This study extends the idea of BS B(1)+ mapping to Carr, Purcell, Meiboom, Gill (CPMG)-based multi-spin-echo (BS-CPMG-MSE) and turbo spin-echo (BS-CPMG-TSE) imaging. Compared to BS-based spin echo imaging (BS-SE), faster acquisition of the B(1)+ information was possible using the BS-CPMG-TSE sequence. Furthermore, signal loss by T(2)* effects could be minimized using these spin echo-based techniques. These effects are critical for gradient echo based BS methods at high field strengths. However, multi-spin-echo-based BS B(1) methods inherently possess high specific absorption rates. Thus, the relative specific absorption rate of BS-CPMG-TSE sequences was estimated and compared with the specific absorption rate produced by BS-SE sequences. PMID- 21688315 TI - Quantitative tissue oxygen measurement in multiple organs using 19F MRI in a rat model. AB - Measurement of individual organ tissue oxygen levels can provide information to help evaluate and optimize medical interventions in many areas including wound healing, resuscitation strategies, and cancer therapeutics. Echo planar (19) F MRI has previously focused on tumor oxygen measurement at low oxygen levels (pO(2)) <30 mmHg. It uses the linear relationship between spin-lattice relaxation rate (R(1)) of hexafluorobenzene (HFB) and pO(2). The feasibility of this technique for a wider range of pO(2) values and individual organ tissue pO(2) measurement was investigated in a rat model. Spin-lattice relaxation times (T(1) = 1/R(1)) of hexafluorobenzene were measured using (19) F saturation recovery echo planar imaging. Initial in vitro studies validated the linear relationship between R(1) and pO(2) from 0 to 760 mmHg oxygen partial pressure at 25, 37, and 41 degrees C at 7 Tesla for hexafluorobenzene. In vivo experiments measured rat tissue oxygen (ptO2) levels of brain, kidney, liver, gut, muscle, and skin during inhalation of both 30 and 100% oxygen. All organ ptO(2) values significantly increased with hyperoxia (P < 0.001). This study demonstrates that (19) F MRI of hexafluorobenzene offers a feasible tool to measure regional ptO2 in vivo, and that hyperoxia significantly increases ptO2 of multiple organs in a rat model. PMID- 21688318 TI - A B1-insensitive high resolution 2D T1 mapping pulse sequence for dGEMRIC of the HIP at 3 Tesla. AB - Early detection of cartilage degeneration in the hip may help prevent onset and progression of osteoarthritis in young patients with femoroacetabular impingement. Delayed gadolinium-enhanced MRI of cartilage is sensitive to cartilage glycosaminoglycan loss and could serve as a diagnostic tool for early cartilage degeneration. We propose a new high resolution 2D T1 mapping saturation recovery pulse sequence with fast spin echo readout for delayed gadolinium enhanced magnetic resonance imaging of cartilage of the hip at 3 T. The proposed sequence was validated in a phantom and in 10 hips, using radial imaging planes, against a rigorous multipoint saturation-recovery pulse sequence with fast spin echo readout. T1 measurements by the two pulse sequences were strongly correlated (R2>0.95) and in excellent agreement (mean difference=-8.7 ms; upper and lower 95% limits of agreement=64.5 and -81.9 ms, respectively). T1 measurements were insensitive to B1+ variation as large as 20%, making the proposed T1 mapping technique suitable for 3 T. PMID- 21688319 TI - Volume measurement of bone erosions in magnetic resonance images of patients with rheumatoid arthritis. AB - The volume of bone erosions in the metacarpophalangeal joints is a radiological feature that can be used to track the progression of rheumatoid arthritis. We introduce a hybrid segmentation algorithm that combines region growing and level set segmentation algorithms to semiautomatically measure the volume of bone erosions in magnetic resonance images. A total of 40 rheumatoid arthritis patients were included in the study. The scans of eight patients were used for training, whereas the remaining 32 scans were used to determine the accuracy, precision, and speed of the technique. The reproducibility of the semiautomated technique and that of manual segmentation was defined in terms of intraclass correlation coefficients. Both techniques were equally precise with intraclass correlation coefficient values greater than 0.9. The hybrid algorithm was highly accurate: the least squares fit between the semiautomated segmentations to those manually traced by a musculoskeletal radiologist resulted in a slope of 1.030 with an x-intercept of 1.385 mm(3) and an R(2) value of 0.923. The semiautomated technique was significantly faster than manual segmentation, which took two to four times longer to complete. Our hybrid algorithm shows promise in the quantitative assessment of radiological features of rheumatoid arthritis in a clinical setting. PMID- 21688320 TI - Efficient sample density estimation by combining gridding and an optimized kernel. AB - The reconstruction of non-Cartesian k-space trajectories often requires the estimation of nonuniform sampling density. Particularly for 3D, this calculation can be computationally expensive. The method proposed in this work combines an iterative algorithm previously proposed by Pipe and Menon (Magn Reson Med 1999;41:179-186) with the optimal kernel design previously proposed by Johnson and Pipe (Magn Reson Med 2009;61:439-447). The proposed method shows substantial time reductions in estimating the densities of center-out trajectories, when compared with that of Johnson. It is demonstrated that, depending on the trajectory, the proposed method can provide reductions in execution time by factors of 12 to 85. The method is also shown to be robust in areas of high trajectory overlap, when compared with two analytical density estimation methods, producing a 10-fold increase in accuracy in one case. Initial conditions allow the proposed method to converge in fewer iterations and are shown to be flexible in terms of the accuracy of information supplied. The proposed method is not only one of the fastest and most accurate algorithms, it is also completely generic, allowing any arbitrary trajectory to be density compensated extemporaneously. The proposed method is also simple and can be implemented on parallel computing platforms in a straightforward manner. PMID- 21688321 TI - Instruments for comprehensive needs assessment in individuals with cognitive complaints, mild cognitive impairment or dementia: a systematic review. AB - OBJECTIVE: In recent years, it has become more common to complement the objective assessment of symptoms with an assessment of individual needs patterns that are created by the individual pattern of symptoms. However, little is known on needs patterns in individuals with subjective cognitive impairment, mild cognitive impairment and dementia. Thus, on the basis of an analysis of the development of needs in the course of cognitive decline, we provide an overview of the existing needs assessment instruments with respect to feasibility, validity and reliability. METHOD: We conducted a literature search in PsycINFO and PubMed including all publications up to September 2009. We included needs assessment instruments for use in older individuals with mental or cognitive disorders and dementia. RESULTS: We identified 17 needs assessment instruments for individuals with mental disorders, cognitive impairment or dementia. The analysis of selected articles demonstrated a wide range of needs indicators within different subgroups. Validity and reliability range between moderate and good. CONCLUSIONS: Even though a wide range of needs assessment instruments is available, most instruments assess the needs of individuals with subjective cognitive impairment, mild cognitive impairment and dementia on a general level rather than on a more concrete level that may serve better to inform interventions for this growing population. In addition, we suggest basing the development of instruments firmly on an adequate theoretical framework and standardised procedural guidelines. PMID- 21688323 TI - McBurney's button-hole to the posterior interosseous nerve. AB - McBurney's button-hole is an exposure technique for the posterior interosseous nerve quoted in Anrold Kirkpatrick Henry's famous book Extensile Exposures. This short article discusses the overlap between three historical surgeons, Thompson, Henry and McBurney to discover the meaning of the reference and technique, which is used by surgeons to this day. PMID- 21688322 TI - Translational characterization of [11C]GSK931145, a PET ligand for the glycine transporter type 1. AB - The current interest in developing Glycine transporter Type 1 (GlyT-1) inhibitors, for diseases such as schizophrenia, has led to the demand for a GlyT 1 PET molecular imaging tool to aid drug development and dose selection. We report on [(11) C]GSK931145 as a novel GlyT-1 imaging probe in primate and man. Primate PET studies were performed to determine the level of specific binding following homologous competition with GSK931145 and the plasma-occupancy relationship of the GlyT-1 inhibitor GSK1018921. Human PET studies were performed to determine the test-retest reproducibility of [(11) C]GSK931145 and the plasma occupancy relationship of GSK1018921. [(11) C]GSK931145 entered primate and human brain and yielded a heterogeneous pattern of uptake which was similar in both species with highest uptake in midbrain, thalamus, and cerebellum. Homologous competition in primates indicated no viable reference region and gave binding potential estimates between 1.5 and 3 for midbrain, thalamus and cerebellum, While the distribution and binding potential values were similar across species, both the plasma free fraction (f(P) : 0.8 vs. 8%) and delivery (K(1) : 0.025 vs. 0.126 ml cm(-3) min(-1) ) were significantly lower in humans. Test-retest reproducibility in humans calculated using a two tissue compartmental model was poor (VAR(V(T) ): 29-38%), but was improved using a pseudo reference tissue model (VAR(BP(ND) ): 16-23%). GSK1018921 EC(50) estimates were 22.5 and 45.7 ng/ml in primates and humans, respectively. PMID- 21688324 TI - Apolipoprotein D mediates autocrine protection of astrocytes and controls their reactivity level, contributing to the functional maintenance of paraquat challenged dopaminergic systems. AB - The study of glial derived factors induced by injury and degeneration is important to understand the nervous system response to deteriorating conditions. We focus on Apolipoprotein D (ApoD), a Lipocalin expressed by glia and strongly induced upon aging, injury or neurodegeneration. Here we study ApoD function in the brain of wild type and ApoD-KO mice by combining in vivo experiments with astrocyte cultures. Locomotor performance, dopamine concentration, and gene expression levels in the substantia nigra were assayed in mice treated with paraquat (PQ). The regulation of ApoD transcription, a molecular screening of oxidative stress (OS)-related genes, cell viability and oxidation status, and the effects of adding human ApoD were tested in astrocyte cultures. We demonstrate that (1) ApoD is required for an adequate locomotor performance, modifies the gene expression profile of PQ-challenged nigrostriatal system, and contributes to its functional maintenance; (2) ApoD expression in astrocytes is controlled by the OS-responsive JNK pathway; (3) ApoD contributes to an autocrine protecting mechanism in astrocytes, avoiding peroxidated lipids accumulation and altering the PQ transcriptional response of genes involved in ROS managing and the inflammatory response to OS; (4) Addition of human ApoD to ApoD-KO astrocytes promotes survival through a mechanism accompanied by protein internalization and modulation of astroglial reactivity. Our data support that ApoD contributes to the endurance of astrocytes and decreases their reactivity level in vitro and in vivo. ApoD function as a maintenance factor for astrocytes would suffice to explain the observed protection by ApoD of OS-vulnerable dopaminergic circuits in vivo. PMID- 21688327 TI - A robust inter-connecting layer for achieving high performance tandem polymer solar cells. PMID- 21688328 TI - Synthesis and C(2) -symmetric structure of a cyclotetrapeptide composed of anthranilic acid and leucine. AB - A chiral cyclotetrapeptide (1) was synthesized from 2-nitrobenzoic acid and leucine. A single-crystal X-ray of the compound revealed a C(2) -symmetric bowl shaped structure. The cyclic compound had a unique hydrogen-bonding network composed of three-centered hydrogen bonds and bifurcated hydrogen bonds between NH and CO of anthranilic residue. The NMR spectra and molecular modeling of 1 also suggested the chiral bowl structure. PMID- 21688329 TI - Enhancing the photothermal stability of plasmonic metal nanoplates by a core shell architecture. PMID- 21688330 TI - Pen-on-paper flexible electronics. PMID- 21688331 TI - Pyrazolate-based cobalt(II)-containing metal-organic frameworks in heterogeneous catalytic oxidation reactions: elucidating the role of entatic states for biomimetic oxidation processes. AB - Crystal structures of two metal-organic frameworks (MFU-1 and MFU-2) are presented, both of which contain redox-active Co(II) centres coordinated by linear 1,4-bis[(3,5-dimethyl)pyrazol-4-yl] ligands. In contrast to many MOFs reported previously, these compounds show excellent stability against hydrolytic decomposition. Catalytic turnover is achieved in oxidation reactions by employing tert-butyl hydroperoxide and the solid catalysts are easily recovered from the reaction mixture. Whereas heterogeneous catalysis is unambiguously demonstrated for MFU-1, MFU-2 shows catalytic activity due to slow metal leaching, emphasising the need for a deeper understanding of structure-reactivity relationships in the future design of redox-active metal-organic frameworks. Mechanistic details for oxidation reactions employing tert-butyl hydroperoxide are studied by UV/Vis and IR spectroscopy and XRPD measurements. The catalytic process accompanying changes of redox states and structural changes were investigated by means of cobalt K edge X-ray absorption spectroscopy. To probe the putative binding modes of molecular oxygen, the isosteric heats of adsorption of O(2) were determined and compared with models from DFT calculations. The stabilities of the frameworks in an oxygen atmosphere as a reactive gas were examined by temperature-programmed oxidation (TPO). Solution impregnation of MFU-1 with a co-catalyst (N hydroxyphthalimide) led to NHPI@MFU-1, which oxidised a range of organic substrates under ambient conditions by employing molecular oxygen from air. The catalytic reaction involved a biomimetic reaction cascade based on free radicals. The concept of an entatic state of the cobalt centres is proposed and its relevance for sustained catalytic activity is briefly discussed. PMID- 21688332 TI - Pyrogallol[4]arenes show highly variable amphiphilic behavior at the air-water interface dependent upon side chain length and branching. AB - The behavior of pyrogallol[4]arenes (Pgs) substituted with normal and branched alkyl side chains at the air-water interface was examined on a Langmuir trough. The amphiphilic systems studied form stable monolayers when the straight chains are as short as n-propyl. Remarkably, n-propylpyrogallol[4]arene shows a behavior at the air-water interface that is indistinguishable from that of pyrogallolarenes bearing n-hexyl, n-nonyl, and n-dodecyl side chains. There is no report of amphiphilic side-chain-length dependence or Langmuir trough behavior for families of branched alkyl chain calixarenes or resorcinarenes. In the Pg family reported here, Pgs with straight chains (except for methyl and ethyl) behave very similarly to each other and very differently from symmetrical branched chain analogues having the same total number of carbon atoms. For example, the shortest possible branched side chain of a Pg, isopropyl-Pg, forms stable monolayers by a unique molecular subduction mechanism. Isopropyl-Pg (dimethylmethyl side chain, iPrPg) and 3-pentyl-Pg (diethylmethyl side chain, 3 pentylPg) both show high levels of organization, albeit by quite different mechanisms, at the air-water interface. Both iPrPg and 3-pentylPg differ in behavior from 4-heptylPg. Brewster angle microscopy revealed differences in organization of the Pgs that supports the mechanistic suggestions offered herein. PMID- 21688333 TI - Site-specific recognition of guanosine by manganese(III) corroles in DNA non duplex regions through active oxygen transfer. AB - DNA damage plays an important role in cellular processes. Besides natural protein nucleases, different types of efficient agents for DNA damage have been developed over recent decades in the search for new anticancer and antiviral drugs. In addition to the double-stranded configuration, DNA structures also include some non-duplex regions, which are considered to be from spontaneous errors in DNA replication, thus playing an important role for cells. Herein, we focused on these non-duplex regions of DNA and generated manganese(III) corroles, which exhibit a highly selective cleavage ability for guanosine units located at non duplex portions, such as loops and bulges. The cleavage mechanism was demonstrated to be a manganese-induced oxidation process. The results given herein show a molecular approach that could specifically probe the guanosine units in DNA non-duplex structures, thus representing a promising step in the construction of tools to target non-duplex structures in chromosomes. PMID- 21688335 TI - Gamete membrane microdomains and their associated molecules in fertilization signaling. AB - Fertilization is the fundamental system of biological reproduction in many organisms, including animals, plants, and algae. A growing body of knowledge has emerged to explain how fertilization and activation of development are accomplished. Studies on the molecular mechanisms of fertilization are in progress for a wide variety of multicellular organisms. In this review, we summarize recent findings and debates about the long-standing questions concerning fertilization: how egg and sperm become competent for their interaction with each other, how the binding and fusion of these gamete cells are made possible, and how the fertilized eggs initiate development to a newborn. We will focus on the structure and function of the membrane microdomains (MDs) of egg and sperm that may serve as a platform or signaling center for the aforementioned cellular functions. In particular, we provide evidence that MDs of eggs from the African clawed frog, Xenopus laevis, play a pivotal role in receiving extracellular signals from fertilizing sperm and then transmitting them to the egg cytoplasm, where the tyrosine kinase Src is present and responsible for the subsequent signaling events collectively called egg activation. The presence of a new signaling axis involving uroplakin III, an MD-associated transmembrane protein, and Src in this system will be highlighted and discussed. PMID- 21688336 TI - Cows are not mice: the role of cyclic AMP, phosphodiesterases, and adenosine monophosphate-activated protein kinase in the maintenance of meiotic arrest in bovine oocytes. AB - Meiotic maturation in mammalian oocytes is initiated during fetal development, and is then arrested at the dictyate stage - possibly for several years. Oocyte meiosis resumes in preovulatory follicles in response to the lutenizing hormone (LH) surge or spontaneously when competent oocytes are removed from follicles and cultured. The mechanisms involved in meiotic arrest and resumption in bovine oocytes are not fully understood, and several studies point to important differences between oocytes from rodent and livestock species. This paper reviews earlier and contemporary studies on the effects of cAMP-elevating agents and phosphodiesterase (PDE) enzyme inhibitors on the maintenance of meiotic arrest in bovine oocytes in vitro. Contrary to results obtained with mouse oocytes, bovine oocyte meiosis is inhibited by activators of the energy sensor adenosine monophosphate-activated protein kinase (AMPK, mammalian gene PRKA), which is activated by AMP, the degradation product of cAMP. It is not clear whether or not the effects were due to AMPK activation, and they may depend on culture conditions. Evidence suggests that other signaling pathways (for example, the cGMP/nitric oxide pathway) are involved in bovine oocyte meiotic arrest, but further studies are needed to understand the interactions between the signaling pathways that lead to maturation promoting factor (MPF) being inactive or active. An improved understanding of the mechanisms involved in the control of bovine oocyte meiosis will facilitate better control of the process in vitro, resulting in increased developmental competence and increased efficiency of in vitro embryo production procedures. PMID- 21688337 TI - Conditional repression of STAT5 expression during lactation reveals its exclusive roles in mammary gland morphology, milk-protein gene expression, and neonate growth. AB - The role of Stat5 in maintaining adequate lactation was studied in Stat5a(-/-) mice expressing a conditionally suppressed transgenic STAT5 in their mammary glands. This system enables distinguishing STAT5's effects on lactation from its contribution to mammary development during gestation. Females were allowed to express STAT5 during their first pregnancy. After delivery, STAT5 levels were manipulated by doxycycline administration and withdrawal. In two lines of genetically modified mice, the absence of STAT5 expression during the first 10 days of lactation resulted in a decrease of 29% or 41% in newborn weight gain. The STAT5-dependent decrease in growth was recoverable, but not completely reversible, particularly when STAT5 expression was omitted for the first 4 days of lactation. Within the first 10 days of STAT5-omitted lactation, alveolar occupancy regressed by 50% compared to that measured at delivery. By Day 10, only 18% of the fat-pad area was involved in milk production. The alveolar regression caused by 4 days of STAT5 deficiency was reversible, but neonate growth remained delayed. STAT5 deficiency resulted in reduced estrogen receptor alpha and connexin 32 gene expression, accompanied by delayed induction of both anti- and pro-apoptotic Bcl-2 family members. An increase in Gata-3 expression may reflect an attempt to maintain alveolar progenitors. A decrease of 39% and 23% in WAP and alpha-lactalbumin expression, respectively, with no associated effects on beta casein, also resulted from lack of STAT5 expression in the first 10 days of lactation. This deficiency enhances the major effect of alveolar regression on delayed weight gain in newborns. PMID- 21688338 TI - Correlates of physical activity and inactivity in urban Mexican youth. AB - OBJECTIVES: To evaluate correlates of physical activity in Mexico City school youth. METHODS: A cross-sectional survey was conducted with 1,004 school youth (490 males and 514 females), 9-18 years of age resident in Mexico City. Age, height, body mass index (BMI), socioeconomic status (SES), time viewing television and playing video games (physical inactivity), and perceived sport/physical activity status of mother and father were evaluated as potential correlates of physical activity [Physical Activity Questionnaire (PAQ)]. Multiple linear regression analyses (backward elimination) by age group and sex were used. RESULTS: Physical activity declined in older adolescents, while differences between the two younger age groups were minimal. Television time showed a similar tendency. Overall, fathers were perceived as being active in sport/physical activity more frequently than mothers. Significant predictors of activity differed by age group and sex. For the total sample, age (negative) and perceived sport/activity status of the mother (positive) were significant predictors of the PAQ in boys, and age and the BMI (negative) and height and perceived sport/activity status of both parents (positive) were significant predictors for girls. Age (negative) was the main predictor for inactivity in both males and females. CONCLUSIONS: Potential correlates of physical activity and inactivity considered in this analysis were limited and accounted for relatively little of the variance in physical activity. The role of perceived sport/activity of the parents, especially among younger boys and girls, is particularly of interest and merits more detailed study. Nevertheless, many other variables also need to be considered. PMID- 21688339 TI - Role of prophylactic thyroidectomy in RET 790 familial medullary thyroid carcinoma. AB - BACKGROUND: We describe a family harboring RET 790 mutation and review the role of prophylactic thyroidectomy for medullary thyroid carcinoma. METHODS: We evaluated in detail both clinical and biological follow-up and reviewed literature reports. RESULTS: Among 86 family members, 15 of 22 members screened harbored the 790 mutation. Abnormal calcitonin levels were found in 8/15. Total thyroidectomy with lymph node dissection cured the 5 operated patients (range, 45 76 years). Tumor staging was pT1N0M0. Among 10 carriers who did not undergo surgery, 3 patients had abnormal calcitonin levels. For the others, calcitonin levels remained <30 pg/mL. Two asymptomatic carriers were older than 70 years. Four subjects were lost to follow-up. CONCLUSIONS: In RET codon 790 mutations families, a case-by-case decision instead of systematic prophylactic thyroidectomy should be discussed. Difficulties of follow-up should be taken into account and represent the main challenge. PMID- 21688341 TI - Botulinum toxin type b for the treatment of a sialocele after parotidectomy. AB - BACKGROUND: A 41-year-old male patient developed a sialocele after partial parotidectomy for a parotid pleomorphic adenoma. The sialocele was effectively treated by a single injection with botulinum toxin type B combined with multiple needle aspirations. METHODS: Ultrasound-guided infiltration of 2500 mouse-units of botulinum toxin type B in the residual parotid gland tissue under local anesthesia. Repeated needle aspirations were performed before and after the infiltration. RESULTS: Ten days after the injection, the patient was free of any discomfort. CONCLUSION: Botulinum toxin type B is effective in the management of postoperative sialocele after parotid gland surgery. PMID- 21688340 TI - Sentinel node navigation surgery versus observation as a management strategy for early tongue carcinoma. AB - BACKGROUND: The status of lymph nodes in the neck is the most important prognostic factor for the outcomes of patients with oral tongue cancer. However, surgical prophylaxis of the neck is controversial. METHODS: We reviewed 22 patients with clinically T1/T2, N0 Union Internationale Contre le Cancer oral squamous cell carcinoma of the tongue. Patients were assigned to groups according to the management strategy selected for the neck. One group underwent a "watchful waiting" policy and the other underwent sentinel node navigation surgery (SNNS). RESULTS: Three of 11 patients (27%) in the watchful waiting group developed regional recurrence and underwent neck dissection. Only 1 of 11 patients (9.1%) in the SNNS group developed regional recurrence. Although the groups did not significantly differ, the SNNS group tended to have less regional recurrence. CONCLUSION: SNNS should be the third strategy formanaging early oral tongue carcinoma. PMID- 21688342 TI - Efficacy of neck dissection for locoregional failures versus isolated nodal failures in nasopharyngeal carcinoma. AB - BACKGROUND: Neck dissection has been shown to be effective in controlling nodal failures in nasopharyngeal carcinoma. Its efficacy in controlling the disease in patients with synchronous locoregional failure is, however, not documented. METHOD: A retrospective review of all patients who underwent neck dissection for nodal failures with or without treated local failure within 6 months was conducted for this study. The survivals of these 2 groups of patients were analyzed. RESULTS: The 5-year overall survival of the whole cohort was 58%. There was no difference in 5-year disease specific survival (68% vs 40%; p = .121) and 5-year progression free survival (44% vs 36%; p = .334) when comparing patients with isolated nodal failures and synchronous locoregional failures. Multivariate analysis showed that only the initial N classification affects survival. CONCLUSION: Neck dissection is efficacious in patients with nasopharyngeal carcinoma with nodal failure, with or without synchronous local failures. PMID- 21688343 TI - Early surgical outcomes of robotic thyroidectomy by a gasless unilateral axillo breast or axillary approach for papillary thyroid carcinoma: 2 years' experience. AB - BACKGROUND: The efficacy of robotic thyroidectomy for thyroid cancer has not yet been assessed. The aim of this study was to evaluate the technical feasibility and completeness of robotic thyroidectomy for papillary thyroid carcinoma (PTC). METHODS: We analyzed 75 patients with PTC who underwent robotic thyroidectomy from October 2008 to August 2010 using a gasless unilateral axillo-breast or axillary approach with a da Vinci S Surgical System Robot and compared them with 226 patients who received conventional open thyroidectomy. RESULTS: The robotic thyroidectomy procedure was successfully completed in all the patients. The complication rate did not differ between the 2 groups, except for transient hypoparathyroidism. The surgical completeness of robotic thyroidectomy was comparable to that of conventional open thyroidectomy, and cosmetic satisfaction was superior in the robotic group. CONCLUSION: Robotic thyroidectomy is a safe, feasible, and cosmetically excellent procedure in properly selected patients with PTC. PMID- 21688344 TI - Effects of KRAS mutation and polymorphism on the risk and prognosis of oral squamous cell carcinoma. AB - BACKGROUND: Mutations or single nucleotide polymorphism (SNP) of relevant genes may affect the risk and prognosis of malignancies. The purpose of this study was to analyze whether the KRAS polymorphisms and mutations can be useful prognostic or risk markers in oral squamous cell carcinoma (OSCC). METHODS: DNA was extracted from tumor tissues of 47 patients with OSCC and blood cells of 84 normal controls and subjected to sequencing for the KRAS. RESULTS: No mutation in the KRAS was found in 47 OSCC samples. However, 2 polymorphisms (rs1137282 and rs712) were detected. Individuals with KRAS SNP rs712 genotypes of G/T or T/T have a reduced risk for OSCC than those with genotype G/G (hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.10-0.60; p = .004). The overall survival between different SNPs were not statistically significant (p = .147 for rs1137282 and p = .202 for rs712). CONCLUSION: These data demonstrate a role for rs712 polymorphism of the KRAS in susceptibility of OSCC. PMID- 21688345 TI - Hospitalization and surgical rates in patients with Crohn's disease treated with infliximab: a matched analysis. AB - PURPOSE: The majority of subjects with Crohn's Disease (CD) will be hospitalized and will receive surgery for their disease. These interventions account for most of the direct costs of the disease. We sought to explore the association between infliximab use and CD-related surgery and hospitalizations. METHODS: We obtained patient-level health claims between 1996 and 2007 from the Regie de l'Assurance Maladie du Quebec (RAMQ), a Canadian provincial health care insurer. Subjects who were i) enrolled in the RAMQ for at least 2 years, ii) received prescription drug benefits for each year of enrolment and iii) were identified as having CD using a validated algorithm were eligible for the study. For each subject treated with infliximab, up to two closely matched comparison subjects were selected using propensity score methods. We compared time to first CD-related intra-abdominal surgery or hospitalization in infliximab users and non-users. RESULTS: We matched 338 infliximab users (mean age 34, 45% male) to at least one comparison subject using propensity score matching. Subjects who received infliximab had a significantly lower risk of experiencing a CD-related intra-abdominal surgery (hazard ratio [HR] = 0.64; 95% confidence interval [CI] 0.51-0.81) or hospitalization (HR = 0.73; 95% CI 0.63-0.85). Infliximab users also experienced lower rates of hospitalized days (Rate Ratio = 0.69; 95% CI 0.49-0.97). CONCLUSIONS: Our results support the real world effectiveness of infliximab therapy in reducing CD-related surgeries and hospitalizations. PMID- 21688346 TI - Association between non-steroidal anti-inflammatory drugs and keratinocyte carcinomas of the skin among participants in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. AB - PURPOSE: Observational studies have reported significant negative associations between sporadic non-steroidal anti-inflammatory drug (NSAID) use and keratinocyte carcinoma (KC) while reporting null results for regular use. This pattern may be partially explained by the operational expression of NSAID exposure and analytic model assumptions. Our goals were to quantify the association between NSAIDs and KC and to explore the impact of exposure metrics and modeling assumptions on observed associations. METHODS: We conducted a prospective cohort study by linking data from the Veterans Affairs Topical Tretinoin Chemoprevention Trial and the VA Pharmacy Benefits Management database. NSAID use was categorized according to cyclooxygenase selectivity, timing of initiation, and frequency of use. Data were analyzed using time-varying and time fixed multivariable-adjusted Cox proportional hazard models [Correction made here after initial online publication]. Simulated null data were generated and analyzed to explore potential biases introduced by the models and the exposure metrics. RESULTS: During a median follow-up time of 2 years for basal cell carcinoma and 2.5 years for squamous cell carcinoma, 472 occurrences of BCC and 309 occurrences of SCC were observed. Time-fixed analyses of NSAID exposure metrics produced significant negative associations, whereas time-varying analyses produced null results. Analysis of simulated null data revealed the potential for strong bias in the time-fixed analyses. CONCLUSIONS: This study did not identify a negative association between NSAIDs and KC. The disparity between the time fixed and the time-varying analyses highlights the extent to which operational definitions of drug exposures and reliance on time-fixed methods may introduce bias. PMID- 21688348 TI - Adherent-invasive Escherichia coli induce claudin-2 expression and barrier defect in CEABAC10 mice and Crohn's disease patients. AB - BACKGROUND: Abnormal expression of CEACAM6 observed on the ileal epithelium in Crohn's disease (CD) patients allows adherent-invasive Escherichia coli (AIEC) to colonize gut mucosa. Since intestinal permeability is significantly increased in CD patients, we aimed at investigating whether and how AIEC alter barrier function. METHODS: Tissue microarray was performed on ileal biopsies from CD patients in quiescent and active phases. CEABAC10 or wildtype mice were orally challenged with 10(9) bacteria. Intestinal permeability was assessed by measuring 4 kDa dextran-FITC flux in serum, barrier integrity was analyzed using biotin tracer experiment, and claudin-2 protein immunostaining. Bacterial translocation was analyzed in Ussing chambers. RESULTS: Pore-forming tight junction protein claudin-2 is strongly expressed in the ileum of 51% patients in quiescent phase and in 49% of the patients with active CD. Infection of CEABAC10 transgenic mice expressing human CEACAMs with AIEC, but not with nonpathogenic E. coli, led to a significant 3.0-fold increase in intestinal permeability and to disruption of mucosal integrity in a type 1 pili-dependent mechanism. This is consistent with the claudin-2 abnormal expression at the plasma membrane of intestinal epithelial cells observed in AIEC-infected CEABAC10 mice. AIEC bacteria were able to translocate through CEABAC10 intestinal mucosa. CONCLUSIONS: These findings strongly support the hypothesis that AIEC type 1 pili-mediated interaction with CEACAM6 abnormally expressed in the quiescent phase of CD may disrupt intestinal barrier integrity before the onset of inflammation. Thus, therapeutic targeting claudin-2 induced by AIEC infection could be a new clinical strategy for preserving intestinal barrier function in CD patients. PMID- 21688347 TI - Aberrant expression of genes necessary for neuronal development and Notch signaling in an epileptic mind bomb zebrafish. AB - Mutation within an ubiquitin E3 ligase gene can lead to a failure in Notch signaling, excessive neurons, and depletion of neural progenitor cells in mind bomb mutants. Using mib(hi904) zebrafish, we reported seizures and a down regulation of gamma-aminobutyric acid (GABA) signaling pathway genes. A transcriptome analysis also identified differential expression pattern of genes related to Notch signaling and neurodevelopment. Here, we selected nine of these genes (her4.2, hes5, bhlhb5, hoxa5a, hoxb5b, dmbx1a, dbx1a, nxph1, and plxnd1) and performed a more thorough analysis of expression using conventional polymerase chain reaction, real-time polymerase chain reaction and in situ hybridization. Transgenic reporter fish (Gfap:GFP and Dlx5a-6a:GFP) were used to assess early brain morphology in vivo. Down-regulation of many of these genes was prominent throughout key structures of the developing mib(hi904) zebrafish brain including, but not limited to, the pallium, ventral thalamus, and optic tectum. Brain expression of Dlx5a-6a and Gfap was also reduced. In conclusion, these expression studies indicate a general down-regulation of Notch signaling genes necessary for proper brain development and suggest that these mutant fish could provide valuable insights into neurological conditions, such as Angelman syndrome, associated with ubiquitin E3 ligase mutation. PMID- 21688349 TI - Relationship between social support and autonomic function during a stress protocol in ulcerative colitis patients in remission. AB - BACKGROUND: The relationship of psychological stress to relapse in ulcerative colitis (UC) is inconsistent. This may be due to a failure to identify patient characteristics, such as social support, which moderate the transduction of stress from the central nervous system to the immune system. In this study we tested the hypothesis that social support enhances parasympathetic modulation of heart rate in UC. METHODS: An indirect measure of autonomic function (heart rate variability; HRV) was measured in 108 patients with UC in remission during a standard protocol involving periods of stress, paced breathing, and relaxation. Social support was measured with the Social Support Questionnaire. RESULTS: After controlling for age, which is strongly related to HRV, both satisfaction with social support (F = 5.7, significance = 0.002) and its interaction with age (F = 7.8, significance <0.001) were associated with high-frequency HRV, which measures parasympathetic modulation of heart rate. Social support was associated with higher levels of high-frequency HRV at almost all points in the stress protocol. Neither age nor social support was associated with differences in the LF/HF ratio, which measures sympathetic modulation of heart rate. CONCLUSIONS: Social support is related to parasympathetic activity in UC. Given previous evidence of an antiinflammatory role for the parasympathetic nervous system, this suggests that autonomic function could serve as a mediating link between social support and reduced inflammatory activity. PMID- 21688350 TI - Randomized, controlled trial of home telemanagement in patients with ulcerative colitis (UC HAT). AB - BACKGROUND: Outcomes are suboptimal in ulcerative colitis (UC). Telemedicine for UC is feasible and improves outcomes. Our goals were to evaluate a home telemanagement system for UC (UC HAT) on disease activity, quality of life (QoL), and adherence compared to best available care (BAC) in a randomized, controlled trial. METHODS: Adults with UC were randomly assigned to receive UC HAT or BAC for 12 months. UC HAT recruits answered questions regarding disease activity, adherence, side effects, and measured their weight weekly. An educational curriculum was delivered after each session. Alerts and action plans were generated based on the results. BAC underwent routine follow-up, received written action plans, and were given educational fact sheets. Seo Index scores, Inflammatory Bowel Disease Questionnaire (IBDQ) scores, and adherence rates were compared between UC HAT and BAC at 1 year. RESULTS: Twenty-five patients were randomized to UC HAT and 22 to BAC. After 12 months, 11 withdrew in UC HAT compared to 5 in BAC. Disease activity, QoL, and adherence were not different between groups at any timepoint postbaseline. Adjusted analyses of trial completers using all available data demonstrated decreased Seo Index (11.9 in UC HAT (P = 0.08) versus 1.2 in BAC (P = 0.84) and increased IBDQ scores (12.5 in UC HAT (P = 0.04) versus to -3.8 in BAC (P = 0.47) from baseline in UC HAT compared to BAC. CONCLUSIONS: UC HAT did not improve disease activity, QoL, or adherence compared to BAC after 1 year. After adjustment for baseline disease knowledge, UC HAT trial completers experienced significant gains in disease-specific QoL from baseline compared to BAC trial completers. Our results suggest a potential benefit of UC HAT. Further research is indicated to determine if telemedicine improves outcomes in patients with IBD. PMID- 21688351 TI - Comparison of the natural history of ulcerative colitis in African Americans and non-Hispanic Caucasians: a historical cohort study. AB - BACKGROUND: There has been an increase in the number of studies on the interaction of African American race and the natural history of inflammatory bowel disease (IBD). However, the results from these studies have been conflicting. We aimed to characterize the natural history of ulcerative colitis (UC) in a cohort of African American patients compared with Caucasian controls. METHODS: We performed a retrospective chart review of patients with UC who were seen in our IBD Center from 2000 to 2010. In all, 102 African American patients and 209 Caucasian patients were included. We assessed clinical variables related to the natural history of UC as well as outcome variables that reflected disease severity. RESULTS: African American patients had a shorter median duration (8.0, interquartile range [IQR] = 4.0, 14.0) of UC than Caucasians (10.0, IQR = 6.0, 18.0) (P = 0.006). African American disease patients had more distal disease than controls. African Americans were significantly less likely to use corticosteroids (74.2% vs. 88.8%, P = 0.002), or use immunomodulators (25.8% vs. 69.7%, P < 0.001) than Caucasians. Adjusted multivariate analysis showed that ethnicity was not a risk factor for colectomy (hazard ratio [HR] = 1.6; 95% confidence interval [CI]: 0.78, 3.3). CONCLUSIONS: There appear to be differences in the natural history of UC in our African American patients when compared with Caucasian controls, while ethnicity was not shown to be a risk factor for colectomy. PMID- 21688352 TI - Rising incidence of pediatric inflammatory bowel disease in Scotland. AB - BACKGROUND: An accurate indication of the changing incidence of pediatric inflammatory bowel disease (PIBD) within a population is useful in understanding concurrent etiological factors. We aimed to compare the current incidence and other demographic attributes of PIBD in the Scottish population to previous data. METHODS: A national cohort of prospectively and retrospectively acquired incident cases of PIBD diagnosed less than 16 years old in pediatric services in Scotland was captured for the period 2003-2008; historical Scottish data were used for comparison (1990-1995). Age/sex-adjusted incidences were calculated and statistical comparisons made using Poisson regression. RESULTS: During the 2003 2008 study period 436 patients were diagnosed with PIBD in Scotland, giving an adjusted incidence of 7.82/100,000/year. The incidence of Crohn's disease (CD) was 4.75/100,000/year, ulcerative colitis (UC) 2.06/100,000/year, and inflammatory bowel disease-unclassified (IBDU) 1.01/100,000/year. Compared with data from 1990-1995 when 260 IBD patients were diagnosed, significant rises in the incidence of IBD (from 4.45/100,000/year, P < 0.0001), CD (from 2.86/100,000/year, P < 0.0001), and UC (from 1.59/100,000/year, P = 0.023) were seen. There was also a significant reduction in the median age at IBD diagnosis from 12.7 years to 11.9 years between the periods (P = 0.003), with a continued male preponderance. CONCLUSIONS: The number of Scottish children diagnosed with IBD continues to rise, with a statistically significant 76% increase since the mid-1990 s. Furthermore, PIBD is now being diagnosed at a younger age. The reason for this continued rise is not yet clear; however, new hypotheses regarding disease pathogenesis and other population trends may provide further insights in future years. PMID- 21688353 TI - Inhibition of colitis by IL-25 associates with induction of alternatively activated macrophages. AB - BACKGROUND: Interleukin (IL)-25, a Th2-related factor, inhibits the synthesis of inflammatory cytokines by macrophages and attenuates experimental colitis in mice. The mechanism underlying the counterregulatory effect of IL-25, however, remains unknown. Since Th2-cytokines can abrogate inflammatory pathways by inducing alternatively activated macrophages (AAMs), we evaluated whether AAMs are involved in the IL-25-mediated anticolitic effect. METHODS: AAM-related markers were evaluated in peritoneal and lamina propria mononuclear cells of mice with or without 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced colitis treated with IL-25 and/or neutralizing IL-4, IL-13, and transforming growth factor beta 1 (TGF-beta1) antibodies. Peritoneal AAMs induced in vivo by injecting mice with IL-25 were transferred to mice with TNBS colitis. Finally, we assessed the in vitro effect of IL-25 on the alternative activation of peritoneal F4/80+ cells. RESULTS: IL-25 enhanced the expression of AAM-related markers in F4/80(+) cells infiltrating the peritoneum and colon of naive and colitic mice. Peritoneal F4/80(+) cells isolated from IL-25-treated mice reduced the severity of TNBS colitis when injected intraperitoneally to recipient mice. Since IL-25 did not directly induce AAM in vitro and in vivo in mice, IL-25 administration enhanced the expression of IL-4, IL-13, and TGF-beta1, which are known to promote AAM differentiation, we finally assessed whether such cytokines were involved in the IL-25-driven AAM induction. Blockade of IL-4, IL-13, and TGF-beta1 with neutralizing antibodies in mice did not inhibit the stimulatory effect of IL-25 on AAM gene expression. CONCLUSIONS: The IL-25-mediated anticolitic effect is associated with induction of AAMs, a subset of macrophages with antiinflammatory properties. PMID- 21688354 TI - pH-responsive release of acetal-linked melittin from SBA-15 mesoporous silica. PMID- 21688355 TI - A mesoporous gamma-alumina film with vertical mesoporosity: the unusual conversion from a Im3m mesostructure to vertically oriented gamma-alumina nanowires. PMID- 21688356 TI - Dimethylformamide: an unusual glycosylation modulator. PMID- 21688357 TI - Insulin-directed synthesis of fluorescent gold nanoclusters: preservation of insulin bioactivity and versatility in cell imaging. PMID- 21688358 TI - Detection of a protein conformational equilibrium by electrospray ionisation-ion mobility-mass spectrometry. PMID- 21688359 TI - C(sp3)-O bond-forming reductive elimination of ethers from bisphosphine-ligated benzylpalladium(II) aryloxide complexes. PMID- 21688360 TI - Thermoresponsive chlorambucil derivatives for tumour targeting. PMID- 21688361 TI - Spin transition and exchange interaction: Janus visions of supramolecular spin coupling between face-to-face verdazyl radicals. PMID- 21688362 TI - Membrane anchored immunostimulatory oligonucleotides for in vivo cell modification and localized immunotherapy. PMID- 21688363 TI - Boron-doped carbon nanotubes as metal-free electrocatalysts for the oxygen reduction reaction. PMID- 21688364 TI - Dual Ti-Ru catalysis in the direct radical haloalkylation of N-acyl oxazolidinones. PMID- 21688365 TI - 5-Hydroxymethylcytosine, the sixth base of the genome. AB - 5-Hydroxymethylcytosine (hmC) was recently discovered as a new constituent of mammalian DNA. Besides 5-methylcytosine (mC), it is the only other modified base in higher organisms. The discovery is of enormous importance because it shows that the methylation of cytosines to imprint epigenetic information is not a final chemical step that leads to gene silencing but that further chemistry occurs at the methyl group that might have regulatory function. Recent progress in hmC detection--most notably LC-MS and glucosyltransferase assays--helped to decipher the precise distribution of hmC in the body. This led to the surprising finding that, in contrast to constant mC levels, the hmC levels are strongly tissue-specific. The highest values of hmC are found in the central nervous system. It was furthermore discovered that hmC is involved in regulating the pluripotency of stem cells and that it is connected to the processes of cellular development and carcinogenesis. Evidence is currently accumulating that hmC may not exclusively be an intermediate of an active demethylation process, but that it functions instead as an important epigenetic marker. PMID- 21688366 TI - Conversion of metallabenzynes into carbene complexes. PMID- 21688367 TI - Biomimetic synthesis of 5,6-dihydro-glaucogenin C: construction of the disecopregnane skeleton by iron(II)-promoted fragmentation of an alpha-alkoxy hydroperoxide. PMID- 21688368 TI - Transition-metal-free diboration reaction by activation of diboron compounds with simple Lewis bases. PMID- 21688369 TI - Controlled alcohol-carbonyl interconversion by nickel catalysis. PMID- 21688370 TI - Direct and highly diastereoselective synthesis of azaspirocycles by a dysprosium(III) triflate catalyzed aza-Piancatelli rearrangement. PMID- 21688371 TI - Highly diastereoselective and enantioselective synthesis of alpha-hydroxy beta amino acid derivatives: Lewis base catalyzed hydrosilylation of alpha-acetoxy beta-enamino esters. PMID- 21688372 TI - Controlled shape transformation of polymersome stomatocytes. PMID- 21688373 TI - Layered host-guest materials with reversible piezochromic luminescence. PMID- 21688375 TI - Spectroscopic evidence for a triplet ground state in the naphthyl cation. PMID- 21688374 TI - Benzylic ligand hydroxylation starting from a dicopper MU-eta2:eta2 peroxo intermediate: dramatic acceleration of the reaction by hydrogen-atom donors. PMID- 21688376 TI - NHC-Cu-catalyzed enantioselective hydroboration of acyclic and exocyclic 1,1 disubstituted aryl alkenes. PMID- 21688377 TI - Spatially oriented and reversible surface assembly of single-walled carbon nanotubes: a strategy based on pi-pi interactions. PMID- 21688378 TI - A synthetic route to the saxitoxin skeleton: synthesis of decarbamoyl alpha saxitoxinol, an analogue of saxitoxin produced by the cyanobacterium Lyngbya wollei. PMID- 21688379 TI - Generation of small gold clusters with unique geometries through cluster-to cluster transformations: octanuclear clusters with edge-sharing gold tetrahedron motifs. PMID- 21688380 TI - A pre-operative approach of range of motion simulation and verification for femoroacetabular impingement. AB - BACKGROUND: Femoroacetabular impingement (FAI) is increasingly recognized as a potential cause of hip osteoarthritis. A system capable of pre-operatively simulating hip range of motion (ROM) by given surface models from either healthy or FAI diseased bone is desirable. METHODS: An impingement detection system using bounding sphere hierarchies was first developed. Both precision and accuracy of the impingement detection system were verified by a custom-designed phantom to imitate ball-and-socket hip movement. The impingement detection system was then implemented into the hip ROM simulation system to simulate the ROM of (1) healthy pelvis and femur, and (2) healthy pelvis and pathologic femur. The ROM simulation system was also verified by manipulating sawbones under the navigation of an optical tracking system. RESULTS: The impingement detection system achieved a distance error of 0.53 +/- 0.06 mm and an angular error of 0.28 +/- 0.03 degrees . The impingement detection accuracies were 100%, 100%, and 96% in three different phantom orientations, respectively. The mean errors between simulated and verified ROM were 0.10 +/- 1.39 degrees for the 'healthy pelvis and femur' group, and - 2.38 +/- 3.49 degrees for the 'healthy pelvis and pathologic femur' group. CONCLUSION: The present study demonstrates a pre-operative approach to virtually simulate and predict the functional hip ROM based on the given bone models. The impingement detection and ROM simulation systems developed may also be used for other orthopedic applications. PMID- 21688381 TI - Training program for fundamental surgical skill in robotic laparoscopic surgery. AB - BACKGROUND: Although the use of robotic laparoscopic surgery has increased in popularity, training protocols for gaining proficiency in robotic surgical skills are not well established. The purpose of this study was to examine a fundamental training program that provides an effective approach to evaluate and improve robotic surgical skills performance using the da Vinci(TM) Surgical System. METHODS: Fifteen medical students without any robotic surgical experience were recruited. Participants went through a 4-day training program for developing fundamental robotic surgical skills and received a retention test 1 day after the completion of training. Data analysis included time to task completion, average speed, total distance traveled and movement curvature of the instrument tips, and muscle activities of the participants' forearms. Surgical performance was graded by the modified Objective Structured Assessment of Technical Skills for robotic laparoscopic surgery. Finally, participants evaluated their own performance after each session through questionnaires. RESULTS: Significant training effects were shown for the time to task completion (p < 0.001), average speed (p < 0.01), and movement curvature (p < 0.05) for the test conditions. Significant learning effects were also found for EMG activation (p < 0.05). Participants reported more mastery, familiarity, and self-confidence and less difficulty in performing fundamental tasks with the surgical robot in both post-testing and retention sessions. CONCLUSIONS: Our 4-day training program comprising of a series of training tasks from fundamental to surgical skill levels was effective in improving surgical skills. Further studies are required to verify these findings with a longer period of retention. PMID- 21688382 TI - Treatment of recurrent hepatocellular carcinoma after liver transplantation. PMID- 21688383 TI - Can positron emission tomography with the dual tracers [11 C]acetate and [18 F]fludeoxyglucose predict microvascular invasion in hepatocellular carcinoma? AB - Microvascular invasion is a poor prognostic indicator of the recurrence of hepatocellular carcinoma (HCC) after surgical treatment. Positron emission tomography (PET) with [(18) F]fludeoxyglucose ([(18) F]FDG) as a tracer has been employed to predict the prognosis before surgery for various kinds of tumors, but it has not been found to be sensitive enough for HCC. Thus, [(11) C]acetate has been adopted as an additional tracer. This study was designed to evaluate the ability of dual-tracer PET ([(18) F]FDG and [(11) C]acetate) to predict microvascular invasion before liver resection or transplantation. Fifty-eight HCC patients who were preoperatively examined with whole-body dual-tracer PET were studied. Twenty-five patients were [(18) F]FDG-positive, and 56 were [(11) C]acetate-positive. The sensitivity of [(18) F]FDG in detecting primary HCC was 43%, and the sensitivity of [(11) C]acetate was 93%. Twenty-nine patients had HCC with microvascular invasion according to the final pathological examination. The sensitivity, specificity, positive predictive value, and negative predictive value of [(18) F]FDG PET in predicting microvascular invasion were 55.2%, 69%, 64%, and 60.6%, respectively; the corresponding rates for [(11) C]acetate PET were 93.1%, 0%, 48.2%, and 0%. The factors associated with HCC recurrence, which included multifocal involvement, a large tumor size, microsatellite lesions, poor HCC differentiation, and an advanced stage of disease, were analyzed and compared with positive PET results. A tumor size greater than 5 cm was significantly associated with positive [(18) F]FDG PET results; [(11) C]acetate was not associated with poor prognostic indicators. Preoperative [(18) F]FDG PET may predict microvascular invasion. The addition of [(11) C]acetate improves the overall sensitivity of PET, but it has no incremental value in predicting microvascular invasion. PMID- 21688384 TI - Genome-wide association analysis of age at onset in schizophrenia in a European American sample. AB - We performed a genome-wide association analysis to identify genetic variants influencing age at onset (AAO) and examine gene * gender interactions for AAO in schizophrenia (SCZ) using a European-American sample (1,162 cases). Linear regression model in PLINK was used to test for associations with AAO while the GxE option was chosen to test for the influence of gene * gender interactions. The most significant association with AAO was observed with SNP rs7819815 (P = 3.10*10(-7)) at 8q24.22. The next best signal was at 4q25 in COL25A1 gene (rs17039583, P = 4.30*10(-6)) and the third region was at 4p16.1 (rs17407555, P = 4.56*10(-6) , near RAF1P1, and rs4697924, P = 1.23*10(-5) within WDR1 gene). Conditional analysis on chromosome 4 indicated that 4p16.1 and 4q25 loci were independent. Furthermore, 2 SNPs (rs16834822 and rs16834824) at 1q43 in RYR2 showed strong associations in the female sample (P = 2.10*10(-6) and 2.33*10(-6) , respectively) and strong gene * gender interactions in influencing AAO (P = 9.23*10(-7) and 1.15*10(-6) , respectively) while the second best region showing gene * gender interaction was at 7q22.3 (rs179863, P = 2.33*10(-6) ). Using an independent sample of 1,068 cases, we could not replicate the associations for above top SNPs; however, we found nominal significance associations for their flanking SNPs (P < 0.05). These findings provide evidence of several genetic variants influencing AAO of SCZ. PMID- 21688385 TI - No association observed between schizophrenia and non-HLA coeliac disease genes: integration with the initial MYO9B association with coeliac disease. AB - Schizophrenia is a severe psychotic illness with a heterogeneous presentation and a devastating impact on social and occupational function. Worldwide variations in schizophrenia incidence rates suggest that local conditions may modify disease risk. The human leukocyte antigen (HLA) region has been confirmed to be associated with schizophrenia by genome-wide association studies in populations across the world. While the presence of autoimmune processes in a subgroup of schizophrenia cases is contentious, the immune system could allow environmental exposures to lead to schizophrenia by generating improper immune response. To investigate this topic, we reviewed the current evidence of the relationship between schizophrenia and coeliac disease. Based on this review, we performed genetic analysis of the MYO9B gene and the IL-2/IL-21 locus by genotyping SNPs that have been previously associated with coeliac disease or schizophrenia in 223 families, 108 unrelated individuals with schizophrenia and 120 controls. Finding no evidence for association with these two loci in our study samples, we applied meta-analytic techniques to combine our findings with previous reports. This synthesis, in light of our review of previous reports, suggests a differing developmental trajectory for schizophrenia and coeliac disease. It is possible that these two conditions do not share any functional overlap. PMID- 21688386 TI - Synthesis and characterization of biodegradable microcapsules for the controlled delivery of calcium hydroxide. AB - This study aimed to synthesize and characterize biodegradable microcapsules based on poly(lactic acid) (PLA) and ethylcellulose (EC) for a controlled delivery of calcium hydroxide. Phase separation technique was adopted to synthesize calcium hydroxide-loaded PLA/EC microcapsules. Four PLA/EC blends (4/1, 1/1, 1/4, pure EC) were used as shell materials and the input ratio of calcium hydroxide to shell polymer was 4:1 for all microcapsules. The morphology and composition were studied using SEM-EDS and TEM. Particle size distribution, glass-transition temperature, drug loading, and encapsulation efficiency were characterized. In vitro release of the microcapsules was evaluated using a pH microelectrode and an auto-biochemistry analyzer. SEM images of microcapsules showed uniform spherical structures with smooth surfaces. Core-shell, hetero-structures were confirmed using TEM. The presence of calcium in the microcapsules was verified with EDS. Pure calcium hydroxide was 160 nm in diameter and the particle size of the microcapsules ranged between 500 nm and 4 MUm. With an increase of PLA in PLA/EC blend, the size of microcapsules increased accordingly. Encapsulation efficiency of these microcapsules was higher than 57% and drug loading was higher than 80%, which were not significantly different among four microcapsules. Pure calcium hydroxide powder was used as a control and 90% was released within 48 h, while release of calcium hydroxide from microcapsules took between 168 and 456 h, depending on the PLA/EC ratio. Compared with calcium hydroxide powder, the calcium hydroxide-loaded microcapsules showed a sustained and prolonged release, which could be controlled via the regulation of the PLA/EC ratio. PMID- 21688387 TI - Hox clusters of the bichir (Actinopterygii, Polypterus senegalus) highlight unique patterns of sequence evolution in gnathostome phylogeny. AB - Teleost fishes have extra Hox gene clusters owing to shared or lineage-specific genome duplication events in rayfinned fish (actinopterygian) phylogeny. Hence, extrapolating between genome function of teleosts and human or even between different fish species is difficult. We have sequenced and analyzed Hox gene clusters of the Senegal bichir (Polypterus senegalus), an extant representative of the most basal actinopterygian lineage. Bichir possesses four Hox gene clusters (A, B, C, D); phylogenetic analysis supports their orthology to the four Hox gene clusters of the gnathostome ancestor. We have generated a comprehensive database of conserved Hox noncoding sequences that include cartilaginous, lobe finned, and ray-finned fishes (bichir and teleosts). Our analysis identified putative and known Hox cis-regulatory sequences with differing depths of conservation in Gnathostoma. We found that although bichir possesses four Hox gene clusters, its pattern of conservation of noncoding sequences is mosaic between outgroups, such as human, coelacanth, and shark, with four Hox gene clusters and teleosts, such as zebrafish and pufferfish, with seven or eight Hox gene clusters. Notably, bichir Hox gene clusters have been invaded by DNA transposons and this trend is further exemplified in teleosts, suggesting an as yet unrecognized mechanism of genome evolution that may explain Hox cluster plasticity in actinopterygians. Taken together, our results suggest that actinopterygian Hox gene clusters experienced a reduction in selective constraints that surprisingly predates the teleost-specific genome duplication. PMID- 21688388 TI - Diet high in oat beta-glucan activates the gut-hypothalamic (PYY3-36-NPY) axis and increases satiety in diet-induced obesity in mice. AB - This study tested the effects of (1->3),(1->4) beta-D-glucan from oats, on activation of the gut-hypothalamic (PYY3-36-NPY) axis, satiety, and weight loss in diet-induced obesity (DIO) mice. DIO mice were fed standard lab chow diets or varied doses of beta-glucan for 6 weeks. Energy intake, satiety, body weight changes and peptide Y-Y3-36 (PYY3-36) were measured together with a satiety test and measurement of neuropeptide Y (NPY) mRNA expression in the hypothalamic arcuate nucleus (Arc). The average energy intake (-13%, p<0.05) and body weight gain was lower with increasing beta-glucan over 6 wk with acute suppression of energy intake over 4 h. The highest beta-glucan diet significantly increased plasma PYY3-36, with suppression of Arc NPY mRNA. PMID- 21688389 TI - Resveratrol and health--a comprehensive review of human clinical trials. AB - In the past decade, the small polyphenol resveratrol has received widespread attention as either a potential therapy or as a preventive agent for numerous diseases. Studies using purified enzymes, cultured cells, and laboratory animals have suggested that resveratrol has anti-aging, anti-carcinogenic, anti inflammatory, and anti-oxidant properties that might be relevant to chronic diseases and/or longevity in humans. Although the supporting research in laboratory models is quite substantial, only recently data has emerged to describe the effects of resveratrol supplementation on physiological responses in humans. The limited number of human clinical trials that are available has largely described various aspects of resveratrol's safety and bioavailability, reaching a consensus that it is generally well-tolerated, but have poor bioavailability. Very few published human studies have explored the ability of resveratrol to achieve the physiological benefits that have been observed in laboratory models, although many clinical trials have recently been initiated. This review aims to examine the current state of knowledge on the effects of resveratrol on humans and to utilize this information to develop further guidelines for the implementation of human clinical trials. PMID- 21688390 TI - Tumor targeting and imaging using cyclic RGD-PEGylated gold nanoparticle probes with directly conjugated iodine-125. AB - Radioactive iodine-labeled, cyclic RGD-PEGylated gold nanoparticle (AuNP) probes are designed and synthesized for targeting cancer cells and imaging tumor sites. These iodine-125-labeled cRGD-PEG-AuNP probes are stable in various conditions including a range of pHs and high salt and temperature conditions. These probes can target selectively and be taken up by tumor cells via integrin alphavbeta3 receptor-mediated endocytosis with no cytotoxicity. The probes show a significant increase in the avidity of alphavbeta3 integrin compared to the corresponding free cRGD peptides. In-vivo SPECT/CT imaging results show that the iodine-125 labeled cRGD-PEG-AuNP probes can target the tumor site as soon as 10 min after injection, and also that cyclic RGD peptides are needed for efficient and long term in-vivo monitoring. The results suggest that the probes circulate through the whole body, including renal filtration, and are excretable. These promising results show that radioactive-iodine-labeled gold nanoprobes have potential for highly specific and sensitive tumor imaging or for use as angiogenesis-targeted SPECT/CT imaging probes. PMID- 21688391 TI - Aminopropyltriethoxysilane-silica hybrid monolithic capillary microextraction combined with inductively coupled plasma mass spectrometry for the determination of trace elements in biological samples. AB - A simple and sensitive method based on aminopropyltriethoxysilane (APTES)-silica hybrid monolithic capillary microextraction (CME) combined with inductively coupled plasma mass spectrometry (ICP-MS) was developed for the determination of trace elements in biological samples. Under the optimized conditions, the adsorption capacities of APTES-silica hybrid monolithic capillary were 42.5, 55, 57.5, 82.5, 52.5, and 40 MUg/m for Mn(II), Co(II), Ni(II), Cu(II), Cd(II), and Pb(II), respectively. The LODs were in the range of 1.2 (Cd)-14 (Pb) ng/L with the relative standard deviations (RSDs) of <5.1% (c=1 MUg/L, n=7). The reproducibility of APTES-silica hybrid monolithic preparation ranged from 1.6 to 5.6% in one batch, and from 2.3 to 6.2% in batch-to-batch, respectively. To validate the developed method, two certified reference materials of NIES No. 10-b rice flour and GBW 07601 (GSH-1) human hair were analyzed and the determined values were in good agreement with the certified values. The proposed method has also been applied for the analysis of human hair and urine samples with the recoveries for the spiked samples in the range of 89-106%. PMID- 21688392 TI - Determination of lumiracoxib by a validated stability-indicating MEKC method and identification of its degradation products by LC-ESI-MS studies. AB - A stability-indicating MEKC method was developed and validated for the analysis of lumiracoxib (LMC) in pharmaceutical formulations using nimesulide as the internal standard (IS). Optimal conditions for the separation of LMC and degradation products were investigated. The method employed 50 mM borate buffer and 50 mM anionic detergent SDS solution at pH 9.0. MEKC method was performed on a fused-silica capillary (50 MUm id; effective length, 40 cm) maintained at 30 degrees C. The applied voltage was 20 kV and photodiode array (PDA) detector was set at 208 nm. The method was validated in accordance with the International Conference on Harmonisation requirements. The stability-indicating capability of the method was established by enforced degradation studies combined with peak purity assessment using PDA detection. The degradation products formed under stressed conditions were investigated by LC-ESI-MS and the two degraded products were identified. MEKC method was linear over the concentration range of 5-150 MUg/mL (r(2) =0.9999) of LMC. The method was precise, accurate, with LOD and LOQ of 1.34 and 4.48 MUg/mL, respectively. The robustness was proved by a fractional factorial design evaluation. The proposed MEKC method was successfully applied for the quantitative analysis of LMC in tablets to support the quality control. PMID- 21688393 TI - Improved preparation of chiral stationary phases via immobilization of polysaccharide derivative-based selectors using diisocyanates. AB - The classical method for the preparation of immobilized polysaccharide-based chiral stationary phases (CSPs) with a diisocyanate was improved. Cellulose or amylose was directly coated onto 3-aminopropyl silica gel after it was dissolved in a mixture of N,N-dimethylacetamide, LiCl, and pyridine, then immobilized onto silica gel with a diisocyanate, and finally allowed to react with an excess of corresponding isocyanate. Four polysaccharide derivatives, 3,5 dimethylphenylcarbamate and 3,5-dichlorophenylcarbamate of cellulose, and 3,5 dimethylphenylcarbamate and 5-chloro-2-methylphenylcarbamate of amylose, were immobilized onto silica gel utilizing this method. Compared with the classical diisocyanate method, the improved procedure avoided the derivatization and regeneration of 6-hydroxyl groups of cellulose and amylose, and thus showed an advantage for simple and economical preparation. The relationships among the amount of diisocyanate used, immobilization efficiency, and enantioseparation on the cellulose-based CSPs were investigated. Also, the solvent durability of the obtained CSPs was examined with eluents containing chloroform or THF. By utilizing these eluents, the chiral recognition abilities of the obtained CSPs for some of the tested racemates were improved. PMID- 21688394 TI - An amphiphilic conjugate approach toward the design and synthesis of betulinic acid-polyphenol conjugates as inhibitors of the HIV-1 gp41 fusion core formation. AB - Exploration of potent inhibitors of the HIV-1 gp41 fusion core formation is a promising strategy to discover small-molecule HIV-1 entry inhibitors for the treatment of HIV-1 infection. In this paper, a series of novel betulinic acid polyphenol conjugates was designed, guided by molecular modeling of the binding of betulinic acid (BA) and phenolic galloyl/caffeoyl groups in the groove on the gp41 N-terminal heptad repeat (NHR) trimeric coiled coil. These conjugates were synthesized via conjugation of galloyl and caffeoyl groups with BA at the C-28 position. Their inhibitory activities of HIV gp41 six-helix bundle (6-HB) formation between the NHR peptide N36 and the C-terminal heptad repeat (CHR) peptide C34 were evaluated with size-exclusion HPLC. Conjugates bearing a galloyl group were found to exhibit four to sixfold higher inhibitory activities than that of parent compound BA, suggesting that they may be exploitable as HIV-1 fusion/entry inhibitors targeting gp41. The docking study on BA and its derivatives suggests that hydrophobic and hydrogen-bonding pockets exist in the groove of the gp41 NHR trimeric coiled coil and that a potent inhibitor should have amphiphilic structures to cooperatively interact with both pockets. This possibility was explored by incorporating both lipophilic and hydrophilic groups into the conjugates in a well-defined orientation to bind with both pockets in the gp41 NHR-trimer. PMID- 21688395 TI - Impact of anions on electrocatalytic activity in palladium nanoparticles supported on ionic liquid-carbon nanotube hybrids for the oxygen reduction reaction. AB - A series of palladium nanoparticles supported on carbon nanotubes (CNTs), which were functionalized covalently with imidazolium polymer salts with different anions, Pd/polyIL(X)-CNTs (IL=ionic liquid; X=Cl, Br, I, ClO(4), BF(4), PF(6)), were prepared to investigate the influence of imidazolim salt anions on electrocatalytic activity in the oxygen reduction reaction (ORR). The anions of the imidazolium moiety significantly impacted on the ORR kinetics in a 0.1 M solution of HClO(4). The electronically active surface area results are in good agreement with the order of the ORR kinetic activity of the supported Pd/polyIL(X)-CNTs (X: Cl>ClO(4)>BF(4)>Br~PF(6)?I). In contrast, owing to the facile anion exchange of halide anions with hydroxide anions, anion-dependent catalytic activity has not been observed in 0.1 M NaOH. Iterative ORR experiments in acid-base solutions demonstrated anion exchange on the electrode. These results indicate that subtly varied structures of the IL moiety profoundly influence the performance of IL-CNT hybrid materials and molecular-level control of interfacial interactions between the support material, catalysts, and electrolytes is important in the design of supported metal nanoparticle catalysts for fuel cells. PMID- 21688396 TI - In vivo imaging of near-membrane calcium ions with two-photon probes. AB - We report a two-photon (TP) probe (ACaLN) for near-membrane Ca(2+) that shows a 13-fold TP excited fluorescence (TPEF) enhancement in response to Ca(2+), dissociation constants (K(d)(TP)) of (1.9+/-0.2) MUM, pH-insensitivity at the biologically relevant pH, and can detect near-membrane Ca(2+) in live cells for more than 1500 s and in living tissues at 120 MUm depth without interference from other metal ions. Comparison with existing probes provides a useful strategy for the design of efficient TP probes for the near-membrane metal ions. PMID- 21688397 TI - Ruthenium-catalyzed three-component coupling via hydrative conjugate addition of alkynes to alkenes: one-pot synthesis of 1,4-dicarbonyl compounds. PMID- 21688398 TI - Double hydroacylation reactions of acyclic and cyclic alpha,beta-unsaturated aldehydes. PMID- 21688399 TI - NIR spectroscopic imaging to map hemoglobin + myoglobin oxygenation, their concentration and optical pathlength across a beating pig heart during surgery. AB - The purpose of this paper is to demonstrate that near-infrared (NIR) spectroscopic imaging can provide spatial distribution (maps) of the absolute concentration of hemoglobin + myoglobin, oxygen saturation parameter and optical pathlength, reporting on the biochemico-physiological status of a beating heart in vivo. The method is based on processing the NIR spectroscopic images employing a first-derivative approach. Blood-pressure-controlled gating compensated the effect of heart motion on the imaging. All the maps are available simultaneously and noninvasively at a spatial resolution in the submillimeter range and can be obtained in a couple of minutes. The equipment has no mechanical contact with the tissue, thereby leaving the heart unaffected during the measurement. PMID- 21688400 TI - Selective hydrogenation of trans,trans-muconic acid to adipic acid over a titania supported rhenium catalyst. PMID- 21688403 TI - Student-directed fresh tissue anatomy course for physician assistants. AB - Healthcare providers in all areas and levels of education depend on their knowledge of anatomy for daily practice. As educators, we are challenged with teaching the anatomical sciences in creative, integrated ways and often within a condensed time frame. This article describes the organization of a clinical anatomy course with a peer taught unembalmed (fresh-tissue) cadaver laboratory in the 2010 summer term of a new physician assistant program. To fit within the allotted 12 week time frame, students meet every Monday for both the classroom and laboratory component of the course. Students prepare for these sessions by reviewing a list of learning objectives and completing assigned textbook readings. Classroom sessions involve faculty presentations and are facilitated with the use of self-assessment questions and accompanying images. The afternoon laboratory sessions which follow the classroom sessions are comprised of four to five stations presented by first- and second-year medical students and a resident radiologist. End of course evaluations indicate that students felt that the course objectives were clear, achievable, and taught effectively with relevant clinical correlates. PMID- 21688404 TI - [From tick bite to borreliosis: the dreaded small blood sucker]. PMID- 21688402 TI - Presynaptic modulation of early olfactory processing in Drosophila. AB - Most animals are endowed with an olfactory system that is essential for finding foods, avoiding predators, and locating mating partners. The olfactory system must encode the identity and intensity of behaviorally relevant stimuli in a dynamic environmental landscape. How is olfactory information represented? How is a large dynamic range of odor concentrations represented in the olfactory system? How is this representation modulated to meet the demands of different internal physiological states? Recent studies have found that sensory terminals are important targets for neuromodulation. The emerging evidence suggests that presynaptic inhibition scales with sensory input and thus provides a mechanism to increase dynamic range of odor representation. In addition, presynaptic facilitation could be a mechanism to alter behavioral responses in hungry animals. This review will focus on the GABA(B) (gamma-aminobutyric acid) receptor mediated presynaptic inhibition, and neuropeptide-mediated presynaptic modulation in Drosophila. PMID- 21688405 TI - [Hemochromatosis after chemotherapy. Is there a treatment recommendation?]. PMID- 21688406 TI - Aleksandr Prokhorov--lasers and masers. PMID- 21688407 TI - The remarkable enhancement of CO-pretreated CuO-Mn2O3/gamma-Al2O3 supported catalyst for the reduction of NO with CO: the formation of surface synergetic oxygen vacancy. AB - NO reduction by CO was investigated over CuO/gamma-Al2O3, Mn2O3/gamma-Al2O3, and CuOMn2O3/gamma-Al2O3 model catalysts before and after CO pretreatment at 300 degrees C. The CO-pretreated CuO-Mn2O3/gamma-Al2O3 catalyst exhibited higher catalytic activity than did the other catalysts. Based on X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), UV/Vis diffuse reflectance spectroscopy (DRS), Raman, and H2-temperature-programmed reduction (TPR) results, as well as our previous studies, the possible interaction model between dispersed copper and manganese oxide species as well as gamma-Al2O3 surface has been proposed. In this model, Cu and Mn ions occupied the octahedral vacant sites of gamma-Al2O3, with the capping oxygen on top of the metal ions to keep the charge conservation. For the fresh CuO/gamma-Al2O3 and Mn2O3/gamma-Al2O3 catalysts, the Cu-O-Cu- and -Mn-O-Mn- species were formed on the surface of gamma-Al2O3, respectively; but for the fresh CuO-Mn2O3/gamma-Al2O3 catalyst, -Cu-O-Mn- species existed on the surface of -Al2O3. After CO pretreatment, -Cu-?-Cu- and -Mn-?-Mn- (? represents surface oxygen vacancy (SOV)) species would be formed in CO pretreated CuO/gamma-Al2O3 and CO-pretreated Mn2O3/gamma-Al2O3 catalysts, respectively; whereas -Cu-?-Mn- species existed in CO-pretreated CuO-Mn2O3/gamma Al2O3. Herein, a new concept, surface synergetic oxygen vacancy (SSOV), which describes the oxygen vacancy formed between the individual Mn and Cu ions, is proposed for CO-pretreated CuO-Mn2O3/gamma-Al2O3 catalyst. In addition, the role of SSOV has also been approached by NO temperature-programmed desorption (TPD) and in situ FTIR experiments. The FTIR results of competitive adsorption between NO and CO on all the CO-pretreated CuO/gamma-Al2O3, Mn2O3/gamma-Al2O3, and CuO Mn2O3/gamma-Al2O3 samples demonstrated that NO molecules mainly were adsorbed on Mn2+ and CO mainly on Cu+ sites. The current study suggests that the properties of the SSOVs in CO-pretreated CuO-Mn2O3/gamma-Al2O3 catalyst were significantly different to SOVs formed in CO-pretreated CuO/gamma-Al2O3 and Mn2O3/gamma-Al2O3 catalysts, and the SSOVs played an important role in NO reduction by CO. PMID- 21688408 TI - Energy-level tailoring in a series of redox-rich quinonoid-bridged diruthenium complexes containing tris2-pyridylmethyl)amine as a co-ligand. AB - Reactions of [{Ru(tmpa)}2(MU-Cl)2][ClO4]2, (2[ClO4]2, tmpa=tris(2 pyridylmethyl)amine) with 2,5-dihydroxy-1,4-benzoquinone (L1), 2,5-di-[2,6 (dimethyl)-anilino]-1,4-benzoquinone (L2), or 2,5-di-[2,4,6-(trimethyl)-anilino)] 1,4-benzoquinone (L3) in the presence of a base led to the formation of the dinuclear complexes [{Ru(tmpa)}2(MU-L1-2H)][ClO4]2 (3[ClO4]2), [{Ru(tmpa)}2(MU-L2 2H)][ClO4]2 (4[ClO4]2), and [{Ru(tmpa)}2(MU-L3-2H)][ClO4]2 (5[ClO4]2). Structural characterization of 5[ClO4]2 showed the localization of the double bonds within the quinonoid ring and a twisting of the mesityl substituents with respect to the quinonoid plane. Cyclic voltammetry of the complexes show two reversible oxidation and quinonoid-based reduction processes. Results obtained from UV/Vis/NIR and EPR spectroelectrochemistry are invoked to discuss ruthenium- versus quinonoid-ligand-centered redox activity. The complex 3[ClO4]2 is compared to the reported complex [{Ru(bpy)}2(MU-L1-2 H)]2+ (12+, bpy=2,2'-bipyridine). The effects of substituting the bidentate and better pi-accepting bpy co-ligands with tetradentate tmpa ligands [pure sigma-donating (amine) as well as sigma-donating and pi-accepting (pyridines)] on the redox and electronic properties of the complexes are discussed. Comparisons are also made between complexes containing the dianionic forms of the all-oxygen-donating L1 ligand with the L2 and L3 ligands containing an [O,N,O,N] donor set. The one-electron oxidized forms of the complexes show absorption in the NIR region. The position as well as the intensity of this band can be tuned by the substituents on the quinonoid bridge. In addition, this band can be switched on and off by using tunable redox potentials, making such systems attractive candidates for NIR electrochromism. PMID- 21688401 TI - Extracellular matrix and its receptors in Drosophila neural development. AB - Extracellular matrix (ECM) and matrix receptors are intimately involved in most biological processes. The ECM plays fundamental developmental and physiological roles in health and disease, including processes underlying the development, maintenance, and regeneration of the nervous system. To understand the principles of ECM-mediated functions in the nervous system, genetic model organisms like Drosophila provide simple, malleable, and powerful experimental platforms. This article provides an overview of ECM proteins and receptors in Drosophila. It then focuses on their roles during three progressive phases of neural development: (1) neural progenitor proliferation, (2) axonal growth and pathfinding, and (3) synapse formation and function. Each section highlights known ECM and ECM receptor components and recent studies done in mutant conditions to reveal their in vivo functions, all illustrating the enormous opportunities provided when merging work on the nervous system with systematic research into ECM-related gene functions. PMID- 21688409 TI - UK government hits the pause button over NHS reforms. PMID- 21688410 TI - Australia to be first country to use plain cigarette packaging. PMID- 21688411 TI - Cancer mortality in Northern Ireland. PMID- 21688412 TI - Does prevention really pay? AB - The battles over budget deficits and healthcare policy are colliding as lawmakers and federal officials wrestle with the administration's ambitious preventive health agenda. "Clearly, we have to get our budget under control and some of that is going to require painful choices, but one of the things that we want to make clear is that prevention is a best buy," says Dr. Thomas Frieden, left, director of the CDC. PMID- 21688413 TI - Renewed efforts. GOP pushes ahead with deficit-reduction plans. PMID- 21688415 TI - Tug of war. Community raises offer as Tenet proceeds with suit. PMID- 21688414 TI - Beyond SGR reform. Docs urge broad approach to payment changes. PMID- 21688416 TI - Settlement holdout. Whistle-blower in WellCare case refuses deal. PMID- 21688417 TI - Cost trends expected to rise. Earnings are strong despite reform, insurers say. PMID- 21688418 TI - Exiting two states ... Catholic Health Partners sheds hospitals, debt. PMID- 21688419 TI - Most influential Physician Executives in Healthcare, 2011. PMID- 21688420 TI - Largest healthcare system employers. PMID- 21688421 TI - Public health. Alcohol harm is causing a nasty headache. PMID- 21688422 TI - Competition. Commissioners flouting choice rules. PMID- 21688423 TI - Public health. Drink causes over 7pc of hospital admissions. PMID- 21688424 TI - NICE'S new mission. PMID- 21688425 TI - Nasty side-effects anticipated. PMID- 21688426 TI - Constitutional change undemocratic. PMID- 21688427 TI - Treatments no better than placebos. PMID- 21688428 TI - Author breaches ethics. PMID- 21688429 TI - Health bill pause. NHS market expansion set to decelerate. PMID- 21688430 TI - Nick Bosanquet five steps to avert a crisis. PMID- 21688431 TI - We are on the edge of calamity. PMID- 21688432 TI - Missed opportunities. PMID- 21688433 TI - Health Secretary. Why Andrew Lansley should stay--and why he might go. PMID- 21688434 TI - Consortia pick up PCT savings burden. PMID- 21688435 TI - Health bill. One month 'pause' for reforms. PMID- 21688436 TI - Public health cannot survive on 4bn pound sterling. PMID- 21688437 TI - On getting to grips with localism. The centre is learning to let go. PMID- 21688438 TI - Provider landscape. Quarter of acutes' FT paln slip back a year. PMID- 21688440 TI - Technology. No line, no waiting; electronic kiosks speed up patient registration. PMID- 21688439 TI - Passing judgement on Lansley's vision. PMID- 21688441 TI - [Internal migrations in the USSR between 1926 and 1939]. PMID- 21688442 TI - "The highest pleasure of which woman's nature is capable": breast-feeding and the sentimental maternal ideal in America, 1750-1860. PMID- 21688443 TI - Consuming relief: food stamps and the new welfare of the New Deal. PMID- 21688444 TI - Disability, antiprofessionalism, and civil rights: the National Federation of the Blind and the "right to organize" in the 1950s. PMID- 21688445 TI - Getting the pox off all their houses: Cotton Mather and the rhetoric of Puritan science. PMID- 21688446 TI - African medical knowledge, the plain style, and satire in the 1721 Boston Inoculation controversy. PMID- 21688447 TI - The ethos aquatic: Benjamin Franklin and the art of swimming. PMID- 21688448 TI - In Werther's Thrall: suicide and the power of sentimental reading in Early National America. PMID- 21688449 TI - Satire, inoculation, and Crevecoeur's letters concerning the English nation: new evidence from the archives. PMID- 21688450 TI - Behaviorism and the beginnings of close reading. AB - Many of close reading's most enduring assumptions and techniques have their origins in psychological behaviorism. Beginning with I. A. Richards's critical work from the 1920s, this article demonstrates the central place of behaviorist ideas in New Critical theories of poetry. Despite explicitly disparaging Richards's behavioristic poetics, Brooks's Well Wrought Urn and Wimsatt and Beardsley's "intentional fallacy" perpetuated behaviorism's influence on literary criticism. This article traces how the New Critics translated behavioristic psychology into poetic formalism and discusses the implications of this for contemporary critical practice. PMID- 21688451 TI - Parting Shots: eighteenth-century displacements of the male body at war. AB - "Parting Shots" views eighteenth-century literature from across the body-strewn battlefields of the English Civil Wars, and analyzes the transformation of shattered men into cultural embodiments of meaning. The essay analyzes the processes of indirection and displacement through which texts, over several generations, negotiate conflicts and problems too difficult to be confronted whole and entire. In order to develop an argument about lingering anxiety over civil conflict, the essay draws on Defoe's Memoirs of a Cavalier and Robinson Crusoe, soldier's manuals and examples from works by Swift, Manley, Sterne, Pope, and Smollett. PMID- 21688452 TI - What happens when pornography ends in marriage: the uniformity of pleasure in Fanny Hill. AB - This essay argues that John Cleland's pornographic novel, Fanny Hill, conceals coercion by employing the language of materialism to suggest that all sex, commercial or not, produces pleasure. While the ostensible benevolence of human instinct allows the novel to sidestep questions of injury and rape, they persist until Fanny's marriage, which delivers her to conjugal felicity. Fanny Hill presents an extreme version of the marriage plot, showing that marriage's claim to retroactively pardon harm allows it to sanction violent means. Cleland's novel implicates Pamela by demonstrating that they share a basic structure: materialist pornography, like the marriage plot, transforms injury into the impossibility thereof, forcefully restricting first-person narrative in the process. PMID- 21688453 TI - "A great break in the common course of confession": narrating loss in Charlotte Bronte's Villette. AB - This essay suggests that a complex understanding of trauma can significantly explain both the narrative structure and the subject matter of Charlotte Bronte's Villette. The narrative structures attendant on traumatic experience provide a model for understanding Lucy Snowe's silences, repetitions, and evasions in a way that moves past the longstanding critical dichotomy that casts them as either an indication of oppression or a strategy for empowerment and instead explores how they both represent and enact a model of communication that seeks to render accessible experiences and perspectives generally marginalized in both Bronte's contemporary culture and the traditional realist novel. PMID- 21688454 TI - [Surgical risk of the patients treated with DES and dual anti-platelet therapy]. PMID- 21688455 TI - [Infrastructure to conduct new device clinical trials may be the solution for the shrinking Japanese economy]. PMID- 21688456 TI - [English medical journal, Surgery Today: current status and future perspectives]. PMID- 21688457 TI - [Current status and problems of diagnositic and therapeutic strategies for O adenocarcinoma of the pancreas]. PMID- 21688458 TI - [Pancreatoduodenectomy for invasive carcinoma of the head of the pancreas with ligation of the inferior pancreaticoduodenal artery performed first]. AB - The ideal surgical procedure for treating pancreatic cancer achieves radical excision in a minimally invasive manner and allows rapid transition to adjuvant chemotherapy. If the afferent artery to the pancreatic head is not ligated until the latter half of the surgery, congestion of the pancreaticoduodenal vein may occur, leading to phleborrhagia and increased intraoperative hemorrhage. Ligation of the afferent artery, i.e., the inferior pancreaticoduodenal artery (IPDA), in the first half of the surgery may prevent the occurrence of hemorrhage due to congestion. Early ligation of the IPDA is also useful in ensuring the success of radical dissection of the plexus around the superior mesenteric artery or the no. 14 lymph node. We have been performing pancreaticoduodenectomies with antecedent IPDA ligation since 2005 and have found that the percentage of R0 versus R1 and R2 has increased compared with that when standard pancreaticoduodenectomies were performed. Preemptive ligation of the IPDA early in pancreaticoduodenectomy for invasive pancreatic cancer is a useful method for reducing blood loss and achieving R0 resection in a thorough yet efficient manner. PMID- 21688459 TI - [En bloc resection including the superior mesenteric artery and vein of locally advanced pancreatic carcinomas]. AB - Curative resection has been shown to be one of the key factors affecting the survival of patients with carcinomas of the head of the pancreas. However, local recurrence is very common, and Esposito and colleagues stated that: "Most pancreatic cancer resections are R1 resections." In 2002, we developed a new method for en bloc resection of the pancreatic head including the superior mesenteric artery (SMA) and vein (SMV) for pancreatic head carcinoma with portomesenteric invasion, called "augmented regional pancreatoduodenectomy (ARPD)." The technical and general eligibility criteria for ARPD are: 1) presumed achievement of R0 status; 2) tumor infiltration proximal to the SMV and SMA; and 3) tumor respecting the hepatic artery, splenic artery, and celiac trunk and neither hepatic nor paraaortic nodal metastasis. Between 2002 and 2010, 17 patients underwent ARPD in our institution. Postoperative death occurred in 2 patients. One death occurred after full-dose radiotherapy and the other after rupture of an aortic aneurysm. The surgical margins (R0) were histologically negative in 14 patients (82%). The overall 5-year survival probabilities were 24% in R0. Three patients survived more than 5 years. The ARPD procedure has advantages in obtaining sufficient margins at the uncinate and posterior site in patients with pancreatic head carcinoma. PMID- 21688460 TI - [Anatomy of the pancreatic nerve plexuses and significance of their dissection]. AB - Although various therapeutic modalities for carcinoma of the pancreas are available, curative resection is the most important. Thus, the aim of surgery for carcinoma of the pancreas is local complete resection of the carcinoma. All of the important pancreaticoduodenal arcades of arteries, veins, and nerves are situated on the fusion fascia of Treits. The pancreatic parenchyma, extrapancreatic nerve plexuses, superior mesenteric artery (SMA), and portal vein are also covered within the fusion fascia and exist in the same area. Carcinoma of the head of the pancreas invades through the pancreatic parenchyma, following the arteries, veins, and especially nerves between the parenchyma and fusion fascia, and then spreads horizontally toward the SMA or celiac axis. The entire dissected end of the nerve plexus should be investigated during surgery using frozen specimens and confirmed to be negative for cancer. If the dissected end is positive for cancer, additional resection of the nerve plexus should be performed to achieve curative resection. It is not possible to investigate thoroughly whether the dissected end of the nerve plexus is positive or negative for carcinoma after surgery, since the end may be long and some specimens may be deformed by formalin fixation; thus it is difficult to identify the true surgically dissected end. The pancreaticoduodenal artery arises from the left side of the SMA and divides into two arteries: jejunal artery 1; and the inferior pancreaticoduodenal artery (IPDA), which runs behind and transversely to the right of both the anterior and posterior IPDA. A common origin of the anterior and posterior IPDA is found in 80% of cases. The postoperative course of patients with pancreatic head carcinoma with invasion of the perineural plexuses immediately behind the SMA is not as good as in that of patients without cancerous invasion, even if additional resection is performed so that the dissected end is confirmed to be negative during surgery. Nevertheless, intraoperative pathologic examination of the entire dissected end of the neural plexues remains necessary for curative R Zero resection. PMID- 21688461 TI - [Indications for and postoperative problems of distal pancreatectomy with en bloc celiac axis resection for locally advanced pancreatic body cancer]. AB - To treat locally advanced cancer of the pancreatic body involving the common hepatic artery and/or celiac axis with perineural invasion in the nerve plexus surrounding these arteries, we have employed distal pancreatectomy with en bloc celiac axis resection (DP-CAR) without arterial reconstruction. DP-CAR has been performed in patients in whom the gastroduodenal artery and superior mesenteric artery could be preserved. Between April 1998 and December 2007, 37 patients underwent DP-CAR in our institution. The surgical margins were histologically clear (R0) in 35 (95%) patients. The postoperative morbidity rate was 59%. The primary complications were pancreatic fistula occurring in 19 patients and ischemic gastropathy in 5. Estimated overall 1- and 5-year survival rates were 72% and 17%, respectively, and the median survival was 21 months. The most common site of recurrence was the liver, where recurrence appeared significantly earlier than in other metastatic sites. DP-CAR, with its potential to achieve complete local control, has been confirmed to be advantageous only in cases that are unlikely to develop hepatic metastasis. In principle, since 2006 patients who have undergone DP-CAR also receive postoperative adjuvant chemotherapy. Patients must achieve feasible general status within 3 months after DP-CAR to be able to start adjuvant chemotherapy. PMID- 21688462 TI - [Laparoscopic pancreatic resection of pancreatic cancer]. AB - Laparoscopic pancreatic resection of pancreatic cancer is still not universally accepted as an alternative approach to open surgery because of technical difficulties and a lack of consensus regarding the adequacy of this approach for malignancy. Ten patients with pancreatic cancer underwent laparoscopic pancreatic resection, including pancreaticoduodenectomy and distal pancreatectomy in our institution. Eight of the 10 patients recovered without any complications and were discharged on the 10-29th postoperative day. The remaining 2 patients developed pancreatic fistula and were discharged on the 46 and 60th postoperative day, respectively. All lesions were well clear of surgical margins in 6 patients (R0). In the remaining 4 patients, microscopic neoplastic change was found at the surgical margin (R1). Those 4 patients developed tumor recurrence, including liver metastases or peritoneal dissemination, and 3 of the 4 died of the primary disease. Although experience is limited, laparoscopic pancreatic resection of pancreatic cancer can be feasible, safe, and effective in carefully selected patients. However, the benefit of this procedure has yet to be confirmed. Not only adequate experience in pancreatic surgery but also expertise in laparoscopy is mandatory, and careful selection of patients is essential for successful application of this procedure. PMID- 21688464 TI - [Foreword: training system of surgeons]. PMID- 21688463 TI - [Postoperative adjuvant treatment for pancreatic cancer]. AB - To improve surgical results after resection of pancreatic cancer, clinical trials of postoperative adjuvant treatment have been aggressively performed worldwide. In the USA, postoperative chemoradiation therapy is supported on the basis of the results of the Gastrointestinal Tumor Study Group (GITSG) trial published in 1985. In Europe, chemotherapy was approved as postoperative adjuvant therapy based on the results of the European Study Group for Pancreatic Cancer-1 (ESPAC 1) trial published in 2004 and Charite Onkologie (CONKO)-001 study published in 2007. As in Europe, postoperative chemotherapy is recommended in Japan based on the results of the Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer 02 (JSAP-02) trial published in 2009. In recent years, gemcitabine has been recognized as the first choice for adjuvant chemotherapy after surgery. Clinical trials with gemcitabine, fluorouracil, and molecular targeting agents are currently under way. PMID- 21688465 TI - [Surgical training system using experimental animals]. PMID- 21688466 TI - [What we can learn from a case of medical malpractice--submucous inferior turbinectomy using laser for allergic rhinitis results in partial defect of inferior turbinate]. PMID- 21688467 TI - [Mitral valve repair: tips and pitfalls]. PMID- 21688468 TI - [A practical view of team practice in the UK]. PMID- 21688469 TI - [Nurse practitioners in surgical services in the United States]. PMID- 21688470 TI - [Expanding the professional role of nurses in the surgical field in Japan]. PMID- 21688471 TI - [Women surgeon's problem in the future]. PMID- 21688472 TI - [Gastrointestinal stromal tumors]. AB - Gastrointestinal stromal tumor (GIST) account for 1% of all gastrointestinal neoplasms and are the most common mesenchymal tumor of gastrointestinal tract. There are considered to originate fom the intestinal cell of Cajal, an intestinal pacemaker cell, characterized usually express the KIT protein on immunohistochemistry. The stomach (40-60%) and small intestine (30-40%) are the most common locations. Diagnosis of these tumors is difficult to establish, because symptoms are vague and traditional diagnostic tests are not specific. GISTs shows a wide variety of clinical behaviours ranging fom benign to frankly malignant, making the outcome totally unpredictable. Surgery is the standard treatment of local GIST while Imatinib (tyrosine kinasi inhibitor) is considered as the standard treatment of metastatic disease. Resistence to Imatinib is also becoming a major clinical problem but new tirosyne kinase inibitor are being studied to improve the treatment and survival. The present paper is a review of the salient features of epidemiology, pathophysiology, diagnosis, therapy and prognostic factors of GIST PMID- 21688473 TI - [IPTH dosage as a prognosis predictor of postoperatory hypocalcemia in patients submitted to total thyroidectomy]. AB - INTRODUCTION: Hypocalcemia is the most frequent complication after total thyroidectomy (TT) and represents the main cause of prolonged hospital stay because of the need to monitor the calcemic status of the patients. The aim of this study is to evaluate the role of serum iPTH as a predictor of post thyroidectomy hypocalcemia in order to allow patients' early and safe discharge. MATERIALS AND METHODS: Fifty patients who underwent TT without autotransplantation of parathyroid tissue were prospectively included in the study The mean age was 52 years and the male/female ratio was 1/6. The iPTH serum level were determined 1 hour after the operation and the calcium serum values after 24 and 48 hours. The cut-off value assumed for testing the sensitivity, specificity, PPV and NPV was 16 pg/ml. RESULTS: Nineteen patients (38%) presented hypocalcemia within 48 hours after TT and 16 of them (84.2%) had iPTH serum levels lower than 16 pg/ml. The normocalcemic patients were 31 (62%) and only 4 of them had iPTH serum levels inferior to the cut-off value. Postoperative iPTH serum level determined 1 hour after the operation had a sensibility of 84.2%, specificity of 87.1%, PPV and NPV of 90% and 80% respectively. CONCLUSIONS: The dosage of iPTH serum levels after total thyroidectomy reliably predicts patients who are likely to develop hypocalcaemia. It may be useful in clinical practice in order to reduce the number of postoperative blood tests and the hospital length of stay for the patients who are not at risk of postoperative hypocalcemia. PMID- 21688474 TI - [Guidelines for the treatment of rapidly progressive glomerulonephritis, second version]. PMID- 21688475 TI - [Clinical guidelines for the management of polycystic kidney disease]. PMID- 21688476 TI - [Preface: recent topics of tubulointerstitial renal injury]. PMID- 21688477 TI - [Let's try some approaches to interpretation for tubulointerstitial lesions]. PMID- 21688478 TI - [Evaluation of tubulointerstitial injury by new biomarkers]. PMID- 21688479 TI - [IgG4-related disease]. PMID- 21688480 TI - [Tubulointerstitial nephritis associated with ANCA-associated vasculitis]. PMID- 21688481 TI - [Calcineurin inhibitor nephrotoxicity in renal allografts]. PMID- 21688483 TI - [Interstitial kidney injury due to viral infection]. PMID- 21688482 TI - [Calcineurin inhibitor nephrotoxicity in nephrotic syndrome]. PMID- 21688484 TI - [Ischemic tubulointerstitial injury]. PMID- 21688485 TI - [Congenital disorders of renal tubulointerstitial tissue]. PMID- 21688486 TI - [N-terminal pro brain natriuretic peptide predicts hospitalization of hemodialysis patients for cardiovascular disease]. AB - We investigated whether or not N-terminal pro brain natriuretic peptide (NT proBNP) could predict hospitalization for cardiovascular disease (CVD) among Japanese hemodialysis patients. A total of 104 patients on maintenance dialysis 3 times per week were enrolled. We followed the patients for 23.9 +/- 4.2 months and 19 hospitalizations for CVD occurring during this period. The area under the curve (AUC) for the risk of CVD hospitalization was calculated after drawing a receiver operating characteristic curve. Predialysis NT-proBNP showed a larger AUC value than both postdialysis NT-proBNP and brain natriuretic peptide. The optimal cut-off value of predialysis NT-proBNP for predicting CVD hospitalization was 5,894 pg/mL, (sensitivity of 60 % and specificity of 76 %). Diabetes mellitus, a history of CVD, and the predialysis NT-proBNP level were significant determinants of CVD hospitalization according to Cox proportional hazards analysis. In conclusion, predialysis NT-proBNP is useful for predicting CVD hospitalization in hemodialysis patients. PMID- 21688487 TI - [ANCA-related glomerulonephritis in an aged patient with diabetes mellitus successfully released from hemodialysis by low dose steroid therapy: a case report]. AB - A 86-year-old man had been treated for hypertension, diabetes mellitus (DM), and dyslipidemia in Nihonkoukan Hospital. His renal function was within the normal range in August 2007. He showed common cold-like symptoms, which were not improved by anti-inflammatory drugs in December 2007. He was admitted to our hospital because of renal failure, urine protein and urine occult blood. He was also positive for anti-myeloperoxidase antibody (MPO-ANCA; 129 IU/mL). A renal biopsy revealed idiopathic crescentic glomerulonephritis of the pauci immune type. Considering his advanced age and DM, he was treated with the low dose of 20 mg/day of prednisolone. Although his symptoms, such as low grade fever and general fatigue, were improved after steroid therapy, renal failure accelerated, necessitating hemodialysis (HD), and insulin administration was needed for his DM. Subsequently, an AV fistule operation for HD was performed. Prednisolone was tapered to 17.5 mg/day after 4 weeks, and his MPO-ANCA titer decreased to 87 IU/mL. After steroid treatment and HD, his condition gradually recovered and he was discharged on March 5, 2008. Following about 6 months of treatment with prednisolone (3.5 months after HD administration), his renal function gradually recovered, allowing the discontinuation of HD. High-dose steroid therapy is very effective for ANCA-related glomerulonephritis. However, there is a high risk of infection, especially in aged and DM patients. Low-dose steroid therapy (PSL 20 mg/day) is safe and effective in such high-risk patients and in some cases, they can be released from HD. PMID- 21688488 TI - [Case of microscopic polyangiitis accompanied by central nervous system symptoms and brain vasculitis observed histopathologically]. AB - A 65-year-old-man complained of coughing and fever. The urine showed microscopic hematuria. The level of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO ANCA) was 167 EU. Two months later, he was admitted to our hospital with pulmonary hemorrhage and progressive renal dysfunction. He was treated with intravenous methylprednisolone followed by oral prednisolone with plasma exchanges, and his first pulmonary hemorrhage was relieved. Three weeks later, he suffered from a second diffuse pulmonary hemorrhage with central nervous system symptoms. He was treated again with intravenous methylprednisolone, plasma exchanges, and also intravenous pulse cyclophosphamide (IVCY), but he died of respiratory failure. Autopsy findings revealed microscopic polyangiitis (MPA)in the brain as well as in the lung, kidney and gastrointestinal system. The histopathological findings suggested that cerebral nervous system symptoms could have been caused by brain vasculitis in this case. PMID- 21688489 TI - [How would you have managed this finding? "Only" a small indistinct nodule. Medullary thyroid carcinoma]. PMID- 21688490 TI - [Severe headache in a patient with migraine. Here "diagnosis at a glance" provided the clue. Acute glaucoma attack]. PMID- 21688491 TI - [Difficult search for a cause. When children constantly cough.]. PMID- 21688492 TI - [CT screening in smokers. Value not established]. PMID- 21688493 TI - [30 CEM credits at one swoop. Enjoy continuing education with MMW]. PMID- 21688494 TI - [Chronic pruritus--early diagnostic and therapy necessary]. PMID- 21688495 TI - [Otitis externa]. PMID- 21688496 TI - [Acute chest pain--what the general practitioner should do?]. PMID- 21688497 TI - [Insulin therapy in type 2 diabetes]. PMID- 21688498 TI - [Common diseases of the nails in the general practitioner's office]. PMID- 21688499 TI - [Pale and fatigued: rational approach to anemia]. PMID- 21688500 TI - [Ulcerative colitis--state of the art in diagnosis and therapeutic strategies]. PMID- 21688501 TI - [Colon cancer screening--adopt the chance of early detection!]. PMID- 21688502 TI - [Breakthrough pain--what to consider when treating with rapid onset opioids]. PMID- 21688503 TI - [Successful acupuncture. Needles against pain]. PMID- 21688504 TI - [Current situation of postoperative pain in the Global Year Against Acute pain]. PMID- 21688505 TI - [Comparison of 2 methods of clinical data collection, one using the PAINOUT questionnaire (a European database for the management of postoperative pain)]. AB - OBJECTIVE: To compare postoperative pain intensity and incidence of adverse events when the evaluation is performed by a visual numerical scale completed by the patient (PAINOUT), or using a verbal numerical scale completed by ward nurses or the staff of the acute pain unit. METHODS: Fifty-two postsurgical patients of both sexes (age range 31-80 years) admitted to the general surgery ward were sequentially recruited and evaluated on postoperative day 1. All patients were assessed using both questionnaires, which measure postoperative outcomes using scales of 0 to 10; values > or =4 were considered clinically relevant. The test and Cohen coefficient were used for statistical analysis. RESULTS: Using the PAINOUT questionnaire, the mean maximum intensity of referred pain was 5.40 (range, 0-10) and the minimum intensity was 1.83 (range, 0-5). Mean values obtained with the verbal numerical scales used by staff on the ward and in the pain clinic were 3.76 (range, 0-10) and 0.97 (range, 0-5), respectively. The differences between the 2 methods of pain assessment were statistically (P = .006) and clinically significant. When evaluating nausea with PAINOUT questionnaire, all patients provided a response; in 88.5% the intensity was less than 4. Six patients reported nausea on the PAINOUT but not in the UDA questionnaire. Moreover, 61% of patients reported drowsiness/sedation in PAINOUT instrument, whereas none reported that effect on the verbal scale. CONCLUSIONS: The intensity of pain and adverse events is significantly higher when the patient evaluates and records its intensity on visual numerical scales compared with verbal numerical scales. PMID- 21688506 TI - [Agreement between verbal numerical scale and visual analog scale assessments in monitoring acute postoperative pain]. AB - OBJECTIVE: To determine the agreement between verbal numerical and visual analog scale assessments of acute postoperative pain on 3 consecutive days. METHODS: Pain data were recorded for 2 months for sequentially enrolled patients receiving parenteral opioids or neuraxial blocks for analgesia after major surgery in a tertiary level hospital. Each patient was asked to assess pain on the visual analog and verbal numerical scales every 24 hours for 3 consecutive days. Agreement was estimated by the intraclass correlation coefficient and the Spearman correlation coefficient. The results were analyzed in 2 age strata: age 65 years or younger and older than 65 years. RESULTS: Data for 159 patients (105 < or =65 years; 54 >65 years) were analyzed. The visual analog scale could not be used with 12 patients; all patients were able to assess pain on the verbal numerical scale. The intraclass correlation coefficient was > 0.70 for all 3 days; the highest coefficients were for patients over 65 years of age. CONCLUSIONS: Agreement between pain assessments on the visual analog and verbal numerical scales can be considered good or very good on all 3 days, with stronger agreement when the scales are used in patients over the age of 65 years. Cooperation was better for the numerical scale than for the visual analog scale. Scores on the verbal numerical scale were consistently higher than scores on the visual analog scale. PMID- 21688507 TI - [Opioids for chronic noncancer pain: recommendations based on clinical practice guidelines]. AB - OBJECTIVE: The need for major opioids in the treatment of chronic pain unrelated to cancer is increasing. We therefore appraised available clinical practice guidelines in order to identify recommendations for good practice in the use of these drugs. MATERIAL AND METHODS: By searching the main guideline repositories as well as resources provided by medical associations, we identified clinical practice guidelines on the use of major opioids published up to 2007. Fourteen of the 28 guidelines we found met the inclusion criteria. To appraise the guidelines we applied the criteria for scientific evidence of the AGREE collaboration (Appraisal of Guidelines Research and Evaluation). The AGREE instrument consists of 23 items organized in 6 areas for appraisal. RESULTS: Of the 14 guidelines appraised, 5 were judged to be of high quality. In each of the 5 selected guidelines, the relation between a recommendation and the evidence it was based on was stated explicitly; all 5 had overall quality scores over 60%. The recommendations drawn from these guidelines deal with 3 sequential moments in the use of opioids: start of treatment, maintenance therapy, and withdrawal of the drug. CONCLUSION: The use of opioids to treat chronic noncancer pain is controversial in terms of effectiveness, safety, and the possibility of addiction or abuse. The opioid should be indicated for the pain and prescribed with caution; each case should be assessed individually. Following the recommendations drawn from these guidelines will be important for achieving control of both pain and the accompanying symptoms. The use of major opioids to relieve chronic pain unrelated to cancer, and therefore to improve the quality of life of patients who experience this type of pain, is a legitimate treatment approach. PMID- 21688508 TI - [Pharmacoeconomics: basic concepts and applications to clinical anesthesia]. AB - The economic evaluation of medications and health care technology has gained importance in recent years. Health care resources are limited and their use must be optimized so that we can take the greatest possible advantage. Pharmacoeconomics seeks to analyze the best therapeutic drug choices to obtain the desired outcome in specific cases or in populations. The 4 approaches used in pharmacoeconomics are cost-minimization analysis, cost-benefit analysis, cost effectiveness analysis, and cost-utility analysis. This review examines the characteristics of each type of study using examples from anesthesiology, a field in which pharmacoeconomics is beginning to play a role. PMID- 21688509 TI - [Algorithm for pediatric difficult airway]. PMID- 21688510 TI - [Ultrasound-guided interscalene block in a patient with supraclavicular anatomical abnormalities due to radiotherapy and surgery]. AB - Regional blocks can be difficult in surgical patients with certain superficial anatomical abnormalities. Such blocks may be possible, however, under ultrasound guidance. We report a case in which a man with a fractured right humerus required an ultrasound-guided interscalene brachial plexus block. Secondary to radiotherapy, the patient had right cervical and facial abnormalities that had altered the location of external anatomical landmarks. We describe the approach used to insert the catheter and the exploration of the region by ultrasound. Nerve stimulation was not used to avoid painful contractions. Analgesia was excellent during surgery and over the following 24 hours. PMID- 21688511 TI - [Double lumen tube insertion in awake patients through the AirTraq laryngoscope in 2 cases of expected difficult airway]. AB - The likelihood of difficult airway in thoracic surgery increases in the presence of associated cancer of the pharynx or larynx. The difficulty is greater when a double lumen tube must be inserted in these conditions, and various newly developed optical devices offer solutions for managing such cases. We report on 2 patients with expected difficult airway who were scheduled for lung resection. In both cases, intubation was accomplished through the AirTraq laryngoscope while the patient remained awake. Awake patient tolerance is facilitated by this laryngoscope, because the tube can be inserted without changing the position of the tongue or placing pressure on the vallecula. PMID- 21688512 TI - [Pharmacologic treatment for 2 thrombocytopenic patients prior to neurosurgery]. AB - Preoperative prophylaxis of hemorrhage for patients with thrombocytopenia or a platelet disorder is controversial. Platelet count correlates to a certain degree with risk of hemorrhage, and risk factors for hemorrhage should be assessed and treated before deciding on perioperative treatments. Thirteen percent of cirrhotic patients have a platelet count between 50,000 and 75,000/microL and thrombocytopenia is multifactorial in origin. Idiopathic thrombocytopenic purpura is an acquired disease; since it may be either primary or secondary to other conditions, treatment may vary considerably. No clinical method has been established for predicting risk of perioperative bleeding in patients with thrombocytopenia. We describe 2 thrombocytopenic patients scheduled for intracranial surgery who were treated with thrombopoietic growth factors; in both cases, platelet counts increased sufficiently for this type of surgery. Controlled clinical trials are needed to ascertain the safety and prophylactic utility of platelet transfusion and thrombopoietin analogs in certain situations of refractory thrombocytopenia. PMID- 21688513 TI - [Analgesic intervention for drug-resistant headaches: reflections on treating a case of cluster headache]. PMID- 21688514 TI - [Qualitative research in anesthesiology: perception of quality studied by means of a focus group]. PMID- 21688515 TI - [Sans serif]. PMID- 21688516 TI - [Catheterization of the femoral vein in a patient following femoro-femoral cardiopulmonary bypass]. PMID- 21688517 TI - [Postpartum cerebral venous sinus thrombosis: a case report]. PMID- 21688518 TI - [Echocardiographic image of a left atrial myxoma causing acute heart failure]. PMID- 21688519 TI - [Severe bronchospasm and dehiscence of a sternotomy]. PMID- 21688520 TI - [Intraoperative transesophageal ultrasound imaging in a case of giant atrial myxoma]. PMID- 21688521 TI - [Nepenthe]. AB - Iliad and Odyssey are two major literary sources on various phenomena related to human experience and knowledge. In the Odyssey we find references to the nepenthes, a mythical substance which can change the mood, causing sorrow and anger to be forgotten. We can not identify it with any of the well known substances that have these properties, such as opium from the opium poppy, the Egyptian kyfi or cannabis in the Scythians. Ancient Greeks used various anxiolytic, hypnotic and narcotic substances, but phenomena of addiction or withdrawal are not clearly described, with the exception of wine. Wine was used to lighten peoples minds and hearts, as well as a vehicle for drugs. Many ancient sources describe the negative effects of wine abuse. The study of ancient texts, from Homer's epics to Christian literature, allows a fundamental insight into the influence of psychotropic substances and alcohol on the human psyche. PMID- 21688522 TI - [Behavioral and psychological symptoms of dementia and their management]. AB - The decline in cognitive function is a core feature of dementias. However, other symptoms of the disease are also crucial. These symptoms are the behavioral and psychological manifestations of dementia and include symptoms such as delusions, hallucinations, delusional misindentification syndromes (DMS), illusions, anxiety, aggression, depression, personality changes, disinhibition-impulsivity, violation of social and moral norms, changes in dietary or eating behavior and repetitive behaviors. Delusions, hallucinations, anxiety, depression and aggression are highly prevalent in Alzheimer's disease, vascular dementia and dementia with Lewy bodies, whereas symptoms that include severe disturbance of behavior are highly prevalent in frontotemporal dementias. Psychotic symptoms are associated with subcortical disturbances mainly of the limbic system. Patients with depression present greater loss of noradrenergic cells in the locus coeruleus and loss of serotonergic nuclei of dorsal raphe. Furthermore, disturbances of behavior are associated with frontal lobe dysfunction. Atypical antipsychotics is the first treatment option for delusions, hallucinations, misidentifications, anxiety and aggression. Furthermore, antidepressants may be useful for moderate or severe depression as well as for disinhibition impulsivity, aggression, changes in dietary or eating behavior and repetitive behaviors. Cholinesterase inhibitors may also improve apathy, anxiety, disinhibition, aberrant behavior, mood disorders and hallucinations. Moreover, non-pharmacological methods alone or in combination with psychotropic drugs may also improve patient's symptomatology. PMID- 21688523 TI - [Cosmetic breast augmentation and suicide risk: a puzzling association]. AB - The goal of the present article is to examine the unexpected association between cosmetic breast augmentation and suicide found in recent epidemiological investigations. During the last decade, seven epidemiological studies coincide in the high risk of suicidality among women with breast implants. More specifically, the rate of suicide among these patients appears doubled or tripled than expected in the general population. The absence of etiological answers that could interpret this association remains a serious limitation in this field of research. However, the preoperative psychopathology among women with breast implants, their motives and expectations, and their psychosocial characteristics are important factors that may contribute in the relationship between cosmetic breast augmentation and risk of suicide. Body image disorders, most common of which is the body dysmorphic disorder, along with high rates of depression and anxiety disorders are psychopathologic features found in a substantial number of cosmetic breast implant patients. Possible future research directions are proposed, in order to better understand the relationship between breast augmentation and suicide. In the meantime, the consistency of epidemiologic results on the high risk of suicide among breast implant patients suggests the need for interdisciplinary collaboration between plastic surgeons and mental health professionals, at least for those breast implant patients who present with preoperative psychopathology. PMID- 21688524 TI - [Psycho-immunological mechanisms in schizophrenia]. AB - Immune alterations in schizophrenia have been described for decades. Both the unspecific and specific arms of the immune system seem to be involved. Several lines of evidence support that an infectious and/or autoimmune process might play a role in the etiopathogenesis of a group of psychotic disorders. Signs of inflammation and microglia activation in postmortem brains, in the CSF, the dysfunctional Blood Brain Barrier, the increased retroviral activity, the proof of antibodies against brain structures, the signs of T cell activation and the imbalance of cytokine levels in serum, in CSF in in vivo, in vitro and ex vivo conditions, are all strong indicators of the immunological basis of the aetiopathology in schizophrenia. There is a large body of literature aiming at the evaluation of cytokines secreted by different type of cells, not necessarily the immune ones, with the disease being in different states in terms of type of psychosis, course throughout time, type of medication. An inconsistency of the results is common but the majority of the immune alterations favors the hypothesis of activation of the immune system. Furthermore, the immune response of T helper cells in schizophrenia in the literature is characterized by the imbalance between type 1 and type 2, pro-inflammatory and anti-inflammatory respectively, depending on the estimated type of cytokines. The most implicated ones are the IL-1, IL-2, slL-2R, IL-RA, IL-6, slL-6R, IFN, IL-4, IL-10, TNF-alpha and the only quantitave review refutes the current hypothesis of a Th2 slant. On the other hand, it seems that the treatment with antipsychotic drugs affects the cytokine network probably through a shift towards an immune response of Th2-type. PMID- 21688525 TI - [Kleptomania: an irresistible impulse]. AB - This review presents the historical-epidemiological and clinical aspects of Kleptomania. The diagnostic criteria, on the basis of which it is categorized in the group of Impulse Control Disorders, are defined precisely. All the aspects of its causative pathogenesis are deeply analyzed, as they are projected through its phenomenological, psychoanalytical and psycho-biological approach. Particular emphasis is given on its differential diagnosis from other psycho-pathological conditions and especially from the co-morbidities that often accompany it. The frame of treatment is established and its course and the final outcome are analyzed. Finally, it is determined what should be the objectives of future research, which will contribute decisively to the ascertainment of the exact incidence of Kleptomania in the general population, to the clarification of its causative pathogenesis and especially to the most effective treatment of this serious mental disorder. PMID- 21688526 TI - [Charles Bonnet syndrome: case reports and short review]. AB - Charles Bonnet first described visual hallucinations in a ground of visual deprivation in the 18th century. In this paper, two case reports with the syndrome are presented (female 83 years old, male 68 years old) along with a short literature review. The distinction of the syndrome from other psychiatric disorders (delirium, dementia), where visual hallucinations are also present, demands the presence of the diagnostical triad: visual hallucinations, visual impairment, intact cognitive status. The hallucinations are rich in colors and tension, people usually have the "leading roles" and patients mostly are curious, enjoy the hallucinations and are not afraid of them. More often hallucinations appear after acute visual impairment and in older patients. There are several theories concerning the mechanisms that lead to the syndrome. The Charles Bonnet syndrome appears to be self-restricted and there are no clear guidelines regarding its treatment. PMID- 21688527 TI - [Individualized treatment of the femoral intertrochanteric fractures]. PMID- 21688528 TI - [Application of dynamic hip screw with modified reamer in intertrochanteric fracture in the elderly]. AB - OBJECTIVE: To investigate the therapeutic effect and characteristic of dynamic hip screw with modified reamer (MDHS for short) in the treatment of the intertrochanteric fracture in the elderly. METHODS: Fifty-four patients with intertrochanteric fracture from Aug. 2007 to Dec. 2008 were retrospectively analyzed. Among them, 27 patients were treated with MDHS, including 12 males and 15 females with an average age of 79.4 years old ranging from 69 to 93 years; according to modified Evans classification, there were 3 cases of type I , 12 cases of type II, 8 cases of type III, 4 cases of type IV. The other 27 patients (10 males and 17 females), aged from 66 to 88 years old (average 77.2), were composed of 4 cases of type I, 14 cases of type II, 6 cases of type III, 3 cases of type IV. The fracture healing time,forepart movement time,percentage of loosening screw and hip joint function were compared between two groups. RESULTS: All 54 patients were followed up for 21 to 36 months (means 27.6 months). All fractures were bone healing. The time of fracture healing were compared between two groups,there were no significant difference (P>0.05). The forepart movement time of MDHS group (14.2 +/- 2.1) was shorter than that of DHS group (18.9 +/- 3.1) (P<0.05). The loosening screw of MDHS group (1 case) was less than that of DHS group (8 cases) (P<0.05). The Harris score of hip joint function of MDHS group (87.8 +/- 4.7) was higher than that of DHS group (83.3 +/- 7.5) (P<0.05). CONCLUSION: MDHS has several advantages on wider indications, stronger holding power,early forepart movement time, fewer complications, which is a good choice for osteoporotic intertrochanteric fracture. PMID- 21688529 TI - [Comparison of the effect of inverted less invasive stabilization system (LISS) and proximal femoral nail anti-rotation (PFNA) in the treatment of complex unstable intertrochanteric fracture in aged]. AB - OBJECTIVE: To compare the therapeutic effectiveness of inverted less invasive stabilization system (LISS) and proximal femoral nail anlirotafion (PFNA) in treatment of complex unstable intertrochanteric fracture in aged, and to investigate the selective strategy of the internal fixation. METHODS: From February 2007 to June 2009, 47 senior patients with complex and unstable intertrochanteric fractures (Evans IV, V, R-type) were treated. Among them 23 patients were treated by inverted LISS, including 7 males and 16 females, aged from 76 to 97 years; 24 patients were treated by PFNA, including 9 males and 15 females, aged from 73 to 90 years old. The mean operating time,blood loss, intraoperative photographs frequency, incision length, length of stay, bone healing,hip function were analyzed and compared. RESULTS: All patients were followed up for 8 to 18 months (averaged 13.1 months). All fractures got bone healing. No complications such as wound infection, varus and internal fixation cut out occurred. The operative time, incision length, in PFNA group had a slight ascendant than that in LISS inversion group, but there were no significant differences. According to postoperative Harris hip score outcome of LISS inversion group compared with the PFNA group, there was no significant difference. CONCLUSION: Both of PFNA and LISS have ideal effect in treatment of complex unstable intertrochanteric fracture in aged, and are good internal fixations. PMID- 21688530 TI - [Comparative study of intertrochanteric fractures treated with proximal femur locking compress plate in aged]. AB - OBJECTIVE: To compare the clinic outcomes of dynamic hip screw (DHS), intramedullary fixation (IF) and proximal femur locking plate (PF-LCP) in the treatment of intertrochanteric fractures in the elderly patients. METHODS: From July 2000 to August 2009, 165 old patients with intertrochanteric fractures were treated respectively by DHS, IF, PF-LCP. Fifty-eight patients were in DHS group including 30 males and 28 females with an average age of 71 years old; there were 30 cases of type II fracture of Jensen, 28 cases of type III fracture. Sixty-five patients were in IF group including 35 males and 30 females with an average age of 73 years old; there were 37 cases of type II fracture of Jensen, 28 cases of type III fracture. Forty-two patients were in PF-LCP group including 23 males and 19 females with an average age of 74 years old; there were 22 cases of type II fracture of Jensen,20 cases of type III fracture. The operative procedures,complications and therapeutic effects were compared among 3 groups. RESULTS: All patients were followed up from 15 to 21 months (averaged 18.3 months). The incision length and the operation time of IF group were shorter than that of DHS and PF-LCP, but there were no significant difference between DHS group and PF-LCP group. The intraoperattive blood loss, rehabilitation and healing time of IF and PF-LCP were less or shorter than that of DHS group, but there were no significant difference between IF group and PF-LCP group. The functional recovery of IF group and PF-LCP were better than that of DHS group, there were significant difference among 3 groups. The complications of PF-LCP group was fewer than that of IF group and DHS group. CONCLUSION: PF-LCP is the credible method for intertrochanteric fractures in the elderly patients, especially for severe comminuted fracture and osteoporosis, for it can reduce operation complications and benefit for fracture healing and hip functional recovery. PMID- 21688531 TI - [Analysis of the clinical effects of anatomical plate and combined external fixator for the treatment of the elderly intertrochanteric hip fractures]. AB - OBJECTIVE: To summarize the therapeutic experience and analyse the clinical effects of anatomical plate and combined external fixator for the treatment of elderly intertrochanteric hip fractures. METHODS: From Oct.2006 to Jun.2009, 42 patients with intertrochanteric hip fractures were treated. Among them, 19 patients were treated with combined external fixator, included 7 males and 12 females, aged from 71 to 103 years old; according to Evans classification there were 3 of type 1, 5 of type II, 6 of type III, 5 of type IV. The other 23 patients were treated with anatomical plate, included 9 males and 14 females, aged from 73 to 97 years old; there were 5 of type I , 4 of type II, 10 of type II, 2 of type IV, 2 of type V. Comparisons and statistical analysis were made on operation time, blood loss during operation, hospitalization time, the time of loaded walking, fracture healing time and therapeutic effect. RESULTS: All the patients were followed up for 6 to 15 months with an average of 8.6 months. In combined external fixator group, the average operation time was (29.368 +/- 3.253) min, the average blood loss during operation was (30.526 +/- 5.242) ml, the average hospitalization time was (4.368 +/- 1.165) d, the average time of loaded walking was (14.526 +/- 1.867) weeks, the fracture healing time was (14.632 +/- 2.798) weeks; in the anatomical plate group above-mentioned indexes were (58.987 +/- 8.600) min, (256.090 +/- 30.112) ml, (13.783 +/- 1.976) d, (11.391+/- 1.644) weeks, (11.391 +/- 2.327) weeks,respectively; and there were significant differences between two groups (P<0.05). According to Harris score criterion, the scores of combined external fixator group was (86.368 0 +/- 3.640) scores,and the scores of anatomical plate group was (86.435 +/- 4.198) scores; there were no significant differences between two groups (P>0.05). CONCLUSION: The effect of combined external fixator and anatomical plate for the elderly intertrochanteric hip fractures are both satisfactory and each has its own merits. Combined external fixator has advantages such as fewer complications and operative injuries than that of anatomical plate and is more suitable for the weaker with elderly intertrochanteric hip fractures. PMID- 21688533 TI - [Clinical application study of modified Moore classification in lower cervical spine injuries]. AB - OBJECTIVE: To analyze the clinical application of modified Moore classification in lower cervical spine injuries. METHODS: Modified Moore classification was applied in the morphologic description of 200 patients (including 165 males, 35 females,age ranging from 19 to 88 years,with an average age of 52 years) with lower cervical spine injuries from August 2006 to March 2010, cervical spine injury severity score (quantification of stability) in combination with yes/no neurological injury status to classify their clinical diagnosis and management. The treatment was selected according to the fracture type, stability, compression injury of spinal cord or nerve roots, stability of ligamentous injury and other reference factors. According to the ASIA score, 130 cases with injury of spinal cord or nerve root (i.e. 6 cases in Grade A,13 cases in Grade B,43 cases in Grade C, 68 cases in Grade D); and 70 cases with no injury of spinal cord or nerve root. The ASIA score was applied in the evaluation of curative effect in cases with injury of spinal cord or nerve root. Radiodiagnostics was used to observe sequential measurement of cervical vertebrae and height in cases without spinal cord or nerve root injuries. RESULTS: The cervical spine injury distribution is that 35 cases of anterior, left, right lateral and posterior column injury; 33 cases of anterior column injury; 90 cases of anterior and posterior column injury; 5 cases of anterior, left lateral and posterior column injury; 3 cases of anterior, right lateral and posterior column injuries; 3 cases of anterior, left and right lateral column injuries; 2 cases of anterior and right lateral column injuries; 5 cases of anterior and left lateral column injury; 12 cases of posterior column injury; 7 cases of left lateral column injury; 5 cases of right lateral column injury. Surgery operation was given in 98 patients out of 200 cases. Non-surgical treatment was given to 102 patients (including 39 patients who are qualified to receive operation, but patient's relative required non surgical treatment). Three cases of complete injury of spinal cord showed no recovery of the spinal cord function after operation, no change on the ASIA score, but pain and numbness of limb relieved slightly. Three non-surgical treatment cases showed no change after the treatment. Cases of incomplete injury of spinal cord showed certain recovery on spinal cord function after operation, and the ASIA score was raised 1.2 grades averagely. The ASIA score of cases of incomplete injury of spinal cord after non-surgical treatment was raised 0.3 grades averagely. The alignment and height of cervical vertebras were normal on post-operative radiodiagnostics in patients without injury of spinal cord or nerve root. CONCLUSION: According to modified Moore classification, when the stability quantification score is higher than or equal to 4, it indicated that the cervical vertebras are instability in lower cervical spine injuries. Surgery operation is required in higher score and less stability cases. Cases associated with neurological injury must receive surgery operation. Cases with stability quantification score equals to 3 and neurological injury should also receive surgery operation in general. Surgery operation is not required in cases of stability quantification equal to 3 and without neurological injury,or cases of stability quantification score lower than 3. Applying modified Moore classification in the treatment of lower cervical spine injuries is beneficial for the clinical standardization, diagnosis and treatment and receives satisfactory therapeutic effects. PMID- 21688532 TI - [Analysis of treatment of osteoporotic intertrochanteric fracture of femur with the locking compression plate (LCP)]. AB - OBJECTIVE: To investigate the therapeutic effect and operating technique on the treatment of osteoporotic intertrochanteric fracture of femur with the locking compression plate (LCP). METHODS: From Feb. 2006 to Oct. 2009, 49 patients with osteoporotic intertrochanteric fracture of femur were treaded with different internal fixation methods, concluded 22 males and 27 females with an average age of (74.68 +/- 5.94) years old ranging from 63 to 90 years. Among them, 29 patients were treaded with LCP, and the other 22 cases with DHS. According to X ray and Ultrasound bone mineral desity, all cases were diagnosed in osteoporosis. The operative time, blood loss, fluoroscopy exposure frequency, bone healing time and the time of first away from bed. RESULTS: All patients were followed up from 6 to 35 months. The operative time, fluoroscopy exposure frequency, the bone healing time and the time of being away from bed were compared between two groups, there were no statistical differences (t=1.347, 1.603, 1.973, 1.032, P>0.05). As compared with DHS group, the intraoperative blood loss in LCP group was less than that of DHS group, there were statistical differences (t=2.14, P<0.05). CONCLUSION: The LCP is an effective method in the treatment of intertrochanteric fracture of femur. The method has the advantages such as small wound and early recovery, especially appropriate for older patients. But the procedure as well should be demanded strictly. PMID- 21688534 TI - [Effects of Bushen qiangdu decoction on MMP-9 and TIMP-1 produced by peripheral blood mononuclear cells in patients with ankylosing spondylitis]. AB - OBJECTIVE: In order to investigate the roles of metalloproteinase in inflammatory bone destruction in ankylosing spondylitis (AS), and analyze the mechanism of preventing inflammatory bone destruction of Bushen Qiangdu decoction (BSQDD) in AS cases. Comparisons were made on the expressions of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) by peripheral blood mononuclear cells (PBMC) between AS patients and healthy controls. The effect of BSQDD was investigated on the expression and of MMP-9 and TIMP-1 produced by PBMC in AS patients. METHODS: From March 2005 to March 2006, 30 active AS cases of Kidney-asthenia, Du-cold and blood-stasis syndrome were selected as patients group in the China-Japan Friendship Hospital. There are 27 male patients and 3 female patients. The age range is from 16 to 45, averaging (30.8 +/- 8.8) years. Disease duration is from 0.5 to 10 years. Cases received three-month BSQDD treatment were considered as the treatment group. Twenty healthy persons were included in the control group. Serum and PBMC were separated. The PBMC were stimulated by PHA and PMA, and the supernatant was collected. The mRNA expression of MMP-9 and TIMP-1 in PBMC was analyzed by RT-PCR. The content of MMP-9 and TIMP 1 in serum and culture supernatant of PBMC were detected by ELISA. RESULTS: Compared with health control group, the serum concentration of MMP-9 and TIMP-1 in patients group before treatment increased (P<0.01, P<0.05), but the level of MMP-9 and TIMP-1 in the serum of patients after treatment decreased compared with pre-treatment cases (P<0.05). Furthermore,compared with health control group, PBMC of patients group before treatment expressed higher levels of MMP-9 and TIMP 1 both on transcript level and at protein level (P<0.01, P<0.05), and the expression levels of MMP-9 and TIMP-1 in PBMC in patients after treatment both on transcript level and at protein level was down-regulated compared with pre treatment (P<0.01, P<0.05). CONCLUSION: PBMC of AS patients had a higher potential capacity for MMP-9 and TIMP-1. BSQDD possibly prevented inflammatory bone destruction of AS through inhibiting production of MMP-9 and TIMP-1 produced by PBMC. PMID- 21688535 TI - [Treatment of humeral shaft fracture nonunion with quadrilateral bone lamella grafting and interlocking intramedullary nails]. PMID- 21688536 TI - [Surgical treatment of lower lumbar tuberculosis with different operative procedures]. AB - OBJECTIVE: To evaluate the surgical indications and clinical effectiveness of different operative procedures in the treatment of lower lumbar tuberculosis. METHODS: From June 2001 to Oct 2008, 72 patients with lower lumbar tuberculosis were treated by different operative procedures. Including 38 males and 34 females, with an average age of 38.5 years old ranging from 16 to 70 years. The average duration of symptom was 6.8 months (ranging from 4 months to 2 years). A single vertebrae was involved in 10 patients,two contiguous vertebrae in 50 cases and three vertebrae in 12 cases. The average preoperative lordotic angle was 13.1 degree (ranging from -5.0 degrees to 34.0 degrees). Three different operative procedures included: (1) posterior debridement and posterolateral fusion and posterior instrumentation in 28 patients; (2) anterior radical debridement and anterior fusion and anterior instrumentation in 32 patients; (3) image-guided percutaneous drainage (PCD) of tuberculous abscesses in 12 patients. The selection of the procedure was made according to the degree of the lesions. The resolution of inflammatory process, bony fusion, correction of sagittal angles and JOA scores were used for evaluating the result of the surgery and the complications were analyzed. RESULTS: All patients were followed up from 1.5 to 8.0 years (means 3.6 years). PCD was an effective treatment in 11 out of the 12 patients, one required surgical debridement and fusion. Among them, 57 (95%, 57/60) patients were treated by open operation showed successful bony fusion. The complications maily included common iliac vein injury in 3 patients, dural tear in 2 patients, they were all cured by intro-or postoperative treatment. The average immediate post-operative lordotic angle was 27.3 degree (35.0 degrees to 16.0 degrees), the average lordotic angle was 25.6 degree (33.0 degrees to 15.0 degrees) at final follow-up. Preoperatively and at final follow-up, JOA scores were respectively (15.2 +/- 3.4), (25.6 +/- 2.4) (P<0.01). CONCLUSION: Different operative procedures should be selected to treat lower lumbar tuberculosis according to the degree of lesions. Aggressive surgical treatment was found helpful in the resolution of inflammatory process and correcting the loss of lordosis, preventing progression of kyphosis. PMID- 21688537 TI - [Comparative study of serum levels of BMP-2 and heterotopic ossification in traumatic brain injury and fractures patients]. AB - OBJECTIVE: To investigate the relationship between serum level of bone morphogenetic proteins-2 (BMP-2) and heterotopic ossification (HO) in traumatic brain injury (TBI) and fractures patients, providing the theoretical evidence for the clinical prevention of HO. METHODS: From December 2007 to January 2009, 145 with trama patients were selected. There were 96 closed primary traumatic brain injury patients, 1 penetrating primary traumatic brain injury, 29 fractures of the radius and ulna, 11 fractures of the humerus, 32 fractures of the tibia and fibula, 27 fractures of the femur. All patients were divided into three groups (i.e., group A, group B and group C) by the type of fracture. Fifty-seven patients in group A (TBI only), including 37 males and 20 females, ranged in the age from 29 to 61 years, with an average age of (43.91 +/- 11.09) years. The disease course was from 13 to 67 d, with an average duration of (18.96 +/- 10.46) d. Forty-eight patients in group B (fractures only), 25 males and 23 females, ranged in age from 31 to 54 years, with an average age of (41.73 +/- 8.41) years. The disease course was from 6 to 48 d, with an average duration of (16.02 +/- 8.71) d. Forty patients in group C (TBI combined with extremities fractures), including 23 males and 17 females, ranged in age from 30 to 60 years, with an average age of (45.87 +/- 14.15) years. The disease course was from 18 to 76 d, with an average of (21.28 +/- 13.02) d. Thirty-one extremities fractures with no significant separations or displacements of fragments were treated with traction reductions, cast immobilization or splint fixations. Sixty-eight fractures with significant separations and displacements of fragments were treated with intramedullary nail fixations or screw internal fixations. Sixty-three TBI patients were treated with open-skull surgeries immediately while 34 TBI patients were treated with stanching bleeding, reducing intracranial pressure and improving cerebral blood circulation. All patients were also divided into two groups (group D and group E) according to the 14-to 16-month follow-up X-ray film results. Seventeen patients in group D (HO had been found), including 11 males and 6 females, ranged in age from 29 to 55 years old, with an average age of (46.88 +/- 7.13) years. The disease course was from 6 to 30 d, with an average of (20.18 +/- 9.78) d. All 128 patients in group E (HO had been not found), including 74 males and 54 females, ranged in age from 33 to 61 years, with an average age of (43.31 +/- 12.94) years. The disease course was from 15 to 76 d, with an average of (18.42 +/- 11.58) d. The 49 subjects in group F (normal controls), 29 males and 20 females, ranged in age from 31 to 60 years, average (43.50 +/- 14.40) years. Peripheral blood samples were taken for the determination of BMP-2 in blood serum on 0.5, 3, 15 d and 30 d after fractures by enzyme-linked immunosorbent assay (ELISA). Analysis of variance and least significant difference test were done with the help of SPSS 13.0 statistic software. RESULTS: The incidence rates of HO between the TBI only patients (21.05%, 12/57) and the fractures only patients(4.17%, 2/48) were significant different (chi2=5.05, P<0.05). Serum levels of BMP-2 at 0.5, 3 d and 15 d between group A and group B were significant different. Serum levels of BMP-2 at 0.5, 3, 15 d and 30 d between group D and group E were significant different. Serum levels of BMP-2 at each time in each group were higher than the control group (51.30 +/- 23.41 ng/L) (P<0.01). CONCLUSION: High serum levels of BMP-2 in TBI only group is one of factors in causing HO. Serum level of BMP-2 at 15 d since fractures may be the obvervational index of HO prevention. PMID- 21688538 TI - [Observation on biochemical indicator of multiple organ functional dysfunction after femoral shaft fracture combined with brain injury in rats]. AB - OBJECTIVE: To explore the features of rats organs functional changes after femur shaft fracture combined with brain injury through testing biochemical indicators in rats. METHODS: Thirty 4-month-old male SD rats, weight (280 +/- 10) g, were divided into 5 groups according to random number table involving normal control group, at the 1st day of injured group, the 2nd day injured group, the 3rd day injured group, the 5th day injured group, the 7th day injured group, 5 rats in each group. The animal injury model of right femur shaft fracture combined with brain injury were made by instruments in 5 injured groups. At the 1st, 2nd, 3rd, 5th, 7th day after made model, the biochemical indicators of blood serum from abdominal aorta including AST, ALT ,Cr, BUN, LDH and CK were detected and compared. RESULTS: The biochemical indicator of blood serum (AST, ALT, Cr, BUN, LDH, CK) changed significantly among different groups. AST, ALT, BUN and CK reached peaks at the 1st day after injured (P<0.05). Cr reached peaks at the 3rd day after injured (P<0.05). LDH reached peak at the 2nd day after injured (P<0.05). CONCLUSION: After brain injury combined with right femoral fractures in rats, a variety of serum biochemical indicators increase significantly, especially in early 3 days after injured. These indicators shows indirectly heart, liver and kidney organ dysfunction by trauma. PMID- 21688539 TI - [Ankylosed hip caused by heterotopic ossification after paraplegia]. PMID- 21688540 TI - [Treatment of lumbar spinal stenosis in the elder by micro-endoscopic discectomy]. AB - OBJECTIVE: To explore the clinical effects of micro-endoscopic discectomy(MED) in treatment of lumbar spinal stenosis in the elder. METHODS: The data of 376 cases of the lumbar spinal stenosis were treated by MED from December 2003 to December 2009, 47 cases of them aged above 60 years old. Of them, 43 old patients were followed up for 3 months to 6 years. There were 27 males and 16 females,with an average age of 68.3 years old ranging from 60 to 91 years. The average age was 68.3 years. The course was from 3 months to 15 years (averaged 3.5 years). The clinical effects of postoperation were observed and evaluated according to Nakai standard. RESULTS: Forty-three patients were followed up for 3 months to 6 years. The incision of all the patients had no infection and achieved primary healing. The clinical effect of the patients were evaluated by Nakai standard. The results were excellent in 26 cases,good in 12,fair in 5. CONCLUSION: MED has characteristics of less injury,fast recovery and thorough decompression to nerve roots. It is a kind of good method for treating lumbar spinal stenosis in the elder if the indication were grasped strictly. PMID- 21688541 TI - [Preparation and ectopic osteoinduction study of macroporous bone substitute with calcium phosphate cements and rhBMP-2 loaded gelatin microspheres]. AB - OBJECTIVE: To prepare macroporous bone substitute composed of calcium phosphate cements and rhBMP-2 loaded gelatin microspheres, and to investigate ectopic osteoinduction of the composite. METHODS: After being prepared by improved emulsified cold-condensation method and crosslinked by 5% genipin solution,gelatin microspheres (GMs) were observed by scanning electron microscope (SEM) and loaded with rhBMP-2 by adsorption. Macroporous bone substitute was developed by mixing calcium phosphate cement (CPC) with 2.5% GMs, being as the experimental group,and CPC with rhBMP-2 was the control group. After the both composites had been soaked in the sodium chloride for 1 week or 3 weeks, compressive strength of the composites were tested, and the cross-sections were observed by SEM. Concentrations of rhBMP-2 in the solutions at different time by ELISA method and the cumulative drug release amount was calculated. The composites had been implanted in the muscle bags of the mouses for 3 weeks. Then the tissues around the materials were collected, stained by hematoxylin and eosin, and Ca and ALP in the tissues were also measured. RESULTS: Gelatin microspheres were spherical with diameters of (62 +/- 18) microm. Macropores appeared in the experimental materials 1 week and 3 weeks after being soaked,and total porosity, macroporosity, cumulative release amount of rhBMP-2 in the experimental group were higher than that in the control. But compressive strength of the experimental group was lower than that of the control group 3 weeks after being soaked. Results of HE stain showed chondral formation in both groups, but there were more chondral tissues in the experiment group, and so were the concentrations of Ca and ALP. CONCLUSION: Macroporous calcium phosphate cement can be prepared by using rhBMP-2 loaded gelatin microspheres, and it is an excellent bone substitute due to it's proterty of promoting rhBMP release and powerful ectopic osteoinduction. PMID- 21688542 TI - [Arthroscopic treatment of anterior cruciate ligament avulsion fracture from the tibial eminence with reduction and suture combined with button plate fixation]. PMID- 21688543 TI - [Containing negative pressure drainage technology combined dermatoplasty of full thick skin graft to repair surgical donor site of hallux toe]. AB - OBJECTIVE: To evaluate the effectiveness of vacuum sealing drainage (VSD) combined with skin grafting to repair donor site for wrap around flap of hallux toe. METHODS: From Jan. 2009 to Apr. 2010,20 patients with injury of hallux toe were repaired by wrap around flap of hallux. There were 16 males and 4 females,with ranging in age from 18 to 45 years (averaged 36 years). The causes of injury: mechanical injury in 18 cases, road accident in 1 and postoperative hemangioma of hallux in 1. The degree of hallux defect as follow: grade I 10 cases, grade II 6 cases, grade III 4 cases. All patients' feet underwent 64-row CT angiography pre-operation, there were exposed bone and tendon tissue, the area of hallux ranged from 5 cm x 3 cm to 7 cm x 5 cm, all cases underwent vacuum sealing drainage combined with dermatoplasty of full thick skin graft for repair of donor site for wrap around flap of hallux toe. RESULTS: The raw surface of donor site in all patients survived without complications such as skin ulceration and exudation. After follow-up for 3 to 12 months, the skin appearance of raw surface was excellent with well function. CONCLUSION: VSD associated with dermatoplasty of full thick skin graft to repair donor site for wrap around flap of hallux toe can obtain satisfactory effect in treating injury of hallux toe, which can reduce difficulty of wound healing, improve skin appearance of donor site and relieve pain of patients. PMID- 21688544 TI - [A case report of gluteus maximus tendon calcification combined with sciatica]. PMID- 21688545 TI - [Repair of finger pulp defect with the homodigital spiral neurovascular island flap]. AB - OBJECTIVE: To investigate the method and clinical outcome of reconstructing large pulp defects of the fingertips with a homodigital neurovascular island flap. METHODS: Form June 2007 to October 2009, 16 patients with the defects of pulp were repaired by the spiral flap that was a homodigital neurovascular island flap with a unique spiral advancement and transposition design allowed pulp reconstruction using sensate glabrous skin while restricting donor morbidity to the injured digit. There were 12 males and 4 females with an average age of 37 years ranging from 18 to 49 years. The defect were caused by machine crush injury 11 cases, pressure injury by heavy objects in 2 cases, crush injury by door of car 1 case, injury by saw in 2 cases. The defect was located in the index finger in 5 cases, the middle finger in 9 cases,the ring finger in 2 cases. All injuries had large pulp defects averaging 1.6 cm (long) x 1.2 cm (wide) to 2.5 cm (long) x 1.7 cm (wide). Short-term results for all patients were reviewed. Outcome measures included static 2-point discrimination, total active motion, and hypersensitivity or cold intolerance. RESULTS: All flaps achieved primary healing with no complications. Sensory recovery was excellent with an average 2-point discrimination of 5.1 mm. All patients were followed-up for 8 to 20 months (averaged 12 months) with highly satisfactory with both aesthetic and functional outcome. There was no hypersensitivity or cold intolerance. According to the evaluation of total active motion (TAM) scales, the results were excellent in 7 cases, good in 8 cases (9 lesions) and fair in 1 case. CONCLUSION: The spiral advancement-transposition flap is suitable for resurfacing large pulp defects with excellent short-term functional and aesthetic results and high patient satisfaction. PMID- 21688546 TI - [Changes of the content of hydroxyapatite and collagen in bone tissue of ovariectomized rats]. PMID- 21688547 TI - [Reconstruction intramedullary nailing for the treatment of ipsilateral fractures of shaft of femur and hip]. AB - OBJECTIVE: To evaluate the curative effect and surgical skills of reconstruction intramedullary nailing for ipsilateral fractures of shaft of femur and hip. METHODS: Fifteen patients with ipsilateral femoral shaft and hip fractures from June 2002 to June 2008 were treated with reconstruction intramedullary nails. All of them were male with an average age of 45 years (range,34-85 years). According to the Winquist-Hansen classification, there were 2 type I, 6 type II, 2 type III, and 2 type IV shaft fractures. Hip fractures consisted of 7 intertrochanteric and 8 (53.3%) neck fractures. According to Garden's classification, 1 femoral neck fracture was type I, 3 were type II, 2 were type III and 2 were type IV. RESULTS: All of the patients were followed up for an average of 30.9 months (range, 12 to 55 months). Due to other combined severe injuries, operations were delayed for 1-14 days (average is 5 days). Delayed union of femoral shaft occurred in 1 case; nonunion of femoral shaft occurred in 2 cases. Nonunion of femoral neck occurred in 1 and coxa vara occurred in 1. Hip fractures healed in 14 (93.3%) patients, and shaft fractures healed in 13 (86.7%)patients. The average union time was 4 months (range, 2-6 months) for the hip fractures and 5.5 months (range, 4-9 months) for the shaft fractures. No femoral head osteonecrosis, wound infection or shortening more than 2 cm occurred. Functional results using Friedman-Wyman criteria were good in 13 cases, fair in 1 case, and poor in 1 case. CONCLUSION: Reconstruction intramedullary nails can provide biological fixation of both fractures with fewer complications, and is an effective device to treat this kind of combined fractures. PMID- 21688548 TI - [Reasonable application of minimally invasive percutaneous plate osteosynthesis for the treatment of distal fractures of tibia]. AB - OBJECTIVE: To investigate the technique and clinical results of minimally invasive percutaneous plate osteosynthesis (MIPPO) for the treatment of the distal fractures of tibia by an appropriate plate. METHODS: From Jan. 2005 to Dec. 2007, 56 patients with the distal tibia fractures were treated with MIPPO through two approaches and three types of plate involving clover plate in 35 cases, anterior L-shape anatomic plate in 12 cases, medial LCP in 9 cases. There were 38 males and 18 females with an average age of 41 years old ranging from 17 to 72 years. According to AO fracture classification for the distal tibial fractures, there were 28 cases of type A, 11 of type B, 17 type C. RESULTS: All the patients were followed up from 12 to 24 months (averaged 16 months). All of the fractures showed bone union. The time required for the bony union ranged from 3 to 11 months (averaged 4 months). The patients were evaluated on functional recovery according to Mazur Grating System for the Ankle. The results were excellent in 51 cases, good in 5. CONCLUSION: Choosing effective reasonable approach and plate for the treatment of the distal tibial fractures can obtain satisfactory function, high rate of bone union and less complications. PMID- 21688549 TI - [Manipulative reduction and internal fixation by percutaneous locking compression plate for the treatment of mid-distal tibiofibula shaft fractures]. AB - OBJECTIVE: To investigate the clinical effects of manipulative reduction and percutaneous locking compression plate internal fixation for the treatment of mid distal tibiofibula shaft fractures. METHODS: From January 2006 to October 2009,46 patients suffering from mid-distal tibiofibula shaft fractures were treated with closed manipulative reduction and LCP, involved 27 males and 19 females with an average age of 39 years old ranging from 17 to 56 years. According to AO classification, there were 12 cases of type A, 24 of type B, 10 of type C. The duration of visiting hospital were from 2 hours to 3 days after being injured for these patients. The injured limbs of the patients were swollen and painful,even with bony crepitus. The wound, function of the injured limb and union of fractures were observed after operation. RESULTS: All the patients were followed up from 12 to 18 months (averaged 15 months). It was found that the wound of all patients had primary healing without any infection. The fracture healing time was 12 to 18 weeks (means 14 weeks). The results were excellent in 40 cases,good in 4 and fair in 2. CONCLUSION: Less invasive, more stable fixation, shorter healing time and better functional rehabilitation are observed in the treatment of mid distal tibiofibula shaft fractures after manipulative reduction and percutaneous locking compression plate internal fixation. PMID- 21688550 TI - [Analysis of therapeutic methods and effects for talar fractures]. AB - OBJECTIVE: To explore the choice of therapeutic methods for talar fractures and analyze its clinical effects. METHODS: From October 1998 to October 2009, 44 patients with talar fractures were treated in the study, of them, 38 cases obtained follow-up, in which 10 cases with plaster external fixation, 22 cases with open reduction and internal fixation, 6 cases with Blair joint fusion. There were 28 males and 10 females,ranging in age from 19 to 65 year with an average of 33.5 years. According to classification of Matti-Weber, type I was in 3 cases, type II in 15, type III in 16, type IV in 4. The clinical effects were evaluated by the Hawkins standard including pain, active range of the joint, limping. RESULTS: The mean time of follow up was 4.8 years (range, 1 to 11 years). According to the Hawkins standard, in 10 cases with plaster external fixation, 4 cases obtained excellent results, 2 good, 3 fair, 1 poor; in 22 cases with open reduction and internal fixation, 2 case obtained excellent results, 6 good, 6 fair, 8 poor (the 8 patients accepted second treatment with joint fusion at 3 to 5 years after operation, affected limb of 1 patient occurred crispation for 3 cm, walking with limp, and further treatment was refused result in poor,and others got fair results); in 6 cases with Blair joint fusion, 1 case obtained good results, 4 fair, 1 poor. Diaz disease was found in 12 cases and traumatic arthritis was found in 13 cases in the period of follow-up. CONCLUSION: Talar fracture usually results in complications and gets bad prognosis. The prognosis is relative with the traumatic degree. Plaster external fixation beseems to the displacement of fracture less than 2 mm; open reduction and internal fixation beseems to the displacement of fracture more than 2 mm; Blair joint fusion beseems to talar body fracture with total dislocation or whose talar body fracture is comminuted severely and the surface of joint can not be repaired. PMID- 21688551 TI - [Current research of the excessive lateral pressure syndrome of patellofemoral joint]. AB - As modern medicine getting deeply to understand ever-detailed anatomy,structure and animal mechanics of the patellofemoral joint, excessive lateral pressure syndrome, a very common patellofemoral disorder, has been reacquainted by the clinicians. On account to the complexity and variety of the etiology and the mechanism of the pain, still, there are many difficulties and arguments on the exact description of the clinical symptoms and the establishment of a universally accepted diagnostic criteria. Accurately grasping different causes, pathomechanisms and developmental stages of the disease would be especially important. As a result, rational choice of the pertinent procedures become the clinical lynchpin. This paper reviews domestic and international pertinent literatures in the past 10 years, and provide an overview of the latest study of anatomy, biomechanic, pathomechanism and clinical experience, anticipating to offer help on standardizing the diagnosis and treatment of ELPS. PMID- 21688552 TI - [Application of MR arthrography for diagnosis of femoral acetabular impingement syndrome]. AB - Femora acetabular impingement (FAI) is thought as the major reason leds to hip osteoarthritis. FAI results to destruction of the arthrodial cartilage. Prognoses of hip osteoarthritis is affected by the degree of arthrodial cartilage destruction. The hip osteoarthritis could be prevented if FAI is diagnosed and treated in earlier period. How can we diagnose FAI in earlier period? Recent studies showed that MRI was the best way for FAI diagnosis. It has higher resolution and signal-noise ratio. Cartilage and gleniod labrum of hip could be shown by MRI. The paper reviewed the standard and difficulties of diagnosis about FAI. High magnet MRI maybe is one way to solve the problems. PMID- 21688553 TI - [A decade beginning with only some certainties]. PMID- 21688554 TI - [Pathogenesis of thrombotic and hemorrhagic complications in myeloproliferative and myelodysplastic syndromes]. AB - Chronic myeloproliferative disorders (CMD) and Myelodisplastic Syndromes (MDS) represents a group of clonal pluripotent stem-cell pathologies. During their natural history, the clinical picture reveals both thrombosis and hemorrhage. The thrombosis could affect the microvessels, and also the large vessels, including even less usual territories (suprahepatic veins, porta vein, pulmonary vein). There are many factors contributing to thrombosis in myeloproliferative chronic disorders--the associated comorbidities, the numeric alterations of blood elements and also the disorders of the platelet's function. Thus, there were described quantitative and qualitative anomalies of platelet's receptors: GP Ib, GP IIb/IIIa, GP IV, GP VI, thrombopoietin receptor of the platelet cMPL, the increase of platelet activation; the increase of P selectin and thrombospondin and the increase on GP IIb/IIIa expression--they were all correlated with thrombosis. An important role has been attributed to JAK2 mutation, which affects the platelet receptor for thrombopoietin cMPL. Regarding the hemorrhage in chronic myeloproliferative syndrome, it is favored by many disorders in platelet's function, such as: the decrease of von Willebrand factor's receptor of the platelet, which leads to acquired Bernard Soulier syndrome; quantitative and qualitative disorders of dense granules of the platelet, decrease of the secretion and platelet aggregation after epinephrine, ADP and collagen stimulation. It was also described the acquired von Willebrand syndrome, most frequently type 2. PMID- 21688555 TI - [Locally advanced or metastatic gastric cancer--new therapeutic solutions]. AB - Gastric cancer represents a major health problem worldwide. It is often diagnosed at an advanced stage, because screening, which would help an early detection is performed only in Japan. Gastric cancer rates may be decreased by reducing smoking and alcohol consumption and by increasing the number of fresh fruits and vegetables eaten. Eradication of Helicobacter pylori may also decrease gastric cancer incidence. Seventy-five percent of the patients are diagnosed in unresectable stage. They represent a challenge for clinicians as they have to choose between a strictly supportive approach or to expose patients to the side effects of a potentially ineffective treatment. The treatment of advanced gastric cancer is essentially palliative. Therapy's main aim in this common group of patients with unresectable or metastatic disease is to achieve good symptomatic control, to improve quality of life, to avoid tumor progression and to prolong survival. PMID- 21688556 TI - [Peptic ulcer disease in liver cirrhosis: role of Helicobacter pylori infection and therapeutic approach]. AB - Peptic ulcer has frequently been associated with liver cirrhosis. The death rate for peptic ulcer in cirrhotics has been reported to be five times higher than in general population. The underlying mechanisms are poorly understood. Different factors have been claimed to be involved, such as alterations in serum gastrin level, gastric acid secretions, mucosal blood flow and decreased prostaglandin production in gastric mucosa. Moreover, Helicobacter pylori infection, when accurately assessed, is detectable in most peptic ulcer cirrhotics. Since the H. pylori infection strongly correlates with peptic ulcer in general population, it is necessary to clarify the role of H. pylori in the pathogenesis of peptic ulcer in cirrhosis before eradication can be proposed as a preventive measure. PMID- 21688557 TI - [High levels of sterigmatocystin in patients with chronic liver diseases]. AB - Sterigmatocystin (STC) is a wide spread mycotoxin produced by Aspergillus fungi, with hepatotoxic and carcinogenetic proprieties. OBJECTIVES: To determine the STC concentration in blood and urine from patient with liver cirrhosis (LC) and hepatocellular carcinoma (HCC), with correlation with liver function parameters. MATERIAL AND METHODS: The study enrolled 166 patients divided in three groups: control--55 patients (27M, 28F); LC--58 patients (31M, 27F); HCC--53 patients (26M, 27F). 20 ml of blood and 50 ml of urine were collected from each patient and liver enzymes and alfa-fetoprotein (AFP) were measured. STC was determined by high performance liquid chromatography, with concomitant detection in ultraviolet and fluorescence. RESULTS: STC was detected in 26.2% of samples, more frequently in LC and HCC groups (p < 0.001). STC mean values were 0.014 ng/ml and 0.005 ng/ml in blood, respective urine of controls, rising to 0.626 ng/ml (p = 0.003) respective 1.053 ng/ml (p = 0.049) in LC and 2.02 ng/ml in blood (p < 0.0001) and 9.39 ng/ml in urine (p = 0.003) in patients with HCC. There is a perfect correlation between serum and urinary levels of STC in controls (r = 1), that become weak in patients with LC (r = 0.48) and insignificant in HCC (r = 0.15). AFP values were significantly correlated with STC concentration in patient with HCC, in both blood (r = 0.31) and urine (r = 0.84). CONCLUSIONS: STC values in patients with LC and HCC were significantly higher compared to controls. Strong positive correlation of STC with AFP in patients with liver cancer suggested a possible role of this mycotoxin in pathogenesis of the disease. PMID- 21688558 TI - [Spontaneous bacterial peritonitis: a severe complication of liver cirrhosis]. AB - Spontaneous bacterial peritonitis (SBP) is a frequent and severe complication of decompensated cirrhosis. SBP is defined as an infection of initially sterile ascitic fluid (AF) without a detectable, surgically treatable source of infection. AIM: To evaluate the prevalence, incidence, pathogens and clinical outcome of patients with liver cirrhosis and SBP. METHODS: A prospective study evaluated 34 episodes of SBP developed in 29 patients with cirrhosis and ascites admitted in hospital. SBP was diagnosed based on a polymorphonuclear cell count in ascitic fluid of > 250 cells/mm3 in the absence of data compatible with secondary peritonitis. RESULTS: The mean age of the group was 56.89 +/- 8.79 years, more frequently occurred in men 21 of 29 cases (72.41%). Microorganisms were isolated in 12 episodes (35.29%): Gram-negative bacteria in 8 (66.67%) and Gram-positive in 4 (33.33%). The first-line treatment failure and in-hospital mortality rates were 26.47% and 17.64%, respectively. The low in-hospital mortality seems to be related to earlier diagnosis and treatment. In the multivariate analysis, three significant independent predictive factors of in hospital mortality were identified: a high Model of End-Stage Liver Disease (MELD) score, renal failure and SBP caused by extended-spectrum a-lactamase producing organisms. The relapse rate of PBS was 21.73%. CONCLUSIONS: SBP remains to be a serious complication, especially in patients with a high MELD score. Ceftazidim represents a good choice in empirical treatment of SBP. PMID- 21688559 TI - [Study of several factors influencing antioxidant enzyme defense in obese patients]. AB - The notion of "oxidative stress" was introduced by Sies, in 1985, and designates all the oxidative damages caused by the free radicals of oxygen. Oxidative stress represents the imbalance of pro-oxidant and antioxidant ratio, in favor of the former, following the excessive action of the "aggressor" and/or the decrease of the "defender's" capacity to oppose. MATERIAL AND METHOD: In the current study we had 82 overweight patients (42 patients less than 65 years old and 40 patients over 65). The criteria for inclusion was weight over 80 Kg and BMI > 30. Patients were monitored and assessed every three, six, nine months and each year. RESULTS: Obesity together with dyslipidemia, smoking, diabetes and high blood pressure intensifies oxidative stress. The improvement of these factors determines the growth of antioxidant enzyme level (SOD and GPX) and the reduction of malondialdehyde level. PMID- 21688560 TI - [Assessment of the quality of life of women with breast cancer in adjuvant treatment with tamoxifen or aromatase inhibitors--a randomized trial]. AB - PURPOSE: To evaluate and compare the impact on quality of life of tamoxifen and aromatase inhibitors (AIN's) in adjuvant settings, at women with breast cancer. METHODS: From a total of 441 patients with breast cancer with hormonal treatment, were selected 177 of patients with adjuvant hormonal treatment (95 with tamoxifen treatment and 82 with AIN's treatment). These patients have completed the EORTC QLQ C-30 and EORTC QLQ BR23 questionnaires after 1 month of treatment (baseline), at 2 year of treatment with tamoxifen versus aromatase inhibitors (exemestane, anastrazole, letrozole). Mean change score from baseline and 2 years of treatment were compared in the both arms (tamoxifen vs. AIN's). RESULTS: In both arms, after two years, a decreased QOL was observed as compared with the baseline. In the tamoxifen arm, global health status (GHS) and breast symptoms score (BRBS) were similar comparative with AIN's arm at baseline, with a similar status at 2 years measurement. CONCLUSIONS: The global health status (GHS) and breast symptoms score (BRBS) shows that there is no difference in the QOL at the women with breast cancer treated with tamoxifen, comparative with the women treated with AIN's. We conclude that AIN's did not have an adverse impact on overall QOL, comparative with tamoxifen, in adjuvant settings. PMID- 21688561 TI - [Non-invasive markers of esophageal varices in compensated liver cirrhosis]. AB - MATERIAL AND METHODS: There were 91 patients in this study, with liver cirrhosis classified as Child A, diagnosed using clinical, biological and ultrasound methods, and a control group. We used a special questionnaire and biostatistical methods in order to assess the presence of esophageal varices (EV), followed by performing upper gastrointestinal endoscopy (UGE). RESULTS: Models made with biostatistical methods differentiated the cases with or without EV. ROC curve showed sensitivity and specificity values of various parameters. We obtained an overall rate of correct classification of 84.62% for the presence of EV and 71.30% scale assessment. CONCLUSIONS: Using non-invasive tests may be useful as therapeutic and prognostic considerations, to reduce the number of upper gastrointestinal endoscopy in the disease surveillance also. PMID- 21688562 TI - [Considerations based on the etiology of acute renal failure in children (study on 110 cases)]. AB - The Article highlights the fact that without a homogeneous definition of acute renal injuries of adults and infants, for the last 5 years a new classification system has appeared. The RIFLE pediatric criteria are looked over, validated in 2007 which allow a better IRA classification at infants and allow comparisons between the intensive care units and also allow assumptions on the predictions of the disease. The list of certain causes of IRA at infants is rendered, the genetic background of children with IRA risk is highlighted, the necessity of reevaluating and criteria of evaluating renal functions is underlined. The etiology of renal failure was studied on 110 infants interned on a period of 5 years (2003- 2008) in 2 centers with different profile: The Clinic Of Pediatric Nephrology "Sf. Maria" Iasi and the Intensive Care Compartment of The Pediatric Hospital "Sf. Ioan" Galati. PMID- 21688563 TI - [Correlation between essential hypertension and carotid intima media thickness in children]. AB - Essential hypertension is no longer un uncommon disease in children. This study try to determine if carotid intima thickness is increased in children with essential hypertension. MATERIAL AND METHOD: This subjects are compared with control group with normal blood pressure. The study group consists of 78 children with essential hypertension; there were excluded cases with secondary hypertension. These children had carotid intima media thickness, left ventricular mass index and body mass index performed. In control group there were 53 subjects and there were performed the same investigations for them. RESULTS: Sixtyfour cases (82.05%) from study group had obesity (body mass index > or = 85 percentile). Left ventricular mass index was increased in 40 cases (51.28%). Increased carotid intima media thickness was found in fiftyone subjects (65.38%) in the group of hypertensive children and it range between 0.52 si 0.69 mm. In the control group carotid intima media thickness varies between 0.32 si 0.54 mm. The carotid intima media thickness correlated with sistolic blood pressure (P = 0.00000), with diastolic blood pressure (p = 0.000002), with body mass index (p = 0.00000) and with body mass index(p = 0,000001). CONCLUSION: The study could not state if increased carotid intima media thickness is due to hypertension or to obesity, because in children there is a strong association between these two diseases. Anyway, evaluation of this parameter may offer information about early endothelial disfunction. PMID- 21688564 TI - [The influence and prevalence of nonalcoholic steatohepatitis in chronic hepatitis B]. AB - The prevalence and the impact of nonalcoholic fatty liver disease (NAFLD) on chronic hepatitis B (CHB) are not well known. NAFLD as the hepatic manifestation of the metabolic syndrome (MS) is associated with obesity, diabetes mellitus and dislipidemia. AIM: To evaluate the prevalence and the impact of NAFLD on CHB. METHODS: 120 patients diagnosed serologically and histological with CHB in 2006 in our center were retrospectively analyzed. Patients with self declared excessive alcohol consumption (above 20 g/day for males and 10 g/day for females) have been excluded. NAFLD was evaluated according to Brunt's score, while histology activity index (HAI) and fibrosis stage for CHB were estimated using Knodell score. The patients were divided in 2 groups: patients with CHB without steatosis (n = 61) and with steatosis (n = 59). RESULTS: Out of 120 patients with CHB (male/female = 76/44, median age = 40.41), 49.15% had steatosis. No statistically significant differences among fibrosis stages, HAI and the aminotransferase levels was found between the two groups (p = 0.320, p = 0.228, and p = 0.128). The presence of NAFLD associated with CHB was significantly correlated with age (p = 0.001) and MS (p = 0.051). In patients with CHB and steatosis, significant correlations between female sex and the presence of MS (p = 0.007) as between HAI and age (p = 0.003) were found. CONCLUSIONS: NAFLD was detected at 49.16% of patients with CHB. A positive correlation with age and MS (obesity, diabetes mellitus and/or dislipidemia) was observed. No significant correlations between NAFLD and the aminotransferase levels or histological features have been found. PMID- 21688565 TI - [A trap "fold" in a Takayasu arteritis]. AB - Sometimes, acute aortic dissection diagnosis, a significant cardiological and surgical emergency, is particularly difficult. Therefore, Takayasu arteritis associated dissection fold may be a real diagnostic "trap", in spite of all modern exploratory techniques. PMID- 21688566 TI - [Total parathyroidectomy without autotransplantation in the management of "refractory" renal hyperparathyroidism]. AB - The optimal surgical treatment in patients with refractory renal hyperparathyroidism (RHP) on hemodialysis for end stage renal disease is still a point of controversy. The high percentage of recurrences after standard surgical procedures i.e. subtotal parathyroidectomy (SPTx) and total parathyroidectomy with autotransplantation (TPTx + At) reactualised the practice of total parathyroidectomy (TPTx). MATERIAL AND METHOD: Fortythree patients with RHP underwent surgery between 1994-2009. There were 24 SPTx and 6 TPTx + At, both procedures determining 20.7% (6 cases) recurrences so in the last five years TPTx was performed in a series of 13 cases (7 men and 6 women, with median age 43, 6 years; range 22 - 65 years and median dialysis time before PTx 8,2 years; range 3 -12 years. Parameters studies included demographics, preoperative and follow-up laboratory tests, surgical techniques, pathology results and postoperative immediate and medium term results. RESULTS: Main indications for PTx were severe bone disease, soft tissue calciphycations, neuro muscular phenomena, grossly elevated iPTH and sometimes hypercalcemia. TPTx was done in 12 patients, the 13th one suffering a completion PTx one year after outward exeresis of only two glands. Postoperatively the majority of symptoms markedly improved and the values of calcaemia, phosphatemia and alkaline phosphatasis normalised together with low or no measurable level of iPTH. One patient required a re-exploration for a cervical hematoma but no one presented permanent hypocalcemia or recurrent hyperparathyroidism. Pathology revealed nodular hyperplasia in all the cases, a parathyroid carcinoma but also an incidental thyroid papillary microcarcinoma in a complementary thyroidectomy. CONCLUSIONS: TPTx alone proves to be an equally safe and successful as another techniques currently used in management of RHP eliminating the hyperparathyroid status but being superior with regard to aparition of recurrences. The procedure is indicated especially in cases with aggressive, refractory forms of RHP without the prospect of renal transplantation. PMID- 21688567 TI - [Stromal tumors of jejunum and ileum]. AB - Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the digestive tract and 25% are in the small intestine. MATERIAL AND METHOD: A retrospective study was performed on 73 patients diagnosed with intestinal cancer in three hospitals in Iasi and Galati, in a period of 12 years (1998-2009). RESULTS: Stromal tumors represents 11.5% of malignant tumors of jejunum and ileum, and the average age of diagnosis was 55 years; male to female incidence was 1 : 2 (chi2 = 0.66, p > 0.05). 66.66% of patients came from urban areas (chi2 = 0.66, p > 0.05). The most frequent signs and symptoms were abdominal meteorism and abdominal pain (83%). There were no correlations between admission and discharge diagnosis. CD117 was present in all patients; CD34 was present in 66.66% of them. Survival at 2 years was 66.67% and at 5 years was 33.33%. CONCLUSIONS: Preoperative diagnosis is often difficult to make, many patients come to doctors in advanced-stage and the five-year survival rate is slow. The most frequent tumor markers were CD117 and CD34. PMID- 21688568 TI - [Contributions to know the involvement of cardio-vascular diseases in glaucoma etiology, studied on a sample of 996 patients assisted in Clinic of Ophthalmology, "Prof. N. Oblu" Emergency Hospital, Iasi]. AB - MATERIAL AND METHOD: The authors present the results of clinical and epidemiological research on a sample of 8118 patients assisted in the Ophthalmology Clinic of the Hospital "Prof. Dr. N. Oblu", including 996 (12.1%) with glaucoma, of which 54.1% primary open angle glaucoma (POAG), 22.6%, normal tension glaucoma (NTG), 5.7% primary angle closure-glaucoma (PACG) and 17.6% secondary glaucoma, during 2006-2010. RESULTS: For patients with glaucoma authors assessed the prevalence of arterial hypertension (POAG: 33.1%; NTG: 32%; PACG: 8.7%, secondary: 8%), diabetes mellitus (POAG : 19.9%, TNG : 12.9%; PACG : 5.3%, secondary : 5.2%), atherosclerosis (POAG: 10.2%, TNG: 12%; PACG: 5.2%, secondary: 2.9%), vasospasm (POAG: 45 2%, TNG: 47.3%; PACG: 39.3%, secondary: 44.3%). PMID- 21688569 TI - [Comprehensive study of placenta praevia]. AB - MATERIAL AND METHODS: The study was carried out on 53 cases with placenta praevia, admitted to the "Cuza Voda" Obstetrics and Gynecology Hospital, Iasi, where the prevalence was 3.84% between 2006 and 2009. RESULTS: The onset, increased with parity, was during the 8th month (30.19%), with hemorrhage (77.35%). An obstetrical pathological history was found in 33 cases (62.26%). PMID- 21688570 TI - [Clinical epidemiological assessments on 3521 patients suffering from road traffic injuries, in relation with trauma localisation and severity, assisted in "Sf. Ioan" Emergency Unit, during 2002-2009]. AB - The aim of study was to assess road traffic injuries in relation with their localisation and severity. MATERIAL AND METHODS: A sample of 3521 patients suffering from road traffic injuries and assisted in "Sf. Ioan" Emergency Unit, Iasi, Romania was assess regarding age group, sex and residence area, type of lesions and ther localisation and severity, between 2002-2009. Data were collected using a special epidemiological inquiry and processed using SPSS and MS Excel statistical softs. RESULTS: The incidence of road traffic injuries increased during the last decade, with a report men/women of 1.5, urban and 21-30 age group predominance. The most frequent were leg fractures (16.7%) and thoracal contusions (19.1%), cranial and facial trauma (32.4%), with open injuries (10.5%). CONCLUSIONS: Prevention programmes with a high efficiency at the national level, as well as a concret identification of risk factors with a multidisciplinar approach of road traffic accidents, are needed. PMID- 21688571 TI - [Peripheral vestibular syndrome intricated pathogenic issues. A case report]. AB - BACKGROUND: Meniere's syndrome appears to be the final common pathway of the mechanisms the inner ear responds to almost any injury. Although the autoimmune disease seems to play a major role, exposure to intense noise can also be a trigger in the appearance and/or aggravation of the disease. MATERIAL AND METHODS: The case of 41 years old musician with a history of ankylosing spondylitis, diagnosed with Meniere's syndrome 5 years ago, is presented. Recently the symptoms became more polymorphic, revealing the association between benign paroxysmal positional vertigo (BPPV), Meniere's syndrome and high frequency hearing loss in an autoimmune background. Besides general, neurological and ENT examination, the diagnostic workup comprised of tonal audiogram, brain stem auditory evoked potentials, computerized dynamic posturography and videonistagmography. RESULTS: The final diagnosis was acute noise trauma, Meniere's syndrome, left horizontal semicircular canal BPPV, bilateral sensorineural sudden aggravated hearing loss in high frequencies (above 9 kHz) and allegedly autoimmune inner ear disease. Treatment with an association of corticosteroids, vasodilators and vitamins combined with Vannucchi's maneuver were followed by a significant relief of the symptoms. CONCLUSION: Although no causal relationship was found between acoustic trauma and increased endolymphatic pressure, both literature data and the case presented show that intense and prolonged noise exposure may aggravate peripheral vestibular syndrome. PMID- 21688572 TI - [Membrane fluidity--biophysical parameter in relation to membrane transport processes]. AB - Membrane fluidity is a complex parameter, influenced both through some biophysical (temperature, electrical charges, pH) and biochemical factors (protein/phospholipids ratio, phospholipids/cholesterol ratio, degree of fatty acids unsaturation). It is a parameter that reflects the main membrane characteristic organization (gel or liquid crystal structure). Experiments provide consistent data about membrane fluidity relations to various cellular processes, especially membrane processes. Passive transport is influenced directly by membrane lipid composition, and consequently, membrane fluidity, or by channels and carriers molecules interactions with adjacent membrane lipids. Membrane diffusion is related both to the hydrophobic nature of the particles and of the membrane environment. Depending on the mode of interaction with membrane proteins, lipids may be classified as non-annular lipids, annular and "mass" lipids. Different types of fatty acids affect the function of many channels, by stimulating or inhibiting them. These effects might be mediated through direct binding of the lipids to the channel or through indirect hydrophobic interactions. Active transport pumps conformation could be modulated, also, through interactions with adjacent lipids of the bilayer (especially cholesterol) and membrane micro-domains organization. In conclusion, membrane fluidity is close related both to passive and active transport. PMID- 21688573 TI - [Assessment of some laboratory, imaging and anatomical-pathological investigations on a lot of 104 patients diagnosed with breast cancer and appear in the list of family doctor from the city of Iasi]. AB - The aim of study was to assess some investigations in female patients with benign and malignant breast diseases. MATERIAL AND METHODS: The study was performed on a sample of 104 patients registered with breast tumors, at family physicians' offices from Iasi, Romania. RESULTS: Impaired glucose tolerance was associated with 34.2% of patient with breast tumors, and hypercholesterolemia with 25.9% of them. Anatomo-pathological assessments included aspiration puncture and biopsy, extemporaneous biopsy, and paraffin-embedded exam. Invasive carcinoma was the most frequent histo-pathological type (42.1%). CONCLUSIONS; Further investigations on tumor markers are needed in all patients with in situ neoplasia and breast carcinomas. PMID- 21688574 TI - [Effect of environmental and individual factors in renal lithiasis]. AB - The large number of cases with renal lithiasis occurring in the population of the south-east region of Iasi county has determined us to make a study in this region for the identification of environmental and individual factors involved in the etiopathogenesis of this disease. This study is performed to assert the corelation between the clinical and paraclinical patients data with those obtained through water and soil chemical analisys for identification of determinant environmental and individual factors involved in etiopathogenesis of this disease. This study indicates that the environment factors (water, soil) correlated with personal factors, especially the diet and standard of living are the favouring factors of renal lithiasis. PMID- 21688575 TI - [Food intake--family income in a group of teenagers from Iasi "Dimitrie Cantemir" High School]. AB - Food intake is influenced by a series of factors, including family, income, school and mass-media. MATERIAL AND METHOD: A group of 78 teenagers were investigated using a food intake questionary, correlating the results with family income. RESULTS: Our results show that the food intake is influenced more by family dietary habits rather than family income, with no significant differences between families with different socio-economic status. CONCLUSION: Educational programs for changing the nutritional habits must be implemented. PMID- 21688576 TI - [Evaluation of the quality of life in patients with uterine cervical cancer using a holistic psychological and medical approach]. AB - Assessment of quality of life requires a multidimensional measurement of health and wellness, as reported by the patient. The central objective of this research was to capture the phenomenon of impact on cancer diagnosis; disease and treatment have on physical and emotional status of patients with cervical cancer. MATERIAL AND METHOD: The study was realized on a group of 70 patients diagnosed with this disease, aged 25-55 years and from different intellectual categories both in rural and urban. We used an experimental design of type 2 (early disease stage/advanced) x 5 (surgical therapeutic method / surgery with radiotherapy/surgery with chemotherapy/surgery with radiotherapy and chemotherapy/palliative) x 2 (low therapeutic compliance/high) x 2 (low depression/high). As data collection instruments were used histopathological examinations and psychological tests (to measure quality of life SF-36 test and test sensory and affective pain McGill and independent variables Beck Depression Scale and IPQ-R), and to verify hypotheses T test for independent samples and comparing Univariate ANOVA. RESULTS: The results showed the importance of emotional state on the development of cancer disease and its quality of life. PMID- 21688577 TI - [Epidemiological and forensic medical considerations regarding frequency and causes of violent deaths in Iasi. County, between 1997-2006]. AB - Authors present some epidemiological aspects of violent deaths in Iasi County, with certain comparisons with Romania, during the period 1997-2006. MATERIAL AND METHOD: The study included information collected by Institutes of Forensic Medicine at the national level. RESULTS: In Romania, violent deaths registered values between 2.6 and 4.5%, with yearly non-significant statistical differences when reported to causes of death, excepted years 2005 and 2006. Violent deaths situated Iasi County over the national level (8-11 / 2.7% per hundred thousand). Homicides registered 9.3% per hundred thousand, as compared with much more reduced values in other 12 Romanian counties, in the same period of study. CONCLUSIONS: Violent death in Romania and Iasi County highlighted a dependence of difficulties to carry out efficient programmes of prevention and emergency assistance. PMID- 21688578 TI - [Public health in Orhei County--realities and opportunities]. AB - Orhei District Hospital has 420 beds located in 17 wards. Providing beds in 2010 is 39.2 to 10 000 people compared with 47.7 in 2008, but it is still more than the regional average for the country- 32.6. Rotation bed, the lethality rate of hospitalization of people have not changed in the previous year. The average duration of treatment and average bed occupancy rose in 2010 compared with 2009, but the bed occupancy rate is still small--about 60%. Share divergence diagnostic is lower than the previous year--this is a good indicator of quality. Enough old equipment is still an issue for the District Hospital Orhei. Making an analysis of the distinctive features of health care evaluations, where resources are expressed by the cost and the results are expressed as effects on health, we conclude that it is necessary to change the conceptual aspects regarding health care financing. For redress the economic and financial situation, is proposed following strategy: 1. Reduced costs for hotel accommodation, by introducing "a day hospital". This system implies investigation and medical advice, and writing medication without the patient to remain hospitalized for a long time (for cases that do not require prolonged hospitalization) 2. Reducing costs the necessary material resources with, the introduction of electronic auction. 3. Introducing the concept of health management, need for hospital management, better management the four types of resources available (human resources, material resources, financial resources, time). 4. Increasing managerial capacity, through a competitive selection manager, will be combine short-term planning and the long term strategy (more flexible) to raise the efficiency of medical care. In this respect spaces allocated section of Pulmonology, will be reassembled in geriatric beds, and the space available, will be outsourced of other persons (individuals or corporate person), under the law where they will earn additional income. It is noted that the actual development costs are increasing. PMID- 21688579 TI - [Orthodontic treatment needs of students of the School of Dental Medicine in Iasi]. AB - Nowadays, people are becoming more aware of the importance of aesthetics in the integration of the individual in society. The purpose of this study was to determine the need for orthodontic treatment and their aesthetic perception in a group of medical students in Iasi. MATERIAL AND METHODS: The clinical study was conducted on a sample of 254 subjects. Data were collected after completion of the clinical examination.The clinical evaluation of the status we used orthodontic index IOTN (Index Orthodontic Treatment Needs) and a questionnaire on aesthetic appreciation by the student. All subjects included in the study were informed verbally about the purpose of the study noting the consent form. Statistical data processing was done with SPSS14.00 program for Windows. RESULTS: 20% of the subjects were dental IOTN 0, 33% of the value of a IOTN subjects, 28% of subjects IOTN value 2, 3 and 9% IOTN value IOTN 4 and 5 values of 4% and 6% respectively. The need for orthodontic treatment is greater in subjects with IOTN 4 and 5 and 10% of the subjects presented severe dento-maxillary. IOTN aesthetic component of the index is divided into three groups: Group 1 - 4 with 91% of subjects, group 5-7 with 5% of subjects and group 8-10 with 4% of subjects. CONCLUSIONS: The need for orthodontic treatment for subjects with IOTN 4 and 5 is mare. There is an increasing number of orthodontic treatment in young people, the primary motivation being to improve the aesthetic appearance. PMID- 21688580 TI - [Preprosthetic orthodontic treatment--retrospective statistic study]. AB - Orthodontic treatment as a help is the teeth movement made in order to facilitate the odontal,prosthetic and periodontal proceedures which are needed in the dentomaxilar and/or facial reabilitation. The aim of the study was to follow for 5 years which is the percentage of patients who asked for orthodontic treatment in the Orthodontic and Dentofacial Orthopedie Clinic from UMF 'Carol Davila'. We also followed the frequency related to the etiology of the loss of some teeth and also the relationship between the loss of the teeth and periodontal disease. In our country, the number of patients who ask for preprosthetic orthodontic treatment is lower comparing with Western and Northtern Europe, but the percentage is increasing due to the dentists calification. We can conclude by saying that the frequency of losing teeth by cavities is increased by age because all patients from the study group aged 35 and above lost their teeth from cavity etiology and the patients aged 18 and lower had genetic etiology in losing their teeth. PMID- 21688581 TI - [Assessment of the dyshomeostasis of the stomatognathic system in the elderly]. AB - Old age (over 65) is considered to be a fragile stage, a stage of involution and regression and very often raises multiple psychological and clinical problems. Just like the other stages of life, old age is characterized by certain psychological features, a certain psychical state that depends of the nervous central system's state and of past experiences of life as well. The effects of aging on the stomatognat system can be identified at all the system's elements; it is sometimes difficult to differentiate them from the physiological or pathological phenomena and their mechanisms. After analyzing the dishomeostasis of the stomatognat system from a gerontologic perspective it resulted that the stomatologic geroindex established in relation to the dental chronology is dominated by the prevalence of mono or bi maxillary total edentation to which stomatologic treatment is associated. In order to be a success, from a therapeutic, functional and aesthetic point of view, specific techniques must be used on elderly patients. These techniques have to be integrated into the aging process and must be related to the elderly patient's energy to adjust to changes, an energy that decreases with the passing of time. PMID- 21688582 TI - [Clinical and therapeutic aspects of early childhood caries and severe early childhood caries--clinical cases]. AB - ECC (early childhood caries) and SECC(severe early childhood caries), as a particularization of the dental caries during the early childhood (0-3 years) and the middle childhood (3-6 years), generate important oro-dental problems, with long-term impact, psycho-somatic, psycho-aesthetic, and social-behaviour, in little children as in adults. MATERIAL AND METHODS: 35 subjects (20 girls and 15 boys), were evaluated, aged between 3-6 years old, diagnosticated with ECC and SECC. The children were evaluated clinical, paraclinical and psycho-sociological in the Clinic of Paediatric Dentistry, Iasi, Romania. RESULTS: In this article, we present 3 clinical cases that show the implication of the socio-emotional factors that produce the early childhood caries, pacient C.L., 6 years old, pacient C.F., 5, 6 years old, and pacient A.D., 6 years old. CONCLUSION: In this study we have evaluated a heterogen structure with major impact on caries risk, clinical variability of the carioactivity in decidual dentition. It is known that more than 64% non-cavitary lesions that appear in a 2 year-old child develop to cavitary lesions in less than a year. PMID- 21688583 TI - [The value of 3-dimensional model in the reconstruction of mandibular segment defect. Observations in a clinical case]. AB - The use of autogenous bone graft in the reconstruction of mandibular defects following tumor extirpation is a reliable method for further functional rehabilitation. The exact amount of bone needed for harvesting is usually achieved by estimation of the gap and direct measuring. We present the case of a 51-years old patient referred to our clinic for a recurrent mandibular keratocyst. Besides clinical examination, the diagnosis work-up consisted of ortopantomography and computertomography (CT). Based on CT images, a graphic reconstruction of the mandible was realized and a 3D negative template of the scheduled mandibular defect was printed. The tumor was removed by a segmental resection of the mandible, while a fragment of bone tissue similar to the 3D model was harvested from the iliac crest. This bone fragment replaced the mandible defect and was fixed by means of four plates and titanium screws. No postoperative complications occurred. The pathology result confirmed the diagnosis of keratocyst. In conclusion, this method proved to be useful for precise planning of the shape and size of the graft in addition to exact placement of the graft in an acceptable prosthodontically position for future dental implant rehabilitation. PMID- 21688584 TI - [Histo-anatomical researches of two subspecies of Lavandula angustifolia Mill]. AB - AIM: The structure of the inflorescences of two subspecies of Lavandula angustifolia sL. angustifolia ssp. angustifolia and. L. angustifolia ssp. pyrenaica (D.C.) Guineat was studied to determine the range of variation in certain histo-anatomical characters. METHODS: The flower and leaf structure has been analysed on cross and superficial section using the usual techniques and methods applied in plant histo-anatomical research. RESULTS: In cross-section, inflorescence axis has a squared-shape contour, with four proeminent ribs. On the epiderme of inflorescence axis there are present stomata, trichoms and secretory hairs. The trichoms are pluricelullar and T-branched. The secretory hairs have a short pedicel and a uni-or bicellular head. CONCLUSIONS: The study revealed that there are only quantitative differences, referring to the degree of sclerification and lignification of mechanical elements and the size of the vascular bundles. PMID- 21688585 TI - [Contribution to the mobile phase selection for HPLC separation in order to make the identification and quantitative determination using the UV-VIS detector]. AB - The aim of this study is to elaborate a HPLC with UV detection method for the analysis of some AINS, method which can be transferred in a system with mass spectrometry detection. MATERIAL AND METHODS: More AINS drugs (diclofenac sodium, ibuprophen, ketoprofen, meloxicame, piroxicame, tenoxicame, nimesulide, phenylbutazone and indomethacin) were studied by UV spectrophotometry and by HPLC. RESULTS: The UV spectra of the studied AINS were recorded in pure solvents or in a mixture of solvents in order to establish the absorbance that will be used for HPLC detection in UV. To establish the optimum chromatographic parameters, the influence of the flow and of the composition of the mobile phase (both of the aqueous and organic phases) were studied too. CONCLUSIONS: The proposed procedure is easy and relatively with low cost regarding the MS detection. PMID- 21688586 TI - [Scoliosis screening using plantar pressure analysis]. AB - Earlier scoliosis detection is one of the orthopedics and family doctor challenge. Normally, the first observation about a child deformity should be done by the family doctor in order to announce or not the need of special investigations by a specialist. Usually, the so called idiopathic scoliosis is determined by some factor that interfere during the growing period and most of the time a wrong body attitude static and dynamic during daily activities (learning, sleeping, playing, sitting) and/or angular discrepancy or limb length discrepancy. MATERIAL AND METHOD: All those factors effects can be seen in a plantar pressure analysis evaluation witch soft give us information about the center of gravity of the body and the pressure on the foot that can be correlate in order to discover any articulation imbalance, even the spine deformity. RESULTS: It has been demonstrated through algorithms and case studies that a specific pattern of the plantar pressure analysis image is characteristic for the scoliotic persons. PMID- 21688587 TI - [Succinic acid production using mobile bed of immobilized Actinobacillus succinogenes in alginate]. AB - This work investigates the production of succinic acid by immobilized A. succinogenes cells, using a bioreactor with stirred/mobile bed of biocatalysts. MATERIAL AND METHOD: The experiments have been carried out for different sizes of biocatalysts particle, under substrate and product inhibitory effects. RESULTS: The results indicated that the inhibitory effects could be diminished by cells immobilization, the substrate consumption rate increasing with the increase of biocatalyst particle size. Moreover, the biocatalysts can be used for many fermentation cycles. PMID- 21688588 TI - [Correlational aspects of hematogenous osteomyelitis in children and adults]. AB - Osteomyelitis is an inflammation of the bone caused by an infecting organism. The infection may be limited to a single portion of the bone or may involve a number of regions such as the marrow, cortex, periostium and even the surrounding soft tissue. MATERIAL AND METHOD: This retrospective study included a number of 256 cases made by 152 children (56%) and 115 adults (44%). RESULTS: Hematogenous osteomyelitis appears at any age, most frequently in growth period, 85% cases until 16 years. This study relieve a high frequency of subacute (40.1%) and acute (31.1%) hematogenous osteomyelitis compare with chronic form (28.8%). Regarding the distribution of cases by sex, there are no differences between man and woman in chronic osteomyelitis, but subacute form is most frequently at men. The analysis of the cases distribution by location and sex relieve that at womans metaphysis and diaphysis are most interested (70.09%) but only 53.7% at men. Regarding the treatment, the distribution of cases relieve that chronic osteomyelitis generally cannot be eradicated without surgical treatment (sequestrectomy and resection followed by reconstruction with material. Those others forms, acute and subacute hematogenous osteomyelitis, were resolved with medical and surgical treatment, equally. CONCLUSION: Prompt diagnosis and early treatment are required to prevent further destruction and growth disturbance. Generally, a multidisciplinary approach is required, involving an orthopaedic surgeon, an infectious disease specialist and a plastic surgeon in complex cases with soft tissue loss. PMID- 21688589 TI - [The centennial of the Department of Microbiology Iasi--tribute to predecessors]. AB - 1892-1913 Bacteriological investigations conducted in Iasi's hospitals. * 1896 Up to date lectures featuring chapters on microbiology. 1899-1911 The first interim of the Department. 1 februarie 1912 Bacteriology Department de iure et facto: Alexandru Slatineanu. * 1938-39 Second intermediate period. * 1939-1942 Romanian inframicrobiology first started in Iasi : Stefan S. Nicolau. 1942-1946 Third intermediate period. * 1946 The Bacteriology Department redivivus: Professor Petru Condrea * 1953 The Discipline of Virology: Professor Mihai Duca. PMID- 21688590 TI - [Thrombin generation test: establishment of reference values according to age and tissue factor concentration is essential before implementation into the laboratory]. AB - The calibrated and automated thrombinography (CAT) developed by H.C. Hemker is a simple and reproducible technique that can be potentially used in coagulation laboratories. This test is able to record the complete thrombin generation in vitro, giving an interesting approach in the evaluation of the haemostatic potential at the individual level. We aimed to implement this test in our laboratory to follow patients with haemorrhagic or thrombotic pathologies. Haemorrhagic and thrombotic disorders are incompletely explored by the coagulation tests used presently in routine labs. These tests don't indeed reflect the real haemostatic phenotype of the patient neither the individual response to haemostatic treatments. Furthermore, they don't have any predictive value for the occurrence of haemorrhage and/or thrombosis. We report here reference values we established in a population of children and adults in pre analytical conditions easily applicable in coagulation labs. Platelet poor plasma is prepared by a double centrifugation and analyzed immediately or frozen at -80 degrees C for delayed analysis. PMID- 21688591 TI - [Febrile neutropenia at the emergency department of a cancer hospital]. AB - Febrile neutropenia is an important cause of fever in the cancer patient. When he/she is undergoing chemotherapy, the priority is to exclude that complication because it requires rapid administration of empiric broad-spectrum antibiotics. We have studied the rate and characteristics of febrile neutropenia in cancer patients consulting in a emergency department. We have conducted a retrospective study in the emergency department of a cancer hospital over the year 2008. Every patient with cancer and fever > or = 38 degrees C was included. Over 2.130 consultations, 408 were selected (313 patients) including 21.6% (88) for febrile neutropenia. A focal symptom or physical sign was present in the majority of the cases. 88% were assessed as low risk for severe complications and about half of them received oral antibiotics. There were only a few patients with a nude fever for which it was difficult to make a hypothetical diagnosis in order to administer a probabilistic treatment. The majority of the consultations lead to hospital admission. Over the 80 hospitalisations, 6 deaths occurred. There was no death among the patients who remained ambulatory. In conclusion, our study shows that febrile neutropenia is frequent in ambulatory cancer patients presenting with fever and that in the majority of the cases, it is associated with a low risk. In such a situation, ambulatory management is more and more often considered or, at least, a rapid discharge after a short admission in case of low risk febrile neutropenia. In that context, the role of the general practioner has to be emphasised and to facilitate the outpatient management, we propose an algorithm that requires validation. PMID- 21688592 TI - [Non Hodgkin's lymphomas: a major breakthrough with immunotherapy]. AB - Non hodgkin's lymphomas are a group of haematological malignancies in which spectacular progress has been made over the last ten years thanks to immunotherapy. Furthermore, the new WHO classification, based upon tumour immunology, the degree of tumour differentiation and cytogenetic abnormalities, has finally improved identification of each lymphoma and has enabled comparison of homogeneous populations between different clinical studies. The increase in the incidence of non hodgkin's lymphoma is related to the aging of the population and to other factors that are yet to be elucidated--a real challenge for the future. We have tried to offer an overview of the latest therapeutic advances, with a focus on (radio-) immunotherapy and haemopoietic stem cell transplantation. PMID- 21688593 TI - [Pulmonary granulomatous necrotizing vasculitis: an extra-intestinal manifestation of ulcerative colitis or Wegener's granulomatosis?]. AB - Respiratory symptoms are rare manifestations of ulcerative colitis as well as intestinal manifestations in Wegener granulomatosis. We report the case of a 17 year old man previously diagnosed as having ulcerative colitis who presented with diffuse thoracic pain. Hypermetabolic pulmonary nodules were discovered at the positron emission tomographic scan. Necrotizing granulomatous vasculitis was demonstrated at lung biopsy. In this paper, we describe the association between pulmonary nodules and ulcerative colitis and we discuss the possibility of an overlap syndrome between ulcerative colitis and Wegener granulomatosis. PMID- 21688594 TI - [Chronic maxillary rhinosinusitis of dental origin: report of 2 cases]. AB - Chronic maxillary rhinosinusitis of dental origin represents approximately 5 % of chronic maxillary rhinosinusitis. The diagnosis of this pathology is often delayed and mainly based on endoscopy and medical imaging. Its treatment is complex and requires the involvement of several teams. This article discusses two cases of chronic maxillary rhinosinusitis secondary to dental treatment. A literature review on the epidemiology, diagnosis, treatment and complications are also introduced. PMID- 21688595 TI - [Summary of the 6th Conference of postgraduate physicians of the Medical School of the ULB]. PMID- 21688596 TI - [Food allergies: clinical research and the contribution of biology]. PMID- 21688597 TI - [Oral desensitization: new features]. PMID- 21688598 TI - [Allergies and emergencies]. PMID- 21688599 TI - [The 12th Annual Conference on Thoracic Oncology]. PMID- 21688600 TI - [Henri Tagnon, initiator of the clinical oncology at the Institut Jules Bordet]. AB - The career of Henri Tagnon, medical doctor of the "Universite libre de Bruxelles", is devoted to medical oncology. Trained in the United States, he accomplished a brilliant career in the United States before coming back to Brussels where he created, in 1953, the first medical oncology department in Belgium at the Institut Bordet, cancer center of the Universite libre de Bruxelles. He was the initiator of the European Organization for Research and Treatment of Cancer. PMID- 21688601 TI - [A very old rhinolithe]. PMID- 21688602 TI - [Prevalence of Helicobacter pylori detected by real-time PCR in the subgingival plaque of patients with chronic periodontitis]. AB - BACKGROUND: Helicobacter pylori plays a significant role in gastric disease. The aim of the present pilot study was to evaluate the prevalence of H. pylori detected by real-time polymerase chain reaction (real-time PCR) in the sub gingival plaque of chronic periodontitis patients and to determine periodontopathogens profile of positive sites at H. pylori. METHODOLOGY: 109 subgingival samples collected from 17 subjects with chronic periodontitis were studied. The DNA was extracted from the oral samples and analyzed for the presence of H. pylori by real-time PCR (LightCycler) using 16S rRNA#120 primers which targeted the 16S rRNA gene. DNA from H. pylori DSM 4867 was used as a positive control. Seven bacteria implicated in chronic periodontitis were selected to explore the presence of these periodontopathic species in the oral positive sites for H. pylori. RESULTS: 16 of 109 samples (14.7%) were positives of H. pylori. All the positives sites were also positives to Fusobacterium nucleatum and Eikenella corrodens, 62.5% to Porphyromonas gingivalis, 31.25% to Treponema denticola, 25% to Prevotella intermedia, 12.5% to Aggregatibacter actinomycetemcomitans and 6.25% to Tannerella forsythia. CONCLUSIONS: H. pylori may be present in the subgingival plaque samples of patients with chronic periodontitis who are resident in a developing country. F. nucleatum and E. corrodens could coaggregate with H. pylori in the subgingival dental plaque. PMID- 21688603 TI - [Traditional practices and exploitation of medicinal plants in odontostomatology in Ivory Coast]. AB - Traditional medicine of which is a part traditional odontology occupies an important place within the African societies. It often constitutes the first appeal (80 % of the population) because of the high cost of the care, the incapacity of the human and material resources but also the faiths of the populations. This reality makes valuation of the traditional odontology a necessity. This study comes within this framework. It's a contribution for a better knowledge of practices and plants used in traditional odontology in Ivory Coast. So, after a presentation of some traditional knowledge's and their fields of application, the authors review studies made on the efficiency of plants in the prevention of tooth decay and the treatment of some oral diseases. The objective of these researches is to elaborate effective and financially affordable traditional improved drugs. PMID- 21688604 TI - [Early treatment of mandibular incisor-canine crowding]. AB - In the mixed dentition, lower incisor crowding can exist. He may be transitory or increase with dental arch evolution because of reduction of arch length by loss of leeway space. Early diagnosis allows the instauration of interceptive therapy, to ovoid extractions. Preserve or loss leeway space will depend of orthodontic space management. The clinical case presented in this article shows the interest of early treatment of incisor crowding to preserve arch length and make the leeway space available to resolve the crowding. PMID- 21688605 TI - [Factors of failure of prosthetic restoration of the acquired losses of substance of the jawbone and the mandible in sub-Saharan Africa]. AB - The obturating prostheses of the jawbone and the prostheses of rebuilding of the mandible make it possible to restore the losses of substance of the jawbone and of the mandible and to cure the functional and Aesthetic disorders which result from these losses of substance. The success of these prosthetic restorations can be compromised by technical, economic and cultural factors. The principal factors are the importance of the losses of substance, the reduced number of teeth, the poverty of the technical plate, the persistence of certain traditional concepts. The fight against these factors requires the promotion of therapeutic associations in maxillo-facial cancerology, the sensitizing of the populations to the early hospital consultations, the improvement of the technical plate of the prosthesis of the jawbone and the face, the facilitation of the access of the most underprivileged groups to the prosthetic restorations, the promotion of multi-field collaboration, the whole co-operation of the patient throughout the treatment and the follow-up postprothetic. PMID- 21688606 TI - [Does Lp-PLA2 determination help predict atherosclerosis and cardiocerebrovascular disease?]. AB - Thorough control of risk factors is pivotal for cardiocerebrovascular diseases. As classic risk assessment accounts for only 50% of risk variability and due to the role of inflammatory processes in endothelial dysfunction and atherosclerotic plaque rupture, it is necessary to identify new biomarkers for risk prediction. In addition to the inflammatory marker high sensibility C-reactive protein (hs CRP), lipoprotein associated phospholipase A2 (Lp-PLA2) is gaining increasing significance, since it is directly involved in the pathogenesis of atherosclerotic plaque progression. Lp-PLA2 is highly specific for vascular inflammation, has low biological variability, and plays a causative role in atherosclerotic plaque inflammation. It belongs to the group of intracellular and secretory phospholipase enzymes that can hydrolyze sn-2 phospholipid ester bond of cellular membranes and lipoproteins. Lp-PLA2 enzyme is formed by macrophages and foam cells in atherosclerotic plaque, and is associated primarily with LDL particles in blood. Lp-PLA2 that is bound to LDL is the sole enzyme responsible for hydrolysis of oxidized phospholipids (oxPL) on LDL particles. Lp-PLA2 hydrolyzes oxPL at the surface of lipoproteins, but has weak activity against non oxPL. Lp-PLA2 is also the enzyme that hydrolyzes oxPL on HDL particles, where it may have a role in the antioxidative function of HDL. The distribution of Lp-PLA2 between LDL and HDL particles depends on the extent of Lp-PLA2 glycosylation, which may affect the activity of Lp-PLA2 in plasma. Stable atherosclerotic plaques contain few inflammatory cells and a small amount of Lp-PLA2. In contrast, unstable plaques most often do not have significant impact on arterial lumen but may be detected by its thin connective tissue cap, low collagen and high lipid content. A distinguishing factor between stable and unstable atherosclerotic plaque may also be the presence of activated inflammatory cells and increased Lp-PLA2 concentration in unstable plaque. These new insights indicate that Lp-PLA2 may be a risk factor, which is important for the formation of atherosclerotic plaque but also for its rupture. The purpose of applying markers of inflammation is to improve stratification of patients at risk, so that treatment intensity may be adjusted to the risk level. Lp-PLA2 inhibition is associated with decreased cytokines. Lipid-affecting drugs stabilize atherosclerotic plaque by reducing the central lipid core, decreasing macrophage infiltration, and thickening of the connective tissue cap. These drugs reduce Lp PLA2 concentration and the frequency of cardiocerebrovascular events as well. Besides acting as a specific marker of atherosclerotic plaque inflammation, Lp PLA2 has a significant prognostic value because of its direct role in the formation of rupture-prone atherosclerotic plaque, unlike classic risk factors, for example lipid measurement or vascular imaging, which do not directly estimate acute ischemic potential in the arterial wall. Studies have demonstrated correlation between increased Lp-PLA2 concentrations and enhanced risk of cardiocerebrovascular events, even after multivariate adjustment to classic risk factors. In addition to its high specificity for vascular inflammation, Lp-PLA2 concentration is stable in terms of time, unlike, for instance, CRP levels. Lp PLA2 has been confirmed as an independent risk predictor, which is complementary to hsCRP. It could be used in clinical practice for improved risk assessment in patients with transient cardiocerebrovascular risk, particularly in those with metabolic syndrome (obese patients with mixed dyslipidemia, hyperglycemia, insulin resistance, and arterial hypertension). Lp-PLA2 levels allow for further risk stratification of high-risk patients into a very high risk group where more aggressive therapy is recommended, as well as the achievement of LDL-cholesterol levels < 2.5 or, even better, < 2.0 mmol/L as a feasible therapeutic target. Similar to hsCRP, the levels of Lp-PLA2 are reduced by lipid-affecting drugs, while its low concentrations are associated with a very low risk of cardiocerebrovascular events both in low- and high-risk population. According to recent American guidelines for assessing the risk of cardiovascular disease, Lp PLA2 determination is recommended as an additional marker to the classic risk assessment in patients with moderate and high risk. PMID- 21688607 TI - [Quality-of-life of adolescents with acne vulgaris]. AB - OBJECTIVE: To determine the quality of life in adolescents with acne vulgaris in relation to the severity of clinical picture and sex using the Skindex-29 general questionnaire. PATIENTS AND METHODS: Using a sectional study, the quality of life was analyzed in 90 adolescents of both sexes, aged 16 to 21 years, who were suffering from acne vulgaris. The study was conducted between January 1, 2008 and January 31, 2009, at Department of Dermatovenereology, Dr. Irfan Ljubijankic Cantonal Hospital in Biha6. According to the type of efflorescence, its localization and severity of clinical features, respondents were classified in three groups: group 1 consisted of adolescents with acne comedonica, group 2 with acne papulopustulosa, and group 3 with acne conglobata. The quality of life in these adolescents suffering from acne vulgaris was evaluated by using the general Skindex-29 questionnaire consisting of 30 questions grouped into three scales (scale of emotions, symptom scale, and scale of social and physical functioning) about the psychological impact of acne on the quality of life. RESULTS: In the study group, there were 54 (60%) female and 36 (40%) male respondents, mean age 17.5 (range 15.6-20.6) years. Of the total number of patients with acne vulgaris, nine (4 female and 5 male; 10%) had acne comedonica (group 1), 72 (46 female and 26 male; 80%) acne papulopustulosa (group 2) and nine (4 female and 5 male; 10%) acne conglobata (group 3) (p > 0.95). Skindex-29 values expressed as mean +/- SD or median (range) in groups 1,2 and 3 were as follows: on the scale of emotions 43.1 +/- 22.2, 60.4 +/- 20.1 and 52.5 +/- 28.7 (p = 0.084); on the scale of symptoms 26.5 +/- 15.4, 49.0 +/- 20.5 and 42.95 +/- 26.1 (p = 0.039); and on the scale of functioning 23.4 +/- 24.6, 36.0 +/- 23.2 and 34.8 +/- 30.9 (p = 0.341), with cumulative score of 31.0 +/- 10.5, 47.5 +/- 12.0 and 43.44 +/- 8.8 (p = 0.069), respectively. Skindex-29 values were expressed as median (range) in women and men in all three groups, as follows: women, scale of emotions 44.0 (27.5-60), 64.0 (10-90) and 62.5 (5-83) (p = 0.25); scale of symptoms 32.7 (21.5-42.4), 54.2 (17.6-90) and 63.5 (17.8-92) (p = 0.17); scale of functioning 22.2 (2-46.5), 39.2 (0-90) and 51.6 (0-83) (p = 0.31); and men, scale of emotions 30.0 (22.5-90), 55.5 (7.5-100) and 40.2 (30-97.5) (p = 0.26); scale of symptoms 11.9 (4-50), 54.0 (0-75) and 28.5 (17.8-42.8) (p = 0.003); and scale of functioning 13.0 (5-77), 31.7 (0-84) and 14.6 (4.5-72.9) (p = 0.58). CONCLUSION: Acne vulgaris affects the quality of life in adolescents involved regardless of the severity of the clinical picture, with a pronounced impact in women. PMID- 21688608 TI - [Adipocytokines as mediators of metabolic role of adipose tissue]. AB - The discovery of adipocytokines, products of adipose tissue, has been a turning point in the understanding of metabolic disorders. Historically considered as a passive depot of energy, adipose tissue has become an important active participant and adipocytokines crucial mediators of its metabolic role. Among a number of adipose tissue products, leptin and adiponectin are exclusively secreted by adipocytes. Leptin regulates energy homeostasis and interferes with several neuroendocrine and immune functions. Adiponectin is an intriguing adipocytokine with its serum level inversely correlated with fatness. It has been related to enhanced insulin sensitivity, anti-inflammatory and anti-atherogenic actions. Recent investigations have also emphasized the important role of resistin, visfatin, retinol binding protein 4, and of a whole list of cytokines like interleukin-6, tumor necrosis factor a, plasminogen activator inhibitor-1, or a chemokine, monocyte chemoattractant protein-1. The fact that secretory balance of adipose tissue in obesity is shifted towards the proinflammatory spectrum has supported the hypothesis on the development of dysfunctional adipose tissue in these circumstances. It contributes to the state of chronic inflammation and insulin resistance, and it seems to be a fundamental link between obesity and atherosclerosis. PMID- 21688609 TI - [Palliative medicine--linkage of expert human care for the terminally ill and medical ethics]. AB - Palliative medicine is a new branch of medicine dealing with optimal quality of life and death, and is primarily a medical area of interest. Palliative care is a care provided by interdisciplinary palliative team. Let us remember that palliative care is a specific form of medical care for patients in the terminal phase of life. It is an approach to improve the quality of life of patients faced with fatal diseases, and of their families. Palliative care starts when classic methods of treatment have been exhausted, or when the symptoms of a malignant disease reach a level that the patient can hardly endure. It encompasses three areas: alleviating the symptoms, giving psycho-sociological support to patients and their caregivers, and dealing with ethical problems concerning the end of life. Particularly important is the ethics of palliative care, because it is focused on the aspects of care aimed at the patient and critical decision-making. The decisions made in palliative medicine require moral, legal and medical judgments. At the same time, one must strike a balance between clinical aspects of care and the patient's autonomy regarding his wishes, beliefs, and finally decisions about his own medical treatment. Ethical aspects of decision-making cannot be separated from clinical circumstances in the individual case, in the same way as medical decision-making cannot neglect the four (bio)ethical principles: beneficence, non-maleficence, autonomy of the person, and justice. PMID- 21688611 TI - [Laparoscopic diagnosis and desincarceration of inguinal Richter hernia: a case report]. AB - In the cases of incarcerated Richter hernia the diagnosis is difficult especially for obese patients. Laparoscopic diagnostics and desincarceration, can be combined with mini laparotomy in lieu of bowel resection and open hernioplasty, or conversion to classic laparotomy and open hernioplasty. Here is presented a case of incarcerated Richter inguinal hernia managed through the combination of laparoscopy, mini laparotomy for segmental bowel resection and open hernioplasty. PMID- 21688610 TI - [Changes in the activity of sympathetic-adrenal medullary system and hypothalamic pituitary-adrenal system in humans exposed to psychogenic stressors and their effects on immunoreactivity]. AB - This paper gives an account of the functioning of the two systems in different stress induced situations. The activation of the sympathetic-adrenal medullary system is accompanied by the release of catecholamines, while the increased activity of the hypothalamic-pituitary-adrenal system results in the increased release of corticosteroids, especially cortisol. The role of the sympathetic adrenal medullary system was investigated in immunologic changes induced by laboratory stressors. In the real, as in laboratory conditions, the effects of different stressors on the level of cortisol were studied, as it is the final product of the hypothalamic-pituitary-adrenal system activity. Additional (negative) effects on the functioning of these systems could induce some variables, as an increased consumption of alcohol, smoking, and sleeping disorder. Furthermore, the methodological shortcomings and the selection of subjects in previous studies are discussed. Previous results are also discussed, such as the immunosuppressive effects of cortisol, as well as the mediator and moderator variables in relation to stress and immunoreactivity. PMID- 21688612 TI - [Prevalence of hepatitis B, hepatitis C and HIV among injecting drug users treated outpatiently and in therapeutic community in Brod-Posavina County, Croatia]. AB - Blood transmitted diseases (hepatitis B, hepatitis C, HIV) are major public health problems. Drug users, especially injecting drug users (IDU), are by nature of their illness, a risk population for these diseases. The aim of the study was to determine the prevalence of blood transmitted diseases among IDU in the Brod Posavina County due to shared use of needle/syringe in outpatients and those treated in a therapeutic community, and to compare the results obtained. First, we analyzed data separately for hepatitis B and C, and then we selected patients with coinfection. The prevalence of HBsAg positive patients in both groups was significantly lower than the prevalence among drug addicts in Croatia (1.16% and 3.28% vs. 13.2%). Significant correlation was found in outpatients with anti HBs+anti-HBc antibody (p < 0.05) between those who shared needles/syringes and those who did not. Significant correlation was also found among patients treated at therapeutic community (p < 0.01). Comparing the patients treated as outpatients and in therapeutic community, significant correlation was only found between vaccinated patients. HCV positive outpatients had lower and drug addicts in therapeutic communities significantly higher prevalence as compared with the prevalence of HCV among addicts in Croatia (41.86% and 60.66% vs. 44.6%). A significant correlation between those who shared needles/syringes and those who did not was found in both outpatients and patients treated in therapeutic community (P < 0.01). Comparison of HCV positive patients treated as outpatients and those in therapeutic community also yielded significant correlation (p < 0.05). The prevalence of HBV/HCV coinfection was similar in both groups of patients. Significant correlation (P < 0.05) was only found in the group of patients with anti HBC/anti HCV antibodies. There was no HIV-positive patient in any group. We also found a low prevalence of HBsAg/anti-HCV in both groups of patients (1.16% and 2.46%). Upon establishing a network of centers for the treatment of addicts, constant work on prevention and education, systematic testing and vaccination, and implementation of harm reduction programs, we noticed a trend of reducing the number of people with HBV and HCV in the younger population of addicts. PMID- 21688613 TI - [Central sleep apnea (Ondine's curse syndrome) in medullary infarction]. AB - Ondine's curse syndrome primarily refers to cases with congenital central alveolar hypoventilation, but the term can also be used for acquired cases and implies central sleep apnea that occurs as a manifestation or complication of focal lesion in the area of the dorsolateral segment of medulla oblongata. It occurs rarely, but can lead to fatal outcome. Based on our own case report, the aim of this article is to review its clinical symptoms, and appropriate diagnostic and therapeutic procedures. We present a patient who had symptoms of vascular lesion of the dorsolateral segment of the medulla, which was verified by magnetic resonance imaging. On day 12 of his hospital stay, in the early morning, rapid development of coma was observed, which was an expression of serious respiratory failure with dominant hypercapnia. In the beginning, urgent intubation and mechanical ventilation were necessary, while in the later course of the disease breathing was assisted by noninvasive methods of Bilevel Positive Airway Pressure (BiPAP) and Continuous Positive Airway Pressure (CPAP). Throughout the night, polygraph recording confirmed the diagnosis of the central sleep apnea syndrome. The course of the disease was favorable, with a very slow but constant improvement of respiratory function. According to literature data, the disease course is not always favorable. There are published cases where it was concluded that ventilatory support was no longer needed but after a long period of normal breathing hypoventilation and death occurred suddenly during sleep. The treatment of central hypoventilation consists of ventilatory support, but there were also attempts of medicamentous treatment with the common aim of raising alertness and reactibility of the automatic breathing center. It is important to emphasize that patients with the risk of central sleep apnea should not be supplied with oxygen without arterial blood gas monitoring because of the possibility of delaying the right diagnosis. The use of oxygen in patients who already have hypercapnia due to hypoventilation could further intensify hyporeactivity of the breathing center and lead to respiratory arrest. PMID- 21688614 TI - [Endoscopic findings and characteristics of NSAIDs-induced mucosal injuries in the upper/lower gastrointestinal tract]. PMID- 21688615 TI - [Low-dose aspirin (LDA)/nonsteroidal anti-inflammatory drugs(NSAIDs)-induced gastrointestinal injury in Japan]. AB - Low-dose aspirin (LDA) and nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed in Japan mostly due to increasing elderly population. Since LDA/NSAIDs cause gastrointestinal injury, serious side effects such as bleeding accompanied with their usage have been frequently reported. Awareness of such problems prompted clinical trials to facilitate a more effective approach to prevent LDA/NSAIDs-induced gastrointestinal ulcer. Two drugs recently approved for health insurance reimbursement, celecoxib, a cyclooxygenase (COX)-2 specific inhibitor and low-dose lansoprazole for prevention of recurrent peptic ulcer due to LDA/NSAIDs will be instrumental in mitigating the gastrointestinal injuries. However, continuous, intensive educational programs will be required to the change in the prescription behaviors of the general physicians. Furthermore, we need to search for effective measures to detect and prevent mid and lower gastrointestinal injury caused by LDA/NSAIDs which account for about 30% of all GI bleedings. PMID- 21688616 TI - [Japanese epidemiologic investigation for non-steroidal anti-inflammatory drugs induced ulcers]. AB - This review summaried epidemiologic investigation for non-steroidal anti inflammatory drugs (NSAIDs)-induced ulcers to focus on the Japanese evidence. In Japan, national health insurance does not cover procedures that prevent or lower the risk for NSAIDs-induced ulcer. In NSAIDs treatment to patients with risk factors, it is desirable to administer antiulcer agents. However, in Japan, there are no large-scale studies on the efficacy of co-medication such as proton pump inhibitors, prostaglandin analogs (misoprostol) or histamine-H2 receptor antagonists or on the effectiveness of H. pylori eradication or selective COX-2 antagonists. In the future, large-scale clinical studies should be conducted to accumulate high quality evidence including cost-effectiveness and overall safety including cardiovascular events, because Japanese differ from Westerners in several genetical or acquired factors. PMID- 21688617 TI - [Prophylaxis and treatment of NSAID-related peptic ulceration: present status and prospects]. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) including low dose aspirin have been widely prescribed to elderly patients for treatment of OA and RA as well as for primary and secondary prevention of atherosclerotic thrombotic events. Nonetheless, NSAIDs' effectiveness in the treatment and prophylaxis of such diseases may be limited by the risk of upper gastrointestinal (GI) complications such as ulceration, hemorrhage and perforation. NSAID administration is associated with several-fold increase in the upper GI bleeding in the Japanese general population. Such GI risk is known to increase in patients with a prior history of peptic ulcer disease, advanced age, and concomitant use of corticosteroids, clopidogrel, or anticoagulants with NSAIDs or aspirin. Mechanisms of NSAID-induced GI injury are believed to be through local effects within the GI mucosa that cause topical injury and through systemic inhibition of cyclo-oxygenase (CO) resulting in depletion of mucosal protective prostaglandins. Herein, we focus on the strategy to manage NSAID- or aspirin-induced peptic ulcerations and their complications, based on the scientific evidence. PMID- 21688619 TI - [Pathologic condition and prognosis of NSAids ulcer]. AB - Recently, H. pylori infection rate has decreased and non-steroidal anti inflammatory drugs(NSAIDs including aspirin) induced ulcers have increased more and more with aging in Japan. Pathological and clinical conditions of NSAIDs ulcer are different from that of H. pylori-related peptic ulcer. In other words, main pathologic condition of NSAIDs ulcer is not only gastric acid secretion but also destruction of defense mechanisms of upper gastrointestinal mucosa, because NSAIDs inhibit both cyclooxygenase (COX)-1 and COX-2 which block production of prostaglandins, consequently resulting in impairing gastroduodenal protective factors. Moreover, it is not rare that NSAIDs ulcer has serious complications such as bleeding and/or perforation. These should be paid attention in NSAIDs users in routine practice. PMID- 21688618 TI - [Pathogenesis of NSAIDs-induced gastrointestinal ulcers]. AB - It is necessary for some conditions to occur at the same time so that NSAIDs induced gastrointestinal ulcers occur. The definite condition that is necessary for the development of ulcers by NSAIDs is the direct injury with NSAIDs and the presence and influences of the luminal factors, including gastric acid, bacteria, and bile acids. The pathologic central mechanism is the inhibition of cyclooxygenase, the disturbance of microcirculation and pro-apoptotic signaling. At all events, it is a theme for gastroenterologists to establish a mean to prevent the gastrointestinal ulcers induced by NSAIDs. PMID- 21688620 TI - [Pharmacology of preventive and therapeutic drugs for NSAIDs ulcers in the gastrointestinal tract]. AB - NSAIDs have been associated with gastrointestinal (GI) toxicity. Proton pump inhibitors (PPIs) may be the first line in the treatment as well as in the prevention of NSAIDs-induced ulcers. Although there are no definite differences among three PPIs(omeprazole, lansoprazole, and rabeprazole) in the clinical field, it should be considered to inhibit gastric acid secretion rapidly and strongly in case of the treatment with acute gastric ulcer in patients who should be continued to be NSAIDs treatment. Recently, the serious problem of NSAID induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and balloon enteroscopy are available for the detection of small intestinal lesions. Further understanding of the pathogenesis of NSAID-induced intestinal ulcers is important to enable the development of novel and effective preventive strategies. PMID- 21688621 TI - [Clinical features and diagnosis of non-steroidal anti-inflammatory drugs induced ulcers of the stomach]. AB - Helicobacter pylori (H. pylori) infection and non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin induce serious gastrointestinal ulcer and bleeding. Also both H. pylori infection and NSAIDs or aspirin use independently and significantly increase the risk of peptic ulcer and its complications. Interestingly, it has been reported that no evidence exists that reducing the dose or using modified release formulations such as enteric-coated of aspirin would reduce the incidence of ulcer bleeding. Selective COX-2 inhibitors use shows a low relative risk of ulcer bleeding than NSAIDs. However, when combined with aspirin, the differences between selective COX-2 inhibitors and NSAIDs tend to disappear. NSAIDs/aspirin dominantly develops multiple ulcers from the angulus to the antrum regardless of H. pylori infection. In contrast, the irregular shape of ulcer is more frequently detected in patients taking NSAIDs in comparison with H. pylori-associated ulcer, but the association was not seen in cases taking aspirin. This result indicates that the mechanism of ulcer formation may be different between NSAIDs and aspirin. PMID- 21688622 TI - [Guideline of prevention and treatment for NSAIDs induced ulcer]. AB - The guideline for peptic ulcer treatment was reported by Japanese Society of Gastroenterology in 2009. In the guideline, 23 clinical questions were chosen for NSAIDs induced ulcer. Nine questions out of them were related to the prevention, eight were low dose aspirin, three were COX-2 inhibitors and three were the treatment. The recommendations were made for these questions according to evidence-based medicine. In the recommendations, the grade of recommendation, the evidence level of literatures and the applications to Japanese medical insurance were mentioned. PMID- 21688623 TI - [Proton pump inhibitor H2 receptor antagonist]. AB - Recently, Japanese guidelines for the treatment and prevention of peptic ulcers were established by the Japanese Society of Gastroenterology. Herein, we focus on proton pump inhibitor(PPI) and H2 receptor antagonist (H2RA) for prophylaxis and treatment of peptic ulcer associated with NSAIDs including low dose of aspirin. Double dose of H2RAs are effective at preventing chronic NSAID related ulcers, however, the effect is not superior to PPI. Full-dose misoprostol and PPI are clinically equivalent, although the potential adverse effects of misoprostol are a major cause of poor compliance. Overall, PPIs have the best profile of efficacy and side-effects for the healing and prevention of NSAID-associated ulcers, especially in the patients with high risk, such as history of peptic ulcer. PMID- 21688624 TI - [Efficacy of prostaglandin derivatives and mucoprotective drugs in treatment and prevention for NSAIDs-induced ulcer]. AB - Deficiency of prostaglandins (PGs) by non-steroidal anti-inflammatory drugs (NSAIDs) causes a loss of gastroduodenal mucosal integrity, leading to development of ulceration. PG derivatives such as misoprostol and enprostil have been proven effective in prevention and treatment of NSAIDs-induced gastroduodenal ulcers. Although side effects such as diarrhea limit the use of PG derivatives, the efficacy of these drugs in NSAIDs-induced injuries is approximately equal to that of proton pump inhibitors. Mucoprotective drugs such as rebamipide also have been reported to be effective for prevention of NSAIDs induced ulcers. Since misoprostol and some mucoprotective drugs can prevent NSAIDs-induced small intestinal injuries, these drugs, especially misoprostol, should be used as first-line therapy for NSAIDs-induced gastrointestinal injuries with attention paid to the side effects. PMID- 21688625 TI - [Points that should be considered for selecting drugs for the prevention and treatment of NSAIDs-related ulcers]. AB - Many factors including past-history of ulcers, co-administration of glucocorticoid, and age of a case are important for selecting anti-ulcer medications to prevent the occurrence of gastro-duodenal ulcers during the administration of non-steroidal anti-inflammatory drugs (NSAIDs). In Japan, lansoprazole is a first line therapeutic drug for high risk patients with a past history of ulcers, since lansoprazole is approved by the Japanese regulating agency to be administered to chromic NSAIDs users with a history of gastro duodenal ulcers for preventing the recurrence of ulcers. Other high risk patients without ulcer history may be treated by the preventive administration of misoprostol. When misoprostol can not be used because of side effects etc, rebamipide and histamine-H2-recepter antagonists like famotidine are considered to be good options. For the treatment of NSAIDs-related gastro-duodenal ulcers, proton pump inhibitors or prostaglandins are selected if NSAIDs administration can not be interrupted. For the prevention and treatment of NSAIDs-related intestinal ulcers, the information we have is not clear enough for the appropriate drug selection. PMID- 21688626 TI - [The significance of H. pylori eradication in NSAIDs ulcer]. AB - The significance of H. pylori eradication for NSAIDs induced gastroduodenal ulcer has not been clarified. NSAIDs and H. pylori infection are independent causal factors for gastroduodenal mucosal injuries. However, the interaction between these two factors is complicated. H. pylori eradication can reduce the risk of NSAIDs induced ulcer in NSAIDs naive patients. However, H. pylori eradication is not recommended in NSAIDs user because of no ulcer suppression and ulcer healing delay. In prevention of NSAIDs induced ulcer recurrence, H. pylori eradication plus PPI treatment is necessary. PMID- 21688627 TI - [The region of orthopaedic surgery and rheumatology]. AB - NSAIDs can cause serious GI complications such as peptic ulcers, perforations and bleeds and this risk increases with age, concurrent use of other medications, and probably with the duration of therapy. The recommendation that in patients with increased GI risk, either a COX-2 selective agent or a non-selective NSAID with co-prescription of a PPI or misoprostol for gastroprotection should be considered is supported by evidence from a systematic review of RCTs. There was no evidence for similar gastroprotection with H2 receptor antagonists and treatment with misoprostol is associated with an increase risk of diarrhea. The GI protection that is associated with the use of COX-2 selective agents is largely lost when low-dose aspirin is administered concurrently for CV prophylaxis. PMID- 21688628 TI - [Prevention and treatment of low-dose aspirin induced gastric ulcer in coronary artery disease after coronary intervention]. AB - Low-dose aspirin has been increasingly used to prevent cardiovascular and cerebrovascular disease through its antiplatelet effect, mainly in the patients with ischemic heart disease, but aspirin has been associated with gastrointestinal injuries, especially peptic ulcer bleeding. However, discontinuation of aspirin may cause cardiovascular and cerebrovascular events. Therefore, high-risk patients for peptic ulcers should be prevented with anti secretory drugs, such as proton pump inhibitor of H2-receptor antagonists, because ulcer bleedings in patients with treatment of low-dose aspirin can be serious. PMID- 21688629 TI - [Management of NSAIDs and low-dose-aspirin-induced ulcer in patients with cerebral infarction]. AB - Use of low-dose aspirin (LDA) is increasing with guideline recommendation for stroke prevention. The risk of gastrointestinal symptoms and bleeding with aspirin is dose-dependent, but still increases even at low doses. The principal treatment for NSAIDs-induced ulcer is discontinuation of NSAIDs use. However, discontinuation of LDA administration in stroke patients can increase the risk of stroke recurrence. Therefore, use of LDA cannot easily be discontinued. In patients who experience gastric intolerance to aspirin, options are to reduce the dose of aspirin to the minimum effective dose; to change to dispersable or enteric-coated preparations; to add concomitant gastro-protective drugs such as antacids, misoprostol, proton pump inhibitors, or H2-receptor antagonists; or to change to another antithrombotic agent: clopidogrel, cilostazol or warfarin if appropriate. PMID- 21688630 TI - [Treatment and prevention of NSAIDs-induced gastrointestinal injury--the role of gastroenterologist]. AB - According to many clinical researches, it is obvious that patients taking NSAIDs including low-dose aspirin have upper GI injury frequently than those without. Recently, the GI event of those medicines becomes more serious clinical problem in Japan in which aging population is getting larger year by year. Evaluation of GI risk and appropriate use of anti -ulcer drugs, especially proton-pump inhibitors, are recommended for the prevention. Additionally, the close communication and cooperation between doctors who prescribe the medicines and gastroenterologists is essential for minimizing such adverse reaction. Here we describe on the role of gastroenterologists on the prevention of GI event caused by NSAIDs and aspirin. PMID- 21688631 TI - [Actual status and vision of NSAIDs-induced intestinal injuries]. AB - Recent studies, included using capsule endoscopy and balloon endoscopy, have revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) can cause a variety of abnormalities in the intestine. Several reports show that NSAIDs included acetylsalicylic acid can induce small intestinal injuries with high prevalence in patients taken these drugs. These reports have shown that the preventive effect of proton pump inhibitors (PPIs) does not extend to the small intestine, suggesting that concomitant therapy may be required to prevent small intestinal side effects associated with NSAIDs use. Recently, several randomized controlled trials evaluated the preventive effect of mucoprotective drugs and cyclooxygenase 2 selective inhibitors against traditional NSAIDs-induced small intestinal injury. However, those studies were limited to a small number of subjects and tested short-term NSAIDs treatment. Therefore, further extensive studies are clearly required to ascertain the beneficial effect of these drugs. PMID- 21688632 TI - [Pathogenic mechanism of NSAIDs-induced mucosal injury in lower gastrointestinal tract]. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for musculoskeletal pain and inflammation. Because low-dose aspirins reduce the risk of coronary and cerebrovascular events, consumption of them are rising worldwide. However, NSAIDs induce ulcers and bleeding not only in upper gastrointestinal tract but also in the small and large intestine. The recent advanced modalities such as double balloon endoscopy and video-capsule endoscopy enable the detection of NSAIDs-induced mucosal injury in the small intestine accurately. Topical direct injury of NSAIDs and cyclooxygenase (COX) inhabitation resulting in prostaglandin (PG) suppression are two main pathogenic mechanisms of lower gastrointestinal damage. Further analysis for the mechanism of effect and side effect of NSAIDs are warranted to develop the therapeutic and prevention method of NSAIDs-induced lower gastrointestinal mucosal injury. PMID- 21688633 TI - [The diagnosis and clinical feature of NSAIDs-associated enteritis]. AB - Double-balloon endoscopy (DBE) is very useful for the diagnosis and treatment of non-steroidal anti-inflammatory drugs (NSAIDs)-associated enteritis. In cases of long-term NSAIDs administration, aphtha, specific diaphragm-like strictures and circular ulcers are pointed out into details by DBE. Even if on-demand use of NSAIDs, some patients have small bowel injuries when NSAIDs are administered for over several years. Moreover, there are variations for the type and indication of NSAIDs among patients. The cytolysis image and the apoptosis in the base of mucosa were reported as the characteristic histological findings of NSAIDs associated enteritis. In consideration of widespread use of NSAIDs, a strategy for the management of NSAID-associated enteritis should be discussed and established. PMID- 21688634 TI - [Prevention and treatment of NSAIDs-induced small intestinal lesions]. AB - Recently, the serious problem of non-steroidal anti-inflammatory drugs(NSAIDs) induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and double-balloon enteroscopy are available for the detection of small intestinal lesions. We found some of mucoprotective agents, PPIs and H2-blockers prevented NSAIDs-induced small intestinal lesions in rat. The clinical trials suggested that some of mucoprotective agents and prostaglandin analog, not acid suppressants inhibited small intestinal lesions in healthy volunteers. Considering the cost benefit and the load of patients, we hope that one drug can prevent NSAIDs-induced lesions from esophagus to small intestines. We should use mucoprotective drugs well for these diseases. PMID- 21688635 TI - [Characteristics of nonsteroidal anti-inflammatory drugs-induced colopathy]. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) induce a broad spectrum of toxicologic manifestations throughout the gastrointestinal tract, including the large intestine. Even though several studies indicated that NSAIDs can cause perforation and bleeding of diverticula or they exacerbate inflammatory bowel disease, NSAIDs possibly damage the normal large intestine; such involvement has been characterized by ulceration, stricture and colitis. And NSAIDs might be an etiological factor in collagenous colitis. While severe stricture, which has been referred to as "diaphragm-like stricture", has been known to be the most characteristic phenotype of the colonic involvement, NSAIDs-induced colonic ulceration should be regarded as a preceding stage for the stricture formation. Further epidemiological studies and therapeutic trials are warranted to clarify NSAIDs-induced colopathy. PMID- 21688636 TI - [Treatment and prevention of NSAIDs induced colonic mucosal lesions]. AB - Individuals who regularly take NSAIDs have a significantly higher incidence of lower intestinal lesions when compared with non-NSAID takers. Based on this understanding, NSAID induced colonic mucosal lesions are found in about 3% of NSAID takers and this risk can increase further with the duration of NSAID ingestion. The essential step in the treatment of NSAIDs induced colonic lesions is discontinuation of NSAID ingestion, which is factored in the diagnostic criteria for NSAID induced colonic mucosal lesions. Accordingly, subjects who adhere to the recommended prognostic criteria achieve a rapid mucosal healing. However, there is lack of knowledge on medications which should be effective both in promoting healing of the lesions and also preventing a future relapse of NSAID induced colonic lesions. Based on this thinking, further studies and therapeutic trials are warranted to better treat not only gastro-duodenal ulcers but also lower intestinal lesions associated with NSAIDs. PMID- 21688637 TI - [Can COX-2 selective inhibitor prevent NSAIDs-related GI toxicity?]. AB - The gastrointestinal (GI) toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) is well recognized. Risk factors for NSAIDs-related GI toxicity includes advanced age, generalized disease, past history of peptic ulcer, concomitant use of steroid, duplicated use of various NSAIDs. The guidelines recommended using a proton pump inhibitor or a prostaglandin for the treatment and prevention of NSAIDs-related GI toxicity. The updated guideline added cyclooxygenase-2 (COX-2) selective inhibitors, which have demonstrated equivalent efficacy to nonspecific NSAIDs in the management of arthritis and pain, to the prevention strategy. Several large, randomized, clinical trials compared the rates of serious GI events in patients taking COX-2 selective inhibitors and nonspecific NSAIDs but came to different conclusions. More recently, the overall safety profile of COX-2 selective inhibitors and traditional NSAIDs has come under intense debate especially due to the recently shown cardiovascular risk of COX-2 selective inhibitors. Therefore, it is essential to determine the actual risk of GI toxicity with COX-2 selective and traditional NSAIDs alone or combined with other compounds from independent Japan studies. PMID- 21688638 TI - [Physiological importance of calpains in gastric mucosal defense]. AB - The continuous and/or improper ingestion of irritants, including alcohol, NSAIDs, and Helicobacter pylori, often leads to serious gastropathies, affecting a wide range of people. A complex gastric defense system works to protect against these threats, for example by secreting mucus. Recently, by analysis of gene targeting mice for two gastrointestinal-tract-specific calpains, calpain-8 and calpain-9, we have demonstrated that they are cooperatively involved in the mucosal defense against stress-induced gastropathies. Calpains-8 and -9 are members of Ca2+ dependent intracellular proteases comprising a superfamily in almost all eukaryotes, and form a functional complex, "G-calpain", expressed specifically in the mucus-producing cells. In this review, we show our recent results on calpains -8 and -9, and discuss gastric mucosal defense mechanisms involving them. PMID- 21688639 TI - [Development and repair of NSAIDs-induced small intestinal lesions: relation to COX isozymes and EP receptor subtypes]. AB - Intestinal ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2, and inhibition of COX-1 up-regulates COX-2 expression and PGs produced by COX-2 counteract the deleterious influences of the COX-1 inhibition. These lesions are prevented by PGE2 mediated by EP3/EP4 receptors and functionally associated with stimulation of mucus secretion, inhibition of intestinal contraction or enterobacterial invasion, and down-regulation of cytokine expression. COX/PGE2 also plays an important role in the healing of these lesions, but the COX isozyme responsible for PG production differs depending on the stage of healing; COX-2 in the early stage and COX-1 in the late stage, and the healing-promoting action of PGE2 is mediated by the activation of EP4 receptors, through enhancing angiogenesis via an increase in VEGF expression. PMID- 21688640 TI - [Comprehensive strategy for extermination of hepatocellular carcinoma- prevention, diagnosis and treatment]. AB - In this symposium, we explained etiology, prevention and treatment for hepatocellular carcinoma (HCC). It has been revealed that the carcinogenesis in hepatocellular carcinoma is almost caused by the infection of hepatitis virus B and/or C. Therefore, the carcinogenesis in hepatocellular carcinoma is able to be prevented. Even if the carcinogenesis in hepatocellular carcinoma occurs, the diagnosis and treatment in the worldwide level; radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), hepatectomy, and liver transplantation will be offered to patients with HCC in Japan. We hope that this symposium would help the attendance to understand the prevention and treatment for HCC. PMID- 21688641 TI - [Comparison of pneumonia severity indices between modified A-DROP system and current A-DROP system predicting outcomes for patients hospitalized with community-acquired pneumonia]. AB - BACKGROUND: The A-DROP is a predicting pneumonia severity index which is adopted in the Japanese Respiratory Society (JRS) guidelines. For community-acquired pneumonia, we made a modified A-DROP, adding two new index items to the current A DROP. Then, we retrospectively compared the modified A-DROP with the current A DROP regarding 30-day mortality. METHODS AND RESULTS: We analyzed consecutive 227 patients hospitalized with community-acquired pneumonia (mean age 79.0 years). The added index items were respiratory rate > or = 30/min and the presence or absence of underlying diseases. There were 16 fatalities (7.0%). In the extremely severe group, the sensitivities of the 30-day death and odds ratios were 19.9% and 9.5 in the current A-DROP, but 75.0% and 14.1 for the modified A-DROP, respectively. In addition, regarding the receiver-operating characteristic (ROC) area under the curve for the 30-day death ratio, the current A-DROP and modified A-DROP were 0.807 and 0.840, respectively. CONCLUSIONS: The modified A-DROP improved the ability to predict outcomes compared with the current A-DROP. PMID- 21688642 TI - [Synchronous pulmonary hamartoma and lung cancer in a young patient]. AB - A 23-year-old man was admitted for examination of an abnormal shadow in the right lower lung field. A chest CT scan revealed a nodule in the right lower lobe and a calcified nodule in the right upper lobe. A diagnosis of lung adenocarcinoma in the right lower lobe was made by transbronchial cytology. After resection of the right lower lobe and partial resection of the nodule in the right upper lobe were performed, we diagnosed lung adenocarcinoma in the right lower lobe (pathological stage IIIA) and hamartoma in the right upper lobe. Although several authors have reported cases of synchronous pulmonary hamartoma and lung cancer, it is uncommon in young patients. Since patients with hamartoma could also have lung carcinoma, careful observation is needed. PMID- 21688643 TI - [A case of multifocal micronodular pneumocyte hyperplasia without clinical findings of tuberous sclerosis]. AB - A 30-year-old woman was referred because of multiple ground-glass opacities (GGOs) on chest CT examination. Lung biopsy was performed. Histologically, multifocal well-demarcated nodular lesions comprising proliferation of type II pneumocytes with mild fibrous thickening of the alveolar septa were observed in the lung tissue. We made a histopathologic diagnosis of multifocal micronodular pneumocyte hyperplasia (MMPH). Neither the clinical findings nor the family history of the patient suggested tuberous sclerosis (TSC). MMPH is a pulmonary manifestation of tuberous sclerosis, together with lymphangioleiomyomatosis (LAM). MMPH should be considered as a differential diagnosis of multiple GGOs in the lung even when findings of TSC and LAM are not recognized. PMID- 21688645 TI - [A case of Pneumocystis jirovecii pneumonia after kidney transplantation with re exacerbation following therapy]. AB - A 55-year-old man who had a living kidney transplant 3 months previously was admitted complaining of 4 days of non-productive cough and fever. Because of his low oxygen saturation (SpO2 83% on room air), ground-glass opacities in both lung fields, and marked elevation of beta-D-glucan, a diagnosis of Pneumocystis jirovecii pneumonia (PCP) was considered. The diagnosis of PCP was confirmed by bronchoalveolar lavage. Subsequently, his oxygenation level decreased even after the administration of trimethoprim-sulfamethoxazole, therefore we concurrently administered 60 mg of prednisolone. His clinical symptoms and radiographic findings gradually improved. However, his respiratory condition and radiographic findings exacerbated again after the tapering of prednisolone. His condition improved after the prednisolone dose was returned to 30 mg per day. This case suggested that, in the treatment of PCP in patients without human immunodeficiency virus (HIV) infection, reduction of steroids may cause exacerbation of PCP, similar to immune reconstitution inflammatory syndrome which occurs in HIV patients. PMID- 21688644 TI - [Diffuse alveolar hemorrhage arising after use of a waterproofing spray]. AB - A 33-year-old woman used waterproofing spray and subsequently developed cough, sputum and chest pain about 8 hours later accompanied by dyspnea, fever and general fatigue. She was admitted to our hospital 4 days after the symptoms appeared. A chest CT scan on the first visit revealed diffuse mild centrilobular nodular opacities and ground-glass opacities in both lung fields. Hemosiderin laden macrophages accounted for 11% of the histiocytes found in her bronchoalveolar lavage fluid, which also contained blood. Based on these findings, the patient was given a diagnosis of diffuse alveolar hemorrhage. This is the first report in Japan of diffuse alveolar hemorrhage occurring after the use of a waterproofing spray. PMID- 21688646 TI - [Hyponatremia caused by pituitary metastasis of lung cancer]. AB - A 57-year-old man was admitted with headache, vomiting, and bloody sputum. We diagnosed large cell lung cancer T4N2M1 (pituitary metastasis), Stage IV. When hospitalized, low values of cortisol and hyponatremia were found. A hormone stimulation test was performed, because we suspected hypopituitarism. The reaction of adrenocorticotropic hormone (ACTH) to the corticotropin-releasing hormone (CRH) loading test was good, but the reaction of serum cortisol was minimal. After corticosteroid administration, his serum sodium normalized. Limited ACTH reserve according to insufficient pituitary function was suggested as a cause of the hyponatremia. He received gamma-knife therapy, however his pituitary gland tumor did not decrease in size. Clinical symptoms such as visual field disturbance, oculomotor paresis, and visual impairment progressed, and he died about 5 months later. We report a case of hyponatremia in a patient with pituitary metastasis of lung cancer, as it is comparatively rare. PMID- 21688647 TI - [A case of pulmonary aspergilloma concomitant with allergic bronchopulmonary aspergillosis]. AB - A 69-year-old man with pulmonary aspergilloma was admitted to the hospital because of persistent cough and slight fever. Antifungal agents were administered on a diagnosis of chronic necrotizing pulmonary aspergillosis or symptomatic aspergilloma. Despite the antifungal treatment, wheezing developed, suggesting a complication of allergic bronchopulmonary aspergillosis (ABPA). Finally, a definitive diagnosis of ABPA was made using the Rosenberg-Patterson criteria. Inhaled corticosteroid therapy reduced his wheezing. This case study indicates that there is a possibility that aspergilloma might coexist with ABPA. Therefore, we should pay attention to the possible complication of ABPA when treating pulmonary aspergilloma. PMID- 21688648 TI - [A case of pulmonary Mycobacterium abscessus infection with asbestosis in a patient given multidisciplinary treatment]. AB - A 68-year-old man consulted our hospital because of a giant cavity in the upper lobe of the right lung, which was detected in a medical examination for asbestosis. Mycobacterium abscessus was cultured from his sputum in 2 separate cultures. Therefore we diagnosed pulmonary Mycobacterium abscessus infection and prescribed amikacin, imipenem/cilastatin, and clarithromycin. After 2 months, lobectomy of the upper lobe of the right lung was performed. The 3 antibiotics were continued for another 6 months, and the patient recovered completely. Mycobacterium abscessus infection is one of the most intractable non-tuberculous mycobacterial infections, and it is important to include surgery in the primary treatment plan. PMID- 21688649 TI - [A case of lung scedosporiosis successfully treated with monitoring of plasma voriconazole concentration level]. AB - A 71-year-old man was referred because of fever and productive cough. His chest radiograph showed a large cavitary mass with an intracavitary mycetoma-like lesion in the left middle lung field. We undertook bronchoscopy and CT-guided biopsy, and both bronchial lavage fluid culture and CT-guided biopsy culture revealed Scedosporium apiospermum. On a diagnosis of lung scedosporiosis, he was treated with 200 mg/day voriconazole for 2 months, but his symptoms did not improve. Measurement of the plasma voriconazole level showed low plasma concentration levels (peak level: 2.15 microg/ml, trough level: 0.72 microg/ml). We then increased the voriconazole dosage from 200 mg/day to 400 mg/day. After that, his symptoms and chest radiograph findings improved immediately, accompanied by an elevated plasma voriconazole level (peak level: 5.13 microg/ml, trough level: 3.13 microg/ml). We believe that measurement of plasma voriconazole levels is useful to determine its dosage in lung scedosporiosis. PMID- 21688650 TI - [A case of organizing pneumonia with a reversed halo sign following postoperative irradiation for breast cancer]. AB - A 69-year-old woman received radiation therapy of 50 Gy following surgery for left breast cancer. Eleven months later, chest computed tomography revealed infiltrative shadows with air bronchograms in both lower lung fields and a reversed halo sign in the right lower lobe. Transbronchial lung biopsy revealed polypoid granulation tissue in the terminal air spaces, which was consistent with organizing pneumonia (OP). Prednisolone therapy resolved the radiographic abnormalities. The reversed halo sign was believed to be specific to cryptogenic organizing pneumonia. We reported a case of OP with a reversed halo sign following postoperative irradiation for breast cancer. PMID- 21688651 TI - [A case of pulmonary toxocariasis successfully treated with ivermectin]. AB - A 36-year-old man who often ate raw chicken meat had abnormal chest radiograph findings on a health check-up in July 2009, and visited our department. A chest computed tomographic scan revealed 6 nodular shadows in both lungs, and a hematologic examination revealed eosinophilia and elevation of IgE. Because of his history of eating raw chicken meat, antiparasite antibody testing was performed which revealed antibodies to Toxocara canis, leading to the diagnosis of pulmonary toxocariasis due to Toxocara canis. Although treatment with albendazole was performed, it was discontinued because of hepatic impairment. However, hematological examination showed that his eosinophil count and IgE increased again, and chest image findings were exacerbated. Therefore, ivermectin, reported as effective in cases outside Japan, was administered, resulting in decreased peripheral eosinophils, normalized IgE level, and disappearance of the shadows on chest images. In Japan, no cases of pulmonary toxocariasis responding well to ivermectin have previously been reported. Administration of ivermectin should be considered when albendazol cannot be used due to hepatic impairment or related problems. PMID- 21688652 TI - [Does lung age help smokers quit?]. PMID- 21688653 TI - [Analysis of sevoflurane stability during low flow anesthesia]. AB - Using the mass spectrometric method we studied the interaction of volatile anesthetic sevoflurane with a CO2 absorber during low flow anesthesia (0.5 l/min fresh gas mixture). The results of measurements of sevoflurane and one of the most toxic breakdown products of sevoflurane CF = C(CF3)-O-CH2F (substance A) throughout the anesthesia in the mode of inhalation-exhalation. The highest recorded concentration of substance A was 65 ppm. Biochemical analysis of blood before and after anesthesia did not show connection with nephropathy and function of liver toxicity. PMID- 21688654 TI - [High level thoracic epidural analgesia as a special component of anesthesia during thoracic surgeries]. AB - This article is devoted to assessing the adequacy and safety of total intravenous anesthesia based on constant dosed infusion of propofol and high thoracic epidural analgesia in thoracic surgical procedures requiring an artificial one lung ventilation in patients with concomitant chronic cardiorespiratory disorders compared to TIVA without a high thoracic epidural analgesia. Comparative analysis of gas exchange, metabolic rate, pressor, resistance and volumetric characteristics of pulmonary blood flow, central and intracardiac hemodynamics was conducted. We used high technology invasive monitoring system PICCOplus for transpulmonary thermodilution in combination with VoLEF for pulmonary thermodilution in changing modes of ventilation MV-MSL V-MV. MSL V lasted more than 1.5 hours. PMID- 21688655 TI - [Etiology, prophylaxis and treatment of extensive, multifocal cicatricial tracheal stenosis at the junction of sciences--surgery and anesthesia]. AB - 759 patients with cucatritial stenosis of trachea were treated in the Russian Scientific Center of Surgery in the period from 1963 to 2009. Extensive or multifocal stenosis was diagnosed in 172 patients. 157 patients were previously operated in other hospitals. The lesion of larynx during admission was diagnosed in 122 cases. All patients were operated in compliance with the principle of alternation methods of anesthesia and respiratory support. As a result of consistent application of the landmark reconstructive-plastic operations and resection in combination with endoscopic surgery good results were achieved. Based on the data, treatment algorithm of extended and multifocal cicatricial stenosis of the trachea was developed. PMID- 21688656 TI - [Paracetamol (perfalgane) as analgesic component of medicinal sedation]. AB - This article reviews the possibility of the use of paracetamol (perfalgane) as an analgesic component of medical sedation. The actuality of the problem is the choice effective pharmacological means of protection from peri-operative pain. The theoretical advantages of paracetamol in the scheme of sedoanalgesia are exquisite. We describe a personal experience of efficacy assessment and safety of paracetamol as an analgesic component of the methodology of drug sedation for bronchoscopy in the early postoperative period. We compare analgesia by the means of paracetamol 1000 mg (IV) and tramadol 100 mg (IV). The sedative agent in both groups was midazolam. It turned out, that despite the high efficacy of tramadol as a component of sedoanalgesia, the quality of anialgesia when using perfalagane is almost 5 times higher, both due to the significant number of good results, and to reduced number of adverse events. Use of paracetamol (Perfalgane) instead of tramadol for medical sedation during fibrotracheoscopy in patients in the early postoperative period leads to better quality of analgesia, thus avoiding such undesirable phenomena as hypersedation, respiratory depression, dizziness, and nausea. PMID- 21688657 TI - [Effective use of third generation fat emulsion in total parenteral nutrition program in patients with severe sepsis]. AB - The aim of the current research was to measure the clinical efficacy of 3rd generation fat emulsion in the program of complete parenteral nutrition of patients with severe sepsis. The work demonstrates the results of treatment of 25 patients with severe sepsis divided into 2 groups depending on the way of parenteral nutrition. In the 1st group (13 patients) the parenteral nutrition was carried out by 20% glucose, 15% solution of crystallic aminoacids and 20% of 2nd generation fat emulsion. In the 2nd group (12 patients) parenteral nutrition was carried out by 20% glucose, 15% solution of crystallic aminoacids and 20% of 3rd generation fat emulsion. The parenteral nutrition of Ist and 2nd group contributed to the correction of hypermetabolism syndrome and stabilization of the nutritive status parameters. It was observed that the parenteral nutrition used in the 2nd group showed statistically higher positive effect on the parameters of systemic inflammation and cellular part of immunity, rather than parenteral nutrition used in the 1st group. It is revealed that, the used methods of complete parenteral nutrition in patients with severe sepsis effectively eliminate the hypermetabolism syndrome. Parenteral nutrition of patients with severe sepsis by 3rd generation fat emulsion has a positive effect of parapeters of systemic inflammation. PMID- 21688658 TI - [Immunity and cytokine status after surgeries on the large intestine]. AB - The aim of our study was to examine the effect of individual schemes of multimodal analgesia on indicators of immunity and inflammation markers after operations on the colon. Patients of group 1 (n=15) received paracetamol, lornoxicam and epidural ropivacaine, 2nd group of patients (n=15)-paracetamol, epidural ropivacaine and tramadol. Comparison group (n=10) patients underwent patient controlled analgesia by promedol. Before surgery, 1st and 3rd days after surgery we examined the contents of cytokines in plasma: interleukin 12p70, interleukin 10, interleukin 6, and TNF. Before surgery and at 5-7 days after surgery indicators of cellular, fagocytal and humoral immunity were monitored. Before surgery patients with colorectal cancer revealed changes in the indices of different components of immunity, as well as an increase in pro-and anti inflammatory cytokines compared with healthy donors. Multimodal analgesia in patients after operations on the colon is not accompanied by changes in plasma concentrations of cytokines and parameters of immune status in comparison with monoanalgesia by promedol. PMID- 21688659 TI - [First experience of using CoolGard system in intensive care patients after neurosurgical interventions: series of 10 observations]. AB - Fever is a proven factor in secondary brain damage and worsens outcome in neuro intensive care patients. However, large randomized studies have shown neuroprotective effects of induced hypothermia only in patients with cardiac arrest and in neonates with perinatal hypoxic-ischemic brain damage. Nevertheless, now there is an active search for alternative modes of temperature correction, which would have been effective in other groups of patients with brain damage. Moreover, new management techniques of body temperature are being created. In this paper we presented a series of 10 observations when the used cooling system was CoolGard/CoolLine. 5 patients underwent hypothermia, 5 patients normothermia . Hypothermia was used for cerebroprotection in 1 case and for the correction of resistance to the therapy of intracranial hypertension in 4 cases. Normothermia was used for correction of resistance to pharmacological treatment of fever. In all cases the target temperature was achieved, and only for 1 patient to achieve hypothermia additional external cooling was used. Patients with normothermia did not need sedation, because they have not developed discomfort and muscle tremor. 2 patients died, in one case was due to intracranial hypertension and hemotamponade of brain ventricular system. Cause of second death was pulmonary embolism. Thus, the CoolGard system effectively lowers the body temperature to the target values for neuro intensive care patients. Application of this system is relatively safe. However, the most dangerous are the thromboembolic complications, thus the daily ultrasound scanning of lower limb veins and the possible early use of low molecular weight heparins is crucial. PMID- 21688660 TI - [Bilateral bispectral index monitoring during surgery for posterior cranial fossa tumors]. AB - The analysis of the results of bilateral monitoring of the depth of anesthesia in 22 patients with neurosurgical pathology of the posterior cranial fossa using the technique bispectral index (BIS). The results showed that more than half of the observations (at 19 and 22 patients) during the main phase of the operation (removal of the tumor) were observed differences in the BIS index values between the right and left side. In 1/3 of patients, these differences were driven by higher values of BIS on the side of surgery. By the end of removal of the tumor and, particularly, by the end of surgery there was a complete alignment of values of the BIS on the right and left. PMID- 21688661 TI - [Circulatory shock: pathophysiology, principles of diagnostics and treatment]. PMID- 21688662 TI - [Systemic inflammation complication of acute coronary syndrome with diabetes mellitua type 2]. AB - The basic indicators of systemic inflammatory reaction syndrome, as well as the dynamics of the content of low and medium molecular weight glycopeptides and in biological media in patients with acute coronary syndrome. Analysis of the results showed that the presence of background type 2 diabetes mellitus in patients with acute coronary syndrome is associated with higher non-infective resorbtion of necrotic syndrome. This is the rationale for inclusion in the complex intensive therapy of more active desintocsication activities and metabolically significant effects on myocarde and for type 2 diabetes with acute coronary syndrome. PMID- 21688663 TI - [Influence of a glucocorticoid kenalog on functional activity of macrophages and neutrophils both in lungs and in peritoneal cavity]. AB - The work purpose was comparative studying the number change and functional activity of macrophages and neutrophils both in lungs and in peritoneal cavity under the influence of a synthetic glucocorticoid kenalog (Kn). Kn was entered to rats Wistar unitary subcutaneously in a dose of 2 mg/kg (experience), the control rats obtained similarly 0.9% solution NaCl. The cell number of rat bronchoalveolar lavage liquid (BALL) and peritoneal lavage liquid (PLL) was defined in different terms after that. In cell monolayers of BALL we estimated ability of alveolar macrophages (AMph) and neutrophils to engulf of Staphylococcus and to generate of superoxide-anionradicals. In cell monolayers of PLL we estimated the functional activity of peritoneal macrophages (PMph) and neutrophils by means of the same tests. Through 6 (see symbol) after introduction Kn in BALL there was the reduction, and through 5 days--the increase of total cell number with the maximum of neutrophil accumulation and their considerable prevalence over AMph on number, phagocyte and superoxide-producing activity. At the same time the cell number in PLL was decreased and reached a minimum for 5 days after Kn-introduction with considerable decrease of phagocyte and superoxide producing ability both PMph and neutrophils. The differing action of glucocorticoids on macrophages and neutrophils of different organism compartments and recruitment of considerable quantity of neutrophils, possessing in destructive potential, into lungs can serve as an explanation of many cases when high-dose glucocorticoid therapy is not effective and may be even harmful at attempts of preventing acute respiratory distress-syndrome. PMID- 21688664 TI - [Lipid composition in erythrocytic membranes of rats with various stress resistance during repeated immobilization]. AB - The dependence between variation of erythrocyte phospholipid composition and stress resistance was studied in chronic experiment on nonline male albino rats, previously differed by their behavior in the 'open field' test. A significant exhausting of membrane pool by the basic classes of phospholipids was registered under influence of 2 hours daily immobilization during 5, 10, 20, 30 days, however, their metabolism for resistant and predisposed to stress animals flows variously. PMID- 21688665 TI - [IL-1beta, IL-10, INF-gamma, TNF-alpha, S100beta, AMA-M2 and cell immune response in stroke]. AB - Clinical data showed a role for stress, inflammatory, innate immune and adaptive immune mechanisms is stroke. Absolute and relative count of lymphocytes decrease, CD3 HLA DR+ and immunoregulatory balance (CD4+/CD8+) increase, concentration of IL-1beta, INF-gamma, TNF-alpha, S100beta, AMA-M2 increase, IL-10 decrease were detected in peripheral blood of 25 patients with stroke. It is explained that the products of brain cell stroke destruction (AMA-M2) play in autoimmune stroke progress mechanisms the same role as neurospecific proteins as S100beta. It is concluded that both stereotype and autoimmune mechanisms are involved in the development of stroke. PMID- 21688667 TI - [Changes gas and electrolyte structure of blood under influence terahertz radiations on frequencies nitrogen oxide 150,176-150,664 GHz in the conditions of stress]. AB - Influence terahertz radiations nitrogen oxide frequencies of 150,176 - 150,664 GHz on gas and electrolyte structure of blood of white rats being in condition of sharp stress. It is shown that at 15 minute mode of influence terahertz waves on frequencies nitrogen oxide observe partial restoration of studied indicators gas and electrolyte structure of blood at stress animals. At 30 minute mode of influence the specified waves observe complete recovery of the broken indicators gas and electrolyte blood structure. PMID- 21688666 TI - [Role of activation of lipid peroxidation in pathogenesis of experimental plague intoxication]. AB - Activation of lipid peroxidation, increasing during the elevation of clinical symptoms of Y. pestis intoxication and hypoxic syndrome development, is the efferent link in cytopathogenic effects of toxic and enzymatic factors of this microorganism. Absolute or relative insufficiency of enzymatic mechanisms of blood antioxidant protection systems is the main pathogenic factor in lipid components of biomembrane destruction leading to the haemorrhagic syndrome development in Y. pestis intoxication. PMID- 21688668 TI - [Airway hyperreactivity]. AB - The airway hyperreactivity (AHR) is a symptom occurring in various diseases of the respiratory system. It is defined as an abnormal bronchoconstriction response to a different spectrum of biological, chemical and pharmacological stimuli. Pathogenesis of airway hyperreactivity is not well understood. The available literature data shows that in the AHR pathogenesis is important not only genetic predisposition or influence of combination environmental and genetic factors, but also the presence and activity of various inflammatory mediators and other endogenous factors (growth factors, nuclear transcription factors). In this process is also important role of neural regulation and release of pro inflammatory neurotransmitters. Our aim was to provide a comprehensive overview of knowledge about the symptoms--from the risk factors and pathogenesis through the clinical importance to the need for better understanding new options in therapeutic interventions. PMID- 21688669 TI - [Adrenergic regulation of the mammalian heart]. AB - Adrenergic system in the mammalian heart plays a pivotal role in regulation of contractility and/or heart rate. At present, nine subtypes of adrenergic receptors (AR) have been identified. Among these there are six AR localized in the plasma membrane of cardiomyocytes. They mediate their effects by increases in the intracellular level of various signaling molecules which initiate diverse cellular responses. The effects of stimulation of both beta-AR by catecholamines noradrenaline and adrenaline are consistent with coupling to the Gs protein adenylyl cyclase-cAMP-protein kinase classical pathway, with consequent protein kinase A-catalysed phosphorylation of target enzymes responsible for increased contractility and hastening of relaxation. In contrast to beta1-AR, beta2-AR can also couple to G(i) protein which causes cAMP-independent control of calcium signaling and contraction. Activation of beta-AR obviously couples to a G(i)/ nitric oxide pathway and mediates a decrease in contractile force, whereas stimulation of alpha-AR increases contractility via G protein/phospholipase C/diacylglycerol/inositoltrisphosphate/protein kinase C pathway. These findings reveal the diversity and specifity of AR subtypes and G protein interactions. They also provide new insights in understanding the differential regulation and functionality of AR subtypes in healthy and diseased hearts. PMID- 21688670 TI - [Non-specific symptoms of inflammation in its experimental models: influence of interleukin-1]. AB - The local signs of inflammation are redness, oedema, increased temperature and pain. Local inflammatory changes are often followed by systemic non- specific alterations. Fever, which is usually the first sign of systemic inflammation, is accompanied by other systemic inflammatory changes like pain and anorexia. The systemic non-specific inflammatory symptoms also include changes in general activity, cognition, and affection. Sickness behaviour syndrome increases survival of the organism affected by inflammation. Many of sickness symptoms are regulated centrally by the brain. IL-1beta holds a privilege in regulation of sickness symptoms. PMID- 21688672 TI - [The family physician: actor, observer and beyond]. PMID- 21688671 TI - [Programming of cardiovascular phenotype by pharmacological intervention in early developmental stages: prevention of hypertension]. AB - Cardiovascular diseases, including hypertension, represent serious medical and social problem because they affect many people in industrialized countries in the world and, unfortunately, their incidence has not decreasing tendency. Human essential hypertension is a chronic, slowly developing disease, which is a consequence of abnormalities in the development of cardiovascular system and its regulation, which are subsequently reflected in pathological rise of blood pressure. In general, blood pressure increases slowly and gradually and this may last several years. Myocardial hypertrophy and structural alterations of the vessel system frequently occur. As hypertension is already established, then complete normalization of blood pressure is difficult to obtain. Therefore, it is necessary to focus on its prevention, this means, to intervene before blood pressure elevation in individuals with significant genetic predisposition to this disease. Moreover, it is well known that cardiovascular system of the young organism is very sensitive to various environmental influences, and one can expect that it may also be more susceptible to vasoactive substances in prevention and treatment of cardiovascular diseases. Hypertension and its pharmacological treatment should therefore be studied with regard to the maturity of an individual. In accordance with the hypothesis of developmental plasticity of organisms, it may be possible (by pharmacological intervention in early ontogenetic stages of predisposed individual) to achieve such a setting of structural and functional parameters which could reduce the subsequent clinical manifestation of genetically induced hypertensive state. PMID- 21688673 TI - [Teaching about practice guidelines: osteoporosis]. AB - Family physicians need to know how to teach students practical guidelines for frequent diseases such as osteoporosis. After the age of 50 years, the risk for osteoporotic fractures is 50% for women and 20% for men. It is therefore useful to prevent and screen for osteoporosis. Family physicians need to know how to recognize the clinical and biological risk factors for osteoporosis; they must know when to request a bone densitometry, the "gold standard" for diagnosis. They must also be able to integrate these factors within the clinical context to evaluate the absolute risk of osteoporosis-related fracture that determines the need for specific treatment. Numerous treatments with proven efficacy to reduce global fractures are available but it is important to know their different indications, risk/benefits and potential harmful side-effects. PMID- 21688674 TI - [Development, implementation and practical use of a diagnostic score]. AB - In recent years many clinical prediction rules (CPR) have been developed. Before a CPR can be used in clinical practice, different methodical steps are necessary, from the development of the score, the internal and external validation to the impact study. Before using a CPR in daily practice family doctors have to verify how the rules have been developed and whether this has been done in a population similar to the population in which they would use them. The aim of this paper is to describe the development of a CPR, and to discuss advantages and risks related to the use of CPR in order to help family doctors in their choice of scores for use in their daily practice. PMID- 21688675 TI - [Epidemiological surveillance: family doctors' responsibility]. AB - Epidemiological surveillance systems are essential and require efficient collaborations between family doctors and public health services. Such a system has to take into account the increase in the number of health problems to be studied. Information gathered at an individual level should imply decisions at a population level which in turn should impact on the individual patient. Epidemiological surveillance requires a well organized, representative and constantly revised system led by motivated, adequately trained doctors. PMID- 21688676 TI - [Scientific research in family medicine: practitioners' experience, barriers and needs]. AB - Scientific data from family medicine are relevant for the majority of the population. They are therefore essential from an ethical and public health perspective. We need to promote quality research in family medicine despite methodological, financial and logistic barriers. To highlight the strengths and weaknesses of research in family medicine in the French-speaking part of Switzerland we asked practitioners from this region to share their experience, critics and needs in relation to research. This article summarizes their contribution in light of the international literature. PMID- 21688677 TI - [Added value of family practitioners' supervision of junior doctors in a walk-in clinic]. AB - The pending workforce crisis in family medicine has triggered various initiatives. This article describes the PMU-FLON walk-in clinic, a project of the Institute of General Medicine University of Lausanne. The working conditions in this clinic are close to that of a family practice. Doctors in training are supervised by family doctors who work part-time in the clinic. The objective is to improve training in the various fields of family medicine, from technical skills (improving optimal use of diagnostic tools), to integrating patients' requests in a more global patient-centered approach. This new educational model allows doctors in training to benefit from the specific approaches of different trainers. It will contribute to promoting quality family medicine in the future. PMID- 21688678 TI - [Learning about family medicine and the doctor-patient relationship: student views]. AB - The five university institutes/units for family medicine in Switzerland are now responsible for teaching family medicine to medical students, particularly through the introductory cleckship in primary care in the 2nd year. During four half-days, the students attend the office of a family doctor and discover the characteristics of family medicine according to the definition of the World Association of Family Doctors (WONCA). This article shows how these training sessions are a profound and enriching learning experience for students. Different skills are presented and are illustrated by extracts from the reports students write at the end of the four half-days. PMID- 21688679 TI - [Food allergy in children: anything new in its management?]. AB - The prevalence of food allergy in children is increasing, in particular in its most severe presentation, i.e. anaphylaxis. Food allergy has an important impact on children's and their parent's quality of life, because of the fear of accidental ingestion and limitations of social activities. Quality of life questionnaires adapted to food allergy are now available, as well as new diagnostic procedures using recombinant technology. Their interpretation and their clinical correlation remain difficult, especially in children, in the absence of references values. Various oral and subcutaneous immunotherapy strategies are currently under evaluation, using modified or native allergens. PMID- 21688680 TI - [Suicidal behavior associated with atrophied corpus callosum in the elderly]. PMID- 21688681 TI - [Consumption of generics in 7 European countries]. PMID- 21688682 TI - [The Cardinal don't always have old bones]. PMID- 21688683 TI - [Change his life?]. PMID- 21688684 TI - Coadministration of clopidogrel and proton pump inhibitors. PMID- 21688685 TI - Geriatric medicine. PMID- 21688686 TI - Pulmonary disease. PMID- 21688687 TI - Supplement: scope of practice for surgical technologist. PMID- 21688688 TI - Pediatric cardiology. PMID- 21688689 TI - Gynecologic oncology. PMID- 21688690 TI - Transoral incisionless fundoplication. PMID- 21688691 TI - The pay-off on nursing home report cards. AB - For the past decade, policymakers have used public reporting of quality measures as a strategy to improve quality in nursing homes. In theory, public reporting might improve overall quality in two ways: first, if consumers choose nursing homes with better performance, and second, if public reporting encourages nursing homes to improve their performance. Has public reporting had its intended effects? Does improving quality give nursing homes a competitive advantage in the marketplace, thereby improving their bottom line? This Issue Brief summarizes a series of studies that assess the impact of public reporting on nursing home quality and on the financial performance of these facilities. PMID- 21688692 TI - The health status and unique health challenges of rural older adults in California. AB - Despite living in the countryside where open space is plentiful and there is often significant agricultural production, rural older adults have higher rates of overweight/obesity, physical inactivity and food insecurity than older adults living in suburban areas. All three conditions are risk factors for heart disease, diabetes and repeated falls. This policy brief examines the health of rural elders and, by contrast, their urban counterparts, and finds that both groups are more likely to be unhealthy than suburban older adults. Yet rural elders, because of their geographical isolation and lack of proximity to health care providers, experience unique environmental and other risk factors that require context-specific solutions to these health issues. In both policies and programs that impact health, policymakers need to take into account the distinctive environmental and social context of older adults living in California's countryside. PMID- 21688693 TI - Adolescent physical education and physical activity in California. AB - In California, more than 1.3 million adolescents (38%) do not participate in physical education (PE) at school, and this rate increases dramatically with age, from just 5% at age 12 to 77% at age 17. In addition, only 19% of teens meet current physical activity recommendations. Participation in PE at school is associated with more overall physical activity. Policies that promote more opportunities for physical activity, including those that help schools meet or exceed current PE requirements, can contribute to greater levels of physical activity for adolescents. PMID- 21688694 TI - Californians newly eligible for Medi-Cal under health care reform. AB - About 2.13 million nonelderly Californians who were uninsured for all or part of 2009 are newly-eligible for Medi-Cal under the Patient Protection and Affordable Care Act (ACA) of 2010. Analysis of the 2009 California Health Interview Survey indicates that this newly-eligible population is often single, working-age and employed. Their rates of most chronic conditions are similar to those currently enrolled in Medi-Cal, but they have less access to care. The characteristics of the population of the newly-eligible for Medi-Cal under ACA are likely to change by 2014 when the major provisions of the law are fully implemented. However, coverage of this newly-eligible low-income population is likely to improve their access to health services. PMID- 21688695 TI - Euthanasia. PMID- 21688696 TI - Who can participate in the California health benefit exchange? A profile of subsidy-eligible uninsured and individually insured. AB - About 1.71 million nonelderly Californians were uninsured for all or part of 2009 and are estimated to be eligible to participate and receive subsidies in the new California Health Benefit Exchange marketplace under the Patient Protection and Affordable Care Act (ACA) of 2010. Another 737,000 are currently insured with individual policies and will also be eligible for participation in the Exchange based on their employment, income and citizenship status. This policy brief examines the characteristics of these Exchange-eligible with subsidies groups, based on 2009 California Health Interview Survey data. Among the findings, these Exchange-eligible populations are often single, young working-age adults, and are employed in small firms. Most are healthy and the prevalence rates of most chronic conditions are similar to those with employment-based insurance. However, several indicators show poorer access to care for those who are uninsured. The characteristics of the Exchange-eligible with subsidies are likely to change by 2014 when the major provisions of the ACA are implemented. Nevertheless, these data indicate that the California Health Benefit Exchange is likely to improve access to care for the uninsured, and has the potential to improve coverage and access to care of those with individual policies. PMID- 21688697 TI - Chemical translation: the case of Robert Boyle's experiments on sensible qualities. AB - The purpose of this work is to translate some of Robert Boyle's chemical experiments into the terms of modern chemistry. Most of the reactions involve sensible qualities, since there are on it considerable helpful tracking descriptions like heating, hissing, colour changing, etc. For a long time in the history of science, this procedure was seen as an exercise in anachronism which should be avoided at all costs. Recently many scholars have demonstrated that chemical translation can assist with historical work instead of causing confusion, and it may be very useful as a tool for the history of chemistry and for reproducing past chemical experiments. PMID- 21688698 TI - Legislative and policy analysis of HIV prevention, treatment and care for people who use drugs and incarcerated people in Central Asia and Azerbaijan. AB - In January 2011, the Regional Office for Central Asia of the UN Office on Drugs and Crime (UNODC) and the Canadian HIV/AIDS Legal Network released an extensive report assessing the legislative and policy environment affecting the response to HIV in six countries of the Commonwealth of Independent States (CIS). The report, which draws in part upon the work of a national expert group in each country, puts forward dozens of recommendations for legislative and policy reform, including recommendations for specific reform tailored to the situation in each of the participating countries, with a particular focus on addressing the fast growing HIV epidemic linked to injection drug use and in prisons. PMID- 21688699 TI - Supervised injection sites in Quebec: one step closer to reality. AB - Thanks to the efforts of community groups CACTUS Montreal and Point de reperes, two supervised injection sites could soon be opening in Montreal and Quebec City. PMID- 21688700 TI - Correctional investigator highlights pending adverse impacts of the government's "tough on crime" agenda. AB - Released in November 2010, the 2009-2010 annual report of the Correctional Investigator--the ombudsman for federal prisoners--presents a bleak picture of over-crowded prisons lacking in rehabilitative programming and increasingly populated by mentally ill and substance-dependant inmates in need of services. PMID- 21688701 TI - Phylogenetic analysis alone cannot prove source of HIV infection: experts. AB - According to a recent report from the United States of America published in the Proceedings of the National Academy of Sciences, scientists could prove with certainty which person was the source of an HIV infection. However, international experts have disputed the claim. PMID- 21688702 TI - Proposed EU-India free trade agreement could impede manufacture of generic HIV drugs. AB - Medical experts are warning that an international trade agreement being brokered between the European Union (EU) and India could greatly restrict the access of people living with HIV in the developing world to life-saving antiretroviral medication. PMID- 21688703 TI - Ukraine: HIV policy advances overshadowed by police crackdown on drug therapy clinics. AB - In October 2010, the government of Ukraine made progressive revisions to a law aimed at reducing the spread of HIV/AIDS and supporting the rights of people living with HIV/AIDS (PHAs). However, policing methods continue to constrain access to harm reduction services. PMID- 21688704 TI - Africa: sexual minorities at risk. AB - Violence against homosexuality is growing in Africa, where most of the countries on the continent continue to criminalize same-sex relations, fostering a climate of hate that, in some cases, is abetted by politicians. PMID- 21688705 TI - Ontario: prostitution-related provisions of Criminal Code struck down. AB - In September 2010, the Ontario Superior Court of Justice held that three provisions of the Criminal Code dealing with prostitution violated sex workers' constitutional rights, were not in accordance with the principles of fundamental justice and must be struck down. PMID- 21688706 TI - British Columbia: sex workers granted standing to challenge Criminal Code. AB - On 12 October 2010, a majority of the Court of Appeal of British Columbia allowed the appeal of Shari Kiselbach and the Downtown Eastside Sex Workers United against Violence Society (SWUAV) regarding their standing to challenge provisions of the Criminal Code concerning prostitution. PMID- 21688707 TI - Swazi man's refugee claim rejected: PHAs not a "particular social group". AB - On 14 July 2009, the Refugee Protection Division of the Immigration and Refugee Board (IRB) rejected the claim for refugee protection of B.L.H., an HIV-positive man from Swaziland. B.L.H. made a Convention refugee claim on the basis of his membership in a particular social group, claiming a fear of persecution based on his HIV-positive status. B.L.H. also claimed that he was in need of protection in accordance with Section 97 of the Immigration and Refugee Protection Act (IRPA). PMID- 21688708 TI - Federal court allows application for judicial review of HIV-positive woman from Jamaica. AB - On 26 January 2011, the Federal Court allowed an application for judicial review by Ferona Elaine Mings-Edwards, who based her application for permanent residence on humanitarian and compassionate grounds, including the hardship that she claimed that she would face in Jamaica from her former domestic partner and because of her HIV-positive status. PMID- 21688709 TI - Quebec: employer who disclosed employee's HIV-positive status violated rights to dignity and freedom from discrimination. AB - The Quebec human rights tribunal held that an employer who disclosed the HIV positive status of an employee to his staff violated the employee's right to the safeguard of his dignity, without distinction or exclusion based on disability, contrary to Sections 4 and 10 of the Charter of Human Rights and Freedoms (the Quebec Charter). PMID- 21688710 TI - Court of Appeal reaffirms long-term income support for alcohol and drug dependence. AB - On 16 September 2010, the Ontario Court of Appeal upheld a decision of the Social Benefits Tribunal that found discriminatory the exclusion from long-term income support of people suffering from alcohol or drug dependency. PMID- 21688711 TI - Federal Court: incarcerated man did not have right to choice of doctor. AB - In December 2010, the Federal Court rejected a former prisoner's request for judicial review of a decision of the Correctional Service of Canada (CSC) regarding his choice of physician while incarcerated. PMID- 21688712 TI - Blood donor ban upheld. AB - On 8 September 2010, the Ontario Superior Court rejected a claim that Canadian Blood Services (CBS) is violating Section 15 of the Canadian Charter of Rights and Freedoms (Charter) by refusing blood donations from men who have had sex with other men (MSM) since 1977. The case arose because CBS sued Kyle Freeman, a gay man, for lying about his sexuality on the screening questionnaire in order to give blood. PMID- 21688713 TI - Saskatchewan Court of Appeal: marriage commissioners cannot discriminate. AB - The Saskatchewan Court of Appeal has ruled that proposed legislation allowing marriage commissioners to refuse to solemnize same-sex marriages based on religious objections would violate the equality rights of gays and lesbians under the Canadian Charter of Rights and Freedoms (Charter). The Court expressed its opinion in a Reference involving proposed amendments to the Marriage Act. PMID- 21688714 TI - Criminal law and HIV transmission or exposure. PMID- 21688715 TI - China: court rules school board did not discriminate against prospective HIV positive employee. AB - On 11 November 2010, the AnqingYinjiang District Court ruled that a local education board did not unlawfully discriminate against an HIV-positive college graduate when it decided not to employ him upon discovering his HIV status. PMID- 21688716 TI - South Africa: HIV-positive man wins wrongful dismissal suit. AB - An award-winning horse-riding instructor and stable manager dismissed by his former employer in 2008 for being HIV-positive won his case in a Johannesburg court in February 2011. The employer was ordered to pay the man a year's salary and cover his legal costs. PMID- 21688717 TI - City of Moscow decision to forbid gay pride marches violates European Convention on Human Rights. AB - On 21 October 2010, the European Court of Human Rights ruled that the office of then-mayor of MoscowYuri Luzhkov violated the rights to freedom of assembly and from discrimination of Russians who had sought to organize and participate in gay pride marches in the Russian capital of Moscow. PMID- 21688718 TI - Romania: European Court of Human Rights rules degrading treatment for man who contracted TB in prison. AB - In December 2010, the European Court of Human Rights ruled that a Romanian man who contracted tuberculosis (TB) while in prison had his rights violated pursuant to Article 3 of the European Convention on Human Rights, which prohibits torture and degrading treatment. PMID- 21688719 TI - Criminal law and cases of HIV transmission or exposure. PMID- 21688720 TI - Our clinical experience with zonisamide in resistant generalized epilepsy syndromes. AB - PURPOSE: Zonisamide is licensed in the European Union for adjunctive therapy for partial epilepsy, but its efficacy in generalized epilepsy was less explored. METHODS: This prospective observational study included 47 patients (mean age 29 years, range 3-50) with different resistant generalized epilepsy syndromes: idiopathic generalized syndromes (IGE) 15 patients, (juvenile myoclonic epilepsy four, absence epilepsy four, myoclonic absence two, unclassified IGE five), progressive myoclonic epilepsy type 1 (PME1) four, severe myoclonic epilepsy of infancy (SMEI) three, borderline SMEI three, Lennox-Gastaut syndrome/secondary generalized epileptic encephalopties 23 patients. All patients were followed up for at least six months. The mean dose given was 367 mg/day (range 100-600 mg/day), the patients received at least one and no more than two concomitant AE. Response was defined as more than 50% seizure reduction or seizure freedom. RESULTS: The best effect was achieved in PME one, all the patients were responders. Myoclonic seizures were reduced 80%, none of the patients had generalized tonic clonic (GTC) seizures. In two of the four patients all other antiepileptics were tapered of (including piracetam), so they were GTC seizure and almost myoclonia free on zonisamide only. Responder rates were in GEFS +/- SME 62.5%, in resistant IGE 62.5%, and in epileptic encephalopathies 33.3% patients. Tolerance after initial efficacy developed in six patients. Adverse effects were mild: weight loss, somnolence and confusion were repeatedly reported. Three patients reported cognitive improvement. CONCLUSION: Clinical benefit of a broad spectrum antiepileptic zonisamide extends across seizure types, ages and epilepsy syndromes. The efficacy in PME proved to be excellent. PMID- 21688721 TI - Antinociception by endogenous ligands at peripheral level. AB - It is well known that a multitude of ligands and receptors are involved in the nociceptive system, and some of them increase, while others inhibit the pain sensation both peripherally and centrally. These substances, including neurotransmitters, neuromodulators, hormones, cytokines etc., may modify the activity of nerves involved in the pain pathways. It is also well known that the organism can express very effective antinociception in different circumstances, and during such situations the levels of various endogenous ligands change. Accordingly, a very exciting field of pain research relates to the roles of endogenous ligands. The peripheral action may possibly be extremely important, because low doses of the endogenous ligands may reduce pain without disphoric side-effects, and without the abused potential typical of centrally acting ligands. This review provides a comprehensive overview of the endogenous ligands that can induce antinociception, discusses their effects on different receptors and focuses on their action at peripheral level. We found 17 different endogenous ligands which produced antinociception after their topical administration. The results suggest an important direction for the development of pain strategies that focus on the local administrations of different endogenous ligands. PMID- 21688722 TI - Press coverage of the new psychology by the New York Times during the progressive era. AB - Press coverage of psychology by the New York Times was examined for the Progressive Era. Following a period in which psychology was associated with spiritualism, psychoanalysis, and the Emmanuel movement, the Times gave editorial preference to reports about psychology's applications. Reaching an audience that was both affluent and influential, the topics emphasized by the Times included the lie detector, psychological applications in the work place, mental tests, and child psychology. These areas reflected issues of social concern to Progressives, publicized the rise of the psychologist as expert, and aided psychology in its challenge to common sense. PMID- 21688723 TI - Look-normal: the colonized child of developmental science. AB - This article provides an analysis of the techniques, methods, materials, and discourses of child study observation to illuminate its role in the sociohistorical colonization of childhood. Through analysis of key texts it explains how early 20th-century child study provided for the transcendence of historical, racial, and social contexts for understanding human development. The colonizing project of child study promoted the advancement of Eurocentric culture through a generic "White" development. What a child is and can be, and the meaning of childhood has been disembodied through observation, record keeping, and analytical processes in which time and space are abstracted from behavior, and development symbolized as a universal ideal. PMID- 21688724 TI - Space perception and William James's metaphysical presuppositions. AB - William James's overtly philosophical work may be more continuous with his psychological work than is sometimes thought. His Essays in Radical Empiricism can be understood as an explicit statement of the absolute presupposition that formed the basis of Jamesian psychology: that direct experience is primary and has to be taken at face value. An examination of James's theory of space perception suggests that, even in his early work, he presupposed the primacy of direct experience, and that later changes in his account of space perception can be understood as making his view more consistent with this presupposition. In his earlier view of space perception, James argued that sensations were directly experienced as spatial, though he accepted that spatial relations between sensations may be constructed by higher order thought. In his later view, however, James argued that spatial relations were just as directly experienced as sensations. The work of T. H. Green may have prompted James to recognize the full consequence of his ideas and to realize that taking experience at face value required that spatial relations be thought of as intrinsic to experience rather than the result of intellectual construction. PMID- 21688725 TI - The concept of psychological regression: metaphors, mapping, Queen Square, and Tavistock Square. AB - The term "regression" refers to events in which an individual changes from his or her present level of maturity and regains mental and behavioral characteristics shown at an earlier point in development. This definition has remained constant for over a century, but the implications of the concept have changed systematically from a perspective in which regression was considered pathological, to a current view in which regression may be seen as a positive step in psychotherapy or as a part of normal development. The concept of regression, famously employed by Sigmund Freud and others in his circle, derived from ideas suggested by Herbert Spencer and by John Hughlings Jackson. By the 1940s and '50s, the regression concept was applied by Winnicott and others in treatment of disturbed children and in adult psychotherapy. In addition, behavioral regression came to be seen as a part of a normal developmental trajectory, with a focus on expectable variability. The present article examines historical changes in the regression concept in terms of mapping to biomedical or other metaphors, in terms of a movement from earlier nativism toward an increased environmentalism in psychology, and with respect to other historical factors such as wartime events. The role of dominant metaphors in shifting perspectives on regression is described. PMID- 21688726 TI - Invoking history to teach about the scientist-practitioner gap. AB - The scientist-practitioner gap refers to the division between psychologists who believe that clinical practice should be heavily informed by empirical studies and those who believe clinical judgment and intuition should be paramount. Although the gap widened in the late 1980s and early 1990s, owing to the recovered memory controversy, the intradisciplinary schism between scientists and practitioners significantly predates this particular debate. Without an appreciation of the historical context of the term's emergence, however, students may come to regard the scientist-practitioner gap as a discrete and recent phenomenon. In this paper, the historical and philosophical roots of the gap are described, and it is argued that an appreciation of the historical circumstances from which the term emerged can enable students to better appreciate the past, present, and future of the discipline. PMID- 21688727 TI - An overview of home health aides: United States, 2007. AB - OBJECTIVES: This report presents national estimates of home health aides providing assistance in activities of daily living (ADLs) and employed by agencies providing home health and hospice care in 2007. Data are presented on demographics, training, work environment, pay and benefits, use of public benefits, and injuries. METHODS: Estimates are based on data collected in the 2007 National Home Health Aide Survey. Estimates are derived from data collected during telephone interviews with home health aides providing assistance with ADLs and employed by agencies providing home health and hospice care. RESULTS: In the United States in 2007, 160,700 home health and hospice aides provided ADL assistance and were employed by agencies providing home health and hospice care. Most home health aides were female; approximately one-half were white and one third black. Approximately one-half of aides were at least 35 years old. Two thirds had an annual family income of less than $40,000. More than 80% received initial training to become a home health aide and more than 90% received continuing education classes in the previous 2 years. Almost three-quarters of aides would definitely become a home health aide again, and slightly more than one-half of aides would definitely take their current job again. The average hourly pay was $10.88 per hour. Almost three-quarters of aides reported that they were offered health insurance by their employers, but almost 19% of aides had no health insurance coverage from any source. More than 1 in 10 aides had had at least one work-related injury in the previous 12 months. CONCLUSIONS: The picture that emerges from this analysis is of a financially vulnerable workforce, but one in which the majority of aides are satisfied with their jobs. The findings may be useful in informing initiatives to train, recruit, and retain these direct care workers. PMID- 21688728 TI - 2010 Kremers Award Lecture. Reflections. PMID- 21688729 TI - Ram Nath Chopra--father of Indian pharmacology. PMID- 21688730 TI - Marketing of patent medicines in the nineteenth century via a corkscrew medicine spoon. AB - The C. T. Williamson spoon with manufactured products from a pharmaceutical company engraved on the bowl of the spoon is one of the earliest examples of a manufacturer marketing products via a drug delivery device. The Burroughs, Wellcome and Company, a British corporation using initially an American patented, and later a British patented, Williamson corkscrew spoon marketed British manufactured medicinal products in the U.S. and England to physicians and pharmacists in the late nineteenth and early twentieth century. Other corkscrew spoons were manufactured in this era without product specific notations contained on the spoons. 40 These corkscrew spoons, such as the Williamson and Noe patented apparatuses, helped patients in more easily consuming liquid medications. They also were items potentially favored by physicians and pharmacists for patient's pro- vided liquid medications. Finally, they allowed patients to open corked containers, consume liquid dosage amounts, and hopefully more appropriately comply with necessary regimens in the late nineteenth and early twentieth century. Not surprisingly, Burroughs, Wellcome and Company used the Williamson spoon to successfully market company products to physicians, pharmacists, and patients on several continents. PMID- 21688732 TI - The 1928 Carlisle conference: Knight Dunlap and a national laboratory for psychology. AB - In late March 1928, 32 experimental psychologists met in Carlisle, Pennsylvania. The National Research Council (NRC) sponsored the conference, which was organized by Knight Dunlap, chair of the NRC's Division of Anthropology and Psychology. The purpose of the Carlisle conference was to examine the status of experimental psychology, and Dunlap used it to propose a national laboratory for psychology, to be created in Washington, DC. This vision clashed with the traditional university-centered research model and the group resisted Dunlap's plan. Dunlap persisted, the eventual result being a National Institute of Psychology, which accomplished little. The Carlisle conference did succeed in being the impetus for small NRC-funded grants-in-aid to researchers, and it set in motion events that eventually led to the American Psychological Association publication manual. PMID- 21688731 TI - Reaching beyond Uncle William: a century of William James in theory and in life. AB - During the hundred years since his death, James's works have developed a reputation for literary flair and personal appeal, but also for inconsistency and lack of rigor; this has contributed to more admiration than influence. He had a talent rare among intellectuals for popularization of complex ideas. Meanwhile, his difficult coming of age and his compelling personality have contributed to an iconic status as a kind of uncle figure in philosophy, psychology, religious studies, and more fields that he influenced, and in American intellectual life in general, rather than as a major philosopher and scholar. Often reflecting these ways of depicting James, his biographies have gone through three phases: in the early-to-middle twentieth century, emphasis on his development of theories as solutions to personal problems; since the 1960s, increased scrutiny of deep troubles in his private life; and recently renewed attention to intellectual factors especially as amplified by greater appreciation of James's theories in the last generation. Now, with so much knowledge and insight achieved for understanding his personal life and his contributions to many fields, a next frontier for biographical work will be in synthesis of these strands of the life of William James. Recent and prospective work offers the promise of finding deeper meaning and implications in his work beyond, and even through, his informal style, and with integration of his apparent inconsistencies. PMID- 21688733 TI - Reflexivity, the role of history, and the case of mesmerism in early Victorian Britain. AB - As part of a wider argument that history is essential to psychological understanding because of the reflexive nature of psychological knowledge, this article examines the case of mesmerism in early Victorian Britain as an example of how psychological knowledge is both constructive and constructed. It is argued that the shift from "mesmerism" to "hypnotism" was a change in understanding that created a new kind of psychological experience. It is also argued that demonstrations of mesmerism, far from being self-evident facts, could be framed as evidence either for or against the central claims of mesmerism. It is concluded that the case of mesmerism in early Victorian Britain provides a further example of the need for historical understanding within Psychology. PMID- 21688734 TI - Gustav Theodor Fechner: life and work in the mirror of his diary. AB - The diaries of Gustav Fechner reveal much about his motivations to develop the field of psychophysics, as well as some of the steps toward its formulation. Together with his publications on various subjects, the diaries show how psychophysics fits into Fechner's broader scientific program, illuminate his worldview, and reveal his hopes for acceptance of his work by his colleagues. PMID- 21688735 TI - Fechner's "inner psychophysics". AB - Though psychologists are generally aware that Gustav Fechner introduced psychophysics and set down its essential methodology, most of them only know about the part that Fechner called "outer psychophysics." In his classic publication of 1860, Fechner insisted that "inner psychophysics" was more important, yet this aspect of Fechner's work failed to receive any attention. The article reviews Fechner's presentation of inner psychophysics and suggests reasons why that part of his work was neglected and has been forgotten. PMID- 21688736 TI - French and British influence in the birth of a profession: pharmacy in Quebec. PMID- 21688737 TI - Pharmacy and empire: the British Pharmacopoeia as an instrument of imperialism 1864 to 1932. PMID- 21688738 TI - Vectors of French cultural imperialism: training in medicine and pharmacy at the schools of Hanoi and Dakar (1904-1953). PMID- 21688739 TI - Foreign influences, national styles, and the creation of a modern pharmaceutical industry in Britain and France. PMID- 21688740 TI - An unusual personalized cough mixture from the early twentieth century. AB - There is no way at this point to determine the financial or marketing impact of the personalized cough mixture upon the Randall Drug Store. Nor can there be an estimate of the influence that the likeness of Dr. Randall's daughter on the label might have had upon sales or use of the product. However, in an era of uncertainty and naivete regarding health options in general and medicinal products in particular, it could be assumed that this photograph-adorned personalized cough mixture bottle would have been promoted in-store by Dr. Randall with confidence, and used with assurance by purchasers. This uniquely presented cough mixture was no doubt a point of pride for the pharmacist, as well as his lovely daughter. PMID- 21688741 TI - Quality of care: the role of disease registries. PMID- 21688742 TI - Comparisons of directly coded SEER Summary Stage 2000 and Collaborative Staging Derived SEER Summary Stage 2000. AB - This study assessed comparability of the directly coded Summary Stage 2000 and the Collaborative Stage (CS) Derived Summary Stage 2000 (SS2000) using 2001-2004 data from 40 population-based cancer registries in the United States that met the high quality criteria. The likelihood ratio test was employed to determine whether stage differences between 2003 (pre-CS) and 2004 (CS) were attributable to 2001-2004 linear trends, decreases in percentage of unknown stage cases, or both. Statistically significant differences in stage distribution between 2003 and 2004 were observed for 30 out of the 34 cancer sites. For 4 cancer sites, the differences were attributable to 2001-2004 linear trends of stage distribution. For 8 cancer sites, the differences were attributable to decreases in percentage of unknown stage cases alone or in combination with the temporal trends of stage distribution. For the remaining 18 cancer sites, either (1) no linear trends of stage distribution were identified or (2) the combination of the decline in cases with unknown stage plus linear trends did not explain the stage differences between 2003 and 2004. By comparing the SS2000 and CS manuals, we found differences in coding definitions for direct extension and/or lymph node involvement for all cancer sites except cancers of the breast, cervix, and cranial nervous and other nervous system. Evidence showed that the stage differences between 2003 and 2004 may be attributable in part to the implementation of the CS System for some cancer sites. PMID- 21688743 TI - Impact of automated data collection from urology offices: improving incidence and treatment reporting in urologic cancers. AB - BACKGROUND: Urologic cancers represent a substantial proportion of the total cancer burden, yet the true burden of these cancers is unknown due to gaps in current cancer surveillance systems. Prostate and bladder cancers in particular may be underreported due to increased availability of outpatient care. Thus, there is a critical need to develop systems to completely and accurately capture longitudinal data to understand the true patterns of care and outcomes for these cancers. METHODS: We determined the accuracy and impact of automated software to capture and process billing data to supplement reporting of cancers diagnosed and treated in a large community urology practice. From these data, we estimated numbers of unreported cancers for an actively reporting and for a non-reporting practice and the associated impact for a central cancer registry. RESULTS: The software automatically processed billing data representing 26,133 visits for 15,495 patients in the 3.5-month study period. Of these, 2,275 patients had a cancer diagnosis and 87.2% of these matched with a central registry case. The estimated annual number of prostate and bladder cancers remaining unreported from this practice was 158. If the practice were not actively reporting, the unreported cases were estimated at 1,111, representing an increase of 12% to the registry. Treatments added from billing varied by treatment type with the largest proportion of added treatments for biologic response modifiers (BRMs) (127%-166%) and chemotherapy (22%). CONCLUSION: Automated processing of billing data from community urology practices offers an opportunity to enhance capture of missing prostate and bladder cancer surveillance data with minimal effort to a urology practice. IMPACT: Broader implementation of automated reporting could have a major impact nationally considering the more than 12,000 practicing urologists listed as members of the American Urological Association. PMID- 21688744 TI - Towards the use of a census tract poverty indicator variable in cancer surveillance. AB - Incidence rates for many cancer sites are strongly correlated with area measures of socioeconomic conditions such as poverty rate. Analyzing such measures at the county scale produces misleading results by masking enormous within-county variations. The census tract is a more suitable scale for assessing the relationship between cancer and socioeconomics. The North American Association of Central Cancer Registries (NAACCR) developed a census tract-level poverty indicator variable which was included as an optional item in its 2010 Call for Data. This variable does not allow the identification of individual census tracts as long as the county of diagnosis is not known. It is expected that this data item will be made available to researchers in future releases of the CINA Deluxe file. PMID- 21688745 TI - Economic assessment of central cancer registry operations, Part III: Results from 5 programs. AB - In this article, we report results from the cost analysis of 5 central cancer registries funded by the National Program of Cancer Registries (NPCR). To estimate the true economic costs of operating a cancer registry, we used a cost assessment tool (CAT) to collect data on all registry activities, not just those funded by the NPCR. Data were collected on actual, rather than budgeted, expenditures, including personnel, consultants, information technology (IT) support, and other factors influencing costs. Factors that can affect registry costs include the amount of consolidation from abstract to incident cases, the method of data reporting, the number of edits that must be performed manually versus electronically, and the amount of interstate data exchange required of a registry. Expenditures were allocated to specific surveillance and data enhancement and analysis activities. Our study confirmed that cost per case varies across registry activities. The cost of surveillance activities per case ranges from $24.79 to $95.78 while the cost of data enhancement and analysis registry activities per reported cancer case ranges from $2.91 to $9.32. Total cost per reported cancer case also varies, ranging from $30 to slightly more than $100, with a median of $45.84. Further research using data from all NPCR-funded registries is required to assess reasons for this variation. Information gained from such an assessment will improve efficiency in registry operations and provide data to better quantify the funding requirements for expanding registry activities. PMID- 21688746 TI - Analysis of histiocytosis deaths in the US and recommendations for incidence tracking. AB - OBJECTIVE: We determined the frequency of deaths associated with histiocytosis in the United States (US) for which incidence data are lacking and could be potentially important in understanding outcomes for patients with these disorders. METHODS: National death data collected by the US Vital Statistics Reporting System and aggregated using wonder.cdc.gov were analyzed for underlying cause of death due to malignant histiocytosis (MH), Langerhans cell histiocytosis (LCH) and Letterer-Siwe disease (LS, a form of LCH) for 3 periods: 1979-1988, 1989-1998, and 1999-2006. To capture histiocytosis, International Classification of Diseases (ICD)-9 codes 202.3, 202.5, and 277.8 and ICD-10 codes C96.1, C96.0, and D76.0-76.1 were used. Deaths were calculated for US residents stratified according to sex, race, region, and age. Other listed contributing causes of death with a histiocytosis diagnosis were also examined. RESULTS: A total of 2,416 deaths primarily due to histiocytosis as underlying cause occurred between 1979 and 2006. On comparison of the underlying and contributory cause for the period 1999-2006, histiocytosis mentioned on the death certificate as a contributory cause (N=562) occurs nearly as often as does underlying cause alone (N=648). The age-adjusted (year 2000) death rate was highest for MH (2.62 deaths per 10 million, 95% CI: 2.40-2.83) and for LCH and LS disease (2.17, 95% CI: 1.98 2.36) during the period 1979-1988. Death rates of each type of histiocytosis dropped significantly from 1979 to 1988 to 1999-2006 (p-value <0.0001). Distribution of the conditions showed the majority of deaths were due to LCH and LS (67%) across all time periods. LCH/LS was significantly more common in persons younger than 5 years of age irrespective of gender (p-value <0.0001) whereas death rates from MH were significantly greater in ages >54 years (p-value <0.00001). There were more MH deaths among males than females whereas no gender differences were seen for LCH/LS. CONCLUSIONS/DISCUSSION: Death due to histiocytosis or histiocytosis-related causes is a rare event that is trackable in the US by person, place and time characteristics. However, a population-based, disease incidence registry has begun to accurately ascertain incidence cases, which will facilitate study of these conditions. PMID- 21688747 TI - Experiencing change: the users' perspective (CSv2). PMID- 21688748 TI - Data directions. PMID- 21688749 TI - Raising the bar: speaking your customer's language. PMID- 21688750 TI - The evolving vocabulary of the social sciences: the case of "socialization". AB - While the term "socialization" stands as a common and clearly understood term regularly used in social science and lay conversations alike, its history is complex. In the 19th century, socialization was introduced to refer to societal activities or projects, and only in the early 20th century did it gain usage as a term describing psychological processes transpiring within the individual. The architecture of the newer meaning harbored ambitions and problems of modern social science, including ideals of interdisciplinary theory and theoretic resolution of the individual/society dualism. Nevertheless, socialization became a central object of social scientific inquiry after World War II. This significant social scientific object was repeatedly altered: initially representing a vision of conforming citizens who were free from certain troubling characteristics depicted in psychoanalysis and well-suited to democracy, it later was engaged to create a vision of autonomous, resilient, and cognitively active actors able to negotiate a complex social world. PMID- 21688751 TI - Between psychology and pedagogy: "moral orthopedics" and case studies of children in fin-de-siecle French medicine. AB - In the latter decades of the 19th century, European physicians debated a controversial practice that mixed placebos with suggestion therapy to treat children diagnosed with neurotic disorders and behavioral problems. Designed to optimize suggestibility in juvenile patients, this "moral orthopedics" offered parents and therapists the message that children could be saved from becoming victims of their own personalities, of familial neuroses, or even of public health problems. Case studies, published in medical journals and books, circulated accounts of innovative strategies to treat childhood hysteria and to change habits that were considered destructive. Moral orthopedics actualized the insight that suggestibility could be therapeutically productive for juvenile subjects. However, because its adherents sought to manipulate patients' behavior and health by influencing unconscious thought, moral orthopedics provoked questions of expertise and disciplinary propriety among domains of medicine, law, and philosophy. This article reconstructs the controversy surrounding moral orthopedics by examining case studies. I argue that adherents of moral orthopedics did overcome philosophical objections raised against the method, and that they did so through what physician Edgar B6rillon referred to as "education of the will." PMID- 21688752 TI - Renata Calabresi: the experimental analysis of the present. AB - Between the 1920s and 1930s, Renata Calabresi conducted pioneering laboratory researches on the nature, extensity, and quality of the psychic present. Her analyses stemmed from the Central European tradition initiated by Stern, Brentano, Meinong, and Benussi. Her work has remained largely unrecognized, because of both the decline of the underlying theoretical paradigm, namely descriptive psychology, and the historical events of the time that swept aside the lives of those involved. This article presents her researches on the roots of phenomenal consciousness. She proved that in the subjective time there occur perceptual events that are at least partially independent from those of the time of objective sequences. Subjective and objective time, therefore, do not flow in unison, and the continuum of perceptive sequences has modalities of existence that differ from those of the continuum of physical sequences. PMID- 21688753 TI - Comparing premodern melancholy/mania and modern trauma: an argument in favor of historical experiences of trauma. AB - Historians and psychiatrists have repeatedly looked to both real and imagined individuals of the past, like Achilles and Samuel Pepys, and found evidence that they were suffering from symptoms of trauma and posttraumatic stress disorder. The assumptions that allow such historical "diagnoses" have, however, recently been called into question by philosophers such as lan Hacking, anthropologists like Allan Young and psychiatrists such as Patrick Bracken. These scholars have all suggested in various ways that experiences of trauma could not have occurred until the diagnosis of trauma and its symptoms had been formalized and the language of trauma had been developed in the late 19th century. This article attempts to resolve this bifurcation of opinion on the universality of the mind and historical experiences of trauma in two ways. First, it argues for the necessity of applying modern categories of analysis to further present understandings of the past. Second, it considers discussions of"melancholia" and "mania" in premodern medical literature and argues that there are enough similarities between the causes and symptoms of these premodern disorders and modern trauma to suggest that experiences of trauma may not be wholly culturally bound to the modern world, as the above scholars have suggested. While melancholy or mania cannot simply be understood as premodern names for trauma, and it is not always correct to "diagnose" a premodern person who exhibits symptoms of these illnesses with trauma, such an assumption is not always ahistorical or incorrect either. PMID- 21688754 TI - Cattell, Columbia, and academic freedom: rarely used sources enrich analyses of this significant episode. AB - This note seeks to illustrate the value for research into psychology's past of several primary sources rarely used by historians of psychology. It does so by showing how 3 such sources-a university song book, an editorial cartoon, and FBI files about a distinguished psychologist-provide additional insights about a major historical incident previously discussed at length in History of Psychology. It closes by urging historians of psychology to look beyond the obvious as they do their research. PMID- 21688755 TI - Treatment, care and support for people co-infected with HIV and hepatitis C: a scoping review. AB - BACKGROUND: Providing care for people who are co-infected with both HIV and hepatitis C virus (HCV) is becoming increasingly complex and requires integrated prevention, screening, support and programming efforts. We undertook a scoping review to provide a summary of the existing evidence base and to identify and assess the quality of treatment guidelines and systematic reviews related to 3 domains of interest: treatment; epidemiology; and care, support, programming and prevention. METHODS: We searched 7 databases, hand-searched 8 journals and contacted key informants to identify relevant literature. We included all primary research (including systematic reviews and meta-analyses) or treatment guidelines that assessed pegylated interferon and ribavirin for HCV or highly active antiretroviral therapy for HIV treatment, or both. In the epidemiology domain, we included all primary research (including systematic reviews and meta-analyses). Studies that included only people with hemophilia and those conducted in developing countries were excluded. In the care, support, programming and prevention domain, we included all studies and reports that focused on co infection. Two reviewers independently applied coding criteria and assessed the quality of the treatment guidelines and systematic reviews using the Appraisal of Guidelines Research and Evaluation and A MeaSurement Tool to Assess Reviews instruments. RESULTS: Our search strategy yielded 1633 unique references. Of these, 227 references met the final inclusion criteria: 114 addressed treatment, 52 epidemiology and 79 care, support, programming or prevention. The references included 9 treatment guidelines: 4 were assessed as "strongly recommend," 3 as "recommend (with provisos or alterations)" and 1 as "would not recommend" (1 could not be located). Of 10 systematic reviews that were located, 7 were assessed as being high quality, 2 as medium quality and 1 as low quality. CONCLUSION: This quality-assessed inventory of treatment guidelines and systematic reviews can be used by physicians and service providers to rapidly locate research about HIV-HCV co-infection. However, many treatment guidelines and reviews often indicate that treatment of current injection drug users and/or people with mental health issues should proceed on a "case-by-case basis." Therefore, much of the evidence (particularly in the treatment literature) is limited in its scope and applicability to important populations that are vulnerable to HIV or HCV infection or co-infection. PMID- 21688757 TI - Factors predicting completion and time to publication of Cochrane reviews. AB - BACKGROUND: Cochrane reviews are regarded as scientifically rigorous, yet a review's time to publication can be affected by factors such as the statistical significance of the findings. When this happens, misrepresentation of the literature and subsequent inappropriate decisions may result. We aimed to examine the factors associated with the time to publication of Cochrane reviews. METHODS: Review protocols published in issue 2, 2000, of the Cochrane Database of Systematic Reviews were included in this analysis if the corresponding review was published by issue 1, 2008. We used univariable and multivariate analyses to examine the time from publication of the protocol to publication of the first review and review-related factors predicting the time to publication. RESULTS: Of 118 eligible protocols published in issue 2, 2000, we identified 93 Cochrane reviews that had been published by January 2008. Of these, 36 (39%) were updates. The median time to publication was 1.63 years (range 0.15-7.31 years). A change in authors between publication of the protocol and publication of the final review was associated with longer time to publication (p = 0.002), whereas updated reviews were associated with shorter time to publication (p = 0.030). INTERPRETATION: In our study, 79% of the Cochrane protocols were published as a final review, and some Cochrane reviews took over 7 years from publication of the protocol to publication of the final review. Strategies to increase the number of published Cochrane reviews and decrease the time to publication should be considered, such as providing support to reviewers when a change in authorship occurs. PMID- 21688756 TI - Renal outcomes and mortality following hydroxyethyl starch resuscitation of critically ill patients: systematic review and meta-analysis of randomized trials: ATTENTION: The analysis and conclusions of this article are being revised by the authors. This is due to the journal Anesthesia and Analgesia's retraction of a paper by Dr. Joachim Boldt, an author in seven of the studies analyzed in this review. As such, the editors of Open Medicine recommend interpreting this review with extreme caution until Zarychanski et al. publish a new analysis and interpretation in Open Medicine. For more information, see Anesthesia and Analgesia's press release. AB - BACKGROUND: Hydroxyethyl starch (HES) is a type of colloid fluid that is commonly used for volume resuscitation of patients admitted to the intensive care unit. Data regarding the renal consequences of HES are conflicting. PURPOSE: To evaluate the effect of HES solutions on renal outcomes and mortality among critically ill patients requiring acute volume resuscitation. DATA SOURCES: We searched electronic databases (MEDLINE, EMBASE, the Cochrane Central Registry of Controlled Trials and the SCOPUS database) from 1950 to 2008. Conference proceedings and grey literature sources were searched from 2002 to 2007. STUDY SELECTION: We included only randomized controlled trials of acute volume resuscitation of critically ill patients comparing HES fluid with an alternative resuscitation fluid. DATA SYNTHESIS: Two reviewers independently assessed trial eligibility, extracted data and evaluated trial quality. Random-effects models were used for all summary measures of effect. RESULTS: Twenty-two trials (n = 1865 patients) were included. Patients who received HES were more likely to have received renal replacement therapy (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.22-2.96, I(2) 9.5%, n = 749). There was no difference in overall mortality (OR 1.07, 95% CI 0.85-1.34, n = 1657). However, in trials that included patients with severe sepsis and septic shock, in high-quality and multicentre trials, and in trials with adequate allocation concealment, there was a trend toward increased risk of death in association with HES. LIMITATIONS: Data regarding adverse events, including renal outcomes, were not reported in the majority of published randomized trials. Considerable clinical and methodologic heterogeneity existed among trials. CONCLUSIONS: The use of HES for acute volume resuscitation of critically ill patients, and in particular those with severe sepsis and septic shock, appeared to be associated with increased use of renal replacement therapy. Further randomized controlled trials evaluating clinically important end points are required to examine the efficacy and safety of HES fluids for critically ill patients. PMID- 21688758 TI - New thinking about postoperative hypoalbuminemia: a hypothesis of occult protein losing enteropathy. PMID- 21688759 TI - Prevalence and incidence of hepatitis C virus infection among Aboriginal young people who use drugs: results from the Cedar Project. AB - BACKGROUND: We sought to estimate the prevalence and incidence of hepatitis C virus (HCV) infection among Aboriginal young people who use drugs and to identify risk factors associated with HCV infection in this population. METHODS: The Cedar Project is a longitudinal study involving Aboriginal young people living in Vancouver and Prince George, British Columbia. Eligibility criteria include age from 14 to 30 years and self-reported use (smoking or injection) of illicit drugs (e.g., crystal methamphetamine, crack cocaine, heroin or other opiates, and cocaine) at least once in the month before enrolment. At each visit, participants completed a detailed questionnaire administered by an Aboriginal interviewer. For this analysis, we included information for 512 participants who were recruited between September 2003 and April 2005. RESULTS: Among the 512 participants, the prevalence of HCV infection was 34.8% (95% confidence interval [CI] 30.6%-38.9%); the rates were similar in Prince George and Vancouver (34.5% and 35.0% respectively, p = 0.37). Among those who reported the use of injection drugs at baseline (n = 286), the prevalence of HCV infection was 59.4% (95% CI 53.8% 65.1%); the rate in this group was slightly higher in Prince George than in Vancouver (62.4% v. 57.1% respectively, p = 0.37). The prevalence was 3.5% among participants who reported smoking drugs (n = 226). In the multivariate logistic regression analysis, factors significantly associated with HCV infection among participants who used injection drugs included daily injection of opiates (adjusted odds ratio [OR] 2.7, 95% CI 1.0-7.4), reuse of syringes (adjusted OR 2.4, 95% CI 1.3-4.4), having at least 1 parent who attended residential school (adjusted OR 1.9, 95% CI 1.1-3.4), female sex (adjusted OR 1.9, 95% CI 1.1-3.4) and duration of injection drug use (per year) (adjusted OR 1.4, 95% CI 1.3-1.5). The crude incidence rate of HCV infection was 10.6% and the incidence density estimate was 9.9 per 100 person-years in this cohort. INTERPRETATION: The prevalence of HCV infection was elevated among Aboriginal young people living in Prince George and Vancouver who use drugs. Culturally based prevention, treatment and harm-reduction programs are urgently needed in this population. PMID- 21688760 TI - A culture of mutual support: discovering why new nurses stay in nursing. AB - New nurse retention and satisfaction has been a recurring topic of research and concern for nursing administrators and educators. As the nursing shortage continues to grow, the retention of new nurses becomes even more important. Most research has focused on why new nurses leave nursing. This article describes the experiences of six new nurses who chose to stay in their first nursing position for 2 years. The qualitative results suggest that even though they felt underprepared, the nurses persevered and remained resilient because of a culture of mutual support. The study participants suggested that individuals contemplating nursing as a career need to "enter with their eyes open," stay strong and "persevere," and foster a "culture of mutual support." PMID- 21688761 TI - Making a difference: the value of preceptorship programs in nursing education. AB - The benefits of clinical nursing experience in nursing education cannot be overemphasized. Literature has shown that proficient clinical nursing education enhances nursing practice through the development of professional growth with opportunities for the application of theoretical knowledge. Clinical preceptorship has been shown to be an effective method in the development of professional nurses through clinical education. The role of a clinical nursing preceptor is complex and not necessarily applicable to all nurses. Understanding the clinical environment, comprehending individual learning styles, and dealing effectively with conflict are skills that an effective preceptor needs to acquire before participating in the role. This article describes the origin of the preceptor role in clinical nursing education and discusses how the role can be enhanced through a proficient and well-planned preceptorship education program. PMID- 21688762 TI - Lenticular abnormalities in children. AB - PURPOSE: To study the lenticular problems in children presenting at an apex institute. METHODS: Retrospective analysis of records (< 14 years) of new lens clinic cases was done. RESULTS: Of 1,047 children, 687 were males. Mean age at presentation was 6.35 +/- 4.13 years. Developmental cataract was seen in 45.6% and posttraumatic cataract in 29.7% of patients. Other abnormalities were cataract with retinal detachment, persistent hyperplastic primary vitreous, subluxated lens, micro/spherophakia, cataract secondary to uveitis, intraocular lens complications, cataract with choroidal coloboma, and visual axis opacification. CONCLUSION: Developmental and posttraumatic cataracts were the most common abnormalities. Delayed presentation is of concern. PMID- 21688763 TI - Corneal crosslinking for progressive keratoconus in four children. AB - The authors describe four children with progressive keratoconus treated by corneal crosslinking (CXL). The current CXL guidelines recommend treatment of patients 18 years and older. Nevertheless, keratoconus can rapidly progress in young teenagers. CXL could be a safe procedure to prevent a keratoplasty at a young age. PMID- 21688765 TI - Comparison of intraocular lens decentration parameters after femtosecond and manual capsulotomies. AB - PURPOSE: To evaluate a laser technique and manual technique to perform capsulorrhexis in cataract eyes. METHODS: Anterior capsulotomy was performed with an intraocular femtosecond laser (LenSx Lasers Inc) in 54 eyes (FS group) and manual continuous curvilinear capsulorrhexis was performed in 57 eyes (CCC group). Circularity and area of capsulotomy and IOL decentration were measured using Photoshop CS4 Extended (Adobe Systems Inc) 1 week after surgery. Average keratometry, axial length, and preoperative anterior chamber depth were examined with the Lenstar LS 900 (Haag-Streit AG). RESULTS: No statistically significant differences were noted between groups in axial length, preoperative refractive state, and in the area of capsulotomy. Circularity values were significantly better in the FS group (P=.032). We found incomplete overlap of capsulotomies in 28% of eyes in the CCC group and 11% in the FS group (P=.033). Significant correlations were noted between axial length and area of capsulotomy, and between average keratometry and area of the capsulotomy in the CCC group (R=0.278, P=.036; and R=-0.29, P=.033, respectively), but both did not correlate in the FS group (P>.05). In the CCC group, the pupillary area correlated significantly with the area of the capsulotomy (R=0.27, P=.039). Significant correlation was noted between IOL decentration and axial length in the CCC group (R=0.30, P=.026), but there was no correlation in the FS group (P>.05). CONCLUSIONS: Femtosecond laser capsulorrhexis was more regularly shaped, showed better centration, and showed a better intraocular lens/capsule overlap than manual capsulorrhexis. PMID- 21688764 TI - Health behaviors of Operating Engineers. AB - Operating Engineers (heavy equipment operators in construction) may be at particular risk for heart disease and cancer related to their exposure to environmental dust and smoking, the sedentary nature of their job, and long hours of exposure to the sun. The aim of this study was to characterize the health behaviors of Operating Engineers. This cross-sectional survey from a convenience sample of Operating Engineers (N = 498) used validated instruments to measure smoking, drinking, diet, exercise, sleep, and sun exposure. Univariate and bivariate analyses to detect differences by age were conducted. The sample scored significantly worse on all five health behaviors compared to population norms. Those who were older were less likely to smoke and chew tobacco and more likely to eat fruits and vegetables. Many were interested in services to improve their health behaviors. Health behavior interventions are needed and wanted by Operating Engineers. PMID- 21688766 TI - Photographic diabetic retinopathy screening in an urban family practice clinic: effect on compliance to eye examination. AB - BACKGROUND AND OBJECTIVE: This study assessed the effect of introduction of diabetic retinopathy screening using non-mydriatic digital fundus photography (nDFP) in an urban academic family practice clinic on patient compliance to recommended dilated eye examination (REE). PATIENTS AND METHODS: Two hundred four patients with diabetes mellitis who were noncompliant to annual REE were screened for diabetic retinopathy using nDFP. The images were electronically transmitted to the retinal specialist to triage them for follow-up REE based on the photographic findings. Retrospective review of their medical records compared the compliance to REE before and after nDFP screening. RESULTS: Compliance to REE increased from 9% before screening to 66.5% after screening (P < .0001). Good quality fundus images were obtained in 93% of the eyes. CONCLUSION: Introduction of nDFP for diabetic retinopathy screening in the family practice clinic can result in a dramatic increase in compliance to REE among patients with diabetes mellitis previously poorly compliant to REE. PMID- 21688768 TI - High on/off ratios in bilayer graphene field effect transistors realized by surface dopants. AB - The unique property of bilayer graphene to show a band gap tunable by external electrical fields enables a variety of different device concepts with novel functionalities for electronic, optoelectronic, and sensor applications. So far the operation of bilayer graphene-based field effect transistors requires two individual gates to vary the channel's conductance and to create a band gap. In this paper, we report on a method to increase the on/off ratio in single gated bilayer graphene field effect transistors by adsorbate doping. The adsorbate dopants on the upper side of the graphene establish a displacement field perpendicular to the graphene surface breaking the inversion symmetry of the two graphene layers. Low-temperature measurements indicate that the increased on/off ratio is caused by the opening of a mobility gap. PMID- 21688767 TI - Surgical outcomes of 23- and 20-gauge vitrectomies for rhegmatogenous retinal detachment associated with posterior vitreous detachment. AB - BACKGROUND AND OBJECTIVE: To compare the outcomes of 23- and 20-gauge vitrectomies 1 year after primary repair of rhegmatogenous retinal detachments (RRDs) associated with a posterior vitreous detachment (PVD). PATIENTS AND METHODS: One hundred seventy-five consecutive eyes were reviewed that had undergone 23- or 20-gauge vitrectomy for RRDs associated with PVD. RESULTS: Retinal reattachment during the year after the first vitrectomy occurred in 88 (91%) of 97 eyes in the 23-gauge group and 70 (90%) of 78 eyes in the 20-gauge group. All eyes in both groups achieved anatomic success after another procedure. The surgical time in the 23-gauge group was significantly (P = .03) shorter than in the 20-gauge group. No significant difference was found between the preoperative and postoperative visual acuities in both groups. CONCLUSION: Twenty three-gauge vitrectomy can obtain anatomic and visual acuity results similar to those obtained with 20-gauge vitrectomy after primary repair of RRDs and may be a surgical option for treating the disorder. PMID- 21688769 TI - Total synthesis of (+/-)-platencin. AB - A novel route to (+/-)-platencin is reported, in which the highly stereoselective alkylative quaternization of a cyclohexenone scaffold via 1,4-diastereoinduction and two radical carbon-carbon bond-forming reactions that involve titanium(III) mediated cyclization and stannyl-radical-mediated skeletal rearrangement are utilized. PMID- 21688770 TI - Proteomic characterization of influenza H5N1 virus-like particles and their protective immunogenicity. AB - Recombinant virus-like particles (VLPs) have been shown to induce protective immunity. Despite their potential significance as promising vaccine candidates, the protein composition of VLPs produced in insect cells has not been well characterized. Here we report a proteomic analysis of influenza VLPs containing hemagglutinin (HA) and matrix M1 proteins from a human isolate of avian influenza H5N1 virus (H5 VLPs) produced in insect cells using the recombinant baculovirus expression system. Comprehensive proteomic analysis of purified H5 VLPs identified viral proteins and 37 additional host-derived proteins, many of which are known to be present in other enveloped viruses. Proteins involved in different cellular structures and functions were found to be present in H5 VLPs including those from the cytoskeleton, translation, chaperone, and metabolism. Immunization with purified H5 VLPs induced protective immunity, which was comparable to the inactivated whole virus containing all viral components. Unpurified H5 VLPs containing excess amounts of noninfluenza soluble proteins also conferred 100% protection against lethal challenge although lower immune responses were induced. These results provide important implications consistent with the idea that VLP production in insect cells may involve similar cellular machinery as other RNA enveloped viruses during synthesis, assembly, trafficking, and budding processes. PMID- 21688771 TI - Conserved residues in the extracellular loops of short-wavelength cone visual pigments. AB - The role of the extracellular loop region of a short-wavelength sensitive pigment, Xenopus violet cone opsin, is investigated via computational modeling, mutagenesis, and spectroscopy. The computational models predict a complex H bonding network that stabilizes and connects the EC2-EC3 loop and the N-terminus. Mutations that are predicted to disrupt the H-bonding network are shown to produce visual pigments that do not stably bind chromophore and exhibit properties of a misfolded protein. The potential role of a disulfide bond between two conserved Cys residues, Cys(105) in TM3 and Cys(182) in EC2, is necessary for proper folding and trafficking in VCOP. Lastly, certain residues in the EC2 loop are predicted to stabilize the formation of two antiparallel beta-strands joined by a hairpin turn, which interact with the chromophore via H-bonding or van der Waals interactions. Mutations of conserved residues result in a decrease in the level of chromophore binding. These results demonstrate that the extracellular loops are crucial for the formation of this cone visual pigment. Moreover, there are significant differences in the structure and function of this region in VCOP compared to that in rhodopsin. PMID- 21688772 TI - Amidophenol-modified amphiphilic calixarenes: synthesis, interfacial self assembly, and acetaminophen crystal nucleation properties. AB - Three amidophenol-modified calixarenes have been produced reacting the parent 5,11,17,23-tetracarboxy-25,26,27,28-tetradodecyloxycalix[4]arene with o-, m-, and p-aminophenol. The produced amphiphiles have been shown to form stable monomolecular Langmuir layers on water. Working on subphases containing 1 mM acetaminophen (APAP), it has been demonstrated that the produced amphiphiles interact with this active pharmaceutically ingredient (API) with a relevant preference for the para-derivative that possesses in its structure substituents that are analogous to the target. Working at supersaturating concentrations of APAP, it has been demonstrated that the so-produced calixarene Langmuir monolayers do favor crystallization of APAP (polymorph I), with a clear effect of the packing density of the amphiphile at the interface on the quantity of produced crystals. Monolayers of the para-derivative have been transferred on solid substrates using the Langmuir-Blodgett technique; the so-produced ultrathin films have been shown to initiate surface crystal nucleation of APAP. The produced solids have been analyzed by single-crystal X-ray crystallography and shown to preferentially grow in the [010] direction. PMID- 21688773 TI - Observation of inhomogeneity in the lipid composition of individual nanoscale liposomes. AB - Liposomes, or vesicles, have been studied extensively both as models of biological membranes and as drug delivery vehicles. Typically it is assumed that all liposomes within the same preparation are identical. Here by employing pairs of fluorescently labeled lipids we demonstrated an up to 10-fold variation in the relative lipid composition of individual liposomes with diameters between 50 nm and 15 MUm. Since the physicochemical properties of liposomes are directly linked to their composition, a direct consequence of compositional inhomogeneities is a polydispersity in the properties of the individual liposomes in an ensemble. PMID- 21688774 TI - Changes in the hydrogen-bond network around the chromophore of photoactive yellow protein in the ground and excited states. AB - Changes in the hydrogen-bond (HB) network around the chromophore, p-coumaric acid (pCA), in the ground pG and excited pG* states were investigated for wild type (WT) photoactive yellow protein (PYP) and its mutants using ultraviolet resonance Raman (UVRR) spectroscopy. The intensity depletion of Tyr UVRR bands was observed upon photoexcitation of pCA to the pG* state. The spectral change was ascribed to strengthening of HB between pCA and Tyr42. Comparison of Raman intensities indicated that, in the pG state, the HB between pCA and Tyr42 in WT is a short HB, which is weaker than that in E46Q mutant. In the pG* state, the HB network around pCA of WT is similar to that of E46Q mutant. The present results demonstrate that the HB between pCA and Tyr42 and that between pCA and Glu46 are correlated with each other in the HB network. PMID- 21688775 TI - Ions and the protein surface revisited: extensive molecular dynamics simulations and analysis of protein structures in alkali-chloride solutions. AB - Proteins interact with ions in various ways. The surface of proteins has an innate capability to bind ions, and it is also influenced by the screening of the electrostatic potential owing to the presence of salts in the bulk solution. Alkali metal ions and chlorides interact with the protein surface, but such interactions are relatively weak and often transient. In this paper, computer simulations and analysis of protein structures are used to characterize the interactions between ions and the protein surface. The results show that the ion binding properties of protein residues are highly variable. For example, alkali metal ions are more often associated with aspartate residues than with glutamates, whereas chlorides are most likely to be located near arginines. When comparing NaCl and KCl solutions, it was found that certain surface residues attract the anion more strongly in NaCl. This study demonstrates that protein salt interactions should be accounted for in the planning and execution of experiments and simulations involving proteins, particularly if subtle structural details are sought after. PMID- 21688776 TI - Multifunctional colloids with optical, magnetic, and superhydrophobic properties derived from nucleophilic substitution-induced layer-by-layer assembly in organic media. AB - We demonstrate the successful preparation of multifunctional silica colloids by coating with 2-bromo-2-methylpropionic acid (BMPA)-stabilized quantum dots (BMPA QDs) and BMPA-stabilized iron oxide particles (BMPA-Fe(3)O(4)), along with amine functionalized poly(amidoamine) (PAMA) dendrimers, using layer-by-layer (LbL) assembly based on a nucleophilic substitution (NS) reaction between the bromo and amine groups in organic media. The QDs and Fe(3)O(4) nanoparticles used in this study were directly synthesized in a nonpolar solvent (chloroform or toluene), and the oleic acid stabilizers were exchanged with BMPA in the same solvent to minimize chemical and physical damage to the nanoparticles. The direct adsorption of nanoparticles via an NS reaction in organic solvent significantly increased the packing density of the nanoparticles in the lateral dimensions because electrostatic repulsion between neighboring nanoparticles was absent. The multifunctional colloids densely coated with nanoparticles showed excellent characteristics (i.e., superparamagnetism, photoluminescence, and magneto-optical tuning properties) with long-term stability in nonpolar solvents. Furthermore, deposition of the nanocomposite colloids onto flat substrates, followed by coating with a low-surface-energy fluoroalkylsilane polymer, produced a densely packed rugged surface morphology in the colloidal films that displayed superhydrophobic properties with water contact angles greater than 150 degrees . PMID- 21688777 TI - Characterization of three berry standard reference materials for nutrients. AB - The National Institute of Standards and Technology (NIST) has been working with the National Institutes of Health Office of Dietary Supplements to produce Standard Reference Materials (SRMs) of interest to analysts of dietary supplements. Some of these SRMs are traditional foods including SRM 3281 Cranberry (Fruit), SRM 3282 Low-Calorie Cranberry Juice Cocktail, and SRM 3287 Blueberry (Fruit), which have been characterized for nine nutritional elements and sugars. The blueberries have also been characterized for proximates, two water-soluble vitamins, and amino acids. These new materials are intended for use in method development and validation as well as for quality assurance and traceability in the assignment of values to in-house control materials. Foods can be difficult to analyze because of matrix effects. With the addition of these three new SRMs, it is now possible to more closely match controls to matrices and analyte levels for fruit and vegetable test samples. Several nutritional elements in these three SRMs are present at lower levels than in other food-matrix SRMs. PMID- 21688778 TI - Membrane-based electrochemical nanobiosensor for Escherichia coli detection and analysis of cells viability. AB - A sensitive and selective membrane-based electrochemical nanobiosensor is developed for specific quantitative label-free detection of Escherichia coli (E. coli) cells and analysis of viable but nonculturable (VBNC) E. coli cells which remain mostly undetected using current methods. The sensing mechanism relies on the blocking of nanochannels of a nanoporous alumina-membrane modified electrode, upon the formation of immune complexes at the nanoporous membrane. The resulting obstacle to diffusive mass transfer of a redox probe in the analysis solution to the underlying platinum electrode reduces the Faradaic signal response of the biosensor, measured using cyclic voltammetry. Antibody loading under conditions of varying antibody concentrations and pHs are optimized. The biosensor gives a low detection limit of 22 cfu mL(-1) (R(2) = 0.999) over a wide linear working range of 10 to 10(6) cfu mL(-1). It is specific toward E. coli with minimal cross reactivity to two other pathogenic bacteria (commonly found in waters). Relative standard deviation (RSD) for triplicate measurements of 2.5% indicates reasonably useful level of reproducibility. Differentiation of live, VBNC, and dead cells are carried out after the cell capture and quantitation step, by simple monitoring of the cells' enzyme activity using the same redox probe in the analysis solution, in the presence of glucose. PMID- 21688779 TI - Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators. AB - There is an increasing amount of evidence to support that activation of the metabotropic glutamate receptor 4 (mGlu4 receptor), either with an orthosteric agonist or a positive allosteric modulator (PAM), provides impactful interventions in diseases such as Parkinson's disease, anxiety, and pain. mGlu4 PAMs may have several advantages over mGlu4 agonists for a number of reasons. As part of our efforts in identifying therapeutics for central nervous system (CNS) diseases such as Parkinson's disease, we have been focusing on metabotropic glutamate receptors. Herein we report our studies with a series of tricyclic thiazolopyrazoles as mGlu4 PAMs. PMID- 21688780 TI - Microfluidic electrochemical sensor array for characterizing protein interactions with various functionalized surfaces. AB - We present a unique microfluidic platform to allow for quick and sensitive probing of protein adsorption to various functionalized surfaces. The ability to tailor a sensor surface for a specific analyte is crucial for the successful application of portable gas and fluid sensors and is of great interest to the drug screening community. However, choosing the correct surface chemistry to successfully passivate against nonspecific binding typically requires repeated trial and error experiments. The presented device incorporates an array of integrated electrochemical sensors for fast, sensitive, label-free detection of these binding interactions. The layout of the electrodes allows for loading various surface chemistries in one direction while sensing their interactions with particular compounds in another without any cross-contamination. Impedance data is collected for three commonly used passivation compounds (mercaptohexanol, polyethylene glycol, and bovine serum albumin) and demonstrates their interaction with three commonly studied proteins in genetic and cancer research (cAMP receptor protein, tumor necrosis factor alpha, and tumor necrosis factor beta). The ability to quickly characterize various surface interactions provides knowledge for selecting optimal functionalization for any biosensor. PMID- 21688782 TI - Selective ortho-bromination of substituted benzaldoximes using Pd-catalyzed C-H activation: application to the synthesis of substituted 2-bromobenzaldehydes. AB - Substituted 2-bromobenzaldehydes were synthesized from benzaldehydes using a three-step sequence involving a selective palladium-catalyzed ortho-bromination as the key step. O-Methyloxime serves as a directing group in this reaction. A rapid deprotection of substituted 2-bromobenzaldoximes afforded substituted 2 bromobenzaldehydes with good overall yields. PMID- 21688781 TI - Triple isotopic labeling and kinetic isotope effects: exposing H-transfer steps in enzymatic systems. AB - Kinetic isotope effect (KIE) studies can provide insight into the mechanism and kinetics of specific chemical steps in complex catalytic cascades. Recent results from hydrogen KIE measurements have examined correlations between enzyme dynamics and catalytic function, leading to a surge of studies in this area. Unfortunately, most enzymatic H-transfer reactions are not rate limiting, and the observed KIEs do not reliably reflect the intrinsic KIEs on the chemical step of interest. Given their importance to understanding the chemical step under study, accurate determination of the intrinsic KIE from the observed data is essential. In 1975, Northrop developed an elegant method to assess intrinsic KIEs from their observed values [Northrop, D. B. (1975) Steady-state analysis of kinetic isotope effects in enzymic reactions. Biochemistry 14, 2644-2651]. The Northrop method involves KIE measurements using all three hydrogen isotopes, where one of them serves as the reference isotope. This method has been successfully used with different combinations of observed KIEs over the years, but criteria for a rational choice of reference isotope have never before been experimentally determined. Here we compare different reference isotopes (and hence distinct experimental designs) using the reduction of dihydrofolate and dihydrobiopterin by two dissimilar enzymes as model reactions. A number of isotopic labeling patterns have been applied to facilitate the comparative study of reference isotopes. The results demonstrate the versatility of the Northrop method and that such experiments are limited only by synthetic techniques, availability of starting materials, and the experimental error associated with the use of distinct combinations of isotopologues. PMID- 21688784 TI - Rational design of a ternary supramolecular system: self-assembly of pentanuclear lanthanide helicates. AB - The self-assembly of the first pentanuclear helicate was predicted on the structural basis obtained for linear and tetranuclear parent supramolecular compounds. Accordingly, the designed ternary supramolecular system requires appropriate polytopic organic receptors, which were successfully synthesized. Indeed, the formation of pentanuclear complexes was experimentally evidenced with NMR and ESMS spectra that perfectly reflect the expected pattern. The structural features in the europium pentanuclear complex are highlighted with semiempirical molecular modeling. The present work validates the combinatorial approach leading to the thermodynamically driven formation of tower-like pentanuclear edifices. PMID- 21688785 TI - Steric control of the donor/acceptor interface: implications in organic photovoltaic charge generation. AB - The performance of organic photovoltaic (OPV) devices is currently limited by modest short-circuit current densities. Approaches toward improving this output parameter may provide new avenues to advance OPV technologies and the basic science of charge transfer in organic semiconductors. This work highlights how steric control of the charge separation interface can be effectively tuned in OPV devices. By introducing an octylphenyl substituent onto the investigated polymer backbones, the thermally relaxed charge-transfer state, and potentially excited charge-transfer states, can be raised in energy. This decreases the barrier to charge separation and results in increased photocurrent generation. This finding is of particular significance for nonfullerene OPVs, which have many potential advantages such as tunable energy levels and spectral breadth, but are prone to poor exciton separation efficiencies. Computational, spectroscopic, and synthetic methods were combined to develop a structure-property relationship that correlates polymer substituents with charge-transfer state energies and, ultimately, device efficiencies. PMID- 21688786 TI - Synthesis of azaheterocycles from aryl ketone O-acetyl oximes and internal alkynes by Cu-Rh bimetallic relay catalysts. AB - A synthetic method for azaheterocycles from aryl ketone O-acetyl oximes and internal alkynes has been developed by using the Cu(OAc)(2)-[Cp*RhCl(2)](2) bimetallic catalytic system. The reactions proceeded with both of anti- and syn isomers of oximes with a wide scope of substituents. The Cu-Rh bimetallic system could be applied for the synthesis of isoquinolines as well as beta-carboline, furo[2.3-c]pyridine, pyrrolo[2,3-c]pyridine, and thieno[2,3-c]pyridine derivatives. PMID- 21688787 TI - New, potent, selective, and short-acting peptidic V1a receptor agonists. AB - [Arg(8)]vasopressin (AVP) produces vasoconstriction via V(1a) receptor (V(1a)R) mediated vascular smooth muscle cell contraction and is being used to increase blood pressure in septic shock, a form of vasodilatory hypotension. However, AVP also induces V(2) receptor (V(2)R)-mediated antidiuresis, vasodilation, and coagulation factor release, all deleterious in septic shock. The V(1a)R agonist terlipressin (H-Gly(3)[Lys(8)]VP) also lacks selectivity vs the V(2)R and has sizably longer duration of action than AVP, preventing rapid titration of its vasopressor effect in the clinic. We designed and synthesized new short acting V(1a)R selective analogues of general structure [Xaa(2),Ile(3),Yaa(4),Zaa(8)]VP. The most potent and selective compounds in in vitro functional assays (e.g., [Phe(2),Ile(3),Asn(Me(2))(4),Orn(8)]VP (31), [Phe(2),Ile(3),Asn((CH(2))(3)OH)(4),Orn(8)]VP (34), [Phe(2),Ile(3),Hgn(4),Orn(iPr)(8)]VP (45), [Phe(2),Ile(3),Asn(Et)(4),Dab(8)]VP (49), [Thi(2),Ile(3),Orn(iPr)(8)]VP (59), [Cha(2),Ile(3),Asn(4),Orn(iPr)(8)]VP (68)) were tested by intravenous bolus in rats for duration of vasopressive action. Analogues 31, 34, 45, and 49 were as short-acting as AVP. Compound 45, FE 202158, is currently undergoing clinical trials in septic shock. PMID- 21688788 TI - Pellicular particles with spherical carbon cores and porous nanodiamond/polymer shells for reversed-phase HPLC. AB - A new stationary phase for reversed-phase high performance liquid chromatography (RP HPLC) was created by coating spherical 3 MUm carbon core particles in a layer by-layer (LbL) fashion with poly(allylamine) (PAAm) and nanodiamond. Unfunctionalized core carbon particles were characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), time-of-flight secondary ion mass spectrometry (ToF-SIMS), and Raman spectroscopy. After LbL of PAAm and nanodiamond, which yields ca. 4 MUm core-shell particles, the particles were simultaneously functionalized and cross-linked using a mixture of 1,2 epoxyoctadecane and 1,2,7,8-diepoxyoctane to obtain a mechanically stable C(18)/C(8) bonded outer layer. Core-shell particles were characterized by SEM, and their surface area, pore diameter, and volume were determined using the Brunauer-Emmett-Teller (BET) method. Short stainless steel columns (30 * 4.6 mm i.d.) were packed and the corresponding van Deemter plots obtained. The Supporting Information contains a MATLAB program used to fit the van Deemter data. The retentions of a suite of analytes were investigated on a conventional HPLC at various organic solvent compositions, pH values of mobile phases, including extreme pH values, and column temperatures. At 60 degrees C, a chromatogram of 2,6-diisopropylphenol showed 71,500 plates/m (N/m). Chromatograms obtained under acidic conditions (pH 2.7) of a mixture of acetaminophen, diazepam, and 2,6-diisopropylphenol and a mixture of phenol, 4-methylphenol, 2 chlorophenol, 4-chlorophenol, 4-bromophenol, and 1-tert-butyl-4-methylphenol are presented. Retention of amitriptyline, cholesterol, and diazinon at temperatures ranging from 35 to 80 degrees C and at pH 11.3 is reported. A series of five basic drugs was also separated at this pH. The stationary phase exhibits considerable hydrolytic stability at high pH (11.3) and even pH 13 over extended periods of time. An analysis run on a UHPLC with a "sandwich" injection appeared to reduce extra column band broadening and gave best efficiencies of 110,000 120,000 N/m. PMID- 21688789 TI - Re-radiation enhancement in polarized surface-enhanced resonant Raman scattering of randomly oriented molecules on self-organized gold nanowires. AB - We explore the effect of re-radiation in surface-enhanced Raman scattering (SERS) through polarization-sensitive experiments on self-organized gold nanowires on which randomly oriented Methylene Blue molecules are adsorbed. We provide the exact laws ruling the polarized, unpolarized, and parallel- and cross-polarized SERS intensity as a function of the field polarizations. We show that SERS is polarized along the wire-to-wire nanocavity axis, independently from the excitation polarization. This proves the selective enhancement of the Raman dipole component parallel to the nanocavity at the single molecule level. Introducing a field enhancement tensor to account for the anisotropic polarization response of the nanowires, we work out a model that correctly predicts the experimental results for any excitation/detection polarization and goes beyond the E(4) approximation. We also show how polarization-sensitive SERS experiments permit one to evaluate independently the excitation and the re radiation enhancement factors accessing the orientation-averaged non-diagonal components of the molecular Raman polarizability tensor. PMID- 21688790 TI - Regioselective synthesis of tetrahydrothiochromen-5-ones via a one-pot three component solvent-free domino protocol. AB - A highly efficient one-pot three-component regioselective synthesis of 4-aryl-3 aroyl-2-methylsulfanyl-4,6,7,8-tetrahydrothiochromen-5-ones has been developed by annulation of beta-oxodithioesters with aldehydes and cyclic 1,3-diketones under solvent-free conditions promoted by P(2)O(5). No cocatalyst or activator is needed in this protocol. The merit of this process is highlighted by its high efficiency of producing three new bonds and a stereocenter in one operation. PMID- 21688791 TI - Red-emission fluorescent probe sensing cadmium and pyrophosphate selectively in aqueous solution. AB - A fluorescent sensor for cadmium (CS) based on the BODIPY fluorophore exploiting the PET (Photoinduced Electron Transfer) mechanism was prepared. CS exhibited high selectivity and sensitivity for detecting cadmium in aqueous buffer solution. In addition, the complex of CS with cadmium could detect pyrophosphate (PPi) selectively and sensitively. PMID- 21688792 TI - Anisotropic elasticity of quasi-one-component polymer nanocomposites. AB - The in-plane and out-of-plane elastic properties of thin films of "quasi-one component" particle-brush-based nanocomposites are compared to those of "classical" binary particle-polymer nanocomposite systems with near identical overall composition using Brillouin light scattering. Whereas phonon propagation is found to be independent of the propagation direction for the binary particle/polymer blend systems, a pronounced splitting of the phonon propagation velocity along the in-plane and out-of-plane film direction is observed for particle-brush systems. The anisotropic elastic properties of quasi-one-component particle-brush systems are interpreted as a consequence of substrate-induced order formation into layer-type structures and the associated breaking of the symmetry of the film. The results highlight new opportunities to engineer quasi one-component nanocomposites with advanced control of structural and physical property characteristics based on the assembly of particle-brush materials. PMID- 21688793 TI - Perfluorinated carboxylic acids in directly fluorinated high-density polyethylene material. AB - Perfluorinated carboxylic acids (PFCAs) are ubiquitous in the environment and have been detected in human blood worldwide. One potential route is direct exposure to PFCAs through contact with polymers that have been fluorinated through a process referred to as direct fluorination. PFCAs are hypothesized to be reaction byproducts of direct fluorination when trace amounts of oxygen are present. The objective of this research was to investigate whether PFCAs could be measured in directly fluorinated high-density polyethylene (HDPE) bottles. PFCAs were quantified using Soxhlet extraction with methanol, followed by LC-MS/MS analysis. Total concentrations of PFCAs ranged from 8.5 +/- 0.53 to 113 +/- 2.5 ng/bottle (1 L), with the short-chain PFCAs, perfluoropropanoic, perfluorobutanoic, perfluoropentanoic, and perfluorohexanoic acids, being the dominant congeners observed. Relative PFCA concentrations varied depending on fluorination level. Structural isomers were detected using (19)F NMR and are hypothesized to have formed during the fluorination process; NMR data revealed the linear isomer typically comprised 55% of the examined sample. Internally branched, isopropyl branched, and t-butyl PFCA isomers of varying chain length were also identified. Electrochemical fluorination was previously thought to be the only source of branched PFCA isomers. The observation here of branched isomers suggests direct fluorination may be an additional source of exposure to these chemicals. The purpose of this study was to measure PFCAs in directly fluorinated material, serving as a previously unidentified source contributing to the environmental load of PFCAs, with potential for human exposure. PMID- 21688795 TI - Adsorption-site-dependent electronic structure of catechol on the anatase TiO2(101) surface. AB - The adsorption of catechol (1,2-benzendiol) on the anatase TiO(2)(101) surface was studied with synchrotron-based ultraviolet photoemission spectroscopy (UPS), X-ray photoemission spectroscopy (XPS), and scanning tunneling microscopy (STM). Catechol adsorbs with a unity sticking coefficient and the phenyl ring intact. STM reveals preferred nucleation at step edges and subsurface point defects, followed by 1D growth and the formation of a 2 * 1 superstructure at full coverage. A gap state of ~1 eV above the valence band maximum is observed for dosages in excess of ~0.4 Langmuir, but such a state is absent for lower coverages. The formation of the band gap states thus correlates with the adsorption at regular lattice sites and the onset of self-assembled superstructures. PMID- 21688794 TI - Cytotoxicity screening of single-walled carbon nanotubes: detection and removal of cytotoxic contaminants from carboxylated carbon nanotubes. AB - This study compares the cytotoxicity to cultured mammalian cells of nine different single-walled carbon nanotube (SWNT) products synthesized by a variety of methods and obtained from a cross section of vendors. A standard procedure involving sonication and centrifugation in buffered bovine serum albumin was developed to disperse all the SWNTs in a biocompatible solution to facilitate comparisons. The effect of the SWNTs on the proliferative ability of a standard cell line was then assessed. Of the nine different SWNT materials tested, only two were significantly toxic, and both were functionalized by carboxylation from different vendors. This was unexpected because carboxylation makes SWNTs more water-soluble, which would presumably correlate with better biocompatibility. However, additional purification work demonstrated that the toxic material in the carboxylated SWNT preparations could be separated from the SWNTs by filtration. The filtrate that contained the toxic activity also contained abundant small carbon fragments that had Raman signatures characteristic of amorphous carbon species, suggesting a correlation between toxicity and oxidized carbon fragments. The removal of a toxic contaminant associated with carboxylated SWNTs is important in the development of carboxylated SWNTs for pharmacological applications. PMID- 21688796 TI - Formation of host-guest complexes of beta-cyclodextrin and perfluorooctanoic acid. AB - Structural characterization and dynamic properties of solid-state inclusion complexes of beta-cyclodextrin (beta-CD) with perfluorooctanoic acid (PFOA) were investigated by (19)F/(13)C solid-state and (19)F/(1)H solution NMR spectroscopy. The complexes in the solid state were prepared using dissolution and slow cool methods, where thermal analyses (DSC and TGA), PXRD, and FT-IR results provided complementary support that inclusion complexes were formed between beta-CD and PFOA with variable stoichiometry and inclusion geometry. (19)F DP (direct polarization) and (13)C CP (cross-polarization) with magic-angle spinning (MAS) solids NMR, along with (19)F/(1)H solution NMR were used to characterize the complexes in the solid and solution phases, respectively. The dynamics of the guest molecules in the inclusion complexes (ICs) were studied using variable temperature (VT) (19)F DP/MAS NMR experiments in the solid state. The guest molecules were observed to be in several different molecular environments, providing strong evidence of variable host-guest stoichiometry and inclusion geometry, in accordance with the preparation method of the complex and the conformational preference of PFOA. It was concluded from PXRD that beta-CD and PFOA form inclusion complexes with "channel-type" structures. Variable spin rate (VSR) (19)F DP/MAS NMR was used to assess the phase purity of the complexes, and it was revealed that slow cooling resulted in relatively pure phases. In the solution state, (1)H and (19)F NMR complexation-induced chemical shifts (CISs) of beta-CD and PFOA, respectively, provided strong support for the formation of 1:1 and 2:1 beta-CD/PFOA inclusion complexes. The dynamics of the guest molecule in the beta-CD/PFOA complexes in D(2)O solutions were probed using VT (19)F NMR and revealed some guest conformational and exchange dynamics as a function of temperature and the relative concentrations of the host and guest. PMID- 21688797 TI - Effect of garlic oil on neutrophil infiltration in the small intestine of endotoxin-injected rats and its association with levels of soluble and cellular adhesion molecules. AB - Garlic ( Allium sativum ) possesses anti-inflammatory effects. This study investigated the effects of garlic oil on endotoxin-induced neutrophil infiltration in the small intestine. Wistar rats received by gavage 10, 50, or 100 mg/kg body wt garlic oil (GO) or the vehicle (corn oil; 2 mL/kg body wt) every other day for 2 weeks before being injected with endotoxin (ip, 5 mg/kg body wt). Control rats were administered corn oil and injected with sterile saline. Blood samples for the measurement of soluble adhesion molecules were collected at various time points after injection, and all other samples were collected 18 h after injection. The 10 and 50 mg/kg doses suppressed endotoxin induced neutrophilia, serum levels of sL-selectin and sICAM-1, cellular CD11b on neutrophils, intestinal ICAM-1 content, and neutrophil infiltration (P < 0.05). The 100 mg/kg dose significantly lowered local ICAM-1 and cellular CD11b on neutrophils (P < 0.05) but did not have a beneficial effect on neutrophil infiltration. In addition, 100 mg/kg of GO worsened the elevation of the local TNF-alpha level and neutrophilia. Appropriate doses of garlic oil have a preventive effect on endotoxin-induced neutrophil infiltration and damage to the small intestine. PMID- 21688798 TI - Redox-active bridging ligands based on indigo diimine ("Nindigo") derivatives. AB - Reactions of indigo with a variety of substituted anilines produce the corresponding indigo diimines ("Nindigos") in good yields. Nindigo coordination complexes are subsequently prepared by reactions of the Nindigo ligands with Pd(hfac)(2). In most cases, binuclear complexes are obtained in which the deprotonated Nindigo bridges two Pd(hfac) moieties in the expected bis-bidentate binding mode. When the Nindigo possesses bulky substituents on the imine (mesityl, 2,6-dimethylphenyl, 2,6-diisopropylphenyl, etc.), mononuclear Pf(hfac) complexes are obtained in which the Nindigo core has isomerized from a trans- to a cis-alkene; in these structures, the palladium is bound to the cis-Nindigo ligand at the two indole nitrogen atoms; the remaining proton is bound between the imine nitrogen atoms. The palladium complexes possess intense electronic absorption bands [near 920 nm for the binuclear complexes and 820 nm for the mononuclear cis-Nindigo complexes; extinction coefficients are (1.0-2.0) * 10(4) M(-1) cm(-1)] that are ligand-centered (pi-pi*) transitions. Cyclic voltammetry investigations reveal multiple redox events that are also ligand-centered in origin. All of the palladium complexes can be reversibly oxidized in two sequential one-electron steps; the binuclear complexes are reduced in a two electron process whose reversibility depends on the Nindigo ligand substituent; the mononuclear palladium species show two one-electron reductions, only the first of which is quasi-reversible. PMID- 21688799 TI - Synthesis of oligodiaminosaccharides having alpha-glycoside bonds and their interactions with oligonucleotide duplexes. AB - Syntheses of the novel oligodiaminosaccharides, alpha-(1->4)-linked-2,6-diamino 2,6-dideoxy-D-glucopyranose oligomers, and their interactions with nucleic acid duplexes DNA-DNA, RNA-RNA, and DNA-RNA are described. Monomers to tetramers of oligodiaminoglucose derivatives having alpha-glycosyl bonds were successfully synthesized using a chain elongation cycle including glycosylation reactions of a 6-phthalimide glycosyl donor. UV melting experiments for a variety of nucleic acid duplexes in the absence and presence of the oligodiaminosaccharides were performed. The synthesized oligodiaminosaccharides exhibited notable thermodynamic stabilization effects on A-type RNA-RNA and DNA-RNA duplexes, whereas B-type DNA-DNA duplexes were not stabilized by the synthesized oligodiaminosaccharides. Among the oligodiaminosaccharides, the tetramer exhibited the highest ability to stabilize A-type duplexes, and the increase in T(m) values induced by the tetramer were higher than those induced by neomycin B and tobramycin, which are known aminoglycosides having ability to bind and stabilize a variety of RNA molecules. CD spectrometry experiments revealed that the oligodiaminosaccharides caused small structural changes in RNA-RNA duplexes, whereas no appreciable changes were observed in the structure of DNA-DNA duplexes. ITC (isothermal titration calorimetry) experiments demonstrated that the amount of heat generated by the interaction between RNA-RNA duplexes and the tetradiaminosaccharides was approximately double that generated by that between DNA-DNA duplexes and the tetradiaminosaccharides. These results strongly suggested the existence of an A-type nucleic acid specific-binding mode of the oligodiaminosaccharides, which bind to these duplexes and cause small structural changes. PMID- 21688800 TI - Two-step synthesis of hexaammonium triptycene: an air-stable building block for condensation reactions to extended triptycene derivatives. AB - A simple two-step synthesis of an air-stable hexaammoniumtriptycene is introduced, which can be used for a variety of transformations by condensation reactions, e.g., to benzimidazole, benzotriazole, and quinoxaline derivatives in high yields. PMID- 21688802 TI - Femtosecond photoelectron imaging of transient electronic states and Rydberg atom emission from electronically excited he droplets. AB - Ultrafast relaxation of electronically excited pure He droplets is investigated by femtosecond time-resolved photoelectron imaging. Droplets are excited by extreme ultraviolet (EUV) pulses with photon energies below 24 eV. Excited states and relaxation products are probed by ionization with an infrared (IR) pulse with 1.6 eV photon energy. An initially excited droplet state decays on a time scale of 220 fs, leading predominantly to the emission of unaligned 1s3d Rydberg atoms. In a second relaxation channel, electronically aligned 1s4p Rydberg atoms are emitted from the droplet within less than 120 fs. The experimental results are described within a model that approximates electronically excited droplet states by localized, atomic Rydberg states perturbed by the local droplet environment in which the atom is embedded. The model suggests that, below 24 eV, EUV excitation preferentially leads to states that are localized in the surface region of the droplet. Electronically aligned 1s4p Rydberg atoms are expected to originate from excitations in the outermost surface regions, while nonaligned 1s3d Rydberg atoms emerge from a deeper surface region with higher local densities. The model is used to simulate the He droplet EUV absorption spectrum in good agreement with previously reported fluorescence excitation measurements. PMID- 21688803 TI - From highly enantioselective catalytic reaction of 1,3-diynes with aldehydes to facile asymmetric synthesis of polycyclic compounds. AB - (S)-1,1'-Binaphth-2-ol (BINOL) in combination with ZnEt(2), Ti(O(i)Pr)(4), and biscyclohexylamine was found to catalyze the highly enantioselective (83-95% ee) addition of various 1,3-diynes to aldehydes of diverse structures. This method provides a convenient pathway to generate a number of optically active dienediynes as the acyclic precursors to polycyclic compounds. The chiral dienediynes undergo highly chemoselective Pauson-Khand (PK) cycloaddition in benzaldehyde by using [Rh(cod)Cl](2) as the catalyst in the presence of rac BINAP. High diastereoselectivity (up to >20:1) has also been achieved with the chiral dienediyne substrates containing a bulky substituent adjacent to the chiral center. In the presence of the Grubbs II catalyst, ring-closing enyne metathesis of the PK cycloaddition products led to the formation of the desired 5,5,7- and 5,5,8-fused tricyclic compounds. Further highly diastereoselective Diels-Alder reaction of a 5,5,7-tricyclic compound with maleic anhydride produced a 5,5,7,6-polycyclic product. The asymmetric synthesis of polycyclic compounds from optically active dienediynes has established a novel and efficient synthetic route to the structural framework of many biologically significant molecules. PMID- 21688804 TI - Nonadiabatic molecular dynamics study of the cis-trans photoisomerization of azobenzene excited to the S1 state. AB - Ab initio nonadiabatic dynamics simulations of cis-to-trans isomerization of azobenzene upon S(1) (n-pi*) excitation are carried out employing the fewest switches surface hopping method. Azobenzene photoisomerization occurs purely as a rotational motion of the central CNNC moiety. Two nonequivalent rotational pathways corresponding to clockwise or counterclockwise rotation are available. The course of the rotational motion is strongly dependent on the initial conditions. The internal conversion occurs via an S(0)/S(1) crossing seam located near the midpoint of both of these rotational pathways. Based on statistical analysis, it is shown that the occurrence of one or other pathway can be completely controlled by selecting adequate initial conditions. PMID- 21688805 TI - Nickel-catalyzed amination of aryl phosphates through cleaving aryl C-O bonds. AB - The amination of triaryl phosphates was achieved using a Ni(II)-(sigma-Aryl) complex/NHC catalyst system in dioxane at 110 degrees C in the presence of NaH as base. Electron-neutral, -rich, and -deficient triaryl phosphates were coupled with a wider range of amine partners including cyclic and acyclic secondary amines, aliphatic primary amines, and anilines in good to excellent yields. PMID- 21688806 TI - Structure and opto-electrochemical properties of ZnO nanowires grown on n-Si substrate. AB - Zinc oxide (ZnO) nanostructures have attracted great attention as a promising functional material with unique properties suitable for applications in UV lasers, light emitting diodes, field emission devices, sensors, field effect transistors, and solar cells. In the present work, ZnO nanowires have been synthesized on an n-type Si substrate using a hydrothermal method where surfactant acted as a modifying and protecting agent. The surface morphology, electrochemical properties, and opto-electrochemical properties of ZnO nanowires are investigated by using scanning electron microscopy (SEM), energy dispersive X ray spectroscopy (EDS), cyclic voltammetry, and impedance spectroscopy techniques. The cycling characteristics and rate capability of the ZnO nanowires are explored through electrochemical studies performed under varying electrolytes. The photo response is observed using UV radiation. It is demonstrated that crystallinity, particle size, and morphology all play significant roles in the electrochemical performance of the ZnO electrodes. PMID- 21688807 TI - Synthesis of para- or ortho-substituted triarylbilindiones and tetraarylbiladienones by coupled oxidation of tetraarylporphyrins. AB - Coupled oxidation of [tetraarylporphyrinato]iron(III) chloride carrying substituents in the ortho or para positions was performed by allowing the iron porphyrin to react with dioxygen, ascorbic acid, and pyridine to give biladienone as the major product and bilindione as a minor one. Efforts to find reaction conditions and workup procedures to obtain bilindione improved the yields of triarylbilindiones ranging between 2% and 19%. Electron-withdrawing substituents in the para position on the aryl groups increased the selectivity of bilindione relative to biladienone: the isolated yields of bilindione and biladienone were 2% and 85% (OMe), 6% and 44% (COOMe), and 7% and 28% (CN), respectively. Electronic effects of substituents affected both isolation procedures and the spectroscopic properties of bilindiones. Tri(4-methoxyphenyl)bilindione showed a red-shifted electronic absorption compared to unsubstituted and 4-methoxycarbonyl substituted analogues. This was ascribed to the destabilization of the HOMO-1 level by the methoxy groups. PMID- 21688808 TI - Transparent, luminescent, antibacterial and patternable film forming composites of graphene oxide/reduced graphene oxide. AB - Multifunctional graphene oxide/reduced graphene oxide (GO/RGO) composites were prepared through electrostatic interaction using biocompatible ingredients. Different functionalities were added to GO/RGO by anchoring materials such as native lactoferrin (NLf), NLf protected Au clusters (designated as Au@NLf), chitosan (Ch) and combinations thereof. Anchoring of Ch and NLf enhances the antibacterial property of RGO/GO. The addition of Ch to RGO/GO not only helped in forming stable dispersions but also helped in fabricating large (cm(2)) area films through a simple solvent evaporation technique. Functionalities such as photoluminescence were added to Ch-RGO/GO composites by anchoring Au@NLf on it. The composites thus formed showed stable luminescence in presence of various metal ions in the solid state. The composite showed reasonable stability against pH and temperature variations as well. The as-prepared films were transparent and the transparency could be modulated by controlling the concentration of RGO/GO in the composite. The antibacterial property and ability to form stable thin films may provide an opportunity to use such composites for medical and environmental remediation applications as well. Erasable patterns were fabricated on the film by stamping required patterns under compressive pressure. Luminescent patterns can be inscribed on the film and can be erased by simply wetting it. Such films with erasable information may be useful for security applications. PMID- 21688809 TI - General procedure for the synthesis of dinucleoside polyphosphates. AB - Dinucleoside 5',5'-polyphosphates (N(p)(n)N) play important roles in biological processes and have been developed into drugs. However, their synthesis still remains a challenge. Here we report a rapid and general approach to the synthesis of dinucleoside 5',5'-polyphosphates by coupling highly reactive nucleoside 5' monophosphate-N-methylimidazolium salts donors with nucleoside 5'-mono-, -di-, and -triphosphate acceptors. PMID- 21688810 TI - Improving bioavailability and stability of genistein by complexation with high amylose corn starch. AB - Genistein, like other phytochemicals, has beneficial health effects, but its bioavailability is limited. This research studied the effect of complexation of genistein with starch on genistein bioavailability. Genistein release from these complexes was tested in vitro under simulated intestinal conditions and in vivo in rats fed high-amylose corn starch (HACS)-genistein complexes (experimental group) as compared to those fed a physical mixture of HACS and genistein (controls). In vitro results showed that genistein release is sustained and fits the normal transit time of food in the intestine. The genistein concentration in the plasma was twice as high in the experimental group versus controls; the genistein concentration in the urine was also higher in the experimental group but lower in the feces. These results indicate that starch-genistein complexes increase genistein bioavailability and suggest that starch can affect the bioavailability of additional food components. PMID- 21688811 TI - Azobenzene-functionalized carbon nanotubes as high-energy density solar thermal fuels. AB - Solar thermal fuels, which reversibly store solar energy in molecular bonds, are a tantalizing prospect for clean, renewable, and transportable energy conversion/storage. However, large-scale adoption requires enhanced energy storage capacity and thermal stability. Here we present a novel solar thermal fuel, composed of azobenzene-functionalized carbon nanotubes, with the volumetric energy density of Li-ion batteries. Our work also demonstrates that the inclusion of nanoscale templates is an effective strategy for design of highly cyclable, thermally stable, and energy-dense solar thermal fuels. PMID- 21688812 TI - NOx emission reduction and its effects on ozone during the 2008 Olympic Games. AB - We applied a daily assimilated inversion method to estimate NO(x) (NO + NO(2)) emissions for June-September 2007 and 2008 on the basis of the Aura Ozone Monitoring Instrument (OMI) observations of nitrogen dioxide (NO(2)) and model simulations using the Regional chEmistry and trAnsport Model (REAM). This method allows for estimating emission changes with a finer temporal resolution than previous studies and shows that the progression of the emission reduction corresponds roughly to the scheduled implementation of emission controls over Beijing. OMI column NO(2) reductions are approximately 45%, 33%, and 14% over urban Beijing, rural Beijing, and the Huabei Plain, respectively, while the corresponding anthropogenic NO(x) emission reductions are only 28%, 24%, and 6%, during the full emission control period (July 20-Sep 20, 2008). Meteorological changes from summer 2007 to 2008 are the main factor contributing to the column NO(2) decreases not accounted for by the emission reduction. The surface ozone changes due to NO(x) emission reduction are negligible using a standard VOC emission inventory. When using enhanced VOC (particularly aromatics) emissions derived from in situ observations, urban Beijing shifted O(3) production from the VOC-limited regime toward the NO(x)-limited regime resulting in a more substantial ozone decrease (up to 10 ppbv). PMID- 21688813 TI - n-Type transition metal oxide as a hole extraction layer in PbS quantum dot solar cells. AB - The n-type transition metal oxides (TMO) consisting of molybdenum oxide (MoO(x)) and vanadium oxide (V(2)O(x)) are used as an efficient hole extraction layer (HEL) in heterojunction ZnO/PbS quantum dot solar cells (QDSC). A 4.4% NREL certified device based on the MoO(x) HEL is reported with Al as the back contact material, representing a more than 65% efficiency improvement compared with the case of Au contacting the PbS quantum dot (QD) layer directly. We find the acting mechanism of the hole extraction layer to be a dipole formed at the MoO(x) and PbS interface enhancing band bending to allow efficient hole extraction from the valence band of the PbS layer by MoO(x). The carrier transport to the metal anode is likely enhanced through shallow gap states in the MoO(x) layer. PMID- 21688814 TI - Iron-catalyzed carbonylation-peroxidation of alkenes with aldehydes and hydroperoxides. AB - A three-component reaction of alkenes, aldehydes, and hydroperoxides catalyzed by FeCl(2) to beta-peroxy ketones has been achieved. This three-component reaction can be also applied to the synthesis of alpha-carbonyl epoxides, through either a stepwise base-induced epoxidation of the separated beta-peroxy ketone products or a one-pot process by simply adding base to the reaction mixture after the completion of the three-component reaction. PMID- 21688815 TI - Bovine insulin-phosphatidylcholine mixed Langmuir monolayers: behavior at the air water interface. AB - The behavior of the binary mixed Langmuir monolayers of bovine insulin (INS) and phosphatidylcholine (PC) spread at the air-water interface was investigated under various subphase conditions. Pure and mixed monolayers were spread on water, on NaOH and phosphate-buffered solutions of pH 7.4, and on Zn(2+)-containing solutions. Miscibility and interactions between the components were studied on the basis of the analysis of the surface pressure (pi)-mean molecular area (A) isotherms, surface compression modulus (C(s)(-1))-pi curves, and plots of A versus mole fraction of INS (X(INS)). Our results indicate that intermolecular interactions between INS and PC depend on both the monolayer state and the structural characteristics of INS at the interface, which are strongly influenced by the subphase pH and salt content. Brewster angle microscopy (BAM) was applied to investigate the peptide aggregation pattern at the air-water interface in the presence of the studied lipid under any experimental condition investigated. The influence of the lipid on the INS behavior at the interface strongly depends on the subphase conditions. PMID- 21688816 TI - Charge reversal of sulfate latex particles by adsorbed linear poly(ethylene imine) probed by multiparticle colloidal probe technique. AB - Interactions between negatively charged latex particles in the presence of cationic linear poly(ethylene imine) (LPEI) were studied with atomic force microscopy (AFM) and electrophoresis. Forces were measured directly with the recently developed multiparticle colloidal probe technique, which permits colloidal particles to attach to the cantilever in aqueous dispersions in situ and ensures a large surface area during experiment. It was observed that the forces vary from repulsive to attractive and back to repulsive with increasing polymer dose. The repulsive forces are due to overlap of the diffuse layers around charged surfaces. The attractive forces are independent of the ionic strength and the molecular mass of the polymer and can be rationalized in terms of classical van der Waals interactions. Additional electrostatic attractive forces due to patch-charge heterogeneities observed in other particle polyelectrolyte systems are absent here. Their absence indicates that the adsorbed layer of LPEI has a high lateral homogeneity. PMID- 21688801 TI - Metabolism and biomarkers of heterocyclic aromatic amines in molecular epidemiology studies: lessons learned from aromatic amines. AB - Aromatic amines and heterocyclic aromatic amines (HAAs) are structurally related classes of carcinogens that are formed during the combustion of tobacco or during the high-temperature cooking of meats. Both classes of procarcinogens undergo metabolic activation by N-hydroxylation of the exocyclic amine group to produce a common proposed intermediate, the arylnitrenium ion, which is the critical metabolite implicated in toxicity and DNA damage. However, the biochemistry and chemical properties of these compounds are distinct, and different biomarkers of aromatic amines and HAAs have been developed for human biomonitoring studies. Hemoglobin adducts have been extensively used as biomarkers to monitor occupational and environmental exposures to a number of aromatic amines; however, HAAs do not form hemoglobin adducts at appreciable levels, and other biomarkers have been sought. A number of epidemiologic studies that have investigated dietary consumption of well-done meat in relation to various tumor sites reported a positive association between cancer risk and well-done meat consumption, although some studies have shown no associations between well-done meat and cancer risk. A major limiting factor in most epidemiological studies is the uncertainty in quantitative estimates of chronic exposure to HAAs, and thus, the association of HAAs formed in cooked meat and cancer risk has been difficult to establish. There is a critical need to establish long-term biomarkers of HAAs that can be implemented in molecular epidemioIogy studies. In this review, we highlight and contrast the biochemistry of several prototypical carcinogenic aromatic amines and HAAs to which humans are chronically exposed. The biochemical properties and the impact of polymorphisms of the major xenobiotic-metabolizing enzymes on the biological effects of these chemicals are examined. Lastly, the analytical approaches that have been successfully employed to biomonitor aromatic amines and HAAs, and emerging biomarkers of HAAs that may be implemented in molecular epidemiology studies are discussed. PMID- 21688817 TI - Minimizing graphene defects enhances titania nanocomposite-based photocatalytic reduction of CO2 for improved solar fuel production. AB - With its unique electronic and optical properties, graphene is proposed to functionalize and tailor titania photocatalysts for improved reactivity. The two major solution-based pathways for producing graphene, oxidation-reduction and solvent exfoliation, result in nanoplatelets with different defect densities. Herein, we show that nanocomposites based on the less defective solvent exfoliated graphene exhibit a significantly larger enhancement in CO(2) photoreduction, especially under visible light. This counterintuitive result is attributed to their superior electrical mobility, which facilitates the diffusion of photoexcited electrons to reactive sites. PMID- 21688818 TI - Manganese(III)-containing Wells-Dawson sandwich-type polyoxometalates: comparison with their manganese(II) counterparts. AB - We present the synthesis and structural characterization, assessed by various techniques (FTIR, TGA, UV-vis, elemental analysis, single-crystal X-ray diffraction for three compounds, magnetic susceptibility, and electrochemistry) of five manganese-containing Wells-Dawson sandwich-type (WDST) complexes. The dimanganese(II)-containing complex, [Na(2)(H(2)O)(2)Mn(II)(2)(As(2)W(15)O(56))(2)](18-) (1), was obtained by reaction of MnCl(2) with 1 equiv of [As(2)W(15)O(56)](12-) in acetate medium (pH 4.7). Oxidation of 1 by Na(2)S(2)O(8) in aqueous solution led to the dimanganese(III) complex [Na(2)(H(2)O)(2)Mn(III)(2)(As(2)W(15)O(56))(2)](16-) (2), while its trimanganese(II) homologue, [Na(H(2)O)(2)Mn(II)(H(2)O)Mn(II)(2)(As(2)W(15)O(56))(2)](17-) (3), was obtained by addition of ca. 1 equiv of MnCl(2) to a solution of 1 in 1 M NaCl. The trimanganese(III) and tetramanganese(III) counterparts, [Mn(III)(H(2)O)Mn(III)(2)(As(2)W(15)O(56))(2)](15-) (4) and [Mn(III)(2)(H(2)O)(2)Mn(III)(2)(As(2)W(15)O(56))(2)](12-) (6), are, respectively, obtained by oxidation of aqueous solutions of 3 and [Mn(II)(2)(H(2)O)(2)Mn(II)(2)(As(2)W(15)O(56))(2)](16-) (5) by Na(2)S(2)O(8). Single-crystal X-ray analyses were carried out on 2, 3, and 4. BVS calculations and XPS confirmed that the oxidation state of Mn centers is +II for complexes 1, 3, and 5 and +III for 2, 4, and 6. A complete comparative electrochemical study was carried out on the six compounds cited above, and it was possible to observe the distinct redox steps Mn(IV/III) and Mn(III/II). Magnetization measurements, as a function of temperature, confirm the presence of antiferromagnetic interactions between the Mn ions in these compounds in all cases with the exception of compound 2. PMID- 21688819 TI - Effects of Hofmeister anions on the aggregation behavior of PEO-PPO-PEO triblock copolymers. AB - The effects of a series of Hofmeister anions on the phase behaviors of a poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymer were investigated with an automated melting point system. Well hydrated anions and poorly hydrated anions interacted with the polymer differently and further affected the phase transition of the polymer. Poorly hydrated anions worked through changing the interfacial tension at the polymer/aqueous interface and in enhancing the polymer hydration by ion binding. The phase transition of the polymer in the presence of well hydrated anions correlated directly to the hydration entropy of the anions. As a consequence, the polymer showed a two-step phase transition in solutions containing poorly hydrated anions while displayed a single-step phase transition in the presence of well hydrated anions. The mechanisms of how ions interact with the polymer and further modulate its phase behaviors were discussed. PMID- 21688820 TI - Nickel-catalyzed cycloaddition of o-arylcarboxybenzonitriles and alkynes via cleavage of two carbon-carbon sigma bonds. AB - An intermolecular cycloaddition reaction has been developed, where o arylcarboxybenzonitriles react with alkynes to afford coumarins in the presence of Ni(0)/P(CH(2)Ph)(3)/MAD as a catalyst. The reaction process displays an unusual mechanistic feature-the cleavage of two independent C-CN and C-CO bonds. PMID- 21688821 TI - Formation of carbon-sulfur and carbon-selenium bonds by palladium-catalyzed decarboxylative cross-couplings of hindered 2,6-dialkoxybenzoic acids. AB - A simple route to diaryl sulfides using a decarboxylative palladium-catalyzed reaction between electron-rich 2,6-dialkoxybenzoic acid derivatives and diaryl disulfides is reported. This coupling proceeds efficiently in the presence of Pd(CF(3)CO(2))(2) and Ag(2)CO(3) in a 65:1 mixture of 1,4-dioxane and tetramethylene sulfoxide (TMSO). We present also the first formation of a carbon selenium bond via a palladium-catalyzed decarboxylative cross-coupling. PMID- 21688822 TI - Solution fabrication and photoelectrical properties of CuInS2 nanocrystals on TiO2 nanorod array. AB - One-dimensional semiconductor architectures are receiving attention in preparing photovoltaic solar cells because of its superior charge transport as well as excellent light-harvesting efficiency. In this study, vertically aligned single crystalline TiO(2) nanorods array was grown directly on transparent conductive glass (FTO), and then CuInS(2) nanocrystals were deposited on nanorods array by spin coating method to form TiO(2)/CuInS(2) heterostructure films. The resulting nanostructure assembly and composition was confirmed by field-emission scanning electron microscope (FESEM) , transmission electron microscopy (TEM), high resolution TEM, and X-ray diffraction(XRD). Ultraviolet-visible absorption spectroscopy (UV-vis) data indicates that the absorbance of the nanocomposite film extended into the visible region compared with bare TiO(2) nanorod arrays. The surface photovoltage spectra (SPS) also showed a new and enhanced response region corresponding to the absorption spectrum. These results suggest that the novel CuInS(2) nanocrystals sensitized TiO(2) nanorod array on FTO photoelectrodes has a potential application in photovoltaic devices. PMID- 21688823 TI - Field emission properties of low-temperature, hydrothermally grown tungsten oxide. AB - Tungsten oxide layers have been prepared on conductive glass substrates using aqueous chemical growth from a sodium tungstate precursor at low-temperature hydrothermal conditions. The deposits were then tested as cold electron emitters. Traceable layers could be deposited only within a narrow pH range of 1.5-2 at a time length not exceeding 4 h. Transmittance in the visible spectrum was found to decrease with deposition time. The presence of both monoclinic and hexagonal phases was always detected. At the longest deposition times and highest precursor concentrations, morphologies comprise randomly oriented spikes or rods. The overall emission performance is found to improve with growth time and precursor concentration. The role of morphology on the emission properties of the films is discussed. PMID- 21688824 TI - Theoretical study on reaction scheme of silver(I) containing 5-substituted uracils bridge formation. AB - We present a reaction scheme of silver containing 5-substituted uracils (N) bridge formation with two silver ions to a silver-mediated base pair [N-Ag(2)-N] by using the conductor-like polarizable continuum model (CPCM)-B3LYP/aug-cc-pVDZ level of theory. The whole reaction scheme is divided into the following three steps: (1) silver ion binding and deprotonation, (2) silver ion transfer, and (3) dimer formation and structural fluctuation. With a new pK(a) computing scheme proposed in our previous studies, it is found that a silver coordination decreases the pK(a) of N by 2.5-3.0 pK(a) units, which is an important clue for silver-ion selectivity by N. Judging from the calculation, we revealed that the silver ion transfer reaction and the dimerization reaction occur spontaneously. Moreover, both reactions are independent of the C5 ligand in N so that the deprotonation reaction, which is the first step of this scheme, plays a key role in forming the [N-Ag(2)-N] pairing. PMID- 21688825 TI - Moisture swing sorbent for carbon dioxide capture from ambient air. AB - An amine-based anion exchange resin dispersed in a flat sheet of polypropylene was prepared in alkaline forms so that it would capture carbon dioxide from air. The resin, with quaternary ammonium cations attached to the polymer structure and hydroxide or carbonate groups as mobile counterions, absorbs carbon dioxide when dry and releases it when wet. In ambient air, the moist resin dries spontaneously and subsequently absorbs carbon dioxide. This constitutes a moisture induced cycle, which stands in contrast to thermal pressure swing based cycles. This paper aims to determine the isothermal performance of the sorbent during such a moisture swing. Equilibrium experiments show that the absorption and desorption process can be described well by a Langmuir isothermal model. The equilibrium partial pressure of carbon dioxide over the resin at a given loading state can be increased by 2 orders of magnitude by wetting the resin. PMID- 21688826 TI - Galactosylated N-2-hydroxypropyl methacrylamide-b-N-3-guanidinopropyl methacrylamide block copolymers as hepatocyte-targeting gene carriers. AB - As alternatives of viral and cationic lipid gene carriers, cationic polymer-based vectors may provide flexible chemistry for the attachment of targeting moieties. In this report, galactosylated N-2-hydroxypropyl methacrylamide-b-N-3 guanidinopropyl methacrylamide block copolymers (galactosylated HPMA-b-GPMA block copolymers, or abbreviated as GHG) were prepared in order to develop hepatocyte targeting gene transfection carriers. The block copolymers were synthesized by aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization of N-2-hydroxypropyl methacrylamide (HPMA) and N-3-aminopropyl methacrylamide (APMA), followed by galactosylation and guanidinylation. The molecular weight of GHG copolymers determined by static light scattering method was in the range from 48 600 to 76 240 g/mol. In addition, the galactose content in the GPMA block in the copolymers was determined to be 6.5-8.0 mol % according to the sulfuric acid method. The GHG copolymers complexed completely with plasmid DNA (pDNA) to show positive zeta-potential values with diameter 100-250 nm from charge ratio of 4, which demonstrated the excellent DNA condensing ability of guanidino groups. Furthermore, the MTT assay data of GHG/pDNA complexes on HepG2 cells and HeLa cells indicated that GHG copolymers had significantly lower cytotoxicity than PEI. In addition, the copolymers with GPMA component from 30.23% showed higher transfection efficiency than PEI at charge ratio of 12 in HepG2 cells. The result revealed that the conjugation of galactose groups in the copolymers brought asialoglycoprotein-receptor (ASGP-R) mediated transfection. The employing of HPMA component decreased the aggregation of protein in transfection presence of serum. The GHG copolymers combined the advantages of galactose moieties, guanidino groups, and HPMA component might show potential in safe hepatocyte targeting gene therapy. PMID- 21688828 TI - Kinetics of hydrogen bonding between anthracene urea derivatives and anions in the excited state. AB - Urea compounds are useful anion sensors due to their hydrogen-bonding capabilities. We investigated the emissive properties of complexes consisting of urea-anthracene (nPUA, n = 1, 2) host compounds and acetate anions held as guests through intermolecular hydrogen bonding. The kinetics of a new emission band formed by conformational changes in the excited singlet state were revealed. The new band is thought to arise from a charge-transfer interaction between the anthracene and urea moieties after intermolecular hydrogen-bond reconfiguration in the excited state, with rate constants of 2.4 * 10(9) and 4.0 * 10(7) s(-1) for 1PUA and 2PUA, respectively. PMID- 21688827 TI - Mutational and structural studies of the PixD BLUF output signal that affects light-regulated interactions with PixE. AB - PixD (Slr1694) is a BLUF (blue-light-using FAD) photoreceptor used by the cyanobacterium Synechocystis sp. PCC6803 to control phototaxis toward blue light. In this study, we probe the involvement of a conserved Tyr8-Gln50-Met93 triad in promoting an output signal upon blue light excitation of the bound flavin. Analysis of acrylamide quenching of Trp91 fluorescence shows that the side chain of this residue remains partially solvent exposed in both the lit and dark states. Mutational analysis demonstrates that substitution mutations at Tyr8 and Gln50 result in the loss of the photocycle while a mutation of Met93 does not appreciably disturb the formation of the light-excited state and only minimally accelerates its decay from 5.7 to 4.5 s. However, mutations of Tyr8, Gln50, and Met93 disrupt the ability of PixD dimers to interact with PixE to form a higher order PixD(10)-PixE(5) complex, which is indicative of a lit conformational state. Solution nuclear magnetic resonance spectroscopy and X-ray crystallographic analyses confirm that a Tyr8 to Phe mutation is locked in a pseudo-light-excited state revealing flexible areas in PixD that likely constitute part of an output signal upon light excitation of wild-type PixD. PMID- 21688829 TI - Streamlined process for the chemical synthesis of RNA using 2'-O-thionocarbamate protected nucleoside phosphoramidites in the solid phase. AB - An improved method for the chemical synthesis of RNA was developed utilizing a streamlined method for the preparation of phosphoramidite monomers and a single step deprotection of the resulting oligoribonucleotide product using 1,2-diamines under anhydrous conditions. The process is compatible with most standard heterobase protection and employs a 2'-O-(1,1-dioxo-1lambda(6)-thiomorpholine-4 carbothioate) as a unique 2'-hydroxyl protective group. Using this approach, it was demonstrated that the chemical synthesis of RNA can be as simple and robust as the chemical synthesis of DNA. PMID- 21688830 TI - Diffraction-based tracking of surface plasmon resonance enhanced transmission through a gold-coated grating. AB - Surface plasmon resonance enhanced transmission through metal-coated nanostructures represents a highly sensitive yet simple method for quantitative measurement of surface processes and is particularly useful in the development of thin film and adsorption sensors. Diffraction-induced surface plasmon excitation can produce enhanced transmission at select regions of the visible spectrum, and wavelength shifts associated with these transmission peaks can be used to track adsorption processes and film formation. In this report, we describe a simple optical microscope-based method for monitoring the first-order diffracted peaks associated with enhanced transmission through a gold-coated diffraction grating. A Bertrand lens is used to focus the grating's diffraction image onto a CCD camera, and the spatial position of the diffracted peaks can be readily transformed into a spectral signature of the transmitted light without the use of a spectrometer. The surface plasmon peaks appear as a region of enhanced transmission when the sample is illuminated with p-polarized light, and the peak position reflects the local dielectric properties of the metal interface, including the presence of thin films. The ability to track the position of the plasmon peak and, thus, measure film thickness is demonstrated using the diffracted peaks for samples possessing thin films of silicon oxide. The experimental results are then compared with calculations of optical diffraction through a model, film-coated grating using the rigorously coupled wave analysis simulation method. PMID- 21688831 TI - Synthesis of a dibromoperylene phosphoramidite building block and its incorporation at the 5' end of a G-quadruplex forming oligonucleotide: spectroscopic properties and structural studies of the resulting dibromoperylene conjugate. AB - Previous studies indicate that some perylene bisimide derivatives can drive the assembly of DNA G-quadruplexes, thus suggesting the possible advantage in the adoption of perylene-conjugated G-rich oligonucleotides in biological and biotechnological applications. Nevertheless, the typical poor solubility of perylene bisimides strongly limits the number of suitable chemical strategies to prepare perylene-conjugated oligonucleotides. In order to overcome these difficulties, we employed the earlier described core twisted perylene derivatives possessing unique optical and electronic properties, besides good solubility in common solvents. As a first result, the large-scale synthesis of a new dibromoperylene derivative (PEOEBr) phosphoramidite building block is herein reported. Furthermore, the structural behavior of the conjugated PEOEBr-GGGTTAGGG (HTRp2) human telomeric repeat was investigated by using CD, UV, fluorescence, and gel electrophoresis techniques in desalted water and in K(+)- and Na(+) containing buffers. We observed that the peculiar property of PEOEBr moieties to form dimers instead of extended aggregates drives the HTRp2 strands toward dimerization and mainly promotes the formation of quadruplex species having both the 5'-ends located at the same side of the structures. However, the counterions present in solutions (K(+) or Na(+)) as well as the strand concentration, also contribute to influence the topology and the stoichiometry of formed structures. Furthermore, unlike the unmodified sequence GGGTTAGGG (HTR2), HTRp2 strands quickly associate into G-quadruplexes even in desalted water, as assessed by CD experiments. PMID- 21688832 TI - Restriction endonuclease SsoII with photoregulated activity--a "molecular gate" approach. AB - A novel method for regulating the activity of homodimeric proteins--"molecular gate" approach--was proposed and its usefulness illustrated for the type II restriction endonuclease SsoII (R.SsoII) as a model. The "molecular gate" approach is based on the modification of R.SsoII with azobenzene derivatives, which allows regulating DNA binding and cleavage via illumination with light. R.SsoII variants with single cysteine residues introduced at selected positions were obtained and modified with maleimidoazobenzene derivatives. A twofold change in the enzymatic activity after illumination with light of wavelengths of 365 and 470 nm, respectively, was demonstrated when one or two molecules of azobenzene derivatives were attached to the R.SsoII at the entrance of or within the DNA binding site. PMID- 21688833 TI - Targeted delivery in breast cancer cells via iodine: nuclear localization sequence conjugate. AB - The nonviral vector with iodine-nuclear localization sequence (namely, NLS-I) targeting breast cancer cells was fabricated. Ternary complexes were formed via charge interactions among NLS-I peptides, PEI 1800, and DNA, and we investigated their cellular internalization, nuclear accumulation as well as transfection efficiency. All the experiments were assessed by employing MCF-7 cells that express sodium/iodide symporter and HeLa cells that lack the expression of the symporter. In MCF-7 cells, cell internalization and nuclear accumulation of NLS-I was markedly increased compared to that in NLS. In addition, compared to that of the PEI1800/DNA complex, PEI1800/DNA/NLS-I complexes exhibited much enhanced luciferase reporter gene expression by up to 130-fold. By contrast, in HeLa cells, the evident improvements of cellular internalization, nuclear accumulation, and transfection efficiency by NLS-I were not observed. This study demonstrates an alternative method to construct a nonviral delivery system for targeted gene transfer into breast cancer cells. PMID- 21688834 TI - Direct photoreduction and ketone-sensitized reduction of nitrospirobenzopyranindolines by aliphatic amines. AB - The photoreduction of 6-nitrospiro[2H-1-benzopyran-2,2'-indoline] (N1) and two derivatives (N2 and N3) by diethylamine or triethylamine (TEA) in solution was studied by pulsed and steady-state photolysis. The quantum yield of coloration of the ring-closed Sp form, due to photoinduced ring opening, decreases in acetonitrile with increasing the TEA concentration. The main reason is reaction of TEA with the triplet-excited open merocyanine form. Quenching of this triplet state by amines is rather inefficient for N1-N3; the rate constant for triplet quenching by TEA is k(6) = (2-3) * 10(6) M(-1) s(-1). The secondary transient with an absorption maximum at 420 nm is ascribed to the radical anion. This and the corresponding alpha-aminoethyl radical subsequently undergo slow termination reactions, yielding a relatively stable product with a maximum at 420-450 nm, which is attributed to a ring-opened dihydromerocyanine (MH(-)). The mechanisms of the two subsequent reduction reactions are discussed. Using acetone as sensitizer the same dihydroproduct was obtained with the Sp form as acceptor, indicating a reaction sequence from photogenerated radicals via a ring-opened radical to MH(-)/MH(2). The effect of TEA concentration on the direct and ketone sensitized reduction mechanisms was analyzed. Photoreduction by amines, due to competing triplet quenching, is strongly decreased on admission of oxygen. PMID- 21688835 TI - FRET-FCS detection of intralobe dynamics in calmodulin. AB - Fluorescence correlation spectroscopy (FCS) can be coupled with Forster resonance energy transfer (FRET) to detect intramolecular dynamics of proteins on the microsecond time scale. Here we describe application of FRET-FCS to detect fluctuations within the N-terminal and C-terminal domains of the Ca(2+)-signaling protein calmodulin. Intramolecular fluctuations were resolved by global fitting of the two fluorescence autocorrelation functions (green-green and red-red) together with the two cross-correlation functions (green-red and red-green). To match the Forster radius for FRET to the dimensions of the N-terminal and C terminal domains, a near-infrared acceptor fluorophore (Atto 740) was coupled with a green-emitting donor (Alexa Fluor 488). Fluctuations were detected in both domains on the time scale of 30 to 40 MUs. In the N-terminal domain, the amplitude of the fluctuations was dependent on occupancy of Ca(2+) binding sites. A high amplitude of dynamics in apo-calmodulin (in the absence of Ca(2+)) was nearly abolished at a high Ca(2+) concentration. For the C-terminal domain, the dynamic amplitude changed little with Ca(2+) concentration. The Ca(2+) dependence of dynamics for the N-terminal domain suggests that the fluctuations detected by FCS in the N-terminal domain are coupled to the opening and closing of the EF hand Ca(2+)-binding loops. PMID- 21688836 TI - Synthesis of aminoglycoside-3'-conjugates of 2'-O-methyl oligoribonucleotides and their invasion to a 19F labeled HIV-1 TAR model. AB - The potential of aminoglycosides to induce RNA-invasion has been demonstrated. For this purpose, aminoglycoside-3'-conjugates of 2'-O-methyl oligoribonucleotides have been synthesized entirely on a solid phase. The synthesis includes an automated oligonucleotide chain elongation to solid supported neomycin, ribostamycin, and methyl neobiosamine, and a two-step deprotection/release of the solid-supported conjugate, which allows exploitation of a simple protecting group scheme. Conjugates have been targeted to a (19)F labeled HIV-1 TAR RNA model (Trans Activation Response element of HIV), which allows monitoring of the invasion by (19)F NMR spectroscopy. A remarkably enhanced invasion, compared to that resulting from the corresponding unmodified 2'-O-methyl oligoribonucleotide (5'-CAGGCUCA-3'), has been obtained by the neomycin conjugate. The increased affinity results from a cooperative binding of the neomycin moiety and hybridization, though the invasion may also follow a mechanism, in which the first molar equivalent of the conjugate induces hybridization of the second. PMID- 21688837 TI - Enhanced interfacial adhesion between an amorphous polymer (polystyrene) and a semicrystalline polymer [a polyamide (nylon 6)]. AB - We studied enhanced interfacial adhesion between an amorphous polymer (polystyrene, PS) and a semicrystalline polymer (a polyamide, Ny6). The fracture mechanism for this system was investigated to elicit a universal description on the fracture mechanism. The surface modification of PS to provide functional groups that can react with the functional groups of Ny6 was carried out with ion beam and/or plasma treatment. These surface modifications were found to alter the interfacial adhesion strength between PS and Ny6. A remarkable enhancement was found with the surface functionalization of PS. Though the fracture toughness was varied depending on the process, its overall behavior was quite similar to that of others; the fracture toughness increased with increasing bonding temperature and bonding time, passed through a peak, and then decreased with a further increase of the bonding time or temperature. The variation of the fracture toughness with the bonding time and temperature can be plausibly explained in terms of two different failure mechanisms of adhesive failure and cohesive failure. This change appears more evidently for the interface between an amorphous polymer and a semicrystalline polymer than the interface between semicrystalline polymer pairs. Surface functionalization could exclude the effect of diffusion, thus clarifying the failure mechanisms occurring at the interface. PMID- 21688838 TI - An arginine residue instead of a conserved leucine residue in the recognition helix of the finger 3 of Zif268 stabilizes the domain structure and mediates DNA binding. AB - The Cys(2)His(2)-type zinc finger is a common DNA binding motif that is widely used in the design of artificial zinc finger proteins. In almost all Cys(2)His(2) type zinc fingers, position 4 of the alpha-helical DNA-recognition site is occupied by a Leu residue involved in formation of the minimal hydrophobic core. However, the third zinc finger domain of native Zif268 contains an Arg residue instead of the conserved Leu. Our aim in the present study was to clarify the role of this Arg in the formation of a stable domain structure and in DNA binding by substituting it with a Lys, Leu, or Hgn, which have different terminal side chain structures. Assessed were the metal binding properties, peptide conformations, and DNA-binding abilities of the mutants. All three mutant finger 3 peptides exhibited conformations and thermal stabilities similar to the wild type peptide. In DNA-binding assays, the Lys mutant bound to target DNA, though its affinity was lower than that of the wild-type peptide. On the other hand, the Leu and Hgn mutants had no ability to bind DNA, despite the similarity in their secondary structures to the wild-type. Our results demonstrate that, as with the Leu residue, the aliphatic carbon side chain of this Arg residue plays a key role in the formation of a stable zinc finger domain, and its terminal guanidinium group appears to be essential for DNA binding mediated through both electrostatic interaction and hydrogen bonding with DNA phosphate backbone. PMID- 21688839 TI - Selective sulfuration at the corner sites of a silver nanocrystal and its use in stabilization of the shape. AB - This paper describes a new approach to site-selective sulfuration at the corner sites of Ag nanocrystals including triangular nanoplates and nanocubes. The reaction simply involved mixing an aqueous suspension of the Ag nanocrystals with an aqueous solution of polysulfide at room temperature. As a precursor to elemental S, polysulfide is highly soluble in water and can directly react with elemental Ag upon contact to generate Ag(2)S in the absence of oxygen. The reaction was easily initiated at the corner sites and then pushed toward the center. By controlling the reaction time and/or the amount of polysulfide added, the reaction could be confined to the corner sites only, generating Ag-Ag(2)S hybrid nanocrystals with greatly improved stability against aging at 80 and 100 degrees C in air than their counterparts made of pure Ag. PMID- 21688840 TI - Multiple conformations of the cytidine repressor DNA-binding domain coalesce to one upon recognition of a specific DNA surface. AB - The cytidine repressor (CytR) is a member of the LacR family of bacterial repressors with distinct functional features. The Escherichia coli CytR regulon comprises nine operons whose palindromic operators vary in both sequence and, most significantly, spacing between the recognition half-sites. This suggests a strong likelihood that protein folding would be coupled to DNA binding as a mechanism to accommodate the variety of different operator architectures to which CytR is targeted. Such coupling is a common feature of sequence-specific DNA binding proteins, including the LacR family repressors; however, there are no significant structural rearrangements upon DNA binding within the three-helix DNA binding domains (DBDs) studied to date. We used nuclear magnetic resonance (NMR) spectroscopy to characterize the CytR DBD free in solution and to determine the high-resolution structure of a CytR DBD monomer bound specifically to one DNA half-site of the uridine phosphorylase (udp) operator. We find that the free DBD populates multiple distinct conformations distinguished by up to four sets of NMR peaks per residue. This structural heterogeneity is previously unknown in the LacR family. These stable structures coalesce into a single, more stable udp bound form that features a three-helix bundle containing a canonical helix-turn helix motif. However, this structure differs from all other LacR family members whose structures are known with regard to the packing of the helices and consequently their relative orientations. Aspects of CytR activity are unique among repressors; we identify here structural properties that are also distinct and that might underlie the different functional properties. PMID- 21688842 TI - Cold chemistry with ionic partners: quantum features of HeH+(1Sigma) with H(1S) at ultralow energies. AB - Quantum reactive calculations are presented for an ion-atom reaction involving the HeH(+)cation and its destruction via a barrierless interaction with H atoms. The range of collision energies considered is that of a cold trap regime (around and below millikelvin) where the ionic partner could be spatially confined. Specific resonant features caused by the interplay of the strong ionic interaction with the very slow partners' dynamics are found and analyzed. Indications are also given on the consequences of the abstraction mechanism that acts for this reaction at low energies. PMID- 21688841 TI - Folate receptor-targeted aggregation-enhanced near-IR emitting silica nanoprobe for one-photon in vivo and two-photon ex vivo fluorescence bioimaging. AB - A two-photon absorbing (2PA) and aggregation-enhanced near-infrared (NIR) emitting pyran derivative, encapsulated in and stabilized by silica nanoparticles (SiNPs), is reported as a nanoprobe for two-photon fluorescence microscopy (2PFM) bioimaging that overcomes the fluorescence quenching associated with high chromophore loading. The new SiNP probe exhibited aggregate-enhanced emission producing nearly twice as strong a signal as the unaggregated dye, a 3-fold increase in two-photon absorption relative to the DFP in solution, and approximately 4-fold increase in photostability. The surface of the nanoparticles was functionalized with a folic acid (FA) derivative for folate-mediated delivery of the nanoprobe for 2PFM bioimaging. Surface modification of SiNPs with the FA derivative was supported by zeta potential variation and (1)H NMR spectral characterization of the SiNPs as a function of surface modification. In vitro studies using HeLa cells expressing a folate receptor (FR) indicated specific cellular uptake of the functionalized nanoparticles. The nanoprobe was demonstrated for FR-targeted one-photon in vivo imaging of HeLa tumor xenograft in mice upon intravenous injection of the probe. The FR-targeting nanoprobe not only exhibited highly selective tumor targeting but also readily extravasated from tumor vessels, penetrated into the tumor parenchyma, and was internalized by the tumor cells. Two-photon fluorescence microscopy bioimaging provided three dimensional (3D) cellular-level resolution imaging up to 350 MUm deep in the HeLa tumor. PMID- 21688843 TI - Inflammation responsive logic gate nanoparticles for the delivery of proteins. AB - Oxidative stress and reduced pH are important stimuli targets for intracellular delivery and for delivery to diseased tissue. However, there is a dearth of materials able to deliver bioactive agents selectively under these conditions. We employed our recently developed dual response strategy to build a polymeric nanoparticle that degrades upon exposure to two stimuli in tandem. Our polythioether ketal based nanoparticles undergo two chemical transformations; the first is the oxidation of the thioether groups along the polymer backbone of the nanoparticles upon exposure to reactive oxygen species (ROS). This transformation switches the polymeric backbone from hydrophobic to hydrophilic and thus allows, in mildly acidic environments, the rapid acid-catalyzed degradation of the ketal groups also along the polymer backbone. Dynamic light scattering and payload release studies showed full particle degradation only in conditions that combined both oxidative stress and acidity, and these conditions led to higher release of encapsulated protein within 24 h. Nanoparticles in neutral pH and under oxidative conditions showed small molecule release and swelling of otherwise intact nanparticles. Notably, cellular studies show absence of toxicity and efficient uptake of nanoparticles by macrophages followed by cytoplasmic release of ovalbumin. Future work will apply this system to inflammatory diseases. PMID- 21688844 TI - Lamination of alumina membranes to polymer surfaces: thick, hard, transparent, crack-free alumina films on polymers with excellent adhesion. AB - Hard and transparent alumina (Al(2)O(3)) films with thicknesses in the range of 500 nm to 5 MUm were successfully formed on polymethylmethacrylate (PMMA) and polystyrene (PS) surfaces. Our process is based on a lamination of anodized aluminum membranes (AAMs) to the polymer surfaces, followed by chemical etching. Because of capillary force, molten PS and liquid PMMA precursor were successfully pulled into the nanopores (10 nm diameter) within the Al(2)O(3) layers and solidified by cooling or polymerization, respectively. Our resulting AAM laminated surfaces exhibited excellent adhesion and surface mechanical properties similar to those of fused silica, remaining crack-free and transparent even with Al(2)O(3) thicknesses exceeding 1 MUm. PMID- 21688845 TI - Dissociation of strong acid revisited: X-ray photoelectron spectroscopy and molecular dynamics simulations of HNO3 in water. AB - Molecular-level insight into the dissociation of nitric acid in water is obtained from X-ray photoelectron spectroscopy and first-principles molecular dynamics (MD) simulations. Our combined studies reveal surprisingly abrupt changes in solvation configurations of undissociated nitric acid at approximately 4 M concentration. Experimentally, this is inferred from shifts of the N1s binding energy of HNO(3)(aq) as a function of concentration and is associated with variations in the local electronic structure of the nitrogen atom. It also shows up as a discontinuity in the degree of dissociation as a function of concentration, determined here from the N1s photoelectron signal intensity, which can be separately quantified for undissociated HNO(3)(aq) and dissociated NO(3)( )(aq). Intermolecular interactions within the nitric acid solution are discussed on the basis of MD simulations, which reveal that molecular HNO(3) interacts remarkably weakly with solvating water molecules at low concentration; around 4 M there is a turnover to a more structured solvation shell, accompanied by an increase in hydrogen bonding between HNO(3) and water. We suggest that the driving force behind the more structured solvent configuration of HNO(3) is the overlap of nitric acid solvent shells that sets in around 4 M concentration. PMID- 21688846 TI - New nitric oxide or hydrogen sulfide releasing aspirins. AB - A new series of (((R-oxy)carbonyl)oxy)methyl esters of aspirin (ASA), bearing nitric oxide (NO) or hydrogen sulfide (H(2)S) releasing groups, was synthesized, and the compounds were evaluated as new ASA co-drugs. All the products were quite stable in buffered solution at pH 1 and 7.4. Conversely, they were all rapidly metabolized, producing ASA and the NO/H(2)S releasing moiety used for their preparation. Consequent on ASA release, the compounds were capable of inhibiting collagen-induced platelet aggregation of human platelet-rich plasma (PRP). The simple NO/H(2)S donor substructures were able to relax contracted rat aorta strips, with a NO- and H(2)S-dependent mechanism, respectively, but they either did not trigger antiaggregatory activity or displayed antiplatelet potency markedly below that of the related co-drug. The new products might provide a safer and improved alternative to the use of ASA principally in its anti inflammatory and antithrombotic applications. PMID- 21688847 TI - Acaricidal activities of apiol and its derivatives from Petroselinum sativum seeds against Dermatophagoides pteronyssinus, Dermatophagoides farinae, and Tyrophagus putrescentiae. AB - The acaricidal effects of an active constituent derived from Petroselinum sativum seeds and its derivatives were determined using impregnated fabric disk bioassay against Dermatophagoides farinae , Dermatophagoides pteronyssinus , and Tyrophagus putrescentiae and compared with that of synthetic acaricide. The acaricidal constituent of P. sativum was isolated by various chromatographic techniques and identified as apiol. On the basis of LD(50) values against D. farinae and D. pteronyssinus, apiol (0.81 and 0.94 MUg/cm(2)) was 12.4 and 10.2 times more toxic than benzyl benzoate (10.0 and 9.58 MUg/cm(2)), respectively. In acaricidal studies of apiol derivatives, 3,4-methylenedioxybenzonitrile (0.04, 0.03, and 0.59 MUg/cm(2)) was 250, 319, and 20.7 times more toxic than benzyl benzoate (10.0, 9.58, and 12.2 MUg/cm(2)) against D. farinae, D. pteronyssinus, and T. putrescentiae. In structure-activity relationships, the acaricidal activities of apiol derivatives could be related to allyl (-C(3)H(5)) and methoxy (-OCH(3)) functional groups. Furthermore, apiol and its derivatives could be useful for natural acaricides against these three mite species. PMID- 21688848 TI - Protein-nanoparticle interactions: opportunities and challenges. PMID- 21688849 TI - Luminescent functional metal-organic frameworks. PMID- 21688850 TI - Discorhabdins and pyrroloiminoquinone-related alkaloids. PMID- 21688851 TI - Acoustic vibrations of metal-dielectric core-shell nanoparticles. AB - The acoustic vibrations of metal nanoparticles encapsulated in a dielectric shell (Ag@SiO(2)) were investigated using a time-resolved femtosecond technique. The measured vibration periods significantly differ from those predicted for the bare metal cores and, depending on the relative core and shell sizes, were found to be either larger or smaller than them. These results show that the vibration of the whole core-shell particle is excited and detected. Moreover, vibrational periods are in excellent agreement with the predictions of a model based on continuum thermoelasticity. However, such agreement is obtained only if a good mechanical contact of the metal and dielectric parts of the core-shell particle is assumed, providing a unique way to probe this contact in multimaterial or hybrid nano objects. PMID- 21688852 TI - Determinants of cyanuric acid and melamine assembly in water. AB - While the recognition of cyanuric acid (CA) by melamine (M) and their derivatives has been known to occur in both water and organic solvents for some time, analysis of CA/M assembly in water has not been reported (Ranganathan, A.; Pedireddi, V. R.; Rao, C. N. R. J. Am. Chem. Soc.1999, 121, 1752-1753; Mathias, J. P.; Simanek, E. E.; Seto, C. T.; Whitesides, G. M. Macromol. Symp.1994, 77, 157-166; Zerkowski, J. A.; MacDonald, J. C.; Seto, C. T.; Wierda, D. A.; Whitesides, G. M. J. Am. Chem. Soc.1994, 116, 2382-2391; Mathias, J. P.; Seto, C. T.; Whitesides, G. M. Polym. Prepr.1993, 34, 92-93; Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc.1993, 115, 905-916; Zerkowski, J. A.; Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc.1992, 114, 5473-5475; Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc.1990, 112, 6409-6411; Wang, Y.; Wei, B.; Wang, Q. J. Chem. Cryst.1990, 20, 79-84; ten Cate, M. G. J.; Huskens, J.; Crego-Calama, M.; Reinhoudt, D. N. Chem.-Eur. J.2004, 10, 3632-3639). We have examined assembly of CA/M, as well as assembly of soluble trivalent CA and M derivatives (TCA/TM), in aqueous solvent, using a combination of solution phase NMR, isothermal titration and differential scanning calorimetry (ITC/DSC), cryo-transmission electron microscopy (cryo-TEM), and synthetic chemistry. While the parent heterocycles coprecipitate in water, the trivalent system displays more controlled and cooperative assembly that occurs at lower concentrations than the parent and yields a stable nanoparticle suspension. The assembly of both parent and trivalent systems is rigorously 1:1 and proceeds as an exothermic, proton transfer coupled process in neutral pH water. Though CA and M are considered canonical hydrogen-bonding motifs in organic solvents, we find that their assembly in water is driven in large part by enthalpically favorable surface-area burial, similar to what is observed with nucleic acid recognition. There are currently few synthetic systems capable of robust molecular recognition in water that do not rely on native recognition motifs, possibly due to an incomplete understanding of recognition processes in water. This study establishes a detailed conceptual framework for considering CA/M heterocycle recognition in water which enables the future design of molecular recognition systems that function in water. PMID- 21688853 TI - Reactivity of aqueous phase hydroxyl radical with halogenated carboxylate anions: experimental and theoretical studies. AB - With concerns about emerging contaminants increasing, advanced oxidation processes have become attractive technologies because of potential mineralization of these contaminants via radical involved reactions that are induced by highly reactive hydroxyl radical. Considering the expensive and time-consuming experimental studies of degradation intermediates and byproduct, there is a need to develop a first-principles computer-based kinetic model that predict reaction pathways and associated reaction rate constants. In this study, we measured temperature-dependent hydroxyl radical reaction rate constants for a series of haloacetate ions and obtained their Arrhenius kinetic parameters. We found a linear correlation between these reaction rate constants and theoretically calculated aqueous-phase free energies of activation. To understand the quantitative effects on entropy of solvation due to solvent water molecules, we calculate each portion of the entropic energies that contribute to the overall aqueous phase entropy of activation; cavity formation is a dominant portion. For the series of reactions of hydroxyl radical with carboxylate ions, the increase in the entropy of activation during the solvation process is approximately 10-15 cal mol(-1)K(-1) because of interactions with solvent water molecules and the transition state. Finally, charge distribution analysis for the aqueous-phase reactions of hydroxyl radical with acetate/haloacetate ions reveals that in the aqueous phase, the degree of polarizability at the transition state is less substantial than those that are in the gaseous phase resulting in a high charge density. In the presence of electronegative halogenated functional groups, the transition state is less polarized and hydrogen bonding interactions are expected to be weaker. PMID- 21688854 TI - Identification of mtDNA lineages of Sus scrofa by multiplex single base extension for the authentication of processed food products. AB - A genetic method to identify the breed of origin could serve as a useful tool for inspecting the authenticity of the increasing number of monobreed foodstuffs, such as those derived from small local European pig breeds. Mitochondrial DNA (mtDNA) is practically the only reliable genomic target for PCR in processed products, and its haploid nature and strict maternal inheritance greatly facilitate genetic analysis. As a result of strategies that sought to improve the production traits of European pigs, most industrial breeds presently show a high frequency of Asian alleles, while the absence or low frequency of such Asian alleles has been observed in small rustic breeds from which highly prized dry cured and other traditional products are derived. Therefore, the detection of Asian ancestry would indicate nonconformity in Protected Denomination of Origin products. This study presents a single base extension assay based on 15 diagnostic mtDNA single nucleotide polymorphisms to discriminate between Asian and European Sus scrofa lineages. The test was robust, sensitive and accurate in a wide range of processed foodstuffs and allowed accurate detection of pig genetic material and identification of maternal ancestry. A market survey suggested that nonconformity of products derived from Portuguese breeds is an unusual event at present, but regular surveys both in the local populations and in commercial products would be advisible. Taking into consideration the limitations presented by other methodologies, this mtDNA-based test probably attains the highest resolution for the direct genetic test for population of origin in Sus scrofa food products. PMID- 21688856 TI - Concise, convergent syntheses of (+/-)-trichostatin A utilizing a Pd-catalyzed ketone enolate alpha-alkenylation reaction. AB - Two concise, convergent syntheses of (+/-)-trichostatin A (1), a potent histone deacetylase inhibitor, have been accomplished. The key step in both is a Pd catalyzed alpha-alkenylation reaction between ketone 2 and either dienyl bromide 3 or alkenyl bromide 9 using a modification of cross-coupling conditions described by Negishi and Hartwig. A brief investigation has shown the potential utility of a Ni-catalyzed version of this reaction. The overall synthetic routes are short and amenable to scaleup, providing access to trichostatin A via trichostatic acid as a direct precursor. PMID- 21688855 TI - New ligands that promote cross-coupling reactions between aryl halides and unactivated arenes. AB - Several ligands were designed to promote transition-metal-free cross-coupling reactions of aryl halides with benzene derivatives. Among the systems probed, quinoline-1-amino-2-carboxylic acid was found to serve as an excellent catalyst for cross-coupling between aryl halides and unactivated benzene. Reactions using this inexpensive catalytic system displayed a high functional group tolerance as well as excellent chemoselectivities. PMID- 21688857 TI - Fluorescent 3-methylene-2,3-dihydrochalcogenophenes incorporated in a rigid dibenzobarrelene skeleton. AB - The fluorescent 3-methylene-2,3-dihydroselenophene derivative (Phi(F) = 0.86 in CH(2)Cl(2)) incorporated in a dibenzobarrelene skeleton was synthesized by the reaction of a four-membered selenaplatinacycle with dimethyl acetylenedicarboxylate (DMAD) or reaction of bis(dibenzobarrelenyl) diselenide with DMAD in the presence of Pd(PPh(3))(4) and PPh(3). A fluorescent sulfur homologue (Phi(F) = 1.0 in CH(2)Cl(2)) was also synthesized by the reaction of bis(dibenzobarrelenyl) disulfide with DMAD in the presence of Pd(PPh(3))(4). Selected chemical transformations of these diesters were also investigated. PMID- 21688858 TI - A new type of monoterpenoid indole alkaloid precursor from Alstonia rostrata. AB - Currently, all monoterpenoid indole alkaloids (MIAs) have been derived from strictosidine, which originates from the condensation of tryptophan with secologanin in a 1:1 ratio. However, our phytochemical research on Alstonia rostrata revealed a potential new precursor for these compounds. We isolated the alstrostines A and B, and it was determined that they were derived from tryptophan and secologanin in a 1:2 ratio, which supported the presence of a new type of MIA precursor. PMID- 21688859 TI - A metal-free amination of benzoxazoles--the first example of an iodide-catalyzed oxidative amination of heteroarenes. AB - An efficient transition-metal-free amination of benzoxazoles has been developed. With catalytic amounts of tetrabutylammoniumiodide (TBAI), aqueous solutions of H(2)O(2) or TBHP as co-oxidant and under mild reaction conditions, highly desirable 2-aminobenzoxazoles were isolated in excellent yields of up to 93%. First mechanistic experiments indicate the in situ iodination of the secondary amine as the putative mode of activation. PMID- 21688860 TI - Regioselective oxidative coupling reactions of 3-substituted thiophenes with arylboronic acids. AB - Under optimized conditions, 3-substituted thiophenes (EWG = COOEt, PO(OEt)(2)) undergo a facile and regioselective oxidative coupling reaction at carbon atom C4. The reactions were performed with various aryl boronic acids as nucleophiles in the presence of silver oxide (2.0 equiv), cesium trifluoroacetate (tfa) (1.0 equiv), benzoquinone (BQ) (0.5 equiv), and catalytic amounts of Pd(tfa)(2) (10 mol %) employing trifluoroacetic acid (TFA) as the solvent. PMID- 21688861 TI - Total synthesis and absolute configuration of (-)-gummiferol. AB - Stereoselective synthesis of two possible diastereomers of (-)-gummiferol was accomplished by the stepwise epoxidation and Cadiot-Chodkiewicz reaction as the key transformations. Detailed comparison of their (1)H and (13)C NMR data and specific rotation with those of the natural product led to the absolute structural elucidation of (-)-gummiferol. PMID- 21688862 TI - Stereoselective total synthesis of (-)-kumausallene. AB - A stereoselective total synthesis of (-)-kumausallene was completed in 12 steps from acetylacetone. The hidden symmetry of (-)-kumausallene was recognized, and its skeleton was constructed efficiently from a C(2)-symmetric diol by a palladium-catalyzed cascade reaction. High diastereoselectivity was observed for the DMF-promoted biomimetic 1,4-bromocyclization of a conjugated enyne. PMID- 21688863 TI - Catalytic asymmetric conjugate allylation of coumarins. AB - A catalytic asymmetric conjugate allylation was successfully developed to synthesize potential pharmacologically active 4-allyl-2-oxochroman skeletons. A dual activation strategy was employed by using N,N'-dioxide-Yb(OTf)(3) to activate coumarins and using (CuOTf)(2)*C(7)H(8) to activate tetraallyltin via transmetalation, respectively. Good yields and enantioselectivities were obtained under mild conditions. PMID- 21688864 TI - Chiral diene-phosphine tridentate ligands for rhodium-catalyzed asymmetric cycloisomerization of 1,6-enynes. AB - Asymmetric cycloisomerization of nitrogen-bridged 1,6-enynes proceeded in the presence of a cationic rhodium complex coordinated with a chiral diene/phosphine tridentate ligand to give high yields of chiral 3-azabicyclo[4.1.0]heptenes with high enantioselectivity. PMID- 21688866 TI - Low molecular weight fluorescent organogel for fluoride ion detection. AB - The design, synthesis, and the photophysical properties of a Low Molecular Weight Gel (LMWG) based on AB(3) and AB(2) type poly(aryl ether) dendrons with an anthracene chromophore attached through an acylhydrazone linkage are described. The gel is utilized for an efficient 'naked eye' detection of fluoride ions (as low as 0.1 equiv with respect to the gelator concentration), through a reversible gel-sol transition, which is associated with a color change from deep yellow to bright red. PMID- 21688867 TI - Influence of exercise on skill proficiency in soccer. AB - The ability to maintain technical performances (i.e. skills) throughout soccer match-play is considered to be crucial in determining the outcome of competitive fixtures. Consequently, coaches dedicate a large proportion of time to practicing isolated skills, such as passing, shooting and dribbling. Unlike other elements that contribute to team-sport performances, it is unusual for coaches to use methods other than observations to assess changes resulting from technical training. Researchers have employed various tests to measure isolated soccer skills; however, reliance on outcome measures that include number of contacts (ball juggling tasks), time (dribbling tasks) and points scored (criterion-based passing and shooting tests) means that the outcomes are difficult for coaches to interpret. Skill tests that use video-analysis techniques to measure ball speed, precision and success of soccer skills offer valid and reliable alternatives. Although equivocal results are published, skill performances can be affected by assorted factors that threaten homeostasis, including match-related fatigue, dehydration and reductions in blood glucose concentrations. While acknowledging methodological constraints associated with using skill tests with limited ecological validity and cognitive demands, the effects of these homeostatic disturbances might vary according to the type of skill being performed. Shooting performances appear most susceptible to deterioration after exercise. Strategies such as aerobic training, fluid-electrolyte provision and acute carbohydrate supplementation have been found to improve proficiency in technical actions performed after soccer-specific exercise. However, mechanisms that cause deterioration in skill during soccer-specific exercise remain to be fully elucidated and strategies to optimize technical performance throughout match-play are warranted. PMID- 21688868 TI - Sex differences in proximal control of the knee joint. AB - Following the onset of maturation, female athletes have a significantly higher risk for anterior cruciate ligament (ACL) injury compared with male athletes. While multiple sex differences in lower-extremity neuromuscular control and biomechanics have been identified as potential risk factors for ACL injury in females, the majority of these studies have focused specifically on the knee joint. However, increasing evidence in the literature indicates that lumbo-pelvic (core) control may have a large effect on knee-joint control and injury risk. This review examines the published evidence on the contributions of the trunk and hip to knee-joint control. Specifically, the sex differences in potential proximal controllers of the knee as risk factors for ACL injury are identified and discussed. Sex differences in trunk and hip biomechanics have been identified in all planes of motion (sagittal, coronal and transverse). Essentially, female athletes show greater lateral trunk displacement, altered trunk and hip flexion angles, greater ranges of trunk motion, and increased hip adduction and internal rotation during sport manoeuvres, compared with their male counterparts. These differences may increase the risk of ACL injury among female athletes. Prevention programmes targeted towards trunk and hip neuromuscular control may decrease the risk for ACL injuries. PMID- 21688869 TI - Carbohydrate ingestion during team games exercise: current knowledge and areas for future investigation. AB - There is a growing body of research on the influence of ingesting carbohydrate electrolyte solutions immediately prior to and during prolonged intermittent, high-intensity exercise (team games exercise) designed to replicate field-based team games. This review presents the current body of knowledge in this area, and identifies avenues of further research. Almost all early work supported the ingestion of carbohydrate-electrolyte solutions during prolonged intermittent exercise, but was subject to methodological limitations. A key concern was the use of exercise protocols characterized by prolonged periods at the same exercise intensity, the lack of maximal- or high-intensity work components and long periods of seated recovery, which failed to replicate the activity pattern or physiological demand of team games exercise. The advent of protocols specifically designed to replicate the demands of field-based team games enabled a more externally valid assessment of the influence of carbohydrate ingestion during this form of exercise. Once again, the research overwhelmingly supports carbohydrate ingestion immediately prior to and during team games exercise for improving time to exhaustion during intermittent running. While the external validity of exhaustive exercise at fixed prescribed intensities as an assessment of exercise capacity during team games may appear questionable, these assessments should perhaps not be viewed as exhaustive exercise tests per se, but as indicators of the ability to maintain high-intensity exercise, which is a recognized marker of performance and fatigue during field-based team games. Possible mechanisms of exercise capacity enhancement include sparing of muscle glycogen, glycogen resynthesis during low-intensity exercise periods and attenuated effort perception during exercise. Most research fails to show improvements in sprint performance during team games exercise with carbohydrate ingestion, perhaps due to the lack of influence of carbohydrate on sprint performance when endogenous muscle glycogen concentration remains above a critical threshold of ~200 mmol/kg dry weight. Despite the increasing number of publications in this area, few studies have attempted to drive the research base forward by investigating potential modulators of carbohydrate efficacy during team games exercise, preventing the formulation of optimal carbohydrate intake guidelines. Potential modulators may be different from those during prolonged steady-state exercise due to the constantly changing exercise intensity and frequency, duration and intensity of rest intervals, potential for team games exercise to slow the rate of gastric emptying and the restricted access to carbohydrate-electrolyte solutions during many team games. This review highlights fluid volume, carbohydrate concentration, carbohydrate composition and solution osmolality; the glycaemic index of pre-exercise meals; fluid and carbohydrate ingestion patterns; fluid temperature; carbohydrate mouthwashes; carbohydrate supplementation in different ambient temperatures; and investigation of all of these areas in different subject populations as important avenues for future research to enable a more comprehensive understanding of carbohydrate ingestion during team games exercise. PMID- 21688871 TI - Comments on 'expert performance in sport and the dynamics of talent development'. PMID- 21688873 TI - Motives for cannabis use in high-risk adolescent users. AB - The present investigation examined the relationships between motives for cannabis use and negative consequences associated with cannabis use following a brief intervention. The sample consisted of 205 adolescent cannabis users (66.3% male), who were recruited in high schools and randomly assigned to a brief two-session motivational enhancement therapy (MET) or an educational feedback control (EFC). Results supported the hypothesis that using cannabis to cope with negative affect would predict the number of problems and dependence symptoms related to cannabis use, after controlling for age, gender, years and frequency of cannabis use, and internalizing and externalizing behavior problems. Significant interactions between internalizing behavior problems and the coping motive showed that using to cope was associated with a higher number of cannabis dependence symptoms among adolescents reporting lower levels internalizing behavior problems. Findings support the potential utility of conducting further research to explore the coping motive as an important indicator of problematic cannabis use. PMID- 21688870 TI - Obstacles in the optimization of bone health outcomes in the female athlete triad. AB - Maintaining low body weight for the sake of performance and aesthetic purposes is a common feature among young girls and women who exercise on a regular basis, including elite, college and high-school athletes, members of fitness centres, and recreational exercisers. High energy expenditure without adequate compensation in energy intake leads to an energy deficiency, which may ultimately affect reproductive function and bone health. The combination of low energy availability, menstrual disturbances and low bone mineral density is referred to as the 'female athlete triad'. Not all athletes seek medical assistance in response to the absence of menstruation for 3 or more months as some believe that long-term amenorrhoea is not harmful. Indeed, many women may not seek medical attention until they sustain a stress fracture. This review investigates current issues, controversies and strategies in the clinical management of bone health concerns related to the female athlete triad. Current recommendations focus on either increasing energy intake or decreasing energy expenditure, as this approach remains the most efficient strategy to prevent further bone health complications. However, convincing the athlete to increase energy availability can be extremely challenging. Oral contraceptive therapy seems to be a common strategy chosen by many physicians to address bone health issues in young women with amenorrhoea, although there is little evidence that this strategy improves bone mineral density in this population. Assessment of bone health itself is difficult due to the limitations of dual-energy X-ray absorptiometry (DXA) to estimate bone strength. Understanding how bone strength is affected by low energy availability, weight gain and resumption of menses requires further investigations using 3-dimensional bone imaging techniques in order to improve the clinical management of the female athlete triad. PMID- 21688874 TI - Time course of attentional bias for gambling information in problem gambling. AB - There is a wealth of evidence showing enhanced attention toward drug-related information (i.e., attentional bias) in substance abusers. However, little is known about attentional bias in deregulated behaviors without substance use such as abnormal gambling. This study examined whether problem gamblers (PrG, as assessed through self-reported gambling-related craving and gambling dependence severity) exhibit attentional bias for gambling-related cues. Forty PrG and 35 control participants performed a change detection task using the flicker paradigm, in which two images differing in only one aspect are repeatedly flashed on the screen until the participant is able to report the changing item. In our study, the changing item was either neutral or related to gambling. Eye movements were recorded, which made it possible to measure both initial orienting of attention as well as its maintenance on gambling information. Direct (eye movements) and indirect (change in detection latency) measures of attention in individuals with problematic gambling behaviors suggested the occurrence of both engagement and of maintenance attentional biases toward gambling-related visual cues. Compared to nonproblematic gamblers, PrG exhibited (a) faster reaction times to gambling-cues as compared to neutral cues, (b) higher percentage of initial saccades directed toward gambling pictures, and (c) an increased fixation duration and fixation count on gambling pictures. In the PrG group, measures of gambling-related attentional bias were not associated with craving for gambling and gambling dependence severity. Theoretical and clinical implications of these results are discussed. PMID- 21688875 TI - Associations between posttraumatic stress disorder symptom clusters and cigarette smoking. AB - Understanding the relationship between Posttraumatic stress disorder (PTSD) and cigarette smoking has been difficult because of PTSD's symptomatic heterogeneity. This study examined common and unique lifetime cross-sectional relationships between PTSD symptom clusters [Re-experiencing (intrusive thoughts and nightmares about the trauma), Avoidance (avoidance of trauma-associated memories or stimuli), Emotional Numbing (loss of interest, interpersonal detachment, restricted positive affect), and Hyperarousal (irritability, difficulty concentrating, hypervigilance, insomnia)] and three indicators of smoking behavior: (1) smoking status; (2) cigarettes per day; and (3) nicotine dependence. Participants were adult respondents in the National Epidemiologic Survey of Alcohol and Related Conditions with a trauma history (n = 23,635). All four symptom clusters associated with each smoking outcome in single-predictor models (ps <. 0001). In multivariate models including all of the symptom clusters as simultaneous predictors, Emotional Numbing was the only cluster to retain a significant association with lifetime smoking over and above the other clusters, demographics, and Axis-I comorbidity (OR = 1.30, p < .01). While Avoidance uniquely associated with smoking status and nicotine dependence in multivariate models, these relations fell below significance after adjusting for demographics and comorbidity. No clusters uniquely associated with cigarettes per day. Hyperarousal uniquely related with nicotine dependence over and above the other clusters, demographics, and Axis-I comorbidity (OR = 1.51, p < .001). These results suggest the following: (a) common variance across PTSD symptom clusters contribute to PTSD's linkage with smoking in the American population; and (b) certain PTSD symptom clusters may uniquely associate with particular indicators of smoking behavior. These findings may clarify the underpinnings of PTSD-smoking comorbidity and inform smoking interventions for trauma-exposed individuals. PMID- 21688876 TI - Event-level associations between objective and subjective alcohol intoxication and driving after drinking across the college years. AB - Heavy episodic drinking is strongly associated with driving after drinking, yet there has been mixed evidence regarding whether the disinhibiting effects of alcohol intoxication contribute to the decision to drive after drinking. This investigation tested whether greater alcohol intoxication increased the probability of driving after drinking particularly during drinking episodes in which students experienced reduced subjective feelings of intoxication. A sample of 1,350 college students completed up to 30 days of web-based daily diary monitoring in each of 4 consecutive years. Participants reported daily on their alcohol consumption, subjective intoxication, and whether they drove after drinking on the previous day or night. In generalized estimating equation models, daily estimated blood alcohol concentration (eBAC) was more strongly associated with driving after drinking during episodes in which subjective intoxication was lower. That is, students were most likely to drive after drinking when they were objectively more intoxicated but perceived themselves as less intoxicated. These event-level associations did not change over time nor did they differ as a function of gender. Further, the effects persisted when predicting driving at eBACs above the legal limit for operating a motor vehicle. Greater subjective intoxication may serve to inhibit driving after drinking, particularly when students are objectively more intoxicated. In the absence of subjective intoxication, however, other salient pressures might impel driving after drinking. Prevention efforts should incorporate the importance of variability in subjective intoxication. PMID- 21688877 TI - Randomized controlled trial of motivational enhancement therapy with nontreatment seeking adolescent cannabis users: a further test of the teen marijuana check-up. AB - Cannabis use adversely affects adolescents and interventions that are attractive to adolescents are needed. This trial compared the effects of a brief motivational intervention for cannabis use with a brief educational feedback control and a no-assessment control. Participants were randomized into one of three treatment conditions: Motivational Enhancement Therapy (MET), Educational Feedback Control (EFC), or Delayed Feedback Control (DFC). Those who were assigned to MET and EFC were administered a computerized baseline assessment immediately following randomization and completed assessments at the 3- and 12 month follow-up periods. Participants in the DFC condition were not assessed until the 3-month follow-up. Following the completion of treatment sessions, all participants were offered up to four optional individual treatment sessions aimed at cessation of cannabis use. The research was conducted in high schools in Seattle, Washington. The participant s included 310 self-referred adolescents who smoked cannabis regularly. The main outcome measures included days of cannabis use, associated negative consequences, and engagement in additional treatment. At the 3-month follow-up, participants in both the MET and EFC conditions reported significantly fewer days of cannabis use and negative consequences compared to those in the DFC. The frequency of cannabis use was less in MET relative to EFC at 3 months, but it did not translate to differences in negative consequences. Reductions in use and problems were sustained at 12 months, but there were no differences between MET and EFC interventions. Engagement in additional treatment was minimal and did not differ by condition. Brief interventions can attract adolescent cannabis users and have positive impacts on them, but the mechanisms of the effects are yet to be identified. PMID- 21688878 TI - Managing a new collaborative entity in business organizations: understanding organizational communities of practice effectiveness. AB - Companies worldwide are turning to organizational communities of practice (OCoPs) as vehicles to generate learning and enhance organizational performance. OCoPs are defined as groups of employees who share a concern, a set of problems, or a passion about a topic and who strengthen their knowledge and expertise by interacting on a consistent basis. To date, OCoP research has drawn almost exclusively from the community of practice (CoP) literature, even though the organizational form of CoPs shares attributes of traditional CoPs and of organizational teams. Drawing on Lave and Wenger's (1991) original theory of legitimate peripheral participation, we integrate theory and research from CoPs and organizational teams to develop and empirically examine a model of OCoP effectiveness that includes constructs such as leadership, empowerment, the structure of tasks, and OCoP relevance to organizational effectiveness. Using data from 32 OCoPs in a U.S.-based multinational mining and minerals processing firm, we found that external community leaders play an important role in enhancing OCoP empowerment, particularly to the extent that task interdependence is high. Empowerment, in turn, was positively related to OCoP effectiveness. We also found that OCoPs designated as "core" by the organization (e.g., working on critical issues) were more effective than those that were noncore. Task interdependence also was positively related to OCoP effectiveness. We provide scholars and practitioners with insights on how to effectively manage OCoPs in today's organizations. PMID- 21688879 TI - The role of organizational insiders' developmental feedback and proactive personality on newcomers' performance: an interactionist perspective. AB - Drawing from an interactionist approach and feedback research, we examine the role of developmental feedback and proactive personality on newcomer task performance and helping behavior. Data were collected from 2 high-tech joint ventures within the information technology and manufacturing industries located in Shanghai, China. Results based on 151 newcomer-manager dyads showed that supervisor developmental feedback (SDF) positively related to newcomer helping behavior and that SDF and coworker developmental feedback interactively predicted newcomer task performance. We also found differential moderating effects of proactive personality: SDF more strongly related to helping behavior when proactive personality was lower; conversely, coworker developmental feedback more strongly related to helping behavior when proactive personality was higher. PMID- 21688880 TI - Hot or cold: is communicating anger or threats more effective in negotiation? AB - Is communicating anger or threats more effective in eliciting concessions in negotiation? Recent research has emphasized the effectiveness of anger communication, an emotional strategy. In this article, we argue that anger communication conveys an implied threat, and we document that issuing threats is a more effective negotiation strategy than communicating anger. In 3 computer mediated negotiation experiments, participants received either angry or threatening messages from a simulated counterpart. Experiment 1 showed that perceptions of threat mediated the effect of anger (vs. a control) on concessions. Experiment 2 showed that (a) threat communication elicited greater concessions than anger communication and (b) poise (being confident and in control of one's own feelings and decisions) ascribed to the counterpart mediated the positive effect of threat compared to anger on concessions. Experiment 3 replicated this positive effect of threat over anger when recipients had an attractive alternative to a negotiated agreement. These findings qualify previous research on anger communication in negotiation. Implications for the understanding of emotion and negotiation are discussed. PMID- 21688881 TI - Using Lancaster's mid-P correction to the Fisher's exact test for adverse impact analyses. AB - Adverse impact is often assessed by evaluating whether the success rates for 2 groups on a selection procedure are significantly different. Although various statistical methods have been used to analyze adverse impact data, Fisher's exact test (FET) has been widely adopted, especially when sample sizes are small. In recent years, however, the statistical field has expressed concern regarding the default use of the FET and has proposed several alternative tests. This article reviews Lancaster's mid-P (LMP) test (Lancaster, 1961), an adjustment to the FET that tends to have increased power while maintaining a Type I error rate close to the nominal level. On the basis of Monte Carlo simulation results, the LMP test was found to outperform the FET across a wide range of conditions typical of adverse impact analyses. The LMP test was also found to provide better control over Type I errors than the large-sample Z-test when sample size was very small, but it tended to have slightly lower power than the Z-test under some conditions. PMID- 21688882 TI - Demographic faultlines: a meta-analysis of the literature. AB - We propose and test a theoretical model focusing on antecedents and consequences of demographic faultlines. We also posit contingencies that affect overall team dynamics in the context of demographic faultlines, such as the study setting and performance measurement. Using meta-analysis structural equation modeling with a final data set consisting of 311 data points (i.e., k [predictor-criterion relationships]), from 39 studies that were obtained from 36 papers with a total sample size of 24,388 individuals in 4,366 teams, we found that sex and racial diversity increased demographic faultline strength more than did diversity on the attributes of functional background, educational background, age, and tenure. Demographic faultline strength was found to increase task and relationship conflict as well as decrease team cohesion. Furthermore, although demographic faultline strength decreased both team satisfaction and team performance, there was a stronger decrease in team performance than in team satisfaction. The strength of these relationships increased when the study was conducted in the lab rather than in the field. We describe the theoretical and practical implications of these findings for advancing the study of faultlines. PMID- 21688883 TI - The five-factor model of personality traits and organizational citizenship behaviors: a meta-analysis. AB - Using meta-analytic tests based on 87 statistically independent samples, we investigated the relationships between the five-factor model (FFM) of personality traits and organizational citizenship behaviors in both the aggregate and specific forms, including individual-directed, organization-directed, and change oriented citizenship. We found that Emotional Stability, Extraversion, and Openness/Intellect have incremental validity for citizenship over and above Conscientiousness and Agreeableness, 2 well-established FFM predictors of citizenship. In addition, FFM personality traits predict citizenship over and above job satisfaction. Finally, we compared the effect sizes obtained in the current meta-analysis with the comparable effect sizes predicting task performance from previous meta-analyses. As a result, we found that Conscientiousness, Emotional Stability, and Extraversion have similar magnitudes of relationships with citizenship and task performance, whereas Openness and Agreeableness have stronger relationships with citizenship than with task performance. This lends some support to the idea that personality traits are (slightly) more important determinants of citizenship than of task performance. We conclude with proposed directions for future research on the relationships between FFM personality traits and specific forms of citizenship, based on the current findings. PMID- 21688884 TI - Involvement of retrosplenial cortex in forming associations between multiple sensory stimuli. AB - The retrosplenial cortex (RSP) is highly interconnected with medial temporal lobe structures, yet relatively little is known about its specific contributions to learning and memory. One possibility is that RSP is involved in forming associations between multiple sensory stimuli. Indeed, damage to RSP disrupts learning about spatial or contextual cues and also impairs learning about co occurring conditioned stimuli (CSs). Two experiments were conducted to test this notion more rigorously. In Experiment 1, rats were trained in a serial feature negative discrimination task consisting of reinforced presentations of a tone alone and nonreinforced serial presentations of a light followed by the tone. Thus, in contrast to prior studies, this paradigm involved serial presentation of conditioned stimuli (CS), rather than simultaneous presentation. Rats with damage to RSP failed to acquire the discrimination, indicating that RSP is required for forming associations between sensory stimuli regardless of whether they occur serially or simultaneously. In Experiment 2, a sensory preconditioning task was used to determine if RSP was necessary for forming associations between stimuli even in the absence of reinforcement. During the first phase of this procedure, one auditory stimulus was paired with a light while a second auditory stimulus was presented alone. In the next phase of training, the same light was paired with food. During the final phase of the procedure both auditory stimuli were presented alone during a single session. Control, but not RSP-lesioned rats, exhibited more food cup behavior following presentation of the auditory cue that was previously paired with light compared with the unpaired auditory stimulus, indicating that a stimulus-stimulus association was formed during the first phase of training. These results support the idea that RSP has a fundamental role in forming associations between environmental stimuli. PMID- 21688885 TI - Tap withdrawal circuit interneurons require CREB for long-term habituation in Caenorhabditis elegans. AB - We investigated the role of the Caenorhabditis elegans CREB (cAMP response element binding protein) homologue, crh-1, in response to tap (nonlocalized mechanosensory stimulation) and tap habituation. Worms with a loss-of-function mutation in crh-1 performed smaller reversals in response to tap than did wild type worms and did not show long-term memory for spaced training 24-hr posttraining; however, they did show short-term habituation to tap stimuli when stimuli were presented at both 10-s and 60-s interstimulus intervals, and showed 12-hr intermediate memory for spaced habituation training (intermediate-term memory). Expressing CRH-1 broadly throughout the nervous system and in a subset of interneurons of the tap withdrawal circuit, but not in the mechanosensory neurons, rescued the long-term memory defects observed in crh-1 mutants. Here we show for the first time that CREB is required for long-term habituation and show that the interneurons of the tap withdrawal response circuit are the locus of plasticity for long-term mechanosensory habituation in C. elegans. PMID- 21688886 TI - Early-life maternal separation and social isolation produce an increase in impulsive action but not impulsive choice. AB - Early life environment, events, and context, such as mother-offspring relationship, can have profound effects on future behavior and physiology. We investigated the effects of long-term maternal and social separation, through artificial rearing, on adult impulsivity. Rats were maternally reared (MR) or artificially reared (AR) and half of the AR rats were provided with replacement somatosensory stimulation intended to simulate maternal licking. There are at least 2 forms of impulsivity and we compared rats on 1 test of impulsive action (differential reinforcement of low rates of responding-DRL-20s) and 2 tests of impulsive choice (delay discounting and fixed consecutive number schedule-FCN). We found that AR rats are more action impulsive; however, this effect can be reduced by maternal licking-like stimulation. In contrast, AR rats did not display an increase in impulsive choice. Overall, these experiments show that early life maternal and social separation have different effects on the 2 forms of impulsivity. PMID- 21688887 TI - Conditioned diminution of the unconditioned skin conductance response. AB - During Pavlovian conditioning the expression of a conditioned response typically serves as evidence that an association between a conditioned stimulus (CS) and an unconditioned stimulus (UCS) has been learned. However, learning-related changes in the unconditioned response (UCR) produced by a predictable UCS can also develop. In the present study, we investigated learning-related reductions in the magnitude of the unconditioned skin conductance response (SCR). Healthy volunteers participated in a differential conditioning study in which one tone (CS+) was paired with a loud white-noise UCS and a second tone (CS-) was presented alone. In addition, probe trials that consisted of UCS presentations paired with the CS+ (CS + UCS) and CS- (CS - UCS), as well as presentations of the UCS alone were included to assess UCR diminution. SCR and participants' expectations of UCS presentation were monitored during conditioning. Greater diminution of the UCR was observed to the UCS when it followed the CS+ compared to when it followed the CS- or was presented alone. Further, UCR amplitude showed an inverse relationship with the participants' ratings of UCS expectancy. However, conditioned UCR diminution was also observed independent of differential UCS expectancies. Our findings demonstrate conditioned diminution of the unconditioned SCR. Further, these findings suggest that although UCR amplitude is modified by conscious expectations of the UCS, conditioned diminution of the UCR can be expressed independent of learning-related changes in these expectations. PMID- 21688888 TI - Videos of conspecifics elicit interactive looking patterns and facial expressions in monkeys. AB - A broader understanding of the neural basis of social behavior in primates requires the use of species-specific stimuli that elicit spontaneous, but reproducible and tractable behaviors. In this context of natural behaviors, individual variation can further inform about the factors that influence social interactions. To approximate natural social interactions similar to those documented by field studies, we used unedited video footage to induce in viewer monkeys spontaneous facial expressions and looking patterns in the laboratory setting. Three adult male monkeys (Macaca mulatta), previously behaviorally and genetically (5-HTTLPR) characterized, were monitored while they watched 10 s video segments depicting unfamiliar monkeys (movie monkeys) displaying affiliative, neutral, and aggressive behaviors. The gaze and head orientation of the movie monkeys alternated between "averted" and "directed" at the viewer. The viewers were not reinforced for watching the movies, thus their looking patterns indicated their interest and social engagement with the stimuli. The behavior of the movie monkey accounted for differences in the looking patterns and facial expressions displayed by the viewers. We also found multiple significant differences in the behavior of the viewers that correlated with their interest in these stimuli. These socially relevant dynamic stimuli elicited spontaneous social behaviors, such as eye-contact induced reciprocation of facial expression, gaze aversion, and gaze following, that were previously not observed in response to static images. This approach opens a unique opportunity to understanding the mechanisms that trigger spontaneous social behaviors in humans and nonhuman primates. PMID- 21688889 TI - Inactivation of the median raphe nucleus increases intake of sucrose solutions: a microstructural analysis. AB - Previous studies have shown that microinjections of the GABA-A agonist muscimol into the median raphe nucleus (MR) result in large increases in the intake of solid foods. In the current study, we used microstructural techniques to characterize the effects of intra-MR muscimol injections on the consumption of either a 0.05 M or a 0.29 M sucrose solution. After injections of either saline or muscimol, animals consumed more of the 0.29 M than the 0.05 M solution, an effect which resulted primarily from increases in the initial rate of consumption with no change in the rate at which licking decayed across the test session. In contrast, intra-MR muscimol injections had little effect on the initial licking rate, but greatly increased meal duration, indicating that this treatment affected ingestion in a different way than did altering the sucrose concentration. Muscimol injections produced a significantly larger increase in the intake of the 0.29 M than of the 0.05 M solution. Intra-MR muscimol injections did not alter the within burst rate of licking, suggesting that they did not affect the functioning of the licking pattern generator. In contrast, these injections did increase the number of licks contained within "clusters," that is groups of licks separated from each other by intervals of more than 0.5 sec. These findings show that inactivation of the MR produces a powerful effect on the intake of liquid diets, and that the nature of this effect is different from that produced here by changes in sucrose concentration and from those reported after pharmacological manipulations of a number of other brain systems. We additionally discuss several theoretical issues arising in the interpretation of microstructural data. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PMID- 21688890 TI - Fat substitutes promote weight gain in rats consuming high-fat diets. AB - The use of food products designed to mimic the sensory properties of sweet and fat while providing fewer calories has been promoted as a method for reducing food intake and body weight. However, such products may interfere with a learned relationship between the sensory properties of food and the caloric consequences of consuming those foods. In the present experiment, we examined whether use of the fat substitute, olestra, affect energy balance by comparing the effects of consuming high-fat, high-calorie potato chips to the effects of consuming potato chips that sometimes signaled high calories (using high-fat potato chips) and that sometimes signaled lower calories (using nonfat potato chips manufactured with the fat substitute olestra). Food intake, body weight gain and adiposity were greater for rats that consumed both the high-calorie chips and the low calorie chips with olestra compared to rats that consumed consuming only the high calorie chips, but only if animals were also consuming a chow diet that was high in fat and calories. However, rats previously exposed to both the high- and low calorie chips exhibited increased body weight gain, food intake and adiposity when they were subsequently provided with a high fat, high calorie chow diet suggesting that experience with the chips containing olestra affected the ability to predict high calories based on the sensory properties of fat. These results extend the generality of previous findings that interfering with a predictive relationship between sensory properties of foods and calories may contribute to dysregulation of energy balance, overweight and obesity. PMID- 21688891 TI - Classical conditioning and conditioning-specific reflex modification of rabbit heart rate as a function of unconditioned stimulus location. AB - Heart rate conditioning is used as an index of conditioned fear and is important for understanding disorders of anxiety and stress, including post traumatic stress disorder (PTSD). One important feature of PTSD is that patients generalize conditioned fear from danger signals to safety signals especially when the two signals have overlapping features. What has not been determined is whether generalization occurs between unconditioned stimuli with overlapping features. In the current experiment, heart rate conditioning and conditioning-specific reflex modification of rabbit heart rate were examined as a function of two different unconditioned stimulus locations. Heart rate conditioning occurred at identical terminal levels whether electrical stimulation was presented near the eye or on the back. Despite different heart rate response topographies to electrical stimulation at the two locations, conditioning-specific reflex modification was detected near the eye and on the back and appeared to generalize between the locations. Interestingly, only conditioning-specific reflex modification detected on the back persisted for a week after heart rate conditioning. This persistence may be a model for some features of post traumatic stress disorder. Overgeneralization of unconditioned responses to unconditioned stimuli similar to the trauma may also be an important aspect of PTSD modeled here. PMID- 21688892 TI - Systemic mifepristone blocks reconsolidation of cue-conditioned fear; propranolol prevents this effect. AB - Reducing reconsolidation of reactivated traumatic memories may offer a novel pharmacological treatment for posttraumatic stress disorder (PTSD). Preclinical research is needed to identify candidate drugs. We evaluated the ability of postreactivation mifepristone (RU38486, a glucocorticoid antagonist), alone and in combination with propranolol (a beta-adrenergic blocker), both given systemically, to reduce cue-conditioned fear in rats. On Day 1, a 30-s tone conditioned stimulus (CS) was paired with an electric shock unconditioned stimulus (US). On Day 2, the CS was presented without the US (reactivation), and the freezing conditioned response (CR) was measured. This was immediately followed by subcutaneous injection of vehicle, mifepristone 30 mg/kg, propranolol 10 mg/kg, or both. On Day 3, the CR was again measured as a test of postreactivation long-term memory (PR-LTM). On Day 10, the CR was again measured to evaluate spontaneous recovery. On Day 11, the US was presented alone (reinstatement). On Day 12, the CR was again measured. A fifth group received mifepristone without the CS presentation (nonreactivation) on Day 2. A sixth group was tested four hours after the Day 2 mifepristone injection to measure postreactivation short-term memory. Postreactivation, but not nonreactivation, mifepristone produced a decrement in the CR that did not undergo spontaneous recovery and underwent only modest reinstatement. Mifepristone did not exert its effect when administered concurrently with propranolol. Postreactivation mifepristone did not impair short-term memory. Systemic mifepristone blocks the reconsolidation of cue-conditioned fear in rats. Concurrent administration of propranolol prevents this effect. Postreactivation mifepristone may be a promising treatment for PTSD, but not necessarily in combination with propranolol. PMID- 21688893 TI - Genitosensory nerve modulation of paced mating behavior: evidence for pelvic, but not hypogastric, nerve influence. AB - The pelvic nerve is known to play a role in the behavioral and neurochemical responses exhibited during paced mating behavior. The present study extended the analysis of the contribution of the genitosensory nerves to the display of paced mating behavior to include bilateral hypogastric nerve transection, bilateral pelvic nerve transection, or transection of both the hypogastric and pelvic nerves. Rats with pelvic nerve transection were less likely to exit the male compartment, took longer to exit the male compartment following intromissions, and returned to the male more quickly following intromissions compared to rats with an intact pelvic nerve. In contrast, hypogastric nerve transection alone did not affect paced mating and had no modulating effect on the paced mating behavior of rats with pelvic nerve transection. Our results support the view that key aspects of paced mating behavior are modulated by signals transmitted via the pelvic nerve, without any discernable contribution from the hypogastric nerve. PMID- 21688894 TI - Effects of D-cycloserine on the extinction of appetitive operant learning. AB - Four experiments with rat subjects examined whether D-cycloserine (DCS), a partial NMDA agonist, facilitates the extinction of operant lever-pressing reinforced by food. Previous research has demonstrated that DCS facilitates extinction learning with methods that involve Pavlovian extinction. In the current experiments, operant conditioning occurred in Context A, extinction in Context B, and then testing occurred in both the extinction and conditioning contexts. Experiments 1A and 1B tested the effects of three doses of DCS (5, 15, and 30 mg/kg) on the extinction of lever pressing trained as a free operant. Experiment 2 examined their effects when extinction of the free operant was conducted in the presence of nonresponse-contingent deliveries of the reinforcer (that theoretically reduced the role of generalization decrement in suppressing responding). Experiment 3 examined their effects on extinction of a discriminated operant, that is, one that had been reinforced in the presence of a discriminative stimulus, but not in its absence. A strong ABA renewal effect was observed in all four experiments during testing. However, despite the use of DCS doses and a drug administration procedure that facilitates the extinction of Pavlovian learning, there was no evidence in any experiment that DCS facilitated operant extinction learning assessed in either the extinction or the conditioning context. DCS may primarily facilitate learning processes that underlie Pavlovian, rather than purely operant, extinction. PMID- 21688895 TI - Music-induced context preference following cocaine conditioning in rats. AB - Traditional models of drug-seeking behavior have shown that exposure to associated environmental cues can trigger relapse. These learned associations take place during repeated drug administration, resulting in conditioned reinforcement. Although considerable investigation has occurred regarding simple conditioned stimuli, less is known about complex environmental cues, particularly those that may be salient in human addiction. Recent studies indicate that music can serve as a contextual conditioned stimulus in rats and influence drug-seeking behavior during abstinence. The purpose of the present study was to further assess the effectiveness of music as a conditioned stimulus in rats, to determine rats' preferences for two contrasting pieces of music, and to determine rats' preferences for music versus silence. To this end, we created an apparatus that gave instrumental control of musical choice (Miles Davis vs. Beethoven) to the rats themselves. After determining baseline musical preference, animals were conditioned with cocaine (10 mg/kg) to the music they initially preferred least, with alternating conditioning sessions pairing saline with the music preferred most. The animals were subsequently tested in a drug-free state to determine what effect this conditioning had on musical preference. The results indicate that music serves as an effective contextual conditioned stimulus, significantly increasing both musical preference and locomotor activity after repeated cocaine conditioning. Furthermore, we found that rats initially favor silence over music, but that this preference can be altered as a result of cocaine-paired conditioning. These findings demonstrate that, after repeated association with reward (cocaine), music can engender a conditioned context preference in rats; these findings are consistent with other evidence showing that musical contextual cues can reinstate drug-seeking behavior in rats. PMID- 21688896 TI - Perceptual load influences selective attention across development. AB - Research suggests that visual selective attention develops across childhood. However, there is relatively little understanding of the neurological changes that accompany this development, particularly in the context of adult theories of selective attention, such as N. Lavie's (1995) perceptual load theory of attention. This study examined visual selective attention across development from 7 years of age to adulthood. Specifically, the author examined if changes in processing as a function of selective attention are similarly influenced by perceptual load across development. Participants were asked to complete a task at either low or high perceptual load while processing of an unattended probe stimulus was examined using event related potentials. Similar to adults, children and teens showed reduced processing of the unattended stimulus as perceptual load increased at the P1 visual component. However, although there were no qualitative differences in changes in processing, there were quantitative differences, with shorter P1 latencies in teens and adults compared with children, suggesting increases in the speed of processing across development. In addition, younger children did not need as high a perceptual load to achieve the same difference in performance between low and high perceptual load as adults. Thus, this study demonstrates that although there are developmental changes in visual selective attention, the mechanisms by which visual selective attention is achieved in children may share similarities with adults. PMID- 21688897 TI - Classroom emotional climate as a moderator of anxious solitary children's longitudinal risk for peer exclusion: a child * environment model. AB - This study tests the ability of classroom emotional climate to moderate anxious solitary children's risk for peer exclusion over a 3-year period from 3rd through 5th grade. Six hundred eighty-eight children completed peer nominations for anxious solitude and peer exclusion in the fall and spring semesters of each grade, and observations of classroom emotional climate were conducted at the same time points. Results revealed a positive relation between anxious solitude and peer exclusion in the fall semester of each grade. However, in classrooms with supportive versus unsupportive emotional climates, this relation demonstrated a different pattern of change from fall to spring semesters. In classrooms with supportive emotional climates, children with high versus low levels of anxious solitude experienced relative elevation in fall peer exclusion, but this disappeared by the spring, such that spring peer exclusion levels were equalized among children who differed in anxious solitude. This result is consistent with hypotheses guided by the Child * Environment model. However, in classrooms with unsupportive emotional climates, results did not conform to expectations that children with high anxious solitude would experience stable or increased peer exclusion over time. PMID- 21688898 TI - Inhibition and exuberance in preschool classrooms: associations with peer social experiences and changes in cortisol across the preschool year. AB - Associations between behavioral inhibition and activity of the hypothalamic pituitary-adrenocortical (HPA) system, a stress-sensitive neuroendocrine system indexed by salivary cortisol, have varied widely across studies. In the current study, we examined the role of peer social experiences in moderating patterns of association between inhibition/risk-aversion and cortisol reactivity. As expected based on previous research, preschool children (N = 165, 78 boys, 87 girls, 3.0 5.0 years) had significantly different social experiences in their preschool classrooms depending on temperament. Highly inhibited/risk-averse children were less socially integrated, less dominant, and less involved in aggressive encounters than both average and highly exuberant/risk-seeking children, but they were no more likely to be peer rejected. Highly exuberant children were more dominant, exhibited anger more often, and had friendships characterized by higher conflict. Cortisol levels fell from fall to spring for average and highly exuberant children but not for highly inhibited children. Unexpectedly, for highly inhibited children, having friends and being more dominant and popular than other highly inhibited children was associated with increasing cortisol levels over the school year. In contrast, highly exuberant children who were less socially integrated than other highly exuberant children maintained higher cortisol levels. Results indicate that the types of social experiences that affect stress-responsive biological systems may differ markedly for highly inhibited and highly exuberant children. PMID- 21688899 TI - Trajectories of family management practices and early adolescent behavioral outcomes. AB - Stage-environment fit theory was used to examine the reciprocal lagged relations between family management practices and early adolescent problem behavior during the middle school years. In addition, the potential moderating roles of family structure and of gender were explored. Hierarchical linear modeling was used to describe patterns of growth in family management practices and adolescents' behavioral outcomes and to detect predictors of interindividual differences in initial status and rate of change. The sample comprised approximately 1,000 adolescents between ages 11 years and 15 years. The results indicated that adolescents' antisocial behaviors and substance use increased and their positive behavioral engagement decreased over time. As adolescent age increased, parental knowledge of their adolescent's activities decreased, as did parental rule making and support. The level and rate of change in family management and adolescent behavioral outcomes varied by family structure and by gender. Reciprocal longitudinal associations between parenting practices and adolescent problem behavior were found. Specifically, parenting practices predicted subsequent adolescent behavior, and adolescent behavior predicted subsequent parenting practices. In addition, parental warmth moderated the effects of parental knowledge and rule making on adolescent antisocial behavior and substance use over time. PMID- 21688900 TI - Does money really matter? Estimating impacts of family income on young children's achievement with data from random-assignment experiments. AB - Social scientists do not agree on the size and nature of the causal impacts of parental income on children's achievement. We revisit this issue using a set of welfare and antipoverty experiments conducted in the 1990s. We utilize an instrumental variables strategy to leverage the variation in income and achievement that arises from random assignment to the treatment group to estimate the causal effect of income on child achievement. Our estimates suggest that a $1,000 increase in annual income increases young children's achievement by 5%-6% of a standard deviation. As such, our results suggest that family income has a policy-relevant, positive impact on the eventual school achievement of preschool children. PMID- 21688901 TI - Predictors of parenting stress among gay adoptive fathers in the United States. AB - The authors examined correlates of parenting stress among 230 gay adoptive fathers across the United States through an Internet survey. As with previous research on adoptive parents, results showed that fathers with less social support, older children, and children who were adopted at older ages reported more parenting stress. Moreover, gay fathers who had a less positive gay identity also reported more parenting stress. These 4 variables accounted for 33% of the variance in parenting stress; effect sizes were medium to large. Our results suggest the importance of social support and a positive gay identity in facilitating successful parenting outcomes among gay adoptive fathers. PMID- 21688902 TI - Considerations of culture and social class for families facing cancer: the need for a new model for health promotion and psychosocial intervention. AB - Cancer is a family experience, and family members often have as much, or more, difficulty in coping with cancer as does the person diagnosed with cancer. Using both family systems and sociocultural frameworks, we call for a new model of health promotion and psychosocial intervention that builds on the current understanding that family members, as well as the individuals diagnosed with cancer, are themselves survivors of cancer. We argue that considering culture, or the values, beliefs, and customs of the family, including their choice of language, is necessary to understand fully a family's response to cancer. Likewise, acknowledging social class is necessary to understand how access to, and understanding of, otherwise available interventions for families facing cancer can be limited. Components of the model as conceptualized are discussed and provide guidance for psychosocial cancer health disparities research and the development of family-focused, strength-based, interventions. PMID- 21688903 TI - The moderating effect of relationship quality on partner secondary traumatic stress among couples coping with cancer. AB - A considerable amount of research has investigated symptoms of posttraumatic stress in cancer patients while the occurrence and correlates of secondary traumatic stress on patients' intimate partners has yet to be explored. This study examined the prevalence of secondary traumatic stress symptoms (Modified Secondary Trauma Questionnaire) in partners of cancer patients and evaluated the association of these symptoms with patients' posttraumatic stress symptoms (Impact of Event Scale-Revised). The study also investigated the moderation effect of relationship quality (Marital Satisfaction Inventory-Revised) on the association between patients' and partners' posttraumatic and secondary traumatic stress respectively. A heterogeneous sample of 90 patient-partner dyads was recruited through a provincial cancer agency. Multiple symptoms of secondary traumatic stress were reported by 23% of partners. These symptoms were experienced at a clinically significant level by 10% of all participating partners. Although patients' and partners' traumatic stress symptoms were correlated (r = .44, p < .001), only one dyad consisted of both a patient and a partner scoring clinically significant levels of traumatic stress symptoms. Therefore, of the 90 dyads in the study, 18% included at least one partner reporting clinically significant levels of traumatic stress. Relationship quality accounted for 11% of the variance in secondary traumatic stress, in addition to the 19% already accounted for by patients' posttraumatic stress. Relationship quality also exhibited buffering effects benefiting couples with higher quality relationships. Implications of results for future research and holistic health care models are discussed. PMID- 21688904 TI - Managing the impact of posttreatment fatigue on the family: breast cancer survivors share their experiences. AB - With improvements in both early detection and treatments for breast cancer, the number of survivors has increased dramatically in recent decades. One of the most common lingering symptoms posttreatment for cancer survivors is chronic fatigue. Based on family stress theory and Rolland's typology of illness, this qualitative study extends our understanding of the impact of persistent posttreatment fatigue on families and how breast cancer survivors manage the family issues that arise because of this chronic stressor. Participants included 35 female survivors of breast cancer (mean age = 54 years) who experienced fatigue after the completion of active cancer treatment, with the exception of long-term hormonal therapy. Data were generated from (a) observations of group sessions from a randomized controlled fatigue intervention designed to reduce fatigue in breast cancer survivors, (b) individual in-depth interviews, and (c) family sessions. Qualitative analysis revealed two broad themes that illustrate how the survivors manage the impact of fatigue on their families: Interpreting the meaning of the fatigue and Dealing with the inability to perform family roles. Study findings describe the difficulties in family adaptation when the family is not able to assign a clear meaning to a chronic symptom posttreatment and build upon family stress theory by highlighting interrelationships among communication patterns and role shifts in the family system. PMID- 21688905 TI - The importance of time in treating mental health in primary care. PMID- 21688912 TI - Electronic monitoring feedback to promote adherence in an adolescent with Fanconi Anemia. AB - OBJECTIVE: This report describes an intervention to promote medication adherence and treat comorbid psychological symptoms in a 17 year-old female with Fanconi Anemia. The patient presented with a typical adherence rate estimated at 25% and self-reported symptoms of depressed mood and anxiety. METHOD: Our comprehensive treatment approach integrated electronic monitoring (EM), an emerging strategy for adherence promotion, and motivational interviewing (MI) within an evidence based cognitive-behavioral therapy (CBT) framework. We used EM data to assess and track medication adherence. The therapist reviewed these data with the patient and family in session and used MI techniques to promote health behavior change. We analyzed changes in adherence rates over time using a time series analysis (Auto-Regressive Moving Average [ARIMA]). In addition, the patient and her mother reported on depression, anxiety, and quality of life at intake and after 12 months, and the therapist treated psychological symptoms with CBT. RESULTS: The average adherence rate during the baseline EM phase was ~53%. The mean adherence rate across treatment was ~77%, and after 17 months, the final weekly adherence rate was 82%. Adherence rates significantly improved over the treatment period, ARIMA t = 36.16, p < .01. CONCLUSIONS: EM feedback and MI are viable additions to CBT to promote medication adherence in adolescence. This approach has the potential to effectively treat adolescents with adherence problems and psychological symptoms across multiple chronic illness diagnoses, and ultimately to improve health and quality of life outcomes. PMID- 21688913 TI - Is self-disclosure in couples coping with cancer associated with improvement in depressive symptoms? AB - OBJECTIVE: This study examined associations between the degree of self-disclosure and changes in depressive symptoms in couples coping with colorectal cancer. METHOD: Sixty-four newly diagnosed patients and their partners completed a measure of depressive symptoms (Center of Epidemiologic Studies Depression Scale) 3 and 9 months postdiagnosis. Furthermore, approximately 2 months after the first assessment, they engaged in a cancer-related conversation in which the patient was asked to introduce a concern. Each partner's verbalizations of emotions, thoughts, and wishes (i.e., self-disclosures) were coded by independent observers. RESULTS: Patients who reported more depressive symptoms at baseline showed more self-disclosures. Mutual self-disclosure was not associated with lower levels of depressive symptoms in patients and partners as compared with one sided self-disclosure or low disclosure in both patients and partners. It is important to note that decreases in depressive symptoms over time were least prominent in couples in which the partner disclosed a lot whereas the patient disclosed little. CONCLUSION: These results suggest that mere disclosure of emotions and thoughts to one's intimate partner is not beneficial in reducing distress. Partners' self-disclosure toward patients who disclose few emotions and concerns even appears to be harmful both for patients and partners, given that it reduces the decrease of depressive symptoms over time. If there is a mismatch in the need for self-disclosure within couples, partners with a strong need to talk about their emotions and concerns may be recommended to confide in someone else in their social network or to consult a health care professional. PMID- 21688914 TI - Optimism and adolescent perception of skin cancer risk. AB - OBJECTIVES: The present study examined comparative optimism for skin cancer (the belief that one is at lower risk for skin cancer than one's peers) among adolescents in two age groups: 11- and 12-year-olds versus 13- and 14-year-olds. Specifically, we tested whether optimism was enhanced when adolescents at lower relative risk (i.e., nontanners) were exposed to higher-risk comparison targets (photos of tanned models) and whether this effect was moderated by age. METHODS: Students (N = 211) viewed pictures of either tanned or fair-skinned models, and then responded to a questionnaire that included an assessment of their comparative optimism for skin cancer in later life. RESULTS: Students, as a whole, were comparatively optimistic about their likelihood of developing skin cancer, despite the fact that more than half (55.6%) of them reported intentionally tanning. Analysis of variance revealed a significant 3-way interaction among behavior (tanner vs. nontanner), target (pale vs. tanned model), and age (early vs. mid-adolescents). The interaction was driven by a particularly strong amount of comparative optimism in one group: mid-adolescent, nontanning students in the tan-target condition. CONCLUSIONS: Most adolescents believe they are less likely than their peers to experience a negative health outcome. It also appears that the relation between social comparison and comparative optimism develops with age, as only the midadolescent students showed evidence of making a self-to-target comparison. PMID- 21688915 TI - Moderators and mediators of exercise-induced objective sleep improvements in midlife and older adults with sleep complaints. AB - OBJECTIVE: Exercise can improve sleep quality, but for whom and by what means remains unclear. We examined moderators and mediators of objective sleep improvements in a 12-month randomized controlled trial among underactive midlife and older adults reporting mild/moderate sleep complaints. METHODS: Participants (N = 66, 67% women, 55-79 years) were randomized to moderate-intensity exercise or health education control. Putative moderators were gender, age, physical function, self-reported global sleep quality, and physical activity levels. Putative mediators were changes in BMI, depressive symptoms, and physical function at 6 months. Objective sleep outcomes measured by in-home polysomnography were percent time in Stage I sleep, percent time in Stage II sleep, and number of awakenings during the first third of sleep at 12 months. RESULTS: Baseline physical function and sleep quality moderated changes in Stage I sleep; individuals with higher initial physical function (p = .01) and poorer sleep quality (p = .03) had greater improvements. Baseline physical activity level moderated changes in Stage II sleep (p = .04) and number of awakenings (p = .01); more sedentary individuals had greater improvements. Decreased depressive symptoms (CI:-1.57 to -0.02) mediated change in Stage I sleep. Decreased depressive symptoms (CI:-0.75 to -0.01), decreased BMI (CI:-1.08 to -0.06), and increased physical function (CI: 0.01 to 0.72) mediated change in number of awakenings. CONCLUSIONS: Initially less active individuals with higher initial physical function and poorer sleep quality improved the most. Affective, functional, and metabolic mediators specific to sleep architecture parameters were suggested. These results indicate strategies to more efficiently treat poor sleep through exercise in older adults. PMID- 21688916 TI - The differential effects of interpersonal conflict from customers and coworkers: trait anger as a moderator. AB - Interpersonal conflict (IC) at work is a frequently experienced type of workplace mistreatment that has been linked to a host of negative workplace outcomes. Previous research has shown that IC can have differential effects based on source, but this has not yet been investigated in terms of customer IC versus coworker IC. To remedy this oversight in the literature, we used a multimethod, multitime point design to compare IC from customers and coworkers experienced by 75 call center employees. Primarily, we investigated burnout, physical health symptoms, and task performance. Results indicated that customer IC was more strongly related to both personal and organizational outcomes. Additionally, trait anger was investigated as a moderator of these relationships, and the results indicated that people who are easy to anger may be more likely to experience negative effects as a result of customer IC. Implications of these findings, limitations, and areas for future research are discussed. PMID- 21688917 TI - Effects of customer entitlement on service workers' physical and psychological well-being: a study of waitstaff employees. AB - This exploratory study examines the nature of customer entitlement and its impact on front-line service employees. In an open-ended qualitative inquiry, 56 individuals with waitstaff experience described the types of behaviors entitled customers engage in and the kinds of service-related "perks" these individuals feel deserving of. Participants explained how they responded to entitled customers, how and when managers became involved, and how their dealings with these patrons influenced their subjective physical and psychological well-being. We found that the behaviors of entitled customers negatively impacted waitstaff employees. Participants reported physiological arousal, negative affect, burnout, and feelings of dehumanization as a result of dealing with these patrons. While respondents drew on a variety of strategies to manage their encounters with entitled customers, they indicated workplace support was often informal and described feeling abandoned by management in dealing with this workplace stressor. Approaching customer entitlement as a form of microaggression, we offer recommendations for practice and suggest new directions for future research. PMID- 21688919 TI - Stress resilience in early marriage: can practice make perfect? AB - As all couples experience stressful life events, addressing how couples adapt to stress is imperative for understanding marital development. Drawing from theories of stress inoculation, which suggest that the successful adaptation to moderately stressful events may help individuals develop a resilience to future stress, the current studies examined whether experiences with manageable stressors early in the marriage may serve to make the relationship more resilient to future stress. In Study 1, 61 newlywed couples provided data regarding their stressful life events, relationship resources (i.e., observed problem-solving behaviors), and marital satisfaction at multiple points over 21/2 years. Results revealed that among spouses displaying more effective problem-solving behaviors, those who experienced moderate stress during the early months of marriage exhibited fewer future stress spillover effects and reported greater increases in felt efficacy than did spouses who had less experience with early stress. Study 2 examined stress resilience following the transition to parenthood in a new sample of 50 newlywed couples. Again, spouses who experienced moderate stress during the early months of marriage and had good initial relationship resources (i.e., observed support behaviors) reported greater marital adjustment following the transition to parenthood than did spouses who had good initial resources but less prior experience coping with stress. Together, results indicate that entering marriage with better relationship resources may not be sufficient to shield marital satisfaction from the detrimental effects of stress; rather, couples may also need practice in using those resources to navigate manageable stressful events. PMID- 21688920 TI - Meta-insight: do people really know how others see them? AB - Although people can accurately guess how others see them, many studies have suggested that this may only be because people generally assume that others see them as they see themselves. These findings raise the question: In their everyday lives, do people understand the distinction between how they see their own personality and how others see their personality? We examined whether people make this distinction, or whether people possess what we call meta-insight. In 3 studies, we assessed meta-insight for a broad range of traits (e.g., Big Five, intelligent, funny) across several naturalistic social contexts (e.g., first impression, friends). Our findings suggest that people can make valid distinctions between how they see themselves and how others see them. Thus, people seem to have some genuine insight into their reputation and do not achieve meta-accuracy only by capitalizing on the fact that others see them similarly to how they see themselves. PMID- 21688921 TI - What we think we do (to each other): how personality can bias behavior schemas through the projection of if-then profiles. AB - People's knowledge about others includes not only person schemas about the typical traits of others but also behavior schemas about the likely interpersonal consequences of different behaviors. In this article, it is argued that perceiver effects can be interactive at the level of behavior schemas. A person's own personality configuration of if-then responses in social interactions (Mischel & Shoda, 1995) may contribute to that person's beliefs about the meaning and impact of relational behaviors more generally. In consequence, people who experience strong (or weak) responses to behaviors that vary along a particular trait dimension, such as warmth-coldness, may expect others to experience similarly strong (or weak) responses to those same kinds of behaviors. In 3 studies, people who were high in trait communion expected others to respond more strongly to behaviors that varied in warmth-coldness than did people who were low in trait communion, and people who were low in trait agency expected others to respond more strongly to behaviors that varied in assertiveness-unassertiveness than did people who were high in trait agency. Studies 2 and 3 provided evidence that participants' behavior schemas were based on assumptions derived from their own if-then personality profiles. PMID- 21688922 TI - Needs and subjective well-being around the world. AB - Across a sample of 123 countries, we examined the association between the fulfillment of needs and subjective well-being (SWB), including life evaluation, positive feelings, and negative feelings. Need fulfillment was consistently associated with SWB across world regions. Life evaluation was most associated with fulfilling basic needs; positive feelings were most associated with social and respect needs; and negative feelings were most associated with basic, respect, and autonomy needs. Societal need fulfillment predicted SWB, particularly for life evaluation, beyond individuals' fulfillment of their own needs, indicating the desirability of living in a flourishing society. In addition, the associations of SWB with the fulfillment of specific needs were largely independent of whether other needs were fulfilled. These trends persisted when household income was taken into account. The emergent ordering of need fulfillment for psychosocial needs were fairly consistent across country conditions, but the fulfillment of basic and safety needs were contingent on country membership. PMID- 21688923 TI - Self-presentational persona: simultaneous management of multiple impressions. AB - Most research on self-presentation has examined how people convey images of themselves on only 1 or 2 dimensions at a time. In everyday interactions, however, people often manage their impressions on several image-relevant dimensions simultaneously. By examining people's self-presentations to several targets across multiple dimensions, these 2 studies offer new insights into the nature of self-presentation and provide a novel paradigm for studying impression management. Results showed that most people rely on a relatively small number of basic self-presentational personas in which they convey particular profiles of impressions as a set and that these personas reflect both normative influences to project images that are appropriate to a particular target and distinctive influences by which people put an idiosyncratic spin on these normative images. Furthermore, although people's self-presentational profiles correlate moderately with their self-views, they tailor their public images to specific targets. The degree to which participants' self-presentations were normative and distinctive, as well as the extent to which they reflected their own self-views, were moderated by individual differences in agreeableness, self-esteem, authenticity, and Machiavellianism. PMID- 21688924 TI - Consider it done! Plan making can eliminate the cognitive effects of unfulfilled goals. AB - Unfulfilled goals persist in the mind, as asserted by ample theory and evidence (e.g., the Zeigarnik effect). The standard assumption has been that such cognitive activation persists until the goal is fulfilled. However, we predicted that contributing to goal pursuit through plan making could satisfy the various cognitive processes that usually promote goal pursuit. In several studies, we activated unfulfilled goals and demonstrated persistent goal activation over time. Unfinished goals caused intrusive thoughts during an unrelated reading task (Studies 1 and 5B), high mental accessibility of goal-related words (Studies 2 and 3), and poor performance on an unrelated anagram task (Study 4). Allowing participants to formulate specific plans for their unfulfilled goals eliminated the various activation and interference effects. Reduction of the effects was mediated by the earnestness of participants' plans: Those who ultimately executed their plans were those who also exhibited no more intrusions (Study 4). Moreover, changes in goal-related emotions did not appear to be a necessary component of the observed cognitive effects (Studies 5A and 5B). Committing to a specific plan for a goal may therefore not only facilitate attainment of the goal but may also free cognitive resources for other pursuits. Once a plan is made, the drive to attain a goal is suspended--allowing goal-related cognitive activity to cease- and is resumed at the specified later time. PMID- 21688925 TI - Beliefs about emotional residue: the idea that emotions leave a trace in the physical environment. AB - Drawing upon the literatures on beliefs about magical contagion and property transmission, we examined people's belief in a novel mechanism of human-to-human contagion, emotional residue. This is the lay belief that people's emotions leave traces in the physical environment, which can later influence others or be sensed by others. Studies 1-4 demonstrated that Indians are more likely than Americans to endorse a lay theory of emotions as substances that move in and out of the body, and to claim that they can sense emotional residue. However, when the belief in emotional residue is measured implicitly, both Indians and American believe to a similar extent that emotional residue influences the moods and behaviors of those who come into contact with it (Studies 5-7). Both Indians and Americans also believe that closer relationships and a larger number of people yield more detectable residue (Study 8). Finally, Study 9 demonstrated that beliefs about emotional residue can influence people's behaviors. Together, these finding suggest that emotional residue is likely to be an intuitive concept, one that people in different cultures acquire even without explicit instruction. PMID- 21688926 TI - The surprising potency of implicit egotism: A reply to Simonsohn. AB - This article addresses Simonsohn's (2011) critique of field studies of implicit egotism. We argue that Simonsohn provides no compelling theoretical reason to believe that implicit egotism should be valid only in the laboratory. In addition, we argue that a careful analysis of most of Simonsohn's studies of implicit egotism shows that they provide little or no power to reveal real effects of implicit egotism. We conclude that it is more constructive to try to identify theoretically derived moderators of implicit egotism than to try to document that it is always spurious in the field. PMID- 21688928 TI - Supervisor self-disclosure: supervisees' experiences and perspectives. AB - Twelve graduate-level supervisees were interviewed regarding their experiences of supervisor self-disclosure (SRSD); data were analyzed using consensual qualitative research. When describing a specific SRSD experience, supervisees reported a range of antecedents (e.g., difficult clinical situation, self-doubt, tension in supervision relationship) followed by supervisor disclosures about clinical experiences or personal information. Supervisees perceived that their supervisors disclosed primarily to normalize, but also to build rapport and to instruct. The SRSDs had mostly positive effects (e.g., normalization), though some negative effects (e.g., deleterious impact on supervision relationship) were reported. Implications of these findings for supervision, training, and research are addressed. PMID- 21688929 TI - Recollections of a secure base in psychotherapy: considerations of the real relationship. AB - Empirical research has recently addressed the real or personal relationship between patients and psychotherapists. The present study examined the interrelations of client attachment security, recollections of real relationship, and client attachment to therapist in a sample of 143 college students who had completed at least five sessions of previously terminated psychotherapy. As expected, client-rated real relationship was found to have positive associations with both client attachment security and security of client attachment to therapist. Additional associations were found between client attachment and avoidant attachment tendencies to therapist. The possibilities for future research expanding on these results are discussed. PMID- 21688930 TI - Therapist differences in cognitive-behavioral psychotherapy for generalized anxiety disorder: a pilot study. AB - Little is known about factors differentiating more and less effective therapists or the mechanisms through which therapists influence outcome. In the present study, the performance of a small sample of 4 therapists was compared in the context of delivering cognitive-behavioral psychotherapy (CBT) to 32 clients with generalized anxiety disorder. More effective therapists were characterized by higher observer-rated CBT competence, higher client outcome expectations and client treatment credibility assessments, and higher early treatment client ratings of therapeutic alliance quality. Higher early CBT competence was associated with higher client midtreatment outcome expectations, which in turn were associated with better posttreatment outcomes. Although these findings are preliminary given the small sample of therapists and clients, they suggest that the common factor of outcome expectations might be a mechanism through which the specific factor of psychotherapist competence exerts its influence on treatment outcome. The implications of these findings and directions for future research are discussed. PMID- 21688931 TI - Therapist emotional reactions and client resistance in cognitive behavioral therapy. AB - Although extensively discussed in theoretical papers, empirical studies of therapist emotional reactions to clients are lacking, particularly within the context of client resistance and cognitive-behavioral therapy (CBT). The present study examined the early positive and negative emotional reactions to clients of four therapists, together with observed client in-session resistance, and changes in resistance from early to midtreatment, in a sample of 30 outpatients receiving eight sessions (14 hr) of CBT for generalized anxiety disorder. Findings indicated that greater therapist early positive reactions to clients, especially liking, enjoyment, and attachment, were associated with significantly lower levels of client resistance midtreatment and greater reductions in client resistance from early to midtreatment. These effects were independent of therapist competence in delivering CBT, suggesting a potentially unique and important role for therapist feelings about clients beyond the skillful delivery of treatment techniques. Greater early negative therapist reactions to clients were less consistently related to client resistance but power struggles, and feeling drained, helpless, guilty, and frustrated were associated with higher levels of client subsequent resistance. PMID- 21688932 TI - Individual differences in response to automation: the five factor model of personality. AB - This study examined the relationship of operator personality (Five Factor Model) and characteristics of the task and of adaptive automation (reliability and adaptiveness-whether the automation was well-matched to changes in task demand) to operator performance, workload, stress, and coping. This represents the first investigation of how the Five Factors relate to human response to automation. One hundred-sixty-one college students experienced either 75% or 95% reliable automation provided with task loads of either two or four displays to be monitored. The task required threat detection in a simulated uninhabited ground vehicle (UGV) task. Task demand exerted the strongest influence on outcome variables. Automation characteristics did not directly impact workload or stress, but effects did emerge in the context of trait-task interactions that varied as a function of the dimension of workload and stress. The pattern of relationships of traits to dependent variables was generally moderated by at least one task factor. Neuroticism was related to poorer performance in some conditions, and all five traits were associated with at least one measure of workload and stress. Neuroticism generally predicted increased workload and stress and the other traits predicted decreased levels of these states. However, in the case of the relation of Extraversion and Agreeableness to Worry, Frustration, and avoidant coping, the direction of effects varied across task conditions. The results support incorporation of individual differences into automation design by identifying the relevant person characteristics and using the information to determine what functions to automate and the form and level of automation. PMID- 21688934 TI - Eye movements and display change detection during reading. AB - In the boundary change paradigm (Rayner, 1975), when a reader's eyes cross an invisible boundary location, a preview word is replaced by a target word. Readers are generally unaware of such changes due to saccadic suppression. However, some readers detect changes on a few trials and a small percentage of them detect many changes. Two experiments are reported in which we combined eye movement data with signal detection analyses to investigate display change detection. On each trial, readers had to indicate if they saw a display change in addition to reading for meaning. On half the trials the display change occurred during the saccade (immediate condition); on the other half, it was slowed by 15-25 ms (delay condition) to increase the likelihood that a change would be detected. Sentences were presented in an alternating case fashion allowing us to investigate the influence of both letter identity and case. In the immediate condition, change detection was higher when letters changed than when case changed corroborating findings that word processing utilizes abstract (case independent) letter identities. However, in the delay condition (where d' was much higher than the immediate condition), detection was equal for letter and case changes. The results of both experiments indicate that sensitivity to display changes was related to how close the eyes were to the invalid preview on the fixation prior to the display change, as well as the timing of the completion of this change relative to the start of the post-change fixation. PMID- 21688935 TI - Fusion prevents the redundant signals effect: evidence from stereoscopically presented stimuli. AB - In a simple reaction time (RT) experiment, visual stimuli were stereoscopically presented either to one eye (single stimulation) or to both eyes (redundant stimulation), with brightness matched for single and redundant stimulations. Redundant stimulation resulted in two separate percepts when noncorresponding retinal areas were stimulated, whereas it resulted in a single fused percept when corresponding areas were stimulated. With stimulation of noncorresponding areas, mean RT was shorter to redundant than to single stimulation, replicating the redundant signals effect (RSE) commonly found with visual stimuli. With stimulation of corresponding areas, however, no RSE was observed. This suggests that the RSE is driven by the number of percepts rather than by the number of stimulated receptors or sensory organs. These results are consistent with previous findings in the auditory modality and have implications for models of the RSE. PMID- 21688937 TI - Spatial grouping resolves ambiguity to drive temporal recalibration. AB - Cross-modal temporal recalibration describes a shift in the point of subjective simultaneity (PSS) between 2 events following repeated exposure to asynchronous cross-modal inputs--the adaptors. Previous research suggested that audiovisual recalibration is insensitive to the spatial relationship between the adaptors. Here we show that audiovisual recalibration can be driven by cross-modal spatial grouping. Twelve participants adapted to alternating trains of lights and tones. Spatial position was manipulated, with alternating sequences of a light then a tone, or a tone then a light, presented on either side of fixation (e.g., left tone--left light--right tone--right light, etc.). As the events were evenly spaced in time, in the absence of spatial-based grouping it would be unclear if tones were leading or lagging lights. However, any grouping of spatially colocalized cross-modal events would result in an unambiguous sense of temporal order. We found that adapting to these stimuli caused the PSS between subsequent lights and tones to shift toward the temporal relationship implied by spatial based grouping. These data therefore show that temporal recalibration is facilitated by spatial grouping. PMID- 21688936 TI - Perceptual adaptation to sinewave-vocoded speech across languages. AB - Listeners rapidly adapt to many forms of degraded speech. What level of information drives this adaptation, however, remains unresolved. The current study exposed listeners to sinewave-vocoded speech in one of three languages, which manipulated the type of information shared between the training languages (German, Mandarin, or English) and the testing language (English) in an audio visual (AV) or an audio plus still frames modality (A + Stills). Three control groups were included to assess procedural learning effects. After training, listeners' perception of novel sinewave-vocoded English sentences was tested. Listeners exposed to German-AV materials performed equivalently to listeners exposed to English AV or A + Stills materials and significantly better than two control groups. The Mandarin groups and German-A + Stills group showed an intermediate level of performance. These results suggest that full lexical access is not absolutely necessary for adaptation to degraded speech, but providing AV training in a language that is similar phonetically to the testing language can facilitate adaptation. PMID- 21688938 TI - Haptic distal spatial perception mediated by strings: haptic "looming". AB - Five experiments tested a haptic analog of optical looming, demonstrating string mediated haptic distal spatial perception. Horizontally collinear hooks supported a weighted string held taut by a blindfolded participant's finger midway between the hooks. At the finger, the angle between string segments increased as the finger approached collinearity with the hooks, just as the optical angle subtended by an approaching object increases. The vertical force component at the finger is potentially informative for perception, approaching zero at finger-hook collinearity. In Experiment 1, participants judged hook height reasonably accurately. To retain force relationships but eliminate immediate skin contact, Experiment 2 employed a hand-held rod; results replicated those of Experiment 1. Experiment 3 replicated Experiment 2 using a ring instead of a rod. In all three experiments, estimated hook height closely paralleled actual height, r > .9. Experiments 4 and 5 showed that participants could project impending finger-hook collinearity when finger contact with the string was interrupted during its traverse. Perceivers' estimate errors were nearly perfectly predicted by height force ratio relationships (Rs > .96). Outcomes are related to optical and acoustic looming, dynamic touch, tau theory, and Gibsonian perceptual theory. PMID- 21688940 TI - Eye gaze versus arrows as spatial cues: two qualitatively different modes of attentional selection. AB - This study aimed to evaluate the type of attentional selection (location- and/or object-based) triggered by two different types of central noninformative cues: eye gaze and arrows. Two rectangular objects were presented in the visual field, and subjects' attention was directed to the end of a rectangle via the observation of noninformative directional arrows or eye gaze. Similar experiments with peripheral cues have shown an object-based effect: faster target identification when the target is presented on the cued object as compared to the uncued object, even when the distance between target and cue was the same. The three reported experiments aimed to compare the location- and object-based attentional orienting observed with arrows and eye gaze, in order to dissociate the orienting mechanisms underlying the two types of orienting cues. Results showed similar cueing effects on the cued versus oppositely cued locations for the two cue types, replicating several studies with nonpredictive gaze and arrow cues. However, a pure object-based effect occurred only when an arrow cue was presented, whereas a pure location-based effect was only found for eye-gaze cues. It is suggested that attention is nonspecifically directed to nearby objects when a noninformative arrow is used as cue, whereas it is selectively directed to a specific cued location when noninformative eye gaze is used. This may be mediated by theory of mind mechanisms. PMID- 21688941 TI - What top-down task sets do for us: an ERP study on the benefits of advance preparation in visual search. AB - When target-defining features are specified in advance, attentional target selection in visual search is controlled by preparatory top-down task sets. We used ERP measures to study voluntary target selection in the absence of such feature-specific task sets, and to compare it to selection that is guided by advance knowledge about target features. Visual search arrays contained two different color singleton digits, and participants had to select one of these as target and report its parity. Target color was either known in advance (fixed color task) or had to be selected anew on each trial (free color-choice task). ERP correlates of spatially selective attentional target selection (N2pc) and working memory processing (SPCN) demonstrated rapid target selection and efficient exclusion of color singleton distractors from focal attention and working memory in the fixed color task. In the free color-choice task, spatially selective processing also emerged rapidly, but selection efficiency was reduced, with nontarget singleton digits capturing attention and gaining access to working memory. Results demonstrate the benefits of top-down task sets: Feature-specific advance preparation accelerates target selection, rapidly resolves attentional competition, and prevents irrelevant events from attracting attention and entering working memory. PMID- 21688939 TI - When does repeated search in scenes involve memory? Looking at versus looking for objects in scenes. AB - One might assume that familiarity with a scene or previous encounters with objects embedded in a scene would benefit subsequent search for those items. However, in a series of experiments we show that this is not the case: When participants were asked to subsequently search for multiple objects in the same scene, search performance remained essentially unchanged over the course of searches despite increasing scene familiarity. Similarly, looking at target objects during previews, which included letter search, 30 seconds of free viewing, or even 30 seconds of memorizing a scene, also did not benefit search for the same objects later on. However, when the same object was searched for again memory for the previous search was capable of producing very substantial speeding of search despite many different intervening searches. This was especially the case when the previous search engagement had been active rather than supported by a cue. While these search benefits speak to the strength of memory-guided search when the same search target is repeated, the lack of memory guidance during initial object searches-despite previous encounters with the target objects-demonstrates the dominance of guidance by generic scene knowledge in real-world search. PMID- 21688942 TI - Crossmodal semantic priming by naturalistic sounds and spoken words enhances visual sensitivity. AB - We propose a multisensory framework based on Glaser and Glaser's (1989) general reading-naming interference model to account for the semantic priming effect by naturalistic sounds and spoken words on visual picture sensitivity. Four experiments were designed to investigate two key issues: First, can auditory stimuli enhance visual sensitivity when the sound leads the picture as well as when they are presented simultaneously? And, second, do naturalistic sounds (e.g., a dog's "woofing") and spoken words (e.g., /dog/) elicit similar semantic priming effects? Here, we estimated participants' sensitivity and response criterion using signal detection theory in a picture detection task. The results demonstrate that naturalistic sounds enhanced visual sensitivity when the onset of the sounds led that of the picture by 346 ms (but not when the sounds led the pictures by 173 ms, nor when they were presented simultaneously, Experiments 1 3A). At the same SOA, however, spoken words did not induce semantic priming effects on visual detection sensitivity (Experiments 3B and 4A). When using a dual picture detection/identification task, both kinds of auditory stimulus induced a similar semantic priming effect (Experiment 4B). Therefore, we suggest that there needs to be sufficient processing time for the auditory stimulus to access its associated meaning to modulate visual perception. Besides, the interactions between pictures and the two types of sounds depend not only on their processing route to access semantic representations, but also on the response to be made to fulfill the requirements of the task. PMID- 21688943 TI - Time-course of feature-based top-down control in saccadic distractor effects. AB - Saccadic reaction time (SRT) is more strongly slowed by target-similar than dissimilar distractors (similarity effect). The time course of this similarity effect was investigated by varying target contrast and analyzing SRT distributions. With foveal distractors, the similarity effect increased with increasing SRT, suggesting that top-down enhancement of target features increased over time. This allowed for successful saccades to the peripheral target, but also entailed larger distraction by target-similar stimuli. Similarity effects with peripheral distractors did not increase with SRT, which we attribute to location-based inhibition containing the growing enhancement of target features. Strong inhibition was likely with peripheral distractors because they always appeared at the same task-irrelevant location. Prior inhibition with foveal distractors was weaker because this would have partially released fixation and entailed anticipations. PMID- 21688945 TI - Independent dimension-weighting mechanisms for visual selection and stimulus identification. AB - Observers respond faster when the task-relevant perceptual dimension (e.g., color) repeats across consecutive trials relative to when it changes. Such dimension repetition benefits (DRBs) occur in different tasks, from singleton feature search to feature discrimination of a stimulus presented on its own. Here, we argue that the DRBs observed in different tasks originate from distinct mechanisms: preselective weighting of dimension-specific feature contrast signals and, respectively, postselective stimulus processing. The multiple-weighting systems hypothesis predicts significant DRBs across trials of different tasks that share the same weighting mechanism, but not across tasks involving different mechanisms. Experiments 1, 2, and 3 examined DRBs across localization and detection tasks (both involving feature contrast computations); across detection and identification tasks (which presumably involved different weighting systems); and across identification and discrimination tasks (both involving stimulus identification). As expected, significant DRBs were observed across different tasks in Experiments 1 and 3, but not in Experiment 2. These findings support the multiple-weighting-systems hypothesis. PMID- 21688946 TI - Pivots for pointing: visually-monitored pointing has higher arm elevations than pointing blindfolded. AB - Observers pointing to a target viewed directly may elevate their fingertip close to the line of sight. However, pointing blindfolded, after viewing the target, they may pivot lower, from the shoulder, aligning the arm with the target as if reaching to the target. Indeed, in Experiment 1 participants elevated their arms more in visually monitored than blindfolded pointing. In Experiment 2, pointing to a visible target they elevated a short pointer more than a long one, raising its tip to the line of sight. In Experiment 3, the Experimenter aligned the participant's arm with the target. Participants judged they were pointing below a visually monitored target. In Experiment 4, participants viewing another person pointing, eyes-open or eyes-closed, judged the target was aligned with the pointing arm. In Experiment 5, participants viewed their arm and the target via a mirror and posed their arm so that it was aligned with the target. Arm elevation was higher in pointing directly. PMID- 21688947 TI - Integration of hand and finger location in external spatial coordinates for tactile localization. AB - Tactile stimulus location is automatically transformed from somatotopic into external spatial coordinates, rendering information about the location of touch in three-dimensional space. This process is referred to as tactile remapping. Whereas remapping seems to occur automatically for the hands and feet, the fingers may constitute an exception in that some studies have implied purely somatotopic coding of touch to the fingers. When participants judge the order of two tactile stimuli, they often err when the stimulated body parts (usually the two hands) are crossed, presumably because somatotopic and external coordinates are in conflict in crossed postures. Using this task, we investigated, first, whether the fingers are unlike other limbs with regard to spatial coding, by testing whether crossing effects, indicative of external coding, were observable when stimulating two fingers, either on the same or on different hands. Second, we investigated the interaction of hand and finger posture in tactile localization of finger stimuli. Crossing effects emerged when fingers and hands were crossed, suggesting external coding for all body parts. Crossing effects were larger when both hand and finger were located in the hemifield opposite to their body side, and smaller when only hand or finger lay in the opposite hemifield. We suggest that tactile location is estimated by integrating the external location of all relevant body parts, here of a finger and its belonging hand, and that such integrative coding may represent a general principle for body part processing as well as for tool use. PMID- 21688948 TI - 'Gotta be sit down and worked out together': views of Aboriginal caregivers and service providers on ways to improve dementia care for Aboriginal Australians. AB - INTRODUCTION: Dementia is five-fold more prevalent among Aboriginal than non Aboriginal Australians. Despite this, the quality of care available to people living with dementia in remote Aboriginal communities is poor. The objective of this study was to determine ways to overcome factors affecting the successful delivery of services to Aboriginal people with dementia living in remote communities, and to their families and communities. METHODS: This qualitative research took place in the Kimberley Region of Western Australia. Data collection occurred in three stages: (1) interviews with service providers to identify the services available; (2) interviews with the caregivers of Aboriginal people living with dementia and community-based care workers; and (3) focus groups with community representatives and community care staff. Each stage was concluded when no new themes emerged. At each stage the transcribed information was analysed and joint interpretation identified common themes. RESULTS: In total, 42 service providers, 31 caregivers and community-based care workers were interviewed and 3 focus groups were conducted. Obstacles to accessing quality care were mentioned and recommendations on ways to improve care were made. The key themes that emerged were caregiver role, perspectives of dementia, community and culturally appropriate care, workforce, education and training, issues affecting remote communities and service issues. Detailed information on how each theme affects the successful delivery of dementia care is provided. CONCLUSIONS: These research findings indicate that people living with dementia and their caregivers in remote Aboriginal communities are struggling to cope. They are requesting and require better community care. Implementing a culturally safe model of dementia care for remote Aboriginal communities that encompasses the recommendations made and builds on the strengths of the communities could potentially deliver the required improvements to dementia care for this population. PMID- 21688949 TI - Ideas and approaches towards strengthening the quantitative science for the interprofessional field. PMID- 21688950 TI - 2010 Baldwin Award winner. AB - The Baldwin Prize, in honour of Bud Baldwin's sustained contribution to the interprofessional field, was first awarded in 2009 for the best article of the 2008 volume of the Journal of Interprofessional Care. Each year since, a panel of judges recruited from the Journal's editorial board reviews all the articles published in a single volume and decides upon the winner based upon five key criteria for quality. Below, Chair of the judging panel, Professor Alan Bleakley details the process and outcome of the Baldwin Award winner for 2010. PMID- 21688951 TI - Nurse practitioners and interprofessional collaboration. PMID- 21688952 TI - Interaction in online interprofessional education case discussions. AB - This study investigated online interaction within a curriculum unit at the University of Toronto, Canada that included an interprofessional case study discussion in a mixed-mode (face-to-face and online) format. Nine of the 81 teams that completed the four-day curriculum were selected for detailed review based on the attitudes students expressed on a survey about the value of collaborating online for enhancing their appreciation of other health care professions. Five of the teams selected were 'positive' and four were 'negative'. The responses to other survey items by members of these teams were then compared, as well as their message posting patterns and the content of their online discussions. Differences between the two sets were situated within a theoretical framework drawn from the contact theory, social interdependence theory, and the Community of Inquiry model. Institutional support in the form of facilitator involvement, individual predispositions to online and group learning, the group composition, the learning materials, task and assignment, and technical factors all affected the levels of participation online. Discourse and organizational techniques were identified that related to interactivity within the online discussions. These findings can help curriculum planners design interprofessional case studies that encourage the interactivity required for successful online discussions. PMID- 21688957 TI - When a soldier commits suicide in Iraq: impact on unit and caregivers. AB - There have been studies about the impact of a suicide on family members and friends, but none to date on a military unit in a combat zone. This is the first description, to my knowledge, of the effects of the suicide of a U.S. Army soldier deployed to Iraq. A narrative from the treating psychiatrist's perspective describes both the acute and longer-term (four months) effects of the suicide on members of the soldier's unit, other soldiers at the same base, members of the medical team who attempted to resuscitate him, and mental health care providers. This account describes how the suicide affected at least thirteen other soldiers on the base. The effects of the soldier's suicide showed a few similarities to those described in the literature, including stigmatization of the survivors and the stress experienced by the mental health providers. There were additional repercussions that have not been previously described, including the impact on the soldier's peers within his unit and other soldiers on the base, the need for medical evacuation from Iraq of soldiers following the event, and the reported stress on the medical staff due to the attempted resuscitation of someone known to them. Future research is needed to understand the impact of a suicide on the survivors in a deployed military setting and to establish best practices for postvention strategies. PMID- 21688958 TI - A soldier's suicide: understanding its effect on fellow soldiers. PMID- 21688959 TI - Fighting the war within: suicide as an individual and public health challenge in the u.s. Army. PMID- 21688960 TI - Lessons Learned from a Soldier's Suicide in Iraq. PMID- 21688961 TI - Implications for civilian postvention research and practice. PMID- 21688962 TI - The impact of soldier suicide on a base in afghanistan: lessons for prevention and postvention. PMID- 21688963 TI - Impact of soldier suicide on unit and care givers: implications for education and training. PMID- 21688964 TI - Suicide prevention in a deployed military unit. AB - OBJECTIVE: Military suicide and parasuicidal behaviors have been increasing over the last several years, with rates highest in the deployed environment. This article presents a deployment cycle-specific suicide prevention plan utilized during one U.S. Army division's 15-month deployment to Iraq. METHODS: Education, identification, and intervention programs were implemented at each phase of the deployment cycle based on the specific unit activities and predicted stressors. RESULTS: During the deployment, there was an annual suicide rate of 16/100,000 within the trial cohort, compared to a theater rate of 24/100,000. Peaks in suicidal ideation and behaviors occurred during months two, six, and twelve of deployment. CONCLUSIONS: A deployment cycle prevention program may decrease rates of suicide in the combat environment. This program may serve as a model for other suicide prevention programs. PMID- 21688965 TI - Addressing and interpreting defense mechanisms in psychotherapy: general considerations. AB - Defense interpretations are commonly used techniques that clinicians employ more frequently than transference interpretations. How and when clinicians interpret defenses, however, has received little empirical examination. In an effort to facilitate the empirical study of defense interpretation, we reviewed 15 works by noted authors who gave a prominent role to interpreting defenses in discussing clinical work in general patient populations. Our goal was to identify and systematize distinct themes from these authors that might be testable hypotheses. We identified 74 themes related to the interpretation of defenses in psychotherapy-for example, "interpreting too frequently diminishes the emotional impact of interpretation"-which we organized into 17 distinct categories (e.g., factors associated with positive outcome). We subsequently selected 19 themes that were readily operationalizable as hypotheses and examination of which would advance clinical practice. These hypotheses address issues such as when, in what order, and how to interpret defensive material and what successful outcomes would be. We then describe prototypes of research designs, employing naturalistic observation, randomized controlled trials, or experimental laboratory studies, which could investigate these important hypotheses. Overall, this report codifies current clinical maxims and then provides future research directions for determining how clinicians can most effectively address defenses in psychotherapy. PMID- 21688970 TI - Membrane topology of the cyanobacterial bicarbonate transporter, SbtA, and identification of potential regulatory loops. AB - The transporter SbtA is a high affinity Na+-dependent HCO3- uptake system present in a majority of cyanobacterial clades. It functions in conjunction with CO2 uptake systems and other HCO3- uptake systems to allow cyanobacteria to accumulate high levels of HCO3- used to support efficient photosynthetic CO2 fixation via the CO2 concentrating mechanism in these species. The phoA/lacZ fusion reporter method was used to determine the membrane topology of the cyanobacterial bicarbonate transporter, SbtA (predicted size of ~39.7 kD), cloned from the freshwater strain, Synechocystis PCC6803. The structure conforms to a model featuring 10 transmembrane helices (TMHs), with a distinct 5+5 duplicated structure. Both the N- and C-terminus are outside the cell and the second half of the protein is inverted relative to the first. The first putative helix appears to lack sufficient topogenic signals for its correct orientation in the membrane and instead relies on the presence of later helices. The cytoplasmic loop between helices 5 and 6 is a likely location for regulatory mechanisms that could govern activation of the transporter, and the cytoplasmic loop between helices 9 and 10 also contains some conserved putative regulatory residues. PMID- 21688971 TI - Assessing toxicity of polyamidoamine dendrimers by neuronal signaling functions. AB - We report for the first time on neuronal signaling for the evaluation of interactions between native plasmamembrane and polyamidoamine (PAMAM) dendrimers. Generation 5 polycationic (G5-NH(2)), novel beta-D-glucopyranose-conjugated G5 NH(2) and generation 4.5 polyanionic (G4.5-COONa) polyamidoamine (PAMAM) dendrimers (1-0.0001 mg/ml) were applied in acute brain slices. Functional toxicity assessments-validated by fluorescence imaging of dead cells-were performed by employing electrophysiological indicators of plasma membrane breakdown and synaptic transmission relapse. Irreversible membrane depolarization and decrease of membrane resistance predicted substantial functional neurotoxicity of unmodified G5-NH(2), but not of the G4.5-COONa PAMAM dendrimers. Model calculations suggested that freely moving protonated NH(2) groups of terminal monomeric units of PAMAM dendrimers may be able directly destroy the membrane or inhibit important K(+) channel function via contacting the positively charged NH(2). In accordance, conjugation of surface amino groups by beta-D glucopyranose units reduced functional neurotoxicity that may hold great potential for biomedical applications. PMID- 21688972 TI - Helicobacter pylori and type 1 diabetes mellitus: possibility of modifying chronic disease susceptibility with vaccinomics at the anvil. AB - The human gastric pathogen, Helicobacter pylori, colonizes more than 50% of the world population and is a well-known cause of peptic ulcer disease. H. pylori has been epidemiologically linked to various other diseases, among which its putative link with certain complex diseases such as type 1 diabetes mellitus (T1DM) is of interest. Although antibiotic resistance is a significant clinical problem in H. pylori infection control, the exact cause and much of the underlying mechanisms of T1DM are not clearly understood. In addition, commensal microflora, gut adapted microbial communities, and plausible roles of some of the chronic human pathogens add an important dimension to the control of T1DM. Given this, the present review attempts to analyze and examine the confounding association of H. pylori and T1DM and the approaches to tackle them, and how the emerging field of vaccinomics might help in this pursuit. PMID- 21688973 TI - Ethinylestradiol liposome preparation and its effects on ovariectomized rats' osteoporosis. AB - Ethinylestradiol liposome (EEL) was prepared by thin film evaporation-extrusion technique and its effects on ovariectomized rat osteoporosis were investigated. The liposomes were characterized with clear homogeneous lamellar vesicles and had the average size of 200 +/- 1.5 nm. The long term stability of liposome formulations were tested over a 28-day period at 4 degrees C and ethinylestradiol retention was approximately 80% up to 28 day. Release data of ethinylestradiol was tested in PBS pH 7.4 at 37 degrees C using a dialysis method and its release profiles were biphasic, showing a relatively large burst effect over the first four hours, followed by a slower release phase. Ovariectomized rat model was used to investigate EEL effects on osteoporosis. After three months post-surgery, the rats were divided into two groups and injected intraperitoneally (IP) with 2 MUg per kilogram per day of either free ethinylestradiol (EE) or encapsulated ethinlyestradiol (EEL). At termination of one month IP injection, the rats were killed and the bone mineral density (BMD) and alkaline phosphatase (ALP) were measured. BMD value in free EE group increased by 20.3 %, while it increased by 37.8 % in EEL group. According to ALP value, the two treatment groups increased by 28.6 % and 42.0 %, respectively. These data indicated that ethinlyetradiol liposome had better effect than that of free ethinylestradiol did in treatment of the ovariectomized rats' osteoporosis. But the metabolites and biodistribution of ethinylestradiol liposome in vivo need to investigate in the further research work. PMID- 21688976 TI - Tissue fluid pressure and flow during pneumatic compression in lymphedema of lower limbs. AB - BACKGROUND: Physiotherapy of edema in cases with obstructed main lymphatics of lower limbs requires knowledge of how high external pressures should be applied manually or set in compression devices in order to generate tissue pressures high enough to move tissue fluid to nonswollen regions and to measure its flow rate. METHODS: We measured tissue fluid pressure and flow in subcutaneous tissue of lymphedematous limbs stages II to IV at rest and during pneumatic compression under various pressures and inflation timing. An 8-chamber sequential compression device inflated to pressures 50-120 mmHg, for 50 sec each chamber, with no distal deflation, was used. Pressures were measured using a wick-in-needle and electronic manometer. Fluid flow was calculated from continuously recorded changes in limb circumference using strain gauge plethysmography. RESULTS: Before massage, in all stages of lymphedema, stagnant tissue fluid pressures in subcutaneous tissue ranged between -1 and +10 mmHg and did not differ from those measured in normal subjects. Pressures generated in tissue fluid by pneumatic compression reached 40-100 mmHg and were lower than those in inflated chambers. High pressure gradient through the skin was caused by its rigidity (fibrosis) and dissipation of applied compression force to proximal noncompressed limb regions. The calculated volumes of displaced tissue fluid ranged from 10 to 30 ml per compression cycle, to reach in some cases 100 ml in the groin region. CONCLUSIONS: Tissue fluid pressures generated by a pneumatic device were found lower than in the compression chambers. The obtained results point to the necessity of applying high pressures and longer compression times to generate effective tissue fluid pressures and to provide enough time for moving the stagnant fluid. PMID- 21688974 TI - Ixodes scapularis and Borrelia burgdorferi among diverse habitats within a natural area in east-central Illinois. AB - The distributions of the tick vector, Ixodes scapularis, and of the etiologic agent of Lyme disease, Borrelia burgdorferi (Bb), have continued expanding in Illinois over the past 20 years, but the extent of their spread is not well known. The role of multiple habitats in the establishment and maintenance of I. scapularis and Bb at local scales is not well understood, and the use of integrated approaches to evaluate local scale dynamics is rare. We evaluated habitat diversity and temporal changes of I. scapularis occurrence and Bb infection within a natural area in Piatt County, Illinois, where I. scapularis were first detected in 2002. Small mammals were trapped and attached ticks were collected in young forest, prairie, mature forest, and flood plain sites from 2005 to 2009. Small mammal abundance, and the prevalence (% mammals infested), mean intensity (I. scapularis per infested mammal), and relative density (I. scapularis per mammal trapped) of I. scapularis were computed for each habitat type and compared. Immature I. scapularis were tested for Bb infection using polymerase chain reaction techniques. Out of 2446 trapped small mammals, 388 were infested with I. scapularis. The prairie had the highest diversity of small mammal hosts. Prevalence, mean intensity, and relative density of I. scapularis and prevalence of Bb infection were highest for the prairie and young forest sites; in the former, all infection was associated with the prairie vole, Microtus ochrogaster. The minimum Bb infection prevalence of on-host I. scapularis collected in the natural area was 14% (n=56). Unlike previous studies solely focused on forested areas and Peromyscus leucopus, our study is the first to provide evidence of I. scapularis collected from prairie habitat and other reservoir hosts, particularly M. ochrogaster. PMID- 21688977 TI - Tertiary lymphoid organs in lymphatic malformations. AB - BACKGROUND: Examine lymphatic malformation lymphoid aggregates for the expression of tertiary lymphoid organ markers. Determine how lymphoid aggregate density relates to lymphatic malformation clinical features. METHODS AND RESULTS: Retrospective cohort study. Tissue and clinical data were reviewed from 29 patients in the Vascular Anomaly Database who represented the spectrum of head and neck lymphatic malformations and had >5 years of follow-up. Archived formalin fixed, paraffin-embedded lymphatic malformation tissue was immunohistochemically stained with antibodies for tertiary lymphoid organ markers, which included follicular and mature myeloid dendritic cells, high endothelial venules, segregated B and T-cells, lymphatic endothelial cells, and lymphoid homing chemokines (CXCL13, CCL21). Lymphoid aggregate density (count/mm(2)) was quantified by 2 independent, blinded reviewers. Lymphoid aggregate density and lymphatic malformation clinical features were characterized using analysis of variance. Larger lymphatic malformation tissue lymphoid aggregates stained consistently for tertiary lymphoid organ markers. In oral cavity and neck specimens from the same patients (n = 9), there were more tertiary lymphoid organ in oral cavity than in neck specimens (p = 0.0235). In lymphatic malformation neck tissue, de Serres stage 4 lymphatic malformations displayed the highest tertiary lymphoid organ density. No significant association was seen between tertiary lymphoid organ density and other clinical features. CONCLUSION: This study demonstrates that some lymphoid aggregates within lymphatic malformations represent tertiary lymphoid organs. There was an association between tertiary lymphoid organ density and lymphatic malformation location. Further study is required to define the role of lymphoid neogenesis and tertiary lymphoid organ formation in lymphatic malformation pathogenesis. PMID- 21688978 TI - Bioimpedance in the assessment of unilateral lymphedema of a limb: the optimal frequency. AB - BACKGROUND: Bioimpedance techniques provide a reliable method of assessing unilateral lymphedema in a clinical setting. Bioimpedance devices are traditionally used to assess body composition at a current frequency of 50 kHz. However, these devices are not transferable to the assessment of lymphedema, as the sensitivity of measuring the impedance of extracellular fluid is frequency dependent. It has previously been shown that the best frequency to detect extracellular fluid is 0 kHz (or DC). However, measurement at this frequency is not possible in practice due to the high skin impedance at DC, and an estimate is usually determined from low frequency measurements. This study investigated the efficacy of various low frequency ranges for the detection of lymphedema. METHODS AND RESULTS: Limb impedance was measured at 256 frequencies between 3 kHz and 1000 kHz for a sample control population, arm lymphedema population, and leg lymphedema population. Limb impedance was measured using the ImpediMed SFB7 and ImpediMed L-Dex((r)) U400 with equipotential electrode placement on the wrists and ankles. The contralateral limb impedance ratio for arms and legs was used to calculate a lymphedema index (L-Dex) at each measurement frequency. The standard deviation of the limb impedance ratio in a healthy control population has been shown to increase with frequency for both the arm and leg. Box and whisker plots of the spread of the control and lymphedema populations show that there exists good differentiation between the arm and leg L-Dex measured for lymphedema subjects and the arm and leg L-Dex measured for control subjects up to a frequency of about 30 kHz. CONCLUSIONS: It can be concluded that impedance measurements above a frequency of 30 kHz decrease sensitivity to extracellular fluid and are not reliable for early detection of lymphedema. PMID- 21688979 TI - Inter-rater reliability of arm circumference measurement. AB - BACKGROUND: Arm lymphedema is routinely assessed by clinicians and researchers, using arm circumference measurements. A protocol was developed for measuring arm circumference independent of medically trained professionals. The aim of this project was to assess the protocol's inter-rater reliability and its coherence with perometry measures. METHODS AND RESULTS: Community-dwelling adults (n = 57), aged 60.2 +/- 12.8 years, in good general health, were included in this study. Circumference of both arms were measured at the ulnar styloid of the wrist and at four 10 cm intervals up the arm by a friend of the participant, as well as the trained assessor using a tape measure. The same measures were also obtained with a perometer. The assessment tools had moderate to high concordance (r(c) = 0.84 0.94 for assessor vs. perometer and r(c) = 0.68-0.93 for assessor vs. participant). Limits of agreement analysis revealed that the mean difference between methods varied based on the measurement location; the bias ranged from 5.5% to 1.5% for assessor-measured vs. perometer methods and from -2.4% to 4.0% for assessor-measured vs. participant-measured methods. CONCLUSIONS: The written instructions and cartoons are reliable tools that could be used by women at risk of lymphedema as well as those with lymphedema following treatment for breast cancer to measure their arm circumference reliably independent of medically trained personnel. PMID- 21688980 TI - Increased lymphangiogenesis and hemangiogenesis in infant cornea. AB - BACKGROUND: Corneal lymphangiogenesis (LG) and hemangiogenesis (HG) accompany many diseases after inflammatory, infectious, traumatic or chemical insults. They also contribute to transplant rejection. It is known that corneal transplants in infants or children have a higher rejection rate than in adults. However, it has never been studied whether infant corneas differ from adult corneas in inflammatory LG, HG, or both, which is the focus of this study. METHODS AND RESULTS: Corneal inflammatory LG and HG were induced by a standard suture placement model in C57BL/6 mice of 3 weeks and 8 weeks of age, respectively. Corneal LG, HG, and macrophage infiltration were assessed by immunofluorescent microscopic studies using specific antibodies against CD31 (a panendothelial cell marker), LYVE-1 (a lymphatic marker), and F4/80 (a macrophage marker). Blood vessels were also examined by ophthalmic slit-lamp microscopic assays in vivo. Digital images were analyzed by NIH Image J software. It was found, for the first time, that infant corneas exhibited a higher level of LG, HG, and macrophage infiltration during inflammation. Infant lymphatic and blood vessels demonstrated greater density and invasion area but similar branching points. Additionally, infant lymphatic vessels were also of larger diameter. CONCLUSIONS: Infant and adult corneas differ greatly in their inflammatory responses of LG, HG, and macrophage infiltration. These novel findings will shed some light on our understanding of the LG and HG processes, as well as the development of new therapeutic protocols for corneal diseases, particularly, in infants or children, where an early restoration of sight is critically important in preventing amblyopia or permanent vision loss. PMID- 21688981 TI - Kikuchi-fujimoto disease: a rare case of axillary lymphadenopathy. AB - BACKGROUND: Kikuchi-Fujimoto disease is a self-limited condition, characterized by benign lymphadenopathy. METHODS AND RESULTS: We describe a case of a 56-year old male who presented with a node growth in the left axilla, without referring any other symptoms. The patient underwent excision and biopsy of the node and the histological examination established the diagnosis of Kikuchi-Fujimoto disease. After 3 days of hospitalization, the patient was released in a perfect condition and no medical treatment was prescribed. In a regular follow-up of 3 years the patient remains asymptomatic. CONCLUSIONS: Kikuchi-Fujimoto disease is an uncommon clinicopathological entity in Greece and it should always been taken under consideration in the differential diagnosis in patients presenting with lymphadenopathy. Surgical excision is the treatment of choice and the course of the disease is usually the spontaneous resolution. PMID- 21688984 TI - The effect of a corporate chair massage program on musculoskeletal discomfort and joint range of motion in office workers. AB - OBJECTIVES: The aim of this study was to determine the effects of workplace manual technique interventions for female participants on the degree of joint range of motion and on the level of musculoskeletal ache, pain, or discomfort experienced when performing workplace responsibilities. DESIGN: Nineteen (19) female volunteers were given chair massages on-site twice per week for 1 month. SETTINGS/LOCATION: Participants included individuals in administration and management from a company in Ljubljana, Slovenia. SUBJECTS: A total of 19 female volunteers 40-54 years of age enrolled for this study. Fifteen (15) of them completed all measurements. INTERVENTIONS: The Cornell Musculoskeletal Discomfort Questionnaire was used, and range-of-motion measurements in degrees were taken. OUTCOME MEASURES: Subjects completed a series of self-report questionnaires that asked for information concerning musculoskeletal discomfort for the neck, upper back, and lower back in the form of a body diagram. A range-of-motion test (to compare the change in joint angles) was performed with a goniometer to assess cervical lateral flexion, cervical flexion, cervical extension, lumbar flexion, and lumbar extension. RESULTS: Between the first and the last measurements, a significant difference (p<0.05) was found in increased range of motion for cervical lateral flexion (28.8%). Wilcoxon signed rank test showed a significant increase (p<0.05) in range of motion for cervical lateral flexion (42.4+/-6.3 to 48.3+/-7.3), cervical extension (63.2+/-12.4 to 67.2+/-12.3), and a significant decrease (p<0.05) in the Cornell Musculoskeletal Discomfort Questionnaire values for the neck (2.7+/-0.8 to 1.9+/-0.6) and the upper back (2.7+/-0.7 to 2.2+/-0.8) from the phase 2 to 3. Significant reductions were also shown in the Cornell Musculoskeletal Discomfort Questionnaire values for the neck (2.8+/-0.8 to 1.9+/ 0.6) and the upper back (2.7+/-0.8 to 2.2+/-0.8) from the phase 1 to 3. CONCLUSIONS: On-site massage sessions twice per week for 1 month are the most effective interventions (compared to one session or no massage intervention) for decreasing the duration of musculoskeletal ache, pain, or discomfort and for increasing range of motion. PMID- 21688985 TI - Diaphragmatic breathing reduces postprandial oxidative stress. AB - OBJECTIVES: A number of studies suggest that postprandial hyperglycemia produces oxidative stress, leading to complications associated with diabetes. However, hyperglycemia-induced oxidative stress may affect groups of people other than diabetics, such as smokers and athletes with specific diet plans. Based on previous reports that seated breathing meditation reduces hyperglycemia, the present study was designed to determine the effects of diaphragmatic breathing on postprandial plasma glycemia, insulin, oxidative stress, and antioxidant levels in athletes with normal glucose metabolism. DESIGN: Data collected before and after consumption of a 900-calorie breakfast composed of 80% carbohydrates, 10% proteins, and 10% lipids were analyzed. Ten (10) minutes after the meal, 8 subjects spent 40 minutes performing diaphragmatic breathing in a quiet place. The other 8 subjects, representing the control group, spent the same time sitting in an equivalent quiet place reading a magazine. SUBJECTS: Data from 16 amateur male cyclists age 30.12+/-4.9 years (+/-SD) were analyzed. Their mean height and weight were 177.81+/-5.3 cm and 71.40+/-5.2 kg, respectively. All subjects underwent a physical examination and were determined to be in good health. OUTCOME MEASURES: Blood samples were collected immediately before the meal as well as 1 hour and 2 hours after the meal, and plasma levels of glucose, insulin, reactive oxygen metabolites, and biologic antioxidant potential were determined. Heart rate was also recorded. RESULTS: Results show that in normal subjects, acute hyperglycemia induces free-radical production while reducing the antioxidant levels (p<0.05). Diaphragmatic breathing reduces heart rates (p<0.01), increases insulin (p<0.05), reduces glycemia (p<0.01), and reduces free radical production as indicated by the higher antioxidants levels (p<0.05). CONCLUSIONS: Diaphragmatic breathing, likely through the activation of the parasympathetic nervous system, increases insulin, reduces glycemia, and reduces reactive oxygen species production. PMID- 21688986 TI - Liver toxicity of antiretroviral combinations including fosamprenavir plus ritonavir 1400/100 mg once daily in HIV/hepatitis C virus-coinfected patients. AB - Abstract Our objective was to evaluate the liver toxicity of antiretroviral regimens including fosamprenavir plus ritonavir (FPV/r) 1400/100 mg once daily (QD) in HIV/hepatitis C virus (HCV)-coinfected patients. This was a prospective cohort study that included 117 HIV/HCV-coinfected patients who started FPV/r 1400/100 mg QD-based antiretroviral therapy (ART) and who neither had received a previous antiretroviral regimen containing FPV nor had a past history of virologic failure while receiving protease inhibitors (PI). The primary end point of the study was the occurrence of grade 3-4 liver enzymes elevations (LEE) within 1 year after starting FPV/r QD. Factors potentially associated with grade 3-4 LEE, including baseline liver fibrosis, were analyzed. Eleven (9%) patients had a grade 3-4 LEE during the follow-up, resulting in an incidence of severe liver toxicity of 9% (95% confidence interval 4.1-14.6%). None of these cases led to FPV/r discontinuation. Baseline liver fibrosis could be assessed in 97 (83%) patients. Six of 71 patients (8%) with significant fibrosis had a grade 3-4 LEE versus 2 of 26 (8%) without significant fibrosis (p=1.0). Twenty (21%) patients had cirrhosis at baseline. There were no cases of LEE among cirrhotics. In conclusion, the incidence of severe liver toxicity after 1 year of therapy with FPV/r QD-based ART in HIV/HCV-coinfected patients is similar to what has been reported with other boosted PIs. In addition, the presence of significant fibrosis or cirrhosis was not associated with the emergence of liver toxicity. Thus, ART regimens containing FPV/r QD may be considered safe in HIV/HCV coinfected patients, including those with cirrhosis. PMID- 21688987 TI - Mortality in Brazilian children with HIV/AIDS: the role of non-AIDS-related conditions after highly active antiretroviral therapy introduction. AB - AIDS-related mortality has been significantly reduced in areas that systematically adopted highly active antiretroviral therapy (HAART). In Brazil, despite advances in control policy, there is still a lack of evidence about trends in children on causes of death related or not related to HIV/AIDS. We evaluate temporal trends in mortality due to non-HIV-related causes of death in relation to HIV/AIDS-related conditions among children with and without HIV infection. This nationwide study included all deaths in children reported from 1999 to 2007. Mortality odds ratios (MOR) and rates were calculated to assess time trends of death in children with or without HIV/AIDS. These data were analyzed by calendar year, as obtained from official national database. A total of 680,763 deaths occurred in Brazilian children under 13 years of age; of these, 2191 (0.32%) had causes related to HIV/AIDS listed on the death certificate. The mortality rate from HIV/AIDS-related causes in Brazilian children ranged from 0.72 per 100,000 children in 1999 to 0.40 per 100,000 children in 2007, while for selected nonrelated causes the rate of death among HIV-infected children was stable at 0.08 per 100,000 Brazilian children. In children with HIV/AIDS, the MOR of having selected conditions unrelated to HIV/AIDS as a cause of death in 2007 (compared to 1999) was 1.85 (95% confidence interval [CI] = 1.11-3.08, p = 0.02), but without a significant temporal trend (p = 0.413) through the analyzed period. In Brazil, deaths related to HIV/AIDS mortality in children significantly decreased, while the unrelated causes in HIV-infected children maintained a stable trend. These data reinforce the success of national public health policies and the need to offer comprehensive care to children with HIV/AIDS. PMID- 21688988 TI - Racial and sexual identity-related maltreatment among minority YMSM: prevalence, perceptions, and the association with emotional distress. AB - Bullying is a form of violence characterized as an aggressive behavior that is unprovoked and intended to cause harm. Prior studies have found that lesbian, gay, bisexual, and transgender (LGBT) youth experience high levels of bullying related to their sexuality and this harassment can lead to engagement in risk behaviors, depression, and suicide. Ethnic/racial minority young men who have sex with men (YMSM) may experience dual levels of stigma and maltreatment due to both their sexuality and their race. The aim of the current study was to assess the prevalence and perceptions of racial and sexual identity-based abuse among a sample of minority YMSM, and whether this maltreatment plays a role in the emotional distress of these youth. We found that overall 36% and 85% of participants experienced racial and sexuality-related bullying, respectively. There was a significant association between experiencing a high level of sexuality-related bullying and depressive symptomatology (p=0.03), having attempted suicide (p=0.03), and reporting parental abuse (p=0.05). We found no association between racial bullying and suicide attempts. In a multivariable logistic regression model, experiencing any racial bullying and high sexuality related bullying were significant predictors of having a CES-D score >=16; adjusted odds ratio (OR) 1.83 and 2.29, respectively. These findings contribute to the existing literature regarding the negative experiences and daily stressors facing LGBT youth with regard to both their minority status and LGBT identities. Future interventions for racial/ethnic minority YMSM should provide assistance to achieve a positive view of self that encompasses both their racial and sexual identities. PMID- 21688989 TI - The effect of the Spanish Ketogenic Mediterranean Diet on nonalcoholic fatty liver disease: a pilot study. AB - The "Spanish Ketogenic Mediterranean Diet" (SKMD) has been shown to be an effective and safe way to cure patients suffering from metabolic syndrome (MS). Keeping in mind that nonalcoholic fatty liver disease (NAFLD) is closely associated with MS, the purpose of this study was to evaluate the potential therapeutic properties under free living conditions of the SKMD in patients with MS (following the International Diabetes Federation [IDF] consensus guidelines) and NAFLD (suspected by using a cutoff value of alanine aminotransferase [ALT] levels of >40 U/L and confirmed by abdominal ultrasonography) over a 12-week period. A prospective study was carried out in 14 obese men meeting the inclusion criteria and whose body mass index (BMI) and age were 36.58+/-0.54 kg/m2 and 41.18+/-2.28 years, respectively. Statistical differences between the parameters studied before and after administration of the SKMD (week 0 and 12) were analyzed by paired Student's t test (continuous variables) and the chi2 test (discontinuous variables). P<.05 was considered statistically significant. There was an extremely significant (P<.001) improvement in body weight (from 109.79 kg to 95.86 kg), low-density lipoprotein-cholesterol (from 123.43 mg/dL to 100.35 mg/dL), ALT (from 71.92 U/L to 37.07 U/L), aspartate aminotransferase (from 47.71 U/L to 29.57 U/L), steatosis degree (complete fatty liver regression was observed in 21.4% of the patients, and an overall reduction was found in 92.86% of the patients), and all the parameters studied associated with the MS: BMI (from 36.99 kg/m2 to 32.42 kg/m2), waist circumference (from 114.01 cm to 98.59 cm), fasting plasma glucose (from 118.57 mg/dL to 90.14 mg/dL), triacylglycerols (from 232.64 mg/dL to 111.21 mg/dL), high-density lipoprotein-cholesterol (HDLc) (from 42.81 mg/dL to 58.71 mg/dL), systolic blood pressure (from 142.86 mm Hg to 125.36 mm Hg), and diastolic blood pressure (from 89.64 mm Hg to 77.86 mm Hg). After the diet all the subjects were free of MS according to the IDF definition, and 100% of them had normal triacylglycerols and HDLc levels, in spite of the fact that 100% of them still had a BMI of >30 kg/m2. We conclude that the SKMD could be an effective and safe way to treat patients suffering from MS and the associated NAFLD. PMID- 21688990 TI - The madness and genius of post-cartesian philosophy: a distant mirror. PMID- 21688991 TI - "You are requested to close an eye": Freud's seduction theory and theory of the Oedipus complex revisited. PMID- 21688992 TI - Conflicts in female sexuality and romantic intimacy. PMID- 21688993 TI - The importance of a "broken heart". PMID- 21688994 TI - Projective identification and countertransference in borderline couples. PMID- 21688995 TI - Celebrating psychoanalytic supervision: considering a century of seminal contribution. PMID- 21688998 TI - Electroporation-aided DNA immunization generates polyclonal antibodies against the native conformation of human endothelin B receptor. AB - Endothelin B receptor (ET(B)R) is a G protein-coupled receptor (GPCR) specific for endothelin peptides (including endothelin-1, ET1), which mediates a variety of key physiological functions in normal tissues, such as modulation of vasomotor tone, tissue differentiation, or cell proliferation. Moreover, ET(B)R, overexpressed in various cancer cells including melanoma, has been implicated in the growth and progression of tumors, as well as in controlling T cell homing to tumors. To gather information on receptor structure and function, antibodies are generally considered choice molecular probes, but generation of such reagents against the native conformation of GPCRs is a real technical challenge. Here, we show that electroporation-aided genetic immunization, coupled to cardiotoxin pretreatment, is a simple and very efficient method to raise large amounts of polyclonal antibodies highly specific for native human ET(B)R (hET(B)R), as assessed by both flow cytometry analysis of different stably transfected cell lines and a new and rapid cell-based enzyme-linked immunosorbent assay that we also describe. The antibodies recognized two major epitopes on hET(B)R, mapped within the N-terminal extracellular domain. They were used to reveal hET(B)R on membranes of three different human melanoma cell lines, by flow cytometry and confocal microscopy, a method that we show is more relevant than mRNA polymerase chain reaction in assessing receptor expression. In addition, ET-1 partially competed with antibodies for receptor binding. The strategy described here, thus, efficiently generated new immunological tools to further analyze the role of ET(B)R under both normal and pathological conditions, including cancers. Above all, it can now be used to raise monoclonal antibodies against hET(B)R and, more generally, against GPCRs that constitute, by far, the largest reservoir of potential pharmacological targets. PMID- 21688999 TI - Reproductive Health Assessment After Disaster: introduction to the RHAD toolkit. AB - This article reviews associations between disaster and the reproductive health of women, describes how Hurricane Katrina influenced our understanding about postdisaster reproductive health needs, and introduces a new toolkit that can help health departments assess postdisaster health needs among women of reproductive age. PMID- 21689000 TI - Prevalence of Salmonella serovars and antimicrobial resistance profiles in poultry of Savar area, Bangladesh. AB - Salmonellosis is one of the major concerns in the poultry industry and some serovars of Salmonella involve in zoonosis. This study determines the seroprevalence of Salmonella in poultry and their drug-resistant patterns, variability in infectivity and mortality rate of birds, and predilection of some serovars to cause zoonoses. The average seroprevalance of Salmonella in three different age groups was found to be 37.9%. A total of 503 samples were examined over a period of 1 year from five different poultry farms of a semiurban area of Savar, Dhaka, Bangladesh. The prevalence of Salmonella was recorded to be 21.1%. Salmonella was found high in dead birds (31.2%) than live birds (18.1%). Salmonella infection was higher (23.6%) in summer than in winter (12.9%) season. Among the 106 isolates, 46 belong to serogroup B (43%) and 60 isolates to serogroup D (57%). The highest Salmonella infection was recorded as 47.9% on the 30-35-week-old birds. A total of 106 Salmonella isolates were used for antimicrobial susceptibility test against 10 common antibiotics and 17 multiple drug resistance patterns were found. Among the isolates, 69 (65%) harbored plasmids 1-4 with size variation between >1.63 and >40 kb and rest 37 (35%) isolates were plasmid free but showed resistance against 5-10 antibiotics. The results of the present investigation suggested that multiple drug resistance is common among the Salmonella isolates of poultry and some of these isolates may have zoonotic implications. PMID- 21689001 TI - Association study between apolipoprotein E gene polymorphism and diabetic nephropathy in a Taiwanese population. AB - BACKGROUND: Diabetic nephropathy (DN) is the most common cause of end-stage renal disease in Taiwan. Recent studies have demonstrated that the gene for apolipoprotein E (APOE) is associated with end-stage renal disease in African Americans. In this study, we aimed to test the hypothesis that common single nucleotide polymorphisms in the APOE gene might contribute to the development of DN in a Taiwanese population with type 2 diabetes (T2D). METHODS: We enrolled 180 patients with T2D found to have DN and 178 age- and sex-matched patients with T2D but without DN. The single-nucleotide polymorphisms rs7412 and rs429358 and common allele variants in the APOE gene were evaluated to test any association with DN. Multivariate logistic regression testing was used to determine factors associated with the risk of DN. RESULTS: The DN group had lower high-density lipoprotein cholesterol levels and longer duration of diabetes, higher systolic and diastolic blood pressure, and higher blood urea nitrogen, creatinine, and triglyceride concentrations than the group with T2D but without DN. Analyses showed no significant effects of APOE rs7412 and APOE rs429358 on the frequencies of the allele and genotype between subjects with T2D with and without DN. There were also no significant effects of APOE2 or E4 carriers on the development of DN, but multivariate logistic regression testing revealed that the duration of diabetes and triglyceride and hemoglobin A1c concentrations had independent effects on the development of DN. CONCLUSION: The APOE gene might not contribute to the risk of DN in Taiwanese patients with T2D. PMID- 21689002 TI - Association between cholesteryl ester transfer protein TaqIB variants and risk of coronary artery disease and diabetes mellitus in the population of western Iran. AB - AIMS: To shed light on the previously inconsistent results about the association of cholesteryl ester transfer protein TaqIB (CETP TaqIB) variants, high-density lipoprotein cholesterol (HDL-C) levels, and the risk of coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). METHODS: To determine the frequency of CETP TaqIB variants and to examine the possible association between CETP TaqIB polymorphism with CAD and T2DM, we studied 207 unrelated patients with CAD, 101 patients with T2DM, and 92 controls. The CETP TaqIB variants were detected by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Logistic regression analysis indicated that the B1 allele of CETP was significantly associated with increased risk of CAD (odds ratio, OR 1.65 [95% confidence interval, CI 1.2-2.3, p=0.005]) and T2DM (OR 1.7 [95% CI 1.13-2.54, p=0.005]). Adjusted logistic regression analysis for the effects of age, sex, hypertension, diabetes, and hyperlipidemia was performed; and a significant association was found between the B1 allele and risk of CAD (OR 1.9 [95% CI 1 3.6, p=0.049]) in patients with CAD. There were no associations between the CETP alleles and the levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol, and HDL-C in studied groups. CONCLUSIONS: The results of the present study revealed that the CETP B1 allele is associated with increased risk of CAD and T2DM independent of plasma HDL-C level in our population. PMID- 21689003 TI - Verification of multiplex ligation-dependent probe amplification probes in the absence of positive samples. AB - Deletions and duplications of single or multiple exons in specific genes are associated with human diseases. Multiplex ligation-dependant probe amplification (MLPA), a technique recently introduced to clinical laboratories, can detect deletions or duplications at the exon level. MLPA kits have a high multiplexing capability containing mixtures of exon-specific probes that target the gene of interest and control probes that hybridize to other genomic areas before PCR amplification. To verify each probe set, known positive samples with a single exon deletion or duplication and normal samples are ideally used. Often, positive samples do not exist for each exon and normal samples are not suited to verify the identity of each probe set. We designed a straightforward approach using mixes of exon-specific PCR products as template to unequivocally verify each probe set in MLPA kits. This method can be used to verify the identity of MLPA probes for exons when positive samples are unavailable. Exon-specific probes from 15 MLPA kits were shown to hybridize to the targeted exons of interest. In one kit, this method identified probes that also bind a pseudogene, making them unreliable for clinical analysis. Incorporating this methodology in the analytical validation process will help ensure that MLPA results are interpreted correctly. PMID- 21689004 TI - Comparison of distal ureteral management strategies during laparoscopic nephroureterectomy. AB - BACKGROUND AND PURPOSE: The optimal approach for management of the distal ureter and bladder cuff (DUBC) during laparoscopic nephroureterectomy (LNU) for upper tract transitional-cell carcinoma (TCC) is controversial. We describe our contemporary experience with LNU and compare several approaches to the DUBC. PATIENTS AND METHODS: A retrospective analysis was performed on 36 patients undergoing LNU. Three approaches to the DUBC were used: Open resection (OR), complete laparoscopic dissection and suture reconstruction (LR), and laparoscopic dissection with DUBC stapling (LS). Patient demographics and intraoperative, perioperative, and pathologic variables were compared. Estimated 2-year recurrence-free survival (RFS) was calculated. RESULTS: A total of 36 patients were analyzed: 10 OR, 12 LR, and 14 LS. The mean age was 69.6 years with a mean follow-up of 15 months. The LR and LS groups had significantly shorter operative times compared with the OR group (163 and 152 vs 276 minutes, respectively (P<0.05). The LR group had the shortest mean length of stay compared with the OR and LS groups (2.0 vs 3.5 and 2.7 days, respectively, P<0.05). No patient had a complete ureteral orifice, but a cystoscopically appreciable remnant of the resected ureteral orifice was noted in 50% of the LS group vs none with the LR and OR groups (P<0.05). The estimated 2-year RFS was 65% for the entire cohort with no significant differences among groups. CONCLUSIONS: Complete laparoscopic resection of the DUBC is feasible, particularly in low-stage, low-grade upper tract TCC and provides benefits such as shorter operative times and length of stay compared with an open bladder cuff excision. PMID- 21689005 TI - Whose choice is mental health rehabilitation? PMID- 21689006 TI - Emissions from diesel versus biodiesel fuel used in a CRDI SUV engine: PM mass and chemical composition. AB - The diesel tailpipe emissions typically undergo substantial physical and chemical transformations while traveling through the tailpipe, which tend to modify the original characteristics of the diesel exhaust. Most of the health-related attention for diesel exhaust has focused on the carcinogenic potential of inhaled exhaust components, particularly the highly respirable diesel particulate matter (DPM). In the current study, parametric investigations were made using a modern automotive common rail direct injection (CRDI) sports utility vehicle (SUV) diesel engine operated at different loads at constant engine speed (2400 rpm), employing diesel and 20% biodiesel blends (B20) produced from karanja oil. A partial flow dilution tunnel was employed to measure the mass of the primary particulates from diesel and biodiesel blend on a 47-mm quartz substrate. This was followed by chemical analysis of the particulates collected on the substrate for benzene-soluble organic fraction (BSOF) (marker of toxicity). BSOF results showed decrease in its level with increasing engine load for both diesel and biodiesel. In addition, real-time measurements for organic carbon/elemental carbon (OC/EC), and polycyclic aromatic hydrocarbons (PAHs) (marker of toxicity) were carried out on the diluted primary exhaust coming out of the partial flow dilution tunnel. PAH concentrations were found to be the maximum at 20% rated engine load for both the fuels. The collected particulates from diesel and biodiesel-blend exhaust were also analyzed for concentration of trace metals (marker of toxicity), which revealed some interesting results. PMID- 21689007 TI - Differential elemental distribution of retained particles along the respiratory tract. AB - CONTEXT: Prolonged exposure to ambient particles is associated with premature mortality due to cardio-respiratory diseases and lung cancer. The size and composition of these particles determine their toxicity, which is aggravated by their long-term retention in the lungs. OBJECTIVE: To compare the elemental profile of particles retained along the bronchial tree and lymph nodes by combining laser capture microdissection (LCM) and elemental composition analysis through energy dispersive x-ray (EDX) and scanning electron microscopy (SEM). MATERIAL AND METHODS: Twenty-four right lung middle lobes from autopsied cases were obtained from two cities with different pollution backgrounds. Lung samples were collected from three distinct sites within the lung at the time of autopsy: peribronchial tissue, peripheral parenchyma and hilar lymph nodes. Areas of potentially increased particle deposition were microdissected using LCM and analyzed for elemental composition through EDX "allied" with SEM. RESULTS: Elemental analyses of the particles retained along the bronchial tree showed two groups of distribution: peribronchiolar or lymph node deposition. The elemental profile of peribronchial areas were significantly different between the two cities and were better discriminators of past air pollution exposure. CONCLUSION: Our data suggest that particle uptake varies along the bronchial tree and human lung tissue retains particles indicative of regional air pollution background. PMID- 21689008 TI - Binding of polystyrene and carbon black nanoparticles to blood serum proteins. AB - CONTEXT: Once inhaled, nanoparticles (NP) deposit on the lung surface and have first contact with the epithelial lung lining fluid (ELF) rich in proteins, which may bind to NP. OBJECTIVE: In this study, we investigate the parameters that influence the binding between NP and proteins. MATERIALS AND METHODS: We used the proteins albumin, transferrin (TF), and apolipoprotein A-1 (all known as proteins from ELF) and different NP (polystyrene NP with negative, positive, and neutral surface coatings, Printex G and Printex 90) as models. RESULTS: In all cases, a linear correlation of the added NP amount and the amount of bound proteins was found and was described quantitatively by binding indices. Bovine serum albumin (BSA), TF, and apo A-1 were bound to the largest extent to hydrophobic NP, which shows the extraordinary importance of the NP's surface properties. DISCUSSION: The binding index indicates the relevance of primary particle size and surface properties, including hydrophobicity. CONCLUSION: Size and surface modifications of NP determine their protein binding. Our results suggest that the formation of conjugates of BSA, TF, and Apo A-1 with NP may play an important role in their translocation across the air-blood-barrier and subsequent biokinetics. PMID- 21689009 TI - Altered pulmonary defense system in lung injury induced by didecyldimethylammonium chloride in mice. AB - Didecyldimethylammonium chloride (DDAC), a representative dialkyl-quaternary ammonium compound (QAC), could contaminate working atmospheres when used in disinfectant operation and adversely affect human health. Furthermore, the development of bacteria resistant to DDAC might become public health concern. We postulated that DDAC instillation in the lungs alters pulmonary antioxidant and antimicrobial responses and increases susceptibility to systemic administration of a bacterial component lipopolysaccharide (LPS). Mice were intratracheally instilled with DDAC and sacrificed 1, 3, or 7 days after treatment. Pulmonary cytotoxicity in recovered bronchoalveolar lavage was evident on Days 1 and 7, and inflammatory cell influx and interleukin-6 expression peaked on Day 7, in association with altered antioxidant and antimicrobial responses, as demonstrated by measuring heme oxygenase-1, glutathione peroxidase 2, lactoferrin, and mouse beta-defensin-2 and -3 mRNA in the lung samples. The impaired defense system tended to enhance the inflammatory reaction caused by a systemic administration of LPS; the effect was in association with increased expression of toll-like receptor-4 mRNA. The results suggest that DDAC alters pulmonary defense system, which may contribute to susceptibility to an exogenous infectious agent. PMID- 21689010 TI - Increased transforming growth factor beta 1 expression mediates ozone-induced airway fibrosis in mice. AB - Ozone (O3), a commonly encountered environmental pollutant, has been shown to induce pulmonary fibrosis in different animal models; the underlying mechanism, however, remains elusive. To investigate the molecular mechanism underlying O3 induced pulmonary fibrosis, 6- to 8-week-old C57BL/6 male mice were exposed to a cyclic O3 exposure protocol consisting of 2 days of filtered air and 5 days of O3 exposure (0.5 ppm, 8 h/day) for 5 and 10 cycles with or without intraperitoneal injection of IN-1233, a specific inhibitor of the type 1 receptor of transforming growth factor beta (TGF-beta), the most potent profibrogenic cytokine. The results showed that O3 exposure for 5 or 10 cycles increased the TGF-beta protein level in the epithelial lining fluid (ELF), associated with an increase in the expression of plasminogen activator inhibitor 1 (PAI-1), a TGF-beta-responsive gene that plays a critical role in the development of fibrosis under various pathological conditions. Cyclic O3 exposure also increased the deposition of collagens and alpha smooth muscle actin (alpha-SMA) in airway walls. However, these fibrotic changes were not overt until after 10 cycles of O3 exposure. Importantly, blockage of the TGF-beta signaling pathway with IN-1233 suppressed O3-induced Smad2/3 phosphorylation, PAI-1 expression, as well as collagens and alpha-SMA deposition in the lung. Our data demonstrate for the first time that O3 exposure increases TGF-beta expression and activates TGF-beta signaling pathways, which mediates O3-induced lung fibrotic responses in vivo. PMID- 21689011 TI - Laboratory evaluation of a prototype photochemical chamber designed to investigate the health effects of fresh and aged vehicular exhaust emissions. AB - Laboratory experiments simulating atmospheric aging of motor vehicle exhaust emissions were conducted using a single vehicle and a photochemical chamber. A compact automobile was used as a source of emissions. The vehicle exhaust was diluted with ambient air to achieve carbon monoxide (CO) concentrations similar to those observed in an urban highway tunnel. With the car engine idling, it is expected that the CO concentration is a reasonable surrogate for volatile organic compounds (VOCs) emissions. Varying the amount of dilution of the exhaust gas to produce different CO concentrations, allowed adjustment of the concentrations of VOCs in the chamber to optimize production of secondary organic aerosol (SOA) needed for animal toxicological exposures. Photochemical reactions in the chamber resulted in nitric oxide (NO) depletion, nitrogen dioxide (NO2) formation, ozone (O3) accumulation, and SOA formation. A stable SOA concentration of approximately 40 MUg m-3 at a chamber mean residence time of 30 min was achieved. This relatively short mean residence time provided adequate chamber flow output for both particle characterization and animal exposures. The chamber was operated as a continuous flow reactor for animal toxicological tests. SOA mass generated from the car exhaust diluted with ambient air was almost entirely in the ultrafine mode. Chamber performance was improved by using different types of seed aerosol to provide a surface for condensation of semivolatile reaction products, thus increasing the yield of SOA. Toxicological studies using Sprague-Dawley rats found significant increases of in vivo chemiluminescence in lungs following exposure to SOA. PMID- 21689012 TI - Development of a method to control the RNA extraction and reverse transcription steps for the detection of dengue virus present in human blood samples. AB - AIMS: Molecular biology techniques based on the detection of genomic sequences by reverse transcription combined with polymerase chain reaction (PCR) have enabled the detection of different RNA viruses in serum or plasma samples. Since the dengue epidemic outbreak declared in Argentina in 2009, numerous patients' samples were analyzed for the acute phase of infection. One of the main methodological drawbacks is the lack of internal control to measure the effectiveness of the viral extraction and reverse transcription process. In this article, we propose to standardize a molecular method to detect beta actin (beta Act) and glucose 6 phosphate dehydrogenase (G6PDH) complementary DNAs (cDNAs) present in patient's plasma/serum, as a control process. RESULTS: RNA extraction, reverse transcription, and PCRs for human G6PDH, beta-Act, and the dengue virus genome were performed. cDNA fragments for beta-Act and G6PDH were amplified for all samples, regardless of the presence or absence of viral RNA. CONCLUSIONS: Amplification of beta-Act and G6PDH cDNAs can be used as a control for the extraction and reverse transcription processes during dengue virus detection. This could also be a useful method for controlling the above steps when infections caused by other RNA viruses are studied, even if another methodology is employed, such as real-time PCR. PMID- 21689013 TI - The use of a reverse hybridization strip assay for the study of hemochromatosis associated gene mutations in Lebanon. AB - AIMS: Hereditary hemochromatosis (HHC) is the most commonly identified autosomal recessive genetic disorder in the Caucasian population and HFE gene mutations are highly concentrated among European populations. This is the first study that screens for HHC-related gene mutations in a healthy Lebanese sample population. METHODS: Using the reverse hybridization Hemochromatosis StripAssay A from ViennaLab, the DNA extracted from a total of 116 healthy volunteers (59 males and 57 females) was analyzed, looking for 18 different mutations in the HFE, ferroportin, and transferrin genes. RESULTS: For the HFE gene, the C282Y mutation was not detected, but the H63D mutation was found with an overall carrier frequency of 25.8% (24.1% heterozygous and 1.7% homozygous). None of the mutations in the transferrin and ferroportin genes was identified. CONCLUSIONS: The Hemochromatosis StripAssay A from ViennaLab provides an easy and reliable technique for simultaneous screening of the different HFE gene mutations. This first study in Lebanon represents a baseline report for further future studies in the field using this easy technique with a reasonable turnaround time for diagnosis. We also note that ferroportin and transferrin gene mutations have not been detected in this population sample and larger clinical studies will be needed to better estimate their prevalence. PMID- 21689014 TI - Population mutation scanning of human GHR by meltMADGE and identification of a paucimorphic variant. AB - Current studies of human genetic diversity are focused in two areas: first, detection of rare mutations in highly selected clinical cases; and second, in common single-nucleotide polymorphism (SNP) and haplotype effects in the general population. Less frequent SNPs and "paucimorphisms" remain underexplored, although lower frequency coding SNPs are more likely to have functional impact. We have developed a cost-efficient mutation scanning technology, meltMADGE, for population mutation scanning. Previous research in GHR has explored its role in extreme (-3 SD) growth retardation and, subsequently, "moderate" (-2 SD) growth retardation cases. Here, we describe meltMADGE assays for the entire coding region of GHR. As a first step we have established long polymerase chain reaction subbanks for GHR from 2423 unselected subjects and have applied meltMADGE scanning assays of exons 4 and 5 to these subbanks. A novel paucimorphism present at 439+30A>C (allele frequency: 0.0021) in intron 5 (location chr5:42,695,221 in GRCh37/hg19) was identified in 10 individuals, confirmed by sequencing and analysis made for major phenotypic effects. This approach is relevant to the deep sampling of populations for less frequent sequence diversity, some of which is expected to exert significant phenotypic effects. PMID- 21689015 TI - Can dogs prime autistic children for therapy? Evidence from a single case study. AB - BACKGROUND AND OBJECTIVES: Canine-assisted therapy has been receiving growing attention as a means of aiding children with autism spectrum disorder (ASD). Yet, only limited studies have been done and a great deal of literature related to this intervention is anecdotal. The present study aims at providing additional quantitative evidence on the potential of dogs to positively modulate the behavior of children with ASD. SETTINGS/LOCATION, SUBJECTS, AND INTERVENTIONS: A 12-year-old boy diagnosed with ASD was exposed, at his usual treatment location (the Portuguese Association for Developmental Disorders and Autism at Vila Nova de Gaia, Portugal), to the following treatment conditions: (1) one-to-one structured activities with a therapist assisted by a certified therapy dog, and (2) one-to-one structured activities with the same therapist alone (as a control). To accurately assess differences in the behavior of the participant between these treatment conditions, the therapist followed a strict research protocol. The behavior of the participant was continuously video-recorded during both treatment conditions for further analysis and comparison. Treatment outcomes: In the presence of the dog, the participant exhibited more frequent and longer durations of positive behaviors (such as smiling and positive physical contacting) as well as less frequent and shorter durations of negative behaviors (such as aggressive manifestations). CONCLUSIONS: These findings are in accordance with previous experimental work and provide additional support for the assertion that dogs can prime autistic children for therapy. Ultimately, this study may contribute toward a change for full acceptance of canine-assisted therapy programs within the medical milieu. Additional studies using a similar research protocol on more autistic children will certainly help professionals to work on the most effective methods to individually serve this population through canine-assisted interventions. PMID- 21689016 TI - Necrotizing nocardial scleritis successfully treated with surgical debridement and topical polyvinyl alcohol iodine and antibiotics. AB - PURPOSE: To report a case of necrotizing nocardial scleritis treated with surgical debridement and topical polyvinyl alcohol iodine (PAI) and antibiotics. CASE: A 78-year-old man underwent phacoemulsification with intraocular lens implantation in the left eye. He had an uncomplicated postoperative course for 2 months but then developed infectious scleritis. The patient received intensive antibiotics treatments; however, the lesion did not respond. Because of the poor response, Nocardia infection was suspected, and the lesion was repeatedly scraped and the patient was treated with systemic trimethoprim/sulfamethoxazole (TMP-SMX, 800 mg/day) and topical PAI (0.033%, 4 times/day). Cultures of the scrapings grew Nocardia. The treatment led to a complete resolution of the infection. CONCLUSIONS: Necrotizing nocardial scleritis can be treated by surgical debridement and systemic TMP-SMX and topical PAI. PMID- 21689017 TI - Mesenchymal stem cells in infantile hemangioma reside in the perivascular region. AB - Infantile hemangioma grows quickly in the first year of life and regresses slowly to fibrofatty tissue during childhood; mesenchymal stem cells (MSCs) have been reported to contribute to this adipogenesis. Recent studies have shown the perivascular origin of MSCs in multiple organs. We hypothesized that MSCs in hemangioma might also reside in the perivascular region. We isolated MSCs from proliferating hemangioma by their selective adhesion to plastic culture dishes. Mesenchymal stem cells from bone marrow (BM-MSCs) and foreskin-derived fibroblasts were used as controls. Flow cytometry and immunofluorescence staining were used to examine their antigen profiles; in vitro induction of multi-lineage differentiation was performed to test their pluripotency. Platelet-derived growth factor R-beta (PDGFR-beta), CD133, and peroxisome-proliferator-activated receptor gamma (PPAR-gamma) were selected as the markers to observe MSCs in hemangioma by immunohistochemistry staining, with costaining of CD31 and alpha-smooth muscle actin (alpha-SMA). Hemangioma-derived MSCs (Hem-MSCs) had fibroblast-like morphology; they expressed the MSC markers CD105, CD90, CD29, and vimentin and did not express the hematopoietic/endothelial markers CD45, CD34, CD31, and flt 1; Hem-MSCs also expressed CD133 and PPAR-gamma. Most Hem-MSCs expressed PDGFR beta and alpha-SMA; in contrast, the expression of PDGFR-beta and alpha-SMA in BM MSCs was very weak. The Hem-MSCs differentiated into adipocytes, osteoblasts, and chondroblasts in vitro. This confirmed their pluripotency. Immunohistochemistry showed the colocalization of PDGFR-beta/alpha-SMA, CD133/alpha-SMA, and PPAR gamma/alpha-SMA in the perivascular region. MSCs were successfully obtained from proliferating hemangioma, revealing the perivascular origin of MSCs in hemangioma. PMID- 21689018 TI - Association between MSX1 variants and oral clefts in Han Chinese in western China. AB - Previous animal and association studies have shown that the MSX1 gene is associated with oral clefts. Our aim was to investigate association between variants in the MSX1 gene and oral clefts in a Han Chinese population. Our study group consisted of 206 nonsyndromic oral cleft (NSOC) nuclear families (including the patients and their parents) and 224 controls. The three variants evaluated in this study were single-nucleotide polymorphisms rs3821949 and rs12532 and a missense mutation P147Q. Polymerase chain reaction-restriction fragment length polymorphism was used to genotype the three markers. Case-control and family based association analyses were carried out. In the case-control analysis, no significant differences in genotypic or allelic frequencies were observed in any of the two single-nucleotide polymorphisms between patients and controls. Although the homozygous T allele for P147Q was not detected in any sample in this population, heterozygotes were more prevalent in NSOC (1.2%) when compared with the controls (0%). The analyses for family-based association did not suggest association between any of the three variants and NSOC. No significant association was found between NSOC and rs3821949 or rs12532 in MSX1 gene, whereas an association was observed between the P147Q variant and cleft lip with cleft palate in the case-control analysis. PMID- 21689019 TI - Formoterol by pressurized metered-dose aerosol or dry powder on airway obstruction and lung hyperinflation in partially reversible COPD. AB - BACKGROUND: We compared the efficacy and safety of formoterol given by a pressurized metered-dose inhaler (pMDI) (Atimos(r), Chiesi Farmaceutici, Italy), using a chlorine-free hydrofluoroalkane (HFA-134a) propellant developed to provide stable and uniform dose delivery (ModuliteTM, Chiesi Farmaceutici, Italy), with formoterol by dry powder inhaler (DPI) (Foradil(r) Aerolizer(r), Novartis Pharmaceuticals) and placebo, in reducing airflow obstruction and lung hyperinflation, in moderate-to-severe, partially reversible chronic obstructive pulmonary disease (COPD). METHODS: Forty-eight patients were randomized to a 1 week, double-blind, double-dummy, three-period crossover study with 12 MUg b.i.d. of formoterol given by pMDI or DPI, or placebo. Spirometry, specific airway conductance, and lung volumes were measured at the beginning and at the end of each treatment period from predose to 4 h postdose. A 6-min walking test was carried out 4 h after the first and the last dose, with dyspnea assessed by Borg scale. Safety was assessed through adverse events monitoring electrocardiography and vital signs. RESULTS: The two formulations of formoterol were significantly superior to placebo but not different from each other in increasing 1-sec forced expiratory volume, specific airway conductance, inspiratory capacity, and inspiratory-to-total lung capacity ratio. The two active treatments were also equivalent and superior to placebo in reducing dyspnea at rest and on exertion. No differences in terms of safety between the two active forms and placebo were detected. CONCLUSIONS: Formoterol given with chlorine-free pMDI was equivalent to DPI in reducing airway obstruction and lung hyperinflation in COPD patients. Both formoterol formulations confirmed the good safety profile similar to placebo. PMID- 21689020 TI - Inhaled insulin: too soon to be forgotten? AB - Inhalation is a potentially viable route of administration for numerous agents. In diabetes mellitus, the need for frequent injections to achieve ideal glycemic control remains a significant limitation for initiating and complying with insulin therapy in a large number of patients. To overcome this barrier, inhaled insulin was developed. The inhalation form of regular human insulin has been tested and administered in a large number of trials. Respiratory capacity was evaluated in patients with normal lung parenchyma in whom inhaled insulin was administered without complications. However, issues like cost, bulky device, fear for lung safety, and the small number of studies in subjects with underlying respiratory disease prevented widespread use of this new mode of delivery. In the present review, we will suggest a number of methods that could be applied in this form of administration to maximize drug absorption and fully exploit the advantages of this route of administration. PMID- 21689021 TI - Assessment of reproducibility of exhaled hydrogen peroxide concentration and the effect of breathing pattern in healthy subjects. AB - BACKGROUND: Hydrogen peroxide (H2O2) is detectable in exhaled breath condensate (EBC) and has been proposed to be a surrogate marker of oxidative stress in the airways. In this study we tested whether the breathing pattern during EBC collection influences the concentration of exhaled H2O2. METHODS: EBC was collected during (1) tidal breathing and (2) breathing with increased tidal volume for 10 min from 16 healthy volunteers. On-line H2O2 measurement was performed by the EcoCheckTM biosensor system. Repeated measurements were also conducted to assess intrasubject reproducibility. RESULTS: Minute ventilation, tidal volume, expiratory flow rate were all increased significantly when subjects were asked to perform breathing with increased tidal volume. In parallel, EBC volume increased (1413+/-59 vs. 1959+/-71 MUL, p<0.001), whereas exhaled H2O2 levels decreased significantly (1400+/-170 vs. 840+/-130 nmol/L, p<0.001). H2O2 levels did not correlate with any individual breathing parameters (p>0.05). Assessment of intersubject variability of H2O2 measurements during the two types of breathing revealed a coefficient of variation of 49 and 54%, respectively. The EBC H2O2 measurement was highly reproducible (888+/-176 vs. 874+/-156 nmol/L) as tested during normal breathing. CONCLUSIONS: These data demonstrate that the concentration of H2O2 in EBC depends on the ventilatory pattern during sample collection that has to be taken into consideration in all EBC H2O2 assays. PMID- 21689024 TI - Why do young women get tested for sexually transmitted infections? Evidence from the National Longitudinal Study of Adolescent Health. AB - PURPOSE: Public health officials promote sexually transmitted infection (STI) testing as a method to reduce the morbidity of STIs. The purpose of this study was to examine what factors are associated with STI testing among young women across various types of STIs and to compare relative influences of factors across models. METHODS: A secondary data analysis of data from Add Health Wave III was conducted (n=2629). Explanatory factors highlighted in qualitative literature were operationalized and built into a logistic regression model used to predict testing for chlamydia, gonorrhea, syphilis, human papillomavirus (HPV), genital herpes, and HIV. RESULTS: STI symptoms and concerns about a recent sexual encounter were important expressed reasons for seeking medical care. Number of sexual partners, sexual orientation, STI symptoms, and going to the gynecologist in the past 12 months were important predictors of testing across STIs. This study supports qualitative work that suggests preventive health consciousness, STI symptoms, and relationship characteristics are important factors in STI testing. Results question the validity of self-report data regarding STI testing. CONCLUSIONS: Education efforts in secondary school health programs and during gynecologic examinations can decrease confusion about STI testing. PMID- 21689023 TI - Comparative immunohistochemical study of multicystic dysplastic kidneys with and without obstruction. AB - Etiology of multicystic dysplastic kidney (MCDK) remains unknown. Not all cases are associated with obstruction. We compared by immunohistochemistry 17 cases of MCDK (10 cases with and seven without obstruction) to 17 controls and 20 fetal kidneys. TGF-beta was negative in obstructive MCDKs and positive in nonobstructive MCDK. IGF2 was overexpressed in obstructive and underexpressed in nonobstructive MCDKs. PAX2, BCL-2, and beta-catenin were expressed equally in obstructive and nonobstructive dysplasia. TGF-beta and IGF2 work by different mechanisms in obstructive and nonobstructive MCDKs, but there are no differences among PAX 2, BCL-2, and beta-catenin in obstructive versus nonobstructive dysplasia. PMID- 21689025 TI - Does increased intake of salmon increase markers of oxidative stress in pregnant women? The salmon in pregnancy study. AB - The Salmon in Pregnancy Study provided two meals of salmon per week to pregnant women from week 20 of gestation; the control group maintained their habitual diet low in oily fish. Salmon is a rich source of marine n-3 fatty acids. Since marine n-3 fatty acids may increase oxidative stress, we investigated whether increased salmon consumption could affect markers of oxidative stress in mid and late pregnancy. Urinary 8-iso-prostaglandin F(2alpha), urinary 8-hydroxy-2' deoxyguanosine, and plasma lipid peroxide concentrations did not change from week 20 to 38 of pregnancy and were not altered by increased consumption of salmon. Thus, increased intake of salmon during pregnancy does not increase oxidative stress, as judged by the markers of oxidative damage to lipids and DNA measured herein. PMID- 21689026 TI - 'Hairy' cells: where are the roots of this leukemia? PMID- 21689027 TI - The role of NK cells in the development of autoantibodies. AB - The systemic lupus erythematosus (Sle1) interval from the NZM2410 mouse strain has been shown to be responsible for high levels of autoantibody production against antinuclear antibodies (ANA) when transferred into C57BL/6 mice. B cells derived from the B6.Sle1 strain are required for the production but help from both T-dependent and independent sources have been documented. Using radiation chimeras constructed in a strain of mice that is chronically depleted of Natural killer (NK) cells, but not NKT cells, we have examined the role of NK cells in the development of ANA in this context. Our results show that in the presence of intact T cell help depletion of NK cells does not affect ANA production. However, when T cell help is compromised, the prevalence of animals producing ANA is significantly decreased suggesting that NK cells can provide help for the T independent production of ANA. Further experiments provide a possible mechanism for the NK-cell dependence. PMID- 21689028 TI - Autoimmunity in Hispanic patients. Preface. PMID- 21689029 TI - Comparison of the 532-nm KTP and 1064-nm Nd:YAG lasers for the treatment of cherry angiomas. AB - BACKGROUND: Laser therapy is the treatment of choice for cherry angiomas since it is more effective and has better cosmetic results. There is no comparative study about the treatment efficacies with KTP and Nd:YAG lasers for cherry angiomas. OBJECTIVE: To compare the efficacy and side effects of 532-nm KTP and 1064-nm Nd:YAG lasers for the treatment of cherry angiomas. METHODS: Two comparable lesions of the same patient were chosen. One of them was treated with the KTP laser while the other was treated with the Nd:YAG laser. Sessions were repeated every 4 weeks until complete clearance was achieved. Side effects were evaluated using a severity scale (0 to 4). RESULTS: The number of sessions was significantly higher with the KTP than with the Nd:YAG laser (p = 0.002). Erythema, edema, pain and scar formation were higher in the Nd:YAG laser group (erythema: p = 0.001; edema: p < 0.001; pain: p < 0.001; scar: p < 0.001). The hyperpigmentation rate was statistically higher with the KTP laser (p = 0.01). CONCLUSION: Both KTP and Nd:YAG lasers were found to be effective methods. The Nd:YAG laser offered fewer treatment sessions, but a higher risk of scar formation. The KTP laser seems more advantageous, but in dark-skinned patients the Nd:YAG laser may be preferable. PMID- 21689030 TI - Response of authors: 'Lift capabilities of hyaluronic acid fillers'. PMID- 21689032 TI - Introduction to special supplement. Monitoring and evaluation of HIV counseling, testing and referral (CTR) and HIV testing services. PMID- 21689033 TI - HIV prevalence estimates and alignment among recent diagnoses, targeted tests, and prevention services by demographic and racial/ethnic group in Wisconsin. AB - The article provides HIV prevalence estimates by demographic group (men who have sex with men [MSM], non-MSM males, and females) and race/ethnicity for Wisconsin. Using the estimate that 4-8% of males aged 15-59 are MSM, we estimate that 14-28% of Black MSM in Wisconsin are HIV-positive. The proportions of HIV diagnoses by racial/ethnic and demographic group were compared with the proportions of targeted tests and HIV prevention clients in 2009. Among Blacks, MSM accounted for 58% of HIV diagnoses in Wisconsin but only 19% of targeted tests and 11% of HIV prevention clients. Disparities between cases and services also exist for Latinos and Whites. Jurisdiction-level testing targets were developed for 2010 using the estimated number of persons presumed to be living with HIV and unaware of their infection by racial/ethnic and demographic group. Targets for 2010 were compared with targeted tests conducted in 2009 to identify groups with the largest discrepancies. PMID- 21689034 TI - Characteristics of first-time and repeat HIV tests among men who have sex with men who test at CDC-supported sites, 2007. AB - This report describes characteristics of HIV test data for men who have sex with men (MSM) tested in 2007 through programs funded by the Centers for Disease Control and Prevention (CDC). HIV test-level data of MSM submitted by 29 health departments were analyzed to explore test characteristics among all tests, first time tests, and repeat tests. Characteristics significantly associated with HIV positive results among first-time tests were identified through logistic regression. Of the 129,893 tests conducted, 18% were first-time tests and 82% were repeat tests. HIV positivity among first-time tests was 4.1% and 3.7% among repeat tests. Among first-time tests, 46% of tests were among White MSM and 48% of HIV-positive test results were among African Americans. An HIV-positive test among first-time tests was strongly associated with being African American, being 40-49 years old, and testing in the southern United States. Race/ethnicity differences exist among MSM testing at CDC-funded sites. African American MSM accounted for the greatest proportion of HIV-positive results but White MSM represented the greatest proportion of tests conducted. HIV prevention strategies that include CDC-funded testing for MSM should increase targeting of African Americans. PMID- 21689035 TI - Utilization of HIV voluntary counseling and testing in Vietnam: an evaluation of 5 years of routine program data for national response. AB - This study evaluated the utilization of HIV voluntary counseling-and-testing (VCT) services targeting high-risk populations in Vietnam in order to inform decisions on program improvement and expansion. A total of 158,888 records collected from 55 VCT sites supported by the U.S. Centers for Disease Control and Prevention's Global AIDS Program in the period of 2002 to 2007 were used to analyze sociodemographic characteristics, risk exposures, seropositivity, test refusal, and failure to return for test results among VCT clients. High-risk exposures, such as injection drug use, commercial sex work, homosexual contacts or heterosexual contacts with high-risk sex partners, were reported in 126,815 (81%) records. Among high-risk clients, any condom use in the past month ranged from 34% to 71%. During the study period, 19% of the VCT encounters resulted in a positive HIV test; of those persons tested, 23% of men and 13% of women were HIV positive. High HIV positivity rates were associated with injection drug use, being ill/recommended by health care provider, and having an HIV-infected sex partner. Of all records, 6.1% documented refusal of HIV testing. Failure to return for results was reported in 3.5% of records for clients who were tested. Previously testing positive was the strongest predictor of test refusal, and being referred by peer educators was associated with failure to return for results. The VCT program in Vietnam successfully targeted high-risk populations, and clients had high return rates using a standard testing strategy. Interventions to increase consistent condom use and promote access to prevention services among sex partners of high-risk individuals should be implemented and evaluated. PMID- 21689036 TI - Costs and effectiveness of finding new HIV diagnoses by using rapid testing in transgender communities. AB - We assessed the costs and effectiveness of rapid HIV testing services provided to transgender communities in New York City and San Francisco from April 2005 to December 2006. Program costs were estimated based on service provider's perspective and included the costs attributable to staff time, incentives, transportation, test kits, office space, equipment, supplies, and utilities. The average annual numbers of persons tested were 195 and 106 persons and numbers notified of new HIV diagnoses were 35 (18.2%) in New York City and 8 (7.3%) in San Francisco, respectively. The estimated annual program costs were $125,879 and $64,323 and average costs per person notified of new diagnosis were $3,563 and $8,284 in New York City and San Francisco, respectively. The primary reason for differences in program costs by site was differences in the proportion of undiagnosed HIV infection among persons tested. Our findings can inform decisions about program planning and allocation of limited HIV testing resources. PMID- 21689037 TI - Emergency department HIV screening with rapid tests: a cost comparison of alternative models. AB - Although previous studies have shown that HIV screening in emergency departments (EDs) is feasible, the costs and outcomes of alternative methods of implementing ED screening have not been examined. We compared the costs and outcomes of a model that used the hospital's ED staff to conduct screening, a supplemental staff model that used non-ED staff hired to conduct screening and a hypothetical hybrid model that combined aspects of both approaches. We developed a decision analytic model to estimate the cost per HIV-infected patient identified using alternative ED testing models. The cost per new HIV infection identified was $3,319, $2,084 and $1,850 under the supplemental, existing staff and hybrid models, respectively. Assuming an annual ED census of 50,000 patients, the existing staff model identified 29 more HIV infections than the supplemental model and the hybrid model identified 76 more infections than the existing staff model. Our findings suggest that a hybrid model should be favored over either a supplemental staff or existing staff model in terms of cost per outcome achieved. PMID- 21689038 TI - General internists' beliefs, behaviors, and perceived barriers to routine HIV screening in primary care. AB - The Centers for Disease Control and Prevention (CDC) recommends routine HIV screening in primary care but little is known about general internists' views of this practice. We conducted a national, cross-sectional, Internet-based survey of 446 general internists in 2009 regarding their HIV screening behaviors, beliefs, and perceived barriers to routine HIV screening in outpatient internal medicine practices. Internists' awareness of revised CDC guidelines was high (88%), but only 52% had increased HIV testing, 61% offered HIV screening regardless of risk, and a median 2% (range 0-67%) of their patients were tested in the past month. Internists practicing in perceived higher risk communities reported greater HIV screening. Consent requirements were a barrier to screening, particularly for VA providers and those practicing in states with HIV consent statutes inconsistent with CDC guidelines. Interventions that promote HIV screening regardless of risk and streamlined consent requirements will likely increase adoption of routine HIV screening in general medicine practices. PMID- 21689039 TI - Barriers and facilitators to enhancing HIV testing in publicly funded primary care clinics: findings from San Francisco. AB - Although the City of San Francisco hosts a number of community-based HIV test sites, about 2,500 infected individuals are unaware of their serostatus. Primary medical care settings may provide improved access to HIV testing, particularly if testing programs are well matched to the setting where they are implemented. To plan for expanding testing in these settings, we assessed trends in testing in publicly supported clinics and conducted qualitative interviews to assess current testing practices, linkage to care and partner services practices, and barriers to implementing and/or expanding HIV testing. We presented the results to stakeholders and asked them to help develop recommendations to expand testing and linkage to care. Since 2007, testing has increased in primary care settings although a gap in access remains. Primary care providers endorsed the concept of routine HIV testing but raised concerns and recommended a staged approach to expanding testing. Stakeholders recommended that the city's public health department provide enhanced capacity building assistance and support a new linkage to care and partner services team. This study holds lessons for other jurisdictions seeking to expand HIV testing in primary care. PMID- 21689040 TI - An evaluation of a routine opt-out rapid HIV testing program in a Rhode Island jail. AB - There is an increased prevalence of HIV among incarcerated populations. We conducted a rapid HIV testing pilot program using oral specimens at the Rhode Island Department of Corrections (RIDOC) jail. Detainees (N = 1,364) were offered rapid testing upon jail entrance and 98% completed testing. Twelve detainees had reactive rapid tests, one of which was a new HIV diagnosis. To evaluate the program qualitatively, we conducted key informant interviews and focus groups with key stakeholders. There was overwhelming support for the oral fluid rapid HIV test. Correctional staff reported improved inmate processing due to the elimination of phlebotomy required with conventional HIV testing. Delivering negative rapid HIV test results in real-time during the jail intake process remained a challenge but completion of confirmatory testing among those with reactive rapid tests was possible. Rapid HIV testing using oral specimens in the RIDOC jail was feasible and preferred by correctional staff. PMID- 21689041 TI - Iterative evaluation in a mobile counseling and testing program to reach people of color at risk for HIV--new strategies improve program acceptability, effectiveness, and evaluation capabilities. AB - This article highlights findings from an evaluation that explored the impact of mobile versus clinic-based testing, rapid versus central-lab based testing, incentives for testing, and the use of a computer counseling program to guide counseling and automate evaluation in a mobile program reaching people of color at risk for HIV. The program's results show that an increased focus on mobile outreach using rapid testing, incentives and health information technology tools may improve program acceptability, quality, productivity and timeliness of reports. This article describes program design decisions based on continuous quality assessment efforts. It also examines the impact of the Computer Assessment and Risk Reduction Education computer tool on HIV testing rates, staff perception of counseling quality, program productivity, and on the timeliness of evaluation reports. The article concludes with a discussion of implications for programmatic responses to the Centers for Disease Control and Prevention's HIV testing recommendations. PMID- 21689042 TI - HIV counseling, testing and referral experiences of persons diagnosed with HIV who have never entered HIV medical care. AB - The HIV counseling, testing, and referral (CTR) encounter represents an important opportunity to actively facilitate entry into medical care for those who test positive for HIV, but its potential is not always realized. Ways to improve facilitation of linkage to care through the CTR encounter haven't been explored among HIV-infected persons who have not entered care. We conducted 42 structured and qualitative interviews among HIV-infected persons, diagnosed 5-19 months previously, in Indiana, Philadelphia and Washington State, who had not received HIV medical care. Respondents related individual and system-level barriers, as well as recommendations for improving the effectiveness of CTR as a facilitator of linkage to HIV medical care through more active referrals, and for strengthening the bridge between CTR and linkage to care services. Our findings suggest that standards for active case referral by CTR staff and integration of CTR and linkage to care services are needed. PMID- 21689045 TI - High-throughput biosensors for multiplexed food-borne pathogen detection. AB - Incidental contamination of foods by pathogenic bacteria and/or their toxins is a serious threat to public health and the global economy. The presence of food borne pathogens and toxins must be rapidly determined at various stages of food production, processing, and distribution. Producers, processors, regulators, retailers, and public health professionals need simple and cost-effective methods to detect different species or serotypes of bacteria and associated toxins in large numbers of food samples. This review addresses the desire to replace traditional microbiological plate culture with more timely and less cumbersome rapid, biosensor-based methods. Emphasis focuses on high-throughput, multiplexed techniques that allow for simultaneous testing of numerous samples, in rapid succession, for multiple food-borne analytes (primarily pathogenic bacteria and/or toxins). PMID- 21689046 TI - Monolithic phases for ion chromatography. AB - Monolithic media are continuing to increase in popularity in chromatographic applications, and the ongoing use of commercially available materials in ion chromatography (IC) has made monoliths a viable alternative to packed-bed columns for routine use. We discuss different strategies for the synthesis of polymeric and silica monoliths with ion-exchange functionality, such as direct incorporation of ion-exchange functionality during monolith preparation and different postpolymerization alterations such as grafting and coating. The formulations and strategies presented are focused on materials intended for use in IC. We also discuss strategies for materials characterization, with emphasis on nondestructive techniques for the characterization of monolith surface functionality, especially those with applicability to in situ analysis. Finally, we describe selected IC applications of polymeric and silica monoliths published from 2008 to 2010. PMID- 21689047 TI - The asphaltenes. AB - Asphaltenes, the most aromatic of the heaviest components of crude oil, are critical to all aspects of petroleum utilization, including reservoir characterization, production, transportation, refining, upgrading, paving, and coating materials. The asphaltenes, which are solid, have or impart crucial and often deleterious attributes in fluids such as high viscosity, emulsion stability, low distillate yields, and inopportune phase separation. Nevertheless, fundamental uncertainties had precluded a first-principles approach to asphaltenes until now. Recently, asphaltene science has undergone a renaissance; many basic molecular and nanocolloidal properties have been resolved and codified in the modified Yen model (also known as the Yen-Mullins model), thereby enabling predictive asphaltene science. Advances in analytical chemistry, especially mass spectrometry, enable the identification of tens of thousands of distinct chemical species in crude oils and asphaltenes. These and other powerful advances in asphaltene science fall under the banner of petroleomics, which incorporates predictive petroleum science and provides a framework for future developments. PMID- 21689048 TI - A music quality rating test battery for cochlear implant users to compare the FSP and HDCIS strategies for music appreciation. AB - OBJECTIVE: The purpose of this study was to develop a music quality rating test battery (MQRTB) and pilot test it by comparing appraisal ratings from cochlear implant (CI) recipients using the fine-structure processing (FSP) and high definition continuous interleaved sampling (HDCIS) speech processing strategies. DESIGN: The development of the MQRTB involved three stages: (1) Selection of test items for the MQRTB; (2) Verification of its length and complexity with normally hearing individuals; and (3) Pilot testing with CI recipients. STUDY SAMPLE: Part 1 involved 65 adult listeners, Part 2 involved 10 normally-hearing adults, and Part 3 involved five adult MED-EL CI recipients. RESULTS: The MQRTB consisted of ten songs, with ratings made on scales assessing pleasantness, naturalness, richness, fullness, sharpness, and roughness. Results of the pilot study, which compared FSP and HDCIS for music, indicated that acclimatization to a strategy had a significant effect on ratings (p < 0.05). When acclimatized to FSP, the group rated FSP as closer to 'exactly as I want it to sound' than HDCIS (p < 0.05), and that HDCIS sounded significantly sharper and rougher than FSP. However when acclimatized to HDCIS, there were no significant differences between ratings. There was no effect of song familiarity or genre on ratings. CONCLUSIONS: Overall the results suggest that the use of FSP as the default strategy for MED-EL recipients would have a positive effect on music appreciation, and that the MQRTB is an effective tool for assessing music sound quality. PMID- 21689049 TI - Comparison of 8-h urine protein and random urinary protein-to-creatinine ratio with 24-h urine protein in pregnancy. AB - OBJECTIVE: To evaluate the relationship between 24-h and 8-h urinary protein excretion and protein-to-ceratinine (p:c) ratio in random urine sample. As well as determining a best cutoff for p:c ratio for accurately diagnose significant proteinuria. METHODS: Fifty hospitalized pregnant women who need 24 h urine collection for medical complications were studied. At first for each patient protein-to-createnin ratio in random urine sample was done. Then 8- and 24-h urinary protein estimation was performed. The 24-h and 8-h urinary protein were compared to urinary p:c ratio in random urine sample. RESULTS: There were significant correlations (p < 0.001) between protein levels of 24-h and 8-h urine collections (r = 0.75), 24-h and random urine p:c ratio (r = 0.97) as well as 8-h and random urine p:c ratio (r = 0.79). Mean protein levels were significantly higher in group with proteinuria >= 300 mg/24 h in these three types of urine samples (p < 0.001). We found cutoff levels of 105 mg for 8-h urine sample and of 0.18 for p:c ratio. CONCLUSIONS: This study showed that 8-h urine protein or random p:c ratio in a single-voided urine can be appropriate methods for detection of proteinuria in the shorter period than 24-h urine protein. PMID- 21689050 TI - Transplacental digoxin therapy for fetal tachyarrhythmia with multiple evaluation systems. AB - BACKGROUND: Sustained fetal tachyarrhythmia may result in congestive heart failure, hydrops fetalis, and fetal/neonatal death, which requires timely and appropriate therapy. AIM: To determine the value of transplacental digoxin therapy for fetal tachyarrhythmia with multiple evaluations. METHODS: Four cases of fetal tachyarrhythmia were diagnosed with fetal echocardiography and treated with transplacental digoxin therapy with an initial dosage of 0.25 mg qd. Fetal echocardiography and measurement of maternal serum digoxin concentrations were performed every 5-7 days. Echocardiographic information was further used for the calculation of three evaluation systems including, Tei index, cardiovascular profile score (CVPS), and umbilical artery resistance index (UARI). The dosage of digoxin was adjusted according to the serum concentration, as well as results from three evaluation systems. RESULTS: During the course of digoxin treatment, our patients show an increase of CVPS and decrease of Tei index and UARI, suggesting the recovery of heart function. Sinus rhythm was restored in 3-10 days in three cases and 42 days in one case. At the time of delivery, the placental transportation efficiency (neonate/mother ratio of serum digoxin concentration) was 76.45-84.31%. Following delivery, the general conditions of neonates were favorable. During the 4- to 14-month follow-up, reoccurrence of arrhythmia, neurological deficit, and retarded growth and development were not observed. CONCLUSIONS: Transplacental digoxin therapy with combined evaluation of Tei index, CVPS, and UARI systems is useful for treating fetal atrial flutter (AF) and supraventricular tachycardia (SVT). PMID- 21689051 TI - Polyhemoglobin-superoxide dismutase-catalase-carbonic anhydrase: a novel biotechnology-based blood substitute that transports both oxygen and carbon dioxide and also acts as an antioxidant. AB - Polyhemoglobin-superoxide dismutase-catalase-carbonic anhydrase (PolyHb-SOD-CAT CA) is a therapeutic antioxidant that also transports both oxygen and carbon dioxide. This is formed by crosslinking Hb with SOD, CAT, and CA using glutaraldehyde. Crosslinking stroma-free Hb from red blood cell (RBC) reduces CA activity to 55%. Addition of more CA resulted in a preparation with the same CA activity as RBC. PolyHb in the complex acts as a buffer to prevent large pH changes as carbon dioxide is converted to carbonic acid. We then prepare and optimize a novel PolyHb-SOD-CAT-CA, a therapeutic antioxidant that also transports both oxygen and carbon dioxide. PMID- 21689052 TI - Preparation and influencing factors of sirolimus liposome by supercritical fluid. AB - We prepared the sirolimus liposome by rapid expansion of supercritical solution (RESS) technology of supercritical fluid, and studied the effects of temperature, pressure, and equilibrium time on the average particle size and envelop rate of liposome. The conditions of the minimal average particle size of liposome were 328K of temperature (35MPa), 35MPa of pressure (333K), and 50 minutes of equilibrium (343K) time, respectively. The conditions of the maximal envelop rate of liposome were 333K of temperature (30MPa), 35MPa of pressure (343K), and 50 minutes of equilibrium (323K) time, respectively. PMID- 21689053 TI - Radiation decreases murine small intestinal HCO3- secretion. AB - PURPOSE: While secretagogue-induced diarrhea is rich in chloride (Cl(-)) and bicarbonate (HCO(3) (-)) anions, little is known about diarrhea or its anionic composition following irradiation. We performed studies to characterize the differences between cyclic adenosine monophosphate (cAMP)-stimulated anion secretions in irradiated and non-irradiated mice. MATERIALS AND METHODS: HCO(3) ( ) secretion was examined in basal, cAMP-stimulated, and irradiated jejunal tissues from BALB/c (Bagg albino) mice. The abdomens of the mice were gamma irradiated using a caesium-137 source. RESULTS: Ussing-chamber experiments performed in an HCO(3)(-)-containing, Cl(-)-free solution on the bath side showed inhibition of HCO(3)(-) in irradiated mice. Non-irradiated mice exhibited bumetanide-sensitive and insensitive current, while irradiated mice displayed bumetanide-sensitive current. pH-stat experiments showed inhibition of basal and cAMP-stimulated HCO(3)(-) secretions in irradiated mice. Immunohistochemistry and Western blot analysis displayed a sodium-bicarbonate cotransporter expression in the villus and not the crypt of non-irradiated mice, while its expression and protein levels decreased in irradiated mice. CONCLUSIONS: Anion secretions in irradiated mice, being primarily Cl(-) and minimally HCO(3)(-), differ from that of secretagogue-induced anion secretions. Understanding anion loss will help us correct electrolyte imbalances, while reduced HCO(3)(-) secretion in the upper gastrointestinal tract might also have implications for irradiation-induced nausea and vomiting. PMID- 21689054 TI - Laparoscopic Pringle's manoeuvre for liver resection?: how I do it. AB - Although experience with the laparoscopic approach for liver resection has increased in recent years, it still remains a challenging procedure. One of the manoeuvres to reduce catastrophic haemorrhage is occlusion of hepatic inflow by compression of the hepato-duodenal ligament, the so-called Pringle's manoeuvre. One of the limitations of laparoscopic liver resection is the safe placement of a tape around the hepato-duodenal ligament to facilitate intermittent clamping of the porta-hepatis (Pringle's manoeuvre) prior to hepatic transection. We present a novel, safe and efficient technique that has evolved during this series of laparoscopic liver resections. PMID- 21689055 TI - The COST - Action 2103 "Advanced Voice Function Assessment". PMID- 21689056 TI - Validity of jitter measures in non-quasi-periodic voices. Part I: perceptual and computer performances in cycle pattern recognition. AB - The limit of about 5% for reliable quantification of jitter in sustained vowels of dysphonic voices-a widely accepted guideline-deserves critical analysis. The present study pertains to the effect of experience and training on the perceptual (visual) capability of correctly identifying periods in (highly) perturbed signals, and to a comparison of the performance of several programs for voice analysis. Synthesized realistic vowels (/a:/) with exactly known jitter (2.7% 31.5%) are used as material. After selection and training, experienced raters demonstrate excellent agreement in correctly identifying periods up to high values of jitter put in. Perceptual rating outperforms all computer programs in accuracy. Most remain reliable up to 10% jitter; one of them correctly measures up to the highest level. PMID- 21689057 TI - Protein disulfide isomerase immunopositive glial cytoplasmic inclusions in patients with multiple system atrophy. AB - BACKGROUND: Glial cytoplasmic inclusions (GCIs) are the pathological hallmarks of multiple system atrophy (MSA) and alpha-synuclein is abnormally deposited in GCIs. Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily and is believed to accelerate the folding of disulfide-bonded proteins by catalyzing the disulfide interchange reaction, which is the rate limiting step during protein folding in the luminal space of the endoplasmic reticulum (ER). Nitric-oxide-induced (NO-induced) S-nitrosylation of PDI inhibits its enzymatic activity, leading to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response in neurodegenerative diseases. MATERIALS AND METHODS: Postmortem brain specimens from five patients with MSA and five normal control brains were utilized in this immunohistochemical study. RESULTS: We found GCIs positive for anti-PDI antibody in the brain of patients with MSA. In addition, we observed colocalization of alpha-synuclein and leucine-rich repeat kinase 2 (LRRK2) with PDI in GCIs. As LRRK2 immunoreactivity is associated with one of the earliest oligodendrocytic abnormalities in MSA, colocalization of LRRK2 and PDI in GCIs may be a link to the ER stress of glial cells in the early stages of MSA. CONCLUSIONS: In MSA, NO may inhibit PDI by inducing S-nitrosylation, which inhibits its enzymatic activity and thus allows protein misfolding to occur. PMID- 21689058 TI - A healing method of tympanic membrane perforations using three-dimensional porous chitosan scaffolds. AB - Both surgical tympanoplasty and paper patch grafts are frequently procedured to heal tympanic membrane (TM) perforation or chronic otitis media, despite their many disadvantages. In this study, we report a new healing method of TM perforation by using three-dimensional (3D) porous chitosan scaffolds (3D chitosan scaffolds) as an alternative method to surgical treatment or paper patch graft. Various 3D chitosan scaffolds were prepared; and the structural characteristics, mechanical property, in vitro biocompatibility, and healing effects of the 3D chitosan scaffolds as an artificial TM in in vivo animal studies were investigated. A 3D chitosan scaffold of 5 wt.% chitosan concentration showed good proliferation of TM cells in an in vitro study, as well as suitable structural characteristics and mechanical property, as compared with either 1% or 3% chitosan. In in vivo animal studies, 3D chitosan scaffold were able to migrate through the pores and surfaces of TM cells, thus leading to more effective TM regeneration than paper patch technique. Histological observations demonstrated that the regenerated TM with the 3D chitosan scaffold consisted of three (epidermal, connective tissue, and mucosal) layers and were thicker than normal TMs. The 3D chitosan scaffold technique may be an optimal healing method used in lieu of surgical tympanoplasty in certain cases to heal perforated TMs. PMID- 21689062 TI - Controlling the fibroblastic differentiation of mesenchymal stem cells via the combination of fibrous scaffolds and connective tissue growth factor. AB - Controlled differentiation of multi-potent mesenchymal stem cells (MSCs) into vocal fold-specific, fibroblast-like cells in vitro is an attractive strategy for vocal fold repair and regeneration. The goal of the current study was to define experimental parameters that can be used to control the initial fibroblastic differentiation of MSCs in vitro. To this end, connective tissue growth factor (CTGF) and micro-structured, fibrous scaffolds based on poly(glycerol sebacate) (PGS) and poly(E-caprolactone) (PCL) were used to create a three-dimensional, connective tissue-like microenvironment. MSCs readily attached to and elongated along the microfibers, adopting a spindle-shaped morphology during the initial 3 days of preculture in an MSC maintenance medium. The cell-laden scaffolds were subsequently cultivated in a conditioned medium containing CTGF and ascorbic acids for up to 21 days. Cell morphology, proliferation, and differentiation were analyzed collectively by quantitative PCR analyses, and biochemical and immunocytochemical assays. F-actin staining showed that MSCs maintained their fibroblastic morphology during the 3 weeks of culture. The addition of CTGF to the constructs resulted in an enhanced cell proliferation, elevated expression of fibroblast-specific protein-1, and decreased expression of mesenchymal surface epitopes without markedly triggering chondrogenesis, osteogenesis, adipogenesis, or apoptosis. At the mRNA level, CTGF supplement resulted in a decreased expression of collagen I and tissue inhibitor of metalloproteinase 1, but an increased expression of decorin and hyaluronic acid synthesase 3. At the protein level, collagen I, collagen III, sulfated glycosaminoglycan, and elastin productivity was higher in the conditioned PGS-PCL culture than in the normal culture. These findings collectively demonstrate that the fibrous mesh, when combined with defined biochemical cues, is capable of fostering MSC fibroblastic differentiation in vitro. PMID- 21689063 TI - Combination therapy with naltrexone and bupropion for obesity. AB - INTRODUCTION: Although pharmacological treatments for obesity represent only one option in managing obesity, they are a useful tool in an otherwise extremely limited armamentarium. Naltrexone/bupropion combination therapy was developed by using technological advances that have improved our understanding of how the brain regulates body weight. AREAS COVERED: This review covers the development of naltrexone/bupropion combination therapy for obesity, as well as the published clinical trials on the safety and efficacy of the combination in overweight and obese humans. The effect of naltrexone/bupropion on food craving seems to be unique, and the implications of this finding for weight loss are discussed. EXPERT OPINION: Safety and tolerability issues seem to be manageable and consistent with the documented effects of each component. Appropriate patient management should address the mild sympathomimetic effect of bupropion, although the FDA has required that a cardiovascular outcomes study be conducted preapproval to determine the effects of long-term use of naltrexone/bupropion in an overweight/obese population. When used in conjunction with diet and exercise, the naltrexone/bupropion combination may be a useful treatment option for obesity, especially for overweight and obese adults who report difficulty controlling eating behavior and their response to food cravings. PMID- 21689064 TI - Emepepimut-S for non-small cell lung cancer. AB - INTRODUCTION: Immunotherapy as a possible therapeutic option for cancer has been of great importance due to the innovative development of vaccines. Various molecules have been tested and emepepimut-S (Biomira Liposomal Peptide 25 (BLP 25)) has emerged as an option, particularly in lung cancer. AREAS COVERED: A PubMed literature and ClinicalTrials.gov search was conducted using the terms: emepepimut, BLP25, NSCLC, cancer immunotherapy, cancer vaccine and MUC1. This review covers how emepepimut-S acts against the mucin 1 (MUC1) tumor-associated antigen producing a cellular immune response against the cells that express MUC1 and the most important clinical data available that led to the ongoing Phase III trial. EXPERT OPINION: The results obtained in the Phase I/II trials are promising, showing a favorable toxicity with a benefit in survival in NSCLC patients. As future trials develop, demonstration of the long-term survival benefit, understanding of the various mechanisms of immune response initiated by the drug and the selection of patients that will highly benefit from the immunotherapy will be elucidated. The safety and extension in survival makes emepepimut-S a very interesting drug and could, therefore, offer a possibility of treatment and maintenance, particularly for good performance status patients with locally advanced NSCLC. PMID- 21689065 TI - Heat-shock protein 90 inhibitors as antitumor agents: a survey of the literature from 2005 to 2010. AB - INTRODUCTION: Heat-shock protein 90 (Hsp90) is a validated novel anticancer target with unique features. As a molecular chaperone, Hsp90 is implicated in maintaining the conformation, stability, activity and cellular localization of several key oncogenic client proteins that are involved in signal transduction pathways leading to proliferation, cell-cycle progression, apoptosis, angiogenesis and metastasis. As a result, inhibitors of Hsp90 achieve their promising anticancer activity through disruption of the Hsp90 protein function, thereby freezing the chaperone cycle; this in turn decreases the affinity of Hsp90 for client proteins, thus leading to proteasome-mediated degradation of oncogenic client proteins within cancer cells. AREAS COVERED: This review provides recent background information on Hsp90 inhibitors. It also highlights a panel of compounds of interest reported in patents and discusses the clinical results of the promising drug candidates. EXPERT OPINION: In the past 5 years, Hsp90 inhibitors have remained the focus of much interest as new potential anticancer agents. A large variety of scaffolds were studied in both academia and industry. Consequently, these significant research efforts have provided several promising drug candidates for further clinical development. Further progress in the development of Hsp90 inhibitors, combined with a deeper understanding of the chaperon characteristics, strengthens their promise in cancer therapy. PMID- 21689066 TI - Three-dimensional spheroid culture of human gingiva-derived mesenchymal stem cells enhances mitigation of chemotherapy-induced oral mucositis. AB - Mesenchymal stem cells (MSCs) are capable of regenerative and immunomodulatory functions in cell-based therapies in a variety of human diseases and injuries; however, their therapeutic efficacy and potential side effects remain major obstacles in clinical applications. We report here a 3D spheroid culture approach to optimize stem cell properties and therapeutic effects of human gingiva-derived mesenchymal stem cells (GMSCs) in mitigation of experimental oral mucositis. Under growth condition of ultra-low attachment, GMSCs spontaneously aggregated into 3D spheroids and exhibited distinct early stem cell phenotype characterized by elevated expression Stro-1 and CXC chemokine receptor 4 (CXCR-4) as well as OCT-4 and Nanog, 2 important transcriptional factors relevant to stem cell properties, and decreased expression of MSC-associated markers, including CD29, CD90, and CD105. Functionally, spheroid GMSCs are capable of enhanced multipotency and augmented secretion of several chemokines and cytokines relevant to cell migration, survival, and angiogenesis. More importantly, spheroid GMSCs expressed increased levels of reactive oxygen species, hypoxia-inducible factor (HIF)-1 and -2alpha, and manganese superoxide dismutase, which correlated with improved resistance to oxidative stress-induced apoptosis. Using an in vivo murine model of chemotherapy-induced oral mucositis, we demonstrated that spheroid-derived GMSCs possessed better therapeutic efficacy than their adherent cells in reversing body weight loss and promoting the regeneration of disrupted epithelial lining of the mucositic tongues. These findings suggest that 3D spheroid culture allows early stemness preservation and potentially precondition GMSCs for enhanced mitigation of oral mucositis. PMID- 21689067 TI - Radical cystectomy and urinary diversion in women: impact on sexual function. AB - OBJECTIVE: The aim of this study was to assess the impact of radical cystectomy and different forms of urinary diversion on female sexual function. MATERIAL AND METHODS: Seventy-three consecutive patients were included in the study. The mean age was 52.3 +/- 6.5 years. All of them had undergone non-nerve-sparing radical cystectomy and urinary diversion for invasive bladder cancer. Patients were questioned about their current general relations with their husbands in comparison to the preoperative status. The Female Sexual Function Index (FSFI) was used to assess libido, lubrication, orgasm, satisfaction and painful sexual dysfunction. Patients were asked about any urinary complaints during or after sexual intercourse. RESULTS: Twenty-nine patients (39%) reported worsening relations with their husbands. The mean frequency of sexual relations was 2.3 +/- 2.3/month; however, sexual relations had ceased completely in 19 patients (26%). Overall satisfaction among sexually active women worsened in 32 (59.2%) and was completely lost in eight patients (14.8%). Absent libido, difficult intromission, dyspareunia, lack of orgasm and sexually related urinary complaints were reported in 89%, 63%, 48%, 63% and 63% of patients, respectively. The mean FSFI score dropped significantly from 18.3 +/- 5.1 to 11.3 +/- 7.4 postoperatively (p < 0.001). FSFI scores were significantly higher among patients with orthotopic versus non-orthotopic forms of diversion and also higher among patients with no stoma versus those with stomal forms of diversion. CONCLUSIONS: Radical cystectomy and urinary diversion have deleterious impacts on all domains of female sexual function. Female patients with orthotopic and non-stomal diversions had better sexual functions than those with stomal diversions. PMID- 21689068 TI - Defining the impaction frequency and threshold force required for femoral impaction grafting in revision hip arthroplasty. A human cadaveric mechanical study. AB - BACKGROUND AND PURPOSE: The two most common complications of femoral impaction bone grafting are femoral fracture and massive implant subsidence. We investigated fracture forces and implant subsidence rates in embalmed human femurs undergoing impaction grafting. The study consisted of two arms, the first examining the force at which femoral fracture occurs in the embalmed human femur, and the second examining whether significant graft implant/subsidence occurs following impaction at a set force at two different impaction frequencies. METHODS: Using a standardized impaction grafting technique with modifications, an initial group of 17 femurs underwent complete destructive impaction testing, allowing sequentially increased, controlled impaction forces to be applied until femoral fracture occurred. A second group of 8 femurs underwent impaction bone grafting at constant force, at an impaction frequency of 1 Hz or 10 Hz. An Exeter stem was cemented into the neomedullary canals. These constructs underwent subsidence testing simulating the first 2 months of postoperative weight bearing. RESULTS: No femurs fractured below an impaction force of 0.5 kN. 15/17 of the femurs fractured at or above 1.6 kN of applied force. In the second group of 8 femurs, all of which underwent femoral impaction grafting at 1.6 kN, there was no correlation between implant subsidence and frequency of impaction. Average subsidence was 3.2 (1-9) mm. INTERPRETATION: It is possible to calculate a force below which no fracture occurs in the embalmed human femur undergoing impaction grafting. Higher impaction frequency at constant force did not reduce rates of implant subsidence in this experiment. PMID- 21689069 TI - A single bisphosphonate infusion does not accelerate fracture healing in high tibial osteotomies. AB - BACKGROUND: Bisphosphonates increase the callus size and strength in animal fracture studies. In a human non-randomized pilot study of high tibial osteotomies in knee osteoarthritis, using the hemicallotasis (HCO) technique, bisphosphonates shortened the healing time by 12 days. In the present randomized study, we wanted to determine whether a single infusion of zoledronic acid reduces the time to clinical osteotomy healing. Results from the same trial, showing improved pin fixation with zoledronate, have been published separately. METHODS: 46 consecutive patients (aged 35-65 years) were operated. At 4 weeks postoperatively, the patients were randomized to an intravenous infusion of either zoledronic acid or sodium chloride. Dual-energy X-ray absorptiometry (DEXA) was performed 10 weeks postoperatively. Radiographs were taken at 10 weeks and every second week until there was radiographic and clinical healing. Healing was evaluated blind, with extraction of the external fixator as the endpoint. At 1.5 years, an additional radiograph was taken and the hip-knee-ankle (HKA) angle measured to evaluate whether correction had been retained. RESULTS: All osteotomies healed with no difference in healing time between the groups (77 (SD 7) days). Bone mineral density and bone mineral content, as assessed with DEXA, were similar between the groups. Radiographically, both groups had retained the acquired correction at the 1.5-year follow-up. INTERPRETATION: In this randomized comparison, a single infusion of zoledronic acid increased the pin fixation of the external frame but did not shorten the healing time. In both groups, the external fixator was extracted almost 2 weeks earlier than in previous studies. The early extraction did not cause a loss of correction in either group. PMID- 21689070 TI - Drosophila Sal and Salr are transcriptional repressors. AB - The SALL (Spalt-like) family of zinc-finger transcription factors is conserved in metazoans. In Drosophila Sal (Spalt) and Salr (Spalt-related) control the expression of genes involved in wing and central nervous system development, including cell adhesion and cytoskeletal proteins. In humans, SALL mutations associate with congenital disorders such as the Townes-Brocks and Okihiro syndromes. Human and Drosophila SALL proteins are modified by SUMO (small ubiquitin-related modifier), which influences their subnuclear localization. In the present study, we have analysed the transcriptional activity of Drosophila Sall proteins in cultured cells. We show that both Sal and Salr act as transcriptional repressors in Drosophila cells where they repress transcription through an AT-rich sequence. Furthermore, using the UAS/Gal4 heterologous system, Drosophila Sal and Salr repress transcription in human cells. Under our experimental conditions, only in the case of Salr is the repression activity dependent on the HDAC (histone deacetylase) complex. This complex might interact with the C-terminal zinc fingers of Salr. We describe the differential subcellular localizations of Sal and Salr fragments and identify their repression domains. Surprisingly, both repressors also contain transcription activation domains. In addition, under our experimental conditions SUMOylation has differential effects on Sal and Salr repressor activity. Phylogenetic comparison between nematodes, insects and vertebrates identifies conserved peptide sequences that are presumably critical for SALL protein function. PMID- 21689071 TI - Cytochrome P450 metabolites of arachidonic acid are elevated in stroke patients compared with healthy controls. AB - CYP450AAM [arachidonic acid metabolites of the CYP450 (cytochrome P450) enzyme system] have a range of biological functions. CYP450AAM are involved in the pathogenesis of hypertension, renal function and vascular function, yet their role in stroke has not been clarified. We aimed at determining the levels of circulating CYP450 metabolites in patients with acute ischaemic stroke (<96 h) compared with healthy age- and gender-matched controls. This was a retrospective case-controlled study of 44 acute ischaemic stroke patients and 44 matched controls. A subset of acute ischaemic stroke patients was available for follow up. Acute ischaemic stroke patients had elevated plasma CYP450AAM, including 20 HETE (20-hydroxyeicosatetraenoic acid) (1921+/-170 compared with 1108+/-170 pmol/l, P<0.001), EETs (epoxyeicosatrienoic acids) (77.88+/-3.34 compared with 35.35+/-3.34 nmol/l, P<0.0001) and DiHETEs (dihydroxyeicosatetraenoic acids) (92.87+/-4.61 compared with 68.17+/-4.61 nmol/l, P<0.0001), as well as increased plasma F2-isoprostane levels (3754+/-538 compared with 1947+/-538 pmol/l, P<0.02), the latter a marker of oxidative stress, compared with controls. In a subset analysis of the stroke patients, plasma 20-HETE, EETs and F2-isoprostanes were attenuated 30 days after the stroke. Baseline 20-HETE levels were also associated with lesion size and functional indices within the stroke patients. The present study highlights the elevation in CYP450AAM and oxidative stress in acute ischaemic stroke patients. Further investigation of the effect this has on long-term clinical outcome or whether this can be modified by treatment is warranted. PMID- 21689075 TI - Improved ventilation-perfusion matching with increasing abdominal pressure during CO(2) -pneumoperitoneum in pigs. AB - BACKGROUND: CO(2) -pneumoperitoneum (PP) is performed at varying abdominal pressures. We studied in an animal preparation the effect of increasing abdominal pressures on gas exchange during PP. METHODS: Eighteen anaesthetized pigs were studied. Three abdominal pressures (8, 12 and 16 mmHg) were randomly selected in each animal. In six pigs, single-photon emission computed tomography (SPECT) was used for the analysis of V/Q distributions; in another six pigs, multiple inert gas elimination technique (MIGET) was used for assessing V/Q matching. In further six pigs, computed tomography (CT) was performed for the analysis of regional aeration. MIGET, CT and central haemodynamics and pulmonary gas exchange were recorded during anaesthesia and after 60 min on each of the three abdominal pressures. SPECT was performed three times, corresponding to each PP level. RESULTS: Atelectasis, as assessed by CT, increased during PP and in proportion to abdominal pressure [from 9 +/- 2% (mean +/- standard deviation) at 8 mmHg to 15 +/- 2% at 16 mmHg, P<0.05]. SPECT during increasing abdominal CO(2) pressures showed a shift of blood flow towards better ventilated areas. V/Q analysis by MIGET showed no change in shunt during 8 mmHg PP (9 +/- 1.9% compared with baseline 9 +/- 1.2%) but a decrease during 12 mmHg PP (7 +/- 0.9%, P<0.05) and 16 mmHg PP (5 +/- 1%, P<0.01). PaO(2) increased from 39 +/- 10 to 52 +/- 9 kPa (baseline to 16 mmHg PP, P<0.01). Arterial carbon dioxide (PCO(2) ) increased during PP and increased further with increasing abdominal pressures. CONCLUSION: With increasing abdominal pressure during PP perfusion was redistributed more than ventilation away from dorsal, collapsed lung regions. This resulted in a better V/Q match. A possible mechanism is enhanced hypoxic pulmonary vasoconstriction mediated by increasing PCO(2) . PMID- 21689072 TI - MicroRNA regulation of expression of the cystic fibrosis transmembrane conductance regulator gene. AB - The CFTR (cystic fibrosis transmembrane conductance regulator) gene shows a complex temporal and spatial pattern of expression that is controlled by multiple cis-acting elements interacting with the basal promoter. Although significant progress has been made towards understanding these genomic elements, there have been no reports of post-transcriptional regulation of CFTR by miRNAs (microRNAs). In the present study, we identify two miRNAs, hsa-miR-145 and hsa-miR-494, which regulate CFTR expression by directly targeting discrete sites in the CFTR 3' UTR (untranslated region). We show that at least 12 miRNAs are capable of repressing endogenous CFTR mRNA expression in the Caco-2 cell line. Ten of these also inhibit expression of a reporter construct containing the CFTR 3' UTR in one or more cell lines, and five repress endogenous CFTR protein expression in Caco-2 cells. Moreover, at least three are expressed in primary human airway epithelial cells, where CFTR expression is maintained at low levels in comparison with intestinal cell lines. Three of the miRNAs that target CFTR, hsa-miR-384, hsa-miR 494 and hsa-miR-1246, also inhibit expression of a reporter carrying the Na(+) K(+)-Cl(-) co-transporter SLC12A2 [solute carrier family 12 (Na(+)-K(+)-Cl(-) transporters), member 2] 3' UTR, suggesting that these miRNAs may play a more general role in regulating chloride transport in epithelial cells. PMID- 21689076 TI - Determining authorship in multicenter trials: a systematic review. AB - The practical and ethical issues in determining authorship in multicenter trials raise significant and unique challenges. This systematic review examines methods of assigning authorship in multicenter clinical trials. A literature search (October 2009) was conducted to identify articles with the terms 'authorship' and 'clinical trial,' 'multicenter' or 'multicentre.' Abstracts were reviewed for potential relevance and the complete manuscript was obtained where indicated. Additional articles were identified by a review of the reference list from sourced articles. Methods for determining authorship were reviewed in terms of practicality, fairness and the time course for decision-making. Eight methods for determining authorship were identified: four used a scoring system, two articles contained guidelines with reference to scoring systems and two articles outlined general guidelines. All methods attempted to provide a fair and practical approach and appeared to achieve this to varying degrees. No one method was applicable across all multicenter trials. The authors propose a guide for determining authorship based on the methods identified and the number of collaborators and anticipated publications. For smaller collaborative groups (e.g. <10 persons), byline inclusion of all authors based on relative contributions is recommended. For larger collaborations (e.g. >= 10 persons), authorship guidelines should be explicit from the outset of the trial with consideration of relevant scoring systems. PMID- 21689077 TI - A note on type II error under random effects misspecification in generalized linear mixed models. AB - Litiere, Alonso, and Molenberghs (2007, Biometrics, 63, 1038-1044) presented the results of simulation studies that they claimed showed that misspecification of the shape of the random effects distribution can produce marked increases in Type II error (decreases in power) of tests based on fits of generalized linear mixed models. However, the article contains a logical fallacy that invalidates this claim. We present logically correct simulation studies that demonstrate little increase in Type II error, consistent with the earlier work that shows little effect due to misspecification. PMID- 21689079 TI - Inference for causal interactions for continuous exposures under dichotomization. AB - Dichotomization of continuous exposure variables is a common practice in medical and epidemiological research. The practice has been cautioned against on the grounds of efficiency and bias. Here we consider the consequences of dichotomization of a continuous covariate for the study of interactions. We show that when a continuous exposure has been dichotomized certain inferences concerning causal interactions can be drawn with regard to the original continuous exposure scale. Within the context of interaction analyses, dichotomization and the use of the results in this article can furthermore help prevent incorrect conclusions about the presence of interactions that result simply from erroneous modeling of the exposure variables. By considering different dichotomization points one can gain considerable insight concerning the presence of causal interaction between exposures at different levels. The results in this article are applied to a study of the interactive effects between smoking and arsenic exposure from well water in producing skin lesions. PMID- 21689080 TI - Modeling adverse birth outcomes via confirmatory factor quantile regression. AB - We describe a Bayesian quantile regression model that uses a confirmatory factor structure for part of the design matrix. This model is appropriate when the covariates are indicators of scientifically determined latent factors, and it is these latent factors that analysts seek to include as predictors in the quantile regression. We apply the model to a study of birth weights in which the effects of latent variables representing psychosocial health and actual tobacco usage on the lower quantiles of the response distribution are of interest. The models can be fit using an R package called factorQR. PMID- 21689081 TI - On estimation in relative survival. AB - Estimation of relative survival has become the first and the most basic step when reporting cancer survival statistics. Standard estimators are in routine use by all cancer registries. However, it has been recently noted that these estimators do not provide information on cancer mortality that is independent of the national general population mortality. Thus they are not suitable for comparison between countries. Furthermore, the commonly used interpretation of the relative survival curve is vague and misleading. The present article attempts to remedy these basic problems. The population quantities of the traditional estimators are carefully described and their interpretation discussed. We then propose a new estimator of net survival probability that enables the desired comparability between countries. The new estimator requires no modeling and is accompanied with a straightforward variance estimate. The methods are described on real as well as simulated data. PMID- 21689082 TI - A Bayesian adjustment for multiplicative measurement errors for a calibration problem with application to a stem cell study. AB - We develop a Bayesian approach to a calibration problem with one interested covariate subject to multiplicative measurement errors. Our work is motivated by a stem cell study with the objective of establishing the recommended minimum doses for stem cell engraftment after a blood transplant. When determining a safe stem cell dose based on the prefreeze samples, the postcryopreservation recovery rate enters in the model as a multiplicative measurement error term, as shown in the model. We examine the impact of ignoring measurement errors in terms of asymptotic bias in the regression coefficient. According to the general structure of data available in practice, we propose a two-stage Bayesian method to perform model estimation via R2WinBUGS (Sturtz, Ligges, and Gelman, 2005, Journal of Statistical Software 12, 1-16). We illustrate this method by the aforementioned motivating example. The results of this study allow routine peripheral blood stem cell processing laboratories to establish recommended minimum stem cell doses for transplant and develop a systematic approach for further deciding whether the postthaw analysis is warranted. PMID- 21689083 TI - Multikinase inhibitor sorafenib exerts cytocidal efficacy against Non-Hodgkin lymphomas associated with inhibition of MAPK14 and AKT phosphorylation. AB - Intracellular signal transduction by kinase-mediated phosphorylation is essential for the survival and growth of lymphoma cells. This study analysed the multikinase inhibitor sorafenib for its cytotoxic activity against lymphoma cells. We found that sorafenib reduced cell viability at low micromolar concentrations in a time-dependent manner in cell lines and primary cell suspensions representing major types of aggressive B- and T-cell lymphomas. In cells surviving short term exposure, proliferative arrest occurred leading to complete loss of in vitro clonogenicity. Previously described sorafenib targets within the RAF kinase family were found to be expressed and phosphorylated in all cell lines, and sorafenib perturbed the activation of classical RAF/MEK/ERK pathway targets. However, using a global phoshoprotein array, the most consistent downstream effect of sorafenib in NHL cells was the inhibition of mitogen activated protein kinase 14 (MAPK14) and panAKT phosphorylation. In conclusion, sorafenib has significant in vitro efficacy against aggressive B- and T-cell lymphoma cells, associated with inhibition of MAPK14 and panAKT. PMID- 21689084 TI - Comparative proteomics reveals deficiency of SLC9A1 (sodium/hydrogen exchanger NHE1) in beta-adducin null red cells. AB - Spherocytosis is one of the most common inherited disorders, yet presents with a wide range of clinical severity. While several genes have been found mutated in patients with spherocytosis, the molecular basis for the variability in severity of haemolytic anaemia is not entirely understood. To identify candidate proteins involved in haemolytic anaemia pathophysiology, we utilized a label-free comparative proteomic approach to detect differences in red blood cells (RBCs) from normal and beta-adducin (Add2) knock-out mice. We detected seven proteins that were decreased and 48 proteins that were increased in beta-adducin null RBC ghosts. Since haemolytic anaemias are characterized by reticulocytosis, we compared reticulocyte-enriched samples from phenylhydrazine-treated mice with mature RBCs from untreated mice. Among the 48 proteins increased in Add2 knockout RBCs, only 11 were also increased in reticulocytes. Of the proteins decreased in Add2 knockout RBCs, alpha-adducin showed the greatest intensity difference, followed by SLC9A1, the sodium-hydrogen exchanger previously termed NHE1. We verified these mass spectrometry results by immunoblot. This is the first example of SLC9A1deficiency in haemolytic anaemia and suggests new insights into the mechanisms leading to fragile RBCs. PMID- 21689085 TI - Tyrosine kinase inhibitor insensitivity of non-cycling CD34+ human acute myeloid leukaemia cells with FMS-like tyrosine kinase 3 mutations. AB - The efficacy of tyrosine kinase (TK) inhibitors on non-cycling acute myeloid leukaemia (AML) cells, previously shown to have potent tumourigenic potential, is unknown. This pilot study describes the first attempt to characterize non-cycling cells from a small series of human FMS-like tyrosine kinase 3 (FLT3) mutation positive samples. CD34+ AML cells from patients with FLT3 mutation positive AML were cultured on murine stroma. In expansion cultures, non-cycling cells were found to retain CD34+ expression in contrast to dividing cells. Leukaemic gene rearrangements could be detected in non-cycling cells, indicating their leukaemic origin. Significantly, the FLT3-internal tandem duplication (ITD) mutation was found in the non-cycling fraction of four out of five cases. Exposure to the FLT3 directed inhibitor TKI258 clearly inhibited the growth of AML CD34+ cells in short-term cultures and colony-forming unit assays. Crucially, non-cycling cells were not eradicated, with the exception of one case, which exhibited exquisite sensitivity to the compound. Moreover, in longer-term cultures, TKI258-treated non-cycling cells showed no growth impairment compared to treatment-naive non cycling cells. These findings suggest that non-cycling cells in AML may constitute a disease reservoir that is resistant to TK inhibition. Further studies with a larger sample size and other inhibitors are warranted. PMID- 21689086 TI - Cardiac iron overload in transfusion-dependent patients with myelodysplastic syndromes. AB - Transfusion-dependent myelodysplastic (MDS) patients are prone to iron overload. We evaluated 43 transfused MDS patients with T2* magnetic resonance imaging scans. 81% had liver and 16.8% cardiac iron overload. Liver R2* (1000/T2*), but not cardiac R2*, was correlated with number of units transfused (r=0.72, P<0.0001) and ferritin (r=0.53, P<0.0001). The area under the curve of a time ferritin plot was found to be much greater in patients with cardiac iron loading (median 53.7x10(5) Megaunits vs. 12.2x10(5) Megaunits, P=0.002). HFE, HFE2, HAMP or SLC40A1 genotypes were not predictors of iron overload in these patients. PMID- 21689087 TI - Early UK experience in the use of clofarabine in the treatment of relapsed and refractory paediatric acute lymphoblastic leukaemia. AB - Clofarabine is a second-generation purine nucleoside analogue, which has shown promising activity in relapsed and refractory paediatric acute lymphoblastic leukaemia (ALL). This report summarizes the early United Kingdom experience of clofarabine for the treatment of paediatric ALL in 23 patients, outside of the context of a clinical trial. Our results demonstrated that clofarabine-based chemotherapy regimes were effective and well-tolerated in this heavily pre treated group, with an overall response rate of 67% when used in combination regimes. Responses were seen in both B and T cell disease and in patients with adverse cytogenetics. PMID- 21689088 TI - Bendamustine in combination with thalidomide and dexamethasone is an effective therapy for myeloma patients with end stage renal disease. PMID- 21689090 TI - Jordan's anomaly in a case of Chanarin-Dorfman syndrome. PMID- 21689089 TI - NT-pro brain natriuretic peptide levels and the risk of death in the cooperative study of sickle cell disease. AB - Epidemiological studies support a hypothesis that pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) that is associated with a high risk of death and evolves as a complication of haemolytic anaemia. This fundamental hypothesis has been recently challenged and remains controversial. In order to further test this hypothesis in a large and independent cohort of SCD patients we obtained plasma samples from the Cooperative Study of Sickle Cell Disease (CSSCD) for analysis of a biomarker, N-terminal-pro brain natriuretic peptide (NT-proBNP), which is elevated in the setting of pulmonary arterial and venous hypertension. A NT-pro-BNP value previously identified to predict PH in adults with SCD was used to determine the association between the risk of mortality in 758 CSSCD participants (428 children and 330 adults). An abnormally high NT-proBNP level >=160ng/l was present in 27.6% of adult SCD patients. High levels were associated with markers of haemolytic anaemia, such as low haemoglobin level (P<0.001), high lactate dehydrogenase (P<0.001), and high total bilirubin levels (P<0.007). A NT-proBNP level >=160ng/l was an independent predictor of mortality (RR 6.24, 95% CI 2.9-13.3, P<0.0001). These findings provide further support for an association between haemolytic anaemia and cardiovascular complications in this patient population. PMID- 21689091 TI - Chromosome abnormalities in advanced stage T-cell lymphoblastic lymphoma of children and adolescents: a report from Japanese Paediatric Leukaemia/Lymphoma Study Group (JPLSG) and review of the literature. AB - T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic lymphoma (T LBL) are combined into one category as T lymphoblastic leukaemia/lymphoma in the current World Health Organization (WHO) classification. However, there is still ongoing discussion on whether T-ALL and T-LBL are two separate entities or represent two variant phenotypes of the same disease. Cytogenetic analysis has been used to identify the molecular background of haematological malignancies. To compare the distribution of chromosomal abnormalities of T-ALL and T-LBL, large series of cytogenetic data are required, but are absent in T-LBL in contrast to the abundant data in T-ALL. Among 111 T-LBL cases in our clinical trial, we obtained complete cytogenetic data from 56 patients. The comparison between our cytogenetic findings and those from three published T-LBL studies revealed no significant difference. However, meta-analysis showed that translocations involving chromosome region 9q34 were significantly more common in T-LBL than in T-ALL. In particular, four out of the 92 T-LBL cases, but none of the 523 paediatric T-ALL cases, showed translocation t(9;17)(q34;q22-23) (P=0.0004). Further studies are needed for the possible linkage between abnormal expression of genes located at 9q34 and/or 17q22-23 and the unique 'lymphoma phenotype' of T LBL. PMID- 21689092 TI - Targeting PIM kinase activity significantly augments the efficacy of cytarabine. PMID- 21689093 TI - Comment on de Brantes, Rastogi, and Painter: reducing avoidable complications in patients with chronic diseases: the Prometheus approach. PMID- 21689094 TI - Comparative Logic Modeling for policy analysis: the case of HIV testing policy change at the Department of Veterans Affairs. AB - OBJECTIVE: Logic models have been used to evaluate policy programs, plan projects, and allocate resources. Logic Modeling for policy analysis has been used rarely in health services research but can be helpful in evaluating the content and rationale of health policies. Comparative Logic Modeling is used here on human immunodeficiency virus (HIV) policy statements from the Department of Veterans Affairs (VA) and Centers for Disease Control and Prevention (CDC). We created visual representations of proposed HIV screening policy components in order to evaluate their structural logic and research-based justifications. DATA SOURCES AND STUDY DESIGN: We performed content analysis of VA and CDC HIV testing policy documents in a retrospective case study. DATA COLLECTION: Using comparative Logic Modeling, we examined the content and primary sources of policy statements by the VA and CDC. We then quantified evidence-based causal inferences within each statement. PRINCIPAL FINDINGS: VA HIV testing policy structure largely replicated that of the CDC guidelines. Despite similar design choices, chosen research citations did not overlap. The agencies used evidence to emphasize different components of the policies. CONCLUSION: Comparative Logic Modeling can be used by health services researchers and policy analysts more generally to evaluate structural differences in health policies and to analyze research-based rationales used by policy makers. PMID- 21689095 TI - Medicaid Personal Care Services and caregivers' reports of children's health: the dynamics of a relationship. AB - OBJECTIVE: To investigate the relationship between Medicaid Personal Care Services (PCS) and caregivers' reports of activity (activities of daily living [ADL]) limitations for children with chronic health problems. DATA SOURCES/STUDY SETTING: Primary data collected in 2008 and 2009. A state Medicaid program was the setting. The focus was children receiving Medicaid PCS. DATA COLLECTION: Medicaid case managers assessed children to determine their need for PCS, using information provided by the child or informal caregivers. Two thousand seven hundred assessments were provided to researchers directly from case managers. PRINCIPAL FINDINGS: Medical conditions and impairments explained 58 percent of the variance in the child's activity limitations. Activity limitations and problem behaviors explained 28 percent of the variance in PCS hours authorized. Which case manager completed the assessment also played a substantial role in determining hours of care. CONCLUSIONS: Caregivers' reports of the severity of a child's activity limitations effectively summarize the effects of conditions and impairments on the child's ADL performance and have a significant impact on the level of services provided. Assessors often respond differently to children's characteristics and circumstances as they move from assessment to decisions concerning care provision. Our results imply that the provision of appropriate services may be enhanced when both case managers and caregivers play an active role in decisions concerning care provision. PMID- 21689096 TI - Comparing patient outcomes across payer types: implications for using hospital discharge records to assess quality. AB - OBJECTIVE: To explain observed differences in patient outcomes across payer types using hospital discharge records. Specifically, we address two mechanisms: hospital-payer matching versus unobserved patient heterogeneity. DATA SOURCE: Florida's hospital discharge records (1996-2000) of major surgery patients with private health insurance between the ages of 18 and 65, Health Maintenance Organization (HMO) market penetration data, hospital systems data, and the Area Resource File. STUDY DESIGN: The dependent variable is occurrence of one or more in-hospital complications as identified by the Complication Screening Program. The key independent variable is patients' primary-payer type (HMO, Preferred Provider Organization, and fee-for-service). We estimate five different logistic regression models, each representing a different assumption about the underlying factors that confound the causal relationship between the payer type and the likelihood of experiencing complications. PRINCIPAL FINDING: We find that the observed differences in complication rates across payer types are largely driven by unobserved differences in patient health, even after adjusting for case mix using available data elements in the discharge records. CONCLUSION: Because of the limitations inherent to hospital discharge records, making quality comparisons in terms of patient outcomes is challenging. As such, any efforts to assess quality in such a manner must be carried out cautiously. PMID- 21689097 TI - Does medication adherence following a copayment increase differ by disease burden? AB - OBJECTIVES: To compare changes in medication adherence between patients with high or low-comorbidity burden after a copayment increase. METHODS: We conducted a retrospective observational study at four Veterans Affairs (VA) medical centers by comparing veterans with hypertension or diabetes required to pay copayments with propensity score-matched veterans exempt from copayments. Disease cohorts were stratified by Diagnostic Cost Group risk score: low- (<1) and high comorbidity (>1) burden. Medication adherence from February 2001 to December 2003, constructed from VA pharmacy claims data based on the ReComp algorithm, were assessed using generalized estimating equations. RESULTS: Veterans with lower comorbidity were more responsive to a U.S.$5 copayment increase than higher comorbidity veterans. In the lower comorbidity groups, veterans with diabetes had a greater reduction in adherence than veterans with hypertension. Adherence trends were similar for copayment-exempt and nonexempt veterans with higher comorbidity. CONCLUSION: Medication copayment increases are associated with different impacts for low- and high-risk patients. High-risk patients incur greater out-of-pocket costs from continued adherence, while low-risk patients put themselves at increased risk for adverse health events due to greater nonadherence. PMID- 21689098 TI - "All the money in the world ..." patient perspectives regarding the influence of financial incentives. AB - OBJECTIVE: To analyze patient perspectives of the use of financial incentives in a hypertension intervention. Study Setting. Twelve Veterans Affairs primary care clinics over a 9-month period. STUDY DESIGN: Qualitative semistructured interviews conducted with 54 hypertensive veterans participating in an intervention to promote guideline-consistent therapy. Intervention components included an intervention letter requesting patients talk with their providers, an offer of U.S.$20 to bring in the letter to their provider, and a health educator phone call. DATA COLLECTION METHODS: Semistructured interviews were conducted. Transcripts were coded for thematic content. The financial incentive theme was then subcoded for more detailed analysis. PRINCIPLE FINDINGS: Most participants (n=48; 88.9 percent) stated the incentive had (or would have) no effect on their decision to initiate a discussion with their provider. Some participants articulated reservations about the effectiveness and/or appropriateness of financial incentives in health care decisions; however, a few expressed the opinion that there may be some potential benefits to the use of financial incentives if they encourage patients to be active in their health care. CONCLUSION: The findings of this study raise questions about the appropriateness and unintended consequences of employing patient-directed financial incentives in health care settings. PMID- 21689099 TI - Analysis of cervical ribs in a series of human fetuses. AB - In humans, an increasing body of evidence has linked the frequency of cervical ribs to stillbirths, other malformations and early childhood cancers. However, the frequency of cervical ribs in a putatively healthy fetal population is not sufficiently known to assess the actual medical risks of these prenatal findings. We therefore analyzed the presence of skeletal anomalies in a series of 199 electively aborted fetuses, which were whole-mount stained with alizarin red specific for skeletal tissues. Results show that approximately 40% of the fetuses had cervical ribs, even though external congenital abnormalities such as craniofacial and limb defects were absent. A literature overview indicates that the observed frequency of cervical ribs is comparable to results previously obtained for deceased fetuses with no or minor congenital anomalies, and higher than expected for healthy fetuses. This unexpected result can probably in part be explained by a higher detection rate of small cervical ribs when using alizarin red staining instead of radiographs. Additionally, studies in the literature suggest that the size of a cervical rib may indicate the severity of abnormalities, but this possibility requires further research. Anomalies of the axial skeleton are known to be caused by a disturbance of early development, which alters Hox gene expression, but in this study the origin of the stress could not be verified as maternal medical data were not available. The co occurrence of rudimentary or absent 12th ribs in 23.6% of the cases with cervical ribs indicates that in approximately 8% of the fetuses a homeotic shift occurred over a larger part of the vertebral column. This suggests that the expression of multiple Hox genes may have been affected in these fetuses. Together, the high incidence of cervical ribs and also their co-occurrence with rudimentary or absent 12th ribs suggests that there may have been a disturbance of early development such that the studied fetuses are probably not informative about the general population. Future studies determining the frequency of cervical ribs in a more healthy fetal population are therefore needed to evaluate their potential as an indicator of medical risks. PMID- 21689101 TI - Effect of montmorillonite organic modification on microstructures and ultraviolet aging properties of bitumen. AB - The effect of montmorillonite (MMT) organic modification on microstructures and ultraviolet (UV) aging properties of bitumen was investigated. The microstructures of MMT modified bitumen were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and atomic force microscopy (AFM), respectively. The binders were aged by UV radiation. The UV aging properties of MMT modified bitumen was studied by determining physical properties and AFM analysis. XRD and FTIR analyses show that the sodium montmorillonite (Na(+) -MMT) modified bitumen forms a phase-separated structure, whereas the organo-montmorillonite (OMMT) modified bitumen forms an intercalated structure. After Na(+) -MMT modification, the contrast between the matrix and the dispersed domains is inverted according to AFM analysis. However, this contrast inversion is prevented with the introduction of OMMT due to the good compatibility between the OMMT and the bitumen. As a result of UV aging, both viscosity aging index and softening point increment of OMMT modified bitumen are lower than that of the unmodified bitumen and Na(+) -MMT modified bitumen. Furthermore, the association interactions and single-phase trend in OMMT modified bitumen are further prevented in comparison with Na(+) -MMT modified bitumen during UV aging, indicating the good aging resistance of OMMT modified bitumen after organic modification of MMT. PMID- 21689102 TI - Going the wrong road: Fyn and targeting of amyloid precursor protein to lipid rafts. PMID- 21689100 TI - Soft-tissue anatomy of the primates: phylogenetic analyses based on the muscles of the head, neck, pectoral region and upper limb, with notes on the evolution of these muscles. AB - Apart from molecular data, nearly all the evidence used to study primate relationships comes from hard tissues. Here, we provide details of the first parsimony and Bayesian cladistic analyses of the order Primates based exclusively on muscle data. The most parsimonious tree obtained from the cladistic analysis of 166 characters taken from the head, neck, pectoral and upper limb musculature is fully congruent with the most recent evolutionary molecular tree of Primates. That is, this tree recovers not only the relationships among the major groups of primates, i.e. Strepsirrhini {Tarsiiformes [Platyrrhini (Cercopithecidae, Hominoidea)]}, but it also recovers the relationships within each of these inclusive groups. Of the 301 character state changes occurring in this tree, ca. 30% are non-homoplasic evolutionary transitions; within the 220 changes that are unambiguously optimized in the tree, ca. 15% are reversions. The trees obtained by using characters derived from the muscles of the head and neck are more similar to the most recent evolutionary molecular tree than are the trees obtained by using characters derived from the pectoral and upper limb muscles. It was recently argued that since the Pan/Homo split, chimpanzees accumulated more phenotypic adaptations than humans, but our results indicate that modern humans accumulated more muscle character state changes than chimpanzees, and that both these taxa accumulated more changes than gorillas. This overview of the evolution of the primate head, neck, pectoral and upper limb musculature suggests that the only muscle groups for which modern humans have more muscles than most other extant primates are the muscles of the face, larynx and forearm. PMID- 21689103 TI - Enhancing survival of photoreceptor cells in vivo using the synthetic progestin Norgestrel. AB - Retinal degenerations such as Retinitis Pigmentosa remain difficult to treat given the diverse array of genes responsible for their aetiology. Rather than concentrate on specific genes, our focus is on identifying therapeutic avenues for the treatment of retinal disease that target general survival mechanisms or pathways. Norgestrel is a synthetic progestin commonly used in hormonal contraception. Here, we report a novel anti-apoptotic role for Norgestrel in diseased mouse retinas in vivo. Dosing with Norgestrel protects photoreceptor cells from undergoing apoptosis in two distinct models of retinal degeneration; the light damage model and the Pde6b(rd10) model. Photoreceptor rescue was assessed by analysis of cell number, structural integrity and function. Improvements in cell survival of up to 70% were achieved in both disease models, indicating that apoptosis had been halted or at least delayed. A speculative mechanism of action for Norgestrel involves activation of survival pathways in the retina. Indeed, Norgestrel increases the expression of basic fibroblast growth factor which is known to both promote cell survival and inhibit apoptosis. In summary, our results demonstrate significant protection of photoreceptor cells which may be attributed to Norgestrel mediated activation of endogenous survival pathways within the retina. PMID- 21689104 TI - Acetyl-L-carnitine ameliorates spatial memory deficits induced by inhibition of phosphoinositol-3 kinase and protein kinase C. AB - Glycogen synthase kinase-3beta (GSK-3beta) plays a crucial role in memory deficits and tau hyperphosphorylation as seen in Alzheimer's disease, the most common dementia in the aged population. We reported that ventricular co-injection of wortmannin and GF-109203X (WT/GFX) can induce tau hyperphosophorylation and memory impairment of rats through activation of GSK-3 [Liu S. J., Zhang A. H., Li H. L., Wang Q., Deng H. M., Netzer W. J., Xu H. X. and Wang J. Z. (2003) J. Neurochem. 87, 1333]. In the present study, we found that feeding the rats with Acetyl-L-Carnitine (ALCAR, 50 mg/day.rat, per os) for 2 weeks rescued the WT/GFX induced spatial memory retention impairment of the rats by antagonizing GSK-3beta activation independent of Akt, PKCzeta and Erk1/2. We also found that ALCAR arrested microtubule-associated protein tau hyperphosphorylation at multiple Alzheimer's disease sites in vivo and in vitro. Moreover, ALCAR enhanced the expression of several memory-associated proteins including c-Fos, synapsin I in rat hippocampus. These results suggest that ALCAR could ameliorate WT/GFX-induced spatial memory deficits through inhibition tau hyperphosphorylation and modulation of memory-associated proteins. PMID- 21689105 TI - Curcumin prevents corticosterone-induced neurotoxicity and abnormalities of neuroplasticity via 5-HT receptor pathway. AB - Curcumin, a major active component of Curcuma longa, possesses antioxidant and neuroprotective activities. The present study explores the mechanisms underlying the neuroprotective effect of curcumin against corticosterone and its relation to 5-hydroxy tryptamine (5-HT) receptors. Exposure of cortical neurons to corticosterone results in decreased mRNA levels for three 5-HT receptor subtypes, 5-HT(1A), 5-HT(2A) and 5-HT(4), but 5-HT(1B,) 5-HT(2B), 5-HT(2C), 5-HT(6) and 5 HT(7) receptors remain unchanged. Pre-treatment with curcumin reversed this effect on mRNA for the 5-HT(1A) and 5-HT(4) receptors, but not for the 5-HT(2A) receptor. Moreover, curcumin exerted a neuroprotective effect against corticosterone-induced neuronal death. This observed effect of curcumin was partially blocked by either 5-HT(1A) receptor antagonist p-MPPI or 5-HT(4) receptor antagonist RS 39604 alone; whereas, the simultaneous application of both antagonists completely reversed the effect. Curcumin was also found to regulate corticosterone-induced morphological changes such as increases in soma size, dendritic branching and dendritic spine density, as well as elevate synaptophysin expression in cortical neurons. p-MPPI and RS 39604 reversed the effect of curcumin-induced change in neuronal morphology and synaptophysin expression of corticosterone-treated neurons. In addition, an increase in cyclic adenosine monophosphate (cAMP) level was observed after curcumin treatment, which was further prevented by RS 39604, but not by p-MPPI. However, curcumin-induced elevation in protein kinase A activity and phosphorylation of cAMP response element-binding protein levels were inhibited by both p-MPPI and RS 39604. These findings suggest that the neuroprotection and modulation of neuroplasticity exhibited by curcumin might be mediated, at least in part, via the 5-HT receptor cAMP-PKA-CREB signal pathway. PMID- 21689106 TI - SKF-83566, a D1-dopamine receptor antagonist, inhibits the dopamine transporter. AB - Dopamine (DA) is an important transmitter in both motor and limbic pathways. We sought to investigate the role of D(1)-receptor activation in axonal DA release regulation in dorsal striatum using a D(1)-receptor antagonist, SKF-83566. Evoked DA release was monitored in rat striatal slices using fast-scan cyclic voltammetry. SKF-83566 caused a concentration-dependent increase in peak single pulse evoked extracellular DA concentration, with a maximum increase of ~ 65% in 5 MUM SKF-83566. This was accompanied by a concentration-dependent increase in extracellular DA concentration clearance time. Both effects were occluded by nomifensine (1 MUM), a dopamine transporter (DAT) inhibitor, suggesting that SKF 83566 acted via the DAT. We tested this by examining [(3)H]DA uptake into LLc-PK cells expressing rat DAT, and confirmed that SKF-83566 is a competitive DAT inhibitor with an IC(50) of 5.7 MUM. Binding studies with [(3)H]CFT, a cocaine analog, showed even more potent action of SKF-83566 at the DAT cocaine binding site (IC(50) = 0.51 MUM). Thus, data obtained using SKF-83566 as a D(1) DA receptor antagonist may be confounded by concurrent DAT inhibition. More positively, however, SKF-83566 might be a candidate to attenuate cocaine effects in vivo because of the greater potency of this drug at the cocaine versus DA binding site of the DAT. PMID- 21689108 TI - Amyloid-beta levels are significantly reduced and spatial memory defects are rescued in a novel neuroserpin-deficient Alzheimer's disease transgenic mouse model. AB - Amyloid-beta (Abeta) plaques are a hallmark of Alzheimer's disease. Several proteases including plasmin are thought to promote proteolytic cleavage and clearance of Abeta from brain. The activity of both plasmin and tissue plasminogen activator are reduced in Alzheimer's disease brain, while the tissue plasminogen activator inhibitor neuroserpin is up-regulated. Here, the relationship of tissue plasminogen activator and neuroserpin to Abeta levels is explored in mouse models. Abeta(1-42) peptide injected into the frontal cortex of tissue plasminogen activator knockout mice is slow to disappear compared to wildtype mice, whereas neuroserpin knockout mice show a rapid clearance of Abeta(1-42). The relationship of neuroserpin and tissue plasminogen activator to Abeta plaque formation was studied further by knocking-out neuroserpin in the human amyloid precursor protein-J20 transgenic mouse. Compared to the J20 transgenic mouse, the neuroserpin-deficient J20-transgenic mice have a dramatic reduction of Abeta peptides, fewer and smaller plaques, and more active tissue plasminogen activator associated with plaques. Furthermore, neuroserpin-deficient J20-transgenic mice have near normal performances in the Morris water maze, in contrast to the spatial memory defects seen in J20-transgenic mice. These results support the concept that neuroserpin inhibition of tissue plasminogen activator plays an important role both in the accumulation of brain amyloid plaques and loss of cognitive abilities. PMID- 21689107 TI - Subsecond regulation of striatal dopamine release by pre-synaptic KATP channels. AB - ATP-sensitive K(+) (K(ATP)) channels are composed of pore-forming subunits, typically Kir6.2 in neurons, and regulatory sulfonylurea receptor subunits. In dorsal striatum, activity-dependent H(2)O(2) produced from glutamate receptor activation inhibits dopamine release via K(ATP) channels. Sources of modulatory H(2)O(2) include striatal medium spiny neurons, but not dopaminergic axons. Using fast-scan cyclic voltammetry in guinea-pig striatal slices and immunohistochemistry, we determined the time window for H(2)O(2)/K(ATP)-channel mediated inhibition and assessed whether modulatory K(ATP) channels are on dopaminergic axons. Comparison of paired-pulse suppression of dopamine release in the absence and presence of glibenclamide, a K(ATP)-channel blocker, or mercaptosuccinate, a glutathione peroxidase inhibitor that enhances endogenous H(2)O(2) levels, revealed a time window for inhibition of 500-1000 ms after stimulation. Immunohistochemistry demonstrated localization of Kir6.2 K(ATP) channel subunits on dopaminergic axons. Consistent with the presence of functional K(ATP) channels on dopaminergic axons, K(ATP)-channel openers, diazoxide and cromakalim, suppressed single-pulse evoked dopamine release. Although cholinergic interneurons that tonically regulate dopamine release also express K(ATP) channels, diazoxide did not induce the enhanced frequency responsiveness of dopamine release seen with nicotinic-receptor blockade. Together, these studies reveal subsecond regulation of striatal dopamine release by endogenous H(2)O(2) acting at K(ATP) channels on dopaminergic axons, including a role in paired-pulse suppression. PMID- 21689109 TI - Efficacy of oral hyposensitization in allergic contact dermatitis caused by nickel. AB - BACKGROUND: Nickel contact allergy remains common in Western countries, and the dermatitis may require prolonged treatment. The development of new strategies aimed at improving the quality of life of affected individuals is needed. OBJECTIVES: To investigate the efficacy of oral hyposensitization in nickel allergic individuals and how this affects in vitro T cell responsiveness to the metal. METHODS: Twenty-eight nickel-allergic patients received a daily dose of 50 ug of elemental nickel (given as NiSO(4) .6H(2) O) in cellulose capsules for 3 months. Severity of clinical manifestations, in vivo nickel responsiveness and in vitro T cell responses to the metal were assessed after 1 and 3 months. RESULTS: Twenty-six patients finished the study. In these patients, oral hyposensitization ameliorated clinical manifestations despite continued nickel exposures, and increased the threshold of skin responsiveness to nickel. The 12 enrolled patients in the immunological study showed decreased in vitro T lymphocyte responsiveness to the metal, in terms of both cell proliferation and cytokine release. In the 1-year follow-up, 50% of the patients experienced relapses of the clinical manifestations at sites of topical exposure to nickel. CONCLUSIONS: Our study suggested therapeutic efficacy of oral hyposensitization in allergic individuals. Placebo-controlled studies are required to confirm the results and determine the optimal therapeutic regimen for prolonged beneficial effects. PMID- 21689110 TI - Value of patch tests in clindamycin-related drug eruptions. AB - BACKGROUND: Patch tests help to confirm the aetiology of the cutaneous adverse drug reactions involving delayed hypersensitivity mechanisms, but the results vary with the pattern of skin reaction and the culprit drug. OBJECTIVES: To analyse the results of patch tests in patients with cutaneous adverse drug reactions imputable to clindamycin and assess their contribution to the diagnosis. PATIENTS AND METHODS: Between 2005 and 2009, we studied patients with delayed cutaneous adverse drug reactions following administration of clindamycin, usually associated with other drugs. After resolution of the cutaneous adverse drug reaction, patch tests were performed with a series of antibiotics, including pure clindamycin 10% in petrolatum. RESULTS: We studied 30 patients (23 females and 7 males) aged 33-86 years (mean 59.97 years) with generalized maculopapular exanthema where clindamycin was among the highly suspected drugs. Two patients had a previous positive involuntary rechallenge. Patch tests with clindamycin were positive in 9 of 30 patients (30%). More than 50 control patients patch tested with clindamycin were negative. DISCUSSION: We considered the positive patch tests results with clindamycin, in the 9 patients with maculopapular exantema, to be specific, versus the negative results observed in the control group. Although the sensitivity is low (30%), they confirmed the responsibility of this antibiotic in cutaneous adverse drug reactions in which, with only chronological criteria, it was not possible to conclude on the culprit drug. PMID- 21689111 TI - A carbon cost-gain model explains the observed patterns of xylem safety and efficiency. AB - Efficient water transport from the soil to the leaves is essential for plant function, while building and maintaining the water transport structure in the xylem require a major proportion of the assimilated carbon of the tree. Xylem transport also faces additional challenges as water in the xylem is under tension and therefore cavitation cannot be completely avoided. We constructed a model that calculates the xylem structure that maximizes carbon-use efficiency while simultaneously taking into account pit structure in increasing the resistance to water transport and constricting the spreading of embolisms. The optimal xylem structure predicted by the model was found to correspond well to the generally observed trends: xylem conduits grew in size from the apex towards the base while simultaneously decreasing in number, and vulnerability to cavitation increased with conduit size. These trends were caused primarily by the axial water potential gradient in the xylem. The pits have to be less porous near the apex where water potential is lower to restrict the spreading of embolisms, while whole-plant carbon-use efficiency demands that conduit size decreases and conduit number increases simultaneously. The model predictions remained qualitatively the same regardless of the exact optimality criterion used for defining carbon-use efficiency. PMID- 21689112 TI - Accelerating yield potential in soybean: potential targets for biotechnological improvement. AB - Soybean (Glycine max Merr.) is the world's most widely grown legume and provides an important source of protein and oil. Global soybean production and yield per hectare increased steadily over the past century with improved agronomy and development of cultivars suited to a wide range of latitudes. In order to meet the needs of a growing world population without unsustainable expansion of the land area devoted to this crop, yield must increase at a faster rate than at present. Here, the historical basis for the yield gains realized in the past 90 years are examined together with potential metabolic targets for achieving further improvements in yield potential. These targets include improving photosynthetic efficiency, optimizing delivery and utilization of carbon, more efficient nitrogen fixation and altering flower initiation and abortion. Optimization of investment in photosynthetic enzymes, bypassing photorespiratory metabolism, engineering the electron transport chain and engineering a faster recovery from the photoprotected state are different strategies to improve photosynthesis in soybean. These potential improvements in photosynthetic carbon gain will need to be matched by increased carbon and nitrogen transport to developing soybean pods and seeds in order to maximize the benefit. Better understanding of control of carbon and nitrogen transport along with improved knowledge of the regulation of flower initiation and abortion will be needed to optimize sink capacity in soybean. Although few single targets are likely to deliver a quantum leap in yields, biotechnological advances in molecular breeding techniques that allow for alteration of the soybean genome and transcriptome promise significant yield gains. PMID- 21689113 TI - Sulphur dioxide evokes a large scale reprogramming of the grape berry transcriptome associated with oxidative signalling and biotic defence responses. AB - The grape and wine industries are heavily reliant on sulphite preservatives. However, the view that sulphites act directly on bacterial and fungal pathogens may be simplistic. Mechanisms of sulphur-enhanced defences are largely unknown; many sulphur-rich compounds enhance plant defences and sulphite can also have oxidative consequences via production of H(2)O(2) or sulphitolysis. To investigate the effects of sulphur dioxide (SO(2) ) on fresh table grapes (Vitis vinifera L. 'Crimson Seedless'), transcriptome analysis was carried out on berries treated with SO(2) under commercial conditions for 21 d. We found a broad perturbation of metabolic processes, consistent with a large-scale stress response. Transcripts encoding putative sulphur-metabolizing enzymes indicated that sulphite was directed towards chelation and conjugation, and away from oxidation to sulphate. The results indicated that redox poise was altered dramatically by SO(2) treatment, evidenced by alterations in plastid and mitochondrial alternative electron transfer pathways, up-regulation of fermentation transcripts and numerous glutathione S-transferases, along with a down-regulation of components involved in redox homeostasis. Features of biotic stress were up-regulated, notably signalling via auxin, ethylene and jasmonates. Taken together, this inventory of transcriptional responses is consistent with a long-term cellular response to oxidative stress, similar to the effects of reactive oxygen species. PMID- 21689114 TI - Neuroculture, active ageing and the 'older brain': problems, promises and prospects. AB - This article explores the characteristics of a newly emergent 'neuroculture' and its relationship to cultures of ageing; in particular, the social meanings associated with 'active ageing' and 'cognitive health' and the discourses and sciences around memory and the 'ageing brain'. The argument proposes a critical perspective on this relationship by looking at the shifting boundaries between standards of normality and abnormality, values of health and illness, practices of therapy and enhancement, and the lines demarcating Third Age (healthy, active and agentic) and Fourth Age (dependency, loss and decline) periods of ageing. Conclusions offer further reflections on the complex questions that arise regarding expectations, hopes and ethics in relation to the promises and perils of a neurocultural future. PMID- 21689115 TI - Effects of a new mild shampoo for preventing hair loss in Asian by a simple hand held phototrichogram technique. AB - This study was conducted to evaluate the effects of a commercially available shampoo in Korean subjects with alopecia using a simple hand-held phototrichogram technique. Forty-four subjects with alopecia were enrolled and forty subjects continued for 16 weeks. In the test group, total hair counts increased significantly at weeks 8 and 16, and the number of shedding hair significantly decreased at week 16. Terminal hair counts significantly increased at week 8. In the control group, hair thickness and the number of vellus hairs significantly decreased at week 16. The number of total hairs significantly increased in the test group than in the control group at weeks 8 and 16. The number of shedding hairs significantly decreased in the test group than in the control group at week 16. Visual assessment using clinical digital images showed that the number of total hairs appeared to increase although there was no statistical significance. In this study, it was found that the test shampoo could prevent hair loss. PMID- 21689116 TI - When small losses do not loom larger than small gains: effects of contextual autonomy support and goal contents on behavioural responses to small losses and small gains. AB - Based on the tenets of self-determination theory, the present studies examined the moderating effects of interpersonal contexts or goal conditions that afforded satisfaction of psychological needs on loss aversion effects. We hypothesized that behavioural responses to small losses would be stronger relative to behavioural responses to small gains under goal conditions or interpersonal contexts that did not support psychological needs. We also expected the effect to be minimized under goal conditions or interpersonal contexts that supported psychological needs. This prediction was supported in Study 1 that induced satisfaction of psychological needs via manipulations of interpersonal context and in Study 2 that instigated satisfaction of psychological needs via manipulations of goal contents. In addition, Studies 1 and 2 demonstrated that psychological needs reduced the classic loss aversion effect by increasing behavioural and affective responses to gains and not because psychological needs altered affective or behavioural responses to losses. Results of the present studies support the conclusion that contextual autonomy support and the distinction between intrinsic and extrinsic goals proposed by self-determination theory define a boundary condition of the loss aversion hypothesis. PMID- 21689117 TI - Measures of current alcohol consumption and problems: two independent twin studies suggest a complex genetic architecture. AB - BACKGROUND: Twin studies demonstrate that measures of alcohol consumption (AC) show evidence of genetic influence, suggesting they may be useful in gene identification efforts. The extent to which these phenotypes will be informative in identifying susceptibility genes involved in alcohol dependence depends on the extent to which genetic influences are shared across measures of AC and alcohol problems. Previous studies have demonstrated that AC reported for the period of heaviest lifetime drinking shows a large degree of genetic overlap with alcohol dependence; however, many studies with genetic material assess current AC. Further, there are many different aspects of AC that can be assessed (e.g., frequency of use, quantity of use, and frequency of intoxication). METHODS: Here, we use data from 2 large, independent, population-based twin samples, FinnTwin 16 and The Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, to examine the extent to which genetic influences are shared across many different measures of AC and alcohol problems. RESULTS: Genetic correlations across current AC measures and alcohol problems were high across both samples. However, both samples suggest a complex genetic architecture with many different genetic factors influencing various aspects of current AC and problems. CONCLUSIONS: These results suggest that careful attention must be paid to the phenotype in efforts to "replicate" genetic effects across samples or combine samples for meta analyses of genetic effects influencing susceptibility to alcohol-related outcomes. PMID- 21689118 TI - Positron emission tomography imaging of mu- and delta-opioid receptor binding in alcohol-dependent and healthy control subjects. AB - BACKGROUND: The endogenous opioid system plays a significant role in alcohol dependence. The goal of the current study was to investigate regional brain mu opioid receptor (MOR) and delta-opioid receptor (DOR) availability in recently abstinent alcohol-dependent and age-matched healthy control men and women with positron emission tomography (PET) imaging. METHODS: Alcohol-dependent subjects completed an inpatient protocol, which included medically supervised withdrawal and PET imaging on day 5 of abstinence. Control subjects completed PET imaging following an overnight stay. PET scans with the MOR-selective ligand [(11)C]carfentanil (CFN) were completed in 25 alcohol-dependent and 30 control subjects. Most of these same subjects (20 alcohol-dependent subjects and 18 controls) also completed PET scans with the DOR-selective ligand [(11)C]methylnaltrindole (MeNTL). RESULTS: Volumes of interest and statistical parametric mapping analyses indicated that alcohol-dependent subjects had significantly higher [(11)C]CFN binding potential (BP(ND) ) than healthy controls in multiple brain regions including the ventral striatum when adjusting for age, gender, and smoking status. There was an inverse relationship between [(11)C]CFN BP(ND) and craving in several brain regions in alcohol-dependent subjects. Groups did not differ in [(11)C]MeNTL BP(ND) ; however, [(11)C]MeNTL BP(ND) in caudate was positively correlated with recent alcohol drinking in alcohol-dependent subjects. CONCLUSIONS: Our observation of higher [(11)C]CFN BP(ND) in alcohol dependent subjects can result from up-regulation of MOR and/or reduction in endogenous opioid peptides following long-term alcohol consumption, dependence, and/or withdrawal. Alternatively, the higher [(11)C]CFN BP(ND) in alcohol dependent subjects may be an etiological difference that predisposed these individuals to alcohol dependence or may have developed as a result of increased exposure to childhood adversity, stress, and other environmental factors known to increase MOR. Although the direction of group differences in [(11)C]MeNTL BP(ND) was similar in many brain regions, differences did not achieve statistical significance, perhaps as a result of our limited sample size. Additional research is needed to further clarify these relationships. The finding that alcohol dependent subjects had higher [(11)C]CFN BP(ND) is consistent with a prominent role of the MOR in alcohol dependence. PMID- 21689119 TI - Promoting behavior change from alcohol use through mobile technology: the future of ecological momentary assessment. AB - BACKGROUND: Interactive and mobile technologies (i.e., smartphones such as Blackberries, iPhones, and palm-top computers) show promise as an efficacious and cost-effective means of communicating health-behavior risks, improving public health outcomes, and accelerating behavior change. The present study was conducted as a "needs assessment" to examine the current available mobile smartphone applications (e.g., apps) that utilize principles of ecological momentary assessment (EMA)-daily self-monitoring or near real-time self assessment of alcohol-use behavior-to promote positive behavior change, alcohol harm reduction, psycho-education about alcohol use, or abstinence from alcohol. METHODS: Data were collected and analyzed from iTunes for Apple iPhone((c)) . An inventory assessed the number of available apps that directly addressed alcohol use and consumption, alcohol treatment, or recovery, and whether these apps incorporated empirically based components of alcohol treatment. RESULTS: Findings showed that few apps addressed alcohol-use behavior change or recovery. Aside from tracking drinking consumption, a minority utilized empirically based components of alcohol treatment. Some apps claimed they could serve as an intervention; however, no empirical evidence was provided. CONCLUSIONS: More studies are needed to examine the efficacy of mobile technology in alcohol intervention studies. The large gap between availability of mobile apps and their use in alcohol treatment programs indicates several important future directions for research. PMID- 21689120 TI - Alcohol in pregnancy: attitudes, knowledge, and information practice among midwives in Denmark 2000 to 2009. AB - BACKGROUND: Most pregnant women in Denmark say they have not talked to their midwives about alcohol in pregnancy, and they have mostly been advised that some alcohol intake is all right. From 1999 to 2007, the Danish National Board of Health advised pregnant women that some alcohol intake was acceptable. Since 2007, the recommendation has been alcohol abstinence. The aim of this study was to describe the attitudes toward, knowledge about, and information practice concerning alcohol drinking in pregnancy among midwives in Denmark in 2000 and 2009 and how their answers related to the 2 different official recommendations at the time. METHODS: In 2000, we invited all midwives in the antenatal care center at Aarhus University Hospital. Ninety-four percent were interviewed about their attitudes toward and beliefs and knowledge about alcohol during pregnancy. Questions were also asked about information on alcohol provided to pregnant women. Identical questions were asked to all midwives (100%) in the antenatal care center in 2009. RESULTS: In 2000, most midwives (69%) considered some alcohol intake in pregnancy acceptable, mostly on a weekly level, and only 28% advised abstinence. Binge drinking, on the other hand, was considered harmful by most. There was considerable inter-person variation in the participants' attitudes and what they recommended to pregnant women. In 2009, substantially more midwives (48%) considered abstinence to be best, and significantly, more midwives (61%) gave this advice to pregnant women. Participants had received information on alcohol mostly in a professional context. Their knowledge about the official recommendations about alcohol was good, but many did not inform about the official recommendation. CONCLUSIONS: The attitudes toward and beliefs and knowledge about drinking in pregnancy among midwives have changed along with a change in official policy. The change was mostly independent of personal characteristics of the midwives, including age, gender, and place of work. PMID- 21689121 TI - Do women differ from men on Alcoholics Anonymous participation and abstinence? A multi-wave analysis of treatment seekers. AB - BACKGROUND: Given the widespread use of Alcoholics Anonymous (AA) and other similar groups in the United States and the increasing membership of women, this study compares women with men on their meeting attendance and AA-prescribed behaviors, factors associated with that AA participation, and tests how these relate to women's and men's abstinence across time. METHODS: All consecutive new admissions (age >= 18) from county-wide public and private treatment programs representing the larger population of treatment seekers were approached to be in the study at treatment entry. Those consenting at baseline (n = 926) were sought for follow-up interviews 1, 3, 5, and 7 years later. Generalized linear models were used to test whether various help-seeking factors were associated with AA participation differentially by gender and, controlling for AA and other confounders, whether women differ from men on abstinence. RESULTS: At each follow up interview, women and men attended AA at similar rates and similarly practiced specific AA behaviors, and they were alike on most factors associated with AA participation and abstention across time including abstinence goal, drink volume, negative consequences, prior treatment, and encouragement to reduce drinking. Relative to men, women with higher drug severity were less likely to participate in AA. Although higher AA participation was a predictor of abstinence for both genders, men were less likely to be abstinent across time. Men were also more likely to reduce their AA participation across time. CONCLUSIONS: These findings add to an emerging literature on how women compare with men on factors related to AA participation and subsequent drinking outcomes across time. Findings have clinical implications for service providers referring clients to such groups. PMID- 21689123 TI - Influence of liver pathology on markers of postmortem brain tissue quality. AB - BACKGROUND: Postmortem brain tissue provides an important resource to investigate various brain disorders, including those resulting from the effects of alcohol abuse. Unlike the traditionally recognized confounders to tissue quality (e.g., coma, hypoxia), our understanding of the effects of liver disease is incomplete. The aim of this study was to determine the effects of liver pathology, and in particular cirrhosis resulting in hepatic encephalopathy (HE), on 2 postmortem brain tissue quality markers, brain pH and RNA integrity. METHODS: We measured tissue quality markers in a cohort of alcohol abuse and control cases collected by the NSW Tissue Resource Centre. Cerebellar tissue was used to evaluate both brain pH and RNA quality (as indicated by the RNA integrity number: RIN). A histological assessment was performed on each case to exclude coexisting pathologies (e.g., cerebrovascular disease, hypoxic encephalopathy, neurodegenerative disease) and to assess the presence or absence of HE. Autopsy reports were reviewed for liver pathology and toxicology. RESULTS: Analysis revealed that cases of alcohol abuse had a lower mean (+/-SD) brain pH, 6.46 (+/ 0.3) as compared with the control mean 6.64 (+/-0.2). The mean RIN for the alcohol abuse group was 6.97 (+/-1.3) and controls 7.66 (+/-0.5). The severity of liver pathology affected both brain pH (p < 0.0001) and RIN (p < 0.0001). The comparison between cirrhotic cases highlighted increased degradation of RNA in cases with cirrhosis resulting in HE (p = 0.0095). A similar effect was seen on brain pH (p = 0.0019). CONCLUSIONS: The results show that the presence of cirrhosis and, more so, HE reduces the pH and RIN of postmortem brain tissue. PMID- 21689124 TI - First outbreak of norovirus in Albania. AB - AIMS: Noroviruses (NoVs) represent the most important enteric viruses responsible for acute gastroenteritis world-wide. This study objective is to characterize the first outbreak of NoV that occurred in Ballsh, a small city in Albania. METHODS AND RESULTS: Stool specimens were collected from people attending to the hospital. Samples were also collected from the aqueduct for bacteriological and virological tests. Overall 33 stools and five drinking water samples were collected, respectively, from the hospital in Ballsh and from the municipal aqueduct. No water samples were scored positive whereas ten stool samples (30.3%) were scored GGII NoV positive. All the GGII isolates were identified as GGII.4 genotype, and no GGI was identified. The alignment and protein analysis were performed using, respectively, ClustalV and the mega 4 software. CONCLUSIONS: This is the first report of NoV GGII.4 in Albania causing an outbreak. The genetic analysis showed several point mutations and amino acid substitutions with respect to the international strains. SIGNIFICANCE AND IMPACT OF STUDY: Over the last decades, Albania has suffered from different outbreaks as cholera, poliomyelitis, hepatitis A and now, for the first time, it has been documented an outbreak of NoV. PMID- 21689122 TI - Nicotine modulates alcohol-seeking and relapse by alcohol-preferring (P) rats in a time-dependent manner. AB - BACKGROUND: Alcohol is frequently co-abused with smoking. In humans, nicotine use can increase alcohol craving and consumption. The objectives of the current study were to assess the acute effects of nicotine on alcohol seeking and relapse at 2 different time points. METHODS: Adult female alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% ethanol (EtOH) (v/v) and water on a concurrent fixed-ratio 5-fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1-hour sessions. Following 10 weeks of daily 1-hour sessions, rats underwent 7 extinction sessions, followed by 2 weeks in their home cages. Rats were then returned to the operant chambers without EtOH or water being present for 4 sessions (Pavlovian Spontaneous Recovery [PSR]). Rats were then given a week in their home cage before being returned to the operant chambers with access to EtOH and water (relapse). Nicotine (0, 0.1, 0.3, or 1.0 mg/kg) was injected subcutaneously immediately or 4 hours prior to PSR or relapse testing. RESULTS: Injections of nicotine immediately prior to testing reduced (5 to 10 responses PSR; 50 to 60 responses relapse), whereas injections of nicotine 4 hours prior to testing increased (up to 150 responses for PSR; up to 400 responses for relapse with 1.0 mg/kg dose) responses on the EtOH lever during PSR and relapse tests. CONCLUSIONS: The results of this study demonstrate that acute effects of nicotine on EtOH-seeking and relapse behaviors may be time dependent, with the immediate effects being a result of nicotine possibly acting as a substitute for EtOH, whereas with a delay of 4 hours, priming effects of nicotine alterations in nicotinic receptors, and/or the effects of nicotine's metabolites (i.e., cotinine and nornicotine) may enhance the expression of EtOH-seeking and relapse behaviors. PMID- 21689125 TI - An autodissemination station for the transfer of an insect growth regulator to mosquito oviposition sites. AB - A prototype autodissemination station to topically contaminate oviposition seeking container-dwelling mosquitoes with the insect growth regulator, pyriproxyfen, was developed and tested in the laboratory. Our test subject was the Asian tiger mosquito, Aedes albopictus (Skuse) (Diptera: Culicidae), an urban species that colonizes small-volume cryptic larval habitats and is a skip ovipositor that visits multiple containers. The station consists of a water reservoir to attract gravid females, which is joined to a transfer chamber designed to contaminate visiting mosquitoes. The unit is easily constructed by moulding wet shredded cardboard using corn starch as a binder. The essential criteria that must be met to prove the efficacy of an autodissemination station require it to demonstrate effectiveness in attracting the target insect, in transferring the toxicant to the insect that will disperse the agent, and in facilitating the subsequent transfer of the toxicant from the insect to target habitats at a lethal concentration. Cage experiments demonstrated that the unit was readily accepted by gravid females as an oviposition site. A powder formulation of pyriproxyfen-impregnated silica particles adhered to visiting Ae. albopictus females (mean: 66 particles/female), although particles were lost over time. In cage (2.2 m(3) ) trials, pyriproxyfen-charged stations resulted in 100% inhibition of adult emergence, whereas in small-room (31.1 m(3) ) trials, 81% emergence inhibition was recorded. The venereal transfer of pyriproxyfen from contaminated males to virgin females was also observed, and pyriproxyfen was subsequently transferred to water-holding containers at concentrations that inhibited emergence. Key autodissemination station features include lack of maintenance requirements, biodegradable construction, low cost and low risk. PMID- 21689126 TI - Affective and cognitive factors influencing sensitivity to probabilistic information. AB - In study 1 different groups of female students were randomly assigned to one of four probabilistic information formats. Five different levels of probability of a genetic disease in an unborn child were presented to participants (within-subject factor). After the presentation of the probability level, participants were requested to indicate the acceptable level of pain they would tolerate to avoid the disease (in their unborn child), their subjective evaluation of the disease risk, and their subjective evaluation of being worried by this risk. The results of study 1 confirmed the hypothesis that an experience-based probability format decreases the subjective sense of worry about the disease, thus, presumably, weakening the tendency to overrate the probability of rare events. Study 2 showed that for the emotionally laden stimuli, the experience-based probability format resulted in higher sensitivity to probability variations than other formats of probabilistic information. These advantages of the experience-based probability format are interpreted in terms of two systems of information processing: the rational deliberative versus the affective experiential and the principle of stimulus-response compatibility. PMID- 21689127 TI - Communicating actionable risk for terrorism and other hazards. AB - We propose a shift in emphasis when communicating to people when the objective is to motivate household disaster preparedness actions. This shift is to emphasize the communication of preparedness actions (what to do about risk) rather than risk itself. We have called this perspective "communicating actionable risk," and it is grounded in diffusion of innovations and communication theories. A representative sample of households in the nation was analyzed using a path analytic framework. Preparedness information variables (including content, density, and observation), preparedness mediating variables (knowledge, perceived effectiveness, and milling), and preparedness actions taken were modeled. Clear results emerged that provide a strong basis for communicating actionable risk, and for the conclusion both that information observed (seeing preparedness actions that other have taken) and information received (receiving recommendations about what preparedness actions to take) play key, although different, roles in motivating preparedness actions among the people in our nation. PMID- 21689128 TI - Psychological mediators of the sport injury--perceived risk relationship. AB - Drawing upon both heuristic- and threat-based approaches, we sought to examine whether perceived similarity with injury-prone people and perceived control over injury occurrence would directly contribute to perceived risk and whether these variables would mediate the previous injury-perceived risk relationship. Judokas (n = 207) reported the number of injuries experienced in the past year and then completed measures of perceived similarity, perceived control, and injury risk perception. Analyses revealed that perceived similarity and perceived control directly contributed to perceived risk of injury; only perceived similarity acted as a partial mediator of the injury-perceived risk relationship. These findings are discussed in relation to the potential influence of the sport context, which universally involves the acceptance of a high risk of injury. PMID- 21689129 TI - The protective action decision model: theoretical modifications and additional evidence. AB - The Protective Action Decision Model (PADM) is a multistage model that is based on findings from research on people's responses to environmental hazards and disasters. The PADM integrates the processing of information derived from social and environmental cues with messages that social sources transmit through communication channels to those at risk. The PADM identifies three critical predecision processes (reception, attention, and comprehension of warnings or exposure, attention, and interpretation of environmental/social cues)--that precede all further processing. The revised model identifies three core perceptions--threat perceptions, protective action perceptions, and stakeholder perceptions--that form the basis for decisions about how to respond to an imminent or long-term threat. The outcome of the protective action decision making process, together with situational facilitators and impediments, produces a behavioral response. In addition to describing the revised model and the research on which it is based, this article describes three applications (development of risk communication programs, evacuation modeling, and adoption of long-term hazard adjustments) and identifies some of the research needed to address unresolved issues. PMID- 21689130 TI - High frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency. AB - BACKGROUND: Increased frequencies of adrenal tumours and testicular adrenal rest tumours (TART) have been reported in patients with 21-hydroxylase deficiency (21OHD). OBJECTIVE: Patients, methods and design From a cross-sectional population-based study of 101 adult Norwegian patients with 21OHD, sixty-two participated in this study (23 men, 39 women; age range 18-75); thirty-two were salt wasting (SW) and 30 simple virilizing (SV); they were assessed with adrenal computed tomography (CT), testicular ultrasound and hormone measurement in the morning after overnight medication fast. RESULTS: Nine adrenal tumours were detected in seven (11%) patients (bilateral in 2); four were myelolipomas and one a phaeochromocytoma. Seventeen (27%) had normal adrenal size, whereas 36 (58%) had persisting hyperplasia, and seven (11%) adrenal hypoplasia. Abnormal adrenals were more common in SW than in SV. TART occurred exclusively in SW and was present in seven (57%) of these men. Testicular volumes were small compared with normative data. Morning ACTH and 17-hydroxyprogesterone levels correlated positively with adrenal dimensions and frequency of TART. CONCLUSION: In this unselected population of patients with classical 21OHD, we found high frequencies of adrenal tumours, particularly myelolipomas, and of hyperplasia and hypoplasia, and TART in SW. It is important that physicians are aware that benign adrenal and testicular tumours occur frequently in 21OHD. Furthermore, these findings may reflect inappropriate glucocorticoid therapy, making a case for the advancement of novel physiological treatment modalities. PMID- 21689131 TI - Efficacy and safety of the 2% formulation of testosterone topical solution applied to the axillae in androgen-deficient men. AB - OBJECTIVES: Testosterone replacement therapy in hypogonadal men relieves symptoms and restores serum testosterone levels to the physiological range. In this study, we assessed the safety, pharmacokinetics, and efficacy of the 2% formulation of testosterone topical solution applied daily to the axillae. DESIGN AND PATIENTS: An open-label trial was conducted in testosterone-deficient men who started on a daily dose of 60 mg of testosterone. Dose was adjusted on Days 45 and 90 when necessary to maintain serum testosterone levels within the physiological range (10.41-36.44 nmol/l) based on average serum testosterone levels on Days 15 and 60, respectively. Sexual function and mood changes were assessed by the Psychosexual Daily Questionnaire (PDQ) for the 7 days preceding visits at Days 1, 15, 60, and 120; and quality of life by SF-36 questionnaire on Days 1, 60, and 120. Safety parameters, laboratory tests, and adverse events were collected at each visit. RESULTS: Among the Completer Set (135 study completers and 3 patients who discontinued due to adverse events), 76.1% (Days 15/16), 84.8% (Days 60/61), and 84.1% (Days 120/121) had an average total testosterone level between 10.41 36.44 nmol/l. PDQ scores increased significantly from baseline to 120 days of treatment (p < 0.0001). Significant improvement was observed in the physical (p < 0.05) and mental (p < 0.0001) components of the SF-36 after 120 days of treatment. Adverse events reported in >2% of the 155 subjects who received >= 1 dose were application site irritation (7.1%), application site erythema (5.2%), headache (5.2%), increased hematocrit (3.9%), nasopharyngitis (3.9%), diarrhea (2.6%), and vomiting (2.6%). CONCLUSIONS: These results indicate that once-daily application of the testosterone topical solution 2% to the axillae is a safe and effective treatment for androgen replacement in hypogonadal men. PMID- 21689132 TI - Molecular analysis of the PAX8 gene in a sample of Mexican patients with primary congenital hypothyroidism: identification of the recurrent p.Arg31His mutation. PMID- 21689133 TI - Selectivity of porcine zona pellucida to bind spermatozoa with normal chromatin structure. AB - This study aimed to investigate the selective ability of swine zona pellucida (ZP) to bind spermatozoa with normal nuclear chromatin. Ten ejaculates of four boars were used, while hemizona assay was applied for evaluation of binding capability. The results of this study showed that swine ZP has the ability to select spermatozoa with normal chromatin structure for sperm-zona binding process. PMID- 21689134 TI - Association study of human leucocyte antigen-A gene with idiopathic male infertility in Han population of China. AB - Human leucocyte antigen (HLA) is a complex gene family that contains several highly polymorphic genes. Some studies have reported HLA-A gene to have a strong role in idiopathic male infertility in Japanese and Yugoslavia populations. Prompted by these findings, we investigated the distributions of HLA-A gene to ascertain their associations with idiopathic male infertility in Chinese population. Polymerase chain reaction-sequence-based typing (PCR-SBT) method was used for DNA typing at HLA-A locus in 109 patients with idiopathic male infertility and 152 healthy controls in Han male population of Shaanxi Province, situated in north-western China. In total, we detected 23 HLA-A alleles in all infertile patients, 22 HLA-A alleles in control subjects. However, no significant differences of these allelic frequencies were found between the patients and the control subjects, suggesting that the HLA-A gene was unlikely a major risk factor of idiopathic male infertility in this sample population. As different populations have different HLA polymorphisms, investigation into the relationship of other HLA genes and idiopathic male infertility in our population is needed in the future. PMID- 21689135 TI - Chromatin intact human sperm recovery is higher following glass wool column filtration as compared with density gradient centrifugation. AB - The sperm DNA quality as determined by chromatin integrity has been reported to be associated with in vivo and in vitro fertility. However, previous studies have evaluated preparation procedures to select motile, morphologically normal and mature spermatozoa, but not the spermatozoa with intact sperm chromatin. To determine which technique yields a population of spermatozoa with improved DNA quality, split ejaculate was processed with density gradient centrifugation (DGC) procedure and glass wool column filtration (GWF) procedure. The processed samples were analysed for sperm DNA quality using the acridine orange staining method on flow cytometry. The GWF procedure decreases the percentage of spermatozoa with DNA fragmentation resulting in more intact chromatin in the processed sample. There is a need to design a clinical study with GWF for assisted reproductive technology. PMID- 21689136 TI - Quantification of ZP1, ZP2 and ZP3 mRNA of marmoset monkey (Callithrix jacchus) oocytes from periantral and antral follicles. AB - In mammals, the oocyte and preimplantation embryo are protected by the zona pellucida (ZP) consisting mainly of ZP glycoproteins, which are responsible for sperm binding, induction of the acrosome reaction and zona pellucida hardening to prevent polyspermia. The ZP proteins become increasingly important as possible predictors for in vitro cultured oocytes competence. As little is known about the stage-dependent expression of ZP1, ZP2 and ZP3 in marmoset monkey (Callithrix jacchus) oocytes, mRNA expression was investigated with real-time RT-PCR. Total RNA was isolated from three different classes of marmoset oocytes; Class 1 oocytes from periantral follicles (<600 MUm, n = 10), Class 2 oocytes from small antral follicles (600-1000 MUm, n = 10) and Class 3 oocytes from large antral follicles (>1000 MUm, n = 9). Compared with Class 1 oocytes mRNA expression of ZP1, ZP2 and ZP3 in Class 2 oocytes was significantly decreased. In Class 3 oocytes, the transcription of ZP1, ZP2 and ZP3 genes showed also a significant decrease compared with Class 1 oocytes. In this study a differently regulated expression of the ZP genes during late folliculogenesis with an obvious downregulation of ZP1, ZP2 and ZP3 could be demonstrated for the first time in the marmoset monkey. PMID- 21689137 TI - Emerging clinical and experimental evidence for the role of lipocalin-2 in metabolic syndrome. AB - The inflammatory state, which is associated with the current pandemic of obesity, has been established as an important contributing pathogenic factor to the increased prevalence of the so-called metabolic syndrome. Many studies have focused on the contribution of various adipokines to this phenomenon, and in the present study, we provide an update on the emerging evidence that the pro inflammatory factor, lipocalin-2, might influence various aspects of metabolic syndrome. Previous reports indicate a positive correlation of serum lipocalin-2 with fasting glucose, the homeostasis model assessment of insulin resistance index, and the inflammatory marker high-sensitivity C-reactive protein, even after adjustment for body mass index, suggesting that it is an independent risk factor for insulin resistance, diabetes, and inflammation. Direct analysis of lipocalin-2 action now also shows effects on peripheral metabolism and on cardiovascular function. A better understanding of how lipocalin-2 is regulated locally and systemically is crucial for adding to our understanding of the pathogenesis of metabolic syndrome, and to uncover potential new avenues for therapeutic approaches. PMID- 21689138 TI - Modifying prescribing behaviour of angiotensin receptor blockers by selectively rescinding managerial prior authorization requirements for losartan. AB - AIMS: To evaluate whether rescinding the prior authorization (PA) requirement (managerial pre-approval) for losartan in an health maintenance organization (HMO) could reduce prescribing of the more expensive angiotensin receptor blockers (ARBs). METHODS: HMO physicians were notified that losartan would no longer require PA, and appropriate changes were made to the electronic prescribing computer program. The monthly distribution by drug of the number of prescriptions for ARBs dispensed for new patients was calculated before and after the policy change from data captured from electronic records. The proportion of patients (percentage and 95% confidence interval) treated with losartan who met the criteria for treatment with ARBs (hypertension or cardiac insufficiency in patients who have developed adverse effects in response to angiotensin-converting enzyme inhibitors or macroproteinuria) during the first month after the PA requirement was rescinded was calculated. RESULTS: The total number of PA requests for ARBs declined by 48.6% from 961 in December 2008, the month before the policy change, to 494 the following January, rising again to 651 during January 2010. Prescription incidence changed from 121 to 255 patients treated per month (114% increase) for losartan, from 15 to 16 (6.7% increase) for candesartan, and from 89 to 71 (20.2% decrease) for valsartan. The duration of effect for decrease in ARB requests for the more expensive drugs was approximately 1 year. Only 23.3% (95% confidence interval 18.1-28.4) of patients receiving losartan met the criteria for receiving ARBs. CONCLUSIONS: Rescinding the PA requirement for this drug alone was an effective limited-duration strategy for reduction of prescription of relatively expensive drugs. PMID- 21689139 TI - Comparison of anti-diabetic drug prescribing in children and adolescents in seven European countries. AB - AIMS: The aim of this study was to compare the prevalence of diabetes in children across seven European countries, when using prescribing of anti-diabetics as a proxy for diabetes. A secondary aim was to assess the potential for collaboration between countries using different databases in diabetes research. METHODS: Data were obtained from population-based clinical databases in seven European countries. The study population comprised children aged 0-18 years. Prescriptions were categorized using the Anatomic Therapeutic Chemical (ATC) classification. The one-year user prevalence in 2008 was calculated for each country and stratified by age and sex. RESULTS: We studied a total of 5.8 million children and adolescents. The prevalence of insulin prescribing varied between 1.1 and 3.5 per 1000 population, being highest in Sweden and lowest in Italy. In all countries, novel insulin analogues were the most commonly used insulins. The prevalence of oral anti-diabetic prescribing ranged from 0.08 per 1000 individuals in Sweden and Germany to 0.21 per 1000 population in the UK. Overall, the absolute number of oral anti-diabetic users was very low. CONCLUSION: This study shows that there is a varying frequency of type 1 diabetes in children and adolescents across Europe. We also demonstrated that it is possible to obtain similar information from different clinical databases within Europe, which would allow continuous monitoring of type 1 diabetes. Owing to the lack of indications in most of the databases, this approach is less suitable for type 2 diabetes. PMID- 21689140 TI - Use of modelling and simulation techniques to support decision making on the progression of PF-04878691, a TLR7 agonist being developed for hepatitis C. AB - AIM: To use non-linear mixed effects modelling and simulation techniques to predict whether PF-04878691, a toll-like receptor 7 (TLR7) agonist, would produce sufficient antiviral efficacy while maintaining an acceptable side effect profile in a 'proof of concept' (POC) study in chronic hepatitis C (HCV) patients. METHODS: A population pharmacokinetic-pharmacodynamic (PKPD) model was developed using available 'proof of pharmacology' (POP) clinical data to describe PF 04878691 pharmacokinetics (PK) and its relationship to 2',5'-oligoadenylate synthetase (OAS; marker of pharmacology) and lymphocyte levels (marker of safety) following multiple doses in healthy subjects. A second model was developed to describe the relationship between change from baseline OAS expressed as fold change and HCV viral RNA concentrations using clinical data available in HCV patients for a separate compound, CPG-10101 (ACTILONTM), a TLR9 agonist. Using these models the antiviral efficacy and safety profiles of PF-04878691 were predicted in HCV patients. RESULTS: The population PKPD models described well the clinical data as assessed by visual inspection of diagnostic plots, visual predictive checks and precision of the parameter estimates. Using these relationships, PF-04878691 exposure and HCV viral RNA concentration was simulated in HCV patients receiving twice weekly administration for 4 weeks over a range of doses. The simulations indicated that significant reductions in HCV viral RNA concentrations would be expected at doses > 6 mg. However at these doses grade >= 3 lymphopenia was also predicted. CONCLUSIONS: The model simulations indicate that PF-04878691 is unlikely to achieve POC criteria and support the discontinuation of this compound for the treatment of HCV. PMID- 21689141 TI - Effectiveness of three times daily lansoprazole/amoxicillin dual therapy for Helicobacter pylori infection in Korea. AB - AIM: We compared three times daily dual therapy with standard triple therapy for effectiveness and safety in H. pylori infection. METHODS: Two hundred and four H. pylori positive patients with peptic ulcer were randomly assigned to one of two regimens: (i) triple therapy with amoxicillin, clarithromycin and lansoprazole twice daily for 2 weeks or (ii) dual therapy with amoxicillin and lansoprazole three times daily for 2 weeks. The success of eradication was evaluated 4 to 5 weeks after completing treatment. RESULTS: The eradication rate was 82.8% in the triple therapy group and 78.4% in the dual therapy group by per protocol analysis. This difference was not significant (P= 0.573). Adverse events were more frequent in the triple therapy group than in the dual therapy group (P= 0.002). CONCLUSIONS: Because dual therapy had fewer side effects than triple therapy and a similar eradication rate, dual therapy may provide an acceptable alternative first line therapy for H. pylori eradication in Korea. PMID- 21689143 TI - Histiocytoid and signet-ring cell carcinoma of the axilla: a type of cutaneous apocrine carcinoma equivalent to histiocytoid lobular carcinoma of the breast? AB - There is a histopathological similarity between cutaneous apocrine carcinoma (CAC) and breast carcinoma. Cutaneous histiocytoid or signet-ring cell (SRC) carcinoma is a rare neoplasm, which usually occurs on the eyelid, and less commonly on the axilla. The precise histogenesis of this carcinoma remains controversial. We report the case of a man with a cutaneous histiocytoid SRC carcinoma of the axilla having histopathological and immunohistochemical features that were quite similar to histiocytoid lobular carcinoma (histiocytoid LC) of the breast, which is a subtype of classic invasive lobular carcinoma of the breast with apocrine differentiation. We consider this case to be a type of CAC equivalent to histiocytoid LC of the breast, based on the features and the occurrence on the axilla. The patient was treated with adjuvant chemotherapy according to the general guidelines for the treatment of breast carcinoma. PMID- 21689142 TI - Pharmacokinetics and pharmacodynamics following maintenance doses of prasugrel and clopidogrel in Chinese carriers of CYP2C19 variants. AB - AIMS: This open-label, two-period, randomized, crossover study was designed to determine the effect of CYP2C19 reduced function variants on exposure to active metabolites of, and platelet response to, prasugrel and clopidogrel. METHODS: Ninety healthy Chinese subjects, stratified by CYP2C19 phenotype, were randomly assigned to treatment with prasugrel 10 mg or clopidogrel 75 mg for 10 days followed by 14 day washout and 10 day treatment with the other drug. Eighty-three subjects completed both treatment periods. Blood samples were collected at specified time points for measurement of each drug's active metabolite (Pras-AM and Clop-AM) concentrations and determination of inhibition of platelet aggregation (IPA) by light transmittance aggregometry. CYP2C19 genotypes were classified into three predicted phenotype groups: rapid metabolizers [RMs (*1/*1)], heterozygous or intermediate metabolizers [IMs (*1/*2, *1/*3)] and poor metabolizers [PMs (*2/*2, *2/*3)]. RESULTS: Pras-AM exposure was similar in IMs and RMs (90% CI 0.85, 1.03) and slightly lower in PMs than IMs (90% CI 0.74, 0.99), whereas Clop-AM exposure was significantly lower in IMs compared with RMs (90% CI 0.62, 0.83), and in PMs compared with IMs (90% CI 0.53, 0.82). IPA was more consistent among RMs, IMs and PMs in prasugrel treated subjects (80.2%, 84.2% and 80.2%, respectively) than in clopidogrel treated subjects (59.7%, 56.2% and 36.8%, respectively; P < 0.001). CONCLUSIONS: Prasugrel demonstrated higher active metabolite exposure and more consistent pharmacodynamic response across all three predicted phenotype groups compared with clopidogrel, confirming observations from previous research that CYP2C19 phenotype plays an important role in variability of response to clopidogrel, but has no impact on response to prasugrel. PMID- 21689144 TI - Annular elastolytic giant cell granuloma associated with prostate carcinoma: demonstration of human metalloelastase (MMP-12) expression. PMID- 21689145 TI - Relationship between serum levels of interleukin-18, IgE and disease severity in patients with atopic dermatitis. AB - BACKGROUND: Interleukin (IL)-18 is a pleiotropic cytokine. Synergistically with IL-12, IL-18 promotes immune responses of the T helper type, by enhancing synthesis of interferon-gamma and inhibiting IgE production. IL-18 can also enhance production of IL-4 and IL-13 production, and stimulate synthesis of IgE. Moreover, in the presence of IL-3, IL-18 can directly stimulate basophils and mast cells to produce their mediators in an IgE-independent manner. These results indicate a role for IL-18 in the pathogenesis of atopic dermatitis (AD). AIM: To examine the association of serum IL-18 with IgE levels and disease severity in patients with AD. METHODS: ELISA was used to measure IL-18 and total IgE levels in the sera of 67 patients with AD and 50 healthy volunteers. The SCORing Atopic Dermatitis (SCORAD) tool was used to determine the severity of this disease. RESULTS: The mean serum level of IL-18 in study group (155.68 pg/mL) was significantly higher than that of controls. IL-18 was also significantly higher in the sera of the patients with severe AD than in those with milder disease. There was a correlation with IgE and IL-18 levels, as patients who had high IgE levels also had high IL-18 levels, compared with controls. CONCLUSION: IL-18 seems to play an important role in the pathogenesis of AD, but this requires further study. IL-18 could be a useful clinical marker of disease severity in AD. PMID- 21689146 TI - Cutaneous larva migrans induced by swallowing live pond loaches. AB - Freshwater fish, specifically loaches, are potential hosts of Gnathostoma species. Consumption of uncooked freshwater loaches may result in cutaneous larva migrans. We report the case of a 70-year-old Taiwanese man who presented with a serpiginous skin rash on his abdomen. He had eaten live loaches intermittently (sometimes daily) for 5 months before his presentation. On histopathological examination, a transected parasite body and a headbulb were found in the mid dermis. The parasite was confirmed as belonging to the genus Gnathostoma, most likely Gnathostoma doloresi. The patient recovered uneventfully without treatment, and had no symptoms at his 12-month follow-up visit. PMID- 21689147 TI - Higher severity grade of erlotinib-induced rash is associated with lower skin phototype. AB - BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRIs) are associated with a characteristic papulopustular rash, an adverse event considered to be a class effect of these agents. Erlotinib, a small-molecule EGFRI, causes a papulopustular rash in 68-75% of patients. The limited reported data suggest that deleterious effects of ultraviolet radiation (UVR) may enhance the development of EGFRI-induced rash. Because the level of the biological pigment melanin correlates with increased protection against UVR, we hypothesized that lighter levels of skin pigmentation are associated with greater severity of rash. AIM: To characterize the relationship between skin phototype (SPT) and rash severity. METHODS: A retrospective chart review was conducted of 40 patients on erlotinib. Skin sensitivity to UVR was categorized using the Fitzpatrick SPT classification scheme. Grading of rash was performed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 3. RESULTS: There was an inverse relationship between SPT and rash severity. Grade 0 was seen in the majority of patients with SPT V/VI, grade 1/2 in the majority of patients with SPT III/IV, and grade 3/4 rash in the majority of patients with SPT I/II (grade 0: 7% SPT I/II, 32% SPT III/IV and 50% SPT IV/V; grade 1/2: 33%, 63% and 50%, respectively; grade 3/4: 60%, 5% and 0%, respectively) (P < 0.01, Fisher exact test). CONCLUSIONS: Prevention and management of cutaneous side-effects from EGFR inhibitors is important to achieve maximum patient compliance and therapeutic benefit. The results of this study suggest that SPT may be an independent predictive factor for EGFRI-induced papulopustular rash, thus pre therapy counselling and early intervention are important. PMID- 21689148 TI - Donepezil-induced linear IgA disease. PMID- 21689149 TI - Specular light reflectance of flakes in seborrhoeic dermatitis of the scalp: a pilot study. AB - Seborrhoeic dermatitis and dandruff are common scalp conditions. In this study, we set out to explore a new method for rating both the severity of the scalp condition and the efficacy of scalp-care compounds. Scalp flakiness was sampled for 40 volunteers using adhesive-coated clear discs, with image analysis used to quantify the specular light reflectance (SLR) of the flakes Two ultraviolet (UV) emitting charge-coupled device cameras (Visioscan VC98 and Visiopor PP34) were used. SLR clearly highlighted the flakiness with high contrast against a black background, and the recorded appearance could be conveniently submitted to the image-analysis system for quantification. In conclusion, SLR under UV illumination highlights scalp flakiness, allowing objective measurements. PMID- 21689150 TI - Melatonin alleviates lipopolysaccharide-induced hepatic SREBP-1c activation and lipid accumulation in mice. AB - A link between endotoxemia and nonalcoholic fatty liver disease (NAFLD) has been demonstrated in human and rodent animals. Nevertheless, the molecular mechanisms of endotoxin-evoked NAFLD remain poorly understood. We hypothesize that reactive oxygen species (ROS) mediate lipopolysaccharide (LPS)-evoked hepatic lipid accumulation. Melatonin is an antioxidant. In the present study, we investigated the effects of melatonin on LPS-induced hepatic lipid accumulation. We showed that a single dose of LPS significantly increased hepatic triglyceride (TG) contents and caused hepatic lipid accumulation in mice. Further analysis found that hepatic sterol regulatory element-binding protein (SREBP)-1c was activated in LPS-treated mice. In agreement with hepatic SREBP-1c activation, fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), two SREBP-1c target genes, were significantly upregulated in liver of mice injected with LPS. Melatonin significantly attenuated LPS-induced SREBP-1c activation and the expression of SREBP-1c target genes. In addition, melatonin reduced serum and hepatic triglyceride (TG) content and prevented LPS-induced hepatic lipid accumulation. Taken together, these results suggest that ROS might be, at least partially, mediated in LPS-induced SREBP-1c activation and hepatic lipid accumulation. Melatonin may be useful as pharmacological agents to protect against endotoxin evoked NAFLD. PMID- 21689151 TI - Adolescent risk factors for poisonings - a prospective cohort study. AB - AIM: This study assessed whether adolescents' socioeconomic background, health and health behaviours are associated with later risk of poisoning hospitalization. METHODS: A prospective cohort of 54,169 Finns aged 14-18 years was followed for an average of 10.6 years. The end-point of the study was poisoning hospitalization, death or termination of follow-up in 2001. The relationships of socioeconomic background, health and health behaviour characteristics with poisoning hospitalization were studied with adjusted Cox's proportional hazard model. RESULTS: We identified 443 persons (0.8%) with a diagnosed poisoning leading to hospital admission. The mean age at the time of the poisoning hospitalization was 22.7 years. The strongest risk factors for poisoning hospitalization in males were more than three stress symptoms weekly (HR 1.9), poor school success (HR 1.9) and not living with both of the parents in adolescence (HR 1.8). In females, the strongest risk factors were more than three stress symptoms weekly (HR 2.1), poor school success (HR 2.2) and recurring drunkenness as drinking style (HR 1.7). CONCLUSION: Poor school performance, health and health-compromising behaviour adopted in adolescence are associated with a poisoning hospitalization risk in adulthood. Daily smoking and recurring drunkenness were strongly associated with a later poisoning hospitalization. PMID- 21689152 TI - Effect of the probiotic Enterococcus faecium SF68 on presence of diarrhea in cats and dogs housed in an animal shelter. AB - BACKGROUND: Beneficial effects of probiotics have never been analyzed in an animal shelter. HYPOTHESIS: Dogs and cats housed in an animal shelter and administered a probiotic are less likely to have diarrhea of >=2 days duration than untreated controls. ANIMALS: Two hundred and seventeen cats and 182 dogs. METHODS: Double blinded and placebo controlled. Shelter dogs and cats were housed in 2 separate rooms for each species. For 4 weeks, animals in 1 room for each species was fed Enterococcus faecium SF68 while animals in the other room were fed a placebo. After a 1-week washout period, the treatments by room were switched and the study continued an additional 4 weeks. A standardized fecal score system was applied to feces from each animal every day by a blinded individual. Feces of animals with and without diarrhea were evaluated for enteric parasites. Data were analyzed by a generalized linear mixed model using a binomial distribution with treatment being a fixed effect and the room being a random effect. RESULTS: The percentage of cats with diarrhea >=2 days was significantly lower (P = .0297) in the probiotic group (7.4%) when compared with the placebo group (20.7%). Statistical differences between groups of dogs were not detected but diarrhea was uncommon in both groups of dogs during the study. CONCLUSION AND CLINICAL IMPORTANCE: Cats fed SF68 had fewer episodes of diarrhea of >=2 days when compared with controls suggests the probiotic may have beneficial effects on the gastrointestinal tract. PMID- 21689153 TI - Association of cerebrospinal fluid analysis findings with clinical signs and outcome in acute nonambulatory thoracolumbar disc disease in dogs. AB - BACKGROUND: Cerebrospinal fluid (CSF) pleocytosis recently was associated with the severity of neurologic signs in dogs with intervertebral disc disease (IVDD). HYPOTHESIS/OBJECTIVES: To look for an association among CSF cell counts, total protein concentration, and severity of neurologic signs at presentation with outcome in dogs with acute thoracolumbar IVDD. Our hypothesis was that CSF total nucleated cell count (TNCC) and percentage cell types would be associated with the severity of spinal cord damage and therefore with both the presenting clinical signs and the prognosis of affected dogs. ANIMALS: Fifty-four dogs with acute nonambulatory thoracolumbar IVDD were evaluated. METHODS: Retrospective study. Signalment, neurologic grade, CSF TNCC, protein concentration, red blood cells count and differential cell percentages, and short- and long-term outcomes were evaluated. RESULTS: CSF pleocytosis (>5 cells/MUL) was present in 54% of dogs and was positively associated with neurologic grade at presentation and with postoperative time to regaining ambulation. Neutrophils were observed most frequently. The percentage of CSF macrophages and macrophage to monocyte ratio were higher (P = .001, for both) in dogs presented without deep pain sensation (DPS) that did not regain ambulation. Receiver operator characteristics curve analysis yielded a cut-off point of 13% macrophages with a sensitivity and specificity of 100 and 83%, respectively, for prediction of a negative outcome. CONCLUSIONS AND CLINICAL IMPORTANCE: CSF pleocytosis is positively associated with the severity of spinal cord damage in dogs with thoracolumbar IVDD. The percentage of CSF macrophages can be used as a prognostic indicator for regaining ambulation in dogs that have lost DPS. PMID- 21689154 TI - Recurrent demyelination and remyelination in 37 young Bengal cats with polyneuropathy. AB - BACKGROUND: With the exception of diabetic neuropathy, polyneuropathy associated with hyperchylomicronemia, and a few inherited polyneuropathies, peripheral neuropathies are poorly characterized in cats. A chronic polyneuropathy is described in a cohort of young Bengal cats. OBJECTIVE: To characterize the clinical and histopathological features of a chronic-relapsing peripheral neuropathy in young Bengal cats. ANIMALS: Thirty-seven young Bengal cats with clinical weakness consistent with peripheral neuropathy. METHODS: Bengal cats were included in this study after a diagnosis of polyneuropathy was confirmed by muscle and peripheral nerve biopsy specimens. Pathological changes were characterized at the light and electron microscopic level and by morphometry. Clinical information and long-term outcome from case records of Bengal cats with histologically confirmed peripheral neuropathy were then assessed. RESULTS: Nerve fiber loss within distal intramuscular nerve branches was a consistent finding in young Bengal cats with polyneuropathy. The most common abnormalities in peripheral nerve biopsies included inappropriately thin myelin sheaths and thinly myelinated fibers surrounded by supernumerary Schwann cell processes, indicative of repeated cycles of demyelination and remyelination. Recovery was common. Response to treatment could not be determined. CONCLUSIONS AND CLINICAL IMPORTANCE: A chronic-relapsing form of polyneuropathy associated primarily with episodes of demyelination and remyelination was identified in young Bengal cats. The prognosis for recovery is good, although relapses are possible and there can be residual motor deficits. PMID- 21689155 TI - Comparison of polymerase chain reaction with bacterial 16s primers to blood culture to identify bacteremia in dogs with suspected bacterial endocarditis. AB - BACKGROUND: Identification of the bacterial organism in dogs with endocarditis is challenging. Human studies have reported the utility of the polymerase chain reaction (PCR) to amplify and identify bacterial nucleic acid from infected valvular tissue and blood. HYPOTHESIS/OBJECTIVES: We hypothesized that PCR using primers designed to amplify the bacterial 16s gene would identify circulating bacteria in dogs with suspected bacterial endocarditis more consistently than standard blood culture techniques. ANIMALS: Eighteen dogs with suspected bacterial endocarditis based upon clinical and echocardiographic findings. Fifteen clinically normal dogs served as negative controls. METHODS: Prospective study of dogs evaluated for suspect endocarditis at 6 veterinary hospitals. A blood sample was drawn from all dogs and evaluated with both a single-sample PCR and standard 3-sample blood culture techniques. RESULTS: Blood culture identified noncontaminant bacteria in 6/18 study animals (33%) and 1 control dog; PCR identified noncontaminant bacteria in 7/18 study animals (39%). There were no study animals in which the 2 tests identified different bacteria (kappa = 1.0). However, bacteria were identified by both techniques in only 2/18 study animals. When results from both PCR and blood culture were considered together, a noncontaminant bacterial organism was identified in 11/18 study animals (61%). CONCLUSION AND CLINICAL IMPORTANCE: The results of this study suggest that although single sample PCR with 16s primers was not more sensitive than blood culture for detection of bacteremia in dogs with suspect endocarditis, performing both techniques simultaneously did increase the likelihood of identification of bacteria in blood. PMID- 21689156 TI - Prospective randomized clinical trial assessing the efficacy of Denamarin for prevention of CCNU-induced hepatopathy in tumor-bearing dogs. AB - BACKGROUND: Increases in liver enzymes occur in up to 86% of dogs receiving CCNU and can result in treatment delay or early discontinuation of treatment. Denamarin contains S-adenosylmethionine and silybin, both of which have been investigated as treatments for various liver diseases. HYPOTHESIS: Dogs on CCNU receiving Denamarin have lower alanine aminotransferase (ALT) activity than dogs not receiving Denamarin. Dogs on Denamarin are less likely to require treatment delay because of hepatopathy and are more likely to complete their prescribed course of CCNU. ANIMALS: Dogs with lymphoma, mast cell tumor, or histiocytic sarcoma that were prescribed CCNU with or without corticosteroids and with normal ALT activity were eligible for enrollment. METHODS: Dogs were prospectively randomized to receive either concurrent Denamarin during CCNU chemotherapy or to receive CCNU alone. Liver-specific laboratory tests were run before each dose of CCNU. RESULTS: Increased liver enzyme activity occurred in 84% of dogs receiving CCNU alone and in 68% of dogs on concurrent Denamarin. Dogs receiving CCNU alone had significantly greater increases in ALT, aspartate aminotransferase, alkaline phosphatase, and bilirubin and a significantly greater decrease in serum cholesterol concentrations than dogs receiving concurrent Denamarin. Dogs receiving CCNU alone were significantly more likely to have treatment delayed or discontinued because of increased ALT activity. CONCLUSIONS: Increased liver enzyme activity occurs commonly in dogs receiving CCNU chemotherapy. These results support the use of concurrent Denamarin to minimize increased liver enzyme activity in dogs receiving CCNU chemotherapy. Denamarin treatment also increases the likelihood of dogs completing a prescribed CCNU course. PMID- 21689157 TI - Characterization of chronic pancreatitis in English Cocker Spaniels. AB - BACKGROUND: Chronic pancreatitis (CP) is common in dogs. The cause is unknown. In humans, different causes of pancreatitis have histologically distinct appearances. The histopathologic lesions in English Cocker Spaniels (ECS) with CP were noted to be histologically different than those of other breeds with CP. HYPOTHESIS: CP in ECS is distinct from CP in other breeds and is characterized by a duct destruction similar to what is observed in autoimmune CP of humans. ANIMALS: Eight ECS and 9 other breeds with histologically confirmed CP recruited over an 8-year period and 50 postmortem control dogs with CP. METHODS: Clinical, clinicopathological, and ultrasonographic findings were recorded. Histological sections were compared with a normal dog and 59 dogs of other breeds with CP. Immunohistochemistry using anti-CD3, anti-CD79a, and anti-cytokeratin antibodies was used to evaluate distribution and type of lymphocytic inflammation and appearance of pancreatic ducts. RESULTS: Four male and 4 female ECS presented at a mean age of 7.2 years. Clinical signs were similar in ECS and other breeds. The pancreas was enlarged and hypoechoic in 4 ECS and 2 controls. Histopathology was characterized by interlobular and periductular fibrosis and inflammation in ECS compared with intralobular disease in most other breeds. Immunohistochemistry identified prominent anti-CD3(+) lymphocytic infiltrates around venules and ducts and a marked absence of interlobular ducts in ECS compared with mixed T-cell infiltration and ductular hyperplasia in most other breeds with CP. CONCLUSIONS AND CLINICAL IMPORTANCE: CP in ECS is distinct from CP in other breeds and is notably duct destructive. PMID- 21689158 TI - A patient with a 20-year lag phase between JAK2-V617F+ myeloproliferation and NPM1-mutated AML arguing against a common origin of disease. AB - We have sought to unravel the molecular biology of a female patient who in 1985 at the age of 55 was diagnosed with a chronic myeloproliferative neoplasm (MPN) and in whom overt acute myeloid leukemia (AML) developed in 2005. To this end, DNA and RNA (extracted from either paraffin-embedded bone marrow (BM) or from BM and/or peripheral blood stored in an RNA/DNA-preserving buffer) were analyzed by qPCR and by capillary gel electrophoresis of PCR products. We found the patient to be JAK2-V617F mutation positive throughout the course of disease, while a mutation of the nucleophosmin (NPM1) gene emerged at AML diagnosis and relapse. The 20-yr lag phase between the polycythemia vera and the AML adds indirect evidence to the growing realization that the leukemic transformation in patients with MPN occurs from in a JAK2 wild-type stem cell. PMID- 21689160 TI - Increased fibroblast density in actinic cheilitis: association with tryptase positive mast cells, actinic elastosis and epithelial p53 and COX-2 expression. AB - BACKGROUND: Actinic cheilitis (AC) is characterized by epithelial and connective tissue alterations caused by ultraviolet sunlight overexposure known as photodamage. Fibroblasts have been linked to photodamage and tumor progression during skin carcinogenesis; however, their role in early lip carcinogenesis remains unknown. The aim of this study was to assess the density of fibroblasts in AC and normal lip (NL) samples and determine their association with markers of lip photodamage. METHODS: Fibroblasts, mast cells, p53, COX-2, and elastin were detected in NL (n = 20) and AC (n = 28) biopsies using immunohistochemistry/histochemistry. Mast cell and fibroblast density and epithelial p53 and COX-2 expression scores were then obtained. Elastosis was scored 1-4 according to elastin fiber density and tortuosity. RESULTS: Fibroblasts, mast cells, p53, COX-2, and elastosis were increased in AC as compared to NL (P < 0.001). Multivariate analysis showed an association between fibroblast and mast cell density at the papillary and reticular areas of AC and NL (P < 0.05). Papillary fibroblast density was also associated with epithelial p53 and COX-2 expression (P < 0.05). Increased fibroblast density, both papillary and reticular, was found in the high elastosis group (scores 3-4) as compared to the low elastosis group (scores 1-2) (P < 0.01). Increased reticular mast cell density was detected only in the high elastosis group (P < 0.01). CONCLUSIONS: Fibroblasts are increased in AC, and they are associated with mast cell density, epithelial p53 and COX-2 expression, and actinic elastosis. Therefore, fibroblasts may contribute to lip photodamage and could be considered useful markers of early lip carcinogenesis. PMID- 21689159 TI - TGF-beta1 regulates the invasive and metastatic potential of mucoepidermoid carcinoma cells. AB - BACKGROUND: Patients with mucoepidermoid carcinoma exhibit poor long-term prognosis because of the lack of therapeutic strategies that effectively block tumor progression. We have previously characterized the Ms cells as a highly metastatic mucoepidermoid carcinoma cell line that expresses high levels of transforming growth factor beta1 (TGF-beta1). Here, we studied the effect of suppressing TGF-beta1 by RNA silencing on the invasive and metastatic potential of mucoepidermoid carcinoma. METHODS: Cell motility, substratum adhesion, and transmembrane invasion were estimated by migration, matrigel adhesion, and matrigel invasion assay. Matrix metalloproteinase (MMP)-2 and MMP-9 activity were determined using gelatin gel zymography. Balb/c nu/nu nude mice lung metastatic model was used to test the metastatic ability of the Ms cells. Lung metastatic tumors were experimentally induced by mice tail vein inoculation of cancer cells. RESULTS: TGF-beta1 silencing inhibits cell motility, substratum adhesion, and transmembrane invasion. In vivo, a significant decrease in lung metastasis was observed when mice received tail vein injections of TGF-beta1-silenced mucoepidermoid carcinoma cells, as compared to controls. CONCLUSION: These results unveil a critical role for TGF-beta1 in the progression of mucoepidermoid carcinomas and suggest that patients with this malignancy may benefit from therapeutic inhibition of the effectors of the TGF-beta1 pathway. PMID- 21689161 TI - Primary intraosseous squamous cell carcinoma arising in an odontogenic cyst: a clinicopathologic analysis of 116 reported cases. AB - PURPOSE: To review the literature on primary intraosseous squamous cell carcinoma (PIOSCC) associated with odontogenic cyst. METHODS: All well-documented cases of PIOSCC published between 1938 and 2010 were collected. Only cases of PIOSCC arising from the lining of an odontogenic cyst, including the keratocystic odontogenic tumor, were selected. Age, sex, signs and symptoms, affected jaw, cyst type, treatment, histopathology, and outcome were recorded. RESULTS: The mean age was 60.2 years (range 1.3-90). There were 80 (69%) men and 36 (31%) women. Mass and pain were the most common presenting symptoms. The mandible was affected in 92 (79%) patients and the maxilla in 24 (21%). It was a residual/radicular cyst in 70 (60%) patients and a dentigerous cyst or a keratocystic odontogenic tumor in the remaining 40%. The histopathology was well differentiated SCC in 53 (46%) patients and moderately differentiated SCC in 47 (40%) patients. Fifty-three (46%) patients were treated with surgery alone and 44 (38%) with surgery and radiotherapy. Fifty-eight (62%) patients survived 2 years and 36 (38%) survived 5 years. CONCLUSION: PIOSCC has a predilection for men (M/F ratio of 2.22:1), affects mainly adults in their 6-8th decades, occurs most frequently (79%) in the mandible, and is associated mainly with a residual/radicular cyst. Histologically, the well-to-moderately differentiated SCC was the most common. Surgery alone or combined therapy of surgery and radiation was the most common approach. The prognosis is 62% surviving 2 years and 38% 5 years. PMID- 21689162 TI - Influence of the crown-to-implant length ratio on the clinical performance of implants supporting single crown restorations: a cross-sectional retrospective 5 year investigation. AB - PURPOSE: The aim of this study was to investigate the influence of the crown-to implant length ratio (c/i ratio) on the implant survival, changes of the marginal bone level (MBL) and the occurrence of biological and technical complications. MATERIAL AND METHODS: This cross-sectional retrospective study included all patients with implants in the posterior segments supporting single crown restorations with a minimum follow-up of 5 years. All patients were questioned and examined clinically and radiographically. The technical and biological c/i ratio and the MBL were measured on digitized periapical radiographs. The following outcome parameters in relation to the c/i ratio and the co-factors were statistically analyzed: implant survival rate, MBL, occurrence of technical and biological complications. For statistical analysis, regression, correlation and survival analyses were applied (P<0.05). RESULTS: Seventy patients (mean age of 50.7 years [range 19.8-76.6 years]) with a total of 100 implants (24 Straumann type, 76 Branemark type) were included in this study. The mean follow-up period was 6.2 years (range 4.73-11.7 years). Six implants failed during the follow-up period, yielding a cumulative survival rate of 95.8% at 5 years in function. The mean technical c/i ratio was 1.04 (+/-0.26, range 0.59-2.01). The mean biological c/i ratio was 1.48 (+/-0.42, range 0.82-3.24). No statistically significant influence of the technical and biological c/i ratio was found on the implant survival, MBL and occurrence of technical and biological complications. When adjusted for the biological c/i ratio, smoking was the only co-factor significantly associated with implant failure and biological complications. CONCLUSION: In the present study, the c/i ratio did not influence the clinical performance of implants supporting single crown restorations in the posterior segments of the jaw within the range tested. PMID- 21689163 TI - Association of hyaluronic acid with a collagen scaffold may improve bone healing in critical-size bone defects. AB - OBJECTIVES: To evaluate the effects of a 1% hyaluronic acid (HA) gel in combination with an absorbable collagen sponge (ACS) in the healing of critical size calvaria defects in rats. MATERIAL AND METHODS: Thirty-two adult Wistar rats were used. Two 5-mm-diameter critical-size defects were created and the treatments were randomly distributed as follows: (1) 1% HA; (2) 1% HA gel-soaked ACS; (3) control (blood clot); and (4) ACS. The animals were sacrificed 60 days post-surgery, when biopsies were collected and processed for histology and histometric analysis. Bone fill was measured as the difference between the initial and the final defect sizes. Non-parametric tests were used to analyze differences between treatments (alpha=1%) and a t-test for body weight gain in each treatment group (alpha=5%). RESULTS: Histological analysis showed bone formation on the edges of the defects, although very limited, and a thin layer of connective tissue occupying the midportion of the defects in the control and the ACS groups. Defects filled with a 1% HA gel and 1% HA gel+ACS had a thicker layer of connective tissue and more new bone formed in the margins of the defects. Linear histometric measures showed no significant differences in the initial defect sizes between the groups (P>0.05). The association 1% HA gel+ACS (0.96 +/- 0.14 mm) had significantly greater bone fill than the control (0.5 +/- 0.02 mm) and ACS (0.56 +/- 0.05 mm)-treated groups (P=0.0043 and 0.0173, respectively). Treatment with a 1% HA gel (0.7 +/- 0.14 mm) showed no significant differences when compared with the other treatments. CONCLUSION: Within the limits of this study, a 1% HA gel associated with a collagen scaffold can improve new bone formation in critical-size defects. However, this treatment never resulted in complete closure of the defects and healing in the major portion of the defects was characterized by fibrous tissue. PMID- 21689164 TI - Implant-supported mandibular splinting affects temporomandibular joint biomechanics. AB - OBJECTIVES: Mandibular functional movements lead to complex deformations of bony structures. The aim of this study was to test whether mandibular splinting influences condylar kinematics and temporomandibular joint (TMJ) loading patterns. MATERIALS AND METHODS: Six subjects were analyzed by means of dynamic stereometry during jaw opening-closing with mandibles unconstrained as well as splinted transversally by a cast metal bar fixed bilaterally to two implant pairs in the (pre)molar region. Statistical analysis was performed by means of ANOVAs for repeated measurements (significance level alpha=0.05). RESULTS: Transversal splinting reduced mandibular deformation during jaw opening-closing as measured between two implants in the (pre)molar region on each side of the mandible significantly by 54%. Furthermore, splinting significantly reduced the distance between lateral condylar poles (average displacement vector magnitude of each pole: 0.84+/-0.36 mm; average mediolateral displacement component: 45+/-28% of the magnitude) and led to a medial displacement of their trajectories as well as a mediolateral displacement of stress-field paths. CONCLUSIONS: During jaw opening-closing, splinting of the mandible leads to a significant reduction of mandibular deformation and intercondylar distance and to altered stress-field paths, resulting in changed loading patterns of the TMJ structures. PMID- 21689165 TI - Risk factors for pelvic lymphoceles post-radical prostatectomy. AB - BACKGROUND: Lymphoceles (LC) represent a well-described rare complication post radical prostatectomy (RP). Our aim was to determine risk factors and to develop possible prevention strategies for LC in a community-based study. METHODS: Data from 1163 RP-patients from 67 clinics between January 2002 and December 2004 were retrospectively evaluated. Patients underwent pelvic imaging procedures/LC management during 3 weeks of rehabilitation post-RP. RESULTS: LC were identified in 304 patients (26%). Lymphadenectomy was carried out in 92% of patients (1001/1086 patients), from which 28% had LC (n = 277) versus 14% without lymphadenectomy (12/85, P = 0.007). Complications (lower limb edema, pain, thrombosis, infection and bladder compression) were observed in 9% of patients (28/304; 2.4% of total patients); necessitating therapy. LC therapy was carried out in 59 patients (5.9%) with pelvic lymph node dissection (PLND) and in no patients (0%) without PLND (P = 0.021). Risk factors included were patients' age, body mass index, prostate volume, TNM-classification, number of removed lymph nodes, previous surgery/therapy, heparin prophylaxis, surgical instruments and pelvic lymphadenectomy. Univariate analysis showed lymphadenectomy as the only significant risk factor for the development of LC post-RP (P = 0.007). When applying multivariate analyses using stepwise logistic regression, only lymphadenectomy was associated with a significant risk for lymphoceles (odds ratio = 2.6, 95% CI = 1.3-4.9, P = 0.004). Adjusting for other factors, no other factor came close to being significant (P < 0.05). All symptomatic LC were successfully treated without further sequelae. CONCLUSIONS: Subclinical LC post RP are more common than thought, and rarely necessitate intervention. Pelvic lymphadenectomy represents the only significant factor contributing to LC development. Because of this, prevention remains difficult. PMID- 21689166 TI - Excision of apocrine glands and axillary superficial fascia as a single entity for the treatment of axillary bromhidrosis. AB - BACKGROUND: Surgical excision of apocrine glands is the effective treatment for axillary bromhidrosis. Skin necrosis, the most serious adverse result observed postoperatively, results in a prolonged wound healing and leads to unsightly scars in the axillary fossae. It is mainly caused by the skin damage during the operation and postoperative seroma or haematoma formation. OBJECTIVE: To investigate the effects and complications of our surgical modality for axillary bromhidrosis. METHODS: Sixty-three patients with bromhidrosis were treated. An incision about two-thirds of the length of the widest transverse diameter was made on the axillary crease. The loosened layers between the dermis and axillary superficial fascia containing apocrine glands were carefully undermined with an iris scissor. The entire apocrine glands-axillary superficial fascia complex was dissected from the centre to the superior and inferior margins with an electrosurgical pencil. RESULTS: Of the 126 axillae, malodour was eradicated in 112 axillae and reduced sharply in 14. There were three cases of skin necroses. The Dermatology Life Quality Index score decreased significantly and the quality of life improved after the operation. CONCLUSION: Our surgical technique can achieve minimal tissue damage and maintain no hematoma postoperatively. The rate of skin necrosis was low. Quality of life improved after the procedure in this patient population. PMID- 21689167 TI - Associated comorbidities in psoriasis and inflammatory bowel disease. AB - BACKGROUND: The association between psoriasis and inflammatory bowel disease (IBD) has been previously reported although a great deal remains unknown about associated comorbidities. OBJECTIVES: The aim of this study was to examine comorbidities in individuals diagnosed with both psoriasis and IBD, and to compare those with individuals diagnosed with psoriasis-only. We also looked at differences within the IBD group by clearly defining that cohort. METHODS: We included 146 patients diagnosed with both psoriasis and IBD and 146 controls diagnosed of psoriasis-only without previous records of IBD, matched by gender, ethnicity and age (+/-5 years). Patients were obtained from the research patient data repository of Brigham and Women's Hospital (BWH) and Massachusetts General Hospital. Controls were obtained from the psoriatic arthritis and psoriasis follow-up study (PAFS) at BWH. The comparison between the two groups included socio-demographics, comorbidities and laboratory inflammation parameters. RESULTS: Compared to individuals with psoriasis-only, patients with both psoriasis and IBD had significantly higher rates of autoimmune thyroiditis (2.1% vs. 6.8%), hepatitis (0.7 vs. 6.2%) and diabetes (11.0% vs. 26.7%). In addition, of the 146 patients with psoriasis and IBD, 60 (41.1%) were diagnosed with seronegative arthritis. The average C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) of the last visits in our clinics were significantly elevated compared to the individuals with psoriasis-only (ESR, 33.5 vs. 4.0 mm/h; CRP, 9.1 vs. 2.3 mg/L; both P-values <0.0001). CONCLUSIONS: We found that patients with both, psoriasis and IBD have a number of further associated comorbidities, some at significantly higher levels than individuals with psoriasis-only. Common inflammatory pathways and genetic predispositions for specific patterns in the immune response may play an important role in the evolution of associated conditions. PMID- 21689168 TI - Sun behaviour patterns and perception of illness among melanoma patients. AB - BACKGROUND: Melanoma is one of the most aggressive skin tumours for which the major risk factor is ultraviolet radiation. Sun protection is extremely important, especially for melanoma patients who, once diagnosed with melanoma, have 500 times greater chance of developing another melanoma than the general population. OBJECTIVE: In this study, we examined the perception of melanoma and attitudes towards sun protection among melanoma patients and compared their results with the patients suffering from other dermatological disorders. METHODS: In total, 240 participants were included in the study: 120 patients suffering from melanoma and 120 participants in the control group. The Sun Behaviour Patterns Questionnaire and the Brief Illness Perceptions Questionnaire were used in this study to assess sun behaviours and perception of melanoma. RESULTS: Melanoma patients have negative attitude towards sunbathing: 57% avoid sunbathing and 27% spend time in the sun only during swimming, otherwise seeking shade, whereas participants in the control group have more positive attitude towards sunbathing. Results indicate very short time of using sunscreen protection during the year and very small number of people using adequate SPF value, in both melanoma and control group. CONCLUSION: Participants in control group perceive melanoma as a more serious illness than patients who think that melanoma has mild symptoms, is easy to cure and control, has moderate consequences and lasts relatively long. Both melanoma patients and participants in the control group show relatively good sun behaviour patterns and slightly negative attitudes towards sun protection. PMID- 21689169 TI - Intron splicing suppresses RNA silencing in Arabidopsis. AB - Silencing of introduced transgenes constitutes a major bottleneck in the production of transgenic crops. Commonly, these transgenes contain no introns, a feature shared with transposons, which are also prime targets for gene silencing. Given that introns are very common in endogenous genes but are often lacking in transgenes and transposons, we hypothesised that introns may suppress gene silencing. To investigate this, we conducted a genome-wide analysis of small RNA densities in exons from intronless versus intron-containing genes in Arabidopsis thaliana. We found that small RNA libraries are strongly enriched for exon sequences derived from intronless genes. Small RNA densities in exons of intronless genes were comparable to exons of transposable elements. To test these findings in vivo we used a transgenic reporter system to determine whether introns are able to suppress gene silencing in Arabidopsis. Introducing an intron into a transgene reduced silencing by more than fourfold. Compared with intronless transcripts, the spliced transcripts were less effective substrates for RNA-dependent RNA polymerase 6-mediated gene silencing. This intron suppression of transgene silencing requires efficient intron splicing and is dependent on ABH1, the Arabidopsis orthologue of human cap-binding protein 80. PMID- 21689170 TI - De novo genetic variation associated with retrotransposon activation, genomic rearrangements and trait variation in a recombinant inbred line population of Brassica napus derived from interspecific hybridization with Brassica rapa. AB - Interspecific hybridization is a significant evolutionary force as well as a powerful method for crop breeding. Partial substitution of the AA subgenome in Brassica napus (A(n) A(n) C(n) C(n) ) with the Brassica rapa (A(r) A(r) ) genome by two rounds of interspecific hybridization resulted in a new introgressed type of B. napus (A(r) A(r) C(n) C(n) ). In this study, we construct a population of recombinant inbred lines of the new introgressed type of B. napus. Microsatellite, intron-based and retrotransposon markers were used to characterize this experimental population with genetic mapping, genetic map comparison and specific marker cloning analysis. Yield-related traits were also recorded for identification of quantitative trait loci (QTLs). A remarkable range of novel genomic alterations was observed in the population, including simple sequence repeat (SSR) mutations, chromosomal rearrangements and retrotransposon activations. Most of these changes occurred immediately after interspecific hybridization, in the early stages of genome stabilization and derivation of experimental lines. These novel genomic alterations affected yield-related traits in the introgressed B. napus to an even greater extent than the alleles alone that were introgressed from the A(r) subgenome of B. rapa, suggesting that genomic changes induced by interspecific hybridization are highly significant in both genome evolution and crop improvement. PMID- 21689171 TI - The MADS box gene, FOREVER YOUNG FLOWER, acts as a repressor controlling floral organ senescence and abscission in Arabidopsis. AB - The ectopic expression of a MADS box gene FOREVER YOUNG FLOWER (FYF) caused a significant delay of senescence and a deficiency of abscission in flowers of transgenic Arabidopsis. The defect in floral abscission was found to be due to a deficiency in the timing of cell separation of the abscission zone cells. Down regulation of INFLORESCENCE DEFICIENT IN ABSCISSION (IDA) may contribute to the delay of the floral abscission in 35S:FYF flowers. FYF was found to be highly expressed in young flowers prior to pollination and was significantly decreased after pollination, a pattern that correlated with its function. Ethylene insensitivity in senescence/abscission and the down-regulation of ETHYLENE RESPONSE DNA-BINDING FACTOR 1 (EDF1) and EDF2, downstream genes in the ethylene response, in 35S:FYF Arabidopsis suggested a role for FYF in regulating senescence/abscission by suppressing the ethylene response. This role was further supported by the fact that 35S:FYF enhanced the delay of flower senescence/abscission in ethylene response 1 (etr1), ethylene-insensitive 2 (ein2) and constitutive triple response 1 (ctr1) mutants, which have defects in upstream genes of the ethylene signaling pathway. The presence of a repressor domain in the C-terminus of FYF and the enhancement of the delay of senescence/abscission in FYF+SRDX (containing a suppression motif) transgenic plants suggested that FYF acts as a repressor. Indeed, in FYF-DR+VP16 transgenic dominant-negative mutant plants, in which FYF was converted to a potent activator by fusion to a VP16-AD motif, the senescence/abscission of the flower organs was significantly promoted, and the expression of BOP2, IDA and EDF1/2 was up regulated. Our data suggest a role for FYF in controlling floral senescence/abscission by repressing ethylene responses and regulating the expression of BOP2 and IDA in Arabidopsis. PMID- 21689172 TI - A specific role for Arabidopsis TRAPPII in post-Golgi trafficking that is crucial for cytokinesis and cell polarity. AB - Cytokinesis and cell polarity are supported by membrane trafficking from the trans-Golgi network (TGN), but the molecular mechanisms that promote membrane trafficking from the TGN are poorly defined in plant cells. Here we show that TRAPPII in Arabidopsis regulates the post-Golgi trafficking that is crucial for assembly of the cell plate and cell polarity. Disruptions of AtTRS120 or AtTRS130, two genes encoding two key subunits of TRAPPII, result in defective cytokinesis and cell polarity in embryogenesis and seedling development. In attrs120 and attrs130, the organization and trafficking in the endoplasmic reticulum (ER)-Golgi interface are normal. However, post-Golgi trafficking to the cell plate and to the cell wall, but not to the vacuole, is impaired. Furthermore, TRAPPII is required for the selective transport of PIN2, but not PIN1, to the plasma membrane. We revealed that AtTRS130 is co-localized with RAB A1c. Expression of constitutively active RAB-A1c partially rescues attrs130. RAB A1c, which resides at the TGN, is delocalized to the cytosol in attrs130. We propose that TRAPPII in Arabidopsis acts upstream of Rab-A GTPases in post-Golgi membrane trafficking in plant cells. PMID- 21689173 TI - Nitric oxide accumulation in Arabidopsis is independent of NOA1 in the presence of sucrose. AB - Nitric oxide signals diverse responses in animals and plants. Whereas nitric oxide synthesis mechanisms in animals are well understood, how nitric oxide is synthesized and regulated in plants remains controversial. NOA1 is a circularly permuted GTPase that is important for chloroplast function and is implicated in nitric oxide synthesis. However, the reported consequences of a null mutation in NOA1 are inconsistent. Whereas some studies indicate that the noa1 mutant has severe reductions in nitric oxide accumulation, others report that nitric oxide levels are indistinguishable between noa1 and the wild type. Here, we identify a correlation between the reported ability of noa1 to accumulate nitric oxide with growth on sucrose-supplemented media. We report that noa1 accumulates both basal and salicylic acid-induced nitric oxide only when grown on media containing sucrose. In contrast, nitric oxide accumulation in wild type is largely insensitive to sucrose supplementation. When grown in the absence of sucrose, noa1 has low fumarate, pale green leaves, slow growth and reduced chlorophyll content. These phenotypes are consistent with a defect in chloroplast-derived photosynthate production and are largely rescued by sucrose supplementation. We conclude that NOA1 has a primary role in chloroplast function and that its effects on the accumulation of nitric oxide are likely to be indirect. PMID- 21689174 TI - Molar-incisor hypomineralisation: prevalence and defect characteristics in Iraqi children. AB - BACKGROUND. Little prevalence data relating to molar incisor hypomineralisation (MIH) exist for Middle East populations. AIM. To evaluate the prevalence and the clinical features of MIH in school-aged children residing in Mosul City, Iraq. DESIGN. A cluster sample of 823 7- to 9-year-old children had their first permanent molars and incisors (index teeth) evaluated using the European Academy of Paediatric Dentistry (EAPD) criteria for MIH. The examinations were conducted at schools by a calibrated examiner. RESULTS. Of the children examined, 177 (21.5%) had hypomineralisation defects in at least one index tooth, 153 (18.6%) had at least one affected first molar or first molars and incisors and were considered as having MIH. The most commonly affected teeth were maxillary molars. Demarcated creamy white opacities were the most frequent lesion type. Dental restorations and tooth extraction because of MIH were uncommon. Children with three or more affected teeth were 3.7 times more likely to have enamel breakdown when compared with those children having only one or two affected teeth. CONCLUSIONS. Molar incisor hypomineralisation was common amongst Iraqi children. Demarcated opacities were more prevalent than breakdown. The severity of the lesions increased with the number of affected teeth. The more severe the defect, the greater the involved tooth surface area. PMID- 21689175 TI - Peripheral ameloblastic fibro-odontoma or peripheral developing complex odontoma: report of a case. AB - BACKGROUND. Peripheral (extraosseous) odontogenic tumors are rare. CASE REPORT. This report describes a case which illustrates the clinical and histopathological features of a lesion in an 8-year-old, healthy Caucasian girl that on purely morphological grounds would seem to be an ameloblastic fibro-odontoma, but may represent a case of a peripheral developing complex odontoma. CONCLUSION. Conservative surgical enucleation of the lesion was followed by unbcomplicated healing and no recurrence was seen. PMID- 21689176 TI - Genotypic diversity of Streptococcus mutans and Streptococcus sobrinus in 3-4 year-old children with severe caries or without caries. AB - BACKGROUND. The genotypic diversity of both Streptococcus mutans and Streptococcus sobrinus in children with different caries experience remains unclear. AIM. To investigate the genotypic diversity of S. mutans and S. sobrinus in children with severe early childhood caries (SECC) and in caries-free (CF) children. METHODS. Stimulated saliva of 87 SECC and 91 CF children aged 3-4 years was collected and submitted to cultivation, and MS colonies were enumerated. The genomic fingerprint analysis of S. mutans and S. sobrinus was carried out using AP-PCR. RESULTS. One to five genotypes of S. mutans were colonized in an oral cavity of SECC and CF children; 85.5% SECC children and 57.9% CF children harboured more than one genotype of S. mutans. One to three genotypes of S. sobrinus were detected from each SECC child; 31.25% SECC children harboured more than one genotype of S. sobrinus. And one genotype was colonized in each CF child. S. mutans isolates from different individuals displayed distinctive DNA fingerprints. CONCLUSIONS. DNA fingerprints of S. mutans and S. sobrinus isolates from 3- to 4-year-old children displayed genetic polymorphism, and S. mutans has greater genetic diversity than S. sobrinus. SECC children harboured more genotypes of S. mutans and S. sobrinus than CF children. PMID- 21689177 TI - Dental development and tooth agenesis in children with velocardiofacial syndrome. AB - BACKGROUND. Variations in dental development and tooth agenesis have been reported in children with velocardiofacial syndrome (VCFS). AIM. The aim was to evaluate the dental development and missing permanent teeth in children with VCFS. DESIGN. Forty-five children (23 girls) with VCFS who had visited the cleft palate and craniofacial centre were studied retrospectively from orthopantomograms taken at the mean age of 7.9 years (range 5.8-12.9). Thirteen of the children with VCFS had palatal clefts. The deletion of 22q11 was verified by FISH techniques. The dental stages were assessed by the method of Demirjian, and the dental age was calculated according to the Finnish dental maturity reference values. A paired Student's t-test was used in the statistical analysis. RESULTS. Eight children (17%), four with palatal clefts, had tooth agenesis. Four children (9%) had agenesis of mandibular incisors. The missing teeth (n = 19) were mainly mandibular incisors (n = 6), maxillary lateral incisors (n = 2), and maxillary second premolars (n = 4). The dental age of the children with VCFS was not different from their chronological age, but there was great individual variation. CONCLUSIONS. A high prevalence of missing permanent teeth, especially mandibular incisors, was observed. The need for thorough clinical and radiological dental examination in children with VCFS is emphasized. PMID- 21689178 TI - The erosion and abrasion-inhibiting effect of TiF(4) and NaF varnishes and solutions on enamel in vitro. AB - OBJECTIVE. Previous in vitro study has shown that TiF(4) varnish might reduce enamel erosion. No data regarding the effect of this experimental varnish on enamel erosion plus abrasion, however, are available so far. Thus, this in vitro study aimed to analyse the effect of TiF(4) compared with NaF varnishes and solutions, to protect against enamel erosion with or without abrasion. METHODS. Enamel specimens were pre-treated with experimental-TiF(4) (2.45% F), experimental-NaF (2.45% F), NaF-Duraphat (2.26% F), and placebo varnishes; NaF (2.26% F) and TiF(4) (2.45% F) solutions. Controls remained untreated. The erosive challenge was performed using a soft drink (pH 2.6) 4 * 90 s/day (ERO) and the toothbrushing abrasion (ERO+ABR) 2 * 10 s/day, for 5 days. Between the challenges, the specimens were exposed to artificial saliva. Enamel loss was measured profilometrically (MUm). RESULTS. Kruskal-Wallis/Dunn tests showed that all fluoridated varnishes (TiF(4) -ERO:0.53 +/- 0.20, ERO+ABR:0.65 +/- 0.19/NaF ERO:0.94 +/- 0.18, ERO+ABR:1.74 +/- 0.37/Duraphat-ERO:1.00 +/- 0.37, ERO+ABR:1.72 +/- 0.58) were able to significantly reduce enamel loss when compared with placebo varnish (ERO:3.45 +/- 0.41/ERO+ABR:3.20 +/- 0.66) (P < 0.0001). Placebo varnish, control (ERO:2.68 +/- 0.53/ERO+ABR:3.01 +/- 0.34), and fluoridated (NaF ERO:2.84 +/- 0.09/ERO+ABR:2.40 +/- 0.21/TiF(4) -ERO:3.55 +/- 0.59/ERO+ABR:4.10 +/ 0.38) solutions did not significantly differ from each other. CONCLUSION. Based on the results, it can be concluded that the TiF(4) varnish seems to be a promising treatment to reduce enamel loss under mild erosive and abrasive conditions in vitro. PMID- 21689179 TI - Pain, discomfort, and use of analgesics following the extraction of primary canines in children with palatally displaced canines. AB - BACKGROUND. Pain following the extraction of the primary canine in children with palatally displaced canines (PDC) as an interceptive treatment has not been investigated. AIMS. To describe pain, discomfort, dental anxiety, and use of analgesics following the extraction of primary canines in children with PDC. DESIGN. Forty-four children, aged 10-13 with PDC, were included. Pain intensity, discomfort, and analgesic consumption were rated the first evening and 1 week after the extraction of the primary canine. Dental anxiety was assessed pre extraction, using the dental anxiety scale (DAS). A matched reference group also completed the DAS. RESULTS. No significant differences were found between the study and the reference group regarding the pre-extraction assessments. Post extraction pain and discomfort was low. The experience of the injection was graded worse than the extraction, and more pain was rated at the evening post extraction than during the extraction. Analgesics were used only the first evening. High correlation was detected between DAS and pain during injection and extraction. CONCLUSIONS. The experience of pain and discomfort during and after extraction of the primary canines is low, despite that 42% of the children used analgesics. Therefore, appropriate analgesics and recommendation doses pre- and post-extraction should be prescribed. PMID- 21689180 TI - Research utilisation and critical thinking among newly graduated nurses: predictors for research use. A quantitative cross-sectional study. AB - AIM: The aim was to describe research utilisation among newly graduated nurses and to explore critical thinking dispositions and other individual and contextual factors as possible predictors for research use. BACKGROUND: Nurses are expected to be research users, and variations in research utilisation are explained by individual and contextual factors. To our knowledge, critical thinking dispositions have not earlier been explored as predictors for research use. DESIGN: A cross-sectional design was chosen. METHODS: Data collection was carried out from October 2006 to April 2007 using the Research Utilization Questionnaire (RUQ) and the California Critical Thinking Disposition Inventory (CCTDI). The response rate was 33% (n =617). Pearson's chi-square test and regression analyses were used for statistical calculations. RESULTS: The respondents reported a positive attitude towards research, but only 24% (n = 148) were defined as research users. A significantly higher proportion of research users reported high critical thinking scores. Critical thinking explained 20% of the variance in attitude towards research and 11% of the variance in research use. Availability and support to implement research findings was the second strongest predictor for research use. CONCLUSIONS: Critical thinking, a significant predictor for attitude towards research and for the use of research, should be recognised and strengthened in nursing education and clinical practice. Contextual factors seem to be important for newly graduated nurses' use of research. RELEVANCE TO CLINICAL PRACTICE: Nurse leaders play an important role in nurturing newly graduated nurses' critical thinking and assisting them in transferring their positive attitude towards research into research use. Nurse educators play a significant role in supporting, challenging and supervising nursing students to be critical thinkers and strong believers in research utilisation. PMID- 21689181 TI - Registered nurses' thinking strategies on malnutrition and pressure ulcers in nursing homes: a scenario-based think-aloud study. AB - AIM: The aim of this study was to explore the thinking strategies and clinical reasoning processes registered nurses use during simulated care planning for malnutrition and pressure ulcers in nursing home care. BACKGROUND: Clinical reasoning is an essential component of nursing practice. Registered nurses' thinking strategies and clinical reasoning have received limited attention in nursing science. Further research is needed to understand registered nurses' clinical reasoning, especially for prevention of malnutrition and pressure ulcers as they are important quality indicators of resident care in nursing homes. DESIGN: A qualitative explorative design was used with a think-aloud interview technique. METHODS: The transcribed verbalisations were analysed with qualitative deductive content analysis. Data were collected during six months in 2007-2008 from 30 registered nurses at nine nursing homes in Norway. RESULTS: The registered nurses used a variety of thinking strategies, but there were differences in the frequency of use of the different strategies. The three most commonly used thinking strategies were 'making choices', 'forming relationships' and 'drawing conclusions'. None of the nurses performed a structured risk assessment of malnutrition or pressure ulcers. Registered nurses started with assessing data from the scenarios, but after a short and elementary assessment they moved directly to planning. CONCLUSION: Many different thinking strategies were used in registered nurses' clinical reasoning for prevention of malnutrition and pressure ulcers. The thinking strategy 'making choices' was most commonly used and registered nurses' main focus in their reasoning was on planning nursing interventions. RELEVANCE TO CLINICAL PRACTICE: This study showed that most of the registered nurses go directly to planning when reasoning clinically about residents in nursing homes. A lack of systematic risk assessments was identified. The insight gained from this study can be used to recommend improvements in tools designed for nursing homes to support the registered nurses. PMID- 21689182 TI - From limitation to mastery: exercise experience for adolescents with mild congenital heart disease. AB - AIM: To describe the subjective experience of engaging in exercise for adolescents with mild congenital heart disease (CHD). BACKGROUND: Most children with mild CHD are now expected to survive to adolescence and even into adulthood. With early intervention, cardiopulmonary function and exercise capacity in most are comparable to those of normal peers. However, the exercise behaviours of these adolescent patients and their determinants remain largely undefined. DESIGN: A descriptive phenomenological design was used. METHODS: Eight adolescents with CHD who perceived no or only mild symptoms after engaging in exercise were individually interviewed using a semi-structured interview. Interviews were transcribed and non-verbal communication recorded within 24 hours of the interview. Transcriptions were analysed and perceptions and attitudes grouped according to theme expressed. FINDINGS: The essence of the adolescents with mild CHD engaging in exercise was from limitation to mastery. Four themes emerged: (1) self-awareness: understanding the limitations of their disease and its impact on exercise; (2) perception: focusing on strengths and admitting limitations; (3) transcendence: developing coping strategies and maintaining balance; and (4) living with the disease: mastering oneself and living a normal life. CONCLUSIONS: The findings indicated that, when adolescents faced and accepted their exercise limitation, they would assess their condition, develop coping strategies from their accumulated experience and participate in exercise to maintain a healthy body and mind. RELEVANCE TO CLINICAL PRACTICE: The findings provide a scientific knowledge base for nursing professionals to instruct adolescents with mild CHD in exercise and help families build the confidence of these adolescents. PMID- 21689183 TI - Identification of predicted seminal fluid proteins in Tribolium castaneum. AB - In several insect species, seminal fluid proteins (SFPs) have been demonstrated to be key regulators of male and female fitness through their ability to alter female physiology and behaviour. Tribolium castaneum is an economically important pest species and a model system for sexual selection research, but little is known about SFPs in this insect. To create a foundation for the study of T. castaneum SFPs, we used mass spectrometry to identify putative SFPs by comparing proteins detected in the male reproductive glands with those found in the reproductive tracts of virgin and mated females. Fourteen putative SFPs, thirteen with male biased expression, were identified through this approach. We also used reverse transcription PCR (RT-PCR) to examine expression levels across different tissue types. We found strongly male-biased expression in 13 genes, nine of which were expressed only in male accessory gland tissue. This represents the first proteomic-based method of identifying putative SFPs in any coleopteran species, and is the first study in this species to identify putative SFPs that are likely transferred to the female. This work could lead to functional analyses of the role of SFPs in sexual selection, sexual conflict and potential control of a pest species. PMID- 21689184 TI - Molecular evidence for Pleistocene refugia at the eastern edge of the Tibetan Plateau. AB - The role of the Quaternary ice ages in forming the contemporary genetic structure of populations has been well studied in a number of global regions. However, due to the different nature of glaciations and complex topography, their role in shaping eastern Eurasian genetic diversity, particular in areas surrounding the Tibetan Plateau have remained largely unstudied. We aimed to address this question by examining the genetic structure of an alpine forest-associated taxon, the blood pheasant (Ithaginis cruentus) to infer its phylogeographic history. We detected three phylogenetic lineages and four current population groups. By comparing molecular and palaeovegetation data, we found that major glaciations during the Pleistocene have had a major impact upon the current genetic diversity of this species. Coalescent simulations indicate that the populations retreated to different refugia during some glacial periods in the Pleistocene, but persisted through the last glacial maximum (LGM). The most significant recent population expansion was found to have occurred before the LGM, during which palaeoclimatic data indicate that the climate was both warmer and wetter than today. In contrast, during the LGM populations may have adopted an altitudinal shift strategy in order to track changes in alpine glaciers, exemplifying a general response for montane species in the region where alpine glaciations were not large enough to cause qualitative changes in vegetation. Although analysis based on a plumage related gene showed that divergent selection may have contributed to current patterns of intra-specific diversity, demographic isolation is inferred to have played a more dominant role. PMID- 21689185 TI - Synganglion transcriptome and developmental global gene expression in adult females of the American dog tick, Dermacentor variabilis (Acari: Ixodidae). AB - 454 Pyrosequencing was used to characterize the expressed genes from the synganglion and associated neurosecretory organs of unfed and partially fed virgin and mated replete females of the American dog tick, Dermacentor variabilis. A total of 14,881 contiguous sequences (contigs) was assembled, with an average size of 229 bp. Gene ontology terms for Level 2 biological processes were assigned to 4366 contigs. Seven acetylcholinesterases, a muscarinic acetylcholine (ACh) receptor, two nicotinic ACh receptor beta-subunits, two ACh unc-18 regulators, two dopamine receptors, two gamma aminobutyric acid (GABA) receptors, two GABA transporters, two norepinephrine transporters and an octopamine receptor are described. Microarrays were conducted to examine global gene expression and quantitative real-time polymerase chain reaction was used to verify expression of selected neuropeptides. Hierarchical clustering of all differentially expressed transcripts grouped part-fed and replete ticks as being more similar in terms of differentially expressed genes with unfed ticks as the outgroup. Nine putative neuropeptides (allatostatin, bursicon-beta, preprocorazonin, glycoprotein hormone alpha, insulin-like peptide, three orcokinins, preprosulphakinin) and a gonadotropin releasing hormone receptor were differentially expressed, and their developmental expression and role in reproduction was investigated. The presence of eclosion hormone, corazonin and bursicon in the synganglion, which in insects regulate behaviour and cuticle development associated with moulting, suggest that this system may be used in ticks to regulate blood feeding, cuticle expansion and development related to female reproduction; adult ticks do not moult. PMID- 21689186 TI - Differential sensitivity of coral larvae to natural levels of ultraviolet radiation during the onset of larval competence. AB - Scleractinian corals are the major builders of the complex structural framework of coral reefs. They live in tropical waters around the globe where they are frequently exposed to potentially harmful ultraviolet radiation (UVR). The eggs and early embryonic stages of some coral species are highly buoyant and remain near the sea surface for prolonged periods of time and may therefore be the most sensitive life stages with respect to UVR. Here, we analysed gene expression changes in five developmental stages of the Caribbean coral Montastraea faveolata to natural levels of UVR using high-density cDNA microarrays (10 930 clones). We found that larvae exhibit low sensitivity to natural levels of UVR during early development as reflected by comparatively few transcriptomic changes in response to UVR. However, we identified a time window of high UVR sensitivity that coincides with the motile planula stage and the onset of larval competence. These processes have been shown to be affected by UVR exposure, and the transcriptional changes we identified explain these observations well. Our analysis of differentially expressed genes indicates that UVR alters the expression of genes associated with stress response, the endoplasmic reticulum, Ca(2+) homoeostasis, development and apoptosis during the motile planula stage and affects the expression of neurogenesis-related genes that are linked to swimming and settlement behaviour at later stages. Taken together, our study provides further data on the impact of natural levels of UVR on coral larvae. Furthermore, our results might allow a better prediction of settlement and recruitment rates after coral spawning events if UVR climate data are taken into account. PMID- 21689187 TI - Polymorphism in the couch potato gene clines in eastern Australia but is not associated with ovarian dormancy in Drosophila melanogaster. AB - Natural selection can generate parallel latitudinal clines in traits and gene frequencies across continents, but these have rarely been linked. An amino acid (isoleucine to lysine, or I462K) polymorphism of the couch potato (cpo) gene in Drosophila melanogaster is thought to control female reproductive diapause cline in North America (Schmidt et al. 2008, Proc Natl Acad Sci USA, 105, 16207-16211). Here, we show that under standard diapause-inducing conditions (12 degrees C and short photoperiod) (Saunders et al. 1989, Proc Natl Acad Sci USA, 86, 3748-3752), egg maturation in Australian flies is delayed, but not arrested at previtellogenic stages. At 12 degrees C, the phenotypic distribution in egg development was bimodal at stages 8 and 14 and showed a strong nonlinear pattern on the east coast of Australia, with incidence of egg maturation delay (ovarian dormancy) increasing both toward tropical and temperate climates. Furthermore, we found no evidence for an association between the cpo I462K polymorphism and ovarian dormancy at either 12 or 10 degrees C (when egg maturation was often delayed at stage 7). Owing to strong linkage disequilibrium, the latitudinal cline in cpo allele frequencies was no longer evident once variation in the In(3R)P inversion polymorphism was taken into account. Our results suggest that the standard diapause-inducing conditions (12 degrees C and short photoperiod) were not sufficient to cause the typical previtellogenic developmental arrest in Australian flies and that the cpo I462K polymorphism does not explain the observed delay in egg development. In conclusion, ovarian dormancy does not show a simple latitudinal cline, and the lack of cpo-dormancy association suggests a different genetic basis to reproductive dormancy in North America and Australia. PMID- 21689188 TI - Colonization of the Tibetan Plateau by the homoploid hybrid pine Pinus densata. AB - Pinus densata is an intriguingly successful homoploid hybrid species that occupies vast areas of the southeastern Tibetan Plateau in which neither of its parental species are present, but the colonization processes involved are poorly understood. To shed light on how this species colonized and became established on the plateau, we surveyed paternally inherited chloroplast (cp) and maternally inherited mitochondrial (mt) DNA variation within and among 54 populations of P. densata and its putative parental species throughout their respective ranges. Strong spatial genetic structure of both cp and mtDNA were detected in P. densata populations. Mitotypes specific to P. densata were likely generated by complex recombination events. A putative ancestral hybrid zone in the northeastern periphery of P. densata was identified, and we propose that the species then colonized the plateau by migrating westwards. Along the colonization route, consecutive bottlenecks and surfing of rare alleles caused a significant reduction in genetic diversity and strong population differentiation. The direction and intensity of introgression from parental species varied among geographic regions. In western parts of its range, the species seems to have been isolated from seed and pollen flow from its parent species for a long time. The observed spatial distribution of genetic diversity in P. densata also appears to reflect the persistence of this species on the plateau during the last glaciation. Our results indicate that both ancient and contemporary population dynamics have contributed to the spatial distribution of genetic diversity in P. densata, which accordingly reflects its evolutionary history. PMID- 21689189 TI - Latitudinal and voltinism compensation shape thermal reaction norms for growth rate. AB - Latitudinal variation in thermal reaction norms of key fitness traits may inform about the response of populations to climate warming, yet their adaptive nature and evolutionary potential are poorly known. We assessed the contribution of quantitative genetic, neutral genetic and environmental effects to thermal reaction norms of growth rate for populations of the damselfly Ischnura elegans. Among populations, reaction norms differed primarily in elevation, suggesting that time constraints associated with shorter growth seasons in univoltine, high latitude as well as multivoltine, low-latitude populations selected for faster growth rates. Phenotypic divergence among populations is consistent with selection rather than drift as Q(ST) was greater than F(ST) in all cases. Q(ST) estimates increased with experimental temperature and were influenced by genotype by environment interactions. Substantial additive genetic variation for growth rate in all populations suggests that evolution of trait means in different environments is not constrained. Heritability of growth rates was higher at high temperature, driven by increased genetic rather than environmental variance. While environment-specific nonadditive effects also may contribute to heritability differences among temperatures, maternal effects did not play a significant role (where these could be accounted for). Genotype by environment interactions strongly influenced the adaptive potential of populations, and our results suggest the potential for microevolution of thermal reaction norms in each of the studied populations. In summary, the observed latitudinal pattern in growth rates is adaptive and results from a combination of latitudinal and voltinism compensation. Combined with the evolutionary potential of thermal reaction norms, this may affect populations' ability to respond to future climate warming. PMID- 21689190 TI - Genetic variation and seasonal migratory connectivity in Wilson's warblers (Wilsonia pusilla): species-level differences in nuclear DNA between western and eastern populations. AB - There is growing interest in understanding patterns of seasonal migratory connectivity between breeding and wintering sites, both because differences in migratory behaviour can be associated with population differentiation and because knowledge of migratory connectivity is essential for understanding the ecology, evolution and conservation of migratory species. We present the first broad survey of geographic variation in the nuclear genome of breeding and wintering Wilson's warblers (Wilsonia pusilla), which have previously served as a research system for the study of whether genetic markers and isotopes can reveal patterns of migratory connectivity. Using 153 samples surveyed at up to 257 variable amplified fragment length polymorphism markers, we show that Wilson's warblers consist of highly distinct western and eastern breeding groups, with all winter samples grouping with the western breeding group. Within the west, there is weak geographic differentiation, at a level insufficient for use in the assignment of wintering samples to specific areas. The distinctiveness of western and eastern genetic groups, with no known intermediates, strongly suggests that these two groups are cryptic species. Analysis of mitochondrial cytochrome b sequence variation shows that the estimated coalescence time between western and eastern clades is approximately 2.3 Ma, a surprisingly old time of divergence that is more typical of distinct species than of subspecies. Given their morphological similarity but strong genetic differences, western and eastern Wilson's warblers present a likely case of association between divergence in migratory behaviour and the process of speciation. PMID- 21689191 TI - Alien eggs in duck nests: brood parasitism or a help from Grandma? AB - Intraspecific brood parasitism (IBP) is a remarkable phenomenon by which parasitic females can increase their reproductive output by laying eggs in conspecific females' nests in addition to incubating eggs in their own nest. Kin selection could explain the tolerance, or even the selective advantage, of IBP, but different models of IBP based on game theory yield contradicting predictions. Our analyses of seven polymorphic autosomal microsatellites in two eider duck colonies indicate that relatedness between host and parasitizing females is significantly higher than the background relatedness within the colony. This result is unlikely to be a by-product of relatives nesting in close vicinity, as nest distance and genetic identity are not correlated. For eider females that had been ring-marked during the decades prior to our study, our analyses indicate that (i) the average age of parasitized females is higher than the age of nonparasitized females, (ii) the percentage of nests with alien eggs increases with the age of nesting females, (iii) the level of IBP increases with the host females' age, and (iv) the number of own eggs in the nest of parasitized females significantly decreases with age. IBP may allow those older females unable to produce as many eggs as they can incubate to gain indirect fitness without impairing their direct fitness: genetically related females specialize in their energy allocation, with young females producing more eggs than they can incubate and entrusting these to their older relatives. Intraspecific brood parasitism in ducks may constitute cooperation among generations of closely related females. PMID- 21689192 TI - Deep phylogeographic structuring of populations of the trapdoor spider Moggridgea tingle (Migidae) from southwestern Australia: evidence for long-term refugia within refugia. AB - Southwestern Australia has been recognized as a biodiversity hot spot of global significance, and it is particularly well known for its considerable diversity of flowering plant species. Questions of interest are how this region became so diverse and whether its fauna show similar diverse patterns of speciation. Here, we carried out a phylogeographic study of trapdoor spiders (Migidae: Moggridgea), a presumed Gondwanan lineage found in wet forest localities across southwestern Australia. Phylogenetic, molecular clock and population genetic analyses of mitochondrial (mtDNA) COI gene and ITS rRNA (internal transcribed spacer) data revealed considerable phylogeographic structuring of Moggridgea populations, with evidence for long-term (>3 million years) isolation of at least nine populations in different geographic locations, including upland regions of the Stirling and Porongurup Ranges. High levels of mtDNA divergence and no evidence of recent mitochondrial gene flow among valley populations of the Stirling Range suggest that individual valleys have acted as refugia for the spiders throughout the Pleistocene. Our findings support the hypothesis that climate change, particularly the aridification of Australia after the late Miocene, and the topography of the landscape, which allowed persistence of moist habitats, have been major drivers of speciation in southwestern Australia. PMID- 21689193 TI - Footprints of selection in the ancestral admixture of a New World Creole cattle breed. AB - Admixed populations represent attractive biological models to study adaptive selection. Originating from several waves of recent introduction from European (EUT), African (AFT) and zebus (ZEB) cattle, New World Creole cattle allow investigating the response to tropical environmental challenges of these three ancestries. We here provide a detailed assessment of their genetic contributions to the Creole breed from Guadeloupe (CGU). We subsequently look for footprints of selection by combining results from tests based on the extent of haplotype homozygosity and the identification of excess/deficiency of local ancestry. To tackle these issues, 140 CGU individuals and 25 Brahman zebus from Martinique were genotyped at 44 057 SNPs. These data were combined to those available on 23 populations representative of EUT, AFT or ZEB. We found average proportions of 26.1%, 36.0% and 37.9% of EUT, AFT and ZEB ancestries in the CGU genome indicating a higher level of African and zebu ancestries than suggested by historical records. We further identified 23 genomic regions displaying strong signal of selection, most of them being characterized by an excess of ZEB local ancestry. Among the candidate gene underlying these regions, several are associated with reproductive functions (RXFP2, PMEPA1, IGFBP3, KDR, PPP1R8, TBXA2R and SLC7A5) and metabolism (PDE1B and CYP46A1). Finally, two genes (CENTD3 and SAMD12) are involved in cellular signalization of immune response. This study illustrates the relevance of admixed populations to identify footprints of selection by combining several tests straightforward to implement on large data sets. PMID- 21689194 TI - Ecology and life history affect different aspects of the population structure of 27 high-alpine plants. AB - A plant species' genetic population structure is the result of a complex combination of its life history, ecological preferences, position in the ecosystem and historical factors. As a result, many different statistical methods exist that measure different aspects of species' genetic structure. However, little is known about how these methods are interrelated and how they are related to a species' ecology and life history. In this study, we used the IntraBioDiv amplified fragment length polymorphisms data set from 27 high-alpine species to calculate eight genetic summary statistics that we jointly correlate to a set of six ecological and life-history traits. We found that there is a large amount of redundancy among the calculated summary statistics and that there is a significant association with the matrix of species traits. In a multivariate analysis, two main aspects of population structure were visible among the 27 species. The first aspect is related to the species' dispersal capacities and the second is most likely related to the species' postglacial recolonization of the Alps. Furthermore, we found that some summary statistics, most importantly Mantel's r and Jost's D, show different behaviour than expected based on theory. We therefore advise caution in drawing too strong conclusions from these statistics. PMID- 21689195 TI - The relationship between serious injury and blood alcohol concentration (BAC) in fatal motor vehicle accidents: BAC = 0.01% is associated with significantly more dangerous accidents than BAC = 0.00%. AB - AIM: To analyze the severity of automotive injuries associated with blood alcohol concentration (BAC) in increments of 0.01%. DESIGN/SETTING: Epidemiological study using the Fatality Analysis Reporting System. PARTICIPANTS: All people in US fatal automotive accidents, 1994-2008 (n = 1 495 667). MEASUREMENTS: The ratio of serious: non-serious injuries for drivers, by BAC. FINDINGS: Accident severity increases significantly even when the driver is merely 'buzzed', a finding that persists after standardization for various confounding factors. Three mechanisms mediate between buzzed driving and high accident severity: compared to sober drivers, buzzed drivers are significantly more likely to speed, to be improperly seatbelted and to drive the striking vehicle. In addition, there is a strong 'dose-response' relationship for all three factors in relation to accident severity (e.g. the greater the BAC, the greater the average speed of the driver and the greater the severity of the accident). CONCLUSIONS: The severity of life threatening motor vehicle accidents increases significantly at blood alcohol concentrations (BACs) far lower than the current US limit of 0.08%. Lowering the legal limit could save lives, prevent serious injuries and reduce financial and social costs associated with motor vehicle accidents. PMID- 21689196 TI - Where neuroimaging and lesion studies meet. AB - Lesion studies (both patients and nonhuman animals) and functional neuroimaging studies of normal, healthy subjects provide complementary, but different types of information. This article suggests that both study types are necessary for deriving inferentially sound conclusions regarding the neural basis of cognition. PMID- 21689197 TI - Endovascular management of symptomatic extracranial stenosis associated with secondary intracranial tandem stenosis. A multicenter review. AB - BACKGROUND: Several studies have reported variable rates of perioperative risk of stroke in individuals with tandem stenoses after carotid endarterectomy. Endovascular treatment of extracranial lesions associated with tandem lesions is limited to case reports and small case series. METHODS: We retrospectively reviewed clinical records and angiographic findings of 132 symptomatic patients with extracranial atherosclerotic disease who underwent elective stent placement at three tertiary care centers. Tandem stenosis was defined as any lesion with intracranial stenosis >=50% in the same (but not contiguous) vascular distribution distal to primary extracranial stenosis. The study end point was a composite of any stroke or death within 24 hours, at 1- and 6-month postprocedure. The rates of primary end points were compared between patients with or without secondary tandem stenosis. RESULTS: Out of 132 patients (134 procedures), 27 patients were identified with a tandem stenosis. The stroke and/or death rates at 24 hours were (11.1% vs 7.5%, P = . 69) for patients with tandem stenosis and single stenosis, respectively. The cumulative stroke and/or death rate at 1-month postprocedure (15.0% vs 7.5%, P = .10) and at 6-month postprocedure (26.6% vs 12.8%, P = .08) appeared to be higher among those with tandem stenoses without reaching statistical significance. CONCLUSIONS: The high risk of postprocedural stroke and/or death observed in this series requires careful assessment of the risk/benefit ratio of endovascular procedures in patients with tandem stenosis. PMID- 21689199 TI - Reliability of T2-weighted sagittal magnetic resonance images for determining the location of compressive disk herniation in dogs. AB - Magnetic resonance imaging is used commonly to diagnose intervertebral disk herniation in dogs. It is common to locate areas of suspected compression on sagittal T2-weighted (T2-W) images and then obtain limited transverse images in these areas to reduce the acquisition time (a step-by-step approach). Our objective was to assess the frequency of correct localization of spinal cord compression due to disk herniation using only the sagittal images. The results from isolated readings of the sagittal T2-W images alone or combined with a single-shot fast spin echo (SSFSE) slab in 118 dogs were compared with a gold standard, based on a consensual reading of all images available, including complete transverse images across the entire spinal segments under study. The sites of compression were localized correctly from the sagittal images in 89.8% of dogs. If only the most significant lesions were accounted for, the percentage increased up to 95.2%. In 54.9% of the readings with incorrect localization, the actual compressive site was immediately adjacent to the one suspected from review of the sagittal images. The frequency of correct localization was higher in the cervical region, and was increased by examination of the SSFSE slab. The most common cause of disagreement was the presence of multiple degenerate bulging disks. Based on these results we recommend obtaining transverse images across the entire segment when multiple bulging disks are present. It is also recommended to obtain transverse images across the spaces immediately adjacent to the suspected site of herniation from review of the sagittal images. PMID- 21689198 TI - Contrast-enhanced ultrasonography of the small bowel in healthy cats. AB - We characterized the pattern of ultrasonographic contrast enhancement of the small intestinal wall using a commercial contrast medium (Sonovue((r)) ) in 10 healthy awake cats. Subjectively, a rapid intense enhancement of the serosal and submucosal layers was followed by gradual enhancement of the entire wall section during the early phase. At peak enhancement, there was a subjective loss of demarcation between intestinal wall layers. In the late phase, there was a gradual wash out of signal from the intestinal wall. Submucosal wash out occurred last. Time-intensity curves were generated for selected regions in the intestinal wall and multiple perfusion parameters were calculated for each cat. Perfusion parameters included arrival time (7.64 +/- 2.23 s), baseline intensity (1.04 +/- 0.04 a.u.), time to peak from injection (10.74 +/- 2.08 s), time to peak from initial rise (3.1 +/- 1.15), peak intensity (8.92 +/- 3.72 a.u.), wash-in rate (2.06 +/- 0.70 a.u./s) and wash-out rate (-1.07 +/- 0.91 a.u./s). The perfusion pattern of normal feline small bowel may be useful for characterizing feline gastrointestinal disorders that involve the intestinal wall. PMID- 21689200 TI - Imaging diagnosis--gastric pneumatosis in a cat. AB - Gastrointestinal foreign bodies were removed surgically from a 9-year-old Siamese cat. Two days later the cat became lethargic and started regurgitating. A degenerative leukocytosis and drop in packed cell volume were present. Gastric wall thickening with intramural gastric air was detected radiographically and sonographically. Gastric ulceration with a focal necrotic area was seen endoscopically. At surgery, the stomach wall was emphysematous. Clinical signs resolved following partial gastrectomy and medical management. Intramural gastric air with declining clinical course was a significant impetus to return to surgery. PMID- 21689201 TI - Imaging findings in dogs with caudal intervertebral disc herniation. AB - The radiographic and magnetic resonance imaging (MRI) findings for four dogs with herniation of the Cd1-Cd2 intervertebral disc are described. All dogs were 7 years of age at the time of presentation, with one neutered male and three neutered females. Breeds included one Beagle, one Bassett hound, and two large, mixed breed dogs. All dogs had tail pain on manipulation, two had pain during defecation, and two maintained an abnormal tail position. Three dogs had radiographs in which mineralization within the disc space was apparent. Two of these dogs also had mineralization within the vertebral canal. Three dogs underwent MRI, which was characterized by varying degrees of disc herniation and nerve root compression at Cd1-Cd2. Mobility may be a factor predisposing to disc herniation in the cranial aspect of the caudal spine. We documented that caudal disc herniation does occur occasionally in dogs and that radiography and MRI may be used to identify this disease. Caudal intervertebral disc herniation should be considered as a differential for dogs with caudal vertebral pain, pain with tail manipulation, pain during defecation, or abnormal tail carriage. PMID- 21689202 TI - The use of diffusion tensor imaging to evaluate the spinal cord in normal and abnormal dogs. AB - Diffusion tensor imaging (DTI) is a specialized magnetic resonance sequence to determine the direction of water molecule motion. Our hypothesis was that information derived from DTI will be significantly different in dogs with a spinal cord lesion compared with a normal dog. Eleven normal dogs and six dogs with a spinal cord lesions were imaged. DTI was performed along with standard T1- and T2-weighted sequences in transverse and sagittal planes. Fractional anisotrophy and apparent diffusion coefficient (ADC) were obtained using regions of interests centered on the cranial aspect, middle cranial, middle caudal, and caudal aspects of the spinal cord. In normal dogs, the DTI sequence was characterized by normal fiber tracking with no statistical difference between the four sections of spinal cord (P>0.05). In the dogs with a spinal cord lesion, there was a significant difference in fractional anisotropy between the two groups (P=0.0003) and the ADC analysis statistical significance (P=0.048) at the caudal most site. Based on these findings, DTI is a potentially useful method to evaluate the spinal cord in dogs. PMID- 21689203 TI - Correlation of ultrasound findings, liver and spleen cytology, and prognosis in the clinical staging of high metastatic risk canine mast cell tumors. AB - Cytologic sampling of the ultrasonographically normal spleen and liver is not implemented routinely in the clinical staging of canine cutaneous mast cell tumors and normal ultrasound findings are often accepted as sufficient evidence for ruling out splenic or liver metastasis. Our objective was to define the specificity and sensitivity of ultrasound findings for diagnosis of mast cell infiltration when verified with cytologic evaluation, and to define the prognostic role of cytologic evaluation of liver and splenic aspirates. Dogs with a diagnosis of clinically aggressive grade II, or grade III mast cell tumor treated with a combination vinblastine/CCNU chemotherapy protocol, were selected retrospectively based on availability of cytologic evaluation of spleen plus or minus liver for staging. Out of 19 dogs, 10 dogs had a grade II tumor and nine a grade III tumor. Seven dogs had mast cell infiltration of the spleen, liver, or both. The sensitivity of ultrasound for detecting mast cell infiltration was 43% for the spleen and 0% for the liver. Dogs with positive cytologic evidence of mast cell infiltration to spleen, liver, or both had significantly shorter survival (100 vs. 291 days) than dogs without evidence of mast cell infiltration (P<0.0001). Routine splenic aspiration should be performed regardless of ultrasonographic appearance in dogs with a clinically aggressive mast cell tumor. PMID- 21689204 TI - Assessment of optimal condylar position in the coronal and axial planes with limited cone-beam computed tomography. AB - PURPOSE: No quantitative standards for the optimal position of the mandibular condyle in the glenoid fossa are yet available in the coronal and axial planes. We previously reported measurements of this position in the sagittal plane, using recently developed limited cone-beam computed tomography (LCBCT) capable of imaging the craniofacial structures with high accuracy. In this study, we assessed the optimal condylar position in the coronal and axial planes. MATERIALS AND METHODS: The study included 24 joints in 22 asymptomatic patients (10 male, 12 female; age range 12-25 years, mean age 18 years) who had no disc displacement as confirmed by magnetic resonance imaging. Their joints had optimum function with the starting and end points of all functional jaw movements coincident with maximum intercuspation. Joint-space distances between the condyle and glenoid fossa were measured at the medial, central, and lateral positions in the coronal plane, and medial and lateral positions in the axial plane. RESULTS: The mean coronal lateral space (CLS), coronal central space (CCS), and coronal medial space (CMS) were 1.8 +/- 0.4 mm, 2.7 +/- 0.5 mm, and 2.4 +/- 0.5 mm, respectively. The ratio of CLS to CCS to CMS was 1.0 to 1.5 to 1.3. The mean axial medial space (AMS) and axial lateral space (ALS) were 2.1 +/- 0.6 mm and 2.3 +/- 0.6 mm, respectively. There were no significant sex differences in these measurements. CONCLUSIONS: These coronal and axial data, along with previously reported sagittal data, might provide norms for 3D assessment of optimal condylar position with LCBCT. PMID- 21689205 TI - Expression and prognostic relevance of p21WAF1 in stage III esophageal squamous cell carcinoma. AB - The prognostic effect of p21(WAF1) expression on esophageal squamous cell carcinoma patients is controversial. Further clarifying the effect of this protein is beneficial for optimizing the patient outcomes. In the current study, we investigated the expression of p21(WAF1) protein in 189 specimens of stage III ESCC by immunohistochemistry. As shown by the Kaplan-Meier curve, the overall survival rate of the positive-expression group was significantly higher than that of the negative-expression group (P < 0.05). No significant correlation was observed between p21(WAF1) expression and clinicopathological parameters in terms of gender, age, tumor location, tumor grade, pathological stage, and number of regional lymph node metastases (P > 0.05). We concluded that p21(WAF1) played an intricate role in the tumorigenesis and development of ESCC. p21(WAF1) could serve as a positive prognostic predictor for stage III ESCC patients. PMID- 21689206 TI - Fiber-optic assessment of LMA position in children: a randomized crossover comparison of two techniques. AB - BACKGROUND: This crossover study compared fiber-optic assessment of laryngeal mask airway (LMA) position in children using two LMA insertion techniques, i.e., standard and rotational. METHODS: Seventy-eight ASA I children, aged 2.5 months to 10 years, undergoing elective cataract surgery were included in this study. LMA was inserted in random order using either standard or rotational technique, removed, and thereafter crossed over to alternate technique. Positioning of LMA was assessed using fiber-optic bronchoscope with each technique. Change in the incidence of fiber-optic assessment grades 1 and 2 between two insertion techniques was measured as the primary outcome. Secondary outcome measures studied were first-attempt success rate, overall success rate, time for successful insertion, visual analogue scale for placement, complications, and maneuvers used to relieve airway obstruction. RESULTS: Incidence of fiber-optic grades 1 and 2 was 61.5% with standard technique and increased to 92.3% with rotational technique (P < 0.001, McNemar's test) (RR 3.0, 95% CI 2.2-4.2). Median (IQR) fiber-optic grading was significantly better with rotational technique [2 (1-2)] as compared to standard technique [2 (2-3)], (P < 0.001, Wilcoxon signed rank test). First-attempt success rate was significantly higher (96.2%) with rotational technique compared with standard technique (80.7%) (P = 0.04, McNemar's test). Overall success rate (i.e., successful insertion with two attempts) was 100% with rotational technique compared with 89.7% with standard technique (P = 0.003, Fischer's exact test). Time for successful insertion and incidence of complications were significantly lesser with rotational technique. CONCLUSION: Rotational technique of LMA insertion in children is associated with better seating of LMA (as observed on fiber-optic assessment) compared with the standard technique. Also, it is associated with higher success rate and lower incidence of complications. PMID- 21689207 TI - A simple test for the detection of KPC and metallo-beta-lactamase carbapenemase producing Pseudomonas aeruginosa isolates with the use of meropenem disks supplemented with aminophenylboronic acid, dipicolinic acid and cloxacillin. AB - We evaluated the ability of the combination disk test (CDT) and the Modified Hodge Test (MHT) to discriminate between various carbapenemase-producing Pseudomonas aeruginosa isolates (KPC, n = 36; metallo-beta-lactamase (MBL), n = 38) and carbapenemase non-producers (n = 75). For the CDT, the optimal inhibitor concentrations and cut-off values were: 600 MUg of 3-aminophenylboronic acid (APB) per disk (an increment of >=4 mm), 1000 MUg of dipicolinic acid (DPA) per disk (an increment of >=5 mm) and 3000 MUg of cloxacillin per disk (an increment of >=3 mm). APB had excellent sensitivity (97%) and specificity (97%) for the detection of KPC enzymes. DPA detected MBL enzymes with a sensitivity and specificity of 97% and 81%, respectively. The MHT resulted in a low sensitivity (78%) and specificity (57%). The CDT could be very useful in daily practice to provide fast and reliable detection of KPC and MBL carbapenemases among P. aeruginosa isolates. PMID- 21689208 TI - Does it ever make sense to treat a bacterial infection with a drug against which the responsible pathogen possesses a resistance mechanism? PMID- 21689209 TI - Presurgical pharmacokinetic analysis of a von Willebrand factor/factor VIII (VWF/FVIII) concentrate in patients with von Willebrand's disease (VWD) has limited value in dosing for surgery. AB - Optimal doses of von Willebrand Factor/Factor VIII (VWF/FVIII) concentrates for surgical procedures in patients with VWD need to be determined. A prospective, multicenter study was performed that included an initial pharmacokinetic (PK) assessment following a standard dose of VWF/FVIII concentrate (Humate-P(r)) to determine individual PK parameters and guide therapeutic dosing during surgery. Forty one subjects received 60 IU kg-1 VWF: RCo. Median plasma levels, half-life, mean change from baseline and in vivo recovery (IVR) values were determined for VWF:RCo, VWF:Ag, and FVIII: C, and area under the plasma time-concentration curve (AUC), mean residence time (MRT), clearance, volume of distribution and dose linearity were also assessed for VWF:RCo at various time points. Median baseline VWF:RCo level was 13 IU dL-1 (range, 6-124); with a mean change from baseline >100 IU dL-1 immediately after the infusion, decreasing to 10 IU dL-1 at 48 h postinfusion. The group median incremental in vivo recovery (IVR) for VWF:RCo was 2.4 IU dL-1 per IU kg-1, for VWF:Ag 2.3 IU dL-1 kg-1 and for FVIII:C was 2.7 IU dL-1 per IU kg-1. When analysing individual recovery values on repeated infusions, a very weak correlation was observed between presurgery IVR and IVR for both VWF:RCo and FVIII, measured at various times just prior to and after the surgical procedure. Although group median values were fairly consistent among repeated IVR measurements, the intra-individual IVR values for FVIII and VWF:RCo with repeated infusions showed a large degree of variability. IVR values obtained from pharmacokinetic analyses performed in advance of anticipated surgery do not reliably predict postinfusion circulating levels of VWF:RCo or FVIII attained preoperatively or with subsequent peri-operative infusions. PMID- 21689210 TI - Inhibitory effects of bromelain, a cysteine protease derived from pineapple stem (Ananas comosus), on intestinal motility in mice. AB - BACKGROUND: Bromelain (BR) is a cysteine protease with inhibitory effects on intestinal secretion and inflammation. However, its effects on intestinal motility are largely unexplored. Thus, we investigated the effect of this plant derived compound on intestinal contractility and transit in mice. METHODS: Contractility in vitro was evaluated by stimulating the mouse isolated ileum, in an organ bath, with acetylcholine, barium chloride, or electrical field stimulation. Motility in vivo was measured by evaluating the distribution of an orally administered fluorescent marker along the small intestine. Transit was also evaluated in pathophysiologic states induced by the pro-inflammatory compound croton oil or by the diabetogenic agent streptozotocin. KEY RESULTS: Bromelain inhibited the contractions induced by different spasmogenic compounds in the mouse ileum with similar potency. The antispasmodic effect was reduced or counteracted by the proteolytic enzyme inhibitor, gabexate (15 * 10(-6) mol L( 1) ), protease-activated receptor-2 (PAR-2) antagonist, N(1) -3-methylbutyryl N(4) -6-aminohexanoyl-piperazine (10(-4) mol L(-1) ), phospholipase C (PLC) inhibitor, neomycin (3 * 10(-3) mol L(-1) ), and phosphodiesterase 4 (PDE4) inhibitor, rolipram (10(-6) mol L(-1) ). In vivo, BR preferentially inhibited motility in pathophysiologic states in a PAR-2-antagonist-sensitive manner. CONCLUSIONS & INFERENCES: Our data suggest that BR inhibits intestinal motility - preferentially in pathophysiologic conditions - with a mechanism possibly involving membrane PAR-2 and PLC and PDE4 as intracellular signals. Bromelain could be a lead compound for the development of new drugs, able to normalize the intestinal motility in inflammation and diabetes. PMID- 21689211 TI - The burden of HCV treatment in patients with inherited bleeding disorders. AB - Many patients with inherited bleeding disorders are infected with hepatitis C virus (HCV). Antiviral treatment, consisting of pegylated interferon and ribavirin, has many side-effects. The aim of the study was to prospectively assess the occurrence and course of side-effects and changes in health-related quality of life (HRQoL) during antiviral treatment in patients with inherited bleeding disorders and chronic HCV. Forty-seven patients were followed during antiviral treatment. Side-effects of treatment were recorded, and the Beck Depression Inventory and the RAND-36 HRQoL questionnaire were administered at regular intervals. Frequently reported side-effects were fatigue (100%), headache (94%), pruritus and skin rash (94%), concentration problems (89%), decreased appetite (89%), fever, irritability and hair loss (all 85%). Many side-effects disappeared soon after end of treatment, but 4 weeks after cessation fatigue, concentration problems and sleeping problems were still present in more than 30% of patients. Dose reduction was necessary in 21 patients (45%), mostly because of decreasing weight or haemoglobin levels. Two patients stopped treatment prematurely because of side-effects. Depression was present in 28 patients (60%). HRQoL decreased significantly during treatment in all RAND-36 domains, and increased again within 4 weeks after treatment. Major side-effects were similar in patients with successful (n = 31, 66%) and unsuccessful antiviral treatment. In patients with inherited bleeding disorders and chronic HCV, antiviral treatment has many, but mostly transient side-effects and a significant impact on quality of life. Careful follow-up and management of side-effects will ensure optimal compliance and treatment results. PMID- 21689212 TI - Haemophilia utilization group study - Part Va (HUGS Va): design, methods and baseline data. AB - To describe the study design, procedures and baseline characteristics of the Haemophilia Utilization Group Study - Part Va (HUGS Va), a US multi-center observational study evaluating the cost of care and burden of illness in persons with factor VIII deficiency. Patients with factor VIII level <= 30%, age 2-64 years, receiving treatment at one of six federally supported haemophilia treatment centres (HTCs) were enrolled in the study. Participants completed an initial interview including questions on socio-demographical characteristics, health insurance status, co-morbidities, access to care, haemophilia treatment regimen, factor utilization, self-reported joint pain and motion limitation and health-related quality of life. A periodic follow-up survey collected data regarding time lost from usual activities, disability days, health care utilization and outcomes of care. HTC clinicians documented participants' baseline clinical characteristics and pharmacy dispensing records for 2 years. Between July 2005 and July 2007, 329 participants were enrolled. Average age was 9.7 years for children and 33.5 years for adults; two-thirds had severe haemophilia. The distributions of age, marital status, education level and barriers to haemophilia care were relatively consistent across haemophilic severity categories. Differences were found in participants' employment status, insurance status and income. Overall, children with haemophilia had quality of life scores comparable to healthy counterparts. Adults had significantly lower physical functioning than the general US population. As one of the largest economic studies of haemophilia care, HUGS Va will provide detailed information regarding the burden of illness and health care utilization in the US haemophilia A population. PMID- 21689213 TI - Bias in recruitment to cluster randomized trials: a review of recent publications. AB - OBJECTIVES: To assess recruitment bias and the techniques employed to counter this problem in a recent selection of published cluster randomized trials. DESIGN: Review of 24 cluster trials published in 2008 in four leading medical journals. DATA EXTRACTION: Studies were assessed by four reviewers to identify if an alternative design could have been employed using individual randomization. Data were also extracted on the randomization procedure and the likelihood of this introducing bias to the selection of participants into the study. RESULTS: Of the 24 trials, eight could have used individual randomization as an alternative to cluster allocation. Seven studies could have recruited participants prior to cluster randomization but did not. In eight studies where recruitment bias was possible, more than half (five) demonstrated some evidence of differential recruitment rates. CONCLUSIONS: Many cluster trials published in leading medical journals are not clear in their justification for the design. We also found significant proportions of cluster trials used suboptimal designs that increase their risk of introducing selection bias. Better design of cluster trials is possible and should be adopted. PMID- 21689214 TI - Coronary stent use in New York State in the drug-eluting stent era. AB - OBJECTIVES: The drug-eluting stent (DES) was perceived as a revolutionary medical technology because of the lower risk of restenosis compared with bare metal stent (BMS). However, the safety of DES use was called into question in 2006 due to increased incidence of catastrophic late stent thrombosis. This study aims to describe coronary stent use in the DES era in New York State. METHODS: Using New York State statewide hospital discharge database, we conducted descriptive analysis and logistic regression to examine the independent impacts of the introduction of DES and of the DES safety concern on DES utilization, controlling for patient demographics, co-morbidities and hospital effects. RESULTS: In the first year following the introduction of DES technology, there was a 10-fold increase in the odds of DES use versus BMS use (AOR: 10.86, 95% CI: 9.84-11.99, P < 0.001). When the safety of DES use was called into question, the odds of DES utilization decreased by 75% over a 9-month period (AOR: 0.23, 95% CI: 0.20-0.26, P < 0.001). CONCLUSIONS: Following the introduction of DES, there was a rapid adoption of DES by interventional cardiologists, followed by a rapid abandonment of DES when significant safety issues were raised. After the safety of DES was called into question, there was a reduction in the use of DES and in the use of stents in general. PMID- 21689215 TI - Electronic health record identification of prediabetes and an assessment of unmet counselling needs. AB - RATIONALE, AIMS AND OBJECTIVES: Large clinical trials demonstrate that lifestyle modification can prevent or delay the onset of diabetes in those with prediabetes. However, recent National Health and Nutrition Survey data suggest that prediabetes often goes unrecognized, and the majority of prediabetic individuals do not report having received lifestyle advice from physicians. We explored whether electronic health record (EHR) query of glucose measurements can identify prediabetic patients, and we estimated rates of prediabetic lifestyle counselling in a large, urban, primary care practice. METHODS: Electronic search identified patients with plasma glucose levels of 100 to 199 mg dL(-1) between 1 June 2007 and 1 June 2009, excluding those with diabetes or diabetic medications/supplies. From these 5366 patients, 100 randomly selected patients underwent classification into provisional categories based on available EHR data: likely prediabetes, likely diabetes, glucose abnormality in the setting of acute illness, or normal glucose metabolism. In those likely to have prediabetes, we assessed lifestyle modification counselling. RESULTS: Fifty-eight per cent (95% CI 48% to 68%) of patients sampled were likely to have prediabetes. Fourteen per cent of those sampled were likely to have diabetes. Thirty-one per cent of prediabetics (95% CI 22% to 42%) had documented lifestyle counselling. Counselled patients had a significantly higher baseline mean body mass index compared to those not counselled (34.1 versus 29.9, P = 0.037). CONCLUSIONS: EHR query using glucose measurements can identify prediabetic patients and those requiring further glucose metabolism evaluation, including those with undiagnosed diabetes. Future research should investigate EHR-based, population-level interventions to facilitate prediabetes recognition and counselling. PMID- 21689216 TI - Computerized physician order entry system combined with on-ward pharmacist: analysis of pharmacists' interventions. AB - RATIONALE, AIMS AND OBJECTIVES: To analyse pharmacists' interventions in a setting where a computerized physician order entry system (CPOE) is in use and a pharmacist works on the ward. METHOD: A prospective cohort study was conducted in seven wards of a French teaching hospital using CPOE along with the presence of a full-time on-ward pharmacy resident. We documented the characteristics of pharmacists' interventions communicated to physicians during the medication order validation process whenever a drug-related problem was identified. Independent predictors of the physician's acceptance of the pharmacist's intervention were assessed using multiple logistic regression analysis. RESULTS: The 448 pharmacists' interventions concerned: non-conformity to guidelines or contraindications (22%), too high doses (19%), drug interactions (15%) and improper administration (15%). The interventions consisted of changes in drug choice (41%), dose adjustment (23%), drug monitoring (19%) and optimization of administration (17%). Interventions were communicated via the CPOE in 57% of cases and 43% orally. The rate of physicians' acceptance was 79.2%. In multivariate analysis, acceptance was significantly associated with the physician's status [higher for residents vs. seniors: OR = 7.23, CI 95 (2.37 22.10), P < 0.01], method of communication [higher for oral vs. computer communication: OR = 12.5, CI 95 (4.16-37.57), P < 0.01] and type of recommendation [higher for drug monitoring vs. drug choice recommendations: OR = 10.32, CI 95 (3.20-33.29), P < 0.01]. CONCLUSIONS: When a clinical pharmacist is present on a ward in which a CPOE is in use, the pharmacists' interventions are well accepted by physicians. Specific predictors of the acceptance by physicians emerge, but further research as to the impact of CPOE on pharmacist-physician communication is needed. PMID- 21689217 TI - Clinical instruments: reliability and validity critical appraisal. AB - RATIONALE, AIM AND OBJECTIVES: There is a lack of health care practitioners using objective clinical tools with sound psychometric properties. There is also a need for researchers to improve their reporting of the validity and reliability results of these clinical tools. Therefore, to promote the use of valid and reliable tools or tests for clinical evaluation, this paper reports on the development of a critical appraisal tool to assess the psychometric properties of objective clinical tools. METHOD: A five-step process was followed to develop the new critical appraisal tool: (1) preliminary conceptual decisions; (2) defining key concepts; (3) item generation; (4) assessment of face validity; and (5) formulation of the final tool. RESULTS: The new critical appraisal tool consists of 13 items, of which five items relate to both validity and reliability studies, four items to validity studies only and four items to reliability studies. The 13 items could be scored as 'yes', 'no' or 'not applicable'. CONCLUSION: This critical appraisal tool will aid both the health care practitioner to critically appraise the relevant literature and researchers to improve the quality of reporting of the validity and reliability of objective clinical tools. PMID- 21689218 TI - Physician adherence to asthma treatment guidelines in Japan: focus on inhaled corticosteroids. AB - OBJECTIVES: Asthma treatment guidelines recommend inhaled corticosteroids (ICS) as the first-line therapy. However, ICS are prescribed to lower percentages of asthmatic patients in Japan than in other developed countries. The aim of this study was to reveal factors affecting the prescription of ICS for asthmatic adults. METHODS: Using insurance claims data in Kyoto Prefecture, Japan, we performed a cross-sectional study. We assessed whether outpatients aged 15 years or older who were diagnosed with asthma had received ICS or not, and conducted logistic regression analyses to identify patients' and facilities' factors associated with ICS use. RESULTS: We analysed 13,428 asthmatic adults, of which 51% were prescribed ICS. Patients receiving asthma care at facilities with respiratory or allergy specialists were more likely to receive ICS than facilities without specialists (adjusted odds ratio 2.70; 95% confidence interval 2.46-2.97). Those aged 75 years or older were less likely to receive ICS than those aged 15 to 64 (adjusted odds ratio 0.71; 95% confidence interval 0.64 0.78). An examination of the interaction between the presence or absence of specialists and facility training status suggested that whether asthmatic adults received ICS depended on the former factor rather than the latter. CONCLUSION: The presence of specialists in facilities and the age of patients were strong factors affecting ICS prescription. Increases in ICS therapy for the elderly and ICS prescription by non-specialists would lead to an overall increase in patients receiving ICS and consequently achieving the goal of asthma control. PMID- 21689219 TI - Using vote cards to encourage active participation and to improve critical appraisal skills in evidence-based medicine journal clubs. AB - RATIONALE, AIMS AND OBJECTIVES: Evidence-based medicine (EBM) journal clubs are used by health care practitioners to critique and remain updated on relevant health literature. Vote cards, in three different colours (green/yellow/red), allow participants to express their opinions (agree/doubt/reject) on the quality and possibility of clinical application regarding the article being reviewed. Our aim is to assess the efficacy of using vote cards in EBM journal clubs. METHODS: Evidence-based medicine journal club is held on a weekly basis in the Department of Surgery in Taipei Medical University Hospital, Taiwan. The participants of EBM journal clubs include medical students, resident doctors and primary care faculty members. After the presentation, participants use their vote cards to critically appraise the literature and decide if the rationales could be applied in their own practice. After a 12-week period, we evaluated the effectiveness of the vote cards based on survey findings of the participants. RESULTS: The majority of 66 respondents agreed that vote cards can improve the overall quality of EBM journal clubs, may encourage active participation and improve critical appraisal skills. They also rated the vote cards more favourably than traditional hand voting and agree that vote cards should be used in future EBM journal clubs. CONCLUSION: We suggest the regular and routine use of vote cards in EBM journal clubs. PMID- 21689220 TI - Responding to the evidence for the management of severe malaria. PMID- 21689221 TI - Simultaneous administration of praziquantel, ivermectin and albendazole, in a community in rural northern Ghana endemic for schistosomiasis, onchocerciasis and lymphatic filariasis. AB - OBJECTIVES: To compare (i) side effects associated with the simultaneous adminstration of praziquantel, albendazole and ivermectin with side affects associated with albendazole and ivermectin only and (ii) coverage by volunteers distributing three or two drugs. METHODS: Two-arm comparative study in northern Ghana integrated praziquantel distribution into an existing lymphatic filariasis and onchocerciasis control programme using Community Directed Distributors. The control arm continued to distribute only ivermectin and albendazole. Dosages of ivermectin and praziquantel were based on height. Treatment was directly observed, and all two/three drugs were co-administered. Adverse effects were recorded based on passive surveillance. Parasitological, anthropometric and haematological data were collected at baseline. RESULTS: Prevalence of Schistosoma haematobium infection among 1001 (boys: 47.9% girls: 52.1%) school age children (6-15 years) [intervention: 30.0% (CI: 23.1-34.2); control: 23.0% (CI: 18.9-27.0)], mean haemoglobin, weight and age were similar among the intervention and control groups. While 1676 (99.1%) compounds in the control area were visited and 15,020 (96.58%) people were treated, only 1375 (88.5%) compounds in the intervention area were visited and 8454 (80.97%) people treated (P < 0.001). The numbers of adverse effects were similar (intervention: 50/6896; control: 130/15,020). The most reported adverse effects was headache (intervention: 14/50; control: 13/130), followed by body weakness, which was reported more from the intervention group (intervention: 13/50, 95% CI: 14.6 40.3; control: 6/130, 95% CI: 1.7-9.8]. Sixty-six per cent (6896/10,441) of the eligible population received praziquantel. CONCLUSIONS: Reported adverse events were mild and managed at the subdistrict level with no cases of hospitalization; intensive health education will, however, be required to improve coverage. PMID- 21689222 TI - The effect of temperature on the bacterial load and microbial composition in Norway lobster (Nephrops norvegicus) tail meat during storage. AB - AIMS: The aim of this study was to update and extend our knowledge of the bacterial load and microbial composition in Norway lobster (Nephrops norvegicus) under commercially relevant storage conditions to optimize handling procedures. METHODS AND RESULTS: Total viable counts were performed at different storage temperatures (0, 4, 8, 10, 12 or 16 degrees C) and after different storage times (1-7 days). Storage at 16 degrees C was found to be most detrimental, and storage at 0 degrees C was found to be optimal. 16S-rRNA sequencing was utilized to determine the composition of the bacteria within the microflora. In this way, Photobacterium isolates, especially Photobacterium phosphoreum, were identified as the main specific spoilage organisms. The abilities to reduce trimethylamineoxide (TMAO) and to produce H(2)S were analysed in a selection of bacterial isolates. The higher the incubation temperature during storage, the more isolates were found to reduce TMAO and produce H(2)S. CONCLUSIONS: Nephrops norvegicus possesses an unusually high initial microbial load when fresh. Storage temperature is the most crucial factor affecting microbial growth, microbial activity and spoilage potential in N. norvegicus produce. Spoilage can be attributed mainly to P. phosphoreum. SIGNIFICANCE AND IMPACT OF THE STUDY: This study presents significant new findings with regard to the progression and causative agents of spoilage in N. norvegicus. Based on the results, we can recommend that N. norvegicus tails should be stored in a 0 degrees C environment immediately after catch. Stored this way, the growth and spoilage activity of the microflora may be reduced significantly and an extension of shelf life might be attained. PMID- 21689223 TI - The oxidoreductases LivQ and NeoQ are responsible for the different 6' modifications in the aminoglycosides lividomycin and neomycin. AB - AIMS: The 2-deoxystreptamine-containing aminoglycoside antibiotics (AGAs) constitute the largest subgroup of the aminoglycosides. Neomycin (NEO) and lividomycin (LIV) are both representatives of the pseudo-tetrasaccharide group among the NEO-type AGAs. While NEO contains a 6'-NH(2) group, the 6'-position remains unmodified in LIV. The aim of the study was to characterize the substrate specificities of the enzymes involved in the C-6'- and C-6'''-modification in order to explain the different amination patterns. METHODS AND RESULTS: We overproduced and purified the enzymes NeoQ (bifunctional 6'- and 6''' oxidoreductase) and NeoB (bifunctional 6'- and-6'''-aminotransferase), which had been analysed before (Huang et al. 2007), and compared the enzymatic properties with the corresponding enzymes LivQ (postulated 6'''-oxidoreductase, 72% identity to NeoQ) and LivB (postulated 6'''-aminotransferase, 71% identity to NeoB) from the LIV pathway. By applying a newly established photometric assay, we proved that LivQ oxidized only pseudotetrasaccharidic substrates at the 6'''-position. In contrast, NeoQ accepted also the pseudodisaccharidic paromamine as a substrate and oxidized the 6'- and 6'''-positions on two different precursors of NEO. The aminotransferases LivB and NeoB both transfer NH(2) groups to the 6'-position in the precursor 6'-oxo-paromamine and to the 6'''-position of 6'''-oxo-neomycin C. CONCLUSIONS: The difference in the modification pattern of NEO and LIV at their 6'-positions is based only on the difference in the substrate specificities of the oxidoreductases LivQ and NeoQ, respectively. The aminotransferases LivB and NeoB share identical biochemical properties, and both are capable to transaminate the 6' and also the 6'''-position of the tested AGAs. SIGNIFICANCE AND IMPACT OF THE STUDY: Our data provide information to understand the structural variations in aminoglycosides and may be helpful to interpret variations in other natural product bisoynthesis pathways. PMID- 21689224 TI - Detection of Laribacter hongkongensis using species-specific duplex PCR assays targeting the 16S rRNA gene and the 16S-23S rRNA intergenic spacer region (ISR). AB - AIMS: For the rapid detection of Laribacter hongkongensis, which is associated with human community-acquired gastroenteritis and traveller's diarrhoea, we developed a duplex species-specific PCR assay. METHODS AND RESULTS: Full-length of the 16S-23S rRNA intergenic spacer region (ISR) sequences of 52 L. hongkongensis isolates were obtained by PCR-based sequencing. Two species specific primer pairs targeting 16S rRNA gene and ISR were designed for duplex PCR detection of L. hongkongensis. The L. hongkongensis species-specific duplex PCR assay showed 100% specificity, and the minimum detectable level was 2.1 * 10( 2) ng MUl(-1) genomic DNA which corresponds to 5000 CFU ml(-1). CONCLUSIONS: The high specificity and sensitivity of the assay make it suitable for rapid detection of L. hongkongensis. SIGNIFICANCE AND IMPACT OF THE STUDY: This species specific duplex PCR method provides a rapid, simple, and reliable alternative to conventional methods to identify L. hongkongensis and may have applications in both clinical and environmental microbiology. PMID- 21689225 TI - Biosynthesis of novel polyhydroxyalkanoate containing 3-hydroxy-4-methylvalerate by Chromobacterium sp. USM2. AB - AIMS: Polyhydroxyalkanoate (PHA) with enhanced physicochemical properties will be ideal for a wide range of practical applications. The incorporation of 3-hydroxy 4-methylvalerate (3H4MV) into the polymer backbone is known to improve the overall properties of the resulting polymer. However, the most suitable micro organism and PHA synthase that can synthesize this monomer efficiently still remain unknown at present. Therefore, we evaluated the abilities of a locally isolated Chromobacterium sp. USM2 to produce PHA containing 3H4MV. METHODS AND RESULTS: The ability of Chromobacterium sp. USM2 to synthesize poly(3 hydroxybutyrate-co-3-hydroxy-4-methylvalerate) [P(3HB-co-3H4MV)] was evaluated under different culture conditions. It was found that Chromobacterium sp. USM2 can synthesize P(3HB-co-3H4MV) when glucose and isocaproic acid were fed as carbon source. However, the highest molar fraction of 3H4MV, 22 mol% was detected in Chromobacterium sp. USM2 when isocaproic acid was provided as the sole carbon source. In addition, aeration was identified as a crucial factor in initiating the accumulation of high 3H4MV molar fractions. CONCLUSIONS: Chromobacterium sp. USM2 was able to synthesize broad comonomer compositional distribution of P(3HB co-3H4MV). SIGNIFICANCE AND IMPACT OF THE STUDY: Compared with Cupriavidus necator and Burkholderia sp., Chromobacterium sp. USM2 was found to have better ability to bioconvert isocaproic acid to form 3H4MV unit. PMID- 21689226 TI - Sarcopenia negatively impacts short-term outcomes in patients undergoing hepatic resection for colorectal liver metastasis. AB - BACKGROUND: As indications for liver resection expand, objective measures to assess the risk of peri-operative morbidity are needed. The impact of sarcopenia on patients undergoing liver resection for colorectal liver metastasis (CRLM) was investigated. METHODS: Sarcopenia was assessed in 259 patients undergoing liver resection for CRLM by measuring total psoas area (TPA) on computed tomography (CT). The impact of sarcopenia was assessed after controlling for clinicopathological factors using multivariate modelling. RESULTS: Median patient age was 58 years and most patients (60%) were male. Forty-one (16%) patients had sarcopenia (TPA <= 500 mm(2) /m(2) ). Post-operatively, 60 patients had a complication for an overall morbidity of 23%; 26 patients (10%) had a major complication (Clavien grade >=3). The presence of sarcopenia was strongly associated with an increased risk of major post-operative complications [odds ratio (OR) 3.33; P= 0.008]. Patients with sarcopenia had longer hospital stays (6.6 vs. 5.4 days; P= 0.03) and a higher chance of an extended intensive care unit (ICU) stay (>2 days; P= 0.004). On multivariate analysis, sarcopenia remained independently associated with an increased risk of post-operative complications (OR 3.12; P= 0.02). Sarcopenia was not significantly associated with recurrence-free [hazard ratio (HR) = 1.07] or overall (HR = 1.05) survival (both P > 0.05). CONCLUSIONS: Sarcopenia impacts short-, but not long-term outcomes after resection of CRLM. While patients with sarcopenia are at an increased risk of post-operative morbidity and longer hospital stay, long-term survival is not impacted by the presence of sarcopenia. PMID- 21689227 TI - Effect of centre volume and high donor risk index on liver allograft survival. AB - BACKGROUND: A growth in the utilization of high-risk allografts is reflective of a critical national shortage and the increasing waiting list mortality. Using risk-adjusted models, the aim of the present study was to determine whether a volume-outcome relationship existed among liver transplants at high risk for allograft failure. METHODS: From 2002 to 2008, the Scientific Registry of Transplant Recipients (SRTR) database for all adult deceased donor liver transplants (n = 31 587) was queried. Transplant centres (n = 102) were categorized by volume into tertiles: low (LVC; 31 cases/year), medium (MVC: 64 cases/year) and high (HVC: 102 cases/year). Donor risk comparison groups were stratified by quartiles of the Donor Risk Index (DRI) spectrum: low risk (DRI <= 1.63), moderate risk (1.64 > DRI > 1.90), high risk (1.91 > DRI > 2.26) and very high risk (DRI >= 2.27). RESULTS: HVC more frequently used higher-risk livers (median DRI: LVC: 1.82, MVC: 1.90, HVC: 1.97; P < 0.0001) and achieved better risk adjusted allograft survival outcomes compared with LVC (HR: 0.90, 95%CI: 0.85-0.95). For high and very high risk groups, transplantation at a HVC did contribute to improved graft survival [high risk: hazard ratio (HR): 0.85, 95% confidence interval (CI): 0.76-0.96; Very High Risk: HR: 0.88, 95%CI: 0.78-0.99]. CONCLUSION: While DRI remains an important aspect of allograft survival prediction models, liver transplantation at a HVC appears to result in improved allograft survival with high and very high risk DRI organs compared with LVC. PMID- 21689228 TI - Major venous resection during total laparoscopic pancreaticoduodenectomy. AB - BACKGROUND: The feasibility of total laparoscopic pancreaticoduodenectomy (TLPD) has been established. Laparoscopic major venous resection during TLPD has not been reported. The aim of the present study was to describe the technique and outcomes of patients undergoing TLPD with major venous resection. METHODS: Retrospective review of all consecutive patients undergoing TLPD and major venous resection from July 2007 to December 2010 was performed. Patient demographics and peri-operative outcomes were retrieved. Data are presented as mean +/- standard deviation (SD) or median with range. RESULTS: Out of 129 patients undergoing TLPD, major venous resection was performed in 11 patients with a mean age of 71 years. Median operative time and blood loss was 413 (301-666) min and 500 (75 2800) ml, respectively. Venous resection included tangential (n= 10) and segmental resection (n = 1). Venous reconstruction included patch (n = 4), suture (n = 4), stapled (n = 2) and a left renal vein interposition graft (n = 1). Median mesoportal clamp time was 35 (10-82) min. There was no 30-day or in hospital mortality. Post-operative imaging was available in 10 patients with 100% patency at the venous reconstruction site. CONCLUSIONS: Laparoscopic major venous resection during TLPD is feasible in selected patients. Extensive experience with complex laparoscopic pancreatic resection and reconstruction is advocated before attempting this procedure. PMID- 21689229 TI - The role of endoscopic ultrasound and cyst fluid analysis in the initial evaluation and follow-up of incidental pancreatic cystic lesions. AB - PURPOSE: To assess the role of endoscopic ultrasound (EUS) in the initial evaluation and follow-up of incidental pancreatic cystic lesions (PCL). METHODS: Retrospective analysis of patients with incidental PCL on imaging who were evaluated by EUS and had a minimal follow-up of 1 year. RESULTS: There were 62 patients (40 females and 22 males). The mean patient age was 67.7 years (range, 30-89). The Median follow-up was 24 months (range, 12-72). The mean PCL size was 21.6 mm. In all, 13 patients underwent surgery (20.9%). Diagnosis included a mucinous cystic tumour (7), mucinous adenocarcinoma (2), intraductal papillary mucinous neoplasm (1) and a cystic neuroendocrine tumour (1). The overall malignancy rate among patients who underwent surgery was 15.3% (two patients). The mean carcinoembryonic antigen (CEA) level from PCL fluid analysis was also significantly higher in surgically treated group (7760) vs. the stable group (184.7) vs. the enlarging PCL group (361.1). A CEA level above 192 ng/ml predicted mucinous PCL with a sensitivity of 90%. CONCLUSIONS: EUS with cystic fluid analysis can be successfully used to rule out pancreatic neoplasms and to follow-up incidentally discovered PCL. PMID- 21689230 TI - The role of laparoscopic staging in patients with incidental gallbladder cancer. AB - BACKGROUND: The role of staging laparoscopy (SL) in patients with incidental gallbladder cancer (IGBC) is ill defined. This study evaluates the utility of SL with the aim of identifying variables associated with disseminated disease (DD). METHODS: Consecutive patients with IGBC who underwent re-exploration between 1998 and 2009 were identified from a prospective database. The yield and accuracy of SL were calculated. Demographics, tumour- and treatment-related variables were correlated with findings of DD. RESULTS: Of the 136 patients submitted to re exploration for possible definitive resection, 19 (14.0%) had DD. Staging laparoscopy was carried out in 46 (33.8%) patients, of whom 10 (21.8%) had DD (peritoneal disease [n = 6], liver metastases [n = 3], retroperitoneal disease [n = 1]). Disseminated disease was identified by SL in two patients (yield = 4.3%), whereas eight were diagnosed after conversion to laparotomy (accuracy = 20.0%). The likelihood of DD correlated closely with T-stage (T1b, n = 0; T2, n = 5 [7.0%], T3, n = 14 [26.0%]; P = 0.004). A positive margin at initial cholecystectomy (odds ratio [OR] 5.44, 95% confidence interval [CI] 1.51-24.37; P = 0.004) and tumour differentiation (OR 7.64, 95% CI 1.1-NA; P= 0.006) were independent predictors of DD on multivariate analysis. DISCUSSION: Disseminated disease is relatively uncommon in patients with IGBC and SL provides a very low yield. However, patients with poorly differentiated, T3 or positive-margin gallbladder tumours are at high risk for DD and targeting these patients may increase the yield of SL. PMID- 21689231 TI - Refining the definition of perioperative mortality following hepatectomy using death within 90 days as the standard criterion. AB - OBJECTIVES: Defining perioperative mortality as death that occurs within 30 days of surgery may underestimate 'true' mortality among patients undergoing hepatic resection. To better define perioperative mortality, trends in the risk for death during the first 90 days after hepatectomy were assessed. METHODS: Surveillance, Epidemiology and End Results (SEER) Medicare data were used to identify 2597 patients who underwent hepatic resection during 1991-2006. Data on their clinicopathological characteristics, surgical management and perioperative mortality were collected and survival was assessed at 30, 60 and 90 days post surgery. RESULTS: Overall, 5.7% of patients died within the first 30 days. Postoperative mortality at 60 and 90 days were 8.3% and 10.1%. In-hospital mortality after hepatic resection was greater among patients with hepatocellular carcinoma (HCC) than among those with colorectal liver metastases (CRLM) (8.9% and 3.8%, respectively; P < 0.001). In CRLM patients, mortality increased from 4.3% at 30 days to 8.4% at 90 days, whereas mortality in HCC patients increased from 9.7% at 30 days to 15.0% at 90 days (both P < 0.05). Patients with HCC were twice as likely as CRLM patients to die within 30 days [odds ratio (OR) 2.03], 60 days (OR = 1.74) and 90 days (OR = 1.71) (all P < 0.001). Differences in 30- and 90-day mortality were greatest among HCC patients undergoing major hepatic resection (P < 0.05). CONCLUSIONS: Reporting deaths that occur within a maximum of 30 days of surgery underestimates the mortality associated with hepatic resection. Traditional 30-day definitions of mortality are misleading and surgeons should report all perioperative outcomes that occur within 90 days of hepatic resection. PMID- 21689232 TI - Evolution of the surgical management of perihilar cholangiocarcinoma in a Western centre demonstrates improved survival with endoscopic biliary drainage and reduced use of blood transfusion. AB - BACKGROUND: Perihilar cholangiocarcinoma (PHCCA) remains a surgical challenge for which few large Western series have been reported. The aims of this study were to investigate the results of surgical resection for PHCCA and assess how practice has evolved over the past 15 years. METHODS: A prospectively maintained database was interrogated to identify all resections. Clinicopathological data were analysed for impact on survival. Subsequently, data for resections carried out during the periods 1994-1998, 1999-2003 and 2004-2008 were compared. RESULTS: Eighty-three patients underwent resection. Trisectionectomy was required in 67% of resections. Overall survival was 70%, 36% and 20% at 1, 3 and 5 years, respectively. Size of tumour, margin (R0) status, lymph node status, distant metastasis, tumour grade, portal vein resection, microscopic direct vascular invasion, T-stage and blood transfusion requirement significantly affected outcome on univariate analysis. Distant metastasis (P = 0.040), percutaneous biliary drainage (P = 0.015) and blood transfusion requirement (P = 0.026) were significant factors on multivariate analysis. Survival outcomes improved and blood transfusion requirement was significantly reduced in the most recent time period. DISCUSSION: Blood transfusion requirement and preoperative percutaneous biliary drainage were identified as independent indicators of a poor prognosis following resection of PHCCA. Longterm survival can be achieved following the aggressive surgical resection of this tumour, but the emergence of a clear learning curve in our analyses indicates that these patients should be managed in high-volume centres in order to achieve improved outcomes. PMID- 21689233 TI - A standard definition of major hepatectomy: resection of four or more liver segments. AB - BACKGROUND: While commonly used to describe liver resections at risk for post operative complications, no standard definition of 'major hepatectomy' exists. The objective of the present retrospective study is to specify the extent of hepatic resection that should describe a major hepatectomy. METHODS: Demographics, diagnoses, surgical treatments and outcomes from patients who underwent a liver resection at two high-volume centres were reviewed. RESULTS: From 2002 to 2009, 1670 patients underwent a hepatic resection. Post-operative mortality and severe, overall and hepatic-related morbidity occurred in 4.4%, 29.7%, 41.6% and 19.3% of all patients. Mortality (7.4% vs. 2.7% vs. 2.6%) and severe (36.7% vs. 24.7% vs. 24.1%), overall (49.3% vs. 40.6% vs. 35.9%) and hepatic-related (25.6% vs. 16.4% vs. 15.2%) morbidity were more common after resection of four or more liver segments compared with after three or after two or fewer segments (all P < 0.001). There were no significant differences in any post-operative outcome after resection of three and two or fewer segments (all P > 0.05). On multivariable analysis, resection of four or more liver segments was independently associated with post-operative mortality and severe, overall, and hepatic-related morbidity (all P < 0.01). CONCLUSIONS: A major hepatectomy should be defined as resection of four or more liver segments. PMID- 21689234 TI - Pancreatic resection without routine intraperitoneal drainage. AB - BACKGROUND: Most surgeons routinely place intraperitoneal drains at the time of pancreatic resection but this practice has recently been challenged. OBJECTIVE: Evaluate the outcome when pancreatic resection is performed without operatively placed intraperitoneal drains. METHODS: In all, 226 consecutive patients underwent pancreatic resection. In 179 patients drains were routinely placed at the time of surgery and in 47 no drains were placed. Outcomes for these two cohorts were recorded in a prospective database and compared using the chi(2) - /Fisher's exact test for categorical variables, and Wilcoxon's test for continuous variables. RESULTS: Demographic, surgical and pathological details were similar between the two cohorts. Elimination of routine intraperitoneal drainage did not increase the frequency or severity of serious complications. However, when all grades of complications were considered, the number of patients that experienced any complication (65% vs. 47%, P= 0.020) and the median complication severity grade (1 vs. 0, P= 0.027) were increased in the group that had drains placed at the time of surgery. Eliminating intra-operative drains was associated with decreased delayed gastric emptying (24% vs. 9%, P= 0.020) and a trend towards decreased wound infection (12% vs. 2%, P= 0.054). The readmission rate (9% vs. 17% P= 0.007) and number of patients requiring post-operative percutaneous drains (2% vs. 11%, P= 0.001) was higher in patients who did not have operatively placed drains but there was no difference in the re-operation rate (4% vs. 0%, P= 0.210). CONCLUSION: Abandoning the practice of routine intraperitoneal drainage after pancreatic resection may not increase the incidence or severity of severe post-operative complications. PMID- 21689235 TI - Percutaneous transhepatic islet cell autotransplantation after pancreatectomy for chronic pancreatitis: a novel approach. AB - BACKGROUND: In selected patients with chronic pancreatitis, extensive pancreatectomy can be effective for the treatment of intractable pain. The resultant morbid diabetes can be ameliorated with islet autotransplantation (IAT). Conventionally, islet infusion occurs intraoperatively after islet processing. A percutaneous transhepatic route in the immediate postoperative period is an alternative approach. METHODS: A prospectively collected database of patients undergoing pancreatectomy with percutaneous IAT (P-IAT) was reviewed. Hospital billing data were obtained and median charges determined and compared with estimated charges for an intraoperative infusion method of IAT (I-IAT). RESULTS: Thirty-six patients (28 women; median age 48 years) underwent pancreatectomy with P-IAT. Median operative time was 232 min (range: 98-395 min) and median estimated blood loss was 500 cc (range: 75-3000 cc). Median time from pancreatic resection to islet transplantation was 269 min (range: 145-361 min). A median of 208 248 IEq (2298 IEq/kg) were harvested. Median peak portal venous pressure during islet infusion was 13 mmHg (range: 5-37 mmHg). Postoperative complications occurred in 15 patients (42%) and included hepatic artery pseudoaneurysm and portal vein thrombosis; the latter occurred in two patients with portal pressures during infusion > 30 mmHg. At a median follow-up of 10.7 months, eight patients (22%) were insulin-free. Median pertinent charges for P IAT were US$36,318 and estimated median charges for I-IAT were US$56,440. Surgeon time freed by P-IAT facilitated an additional 66 procedures, charges for which amounted to US$463,375. CONCLUSIONS: Percutaneous transhepatic IAT is feasible and safe. Islet infusion in the immediate postoperative period is cost-effective. Further follow-up is needed to assess longterm results. PMID- 21689237 TI - Dermatologic therapy: Alopecia areata update. PMID- 21689238 TI - Alopecia areata: Support groups and meetings - how can it help your patient? AB - Many people with alopecia areata find the fellowship of the support groups provides them with the help they need to cope. They find that they are not alone, how others have coped, what doctors and treatments have been tried, and what the results have been. The National Alopecia Areata Foundation offers support groups throughout the world to refer patients. PMID- 21689239 TI - Camouflage technique for alopecia areata: What is a patient to do? AB - Alopecia areata is a devastating condition for any patient as hair is a prized component of human beauty. Poems and folktales have been written about long, luxuriant, female, golden, and chestnut hair, and even the Bible discusses the diminishment of male power when hair is lost. The question arises as to whether anyone can be beautiful without hair. The answer is a definite yes. No one can dispute the virility of a shaved male head, indicating the absence of hair can make a strikingly beautiful fashion statement. This is sadly not the case for women. With hair loss, the decision can be made to readjust to a personal image devoid of hair, yet there are those who require hair for self-confidence or simply to fit in with the rest of society. This article discusses the currently available options for those who wish to pursue camouflage of hair loss involving the scalp, eyebrows, and eyelashes. PMID- 21689240 TI - Investigative guidelines for alopecia areata. AB - The reported efficacy of various treatments for alopecia is difficult to compare based on a general lack of consideration in case reports/series and clinical trials of the spontaneous regrowth or baseline prognostic factors seen in alopecia areata and a general lack of quantification of hair growth. This report will give both the investigator and clinician guidelines for clinical trial design that will take into account variables known to effect efficacy results such as baseline severity, pattern, and duration of hair loss, age of the subject, and concomitant conditions that may impact on potential regrowth. Reliable methods of assessment of efficacy and response criteria that will enable direct comparison of results between agents will also be discussed. PMID- 21689241 TI - Systemic treatment for alopecia areata. AB - Of the world population, 1.7% is suffering from alopecia areata at some point in their lives. The exact etiology of this disease is still unknown, and the course of the disease is unpredictable. Effective treatments, especially for severe multifocal alopecia areata, alopecia areata totalis, and alopecia areata universalis, are lacking. The present article will discuss side effects and relapse rates of different systemic agents for treatment of severe and rapid progressive alopecia areata. PMID- 21689242 TI - The genetics of alopecia areata: What's new and how will it help our patients? AB - In the United States, alopecia areata (AA) is the most prevalent autoimmune disease, affecting approximately 5.3 million people, including males and females of all ages and across all ethnic groups. AA affects more individuals than most other autoimmune diseases combined, and yet despite its prevalence, there is little information on the underlying pathogenesis and there are currently no evidence-based treatments available to treat or cure this disease. Genetics has provided a valuable tool for gaining insight into disease pathology. We recently completed the first genome-wide association study (GWAS) in AA and successfully identified at least eight regions in the genome with evidence for association to AA. Importantly, this work identifies a discrete set of genes, some of which have been well studied within the context of other autoimmune diseases and already have targeted therapies available or in development. The insight that we have gained through our GWAS sets the stage for the rational development of novel effective therapeutic approaches and heralds in an exciting new era with the commencement of translational research in AA based on genetic findings. PMID- 21689243 TI - Etiopathogenesis of alopecia areata: Why do our patients get it? AB - Alopecia areata (AA) is a nonscarring, inflammatory skin disease that results in patchy hair loss. AA is unpredictable in its onset, severity, and duration making it potentially very stressful for affected individuals. Currently, the treatment options for AA are limited and the efficacy of these treatments varies from patient to patient. The exact etiology of AA is unknown. This article provides some insights into the etiopathogenesis of AA and why some people develop it. The current knowledge on the pathogenesis of AA is summarized and some of the recent hypotheses and studies on AA are presented to allow for a fuller understanding of the possible biological mechanisms of AA. PMID- 21689244 TI - Alopecia areata: Clinical presentation, diagnosis, and unusual cases. AB - Alopecia areata (AA) is a nonscarring hair loss disorder with a 2% lifetime risk. Most patients are below 30 years old. Clinical types include patchy AA, AA reticularis, diffuse AA, AA ophiasis, AA sisiapho, and perinevoid AA. Besides scalp and body hair, the eyebrows, eyelashes, and nails can be affected. The disorder may be circumscribed, total (scalp hair loss), and universal (loss of all hairs). Atopy, autoimmune thyroid disease, and vitiligo are more commonly associated. The course of the disease is unpredictable. However, early, long lasting, and severe cases have a less favorable prognosis. The clinical diagnosis is made by the aspect of hairless patches with a normal skin and preserved follicular ostia. Exclamations mark hairs and a positive pull test signal activity. Dermoscopy may reveal yellow dots. White hairs may be spared; initial regrowth may also be nonpigmented. The differential diagnosis includes trichotillomania, scarring alopecia, and other nonscarring hair loss disorders such as tinea capitis and syphilis. PMID- 21689245 TI - Topical and intralesional therapies for alopecia areata. AB - Alopecia areata is a common form of nonscarring alopecia. It affects males and females equally and has no racial predilection. It usually affects the scalp, but any hair-bearing area can be involved. It presents as patchy hair loss, loss of hair on the entire scalp (alopecia totalis), or the whole body (alopecia universalis). The histopathology varies according to the disease stage, but usually a perifollicular lymphocytic infiltrate is seen. The course of the disease and response to treatment are unpredictable. Various therapeutic modalities are used including topical, intralesional, and systemic agents, although none are curative or preventive. This article will review the available topical and intralesional agents that are used in the treatment of alopecia areata and suggest a management approach based on the age of the patient and extent of the disease. PMID- 21689247 TI - Histopathology of alopecia areata, acute and chronic: Why is it important to the clinician? AB - Alopecia areata (AA) is often easy to diagnose but a scalp biopsy for horizontal sectioning is routine in this research clinic. The characteristic histological feature of AA is the peribulbar and intrabulbar mononuclear cell infiltrate, which occurs in the acute stage of the disease but may be absent in biopsies taken at a later stage. AA evolves through acute, subacute, chronic, and recovery phases. Increased numbers of terminal catagen and telogen hairs are found in the acute and perhaps subacute stages with increased numbers of miniaturized, vellus like hairs in the subacute and chronic stages. Thus, it is important for clinicians and pathologists to recognize the different phases of AA, so that in the absence of the classic findings of a peribulbar lymphocytic infiltrate, a diagnosis of AA can still confidently be made. PMID- 21689246 TI - Treatment of alopecia areata: "What is new on the horizon?". AB - New drug treatment opportunities based on the results of a genome-wide association study, which implicate T cell and natural killer (NK)-cell activation pathways, are leading to new approaches in future clinical trials of alopecia areata. Special attention is being given to the UL 16-binding protein (ULBP3) gene cluster on chromosome 6q25, as these genes make the NKG2D-activating ligand or signal that can trigger the NKG2D receptor, initiating an autoimmune response. A greater expression of ULBP3 has also been found in hair follicles in scalp biopsy specimens from patients with active disease. It is now postulated that the characteristic T cell "swarm of bees" infiltrate seen in alopecia areata is the result of T cells being attracted to the hair follicle by NKG2D-activating ligands. Future treatment approaches for alopecia areata include use of drugs that: (i) block the NKGD-activating ligand and NKG2D receptor interaction, (ii) halt activated T cells, or (iii) modification of the inflammatory cytokine network. Many drugs currently being used or being evaluated for other autoimmune diseases that work through these mechanisms might prove to be very effective in alopecia areata. PMID- 21689248 TI - Imiquimod 5% cream for the treatment of nasal lesion of metastatic renal cell carcinoma. AB - Many reports have shown the efficacy of topical imiquimod in patients with skin carcinoma. This effect is based on the activity of imiquimod as an immune response modifier. The present authors hypothesized that this agent could also be used to treat skin metastatic lesion from renal cell carcinoma. The present authors report the case of a 54-year-old man who presented with a metastasis renal cell carcinoma lesion on his nose. He had a history of right nephrectomy performed 4 years previously. The present authors started him on topical treatment with imiquimod 5% cream three times a week for his nose lesion. A reduction of the lesion was observed after 2 months, and during the following 12 months no sign of recurrence was observed. PMID- 21689249 TI - Lupoid leishmaniasis of the nose responding well to cryotherapy. PMID- 21689250 TI - Intralesional vincristine combined with cryotherapy for recalcitrant verrucas. AB - Verrucas are often recalcitrant to conventional cryotherapy. Since 1970, intralesional bleomycin has been used off-label by dermatologists. But in some cases, the results of intralesional bleomycin were disappointing. Vincristine is a well-known vinca alkaloid antiblastic drug that has been used for treating hematological neoplasm and nephroblastomas. It was reported good efficacy of intralesional vincristine for treating nodular lesion in classic Kaposi sarcoma. Its use in epithelial neoplasm and Kaposi sarcoma may support its efficacy in recalcitrant verrucas. The three patients selected for the study presented severe verrucas on foot, and they had already undergone cryotherapy several times and there was no improvement. They got intralesional vincristine injection on their verrucas. The target lesion was infiltrated with 0.03 mL of vincristine sulphate at a concentration of 1 ug/mL. The injected amount of vincristine was proportional to the diameter of the nodule. After two treatments had been completed, there was a great decrease of lesion size compared with the other lesions. The three patients complained of pain lasting for several days. This pain was generally well tolerated. Intralesional vincristine injection on verruca is an effective and rapid novel method, and when combined with cryotherapy, shows excellent therapeutic response. PMID- 21689251 TI - Risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients and appraisal of strategies for selective use of chemoprophylaxis. AB - Risk stratification-based duration of trimethoprim-sulfamethoxazole (TMP-SMX) chemoprophylaxis to prevent Pneumocystis pneumonia (PCP) in kidney transplant recipients is not a universally adapted strategy and supporting evidence-based sources are limited. We performed a large retrospective study to identify risk factors for PCP in kidney transplant recipients and to define parameters for use in clinical prophylaxis guidelines. Fifty consecutive patients with confirmed PCP and 2 time-matched controls per case were enrolled. All patients were participants of the kidney transplantation program of the Leiden University Medical Center, a tertiary care hospital in the Netherlands. Potential risk factors were compared between groups by uni- and multivariate matched analyses. At transplantation, age >55 years (adjusted odds ratio [OR] 2.7, 95% confidence interval [CI] 1.3-5.9) and not receiving basiliximab induction therapy (adjusted OR 4.3, 95% CI 1.1-17.1) predicted development of PCP. In the final multivariate analysis, only cytomegalovirus infection (adjusted OR 3.0, 95% CI 1.2-7.9) and rejection treatment (adjusted OR 5.8, 95% CI 1.9-18) were found to be independently associated with PCP. Using the variables identified by the multivariate analyses, effects of different hypothetical chemoprophylaxis strategies were systematically evaluated. Exploring different scenarios showed that chemoprophylaxis in the first 6 months for all renal transplant patients - and during the first year posttransplantation for patients >55 years of age or those treated for rejection - would result in very low PCP incidence and optimal avoidance of TMP-SMX toxicity. The results provide a rationale for further prospective study on targeted provision of chemoprophylaxis to prevent PCP in kidney transplant patients. PMID- 21689252 TI - Epstein-Barr virus DNA load in peripheral blood mononuclear cells and whole blood from pediatric transplant recipients. AB - Monitoring of circulating Epstein-Barr virus (EBV) DNA in pediatric transplant patients has been shown to be useful in post-transplant patient management. It still remains unclear which blood sample type is more suitable, and how EBV DNA levels in whole blood (WB) correlate with those in peripheral blood mononuclear cells (PBMCs). The aim of this study was to compare EBV DNA load in WB and PBMCs of pediatric transplant recipients. After liver, kidney, or combined liver-kidney transplantation, 172 matched WB and PBMCs samples were collected from 84 children (130 samples from 42 patients consisted of multiple collections). The EBV DNA level in PBMCs was determined by home-made real-time polymerase chain reaction using TaqMan chemistry. In parallel, the viral load (VL) in WB was measured by a commercial LightCycler EBV Quant Kit. The EBV DNA levels and dynamics of VL changes were assessed and compared between WB and PBMCs. The overall correlation between EBV DNA level in PBMCs and WB was statistically significant and high, r(2) =0.87 (P<0.001). However, the sensitivity of EBV detection was lower in WB (93.9%). Longitudinal analysis of EBV DNA load dynamics in PBMCs and WB indicated that EBV DNA load fluctuations were larger in WB, but the trend of decreases and increases, with minor exceptions, was similar in both sample types. The high correlation of EBV DNA levels, as well as the similar dynamics of EBV DNA changes in both sample types, make WB a good alternative to EBV DNA monitoring in PBMCs of pediatric transplant recipients. However, the subtle increase of the VL may be detected earlier in PBMCs. PMID- 21689253 TI - Osh proteins regulate membrane sterol organization but are not required for sterol movement between the ER and PM. AB - Sterol transport between the endoplasmic reticulum (ER) and plasma membrane (PM) occurs by an ATP-dependent, non-vesicular mechanism that is presumed to require sterol transport proteins (STPs). In Saccharomyces cerevisiae, homologs of the mammalian oxysterol-binding protein (Osh1-7) have been proposed to function as STPs. To evaluate this proposal we took two approaches. First we used dehydroergosterol (DHE) to visualize sterol movement in living cells by fluorescence microscopy. DHE was introduced into the PM under hypoxic conditions and observed to redistribute to lipid droplets on growing the cells aerobically. Redistribution required ATP and the sterol acyltransferase Are2, but did not require PM-derived transport vesicles. DHE redistribution occurred robustly in a conditional yeast mutant (oshDelta osh4-1(ts)) that lacks all functional Osh proteins at 37 degrees C. In a second approach we used a pulse-chase protocol to analyze the movement of metabolically radiolabeled ergosterol from the ER to the PM. Arrival of radiolabeled ergosterol at the PM was assessed in isolated PM enriched fractions as well as by extracting sterols from intact cells with methyl beta-cyclodextrin. These experiments revealed that whereas ergosterol is transported effectively from the ER to the PM in Osh-deficient cells, the rate at which it moves within the PM to equilibrate with the methyl-beta-cyclodextrin extractable sterol pool is slowed. We conclude (i) that the role of Osh proteins in non-vesicular sterol transport between the PM, ER and lipid droplets is either minimal, or subsumed by other mechanisms and (ii) that Osh proteins regulate the organization of sterols at the PM. PMID- 21689255 TI - The polymorphic HCMV glycoprotein UL20 is targeted for lysosomal degradation by multiple cytoplasmic dileucine motifs. AB - Human cytomegalovirus (HCMV) is a widespread and persistent beta-herpesvirus. The large DNA genome of HCMV encodes many proteins that are non-essential for viral replication including numerous proteins subverting host immunosurveillance. One of them is the barely characterized UL20, which is encoded adjacent to the well defined immunoevasins UL16 and UL18. UL20 is a type I transmembrane glycoprotein with an immunoglobulin-like ectodomain that is highly polymorphic among HCMV strains. Here, we show that the homodimeric UL20, by virtue of its cytoplasmic domain, does not reach the cell surface but is targeted to endosomes and lysosomes. Accordingly, UL20 exhibits a short half-life because of rapid lysosomal degradation. Trafficking of UL20 to lysosomes is determined by several, independently functioning dileucine-based sorting motifs in the cytoplasmic domain of UL20 and involves the adaptor protein (AP) complex AP-1. Combined substitution of three dileucine motifs allowed strong cell surface expression of UL20 comparable to UL20 mutants lacking the cytoplasmic tail. Finally, we show that the intracellularly located UL20 also is subject to lysosomal degradation in the context of viral infection. Altogether, from these data, we hypothesize that UL20 is destined to efficiently sequester yet-to-be defined cellular proteins for degradation in lysosomes. PMID- 21689254 TI - Imaging single endocytic events reveals diversity in clathrin, dynamin and vesicle dynamics. AB - The dynamics of clathrin-mediated endocytosis can be assayed using fluorescently tagged proteins and total internal reflection fluorescence microscopy. Many of these proteins, including clathrin and dynamin, are soluble and changes in fluorescence intensity can be attributed either to membrane/vesicle movement or to changes in the numbers of individual molecules. It is important for assays to discriminate between physical membrane events and the dynamics of molecules. Two physical events in endocytosis were investigated: vesicle scission from the plasma membrane and vesicle internalization. Single vesicle analysis allowed the characterization of dynamin and clathrin dynamics relative to scission and internalization. We show that vesicles remain proximal to the plasma membrane for variable amounts of time following scission, and that uncoating of clathrin can occur before or after vesicle internalization. The dynamics of dynamin also vary with respect to scission. Results from assays based on physical events suggest that disappearance of fluorescence from the evanescent field should be re evaluated as an assay for endocytosis. These results illustrate the heterogeneity of behaviors of endocytic vesicles and the importance of establishing suitable evaluation criteria for biophysical processes. PMID- 21689256 TI - Involvement of Rab3A in vesicle priming during exocytosis: interaction with Munc13-1 and Munc18-1. AB - Rab3A is a small G-protein of the Rab family that is involved in the late steps of exocytosis. Here, we studied the role of Rab3A and its relationship with Munc13-1 and Munc18-1 during vesicle priming. Phorbol 12-myristate 13-acetate (PMA) is known to enhance the percentage of fusion-competent vesicles and this is mediated by protein kinase C (PKC)-independent Munc13-1 activation and PKC dependent dissociation of Munc18-1 from syntaxin 1a. Our results show that the effects of PMA varied in cells overexpressing Rab3A or mutants of Rab3A and in cells with Rab3A knockdown. When Munc13-1 was overexpressed in Rab3A knockdown cells, secretion was completely inhibited. In cells overexpressing a Rab interacting molecule (RIM)-binding deficient Munc13-1 mutant, 128-Munc13-1, the effects of Rab3A on PMA-induced secretion was abolished. The effect of PMA, which disappeared in cells overexpressing GTP-Rab3A (Q81L), could be reversed by co expressing Munc18-1 but not its mutant R39C, which is unable to bind to syntaxin 1a. In cells overexpressing Munc18-1, manipulation of Rab3A activity had no effect on secretion. Finally, Munc18-1 enhanced the dissociation of Rab3A, and such enhancement correlated with exocytosis. In summary, our results support the hypothesis that the Rab3A cycle is coupled with the activation of Munc13-1 via RIM, which accounts for the regulation of secretion by Rab3A. Munc18-1 acts downstream of Munc13-1/RIM/Rab3A and interacts with syntaxin 1a allowing vesicle priming. Furthermore, Munc18-1 promotes Rab3A dissociation from vesicles, which then results in fusion. PMID- 21689257 TI - Predictive factors of depression among Asian female marriage immigrants in Korea. AB - This study investigated the prevailing rate of depression in female marriage immigrants in Korea and the predictive factors of their rates of depression. The study included 316 foreign female marriage immigrant participants. Four instruments yielded the data: the Center for Epidemiologic Studies Depression Scale and Multidimensional Scale of Perceived Social Support and questionnaires regarding the participants' Korean language ability and demographic data. The survey scales were translated into Korean, Vietnamese, Chinese, and English. The data collection was conducted by a face-to-face interview and translators were used when needed. The female marriage immigrants were found to have higher depression rates than women in the general Korean population. The predictive factors of depression for the female marriage immigrants included their country of origin, Korean speaking ability, and family support. Far more depression was found to occur in the Chinese participants, while the rate of depression was lower in those with competent Korean speaking ability and family support. An exploration of strategies to improve the speaking ability and family support of female marriage immigrants will be necessary in order to decrease their incidence of depression and the strategies should be differentiated based on the female marriage immigrants' country of origin. PMID- 21689258 TI - The Joanna Briggs Institute best practice information sheet: the effectiveness of pelvic floor muscle exercises on urinary incontinence in women following childbirth. AB - This Best Practice Information Sheet is derived from 21 studies and aims to synthesize the best available evidence on the effectiveness of pelvic floor muscle exercises on urinary incontinence in women following childbirth. The information that is contained in this sheet has been derived from studies that were included in a systematic review that was conducted by the Joanna Briggs Institute. The original references can be sourced from the systematic review. Pregnancy and childbirth are major risk factors for the development of urinary incontinence as the muscles of the pelvic floor become stretched and weakened. For some women, such incontinence after childbirth is temporary, but for others, their suffering can be of much longer-term duration. A number of risk factors has been identified for urinary incontinence following childbirth, including antenatal urinary incontinence, obesity, and significant perineal trauma. The aim of pelvic floor muscle exercises is to strengthen the perivaginal and perianal musculature in order to increase a woman's control of urinary leakage. PMID- 21689262 TI - Comparative analysis of various prognostic nodal factors, adjuvant chemotherapy and survival among stage III colon cancer patients over 65 years: an analysis using surveillance, epidemiology and end results (SEER)-Medicare data. AB - AIM: The prognostic effects of chemotherapy and various lymph node measures [positive nodes, total node count and the positive lymph node ratio (PLNR)] have been established. It is unknown whether the cancer-specific survival benefit of chemotherapy differs across these nodal prognostic categories. METHOD: This retrospective analysis of linked Surveillance, Epidemiology and End Results (SEER) data and Medicare data (SEER-Medicare)included patients >= 65 years of age with a diagnosis of stage III colon cancer between 1997 and 2002. We grouped patients according to the number of positive nodes (N1 and N2), total node count (>= 12 and < 12 total nodes) and PLNR (below the 75th percentile and at least at the 75th percentile of the PLNR). The end point was colon cancer-specific mortality. RESULTS: Fifty-one per cent (3701) of the 7263 patients received adjuvant therapy during the time period 1997-2002. The mean (standard deviation) number of total nodes examined was 13 (9) and the number of positive nodes identified was 3 (3). Patients with N2 disease, < 12 total nodes examined and a high PLNR had a worse survival at 2, 3 and 5 years following colectomy. Utilization of chemotherapy demonstrated a colon cancer-specific survival benefit (hazard ratio at median follow up = 0.7; P < 0.001) that was consistent and statistically significant across the three nodal prognostic categories examined. CONCLUSION: The benefit of chemotherapy did not vary based on N stage, total node count or PLNR. The results favour a broad-based approach towards increasing the chemotherapy treatment rates in stage III patients of >= 65 years of age, rather than an approach that targets clinical subgroups. PMID- 21689263 TI - Time-intensity curve parameters in colorectal tumours measured using double contrast-enhanced ultrasound: correlations with tumour angiogenesis. AB - AIM: The aim of the study was to assess the correlation between time-intensity curve (TIC) parameters and colorectal tumour angiogenesis using double contrast enhanced ultrasound (DCEUS), in which an intraluminal contrast agent was used in combination with an intravascular contrast agent. METHOD: Thirty nine patients with colorectal tumours were examined preoperatively. During hydrocolonal examination with the intraluminal contrast agent, an intravascular contrast agent, SonoVue, was used to perform the DCEUS. The parameter arrival time (AT), time to peak (TTP), peak intensity (PI) and area under the curve (AUC) were measured. Postoperative specimens were assessed for microvessel density (MVD) and vascular endothelial growth factor (VEGF). The correlation between TIC parameters and the expression of VEGF or MVD was studied. RESULTS: The mean values of AT, TTP, PI and AUC of the colorectal tumours were 14.32 +/- 11.36 s, 30.61 +/- 18.65 s, 20.38 +/- 17.45 dB and 221.10 +/- 156.09 dB.s, respectively. Both AUC and MVD were significantly higher in colorectal adenocarcinomas than in adenomas (all P < 0.05). A positive linear correlation was found between the AUC and MVD in colorectal tumours (r = 0.686, P = 0.0019). No correlation was found between VEGF and any TIC parameter. CONCLUSION: DCEUS is a valuable method for evaluating angiogenesis in colorectal tumours in vivo. The AUC has a positive linear correlation with MVD and could form a new index for assessing angiogenesis and the biological behaviour of colorectal tumours. PMID- 21689264 TI - Pouchitis may increase the risk of dysplasia after restorative proctocolectomy in patients with ulcerative colitis. AB - AIM: Dysplasia of the pouch mucosa after restorative proctocolectomy is rare. The aim of this study was to establish whether there is a correlation between pouchitis and dysplasia. METHOD: A group of 276 patients treated for ulcerative colitis by restorative proctocolectomy between 1984 and 2009 was analysed. The presence or absence of pouchitis and dysplasia within the pouch was evaluated. RESULTS: Inflammation was diagnosed in 66 (23.9%) patients, low-grade dysplasia in five (1.8%), high-grade dysplasia in three (1.1%), and cancer in one patient (0.4%). The prevalence of low-grade dysplasia was significantly higher in patients with inflammation than in those without (P < 0.04). High-grade dysplasia was significantly more frequent in pouchitis than in non-inflamed pouches (P < 0.01). Logistic regression analysis suggested that the occurrence of mucosal inflammation increased the risk of low grade dysplasia. CONCLUSION: Patients with chronic pouchitis are at risk of dysplasia and require surveillance of the pouch. PMID- 21689265 TI - Anorectal function evaluation and predictive factors for faecal incontinence in 600 patients. AB - AIM: Anorectal function was assessed in patients with and without faecal incontinence (FI) . Risk factors predictive for FI were determined. METHOD: Between 2003 and 2009, all consecutive patients referred were assessed by questionnaire, anorectal manometry and anal endosonography. Predictive factors were identified and used to develop a statistical model to predict FI. RESULTS: Of 600 patients (519 women), 285 (48%) were faecally incontinent. In comparison with continent women, incontinent women (mean Vaizey score 15.4), were older, had more liquid stools, more deliveries, more urinary incontinence, lower anal pressures, shorter sphincter length, smaller rectal capacity and more sphincter defects. Incontinent men (mean Vaizey score 15.3) were older and had lower anal pressures. Incontinent and continent patients showed an overlap in test results. Predictors in women were age, stool consistency, anal pressures, rectal capacity, and internal and external sphincter defects. The area under the ROC-curve was 0.84 (P < 0.001; 95% confidence interval, 0.80-0.87). Using a cut off point of 0.4, FI was predicted with sensitivity, specificity, positive and negative predictive values of 86%, 68%, 74% and 82%, respectively. The model was studied in five women with a temporary stoma and was accurate in predicting FI after stoma closure. CONCLUSION: Incontinent patients have lower pressures, smaller rectal capacity and more sphincter defects than controls, but show a large overlap. Our model shows a relatively high sensitivity and negative predictive value for predicting FI in women. The model seems promising in the patients studied with a temporary stoma. PMID- 21689266 TI - Global evidence synthesis and UK idiosyncrasy: why have recent UK trials had no significant effects on breastfeeding rates? PMID- 21689267 TI - Relationship of social cognitive theory concepts to mothers' dietary intake and BMI. AB - Women tend to have the greatest responsibility for and influence on the home food environment. Understanding theoretical concepts as they pertain to mothers' food related behaviours could inform the development of interventions that enhance mothers' ability to create healthy family food environments that support optimal child development and help attenuate obesity rates. Likert scales assessed Social Cognitive Theory concepts [i.e. self-efficacy, self-regulation (sets goals, self reward, self-monitoring, environmental structuring), outcome expectations] and coping of 201 mothers in the context food-related activities. ANOVA determined whether diet and BMI differed among mothers scoring in the highest, middle, and lowest tertiles on the Likert scales. For self-efficacy, coping, sets goals, and outcome expectations scales, lowest tertile mothers had significantly higher BMIs than highest tertile mothers. The lowest tertile for self-efficacy, self-reward, and self-monitoring consumed significantly less fibre, vitamin C, magnesium, potassium, and fruit and vegetables than upper tertiles. On the self-efficacy scale, the lowest tertile consumed significantly more calories, fat, and cholesterol than higher tertiles. Environmental structuring scale findings indicate users of television during dinner had significantly lower intakes of fibre, vitamin C, magnesium, potassium, and fruits and vegetables than those almost never using TV during dinner. Stepwise regression revealed self monitoring, environmental structuring, self-reward, and outcome expectations were significant positive predictors of self-efficacy. Self-monitoring was a significant positive predictor of outcome expectations. Associations between theoretical concepts, mothers' dietary intakes, and BMIs point to the need to incorporate components that build self-efficacy, self-regulation, outcome expectations, and coping skills into health promotion interventions. PMID- 21689268 TI - Changes in skinfolds and mid-upper arm circumference during pregnancy in Argentine women. AB - This investigation describes the pattern of changes in mid-upper arm circumference (MUAC), triceps, biceps and subscapular skinfold thicknesses during the course of pregnancy, and its relationship with maternal and newborn outcomes. A prospective cohort of 1066 pregnant women were selected in seven different urban regions in Argentina. Measurements of MUAC were carried out at 16, 28 and 36 gestational weeks. In a subsample of 488 women, triceps, biceps and subscapular skinfold thicknesses were measured. Mean total increase in subscapular, tricipital and bicipital skinfolds from 16 to 36 weeks of gestation were 4.5, 3.6 and 2.6 mm, respectively. MUAC showed a mean increase of 1.7 cm in the same period. Overweight or obese women at the start of pregnancy had lower increases in all measurements compared with women with normal or low body mass index. Maternal anthropometry was related to birthweight; women who gave birth to infants of less than 3000 g had lower average values in all measurements than those who had normal birthweight infants. LMS curves for MUAC and skinfolds by gestational age are presented, which can be used as a reference to assess maternal nutrition status during pregnancy. MUAC, tricipital and subscapular skinfold for gestational age curves are proposed for monitoring maternal nutritional status during pregnancy. MUAC cut-off points of 24.5, 25.5 and 26.5 cm for 16, 28 and 36 weeks of gestation, respectively, are also proposed as a proxy to detect low birthweight. PMID- 21689269 TI - CD-ROM-based program for breastfeeding mothers. AB - The vast majority of breastfeeding mothers in Western countries have routine access to multimedia and Internet resources at home. The aim of this study was to assess the effectiveness of a CD-ROM-based intervention in increasing the rates of breastfeeding. We conducted a pre- and post-intervention study involving four control and four intervention maternity units in France. All breastfeeding mothers in intervention units were given a CD-ROM-based program addressing various breastfeeding topics. The primary outcome was any breastfeeding at 4 weeks assessed by follow-up telephone interview. The secondary outcomes included breastfeeding duration, breastfeeding difficulties after discharge and satisfaction with the breastfeeding experience. The rates of any breastfeeding at 4 weeks varied from 88.6% (209/236) to 87.9% (211/240) and from 86.0% (222/258) to 88.0% (228/259) for mothers enrolled in intervention and control maternity units, respectively (P for interaction=0.54). The hazard of breastfeeding discontinuation for mothers enrolled in intervention units did not vary significantly across study periods after adjusting for education level, epidural anaesthesia, breastfeeding assessment score and return to work (P for interaction=0.18). The rates of breastfeeding at 4 weeks remained unchanged when restricting the analysis to the mothers who actually received (87.8% [173/197]) or used [88.2% (105/119)] the CD-ROM during the post-intervention period. No significant differences were found in secondary outcomes between the two study groups. A CD-ROM-based intervention for breastfeeding mothers provides no additional benefit to usual post-natal care. Further study is needed to assess the effectiveness of multimedia packages as part of more intensive multifaceted interventions. PMID- 21689270 TI - Predictors of breastfeeding cessation among HIV-infected women in Dar es Salaam, Tanzania. AB - This paper examines predictors of breastfeeding cessation among a cohort of human immunodeficiency virus (HIV)-infected women. This was a prospective follow-up study of HIV-infected women who participated in a randomized micronutrient supplementation trial conducted in Dar es Salaam, Tanzania. 795 HIV-infected Tanzanian women with singleton newborns were utilized from the cohort for this analysis. The proportion of women breastfeeding declined from 95% at 12 months to 11% at 24 months. The multivariate analysis showed breastfeeding cessation was significantly associated with increasing calendar year of delivery from 1995 to 1997 [risk ratio (RR), 1.36; 95% confidence interval (CI) 1.13-1.63], having a new pregnancy (RR 1.33; 95% CI 1.10-1.61), overweight [body mass index (BMI) >=25 kg m(-2) ; RR 1.37; 95% CI 1.07-1.75], underweight (BMI <18.5kg m(-2) ; RR 1.29; 95% CI 1.00-1.65), introduction of cow's milk at infant's age of 4 months (RR 1.30; 95% CI 1.04-1.63). Material and social support was associated with decreased likelihood of cessation (RR 0.83; 95% CI 0.68-1.02). Demographic, health and nutritional factors among women and infants are associated with decisions by HIV-infected women to cease breastfeeding. The impact of breastfeeding counselling programs for HIV-infected African women should consider individual maternal, social and health contexts. PMID- 21689271 TI - Infant and young child feeding in the Peruvian Amazon: the need to promote exclusive breastfeeding and nutrient-dense traditional complementary foods. AB - The study objective was to understand the role of traditional Awajun foods in dietary quality and the potential impacts on growth of Awajun infants and young children 0-23 months of age. Research took place in April and May of 2004, along the Cenepa River in six Awajun communities. Anthropometry estimated nutritional status for 32 infants (0-23 months). Repeat dietary recalls and infant feeding histories were completed with 32 mothers. Adequacy of the complementary foods was compared with World Health Organization guidelines. Anthropometry indicated a high prevalence of stunting (39.4% of infants and young children), with nutritional status declining with age. Half of the Awajun mothers practised exclusive breastfeeding. Dietary recalls and infant food histories suggested that many of the infants were getting adequate nutrition from complementary foods and breastfeeding; however, there was variation in breastfeeding and complementary feeding practices among the mothers. Complementary feeding for young children 12 23 months generally met nutrient recommendations, but mean intakes for iron, zinc, calcium and vitamin A were inadequate in infants 6-11 months. Traditional foods provided 85% of energy and were more nutrient dense than market foods. Appropriate infant and complementary feeding was found among some women; however, given the range of feeding practices and introduction of market foods, health promotion targeting infant and young child feeding is warranted. PMID- 21689272 TI - Does low birthweight influence the nutritional status of children at school age? A cohort study in northeast Brazil. AB - Birthweight is recognized to be a determinant of a full term infant's early growth pattern; however, few studies have explored whether this effect is sustained into school age, especially in developing countries. We have used a cohort study from North East Brazil to investigate factors determining the anthropometric status of eight-year-old children born at full-term with low or appropriate weight. A cohort of 375 full-term infants was recruited at birth in six maternity hospitals between 1993 and 1994, in a poor region of the interior of the State of Pernambuco. At the age of 8 years, 86 born with low birthweight and 127 with appropriate birthweight were traced. Multivariable linear regression analyses were used to identify the net effect of socioeconomic conditions, maternal nutritional status and child factors on weight-for-age and height-for age. An enter approach was used to estimate the contribution of different factors on child anthropometry. Birthweight had little influence on child nutritional status at school age. Maternal BMI and height together were the biggest contributors to variation in child weight-for-age (12.3%) and height-for-age (13.2%), followed by family socioeconomic conditions. Maternal height as a proxy of maternal constraint was the single factor that best explained the variation in both indices (6.2% for weight-for-age and 11.1% for height-for-age). Haemoglobin level measured at eight years made a small but significant contribution to variation in height-for-age (5.6%) and weight for age (1.4%). Maternal nutritional status, reflecting genetic inheritance and the poor socioeconomic conditions of this population, was the most important determinant of the nutritional status of children at school age, rather than birthweight. PMID- 21689273 TI - Parents' and boys' perceptions of boys' body size for average and high BMI boys. AB - A study on 49 preadolescent boys and their parents was performed to determine if differences existed in boys' body esteem and body size perceptions and to determine how accurately parents perceive their sons' body size. The boys were grouped by their body mass index (BMI) into average and high BMI groups. The boys completed the Body Esteem Scale; the boys and the parents rated the boys' body size perceptions. No differences were found in the boys' body esteem. The boys in the high BMI group perceived themselves as bigger than the boys in the average BMI group, and the parents of the boys with a high BMI perceived their sons as bigger. The boys in the high BMI group rated their current figure as heavier than their ideal figure. The results supported that the boys and the parents were aware of the boys' current body size. However, the parents of the boys with high BMI were more accepting of a larger ideal body figure. PMID- 21689274 TI - Understanding barriers to implementing the Norwegian national guidelines for healthy school meals: a case study involving three secondary schools. AB - The main goal of the present study was to investigate the barriers to implementing the Norwegian national guidelines for healthy school meals as perceived by principals, project leaders, teachers and students. This study employed a multiple-case design using an explorative approach. Data were collected at three secondary schools in Norway participating in the intervention project Physical activity and healthy school meals. Individual interviews were conducted with school principals and project leaders, and focus group interviews were conducted separately with teachers and students. Four categories of barriers were identified: (1) lack of adaptation of the guidelines to the target group; (2) lack of resources and funding; (3) conflicting values and goals; and (4) access to unhealthy food outside school. The research identified differences in perceived barriers between the staff responsible for implementation and the students as the target group of the measures. All staff groups perceived barriers relating to both resources, and conflicting values and goals. The teachers were more concerned about issues of relevance for adaptation to the target groups than were the principals and project leaders. The students were concerned mostly with issues directly affecting their experience with items offered in the canteen. PMID- 21689275 TI - Can we identify infants at risk of becoming obese, and if so, should we? PMID- 21689276 TI - Preliminary experience with external hemipelvectomy for locally advanced and recurrent pelvic carcinoma. AB - AIM: Eight highly selected patients are reported, undergoing external hemipelvectomy (EHP) for malignant infiltration of the lumbosacral neural plexus. METHOD: All patients were evaluated by positron emission tomography-computed tomography (PET-CT), CT and magnetic resonance imaging. No evidence of disseminated disease was found. With agreement by the multidisciplinary team, surgery was performed by a colorectal surgeon and an orthopaedic sarcoma surgeon and, if needed, by an urologist and vascular surgeon. Patients were reconstructed with either a femoral or a gluteal musculocutaneous flap. RESULTS: Of the eight women [median age 54.5 (40-68) years], two had primary carcinoma and six local recurrence of a previously treated carcinoma. R0 was possible in six patients and R1 resection in two. The median duration of hospital stay was 29.5 (17-102) days. The median follow up was 8.3 (4.7-52.8) months. Three patients have died, one from postoperative complications at 5 months and two from recurrence at 5 and 52.8 months. Phantom-limb was experienced in six patients. Four patients received a prosthesis, one is considering this and one does not want a prosthesis. CONCLUSION: Hemipelvectomy may be considered for a highly selected group of patients with locally advanced carcinoma or recurrence involving the lumbosacral neural plexus. PMID- 21689277 TI - Validation study of the Japanese version of the Faecal Incontinence Quality of Life Scale. AB - AIM: The aim of the present study was to conduct a psychometric validation of the Japanese version of the FIQL (JFIQL). METHOD: A retrospective analysis of data from the JFIQL was conducted. Wexner scores and Faecal Incontinence Severity Index (FISI) scores were collected prospectively in patients with faecal incontinence who visited our centre between 2008 and 2009. For convergent validity, the JFIQL scores were compared with stages on the Wexner scale for lifestyle alteration. To evaluate reliability, Cronbach's alpha was calculated for internal consistency, whereas a test-retest study was performed to evaluate reproducibility. In assessing responsiveness, JFIQL scores before and after treatments were compared in patients whose FISI scores decreased by >= 50%. RESULTS: Convergent validity and internal consistency were determined in 70 patients (49 women; median age 68.5 years). The JFIQL scores were significantly associated with lifestyle alteration stages on the Wexner scale, demonstrating convergent validity in all four domains and the generic score. Cronbach's alpha was > 0.7 for generic scores and all domains except Embarrassment. The intraclass correlations for the 27 patients available for the test-retest study were > 0.7 for generic scores and all domains except Embarrassment. The median JFIQL score improved significantly after treatment in the 23 patients whose FISI scores decreased >= 50%, indicating good responsiveness in all four domains and the generic score. CONCLUSION: The JFIQL has been validated and is now ready for use in evaluating the symptom-specific quality of life in Japanese patients with faecal incontinence. PMID- 21689278 TI - Metabolic syndrome and leptin are associated with adverse pathological features in male colorectal cancer patients. AB - AIM: Metabolic syndrome (MetS) describes a clustering of factors including central obesity, hypertension and raised plasma glucose, triglycerides and high density lipoprotein (HDL) cholesterol. Central obesity is associated with a risk for colorectal cancer, but the impact of MetS on colorectal cancer biology and outcomes is unclear. METHOD: A prospective observational study of colorectal cancer patients was carried out in an Irish population. Patients underwent metabolic and anthropometric assessment before treatment, including measurement of serum hormones and adipokines and CT measurement of visceral fat. MetS was defined according to the International Diabetes Federation definition(3) . RESULTS: One-hundred and thirty consecutive colorectal cancer patients (66 men and 64 women) were recruited. MetS was diagnosed in 38% patients compared with the population norms reported at 21%(21) . Male patients had a significantly greater visceral fat area compared with female patients. MetS was associated with node-positive disease (P = 0.026), percentage nodal involvement (P = 0.033) and extramural vascular invasion (P = 0.049) in male patients but no significant association was observed in female patients. HDL cholesterol was also significantly associated with a more advanced pathological stage (P = 0.014) and node-positive disease (P = 0.028). Leptin was associated with nodal status (P = 0.036), microvascular invasion (P = 0.054), advanced pathological stage (P = 0.046) and more advanced Dukes stage (P = 0.042). CONCLUSION: We report a high prevalence of MetS and visceral obesity in a colorectal cancer population. MetS and plasma leptin are associated with a more aggressive tumour phenotype in male patients only. PMID- 21689279 TI - Excellent response rate of anismus to botulinum toxin if rectal prolapse misdiagnosed as anismus ('pseudoanismus') is excluded. AB - AIM: Anismus causes obstructed defecation as a result of inappropriate contraction of the puborectalis/external sphincter. Proctographic failure to empty after 30 s is used as a simple surrogate for simultaneous electromyography/proctography. Botulinum toxin is theoretically attractive but efficacy is variable. We aimed to evaluate the efficacy of botulinum toxin to treat obstructed defecation caused by anismus. METHOD: Botulinum toxin was administered, under local anaesthetic, into the puborectalis/external sphincter of patients with proctographic anismus. Responders (resolution followed by recurrence of obstructed defecation over a 1- to 2-month period) underwent repeat injection. Nonresponders underwent rectal examination under anaesthetic (EUA). EUA-diagnosed rectal prolapse was graded using the Oxford Prolapse Grade 1-5. RESULTS: Fifty-six patients were treated with botulinum toxin. Twenty-two (39%) responded initially and 21/22 (95%) underwent repeat treatment. At a median follow up of 19.2 (range, 7.0-30.4) months, 20/21 (95%) had a sustained response and required no further treatment. Isolated obstructed defecation symptoms (OR = 7.8, P = 0.008), but not proctographic or physiological factors, predicted response on logistic regression analysis. In 33 (97%) of 34 nonresponders, significant abnormalities were demonstrated at EUA: 31 (94%) had a grade 3-5 rectal prolapse, one had internal anal sphincter myopathy and one had a fissure. Exclusion of these alternative diagnoses revised the initial response rate to 96%. CONCLUSION: Simple proctographic criteria overdiagnose anismus and underdiagnose rectal prolapse. This explains the published variable response to botulinum toxin. Failure to respond should prompt EUA seeking undiagnosed rectal prolapse. A response to an initial dose of botulinum toxin might be considered a more reliable diagnosis of anismus than proctography. PMID- 21689280 TI - The first 3 years of national bowel cancer screening at a single UK tertiary centre. AB - AIM: St Mark's Bowel Cancer Screening Centre commenced screening in October 2006 as a contributor to the national programme. The first 35 months' experience is reported. METHOD: Individuals with a positive faecal occult blood test (FOBT) were offered colonoscopy or alternatives if they had significant comorbidity. All screening data were collected prospectively. RESULTS: Of the 98 815 FOBT kits issued, 42 523 were returned (43% uptake; 20.79% men). In total, 1339/1488 (90%) FOBT-positive participants attended the nurse clinic (57% men). Of these, 1057 had an index colonoscopy, 115 had a computed tomography colonoscopy (CTC) and eight had a flexible sigmoidoscopy. Five hundred and seventeen (44%) procedures were 'normal' (no polyps/cancers). Eighty (6%) individuals had colorectal cancer. The polyp detection rate in index procedures, including colonoscopy, CTC and flexible sigmoidoscopy, was 50%. The adenoma detection rate of all colonoscopies was 62.8%. The median polyp size was 5 (1-80) mm. In total, 1200 colonoscopies were performed by five accredited colonoscopists (96% completion rate). There were 13 (1%) adverse events with < 1 in 500 patients undergoing polypectomy requiring a transfusion. There was one 30-day postsurgical mortality, one perforation and no colonoscopy-related mortality. Almost all 39/40 (97%) patients in the BCS programme felt that the findings were adequately explained compared with 21/32 (64%) elective patients (P < 0.001) within the same unit. CONCLUSIONS: At this bowel cancer screening single centre, colonoscopy completion rates were high (unadjusted caecal intubation rate of 96%) and complication rates were low. In contrast to other published data, the uptake and cancer-detection rates were lower. PMID- 21689281 TI - Sacral nerve stimulation in the elderly. AB - AIM: Increasing life expectancy will increase the number of elderly patients with faecal incontinence. The study aimed to assess the safety and efficacy of sacral nerve stimulation (SNS) in patients over the age of 65 years. METHOD: Patients aged over 65 years, who underwent temporary SNS from 1996 for faecal incontinence unresponsive to conservative treatment, were followed prospectively. RESULTS: Between January 1996 and December 2009, 30 patients [mean age 69.3 years (SD, 3.4)] underwent temporary SNS. Twenty-three (77%) had a >50% improvement in the St Mark's Continence Score and progressed to permanent SNS implantation. Their mean (+/-SD) score increased from 19 (3.2) at baseline to 8 (3.4) during temporary SNS and to 9 (3.4) 3 months after permanent SNS and 10 (3.7) at the latest median follow up (IQR) of 44 (20-150) months. The corresponding values at the same intervals for urgency [mean (+/-SD) min] were 1 (1.4), 8 (5.2), 8 (5) and 8 (5.4) and for incontinence episodes per 2 weeks [median (+/-IQR)] were 10 (7-14), 1 (0-5), 2 (0-5) and 0 (0-6). CONCLUSION: SNS is an effective treatment for faecal incontinence in patients over 65 years. PMID- 21689283 TI - Late recurrence of colorectal cancer following delayed diagnosis. PMID- 21689282 TI - Combination of differentiation and T stage can predict unresponsiveness to neoadjuvant therapy for rectal cancer. AB - AIM: The study aimed to identify the factors predictive for extreme unresponsiveness to neoadjuvant therapy for rectal cancer. METHOD: Ninety-six patients with rectal cancer received neoadjuvant therapy (41 were treated with radiotherapy and 55 with chemoradiotherapy) before surgery. Tumour response, downstaging, pathological complete response (pCR) and disease-free survival were evaluated. RESULTS: Tumour response, downstaging and pCR occurred in 70 (72.9%), 47 (49.0%) and 14 (14.6%) patients, respectively. Univariate analyses showed that a large tumour size, T4 stage, elevated serum tumour markers, poor differentiation, radiotherapy alone and mucinous tumour were indicators of poor tumour response and/or downstaging. On multivariate analysis, chemoradiotherapy was found to be predictive for tumour response and downstaging, whereas mucinous type and T4 stage negatively affected tumour response. No variable was found to be associated with pCR, but poor differentiation and T4 stage together predicted extreme unresponsiveness with a high specificity and a high positive predictive value. Very poor disease-free survival was also observed in patients simultaneously carrying these phenotypes. CONCLUSION: Neoadjuvant chemoradiotherapy is superior to radiotherapy alone in producing a response of rectal cancer. Unresponsiveness was most likely to occur in patients with poor differentiation and T4 disease. PMID- 21689285 TI - Increased use of laparoscopy in acute right iliac fossa pain - is it good for patients? AB - AIM: The use of laparoscopy, with or without appendicectomy, is becoming more common in the management of acute right iliac fossa (RIF) pain, but little is known of the 'unintended' consequences of this change. This study aimed to evaluate the impact of increased use of laparoscopy on the number and type of patients treated surgically and on the rate of negative appendicectomy. METHOD: A prospective audit was carried out of admissions to a teaching hospital over two, 3-month periods during 2007 and 2008. The management, investigations and outcome of patients presenting with RIF pain were studied. RESULTS: Admissions were stable over the two time-periods. There was a significant increase in the number of laparoscopic operations performed, from 22.5% (14/62) in 2007 to 85.7% (72/84) in 2008 (P < 0.0001), and the percentage of patients undergoing surgery rose from 55.4% (n = 62) in 2007 to 71.2% (n = 84) in 2008 (P < 0.01). In 2008, female patients were more likely to have surgery, an increase from 37.1% to 66.2% (P < 0.001), and were more likely to have a laparoscopic procedure, an increase from 50% to 98% (P < 0.0001). The rate of histologically confirmed appendicitis did not increase significantly (50/122 vs 57/118; P = 0.25), but the number of patients with a normal appendix either left in situ because it was macroscopically normal or found to be histologically normal following excision, increased significantly, from 9.01% in 2007 to 21.2% in 2008 (P < 0.01). The diagnostic value of pelvic ultrasound decreased from 75.6% of examinations in 2007 to 54.5% in 2008 (P = 0.039). CONCLUSION: An increase in laparoscopic procedures has resulted in more operations in women, an associated higher negative appendicectomy rate and decreased usefulness of pelvic ultrasound. Increased use of laparoscopy needs to be balanced against the diagnostic benefits of 'negative' laparoscopy. PMID- 21689286 TI - Split stoma in resectional surgery of high-risk patients with ileocolonic Crohn's disease. AB - AIM: The aim of this retrospective study of ileocolonic resection in patients with Crohn's disease was to compare the outcome of primary anastomosis with that of split stoma and delayed anastomosis in a high-risk setting. METHOD: From 1995 to 2006, 132 patients had 146 operations for ileocolonic Crohn's disease. Preoperative data, including risk factors for complications, were obtained from a prospectively registered database. Operations on patients who had two or more preoperative risk factors (n = 76) were considered to be high-risk operations and formed the main study. Primary outcome variables were postoperative anastomotic complications and the alteration in the number of preoperative risk factors achieved by a delayed anastomosis. Secondary outcome was time in hospital and the number of operations performed. RESULTS: Early anastomotic complications were diagnosed in 19% (11/57) of patients receiving a primary anastomosis compared with 0% (0/19) of patients after a delayed anastomosis (P = 0.038). The mean number of risk factors in the split stoma group was 3.5 at the time of resection and 0.2 when the split stoma was reversed (P < 0.0001). The total number of operations was 1.9 +/- 1.5 (mean +/- SD) after a primary anastomosis and 2.0 +/- 0.2 after a split stoma (P = 0.70). Total in-hospital time for all operations was 20.9 +/- 35.6 days after a primary anastomosis and 17.8 +/- 10.4 days after a delayed anastomosis (P = 0.74). CONCLUSION: Delayed anastomosis after ileocolonic resection in high-risk Crohn's disease patients was associated with a reduction in the number of preoperative risk factors and fewer anastomotic complications. Hospital stay and number of operations were similar after delayed and primary anastomosis in high-risk patients. PMID- 21689287 TI - Botulinum A toxin as a treatment for overactive rectum with associated faecal incontinence. AB - AIM: Rectal hypercontractility can lead to faecal incontinence (FI). Botulinum toxin (BT) has been used successfully for the treatment of bladder overactivity. This study aimed to evaluate the therapeutic value of intrarectal injections of BT in inhibiting colorectal contractions and relieving FI in patients suffering from FI as a result of overactive rectal contractions. METHOD: A prospective open study was carried out in Rouen University Hospital. Six patients (four men and two women) with severe FI related to overactive rectal contractions underwent intrarectal submucosal injections of BT placed in three rows of 10, 1-ml injections (50 U/1 ml; Dysport((r))) starting 1 cm above the dentate line and repeated twice, at intervals of 5 cm proximally. The end-points included improvement in the FI score, in faecal incontinence quality of life (FIQL) and of manometric abnormality. RESULTS: All patients reported improvement in the FI score [18.2+/-1.1 at baseline vs 9.0+/-1.7 at 3 months (P=0.04)] and in FIQL. Rectal contractile activity was reduced. The frequency of contractions remained unaffected (28.1+/-6.6/h; P=0.46 vs baseline). High-amplitude contractions of >50 cmH(2)O were significantly decreased in all patients (16.6+/-3.9 vs 6.6+/-4.1/h; P=0.03). CONCLUSION: Patients with an 'overactive rectum' are a heterogeneous group, with varying causes of dysfunction. The dose of BT used was arbitrarily selected. Nevertheless, the study introduces a further therapeutic option in the treatment of FI caused by rectal overactivity. PMID- 21689288 TI - Electrical stimulation of the dorsal clitoral nerve reduces incontinence episodes in idiopathic faecal incontinent patients: a pilot study. AB - AIM: Faecal incontinence (FI) has a significant impact on quality of life. This study investigates whether stimulation of the dorsal genital nerve (DGN) improves FI symptoms. METHOD: Ten female patients suffering from idiopathic FI (median age 60 years) were included in the study. Stimulation was applied twice daily for 3 weeks at the maximal tolerable stimulation amplitude (pulse width, 200 MUs; pulse rate, 20 Hz). Patients kept a 3-week bowel diary prior to stimulation, during stimulation and after the final stimulation. FI severity scores, FI Severity Visual-Analogue Score (VAS), FI Quality of Life Score (FIQL), sphincter function and rectal volume tolerance were assessed at baseline, immediately after stimulation and 3 weeks after stimulation. RESULTS: Nine patients completed the study. The Wexner score (P=0.027) and the St Mark's score (P=0.035) improved after stimulation in seven and six of the patients and improvement was maintained 3 weeks after stimulation (P=0.048 and P=0.049, respectively). The number of incontinent episodes was reduced in seven out of nine patients (P=0.025). Improvement was maintained for 3 weeks after stimulation (P=0.017). Subjective assessments of FI severity using the VAS score and the FIQl score did not improve during stimulation. Sphincter function and rectal volume tolerability were unaffected. CONCLUSION: DGN stimulation reduced the number of FI episodes in most patients suffering from idiopathic FI. Sphincter function and rectal volume tolerability were not affected. DGN stimulation may represent a new treatment for idiopathic FI. PMID- 21689289 TI - Clinical significance of incidental focal colorectal (18)F-fluorodeoxyglucose uptake: our experience and a review of the literature. AB - AIM: The aims of the present study were: (i) to evaluate the focal incidental colorectal uptake of (18)F-fluorodeoxyglucose ([(18)F]FDG) and to correlate it with colonoscopy and histological findings; (ii) to evaluate the relationship between the presence/absence of neoplastic disease and clinical data and the anatomical site of [(18)F]FDG uptake; and (iii) to compare our results with those reported for incidental colorectal uptake of [(18)F]FDG in the literature and those obtained from various screening programmes for colorectal cancer. METHOD: The database of 6000 patients referred for [(18)F]FDG positron emission tomography/computed tomography (PET-CT) to our centre was retrospectively reviewed for incidental colorectal uptake of [(18)F]FDG. Patients with focal uptake were selected and the aetiology of PET findings was verified with a subsequent colonoscopy and histopathological analysis when available. RESULTS: Incidental colorectal uptake of [(18)F]FDG was seen in 144 (2.4%) patients, of whom 64 (1.1%) had focal uptake; 48 out of these 64 patients underwent colonoscopy, which showed malignant tumours in 12 (25%), premalignant lesions in 19 (40%), non-neoplastic lesions in six (12%) and lesions not confirmed by colonoscopy in 11 (23%). Our data agreed with previously published data. Statistical analysis did not show any significant relationship between the presence/absence of neoplastic disease and patient sex or age, type of primary disease and anatomical site of [(18)F]FDG uptake. Comparing our data with various screening programmes, a significant difference was found only with series in which colonoscopy was performed in patients at high risk for colorectal cancer. CONCLUSION: Focal incidental colorectal uptake of [(18)F]FDG is observed in about 1% of PET/CT studies and carries a high risk of neoplastic disease. A PET-CT report should suggest colonoscopy when abnormal findings are reported. PMID- 21689290 TI - Colorectal cancer in nonagenarians. AB - AIM: The aim of the study was to analyze the short-term and long-term outcomes of nonagenarians treated for colorectal cancer. METHOD: A retrospective analysis was performed of 74 patients, >= 90 years of age, diagnosed with colorectal cancer during the period 1986-2009. Comorbidity, American Society of Anesthesiology (ASA) grade, symptoms, diagnosis, treatment, mortality, morbidity and survival were analyzed. RESULTS: Of the 74 patients, 48 (65%) were women. Twenty-two patients were classified as ASA grade I-II, 26 as ASA grade III and 26 as ASA grade IV-V. Thirty-one (42%) had intestinal obstruction at the time of diagnosis. Twenty-two (30%) patients were diagnosed during the period 1986-2000 and 52 (70%) were diagnosed between 2001 and 2009. Forty-four (59%) patients underwent surgery, of whom 19 (49%) were treated as an emergency. Eleven (25%) patients died postoperatively, with mortality rates of 12% (3/25) for elective surgery and 42% (8/19) for emergency surgery. Surgical mortality for ASA grade I and grade II patients was 5% (1/20) and their 5-year survival rate (postoperative mortality excluded) was 44%, whereas 5-year survival for ASA grade III patients who underwent surgery was 12.5% and surgical mortality was 25% (4/16). There were no survivors beyond 36 months among patients who did not receive surgery. CONCLUSION: Our results indicate that elective and emergency colorectal surgery can be performed with acceptable rates of mortality and morbidity on nonagenarian patients in good general condition with low perioperative risk. The 5-year survival rate was related to ASA grade and to the use of surgery. PMID- 21689292 TI - Designer stoma care. PMID- 21689291 TI - Patient and surgeon factors are associated with the use of laparoscopy in appendicitis. AB - AIM: The use of a minimally invasive approach to treat appendicitis has yet to be universally accepted. The objective of this study was to examine recent trends in Ireland in the surgical management of acute appendicitis. METHOD: Data were obtained from the Irish Hospital In-Patient Enquiry system for patients discharged with a diagnosis of appendicitis between 1999 and 2007. An anonymous postal survey was sent to all general surgeons of consultant and registrar level in Ireland to assess current attitudes to the use of laparoscopic appendectomy. RESULTS: The use of laparoscopic appendectomy increased throughout the study and was the most common approach for appendectomy in 2007. Multivariate analysis revealed age under 50 years (OR = 1.51), female sex (OR = 2.84) and residence in high-density population areas (OR = 4.15) as predictive factors for undergoing laparoscopic appendectomy in the most recent year of the study. While 97% of surgeons reported current use of laparoscopy in patients with acute right iliac fossa pain, in most cases it was selective. Surgeons in university teaching hospitals (42 of 77; 55%) were more likely to report using laparoscopic appendectomy for all cases of appendicitis than those in regional (six of 23; 26%) or general (13 of 53; 25%) hospitals (P = 0.048). CONCLUSION: This study has demonstrated a significant increase in laparoscopic appendectomy, yet a variety of patient and surgeon factors contribute to the choice of procedure. Differences in the perception of benefit of the laparoscopic approach amongst surgeons appears to be an important factor in determining the operative approach for appendectomy. PMID- 21689293 TI - The effect of appendectomy on the course of ulcerative colitis: a systematic review. AB - AIM: Previous studies have shown significantly lower appendectomy rates in ulcerative colitis (UC) patients compared with healthy controls. Evidence indicating that the appendix has an immunomodulatory role in UC has been accumulating. To examine the latest evidence on the effect of appendectomy on the disease course of UC. METHOD: PubMed, The Cochrane Library and EMBASE were searched. Primary end-points were number of relapses, use of steroids, number of hospital admissions and number of colectomies. RESULTS: The search resulted in six observational studies (five case-control studies and one cohort study) totalling 2532 patients. Owing to clinical heterogeneity, no meta-analysis could be conducted. One study found lower relapse rates in patients appendectomized before the onset of UC [absolute risk reduction (ARR)=21.5%; 95% CI: 1.71 45.92%]. Another two studies found a reduced requirement for immunosuppression in appendectomized patients (ARR=20.2%; 95% CI: 9.67-30.46% in the first study and ARR=21.4%; 95% CI: 10.32-32.97% in the second study). In addition, one study found lower colectomy rates in nonappendectomized patients (ARR=8.7%; 95% CI: 1.29-18.66%) and two studies found lower colectomy rates in appendectomized patients (ARR=21.4%; 95% CI: 13.17-28.79% in the first study and ARR=18.7%; 95% CI: 7.50-29.97% in the second study). CONCLUSION: There are limited and conflicting data available regarding the effect of appendectomy on the disease course of UC. Most studies suggest a beneficial effect and the minority find no, or a negative, effect. PMID- 21689294 TI - Pulmonary staging in colorectal cancer: a review. AB - AIM: Assessment of the chest in colorectal cancer (CRC) staging is variable. The aim of this review was to look at different chest staging strategies and determine which has the greatest efficacy. METHOD: A review of studies assessing chest staging modalities for patients with CRC was performed. Modalities included chest X-ray (CXR), CT and positron emission tomography (PET). RESULTS: The majority of data consisted of case series. Two studies identified a low pick-up rate for CXR as a staging tool. Five studies showed increased detection rates of pulmonary metastases for chest CT vs CXR and abdominal CT. The clinical benefit of the increased detection rates was not clear. The incidence of indeterminate lung lesions (ILL) on staging chest CT varied from 4 to 42%. The majority (>= 70%) of ILLs did not have any clinical significance. On CT scans, the incidence of pulmonary metastases in patients with rectal cancer ranged from 10 to 18% and in patients with colon cancer the incidence of pulmonary metastases ranged from 5 6%. The incidence of synchronous liver and pulmonary metastases compared with the overall incidence of pulmonary metastases ranged from 45 to 70%. There was no evidence reporting the superiority of PET/CT vs CT for the detection of pulmonary metastases or characterization of ILL. CONCLUSION: Studies show that chest CT scanning increases the detection rates for ILL and pulmonary metastases. The clinical benefit of the increased detection rates is not clear. There is a paucity of data assessing the optimal chest staging strategy for patients presenting with CRC. PMID- 21689295 TI - Humoral hypercalcaemia of malignancy associated with squamous cell carcinoma of the anus. PMID- 21689296 TI - Postoperative perforation secondary to retained endocapsule. PMID- 21689297 TI - Rhodococcus equi colonic lesion mimicking colon cancer. PMID- 21689298 TI - Isolated vaginal metastasis from rectal adenocarcinoma: a rare presentation. PMID- 21689299 TI - Laparoscopic peritoneal lavage for perforated sigmoid diverticulitis. AB - AIM: Currently in the UK the standard surgical practice for the management of perforated sigmoid diverticulitis is a Hartmann's procedure. There have been a number of recent publications on the use of laparoscopic peritoneal lavage for perforated sigmoid diverticulitis, as an alternative to the emergency Hartmann's procedure, with its associated morbidity and mortality. We aim to review the current literature on this topic. METHOD: A search was made on the electronic database MEDLINE from PubMed, EMBASE and the Cochrane library. The keywords 'diverticulitis', 'perforated' and 'laparoscopy' were searched for in the titles and abstracts without language restrictions. Further studies were identified from searches on Google Scholar, as well as manual searches through reference lists of the relevant studies found. All included studies were quality assessed. RESULTS: Twelve relevant studies were included. A total of 301 patients were reported, with a mean age of 57 years. All were non-randomized studies. The majority of patients were of Hinchey classification III. All were treated with intravenous antibiotics followed by laparoscopic lavage and insertion of intra abdominal/pelvic drains. The mean conversion rate was 4.9% and mean length of hospital stay was 9.3 days. The mean complication rate was 18.9% and the overall mortality rate was 0.25%. Subsequent elective resections with primary anastamosis were performed in 51% of patients and the majority were completed laparoscopically. CONCLUSION: Laparoscopic peritoneal lavage for perforated sigmoid diverticulitis appears to be a potentially effective and more conservative alternative to a Hartmann's procedure. Randomized control trials are needed to better evaluate its role. PMID- 21689300 TI - How informative is the print media coverage of colorectal cancer? AB - AIM: To date there has been no assessment of the educational content of colorectal newspaper articles. We aimed to analyse articles in the print media concerning colorectal cancer for their public health content. METHOD: Articles mentioning colorectal cancer in the top 10 UK newspapers were analysed over a 1 year period for their educational content. The number of articles mentioning 'red flag' symptoms, celebrity connections or specific cancer charities was recorded. RESULTS: Of the 349 articles identified, 146 were not relevant. Of the remaining 203 articles, 62 (30%) were concerned with celebrities with colon cancer, 13 (6.4%) made reference to red flag symptoms and 14 (6.9%) mentioned cancer charities by name. CONCLUSION: About 13% of newspaper articles have any educational content. If this increased, the general public might benefit. PMID- 21689301 TI - Late malignancy within rectal duplication and Hirschsprung's disease. PMID- 21689302 TI - Mild colonic diverticulitis can be treated without antibiotics. A case-control study. AB - AIM: Conservative treatment of mild colonic diverticulitis usually consists of observation, restriction of oral intake, intravenous fluids and antibiotics. The beneficiary effect of antibiotics remains unclear. The aim of this study is to evaluate the need for antibiotics in mild colonic diverticulitis. METHOD: A retrospective case-control study was performed in 272 patients with mild colonic diverticulitis admitted to two hospitals with distinctly different treatment regimes concerning antibiotic use. RESULTS: A total of 191 patients were treated without antibiotics and 81 with antibiotics. Groups were comparable at baseline with respect to age, sex, comorbidity, and use of nonsteroid anti-inflammatory drugs, steroids and aspirin. All patients had imaging-confirmed diverticulitis. C reactive protein and white blood count levels did not differ significantly. In the antibiotics group there were significantly more patients with a temperature of 38.5 degrees C or higher on admission. (8 vs 19%; P=0.014). Treatment failure did not differ between groups (4 vs 6%; P=0.350). The risk of recurrence was higher in the antibiotics group on logistic regression analysis but did not reach statistical significance (odds ratio, 2.04; confidence interval, 0.88-4.75; P=0.880). The only factor that increased the risk of recurrence was nonsteroid anti-inflammatory drug use (odds ratio, 7.25; confidence interval, 1.22-46.88; P=0.037). CONCLUSION: Antibiotics can be omitted in selected patients with mild colonic diverticulitis and should be given on indication only. PMID- 21689303 TI - Fresh frozen cadavers: an under-utilized resource in laparoscopic colorectal training in the United Kingdom. AB - AIM: To describe the use of fresh frozen cadavers in laparoscopic colorectal training. METHOD: The cadavers are washed and frozen to -20 degrees C within a week of procurement before being thawed at room temperature prior to use. RESULTS: Fresh frozen cadavers provide perfect anatomy, normal tissue consistency and a realistic operative training experience. CONCLUSION: Fresh frozen cadavers have a number of clear advantages over other training models in laparoscopic colorectal surgery but are currently not widely used. PMID- 21689304 TI - Self-reported depressive symptoms and suicidal feelings in perianal Crohn's disease. AB - AIM: Crohn's disease is a chronic inflammatory condition that has been associated with high rates of mental illness. Perianal lesions are prevalent; however, their specific impact on depression has not been studied. The aim of our study was to investigate the prevalence and associations of self-reported depressive symptoms in the subset of Crohn's patients with perianal disease. METHOD: Patients with perianal Crohn's disease from one institution were surveyed to elicit the frequency of self-reported depressive symptoms. Patients completed a questionnaire and consented to medical records audit. RESULTS: Of the 130 patients invited, 69 (53%) returned a survey. Depressive symptoms were self reported at very high rates, with 73% reporting feeling depressed and 13% reporting feeling suicidal at some point. Associations were found between depressive symptoms and duration of disease, prior surgery, past or present stoma, and anal stenosis. Patients who self-reported depressive symptoms had lower overall utilities, and were willing to trade very significant proportions (upwards of 15%) of their life expectancy for disease cure. CONCLUSION: This study suggests that many patients with perianal Crohn's disease experience significant emotional distress that impairs their overall quality of life. Further controlled studies are required to assess the impact of perianal disease and to address the need to target interventions to meet the mental health needs of this population. PMID- 21689305 TI - Underlying functional bowel disorder may explain patient dissatisfaction after haemorrhoidal surgery. AB - AIM: The aim of this study was to assess patient dissatisfaction and functional symptoms following haemorrhoid surgery, aspects of which are seldom covered in other published series. METHOD: A self-administered questionnaire was mailed to 359 consecutive patients (prospective database; 198 men, 161 women; median follow up, 59 [1-120] months) who underwent either Milligan-Morgan haemorrhoidectomy (n=205) or stapled haemorrhoidopexy (n=154). RESULTS: The response rate was 72%; 2.4% of patients had no opinion, 13.6% were dissatisfied, 33.0% were satisfied, and 51.0% were very satisfied with the treatment. Dissatisfied patients were more likely to be women and more likely to have a long history of constipation and irritable bowel syndrome. The duration of surgery and the rates of pre- and postoperative complications did not differ between groups. Residual bleeding (49% vs 32%), prolapse (67% vs 31%) and pain (91% vs 55%) occurred more frequently in the dissatisfied group compared with the satisfied group (P<0.001). Incontinence (4 [0-16] vs 1 [0-15]; P=0.0003) and constipation (19 [1-34] vs 8 [0-31]; P<0.0001) scores were significantly higher in the dissatisfied group compared with satisfied patients. Anal pain was the predominant symptom associated with dissatisfaction in a logistic regression model. CONCLUSION: Persistent pain remains the major long-term factor associated with dissatisfaction after surgery for haemorrhoids. PMID- 21689306 TI - The impact of practice environment on laparoscopic colectomy utilization following colorectal residency: a survey of the ASCRS Young Surgeons. AB - AIM: It is often thought that practice patterns are different in private (PP) vs university hospital (UH) settings. We aimed to describe the impact of practice environment on the type of laparoscopic colectomy procedures performed by graduating colorectal surgeons. METHOD: A review was carried out of prospectively gathered self-reported questionnaire data. Graduates of American Society of Colon and Rectal Surgeons' (ASCRS)-approved colorectal residencies from 2004 to 2008 underwent an on-line survey, developed by the ASCRS Young Surgeons' Committee. RESULTS: About 177 (52%) of 342 graduates surveyed responded. Practice setting data were available for 157 (89%) surgeons. Gender, geographical location and age were similar in both cohorts. PP surgeons utilized a laparoscopic approach more often for rectal cancer (37% vs 19%; P=0.003). There was no significant difference in the rate of laparoscopic surgery in colon cancer, diverticular disease, inflammatory bowel disease, Clostridium difficile or emergency surgery. PP surgeons operated more often with a partner (43% vs 8%) or surgical assistant (13% vs 4%; both P<0.001), while UH surgeons had a colorectal resident (10% vs 21%) or general surgery resident (15% vs 55%; both P<0.001). Impediments to performing laparoscopic surgery for PP surgeons included a perceived lack of hospital equipment (33% vs 20%) and support (29% vs 17%; both P<0.05). Perception of personal experience, access to trained assistants, financial reimbursement, length of surgery and patient availability were equivalent in both groups. CONCLUSION: While differences such as type of assistant and impediments to laparoscopic utilization exist between PP- and UH-based practices, early laparoscopic practice patterns remain similar. PP surgeons more frequently perform laparoscopic resection for rectal cancer and with hand-assistance. Despite differences, newly trained colorectal surgeons in both settings utilize and require laparoscopic skills. PMID- 21689307 TI - Exfoliated colonocyte DNA levels and clinical features in the diagnosis of colorectal cancer: a cohort study in patients referred for investigation. AB - AIM: Selection of patients for investigation of suspected colorectal cancer is difficult. One possible improvement may be to measure DNA isolated from exfoliated cells collected from the rectum. METHOD: This was a cohort study in a surgical clinic. Participants were aged >=40 years and referred for investigation of suspected colorectal cancer. Exclusion criteria were inflammatory bowel disease, previous gastrointestinal malignancy, or recent investigation. A sample of the mucocellular layer of the rectum was taken with an adapted proctoscope (the Colonix system). Haemoglobin, mean cell volume, ferritin, carcino-embryonic antigen and faecal occult bloods were tested. Analysis was by logistic regression. RESULTS: Participation was offered to 828 patients, of whom 717 completed the investigations. Three were lost to follow up. Seventy-two (10%) had colorectal cancer. Exfoliated cell DNA was higher (P<0.001) in cancer (median 5.4 MUg/ml [inter-quartile range 1.8,12]) compared with those without cancer (2.0 MUg/ml [IQR 0.78,5.5]). Seven variables were independently associated with cancer, including age (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.02,1.08; P<0.001) DNA (OR, 1.05; CI, 1.01,3.6; P=0.01), mean cell volume (OR, 0.93; CI, 0.89,0.97; P=0.001), carcino-embryonic antigen 1.02 per MUg/l (CI, 1.00,1.04; P=0.02), male sex (OR, 2.0; CI, 1.1,3.6; P=0.02), rectal bleeding (OR, 2.4; CI, 1.3,4.5; P=0.007) and positive faecal occult blood (OR, 6.7; CI, 3.4, 13; P<0.001). The area under the receiver-operating characteristic curve for the DNA score was 0.65 (0.58-0.72) and for the seven variable model 0.88 (CI, 0.84 0.92). CONCLUSION: Quantification of exfoliated DNA from rectal cellular material has promise in the diagnosis of colorectal cancer, but this requires confirmation in a larger study. PMID- 21689308 TI - Surgical vs general practitioner assessment: diagnostic accuracy in 2-week-wait colorectal cancer referrals. AB - AIM: It has been recommended that patients with suspected colorectal cancer should proceed straight to an endoscopic test to increase speed of diagnosis, using only the information in the general practitioner's referral letter. This study aims to establish whether the diagnostic accuracy of the first surgical outpatient assessment is significantly greater than the general practitioner's assessment and if so by what means. METHOD: Demographic variables, symptoms and signs were collected from the first surgical outpatient assessment letters and the general practitioners' referral letters in 2-week-wait colorectal cancer referrals made between 2002 and 2005. Multiple logistic regression models derived from both the surgeons' and the general practitioners' letters were compared with receiver operator characteristic curves. RESULTS: Variables were collected from 978 2-week-wait colorectal cancer referrals. The median age was 69 years (range 19-98) and the male to female ratio was 1:2. Seventy-eight referrals were diagnosed with colorectal cancer. Surgeons' models demonstrated significantly greater diagnostic accuracy than general practitioners' models (area under the curve, 0.84 vs 0.73; P < 0.003). General practitioners' letters contained significantly less information than surgeons' letters (P < 0.001), but correcting for this did not account for the difference in diagnostic accuracy. The single variable that accounted for the difference in diagnostic accuracy was examination of the rectum by rigid sigmoidoscopy. CONCLUSION: Rigid sigmoidoscopy significantly improves the diagnostic accuracy of clinical assessment in patients with suspected colorectal cancer. If rigid sigmoidoscopy were omitted in a straight-to-test pathway, some patients would be denied the opportunity for immediate diagnosis. PMID- 21689310 TI - Deep sedation compared with moderate sedation in polyp detection during colonoscopy: a randomized controlled trial: reply to Paspatis et al. PMID- 21689309 TI - Palliative resection of the primary tumour in stage IV rectal cancer. AB - AIM: The aim of this study was to investigate the use of resection in a cohort of palliatively treated patients with stage IV rectal cancer. To avoid selection bias, particular attention was paid to correction for comorbidity and extent of disease. METHOD: Patients with stage IV rectal cancer in two hospitals in Groningen were consecutively included over a 5-year period. Comorbidity was defined as major (dementia, cardiac failure or left ventricle ejection fraction <30%, or severe chronic obstructive pulmonary disease), minor (diabetes, hypertension, mild renal disease or mild pulmonary disease) or none. The effect of patient and disease characteristics on survival was assessed using Kaplan Meier and Cox regression analyses. RESULTS: Of 88 patients, 11 (13%) underwent elective surgical resection without chemotherapy, 15 (17%) received both elective resection and chemotherapy, 21 (24%) underwent palliative chemotherapy only and 41 (47%) had supportive care only. The extent of disease (P<0.01), hospital (P=0.02) and comorbidity (P=0.04) were correlated with worse survival. Patients treated surgically survived for longer than patients treated nonsurgically, when the data were corrected for age, comorbidity, extent of disease and hospital [hazard ratio (HR)=0.4 (95% CI=0.2-0.7)]. Perioperative morbidity was seen in 38% of the patients, and 30-day mortality was 0%. CONCLUSION: In this retrospective cohort, resection was associated with longer survival independently of the extent of distant metastases, age and comorbidity. PMID- 21689311 TI - Risk factors for severe perineal injury during childbirth: a case-control study of 60 consecutive cases. AB - AIM: The study aimed to evaluate the current risk factors for severe perineal tears in a single university-affiliated maternity hospital. METHOD: An obstetric database of 31 784 consecutive women who delivered from January 2007 to December 2009 was screened for cases of third-degree or fourth-degree perineal tears. Four controls, matched by time of delivery, were selected for each case of third- or fourth-degree perineal tear. Maternal and obstetric parameters were analyzed and compared between the study and control groups. RESULTS: Sixty women (0.25% of all vaginal deliveries) had a third-degree (53 women) or a fourth-degree (seven women) perineal tear. The control group comprised 240 matched vaginal deliveries without severe tears. Primiparity, younger maternal age, Asian ethnicity, longer duration of second stage of labour, vacuum-assisted delivery and heavier newborn birth weight were significantly more common among women who had third- or fourth degree perineal tears. Of the variables that were found to be statistically significant in the univariate analysis, only primiparity (OR = 2.809, 95% CI: 1.336-5.905), vacuum delivery (OR = 10.104, 95% CI: 3.542-28.827) and heavier newborn birth weight (OR = 1.002, 95% CI: 1.001-1.003) were found to be statistically significant independent risk factors for severe perineal trauma. CONCLUSION: Identification of women at risk may facilitate the use, or avoidance, of certain obstetric interventions to minimize the occurrence of childbirth associated perineal trauma. PMID- 21689312 TI - How sacral nerve stimulation works in patients with faecal incontinence. AB - AIM: Sacral nerve stimulation (SNS) reduces incontinence episodes and improves the quality of life of patients treated for faecal incontinence. However, the exact mechanism of action of this technique remains unclear. The present article reviews the pertinent neuroanatomy and neurophysiology related to SNS and provides explanations for potential mechanisms of action. METHOD: A systematic review of the literature was performed for studies of the potential mechanisms of action of SNS, using MEDLINE, PubMed, Embase and the Cochrane Library. Articles dealing with the technique, adverse events and economic evaluations of SNS, as well as literature reviews, were excluded, except for reviews dealing with the mechanisms of action of SNS. The following inclusion criteria were used to select articles: (i) articles in English, (ii) randomized, double-blinded, sham controlled studies, and (iii) cohort studies. Case-control studies or retrospective studies were cited only when randomized or cohort studies could not be found. RESULTS: We propose three hypotheses to explain the mechanism of action of SNS: (i) a somato-visceral reflex, (ii) a modulation of the perception of afferent information, and (iii) an increase in external anal sphincter activity. CONCLUSION: The mechanism of action of SNS in patients with faecal incontinence almost certainly depends on the modulation of spinal and/or supraspinal afferent inputs. Further research on humans and animals will be required to gain a better understanding of the mechanisms of action of SNS. PMID- 21689313 TI - Endoscopic decompression of benign large bowel obstruction using a transanal drainage tube. AB - AIM: Endoscopic decompression of malignant colorectal obstruction is often dealt with using expandable metallic stents. Endoscopic decompression of benign large bowel obstruction is more difficult. We report the technique and outcome of transanal endoscopic decompression for benign large bowel obstruction. METHOD: From January 2001 to June 2010, endoscopic decompression using a transanal drainage tube placement was attempted in consecutive patients with benign large bowel obstruction. The clinical features, technical success, complications, treatment after the tube placement and clinical success were retrospectively evaluated. RESULTS: There were 13 patients (seven males, age 47-87, mean 69 years). The sites of obstruction were transverse colon [5 (38%)], sigmoid colon [3 (23%)], ileocecal valve [2 (15%)], splenic flexure [1 (8%)], descending colon [1 (8%)] and rectum [1 (8%)]. The most common cause of obstruction was anastomotic stricture [9 (69%)]. In 12 (92%) patients transanal decompression was technically successful with one perforation. An overtube, the reinsertion of colonoscope along the decompression tube, or the use of a small-diameter endoscope was required for the tube placement in seven (54%). In seven (54%) patients tube placement alone resulted in relief of bowel obstruction without operation. CONCLUSION: Endoscopic decompression using a transanal drainage tube is effective for the management of benign large bowel obstruction. PMID- 21689314 TI - Validation of the seventh edition of the American Joint Committee on Cancer tumor node-metastasis (AJCC TNM) staging in patients with stage II and stage III colorectal carcinoma: analysis of 2511 cases from a medical centre in Korea. AB - AIM: The sixth and seventh editions of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) system for patients with stage II and stage III colorectal carcinoma (AJCC-6 and AJCC-7) were compared. METHOD: Between 2000 and 2007, 2511 stage II/III colorectal carcinoma patients received primary surgical resection at the Asan Medical Center (Seoul, Korea). All patients were staged using AJCC-6 and AJCC-7 TNM systems. Patients with synchronous or other cancers, those given preoperative chemotherapy or radiotherapy and those in whom fewer than 12 lymph nodes were resected, were excluded. Overall survival (OS) and disease-free survival (DFS) were compared. RESULTS: Of 2511 patients, 255 (10.2%) had different stages in the AJCC-6 and AJCC-7. For the AJCC-7, the 5-year OS by stage was 94.2% for stage IIA, 88.8% for stage IIB, 83.5% for stage IIC, 91.8% for stage IIIA, 81.8% for stage IIIB and 72.0% for stage IIIC. The OS and the DFS were not significantly different for the new substages IIB (n = 57) and IIC (n = 34) (P = 0.34 and P = 0.87, respectively). For the 187 patients with stage T3N2a cancer, the OS and the DFS were significantly different from stage IIIB other than T3N2a (P = 0.008 and P = 0.01, respectively) and there were no statistically significant differences in OS between the T3N2a group and the IIIC group (P = 0.46). CONCLUSION: The study indicates that AJCC-7 has better prognostic validity than AJCC-6 for staging of patients with stage II and stage III colorectal carcinoma. PMID- 21689315 TI - Circumferential resection margin involvement after laparoscopic abdominoperineal excision for rectal cancer. AB - AIM: This study aimed to evaluate circumferential resection margin (CRM) involvement in patients with rectal adenocarcinoma after laparoscopic abdominoperineal excision (APR). METHOD: Prospectively collected data were analyzed on consecutive patients who underwent laparoscopic APR for histologically proven rectal cancer following neoadjuvant chemotherapy, from 1998 to 2006. Patients with no sphincter involvement were not included and underwent intersphincteric resection with coloanal anastomosis. CRM involvement was defined as <= 2 mm using a standardized pathology protocol. Data were presented as mean +/- SD or as median (range). RESULTS: Seventy-four patients (60 +/- 14 years of age; body mass index = 29.7 +/- 7.9 kg/m(2) ) underwent laparoscopic APR. The distance of the tumour from the anal verge was 3.1 +/- 0.93 cm. All patients had sphincter involvement. The operative time was 180 +/- 73 min, and estimated blood loss was 269 +/- 149 ml. There were no conversions and no postoperative mortality. The adverse event rate was 11%. There were two reoperations and three readmissions. Seventy-one patients had a T3 tumour and three patients had a T4 tumour. The median tumour size was 3.1 (range, 0-10) * 3 (range, 0-8.5) * 2 (range, 0-3.6) cm, and 26 (range, 3-41) lymph nodes were harvested. The median CRM was 7 (range, 1-11) mm. This was localized at the waist of the specimen in 12 (16.2%) of patients. Adjuvant therapy was given to 92% and 97% of patients with an involved and an uninvolved CRM, respectively. At 50 +/- 27 months of follow up of 73 patients, 12 had CRM involvement and had a significantly decreased cancer specific survival (log rank test, P = 0.002). CONCLUSION: Laparoscopic APR resulted in CRM involvement in 16.2% of patients with rectal cancer. PMID- 21689316 TI - Long-term survival in a case of malignant familial adenomatous polyposis coli with metachronous liver, lung and brain metastases. PMID- 21689318 TI - Factors influencing postoperative adverse events after Hartmann's reversal. AB - AIM: The study was performed to evaluate factors influencing postoperative adverse events after Hartmann's reversal (HR). METHOD: This was a retrospective study of unselected patients who underwent HR after the Hartmann's procedure (HP) for left colonic perforation with peritonitis at a single institution. Data were retrieved from an Institutional Review Board-approved database. The study end point was postoperative adverse events, which included mortality, complications, reoperations and 30-day readmission. Lag time was defined as the time from HP to HR. The results are expressed as mean+/-SD. RESULTS: From 1997 to 2007, 204 (39.1%) of all patients who underwent the HP [60+/-16 years of age; 58% men; body mass index (BMI) 27.6+/-5.7; 2% were American Society of Anesthesiology (ASA) 1, 50.2% were ASA 2, 39.9% were ASA 3 and 7.9% were ASA 4) underwent HR at an interval of 158+/-107 days. There were 24 laparoscopic and 180 open HRs, with no deaths. The operating time was 167+/-64 min, estimated blood loss was 245+/-283 ml and the 30-day readmission rate was 4.9%. Eleven (5.4%) patients developed 14 (6.8%) complications and five (2.4%) of these patients required a new stoma at the time of HR or later. On multivariate analysis controlling for confounders, chronic renal failure requiring dialysis (OR=21.0; 95% CI: 1.5-284; P=0.02) was significantly associated with increased adverse events. CONCLUSION: The study showed that chronic renal failure requiring dialysis was the only independent predictor of postoperative adverse event rates following HR. PMID- 21689317 TI - Prospective randomized multicentre study comparing stapler haemorrhoidopexy with Doppler-guided transanal haemorrhoid dearterialization for third-degree haemorrhoids. AB - AIM: Doppler-guided transanal haemorrhoid dearterialization (THD) and stapler haemorrhoidopexy (SH) have been demonstrated to be less painful than the Milligan Morgan procedure. The aim of this study was to compare the effectiveness of THD vs SH in the treatment of third-degree haemorrhoids in an equivalent trial. METHOD: One hundred and sixty-nine patients with third-degree haemorrhoids were randomized online to receive THD (n = 85) or SH (n = 84) in 10 Colorectal Units in which the staff were well trained in both techniques. The mean follow-up period was 17 (range 15-20) months. RESULTS: Early minor postoperative complications occurred in 30.6% of patients in the THD group and in 32.1% of patients in the SH group. Milder spontaneous pain and pain on defecation were reported in the THD group in the first postoperative week, but this was not statistically significant. Late complications were significantly higher (P = 0.028) in the SH group. Residual haemorrhoids persisted in 12 patients in the THD group and in six patients in the SH group (P = 0.14). Six patients in the SH group and 10 in the THD group underwent further treatment of haemorrhoids (P = 0.34). No differences were found in postoperative incontinence. The obstructed defecation score (ODS) was significantly higher in the SH group (P < 0.02). Improvement in quality of life was similar in both groups. Postoperative in hospital stay was 1.14 days in the THD group and 1.31 days in the SH group (P = 0.03). CONCLUSION: Both THD and SH techniques are effective for the treatment of third-degree haemorrhoids in the medium term. THD has a better cost-effective ratio and lower (not significant) pain compared with SH. Postoperative pain and recurrence did not differ significantly between the two groups. PMID- 21689319 TI - Prospective evaluation of intraoperative peripheral nerve injury in colorectal surgery. AB - AIM: Intraoperative peripheral nerve injury can have permanent neurological consequences. Its incidence is not known and varies according to the location and the surgical specialty. This study was a prospective analysis of intraoperative peripheral nerve injury as a complication of abdominal colorectal surgery. METHOD: All patients who underwent major colorectal abdominal surgery in our Colorectal Unit between 1996 and 2009 were analyzed. Data on nerve injury were prospectively collected. RESULTS: There were 2304 patients, of whom eight (0.3%) experienced intraoperative peripheral nerve injury. This occurred in 5/2211 (0.2%) open procedures and in 3/93 (3%) laparoscopic procedures. There was no association between intraoperative peripheral nerve injury and age, gender, body mass index, surgeon, operation time, American Society of Anesthesiology (ASA) score and urgent surgery. The use of Allen-type stirrups and a vacuum bag (in laparoscopic surgery) seemed to be protective for nerve injury in the lower and upper limbs respectively. CONCLUSION: Adequate positioning and the use of pressure-free positioning devices may prevent intraoperative peripheral nerve injury, particularly during laparoscopy. PMID- 21689320 TI - Haemorrhoids, constipation and faecal incontinence: is there any relationship? AB - AIM: Little is known about the association of haemorrhoids and anorectal function. Moreover, available data on the impact of constipation on the presence of haemorrhoids are conflicting. The present study aimed to assess any potential relationship between haemorrhoids and anorectal dysfunction. METHOD: All participants who attended the Austrian nationwide healthcare programme for colorectal cancer screening at four medical institutions were enrolled prospectively between 2008 and 2009. A colonoscopy and detailed anorectal examination were performed on all patients. Haemorrhoids were classified according to an international grading system. Faecal incontinence was defined as the involuntary loss of solid stool, liquid stool or gas, at least once a month. Constipation was recorded by a constipation scoring system. RESULTS: Of 976 participants, 380 (38.9%) were found to have haemorrhoids. There was an association between healthy individuals, patients with symptomatic and patients with asymptomatic haemorrhoids and incontinence of liquid stool. No association was found regarding incontinence for solid stool and gas. The median constipation score was significantly higher in those patients with haemorrhoids (grade I-IV) compared with patients without haemorrhoids (2.5 points (range, 0-19) and 3 points (range, 0-19); P = 0.0113). 'Painful evacuation effort' and 'assistance for defaecation (stimulant laxatives, digital assistance or enema)' showed a significant correlation with haemorrhoids (P = 0.0394 and P = 0.0143). CONCLUSION: Although the median constipation score was low in both groups, there was a significant association between constipation and haemorrhoids in adult patients. PMID- 21689321 TI - Adherence to national guidelines for surveillance after curative resection of nonmetastatic colon and rectum cancer: a survey among Norwegian gastrointestinal surgeons. AB - AIM: National guidelines recommend enrollment of patients in surveillance programmes following curative resection of colorectal carcinoma (CRC) in order to detect recurrence or distant metastasis at an asymptomatic/early stage when secondary curative treatment can be offered. Little is known about surgeons' adherence to such guidelines. In this national survey we analyse adherence and attitudes to postoperative follow up among Norwegian gastrointestinal surgeons involved in the care of patients with CRC. METHOD: We performed a nationwide survey of all hospitals performing surgery for colon and/or rectum cancer. The presence of a surveillance programme, the type of programme, adherence to national guidelines or report on any deviation thereof, location of follow up at the hospital or with a general practitioner (GPs) and the estimated annual volume of surgery were queried through mail and telephone. RESULTS: All hospitals (n=41) performing colorectal surgery responded, of which 25 (61%) conducted postoperative follow up by surgeons in the hospital outpatient clinics, four (10%) carried out follow up with a combination of hospital outpatient visits and visits to GPs, and 12 (29%) referred surveillance to the GP alone. For total reported patient numbers, almost two-thirds (60%) received surveillance according to national recommendations through outpatient visits with the surgeon or GP, while one-third (37%) were subject to other alternative routines. A small number (2%) received informal 'ad hoc' surveillance only. More liberal use of imaging outside guideline recommendations was reported for rectal cancer patients, while colon cancer patients treated in larger hospitals were more likely to be referred for GP surveillance. CONCLUSION: All hospitals reported having a strategy for surveillance after surgery for colon and rectal cancer, but there was considerable variance in strategy. A scientific audit of the true level of compliance, effectiveness and cost-benefit is warranted at a national level. PMID- 21689322 TI - Gender of the patient may influence perioperative and long-term complications after restorative proctocolectomy. AB - AIM: Gender-related differences in preoperative characteristics and early and long-term outcome for patients undergoing ileal pouch anal anastomosis (IPAA) have not previously been well studied. METHOD: All male and female patients undergoing IPAA at a single centre between 1983 and 2008 were compared for perioperative variables and long-term outcome. Statistical tests were used as appropriate. A multivariate analysis was performed to evaluate the effects of gender on pouch failure. RESULTS: Female patients (n=1495) were younger than male patients (n=1912) (P<0.001). Surgery type and pouch configuration were similar, although male gender was associated with a higher use of ileostomy (P<0.001) and a higher incidence of 30-day anastomotic separation (P=0.001). During a median follow up of 9.9 (female) and 9.3 (male) years, female patients were more likely to develop bowel obstruction (20.8 vs 16.7%, P=0.02) and pouch-related fistula (10.9 vs 7.6%, P=0.001). Women had a higher number of daily bowel movements than men (P=0.001), and more frequently had urgency (P=0.001), daily seepage (P=0.01) and pad use (P<0.001). A higher percentage of female patients reported dietary (P<0.001) and work (P=0.022) restrictions and lower mental component of the Short Form 36 quality of life score (P=0.018). On multivariate analysis of perioperative variables, female gender was associated with pouch failure (P=0.05). CONCLUSION: The gender of the patient seems to be associated with specific differences in preoperative variables and postoperative outcomes for patients undergoing IPAA. PMID- 21689323 TI - Accuracy of radiological staging in identifying high-risk colon cancer patients suitable for neoadjuvant chemotherapy: a multicentre experience. AB - AIM: A pilot study was undertaken to determine the accuracy of computed tomography (CT) staging in identifying patients with high-risk colon cancers who would be considered as candidates for a neoadjuvant therapy trial (FOxTROT) and those at low risk (T1/T2) who would be excluded. METHOD: Participating radiologists from 19 centres attended workshops for standardization of image interpretation according to previously defined prognostic criteria: good prognosis tumours, including, T1/T2; intermediate prognosis, T3 < 5 mm tumour invasion beyond the muscularis propria (MP); and poor prognosis tumours, including T3 with tumour extension >= 5 mm beyond the MP or T4. The CT findings were compared with histopathology as the reference standard. RESULTS: Of 94 patients with radiological and pathological data, 71% were categorized by CT as having a poor prognosis. The sensitivity and specificity of CT in identifying these tumours were 87% (95% CI, 74-94) and 49% (95% CI, 33-65). Sensitivity and specificity for tumour infiltration beyond the MP (T3/T4 vs T1/T2) were 95% (95% CI, 87-98) and 50% (95% CI, 22-77), respectively. Including all CT-staged T3 and T4 patients in the trial would have increased the proportion eligible for entry to 89% (n = 84) without affecting the false-positive rate of 7%. Some 20% of T3/T4 patients would have been ineligible for FOxTROT because of synchronous metastases. CONCLUSION: In a multicentre setting, CT scanning identified high risk (T3/4) colon cancers with minimal overstaging of T1/T2 tumours, thus establishing the feasibility of radiologically guided neoadjuvant chemotherapy. PMID- 21689324 TI - Colorectal carcinoma in inflammatory bowel disease: a comparison between Crohn's and ulcerative colitis. AB - AIM: The study assessed the clinicopathological features and survival rates of inflammatory bowel disease (IBD) patients with colorectal carcinoma (CRC), which accounts for ~ 15% of all IBD associated death. METHOD: The medical records of patients operated on for CRC in three institutions between 1992 and 2009 were reviewed, and those with Crohn's colitis (CC) and ulcerative colitis (UC) were identified. Data on age, gender, disease duration, colitis severity, surgical procedure, tumour stage and survival were retrieved. RESULTS: Fifty-three patients (40 UC and 13 CC, 27 men, mean age at operation 54 years) were found. All parameters were comparable between the groups. Mean disease duration before CRC was 22.7 years for UC and 16.6 years for CC patients (P = 0.04). CRC was diagnosed preoperatively in 43 (81%) patients. Twenty-eight patients had colon cancer, 23 had rectal cancer and two patients had more than one cancer. All malignancies were located in segments with colitis. Over one-half were diagnosed at an advanced stage (36% stage III; 17% stage IV). At a mean follow up of 56 +/- 65 months, 60% were alive (54% disease free) and 40% were dead from cancer related causes. The 5-year survival rate was 61% for the UC and 37% for the CC patients (P = NS). CONCLUSION: CRC in IBD patients is frequently diagnosed at an advanced stage, a factor that contributes to poor prognosis. The risk of CRC in CC patients is comparable to those with UC. Long-term surveillance is recommended for patients with long-standing CC and UC. PMID- 21689325 TI - A clinical and radiological comparison of sigmoid diverticulitis episodes 1 and 2. AB - AIM: After an initial uncomplicated attack, sigmoid diverticulitis may recur, but the morphological characteristics of recurrent diverticulitis have not been investigated. We compared the clinical and radiological severity, the respective location and clinical outcome of the first two episodes of sigmoid diverticulitis. METHOD: We reviewed the charts of 60 patients [median age 61 (range 31-90) years] who were admitted initially for a first episode of uncomplicated left colonic diverticulitis, and who were eventually readmitted for a second episode, both being documented by abdominal computed tomography (CT) scan. RESULTS: The median delay between the two episodes was 19 (3-97) months. Six (10%) patients developed a second complicated episode of diverticulitis [Hinchey II (n = 2), CT-guided percutaneous drainage; Hinchey III (n = 3), emergency Hartmann's operation; colovesical fistula (n = 1), elective sigmoid resection]. Fifty-four (90%) patients were admitted for a second episode of uncomplicated diverticulitis. In this group, the duration of hospital stay [11 (4 22) vs 10 (1-39) days, P = 0.28], serum levels of C-reactive protein [131 (31 350) vs 112 (22-333) mm, P = 0.62] and CT scan-based severity score [3 (1-6) vs 3 (0-7) points, P = 0.07] were similar between the two episodes. In 19 out of 54 (35%) patients with simple recurrent diverticulitis, although disease severity was similar, the disease topography differed and recurrence involved another segment of the left colon. CONCLUSION: The majority of patients who develop recurrence do so in a similar mode and location. However, 10% develop complicated diverticulitis and in 35% of patients recurrent diverticulitis occurs at a different location. PMID- 21689326 TI - Obstructed defaecation: what is the role of rehabilitation? AB - AIM: The study was designed to evaluate the results of rehabilitative treatment in patients suffering from obstructed defaecation. METHOD: Between January 2008 and July 2010, 39 patients (37 women, age range 25-73 years; and two men, aged 57 and 67 years) affected by obstructed defaecation were included in the study. After a preliminary clinical evaluation, including the Obstructed Defaecation Syndrome (ODS) score, defaecography and anorectal manometry were performed. All 39 patients underwent rehabilitative treatment according to the 'multimodal rehabilitative programme' for obstructive defaecation. At the end of the programme, all 39 patients were reassessed by clinical evaluation and anorectal manometry. Postrehabilition ODS scores were used to categorize patients arbitrarily into three classes, as follows: class I, good (score <= 4); class II, fair (score > 4 to <= 8); and class III, poor (score > 8). RESULTS: After rehabilitation, there was significant improvement in the overall mean ODS score (P < 0.001). Thirty (76.9%) patients were included as class I (good results), of whom eight (20.5%) were symptom free. Five (12.8%) patients were considered class III. A significant postrehabilitative direct correlation was found between ODS score and pelvic surgery (rho(s) = 0.54; P < 0.05). Significant differences were found between pre- and postrehabilitative manometric data from the straining test (P < 0.001), duration of maximal voluntary contraction (P < 0.001) and conscious rectal sensitivity threshold (P < 0.02). CONCLUSION: After rehabilitation, some patients become symptom free and many had an improved ODS score. PMID- 21689327 TI - Accuracy of measurement of puborectal contraction by perineal ultrasound in patients with faecal incontinence. AB - AIM: The study aimed to determine the accuracy of measurement of puborectal contraction, measured by perineal ultrasound during anal voluntary contraction in patients with incontinence. METHOD: Puborectalis sling contraction in 32 consecutive patients investigated for faecal incontinence was determined by two examiners on two occasions (four measurements per patient). The examiners were blinded to each other's results. RESULTS: The mean anterior movement of the puborectalis sling was between 11 and 12 mm for both examiners on both occasions. The global intraclass correlation coefficient for examiners and occasions together was 0.92. The absolute agreement on the movement exceeding or not 8 mm was 87.5% (28 of 32), and the corresponding kappa statistic was 0.84. The differences between the two experts were minimal. CONCLUSION: The study confirms the reliability of puborectalis sling contraction measurement and its value as a preoperative predictive tool to assess the prognosis of sphincter repair for postdelivery faecal incontinence. PMID- 21689328 TI - Stapled transanal rectal resection and sacral nerve stimulation - impact on faecal incontinence and quality of life. AB - AIM: The aim of the study was to assess the impact of stapled transanal rectal resection (STARR) on pre-existing faecal incontinence and quality of life in patients suffering from obstructive defaecation syndrome (ODS) and to evaluate the efficiency of sequential sacral nerve stimulation (SNS) for improvement of persistent incontinence after STARR. METHOD: Thirty-one patients with ODS and major faecal incontinence prior to STARR were prospectively enrolled. The outcome was measured using the Cleveland Clinic Constipation and Incontinence score (CCS, CCIS), Faecal Incontinence Qualities-of-Life Index (FIQL), Patient Assessment of Constipation Quality-of-Life (PAC-QOL) and EuroQol visual analogue scale (EQ VAS). RESULTS: The overall levels of constipation (CCS from 13.1 +/- 3.8 to 6.2 +/- 5.4; P < 0.001) and incontinence (CCIS from 12.6 +/- 3.2 to 9.4 +/- 5.1; P = 0.005) were significantly improved after STARR; concordantly, the global and specific quality of life were significantly improved. Following postoperative constipation and incontinence, three different groups of patients were differentially referred to SNS. In group I (n = 16, 52%), both constipation (CCS from 12.6 +/- 4.0 to 3.6 +/- 1.9; P < 0.001) and incontinence (CCSI from 12.43 +/ 3.2 to 5.1 +/- 1.9; P < 0.001) were improved. In group II (n = 8, 25%), only constipation was improved (CCS from 12.3 +/- 2.3 to 3.3 +/- 2.2; P < 0.001), while incontinence persisted (CCIS from 12.8 +/- 2.9 to 13.1 +/- 3.1; P > 0.05). In group III (n = 7, 23%) there was no improvement at all. Sacral nerve stimulation was successfully carried out in six (85%) of seven patients in group II (post-SNS CCSI 6.1 +/- 1.7; P = 0.01) but failed in five of five patients in group III. CONCLUSION: Stapled transanal rectal resection improves quality of life in ODS patients with both severe constipation and faecal incontinence. Sacral nerve stimulation may efficiently improve persisting incontinence after STARR in selected patients. PMID- 21689329 TI - Sacral nerve stimulation for faecal incontinence: optimizing outcome and managing complications. AB - AIM: A knowledge of the principles of neurostimulation is essential to achieve optimal efficacy and minimize adverse effects. The aim of this article was to review the current evidence regarding device programming in the management of patients having sacral nerve stimulation (SNS) for faecal incontinence. METHOD: A Medline search was performed including the keywords and/or MeSH headings of sacral nerve stimulation, neuromodulation, artificial pacemaker, faecal incontinence, programming, adverse effects and complications. Further studies were identified by cross-referencing from relevant articles and by appraisal of recent peer-reviewed conference abstracts and proceedings. RESULTS: Neurostimulator programming is an important component of SNS. Efficacy can be improved or restored with reprogramming. Adverse stimulation is often reversible, and nonstimulation-related complications are correctable. A total loss of efficacy can be explained in over one-half of patients. CONCLUSION: An improved outcome of SNS can be achieved by selecting the best possible stimulation parameters individualized to each patient. Further research into the optimal settings is needed. PMID- 21689330 TI - Sacral nerve stimulation for faecal incontinence: patient selection, service provision and operative technique. AB - AIM: Faecal incontinence is estimated to affect between 2 and 3% of Western adult populations. In recent years sacral nerve stimulation has become an important treatment modality, often as the first-line surgical therapy. The aim of this article was to review the current evidence regarding patient selection and surgical technique and to evaluate the logistics of providing a neurostimulation service. METHOD: A Medline search was performed including the keywords and/or MeSH headings of sacral nerve stimulation, neuromodulation, artificial pacemaker, faecal incontinence, patient selection, predictive factors and anal canal. Further studies were identified by cross-referencing from relevant articles and by appraisal of recent peer-reviewed conference abstracts and proceedings. RESULTS: Despite the success of sacral nerve stimulation for several pathophysiological causes of incontinence, case selection is of paramount importance. Sacral nerve stimulation should not be offered outside a multidisciplinary pelvic floor unit. Temporary evaluation using diary cards can lead to false positive and negative results. Adherence to a meticulous surgical technique, using low amplitude stimulation to guide lead placement, provides optimal clinical outcome. CONCLUSION: The short-term outcome of sacral nerve stimulation is dependent on patient factors and operative technique. Despite this, specific preoperative predictive factors of treatment success have yet to be identified. PMID- 21689331 TI - Antegrade colonic enema for faecal incontinence in adults: long-term results of 75 patients. AB - AIM: Faecal incontinence is a significant source of distress, and a permanent stoma is frequently offered to these patients. The antegrade colonic enema (ACE) procedure is an alternative approach to treat faecal incontinence. The long-term outcome remains unknown in adults with faecal incontinence. The aim of this study was to evaluate the long-term results of the ACE procedure for incontinence in adults and its impact upon quality of life. METHOD: All patients who underwent an ACE procedure between 1999 and 2009 were included. Clinical and demographic data and postoperative course were obtained from a review of medical records and databases. Each patient underwent a telephone interview. Quality of life was assessed using the GIQLI and SF36 scores, and faecal incontinence was evaluated using the Wexner score. RESULTS: Seventy-five patients (54 females; 72%) were included. An ileal neoappendicostomy was performed in 68 patients (90%). The mean hospital stay was 9 days (range 6-24 days). Early complications occurred in four patients and late surgical complications (after 3 months) were observed in 12 (16%) patients. At a median follow up of 48 months, 64 (91%) were still performing enemas, and treatment was judged to be successful in 55 (86%) of 64 patients. The Wexner score was 3.4 +/- 2.4, showing a significant reduction when compared with the preoperative value (P < 0.0001). Quality of life scores were in the range of a control population. CONCLUSION: The ACE procedure is an effective long-term strategy in the treatment of faecal incontinence, with low and acceptable morbidity, and should be preferred before definitive colostomy. PMID- 21689333 TI - Laparoscopic fellowship training can deliver a competent laparoscopic surgeon and trainer. AB - AIM: The study investigated whether experience gained during a UK laparoscopic colorectal fellowship enabled the fellow subsequently to train consultant colleagues in laparoscopic surgery. METHOD: In one unit a newly appointed post laparoscopic fellowship consultant (PFC) mentored his other two colleagues. Prospectively collected data regarding surgical outcome were compared with those of the year preceding the PFC appointment. RESULTS: In the preceding year 18.5% of 260 resections were attempted laparoscopically. This increased to 92.6% (of 270) in the year after (P < 0.0001). Respective conversion rates were 4.2% and 8.4% (P = 0.5524). In the first 6 months after PFC appointment, mentored consultants performed 23 supervised cases. In the second 6 months they carried out 58 procedures independently and trainees performed 38 supervised cases. There was no significant difference in anastomotic leakage and readmission and 30-day mortality rates between the pre- and post-PFC periods. CONCLUSION: A laparoscopic fellowship enables the PFC to mentor consultant colleagues safely and effectively. PMID- 21689334 TI - Sacral nerve modulation in the treatment of chronic pain after pelvic surgery. AB - AIM: The aim of the study was to evaluate the efficacy of sacral nerve modulation for chronic pelvic pain after pelvic or anal surgery for benign disease. METHOD: From January 2004 to December 2009, 17 (14 female; age 56 years) consecutive patients suffering from chronic pelvic pain underwent evaluation for sacral nerve modulation in three pelvic floor units. RESULTS: The previous surgery included stapled transanal rectal resection (five), hysterectomy (four), haemorrhoidectomy (two), stapled haemorrhoidopexy (one), fistulectomy (one), urethral sphincterotomy (one), appendicectomy (one), discectomy (one) and laparoscopy for endometriosis (one). Eight (47%) patients fulfilled the criteria for definitive implantation and were followed for a mean of 39 months. Using a visual analog pain score, pain levels fell from 8.2 preoperatively to 1.9, 2.1, 2.0 and 1.8 at 6, 12, 24 and 36 months, respectively. Age < 60 years and duration of symptoms of < 24 months were good predictors and stapling was a poor predictor of success. CONCLUSION: Sacral nerve modulation seems to be effective over time in some patients with chronic pain related to previous surgery. PMID- 21689335 TI - Acute compartment syndrome following laparoscopic colorectal surgery. PMID- 21689336 TI - Anorectal physiology is not changed following transanal haemorrhoidal dearterialization for haemorrhoidal disease: clinical, manometric and endosonographic features. AB - AIM: The effect of transanal haemorrhoidal dearterialization (THD) on continence and anorectal physiology has not yet been demonstrated. METHOD: Twenty patients suffering from 3rd degree haemorrhoids were enrolled and underwent THD, including both dearterialization and mucopexy. Clinical assessment, anorectal manometry, rectal volumetry and endoanal ultrasound were performed preoperatively and at 6 months postoperatively. RESULTS: Postoperatively two and six patients had transient rectal pain and tenesmus, respectively. No patient reported faecal urgency or minor or major incontinence. All patients remained able to discriminate gas from faeces. No significant variation of the mean values of anal manometric and rectal volumetric parameters was recorded at 6 months of follow-up compared with preoperative values. At 6 months both internal and external sphincters were endosonographically intact. CONCLUSION: THD does not cause trauma to the anal canal and rectum. PMID- 21689337 TI - Diagnostic yield of colonoscopy for constipation as the sole indication. AB - AIM: There is controversy over whether constipation as the only symptom should be an indication for routine diagnostic colonoscopy. The study was carried out to assess the prevalence of abnormal pathology on colonoscopy and to assess the risk factors for colonic neoplasia in patients with constipation but without 'high risk symptoms'. METHOD: A cross-sectional, single-centre study was conducted on individuals who underwent colonoscopy for constipation as the sole indication between 2005 and 2008. Standardized endoscopic and pathology reports were reviewed. Univariable and multivariable analyses were performed. RESULTS: A total of 786 patients (595 women, 75.7%; mean age, 57.4+/-13.5 years) underwent diagnostic colonoscopy for constipation. Forty-three (5.5%) had polyps, of whom 19 (2.4%) had hyperplastic polyps and 19 (2.4%) adenomas. No cancers were found. In patients with adenoma, the detection rate was 2.9% for patients below age 40 years and 1.7% for patients below age 50 years. Older age was associated with a polyp in both univariate and multivariate analysis. Gender, ethnicity and smoking were not associated with polyp or adenoma. CONCLUSION: Colonoscopy for patients with constipation as the sole indication had a lower yield of neoplastic lesions than that for patients undergoing routine screening colonoscopy. Colonoscopy in constipation may only be warranted in patients who are over 50 years of age. PMID- 21689338 TI - Metformin as a cause of high stomal output. PMID- 21689339 TI - Elective sigmoid colectomy for diverticular disease. Laparoscopic vs open surgery: a systematic review. AB - AIM: A meta-analysis of nonrandomized studies and one randomized trial was conducted to compare laparoscopic surgery with open surgery in the elective treatment of patients with diverticular disease. METHOD: Published randomized and controlled clinical trials that directly compared elective open (OSR) with laparoscopic surgical resection (LSR) in patients with diverticular disease were identified using the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. End-points included 30-day mortality and morbidity and were compared by determining the relative risk ratio, odds ratio, and the absolute effects. RESULTS: Eleven nonrandomized studies of 1430 patients were identified and included in the meta-analysis. There was only one randomized study, which included 104 patients. The meta-analysis suggested that elective LSR was a safe and appropriate option for patients with diverticular disease and was associated with lower overall morbidity (P = 0.01) and minor complication rate (P = 0.008). CONCLUSION: The results of the nonrandomized study generally agreed with those of the randomized study, except for the incidence of minor complications, which was higher in both the LSR and OSR groups of the randomized study. In this study, the high overall morbidity of 42.3% reported in the LSR group is a cause for concern. PMID- 21689340 TI - Health-related quality of life after surgery for primary advanced rectal cancer and recurrent rectal cancer: a review. AB - AIM: Health-related quality of life is an important outcome measure in treatment of cancer. A review of the literature was undertaken to provide an overview of health-related quality of life (HRQoL) after surgery for primary advanced or recurrent rectal cancer and to outline proposals for future HRQoL studies in this area. METHOD: A systematic literature search was undertaken. Only studies concerning surgery for primary advanced or recurrent rectal cancer and describing methods used for measuring HRQoL were considered. RESULTS: Seven studies were identified, including two prospective longitudinal studies, three cross-sectional studies and two based on qualitative data. Global quality of life, and physical, social, role and sexual function seemed to be impaired for a varying time after surgery. All the studies had methodical problems due to small sample size (12-44 patients) and different points of time for the assessment of HRQoL (12.3-47 months), which made it difficult to determine the period of time of impaired HRQoL and also if this is different after surgery for locally advanced or recurrent disease compared with after total mesorectal excision used for earlier tumours. CONCLUSION: Several aspects of HRQoL are impaired for a variable time after treatment for locally advanced or recurrence of rectal cancer. Larger prospective longitudinal studies are needed to provide further information regarding the effects of this extensive surgery on quality of life. PMID- 21689341 TI - The prevalence of dysplasia in the ileoanal pouch following restorative proctocolectomy for ulcerative colitis with associated dysplasia. AB - AIM: A recent systematic review indicated that dysplasia present before restorative proctocolectomy is a predictor of subsequent dysplasia in the pouch. This prospective study was carried out to assess the prevalence of dysplasia in the ileal pouch in patients having RPC for ulcerative colitis with co-existing dysplasia in the operation specimen. METHOD: Eligible patients were invited for a surveillance endoscopy. The afferent and blind efferent ileal loop, ileoanal pouch and rectal cuff were examined by standard endoscopy using a dye-spray technique with methylene blue. Mucosal abnormalities were biopsied and random biopsies were taken from the afferent and blind ileal loop, pouch and rectal cuff. RESULTS: Fourty-four patients (25 male, mean 49 years) underwent pouch endoscopy at a mean interval from RPC of 8.6 years. Dysplasia was detected in two (4.5%) patients. In one, low-grade dysplasia was found in the rectal cuff and in the other low-grade dysplasia was detected in random biopsies from the pouch and the efferent ileal loop. CONCLUSION: This prospective pouch-endoscopy study detected dysplasia in < 5% of patients over nearly 10 years. The benefit of routine surveillance for dysplasia in the pouch is uncertain, as the significance of low-grade dysplasia in the pouch is not clear. PMID- 21689342 TI - Previous transanal full-thickness excision increases the morbidity of radical resection for rectal cancer. AB - AIM: The aim of the study was to determine the impact of primary full-thickness transanal excision (TAE) on the morbidity rate following radical rectal resection for cancer. METHOD: Fourteen consecutive patients underwent radical resection for lower third rectal cancer following full-thickness TAE without closure of the defect. They were compared with 25 matched patients from a prospective database of 275 rectal resections who had undergone radical resection without previous TAE for lower third rectal cancer (control group). The confounding factors were: age, sex, body mass index (BMI), classification according to the American Society of Anaesthesiologists, administration of neoadjuvant radiotherapy before rectal resection, tumour stage and type of surgical procedure. RESULTS: There were no deaths. Overall morbidity was 64.3% in the TAE group and 32% in the control group (P = 0.112). Surgical complications were significantly more frequent in the former (57.1%vs 20%; P = 0.048). The frequency of specific surgical site complications, including anastomotic complications and pelvic abscess formation requiring surgical drainage, was significantly higher in the TAE group than in the control group (42.8%vs 8%; P = 0.032). In univariate analysis, the only factors associated with specific surgical site complications were BMI > 27 and TAE before rectal resection. CONCLUSION: This case-matched study suggests that previous full-thickness TAE increases the risk of surgical complications after radical resection for lower third rectal cancer, including anastomotic dehiscence and pelvic sepsis. PMID- 21689343 TI - Lymph node yield following injection of patent blue V dye into colorectal cancer specimens. AB - AIM: The study aimed to assess whether the ex vivo injection of patent blue V dye would increase lymph node yield in operative specimens of colorectal cancer. METHOD: A randomized controlled trial was carried out in which patients undergoing resection for colonic cancer were allocated to patent V blue or no patent blue V dye submucosal injection of the operative specimen. The number of lymph nodes found in each group was compared. RESULTS: Between 1 January and 31 December 2008, 68 patients were randomized. Thirty-three patients received patent blue V dye and 34 did not. In the former group the median number of blue nodes identified was 11, compared with a median of 9 in the no dye group. After the application of Carnoy's solution lymph node count was 16 in each group. There was no significant difference between all these results. CONCLUSION: Ex vivo injection of patent blue V dye submucosally in a peritumour location did not increase the lymph node count or the percentage of specimens having more than 12 lymph nodes identified. PMID- 21689344 TI - Anal encirclement with sphincter repair (AESR procedure) using a biological graft for anal sphincter damage involving the entire circumference. AB - AIM: The effect of a biological material to support an overlapping sphincter repair was investigated in patients with damage to the entire circumference of the external sphincter due to radiation or trauma. METHOD: A tunnel is created under the damaged external anal sphincter muscle to encircle the anal canal. A biological graft (SurgisisTM; 6 ply, 2*20 cm) is then inserted through the tunnel and sutured to the muscle after being pulled firmly to close the patulous anus. An overlapping repair is then carried out. Between January 2009 and June 2010, 13 patients underwent this procedure. RESULTS: The average age at surgery was 68.6 years. The mean follow up was 16.3 (range 6-24) months. The average length of stay was 1 day. No complications were reported. Postoperatively, incontinence severity scores and quality of life scales [39.22 (+/-16.1) to 9.66 (+/-11.9)] showed improvement. Incontinence episodes were markedly decreased to one per week. CONCLUSION: Anal encirclement using a biological graft with sphincter augmentation may achieve continence in patients with circumferential anal sphincter damage. PMID- 21689345 TI - Single port access proctectomy with total mesorectal excision and intersphincteric resection with a primary transanal approach. AB - AIM: Minimally invasive surgery is advancing with single port access (SPA). We describe a technique for a SPA transabdominal combined with transanal approach to perform laparoscopic proctectomy with total mesorectal excision (TME) and intersphincteric resection of low rectal adenocarcinoma. METHOD: Transanal intersphincteric resection was followed by laparoscopic abdominal proctectomy with TME. An SPA device was placed at the site of the future stoma through a 2.5 cm incision. A hand-sewn side-to-end coloanal anastomosis was performed and a terminal loop ileostomy was created at the site of the SPA device. RESULTS: The procedure was performed on two healthy nonobese women who had not had previous abdominal surgery. The operating times were 195 and 210 min, and blood loss < 250 ml. The postoperative course was uneventful, with discharge on postoperative days 5 and 6. Pathological examination revealed adequate surgical margins and lymph node retrieval with an intact mesorectum. Four weeks after stoma closure, the scar in the right lower quadrant was 35 mm in one patient and 45 mm in the other, and the scar from the 5-mm port was barely visible. CONCLUSION: This preliminary experience shows that proctectomy with TME and intersphincteric resection can be safely performed using only two ports. PMID- 21689346 TI - Sacral nerve modulation for defaecation and micturition disorders in patients with spina bifida. AB - AIM: Sacral nerve modulation is a well accepted method for the treatment of defaecation disorders and voiding dysfunction. Results of sacral nerve modulation in patients with spinal cord lesions are not well assessed, but preliminary results look poor. Therefore, the purpose of this study was to assess the effectiveness of sacral nerve modulation for defaecation disorders and voiding dysfunction in patients with spina bifida. METHOD: Consecutive patients with spina bifida suffering from a myelomeningocele and combined faecal and urinary functional disorders that were eligible for peripheral nerve evaluation (PNE) were studied. A permanent sacral nerve modulation implantation was performed after successful PNE. RESULTS: Ten patients (four female) were included in this study with a median age of 26.4 (range 11.1-41.0) years. In two the PNE was not possible. The median faecal incontinence days (6.0 vs 3.5) and episodes (8.5 vs 3.5) per 21 days decreased significantly during the 3-week period of PNE (P = 0.033). Only 3/10 (30%) patients had a more than 50% improvement and proceeded to a permanent sacral nerve modulation implantation. In one patient it was not possible to perform the permanent implant. CONCLUSION: Preliminary results of sacral nerve modulation in a subgroup of spina bifida patients with combined faecal and urinary functional disorders look promising, but long-term results in larger patient groups need to be studied. PMID- 21689347 TI - Renal risks of sodium phosphate tablets for colonoscopy preparation: a review of adverse drug reactions reported to the US Food and Drug Administration. AB - AIM: Sodium-phosphate-containing colonoscopy preparations cause renal failure by the development of calcium phosphate nephropathy. Although Fleet's Phospho-Soda has been removed from the US market, sodium phosphate tablets sold as OsmoPrep and Visicol remain available. Our aim was to analyse renal risks of the sodium phosphate tablets. METHOD: We conducted a retrospective study using the US Food and Drug Administration Adverse Event Reporting System, a voluntary reporting system available for public access. Renal adverse events were identified using search terms including renal impairment, increased blood urea nitrogen, increased creatinine, renal failure, acute renal failure, chronic renal failure, acute phosphate nephropathy, nephrocalcinosis, renal tubular necrosis, haemodialysis, nephropathy toxic, dialysis, peritoneal dialysis, renal injury, renal tubular disorder, decreased glomerular filtration rate and decreased creatinine clearance. Patient age, gender and body weight were compared with data for the general population in the National Health and Nutrition Examination Survey (NHANES). RESULTS: In total 2,097,223 files were extracted from the US Food and Drug Administration website for 2004-2008 and the first 9 months of 2009. Of these, 178 patients on tablet preparations (71% women) were identified, with increasing numbers of renal adverse drug reactions reported from tablet preparations each year. The mean weight for women with renal complications from tablet preparations was 68.57 +/- 1.78 kg, significantly lower than the national average weight of 74 +/- 0.5 kg for the same age group (P = 0.003) in NHANES. CONCLUSION: Renal adverse drug reactions from sodium phosphate tablets are more common in women with a mean body weight lower than the national average weight. PMID- 21689348 TI - Low-volume centre vs high-volume: the role of a quality assurance programme in colon cancer surgery. AB - AIM: The study aimed to determine whether hospitals within a quality assurance programme have outcomes of colon cancer surgery related to volume. METHOD: Data were used from an observational study to determine whether outcomes of colon cancer surgery are related to hospital volume. Hospitals were divided into three groups (low, medium and high) based on annual caseload. Cancer staging, resected lymph nodes, perioperative complications and follow up were monitored. Between 2000 and 2004, 345 hospitals entered 31,261 patients into the study: 202 hospitals (group I) were classified as low volume (<30 operations; 7760 patients; 24.8%), 111 (group II) as medium volume (30-60; 14,008 patients; 44.8%) and 32 (groups III) as high volume (>60; 9493 patients; 30.4%). RESULTS: High-volume centres treated more patients in UICC stages 0, I and IV, whereas low-volume centres treated more in stages II and III (P<0.001). There was no significant difference for intra-operative complications and anastomotic leakage. The difference in 30-day mortality between the low and high-volume groups was 0.8% (P=0.023).Local recurrence at 5 years was highest in the medium group. Overall survival was highest in the high-volume group; however, the difference was only significant between the medium and high-volume groups. For the low and high volume groups, there was no significant difference in the 5-year overall survival rates. CONCLUSION: A definitive statement on outcome differences between low volume and high-volume centres participating in a quality assurance programme cannot be made because of the heterogeneity of results and levels of significance. Studies on volume-outcome effects should be regarded critically. PMID- 21689349 TI - The acute effect of dorsal genital nerve stimulation on rectal wall properties in patients with idiopathic faecal incontinence. AB - AIM: Faecal continence depends on several factors, including rectal wall properties. Stimulation of the dorsal genital nerve (DGN) can suppress bladder contraction and similar effects are anticipated for the rectum. In this study, the acute effect of DGN stimulation on the rectal cross-sectional area is investigated. METHOD: Ten female patients (median age 60 years) with idiopathic faecal incontinence were included in the study. Stimulation was applied via plaster electrodes with the maximum tolerable amplitude (pulse width was 200 MUs at a pulse rate of 20 Hz). Three series of pressure-controlled phasic (10, 20 and 30 cm H(2) O) and stepwise (5-30 cm H(2) O in steps of 5 cm H(2) O) rectal distensions were conducted (unstimulated, stimulated, unstimulated), and the rectal cross-sectional area (CSA) was measured with impedance planimetry. RESULTS: All patients completed the investigation. The median stimulation amplitude was 21 (8.5-27) mA. Comparing stimulated with unstimulated phasic distension, there was no significant difference in the median rectal CSA. Comparing stimulated with unstimulated stepwise distension, there was no significant difference in the median rectal CSA. Neither the rectal pressure-CSA relationship (CSA/P(R) ) nor the rectal wall tension changed during stimulation. CONCLUSION: No acute effect on rectal CSA during pressure-controlled distension was demonstrated during DGN stimulation. PMID- 21689350 TI - Laparoscopic total mesorectal excision can be performed on a nonselective basis in patients with rectal cancer with excellent medium-term results. AB - AIM: Concerns exist regarding laparoscopic rectal cancer surgery due to increased rates of open conversion, complications and circumferential resection margin positivity. This study reports medium-term results from consecutive unselected cases in a single surgeon series. METHOD: The results of laparoscopic total mesorectal excision (TME) for rectal cancer over a 9-year period within the context of an evolving 'enhanced recovery protocol' (ERP) were reviewed from analysis of a prospectively maintained database. RESULTS: One hundred and fifty patients (91 male, median age 69 years, median BMI 26) underwent laparoscopic TME over 9 years. Median follow up was 28.5 months (range 0-88). Sixteen (10.6%) patients underwent neoadjuvant radiotherapy. Six (4.0%) required open conversion and 13 (9.0%) had an anastomotic leakage. The proportion of Dukes stages were: A, 33.3%; B, 30.7%; C, 31.3%; D, 4.7%. Five (3.3%) patients had an R1 and one an R2 resection. Median length of postoperative stay was 6 days. Three (2.0%) patients died within 30 days. Four (2.7%) developed local recurrence and 14 (9.3%) developed distant metastases. Predicted 5-year disease-free and overall survival rates by Kaplan-Meier analysis were 85.8% and 78.7%, respectively. CONCLUSION: Laparoscopic TME surgery can safely be offered to unselected patients with rectal cancer with excellent medium-term results. PMID- 21689351 TI - Laparoscopic total colectomy and ileorectal anastomosis (IRA), supported by an enhanced recovery programme in cases of familial adenomatous polyposis. AB - AIM: Familial adenomatous polyposis (FAP) is associated with an almost 100% chance of colorectal cancer by the age of 50 years. Surgery is the only prophylaxis. The study compared the outcome of prophylactic laparoscopic colectomy and ileorectal anastomosis (IRA) with conventional open surgery. METHOD: A case-control study was carried out including all cases of proven FAP undergoing prophylactic laparoscopic colectomy with IRA between 1 April 2006 and 31 March 2008 using a standardized technique within an enhanced recovery programme (ERAS). All data were collected prospectively. Controls were identified retrospectively from patients who underwent open prophylactic IRA before 31 March 2008 and were matched for age, gender, BMI and ASA. Outcomes included duration of surgery, complications, length of stay, readmission and mortality. RESULTS: During the study period 25 patients underwent laparoscopic IRA. The median operating time was longer in the laparoscopic group (235 vs 180 mins, P < 0.0001) but the median hospital stay was shorter (6 vs 9 days, P = 0.002). Overall there were fewer complications in the laparoscopic group (20%vs 40%, P = 0.3). CONCLUSION: Laparoscopic prophylactic colectomy with IRA in FAP is safe and feasible, and combined with ERAS leads to accelerated recovery and possibly fewer complications than open surgery. FAP patients undergoing prophylactic IRA should be offered laparoscopic surgery. PMID- 21689352 TI - Management of young onset colorectal cancer: divergent practice in the East of England. AB - AIM: According to the revised Bethesda Guidelines, colorectal cancer (CRC) occurring under age 50 years should be screened to exclude Lynch syndrome. However, in current practice in East Anglia, tumour screening is initiated only after genetics referral, reserved for those with a strong pedigree. This study aimed to determine how many patients with young-onset CRC undergo tumour screening in hospitals in East Anglia. METHOD: A retrospective case notes review over 5 years in four hospitals was undertaken to determine what proportion of those with young-onset CRC underwent referral for tumour screening and to assess local practices in terms of patient counselling and management. RESULTS: One hundred and twenty-two patients were included. There was an average yearly caseload of 6-9 patients per hospital. Documented family history was rare, as was counselling concerning metachronous and extra-colonic tumour risk and CRC risk in relatives. The rate of referral for genetic testing varied from 44% to 65%. Postoperative colonoscopic surveillance was inconsistent. CONCLUSION: Many patients with young-onset CRC are managed as sporadic cancers, without Lynch syndrome having been excluded. This may have implications for survival of patients and any affected relatives. A streamlined management algorithm for tumour screening and genetics referral is recommended. PMID- 21689353 TI - Long-term outcome of the use of botulinum toxin injection for functional anal pain. AB - AIM: Anal pain may occur in the absence of demonstrable anal pathology. Spasm of the sphincter muscles has been suggested as a cause in some patients. We aimed to assess the effectiveness of injection of botulinum toxin in treating this condition. METHOD: Patients who had injection of botulinum toxin over a 3-year period were identified retrospectively. Patients were excluded if anal fissure or other organic pathology was found to account for their symptoms on examination under anaesthetic. Long-term outcome was assessed at a minimum 3-year post procedure telephone follow up. RESULTS: Fourteen (eight male) patients were identified, of median age 50 years. Botulinum toxin (20-200 u) was injected into the internal sphincter. Seven of the 14 patients reported significant improvement in symptoms at 3 months. Seven were available for a structured telephone review at a median of 59 (42-68) months. The four patients who had benefited from the injection had remained asymptomatic. CONCLUSION: Injection of botulinum toxin into the internal anal sphincter has a role in alleviating symptoms in a small proportion of patients with functional anal pain. PMID- 21689354 TI - Partial longitudinal resection of the anorectum and sphincter for very low rectal adenocarcinoma: a surgical approach to avoid permanent colostomy. AB - AIM: Abdominoperineal resection has been the standard procedure for low rectal cancer. The present study details a new technique, partial longitudinal resection of the anorectum and sphincter, and assesses the oncological and functional outcomes. METHOD: Between January 2004 and April 2008, 12 patients underwent partial longitudinal resection of the anorectum and sphincter for low rectal cancer. All patients underwent a diverting ileostomy and received biofeedback training before stoma closure. Functional results were assessed by vector manometry, Wexner constipation score and Wexner incontinence score. The quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). RESULTS: There was no postoperative mortality and a R0 curative resection was confirmed in every case. Morbidity included anastomotic leakage in three patients, one of whom underwent reoperation, and stenosis in 11, which was successfully managed with dilatation. The patient who underwent reoperation was not included in the functional analysis. The 11 successful patients received biofeedback training for 1-4 months, and underwent ileostomy closure 6-12 months after surgery. No patient had severe faecal incontinence after stoma closure. The EORTC QLQ-C30 global health status and QoL scores at 12 months after stoma closure were 50.4 +/- 24.3, similar to preoperation scores of 52.3 +/- 25.6 (P = 0.927), and not significantly different to scores for the healthy control population of 63.4 +/- 23.5 (P = 0.539). No patients developed local recurrence during the median observation period (35.5 months). One patient had distant metastases at 24 months, and underwent resection of the left liver. CONCLUSION: Curability and acceptable anal function can be obtained by partial longitudinal resection of the anorectum and sphincter in patients with very low rectal cancers. This technique is recommended as an alternative to abdominoperineal resection in patients with external sphincter muscle invasion or tumours located below the dentate line. PMID- 21689355 TI - Minimally invasive ventral mesh rectopexy for complex rectocoele: impact on anorectal and sexual function. AB - AIM: Minimally invasive surgery for pelvic floor prolapse has recently been shown to be feasible and safe. This study presents the results of robotic-assisted and laparoscopic rectopexy for complex rectocoele, focusing on less frequently reported outcomes of bowel and sexual function. METHOD: We prospectively assessed 41 consecutive patients who underwent ventral mesh rectopexy (robotic-assisted or laparoscopic) for a symptomatic complex rectocoele from January 2009 to January 2010. Complex rectocoele was defined as having one or more of the following features: larger than 3 cm, an enterocoele or internal rectal prolapse. Patients with cystocoele underwent bladder suspension concurrently. Both groups were assessed for anatomical recurrence and function, comparing preoperative and postoperative faecal incontinence, obstructive defaecation syndrome and Gastrointestinal Quality-of-life Index scores, as well as vaginal discomfort and sexual function. RESULTS: Forty-one women underwent the procedure (16 robotic assisted), with four (10.5%) having minor complications and two developing anatomical recurrence. There was significant relief of the commonest predominant symptoms of vaginal bulge/fullness (P<0.0001) and sexual dysfunction (P=0.02). There were three conversions to laparotomy (one robotic-assisted) and five patients declined postoperative functional assessment. In the remaining 33 patients [follow-up median 12 (8-21) months], analysis revealed no significant difference in overall functional score (P>0.740) or between patients with one or two meshes inserted (P>0.486). Only patients with a preoperative obstructive defaecation syndrome score >6 had a significant improvement postoperatively (P=0.030). CONCLUSION: Minimally invasive ventral mesh rectopexy for complex rectocoele offers satisfactory anatomical correction and functional results, with the potential for alleviating symptoms of outlet obstruction and improving vaginal comfort and sexual dysfunction. PMID- 21689356 TI - Comparison of oral polyethylene glycol plus a large volume glycerine enema with a large volume glycerine enema alone in patients undergoing colorectal surgery for malignancy: a randomized clinical trial. AB - AIM: Recent meta-analyses and randomized clinical trials have concluded that mechanical bowel preparation (MBP) before elective colorectal surgery is not associated with a reduction of surgical site infection (SSI). The aim of this randomized clinical trial was to evaluate the impact of preoperative MBP for colon and rectal cancer surgery in comparison with a single glycerine enema. METHOD: Patients scheduled for radical colorectal resection for malignancy with primary anastomosis were randomized to preoperative MBP (4 l of polyethylene glycol) (group 1, 114 patients) plus a glycerine 5% enema (2 l) or a single glycerine 5% enema (2 l) (group 2, 115 patients). The postoperative incidence of SSI was recorded prospectively. Patients undergoing minimally invasive surgery (laparoscopy or robotic) accounted for 55 and 51 in groups 1 and 2 respectively. RESULTS: In all, 229 patients were included in the study, 114 in group 1 and 115 in group 2. At least one SSI was reported in 16 (14.0%) group 1 and in 20 (17.8%) group 2 patients (P=0.475). Perioperative mortality was nil. The incidence of SSI was comparable also in the 73 patients who had a low anterior resection (seven of 33 vs eight of 40, P=1.000), and for the 106 patients who underwent a minimally invasive procedure (nine of 55 vs four of 51, P=0.241). CONCLUSION: A single large-volume glycerine enema is effective bowel preparation before colorectal resection whether performed by an open or minimally invasive technique. PMID- 21689358 TI - Response to 'Colorectal cancer in nonagenarians'. PMID- 21689357 TI - Portal pneumatosis as a complication of neoadjuvant chemoradiotherapy for rectal cancer: a case report. PMID- 21689359 TI - Transanal irrigation improves quality of life in patients with low anterior resection syndrome. AB - AIM: Transanal irrigation (TAI) has been reported to be a cheap and effective treatment for the 'anterior resection syndrome (ARS)'. This study aimed to evaluate its effect on the quality of life (QOL) of patients suffering from ARS. METHOD: In a prospective study involving two colorectal centres, 14 patients (11 male; median age 68 (45-80) years) were included in the study. The median duration of ARS was 19 (9-48) months. The median number of defaecations was 8 (4 12)/day and 3 (2-5)/night. All patients were trained to perform TAI using the PeristeenTM System under the guidance of a stoma nurse. Anal physiology was performed, quality of life (QOL) was estimated by the SF-36 and Rockwood (ASCRS) questionnaires and continence by the Cleveland Incontinence Score. RESULTS: At the last follow up the median time of using TAI was 29 (15-46) months. The median volume of water used for the irrigation was 900 (500-1500) ml. There was a significant decrease in the number of defaecations during the day (baseline, 8 [4 12]; last follow up, 1 [1-2]) and at night (baseline, 3 [2-5]; last follow up, 0 [0-0]). The Cleveland Incontinence Score fell from 17 [15-20] (baseline) to 5 [4 9] (last follow up) and the mental component of the SF-36 and all domains of the Rockwood QOL instrument improved. CONCLUSION: Transanal irrigation is an effective treatment of anterior resection syndrome and results in a marked improvement of the continence score and QOL. PMID- 21689360 TI - Anastomotic leakage, cystic duct stump leakage and local tumour recurrence: 'unhappy triad' following single port access laparoscopic right colectomy for cancer. PMID- 21689361 TI - Female infertility following restorative proctocolectomy. AB - AIM: Females of child-bearing age have been reported to have a two to three-fold increase in infertility after restorative proctocolectomy (RPC). This study aimed to assess aspects of infertility and pregnancy. METHOD: A postal questionnaire was sent to 790 females who had undergone primary RPC in two tertiary centres. Infertility, the number and outcome of pregnancies, delivery method and the use of fertility treatments were determined. RESULTS: Three hundred and six (38.5%) females responded (median age 47.9 years at follow up; 35.3 years at the time of RPC). Eighty-two per cent (n=250) had ulcerative colitis. Forty-five per cent (n=138) had conceived prior to RPC, 5.2% (n=16) conceived both before and after RPC, 5.5% (n=17) conceived after RPC only and 44.1% (n=135) had never conceived. Females delivering before RPC had significantly more vaginal deliveries than those conceiving after (pre-RPC 69.6%, n=96 vs post-RPC 35.3%, n=6; P=0.001). Fifty-seven patients stated they had attempted to conceive after RPC, with 25 (45.5%) being successful. Eighteen females had been referred to a fertility specialist, of whom 16 received in vitro fertilization (IVF). Four (30.7%) females conceived using IVF. CONCLUSION: While RPC is known to be associated with infertility, only a small proportion of patients are referred for fertility management. IVF outcomes and success rates after RPC are similar to the general population. Patients are more likely to have a Caesarean section following RPC. PMID- 21689362 TI - Ablative therapies for colorectal liver metastases: a systematic review. AB - AIM: The standard treatment for colorectal liver metastases (CRLM) is surgical resection. Only 20-30% of patients are deemed suitable for surgery. Recently, much attention has focused on ablative therapies either to treat unresectable CRLM or to extend the margins of resectability. This review aims to assess the long-term outcome and complication rates of various ablative therapies used in the management of CRLM. METHOD: A literature search was performed of electronic databases including Medline, Cochrane Collaboration Library and the National Library of Medicine's ClinicalTrials.gov. Inclusion criteria were ablation for CRLM with minimum 1 year follow-up and >10 patients, published between January 1994 and January 2010. RESULTS: In all, 226 potentially relevant studies were identified, of which 75 met the inclusion criteria. Cryotherapy (26 studies) had local recurrence rates of 12-39%, with mean 1-, 3- and 5-year survival rates of 84%, 37% and 17%. The major complication rate ranged from 7% to 66%. Microwave ablation (13 studies) had a local recurrence rate of 5-13%, with a mean 1-, 3- and 5-year survival of 73%, 30% and 16%, and a major complication rate ranging from 3% to 16%. Radiofrequency ablation (36 studies) had a local recurrence rate of 10-31%, with a mean 1-, 3- and 5-year survival of 85%, 36% and 24%, with major complication rate ranging from 0% to 33%. CONCLUSION: Ablative therapies offer significantly improved survival compared with palliative chemotherapy alone with 5-year survival rates of 17-24%. Complication rates amongst commonly used techniques are low. PMID- 21689363 TI - A prospective randomized comparison of cold vs hot snare polypectomy in the occurrence of postpolypectomy bleeding in small colonic polyps. AB - AIM: Polypectomy techniques in the removal of polyps in the 3-8 mm size range are inconsistent. The aim of our study was to compare cold (CSP) with hot snare polypectomy (HSP) in the occurrence of postpolypectomy bleeding in small colonic polyps 3-8 mm in size. METHOD: In all, 414 consecutive patients with small colorectal polyps 3-8 mm in size were prospectively randomized into the CSP group and the HSP group. RESULTS: There was no early or late postpolypectomy bleeding in either group. Intraprocedural bleeding was significantly more frequent in the CSP group than the HSP group (CSP, 19/208; HSP, 2/206; P<0.001) but resolved spontaneously without any intervention in both groups. CONCLUSION: The data show that the CSP technique is safe, effective and quicker than HSP for patients and it could be considered the ideal procedure for small polyp removal. PMID- 21689364 TI - The use of molecular markers as a method to predict the response to neoadjuvant therapy for advanced stage rectal adenocarcinoma. AB - AIM: The response to combined neoadjuvant therapy for advanced stage rectal adenocarcinoma is predictive of outcome. In addition to both clinical and pathological features, the expression of a variety of molecules may provide another method of identifying tumour responsiveness to pre-operative therapy. The aim of this study was to evaluate several markers in the apoptotic pathway as well as expression of Cox-2 and vascular endothelial growth factor (VEGF) to determine their ability to predict response to neoadjuvant therapy. METHOD: In total, 152 patients with advanced rectal adenocarcinoma were treated with neoadjuvant therapy followed by resection. Paraffin-embedded sections obtained before and after therapy were assessed by immunohistochemical staining for Cox-2, VEGF, p53, p21, p27, Bax, BCL-2 and apoptosis protease-activating factor 1 (APAF 1). These stains were correlated with tumour regression grade, complete pathological response and T-downstaging of the surgical specimen. Clinical and pathological data were also collected. Data were analysed using the chi2 and Spearman's correlation tests. RESULTS: Pathological complete response was seen in 24.5% of patients. Amongst the apoptosis-associated markers, only APAF-1 expression was found to be significantly associated with tumour regression grade (P<0.001), complete pathological response (P<0.031) and T-downstaging (P<0.004). On multivariate analysis, APAF-1 expression was found to be independently associated with good tumour regression grade. In contrast, overexpression of Cox 2 and VEGF in pretreatment biopsies was related to less tumour regression (P<0.003) and less likelihood of T-downstaging (P<0.03). CONCLUSION: Immunohistochemical evaluation of initial biopsy specimens of rectal cancer with APAF-1, Cox-2 and VEGF may predict tumour response to neoadjuvant therapy in patients with advanced rectal adenocarcinoma. Those with an expected limited response may be considered for other investigational neoadjuvant protocols. PMID- 21689365 TI - The outcome of laparoscopic colorectal resection in T4 cancer. AB - AIM: Laparoscopic surgery for locally advanced tumours with extramural involvement is still controversial. It is believed that laparoscopic excision of T4 cancers is technically difficult and may result in prolonged operative time, increased conversion rate, added postoperative morbidity, and suboptimal oncological clearance. METHOD: Our unit has been practising laparoscopic colorectal surgery since 1992, and all data are entered into a database prospectively. Since 1999 we have routinely used the laparoscopic approach for colorectal cancer resections. Data regarding patients with a histologically T4 cancer operated on between 1999 and 2008 were analysed. Outcomes included operating time, conversion rate, postoperative complications and oncological outcome. RESULTS: Over a 10-year period, 146 patients (male 75) with a T4 cancer underwent laparoscopic resection. The median operating time was 125 (range, 46 285) min and the median blood loss was 50 (0-1800) ml. The conversion rate was 16%. Six (4.1%) patients experienced anastomotic leakage. The median number of lymph nodes harvested was 13 (2-40). One hundred and two (70%) patients underwent curative resection. The recurrence rates were 41% and 53% for stage II and III patients, respectively. Four (3.9%) patients had local recurrence. At a median follow up of 18 (1-118) months, the overall survival was 25 months, with median overall survival for patients with stage II, III and IV disease being 63, 36 and 12 months, respectively. CONCLUSION: Laparoscopic colectomy in histologically T4 cancer is safe. Oncological outcomes remain satisfactory. Based on our data, provided expertise is available, patients with locally advanced tumours should not be excluded from a laparoscopic approach. PMID- 21689366 TI - Sigmoid intussusception presenting as rectal prolapse in an adult. PMID- 21689367 TI - Laparoscopy and surface colotomy facilitates colonic stent insertion for malignant colonic lesions not amenable to traditional per anal retrograde dual operator approach. PMID- 21689368 TI - Global and grain-specific accumulation of glycoside hydrolase family 10 xylanases in transgenic maize (Zea mays). AB - In planta expression of cell wall degrading enzymes is a promising approach for developing optimized biomass feedstocks that enable low-cost cellulosic biofuels production. Transgenic plants could serve as either an enzyme source for the hydrolysis of pretreated biomass or as the primary biomass feedstock in an autohydrolysis process. In this study, two xylanase genes, Bacillus sp. NG-27 bsx and Clostridium stercorarium xynB, were expressed in maize (Zea mays) under the control of two different promoters. Severe phenotypic effects were associated with xylanase accumulation in maize, including stunted plants and sterile grains. Global expression of these xylanases from the rice ubiquitin 3 promoter (rubi3) resulted in enzyme accumulation of approximately 0.01 mg enzyme per gram dry weight, or approximately 0.1% of total soluble protein (TSP). Grain-specific expression of these enzymes from the rice glutelin 4 promoter (GluB-4) resulted in higher-level accumulation of active enzyme, with BSX and XynB accumulating up to 4.0% TSP and 16.4% TSP, respectively, in shriveled grains from selected T0 plants. These results demonstrate the potential utility of the GluB-4 promoter for biotechnological applications. The phenotypic effects of xylanase expression in maize presented here demonstrate the difficulties of hemicellulase expression in an important crop for cellulosic biofuels production. Potential alternate approaches to achieve xylanase accumulation in planta without the accompanying negative phenotypes are discussed. PMID- 21689369 TI - The scutellar vascular bundle-specific promoter of the wheat HD-Zip IV transcription factor shows similar spatial and temporal activity in transgenic wheat, barley and rice. AB - An HD-Zip IV gene from wheat, TaGL9, was isolated using a Y1H screen of a cDNA library prepared from developing wheat grain. TaGL9 has an amino acid sequence distinct from other reported members of the HD-Zip IV family. The 3' untranslated region of TaGL9 was used as a probe to isolate a genomic clone of the TaGL9 homologue from a BAC library prepared from Triticum durum L. cv. Langdon. The full-length gene containing a 3-kb-long promoter region was designated TdGL9H1. Spatial and temporal activity of TdGL9H1 was examined using promoter-GUS fusion constructs in transgenic wheat, barley and rice plants. Whole-mount and histochemical GUS staining patterns revealed grain-specific expression of TdGL9H1. GUS expression was initially observed between 3 and 8 days after pollination (DAP) in embryos at the globular stage and adjacent to the embryo fraction of the endosperm. Expression was strongest in the outer cell layer of the embryo. In developed wheat and barley embryos, strong activity of the promoter was only detected in the main vascular bundle of the scutellum, which is known to be responsible for the uptake of nutrients from the endosperm during germination and the endosperm-dependent phase of seedling development. Furthermore, this pattern of GUS staining was observed in dry seeds several weeks after harvesting but quickly disappeared during imbibition. The promoter of this gene could be a useful tool for engineering of early seedling vigour and protecting the endosperm to embryo axis pathway from pathogens during grain desiccation and storage. PMID- 21689370 TI - Aminoterminal natriuretic peptide as a determinant of PAI-1 levels in a sample of the adult male Italian population. PMID- 21689371 TI - Unfractionated heparin for second trimester placental insufficiency: a pilot randomized trial. AB - OBJECTIVE: To conduct a pilot randomized controlled trial of unfractionated heparin (UFH) in women considered at high risk of placental insufficiency in the second trimester. METHODS: Women with either false-positive first trimester (pregnancy-associated placental protein-A [PAPP-A] < 0.35 MoM) or second trimester (alpha-fetoprotein [AFP] > 2.0 MoM, inhibin > 3.0 MoM, human chorionic gonadotropin > 4.0 MoM) serum screening tests or medical/obstetric risk factors were screened for placental insufficiency by sonographic evaluation of the placenta and uterine artery Doppler between 18 and 22 weeks. Thrombophilia screen negative women with two or three abnormal test categories were randomized by 23+6 weeks to self-administration of subcutaneous unfractionated heparin (UFH) 7500 IU twice daily until birth or 34 weeks, or to standard care. Maternal anxiety and other maternal-infant outcomes were determined. RESULTS: Thirty-two out of 41 eligible women consented, with 16 women randomized to UFH and 16 to standard care. There was no statistically significant difference identified between the two treatment groups (standard care vs. UFH) for the following: maternal anxiety score (mean [standard deviation]), 14.2 [+/- 1.6] vs. 14.0 [+/- 1.8]; birth weight (median [range]), 1795 [470-3295]g vs. 1860 [730-3050]g; perinatal death, 3 vs. 0; severe preeclampsia, 2 vs. 6; placental weight < 10th percentile, 7 vs. 4; or placental infarction, 4 vs. 3. CONCLUSION: Our study design identified women at high risk of adverse maternal-infant outcomes attributable to placental insufficiency. Women with evidence of placental insufficiency were willing to undergo randomization and self-administration of UFH without increased maternal anxiety. PMID- 21689372 TI - Deep intronic variations may cause mild hemophilia A. AB - BACKGROUND: In about 10% of patients with mild hemophilia A, no candidate gene mutations are apparent after complete gene sequencing. AIM OF THE STUDY: To analyze factor VIII gene (F8) mRNA for mutations in five families with mild hemophilia A with no apparent genomic mutation and a reduced response to desmopressin. RESULTS: In four cases, mRNA studies revealed the presence of an abnormal mRNA transcript in addition to normal F8 mRNA. Sequencing of the abnormal transcripts revealed complex abnormalities, which allowed the identification of three different intronic variations (c.2113+1152delA, c.5587 93C>T and c.5999-277G>A) at the DNA level, absent from 387 normal alleles. By in silico analysis, c.2113+1152delA and c.5587-93C>T were strongly predicted to result in the generation of new splice sites with the introduction of premature termination codons, while c.5999-277G>A was predicted to generate a new protein with 30 additional amino acids. However, these predictions were not homogeneous across the different mutations and programs used. The detrimental effect of two mutations was also confirmed by in vitro expression studies. These changes were also identified in related female carriers and in other mild HA patients not included in the original study. No mRNA abnormality was identified in the remaining patient. CONCLUSIONS: Although rare, deep intronic variations may be responsible for mild hemophilia A where no other F8 mutations have been identified and may be associated with a reduced biologic response to desmopressin. F8 mRNA analysis is a useful tool for the identification of deep intronic variation not detectable by standard DNA sequencing. PMID- 21689373 TI - Halitosis and oral health-related quality of life: a case report. AB - OBJECTIVES: This is a clinical case of a 36-year-old Dutch male, patient in the Dr. S. van Mesdag Forensic Psychiatric Centre in Groningen. It demonstrates a short-time effect of a tailored oral hygiene self-care intervention in three sessions over a period of 3 months on halitosis and a patient's oral health related quality of life (OH-QoL). METHODS: In addition to a dental screening and professional oral hygiene care, a semi-structured interview was conducted by the dental hygienist, and questionnaires were administered. The questionnaires included were; the Dutch version of the Oral Health Impact Profile-14 (OHIP-14 NL; used as a measurement of OH-QoL), scales for expected social outcomes for having healthy teeth, attitudes towards oral hygiene behaviour (OHB) and dental anxiety. RESULTS: Clinical observations showed an improvement in patient's OHB, while the extreme foetor-ex-ore was reduced to an acceptable level. A retrospective assessment showed that patient's attitude towards the recommended OHB together with his self-perceived OH-QoL had positively increased. CONCLUSIONS: This case highlights the value of professional individual oral hygiene instructions performed by a dental hygienist. It also illustrates that a patient's effective OHB may play an important role in the reduction in halitosis and self-perceived OH-QoL. Finally, the retrospective version of the OHIP-14-NL may be an adequate method to assess self-perceived OH-QoL within a relative short period of time. PMID- 21689374 TI - Development of an auxiliary resource for diagnosis of dental caries in epidemiological surveys. AB - OBJECTIVE: Early dental caries diagnosis within the changing global pattern of dental caries development requires the use of auxiliary resources and adjuncts to diagnosis. The aim of this study was to introduce an alternative resource for drying teeth to enable early diagnosis of dental caries in epidemiological surveys. METHODS: Polyurethane tips and three-in-one syringes were fitted to nebulizers and non-professional portable compressors for dental surface drying. The output air pressure of these sets was compared with the output pressure from the three-in-one syringe in a dental office. RESULTS: Although the output pressure from the alternative resources was lower than the output pressure from the dental office equipment, the dental surfaces were dried satisfactorily, allowing the early diagnosis of the dental caries. CONCLUSION: When a dental setting is not available, these alternative resources for drying teeth can be used satisfactorily. PMID- 21689375 TI - Multi-targeted activity of maslinic acid as an antimalarial natural compound. AB - Most drugs against malaria that are available or under development target a single process of the parasite infective cycle, favouring the appearance of resistant mutants which are easily spread in areas under chemotherapeutic treatments. Maslinic acid (MA) is a low toxic natural pentacyclic triterpene for which a wide variety of biological and therapeutic activities have been reported. Previous work revealed that Plasmodium falciparum erythrocytic cultures were inhibited by MA, which was able to hinder the maturation from ring to schizont stage and, as a consequence, prevent the release of merozoites and the subsequent invasion. We show here that MA effectively inhibits the proteolytic processing of the merozoite surface protein complex, probably by inhibition of PfSUB1. In addition, MA was also found to inhibit metalloproteases of the M16 family by a non-chelating mechanism, suggesting the possible hindrance of plasmodial metalloproteases belonging to that family, such as falcilysin and apicoplast peptide-processing proteases. Finally, in silico target screening was used to search for other potential binding targets that may have remained undetected. Among the targets identified, the method recovered two for which experimental activity could be confirmed, and suggested several putative new targets to which MA could have affinity. One of these unreported targets, phospholipase A2, was shown to be partially inhibited by MA. These results suggest that MA may behave as a multi-targeted drug against the intra-erythrocytic cycle of Plasmodium, providing a new tool to investigate the synergistic effect of inhibiting several unrelated processes with a single compound, a new concept in antimalarial research. PMID- 21689376 TI - Investigation into stereoselective pharmacological activity of phenotropil. AB - Phenotropil [N-carbamoylmethyl-4-aryl-2-pyrrolidone (2-(2-oxo-4-phenyl-pyrrolidin 1-yl) acetamide; carphedon)] is clinically used in its racemic form as a nootropic drug that improves physical condition and cognition. The aim of this study was to compare the stereoselective pharmacological activity of R- and S enantiomers of phenotropil in different behavioural tests. Racemic phenotropil and its enantiomers were tested for locomotor, antidepressant and memory improving activity and influence on the central nervous system (CNS) using general pharmacological tests in mice. After a single administration, the amount of compound in brain tissue extracts was determined using an ultra performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) method in a positive ion electrospray mode. In the open-field test, a significant increase in locomotor activity was observed after a single administration of R-phenotropil at doses of 10 and 50 mg/kg and S-phenotropil at a dose of 50 mg/kg. In the forced swim test, R-phenotropil induced an antidepressant effect at doses of 100 and 50 mg/kg, and S-phenotropil was active at a dose of 100 mg/kg. R-phenotropil significantly enhanced memory function in a passive avoidance response test at a dose of 1 mg/kg; the S-enantiomer did not show any activity in this test. However, the concentrations of R- and S-phenotropils in brain tissue were similar. In conclusion, the antidepressant and increased locomotor activity relies on both R- and S-phenotropils, but the memory-improving activity is only characteristic of R-phenotropil. These results may be important for the clinical use of optically pure isomers of phenotropil. PMID- 21689377 TI - Pharmacophore modeling and density functional theory analysis for a series of nitroimidazole compounds with antitubercular activity. AB - In an attempt to highlight structural features required for potent antitubercular activity, five pharmacophoric features were developed for PA-824 and its analogs. The generated pharmacophore indicated importance of a nitro group, three hydrogen bond acceptor features, and a distal aromatic ring for potent activity. The model based on pharmacophore alignment has good correlation coefficient for the training set (r(2) = 0.81, SD = 0.31, F = 122.9, N = 152), which was evaluated using a test set (Q(2) = 0.77, root-mean-square error = 0.35, Pearson-R = 0.88, N = 49). Structure-activity relationship investigation further revealed that hydrophobic substitutions at the para-position of distal aromatic ring could lead to more potent analogs. The most active and inactive compounds were further studied using density functional theory at B3LYP/3-21*G level. The calculated electrostatic profile indicated that these compounds possess maximum negative potential in the vicinity of nitro group extending laterally to the imidazole ring. Furthermore, the calculated electron affinity values indicate the stability of radical anions, which could form upon one electron reduction in the biological system, thus, indicating the electron acceptor capacity of these compounds. Results of this study are expected to be useful in the design of novel potent nitroimidazoles as antitubercular agents. PMID- 21689378 TI - 3D-QSAR and docking studies on the HEPT derivatives of HIV-1 reverse transcriptase. AB - Three-dimensional Quantitative Structure Activity Relationship (3D-QSAR) has been derived for a set of HEPT derivatives of HIV-1 reverse transcriptase (RT) using Comparative Molecular Field Analysis (CoMFA). The CoMFA models have been developed using two different alignment procedures such as common substructure and bioactive conformation. The CoMFA model I is derived from a common substructure procedure that includes steric and electrostatic fields with the cross-validated q(2) and the non-cross-validated r(2) value of 0.86 and 0.97, respectively. The same for the CoMFA model II that is derived based on the bioactive conformation are 0.19 and 0.77, respectively. It is evident from the results that the common substructure-based alignment model has good statistical significance when compared with that of bioactive conformation for the selected systems in this study. The docking study revealed that the conformational flexibility observed at the R3 position favors different orientations of the substitution at the active site of HIV-1 RT and thereby leads to inconsistency in the CoMFA alignment based on bioactive conformation. PMID- 21689379 TI - Paracrine control of vascular innervation in health and disease. AB - Proper vascular regulation is of paramount importance for the control of blood flow to tissues. In particular, the regulation of peripheral resistance arteries is essential for several physiological processes, including control of blood pressure, thermoregulation and increase of blood flow to central nervous system and heart under stress conditions such as hypoxia. Arterial tone is regulated by the periarterial autonomic nervous plexus, as well as by endothelium-dependent, myogenic and humoral mechanisms. Underscoring the importance of proper vascular regulation, defects in these processes can lead to diseases such as hypertension, orthostatic hypotension, Raynaud's phenomenon, defective thermoregulation, hand foot syndrome, migraine and congestive heart failure. Here, we review the molecular mechanisms controlling the development of the periarterial nerve plexus, retrograde and localized signalling at neuro-effector junctions, the molecular and cellular mechanisms of vascular regulation and adult plasticity and maintenance of periarterial innervation. We particularly highlight a newly discovered role for vascular endothelial growth factor in the structural and functional maintenance of arterial neuro-effector junctions. Finally, we discuss how defects in neuronal vascular regulation can lead to disease. PMID- 21689380 TI - Association of ADAM33 gene polymorphisms with asthma in a Chinese population. AB - BACKGROUND AND AIM: Asthma is a very common disease involving genetic and environmental factors. A disintegrin and metalloproteinase 33 (ADAM33) has been one of the most exciting candidate genes for asthma since its first association with the disease in the white population. Recently, studies on the association of ADAM33 gene polymorphisms with the risk of asthma have been controversial. We therefore focused on testing the hypothesis that either single-nucleotide polymorphisms (SNPs) of the ADAM33 gene may be associated with asthma risk. The aim of this study was to evaluate the potential relationship between polymorphisms of ADAM33 and asthma in a Han population in China. METHODS: A case control study was conducted in a Han population of eastern Chinese population. A total of 329 asthma patients and a control group of 316 healthy volunteers were recruited for this study. Four polymorphic sites (F+1, S2, T2 and V4) were selected for genotyping. Genotypes were determined by the allele-specific polymerase chain reaction with fluorescence melting curves and DNA sequencing method. Data were analysed using the chi-squared test software. RESULTS: Statistically significant differences in the distributions of the S2 site between patients and controls were observed (chi2=7.140, P<0.05). CONCLUSION: These preliminary results suggest an association between ADAM33 polymorphisms S2 C/G and asthma in a Chinese Han population. The SNPs (F+1 C/T, T2 G/A and V4 C/G) of the ADAM33 gene may be the causal variants in asthma disease, but the strength of this evidence is limited by our small sample size. PMID- 21689381 TI - Benefits of smoking cessation with focus on cardiovascular and respiratory comorbidities. AB - Smoking cessation is crucial in preventing premature morbidity, disability and mortality worldwide. The effectiveness of quitting tobacco use surpasses any other intervention to minimise the risk for chronic cardiac and respiratory conditions. The overall health benefits of smoking cessation have been recognised for decades but as tobacco legislation has been changing in recent years, new evidence particularly concerning the effect of less smoke exposure on the vascular system has emerged. Recently, much research in chronic obstructive pulmonary disease (COPD) has concerned the ongoing inflammation - also in former smokers - and disease heterogeneity, which provides new knowledge regarding current and ex-smokers with COPD. Many other cardiovascular and respiratory diseases are associated with smoking, and the course of these diseases is not always studied in the context of smoking cessation versus continued smoking. This review summarises the latest available data on health benefits of smoking cessation with focus on both common and infrequent cardiovascular and respiratory diseases. PMID- 21689382 TI - Exon-primed, intron-crossing (EPIC) loci for five nuclear genes in deep-sea protobranch bivalves: primer design, PCR protocols and locus utility. AB - We describe PCR primers and amplification protocols developed to obtain introns from conserved nuclear genes in deep-sea protobranch bivalves. Because almost no sequence data for protobranchs are publically available, mollusk and other protostome sequences from GenBank were used to design degenerate primers, making these loci potentially useful in other invertebrate taxa. Amplification and sequencing success varied across the test group of 30 species, and we present five loci spanning this range of outcomes. Intron presence in the targeted regions also varied across genes and species, often within single genera; for instance, the calmodulin and beta-tubulin loci contained introns with high frequency, whereas the triose phosphate isomerase locus never contained an intron. In introns for which we were able to obtain preliminary estimates of polymorphism levels in single species, polymorphism was greater than traditional mitochondrial loci. These markers will greatly increase the ability to assess population structure in the ecologically important protobranchs, and may prove useful in other taxa as well. PMID- 21689383 TI - Establishment of a mitochondrial DNA sequence database for the identification of fish species commercially available in South Africa. AB - The limitations intrinsic to morphology-based identification systems have created an urgent need for reliable genetic methods that enable the unequivocal recognition of fish species, particularly those that are prone to overexploitation and/or market substitution. The aim of this study was to develop a comprehensive reference library of DNA sequence data to allow the explicit identification of 53 commercially available fish species in South Africa, most of which were locally caught marine species. Sequences of approximately 655 base pairs were generated for all species from the cytochrome c oxidase I (COI) gene, the region widely adopted for DNA barcoding. Specimens of the genus Thunnus were examined in further detail, employing additional mitochondrial DNA control region sequencing. Cumulative analysis of the sequences from the COI region revealed mean conspecific, congeneric and confamilial Kimura 2-parameter distances of 0.10%, 4.58% and 15.43%, respectively. The results showed that the vast majority (98%) of fish species examined could be readily differentiated by their COI barcodes, but that supplementary control region sequencing was more useful for the discrimination of three Thunnus species. Additionally, the analysis of COI data raised the prospect that Thyrsites atun (snoek) could constitute a species pair. The present study has established the necessary genetic information to permit the unambiguous identification of 53 commonly marketed fish species in South Africa, the applications of which hold a plethora of benefits relating to ecology research, fisheries management and control of commercial practices. PMID- 21689384 TI - DNA barcoding of oomycetes with cytochrome c oxidase subunit I and internal transcribed spacer. AB - Oomycete species occupy many different environments and many ecological niches. The genera Phytophthora and Pythium for example, contain many plant pathogens which cause enormous damage to a wide range of plant species. Proper identification to the species level is a critical first step in any investigation of oomycetes, whether it is research driven or compelled by the need for rapid and accurate diagnostics during a pathogen outbreak. The use of DNA for oomycete species identification is well established, but DNA barcoding with cytochrome c oxidase subunit I (COI) is a relatively new approach that has yet to be assessed over a significant sample of oomycete genera. In this study we have sequenced COI, from 1205 isolates representing 23 genera. A comparison to internal transcribed spacer (ITS) sequences from the same isolates showed that COI identification is a practical option; complementary because it uses the mitochondrial genome instead of nuclear DNA. In some cases COI was more discriminative than ITS at the species level. This is in contrast to the large ribosomal subunit, which showed poor species resolution when sequenced from a subset of the isolates used in this study. The results described in this paper indicate that COI sequencing and the dataset generated are a valuable addition to the currently available oomycete taxonomy resources, and that both COI, the default DNA barcode supported by GenBank, and ITS, the de facto barcode accepted by the oomycete and mycology community, are acceptable and complementary DNA barcodes to be used for identification of oomycetes. PMID- 21689385 TI - Monobenzone-induced depigmentation: from enzymatic blockade to autoimmunity. AB - Autoimmune side-effects such as vitiligo regularly occur during melanoma immunotherapy. As vitiligo development is associated with a superior prognosis, the active induction of vitiligo in melanoma patients can be a useful tactic. The potent skin-depigmenting agent monobenzone can be used successfully for this purpose. However, until recently, the mechanism of action behind monobenzone induced skin depigmentation was unclear. Lately, the mechanistic basis for the augmented immunogenicity of monobenzone-exposed pigmented cells has been unveiled, and their active role in the induction of autoimmune T-cell-mediated vitiligo has become apparent. Here, we provide an immunological framework in which we condense this knowledge to an integrated theory of the generation of monobenzone-induced vitiligo. PMID- 21689387 TI - Influence of dietary iodine deficiency on the thyroid gland in Slc26a4-null mutant mice. AB - BACKGROUND: Pendred syndrome (PDS) is an autosomal recessive disorder characterized by sensorineural hearing impairment and variable degree of goitrous enlargement of the thyroid gland with a partial defect in iodine organification. The thyroid function phenotype can range from normal function to overt hypothyroidism. It is caused by loss-of-function mutations in the SLC26A4 (PDS) gene. The severity of the goiter has been postulated to depend on the amount of dietary iodine intake. However, direct evidence has not been shown to support this hypothesis. Because Slc26a4-null mice have deafness but do not develop goiter, we fed the mutant mice a control diet or an iodine-deficient diet to evaluate whether iodine deficiency is a causative environmental factor for goiter development in PDS. METHODS: We evaluated the thyroid volume in histological sections with the use of three-dimensional reconstitution software, we measured serum levels of total tri-iodothyronine (TT3) and total thyroxine (TT4) levels, and we studied the thyroid gland morphology by transmission electron microscopy. RESULTS: TT4 levels became low but TT3 levels did not change significantly after eight weeks of an iodine-deficient diet compared to levels in the control diet animals. Even in Slc26a4-null mice fed an iodine-deficient diet, the volume of the thyroid gland did not increase although the size of each epithelial cell increased with a concomitant decrease of thyroid colloidal area. CONCLUSIONS: An iodine-deficient diet did not induce goiter in Slc26a4-null mice, suggesting that other environmental, epigenetic or genetic factors are involved in goiter development in PDS. PMID- 21689388 TI - Dissecting protein loops with a statistical scalpel suggests a functional implication of some structural motifs. AB - BACKGROUND: One of the strategies for protein function annotation is to search particular structural motifs that are known to be shared by proteins with a given function. RESULTS: Here, we present a systematic extraction of structural motifs of seven residues from protein loops and we explore their correspondence with functional sites. Our approach is based on the structural alphabet HMM-SA (Hidden Markov Model - Structural Alphabet), which allows simplification of protein structures into uni-dimensional sequences, and advanced pattern statistics adapted to short sequences. Structural motifs of interest are selected by looking for structural motifs significantly over-represented in SCOP superfamilies in protein loops. We discovered two types of structural motifs significantly over represented in SCOP superfamilies: (i) ubiquitous motifs, shared by several superfamilies and (ii) superfamily-specific motifs, over-represented in few superfamilies. A comparison of ubiquitous words with known small structural motifs shows that they contain well-described motifs as turn, niche or nest motifs. A comparison between superfamily-specific motifs and biological annotations of Swiss-Prot reveals that some of them actually correspond to functional sites involved in the binding sites of small ligands, such as ATP/GTP, NAD(P) and SAH/SAM. CONCLUSIONS: Our findings show that statistical over representation in SCOP superfamilies is linked to functional features. The detection of over-represented motifs within structures simplified by HMM-SA is therefore a promising approach for prediction of functional sites and annotation of uncharacterized proteins. PMID- 21689389 TI - Turbot reovirus (SMReV) genome encoding a FAST protein with a non-AUG start site. AB - BACKGROUND: A virus was isolated from diseased turbot Scophthalmus maximus in China. Biophysical and biochemical assays, electron microscopy, and genome electrophoresis revealed that the virus belonged to the genus Aquareovirus, and was named Scophthalmus maximus reovirus (SMReV). To the best of our knowledge, no complete sequence of an aquareovirus from marine fish has been determined. Therefore, the complete characterization and analysis of the genome of this novel aquareovirus will facilitate further understanding of the taxonomic distribution of aquareovirus species and the molecular mechanism of its pathogenesis. RESULTS: The full-length genome sequences of SMReV were determined. It comprises eleven dsRNA segments covering 24,042 base pairs and has the largest S4 genome segment in the sequenced aquareoviruses. Sequence analysis showed that all of the segments contained six conserved nucleotides at the 5' end and five conserved nucleotides at the 3' end (5'-GUUUUA ---- UCAUC-3'). The encoded amino acid sequences share the highest sequence identities with the respective proteins of aquareoviruses in species group Aquareovirus A. Phylogenetic analysis based on the major outer capsid protein VP7 and RNA-dependent RNA polymerase were performed. Members in Aquareovirus were clustered in two groups, one from fresh water fish and the other from marine fish. Furthermore, a fusion associated small transmembrane (FAST) protein NS22, which is translated from a non-AUG start site, was identified in the S7 segment. CONCLUSIONS: This study has provided the complete genome sequence of a novel isolated aquareovirus from marine fish. Amino acids comparison and phylogenetic analysis suggested that SMReV was a new aquareovirus in the species group Aquareovirus A. Phylogenetic analysis among aquareoviruses revealed that VP7 could be used as a reference to divide the aquareovirus from hosts in fresh water or marine. In addition, a FAST protein with a non-AUG start site was identified, which partially contributed to the cytopathic effect caused by the virus infection. These results provide new insights into the virus-host and virus-environment interactions. PMID- 21689390 TI - Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene mutation related dilated cardiomyopathy. AB - BACKGROUND: The purpose of this study was to identify early features of lamin A/C gene mutation related dilated cardiomyopathy (DCM) with cardiovascular magnetic resonance (CMR). We characterise myocardial and functional findings in carriers of lamin A/C mutation to facilitate the recognition of these patients using this method. We also investigated the connection between myocardial fibrosis and conduction abnormalities. METHODS: Seventeen lamin A/C mutation carriers underwent CMR. Late gadolinium enhancement (LGE) and cine images were performed to evaluate myocardial fibrosis, regional wall motion, longitudinal myocardial function, global function and volumetry of both ventricles. The location, pattern and extent of enhancement in the left ventricle (LV) myocardium were visually estimated. RESULTS: Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion abnormalities correlated strongly with the degree of enhancement. Myocardial enhancement was associated with conduction abnormalities. Sixty-nine percent of our asymptomatic or mildly symptomatic patients showed mild ventricular dilatation, systolic failure or both in global ventricular analysis. Decreased longitudinal systolic LV function was observed in 53% of patients. CONCLUSIONS: Cardiac conduction abnormalities, mildly dilated LV and depressed systolic dysfunction are common in DCM caused by a lamin A/C gene mutation. However, other cardiac diseases may produce similar symptoms. CMR is an accurate tool to determine the typical cardiac involvement in lamin A/C cardiomyopathy and may help to initiate early treatment in this malignant familiar form of DCM. PMID- 21689391 TI - DNA binding activities of the Herves transposase from the mosquito Anopheles gambiae. AB - BACKGROUND: Determining the mechanisms by which transposable elements move within a genome increases our understanding of how they can shape genome evolution. Class 2 transposable elements transpose via a 'cut-and-paste' mechanism mediated by a transposase that binds to sites at or near the ends of the transposon. Herves is a member of the hAT superfamily of class 2 transposons and was isolated from Anopheles gambiae, a medically important mosquito species that is the major vector of malaria in sub-Saharan Africa. Herves is transpositionally active and intact copies of it are found in field populations of A gambiae. In this study we report the binding activities of the Herves transposase to the sequences at the ends of the Herves transposon and compare these to other sequences recognized by hAT transposases isolated from other organisms. RESULTS: We identified the specific DNA-binding sites of the Herves transposase. Active Herves transposase was purified using an Escherichia coli expression system and bound in a site specific manner to the subterminal and terminal sequences of the left and right ends of the element, respectively, and also interacted with the right but not the left terminal inverted repeat. We identified a common subterminal DNA-binding motif (CG/AATTCAT) that is critical and sufficient for Herves transposase binding. CONCLUSIONS: The Herves transposase binds specifically to a short motif located at both ends of the transposon but shows differential binding with respect to the left and right terminal inverted repeats. Despite similarities in the overall structures of hAT transposases, the regions to which they bind in their respective transposons differ in sequence ensuring the specificity of these enzymes to their respective transposon. The asymmetry with which the Herves terminal inverted repeats are bound by the transposase may indicate that these differ in their interactions with the enzyme. PMID- 21689392 TI - Identification of serum biomarkers for aging and anabolic response. AB - OBJECTIVE: With the progressive aging of the human population, there is an inexorable decline in muscle mass, strength and function. Anabolic supplementation with testosterone has been shown to effectively restore muscle mass in both young and elderly men. In this study, we were interested in identifying serum factors that change with age in two distinct age groups of healthy men, and whether these factors were affected by testosterone supplementation. METHODS: We measured the protein levels of a number of serum biomarkers using a combination of banked serum samples from older men (60 to 75 years) and younger men (ages 18 to 35), as well as new serum specimens obtained through collaboration. We compared baseline levels of all biomarkers between young and older men. In addition, we evaluated potential changes in these biomarker levels in association with testosterone dose (low dose defined as 125 mg per week or below compared to high dose defined as 300 mg per week or above) in our banked specimens. RESULTS: We identified nine serum biomarkers that differed between the young and older subjects. These age-associated biomarkers included: insulin-like growth factor (IGF1), N-terminal propeptide of type III collagen (PIIINP), monokine induced by gamma interferon (MIG), epithelial-derived neutrophil-activating peptide 78 (ENA78), interleukin 7 (IL-7), p40 subunit of interleukin 12 (IL-12p40), macrophage inflammatory protein 1beta (MIP-1beta), platelet derived growth factor beta (PDGFbeta) and interferon-inducible protein 10 (IP-10). We further observed testosterone dose-associated changes in some but not all age related markers: IGF1, PIIINP, leptin, MIG and ENA78. Gains in lean mass were confirmed by dual energy X-ray absorptiometry (DEXA). CONCLUSIONS: Results from this study suggest that there are potential phenotypic biomarkers in serum that can be associated with healthy aging and that some but not all of these biomarkers reflect gains in muscle mass upon testosterone administration. PMID- 21689393 TI - Comprehensive early intervention for patients with first-episode psychosis in Japan (J-CAP): study protocol for a randomised controlled trial. AB - INTRODUCTION: Comprehensive approaches for patients with psychotic symptoms play essential roles in the symptomatic and functional outcomes of patients, especially during disease onset. In Japan, the shortage of mental health services, particularly for outpatients, and community-based supports has been a major problem. The purpose of this trial is to investigate the effectiveness and affordability of 18-month comprehensive early intervention services for patients with first-episode psychosis compared with typical treatment. METHODS: This interventional, parallel, single-blinded (open but blinded raters trial) was effectively designed. The participants are patients with a diagnosis of F2 or F3 (International Classification of Disease, 10 th revision), with psychotic symptoms. The inclusion criteria were an age of 15-35 years, onset of psychotic symptoms within 5 years, first-episode psychosis, and residence in the catchment area of each site. Allocation will be conducted equally between case management and standard care groups. After enrollment, standard care will be provided for both groups, and community-based care to promote recovery for 18 months will be provided for the comprehensive approach group. The primary outcome will be the function domain of the global assessment of functioning scores at 18 months after enrollment. Data assessment will be performed at enrollment and 18, 36, and 60 months after enrollment. The target sample size will be 150, and registration will occur from March 1, 2011, to September 30, 2012. DISCUSSION: This trial will provide promising results about the effectiveness and cost-effectiveness of early intervention services in Japan to improve the quality and quantity of community mental health services. TRIAL REGISTRATION: This trial was registered in The University Hospital Medical Information Network Clinical Trials Registry (No. UMIN000005092). PMID- 21689394 TI - PRegnancy Outcomes after a Maternity Intervention for Stressful EmotionS (PROMISES): study protocol for a randomised controlled trial. AB - BACKGROUND: There is ample evidence from observational prospective studies that maternal depression or anxiety during pregnancy is a risk factor for adverse psychosocial outcomes in the offspring. However, to date no previous study has demonstrated that treatment of depressive or anxious symptoms in pregnancy actually could prevent psychosocial problems in children. Preventing psychosocial problems in children will eventually bring down the huge public health burden of mental disease. The main objective of this study is to assess the effects of cognitive behavioural therapy in pregnant women with symptoms of anxiety or depression on the child's development as well as behavioural and emotional problems. In addition, we aim to study its effects on the child's development, maternal mental health, and neonatal outcomes, as well as the cost-effectiveness of cognitive behavioural therapy relative to usual care. METHODS/DESIGN: We will include 300 women with at least moderate levels of anxiety or depression at the end of the first trimester of pregnancy. By including 300 women we will be able to demonstrate effect sizes of 0.35 or over on the total problems scale of the child behavioural checklist 1.5-5 with alpha 5% and power (1-beta) 80%.Women in the intervention arm are offered 10-14 individual cognitive behavioural therapy sessions, 6-10 sessions during pregnancy and 4-8 sessions after delivery (once a week). Women in the control group receive care as usual.Primary outcome is behavioural/emotional problems at 1.5 years of age as assessed by the total problems scale of the child behaviour checklist 1.5-5 years.Secondary outcomes will be mental, psychomotor and behavioural development of the child at age 18 months according to the Bayley scales, maternal anxiety and depression during pregnancy and postpartum, and neonatal outcomes such as birth weight, gestational age and Apgar score, health care consumption and general health status (economic evaluation). TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR2242. PMID- 21689395 TI - The non-motile phenotype of Salmonella hha ydgT mutants is mediated through PefI SrgD. AB - BACKGROUND: Two ancestral nucleoid-associated proteins called Hha and YdgT contribute to the negative regulation of several virulence-associated genes in Salmonella enterica serovar Typhimurium. Our previous work showed that Hha and YdgT proteins are required for negative regulation of Salmonella Pathogenicity Island-2 and that hha ydgT double mutants are attenuated for murine infection. Interestingly, hha ydgT mutant bacteria exhibited a non-motile phenotype suggesting that Hha and YdgT have a role in flagellar regulation. RESULTS: In this study we show that the non-motile phenotype of hha ydgT mutants is due to decreased levels of the master transcriptional regulator FlhD4C2 resulting in down-regulation of class II/III and class III flagellar promoters and lack of surface flagella on these cells. The horizontally acquired pefI-srgD region was found to be partially responsible for this phenotype since deletion of pefI-srgD in a hha ydgT deletion background resulted in transient restoration of class II/III and III transcription, expression of surface flagella, and motility in the quadruple mutant. CONCLUSION: These data extend our current understanding of the mechanisms through which Hha and YdgT regulate flagellar biosynthesis and further describe how S. Typhimurium has integrated horizontal gene acquisitions into ancestral regulatory networks. PMID- 21689396 TI - Enjoyment of exercise moderates the impact of a school-based physical activity intervention. AB - BACKGROUND: A school-based physical activity intervention designed to encourage adolescent girls to be more active was more effective for some participants than for others. We examined whether baseline enjoyment of exercise moderated response to the intervention. METHODS: Adolescent girls with a low level of baseline activity who participated in a controlled trial of an intervention to promote increased physical activity participation (n = 122) self-reported their enjoyment of exercise and physical activity participation at baseline, mid-way through the intervention, and at the end of the 9-month intervention period. At all three time points, participants also underwent assessments of cardiovascular fitness (VO2peak) and body composition (percent body fat). Repeated measures analysis of variance examined the relationship of baseline enjoyment to change in physical activity, cardiovascular fitness, body composition and enjoyment of exercise. RESULTS: A significant three-way interaction between time, baseline enjoyment, and group assignment (p < .01) showed that baseline enjoyment moderated the effect of the intervention on vigorous activity. Within the intervention group, girls with low enjoyment of exercise at baseline increased vigorous activity from pre-to post-intervention, and girls with high baseline enjoyment of exercise showed no pre-post change in vigorous activity. No differences emerged in the comparison group between low-and high-enjoyment girls. CONCLUSION: Adolescent girls responded differently to a physical activity promotion intervention depending on their baseline levels of exercise enjoyment. Girls with low enjoyment of exercise may benefit most from a physical-education based intervention to increase physical activity that targets identified barriers to physical activity among low-active adolescent girls. PMID- 21689397 TI - 5-Hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells. AB - BACKGROUND: 5-Hydroxymethylcytosine (5hmC) was recently found to be abundantly present in certain cell types, including embryonic stem cells. There is growing evidence that TET proteins, which convert 5-methylcytosine (5mC) to 5hmC, play important biological roles. To further understand the function of 5hmC, an analysis of the genome-wide localization of this mark is required. RESULTS: Here, we have generated a genome-wide map of 5hmC in human embryonic stem cells by hmeDIP-seq, in which hydroxymethyl-DNA immunoprecipitation is followed by massively parallel sequencing. We found that 5hmC is enriched in enhancers as well as in gene bodies, suggesting a potential role for 5hmC in gene regulation. Consistent with localization of 5hmC at enhancers, 5hmC was significantly enriched in histone modifications associated with enhancers, such as H3K4me1 and H3K27ac. 5hmC was also enriched in other protein-DNA interaction sites, such as OCT4 and NANOG binding sites. Furthermore, we found that 5hmC regions tend to have an excess of G over C on one strand of DNA. CONCLUSIONS: Our findings suggest that 5hmC may be targeted to certain genomic regions based both on gene expression and sequence composition. PMID- 21689398 TI - Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study. AB - INTRODUCTION: Many women who survive breast cancer die of causes unrelated to their cancer diagnosis. This study was undertaken to assess factors that are related to breast cancer mortality versus mortality from other causes and to describe the leading causes of death among older women diagnosed with breast cancer. METHODS: Women diagnosed with breast cancer at age 66 or older between 1992 and 2000 were identified in the Surveillance, Epidemiology and End Results Medicare linked database and followed through the end of 2005. RESULTS: A total of 63,566 women diagnosed with breast cancer met the inclusion criteria and were followed for a median of approximately nine years. Almost one-half (48.7%) were alive at the end of follow-up. Ages and comorbidities at the time of diagnosis had the largest effects on mortality from other causes, while tumor stage, tumor grade, estrogen receptor status, age and comorbidities at the time of diagnosis all had effects on breast cancer-specific mortality. Fully adjusted relative hazards of the effects of comorbidities on breast cancer-specific mortality were 1.24 (95% confidence interval (95% CI) 1.13 to 1.26) for cardiovascular disease, 1.13 (95% CI 1.13 to 1.26) for previous cancer, 1.13 (95% CI 1.05 to 1.22) for chronic obstructive pulmonary disease and 1.10 (95% CI 1.03 to 1.16) for diabetes. Among the total study population, cardiovascular disease was the primary cause of death in the study population (15.9% (95% CI 15.6 to 16.2)), followed closely by breast cancer (15.1% (95% CI 14.8 to 15.4)). CONCLUSIONS: Comorbid conditions contribute importantly to both total mortality and breast cancer-specific mortality among breast cancer survivors. Attention to reducing the risk of cardiovascular disease should be a priority for the long-term care of women following the diagnosis and treatment of breast cancer. PMID- 21689399 TI - Diabetes mellitus type 2 and other chronic non-communicable diseases in the central region, Saudi Arabia (Riyadh cohort 2): a decade of an epidemic. AB - BACKGROUND: Follow-up epidemiologic studies are needed to assess trends and patterns of disease spread. No follow-up epidemiologic study has been done in the Kingdom of Saudi Arabia to assess the current prevalence of major chronic, noncommunicable diseases, specifically in the urban region, where modifiable risk factors remain rampant. This study aims to fill this gap. METHODS: A total of 9,149 adult Saudis ages seven to eighty years (5,357 males (58.6%) and 3,792 females (41.4%)) were randomly selected from the Riyadh Cohort Study for inclusion. Diagnosis of type 2 diabetes mellitus (DMT2) and obesity were based on the World Health Organization definitions. Diagnoses of hypertension and coronary artery disease (CAD) were based on the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and American Heart Association criteria, respectively. RESULTS: The overall crude prevalence of DMT2 was 23.1% (95% confidence interval (95% CI) 20.47 to 22.15). The age-adjusted prevalence of DMT2 was 31.6%. DMT2 prevalence was significantly higher in males, with an overall age-adjusted prevalence of 34.7% (95% CI 32.6 to 35.4), than in females, who had an overall age-adjusted prevalence of 28.6% (95% CI 26.7 to 29.3) (P < 0.001). The overall crude prevalence of obesity was 31.1% (95% CI 30.1 to 32.0). The age-adjusted prevalence of obesity was 40.0%. The prevalence of obesity was higher in females, with an overall prevalence of 36.5% (95% CI 35.1 to 37.83), than in males (25.1% (95% CI 23.7 to 26.3)) (P < 0.001). The age-adjusted prevalence of hypertension and CAD were 32.6% (95% CI 31.7 to 33.6) and 6.9% (95% CI 6.4 to 7.4), respectively. CONCLUSION: Comparisons of our findings with earlier data show that the prevalence of DMT2, hypertension and CAD in Riyadh, Saudi Arabia, has alarmingly worsened. Aggressive promotion of public awareness, continued screening and early intervention are pivotal to boosting a positive response. PMID- 21689400 TI - A cross-sectional study of Tritrichomonas foetus infection among healthy cats at shows in Norway. AB - BACKGROUND: In recent years, the protozoan Tritrichomonas foetus has been recognised as an important cause of chronic large-bowel diarrhoea in purebred cats in many countries, including Norway. The aim of this cross-sectional study was to determine the proportion of animals with T. foetus infection among clinically healthy cats in Norway and to assess different risk factors for T. foetus infection, such as age, sex, former history of gastrointestinal symptoms and concurrent infections with Giardia duodenalis and Cryptosporidium sp. METHODS: The sample population consisted of 52 cats participating in three cat shows in Norway in 2009. Samples were examined for motile T. foetus by microscopy, after culturing and for T. foetus-DNA by species-specific nested PCR, as well as for Giardia cysts and Cryptosporidium oocysts by immunofluorescent antibody test (IFAT). RESULTS: By PCR, T. foetus-DNA was demonstrated in the faeces of 11 (21%) of the 52 cats tested. DNA-sequencing of five positive samples yielded 100% identity with previous isolates of T. foetus from cats. Only one sample was positive for T. foetus by microscopy. By IFAT, four samples were positive for Giardia cysts and one for Cryptosporidium oocysts, none of which was co-infected with T. foetus. No significant associations were found between the presence of T. foetus and the various risk factors examined. CONCLUSIONS: T. foetus was found to be a common parasite in clinically healthy cats in Norway. PMID- 21689401 TI - Baseline predictors of response and discontinuation of tumor necrosis factor alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study. AB - INTRODUCTION: Identifying ankylosing spondylitis (AS) patients who are likely to benefit from tumor necrosis factor-alpha (TNF-alpha) blocking therapy is important, especially in view of the costs and potential side effects of these agents. Recently, the AS Disease Activity Score (ASDAS) has been developed to assess both subjective and objective aspects of AS disease activity. However, data about the predictive value of the ASDAS with respect to clinical response to TNF-alpha blocking therapy are lacking. The aim of the present study was to identify baseline predictors of response and discontinuation of TNF-alpha blocking therapy in AS patients in daily clinical practice. METHODS: AS outpatients who started TNF-alpha blocking therapy were included in the Groningen Leeuwarden Ankylosing Spondylitis (GLAS) study, an ongoing prospective longitudinal observational cohort study with follow-up visits according to a fixed protocol. For the present analysis, patients were excluded if they had previously received anti-TNF-alpha treatment. Predictor analyses of response and treatment discontinuation were performed using logistic and Cox regression models, respectively. RESULTS: Between November 2004 and April 2010, 220 patients started treatment with infliximab (n = 32), etanercept (n = 137), or adalimumab (n = 51). At three and six months, 68% and 63% of patients were Assessments in Ankylosing Spondylitis (ASAS)20 responders, 49% and 46% ASAS40 responders, and 49% and 50% Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)50 responders, respectively. Baseline predictors of response were younger age, male gender, higher ASDAS score, higher erythrocyte sedimentation rate (ESR) level, higher C-reactive protein (CRP) level, presence of peripheral arthritis, higher patient's global assessment of disease activity, and lower modified Schober test. In August 2010, 64% of patients were still using their TNF-alpha blocking agent with a median follow-up of 33.1 months (range 2.4 to 68.2). Baseline predictors of discontinuation of TNF-alpha blocking therapy were female gender, absence of peripheral arthritis, higher BASDAI, lower ESR level, and lower CRP level. CONCLUSIONS: Besides younger age and male gender, objective variables such as higher inflammatory markers or ASDAS score were identified as independent baseline predictors of response and/or continuation of TNF-alpha blocking therapy. In contrast, higher baseline BASDAI score was independently associated with treatment discontinuation. Based on these results, it seems clinically relevant to include more objective variables in the evaluation of anti-TNF-alpha treatment. PMID- 21689402 TI - Analysis of IL-17(+) cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. AB - INTRODUCTION: In this study, we analysed the number of IL-17(+) cells in facet joints, in the peripheral blood (PB) and synovial fluid (SF) of spondyloarthritis (SpA) patients and compared these results with those of patients with other rheumatic diseases and controls. METHODS: Immunohistochemical analysis of IL 17(+) cells was performed in facet joints of 33 ankylosing spondylitis (AS) patients and compared with data from 20 osteoarthritis (OA) patients. The frequency of IL-17(+)CD4(+) T cells in PB and SF of SpA patients (PB n = 30, SF n = 11), rheumatoid arthritis (RA) patients (PB n = 14, SF n = 7), OA patients (PB n = 10) and healthy controls (PB n = 12) was analysed after stimulation with Staphylococcus aureus Enterotoxin B and phorbol 12-myristate 13-acetate/ionomycin and quantified by flow cytometry. RESULTS: In AS facet joints, the frequency of IL-17-secreting cells was significantly higher than in samples obtained from OA patients (P < 0.001), with a slight predominance of IL-17(+) cells among the mononuclear cells (61.5% +/- 14.9%) compared to cells with polysegmental nuclei. Immunofluorescence microscopy revealed that the majority of IL-17(+) cells were myeloperoxidase-positive (35.84 +/- 13.06/high-power field (HPF) and CD15(+) neutrophils (24.25 +/- 10.36/HPF), while CD3(+) T cells (0.51 +/- 0.49/HPF) and AA-1(+) mast cells (2.28 +/- 1.96/HPF) were less often IL-17-positive. The frequency of IL-17(+)CD4(+) T cells in the PB and SF of SpA patients did not differ significantly compared to RA patients, OA patients or healthy controls. CONCLUSIONS: Our data suggest an important role for IL-17 in the inflammatory processes in AS. However, the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. PMID- 21689403 TI - Early acquisition and high nasopharyngeal co-colonisation by Streptococcus pneumoniae and three respiratory pathogens amongst Gambian new-borns and infants. AB - BACKGROUND: Although Haemophilus influenzae type b (Hib), Staphylococcus aureus and Moraxella catarrhalis are important causes of invasive and mucosal bacterial disease among children, co-carriage with Streptococcus pneumoniae during infancy has not been determined in West Africa. METHODS: Species specific PCR was applied to detect each microbe using purified genomic DNA from 498 nasopharyngeal (NP) swabs collected from 30 Gambian neonates every two weeks from 0 to 6 months and bi-monthly up to 12 months. RESULTS: All infants carried S. pneumoniae, H. influenzae and M. catarrhalis at several time points during infancy. S.pneumoniae co-colonized the infant nasopharynx with at least one other pathogen nine out of ten times. There was early colonization of the newborns and neonates, the average times to first detection were 5, 7, 3 and 14 weeks for S. pneumoniae, H. influenzae, M. catarrhalis and S. aureus respectively. The prevalence of S. pneumoniae, H. influenzae and M. catarrhalis increased among the neonates and exceeded 80% by 13, 15 and 23 weeks respectively. In contrast, the prevalence of S. aureus decreased from 50% among the newborns to 20% amongst nine-week old neonates. S. pneumoniae appeared to have a strong positive association with H. influenzae (OR 5.03; 95% CI 3.02, 8.39; p<0.01) and M. catarrhalis (OR 2.20; 95% CI 1.29; p<0.01) but it was negatively associated with S. aureus (OR 0.53; 95% CI 0.30, 0.94; p=0.03). CONCLUSION: This study shows early acquisition and high co carriage of three important respiratory pathogens with S. pneumoniae in the nasopharyngeal mucosa among Gambian neonates and infants. This has important potential implications for the aetiology of respiratory polymicrobial infections, biofilm formation and vaccine strategies. PMID- 21689404 TI - A stabilized HIV-1 envelope glycoprotein trimer fused to CD40 ligand targets and activates dendritic cells. AB - BACKGROUND: One reason why subunit protein and DNA vaccines are often less immunogenic than live-attenuated and whole-inactivated virus vaccines is that they lack the co-stimulatory signals provided by various components of the more complex vaccines. The HIV-1 envelope glycoprotein complex (Env) is no exception to this rule. Other factors that limit the induction of neutralizing antibodies against HIV-1 lie in the structure and instability of Env. We have previously stabilized soluble trimeric mimics of Env by introducing a disulfide bond between gp120 and gp41 and adding a trimer stabilizing mutation in gp41 (SOSIP.R6 gp140). RESULTS: We further stabilized the SOSIP.R6 gp140 using a GCN4-based isoleucine zipper motif, creating SOSIP.R6-IZ gp140. In order to target SOSIP.R6-IZ to immune cells, including dendritic cells, while at the same time activating these cells, we fused SOSIP.R6-IZ to the active domain of CD40 ligand (CD40L), which may serve as a 'cis-adjuvant'. The Env component of the SOSIP.R6-IZ-CD40L fusion construct bound to CD4 and neutralizing antibodies, while the CD40L moiety interacted with CD40. Furthermore, the chimeric molecule was able to signal efficiently through CD40 and induce maturation of human dendritic cells. Dendritic cells secreted IL-6, IL-10 and IL-12 in response to stimulation by SOSIP.R6-IZ-CD40L and were able to activate naive T cells. CONCLUSIONS: Chimeric HIV-1 gp140 - CD40L trimers can target and activate dendritic cells. Targeting and activating immune cells using CD40L and other 'cis-adjuvants' may improve subunit protein vaccine immunogenicity for HIV-1 and other infectious diseases. PMID- 21689405 TI - Comparison of three malignancy risk indices and CA-125 in the preoperative evaluation of patients with pelvic masses. AB - BACKGROUND: Patients with pelvic mass are the most referred patients to gynecologist. The aim of this study was to evaluate the ability of three malignancy risk indices (RMI 1, RMI 2 and RMI 3) and CA-125 to discriminate a benign from a malignant pelvic mass in our region (North of Iran). METHODS: This retrospective study was performed on 182 women with pelvic masses referred to Yahyanejad Hospital from 2007 to 2009. Ultrasound scans were scored as one point for each of the following characteristics: multilocular cyst, solid areas, intra abdominal metastases, ascites, and bilateral lesions. For each patient a total ultrasound score (U) was calculated. The difference of the three RMI was based on the allocation of the U and M scores. The sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) of level of serum CA 125, the RMI 1, 2 and 3 were compared. RESULTS: Mean age of the patients was 39.9 +/- 9.3 years. Most of them were premenopausal (161 women or 88.4%). A significant linear trend for malignancy was found by increasing age, ultrasound score, and serum CA-125. The best performance of CA125 was at a cut-off 88 U/ml, with a sensitivity of 88%, a specificity of 97%, a positive predictive value of 84%, and a negative predictive value of 99%. RMI 1 and 3 at the optimal cut off point of 265 and RMI2 at the optimal cut off point of 355, had a sensitivity of 91%, specificity of 96%, a positive predictive value of 78%, and a negative predictive value of 99%. CONCLUSION: In our population we found that there is no statistically significant difference in the performance of three malignancy risk indices (RMI 1, RMI 2, and RMI 3) and CA125 in differentiating between benign and malignant pelvic masses. PMID- 21689406 TI - Health Alliance for prudent antibiotic prescribing in patients with respiratory tract infections (HAPPY AUDIT) -impact of a non-randomised multifaceted intervention programme. AB - BACKGROUND: Excessive use of antibiotics is worldwide the most important reason for development of antimicrobial resistance. As antibiotic resistance may spread across borders, high prevalence countries may serve as a source of bacterial resistance for countries with a low prevalence. Therefore, bacterial resistance is an important issue with a potential serious impact on all countries. Initiatives have been taken to improve the quality of antibiotic prescribing in primary care, but only few studies have been designed to determine the effectiveness of multifaceted strategies across countries with different practice setting. The aim of this study was to evaluate the impact of a multifaceted intervention targeting general practitioners (GPs) and patients in six countries with different health organization and different prevalence of antibiotic resistance. METHODS: GPs from two Nordic countries, two Baltic Countries and two Hispano-American countries registered patients with respiratory tract infections (RTIs) in 2008 and 2009. After first registration they received individual prescriber feedback and they were offered an intervention programme that included training courses, clinical guidelines, posters for waiting rooms, patient brochures and access to point of care tests (Strep A and C-Reactive Protein). Antibiotic prescribing rates were compared before and after the intervention. RESULTS: A total of 440 GPs registered 47011 consultations; 24436 before the intervention (2008) and 22575 after the intervention (2009). After the intervention, the GPs significantly reduced the percentage of consultations resulting in an antibiotic prescription. In patients with lower RTI the GPs in Lithuania reduced the prescribing rate by 42%, in Russia by 25%, in Spain by 25%, and in Argentina by 9%. In patients with upper RTIs, the corresponding reductions in the antibiotic prescribing rates were in Lithania 20%, in Russia 15%, in Spain 9%, and in Argentina 5%. CONCLUSION: A multifaceted intervention programme targeting GPs and patients and focusing on improving diagnostic procedures in patients with RTIs may lead to a marked reduction in antibiotic prescribing. The pragmatic before-after design used may suffer from some limitations and the reduction in antibiotic prescribing could be influenced by factors not related to the intervention. PMID- 21689407 TI - Specific microtubule-depolymerizing agents augment efficacy of dendritic cell based cancer vaccines. AB - BACKGROUND: Damage-associated molecular patterns (DAMPs) are associated with immunogenic cell death and have the ability to enhance maturation and antigen presentation of dendritic cells (DCs). Specific microtubule-depolymerizing agents (MDAs) such as colchicine have been shown to confer anti-cancer activity and also trigger activation of DCs. METHODS: In this study, we evaluated the ability of three MDAs (colchicine and two 2-phenyl-4-quinolone analogues) to induce immunogenic cell death in test tumor cells, activate DCs, and augment T-cell proliferation activity. These MDAs were further evaluated for use as an adjuvant in a tumor cell lysate-pulsed DC vaccine. RESULTS: The three test phytochemicals considerably increased the expression of DAMPs including HSP70, HSP90 and HMGB1, but had no effect on expression of calreticulin (CRT). DC vaccines pulsed with MDA-treated tumor cell lysates had a significant effect on tumor growth, showed cytotoxic T-lymphocyte activity against tumors, and increased the survival rate of test mice. In vivo antibody depletion experiments suggested that CD8+ and NK cells, but not CD4+ cells, were the main effector cells responsible for the observed anti-tumor activity. In addition, culture of DCs with GM-CSF and IL-4 during the pulsing and stimulation period significantly increased the production of IL-12 and decreased production of IL-10. MDAs also induced phenotypic maturation of DCs and augmented CD4+ and CD8+ T-cell proliferation when co cultured with DCs. CONCLUSIONS: Specific MDAs including the clinical drug, colchicine, can induce immunogenic cell death in tumor cells, and DCs pulsed with MDA-treated tumor cell lysates (TCLs) can generate potent anti-tumor immunity in mice. This approach may warrant future clinical evaluation as a cancer vaccine. PMID- 21689408 TI - Combined treatment with dexamethasone and raloxifene totally abrogates osteoporosis and joint destruction in experimental postmenopausal arthritis. AB - INTRODUCTION: Postmenopausal patients with rheumatoid arthritis (RA) are often treated with corticosteroids. Loss of estrogen, the inflammatory disease and exposure to corticosteroids all contribute to the development of osteoporosis. Therefore, our aim was to investigate if addition of the selective estrogen receptor modulator raloxifene, or estradiol, could prevent loss of bone mineral density in ovariectomized and dexamethasone treated mice with collagen-induced arthritis (CIA). METHODS: Female DBA/1-mice were ovariectomized or sham-operated, and CIA was induced. Treatment with dexamethasone (Dex) (125 MUg/d), estradiol (E2) (1 MUg/d) or raloxifene (Ral) (120 MUg/day) alone, or the combination of Dex + E2 or Dex + Ral, was started after disease onset, and continued until termination of the experiments. Arthritic paws were collected for histology and one of the femoral bones was used for measurement of bone mineral density. RESULTS: Dex-treatment alone protected against arthritis and joint destruction, but had no effect on osteoporosis in CIA. However, additional treatment with either Ral or E2 resulted in completely preserved bone mineral density. CONCLUSIONS: Addition of raloxifene or estradiol to dexamethasone-treatment in experimental postmenopausal polyarthritis prevents generalized bone loss. PMID- 21689409 TI - Cognitive development in patients with Mucopolysaccharidosis type III (Sanfilippo syndrome). AB - BACKGROUND: Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder caused by a deficiency of one of the enzymes involved in the degradation of heparan sulfate. MPS III is characterized by progressive mental deterioration resulting in severe dementia. A number of potentially disease-modifying therapies are studied. As preservation of cognitive function is the ultimate goal of treatment, assessment of cognitive development will be essential in order to evaluate treatment efficacy. However, no large scale studies on cognitive levels in MPS III patients, using formal psychometric tests, have been reported. METHODS: We aimed to assess cognitive development in all 73 living patients with MPS III in the Netherlands. RESULTS: Cognitive development could be assessed in 69 patients. In 39 of them developmental level was estimated > 3 months and formal psychometric testing was attempted. A remarkable variation in the intellectual disability was detected. CONCLUSIONS: Despite special challenges encountered, testing failed in only three patients. The observed broad variation in intellectual disability, should be taken into account when designing therapeutic trials. PMID- 21689410 TI - The Arabidopsis translocator protein (AtTSPO) is regulated at multiple levels in response to salt stress and perturbations in tetrapyrrole metabolism. AB - BACKGROUND: The translocator protein 18 kDa (TSPO), previously known as the peripheral-type benzodiazepine receptor (PBR), is important for many cellular functions in mammals and bacteria, such as steroid biosynthesis, cellular respiration, cell proliferation, apoptosis, immunomodulation, transport of porphyrins and anions. Arabidopsis thaliana contains a single TSPO/PBR-related gene with a 40 amino acid N-terminal extension compared to its homologs in bacteria or mammals suggesting it might be chloroplast or mitochondrial localized. RESULTS: To test if the TSPO N-terminal extension targets it to organelles, we fused three potential translational start sites in the TSPO cDNA to the N-terminus of GFP (AtTSPO:eGFP). The location of the AtTSPO:eGFP fusion protein was found to depend on the translational start position and the conditions under which plants were grown. Full-length AtTSPO:eGFP fusion protein was found in the endoplasmic reticulum and in vesicles of unknown identity when plants were grown in standard conditions. However, full length AtTSPO:eGFP localized to chloroplasts when grown in the presence of 150 mM NaCl, conditions of salt stress. In contrast, when AtTSPO:eGFP was truncated to the second or third start codon at amino acid position 21 or 42, the fusion protein co localized with a mitochondrial marker in standard conditions. Using promoter GUS fusions, qRT-PCR, fluorescent protein tagging, and chloroplast fractionation approaches, we demonstrate that AtTSPO levels are regulated at the transcriptional, post-transcriptional and post-translational levels in response to abiotic stress conditions. Salt-responsive genes are increased in a tspo-1 knock-down mutant compared to wild type under conditions of salt stress, while they are decreased when AtTSPO is overexpressed. Mutations in tetrapyrrole biosynthesis genes and the application of chlorophyll or carotenoid biosynthesis inhibitors also affect AtTSPO expression. CONCLUSION: Our data suggest that AtTSPO plays a role in the response of Arabidopsis to high salt stress. Salt stress leads to re-localization of the AtTSPO from the ER to chloroplasts through its N-terminal extension. In addition, our results show that AtTSPO is regulated at the transcriptional level in tetrapyrrole biosynthetic mutants. Thus, we propose that AtTSPO may play a role in transporting tetrapyrrole intermediates during salt stress and other conditions in which tetrapyrrole metabolism is compromised. PMID- 21689411 TI - Analyzing the impact of 23 mg/day donepezil on language dysfunction in moderate to severe Alzheimer's disease. AB - INTRODUCTION: Progressive language impairment is among the primary components of cognitive decline in Alzheimer's disease (AD). Because expressive and receptive language help to maintain emotional connections to caregivers and support the management of AD patients' functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function. METHODS: In the original randomized, double-blind clinical trial, 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20) were randomized 2:1 to receive donepezil 23 mg/day or to continue on donepezil 10 mg/day for 24 weeks. In this post hoc analysis, the Severe Impairment Battery-Language scale (SIB-L) and a new 21-item SIB-derived language scale (SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician's Interview-Based Impression of Severity-plus caregiver input/Clinician's Interview-Based Impression of Change plus caregiver input (CIBIS-plus/CIBIC-plus) and the MMSE were also investigated. RESULTS: At week 24, treatment with donepezil 23 mg/day was associated with an improvement in language in the full intention-to-treat population, whereas language function declined in the group treated with donepezil 10 mg/day (SIB-L treatment difference 0.8, P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE score 0 to 16). At baseline and week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but the correlations were stronger between the language scales and the MMSE scores. CONCLUSIONS: Patients with moderate to severe AD receiving donepezil 23 mg/day showed greater language benefits than those receiving donepezil 10 mg/day as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/day may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical.ClinicalTrials.gov identifier: NCT00478205. PMID- 21689412 TI - Optimizing diffusion of an online computer tailored lifestyle program: a study protocol. AB - BACKGROUND: Although the Internet is a promising medium to offer lifestyle interventions to large amounts of people at relatively low costs and effort, actual exposure rates of these interventions fail to meet the high expectations. Since public health impact of interventions is determined by intervention efficacy and level of exposure to the intervention, it is imperative to put effort in optimal dissemination. The present project attempts to optimize the dissemination process of a new online computer tailored generic lifestyle program by carefully studying the adoption process and developing a strategy to achieve sustained use of the program. METHODS/DESIGN: A prospective study will be conducted to yield relevant information concerning the adoption process by studying the level of adoption of the program, determinants involved in adoption and characteristics of adopters and non-adopters as well as satisfied and unsatisfied users. Furthermore, a randomized control trial will be conducted to the test the effectiveness of a proactive strategy using periodic e-mail prompts in optimizing sustained use of the new program. DISCUSSION: Closely mapping the adoption process will gain insight in characteristics of adopters and non adopters and satisfied and unsatisfied users. This insight can be used to further optimize the program by making it more suitable for a wider range of users, or to develop adjusted interventions to attract subgroups of users that are not reached or satisfied with the initial intervention. Furthermore, by studying the effect of a proactive strategy using period prompts compared to a reactive strategy to stimulate sustained use of the intervention and, possibly, behaviour change, specific recommendations on the use and the application of prompts in online lifestyle interventions can be developed. TRIAL REGISTRATION: Dutch Trial Register NTR1786 and Medical Ethics Committee of Maastricht University and the University Hospital Maastricht (NL2723506809/MEC0903016). PMID- 21689413 TI - Sniper: improved SNP discovery by multiply mapping deep sequenced reads. AB - SNP (single nucleotide polymorphism) discovery using next-generation sequencing data remains difficult primarily because of redundant genomic regions, such as interspersed repetitive elements and paralogous genes, present in all eukaryotic genomes. To address this problem, we developed Sniper, a novel multi-locus Bayesian probabilistic model and a computationally efficient algorithm that explicitly incorporates sequence reads that map to multiple genomic loci. Our model fully accounts for sequencing error, template bias, and multi-locus SNP combinations, maintaining high sensitivity and specificity under a broad range of conditions. An implementation of Sniper is freely available at http://kim.bio.upenn.edu/software/sniper.shtml. PMID- 21689414 TI - Genetic differentiation between cave and surface-dwelling populations of Garra barreimiae (Cyprinidae) in Oman. AB - BACKGROUND: Phenotypic similarities among cave-dwelling animals displaying troglomorphic characters (e.g. reduced eyes and lack of pigmentation) have induced a long-term discussion about the forces driving convergent evolution. Here we introduce Garra barreimiae Fowler & Steinitz, 1956, as an interesting system to study the evolution of troglomorphic characters. The only hitherto known troglomorphic population of this species lives in Al Hoota Cave (Sultanate of Oman) close to a surface population. As a first approach, we assessed the genetic differentiation between the two morphotypes of G. barreimiae to determine whether gene flow still occurs. RESULTS: We analysed the mitochondrial control region (CR). In G. barreimiae the CR starts immediately downstream of the tRNA Thr gene, while the tRNA-Pro gene is missing at this genomic location. Interestingly, a putative tRNA-Pro sequence is found within the CR. The phylogenetic analyses of the CR sequences yielded a tree divided into three clades: Clade 1 has a high genetic distance to the other clades and contains the individuals of three populations which are separated by a watershed from all the others. Clade 2 comprises the individuals from Wadi Bani Khalid, the geographically most remote population. Clade 3 comprises all other populations investigated including that of Al Hoota Cave. The latter forms a haplogroup which also includes individuals from the adjacent surface population. CONCLUSIONS: Our data indicates that the troglomorphic cave population is of quite recent origin supporting the hypothesis that selection drives the fast evolution of troglomorphic traits. In this context pleiotropic effects might play an important role as it has been shown for Astyanax. There seems to be some gene flow from the cave population into the adjacent surface populations. One blind individual, found at a surface locality geographically distinct from Al Hoota Cave, is genetically differentiated from the other blind specimens indicating the probable existence of another cave population of G. barreimiae. The phylogeographic analyses show that while some of the surface populations are either still in contact or have been until recently, the population Wadi Bani Khalid is genetically separated. One group consisting of three populations is genetically highly differentiated questioning the conspecifity with G. barreimiae. PMID- 21689415 TI - Cross-sectional evaluation of the periapical status as related to quality of root canal fillings and coronal restorations in a rural adult male population of Turkey. AB - BACKGROUND: To determine the prevalence of periapical lesions in root canal treated teeth in a rural, male adult, Turkish population and to investigate the influence of the quality of root canal fillings on prevalence of periapical lesions. METHODS: The sample for this cross-sectional study consisted of 552 adult male patients, 18-32 years of age, presenting consecutively as new patients seeking routine dental care at the Dental Sciences of Gulhane Military Medicine, Ankara. The radiographs of the 1014 root canal-treated teeth were evaluated. The teeth were grouped according to the radiographic quality of the root canal filling and the coronal restoration. The criteria used for the examination were slightly modified from those described by De Moor. Periapical status was assessed by the Periapical Index scores (PAI) proposed by Orstavik. RESULTS: The overall success rate of root canal treatment was 32.1%. The success rates of adequately root canal treatment were significantly higher than inadequately root canal treatment, regardless of the quality or presence of the coronal restoration (P < .001). In addition, the success rate of inadequate root canal treatment was also significantly affected by the quality of coronal restorations. CONCLUSIONS: Our results revealed a high prevalence of periapical lesions in root canal treatment, which is comparable to that reported in other methodologically compatible studies from diverse geographical locations. In addition, the results from the present study confirm the findings of other studies that found the quality of the root canal treatment to be a key factor for prognosis with or without adequate coronal restoration. PMID- 21689416 TI - Virological and clinical characteristics of hepatitis delta virus in South Asia. AB - BACKGROUND & AIMS: There is a paucity of data on the impact of hepatitis D virus (HDV) in patients with hepatitis B virus (HBV) infection from South Asia. We studied the impact of HDV co-infection on virological and clinical characteristics. METHODS: We collected data of 480 patients with HBsAg positive and a detectable HBV DNA PCR, who presented to the Aga Khan University, Karachi and Isra University in Hyderabad, Pakistan in the last 5 years. HDV co-infection was diagnosed on the basis of anti-HDV. ALT, HBeAg, HBeAb and HBV DNA PCR quantitative levels were checked in all patients. We divided all patients into two groups based on anti-HDV, and compared their biochemical, serological & virological labs and clinical spectrum. Clinical spectrum of disease included asymptomatic carrier (AC), chronic active hepatitis (CAH), immuno-tolerant phase (IP), and compensated cirrhosis (CC). RESULTS: HDV co-infection was found in 169 (35.2%). There were 164 (34.6%) HBeAg positive and 316 (65.4%) HBeAg negative patients. Mean ALT level was 66 +/- 73 IU. 233 (48.5%) had raised ALT. HBV DNA level was >= 10e5 in 103(21.5%) patients. Overall, among HBV/HDV co-infection, 146/169 (86.4%) had suppressed HBV DNA PCR as compared to 231/311 (74.3%) patients with HBV mono-infection; p-value = 0.002. Among HBeAg negative patients 71/128(55.5%) had raised ALT levels among HBV/HDV co-infection as compared to 71/188 (37.8%) with HBV mono-infection (p-value = 0.002); levels of HBV DNA were equal in two groups; there were 27/128 (21%) patients with CC among HBV/HDV co infection as compared to 23 (12%) in HBV mono-infection (p-value = 0.009); there were less AC (p-value = 0.009) and more CAH (p-value = 0.009) among HBV/HDV co infection patients. Among HBeAg positive patients, serum ALT, HBV DNA levels and the spectrum of HBV were similar in the two groups. CONCLUSIONS: HBV/HDV co infection results in the suppression of HBV DNA. A fair proportion of HBV/HDV co infected patients with HBeAg negative have active hepatitis B infection and cirrhosis as compared to those with mono-infection. PMID- 21689418 TI - Highly active engineered-enzyme oriented monolayers: formation, characterization and sensing applications. AB - BACKGROUND: The interest in introducing ecologically-clean, and efficient enzymes into modern industry has been growing steadily. However, difficulties associated with controlling their orientation, and maintaining their selectivity and reactivity is still a significant obstacle. We have developed precise immobilization of biomolecules, while retaining their native functionality, and report a new, fast, easy, and reliable procedure of protein immobilization, with the use of Adenylate kinase as a model system. METHODS: Self-assembled monolayers of hexane-1,6-dithiol were formed on gold surfaces. The monolayers were characterized by contact-angle measurements, Elman-reagent reaction, QCM, and XPS. A specifically designed, mutated Adenylate kinase, where cysteine was inserted at the 75 residue, and the cysteine at residue 77 was replaced by serine, was used for attachment to the SAM surface via spontaneously formed disulfide (S-S) bonds. QCM, and XPS were used for characterization of the immobilized protein layer. Curve fitting in XPS measurements used a Gaussian Lorentzian function. RESULTS AND DISCUSSION: Water contact angle (65-70 degrees ), as well as all characterization techniques used, confirmed the formation of self-assembled monolayer with surface SH groups. X-ray photoelectron spectroscopy showed clearly the two types of sulfur atom, one attached to the gold (triolate) and the other (SH/S-S) at the omega-position for the hexane-1,6-dithiol SAMs. The formation of a protein monolayer was confirmed using XPS, and QCM, where the QCM determined amount of protein on the surface was in agreement with a model that considered the surface area of a single protein molecule. Enzymatic activity tests of the immobilized protein confirmed that there is no change in enzymatic functionality, and reveal activity ~100 times that expected for the same amount of protein in solution. CONCLUSIONS: To the best of our knowledge, immobilization of a protein by the method presented here, with the resulting high enzymatic activity, has never been reported. There are many potential applications for selective localization of active proteins at patterned surfaces, for example, bioMEMS (MEMS--Micro-Electro-Mechanical Systems. Due to the success of the method, presented here, it was decided to continue a research project of a biosensor by transferring it to a high aspect ratio platform--nanotubes. PMID- 21689417 TI - Stat3 and CCAAT/enhancer binding protein beta (C/EBP-beta) regulate Jab1/CSN5 expression in mammary carcinoma cells. AB - INTRODUCTION: The c-Jun coactivator, Jun activation-domain binding protein 1 (Jab1) also known as the fifth component of the COP9 signalosome complex (CSN5), is a novel candidate oncogene whose aberrant expression contributes to the progression of breast carcinoma and other human cancers. The mechanism of Jab1 gene expression and its deregulation in cancer cells remains to be identified. We therefore investigated the transcriptional regulatory mechanisms of Jab1 expression in human breast carcinoma cells. METHODS: To identify potential regulators of Jab1 transcription, we cloned the 5' upstream region of the human Jab1 gene and mapped its transcriptional start site. We identified binding sequences for the CCAAT/enhancer binding protein (C/EBP) and GATA, as well as a signal transducer and activator of transcription-3 (Stat3) consensus sequence overlapping the C/EBP site, using 5'- deletion analysis and a gene reporter assay. Mutational analysis of these binding sites was performed to confirm their roles in promoting Jab1 transcription in breast cancer cells. We further confirmed these binding sites using electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) assays. We also analyzed whether the siRNA-mediated inactivation of Stat3 and Src could reduce Jab1-promoter activity and whether interleukine-6 (IL-6) could mediate increased Jab1 expression through Stat3 signaling. RESULTS: We identified binding sequences for C/EBP, GATA, as well as a Stat3 consensus sequence overlapping the C/EBP site in the promoter region of Jab1. C/EBP-beta2 is a potential transcriptional activator of Jab1 and mutation of the C/EBP/Stat3 binding site significantly reduced Jab1-promoter activity. In addition, inhibiting Stat3 significantly reduced Jab1-promoter activation. EMSA and ChIP assays confirmed that C/EBP, GATA1 and Stat3 bind to Jab1 promoter in breast carcinoma cells. We also found that Src, an activator of Stat3, is involved in Jab1-promoter activation. siRNA knockdown of Src reduced the Jab1-promoter activity, similar to the results seen when Stat3 was inhibited in breast carcinoma cells. Interestingly, reactivation of Stat3 in normal mammary epithelial cells (MCF-10A, MCF-10F) is sufficient to reactivate Jab1 expression. Treatment with the cytokine IL-6 resulted in increased Jab1 expression that was blocked by inhibition of Stat3. CONCLUSIONS: These findings reveal a novel mechanism of Jab1 gene regulation and provide functional and mechanistic links between the Src/Stat3 and IL-6/Stat3 signaling axes that are involved in the activation of Jab1 transcription and regulation of this novel oncogenic protein. PMID- 21689419 TI - Functional assays to determine the significance of two common XPC 3'UTR variants found in bladder cancer patients. AB - BACKGROUND: XPC is involved in the nucleotide excision repair of DNA damaged by carcinogens known to cause bladder cancer. Individuals homozygous for the variant allele of XPC c.1496C > T (p.Ala499Val) were shown in a large pooled analysis to have an increased bladder cancer risk, and we found two 3'UTR variants, *611T > A and c.*618A > G, to be in strong linkage disequilibrium with c.1496T. Here we determined if these two 3'UTR variants can affect mRNA stability and assessed the impact of all three variants on mRNA and protein expression. METHODS: In vitro mRNA stability assays were performed and mRNA and protein expression measured both in plasmid-based assays and in lymphocytes and lymphoblastoid cell lines from bladder and breast cancer patients. RESULTS: The two 3'UTR variants were associated with reduced protein and mRNA expression in plasmid-based assays, suggesting an effect on mRNA stability and/or transcription/translation. A near significant reduction in XPC protein expression (p = 0.058) was detected in lymphoblastoid cell lines homozygous for these alleles but no differences in mRNA stability in these lines was found or in mRNA or protein levels in lymphocytes heterozygous for these alleles. CONCLUSION: The two 3'UTR variants may be the variants underlying the association of c.1496C > T and bladder cancer risk acting via a mechanism modulating protein expression. PMID- 21689420 TI - Detection of North American orthopoxviruses by real time-PCR. AB - The prevalence of North American orthopoxviruses in nature is unknown and may be more difficult to ascertain due to wide spread use of vaccinia virus recombinant vaccines in the wild. A real time PCR assay was developed to allow for highly sensitive and specific detection of North American orthopoxvirus DNA in animal tissues and bodily fluids. This method is based on the amplification of a 156 bp sequence within a myristylated protein, highly conserved within the North American orthopoxviruses but distinct from orthologous genes present in other orthopoxviruses. The analytical sensitivity was 1.1 fg for Volepox virus DNA, 1.99 fg for Skunkpox virus DNA, and 6.4 fg for Raccoonpox virus DNA with a 95% confidence interval. Our assay did not cross-react with other orthopoxviruses or ten diverse representatives of the Chordopoxvirinae subfamily. This new assay showed more sensitivity than tissue culture tests, and was capable of differentiating North American orthopoxviruses from other members of Orthopoxvirus. Thus, our assay is a promising tool for highly sensitive and specific detection of North American orthopoxviruses in the United States and abroad. PMID- 21689421 TI - Effects of diet type and supplementation of glucosamine, chondroitin, and MSM on body composition, functional status, and markers of health in women with knee osteoarthritis initiating a resistance-based exercise and weight loss program. AB - BACKGROUND: The purpose of this study was to determine whether sedentary obese women with knee OA initiating an exercise and weight loss program may experience more beneficial changes in body composition, functional capacity, and/or markers of health following a higher protein diet compared to a higher carbohydrate diet with or without GCM supplementation. METHODS: Thirty sedentary women (54 +/- 9 yrs, 163 +/- 6 cm, 88.6 +/- 13 kg, 46.1 +/- 3% fat, 33.3 +/- 5 kg/m2) with clinically diagnosed knee OA participated in a 14-week exercise and weight loss program. Participants followed an isoenergenic low fat higher carbohydrate (HC) or higher protein (HP) diet while participating in a supervised 30-minute circuit resistance-training program three times per week for 14-weeks. In a randomized and double blind manner, participants ingested supplements containing 1,500 mg/d of glucosamine (as d-glucosamine HCL), 1,200 mg/d of chondroitin sulfate (from chondroitin sulfate sodium), and 900 mg/d of methylsulfonylmethane or a placebo. At 0, 10, and 14-weeks, participants completed a battery of assessments. Data were analyzed by MANOVA with repeated measures. RESULTS: Participants in both groups experienced significant reductions in body mass (-2.4 +/- 3%), fat mass ( 6.0 +/- 6%), and body fat (-3.5 +/- 4%) with no significant changes in fat free mass or resting energy expenditure. Perception of knee pain (-49 +/- 39%) and knee stiffness (-42 +/- 37%) was decreased while maximal strength (12%), muscular endurance (20%), balance indices (7% to 20%), lipid levels (-8% to -12%), homeostasis model assessment for estimating insulin resistance (-17%), leptin ( 30%), and measures of physical functioning (59%), vitality (120%), and social function (66%) were improved in both groups with no differences among groups. Functional aerobic capacity was increased to a greater degree for those in the HP and GCM groups while there were some trends suggesting that supplementation affected perceptions of knee pain (p < 0.08). CONCLUSIONS: Circuit style resistance-training and weight loss improved functional capacity in women with knee OA. The type of diet and dietary supplementation of GCM provided marginal additive benefits. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01271218. PMID- 21689422 TI - Assessment of ERBB2 and EGFR gene amplification and protein expression in gastric carcinoma by immunohistochemistry and fluorescence in situ hybridization. AB - BACKGROUND: The goal of this study was to investigate ERBB2(HER2) and EGFR gene amplification and protein expression in gastric cancer. Fluorescence in situ hybridization (FISH) and immunohistochemistry were used to analyze ERBB2 and EGFR gene amplification and protein expression in 69 cases of gastric cancer. RESULTS: FISH analysis revealed that 20.3% of the cases exhibited ERBB2 gene amplification. Increases in ERBB2 copy number and gene amplification were present in 52.2% of the samples. Expression of the ERBB2 protein was observed in 42.0% of cases. FISH analysis detected EGFR gene amplification in 29.0% of samples. Increases in EGFR copy number and gene amplification occurred in 57.9% of samples, and EGFR protein expression was present in 52.2% of samples. Both ERBB2 and EGFR gene amplification were 3 cases (4.3%), but abnormalities in both ERBB2 and EGFR gene copy number were present 36.2% of samples. ERBB2 and EGFR gene amplification were significantly associated with the depth of tumor invasion (P < 0.05) and lymph node metastasis (P < 0.05), but not with sex, age, or histological type (P > 0.05). CONCLUSIONS: Our data indicated that ERBB2 and EGFR genetic abnormalities were associated with the prognosis of gastric cancer. Clinical assessment of ERBB2 and EGFR amplification may represent an important factor for the development of personalized treatment programs for gastic cancer. PMID- 21689423 TI - Dietary red palm oil supplementation decreases infarct size in cholesterol fed rats. AB - BACKGROUND AND AIMS: The effect of red palm oil (RPO) supplementation on infarct size after ischaemia/reperfusion in a cholesterol enriched diet-induced hyperlipidemic animal model has not been reported. Previous studies reported results on the effect of RPO in a normal diet, whilst evidence of protection has been linked to improved functional recovery, prosurvival kinase, anti-apoptosis and NO-cGMP. Therefore, we aimed to investigate the effects of dietary RPO supplementation in a cholesterol-enriched diet-induced hyperlipidemic rat model and to investigate the involvement of matrix metalloproteinase 2 (MMP2) inhibition as a possible mechanism of protection. MATERIALS AND METHODS: Male Wistar rats were fed either a standard rat chow diet (Norm) or a 2% cholesterol enriched diet (Chol) for nine weeks. Additionally, two more groups received the same treatment, however, at the week 4, diet was supplemented with RPO for the last five weeks (Norm+RPO and Chol+RPO), respectively. After the feeding period hearts were isolated, perfused according to Langendorff and subjected to 30 minutes of normothermic global ischaemia followed by two hours of reperfusion. Infarct size was measured by 2,3,5-triphenyltetrazolium chloride staining at the end of reperfusion. RESULTS: Cholesterol-enriched diet increased myocardial infarct size from 23.5+/-3.0% to 37.2+/-3.6% (p<0.05) when compared to normal diet. RPO supplementation significantly reduced infarct size either in Norm+RPO or in Chol+RPO (to 9.2+/-1.0% and 26.9+/-3.0%), respectively. Infarct size in Chol+RPO was comparable to the Norm group. MMP2 activity before ischaemia was significantly reduced in the Chol+RPO group when compared to the Chol group. However, the MMP2 activity of the hearts of the RPO fed rats was significantly increased when compared to the normal diet group after ischaemia. CONCLUSIONS: For the first time it was shown that dietary RPO supplementation attenuated the increased susceptibility of the hearts in cholesterol fed rats to ischaemia/reperfusion injury. This was shown by reduced infarct size. For the first time we also show that red palm oil supplementation altered pre-ischaemic levels of MMP-2, which may indicate that myocardial MMP2 may be implicated as a possible role player in RPO mediated protection against ischaemia/reperfusion injury in hearts of cholesterol supplemented rats. PMID- 21689424 TI - Short term Candida albicans colonization reduces Pseudomonas aeruginosa-related lung injury and bacterial burden in a murine model. AB - INTRODUCTION: Pseudomonas aeruginosa is a frequent cause of ventilator-acquired pneumonia (VAP). Candida tracheobronchial colonization is associated with higher rates of VAP related to P. aeruginosa. This study was designed to investigate whether prior short term Candida albicans airway colonization modulates the pathogenicity of P. aeruginosa in a murine model of pneumonia and to evaluate the effect of fungicidal drug caspofungin. METHODS: BALB/c mice received a single or a combined intratracheal administration of C. albicans (1 * 10(5) CFU/mouse) and P. aeruginosa (1 * 10(7) CFU/mouse) at time 0 (T0) upon C. albicans colonization, and Day 2. To evaluate the effect of antifungal therapy, mice received caspofungin intraperitoneally daily, either from T0 or from Day 1 post colonization. After sacrifice at Day 4, lungs were analyzed for histological scoring, measurement of endothelial injury, and quantification of live P. aeruginosa and C. albicans. Blood samples were cultured for dissemination. RESULTS: A significant decrease in lung endothelial permeability, the amount of P. aeruginosa, and bronchiole inflammation was observed in case of prior C. albicans colonization. Mortality rate and bacterial dissemination were unchanged by prior C. albicans colonization. Caspofungin treatment from T0 (not from Day 1) increased their levels of endothelial permeability and lung P. aeruginosa load similarly to mice receiving P. aeruginosa alone. CONCLUSIONS: P. aeruginosa induced lung injury is reduced when preceded by short term C. albicans airway colonization. Antifungal drug caspofungin reverses that effect when used from T0 and not from Day 1. PMID- 21689425 TI - Retrospective study of the effect of disease progression on patient reported outcomes in HER-2 negative metastatic breast cancer patients. AB - BACKGROUND: This retrospective study evaluated the impact of disease progression and of specific sites of metastasis on patient reported outcomes (PROs) that assess symptom burden and health related quality of life (HRQoL) in women with metastatic breast cancer (mBC). METHODS: HER-2 negative mBC patients (n = 102) were enrolled from 7 U.S. community oncology practices. Demographic, disease and treatment characteristics were abstracted from electronic medical records and linked to archived Patient Care Monitor (PCM) assessments. The PCM is a self report measure of symptom burden and HRQoL administered as part of routine care in participating practices. Linear mixed models were used to examine change in PCM scores over time. RESULTS: Mean age was 57 years, with 72% of patients Caucasian, and 25% African American. Median time from mBC diagnosis to first disease progression was 8.8 months. Metastasis to bone (60%), lung (28%) and liver (26%) predominated at initial metastatic diagnosis. Results showed that PCM items assessing fatigue, physical pain and trouble sleeping were sensitive to either general effects of disease progression or to effects associated with specific sites of metastasis. Progression of disease was also associated with modest but significant worsening of General Physical Symptoms, Treatment Side Effects, Acute Distress and Impaired Performance index scores. In addition, there were marked detrimental effects of liver metastasis on Treatment Side Effects, and of brain metastasis on Acute Distress. CONCLUSIONS: Disease progression has a detrimental impact on cancer-related symptoms. Delaying disease progression may have a positive impact on patients' HRQoL. PMID- 21689427 TI - Interactomes, manufacturomes and relational biology: analogies between systems biology and manufacturing systems. AB - BACKGROUND: We review and extend the work of Rosen and Casti who discuss category theory with regards to systems biology and manufacturing systems, respectively. RESULTS: We describe anticipatory systems, or long-range feed-forward chemical reaction chains, and compare them to open-loop manufacturing processes. We then close the loop by discussing metabolism-repair systems and describe the rationality of the self-referential equation f = f (f). This relationship is derived from some boundary conditions that, in molecular systems biology, can be stated as the cardinality of the following molecular sets must be about equal: metabolome, genome, proteome. We show that this conjecture is not likely correct so the problem of self-referential mappings for describing the boundary between living and nonliving systems remains an open question. We calculate a lower and upper bound for the number of edges in the molecular interaction network (the interactome) for two cellular organisms and for two manufacturomes for CMOS integrated circuit manufacturing. CONCLUSIONS: We show that the relevant mapping relations may not be Abelian, and that these problems cannot yet be resolved because the interactomes and manufacturomes are incomplete. PMID- 21689426 TI - Peritoneal carcinomatosis from ovarian cancer: chemosensitivity test and tissue markers as predictors of response to chemotherapy. AB - BACKGROUND: Platinum-based regimens are the treatments of choice in ovarian cancer, which remains the leading cause of death from gynecological malignancies in the Western world. The aim of the present study was to compare the advantages and limits of a conventional chemosensitivity test with those of new biomolecular markers in predicting response to platinum regimens in a series of patients with peritoneal carcinomatosis from ovarian cancer. METHODS: Fresh surgical biopsy specimens were obtained from 30 patients with primary or recurrent peritoneal carcinomatosis from ovarian cancer. ERCC1, GSTP1, MGMT, XPD, and BRCA1 gene expression levels were determined by Real-Time RT-PCR. An in vitro chemosensitivity test was used to define a sensitivity or resistance profile to the drugs used to treat each patient. RESULTS: MGMT and XPD expression was directly and significantly related to resistance to platinum-containing treatment (p = 0.036 and p = 0.043, respectively). Significant predictivity in terms of sensitivity and resistance was observed for MGMT expression (75.0% and 72.5%, respectively; p = 0.03), while high predictivity of resistance (90.9%) but very low predictivity of sensitivity (37.5%) (p = 0.06) were observed for XPD. The best overall and significant predictivity was observed for chemosensitivity test results (85.7% sensitivity and 91.3% resistance; p = 0.0003). CONCLUSIONS: The in vitro assay showed a consistency with results observed in vivo in 27 out of the 30 patients analyzed. Sensitivity and resistance profiles of different drugs used in vivo would therefore seem to be better defined by the in vitro chemosensitivity test than by expression levels of markers. PMID- 21689428 TI - Bronchogenic cyst associated with pericardial defect: case report and review of the literature. AB - Partial defect of the pericardium combined with bronchogenic cyst is a very rare congenital anomaly. We describe the case of a 32-year-old man with a partial defect of the left pericardium and a bronchogenic cyst arising from the border of the pericardial defect. The cyst was successfully resected with the harmonic scalpel by three-port videothoracoscopic approach. PMID- 21689429 TI - Institutional review boards - a mixed blessing. AB - Institutional Review Boards (IRBs) are an important checkpoint for all types of research in medicine. Although these bodies originated primarily in the developed world, they have special contemporary consideration in the context of developing countries due to the large number of clinical trials being conducted in these regions with the financial support of large pharmaceutical companies. IRBs are vital to ensure that all scientific investigation is conducted in a manner that is transparent, scientifically feasible and ethically sound. However, they have also been variably criticized for introducing unnecessary and often protracted bureaucracy and red tape into the system. There is a need to reorganize and better delineate the exact functions of the IRBs in view of the dynamic changes in the realm of research so that they can function in a more efficient, judicious and effective fashion. PMID- 21689430 TI - Temporal-spatial changes in Sonic Hedgehog expression and signaling reveal different potentials of ventral mesencephalic progenitors to populate distinct ventral midbrain nuclei. AB - BACKGROUND: The ventral midbrain contains a diverse array of neurons, including dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra (SN) and neurons of the red nucleus (RN). Dopaminergic and RN neurons have been shown to arise from ventral mesencephalic precursors that express Sonic Hedgehog (Shh). However, Shh expression, which is initially confined to the mesencephalic ventral midline, expands laterally and is then downregulated in the ventral midline. In contrast, expression of the Hedgehog target gene Gli1 initiates in the ventral midline prior to Shh expression, but after the onset of Shh expression it is expressed in precursors lateral to Shh-positive cells. Given these dynamic gene expression patterns, Shh and Gli1 expression could delineate different progenitor populations at distinct embryonic time points. RESULTS: We employed genetic inducible fate mapping (GIFM) to investigate whether precursors that express Shh (Shh-GIFM) or transduce Shh signaling (Gli1-GIFM) at different time points give rise to different ventral midbrain cell types. We find that precursors restricted to the ventral midline are labeled at embryonic day (E)7.5 with Gli1-GIFM, and with Shh-GIFM at E8.5. These precursors give rise to all subtypes of midbrain dopaminergic neurons and the anterior RN. A broader domain of progenitors that includes the ventral midline is marked with Gli1-GIFM at E8.5 and with Shh-GIFM at E9.5; these fate-mapped cells also contribute to all midbrain dopaminergic subtypes and to the entire RN. In contrast, a lateral progenitor domain that is labeled with Gli1-GIFM at E9.5 and with Shh-GIFM at E11.5 has a markedly reduced potential to give rise to the RN and to SN dopaminergic neurons, and preferentially gives rise to the ventral-medial VTA. In addition, cells derived from Shh- and Gli1-expressing progenitors located outside of the ventral midline give rise to astrocytes. CONCLUSIONS: We define a ventral midbrain precursor map based on the timing of Gli1 and Shh expression, and suggest that the diversity of midbrain dopaminergic neurons is at least partially determined during their precursor stage when their medial-lateral position, differential gene expression and the time when they leave the ventricular zone influence their fate decisions. PMID- 21689431 TI - Potent anti-inflammatory and antinociceptive activity of the endothelin receptor antagonist bosentan in monoarthritic mice. AB - INTRODUCTION: Endothelins are involved in tissue inflammation, pain, edema and cell migration. Our genome-wide microarray analysis revealed that endothelin-1 (ET-1) and endothelin-2 (ET-2) showed a marked up-regulation in dorsal root ganglia during the acute phase of arthritis. We therefore examined the effects of endothelin receptor antagonists on the development of arthritis and inflammatory pain in monoarthritic mice. METHODS: Gene expression was examined in lumbar dorsal root ganglia two days after induction of antigen-induced arthritis (AIA) using mRNA microarray analysis. Effects of drug treatment were determined by repeated assessment of joint swelling, pain-related behavior, and histopathological manifestations during AIA. RESULTS: Daily oral administration of the mixed ET(A) and ET(B) endothelin receptor antagonist bosentan significantly attenuated knee joint swelling and inflammation to an extent that was comparable to dexamethasone. In addition, bosentan reduced inflammatory mechanical hyperalgesia. Chronic bosentan administration also inhibited joint swelling and protected against inflammation and joint destruction during AIA flare-up reactions. In contrast, the ET(A)-selective antagonist ambrisentan failed to promote any detectable antiinflammatory or antinociceptive activity. CONCLUSIONS: Thus, the present study reveals a pivotal role for the endothelin system in the development of arthritis and arthritic pain. We show that endothelin receptor antagonists can effectively control inflammation, pain and joint destruction during the course of arthritis. Our findings suggest that the antiinflammatory and antinociceptive effects of bosentan are predominantly mediated via the ET(B) receptor. PMID- 21689432 TI - Association between novel PLCE1 variants identified in published esophageal cancer genome-wide association studies and risk of squamous cell carcinoma of the head and neck. AB - BACKGROUND: Phospholipase C epsilon 1 (PLCE1) (an effector of Ras) belonging to the phospholipase family plays crucial roles in carcinogenesis and progression of several cancers, including squamous cell carcinoma of the head and neck (SCCHN). A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus in genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) that share similar risk factors with SCCHN. Therefore, we investigated the association between potentially functional SNPs in PLCE1 and susceptibility to SCCHN. METHODS: We genotyped three potentially functional SNPs (rs2274223A/G, rs3203713A/G and rs11599672T/G) of PLCE1 in 1,098 SCCHN patients and 1,090 controls matched by age and sex in a non-Hispanic white population. RESULTS: Although none of three SNPs was alone significantly associated with overall risk of SCCHN, their combined effects of risk alleles (rs2274223G, rs3203713G and rs11599672G) were found to be associated with risk of SCCHN in a locus-dose effect manner (Ptrend=0.046), particularly for non-oropharyngeal tumors (Ptrend=0.017); specifically, rs2274223 was associated with a significantly increased risk (AG vs. AA: adjusted OR=1.29, 95% CI=1.01-1.64; AG/GG vs. AA: adjusted OR=1.30, 95% CI=1.03-1.64), while rs11599672 was associated with a significantly decreased risk (GG vs. TT: adjusted OR=0.54, 95% CI=0.34-0.86; TG/GG vs. TT: adjusted OR=0.76, 95% CI=0.61-0.95). CONCLUSIONS: Our findings suggest that PLCE1 variants may have an effect on risk of SCCHN associated with tobacco and alcohol exposure, particularly for those tumors arising at non oropharyngeal sites. These findings, although need to be validated by larger studies, are consistent with those in esophageal and gastric cancers. PMID- 21689433 TI - Pros and cons of a prion-like pathogenesis in Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder which affects widespread areas of the brainstem, basal ganglia and cerebral cortex. A number of proteins are known to accumulate in parkinsonian brains including ubiquitin and alpha-synuclein. Prion diseases are sporadic, genetic or infectious disorders with various clinical and histopathological features caused by prion proteins as infectious proteinaceous particles transmitting a misfolded protein configuration through brain tissue. The most important form is Creutzfeldt-Jakob disease which is associated with a self propagating pathological precursor form of the prion protein that is physiologically widely distributed in the central nervous system. DISCUSSION: It has recently been found that alpha-synuclein may behave similarly to the prion precursor and propagate between cells. The post-mortem proof of alpha-synuclein containing Lewy bodies in embryonic dopamine cells transplants in PD patient suggests that the misfolded protein might be transmitted from the diseased host to donor neurons reminiscent of prion behavior. The involvement of the basal ganglia and brainstem in the degenerative process are other congruencies between Parkinson's and Creutzfeldt-Jakob disease. However, a number of issues advise caution before categorizing Parkinson's disease as a prion disorder, because clinical appearance, brain imaging, cerebrospinal fluid and neuropathological findings exhibit fundamental differences between both disease entities. Most of all, infectiousness, a crucial hallmark of prion diseases, has never been observed in PD so far. Moreover, the cellular propagation of the prion protein has not been clearly defined and it is, therefore, difficult to assess the molecular similarities between the two disease entities. SUMMARY: At the current state of knowledge, the molecular pathways of transmissible pathogenic proteins are not yet fully understood. Their exact involvement in the pathophysiology of prion disorders and neurodegenerative diseases has to be further investigated in order to elucidate a possible overlap between both disease categories that are currently regarded as distinct entities. PMID- 21689434 TI - PhyloMap: an algorithm for visualizing relationships of large sequence data sets and its application to the influenza A virus genome. AB - BACKGROUND: Results of phylogenetic analysis are often visualized as phylogenetic trees. Such a tree can typically only include up to a few hundred sequences. When more than a few thousand sequences are to be included, analyzing the phylogenetic relationships among them becomes a challenging task. The recent frequent outbreaks of influenza A viruses have resulted in the rapid accumulation of corresponding genome sequences. Currently, there are more than 7500 influenza A virus genomes in the database. There are no efficient ways of representing this huge data set as a whole, thus preventing a further understanding of the diversity of the influenza A virus genome. RESULTS: Here we present a new algorithm, "PhyloMap", which combines ordination, vector quantization, and phylogenetic tree construction to give an elegant representation of a large sequence data set. The use of PhyloMap on influenza A virus genome sequences reveals the phylogenetic relationships of the internal genes that cannot be seen when only a subset of sequences are analyzed. CONCLUSIONS: The application of PhyloMap to influenza A virus genome data shows that it is a robust algorithm for analyzing large sequence data sets. It utilizes the entire data set, minimizes bias, and provides intuitive visualization. PhyloMap is implemented in JAVA, and the source code is freely available at http://www.biochem.uni luebeck.de/public/software/phylomap.html. PMID- 21689435 TI - The prevalence of HBV infection in the cohort of IDPs of war against terrorism in Malakand Division of Northern Pakistan. AB - BACKGROUND: Hepatitis B is an important public health problem in the Pakistani population and is the major cause of chronic hepatitis, cirrhosis, fibrosis and hepatocellular carcinoma. High prevalence of HBV infections has been observed especially in areas of low economic status. In spite of effective immunization programs, no significant change has been observed in the epidemiology of HBV in the rural areas of Pakistan (~67.5% of the total population) mainly due to lack of interest from government authorities and poor hygienic measures. The current study was aimed at estimating the prevalence and risk factors associated with HBV infection within internally displaced persons (IDPs) due to war against terrorism in the Malakand Division of Northern Pakistan. METHODS: Blood samples from 950 IDPs suspected with HBV infection (including both males and females) were collected and processed with commercial ELISA kits for HBsAg, Anti HBs, HBeAg, Anti HBe antibodies. The samples positive by ELISA were confirmed for HBV DNA by real-time PCR analysis. RESULTS: The overall prevalence of HBV observed was 21.05% of which 78.5% were males and 21.5% were females. Most confirmed HBV patients belong to the Malakand and Dir (lower) district. High-risk of infection was found in the older subjects 29.13% (46-60 years), while a lower incidence (11.97%) was observed in children aged <15 years. Lack of awareness, socioecomic conditions, sexual activities and sharing of razor blades, syringes and tattooing needles were the most common risk factors of HBV infection observed during the cohort of patients. CONCLUSION: The present study, revealed for the first time a high degree of prevalence of HBV infection in rural areas of Northern Pakistan. The noticed prevalence is gender- and age-dependent that might be due to their high exposures to the common risk factors. To avoid the transmission of HBV infection proper awareness about the possible risk factors and extension of immunization to the rural areas are recommended. PMID- 21689436 TI - Measuring naturally acquired immune responses to candidate malaria vaccine antigens in Ghanaian adults. AB - BACKGROUND: To prepare field sites for malaria vaccine trials, it is important to determine baseline antibody and T cell responses to candidate malaria vaccine antigens. Assessing T cell responses is especially challenging, given genetic restriction, low responses observed in endemic areas, their variability over time, potential suppression by parasitaemia and the intrinsic variability of the assays. METHODS: In Part A of this study, antibody titres were measured in adults from urban and rural communities in Ghana to recombinant Plasmodium falciparum CSP, SSP2/TRAP, LSA1, EXP1, MSP1, MSP3 and EBA175 by ELISA, and to sporozoites and infected erythrocytes by IFA. Positive ELISA responses were determined using two methods. T cell responses to defined CD8 or CD4 T cell epitopes from CSP, SSP2/TRAP, LSA1 and EXP1 were measured by ex vivo IFN-gamma ELISpot assays using HLA-matched Class I- and DR-restricted synthetic peptides. In Part B, the reproducibility of the ELISpot assay to CSP and AMA1 was measured by repeating assays of individual samples using peptide pools and low, medium or high stringency criteria for defining positive responses, and by comparing samples collected two weeks apart. RESULTS: In Part A, positive antibody responses varied widely from 17%-100%, according to the antigen and statistical method, with blood stage antigens showing more frequent and higher magnitude responses. ELISA titres were higher in rural subjects, while IFA titres and the frequencies and magnitudes of ex vivo ELISpot activities were similar in both communities. DR restricted peptides showed stronger responses than Class I-restricted peptides. In Part B, the most stringent statistical criteria gave the fewest, and the least stringent the most positive responses, with reproducibility slightly higher using the least stringent method when assays were repeated. Results varied significantly between the two-week time-points for many participants. CONCLUSIONS: All participants were positive for at least one malaria protein by ELISA, with results dependent on the criteria for positivity. Likewise, ELISpot responses varied among participants, but were relatively reproducible by the three methods tested, especially the least stringent, when assays were repeated. However, results often differed between samples taken two weeks apart, indicating significant biological variability over short intervals. PMID- 21689437 TI - Concurrency revisited: increasing and compelling epidemiological evidence. AB - Multiple sexual partnerships must necessarily lie at the root of a sexually transmitted epidemic. However, that overlapping or concurrent partnerships have played a pivotal role in the generalized epidemics of sub-Saharan Africa has been challenged. Much of the original proposition that concurrent partnerships play such a role focused on modelling, self-reported sexual behaviour data and ethnographic data. While each of these has definite merit, each also has had methodological limitations. Actually, more recent cross-national sexual behaviour data and improved modelling have strengthened these lines of evidence. However, heretofore the epidemiologic evidence has not been systematically brought to bear. Though assessing the epidemiologic evidence regarding concurrency has its challenges, a careful examination, especially of those studies that have assessed HIV incidence, clearly indicates a key role for concurrency.Such evidence includes: 1) the early and dramatic rise of HIV infection in generalized epidemics that can only arise from transmission through rapid sequential acute infections and thereby concurrency; 2) clear evidence from incidence studies that a major portion of transmission in the population occurs via concurrency both for concordant negative and discordant couples; 3) elevation in risk associated with partner's multiple partnering; 4) declines in HIV associated with declines in concurrency; 5) bursts and clustering of incident infections that indicate concurrency and acute infection play a key role in the propagation of epidemics; and 6) a lack of other plausible explanations, including serial monogamy and non sexual transmission. While other factors, such as sexually transmitted infections, other infectious diseases, biological factors and HIV sub-type, likely play a role in enhancing transmission, it appears most plausible that these would amplify the role of concurrency rather than alter it. Additionally, critics of concurrency have not proposed plausible alternative explanations for why the explosive generalized epidemics occurred. Specific behaviour change messaging bringing the concepts of multiple partnering and concurrency together appears salient and valid in promoting safer individual behaviour and positive social norms. PMID- 21689438 TI - Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post hoc analysis of two 3-week clinical trials. AB - BACKGROUND: Asenapine demonstrated superiority over placebo for mania in bipolar I disorder patients experiencing acute current manic or mixed episodes in 2 randomized, placebo-and olanzapine-controlled trials. We report the results of exploratory pooled post hoc analyses from these trials evaluating asenapine's effects on depressive symptoms in patients from these trials with significant baseline depressive symptoms. METHODS: In the original trials (A7501004 [NCT00159744], A7501005 [NCT00159796]), 977 patients were randomized to flexible dose sublingual asenapine (10 mg twice daily on day 1; 5 or 10 mg twice daily thereafter), placebo, or oral olanzapine 5-20 mg once daily for 3 weeks. Three populations were defined using baseline depressive symptoms: (1) Montgomery Asberg Depression Rating Scale (MADRS) total score >=20 (n = 132); (2) Clinical Global Impression for Bipolar Disorder-Depression (CGI-BP-D) scale severity score >=4 (n = 170); (3) diagnosis of mixed episodes (n = 302) by investigative site screening. For each population, asenapine and olanzapine were independently compared with placebo using least squares mean change from baseline on depressive symptom measures. RESULTS: Decreases in MADRS total score were statistically greater with asenapine versus placebo at days 7 and 21 in all populations; differences between olanzapine and placebo were not significant. Decreases in CGI BP-D score were significantly greater with asenapine versus placebo at day 7 in all categories and day 21 in population 1; CGI-BP-D score reductions were significantly greater with olanzapine versus placebo at day 21 in population 1 and day 7 in populations 2 and 3. CONCLUSIONS: These post hoc analyses show that asenapine reduced depressive symptoms in bipolar I disorder patients experiencing acute manic or mixed episodes with clinically relevant depressive symptoms at baseline; olanzapine results appeared to be less consistent. Controlled studies of asenapine in patients with acute bipolar depression are necessary to confirm the generalizability of these findings. PMID- 21689439 TI - Fully covered self-expanding metal stents placed temporarily in the bile duct: safety profile and histologic classification in a porcine model. AB - BACKGROUND: Fully covered Self-Expanding metal stents (FCSEMS) have been shown efficacious in palliating malignant biliary obstructions. There is little data analyzing mucosal response to their temporary placement in the bile duct. METHODS: Ten mini pigs underwent endoscopic placement of a FCSEMS (Wallflex, Boston Scientific). FCSEMS were kept in place for three months. At the end of the 3 months, FCSEMS were removed endoscopically. Five pigs were euthanized and their bile ducts harvested. The other five were kept alive for another month post removal. A single pathologist, created a scoring system (to determine degree of inflammation, fibrosis, and epithelial injury), examined all specimens in a blinded fashion. RESULTS: Four FCSEMS spontaneously migrated in the duodenum. On post mortem examination, mild mucosal thickness was noted in three bile duct specimens while superficial inflammation of the bile duct was noted in five animals. Histologic examination of the bile duct revealed focal acute inflammation in both groups. For the 5 animals euthanized immediately after stent removal, there was a tendency to have superficial mucosal erosion and fibrosis. In contrast, increased chronic inflammation was more commonly seen in the animals 1 month post stent removal, with all animals in this group showing moderate degrees of mononuclear inflammatory cell mucosal infiltrates. No severe inflammatory or fibrotic duct injury was observed in any of the study animals, with degree of injury graded as mild to moderate. CONCLUSION: FCSEMS appear to induce minimal tissue overgrowth or fibrosis post placement. Ease of removability and no significant histologic injury are advantages noted with FCSEMS., however, further studies are needed to evaluate treating benign biliary strictures with FCSEMS in humans. PMID- 21689440 TI - Natural selection among Eurasians at genomic regions associated with HIV-1 control. AB - BACKGROUND: HIV susceptibility and pathogenicity exhibit both interindividual and intergroup variability. The etiology of intergroup variability is still poorly understood, and could be partly linked to genetic differences among racial/ethnic groups. These genetic differences may be traceable to different regimes of natural selection in the 60,000 years since the human radiation out of Africa. Here, we examine population differentiation and haplotype patterns at several loci identified through genome-wide association studies on HIV-1 control, as determined by viral-load setpoint, in European and African-American populations. We use genome-wide data from the Human Genome Diversity Project, consisting of 53 world-wide populations, to compare measures of FST and relative extended haplotype homozygosity (REHH) at these candidate loci to the rest of the respective chromosome. RESULTS: We find that the Europe-Middle East and Europe South Asia pairwise FST in the most strongly associated region are elevated compared to most pairwise comparisons with the sub-Saharan African group, which exhibit very low FST. We also find genetic signatures of recent positive selection (higher REHH) at these associated regions among all groups except for sub-Saharan Africans and Native Americans. This pattern is consistent with one in which genetic differentiation, possibly due to diversifying/positive selection, occurred at these loci among Eurasians. CONCLUSIONS: These findings are concordant with those from earlier studies suggesting recent evolutionary change at immunity-related genomic regions among Europeans, and shed light on the potential genetic and evolutionary origin of population differences in HIV-1 control. PMID- 21689441 TI - The nursing staff's opinion of falls among older persons with dementia. a cross sectional study. AB - The aim of this study was to describe the nursing staff's opinion of caring for older persons with dementia with the focus on causes of falls, fall-preventing interventions, routines of documentation and report and the nursing staff's experiences and reactions when fall incidents occur. A further aim was to compare these areas between registered nurses (RNs) and enrolled nurses (ENs) and staff with <=5 and >5 years of employment in the care units in question. BACKGROUND: Falls are common among older people and persons with dementia constitute an additional risk group. METHODS: The study had a cross-sectional design and included nursing staff (n = 63, response rate 66%) working in four special care units for older persons with dementia. Data collection was conducted with a questionnaire consisting of 64 questions. RESULTS: The respondents reported that the individuals' mental and physical impairment constitute the most frequent causes of falls. The findings also revealed a lack of, or uncertainty about, routines of documentation and reporting fall-risk and fall-preventing interventions. Respondents who had been employed in the care units more than five years reported to a higher degree that colours and material on floors caused falls. RNs considered the residents' autonomy and freedom of movement as a cause of falls to a significantly higher degree than ENs. RNs also reported a significantly longer time than ENs before fall incidents were discovered, and they used conversation and closeness as fall-preventing interventions to a significantly higher degree than ENs. CONCLUSIONS: Individual factors were the most common causes to falls according to the nursing staff. RNs used closeness and dialog as interventions to a significantly higher degree to prevent falls than ENs. Caring of for older people with dementia consisted of a comprehensive on-going assessment by the nursing staff to balance the residents' autonomy versus-control to minimise fall-risk. This ethical dilemma should initiate development of feasible routines of systematic risk-assessment, report and documentation. PMID- 21689442 TI - Revisiting the dimensional structure of the Edinburgh Postnatal Depression Scale (EPDS): empirical evidence for a general factor. AB - BACKGROUND: The Edinburgh Postnatal Depression Scale (EPDS) has been proposed as a one-dimensional instrument and used as a single 10-item scale. This might be considered questionable since repeated psychometric studies have shown multi dimensionality, which would entail using separate component subscales. This study reappraised the dimensional structure of the EPDS, with a focus on the extent of factor correlations and related factor-based discriminant validity as a foundation for deciding how to effectively scale the component items. METHODS: The sample comprised 811 randomly selected mothers of children up to 5 months attending primary health services of Rio de Janeiro, Brazil. Strict Confirmatory Factor Analysis (CFA) and Exploratory Factor Analysis modeled within a CFA framework (E/CFA) were sequentially used to identify best fitting and parsimonious model(s), including a bifactor analysis to evaluate the existence of a general factor. Properties concerning the related 10-item raw-score scale were also investigated using non-parametric items response theory methods (scalability and monotonicity). RESULTS: An initial CFA rejected the one-dimensional structure, while an E/CFA subscribed a three-dimensional solution. Yet, factors were highly correlated (0.66, 0.75 and 0.82). The ensuing CFA showed poor discriminant validity (some square-roots of average variance extracted below the factor correlations). A general bifactor CFA was then fit. Results suggested that, although still weakly encompassing three specific factors, the EPDS might be better described by a model encompassing a general factor (loadings ranging from 0.51 to 0.81). The related 10-item raw score showed adequate scalability (Loevinger's H coefficient = 0.4208), monotonicity e partial double monotonicity (nonintersections of Item Step Response Functions). CONCLUSION: Although the EPDS indicated the presence of specific factors, they do not qualify as independent dimensions if used separately and should therefore not be used empirically as sub scales (raw scores). An all-encompassing scale seems better suited and continuing its use in clinical practice and applied research should be encouraged. PMID- 21689443 TI - Defensive coping and health-related quality of life in chronic kidney disease: a cross-sectional study. AB - BACKGROUND: Coping with the stresses of chronic disease is considered as a key factor in the perceived impairment of health related quality of life (HRQL). Little is known though about these associations in chronic kidney disease (CKD). The present study aimed to investigate the relationship of defensive coping and HRQL among patients in different CKD stages, after adjusting for psychological distress, sociodemographic and disease-related variables. METHODS: The sample consisted of 98 CKD patients, attending a university nephrology department. Seventy-nine (79) pre-dialysis patients of disease stages 3 to 4 and 19 dialysis patients were included. HRQL was assessed by the 36-item Short-Form health survey (SF-36), defensive coping by the Rationality/Emotional Defensiveness (R/ED) scale of the Lifestyle Defense Mechanism Inventory (LDMI) and psychological distress by the depression and anxiety scales of the revised Hopkins Symptom CheckList (SCL 90-R). Regression analyses were carried out to examine the association between SF 36 dimensions and defensive coping style. RESULTS: Patients on dialysis had worse scores on SF-36 scales measuring physical aspects of HRQL. In the fully adjusted analysis, a higher defensive coping score was significantly associated with a lower score on the mental component summary (MCS) scale of the SF-36 (worse mental health). In contrast, a higher defensive score showed a small positive association with the physical component summary (PCS) scale of the SF-36 (better health), but this was marginally significant. CONCLUSIONS: The results provided evidence that emotional defensiveness as a coping style tends to differentially affect the mental and the physical component of HRQL in CKD. Clinicians should be aware of the effects of long-term denial and could examine the possibility of screening for defensive coping and depression in recently diagnosed CKD patients with the aim to improve both physical and mental health. PMID- 21689444 TI - Capacity building permitting comprehensive monitoring of a severe case of Lassa hemorrhagic fever in Sierra Leone with a positive outcome: case report. AB - Lassa fever is a neglected tropical disease with a significant impact on the health care system of endemic West African nations. To date, case reports of Lassa fever have focused on laboratory characterisation of serological, biochemical and molecular aspects of the disease imported by infected individuals from Western Africa to the United States, Canada, Europe, Japan and Israel. Our report presents the first comprehensive real time diagnosis and characterization of a severe, hemorrhagic Lassa fever case in a Sierra Leonean individual admitted to the Kenema Government Hospital Lassa Fever Ward. Fever, malaise, unresponsiveness to anti-malarial and antibiotic drugs, followed by worsening symptoms and onset of haemorrhaging prompted medical officials to suspect Lassa fever. A recombinant Lassa virus protein based diagnostic was employed in diagnosing Lassa fever upon admission. This patient experienced a severe case of Lassa hemorrhagic fever with dysregulation of overall homeostasis, significant liver and renal system involvement, the interplay of pro- and anti-inflammatory cytokines during the course of hospitalization and an eventual successful outcome. These studies provide new insights into the pathophysiology and management of this viral illness and outline the improved infrastructure, research and real-time diagnostic capabilities within LASV endemic areas. PMID- 21689445 TI - Zingiber officinale acts as a nutraceutical agent against liver fibrosis. AB - BACKGROUND/OBJECTIVE: Zingiber officinale Roscoe (ginger) (Zingiberaceae) has been cultivated for thousands of years both as a spice and for medicinal purposes. Ginger rhizomes successive extracts (petroleum ether, chloroform and ethanol) were examined against liver fibrosis induced by carbon tetrachloride in rats. RESULTS: The evaluation was done through measuring antioxidant parameters; glutathione (GSH), total superoxide dismutase (SOD) and malondialdehyde (MDA). Liver marker enzymes; succinate and lactate dehydrogenases (SDH and LDH), glucose 6-phosphatase (G-6-Pase), acid phosphatase (AP), 5'- nucleotidase (5'NT) and liver function enzymes; aspartate and alanine aminotransferases (AST and ALT) as well as cholestatic markers; alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total bilirubin were estimated. Liver histopathological analysis and collagen content were also evaluated. Treatments with the selected extracts significantly increased GSH, SOD, SDH, LDH, G-6-Pase, AP and 5'NT. However, MDA, AST, ALT ALP, GGT and total bilirubin were significantly decreased. CONCLUSIONS: Extracts of ginger, particularly the ethanol one resulted in an attractive candidate for the treatment of liver fibrosis induced by CCl4. Further studies are required in order to identify the molecules responsible of the pharmacological activity. PMID- 21689446 TI - Synthetic fiber from a teddy bear causing keratitis and conjunctival granuloma: case report. AB - BACKGROUND: To report a case of keratitis and a case of conjunctivitis caused by synthetic fibers from toy teddy bears. CASE PRESENTATION: Case stories with histopathological analysis. 1) A two-year-old girl developed a severe case of keratitis and corneal ulceration. The initial treatment with various antibiotics gave no improvement and eventually the patient developed spontaneous perforation of the cornea. The corneal swabs contained no bacteria or fungi. Corneal grafting was performed and the corneal button was sent for histopathological examination. 2) A five-year-old girl presented with ocular irritation in her left eye. Examination revealed a conjunctival granuloma in the inferior fornix. The lesion was excised and histopathologically examined. RESULTS: Microscopy revealed synthetic fibers embedded in the cornea and in the conjunctival granuloma. The diagnosis was confirmed by demonstration of marked birefringence of the synthetic fibers. Microscopical examination of synthetic fibers from two different types of fur (whiskers and face hairs) from the two-year-old girl's teddy bear was performed. Hairs from the face of the teddy bear were morphologically and microscopically identical with the fibers causing the severe corneal ulceration in the two-year-old girl. CONCLUSIONS: Doctors should especially in small children be aware of the risk of ocular consequences of close exposure of synthetic fibers from stuffed toy animals. Corneal ulceration, clinically presenting as corneal infection with negative culturing and staining, should lead to a different clinical strategy and treatment. The treatment of conjunctival synthetic fiber granuloma is excision and antibiotic eye drops. PMID- 21689447 TI - Simulation methods to estimate design power: an overview for applied research. AB - BACKGROUND: Estimating the required sample size and statistical power for a study is an integral part of study design. For standard designs, power equations provide an efficient solution to the problem, but they are unavailable for many complex study designs that arise in practice. For such complex study designs, computer simulation is a useful alternative for estimating study power. Although this approach is well known among statisticians, in our experience many epidemiologists and social scientists are unfamiliar with the technique. This article aims to address this knowledge gap. METHODS: We review an approach to estimate study power for individual- or cluster-randomized designs using computer simulation. This flexible approach arises naturally from the model used to derive conventional power equations, but extends those methods to accommodate arbitrarily complex designs. The method is universally applicable to a broad range of designs and outcomes, and we present the material in a way that is approachable for quantitative, applied researchers. We illustrate the method using two examples (one simple, one complex) based on sanitation and nutritional interventions to improve child growth. RESULTS: We first show how simulation reproduces conventional power estimates for simple randomized designs over a broad range of sample scenarios to familiarize the reader with the approach. We then demonstrate how to extend the simulation approach to more complex designs. Finally, we discuss extensions to the examples in the article, and provide computer code to efficiently run the example simulations in both R and Stata. CONCLUSIONS: Simulation methods offer a flexible option to estimate statistical power for standard and non-traditional study designs and parameters of interest. The approach we have described is universally applicable for evaluating study designs used in epidemiologic and social science research. PMID- 21689448 TI - A randomized controlled trial of vitamin D dosing strategies after acute hip fracture: no advantage of loading doses over daily supplementation. AB - BACKGROUND: There remains uncertainty regarding the appropriate therapeutic management of hip fracture patients. The primary aim of our study was to examine whether large loading doses in addition to daily vitamin D offered any advantage over a simple daily low-dose vitamin D regimen for increasing vitamin D levels. METHODS: In this randomized controlled study, patients over age 50 with an acute fragility hip fracture were enrolled from two hospital sites in Ontario, Canada. Participants were randomized to one of three loading dose groups: placebo; 50,000 IU vitamin D2; or 100,000 IU D2. Following a placebo/loading dose, all patients received a daily tablet of 1,000 IU vitamin D3 for 90 days. Serum 25-hydroxy vitamin D (25-OHD) was measured at baseline, discharge from acute care (approximately 4-weeks), and 3-months. RESULTS: Sixty-five patients were enrolled in the study (44% male). An immediate rise in 25-OHD occurred in the 100,000 group, however there were no significant differences in 25-OHD between the placebo, 50,000 and 100,000 loading dose groups after 4-weeks (69.3, 84.5, 75.6 nmol/L, p = 0.15) and 3-months (86.7, 84.2, 73.3 nmol/L, p = 0.09), respectively. At the end of the study, approximately 75% of the placebo and 50,000 groups had reached the target therapeutic range (75 nmol/L), and 44% of the 100,000 group. CONCLUSIONS: In correcting vitamin D insufficiency/deficiency in elderly patients with hip fracture, our findings suggest that starting with a lower daily dose of Vitamin D3 achieved similar results as providing an additional large loading dose of Vitamin D2. At the end of the study, all three groups were equally effective in attaining improvement in 25-OHD levels. Given that a daily dose of 1,000 IU vitamin D3 (with or without a loading dose) resulted in at least 25% of patients having suboptimal vitamin D status, patients with acute hip fracture may benefit from a higher daily dose of vitamin D. TRIAL REGISTRATION: Clinical Trials # NCT00424619. PMID- 21689449 TI - Routine invasive management after fibrinolysis in patients with ST-elevation myocardial infarction: a systematic review of randomized clinical trials. AB - BACKGROUND: Patients with ST-elevation myocardial infarction (STEMI) treated with fibrinolysis are increasingly, and ever earlier, referred for routine coronary angiography and where feasible, undergo percutaneous coronary intervention (PCI). We sought to examine the randomized clinical trials (RCTs) on which this approach is based. METHODS: We systematically searched EMBASE, Medline, and references of relevant studies. All contemporary RCTs (published since 1995) that compared systematic invasive management of STEMI patients after fibrinolysis with standard care were included. Relevant study design and clinical outcome data were extracted. RESULTS: Nine RCTs that randomized a total of 3320 patients were identified. All suggested a benefit from routine early invasive management. They were individually reviewed but important design variations precluded a formal quantitative meta-analysis. Importantly, several trials did not compare a routine practice of invasive management after fibrinolysis with a more selective 'ischemia-guided' approach but rather compared an early versus later routine invasive strategy. In the other studies, recourse to subsequent invasive management in the usual care group varied widely. Comparison of the effectiveness of a routine invasive approach to usual care was also limited by asymmetric use of a second anti-platelet agent, differing enzyme definitions of reinfarction occurring spontaneously versus as a complication of PCI, a preponderance of the 'soft' outcome of recurrent ischemia in the combined primary endpoint, and an interpretative bias when invasive procedures on follow-up were tallied as an endpoint without considering initial invasive procedures performed in the routine invasive arm. CONCLUSIONS: Due to important methodological limitations, definitive RCT evidence in favor of routine invasive management following fibrinolysis in patients with STEMI is presently lacking. PMID- 21689450 TI - Ten-color flow cytometry reveals distinct patterns of expression of CD124 and CD126 by developing thymocytes. AB - BACKGROUND: We have developed a 12-parameter/10-color flow cytometric staining method for the simultaneous detection and characterization of 21 mouse thymocyte subpopulations that represent discreet stages of T cell development. To demonstrate the utility of this method, we assessed cytokine receptor expression on mouse thymocyte subsets. These experiments revealed distinct patterns of surface expression of receptors for the cytokines IL-4 and IL-6. RESULTS: The IL 4 receptor alpha chain (CD124) was highly expressed on the earliest thymocyte subsets, then downregulated prior to T cell receptor beta-selection and finally upregulated in the CD4/CD8 double positive cells prior to positive selection. The IL-6 receptor alpha chain (CD126) showed a different pattern of expression. It was expressed on the most mature subsets within the CD4 and CD8 single positive (SP) compartments and was absent on all other thymocytes with the exception of a very small cKit-CD4-CD8- population. Intracellular staining of SP thymocytes for phosphorylated STAT-1 demonstrated that IL-6 signaling was confined to the most mature SP subsets. CONCLUSIONS: This 12-parameter staining methodology uses only commercially available fluorochrome-coupled monoclonal antibodies and therefore could be employed by any investigator with access to a 4-laser flow cytometer. This novel staining scheme allowed us to easily phenotype thymocyte subpopulations that span across development, from the early thymic progenitors (ETPs) to the most mature subsets of the CD4 and CD8 single positive populations. PMID- 21689451 TI - Alcohol and fatal life trajectories in Russia: understanding narrative accounts of premature male death in the family. AB - BACKGROUND: In the post-Soviet period, Russian working-age men have suffered unusually high mortality rates. Earlier quantitative work found that part of this is attributable to hazardous and harmful patterns of alcohol consumption, which increased in the period of transition at a time of massive social and economic disruption and uncertainty. However, there has been very little work done to document and understand in detail the downward life trajectories of individual men who died prematurely from alcohol-related conditions. Building on an earlier case-control study, this unique qualitative study investigates the perceived interplay between men's drinking careers, their employment and family history, health and eventual death. METHODS: In-depth interviews were conducted with close relatives (most often the widow) of 19 men who died between 2003 and 2005 aged 25 54 years whose close relatives reported that alcohol contributed to their death. The study was conducted in a typical medium-sized Russian city. The relative's accounts were analysed using thematic content analysis. RESULTS: The accounts describe how hazardous drinking both contributed to serious employment, family and health problems, and was simultaneously used as a coping mechanism to deal with life crises and a decline in social status. The interviews highlighted the importance of the workplace and employment status for shaping men's drinking patterns. Common themes emerged around a culture of drinking in the workplace, peer pressure from colleagues to drink, use of alcohol as remuneration, consuming non-beverage alcohols, Russian-specific drinking patterns, attitudes to treatment, and passive attitudes towards health and drinking. CONCLUSIONS: The study provides a unique insight into the personal decline that lies behind the extremely high working-age mortality due to heavy drinking in Russia, and highlights how health status and hazardous drinking are often closely intertwined with economic and social functioning. Descriptions of the development of drinking careers, hazardous drinking patterns and treatment experiences can be used to plan effective interventions relevant in the Russian context. PMID- 21689452 TI - Efficacy and outcome of expanded newborn screening for metabolic diseases--report of 10 years from South-West Germany. AB - BACKGROUND: National newborn screening programmes based on tandem-mass spectrometry (MS/MS) and other newborn screening (NBS) technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome. METHODS: In a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated. RESULTS: Optimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre symptomatic start of treatment. Metabolic decompensation does not necessarily result in impairment of intellectual development, but there is a definite association between the two. CONCLUSIONS: Physical and cognitive outcome in patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in phenylketonuria, used as a gold standard for NBS. Extended NBS entails many different interrelated variables which need to be carefully evaluated and optimized. More reports from different parts of the world are needed to allow a comprehensive assessment of the likely benefits, harms and costs in different populations. PMID- 21689453 TI - Mammograms and breast arterial calcifications: looking beyond breast cancer: a preliminary report. AB - BACKGROUND: To find out the prevalence, clinical and biochemical correlates of Breast Artery Calcification (BAC) in the Nigerian women. FINDINGS: This is a cross sectional study involving 54 consecutive adult female subjects sent to the Radiology Department of the Lagos State University Teaching Hospital (LASUTH), Ikeja-Lagos, Nigeria for screening and diagnostic mammography. The study was carried out for a period of five months.The prevalence of BAC was 20%. Ageing was found to be related to BAC. Cardiovascular risk factors including diabetes mellitus (DM), hypertension, obesity, alcohol ingestion, use of oral contraceptives and hormone replacement therapy, were not significantly related to the presence of BAC in this study. CONCLUSION: This study showed that though the presence of BAC in a mammogram is related to age, it may not predict or serve as a significant marker for cardiovascular diseases (CVD) in women in our environment. PMID- 21689456 TI - A technique to remove a well-fixed titanium-coated RM acetabular cup in revision hip arthroplasty. AB - A major concern during revision hip arthroplasty is acetabular bone loss and bleeding during the extraction of well-fixed cementless acetabular cup, because no interface exists between the host bone and the cup. Forceful removal of such component using curved gouges and osteotomes often leads to extended bone loss and compromises reimplantation of a new socket. In the following case report, we removed a well-fixed polyethylene titanium-coated RM acetabular cup with 20 years of follow-up, by significant wear of the polyethylene layer. The isoelastic femoral stem was also removed by mechanical failure. We report a technique for removal of the cementless acetabular cup using powered acetabular reamers. The RM cup was sequentially reamed and when the polyethylene layer was thin enough, the remaining cup was removed easily by hand tools. The acetabular bone stock is preserved and the risks of bone fractures and bleeding are minimized. To our knowledge, these principles were applied only in cemented cups. We have used this technique in 10 cases with excellent results and no complications were noted. This is a simple, reproducible, non-costly, non-timing consuming, safe and successful technique to remove well-fixed titanium-coated RM acetabular cups. PMID- 21689455 TI - Self-care in people with long term health problems: a community based survey. AB - BACKGROUND: Self-care is a key component of current policies to manage long term conditions. Although most people with long-term health problems care for themselves within lay networks, consultation rates for long-term undifferentiated illness remain high. Promotion of self-care in these individuals requires an understanding of their own self-care practices and needs to be understood in the context of health care pluralism. The aim was to investigate the extent and nature of self-care practices in patients experiencing long term health problems, sources of information used for self-care, and use of other forms of health care (conventional health care and complementary and alternative medicine). METHODS: The study involved a cross-sectional community-based survey set in three general practices in South West England: two in urban areas, one in a rural area. Data were collected using a postal questionnaire sent to a random sample of 3,060 registered adult patients. Respondents were asked to indicate which of six long term health problems they were experiencing, and to complete the questionnaire in reference to a single (most bothersome) problem only. RESULTS: Of the 1,347 (45% unadjusted response rate) who responded, 583 reported having one or more of the six long term health problems and 572 completed the survey questionnaire. Use of self-care was notably more prevalent than other forms of health care. Nearly all respondents reported using self-care (mean of four self-care practices each). Predictors of high self-care reported in regression analysis included the reported number of health problems, bothersomeness of the health problem and having received a diagnosis. Although GPs were the most frequently used and trusted source of information, their advice was not associated with greater use of self-care. CONCLUSIONS: This study reveals both the high level and wide range of self-care practices undertaken by this population. It also highlights the importance of GPs as a source of trusted information and advice. Our findings suggest that in order to increase self-care without increasing consultation rates, GPs and other health care providers may need more resources to help them to endorse appropriate self-care practices and signpost patients to trusted sources of self-care support. PMID- 21689454 TI - A global transcriptional analysis of Plasmodium falciparum malaria reveals a novel family of telomere-associated lncRNAs. AB - BACKGROUND: Mounting evidence suggests a major role for epigenetic feedback in Plasmodium falciparum transcriptional regulation. Long non-coding RNAs (lncRNAs) have recently emerged as a new paradigm in epigenetic remodeling. We therefore set out to investigate putative roles for lncRNAs in P. falciparum transcriptional regulation. RESULTS: We used a high-resolution DNA tiling microarray to survey transcriptional activity across 22.6% of the P. falciparum strain 3D7 genome. We identified 872 protein-coding genes and 60 putative P. falciparum lncRNAs under developmental regulation during the parasite's pathogenic human blood stage. Further characterization of lncRNA candidates led to the discovery of an intriguing family of lncRNA telomere-associated repetitive element transcripts, termed lncRNA-TARE. We have quantified lncRNA-TARE expression at 15 distinct chromosome ends and mapped putative transcriptional start and termination sites of lncRNA-TARE loci. Remarkably, we observed coordinated and stage-specific expression of lncRNA-TARE on all chromosome ends tested, and two dominant transcripts of approximately 1.5 kb and 3.1 kb transcribed towards the telomere. CONCLUSIONS: We have characterized a family of 22 telomere-associated lncRNAs in P. falciparum. Homologous lncRNA-TARE loci are coordinately expressed after parasite DNA replication, and are poised to play an important role in P. falciparum telomere maintenance, virulence gene regulation, and potentially other processes of parasite chromosome end biology. Further study of lncRNA-TARE and other promising lncRNA candidates may provide mechanistic insight into P. falciparum transcriptional regulation. PMID- 21689457 TI - The Australian national binge drinking campaign: campaign recognition among young people at a music festival who report risky drinking. AB - BACKGROUND: The Australian Government launched a mass media campaign in 2009 to raise awareness of the harms and costs associated risky drinking among young Australians. The aim of this study was to assess if young people attending a music festival who report frequent risky single occasions of drinking (RSOD) recognise the key message of the campaign, "Binge drinking can lead to injuries and regrets", compared to young people who report less frequent RSOD. METHODS: A cross-sectional behavioural survey of young people (aged 16-29 years) attending a music festival in Melbourne, Australia, was conducted in January 2009. We collected basic demographics, information on alcohol and other drug use and sexual health and behaviour during the previous 12 months, and measured recognition of the Australian National Binge Drinking Campaign key message. We calculated the odds of recognition of the key slogan of the Australian National Binge Drinking Campaign among participants who reported frequent RSOD (defined as reported weekly or more frequent RSOD during the previous 12 months) compared to participants who reported less frequent RSOD. RESULTS: Overall, three-quarters (74.7%) of 1072 participants included in this analysis recognised the campaign message. In the adjusted analysis, those reporting frequent RSOD had significantly lower odds of recognising the campaign message compared to those not reporting frequent RSOD (OR 0.7, 95% CI 0.5-0.9), whilst females had significantly greater odds of recognising the campaign message compared to males (OR 1.8, 95% CI 1.4-2.1). CONCLUSIONS: Whilst a high proportion of the target group recognised the campaign, our analysis suggests that participants that reported frequent RSOD - and thus the most important group to target - had statistically significantly lower odds of recognising the campaign message. PMID- 21689458 TI - Statistics-based model for prediction of chemical biosynthesis yield from Saccharomyces cerevisiae. AB - BACKGROUND: The robustness of Saccharomyces cerevisiae in facilitating industrial scale production of ethanol extends its utilization as a platform to synthesize other metabolites. Metabolic engineering strategies, typically via pathway overexpression and deletion, continue to play a key role for optimizing the conversion efficiency of substrates into the desired products. However, chemical production titer or yield remains difficult to predict based on reaction stoichiometry and mass balance. We sampled a large space of data of chemical production from S. cerevisiae, and developed a statistics-based model to calculate production yield using input variables that represent the number of enzymatic steps in the key biosynthetic pathway of interest, metabolic modifications, cultivation modes, nutrition and oxygen availability. RESULTS: Based on the production data of about 40 chemicals produced from S. cerevisiae, metabolic engineering methods, nutrient supplementation, and fermentation conditions described therein, we generated mathematical models with numerical and categorical variables to predict production yield. Statistically, the models showed that: 1. Chemical production from central metabolic precursors decreased exponentially with increasing number of enzymatic steps for biosynthesis (>30% loss of yield per enzymatic step, P-value = 0); 2. Categorical variables of gene overexpression and knockout improved product yield by 2~4 folds (P-value < 0.1); 3. Addition of notable amount of intermediate precursors or nutrients improved product yield by over five folds (P-value < 0.05); 4. Performing the cultivation in a well-controlled bioreactor enhanced the yield of product by three folds (P value < 0.05); 5. Contribution of oxygen to product yield was not statistically significant. Yield calculations for various chemicals using the linear model were in fairly good agreement with the experimental values. The model generally underestimated the ethanol production as compared to other chemicals, which supported the notion that the metabolism of Saccharomyces cerevisiae has historically evolved for robust alcohol fermentation. CONCLUSIONS: We generated simple mathematical models for first-order approximation of chemical production yield from S. cerevisiae. These linear models provide empirical insights to the effects of strain engineering and cultivation conditions toward biosynthetic efficiency. These models may not only provide guidelines for metabolic engineers to synthesize desired products, but also be useful to compare the biosynthesis performance among different research papers. PMID- 21689459 TI - Expression of phosphorylated raf kinase inhibitor protein (pRKIP) is a predictor of lung cancer survival. AB - BACKGROUND: Raf-1 kinase inhibitor protein (RKIP) has been reported to negatively regulate signal kinases of major survival pathways. RKIP activity is modulated in part by phosphorylation on Serine 153 by protein kinase C, which leads to dissociation of RKIP from Raf-1. RKIP expression is low in many human cancers and represents an indicator of poor prognosis and/or induction of metastasis. The prognostic power has typically been based on total RKIP expression and has not considered the significance of phospho-RKIP. METHODS: The present study examined the expression levels of both RKIP and phospho-RKIP in human lung cancer tissue microarray proteomics technology. RESULTS: Total RKIP and phospho-RKIP expression levels were similar in normal and cancerous tissues. phospho-RKIP levels slightly decreased in metastatic lesions. However, the expression levels of phospho-RKIP, in contrast to total RKIP, displayed significant predictive power for outcome with normal expression of phospho-RKIP predicting a more favorable survival compared to lower levels (P = 0.0118); this was even more pronounced in more senior individuals and in those with early stage lung cancer. CONCLUSIONS: This study examines for the first time, the expression profile of RKIP and phospho RKIP in lung cancer. Significantly, we found that phospho-RKIP was a predictive indicator of survival. PMID- 21689461 TI - The societal benefits of reducing six behavioural risk factors: an economic modelling study from Australia. AB - BACKGROUND: A large proportion of disease burden is attributed to behavioural risk factors. However, funding for public health programs in Australia remains limited. Government and non-government organisations are interested in the productivity effects on society from reducing chronic diseases. We aimed to estimate the potential health status and economic benefits to society following a feasible reduction in the prevalence of six behavioural risk factors: tobacco smoking; inadequate fruit and vegetable consumption; high risk alcohol consumption; high body mass index; physical inactivity; and intimate partner violence. METHODS: Simulation models were developed for the 2008 Australian population. A realistic reduction in current risk factor prevalence using best available evidence with expert consensus was determined. Avoidable disease, deaths, Disability Adjusted Life Years (DALYs) and health sector costs were estimated. Productivity gains included workforce (friction cost method), household production and leisure time. Multivariable uncertainty analyses and correction for the joint effects of risk factors on health status were undertaken. Consistent methods and data sources were used. RESULTS: Over the lifetime of the 2008 Australian adult population, total opportunity cost savings of AUD2,334 million (95% Uncertainty Interval AUD1,395 to AUD3,347; 64% in the health sector) were found if feasible reductions in the risk factors were achieved. There would be 95,000 fewer DALYs (a reduction of about 3.6% in total DALYs for Australia); 161,000 less new cases of disease; 6,000 fewer deaths; a reduction of 5 million days in workforce absenteeism; and 529,000 increased days of leisure time. CONCLUSIONS: Reductions in common behavioural risk factors may provide substantial benefits to society. For example, the total potential annual cost savings in the health sector represent approximately 2% of total annual health expenditure in Australia. Our findings contribute important new knowledge about productivity effects, including the potential for increased household and leisure activities, associated with chronic disease prevention. The selection of targets for risk factor prevalence reduction is an important policy decision and a useful approach for future analyses. Similar approaches could be applied in other countries if the data are available. PMID- 21689460 TI - Lineage diversification and historical demography of a montane bird Garrulax elliotii--implications for the Pleistocene evolutionary history of the eastern Himalayas. AB - BACKGROUND: Pleistocene climate fluctuations have shaped the patterns of genetic diversity observed in many extant species. In montane habitats, species' ranges may have expanded and contracted along an altitudinal gradient in response to environmental fluctuations leading to alternating periods of genetic isolation and connectivity. Because species' responses to climate change are influenced by interactions between species-specific characteristics and local topography, diversification pattern differs between species and locations. The eastern Himalayas is one of the world's most prominent mountain ranges. Its complex topography and environmental heterogeneity present an ideal system in which to study how climatic changes during Pleistocene have influenced species distributions, genetic diversification, and demography. The Elliot's laughing thrush (Garrulax elliotii) is largely restricted to high-elevation shrublands in eastern Himalayas. We used mitochondrial DNA and microsatellites to investigate how genetic diversity in this species was affected by Pleistocene glaciations. RESULTS: Mitochondrial data detected two partially sympatric north-eastern and southern lineages. Microsatellite data, however, identified three distinct lineages congruent with the geographically separated southern, northern and eastern eco-subregions of the eastern Himalayas. Geographic breaks occur in steep mountains and deep valleys of the Kangding-Muli-Baoxin Divide. Divergence time estimates and coalescent simulations indicate that lineage diversification occurred on two different geographic and temporal scales; recent divergence, associated with geographic isolation into individual subregions, and historical divergence, associated with displacement into multiple refugia. Despite long-term isolation, genetic admixture among these subregional populations was observed, indicating historic periods of connectivity. The demographic history of Garrulax elliotii shows continuous population growth since late Pleistocene (about 0.125 mya). CONCLUSION: While altitude-associated isolation is typical of many species in other montane regions, our results suggest that eco-subregions in the eastern Himalayas exhibiting island-like characteristics appear to have determined the diversification of Garrulax elliotii. During the Pleistocene, these populations became isolated on subregions during interglacial periods but were connected when these expanded to low altitude during cooler periods. The resultant genetic admixture of lineages might obscure pattern of genetic variation. Our results provide new insights into sky island diversification in a previously unstudied region, and further demonstrate that Pleistocene climatic changes can have profound effects on lineage diversification and demography in montane species. PMID- 21689462 TI - From Antarctica or Asia? New colonization scenario for Australian-New Guinean narrow mouth toads suggested from the findings on a mysterious genus Gastrophrynoides. AB - BACKGROUND: Microhylidae is a geographically widespread family of anurans. Although several extensive molecular analyses have attempted to elucidate their subfamilial relationships, and correlate these with Mesozoic and Cenozoic continental drifts, consensus has not been reached. Further, generic level relationships have not been well investigated in some microhylid subfamilies, and therefore subfamilial affiliations of some genera are still unclear. To elucidate the phylogenetic positions of two mysterious Asian genera, Gastrophrynoides and Phrynella, and to better understand the trans-continental distributions of microhylid taxa, we performed molecular phylogenetic and dating analyses using the largest molecular dataset applied to these taxa to date. RESULTS: Six nuclear and two mitochondrial genes (approx. 8 kbp) were sequenced from 22 microhylid frog species representing eight subfamilies. The maximum likelihood and Bayesian analyses could not fully elucidate the subfamilial relationships, suggesting a rapid radiation of these taxa between 85 and 66 million years ago. In contrast, generic relationships of Asian microhylines were generally well resolved. CONCLUSION: Our results clearly showed that one of two problematic Asian genera, Phrynella, was nested in the clade of the Asian subfamily Microhylinae. By contrast, Gastrophrynoides occupied the most basal position of the Australian-New Guinean subfamily Asterophryinae. The estimated divergence of Gastrophrynoides from other asterophryine was unexpectedly around 48 million years ago. Although a colonization scenario via Antarctica to the Australian-New Guinean landmass has been suggested for Asterophryinae, our finding suggested a novel colonization route via Indo-Eurasia. PMID- 21689463 TI - Opitz trigonocephaly syndrome presenting with sudden unexplained death in the operating room: a case report. AB - INTRODUCTION: Opitz trigonocephaly C syndrome (OTCS) is a rare malformation syndrome with the following features: synostosis of metopic suture, craniofacial abnormalities, severe mental retardation and a multitude of pathological findings affecting almost every organ system. OTCS is associated with a high mortality rate. CASE PRESENTATION: We describe the case of a Caucasian male baby who died at five months of age during surgical correction of the craniofacial anomaly. CONCLUSION: As previously reported, OTCS may have an increased mortality rate during craniofacial surgery. Careful evaluation of surgery risk-benefit ratio is warranted in such patients. PMID- 21689464 TI - Metastasis of a cecal adenocarcinoma to the prostate five years after a right hemicolectomy: a case report. AB - INTRODUCTION: Prostatic metastasis from a primary bowel adenocarcinoma has been only rarely reported in the medical literature. The case reported here is rare in the fact that the primary tumor was from a right-sided bowel adenocarcinoma. It is unusual because initial immunostaining was not fully conclusive, and so a relatively new method of immunostaining, CDX2, was used to ascertain its histopathology. CASE PRESENTATION: We describe the case of a 54-year-old Caucasian man who had a right hemicolectomy for a primary cecal adenocarcinoma, which was completely excised. Following the procedure, he received adjuvant chemotherapy. Computed tomography scans showed no evidence of local recurrence or metastatic disease. Then, five years later, he presented to his general practitioner with urinary symptoms. An abnormal prostate was palpated on digital rectal examination. Trans-rectal prostatic biopsies were performed, which showed colorectal metastases within the prostate gland. This was confirmed with CDX2 immunohistochemistry. There was no further evidence of distant metastases on positron emission tomography-computed tomography scans. CONCLUSIONS: This case demonstrates a rare isolated hematogenous spread to the prostate from a primary cecal adenocarcinoma, several years after definitive treatment and excision. This highlights the importance of accurate immunohistochemistry and imaging in planning further management and treatment. PMID- 21689466 TI - Hemangioma related to Maffucci syndrome in a man: a case report. AB - INTRODUCTION: Maffucci syndrome is a rare clinical entity (approximately 200 cases have been reported in the medical literature) with a combined occurrence of multiple enchondromas and vascular tumors. CASE PRESENTATION: The case of a 43 year-old Japanese man with multiple chondromas and hemangiomas (Maffucci syndrome) is reported. One of the hemangiomas was removed and examined pathologically. The morphological picture was an admixture of cavernous hemangioma and spindle cell hemangioma without cytological atypia or mitosis. Sheets of vacuolated endothelial cells were also observed. CONCLUSION: A rare case of hemangioma associated with Maffucci syndrome, focusing on the pathologic nature of the submitted tissue, is reported. PMID- 21689465 TI - Virulence gene profiling of enterohemorrhagic (EHEC) and enteropathogenic (EPEC) Escherichia coli strains: a basis for molecular risk assessment of typical and atypical EPEC strains. AB - BACKGROUND: Enterohaemorrhagic E. coli (EHEC) can cause severe disease such as bloody diarrhoea and haemolytic uraemic syndrome in humans. Besides production of Shiga toxins, the presence of LEE (eae-gene) and non-LEE (nle) encoded effector genes harboured on O-islands OI-122, OI-71 and OI-57 is associated with EHEC virulence and their frequency in outbreaks. Genes encoded by the EHEC-plasmid are putative virulence markers of EHEC. EHEC-plasmids, LEE and non-LEE effector genes have also been detected in some strains of enteropathogenic E. coli (EPEC). The objective of this study was to analyze the relationship between EHEC and EPEC for virulence genes encoded by genomic O-islands and by the EHEC-plasmids. RESULTS: Nle genes ent/espL2, nleB and nleE (OI-122), nleA, nleF and nleH1-2 (OI-71), nleG5-2 and nleG6-2 (OI-57), espK (CP-933N) and the EHEC-plasmid encoded genes ehxA, espP, etpD and katP were searched in 73 typical and in 235 atypical enteropathogenic E. coli (EPEC) strains. Typical and atypical EPEC each fall into two clusters. Cluster 1 typical (n = 46) and atypical (n = 129) EPEC strains were characterized by the presence of OI-122 encoded genes and grouped together with 64 investigated EHEC strains. Cluster 2 typical (n = 27) and atypical (n = 106) strains grouped together with 52 LEE-negative, Shiga toxin-producing E. coli (STEC) and with 21 apathogenic E. coli strains. Typical EPEC Cluster 1 strains belonged to serotypes frequently involved in severe illness and outbreaks in children (O111:H2, O114:H2, O55:H6, O127:H6 and O142:H6). Atypical EPEC Cluster 1 strains were characterized by serotypes related to EHEC (O26:H11, O55:H7, O145:H28, O103:H2 and O103:H25). CONCLUSION: The OI-122 encoded nleB gene was found to be most closely associated with Cluster 1 strains and may serve as a diagnostic tool for the identification of virulent EHEC and EPEC seropathotypes. OI-71 encoded genes nleA, nleF and nleH1-2 are less associated with Cluster 1 strains. EHEC-plasmid, OI-57 and CP-933 associated genes showed only weak similarities with virulent Cluster 1 EHEC and EPEC strains. PMID- 21689467 TI - Calcified multilocular thymic cyst associated with thymoma: a case report. AB - INTRODUCTION: There are few case reports of thymoma with a thymic cyst. Such an association renders it difficult for any pathologist to differentiate from other neoplasms, such as a cystic thymoma. CASE PRESENTATION: A 50-year-old Berber woman from Morocco was admitted with a chronic cough of more than 10 years duration. Her medical history and physical examination were normal. Anterior chest radiography demonstrated a calcified opacity in her right anterior mediastinum. A chest-computed tomogram revealed a round cystic tumor, with significant calcification in her right anterior mediastinum. A surgical exploration was performed. The tumor seemed to be a well-encapsulated and totally calcified lesion, arising from the right lobe of her thymus. It was removed by partial resection of her thymus. Through histology, the calcified tumor exhibited some areas of multilocular fibrous-wall cysts. These cysts were partially lined by small cuboidal cells with severe chronic inflammation and an AB thymoma that arose from the wall of the cyst. CONCLUSION: Greater attention should be given to multilocular thymic cysts, to exclude the possibility of neoplasm, especially when the cyst wall is thickened. PMID- 21689468 TI - Computational systems biology: integration of sequence, structure, network, and dynamics. AB - A report of the 4nd International Conference on Computational Systems Biology, 9 11 September 2010, Suzhou, China. PMID- 21689469 TI - Network target for screening synergistic drug combinations with application to traditional Chinese medicine. AB - BACKGROUND: Multicomponent therapeutics offer bright prospects for the control of complex diseases in a synergistic manner. However, finding ways to screen the synergistic combinations from numerous pharmacological agents is still an ongoing challenge. RESULTS: In this work, we proposed for the first time a "network target"-based paradigm instead of the traditional "single target"-based paradigm for virtual screening and established an algorithm termed NIMS (Network target based Identification of Multicomponent Synergy) to prioritize synergistic agent combinations in a high throughput way. NIMS treats a disease-specific biological network as a therapeutic target and assumes that the relationship among agents can be transferred to network interactions among the molecular level entities (targets or responsive gene products) of agents. Then, two parameters in NIMS, Topology Score and Agent Score, are created to evaluate the synergistic relationship between each given agent combinations. Taking the empirical multicomponent system traditional Chinese medicine (TCM) as an illustrative case, we applied NIMS to prioritize synergistic agent pairs from 63 agents on a pathological process instanced by angiogenesis. The NIMS outputs can not only recover five known synergistic agent pairs, but also obtain experimental verification for synergistic candidates combined with, for example, a herbal ingredient Sinomenine, which outperforms the meet/min method. The robustness of NIMS was also showed regarding the background networks, agent genes and topological parameters, respectively. Finally, we characterized the potential mechanisms of multicomponent synergy from a network target perspective. CONCLUSIONS: NIMS is a first-step computational approach towards identification of synergistic drug combinations at the molecular level. The network target-based approaches may adjust current virtual screen mode and provide a systematic paradigm for facilitating the development of multicomponent therapeutics as well as the modernization of TCM. PMID- 21689470 TI - Two-stage flux balance analysis of metabolic networks for drug target identification. AB - BACKGROUND: Efficient identification of drug targets is one of major challenges for drug discovery and drug development. Traditional approaches to drug target identification include literature search-based target prioritization and in vitro binding assays which are both time-consuming and labor intensive. Computational integration of different knowledge sources is a more effective alternative. Wealth of omics data generated from genomic, proteomic and metabolomic techniques changes the way researchers view drug targets and provides unprecedent opportunities for drug target identification. RESULTS: In this paper, we develop a method based on flux balance analysis (FBA) of metabolic networks to identify potential drug targets. This method consists of two linear programming (LP) models, which first finds the steady optimal fluxes of reactions and the mass flows of metabolites in the pathologic state and then determines the fluxes and mass flows in the medication state with the minimal side effect caused by the medication. Drug targets are identified by comparing the fluxes of reactions in both states and examining the change of reaction fluxes. We give an illustrative example to show that the drug target identification problem can be solved effectively by our method, then apply it to a hyperuricemia-related purine metabolic pathway. Known drug targets for hyperuricemia are correctly identified by our two-stage FBA method, and the side effects of these targets are also taken into account. A number of other promising drug targets are found to be both effective and safe. CONCLUSIONS: Our method is an efficient procedure for drug target identification through flux balance analysis of large-scale metabolic networks. It can generate testable predictions, provide insights into drug action mechanisms and guide experimental design of drug discovery. PMID- 21689471 TI - An improved kinetic model for the acetone-butanol-ethanol pathway of Clostridium acetobutylicum and model-based perturbation analysis. AB - BACKGROUND: Comprehensive kinetic models of microbial metabolism can enhance the understanding of system dynamics and regulatory mechanisms, which is helpful in optimizing microbial production of industrial chemicals. Clostridium acetobutylicum produces solvents (acetone-butanol-ethanol, ABE) through the ABE pathway. To systematically assess the potential of increased production of solvents, kinetic modeling has been applied to analyze the dynamics of this pathway and make predictive simulations. Up to date, only one kinetic model for C. acetobutylicum supported by experiment has been reported as far as we know. But this model did not integrate the metabolic regulatory effects of transcriptional control and other complex factors. It also left out the information of some key intermediates (e.g. butyryl-phosphate). RESULTS: We have developed an improved kinetic model featured with the incorporation of butyryl phosphate, inclusion of net effects of complex metabolic regulations, and quantification of endogenous enzyme activity variations caused by these regulations. The simulation results of our model are more consistent with published experimental data than the previous model, especially in terms of reflecting the kinetics of butyryl-phosphate and butyrate. Through parameter perturbation analysis, it was found that butyrate kinase has large and positive influence on butanol production while CoA transferase has negative effect on butanol production, suggesting that butyrate kinase has more efficiency in converting butyrate to butanol than CoA transferase. CONCLUSIONS: Our improved kinetic model of the ABE process has more capacity in approaching real circumstances, providing much more insight in the regulatory mechanisms and potential key points for optimization of solvent productions. Moreover, the modeling strategy can be extended to other biological processes. PMID- 21689472 TI - A trigger model of apoptosis induced by tumor necrosis factor signaling. AB - BACKGROUND: The ability of living cells to respond appropriately to apoptosis signals is crucial for the proper development and homeostasis of multicellular organisms. For example, viable cells must be stable enough to appropriately respond to apoptosis signaling so that an irreversible death program is only induced when apoptosis signaling reaches a certain threshold. Previous studies have introduced bistability models in which signaling by caspase-3 activity represents a key regulator of cell fate in response to apoptosis stimuli. RESULTS: In this study, apoptosis induced by tumor necrosis factor (TNF) signaling is investigated, and a mathematical model without the requirement for bistability is proposed. In this model, rapid degradation of the active forms of caspases -8 and -3 are included, and TNF-signaling is found to induce a pulse of caspase-3 activation and trigger an irreversible death program. This result agrees with experimental observations. The ability of a cell to respond to, or resist, apoptosis stimuli is also discussed. Furthermore, the activation efficiencies of caspases -8 and -3 that are essential to a cell's response to extracellular apoptosis stimuli are defined. Based on the simulations performed, it is observed that activation efficiencies must be sufficiently sensitive to appropriately compromise a cell's resistance and effectiveness in response to apoptosis stimuli. CONCLUSIONS: Our results suggest that bistability may not be a necessary condition for the induction of apoptosis by TNF signaling. Rather, a sharp increase in caspase-3 activity might be sufficient to trigger the induction of an irreversible death program. Accordingly, regulation of caspase activity and degradation of active caspases is essential for a cell's response to apoptosis stimuli. PMID- 21689473 TI - Modeling and analysis of the dynamic behavior of the XlnR regulon in Aspergillus niger. AB - BACKGROUND: In this paper the dynamics of the transcription-translation system for XlnR regulon in Aspergillus niger is modeled. The model is based on Hill regulation functions and uses ordinary differential equations. The network response to a trigger of D-xylose is considered and stability analysis is performed. The activating, repressive feedback, and the combined effect of the two feedbacks on the network behavior are analyzed. RESULTS: Simulation and systems analysis showed significant influence of activating and repressing feedback on metabolite expression profiles. The dynamics of the D-xylose input function has an important effect on the profiles of the individual metabolite concentrations. Variation of the time delay in the feedback loop has no significant effect on the pattern of the response. The stability and existence of oscillatory behavior depends on which proteins are involved in the feedback loop. CONCLUSIONS: The dynamics in the regulation properties of the network are dictated mainly by the transcription and translation degradation rate parameters, and by the D-xylose consumption profile. This holds true with and without feedback in the network. Feedback was found to significantly influence the expression dynamics of genes and proteins. Feedback increases the metabolite abundance, changes the steady state values, alters the time trajectories and affects the response oscillatory behavior and stability conditions. The modeling approach provides insight into network behavioral dynamics particularly for small sized networks. The analysis of the network dynamics has provided useful information for experimental design for future in vitro experimental work. PMID- 21689474 TI - Multi-equilibrium property of metabolic networks: SSI module. AB - BACKGROUND: Revealing the multi-equilibrium property of a metabolic network is a fundamental and important topic in systems biology. Due to the complexity of the metabolic network, it is generally a difficult task to study the problem as a whole from both analytical and numerical viewpoint. On the other hand, the structure-oriented modularization idea is a good choice to overcome such a difficulty, i.e. decomposing the network into several basic building blocks and then studying the whole network through investigating the dynamical characteristics of the basic building blocks and their interactions. Single substrate and single product with inhibition (SSI) metabolic module is one type of the basic building blocks of metabolic networks, and its multi-equilibrium property has important influence on that of the whole metabolic networks. RESULTS: In this paper, we describe what the SSI metabolic module is, characterize the rates of the metabolic reactions by Hill kinetics and give a unified model for SSI modules by using a set of nonlinear ordinary differential equations with multi-variables. Specifically, a sufficient and necessary condition is first given to describe the injectivity of a class of nonlinear systems, and then, the sufficient condition is used to study the multi equilibrium property of SSI modules. As a main theoretical result, for the SSI modules in which each reaction has no more than one inhibitor, a sufficient condition is derived to rule out multiple equilibria, i.e. the Jacobian matrix of its rate function is nonsingular everywhere. CONCLUSIONS: In summary, we describe SSI modules and give a general modeling framework based on Hill kinetics, and provide a sufficient condition for ruling out multiple equilibria of a key type of SSI module. PMID- 21689475 TI - Network screening of Goto-Kakizaki rat liver microarray data during diabetic progression. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a complex systemic disease, with significant disorders of metabolism. The liver, a central energy metabolic organ, plays a critical role in the development of diabetes. Although gene expression levels are able to be measured via microarray since 1996, it is difficult to evaluate the contributions of one altered gene expression to a specific disease. One of the reasons is that a whole network picture responsible for a specific phase of diabetes is missing, while a single gene has to be put into a network picture to evaluate its importance. In the aim of identifying significant transcriptional regulatory networks in the liver contributing to diabetes, we have performed comprehensive active regulatory network survey by network screening in 4 weeks (w), 8-12 w, and 18-20 w Goto-Kakizaki (GK) rat liver microarray data. RESULTS: We identify active regulatory networks in GK rat by network screening in the following procedure. First, the regulatory networks are compiled by using the known binary relationships between the transcriptional factors and their regulated genes and the biological classification scheme, and second, the consistency of each regulatory network with the microarray data measured in GK rat is estimated to detect the active networks under the corresponding conditions. The comprehensive survey of the consistency between the networks and the measured data by the network screening approach in the case of non-insulin dependent diabetes in the GK rat reveals: 1. More pathways are active during inter-middle stage diabetes; 2. Inflammation, hypoxia, increased apoptosis, decreased proliferation, and altered metabolism are characteristics and display as early as 4 weeks in GK strain; 3. Diabetes progression accompanies insults and compensations; 4. Nuclear receptors work in concert to maintain normal glycemic robustness system. CONCLUSION: Notably this is the first comprehensive network screening study of non-insulin dependent diabetes in the GK rat based on high throughput data of the liver. Several important pathways have been revealed playing critical roles in the diabetes progression. Our findings also implicate that network screening is able to help us understand complex disease such as diabetes, and demonstrate the power of network systems biology approach to elucidate the essential mechanisms which would escape conventional single gene-based analysis. PMID- 21689476 TI - Possible linkages between the inner and outer cellular states of human induced pluripotent stem cells. AB - BACKGROUND: Human iPS cells (hiPSCs) have attracted considerable attention for applications to drug screening and analyses of disease mechanisms, and even as next generation materials for regenerative medicine. Genetic reprogramming of human somatic cells to a pluripotent state was first achieved by the ectopic expression of four factors (Sox2, Oct4, Klf4 and c-Myc), using a retrovirus. Subsequently, this method was applied to various human cells, using different combinations of defined factors. However, the transcription factor-induced acquisition of replication competence and pluripotency raises the question as to how exogenous factors induce changes in the inner and outer cellular states. RESULTS: We analyzed both the RNA profile, to reveal changes in gene expression, and the glycan profile, to identify changes in glycan structures, between 51 cell samples of four parental somatic cell (SC) lines from amniotic mesodermal, placental artery endothelial, and uterine endometrium sources, fetal lung fibroblast (MRC-5) cells, and nine hiPSC lines that were originally established. The analysis of this information by standard statistical techniques combined with a network approach, named network screening, detected significant expression differences between the iPSCs and the SCs. Subsequent network analysis of the gene expression and glycan signatures revealed that the glycan transfer network is associated with known epitopes for differentiation, e.g., the SSEA epitope family in the glycan biosynthesis pathway, based on the characteristic changes in the cellular surface states of the hiPSCs. CONCLUSIONS: The present study is the first to reveal the relationships between gene expression patterns and cell surface changes in hiPSCs, and reinforces the importance of the cell surface to identify established iPSCs from SCs. In addition, given the variability of iPSCs, which is related to the characteristics of the parental SCs, a glycosyltransferase expression assay might be established to define hiPSCs more precisely and thus facilitate their standardization, which are important steps towards the eventual therapeutic applications of hiPSCs. PMID- 21689477 TI - Genome-wide analysis of the transcription factor binding preference of human bi directional promoters and functional annotation of related gene pairs. AB - BACKGROUND: Bi-directional gene pairs have received considerable attention for their prevalence in vertebrate genomes. However, their biological relevance and exact regulatory mechanism remain less understood. To study the inner properties of this gene organization and the difference between bi- and uni-directional genes, we conducted a genome-wide investigation in terms of their sequence composition, functional association and regulatory motif discovery. RESULTS: We identified 1210 bi-directional gene pairs based on the GRCh37 assembly data, accounting for 11.6% of all the human genes owning RNAs. CpG islands were detected in 98.42% of bi-directional promoters and 61.07% of unidirectional promoters. Functional enrichment analysis in GO and GeneGO both revealed that bi directional genes tend to be associated with housekeeping functions in metabolism pathways and nuclear processes, and 46.84% of the pair members are involved in the same biological function. By fold-enrichment analysis, we characterized 73 and 43 putative transcription factor binding sites(TFBS) that preferentially occur in bi-directional promoters from TRANSFAC and JASPAR database respectively. By text mining, some of them were verified by individual experiments and several novel binding motifs were also identified. CONCLUSIONS: Bi-directional promoters feature a significant enrichment of CpG-islands as well as a high GC content. We provided insight into the function constraints of bi-directional genes and found that paired genes are biased toward functional similarities. We hypothesized that the functional association underlies the co-expression of bi-directional genes. Furthermore, we proposed a set of putative regulatory motifs in the bi directional promoters for further experimental studies to investigate transcriptional regulation of bi-directional genes. PMID- 21689478 TI - Functional pathway mapping analysis for hypoxia-inducible factors. AB - BACKGROUND: Hypoxia-inducible factors (HIFs) are transcription factors that play a crucial role in response to hypoxic stress in living organisms. The HIF pathway is activated by changes in cellular oxygen levels and has significant impacts on the regulation of gene expression patterns in cancer cells. Identifying functional conservation across species and discovering conserved regulatory motifs can facilitate the selection of reference species for empirical tests. This paper describes a cross-species functional pathway mapping strategy based on evidence of homologous relationships that employs matrix-based searching techniques for identifying transcription factor-binding sites on all retrieved HIF target genes. RESULTS: HIF-related orthologous and paralogous genes were mapped onto the conserved pathways to indicate functional conservation across species. Quantitatively measured HIF pathways are depicted in order to illustrate the extent of functional conservation. The results show that in spite of the evolutionary process of speciation, distantly related species may exhibit functional conservation owing to conservative pathways. The novel terms OrthRate and ParaRate are proposed to quantitatively indicate the flexibility of a homologous pathway and reveal the alternative regulation of functional genes. CONCLUSION: The developed functional pathway mapping strategy provides a bioinformatics approach for constructing biological pathways by highlighting the homologous relationships between various model species. The mapped HIF pathways were quantitatively illustrated and evaluated by statistically analyzing their conserved transcription factor-binding elements. KEYWORDS: hypoxia-inducible factor (HIF), hypoxia-response element (HRE), transcription factor (TF), transcription factor binding site (TFBS), KEGG (Kyoto Encyclopedia of Genes and Genomes), cross-species comparison, orthology, paralogy, functional pathway. PMID- 21689479 TI - Regulatory link mapping between organisms. AB - BACKGROUND: Identification of gene regulatory networks is useful in understanding gene regulation in any organism. Some regulatory network information has already been determined experimentally for model organisms, but much less has been identified for non-model organisms, and the limited amount of gene expression data available for non-model organisms makes inference of regulatory networks difficult. RESULTS: This paper proposes a method to determine the regulatory links that can be mapped from a model to a non-model organism. Mapping a regulatory network involves mapping the transcription factors and target genes from one genome to another. In the proposed method, Basic Local Alignment Search Tool (BLAST) and InterProScan are used to map the transcription factors, whereas BLAST along with transcription factor binding site motifs and the GALF-P tool are used to map the target genes. Experiments are performed to map the regulatory network data of S. cerevisiae to A. thaliana and analyze the results. Since limited information is available about gene regulatory network links, gene expression data is used to analyze results. A set of rules are defined on the gene expression experiments to identify the predicted regulatory links that are well supported. CONCLUSIONS: Combining transcription factors mapped using BLAST and subfamily classification, together with target genes mapped using BLAST and binding site motifs, produced the best regulatory link predictions. More than two thirds of these predicted regulatory links that were analyzed using gene expression data have been verified as correctly mapped regulatory links in the target genome. PMID- 21689480 TI - DBAC: a simple prediction method for protein binding hot spots based on burial levels and deeply buried atomic contacts. AB - BACKGROUND: A protein binding hot spot is a cluster of residues in the interface that are energetically important for the binding of the protein with its interaction partner. Identifying protein binding hot spots can give useful information to protein engineering and drug design, and can also deepen our understanding of protein-protein interaction. These residues are usually buried inside the interface with very low solvent accessible surface area (SASA). Thus SASA is widely used as an outstanding feature in hot spot prediction by many computational methods. However, SASA is not capable of distinguishing slightly buried residues, of which most are non hot spots, and deeply buried ones that are usually inside a hot spot. RESULTS: We propose a new descriptor called "burial level" for characterizing residues, atoms and atomic contacts. Specifically, burial level captures the depth the residues are buried. We identify different kinds of deeply buried atomic contacts (DBAC) at different burial levels that are directly broken in alanine substitution. We use their numbers as input for SVM to classify between hot spot or non hot spot residues. We achieve F measure of 0.6237 under the leave-one-out cross-validation on a data set containing 258 mutations. This performance is better than other computational methods. CONCLUSIONS: Our results show that hot spot residues tend to be deeply buried in the interface, not just having a low SASA value. This indicates that a high burial level is not only a necessary but also a more sufficient condition than a low SASA for a residue to be a hot spot residue. We find that those deeply buried atoms become increasingly more important when their burial levels rise up. This work also confirms the contribution of deeply buried interfacial atomic contacts to the energy of protein binding hot spot. PMID- 21689481 TI - Support vector machine prediction of enzyme function with conjoint triad feature and hierarchical context. AB - BACKGROUND: Enzymes are known as the largest class of proteins and their functions are usually annotated by the Enzyme Commission (EC), which uses a hierarchy structure, i.e., four numbers separated by periods, to classify the function of enzymes. Automatically categorizing enzyme into the EC hierarchy is crucial to understand its specific molecular mechanism. RESULTS: In this paper, we introduce two key improvements in predicting enzyme function within the machine learning framework. One is to introduce the efficient sequence encoding methods for representing given proteins. The second one is to develop a structure based prediction method with low computational complexity. In particular, we propose to use the conjoint triad feature (CTF) to represent the given protein sequences by considering not only the composition of amino acids but also the neighbor relationships in the sequence. Then we develop a support vector machine (SVM)-based method, named as SVMHL (SVM for hierarchy labels), to output enzyme function by fully considering the hierarchical structure of EC. The experimental results show that our SVMHL with the CTF outperforms SVMHL with the amino acid composition (AAC) feature both in predictive accuracy and Matthew's correlation coefficient (MCC). In addition, SVMHL with the CTF obtains the accuracy and MCC ranging from 81% to 98% and 0.82 to 0.98 when predicting the first three EC digits on a low-homologous enzyme dataset. We further demonstrate that our method outperforms the methods which do not take account of hierarchical relationship among enzyme categories and alternative methods which incorporate prior knowledge about inter-class relationships. CONCLUSIONS: Our structure-based prediction model, SVMHL with the CTF, reduces the computational complexity and outperforms the alternative approaches in enzyme function prediction. Therefore our new method will be a useful tool for enzyme function prediction community. PMID- 21689482 TI - MetaDBSite: a meta approach to improve protein DNA-binding sites prediction. AB - BACKGROUND: Protein-DNA interactions play an important role in many fundamental biological activities such as DNA replication, transcription and repair. Identification of amino acid residues involved in DNA binding site is critical for understanding of the mechanism of gene regulations. In the last decade, there have been a number of computational approaches developed to predict protein-DNA binding sites based on protein sequence and/or structural information. RESULTS: In this article, we present metaDBSite, a meta web server to predict DNA-binding residues for DNA-binding proteins. MetaDBSite integrates the prediction results from six available online web servers: DISIS, DNABindR, BindN, BindN-rf, DP-Bind and DBS-PRED and it solely uses sequence information of proteins. A large dataset of DNA-binding proteins is constructed from the Protein Data Bank and it serves as a gold-standard benchmark to evaluate the metaDBSite approach and the other six predictors. CONCLUSIONS: The comparison results show that metaDBSite outperforms single individual approach. We believe that metaDBSite will become a useful and integrative tool for protein DNA-binding residues prediction. The MetaDBSite web-server is freely available at http://projects.biotec.tu dresden.de/metadbsite/ and http://sysbio.zju.edu.cn/metadbsite. PMID- 21689483 TI - Conditional random field approach to prediction of protein-protein interactions using domain information. AB - BACKGROUND: For understanding cellular systems and biological networks, it is important to analyze functions and interactions of proteins and domains. Many methods for predicting protein-protein interactions have been developed. It is known that mutual information between residues at interacting sites can be higher than that at non-interacting sites. It is based on the thought that amino acid residues at interacting sites have coevolved with those at the corresponding residues in the partner proteins. Several studies have shown that such mutual information is useful for identifying contact residues in interacting proteins. RESULTS: We propose novel methods using conditional random fields for predicting protein-protein interactions. We focus on the mutual information between residues, and combine it with conditional random fields. In the methods, protein protein interactions are modeled using domain-domain interactions. We perform computational experiments using protein-protein interaction datasets for several organisms, and calculate AUC (Area Under ROC Curve) score. The results suggest that our proposed methods with and without mutual information outperform EM (Expectation Maximization) method proposed by Deng et al., which is one of the best predictors based on domain-domain interactions. CONCLUSIONS: We propose novel methods using conditional random fields with and without mutual information between domains. Our methods based on domain-domain interactions are useful for predicting protein-protein interactions. PMID- 21689485 TI - Peripartum pubic symphysis separation: a case report and review of the literature. AB - Although peripartum pubic symphysis diastasis is an uncommon complication of delivery, it can lead to considerable and sometimes long-term disability. Although the initial clinical examination and diagnostic workup for this complication are relatively straightforward, the best treatment for a peripartum pubic symphysis diastasis is less clear. Historically, nearly all women were treated conservatively with bed rest and pelvic binders. However, more recent case reports have described more invasive orthopedic procedures being used to help speedy recovery. In this study, we present a case of a 22-year-old primigravida who had a severe pubic symphysis separation after a vaginal delivery complicated by a shoulder dystocia. We also reviewed the literature on this topic over the past 20 years to gain a better understanding of the clinical factors surrounding peripartum pubic symphysis separation and the treatment option available to women with this complication. TARGET AUDIENCE: Obstetricians & Gynecologists. LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to identify the clinical factors that associated with peripartum pubic symphysis separation; perform a diagnostic workup when a peripartum pubic symphysis separation is suspected; distinguish the conservative and invasive orthopedic interventions available for the treatment of peripartum pubic symphysis separation; and show that the degree of patient disability after peripartum pubic symphysis separation varies greatly and no clinical factors or diagnostic studies effectively predict the course of patient recovery. PMID- 21689484 TI - Integrating multiple types of data to predict novel cell cycle-related genes. AB - BACKGROUND: Cellular functions depend on genetic, physical and other types of interactions. As such, derived interaction networks can be utilized to discover novel genes involved in specific biological processes. Epistatic Miniarray Profile, or E-MAP, which is an experimental platform that measures genetic interactions on a genome-wide scale, has successfully recovered known pathways and revealed novel protein complexes in Saccharomyces cerevisiae (budding yeast). RESULTS: By combining E-MAP data with co-expression data, we first predicted a potential cell cycle related gene set. Using Gene Ontology (GO) function annotation as a benchmark, we demonstrated that the prediction by combining microarray and E-MAP data is generally >50% more accurate in identifying co functional gene pairs than the prediction using either data source alone. We also used transcription factor (TF)-DNA binding data (Chip-chip) and protein phosphorylation data to construct a local cell cycle regulation network based on potential cell cycle related gene set we predicted. Finally, based on the E-MAP screening with 48 cell cycle genes crossing 1536 library strains, we predicted four unknown genes (YPL158C, YPR174C, YJR054W, and YPR045C) as potential cell cycle genes, and analyzed them in detail. CONCLUSION: By integrating E-MAP and DNA microarray data, potential cell cycle-related genes were detected in budding yeast. This integrative method significantly improves the reliability of identifying co-functional gene pairs. In addition, the reconstructed network sheds light on both the function of known and predicted genes in the cell cycle process. Finally, our strategy can be applied to other biological processes and species, given the availability of relevant data. PMID- 21689486 TI - Environmental toxicant exposure during pregnancy. AB - This literature review is meant to serve as a brief reference for acute and chronic poisonings in pregnant women, specifically involving environmental toxicants commonly present in the home or workplace. These scenarios are familiar to primary care providers but cause great confusion for practitioners and anxiety in the pregnant patient. Herein, we review metals and metalloids, organic solvents, disinfectant byproducts, pesticides, plasticizers, and multiple air pollutants. Reviews of specific studies involving these toxicants are provided to assist practitioners in providing information to patients regarding potential sources, mechanism of action, current laboratory and epidemiological studies, and possible treatments. Literature-based associations with specific toxicants and various pregnancy outcomes are also outlined. Finally, a contact list of important federal and state toxicology support services is provided. TARGET AUDIENCE: Obstetricians & Gynecologists. LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to assess both acute and chronic consequences of various environmental toxic exposures in pregnancy; to evaluate possible pregnancy related specific events surrounding environmental pollutants; and to identify common exposure routes and implement therapeutic interventions where appropriate. PMID- 21689487 TI - The use of telemedicine in obstetrics: a review of the literature. AB - Telemedicine has been advertised for increasing efficiency, extending the scope of obstetric practice, improving pregnancy outcomes, and reducing costs in the healthcare system. The extent of telemedicine use in obstetrics was identified with a literature search. A total of 268 articles were identified of which 60 are the basis for this review. Telemedicine has been used to read ultrasounds, interpret nonstress tests, counsel patients, manage diabetes, manage postpartum depression, and support parents and children postpartum from remote sites. Reductions in time lost from work, transportation costs, more efficiency for the health care providers, and reducing medical costs all have been suggested as benefits of telemedicine. Despite the information published about telemedicine in obstetrics, this technology has not been shown to have adverse effects in obstetrics but neither has it demonstrated unequivocal benefits. Properly structured and powered investigations will be needed to determine the role of telemedicine in the future. TARGET AUDIENCE: Obstetricians & Gynecologists. LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to diagnose and treat diabetes using telemedicine techniques; assess the current scope of research in telemedicine in obstetrics; implement clinical telemedicine consultations based on the interaction and the needs of the participants; and the opportunities for further research in telemedicine in obstetrics. PMID- 21689488 TI - Developments in MS over the Past 17 Years the MS Forum and The International MS Journal. AB - When The International MS Journal (IMSJ) first appeared in 1994 multiple sclerosis (MS) was an under-recognized disease of little interest therapeutically. Its frequency was not great enough to interest the major pharmaceutical companies, its cause was unknown and evidence of any major therapeutic effect was lacking. PMID- 21689489 TI - MS Forum/MS Over the Past 17 Years. AB - At its final meeting, the MS Forum Executive Committee reviewed highlights of where things stood prior to the immunomodulatory era, and how things have evolved subsequently. What the future might hold was discussed in a second session. Prior to 1990: Genetic predisposition to multiple sclerosis (MS), as determined by human leukocyte antigen expression, was established and an environmental trigger (Epstein-Barr virus?) was suspected, as was lack of sunshine. Substantial evidence for activated T-cells as relapse initiators had accumulated. Defective regulatory cell function that correlated with disease activity was shown. Adrenocorticotropic hormone lessened relapse severity as did its steroid replacement. A trial of cyclosporine, a T-cell inhibitor, in progressive MS failed. The drug, not the patients chosen, was blamed. 1990-2010: Approval of interferon-beta (IFNB)-1b was followed promptly by IFNB-1a, glatiramer acetate, mitoxantrone and then by natalizumab and fingolimod. All reduce MS attack frequency and new lesion accumulation. None have reduced disability progression in progressive MS. Brain atrophy, cognitive loss and axonal interruption in progressive MS depend on innate immune system activation rather than on T-cells. New strategies are needed. PMID- 21689490 TI - 20th meeting of the European neurological society, 19-23 june 2010, berlin, Germany. AB - More than 3000 neurologists attended the 20th Meeting of the European Neurological Society (ENS) and participated in the exciting and highly scientific programme. Eighty per cent of the submitted abstracts, which covered all aspects of neurology, were accepted. One major symposium, 16 oral presentations and 112 posters on multiple sclerosis (MS) were included in the programme. Additionally, there were three teaching courses and one interactive case presentation on MS. PMID- 21689491 TI - The Turbid Crystal Ball: Life Plans Affected by MS. AB - Since multiple sclerosis (MS) has its onset at a young age, it is valuable to know how it affects life plans and future perspectives of patients. Through two narratives, this aspect is discussed in this article. The first is the autobiographical journal: The Journal of a Disappointed Man by WNP Barbellion, published in 1920, and the other one is from a contemporary patient. Despite the fact that both narratives are derived from different centuries, clear similarities have been perceived in the patients life plans and future perspectives. The narratives show that the life plans of both patients were adjusted due to physical limitations. Additionally, both patients experienced sorrows for losing the ability to perform passionate hobbies during their life. Moreover, a strong sense of uncertainty was expressed in both narratives concerning their future. PMID- 21689492 TI - Cutaneous Side-effects of Immunomodulators in MS. AB - Local skin reactions to subcutaneous injections of interferon beta (IFNB) or glatiramer acetate (GA) in multiple sclerosis (MS) are frequent, while severe cutaneous toxicity is rare. Both IFNB and GA are immunomodulatory drugs that have excellent safety profiles and are currently used for treatment of MS. They are administered by SC injection every other day for IFNB-1b, three times a week for IFNB-1a or daily for 20 mg for GA. The most common adverse effects, which occur in approximately 20-60% of patients, include pain, inflammation and induration at the injection sites. Another adverse effect is frank panniculitis followed by localized lipoatrophy at the injection sites, which has been described in half of the patients receiving GA injections but is also described with Subcutaneous IFNB 1b. No guidelines have yet been established for the treatment of skin reactions, which is a frequent point for discussion between neurologists and dermatologists. In addition, no treatment has been found for established lipoatrophy. The prevention and management of cutaneous side-effects include patient education, regular examination and manual palpation of all injection sites. Non-steroid antiinflammatory gels, local corticosteroids or endermology can help patients to resolve side-effects and to continue immunomodulatory treatment. PMID- 21689493 TI - Finding Quality of Life Despite MS: Harnessing Resilience. AB - The ability to cope emotionally and experience quality of life (QoL) do not appear to be correlated with severity of disease or disability amongst people with multiple sclerosis (MS). An exploration of the health-related literature (trauma, chronic illness, disability, loss) from a resiliency perspective identifies a constellation of variables: personality and environmental characteristics, resiliency processes and drives for growth and healing which can guide the health-care practitioner wishing to enable QoL despite MS. PMID- 21689494 TI - Multiple Sclerosis: The Big Questions- The MS Forum Workshop. AB - The American Academy of Neurology (AAN) Annual Meeting was held in Toronto, Canada from 10-17 April, 2010. As usual, multiple sclerosis (MS) featured prominently with about 450 poster and platform presentations on various aspects. Highlights were presentations on the controversial theory of venous obstruction as a cause of MS and updates on promising oral treatments, particularly fingolimod, cladribine and teriflumomide. PMID- 21689495 TI - Epstein-Barr Virus and MS. AB - Epstein-Barr virus (EBV) infection, particularly symptomatic infection, is closely associated with multiple sclerosis (MS). The strength of this association, the interaction of EBV infection with genetic risk factors and emerging immunological data have resulted in some investigators arguing that this association may be causative. Causation, however, is a complex science and more extensive and definitive data is required to convince the wider community that EBV is the pivotal factor in the complex causal pathway that ultimately leads to the development of MS. PMID- 21689497 TI - Russell Brains Review of MS. AB - In 1930 there were many conflicting views on the cause, incidence, precipitating factors, inheritance and treatment of multiple sclerosis (MS). A young, London neurologist summarized the state of understanding of the disease with his personal view of many of the uncertain areas, and clarified the thinking for the neurological community at that time. Although his later career was influential in many fields of medicine, and his personal influence was extraordinary in many areas as an author, educator, administrator, opinion leader and historian, his review was an important milestone in the history of MS. PMID- 21689496 TI - Epstein-Barr Virus and MS:Causality or Association? AB - The search for the aetiology of multiple sclerosis (MS) has led to many theories over the years. It has become clear, however, that MS is complex and multifactorial, involving many interlacing mechanisms, many of which appear to be playing a role in the causation and evolution of the disease. In the large part for epidemiological reasons, an infectious aetiology has always been a prime suspect in this search. Although many agents have been examined over the years, the Epstein-Barr virus (EBV) has re-emerged as a candidate pathogen, based to a large degree on sero-epidemiological evidence, and on the knowledge of the effects this virus is capable of producing in other situations. PMID- 21689498 TI - Acute Psychosis as the Initial Presentation of MS: A Case Report. AB - Psychiatric disorders have been commonly recognized to be associated with multiple sclerosis (MS) during the course of the illness or as a result of the side effects of the drugs used for its management. There have been reports of MS patirents, presenting initially with pure psychiatric symptoms. Amongst these, atypical psychosis has been infrequently reported to be a feature of MS; presentation with typical features of acute psychosis associated with stress appears to be very rare. Hence, this should always prompt for consideration of other diagnoses, including functional psychosis. Nonetheless, as illustrated by the following case report, acute onset of demyelinating diseases with the clinical phenotype of acute psychosis associated with stress may. PMID- 21689499 TI - The clinical usefulness of routine MRI assessment. AB - Although the diagnostic value of magnetic resonance imaging (MRI) in multiple sclerosis (MS) is widely accepted, the clinical usefulness of routine MRI for monitoring the evolution of patients with MS is less widely accepted. It is not uncommon for clinicians to say that they treat the patient, not the MRI. In this review, we highlight some of the evidence that routine MRI surveillance of patients with MS provides important information about disease activity that is not evident clinically, and that this information can help with prognosis and management decisions. Specific recommendations for MRI surveillance of MS patients are provided. PMID- 21689500 TI - Tumour Necrosis Factor Neutralization in MS: A Cautionary Tale. AB - Lenercept, a tumour necrosis factor (TNF) capture molecule, was tested in a double- blind, placebocontrolled Phase II trial in multiple sclerosis (MS). Most patients had relapsing-remitting disease. The code was broken once all patients had been treated for at least 24 weeks. Patients on the drug experienced one and a half times as many MS attacks as those on placebo. MS attacks lasted one and a half times as long in those on the drug as those on placebo. Additionally, MS related complaints voiced by patients on drug were much increased. Prior studies of TNF capture molecules in animals with experimental autoimmune encephalomyelitis turned out to have been counter-predictive. Surprisingly, magnetic resonance imaging scans performed every 4 weeks over the course of the trial, immediately prior to intravenous dosing, were uninformative. The lenercept trial findings raise concerns about other agents that lower TNF levels and that are sometimes given to MS patients. As an example, the possibility is discussed that cyclo propyl-substituted fluoroquinolone antibiotics, of which ciprofloxacin is the most studied, may provoke worsening of MS because of their TNF-inhibiting properties. PMID- 21689501 TI - American academy of neurology annual meeting. AB - The American Academy of Neurology (AAN) Annual Meeting was held in Toronto, Canada from 10 to 17 April, 2010. As usual, multiple sclerosis (MS) featured prominently with about 450 poster and platform presentations on various aspects. Highlights were presentations on the controversial theory of venous obstruction as a cause of MS and updates on promising oral treatments, particularly fingolimod, cladribine and teriflumomide. PMID- 21689502 TI - Clinical effectiveness and cost-effectiveness of imatinib dose escalation for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours that have progressed on treatment at a dose of 400 mg/day: a systematic review and economic evaluation. AB - BACKGROUND: Imatinib dose escalation is advocated for gastrointestinal stromal tumour (GIST) treatment, but its effectiveness compared with sunitinib and best supportive care (BSC) after failure at the 400 mg/day dose is unknown. OBJECTIVES: To assess the effectiveness and cost-effectiveness of imatinib at escalated doses of 600 or 800 mg/day for patients with unresectable and/or metastatic GISTs whose disease had progressed on 400 mg/day. DATA SOURCES: Electronic databases, including MEDLlNE, MEDLINE In-Process, EMBASE, BIOSIS, Science Citation Index, Health Management Information Consortium and the Cochrane Controlled Trials Register, were searched until September 2009. REVIEW METHODS: A systematic review of the literature was carried out according to standard methods. An economic model was constructed to assess the cost-effectiveness of seven alternative pathways for treating patients with unresectable and/or metastatic GISTs. RESULTS: Five primary studies involving 669 people were included for clinical effectiveness; four reported imatinib and one reported sunitinib. The data were essentially observational as none of the studies was designed to specifically assess treatment of patients whose disease had progressed on 400 mg/day imatinib. For 600 mg/day imatinib, between 26% and 42% of patients showed either a partial response (PR) or stable disease (SD). Median time to progression was 1.7 months (range 0.7-24.9 months). For 800 mg/day imatinib, between 29% and 33% of patients showed either a PR or SD. Median overall survival (OS) was 19 months [95% confidence interval (CI) 13 to 23 months]. Progression-free survival ranged from 81 days to 5 months (95% CI 2 to 10 months). Median duration of response was 153 days (range 37-574 days). Treatment progression led to 88% discontinuations but between 16% and 31% of patients required a dose reduction, and 23% required a dose delay. There was a statistically significant increase in the severity of fatigue (p < 0.001) and anaemia (p = 0.015) following dose escalation. For sunitinib, median OS was 90 weeks (95% CI 73 to 106 weeks). For the cost-effectiveness review, only one full text study and one abstract were identified, comparing imatinib at an escalated dose, sunitinib and BSC, although neither was based on a UK context. The definition of BSC was not consistent across the studies, and the pattern of resources (including drugs for treatment) and measures of effectiveness also varied. Within the model, BSC (assumed to include continuing medication to prevent tumour flare) was the least costly and least effective. It would be the care pathway most likely to be cost-effective when the cost per quality-adjusted life-year threshold was < L25,000. Imatinib at 600 mg/day was most likely to be cost-effective at a threshold between L25,000 and L45,000. Imatinib at 600 mg/day followed by further escalation followed by sunitinib was most likely to be cost effective at a threshold > L45,000. LIMITATIONS: The evidence base was sparse, data were non-randomised and potentially biased. The economic model results are surrounded by a considerable degree of uncertainty and open to biases of unknown magnitude and direction. CONCLUSIONS: Around one-third of patients with unresectable and/or metastatic GIST, who fail on 400 mg/day of imatinib, may show response or SD with escalated doses. Between a threshold of L25,000 and L45,000, provision of an escalated dose of imatinib would be most likely to be cost effective. However, these results should be interpreted with caution owing to the limited evidence available on outcomes following imatinib dose escalation or sunitinib for this group of patients. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 21689503 TI - [Diagnosis of prostatic cancer--transrectal biopsy]. PMID- 21689504 TI - [Complications after ultrasound-guided transrectal prostate biopsies]. AB - We present two cases of serious complications after ultrasound-guided transrectal prostate biopsies. Both patients consulted a physician at onset of fever, but no action was taken at this time. At the time of hospitalization, the patients had severe sepsis. They were both treated at the hospital for months. One of the patients was left with renal failure and the other had discitis for two months. To minimize the occurrence of such severe complications, it is important for all physicians to be aware of the primary symptoms of sepsis following prostate biopsies, especially within the first 24 hours. PMID- 21689505 TI - [Psychological consequences of severe overweight in teenagers]. AB - Obese adolescents are adversely affected by the psychosocial consequences of their obesity, which affects their identity development negatively. Further, the obesity-associated psychosocial consequences deteriorate increasingly as the children grow older. Obese adolescents have poor health related quality of life and tend to develop serious emotional and social problems, and a negative body image compared to normal weight peers. Obese adolescents represent approximately 5% of all youths in Denmark, but the treatment options available do not meet the demands of this vulnerable group. PMID- 21689506 TI - [Good experiences with collaboration between research and practice in public health]. AB - In order to evaluate the first year of collaboration between Unit for Health Promotion Research (SDU) and three municipalities a survey was completed with respondents from municipalities. The evaluation showed gains: increased use of research-based working methods, image lift, concrete products delivered, and support in project development. Challenges experienced: different working traditions, translating research into practical know-how, and lack of capacity for knowledge exchange. Future development will include building capacity for knowledge exchange and finding methods for handling the organisational barriers. PMID- 21689507 TI - [Tapentadol is a new, strongly efficative analgeticum with dual effect mechanisms]. AB - Tapentadol exerts its analgesic effects through opioid receptor agonism and noradrenaline reuptake inhibition in the central nervous system. Clinical studies show that tapentadol effectively relieves moderate to severe pain in both post operative and chronic pain. In these trials with equianalgesic doses of tapentadol and oxycodone, treatment with tapentadol was associated with significantly fewer gastrointestinal-related adverse events. Furthermore, in a placebo-controlled study, tapentadol has shown good efficacy in painful diabetic polyneuropathy. PMID- 21689508 TI - [Genu valgum after proximal metaphyseal tibial fracture in children]. AB - Valgus deformity after fracture of the proximal part of the tibia in children was first reported in 1953 by Cozen. Since that time, numerous reports describing this entity have appeared in the literature. There is no consensus regarding the aetiology or the treatment of this posttraumatic deformity. We would like to recommend an algorithm, how to approach and address this complication. PMID- 21689509 TI - [Undocumented regimes after total hip and knee arthroplasty can deteriorate the results]. AB - Undocumented traditions in perioperative care after total hip and knee arthroplasty are passed on as gold standard. However, evidence-based medicine may interfere with traditions. It is therefore essential to revisit traditions or routines once in a while and re-evaluate current practice according to existing evidence. Fast track surgery is an example of replacing traditions with evidence based clinical features in order to optimise perioperative outcome. This article reviews some traditions that may influence outcome regarding pain, infection, blood loss, mobilisation, length of stay in hospital, thromboembolic prophylaxis, and costs. PMID- 21689510 TI - [Protracted case of kerion Celsi in otherwise healthy seven year-old girl]. AB - An otherwise healthy seven year-old girl was admitted to a dermatological department with a severe and progressive scalp infection that had been treated unsuccessfully with conventional antibiotics for over 14 days as well as with surgery. Examination revealed severe tinea capitis with clinical presentation of kerion Celsi, which ultimately resolved with oral antifungals over eight weeks, leaving the patient with a sizeable patch with cicatrical alopecia. The importance of early diagnosis is discussed as are various treatment modalities. PMID- 21689511 TI - [Rupture of the spleen following Caesarean section]. AB - A case of rupture of the spleen after Caesarean section is presented. Rupture of the spleen is a rare complication of pregnancy. The aetiology of splenic rupture is discussed. It is important to keep this rare condition in mind. Fast intervention limits the effects of this potentially lethal condition. PMID- 21689512 TI - [Mega-duodenum and constipation after surgery for congenital atresia of the jejunum]. AB - A 33 year-old female presented with constipation and a right-sided palpable abdominal mass, suspected to be the colon. The colonic transit time was prolonged, but the dilated organ was a mega duodenum that had developed after surgery for three jejunal atresies performed one day after birth. The colon was malrotated, being situated to the left of the columna. Renewed resection surgery was uneventful, and after such surgery the constipation receded and the colonic transit time returned to normal. PMID- 21689513 TI - [Laparoscopic rectum resection with salpingo-oophorectomy via a single incision]. AB - Single-Incision Laparoscopic Surgery (SILS) is an evolving alternative to conventional laparoscopic surgery. We present the case of a low anterior resection combined with left salpingo-oophorectomy performed as a SILS procedure. The patient was a 83-year-old woman, who had a T3N1 rectal cancer 10 cm from the anal verge and a 7 cm left-sided ovarian cyst. Perioperative data and oncological outcomes were comparable to those of conventional laparoscopic procedures. Use of the SILS procedure for pelvic surgery is feasible in carefully selected patients. Prospective comparative studies are needed in the future. PMID- 21689514 TI - [Picture of the month: abscess after intubation]. PMID- 21689517 TI - Nanoscopy in a living multicellular organism expressing GFP. AB - We report superresolution fluorescence microscopy in an intact living organism, namely Caenorhabditis elegans nematodes expressing green fluorescent protein (GFP)-fusion proteins. We also superresolve, by stimulated emission depletion (STED) microscopy, living cultured cells, demonstrating that STED microscopy with GFP can be widely applied. STED with GFP can be performed with both pulsed and continuous-wave lasers spanning a wide wavelength range from at least 556-592 nm. Acquiring subdiffraction resolution images within seconds enables the recording of movies revealing structural dynamics. These results demonstrate that numerous microscopy studies of live samples employing GFP as the marker can be performed at subdiffraction resolution. PMID- 21689518 TI - Mechanophysical stimulations of mucin secretion in cultures of nasal epithelial cells. AB - Nasal epithelial cells secret mucins and are exposed in vivo to airflow-induced mechanophysical stresses, including wall shear stress (WSS), temperature, and humidity. In this work, human nasal epithelial cells cultured under air-liquid interface conditions were subjected to fields of airflow-induced oscillatory WSS at different temperature and humidity conditions. Changes in mucin secretion due to WSS were measured and the role of the cytoskeleton in mucin secretion was explored. Mucin secretion significantly increased in response to WSS in a magnitude-dependent manner with respect to static cultures and independently of the airflow temperature and humidity. In static cultures, mucin secretion decreased at high humidity with or without elevation of the temperature with respect to cultures at a comfortable climate. In cultures exposed to WSS, mucin secretion increased at high temperature with respect to cultures at comfortable climate conditions. The polymerization of actin microfilaments was shown to increase mucin secretion under WSS, whereas the dynamics of microtubule polymerization did not affect secretion. In conclusion, the data in this study show that mucin secretion is sensitive to oscillatory WSS as well as high temperature and humidity conditions. PMID- 21689519 TI - Mechanisms for size-dependent protein segregation at immune synapses assessed with molecular rulers. AB - Immunological synapses are specialized intercellular contacts formed by several types of immune cells in contact with target cells or antigen-presenting cells. A late-stage immune synapse is commonly a bulls-eye pattern of immune cell receptor ligand pairs surrounded by integrin complexes. Based on crystal structures, the intermembrane distance would be ~15 nm for many immune cell receptor-ligand pairs, but ~40 nm for integrin-ligand pairs. Close proximity of these two classes of intermembrane bonds would require significant membrane bending and such proteins can segregate according to their size, which may be key for receptor triggering. However, tools available to evaluate the intermembrane organization of the synapse are limited. Here, we present what we believe to be a novel approach to test the importance of size in the intercellular organization of proteins, using live-cell microscopy of a size-series of fluorescently-labeled molecules and quantum dots to act as molecular rulers. Small particles readily colocalized at the synapse with MHC class I bound to its cognate natural killer cell receptor, whereas particles larger than 15 nm were increasingly segregated from this interaction. Combined with modeling of the partitioning of the particles by scaled-particle adsorption theory, these molecular rulers show how membrane-bending elasticity can drive size-dependent exclusion of proteins within immune synapses. PMID- 21689520 TI - Single-virus tracking reveals a spatial receptor-dependent search mechanism. AB - Viral infection begins with the binding of a virus to a specific target on the surface of the host cell, followed by viral genome delivery into the host and a continuation of the infection process. Before binding occurs, the virus must first find its receptor by a process whose details are largely unknown. We applied high-resolution fluorescence microscopy and single-particle tracking to elucidate the target-finding process in bacteriophage lambda as it infects an Escherichia coli cell. By monitoring the motion of individual viruses through the early stages of infection, we identified a unique spatial focusing process that allows a virus to arrive from its initial random landing site to its destination at the cell pole. The search process is governed by the interaction between the virus and the LamB receptors, and by the spatial organization of the receptor network on the cell surface. Our findings allowed us to develop a theoretical model for the target-finding process that reproduces the key features observed in experiment. We discuss the possible implications of our findings for the process of viral receptor-finding in higher systems. PMID- 21689521 TI - Spatiotemporal constraints on the force-dependent growth of focal adhesions. AB - Focal adhesions (FAs) are the predominant mechanism by which cells mechanically couple to and exert traction forces on their extracellular matrix (ECM). It is widely presumed that FA size is modulated by force to mediate changes in adhesion strength at different levels of cellular tension. However, previous studies seeking correlations between force and FA morphology have yielded variable and often conflicting results. Here we show that a strong correlation between adhesion size and traction force exists only during the initial stages of myosin mediated adhesion maturation and growth. For mature adhesions, no correlation between traction stress and size is observed. Rather, the tension that is sustained at mature adhesions is more strongly influenced by proximity to the cell edge, with peripheral adhesions transmitting higher tension than adhesions near the cell center. Finally, we show that mature adhesions can withstand sixfold increases in tension without changes in size. Thus, although a strong correlation between adhesion size and mechanical tension is observed during the initial stages of myosin-mediated adhesion maturation, no correlation is observed in mature, elongated adhesions. This work places spatiotemporal constraints on the force-dependent growth of adhesions and provides insight into the mechanical regulation of cell-ECM adhesion. PMID- 21689522 TI - Mitochondrial energetics, pH regulation, and ion dynamics: a computational experimental approach. AB - We developed a computational model of mitochondrial energetics that includes Ca(2+), proton, Na(+), and phosphate dynamics. The model accounts for distinct respiratory fluxes from substrates of complex I and complex II, pH effects on equilibrium constants and enzyme kinetics, and the acid-base equilibrium distributions of energy intermediaries. We experimentally determined NADH and DeltaPsi(m) in guinea pig mitochondria during transitions from de-energized to energized, or during state 2/4 to state 3 respiration, or into hypoxia and uncoupling, and compared the results with those obtained in model simulations. The model quantitatively reproduces the experimentally observed magnitude of DeltaPsi(m), the range of NADH levels, respiratory fluxes, and respiratory control ratio upon transitions elicited by sequential additions of substrate and ADP. Simulation results are also able to mimic the change in DeltaPsi(m) upon addition of phosphate to state 4 mitochondria, leading to matrix acidification and DeltaPsi(m) polarization. The steady-state behavior of the integrated mitochondrial model qualitatively simulates the dependence of respiration on the proton motive force, and the expected flux-force relationships existing between respiratory and ATP synthesis fluxes versus redox and phosphorylation potentials. This upgraded mitochondrial model provides what we believe are new opportunities for simulating mitochondrial physiological behavior during dysfunctional states involving changes in pH and ion dynamics. PMID- 21689523 TI - Multiscale modeling of calcium cycling in cardiac ventricular myocyte: macroscopic consequences of microscopic dyadic function. AB - In cardiac ventricular myocytes, calcium (Ca) release occurs at distinct structures (dyads) along t-tubules, where L-type Ca channels (LCCs) appose sarcoplasmic reticulum (SR) Ca release channels (RyR2s). We developed a model of the cardiac ventricular myocyte that simulates local stochastic Ca release processes. At the local Ca release level, the model reproduces Ca spark properties. At the whole-cell level, the model reproduces the action potential, Ca currents, and Ca transients. Changes in microscopic dyadic properties (e.g., during detubulation in heart failure) affect whole-cell behavior in complex ways, which we investigated by simulating changes in the dyadic volume and number of LCCs/RyR2s in the dyad, and effects of calsequestrin (CSQN) as a Ca buffer (CSQN buffer) or a luminal Ca sensor (CSQN regulator). We obtained the following results: 1), Increased dyadic volume and reduced LCCs/RyR2s decrease excitation contraction coupling gain and cause asynchrony of SR Ca release, and interdyad coupling partially compensates for the reduced synchrony. 2), Impaired CSQN buffer depresses Ca transients without affecting the synchrony of SR Ca release. 3), When CSQN regulator function is impaired, interdyad coupling augments diastolic Ca release activity to form Ca waves and long-lasting Ca release events. PMID- 21689524 TI - Transmembrane helix orientation and dynamics: insights from ensemble dynamics with solid-state NMR observables. AB - As the major component of membrane proteins, transmembrane helices embedded in anisotropic bilayer environments adopt preferential orientations that are characteristic or related to their functional states. Recent developments in solid-state nuclear magnetic resonance (SSNMR) spectroscopy have made it possible to measure NMR observables that can be used to determine such orientations in a native bilayer environment. A quasistatic single conformer model is frequently used to interpret the SSNMR observables, but important motional information can be missing or misinterpreted in the model. In this work, we have investigated the orientation of the single-pass transmembrane domain of viral protein "u" (VpuTM) from HIV-1 by determining an ensemble of structures using multiple conformer models based on the SSNMR ensemble dynamics technique. The resulting structure ensemble shows significantly larger orientational fluctuations while the ensemble averaged orientation is compatible with the orientation based on the quasistatic model. This observation is further corroborated by comparison with the VpuTM orientation from comparative molecular dynamics simulations in explicit bilayer membranes. SSNMR ensemble dynamics not only reveals the importance of transmembrane helix dynamics in interpretation of SSNMR observables, but also provides a means to simultaneously extract both transmembrane helix orientation and dynamics information from the SSNMR measurements. PMID- 21689525 TI - Solid-state NMR ensemble dynamics as a mediator between experiment and simulation. AB - Solid-state NMR (SSNMR) is a powerful technique to describe the orientations of membrane proteins and peptides in their native membrane bilayer environments. The deuterium ((2)H) quadrupolar splitting (DQS), one of the SSNMR observables, has been used to characterize the orientations of various single-pass transmembrane (TM) helices using a semistatic rigid-body model such as the geometric analysis of labeled alanine (GALA) method. However, dynamic information of these TM helices, which could be related to important biological function, can be missing or misinterpreted with the semistatic model. We have investigated the orientation of WALP23 in an implicit membrane of dimyristoylglycerophosphocholine by determining an ensemble of structures using multiple conformer models with a DQS restraint potential. When a single conformer is used, the resulting helix orientation (tilt angle (tau) of 5.6 +/- 3.2 degrees and rotation angle (rho) of 141.8 +/- 40.6 degrees ) is similar to that determined by the GALA method. However, as the number of conformers is increased, the tilt angles of WALP23 ensemble structures become larger (26.9 +/- 6.7 degrees ), which agrees well with previous molecular dynamics simulation results. In addition, the ensemble structure distribution shows excellent agreement with the two-dimensional free energy surface as a function of WALP23's tau and rho. These results demonstrate that SSNMR ensemble dynamics provides a means to extract orientational and dynamic information of TM helices from their SSNMR observables and to explain the discrepancy between molecular dynamics simulation and GALA-based interpretation of DQS data. PMID- 21689526 TI - Hofmeister effect in confined spaces: halogen ions and single molecule detection. AB - Despite extensive research in the nanopore-sensing field, there is a paucity of experimental studies that investigate specific ion effects in confined spaces, such as in nanopores. Here, the effect of halogen anions on a simple bimolecular complexation reaction between monodisperse poly(ethylene glycol) (PEG) and alpha hemolysin nanoscale pores have been investigated at the single-molecule level. The anions track the Hofmeister ranking according to their influence upon the on rate constant. An inverse relationship was demonstrated for the off-rate and the solubility of PEG. The difference among anions spans several hundredfold. Halogen anions play a very significant role in the interaction of PEG with nanopores although, unlike K(+), they do not bind to PEG. The specific effect appears dominated by a hydration-dehydration process where ions and PEG compete for water. Our findings provide what we believe to be novel insights into physicochemical mechanisms involved in single-molecule interactions with nanopores and are clearly relevant to more complicated chemical and biological processes involving a transient association of two or more molecules (e.g., reception, signal transduction, enzyme catalysis). It is anticipated that these findings will advance the development of devices with nanopore-based sensors for chemical and biological applications. PMID- 21689527 TI - Model of aquaporin-4 supramolecular assembly in orthogonal arrays based on heterotetrameric association of M1-M23 isoforms. AB - Tetramers of aquaporin-4 (AQP4) water channels form supramolecular assemblies in cell membranes called orthogonal arrays of particles (OAPs). We previously reported evidence that a short (M23) AQP4 isoform produced by alternative splicing forms OAPs by an intermolecular N-terminus interaction, whereas the full length (M1) AQP4 isoform does not by itself form OAPs but can coassemble with M23 in OAPs as heterotetramers. Here, we developed a model to predict number distributions of OAP size, shape, and composition as a function M23:M1 molar ratio. Model specifications included: random tetrameric assembly of M1 with M23; intertetramer associations between M23 and M23, but not between M1 and M23 or M1; and a free energy constraint limiting OAP size. Model predictions were tested by total internal reflection fluorescence microscopy of AQP4-green-fluorescent protein chimeras and native gel electrophoresis of cells expressing different M23:M1 ratios. Experimentally validated model predictions included: 1), greatly increased OAP size with increasing M23:M1 ratio; 2), marked heterogeneity in OAP size at fixed M23:M1, with increased M23 fraction in larger OAPs; and 3), preferential M1 localization at the periphery of OAPs. The model was also applied to test predictions about binding to AQP4 OAPs of a pathogenic AQP4 autoantibody found in the neuroinflammatory demyelinating disease neuromyelitis optica. Our model of AQP4 OAPs links a molecular-level interaction of AQP4 with its supramolecular assembly in cell membranes. PMID- 21689528 TI - The bilayer enhances rhodopsin kinetic stability in bovine rod outer segment disk membranes. AB - Rhodopsin is a kinetically stable protein constituting >90% of rod outer segment disk membrane protein. To investigate the bilayer contribution to rhodopsin kinetic stability, disk membranes were systematically disrupted by octyl-beta-D glucopyranoside. Rhodopsin kinetic stability was examined under subsolubilizing (rhodopsin in a bilayer environment perturbed by octyl-beta-D-glucopyranoside) and under fully solubilizing conditions (rhodopsin in a micelle with cosolubilized phospholipids). As determined by DSC, rhodopsin exhibited a scan rate-dependent irreversible endothermic transition at all stages of solubilization. The transition temperature (T(m)) decreased in the subsolubilizing stage. However, once the rhodopsin was in a micelle environment there was little change of the T(m) as the phospholipid/rhodopsin ratio in the mixed micelles decreased during the fully solubilized stage. Rhodopsin thermal denaturation is consistent with the two-state irreversible model at all stages of solubilization. The activation energy of denaturation (E(act)) was calculated from the scan rate dependence of the T(m) and from the rate of rhodopsin thermal bleaching at all stages of solubilization. The E(act) as determined by both techniques decreased in the subsolubilizing stage, but remained constant once fully solubilized. These results indicate the bilayer structure increases the E(act) to rhodopsin denaturation. PMID- 21689529 TI - Transmembrane signaling of chemotaxis receptor tar: insights from molecular dynamics simulation studies. AB - Transmembrane signaling of chemotaxis receptors has long been studied, but how the conformational change induced by ligand binding is transmitted across the bilayer membrane is still elusive at the molecular level. To tackle this problem, we carried out a total of 600-ns comparative molecular dynamics simulations (including model-building simulations) of the chemotaxis aspartate receptor Tar (a part of the periplasmic domain/transmembrane domain/HAMP domain) in explicit lipid bilayers. These simulations reveal valuable insights into the mechanistic picture of Tar transmembrane signaling. The piston-like movement of a transmembrane helix induced by ligand binding on the periplasmic side is transformed into a combination of both longitudinal and transversal movements of the helix on the cytoplasmic side as a result of different protein-lipid interactions in the ligand-off and ligand-on states of the receptor. This conformational change alters the dynamics and conformation of the HAMP domain, which is presumably a mechanism to deliver the signal from the transmembrane domain to the cytoplasmic domain. The current results are consistent with the previously suggested dynamic bundle model in which the HAMP dynamics change is a key to the signaling. The simulations provide further insights into the conformational changes relevant to the HAMP dynamics changes in atomic detail. PMID- 21689530 TI - Extension of a three-helix bundle domain of myosin VI and key role of calmodulins. AB - The molecular motor protein myosin VI moves toward the minus-end of actin filaments with a step size of 30-36 nm. Such large step size either drastically limits the degree of complex formation between dimer subunits to leave enough length for the lever arms, or requires an extension of the lever arms' crystallographically observed structure. Recent experimental work proposed that myosin VI dimerization triggers the unfolding of the protein's proximal tail domain which could drive the needed lever-arm extension. Here, we demonstrate through steered molecular dynamics simulation the feasibility of sufficient extension arising from turning a three-helix bundle into a long alpha-helix. A key role is played by the known calmodulin binding that facilitates the extension by altering the strain path in myosin VI. Sequence analysis of the proximal tail domain suggests that further calmodulin binding sites open up when the domain's three-helix bundle is unfolded and that subsequent calmodulin binding stabilizes the extended lever arms. PMID- 21689531 TI - Long dwell-time passage of DNA through nanometer-scale pores: kinetics and sequence dependence of motion. AB - A detailed understanding of the kinetics of DNA motion though nanometer-scale pores is important for the successful development of many of the proposed next generation rapid DNA sequencing and analysis methods. Many of these approaches require DNA motion through nanopores to be slowed by several orders of magnitude from its native translocation velocity so that the translocation times for individual nucleotides fall within practical timescales for detection. With the increased dwell time of DNA in the pore, DNA-pore interactions begin to play an increasingly important role in translocation kinetics. In previous work, we and others observed that when the DNA dwell time in the pore is substantial (>1 ms), DNA motion in alpha-hemolysin (alpha-HL) pores leads to nonexponential kinetics in the escape of DNA out of the pore. Here we show that a three-state model for DNA escape, involving stochastic binding interactions of DNA with the pore, accurately reproduces the experimental data. In addition, we investigate the sequence dependence of the DNA escape process and show that the interaction strength of adenine with alpha-HL is substantially lower relative to cytosine. Our results indicate a difference in the process by which DNA moves through an alpha-HL nanopore when the motion is fast (microsecond timescale) as compared with when it is slow (millisecond timescale) and strongly influenced by DNA-pore interactions of the kind reported here. We also show the ability of wild-type alpha-HL to detect and distinguish between 5-methylcytosine and cytosine based on differences in the absolute ionic current through the pore in the presence of these two nucleotides. The results we present here regarding sequence-dependent (and dwell-time-dependent) DNA-pore interaction kinetics will have important implications for the design of methods for DNA analysis through reduced-velocity motion in nanopores. PMID- 21689532 TI - Fluorescence cross-correlation spectroscopy reveals mechanistic insights into the effect of 2'-O-methyl modified siRNAs in living cells. AB - RNA interference (RNAi) offers a powerful tool to specifically direct the degradation of complementary RNAs, and thus has great therapeutic potential for targeting diseases. Despite the reported preferences of RNAi, there is still a need for new techniques that will allow for a detailed mechanistic characterization of RNA-induced silencing complex (RISC) assembly and activity to further improve the biocompatibility of modified siRNAs. In contrast to previous reports, we investigated the effects of 2'-O-methyl (2'OMe) modifications introduced at specific positions within the siRNA at the early and late stages of RISC assembly, as well as their influence on target recognition and cleavage directly in living cells. We found that six to 10 2'OMe nucleotides on the 3'-end inhibit passenger-strand release as well as target-RNA cleavage without changing the affinity, strand asymmetry, or target recognition. 2'OMe modifications introduced at the 5'-end reduced activated RISC stability, whereas incorporations at the cleavage site showed only minor effects on passenger-strand release when present on the passenger strand. Our new fluorescence cross-correlation spectroscopy assays resolve different steps and stages of RISC assembly and target recognition with heretofore unresolved detail in living cells, which is needed to develop therapeutic siRNAs with optimized in vivo properties. PMID- 21689533 TI - Modulation of functionally significant conformational equilibria in adenylate kinase by high concentrations of trimethylamine oxide attributed to volume exclusion. AB - The effect of an inert small molecule osmolyte, trimethyl amine N-oxide (TMAO), upon the conformational equilibria of Escherichia coli adenylate kinase was studied using time-resolved FRET. The relative populations of open and closed clefts between the LID and the CORE domains were measured as functions of the concentrations of the substrate ATP over the concentration range 0-18 mM and TMAO over the concentration range 0-4 M. A model was constructed according to which the enzyme exists in equilibrium among four conformational states, corresponding to combinations of open and closed conformations of the LID-CORE and AMP-CORE clefts. ATP is assumed to bind only to those conformations with the closed LID CORE cleft, and TMAO is assumed to be differentially excluded as a hard spherical particle from each of the four conformations in accordance with calculations based upon x-ray crystallographic structures. This model was found to describe quantitatively the dependence of the fraction of the closed LID-CORE cleft upon the concentrations of both ATP and TMAO over the entire range of concentrations with just five undetermined parameters. PMID- 21689534 TI - Molecular origin of Gerstmann-Straussler-Scheinker syndrome: insight from computer simulation of an amyloidogenic prion peptide. AB - Prion proteins become pathogenic through misfolding. Here, we characterize the folding of a peptide consisting of residues 109-122 of the Syrian hamster prion protein (the H1 peptide) and of a more amyloidogenic A117V point mutant that leads in humans to an inheritable form of the Gerstmann-Straussler-Scheinker syndrome. Atomistic molecular dynamics simulations are performed for 2.5 MUs. Both peptides lose their alpha-helical starting conformations and assume a beta hairpin that is structurally similar in both systems. In each simulation several unfolding/refolding events occur, leading to convergence of the thermodynamics of the conformational states to within 1 kJ/mol. The similar stability of the beta hairpin relative to the unfolded state is observed in the two peptides. However, substantial differences are found between the two unfolded states. A local minimum is found within the free energy unfolded basin of the A117V mutant populated by misfolded collapsed conformations of comparable stability to the beta-hairpin state, consistent with increased amyloidogenicity. This population, in which V117 stabilizes a hydrophobic core, is absent in the wild-type peptide. These results are supported by simulations of oligomers showing a slightly higher stability of the associated structures and a lower barrier to association for the mutated peptide. Hence, a single point mutation carrying only two additional methyl groups is here shown to be responsible for rather dramatic differences of structuring within the unfolded (misfolded) state. PMID- 21689535 TI - Viscoelastic properties of isolated collagen fibrils. AB - Understanding the viscoelastic behavior of collagenous tissues with complex hierarchical structures requires knowledge of the properties at each structural level. Whole tissues have been studied extensively, but less is known about the mechanical behavior at the submicron, fibrillar level. Using a microelectromechanical systems platform, in vitro coupled creep and stress relaxation tests were performed on collagen fibrils isolated from the sea cucumber dermis. Stress-strain-time data indicate that isolated fibrils exhibit viscoelastic behavior that could be fitted using the Maxwell-Weichert model. The fibrils showed an elastic modulus of 123 +/- 46 MPa. The time-dependent behavior was well fit using the two-time-constant Maxwell-Weichert model with a fast time response of 7 +/- 2 s and a slow time response of 102 +/- 5 s. The fibrillar relaxation time was smaller than literature values for tissue-level relaxation time, suggesting that tissue relaxation is dominated by noncollagenous components (e.g., proteoglycans). Each specimen was tested three times, and the only statistically significant difference found was that the elastic modulus is larger in the first test than in the subsequent two tests, indicating that viscous properties of collagen fibrils are not sensitive to the history of previous tests. PMID- 21689536 TI - Modelling of lysozyme binding to a cation exchange surface at atomic detail: the role of flexibility. AB - Different approaches were made to predict the adsorbed orientation based on rigid, flexible, or a mixture of both models. To determine the role of flexibility during adsorption, the orientation of lysozyme adsorbed to a negatively charged ligand surface was predicted by a rigid and a flexible model based on two differing protein structures at atomic resolution. For the rigid model, the protein structures were placed at different distances from the ligand surface and the electrostatic interaction energy was calculated for all possible orientations. The results were compared to a flexible model where the binding to the ligand surface was modeled by multiple molecular dynamics simulations starting with 14 initial orientations. Different aspects of the adsorption process were not covered by the rigid model and only detectable by the flexible model. Whereas the results of the rigid model depended sensitively on the protein surface distance and the protein structure, the preferred orientation obtained by the flexible model was closer to a previous experimental determined orientation, robust toward the initial orientation and independent of the initial protein structure. Additionally, it was possible to obtain insights into the preferred binding process of lysozyme on a negatively charged surface by the flexible model. PMID- 21689537 TI - Molecular-dynamics simulations of the ATP/apo state of a multidrug ATP-binding cassette transporter provide a structural and mechanistic basis for the asymmetric occluded state. AB - ATP-binding cassette transporters use the energy of ATP hydrolysis to transport substrates across cellular membranes. They have two transmembrane domains and two cytosolic nucleotide-binding domains. Biochemical studies have characterized an occluded state of the transporter in which nucleotide is tenaciously bound in one active site, whereas the opposite active site is empty or binds nucleotide loosely. Here, we report molecular-dynamics simulations of the bacterial multidrug ATP-binding cassette transporter Sav1866. In two simulations of the ATP/apo state, the empty site opened substantially by way of rotation of the nucleotide-binding domain (NBD) core subdomain, whereas the ATP-bound site remained occluded and intact. We correlate our findings with elastic network and molecular-dynamics simulation analyses of the Sav1866 NBD monomer, and with existing experimental data, to argue that the observed transition is physiological, and that the final structure observed in the ATP/apo simulations corresponds to the tight/loose state of the NBD dimer characterized experimentally. PMID- 21689538 TI - Simulated self-assembly of the HIV-1 capsid: protein shape and native contacts are sufficient for two-dimensional lattice formation. AB - We report Monte Carlo simulations of the initial stages of self-assembly of the HIV-1 capsid protein (CA), using a coarse-grained representation that mimics the CA backbone structure and intermolecular contacts observed experimentally. A simple representation of N-terminal domain/N-terminal domain and N-terminal domain/C-terminal domain interactions, coupled with the correct protein shape, is sufficient to drive formation of an ordered lattice with the correct hexagonal symmetry in two dimensions. We derive an approximate concentration/temperature phase diagram for lattice formation, and we investigate the pathway by which the lattice develops from initially separated CA dimers. Within this model, lattice formation occurs in two stages: 1), condensation of CA dimers into disordered clusters; and 2), nucleation of the lattice by the appearance of one hexamer unit within a cluster. Trimers of CA dimers are important early intermediates, and pentamers are metastable within clusters. Introduction of a preformed hexamer at the beginning of a Monte Carlo run does not directly seed lattice formation, but does facilitate the formation of large clusters. We discuss possible connections between these simulations and experimental observations concerning CA assembly within HIV-1 and in vitro. PMID- 21689539 TI - Protein-level fluctuation correlation at the microcolony level and its application to the Vibrio harveyi quorum-sensing circuit. AB - Gene expression is stochastic, and noise that arises from the stochastic nature of biochemical reactions propagates through active regulatory links. Thus, correlations in gene-expression noise can provide information about regulatory links. We present what to our knowledge is a new approach to measure and interpret such correlated fluctuations at the level of single microcolonies, which derive from single cells. We demonstrated this approach mathematically using stochastic modeling, and applied it to experimental time-lapse fluorescence microscopy data. Specifically, we investigated the relationships among LuxO, LuxR, and the small regulatory RNA qrr4 in the model quorum-sensing bacterium Vibrio harveyi. Our results show that LuxR positively regulates the qrr4 promoter. Under our conditions, we find that qrr regulation weakly depends on total LuxO levels and that LuxO autorepression is saturated. We also find evidence that the fluctuations in LuxO levels are dominated by intrinsic noise. We furthermore propose LuxO and LuxR interact at all autoinducer levels via an unknown mechanism. Of importance, our new method of evaluating correlations at the microcolony level is unaffected by partition noise at cell division. Moreover, the method is first-order accurate and requires less effort for data analysis than single-cell-based approaches. This new correlation approach can be applied to other systems to aid analysis of gene regulatory circuits. PMID- 21689540 TI - Targeted nonviral gene-based inhibition of Galpha(i/o)-mediated vagal signaling in the posterior left atrium decreases vagal-induced atrial fibrillation. AB - BACKGROUND: Pharmacologic and ablative therapies for atrial fibrillation (AF) have suboptimal efficacy. Newer gene-based approaches that target specific mechanisms underlying AF are likely to be more efficacious in treating AF. Parasympathetic signaling appears to be an important contributor to AF substrate. OBJECTIVE: The purpose of this study was to develop a nonviral gene-based strategy to selectively inhibit vagal signaling in the left atrium and thereby suppress vagal-induced AF. METHODS: In eight dogs, plasmid DNA vectors (minigenes) expressing Galpha(i) C-terminal peptide (Galpha(i)ctp) was injected in the posterior left atrium either alone or in combination with minigene expressing Galpha(o)ctp, followed by electroporation. In five control dogs, minigene expressing scrambled peptide (Galpha(R)ctp) was injected. Vagal- and carbachol-induced left atrial effective refractory periods (ERPs), AF inducibility, and Galpha(i/o)ctp expression were assessed 3 days following minigene delivery. RESULTS: Vagal stimulation- and carbachol-induced effective refractory period shortening and AF inducibility were significantly attenuated in atria receiving a Galpha(i2)ctp-expressing minigene and were nearly eliminated in atria receiving both Galpha(i2)ctp- and Galpha(o1)ctp-expressing minigenes. CONCLUSION: Inhibition of both G(i) and G(o) proteins is necessary to abrogate vagal-induced AF in the left atrium and can be achieved via constitutive expression of Galpha(i/o)ctps expressed by nonviral plasmid vectors delivered to the posterior left atrium. PMID- 21689542 TI - Quality of life of endodontically treated versus implant treated patients: a University-based qualitative research study. AB - INTRODUCTION: Up-to-date studies comparing endodontic treatment versus implant supported prosthesis have shown similar clinical outcome and survival rates. However, no data are available comparing both treatment modalities based on the patient's perception of quality of life. This study was designed to qualitatively describe and compare the quality of life of patients with restored, single endodontically treated teeth versus patients with single implant-supported fixed prostheses. METHODS: Forty-eight patients agreed to participate in the study (n = 24 from each treatment modality). Of those, 37 actually participated in the study: 17 were endodontically treated and 20 had an implant-supported prosthesis. Patients in each of the two groups were randomly selected from the Graduate Endodontics and Graduate Periodontics Departments, respectively. Six focus group discussions (n = 3 per treatment group) were held and audio-recorded for subsequent thematic analysis. Data were analyzed to identify common themes within each category and compared to assess any differences in quality of life between the two treatments. Additionally, a quality of life survey, the shortened version of the Oral Health Impact Profile (OHIP-14), was given before the discussion group and the responses analyzed. RESULTS: The results obtained from this study show similar overall OHIP scores and show a high rate of satisfaction with both treatment modalities. Content analysis of the discussion groups revealed several themes and subthemes. The major themes were importance of overall health, financial implications of the treatments, perception of the treatments and its outcomes, time since treatment, and follow-up dental visits. CONCLUSIONS: The results help identify patients' perception and concerns with each treatment modality and assist the clinician and patient in the selection of an optimal treatment for their given situation. In addition to the prognosis and outcomes, clinicians should consider patients' perceptions and preferences as well as the influence each therapy may have on their quality of life, both short- and long term. Overall, all the participants in this study were pleased with the treatment received and expressed a clear message to save their natural dentition whenever possible. PMID- 21689541 TI - Impact of the quality of coronal restoration versus the quality of root canal fillings on success of root canal treatment: a systematic review and meta analysis. AB - INTRODUCTION: Thorough cleaning and shaping of root canals are essential for periapical healing. Restoration of endodontically treated teeth is also required for them to function and prevent coronal leakage. This study compared the impact of the quality of root canal treatment versus the quality of coronal restoration in treatment outcomes. METHODS: Literature search was conducted using the search terms "coronal restoration," "root canal," "periapical status," and "quality." Articles that evaluated the effect of the quality of root filling and coronal restoration or both on the success of root canal treatment were selected. Nine articles were identified and were reviewed by 3 investigators. Data were collected based on predetermined criteria. Percentages of teeth without apical periodontitis were recorded for each category: adequate root canal treatment (AE), inadequate root canal treatment (IE), adequate restoration (AR), and inadequate restoration (IR). Data were analyzed using meta-analysis for odds ratios (ORs). RESULTS: After adjusting for significant covariates to reduce heterogeneity, the results were combined to obtain pooled estimates of the common OR for the comparison of AR/AE versus AR/IE (OR = 2.734; 95% confidence interval [CI], 2.61-2.88; P < .001) and AR/AE versus IR/AE (OR = 2.808; 95% CI, 2.64-2.97; P < .001). CONCLUSIONS: On the basis of the current best available evidence, the odds for healing of apical periodontitis increase with both adequate root canal treatment and adequate restorative treatment. Although poorer clinical outcomes may be expected with adequate root filling-inadequate coronal restoration and inadequate root filling-adequate coronal restoration, there is no significant difference in the odds of healing between these 2 combinations. PMID- 21689543 TI - Five-year changes in periodontal parameters after apical surgery. AB - INTRODUCTION: Most clinical studies on the outcome of apical surgery concentrate on periapical healing based on radiographic and clinical characteristics (signs and symptoms). This study focuses on long-term changes in periodontal parameters after apical surgery. METHODS: Periodontal parameters (ie, probing depth [PD], level of gingival margin [GM], and calculated clinical attachment level [CAL]) were collected at baseline and at 1 and 5 years after apical surgery. Changes in PD, GM, and CAL were calculated over time and were also evaluated in relation to patient-, tooth-, and treatment-related covariables. RESULTS: One hundred eighty six of 242 initially identified teeth could be evaluated. Significant changes in GM and CAL were observed at facial sites during the first year after surgery (mean recession of GM was 0.29 mm, mean CAL loss was 0.20 mm), but none of the periodontal parameters significantly changed between 1 and 5 years after apical surgery. With regard to covariables, the type of incision technique was found to be the major factor affecting changes in GM and CAL between baseline and 1 year after surgery. Age, smoking, and type of periapical healing were the variables influencing the periodontal parameters over the longer observation period of up to 5 years. CONCLUSIONS: Patients should be informed about possible changes in periodontal parameters (gingival recession and loss of attachment) after apical surgery. The surgery itself appears to account for changes observed during the first year, whereas patient- and healing-related factors seem to affect periodontal changes seen thereafter. PMID- 21689544 TI - Endodontic radiography: who is reading the digital radiograph? AB - INTRODUCTION: Digital radiographic imaging systems have undergone tremendous improvements since their introduction. Advantages of digital radiographs over conventional films include lower radiation doses compared with conventional films, instantaneous images, archiving and sharing images easily, and manipulation of several radiographic properties that might help in diagnosis. METHODS: A total of 6 observers including 2 endodontic residents, 3 endodontists, and 1 oral radiologist evaluated 150 molar digital periapical radiographs to determine which of the following conditions existed: normal periapical tissue, widened periodontal ligament, or presence of periapical radiolucency. The evaluators had full control over the radiograph's parameters of the Planmeca Dimaxis software program. All images were viewed on the same computer monitor with ideal vie-wing conditions. The same 6 observers evaluated the same 150 digital images 3 months later. The data were analyzed to determine how well the evaluators agreed with each other (interobserver agreement) for 2 rounds of observations and with themselves (intraobserver agreement). RESULTS: Fleiss kappa statistical analysis was used to measure the level of agreement among multiple raters. The overall Fleiss kappa value for interobserver agreement for the first round of interpretation was 0.34 (P < .001). The overall Fleiss kappa value for interobserver agreement for the second round of interpretation was 0.35 (P < .001). This resulted in fair (0.2-0.4) agreement among the 6 raters at both observation periods. A weighted kappa analysis was used to determine intraobserver agreement, which showed on average a moderate agreement. CONCLUSIONS: The results indicate that the interpretation of a dental radiograph is subjective, irrespective of whether conventional or digital radiographs are used. The factors that appeared to have the most impact were the years of experience of the examiner and familiarity of the operator with a given digital system. PMID- 21689545 TI - Exploring bacterial diversity of endodontic microbiota by cloning and sequencing 16S rRNA. AB - INTRODUCTION: The characterization of microbial communities infecting the endodontic system in each clinical condition may help on the establishment of a correct prognosis and distinct strategies of treatment. The purpose of this study was to determine the bacterial diversity in primary endodontic infections by 16S ribosomal-RNA (rRNA) sequence analysis. METHODS: Samples from root canals of untreated asymptomatic teeth (n = 12) exhibiting periapical lesions were obtained, 16S rRNA bacterial genomic libraries were constructed and sequenced, and bacterial diversity was estimated. RESULTS: A total of 489 clones were analyzed (mean, 40.7 +/- 8.0 clones per sample). Seventy phylotypes were identified of which six were novel phylotypes belonging to the family Ruminococcaceae. The mean number of taxa per canal was 10.0, ranging from 3 to 21 per sample; 65.7% of the cloned sequences represented phylotypes for which no cultivated isolates have been reported. The most prevalent taxa were Atopobium rimae (50.0%), Dialister invisus, Prevotella oris, Pseudoramibacter alactolyticus, and Tannerella forsythia (33.3%). CONCLUSIONS: Although several key species predominate in endodontic samples of asymptomatic cases with periapical lesions, the primary endodontic infection is characterized by a wide bacterial diversity, which is mostly represented by members of the phylum Firmicutes belonging to the class Clostridia followed by the phylum Bacteroidetes. PMID- 21689546 TI - Prognostic factors for clinical outcomes in endodontic microsurgery: a retrospective study. AB - INTRODUCTION: This retrospective study examined the potential prognostic factors on the outcome after endodontic microsurgery and compared the predictors of isolated endodontic lesion with those of both isolated endodontic lesions and endodontic-periodontal lesions. METHODS: The data were collected from patients with a history of endodontic microsurgery performed between August 2004 and December 2008 and at least 1 year before being evaluated. Surgical procedures were performed by the endodontic faculty and residents. After surgery, an operation record form was made with the preoperative, intraoperative, and postoperative factors from the clinical and radiographic measures. For statistical analysis of the predisposing factors, the dependent variable was the dichotomous outcome (ie, success vs failure). RESULTS: Of 907 cases, 491 were retained at follow-up. At the 0.05 level of significance, age, sex (female), tooth position (anterior), root-filling length (inadequate), [corrected] lesion type (endodontic lesion), root-end filling material (mineral trioxide aggregate and Super EBA; Harry J. Bosworth, Skokie, IL), and restoration at follow-up appeared to have a positive effect on the outcome. On the other hand, with an isolated endodontic lesion, the tooth position (anterior), root-filling length (inadequate), [corrected] and restoration at follow-up were significant factors at the 95% confidence level. CONCLUSIONS: Under the control of the significant variables in logistic regression, the potential prognostic factors on the outcome were sex, tooth position, lesion type, and root-end filling material. On the other hand, the tooth position was a pure predictor of an endodontic lesion affecting the clinical outcome. PMID- 21689547 TI - The effect of orthodontic forces on calcitonin gene-related peptide expression in human dental pulp. AB - INTRODUCTION: The purpose of this study was to quantify the effect of moderate and severe orthodontic forces on calcitonin gene-related peptide (CGRP) expression in healthy human dental pulp. METHODS: Thirty human dental pulp samples were obtained from healthy premolars in which extraction was indicated for orthodontic reasons. Before extraction, teeth were divided into 3 groups of 10 premolars each: (1) the control group: healthy premolars without application of orthodontic forces; (2) the moderate force group: a 56-g force was applied to the premolars for 24 hours; and (3) the severe force group: a 224-g force was applied to the premolars for 24 hours. All dental pulp samples were processed, and CGRP was measured by radioimmunoassay. RESULTS: Greater CGRP expression was found in the severe force group followed by the moderate force group. The lower CGRP values were for the control group. The Kruskal-Wallis test showed statistically significant differences between groups (P < .0001). Least significant difference (LSD) post hoc tests showed statistically significant differences in CGRP expression between the control group and the severe force group (P < .0001) but not with the moderate force group (P = .06). Differences between the moderate and severe force groups were statistically significant (P < .0001). CONCLUSIONS: CGRP expression in human dental pulp increases when teeth are submitted to severe orthodontic forces. PMID- 21689548 TI - A prospective, randomized single-blind study of the anesthetic efficacy of frequency-dependent conduction blockade of the inferior alveolar nerve. AB - INTRODUCTION: The purpose of this prospective, randomized single-blind study was to evaluate the degree of pulpal anesthesia obtained with frequency-dependent conduction blockade of the inferior alveolar nerve (IAN). METHODS: Eighty adult volunteers randomly received two IAN blocks: an IAN block followed by continuous electrical stimulation for 3 minutes of the first molar or lateral incisor for six cycles over a time period of 64 minutes; an IAN block followed by mock electrical stimulation using the same cycles. The IAN blocks were administered at two separate appointments spaced at least 1 week apart in a crossover design. An electric pulp tester was used to test for anesthesia of the first molar and lateral incisor. Anesthesia was considered successful when two consecutive 80 readings were obtained within 15 minutes, and the 80 reading was recorded through the 60th minute. RESULTS: The anesthetic success rate for the stimulated IAN block was 35% and 48% for the lateral incisor and first molar, respectively. For the mock stimulated IAN, success was 18% for the lateral incisor and 62% for the first molar. There was no significant difference between the two IAN block techniques. CONCLUSIONS: We concluded that the stimulation of nerves in the presence of local anesthesia (frequency-dependent nerve block) did not statistically increase the success rate of pulpal anesthesia for an IAN block. PMID- 21689550 TI - KLF4 promotes the odontoblastic differentiation of human dental pulp cells. AB - INTRODUCTION: Kruppel-like factor 4 (KLF4) plays an important role in cytodifferentiation and proliferation. Our previous study showed that KLF4 was specifically expressed in polarizing and elongating odontoblasts. However, the role of KLF4 in odontoblast differentiation was still unknown. The purpose of this study was to investigate the role of KLF4 in odontoblastic differentiation of human dental pulp cells (hDPCs). METHODS: hDPCs were treated with odontoblastic induction medium. Odontoblastic differentiation was determined by the detection of alkaline phosphatase (ALPase) activity and the expression of mineralization-related genes including ALP, dentin sialophosphoprotein (DSPP), and dentin matrix protein-1 (DMP-1). Also, cell proliferation ability was examined by the 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay. Simultaneously, messenger RNA and protein levels of KLF4 were detected. pKLF4 IRES2-EGFP plasmid encoding full-length KLF4 was constructed to overexpress KLF4, and biologic effects of KLF4 on hDPCs were investigated by the evaluation of ALPase activity and the detection of ALP, DSPP, and DMP-1 expression and analysis of cell proliferation ability. RESULTS: ALPase activity and the expression of odontoblastic differentiation markers progressively increased in hDPCs cultured with odontoblastic induction medium. Meanwhile, the proliferation ability decreased in this procedure; messenger RNA and protein levels of KLF4 increased significantly on day 5 after the odontoblastic induction of hDPCs and kept increasing until day 14. hDPCs showed up-regulated activity of ALPase and the expression of mineralization-related genes, including ALP, DMP-1, and dentin sialoprotein (DSP), after KLF4 overexpression. Besides, the proliferation ability of hDPCs decreased significantly in the KLF4 overexpression group by EdU incorporation assay. CONCLUSIONS: Our findings suggest that KLF4 is able to promote odontoblastic differentiation of hDPCs and inhibit proliferation of hDPCs. PMID- 21689551 TI - Effects of heat stress and starvation on clonal odontoblast-like cells. AB - INTRODUCTION: Heat stress during restorative procedures, particularly under severe starvation conditions, can trigger damage to dental pulp. In the present study, we examined effects of heat stress on odontoblastic activity and inflammatory responses in an odontoblast-like cell line (KN-3) under serum starved conditions. METHODS: Viability, nuclear structures, and inflammatory responses of KN-3 cells were examined in culture medium containing 10% or 1% serum after exposure to heat stress at 43 degrees C for 45 minutes. Gene expression of extracellular matrices, alkaline phosphatase activity, and detection of extracellular calcium deposition in cells exposed to heat stress were also examined. RESULTS: Reduced viability and apoptosis were transiently induced in KN-3 cells during the initial phases after heat stress; thereafter, cells recovered their viability. The cytotoxic effects of heat stress were enhanced under serum-starved conditions. Heat stress also strongly up-regulated expression of heat shock protein 25 as well as transient expression of tumor necrosis factor-alpha, interleukin-6, and cyclooxygenase-2 in KN-3 cells. In contrast, expression of type-1 collagen, runt-related transcription factor 2, and dentin sialophosphoprotein were not inhibited by heat stress although starvation suppressed ALP activity and delayed progression of calcification. CONCLUSIONS: Odontoblast-like cells showed thermoresistance with transient inflammatory responses and without loss of calcification activity, and their thermoresistance and calcification activity were influenced by nutritional status. PMID- 21689552 TI - The use of green tea extract as a storage medium for the avulsed tooth. AB - INTRODUCTION: Green tea extract (GTE) has been reported to have remarkable anti inflammatory, antioxidant, and anticarcinogenic effects and to prolong allograft survivals. The purpose of the present study is to investigate in vitro the efficacy of GTE as a storage medium for avulsed teeth. We estimated the possibility for storage medium by maintaining the viability of human periodontal ligament (PDL) cells. METHODS: Human PDL cells were cultured and stored in the following media: (1) Hank's balanced salt solution (HBSS), (2) tap water, (3) milk, (4) GTE, and (5) commercial green tea. After 1, 3, 6, 12, and 24 hours, cells in different media were examined under the optical microscope, and their viabilities were analyzed by using a nucleocounter and 3-(4,5-dimethylthiazol-2 yl)-5(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium assay. The data were statistically analyzed by analysis of variance tests with post analysis using the Duncan method (P < .05). RESULTS: The result indicates that there was no difference in cell viability between GTE and HBSS media, whereas GTE showed higher cell viability than other media (P < .05). CONCLUSIONS: Our study shows that the efficacy of GTE in maintaining the viability of human PDL cells is similar to that of HBSS and higher than that of milk. Therefore, we conclude that GTE could be a suitable, alternative storage medium for avulsed teeth. PMID- 21689549 TI - Insulin-like growth factor 1 and transforming growth factor-beta stimulate cystine/glutamate exchange activity in dental pulp cells. AB - INTRODUCTION: The growth factors insulin-like growth factor (IGF-1) and transforming growth factor-beta (TGF-beta) are protective to dental pulp cells in culture against the toxicity of the composite materials Durafill VS and Flow Line (Henry Schein Inc, New York, NY). Because the toxicity of these materials is mediated by oxidative stress, it seemed possible that the protective effects of IGF-1 and TGF-beta were through the enhancement of an endogenous antioxidant mechanism. METHODS: We used cultured dental pulp cells to determine the mechanism of the protective effects of IGF-1 and TGF-beta, focusing on the glutathione system and the role of cystine/glutamate exchange (system xc-). RESULTS: We found that the toxicity of Durafill VS and Flow Line was attenuated by the addition of glutathione monoethylester, suggesting a specific role for the cellular antioxidant glutathione. Supporting this hypothesis, we found that IGF-1 and TGF beta were protective against the toxicity of the glutathione synthesis inhibitor buthionine sulfoximine. Because levels of cellular cystine are the limiting factor in the production of glutathione, we tested the effects of IGF-1 and TGF beta on cystine uptake. Both growth factors stimulated system xc-mediated cystine uptake. Furthermore, they attenuated the glutathione depletion induced by Durafill VS and Flow Line. CONCLUSIONS: The results suggest that IGF-1 and TGF beta are protective through the stimulation of system xc-mediated cystine uptake, leading to maintenance of cellular glutathione. This novel action of growth factors on dental pulp cells has implications not only for preventing toxicity of dental materials but also for the general function of these cells. PMID- 21689553 TI - Laser raman spectroscopy as a potential chair-side microbiological diagnostic device. AB - INTRODUCTION: Culture-dependent and -independent techniques are time-consuming processes requiring highly trained personnel to identify microorganisms contained within a sample. Rapid chair-side identification of microorganisms could reduce the lag time between patient presentation and ideal treatment. As a first step toward this goal, this study aims to determine if laser Raman spectroscopy (LRS) can discern uniqueness among 10 different species of bacteria contained within a medium in unprocessed and processed samples. METHODS: Ten bacterial species were individually grown on blood agar plates for 3 days. Checkerboard DNA-DNA hybridization was used for species verification. For the unprocessed samples, a 1.0-cm diameter agar sample, with undisturbed bacterial growth, was transferred for each species to a barium fluoride crystal (BaF(2)) slide and laser scanned for a total of 15 seconds per sample. For the processed samples, bacterial cells were harvested, washed, and resuspended in phosphate-buffered saline buffer at 10(9) cells/mL concentration. Each suspension was laser scanned for 15 seconds on a BaF(2) slide. Select regions of Raman spectra for each species/agar and species/suspension combination were processed using a two-sided t test. RESULTS: For the 10 bacterial species, 45 bacteria pair combinations were tested for each group. In both groups, LRS was capable of statistically distinguishing among a majority of bacterial pairings based on RS signature differences of means. CONCLUSIONS: Results show each bacterial species generated restricted ranges of unique spectral signatures that were not masked by their containing medium. Chair side LRS is a promising technique that differentiates among oral bacterial species with a high degree of specificity. PMID- 21689554 TI - The isolation of stem cells from human deciduous teeth pulp is related to the physiological process of resorption. AB - INTRODUCTION: The aim of this study was to isolate and grow cells from sound human deciduous teeth pulp with different levels of resorption and evaluate stem cell parameters. METHODS: Pulp tissue was removed from 30 different patients, aged from 6 to 12 years. From all the teeth, 21 were in advanced levels of resorption (group 1), and the remaining nine teeth did not show any visible resorption (group 2). Pulp tissue was removed and dissociated, and the suspension was seeded onto 12-well plates. The phenotype of the cells (n = 5) was analyzed on fifth and tenth passages by flow cytometry for clusters of differentiation (CD)29/PE, CD34/PE, CD44/FITC, CD45/FITC, CD90/FITC, CD117/PE, CD133/PE, CD146/FITC, CD184/PE, Stromal Cell Surface Marker 1 (STRO-1)/FITC and human leukocyte antigen major histocompatibility complex class II surface receptor (HLA DR)/FITC, and by reverse transcription-polymerase chain reaction (RT-PCR) for octamer-binding transcription factor 4 (OCT-4). On the same passages, cells were differentiated into adipocytes, osteoblasts, and chondrocytes. RESULTS: Cell isolation was successful in 25 samples, but only 17 of these reached 90% confluence. It was not possible to establish cell culture from group 2. Cells on both fifth and tenth passages were positive for CD29, CD44, and CD90 and also for the expression of OCT-4. Moderate labeling was observed for CD117 and CD133, whereas a low expression was detected for CD34, CD45, HLA-DR, CD184, CD146, and STRO-1. All cultures differentiated into three cell types. CONCLUSIONS: The isolated pulp cells can be considered stem cells. The facility for obtaining cells seems to be related to the root resorption process, so, therefore, the cells from group 1 were able to proliferate in vitro, whereas group 2 cells were not. PMID- 21689555 TI - Effect of disinfectant solutions on the surface free energy and wettability of filling material. AB - INTRODUCTION: Gutta-percha (GP) and Resilon (Res) cones are usually disinfected by the use of solutions such as sodium hypochlorite (NaOCl) and chlorhexidine (CHX). The aims of this study were to evaluate the surface free energy of GP and Res cones after disinfection procedures and to investigate the wettability of endodontic sealers in contact with these surfaces. METHODS: GP and Res flat smooth surfaces were prepared. Thirty-six samples of each material were used. The samples were divided into 6 groups as follows: Control group GP, immersed in Milli-Q water (MQW); CHX group GP, immersed in 2% CHX solution and then washed with MQW; NaOCl group GP, immersed in 5.25% NaOCl and then washed with MQW; Control group Res, immersed in MQW; CHX group Res, immersed in 2% CHX solution and then washed with MQW; and NaOCl group Res, immersed in 5.25% NaOCl and then washed with MQW. Samples were analyzed first with a goniometer to measure the contact angle between the test surfaces and 3 solutions (water, ethylene glycol, and diiodomethane) to determine the surface free energy. Then the contact angle between surfaces and each one of the sealers tested, AH Plus and Real Seal SE, was measured. Data were statistically analyzed. RESULTS: The results showed that when disinfectant solutions were used, the surface free energy was greater. When evaluating the interaction between materials and sealers, the use of CHX presented lower values of contact angle, followed by NaOCl. CONCLUSIONS: It was concluded that the solutions used in decontamination increase the surface free energy, promoting high interaction between GP/Res and sealers. PMID- 21689556 TI - An in vitro spectroscopic analysis to determine the chemical composition of the precipitate formed by mixing sodium hypochlorite and chlorhexidine. AB - INTRODUCTION: The purpose of this in vitro study was to determine the chemical composition of the precipitate formed by mixing sodium hypochlorite (NaOCl) and chlorhexidine (CHX) and the relative molecular weight of the components. METHODS: Using commercially available CHX gluconate, a 2% solution was formed and mixed in a 1:1 ratio with commercially available NaOCl producing a brown precipitate. The precipitate as well as a mixture of precipitate and pure CHX diacetate was then analyzed using one-dimensional and two-dimensional NMR spectroscopy. RESULTS: The one-dimensional and two-dimensional NMR spectra were fully assigned in terms of chemical shifts of all proton and carbon atoms in intact CHX. This permitted identification of two major CHX breakdown products, neither of which are parachloroaniline (PCA). Both products are related to PCA in that they are parasubstituted benzene compounds. Based on NMR data and a proposed mechanism of CHX breakdown, the products appear to be parachlorophenylurea (PCU) and parachlorophenylguanidyl-1,6-diguanidyl-hexane (PCGH). CONCLUSIONS: Based on this in vitro study, the precipitate formed by NaOCl and CHX is composed of at least two separate molecules, all of which are smaller in size than CHX. Along with native CHX, the precipitate contains two chemical fragments derived from CHX (PCU and PCGH), neither of which are PCA. PMID- 21689557 TI - Torsional profiles of new and used revo-s rotary instruments: an in vitro study. AB - INTRODUCTION: This study investigated the torsional properties of new and used Revo-S Shaping Universal (SU) endodontic instruments. METHODS: Torsional profiles were established following the American National Standards Institute/American Dental Association Specification No. 28. Unused SU instruments (group 1, control; n = 30) and instruments used in simulated root canals twice (group 2, n = 30) or six times (group 3, n = 30) were tested. Analysis of variance with the Bonferroni/Dunn post hoc test (alpha = 0.05) was used to analyze the torque and angle of rotation at fracture. RESULTS: The maximum torque at fracture did not differ significantly among instruments in group 1 and groups 2 and 3. The angle of rotation at fracture decreased significantly (P < .01) from group 1 to groups 2 and 3. CONCLUSIONS: The repeated use of the SU rotary instruments significantly reduced the angle of rotation at fracture but did not reduce the torque at fracture. PMID- 21689558 TI - Structural analysis of cyclic-loaded nickel-titanium rotary instruments by using resonance frequency as a parameter. AB - INTRODUCTION: The aim of this study was to investigate the relationship between fatigue life and resonance frequency (RF) of various types of nickel-titanium (NiTi) rotary instruments. In addition, the influence of NiTi instruments with different manufacturing methods on cyclic loading was evaluated by using RF as a parameter. METHODS: Twenty-eight ProFile instruments and 10 Twisted File instruments were subjected to cyclic fatigue-loading until fracture by repeated preparation with simulated root canals made of clear resin. The RF of each sample was recorded immediately after the simulated canal block was prepared. For each sample, the microscopic images on the fracture surface, change in lengthening deformation, number of canal blocks prepared, and corresponding RF changes were recorded. RESULTS: For all the tested instruments, RF values decreased gradually before breakdown when the fatigue failure of the instruments was associated with plastic deformation. In addition, there was a linear relationship between the RF change and the corresponding deformation of the failed instruments. CONCLUSIONS: These results demonstrate that the RF analysis has potential as a tool for structural analysis in NiTi instruments. PMID- 21689559 TI - Fatigue testing of controlled memory wire nickel-titanium rotary instruments. AB - INTRODUCTION: To improve the fracture resistance of nickel-titanium (NiTi) files, manufacturers have introduced new alloys to manufacture NiTi files and developed new manufacturing processes. This study was aimed to examine the fatigue behavior of NiTi instruments from a novel controlled memory NiTi wire (CM Wire). METHODS: Instruments of ProFile, Typhoon (TYP), Typhoon CM (TYP CM), DS-SS0250425NEYY (NEYY), and DS-SS0250425NEYY CM (NEYY CM) (DS Dental, Johnson City, TN) all size 25/.04 were subjected to rotational bending at the curvature of 35 degrees and 45 degrees in air at the temperature of 23 degrees +/- 2 degrees C, and the number of revolutions to fracture (N(f)) was recorded. The fracture surface of all fragments was examined by a scanning electron microscope. The crack initiation sites, the percentage of dimple area to the whole fracture cross section, and the surface strain amplitude (epsilon(a)) were noted. RESULTS: The new alloy yielded an improvement of over three to eight times in N(f) of CM files than that of conventional NiTi files (P < .05). The vast majority of CM instruments (50%-92%) showed multiple crack origins, whereas most instruments made from conventional NiTi wire (58%-100%) had one crack origin. The values of the fraction area occupied by the dimple region were significantly smaller on CM NiTi instruments compared with conventional NiTi instruments (P < .01). The square (NEYY CM) versus the triangular (TYP CM) configuration showed a significantly different lifetime on CM wire at both curvatures (P < .01). CONCLUSIONS: The material property had a substantial impact on fatigue lifetime. Instruments made from CM Wire had a significantly higher N(f) and lower surface strain amplitude than the conventional NiTi wire files with identical design. PMID- 21689560 TI - Flat-oval root canal preparation with self-adjusting file instrument: a micro computed tomography study. AB - INTRODUCTION: The aim of this study was to evaluate the root canal preparation in flat-oval canals treated with either rotary or self-adjusting file (SAF) by using micro-tomography analysis. METHODS: Forty mandibular incisors were scanned before and after root canal instrumentation with rotary instruments (n = 20) or SAF (n = 20). Changes in canal volume, surface area, and cross-sectional geometry were compared with preoperative values. Data were compared by independent sample t test and chi(2) test between groups and paired sample t test within the group (alpha = 0.05). RESULTS: Overall, area, perimeter, roundness, and major and minor diameters revealed no statistical difference between groups (P > .05). In the coronal third, percentage of prepared root canal walls and mean increases of volume and area were significantly higher with SAF (92.0%, 1.44 +/- 0.49 mm(3), 0.40 +/- 0.14 mm(2), respectively) than rotary instrumentation (62.0%, 0.81 +/- 0.45 mm(3), 0.23 +/- 0.15 mm(2), respectively) (P < .05). SAF removed dentin layer from all around the canal, whereas rotary instrumentation showed substantial untouched areas. CONCLUSIONS: In the coronal third, mean increases of area and volume of the canal as well as the percentage of prepared walls were significantly higher with SAF than with rotary instrumentation. By using SAF instruments, flat-oval canals were homogenously and circumferentially prepared. The size of the SAF preparation in the apical third of the canal was equivalent to those prepared with #40 rotary file with a 0.02 taper. PMID- 21689561 TI - Disinfection of root canals with photon-initiated photoacoustic streaming. AB - INTRODUCTION: This study set out to compare the efficacy of laser-activated and ultrasonically activated root canal disinfection with conventional irrigation, specifically its ability to remove bacterial film formed on root canal walls. METHODS: Seventy human premolars were shaped to an apical size #20, taper .07, sterilized, and contaminated in situ with oral bacteria for 1 week and incubated for 2 more weeks. Irrigation was done with 6% NaOCl (group 1), NaOCl ultrasonically activated with blunt inserts (group 2), or a pulsed erbium:YAG laser at nonablative settings (group 3) for a total of 60 seconds each. Positive and negative controls were also included. Aerobic bacterial sampling was performed, and the incidence of positive samples after 24 and 48 hours as well as bacterial counts (colony-forming units) were determined. Fixed and demineralized sections 1 mm and 4 mm off the apex were Brown-Brenn stained and assessed for remaining intracanal bacteria/biofilm and dentinal tubule penetration. RESULTS: All 3 canal disinfection protocols significantly reduced bacterial counts (P < .001). None of the 3 techniques predictably generated negative samples, but laser activated disinfection was superior to the other 2 techniques in this aspect (P < .05). Histologic sections showed variable remaining bacterial presence in dentinal tubules at the 4-mm level and significantly less bacterial biofilm/necrotic tissue remaining at the 1-mm level after laser-activated irrigation (P < .05). CONCLUSIONS: Under the conditions of this combined in situ/in vitro study, activated disinfection did not completely remove bacteria from the apical root canal third and infected dentinal tubules. However, the fact that laser activation generated more negative bacterial samples and left less apical bacteria/biofilm than ultrasonic activation warrants further investigation. PMID- 21689562 TI - Cyclic fatigue testing and metallographic analysis of nickel-titanium rotary instruments. AB - INTRODUCTION: The aim of this study was to compare cyclic fatigue resistance of four nickel-titanium rotary systems and to evaluate their surface, fractographic, and matrix morphology. METHODS: Four models of endodontic rotary files (EasyShape [Komet/Gebr. Brasseler, Lemgo, Germany], ProTaper [Dentsply Maillefer, Ballaigues, Switzerland], NRT [MANI Inc, Toshigi-Ken, Japan], and AlphaKite [Komet/Gebr. Brasseler]) were subjected to fatigue testing in artificial canals with angle of curvature of 45 degrees and 60 degrees and a radius of curvature of 5 mm until fracture occurred. Nickel-titanium (NiTi) alloy properties were investigated by light microscopy, environmental scanning electron microscopy (ESEM), and energy dispersive x-ray spectrophotometry (EDS). ESEM analysis was conducted on new files to examine surface characteristics and on fractured samples to identify the crack origin and the fractographic features. RESULTS: Analysis of variance testing revealed significant differences (P < .001) among the groups. NRT files had the highest fatigue resistance followed by AlphaKite, EasyShape, and ProTaper. All the new files presented surface imperfections. Fractographic analysis found the crack initiation to originate at the level of surface irregularities. Optical microscope inspection of the NiTi alloy matrix disclosed different-sized nonmetallic inclusions among models. EDS analysis of these inclusions showed that they were composed of carbon and oxygen in addition to nickel and titanium. Under light microscopy, austenitic grains appeared larger near the handle and smaller near the tip in all instruments. CONCLUSIONS: NRT files presented the longest fatigue life. All samples showed surface irregularities and nonmetallic inclusions. Austenitic grains were smaller near the tip than near the handle. The angle of curvature was confirmed to influence the fatigue life of NiTi instruments. PMID- 21689563 TI - Treatment of tooth discoloration after the use of white mineral trioxide aggregate. AB - INTRODUCTION: A number of vital pulp therapy techniques have been recommended to preserve pulp vitality in teeth with complicated crown fractures, especially in young patients. Calcium hydroxide has been the gold standard as a pulp capping material, but recently mineral trioxide aggregate (MTA) has been recommended. This case report describes the treatment of tooth discoloration caused by white MTA (WMTA) used for the management of a complicated crown fracture. METHODS: A partial pulpotomy was performed with the use of WMTA after a complicated crown fracture of the upper right central incisor. Seventeen months later, the WMTA was removed because of tooth discoloration, and internal bleaching was performed. RESULTS: Upon access, the WMTA was completely discolored. After it was removed, a significant color change was observed in the tooth crown, which was further improved with internal bleaching. The tooth remained vital, and a dentin bridge was confirmed clinically and radiographically. CONCLUSIONS: The recommendation to use WMTA for vital pulp therapy in the esthetic zone may need to be reconsidered. Should discoloration occur with the use of WMTA, the technique described may be used to improve the esthetics. PMID- 21689564 TI - Images in emergency medicine. Man with generalized weakness. Acute coronary syndrome caused by critical myocardial bridging. PMID- 21689565 TI - Effectiveness of interventions targeting frequent users of emergency departments: a systematic review. AB - STUDY OBJECTIVE: Frequent users of emergency departments (EDs) are a relatively small group of vulnerable patients accounting for a disproportionally high number of ED visits. Our objective is to perform a systematic review of the type and effectiveness of interventions to reduce the number of ED visits by frequent users. METHODS: We searched MEDLINE, EMBASE, CINAHL, PsychINFO, the Cochrane Library, and ISI Web of Science for randomized controlled trials, nonrandomized controlled trials, interrupted time series, and controlled and noncontrolled before-and-after studies describing interventions targeting adult frequent users of EDs. Primary outcome of interest was the reduction in ED use. We also explored costs analyses and various clinical (alcohol and drug use, psychiatric symptoms, mortality) and social (homelessness, insurance status, social security support) outcomes. RESULTS: We included 11 studies (3 randomized controlled trials, 2 controlled and 6 noncontrolled before-and-after studies). Heterogeneity in both study designs and definitions of frequent users precluded meta-analyses of the results. The most studied intervention was case management (n=7). Only 1 of 3 randomized controlled trials showed a significant reduction in ED use compared with usual care. Six of the 8 before-and-after studies reported a significant reduction in ED use, and 1 study showed a significant increase. ED cost reductions were demonstrated in 3 studies. Social outcomes such as reduction of homelessness were favorable in 3 of 3 studies, and clinical outcomes trended toward positive results in 2 of 3 studies. CONCLUSION: Interventions targeting frequent users may reduce ED use. Case management, the most frequently described intervention, reduced ED costs and seemed to improve social and clinical outcomes. It appears to be beneficial to patients and justifiable for hospitals to implement case management for frequent users in the framework of a clear and consensual definition of frequent users and standardized outcome measures. PMID- 21689566 TI - What we don't know may hurt us: interventions for frequent emergency department users. PMID- 21689567 TI - Infectious disease. Update on emerging infections: news from the Centers for Disease Control and Prevention. PMID- 21689568 TI - Change of shift. Icicle. PMID- 21689569 TI - Trial registration and wandering outcomes. PMID- 21689570 TI - Images in emergency medicine. Elderly female with syncope. Venous thromboembolism "in transit.". PMID- 21689571 TI - Response to Gayat et al. PMID- 21689574 TI - Specialty hospitals. Policy statement. PMID- 21689575 TI - Boarding of admitted and intensive care patients in the emergency department. Policy statement. PMID- 21689577 TI - Blood-borne infections in emergency medicine. Policy statement. PMID- 21689579 TI - Emergency department utilization during outbreaks of influenza. Policy statement. PMID- 21689580 TI - Drug-assisted intubation in the prehospital setting. Policy statement. PMID- 21689587 TI - [Diagnosis and management of vascular anomalies]. AB - Vascular anomalies are a complex pathological group. They are especially difficult to study because of confusion in the terminology used. The classification developed by the International Society for the Study of Vascular Anomalies (ISSVA) in 1996 allows using a common scientific language. There are two groups of lesions: vascular tumor and vascular malformation. The management of these anomalies is difficult and must involve an interdisciplinary approach including specialists in plastic surgery, radiology, pediatry and dermatology. We propose a simplified approach for the management of these pathologies. This approach is coming from the experience of Marseille (France) multidisciplinary team. PMID- 21689588 TI - [A giant chondroblastic osteosarcoma of the mandible. A case report]. AB - INTRODUCTION: Osteosarcoma of the craniofacial bones location is less common, usually with low grade of malignancy; it has better prognosis when surgical excision is complete. REPORT CASE: We report a case of a 35-year-old male diagnosed with a low-grade chondroblastic osteosarcoma of the mandible. The patient was treated with surgery alone and recovered with pectoralis major myocutaneous flap. After 48 months, the oncology's and aesthetics results are good. DISCUSSION: We will discuss the treatment of chondroblastic osteosarcoma of the mandible. PMID- 21689589 TI - Pushing the envelope of sound. AB - Normal hearing depends on the amplification of sound in the cochlea. In this issue of Neuron, Fettiplace and colleagues show that prestin-based amplification is a viable mechanism as it is not limited by the outer hair cell's membrane time constant as previously surmised. PMID- 21689590 TI - A genetic push to understand motion detection. AB - Two articles in this issue of Neuron (Eichner et al. and Clark et al.) attack the problem of explaining how neuronal hardware in Drosophila implements the Reichardt motion detector, one of the most famous computational models in neuroscience, which has proven intractable up to now. PMID- 21689591 TI - Searching for the neural mechanisms of feature-based attention in the primate brain. AB - In this issue, two studies, one by Zhou and Desimone and another by Cohen and Maunsell, provide new insights into the mechanisms of feature-based attention (FBA). The former demonstrates a new role of the frontal eye fields in the origins of FBA and the latter shows that FBA is coordinated across both hemispheres. PMID- 21689592 TI - Career development for women scientists in Asia. AB - Previously, challenges faced by women scientists have made it difficult for them to realize their dreams. The remarkable growth of Asian bioscience over the past decade, however, has created opportunities for young women in their home countries. The time is ripe for women in Asia to pursue their scientific aspirations. PMID- 21689594 TI - Frontal cortex and reward-guided learning and decision-making. AB - Reward-guided decision-making and learning depends on distributed neural circuits with many components. Here we focus on recent evidence that suggests four frontal lobe regions make distinct contributions to reward-guided learning and decision making: the lateral orbitofrontal cortex, the ventromedial prefrontal cortex and adjacent medial orbitofrontal cortex, anterior cingulate cortex, and the anterior lateral prefrontal cortex. We attempt to identify common themes in experiments with human participants and with animal models, which suggest roles that the areas play in learning about reward associations, selecting reward goals, choosing actions to obtain reward, and monitoring the potential value of switching to alternative courses of action. PMID- 21689593 TI - Mitochondria: the next (neurode)generation. AB - Adult-onset neurodegenerative disorders are disabling and often fatal diseases of the nervous system whose underlying mechanisms of cell death remain unknown. Defects in mitochondrial respiration had previously been proposed to contribute to the occurrence of many, if not all, of the most common neurodegenerative disorders. However, the discovery of genes mutated in hereditary forms of these enigmatic diseases has additionally suggested defects in mitochondrial dynamics. Such disturbances can lead to changes in mitochondrial trafficking, in interorganellar communication, and in mitochondrial quality control. These new mechanisms by which mitochondria may also be linked to neurodegeneration will likely have far-reaching implications for our understanding of the pathophysiology and treatment of adult-onset neurodegenerative disorders. PMID- 21689595 TI - CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA. AB - Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder caused by CAG/polyglutamine repeat expansions in the ataxin-7 gene. Ataxin-7 is a component of two different transcription coactivator complexes, and recent work indicates that disease protein normal function is altered in polyglutamine neurodegeneration. Given this, we studied how ataxin-7 gene expression is regulated. The ataxin-7 repeat and translation start site are flanked by binding sites for CTCF, a highly conserved multifunctional transcription regulator. When we analyzed this region, we discovered an adjacent alternative promoter and a convergently transcribed antisense noncoding RNA, SCAANT1. To understand how CTCF regulates ataxin-7 gene expression, we introduced ataxin-7 mini-genes into mice, and found that CTCF is required for SCAANT1 expression. Loss of SCAANT1 derepressed ataxin-7 sense transcription in a cis-dependent fashion and was accompanied by chromatin remodeling. Discovery of this pathway underscores the importance of altered epigenetic regulation for disease pathology at repeat loci exhibiting bidirectional transcription. PMID- 21689596 TI - Isoform-specific dephosphorylation of dynamin1 by calcineurin couples neurotrophin receptor endocytosis to axonal growth. AB - Endocytic events are critical for neuronal survival in response to target-derived neurotrophic cues, but whether local axon growth is mediated by endocytosis dependent signaling mechanisms remains unclear. Here, we report that Nerve Growth Factor (NGF) promotes endocytosis of its TrkA receptors and axon growth by calcineurin-mediated dephosphorylation of the endocytic GTPase dynamin1. Conditional deletion of calcineurin in sympathetic neurons disrupts NGF-dependent innervation of peripheral target tissues. Calcineurin signaling is required locally in sympathetic axons to support NGF-mediated growth in a manner independent of transcription. We show that calcineurin associates with dynamin1 via a PxIxIT interaction motif found only in specific dynamin1 splice variants. PxIxIT-containing dynamin1 isoforms colocalize with surface TrkA receptors, and their phosphoregulation is selectively required for NGF-dependent TrkA internalization and axon growth in sympathetic neurons. Thus, NGF-dependent phosphoregulation of dynamin1 is a critical event coordinating neurotrophin receptor endocytosis and axonal growth. PMID- 21689597 TI - Overlapping role of dynamin isoforms in synaptic vesicle endocytosis. AB - The existence of neuron-specific endocytic protein isoforms raises questions about their importance for specialized neuronal functions. Dynamin, a GTPase implicated in the fission reaction of endocytosis, is encoded by three genes, two of which, dynamin 1 and 3, are highly expressed in neurons. We show that dynamin 3, thought to play a predominantly postsynaptic role, has a major presynaptic function. Although lack of dynamin 3 does not produce an overt phenotype in mice, it worsens the dynamin 1 KO phenotype, leading to perinatal lethality and a more severe defect in activity-dependent synaptic vesicle endocytosis. Thus, dynamin 1 and 3, which together account for the overwhelming majority of brain dynamin, cooperate in supporting optimal rates of synaptic vesicle endocytosis. Persistence of synaptic transmission in their absence indicates that if dynamin plays essential functions in neurons, such functions can be achieved by the very low levels of dynamin 2. PMID- 21689598 TI - An instructive role for patterned spontaneous retinal activity in mouse visual map development. AB - Complex neural circuits in the mammalian brain develop through a combination of genetic instruction and activity-dependent refinement. The relative role of these factors and the form of neuronal activity responsible for circuit development is a matter of significant debate. In the mammalian visual system, retinal ganglion cell projections to the brain are mapped with respect to retinotopic location and eye of origin. We manipulated the pattern of spontaneous retinal waves present during development without changing overall activity levels through the transgenic expression of beta2-nicotinic acetylcholine receptors in retinal ganglion cells of mice. We used this manipulation to demonstrate that spontaneous retinal activity is not just permissive, but instructive in the emergence of eye specific segregation and retinotopic refinement in the mouse visual system. This suggests that specific patterns of spontaneous activity throughout the developing brain are essential in the emergence of specific and distinct patterns of neuronal connectivity. PMID- 21689599 TI - Multiple forms of activity-dependent competition refine hippocampal circuits in vivo. AB - Efficient memory formation relies on the establishment of functional hippocampal circuits. It has been proposed that synaptic connections are refined by neural activity to form functional brain circuitry. However, it is not known whether and how hippocampal connections are refined by neural activity in vivo. Using a mouse genetic system in which restricted populations of neurons in the hippocampal circuit are inactivated, we show that inactive axons are eliminated after they develop through a competition with active axons. Remarkably, in the dentate gyrus, which undergoes neurogenesis throughout life, axon refinement is achieved by a competition between mature and young neurons. These results demonstrate that activity-dependent competition plays multiple roles in the establishment of functional memory circuits in vivo. PMID- 21689601 TI - Internal structure of the fly elementary motion detector. AB - Recent experiments have shown that motion detection in Drosophila starts with splitting the visual input into two parallel channels encoding brightness increments (ON) or decrements (OFF). This suggests the existence of either two (ON-ON, OFF-OFF) or four (for all pairwise interactions) separate motion detectors. To decide between these possibilities, we stimulated flies using sequences of ON and OFF brightness pulses while recording from motion-sensitive tangential cells. We found direction-selective responses to sequences of same sign (ON-ON, OFF-OFF), but not of opposite sign (ON-OFF, OFF-ON), refuting the existence of four separate detectors. Based on further measurements, we propose a model that reproduces a variety of additional experimental data sets, including ones that were previously interpreted as support for four separate detectors. Our experiments and the derived model mark an important step in guiding further dissection of the fly motion detection circuit. PMID- 21689600 TI - Prestin-driven cochlear amplification is not limited by the outer hair cell membrane time constant. AB - Outer hair cells (OHCs) provide amplification in the mammalian cochlea using somatic force generation underpinned by voltage-dependent conformational changes of the motor protein prestin. However, prestin must be gated by changes in membrane potential on a cycle-by-cycle basis and the periodic component of the receptor potential may be greatly attenuated by low-pass filtering due to the OHC time constant (tau(m)), questioning the functional relevance of this mechanism. Here, we measured tau(m) from OHCs with a range of characteristic frequencies (CF) and found that, at physiological endolymphatic calcium concentrations, approximately half of the mechanotransducer (MT) channels are opened at rest, depolarizing the membrane potential to near -40 mV. The depolarized resting potential activates a voltage-dependent K+ conductance, thus minimizing tau(m) and expanding the membrane filter so there is little receptor potential attenuation at the cell's CF. These data suggest that minimal tau(m) filtering in vivo ensures optimal activation of prestin. PMID- 21689602 TI - Defining the computational structure of the motion detector in Drosophila. AB - Many animals rely on visual motion detection for survival. Motion information is extracted from spatiotemporal intensity patterns on the retina, a paradigmatic neural computation. A phenomenological model, the Hassenstein-Reichardt correlator (HRC), relates visual inputs to neural activity and behavioral responses to motion, but the circuits that implement this computation remain unknown. By using cell-type specific genetic silencing, minimal motion stimuli, and in vivo calcium imaging, we examine two critical HRC inputs. These two pathways respond preferentially to light and dark moving edges. We demonstrate that these pathways perform overlapping but complementary subsets of the computations underlying the HRC. A numerical model implementing differential weighting of these operations displays the observed edge preferences. Intriguingly, these pathways are distinguished by their sensitivities to a stimulus correlation that corresponds to an illusory percept, "reverse phi," that affects many species. Thus, this computational architecture may be widely used to achieve edge selectivity in motion detection. PMID- 21689603 TI - Contrast gain control in auditory cortex. AB - The auditory system must represent sounds with a wide range of statistical properties. One important property is the spectrotemporal contrast in the acoustic environment: the variation in sound pressure in each frequency band, relative to the mean pressure. We show that neurons in ferret auditory cortex rescale their gain to partially compensate for the spectrotemporal contrast of recent stimulation. When contrast is low, neurons increase their gain, becoming more sensitive to small changes in the stimulus, although the effectiveness of contrast gain control is reduced at low mean levels. Gain is primarily determined by contrast near each neuron's preferred frequency, but there is also a contribution from contrast in more distant frequency bands. Neural responses are modulated by contrast over timescales of ~100 ms. By using contrast gain control to expand or compress the representation of its inputs, the auditory system may be seeking an efficient coding of natural sounds. PMID- 21689604 TI - Using neuronal populations to study the mechanisms underlying spatial and feature attention. AB - Visual attention affects both perception and neuronal responses. Whether the same neuronal mechanisms mediate spatial attention, which improves perception of attended locations, and nonspatial forms of attention has been a subject of considerable debate. Spatial and feature attention have similar effects on individual neurons. Because visual cortex is retinotopically organized, however, spatial attention can comodulate local neuronal populations, whereas feature attention generally requires more selective modulation. We compared the effects of feature and spatial attention on local and spatially separated populations by recording simultaneously from dozens of neurons in both hemispheres of V4. Feature and spatial attention affect the activity of local populations similarly, modulating both firing rates and correlations between pairs of nearby neurons. However, whereas spatial attention appears to act on local populations, feature attention is coordinated across hemispheres. Our results are consistent with a unified attentional mechanism that can modulate the responses of arbitrary subgroups of neurons. PMID- 21689607 TI - Hip and knee muscle function following aerobic exercise in individuals with patellofemoral pain syndrome. AB - Patellofemoral pain syndrome (PFPS) is a commonly experienced knee disorder that can result in altered muscle activation of the surrounding musculature. There is little evidence on effects of aerobic exercise on quadriceps torque and EMG activation of the vastus medialis obliquus (VMO), vastus lateralis (VL), and gluteus medius (GM). In this study 20 healthy individuals and 20 patients with PFPS had measures of torque and muscle activation taken following aerobic exercise. A modified Balke-Ware protocol was used for the exercise intervention. Baseline and post-aerobic measurements of knee extension torque and VMO, VL, and GM activation during a single leg anterior reaching task. These measurements were only taken on the injured limb. Following exercise, knee extension torque was lower in PFPS patients when compared to controls (p=0.03). Patients reporting no pain after exercise experienced decreases (p=0.021) in GM activation following exercise. There was a decrease in VMO (p=0.010) and VL (p=0.021) activation in PFPS patients with elevated knee pain. Recreationally active individuals with PFPS may experience different responses in the quadriceps and GM after exercise. Responses may be confounded by whether or not pain is exacerbated by exercise. PMID- 21689608 TI - A fast implementation for EMG signal linear envelope computation. AB - Numerous medical and biomechanical applications involve electromyogram (EMG) signal processing in real time. Amplitude analysis of the EMG often requires computation of the signal's linear envelope. For this purpose, several methods are commonly described in the literature; however, not all match the speed requirement of real-time applications. We introduce an implementation which accelerates the computation of EMG signals linear envelopes, based on the pipeline commonly found in the literature for this kind of operation. The algorithm improves the computation's time requirement, at the expense of memory requirement, by using the result of the envelope's computation at the previous instant. This algorithm saves approximately 96% of the computation time and allows computing linear envelopes of several EMG signals in real time. PMID- 21689606 TI - Disrupted neural synchronization in toddlers with autism. AB - Autism is often described as a disorder of neural synchronization. However, it is unknown how early in development synchronization abnormalities emerge and whether they are related to the development of early autistic behavioral symptoms. Here, we show that disrupted synchronization is evident in the spontaneous cortical activity of naturally sleeping toddlers with autism, but not in toddlers with language delay or typical development. Toddlers with autism exhibited significantly weaker interhemispheric synchronization (i.e., weak "functional connectivity" across the two hemispheres) in putative language areas. The strength of synchronization was positively correlated with verbal ability and negatively correlated with autism severity, and it enabled identification of the majority of autistic toddlers (72%) with high accuracy (84%). Disrupted cortical synchronization, therefore, appears to be a notable characteristic of autism neurophysiology that is evident at very early stages of autism development. PMID- 21689605 TI - Feature-based attention in the frontal eye field and area V4 during visual search. AB - When we search for a target in a crowded visual scene, we often use the distinguishing features of the target, such as color or shape, to guide our attention and eye movements. To investigate the neural mechanisms of feature based attention, we simultaneously recorded neural responses in the frontal eye field (FEF) and area V4 while monkeys performed a visual search task. The responses of cells in both areas were modulated by feature attention, independent of spatial attention, and the magnitude of response enhancement was inversely correlated with the number of saccades needed to find the target. However, an analysis of the latency of sensory and attentional influences on responses suggested that V4 provides bottom-up sensory information about stimulus features, whereas the FEF provides a top-down attentional bias toward target features that modulates sensory processing in V4 and that could be used to guide the eyes to a searched-for target. PMID- 21689609 TI - Hepatocellular carcinoma: its past, present, and future. PMID- 21689611 TI - Anatomic pathology of hepatocellular carcinoma: impact on prognosis and response to therapy. AB - A better understanding of signaling pathways in HCC pathogenesis has led to targeted therapies against HCC. Identification of liver cancer stem cell markers and their related pathways is one of the most important goals of liver cancer research. New therapies should ideally target cancer stem cells and not normal stem/progenitor cells, because the latter are very important in regeneration and repair. Individualized HCC therapy will require better definition of patient subgroups that benefit most or should be protected from therapy failure and unwanted side effects. Tumor tissue acquisition should be mandatory, reversing the practice that was established years ago when targeted HCC therapy was but a pipe dream. PMID- 21689610 TI - The global epidemiology of hepatocellular carcinoma: present and future. AB - The global risk of hepatocellular carcinoma (HCC) has been largely driven by hepatitis B virus (HBV) infection for the past century, along with hepatitis C virus (HCV), aflatoxin, excessive alcohol consumption, and obesity/diabetes. The dominant effect of HBV on global HCC risk should decline as the population vaccinated against HBV grows older. Infection with HCV is also expected to decline. Projections of HCV-related HCC rates remaining high for another 30 years may be overly pessimistic. Alcohol may be less of a factor in HCC in coming years. However, obesity and diabetes may become even more important risk factors for HCC. PMID- 21689612 TI - The role of oncogenic viruses in the pathogenesis of hepatocellular carcinoma. AB - HBV and HCV have major roles in hepatocarcinogenesis. More than 500 million people are infected with hepatitis viruses and, therefore, HCC is highly prevalent, especially in those countries endemic for HBV and HCV. Viral and host factors contribute to the development of HCC. The main viral factors include the circulating load of HBV DNA or HCV RNA and specific genotypes. Various mechanisms are involved in the host-viral interactions that lead to HCC development, among which are genetic instability, self-sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasiveness. Prevention of HBV by vaccination, as well as antiviral therapy against HBV and for HCV seem able to inhibit the development of HCC. PMID- 21689614 TI - Diagnosis of hepatocellular carcinoma: role of tumor markers and liver biopsy. AB - Early diagnosis of hepatocellular carcinoma (HCC) has a significant impact on survival by implementation of effective treatment strategies, including hepatic resection, locoregional ablative therapy, and liver transplantation. The use of serum tumor markers and biopsy are particularly important for diagnosis of small hepatic lesions with atypical features on imaging studies. alpha-Fetoprotein remains the most frequently used tumor marker for the diagnosis of HCC. The development of novel serum biomarkers for HCC, identification of molecular markers for tissue immunohistochemistry, and emergence of new diagnostic techniques such as proteomic profiling may improve the early detection rate of HCC in the future. PMID- 21689613 TI - Insulin resistance and other metabolic risk factors in the pathogenesis of hepatocellular carcinoma. AB - Coinciding with the increased incidence of hepatocellular carcinoma (HCC), there has been a significant increase in the global incidence of obesity and diabetes mellitus (DM), the two major risk factors for nonalcoholic steatohepatitis (NASH). There are many causes of HCC, and nonalcoholic fatty liver disease/NASH is now emerging as a leading risk factor owing to the epidemic of obesity and type 2 DM. The mechanisms leading to HCC in obesity and type 2 DM likely involve interactions between several signaling pathways, including oxidative stress, inflammation, oncogenes, adiponectins, and insulin resistance associated with visceral adiposity and diabetes. PMID- 21689615 TI - Hepatocellular carcinoma: molecular and genomic guideline for the clinician. AB - Understanding of the genetic changes and molecular signaling pathways that are active in hepatocellular carcinoma has improved substantially over the last decade. As more information becomes available, it is clear that the prognostication of hepatocellular carcinoma will soon include molecular and genomic "fingerprints" that are unique to each cancer, which will allow more personalized treatment plans for patients as more targeted therapies become available. This article discusses the molecular and genomic changes that are important in hepatocellular carcinoma in order for clinicians to understand the current and forthcoming treatment options for patients with liver cancer. PMID- 21689616 TI - Hepatocellular carcinoma: screening and staging. AB - Active screening of patients at risk for HCC has led to the identification of early HCCs that are amenable to treatment with a high rate of cure. This requires high-quality ultrasound examinations at 6-month intervals. If widely applied, screening has the potential to substantially reduce the mortality from this disease. The application of the Barcelona Cancer of the Liver Clinic (BCLC) staging system should standardize assessment of prognosis and determination of the most effective treatments for each stage. With new molecular targeted agents coming, it is critical that studies are performed in patients stratified by stage into homogeneous groups. Because it is linked with therapy, the BCLC is ideally suited to this purpose. PMID- 21689617 TI - Imaging of hepatocellular carcinoma: practical guide to differential diagnosis. AB - Hepatocellular carcinoma (HCC) is most commonly seen in patients with cirrhosis. Criteria for diagnosis include arterial-phase enhancement, venous-phase washout, and a capsule on delayed sequences. Tiny HCC are best detected with magnetic resonance imaging using the new hepatocyte-specific gadolinium agents; otherwise, short-term follow up versus biopsy is considered. Diffuse HCC can be difficult to diagnose because of the inherent heterogeneous hepatic parenchyma in cirrhosis, however, portal vein expansion due to thrombosis is a helpful sign. PMID- 21689618 TI - Conventional Surgical Treatment of Hepatocellular Carcinoma. AB - Liver resection remains the standard therapy for solitary hepatocellular carcinoma in patients with preserved hepatic function. In well-selected patients, 5-year survival rates are good and can approach that of liver transplantation for early-stage disease. Patient selection is critical to optimizing therapeutic benefit, and the health of the native liver must be considered in addition to tumor characteristics. Hepatic recurrence after resection is common. The difficulty lies in deciding which patients with chronic liver disease and small solitary tumors are best served by resection and which should proceed with transplant evaluation; this is the focus of this article. PMID- 21689619 TI - Laparoscopic liver resection in the treatment of hepatocellular carcinoma. AB - Laparoscopic liver resection is an emerging technique in liver surgery. Although laparoscopy is well established for several abdominal procedures and is considered by some the preferred approach, laparoscopic hepatic resection has been introduced into clinical practice more widely since 2000. These procedures are performed only in experienced centers and only in a select group of patients. While initially performed only for benign hepatic lesions, the indications for laparoscopic resection have gradually broadened to encompass all kinds of malignant hepatic lesions, including hepatocellular carcinoma in patients with cirrhosis, for whom the advantages of the minimally invasive approach may be most evident. PMID- 21689620 TI - Liver transplantation for hepatocellular carcinoma: expanding frontiers and building bridges. AB - Despite significant advances in nonsurgical treatments of hepatocellular carcinoma, these approaches rarely result in cure. Surgery remains the mainstay of curative therapy for hepatocellular carcinoma. Liver transplantation, in particular, has emerged as one of the most beneficial therapeutic modalities. Questions remain, however, regarding hepatocellular carcinoma surveillance, the choice of surgical resection versus transplantation, the role of chemotherapy, optimal selection criteria for transplantation, and the role of ablative therapies to halt tumor progression and downsize tumors exceeding transplant criteria. PMID- 21689621 TI - Locoregional therapy for hepatocellular carcinoma. AB - Locoregional therapies for hepatocellular carcinoma have progressed greatly in the last 30 years, beginning with the introduction of chemoembolization. Embolization techniques have evolved with the use of drug-eluting beads and radioembolization with yttrium-90. In the last 10 years, several new ablation techniques were developed including radiofrequency ablation, microwave ablation, cryoablation, laser ablation, and irreversible electroporation. Isolated or in combination, these techniques have already shown that they can improve patient survival and/or provide acceptable palliation. PMID- 21689622 TI - Systemic therapy in hepatocellular carcinoma. AB - Many potential systemic therapies are being investigated for the treatment of hepatocellular carcinoma (HCC). The incidence of this malignancy is rising sharply and the vast majority of patients present at advanced stages. Although the earlier dismal results with cytotoxic chemotherapies made way for the development of locoregional therapies that provided improved overall survival, truly personalized therapy will require the selection of phenotypically similar stages of disease and populations, an understanding of the complex molecular and genetic pathways leading to HCC, and a keen understanding of the pathobiology of cirrhosis. Only then will we understand how to offer a particular patient at a specific stage of disease the appropriate therapy to truly prolong survival. PMID- 21689624 TI - So, you want to learn to swim.... PMID- 21689623 TI - Liver neoplasia in children. AB - Management of pediatric liver tumors has significantly improved over the last 2 decades. The management options for hepatocelluar carcinoma (HCC) are not well defined. In the pediatric context, the main clinical aims are to reduce chemotherapy toxicity (predominantly ototoxicity and nephrotoxicity) in children treated for hepatoblastoma and to investigate additional modes of treatment for HCC. An increasing number of children develop HCC in the background of chronic liver disease, and screening methods need to be better observed. PMID- 21689625 TI - The role of Pea3 group transcription factors in esophageal squamous cell carcinoma. AB - The transcription factors Pea3, Erm, and Er81 can promote cancer initiation and progression in various types of solid tumors. However, their role in esophageal squamous cell carcinoma (ESCC) has not been elucidated. In this study, we found that the expression levels of Pea3 and Erm, but not that of Er81, were significantly higher in ESCC compared with nontumor esophageal epithelium. A high level of Pea3 expression was significantly correlated with a shorter overall survival in a cohort of 81 patients with ESCC and the subgroup with N1 stage tumor (Wilcoxon-Gehan test, P = 0.016 and P = 0.001, respectively). Pea3 was overexpressed in seven ESCC cell lines compared with two immortalized esophageal cell lines. Pea3 knockdown reduced cell proliferation and suppressed nonadherent growth, migration, and invasion in ESCC cells in vitro. In addition, Pea3 knockdown in ESCC cells resulted in a down-regulation of phospho-Akt and matrix metalloproteinase 13, whereas a significant positive correlation in the expression levels was observed between Pea3 and phospho-Akt (r = 0.281, P < 0.013) and between Pea3 and matrix metalloproteinase 13 in the human specimens (r = 0.462, P < 0.001). Moreover, Pea3 modulated the sensitivity of EC109 cells to doxorubicin, probably via reduced activity of the phosphatidylinositol 3-kinase Akt-mammalian target of Rapamycin complex 1 pathway on Pea3 knockdown. In conclusion, our results suggest that Pea3 plays an important role in the progression of ESCC. PMID- 21689626 TI - An ENU-induced mutation of Cdh23 causes congenital hearing loss, but no vestibular dysfunction, in mice. AB - Mutations in the human cadherin 23 (CDH23) gene cause deafness, neurosensory, autosomal recessive 12 (DFNB12) nonsyndromic hearing loss or Usher syndrome, type 1D (characterized by hearing impairment, vestibular dysfunction, and visual impairment). Reported waltzer mouse strains each harbor a Cdh23-null mutation and present with hearing loss and vestibular dysfunction. Two additional Cdh23 mouse mutants, salsa and erlong, each carry a homozygous Cdh23 missense mutation and have progressive hearing loss. We report the identification of a novel mouse strain, jera, with inherited hearing loss caused by an N-ethyl-N-nitrosourea induced c.7079T>A mutation in the Cdh23 gene. The mutation generates a missense change, p.V2360E, in Cdh23. Affected mice have profound sensorineural deafness, with no vestibular dysfunction. The p.V2360E mutation is semidominant because heterozygous mice have milder and more progressive hearing loss in advanced age. The mutation affects a highly conserved Ca(2+)-binding motif in extracellular domain 22, thought to be important for Cdh23 structure and dimerization. Molecular modeling suggests that the Cdh23(V2360E/V2360E) mutation alters the structural conformation of the protein and affects Ca(2+)-binding properties. Similar to salsa mice, but in contrast to waltzer mice, hair bundle development is normal in jera and hearing loss appears to be due to the loss of tip links. Thus, jera is a novel mouse model for DFNB12. PMID- 21689627 TI - An extensive tumor array analysis supports tumor suppressive role for nucleophosmin in breast cancer. AB - Nucleophosmin (NPM) is a multifunctional protein involved in a complex network of interactions. The role of NPM in oncogenesis is controversial. The NPM gene (NPM1) is mutated or rearranged in a number of hematological disorders, but such changes have not been detected in solid cancers. However, experiments with cultured NPM-null cells and with mice carrying a single inactivated NPM allele indicate a tumor suppressor function for NPM. To resolve the role of NPM in solid cancers, we examined its expression and localization in histologically normal breast tissue and a large array of human breast carcinoma samples (n = 1160), and also evaluated its association with clinicopathological variables and patient survival. The intensity and localization (nucleolar, nuclear, cytoplasmic) of NPM varied across clinical samples. No mutations explaining the differences were found, but the present findings indicate that expression levels of NPM affected its localization. Our study also revealed a novel granular staining pattern for NPM, which was an independent prognostic factor of poor prognosis. In addition, reduced levels of NPM protein were associated with poor prognosis. Furthermore, luminal epithelial cells of histologically normal breast displayed high levels of NPM and overexpression of NPM in the invasive MDA-MB-231 cells abrogated their growth in soft agar. These results support a tumor suppressive role for NPM in breast cancer. PMID- 21689629 TI - Characterization of glycoprotein digests with hydrophilic interaction chromatography and mass spectrometry. AB - A new hydrophilic interaction chromatography (HILIC) column packed with amide 1.7 MUm sorbent was applied to the characterization of glycoprotein digests. Due to the impact of the hydrophilic carbohydrate moiety, glycopeptides were more strongly retained on the column and separated from the remaining nonglycosylated peptides present in the digest. The glycoforms of the same parent peptide were also chromatographically resolved and analyzed using ultraviolet and mass spectrometry detectors. The HILIC method was applied to glyco-profiling of a therapeutic monoclonal antibody and proteins with several N-linked and O-linked glycosylation sites. For characterization of complex proteins with multiple glycosylation sites we utilized 2D LC, where RP separation dimension was used for isolation of glycopeptides and HILIC for resolution of peptide glycoforms. The analysis of site-specific glycan microheterogeneity was illustrated for the CD44 fusion protein. PMID- 21689628 TI - Follistatin improves skeletal muscle healing after injury and disease through an interaction with muscle regeneration, angiogenesis, and fibrosis. AB - Recovery from skeletal muscle injury is often incomplete because of the formation of fibrosis and inadequate myofiber regeneration; therefore, injured muscle could benefit significantly from therapies that both stimulate muscle regeneration and inhibit fibrosis. To this end, we focused on blocking myostatin, a member of the transforming growth factor-beta superfamily and a negative regulator of muscle regeneration, with the myostatin antagonist follistatin. In vivo, follistatin overexpressing transgenic mice underwent significantly greater myofiber regeneration and had less fibrosis formation compared with wild-type mice after skeletal muscle injury. Follistatin's mode of action is likely due to its ability to block myostatin and enhance neovacularization. Furthermore, muscle progenitor cells isolated from follistatin-overexpressing mice were significantly superior to muscle progenitors isolated from wild-type mice at regenerating dystrophin positive myofibers when transplanted into the skeletal muscle of dystrophic mdx/severe combined immunodeficiency mice. In vitro, follistatin stimulated myoblasts to express MyoD, Myf5, and myogenin, which are myogenic transcription factors that promote myogenic differentiation. Moreover, follistatin's ability to enhance muscle differentiation is at least partially due to its ability to block myostatin, activin A, and transforming growth factor-beta1, all of which are negative regulators of muscle cell differentiation. The findings of this study suggest that follistatin is a promising agent for improving skeletal muscle healing after injury and muscle diseases, such as the muscular dystrophies. PMID- 21689630 TI - Resveratrol inhibits genistein-induced multi-drug resistance protein 2 (MRP2) expression in HepG2 cells. AB - The interactions between various dietary cancer chemopreventive phytochemicals in drug transporter functions are not well studied. In this study, the effects of genistein and resveratrol on the multidrug resistance protein 2 (MRP2) expression and the underlying molecular mechanisms were investigated using HepG2-C3 cells that are stably transfected with a construct containing human MRP2 promoter region conjugated with luciferase reporter gene. A 3-fold induction of MRP2 luciferase activity was observed after genistein (50MUM) treatment to HepG2-C3 cells, but was diminished by the resveratrol (50MUM) cotreatment. This observation was further validated by Western blot analysis and RT-PCR analysis as resveratrol also inhibited genistein-induced MRP2 protein synthesis and mRNA expression. Immunofluorescence study revealed that genistein-induced formation of MRP2 vacuoles was dramatically reduced by resveratrol. The binding affinity between retinoid X receptor alpha (RXRalpha) and MRP2 promoter was examined by DNA-protein pull-down assay. The results showed that resveratrol inhibited the genistein-induced binding of RXRalpha to the promoter sequence of MRP2 gene, and this mechanism could potentially contribute to the inhibition of genistein induced MRP2 expression by resveratrol. Taken together, our present study suggests that naturally occurring phytochemicals can potentially interfere with each other's regulatory function on the cancer chemoprevention-related genes through a competitive mechanism. PMID- 21689631 TI - Structure of Candida albicans methionine synthase determined by employing surface residue mutagenesis. AB - Fungal methionine synthase, Met6p, transfers a methyl group from 5-methyl tetrahydrofolate to homocysteine to generate methionine. The enzyme is essential to fungal growth and is a potential anti-fungal drug design target. We have characterized the enzyme from the pathogen Candida albicans but were unable to crystallize it in native form. We converted Lys103, Lys104, and Glu107 all to Tyr (Met6pY), Thr (Met6pT) and Ala (Met6pA). All variants showed wild-type kinetic activity and formed useful crystals, each with unique crystal packing. In each case the mutated residues participated in beneficial crystal contacts. We have solved the three structures at 2.0-2.8A resolution and analyzed crystal packing, active-site residues, and similarity to other known methionine synthase structures. C. albicans Met6p has a two domain structure with each of the domains having a (betaalpha)(8)-barrel fold. The barrels are arranged face-to-face and the active site is located in a cleft between the two domains. Met6p utilizes a zinc ion for catalysis that is bound in the C-terminal domain and ligated by four conserved residues: His657, Cys659, Glu679 and Cys739. PMID- 21689632 TI - Absence of mitochondrial uncoupling protein 3: effect on thymus and spleen in the fed and fasted mice. AB - Mitochondrial uncoupling protein 3 (UCP3) is constitutively expressed in mitochondria from thymus and spleen of mice, and confocal microscopy has been used to visualize UCP3 in situ in mouse thymocytes. UCP3 is present in mitochondria of thymus and spleen up to at least 16 weeks after birth, but levels decrease by a half in thymus and a fifth in spleen after three weeks, probably reflecting the suckling to weaning transition. UCP3 protein levels increase approximately 3-fold in thymus on starvation, but expression levels in spleen were unaffected by starvation. Lack of UCP3 had little effect on thymus mass or thymocyte number. However, lack of UCP3 affected spleen mass and splenocyte number (in the fasted state) and results in reduced CD4+ single positive cell numbers and reduced double negative cells in the thymus, but as a 2-fold increase in the proportion of CD4(+), CD8(+) and DP cells in spleen. Starvation attenuates these proportionate differences in the spleen. A lack of UCP3 had no apparent effect on basal oxygen consumption of thymocytes or splenocytes or on oxygen consumption due to mitochondrial proton leak. Splenocytes from UCP3 knock-out mice are also more resistant to apoptosis than those from wild-type mice. Overall we can conclude that UCP3 affects thymocyte and spleen cell profiles in the fed and fasted states. PMID- 21689633 TI - Hyperoside attenuates hydrogen peroxide-induced L02 cell damage via MAPK dependent Keap1-Nrf2-ARE signaling pathway. AB - The flavonoid hyperoside has been reported to elicit cytoprotection against oxidative stress partly by increasing the activity of antioxidant enzymes, such as glutathione peroxidase, superoxide dismutase and catalase. However, the cellular and molecular mechanisms underlying this effect remain unclear. Here, hepatic L02 cells exposed to H(2)O(2) (100 MUM) were used to demonstrate that hyperoside protected cells by significantly inhibiting overproduction of intracellular ROS, depletion of the mitochondrial membrane potential and leakage of lactate dehydrogenase. Hyperoside further enhanced the cellular antioxidant defense system through increasing the activity of heme oxygenase-1 (HO-1), and by up-regulating HO-1 expression. Meanwhile, real time PCR, western blot and immunofluorescence studies revealed that hyperoside stimulated nuclear translocation of the Nrf(2) transcription factor in a dose-dependent manner, and this effect was significantly suppressed by pharmacological inhibition of the mitogen-activated protein kinases (MAPK) p38 and ERK. Collectively, our data provide the first description of the mechanism underlying hyperoside's ability to attenuate H(2)O(2)-induced cell damage, namely this compound interacts with the MAPK-dependent Keap(1)-Nrf(2)-ARE signaling pathway to up-regulate HO-1 expression and enhance intracellular antioxidant activity. PMID- 21689634 TI - Functional characterization of the P1059L mutation in the inositol 1,4,5 trisphosphate receptor type 1 identified in a Japanese SCA15 family. AB - Spinocerebellar ataxia type 15 (SCA15) is a group of human neurodegenerative disorders characterized by a slowly progressing pure cerebellar ataxia. The inositol 1,4,5-trisphosphate (IP(3)) receptor type 1 (IP(3)R1) is an intracellular IP(3)-induced Ca(2+) release channel that was recently identified as a causative gene for SCA15. In most case studies, a heterozygous deletion of the IP(3)R1 gene was identified. However, one Japanese SCA15 family was found to have a Pro to Leu (P1059L) substitution in IP(3)R1. To investigate the effect of the P1059L mutation, we analyzed the channel properties of the mutant human IP(3)R1 by expressing it in an IP(3)R-deficient B lymphocyte cell line. The P1059L mutant was a functional Ca(2+) release channel with a twofold higher IP(3) binding affinity compared to wild-type IP(3)R1. The cooperative dependence of the Ca(2+) release activity of the mutant on IP(3) concentration was reduced, but both wild-type and mutant receptors produced similar B cell receptor-induced Ca(2+) signals. These results demonstrate that the Ca(2+) release properties of IP(3)R1 are largely unaffected by the P1059L mutation. PMID- 21689635 TI - Caenorhabditis elegans ciliary protein NPHP-8, the homologue of human RPGRIP1L, is required for ciliogenesis and chemosensation. AB - Nephronophthisis (NPHP) is the most frequent genetic cause of end-stage renal failure in children and young adults. NPHP8/RPGRIP1L is a novel ciliary gene that, when mutated, in addition to causing NPHP, also causes Joubert syndrome (JBTS) and Meckel syndrome (MKS). The exact function of NPHP8 and how defects in NPHP8 lead to human diseases are poorly understood. Here, we studied the Caenorhabditis elegans homolog nphp-8 (C09G5.8) and explored the possible function of NPHP-8 in ciliated sensory neurons. We determined the gene structure of nphp-8 through rapid amplification of cDNA ends (RACE) analysis and discovered an X-box motif that had been previously overlooked. Moreover, NPHP-8 co-localized with NPHP-4 at the transition zone at the base of cilia. Mutation of nphp-8 led to abnormal dye filling (Dyf) and shorter cilia lengths in a subset of ciliary neurons. In addition, chemotaxis to several volatile attractants was significantly impaired in nphp-8 mutants. Our data suggest that NPHP-8/RPGRIP1L plays an important role in cilia formation and cilia-mediated chemosensation in a cell type-specific manner. PMID- 21689636 TI - Expression of POEM, a positive regulator of osteoblast differentiation, is suppressed by TNF-alpha. AB - POEM, also known as nephronectin, is an extracellular matrix protein considered to be a positive regulator of osteoblast differentiation. In the present study, we found that tumor necrosis factor-alpha (TNF-alpha), a key regulator of bone matrix properties and composition that also inhibits terminal osteoblast differentiation, strongly inhibited POEM expression in the mouse osteoblastic cell line MC3T3-E1. TNF-alpha-induced down-regulation of POEM gene expression occurred in both time- and dose-dependent manners through the nuclear factor kappa B (NF-kappaB) pathway. In addition, expressions of marker genes in differentiated osteoblasts were down-regulated by TNF-alpha in a manner consistent with our findings for POEM, while over-expression of POEM recovered TNF-alpha-induced inhibition of osteoblast differentiation. These results suggest that TNF-alpha inhibits POEM expression through the NF-kappaB signaling pathway and down-regulation of POEM influences the inhibition of osteoblast differentiation by TNF-alpha. PMID- 21689637 TI - Controlling nuclear JAKs and STATs for specific gene activation by IFNgamma. AB - We previously showed that gamma interferon (IFNgamma) and its receptor subunit, IFNGR1, interacted with the promoter region of IFNgamma-activated genes along with transcription factor STAT1alpha. Recent studies have suggested that activated Janus kinases pJAK2 and pJAK1 also played a role in gene activation by phosphorylation of histone H3 on tyrosine 41. This study addresses the question of the role of activated JAKs in specific gene activation by IFNgamma. We carried out chromatin immunoprecipitation (ChIP) followed by PCR in IFNgamma treated WISH cells and showed association of pJAK1, pJAK2, IFNGR1, and STAT1 on the same DNA sequence of the IRF-1 gene promoter. The beta-actin gene, which is not activated by IFNgamma, did not show this association. The movement of activated JAK to the nucleus and the IRF-1 promoter was confirmed by the combination of nuclear fractionation, confocal microscopy and DNA precipitation analysis using the biotinylated GAS promoter. Activated JAKs in the nucleus was associated with phosphorylated tyrosine 41 on histone H3 in the region of the GAS promoter. Unphosphorylated JAK2 was found to be constitutively present in the nucleus and was capable of undergoing activation in IFNgamma treated cells, most likely via nuclear IFNGR1. Association of pJAK2 and IFNGR1 with histone H3 in IFNgamma treated cells was demonstrated by histone H3 immunoprecipitation. Unphosphorylated STAT1 protein was associated with histone H3 of untreated cells. IFNgamma treatment resulted in its disassociation and then re-association as pSTAT1. The results suggest a novel role for activated JAKs in epigenetic events for specific gene activation. PMID- 21689638 TI - The role of the BH3-only protein Noxa in bone homeostasis. AB - Bone homeostasis is maintained by a dynamic balance between bone resorption by osteoclasts and bone formation by osteoblasts. Since excessive osteoclast activity is implicated in pathological bone resorption, understanding the mechanism underlying osteoclast differentiation, function and survival is of both scientific and clinical importance. Osteoclasts are monocyte/macrophage lineage cells with a short life span that undergo rapid apoptosis, the rate of which critically determines the level of bone resorption in vivo. However, the molecular basis of rapid osteoclast apoptosis remains obscure. Here we report the role of a BH3-only protein, Noxa (encoded by the Pmaip1 gene), in bone homeostasis using Noxa-deficient mice. Among the Bcl-2 family members, Noxa was selectively induced during osteoclastogenesis. Mice lacking Noxa exhibit a severe osteoporotic phenotype due to an increased number of osteoclasts. Noxa deficiency did not have any effect on the number of osteoclast precursor cells or the expression of osteoclast-specific genes, but led to a prolonged survival of osteoclasts. Furthermore, adenovirus-mediated Noxa overexpression remarkably reduced bone loss in a model of inflammation-induced bone destruction. This study reveals Noxa to be a crucial regulator of osteoclast apoptosis, and may provide a molecular basis for a new therapeutic approach to bone diseases. PMID- 21689639 TI - A Tcf/Lef element within the enhancer region of the human NANOG gene plays a role in promoter activation. AB - NANOG is a homeodomain-containing transcription factor that is essential for the maintenance of pluripotency and self-renewal in embryonic stem cells. However, the molecular mechanisms underlying the regulation of NANOG expression in human cells remain largely unknown. Here, we investigated the role of Tcf/Lef response elements located in the enhancer of the human NANOG gene. We found that forced expression of Lef1 or beta-catenin stimulated human NANOG promoter activity, while shRNA-mediated knockdown of beta-catenin reduced Lef1-induced NANOG promoter activation. Deletion or mutation of the Tcf/Lef element within the enhancer region of the human NANOG gene completely abrogated Lef1-induced NANOG promoter activity. The results of a chromatin immunoprecipitation assay demonstrated that Lef1 and beta-catenin bind to the Tcf/Lef element in the enhancer region of the NANOG gene. Forced expression of GSK-3beta inhibited basal, Lef1-induced, and beta-catenin-induced NANOG promoter activity, while treatment with the GSK-3beta inhibitor SB216763 resulted in the accumulation of beta-catenin and NANOG protein. Furthermore, Dvl-1-induced NANOG promoter activity was abrogated by the expression of beta-catenin shRNA. Stable overexpression of Dvl-1 caused beta-catenin and NANOG to accumulate. These results indicate that the Tcf/Lef response element in the enhancer region of the human NANOG gene is able to stimulate NANOG gene transcription. PMID- 21689640 TI - Yellow submarine of the Wnt/Frizzled signaling: submerging from the G protein harbor to the targets. AB - The Wnt/Frizzled signaling pathway plays multiple functions in animal development and, when deregulated, in human disease. The G-protein coupled receptor (GPCR) Frizzled and its cognate heterotrimeric Gi/o proteins initiate the intracellular signaling cascades resulting in cell fate determination and polarization. In this review, we summarize the knowledge on the ligand recognition, biochemistry, modifications and interacting partners of the Frizzled proteins viewed as GPCRs. We also discuss the effectors of the heterotrimeric Go protein in Frizzled signaling. One group of these effectors is represented by small GTPases of the Rab family, which amplify the initial Wnt/Frizzled signal. Another effector is the negative regulator of Wnt signaling Axin, which becomes deactivated in response to Go action. The discovery of the GPCR properties of Frizzled receptors not only provides mechanistic understanding to their signaling pathways, but also paves new avenues for the drug discovery efforts. PMID- 21689641 TI - Endogenous activation of nAChRs and NMDA receptors contributes to the excitability of CA1 stratum radiatum interneurons in rat hippocampal slices: effects of kynurenic acid. AB - CA1 stratum radiatum interneurons (SRIs) express alpha7 nicotinic receptors (nAChRs) and receive inputs from glutamatergic neurons/axons that express alpha3beta4beta2 nAChRs. To test the hypothesis that endogenously active alpha7 and/or alpha3beta4beta2 nAChRs control the excitability of CA1 SRIs in the rat hippocampus, we examined the effects of selective receptor antagonists on spontaneous fast current transients (CTs) recorded from these interneurons under cell-attached configuration. The frequency of CTs, which represent action potentials, increased in the absence of extracellular Mg(2+) and decreased in the presence of the alpha3beta4beta2 nAChR antagonist mecamylamine (3 MUM) or the NMDA receptor antagonist APV (50 MUM). However, it was unaffected by the alpha7 nAChR antagonist MLA (10 nM) or the AMPA receptor antagonist CNQX (10 MUM). Thus, in addition to synaptically and tonically activated NMDA receptors, alpha3beta4beta2 nAChRs that are present on glutamatergic axons/neurons synapsing onto SRIs and are activated by basal levels of acetylcholine contribute to the maintenance of the excitability of these interneurons. Kynurenic acid (KYNA), an astrocyte-derived kynurenine metabolite whose levels are increased in the brains of patients with schizophrenia, also controls the excitability of SRIs. At high micromolar concentrations, KYNA, acting primarily as an NMDA receptor antagonist, decreased the CT frequency recorded from the interneurons. At 2 MUM, KYNA reduced the CA1 SRI excitability via mechanisms independent of NMDA receptor block. KYNA induced reduction of excitability of SRIs may contribute to sensory gating deficits that have been attributed to deficient hippocampal GABAergic transmission and high levels of KYNA in the brain of patients with schizophrenia. PMID- 21689642 TI - Catalase overexpression in mammary cancer cells leads to a less aggressive phenotype and an altered response to chemotherapy. AB - Because reactive oxygen species (ROS) are naturally produced as a consequence of aerobic metabolism, cells have developed a sophisticated set of antioxidant molecules to prevent the toxic accumulation of these species. However, compared with normal cells, malignant cells often exhibit increased levels of intracellular ROS and altered levels of antioxidant molecules. The resulting endogenous oxidative stress favors tumor growth by promoting genetic instability, cell proliferation and angiogenesis. In this context, we assessed the influence of catalase overexpression on the sensitivity of breast cancer cells towards various anticancer treatments. Our data show that catalase overexpression in MCF 7 cells leads to a 7-fold increase in catalase activity but provokes a 40% decrease in the expression of both glutathione peroxidase and peroxiredoxin II. Interestingly, proliferation and migration capacities of MCF-7 cells were impaired by the overexpression of catalase, as compared to parental cells. Regarding their sensitivity to anticancer treatments, we observed that cells overexpressing catalase were more sensitive to paclitaxel, etoposide and arsenic trioxide. However, no effect was observed on the cytotoxic response to ionizing radiations, 5-fluorouracil, cisplatin or doxorubicin. Finally, we observed that catalase overexpression protects cancer cells against the pro-oxidant combination of ascorbate and menadione, suggesting that changes in the expression of antioxidant enzymes could be a mechanism of resistance of cancer cells towards redox-based chemotherapeutic drugs. PMID- 21689643 TI - Biochemistry of uridine in plasma. AB - Uridine is a pyrimidine nucleoside that plays a crucial role in synthesis of RNA, glycogen, and biomembrane. In humans, uridine is present in plasma in considerably higher quantities than other purine and pyrimidine nucleosides, thus it may be utilized for endogenous pyrimidine synthesis. Uridine has a number of biological effects on a variety of organs with or without disease, such as the reproductive organs, central and peripheral nervous systems, and liver. In addition, it is used in clinical situations as a rescue agent to protect against the adverse effects of 5-fluorouracil. Since the biological actions of uridine may be related to its plasma concentration, it is important to examine factors that have effects on that concentration. Factors associated with an increase in plasma concentration of uridine include enhanced ATP consumption, enhanced uridine diphosphate (UDP)-glucose consumption via glycogenesis, inhibited uridine uptake by cells via the nucleoside transport pathway, increased intestinal absorption, and increased 5-phosphribosyl-1-pyrophosphate and urea synthesis. In contrast, factors that decrease the plasma concentration of uridine are associated with accelerated uridine uptake by cells via the nucleoside transport pathway and decreased pyrimidine synthesis. PMID- 21689644 TI - The diagnostic accuracy of the percentage of hypochromic red blood cells (%HYPOm) and cellular hemoglobin in reticulocytes (CHr) in differentiating iron deficiency anemia and anemia of chronic diseases. AB - BACKGROUND: The percentages of hypochromic red blood cells (%HYPOm) and cellular hemoglobin in reticulocytes (CHr) are suggested to be useful screening markers of iron deficiency. The aim of this study was to investigate the diagnostic accuracy of %HYPOm and CHr in differentiating iron deficiency anemia (IDA) and anemia of chronic disease (ACD). METHODS: The retrospective population consisted of 58 IDA patients, 129 ACD patients and 63 controls, on whom bone marrow examination and blood count with %HYPOm and CHr had been performed. Receiver operating characteristic (ROC) analyses with area under the ROC curves (AUC) were used as statistical tests. RESULTS: AUCs for differentiating the groups using %HYPOm were as follows: IDA vs. controls 0.99, ACD vs. controls 0.85 and IDA vs. ACD 0.88. AUCs for CHr in distinguishing the groups were as follows: IDA vs. controls 0.95, ACD vs. controls 0.65 and IDA vs. ACD 0.83. CONCLUSIONS: IDA and ACD patients were efficiently differentiated by using %HYPOm and CHr. Additionally, %HYPOm was higher and CHr was lower in IDA patients and in ACD patients than in controls. Thus, %HYPOm is higher and CHr is lower not only in absolute iron deficiency, but also when iron availability for erythropoiesis is restricted. PMID- 21689645 TI - prdm1a and olig4 act downstream of Notch signaling to regulate cell fate at the neural plate border. AB - The zinc finger domain transcription factor prdm1a plays an integral role in the development of the neural plate border cell fates, including neural crest cells and Rohon-Beard (RB) sensory neurons. However, the mechanisms underlying prdm1a function in cell fate specification is unknown. Here, we test more directly how prdm1a functions in this cell fate decision. Rather than affecting cell death or proliferation at the neural plate border, prdm1a acts explicitly on cell fate specification by counteracting olig4 expression in the neighboring interneuron domain. olig4 expression is expanded in prdm1a mutants and olig4 knockdown can rescue the reduced or abrogated neural crest and RB neuron phenotype in prdm1a mutants, suggesting a permissive role for prdm1a in neural plate border-derived cell fates. In addition, prdm1a expression is upregulated in the absence of Notch function, and inhibiting Notch signaling fails to rescue prdm1a mutants. This suggests that prdm1a functions downstream of Notch in the regulation of cell fate at the neural plate border and that Notch regulates the total number of progenitor cells at the neural plate border. PMID- 21689646 TI - Variations in aggrecan localization and gene expression patterns characterize increasing stages of human intervertebral disk degeneration. AB - During disk degeneration, annulus dehydration and matrix fraying culminate in the formation of tears through which nucleus and annulus disk material may rupture, causing radicular pain. Annular tears are present in more than half of the patients in early adulthood and are almost always present in the elderly. Aggrecan, which provides the disk with a shock absorber function under loading, is a key disk extracellular matrix (ECM) component. The objective of the present study was to assess the immunolocalization of aggrecan in the annulus, and to assess molecular gene expression patterns in the annulus ECM utilizing microarray analysis. Immunohistochemistry was performed on 45 specimens using an anti-human aggrecan antibody. Affymetrix microarray gene expression studies used the extracellular matrix ontology approach to evaluate an additional 6 grade I-II, 9 grade III, and 4 grade IV disks. Grade III/IV disks were compared to healthier grade I/II disks. Healthy and less degenerated disks showed a general uniform aggrecan immunolocalization; more degenerated disks contained regions with little or no identifiable aggrecan localization. In degenerated disks, molecular studies showed a significant downregulation of aggrecan, ADAMTS-like 3, and ADAMTS10. Collagen types III and VIII, fibronectin, decorin, connective tissue growth factor, TIMP-3, latent TGF-beta binding protein 2 and TGF-beta1 were significantly upregulated with fold changes ranging from 2.4 to 9.8. Findings here help us better understand changes in the immunohistochemical distribution of a key proteoglycan during disk aging. Such information may have application as we work towards biologic therapies to improve the aging/degenerating disk matrix. PMID- 21689647 TI - Assessment of postnatal corneal development in the C57BL/6 mouse using spectral domain optical coherence tomography and microwave-assisted histology. AB - The eyes of newborn mice are relatively underdeveloped and the lids remain closed for the first 2 weeks after birth. There after the eyes undergo a period of rapid growth for several weeks. Eventually the eyes reach an age at which many ocular structures stabilize for the remainder of the animal's life, or for others, growth is significantly slowed. The central corneal thickness (CCT) is a parameter commonly reported in corneal studies. However there is a large discrepancy in values reported for adult mice as well as a lack of comprehensive values covering the time from birth through adulthood. In this study we report, for the first time, the use of spectral domain optical coherence tomography (SD OCT) for in situ and in vivo determination of CCT from P0 to P250 for C57BL/6 mice. SD-OCT provided a reliable measure of CCT and we fit the data to an exponential rise to maximum growth curve resulting in a value of 49 MUm for P0 and a maximum adult value of 106 MUm. By comparison, corneas processed for conventional histology produced CCT values approximately 30-35% thicker and with greater variability. Ex vivo real-time imaging during fixation revealed swelling and gross distortion of the cornea beginning after only 10-15 min in fixative. The fixation artifacts were not observed when the cornea was processed using an optimized microwave fixation protocol. CCT values measured in corneas fixed with the microwave process compared favorably with values obtained with SD-OCT. We conclude that for corneal research, mice younger than 8 weeks of age should not be considered as adults since they are still in a rapid phase of growth up until that time. In addition we report the first use of microwave processed histological specimens for visualizing the murine cornea. Tissue processed in this manner has minimal artifacts, a CCT equivalent to that measured in vivo by SD-OCT and ultrastructural detail comparable to conventional fixation methods. PMID- 21689648 TI - Increase in retinal hypoxia-inducible factor-2alpha, but not hypoxia, early in the progression of diabetes in the rat. AB - Hypoxia and the associated hypoxia-inducible factors (HIFs) may be influential in the progression of diabetic retinopathy. However, little is known of the extent of hypoxia and the levels of HIFs early in the progression of the disease. In the current study, we injected the oxygen-dependent probe pimonidazole (HypoxyprobeTM 1) into diabetic rats, and also performed immunohistochemistry to determine the retinal levels of HIF-1alpha and HIF-2alpha. The rats were made diabetic using a single injection of streptozotocin (STZ; 60 mg/kg), with vehicle-injected rats used as non-diabetic controls. The measurements of hypoxia and HIF levels were obtained three weeks following STZ injection, at which time we have previously found significant decreases in retinal blood flow in the same model. In the current experiments, no increases in either HIF-1alpha or hypoxia were observed in the diabetic rats (compared with controls), and there was even a tendency for hypoxia levels to be decreased (tissue more highly oxygenated). However, we did observe an increase in HIF-2alpha in the retinas of the diabetic rats. Therefore, we conclude that early diabetes-induced increases in HIF-2alpha occur independently of hypoxia. PMID- 21689650 TI - Functional effects of cytoskeletal components on the lateral movement of individual BKCa channels expressed in live COS-7 cell membrane. AB - The lateral diffusion of BK(Ca) channels was previously shown to be highly 'confined' in the COS-7 cell membrane. Here we report that the diffusion coefficient and the confinement area of BK(Ca) channel were significantly increased by the treatment of latrunculin A, an actin-depolymerizing agent, but not by microtubule disruption. Site-directed mutational analyses further demonstrated that a single leucine residue in the C-terminal actin-binding motif was critical for the aforementioned effects of latrunculin A. We conclude that some BK(Ca) channels are directly associated with actin filaments and their lateral mobility can be restricted by the cytoskeletal components. PMID- 21689651 TI - The cataract-associated protein TMEM114, and TMEM235, are glycosylated transmembrane proteins that are distinct from claudin family members. AB - A novel gene, TMEM114, was annotated as a member of the claudin gene family and was subsequently associated as a cause of autosomal dominant cataract because of a translocation in its putative promoter. Our bioinformatic and molecular analyses of TMEM114, and the closely related TMEM235, demonstrate that these proteins are more closely related to members of the voltage dependent calcium channel gamma subunit family. TMEM114 and TMEM235 differed from claudins in terms of localisation in polarised epithelial cells and by the presence of N-linked glycans. By gene expression knockdown in Xenopus tropicalis we also demonstrate a role for Tmem114 in eye development. PMID- 21689649 TI - Graft survival and endothelial outcomes in the new era of endothelial keratoplasty. AB - Corneal endothelial cells do not proliferative in vivo sufficiently to enable endothelial regeneration, and thus diseases of the corneal endothelium, which cause poor vision and discomfort, require treatment by transplantation of cadaveric donor corneal endothelial cells. The two major goals of any corneal transplant procedure are to restore vision and to promote longevity of the donor cornea by maintaining a healthy donor endothelial cell density. Over the last decade, the surgical treatment for endothelial disease has rapidly evolved toward endothelial keratoplasty, or selective tissue transplantation, and away from full thickness penetrating keratoplasty (PK). While endothelial keratoplasty offers distinct advantages over PK in terms of visual outcomes and a smaller incision, the new surgical manipulations of the fragile donor tissue cause significant donor endothelial cell trauma. As a result, donor endothelial cell loss is much higher during the first month after Descemet stripping endothelial keratoplasty (DSEK) compared to after PK, and the primary (or more appropriately, iatrogenic) graft failure rate of 5% remains unacceptably high. Nevertheless, the rate of endothelial cell loss rapidly decreases beyond 6 months after DSEK, and thus endothelial cell loss at 5 years after DSEK appears to be lower than that at 5 years after PK. In the absence of primary (iatrogenic) graft failure, graft survival through 5 years after DSEK is similar to that after PK. Given the promising longer-term endothelial outcomes of DSEK, the quest for optimizing the visual outcomes has spurred interest in Descemet membrane endothelial keratoplasty (DMEK). While early results after DMEK suggest better visual outcomes than after DSEK, the technique needs to be simplified, and longer-term outcomes must show an advantage over DSEK with respect to vision, endothelial cell loss, and graft survival. DMEK also has a high rate of primary (iatrogenic) graft failure, and additional donor tissue wastage occurs when preparation of DMEK grafts is unsuccessful. This review discusses endothelial keratoplasty techniques and the associated endothelial outcomes. PMID- 21689652 TI - Adipocytes as a new source of catecholamine production. AB - Catecholamines are an important regulator of lipolysis in adipose tissue. Here we show that rat adipocytes, isolated from mesenteric adipose tissue, express genes of catecholamine biosynthetic enzymes and produce catecholamines de novo. Administration of tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine, in vitro significantly reduced concentration of catecholamines in isolated adipocytes. We hypothesize that the sympathetic innervation of adipose tissues is not the only source of catecholamines, since adipocytes also have the capacity to produce both norepinephrine and epinephrine. PMID- 21689653 TI - Notch: architect, landscaper, and guardian of the intestine. AB - In the past decade, enormous progress has been made in understanding the role of stem cells in physiologic tissue renewal and in pathologic processes such as cancer. These findings have shed light on the identity and biological properties of such cells and the intrinsic and extrinsic signals that balance stem cell self renewal with differentiation. With its astonishing self-renewal capacity, the intestinal epithelium has provided a unique model to study stem cell biology, lineage specification, and cancer. Here we review the role of Notch signaling in physiologic cell renewal and differentiation in the intestine as well as during its malignant transformation. PMID- 21689655 TI - Urinary oxytocin as a noninvasive biomarker of positive emotion in dogs. AB - A reliable assay based on physiological parameters that does not require subjective input from the owners is required to assess positive emotions in dogs. In addition, when viewed from an animal welfare perspective, physiological parameters should be collected in a noninvasive manner. Oxytocin (OT) is a biomarker that may be associated with a calm, relaxed state, and positive emotion. We measured the time-lapse in the concentration of plasma OT relative to urinary OT using a radioimmunoassay with sufficient sensitivity and low variability, and examined the relationship between OT and cortisol. Six dogs were injected with exogenous OT intravenously to increase the blood OT concentration. As a result, the highest concentration of urinary OT occurred 1h after the injection, although there was little change in urinary cortisol. Moreover, to evaluate the influence of stimuli on urinary OT and cortisol, we provided three stimuli of eating food, exercising and stroking, all of which were assumed to inspire a positive emotion in dogs, and significantly increased urinary OT concentrations. Our findings indicate that urinary OT might be useful as a noninvasive and objective biomarker of positive emotion in dogs. PMID- 21689654 TI - Transient receptor potential ankyrin 1 is expressed by inhibitory motoneurons of the mouse intestine. AB - BACKGROUND & AIMS: Transient receptor potential ankyrin (TRPA) 1, an excitatory ion channel expressed by sensory neurons, mediates somatic and visceral pain in response to direct activation or noxious mechanical stimulation. Although the intestine is routinely exposed to irritant alimentary compounds and inflammatory mediators that activate TRPA1, there is no direct evidence for functional TRPA1 receptors on enteric neurons, and the effects of TRPA1 activation on intestinal function have not been determined. We characterized expression of TRPA1 by enteric neurons and determined its involvement in the control of intestinal contractility and transit. METHODS: TRPA1 expression was characterized by reverse transcription polymerase chain reaction and immunofluorescence analyses. TRPA1 function was examined by Ca(2+) imaging and by assays of contractile activity and transit. RESULTS: We detected TRPA1 messenger RNA in the mouse intestine and TRPA1 immunoreactivity in enteric neurons. The cecum and colon had immunoreactivity for neuronal TRPA1, but the duodenum did not. TRPA1 immunoreactivity was also detected in inhibitory motoneurons and descending interneurons, cholinergic neurons, and intrinsic primary afferent neurons. TRPA1 activators, including cinnamaldehyde, allyl isothiocyanate (AITC), and 4 hydroxynonenal, increased [Ca(2+)](i) in myenteric neurons. These were reduced by a TRPA1 antagonist (HC-030031) or deletion of Trpa1. TRPA1 activation inhibited contractility of the segments of colon but not stomach or small intestine of Trpa1(+/+) but not Trpa1(-/-) mice; this effect was reduced by tetrodotoxin or N(G)-nitro-l-arginine methyl ester. Administration of AITC by gavage did not alter gastric emptying or small intestinal transit, but luminal AITC inhibited colonic transit via TRPA1. CONCLUSIONS: Functional TRPA1 is expressed by enteric neurons, and activation of neuronal TRPA1 inhibits spontaneous neurogenic contractions and transit of the colon. PMID- 21689657 TI - Gendered occupational interests: prenatal androgen effects on psychological orientation to Things versus People. AB - There is considerable interest in understanding women's underrepresentation in science, technology, engineering, and mathematics careers. Career choices have been shown to be driven in part by interests, and gender differences in those interests have generally been considered to result from socialization. We explored the contribution of sex hormones to career-related interests, in particular studying whether prenatal androgens affect interests through psychological orientation to Things versus People. We examined this question in individuals with congenital adrenal hyperplasia (CAH), who have atypical exposure to androgens early in development, and their unaffected siblings (total N=125 aged 9 to 26 years). Females with CAH had more interest in Things versus People than did unaffected females, and variations among females with CAH reflected variations in their degree of androgen exposure. Results provide strong support for hormonal influences on interest in occupations characterized by working with Things versus People. PMID- 21689658 TI - Target-induced natural killer cell loss as a measure of NK cell responses. AB - The interaction of natural killer cells with susceptible target cells triggers NK cell activation, eliciting not only NK cell cytotoxicity and cytokine secretion, but also NK cell death. This study shows that following target cell interaction there is a substantial loss of NK cells, the extent of which correlates with measures of NK cell cytotoxicity assessed by the target cell release of (51)Cr and by the externalisation of the lysosomal marker LAMP-1 (CD107a) which is assessed on the remaining NK cells. This is the case for the killing of K562 (natural killing) and the CD20 mAb (Rituximab)-mediated killing of RAJI cells and autologous B cells (antibody-dependent cell cytotoxicity). This target-induced NK loss (TINKL) provides a sensitive and specific measure of NK cell responses appropriate to a clinical laboratory setting. PMID- 21689656 TI - Thyroid hormone regulation by stress and behavioral differences in adult male rats. AB - Thyroid hormones are essential regulators of growth, development and normal bodily function and their release is coordinated by the hypothalamic-pituitary thyroid (HPT) axis. While the HPT axis has been established as an acutely stress responsive neuroendocrine system, relatively little is known about the mechanisms of its stress regulation. The present study examined acute stress-induced changes in peripheral hormone levels [triiodothyronine (T3); thyroxine (T4), thyroid stimulating hormone (TSH), reverse triiodothyronine (rT3)] and central mRNA levels of regulators of the HPT axis [thyrotropin-releasing hormone (TRH), somatostatin (SST), type II deiodinase (D2)] in response to an inescapable tail shock, a rodent model of stress. Additionally, we examined whether individual differences in spontaneous exploratory behavior in an open field test predicted basal levels of TH or differential susceptibility to the effects of stress. The stress condition was associated with decreases in peripheral T3, T4 and TSH, but not rT3, when compared with controls. No changes were observed in TRH or SST mRNA levels, but there was a trend suggesting stress-related increases in D2 mRNA. We also found that an animal's exploratory behavior in an unfamiliar open field arena was positively related to peripheral thyroid hormone levels and predicted the magnitude of stress-induced changes. In conclusion, we found suggestive evidence for stress-induced decrease in central drive HPT axis, but the central mechanisms of its stress regulation remain to be elucidated. Additionally, we found that individual differences in animals' exploratory behavior were correlated with peripheral TH levels. PMID- 21689659 TI - Flow cytometry based identification of simian immunodeficiency virus Env-specific B lymphocytes. AB - SIV infection of macaques is the most widely employed model for preclinical AIDS vaccine and pathogenesis research. In macaques, high-titer virus-specific antibodies are induced by infection, and antibody responses can drive evolution of viral escape variants. However, neutralizing antibodies (Nabs) induced in response to SIVmac239 and SIVmac251 infection or immunization are generally undetectable or of low titer, and the identification and cloning of potent Nabs from SIVmac-infected macaques remains elusive. Based on recent advances in labeling HIV-specific B lymphocytes [1-3], we have generated recombinant, secreted, soluble SIVmac envelope (Env) proteins (gp120 and gp140) for detection and quantification of SIVmac Env-specific B lymphocytes. In contrast to HIV-1, we found that soluble SIVmac239 gp140 retains the ability to form stable oligomers without the necessity for introducing additional, stabilizing modifications. Soluble oligomeric gp140 reacted with rhesus anti-SIV Env-specific monoclonal antibodies (MAbs), and was used to deplete Env-specific antibodies with SIV neutralization capability from plasma taken from a rhesus macaque immunized with live attenuated SIVmac239?nef. Soluble gp120 and gp140 bound to SIV-specific immortalized B cells, and to SIV Env-specific B lymphocytes in peripheral blood of immunized animals. These reagents will be useful for analyzing development of Env-specific B cell responses in preclinical studies using SIV-infected or vaccinated rhesus macaques. PMID- 21689660 TI - Relevance of urocortins to cardiovascular disease. AB - Acquired cardiovascular diseases such as coronary heart disease, peripheral artery disease and related vascular problems contribute to more than one-third of worldwide morbidity and mortality. In many instances, particularly in the under developed world, cardiovascular diseases are diagnosed at a late stage limiting the scope for improving outcomes. A range of therapies already exist for established cardiovascular disease, although there is significant interest in further understanding disease pathogenesis in order to improve diagnosis and achieve primary and secondary therapeutic goals. The urocortins are a group of recently defined peptide members of the corticotrophin-releasing factor family. Previous pre-clinical work and human association studies suggest that urocortins have potential to exert some beneficial and other detrimental effects on the heart and major blood vessels. More current evidence however favours beneficial effects of urocortins, for example these peptides have been shown to inhibit production of reactive oxygen species and vascular cell apoptosis, and thus may have potential to antagonise the progression of cardiovascular disease. This review summarises published data on the potential role of urocortins in cardiovascular disease. PMID- 21689661 TI - Molecular basis of a million-fold affinity maturation process in a protein protein interaction. AB - Protein engineering is becoming increasingly important for pharmaceutical applications where controlling the specificity and affinity of engineered proteins is required to create targeted protein therapeutics. Affinity increases of several thousand-fold are now routine for a variety of protein engineering approaches, and the structural and energetic bases of affinity maturation have been investigated in a number of such cases. Previously, a 3-million-fold affinity maturation process was achieved in a protein-protein interaction composed of a variant T-cell receptor fragment and a bacterial superantigen. Here, we present the molecular basis of this affinity increase. Using X-ray crystallography, shotgun reversion/replacement scanning mutagenesis, and computational analysis, we describe, in molecular detail, a process by which extrainterfacial regions of a protein complex can be rationally manipulated to significantly improve protein engineering outcomes. PMID- 21689662 TI - Common structural traits across pathogenic mutants of the human prion protein and their implications for familial prion diseases. AB - Human (Hu) familial prion diseases are associated with about 40 point mutations of the gene coding for the prion protein (PrP). Most of the variants associated with these mutations are located in the globular domain of the protein. We performed 50 ns of molecular dynamics for each of these mutants to investigate their structure in aqueous solution. Overall, 1.6 MUs of molecular dynamics data is presented. The calculations are based on the AMBER(parm99) force field, which has been shown to reproduce very accurately the structural features of the HuPrP wild type and a few variants for which experimental structural information is available. The variants present structural determinants different from those of wild-type HuPrP and the protective mutation HuPrP(E219K-129M). These include the loss of salt bridges in alpha(2)-alpha(3) regions and the loss of pi-stacking interactions in the beta(2)-alpha(2) loop. In addition, in the majority of the mutants, the alpha(3) helix is more flexible and Y169 is more solvent exposed. The presence of similar traits in this large spectrum of mutations hints to a role of these fingerprints in their known disease-causing properties. Overall, the regions most affected by disease-linked mutations in terms of structure and/or flexibility are those involved in the pathogenic conversion to the scrapie form of the protein and in the interaction with cellular partners. These regions thus emerge as optimal targets for antibody- and ligand-binding studies. PMID- 21689663 TI - Functional coupling between a distal interaction and the cleavage site in bacterial RNase-P-RNA-mediated cleavage. AB - Bacterial RNase P consists of one protein and one RNA [RNase P RNA (RPR)]. RPR can process tRNA precursors correctly in the absence of the protein. Here we have used model hairpin loop substrates corresponding to the acceptor, T-stem, and T loop of a precursor tRNA to study the importance of the T-loop structure in RPR alone reaction. T-stem/loop (TSL) interacts with a region in RPR [TSL binding site (TBS)], forming TSL/TBS interaction. Altering the T-loop structure affects both cleavage site selection and rate of cleavage at the correct site +1 and at the alternative site -1. The magnitude of variation depended on the structures of the T-loop and the TBS region, with as much as a 150-fold reduction in the rate of cleavage at +1. Interestingly, for one T-loop structure mutant, no difference in the rate at -1 was detected compared to cleavage of the substrate with an unchanged T-loop, indicating that, in this case, the altered T-loop structure primarily influences events required for efficient cleavage at the correct site +1. We also provide data supporting a functional link between a productive TSL/TBS interaction and events at the cleavage site. Collectively, our findings emphasize the interplay between separate regions upon formation of a productive RPR substrate that leads to efficient and accurate cleavage. These new data provide support for an induced-fit mechanism in bacterial RPR-mediated cleavage at the correct site +1. PMID- 21689665 TI - A novel arterial constitutive model in a commercial finite element package: Application to balloon angioplasty. AB - Recently, a novel linearized constitutive model with a new strain measure that absorbs the material nonlinearity was validated for arteries. In this study, the linearized arterial stress-strain relationship is implemented into a finite element method package, ANSYS, via the user subroutine USERMAT. The reference configuration is chosen to be the closed cylindrical tube (no-load state) rather than the open sector (zero-stress state). The residual strain is taken into account by analytic calculation and the incompressibility condition is enforced with Lagrange penalty method. Axisymmetric finite element analyses are conducted to demonstrate potential applications of this approach in a complex boundary value problem where angioplasty balloon interacts with the vessel wall. The model predictions of transmural circumferential and compressive radial stress distributions were also validated against an exponential-type Fung model, and the mean error was found to be within 6%. PMID- 21689664 TI - Conserved C-terminal charge exerts a profound influence on the aggregation rate of alpha-synuclein. AB - alpha-Synuclein (alpha-syn) is the major component of filamentous Lewy bodies found in the brains of patients diagnosed with Parkinson's disease (PD). Recent studies demonstrate that, in addition to the wild-type sequence, alpha-syn is found in several modified forms, including truncated and phosphorylated species. Although the mechanism by which the neuronal loss in PD occurs is unknown, aggregation and fibril formation of alpha-syn are considered to be key pathological features. In this study, we analyze the rates of fibril formation and the monomer-fibril equilibrium for eight disease-associated truncated and phosphorylated alpha-syn variants. Comparison of the relative rates of aggregation reveals a strong monotonic relationship between the C-terminal charge of alpha-syn and the lag time prior to the observation of fibril formation, with truncated species exhibiting the fastest aggregation rates. Moreover, we find that a decrease in C-terminal charge shifts the equilibrium to favor the fibrillar species. An analysis of these findings in the context of linear growth theories suggests that the loss of the charge-mediated stabilization of the soluble state is responsible for the enhanced aggregation rate and increased extent of fibril fraction. Therefore, C-terminal charge is kinetically and thermodynamically protective against alpha-syn polymerization and may provide a target for the treatment of PD. PMID- 21689666 TI - Combinatorial analysis of interacting RNA molecules. AB - Recently several minimum free energy (MFE) folding algorithms for predicting the joint structure of two interacting RNA molecules have been proposed. Their folding targets are interaction structures, that can be represented as diagrams with two backbones drawn horizontally on top of each other such that (1) intramolecular and intermolecular bonds are noncrossing and (2) there is no "zigzag" configuration. This paper studies joint structures with arc-length at least four in which both, interior and exterior stack-lengths are at least two (no isolated arcs). The key idea in this paper is to consider a new type of shape, based on which joint structures can be derived via symbolic enumeration. Our results imply simple asymptotic formulas for the number of joint structures with surprisingly small exponential growth rates. They are of interest in the context of designing prediction algorithms for RNA-RNA interactions. PMID- 21689667 TI - Association between mutation spectra and stable and unstable DNA adduct profiles in Salmonella for benzo[a]pyrene and dibenzo[a,l]pyrene. AB - Benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP) are two polycyclic aromatic hydrocarbons (PAHs) that exhibit distinctly different mutagenicity and carcinogenicity profiles. Although some studies show that these PAHs produce unstable DNA adducts, conflicting data and arguments have been presented regarding the relative roles of these unstable adducts versus stable adducts, as well as oxidative damage, in the mutagenesis and tumor-mutation spectra of these PAHs. However, no study has determined the mutation spectra along with the stable and unstable DNA adducts in the same system with both PAHs. Thus, we determined the mutagenic potencies and mutation spectra of BP and DBP in strains TA98, TA100 and TA104 of Salmonella, and we also measured the levels of abasic sites (aldehydic-site assay) and characterized the stable DNA adducts ((32)P postlabeling/HPLC) induced by these PAHs in TA104. Our results for the mutation spectra and site specificity of stable adducts were consistent with those from other systems, showing that DBP was more mutagenic than BP in TA98 and TA100. The mutation spectra of DBP and BP were significantly different in TA98 and TA104, with 24% of the mutations induced by BP in TA98 being complex frameshifts, whereas DBP produced hardly any of these mutations. In TA104, BP produced primarily GC to TA transversions, whereas DBP produced primarily AT to TA transversions. The majority (96%) of stable adducts induced by BP were at guanine, whereas the majority (80%) induced by DBP were at adenine. Although BP induced abasic sites, DBP did not. Most importantly, the proportion of mutations induced by DBP at adenine and guanine paralleled the proportion of stable DNA adducts induced by DBP at adenine and guanine; however, this was not the case for BP. Our results leave open a possible role for unstable DNA adducts in the mutational specificity of BP but not for DBP. PMID- 21689668 TI - RecQ helicases in DNA double strand break repair and telomere maintenance. AB - Organisms are constantly exposed to various environmental insults which could adversely affect the stability of their genome. To protect their genomes against the harmful effect of these environmental insults, organisms have evolved highly diverse and efficient repair mechanisms. Defective DNA repair processes can lead to various kinds of chromosomal and developmental abnormalities. RecQ helicases are a family of evolutionarily conserved, DNA unwinding proteins which are actively engaged in various DNA metabolic processes, telomere maintenance and genome stability. Bacteria and lower eukaryotes, like yeast, have only one RecQ homolog, whereas higher eukaryotes including humans possess multiple RecQ helicases. These multiple RecQ helicases have redundant and/or non-redundant functions depending on the types of DNA damage and DNA repair pathways. Humans have five different RecQ helicases and defects in three of them cause autosomal recessive diseases leading to various kinds of cancer predisposition and/or aging phenotypes. Emerging evidence also suggests that the RecQ helicases have important roles in telomere maintenance. This review mainly focuses on recent knowledge about the roles of RecQ helicases in DNA double strand break repair and telomere maintenance which are important in preserving genome integrity. PMID- 21689669 TI - Executive function mediates effects of white matter hyperintensities on episodic memory. AB - This study examined the relationship between white matter hyperintensities (WMH) and executive functioning on episodic memory in a group of older adults who were cognitively normal or diagnosed with MCI or dementia. Volumetric magnetic resonance imaging (MRI) measures of total brain volume, white matter hyperintensity volume, and hippocampal volume along with age, education, and gender were evaluated as predictors of episodic memory. WMH were found to influence both episodic memory and executive functioning independently of other variables. The influence WMH on episodic memory was mediated by executive functioning and was completely eliminated when the interaction between executive functioning and hippocampal volume was entered in the regression model. The results indicate that executive functioning mediates the effects of WMH on episodic memory but that executive functioning and hippocampal volume can also interact such that executive functioning can exacerbate or ameliorate the influence of hippocampal volume on episodic memory. PMID- 21689670 TI - Face-name associative memory performance is related to amyloid burden in normal elderly. AB - Cerebral amyloid beta (Abeta) deposition occurs in a substantial fraction of cognitively normal (CN) older individuals. However, it has been difficult to reliably detect evidence of amyloid-related cognitive alterations in CN using standard neuropsychological measures. We sought to determine whether a highly demanding face-name associative memory exam (FNAME) could detect evidence of Abeta-related memory impairment in CN. We studied 45 CN subjects (mean age=71.7 +/- 8.8) with Clinical Dementia Rating (CDR) scores=0 and MMSE >= 28, using Positron Emission Tomography with Pittsburgh Compound B (PiB PET). Memory factor scores were derived from a principal components analysis for FNAME name retrieval (FN-N), FNAME occupation retrieval (FN-O) and the 6-Trial Selective Reminding Test (SRT). Using multiple linear and logistic regression analyses, we related the memory factor scores to PiB distribution volume ratios (DVR, cerebellar reference) as either a continuous or a dichotomous variable in frontal cortex and a posterior cortical region representing the precuneus, posterior cingulate and lateral parietal cortices (PPCLP), co-varying for age and AMNART IQ (a proxy of cognitive reserve (CR)). A significant inverse relationship for FN-N was found with Abeta deposition in frontal (R(2)=0.29, beta=-2.2, p=0.02) and PPCLP cortices (R(2)=0.26, beta=-2.4, p=0.05). In contrast, neither FN-O nor the SRT were significantly related to Abeta deposition. Performance on a demanding test of face-name associative memory was related to Abeta burden in brain regions associated with memory systems. Associative memory for faces and names, a common complaint among older adults, may be a sensitive marker of early Abeta-related impairment. PMID- 21689672 TI - The effects of subjectively significant stimuli on subsequent cognitive brain activity. AB - OBJECTIVE: To study brain activity modulation by preceding subjectively significant stimuli. Brain activity related to emotional and cognitive processing has been typically traced with fMRI's temporal resolution of seconds. In this study, the time course of activation in the brain areas involved was traced with millisecond temporal resolution. METHODS: Electrophysiological brain activity was recorded while 12 normal subjects performed an auditory cued attention task, with subjectively significant verbal distracters. Verbal distracters, administered at different times between the cue and the target in one third of the trials, were first names, whose subjective significance was individually assessed after the experiment using a validated questionnaire. Intracranial sources of scalp recorded electrical activity were estimated and statistical comparisons were conducted to assess the effects and interactions of (1) cue validity; and (2) subjective significance of distracters, on brain activity evoked by the targets. RESULTS: Significant cue validity effects were found. Language-related areas were most involved following neutral distracters. Emotion-related areas were most involved following subjectively significant distracters. Thus, cue validity and distracter effects seem to have distinct effects. SIGNIFICANCE: The results indicate an effect of subjectively significant distracters on subsequent brain activity with an interaction between cognitive and emotional processes. PMID- 21689671 TI - Auditory object cognition in dementia. AB - The cognition of nonverbal sounds in dementia has been relatively little explored. Here we undertook a systematic study of nonverbal sound processing in patient groups with canonical dementia syndromes comprising clinically diagnosed typical amnestic Alzheimer's disease (AD; n=21), progressive nonfluent aphasia (PNFA; n=5), logopenic progressive aphasia (LPA; n=7) and aphasia in association with a progranulin gene mutation (GAA; n=1), and in healthy age-matched controls (n=20). Based on a cognitive framework treating complex sounds as 'auditory objects', we designed a novel neuropsychological battery to probe auditory object cognition at early perceptual (sub-object), object representational (apperceptive) and semantic levels. All patients had assessments of peripheral hearing and general neuropsychological functions in addition to the experimental auditory battery. While a number of aspects of auditory object analysis were impaired across patient groups and were influenced by general executive (working memory) capacity, certain auditory deficits had some specificity for particular dementia syndromes. Patients with AD had a disproportionate deficit of auditory apperception but preserved timbre processing. Patients with PNFA had salient deficits of timbre and auditory semantic processing, but intact auditory size and apperceptive processing. Patients with LPA had a generalised auditory deficit that was influenced by working memory function. In contrast, the patient with GAA showed substantial preservation of auditory function, but a mild deficit of pitch direction processing and a more severe deficit of auditory apperception. The findings provide evidence for separable stages of auditory object analysis and separable profiles of impaired auditory object cognition in different dementia syndromes. PMID- 21689673 TI - Push-pull training reduces foveal sensory eye dominance within the early visual channels. AB - A push-pull training protocol is applied to reduce sensory eye dominance in the foveal region. The training protocol consists of cueing the weak eye to force it to become dominant while the strong eye is suppressed when a pair of dichoptic orthogonal grating stimulus is subsequently presented to it (Ooi & He, 1999). We trained with four pairs of dichoptic orthogonal gratings (0 degrees /90 degrees , 90 degrees /0 degrees , 45 degrees /135 degrees and 135 degrees /45 degrees at 3cpd) to affect the interocular inhibitory interaction tuned to the four trained orientations (0 degrees , 45 degrees , 90 degrees and 135 degrees ). After a 10 day training session, we found a significant learning effect (reduced sensory eye dominance) at the trained orientations as well as at two other untrained orientations (22.5 degrees and 67.5 degrees ). This suggests that the four pairs of oriented training stimuli are sufficient to produce a learning effect at any other orientation. The nearly complete transfer of the learning effect across orientation is attributed to the fact that the trained and untrained orientations are close enough to fall in the same orientation tuning function of the early visual cortical neurons (~37.5 degrees ). Applying the same notion of transfer of learning within the same feature channel, we also found a large transfer effect to an untrained spatial frequency (6cpd), which is 1 octave higher than the trained spatial frequency (3cpd). Furthermore, we found that stereopsis is improved, as is the competitive ability between the two eyes, after the push-pull training. Our data analysis suggests that these improvements are correlated with the reduced sensory eye dominance after the training, i.e., due to a more balanced interocular inhibition. We also found that the learning effect (reduced SED and stereo threshold) can be retained for more than a year after the termination of the push-pull training. PMID- 21689674 TI - The neuro-glial-vascular interrelations in genomic instability symptoms. AB - A hallmark of neurodegenerative diseases is impairment of certain aspects of "brain functionality", which is defined as the total input and output of the brain's neural circuits and networks. A given neurodegenerative disorder is characterized by affected network organization and topology, cell numbers, cellular functionality, and the interactions between neural circuits. Neuroscientists generally view neurodegenerative disorders as diseases of neuronal cells; however, recent advances suggest a role for glial cells and an impaired vascular system in the etiology of certain neurodegenerative diseases. It is now clear that brain pathology is, to a very great extent, pathology of neurons, glia and the vascular system as these determine the degree of neuronal death as well as the outcome and scale of the neurological deficit. This review article is focused on the intricate interrelations among neurons, glia, the vascular system, neuronal cells, and the DNA damage response. Here I describe various aspects of neural and glial cell fate and the vascular system in genomic instability disorders including ataxia telangiectasia (A-T) and Nijmegen breakage syndrome. PMID- 21689675 TI - Diltiazem potentiates pentobarbital-induced hypnosis via 5-HT1A and 5-HT2A/2C receptors: role for dorsal raphe nucleus. AB - It has been reported that the sedative component of pentobarbital is mediated by GABA receptors in an endogenous sleep pathway and the ventrolateral preoptic area (VLPO)-tuberomammillary nucleus (TMN) or VLPO-dorsal raphe nucleus (DRN) neural circuit is important in the sedative response to pentobarbital. Our previous findings indicated that the VLPO-TMN neuronal circuit may play crucial part in the augmentative effect of diltiazem on pentobarbital sleep and the serotonergic system may be involved. This study was designed to investigate the role of DRN and the serotonergic receptors 5-HT(1A) and 5-HT(2A/2C) in the augmentative effect of diltiazem on pentobarbital-induced hypnosis in rats. The results showed that diltiazem (5mg/kg, i.g.) significantly reversed pentobarbital-induced (35 mg/kg, i.p.) reduction of c-Fos expression in 5-HT neurons of DRNV (at -7.5mm Bregma), DRND, DRNVL and MRN (at -8.0mm Bregma). However it did not influence this reducing effect of pentobarbital on non-5-HT neurons either in DRN or in MRN. Moreover, the effect of diltiazem (1 or 2mg/kg, i.g.) on pentobarbital induced (35 mg/kg, i.p.) hypnosis was significantly inhibited by 5-HT(1A) agonist 8-OH-DPAT (0.5mg/kg, i.p.) and 5-HT(2A/2C) agonist DOI (0.5mg/kg, i.p.), and potentiated by 5-HT(1A) antagonist p-MPPI (2mg/kg, i.p.) and 5-HT(2A/2C) antagonist ritanserin (2mg/kg, i.p.), respectively. From these results, it should be presumed that the augmentative effect of diltiazem on pentobarbital-induced sleep may be related to 5-HT(1A) and 5-HT(2A/2C) receptors, and DRN may be involved. In addition, it also suggested that the DRN may play a multi-modulating role in sleep-wake regulation rather than being recognized simply as arousal nuclei. PMID- 21689676 TI - Progesterone prevents depression-like behavior in a model of Parkinson's disease induced by 6-hydroxydopamine in male rats. AB - Hemiparkinsonism induced by 6-hydroxydopamine (6-OHDA) injected in left corpus striatum is a recognized model of motor deficits in rats. Some reports concerning motor deficits indicate a favorable response to steroid administration in hemiparkinsonian animals. However, there is no much information regarding progesterone administration in relation to cognitive and affective dysfunctions. Here we could confirm earlier reports regarding a mild deficit of memory and a noticeable depressive-like behavior 4 weeks after injecting 6-OHDA. We also present some evidence that progesterone could be - when administered 7 days after the injection of 6-OHDA - a possible neuroprotector concerning both motor deficits as well as cognitive - memory- and depression-like behaviors. The affective deficit was reverted by administering the tricyclic antidepressant imipramine. Since Parkinson's disease is a conspicuous cause of psycho-organic decline in human beings, it would be important to be able of dealing early with non-motor indicators in order to use prospective neuroprotectors to prevent the progression of the disease. PMID- 21689677 TI - The response to naltrexone in ethanol-drinking rats depends on early environmental experiences. AB - The opioid receptor antagonist naltrexone is currently used in the treatment of alcohol addiction. However, substantial individual differences have been reported for the efficacy of naltrexone. Genetic factors are known to contribute to these differences; however, little is known about the impact of early environmental influences. Based on previous findings that have suggested a link between ethanol, endogenous opioids and the early environment, it was hypothesised that early environmental factors affect naltrexone efficacy later in life. A population of Wistar rats was subjected to three different rearing conditions where the pups experienced a daily separation from the dam, for either 15 min or 360 min, or were just briefly handled. On postnatal day 26, the rats were given intermittent access to ethanol (5% and 20%) and water for six weeks before naltrexone (0.3mg/kg or 3.0mg/kg) or saline treatment using a randomised injection schedule with a one-week washout period between injections. Naltrexone reduced ethanol consumption, but there was high variability in the efficacy. In addition, there was an association between the rearing condition and the effectiveness of naltrexone. Naltrexone reduced ethanol intake in rats experiencing postnatal conditions that contrasted normal wildlife conditions, i.e., prolonged absence or continuous presence of the dam, and naltrexone had no effect on the total ethanol consumption in rats reared under naturalistic conditions, i.e., short absences of the dam. These rats reduced their intake of 5% ethanol but increased their preference for 20% ethanol. We conclude that rats with a history of early adversity responded well to naltrexone treatment, whereas rats reared in a social context similar to that found in nature did not benefit from treatment. The present study highlights the importance of not only considering genetics but also environmental factors when identifying individual responses to naltrexone. PMID- 21689678 TI - Trends and changes in research on the psychology of physical activity across 20 years: a quantitative analysis of 10 journals. AB - OBJECTIVE: To investigate content of the psychology of physical activity research over the past 20 years. METHOD: Volumes of 10 journals, identified by impact factor and relevance to physical activity were audited every other year, during the period of 1990-2008. Inclusion criteria were studies that measured a physical activity outcome, and/or a psychological outcome as a result of physical activity. Data were extracted and coded based on 15 factors. RESULTS: The review yielded 889 studies for analysis. Total volume of studies (from 127 in the 1990s to 762 in the 2000s), and the proportionate content space allotted to journals has increased significantly across 20 years (effect size w=0.24) (Cohen, 1992). Many study characteristics (assessment of minority/high-risk groups, self-report measurement, cross-sectional designs) have not changed. There was evidence, however, of less growth in research among older adults and young children (effect size w=0.15) compared to other age groups (effect size w=0.24), a move from pure measurement studies (effect size w=0.21) to descriptive research (effect size w=0.27), and considerable growth in environmental correlates research across time (effect size w=0.41) in the 10 journals sampled. CONCLUSION: The behavioral science of physical activity has clearly increased in prominence and volume among the 10 journals sampled, but methodological characteristics of research could be improved in the future. PMID- 21689679 TI - Antitussive and immunomodulating activities of instant coffee arabinogalactan protein. AB - A low molecular mass arabinogalactan-protein (AGP) composed of galactose and arabinose with a low protein content, isolated from the instant coffee powder of Coffea arabica beans, has been tested on antitussive (in vivo) and immunomodulating (ex vivo) activities. The results of antitussive tests revealed a significant dose dependant cough-suppressive effect of coffee AGP. It was observed 30 or 60 min after AGP administration and its efficacy lasted during the entire experiment course. Immunological tests showed that AGP affected some mediators of immunocompetent cells of immune system as TNF-alpha, IFN-gamma and IL-2 cytokines. It seems that coffee AGP is a good inductor of both pro inflammatory cytokines TNF-alpha and IFN-gamma, however, less potent in TNF-alpha induction in comparison with that of beta-D-glucan. Evident induction of TNF alpha, IL-2 and IFN-gamma cytokines, pro-TH1 polarization supports our conclusion about bio-immunological efficacy of AGP with an emphasis on the cellular immunity. PMID- 21689680 TI - Synthesis of gamma-cyclodextrin/chitosan composites for the efficient removal of Cd(II) from aqueous solution. AB - The synthesis of chitosan-graft-gamma-cyclodextrin (Ch-g-gamma-CD) using persulfate/ascorbic acid redox system was done and characterized by FTIR, XRD, TGA and SEM/EDX. The optimum yield of the copolymer was obtained using 16*10(-3) M gamma-cyclodextrins (gamma-CD), 2.8*10(-2) M ascorbic acid (AA), 1.8*10(-2) M K(2)S(2)O(8) and 0.1g chitosan in 25 mL of 2% aqueous formic acid at 45+/-0.2 degrees C. The highest percent grafting samples were evaluated for cadmium metal ion (Cd(II)) removal from the aqueous solutions where the sorption capacities were found proportional to the grafting extent. The sorption was pH and concentration dependent where, pH=8.5 was found to be the optimum value. The adsorption data were modeled using Langmuir and Freundlich isotherms. The equilibrium data followed the Langmuir isotherm model with maximum sorption capacity of 833.33 mg/g. The influence of electrolytes, sodium chloride (NaCl) and sodium sulphate (Na(2)SO(4)) on Cd(II) uptake was also studied. Desorption of the cadmium loaded Ch-g-gamma-CD was accomplished with 0.01 N H(2)SO(4). The adsorbent exhibited high reusability and could be successfully recycled for nine cycles where in the ninth cycle 27% adsorption was feasible. PMID- 21689681 TI - Chemoenzymatic synthesis and hydrogelation of amylose-grafted xanthan gums. AB - This paper reports the chemoenzymatic synthesis of an amylose-grafted xanthan gum. An amine-functionalized maltooligosaccharide was chemically introduced to xanthan gum by condensation with its carboxylates using a condensing agent to produce a maltooligosaccharide-grafted xanthan gum. Then, a phosphorylase catalyzed enzymatic polymerization of glucose 1-phosphate from the graft chain ends on the xanthan gum derivative was performed, giving an amylose-grafted xanthan gum. Furthermore, the product formed a gel with an ionic liquid, which was converted into a hydrogel with high water content by replacement of the ionic liquid with water. The ionically cross-linked hydrogel was also provided by soaking the primary formed hydrogel in FeCl(3) aqueous solution. The mechanical properties of the resulting hydrogels were evaluated by compressive testing. PMID- 21689682 TI - Recording the adult zebrafish cerebral field potential during pentylenetetrazole seizures. AB - Although the zebrafish is increasingly used as a model organism to study epilepsy, no standard electrophysiological technique for recording electrographic seizures in adult fish exists. The purpose of this paper is to introduce a readily implementable technique for recording pentylenetetrazole seizures in the adult zebrafish. We find that we can consistently record a high quality field potential over the zebrafish cerebrum using an amplification of 5000V/V and bandpass filtering at corner frequencies of 1.6 and 16Hz. The cerebral field potential recordings show consistent features in the baseline, pre-seizure, seizure and post-seizure time periods that can be easily recognized by visual inspection as is the case with human and rodent electroencephalogram. Furthermore, numerical analysis of the field potential at the time of seizure onset reveals an increase in the total power, bandwidth and peak frequency in the power spectrum, as is also the case with human and rodent electroencephalogram. The techniques presented herein stand to advance the utility of the adult zebrafish in the study of epilepsy by affording an equivalent to the electroencephalogram used in mammalian models and human patients. PMID- 21689683 TI - OrbitView: Eye movement visualization software. AB - Measurement of eye movements often helps to diagnose ocular motor disorders in the clinic, and is also used as a research tool in ocular motor, vision and vestibular research. Eye movements, however, are usually recorded without simultaneous video recordings, making offline interpretation difficult. We developed a tool that converts the measured eye movement data into a three dimensional (3D) movie of eye movements. Having useful functions such as slow play, pause and exaggeration of the movements, this new software provides a research and teaching tool to aid interpretation of the recorded eye movements. PMID- 21689684 TI - p-Hydroxyamphetamine causes prepulse inhibition disruption in mice: contribution of serotonin neurotransmission. AB - p-Hydroxyamphetamine (p-OHA) has been shown to have a number of pharmacological actions, including causing abnormal behaviors such as increased locomotor activity and head-twitch response in rodents. We have recently reported that intracerebroventricular (i.c.v.) administration of p-OHA dose-dependently induces prepulse inhibition (PPI) disruption in mice, which is attenuated by pretreatment with haloperidol, clozapine or several dopaminergic agents. Haloperidol and clozapine have affinities for serotonergic (especially 5-HT(2A)) receptors. To investigate the involvement of the central serotonergic systems in p-OHA-induced PPI disruption, herein we tested several serotonergic agents to determine their effects on p-OHA-induced PPI disruption. p-OHA-induced PPI disruption was attenuated by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, a neurotoxin which targets serotonin-containing neurons) and p-chlorophenylalanine (PCPA, a serotonin synthesis inhibitor). p-OHA-induced PPI disruption was also attenuated by pretreatment with ketanserin (a 5-HT(2A/2C) receptor antagonist) and MDL100,907 (a selective 5-HT(2A) receptor antagonist). These data suggest that p OHA-induced PPI disruption may involve increased serotonin release into the synaptic cleft, which then interacts with the post-synaptic 5-HT(2A) receptor. PMID- 21689685 TI - Female C57BL/6 mice show consistent individual differences in spontaneous interaction with environmental enrichment that are predicted by neophobia. AB - Environmental enrichment typically improves learning, increases cortical thickness and hippocampal neurogenesis, reduces anxiety, and reduces stereotypic behaviour, yet sometimes such effects are absent or even reversed. We investigated whether neophobia governs how mice interact with enrichments, since this could explain why enrichments vary in impact. Female C57BL/6 mice, previously screened for neophobia, had free access to enriched cages connected to their standard cages. The relative consumption of food in each cage revealed approximate dwelling times; the use of two enrichments was also measured. High neophobia significantly predicted reduced use of the enriched cage. Thus even within this homogeneous population, provided with identical enrichments, differential neophobia predicted differential enrichment use. PMID- 21689686 TI - Spatial integration in human geometry learning. AB - In a 2-D computer based search task, human participants were exposed to a compound stimulus containing both geometric and non-geometric information (a rectangle with colored walls) in such a way that a non-geometric cue, C1, was paired with a geometric cue, G1. Previous reinforcement of either kind of cue (geometric and non-geometric) resulted in second order conditioning (SOC) when the participants were tested with the cue that was never paired with reinforcement (Experiment 1). Similarly, if one of the cues was reinforced following the non-reinforced exposure to the compound, a sensory preconditioning (SPC) effect was observed (Experiment 3). These results show that associations can be formed between geometric and non-geometric cues, a finding that is incompatible with the concept of a geometric module impenetrable to non-geometric information. In Experiments 2 and 4, we found evidence for SOC and SPC using exclusively geometric cues, suggesting that the associative learning principles that apply to other domains also rule spatial geometry learning in humans. This research suggests that spatial representations can be enlarged by successively integrating information bits through the linkage of common elements. PMID- 21689687 TI - Characterization of a new phosphatase from Plasmodium. AB - Plasmodium falciparum malaria is the most important parasitic disease worldwide, responsible for an estimated 1 million deaths annually. Two P. falciparum genes code for putative phosphoglycerate mutases (PGMases), a widespread protein group characterized by the involvement of histidine residues in their catalytic mechanism. PGMases are responsible for the interconversion between 2 and 3 phosphoglycerate, an intermediate step in the glycolysis pathway. We have determined the crystal structures of one of the P. falciparum's PGMases (PfPGM2) and a functionally distinct phosphoglycerate mutase from Cryptosporidium parvum, a related apicomplexan parasite. We performed sequence and structural comparisons between the two structures, another P. falciparum enzyme (PfPGM1) and several other PGM family members from other organisms. The comparisons revealed a distinct conformation of the catalytically active residues not seen in previously determined phosphoglycerate mutase structures. Furthermore, characterization of their enzymatic activities revealed contrasting behaviors between the PfPGM2 and the classical cofactor-dependent PGMase from C. parvum, clearly establishing PfPGM2 as a phosphatase with a residual level of mutase activity. Further support for this function attribution was provided by our structural comparison with previously characterized PGM family members. Genetic characterization of PGM2 in the rodent parasite Plasmodium berghei indicated that the protein might be essential to blood stage asexual growth, and a GFP tagged allele is expressed in both blood and zygote ookinete development and located in the cytoplasm. The P. falciparum PGM2 is either an enzyme implicated in the phosphate metabolism of the parasite or a regulator of its life cycle. PMID- 21689689 TI - TRIM8 regulates Nanog via Hsp90beta-mediated nuclear translocation of STAT3 in embryonic stem cells. AB - TRIM8 is a member of a protein family defined by the presence of a common domain structure composed of a tripartite motif including a RING-finger, one or two B box domains and a coiled-coil motif. Here, we show that TRIM8 interacts with Hsp90beta, which interacts with STAT3 and selectively downregulates transcription of Nanog in embryonic stem cells. Knock-down of TRIM8 increased phosphorylated STAT3 in the nucleus and also enhanced transcription of Nanog. These findings suggest that TRIM8 modulates translocation of phosphorylated STAT3 into the nucleus through interaction with Hsp90beta and consequently regulates transcription of Nanog in embryonic stem cells. PMID- 21689688 TI - Requirements for the catalytic cycle of the N-ethylmaleimide-Sensitive Factor (NSF). AB - The N-ethylmaleimide-Sensitive Factor (NSF) was one of the initial members of the ATPases Associated with various cellular Activities Plus (AAA(+)) family. In this review, we discuss what is known about the mechanism of NSF action and how that relates to the mechanisms of other AAA(+) proteins. Like other family members, NSF binds to a protein complex (i.e., SNAP-SNARE complex) and utilizes ATP hydrolysis to affect the conformations of that complex. SNAP-SNARE complex disassembly is essential for SNARE recycling and sustained membrane trafficking. NSF is a homo-hexamer; each protomer is composed of an N-terminal domain, NSF-N, and two adjacent AAA-domains, NSF-D1 and NSF-D2. Mutagenesis analysis has established specific roles for many of the structural elements of NSF-D1, the catalytic ATPase domain, and NSF-N, the SNAP-SNARE binding domain. Hydrodynamic analysis of NSF, labeled with (Ni(2+)-NTA)(2)-Cy3, detected conformational differences in NSF, in which the ATP-bound conformation appears more compact than the ADP-bound form. This indicates that NSF undergoes significant conformational changes as it progresses through its ATP-hydrolysis cycle. Incorporating these data, we propose a sequential mechanism by which NSF uses NSF-N and NSF-D1 to disassemble SNAP-SNARE complexes. We also illustrate how analytical centrifugation might be used to study other AAA(+) proteins. PMID- 21689690 TI - Construction and evaluation of pMycoFos, a fosmid shuttle vector for Mycobacterium spp. with inducible gene expression and copy number control. AB - Molecular tools for Gram-positive bacteria such as Mycobacterium are less well developed than those for Gram-negatives such as Escherichiacoli. This has slowed the molecular-genetic characterisation of Mycobacterium spp, which is unfortunate, since this genus has high medical, environmental and industrial significance. Here, we developed a new Mycobacterium shuttle vector (pMycoFos, 12.5kb, Km(R)) which combines desirable features of several previous vectors (controllable copy number in E. coli, inducible gene expression in Mycobacterium) and provides a new multiple cloning site compatible with large inserts of high-GC content DNA. Copy number control in E. coli was confirmed by the increased Km(R) of cultures after arabinose induction and the greater DNA yield of vector from arabinose-induced cultures. Measurement of beta-galactosidase activity in pMycoFos clones carrying the lacZ gene showed that in Mycobacterium smegmatis mc(2)-155, expression was inducible by acetamide, but in E. coli EPI300, the expression level was primarily determined by the vector copy number. Examination of protein profiles on SDS-PAGE gels confirmed the beta-galactosidase assay results. Construction of a fosmid library with the new vector confirmed that it could carry large DNA inserts. The new vector enabled the stable cloning and expression of an ethene monooxygenase gene cluster, which had eluded previous attempts at heterologous expression. PMID- 21689692 TI - Development of a Pulsed-Field Gel Electrophoresis (PFGE) method for molecular typing of clinical isolates of Arcanobacterium haemolyticum. AB - We developed a two-block PFGE method to study molecular variation among clinical isolates of Arcanobacterium haemolyticum, an often overlooked human pathogen. Three main macrorestriction profiles were defined among 15 isolates. PFGE was an objective method for characterizing A. haemolyticum and may be useful in molecular epidemiological studies of this organism. PMID- 21689691 TI - A novel method based on high resolution melting (HRM) analysis for MIRU-VNTR genotyping of Mycobacterium tuberculosis. AB - The mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) method is one of the most important methods that have been used in recent years for genotyping Mycobacterium tuberculosis. Agarose gel electrophoresis and capillary electrophoresis have been used to determine the size of amplicons, however, both of these methods have shortcomings. Here, we develop and evaluate a novel method for MIRU-VNTR typing based on high resolution melting (HRM) analysis. The MIRU40 locus was selected to evaluate different real time PCR machines and the accuracy of our method; the Roche LightCycler 480 provided greatest consistency between the T(m) value and repeat number and was used in subsequent evaluations. Our method gives greater accuracy in comparison with conventional agarose gel electrophoresis (98.9% vs. 90.9%, p=0.017), and, with the help of fitting formulae, can be used to obtain the number of MIRU tandem repeats from the T(m) value. To validate our method we analyzed 12 classical MIRU loci to genotype 88 clinical isolates. The number of MIRU tandem repeats was determined accurately, quickly and conveniently. PMID- 21689693 TI - Improved method for calculating the respiratory line length in the Concealed Information Test. AB - The Concealed Information Test (CIT) assesses an examinee's knowledge about a crime based on response differences between crime-relevant and crime-irrelevant items. One effective measure in the CIT is the respiration line length, which is the average of the moving distances of the respiration curve in a specified time interval after the item onset. However, the moving distance differs between parts of a respiratory cycle. As a result, the calculated respiration line length is biased by how the parts of the respiratory cycles are included in the time interval. To resolve this problem, we propose a weighted average method, which calculates the respiration line length per cycle and weights it with the proportion that the cycle occupies in the time interval. Simulation results indicated that the weighted average method removes the bias of respiration line lengths compared to the original method. The results of experimental CIT data demonstrated that the weighted average method significantly increased the discrimination performance as compared with the original method. The weighted average method is a promising method for assessing respiration changes in response to question items more accurately, which improves the respiration-based discrimination performance of the CIT. PMID- 21689694 TI - Affective processing of loved familiar faces: integrating central and peripheral electrophysiological measures. AB - A major problem in the electrophysiological studies of emotional processing linked to recognition of familiar faces is the unambiguous differentiation of effects due to emotional valence, arousal, and familiarity. The present paper summarizes a set of three studies aimed at investigating the affective processing of loved familiar faces using Lang's picture-viewing paradigm, with a special emphasis on teasing apart the individual contributions of affective valence, undifferentiated emotional arousal, and familiarity The results of the three studies support the conclusion that viewing the faces of familiar loved ones elicits an intense positive emotional reaction that cannot be explained either by familiarity or arousal alone. PMID- 21689695 TI - Impact of meditation on emotional processing--a visual ERP study. AB - Impact of meditation on emotional processing, and its clinical applications, has recently drawn significant interest. In this visual event-related potential (ERP) study we investigated whether long-term meditation practitioners exhibit different ERP responses to the emotional load of stimuli (IAPS pictures) than control subjects with no experience in meditation. Differences were observed in the late positive potential (LPP). LPP amplitude is typically greater in ERPs evoked by emotionally arousing scenes, specifically negative images, compared to neutral scenes. This effect was also replicated in our study, but not in case of meditators' frontal scalp regions, who differed significantly in this respect from control subjects. Our findings provide support for different emotional processing in meditation practitioners: at high levels of processing meditators are less affected by stimuli with adverse emotional load, while processing of positive stimuli remains unaltered. To further confirm this observation, a long term longitudinal random assignment study would be desirable. PMID- 21689697 TI - Viral diversity of Junin virus field strains. AB - The Argentine Hemorrhagic Fever, an endemic disease present in a much of Argentina, is caused by the Junin virus (JUNV). Currently, there are sequences available from several strains of this virus, like those belonging to the vaccine lineage (XJ13, XJ#44 and Candid#1), as well as MC2 (rodent isolate) and IV4454 (human isolate). In this article, we report sequence information on two fragments of genomic segment S of viral isolates from the endemic area. A Nested-RT-PCR was used to amplify discrete genomic regions of 13 isolates of rodent and human origin. The bioinformatics studies revealed a great homogeneity of sequences among the JUNV isolates. The phylogenetic classification showed greater evolutionary distance between the old world arenaviruses (Lassa and LCM virus) than between the new world arenaviruses (JUNV and Machupo virus). PMID- 21689696 TI - Cytoplasmic localized infected cell protein 0 (bICP0) encoded by bovine herpesvirus 1 inhibits beta interferon promoter activity and reduces IRF3 (interferon response factor 3) protein levels. AB - Bovine herpesvirus 1 (BHV-1), an alpha-herpesvirinae subfamily member, establishes a life-long latent infection in sensory neurons. Periodically, BHV-1 reactivates from latency, infectious virus is spread, and consequently virus transmission occurs. BHV-1 acute infection causes upper respiratory track infections and conjunctivitis in infected cattle. As a result of transient immune suppression, BHV-1 infections can also lead to life-threatening secondary bacterial pneumonia that is referred to as bovine respiratory disease. The infected cell protein 0 (bICP0) encoded by BHV-1 reduces human beta-interferon (IFN-beta) promoter activity, in part, by inducing degradation of interferon response factor 3 (IRF3) and interacting with IRF7. In contrast to humans, cattle contain three IFN-beta genes. All three bovine IFN-beta proteins have anti-viral activity: but each IFN-beta gene has a distinct transcriptional promoter. We have recently cloned and characterized the three bovine IFN-beta promoters. Relative to the human IFN-beta promoter, each of the three IFN-beta promoters contain differences in the four positive regulatory domains that are required for virus induced activity. In this study, we demonstrate that bICP0 effectively inhibits bovine IFN-beta promoter activity following transfection of low passage bovine cells with interferon response factor 3 (IRF3) or IRF7. A bICP0 mutant that localizes to the cytoplasm inhibits bovine IFN-beta promoter activity as efficiently as wt bICP0. The cytoplasmic localized bICP0 protein also induced IRF3 degradation with similar efficiency as wt bICP0. In summary, these studies suggested that cytoplasmic localized bICP0 plays a role in inhibiting the IFN beta response during productive infection. PMID- 21689698 TI - A novel glutathione modified chitosan conjugate for efficient gene delivery. AB - A novel non-viral gene vector based on poly[poly(ethylene glycol) methacrylate] (PMPEG) and l-glutathione (GSH) grafted chitosan (CS) has been fabricated. First, well-defined brush-like PMPEG living polymers with dithioester residues were prepared by the reversible addition-fragmentation chain transfer (RAFT) polymerization and grafted onto the allylchitosan via radical coupling method. Then, the tripeptide GSH was introduced onto the end of PMPEG chain to give a CS PMPEG-GSH conjugate. In comparison with pristine chitosan, CS-PMPEG-GSH conjugate could not only condense plasmid DNA (pDNA) and prevent the condensed CS-PMPEG GSH/pDNA nanoparticle self-aggregation, but also increase the binding ability to cell membrane efficiently and improve decondensed ability of pDNA from the nanoparticles in cytoplasm which thus has resulted in the higher transfection efficiency in mouse embryonic fibroblast cells (NIH3T3). In addition, cytotoxicity assays showed that the conjugate is less cytotoxic than CS, and still retain the cationic polyelectrolyte characteristic as chitosan. These results indicate that the non-viral vector is a promising candidate for gene therapy in clinical application. PMID- 21689699 TI - Ultrasound-mediated intracellular drug delivery using microbubbles and temperature-sensitive liposomes. AB - A novel two-step protocol for intracellular drug delivery has been evaluated in vitro. As a first step TO-PRO-3 (a cell-impermeable dye that displays a strong fluorescence enhancement upon binding to nucleic acids) encapsulated in thermosensitive liposomes was released after heating to 42 degrees C. A second step consisted of ultrasound-mediated local permeabilization of cell membrane allowing TO-PRO-3 internalization observable as nuclear staining. Only the combination of two consecutive steps - heating and sonication in the presence of SonoVue microbubbles led to the model drug TO-PRO-3 release from the thermosensitive liposomes and its intracellular uptake. This protocol is potentially beneficial for the intracellular delivery of cell impermeable drugs that suffer from rapid clearance and/or degradation in blood and are not intrinsically taken up by cells. PMID- 21689700 TI - Dendrimer phthalocyanine-encapsulated polymeric micelle-mediated photochemical internalization extends the efficacy of photodynamic therapy and overcomes drug resistance in vivo. AB - Clinically, the efficacy of chemotherapeutic agents can be dramatically reduced in cancer cells with multiple drug resistance (MDR). In doxorubicin-resistant breast cancer cells, drugs accumulate only within discrete cytosolic organelles that abrogate their therapeutic effects in vitro and in vivo. Photochemical internalization (PCI), a specific branch of photodynamic therapy (PDT), is a novel strategy utilized for the site-specific triggered drug/gene release. The objective of this study was to evaluate the nanoparticle-based PDT/PCI effects on the reversal of drug resistance. Dendrimer phthalocyanine-encapsulated polymeric micelle (DPc/m)-mediated PCI, combined with doxorubicin, was studied in drug resistant MCF-7 cells and a xenograft model. Our results show that the internalized DPc/m showed unique PCI properties inside the cells and thereby facilitating doxorubicin release from the endo-lysosomes to nuclei after photoirradiation. Moreover, 'light before' PCI showed the highest antitumor efficacy and the depth of the proliferating cell nuclear antigen-negative area in tumor sections after DPc/m-mediated PDT was obviously increased by combination therapy with doxorubicin; this indicates the limitation of depth of light penetration in PDT, which may be improved by PCI. We conclude that nanotechnology based PCI possesses several clinical benefits, such as overcoming drug resistance and treating deeper lesions that are intractable by PDT alone. PMID- 21689701 TI - Material properties in complement activation. AB - Uncontrolled complement activation can induce many inflammatory and life threatening conditions. Accordingly, the role of complement in initiation of adverse reactions to polymers and nanoparticulate drug carriers is receiving increasing attention and has prompted extensive 'structure-immune performance' relationship studies in nanomedicine research at many fronts. The interaction between nanomaterials and the complement system is complex and regulated by inter related factors that include nanoscale size, morphology and surface characteristics. Each of these parameters may affect complement activation differently and through different sensing molecules and initiation pathways. The importance of material properties in triggering complement is considered and mechanistic aspects discussed. Mechanistic understanding of complement events could provide rational approaches for improved material design and nanoengineering strategies for clinical medicine. PMID- 21689702 TI - Intestinal lymphatic transport for drug delivery. AB - Intestinal lymphatic transport has been shown to be an absorptive pathway following oral administration of lipids and an increasing number of lipophilic drugs, which once absorbed, diffuse across the intestinal enterocyte and while in transit associate with secretable enterocyte lipoproteins. The chylomicron associated drug is then secreted from the enterocyte into the lymphatic circulation, rather than the portal circulation, thus avoiding the metabolically active liver, but still ultimately returning to the systemic circulation. Because of this parallel and potentially alternative absorptive pathway, first-pass metabolism can be reduced while increasing lymphatic drug exposure, which opens the potential for novel therapeutic modalities and allows the implementation of lipid-based drug delivery systems. This review discusses the physiological features of the lymphatics, enterocyte uptake and metabolism, links between drug transport and lipid digestion/re-acylation, experimental model (in vivo, in vitro, and in silico) of lymphatic transport, and the design of lipid- or prodrug based drug delivery systems for enhancing lymphatic drug transport. PMID- 21689704 TI - Stress, glucocorticoids and glutamate release: effects of antidepressant drugs. AB - Stressful life events impact on memory, cognition and emotional responses, and are known to precipitate mood/anxiety disorders. It is increasingly recognized that stress and its neurochemical and endocrine mediators induce changes in glutamate synapses and circuitry, and this in turn modify mental states. Half a century after the monoamine hypothesis, it is widely accepted that maladaptive changes in excitatory/inhibitory circuitry have a primary role in the pathophysiology of mood/anxiety disorders. The neuroplasticity hypothesis posits that volumetric changes consistently found in limbic and cortical areas of depressed subjects are in good part due to remodeling of neuronal dendritic arbors and loss of synaptic spines. A considerable body of work, carried out with in vivo microdialysis as well as alternative methodologies, has shown that both stress and corticosterone treatment induce enhancement of activity-dependent glutamate release. Accordingly, results from preclinical studies suggest that stress- and glucocorticoid-induced enhancement of glutamate release and transmission plays a main role in the induction of maladaptive cellular effects, in turn responsible for dendritic remodeling. Additional recent work has showed that drugs employed for therapy of mood/anxiety disorders (antidepressants) prevent the enhancement of glutamate release induced by stress. Understanding the action of traditional drugs on glutamate transmission could be of great help in developing drugs that may work directly at this level. PMID- 21689703 TI - Caveolae are essential for angiotensin II type 1 receptor-mediated ANP secretion. AB - Caveolae may act as mechanosensors and function as binding sites for calcium ions. The intracaveolar localization of atrial natriuretic peptide (ANP) derived from the direct interaction of atrial granules with caveolae has been demonstrated. The aim of this study was to define the effect of caveolae on ANP secretion induced by stretch and angiotensin II. The isolated perfused beating atria from Sprague-Dawley rats were used. To disrupt caveolae, 10mM methyl-beta cyclodextrin (MbCD) was applied for 1h and the number of caveoli were markedly decreased. MbCD increased basal ANP secretion and atrial diastolic pressure. The molecular profile of ANP in perfusate from control atria showed mainly one major peak corresponded to synthetic ANP whereas that from MbCD-treated atria showed two major immunoreactive peaks corresponded to synthetic rat ANP and proANP. High atrial stretch induced by elevating the height of outflow catheter from 5 cm H2O to 7.5 cm H2O increased atrial contractility and ANP secretion. The response of ANP secretion to high stretch was attenuated in MbCD-pretreated atria. Pretreatment with MbCD abolished angiotensin II-induced suppression and losartan induced stimulation of ANP secretion. However, the effect of angiotenisin (1-7) on ANP secretion was not altered by MbCD treatment. The expression of angiotensin II type 1 receptor protein was reduced by MbCD treatment. These data suggest that caveolae are essential for angiotensin II type 1 receptor-mediated ANP secretion and relate to the processing of proANP. PMID- 21689705 TI - Hepatitis B virus core particles displaying Mycobacterium tuberculosis antigen ESAT-6 enhance ESAT-6-specific immune responses. AB - Early secreted antigenic target-6 (ESAT-6), an important Mycobacterium tuberculosis T-cell antigen, is an attractive candidate antigen for tuberculosis subunit vaccine development. Because ESAT-6 has a low inherent immunogenicity, we used Hepatitis B virus core (HBc) protein as an immune carrier to enhance ESAT-6 immunogenicity. The ESAT-6 gene was inserted into the major immunodominant region of the HBc molecule by fusion PCR. The recombinant protein, HBc-ESAT-6 (HE6), was expressed in Escherichia coli, and electron microscopy confirmed the formation of virus-like particles. The immunogenicity of the chimeric particles was assessed in mice. Serological assays and in vitro Th1-biased cytokine assays found that immunization with HE6 particles elicited significantly higher ESAT-6-specific antibodies and CD4+/CD8+ T cell responses in mice compared to immunization with recombinant ESAT-6 protein. These data demonstrate the feasibility of HBc particles serving as an efficient immune carrier for ESAT-6 and suggest that HE6 has potential for use in a tuberculosis subunit vaccine. PMID- 21689706 TI - A recombinant Hendra virus G glycoprotein-based subunit vaccine protects ferrets from lethal Hendra virus challenge. AB - The henipaviruses, Hendra virus (HeV) and Nipah virus (NiV), are two deadly zoonotic viruses for which no vaccines or therapeutics have yet been approved for human or livestock use. In 14 outbreaks since 1994 HeV has been responsible for multiple fatalities in horses and humans, with all known human infections resulting from close contact with infected horses. A vaccine that prevents virus shedding in infected horses could interrupt the chain of transmission to humans and therefore prevent HeV disease in both. Here we characterise HeV infection in a ferret model and show that it closely mirrors the disease seen in humans and horses with induction of systemic vasculitis, including involvement of the pulmonary and central nervous systems. This model of HeV infection in the ferret was used to assess the immunogenicity and protective efficacy of a subunit vaccine based on a recombinant soluble version of the HeV attachment glycoprotein G (HeVsG), adjuvanted with CpG. We report that ferrets vaccinated with a 100 MUg, 20 MUg or 4 MUg dose of HeVsG remained free of clinical signs of HeV infection following a challenge with 5000 TCID50 of HeV. In addition, and of considerable importance, no evidence of virus or viral genome was detected in any tissues or body fluids in any ferret in the 100 and 20 MUg groups, while genome was detected in the nasal washes only of one animal in the 4 MUg group. Together, our findings indicate that 100 MUg or 20 MUg doses of HeVsG vaccine can completely prevent a productive HeV infection in the ferret, suggesting that vaccination to prevent the infection and shedding of HeV is possible. PMID- 21689708 TI - Vaccine Technology III: an ECI Conference held in Puerto Vallarta, Mexico from June 6-11, 2010. PMID- 21689707 TI - The 13-valent pneumococcal conjugate vaccine (PCV13) elicits cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae serotypes 6C and 7A. AB - The introduction of a 7-valent pneumococcal conjugate vaccine (PCV7) in 2000 dramatically reduced the incidence of invasive pneumococcal disease (IPD) caused by the seven serotypes covered by the vaccine. Following the introduction of PCV7, which contains a serotype 6B conjugate, some decrease in IPD due to serotype 6A was noted suggesting that the serotype 6B conjugate provided some partial cross-protection against serotype 6A. However, no effect on serotype 6C was observed. In 2010, a pneumococcal conjugate vaccine with expanded serotype coverage (PCV13) was introduced that expanded the serotype coverage to 13 serotypes including serotype 6A. To assess whether the 6A conjugate in PCV13 could potentially induce functional anti-6C antibody responses, an opsonophagocytic assay (OPA) for serotype 6C was developed. Randomly chosen subsets of immune sera collected from infants receiving three doses of PCV7 or PCV13 were tested in OPA assays for serotype 6A, 6B and 6C. PCV7 immune sera demonstrated strong OPA responses, defined as percentage of subjects having an OPA titer >=1:8, to serotype 6B (100% responders), partial responses to serotype 6A (70% responders) but only minimal responses to serotype 6C (22% responders). In contrast, PCV13 immune sera showed strong OPA responses to serotypes 6A (100% responders), 6B (100% responders) and 6C (96% responders). Furthermore, during pre-clinical work it was observed that serotype 7F (included in PCV13) and serotype 7A (not included in PCV13) shared serogroup-specific epitopes. To determine whether such epitopes also may be eliciting cross-functional antibody, PCV13 immune sera were also tested in serotype 7A and 7F OPA assays. All PCV13 immune sera demonstrated OPA responses to both of these serotypes. Taken together these results suggest that immunization with PCV13 has the potential to induce cross-protective responses to related serotypes not directly covered by the vaccine. PMID- 21689709 TI - Reduced immune response to influenza A (H1N1) 2009 monovalent vaccine in HIV infected Japanese subjects. AB - We evaluated the immunogenicity and safety of the influenza A (H1N1) 2009 monovalent vaccine in HIV-infected Japanese subjects. A total of 182 HIV-infected and 42 HIV-uninfected subjects were enrolled, and antibody (ab) titers were measured by hemagglutination-inhibition assay at baseline and 32.3+/-10.4 and 29.7+/-3.3 days after vaccination, respectively. In the HIV-infected cohort, ab titers >= 1:40 at baseline and post-vaccination were 12.6% and 49.5%, respectively. The seroconversion rate, defined as either an ab titer <= 1:10 before and >= 1:40 after or >= 1:10 before and >= 4-fold increase in ab titer, was only 38.5% in the HIV-infected cohort, whereas the rate was 85.7% in the HIV uninfected cohort. Multivariate logistic regression analysis showed that the CD4 cell count was the only significant predictor of a positive vaccine response. There were no serious adverse events in any of the subjects receiving the vaccine. Additional study is warranted to identify a more effective method of vaccinating HIV-infected Japanese subjects. PMID- 21689710 TI - Horizontal transmission dynamics of a glycoprotein G deficient candidate vaccine strain of infectious laryngotracheitis virus and the effect of vaccination on transmission of virulent virus. AB - Infectious laryngotracheitis virus (ILTV) is an alphaherpesvirus that causes acute respiratory disease in chickens worldwide. The virus is horizontally transmitted and causes large outbreaks of disease. Recent studies have shown that a glycoprotein G deficient candidate vaccine strain of ILTV (DeltagG ILTV) is safe and protects birds from disease following challenge with virulent virus. This study examined the transmission dynamics of this candidate vaccine and of ILTV in field and experimental settings. The reproduction ratio (R0, average number of secondary infectious cases from a typical infectious case) was calculated from the growth rate of disease epidemics in broiler flocks. Assuming a latent period of 2 days and an infectious period of 4 days R0 was estimated to be 2.43 (95% CI 2.25-2.69). In experimental settings the transmission characteristics of DeltagG ILTV were similar to those of wildtype virus, and importantly DeltagG ILTV remained safe following one in vivo passage and subsequent infection via contact-exposure. There was minimal transmission of wildtype virus in vaccinated birds. The findings from this study further demonstrate the suitability of DeltagG ILTV for use as a live attenuated vaccine. Knowledge of the basic reproduction ratio of ILTV will be valuable for future studies that aim to improve disease control using vaccination programs. PMID- 21689711 TI - The evolution of skin notations for occupational risk assessment: a new NIOSH strategy. AB - This article presents an overview of a strategy for assignment of hazard-specific skin notations (SK), developed by the National Institute for Occupational Safety and Health (NIOSH). This health hazard characterization strategy relies on multiple SKs capable of delineating systemic (SYS), direct (DIR), and immune mediated (SEN) adverse effects caused by dermal exposures to chemicals. One advantage of the NIOSH strategy is the ability to combine SKs when it is determined that a chemical may cause multiple adverse effects following dermal contact (e.g., SK: SYS-DIR-SEN). Assignment of the SKs is based on a weight-of evidence (WOE) approach, which refers to the critical examination of all available data from diverse lines of evidence and the derivation of a scientific interpretation based on the collective body of data including its relevance, quality, and reported results. Numeric cutoff values, based on indices of toxic potency, serve as guidelines to aid in consistently determining a chemical's relative toxicity and hazard potential. The NIOSH strategy documents the scientific rationale for determination of the hazard potential of a chemical and the subsequent assignment of SKs. A case study of acrylamide is presented as an application of the NIOSH strategy. PMID- 21689712 TI - Myricitrin, a nitric oxide and protein kinase C inhibitor, exerts antipsychotic like effects in animal models. AB - Myricitrin is a nitric oxide (NO) and protein kinase C (PKC) inhibitor that has central nervous system activity, including anxiolytic-like action. Nitric oxide inhibitors blocked the behavioral effects of apomorphine, suggesting an antipsychotic-like effect. Furthermore, PKC inhibition reduced psychotic symptoms in acute mania patients and blocked amphetamine-induced hyperlocomotion, suggesting a potential antipsychotic-like effect. The present study evaluated the effects of myricitrin in animal models that assess antipsychotic-like effects (apomorphine-induced stereotypy and climbing and the paw test) and extrapyramidal side effects (catalepsy test and paw test). Olanzapine was used as a positive control. 7-Nitroindazole (7-NI), a NOS inhibitor, and l-arginine, a NO precursor, were used to evaluate nitrergic modulation, and tamoxifen was used to test the effect of PKC inhibition. In mice, myricitrin dose-dependently and olanzapine blocked the stereotypy and climbing induced by apomorphine at doses that did not induce catalepsy. 7-Nitroindazole also blocked apomorphine-induced stereotypy and climbing, which were reversed by l-arginine pretreatment. l-arginine only attenuated the effects of myricitrin on apomorphine's effects. Tamoxifen also blocked apomorphine-induced stereotypy and climbing. In the paw test in rats, myricitrin and olanzapine increased hindlimb retraction time at doses that did not affect forelimb reaction time, whereas haloperidol affected both parameters at the same dose. Myricitrin did not induce catalepsy in the bar test. Tamoxifen did not affect hindlimb retraction time or forelimb retraction time, whereas 7-NI significantly increased hindlimb reaction time. Thus, myricitrin exhibited an antipsychotic-like profile at doses that did not induce catalepsy, and this effect may be related to nitrergic action. PMID- 21689714 TI - Pycnogenol modulates apoptosis by suppressing oxidative stress and inflammation in high glucose-treated renal tubular cells. AB - Compelling evidence indicates that polyphenolic antioxidants protect against diabetic nephropathy. Pycnogenol is made up of flavonoids, mainly procyanidins and phenolic compounds, and is a known powerful antioxidant. Hyperglycemia is characteristic of diabetic nephropathy and induces renal tubular cell apoptosis. Thus, in this study, we used high glucose-treated renal tubular cells to investigate the protective action of pycnogenol against high glucose-induced apoptosis and diabetic nephropathy. We also sought to further delineate the underlying mechanisms elicited by oxidative stress and inflammation and suppressed by pycnogenol. Results show that pycnogenol significantly suppressed the high glucose-induced morphological changes and the reduction in cell viability associated with cytotoxicity. Bcl2/Bax protein levels indicated pycnogenol's anti-apoptotic effect against high glucose-induced apoptotic cell death. In addition, several key markers of oxidative stress and inflammation were measured for pycnogenol's beneficial effects. Results indicate pycnogenol's anti oxidative and anti-inflammatory efficacy in suppressing lipid peroxidation, total reactive species (RS), superoxide ((.)O(2)), nitric oxide (NO(.)), peroxynitrite (ONOO(-)), pro-inflammatory inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and nuclear factor-kappa B (NF-kappaB) nuclear translocation. Based on these results, we conclude that pycnogenol's anti oxidative and anti-inflammatory properties underlie its anti-apoptotic effects, suggesting further investigation of pycnogenol as a promising treatment against diabetic nephropathy. PMID- 21689715 TI - 13-Desmethyl spirolide-c and 13,19-didesmethyl spirolide-c trans-epithelial permeabilities: human intestinal permeability modelling. AB - Human intestinal permeability prediction is an increasingly important field that helps to explain how efficient the absorption of drugs is. Spirolides, cyclic imines produced by dinoflagellates from the genera Alexandrium, can be accumulated in mollusks usually consumed by humans. These compounds exert neurological symptoms when injected intra-peritoneally in mice, although they seem to be less toxic by oral administration. In this study, we evaluate two of the most abundant analogues, 13-desmethyl spirolide C and 13,19-didesmethyl spirolide C and their ability to cross the human intestinal epithelium by the use of Caco-2 trans-epithelial permeability assays as a model. Toxin quantifications were carried out by using the liquid chromatography-tandem mass spectrometry analytical technique. We found that both compounds cross the Caco-2 epithelial barrier without altering the trans-epithelial electric resistance of the monolayer. The apparent permeability (P(app)) coefficient calculated was 18.65+/ 1.2*10(-6)cm/s for 13-desmethyl spirolide C while a little lesser, 12.32+/ 3.18*10(-6)cm/s, for 13,19-didesmethyl spirolide C. P(app) coefficients allow us to predict a human intestinal permeability >=80% and >=50%, respectively for each compound. Those results demonstrate that spirolides would be highly absorbed in the human intestine, thus being able to enter the circulatory system and to reach different organs where they could be accumulated or exert an unpredictable effect. Thus, it is necessary to carry out new studies about their pharmacokinetics and evaluate their potential acute and/or chronic effect on the human body. PMID- 21689713 TI - Effects of haloperidol on cognition in schizophrenia patients depend on baseline performance: a saccadic eye movement study. AB - Schizophrenic patients are heterogeneous with respect to voluntary eye movement performance, with some showing impairment (e.g., high antisaccade error rates) and others having intact performance. To investigate how this heterogeneity may correlate with different cognitive outcomes after treatment, we used a prosaccade and antisaccade task to investigate the effects of haloperidol in schizophrenic subjects at three time points: baseline (before medication), 3-5 days post medication, and 12-14 days post-medication. We also investigated changes on the Stroop Task and the Positive and Negative Syndrome Scale (PANSS) in these same subjects. Results were compared to matched controls. When considered as a single patient group, haloperidol had no effects across sessions on reflexive and voluntary saccadic eye movements of schizophrenic patients. In contrast, the performance of the Control group improved slightly but significantly across sessions on the voluntary eye movement task. When each subject was considered separately, interestingly, for schizophrenic patients change in voluntary eye movement performance across sessions depended on the baseline performance in a non-monotonic manner. That is, there was maximal worsening of voluntary eye movement performance at an intermediate level of baseline performance and the worsening decreased on either side of this intermediate baseline level. When patients were divided into categorical subgroups (nonimpaired and impaired), consistent with the non-monotonic relationship, haloperidol worsened voluntary eye movement performance in the nonimpaired patients and improved performance in the impaired patients. These results were only partially reflected in the Stroop Test. Both patient subgroups showed clinically significant improvement over time as measured by the PANSS. These findings suggest that haloperidol has different effects on cognitive performance in impaired and nonimpaired schizophrenic patients that are not evident in clinical ratings based on the PANSS. Given that good cognitive function is important for long-term prognosis and that there is heterogeneity in schizophrenia, these findings are critical for optimal evaluation and treatment of schizophrenic patients. PMID- 21689716 TI - Identification of enzyme inhibitory mechanisms from steady-state kinetics. AB - Enzyme inhibitors are used in many areas of the life sciences, ranging from basic research to the combat of disease in the clinic. Inhibitors are traditionally characterized by how they affect the steady-state kinetics of enzymes, commonly analyzed on the assumption that enzyme-bound and free substrate molecules are in equilibrium. This assumption, implying that an enzyme-bound substrate molecule has near zero probability to form a product rather than dissociate, is valid only for very inefficient enzymes. When it is relaxed, more complex but also more information-rich steady-state kinetics emerges. Although solutions to the general steady-state kinetics problem exist, they are opaque and have been of limited help to experimentalists. Here we reformulate the steady-state kinetics of enzyme inhibition in terms of new parameters. These allow for assessment of ambiguities of interpretation due to kinetic scheme degeneracy and provide an intuitively simple way to analyze experimental data. We illustrate the method by concrete examples of how to assess scheme degeneracy and obtain experimental estimates of all available rate and equilibrium constants. We suggest simple, complementary experiments that can remove ambiguities and greatly enhance the accuracy of parameter estimation. PMID- 21689717 TI - Analysis of interaction partners for eukaryotic translation elongation factor 1A M-domain by functional proteomics. AB - The eukaryotic translation elongation factor 1A (eEF1A), besides to its canonical role in protein synthesis, is also involved in several other cellular processes, depending on changes in cellular location, cell type, concentration of ligands, substrates or cofactors. Therefore eEF1A is a moonlighting protein that participates to a network of molecular interactions involving its structural domains. Since the identification of novel protein-protein interactions represents important tasks in post-genomic era, the interactome of eEF1A1 M domain was investigated by using a proteomic approach. To this purpose, the eEF1A1 M-domain was fused with glutathione-S-transferase (GST) and Strep-tag (ST) at it's N- and C-terminal, respectively. The recombinant protein (GST-M-ST) was purified and incubated with a mouse embryo lysate by applying an affinity chromatography strategy. The interacting proteins were separated by SDS-PAGE and identified by peptide mass fingerprinting using MALDI-TOF mass spectrometry. Besides the known partners, the pool of interacting proteins contained sorbin, a polypeptide of 153 amino acids present in SH3 domain-containing adaptor proteins, such as SORBS2. This interaction was also assessed by Western blot on immunoprecipitate from mouse embryo or H1355 cell lysates with anti-eEF1A or anti SORBS2 antibodies and on eEF1A1-His pull-down from H1355 cell lysate with antibody anti-SORBS2. Furthermore, the interaction between eEF1A and SORBS2 was also confirmed by confocal microscopy and FRET analysis. Interestingly, a co localization of SORBS2 and eEF1A was evidenced at level of plasma membrane, thus suggesting the involvement of eEF1A1 in novel key signal transduction complexes. PMID- 21689718 TI - cDNA cloning of an alginate lyase from a marine gastropod Aplysia kurodai and assessment of catalytically important residues of this enzyme. AB - Herbivorous marine gastropods such as abalone and sea hare ingest brown algae as a major diet and degrade the dietary alginate with alginate lyase (EC 4.2.2.3) in their digestive fluid. To date alginate lyases from Haliotidae species such as abalone have been well characterized and the primary structure analyses have classified abalone enzymes into polysaccharide-lyase-family 14 (PL-14). However, other gastropod enzymes have not been so well investigated and only partial amino acid sequences are currently available. To improve the knowledge for primary structure and catalytic residues of gastropod alginate lyases, we cloned the cDNA encoding an alginate lyase, AkAly30, from an Aplysiidae species Aplysia kurodai and assessed its catalytically important residues by site-directed mutagenesis. Alginate lyase cDNA fragments were amplified by PCR followed by 5'- and 3'-RACE from A. kurodai hepatopancreas cDNA. The finally cloned cDNA comprised 1313 bp which encoded an amino-acid sequence of 295 residues of AkAly30. The deduced sequence comprised an initiation methionine, a putative signal peptide for secretion (18 residues), a propeptide-like region (9 residues), and a mature AkAly30 domain (267 residues) which showed ~40% amino-acid identity with abalone alginate lyases. An Escherichia coli BL21(DE3)-pCold I expression system for recombinant AkAly30 (recAkAly30) was constructed and site-directed mutagenesis was performed to assess catalytically important amino-acid residues which had been suggested in abalone and Chlorella virus PL-14 enzymes. Replacements of K99, S126, R128, Y140 and Y142 of recAkAly30 by Ala and/or Phe greatly decreased its activity as in the case of abalone and/or Chlorella virus enzymes. Whereas, H213 that was essential for Chlorella virus enzyme to exhibit the activity at pH 10.0 was originally replaced by N120 in AkAly30. The reverse replacement of N120 by His in recAkAly30 increased the activity at pH 10.0 from 8 U/mg to 93 U/mg; however, the activity level at pH 7.0, i.e., 774.8 U/mg, was still much higher than that at pH 10.0. This indicates that N120 is not directly related to the pH dependence of AkAly30 unlike H213 of vAL-1. PMID- 21689720 TI - Primer on genes encoding enzymes in sialic acid metabolism in mammals. AB - Sialic acid, a nine-carbon sugar acid usually is present in the non-reducing terminal position of free oligosaccharides and glycoconjugates. Sialylated conjugates in mammals perform important roles in cellular recognition, signaling, host-pathogen interaction and neuronal development. Metabolism of sialylated conjugates involves a complex pathway consisting of enzymes distributed among the different compartments in the cell. These enzymes are encoded by 32 genes diversely distributed throughout the mammalian genome. Genetic variants in some of these genes are associated with embryonic lethality and abnormal phenotypes in mice and neuromuscular diseases, carcinomas and immune-mediated diseases in humans. In humans, the CMP-NeuAc-hydroxylase (CMAH) enzyme is inactivated due to a deletion mutation in the encoded enzyme. This lack of Neu5Gc phenotype makes humans unique among mammals. This review focuses on genes encoding enzymes in sialic acid metabolism pathways in mammalian cells with special emphasis on the human, mouse and cow. PMID- 21689719 TI - Substrate specificity of kallikrein-related peptidase 13 activated by salts or glycosaminoglycans and a search for natural substrate candidates. AB - KLK13 is a kallikrein-related peptidase preferentially expressed in tonsils, esophagus, testis, salivary glands and cervix. We report the activation of KLK13 by kosmotropic salts and glycosaminoglycans and its substrate specificity by employing a series of five substrates derived from the fluorescence resonance energy transfer (FRET) peptide Abz-KLRSSKQ-EDDnp. KLK13 hydrolyzed all these peptides only at basic residues with highest efficiency for R; furthermore, the S(3) to S(2)' subsites accepted most of the natural amino acids with preference also for basic residues. Using a support-bound FRET peptide library eight peptide substrates were identified containing sequences of proteins found in testis and one with myelin basic protein sequence, each of which was well hydrolyzed by KLK13. Histatins are salivary peptides present in higher primates with broad antifungal and mucosal healing activities that are generated from the hydrolysis from large precursor peptides. KLK13 efficiently hydrolyzed synthetic histatin 3 exclusively at R(25) (DSHAKRHHGYKRKFHEKHHSHRGYR(25)?SNYLYDN) that is the first cleavage observed inside the salivary gland. In conclusion, the observed hydrolytic activities of KLK13 and its co-localization with its activators, glycosaminoglycans in the salivary gland and high concentration of sodium citrate in male reproductive tissues, indicates that KLK13 may play a role in the defense of the upper digestive apparatus and in male reproductive organs. PMID- 21689721 TI - Commercial reverse transcriptase as source of false-positive strand-specific RNA detection in human cells. AB - Recently, an increasing number of studies describe the existence of non-coding RNAs (ncRNAs) involved in gene expression modulation. Since the observation that antisense ncRNAs are implicated in human disorders, there is more and more interest in ncRNAs. A commonly used technique to investigate the expression of an antisense ncRNAs is strand-specific reverse transcription coupled with polymerase chain reaction (RT-PCR). The advantage of this accurate technique is that it does not require any special equipment or expertise. The disadvantage is that it can lead easily to false-positive results. We applied strand-specific RT-PCR to investigate the presence of antisense ncRNA associated to Retinoic Acid Receptor Beta 2 (RARbeta2) in different human tumoral cell lines. By performing this technique, we observed false-positive detection of ncRNA. For accurate interpretation of the results in RT-PCR experiments, we introduced a "No primer" control that reveals non-specific cDNA synthesis. Moreover, we report the presence of non-specific cDNA amplification with five of the most frequently used reverse transcriptase in absence of added primers. We found that the choice of the reverse transcriptase as well as the conditions of the reaction (RT temperature and PCR cycle number) are important parameters to choose as the different reverse transcriptases do not display the same cDNA synthesis background. This previously observed phenomenon was reported to originate from the "self-priming" of RNA template. Here, we report rather the presence of RNA contaminants associated with one of the reverse transcriptase studied that might contribute to non-specific cDNA synthesis. PMID- 21689722 TI - Pathophysiological condition changes the conformation of a flexible FBG-related protein, switching it from pathogen-recognition to host-interaction. AB - Although homeostatic disturbance of the blood pH and calcium in the vicinity of tissue injury/malignancy/local infection seems subtle, it can cause substantial pathophysiological consequences, a phenomenon which has remained largely unexplored. The fibrinogen-related proteins (FREPs) containing fibrinogen-like domain (FBG) represent a conserved protein family with a common calcium-binding region, implying the presence of elements responsive to physiological perturbation. Here, we studied the molecular interaction between a representative FREP, the M-ficolin, and an acute phase blood protein, the C-reactive protein (CRP), both of which are known to trigger and control seminal pathways in infection and injury. Using hydrogen-deuterium exchange mass spectrometry, we showed that the C-terminal region of M-ficolin FBG underwent dramatic conformational change upon pH and calcium perturbations. Biochemical and biophysical assays showed that under defined pathophysiological condition (pH 6.5, 2.0 mM calcium), the FBG:CRP interaction occurred more strongly compared to that under physiological condition (pH 7.4, 2.5 mM calcium). We identified the binding interface between CRP and FBG, locating it to the pH- and calcium sensitive C-terminal region of FBG. By site-directed mutagenesis, we determined H284 in the N-acetylglucosamine (GlcNAc)-binding pocket of the FBG, to be the critical CRP-binding residue. This conformational switch involving H284, explains how the pathophysiologically-driven FBG:CRP interaction diverts the M-ficolin away from GlcNAc/pathogen-recognition to host protein-protein interaction, thus enabling the host to regain homeostatic control. Our elucidation of the binding interface at the flexible FBG domain provides insights into the bioactive centre of the M-ficolin, and possibly other FREPs, which might aid future development of immunomodulators. PMID- 21689723 TI - Improvement of porphyrins for G-quadruplex DNA targeting. AB - G-quadruplex nucleic acids are emerging as therapeutic targets for small molecules referred to as small-molecule G-quadruplex ligands. The porphyrin H(2) TMPyP4 was early reported to be a suitable motif for G-quadruplex DNA recognition. It probably binds to G-quadruplex nucleic acid through pi-pi stacking with the external G-quartets. We explored chemical modifications of this porphyrin such as insertion of various metal ions in the centre of the aromatic core and addition of bulky substituents that may improve the specificity of the compound toward G-quadruplex DNA. Porphyrin metallation, affording a G4-ligand with two symmetric faces, allowed the conclusion that the presence of an axial water molecule perpendicular to the aromatic plane lowered but did not hamper pi pi stacking interactions between the aromatic parts of the ligand on the one hand and the external G-quartet on the other. The charge introduced in the centre of the porphyrin had little influence on binding. Thus, the ionic channel in the centre of G-quadruplex nucleic acids was not found to provide clear additional molecular clues for G-quadruplex nucleic acids targeting by porphyrins tested in the present study. Furthermore, we confirmed the unique G-quadruplex selectivity of a porphyrin modified with four bulky substituents at the meso positions and showed that although the compound is not "drug-like" it was capable of entering cells in culture and mediated some of the typical cellular effects of small molecule G-quadruplex ligands. PMID- 21689724 TI - Allogeneic stem cell transplantation as treatment for heavily treated, refractory acute graft-versus-host disease after HLA-mismatched stem cell transplantation. AB - OBJECTIVE: No effective treatment has been established for patients with steroid refractory acute graft-versus-host disease (GVHD). Recently, we demonstrated in a murine tandem bone marrow transplantation model that life-threatening GVHD established by the first bone marrow transplantation was successfully treated by engraftment of a second donor graft after reduced-intensity conditioning. We named the effect by which allografts counteract GVHD "graft-versus-GVHD." MATERIALS AND METHODS: To investigate the efficacy of graft-versus-GVHD treatment clinically, 16 patients who developed, after human leukocyte antigen-mismatched stem cell transplantation, severe GVHD, refractory to three to five lines of GVHD specific treatments, underwent 17 allogeneic stem cell transplantations using reduced-intensity conditioning regimens with grafts from a second donor. RESULTS: Among the 15 transplantations that could be evaluated, rescue donor grafts were engrafted in 11 cases and rejected in 4 cases. For patients who achieved rescue donor engraftment, the response rate was 90.9% (eight complete response, two partial response, and one stable disease). Six of the eight patients with complete response survived without GVHD symptoms, with a median follow-up of 2128 days. No new development of GVHD by the second graft was observed. No patients had recurrence of the original malignant disease. In contrast, no long-term survivors were observed in patients who rejected rescue donor grafts. CONCLUSIONS: We propose here a novel graft-versus-GVHD treatment to treat refractory GVHD, and these results strongly suggest that GVHD can be successfully treated by eliminating the harmful lymphocytes responsible for GVHD by a second allogeneic stem cell transplantation. PMID- 21689725 TI - Novel, activating KIT-N822I mutation in familial cutaneous mastocytosis. AB - OBJECTIVE: We report the rare family in which cutaneous mastocytosis was diagnosed in the father and two children, with urticaria pigmentosa as the only manifestation of the disease. The diagnosis of mastocytosis in the father included bone marrow histopathological and cytological examinations and flow cytometry, and histopathological examination of the skin. In the children, tryptase measurement and skin histopathological examination were performed. MATERIALS AND METHODS: Blood, urine, and buccal swab specimens were collected from the family members. HEK293T cells were transiently transfected with plasmids expressing KIT-WT and KIT-N882I. In addition, Ba/F3 cell lines expressing KIT N822I, KIT-D816V, and KIT-V559D mutants were treated with imatinib and dasatinib. The effect of treatment on proliferation, survival, and signaling was determined. RESULTS: Germ-line KIT-N822I missense mutation was detected in the affected members of the family. Western blot analysis using HEK293T and Ba/F3 cells expressing KIT-N822I isoform showed that KIT-N822I constitutively activated KIT tyrosine phosphorylation. In vitro assays on KIT-N822I-expressing Ba/F3 cells confirmed that the N822I mutant is resistant to imatinib mesylate. In contrast, a high efficacy of dasatinib toward the KIT-N822I-expressing Ba/F3 cells was observed. CONCLUSIONS: We provided evidence that KIT p.N822I mutation has transforming potential and can cause a constitutive activation of KIT. In addition, we demonstrated that KIT-N822I is resistant to imatinib and sensitive to dasatinib. Finally, our findings support the hypothesis that not only KIT mutations but other additional genetic abnormalities are contributing to more advanced forms of the disease. PMID- 21689726 TI - Retinoblastoma-binding proteins 4 and 9 are important for human pluripotent stem cell maintenance. AB - OBJECTIVE: The molecular mechanisms that maintain human pluripotent stem (PS) cells are not completely understood. Here we sought to identify new candidate PS cell regulators to facilitate future improvements in their generation, expansion, and differentiation. MATERIALS AND METHODS: We used bioinformatic analyses of multiple serial-analysis-of-gene-expression libraries (generated from human PS cells and their differentiated derivatives), together with small interfering RNA (siRNA) screening to identify candidate pluripotency regulators. Validation of candidate regulators involved promoter analyses, Affymetrix profiling, real-time PCR, and immunoprecipitation. RESULTS: Promoter analysis of genes differentially expressed across multiple serial-analysis-of-gene-expression libraries identified E2F motifs in the promoters of many PS cell-specific genes (e.g., POU5F1, NANOG, SOX2, FOXD3). siRNA analyses identified two retinoblastoma binding proteins (RBBP4, RBBP9) as required for maintenance of multiple human PS cell types. Both RBBPs were bound to RB in human PS cells, and E2F motifs were present in the promoters of genes whose expression was altered by decreasing RBBP4 and RBBP9 expression. Affymetrix and real-time PCR studies of siRNA-treated human PS cells showed that reduced RBBP4 or RBBP9 expression concomitantly decreased expression of POU5F1, NANOG, SOX2, and/or FOXD3 plus certain cell cycle genes (e.g., CCNA2, CCNB1), while increasing expression of genes involved in organogenesis (particularly neurogenesis). CONCLUSIONS: These results reveal new candidate positive regulators of human PS cells, providing evidence of their ability to regulate expression of pluripotency, cell cycle, and differentiation genes in human PS cells. These data provide valuable new leads for further elucidating mechanisms of human pluripotency. PMID- 21689727 TI - Androgen receptor gene polymorphisms and alterations in prostate cancer: of humanized mice and men. AB - Germline polymorphisms and somatic mutations of the androgen receptor (AR) have been intensely investigated in prostate cancer but even with genomic approaches their impact remains controversial. To assess the functional significance of AR genetic variation, we converted the mouse gene to the human sequence by germline recombination and engineered alleles to query the role of a polymorphic glutamine (Q) tract implicated in cancer risk. In a prostate cancer model, AR Q tract length influences progression and castration response. Mutation profiling in mice provides direct evidence that somatic AR variants are selected by therapy, a finding validated in human metastases from distinct treatment groups. Mutant ARs exploit multiple mechanisms to resist hormone ablation, including alterations in ligand specificity, target gene selectivity, chaperone interaction and nuclear localization. Regardless of their frequency, these variants permute normal function to reveal novel means to target wild type AR and its key interacting partners. PMID- 21689728 TI - Amphioxus IGF-like peptide induces mouse muscle cell development via binding to IGF receptors and activating MAPK and PI3K/Akt signaling pathways. AB - Insulin-like growth factors (IGFs) are identified in all vertebrates. An insulin/IGF hybrid polypeptide has also been identified in protochordate amphioxus. However, whether this hybrid polypeptide functions as vertebrate IGFs remains unknown. Here we established a primary culture system of mouse muscle satellite cells as an in vitro model to investigate the effects of amphioxus IGF like molecule on muscle cell development. Like human IGF, recombinant IGF-like molecule was able to stimulate the proliferation of mouse muscle cells. Besides, it was able to bind to the cells and the partially purified IGF receptors from mouse muscle cells. Moreover, recombinant IGF-like molecule was capable of activating MAPK and PI3K/Akt pathways by stimulating phosphorylation of MAPK and Akt. This interaction of amphioxus IGF-like molecule with mammalian (mouse) IGF receptors and its induction of similar downstream signaling pathways add substantially to the hypothesis of the presence of IGF signaling in the common ancestor of protochordate/vertebrates. PMID- 21689729 TI - Bacterial growth rate reflects a bottleneck in resource allocation. AB - BACKGROUND: Growth rate management in fast-growing bacteria is currently an active research area. In spite of the huge progress made in our understanding of the molecular mechanisms controlling the growth rate, fundamental questions concerning its intrinsic limitations are still relevant today. In parallel, systems biology claims that mathematical models could shed light on these questions. METHODS: This review explores some possible reasons for the limitation of the growth rate in fast-growing bacteria, using a systems biology approach based on constraint-based modeling methods. RESULTS: Recent experimental results and a new constraint-based modelling method named Resource Balance Analysis (RBA) reveal the existence of constraints on resource allocation between biological processes in bacterial cells. In this context, the distribution of a finite amount of resources between the metabolic network and the ribosomes limits the growth rate, which implies the existence of a bottleneck between these two processes. Any mechanism for saving resources increases the growth rate. GENERAL SIGNIFICANCE: Consequently, the emergence of genetic regulation of metabolic pathways, e.g. catabolite repression, could then arise as a means to minimise the protein cost, i.e. maximising growth performance while minimising the resource allocation. This article is part of a Special Issue entitled Systems Biology of Microorganisms. PMID- 21689730 TI - Dcdc2 knockout mice display exacerbated developmental disruptions following knockdown of doublecortin. AB - The dyslexia-associated gene DCDC2 is a member of the DCX family of genes known to play roles in neurogenesis, neuronal migration, and differentiation. Here we report the first phenotypic analysis of a Dcdc2 knockout mouse. Comparisons between Dcdc2 knockout mice and wild-type (wt) littermates revealed no significant differences in neuronal migration, neocortical lamination, neuronal cilliogenesis or dendritic differentiation. Considering previous studies showing genetic interactions and potential functional redundancy among members of the DCX family, we tested whether decreasing Dcx expression by RNAi would differentially impair neurodevelopment in Dcdc2 knockouts and wild-type mice. Consistent with this hypothesis, we found that deficits in neuronal migration, and dendritic growth caused by RNAi of Dcx were more severe in Dcdc2 knockouts than in wild type mice with the same transfection. These results indicate that Dcdc2 is not required for neurogenesis, neuronal migration or differentiation in mice, but may have partial functional redundancy with Dcx. PMID- 21689731 TI - Histamine H1, H3 and H4 receptors are involved in pruritus. AB - Histamine has long been recognised as a classical inducer of pruritus. However, the specific mechanism of histamine-induced itch has still not been fully understood. The H1 and H4 receptor appear to be key components in the induction of itch. The specific role of the H3 receptor in histamine-induced itch remains unclear. The aim of our study was to investigate the role of the four known histamine receptors (H1-4) in acute itch in mice. Intradermal injection of the selective H3R inverse agonist pitolisant induced strong itch in mice. Pitolisant (50 nmol/injection)-induced pruritus could be completely blocked by a combined treatment with the H1R antagonist cetirizine (15 mg/kg) and the H4R antagonist JNJ 7777120 (15 mg/kg), whereas the H2R antagonist ranitidine (15 mg/kg) failed to inhibit the scratch response. Next, expression and function of histamine receptors on sensory neurons isolated from dorsal root ganglia of mice were investigated. As the itch sensation results from the excitation of sensory nerves in the skin, we further focused on skin specific sensory neurons. Therefore, neurons were retrograde labelled from the skin by means of a fluorescent tracer. Expression of H1R, H3R and H4R on skin innervating sensory neurons was detected. By single-cell calcium imaging, it was demonstrated that histamine induces a calcium increase in a subset of (skin-specific) sensory neurons via activation of the H1R and H4R as well as inhibition of the H3R. It is assumed that the decreased threshold in response to H3R antagonism activates H1R and H4R on sensory neurons, which in turn results in the excitation of histamine-sensitive afferents and therefore elicits the sensation of itch. PMID- 21689733 TI - Synaptogyrin-dependent modulation of synaptic neurotransmission in Caenorhabditis elegans. AB - The tetraspan membrane proteins of the synaptogyrin and synaptophysin type are abundant and evolutionary conserved synaptic vesicle membrane proteins whose functions are poorly defined. Their depletion does not interfere with proper neuronal development and basic neuronal function. In the search for their function we use the genetic model organism Caenorhabditis elegans in which, in contrast to vertebrates, the synaptogyrin but not the synaptophysin orthologue is predominant in neurons. Employing fluorescent reporter constructs we find that synaptogyrin is expressed in all GABAergic neurons and most, though not all other neurons. Subjecting animals either lacking or overexpressing synaptogyrin to the epileptogenic GABA antagonist pentylenetetrazole reveals increased sensitivity in comparison to the wild-type. Detailed analyses further uncover mildly altered motility, slightly reduced sensitivity to the acetylcholine esterase inhibitor aldicarb and decreased recruitment of synaptobrevin but not of RAB-3 to synapses. Furthermore, synthetic phenotypes are observed with mutants of the synaptic vesicle recycling machinery, notably with synaptotagmin, synaptojanin and endophilin rather than with mutants involved in clathrin-dependent endocytosis. Taken together, these observations assign a distinct modulatory and redundant neuronal function to synaptogyrin. PMID- 21689732 TI - MicroRNA machinery responds to peripheral nerve lesion in an injury-regulated pattern. AB - Recently, functional and potent RNA interference (RNAi) has been reported in peripheral nerve axons transfected with short-interfering RNA (siRNA). In addition, components of RNA-induced silencing complex (RISC) have been identified in axotomized sciatic nerve fibers as well as in regenerating dorsal root ganglia (DRG) neurons in vitro. Based on these observations, and on the fact that siRNA and microRNA (miRNA) share the same effector enzymes, we hypothesized that the endogenous miRNA biosynthetic pathway would respond to peripheral nerve injury. To answer this question, we investigated changes in the expression of miRNA biosynthetic enzymes following peripheral nerve crush injury in mice. Here, we show that several pivotal miRNA biosynthetic enzymes are expressed in an injury regulated pattern in sciatic nerve in vivo, and in DRG axons in vitro. Moreover, the sciatic nerve lesion induced expression of mRNA-processing bodies (P-bodies), which are the local foci of mRNA degradation in DRG axons. In addition, a group of injury-regulated miRNAs was identified by miRNA microarray and validated by real-time quantitative PCR (qPCR) and in situ hybridization analyses. Taken together, our data support the hypothesis that the peripheral nerve regeneration processes may be regulated by miRNA pathway. PMID- 21689734 TI - Delayed neuroprotection by riluzole against excitotoxic damage evoked by kainate on rat organotypic spinal cord cultures. AB - Kainate-mediated excitotoxicity of organotypic spinal cord cultures is an in vitro model advantageous to investigate basic mechanisms of acute spinal injury and its pharmacological neuroprotection. Using such cultures, the putative neuroprotective agent riluzole applied at 5 MUM (plasma therapeutic concentration) was studied for its ability to prevent neurotoxicity evoked by 1 h administration of kainate. We monitored real-time release of glutamate, release of lactate dehydrogenase (LDH) (cell damage marker), occurrence of cell pyknosis, the number of surviving neurons and motoneurons, and cell culture metabolic activity. Co-applied riluzole strongly blocked the kainate-evoked early rise in extracellular glutamate (via calcium dependent or independent processes) and suppressed LDH release (limited to <20% of total). Although there were no significant cell losses within the first h after kainate washout, pyknosis, fewer neurons and motoneurons were observed 24 h later. MTT assay demonstrated that surviving cells were metabolically competent. Co-application of kainate and tetrodotoxin also failed to protect spinal cord slices 24 h later. When riluzole application begun at kainate washout and continued for 24 h, significant neuroprotection was observed for neurons in the central and dorsal regions, while ventral horn cells (including motoneurons) were not protected. Our data suggest that riluzole neuroprotection against excitotoxicity was feasible, although it paradoxically required delayed drug administration, and was not extended to the ventral horn. We propose that riluzole was acting on yet-unidentified processes downstream of glutamate release and receptor activation. Deciphering their identity and role in cell death mechanisms may be an important goal to develop neuroprotection. PMID- 21689735 TI - Plasticity of non-adrenergic non-cholinergic bladder contractions in rats after chronic spinal cord injury. AB - The purpose of this study was to examine the pharmacologic plasticity of cholinergic, non-adrenergic non-cholinergic (NANC), and purinergic contractions in neurogenic bladder strips from spinal cord injured (SCI) rats. Bladder strips were harvested from female rats three to four weeks after T(9)-T(10) spinal cord transection. The strips were electrically stimulated using two experimental protocols to compare the contribution of muscarinic and NANC/purinergic contractions in the presence and the absence of carbachol or muscarine. The endpoints of the study were: (1) percent NANC contraction that was unmasked by the muscarinic antagonist 4-DAMP, and (2) P2X purinergic contraction that was evoked by alpha,beta-methylene ATP. NANC contraction accounted for 78.5% of the neurally evoked contraction in SCI bladders. When SCI bladder strips were treated with carbachol (10 MUM) prior to 4-DAMP (500 nM), the percent NANC contraction decreased dramatically to only 13.1% of the neurally evoked contraction (P=0.041). This was accompanied by a substantial decrease in alpha,beta-methylene ATP evoked P2X contraction, and desensitization of purinergic receptors (the ratio of subsequent over initial P2X contraction decreased from 97.2% to 42.1%, P=0.0017). Sequential activation of the cholinergic receptors with carbachol (or with muscarine in neurally intact bladders) and unmasking of the NANC response with 4-DAMP switched the neurally evoked bladder contraction from predominantly NANC to predominantly cholinergic. We conclude that activation of muscarinic receptors (with carbachol or muscarine) blocks NANC and purinergic contractions in neurally intact or in SCI rat bladders. The carbachol-induced inhibition of the NANC contraction is expressed more in SCI bladders compared to neurally intact bladders. Along with receptor plasticity, this change in bladder function may involve P2X-independent mechanisms. PMID- 21689736 TI - Molecular evolution of bacterial indoleamine 2,3-dioxygenase. AB - Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are tryptophan-degrading enzymes that catalyze the first step in L-Trp catabolism via the kynurenine pathway. In mammals, TDO is mainly expressed in the liver and primarily supplies nicotinamide adenine dinucleotide (NAD(+)). TDO is widely distributed from mammals to bacteria. Active IDO enzymes have been reported only in vertebrates and fungi. In mammals, IDO activity plays a significant role in the immune system while in fungal species, IDO is constitutively expressed and supplies NAD(+), like mammalian TDO. A search of genomic databases reveals that some bacterial species also have a putative IDO gene. A phylogenetic analysis clustered bacterial IDOs into two groups, group I or group II bacterial IDOs. The catalytic efficiencies of group I bacterial IDOs were very low and they are suspected not to contribute significantly to L-Trp metabolism. The bacterial species bearing the group I bacterial IDO are scattered across a few phyla and no phylogenetically close relationship is observed between them. This suggests that the group I bacterial IDOs might be acquired by horizontal gene transmission that occurred in each lineage independently. In contrast, group II bacterial IDOs showed rather high catalytic efficiency. Particularly, the enzymatic characteristics (K(m), V(max) and inhibitor selectivity) of the Gemmatimonas aurantiaca IDO are comparable to those of mammalian IDO1, although comparison of the IDO sequences does not suggest a close evolutionary relationship. In several bacteria, TDO and the kynureninase gene (kynU) are clustered on their chromosome suggesting that these genes could be transcribed in an operon. Interestingly, G. aurantiaca has no TDO, and the IDO is clustered with kynU on its chromosome. Although the G. aurantiaca also has NadA and NadB to synthesize a quinolinic acid (a precursor of NAD(+)) via the aspartate pathway, the high activity of the G. aurantiaca IDO flanking the kynU gene suggests its IDO has a function similar to eukaryotic enzymes. PMID- 21689737 TI - Synthesis and characterization of a novel ester-based nucleoamino acid for the assembly of aromatic nucleopeptides for biomedical applications. AB - In this work, we report a technological approach to a novel Fmoc-protected nucleoamino acid, based on l-tyrosine, carrying the DNA nucleobase on the hydroxyl group by means of an ester bond, suitable for the solid-phase synthesis of novel aromatic nucleopeptides of potential interest in biomedicine. After ESI MS and NMR characterization this building block was used for the assembly of a thymine-functionalized tetrapeptide, composed of nucleobase-containing and underivatized l-tyrosine moieties alternated in the backbone. PMID- 21689738 TI - Two-phase systems: potential for in situ extraction of microalgal products. AB - Algae are currently used for production of niche products and are becoming increasingly interesting for the production of bulk commodities, such as biodiesel. For the production of these goods to become economically feasible, production costs will have to be lowered by one order of magnitude. The application of two-phase systems could be used to lower production costs. These systems circumvent the costly step of cell harvesting, whilst the product is extracted and prepared for downstream processing. The mechanism of extraction is a fundamental aspect of the practical question whether two-phase systems can be applied for in situ extraction, viz, simultaneous growth, product formation and extraction, or as a separate downstream processing step. Three possible mechanisms are discussed; 1) product excretion 2) cell permeabilization, and 3) cell death. It was shown that in the case of product excretion, the application of two-phase systems for in situ extraction can be very valuable. With permeabilization and cell death, in situ extraction is not ideal, but the application of two-phase systems as downstream extraction steps can be part of a well-designed biorefinery process. In this way, processing costs can be decreased while the product is mildly and selectively extracted. Thus far none of the algal strains used in two-phase systems have been shown to excrete their product; the output has always been the result of cell death. Two-phase systems can be a good approach as a downstream processing step for these species. For future applications of two-phase in situ extraction in algal production processes, either new species that show product excretion should be discovered, or existing species should be modified to induce product excretion. PMID- 21689739 TI - Modified phages: novel antimicrobial agents to combat infectious diseases. AB - Researchers increasingly believe that microbial, molecular and synthetic biology techniques along with genetic engineering will facilitate the treatment of persistent infectious diseases. However, such therapy has been plagued by the emergence of antibiotic-resistant bacteria, resulting in significant obstacles to treatment. Phage therapy is one promising alternative to antibiotics, especially now that recent modifications to ubiquitous phages have made them more controllable. Additionally, convincing in vitro and in vivo studies of genetically modified lytic phages and engineered non-lytic phages have confirmed the advantages of novel, specific bactericidal agents over antibiotics in some cases. There is still a need for a better understanding of phage therapy, however, before it can be adopted widely. PMID- 21689740 TI - Searching for a needle in the haystack: comparing six methods to evaluate heteroplasmy in difficult sequence context. AB - Mitochondrial DNA (mtDNA) mutations have been involved in disease, aging and cancer and furthermore exploited for evolutionary and forensic investigation. When investigating mtDNA mutations the peculiar aspects of mitochondrial genetics, such as heteroplasmy and threshold effect, require suitable approaches which must be sensitive enough to detect low-level heteroplasmy and, precise enough to quantify the exact mutational load. In order to establish the optimal approach for the evaluation of heteroplasmy, six methods were experimentally compared for their capacity to reveal and quantify mtDNA variants. Drawbacks and advantages of cloning, Fluorescent PCR (F-PCR), denaturing High Performance Liquid Chromatography (dHPLC), quantitative Real-Time PCR (qRTPCR), High Resolution Melting (HRM) and 454 pyrosequencing were determined. In particular, detection and quantification of a mutation in a difficult sequence context were investigated, through analysis of an insertion in a homopolymeric stretch (m.3571insC). PMID- 21689741 TI - Characteristics of yeast lectins and their role in cell-cell interactions. AB - Lectins are ubiquitous proteins with the ability to induce cell agglutination and, mediate cellular and molecular recognition processes in a variety of biological interactions. Fungi display exquisite specificity for target tissues and attach to host glycoconjugates via these sugar-binding proteins. Although only few reports are available on lectin activity of yeasts, these sugar binding proteins have been embraced for their role in cell flocculation, a commercially beneficial property, that simplifies downstream recovery operations in yeast fermentations. The lectins bind to cell wall mannans of the neighboring cells via hydrogen bonds leading to the formation of cell aggregates which get interrupted in the presence of specific sugars. Attachment of pathogenic yeasts to host cell surface is also a consequence of lectin-mediated recognition process. This review provides a brief overview of yeast lectins, with an insight to lectin-mediated cellular recognition phenomenon in yeasts. PMID- 21689742 TI - Effects of the polycyclic ketone tonalide (AHTN) on some cell viability parameters and transcription of P450 and immunoregulatory genes in rainbow trout RTG-2 cells. AB - To assess the potential effects of environmental pollutants belonging to the musk fragrances group in the physiology of aquatic animal species, in this work we treated rainbow trout RTG-2 cells with the polycyclic ketone tonalide (AHTN) at dilutions ranging from 3.5 to 500 ng/ml. The following parameters were monitored: intracellular ATP concentration (energy production), mitochondrial membrane potential (early apoptosis marker), cell viability (vital staining with DFP), quantitative expression of genes coding for the cytochrome P450 detoxifying enzymes CYP1A1 and CYP3A27, and of genes coding for the immunoregulatory peptides IL-1beta, IL-8, TNFalpha, Cox-2 and TGF-beta. Obtained results showed that incubation with tonalide induced in RTG-2 cells no effects on cell viability, a slight increase of mitochondrial membrane potential activity, and a significant increase in intracellular ATP concentration. However, dramatic effects were observed in transcription levels of some tested genes, with upregulation levels of 300 and 600 times measured for TGF-beta and TNFalpha, respectively and of 150 times for the CYP3A27 gene. Our results show for the first time the potent effects exerted by tonalide on immunoregulatory genes of RTG-2 cells and also indicate that the measured sensitivity of RTG-2 towards tonalide was in the same range of that currently available using chemical methods. A possible use of the panel of genes we employed as a tool for the monitoring of musk fragrances in biological samples is discussed. PMID- 21689743 TI - CNTF protects MIN6 cells against apoptosis induced by Alloxan and IL-1beta through downregulation of the AMPK pathway. AB - Our group previously demonstrated that CNTF protects pancreatic islets against apoptosis induced by IL1beta. In addition, it is known that AMPK knockout protects beta cells from IL1beta-mediated apoptosis, however how AMPK activation leads to apoptosis remains unknown. The present study was designed to investigate the possible role of AMPK pathway modulation in CNTF protective effects against apoptosis induced by IL1beta or Alloxan and how AMPK activation leads to beta cells apoptosis. First, we observed that apoptosis of MIN6 cells, induced by Alloxan as well as IL-1beta, requires activation of the AMPK pathway, and also that CNTF protective effects are dependent on downregulation of AMPK. In addition, we found that Alloxan induces AMPK differently from IL1beta, as Alloxan acts mainly through CaMKII while IL1beta acts through LKB1 phosphorylation. Meanwhile, CNTF by itself inhibited the AMPK pathway and protected against AMPK activation induced by Alloxan or IL1beta via downregulation of CaMKII. Finally, AMPK-dependent MIN6 cell apoptosis, induced by IL1beta or Alloxan, required increased iNOS expression, an effect that was reversed by CNTF downregulation of AMPK pathway and iNOS expression. In conclusion, IL1beta upregulates the LKB1 AMPK-INOS pathway, while Alloxan acts through CaMKII-AMPK-INOS, both ultimately leading to beta cell death. In this context, CNTF protects beta cells against apoptosis, induced by either IL1beta or Alloxan, through downregulation of the CaMKII-AMPK-INOS pathway. PMID- 21689744 TI - CaMK IV phosphorylates prohibitin 2 and regulates prohibitin 2-mediated repression of MEF2 transcription. AB - Prohibitin 2 (PHB2) is an evolutionarily conserved and ubiquitously expressed multifunctional protein which is present in various cellular compartments including the nucleus. However, mechanisms underlying various functions of PHB2 are not fully explored yet. Previously we showed that PHB2 interacts with Akt and inhibits muscle differentiation by repressing the transcriptional activity of both MyoD and MEF2. Here we show that Calcium/Calmodulin-dependent kinase IV (CaMK IV) specifically binds to the C terminus of PHB2 and phosphorylates PHB2 at serine 91. Ectopic expression of CaMK IV and PHB2 in C2C12 cells results effectively in decreased PHB2-mediated repression of MEF2-dependent gene expression. Conversely, PHB2 mutant (S91A) resistant to CaMK IV phosphorylation has less effective in relieving the inhibition of MEF2 transcription by PHB2. Our findings suggest that CaMK IV interacts with and regulates PHB2 through phosphorylation, which could be one of the mechanisms underlying the CaMK mediated activation of MEF2. PMID- 21689745 TI - Prednisolone-induced beta cell dysfunction is associated with impaired endoplasmic reticulum homeostasis in INS-1E cells. AB - Glucocorticoids (GCs), such as prednisolone (PRED), are widely prescribed anti inflammatory drugs, but their use may induce glucose intolerance and diabetes. GC induced beta cell dysfunction contributes to these diabetogenic effects through mechanisms that remain to be elucidated. In this study, we hypothesized that activation of the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress could be one of the underlying mechanisms involved in GC-induced beta cell dysfunction. We report here that PRED did not affect basal insulin release but time-dependently inhibited glucose-stimulated insulin secretion in INS-1E cells. PRED treatment also decreased both PDX1 and insulin expression, leading to a marked reduction in cellular insulin content. These PRED-induced detrimental effects were found to be prevented by prior treatment with the glucocorticoid receptor (GR) antagonist RU486 and associated with activation of two of the three branches of the UPR. Indeed, PRED induced a GR-mediated activation of both ATF6 and IRE1/XBP1 pathways but was found to reduce the phosphorylation of PERK and its downstream substrate eIF2alpha. These modulations of ER stress pathways were accompanied by upregulation of calpain 10 and increased cleaved caspase 3, indicating that long term exposure to PRED ultimately promotes apoptosis. Taken together, our data suggest that the inhibition of insulin biosynthesis by PRED in the insulin-secreting INS-1E cells results, at least in part, from a GR-mediated impairment in ER homeostasis which may lead to apoptotic cell death. PMID- 21689747 TI - The ESR2 AluI gene polymorphism is associated with bone mineral density in postmenopausal women. AB - Multiple factors may contribute to the pathogenesis of postmenopausal osteoporosis including environmental, life-style and genetic factors. Common variants in ESR2 gene encoding for ER-beta, highly expressed in bone tissue, have recently been proposed as candidates for affecting bone phenotype at the population level, particularly in postmenopausal women. In this study, we examined the genetic background at ESR2 AluI (rs4986938, 1730G>A) locus in 89 osteopenic, postmenopausal women (age range 49-56 years) together with BMD at lumbar spine and femoral neck sites as well as variations in plasma levels of bone metabolism and turnover markers. Genotyping for ESR2 G1730A polymorphism showed that the frequency of A mutated allele accounted for 0.4 in our cohort of postmenopausal women; moreover, the GA1730 heterozygous individuals were the most represented (50.6%) compared with GG (37.8%) and AA homozygous ones (14.6%). A regression analysis showed that lumbar spine BMD values were significantly associated with both ESR2 AA1730 genotype (p=0.044) and time since the onset of menopause (p=0.031), while no significant association was detected between biochemical markers and genetic background. Interestingly, 85% of patients with AA1730 genotype presented the smallest lumbar spine BMD values. These findings first indicate a worsening effect of ESR2 AluI polymorphism on lumbar spine BMD reduction in postmenopause, suggesting that the detection of this ESR2 variant should be recommended in postmenopausal women, particularly in populations with a high prevalence of ESR2 AA1730 homozygous genotype. PMID- 21689748 TI - Endocrine disruptors in bottled mineral water: estrogenic activity in the E Screen. PMID- 21689746 TI - TRIP6: an adaptor protein that regulates cell motility, antiapoptotic signaling and transcriptional activity. AB - Thyroid hormone receptor interacting protein 6 (TRIP6), also known as zyxin related protein-1 (ZRP-1), is an adaptor protein that belongs to the zyxin family of LIM proteins. TRIP6 is primarily localized in the cytosol or focal adhesion plaques, and may associate with the actin cytoskeleton. Additionally, it is capable of shuttling to the nucleus to serve as a transcriptional coregulator. Structural and functional analyses have revealed that through multidomain mediated protein-protein interactions, TRIP6 serves as a platform for the recruitment of a wide variety of signaling molecules involved in diverse cellular responses, such as actin cytoskeletal reorganization, cell adhesion and migration, antiapoptotic signaling, osteoclast sealing zone formation and transcriptional control. Although the physiological functions of TRIP6 remain largely unknown, it has been implicated in cancer progression and telomere protection. Together, these studies suggest that TRIP6 plays multifunctional roles in different cellular responses, and thus may represent a novel target for therapeutic intervention. PMID- 21689749 TI - LKB1 expression is inhibited by estradiol-17beta in MCF-7 cells. AB - The liver kinase B1 (LKB1) is encoded by the STK11 gene and acts as a tumour suppressor and a regulator of energy homeostasis. LKB1 expression is reduced in primary breast tumours compared to normal breast epithelium. Although its expression in primary tumours does not appear to correlate with estrogen receptor (ER) status, it is differentially expressed in breast cancer cell lines where ER negative cells have lower LKB1 expression than ER-positive cells. The present study aimed to examine the effects of estradiol on LKB1 expression and activity in the ER-positive breast cancer cell line MCF-7. Results demonstrate that estradiol causes a dose-dependent decrease in LKB1 transcript and protein expression and consistent with this, a significant decrease in the phosphorylation of the LKB1 target AMPK (P <= 0.05). In order to assess whether effects of estradiol were due to effects on ERalpha binding to the STK11 promoter, ChIP was performed. Results demonstrate that ERalpha binds to the STK11 promoter in a ligand-independent manner and that this interaction is decreased in the presence of estradiol. Moreover, STK11 promoter activity is significantly decreased in the presence of estradiol (P <= 0.05). LKB1 transcript and IHC score were assessed in primary tumours of 18 patients and demonstrated no significant correlation with ER status (n = 18). Our results thereby provide a mechanism whereby LKB1 is decreased in ER-positive breast tumours. PMID- 21689750 TI - Contribution of Ldace1 gene to acetylcholinesterase activity in Colorado potato beetle. AB - The Colorado potato beetle (CPB), Leptinotarsa decemlineata is an important economic pest of potato worldwide. Resistance to organophosphates and carbamates in CPB has been associated in some cases to point mutations in the acetylcholinesterase (AChE) gene Ldace2, an orthologue of Drosophila melanogaster Dmace2. In this paper we report cloning and sequencing of Ldace1, an orthologue of Anopheles gambiae Agace1 that was previously unknown in CPB. The Ldace1 coding enzyme contains all residues conserved in a functionally active AChE. Ldace1 is expressed at higher levels (between 2- and 11-fold) than Ldace2 in embryos, in the four larval instars and in adults. Specific interference of Ldace1 by means of dsRNA injection resulted in a reduction of AChE activity to an approximate 50% compared to control, whilst interference of Ldace2 reduced AChE activity to an approximate 85%. Analysis of zymograms of AChE activity after interference indicates that LdAChE1 is the enzyme predominantly responsible for the activity visualised. Interference of Ldace1 in CPB adults caused a significant increase in mortality (43%) as early as three days post-injection (p.i.), suggesting the essential role of Ldace1. Interference of Ldace2 also caused a significant increase in mortality (29%) compared to control, although at seven days p.i. The effect of the interference of Ldace1 on susceptibility to the organophosphate chlorpyrifos points out that LdAChE1 could be a main target for this insecticide. In the light of our results, studies associating resistance in CPB to mutations in Ldace2 should be reviewed, taking into consideration analysis of the Ldace1 gene. PMID- 21689751 TI - Effective inhibition of substantia nigra by deep brain stimulation fails to suppress tonic epileptic seizures. AB - Experimental and clinical data suggest that high-frequency deep brain stimulation (DBS) of different subcortical structures can be used to control or modulate epileptic seizures. Recent studies showed that DBS of the substantia nigra reticulata (SNr) in rats has an anticonvulsant effect on forebrain clonic seizures. The aim of this study was to determine whether DBS of SNr could also suppress tonic epileptic seizures evoked in hindbrain structures. DBS with high frequency often mimics the effects of surgical ablation of a particular area of the brain. However, the optimal parameters of DBS stimulation to induce ablation like effects on seizures are not well defined. Consequently, in the first experiment we examined the effects of different stimulation frequencies (80, 130, 260 and 390 Hz) on neuronal activation induced in SNr, using c-fos immunocytochemistry. The results showed that the stimulation of the SNr with 80 Hz has no inhibitory effect while stimulation with 130, 260 and 390 Hz produced a remarkable suppressive effect compared with the control unstimulated side. The aim of the second experiment was to determine whether bilateral inhibition of SNr with DBS could suppress tonic seizures induced by electric shock. Statistical analysis showed that the mean tonic seizure scores following SNr stimulation with either 130 or 260 Hz were not significantly different from scores following the application of the electrode without current. The data suggest that DBS of the SNr produces neuronal inhibition but fails to suppress tonic seizures. We conclude, therefore, that DBS of SNr with frequencies used in this study might not be effective for treatment of patients who suffer from tonic epileptic seizures. PMID- 21689752 TI - Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia. AB - Previous studies have shown that erythropoietin (EPO) is neuroprotective in both in vivo and in vitro models of hypoxia ischemia. However these studies hold limited clinical translations because the underlying mechanism remains unclear and the key molecules involved in EPO-induced neuroprotection are still to be determined. This study investigated if tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and its upstream regulator signaling molecule Janus kinase-2 (JAK-2) are critical in EPO-induced neuroprotection. Hypoxia ischemia (HI) was modeled in-vitro by oxygen and glucose deprivation (OGD) and in-vivo by a modified version of Rice-Vannucci model of HI in 10-day-old rat pups. EPO treated cells were exposed to AG490, an inhibitor of JAK-2 or TIMP-1 neutralizing antibody for 2h with OGD. Cell death, phosphorylation of JAK-2 and signal transducers and activators of transcription protein-3 (STAT-3), TIMP-1 expression, and matrix metalloproteinase-9 (MMP-9) activity were measured and compared with normoxic group. Hypoxic ischemic animals were treated one hour following HI and evaluated 48 h after. Our data showed that EPO significantly increased cell survival, associated with increased TIMP-1 activity, phosphorylation of JAK-2 and STAT-3, and decreased MMP-9 activity in vivo and in vitro. EPO's protective effects were reversed by inhibition of JAK-2 or TIMP-1 in both models. We concluded that JAK-2, STAT-3 and TIMP-1 are key mediators of EPO induced neuroprotection during hypoxia ischemia injury. PMID- 21689753 TI - Gene expression profiling of the brain: pondering facts and fiction. AB - During the last decade brain transcriptome profiling by DNA microarrays has matured, developed sound experimental design standards, reporting practices, analytical procedures, and data sharing resources. It has become a powerful scientific tool in the exploratory research portfolio. Along this journey by trial and error, we encountered a number of intriguing questions and comments- pondering the value of hypothesis-driven research, appropriate sample size, the importance and interpretation of transcripts changes vis-a-vis protein changes, the role of statistical stringency, false discovery and magnitude of expression change, and many other interesting questions. Our field fully acknowledges and tries to address all of these challenges associated with high-throughput, data driven transcriptomics. As a research field, we strongly advocate implementing the highest standards of our trade, and we deeply believe that transcriptome profiling studies will continue to be essential for deciphering the pathophysiological mechanisms leading to complex brain disorders. PMID- 21689754 TI - Enalapril treatment discloses an early role of angiotensin II in inflammation- and oxidative stress-related muscle damage in dystrophic mdx mice. AB - Inhibitors of angiotensin converting enzymes (ACE) are clinically used to control cardiomyopathy in patients of Duchenne muscular dystrophy. Various evidences suggest potential usefulness of long-term treatment with ACE inhibitors to reduce advanced fibrosis of dystrophic muscle in the mdx mouse model. However, angiotensin II is known to exert pro-inflammatory and pro-oxidative actions that might contribute to early events of dystrophic muscle degeneration. The present study has been aimed at evaluating the effects of an early treatment with enalapril on the pathology signs of exercised mdx mouse model. The effects of 1 and 5 mg/kg enalapril i.p. for 4-8 weeks have been compared with those of 1 mg/kg alpha-methyl-prednisolone (PDN), as positive control. Enalapril caused a dose dependent increase in fore limb strength, the highest dose leading to a recovery score similar to that observed with PDN. A dose-dependent reduction of superoxide anion production was observed by dihydroethidium staining in tibialis anterior muscle of enalapril-treated mice, approaching the effect observed with PND. In parallel, a significant reduction of the activated form of the pro-inflammatory Nuclear Factor-kB has been observed in gastrocnemious muscle. Histologically, 5 mg/kg enalapril reduced the area of muscle necrosis in both gastrocnemious muscle and diaphragm, without significant effect on non-muscle area. In parallel no significant changes have been observed in both muscle TGF-beta1 and myonuclei positive to phosphorylated Smad2/3. Myofiber functional indices were also monitored by microelectrodes recordings. A dose-dependent recovery of macroscopic chloride conductance has been observed upon enalapril treatment in EDL muscle, with minor effects being exerted in diaphragm. However a modest effect, if any, was found on mechanical threshold, a functional index of calcium homeostasis. No recovery was observed in creatine kinase and lactate dehydrogenase. Finally the results suggest the ability of enalapril to blunt angiotensin-II dependent activation of pro-inflammatory and pro-oxidant pathways which may be earlier events with respect to the pro-fibrotic ones, and may in part account for both functional impairment and muscle necrosis. The PDN-like profile may corroborate the combined use of the two classes of drugs in DMD patients so to potentiate the beneficial effects at skeletal muscle level, while reducing both spontaneous and PDN-aggravated cardiomyopathy. PMID- 21689755 TI - Matrix metalloproteinase inhibitor properties of tetracyclines: therapeutic potential in cardiovascular diseases. AB - Matrix metalloproteinases (MMPs) are a family of proteases best known for their capacity to proteolyse several proteins of the extracellular matrix. Their increased activity contributes to the pathogenesis of several cardiovascular diseases. MMP-2 in particular is now considered to be also an important intracellular protease which has the ability to proteolyse specific intracellular proteins in cardiac muscle cells and thus reduce contractile function. Accordingly, inhibition of MMPs is a growing therapeutic aim in the treatment or prevention of various cardiovascular diseases. Tetracyclines, especially doxycycline, have been frequently used as important MMP inhibitors since they inhibit MMP activity independently of their antimicrobial properties. In this review we will focus on the intracellular actions of MMPs in some cardiovascular diseases including ischemia and reperfusion (I/R) injury, inflammatory heart diseases and septic shock; and explain how tetracyclines, as MMP inhibitors, have therapeutic actions to treat such diseases. We will also briefly discuss how MMPs can be intracellularly regulated and activated by oxidative stress, thus cleaving several important proteins inside cells. In addition to their potential therapeutic effects, MMP inhibitors may also be useful tools to understand the biological consequences of MMP activity and its respective extra- and intracellular effects. PMID- 21689756 TI - A systematic assessment of mature MBP in membrane protein production: overexpression, membrane targeting and purification. AB - Obtaining enough membrane protein in native or native-like status is still a challenge in membrane protein structure biology. Maltose binding protein (MBP) has been widely used as a fusion partner in improving membrane protein production. In the present work, a systematic assessment on the application of mature MBP (mMBP) for membrane protein overexpression and purification was performed on 42 membrane proteins, most of which showed no or poor expression level in membrane fraction fused with an N-terminal Histag. It was found that most of the small membrane proteins were overexpressed in the native membrane of Escherichia coli when using mMBP. In addition, the proteolysis of the fusions were performed on the membrane without solubilization with detergents, leading to the development of an efficient protocol to directly purify the target membrane proteins from the membrane fraction through a one-step affinity chromatography. Our results indicated that mMBP is an excellent fusion partner for overexpression, membrane targeting and purification of small membrane proteins. The present expression and purification method may be a good solution for the large scale preparation of small membrane proteins in structural and functional studies. PMID- 21689757 TI - Molecular characterization and expression analysis of an inhibitor of NF-kappaB (IkappaB) from Asiatic hard clam Meretrix meretrix. AB - Inhibitor of NF-kappaB (IkappaB) is an important member of Rel/NF-kappaB signaling pathway, which is an important mediator of immune responses in innate immune system. In this study, the IkappaB cDNA of hard clam Meretrix meretrix (designated as Mm-IkappaB) was cloned and characterized. The full-length cDNA of Mm-IkappaB was of 2098 bp, containing a 5' untranslated region (UTR) of 123 bp, a 3' UTR of 810 bp with a poly (A) tail, and an open reading frame (ORF) of 1164 bp encoding a polypeptide of 387 amino acids. The high similarity of Mm-IkappaB with other IkappaBs from invertebrates indicated that Mm-IkappaB should be a member of IkappaB family. Similar to most IkappaBs, Mm-IkappaB possessed all conserved features critical for the fundamental structure and function of IkappaBs, such as five ankyrin repeats and a conserved degradation motif (DS(44)RYSS(48)). Two PEST domains and a phosphorylation site motif (S(367)EEE(370)) at the C-terminus of Mm IkappaB were identified. By quantitative real-time RT-PCR analysis, mRNA level of Mm-IkappaB was found to be most abundantly expressed in the tissues of mantle, gill and hepatopancreas, weakly expressed in muscle, foot and haemocyte. The Mm IkappaB gene expression was significantly up-regulated at 24 h in haemocyte and at 12 h in gill after Vibrio anguillarum challenge, respectively. The results suggested the involvement of Mm-IkappaB in response against bacterial infection and further highlighted its functional importance in the immune system of M. meretrix. PMID- 21689758 TI - Toll-like receptors and interferon associated immune factors in viral haemorrhagic septicaemia virus-infected olive flounder (Paralichthys olivaceus). AB - Pattern recognition receptor (PRR) toll-like receptors (TLRs), antiviral agent interferon (IFN) and the effector IFN stimulated genes (ISGs) play pivotal role in antiviral innate immunity of a host. The present in-vivo experiment was conducted to investigate the role of these innate immune factors in early phase as well as during recovery of viral haemorrhagic septicaemia virus (VHSV) infection by quantitative real-time reverse transcriptase polymerase chain reaction. A less lethal VHSV infection was generated in olive flounder (Paralichthys olivaceus) and was sampled at 3, 6, and 12h post infection (hpi), and 1, 2, 4, and 7 days post infection (dpi). At 3 hpi, the VHSV N gene was detected in three out of five fish and all five fish showed a relative fold increase of TLR 2, TLR 7, interleukin 8 (IL 8), IFN regulatory factor 3 (IRF 3), IRF 7, and ISG 15. Viral copies rapidly increased at 12 hpi then remained high until 2 dpi. When viral copy numbers were high, a higher expression of immune genes IL 1beta, IRF 3, IRF 7, Type I IFN, ISG 15 and Mx was observed. Viral copies were drastically reduced in 4 and 7 dpi fish, and also the immune response was considerably reduced but remained elevated, except for ISG 15 which found equal to control in 7 dpi fish. A high degree of correlation was observed between immune genes and viral copy number in each of the sampled fish at 12 hpi. A fish with ascites sampled at 7 dpi displayed high viral copy but under-expressed immune genes except for Mx. When viral copies were high at 1 and 2 dpi, both TLR 2 and TLR 7 were down-regulated, perhaps indicating immune suppression by the virus. The quick and prolonged elevated expression of the immune genes indicates their crucial role in survival of host against VHSV. PMID- 21689759 TI - A catalase from the freshwater mussel Cristaria plicata with cloning, identification and protein characterization. AB - Catalase is an important antioxidant protein which can protect organisms against various oxidative stresses by eliminating hydrogen peroxide. The catalase cDNA of Cristaria plicata (cpCAT) was cloned from the haemocytes using degenerate primers by the method of 3' and 5' rapid amplification of cDNA ends PCR. The gene is 4863 bp long and has a total of two introns and three exons. The precise size and location of the introns and exons have been determined. In addition the full length cDNA of cpCAT contained 2618 bp, The cDNA contained a 5' untranslated region (UTR) of 136 nucleotides, the 3' UTR of 979 bp with a canonical polyadenylation signal sequence AATAAA and a polyA tail, and an open reading frame (ORF) of 1503 bp, encoding 501 amino acid residues with 56.86 kDa predicted molecular weight. The theoretical isoelectric point was 6.77. BLAST analysis showed that the deduced amino acid sequence of cpCAT had significant homology to catalases from animals, plants and bacteria. The deduced amino acid sequence of cpCAT had characteristic features of catalase family such as catalytic site motif (61FNRERIPERVVHAKGAG77), heme-ligand signature motif (351RLYSYSDTH359), two glycosylation sites (N145, N436), NADPH binding site and the three catalytic amino acid residues (His72, Asn145 and Tyr355). It had no signal peptide. The phylogenetic tree indicated that cpCAT gene was very close to the gene of scallops, Chlamys farreri. The enzymatic activity of purified recombinant cpCAT was 11194.4 +/- 40.4 U/mg, it might resist against H(2)O(2). The recombinant enzyme held higher thermal stability, the optimum temperature was 25 degrees C, it retained more than 82% activity between 25 and 60 degrees C. The stability of the recombinant enzyme were higher between pH 5 and 10, and the optimal pH value was 7.0. When cpCAT was treated with 2-4 moL/L urea and 1%-3% SDS, the activity was also stable, it kept more than 80% activity. PMID- 21689760 TI - Molecular characterization of MHC class I and beta-2 microglobulin in a clonal strain of ginbuna crucian carp, Carassius auratus langsdorfii. AB - Clonal ginbuna crucian carp is, a naturally gynogenetic fish, and is a useful model animal for studying T-cell-mediated immunity. To gain molecular information on MHC class I molecules from this species, we have identified four types of MHC class I (caauUA-S3n, caauUF-S3n, caauZE-S3n, and caauZB-S3n) and five beta 2 microglobulin (beta(2)m) (caaubeta2m-1a, caaubeta2m-1b, caaubeta2m-2, caaubeta2m 3a and caaubeta2m-3b) by an expressed sequence tag (EST) analysis and using homology cloning with degenerated primers. Like UA class I genes in other cyprinid fish, the caauUA-S3n shows features of classical MHC class I, such as conservation of all key amino acids interacting with antigenic peptides, and ubiquitous tissue expression. A phylogenetic analysis shows that the beta(2)m-1 and beta(2)m-2 isoforms are clustered with those of other cyprinid fishes, while beta(2)m-3 isoforms make a cluster that is separated from a common ancestor of salmonid and cyprinid fishes. This finding suggests that the beta(2)m isoforms of ginbuna cruician carp comprise two lineages and may possess different functions. The MHC class I and beta(2)m sequences from one clonal strain will facilitate our understanding of the interaction of MHC class I with beta(2)m in teleosts. PMID- 21689761 TI - Arterial spin labeling for motor activation mapping at 3T with a 32-channel coil: reproducibility and spatial accuracy in comparison with BOLD fMRI. AB - Functional arterial spin labeling (fASL) is an innovative biomarker of neuronal activation that allows direct and absolute quantification of activation-related CBF and is less sensitive to venous contamination than BOLD fMRI. This study evaluated fASL for motor activation mapping in comparison with BOLD fMRI in terms of involved anatomical area localization, intra-individual reproducibility of location, quantification of neuronal activation, and spatial accuracy. Imaging was performed at 3T with a 32-channel coil and dedicated post-processing tools were used. Twelve healthy right-handed subjects underwent fASL and BOLD fMRI while performing a right hand motor activation task. Three sessions were performed 7days apart in similar physiological conditions. Our results showed an activation in the left primary hand motor area for all 36 sessions in both fASL and BOLD fMRI. The individual functional maps for fASL demonstrated activation in ipsilateral secondary motor areas more often than the BOLD fMRI maps. This finding was corroborated by the group maps. In terms of activation location, fASL reproducibility was comparable to BOLD fMRI, with a distance between activated volumes of 2.1mm and an overlap ratio for activated volumes of 0.76, over the 3 sessions. In terms of activation quantification, fASL reproducibility was higher, although not significantly, with a CVintra of 11.6% and an ICC value of 0.75. Functional ASL detected smaller activation volumes than BOLD fMRI but the areas had a high degree of co-localization. In terms of spatial accuracy in detecting activation in the hand motor area, fASL had a higher specificity (43.5%) and a higher positive predictive value (69.8%) than BOLD fMRI while maintaining high sensitivity (90.7%). The high intra-individual reproducibility and spatial accuracy of fASL revealed in the present study will subsequently be applied to pathological subjects. PMID- 21689762 TI - Emotion-dependent responses in spinal cord neurons: a spinal fMRI study. AB - Previous research has demonstrated that emotional stimuli receive preferential processing in the brain. In the current study, functional magnetic resonance imaging was utilized to determine if emotion-specific responses are detectable in the cervical spinal cord. During the passive (i.e., non-motoric) perception of images, activity was detected in the left dorsal and right ventral spinal cord in response to negative emotional stimuli; however, this pattern was reversed in response to neutral and positive stimuli. Critically, during active motoric responses to images, there was greater activity in the ventral cervical spinal cord in response to negative emotional stimuli than to neutral stimuli. These results demonstrate preferential motor responses to negative emotional images by the spinal cord, likely indicating an enhancement of activity in response to threat. PMID- 21689763 TI - Dynamic correction of artifacts due to susceptibility effects and time-varying eddy currents in diffusion tensor imaging. AB - In diffusion tensor imaging (DTI), spatial and temporal variations of the static magnetic field (B(0)) caused by susceptibility effects and time-varying eddy currents result in severe distortions, blurring, and misregistration artifacts, which in turn lead to errors in DTI metrics and in fiber tractography. Various correction methods have been proposed, but typically assume that the eddy current induced magnetic field can be modeled as a constant or a single exponential decay within the DTI readout window. Here, we show that its temporal dependence is more complex because of the interaction of multiple eddy currents with different time constants, but that it remains very consistent over time. As such, we propose a novel dynamic B(0) mapping and off-resonance correction method that measures the exact spatial, temporal, and diffusion-weighting direction dependence of the susceptibility- and eddy current-induced magnetic fields to effectively and efficiently correct for artifacts caused by both susceptibility effects and time varying eddy currents, thereby resulting in a high spatial fidelity and accuracy. PMID- 21689764 TI - Magnetic resonance microimaging of the spinal cord in the SOD1 mouse model of amyotrophic lateral sclerosis detects motor nerve root degeneration. AB - Amyotrophic lateral sclerosis (ALS) is characterized by selective degeneration of motor neurons. Current imaging studies have concentrated on areas of the brain and spinal cord that contain mixed populations of sensory and motor neurons. In this study, ex vivo magnetic resonance microimaging (MRM) was used to separate motor and sensory components by visualizing individual dorsal and ventral roots in fixed spinal cords. MRM at 15MUm in plane resolution enabled the axons of pure populations of sensory and motor neurons to be measured in the lumbar region of the SOD1 mouse model of ALS. MRM signal intensity increased by 38.3% (p<0.05) exclusively in the ventral motor nerve roots of the lumbar spinal cord of ALS affected SOD1 mice compared to wildtype littermates. The hyperintensity was therefore limited to white matter tracts arising from the motor neurons, whereas sensory white matter fibers were unchanged. Significant decreases in ventral nerve root volume were also detected in the SOD1 mice, which correlated with the axonal degeneration observed by microscopy. These results demonstrate the usefulness of MRM in visualizing the ultrastructure of the mouse spinal cord. The detailed 3D anatomy allowed the processes of pure populations of sensory and motor neurons to be compared. PMID- 21689766 TI - Algebraic T2 estimation improves detection of right temporal lobe epilepsy by MR T2 relaxometry. AB - Seizure related abnormalities may be detected with T2 relaxometry, which involves quantitative estimation of T2 values. Accounting for the partial-volume effect of cerebrospinal fluid (CSF) is important, especially for voxel-based relaxometry, VBR. With a mono-exponential decay model, this can be accomplished by including a baseline constant. An algebraic calculation, which accommodates this constant, offers improved T2 estimation speed over the commonly used non-linear fitting approach. Our objective was to compare the algebraic approach against three fitting approaches for the detection of seizure related abnormalities. We tested the performance of the four methods in the presence of noise using simulated data as well as real data acquired at 3 T with a Carr-Purcell-Meiboom-Gill sequence from 45 healthy subjects and 24 patients with confirmed right temporal lobe epilepsy. A quantitative analysis was performed on spatially normalized data by measuring T2 in various regions and with a whole brain tissue segmentation analysis. The detection rate of hippocampal T2 changes in patients was assessed by comparing the regional T2 measurements from each patient against the control data with a z-score threshold of 2.33. The algebraic method yielded high sensitivity for detection of hippocampal abnormalities in the epileptic patients in regional assessment and in follow-up single-subject VBR. This can be attributed to the relatively small variance across healthy subjects and improved precision in the presence of CSF and noise in simulation. In conclusion, the algebraic method is better than fitting based on faster calculation speed and better sensitivity for detecting seizure-related T2 changes. PMID- 21689767 TI - Impact of personality on the cerebral processing of emotional prosody. AB - While several studies have focused on identifying common brain mechanisms governing the decoding of emotional speech melody, interindividual variations in the cerebral processing of prosodic information, in comparison, have received only little attention to date: Albeit, for instance, differences in personality among individuals have been shown to modulate emotional brain responses, personality influences on the neural basis of prosody decoding have not been investigated systematically yet. Thus, the present study aimed at delineating relationships between interindividual differences in personality and hemodynamic responses evoked by emotional speech melody. To determine personality-dependent modulations of brain reactivity, fMRI activation patterns during the processing of emotional speech cues were acquired from 24 healthy volunteers and subsequently correlated with individual trait measures of extraversion and neuroticism obtained for each participant. Whereas correlation analysis did not indicate any link between brain activation and extraversion, strong positive correlations between measures of neuroticism and hemodynamic responses of the right amygdala, the left postcentral gyrus as well as medial frontal structures including the right anterior cingulate cortex emerged, suggesting that brain mechanisms mediating the decoding of emotional speech melody may vary depending on differences in neuroticism among individuals. Observed trait-specific modulations are discussed in the light of processing biases as well as differences in emotion control or task strategies which may be associated with the personality trait of neuroticism. PMID- 21689765 TI - Changes occur in resting state network of motor system during 4 weeks of motor skill learning. AB - We tested whether the resting state functional connectivity of the motor system changed during 4 weeks of motor skill learning using functional magnetic resonance imaging (fMRI). Ten healthy volunteers learned to produce a sequential finger movement by daily practice of the task over a 4 week period. Changes in the resting state motor network were examined before training (Week 0), two weeks after the onset of training (Week 2), and immediately at the end of the training (Week 4). The resting state motor system was analyzed using group independent component analysis (ICA). Statistical Parametric Mapping (SPM) second-level analysis was conducted on independent z-maps generated by the group ICA. Three regions, namely right postcentral gyrus, and bilateral supramarginal gyri were found to be sensitive to the training duration. Specifically, the strength of resting state functional connectivity in the right postcentral gyrus and right supramarginal gyrus increased from Week 0 to Week 2, during which the behavioral performance improved significantly, and decreased from Week 2 to Week 4, during which there was no more significant improvement in behavioral performance. The strength of resting state functional connectivity in left supramarginal gyrus increased throughout the training. These results confirm changes in the resting state network during slow-learning stage of motor skill learning, and support the premise that the resting state networks play a role in improving performance. PMID- 21689768 TI - Diversification in the Andes: age and origins of South American Heliotropium lineages (Heliotropiaceae, Boraginales). AB - The uplift of the Andes was a major factor for plant diversification in South America and had significant effects on the climatic patterns at the continental scale. It was crucial for the formation of the arid environments in south-eastern and western South America. However, both the timing of the major stages of the Andean uplift and the onset of aridity in western South America remain controversial. In this paper we examine the hypothesis that the Andean South American groups of Heliotropium originated and diversified in response to Andean orogeny during the late Miocene and a the subsequent development of aridity. To this end, we estimate divergence times and likely biogeographical origins of the major clades in the phylogeny of Heliotropium, using both Bayesian and likelihood methods. Divergence times of all Andean clades in Heliotropium are estimated to be of late Miocene or Pliocene ages. At least three independent Andean diversification events can be recognized within Heliotropium. Timing of the diversification in the Andean lineages Heliotropium sects.Heliothamnus, Cochranea, Heliotrophytum, Hypsogenia, Plagiomeris, Platygyne clearly correspond to a rapid, late Miocene uplift of the Andes and a Pliocene development of arid environments in South America. PMID- 21689769 TI - Safety pharmacology in 2010 and beyond: survey of significant events of the past 10 years and a roadmap to the immediate-, intermediate- and long-term future in recognition of the tenth anniversary of the Safety Pharmacology Society. AB - In recognition of the tenth anniversary of the Safety Pharmacology Society (SPS), this review summarizes the significant events of the past 10years that have led to the birth, growth and evolution the SPS and presents a roadmap to the immediate-, intermediate- and long-term future of the SPS. The review discusses (i) the rationale for an optimal non-clinical Safety Pharmacology testing, (ii) the evolution of Safety Pharmacology over the last decade, (iii) its impact on drug discovery and development, (iv) the merits of adopting an integrated risk assessment approach, (v) the translation of non-clinical findings to humans and finally (vi) the future challenges and opportunities facing this discipline. Such challenges include the emergence of new molecular targets and new approaches to treat diseases, the rapid development of science and technologies, the growing regulatory concerns and associated number of guidance documents, and the need to train and educate the next generation of safety pharmacologist. PMID- 21689770 TI - Dorsomedial pallium lesions impair taste aversion learning in goldfish. AB - The present work shows that the dorsomedial telencephalic pallium of teleost fish, proposed as homologous to the amygdala of mammals, is involved in taste aversion learning (TAL). To analyze the behavioral properties of TAL in goldfish, in Experiment 1, we used a delayed procedure similar to that employed with mammals, which consists of the presentation of two flavors on different days, one followed by lithium chloride and the other by saline, both after a 10-min delay. The results showed that goldfish developed a strong aversion to the gustatory stimulus followed by visceral discomfort and that, as in mammals, this learning was rapidly acquired, highly flexible and maintained for a long time. Experiment 2 showed that dorsomedial pallium lesions and the ablation of the telencephalic lobes impaired the acquisition of taste aversion in goldfish, whereas damage to the dorsolateral pallium (hippocampus homologue) or cerebellar corpus did not produce significant changes in this learning. Experiment 3 showed that these TAL deficits were not due to a lesion-related disruption of taste discrimination; goldfish with telencephalon ablation were able to learn to distinguish between the two tested flavors in a differential conditioning procedure. These functional data demonstrate that the dorsomedial pallium in teleosts is, like the amygdala, an essential component of the telencephalon-dependent taste aversion memory system and provide further support concerning the homology between both structures. PMID- 21689771 TI - Gami-Chunghyuldan ameliorates memory impairment and neurodegeneration induced by intrahippocampal Abeta 1-42 oligomer injection. AB - Soluble oligomeric forms of amyloid beta (AbetaO) are regarded as a main cause of synaptic and cognitive dysfunction in Alzheimer's disease (AD) and have been a primary target in the development of drug treatments for AD. The present study utilized a mouse model of AD induced by intrahippocampal injection of AbetaO (10 MUM) to investigate the effects of Gami-Chunghyuldan (GCD), a standardized multi herbal medicinal formula, on the presentation of memory deficits and neurohistological pathogenesis. GCD (10 and 50mg/kg/day, 5 days, p.o.) improved AbetaO-induced memory impairment as well as reduced neuronal cell death, astrogliosis, and microgliosis in the hippocampus. In addition, GCD prevented AbetaO-triggered synaptic disruption and cholinergic fiber loss. These results suggest that GCD may be useful in the prevention and treatment of AD. PMID- 21689772 TI - Role of amygdala-prefrontal cortex circuitry in regulating the expression of contextual fear memory. AB - The basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) are inter connected regions involved in fear memory expression. The reciprocal nature of projections between these areas differs along the rostrocaudal extent of BLA. This study investigated the role of functional interactions between BLA and the prelimbic (PL) subregion of mPFC in mediating contextual fear memory. Freezing served as the measure of conditioned fear. Experiments 1-3 examined the effects of left, right or bilateral infusion of bupivacaine into anterior BLA (aBLA), posterior BLA (pBLA) or PL on fear memory expression. Reversible inactivation of left, right or bilateral aBLA impaired fear memory expression. Bilateral inactivation of pBLA or PL also disrupted the expression of fear memory, although left or right inactivation alone had no significant effects in either region. Experiment 4 examined the effects of functionally disconnecting pBLA and PL on contextual fear memory by infusing bupivacaine unilaterally into pBLA and PL in the ipsilateral or contralateral hemisphere. Fear memory expression was impaired by asymmetric inactivation of pBLA and PL; however, a similar effect was also observed with symmetric inactivation of these regions. Bupivacaine infusion did not affect behavior in the open field, likely ruling out non-specific effects of inactivation on innate fear and locomotor activity. These results demonstrate different roles for rostral and caudal BLA in mediating the expression of contextual fear memory. They also raise the possibility that pBLA-PL circuitry is involved in subserving fear memory expression via complex processing mechanisms, although further research is needed to confirm this preliminary finding. PMID- 21689773 TI - Randomized trial of hydroxychloroquine for newly diagnosed chronic graft-versus host disease in children: a Children's Oncology Group study. AB - The Children's Oncology Group conducted a multicenter Phase III trial for chronic graft-versus-host disease (cGVHD). The double-blind, placebo-controlled, randomized study evaluated hydroxychloroquine added to standard therapy for children with newly diagnosed cGVHD. The study also used a novel grading and response scoring system and evaluated clinical laboratory correlates of cGVHD. The primary endpoint was complete response (CR) after 9 months of therapy. Fifty four patients (27 on each arm) were enrolled before closure because of slow accrual. The CR rate was 28% in the hydroxychloroquine arm versus 33% in the placebo arm (odds ratio [OR] = 0.77, 95% confidence interval [CI]: 0.20-2.93, P = .75) for 42 evaluable patients. For 41 patients with severity assessment at enrollment, 20 (49%) were severe and 18 (44%) moderate according to the National Institutes of Health Consensus Conference global scoring system. The CR rate was 15% for severe cGVHD and 44% for moderate cGVHD (OR = 0.24, 95% CI: 0.05-1.06, P = .07). Although the study could not resolve the primary question, it provided important information for future cGVHD study design in this population. PMID- 21689774 TI - CMV infection after transplant from cord blood compared to other alternative donors: the importance of donor-negative CMV serostatus. AB - Cytomegalovirus (CMV) infection and disease are important complications after hematopoietic stem cell transplant, particularly after transplant from alternative donors. Allogeneic cord blood transplantation (CBT) is being increasingly used, but immune recovery may be delayed. The aim of this study was to compare CMV infection in CBT with transplants from unrelated or mismatched related donors, from now on defined as alternative donors. A total of 165 consecutive transplants were divided in 2 groups: (1) alternative donors transplants (n = 85) and (2) CBT recipients (n = 80). Donor and recipient (D/R) CMV serostatus were recorded. The incidence of CMV infection, its severity, timing, and outcome were compared. Median follow-up was 257 days (1-1328). CMV infection was monitored by CMV antigenemia and expressed as CMV Ag positive cell/2 * 10(5) polymorphonuclear blood cells. There was a trend toward a higher cumulative incidence of CMV infection among CBT than alternative donor transplant recipients (64% vs 51%, P = .12). The median time to CMV reactivation was 35 days, and was comparable in the 2 groups (P = .8). The maximum number of CMV positive cells was similar in the 2 groups (11 versus 16, P = .2). The time interval between the first and the last positive CMV antigenemia was almost 4 times longer in CBT compared with alternative donor transplants (109 vs 29 days, respectively, P = .008). The incidence of late CMV infection was also higher in CBT (62% vs 24%, P < .001). The incidence of early and late CMV infection in CBT was similar to D-/R+ alternative transplants, and higher than in D+/R+ alternative transplants: early infection, 72% in CBT versus 69% in D-/R+ alternative versus 55% in D+/R+ alternative (P = .21); and late infection, 67% in CBT versus 60% in D-/R+ alternative versus 7% in D+/R+ alternative (P < .001). Transplant-related mortality and overall survival were similar between the groups: 34% versus 36% (P = .6) and 54% versus 46% (P = .3) for alternative transplant and CBT, respectively. Longer duration and higher incidence of late CMV infection was seen in CBT patients, when compared with alternative donor transplants, whereas no difference in mortality was observed. The duration and incidence of late CMV infection were similar when D-/R+ CBT were compared with D /R+ alternative donor transplants. PMID- 21689775 TI - Effects of inhaled tiotropium plus transdermal tulobuterol versus tiotropium alone on impulse oscillation system (IOS)-assessed measures of peripheral airway resistance and reactance, lung function and quality of life in patients with COPD: a randomized crossover study. AB - BACKGROUND: The addition of transdermal tulobuterol (Tulo) to inhaled tiotropium bromide (Tio) produced beneficial effects on spirometry-assessed parameters of respiratory function, disease-related symptoms and quality of life in patients with chronic obstructive pulmonary disease (COPD). AIM: To compare the effects of Tio plus Tulo versus Tio alone on peripheral airway obstruction and quality of life in Japanese patients with COPD using impulse oscillation system (IOS) assessed measures. PATIENTS AND METHODS: Patients aged 50-80 years with clinically stable COPD and a forced expiratory volume in 1 s (FEV(1)) that was 30 80% of the predicted value were randomized to receive Tio 18 MUg once daily, or combination therapy with Tio 18 MUg once daily plus Tulo 2 mg once daily for 4 weeks. Patients then switched treatments for a further 4 weeks. RESULTS: Sixteen patients completed the study. Tio plus Tulo was associated with significantly greater improvements than Tio in IOS-assessed markers of resistance (R5 and R5 R20), reactance and reactance area, from baseline to week 4. Both treatments significantly improved these markers over the 4-week treatment period, with the exception of R20 for which improvements were not significant. Tio plus Tulo improved symptoms of dyspnea to a significantly greater extent than Tio alone. St. George's Respiratory Questionnaire Score-Total was not significantly different between the two groups, but improvement from baseline in the 'impact' component was significantly greater with Tio plus Tulo than with Tio alone. CONCLUSIONS: Coadministration of transdermal Tulo with inhaled Tio, as well as Tio alone, is associated with beneficial effects on IOS-assessed measures of peripheral airway obstruction in patients with COPD. PMID- 21689776 TI - Effects of LED light spectra on oxidative stress and the protective role of melatonin in relation to the daily rhythm of the yellowtail clownfish, Amphiprion clarkii. AB - The present study aimed to test the effects of melatonin on oxidative stress in the yellowtail clownfish, Amphiprion clarkii, as produced by light emitting diodes (LEDs): red, green, and blue. We investigated the effects of the different LEDs on oxidative stress by measuring the mRNA expression of arylalkylamine N acetyltransferase (AANAT2), the expression and activities of antioxidant enzymes (superoxide dismutase, SOD (EC 1.15.1.1); and catalase, CAT (EC 1.11.1.6)), and plasma H2O2 and plasma melatonin levels. In red light, the expression of AANAT2, SOD, and CAT mRNA was significantly higher than those under the other light spectra. SOD and CAT activities and plasma H2O2 and melatonin levels were also significantly higher for the red spectra than those for the other light spectra. These results indicate that red light induces oxidative stress. To investigate the effects of melatonin on oxidative stress, we injected melatonin into live fish (in vivo) or treated cultured pineal organ (in vitro) with melatonin. We found that AANAT2, SOD, and CAT mRNA expression levels, SOD and CAT activities, and plasma H2O2, lipid peroxidation (LPO) and melatonin levels were significantly lower than those for the controls. Therefore, our results indicate that red light induces oxidative stress and melatonin plays the role of a strong antioxidant in yellowtail clownfish. PMID- 21689777 TI - Seasonal variations in the physiological stress response to discrete bouts of aerial exposure in the little skate, Leucoraja erinacea. AB - Aerial exposure and acute thermal stress have been shown to elicit profound physiological disruptions in obligate water-breathing teleosts. However, no study has investigated these responses in an elasmobranch. To address this, venous blood samples were collected and evaluated from little skates (Leucoraja erinacea) subjected to discrete aerial exposure durations (0, 15, and 50 min) coupled with differing abrupt thermal changes (gradient between seawater and air; winter: DeltaT=-3 degrees C; summer: DeltaT=+9 degrees C) in two distinct laboratory studies. In general, blood acid-base properties (e.g. decline in pH; elevation in PCO(2)) and select metabolites (elevated whole-blood lactate) and electrolytes (elevated plasma K(+)) were significantly disrupted by aerial exposure, and were most disturbed after skates were exposed to air for 50 min. However, the magnitude of the blood acid-base perturbations, metabolic contribution to the resulting blood acidosis, elevations to ionic and metabolic parameters, and delayed mortality were more extreme during the summer study, suggesting that acute thermal stress exacerbates the physiological impairments associated with aerial exposure in little skates. Conversely, a reduced thermal gradient (from seawater to air) may attenuate the magnitude of metabolic and ionic perturbations, resulting in a high physiological threshold for coping with extended aerial exposure. PMID- 21689778 TI - Phylogenetic constraints on digesta separation: Variation in fluid throughput in the digestive tract in mammalian herbivores. AB - The relevance of the mean retention time (MRT) of particles through the gastrointestinal tract (GIT) is well understood and MRT(particle)GIT is an important parameter in digestion models. Solute markers have been used to estimate MRT(solute)GIT (or 'fluid passage') in animals, but the relevance of this measure is less evident and is usually sought in its relation to MRT(particle)GIT. The ratio between the two measures indicates the degree of 'digesta washing', with little washing occurring at ratios of 1, aborad washing at ratios >1 (where the solute marker travels faster than the particle marker), and orad (retrograde) washing at ratios <1 (where the solute marker travels slower than the particle marker). We analysed digesta washing in a dataset of 98 mammalian species including man of different digestion types (caecum, colon and nonruminant foregut fermenters, and ruminants), controlling for phylogeny; a subset of 72 species allowed testing for the influence of food intake level. The results indicate that MRT(solute)GIT and the degree of digesta washing are related to digestion type, whereas variation in MRT(particle)GIT is influenced mainly by effects of body mass and food intake. Thus, fluid throughput and digesta washing emerge as important correlates of digestive anatomy. Most importantly, primates appear constrained to little digesta washing compared to non-primate mammalian herbivores, regardless of their digestion type. These results may help explain the absence of primates from certain herbivore niches and represent a drastic example of a physiologic limitation in a phylogenetic group. More experimental research is required to illuminate relative benefits and costs of digesta washing. PMID- 21689779 TI - Metabolic engineering in strawberry fruit uncovers a dormant biosynthetic pathway. AB - Wild strawberry (Fragaria vesca) fruit contains several important phenylpropene aroma compounds such as eugenol, but cultivated varieties are mostly devoid of them. We have redirected the carbon flux in cultivated strawberry (Fragaria*ananassa) fruit from anthocyanin pigment biosynthesis to the production of acetates of hydroxycinnamyl alcohols, which serve as the precursors of the phenylpropenes, by downregulating the strawberry chalcone synthase (CHS) via RNAi mediated gene silencing and, alternatively, by an antisense CHS construct. Simultaneous heterologous overexpression of a eugenol (EGS) and isoeugenol synthase (IGS) gene in the same cultivated strawberry fruits boosted the formation of eugenol, isoeugenol, and the related phenylpropenes chavicol and anol to concentrations orders of magnitude greater than their odor thresholds. The results show that Fragaria*ananassa still bears a phenylpropene biosynthetic pathway but the carbon flux is primarily directed to the formation of pigments. Thus, partial restoration of wild strawberry flavor in cultivated varieties is feasible by diverting the flavonoid pathway to phenylpropene synthesis through metabolic engineering. PMID- 21689780 TI - Purinergic signaling involved in Muller cell function in the mammalian retina. AB - Purines (in particular, ATP and adenosine) act as neuro- and gliotransmitters in the sensory retina where they are involved in bidirectional neuron-glia signaling. This review summarizes the present knowledge about the expression and functional importance of P1 (adenosine) and P2 (nucleotide) receptors in Muller glial cells of the mammalian retina. Mammalian Muller cells express various subtypes of adenosine receptors and metabotropic P2Y receptors. Human Muller cells also express ionotropic P2X(7) receptors. Muller cells release ATP upon activation of metabotropic glutamate receptors and/or osmotic membrane stretching. The osmotic mechanism is abrogated under conditions associated with ischemia-hypoxia and inflammation, resulting in swelling of the Muller cells when the extracellular milieu is hypoosmotic. However, exogenous glutamate, which induces the release of ATP and adenosine, and thus activates P2Y(1) and A(1) adenosine receptors, respectively, prevents such osmotic swelling under pathological conditions, suggesting unimpaired receptor-induced release of ATP. In addition to the inhibition of swelling, which is implicated in regulating the volume of the extracellular space, purinergic signaling is involved in mediating neurovascular coupling. Furthermore, purinergic signals stimulate the proliferation of retinal precursor cells and Muller cells. In normal retinal information processing, Muller cells regulate the synaptic activity by the release of ATP and adenosine. In retinopathies, abrogation of the osmotic release of ATP, and the upregulation of ecto-apyrase (NTPDase1), may have neuroprotective effects by preventing the overactivation of neuronal P2X receptors that are implicated in apoptotic cell death. Pharmacological modulation of purinergic receptors of Muller cells may have clinical importance, e.g., for the clearance of retinal edema and for the inhibition of dysregulated cell proliferation in proliferative retinopathies. PMID- 21689781 TI - Progesterone synthesis by human placental mitochondria is sensitive to PKA inhibition by H89. AB - The transfer of cholesterol to mitochondria, which might involve the phosphorylation of proteins, is the rate-limiting step in human placental steroidogenesis. Protein kinase A (PKA) activity and its role in progesterone synthesis by human placental mitochondria were assessed in this study. The results showed that PKA and phosphotyrosine phosphatase D1 are associated with syncytiotrophoblast mitochondrial membrane by an anchoring kinase cAMP protein 121. The 32P-labeled of four major proteins was analyzed. The specific inhibitor of PKA, H89, decreased progesterone synthesis in mitochondria while in mitochondrial steroidogenic contact sites protein-phosphorylation was diminished, suggesting that PKA plays a role in placental hormone synthesis. In isolated mitochondria, PKA activity was unaffected by the addition of cAMP suggesting a constant activity of this kinase in the syncytiotrophoblast. The presence of PKA and phosphotyrosine phosphatase D1 anchored to mitochondria by an anchoring kinase cAMP protein-121 indicated that syncytiotrophoblast mitochondria contain a full phosphorylation/dephosphorylation system. PMID- 21689782 TI - High-throughput lipidomic analysis of fatty acid derived eicosanoids and N acylethanolamines. AB - Fatty acid-derived eicosanoids and N-acylethanolamines (NAE) are important bioactive lipid mediators involved in numerous biological processes including cell signaling and disease progression. To facilitate research on these lipid mediators, we have developed a targeted high-throughput mass spectrometric based methodology to monitor and quantitate both eicosanoids and NAEs, and can be analyzed separately or together in series. Each methodology utilizes scheduled multiple reaction monitoring (sMRM) pairs in conjunction with a 25 min reverse phase HPLC separation. The eicosanoid methodology monitors 141 unique metabolites and quantitative amounts can be determined for over 100 of these metabolites against standards. The analysis covers eicosanoids generated from cycloxygenase, lipoxygenase, cytochrome P450 enzymes, and those generated from non-enzymatic pathways. The NAE analysis monitors 36 metabolites and quantitative amounts can be determined for 33 of these metabolites against standards. The NAE method contains metabolites derived from saturated fatty acids, unsaturated fatty acids, and eicosanoids. The lower limit of detection for eicosanoids ranges from 0.1pg to 1pg, while NAEs ranges from 0.1pg to 1000pg. The rationale and design of the methodology is discussed. PMID- 21689783 TI - Dynamic categorization of clinical research eligibility criteria by hierarchical clustering. AB - OBJECTIVE: To semi-automatically induce semantic categories of eligibility criteria from text and to automatically classify eligibility criteria based on their semantic similarity. DESIGN: The UMLS semantic types and a set of previously developed semantic preference rules were utilized to create an unambiguous semantic feature representation to induce eligibility criteria categories through hierarchical clustering and to train supervised classifiers. MEASUREMENTS: We induced 27 categories and measured the prevalence of the categories in 27,278 eligibility criteria from 1578 clinical trials and compared the classification performance (i.e., precision, recall, and F1-score) between the UMLS-based feature representation and the "bag of words" feature representation among five common classifiers in Weka, including J48, Bayesian Network, Naive Bayesian, Nearest Neighbor, and instance-based learning classifier. RESULTS: The UMLS semantic feature representation outperforms the "bag of words" feature representation in 89% of the criteria categories. Using the semantically induced categories, machine-learning classifiers required only 2000 instances to stabilize classification performance. The J48 classifier yielded the best F1-score and the Bayesian Network classifier achieved the best learning efficiency. CONCLUSION: The UMLS is an effective knowledge source and can enable an efficient feature representation for semi-automated semantic category induction and automatic categorization for clinical research eligibility criteria and possibly other clinical text. PMID- 21689784 TI - Phylogenetic analysis of rotavirus A NSP2 gene sequences and evidence of intragenic recombination. AB - The rotavirus non-structural protein NSP2 is one of the earliest and most abundant viral proteins produced during infection. This protein has multiple essential roles in the replication cycle involving RNA binding, viroplasm formation, helicase and can hydrolyse the gamma-phosphate of RNA and NTPs acting as an RTPase and NTPase. In studying sequences from rotavirus strains isolated in Australia between 1984 and 2009, the NSP2 gene was seen to be highly conserved and clustered with defined NSP2 genotypes N1 and N2 according to the full genome based rotavirus classification system. Phylogenetic analysis indicated that NSP2 gene sequences isolated from Australian rotavirus strains formed four distinct lineages. Temporal variation was observed in several clusters during the 26 year period, with lineage D identified throughout the entire study period and lineage A only detected since 1999. Phylogenetic analysis and dendrograms identified NSP2 genes that exhibited reassortment between different virus VP7 genotypes, as well as a sequence from a human strain that grouped closely with the NSP2 genes of bovine rotavirus strains. This study also identified a sequence that fell between lineages and exhibited evidence of recombination, the first time that intergenic recombination has been detected in a NSP2 gene sequence. This study increases the understanding of the evolution mechanisms of NSP2 in view of improved vaccine design. PMID- 21689785 TI - Genetic evolution and clinical impact in extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae. AB - The emergence of extended-spectrum beta-lactamase (ESBL)-producing bacteria, particularly Escherichia coli and Klebsiella pneumoniae, is now a critical concern for the development of therapies against bacterial infection. ESBLs consist of three major genetic groups: TEM, SHV, and CTX-M types. Nosocomial infections due to TEM and SHV-producing K. pneumoniae strains were frequently documented until the late 1990s. The number of reports on community-acquired infections caused by CTX-M-producing E. coli strains have dramatically increased over the last decade; however, K. pneumoniae strains, of either the TEM or SHV types, are persistent and important ESBL producers. The spread of ESBL genes is associated with various mobile genetic elements, such as transposons, insertion sequences, and integrons. The rapid dissemination of ESBL genes of the CTX-M type may be related to highly complicated genetic structures. These structures harboring ESBL genes and mobile elements are found in a variety of plasmids, which often carry many other antibiotic resistance genes. Multidrug-resistant CTX M-15-producing E. coli strains disseminate worldwide. Efficient mobile elements and plasmids may have accelerated the genetic diversity and the rapid spread of ESBL genes, and their genetic evolution has caused an emerging threat to the bacteria for which few effective drugs have been identified. PMID- 21689786 TI - Development of a human whole blood assay for prediction of cytokine release similar to anti-CD28 superagonists using multiplex cytokine and hierarchical cluster analysis. AB - Anti-CD28 superagonist (SA) mediated cytokine release syndrome (CRS), an adverse event resulting in systemic release of cytokines, is an emergent issue in drug development. CRS is of potential concern for all monoclonal antibodies (mAbs) particularly those directed against cell surface targets on lymphocytes. Concern regarding patient safety requires development of novel methods to predict these adverse reactions. Due to the inability of animal studies to predict CRS, we have developed a whole blood in vitro screen to support First in Human studies and assess the potential for mAbs to cause anti-CD28 SA-like CRS. For this purpose we have immobilized marketed mAbs, whose potential for causing CRS and milder infusion reactions is known, on Protein A beads and used these beads to stimulate cytokine release. After culture, supernatants are harvested and frozen for later multiplex analysis of cytokines using SearchlightTM technology. We have employed hierarchicalluster analysis (HCA) to allow comparison of 12 different cytokine levels across numerous donors, treatments, and experiments. Results conclusively distinguish test mAb responses from an anti-CD28 superagonist mAb response. As part of a global analysis of preclinical data, the results of this assay can facilitate entry into First in Human clinical trials, help with selection of starting doses and may allow more rapid dose escalation using smaller cohorts. PMID- 21689787 TI - MicroRNAs as a novel cellular senescence regulator. AB - Cellular senescence is a program activated in normal cells in response to various types of stresses and is manifested by permanent arrest of cell cycle. Cellular senescence is closely related to tumor suppression, and may contribute to the ageing of organisms. The complex senescence cell phenotype has many different mechanisms. Recent studies have provided important insights regarding the role played by miRNAs during cellular senescence as a novel molecular mechanism. In this article, we will review the latest advances in the identification and validation of senescence-regulatory miRNAs and the possible mechanisms. PMID- 21689788 TI - Arterial H+ regulation during exercise in humans. AB - Resting arterial H+ concentration ([H+]a) is in the nanomolar range (40+/-2 nm/L) while its production is in the millimolar range/min, with little variation from subject to subject. To determine the precision with which [H(+)]a is regulated during exercise, [H+]a, PaCO2 and ventilation (V(E)) were measured during progressively increasing work rate exercise in 16 normal subjects. (V(E)) increased with [H+]a, the latter attributable to PaCO2 increase below the lactic acidosis threshold (LAT) (DeltaV(E)/Delta[H+]a ~ 15 L min(-1) nanomol(-1)). [H+]a and PaCO2 increased, simultaneously, as work rate was increased below LAT. PaCO2 reversed direction of change between LAT and ventilatory compensation point (VCP). Above LAT, [H+]a increase relative to (V(E)) increase was greater than below LAT. PaCO2 decreased above the LAT, while [H+]a continued to increase. Thus the exercise acidosis was converted from respiratory, below, to a metabolic, above the LAT. We conclude that [H+]a is increased and regulated over the full range of exercise, but with less sensitivity above the LAT. PMID- 21689789 TI - Substance P, tyrosine hydroxylase and serotonin terminals in the rat caudal nucleus ambiguus. AB - Substance P (SP), tyrosine hydroxylase (TH) and serotonin inputs onto laryngeal motoneurons (LMNs) are known to exist, but the distribution of their terminals in the caudal nucleus ambiguus (NA), remains unclear. Using immunofluorescence and confocal microscopy, we assessed simultaneously the distribution of SP, TH, serotonin and synaptophysin immunoreactive (ir) terminals in the caudal NA. SP, TH and serotonin-ir varicosities were considered to represent immunoreactive synapses if, using confocal microscopy, they were co-localized with the presynaptic protein, synaptophysin. Relative to the total number of synapses, we found only a modest number of SP, TH or serotonin-ir synaptic terminals in the caudal NA. The density of SP-ir synaptic terminals was higher than that of TH-ir and serotonin-ir synaptic terminals. Our results suggest that SP, TH, and serotonin-ir inputs may play only a modest role in regulating the activity of LMN. We conclude that SP, TH and serotonin are not always co-localized in terminals forming inputs with LMN and that they arise from separate subpopulations of neurons. PMID- 21689790 TI - Aggregation and structural changes of alpha(S1)-, beta- and kappa-caseins induced by homocysteinylation. AB - Elevated homocysteine levels are resulting in N-homocysteinylation of lysyl residues in proteins and they correlate with a number of human pathologies. However, the role of homocysteinylation of lysyl residues is still poorly known. In order to study the features of homocysteinylation of intrinsically unstructured proteins (IUP) bovine caseins were used as a model. alpha(S1)-, beta and kappa-caseins, showing different aggregations and micelle formation, were modified with homocysteine-thiolactone and their physico-chemical properties were studied. Efficiency of homocysteine incorporation was estimated to be about 1.5, 2.1 and 1.3 homocysteyl residues per one beta-, alpha(S1)-, and kappa-casein molecule, respectively. Use of intrinsic and extrinsic fluorescent markers such as Trp, thioflavin T and ANS, reveal structural changes of casein structures after homocysteinylation reflected by an increase in beta-sheet content, which in some cases may be characteristic of amyloid-like transformations. CD spectra also show an increase in beta-sheet content of homocysteinylated caseins. Casein homocysteinylation leads in all cases to aggregation. The sizes of aggregates and aggregation rates were dependent on homocysteine thiolactone concentration and temperature. DLS and microscopic studies have revealed the formation of large aggregates of about 1-3MUm. Homocysteinylation of alpha(S1)- and beta-caseins results in formation of regular spheres. Homocysteinylated kappa-casein forms thin unbranched fibrils about 400-800nm long. In case of kappa-casein amyloidogenic effect of homocysteinylation was confirmed by Congo red spectra. Taken together, data indicate that N-homocysteinylation provokes significant changes in properties of native caseins. A comparison of amyloidogenic transformation of 3 different casein types, belonging to the IUP protein family, shows that the efficiency of amyloidogenic transformation upon homocysteinylation depends on micellization capacity, additional disulphide bonds and other structural features. PMID- 21689791 TI - Fabrication and characterization of sol-gel derived 45S5 Bioglass(r)-ceramic scaffolds. AB - Although Bioglass(r) has existed for nearly half a century its ability to trigger bone formation and tuneable degradability is vastly superior to other bioceramics, such as SiO(2)-CaO bioactive glasses. The sol-gel process of producing glass foams is well established for SiO(2)-CaO compositions, but not yet established for 45S5 composites containing Na(2)O. In this work the sol-gel derived 45S5 Bioglass(r) has for the first time been foamed into highly porous three-dimensional scaffolds using a surfactant, combined with vigorous mechanical stirring and subsequent sintering at 1000 degrees C for 2 h. It was found that the mechanical strength of the sintered sol-gel derived Bioglass(r) scaffolds was significantly improved, attributable to the small fraction of material on the pore walls. More importantly, the compressive strength of the three-dimensional scaffolds produced by this surfactant foaming method could be predicted using Gibson and Ashby's closed cell model of porous networks. A comparative experiment revealed that ion release from the sol-gel derived Bioglass(r) foams was faster than that of counterparts produced by the replication technique. In vitro evaluation using osteoblast-like cells demonstrated that the sol-gel derived 45S5 Bioglass foams supported the proliferation of viable cell populations on the surface of the scaffolds, although few cells were observed to migrate into the virtually closed pores within the foams. Further work should be focused on modifications of the reaction conditions or alternative foaming techniques to improve pore interconnection. PMID- 21689792 TI - Regeneration and repair of tendon and ligament tissue using collagen fibre biomaterials. AB - Collagen fibres are ubiquitous macromolecular assemblies in nature, providing the structures that support tensile mechanical loads within the human body. Aligned type I collagen fibres are the primary structural motif for tendon and ligament, and therefore biomaterials based on these structures are considered promising candidates for mediating regeneration of these tissues. However, despite considerable investigation, there remains no collagen-fibre-based biomaterial that has undergone clinical evaluation for this application. Recent research in this area has significantly enhanced our understanding of these complex and challenging biomaterials, and is reinvigorating interest in the development of such structures to recapitulate mechanical function. In this review we describe the progress to date towards a ligament or tendon regeneration template based on collagen fibre scaffolds. We highlight reports of particular relevance to the development of the underlying biomaterials science in this area. In addition, the potential for tailoring and manipulating the interactions between collagen fibres and biological systems, as hybrid biomaterial-biological ensembles, is discussed in the context of developing novel tissue engineering strategies for tendon and ligament. PMID- 21689793 TI - Chemical surface modification of parylene C for enhanced protein immobilization and cell proliferation. AB - To introduce the adhesion site of proteins and/or cells on parylene C (PC)-coated medical devices that can be used as implantable biosensors or drug delivery capsules, the PC surfaces were initially modified by the Friedel-Crafts acylation reaction to generate active chlorines. These chlorines were then employed to initiate the atom transfer radical polymerization of tert-butyl acrylate (TBA) and form a polymer brush layer of polyTBA on PC; the acrylate groups in the polymer brushes were hydrolyzed to carboxylic acid groups and further activated into succinimidyl ester groups via the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide coupling reaction. The PC surface grafted with polymer brushes and activated by succinimide showed efficient attachment of proteins, including gelatin, contortrostatin (CN) and bovine serum albumin (BSA), all at high density on the PC surface. The CN density on the surface was evaluated for both monolayer and polymer brush-based coatings. Based on fluorescence measurements, the polymer brush gives a 60-fold higher surface protein density than the monolayer-based system. Gelatin was used as a model protein and covalently coated onto the modified PC surface for cell culture study. Substrates with gelatin coating showed a significantly higher cell attachment and proliferation in 7 days cultures as compared to the uncoated substrates. In addition, a conventional photolithography technique was coupled with the surface chemistry to successfully pattern the BSA labeled with fluorescein isothiocyanate on the modified PC surfaces. PMID- 21689794 TI - In vitro degradation rate of apatitic calcium phosphate cement with incorporated PLGA microspheres. AB - Calcium phosphate cements (CPCs) are frequently used as bone substitute material. Despite their superior clinical handling and excellent biocompatibility, they exhibit poor degradability, which limits bone ingrowth into the implant. Microspheres were prepared from poly(d,l-lactic-co-glycolic acid) (PLGA) and included in injectable CPCs as porogens in order to enhance its macroporosity after the polymeric microspheres had degraded. Upon degradation of the PLGA microspheres, acid is produced that enhances the dissolution rate of the CPC. However, the effect of the characteristics of PLGA microspheres on the degradation rate of CPCs has never been studied before. Therefore, the purpose of the current study was to investigate the dependence of CPC degradation on the chemical and morphological characteristics of incorporated PLGA microspheres. With respect to the chemical characteristics of the PLGA microspheres, the effects of both PLGA molecular weight (5, 17 and 44kDa) and end-group functionalization (acid-terminated or end-capped) were studied. In addition, two types of PLGA microspheres, differing in morphology (hollow vs. dense), were tested. The results revealed that, although both chemical parameters clearly affected the polymer degradation rate when embedded as hollow microspheres in CPC, the PLGA and CPC degradation rates were mainly dependent on the end-group functionalization. Moreover, it was concluded that dense microspheres were more efficient porogens than hollow ones by increasing the CPC macroporosity during in vitro incubation. By combining all test parameters, it was concluded that dense PLGA microspheres consisting of acid-terminated PLGA of 17kDa exhibited the highest and fastest acid-producing capacity and correspondingly the highest and fastest amount of porosity. In conclusion, the data presented here indicate that the combination of dense, acid-terminated PLGA microspheres with CPC emerges as a successful combination to achieve enhanced apatitic CPC degradation. PMID- 21689795 TI - Production, structure and in vitro degradation of electrospun honeybee silk nanofibers. AB - Honeybees produce silken cocoons containing four related fibrous proteins. High levels of each of the honeybee silk proteins can be produced recombinantly by fermentation in Escherichia coli. In this study we have used electrospinning to fabricate a single recombinant honeybee silk protein, AmelF3, into nanofibers of around 200 nm diameter. Infrared spectroscopy found that the molecular structure of the nanofibers was predominantly coiled coil, essentially the same as native honeybee silk. Mats of the honeybee nanofibers were treated with methanol or by water annealing, which increased their beta-sheet content and rendered them water insensitive. The insoluble mats were degraded by protease on a time scale of hours to days. The protease gradually released proteins from the solid state and these were subsequently rapidly degraded into small peptides without the accumulation of partial degradation products. Cell culture assays demonstrated that the mats allowed survival, attachment and proliferation of fibroblasts. These results indicate that honeybee silk proteins meet many prerequisites for use as a biomaterial. PMID- 21689796 TI - Phenotypic spectrum associated with duplication of Xp11.22-p11.23 includes Autism Spectrum Disorder. AB - Dup(X)(p11.22-p11.23) has been shown to be associated with intellectual disability (ID, also referred to as mental retardation). Here, we characterize a 4.64 Mb de novo duplication of the same Xp11.22-p11.23 ID region in a female, but for this reference case the diagnosis was Autism Spectrum Disorder (ASD). Besides ASD, she also had very persistent trichotillomania, anxiety symptoms and some non specific dysmorphic features. We report the detailed clinical features, as well as refine the rearrangement breakpoints of this disease-associated copy number variation region, which encompasses more than 50 genes. We propose that in addition to ID, the phenotypic spectrum associated with dup(X)(p11.22-p11.23) can include ASD, language impairment, and/or other primary psychiatric disorders. PMID- 21689797 TI - Fungi isolated from olive ecosystems and screening of their potential biotechnological use. AB - This study investigated the fungi diversity of fresh olive (Olea europaea L.) fruits, olive paste (crushed olives) and olive pomace (solid waste) and screened and quantified enzymatic activities with biotechnological applications. Fungi were randomly isolated from olive cultivars from Castilla La Mancha region (Spain). Identification included comparison of their polymerase chain reaction (PCR) amplicons of the ITS1-5.8S-ITS2 ribosomal DNA region, followed by nucleotide sequence analysis. Fourteen different species with DNA sequences of different similarities were identified, belonging to seven different genera (Aspergillus, Penicillium, Rhizomucor, Mucor, Rhizopus, Lichtheimia and Galactomyces). Aspergillus fumigatus, followed by Galactomyces geotrichum, Penicillium commune and Rhizomucor variabilis var. regularior were the most frequent species. Specific enzyme screening was assayed on agar plates, using cellobiose, carboxymethylcellulose (CMC), polygalacturonic acid and CaCl(2)/Tween 80 as substrates for beta-glucosidase, carboxymethylcellulase (CMCase), polygalacturonase and lipase, respectively. Species exhibiting the best activities were: Aspergillus fumigatus (for beta-glucosidase, CMCase and lipase); Rhizopus oryzae (for beta-glucosidase and lipase); Rhizomucor variabilis (for beta-glucosidase, CMCase and polygalacturonase); Mucor fragilis (beta glucosidase, CMCase and lipase); Galactomyces geotrichum (for beta-glucosidase, polygalacturonase and lipase) and Penicillium commune and Penicillium crustosum (for lipase). The species that had shown the best enzymatic activities were grown on hemicellulose, cellulose and pectin and some activities were quantified (xylanase, cellulase, beta-glucosidase and pectinase). An isolate of A. fumigatus and one of A. niger showed the best cellulase and xylanase activities, while no species presented good pectinase and beta-glucosidase activities. The selected species with potential enzymatic activities could be used for future applications of industrial interest. PMID- 21689798 TI - A comparative study of solvent-assisted pretreatment of biodiesel derived crude glycerol on growth and 1,3-propanediol production from Citrobacter freundii. AB - The rapidly growing biodiesel industry has created a scenario, where it is both important and challenging to deal with the enormous amount of crude glycerol generated as an inherent by-product. With every 100 gallons of biodiesel produced, 5-10 gallons of the crude glycerol is left behind containing several impurities which makes its disposal difficult. The objective of the present investigation was to evaluate the impact of biodiesel-derived crude glycerol upon microbial growth and production of 1,3-propanediol by Citrobacter freundii. Five different grades of crude glycerol (obtained from biodiesel preparation using jatropha, soybean, sunflower, rice bran and linseed oils) were used. Crude glycerol caused significant inhibition of microbial growth and subsequently 1,3 propanediol production as compared to pure glycerol. Therefore, a process was developed for the treatment of crude glycerol using solvents before fermentation wherein four different non-polar solvents were examined yielding different grades of pretreated glycerol. Subsequently, the potential toxic effects of pretreated glycerol on the growth and 1,3-propanediol production by C. freundii was evaluated. In case of petroleum ether-treated crude glycerol obtained from jatropha & linseed and hexane-treated crude glycerol obtained from rice bran, the yields obtained were comparable to the pure glycerol. Similarly, soybean-derived glycerol gave comparable results after treatment with either hexane or petroleum ether. PMID- 21689799 TI - The processive endoglucanase EngZ is active in crystalline cellulose degradation as a cellulosomal subunit of Clostridium cellulovorans. AB - Clostridium cellulovorans produces an efficient enzyme complex for the degradation of lignocellulosic biomass. In our previous study, we detected and identified protein spots that interacted with a fluorescently labeled cohesin biomarker via two-dimensional gel electrophoresis. One novel, putative cellulosomal protein (referred to as endoglucanase Z) contains a catalytic module from the glycosyl hydrolase family (GH9) and demonstrated higher levels of expression than other cellulosomal cellulases in Avicel-containing cultures. Purified EngZ had optimal activity at pH 7.0, 40 degrees C, and the major hydrolysis product from the cellooligosaccharides was cellobiose. EngZ's specific activity toward crystalline cellulose (Avicel and acid-swollen cellulose) was 10 20-fold higher than other cellulosomal cellulase activities. A large percentage of the reducing ends that were produced by this enzyme from acid-swollen cellulose were released as soluble sugar. EngZ has the capability of reducing the viscosity of Avicel at an intermediate-level between exo- and endo-typing cellulases, suggesting that it is a processive endoglucanase. In conclusion, EngZ was highly expressed in cellulolytic systems and demonstrated processive endoglucanase activity, suggesting that it plays a major role in the hydrolysis of crystalline cellulose and acts as a cellulosomal enzyme in C. cellulovorans. PMID- 21689800 TI - Pseudomonas resinovorans SPR1, a newly isolated strain with potential of transforming eugenol to vanillin and vanillic acid. AB - In this study a novel strain was isolated with the capability to grow on eugenol as a source of carbon and energy. This strain was identified as Pseudomonas resinovorans (GenBank accession no. HQ198585) based on phenotypic characterization and phylogenetic analysis of 16S rDNA gene. The intermediates coniferyl alcohol, coniferyl aldehyde, ferulic acid, vanillin and vanillic acid were detected in the culture supernatant during eugenol biotransformation with this strain. The products were confirmed by thin layer chromatography (TLC), high performance liquid chromatography (HPLC) and spectral data achieved from UV-vis, FTIR and mass spectroscopy. Using eugenol as substrate and resting cells of P. resinovorans SPR1, which were harvested at the end of the exponential growth phase, without further optimization 0.24 g/L vanillin (molar yield of 10%) and 1.1g/L vanillic acid (molar yield of 44%) were produced after 30 h and 60 h biotransformation, respectively. The current work gives the first evidence for the eugenol biotransformation by P. resinovorans. PMID- 21689801 TI - Effects of cobalt and chromium ions at clinically equivalent concentrations after metal-on-metal hip replacement on human osteoblasts and osteoclasts: implications for skeletal health. AB - Metal-on-metal hip replacement (MOMHR) using large diameter bearings has become a popular alternative to conventional total hip arthroplasty, but is associated with elevated local tissue and circulating levels of chromium (Cr) and cobalt (Co) ions that may affect bone health. We examined the effects of acute and chronic exposure to these metals on human osteoblast and osteoclast formation and function over a clinically relevant concentration range previously reported in serum and within hip synovial fluid in patients after MOMHR. SaOS-2 cells were cultured with Co(2+), Cr(3+) and Cr(6+) for 3 days after which an MTS assay was used to assess cell viability, for 13 days after which alkaline phosphatase and cell viability were assessed and for 21 days after which nodule formation was assessed. Monocytes were isolated from human peripheral blood and settled onto dentine disks then cultured with M-CSF and RANKL plus either Co(2+), Cr(3+) or Cr(6+) ions for 21 days from day 0 or between days 14 and 21. Cells were fixed and stained for TRAP and osteoclast number and amount of resorption per dentine disk determined. Co(2+) and Cr(3+) did not affect osteoblast survival or function over the clinically equivalent concentration range, whilst Cr(6+) reduced osteoblast survival and function at concentrations within the clinically equivalent serum range after MOMHR (IC(50) =2.2 MUM). In contrast, osteoclasts were more sensitive to metal ions exposure. At serum levels a mild stimulatory effect on resorption in forming osteoclasts was found for Co(2+) and Cr(3+), whilst at higher serum and synovial equivalent concentrations, and with Cr(6+), a reduction in cell number and resorption was observed. Co(2+) and Cr(6+) within the clinical range reduced cell number and resorption in mature osteoclasts. Our data suggest that metal ions at equivalent concentrations to those found in MOMHR affect bone cell health and may contribute to the observed bone-related complications of these prostheses. PMID- 21689802 TI - Risk factors for in-hospital post-hip fracture mortality. AB - INTRODUCTION: Approximately 10% of hip fracture patients die during hospitalization; however, it is not clear what risk factors contribute to the excess mortality. This study sought to examine risk factors of, and to develop prognostic model for, predicting in-hospital mortality among hip fracture patients. METHODS: We studied outcomes among 410 men and 1094 women with a hip fracture who were admitted to a major-teaching-hospital in Sydney (Australia) between 1997 and 2007. Clinical data, including concomitant illnesses, were obtained from inpatient data. The primary outcome of the study was in-hospital mortality regardless of length of stay. A Log-binomial regression model was used to identify risk factors for in-hospital mortality. Using the identified risk factors, prognostic nomograms were developed for predicting short term risk of mortality for an individual. RESULTS: The median duration of hospitalization was 9 days. During hospitalization, the risk of mortality was higher in men (9%) than in women (4%). After adjusting for multiple risk factors, increased risk of in hospital mortality was associated with advancing age (rate ratio [RR] for each 10 year increase in age: 1.91 95% confidence interval [CI]: 1.47 to 2.49), in men (RR 2.13; 95% CI 1.41 to 3.22), and the presence of comorbid conditions on admission (RR for one or more comorbid conditions vs. none: 2.30; 95% CI 1.52 to 3.48). Specifically, the risk of mortality was increased in patients with a pre existing congestive heart failure (RR 3.02; 95% CI: 1.65 to 5.54), and liver disease (RR 4.75; 95% CI: 1.87 to 12.1). These factors collectively accounted for 69% of the risk for in-hospital mortality. A nomogram was developed from these risk factors to individualize the risk of in-hospital death following a hip fracture. The area under the receiver operating characteristic curve of the final model containing age, sex and comorbid conditions was 0.76. CONCLUSION: These data suggest that among hip fracture patients, advancing age, gender (men), and pre-existing concomitant diseases such as congestive heart failure and liver disease were the main risk factors for in-hospital mortality. The nomogram developed from this study can be used to convey useful prognostic information to help guide treatment decisions. PMID- 21689803 TI - Radionuclide studies of bone metabolism: do bone uptake and bone plasma clearance provide equivalent measurements of bone turnover? AB - Quantitative radionuclide imaging using (18)F-fluoride positron emission tomography (18F-PET) or (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) bone scans provides a novel tool for studying regional and whole skeleton bone turnover that complements the information provided by biochemical markers. Radionuclide bone scans can be quantified by measuring either tracer uptake or, if blood sampling is performed, bone plasma clearance. This study examines whether these two methods provide equivalent information about bone turnover. We examined data from two clinical trials of the bone anabolic agent teriparatide. In Study 1 twenty osteoporotic women had 18F-PET scans of the lumbar spine at baseline and after 6 months treatment with teriparatide. Bone uptake in the lumbar spine was expressed as standardised uptake values (SUV) and blood samples taken to evaluate plasma clearance. In Study 2 ten women had (99m)Tc-MDP scans at baseline, 3 and 18 months after starting teriparatide. Blood samples were taken and whole skeleton plasma clearance and bone uptake calculated. In Study 1 spine plasma clearance increased by 23.8% after 6-months treatment (P=0.0003), whilst SUV increased by only 3.0% (P=0.84). In Study 2 whole skeleton plasma clearance increased by 37.1% after 18-months treatment (P=0.0002), whilst the 4-hour whole skeleton uptake increased by only 25.5% (P=0.0001). During treatment the 18F- plasma concentration decrease by 20% and (99m)Tc-MDP concentration by 13%, and these latter changes were sufficient to explain the differences between the uptake and plasma clearance results. Measurements of response to treatment using bone uptake and plasma clearance gave different results because the effects of teriparatide on bone resulted in a sufficiently increased demand for radionuclide tracer from the skeleton that the concentration in the circulation decreased. Similar effects may occur with other therapies that have a large enough effect on bone metabolism. In these circumstances changes in bone plasma clearance give a truer impression of response to treatment than those in SUV or uptake. PMID- 21689804 TI - Low bone accrual is associated with osteocyte apoptosis in alcohol-induced osteopenia. AB - INTRODUCTION: Alcohol is known to decrease bone mineral density (BMD) and to induce trabecular microarchitecture deterioration. However, little is known about the effects of chronic alcohol consumption on osteocytes in situ. The aim of this study was to assess the effects of a high alcohol dose on osteocytes in an alcohol-induced osteopenia model. MATERIALS AND METHODS: 24 male Wistar rats, 2 months old were separated in 2 groups: Control (C) or Alcohol (A35). The rats in the A35 group drank a beverage composed of 35% ethanol v/v mixed to water for 17 weeks. BMD was assessed by DXA, while the microarchitecture was analyzed using MUCT. Bone remodeling was studied measuring serum concentration of osteocalcin, NTx and TRAP. Bone marrow adiposity, osteoblastic lineage differentiation, osteocyte morphology and apoptosis were assessed using bright field, epifluorescence, transmission electron and confocal microscopy. RESULTS: BMD, trabecular thickness, TRAP and NTx concentration were significantly decreased in A35, while cortical thickness was thinner. There were 10 fold more cells stained with cleaved caspase-3, and 35% more empty lacunae in A35, these data indicating a large increase in osteocyte apoptosis in the A35 group. The number of lipid droplets in the marrow was increased in A35 (7 fold). Both the osteocyte apoptosis and the fat bone marrow content strongly correlated with femur BMD (p=0.0017, r = -0.72 and p=0.002, r = -0.70) and whole body BMD. CONCLUSION: These data suggest that low BMD is associated with osteocyte apoptosis and bone marrow fat content in alcohol-induced osteopenia. PMID- 21689805 TI - Surgically managed stage I endometrial cancer in a low-volume center: outcomes and complications in a military residency program. AB - OBJECTIVE: The purpose of this study was to compare operative outcomes and complications for patients with endometrial cancer who underwent staging by laparoscopy vs laparotomy in a low-volume facility. STUDY DESIGN: Research was conducted with a retrospective cohort of surgical patients with clinical stage I endometrial cancer from 2004-2009. RESULTS: Eighty-six demographically similar patients (50 laparotomy and 36 laparoscopy) were identified. Laparoscopy had less estimated blood loss (339 vs 558 mL; P = .013) and lower rates of transfusion (5.6% vs 24%; P = .02). Laparoscopy was longer (281 vs 202 minutes; P < .0005) but required a shorter hospital stay (2.2 vs 5.5 days; P < .0005). Laparoscopy patients had fewer overall complications (16.7% vs 32%; P = .11). No differences in final surgical stage or lymph node yields between the groups were present. CONCLUSION: Although a longer procedure, laparoscopy had fewer complications and shorter hospital stays. Prolonged operative time, compared with published experience, is potentially the result of unique factors in our center. PMID- 21689807 TI - Physician knowledge of and adherence to the revised breast cancer screening guidelines by the United States Preventive Services Task Force. AB - OBJECTIVE: We sought to assess knowledge and adherence to the revised US Preventive Services Task Force breast cancer screening guidelines among gynecologic care providers. STUDY DESIGN: This was a cross-sectional descriptive study based on a survey conducted among gynecologic care providers. RESULTS: Forty providers completed the survey (80%). In response to the statement "The current recommended age to initiate breast cancer screening is ... .," 48.7% of providers responded in accordance with revised guidelines. For the statement "Women between the age of 50 and 74 years old are recommended to have screening mammography," 46.2% of respondents answered in accordance. In response to the statement "The United States Preventative Services Task Force recommends teaching breast self-examination," 71.8% of providers responded in accordance. A total of 37 respondents (92.5%) stated that they were aware of the revised guidelines, but 17 (42.4%) stated that they were applicable to their patient population. CONCLUSION: Knowledge of the revised guidelines appeared to be relatively low in our provider sample. PMID- 21689808 TI - Home tonometry for management of pediatric glaucoma. AB - PURPOSE: To use iCare rebound tonometry in the home setting for documentation of diurnal intraocular pressure (IOP) fluctuations in children. DESIGN: Nonrandomized, prospective clinical study. METHODS: Pediatric ophthalmology clinic patients were recruited between October 2009 and February 2010 who were able to cooperate with IOP measurement by iCare rebound tonometry and whose caregiver was willing and able to obtain iCare measurements at home. The child's IOP was measured first by iCare tonometry followed by a second method (Goldmann applanation [GAT]). The caregiver was instructed on the use of the iCare tonometer. The subject's IOP was measured by the caregiver at home at designated time periods for at least 2 consecutive days. RESULTS: Seventeen children (17 eyes) with known or suspected glaucoma and 11 normal children were included. Excellent reliability was obtained by caregivers in 70% of iCare measurements. Mean difference between iCare and GAT in clinic was 2.0 +/- 4.0 mm Hg, P = .08. Daily IOP fluctuation occurred in both subjects with glaucoma and normal subjects. In children with known or suspected glaucoma, relative peak and trough IOPs occurred in the early morning (45%) and late evening (43.5%), respectively. Comparison of the peak IOP measured at home vs in the clinic was >6 mm Hg in 5 of 16 subjects (31%) and affected glaucoma management in several subjects. CONCLUSIONS: In selected children with glaucoma, home tonometry by iCare rebound tonometry was reliable, easily performed by caregivers, and well tolerated, and offered IOP information valuable in clinical management. PMID- 21689809 TI - Selective improvement of cognitive function in adult and aged APP/PS1 transgenic mice by continuous non-shock treadmill exercise. AB - Exercise may contribute to prevention of the cognitive decline and delay the onset of the Alzheimer's disease (AD). We evaluated the effects of continuous non shock treadmill exercise in adult and aged male APP/PS1 double mutant transgenic mice. Adult (7-8 month-old) and aged (24 month-old) male APP/PS1 transgenic and wild-type mice were randomly assigned to either sedentary or exercise groups. The exercise program included a one-week treadmill acclimatization to adapt to the novel environment. After acclimation, mice ran on a treadmill 5 days/week until sacrificed for pathological analyses. During exercise training, no tail shock was used in the exercise paradigm; only gentle tail touching was used to induce the mice to run, to minimize the stress otherwise associated with treadmill exercise. We found that the exercise program selectively improved the spatial learning and memory associated with an increase in both cholinergic neurons in the medial septum (MS)/vertical diagonal band (VDB) and serotonergic neurons in the raphe nucleus of aged APP/PS1 transgenic mice. In adult APP/PS1 transgenic mice, the exercise paradigm increased exploratory activity and reduced anxiety with an associated increase in numbers of serotonergic neurons in the raphe nucleus. In addition, the exercise paradigm also reduced amyloid-beta peptide (Abeta) levels and microglia activation, but not enough to reduce the plaque loading in the hippocampus of the APP/PS1 transgenic mice. Therefore, these findings suggest that there may exist an age-related difference in the effect of continuous non shock treadmill exercise training on AD. PMID- 21689810 TI - Synthesis of a dimeric monosaccharide lipid A mimic and its synergistic effect on the immunostimulatory activity of lipopolysaccharide. AB - Bacterial endotoxin lipopolysaccharide (LPS) is a potent immune stimulant, with the recognition of LPS and its active principal lipid A mediated by the Toll-like receptor 4 (TLR4)/MD-2 receptor complex. Due to the broad downstream implications of TLR4-mediated signalling, TLR4 ligands show great potential for immunotherapeutic manipulations. In this paper a dimeric monosaccharide lipid A mimic (3) has been designed as a potential TLR4 ligand. The chemical synthesis and the preliminary biological studies are described. Compound 3 shows a significant synergistic effect on LPS-induced ICAM-1 expression in human monocytic THP-1 cells. PMID- 21689811 TI - Word form encoding in Chinese word naming and word typing. AB - The process of word form encoding was investigated in primed word naming and word typing with Chinese monosyllabic words. The target words shared or did not share the onset consonants with the prime words. The stimulus onset asynchrony (SOA) was 100ms or 300ms. Typing required the participants to enter the phonetic letters of the target word, which correspond roughly to the onset and the rhyme of the word's syllable. Regardless of SOAs, response times were shorter in the related condition than in the unrelated condition (an onset priming effect) for word typing, but were similar for word naming. The results suggest that naming and typing in Chinese may involve somewhat different word form encoding processes (syllable driven in naming, but segment driven in typing) even though both tasks require accessing the phonological codes. It appears, then, that the kind of outputs a production system is designed to produce can flexibly and adaptively alter the way the system is organized and operates. PMID- 21689812 TI - Script-event representation in patients with severe traumatic brain injury. AB - The aim of the present study was to examine the syntactic and semantic dimensions of script representation in patients with structural damage within the cerebral cortex following a severe traumatic brain injury (TBI). Forty TBI patients and 38 healthy control subjects (HC) were asked to sort cards describing actions belonging to eight scripts according to the script to which they belonged and according to their order of execution. Each script included actions which were low in centrality and distinctiveness (NCA & NDA), and high in centrality (CA), distinctiveness (DA), and CA and DA. Actions were presented in three conditions. In the scripts with headers (SH) condition, the actions were given with each script header written on a separate card. In the scripts without headers condition (SwH) no script header was provided. In the scripts with distractor header (SDH) condition, the actions were given with each script header and a distractor header written on separate cards. The results showed that performance of TBI patients was significantly lower in all conditions. Overall, TBI patients made significantly more sequencing and sorting errors (for all types of actions) than HC subjects. These data are consistent with the view that TBI produces impairment of both the syntactic and semantic dimensions of script representation. PMID- 21689813 TI - The association between mountaintop mining and birth defects among live births in central Appalachia, 1996-2003. AB - Birth defects are examined in mountaintop coal mining areas compared to other coal mining areas and non-mining areas of central Appalachia. The study hypothesis is that higher birth-defect rates are present in mountaintop mining areas. National Center for Health Statistics natality files were used to analyze 1996-2003 live births in four Central Appalachian states (N=1,889,071). Poisson regression models that control for covariates compare birth defect prevalence rates associated with maternal residence in county mining type: mountaintop mining areas, other mining areas, or non-mining areas. The prevalence rate ratio (PRR) for any birth defect was significantly higher in mountaintop mining areas compared to non-mining areas (PRR=1.26, 95% CI=1.21, 1.32), after controlling for covariates. Rates were significantly higher in mountaintop mining areas for six of seven types of defects: circulatory/respiratory, central nervous system, musculoskeletal, gastrointestinal, urogenital, and 'other'. There was evidence that mountaintop mining effects became more pronounced in the latter years (2000 2003) versus earlier years (1996-1999.) Spatial correlation between mountaintop mining and birth defects was also present, suggesting effects of mountaintop mining in a focal county on birth defects in neighboring counties. Elevated birth defect rates are partly a function of socioeconomic disadvantage, but remain elevated after controlling for those risks. Both socioeconomic and environmental influences in mountaintop mining areas may be contributing factors. PMID- 21689814 TI - Direct transnasal cholangioscopy with ultraslim endoscopes: a one-step intraductal balloon-guided approach. AB - BACKGROUND: Direct cholangioscopy using an ultraslim endoscope is an attractive alternative to the conventional mother-baby endoscope system because it provides a single-operator platform and high-resolution image quality and allows advanced therapeutic interventions. However, biliary access is cumbersome and usually requires previous guidewire placement via retrograde cholangiography. OBJECTIVE: To evaluate the feasibility of a 1-step transnasal cholangioscopy (TNC) technique using an ultraslim endoscope with an intraductal balloon to maintain access without previous guidewire placement. DESIGN: Prospective, observational clinical feasibility study. SETTING: Single tertiary referral center. MAIN OUTCOME MEASUREMENTS: Overall procedure success rates and complications. A successful procedure was defined as one in which the endoscope was advanced into the bifurcation or stenotic segment of the biliary system. PATIENTS AND METHODS: Twenty-five patients with biliary disease and previous sphincterotomy underwent direct TNC. RESULTS: TNC was successful in 18 of the 25 patients (72%). The procedure revealed 3 common bile duct stones, 4 benign biliary strictures, 1 intraductal adenoma, and 3 cholangiocarcinomas. Eight patients underwent forceps biopsies under direct visualization, and 7 patients underwent therapeutic interventions, including argon plasma coagulation (n = 2), laser lithotripsy (n = 1), stent (n = 1), and stone extraction (n = 3). Other than 1 patient with procedure-related cholangitis, no complications were observed. LIMITATIONS: Small number of patients and no comparison with conventional cholangioscopy. CONCLUSIONS: One-step TNC with an ultraslim endoscope allows direct visual examination and therapeutic intervention in the bile ducts in the majority of patients with biliary disease. However, development of further accessory instruments will be needed to improve the success rate. PMID- 21689815 TI - Push enteroscopy has a 96% cecal intubation rate in colonoscopies that failed because of redundant colons. AB - BACKGROUND: Performing a complete colonoscopy to the cecum is important for ruling out malignancy and other lesions, but failure rates are significant with a standard colonoscope. A previous study using a push enteroscope for failed colonoscopies had a completion rate of 68.7%. OBJECTIVE: To improve the cecal intubation rate by using a newer version of a push enteroscope. DESIGN: Retrospective study at first, then a prospective study. SETTING: Single-center veterans health care system. PATIENTS: A total of 47 patients in whom the cecum was not reached with a regular adult colonoscope between January 2007 and December 2010 were included. Those with poor bowel preparation were excluded. INTERVENTIONS: Repeat colonoscopy using a new version of a push enteroscope. MAIN OUTCOME MEASUREMENTS: The rate of cecal intubation and additional pathological findings. RESULTS: The cecum or terminal ileum was reached in 45 patients (96%). Additional significant pathological findings in the previously unexamined colon were seen in 18 patients (38%). LIMITATIONS: Small sample size, lack of comparison with other endoscopes. CONCLUSIONS: Colonoscopy with a push enteroscope could be advanced to either the terminal ileum or cecum in 96% of patients, which is one of the highest known completion rates in patients in whom colonoscopy failed. Clinical management changed in all patients with additional findings. PMID- 21689816 TI - Afferent limb syndrome and delayed GI problems after pancreaticoduodenectomy for pancreatic cancer: single-center, 14-year experience. AB - BACKGROUND: There are limited data on the incidence of afferent limb syndrome and other delayed GI problems in pancreatic cancer (PaC) patients, especially among long-term survivors (>2 years). OBJECTIVE: To evaluate the incidence of afferent limb syndrome (chronic afferent limb obstruction resulting in pancreatobiliary obstruction) and delayed GI problems in PaC patients after pancreaticoduodenectomy (PD). DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: PaC patients treated with PD (N = 186) over a 14-year period (January 1995-October 2009). INTERVENTIONS: Endoscopic balloon dilation and stent placement, percutaneous biliary drainage. MAIN OUTCOME MEASUREMENTS: Incidence of afferent limb syndrome and delayed GI complications (marginal ulcers, radiation enteropathy, anastomotic strictures). RESULTS: Mean age was 63 +/- 10 years; 55% of patients were male. Afferent limb syndrome was noted in 24 patients (13%). Median time to diagnosis was 1.2 years (range 0.03 12.3 years); obstruction was primarily caused by recurrent PaC (8 patients, 33%) and radiation enteropathy (9 patients, 38%). Afferent limb syndrome was more likely to develop in patients with 2 years or longer of follow-up (n = 71, [38%]) compared with patients with 2 years or less of follow-up, after controlling for age, sex, surgery type, and adjuvant treatment (adjusted odds ratio, 4.5; 95% CI, 1.8-11.7). Other delayed GI problems included radiation enteropathy (6%), marginal ulcers (5%), anastomotic strictures (4%), cholangitis/liver abscesses (5%), and GI bleeding (6%). LIMITATIONS: Retrospective, single-center study. CONCLUSIONS: GI problems, including afferent limb syndrome, are relatively common in PaC patients after surgery and adjuvant therapy. Clinicians should recognize and effectively treat these delayed GI problems, especially in long-term survivors. PMID- 21689817 TI - Urine matrix metalloproteinases (MMPs) as biomarkers for the progression of fracture healing. AB - Whilst the majority of fractures heal normally, it is estimated that ~10% of fractures exhibit some level of delayed or impaired healing. Although radiography is the primary diagnostic tool to assess the progression of fracture healing, radiographic features only qualitatively correlate with tissue level increases in mineral content and do not quantitatively measure underlying biological processes that are associated with the progression of healing. Specific metaloproteinases have been shown to be essential to processes of both angiogenesis and mineralised cartilage resorption and bone remodelling at different phases of fracture healing. The aim of this study was to determine the potential of using a simple urine based assay of the activity of two MMPs as a means of assessing the biological progression of fracture healing through the endochondral phase of healing. Using a standard mid-diaphyseal murine model of femoral fracture, MMP9 and MMP13 proteins and enzymatic activity levels were quantified in the urine of mice across the time-course of fracture healing and compared to the mRNA and protein expression profiles in the calluses. Both urinary MMP9 and MMP13 protein and enzymatic activity levels, assessed by Western blot, zymogram and specific MMP fluorometric substrate assays, corresponded to mRNA expression and immunohistologic assays of the proteins within callus tissues. These studies suggest that urinary levels of MMP9 and MMP13 may have potential as metabolic markers to monitor the progression of fracture healing. PMID- 21689818 TI - The role of toll-like receptor-4 in the development of multi-organ failure following traumatic haemorrhagic shock and resuscitation. AB - Haemorrhagic shock and resuscitation (HS/R) following major trauma results in a global ischaemia and reperfusion injury that may lead to multiple organ dysfunction syndrome (MODS). Systemic activation of the immune system is fundamental to the development of MODS in this context, and shares many features in common with the systemic inflammatory response syndrome (SIRS) that complicates sepsis. An important advancement in the understanding of the innate response to infection involved the identification of mammalian toll-like receptors (TLRs) expressed on cells of the immune system. Ten TLR homologues have been identified in humans and toll-like receptor-4 (TLR4) has been studied most intensively. Initially found to recognise bacterial lipopolysaccharide (LPS), it has also recently been discovered that TLR4 is capable of activation by endogenous 'danger signal' molecules released following cellular injury; this has since implicated TLR4 in several non-infectious pathophysiologic processes, including HS/R. The exact events leading to multi-organ dysfunction following HS/R have not yet been clearly defined, although TLR4 is believed to play a central role as has been shown to be expressed at sites including the liver, lungs and myocardium following HS/R. Multi-organ dysfunction syndrome remains an important cause of morbidity and mortality in trauma patients, and current therapy is based on supportive care. Understanding the pathophysiology of HS/R will allow for the development of targeted therapeutic strategies aimed at minimising organ dysfunction and improving patient outcomes following traumatic haemorrhage. A review of the pathogenesis of haemorrhagic shock is presented, and the complex, yet critical role of TLR4 as both a key mediator and therapeutic target is discussed. PMID- 21689819 TI - On-line concentration sample stacking coupled with water-in-oil microemulsion electrokinetic chromatography. AB - This study describes for the first time, the ability of a normal stacking mode (NSM) on-line concentration step coupled with water-in-oil (W/O) microemulsion electrokinetic chromatography (MEEKC), using six common penicillin antibiotics (oxacillin, penicillin V, penicillin G, nafcillin, ampicillin, and amoxicillin) as test analytes. Optimization of penicillin separation in the conventional W/O MEEKC system demonstrated that change in the type and concentration of the oil phase (1-butanol) and column temperature had a pronounced effect on the separation. With the subsequent development of the NSM coupled with W/O MEEKC, improved separation and detection sensitivities were observed when an organic solvent plug (1-propanol; 1.04 cm) was placed between the W/O microemulsion and the sample solutions. This could be attributed to the solution viscosity difference between the aqueous sample zone and the organic solvent plug causing the penicillin to be stacked in this 1-propanol plug. The optimal NSM W/O MEEKC provided about 12-fold increase in detection sensitivity compared with conventional sample injection (50 mbar, 3 s). Finally, this proposed method was successfully applied in the analyses of several food samples (porcine organs) spiked with penicillin. PMID- 21689820 TI - Microcalorimetric study of the adsorption of PEGylated lysozyme on a strong cation exchange resin. AB - Adsorption of native as well as mono-, di-, and tri-PEGylated lysozyme on Toyopearl Gigacap S-650M in sodium phosphate buffer is studied by isothermal titration calorimetry and by independent adsorption equilibrium measurements at pH 6 and 25 degrees C. The production and separation of PEGylated lysozyme is discussed. Two different PEG sizes are used (5 kDa and 10 kDa) which leads to six different forms of PEGylated lysozyme which were systematically studied. The sodium chloride concentration is varied according to the elution conditions in the production process. The specific enthalpy of adsorption Deltah(p)(ads) is determined from the calorimetric and the adsorption equilibrium data. It was found to be exothermal and constant with increasing adsorber loading for native lysozyme. For all PEGylated forms there is an influence of the adsorber loading on Deltah(p)(ads) which is found to become more important with increasing PEGylation degree (total molecular weight of conjugated PEG). At low loadings the adsorption of all PEGylated lysozyme forms is exothermal. With increasing loading the adsorption becomes less exothermal and for the species with higher PEGylation degree also endothermal effects are observed at higher loadings. A thermodynamic analysis is carried out by which the enthalpic and entropic contributions to the binding constants are quantified. The findings are discussed on a molecular level. The results provide insight into the adsorption mechanisms of polymer modified proteins on chromatographic resins. PMID- 21689821 TI - Comprehensive chromatographic separations in proteomics. AB - In such a complicated field as proteomic analysis, scientists are more and more challenged in implementing separation systems capable to provide enhanced separation power, as well as sensitivity of detection for adequate identification and, to a lesser extent, quantification of the separated compounds. To address such issues, several combinations of different separation modes have been investigated in comprehensive liquid chromatographic platforms, in which the entire sample eluted from the first dimension is subjected to a secondary chromatographic separation. The different applications exploited for comprehensive LC analysis of intact or digested proteins are the focus of this review, in which advantages and disadvantages of the different columns combinations, interfaces, and operating modes are pointed out. The combination with mass spectrometry as part of the total system is stressed, and illustrated in more detail. Theoretical concerns and practical requirements will be briefly discussed, as well. PMID- 21689822 TI - On-line analysis of carbonyl compounds with derivatization in aqueous extracts of atmospheric particulate PM10 by in-tube solid-phase microextraction coupled to capillary liquid chromatography. AB - A new device for carbonyl compounds based on coupling on-line and miniaturizing both, sample pretreatment and chromatographic separation, is reported. Two capillary columns, a GC capillary column (95% methyl-5% phenyl substituted backbone, 70 cm * 0.32 mm i.d., 3 MUm film thickness) in the injection valve for in-tube solid-phase microextraction (IT-SPME) and a Zorbax SB C18 (150 mm * 0.5 mm i.d., 5 MUm particle diameter) LC capillary column were employed. Different combinations of IT-SPME and derivatization using 2,4-dinitrophenylhydrazine (DNPH) were examined for mixtures containing 15 carbonyl compounds (aliphatic, aromatic and unsaturated aldehydes and ketones). A screening analysis of aqueous extracts of atmospheric particulate PM(10) was carried out. Moreover, the possibility of coupling IT-SPME and conventional liquid chromatography is also tested. Derivatization solution and IT-SPME coupled to capillary liquid chromatography provided the best results for achieving the highest sensitivity for carbonyl compounds in atmospheric particulate analysis. Detection limits (LODs) using a photodiode array detector (DAD) were ranged from 30 to 198 ng L( 1), improving markedly those LODs reported by conventional SPME-LC-DAD. PMID- 21689823 TI - Intact protein separation by chromatographic and/or electrophoretic techniques for top-down proteomics. AB - Mass spectrometry used in combination with a wide variety of separation methods is the principal methodology for proteomics. In bottom-up approach, proteins are cleaved with a specific proteolytic enzyme, followed by peptide separation and MS identification. In top-down approach intact proteins are introduced into the mass spectrometer. The ions generated by electrospray ionization are then subjected to gas-phase separation, fragmentation, fragment separation, and automated interpretation of mass spectrometric and chromatographic data yielding both the molecular weight of the intact protein and the protein fragmentation pattern. This approach requires high accuracy mass measurement analysers capable of separating the multi-charged isotopic cluster of proteins, such as hybrid ion trap-Fourier transform instruments (LTQ-FTICR, LTQ-Orbitrap). Front-end separation technologies tailored for proteins are of primary importance to implement top-down proteomics. This review intends to provide the state of art of protein chromatographic and electrophoretic separation methods suitable for MS coupling, and to illustrate both monodimensional and multidimensional approaches used for LC-MS top-down proteomics. In addition, some recent progresses in protein chromatography that may provide an alternative to those currently employed are also discussed. PMID- 21689824 TI - Synthesis and characterization of pore size-tunable magnetic mesoporous silica nanoparticles. AB - Magnetic mesoporous silica nanoparticles (M-MSNs) are emerging as one of the most appealing candidates for theranostic carriers. Herein, a simple synthesis method of M-MSNs with a single Fe(3)O(4) nanocrystal core and a mesoporous shell with radially aligned pores was elaborated using tetraethyl orthosilicate (TEOS) as silica source, cationic surfactant CTAB as template, and 1,3,5 triisopropylbenzene (TMB)/decane as pore swelling agents. Due to the special localization of TMB during the synthesis process, the pore size was increased with added TMB amount within a limited range, while further employment of TMB lead to severe particle coalescence and not well-developed pore structure. On the other hand, when a proper amount of decane was jointly incorporated with limited amounts of TMB, effective pore expansion of M-MSNs similar to that of analogous mesoporous silica nanoparticles was realized. The resultant M-MSN materials possessed smaller particle size (about 40-70 nm in diameter), tunable pore sizes (3.8-6.1 nm), high surface areas (700-1100 m(2)/g), and large pore volumes (0.44 1.54 cm(3)/g). We also demonstrate their high potential in conventional DNA loading. Maximum loading capacity of salmon sperm DNA (375 mg/g) was obtained by the use of the M-MSN sample with the largest pore size of 6.1 nm. PMID- 21689825 TI - Evaluation of an indirect enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies against Anaplasma phagocytophilum in sheep. AB - An indirect enzyme-linked immunosorbent assay (ELISA) for detection of antibodies against Anaplasma phagocytophilum in ovine serum samples was evaluated. The assay used purified A. phagocytophilum grown in tick cell cultures as antigen. Serum samples were diluted 1 in 200 and binding was detected with anti-sheep IgG conjugated to horseradish peroxidase. All tests were carried out in the presence of positive and negative control samples. Optical density (OD) values obtained for each test sample at 490 nm were used to calculate percentage positivity (PP) of each sample based on the ratio of the OD of the test sample that of the positive reference sample. Known negative samples (n=69) obtained from uninfected sheep bred and maintained in a tick-free environment and subsequently shown to be susceptible to A. phagocytophilum were used to establish the cut-off point between negative and positive samples and to establish the specificity of the test. Serum samples obtained from 92 animals 14-21 days after infection were used to establish the sensitivity of the test. Using a cut-off point of 20PP (mean+2 standard deviations of the PP of 69 control samples) the test was shown to have a sensitivity of 84.8% and a specificity of 95.7%. Lowering the cut-off point to 15PP increased the sensitivity to 94.6%, but reduced the specificity to 92.8%. PMID- 21689826 TI - Equid herpesvirus type-1 exhibits neurotropism and neurovirulence in a mouse model. AB - Intranasal inoculation of equid herpesvirus type-1 (EHV-1) Brazilian strains A4/72 and A9/92 induced an acute and lethal infection in four different inbred mouse strains. Clinical and neurological signs appeared between the 2nd and 3rd day post inoculation (dpi) and included weight loss, ruffled fur, a hunched posture, crouching in corners, nasal and ocular discharges, dyspnoea, dehydration and increased salivation. These signs were followed by increased reactivity to external stimulation, seizures, recumbency and death. The virus was recovered consistently from the brain and viscera of all mice with neurological signs. Histopathological changes consisted of leptomeningitis, focal haemorrhage, ventriculitis, neuronal degeneration and necrosis, neuronophagia, non-suppurative inflammation, multifocal gliosis and perivascular infiltration of polymorphonuclear and mononuclear cells. Immunohistochemical examination demonstrated that EHV-1 strains A4/72 and A9/92 replicated in neurons of the olfactory bulb, the cortex and the hippocampus. In contrast, mice inoculated with the EHV-1 Brazilian strain A3/97 showed neither weight loss nor apparent clinical or neurological signs; however, the virus was recovered consistently from their lungs at 3 dpi. These three EHV-1 strains showed distinct degrees of virulence and tissue tropism in mice. EHV-1 strains A4/72 and A9/92 exhibited a high degree of central nervous system tropism with neuroinvasion and neurovirulence. EHV-1 strain A3/97 was not neurovirulent despite being detected in the brains of infected BALB/c nude mice. These findings indicate that several inbred mouse strains are susceptible to neuropathogenic EHV-1 strains and should be useful models for studying the pathogenesis and mechanisms contributing to EHV-induced myeloencephalopathy in horses. PMID- 21689827 TI - Neosporosis in a captive Parma wallaby (Macropus parma). AB - Infection with Neospora caninum has been diagnosed in a variety of animal species; however, reports in marsupials are rare. A captive Parma wallaby (Macropus parma) died suddenly and was subjected to necropsy examination. The main finding was necrotizing myocarditis associated with protozoan parasites. The protozoa were identified as N. caninum by use of immunohistochemistry and partial gene sequence analysis. Neospora and Toxoplasma should be considered a possible cause of disease in captive marsupials. Further work is required to determine whether marsupials are an accidental or terminal host of this protozoan in order to better understand the host-parasite relationship. PMID- 21689828 TI - Effects of methylphenidate on olfaction and frontal and temporal brain oxygenation in children with ADHD. AB - OBJECTIVE: Olfaction and attention-deficit-/hyperactivity disorder (ADHD) are mediated by dopamine metabolism and fronto-temporal functioning converging in recent findings of increased olfactory sensitivity in children with ADHD modulated by methylphenidate (MPH) and altered frontal and temporal oxygenation in adults with ADHD. METHOD: We investigated olfactory sensitivity, discrimination, and identification (Sniffin' Sticks) in 27 children and adolescents with ADHD under chronic MPH medication and after a wash-out period of at least 14 half-lives in balanced order and 22 controls comparable for handedness, age, and intelligence. In addition, inferior frontal and temporal oxygenation was measured by means of functional near-infrared spectroscopy (fNIRS) during the presentation of 2-phenylethanol. Group differences in regard to sex distribution were statistically controlled for by analysis of covariance. RESULTS: Patients did not differ from controls in any olfactory domain under treatment with MPH. Cessation of medication led to a significant increase in olfactory discrimination. Controls displayed typical inferior frontal and temporal brain activity in response to passive olfactory stimulation, while brain oxygenation was diminished in the patient group when assessed without medication. Under medication ADHD patients showed a trend for a normalisation of brain activity in the temporal cortex. CONCLUSIONS: The here reported effects of MPH cessation on olfactory discrimination and frontal and temporal oxygenation along with previous findings of increased olfactory sensitivity in medication-naive ADHD children and its normalisation under chronic MPH treatment lead to the conclusion that MPH exerts differential chronic effects vs. acute cessation effects on altered olfactory function in ADHD. These effects are most probably mediated by modulation of the dopaminergic system. PMID- 21689829 TI - Apathy and depression scales in Parkinson's disease: are they good enough? AB - The choice of a scale has important implications for the results of clinical research, including epidemiological and treatment studies. In addition to the requirements for any clinical scale, evaluation of rating scales for depression and apathy in Parkinson's disease (PD) faces additional challenges, reflecting the overlap of syndromes, controversies on the concept particularly of apathy, fluctuations related to medication, and difficulties in assessment. However, a number of rating scales are available which have been assessed for use in patients with PD, and the evidence for the use of these scales is discussed. A number of scales fulfil the basic requirements but further studies on their properties are required. Scales for screening need to have different properties than scales for rating severity. Overall, there is no perfect scale, but the choice of scale needs to take into account clinimetric properties, validity in the sample examined, content and purpose. PMID- 21689830 TI - Multiple paraneoplastic syndromes: myasthenia gravis, vitiligo, alopecia areata, and oral lichen planus associated with thymoma. AB - Thymomas are associated with paraneoplastic autoimmune diseases at a high frequency. It is rare that four paraneoplastic autoimmune disorders co-occur in a single patient. We describe a thymoma patient with diagnoses of myasthenia gravis, vitiligo, alopecia areata, and oral lichen planus associated with a thymoma. After thymectomy, the weakness, vitiligo, alopecia and mucocutaneous lesions were improving progressively, possibly implicating the thymoma in initiating these autoimmune conditions. We believe that this is the first report of this particular combination of multiple paraneoplastic syndromes associated with thymoma. PMID- 21689832 TI - Peripheral Lewy body pathology in Parkinson's disease and incidental Lewy body disease: four cases. AB - The accumulation of Lewy pathology (LP) within autonomic nervous system tissues has received increased attention recently as a possible induction site for Lewy neurodegeneration and a possible source of biopsy material for biomarkers of early Parkinson's disease (PD). Here, we describe LP accumulation within various tissues involving peripheral autonomic nervous system neurons in three PD cases and one case of incidental Lewy body disease. Findings highlight the value of examining pathology within functional neuroanatomical systems and particularly the importance of Lewy neurites (LNs) in the pathophysiology of PD. PMID- 21689833 TI - 6th International Conference on Marine Pollution and Ecotoxicology. PMID- 21689831 TI - Two novel mutations in PEO1 (twinkle) gene associated with chronic external ophthalmoplegia. AB - Maintenance and replication of mitochondrial DNA require the concerted action of several factors encoded by nuclear genome. The mitochondrial helicase Twinkle is a key player of replisome machinery. Heterozygous mutations in its coding gene, PEO1, are associated with progressive external ophthalmoplegia (PEO) characterised by ptosis and ophthalmoparesis, with cytochrome c oxidase (COX) deficient fibres, ragged-red fibres (RRF) and multiple mtDNA deletions in muscle. Here we describe clinical, histological and molecular features of two patients presenting with mitochondrial myopathy associated with PEO. PEO1 sequencing disclosed two novel mutations in exons 1 and 4 of the gene, respectively. Although mutations in PEO1 exon 1 have already been described, this is the first report of mutation occurring in exon 4. PMID- 21689834 TI - At-sea detection of derelict fishing gear in the North Pacific: an overview. AB - There are numerous known impacts of derelict fishing gear (DFG) to marine ecosystems and safe navigation around the world. To mitigate these impacts, the preemptive detection and removal of DFG at sea are being pursued. This special issue focuses on the North Pacific Ocean because of historic and ongoing research on DFG in the area, particularly as it relates to the Hawaiian Archipelago. In order to develop an effective detection strategy, information and expertise from three disciplines must be integrated: marine debris, oceanography, and remote sensing technology. Building upon results and discussions during a workshop held in December 2008, this special issue provides both results of original research and review papers, pursuing each discipline as it relates to DFG and outlining a multi-faceted strategy to effectively detect DFG at sea. This strategy serves as a roadmap, taking us closer to realizing the goal of detecting and removing DFG at sea. PMID- 21689835 TI - Study of peripheral blood cell populations involved in the immune response of goats naturally infected with Mycobacterium caprae. AB - Tuberculosis in goats caused by Mycobacterium bovis and Mycobacterium caprae has noteworthy sanitary and economic implications. Current diagnostic assays are based on cellular immunity and although they have demonstrated a high sensitivity, some animals remain undetected. In the present study, flow cytometry has been used to determine changes in CD4+, CD8+ and CD25+ T cell populations in peripheral blood from naturally infected goats. Proportion of lymphocytes producing PPD-specific interferon-gamma (IFN-gamma) was calculated and an ELISA for detection of PPD-specific IFN-gamma was performed to measure the cytokine in plasma. The infected goats showed percentages of CD4+ T cells between 27.31% and 47.23% and there were not significant differences (p=0.113) with the non-infected control goats although the mean percentage was lower in this group. Regarding CD8+ T cells, a higher percentage was observed in healthy goats compared to controls (p=0.081). The mean percentage of lymphocytes expressing CD25 without antigen stimulation (30.65+/-3.91) was higher in lesion and/or culture-positive animals than in the controls (21.84+/-1.21; p=0.053). The percentage of CD4+/IFN+ T cell population stimulated with bovine PPD was a reliable marker of infection, since the mean percentage in the infected goats was significantly higher than in the controls (p<0.05). Tuberculosis in goats caused by M. caprae induced changes in cellular populations similar to those described for M. bovis in cattle. PMID- 21689836 TI - Stable cavitation induces increased cytoplasmic calcium in L929 fibroblasts exposed to 1-MHz pulsed ultrasound. AB - An increase in cytoplasmic calcium (Ca(2+) increase) is a second messenger that is often observed under ultrasound irradiation. We hypothesize that cavitation is a physical mechanism that underlies the increase in Ca(2+) in these experiments. To control the presence of cavitation, the wave type was controlled in a sonication chamber. One wave type largely contained a traveling wave (wave type A) while the other wave type largely contained a standing wave (wave type B). Fast Fourier transform (FFT) analysis of a sound field produced by the wave types ascertained that stable cavitation was present only under wave type A ultrasound irradiation. Under the two controlled wave types, the increase in Ca(2+) in L929 fibroblasts was observed with fluorescence imaging. Under wave type A ultrasound irradiation, an increase in Ca(2+) was observed; however, no increase in Ca(2+) was observed under wave type B ultrasound irradiation. We conclude that stable cavitation is involved in the increase of Ca(2+) in cells subjected to pulsed ultrasound. PMID- 21689837 TI - Variability of fresh- and salt-water marshes characteristics on the west coast of France: a spatio-temporal assessment. AB - The degradation of water quality and the multiple conflicts of interest between users make marsh restoration very important. A Water Quality Evaluation System (WQES) was developed for river systems by the European Water Framework Directive (WFD). Some form of biologically-based, habitat-specific reference standard seems absolutely essential for wise management and stewardship of marsh ecosystems. The goal of this study was to develop a statistical method to define and to characterize a water body typology for drained marshes of the Charente-Maritime wetlands on the French Atlantic coast, placing particular emphasis on environmental factors as hydraulic functioning, human activities and pedological substratum. The Charente-Maritime marshes represent a good field study because of his high diversity of types of marshes and of anthropogenic activities in a restrictive area thus erasing spatial climatic effect (latitude effect). The statistical method developed here had permitted to define and characterize 12 different water bodies, 7 in freshwater (F1 to F7) and 5 in salt water marshes for the Charente-Maritime area. This typology demonstrated an important link between the size catchment area, nitrate concentrations, and leaching of precipitation from cultured soils. Even though the Charente-Maritime marshes are strongly impacted by humans, they may still retain the ability to remove nitrate. The increasing gradient of water renewal in the freshwater marshes from F1 to F7 explained the decreasing gradient of eutrophication. A better management of the hydrodynamic of the marshes can avoid eutrophication risk on the coastal sea area. Reliance on the WFD parameter set necessarily placed limits on the kinds of interpretations that could be made and on the study's potential contribution to the basic science of marshes. Ecologically-based insights regarding both external flows (links between ecosystems, meta-ecosystem theory) and internal flows (structure of the planktonic food web) seem an essential prerequisite for further advances in the study of marsh ecosystems. PMID- 21689838 TI - Detection of the human specific Bacteroides genetic marker provides evidence of widespread sewage contamination of stormwater in the urban environment. AB - Human sewage contamination of surface waters is a major human health concern. We found urban stormwater systems that collect and convey runoff from impervious surfaces act as a conduit for sewage originating from breeches in sanitary sewer infrastructure. A total of 828 samples at 45 stormwater outfalls were collected over a four-year period and assessed by culture based methods, PCR, and quantitative PCR (qPCR) to test for traditional and alternative indicators of fecal pollution. All outfalls had the HF183 (human) Bacteroides genetic marker detected in at least one sample, suggesting sewage contamination is nearly ubiquitous in the urban environment. However, most outfalls were intermittently positive, ranging from detection in 11%-100% of the samples. Positive results did not correlate with seasonality, rainfall amounts, or days since previous rainfall. Approximately two-thirds of the outfalls had high (>5000 copy number, i.e. CN, per 100 ml) or moderate levels (1000-5000 CN per 100 ml) of the human Bacteroides genetic marker. Escherichia coli (E. coli) and enterococci levels did not correlate to human Bacteroides. A total of 66% of all outfall samples had standard fecal indicator levels above 10,000 CFU per 100 ml. A tiered assessment using this benchmark to identify high priority sites would have failed to flag 35% of the samples that had evidence of sewage contamination. In addition, high fecal indicators would have flagged 33% of samples as priority that had low or no evidence of sewage. Enteric virus levels in one outfall with high levels of the human Bacteroides genetic marker were similar to untreated wastewater, which illustrates stormwater can serve as a pathway for pathogen contamination. The major source of fecal pollution at four of five river sites that receive stormwater discharge appeared to be from sewage sources rather than non-human sources based on the ratios of human Bacteroides to total Bacteroides spp. This study shows the feasibility and benefits of employing molecular methods to test for alternative indicators of fecal pollution to identify sewage sources and potential health risks and for prioritization of remediation efforts. PMID- 21689839 TI - Phenanthrene sorption/desorption sequences provide new insight to explain high sorption coefficients in field studies. AB - The sorption coefficients obtained in field investigation vary greatly from laboratory sorption experiments. The possible reasons were discussed in literature. Observing the commonly reported desorption hysteresis, this study proposed that the unclear sorption history of the field study could also result in the diverse sorption coefficients. This study conducted a comparative study regarding phenanthrene sorption/desorption behavior in low-concentration multi time sorption process and the commonly applied high-concentration one-time sorption process. The sorption coefficients determined during the desorption process were much higher than those at sorption process. Thus, the prediction of sorption coefficient should be related with sorption history. Desorption hysteresis was increased with increased equilibration time and decreased solid phase concentration. In addition, although the apparent contact time between sorbate and sorbent was shorter for low-concentration multi-time sorption, the desorption hysteresis was much stronger, which consequently result in higher sorption coefficients in comparison to high-concentration one-time sorption. Pore swelling or diffusion-controlled sorption kinetics could not explain this phenomenon. This study calls for research attention on sorption history, especially for field investigations. PMID- 21689840 TI - Principle and applications of microbubble and nanobubble technology for water treatment. AB - In recent years, microbubble and nanobubble technologies have drawn great attention due to their wide applications in many fields of science and technology, such as water treatment, biomedical engineering, and nanomaterials. In this paper, we discuss the physics, methods of generation of microbubbles (MBs) and nanobubbles (NBs), while production of free radicals from MBs and NBs are reviewed with the focuses on degradation of toxic compounds, water disinfection, and cleaning/defouling of solid surfaces including membrane. Due to their ability to produce free radicals, it can be expected that the future prospects of MBs and NBs will be immense and yet more to be explored. PMID- 21689841 TI - Association between testicular Aryl hydrocarbon Receptor levels and idiopathic male infertility: a case-control study in Iran. AB - Increased urinary concentrations of Polycyclic Aromatic Hydrocarbons (PAHs) and their metabolites are associated with increased risk of unexplained infertility in males. The toxicity of PAHs and dioxins are exclusively mediated through Aryl hydrocarbon Receptor (AhR). AhR overexpression contributes to the loss of normal ovarian function in polluted environments but its expression level in unexplained male infertility has remained unclear. This study aimed to compare the differential testicular levels of AhR and its interactions with other fundamental genes (ER, AR, PgR and MMP9) in a case control study. To conduct the immunohistochemical studies, 29 unexplained infertile and 10 fertile males were selected retrospectively from Jahad pathology center of Tehran from 2007 to 2009. Differential expression of AhR in Leydig, Sertoli, spermatogonia, spermatocyte, spermatid, and spermatozoa cells was determined and AhR association with other genes was compared between cases and controls. Higher levels of AhR in Leydig cells (p=0.024), Sertoli cells (p=0.041) and spermatid cells (p=0.028) of infertile men have emphasized the susceptibility of these cells to environmental induced impaired testicular functions. Moreover 85% of infertile cases showed coexpression of AhR and MMP9 in their Leydig cells (p=0.02). Inactivation of ER, PgR and AR in AhR positive testicular cells suggests the antagonistic interactions between AhR ligands and sex steroid hormones receptors. It seems that unexplained male infertility could be originated from environmental AhR ligands which overexpress the AhR in Leydig cells, downregulate the expression of sex steroid receptors and upregulate the MMP9 in Leydig cells as the main testicular target cell of AhR ligands. PMID- 21689842 TI - Influence of temperature on styrene emission from a vinyl ester resin thermoset composite material. AB - Composite materials made with vinyl ester resins are lighter, stronger and corrosion resistant compared to most metals, and are increasingly being used as building materials and in public transportation. Styrene monomer is used as both a diluent and strengthener in the production of vinyl ester resin (VER) composites. Some researchers contend that free styrene in VER composites is available to diffuse out of the material into air, perhaps leading to adverse health effects via inhalation exposures in humans, yet there is no known data on styrene emissions from these materials in the literature. In this study, a typical VER composite made with resin containing 38% by weight styrene, reinforced with E-glass fiber and formed using a vacuum assisted resin transfer method was characterized for styrene emissions by environmental test chamber (ETC) methodology. Styrene concentrations in the ETC were measured over a temperature range of 10 to 50 degrees C. Initial evaporative styrene emissions increase with increasing temperature. There is a nearly linear relationship in the total mass of styrene emitted and emission factor as emissions increase with increasing temperature. Styrene emission factors appear to vary for different materials, which could indicate more complex processes or the influence of material physical properties on emission rates. These results can be used to validate and improve mass transfer emission models for the prediction of volatile organic compound concentrations in indoor environments. PMID- 21689843 TI - Global and regional analysis of climate and human drivers of wildfire. AB - Identifying and quantifying the statistical relationships between climate and anthropogenic drivers of fire is important for global biophysical modelling of wildfire and other Earth system processes. This study used regression tree and random forest analysis on global data for various climatic and human variables to establish their relative importance. The main interactions found at the global scale also apply regionally: greatest wildfire burned area is associated with high temperature (> 28 degrees C), intermediate annual rainfall (350-1100 mm), and prolonged dry periods (which varies by region). However, the regions of highest fire incidence do not show clear and systematic behaviour. Thresholds seen in the regression tree split conditions vary, as do the interplay between climatic and anthropogenic variables, so challenges remain in developing robust predictive insight for the most wildfire-threatened regions. Anthropogenic activities alter the spatial extent of wildfires. Gross domestic product (GDP) density is the most important human predictor variable at the regional scale, and burned area is always greater when GDP density is minimised. South America is identified as a region of concern, as anthropogenic factors (notably land conversions) outweigh climatic drivers of wildfire burned area. PMID- 21689844 TI - Caloric restriction improves coagulation and inflammation profile in obese mice. AB - To evaluate associations between adiposity and coagulation or inflammation profile, obese wild-type C57Bl/6 mice were subjected to drastic caloric restriction by switching from a high fat diet to restricted normal chow. After 6 weeks, total body weights as well as subcutaneous and gonadal adipose tissue mass were markedly reduced, associated with adipocyte hypotrophy (all p<0.001). Weight reduction was associated with markedly reduced plasma levels of plasminogen activator inhibitor-1, Factor VII and Factor VIII. Reduced oxidative stress and inflammation following weight reduction is supported by significantly lower expression in adipose tissues of pro-inflammatory interleukin-6, higher expression of anti-oxidant catalase, superoxide dismutase 1 and glutathione peroxidase 1, and lower plasma levels of C-reactive protein. Furthermore, reduced levels of leptin and enhanced levels of adiponectin were observed, whereas cholesterol and triglyceride levels were reduced. The content of structurally intact collagen fibers was significantly higher in subcutaeneous and gonadal adipose tissues after caloric restriction. Thus, caloric restriction and drastic weight loss in obese mice is associated with improved plasma coagulation profile and with reduced oxidative stress and inflammation in the adipose tissues. PMID- 21689845 TI - Patterns of management of urethral stricture disease in the Veterans Affairs system. AB - OBJECTIVES: To describe the number of urethral dilations, urethrotomies, and urethroplasties performed on men with a diagnosis of urethral stricture disease seeking care in the Veterans Affairs (VA) health care system in southern California and southern Nevada over a 5-year period. To date, few health services research studies have evaluated patterns of care for urethral stricture disease using national datasets. METHODS: We analyzed stricture treatment for male veterans with an ICD-9 diagnosis code for urethral stricture in the National Patient Care Database (NPCD). Encounters for urethral stricture procedures performed were identified based on the presence of Physicians Current Procedural Terminology Coding System (4th edition, CPT-4) codes for treatments performed during the fiscal years 2002-2006. RESULTS: A total of 1457 men carried a diagnosis of urethral stricture disease during the index time period. Of these, 333 men (23%) underwent 431 procedures. Of the 216 men who underwent urethral dilations, 170 (79%) underwent only 1 procedure and 26 (12%) underwent 2 procedures. Of the 79 men who underwent urethrotomy, 76 (96%) underwent 1 procedure. Sixteen men (5%) underwent a urethroplasty, 8 of whom underwent a perineal urethrostomy. CONCLUSIONS: The vast majority of men treated for stricture disease underwent only 1 such procedure over a 5-year time period. Further research is required to investigate whether this is a quality-of-care issue or patients refusing intervention. It is possible that some patients may be temporized for a significant period with dilation/urethrotomy, whereas those with rapid recurrence require early urethroplasty. PMID- 21689846 TI - Contemporary use of nephron-sparing surgery for children with malignant renal tumors at freestanding children's hospitals. AB - OBJECTIVE: It is widely accepted that, when feasible, nephron-sparing surgery (NSS) is preferable to radical nephrectomy (RN) for treatment of renal tumors in adults. However, RN is more frequently used in children. We sought to compare in hospital outcomes after NSS and RN for malignant pediatric renal tumors. MATERIAL AND METHODS: The pediatric health information system (PHIS) combines data from more than 40 North American pediatric hospitals. We queried PHIS to identify children with malignant renal tumors who underwent surgery from 2003 to 2009. We examined whether outcomes (complication rates, cost, and length of stay) differed by procedure type. Multivariate regression models were used to adjust for confounding, and generalized estimating equations were used to adjust for hospital clustering. RESULTS: We identified 1235 children with renal tumors who underwent RN (91%) or NSS (9%). Patients undergoing RN and NSS had similar median comorbidity scores (P = .98), hospital lengths of stay (each 6.0 days, P = .54), in-hospital charges, ($25,700 vs $37,000, P = .11), and surgical complication rates (16.4 vs 20.5%, P = .24). These outcomes remained similar after adjusting for other patient and hospital factors. CONCLUSIONS: Most children with malignant renal tumors treated at children's hospitals undergo RN. RN and NSS use were not significantly different in terms of their length of hospital stay, in-hospital charges, and complication rates. Although oncological outcomes are lacking, these data suggest that NSS may be performed in selected children with malignant renal tumors without significantly increasing their hospital charges, length of stay, or surgical complication rates. PMID- 21689847 TI - Influence of prostatic calculi on lower urinary tract symptoms in middle-aged men. AB - OBJECTIVES: To investigate the incidence and echographic patterns of prostatic calculi, and to determine whether the presence of prostatic calculi is an associated factor for moderate lower urinary tract symptom (LUTS) in middle-aged men. METHODS: Between October 2007 and June 2010, 1575 consecutive ostensibly healthy Korean men aged 40-59 years visited the health promotion center for a routine check-up and were enrolled. All men had a complete history, physical examination, and an international prostate symptom score (IPSS) questionnaire. Based on the echo patterns of the prostatic calculi by transrectal ultrasound, the men were divided in 3 groups-no calculi; type A calculi (discrete, small echoes); and type B calculi (large masses of multiple echoes, much coarser). RESULTS: In total, 1563 men were included. Measurable calcifications in the prostate gland were found in 799 men (51.1%). Small calculi (type A) were found in 615 men (39.3%) and large calculi (type B) were found in 184 men (11.8%). In the multivariate analysis, old age (>50 years), obesity (body mass index >25 kg/m(2)), and large calculi (type B) were significant associated factors for higher IPSS >=8. The likelihood of IPSS being >=8 was related to large calculi group with a 1.784-fold increase in risk over no and small calculi (P <.001). CONCLUSIONS: The presence of large prostatic calculi is a significant associated factor of moderate LUTS, whereas there was no statistical difference in IPSS analyzed between the no calculi and small calculi group. PMID- 21689848 TI - A randomised controlled trial testing the feasibility and efficacy of a physical activity behavioural change intervention in managing fatigue with gynaecological cancer survivors. AB - OBJECTIVE: To determine the feasibility and efficacy of a physical activity behavioural change intervention in managing cancer-related fatigue among gynaecological cancer survivors during and post anti-cancer treatments. METHODS: A two arm, single blind, randomised controlled trial was conducted within the Northern Ireland regional Cancer Centre. Thirty three sedentary gynaecological cancer survivors (stage I-III; <=3 years post diagnosis), experiencing cancer related fatigue (mild-severe) took part. Participants were randomly assigned to a behavioural change, moderate intensity physical activity intervention (n=16) or a Contact Control group (n=17). The primary outcome was fatigue (Multidimensional Fatigue Symptom Inventory-Short Form and Functional Assessment in Chronic Illness Therapy-Fatigue subscale). Secondary outcomes included quality of life, physical functioning, positive and negative affect, depression, body composition, sleep dysfunction and self-reported physical activity. Feasibility was assessed based on the recruitment rate, programme and physical activity adherence and participants' programme evaluation, including optional focus groups (n=16). RESULTS: Twenty five percent of eligible women took part (33/134). Participants were 8.7 (SD=9.1) months post diagnosis, with a mean age of 53 (SD=10.3) years. The majority of the sample had a diagnosis of ovarian (n=12) or endometrial cancer (n=11). Significant differences favouring the intervention group were observed for fatigue at 12 weeks and 6 months follow-up (12 week: mean difference=-11.06; 95% confidence interval (CI)=-21.89 to -0.23; effect size (d)=0.13; p=0.046; 6 month: mean difference=-19.48; 95% CI=-19.67 to -19.15; effect size (d)=0.20; p=0.01). A mean of 10 calls (SD=1.2 calls) were delivered to the Physical Activity Group, and 10 (SD=1.6 calls) to the CC group. The intervention was positively perceived based on exit questionnaire and focus group findings. CONCLUSIONS: A physical activity behavioural change intervention for gynaecological cancer survivors is feasible in terms of participants' programme adherence and evaluation, and the intervention demonstrates improvements in fatigue. However, confirmation in the form of a larger fully powered RCT is warranted. PMID- 21689849 TI - Redundant ability of phagocytes to kill Aspergillus species. PMID- 21689853 TI - Nuclear factor (NF)-kappaB controls expression of the immunoregulatory glycan binding protein galectin-1. AB - The inflammatory response is a self-limiting process which involves the sequential activation of signaling pathways leading to the production of both pro and anti-inflammatory mediators. Galectin-1 (Gal-1), an endogenous lectin found in peripheral lymphoid organs and inflammatory sites, elicits a broad spectrum of biological functions predominantly by acting as a potent anti-inflammatory factor and as a suppressive agent for T-cell responses. However, the molecular pathways underlying Gal-1 expression and function remain poorly understood. Here we identified a regulatory loop linking Gal-1 expression and function to NF-kappaB activation. NF-kappaB-activating stimuli increased Gal-1 expression on T cells, an effect which could be selectively prevented by inhibitors of NF-kappaB signaling. Accordingly, transient transfection of the p65 subunit of NF-kappaB was sufficient to induce high Gal-1 expression. Using in silico studies and chromatin immunoprecipitation analysis we have identified a functional NF-kappaB binding site within the first intron of the LGALS1 gene. In addition, our results show that exogenous Gal-1 can attenuate NF-kappaB activation, as shown by inhibition of IkappaB-alpha degradation induced by pro-inflammatory stimuli, higher cytoplasmic retention of p65, lower NF-kappaB DNA binding activity and impaired transcriptional activation of target genes. The present study suggest a novel regulatory loop by which NF-kappaB induces expression of Gal-1, which in turn may lead to negative control of NF-kappaB signaling. PMID- 21689854 TI - Effects of a long-term military mission on arterial stiffness, inflammation markers, and vitamin D level. PMID- 21689850 TI - Gene polymorphisms, breast-feeding, and development of food sensitization in early childhood. AB - BACKGROUND: The effect of breast-feeding on the development of allergic disease is uncertain. There are no data that show whether this relationship varies by individual genotypes. OBJECTIVE: We sought to evaluate the effect of breast feeding and gene-breast-feeding interactions on food sensitization (FS) in a prospective US birth cohort. METHODS: This study included 970 children who were prospectively followed since birth. Breast-feeding history was obtained from a standardized questionnaire interview. FS was defined as a specific IgE level of 0.35 kU(A)/L or greater to any of 8 common food allergens. Eighty-eight potentially functional single nucleotide polymorphisms (SNPs) were genotyped from 18 genes involved in innate immunity or T(H)1/T(H)2 balance. Logistic regression models were used to test the effects of breast-feeding and gene-breast-feeding interactions on FS, with adjustment for pertinent covariates. RESULTS: Children who were ever breast-fed (n = 739), including exclusively breast-fed children, were at a 1.5 (95% CI, 1.1-2.1; P = .019) times higher risk of FS than never breast-fed children (n = 231). This association was significantly modified by rs425648 in the IL-12 receptor beta1 gene (IL12RB1; P for interaction = .0007): breast-feeding increased the risk of FS (odds ratio, 2.0; 95% CI, 1.4-3.1; P = .0005) in children carrying the GG genotype but decreased the risk (odds ratio, 0.6; 95% CI, 0.3-1.4; P = .252) in children carrying the GT/TT genotype. Similar interactions were observed for SNPs in the Toll-like receptor 9 (TLR9; rs352140) and thymic stromal lymphopoietin (TSLP; rs3806933) genes. The interaction between the combined genotypes of the 3 SNPs and breast-feeding on FS was even stronger (P for interaction < 10-5). CONCLUSION: Our data suggest that the effect of breast-feeding on FS was modified by SNPs in the IL12RB1, TLR9, and TSLP genes both individually and jointly. Our findings underscore the importance of considering individual genetic variations in assessing this relationship. PMID- 21689852 TI - The organization of narrative discourse in Lewy body spectrum disorder. AB - Narrative discourse is an essential component of day-to-day communication, but little is known about narrative in Lewy body spectrum disorder (LBSD), including Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB). We performed a detailed analysis of a semi-structured speech sample in 32 non-aphasic patients with LBSD, and we related their narrative impairments to gray matter (GM) atrophy using voxel-based morphometry. We found that patients with PDD and DLB have significant difficulty organizing their narrative speech. This was correlated with deficits on measures of executive functioning and speech fluency. Regression analyses associated this deficit with reduced cortical volume in inferior frontal and anterior cingulate regions. These findings are consistent with a model of narrative discourse that includes executive as well as language components and with an impairment of the organizational component of narrative discourse in patients with PDD and DLB. PMID- 21689855 TI - First-line evaluation of coronary artery disease with coronary calcium scanning or exercise electrocardiography. AB - BACKGROUND: Although conventional (CAG) and computed tomography angiography (CTA) are reliable diagnostic modalities for exclusion of obstructive coronary artery disease (CAD), they are costly and with considerable exposure to radiation and contrast media. We compared the accuracy of coronary calcium scanning (CCS) and exercise electrocardiography (X-ECG) as less expensive and non-invasive means to rule out obstructive CAD. METHODS: In a rapid-access chest pain clinic, 791 consecutive patients with stable chest pain were planned to undergo X-ECG and dual-source CTA with CCS. According to the Duke pre-test probability of CAD patients were classified as low (<30%), intermediate (30-70%) or high risk (>70%). Angiographic obstructive CAD (>50% stenosis by CAG or CTA) was found in 210/791 (27%) patients, CAG overruling any CTA results. RESULTS: Obstructive CAD was found in 12/281 (4%) patients with no coronary calcium and in 73/319 (23%) with a normal X-ECG (p<0.001). No coronary calcium was associated with a substantially lower likelihood ratio compared to X-ECG; 0.11, 0.13 and 0.13 vs. 0.93, 0.55 and 0.46 in the low, intermediate and high risk group. In low risk patients a negative calcium score reduced the likelihood of obstructive CAD to less than 5%, removing the need for further diagnostic work-up. CCS could be performed in 754/756 (100%) patients, while X-ECG was diagnostic in 448/756 (59%) patients (p<0.001). CONCLUSIONS: In real-world patients with stable chest pain CCS is a reliable initial test to rule out obstructive CAD and can be performed in virtually all patients. PMID- 21689856 TI - Kounis syndrome in a patient with allergy to iodinated contrast media. PMID- 21689857 TI - Magnetic resonance imaging (MRI) of inflamed myocardium using iron oxide nanoparticles in patients with acute myocardial infarction - preliminary results. AB - OBJECTIVES: Superparamagnetic iron oxide nanoparticle (SPIO)-based molecular imaging agents targeting macrophages have been developed and successfully applied in animal models of myocardial infarction. The purpose of this clinical trial was to investigate whether magnetic resonance imaging (MRI) of macrophages using ferucarbotran (Resovist(r)) allows improved visualisation of the myocardial (peri )infarct zone compared to conventional gadolinium-based necrosis/fibrosis imaging in patients with acute myocardial infarction. MATERIAL AND METHODS: The clinical study NIMINI-1 was performed as a prospective, non-randomised, non-blinded, single agent phase III clinical trial (NCT0088644). Twenty patients who had experienced either an acute ST-elevation or non-ST-elevation myocardial infarction (STEMI/NSTEMI) were included to this study. Following coronary angiography, a first baseline cardiovascular magnetic resonance (CMR) study (pre SPIO) was performed within seven days after onset of cardiac symptoms. A second CMR study (post-SPIO) was performed either 10 min, 4h, 24h or 48h after ferucarbotran administration. The CMR studies comprised cine-CMR, T2-weighted "edema" imaging, T2-weighted cardiac imaging and T1-weighted late-gadolinium enhancement (LGE) imaging. RESULTS: The median extent of short-axis in-plane LGE was 28% (IQR 19-31%). Following Resovist(r) administration the median extent of short-axis in-plane T2-weighted hypoenhancement (suggestive of intramyocardial haemorrhage and/or SPIO accumulation) was 0% (IQR 0-9%; p=0.68 compared to pre SPIO). A significant in-slice increase (>3%) in the extent of T2-weighted "hypoenhancement" (post-SPIO compared to pre-SPIO) was seen in 6/16 patients (38%). However, no patient demonstrated "hypoenhancement" in T2-weighted images following Resovist(r) administration that exceeded the area of LGE. CONCLUSIONS: T2/T2-weighted MRI aiming at non-invasive myocardial macrophage imaging using the approved dose of ferucarbotran does not allow improved visualisation of the myocardial (peri-) infarct zone compared to conventional gadolinium-based necrosis/fibrosis imaging. PMID- 21689858 TI - Dynamic modulation of coronary arterio-venous communications. PMID- 21689859 TI - Transcardiac gradients of B-type natriuretic peptides are increased in human pulmonary arterial hypertension. PMID- 21689860 TI - An approach based on wavelet analysis for feature extraction in the a-wave of the electroretinogram. AB - Most biomedical signals are non-stationary. The knowledge of their frequency content and temporal distribution is then useful in a clinical context. The wavelet analysis is appropriate to achieve this task. The present paper uses this method to reveal hidden characteristics and anomalies of the human a-wave, an important component of the electroretinogram since it is a measure of the functional integrity of the photoreceptors. We here analyse the time-frequency features of the a-wave both in normal subjects and in patients affected by Achromatopsia, a pathology disturbing the functionality of the cones. The results indicate the presence of two or three stable frequencies that, in the pathological case, shift toward lower values and change their times of occurrence. The present findings are a first step toward a deeper understanding of the features of the a-wave and possible applications to diagnostic procedures in order to recognise incipient photoreceptoral pathologies. PMID- 21689861 TI - Overexpression of KIAA0101 predicts poor prognosis in primary lung cancer patients. AB - High expression of KIAA0101 (p15(PAF)/OEATC-1) which contains a proliferating cell nuclear antigen (PCNA)-binding motif, a key factor in DNA repair and/or apoptosis and cell cycle regulation, has been observed in a variety of human malignancies. The aim of this study was to observe the expression of KIAA0101 in human non-small-cell lung cancer (NSCLC), explore its clinicopathological significance and evaluate KIAA0101 expression as a potential prognostic marker. KIAA0101 transcript was found to be overexpressed in the great majority of lung cancers by semi-quantitative RT-PCR. A total of 357 NSCLCs were analyzed immunohistochemically on tissue microarrays. High-level KIAA0101 expression was observed in 33.9% (121 of 357 cases), and correlated with male gender (P<0.0001), tumor progression (pT status) (P=0.0008), lymph node metastasis (pN status) (P=0.0003), non-adenocarcinoma histological classification (P<0.0001), and smoking history (P<0.0001), but not with patient age or pleural invasion. Patients with tumors displaying high-level KIAA0101 expression showed significantly shorter survival (P<0.0001, log-rank test). Similarly, gender, pT status, pN status, pleural invasion, histological classification, and smoking history were significant prognostic markers in univariate Cox survival analysis. Importantly, high-level KIAA0101 expression was also identified as an independent prognostic factor by multivariate analysis (P=0.0320). These results provide additional information for determining postoperative adjuvant treatment of NSCLC. PMID- 21689862 TI - Genotypes and infection sites in an outbreak of multidrug-resistant Pseudomonas aeruginosa. AB - An outbreak of multidrug-resistant (MDR) Pseudomonas aeruginosa occurred in an acute care hospital in Japan, which lasted for more than three years. During January 2006 to June 2009, 59 hospitalised patients with MDR P. aeruginosa were mainly detected by urine culture in the first half, whereas isolation from respiratory tract samples became dominant in the latter half of the outbreak. Non duplicate MDR P. aeruginosa isolates were available from 51 patients and all isolates were positive for bla(VIM-2). Pulsed-field gel electrophoresis (PFGE) analysis categorised the isolates into three major clusters; types A, B and C with eight, 19 and 21 isolates, respectively. The outbreak started with patients harbouring PFGE type A strains, followed by type B, and type C strains. Multivariate analysis demonstrated that patients with PFGE type C strains were more likely to be detected by respiratory tract samples (odds ratio: 11.87; 95% confidence interval: 1.21-116.86). Improved aseptic urethral catheter care controlled PFGE type A and type B strains and improvement in respiratory care procedures finally contained the transmission of PFGE type C strains. PMID- 21689863 TI - Can rapid viral testing in the emergency department reduce antibiotic use in children? PMID- 21689864 TI - Factors affecting the likelihood of presentation to the emergency department of trauma patients after discharge. AB - STUDY OBJECTIVE: We determine the rate at which trauma patients re-present to the emergency department (ED) after discharge from the hospital and determine whether re-presentation is related to race, insurance, and socioeconomic factors such as neighborhood income level. METHODS: Trauma patients admitted to a Level I trauma center between January 1, 1997, and December 31, 2007, were identified with the hospital's trauma registry. These patients were linked to administrative data to obtain information about re-presentation to the hospital. Neighborhood income was obtained with census block data; multiple imputation was implemented to account for missing income data. Logistic regression analysis was used to determine the predictors of re-presentation. RESULTS: There were 6,675 patients who were included in the study. A total of 886 patients (13.3%) returned to the ED within 30 days of discharge from the hospital. Uninsured patients (odds ratio [OR]=1.64; 95% confidence interval [CI] 1.30 to 2.06) and publicly insured patients (OR=1.60; 95% CI 1.20 to 2.14) were more likely to re-present to the ED than those with commercial insurance. Residing in a neighborhood with a median household income less than $20,000 was associated with a higher odds of re presentation (OR=1.77; 95% CI 1.37 to 2.29). Only 13.2% of patients who came to the ED were readmitted to the hospital. CONCLUSION: A substantial number of trauma patients return to the ED within 30 days of being discharged, but only a small proportion of these patients required readmission. Re-presentation is associated with being uninsured or underinsured and with lower neighborhood income level. PMID- 21689865 TI - A randomized clinical trial comparing oral, aerosolized intranasal, and aerosolized buccal midazolam. AB - STUDY OBJECTIVE: We determine whether aerosolized intranasal or buccal midazolam reduces the distress of pediatric laceration repair compared with oral midazolam. METHODS: Children aged 0.5 to 7 years and needing nonparenteral sedation for laceration repair were randomized to receive oral, aerosolized intranasal, or aerosolized buccal midazolam. Patient distress was rated by blinded review of videotapes, using the Children's Hospital of Eastern Ontario Pain Score. Secondary outcomes included activity scores, sedation adequacy, sedation onset, satisfaction, and adverse events. RESULTS: For the 169 subjects (median age 3.1 years) evaluated for the primary outcome, we found significantly less distress in the buccal midazolam group compared with the oral route group (P=.04; difference 2; 95% confidence interval -4 to 0) and a corresponding nonsignificant trend for the intranasal route (P=.08; difference -1; 95% confidence interval -3 to 1). Secondary outcomes (177 subjects) favored the intranasal group, including a greater proportion of patients with an optimal activity score (74%), a greater proportion of parents wanting this sedation in the future, and faster sedation onset. Intranasal was the route least tolerated at administration. Adverse events were similar between groups. CONCLUSION: When comparing the administration of midazolam by 3 routes to facilitate pediatric laceration repair, we observed slightly less distress in the aerosolized buccal group. The intranasal route demonstrated a greater proportion of patients with optimal activity scores, greater proportions of parents wanting similar sedation in the future, and faster onset but was also the most poorly tolerated at administration. Aerosolized buccal or intranasal midazolam represents an effective and useful alternative to oral midazolam for sedation for laceration repair. PMID- 21689866 TI - Does bed rest prevent post-lumbar puncture headache? PMID- 21689867 TI - Understanding better how clinicians work. PMID- 21689868 TI - Synthesis and biological evaluation of analogues of M6G. AB - Synthesis and biological evaluation of new derivatives of Morphine-6-Glucuronide (M6G) are described. M6G is an active metabolite of morphine which displays more analgesia than morphine with a superior side effect profile but with a less efficiently BBB penetration. These phenomena could be explained by the presence of the glucuronide moiety, which confers a higher hydrophilic character compare to morphine. In this context, we have prepared three analogues of M6G possessing a tetrazole, an oxadiazole, and a triazolopyrimidine moiety instead of the carboxylic acid function on position 5 of the sugar. These three analogues showed higher analgesic properties than morphine and M6G even by oral administration. PMID- 21689869 TI - Synthesis and antitumour activity of beta-hydroxyisovalerylshikonin analogues. AB - A series of novel beta-hydroxyisovalerylshikonin analogues bearing oxygen containing substituents at the side-chain hydroxyl of shikonin were designed and synthesized. The cytotoxicities of these compounds were evaluated in vitro against multi-drug resistant (MDR) cell lines DU-145 and HeLa. Most compounds exhibited significant inhibitory activity on both cell lines. The structure activity relationship showed the analogues with ether substituents displayed the most potent antitumour activity and selective cytotoxicity towards DU-145. Among the compounds with ether substituents, increasing the steric hindrance in the carbon bearing beta-hydroxyl or replace the beta-hydroxyl with acetoxy or methoxy would lead to the decline of cytotoxicity. PMID- 21689870 TI - Synthesis, antibacterial evaluation and QSAR studies of 7-[4-(5-aryl-1,3,4 oxadiazole-2-yl)piperazinyl] quinolone derivatives. AB - A series of 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl)piperazinyl] quinolones (I-XXI) were synthesized using an appropriate synthetic route and characterized by elemental and spectral analysis. The antibacterial activities of all the synthesized compounds were evaluated against identifiable bacterial strains. Compounds III, IV, VII, VIII, IX, X, XI, XV, &XVIII showed better activity than parent compound against all the selected strains. QSAR study on the synthesized molecules tested for their antibacterial activity was performed using multiple linear regression method. Generated models revealed a decrease in HOMO energy as favorable descriptor for determining and predicting the antibacterial activity of the synthesized compounds. Further, the developed models were cross validated using LOO method for their predictive nature. PMID- 21689871 TI - Fukushima fallout in Northwest German environmental media. AB - Traces of short- and long-lived fallout isotopes ((131)I, (134)Cs and (137)Cs) were found in environmental samples collected in Northwest Germany (rain water, river sediment, soil, grass and cow milk) from March to May 2011, following the radioactivity releases after the nuclear accident in Fukushima, Japan. The measured concentrations are consistent with reported concentrations in air, amount of rainfall and expected values applying simple radioecological models. The [(134)Cs]/[(137)Cs] ratio reported for air (about 1) allows for discrimination between "recent" and "old"(137)Cs. Expected (136)Cs values fell below the detection limits of the instrumentation, despite large sample masses and long counting times. PMID- 21689872 TI - What are we reading? A study of downloaded and cited articles from the British Journal of Oral and Maxillofacial Surgery in 2010. AB - A large number of papers related to oral and maxillofacial surgery are published in many specialist journals. With the ever-increasing use of the internet it is easy to download them as part of a journal subscription on a fee per paper basis, or in some cases for free. Online access to the British Journal of Oral and Maxillofacial Surgery (BJOMS) is free to British Association (BAOMS) members with a $30 fee per paper download for non-members. Many colleagues use the online version of the journal, and this provides valuable information about downloading trends. Other data on articles that have been cited in subsequent publications are also readily available, and they form the basis for the calculation of a journal's impact factor. We evaluated the top 50 downloaded papers from the BJOMS website in 2010 to ascertain which articles were being read online. We also obtained data on the number of citations for papers published in 2009-2010 to see whether these papers were similar to the articles being downloaded. In 2010 there were over 360000 downloaded articles. The most popular papers were leading articles, reviews, and full length articles; only one short communication featured in the top 50 downloads. The papers most cited in subsequent publications were full length articles and leading articles or reviews, which represent 80% of the total citations of the 50 papers. Ten papers were in both the top 50 downloaded and most cited lists. We discuss the implications of this study for the journal and our readers. PMID- 21689873 TI - Tendon fixation in arthroscopic latissimus dorsi transfer for irreparable posterosuperior cuff tears: an in vitro biomechanical comparison of interference screw and suture anchors. AB - BACKGROUND: The fixation of the tendon to the bone remains a challenging problem in the latissimus dorsi tendon transfer for irreparable cuff tears and can lead to unsatisfactory results. A new arthroscopic method of tendon to bone fixation using an interference screw has been developed and the purpose of this study was to compare its biomechanical properties to the ones of a standard fixation technique with anchors. METHODS: Six paired fresh frozen cadaveric human humeri were used. The freed latissimus dorsi tendon was randomly fixed to the humeral head with anchors or with interference screw after a tubularization procedure. Testing consisted to apply 200 cycles of tensile load on the latissimus dorsi tendon with maximal loads of 30 N and 60 N, followed by a load to failure test. The stiffness, displacements after cyclic loadings, ultimate load to failure, and site of failure were analysed. FINDINGS: The stiffness was statistically higher for the tendons fixed with interference screws than for the ones fixed with anchors for both 30 N and 60 N loadings. Likewise, the relative bone/tendon displacements after cyclic loadings were lower with interference screws compared to anchors. Load to failure revealed no statistical difference between the two techniques. INTERPRETATION: Compared to the standard anchor fixation, the interference screw fixation technique presents higher or similar biomechanical performance. These results should be completed by further biomechanical and clinical trials to confirm the interest of this new technique as an alternative in clinical use. PMID- 21689874 TI - Improvement of hand function in children with cerebral palsy via an orthosis that provides wrist extension and thumb abduction. AB - BACKGROUND: The present study examines the hand movements of children with cerebral palsy during functional tests and compares the childrens' performance with and without the aid of an orthosis that provides wrist extension and thumb abduction. METHODS: The range of motion of the trapeziometacarpal joint was assessed for 32 participants via a reflexive markers image system. Observed motions included flexion-extension and abduction-adduction motions performed in the course of four tests for manual ability; the rest position, lateral and tripod pinches and cylindrical grasp. Muscle strength and manual ability were evaluated using dynamometry and the Jebsen-Taylor test. FINDINGS: The range of motion tests for the rest position, lateral and tripod pinches and cylindrical grasp demonstrated improvements from 17% to 42% (P<0.001) for flexion/extension and from 36% to 54% for abduction/adduction (P<0.001) with the use of the orthosis. Dynamometry measurements showed that the improvement in muscle strength obtained through use of the orthosis was 50% (P<0.001). Improvements in the time required to perform the movements as determined using the Jebsen-Taylor test varied from 13% to 24% (P<0.01) for the four considered tests of manual ability. INTERPRETATION: The orthosis improved the range of motion of the trapeziometacarpal joint, muscle strength and manual ability. The combination of the three techniques may provide the basis for a quantitative assessment of hand dysfunction/improvement in cerebral palsy that will ultimately guide health professionals in their clinical interventions. PMID- 21689875 TI - Resisting market-inspired reform in healthcare: the role of professional subcultures in medicine. AB - The reorganisation efforts of the hospital sector in many Western countries in recent decades have challenged the role, identity and autonomy of medical professionals. This has led to increased focus on the role and impact of physicians who are also managers and on the unique discourse being formed through the integration of medical and managerial knowledge. Following the line of studies addressing the professional subcultures in medicine, we investigated whether assessments of health reform differ between medical doctors with managerial responsibilities and their colleagues at the clinical level as well as between those involved in direct patient care and those who are not. The analysis was performed within the context of the Norwegian hospital sector, where a major reform was implemented in 2002, and it was based on a survey of a representative sample of hospital physicians in 2006. The analysis focused on how the respondents viewed the overall effect of the reform and on the reform's effect on three central health policy goals: equity, quality and productivity. Combining data from the survey with organisational and financial data from the hospitals, we employed multilevel techniques to control for a number of individual and hospital-specific factors that could explain the physicians' views. As expected, respondents with managerial responsibilities were more positive in their evaluations of the reform, whereas respondents who spent time on direct patient related work showed the opposite pattern. Of the hospital-specific factors of interest, the share of department managers with medical backgrounds and the economic situation positively affected the evaluations. Our findings support the view that, rather than managerialist values colonising the medical profession through a process of hybridisation, there is heterogeneity within the profession: some physician managers are adopting management values and tools, whereas others remain alienated from them. PMID- 21689876 TI - "Too much of that stuff can't be good": Canadian teens, morality, and fast food consumption. AB - Recently, public health agents and the popular media have argued that rising levels of obesity are due, in part, to "obesogenic" environments, and in particular to the clustering of fast food establishments in Western urban centers that are poor and working class. Our findings from a multi-site, cross-national qualitative study of teenaged Canadians' eating practices in urban and rural areas offer another perspective on this topic, showing that fast food consumption is not simply a function of the location of fast food outlets, and that Canadian teens engage in complex ways with the varied dimensions of choosing (or rejecting) fast foods. Drawing on evidence gleaned from semi-structured interviews with 132 teenagers (77 girls and 55 boys, ages 13-19 years) carried out between 2007 and 2009, we maintain that no easy relationship exists between the geographical availability of fast food and teen eating behaviors. We use critical obesity literature that challenges widely accepted understandings about obesity prevalence and etiology, as well as Lamont's (1992, 2000) concept of "moral boundary work," to argue that teen fast food consumption and avoidance is multifaceted and does not stem exclusively nor directly from spatial proximity or social class. Through moral boundary work, in which teens negotiated with moralistic notions of healthy eating, participants made and re-made themselves as "good" and successful subjects by Othering those who were "bad" in references to socially derived discourses of healthy eating. PMID- 21689877 TI - The importance of gender and conceptualization for understanding the association between collective social capital and health: a multilevel analysis from northern Sweden. AB - Growing research on social capital and health has fuelled the debate on whether there is a place effect on health. A central question is whether health inequality between places is due to differences in the composition of people living in these places (compositional effect) or differences in the local social and physical environments (contextual effects). Despite extensive use of multilevel approaches that allows controlling for whether the effects of collective social capital are confounded by access to social capital at the individual level, the picture remains unclear. Recent studies indicate that contextual effects on health may vary for different population subgroups and measuring "average" contextual effects on health for a whole population might therefore be inappropriate. In this study from northern Sweden, we investigated the associations between collective social capital and self-rated health for men and women separately, to understand if health effects of collective social capital are gendered. Two measures of collective social capital were used: one conventional measure (aggregated measures of trust, participation and voting) and one specific place-related (neighbourhood) measure. The results show a positive association between collective social capital and self-rated health for women but not for men. Regardless of the measure used, women who live in very high social capital neighbourhoods are more likely to rate their health as good-fair, compared to women who live in very low social capital neighbourhoods. The health effects of collective social capital might thus be gendered in favour for women. However, a more equal involvement of men and women in the domestic sphere would potentially benefit men in this matter. When controlling for socioeconomic, sociodemographic and social capital attributes at the individual level, the relationship between women's health and collective social capital remained statistically significant when using the neighbourhood-related measure but not when using the conventional measure. Our results support the view that a neighbourhood-related measure provides a clearer picture of the health effects of collective social capital, at least for women. PMID- 21689878 TI - The impact of adding an extra dimension to a preference-based measure. AB - The ability to compare incremental changes in Quality Adjusted Life Years (QALYs) generated by different condition-specific preference-based measures (CSPBMs), or indeed between generic measures, is often criticised even where the valuation methods and source of values are the same. A key concern is the impact of excluding key dimensions from a descriptive system. This study examines the impact of adding a generic pain/discomfort dimension to a CSPBM, the AQL-5D (an asthma-specific CSPBM), by valuing samples of states from the AQL-5D with and without the new dimension using an interviewer administered time trade-off with a sample of the U.K. general public. 180 respondents provided 720 valuations for states with and without pain/discomfort. As expected the additional pain/discomfort dimension was found to have a significant and relatively large coefficient. More importantly for comparing changes in QALYs across populations the addition of pain/discomfort significantly impacts on the coefficients of the other dimensions and the degree of impact differs by dimension and severity level. The net effect on the utility value depends on the severity of their state: the addition of pain/discomfort at level 1 (no pain/discomfort) or 2 (moderate pain/discomfort) significantly increased the mean health state values in an asthma patient population; whereas level 3 pain/discomfort (extreme) reduced values. Comparability between measures requires that the impact of different dimensions on preferences is additive, whether or not they are included in the classification system. Our results cast doubt on this assumption, implying that the chosen measure must contain all important and relevant dimensions in its classification system. PMID- 21689879 TI - Health-related quality of life after a drowning incident as a child. AB - AIM OF THE STUDY: To describe health-related quality of life (HRQoL), quality adjusted life years (QALYs) gained and school performance in subjects having received either bystander or emergency medical service personnel initiated cardiopulmonary resuscitation (CPR) after a drowning incident in childhood. MATERIALS AND METHODS: 64 children admitted to pediatric intensive care (PICU) after successful CPR between 1985 and 2007. Eleven died in the PICU, 9 other within 6 months. In 2009 all long-term survivors, except for two, lived at home. Of the 40 patients eligible for the study, 29 (73%) responded to a questionnaire. HRQoL was assessed with the generic 15D, or its versions for adolescents (16D) or children (17D), and compared to that of general population. These HRQoL scores, age-specific survival probabilities, and HRQoL scores of the general population were used in a Markov model to estimate the number of QALYs gained. RESULTS: Median age of the respondents was 17.3 (range: 3.0-28.4) years and 62% were male. At the time of drowning their median age had been 3.0 (range: 1.2-15.7) years. The drowning incident was associated with a significant loss in HRQoL in the oldest age group (total HRQoL total score 0.881 compared to 0.971 in the general population, P<0.01) but not in children (HRQoL score 0.944 vs. 0.938). When submersion time exceeded 10min mean HRQoL score was significantly lower than in patients with a shorter submersion (0.844 vs. 0.938, P=0.032). The mean undiscounted and discounted (at 3%) number of QALYs gained by treatment were 40.8 and 17.0, respectively. CONCLUSIONS: A good HRQoL will be achieved in the majority of patients surviving long-term after a drowning incident in childhood, although HRQoL is affected by the submersion time. PMID- 21689880 TI - Prevalence of radiological and clinical cerebrovascular disease in idiopathic Parkinson's disease. AB - Comorbid cerebrovascular disease (CVD) can occur in idiopathic Parkinson's disease (IPD) but its reported prevalence varies considerably. CVD may alter the clinical presentation, course and prognosis in IPD. We aimed to determine the prevalence of radiological and clinical CVD in a neurology clinic IPD population. We undertook a retrospective case-control study of neurology clinic patients with IPD for whom cerebral imaging was available, and excluding probable vascular parkinsonism. IPD diagnosis was validated against UK PDS brain bank criteria. Age and sex-matched controls were identified from patients attending neurology clinics with headache. The presence of radiological cerebrovascular disease, symptomatic CVD (stroke and TIA), and CVD risk factors was recorded for cases and controls. Radiological findings were validated by an experienced consultant neuroradiologist using a structured proforma. Eighty-five cases and 85 controls were studied, based on the number of cases for whom brain imaging existed (CT in 50, MRI in 35) and the number of cases for whom suitable controls could be identified. Indications for brain imaging amongst cases were varied. Cases and controls comprised 55(65%) males, mean (+/- SD) age (years) 67.4 +/- 10.1 (cases), 66.6 +/- 9.9 (controls). Radiological CVD was significantly commoner amongst cases (39%) than controls (22%) (p=0.02, chi-square; odds ratio 2.2, 95% CI: 1.1-4.6). Cases also had significantly more symptomatic CVD, but not CVD risk factors, than controls. Our findings suggest a higher prevalence of radiological and clinical CVD in patients with IPD compared to controls. PMID- 21689881 TI - In situ degradation of phenol and promotion of plant growth in contaminated environments by a single Pseudomonas aeruginosa strain. AB - For bioremediation of contaminated environments, a bacterial strain, SZH16, was isolated and found to reduce phenol concentration in a selective medium. Using the reaction vessel containing the soil mixed with phenol and bacteria, we found that the single strain degraded efficiently the phenol level in soil samples. The strain was identified as Pseudomonas aeruginosa on the basis of biochemical tests and by comparison of 16S rDNA sequences, and phosphate solubilization and IAA production were not observed in the strain. Simultaneous examination of the role of strain SZH16 in the plant growth and phenol biodegradation was performed. Results showed that inoculation of the single strain in the phenol-spiked soil resulted in corn growth promotion and in situ phenol degradation and the increase in plant biomass correlated with the decrease in phenol content. Colonization experiments showed that the population of the SZH16 strain remained relatively constant. All these findings indicated that the corn growth promotion might be due to reduction in phytotoxicity, a result of phenol biodegradation by the single strain SZH16. Furthermore, the strain was found to stimulate corn growth and reduce phenol concentration simultaneously in phenol-containing water, and even historically contaminated field soils. It is attractive for environment remediation and agronomic applications. PMID- 21689882 TI - Ecotoxicological evaluation of three tertiary wastewater treatment techniques via meta-analysis and feeding bioassays using Gammarus fossarum. AB - Advanced treatment techniques, like ozone, activated carbon and TiO(2) in combination with UV, are proposed to improve removal efficiency of micropollutants during wastewater treatment. In a meta-analysis of peer-reviewed literature, we found significantly reduced overall ecotoxicity of municipal wastewaters treated with either ozone (n=667) or activated carbon (=113), while TiO(2) and UV was not yet assessed. As comparative investigations regarding the detoxification potential of these advanced treatment techniques in municipal wastewater are scarce, we assessed them in four separate Gammarus-feeding trials with 20 replicates per treatment. These bioassays indicate that ozone concentrations of approximately 0.8mg ozone/mg DOC may produce toxic transformation products. However, referred effects are removed if higher ozone concentrations are used (1.3mg ozone/mg DOC). Moreover, the application of 1g TiO(2)/l and ambient UV consistently reduced ecotoxicity. Although activated carbon may remove besides micropollutants also nutrients, which seemed to mask its detoxification potential, this treatment technique reduced the ecotoxicity of the wastewater following its amendment with nutrients. Hence, all three advanced treatment techniques are suitable to reduce the ecotoxicity of municipal wastewater mediated by micropollutants and may hence help to meet the requirements of the European Water Framework Directive. PMID- 21689883 TI - Source identification and health risk of polycyclic aromatic hydrocarbons associated with electronic dismantling in Guiyu town, South China. AB - In this study the concentrations and distribution of sixteen polycyclic aromatic hydrocarbons (PAHs) were investigated in gas and total suspended particle (TSP) samples collected during daytime and night time. The sampling locations included an electronic waste dismantling workshop (EW), a plastic recycling workshop (PW) and a waste incineration field (WF) in Guiyu, China. A large residential area (RA) in this region was used as a control site. In the daytime, the highest concentration was found at WF (1041 ng m(-3)); while in the night time the highest concentration was found outside of EW (744 ng m(-3)). Comparison between work hours (daytime) and rest hours (night time) displayed that the total PAHs (gas+particulate phase) concentrations and the percentages of PAHs associated with TSP were higher at night than those in the daytime in all sampling workshops except WF. Source diagnostic-ratio analysis revealed that unwanted materials and smoldering honeycomb coals were the main sources of PAHs in EW, WF and PW. Benzo[a]pyrene equivalent [BaPeq] concentrations calculated by using the toxic equivalent factors [TEFs] suggested that the occupational exposure levels were not significantly high when compared with other occupational exposure. Additionally, our study suggested that the smoldering of unwanted materials could produce much more toxic PAHs compounds. PMID- 21689884 TI - Effect of magnetic field on the zero valent iron induced oxidation reaction. AB - The magnetic field (MF) effect on the zero valent iron (ZVI) induced oxidative reaction was investigated for the first time. The degradation of 4-chlorophenol (4-CP) in the ZVI system was employed as the test oxidative reaction. MF markedly enhanced the degradation of 4-CP with the concurrent production of chlorides. The consumption of dissolved O(2) by ZVI reaction was also enhanced in the presence of MF whereas the competing reaction of H(2) production from proton reduction was retarded. Since the ZVI-induced oxidation is mainly driven by the in situ generated hydroxyl radicals, the production of OH radicals was monitored by the spin trap method using electron spin resonance (ESR) spectroscopy. It was confirmed that the concentration of trapped OH radicals was enhanced in the presence of MF. Since both O(2) and Fe(0) are paramagnetic, the diffusion of O(2) onto the iron surface might be accelerated under MF. The magnetized iron can attract oxygen on itself, which makes the mass transfer process faster. As a result, the surface electrochemical reaction between Fe(0) and O(2) can be accelerated with the enhanced production of OH radicals. MF might retard the recombination of OH radicals as well. PMID- 21689885 TI - Characteristics of PCDD/F content in fly ash discharged from municipal solid waste incinerators. AB - Different from most previous studies with quantity-limited data, this paper presents PCDD/F content characterization in the fly ash discharged from sixteen large-scale commercial MSWIs. From the results with over hundreds of data using periodically sampling and analysis, it was found that the PCDD/F contents in the fly ash were from 9.07 to 46.68ng/g, d.w., and if based on international toxicity equivalent quantity, they were from 0.78 to 2.86ng I-TEQ/g, d.w. The higher chlorinated PCDDs likely dominated more than lower chlorinated PCDDs, but this tendency was not for PCDFs. The OCDD had the highest contribution to the total PCDD/F content, but if based on I-TEQ content, 2,3,4,7,8-PeCDF is the PCDD/F congener with the highest toxicity contribution. Moreover, the PCDD/F characteristic index (DCI) is suggested using the representative congener content of 2,3,4,7,8-PeCDF to characterize the fly ash. The DCI is 0.875+/-7.6% for the fly ash discharged from the MSWI with the APCD assembly of SD, AC and BF. The findings obtained in this work provide overview information on the PCDD/F content characterization in fly ash. They will provide PCDD/F fingerprint information to distinguish from other PCDD/F sources, like steel refinery industry, hazardous waste incinerators, or cement kilns, and thus be applied to fly ash management in the environment. PMID- 21689886 TI - Impaired efficacy of ivermectin against Parascaris equorum, and both ivermectin and pyrantel against strongyle infections in trotter foals in Finland. AB - In order to assess the resistance situation against macrocyclic lactones in Parascaris equorum and against tetrahydropyrimidine derivatives in strongyles in Finnish trotter horses, 112 foals on 18 farms, mostly 1 year old, were examined for these parasites with a modified McMaster faecal flotation method. P. equorum positive foals (n=24) were given ivermectin orally at a dose of 200 MUg/kg b.w., while strongyle positive but P. equorum negative foals (n=38) received pyrantel embonate orally at a dose of 19 mg/kg. Sixteen P. equorum infected foals, treated with ivermectin, also harboured strongyles. During the anthelmintic treatment visit to the farm, Faecal Egg Count Reduction Test (FECRT) reference (first) samples were collected. Fourteen days later, the second sampling (reduction samples) was done. The FECR was calculated for each foal/parasite combination. The reduction efficacies of ivermectin against P. equorum (mean 52%, calculated from the individual egg count reductions) and pyrantel against strongyles (43%) were strongly indicative of widespread resistance. Also indication of ivermectin resistance among strongyles was seen. The widespread use of anthelmintics for Finnish horses obviously has resulted in resistance, as has happened elsewhere, too. PMID- 21689887 TI - Biomarkers of regimen-related mucosal injury. AB - Regimen-related mucosal toxicity is extremely common following cytotoxic chemotherapy and radiotherapy. The alimentary mucosa is particularly susceptible to injury and dysfunction, leading to a constellation of adverse side effects. Currently there is no "one fit" biomarker of such injury. A number of biomarkers have been investigated in the context of gastrointestinal diseases, which may prove useful in the oncology arena. Two of significant potential include citrulline and calprotectin, however more work is required to define the most appropriate settings for their use. Identification of a biomarker that is easily obtained, measured, and accurately indicates mucosal damage, would allow for improved patient diagnosis of toxicities and prompt appropriate intervention. In this review, we highlight the effectiveness of currently examined biomarkers and discuss future avenues for research in this exciting area. PMID- 21689888 TI - Multidisciplinary management of metastatic renal cell carcinoma in the era of targeted therapies. AB - The use of targeted agents to treat metastatic renal cell carcinoma (mRCC) has significantly extended progression-free and overall survival but raises issues relating to the long-term delivery of care and the sustained monitoring of efficacy and toxicities, certain of which have not previously been experienced. In this paper, an expert group of medical oncologists, urologists and oncology nurses and pharmacists review and make informal recommendations on the multidisciplinary management of mRCC in the light of progress made and problems that have arisen. Decentralisation of care, with a shift in emphasis from large to small hospitals and possibly to the community, may offer advantages of cost and convenience. However, the major responsibility for care should continue to lie with clinicians (either medical oncologists or urologists) with extensive experience in mRCC, assisted by specialist nurses, and working in centres with facilities adequate to monitor efficacy and manage toxicities. That said, the extended survival of patients emphasises the importance of compliance and the long-term prevention, detection and management of side effects. Much of this will take place in the community. There is therefore a need for multidisciplinary working to extend beyond specialist centres to include general practitioners, community nurses and pharmacists. Although this paper focuses on mRCC, many of the considerations discussed are also relevant to the management of more common solid tumours in the era of targeted therapy. PMID- 21689890 TI - The physiological response to Trier Social Stress Test relates to subjective measures of stress during but not before or after the test. AB - The Trier Social Stress Test (TSST) is an effective psychosocial laboratory protocol for inducing stress in humans and has been used in numerous research studies. The stressor leads to a physiological response of the hypothalamus pituitary-adrenal axis (HPAA) and the autonomous nervous system (ANS). Common biomarkers are cortisol levels and heart rate. In addition to the physiological stress response, the TSST also triggers a psychological response such as an increase in perceived stress, anxiety and emotional insecurity. Whereas HPA and ANS measures can easily be obtained for the TSST period itself, psychological measures are usually determined prior to (baseline) and after the TSST. This may exclude information of the stressful event itself. In the present study, we assessed perceived stress, anxiety and emotional insecurity before, during and after the TSST using visual analogue scales. In addition, cortisol levels and heart rates were assessed. Data of 260 healthy non-smoking males aged 16-60 yrs were used for analyses. Our results show that stress perception, anxiety and emotional insecurity were significantly higher during the TSST as compared to post-TSST ratings. Furthermore, our results suggest a covariance of the psychological stress response during the TSST and the physiological stress responses (cortisol and heart rate) for stress perception though the explained variance was small. This observation was not found for pre- and post-TSST ratings suggesting that assessing psychological stress measures during the stressor itself present a more informative measure of the stress response. PMID- 21689889 TI - Differential effects of perceived discrimination on the diurnal cortisol rhythm of African Americans and Whites. AB - The current study considered the influence of perceived discrimination on the diurnal cortisol rhythm of 50 African American older adults and a matched comparison groups of 100 Whites (M(age)=56.6; 58% female). The role of socioeconomic status (SES) as a moderator of the effects of discrimination on the diurnal decline was also considered for each group. In support of the idea that perceptions of unfair treatment take on a unique meaning for stigmatized minority groups, results suggest that perceived discrimination is associated with a flatter (less healthy) diurnal slope among Whites but a steeper (more healthy) diurnal slope among African Americans. Perceived discrimination was also found to be more strongly associated with a steepening of the diurnal slope among lower SES African Americans than higher SES African Americans. PMID- 21689891 TI - Resveratrol may be beneficial in treatment of diabetic foot syndrome. AB - Diabetic foot syndrome (DFS) is a late-stage complication of type 2 diabetes which originates from interplay among impaired tissue regeneration, vasculopathy, neuropathy and inflammation all on the background of insulin resistance. Despite astonishing mortality rate pharmacological approach in management of diabetic ulceration is almost non-existent. Foot pressure relief, wound debridement and infection control remain widely accepted options in the treatment of DFS. We hypothesize that resveratrol treatment and subsequent activation of SIRT1 pathway might be highly beneficial for patients with DFS. This prediction is based on multiple lines of evidence implicating resveratrol and sirtuins in restoration of insulin sensitivity, microcirculation, tissue regeneration, function of peripheral nerves and production of cytokines. Stabilized "nutraceutical" formulations of resveratrol with high absorption rate are essential to examine its potential medical benefits since dietary polyphenols are known to be rapidly metabolized by gut microflora and oxidized during absorption. Clinical trials with nutraceutical formulations and placebo are required to understand if resveratrol indeed holds the promise for treatment of DFS. PMID- 21689892 TI - Purification and characterization of myosin-tripolyphosphatase from rabbit Psoas major muscle: research note. AB - In this study, we investigated the tripolyphosphatase (TPPase) activity responsible for the hydrolysis of tripolyphosphates (TPP) in rabbit Psoas major muscle tissue. After a series of extraction and purification steps, myosin was identified to be a TPPase. Optimum pH and temperature for myosin-TPPase activity were 6.0 and 35 degrees C, respectively. We also found that myosin-TPPase activity was significantly influenced by Mg(2+) and Ca(2+) levels, whose optimal concentrations were determined to be 3 and 6mM, respectively. Furthermore, myosin TPPase was strongly inhibited by EDTA-4Na(+) and KIO(3), and was slightly activated by EDTA-2Na(+). These results suggest that it may be useful to regulate tripolyphosphate hydrolysis to enhance its function in meat processing. PMID- 21689893 TI - Multifocal nodular oncocytic hyperplasia of bilateral parotid glands: A case report with a histological variant of clear cells. AB - A case of multifocal nodular oncocytic hyperplasia (MNOH) of the bilateral parotid gland is presented. An 80-year-old woman was admitted to hospital because of painless swellings in bilateral parotid regions. Histologically, the nodular lesion had incomplete capsules and engulfed the surrounding parotid gland at the periphery. The lesions were mostly composed of clear cells, while the peripheries of the lesions had typical oncocytic cells with abundant fine granules. The histological existence of the clear cell component in the lesions led to misdiagnoses of other clear cell neoplasms. However, this case had multiple nodules in bilateral glands. No evidence of malignant histological findings was found. Moreover, the clear cells, as well as the oncocytic cells, were demonstrated to have mitochondria and glycogen in their cytoplasm using special staining. Based on these findings, the diagnosis of this case was MNOH in the parotid gland. We also discuss the differential diagnosis for clear cell lesions. PMID- 21689894 TI - Chronic lymphocytic leukemia mimicking recurrent carcinoma of the breast: case report and review of the literature. AB - Secondary localization of chronic lymphocytic leukemia (CLL) in breast is rare, while concurrent invasive ductal carcinoma and CLL manifesting as a collision tumor in breast is extremely rare. The observation of a CLL infiltration closely associated with a distinct breast neoplasm with the absence of any other localization for the leukemia is an indisputable argument for a relationship between the two diseases. The presence of both tumors is not simply due to chance. This association (CLL and carcinoma) has also been described in other organs. Hereafter, we report a second case of an 80 year-old woman in whom a leukemic infiltrate was confined to the region immediately surrounding poorly differentiated primary breast carcinoma, and we will discuss the association between CLL and carcinoma. PMID- 21689895 TI - Can we identify the group of small invasive (T1a,b) breast cancers with minimal risk of axillary lymph node involvement? A pathohistological and DNA flow cytometric study. AB - The goal of this study was to identify a group of small (<=1cm) breast cancers (T1a,b) with a particularly low probability of axillary lymph node metastases, where routine axillary staging may be unnecessary. We retrospectively analyzed 152 T1a,b breast carcinomas with axillary dissection surgically removed at Clinical Hospital Center Split (Croatia) in the period from 1997 to 2006. The analysis included 40 T1a,b cancers with, and 112 T1a,b cancers without axillary lymph node metastases. The basic morphological features of cancers were investigated histologically, while hormone receptors and HER2/neu were investigated immunohistochemically with an additional CISH analysis of HER2/neu 2+ cases. The ploidy and S-phase fraction were determined by DNA flow cytometry. The association of the investigated features with the likelihood of axillary lymph node metastases was analyzed by univariate and multivariate analysis. The univariate analysis showed that lymph node metastases were associated with tumor size (T1a/T1b; p=0.026), histological type (ductal/non-ductal; p=0.014), lymphovascular invasion (p<0.001), HER2/neu expression (p=0.04), ploidy (p=0.027), and combined values of ploidy and S-phase fraction (p=0.025). The lymphovascular invasion was the only independent factor associated with axillary nodal metastases (p=0.01). In the group of T1a,b cancers without lymphovascular invasion, HER2/neu expression (p=0.021) and combined values of ploidy and S-phase fraction (p=0.016) were independent factors associated with axillary lymph node metastases. This study showed that diploid T1a,b cancers with low S-phase fraction, which are also without lymphovascular invasion and HER2/neu amplification, represented the group of cancers with a low probability of axillary lymph node metastases. PMID- 21689896 TI - Acute administration of vinpocetine, a phosphodiesterase type 1 inhibitor, ameliorates hyperactivity in a mice model of fetal alcohol spectrum disorder. AB - BACKGROUND: Maternal alcohol use during pregnancy causes a continuum of long lasting disabilities in the offspring, commonly referred to as fetal alcohol spectrum disorder (FASD). Attention-deficit/hyperactivity disorder (ADHD) is possibly the most common behavioral problem in children with FASD and devising strategies that ameliorate this condition has great clinical relevance. Studies in rodent models of ADHD and FASD suggest that impairments in the cAMP signaling cascade contribute to the hyperactivity phenotype. In this work, we investigated whether the cAMP levels are affected in a long-lasting manner by ethanol exposure during the third trimester equivalent period of human gestation and whether the acute administration of the PDE1 inhibitor vinpocetine ameliorates the ethanol induced hyperactivity. METHODS: From postnatal day (P) 2 to P8, Swiss mice either received ethanol (5g/kg i.p.) or saline every other day. At P30, the animals either received vinpocetine (20mg/kg or 10mg/kg i.p.) or vehicle 4h before being tested in the open field. After the test, frontal cerebral cortices and hippocampi were dissected and collected for assessment of cAMP levels. RESULTS: Early alcohol exposure significantly increased locomotor activity in the open field and reduced cAMP levels in the hippocampus. The acute treatment of ethanol exposed animals with 20mg/kg of vinpocetine restored both their locomotor activity and cAMP levels to control levels. CONCLUSIONS: These data lend support to the idea that cAMP signaling system contribute to the hyperactivity induced by developmental alcohol exposure and provide evidence for the potential therapeutic use of vinpocetine in FASD. PMID- 21689897 TI - Gender, race, and group behavior in group drug treatment. AB - BACKGROUND: Group drug counseling is the primary treatment modality used to treat drug dependence in community settings in the United States. Findings from the social psychology literature suggest that gender may influence how individuals participate in groups, and that race may moderate the effects of gender on group behavior. This study examined gender, race, and their interaction as predictors of alliance, participation, self-disclosure, and receipt of advice and feedback in drug counseling groups, and explored how gender and racial differences in drug counseling group behavior related to outcome of cocaine dependence treatment. METHOD: Ratings of group behavior were made from videotaped sessions of group drug counseling drawn from a randomized trial of treatment for cocaine-dependent individuals (n=438). Analyses examined the effects of race (African American or non-Hispanic White), gender, and the race by gender interaction on group behavior. Additional analyses examined race, gender, and group behavior, and interactions among these variables in predicting monthly cocaine use. RESULTS: Race and the race by gender interaction, but not gender alone, predicted many group behaviors. Non-Hispanic White women had the highest rates of self disclosure and receipt of advice and non-positive feedback, followed by men of both races, with African American women having the lowest levels. These differences were unrelated to cross-sectional cocaine outcome. CONCLUSIONS: Women, but not men, of different races acted differently in mixed-race, mixed gender cocaine treatment groups, with African American women exhibiting less of several behaviors. Additional research on causes and consequences of these differences could inform interventions for drug-dependent women. PMID- 21689898 TI - Calcium and vitamin D supplementation and cardiovascular disease: quo vadis? PMID- 21689899 TI - Tracheal intubation in the emergency department: a comparison of GlideScope(r) video laryngoscopy to direct laryngoscopy in 822 intubations. AB - BACKGROUND: Video laryngoscopy has, in recent years, become more available to emergency physicians. However, little research has been conducted to compare their success to conventional direct laryngoscopy. OBJECTIVES: To compare the success rates of GlideScope((r)) (Verathon Inc., Bothell, WA) videolaryngoscopy (GVL) with direct laryngoscopy (DL) for emergency department (ED) intubations. METHODS: This was a 24-month retrospective observational study of all patients intubated in a single academic ED with a level I trauma center. Structured data forms were completed after each intubation and entered into a continuous quality improvement database. All patients intubated in the ED with either the GlideScope((r)) standard, Cobalt, Ranger, or traditional Macintosh or Miller laryngoscopes were included. All patients intubated before arrival were excluded. Primary analysis evaluated overall and first-attempt success rates, operator experience level, performance characteristics of GVL, complications, and reasons for failure. RESULTS: There were 943 patients intubated during the study period; 120 were excluded due to alternative management strategies. DL was used in 583 (62%) patients, and GVL in 360 (38%). GVL had higher first-attempt success (75%, p = 0.03); DL had a higher success rate when more than one attempt was required (57%, p = 0.003). The devices had statistically equivalent overall success rates. GVL had fewer esophageal intubations (n = 1) than DL (n = 18); p = 0.005. CONCLUSION: The two techniques performed equivalently overall, however, GVL had a higher overall success rate, and lower number of esophageal complications. In the setting of ED intubations, GVL offers an excellent option to maximize first attempt success for airway management. PMID- 21689900 TI - The effectiveness and adverse events of morphine versus fentanyl on a physician staffed helicopter. AB - BACKGROUND: Morphine and fentanyl are both frequently used in prehospital trauma patients, but due to limited formulary size, we sought to study whether both drugs should be included. OBJECTIVES: The purpose of this study was to evaluate the effectiveness and safety of fentanyl as compared to morphine for patients requiring analgesic medications for a traumatic injury during transport via a physician-staffed air medical service. METHODS: Trauma patients were grouped by even and odd days (even - morphine 4 mg, odd - fentanyl 50 MUg). Patients were excluded based on age (< 18 or > 64 years), hypotension, inability to communicate a pain score (intubated), or known allergy to the study drugs. During the flight, medical crew assessed numeric pain score, vital signs, and incidence of pruritis or nausea. RESULTS: There were 103 patients enrolled in the morphine arm and 97 patients in the fentanyl arm. The mean pain score at the beginning of enrollment was 8.0 +/- 2.0 in the morphine arm and 8.0 +/- 1.8 in the fentanyl arm. The mean final pain score was 5.8 +/- 2.7 in the morphine arm and 5.5 +/- 2.4 in the fentanyl arm (n.s. by either t-test or non-parametric testing). There was no significant difference in analgesia between fentanyl and morphine. There were no significant differences in the incidence of pruritis or vomiting between the two groups. Average transport time was 37 +/- 8 min in the morphine group, and 43 +/- 11 min in the fentanyl group. Average number of morphine doses was 3 +/- 1.2. For fentanyl, average number of doses was 3 +/- 1.3. CONCLUSION: In our study, there was not a significant difference in analgesic effectiveness between morphine and fentanyl. There was no significant difference in the incidence of adverse effects between the two drugs. Our study suggests that either drug can be used safely with equivalent effectiveness. PMID- 21689901 TI - Japanese people's preference for place of end-of-life care and death: a population-based nationwide survey. AB - CONTEXT: Japanese people's preferred place of end-of-life care may be affected by their experiences, perceptions, and knowledge related to the end of life. OBJECTIVES: The aims of this study were to clarify the Japanese population's preferences for the place of end-of-life care and death and to identify the determinants of each choice of preferred place of end-of-life care within their experiences, perceptions, and knowledge. METHODS: A total of 2000 Japanese people aged 40-79 years participated in a cross-sectional nationwide survey. RESULTS: Fifty-five percent (n=1042) responded. Regarding place of end-of-life care, approximately 44% of the general population preferred home, 15% preferred hospital, 19% preferred palliative care unit, 10% preferred public nursing home, 2% preferred private nursing home, and the remaining 11% was unsure. Multinomial logistic regression analysis revealed that the following factors affect people's preferences regarding place of care: 1) experiences, such as "visiting hospital regularly" and "experiencing home death of relatives," 2) perceptions, such as "giving due thought to their own death on a daily basis" and "perceiving lower home palliative care costs to be appropriate after comparing hospital admission fees," and 3) knowledge of "home care nursing" and "24-hour home palliative system by physicians and nurses using insurance." These factors correlated with preference for hospital, palliative care unit, or public nursing home, when compared with the preference of home. CONCLUSION: The present findings may help to develop an effective end-of-life care system in Japan, in line with people's various preferred locations for such care. PMID- 21689902 TI - Cognitive behavior therapy in medication non-responders with obsessive-compulsive disorder: a prospective 1-year follow-up study. AB - Evidence of efficacy of cognitive behavior therapy (CBT) in obsessive-compulsive disorder (OCD) non-responsive to multiple trials of serotonin reuptake inhibitors (SRI) is limited. We examined the efficacy of CBT in 31 adult patients with DSM IV OCD who were non-responders to at least two SRI trials. They received 20-25 sessions of CBT over 3-month duration. The primary outcome measure was "response" to treatment [Clinical Global Impressions-Improvement score 1 or 2 and >=35% reduction in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) severity score]. Patients were assessed at baseline, post-treatment and at 3-, 6- and 12-month follow-up. Twenty-six (84%) patients completed treatment and number of responders at post-treatment, 3-, 6- and 12-month follow-up were 23 (74%), 20 (64%), 20 (64%) and 19 (61%) respectively. Quality of homework compliance and baseline Y BOCS severity predicted remission (Y-BOCS<16) to CBT. CBT is useful in OCD non responsive to multiple trials of SRI. PMID- 21689903 TI - Moral judgment of young sex offenders with and without intellectual disabilities. AB - This study examined differences in moral judgment between juvenile sex offenders with and without intellectual disabilities. The Sociomoral Reflection Measure Short Form (SRM-SF) was used to assess moral judgment, and was extended with questions referring to general sexual situations and to the offenders' abuse victim(s). Juvenile sex offenders with and without ID significantly differed in moral judgment stage regarding general life, sexual and own abuse victim situations. Juvenile sex offenders with ID generally showed stage 2 moral reasoning, which indicated that their justifications for moral decisions were dominated by instrumental and pragmatic reciprocity, whereas juvenile sex offenders without ID used reasons and justifications representing transitional moral stage 2/3 moral judgment, indicating that the maintenance of interpersonal relationships was considered to a certain extent in their justifications for moral decisions. Future research should examine to what extent moral judgment of offenders with ID should be targeted in treatment. PMID- 21689904 TI - Nijmegen Continuity Questionnaire: development and testing of a questionnaire that measures continuity of care. AB - OBJECTIVE: To develop and pilot test a generic questionnaire to measure continuity of care from the patient's perspective across primary and secondary care settings. STUDY DESIGN AND SETTING: We developed the Nijmegen Continuity Questionnaire (NCQ) based on a systematic literature review and analysis of 30 patient interviews. The questionnaire consisted of 16 items about the patient provider relationship to be answered for five different care providers and 14 items each on the collaboration between four groups of care providers. The questionnaire was distributed among patients with a chronic disease recruited from general practice. We used principal component analysis (PCA) to identify subscales. We refined the factors by excluding several items, for example, items with a high missing rate. RESULTS: In total, 288 patients filled out the questionnaire (response rate, 72%). PCA yielded three subscales: "personal continuity: care provider knows me," "personal continuity: care provider shows commitment," and "team/cross-boundary continuity." Internal consistency of the subscales ranged from 0.82 to 0.89. Interscale correlations varied between 0.42 and 0.61. CONCLUSION: The NCQ shows to be a comprehensive, reliable, and valid instrument. Further testing of reliability, construct validity, and responsiveness is needed before the NCQ can be more widely implemented. PMID- 21689905 TI - Targeting pre-ligand assembly domain of TNFR1 ameliorates autoimmune diseases - an unrevealed role in downregulation of Th17 cells. AB - The pre-ligand assembly domain (PLAD) of tumor necrosis factor receptors mediates specific ligand-independent receptor assembly and subsequent signaling. However, the physiological role of PLAD in the regulation of TNFR-mediated immune responses in autoimmunity is still unclear. By using the recombinant PLAD.Fc protein to block TNFR1 assembly, we demonstrated that PLAD.Fc treatment significantly reduced the TNFR1-driving proinflammatory cytokines and protected NOD mice from diabetes. Strikingly, Th17 differentiation was significantly inhibited in PLAD.Fc-treated NOD and TNFR1-deficient mice, indicating a TNFR1 dependent Th17 development. PLAD.Fc-modulated effects on DCs, in terms of the downregulation of Th17-inducing cytokines, IL-6 and TGF-beta, explained the potential mechanism for Th17 suppression. Finally, we provided an additional result that PLAD.Fc administration diminished the infiltration of Th17 cells in the central nervous system and ameliorated the experimental autoimmune encephalomyelitis in mice. Collectively, these data demonstrated that targeting PLAD of TNFR1 provides protection from autoimmune diseases through the downregulation of Th17 and suggested a therapeutic potential of PLAD-modulation in TNF-involved inflammatory diseases. PMID- 21689906 TI - TLR9 responses of B cells are repressed by intravenous immunoglobulin through the recruitment of phosphatase. AB - One way for intravenous Ig (IVIg) to affect responses of the B cells might be to operate through their TLR7 and TLR9. We confirm the ability of TLR agonists to induce CD25 expression in B cells. For this to occur, sialylated Fc-gamma of IgG included in the IVIg preparation are required. As a result, IVIg suppresses TLR induced production of the proinflammatory IL-6, but not that of the anti inflammatory IL-10. That is, IVIg mimics the effects of the MyD88 inhibitor. Finally, as we previously showed that IVIg induces CD22 to recruit the inhibitory SHP-1, we established that this enzyme was also involved in IVIg-induced inhibition of TLR9 signaling. This is the first report to demonstrate such a mechanism underlying the negative impact of IVIg on B lymphocytes. PMID- 21689907 TI - Medial prefrontal cortical synapsin II knock-down induces behavioral abnormalities in the rat: examining synapsin II in the pathophysiology of schizophrenia. AB - Synapsin II is a synaptic vesicle-associated phosphoprotein that has been implicated in the pathophysiology of schizophrenia. Studies have demonstrated reductions in synapsin II mRNA and protein in medial prefrontal cortical post mortem samples from patients with schizophrenia, genetic associations between synapsin II and schizophrenia, and synapsin II protein regulation by dopamine receptor activation. Collectively, this research indicates a relationship between synapsin II dysregulation and schizophrenia; however, it remains unknown whether perturbations in synapsin II play a role in the pathophysiology of this disease. The aim of this project was to evaluate animals with selective knock-down of synapsin II in the medial prefrontal cortex. After continuous infusion of synapsin II antisense sequences, animals were examined for the presence of schizophrenic-like behavioral phenotypes and assessed on the response to clinically relevant antipsychotic drugs. Our results indicate that rats with selective reductions in medial prefrontal cortical synapsin II demonstrate deficits in sensorimotor gating (prepulse inhibition), reduced social behavior, and hyperlocomotion, which are corrected by the atypical antipsychotic drug olanzapine. Additionally, synapsin II knock-down disrupts serial search efficiency. These behavioral changes are accompanied by reductions in vesicular neurotransmitter transporter protein concentrations for glutamate (VGLUT1 and VGLUT2) and GABA (VGAT), without affecting dopamine (VMAT2). These results implicate a causal role for decreased synapsin II in the medial prefrontal cortex in the pathophysiology of schizophrenia and the mechanisms of aberrant prefrontal cortical circuitry, and suggest that synapsin II may potentially serve as a novel therapeutic target for this disorder. PMID- 21689908 TI - Dopamine D2/D3 receptor availability and venturesomeness. AB - The construct of impulsivity is considered as a major trait of personality. There is growing evidence that the mesolimbic dopamine system plays an important role in the modulation of impulsivity and venturesomeness, the two key components within the impulsivity-construct. The aim of the present study was to explore an association between trait impulsivity measured with self-assessment and the dopaminergic neurotransmission as measured by positron emission tomography (PET) in a cohort of healthy male subjects. In vivo D2/D3 receptor availability was determined with [(18)F]fallypride PET in 18 non-smoking healthy subjects. The character trait impulsivity was measured using the Impulsiveness-Venturesomeness Empathy questionnaire (I7). Image processing and statistical analysis was performed on a voxel-by-voxel basis using statistical parametric mapping (SPM) software. The I7 subscale venturesomeness correlated positively with the D2/D3 receptor availability within the left temporal cortex and the thalamus. Measures on the I7 subscale impulsiveness and empathy did not correlate with the D2/D3 receptor availability in any brain region investigated. Our results suggest the involvement of extrastriatal dopaminergic neurotransmission in venturesomeness, a component of impulsivity. PMID- 21689909 TI - Enhancement in antifungal activity of eugenol in immunosuppressed rats through lipid nanocarriers. AB - In the present study eugenol loaded solid lipid nanoparticles (SLN) was prepared and characterized for particle size, polydispersity index, zeta potential, encapsulation efficiency, in vitro release and in vivo antifungal activity. Effect of addition of liquid lipid (caprylic triglyceride) to solid lipid (stearic acid) on crystallinity of lipid matrix of SLN was determined by using Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) techniques. Transmission electron microscopy (TEM) was carried out to determine the morphology of SLN. In vivo antifungal activity of eugenol loaded lipid nanoparticles was evaluated by using a model of oral candidiasis in immunosuppressed rats. Particle size results showed that d(90) of SLN(1) (single lipid matrix) and SLN(2) (binary lipid matrix) was 332+/-14.2 nm and 87.8+/-3.8 nm, respectively. Polydispersity index was found to be in the range of 0.27-0.4 which indicate moderate size distribution. Encapsulation efficiency of SLN(2) (98.52%) was found to be more than that of SLN(1) (91.80%) at same lipid concentration (2%, w/v). Increasing of the solid lipid concentration from 2% (w/v) to 4% (w/v) resulted in increase in encapsulation efficiency and the particle size. SLN(2) shows faster release of eugenol than that of SLN(1) due to smaller size and presence of liquid lipid which provide less barriers to the diffusion of drug from matrix. TEM study reveals the spherical shape of SLN. FT-IR, DSC and XRD results indicate less crystallinity of SLN(2) than that of SLN(1). In vivo studies show no significant difference in log cfu value of all the groups at 0 day. At 8th day, log cfu value of group treated with saline (control), standard antifungal agent, eugenol solution, SLN(1) and SLN(2) was found to be 3.89+/-.032, 2.69, 3.39+/-.088, 3.19+/-.028 and 3.08+/-0.124, respectively. The in vivo study results indicate improvement in the antifungal activity of eugenol when administrated in the form of SLN. PMID- 21689910 TI - Stability of monomolecular films of archaebacterial tetraether lipids on silicon wafers: a comparison of physisorbed and chemisorbed monolayers. AB - The monomolecular organisation of symmetric, chemically modified tetraether lipids caldarchaeol-PO(4) was studied using Langmuir film balance, ellipsometry, and atomic force microscopy (AFM). Solid silicon wafer substrates were modified to hydrophobic, hydrophilic, and amino-silanised surfaces; and Langmuir-Blodgett (LB)-films were transferred onto each. LB-caldarchaeol-PO(4) films were subjected to further rinsing with organic solvent and additional physical treatments, to compare their resistance and stability on chemisorbed (amino-silanised) and physisorbed (hydrophobic and hydrophilic) surfaces. The resistance and stability of these monolayer films was characterized by ellipsometry and AFM, and film thickness was determined using ellipsometry. AFM was also employed to observe surface morphology. Monolayer films on hydrophobic surfaces were found to be more resistant to rinsing with organic solvent and additional physical treatments than monolayer films on either amino-silanised or hydrophilic surfaces. The hydrophobic effect with hydrophobic surfaces appears to support the formation of stronger caldarchaeol-PO(4) films on silicon wafer substrates, with increased resistance and stability. PMID- 21689911 TI - Transmembrane glutathione cycling in growing Escherichia coli cells. AB - Glutathione (GSH) plays an important role in bacterial cells, participating in maintenance of redox balance in the cytoplasm and in defense against many toxic compounds and stresses. In this study we demonstrate that in aerobic, exponentially growing Escherichia coli culture endogenous reduced glutathione undergoes continuous transmembrane cycling between the cells and medium. As a result of an establishment of a dynamic balance between GSH efflux and uptake, a constant extracellular concentration of GSH counting per biomass unit is maintained. The magnitude of this concentration strictly depends on external pH. GSH cycling is carried out in respiring cells and disturbed by influences, which change the level of DeltaMUH(+) and ATP. Export of GSH is modified by phosphate deficiency in the medium. PMID- 21689913 TI - Predicted versus absolute values in the application of exhaled nitric oxide measurements. AB - BACKGROUND: Constitutional factors such as age, sex and height, and acquired factors such as atopy and smoking, influence exhaled nitric oxide (F(E)NO) levels. The utility of predicted values based on reference equations which account for these factors has not been evaluated. AIM: To compare the performance characteristics of absolute versus % predicted values for F(E)NO as predictors of diagnosed asthma and steroid response. METHODS: We compared the sensitivities, specificities and likelihood ratios using F(E)NO (% predicted) with absolute values for F(E)NO (ppb) in 52 steroid-naive subjects with non-specific respiratory symptoms. The reference equations of Olin et al. (Chest, 2007) and Dressel et al. (Resp. Med., 2008) were used to derive predicted values. Receiver operating curve analyses were performed and the areas under the curve (AUC) were calculated for two outcomes: diagnosed asthma (yes/no), and steroid response after fluticasone for 4 weeks (defined as >= 12% increase in FEV(1); increase in mean morning PEF >= 15%; reduction in symptoms >= 1 point; increase in PC(20)AMP of >= 2 doubling doses). RESULTS: The AUCs for diagnosed asthma were: F(E)NO (absolute) 0.770; F(E)NO (% pred.): 0.758 (Olin) and 0.775 (Dressel) (NS). The AUCs for F(E)NO (abs.) and F(E)NO (% pred.) with respect to the four indices of steroid response were likewise not significantly different. CONCLUSION: Correcting F(E)NO for combinations of age, sex, height, smoking and atopy using reference equations did not enhance the performance characteristics of F(E)NO as a predictor of either the diagnosis of asthma or steroid responsiveness in patients with chronic airways-related symptoms. PMID- 21689914 TI - Letter to Respiratory Medicine: "Drugs reducing transepithelial leukocyte traffic may worsen lung disease". PMID- 21689912 TI - Isolation and identification of lactic acid bacteria from Tarag in Eastern Inner Mongolia of China by 16S rRNA sequences and DGGE analysis. AB - Tarag is a characteristic fermented dairy product with rich microflora (especially lactic acid bacteria), developed by the people of Mongolian nationality in Inner Mongolia of China and Mongolia throughout history. One hundred and ninety-eight samples of Tarag were collected from scattered households in Eastern Inner Mongolia, and total of 790 isolates of lactic acid bacteria (LAB) were isolated by traditional pure culture method. To identify these isolates and analyze their biodiversity, 16S rRNA gene sequences analysis and PCR-DGGE were performed respectively. The results showed that 790 isolates could be classified as 31 species and subspecies. Among these isolates, Lactobacillus helveticus (153 strains, about 19.4%), Lactococcus lactis subsp. lactis (132 strains, about 16.7%) and Lactobacillus casei (106 strains, about 11.0%) were considered as the predominated species in the traditional fermented dairy products (Tarag) in Eastern Inner Mongolia. It was shown that the biodiversity of LAB in Tarag in Inner Mongolia was very abundant, and this traditional fermented dairy product could be considered as valuable resources for LAB isolation and probiotic selection. PMID- 21689915 TI - Peroxisome biogenesis: recent advances. AB - In recent years, it has become evident that peroxisomes form part of the endomembrane system. Peroxisomes can form from the ER via a maturation process and they can multiply by growth and division, whereby the ER provides membrane for growth and ongoing fission (Figure 1). Until very recently, it was widely accepted that most peroxisomal membrane proteins (PMPs) insert directly into peroxisomes, whereas a small subset of PMPs traffic via the ER. In this minireview, we focus mainly on PMP biogenesis, and highlight recent advances in peroxisomal matrix protein import, fission and segregation in yeast. PMID- 21689916 TI - Predictors of incident and recurrent participation in the sale or delivery of drugs for profit amongst young methamphetamine users in Chiang Mai Province, Thailand, 2005-2006. AB - BACKGROUND: Despite Thailand's war on drugs, methamphetamine ("yaba" in Thai) use and the drug economy both thrive. This analysis identifies predictors of incident and recurrent involvement in the sale or delivery of drugs for profit amongst young Thai yaba users. METHODS: Between April 2005 and June 2006, 983 yaba users, ages 18-25, were enrolled in a randomized behavioural intervention in Chiang Mai Province (415 index and 568 of their drug network members). Questionnaires administered at baseline, 3-, 6-, 9-, and 12-month follow-up visits assessed socio-demographic factors, current and prior drug use, social network characteristics, sexual risk behaviours and drug use norms. Exposures were lagged by three months (prior visit). Outcomes included incident and recurrent drug economy involvement. Generalized linear mixed models were fit using GLIMMIX (SASv9.1). RESULTS: Incident drug economy involvement was predicted by yaba use frequency (adjusted odds ratio [AOR]: 1.05; 95% confidence interval [CI]: 1.01, 1.10), recent incarceration (AOR: 2.37; 95% CI: 1.07, 5.25) and the proportion of yaba-using networks who quit recently (AOR: .34; 95% CI: .15, .78). Recurrent drug economy involvement was predicted by age (AOR: 0.81; 95% CI: 0.68, 0.96), frequency of yaba use (AOR: 1.06; 95% CI: 1.02, 1.09), drug economy involvement at the previous visit (AOR: 2.61; CI: 1.59, 4.28), incarceration in the prior three months (AOR: 2.29; 95% CI: 1.07, 4.86), and the proportion of yaba-users in his/her network who quit recently (AOR: .38; 95% CI: .20, .71). CONCLUSION: Individual drug use, drug use in social networks and recent incarceration were predictors of incident and recurrent involvement in the drug economy. These results suggest that interrupting drug use and/or minimizing the influence of drug-using networks may help prevent further involvement in the drug economy. The emergence of recent incarceration as a predictor for both models highlights the need for more appropriate drug rehabilitation programmes and demonstrates that continued criminalization of drug users may fuel Thailand's yaba epidemic. PMID- 21689917 TI - Initiation into prescription opioid misuse amongst young injection drug users. AB - BACKGROUND: Prescription opioids are the most frequently misused class of prescription drugs amongst young adults. Initiation into prescription opioid misuse is an important public health concern since opioids are increasingly associated with drug dependence and fatal overdose. Descriptive data about initiation into prescription opioid misuse amongst young injection drug users (IDUs) are scarce. METHODS: An exploratory qualitative study was undertaken to describe patterns of initiation into prescription opioid misuse amongst IDUs aged 16-25 years. Those young IDUs who had misused a prescription drug at least three times in the past three months were recruited during 2008 and 2009 in Los Angeles (n=25) and New York (n=25). Informed by an ethno-epidemiological approach, descriptive data from a semi-structured interview guide were analysed both quantitatively and qualitatively. RESULTS: Initiation into prescription opioid misuse was facilitated by easy access to opioids via participant's own prescription, family, or friends, and occurred earlier than misuse of other illicit drugs, such as heroin. Nearly all transitioned into sniffing opioids, most injected opioids, and many initiated injection drug use with an opioid. Motives for transitions to sniffing and injecting opioids included obtaining a more potent high and/or substituting for heroin; access to multiple sources of opioids was common amongst those who progressed to sniffing and injecting opioids. CONCLUSION: Prescription opioid misuse was a key feature of trajectories into injection drug use and/or heroin use amongst this sample of young IDUs. A new pattern of drug use may be emerging whereby IDUs initiate prescription opioid misuse before using heroin. PMID- 21689918 TI - If supply-oriented drug policy is broken, can harm reduction help fix it? Melding disciplines and methods to advance international drug-control policy. AB - Critics of the international drug-control regime contend that supply-oriented policy interventions are not just ineffective, but, in focusing almost exclusively on supply reduction, they also produce unintended adverse consequences. Evidence from the world heroin market supports their claims. The balance of the effects of policy is yet unknown, but the prospect of adverse consequences underlies a central paradox of contemporary supply-oriented policy. In this paper, we evaluate whether harm reduction, a subject of intense debate in the demand-oriented drug-policy community, can provide a unifying foundation for supply-oriented drug policy and speak more directly to policy goals. Our analysis rests on an extensive review of the literature on harm reduction and draws insight from other policy communities' disciplines and methods. First, we explore the paradoxes of supply-oriented policy that initially motivated our interest in harm reduction; second, we consider the conceptual and technical challenges that have contributed to the debate on harm reduction and assess their relevance to a supply-oriented application; third, we examine responses to those challenges, i.e., various tools (taxonomies, models, and measurement strategies), that can be used to identify, categorize, and assess harms. Despite substantial conceptual and technical challenges, we find that harm reduction can provide a basis for assessing the net consequences of supply-oriented drug policy, choosing more rigorously amongst policy options, and identifying new options. In addition, we outline a practical path forward for assessing harms and policy options. On the basis of our analysis, we suggest pursuing a harm-based approach and making a clearer distinction between supply-oriented and supply-reduction policy. PMID- 21689919 TI - Material and energy recovery in integrated waste management systems: the potential for energy recovery. AB - This article is part of a set of six coordinated papers reporting the main findings of a research project carried out by five Italian universities on "Material and energy recovery in Integrated Waste Management Systems (IWMS)". An overview of the project and a summary of the most relevant results can be found in the introductory article of the series. This paper describes the work related to the evaluation of mass and energy balances, which has consisted of three major efforts (i) development of a model for quantifying the energy content and the elemental compositions of the waste streams appearing in a IWMS; (ii) upgrade of an earlier model to predict the performances of Waste-to-Energy (WtE) plants; (iii) evaluation of mass and energy balances of all the scenarios and the recovery paths considered in the project. Results show that not only the amount of material available for energy recovery is significantly higher than the Unsorted Residual Waste (URW) left after Separate Collection (SC), because selection and recycling generate significant amounts of residues, but its heating value is higher than that of the original, gross waste. Therefore, the energy potential of what is left after recycling is always higher than the complement to 100% of the Source Separation Level (SSL). Also, increasing SSL has marginal effects on the potential for energy recovery: nearly doubling SSL (from 35% to 65%) reduces the energy potential only by one fourth. Consequently, even at high SSL energy recovery is a fundamental step of a sustainable waste management system. Variations of SSL do bring about variations of the composition, heating value and moisture content of the material fed to WtE plants, but these variations (i) are smaller than one can expect; (ii) have marginal effects on the performances of the WtE plant. These considerations suggest that the mere value of SSL is not a good indicator of the quality of the waste management system, nor of its energy and environmental outcome. Given the well-known dependence of the efficiency of steam power plants with their power output, the efficiency of energy recovery crucially depends on the size of the IWMS served by the WtE plant. A fivefold increase of the amount of gross waste handled in the IWMS (from 150,000 to 750,000 tons per year of gross waste) allows increasing the electric efficiencies of the WtE plant by about 6-7 percentage points (from 21-23% to 28.5% circa). PMID- 21689920 TI - Pyrolysis of municipal plastic wastes II: Influence of raw material composition under catalytic conditions. AB - In this work, the results obtained in catalytic pyrolysis of three plastic waste streams which are the rejects of an industrial packing wastes sorting plant are presented. The samples have been pyrolysed in a 3.5 dm(3) reactor under semi batch conditions at 440 degrees C for 30 min in nitrogen atmosphere. Commercial ZSM-5 zeolite has been used as catalyst in liquid phase contact. In every case, high HHV gases and liquids which can be useful as fuels or source of chemicals are obtained. A solid fraction composed of the inorganic material contained in the raw materials and some char formed in the pyrolysis process is also obtained. The zeolite has shown to be very effective to produce liquids with great aromatics content and C3-C4 fraction rich gases, even though the raw material was mainly composed of polyolefins. The characteristics of the pyrolysis products as well as the effect of the catalyst vary depending on the composition of the raw material. When paper rich samples are pyrolysed, ZSM-5 zeolite increases water production and reduces CO and CO(2) generation. If stepwise pyrolysis is applied to such sample, the aqueous liquid phase can be separated from the organic liquid fraction in a first low temperature step. PMID- 21689921 TI - Municipal solid waste generation in municipalities: quantifying impacts of household structure, commercial waste and domestic fuel. AB - Waste management planning requires reliable data concerning waste generation, influencing factors on waste generation and forecasts of waste quantities based on facts. This paper aims at identifying and quantifying differences between different municipalities' municipal solid waste (MSW) collection quantities based on data from waste management and on socio-economic indicators. A large set of 116 indicators from 542 municipalities in the Province of Styria was investigated. The resulting regression model included municipal tax revenue per capita, household size and the percentage of buildings with solid fuel heating systems. The model explains 74.3% of the MSW variation and the model assumptions are met. Other factors such as tourism, home composting or age distribution of the population did not significantly improve the model. According to the model, 21% of MSW collected in Styria was commercial waste and 18% of the generated MSW was burned in domestic heating systems. While the percentage of commercial waste is consistent with literature data, practically no literature data are available for the quantity of MSW burned, which seems to be overestimated by the model. The resulting regression model was used as basis for a waste prognosis model (Beigl and Lebersorger, in preparation). PMID- 21689922 TI - Computation and physiology of sensory-motor processing in eye movements. AB - Performance in sensory-motor behaviors guides our understanding of many of the key computational functions of the brain: the representation of sensory information, the translation of sensory signals to commands for movement, and the production of behavior. Eye movement behaviors have become a valuable testing ground for theories of neural computation because the neural circuitry has been well characterized and the mechanical control of the eye is comparatively simple. Here I review recent studies of eye movement behaviors that provide insight into sensory-motor computation at the single neuron and systems levels. They show that errors in sensory estimation dominate eye movement variability and that the motor system functions to reduce the behavioral impact of its own intrinsic noise sources. PMID- 21689923 TI - Representations of uncertainty in sensorimotor control. AB - Uncertainty is ubiquitous in our sensorimotor interactions, arising from factors such as sensory and motor noise and ambiguity about the environment. Setting it apart from previous theories, a quintessential property of the Bayesian framework for making inference about the state of world so as to select actions, is the requirement to represent the uncertainty associated with inferences in the form of probability distributions. In the context of sensorimotor control and learning, the Bayesian framework suggests that to respond optimally to environmental stimuli the central nervous system needs to construct estimates of the sensorimotor transformations, in the form of internal models, as well as represent the structure of the uncertainty in the inputs, outputs and in the transformations themselves. Here we review Bayesian inference and learning models that have been successful in demonstrating the sensitivity of the sensorimotor system to different forms of uncertainty as well as recent studies aimed at characterizing the representation of the uncertainty at different computational levels. PMID- 21689924 TI - The neural encoding of self-motion. AB - As we move through the world, information can be combined from multiple sources in order to allow us to perceive our self-motion. The vestibular system detects and encodes the motion of the head in space. In addition, extra-vestibular cues such as retinal-image motion (optic flow), proprioception, and motor efference signals, provide valuable motion cues. Here I focus on the coding strategies that are used by the brain to create neural representations of self-motion. I review recent studies comparing the thresholds of single versus populations of vestibular afferent and central neurons. I then consider recent advances in understanding the brain's strategy for combining information from the vestibular sensors with extra-vestibular cues to estimate self-motion. These studies emphasize the need to consider not only the rules by which multiple inputs are combined, but also how differences in the behavioral context govern the nature of what defines the optimal computation. PMID- 21689925 TI - Visual control of navigation in insects and its relevance for robotics. AB - Flying insects display remarkable agility, despite their diminutive eyes and brains. This review describes our growing understanding of how these creatures use visual information to stabilize flight, avoid collisions with objects, regulate flight speed, detect and intercept other flying insects such as mates or prey, navigate to a distant food source, and orchestrate flawless landings. It also outlines the ways in which these insights are now being used to develop novel, biologically inspired strategies for the guidance of autonomous, airborne vehicles. PMID- 21689926 TI - Neural circuit flexibility in a small sensorimotor system. AB - Neuronal circuits underlying rhythmic behaviors (central pattern generators: CPGs) can generate rhythmic motor output without sensory input. However, sensory input is pivotal for generating behaviorally relevant CPG output. Here we discuss recent work in the decapod crustacean stomatogastric nervous system (STNS) identifying cellular and synaptic mechanisms whereby sensory inputs select particular motor outputs from CPG circuits. This includes several examples in which sensory neurons regulate the impact of descending projection neurons on CPG circuits. This level of analysis is possible in the STNS due to the relatively unique access to identified circuit, projection, and sensory neurons. These studies are also revealing additional degrees of freedom in sensorimotor integration that underlie the extensive flexibility intrinsic to rhythmic motor systems. PMID- 21689927 TI - Health-related quality of life in patients with advanced renal cell carcinoma receiving pazopanib or placebo in a randomised phase III trial. AB - BACKGROUND: In a double-blind, randomised phase III trial of advanced renal cell carcinoma patients, pazopanib 800mg QD (n=290) versus placebo (n=145) significantly prolonged progression-free survival (hazard ratio (HR)=0.46, 95% confidence interval [CI] 0.34-0.62, p-value<0.0001), without important differences in health-related quality of life (HRQoL). This post-hoc analysis evaluated time to HRQoL deterioration and whether tumour response/stabilisation was associated with HRQoL improvement. METHODS: HRQoL was assessed using EORTC QLQ-C30 and EQ-5D. Effect of pazopanib on time to ?20% decline from baseline in summary scores was estimated for all patients and by prior treatment. Analyses were conducted for different HRQoL deterioration thresholds. HRQoL changes were stratified by benefit and compared: complete response (CR) or partial response (PR) versus progressive disease (PD); CR/PR versus stable disease (SD), and SD versus PD. RESULTS: There was a trend for pazopanib patients to be less likely than placebo patients to experience ?20% HRQoL deterioration in EORTC-QLQ-C-30 global health status/QOL scale (HR=0.77; 95% CI 0.57-1.03, not significant). Results by prior treatment and different HRQoL deterioration thresholds were similar. Patients with CR/PR and SD experienced significantly less HRQoL deterioration than those with PD (p<0.001, p=0.0024, respectively); mean differences between patients with CR/PR and PD exceeded the pre-determined minimally important difference (MID). Differences between patients with SD and PD did not exceed pre-determined MID. Results were generally consistent across treatment and EQ-5D summary scores. CONCLUSION: Results support the favourable benefit-risk profile of pazopanib and suggest patients experiencing tumour response/stabilisation also may have better HRQoL compared to those without this response. PMID- 21689928 TI - Bacillus mojavensis strain 32A, a bioflocculant-producing bacterium isolated from an Egyptian salt production pond. AB - Bacillus mojavensis strain 32A that exhibited 96.11% flocculation efficiency for clay suspensions was selected from other 15 comparative strains. Under growth condition, strain 32A was able to produce 5.2g/L of purified biopolymer. Its constituent was mainly polysaccharide and protein with proportional of 98.4-1.6% respectively. FTIR spectrum was confirming its chemical analysis. This biopolymer attain very fast sedimentation rate. The cost-effective biopolymer and CaCl(2) dosages were 3mg/L and 5 ml/L respectively that posed 89.7% flocculation efficiency. These dosages were suitable only for clay concentrations <=5g/L. The maximum flocculation efficiency of the biopolymer recorded at pH 1.0 of clay suspension. The too high (>75 degrees C) or too low (<25 degrees C) clay suspension temperature was unfavorable for the biopolymer flocculation performance. The biopolymer solution utilized high thermal stability over the temperature range of 5-60 degrees C. Furthermore, its pH stability recorded at pH range of 5-9. PMID- 21689930 TI - Applying the pro-drug approach to afford highly bioavailable antagonists of P2Y(14). AB - Our series of competitive antagonists against the G-protein coupled receptor P2Y(14) were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323 fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared (7a-7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile. PMID- 21689929 TI - Production of bioethanol, methane and heat from sugarcane bagasse in a biorefinery concept. AB - The potential of biogas production from the residues of second generation bioethanol production was investigated taking into consideration two types of pretreatment: lime or alkaline hydrogen peroxide. Bagasse was pretreated, enzymatically hydrolyzed and the wastes from pretreatment and hydrolysis were used to produce biogas. Results have shown that if pretreatment is carried out at a bagasse concentration of 4% DM, the highest global methane production is obtained with the peroxide pretreatment: 72.1 Lmethane/kgbagasse. The recovery of lignin from the peroxide pretreatment liquor was also the highest, 112.7 +/- 0.01 g/kg of bagasse. Evaluation of four different biofuel production scenarios has shown that 63-65% of the energy that would be produced by bagasse incineration can be recovered by combining ethanol production with the combustion of lignin and hydrolysis residues, along with the anaerobic digestion of pretreatment liquors, while only 32-33% of the energy is recovered by bioethanol production alone. PMID- 21689932 TI - Structural investigation into the inhibitory mechanisms of indomethacin and its analogues towards human glyoxalase I. AB - In the present work, a combined study of kinetic analysis, molecular docking, and molecular dynamics simulations on indomethacin and its analogues is performed to better understand their inhibitory mechanisms towards human glyoxalase I (GLOI). A remarkable correlation (R(2)=0.974) was observed for six inhibitors including indomethacin between their experimental inhibitory affinities and predicted binding free energy parameter (DeltaG(bind,pred)). This suggests that DeltaG(bind,pred) of a GLOI/inhibitor complex can be efficiently used to interpolate the experimental inhibitory affinity of a ligand of similar nature in the GLOI enzyme system. Energetic analyses revealed that electrostatic contribution plays an important role in their inhibitory mechanisms, which reflects the significant contribution of the coordination bond between zinc and ligands. The present work highlights that indomethacin is a promising lead as GLOI inhibitors for further development since it may bind all subsites in the active site pocket of GLOI and stabilize the flexible loop (152-159). PMID- 21689931 TI - Reproducible enrichment of extracellular heat shock proteins from blood serum using monomeric avidin. AB - Extracellular heat shock proteins (eHsps) in blood circulation have been associated with various diseases, including cancer. However, the lack of methods to enrich eHsps from serum samples has hampered the characterization of eHsps. This Letter presents our serendipitous finding that the monomeric avidin resin can serve as an affinity resin to enrich eHsps from blood serum. Biochemical mechanism of this eHsp enrichment as well as implications in biomarker discovery is discussed. PMID- 21689933 TI - Aryl 1,4-diazepane compounds as potent and selective CB2 agonists: optimization of drug-like properties and target independent parameters. AB - A high throughput screening campaign identified aryl 1,4-diazepane compounds as potent and selective cannabinoid receptor 2 agonists as compared to cannabinoid receptor 1. This class of compounds suffered from poor drug-like parameters as well as low microsomal stability and poor solubility. Structure-activity relationships are described with a focus on improving the drug-like parameters resulting in compounds with improved solubility and permeability. PMID- 21689935 TI - Generation of 3,8-substituted 1,2,4-triazolopyridines as potent inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1). AB - A series of pyridyl amide/sulfonamide inhibitors of 11beta-HSD-1 were modified to incorporate a novel 1,2,4-triazolopyridine scaffold. Optimization of substituents at the 3 and 8 position of the TZP core, with a special focus on enhancing metabolic stability, resulted in the identification of compound 38 as a potent and metabolically stable inhibitor of the enzyme. PMID- 21689934 TI - Profiling base excision repair glycosylases with synthesized transition state analogs. AB - Two base excision repair glycosylase (BER) transition state (TS) mimics, (3R,4R) 1-benzyl (hydroxymethyl) pyrrolidin-3-ol (1NBn) and (3R,4R)-(hydroxymethyl) pyrrolidin-3-ol (1N), were synthesized using an improved method. Several BER glycosylases that repair oxidized DNA bases, bacterial formamidopyrimdine glycosylase (Fpg), human OG glycosylase (hOGG1) and human Nei-like glycosylase 1 (hNEIL1) exhibit exceptionally high affinity (K(d)~pM) with DNA duplexes containing the 1NBn and 1N nucleotide. Notably, comparison of the K(d) values of both TS mimics relative to an abasic analog (THF) in duplex contexts paired opposite C or A suggest that these DNA repair enzymes use distinctly different mechanisms for damaged base recognition and catalysis despite having overlapping substrate specificities. PMID- 21689936 TI - Synthesis and anti-inflammatory activity of some novel 3-phenyl-N-[3-(4 phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives. AB - A new series of 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5 carboxamide derivatives were synthesized and investigated their anti-inflammatory activities using carrageenan-induced rat paw edema model in vivo. All the synthesized compounds were found to be potent anti-inflammatory agents. PMID- 21689937 TI - 179th ENMC international workshop: pregnancy in women with neuromuscular disorders 5-7 November 2010, Naarden, The Netherlands. PMID- 21689938 TI - Feasibility of breast conserving surgery for Paget's disease. AB - INTRODUCTION: The standard treatment for Paget's disease of the breast is mastectomy. Since it is frequently associated with underlying carcinoma, many surgeons are reluctant to choose breast conserving surgery for Paget's disease. PATIENTS AND METHODS: We retrospectively analyzed a series of 59 patients with Paget's disease who had undergone mastectomy at the National Cancer Center Hospital between 1963 and 2009. RESULTS: In 55 of 59 cases (93%) there was underlying carcinoma in the ipsilateral breast. Clinically, 27 (46%) patients had no evidence of other tumors, but 23 (85%) had underlying histopathologically confirmed carcinoma. Based on the data from this subset, cone excision with a 3 cm radius and a 4-cm radius could completely resect any underlying malignancy in 74% and 85% of patients, respectively. CONCLUSION: As Paget's disease is frequently accompanied by underlying intraductal and/or invasive carcinoma, patients should be carefully selected for breast conserving surgery. PMID- 21689939 TI - Synthesis and biological evaluation of naphthyl phenyl ethers (NPEs) as novel nonnucleoside HIV-1 reverse transcriptase inhibitors. AB - A novel series of naphthyl phenyl ether analogues (NPEs) have been synthesized and evaluated for their in vitro activities against HIV in C8166 cells. Most of the compounds exhibited moderate to excellent anti-HIV activities. Among them the most active compound 12o showed excellent activities against wild-type HIV-1 with an EC(50) value of 4.60 nM, along with moderate activities against the double mutant strain HIV-1(IIIB) A17 (K103N+Y181C) and HIV-2 strain ROD with an EC(50) value of 0.82 and 4.40 MUM, respectively. Preliminary structure-activity relationship (SAR) among the newly synthesized NPEs was also investigated. PMID- 21689940 TI - Synthesis and structure-activity relationship of new 1,5-dialkyl-1,5 benzodiazepines as cholecystokinin-2 receptor antagonists. AB - This article deals with the synthesis and the activities of some 1,5-dialkyl-3 arylureido-1,5-benzodiazepin-2,4-diones which were prepared as potential CCK2 antagonists, with the intention to find a possible follow up of our lead compound GV150013, showing an improved pharmacokinetic profile. The phenyl ring at N-5 was replaced with more hydrophilic substituents, like alkyl groups bearing basic functions. In some cases, the resolution of the racemic key intermediates 3-amino benzodiazepines was also accomplished. Among the compounds synthesized and characterised so far in this class, the 5-morpholinoethyl derivative 54, was selected as potential follow up of GV150013 and submitted for further evaluation. PMID- 21689941 TI - Delocalized radiation damage in polymers. AB - We present and discuss measurements of electron-irradiation damage in polystyrene and other polymers, based on fading of the 7-eV energy-loss peak. These measurements suggest a large increase in characteristic dose as the electron-beam diameter is reduced from 1 MUm to below 1 nm. This finding is discussed in terms of secondary-electron production and delocalization of the inelastic scattering, both as it affects the volume of specimen in which the energy is deposited and the volume giving rise to the inelastic signal used to assess the damage. PMID- 21689942 TI - Revisiting lithium K and iron M2,3 edge superimposition: the case of lithium battery material LiFePO4. AB - Experimental electron energy-loss spectra are presented for FePO4, LiFePO4 and NaFePO4 from 0 to 80 eV. With the help of the NaFePO4 spectrum in the 50-80 eV range, the double peak observed in LiFePO4 could be ascribed to the presence of Fe(II) and not to the Li K edge, contrary to what was thought previously. Crystal field multiplet calculations confirm this attribution. Using VASP programme based on density functional theory, dielectric response calculations including local field effects in the Hartree approximation are then proven to properly simulate the fine structures due to the lithium K edge. By comparing absolute spectrum intensities, it is shown that the lithium K edge cannot be used to quantify lithium in such compounds. This detailed comparison between theoretical calculations and experimental spectra helps defining the relevant parameters governing intensities in the 50-80 energy range. PMID- 21689943 TI - Biochemical characterisation of prolyl aminopeptidase from shoots of triticale seedlings and its activity changes in response to suboptimal growth conditions. AB - Prolyl aminopeptidase (PAP) was isolated from the shoots of three-day-old triticale seedlings and was purified using a five-step purification procedure (acid precipitation, gel filtration, anion-exchange chromatography, hydrophobic chromatography and rechromatography). The enzyme was purified 460-fold with a recovery of 6%. Prolyl aminopeptidase appears to be a tetramer consisting of four subunits, each with a molecular weight of approximately 54kDa. Its pH and temperature optimum are pH 7.5 and 37 degrees C, respectively. The enzyme prefers substrates with Pro and Hyp at the N-terminus, but is also capable of hydrolysing beta-naphthylamides (beta-NA) of Ala, Phe, and Leu. The K(m) value of PAP against Pro-beta-NA was the lowest among the substrates tested and it was 1.47*10(-5)M. The activity of PAP was not inhibited by EDTA, 1,10-phenantroline, or pepstatin A. The most effective inhibitors were DFP, Pefabloc, and PMSF, which are serine protease inhibitors. However, significant inhibition was also observed in the presence of E-64, which modifies sulfhydryl groups. A significant increase of the aminopeptidase activity against Pro-beta-NA was observed in shoots of triticale plants grown under salinity, drought stress, and in the presence of cadmium and aluminium ions in the nutrient solution. PMID- 21689944 TI - Association between interleukin 15 receptor, alpha (IL15RA) polymorphism and Korean patients with ossification of the posterior longitudinal ligament. AB - OBJECTIVES: Recently, a number of evidences have been reported concerning the genetic factor involved in the development of ossification of the posterior longitudinal ligament (OPLL). The purpose of this study was to investigate single nucleotide polymorphisms (SNPs) of the interleukin 15 receptor, alpha (IL15RA) gene as a risk factor in Korean patients with OPLL. DESIGN: To investigate the genetic association, two coding SNPs (rs2296139, Thr73Thr; rs2228059, Asn182Thr) in IL15RA were genotyped in 166 OPLL patients and 230 control subjects. SNPStats, SNPAnalyzer, and Helixtree programs were used for association analysis. RESULTS: In the present study, we found the association between a missense SNP (rs2228059) and the risk of OPLL in codominant (p = 0.0028, OR = 1.58, 95% CI = 1.17-2.14), dominant (p = 0.0071, OR = 1.82, 95% CI = 1.17-2.82), and recessive models (p = 0.036, OR = 1.79, 95% CI = 1.04-3.09). The frequency of rs2228059 allele was significantly associated with the susceptibility of OPLL (p = 0.0043, OR = 1.52, 95% CI = 1.14-2.02). After Bonferroni correction, the missense SNP (rs2228059, Asn182Thr) still had significant correlations (p = 0.0056 in codominant model; p = 0.0142 in dominant model; p = 0.0086 in allele analysis). Haplotype variation in IL15RA was associated with OPLL (global haplotype test, p = 0.025). CONCLUSIONS: These results suggest that IL15RA polymorphism may be associated with the susceptibility of OPLL in Korean population. PMID- 21689945 TI - Maternal marital status and the risk of stillbirth and infant death: a population based cohort study on 40 million births in the United States. AB - OBJECTIVE: The objective of our study was to evaluate the association between maternal marital status and the risk of fetal and infant death, including sudden infant death syndrome (SIDS). METHODS: We conducted a population-based cohort study using the Centers for Disease Control and Prevention's Linked Birth-Infant Death and Fetal Death data on all births in the United States between 1995 and 2004. Marital status was obtained from the birth certificate. The adjusted effect of marital status on the risk of fetal and infant mortalities was estimated using unconditional logistic regression analysis. RESULTS: The cohort consisted of 40,529,306 births, of which 37,461,715 met study criteria. There were 130,353 stillbirths (3.5/1,000 births) and 140,175 infant deaths (3.8/1,000 births), of which 24,066 were due to SIDS (0.6/1,000 births). Rates of nonmarital births increased from 31.3% to 35.4% over the study period. As compared with births from married women, births from unmarried women were at an increased risk of stillbirths (relative rise [RR], 1.24; 95% confidence interval [CI], 1.21-1.26), total infant deaths (RR, 1.45; 95% CI, 1.42-1.47), and SIDS (RR, 1.70; 95% CI, 1.63-1.78). Among unmarried women, those at a higher risk of fetal and infant death were women under 15 or over 40 years of age, African-American women, and those who received no prenatal care. CONCLUSION: Nonmarital childbearing seems to be associated with an increased risk of fetal and infant death, including SIDS. Promoting access to care and targeting unmarried mothers-to-be with the goal of educating, increasing awareness, and providing resources for proper obstetrical and maternal care may be of great benefit to their pregnancies. PMID- 21689946 TI - Combined effects of speed and directional change on postural adjustments during gait initiation. AB - The study of gait initiation (GI) has primarily focused on gait initiated in a forward direction, however, in everyday life, GI is often combined with a directional change. Ten young adults initiated gait with their right foot in four directions (to the left: -15 degrees , straight ahead: 0 degrees , to the right: 15 degrees and 30 degrees ) at self-selected and fast gait speeds. The relationship between starting direction of GI and the lateral center of foot pressure displacement for normal (r(2)=0.57) and fast gait speed (r(2)=0.75) indicated that the lateral component plays an important role with regards to controlling the desired direction of gait. At the first step of the swing limb, the progression velocity of the center of mass (CM) remained slower for the 30 degrees condition only, whereas no difference was found between directions for CM velocity perpendicular to the intended direction. These results suggest that postural adjustments are scaled to initiate gait in a predetermined direction. By the first step, the orientation of CM is toward the intended direction of gait, however, when gait is initiated in combination with a large change in direction, additional adjustments may be required to reach the intended progression velocity. PMID- 21689947 TI - Neuromuscular efficiency during sit to stand movement in women with knee osteoarthritis. AB - The purpose of this study was to investigate the neuromuscular efficiency of women with knee osteoarthritis (OA) when performing a sit-to-stand movement and during maximum strength efforts. Twelve women with unilateral knee OA (age 60.33+/-6.66 years, height 1.61+/-0.05 m, mass 77.08+/-9.2 kg) and 11 controls (age 56.54+/-5.46 years, height 1.64+/-0.05 m, mass 77.36+/-13.34 kg) participated in this study. Subjects performed a sit-to-stand movement from a chair while position of center of pressure and knee angular speed were recorded. Furthermore, maximal isokinetic knee extension and flexion strength at 60 degrees /s, 120 degrees /s and 150 degrees /s was measured. Surface, electromyography (EMG) from the biceps femoris (BF), vastus lateralis (VL) and vastus medialis (VM) was recorded during all tests. Analysis of variance (ANOVA) showed that during the sit-to-stand OA group demonstrated significantly lower knee angular speed (44.49+/-9.61 degrees /s vs. 71.68+/-19.86 degrees /s), a more posterior position of the center of pressure (39.20+/-7.02% vs. 41.95+/-2.49%) and a higher antagonist BF activation (57.13+/-20.55% vs. 32.01+/-19.5%) compared with controls (p<0.05). Further, women with knee OA demonstrated a lower Moment-to-EMG ratio than controls in extension and eccentric flexion at 60 degrees /s and 150 degrees /s, while the opposite was found for concentric flexion at 60 degrees /s (p<0.05). Among other factors, the slower performance of the sit-to-stand movement in women with OA is due to a less efficient use of the knee extensor muscles (less force per unit of EMG) and, perhaps, a higher BF antagonist co activation. This may lead subjects with OA to adopt a different movement strategy compared with controls. PMID- 21689948 TI - The metaphysics & phenomenology of perceptual experience: a reply to Conduct. PMID- 21689949 TI - The impact of employment of part-time surgeons on the expected surgeon shortage. AB - BACKGROUND: The trend for choosing to work part-time (PT) in medicine is increasing. We hypothesize that strategies to employ PT surgeons and prolong the duration of practice might reduce the surgeon shortage considerably. We calculated the effects of PT employment on the surgical workforce. STUDY DESIGN: We estimated the surgical workforce in obstetrics and gynecology, general surgery, thoracic surgery, ENT, orthopaedic surgery, urology, and neurosurgery to be 99,000 in 2005. We assumed 3,635 Board Certificates would be granted each year and surgeons will practice for 30 years, with 3,300 retiring each year. Scenarios were constructed with one-quarter (scenario 1), one-half (scenario 2), or three quarters (scenario 3) of potential retirees working half-time for an additional 10 years. RESULTS: By 2030, with other variables unchanged, the United States would have 4,125; 8,250; and 12,375 additional PT surgeons under scenario 1 (4% increase), scenario 2 (8% increase), and scenario 3 (12% increase), respectively, with a corresponding reduction in the shortage of surgeons. CONCLUSIONS: An opportunity exists to reduce the shortage of surgeons by offering models for PT employment particularly to mid-career women and retiring surgeons. Employment models should address flexible work schedules, malpractice premium adjustments, academic promotion, maintenance of certification and licensure, and employment benefits. PMID- 21689950 TI - A novel technique for natural orifice endoscopic full-thickness colon wall resection: an experimental pilot study. AB - BACKGROUND: Natural orifice endoscopic full-thickness colon resection attempts to overcome the need for invasive surgery in selected colorectal indications. Because basic technical requirements have not been met so far, the aim of this study was to develop a novel technique for endolumenal colon-wedge resection addressing current shortcomings. STUDY DESIGN: Endoscopic full-thickness colon resection was attempted in a human cadaver model (n = 2), explanted porcine colon stumps (n = 10), and 3 acute pig models. A hypothesized colon lesion was created and retracted into an endoscopic clip closure system (ECCS). Initially used endoscopic graspers (n = 2) were replaced by a T-tag suture approach for retraction (n = 13). T-type anchors were deployed circumferentially to the lesion, which simultaneously marked resection margins. The clip was then applied for pre-resection tissue closure. The inverted tissue was excised by snare resection and was removed together with the sutures. Air leak-pressure of tissue closure was tested. RESULTS: Endoscopic full-thickness colon resection was achieved in 14 of 15 attempts. The mean diameter (+/-SD) of resected animal specimen, including the predetermined margins, was 26 +/- 4 mm. Using the T-tag sutures for retraction, the defined lesion was neither touched by an endoscopic grasper nor compromised by puncturing the center. Leak pressure tests revealed a significantly higher air pressure resistance of the pre-resection ECCS closure (61 +/- 5 mmHg) compared with the hand-sewn control (26 +/- 7 mmHg). CONCLUSIONS: A novel endoscopic technique for full-thickness colon wall resection using tissue anchors for traction and an ECCS for pre-resection tissue closure appears to address several fundamental surgical principles. However, further studies are necessary before initial clinical application. PMID- 21689951 TI - That was then, this is now. PMID- 21689952 TI - Predicting aneurysmal dilatation after type B aortic dissection. PMID- 21689954 TI - An in vitro evaluation of antifungal activity of bioaggregate. AB - OBJECTIVE: The aim of this study was to evaluate, in vitro, the antifungal effect of bioaggregate (BA) against Candida albicans by using the direct contact method. STUDY DESIGN: BA was tested freshly mixed and after 24-hour set on C. albicans. The tested BA was incubated with C. albicans in plastic tissue clusters for 1 hour, 24 hours, and 3 and 5 days. Aliquots of 0.1 mL were taken from each well at the end of the incubation periods and transfered to tubes containing 5 mL fresh Sabouraud broth. All tubes were vortexed and then incubated at 37 degrees C and observed for the subsequent 5 days. Growth of the fungi was observed daily by the presence of turbidity in the tubes. The results were statistically analyzed by using Kaplan-Meier test. RESULTS: The freshly mixed and set BA had no antifungal effect at 1 and 24 hours of contact. Both mixes demonstrated complete fungicidal activity after 24 hours' contact. Statistical analysis showed a highly significant difference between the negative and positive control groups (P < .001) and a significant difference between the freshly mixed and 24-hour set BA groups (P < .001) at 24 hours. CONCLUSIONS: BA (freshly mixed and 24-hour set) was effective against C. albicans after 24 hours. PMID- 21689955 TI - Conservative treatment of dentigerous cyst associated with primary teeth. AB - Dentigerous cyst is the most common odontogenic cyst. It is characterized by a unilocular radiolucent lesion that encloses permanent tooth buds or, under certain circumstances, displaced tooth buds. Buccal bony expansion is the most common clinical feature. Several treatment modalities have been mentioned in the literature for management of dentigerous cysts. The purpose of this article was to report an extensive right mandibular dentigerous cyst on a 10-year-old boy. Marsupialization was chosen to preserve the permanent tooth bud and a denturelike obturator was then provided for space maintenance and masticatory function. Long term follow-up revealed good healing of the bony lesion with converted tooth eruption. PMID- 21689957 TI - Lawsonia intracellularis-specific interferon gamma gene expression by peripheral blood mononuclear cells in vaccinated and naturally infected foals. AB - The cell-mediated immune response to Lawsonia intracellularis, the agent of equine proliferative enteropathy (EPE), was investigated in vaccinated and naturally infected foals. Interferon (IFN)-gamma gene expression was determined in peripheral blood mononuclear cells collected from vaccinated (n=6) and control foals (n=6) every 30 days for 180 days following first vaccine administration, and from clinically affected foals (n=16) within 7-10 days of diagnosing EPE. Seroconversion (immunoperoxidase monolayer assay titer >=60) occurred in 5/6 vaccinated foals between 60 and 90 days following the first vaccine administration and these foals remained seropositive for the remaining study period. IFN-gamma gene expression in all vaccinated foals was significantly higher (P<0.05) on days 60-180 following first vaccine administration compared to IFN-gamma gene expression in control foals. When IFN-gamma gene transcription was compared between naturally infected and vaccinated foals, a significant difference (P<0.05) was observed only for day 0. PMID- 21689958 TI - The rapidly evolving field of biomarkers of cardiac function and injury in dogs: challenges and next steps. PMID- 21689959 TI - Fetal protection against bovine viral diarrhoea type 1 virus infection after one administration of a live-attenuated vaccine. AB - A modified-live vaccine has been shown previously to prevent fetal infection with bovine viral diarrhoea virus (BVDV)-2 and, to some extent BVDV-1, when used in association with an inactivated vaccine in a two-step vaccination protocol. In this challenge study, the modified-live vaccine used alone was able to protect 13 heifers between 49 and 96 days of gestation at challenge from leucopenia and virus replication and, for a 4-month period, to prevent fetal infection. The efficacy of the BVDV-1f 22146/Han81 challenge was demonstrated by virus isolation from the fetuses of all nine non-vaccinated, control heifers. However, the small number of heifers tested meant that the vaccination failure rate could be as high as 10% in the field. PMID- 21689960 TI - In vitro permissivity of bovine peripheral blood mononuclear cells to bovine viral diarrhoea virus is dependent on the animal specific immune status. AB - The in vitro permissivity to infection with homologous and heterologous bovine viral diarrhoea virus (BVDV) strains of bovine peripheral blood mononuclear cells (PBMCs) from eight naive and eight BVDV-1b immune animals was studied. Four reference strains (BVDV-1a NADL, BVDV-1b NY-1, BVDV-2 125 and BVDV-2 890) were selected, based on genotype, prevalence and biotype. Virus neutralizing antibody titres were determined at bleeding and the viral loads were measured in PBMCs by end point titration in cell culture and by real-time PCR. PBMCs from both naive and immune animals became infected by all BVDV strains tested, although virus titres were lower for immune heifers than naive ones; the differences were significant for NADL (P<0.05) and 890 (P<0.001) strains. The in vitro model used in this study showed that PBMCs from immune animals are susceptible to re infection with both homologous and heterologous BVDV strains, albeit at a lower extent than naive cattle. PMID- 21689962 TI - The prevalence of symptomatic orthostatic hypotension in patients with Parkinson's disease and atypical parkinsonism. AB - Non-motor symptoms in Parkinson disease (PD) have been increasingly recognized as a major cause of declining health-related quality of life. We aimed to determine the prevalence of symptomatic orthostatic hypotension (OH) in patients with PD and atypical parkinsonism, and to evaluate the risk factors for OH in this population. We reviewed the records of 1318 patients diagnosed with PD or atypical parkinsonism at the Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine. The frequency of symptomatic OH was 81% (21/26) in patients with multiple system atrophy (MSA), 18% (198/1125) of PD patients, and 19% (31/167) of patients with non-MSA atypical parkinsonism. Among PD patients, those with symptoms of OH were significantly older (p = 0.001), had more advanced Hoehn & Yahr stage (p = 0.007), a longer duration of PD symptoms (p = 0.031), and a greater range between their highest and lowest sitting systolic and diastolic BPs (p = 0.0001) over time. In the atypical parkinsonism group, excluding MSA, patients with symptoms of OH were taking more anti-hypertensive medications than those without symptoms of OH (p = 0.043). On the other hand, MSA patients with symptoms of OH were less likely to be taking anti-hypertensive medications than those without symptoms (p = 0.035). In conclusion, symptomatic OH is a common cause of disability in patients with PD, atypical parkinsonian disorders, and especially in patients with MSA. PMID- 21689963 TI - Neurotrophic factors for the treatment of Parkinson's disease. AB - Parkinson's disease (PD) is a common neurodegenerative disorder caused by the progressive degeneration of the nigrostriatal dopaminergic pathway. The resulting loss of dopamine neurotransmission is responsible for the symptoms of the disease. Available treatments are initially successful in treating PD symptoms; however, their long-term use is associated with complications and they cannot stop the neurodegeneration. Current research aims at developing new therapies to halt/reverse the neurodegenerative process, rather than treating symptoms. Neurotrophic factors are proteins critical for maintenance and protection of neurones in the developing and adult brain. Several neurotrophic factors have been investigated for their protective effects on dopaminergic neurones. Here we review some of the most promising factors and provide an update on their status in clinical trials. PMID- 21689961 TI - Production of uniformly sized serum albumin and dextrose microbubbles. AB - Uniformly-sized preparations with average microbubble (MB) diameters from 1 to 7 MUm were produced reliably by sonicating decafluorobutane-saturated solutions of serum albumin and dextrose. Detailed protocols for producing and size-separating the MBs are presented, along with the effects that changing each production parameter (serum albumin concentration, sonication power, sonication time, etc.) had on MB size distribution and acoustic stability. These protocols can be used to produce MBs for experimental applications or serve as templates for developing new protocols that yield MBs with physical and acoustic properties better suited to specific applications. Size stability and ultrasonic performance quality control tests were developed to assure that successive MB preparations perform identically and to distinguish the physical and acoustic properties of identically sized MBs produced with different serum albumin-dextrose formulations and sonication parameters. MBs can be stored at 5 degrees C for protracted periods (2 weeks to one year depending on formulation). PMID- 21689964 TI - Contextual computer-aided detection: improving bright lesion detection in retinal images and coronary calcification identification in CT scans. AB - Contextual information plays an important role in medical image understanding. Medical experts make use of context to detect and differentiate pathologies in medical images, especially when interpreting difficult cases. The majority of computer-aided diagnosis (CAD) systems, however, employ only local information to classify candidates, without taking into account global image information or the relation of a candidate with neighboring structures. In this paper, we present a generic system for including contextual information in a CAD system. Context is described by means of high-level features based on the spatial relation between lesion candidates and surrounding anatomical landmarks and lesions of different classes (static contextual features) and lesions of the same type (dynamic contextual features). We demonstrate the added value of contextual CAD for two real-world CAD tasks: the identification of exudates and drusen in 2D retinal images and coronary calcifications in 3D computed tomography scans. Results show that in both applications contextual CAD is superior to a local CAD approach with a significant increase of the figure of merit of the Free Receiver Operating Characteristic curve from 0.84 to 0.92 and from 0.88 to 0.98 for exudates and drusen, respectively, and from 0.87 to 0.93 for coronary calcifications. PMID- 21689965 TI - Treatment of dry eye: an analysis of the British Sjogren's syndrome association comparing substitute tear viscosity and subjective efficacy. AB - PURPOSE: This study aims to address the lack of independent subjective efficacy data on artificial tear substitutes in the treatment of dry eye due to the anecdotal association of 'thicker' products being more effective. METHODS: This is an independent study of the subjective use and efficacy of topical treatments used by members of the British Sjogren's Syndrome Association (BSSA) related to product viscosity. 2000 members of the BSSA were sent a questionnaire regarding their physical condition and the use of artificial tear substitutes. Viscosity analysis was performed on the most popular preparations. Statistical comparison is made between subjective efficacies related to substitute tear viscosity. RESULTS: 1088 patients responded giving information regarding their condition together with the subjective use and efficacy data of artificial tear substitutes. Visco-analysis was performed on the most popular preparations; these had more than 50 patients using them. In terms of subjective benefits related to viscosity for 'frequency' and 'duration' the data suggests a general trend toward viscous preparations being instilled less frequently and lasting longer; however this was not shown to be significantly correlated and some interesting comparisons are reported. CONCLUSIONS: The results confirm high levels of ocular lubricant use in the BSSA population. Our data investigates the often-anecdotal evidence that thicker preparations are more effective. However, we did not find this correlation to be statistically significant suggesting further study into factors related to subjective product efficacy. These results lay foundations for the development of future products in the treatment of severe dry eye. PMID- 21689966 TI - Sox2 nuclear expression is closely associated with poor prognosis in patients with histologically node-negative oral tongue squamous cell carcinoma. AB - Sox2 is a marker of embryonic stem cell pluripotency and plays an important role in tumor progression. However, Sox2 expression in oral tongue squamous cell carcinoma (OTSCC) and its correlation with patients' prognosis have not been investigated so far. In this study, we detected the expression of Sox2 in 82 patients with histologically node-negative (pN0) OTSCC by immunohistochemistry, and evaluated its correlation with clinicopatologic factors and disease prognosis. Sox2 positive expression was detected in 62.2% patients and showed a significant association with large tumor size. Survival analysis showed that patients with Sox2 positive expression had significantly poorer overall, cancer specific and disease-free survivals than those with Sox2 negative expression at 5years after operation (P=0.004, 0.004 and 0.001, respectively). Multivariate analysis demonstrated that Sox2 positive expression was an independent prognosticator of unfavorable overall, cancer-specific and disease-free survivals (P=0.032, 0.035 and 0.011, respectively). According to our results, Sox2 positive expression was frequent in pN0 OTSCC and involved in tumor progression. The measurement of Sox2 expression may be helpful in predicting relapse and prognosis of patients with pN0 OTSCC. PMID- 21689967 TI - Squamous cell carcinoma of the oral cavity rarely harbours oncogenic human papillomavirus. AB - Although it is now well established that a significant proportion of oropharyngeal squamous cell carcinomas (SCC) harbour oncogenic human papillomavirus (HPV) sequences, the frequency with which these sequences are detected in oral SCC (excluding oropharyngeal subsites) is highly variable. In an attempt to establish the true prevalence of HPV-16 and HPV-18 subtypes in oral SCC, we screened 142 consecutive cases from a UK cohort using both conventional PCR with consensus primers and type-specific quantitative PCR (Q-PCR), while at the same time employing a rigorous protocol to avoid sample contamination. Q-PCR revealed HPV sequences in five cases; two contained HPV-16 alone, two HPV-18 alone, and one sample carried both genotypes. However, only two of these cases (both HPV-16-positive) had moderate viral loads (51 and 91 viral copies per 100 cells respectively) and were positive for HPV DNA by conventional PCR. Both cases contained HPV DNA in tumour cells as shown by Q-PCR analysis of micro-dissected tissue and by in situ hybridisation. The remaining three cases had only very low viral loads (between 3 and 7 viral copies per 100 cells), were negative by conventional PCR and lacked HPV DNA in tumour cells. Our data provide strong evidence that oncogenic HPV is uncommon in oral SCC and that routine HPV testing of these tumours cannot be advocated. PMID- 21689968 TI - Spectral study of Eriochrome Blue Black R in different cationic surfactant solutions. AB - Interactions of anionic dye Eriochrome Blue Black R (EBBR) with various cationic micelles of surfactants n-alkyltrimethylammonium CnTAB (n=12; 14; 16 and 18) have been investigated spectrophotometrically at 25 degrees C in premicellar and postmicellar region. The results have shown that with increasing the alkyl chain length of surfactants, the maximum absorbance of EBBR shifted to a higher wavelength and the binding constants of EBBR to cationic micelles (Kb) increases. This confirms that the surfactant micelle, which has a longer alkyl hydrocarbon chain, enables greater solubilization of dye. Thus, the hydrophobic interaction of the dye with micelles increases in the order: C12TABX2Pi), OH (A2Sigma->X2Pi, 0-0), N2 (C3Piu >B3Pig, 0-0, 337.1 nm), and N2+ (B2Sigmau+->X2Sigmag+, 0-0, 391.4 nm) are investigated. The effects of the concentrations of Ar and O2 on the discharge diffuse performance are also studied. It is found that the emission intensities of NO (A2Sigma->X2Pi), OH (A2Sigma->X2Pi, 0-0), N2 (C3Piu->B3Pig, 0-0, 337.1 nm), and N2+ (B2Sigmau+->X2Sigmag+, 0-0, 391.4 nm) rise with increasing pulse peak voltage, pulse repetition rate, and the concentration of Ar, but decrease with increasing the concentration of O2. The main physicochemical processes involved are also discussed. PMID- 21689970 TI - A novel 5-mercapto triazole Schiff base as a selective chromogenic chemosensor for Cu2+. AB - A novel colorimetric cation sensor bearing phenol, thiol and HCN groups was designed and synthesized. In a DMSO/H2O (9:1, v/v) solution, the sensor exhibited highly selective recognition of Cu2+ among a range of metal ions tested. In the presence of Cu2+, solutions of the sensor underwent a dramatic color change from colorless to yellow, while the presence of other metal cations such as Zn2+, Pb2+, Cd2+, Ni2+, Co2+, Fe3+, Hg2+, Ag+ and Ca2+ had no effect on the color. The detection limit of the sensor toward Cu2+ is 8.0*10(-7) M and an association constant Ka of 4.3*10(5) M(-1) was measured. The sensing of Cu2+ by this sensor was found to be reversible, with the Cu2+-induced color being lost upon addition of EDTA. PMID- 21689971 TI - The charge ratio between O and N on amide bonds: a new approach to the mobile proton model. AB - The influence of charge distribution on the cleavage of the peptides was investigated by fragmentation efficiency curves and quantum chemical calculations in order to clarify the fragmentation mechanism in this paper. The peptide Arg Gly-Asp-Cys (RGDC) was oxidized to change the charge distribution, but its main sequence was retained. Under this study, it was illustrated that the fragmentation of the peptide RGDC became easier with each addition of an O atom to the Cys hydrosulfide group and the relative charge ratios between O and N (QO/QN) in the amide bonds had much to do with the cleavage of the peptide RGDC. For each amide bond, the situations coincided with overall conclusion: the increase of the QO/QN values results in a higher fragmentation efficiency and vice versa. The methods which combined fragmentation efficiency curves with the charge distribution of peptides provided a way to refine the mobile proton model for peptide fragmentation and to probe the discrepant fragmentation of peptides in peptide/protein identification. PMID- 21689972 TI - Synthesis and luminescent properties and theoretical investigation on electronic structure of nitrile-based 2-pyridone molecules. AB - 3-Cyano-4,6-dimethyl-2-pyridone and 3-cyano-4-methyl-6-phenyl-2-pyridone were synthesized effectively by the reaction of readily available 1,3-diketone and malononitrile directly and in good yield. Upon photoexcitation, 3-cyano-4-methyl 6-phenyl-2-pyridone in ethanol shows strong blue emission. The ground- and excited-state geometries, charge distributions, and excitation energies of 2 pyridone derivatives were evaluated by ab initio calculations. Organic light emitting diodes (OLED) made using 3-cyano-4-methyl-6-phenyl-2-pyridone as dopant showed blue light emission with a maximum electroluminescence (EL) emission at around 456 nm. PMID- 21689973 TI - A simple and green analytical method for determination of glyphosate in commercial formulations and water by diffuse reflectance spectroscopy. AB - This article describes a simple, inexpensive, and environmentally friendly method for the monitoring of glyphosate using diffuse reflectance spectroscopy. The proposed method is based on reflectance measurements of the colored compound produced from the spot test reaction between glyphosate and p dimethylaminocinnamaldehyde (p-DAC) in acid medium, using a filter paper as solid support. Experimental designs were used to optimize the analytical conditions. All reflectance measurements were carried out at 495 nm. Under optimal conditions, the glyphosate calibration graphs obtained by plotting the optical density of the reflectance signal (AR) against the concentration were linear in the range 50-500 MUg mL(-1), with a correlation coefficient of 0.9987. The limit of detection (LOD) for glyphosate was 7.28 MUg mL(-1). The technique was successfully applied to the direct determination of glyphosate in commercial formulations, as well as in water samples (river water, pure water and mineral drinking water) after a previous clean-up or pre-concentration step. Recoveries were in the ranges 93.2-102.6% and 91.3-102.9% for the commercial formulations and water samples, respectively. PMID- 21689974 TI - Spectroscopic and structural characterization of pascoite. AB - Pascoite mineral having yellow-orange colour of Colorado, USA origin has been characterized by EPR, optical and NIR spectroscopy. The colour dark red-orange to yellow-orange colour of the pascoite indicates that the mineral contain mixed valency of vanadium. The optical spectrum exhibits a number of electronic bands due to presence of VO(II) ions in the mineral. From EPR studies, the parameters of g, A are evaluated and the data confirm that the ion is in distorted octahedron. Optical absorption studies reveal that two sets of VO(II) is in distorted octahedron. The bands in NIR spectra are due to the overtones and combinations of water molecules. PMID- 21689975 TI - A novel fluoride ion colorimetric chemosensor based on coumarin. AB - A novel visible colorimetric sensor (L1) with high selectivity for fluoride ion based on coumarin has been synthesized by a simple modification of our earlier report. The chemosensor L1 shows an obvious color change from yellow to blue upon addition of fluoride ion with a large red shift of 145 nm in acetonitrile, and without interference of other anions such as Cl-, Br-, I-, NO3-, H2PO4-, HSO4-, and AcO-. The investigation of 1H NMR spectrum titration indicates the proposed mechanism is that F- first establishes a hydrogen bonding interaction with L1, and then the formation of [F-H-F]- induces deprotonation. PMID- 21689976 TI - Structural, vibrational and quantum chemical investigations on 5-chloro-2 hydroxybenzamide and 5-chloro-2-hydroxybenzoic acid. AB - The Fourier transform infrared (FTIR) and FT-Raman spectra of 5-chloro-2 hydroxybenzamide (5CBA) and 5-chloro-2-hydroxybenzoic acid (5C2HBA) have been recorded in the range 4000-400 and 4000-100 cm(-1), respectively. The complete vibrational fundamental modes of the compounds were assigned and analysed using the observed FTIR and FT-Raman data. The vibrational frequencies determined experimentally were compared with the theoretical wavenumbers calculated from ab initio HF and DFT-B3LYP gradient methods employing 6-31G** and 6-311++G** basis sets. The effect of halogen, hydroxyl groups and hydrogen bonding on the characteristic frequencies of the -COOH and -CONH2 group frequencies have been investigated. In 5CBA and 5C2HBA intramolecular hydrogen bond between a hydroxyl group and CO group makes a six membered ring, which causes the O?H interaction onto the resonance of the benzene ring. Comparison of the positions of the nu(OH) bands shows the nu(OH) band of 5CBA is located at considerably higher frequency which confirms a weaker hydrogen bond than in 5C2HBA. PMID- 21689977 TI - Infrared and Raman spectra, ab initio calculations, conformational stability and vibrational assignment of 1-bromo-1-silacyclopentane. AB - Infrared and Raman spectra (3500-60 cm(-1)) of gas and/or liquid and solid 1 bromo-1-silacyclopentane (c-C4H8SiBrH) have been recorded and the vibrational data indicate the presence of a single conformer with no symmetry which is consistent with the twisted form. Ab initio calculations with a variety of basis sets up to MP2(full)/6-311+G(2df,2pd) predict the envelope-axial and envelope equatorial conformers to be saddle points with nearly the same energies but approximately 900 cm(-1) (5.98 kJ/mol) lower in energy than the planar conformer. Density functional theory calculations by the B3LYP method predict slightly lower energies for the two envelope forms and considerably lower energy for the planar form compared to the MP2 predictions. By utilizing the MP2(full)/6-31G(d) calculations the force constants, frequencies, infrared intensities, band contours, Raman activities, and depolarization values have been obtained to support the vibrational assignment. Estimated r0 structural parameters have been obtained from adjusted MP2(full)/6-311+G(d,p) calculations. These experimental and theoretical results are compared to the corresponding quantities of some other five-membered rings. PMID- 21689978 TI - Synthesis, molecular modeling and spectroscopic characterization of nickel(II), copper(II), complexes of new 16-membered mixed-donor macrocyclic schiff base ligand incorporating a pendant alcohol function. AB - Complexes of Cu(II) and Ni(II) of the composition [M(L)X] [where M=Ni(II), Cu(II) and X=Cl-, NO3-, CH3COO-] were synthesized with 1,5-dioxo-9,10-diaza-3,ol tribenzo-(7,6,10,11,14,15) peptadecane, a N2O2 macrocyclic ligand. The complexes were characterized by elemental analysis, molar conductance measurements, UV-vis, IR, 1H NMR, 13C NMR, EPR and molecular modeling studies. All the complexes are non-electrolyte in nature. On the basis of spectral studies, an octahedral geometry has been assigned for Ni(II) complexes and a tetragonal geometry for Cu(II) complexes. PMID- 21689979 TI - A Ru(II) complex with 2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5 f][1,10]phenanthroline: synthesis, characterization, and acid-base and DNA binding properties. AB - A new Ru(II) complex of [Ru(bpy)2(Hmspip)]Cl2 {in which bpy=2,2'-bipyridine, Hmspip=2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline} have been synthesized and characterized. The ground- and excited-state acid-base properties of [Ru(bpy)2(Hmspip)]Cl2 and its parent complex of [Ru(bpy)2(Hpip)]Cl2 {Hpip=2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline} have been studied by UV visible (UV-vis) and emission spectrophotometric pH titrations. [Ru(bpy)2(Hmspip)]Cl2 acts as a calf thymus DNA intercalators with a binding constant of 4.0*10(5) M(-1) in buffered 50 mM NaCl, as evidenced by UV-vis and luminescence titrations, steady-state emission quenching by [Fe(CN)6]4-, DNA competitive binding with ethidium bromide, reverse salt titrations and viscosity measurements. PMID- 21689980 TI - Optical band gap and spectroscopic study of lithium alumino silicate glass containing Y3+ ions. AB - The effect of different amounts of Y2O3 dopant on lithium alumino silicate (LAS) glass has been studied in this work. Glasses having 14.8Li2O-20Al2O3-65.2SiO2 (wt%) composition accompanied with Y2O3 dopant were prepared by normal melting process. In order to calculate the absorption coefficient of samples, transmittance and reflectance spectra of polished samples were measured in the room temperature. Optical properties i.e. Fermi energy level, direct and indirect optical band gaps and Urbach energy were calculated using functionality of extinction coefficient from Fermi-Dirac distribution function, Tauc's plot and the exponential part of absorption coefficient diagram, respectively. It has been clarified that variation in mentioned optical parameters is associated with the changes in physical properties of samples i.e. density or molar mass. On the other hand, increasing of Y3+ ions in the glassy microstructure of samples provides a semiconducting character to LAS glass by reducing the direct and indirect optical band gaps of glass samples from 1.97 to 1.67 and 3.46 to 2.1 (eV), respectively. These changes could be attributed to the role of Y3+ ions as the network former in the track of SiO4 tetrahedrals. PMID- 21689981 TI - Motor Unit Number Index (MUNIX): reference values of five different muscles in healthy subjects from a multi-centre study. PMID- 21689982 TI - Echocardiographic findings in ischemic stroke patients with obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) has been associated with cardiac abnormalities. Whether any cardiac dysfunction is present in ischemic stroke patients with OSA is not known. The purpose of this study was to compare echocardiographic findings in ischemic stroke patients with and without OSA. METHODS: Nocturnal polysomnography was performed on 28 ischemic stroke subjects within 7 days of symptom onset. OSA was defined as an apnea-hypopnea index of >=10. Echocardiographic variables were compared between the OSA and non OSA groups using Wilcoxon signed-rank, chi-square, or Fisher's exact tests. RESULTS: The 14 (50%) subjects with OSA had comparable cardiac function and structure to those without OSA (n=14). Left ventricular (LV) mass index, LV ejection fraction, LV diastolic function, left atrial area, and right ventricular systolic function were not different between groups. Ischemic stroke subjects, regardless of their OSA status, had LV diastolic dysfunction with preserved systolic function. CONCLUSIONS: Subjects with and without OSA, based on polysomnography in the first 7 days after stroke, have comparable right and left ventricular function. PMID- 21689983 TI - A comparison of actigraphy scoring rules used in pediatric research. AB - BACKGROUND: The use of actigraphy in pediatric sleep research has increased over the past decade, yet few guidelines exist to help investigators with scoring and interpretation. The primary aim of this study was to compare two commonly reported non-automated rules for scoring sleep-onset and sleep-offset. METHODS: Forty children (8-12 years) wore an actigraph for one week and completed a daily sleep diary. Sleep-onset and sleep-offset were scored using the "15 minute rule" (onset: 1st of >= 15 consecutive minutes of sleep after reported bedtime; offset: last minute of >= 15 consecutive minutes of sleep prior to reported wake time) and the "3/5 minute rule" (onset: 1st of >= 3 consecutive minutes of sleep after reported bedtime; offset: last minute of >= 5 consecutive minutes of sleep prior to reported wake time). A blinded "no diary" rule was also examined (using unaided judgment to identify sleep-onset and sleep-offset). RESULTS: Statistical differences were found between scoring rules for sleep-offset [F (2,74)=7.68, p=.001], sleep period [F (2,74)=5.05, p=.009], wake after sleep-onset [F (2,74)=7.68, p=.001], sleep minutes [F (2,74)=3.62, p=.03], and sleep efficiency [F (2,74)=6.50, p=.003]; however, these differences were not clinically meaningful. CONCLUSIONS: While the findings from this study suggest that data can be compared across studies that use different scoring rules, standard scoring rules are needed to ensure that reported results are valid and meaningful. PMID- 21689984 TI - Associations of sleep duration with obesity and serum lipid profile in children and adolescents. AB - INTRODUCTION: The association between sleep duration, obesity, and serum lipid profile in the youth population is under-explored. OBJECTIVE: To evaluate the association between sleep duration, obesity and serum lipid profile in the youth population. METHODS: We conducted a cross-sectional population-based study with students recruited from primary and secondary schools in Hong Kong. Anthropometric measurements, fasting lipid profiles and validated questionnaires on sleep duration were performed. A subgroup (n=138) was randomly selected for both questionnaires and actigraphy to assess the agreement between subjective and objective measurements of sleep duration. RESULTS: We studied 2053 healthy children and adolescents aged 6-20 years. Their mean ages were 13.0+/-3.3 (boys) and 13.6+/-3.3 (girls) years. The average sleep duration during schooldays, weekends, and long holidays was 8.0+/-1.1, 9.6+/-1.2, and 9.8+/-1.2h in boys and 7.7+/-1.1, 9.9+/-1.2, and 10.1+/-1.2h in girls, respectively. Using logistic regression, age, and pubertal stage were associated with obesity in secondary school students, whereas male gender and short sleep duration were associated with obesity in primary school children. In secondary school children, those with long sleep duration, as compared to those with short sleep duration, were significantly associated with reduced risk to have high TC and LDL-C levels after adjustment for age, gender, BMI, and pubertal stage. There was no significant association between sleep duration and lipid levels in primary school children. CONCLUSION: Reduced sleep duration was associated with obesity and atherogenic dyslipidemia in young school children in Hong Kong. PMID- 21689985 TI - Narcolepsy and psychiatry: an evolving association of increasing interest. AB - Gelineau originally described narcolepsy as a disease with an organic cause. However, the disorder had undeniable emotional triggers and psychiatric-like expressions, and soon a psychiatric etiology of narcolepsy became a seriously considered option. In fact, the psychiatric view dominated scientific thinking for a long time, not necessarily to the benefit of patients. When hypocretin (orexin) defects were proven to be the cause of narcolepsy Gelineau's original disease model was shown to be right. However, the psychiatric symptoms of the disease were not forgotten afterwards, but gained a different significance: as psychiatric expressions of a brain disease. These symptoms, such as anxiety and eating disorders, can be highly debilitating and warrant clinical attention. Here, we describe the role of psychiatry in the history of narcolepsy, showing their evolving association. PMID- 21689986 TI - An investigation of shoulder forces in active shoulder tackles in rugby union football. AB - In rugby union football the tackle is the most frequently executed skill and one most associated with injury, including shoulder injury to the tackler. Despite the importance of the tackle, little is known about the magnitude of shoulder forces in the tackle and influencing factors. The objectives of the study were to measure the shoulder force in the tackle, as well as the effects of shoulder padding, skill level, side of body, player size, and experimental setting on shoulder force. Experiments were conducted in laboratory and field settings using a repeated measures design. Thirty-five participants were recruited to the laboratory and 98 to the field setting. All were male aged over 18 years with rugby experience. The maximum force applied to the shoulder in an active shoulder tackle was measured with a custom built forceplate incorporated into a 45 kg tackle bag. The overall average maximum shoulder force was 1660 N in the laboratory and 1997 N in the field. This difference was significant. The shoulder force for tackling without shoulder pads was 1684 N compared to 1635 N with shoulder pads. There was no difference between the shoulder forces on the dominant and non-dominant sides. Shoulder force reduced with tackle repetition. No relationship was observed between player skill level and size. A substantial force can be applied to the shoulder and to an opponent in the tackle. This force is within the shoulder's injury tolerance range and is unaffected by shoulder pads. PMID- 21689987 TI - Cervical screening strategies in resourced and resource-constrained countries. AB - Screening for cervical cancer is well established in resourced countries, but in resource-constrained countries, it is almost non-existent at national level. In resourced countries, the Pap test forms the hallmark of screening, with the human papillomavirus DNA test a recent adjunct. In many resourced countries, however, screening for cervical cancer is still far from ideal. A coverage around 50% prevails in some countries, and few have reached the target of 80% or more. Furthermore, the human papillomavirus test and newly developed biomarkers may lead to the development of a 'super test', which could be applied less frequently compared with present-day cytological screening. In resource-constrained countries, the movement is towards a 'screen and treat' approach. The main screening methods under investigation are the visual inspection after diluted acetic acid application test and the human papillomavirus test. Cryotherapy and large loop excision of the transformation zone have been used most often as treatment methods. The ideal seems to be the human papillomavirus test with large loop excision of the transformation zone, provided a low-cost human papillomavirus test becomes available. Coverage is even a greater problem in resource-constrained countries, a problem in need of urgent attention. Resource constrained countries, however, must curtail the high incidence of cervical cancer, which is often a lower priority than other pressing healthcare needs. PMID- 21689988 TI - The long-term effect of listening to Mozart K.448 decreases epileptiform discharges in children with epilepsy. AB - Mozart's Sonata for Two Pianos in D major, K.448 (Mozart K.448), has been shown to improve mental function, leading to what is known as the Mozart Effect. Our previous work revealed that epileptiform discharges in children with epilepsy decrease during and right after listening to Mozart K.448. However, the duration of the effect was not studied. In the study described here, we evaluated the long term effect of Mozart K.448 on epileptiform discharges in children with epilepsy. Eighteen children with epilepsy whose seizures were clinically well controlled with antiepileptic drugs were included. For each child, EEGs had revealed persistent epileptiform discharges for at least 6 months. These patients listened to Mozart K.448 for 8 minutes once a day before bedtime for 6 months. Epileptiform discharges were recorded and compared before and after 1, 2, and 6 months of listening to Mozart K.448. All of the children remained on the same antiepileptic drug over the 6 months. Relationships between number of epileptiform discharges and foci of discharges, intelligence, epilepsy etiology, age, and gender were analyzed. Epileptiform discharges significantly decreased by 53.2+/-47.4, 64.4+/-47.1, and 71.6+/-45.8%, respectively, after listening to Mozart K.448 for 1, 2, and 6 months. All patients except those with occipital discharges showed a significant decrease in epileptiform discharges. Patients with normal intelligence and idiopathic epilepsy had greater decreases than those with mental retardation and symptomatic epilepsy. Age and gender did not affect the results. We conclude that long-term listening to Mozart K.448 may be effective in decreasing epileptiform discharges in children with epilepsy in a chronologically progressive manner. PMID- 21689989 TI - Ethosuximide-induced mania in a 10-year-old boy. AB - Psychosis and suicidal ideation have been reported as side effects of ethosuximide treatment, but previous reports seldom place these symptoms in the context of mania. Given the recent renewed interest in ethosuximide as first-line therapy in children and adolescents, it is important for clinicians to be aware of the potential psychiatric complication of mania with this medication. Described here is the case of a 10-year-old boy who developed acute mania, as well as psychotic symptoms and suicidal ideation, on ethosuximide. PMID- 21689990 TI - Cervical spine bone mineral density as a function of vertebral level and anatomic location. AB - BACKGROUND CONTEXT: Bone mineral density (BMD) measurements acquired from quantitative computed tomography scans have been shown to correlate with bone mechanical properties such as strength, stiffness, and yield load. There are currently no reports of BMD as a function of anatomic location within each vertebra. PURPOSE: The overall objective of this study was to characterize BMD in the cervical spine as a function of level and anatomic location. STUDY DESIGN: Cervical spine BMD was evaluated in vivo using a clinically relevant age group. PATIENT SAMPLE: Twenty-two subjects (13 women and 9 men) were included with an average age of 48 +/- 7 years (range, 35-61 years). Ten subjects were recently diagnosed with cervical radiculopathy (age 49 +/- 8 years; six women and four men; and two smokers and eight nonsmokers), and 12 subjects were asymptomatic controls (age 46 +/- 6 years; seven women and five men; and three smokers, three quit smoking, and six nonsmokers). OUTCOME MEASURES: Physiologic measures included overall BMD for C3-C7, average BMD within 11 anatomically defined regions of interest for each vertebra, and density distribution (by volume) within each anatomic region and vertebral level. METHODS: Subject-specific three dimensional bone models were created from high-resolution computed tomography scans of the subaxial cervical spine (C3-C7). Custom software calculated the average BMD within 11 anatomically defined regions of interest for each three dimensional bone model. Bone mineral density values for each voxel of bone tissue were binned into 50 mg/cc ranges to determine the density distribution by volume. Repeated-measures analysis of variance was used to test for differences within subjects by level (C3-C7) and anatomic location. The correlation between BMD in the central vertebral body and the pedicle and lateral mass regions was tested using Pearson correlation. RESULTS: Average BMDs by level were 476, 503, 507, 473, and 414 mg/cm(3) for C3-C7, respectively. C3 and C6 BMDs were significantly less than those of C4 and C5 (p<.007). C7 BMD was significantly less than those of all other levels (all p<.001). Control and female subjects showed a trend toward higher BMD than radiculopathy and male subjects across all levels (p value: .06-.17). Wide variation in BMD was observed over anatomical regions, with the pedicles having significantly higher BMD than all other anatomic locations and the anterior portion of the central vertebral body having significantly lower BMD than all other anatomic locations. There was a significant positive correlation between central vertebral body BMD and lateral mass BMD at each level. Bone mineral density distribution by volume plots revealed women had a higher volume of very high-density bone than men but only in the posterior elements. CONCLUSIONS: This study has characterized BMD in the cervical spine according to vertebral level and anatomic location within each vertebral level using live subjects from a clinically relevant age group. The results indicate significant differences in BMD according to vertebral level and among anatomical regions within each vertebra. The results suggest to the surgeon and device manufacturer that surgical procedures involving instrumentation attached to C7 may require a modification in instrumentation or in surgical technique to attain results equivalent to more superior levels. The results suggest to the basic scientist that computational models may be improved by taking into account the wide variation in BMD over different anatomical regions. PMID- 21689991 TI - Surgically induced weight loss, including reduction in waist circumference, is associated with improved pulmonary function in obese patients. AB - BACKGROUND: Obesity is associated with impaired pulmonary function. We evaluated the effect of bariatric surgery on pulmonary function among obese patients and identified potential anthropometric factors of obesity corresponding to the reversal of impaired pulmonary function. METHODS: Pulmonary function and anthropometric factors were studied in 94 obese patients aged 18-65 years with a body mass index >32 kg/m(2). Pulmonary function tests were performed preoperatively and 3 months after bariatric surgery. The measurements included forced vital capacity (FVC), forced expiratory volume in the first second (FEV(1)), total lung capacity, expiratory reserve volume, residual volume, and diffusing capacity of the lung for carbon monoxide. The anthropometric factors included the body weight, body mass index, waist circumference (WC), hip circumference, waist/height ratio, and waist/hip ratio. The changes in anthropometric parameters were analyzed in relation to pulmonary function test results. Multiple linear regression models were applied to identify the factors that influenced pulmonary function after bariatric surgery. RESULTS: When measured 3 months after surgery, all anthropometric parameters for the 94 patients studied had significantly decreased, and the pulmonary function test parameters had significantly improved. Of the anthropometric parameters, the reduction in body weight, WC, and waist/height ratio correlated significantly with increases in the FEV(1) and FVC. In the multiple linear regression analysis, only the reduction in WC correlated significantly with the reductions in the FEV(1) and FVC. CONCLUSION: After bariatric surgery, all anthropometric parameters of obesity decreased significantly and the pulmonary function improved. This improvement correlated best with the reduction in the WC and perhaps a decreased intra-abdominal pressure. PMID- 21689992 TI - Effects of obesity and gender on exercise capacity in urban children. AB - BACKGROUND: The prevalence of childhood and adolescent obesity has been rising steadily over the last few decades and is now considered one of the most important issues worldwide. OBJECTIVE: The goal of this study was to investigate the influence of body mass on fitness in a healthy cohort of urban children and adolescents and to evaluate the difference in the cardiovascular responses, as measured by heart rate and endurance time, elicited with exercise in each gender. METHODS: This observational study was conducted in an exercise laboratory. Participants were healthy boys and girls aged 4 to 18 years. The study evaluated heart rate and endurance time during exercise testing on a treadmill. Outcome measures were endurance time and heart rate. RESULTS: The study comprised 303 boys and 222 girls ranging in age from 4 to 18 years (mean [SD], 12.2 [3.48] years). Obese children had a significantly lower endurance time than nonobese children (boys, P < 0.0001; girls, P = 0.0001). The mean (SEM) decrease in endurance time for obese versus nonobese children was 1.90 (0.38) minutes for boys and 1.52 (0.39) minutes for girls. A decrease in mean endurance time of 0.69 minute for each unit increase in BMI was noted. Obese boys and girls performed at a higher heart rate than their nonobese counterparts, although there was no statistically significant difference in maximum heart rate achieved by obese and nonobese children (boys, P = 0.71; girls, P = 0.79). CONCLUSIONS: Endurance time was significantly decreased in these obese boys and girls, and they performed at a higher heart rate earlier in exercise than nonobese children. There was no significant difference in maximum heart rate between obese and nonobese children. PMID- 21689993 TI - Coexistence of advanced age and female gender in diabetics with extrapulmonary tuberculosis: four culture-proven cases. AB - BACKGROUND: The relationship between diabetes mellitus (DM) and tuberculosis (TB) has long been known, but the extent of the relationship has only recently been demonstrated. It has been suggested that the presence of DM could triple the risk of TB. OBJECTIVE: Within the clinical picture of culture-proven TB, we examined the coexistence of TB, DM, and advanced age in 4 diabetic female elderly patients. CASE SUMMARY: Four cases of women with meningitis, bone TB, spondylodiscitis, and meningitis and spondylodiscitis are presented. All patients were diabetic and aged 50 to 79 years. Mycobacterium tuberculosis was isolated from the abscess from lesion areas, cerebrospinal fluid, and synovial fluid samples. CONCLUSION: Presence of DM is known to trigger reactivation of TB. These 4 diabetic female patients are noteworthy because they show that coexistence of DM and TB might lead to progressive forms of extrapulmonary TB in advanced age. PMID- 21689994 TI - Central mechanisms involved in pilocarpine-induced pressor response. AB - Pilocarpine (cholinergic muscarinic agonist) injected peripherally may act centrally to produce pressor responses; in the present study, using c-fos immunoreactive expression, we investigated the forebrain and brainstem areas activated by pressor doses of intravenous (i.v.) pilocarpine. In addition, the importance of vasopressin secretion and/or sympathetic activation and the effects of lesions in the anteroventral third ventricle (AV3V) region in awake rats were also investigated. In male Holtzman rats, pilocarpine (0.04 to 4MUmol/kg b.w.) i.v. induced transitory hypotension followed by long lasting hypertension. Sympathetic blockade with prazosin (1mg/kg b.w.) i.v. or AV3V lesions (1 day) almost abolished the pressor response to i.v. pilocarpine (2MUmol/kg b.w.), whereas the vasopressin antagonist (10MUg/kg b.w.) i.v. reduced the response to pilocarpine. Pilocarpine (2 and 4MUmol/kg b.w.) i.v. increased the number of c fos immunoreactive cells in the subfornical organ, paraventricular and supraoptic nuclei of the hypothalamus, organ vasculosum of the lamina terminalis, median preoptic nucleus, nucleus of the solitary tract and caudal and rostral ventrolateral medulla. These data suggest that i.v. pilocarpine activates specific forebrain and brainstem mechanisms increasing sympathetic activity and vasopressin secretion to induce pressor response. PMID- 21689995 TI - Measurement of nicotine, cotinine and trans-3'-hydroxycotinine in meconium by liquid chromatography-tandem mass spectrometry. AB - Nicotine (NIC), cotinine (COT) and trans-3'-hydroxycotinine (OHCOT) are the most prevalent and abundant tobacco biomarkers in meconium. We have developed and validated an accurate and precise method for the measurement of these analytes in meconium in which potassium hydroxide is used to digest the meconium sample, followed by solid phase extraction from the liquified sample. The precision of OHCOT, COT and NIC measurements (intra-day and inter-day) were 4.8-10.6%, 3.4 11.6% and 9.3-15.8%, respectively. Evaluation of accuracy indicated bias of -4.0, 2.0 and 0.8% for OHCOT at concentrations of 0.5, 2.5 and 7.5 ng/g. The accuracy estimates for COT at concentrations of 0.5, 2.5 and 7.5 ng/g are 4.0, 4.0 and 5.7%, respectively. For NIC at 2, 10 and 30 ng/g the accuracy was calculated to be 3.0, 5.0 and 5.1%, respectively. The linear range of standard solutions was 0.125-37.5 ng/mL for OHCOT and COT, and 0.75-150 ng/mL for NIC. This method was applied to the analysis of 374 meconium samples from infants of both smoking and nonsmoking mothers. Positive correlations with r(2)>=0.63 were observed between NIC and COT, COT and OHCOT, NIC and OHCOT, and NIC and (OHCOT+COT) in these samples. PMID- 21689996 TI - Two dimensional liquid chromatography-ultraviolet/mass spectrometric (2DLC-UV/MS) analyses for quantitation of intact proteins in complex biological matrices. AB - A conventional scale online two dimensional liquid chromatography ultraviolet/mass spectrometric (2DLC-UV/MS) method was developed for simultaneous quantitation of intact proteins. A series of valve switches were utilized between the two LC dimensions and the mass spectrometer to resolve and confirm the proteins of interest from a complex biological matrix. Two model proteins, myoglobin and serum albumin were simultaneously resolved and quantitated from Escherichia coli lysate using a strong anion-exchange chromatography and reversed phase chromatography as the first and second dimension respectively. The method validation consisted of evaluating linearity, precision, and accuracy. A linear relationship (R(2)>0.99) between the concentrations of the two proteins and peak areas was observed over the concentration range; 12.0-120.4 MUg/mL and 8.5-85.4 MUg/mL for serum albumin and myoglobin, respectively. The average RSD of peak areas for intra-day and inter-day analyses were 5.9% and 9.4% for myoglobin and 6.2% and 10.1% for serum albumin respectively. Over the linear range, the recoveries ranged from -15.4 to 9.0% for serum albumin and -2.5 to 9.4% for myoglobin. The system presented in this work is amenable to a quality control environment for evaluation and quantitation of expression levels of multiple target proteins. To our knowledge, this represents the first 2DLC-UV/MS method depicting the viability of simultaneous quantitation of more than one intact protein from complex biological mixtures in a single run. PMID- 21689997 TI - Isolation of a Aspergillus niger lipase from a solid culture medium with aqueous two-phase systems. AB - The aim of this work is to find the best conditions to isolate lipase from a solid culture medium of Aspergillus niger NRRL3 strains using aqueous two-phase systems formed with polyethylene glycol and potassium phosphate or polyethylene glycol and sodium citrate. We studied the partitioning of a commercial lyophilizate from A. niger. Also, the lipase enzymatic activity was studied in all the phases of the systems and the results indicate that citrate anion increases lipase activity. An analysis by fluorescence spectroscopy of the interaction between lipase and the bottom and top phases of the systems shows that the protein tryptophan-environments are modified by the presence of PEG and salts. Separation of the enzyme from the rest of the proteins that make up the lyophilized was achieved with good yield and separation factor by ATPS formed by PEG 1000/Pi at pH 7, PEG 2000/Ci at pH 5.2 and PEG 4000/Ci at pH 5.2. The above mentioned systems were used in order to isolate extracellular lipase from a strain of A. niger in submerged culture and solid culture. The best system for solid culture, with high purification factor (30.50), is the PEG 4000/Ci at pH 5.2. The enzyme was produced in a solid culture medium whose production is simple and recovered in a phase poor in polymer, bottom phase. An additional advantage is that the citrate produces less pollution than the phosphate. This methodology could be used as a first step for the isolation of the extracellular lipase from A. niger. PMID- 21689998 TI - Method development for analysis of proteins extracted from the leaves of Orthosiphon aristatus. AB - Orthosiphon aristatus is a traditionally used medicinal plant. In order to study the proteome of the plant, we have developed a simple plant protein extraction method by direct extraction of protein using a modified 2D-gel compatible tris sucrose buffer followed by a double TCA-acetone precipitation. This method omitted the use of toxic phenol which is widely used in the studies of plants proteins. Moreover, it shortens the lengthy extraction procedure of phenol extraction and back-extraction method and therefore reduced the extraction time (by 2h) while increased in protein yields (by 50%). Comparison of the 2D-gel images of the two extracts revealed that >60 extra protein spots were detected in the extract of our current method. The method was applied on the leaves of O. aristatus collected from six geographical areas in Malaysia. The correlation coefficient of each replicate gels from the six areas ranged from 0.70 to 0.90 indicating good reproducibility of the method. PMID- 21689999 TI - Real-time multimodal retinal image registration for a computer-assisted laser photocoagulation system. AB - An algorithm for the real-time registration of a retinal video sequence captured with a scanning digital ophthalmoscope (SDO) to a retinal composite image is presented. This method is designed for a computer-assisted retinal laser photocoagulation system to compensate for retinal motion and hence enhance the accuracy, speed, and patient safety of retinal laser treatments. The procedure combines intensity and feature-based registration techniques. For the registration of an individual frame, the translational frame-to-frame motion between preceding and current frame is detected by normalized cross correlation. Next, vessel points on the current video frame are identified and an initial transformation estimate is constructed from the calculated translation vector and the quadratic registration matrix of the previous frame. The vessel points are then iteratively matched to the segmented vessel centerline of the composite image to refine the initial transformation and register the video frame to the composite image. Criteria for image quality and algorithm convergence are introduced, which assess the exclusion of single frames from the registration process and enable a loss of tracking signal if necessary. The algorithm was successfully applied to ten different video sequences recorded from patients. It revealed an average accuracy of 2.47 +/- 2.0 pixels (~23.2 +/- 18.8 MUm) for 2764 evaluated video frames and demonstrated that it meets the clinical requirements. PMID- 21690000 TI - Application of independent component analysis with adaptive density model to complex-valued fMRI data. AB - Independent component analysis (ICA) has proven quite useful for the analysis of real world datasets such as functional resonance magnetic imaging (fMRI) data, where the underlying nature of the data is hard to model. It is particularly useful for the analysis of fMRI data in its native complex form since very little is known about the nature of phase. Phase information has been discarded in most analyses as it is particularly noisy. In this paper, we show that a complex ICA approach using a flexible nonlinearity that adapts to the source density is the more desirable one for performing ICA of complex fMRI data compared to those that use fixed nonlinearity, especially when noise level is high. By adaptively matching the underlying fMRI density model, the analysis performance can be improved in terms of both the estimation of spatial maps and the task-related time courses, especially for the estimation of phase of the time course. We also define a procedure for analysis and visualization of complex-valued fMRI results, which includes the construction of bivariate t-maps for multiple subjects and a complex-valued ICASSO scheme for evaluating the consistency of ICA algorithms. PMID- 21690001 TI - Determining energy expenditure from treadmill walking using hip-worn inertial sensors: an experimental study. AB - We describe an experimental study to estimate energy expenditure during treadmill walking using a single hip-mounted inertial sensor (triaxial accelerometer and triaxial gyroscope). Typical physical-activity characterization using commercial monitors use proprietary counts that do not have a physically interpretable meaning. This paper emphasizes the role of probabilistic techniques in conjunction with inertial data modeling to accurately predict energy expenditure for steady-state treadmill walking. We represent the cyclic nature of walking with a Fourier transform and show how to map this representation to energy expenditure (VO(2), mL/min) using three regression techniques. A comparative analysis of the accuracy of sensor streams in predicting energy expenditure reveals that using triaxial information leads to more accurate energy-expenditure prediction compared to only using one axis. Combining accelerometer and gyroscope information leads to improved accuracy compared to using either sensor alone. Nonlinear regression methods showed better prediction accuracy compared to linear methods but required an order of higher magnitude run time. PMID- 21690003 TI - Identification of adequate neurally adjusted ventilatory assist (NAVA) during systematic increases in the NAVA level. AB - Neurally adjusted ventilatory assist (NAVA) delivers airway pressure (P(aw)) in proportion to the electrical activity of the diaphragm (EAdi) using an adjustable proportionality constant (NAVA level, cm.H(2)O/MUV). During systematic increases in the NAVA level, feedback-controlled down-regulation of the EAdi results in a characteristic two-phased response in P(aw) and tidal volume (Vt). The transition from the 1st to the 2nd response phase allows identification of adequate unloading of the respiratory muscles with NAVA (NAVA(AL)). We aimed to develop and validate a mathematical algorithm to identify NAVA(AL). P(aw), Vt, and EAdi were recorded while systematically increasing the NAVA level in 19 adult patients. In a multistep approach, inspiratory P(aw) peaks were first identified by dividing the EAdi into inspiratory portions using Gaussian mixture modeling. Two polynomials were then fitted onto the curves of both P(aw) peaks and Vt. The beginning of the P(aw) and Vt plateaus, and thus NAVA(AL), was identified at the minimum of squared polynomial derivative and polynomial fitting errors. A graphical user interface was developed in the Matlab computing environment. Median NAVA(AL) visually estimated by 18 independent physicians was 2.7 (range 0.4 to 5.8) cm.H(2)O/MUV and identified by our model was 2.6 (range 0.6 to 5.0) cm.H(2)O/MUV. NAVA(AL) identified by our model was below the range of visually estimated NAVA(AL) in two instances and was above in one instance. We conclude that our model identifies NAVA(AL) in most instances with acceptable accuracy for application in clinical routine and research. PMID- 21690002 TI - Automatic generation of boundary conditions using demons nonrigid image registration for use in 3-D modality-independent elastography. AB - Modality-independent elastography (MIE) is a method of elastography that reconstructs the elastic properties of tissue using images acquired under different loading conditions and a biomechanical model. Boundary conditions are a critical input to the algorithm and are often determined by time-consuming point correspondence methods requiring manual user input. This study presents a novel method of automatically generating boundary conditions by nonrigidly registering two image sets with a demons diffusion-based registration algorithm. The use of this method was successfully performed in silico using magnetic resonance and X ray-computed tomography image data with known boundary conditions. These preliminary results produced boundary conditions with an accuracy of up to 80% compared to the known conditions. Demons-based boundary conditions were utilized within a 3-D MIE reconstruction to determine an elasticity contrast ratio between tumor and normal tissue. Two phantom experiments were then conducted to further test the accuracy of the demons boundary conditions and the MIE reconstruction arising from the use of these conditions. Preliminary results show a reasonable characterization of the material properties on this first attempt and a significant improvement in the automation level and viability of the method. PMID- 21690004 TI - Embedding a cardiac pulsatile model into an integrated model of the cardiovascular regulation for heart failure followup. AB - The analysis of followup data from patients suffering from heart failure is a difficult task, due to the complex and multifactorial nature of this pathology. In this paper, we present a coupled model, integrating a pulsatile heart into a model of the short to long-term regulations of the cardiovascular system. An interface method is proposed to couple these models, which present significantly different time scales. Results from a sensitivity analysis of the original and integrated models are proposed with simulations reproducing the main effects of the short- and long-term responses of an acute decompensated heart failure episode on a patient undergoing cardiac resynchronization therapy. PMID- 21690005 TI - Multiscale modeling of tumorigenesis induced by mitochondrial incapacitation in cell death. AB - There is a renewed interest in tumorigenesis provoked by glycolysis and prosurvival autophagy following the mitochondrial permeability transition during cell death. To investigate such mitochondrial dysfunction, we have developed a multiscale model by integrating the dynamic behaviors of essential oncogenic proteins, cells, and their microenvironment. We found that 1) the concentration of cellular ATP (adenosine triphosphate) available during the autophagy-related processes is a critical factor in determining tumorigenesis; 2) mitochondrial aging rate has a significant influence on this tumorigenic effect, 3) specific hypoxic and oxidative stresses work cooperatively for tumorigenesis during cell death. We conclude that the cellular mitochondrial status is critical in triggering tumorigenesis during the cell death process, particularly under harsh microenvironments. PMID- 21690006 TI - A framework for connecting gene expression to morphogenetic movements in embryos. AB - Although much has been learned about genetic networks, cell mechanics, and whole embryo mechanics through experimental and computational studies, the challenge of connecting these separate bodies of knowledge into an integrated whole remains. Here, we offer a multiscale biochemical-mechanical framework from which such integration might proceed. We identify components of the framework for which quantitative descriptions are currently available, and use the framework to gain insight into convergent extension and gastrulation--crucial tissue movements that occur in early stage amphibian embryos. PMID- 21690007 TI - A miniaturized system for spike-triggered intracortical microstimulation in an ambulatory rat. AB - This paper reports on a miniaturized system for spike-triggered intracortical microstimulation (ICMS) in an ambulatory rat. The head-mounted microdevice comprises a previously developed application-specific integrated circuit fabricated in 0.35-MUm two-poly four-metal complementary metal-oxide semiconductor technology, which is assembled and packaged on a miniature rigid flex substrate together with a few external components for programming, supply regulation, and wireless operation. The microdevice operates autonomously from a single 1.55-V battery, measures 3.6 cm * 1.3 cm * 0.6 cm, weighs 1.7 g (including the battery), and is capable of stimulating as well as recording the neural response to ICMS in biological experiments with anesthetized laboratory rats. Moreover, it has been interfaced with silicon microelectrodes chronically implanted in the cerebral cortex of an ambulatory rat and successfully delivers electrical stimuli to the second somatosensory area when triggered by neural activity from the rostral forelimb area with a user-adjustable spike-stimulus time delay. The spike-triggered ICMS is further shown to modulate the neuronal firing rate, indicating that it is physiologically effective. PMID- 21690008 TI - Automated measurement of the arteriolar-to-venular width ratio in digital color fundus photographs. AB - A decreased ratio of the width of retinal arteries to veins [arteriolar-to venular diameter ratio (AVR)], is well established as predictive of cerebral atrophy, stroke and other cardiovascular events in adults. Tortuous and dilated arteries and veins, as well as decreased AVR are also markers for plus disease in retinopathy of prematurity. This work presents an automated method to estimate the AVR in retinal color images by detecting the location of the optic disc, determining an appropriate region of interest (ROI), classifying vessels as arteries or veins, estimating vessel widths, and calculating the AVR. After vessel segmentation and vessel width determination, the optic disc is located and the system eliminates all vessels outside the AVR measurement ROI. A skeletonization operation is applied to the remaining vessels after which vessel crossings and bifurcation points are removed, leaving a set of vessel segments consisting of only vessel centerline pixels. Features are extracted from each centerline pixel in order to assign these a soft label indicating the likelihood that the pixel is part of a vein. As all centerline pixels in a connected vessel segment should be the same type, the median soft label is assigned to each centerline pixel in the segment. Next, artery vein pairs are matched using an iterative algorithm, and the widths of the vessels are used to calculate the AVR. We trained and tested the algorithm on a set of 65 high resolution digital color fundus photographs using a reference standard that indicates for each major vessel in the image whether it is an artery or vein. We compared the AVR values produced by our system with those determined by a semi-automated reference system. We obtained a mean unsigned error of 0.06 (SD 0.04) in 40 images with a mean AVR of 0.67. A second observer using the semi-automated system obtained the same mean unsigned error of 0.06 (SD 0.05) on the set of images with a mean AVR of 0.66. The testing data and reference standard used in this study has been made publicly available. PMID- 21690009 TI - Spectral clustering on multiple manifolds. AB - Spectral clustering (SC) is a large family of grouping methods that partition data using eigenvectors of an affinity matrix derived from the data. Though SC methods have been successfully applied to a large number of challenging clustering scenarios, it is noteworthy that they will fail when there are significant intersections among different clusters. In this paper, based on the analysis that SC methods are able to work well when the affinity values of the points belonging to different clusters are relatively low, we propose a new method, called spectral multi-manifold clustering (SMMC), which is able to handle intersections. In our model, the data are assumed to lie on or close to multiple smooth low-dimensional manifolds, where some data manifolds are separated but some are intersecting. Then, local geometric information of the sampled data is incorporated to construct a suitable affinity matrix. Finally, spectral method is applied to this affinity matrix to group the data. Extensive experiments on synthetic as well as real datasets demonstrate the promising performance of SMMC. PMID- 21690010 TI - Adaptive learning and control for MIMO system based on adaptive dynamic programming. AB - Adaptive dynamic programming (ADP) is a promising research field for design of intelligent controllers, which can both learn on-the-fly and exhibit optimal behavior. Over the past decades, several generations of ADP design have been proposed in the literature, which have demonstrated many successful applications in various benchmarks and industrial applications. While many of the existing researches focus on multiple-inputs-single-output system with steepest descent search, in this paper we investigate a generalized multiple-input-multiple-output (GMIMO) ADP design for online learning and control, which is more applicable to a wide range of practical real-world applications. Furthermore, an improved weight updating algorithm based on recursive Levenberg-Marquardt methods is presented and embodied in the GMIMO approach to improve its performance. Finally, we test the performance of this approach based on a practical complex system, namely, the learning and control of the tension and height of the looper system in a hot strip mill. Experimental results demonstrate that the proposed approach can achieve effective and robust performance. PMID- 21690011 TI - Gradient-based image recovery methods from incomplete Fourier measurements. AB - A major problem in imaging applications such as magnetic resonance imaging and synthetic aperture radar is the task of trying to reconstruct an image with the smallest possible set of Fourier samples, every single one of which has a potential time and/or power cost. The theory of compressive sensing (CS) points to ways of exploiting inherent sparsity in such images in order to achieve accurate recovery using sub-Nyquist sampling schemes. Traditional CS approaches to this problem consist of solving total-variation (TV) minimization programs with Fourier measurement constraints or other variations thereof. This paper takes a different approach. Since the horizontal and vertical differences of a medical image are each more sparse or compressible than the corresponding TV image, CS methods will be more successful in recovering these differences individually. We develop an algorithm called GradientRec that uses a CS algorithm to recover the horizontal and vertical gradients and then estimates the original image from these gradients. We present two methods of solving the latter inverse problem, i.e., one based on least-square optimization and the other based on a generalized Poisson solver. After a thorough derivation of our complete algorithm, we present the results of various experiments that compare the effectiveness of the proposed method against other leading methods. PMID- 21690012 TI - A coarse-to-fine subpixel registration method to recover local perspective deformation in the application of image super-resolution. AB - In this paper, a coarse-to-fine framework is proposed to register accurately the local regions of interest (ROIs) of images with independent perspective motions by estimating their deformation parameters. A coarse registration approach based on control points (CPs) is presented to obtain the initial perspective parameters. This approach exploits two constraints to solve the problem with a very limited number of CPs. One is named the point-point-line topology constraint, and the other is named the color and intensity distribution of segment constraint. Both of the constraints describe the consistency between the reference and sensed images. To obtain a finer registration, we have converted the perspective deformation into affine deformations in local image patches so that affine refinements can be used readily. Then, the local affine parameters that have been refined are utilized to recover precise perspective parameters of a ROI. Moreover, the location and dimension selections of local image patches are discussed by mathematical demonstrations to avoid the aperture effect. Experiments on simulated data and real-world sequences demonstrate the accuracy and the robustness of the proposed method. The experimental results of image super-resolution are also provided, which show a possible practical application of our method. PMID- 21690013 TI - Anomaly detection and reconstruction from random projections. AB - Compressed-sensing methodology typically employs random projections simultaneously with signal acquisition to accomplish dimensionality reduction within a sensor device. The effect of such random projections on the preservation of anomalous data is investigated. The popular RX anomaly detector is derived for the case in which global anomalies are to be identified directly in the random projection domain, and it is determined via both random simulation, as well as empirical observation that strongly anomalous vectors are likely to be identifiable by the projection-domain RX detector even in low-dimensional projections. Finally, a reconstruction procedure for hyperspectral imagery is developed wherein projection-domain anomaly detection is employed to partition the data set, permitting anomaly and normal pixel classes to be separately reconstructed in order to improve the representation of the anomaly pixels. PMID- 21690014 TI - Nonrigid brain MR image registration using uniform spherical region descriptor. AB - There are two main issues that make nonrigid image registration a challenging task. First, voxel intensity similarity may not be necessarily equivalent to anatomical similarity in the image correspondence searching process. Second, during the imaging process, some interferences such as unexpected rotations of input volumes and monotonic gray-level bias fields can adversely affect the registration quality. In this paper, a new feature-based nonrigid image registration method is proposed. The proposed method is based on a new type of image feature, namely, uniform spherical region descriptor (USRD), as signatures for each voxel. The USRD is rotation and monotonic gray-level transformation invariant and can be efficiently calculated. The registration process is therefore formulated as a feature matching problem. The USRD feature is integrated with the Markov random field labeling framework in which energy function is defined for registration. The energy function is then optimized by the alpha-expansion algorithm. The proposed method has been compared with five state-of-the-art registration approaches on both the simulated and real 3-D databases obtained from the BrainWeb and Internet Brain Segmentation Repository, respectively. Experimental results demonstrate that the proposed method can achieve high registration accuracy and reliable robustness behavior. PMID- 21690015 TI - Incremental Multi-Scale Search Algorithm for Dynamic Path Planning With Low Worst Case Complexity. AB - Path-planning (equivalently, path-finding) problems are fundamental in many applications, such as transportation, VLSI design, robot navigation, and many more. In this paper, we consider dynamic shortest path-planning problems on a graph with a single endpoint pair and with potentially changing edge weights over time. Several algorithms exist in the literature that solve this problem, notably among them the Lifelong Planning algorithm. The algorithm is an incremental search algorithm that replans the path when there are changes in the environment. In numerical experiments, however, it was observed that the performance of is sensitive in the number of vertex expansions required to update the graph when an edge weight value changes or when a vertex is added or deleted. Although, in most cases, the classical requires a relatively small number of updates, in some other cases the amount of work required by the to find the optimal path can be overwhelming. To address this issue, in this paper, we propose an extension of the baseline algorithm, by making efficient use of a multiscale representation of the environment. This multiscale representation allows one to quickly localize the changed edges, and subsequently update the priority queue efficiently. This incremental multiscale ( for short) algorithm leads to an improvement both in terms of robustness and computational complexity-in the worst case-when compared to the classical . Numerical experiments validate the aforementioned claims. PMID- 21690016 TI - Exploiting Local Coherent Patterns for Unsupervised Feature Ranking. AB - Prior to pattern recognition, feature selection is often used to identify relevant features and discard irrelevant ones for obtaining improved analysis results. In this paper, we aim to develop an unsupervised feature ranking algorithm that evaluates features using discovered local coherent patterns, which are known as biclusters. The biclusters (viewed as submatrices) are discovered from a data matrix. These submatrices are used for scoring relevant features from two aspects, i.e., the interdependence of features and the separability of instances. The features are thereby ranked with respect to their accumulated scores from the total discovered biclusters before the pattern classification. Experimental results show that this proposed method can yield comparable or even better performance in comparison with the well-known Fisher score, Laplacian score, and variance score using three UCI data sets, well improve the results of gene expression data analysis using gene ontology annotation, and finally demonstrate its advantage of unsupervised feature ranking for high-dimensional data. PMID- 21690017 TI - Nonrigid image registration using an entropic similarity. AB - In this paper, we propose a nonrigid image registration technique by optimizing a generalized information-theoretic similarity measure using the quasi-Newton method as an optimization scheme and cubic B-splines for modeling the nonrigid deformation field between the fixed and moving 3-D image pairs. To achieve a compromise between the nonrigid registration accuracy and the associated computational cost, we implement a three-level hierarchical multiresolution approach such that the image resolution is increased in a coarse to fine fashion. Experimental results are provided to demonstrate the registration accuracy of our approach. The feasibility of the proposed method is demonstrated on a 3-D magnetic resonance data volume and also on clinically acquired 4-D CT image datasets. PMID- 21690018 TI - EEG signal description with spectral-envelope-based speech recognition features for detection of neonatal seizures. AB - In this paper, features which are usually employed in automatic speech recognition (ASR) are used for the detection of seizures in newborn EEG. In particular, spectral envelope-based features, composed of spectral powers and their spectral derivatives are compared to the established feature set which has been previously developed for EEG analysis. The results indicate that the ASR features which model the spectral derivatives, either full-band or localized in frequency, yielded a performance improvement, in comparison to spectral-power based features. Indeed it is shown here that they perform reasonably well in comparison with the conventional EEG feature set. The contribution of the ASR features was analyzed here using the support vector machines (SVM) recursive feature elimination technique. It is shown that the spectral derivative features consistently appear among the top-rank features. The study shows that the ASR features should be given a high priority when dealing with the description of the EEG signal. PMID- 21690019 TI - A learning-based similarity fusion and filtering approach for biomedical image retrieval using SVM classification and relevance feedback. AB - This paper presents a classification-driven biomedical image retrieval framework based on image filtering and similarity fusion by employing supervised learning techniques. In this framework, the probabilistic outputs of a multiclass support vector machine (SVM) classifier as category prediction of query and database images are exploited at first to filter out irrelevant images, thereby reducing the search space for similarity matching. Images are classified at a global level according to their modalities based on different low-level, concept, and keypoint based features. It is difficult to find a unique feature to compare images effectively for all types of queries. Hence, a query-specific adaptive linear combination of similarity matching approach is proposed by relying on the image classification and feedback information from users. Based on the prediction of a query image category, individual precomputed weights of different features are adjusted online. The prediction of the classifier may be inaccurate in some cases and a user might have a different semantic interpretation about retrieved images. Hence, the weights are finally determined by considering both precision and rank order information of each individual feature representation by considering top retrieved relevant images as judged by the users. As a result, the system can adapt itself to individual searches to produce query-specific results. Experiment is performed in a diverse collection of 5 000 biomedical images of different modalities, body parts, and orientations. It demonstrates the efficiency (about half computation time compared to search on entire collection) and effectiveness (about 10%-15% improvement in precision at each recall level) of the retrieval approach. PMID- 21690020 TI - [Disability or loss of autonomy]. PMID- 21690021 TI - [Frailty: learnings from the SAFEs cohort study and future perspectives for the research]. AB - Even though the efforts in research have detailed further the physiopathology and the dynamics of the frailty process an operational definition of frailty is still far from being unequivocal. Studies carried out from the SAFEs cohort study allowed a pragmatic approach in the identification of the at-risk groups for the lost of independency during the hospital stay and factors influencing their future at short-, mid- and long-term. Based upon these results, we propose to discuss the relevance of the current operational indicators of frailty in order to show that clinical markers or indicators are insufficient to differentiate the frailty process from normal ageing. Finally we give rise to the imperative necessity to detect frailty at a preclinical stage with the help of biological and more particularly inflammatory markers. PMID- 21690022 TI - [The WHO age-friendly cities program raises the issue of strategic planning, coordination and local political structure]. AB - In 2005 the World Health Organization initiated the "global age-friendly cities project" which encourages cities to be more inclusive of older people and to develop seniors' involvement by setting up a continuous cycle of assessment and improvement of urban living. The conclusions of the first french audit, which was made in Lyon in 2011, raise the issue of the capacity of cities to implement projects in all the areas fostering active aging. The question of strategic planning and of the level of intervention is relevant for the topics selected, and especially that of health. Is the present organization between the different actors satisfactory, or should large cities have more power? Co-ordination is necessary, and the creation of "gerontopoles" could bring an answer. PMID- 21690023 TI - [Dipeptidyl peptidase-4 inhibitors in type 2 diabetic elderly patient]. AB - The increase in prevalence and the particularities of care in old diabetic patients, which accumulate consequences of both, age and diabetes, the treatment must be well tolerated. The main adverse event is a hypoglycemia risk because of its major consequences for the elderly diabetic subjects. Since few years, three dipeptydil-peptidase-4 inhibitors (DPP-4), for which some studies have included type 2 diabetic old subjects are available in Europe. Their efficiency and their tolerance do not differ significantly from those noted at the younger diabetics. The reduced risk of hypoglycemia and the absence of influence on the weight are two interesting arguments to use them in the old diabetic patients. It remains however necessary to realize studies led specifically to old and even oldest subjects, corresponding to those in daily practice. If the data on their tolerance is confirmed, it could intend to revise therapeutic target for the old diabetic patients. PMID- 21690024 TI - [Adaptations of psychotropic drugs in patients aged 75 years and older in a departement of geriatric internal medecine: report of 100 cases]. AB - The elderly often with multiple diseases are particularly at risk from adverse drug reactions. Nearly half of iatrogenic drug in the elderly are preventable. Some medications such as psychotropic drugs are particularly involved in iatrogenic accidents. We wanted to know if the tools of the comprehensive geriatric assessment or other factors could influence the changes of psychotropic drugs in a geriatric departement. Our prospective study of four months in 100 patients aged 75 years and older hospitalized in the Geriatric Internal Medecine Departement of University Hospital of Nice investigated what were the clinical or biological reasons and tools used during changes of psychotropic drugs. We compared these changes according to the comprehensive geriatric assessment tools and we analyzed the changes based on lists of potentially inappropriate medications by Laroche et al. and from the instrument STOPP/START. The Mini Mental State Examination (MMSE) was the tool that has most influenced the changes in psychotropic including a tendency to increase and the introduction of anxiolytics when MMSE < 20 (p = 0.007) while neuroleptics instead arrested and decreased (p = 0.012). The comprehensive geriatric assessment has its place in decision support during the potentially iatrogenic prescriptions of drugs such as psychotropic and new tools such as STOPP/START can also be a help to the prescriber informed. PMID- 21690025 TI - [Divisibility of warfarin and fluindione tablets tested in elderly patients and their family circle]. AB - BACKGROUND: Vitamin K antagonist tablets are often split to fractionate the dose by elderly patients. We performed a study in order to assess the divisibility of one dosage strength of score-lined warfarin and of score-lined fluindione. METHODS: Due to a recent change in the pharmaceutical form of fluindione in order to improve the divisibility, the study was performed over 2 different periods (with the " old " and with the " new " pharmaceutical form). In each period, 10 patients mean aged 82 years, 10 relatives, 10 nurses, 10 medical doctors) were asked to split in half warfarin tablets (W2 1(st) period et W2 2(d) period) and fluindione tablets (F2 et F'2), and to split fluindione tablets into 4 fragments (F4 et F'4). The first end-point was the accuracy of splitting estimated by the difference between the real and the expected weight of fragmented tablets. The statistical analysis was performed using an ANOVA test with 2 variables, subject and drug. The difference between the 2 periods were analyzed using an ANOVA test with 2 variables, subject and period. RESULTS: Over the 2 periods, the differences between real and expected weight were of 4.65% for W2 1(st) phase, 9.48% for F2, 15.35% for F4, 5.56% for W2 2(d )period, 4.30% for F'2, and 6.98% for F'4. The quality of splitting was statistically poorer in the elderly patient group compared to other subjects. CONCLUSION: This study was not design to assess the clinical relevance (bleeding or thromboembolism) or the anticoagulation control of the variations in drug mass due to inappropriate splitting of tablets. However, split form of drugs should be prescribe with caution to elderly patients. PMID- 21690026 TI - [Impact of low-molecular-weight heparin practice guidelines in a geriatric hospital]. AB - The purpose of this study was to assess the impact of good use of anticoagulants guidelines implementation on low molecular weight heparin (LMWH) prescription in a french geriatric hospital. This interventional "before and after" study was conduced by the same geriatrician on a d-day in 2006 and 2009. Guidelines for anticoagulant's prescription based on selected references in the literature was established by an expert's consensus and implemented in 2008. Data were collected in all departments at the Sainte-Perine geriatric hospital for each patient with an LMWH prescription. Assessment was based on quality judgment criteria (indication, dosage, treatment duration, biological monitoring of LMWH). Data were collected for 72 prescriptions prior to the guidelines implementation and for 54 after. Sex-ratio, mean age and percentage of LMWH prescription did not differ significantly between the two periods. There was a better conformity for LMWH dosage prescription (p = 0.002) and biological monitoring prescription (p = 0.036) after the guidelines implementation. Conformity of LMWH indication and treatment duration were improved but the difference remained not significant (respectively p = 0.49 and p = 0.80). Implementing guidelines for LMWH use in geriatrics can improve quality of prescription. The impact was effective but limited. These guidelines are now in general use in the Sainte-Perine hospital. PMID- 21690027 TI - [Curable dementia]. PMID- 21690028 TI - [Progressive supranuclear palsy: what's new?]. AB - Progressive supranuclear palsy (PSP) has been described as a clinical syndrome characterized by an impairment of voluntary control of gaze (supranuclear palsy), postural and gait instability, and behavioral and cognitive deficits including a frontal syndrome and psychic retardation. However, in the recent years, at least four other clinical forms of PSP have been recognized: PSP-Parkinsonism, "pure akinesia with gait freezing", PSP with cortico-basal syndrome, and PSP with speech apraxia. PSP-Parkinsonism mimics the signs and symptoms of idiopathic Parkinson's disease, including a significant reactivity to levodopa. "Pure akinesia with gait freezing" is characterized by a difficulty of self-initiation of motor programs, usually walking program. PSP with cortico-basal syndrome mimics cortico-basal degeneration (CBD) in that unilateral or asymmetric limb dystonia and apraxia are prominent signs. PSP with speech apraxia is an isolated syndrome of progressive anarthria. All these clinical syndromes are due to brain accumulation of phosphorylated tau protein. The differences in clinical expression within the framework of PSP can be explained by the differences in the topographical distribution of the lesions. PSP is considered as a primary tau disease ("tauopathy") such as CBD and some forms of fronto-temporal lobar degeneration. At the level of neuropathology, the pattern of tau abnormal inclusions differentiates PSP from other tau diseases, but some overlaps are reported. Moreover, several of the clinical forms of PSP partially or fully overlap with the other tauopathies. As a whole, the emergence of new clinical forms of PSP challenges the nosology of tauopathies and our understanding of these diseases. PMID- 21690029 TI - [Autonomy and dementia Part II: autonomy and representation: a possible combination?]. AB - This paper, based on a critical review of the medico-social literature, questions the representation of patients with dementia in relation to the autonomy perspectives presented in a previous article. In the canonical perspective of autonomy (defined as a rational decision-making by a stand alone self), the surrogate is the spokeperson of the subject's wills when he was competent because he knows these wills through advance directives or assuming them via substituted judgment. Best patient's interest is then depreciated because it is focused on the present incompetent self. In the relational perspective, where autonomy is constructed through a dialogue with others, the surrogate is the present interlocutor, making the decisions with the patient and care-givers in a way varying with the disease process. He represents the subject with dementia as he was before the disease but also as he has become. Therefore, there is a continuum between autonomy and representation. Autonomy and well being are both the surrogate aims. The relational perspective allows care continuity of patients with dementia even when considered as incompetent. It offers a more balanced perspective on the patient autonomy since it is embedded in all others, and opens a richer view on what good life is, untill the end of dementia. PMID- 21690030 TI - ["Reversible" dementia in 2011]. AB - Reversible dementias are rare and account for approximately 1.5% of all dementias. The most frequent etiology is represented by neurosurgical causes such as benign tumours, adult chronic hydrocephalus (so-called " normal pressure " hydrocephalus) or subdural hematoma, which are easily revealed by neuroimaging. Systematic ancillary investigations aimed at detecting an infectious disease (syphilis, HIV infection, Lyme neuroborreliosis or, more rarely, Whipple disease), an endocrine aetiology or a vitamin deficiency are rarely contributory, but remain relevant since these dementias could be reversible. Discovering a reversible cause of dementia does not always allow full recovery after treatment. However, systematic ancillary investigations can identify and treat concomitant reversible conditions, which contribute to worsening the main clinical condition in nearly 25% of dementia cases. PMID- 21690031 TI - [Dopamine dysregulation syndrome in Parkinson's disease and restless legs syndrome]. AB - Dopamine replacement therapy in Parkinson's disease (PD) improves the motor symptoms. However, it has recently been shown that a small sub-group of patients suffers from motor and behavioral disturbances associated with the use of dopamine agonists (DAs). The behavioral disorders are incentive- or reward-based repetitive symptoms regrouped under the term " dopamine dysregulation syndrome " (DDS). They include pathological gambling, hypersexuality, compulsive shopping, compulsive eating, punding, and compulsive medication use. Whether these behaviors are related to the dopaminergic medications interacting with an underlying individual vulnerability or whether the primary pathological features of Parkinson's disease play a role is not entirely understood. This review is devoted to the phenomenology of the DDS and factors influencing its susceptibility. We further review the literature studies that investigated the decision-making profile using the Iowa Gambling Task in Parkinson's disease, and the recent literature devoted to these abnormal behaviors in the restless legs syndrome (RLS). Given the potential substantial impact of the DDS on personal, familial, social, and financial well-being, patients with PD or RLS should be informed that DAs use may lead to the development of impulsive and compulsive disorders, and clinicians should include the investigation of these disorders as part of routine clinical care. The refinement of clinical strategies to predict, identify and manage DDS will help the future care of motor and non-motor symptoms of Parkinson's disease. PMID- 21690032 TI - [Semantic memory training in Alzheimer's disease]. AB - The purpose of this study was to assess the effects of semantic stimulation of Alzheimer's patients on semantic memory comparatively to psychological support. We conducted semantic training with two target categories (musical instruments and human actions), because these concepts were massively failed in previous data collected in Alzheimer's disease. Ten patients (57-78 year old, MMSE scores from 17 to 26) were divided in an experimental and a control group where patients received psychological support instead of semantic cognitive training. Semantic abilities were significantly improved in patients from the experimental group, but only after semantic stimulation involving examples from musical instrument category. However, further analysis failed to show an item-specific improvement, suggesting that our results could be explained by a general increase of semantic retrieval. Results could also be explained by some motivational effect caused by more attractive material. Implications for future research and clinical applications are discussed. PMID- 21690034 TI - [Assessment of daily physical activity of breast cancer patients and comparison with two control populations]. AB - OBJECTIVE: The purpose is to assess the physical activity of breast cancer patients using a questionnaire, the Population Physical Activity Questionnaire (POPAQ) and to compare the data with those from two female populations: one healthy population and one with a previous history of cardiovascular disease. PATIENTS AND METHODS: This prospective study included 104 consecutive breast cancer patients who were addressed at the radiation oncology department, Institut de cancerologie de la Loire from March to July 2010. A questionnaire using factorial method was used for assessment of physical activity. RESULTS: In the study population, the rest energetic expenditures of physical energy related to both rest activity and low intensity activity were higher than in the healthy patients (5,292+/-1,376 versus 5,520+/-1,248 kJ/24 h, P<0.05 and 2,583+/-681 versus 2,494+/-558 kJ/24 h, P<0.05, respectively). Conversely, the energetic expenditures of physical energy related to both high physical activity and intensive physical activity were lower than in the healthy population (882+/-441 versus 1,560+/-868 kJ/24 h, P<0.05 et 210+/-274 versus 340+/-621 kJ/24 h, P<0.05, respectively). CONCLUSION: The POPAQ allows quantifying the daily physical activity and seems feasible in clinical routine in breast cancer patients. In our study, it was found that the physical activity of those patients was significantly different from that of a healthy population. Further investigations are necessary for better defining the true impact of such differences in terms of incidence and prognostic for mammary carcinoma. PMID- 21690035 TI - [Salivary gland tumors in children]. AB - Salivary gland tumors in children are rare: they correspond to 8-10% of head and neck pediatric tumors. Clinicians of all disciplines should be aware of this diagnosis in front of non-inflammatory mass of the parotid or in the territory of other salivary glands. In children, 50% of salivary gland tumors are malignant which contrasts with a 10-25% risk in adults. Epithelial tumors are the most common, mucoepidermoid carcinomas of the parotid in particular. Surgery is the treatment of choice in epithelial tumors. Adjuvant radiotherapy may be indicated in case of unfavorable prognostic factors but must be balanced with the risk of radiation-induced growth defects and secondary cancer. The role of chemotherapy is limited in these tumors, but should be discussed in case of an inoperable or metastatic lesion. PMID- 21690036 TI - [Phase 0 exploratory clinical trials: literature review 2006-2009]. AB - Currently in oncology a novel agent entering development has only 5% chance of making it to commercial use. One of the ways to mitigate this problem would be to conduct exploratory or 'phase 0' clinical trials, conducted before phase 1 dose escalation safety and tolerance studies. These phase 0 studies are a first administration of the novel agent to humans, at limited doses, on a small number of patients and over a short period. The objectives are to validate preclinical development and to acquire pharmacokinetic and pharmacodynamic data in order to better justify the scientific rational. In this article, we focus on phase 0 trials and their usefulness for the development of new drugs in oncology. We performed a literature review of questions related to phase 0 trials in articles published during 2006 to 2009. Thirty articles on phase 0 clinical trials have been published. The affected fields are oncology and pharmacology. Phase 0 clinical trials are discussed in the literature in terms of theoretical issues and from academic, pharmaceutical industry and patient point of views. If phase 0 clinical trials are a future prospect for drug development against cancer, the clinical applications of these trials need to be specified. PMID- 21690037 TI - [Binary logistic regression for the risk factors of osteopenia in youths]. AB - OBJECTIVE: To screen the risk factors for osteopenia in youths. METHODS: Ninety nine subjects aged 15 to 43 years with primary osteopenia(-2.580%). Joint clicking and skeletal pain were the most common symptoms, and most of the patients had complaints of fatigue, insomnia and gastric discomforts. CONCLUSIONS: Inactivity, prolonged use of computers, imbalanced diet, staying up late at night, and alcohol drinking are the risk factors for osteopenia in youths. Most of the patients have a sub-health status, indicating the necessity of relevant interventions to prevent the occurrence of osteoporosis. PMID- 21690038 TI - [Endogenous neuregulin-1 expression in the anterior pituitary of female Wistar Furth rats during the estrous cycle]. AB - OBJECTIVE: To study the changes in endogenous neuregulin-1 (Nrg1) expression in the anterior pituitary of female Wistar-Furth rats in different phases of the estrous cycle. METHODS: Female Wistar-Furth rats during estrous cycles were used. RT-PCR was employed to study the changes in the expression of Nrg1 isoforms and their cognate receptors ErbB-2 and ErbB-4 in the anterior pituitary in different phases of the estrous cycle. Western blotting was used to detect Nrg1 expression at the protein level. Immunofluorescence staining was used to identify hypophyseal cells expressing Nrg1 and observe the localization and distribution of Nrg1 and functional phosphorylation of ErbB-4. The co-expression of Nrg1 and ErbB-4 in the anterior pituitary of Rhesus monkey was also investigated. RESULTS: Some of the Nrg1 isoforms, especially type III Nrg1s, were expressed at a higher level during the estrous cycle I (E1) and estrous cycle II (E2), a result consistent with that of Western blotting for samples of the anterior pituitaries collected at these phases. Immunofluorescence staining identified the gonadotrophs as the main source of Nrg1, and showed an extensive distribution of Nrg1 in the anterior pituitary in E1 and E2 phases accompanied by apparent phosphorylated activation of ErbB-4. Adjacent distribution of Nrg1- and ErbB-4 positive cells was also observed in the anterior pituitary of male Rhesus monkeys. CONCLUSION: Our results provide evidence for the expression of multiple Nrg1 isoforms and the presence of Nrg1/ErbB-4 signaling in the anterior pituitary of female Wistar-Furth rats. This signaling demonstrates an estrous cycle phase related pattern. Additionally, Nrg1/ErbB-4-based juxtacrine signaling may exist in the anterior pituitary of male non-human primate. PMID- 21690039 TI - [Localization and expression of Slingshot-1L in peripheral eosinophils from patients with acute asthma exacerbation]. AB - OBJECTIVE: Eosinophils play a pivotal role in asthmatic airway inflammation. We previously found a significantly high expression of Slingshot-1L (SSH-1L) in peripheral eosinophils in acute exacerbations of asthma. Objective To investigate the expression and localization patterns of SSH-1L in peripheral blood eosinophils of asthmatic patients and their changes after treatment with inhaled corticosteroids. METHODS: We recruited 4 outpatients with acute exacerbations of asthma who received no previous corticosteroid treatment and 1 healthy volunteer. From all the subjects 30 ml peripheral venous blood samples were collected before and after a 3-month treatment with inhaled fluticasone. The eosinophils were isolated, purified and counted, and the expressions of SSH-1L in the eosinophils were examined by RT-PCR and Western blotting. The localization of SSH-1L phosphatases in the peripheral eosinophils was detected by immunofluorescence assay in one patient. RESULTS: SSH-1L phosphatases distributed diffusely in the cytoplasm, especially dense near the membrane of the peripheral eosinophils. Glucocorticoids treatment resulted in a significant reduction in both the SSH-1L mRNA expression (0.7403?0.1124 vs 0.4101?0.0363, P=0.001) and SSH-1L protein expression (0.3410?0.1337 vs 0.1543?0.0551, P=0.039). CONCLUSION: A high expression of SSH-1L in peripheral eosinophils in acute exacerbations of asthma may play a role in the activation and migration of eosinophils. The efficacy of inhaled corticosteroids in asthma control might be partly attributed to a down regulated expression of SSH-1L. PMID- 21690040 TI - [Laparoendoscopic single-site surgery for male pseudohermaphroditism: the initial report]. AB - OBJECTIVE: To evaluate the therapeutic effect of laparoendoscopic single-site surgery (LESS) for treatment of male pseudohermaphroditism. METHODS: A 17-year old patient with male pseudohermaphroditism and a female social sex was admitted. According to the request by the patient and the relatives for a female gender, LESS vaginoplasty and cryptorchidectomy were performed using a single multilumen port inserted through a 2.5 cm incision below the umbilicus, followed by reconstruction of the perineal region by open surgery. RESULTS: The total operative time was 7 h, and the LESS procedure lasted for about 3.5 h. No other port incision was needed. The estimated intraoperative blood loss was 400 ml. No electrolyte or metabolic acid-base balance disorders were observed perioperatively. In the follow-up examination at 6 months after the operation, the reconstructed vagina healed smoothly without obvious contraction or fixation failure, and the perineal region showed good appearance. CONCLUSION: With minimal invasiveness, LESS surgery produces good cosmetic effect and allows rapid postoperative recovery, thus may become a promising alternative to the management of pseudohermaphroditism. PMID- 21690041 TI - [Construction of a replicative anti-tumor DNA vaccine PSCK-2PFcGB and its expression in vivo and in vitro]. AB - OBJECTIVE: To construct a replicative anti-tumor DNA vaccine PSCK-2PFcGB based on Semliki Forest Virus (SFV) replicon vector and observe its expression in vivo and in vitro. METHODS: The plasmid pVAX1-2PFcGB was digested with Nhe I, and the digestion product was blunted prior to further digestion with BssH II to obtain the fragment 2PFcGB, a fusion gene containing the multitarget complex antigen 2PAG encoding both the most cytotoxic T lymphocyte epitopes of human survivin and chorionic gonadotropin beta chain-CTP37 of human and monkey. The 2PFcGB fragment was inserted into the PSCK vector digested by Sma I. The products with the expected size were extracted and ligated, and the positive clones were screened by kanamycin and amplified. The recombinant PSCK-2PFcGB, following identification by colony PCR and restriction endonuclease Nde I, was transfected into 293T cells via lipofectamine 2000 and its expression was detected. The recombinant plasmid was also transfected into mouse quadriceps femoris muscle to observe its expression in vivo by immunohistochemistry. RESULTS: Nde I digestion resulted in a fragment of the expected size. Transfection with the recombinant plasmid PSCK 2PFcGB resulted in successful expression of the antigen and adjuvant molecular protein in 293T cells, with the positivity rates of 5.70% and 19.75%, respectively. The fusion tumor antigen survivin and hCGbeta-CTP37 were also detected in the muscular tissues of the mice. CONCLUSION: A novel replicative anti-tumor DNA vaccine PSCK-2PFcGB has been successfully constructed and can be expressed in 293T cells and in the muscular tissues of immunized mice, which provide a basis for further studies of the antitumor activity and immunological mechanism of the DNA vaccine. PMID- 21690042 TI - [Acute toxicity of CCR5 antagonist C25P polypeptide in mice and its carcinogenicity in vitro]. AB - OBJECTIVE: To study the acute toxicity of C25P polypeptide, a CCR5 antagonist, in mice and its carcinogenic effect in vitro. METHODS: The acute toxicity of C25P polypeptide in mice was assessed by determining the maximum tolerated dose (MTD). The mice were given C25P at the dose of 3.64 g/kg by tail vein injection, and the control mice received saline (40 ml/kg) injection. The mice were continuously observed for 14 days after the administration and sacrificed on day 14 for routine blood test, examination of the blood biochemistry and pathological examination. The carcinogenicity of C25P polypeptide in vitro was evaluated in cultured cell lines by chromosome aberration test, cell transformation test and non-anchorage dependent growth test. RESULTS: No mice died following administration of the drug, but 3 mice showed mild adverse reactions. The rats in both groups showed an increase in the body weight at a comparable rate. GPT increased and ALP decreased significantly in C25P polypeptide group (P<0.05). Most of the organs of the rats treated with in C25P polypeptide remained normal, but 3 mice showed pathologies in the lung, spleen and liver. Chromosome aberration test, cell transformation test and non-anchorage-dependent growth test all yielded negative results for C25P polypeptide. CONCLUSION: C25P polypeptide is a low-toxicity drug that produces no apparent acute toxicity in mice or obvious carcinogenicity in vitro. PMID- 21690043 TI - [Application of three-dimensional visualization technology in precise diagnosis and treatment for hepatolithiasis]. AB - OBJECTIVE: To assess the value of three-dimensional (3D) visualization technique in preoperative diagnosis, preoperative evaluation and surgical guidance for hepatolithiasis. METHODS: The 64-slice spiral CT data of 30 hepatolithiasis cases were imported in a self-designed medical image processing system for 3D reconstruction of the intrahepatic bile duct. The preoperative diagnosis and pathological classification were derived from the reconstructed model, with which the feasibility and safety of the surgical plan were assessed by simulation of the surgical procedures. The consistency between the simulated procedure and the actual operation was evaluated, and the residual stones were detected using cholangiography with a T-shaped tube. RESULTS: When the model setting was configured to render the liver translucent, the system clearly displayed the site and number of the bile duct calculi as well as the expansion or narrowing of the intrahepatic bile duct. A total consistency (100%) was found between the surgical findings and the preoperative findings based on the 3D model, and also between the actual surgical procedures and the preoperative simulation in 30 cases. The consistency rate between the actual surgical protocols and the preoperative surgical plan was 90%. Follow-up of 27 of the patients for 6 months showed a recurrence rate of 7.4% (2/27) after the operation. CONCLUSION: The 3D visualization system allows accurate preoperative diagnosis and precise surgical operation to reduce the postoperative recurrence rate, and can be of value as a new diagnostic and treatment modality in biliary surgery. PMID- 21690044 TI - [Preparation and characterization of reference samples of Mycobacterium tuberculosis culture filtrate protein-10 for time-resolved fluoroimmunoassay]. AB - OBJECTIVE: To prepare reference samples of Mycobacterium tuberculosis culture filtrate protein-10 (CFP-10) and CFP10-streptavidin fusion proteins (CFP10/SA) for time-resolved fluoroimmunoassay (TRFIA). METHODS: The CFP10 gene was amplified by PCR from Mycobacterium tuberculosis strain H37Rv and cloned into pET24b, pET24b-streptavidin (SA) or pET21a-SA expression vectors. The recombinant proteins CFP10, CFP10-SA and SA-CFP10 were expressed in Rosetta cells, purified via nickel affinity chromatography and refolded by dialysis. The sensitivity and stability of the resultant proteins as reference samples were evaluated by double antibody sandwich TRFIA. RESULTS: CFP10-SA and SA-CFP10 fusion proteins were expressed as inclusion bodies, whereas CFP10 was expressed in a soluble form. The resultant purity of the 3 recombinant proteins all exceeded 95%. TRFIA results showed that CFP-SA fusion protein possessed the best sensitivity (0.02 ug/L) and stability. CONCLUSION: The reference samples of CFP10 for TRFIA detection have been successfully prepared and can be used in the development of a diagnostic kit for Mycobacterium tuberculosis. PMID- 21690045 TI - [Impact of transfusion of apoptotic and necrotic thymocytes on the survival of mice with sepsis]. AB - OBJECTIVE: To investigate the effect of transfusion of apoptotic and necrotic thymocytes prior to sepsis on the survival rate of mice. METHODS: BALB/c mice are divided into 3 groups and received intravenous injection of PBS (control), apoptotic thymocytes, or necrotic thymocytes. Three days later, cecal ligation and puncture (CLP) were performed to induce sepsis in these mice, and their survival and organ damage were observed. RESULTS: The survival rates of mice in PBS group was 44.6% at the end of first week after CLP, and obvious lung and kidney damages were observed. A significant increase in the survival rate was found in apoptotic cell transfusion group (69.6%, P=0.012), with also lessened lung and kidney damages. The survival rate of mice in necrotic cell transfusion group was only 31.6% at 2 weeks, significantly lower than that in PBS group (P=0.035), and the lung and kidney damage was even more obvious. CONCLUSION: Transfusion of apoptotic thymocytes 3 days before induction of sepsis can reduce organ damage and improve the survival rate of mice, while necrotic cell transfusion produces the opposite effect. PMID- 21690046 TI - [Protective effects of nerve growth factor vs Danshen on hippocampal neuron against global ischemia-reperfusion injury in gerbils]. AB - OBJECTIVE: To study the protective effects of nerve growth factor (NGF) and Danshen on hippocampal neurons in gerbils (Meriones unguiculatus) with global ischemia-reperfusion injury. METHODS: Global ischemia-reperfusion model was established in 54 male Z:ZCLA gerbils by occlusion of the bilateral carotid arteries. The animal models were randomized into 3 groups to receive treatment with normal saline, NGF, and Danshen 30 min after the reperfusion. At 6 h, 3 and 7 days after the reperfusion, the survival of the hippocampal CA1 pyramidal neurons was observed using optical and electron microscopy, and immunohistochemistry was employed to detect the expressions of Bcl-2 and Bax in the neurons. RESULTS: Neuronal apoptosis was not observed in the hippocampus 6 h after the reperfusion, but at 3 and 7 days, the number of apoptotic neurons increased significantly in the CA1 region. Compared with normal saline, treatments with NGF and Danshen both significantly reduced the number of apoptotic neurons at 3 and 7 days. The number of apoptotic neurons showed no significant difference between NGF and Danshen treatment groups at 3 days, but at 7 days, the apoptotic cell number was significantly lower in NGF group (P<0.05). Bcl-2 expression was the highest in NGF group, and its highest expression occurred at 6 h after the reperfusion; Bax expression was detected in saline group, and underwent no significant changes with the passage of time. CONCLUSION: Both NGF and Danshen show protective effects against global ischemia-reperfusion injury. NGF has a stronger protective effect than Danshen, and this finding provides experimental evidence for selecting appropriate protective agents in the treatment of ischemic brain damage. PMID- 21690047 TI - [Relationship between alpha-actinin and cardiac function in rats with myocardial ischemia-reperfusion]. AB - OBJECTIVE: To explore the relationship between alpha-actinin content and cardiac function in rats during myocardial ischemia-reperfusion. METHODS: Thirty-two rats were randomized equally into sham-operated group, 30 min ischemia group, 1 h ischemia group, and 1 h ischemia with 2 h reperfusion group. Acute myocardial ischemia was induced in the 3 ischemia groups by ligation of the left anterior descending coronary artery, and the cardiac functions were evaluated. The myocardial contents of alpha-actinin was measured by immunohistochemistry, and phospholipase C (PLC) and phosphatidylinositol-3-kinase (PI3K) contents were determined by ELISA after the operations. RESULTS: The left ventricular systolic pressure (LVSP), +dp/dt max, and -dp/dt max tended to decrease during myocardial ischemia, and increased after reperfusion, and the left ventricular end-diastolic pressure (LVEDP) showed reverse changes. The levels of alpha-actinin decreased with prolonged ischemia, showing a significant difference in 1 h ischemia group from those in the other 3 groups. PI3K and PLC contents were significantly increased with prolonged myocardial ischemia. Stimulation by LY-294002 and U 73122 caused enhanced contraction of single cardiomyocytes, and also increased the fluorescence intensity of alpha-actinin in the cardiomyocytes compared with that in 1 h ischemia group. CONCLUSIONS: The cardiac dysfunction during acute ischemia-reperfusion in rats may be related with the changes of myocardial alpha actinin content, which are probably a result of increased PI3K and PLC contents in the ischemic myocardium. PMID- 21690048 TI - [Expression of dopamine receptor D2 in pulmonary carcinoma cells and effects of dopamine on the cell apoptosis]. AB - OBJECTIVE: To detect the expression of dopamine receptor D2 in different pulmonary carcinoma cells and investigate the effect of dopamine in inducing apoptosis of A549 cells. METHODS: Western blotting and RT-PCR were employed to detect the expression of dopamine receptor D2 in different pulmonary carcinoma cells (95D, H460, GLC-82, A549 and H446 cells). The apoptosis of A549 cells after a 6-hour exposure to 0.02%, 0.04%, 0.08% and 0.1% dopamine was analyzed by flow cytometry. The apoptosis-inducing effect of dopamine in vivo was also tested by intratumoral injection of 1% dopamine in 2 BALB/c-nu mice bearing A549 tumor xenograft using flow cytometry. RESULTS: The presence of dopamine receptor D2 expression was detected by Western blotting and RT-PCR in 95D, H460, GLC-82, A549 and H446 cells. Flow cytometry detected obvious apoptosis of A549 cells following dopamine exposure in vitro in positive correlation to dopamine concentration. In the tumor-bearing mice, dopamine also showed an obvious apoptosis-inducing effect on A549 cells. CONCLUSION: Dopamine receptor D2 exists extensively in different pulmonary carcinoma cells. Dopamine may promote the apoptosis of pulmonary carcinoma cells through dopamine receptor D2. PMID- 21690049 TI - [Change of IL-22R1 expression in human airway smooth muscle cells in response to different stimulating agents]. AB - OBJECTIVE: To explore the effects of serum of asthmatic patients, dexamethasone, interleukin-4 (IL-4), interferon-gamma (IFN-gamma) and transforming growth factor beta (TGF-beta) on the expression of interleukin-22 receptor 1 (IL-22R1) mRNA and protein in HASMCs in vitro. METHODS: IL-22R1 mRNA and protein expressions in HASMCs treated with different stimulating agents were measured by real-time PCR and Western blotting, respectively. RESULTS: IL-22R1 mRNA and protein expressions in HASMCs were significantly increased after stimulation by serum from asthmatic patients, but decreased after co-stimulation with dexamethasone. IL-22R1 mRNA and protein expressions in the cells both increased after stimulation by IL-4, IFN gamma and TGF-beta. CONCLUSION: IL-22R1 in HASMCs might be involved in the pathogenesis of asthma, and the therapeutic effect of dexamethasone on asthma is mediated, at least partially, by IL-22R1. The effects of IFN-gamma, IL-4, and TGF beta on asthma may also be attributed to their actions on HASMCs. PMID- 21690050 TI - [Clinical application of digitized three-dimensional image reconstruction for surgical simulation in living-related kidney transplantation]. AB - OBJECTIVE: To study the application of digitized three-dimensional (3D) image reconstruction in living-related kidney transplantation. METHODS: The image data of 16-slice spiral CT in 5 cases of living-related kidney transplantation were collected to reconstruct the 3D model of the donor and recipient, which were then imported in the FreeForm Modeling System. The optimal surgical approach for each individual case was planned and simulated for verification. During the actual surgeries, the surgical findings were compared against the reconstructed model and the results of simulated surgery. RESULTS: The 3D model clearly displayed the anatomy of the kidney and the variation of the related vessels. The optimal surgical approaches were planned through the simulated surgery. The anatomy of the kidney and the related vessels found in the actual surgeries were consistent with that displayed by the reconstructed 3D model. All the operations were completed successfully according to the surgical plan, and the patients recovered uneventfully without obvious complications. CONCLUSION: Three-dimensional reconstruction and simulated surgery allow optimization of the surgical approaches of living-related kidney transplantation to ensure successful operation and minimize the surgical risks. PMID- 21690051 TI - [Perinatal management and outcome of different types of fetal arrhythmia]. AB - OBJECTIVE: To evaluate the perinatal management and outcome of different types of fetal arrhythmia. METHODS: A retrospective analysis was conducted among the fetuses with arrhythmia identified by M-mode and pulsed Doppler echocardiography in a single institution between October 2003 and December 2010. RESULTS: A total of 130 fetuses were found to have fetal arrhythmia. The most common arrhythmia during pregnancy was extrasystole (n=59), followed by bradycardia (n=23), tachycardia (n=16), atrial flutter (AF, n=3), atrioventricular block (AVB, n=12) and other arrhythmia (n=17). The overall incidence of cardiac anomalies (commonly fetal bradycardia) was 9.2% in these cases. The prognosis of arrhythmia differed significantly between cases of different classifications. The type of fetal arrhythmia (P=0.024), presence of congenital heart defect (CHD, P=0.000) and fetal hydrops (P=0.008) were significant risk factors associated with termination of pregnancy. CONCLUSION: Fetal arrhythmias without CHD or hydrops under close monitoring often have good clinical outcome, while fetal bradycardia is associated with a high mortality rate. CHD and the presence of fetal hydrops are significant risk factors for pregnancy termination. PMID- 21690052 TI - [Gefitinib enhances the radiosensitivity of nasopharyngeal carcinoma cell line CNE2 in vitro]. AB - OBJECTIVE: To study the radiosensitizing effect of gefitinib on nasopharyngeal carcinoma cell line CNE2 in vitro. METHODS: Nasopharyngeal carcinoma cell line CNE2 was cultured in RP2MI 1640. MTT assay was performed to evaluate the cell proliferation changes in response to gefitinib treatment and the radiosensitizing effect of gefitinib. The cell survival curves and sensitive enhancement ratio (SERs) were obtained with a clonogenic assay. Flow cytometry analysis was applied to detect the cell cycle changes and cell apoptosis. RESULTS: MTT assay showed that cells exposed to gefitinib and radiation had a significantly lower survival ratio compared to the cells with radiation exposure only (0.582?0.012 vs 0.398?0.016, P=0.002), with a SER of 1.535?0.134. The S phase cell percentage was significantly decreased and G(2)-M phase cells increased in gefitinib plus radiation group (P=0.000), suggesting a synergistic effect of gefitinib and radiation. CONCLUSION: Gefitinib can enhance the radiosensitivity of nasopharyngeal carcinoma CNE2 cells in vitro possibly by inhibiting cell proliferation, inducing cell apoptosis, and causing changes in the cell cycle distribution. PMID- 21690053 TI - [The comparison between the vascular endothelial cells special cdc42-deficient heterozygous mice and the non-knockout mice on lung tissue pathological change and vasopermeability in acute lung injury]. AB - OBJECTIVE: To compare the change of lung tissue and vasopermeability between the vascular endothelial cells special cdc42-deficient heterozygous mice and the non knockout mice in acute lung injury. METHODS: The mice with vascular endothelial cell-specific expression of cre recombinase were crossed with cdc42(flox/flox) mice. The cdc42(flox/+)Cre(+/-) F1 offspring mice were crossed back with cdc42(flox/flox) mice, resulting in the F2 generation mice with three genotypes, namely cdc42(flox/+)Cre(+/-), cdc42(flox/flox)Cre(-/-) and cdc42(flox/+)Cre(+/-). The heterozygous mice with cdc42(flox/+)Cre(+/-) genotype were selected as the model mice, with the other two genotype groups as the control. After intratracheal instillation of 2 mg/kg LPS to induce acute lung injury, the mice were sacrificed to examine the lung pathologies, lung wet/dry ratio and lung microvascular permeability. RESULTS: The heterozygous mice with cdc42 gene knockout (cdc42(flox/+)Cre(+/-)) showed no significant differences from the two control groups in the lung pathological score, lung wet/dry ratio or the lung microvascular permeability coefficient. CONCLUSION: There were no significant difference on lung tissue and vasopermeability between the vascular endothelial cells special cdc42-deficient heterozygous mice and the non-knockout mice. PMID- 21690054 TI - [Pathogenic and tumorigenic effect of 1,2-dimethylhydrazine in mouse colon and ovarian]. AB - OBJECTIVE: To study the pathogenic and tumorigenic effect of 1,2 dimethylhydrazine (DMH) on the colon and ovaries of mice. METHODS: Sixty ICR female mice were randomly divided into groups A and B for intraperitoneal injection of DMH (20 mg/kg) and saline (control) once a week for 24 weeks, respectively. The mice were sacrificed at 12, 16, 20, 24, 28 and 32 weeks after the first DMH injection for pathological examination of the colon and ovaries. RESULTS: In group A, colorectal adenomas were found in 7, colorectal adenocarcinomas in 5, and hemorrhagic lesions of the ovaries with chronic inflammatory in 21 mice. Choriocarcinoma in the ovaries were detected in one mouse at 28 weeks and in another at 32 weeks. No obvious pathological changes were found in group B following the injections. CONCLUSION: Intraperitoneal injection of DMH may induce colon tumors and ovarian diseases in mice. PMID- 21690055 TI - [Immune function changes in patients with obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To explore the potential changes in the immune function of patients with obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: We carried out a retrospective cross-sectional study of 187 patients with established OSAHS and 20 healthy subjects (control). For all the patients, the medical history was carefully examined, and overnight sleep monitoring was carried out with detection of the humoral and cellular immunity. RESULTS: We found a significant increase in the levels of C3 and a decrease in both the IgM level and NK cell percentage in OSAHS patients as compared to the control group (P<0.01). Correlation analysis indicated that C3 was positive correlated to AHI but inversely to the lowest pulse oxygen saturation (LSpO(2)); IgM showed a mild positively correlation to LSpO(2), and NK cells had a mild inverse correlation to AHI. The other immunological indices were not found to undergo noticeable changes or show correlations in OSAHS. CONCLUSION: Immune function changes occur in patients with OSAHS, characterized primarily by deteriorations in the humoral and cellular immunity. PMID- 21690056 TI - [Quality inspection of commercial Bupluri Radix samples in Guangzhou: an ELISA for determining saikosaponin A content using anti-saikosaponin A monoclonal antibody]. AB - OBJECTIVE: To inspect the quality of commercially available Chaihu (Bupluri Radix, a common traditional Chinese herbal drug) in Guangzhou by determining the content of saikosaponin A (SSa) using enzyme-linked immunosorbent assay (ELISA). METHODS: A competitive ELISA system using mouse anti-saikosaponin A monoclonal antibody was established for determining SSa content. Commercial samples of Chaihu were obtained from 10 drug stores in Guangzhou, and SSa contents in the methanol extracts of these samples were determined using the ELISA system. RESULTS: The detection range of this competitive assay was 0.16-2.5 ug/ml for determining SSa contents. In the 10 commercial Chaihu samples, SSa contents in the methanol extract determined by this method ranged from 0.32 ug/mg to 6.87 ug/mg, and 3 samples showed a SSa content lower than the minimum requirement documented in the Chinese Pharmacopeia. CONCLUSION: This competitive ELISA is sensitive, rapid, economic and environment-friendly for SSa determination, especially suitable for batch determination. The results of SSa detection for the commercial Chaihu samples demonstrate an uneven quality of Chaihu in Guangzhou market, suggesting the necessity of more rigorous quality control measures for this drug. PMID- 21690057 TI - [Safety and efficacy of Entecavir combined with Adefovir in patients with chronic hepatitis B who fail to respond to nucleoside analog treatment]. AB - OBJECTIVE: To evaluate the safety and efficacy of the combined therapy with entecavir (ETV) and adefovir (ADV) in patients with chronic hepatitis B (CHB) who experienced failure of treatment with single or multiple nucleoside analogs, and analyze the factors that affect the patients response to the treatment. METHODS: Forty-five CHB patients who experienced treatment failure with sequential or/and combined nucleoside analogs received the combined therapy with entecavir and adefovir lasting for at least 6 months. The viroloigcal response (VR), biochemical response (BR) and combined response (CR) at 24 and 48 weeks of the treatment were evaluated. Univairante analysis was used to identify the factors that affect the response to the anti-viral therapy. RESULTS: The VR, BR and CR were 67.7%, 77.8% and 57.8% at 24 weeks, as compared to 76.2%, 78.6% and 61.9% at 48 weeks, respectively. The VR differed significantly between patients with a baseline HBV DNA level [lg(copies/ml)] of 3-6 and those with a level over 6 (85.2% vs 40%, Z=-4.796, P=0.037) at 48 weeks. The presence and absence of cirrhosis at the initial treatment significantly affected the BR at 24 weeks (17.1% vs 82.9%, P=0.048) and at 48 weeks (23.8% vs 76.2%, P=0.023). CONCLUSION: Entecavir combined with adefovir is an effective rescue therapy in CHB patients after failure of treatment with nucleoside analogs. Patients with a lower baseline HBV DNA level without cirrhosis may have better response to the combined treatment. PMID- 21690058 TI - [Hypoadiponectinemia leads to insulin resistance in OLETF rats: a preliminary study]. AB - OBJECTIVE: To investigate the association between plasma adiponectin and insulin resistance in OLETF rats. METHODS: Twenty male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and 10 male Long-evans Tokushima Otsuka (LETO) rats underwent oral glucose tolerance test (OGTT) at 13 and 40 weeks of age. At 8, 32 and 40 weeks of age, the rats were sacrificed to measure the blood glucose, plasma insulin and adiponectin levels, and serum levels of TG, CHOL and FFA. RESULTS: The plasma adiponectin level was significantly decreased in 8-week-old OLETF rats compared with that of LETO rats (P<0.05). The plasma insulin level, TG, CHOL, and FFA were significantly higher in OLETF rats than in LETO rats at 32 and 40 weeks of age. CONCLUSION: A decreased plasma level of adiponectin preludes insulin resistance and is inversely correlated to insulin sensitivity. Hypoadiponectinemia may be an important reason leading to insulin resistance. PMID- 21690059 TI - [Detection and genotype analysis of sapovirus associated with sporadic diarrhea in Shenzhen in 2009]. AB - OBJECTIVE: To conduct an epidemiological and genotype analysis of sapovirus (SaV) associated with sporadic diarrhea in Shenzhen in the year 2009. METHODS: A total of 852 fecal samples were collected from sporadic cases of diarrhea in Shenzhen in 2009 and detected by reverse-transcription polymerase chain reaction (RT-PCR) using the primers of SLV5317/5749. The PCR products were analyzed with 1.5% agarose gel electrophoresis and sequenced to construct the phylogenetic tree. RESULTS: Sixteen samples were found positive for SaV, with a positivity rate of 1.88%. Sequence analysis identified 8 isolates as SaV GI genotype (including 3 SaV GI.1 and 5 SaV GI.2), 7 as SaV GIV genotype, and 1 as GII genotype. CONCLUSIONS: SaV infection is present in Shenzhen with GI as the predominant genotype. This is the first report of SaV GIV strains in China, which differs from the strains of Anhui-A141 and Beijing-CHN99/BJ360, suggesting the genotypic variety of SaV infection in China. PMID- 21690060 TI - [Effect of simulated microgravity on human monocytic cell proliferation and tissue factor mRNA expression]. AB - OBJECTIVE: To investigate the effect of simulated microgravity on the proliferation of human monocytic cells THP-1 and the expression of tissue factor (TF) mRNA. METHODS: THP-1 cells were cultured under a simulated microgravity environment using the rotating cell culture system (RCCS). The changes in the cell proliferation after microgravity culture were assessed by cell counting and cell cycle analysis with flow cytometry. RT-PCR was used to detect the changes in the expression of TF mRNA in THP-1 cells. RESULTS: Culture under simulated microgravity resulted in a significant decrease in the cell number of THP-1 cells in comparison with that of the control cells (P<0.01). After a 24-h culture under microgravity, the G0-Gl phase cells increased from the control level of (46.57?1.64)% to (67.64?2.71)% (P<0.05). The cells in both groups showed a low level of TF mRNA expression in the absence of LPS stimulation. A 4-h stimulation with LPS caused up-regulated expression of TF mRNA in both cells, but the microgravity group showed a significantly smaller increase in the expression (2.301?0.179) than the control group (9.210?1.328) (P<0.05). CONCLUSION: Microgravity can inhibit the proliferation of THP-1 cells and suppress the cellular expression of TF mRNA. PMID- 21690061 TI - [Preparation of podophyllotoxin nanostructured lipid carriers and its effects on immortalized human cervical epithelial cells with HPV infection in vitro]. AB - OBJECTIVE: To study the effect of podophyllotoxin nanostructured lipid carriers (POD-NLC) on immortalized human cervical epithelial cells (H8) infected with HPV in vitro. METHODS: POD-NLC was prepared by emulsion evaporation method and characterized using transmission electron microscopy, Zetasizer analyzer and high performance liquid chromatography (HPLC). H8 cells were treated with different concentrations (0.0001-1 ug/ml) of POD-NLC, free POD, or blank nanostructured lipid carriers (NLC), and the cell proliferation was assessed using MTT assay to evaluate the cytotoxic effects. The changes of cell morphology were observed using fluorescence microscopy, and the cell cycle changes and cell apoptosis were analyzed using flow cytometry. RESULTS: POD-NLC showed a spherical or elliptical shape with good stability in vitro. The average particle size of POD-NLC was 85.6?10.25 nm, with a Zeta potential of 26.2?4.1 mV and entrapment efficiency of POD of (88.56?3.1)%. POD-NLC caused a significant inhibition of H8 cell proliferation in a concentration- and time-dependent manner. At an equivalent concentration, POD-NLC produced a stronger inhibitory effect on cell proliferation than POD. The inhibition rate of H8 cells after a 48-h exposure to POD-NLC and POD reached 95.8% and 65.6%, respectively, and at the highest concentration of 1 ug/ml, the IC(50) of POD-NLC and POD was 0.015 ug/ml and 0.13 ug/ml, respectively. Blank NLC did not obviously affect the proliferation of H8 cells. POD-NLC and POD both caused obvious increases in G(2)/M phase cell percentages and induced typical apoptotic changes of the cells, and their effects were comparable (P>0.05). CONCLUSION: Compared with POD, POD-NLC has more potent effect in inhibiting H8 cell proliferation and inducing cell apoptosis, suggesting its potential in the treatment of cervical HPV infection. PMID- 21690062 TI - [Expressions of p53 pathway genes and EZH2 in undifferentiated nasopharyngeal carcinoma]. AB - OBJECTIVE: To investigate the relationship between the expressions of p53 pathway genes and EZH2 in nasopharyngeal carcinoma (NPC). METHODS: The expression levels of p53, mdm2, p63 and EZH2 proteins were detected by immunohistochemistry in 47 cases of undifferentiated NPC and 12 cases of chronic nasopharyngitis, and their correlation to the clinical parameters and prognosis were analyzed. RESULTS: The protein expressions of p53, mdm2, p63 and EZH2 in NPC were 31.9%, 85.1%, and 95.7%, respectively. mdm2 and EZH2 was not correlated to p53 protein expression (P>0.05); positive correlations was found between EZH2 and p63 expressions and between p53 and p63. The high expression of EZH2 and p63 proteins was correlated to advanced T stage and clinical stage of NPC (P<0.05). The five-year disease free survival rate in patients with high EZH2 protein expression was significantly lower than that in patients with low EZH2 expression. CONCLUSION: mdm2 does not show an obvious correlation to p53 protein inactivation in NPC. p63 protein overexpression may be associated with p53 protein inactivation. The overexpression of EZH2 is correlated to NPC progression and poor prognosis. PMID- 21690063 TI - [Short-term therapeutic effect of posterior pedicle screw fixation for treatment of degenerative lumbar scoliosis]. AB - OBJECTIVE: To evaluate the short-term outcomes of patients receiving orthopedic surgery with posterior pedicle screw fixation for degenerative lumbar scoliosis. METHODS: Between March, 2006 and August, 2009, 36 patients with degenerative lumbar scoliosis (19 males and 17 females) underwent procedures of decompression, bone implantation and pedicle screw fixation. Fifteen patients were also treated by PLIF and 21 cases received posterior-lateral fusion. The JOA scores, Oswestry disability index (ODI), and Cobb angle were recorded before and after the operation, and the surgical complications were also observed. RESULTS: The JOA scores increased significantly by 83.3% after the operation (P<0.05). The procedures resulted in significantly lowered ODI from (67.1?11.4)% before the operation to (32.1?10.8)% after the operation (P<0.01). A significant improvement of the coronal Cobb's angle was achieved after the operation (26.7 degrees preoperatively vs 12.3 degrees postoperatively, P<0.01), and the lordosis angle was improved from 10.7 degrees to 36.6 degrees after the operation (P<0.01). All the patients were followed up for 12 to 50 months (mean 38 months), and no implant loosening, displacement or fragmentation, or pseudarthrosis was found at the final follow-up. CONCLUSION: Posterior pedicle screw fixation shows good short-term therapeutic effect in treatment of degenerative lumbar scoliosis. Individualized surgical plans and adequate preoperative evaluation are keys to successful operations. PMID- 21690064 TI - [Effects of ginsenoside Rg1 on learning and memory function and morphology of hippocampal neurons of rats with electrical hippocampal injuries]. AB - OBJECTIVE: To investigate the effect of ginsenoside Rg1 (G-Rg1) on the morphology of the hippocampal neurons of rats with electrical hippocampal injuries and evaluate its protective effects on the learning and memory function. METHODS: Forty female SD rats were randomly divided into G-Rg1 group, saline group, sham operated group and G-Rg1+Sham operation group. Using the stereotactic apparatus, electrical hippocampal injury was induced, not in the two sham groups, by application of direct electrical current, followed by treatments with intragastric administration of G-Rg1 or saline for 14 consecutive days. The learning and memory function of the rats was assessed with Morris water maze test. The viability and arrangement of the hippocampal neurons and the number of Nissl bodies were observed after the treatments. RESULTS: Treatment with G-Rg1 significantly improved the learning and memory function of rats with electrical hippocampal injury. The viability of the hippocampal neurons showed no significant changes in the two sham-operated groups (P>0.05), and the number of Nissl bodies was much lower in saline group than in the other groups (P<0.05). CONCLUSIONS: G-Rg1 can improve the learning and memory function of rats with electrical hippocampal injury, the mechanism of which is probably associated with its protective effect on the hippocampal neurons against electrical injury. PMID- 21690065 TI - [Value of multi-detector row CT and magnetic resonance imaging in the diagnosis of retinal detachment]. AB - OBJECTIVE: To summarize multi-detector row CT (MDCT) and magnetic resonance imaging (MRI) features of retinal detachment and evaluate the diagnostic value of these two imaging modalities. METHODS: The MDCT and MRI manifestations were reviewed in 45 cases (47 eyes) of retinal detachment, among which 16 cases (17 eyes) were examined by MDCT and 29 cases (30 eyes) by MRI. Thirty-two cases (33 eyes) were confirmed by operation, and the other 13 cases (14 eyes) were confirmed based on the clinical findings. RESULTS: MDCT and MRI displayed signs of fluid retention between the detached retina and the posterior wall of the eyeball in the cases. Among all these cases, 21 eyes showed simple retinal detachment and 26 had also other pathologies (hemorrhage in 20 eyes and calcification in 6 eyes). Choroidal osteoma was identified in 3 eyes and melanoma of choroid in 5 eyes. CONCLUSION: MDCT is sensitive in detecting calcification in the eyes and MRI with a minimal risk of radiation, and shows advantages in displaying hemorrhage and confined retinal detachment. Both MDCT and MR have high clinical value in the diagnosis of retinal detachment, and their choice depends on the individual condition of the patients. PMID- 21690066 TI - [Value of cardiac troponin I measurement in prediction of anthracycline-induced cardiotoxicity in breast cancer patients]. AB - OBJECTIVE: To evaluate the value of cardiac troponin I (CTnI) measurement in predicting anthracycline-induced cardiotoxicity in patients with breast cancer. METHODS: This study was conducted among 186 breast cancer patients receiving anthracycline-based chemotherapy. Serum cTnI concentrations before and after each cycle of the chemotherapy and the left ventricular ejection fraction (LVEF) before and at the 2nd, 4th and 6th months of the treatment were recorded. According to serum cTnI concentration, the patients were divided into CTnI+ group (with serum CTnI concentration of no less than 0.1 ng/ml, n=60) and CTnI- (<0.1 ng/ml) group (n=126). RESULTS: No patients in this series experienced cardiac heart failure (CHF). The number of patients with a LVEF reduction by over 10% from the baseline was 16 (26.7%) in CTnI+ group, as compared to 7 (5.6%) in CTnI- group, showing a significant difference between the two groups (P<0.01). CONCLUSION: CTnI can be a useful marker for early prediction of anthracycline induced cardiotoxicity in patients with breast cancer. PMID- 21690067 TI - [Role of miR-145 in erectile dysfunction in diabetic rats]. AB - OBJECTIVE: To investigate the role of miR-145 in the corpus cavernosum smooth muscle tissue in the pathogenesis of erectile dysfunction (ED) in diabetic rats. METHODS: The total RNA was extracted from the corpus cavernosum of a diabetic rat model with ED, diabetic rats with normal erectile function and normal rats, and the expression levels of miR145 were compared between the groups. RESULTS: The expression of miR-145 was decreased in the corpus cavernosum of diabetic rats with ED. CONCLUSION: Diabetes mellitus can cause ED in rats, in which process decreased expression of miR145 in the corpus cavernosum may play a role. PMID- 21690068 TI - [Effect of intra-articular ozone injection on serum and synovial TNF-alpha, TNFR I, and TNFR II contents in rats with rheumatoid arthritis]. AB - OBJECTIVE: To observe the effects of intra-articular ozone injection at different concentrations on the contents of tumor necrosis factor-alpha (TNF-alpha), TNF receptor I (TNFR I), and TNFR II in the serum and synovium of rats with rheumatoid arthritis (RA) and explore the therapeutic mechanism of ozone in RA treatment. METHODS: Forty-eight Wistar rats were randomized into 8 groups, including 5 ozone groups receiving intra-articular injection of 10, 20, 30, 40 or 50 ug/ml ozone, a blank control group, an oxygen group and a RA model group. All the rats, except for those in the blank control group, were subjected to hypodermic injection of bovine collagen II and complete Freunds adjuvant to induce RA. Ozone treatment was administered once weekly for 3 weeks starting at 21 days after the modeling. The swelling and thickness of the hind paws were observed, and the serum and synovial contents of TNF-alpha, TNFR I, and TNFR II were detected. RESULTS: At the end of treatment, the paw thickness was reduced significantly in rats with 40 ug/ml ozone injection compared with that in the model RA group (P<0.01). The serum contents of TNF-alpha, TNFR I and TNFR II showed no significant difference between the RA model group, oxygen group and the ozone groups, but their synovial contents showed significant reductions in rats with 40 and 50 ug/ml ozone injection (P<0.01); the synovial TNFR I was significantly higher in 40 ug/ml ozone group than in the model group (P<0.05). CONCLUSION: Intra-articular injection of 40 ug/ml ozone can attenuate synovitis in rats with RA, the mechanism of which may involve the inhibition of TNF-alpha and TNFR II activity and enhancement of TNFR I activity in the synovium. PMID- 21690069 TI - [Transforming growth factor-beta1 regulates renal alpha3 and beta1 integrin expressions in diabetic rats: a new insight into the renoprotective effect of irbesartan]. AB - OBJECTIVE: To explore the association between renal transforming growth factor beta1 (TGF-beta1) and the expressions of alpha3 and beta1 integrins and observe the effect of irbesartan on their expressions in diabetic rats. METHODS: Thirty 8 week-old male Wistar rats were randomly divided into normal control group (n=7), diabetic control group (n=14) and irbesartan group (n=9). Rat models of diabetes were established by a single peritoneal injection of streptozotocin (STZ), and 4 weeks later the rats received irbesartan treatment for 8 weeks. Enzyme-linked immunosorbent assay (ELISA) was used to measure the urinary albumin excretion rate, and PAS staining was utilized to observe the renal pathologies. Immunohistochemistry was performed for semi-quantitative determination of podocyte density, and real-time RT-PCR was used to detect the renal TGF-beta1 and alpha3/beta1 integrin mRNA expressions. RESULTS: In diabetic rats, the expression of renal TGF-beta1 mRNA was significantly increased, while alpha3 and beta1 integrin mRNA expressions and podocyte density significantly decreased with increased proteinuria. Irbesartan obviously improved such changes. CONCLUSION: In diabetic rats renal TGF-beta1 can regulate alpha3 and beta1 integrin mRNA expressions to reduce the number of podocytes, and inhibition of this pathway may be one of the mechanisms of the renal protective effect of irbesartan. PMID- 21690070 TI - [Effect of hypervolemic hemodilution on C-reactive protein level in patients receiving spinal surgery]. AB - OBJECTIVE: To investigate the changes in high-sensitivity C-reactive protein (hs CRP) levels following acute hypervolemic hemodilution (AHH) in patients undergoing spinal surgery and assess the safety of AHH in terms of postoperative infection. METHODS: Forty patients undergoing spinal operation were randomly assigned into observation group and control group (n=20). Each patient was infused 4 ml/kg/h lactated Ringers solution for maintenance of the total blood volume, and in the observation group, the patients received additional infusion of 4% gelofusine solution at the rate of 20 ml/kg/h 30 min before the operation. Venous blood samples were collected to monitor the hematocrit (Hct), prothrombin time (PT), activated partial thromboplastin time (APTT) and hs-CRP before anesthesia (T0), 2 h after the beginning of the operation (T1), at the end of the operation (T2), and 24 h after the operation (T3). RESULTS: After AHH, Hct decreased significantly at T1 as compared with that at T0 (P<0.05) and that of the control group (P<0.01), but showed no significant difference between the two groups at T2. PT and APTT showed significant changes at T1 compared with T0 (P<0.05) but within the normal range, and were similar between the two groups at T3. hs-CRP increased significantly in the two groups at T3 compared with that at T0 (P<0.05), and a significant difference was noted between the two groups (P<0.01). CONCLUSION: AHH does not affect the hemodynamics and blood coagulation of the patients undergoing spinal surgery but causes a significant elevation of hs-CRP, suggesting an increased risk of postoperative infection. PMID- 21690071 TI - [Effect of 5-fluorouracil aerosol on the growth of human gastric cancer cell line MKN-45 in vitro]. AB - OBJECTIVE: To evaluate the effect of simulated intraperitoneal 5-fluorouracil (5 Fu) aerosol chemotherapy (AIPC) on the proliferation, apoptosis, and cell cycle of human gastric cancer cell line MKN-45 in vitro. METHODS: The gastric cancer cells MKN-45 were treated with 5-Fu aerosol for 30 min under the pressure of 8 mmHg, and those treated with normal saline (NS) aerosol served as the control. The cell proliferation after the treatment was detected by MTT assay, and flow cytometry and FITC Annexin V/PI kit were used to detect the cell apoptosis and changes in the cell cycle. RESULTS: MTT assay showed a significantly greater inhibition rate of the cell proliferation in 5-Fu aerosol group than in NS group [(31.13?3.51)% vs (4.65?1.99)%, P<0.001]. FCM analysis also showed a significantly higher cell apoptotic rate in 5-Fu aerosol group than in NS group [(12.00?0.92)% vs (2.65?0.52)%, P<0.001]. Compared with saline treatment, treatment with 5-Fu aerosol resulted in a greater proportion of G1 phase cells [(51.83?1.95)% vs (36.41?2.33)%, P<0.001] with a lowered proportion of S phase cells [(16.72?2.36)% vs (45.20?3.27)%, P<0.001]. CONCLUSION: Simulated 5-Fu AIPC can inhibit the proliferation, induce cell apoptosis and cause cell cycle arrest at G1 phase in gastric cancer cells. PMID- 21690072 TI - [Simultaneous determination of serum concentrations of amoxicillin and clavulanate potassium in human blood using high-performance liquid chromatography]. AB - OBJECTIVE: To establish a chromatography-based method for simultaneous analysis of the concentrations of amoxicillin and clavulanate potassium in human blood. METHODS: With paracetamol as the internal control, human plasma samples, after treatment with methanol for protein sedimentation and centrifugation, were loaded for analysis with high-performance liquid chromatography (HPLC). HPLC analysis was carried out using a C18 column (5 um, 4.6 mm*150 mm) with the mobile phase of acetonitrile-PBS (0.05 mol/L) of 10:90 (pH 2.3), UV detection wavelength of 220 nm, flow rate of 1.0 ml/min, and column temperature of 25 degrees celsius;. RESULTS: The retention time of acetaminophen for potassium clavulanate, amoxicillin sodium and the internal control was 5.3, 7.2, and 8.5 min, respectively, and no interference by the endogenous impurities in the plasma samples was found. Amoxicillin sodium showed a good linearity within the concentration range of 0.52-4.16 ug/ml (r(2)=0.9996), and potassium clavulanate had a good linearity within the range of 0.266-2.14 ug/ml (r(2)=0.9998). The minimum detectable concentrations of amoxicillin sodium and potassium clavulanate were 0.065 ug/ml and 0.066 ug/ml, respectively. The relative recoveries of amoxicillin sodium were 95.9%-96.5% (n=5), and those of clavulanate potassium were 92.5%-98.8% (n=5); the intra- and inter-day RSD of amoxicillin sodium was 1.84%-6.4% and 2.1%-7.8%, as compared to that of potassium clavulanate of 3.57% 8.6% and 1.8%-9.1%, respectively. CONCLUSION: This method is simple, accurate, sensitive, specific and reproducible for analyzing the concentrations of amoxicillin and clavulanate potassium simultaneously in human plasma. PMID- 21690073 TI - [Early surgical outcomes of coronary heart disease with severe ischemic mitral regurgitation]. AB - OBJECTIVE: To summarize the experience with surgical treatment of coronary artery disease with severe ischemic mitral valve regurgitation (IMR). METHODS: From January 2006 to December 2009, 45 patients (35 males, 10 females aged 32-74 years) with the diagnosis of coronary artery disease complicated by IMR underwent coronary artery bypass grafting (CABG) combined with mitral valve plasty (MVP, 24 cases) or mitral valve replacement (MVR, 21 cases). RESULTS: Perioperative deaths occurred in 2 cases due to multiple organ failure (MOF). Echocardiography showed a significant reduction of the mitral regurgitation area (from 11.80?2.45 cm(2) to 2.83?0.98 cm(2), t=22.80, P=0.00) after CABG combined with mitral valve surgery, with also significantly reduced postoperative left ventricular end diastolic diameter (LVEDD) (from 57.61?10.06 mm to 51.84?8.98 mm, t=2.85, P=0.005). No significant difference was detected in the left ventricular ejection fraction after the operation [(52.7?15.4)% vs (53.2?13.2)%, t=0.16, P=0.87)]. CONCLUSIONS: CABG combined with mitral valve surgery can improve early postoperative left ventricular function in patients with ischemic coronary heart disease complicated by severe mitral regurgitation, but further follow-up study is still needed for evaluation of the long-term results. PMID- 21690074 TI - [Analysis of causes of death and potential years of life lost in 7 districts of Guangzhou]. AB - OBJECTIVE: To analyze the causes of death and potential years of life lost (PYLL) in 7 districts of Guangzhou from 2003 to 2005. METHODS: The bureau of Health of Guangzhou provided the data of 70 201 cases of death occurring between 2003 and 2005. The top 10 causes of death were analyzed and the PYLL and crude death rate were calculated using mortality difference dissembling method. RESULTS: Between 2003 and 2005, the top 3 causes of death in Guangzhou were diseases of the circulatory system, neoplasms and respiratory diseases. Aging of the population led to an increased death rate. The major causes of death affecting PYLL consisted of neoplasms, diseases of the circulatory system, injuries and poisoning. CONCLUSION: Priority should be given to the control of diseases of the circulatory system in the health care in Guangzhou. Neoplasms, injuries and poisoning all contribute to a high PYLL. PMID- 21690075 TI - [Effect of exogenous adrenomedullin on renal and hypothalamus adrenomedullin expression in rats early after mechanical renal trauma]. AB - OBJECTIVE: To observe the effects of exogenous adrenomedullin (ADM) on endogenous expression of ADM in the kidney and hypothalamus of rats early after mechanical renal trauma. METHODS: Adult Wistar rats were randomized into 4 groups (n=32), namely the control group, renal impact trauma group, preventive ADM injection group, and therapeutic ADM injection group. In the latter two groups, ADM (0.1 nmol/kg) was administrated by intraperitoneal injection 10 min before and 10 min after renal trauma. The rats were executed at 1, 6, 12, and 24 h after the trauma to examine the expression of ADM in the kidney and hypothalamus. RESULTS: In preventive ADM injection group, the renal expression of ADM increased significantly at 1 h after the trauma (P<0.05) and tended to further increase with time till 24 h when its expression recovered the normal level. In the therapeutic ADM injection group, strong renal ADM positivity was found at 1 and 6 h after the injury (P<0.05) followed by gradual decrease till recovering the normal level at 24 h. Low renal ADM expression was detected, which was the strongest at 1 and 12 h (P<0.05) and became normal at 24 h. The time course of ADM expression in the hypothalamus was similar to that in the kidney in the therapeutic ADM injection group, and in the preventive injection group, the strongest ADM expression in the hypothalamus occurred at 6 and 24 h, and the lowest expression occurred at 12 h (P<0.05). The trauma group showed significantly decreased ADM expression in the hypothalamus compared with the control group (P<0.05). CONCLUSION: The hypothalamic ADM expression can upregulate renal ADM expression. ADM maintains the relative stability of the internal environment and physiological activity by local and systemic positive and negative feedback mechanisms. PMID- 21690076 TI - [Effect of protease in the lumen of rat intestine on inflammatory reaction during hemorrhagic shock]. AB - OBJECTIVE: To investigate the effect of intraluminal administration of ulinastatin (a protease inhibitor) in the intestine on intestinal inflammation in rats with hemorrhagic shock. METHODS: Twenty-eight Wistar rats were randomized into control group (A), intestinal saline perfusion group (B), ulinastatin intestinal perfusion group (C), and intravenous ulinastatin injection group (D) (n=7). The mean arterial blood pressure (MAP) and survival time of the rats were recorded. The changes in human polymorphonuclear cell (PMN) CD11b expression were detected by flow cytometry. The leukocyte count was recorded at different time points after the treatment, and the pathology of the intestinal mucosa was observed comparatively. RESULTS: Groups C and D showed significantly slower reduction of the MAP than groups A and B after hemorrhagic shock (P<0.05). The survival time of the rats was the longest in group C (P<0.05). CD11b expression increased gradually during hemorrhagic shock in all the groups, but the expression level was the lowest in group C (P<0.05). Hemorrhagic shock caused a reduction in leukocyte counts, which remained the highest in group C (P<0.05). Group C also showed the least intestinal pathology among the 4 groups. CONCLUSION: Intestinal perfusion of ulinastatin can lower the reduction rate of MAP, attenuate plasma activation and intestinal inflammation, and prolong the survival of rats with hemorrhagic shock. These results indicate an important role of protease in intestinal inflammation during hemorrhagic shock. PMID- 21690077 TI - [Effect of methylprednisolone pretreatment on pulmonary permeability and dipalmitoylphosphatidylcholine content in rabbits with reexpansion pulmonary edema]. AB - OBJECTIVE: To investigate the effects of methylprednisolone pretreatment on pulmonary lung permeability index and the content of the pulmonary surfactant dipalmitoylphosphatidylcholine (DPPC) in a rabbit model of reexpansion pulmonary edema. METHODS: Twenty-one male New Zealand white rabbits were randomly divided into control group, reexpansion, and reexpansion+methylprednisolone pretreatment groups. The rabbit model of reexpansion pulmonary edema was established using Sakaos method. A bolus dosage of methylprednisolone (3 mg/kg) in reexpansion+methylprednisolone group group or 2.0 ml/kg normal saline in the other two groups was administered intravenously 20 min before reexpansion pulmonary edema. Bronchoalveolar lavage fluid (BALF) and arterial blood samples were collected for measurement of the total protein (TP) and DPPC contents 4 h after reexpansion, and the pulmonary permeability index was calculated. RESULTS: The pulmonary permeability index in methylprednisolone pretreatment group was significantly lower than that in the reexpansion group (0.007?0.002 vs 0.177?0.004, P<0.05). Methylprednisolone pretreatment significantly increased DPPC concentration in the BALF as compared with saline treatment in the reexpansion group (61.815?28.307 vs 101.955?24.544 ug/ml, P<0.05). CONCLUSION: Methylprednisolone pretreatment can increase pulmonary surfactant content and improve pulmonary permeability in the rabbit model of reexpansion pulmonary edema. PMID- 21690078 TI - [Clinical significance of glycosylated serum protein in patients with diabetic nephropathy]. AB - OBJECTIVE: To explore the relations between fasting blood glucose (FBG), glycosylated hemoglobin A1c (HbA1c) and glycosylated serum protein (GSP). METHODS: FBG, HbA1c and GSP were measured in 303 patients with diabetic nephropathy and in 167 non-diabetic patients with comparable baseline data, and the correlations between FBG, HbA1c and GSP were analyzed. RESULTS: GSP levels were significantly higher in patients with diabetic nephropathy than in the non diabetic patients (P<0.01). In patients with diabetic nephropathy, GSP levels were found to positively correlate to FBG (r=0.606) and HbA1c (r=0.733). CONCLUSION: Patients with diabetic nephropathy show strong correlations between FBG, HbA1c and GSP. GSP detection is convenient, stable, and practical in evaluating the average FBG over a short term, which reduces the interference by FBG fluctuations in conventional blood glucose monitoring. PMID- 21690079 TI - [Clinical application of T2*GRE multiple echo sequence on articular cartilage disease in the knee]. AB - OBJECTIVE: To evaluate the correlation between T2* relaxation time and the pathological changes in the knee joint of patients with osteoarthritis (OA) and analyze the changes of T2* relaxation time in early cartilage injury. METHODS: Sixty-two patients with OA in different phases underwent magnetic resonance imaging (MRI) of the knee and the articular cartilage T2* relaxation time was recorded, with 20 young healthy volunteers as the control group. RESULTS: Patients with mild OA showed significantly different T2* relaxation time for most of the articular cartilage from that of the healthy volunteers (P<0.05), but no such difference was found between serious OA group and the healthy volunteers. The change of T2* relaxation time of the cartilage was also associated with age, weight and body height, and the potential effects of other factors could not be excluded. CONCLUSION: The articular cartilage shows no obvious morphological changes in early OA of the knee, a stage characterized mostly by alterations of the tissue structure and compositions. Cartilage pathologies can be the most obvious on the weight-bearing surface of the medial condyle of the femur or in the patella. T2* relaxation time measurement can be helpful in the detection of early cartilage pathologies. PMID- 21690080 TI - [Effects of exendin-4 on rat cardiomyocyte apoptosis early after severe scald injury]. AB - OBJECTIVE: To observe the effect of exendin-4 on cardiomyocyte apoptosis in the early stage after scald injury in rats and explore the mechanisms. METHODS: Fifty four healthy adult SD rats were randomly divided into normal control group (n=6), scald group (n=24) and scald with exendin-4 treatment group (n=24). In the latter two groups, the rats were subjected to 30% TBSA full-thickness scald burns on the back, and Parkland formula was used for determining the resuscitation fluid volume. In exendin-4 treatment group, the rats received intraperitoneal injection of 5 ug/kg exendin-4 after the scald. Apoptosis of the cardiomyocytes from the left ventricle was determined by TUNEL assay and the activity of caspase-3 in the myocardium was assessed. RESULTS: In the scald group, the apoptotic index of the cardiomyocytes was increased at 6 h post-burn, reaching the peak level at 12 h, and maintained a significantly higher level than that in the normal control at 48 h (P<0.05). Myocardial caspase-3 activity in the scald group was increased at 6 h post-burn and reached the peak at 12 h, still maintaining a high levels at 24 h (P<0.05). In exendin-4 treatment group, the apoptotic index of the cardiomyocytes was significantly lower than that in the scald group at 6, 12, 24 and 48 h post burn (P<0.05), and so was the caspase-3 activity at 6, 12 and 48 h (P<0.05). A significant positive correlation was found between the apoptotic index of the cardiomyocytes and myocardial caspase-3 activity in the rats (P<0.05). CONCLUSION: Exdendin-4 can inhibit rat cardiomyocyte apoptosis early after scald injury possibly by suppressing caspase-3 activity in the myocardium. PMID- 21690081 TI - [Correlation between renal artery resistance index and serum creatinine level early after renal transplantation]. AB - OBJECTIVE: To investigate the relationship between the resistance index (RI) of the renal artery and serum creatinine (Cr) level in patients early (within one month) after renal transplantation. METHODS: A total of 123 patients receiving renal transplantation underwent examinations by color Doppler ultrasound for measurement of the RI of the renal artery within one month after the operation. According to the results of RI measurement, the patients were divided into RI>=0.75 and RI<0.75 groups for analyzing the correlation between RI and serum Cr level measured at the same time points. RESULTS: The RI and Cr levels in patients with RI>=0.75 showed a significant positive correlation (P<0.05), whereas they showed an inverse correlation in patients with RI<0.75 (P<0.05). The patients with RI>=0.75 had significantly lower RI of the renal artery and Cr level than those with RI>=0.75. CONCLUSION: RI is significantly correlated to Cr, and may serve as an indicator for predicting renal graft function after transplantation. PMID- 21690082 TI - Evaluation of the criterion and convergent validity of the Diagnostic Interview for Social and Communication Disorders in young and low-functioning children. AB - The Diagnostic Interview for Social and Communication Disorders (DISCO; Wing, 2006) is a standardized, semi-structured and interviewer-based schedule for diagnosis of autism spectrum disorder (ASD). The objective of this study was to evaluate the criterion and convergent validity of the DISCO-11 ICD-10 algorithm in young and low-functioning children. The DISCO-11, Autism Diagnostic Observation Schedule (ADOS), and Social Communication Questionnaire (SCQ) were administered to a Dutch sample of 115 children comprising 52 children with ASD (both with and without intellectual disability), 26 children with intellectual disability (non-ASD), and 37 typically developing children. Results indicated high sensitivity and specificity for DISCO-11 classifications in differentiating ASD from non-ASD according to the clinical classification in children with mild intellectual disability or average intelligence. Among children with a moderate or severe intellectual disability the sensitivity was equally high, but the specificity was significantly lower. The agreement between DISCO-11 and ADOS classifications was substantial, between DISCO-11 and SCQ moderate. The correlations between raw scores of the DISCO and ADOS algorithm or SCQ were both high. In conclusion, the DISCO-11 differentiates accurately between autistic disorder and non-ASD in young children with an average intelligence or mild intellectual disability, but is over inclusive in the lower levels of intellectual disability. PMID- 21690083 TI - A pilot randomized controlled trial of DIR/FloortimeTM parent training intervention for pre-school children with autistic spectrum disorders. AB - This pilot study was designed to test the efficacy of adding home-based Developmental, Individual-Difference, Relationship-Based (DIR)/FloortimeTM intervention to the routine care of preschool children with autistic spectrum disorder. Measures of functional emotional development and symptom severity were taken. It was found that after the parents added home-based DIR/FloortimeTM intervention at an average of 15.2 hours/week for three months, the intervention group made significantly greater gains in all three measures employed in the study: Functional Emotional Assessment Scale (FEAS) (F = 5.1, p = .031), Childhood Autism Rating Scale (F = 2.1, p = .002), and the Functional Emotional Questionnaires (F = 6.8, p = .006). This study confirms the positive results obtained by a previous DIR pilot study (Solomon et al., 2007). PMID- 21690084 TI - A comparison of the trait emotional intelligence profiles of individuals with and without Asperger syndrome. AB - The extent to which the socioemotional impairments of Asperger syndrome (AS) might be extreme manifestations of individual differences within the general population remains under-explored. We compared the trait emotional intelligence (trait EI) profiles of 30 individuals with AS against the profiles of 43 group matched controls using the Trait Emotional Intelligence Questionnaire (TEIQue). Participants with AS scored significantly lower than controls on 12 of the 15 TEIQue facets (eta(p) (2) = 0.09 to 0.49) as well as on all four factors and the global score of the construct (eta(p) (2) = 0.07 to 0.41). There was a significant main effect of gender, with men generally scoring higher than women. Results are discussed from the perspective of trait EI theory, with emphasis on its implications for the socioemotional impairments associated with AS. PMID- 21690086 TI - Munc18-1 and Munc18-2 proteins modulate beta-cell Ca2+ sensitivity and kinetics of insulin exocytosis differently. AB - Fast neurotransmission and slower hormone release share the same core fusion machinery consisting of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. In evoked neurotransmission, interactions between SNAREs and the Munc18-1 protein, a member of the Sec1/Munc18 (SM) protein family, are essential for exocytosis, whereas other SM proteins are dispensable. To address if the exclusivity of Munc18-1 demonstrated in neuroexocytosis also applied to fast insulin secretion, we characterized the presence and function of Munc18-1 and its closest homologue Munc18-2 in beta-cell stimulus-secretion coupling. We show that pancreatic beta-cells express both Munc18-1 and Munc18-2. The two Munc18 homologues exhibit different subcellular localization, and only Munc18-1 redistributes in response to glucose stimulation. However, both Munc18-1 and Munc18-2 augment glucose-stimulated hormone release. Ramp-like photorelease of caged Ca(2+) and high resolution whole-cell patch clamp recordings show that Munc18-1 and Munc18-2 overexpression shift the Ca(2+) sensitivity of the fastest phase of insulin exocytosis differently. In addition, we reveal that Ca(2+) sensitivity of exocytosis in beta-cells depends on the phosphorylation status of the Munc18 proteins. Even though Munc18-1 emerges as the key SM-protein determining the Ca(2+) threshold for triggering secretory activity in a stimulated beta-cell, Munc18-2 has the ability to increase Ca(2+) sensitivity and thus mediates the release of fusion-competent granules requiring a lower cytoplasmic-free Ca(2+) concentration, [Ca(2+)](i)(.) Hence, Munc18-1 and Munc18 2 display distinct subcellular compartmentalization and can coordinate the insulin exocytotic process differently as a consequence of the actual [Ca(2+)](i). PMID- 21690085 TI - Single-molecule force spectroscopy reveals the individual mechanical unfolding pathways of a surface layer protein. AB - Surface layers (S-layers) represent an almost universal feature of archaeal cell envelopes and are probably the most abundant bacterial cell proteins. S-layers are monomolecular crystalline structures of single protein or glycoprotein monomers that completely cover the cell surface during all stages of the cell growth cycle, thereby performing their intrinsic function under a constant intra- and intermolecular mechanical stress. In gram-positive bacteria, the individual S layer proteins are anchored by a specific binding mechanism to polysaccharides (secondary cell wall polymers) that are linked to the underlying peptidoglycan layer. In this work, atomic force microscopy-based single-molecule force spectroscopy and a polyprotein approach are used to study the individual mechanical unfolding pathways of an S-layer protein. We uncover complex unfolding pathways involving the consecutive unfolding of structural intermediates, where a mechanical stability of 87 pN is revealed. Different initial extensibilities allow the hypothesis that S-layer proteins adapt highly stable, mechanically resilient conformations that are not extensible under the presence of a pulling force. Interestingly, a change of the unfolding pathway is observed when individual S-layer proteins interact with secondary cell wall polymers, which is a direct signature of a conformational change induced by the ligand. Moreover, the mechanical stability increases up to 110 pN. This work demonstrates that single-molecule force spectroscopy offers a powerful tool to detect subtle changes in the structure of an individual protein upon binding of a ligand and constitutes the first conformational study of surface layer proteins at the single-molecule level. PMID- 21690087 TI - A minimal nuclear localization signal (NLS) in human phospholipid scramblase 4 that binds only the minor NLS-binding site of importin alpha1. AB - Importin alpha1 can bind classical nuclear localization signals (NLSs) in two NLS binding sites, known as "major" and "minor." The major site is located between ARM repeats 2-4, whereas the minor site spans ARM 7-8. In this study, we have characterized the cellular localization of human phospholipid scramblase 4 (hPLSCR4), a member of the phospholipid scramblase protein family. We identified a minimal NLS in hPLSCR4 ((273)GSIIRKWN(280)) that contains only two basic amino acids. This NLS is both necessary for nuclear localization of hPLSCR4 in transfected HeLa cells and sufficient for nuclear import of a non-diffusible cargo in permeabilized cells. Mutation of only one of the two basic residues, Arg(277), correlates with loss of nuclear localization, suggesting this amino acid plays a key role in nuclear transport. Crystallographic analysis of mammalian importin alpha1 in complex with the hPLSCR4-NLS reveals this minimal NLS binds specifically and exclusively to the minor binding site of importin alpha. These data provide the first structural and functional evidence of a novel NLS-binding mode in importin alpha1 that uses only the minor groove as the exclusive site for nuclear import of nonclassical cargos. PMID- 21690088 TI - Retinoic acid-induced gene-I (RIG-I) associates with nucleotide-binding oligomerization domain-2 (NOD2) to negatively regulate inflammatory signaling. AB - Cytoplasmic caspase recruiting domain (CARD)-containing molecules often function in the induction of potent antimicrobial responses in order to protect mammalian cells from invading pathogens. Retinoic acid-induced gene-I (RIG-I) and nucleotide binding oligomerization domain 2 (NOD2) serve as key factors in the detection of viral and bacterial pathogens, and in the subsequent initiation of innate immune signals to combat infection. RIG-I and NOD2 share striking similarities in their cellular localization, both localize to membrane ruffles in non-polarized epithelial cells and both exhibit a close association with the junctional complex of polarized epithelia. Here we show that RIG-I and NOD2 not only colocalize to cellular ruffles and cell-cell junctions, but that they also form a direct interaction that is mediated by the CARDs of RIG-I and multiple regions of NOD2. Moreover, we show that RIG-I negatively regulates ligand-induced nuclear factor-kappaB (NF-kappaB) signaling mediated by NOD2, and that NOD2 negatively regulates type I interferon induction by RIG-I. We also show that the three main Crohn disease-associated mutants of NOD2 (1007fs, R702W, G908R) form an interaction with RIG-I and negatively regulate its signaling to a greater extent than wild-type NOD2. Our results show that in addition to their role in innate immune recognition, RIG-I and NOD2 form a direct interaction at actin enriched sites within cells and suggest that this interaction may impact RIG-I- and NOD2-dependent innate immune signaling. PMID- 21690089 TI - Cysteine scanning mutagenesis (residues Glu52-Gly96) of the human P2X1 receptor for ATP: mapping agonist binding and channel gating. AB - P2X receptors are ATP-gated cation channels. The x-ray structure of a P2X4 receptor provided a major advance in understanding the molecular basis of receptor properties. However, how agonists are coordinated, the extent of the binding site, and the contribution of the vestibules in the extracellular domain to ionic permeation have not been addressed. We have used cysteine-scanning mutagenesis to determine the contribution of residues Glu(52)-Gly(96) to human P2X1 receptor properties. ATP potency was reduced for the mutants K68C, K70C, and F92C. The efficacy of the partial agonist BzATP was also reduced for several mutants forming the back of the proposed agonist binding site. Molecular docking in silico of both ATP and BzATP provided models of the agonist binding site consistent with these data. Individual cysteine mutants had no effect or slightly increased antagonism by suramin or pyridoxal-phosphate-6-azophenyl-2',4' disulfonate. Mutants at the entrance to and lining the upper vestibule were unaffected by cysteine-reactive methanethiosulfonate (MTS) reagents, suggesting that it does not contribute to ionic permeation. Mutants that were sensitive to modification by MTS reagents were predominantly found either around the proposed ATP binding pocket or on the strands connecting the binding pocket to the transmembrane region and lining the central vestibule. In particular, ATP sensitivity and currents were increased by a positively charged MTS reagent at the G60C mutant at the interface between the central and extracellular vestibule. This suggests that dilation of the base of the central vestibule contributes to gating of the receptor. PMID- 21690090 TI - Hepatitis B virus X protein regulates hepatic glucose homeostasis via activation of inducible nitric oxide synthase. AB - Dysregulation of liver functions leads to insulin resistance causing type 2 diabetes mellitus and is often found in chronic liver diseases. However, the mechanisms of hepatic dysfunction leading to hepatic metabolic disorder are still poorly understood in chronic liver diseases. The current work investigated the role of hepatitis B virus X protein (HBx) in regulating glucose metabolism. We studied HBx-overexpressing (HBxTg) mice and HBxTg mice lacking inducible nitric oxide synthase (iNOS). Here we show that gene expressions of the key gluconeogenic enzymes were significantly increased in HepG2 cells expressing HBx (HepG2-HBx) and in non-tumor liver tissues of hepatitis B virus patients with high levels of HBx expression. In the liver of HBxTg mice, the expressions of gluconeogenic genes were also elevated, leading to hyperglycemia by increasing hepatic glucose production. However, this effect was insufficient to cause systemic insulin resistance. Importantly, the actions of HBx on hepatic glucose metabolism are thought to be mediated via iNOS signaling, as evidenced by the fact that deficiency of iNOS restored HBx-induced hyperglycemia by suppressing the gene expression of gluconeogenic enzymes. Treatment of HepG2-HBx cells with nitric oxide (NO) caused a significant increase in the expression of gluconeogenic genes, but JNK1 inhibition was completely normalized. Furthermore, hyperactivation of JNK1 in the liver of HBxTg mice was also suppressed in the absence of iNOS, indicating the critical role for JNK in the mutual regulation of HBx- and iNOS-mediated glucose metabolism. These findings establish a novel mechanism of HBx-driven hepatic metabolic disorder that is modulated by iNOS mediated activation of JNK. PMID- 21690091 TI - Critical role of monoubiquitination of histone H2AX protein in histone H2AX phosphorylation and DNA damage response. AB - DNA damage response is an important surveillance mechanism used to maintain the integrity of the human genome in response to genotoxic stress. Histone variant H2AX is a critical sensor that undergoes phosphorylation at serine 139 upon genotoxic stress, which provides a docking site to recruit the mediator of DNA damage checkpoint protein 1 (MDC1) and DNA repair protein complex to sites of DNA breaks for DNA repair. Here, we show that monoubiquitination of H2AX is induced upon DNA double strand breaks and plays a critical role in H2AX Ser-139 phosphorylation (gamma-H2AX), in turn facilitating the recruitment of MDC1 to DNA damage foci. Mechanistically, we show that monoubiquitination of H2AX induced by RING finger protein 2 (RNF2) is required for the recruitment of active ataxia telangiectasia mutated to DNA damage foci, thus affecting the formation of gamma H2AX. Importantly, a defect in monoubiquitination of H2AX profoundly enhances ionizing radiation sensitivity. Our study therefore suggests that monoubiquitination of H2AX is an important step for DNA damage response and may have important clinical implications for the treatment of cancers. PMID- 21690092 TI - NADH oxidase activity of indoleamine 2,3-dioxygenase. AB - The heme enzyme indoleamine 2,3-dioxygenase (IDO) was found to oxidize NADH under aerobic conditions in the absence of other enzymes or reactants. This reaction led to the formation of the dioxygen adduct of IDO and supported the oxidation of Trp to N-formylkynurenine. Formation of the dioxygen adduct and oxidation of Trp were accelerated by the addition of small amounts of hydrogen peroxide, and both processes were inhibited in the presence of either superoxide dismutase or catalase. Anaerobic reaction of IDO with NADH proceeded only in the presence of a mediator (e.g. methylene blue) and resulted in formation of the ferrous form of the enzyme. We propose that trace amounts of peroxide previously proposed to occur in NADH solutions as well as solid NADH activate IDO and lead to aerobic formation of superoxide and the reactive dioxygen adduct of the enzyme. PMID- 21690093 TI - Delineation of the role of Toll-like receptor signaling during peritonitis by a gradually growing pathogenic Escherichia coli. AB - In a mouse model of Escherichia coli sepsis characterized by a primary peritoneal infection with 10(4) E. coli and a gradually growing bacterial load, we here show that the early cytokine response and antibacterial defense are dominated by TLR4 via a cooperative action of MyD88 and Trif. Although MyD88(-/-) mice succumbed earlier than WT mice in this E. coli peritonitis model, Trif(-/-) mice displayed a small but significant survival advantage. Despite a large early deficit in antimicrobial defense, TLR4(-/-) mice showed an unaltered survival with normal neutrophil attraction to the peritoneal cavity and normal or even elevated late cytokine release. TLR2 compensated for the lack of TLR4 because TLR2(-/-)/TLR4(-/ ) mice did show decreased neutrophil attraction and increased mortality compared with WT mice. Nearly normal early peritoneal TNFalpha production and lack of early counterregulating systemic levels of the chemoattractant KC were associated with normal peritoneal neutrophil attraction in TLR4(-/-) mice. Late stage increased TNF, IL-1beta, IFN-beta, and typical IFN-gamma production in TLR4(-/-) mice prompted us to evaluate expression of the negative feedback regulator SOCS 1. Lack of early hepatic SOCS-1 expression in TLR4(-/-) mice explained the late innate production of IFN-gamma by the liver in TLR4(-/-) mice in this low dose E. coli peritonitis model. In contrast, early TLR4-induced IFN-gamma production is described as a hallmark in high dose E. coli peritonitis models. The present study displays how the kinetics of pro- and anti-inflammatory mechanisms are regulated by TLRs during peritonitis by a gradually growing E. coli load and how these kinetics may affect outcome. PMID- 21690094 TI - A novel chimeric protein-based HIV-1 fusion inhibitor targeting gp41 glycoprotein with high potency and stability. AB - T20 (enfuvirtide, Fuzeon) is the first generation HIV-1 fusion inhibitor approved for salvage therapy of HIV-1-infected patients refractory to current antiretroviral drugs. However, its application is limited by the high cost of peptide synthesis, rapid proteolysis, and poor efficacy against emerging drug resistant strains. Here we reported the design of a novel chimera protein-based fusion inhibitor targeting gp41, TLT35, that uses a flexible 35-mer linker to couple T20 and T1144, the first and next generation HIV-1 fusion inhibitors, respectively. TLT35, which was expressed in Escherichia coli with good yield, showed low nm activity against HIV-1-mediated cell-cell fusion and infection by laboratory-adapted HIV-1 strains (X4 or R5), including T20-resistant variants and primary HIV-1 isolates of clades A to G and group O (R5 or X4R5). TLT35 was stable in human sera and in peripheral blood mononuclear cell culture and was more resistant to proteolysis than either T20 or T1144 alone. Circular dichroism spectra showed that TLT35 folded into a thermally stable conformation with high alpha-helical content and T(m) value in aqueous solution. It formed a highly stable complex with gp41 N-terminal heptad repeat peptide and blocked formation of the gp41 six-helix-bundle core. These merits combined with an anticipated low production cost for expression of TLT35 in E. coli make this novel protein-based fusion inhibitor a promising candidate for further development as an anti-HIV-1 microbicide or therapeutic for the prevention and treatment of HIV-1 infection. PMID- 21690095 TI - Restricted lateral diffusion of luteinizing hormone receptors in membrane microdomains. AB - Single particle tracking was used to evaluate lateral motions of individual FLAG tagged human luteinizing hormone (LH) receptors expressed on CHO cells and native LH receptors on both KGN human granulosa-derived tumor cells and M17 human neuroblastoma cells before and after exposure to human chorionic gonadotropin (hCG). Compared with LH receptors on untreated cells, LH receptors on cells treated with 100 nm hCG exhibit restricted lateral diffusion and are confined in small, nanometer-scale, membrane compartments. Similar to LH receptors labeled with Au-hCG, LH receptors labeled with gold-deglycosylated hCG, an hCG antagonist, also exhibit restricted lateral diffusion and are confined in nanoscale membrane compartments on KGN cells treated with 100 nm hCG. LH receptor point mutants lacking potential palmitoylation sites remain in large compartments despite treatment with 100 nm hCG as do LH receptors on cells treated with cytochalasin D. Finally, both polarization homotransfer fluorescence resonance energy transfer imaging and photon counting histogram analysis indicate that treatment with hCG induces aggregation of YFP-coupled LH receptors stably expressed on CHO cells. Taken together, our results demonstrate that binding of hCG induces aggregation of LH receptors within nanoscale, cell surface membrane compartments, that hCG binding also affects the lateral motions of antagonist binding LH receptors, and that receptor surface densities must be considered in evaluating the extent of hormone-dependent receptor aggregation. PMID- 21690097 TI - Neuropsychological deficits in adolescent unipolar depression. AB - Although neuropsychological deficits in adult depression are relatively well established, findings in children/adolescents have been inconsistent and thus require further investigation. The current study investigated verbal fluency (VF), cognitive speed, motor speed, and executive functions in adolescents with unipolar depression. Results indicated that adolescents with minor depression showed working memory deficits and poorer VF (letter task). Adolescents with major depression showed working memory deficits and processing speed deficits from the early stages of information processing to the later stages of motor output. Executive function deficits of set-shifting and response inhibition that are well established in adults were not found, but may reflect task differences. Thus, it appears that depression subtype or severity of symptoms may impact on neuropsychological functioning and may in part explain previous inconsistent results. PMID- 21690096 TI - Src subfamily kinases regulate nuclear export and degradation of transcription factor Nrf2 to switch off Nrf2-mediated antioxidant activation of cytoprotective gene expression. AB - Nrf2 (NF-E2-related factor 2) is a nuclear transcription factor that in response to chemical and radiation stress regulates coordinated induction of a battery of cytoprotective gene expressions leading to cellular protection. In this study, we investigated the role of Src kinases in the regulation of Nrf2 and downstream signaling. siRNA-mediated inhibition of Fyn, Src, Yes, and Fgr, but not Lyn, in mouse hepatoma Hepa-1 cells, led to nuclear accumulation of Nrf2 and up regulation of Nrf2 downstream gene expression. Mouse embryonic fibroblasts with combined deficiency of Fyn/Src/Yes/Fgr supported results from siRNA. In addition, steady-state overexpression of Fyn, Src, and Yes phosphorylated Nrf2Tyr568 that triggered nuclear export and degradation of Nrf2 and down-regulation of Nrf2 downstream gene expression. Exposure of cells to antioxidant, oxidant, or UV radiation increased nuclear import of Fyn, Src, and Yes kinases, which phosphorylated Nrf2Tyr568 resulting in nuclear export and degradation of Nrf2. Further analysis revealed that stress-activated GSK3beta acted upstream to the Src kinases and phosphorylated the Src kinases, leading to their nuclear localization and Nrf2 phosphorylation. The overexpression of Src kinases in Hepa 1 cells led to decreased Nrf2, increased apoptosis, and decreased cell survival. Mouse embryonic fibroblasts deficient in Src kinases showed nuclear accumulation of Nrf2, induction of Nrf2 and downstream gene expression, reduced apoptosis, and increased cell survival. The studies together demonstrate that Src kinases play a critical role in nuclear export and degradation of Nrf2, thereby providing a negative feedback mechanism to switch off Nrf2 activation and restore normal cellular homeostasis. PMID- 21690098 TI - An intuitive graphical visualization technique for the interrogation of transcriptome data. AB - The complexity of gene expression data generated from microarrays and high throughput sequencing make their analysis challenging. One goal of these analyses is to define sets of co-regulated genes and identify patterns of gene expression. To date, however, there is a lack of easily implemented methods that allow an investigator to visualize and interact with the data in an intuitive and flexible manner. Here, we show that combining a nonlinear dimensionality reduction method, t-statistic Stochastic Neighbor Embedding (t-SNE), with a novel visualization technique provides a graphical mapping that allows the intuitive investigation of transcriptome data. This approach performs better than commonly used methods, offering insight into underlying patterns of gene expression at both global and local scales and identifying clusters of similarly expressed genes. A freely available MATLAB-implemented graphical user interface to perform t-SNE and nearest neighbour plots on genomic data sets is available at www.nimr.mrc.ac.uk/research/james-briscoe/visgenex. PMID- 21690099 TI - A systems biology approach sheds new light on Escherichia coli acid resistance. AB - In order to develop an infection, diarrhogenic Escherichia coli has to pass through the stomach, where the pH can be as low as 1. Mechanisms that enable E. coli to survive in low pH are thus potentially relevant for pathogenicity. Four acid response systems involved in reducing the concentration of intracellular protons have been identified so far. However, it is still unclear to what extent the regulation of other important cellular functions may be required for survival in acid conditions. Here, we have combined molecular and phenotypic analysis of wild-type and mutant strains with computational network inference to identify molecular pathways underlying E. coli response to mild and strong acid conditions. The interpretative model we have developed led to the hypothesis that a complex transcriptional programme, dependent on the two-component system regulator OmpR and involving a switch between aerobic and anaerobic metabolism, may be key for survival. Experimental validation has shown that the OmpR is responsible for controlling a sizeable component of the transcriptional programme to acid exposure. Moreover, we found that a DeltaompR strain was unable to mount any transcriptional response to acid exposure and had one of the strongest acid sensitive phenotype observed. PMID- 21690101 TI - Exploiting drug-disease relationships for computational drug repositioning. AB - Finding new uses for existing drugs, or drug repositioning, has been used as a strategy for decades to get drugs to more patients. As the ability to measure molecules in high-throughput ways has improved over the past decade, it is logical that such data might be useful for enabling drug repositioning through computational methods. Many computational predictions for new indications have been borne out in cellular model systems, though extensive animal model and clinical trial-based validation are still pending. In this review, we show that computational methods for drug repositioning can be classified in two axes: drug based, where discovery initiates from the chemical perspective, or disease based, where discovery initiates from the clinical perspective of disease or its pathology. Newer algorithms for computational drug repositioning will likely span these two axes, will take advantage of newer types of molecular measurements, and will certainly play a role in reducing the global burden of disease. PMID- 21690102 TI - False positive peaks in ChIP-seq and other sequencing-based functional assays caused by unannotated high copy number regions. AB - MOTIVATION: Sequencing-based assays such as ChIP-seq, DNase-seq and MNase-seq have become important tools for genome annotation. In these assays, short sequence reads enriched for loci of interest are mapped to a reference genome to determine their origin. Here, we consider whether false positive peak calls can be caused by particular type of error in the reference genome: multicopy sequences which have been incorrectly assembled and collapsed into a single copy. RESULTS: Using sequencing data from the 1000 Genomes Project, we systematically scanned the human genome for regions of high sequencing depth. These regions are highly enriched for erroneously inferred transcription factor binding sites, positions of nucleosomes and regions of open chromatin. We suggest a simple masking procedure to remove these regions and reduce false positive calls. AVAILABILITY: Files for masking out these regions are available at eqtl.uchicago.edu PMID- 21690100 TI - Computational methods for Gene Orthology inference. AB - Accurate inference of orthologous genes is a pre-requisite for most comparative genomics studies, and is also important for functional annotation of new genomes. Identification of orthologous gene sets typically involves phylogenetic tree analysis, heuristic algorithms based on sequence conservation, synteny analysis, or some combination of these approaches. The most direct tree-based methods typically rely on the comparison of an individual gene tree with a species tree. Once the two trees are accurately constructed, orthologs are straightforwardly identified by the definition of orthology as those homologs that are related by speciation, rather than gene duplication, at their most recent point of origin. Although ideal for the purpose of orthology identification in principle, phylogenetic trees are computationally expensive to construct for large numbers of genes and genomes, and they often contain errors, especially at large evolutionary distances. Moreover, in many organisms, in particular prokaryotes and viruses, evolution does not appear to have followed a simple 'tree-like' mode, which makes conventional tree reconciliation inapplicable. Other, heuristic methods identify probable orthologs as the closest homologous pairs or groups of genes in a set of organisms. These approaches are faster and easier to automate than tree-based methods, with efficient implementations provided by graph theoretical algorithms enabling comparisons of thousands of genomes. Comparisons of these two approaches show that, despite conceptual differences, they produce similar sets of orthologs, especially at short evolutionary distances. Synteny also can aid in identification of orthologs. Often, tree-based, sequence similarity- and synteny-based approaches can be combined into flexible hybrid methods. PMID- 21690103 TI - RIP: the regulatory interaction predictor--a machine learning-based approach for predicting target genes of transcription factors. AB - MOTIVATION: Understanding transcriptional gene regulation is essential for studying cellular systems. Identifying genome-wide targets of transcription factors (TFs) provides the basis to discover the involvement of TFs and TF cooperativeness in cellular systems and pathogenesis. RESULTS: We present the regulatory interaction predictor (RIP), a machine learning approach that inferred 73 923 regulatory interactions (RIs) for 301 human TFs and 11 263 target genes with considerably good quality and 4516 RIs with very high quality. The inference of RIs is independent of any specific condition. Our approach employs support vector machines (SVMs) trained on a set of experimentally proven RIs from a public repository (TRANSFAC). Features of RIs for the learning process are based on a correlation meta-analysis of 4064 gene expression profiles from 76 studies, in silico predictions of transcription factor binding sites (TFBSs) and combinations of these employing knowledge about co-regulation of genes by a common TF (TF-module). The trained SVMs were applied to infer new RIs for a large set of TFs and genes. In a case study, we employed the inferred RIs to analyze an independent microarray dataset. We identified key TFs regulating the transcriptional response upon interferon alpha stimulation of monocytes, most prominently interferon-stimulated gene factor 3 (ISGF3). Furthermore, predicted TF-modules were highly associated to their functionally related pathways. CONCLUSION: Descriptors of gene expression, TFBS predictions, experimentally verified binding information and statistical combination of this enabled inferring RIs on a genome-wide scale for human genes with considerably good precision serving as a good basis for expression profiling studies. CONTACT: r.koenig@dkfz.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21690104 TI - SpEED: fast computation of sensitive spaced seeds. AB - SUMMARY: Multiple spaced seeds represent the current state-of-the-art for similarity search in bioinformatics, with applications in various areas such as sequence alignment, read mapping, oligonucleotide design, etc. We present SpEED, a software program that computes highly sensitive multiple spaced seeds. SpEED can be several orders of magnitude faster and computes better seeds than the existing leading software programs. AVAILABILITY: The source code of SpEED is freely available at www.csd.uwo.ca/~ilie/SpEED/ CONTACT: ilie@csd.uwo.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21690105 TI - Varying coefficient model for gene-environment interaction: a non-linear look. AB - MOTIVATION: The genetic basis of complex traits often involves the function of multiple genetic factors, their interactions and the interaction between the genetic and environmental factors. Gene-environment (G*E) interaction is considered pivotal in determining trait variations and susceptibility of many genetic disorders such as neurodegenerative diseases or mental disorders. Regression-based methods assuming a linear relationship between a disease response and the genetic and environmental factors as well as their interaction is the commonly used approach in detecting G*E interaction. The linearity assumption, however, could be easily violated due to non-linear genetic penetrance which induces non-linear G*E interaction. RESULTS: In this work, we propose to relax the linear G*E assumption and allow for non-linear G*E interaction under a varying coefficient model framework. We propose to estimate the varying coefficients with regression spline technique. The model allows one to assess the non-linear penetrance of a genetic variant under different environmental stimuli, therefore help us to gain novel insights into the etiology of a complex disease. Several statistical tests are proposed for a complete dissection of G*E interaction. A wild bootstrap method is adopted to assess the statistical significance. Both simulation and real data analysis demonstrate the power and utility of the proposed method. Our method provides a powerful and testable framework for assessing non-linear G*E interaction. PMID- 21690106 TI - Safety concerns of angiotensin II receptor blockers in preschool children. AB - Two recent trials of angiotensin II receptor blockers (ARBs) were performed in children 0-5 years of age. Data from the published reports of these trials together with additional information from the sponsoring drug companies were obtained. Three deaths occurred in the 183 (1.6%) hypertensive children participating in the two trials. At least two of these deaths occurred in children known to be susceptible to drugs acting on the renin-angiotensin system, that is, children with ongoing nephrotic syndrome and acute gastroenteritis. Clinicians who prescribe ARBs in preschool children need to be aware of the risk of drug toxicity especially in children susceptible to intravascular dehydration. Clinicians should consider discontinuing the drugs in the presence of acute diarrhoea. PMID- 21690107 TI - Pathogen pressure puts immune defense into perspective. AB - The extent to which organisms can protect themselves from disease depends on both the immune defenses they maintain and the pathogens they face. At the same time, immune systems are shaped by the antigens they encounter, both over ecological and evolutionary time. Ecological immunologists often recognize these interactions, yet ecological immunology currently lacks major efforts to characterize the environmental, host-independent, antigenic pressures to which all animals are exposed. Failure to quantify relevant diseases and pathogens in studies of ecological immunology leads to contradictory hypotheses. In contrast, including measures of environmental and host-derived commensals, pathogens, and other immune-relevant organisms will strengthen the field of ecological immunology. In this article, we examine how pathogens and other organisms shape immune defenses and highlight why such information is essential for a better understanding of the causes of variation in immune defenses. We introduce the concept of "operative protection" for understanding the role of immunologically relevant organisms in shaping immune defense profiles, and demonstrate how the evolutionary implications of immune function are best understood in the context of the pressures that diseases and pathogens bring to bear on their hosts. We illustrate common mistakes in characterizing these immune-selective pressures, and provide suggestions for the use of molecular and other methods for measuring immune-relevant organisms. PMID- 21690108 TI - Adaptive thermoregulation in endotherms may alter responses to climate change. AB - Climate change is one of the major issues facing natural populations and thus a focus of recent research has been to predict the responses of organisms to these changes. Models are becoming more complex and now commonly include physiological traits of the organisms of interest. However, endothermic species have received less attention than have ectotherms in these mechanistic models. Further, it is not clear whether responses of endotherms to climate change are modified by variation in thermoregulatory characteristics associated with phenotypic plasticity and/or adaptation to past selective pressures. Here, we review the empirical data on thermal adaptation and acclimatization in endotherms and discuss how those factors may be important in models of responses to climate change. We begin with a discussion of why thermoregulation and thermal sensitivity at high body temperatures should be co-adapted. Importantly, we show that there is, in fact, considerable variation in the ability of endotherms to tolerate high body temperatures and/or high environmental temperatures, but a better understanding of this variation will likely be critical for predicting responses to future climatic scenarios. Next, we discuss why variation in thermoregulatory characteristics should be considered when modeling the effects of climate change on heterothermic endotherms. Finally, we review some biophysical and biochemical factors that will limit adaptation and acclimation in endotherms. We consider both long-term, directional climate change and short-term (but increasingly common) anomalies in climate such as extreme heat waves and we suggest areas of important future research relating to both our basic understanding of endothermic thermoregulation and the responses of endotherms to climate change. PMID- 21690109 TI - The risk of necrotizing enterocolitis after indomethacin tocolysis. AB - BACKGROUND: Postnatal indomethacin is reportedly associated with an increased incidence of necrotizing enterocolitis (NEC) in preterm infants. Because indomethacin readily crosses the placenta, we hypothesized that antenatal indomethacin (AI) would increase the risk for NEC in preterm infants. OBJECTIVE: The goal of this study was to explore the association between AI and NEC in preterm infants. METHODS: Medical records of preterm infants, 23 to 32 weeks' gestational age, without major congenital anomalies, were reviewed. Maternal and neonatal data were abstracted. Association of AI within 15 days before delivery (predictor variable) and classification of NEC according to modified Bell's stage 2a or higher in the first 15 days after delivery (early NEC [primary outcome variable]) was explored by using bivariate analyses, multivariate logistic regression, and propensity score analysis. RESULTS: Of 628 eligible infants, 63 received AI and 28 developed early NEC. AI exposure was significantly associated with multiple gestation, race, antenatal corticosteroids and magnesium sulfate, lower birth weight and gestational age, umbilical arterial catheter placement, respiratory distress syndrome, postnatal vasopressors and antibiotics, patent ductus arteriosus, sepsis, NEC, intraventricular hemorrhage, and mortality. On multivariate logistic regression controlling for covariates, AI was significantly associated with early NEC (adjusted odds ratio: 7.193 [95% confidence interval: 2.514-20.575]; number needed to harm: 5). The results remained significant when analyses were repeated using AI exposure within 5 days before delivery as a predictor variable; on analyses stratified according to gestational age; and on propensity score analysis. CONCLUSIONS: AI was associated with NEC in preterm infants in the first 15 days of life in this study, as were multiple other clinical factors. PMID- 21690110 TI - The prevalence, severity, and distribution of childhood food allergy in the United States. AB - OBJECTIVE: The goal of this study was to better estimate the prevalence and severity of childhood food allergy in the United States. METHODS: A randomized, cross-sectional survey was administered electronically to a representative sample of US households with children from June 2009 to February 2010. Eligible participants included adults (aged 18 years or older) able to complete the survey in Spanish or English who resided in a household with at least 1 child younger than 18 years. Data were adjusted using both base and poststratification weights to account for potential biases from sampling design and nonresponse. Data were analyzed as weighted proportions to estimate prevalence and severity of food allergy. Multiple logistic regression models were constructed to identify characteristics significantly associated with outcomes. RESULTS: Data were collected for 40 104 children; incomplete responses for 1624 children were excluded, which yielded a final sample of 38 480. Food allergy prevalence was 8.0% (95% confidence interval [CI]: 7.6-8.3). Among children with food allergy, 38.7% had a history of severe reactions, and 30.4% had multiple food allergies. Prevalence according to allergen among food-allergic children was highest for peanut (25.2% [95% CI: 23.3-27.1]), followed by milk (21.1% [95% CI: 19.4-22.8]) and shellfish (17.2% [95% CI: 15.6-18.9]). Odds of food allergy were significantly associated with race, age, income, and geographic region. Disparities in food allergy diagnosis according to race and income were observed. CONCLUSIONS: Findings suggest that the prevalence and severity of childhood food allergy is greater than previously reported. Data suggest that disparities exist in the clinical diagnosis of disease. PMID- 21690111 TI - News media framing of childhood obesity in the United States from 2000 to 2009. AB - The American public holds mixed views about the desirability of government action to combat childhood obesity. The framing of coverage by news media may affect citizens' views about the causes of childhood obesity and the most appropriate strategies for addressing the problem. We analyzed the content of a 20% random sample of news stories on childhood obesity published in 18 national and regional news sources in the United States over a 10-year period (2000-2009). News media coverage patterns indicated that by 2003, childhood obesity was firmly on the news media's agenda and remained so until 2007, after which coverage decreased. We identified changes in news media framing over time and significant differences according to news source. News coverage of causes of childhood obesity that were linked to the food and beverage industry increased in the early years of the study but then decreased markedly in later years. Similarly, mention of solutions to the problem of childhood obesity that involved restrictions on the food and beverage industry followed a reverse U-shaped pattern over the 10-year study period. News stories consistently mentioned individual behavioral changes most often as a solution to the problem of childhood obesity. Television news was more likely than other news sources to focus on behavior change as a solution, whereas newspapers were more likely to identify system-level solutions such as changes that would affect neighborhoods, schools, and the food and beverage industry. PMID- 21690112 TI - Correlation between ventriculoperitoneal shunts and inguinal hernias in children: an 8-year follow-up. AB - OBJECTIVE: The goal of this study was to investigate the correlation between ventriculoperitoneal shunts (VPSs) and inguinal hernias (IHs) in children. METHODS: Study subjects were identified from a nationwide cohort of 1 537 843 children aged 0 to 5 years from 1996 to 2000. They were assigned to the VPS group (n=675), who received VPS, or a control group (n=6704) of age- and gender-matched children. Both groups (N=7379) were followed up for 8 years for IH. Kaplan-Meier and Cox regression analyses were performed. RESULTS: After the 8-year follow-up, 353 of the 7379 study subjects (78 from the VPS group and 275 from the control group) underwent IH surgery. The 8-year cumulative incidence rate of IH-repair surgery was 13.3% in the VPS group, significantly higher than that in the control group (4.1%; P<.001). Children in the VPS group were more likely to develop IH than the control group (hazard ratio: 3.62; P<.001), even after adjusting for age, gender, and comorbidities (adjusted hazard ratio: 6.63; P<.001). The average time interval between VPS and IH surgery was 1.73 years earlier in the VPS group than those in the control group (1.29 vs 3.02 years; P<.001). CONCLUSIONS: Children who received a VPS when younger than 5 years were more likely to have IH; the highest risk was during the first 2 years after VPS surgery. A high index of suspicion for inguinal manifestations is recommended during their follow-up. PMID- 21690113 TI - Implementation of a multicenter rapid response system in pediatric academic hospitals is effective. AB - OBJECTIVES: This is the first large multicenter study to examine the effectiveness of a pediatric rapid response system (PRRS). The primary objective was to determine the effect of a PRRS using a physician-led team on the rate of actual cardiopulmonary arrests, defined as an event requiring chest compressions, epinephrine, or positive pressure ventilation. The secondary objectives were to determine the effect of PRRSs on the rate of PICU readmission within 48 hours of discharge and PICU mortality after readmission and urgent PICU admission. METHODS: A PRRS was developed, implemented, and evaluated in a standardized manner across 4 pediatric academic centers in Ontario, Canada. The team responded to activations for inpatients and followed patients discharged from the PICU for 48 hours. A 2-year, prospective, observational study was conducted after implementation, and outcomes were compared with data collected 2 years before implementation. RESULTS: After PRRS implementation, there were 55 963 hospital admissions and a team activation rate of 44 per 1000 hospital admissions. There were 7302 patients followed after PICU discharge. Implementation of the PRRS was not associated with a reduction in the rate of actual cardiopulmonary arrests (1.9 vs 1.8 per 1000 hospital admissions; P=.68) or PICU mortality after urgent admission (1.3 vs 1.1 per 1000 hospital admissions; P=.25). There was a reduction in the PICU mortality rate after readmission (0.3 vs 0.1 death per 1000 hospital admissions; P=.05). CONCLUSION: The standardized implementation of a multicenter PRRS was associated with a decrease in the rate of PICU mortality after readmission but not actual cardiopulmonary arrests. PMID- 21690114 TI - Folic acid use in pregnancy and the development of atopy, asthma, and lung function in childhood. AB - BACKGROUND: Recently, folic acid supplementation during pregnancy was implicated as a potential risk factor for atopic diseases in childhood. OBJECTIVE: To investigate whether folic acid supplementation and higher intracellular folic acid (ICF) levels during pregnancy increase the risk of childhood atopic diseases. METHODS: In the KOALA Birth Cohort Study (N=2834), data on eczema and wheeze were collected by using repeated questionnaires at 3, 7, 12, and 24 months, 4 to 5 years, and 6 to 7 years after delivery. Atopic dermatitis and total and specific immunoglobulin E levels were determined at age 2 years and asthma and lung function at age 6 to 7 years. We defined folic acid use as stand alone and/or multivitamin supplements according to the period of use before and/or during pregnancy. ICF levels were determined in blood samples taken at ~35 weeks of pregnancy (n=837). Multivariable logistic and linear regression analyses were conducted, with generalized estimating equation models for repeated outcomes. RESULTS: Maternal folic acid supplement use during pregnancy was not associated with increased risk of wheeze, lung function, asthma, or related atopic outcomes in the offspring. Maternal ICF level in late pregnancy was inversely associated with asthma risk at age 6 to 7 years in a dose-dependent manner (P for trend=.05). CONCLUSIONS: Our results do not confirm any meaningful association between folic acid supplement use during pregnancy and atopic diseases in the offspring. Higher ICF levels in pregnancy tended, at most, toward a small decreased risk for developing asthma. PMID- 21690115 TI - Parents' evaluation of media ratings a decade after the television ratings were introduced. AB - OBJECTIVE: The 3 national studies reported here were designed to find out how satisfied parents are with media rating systems, how regularly they use them, and what types of information they ideally would like to have. METHODS: Parents (n=745, study 1; n=768, study 2; n=769, study 3) were surveyed nationally by independent research firms. Studies 1 and 2 were conducted by Harris Interactive, and study 3 was conducted by Research Now. All of them were cross-sectional national surveys. RESULTS: Parents desire ratings for many types of media, but they do not think the existing ratings accurately provide the information they want. They would prefer ratings to provide detailed content information. In general, parents tend to agree on the types and descriptors of content about which they would like to know. They do not, however, agree on the ages for which different content aspects are appropriate. Parents would support the creation of a universal rating system that could be applied to multiple types of media. CONCLUSIONS: Ratings can be effective only if they are useful for parents. This set of studies reveals that improvements in media ratings are needed to make them valuable for parents. PMID- 21690116 TI - Decoding motor signals from the pediatric cortex: implications for brain-computer interfaces in children. AB - OBJECTIVE: To demonstrate the decodable nature of pediatric brain signals for the purpose of neuroprosthetic control. We hypothesized that children would achieve levels of brain-derived computer control comparable to performance previously reported for adults. PATIENTS AND METHODS: Six pediatric patients with intractable epilepsy who were invasively monitored underwent screening for electrocortical control signals associated with specific motor or phoneme articulation tasks. Subsequently, patients received visual feedback as they used these associated electrocortical signals to direct one dimensional cursor movement to a target on a screen. RESULTS: All patients achieved accuracies between 70% and 99% within 9 minutes of training using the same screened motor and articulation tasks. Two subjects went on to achieve maximum accuracies of 73% and 100% using imagined actions alone. Average mean and maximum performance for the 6 pediatric patients was comparable to that of 5 adults. The mean accuracy of the pediatric group was 81% (95% confidence interval [CI]: 71.5-90.5) over a mean training time of 11.6 minutes, whereas the adult group had a mean accuracy of 72% (95% CI: 61.2-84.3) over a mean training time of 12.5 minutes. Maximum performance was also similar between the pediatric and adult groups (89.6% [95% CI: 83-96.3] and 88.5% [95% CI: 77.1-99.8], respectively). CONCLUSIONS: Similarly to adult brain signals, pediatric brain signals can be decoded and used for BCI operation. Therefore, BCI systems developed for adults likely hold similar promise for children with motor disabilities. PMID- 21690117 TI - Epidemiology of sudden death in young, competitive athletes due to blunt trauma. AB - BACKGROUND: Sudden deaths of young competitive athletes are highly visible events that have a substantial effect on families and communities. Recent attention has focused predominantly on cardiovascular causes, and less on traumatic organ damage. OBJECTIVE: To define the clinical profile, epidemiology, and frequency of trauma-related deaths in young US athletes. METHODS: We analyzed the 30-year US National Registry of Sudden Death in Young Athletes (1980-2009) by using systematic identification and tracking strategies. RESULTS: Of 1827 deaths of athletes aged 21 years or younger, 261 (14%) were caused by trauma-related injuries, usually involving the head and/or neck (mean: 16 +/- 2 years; 90% male) in 22 sports. The highest number of events in a single year was 16 (1986), with an average of 9 per year throughout 30 years. The mortality rate was 0.11 in 100 000 participations (95% confidence interval: 0.08-0.15). The largest number of deaths was in football (148 [57%]), including 17 high school athletes who sustained concussions shortly before fatal head trauma ("second-impact syndrome"). Football deaths were more frequent in defensive players, although the single most common position involved was running back (61% of offensive players). CONCLUSIONS: In a large community-based national registry, sudden deaths caused by blunt trauma in young athletes aged 21 years or younger were relatively uncommon with 16 or fewer per year, about fourfold less than cardiovascular deaths. These fatalities were most frequent in football, and an important proportion of deaths after head blows in high school football were associated with a recent history of symptomatic concussion. PMID- 21690118 TI - Importance of early weight change in a pediatric weight management trial. AB - OBJECTIVE: Early weight change is associated with overall weight loss treatment response in adults but has been relatively unexplored in youth. We investigated the importance of early weight change in a pediatric weight control trial. METHODS: Overweight children aged 7 to 12 years (n=204) participated in a randomized controlled trial of 2 weight maintenance treatments (MTs) after a 20 week family-based behavioral weight loss treatment (FBT). Hierarchical regression was used to investigate the relation between children's percentage weight change at sessions 4, 6, and 8 of FBT and BMI z-score reductions after FBT and at the 2 year follow-up. Correlations and hierarchical regression were used to identify child and parent factors associated with children's early weight change. RESULTS: Children's percentage weight change by FBT session 8 was the best predictor of BMI z-score reductions after FBT and at 2-year follow-up. Percentage weight change in children at session 8 was associated with better FBT attendance and with greater percentage weight change in parents at FBT session 8. CONCLUSIONS: Early weight change seems to be related to treatment response through the end of treatment and 2-year follow-up. Future research should include investigation of strategies to promote early weight change in children and parents and identification of mechanisms through which early weight change is related to overall treatment response. PMID- 21690119 TI - Pediatric submersion events in portable above-ground pools in the United States, 2001-2009. AB - OBJECTIVE: The goal of this study was to describe the epidemiology of pediatric submersion events occurring in portable pools in the United States. METHODS: A retrospective analysis of fatal and nonfatal submersion events involving children younger than 12 years in portable pools was conducted using injury and fatality data compiled by the US Consumer Product Safety Commission from 2001 through 2009. RESULTS: There were 209 fatal and 35 nonfatal submersion cases reported to the commission from 2001 through 2009. The majority (94%) involved children younger than 5 years, 56% involved boys, 73% occurred in the child's own yard, and 81% occurred during the summer months. The number of submersion events increased rapidly from 2001 to 2005 and then leveled off from 2005 to 2009. CONCLUSIONS: The use of portable pools in residential settings poses a significant risk of submersion-related morbidity and mortality to children, especially in the <5-year-old age group. No single strategy will prevent all submersion deaths and injuries; therefore, layers of protection are recommended. Industry is advised to engage in development of protective devices that are effective and affordable for portable pools, including isolation fencing, pool alarms, and safety covers. A strong and pervasive consumer education campaign is needed to make consumers aware of the dangers of portable pools, because these small, inexpensive, consumer-installed pools may not generate the same sense of risk as an in-ground pool. PMID- 21690120 TI - The efficacy of motivational interviewing versus brief advice for adolescent smoking behavior change. AB - OBJECTIVE: In this study we sought to evaluate the efficacy of motivational interviewing (MI) compared with structured brief advice (SBA) for adolescent smoking behavior change. METHODS: Participants (N=355) were randomly assigned to 5 sessions of either MI or SBA. The primary outcomes were attempts to reduce and to quit smoking, smoking reduction, and cotinine-validated 7-day point-prevalence smoking abstinence at the end of treatment (week 12) and the 24-week follow-up. RESULTS: White adolescents were ~80% less likely to attempt to cut back (odds ratio [OR]: 0.21; confidence interval [CI]: 0.08-0.53) and >80% less likely to attempt to quit smoking compared with black adolescents (OR: 0.17 [CI: 0.06 0.46]). Adolescents who were at least planning to cut back or quit smoking at baseline were almost 3 times more likely to attempt to cut back (OR: 2.87 [CI: 1.26-6.52]) and to attempt to quit smoking (OR: 3.13 [CI: 1.19-8.26]). Adolescents who received MI were ~60% less likely than adolescents who received SBA to try to quit smoking (OR: 0.41 [CI: 0.17-0.97]). However, adolescents who received MI showed a greater reduction in cigarettes smoked per day than adolescents who received SBA (5.3 vs 3.3 fewer cigarettes per day). There were no statistically significant differences between MI and SBA in smoking abstinence (5.7% vs 5.6%, respectively). CONCLUSIONS: The effects of MI on adolescent smoking behavior change are modest, and MI may best fit within a multicomponent smoking cessation treatment approach in which behavior change skills can support and promote smoking behavior change decisions. PMID- 21690121 TI - Adherence to discharge guidelines for late-preterm newborns. AB - OBJECTIVE: To evaluate trends in adherence to American Academy of Pediatrics recommendations for early discharge of late-preterm newborns and to test the association between hospital characteristics and early discharge. PATIENTS AND METHODS: This study was a population-based cohort study using statewide birth certificate and hospital-discharge data for newborns in California, Missouri, and Pennsylvania from 1993 to 2005. A total of 282 601 late-preterm newborns at 611 hospitals were included. Using logistic regression, we studied the association of early discharge with regional and hospital factors, including teaching affiliation, volume, and urban versus rural location, adjusting for patient factors. RESULTS: From 1995 to 2000, early discharge decreased from 71% of the sample to 40%. However, by 2005, 39% were still discharged early. Compared with Pennsylvania, California (adjusted odds ratio [aOR]: 5.95 [95% confidence interval (CI): 5.03-7.04]), and Missouri (aOR: 1.56 [95% CI: 1.26-1.93]) were associated with increased early discharge. Nonteaching hospitals were more likely than teaching hospitals to discharge patients early if they were uninsured (aOR: 1.91 [95% CI: 1.35-2.69]) or in a health maintenance organization plan (aOR: 1.40 [95% CI: 1.06-1.84]) but not patients with fee-for-service insurance (aOR: 1.04 [95% CI: 0.80-1.34]). A similar trend for newborns on Medicaid was not statistically significant (aOR: 1.77 [95% CI: 0.95-3.30]). CONCLUSIONS: Despite a decline in the late 1990s, early discharge of late-preterm newborns remains common. We observe differences according to state, hospital teaching affiliation, and patient insurance. Additional research on the safety and appropriateness of early discharge for this population is necessary. PMID- 21690122 TI - A "narcotics contract" for a patient with sickle cell disease and chronic pain. PMID- 21690123 TI - Performance of HIV care decentralization from the patient's perspective: health related quality of life and perceived quality of services in Cameroon. AB - OBJECTIVE: (i) To assess HIV care decentralization in Cameroon from the patients' point of view, in terms of health-related quality of life (HRQL) and perceived quality of services; (ii) to identify patient- and hospital-related factors undermining HRQL. METHODS: Perceived quality of services was compared among 1985 HIV-infected patients treated with antiretroviral therapy (ART) for at least 6 months in 27 treatment centres at different levels of health care delivery (central, provincial and district) (EVAL-ANRS 12-116 survey, 2007) using chi square and non-parametric tests. Correlates of the SF-12 physical (PCS) and mental (MCS) HRQL scores were identified using two-level linear models. RESULTS: Patients followed-up at central and district levels had similar physical HRQL, while those followed-up at the more decentralized district level reported significantly better mental HRQL. Patients at district level also expressed better relationships with caregivers, easier access to consultations and more reliable drug supply. Financial barriers to access to HIV care and self-reported side-effects were independently associated with both lower PCS and lower MCS. Caregivers' heavy workload tended to impair both PCS and MCS, while availability of counselling by social workers in the hospital was independently associated with higher MCS. CONCLUSIONS: Despite limited resources, the decentralization of ART delivery can improve quality of care, providing a positive impact on HIV infected patients' well-being. The development of psychosocial support interventions is necessary but not sufficient for improving quality of care in ART scaling-up programmes, and should be related to global strengthening of health human resources. PMID- 21690125 TI - Evo-devo and accounting for Darwin's endless forms. AB - Evo-devo has led to dramatic advances in our understanding of how the processes of development can contribute to explaining patterns of evolutionary diversification that underlie the endless forms of animal life on the Earth. This is increasingly the case not only for the origins of evolutionary novelties that permit new functions and open up new adaptive zones, but also for the processes of evolutionary tinkering that occur within the subsequent radiations of related species. Evo-devo has time and again yielded spectacular examples of Darwin's notions of common ancestry and of descent with modification. It has also shown that the evolution of endless forms is more about the evolution of the regulatory machinery of ancient genes than the origin and elaboration of new genes. Evolvability, especially with respect to the capacity of a developmental system to evolve and to generate the variation in form for natural selection to screen, has become a pivotal focus of evo-devo. As a consequence, a balancing of the concept of endless forms in morphospace with a greater awareness of the potential for developmental constraints and bias is becoming more general. The prospect of parallel horizons opening up for the evolution of behaviour is exciting; in particular, does Sean Carroll's phrase referring to old genes learning new tricks in the evolution of endless forms apply equally as well to patterns of diversity and disparity in behavioural trait-space? PMID- 21690124 TI - Morphology and behaviour: functional links in development and evolution. AB - Development and evolution of animal behaviour and morphology are frequently addressed independently, as reflected in the dichotomy of disciplines dedicated to their study distinguishing object of study (morphology versus behaviour) and perspective (ultimate versus proximate). Although traits are known to develop and evolve semi-independently, they are matched together in development and evolution to produce a unique functional phenotype. Here I highlight similarities shared by both traits, such as the decisive role played by the environment for their ontogeny. Considering the widespread developmental and functional entanglement between both traits, many cases of adaptive evolution are better understood when proximate and ultimate explanations are integrated. A field integrating these perspectives is evolutionary developmental biology (evo-devo), which studies the developmental basis of phenotypic diversity. Ultimate aspects in evo-devo studies -which have mostly focused on morphological traits--could become more apparent when behaviour, 'the integrator of form and function', is integrated into the same framework of analysis. Integrating a trait such as behaviour at a different level in the biological hierarchy will help to better understand not only how behavioural diversity is produced, but also how levels are connected to produce functional phenotypes and how these evolve. A possible framework to accommodate and compare form and function at different levels of the biological hierarchy is outlined. At the end, some methodological issues are discussed. PMID- 21690126 TI - The levels of analysis revisited. AB - The term levels of analysis has been used in several ways: to distinguish between ultimate and proximate levels, to categorize different kinds of research questions and to differentiate levels of reductionism. Because questions regarding ultimate function and proximate mechanisms are logically distinct, I suggest that distinguishing between these two levels is the best use of the term. Integrating across levels in research has potential risks, but many benefits. Consideration at one level can help generate novel hypotheses at the other, define categories of behaviour and set criteria that must be addressed. Taking an adaptationist stance thus strengthens research on proximate mechanisms. Similarly, it is critical for researchers studying adaptation and function to have detailed knowledge of proximate mechanisms that may constrain or modulate evolutionary processes. Despite the benefits of integrating across ultimate and proximate levels, failure to clearly identify levels of analysis, and whether or not hypotheses are exclusive alternatives, can create false debates. Such non alternative hypotheses may occur between or within levels, and are not limited to integrative approaches. In this review, I survey different uses of the term levels of analysis and the benefits of integration, and highlight examples of false debate within and between levels. The best integrative biology reciprocally uses ultimate and proximate hypotheses to generate a more complete understanding of behaviour. PMID- 21690127 TI - Neural mechanisms underlying the evolvability of behaviour. AB - The complexity of nervous systems alters the evolvability of behaviour. Complex nervous systems are phylogenetically constrained; nevertheless particular species specific behaviours have repeatedly evolved, suggesting a predisposition towards those behaviours. Independently evolved behaviours in animals that share a common neural architecture are generally produced by homologous neural structures, homologous neural pathways and even in the case of some invertebrates, homologous identified neurons. Such parallel evolution has been documented in the chromatic sensitivity of visual systems, motor behaviours and complex social behaviours such as pair-bonding. The appearance of homoplasious behaviours produced by homologous neural substrates suggests that there might be features of these nervous systems that favoured the repeated evolution of particular behaviours. Neuromodulation may be one such feature because it allows anatomically defined neural circuitry to be re-purposed. The developmental, genetic and physiological mechanisms that contribute to nervous system complexity may also bias the evolution of behaviour, thereby affecting the evolvability of species-specific behaviour. PMID- 21690128 TI - Conservation of gene function in behaviour. AB - Behaviour genetic research has shown that a given gene or gene pathway can influence categorically similar behaviours in different species. Questions about the conservation of gene function in behaviour are increasingly tractable. This is owing to the surge of DNA and 'omics data, bioinformatic tools, as well as advances in technologies for behavioural phenotyping. Here, we discuss how gene function, as a hierarchical biological phenomenon, can be used to examine behavioural homology across species. The question can be addressed independently using different levels of investigation including the DNA sequence, the gene's position in a genetic pathway, spatial-temporal tissue expression and neural circuitry. Selected examples from the literature are used to illustrate this point. We will also discuss how qualitative and quantitative comparisons of the behavioural phenotype, its function and the importance of environmental and social context should be used in cross-species comparisons. We conclude that (i) there are homologous behaviours, (ii) they are hard to define and (iii) neurogenetics and genomics investigations should help in this endeavour. PMID- 21690129 TI - Mapping behavioural evolution onto brain evolution: the strategic roles of conserved organization in individuals and species. AB - The pattern of individual variation in brain component structure in pigs, minks and laboratory mice is very similar to variation across species in the same components, at a reduced scale. This conserved pattern of allometric scaling resembles robotic architectures designed to be robust to changes in computing power and task demands, and may reflect the mechanism by which both growing and evolving brains defend basic sensory, motor and homeostatic functions at multiple scales. Conserved scaling rules also have implications for species-specific sensory and social communication systems, motor competencies and cognitive abilities. The role of relative changes in neuron number in the central nervous system in producing species-specific behaviour is thus highly constrained, while changes in the sensory and motor periphery, and in motivational and attentional systems increase in probability as the principal loci producing important changes in functional neuroanatomy between species. By their nature, these loci require renewed attention to development and life history in the initial organization and production of species-specific behavioural abilities. PMID- 21690131 TI - Evolution of time-keeping mechanisms: early emergence and adaptation to photoperiod. AB - Virtually all species have developed cellular oscillations and mechanisms that synchronize these cellular oscillations to environmental cycles. Such environmental cycles in biotic (e.g. food availability and predation risk) or abiotic (e.g. temperature and light) factors may occur on a daily, annual or tidal time scale. Internal timing mechanisms may facilitate behavioural or physiological adaptation to such changes in environmental conditions. These timing mechanisms commonly involve an internal molecular oscillator (a 'clock') that is synchronized ('entrained') to the environmental cycle by receptor mechanisms responding to relevant environmental signals ('Zeitgeber', i.e. German for time-giver). To understand the evolution of such timing mechanisms, we have to understand the mechanisms leading to selective advantage. Although major advances have been made in our understanding of the physiological and molecular mechanisms driving internal cycles (proximate questions), studies identifying mechanisms of natural selection on clock systems (ultimate questions) are rather limited. Here, we discuss the selective advantage of a circadian system and how its adaptation to day length variation may have a functional role in optimizing seasonal timing. We discuss various cases where selective advantages of circadian timing mechanisms have been shown and cases where temporarily loss of circadian timing may cause selective advantage. We suggest an explanation for why a circadian timing system has emerged in primitive life forms like cyanobacteria and we evaluate a possible molecular mechanism that enabled these bacteria to adapt to seasonal variation in day length. We further discuss how the role of the circadian system in photoperiodic time measurement may explain differential selection pressures on circadian period when species are exposed to changing climatic conditions (e.g. global warming) or when they expand their geographical range to different latitudes or altitudes. PMID- 21690130 TI - Evo-devo, deep homology and FoxP2: implications for the evolution of speech and language. AB - The evolution of novel morphological features, such as feathers, involves the modification of developmental processes regulated by gene networks. The fact that genetic novelty operates within developmental constraints is the central tenet of the 'evo-devo' conceptual framework. It is supported by findings that certain molecular regulatory pathways act in a similar manner in the development of morphological adaptations, which are not directly related by common ancestry but evolved convergently. The Pax6 gene, important for vision in molluscs, insects and vertebrates, and Hox genes, important for tetrapod limbs and fish fins, exemplify this 'deep homology'. Recently, 'evo-devo' has expanded to the molecular analysis of behavioural traits, including social behaviour, learning and memory. Here, we apply this approach to the evolution of human language. Human speech is a form of auditory-guided, learned vocal motor behaviour that also evolved in certain species of birds, bats and ocean mammals. Genes relevant for language, including the transcription factor FOXP2, have been identified. We review evidence that FoxP2 and its regulatory gene network shapes neural plasticity in cortico-basal ganglia circuits underlying the sensory-guided motor learning in animal models. The emerging picture can help us understand how complex cognitive traits can 'descend with modification'. PMID- 21690134 TI - The mathematical challenges and modelling of hydroelasticity. AB - Hydroelasticity brings together hydrodynamics and elastic theories. It is concerned with deformations of elastic bodies responding to hydrodynamic excitations, which themselves depend on elastic deformation. This Theme Issue is intended to identify and to outline mathematical problems of modern hydroelasticity and to review recent developments in this area, including physically and mathematically elaborated models and the techniques used in their analysis. PMID- 21690132 TI - Social molecular pathways and the evolution of bee societies. AB - Bees provide an excellent model with which to study the neuronal and molecular modifications associated with the evolution of sociality because relatively closely related species differ profoundly in social behaviour, from solitary to highly social. The recent development of powerful genomic tools and resources has set the stage for studying the social behaviour of bees in molecular terms. We review 'ground plan' and 'genetic toolkit' models which hypothesize that discrete pathways or sets of genes that regulate fundamental behavioural and physiological processes in solitary species have been co-opted to regulate complex social behaviours in social species. We further develop these models and propose that these conserved pathways and genes may be incorporated into 'social pathways', which consist of relatively independent modules involved in social signal detection, integration and processing within the nervous and endocrine systems, and subsequent behavioural outputs. Modifications within modules or in their connections result in the evolution of novel behavioural patterns. We describe how the evolution of pheromonal regulation of social pathways may lead to the expression of behaviour under new social contexts, and review plasticity in circadian rhythms as an example for a social pathway with a modular structure. PMID- 21690135 TI - Past, present and impendent hydroelastic challenges in the polar and subpolar seas. AB - Current and emergent advances are examined on the topic of hydroelasticity theory applied to natural sea ice responding to the action of ocean surface waves and swell, with attention focused on methods that portray sea ice more faithfully as opposed to those that oversimplify interactions with a poor imitation of reality. A succession of authors have confronted and solved by various means the demanding applied mathematics associated with ocean waves (i) entering a vast sea-ice plate, (ii) travelling between plates of different thickness, (iii) impinging on a pressure ridge, (iv) affecting a single ice floe with arbitrarily specified physical and material properties, and (v) many such features or mixtures thereof. The next step is to embed simplified versions of these developments in an oceanic general circulation model for forecasting purposes. While targeted on specific sea-ice situations, many of the reported results are equally applicable to the interaction of waves with very large floating structures, such as pontoons, floating airports and mobile offshore bases. PMID- 21690133 TI - A comparative analysis of neural taste processing in animals. AB - Understanding taste processing in the nervous system is a fundamental challenge of modern neuroscience. Recent research on the neural bases of taste coding in invertebrates and vertebrates allows discussion of whether labelled-line or across-fibre pattern encoding applies to taste perception. While the former posits that each gustatory receptor responds to one stimulus or a very limited range of stimuli and sends a direct 'line' to the central nervous system to communicate taste information, the latter postulates that each gustatory receptor responds to a wider range of stimuli so that the entire population of taste responsive neurons participates in the taste code. Tastes are represented in the brain of the fruitfly and of the rat by spatial patterns of neural activity containing both distinct and overlapping regions, which are in accord with both labelled-line and across-fibre pattern processing of taste, respectively. In both animal models, taste representations seem to relate to the hedonic value of the tastant (e.g. palatable versus non-palatable). Thus, although the labelled-line hypothesis can account for peripheral taste processing, central processing remains either unknown or differs from a pure labelled-line coding. The essential task for a neuroscience of taste is, therefore, to determine the connectivity of taste-processing circuits in central nervous systems. Such connectivity may determine coding strategies that differ significantly from both the labelled-line and the across-fibre pattern models. PMID- 21690136 TI - Hydroelastic wave diffraction by a vertical cylinder. AB - A linear three-dimensional problem of hydroelastic wave diffraction by a bottom mounted circular cylinder is analysed. The fluid is of finite depth and is covered by an ice sheet, which is clamped to the cylinder surface. The ice stretches from the cylinder to infinity in all lateral directions. The hydroelastic behaviour of the ice sheet is described by linear elastic plate theory, and the fluid flow by a potential flow model. The two-dimensional incident wave is regular and has small amplitude. An analytical solution of the coupled problem of hydroelasticity is found by using a Weber transform. We determine the ice deflection and the vertical and horizontal forces acting on the cylinder and analyse the strain in the ice sheet caused by the incident wave. PMID- 21690137 TI - Sound scattering by free surface piercing and fluid-loaded cylindrical shells. AB - A vertical flexible, thin, cylindrical shell is considered to be clamped to a rigid base in shallow water and piercing its surface. The shell is composed of an isotropic and homogeneous material and may be empty inside or filled with compressible fluid. Linear acoustics and structural dynamics are used to model sound scattering caused by an external incident sound wave. A solution is derived using a Fourier transform in the tangential and vertical directions. A collocation technique coupled with an orthogonalization procedure is used to account for the edge conditions of the shell. It is shown that zero sound scattering, indicating acoustic invisibility, is theoretically attainable and can be achieved when a continuous distribution of an oscillating pressure load is applied on the shell's wall. Similarly, zero sound transmission into the shell's inner fluid can also be considered. The possibility of using a pre-determined discrete distribution of the applied pressure load is also discussed. The derived equations are numerically solved to examine sound scattering by a thin aluminium shell in shallow water. PMID- 21690138 TI - Mathematical and numerical model for nonlinear viscoplasticity. AB - A macroscopic model describing elastic-plastic solids is derived in a special case of the internal specific energy taken in separable form: it is the sum of a hydrodynamic part depending only on the density and entropy, and a shear part depending on other invariants of the Finger tensor. In particular, the relaxation terms are constructed compatible with the von Mises yield criteria. In addition, Maxwell-type material behaviour is shown up: the deviatoric part of the stress tensor decays during plastic deformations. Numerical examples show the ability of this model to deal with real physical phenomena. PMID- 21690139 TI - Transient motions of an oscillating system caused by forcing terms proportional to the velocity of the structural motion. AB - Damping limits the motions of an oscillator, which is a dynamic system. The selection of formulations for damping is discussed. If the forcing of the dynamic system contains terms that are proportional to the velocity of motion of the oscillator (drag-type forcing functions), these effects will additionally contribute to dampening the oscillations. Should the total damping under certain conditions become apparently negative, the oscillations will grow until the damping has again become positive. Investigations into damping effects that apparently are negative, and discussions where apparent negative damping might appear in practical applications are of great interest. PMID- 21690140 TI - Slamming of ships: where are we now? AB - Literature published on the problem of ship slamming in waves is reviewed from the point of view of someone working at a ship research institute. Such an institute is confronted with rather practical questions regarding the acceptability of certain design parameters such as the acceptable amount of bow flare angle for use at sea. The importance of these questions is illustrated by noting that actual slamming or the presumed danger of slamming is the main reason for ship operators to reduce speed or to change heading. The review shows that such questions cannot yet be answered. The problem of the local effect of the impact is very complicated owing to the importance of air inclusions, bubbles in the water, compressibility of water and cavitation effects. Only a computational method properly including all these effects will give an accurate answer; also model tests will not be capable of doing this, if only because the methods to extrapolate the results of models to full scale are not yet developed. The problem of the global response of the ship to a wave impact is closer to being solved. A two-stage approach is proposed, consisting of a computational fluid dynamics method for individual impacts and an approximate method to be included in long-term simulations. However, to arrive at a realistic long-term distribution, one has to account for the seamanship of the captain; avoiding the worst conditions or adapting the ship speed and course has a large effect on the actual extremes. Research on this topic has hardly begun. PMID- 21690141 TI - Semi-analytical models of hydroelastic sloshing impact in tanks of liquefied natural gas vessels. AB - The present paper deals with the methods for the evaluation of the hydroelastic interactions that appear during the violent sloshing impacts inside the tanks of liquefied natural gas carriers. The complexity of both the fluid flow and the structural behaviour (containment system and ship structure) does not allow for a fully consistent direct approach according to the present state of the art. Several simplifications are thus necessary in order to isolate the most dominant physical aspects and to treat them properly. In this paper, choice was made of semi-analytical modelling for the hydrodynamic part and finite-element modelling for the structural part. Depending on the impact type, different hydrodynamic models are proposed, and the basic principles of hydroelastic coupling are clearly described and validated with respect to the accuracy and convergence of the numerical results. PMID- 21690142 TI - Modelling nonlinear hydroelastic waves. AB - This paper uses the special Cosserat theory of hyperelastic shells satisfying Kirchoff's hypothesis and irrotational flow theory to model the interaction between a heavy thin elastic sheet and an infinite ocean beneath it. From a general discussion of three-dimensional motions, involving an Eulerian description of the flow and a Lagrangian description of the elastic sheet, a special case of two-dimensional travelling waves with two wave speed parameters, one for the sheet and another for the fluid, is developed only in terms of Eulerian coordinates. PMID- 21690143 TI - Two-dimensional generalized solitary waves and periodic waves under an ice sheet. AB - Two-dimensional gravity waves travelling under an ice sheet are studied. The flow is assumed to be potential. Weakly nonlinear solutions are derived and fully nonlinear solutions are calculated numerically. Periodic waves and generalized solitary waves are studied. PMID- 21690144 TI - Three-dimensional waves beneath an ice sheet due to a steadily moving pressure. AB - Solutions of the nonlinear water wave equations under an ice sheet are computed using a boundary integral equation method. The ice sheet is modelled as a thin elastic plate and the fluid equations are nonlinear. Depending on the velocity of the moving disturbance generating the flow, different types of responses of the floating ice sheet are discussed. PMID- 21690145 TI - The energetics of flow through a rapidly oscillating tube with slowly varying amplitude. AB - Motivated by the problem of self-excited oscillations in fluid-filled collapsible tubes, we examine the flow structure and energy budget of flow through an elastic walled tube. Specifically, we consider the case in which a background axial flow is perturbed by prescribed small-amplitude high-frequency long-wavelength oscillations of the tube wall, with a slowly growing or decaying amplitude. We use a multiple-scale analysis to show that, at leading order, we recover the constant-amplitude equations derived by Whittaker et al. (Whittaker et al. 2010 J. Fluid Mech. 648, 83-121. (doi:10.1017/S0022112009992904)) with the effects of growth or decay entering only at first order. We also quantify the effects on the flow structure and energy budget. Finally, we discuss how our results are needed to understand and predict an instability that can lead to self-excited oscillations in collapsible-tube systems. PMID- 21690146 TI - Fluid-body interactions: clashing, skimming, bouncing. AB - Solid-solid and solid-fluid impacts and bouncing are the concern here. A theoretical study is presented on fluid-body interaction in which the motion of the body and the fluid influence each other nonlinearly. There could also be many bodies involved. The clashing refers to solid-solid impacts arising from fluid body interaction in a channel, while the skimming refers to another area where a thin body impacts obliquely upon a fluid surface. Bouncing usually then follows in both areas. The main new contribution concerns the influences of thickness and camber which lead to a different and more general form of clashing and hence bouncing. PMID- 21690147 TI - Effect of vitamin D(3) supplementation on peripheral B cell differentiation and isotype switching in patients with multiple sclerosis. AB - BACKGROUND: Vitamin D has been proposed as a promoter of immune homeostasis in multiple sclerosis (MS). During the past decade, the focus of the effects of vitamin D has been on dendritic cells and on T cells. Since there is an increasing interest in the role of B cells in the pathophysiology of MS, we studied the role of vitamin D on B cells in vivo in patients with MS. OBJECTIVE: We explored the effects of 12 weeks high-dose vitamin D(3) supplementation on peripheral B cell differentiation, immunoglobulin production and levels of B cell activating factor (BAFF) in 15 patients with MS. METHODS: Circulating B cell subsets were characterized by flow cytometry. Plasma immunoglobulin levels were assessed by nephelometry. Plasma BAFF levels were assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Although a significant increase serum 25 hydroxyvitamin D was induced, we found no significant shift in B cell differentiation, isotype switching, or plasma BAFF levels. CONCLUSION: In patients with MS, supplementation of high doses vitamin D(3) does not have substantial effects on phenotypic markers of B cell differentiation in circulating B cells. Future studies may unravel more subtle changes in the B cell compartment, either in the circulation or in the central nervous system. PMID- 21690148 TI - An early case of neuromyelitis optica: on a forgotten report by Jacob Lockhart Clarke, FRS. AB - We discuss a forgotten report by the famous British neuroanatomist, neuropathologist and neurologist Jacob Augustus Lockhart Clarke (1817-1880) about a 17-year-old girl with bilateral optic neuritis and longitudinally extensive transverse myelitis. This report, which appeared in 1865, i.e. 15 years prior to Wilhelm Erb's much-cited paper on the coincidence of optic neuritis and acute myelitis, represents the first known account of a case of Devic's syndrome or neuromyelitis optica in the English-language medical literature. PMID- 21690149 TI - How to meet the challenge of ageing populations. PMID- 21690150 TI - Future Forum was truly independent and not influenced by government, claims chairman. PMID- 21690151 TI - Misprescribing is widespread among German doctors, says report. PMID- 21690152 TI - Hospital trust director is cleared of dishonesty in case of misdiagnosed diabetes. PMID- 21690153 TI - NICE will retain drug approval role in government U turn. PMID- 21690154 TI - Front line musculoskeletal care. PMID- 21690155 TI - Physiotherapists supporting GPs. PMID- 21690156 TI - Test for inflammatory markers. PMID- 21690157 TI - Don't forget amaurosis fugax. PMID- 21690158 TI - World Health Organization responds to Fiona Godlee and Ray Moynihan. PMID- 21690159 TI - EMA urgently needs a cure. PMID- 21690160 TI - Still waiting for functional EU Clinical Trials Register. PMID- 21690161 TI - Don't forget orthoses and acupuncture. PMID- 21690162 TI - Tennis elbow myths. PMID- 21690163 TI - EMA's response to articles. PMID- 21690164 TI - Proactive transparency? PMID- 21690165 TI - Collective commissioning is better. PMID- 21690166 TI - Number of midwives is critically low in many poor countries, study shows. PMID- 21690167 TI - US academic researchers hold divided views on ties to industry. PMID- 21690168 TI - Doctors consider whether to back industrial action over pension changes. PMID- 21690169 TI - Intervention against excessive alcohol consumption in primary health care: a survey of GPs' attitudes and practices in England 10 years on. AB - AIMS: To ascertain the views of general practitioners (GPs) regarding the prevention and management of alcohol-related problems in practice, together with perceived barriers and incentives for this work; to compare our findings with a comparable survey conducted 10 years earlier. METHODS: In total, 282 (73%) of 419 GPs surveyed in East Midlands, UK, completed a postal questionnaire, measuring practices and attitudes, including the Shortened Alcohol and Alcohol Problems Perception Questionnaire (SAAPPQ). RESULTS: GPs reported lower levels of post graduate education or training on alcohol-related issues (<4 h for the majority) than in 1999 but not significantly so (P = 0.031). In the last year, GPs had most commonly requested more than 12 blood tests and managed 1-6 patients for alcohol. Reports of these preventive practices were significantly increased from 1999 (P < 0.001). Most felt that problem or dependent drinkers' alcohol issues could be legitimately (88%, 87%) and adequately (78%, 69%) addressed by GPs. However, they had low levels of motivation (42%, 35%), task-related self-esteem (53%, 49%) and job satisfaction (15%, 12%) for this. Busyness (63%) and lack of training (57%) or contractual incentives (48%) were key barriers. Endorsement for government policies on alcohol was very low. CONCLUSION: Among GPs, there still appears to be a gap between actual practice and potential for preventive work relating to alcohol problems; they report little specific training and a lack of support. Translational work on understanding the evidence-base supporting screening and brief intervention could incentivize intervention against excessive drinking and embedding it into everyday primary care practice. PMID- 21690170 TI - Preproghrelin expression is a key target for insulin action on adipogenesis. AB - This study aimed to investigate the role of preproghrelin-derived peptides in adipogenesis. Immunocytochemical analysis of 3T3-L1 adipocyte cells showed stronger preproghrelin expression compared with that observed in 3T3-L1 preadipocyte cells. Insulin promoted this expression throughout adipogenesis identifying mTORC1 as a critical downstream substrate for this profile. The role of preproghrelin-derived peptides on the differentiation process was supported by preproghrelin knockdown experiments, which revealed its contribution to adipogenesis. Neutralization of endogenous O-acyl ghrelin (acylated ghrelin), unacylated ghrelin, and obestatin by specific antibodies supported their adipogenic potential. Furthermore, a parallel increase in the expression of ghrelin-associated enzymatic machinery, prohormone convertase 1/3 (PC1/3) and membrane-bound O-acyltransferase 4 (MBOAT4), was dependent on the expression of preproghrelin in the course of insulin-induced adipogenesis. The coexpression of preproghrelin system and their receptors, GHSR1a and GPR39, during adipogenesis supports an autocrine/paracrine role for these peptides. Preproghrelin, PC1/3, and MBOAT4 exhibited dissimilar expression depending on the white fat depot, revealing their regulation in a positive energy balance situation in mice. The results underscore a key role for preproghrelin-derived peptides on adipogenesis through an autocrine/paracrine mechanism. PMID- 21690171 TI - Superficial thrombophlebitis in varicose vein disease: the particular role of methylenetetrahydrofolate reductase. PMID- 21690172 TI - Using magnetic resonance phase-contrast velocity mapping for diagnosing pelvic congestion syndrome. AB - OBJECTIVE: To evaluate phase-contrast velocity mapping (PCVM) as a diagnostic tool for pelvic congestion syndrome and comparing this approach with direct venography. METHOD: We prospectively include nine women with clinical suspicion of pelvic congestion syndrome during a six-month period. All patients underwent a magnetic resonance phase-contrast scan before a direct venography. We considered a case of pelvic congestion syndrome when the PCVM showed a retrograde or slow (less than 5 cm/second) flow in any gonadal vein. This criterion was compared with the standard diagnostic criterion observed from a direct venography. RESULTS: Using direct venography we found 14 abnormal veins and all of them were correctly identified by the PCVM. The other four veins were found to be normal by the direct venography. However, two of them (the same patient) were abnormal in the PCVM, even though this patient had the classical symptoms of pelvic congestion syndrome. CONCLUSION: PCVM is a useful tool for diagnosing pelvic contrast syndrome and can avoid invasive procedures such as direct venography. PMID- 21690173 TI - Analysing censored data using Kaplan-Meier methods; survival analysis. PMID- 21690174 TI - Enhanced K(+)-channel-mediated endothelium-dependent local and conducted dilation of small mesenteric arteries from ApoE(-/-) mice. AB - AIMS: Agonists that evoke smooth muscle cell hyperpolarization have the potential to stimulate both local and conducted dilation. We investigated whether the endothelium-dependent vasodilators acetylcholine (ACh) and SLIGRL stimulated conducted dilation and whether this was altered by deficiency in apolipoprotein E (ApoE(-/-)). METHODS AND RESULTS: Isolated mesenteric arteries were cannulated, pressurized, and precontracted with phenylephrine. Agonists were either added to the bath to study local dilation or were restricted to one end of arteries to study conducted dilation. An enhanced sensitivity to both ACh and SLIGRL was observed in mesenteric arteries from ApoE(-/-) mice compared with wild-type controls. Inhibition of nitric oxide (NO) synthase blocked ACh responses, but had no effect on maximum dilation to SLIGRL. SLIGRL increased endothelial cell Ca(2+), hyperpolarized smooth muscle cells, and fully dilated arteries. The NO independent dilation to SLIGRL was blocked with high [KCl] or Ca(2+)-activated K(+)-channel blockers. The hyperpolarization and dilation to SLIGRL passed through the artery to at least 2.5 mm upstream. The conducted dilation was not affected by a deficit in ApoE and could also be stimulated by ACh, suggesting NO itself could stimulate conducted dilation. CONCLUSION: In small mesenteric arteries of ApoE(-/-) mice, NO-independent dilation is enhanced. Since both NO dependent and -independent pathways can stimulate local and conducted dilation, the potential for reducing vascular resistance is improved in these vessels. PMID- 21690175 TI - The International Burden of Migraine Study (IBMS): study design, methodology, and baseline cohort characteristics. AB - OBJECTIVE: To describe a survey methodology to evaluate headache characteristics and burden and to present baseline characteristics for the international cohort of survey participants. METHODS: A targeted, web-based methodology was used to recruit and survey subjects with migraine in 10 countries. Based on reported symptoms, subjects meeting ICHD-2 criteria for migraine were included; eligible subjects were classified as chronic (>= 15 headache days per month) or episodic (< 15 headache days per month). Outcomes included sociodemographic and clinical characteristics, resource utilization, disability, health-related quality of life, anxiety, depression and productivity. RESULTS: Of 23,312 survey respondents, 11,897 were eligible and 9715 (81.7%) completed the survey; subjects were 81.5% female; 5.7% (n = 555) had chronic migraine. CONCLUSIONS: This is the first large international cohort of persons with chronic and episodic migraine studied using a web-based approach, a methodology well suited to the study of the burden of migraines. PMID- 21690176 TI - Cell type-specific regulation of ion channels within the maize stomatal complex. AB - The stomatal complex of Zea mays is composed of two pore-forming guard cells and two adjacent subsidiary cells. For stomatal movement, potassium ions and anions are thought to shuttle between these two cell types. As potential cation transport pathways, K(+)-selective channels have already been identified and characterized in subsidiary cells and guard cells. However, so far the nature and regulation of anion channels in these cell types have remained unclear. In order to bridge this gap, we performed patch-clamp experiments with subsidiary cell and guard cell protoplasts. Voltage-independent anion channels were identified in both cell types which, surprisingly, exhibited different, cell-type specific dependencies on cytosolic Ca(2+) and pH. After impaling subsidiary cells of intact maize plants with microelectrodes and loading with BCECF [(2',7'-bis-(2 carboxyethyl)-5(and6)carboxyflurescein] as a fluorescent pH indicator, the regulation of ion channels by the cytosolic pH and the membrane voltage was further examined. Stomatal closure was found to be accompanied by an initial hyperpolarization and cytosolic acidification of subsidiary cells, while opposite responses were observed during stomatal opening. Our findings suggest that specific changes in membrane potential and cytosolic pH are likely to play a role in determining the direction and capacity of ion transport in subsidiary cells. PMID- 21690177 TI - Succinic semialdehyde dehydrogenase is involved in the robust patterning of Arabidopsis leaves along the adaxial-abaxial axis. AB - Polarity along the adaxial-abaxial axis of the leaf is essential for leaf development and morphogenesis. One of the genes that encodes a putative transcription factor regulating adaxial-abaxial polarity, FILAMENTOUS FLOWER (FIL), is expressed in the abaxial region of the leaf primordia. However, the molecular mechanisms controlling the polarized expression of FIL remain unclear. Here, we analyzed an enlarged fil expression domain1 (enf1) mutant of Arabidopsis, which forms both abaxialized leaves and adaxialized leaves. The ENF1 gene encodes SUCCINIC SEMIALDEHYDE DEHYDROGENASE (SSADH), which catalyzes the conversion of succinic semialdehyde (SSA) to succinate. The enf1 phenotype was suppressed by an additional mutation in GAMMA-AMINOBUTYRIC ACID AMINOTRANSFERASE1 (GABAT1), which encodes an SSA-producing enzyme, suggesting that SSA or its derivatives is the metabolite responsible for the defect in the adaxial-abaxial axis-dependent gene expression of enf1. In the shoot apical meristem, GABAT1 was expressed in the outermost layer but SSADH was not. Exogenous application of SSA induced adaxial characters on the abaxial side of the newly developed leaves. We suggest that a GABA shunt metabolite, SSA or its close derivatives, is involved in the robust leaf patterning and structure along the adaxial-abaxial axis. PMID- 21690178 TI - The great cholesterol myth; unfortunate consequences of Brown and Goldstein's mistake. AB - Following their Nobel Prize-winning discovery of the defective gene causing familial hypercholesterolaemia, Brown and Goldstein misunderstood the mechanism involved in the pathogenesis of the associated arterial disease. They ascribed this to an effect of the high levels of cholesterol circulating in the blood. In reality, the accelerated arterial damage is likely to be a consequence of more brittle arterial cell walls, as biochemists know cholesterol to be a component of them which modulates their fluidity, conferring flexibility and hence resistance to damage from the ordinary hydrodynamic blood forces. In the absence of efficient receptors for LDL cholesterol, cells will be unable to use this component adequately for the manufacture of normally resilient arterial cell walls, resulting in accelerated arteriosclerosis. Eating cholesterol is harmless, shown by its failure to produce vascular accidents in laboratory animals, but its avoidance causes human malnutrition from lack of fat-soluble vitamins, especially vitamin D. PMID- 21690179 TI - Battling about equations. PMID- 21690180 TI - The adjuvant role of thyroxine in the treatment of chronic hepatitis C infection. PMID- 21690181 TI - Stillbirth risk by maternal socio-economic status and country of origin: a population-based observational study in Spain, 2007-08. AB - BACKGROUND: Socio-economic differences are a major determinant of perinatal outcomes. The impact of low socio-economic status on the risk of stillbirth, and the association between socio-economic status and stillbirth by maternal country of origin at a national level in Spain are unknown. We aimed to analyse the effect of maternal socio-economic status on the risk of stillbirth by maternal country of origin in Spain for the years 2007 and 2008. METHODS: We designed a population-based observational study that included 970,740 live births and 2464 stillbirths from 2007 to 2008. Univariate risk ratios (RRs) of stillbirth were calculated by maternal education, country of origin, age, parity, and gestational age. Adjusted stillbirth RRs were calculated using a generalized linear model with the Poisson family. Then, adjusted attributable risks and aetiological fractions in the population were calculated as measures of impact. RESULTS: Stillbirth rate ranged from 1.0 to 4.7 deaths per 1000 births. The stillbirth risk among mothers having secondary or lower education was double than that of mothers with a tertiary education with an adjusted RR of 2.13 [95% confidence interval (CI): 1.74-2.60]. African mothers, compared with mothers from Spain, showed an adjusted stillbirth RR of 1.75 (95% CI: 1.54-2.00). DISCUSSION: This study confirms the differences of stillbirth risk by maternal socio-economic status. Regardless of socio-economic status, African mothers had the highest risk of stillbirth. These results point out the necessity to reduce factors related to social and health inequalities in perinatal mortality in Spain, and more specifically, to take into consideration the special vulnerability of African mothers. PMID- 21690182 TI - The association between physical activity and perceived environment in German adults. AB - BACKGROUND: There is a growing body of international data on the association between physical activity (PA) and variables of the perceived environment. German data is still lacking. The purpose of this study was to provide data on PA (moderate-to-vigorous PA (MVPA) vs. walking) and the perceived environment in urban and rural areas. METHODS: We conducted a cross-sectional survey with inhabitants of urban (n = 310) and rural (n = 345) areas in the western part of Germany. The sample consisted of 655 adults [49.8% women; mean age = 43.3 (SD = 12.7)]. The International Physical Activity Questionnaire (IPAQ)-short version and the IPAQ environmental module were used. Outcome variables were time in MVPA as well as in walking. We analysed the association between perceived environmental variables and PA by a series of linear regressions. RESULTS: We observed associations between PA and access to destinations, well-maintained sidewalks, seeing physically active people in the neighbourhood, higher residential density and neighbourhood safety. The associations varied as a function of PA (MVPA vs. walking) and area (urban vs. rural). The variance explaining the models including environmental variables as well as sex and age ranged from 1% (model: MVPA in rural area) up to 9.9% (model MVPA in urban area). CONCLUSIONS: Our findings suggest that the perceived environment is important to promote both MVPA and walking in rural and urban areas. To better understand environmental correlates in rural structures, we particularly need more specific studies. PMID- 21690183 TI - Development and assessment of criteria to select projects for funding in the EU health programme. AB - BACKGROUND: Projects are the main financing mechanism within the EU community action programme for public health. This article reports the process of establishing and validating evaluation criteria for projects submitted for funding within this programme, to ensure that projects selected for funding conform with quality standards. METHODS: An evaluation checklist was developed, drawing on project management and health promotion literature, to Score 3 aspects of project quality: policy and contextual relevance (five criteria, scores 0-8), technical quality (five criteria, scored 0-6) and management quality (six criteria, scored 0-5). Teams of three people made consensus ratings with the checklist on each of 215 eligible applications submitted in response to Calls for Proposals in 2007 and 151 submitted in 2008. Construct validity, internal consistency and predictive validity were assessed on the grouped consensus ratings using psychometric test statistical methods. RESULTS: Principal component analyses on both the 2007 and 2008 data gave a three component solution, which largely coincides with the dimensions of contextual relevance, technical quality and management quality. Reliability analyses show high Cronbach alpha's (>0.86) for each of the three scales. Discriminant analyses indicate that all three of the dimensions contributed to the decision to fund a project. Over the 2 years, innovation, content specification, EU added value and geographical coverage contributing most consistently to the success of an application. CONCLUSION: The study shows the successful development and validation of criteria to evaluate EU health project grant proposals. PMID- 21690185 TI - Safety of anti-tumour necrosis factor agents in patients with chronic hepatitis C infection: a systematic review. AB - OBJECTIVES: To identify all of the patients affected by chronic hepatitis C infection treated with TNF-alpha blockers (adalimumab, certolizumab pegol, etanercept, golimumab and infliximab) in order to evaluate the safety profile. METHODS: A systematic review of the literature from January 1990 to October 2010. RESULTS: In total, 37 publications with data on 153 patients who were treated with anti-TNF-alpha agents in the setting of HCV infection were found. The mean anti-TNF-alpha treatment duration was 11.9 months. Ninety-one patients had RA, 22 had psoriasis, 6 had Crohn's disease and 14 patients had other chronic inflammatory diseases. To date, etanercept is the biological agent that has been most extensively used in the patients with HCV infection, with only one definitely confirmed case of HCV hepatitis worsening and five suspected cases (elevation of transaminases not associated with an increase in the HCV viral load and vice versa) in 110 treated patients. Treatment with this agent resulted in stable levels of liver transaminases and a stable viral load in 74 patients, with an improvement in HCV chronic liver disease in combination with IFN-ribavirin therapy in 29 patients. CONCLUSIONS: The safety profile of anti-TNF-alpha agents in the setting of HCV infection seems to be acceptable, even if differences in the hepatotoxic profile are apparent between different agents. In the absence of long-term and large, controlled clinical trials a definitive statement on the safety of anti-TNF-alpha therapies in the setting of chronic HCV infection cannot be made. PMID- 21690187 TI - Can observers judge future circular path relative to a target from retinal flow? AB - We investigated the ability of observers to judge whether they will pass left or right of a visible target from simulated motion along a circular path. Strategies based on optic flow would generally require compensation for pursuit eye movements. J. P. Wann and D. K. Swapp (2000) proposed an alternative strategy that requires only retinal flow. The experiments compared three conditions that provide the same retinal flow but different observer-relative optic flow. In the heading-relative view condition, simulated view direction rotated with change in heading, as naturally occurs when driving a car. In target-relative view condition, simulated view direction rotated to keep the direction of the target constant. In world-relative view condition, the simulated view direction was fixed relative to the environment. If an observer fixates the target, these conditions produce the same retinal flow. The initial heading direction of simulated motion was varied across trials, and responses were used to compute PSEs representing perceptual bias. Judgments were most accurate in the heading relative condition. In the target-relative and world-relative view conditions, PSEs indicated large biases consistent with underestimation of path curvature. The large biases suggest that retinal flow is not sufficient to judge future circular path relative to a target. PMID- 21690186 TI - Integrative analysis of environmental sequences using MEGAN4. AB - A major challenge in the analysis of environmental sequences is data integration. The question is how to analyze different types of data in a unified approach, addressing both the taxonomic and functional aspects. To facilitate such analyses, we have substantially extended MEGAN, a widely used taxonomic analysis program. The new program, MEGAN4, provides an integrated approach to the taxonomic and functional analysis of metagenomic, metatranscriptomic, metaproteomic, and rRNA data. While taxonomic analysis is performed based on the NCBI taxonomy, functional analysis is performed using the SEED classification of subsystems and functional roles or the KEGG classification of pathways and enzymes. A number of examples illustrate how such analyses can be performed, and show that one can also import and compare classification results obtained using others' tools. MEGAN4 is freely available for academic purposes, and installers for all three major operating systems can be downloaded from www ab.informatik.uni-tuebingen.de/software/megan. PMID- 21690188 TI - Vertical torque responses to vestibular stimulation in standing humans. AB - The effects of electrical vestibular stimulation upon movement and perception suggest two evoked sensations: head roll and inter-aural linear acceleration. The head roll vector causes walking subjects to turn in a direction dependent on head pitch, requiring generation of torque around a vertical axis. Here the effect of vestibular stimulation upon vertical torque (T(z)) was investigated during quiet stance. With the head tilted forward, square-wave stimuli applied to the mastoid processes evoked a polarity-specific T(z) response accompanied by trunk yaw. Stochastic vestibular stimulation (SVS) was used to investigate the effect of head pitch with greater precision; the SVS-T(z) cross-correlation displayed a modulation pattern consistent with the head roll vector and this was also reflected by changes in coherence at 2-3 Hz. However, a separate response at 7-8 Hz was unaffected by head pitch. Head translation (rather than rotation) had no effect upon this high frequency response either, suggesting it is not caused by a sense of body rotation induced by an inter-aural acceleration vector offset from the body. Instead, high coherence between medio-lateral shear force and T(z) at the same frequency range suggests it is caused by mechanical coupling to evoked medio-lateral sway. Consistent with this explanation, the 7-8 Hz response was attenuated by 90 deg head roll or yaw, both of which uncouple the inter-aural axis from the medio-lateral sway axis. These results demonstrate two vertical torque responses to electrical vestibular stimulation in standing subjects. The high frequency response can be attributed to mechanical coupling to evoked medio lateral sway. The low frequency response is consistent with a reaction to a sensation of head roll, and provides a novel method for investigating proprioceptive-vestibular interactions during stance. PMID- 21690189 TI - Regulation of bradykinin-induced activation of volume-sensitive outwardly rectifying anion channels by Ca2+ nanodomains in mouse astrocytes. AB - Volume-sensitive outwardly rectifying (VSOR) anion channels play a key role in a variety of essential cell functions including cell volume regulation, cell death induction and intercellular communications. We previously demonstrated that, in cultured mouse cortical astrocytes, VSOR channels are activated in response to an inflammatory mediator, bradykinin, even without an increase in cell volume. Here we report that this VSOR channel activation must be mediated firstly by 'nanodomains' of high [Ca2+]i generated at the sites of both Ca2+ release from intracellular Ca2+ stores and Ca2+ entry at the plasma membrane. Bradykinin elicited a [Ca2+]i rise, initially caused by Ca2+ release and then by Ca2+ entry. Suppression of the [Ca2+]i rise by removal of extracellular Ca2+ and by depletion of Ca2+ stores suppressed the VSOR channel activation in a graded manner. Quantitative RT-PCR and suppression of gene expression with small interfering RNAs indicated that Orai1, TRPC1 and TRPC3 channels are involved in the Ca2+ entry and especially the entry through TRPC1 channels is strongly involved in the bradykinin-induced activation of VSOR channels. Moreover, Ca2+-dependent protein kinases Calpha and beta were found to mediate the activation after the [Ca2+]i rise through inducing generation of reactive oxygen species. Intracellular application of a slow Ca2+ chelator, EGTA, at 10 mM or a fast chelator, BAPTA, at 1 mM, however, had little effect on the VSOR channel activation. Application of BAPTA at 10 mM suppressed significantly the activation to one-third. These suggest that the VSOR channel activation induced by bradykinin is regulated by Ca2+ in the vicinity of individual Ca2+ release and entry channels, providing a basis for local control of cell volume regulation and intercellular communications. PMID- 21690190 TI - Subthalamic nucleus high-frequency stimulation generates a concomitant synaptic excitation-inhibition in substantia nigra pars reticulata. AB - Deep brain stimulation is an efficient treatment for various neurological pathologies and a promising tool for neuropsychiatric disorders. This is particularly exemplified by high-frequency stimulation of the subthalamic nucleus (STN-HFS), which has emerged as an efficient symptomatic treatment for Parkinson's disease. How STN-HFS works is still not fully elucidated. With dual patch-clamp recordings in rat brain slices, we analysed the cellular responses of STN stimulation on SNr neurons by simultaneously recording synaptic currents and firing activity. We showed that STN-HFS caused an increase of the spontaneous spiking activity in half of SNr neurons while the remaining ones displayed a decrease. At the synaptic level, STN stimulation triggered inward current in 58% of whole-cell recorded neurons and outward current in the remaining ones. Using a pharmacological approach, we showed that STN-HFS-evoked responses were mediated in all neurons by a balance between AMPA/NMDA receptors and GABA(A) receptors, whose ratio promotes either a net excitation or a net inhibition. Interestingly, we observed a higher excitation occurrence in 6-hydroxydopamine (6-OHDA)-treated rats. In vivo injections of phaseolus revealed that GABAergic pallido-nigral fibres travel through the STN whereas striato-nigral fibres travel below it. Therefore, electrical stimulation of the STN does not only recruit glutamatergic axons from the STN, but also GABAergic passing fibres probably from the globus pallidus. For the first time, we showed that STN-HFS induces concomitant excitatory-inhibitory synaptic currents in SNr neurons by recruitment of efferences and passing fibres allowing a tight control on basal ganglia outflow. PMID- 21690191 TI - A novel opioid receptor-mediated enhancement of GABAA receptor function induced by stress in ventral tegmental area neurons. AB - Opioid receptors are G-protein-coupled receptors (GPCRs) that modulate synaptic function. Depending upon their nervous system site of action, opioid receptor agonists alter food consumption, pain perception, responses to stress, and drug reward. Opioid receptors signal primarily via G(i/o)-proteins that modulate ion channels to directly inhibit neurons or decrease neurotransmitter release from nerve terminals. Here we report that following stress, activating delta opioid receptors (DORs) on midbrain ventral tegmental area (VTA) neurons causes a novel synaptic effect: the augmentation of GABA(A) receptor (GABA(A)R)-mediated inhibitory postsynaptic currents. Most neurons showing this augmentation were identified as dopaminergic. In addition, in both stressed and unstressed animals, DOR activation decreases GABA(A)R currents in some VTA neurons. Surprisingly, both augmentation and inhibition were also observed when we bypassed the presynaptic terminal by iontophoretically applying GABA, indicating that postsynaptic mechanisms are responsible for both effects. Using a variety of blockers we determined that the augmentation is probably due to insertion of GABA(A)Rs into the synapse by a mechanism that is G-protein independent and mediated by activation of Akt via PI3K. GABA(A)Rs are inserted into the extra synaptic plasma membrane before trafficking to the synapse, a mechanism consistent with our observation that the DOR-mediated increase in GABA(A)R signalling occurs significantly earlier in iontophoretically applied than in electrically evoked synaptic GABA. This G-protein-independent signalling pathway is not only a novel mechanism of opioid receptor-mediated inhibition, but it also represents the first reported link between activation of a GPCR and insertion of GABA(A)Rs into the plasma membrane. PMID- 21690192 TI - State-dependent changes in astrocyte regulation of extrasynaptic NMDA receptor signalling in neurosecretory neurons. AB - Despite the long-established presence of glutamate NMDA receptors at extrasynaptic sites (eNMDARs), their functional roles remain poorly understood. Factors influencing the concentration and time course of glutamate in the extrasynaptic space, such as the topography of the neuronal-glial microenvironment, as well as glial glutamate transporters, are expected to affect eNMDAR-mediated signalling strength. In this study, we used in vitro and in vivo electrophysiological recordings to assess the properties, functional relevance and modulation of a persistent excitatory current mediated by activation of eNMDARs in hypothalamic supraoptic nucleus (SON) neurons. We found that ambient glutamate of a non-synaptic origin activates eNMDARs to mediate a persistent excitatory current (termed tonic I(NMDA)), which tonically stimulates neuronal activity. Pharmacological blockade of GLT1 astrocyte glutamate transporters, as well as the gliotoxin alpha-aminodadipic acid, enhanced tonic I(NMDA) and neuronal activity, supporting an astrocyte regulation of tonic I(NMDA) strength. Dehydration, a physiological challenge known to increase SON firing activity and to induce neuroglial remodelling, including reduced neuronal ensheathment by astrocyte processes, resulted in blunted GLT1 efficacy, enhanced tonic I(NMDA) strength, and increased neuronal activity. Taken together, our studies support the view that glial modulation of tonic I(NMDA) activation contributes to regulation of SON neuronal activity, contributing in turn to neuronal homeostatic responses during a physiological challenge. PMID- 21690193 TI - Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. AB - MicroRNAs (miRNAs) are intracellular mediators of essential biological functions. Recently, plasma-based 'circulating' miRNAs (c-miRNAs) have been shown to control cellular processes, but the c-miRNA response to human exercise remains unknown. We sought to determine whether c-miRNAs are dynamically regulated in response to acute exhaustive cycling exercise and sustained rowing exercise training using a longitudinal, repeated measures study design. Specifically, c-miRNAs involved in angiogenesis (miR-20a, miR-210, miR-221, miR-222, miR-328), inflammation (miR-21, miR-146a), skeletal and cardiac muscle contractility (miR-21, miR-133a), and hypoxia/ischaemia adaptation (miR-21, miR-146a, and miR-210) were measured at rest and immediately following acute exhaustive cycling exercise in competitive male rowers (n = 10, age = 19.1 +/- 0.6 years) before and after a 90 day period of rowing training. Distinct patterns of c-miRNA response to exercise were observed and adhered to four major profiles: (1) c-miRNA up-regulated by acute exercise before and after sustained training (miR-146a and miR-222), (2) c-miRNA responsive to acute exercise before but not after sustained training (miR-21 and miR-221), (3) c-miRNA responsive only to sustained training (miR-20a), and (4) non-responsive c-miRNA (miR-133a, miR-210, miR-328). Linear correlations were observed between peak exercise levels of miR-146a and VO2max (r = 0.63, P = 0.003) and between changes in resting miR-20a and changes in VO2max (pre-training vs. post-training, r = 0.73; P = 0.02). Although future work is required, these results suggest the potential value of c-miRNAs as exercise biomarkers and their possible roles as physiological mediators of exercise-induced cardiovascular adaptation. PMID- 21690194 TI - Reductions in cerebral blood flow during passive heat stress in humans: partitioning the mechanisms. AB - Cerebral blood flow (CBF) is reduced during passive heat stress, with 50% of this reduction associated with hyperventilatory-induced hypocapnia and subsequent cerebral vasoconstriction. It remains unknown, however, what other factors may contribute to the remaining 50%. We tested the hypothesis that the distribution of cardiac output plays an important role in maintaining cerebral perfusion during mild and severe heat stress. Middle cerebral artery and posterior cerebral artery blood flow velocity (MCAv and PCAv; transcranial Doppler) and left ventricular end-diastolic and end-systolic volumes (2-D echocardiography) were measured under conditions of normothermia and mild and severe passive heat stress (core temperature +0.8 +/- 0.1 degrees C (Protocol I; n = 10) and 1.8 +/- 0.1 degrees C (Protocol II; n = 8) above baseline). Venous return was manipulated by passive tilt table positioning (30 deg head-down tilt (HDT) and 30 deg head-up tilt (HUT)). Measurements were made under poikilocapnic and isocapnic conditions. Protocol I consisted of mild heat stress which resulted in small reductions in end-tidal CO2 (-5.6 +/- 3.5%), MCAv/PCAv (-7.3 +/- 2.3% and -10.3 +/- 2.9%, respectively) and stroke volume (-8.5 +/- 4.2%); while end-diastolic volume was significantly reduced (-16.9 +/- 4.0%) and cardiac output augmented (17.2 +/- 7.4%). During mild heat stress, CBF was related to left ventricular end-diastolic volume (MCAv, r2 = 0.81; PCAv, r2 = 0.83; P < 0.05) and stroke volume (MCAv, r2 = 0.38; PCAv, r2 = 0.43), but not with cardiac output. Protocol II consisted of severe heat stress which resulted in much greater reductions in end-tidal CO2 ( 87.5 +/- 31.5%) and CBF (MCAv, -36.4 +/- 6.1%; PCAv, -30.1 +/- 4.8%; P < 0.01 for all variables), while end-diastolic volume and stroke volume decreased to a similar extent as for mild heat stress. Importantly, isocapnia restored MCAv and PCAv back to normothermic baseline. This investigation therefore produced two novel findings: first, that venous return and stroke volume are related to CBF during mild heat stress; and second, that hyperventilatory hypocapnia has a major influence on CBF during severe passive heat stress. PMID- 21690195 TI - Reflexes from pulmonary arterial baroreceptors in dogs: interaction with carotid sinus baroreceptors. AB - In contrast to the reflex vasodilatation occurring in response to stimulation of baroreceptors in the aortic arch, carotid sinuses and coronary arteries, stimulation of receptors in the wall of pulmonary arteries results in reflex systemic vasoconstriction. It is rare for interventions to activate only one reflexogenic region, therefore we investigated how these two types of reflexes interact. In anaesthetized dogs connected to cardiopulmonary bypass, reflexogenic areas of the carotid sinuses, aortic arch and coronary arteries and the pulmonary artery were subjected to independently controlled pressures. Systemic perfusion pressure (SPP) measured in the descending aorta (constant flow) provided an index of systemic vascular resistance. In other experiments, sympathetic efferent neural activity was recorded in fibres dissected from the renal nerve (RSNA). Physiological increases in pulmonary arterial pressure (PAP) induced significant increases in SPP (+39.1 +/- 10.4 mmHg) and RSNA (+17.6 +/- 2.2 impulses s(-1)) whereas increases in carotid sinus pressure (CSP) induced significant decreases in SPP (-42.6 +/- 10.8 mmHg) and RSNA (-42.8 +/- 18.2 impulses s(-1)) (P < 0.05 for each comparison; paired t test). To examine possible interactions, PAP was changed at different levels of CSP in both studies. With CSP controlled at 124 +/ 2 mmHg, the threshold, 'set point' and saturation pressures of the PAP-SPP relationship were higher than those with CSP at 60 +/- 1 mmHg; this rightward shift was associated with a significant decrease in the reflex gain. Similarly, increasing CSP produced a rightward shift of the PAP-RSNA relationship, although the effect on reflex gain was inconsistent. Furthermore, the responses to changes in CSP were influenced by setting PAP at different levels; increasing the level of PAP from 5 +/- 1 to 33 +/- 3 mmHg significantly increased the set point and threshold pressures of the CSP-SPP relationship; the reflex gain was not affected. These results indicate the existence of interaction between pulmonary arterial and carotid sinus baroreceptor reflexes; physiological and pathological states that alter the stimulus to one may alter the reflex responses from the other. PMID- 21690196 TI - GluA4 is indispensable for driving fast neurotransmission across a high-fidelity central synapse. AB - Fast excitatory synaptic transmission in central synapses is mediated primarily by AMPA receptors (AMPARs), which are heteromeric assemblies of four subunits, GluA1-4. Among these subunits, rapidly gating GluA3/4 appears to be the most abundantly expressed to enable neurotransmission with submillisecond precision at fast rates in subsets of central synapses. However, neither definitive identification of the molecular substrate for native AMPARs in these neurons, nor their hypothesized functional roles in vivo has been unequivocally demonstrated, largely due to lack of specific antagonists. Using GluA3 or GluA4 knockout (KO) mice, we investigated these issues at the calyx of Held synapse, which is known as a high-fidelity synapse involved in sound localization. Patch-clamp recordings from postsynaptic neurons showed that deletion of GluA4 significantly slowed the time course of both evoked and miniature AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), reduced their amplitude, and exacerbated AMPAR desensitization and short-term depression (STD). Surprisingly, presynaptic release probability was also elevated, contributing to severe STD at GluA4-KO synapses. In contrast, only marginal changes in AMPAR-EPSCs were found in GluA3 KO mice. Furthermore, independent of changes in intrinsic excitability of postsynaptic neurons, deletion of GluA4 markedly reduced synaptic drive and increased action potential failures during high-frequency activity, leading to profound deficits in specific components of the auditory brainstem responses associated with synchronized spiking in the calyx of Held synapse and other related neurons in vivo. These observations identify GluA4 as the main determinant for fast synaptic response, indispensable for driving high-fidelity neurotransmission and conveying precise temporal information. PMID- 21690197 TI - Kinetic control of oxygen consumption during contractions in self-perfused skeletal muscle. AB - Fast kinetics of muscle oxygen consumption (VO2) is characteristic of effective physiological systems integration. The mechanism of VO2 kinetic control in vivo is equivocal as measurements are complicated by the twin difficulties of making high-frequency direct measurements of VO2 and intramuscular metabolites, and in attaining high [ADP]; complexities that can be overcome utilising highly aerobic canine muscle for the investigation of the transition from rest to contractions at maximal VO2. Isometric tetanic contractions of the gastrocnemius complex of six anaesthetised, ventilated dogs were elicited via sciatic nerve stimulation (50 Hz; 200 ms duration; 1 contraction s(-1)). Muscle VO2 and lactate efflux were determined from direct Fick measurements. Muscle biopsies were taken at rest and every ~10 s during the transient and analysed for [phosphates], [lactate] and pH. The temporal VO2 vs. [PCr] and [ADP] relationships were not well fitted by linear or classical hyperbolic models (respectively), due to the high sensitivity of VO2 to metabolic perturbations early in the transient. The time course of this apparent sensitisation was closely aligned to that of ATP turnover, which was lower in the first ~25 s of contractions compared to the steady state. These findings provide the first direct measurements of skeletal muscle VO2 and [PCr] in the non-steady state, and suggest that simple phosphate feedback models (which are adequate for steady-state observations in vitro) are not sufficient to explain the dynamic control of VO2 in situ. Rather an allosteric or 'parallel activation' mechanism of energy consuming and producing processes is required to explain the kinetic control of VO2 in mammalian skeletal muscle. PMID- 21690198 TI - The inactive X chromosome adopts a unique three-dimensional conformation that is dependent on Xist RNA. AB - Three-dimensional topology of DNA in the cell nucleus provides a level of transcription regulation beyond the sequence of the linear DNA. To study the relationship between the transcriptional activity and the spatial environment of a gene, we used allele-specific chromosome conformation capture-on-chip (4C) technology to produce high-resolution topology maps of the active and inactive X chromosomes in female cells. We found that loci on the active X form multiple long-range interactions, with spatial segregation of active and inactive chromatin. On the inactive X, silenced loci lack preferred interactions, suggesting a unique random organization inside the inactive territory. However, escapees, among which is Xist, are engaged in long-range contacts with each other, enabling identification of novel escapees. Deletion of Xist results in partial refolding of the inactive X into a conformation resembling the active X without affecting gene silencing or DNA methylation. Our data point to a role for Xist RNA in shaping the conformation of the inactive X chromosome at least partially independent of transcription. PMID- 21690199 TI - Induction of triggering receptor expressed on myeloid cells (TREM-1) in airway epithelial cells by 1,25(OH)2 vitamin D3. AB - The airway epithelium plays a role in host defense through the binding of innate immune receptors, which leads to the activation of inflammatory mediators, including antimicrobial peptides. The active form of vitamin D, 1,25(OH)(2)D(3), induces the expression of the antimicrobial peptide LL-37 in both myeloid cells and airway epithelial cells (AEC). Here, we demonstrate that mRNA encoding triggering receptor expressed on myeloid cells (TREM)-1 was induced up to 12-fold by 1,25(OH)(2)D(3) in normal human bronchial epithelial (NHBE) cells and in well differentiated cultures of six airway epithelial cell lines from patients with cystic fibrosis and healthy individuals. TREM-2 and DAP12 were also expressed in airway cultures, but not induced by vitamin D. Induction occurs through a vitamin D response element identified in its proximal promoter region, and was regulated by PU.1 expressed in the AEC. Activation of TREM-1 by a cross-linking antibody led to an induction of both human beta-defensin-2 and TNF-alpha mRNA, demonstrating its functionality in these cells. Our results expand on the role played by the airway epithelium in innate immunity and suggest that vitamin D can modulate the innate immune defense of the airway epithelium, and could potentially be developed as an adjunctive therapy for airway infections. PMID- 21690201 TI - Pitfalls in assessing renal function in patients with cirrhosis--potential inequity for access to treatment of hepatorenal failure and liver transplantation. AB - Serum creatinine is universally used to assess renal function in clinical practice. Creatinine and changes in serum creatinine are used to define acute kidney injury and hepatorenal syndrome (HRS) in patients with progressive liver disease. In addition, creatinine is a key variable in the calculation used to determine priority for liver transplantation in many countries. As there is no universal standardized creatinine assay, there is variation in creatinine determinations between laboratory assays, compounded by assay interference due to chromogens, including bilirubin. This leads to patients with the same actual renal function potentially being offered different treatment options, in terms of access to therapy for HRS and priority waiting time for liver transplantation. Alternative methods for assessing renal function either also tend to overestimate renal function or are too time consuming and expensive to provide practical alternatives for standard clinical practice. Standardization of creatinine assays with readily available reference standards would help minimize interlaboratory variation; of the current creatinine assays, enzymatic creatinine appears more accurate, but even this is inaccurate at high bilirubin concentrations. Further work is required to determine whether interpatient variation can be reduced by correcting creatinine and cystatin measurements for muscle mass. PMID- 21690200 TI - Renal perfusion evaluation with contrast-enhanced ultrasonography. AB - BACKGROUND: Contrast-enhanced ultrasonography (CEUS) is a novel imaging technique that is safe and applicable on the bedside. Recent developments seem to enable CEUS to quantify organ perfusion. We performed an exploratory study to determine the ability of CEUS to detect changes in renal perfusion and to correlate them with effective renal plasma flow. METHODS: CEUS with destruction-refilling sequences was studied in 10 healthy subjects, at baseline and during infusion of angiotensin II (AngII) at low (1 ng/kg/min) and high dose (3 ng/kg/min) and 1 h after oral captopril (50 mg). Perfusion index (PI) was obtained and compared with the effective renal plasma flow (ERPF) obtained by parallel para-aminohippurate (PAH) clearance. RESULTS: Median PI decreased from 188.6 (baseline) to 100.4 with low-dose AngII (-47%; P < 0.02) and to 66.1 with high-dose AngII (-65%; P < 0.01) but increased to 254.7 with captopril (+35%; P > 0.2). These changes parallelled those observed with ERPF, which changed from a median of 672.1 mL/min (baseline) to 572.3 (low-dose AngII, -15%, P < 0.05) and to 427.2 (high-dose AngII, -36%, P < 0.001) and finally 697.1 (captopril, +4%, P < 0.02). CONCLUSIONS: This study demonstrates that CEUS is able to detect changes in human renal cortical microcirculation as induced by AngII infusion and/or captopril administration. The changes in perfusion indices parallel those in ERPF as obtained by PAH clearance. PMID- 21690202 TI - Metabolic profiling of diabetes: from black-box epidemiology to systems epidemiology. PMID- 21690203 TI - I detected my cancer with my smart phone. PMID- 21690204 TI - Gross overestimation of total allowable error based on biological variation. PMID- 21690205 TI - An updated GA signaling 'relief of repression' regulatory model. AB - Gibberellic acid (GA) regulates many aspects of plant growth and development. The DELLA proteins act to restrain plant growth, and GA relieves this repression by promoting their degradation via the 26S proteasome pathway. The elucidation of the crystalline structure of the GA soluble receptor GID1 protein represents an important breakthrough for understanding the way in which GA is perceived and how it induces the destabilization of the DELLA proteins. Recent advances have revealed that the DELLA proteins are involved in protein-protein interactions within various environmental and hormone signaling pathways. In this review, we highlight our current understanding of the 'relief of repression' model that aims to explain the role of GA and the function of the DELLA proteins, incorporating the many aspects of cross-talk shown to exist in the control of plant development and the response to stress. PMID- 21690206 TI - Paradigms and paradox in the ethylene signaling pathway and interaction network. AB - Phytohormone ethylene plays pivotal roles in plant response to developmental and environmental signals. During the past few years, the emerging evidence has led us to a new understanding of the signaling mechanisms and regulatory networks of the ethylene action. In this review, we focus on the major advances made in the past three years, particularly the findings leading to new paradigms and the observations under debate. With the recent demonstration of the regulation of the protein stability of numerous key signaling components including EIN3, EIL1, EIN2, ETR2, EBF1/EBF2, and ETP1/ETP2, we highlight proteasome-dependent protein degradation as an essential regulatory mechanism that is widely adopted in the ethylene signaling pathway. We also discuss the implication of the negative feedback mechanism in the ethylene signaling pathway in light of ethylene-induced ETR2 and EBF2 gene expression. Meanwhile, we summarize the controversy on the involvement of MKK9-MPK3/6 cascade in the ethylene signaling versus biosynthesis pathway, and discuss the possible role of this MAPK module in the ethylene action. Finally, we describe the complex interactions between ethylene and other signaling pathways including auxin, light, and plant innate immunity, and propose that EIN3/EIL1 act as a convergence point in the ethylene-initiated signaling network. PMID- 21690207 TI - Distribution of strontium and mineralization in iliac bone biopsies from osteoporotic women treated long-term with strontium ranelate. AB - OBJECTIVE: To investigate interactions between strontium (Sr) and bone mineral and its effects on mineralization in osteoporotic women treated long-term with Sr ranelate (SrRan). DESIGN: In this study, 34 iliac bone biopsies were analyzed after 2, 12, 24, 36, 48, and 60 months of treatment with SrRan. METHODS: Sr global distribution was analyzed by X-ray cartography and the percentage of bone area containing Sr was calculated in the bone samples. The focal distribution of Sr in all bone samples was investigated by X-ray microanalysis. The degree of mineralization was assessed by quantitative microradiography. RESULTS: Absent from old bone formed before the beginning of treatment, Sr was exclusively present in bone formed during this treatment with a much higher focal Sr content in new bone structural units than in old ones. A progressive increase in the extent of areas containing Sr was observed during treatment. The focal bone Sr content in recently formed bone was constant over treatment. Secondary mineralization was maintained at a normal level during treatment. CONCLUSION: Thus, the quality of bone mineralization (density and heterogeneity at tissue level) was preserved after a long-term treatment with SrRan. PMID- 21690208 TI - Development of deaf identity: an ethnographic study. AB - This ethnographic study explores the identity development of 9 deaf participants through the narratives of their educational experiences in either mainstream or special schools for the Deaf. This exploration goes beyond a binary conceptualization of deaf identity that allows for only the medical and social models and proposes a bicultural "dialogue model." This postmodern theoretical framework is used to examine the diversity of identities of deaf learners. The inclusion of the researcher's own fluid cross-cultural identity as a bicultural "DeaF" participant in this study provides an auto-ethnographic gateway into exploring the lives of other deaf, Deaf, or bicultural DeaF persons. The findings suggest that deaf identity is not a static concept but a complex ongoing quest for belonging, a quest that is bound up with the acceptance of being deaf while "finding one's voice" in a hearing-dominant society. Through the use of dialogue and narrative tools, the study challenges educators, parents, and researchers to broaden their understanding of how deaf identity, and the dignity associated with being a deaf person is constructed. PMID- 21690209 TI - Placental markers of folate-related metabolism in preeclampsia. AB - The etiology and degree of clinical symptoms of preeclampsia depend on genotypic and phenotypic maternal and trophoblast factors, and elevated levels of plasma homocysteine (Hcy) are one of the pathogenetic factors of preeclampsia. To assess the impact of the folate-related metabolism, we characterized the indices of this metabolism in 40 samples from uncomplicated term placentas and 28 samples from preeclamptic pregnancies by quantifying the total content of folate, methionine (Met), Hcy and related cysteine, and glutathione (GSH) in compliance with the 677 C/T genotype of methylene tetrahydrofolate reductase (MTHFR). The prevalence of MTHFR genotypes was not significantly different between the two groups. The polymorphism of MTHFR was not unambiguously connected with the content of total placental Met, Hcy and related cysteine, and GSH either in uncomplicated or in complicated pregnancies. By contrast, the combination of the heterozygous MTHFR genotype with folate deficiency in the samples from preeclamptic pregnancies was characterized by a statistically significant decrease in the Met content, a trend toward increased Hcy levels and a tight association between metabolically directly and indirectly related compounds, e.g. positive relation between Hcy versus cysteine and folate versus GSH and negative relation between folate versus Hcy and both Hcy and cysteine versus GSH. We demonstrated the expression of cystathionine-beta-synthase (CBS) in human placenta at term by RT-PCR and western blot analysis, for the first time, and confirmed its catalytic activity and the accumulation of cysteine and CBS in placental explants cultivated in the presence of elevated Hcy concentrations. We suggest that disturbance in placental folate related metabolism may be one of the pathogenetic factors in preeclampsia. PMID- 21690210 TI - Cerebellar dysfunction, cognitive flexibility and autistic traits in a non clinical sample. AB - Cerebellar dysfunction and impaired cognitive flexibility are key features of autism spectrum disorders (ASD). However, despite the increasing interest in subclinical autism, no research has yet examined the relationship between these signs and autistic traits in the wider population. This study used the Autism Spectrum Quotient (AQ) questionnaire to assess autistic traits in university students enrolled in either systems-oriented or humanities degree programmes. Participants also completed a battery of motor tasks designed to assess cerebellar function, and subscales from the Delis-Kaplan Executive Function System (D-KEFS) battery. Students enrolled in systems-oriented degrees had on average higher AQ scores than students enrolled in humanities degrees. The data showed a significant correlation between autistic traits and motor function scores, as well as between autistic traits and verbal set-shifting ability, as assessed on the D-KEFS. These data provide support for the autistic spectrum hypothesis, in indicating that key cognitive, neurological and behavioural features of autism carry over into non-clinical populations. PMID- 21690211 TI - Validation of the Autism Spectrum Screening Questionnaire, Mandarin Chinese Version (CH-ASSQ) in Beijing, China. AB - BACKGROUND: This study screened children in Beijing, China, in order to establish the validity of a Mandarin Chinese translation of the ASSQ. METHODS: We recruited children diagnosed with autism spectrum disorders (ASDs), attention deficit/hyperactivity disorder (ADHD), childhood-onset schizophrenia (COS) (DSM IV diagnoses made independently by two senior psychiatrists) and unaffected children attending a public school in Beijing. Their parents were asked to complete the CH-ASSQ. RESULTS: Data from the parents of 94 children with ASD (mean age: 81 +/- 47 months), 45 with ADHD (106 +/- 27 months), 26 with COS (166 +/- 36 months), and 120 unaffected control (72 +/- 16 months) were collected. The total scores of ASSQ in children with ASD, ADHD, COS, and unaffected controls were 25.3 +/- 9.2, 10.4 +/- 7.1, 12.2 +/- 10.6, and 5.2 +/- 6.6 respectively. Total ASSQ scores of children with ASD were significantly higher than in any other group (all p < .0001). ROC analysis of ASD versus unaffected control subjects showed the area under curve was 0.957, with a cutoff of 12 having the maximum sensitivity (0.957) and specificity (0.825). CONCLUSIONS: Our pilot data suggest that CH-ASSQ successfully differentiates clinically diagnosed ASD patients from unaffected controls, as well as from patients with ADHD and COS. The instrument might therefore be useful for screening for ASD in urban Mandarin Chinese-speaking populations. PMID- 21690212 TI - Flexibility in young people with autism spectrum disorders on a card sort task. AB - Adults with autism spectrum disorders (ASD) have shown deficits in switching between rules governing their behaviour, as have high-functioning children with ASD. However, there are few studies of flexibility in lower-functioning children with ASD. The current study investigated this phenomenon with a group of low functioning children with ASD compared to a mental-age-matched comparison group. The ASD group learned an initial discrimination task as quickly as the matched comparison group, but when the rule governing the discrimination was shifted, the comparison group learned the task with fewer errors, and made the discrimination more quickly than the groups with ASD. These findings suggest that low functioning children with ASD do display the predicted deficits in extra dimensional shift. PMID- 21690213 TI - Translational control in oocyte development. AB - Translational control of specific mRNAs is a widespread mechanism of gene regulation, and it is especially important in pattern formation in the oocytes of organisms in which the embryonic axes are established maternally. Drosophila and Xenopus have been especially valuable in elucidating the relevant molecular mechanisms. Here, we comprehensively review what is known about translational control in these two systems, focusing on examples that illustrate key concepts that have emerged. We focus on protein-mediated translational control, rather than regulation mediated by small RNAs, as the former appears to be predominant in controlling these developmental events. Mechanisms that modulate the ability of the specific mRNAs to be recruited to the ribosome, that regulate polyadenylation of specific mRNAs, or that control the association of particular mRNAs into translationally inert ribonucleoprotein complexes will all be discussed. PMID- 21690214 TI - Golgi biogenesis. AB - The Golgi is an essential membrane-bound organelle in the secretary pathway of eukaryotic cells. In mammalian cells, the Golgi stacks are integrated into a continuous perinuclear ribbon, which poses a challenge for the daughter cells to inherit this membrane organelle during cell division. To facilitate proper partitioning, the mammalian Golgi ribbon is disassembled into vesicles in early mitosis. Following segregation into the daughter cells, a functional Golgi is reformed. Here we summarize our current understanding of the molecular mechanisms that control the mitotic Golgi disassembly and postmitotic reassembly cycle in mammalian cells. PMID- 21690216 TI - In vivo pharmacology and toxicology evaluation of polyethylene glycol-conjugated interferon beta-1a. AB - Human interferon (IFN) beta has well established beneficial effects in treating relapsing forms of multiple sclerosis, but current first-line treatment requires frequent (from daily to weekly) parenteral administration. A 20-kDa polyethylene glycol (PEG)-conjugated IFN beta-1a (PEG-IFN beta-1a) is being developed to decrease the frequency of administration and improve patient convenience and compliance. We present pharmacokinetic (PK) and pharmacodynamic (PD) parameters, immunogenicity, and safety of PEG-IFN beta-1a in Rhesus monkeys in support of a phase 1 clinical trial. Two single-dose PK/PD studies and one 5-week repeat-dose toxicity study compliant with good laboratory practice were conducted. The PK of IFN beta-1a and PEG-IFN beta-1a were modeled with a two-compartment model, and the link between drug concentration and neopterin response (PD marker) was described with an indirect stimulatory model. PEG-IFN beta-1a showed greater exposure, longer half-life, lower clearance, and reduced volume of distribution than unmodified IFN beta-1a. Consistent with the pharmacology of type I IFNs, PEG IFN beta-1a resulted in the elevation of neopterin concentration, a transient body temperature increase, and a reversible lymphocyte count decrease. As expected, neutralizing antibodies to PEG-IFN beta-1a formed in almost all monkeys after 5 weeks of treatment, which resulted in significantly reduced drug exposure and abrogation of neopterin induction. There were no drug-related adverse effects at doses up to 100 MUg/kg (11 MIU/kg) given subcutaneously or intramuscularly once weekly for 5 weeks. The no-observed-adverse-effect level was determined to be 100 MUg/kg (11 MIU/kg), the highest dose tested. PMID- 21690217 TI - Systemic health reform should be a higher priority in African aid projects, experts say. PMID- 21690218 TI - Dilating pupils. PMID- 21690219 TI - Canadian students develop mediwiki to share classroom notes with the world. PMID- 21690220 TI - Reducing lifelong disability from sports injuries in children. PMID- 21690215 TI - Heparan sulfate proteoglycans. AB - Heparan sulfate proteoglycans are found at the cell surface and in the extracellular matrix, where they interact with a plethora of ligands. Over the last decade, new insights have emerged regarding the mechanism and biological significance of these interactions. Here, we discuss changing views on the specificity of protein-heparan sulfate binding and the activity of HSPGs as receptors and coreceptors. Although few in number, heparan sulfate proteoglycans have profound effects at the cellular, tissue, and organismal level. PMID- 21690221 TI - Risk of injury associated with bodychecking experience among youth hockey players. AB - BACKGROUND: In a previous prospective study, the risk of concussion and all injury was more than threefold higher among Pee Wee ice hockey players (ages 11 12 years) in a league that allows bodychecking than among those in a league that does not. We examined whether two years of bodychecking experience in Pee Wee influenced the risk of concussion and other injury among players in a Bantam league (ages 13-14) compared with Bantam players introduced to bodychecking for the first time at age 13. METHODS: We conducted a prospective cohort study involving hockey players aged 13-14 years in the top 30% of divisions of play in their leagues. Sixty-eight teams from the province of Alberta (n = 995), whose players had two years of bodychecking experience in Pee Wee, and 62 teams from the province of Quebec (n = 976), whose players had no bodychecking experience in Pee Wee, participated. We estimated incidence rate ratios (IRRs) for injury and for concussion. RESULTS: There were 272 injuries (51 concussions) among the Bantam hockey players who had bodychecking experience in Pee Wee and 244 injuries (49 concussions) among those without such experience. The adjusted IRRs for game related injuries and concussion overall between players with bodychecking experience in Pee Wee and those without it were as follows: injury overall 0.85 (95% confidence interval [CI] 0.63 to 1.16); concussion overall 0.84 (95% CI 0.48 to 1.48); and injury resulting in more than seven days of time loss (i.e., time between injury and return to play) 0.67 (95% CI 0.46 to 0.99). The unadjusted IRR for concussion resulting in more than 10 days of time loss was 0.60 (95% CI 0.26 to 1.41). INTERPRETATION: The risk of injury resulting in more than seven days of time loss from play was reduced by 33% among Bantam hockey players in a league where bodychecking was allowed two years earlier in Pee Wee compared with Bantam players introduced to bodychecking for the first time at age 13. In light of the increased risk of concussion and other injury among Pee Wee players in a league where bodychecking is permitted, policy regarding the age at which hockey players are introduced to bodychecking requires further consideration. PMID- 21690222 TI - "Seniors emergency departments" yield health improvements, advocates say. PMID- 21690223 TI - Leaked internal report criticizes government oversight of antimicrobial resistance. PMID- 21690224 TI - Bye, bye blockbusters, hello niche busters. PMID- 21690226 TI - Enteric fever in two vaccinated travellers to Latin America. PMID- 21690227 TI - Executive dysfunction in delayed radiation-induced leukoencephalopathy. PMID- 21690229 TI - What do patients expect from their physicians? Qualitative research on the ethical aspects of patient statements. AB - This study aimed to examine the thoughts and expectations of patients receiving healthcare from their physicians and evaluate the ethical aspects of these thoughts and expectations. To determine the ethical aspects of the thoughts and expectations of patients, an open-ended question was asked on the web page of the Turkish Armed Forces (TAF) Health Care Command, which is accessible to the users of the TAF intranet system (the internet system used within TAF institutions). The participants were asked to express their thoughts in their own words. A total of 804 participants answered the question by providing their input. The statements of the participants were classified separately by two public health specialists. The classification was made in accordance with the basic principles of patient rights, and they were collected under various headings including expectations about respect and care, good communication, informed consent, and fair and non-privileged distribution of healthcare services. The results show that patients tend to consider the physicians they see as solely responsible for all the negative issues that they encounter during their healthcare. This indicates that there is a need for extensive research on the underlying factors involved in the negative thoughts and feelings toward healthcare professionals in both TAF and Turkey in general. PMID- 21690230 TI - When should conscientious objection be accepted? AB - This paper makes two main claims: first, that the need to protect health professionals' moral integrity is what grounds the right to conscientious objection in health care; and second, that for a given claim of conscientious objection to be acceptable to society, a certain set of criteria should be fulfilled. The importance of moral integrity for individuals and society, including its special role in health care, is advocated. Criteria for evaluating the acceptability of claims to conscientious objection are outlined. The precise content of the criteria is dictated by the two main interests that are at stake in the dilemma of conscientious objection: the patient's interests and the health professional's moral integrity. Alternative criteria proposed by other authors are challenged. The bold claim is made that conscientious objection should be recognised by society as acceptable whenever the five main criteria of the proposed set are met. PMID- 21690228 TI - Combinatorial effects of lapatinib and rapamycin in triple-negative breast cancer cells. AB - Triple-negative breast cancers, which lack estrogen receptor, progesterone receptor, and HER2/neu overexpression, account for approximately 15% of breast cancers, but occur more commonly in African Americans. The poor survival outcomes seen with triple-negative breast cancers patients are, in part, due to a lack of therapeutic targets. Epidermal growth factor receptor (EGFR) is overexpressed in 50% of triple-negative breast cancers, but EGFR inhibitors have not been effective in patients with metastatic breast cancers. However, mTOR inhibition has been shown to reverse resistance to EGFR inhibitors. We examined the combination effects of mTOR inhibition with EGFR inhibition in triple-negative breast cancer in vitro and in vivo. The combination of EGFR inhibition by using lapatinib and mTOR inhibition with rapamycin resulted in significantly greater cytotoxicity than the single agents alone and these effects were synergistic in vitro. The combination of rapamycin and lapatinib significantly decreased growth of triple-negative breast cancers in vivo compared with either agent alone. EGFR inhibition abrogated the expression of rapamycin-induced activated Akt in triple negative breast cancer cells in vitro. The combination of EGFR and mTOR inhibition resulted in increased apoptosis in some, but not all, triple-negative cell lines, and these apoptotic effects correlated with a decrease in activated eukaryotic translation initiation factor (eIF4E). These results suggest that mTOR inhibitors could sensitize a subset of triple-negative breast cancers to EGFR inhibitors. Given the paucity of effective targeted agents in triple-negative breast cancers, these results warrant further evaluation. PMID- 21690231 TI - Prospective evaluation of corrected QT intervals and arrhythmias after exposure to epirubicin, cyclophosphamide, and 5-fluorouracil in women with breast cancer. AB - BACKGROUND: Corrected QT (QTc) interval prolongation can induce fatal arrhythmias such as torsade de pointes. PATIENTS AND METHODS: To assess the characteristics of QTc intervals and arrhythmias in women with early breast cancer who received FEC100 adjuvant chemotherapy, electrocardiograms (ECGs) were recorded before and after each chemotherapy. Associations between QTc interval prolongation and single nucleotide polymorphisms (SNPs) of potassium channel genes were also investigated. RESULTS: A total of 131 ECG records were obtained in 34 patients who received 153 cycles of FEC100. QTc intervals could be measured in 127 records. There was a significant trend toward QTc interval prolongation after each treatment, persisting through four cycles of chemotherapy (P < 0.001). Median QTc interval prolongations were 13, 11, 18, and 14 ms in the first through fourth cycles of chemotherapy, respectively. QTc intervals differed significantly between cycles 1 and 4 before treatment as well as after treatment (P < 0.05). A single supraventricular premature contraction was noted in 3 (2.3%) of the 131 cycles in 2 (5.9%) of the 34 patients. There was no significant association between QTc interval prolongation and SNPs of potassium channel genes. CONCLUSION: This prospective study confirmed that FEC100 is associated with significant QTc interval prolongation in women with early breast cancer. PMID- 21690232 TI - Genetic polymorphism of IGF-I predicts recurrence in patients with gastric cancer who have undergone curative gastrectomy. AB - BACKGROUND: To our knowledge, no reports have evaluated the effects of genetic polymorphisms of insulin-like growth factor-I (IGF-I) on clinical outcomes of gastric cancer patients. METHODS: We retrospectively analyzed the impact of IGF-I polymorphisms on recurrence-free survival (RFS) in 430 patients with gastric cancer who underwent curative gastrectomy between 2001 and 2005 in our institution. RESULTS: Among the 430 gastric cancer patients, 345 were pathological stage I or II, while 85 were stage III or IV. The median 5-year RFS rate was 85.3% (95% confidence interval [CI] 81.4-88.5). In a multivariate Cox model (adjusted for age, gender, histology, pathological stage, adjuvant chemotherapy, and history of diabetes), two IGF-I polymorphisms, rs1520220 and rs2195239, were significantly associated with RFS (hazard ratio [HR] 0.60, 95% CI 0.40-0.91; and HR 0.60, 95% CI 0.41-0.89, respectively, in a per-allele model). When stratified by stage (I-II versus III-IV), rs1520220 in particular was associated with RFS in patients with stage III-IV disease, with a P-value for interaction of 0.01. CONCLUSIONS: Our findings indicate that genetic polymorphisms of IGF-I may have a substantial effect on recurrence for gastric cancer patients who have undergone curative gastrectomy. This information may help identify population subgroups that could benefit from IGF-I-targeting agents. PMID- 21690233 TI - Treatment and survival of patients with small-cell lung cancer: small steps forward, but not for patients >80. AB - BACKGROUND: Seventy-five percent of newly diagnosed patients with small-cell lung cancer (SCLC) are aged 60+ and quite a few are treated less aggressively because of fear of toxic effects. We described trends in treatment and survival of unselected SCLC patients. PATIENTS AND METHODS: For the present study, all 13,007 SCLC patients aged 60+ diagnosed in The Netherlands from 1997 to 2007 were included. RESULTS: Among patients with limited disease, the proportion receiving chemoradiation increased from 35% to almost 60% for those aged 60-69, from 28% to 48% in age group 70-74, from 17% to 33% in age group 75-79, but remained <10% for those aged 80+. Among patients with extensive disease, the proportion receiving chemotherapy (CT) decreased from 81% of patients aged 60-64 to 23% of those aged 85+, without substantial changes over time. Survival has only improved for patients <80 years. CONCLUSIONS: CT (+radiotherapy) has improved survival for unselected SCLC patients <80. A better understanding of the impact of frailty on completion of treatment and toxic effects among patients aged 80+ would enable the treating physician to anticipate toxic effects better and to discuss risks and benefits of treatment with the patient. PMID- 21690234 TI - Are cohort data on smokeless tobacco use and pancreatic cancer confounded by alcohol use? PMID- 21690235 TI - Characterization of the fibrinogen binding domain of bacteriophage lysin from Streptococcus mitis. AB - The binding of bacteria to human platelets is a likely central mechanism in the pathogenesis of infective endocarditis. Platelet binding by Streptococcus mitis SF100 is mediated in part by a lysin encoded by the lysogenic bacteriophage SM1. In addition to its role in the phage life cycle, lysin mediates the binding of S. mitis to human platelets via its interaction with fibrinogen on the platelet surface. To better define the region of lysin mediating fibrinogen binding, we tested a series of purified lysin truncation variants for their abilities to bind this protein. These studies revealed that the fibrinogen binding domain of lysin is contained within the region spanned by amino acid residues 102 to 198 (lysin(102-198)). This region has no sequence homology to other known fibrinogen binding proteins. Lysin(102-198) bound fibrinogen comparably to full-length lysin and with the same selectivity for the fibrinogen Aalpha and Bbeta chains. Lysin(102-198) also inhibited the binding in vitro of S. mitis to human fibrinogen and platelets. When assessed by platelet aggregometry, the disruption of the lysin gene in SF100 resulted in a significantly longer time to the onset of aggregation of human platelets than that of the parent strain. The preincubation of platelets with purified lysin(102-198) also delayed the onset of aggregation by SF100. These results indicate that the binding of lysin to fibrinogen is mediated by a specific domain of the phage protein and that this interaction is important for both platelet binding and aggregation by S. mitis. PMID- 21690236 TI - Beta interferon-mediated activation of signal transducer and activator of transcription protein 1 interferes with Rickettsia conorii replication in human endothelial cells. AB - Infection of the endothelial cell lining of blood vessels with Rickettsia conorii, the causative agent of Mediterranean spotted fever, results in endothelial activation. We investigated the effects of R. conorii infection on the status of the Janus kinase (JAK)-signal transducer and activator of transcription protein (STAT) signaling pathway in human microvascular endothelial cells (HMECs), the most relevant host cell type, in light of rickettsial tropism for microvascular endothelium in vivo. R. conorii infection induced phosphorylation of STAT1 on tyrosine 701 and serine 727 at 24, 48, and 72 h postinfection in HMECs. Employing transcription profile analysis and neutralizing antibodies, we further determined that beta interferon (IFN-beta) production and secretion are critical for STAT1 activation. Secreted IFN-beta further amplified its own expression via a positive-feedback mechanism, while expression of transcription factors interferon regulatory factor 7 (IRF7) and IRF9, implicated in the IFN-beta-STAT1 feedback loop, was also induced. Metabolic activity of rickettsiae was essential for the IFN-beta-mediated response(s) because tetracycline treatment inhibited R. conorii replication, IFN-beta expression, and STAT1 phosphorylation. Inclusion of IFN-beta-neutralizing antibody during infection resulted in significantly enhanced R. conorii replication, whereas addition of exogenous IFN-beta had the opposite inhibitory effect. Finally, small interfering RNA-mediated knockdown further confirmed a protective role for STAT1 against intracellular R. conorii replication. In concert, these findings implicate an important role for IFN-beta-mediated STAT1 activation in innate immune responses of vascular endothelium to R. conorii infection. PMID- 21690237 TI - Proteomics and pathway analyses of the milk fat globule in sheep naturally infected by Mycoplasma agalactiae provide indications of the in vivo response of the mammary epithelium to bacterial infection. AB - Milk fat globules (MFGs) are vesicles released in milk as fat droplets surrounded by the endoplasmic reticulum and apical cell membranes. During formation and apocrine secretion by lactocytes, various amounts of cytoplasmic crescents remain trapped within the released vesicle, making MFGs a natural sampling mechanism of the lactating cell contents. With the aim of investigating the events occurring in the mammary epithelium during bacterial infection, the MFG proteome was characterized by two-dimensional difference gel electrophoresis (2-D DIGE), SDS PAGE followed by shotgun liquid chromatography-tandem mass spectrometry (GeLC MS/MS), label-free quantification by the normalized spectral abundance factor (NSAF) approach, Western blotting, and pathway analysis, using sheep naturally infected by Mycoplasma agalactiae. A number of protein classes were found to increase in MFGs upon infection, including proteins involved in inflammation and host defense, cortical cytoskeleton proteins, heat shock proteins, and proteins related to oxidative stress. Conversely, a strikingly lower abundance was observed for proteins devoted to MFG metabolism and secretion. To our knowledge, this is the first report describing proteomic changes occurring in MFGs during sheep infectious mastitis. The results presented here offer new insights into the in vivo response of mammary epithelial cells to bacterial infection and open the way to the discovery of protein biomarkers for monitoring clinical and subclinical mastitis. PMID- 21690238 TI - Immune activation and suppression by group B streptococcus in a murine model of urinary tract infection. AB - Group B streptococcus (GBS) is a common commensal of the gastrointestinal and vaginal mucosa and a leading cause of serious infections in newborns, the elderly, and immunocompromised populations. GBS also causes infections of the urinary tract. However, little is known about host responses to GBS urinary tract infection (UTI) or GBS virulence factors that participate in UTI. Here we describe a novel murine model of GBS UTI that may explain some features of GBS urinary tract association in the human host. We observed high titers and heightened histological signs of inflammation and leukocyte recruitment in the GBS-infected kidney. However, extensive inflammation and leukocyte recruitment were not observed in the bladder, suggesting that GBS may suppress bladder inflammation during cystitis. Acute GBS infection induced the localized expression of proinflammatory cytokines interleukin-1alpha (IL-1alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and IL-9, as well as IL-10, more commonly considered an anti-inflammatory cytokine. Using isogenic GBS strains with different capsule structures, we show that capsular sialic acid residues contribute to GBS urinary tract pathogenesis, while high levels of sialic acid O-acetylation attenuate GBS pathogenesis in the setting of UTI, particularly in direct competition experiments. In vitro studies demonstrated that GBS sialic acids participate in the suppression of murine polymorphonuclear leukocyte (PMN) bactericidal activities, in addition to reducing levels of IL 1alpha, tumor necrosis factor alpha, IL-1beta, MIP-1alpha, and KC produced by PMNs. These studies define several basic molecular and cellular events characterizing GBS UTI in an animal model, showing that GBS participates simultaneously in the activation and suppression of host immune responses in the urinary tract. PMID- 21690240 TI - Burkholderia cenocepacia ShvR-regulated genes that influence colony morphology, biofilm formation, and virulence. AB - Burkholderia cenocepacia is an opportunistic pathogen that primarily infects cystic fibrosis (CF) patients. Previously, we reported that ShvR, a LysR regulator, influences colony morphology, virulence, and biofilm formation and regulates the expression of an adjacent 24-kb genomic region encoding 24 genes. In this study, we report the functional characterization of selected genes in this region. A Tn5 mutant with shiny colony morphology was identified with a polar mutation in BCAS0208, predicted to encode an acyl-coenzyme A dehydrogenase. Mutagenesis of BCAS0208 and complementation analyses revealed that BCAS0208 is required for rough colony morphology, biofilm formation, and virulence on alfalfa seedlings. It was not possible to complement with BCAS0208 containing a mutation in the catalytic site. BCAS0201, encoding a putative flavin adenine dinucleotide (FAD)-dependent oxidoreductase, and BCAS0207, encoding a putative citrate synthase, do not influence colony morphology but are required for optimum levels of biofilm formation and virulence. Both BCAS0208 and BCAS0201 contribute to pellicle formation, although individual mutations in each of these genes had no appreciable effect on pellicle formation. A mutant with a polar insertion in BCAS0208 was significantly less virulent in a rat model of chronic lung infection as well as in the alfalfa model. Genes in this region were shown to influence utilization of branched-chain fatty acids, tricarboxylic acid cycle substrates, l arabinose, and branched-chain amino acids. Together, our data show that the ShvR regulated genes BCAS0208 to BCAS0201 are required for the rough colony morphotype, biofilm and pellicle formation, and virulence in B. cenocepacia. PMID- 21690239 TI - IglG and IglI of the Francisella pathogenicity island are important virulence determinants of Francisella tularensis LVS. AB - The Gram-negative bacterium Francisella tularensis is the causative agent of tularemia, a disease intimately associated with the multiplication of the bacterium within host macrophages. This in turn requires the expression of Francisella pathogenicity island (FPI) genes, believed to encode a type VI secretion system. While the exact functions of many of the components have yet to be revealed, some have been found to contribute to the ability of Francisella to cause systemic infection in mice as well as to prevent phagolysosomal fusion and facilitate escape into the host cytosol. Upon reaching this compartment, the bacterium rapidly multiplies, inhibits activation of the inflammasome, and ultimately causes apoptosis of the host cell. In this study, we analyzed the contribution of the FPI-encoded proteins IglG, IglI, and PdpE to the aforementioned processes in F. tularensis LVS. The DeltapdpE mutant behaved similarly to the parental strain in all investigated assays. In contrast, DeltaiglG and DeltaiglI mutants, although they were efficiently replicating in J774A.1 cells, both exhibited delayed phagosomal escape, conferred a delayed activation of the inflammasome, and exhibited reduced cytopathogenicity as well as marked attenuation in the mouse model. Thus, IglG and IglI play key roles for modulation of the intracellular host response and also for the virulence of F. tularensis. PMID- 21690241 TI - The poly-gamma-D-glutamic acid capsule of Bacillus anthracis enhances lethal toxin activity. AB - The poly-gamma-D-glutamic acid (PGA) capsule is one of the major virulence factors of Bacillus anthracis, which causes a highly lethal infectious disease. The PGA capsule disguises B. anthracis from immune surveillance and allows its unimpeded growth in the host. The PGA capsule recently was reported to be associated with lethal toxin (LT) in the blood of experimentally infected animals (M. H. Cho, et al., Infect. Immun. 78:387-392, 2010). The effect of PGA, either alone or in combination with LT, on macrophages, which play an important role in the progression of anthrax disease, has not been thoroughly investigated. In this study, we investigated the effect of PGA on LT cytotoxicity using the mouse macrophage cell line J774A.1. PGA produced a concentration-dependent enhancement of the cytotoxicity of LT on J774A.1 cells through an enhancement in the binding and accumulation of protective antigen to its receptors. The increase of LT activity was confirmed using Western blot analysis, which showed that the combination of PGA and LT produced a greater degree of degradation of mitogen activated protein kinase kinases and an increased level of the activation of the proform of caspase-1 to its processed form compared to the effects of LT alone. In addition, mice that received a tail vein injection of both PGA and LT had a significantly increased rate of death compared to that of mice injected with LT alone. PGA had no effect when added to cultures or administered to mice in the absence of LT. These results emphasize the importance of PGA in the pathogenesis of anthrax infection. PMID- 21690242 TI - Evaluation of the safety and immunogenicity in rhesus monkeys of a recombinant malaria vaccine for Plasmodium vivax with a synthetic Toll-like receptor 4 agonist formulated in an emulsion. AB - Plasmodium vivax is the major cause of malaria outside sub-Saharan Africa and inflicts debilitating morbidity and consequent economic impacts in developing countries. In order to produce a P. vivax vaccine for global use, we have previously reported the development of a novel chimeric recombinant protein, VMP001, based on the circumsporozoite protein (CSP) of P. vivax. Very few adjuvant formulations are currently available for human use. Our interest is to evaluate second-generation vaccine formulations to identify novel combinations of adjuvants capable of inducing strong, long-lasting immune responses. In this study rhesus monkeys were immunized intramuscularly three times with VMP001 in combination with a stable emulsion (SE) or a synthetic Toll-like receptor 4 (TLR4) agonist (glucopyranosyl lipid A [GLA]) in SE (GLA-SE). Sera and peripheral blood mononuclear cells (PBMCs) were tested for the presence of antigen-specific humoral and cellular responses, respectively. All groups of monkeys generated high titers of anti-P. vivax IgG antibodies, as detected by enzyme-linked immunosorbent assays (ELISAs) and immunofluorescence assays. In addition, all groups generated a cellular immune response characterized by antigen-specific CD4(+) T cells secreting predominantly interleukin-2 (IL-2) and lesser amounts of tumor necrosis factor (TNF). We conclude that the combination of VMP001 and GLA SE is safe and immunogenic in monkeys and may serve as a potential second generation vaccine candidate against P. vivax malaria. PMID- 21690243 TI - Health inequalities and welfare state regimes: theoretical insights on a public health 'puzzle'. AB - Welfare states are important determinants of health. Comparative social epidemiology has almost invariably concluded that population health is enhanced by the relatively generous and universal welfare provision of the Scandinavian countries. However, most international studies of socioeconomic inequalities in health have thrown up something of a public health 'puzzle' as the Scandinavian welfare states do not, as would generally be expected, have the smallest health inequalities. This essay outlines and interrogates this puzzle by drawing upon existing theories of health inequalities--artefact, selection, cultural- behavioural, materialist, psychosocial and life course--to generate some theoretical insights. It discusses the limits of these theories in respect to cross-national research; it questions the focus and normative paradigm underpinning contemporary comparative health inequalities research; and it considers the future of comparative social epidemiology. PMID- 21690244 TI - HER2 testing in the UK: recommendations for breast and gastric in-situ hybridisation methods. AB - These guidelines supplement existing guidelines on HER2 testing by immunohistochemistry and in-situ hybridisation(ISH) methods in the UK. They provide a specific focus on aspects of guidance relevant to HER2 ISH testing methods, both fluorescent and chromogenic. They are formulated to give advice on methodology, interpretation and quality control for ISH-based testing of HER2 status in common tumour types, including both breast and gastric tumours. The aim is to ensure that all ISH-based testing is accurate, reliable and timely. PMID- 21690245 TI - TET2 promoter methylation in low-grade diffuse gliomas lacking IDH1/2 mutations. AB - BACKGROUND: Miscoding mutations of the TET2 gene, which encodes the alpha ketoglutarate-dependent enzyme that catalyses the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, thus producing DNA demethylation, have been detected in 10-25% of acute myeloid leukaemias lacking IDH1/2 mutations. Most low-grade diffuse gliomas carry IDH1/2 mutations (>85%), but molecular mechanisms of pathogenesis in those lacking IDH1/2 mutations remain to be elucidated. METHODS: Miscoding mutations and promoter methylation of the TET2 gene were screened for in 29 low-grade diffuse gliomas lacking IDH1/2 mutations. RESULTS: Single-strand conformational polymorphism followed by direct sequencing showed the absence of miscoding mutations in TET2. Methylation-specific PCR revealed methylation of the TET2 promoter in 5 of 35 cases (14%). In contrast, none of 38 low-grade diffuse gliomas with IDH1/2 mutations had TET2 promoter methylation (p=0.0216). CONCLUSION: Results suggest that TET2 promoter methylation, but not TET2 mutation, may be an alternative mechanism of pathogenesis in a small fraction of low-grade diffuse gliomas lacking IDH1/2 mutations. PMID- 21690246 TI - Linkage and association analysis of hyperthyrotropinaemia in an Alpine population reveal two novel loci on chromosomes 3q28-29 and 6q26-27. AB - BACKGROUND: Thyroid hormones have important roles in growth, development and control of metabolism, and their dysregulation can lead to disease. OBJECTIVES: To identify genes contributing to hyperthyrotropinaemia. DESIGN, SETTING, PARTICIPANTS: Linkage and association analyses using 1258 individuals from three Alpine villages. OUTCOME MEASURES: The study applied two different upper limits of the reference range (URR) for serum thyroid stimulating hormone (TSH) values (TSH >=4.6 mU/l and TSH >3.0 mU/l), along with normal or low fT4 (free thyroxine) values or thyroid medical treatment to define two groups of individuals for analysis: one hyperthyrotropinaemic or high-TSH (H-TSH) (TSH >=4.6 mU/l) group; and a larger group (TSH >3.0 mU/l) called hyperthyrotropinaemic and upper reference range TSH (H+URR-TSH). RESULTS: Non-parametric genome-wide linkage analysis was performed on pedigrees generated from the two groups. Linkage analysis in the H+URR-TSH group revealed a significant peak on chromosome 3q28 q29 (LOD 3.34) and a suggestive linkage peak on chromosome 6q26-27 (LOD 2.66). Analysis in the smaller hyperthyrotropinaemic (H-TSH) group supported linkage to chromosome 6q26-27. Single SNP and gene based SNP association analyses under the linkage peaks identified the PDE10A and DACT2 genes as candidates at the chromosome 6 locus. CONCLUSIONS: PDE10A or DACT2 were identified as candidate genes contributing to hyperthyrotropinaemia (and possibly hypothyroidism) in this sample. Studies in additional populations support association of variants at this locus with TSH values, especially in the PDE10A gene. Genetic linkage in families with hyperthyrotropinaemia suggests the presence of functional variants that contribute to pathological disruption of the hypothalamus-pituitary-thyroid axis. PMID- 21690247 TI - Hospital survey on patient safety culture: psychometric analysis on a Scottish sample. AB - OBJECTIVE: To investigate the psychometric properties of the Hospital Survey on Patient Safety Culture on a Scottish NHS data set. METHODS: The data were collected from 1969 clinical staff (estimated 22% response rate) from one acute hospital from each of seven Scottish Health boards. Using a split-half validation technique, the data were randomly split; an exploratory factor analysis was conducted on the calibration data set, and confirmatory factor analyses were conducted on the validation data set to investigate and check the original US model fit in a Scottish sample. RESULTS: Following the split-half validation technique, exploratory factor analysis results showed a 10-factor optimal measurement model. The confirmatory factor analyses were then performed to compare the model fit of two competing models (10-factor alternative model vs 12 factor original model). An S-B scaled chi(2) square difference test demonstrated that the original 12-factor model performed significantly better in a Scottish sample. Furthermore, reliability analyses of each component yielded satisfactory results. The mean scores on the climate dimensions in the Scottish sample were comparable with those found in other European countries. CONCLUSIONS: This study provided evidence that the original 12-factor structure of the Hospital Survey on Patient Safety Culture scale has been replicated in this Scottish sample. Therefore, no modifications are required to the original 12-factor model, which is suggested for use, since it would allow researchers the possibility of cross national comparisons. PMID- 21690248 TI - Errors in the administration of intravenous medications in hospital and the role of correct procedures and nurse experience. AB - BACKGROUND: Intravenous medication administrations have a high incidence of error but there is limited evidence of associated factors or error severity. OBJECTIVE: To measure the frequency, type and severity of intravenous administration errors in hospitals and the associations between errors, procedural failures and nurse experience. METHODS: Prospective observational study of 107 nurses preparing and administering 568 intravenous medications on six wards across two teaching hospitals. Procedural failures (eg, checking patient identification) and clinical intravenous errors (eg, wrong intravenous administration rate) were identified and categorised by severity. RESULTS: Of 568 intravenous administrations, 69.7% (n = 396; 95% CI 65.9 to 73.5) had at least one clinical error and 25.5% (95% CI 21.2 to 29.8) of these were serious. Four error types (wrong intravenous rate, mixture, volume, and drug incompatibility) accounted for 91.7% of errors. Wrong rate was the most frequent and accounted for 95 of 101 serious errors. Error rates and severity decreased with clinical experience. Each year of experience, up to 6 years, reduced the risk of error by 10.9% and serious error by 18.5%. Administration by bolus was associated with a 312% increased risk of error. Patient identification was only checked in 47.9% of administrations but was associated with a 56% reduction in intravenous error risk. CONCLUSIONS: Intravenous administrations have a higher risk and severity of error than other medication administrations. A significant proportion of errors suggest skill and knowledge deficiencies, with errors and severity reducing as clinical experience increases. A proportion of errors are also associated with routine violations which are likely to be learnt workplace behaviours. Both areas suggest specific targets for intervention. PMID- 21690249 TI - Increasing medication error reporting rates while reducing harm through simultaneous cultural and system-level interventions in an intensive care unit. AB - OBJECTIVE: This study analyses patterns in reporting rates of medication errors, rates of medication errors with harm, and responses to the Safety Attitudes Questionnaire (SAQ), all in the context of four cultural and three system-level interventions for medication safety in an intensive care unit. METHODS: Over a period of 2.5 years (May 2007 to November 2009), seven overlapping interventions to improve medication safety and reporting were implemented: a poster tracking 'days since last medication error resulting in harm', a continuous slideshow showing performance metrics in the staff lounge, multiple didactic curricula, unit-wide emails summarising medication errors, computerised physician order entry, introduction of unit-based pharmacy technicians for medication delivery, and patient safety report form streamlining. The reporting rate of medication errors and errors with harm were analysed over time using statistical process control. SAQ responses were collected annually. RESULTS: Subsequent to the interventions, the reporting rate of medication errors increased 25%, from an average of 3.16 to 3.95 per 10,000 doses dispensed (p<0.09), while the rate of medication errors resulting in harm decreased 71%, from an average of 0.56 to 0.16 per 10,000 doses dispensed (p<0.01). The SAQ showed improvement in all 13 survey items related to medication safety, five of which were significant (p<0.05). CONCLUSION: Actively developing a transparent and positive safety culture at the unit level can improve medication safety. System-level mechanisms to promote medication safety are likely important factors that enable safety culture to translate into better outcomes, but may be independently ineffective in the face of poor safety culture. PMID- 21690250 TI - Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma gondii. AB - Apicomplexa are important pathogens that include the causative agents of malaria, toxoplasmosis, and cryptosporidiosis. Apicomplexan parasites contain a relict chloroplast, the apicoplast. The apicoplast is indispensable and an attractive drug target. The apicoplast is home to a 1-deoxy-D-xylulose-5-phosphate (DOXP) pathway for the synthesis of isoprenoid precursors. This pathway is believed to be the most conserved function of the apicoplast, and fosmidomycin, a specific inhibitor of the pathway, is an effective antimalarial. Surprisingly, fosmidomycin has no effect on most other apicomplexans. Using Toxoplasma gondii, we establish that the pathway is essential in parasites that are highly fosmidomycin resistant. We define the molecular basis of resistance and susceptibility, experimentally testing various host and parasite contributions in T. gondii and Plasmodium. We demonstrate that in T. gondii the parasite plasma membrane is a critical barrier to drug uptake. In strong support of this hypothesis, we engineer de novo drug-sensitive T. gondii parasites by heterologous expression of a bacterial transporter protein. Mice infected with these transgenic parasites can now be cured from a lethal challenge with fosmidomycin. We propose that the varied extent of metabolite exchange between host and parasite is a crucial determinator of drug susceptibility and a predictor of future resistance. PMID- 21690251 TI - Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope. AB - Type 1 diabetes (T1D) results from the destruction of insulin-secreting pancreatic beta cells by autoreactive T cells. Insulin is an essential target of the autoimmune attack. Insulin epitopes recognized by diabetogenic T cell clones bind poorly to the class II I-A(g7) molecules of nonobese diabetic (NOD) mice, which results in weak agonistic activity of the peptide MHC complex. Here, we describe a strongly agonistic insulin mimetope that effectively converts naive T cells into Foxp3(+) regulatory T cells in vivo, thereby completely preventing T1D in NOD mice. In contrast, natural insulin epitopes are ineffective. Subimmunogenic vaccination with strongly agonistic insulin mimetopes might represent a novel strategy to prevent T1D in humans at risk for the disease. PMID- 21690252 TI - Sustained antibody responses depend on CD28 function in bone marrow-resident plasma cells. AB - Sustained long-term antibody levels are the cornerstone of protective immunity, yet it remains unclear how they are durably maintained. A predominant theory implicates antigen-independent antibody production by a subset of long-lived plasma cells (LLPCs) that survive within bone marrow (BM). Central tenets of this model--that BM LLPCs constitute a subset defined by intrinsic biology distinct from PCs in other tissues and contribute to long-term antibody titers--have not been definitively demonstrated. We now report that long-term humoral immunity depends on the PC-intrinsic function of CD28, which selectively supports the survival of BM LLPC but not splenic short-lived PC (SLPC). LLPC and SLPC both express CD28, but CD28-driven enhanced survival occurred only in the LLPC. In vivo, even in the presence of sufficient T cell help, loss of CD28 or its ligands CD80 and CD86 caused significant loss of the LLPC population, reduction of LLPC half-life from 426 to 63 d, and inability to maintain long-term antibody titers, but there was no effect on SLPC populations. These findings establish the existence of the distinct BM LLPC subset necessary to sustain antibody titers and uncover a central role for CD28 function in the longevity of PCs and humoral immunity. PMID- 21690254 TI - Spontaneous haemopneumothorax: current management. AB - Spontaneous haemopneumothorax (SHP) can be life threatening and is an important cause for unexplained signs of significant hypovolaemia. There is still some debate relating to patient selection and timing of surgery, particularly in those who become stable following chest tube insertion without further blood loss. Review of the literature over the past decade in the management of SHP are presented and discussed. Surgery should be considered early in the management of SHP to reduce morbidity associated with continued haemorrhage and inadequate drainage. Lower postoperative complications and shorter hospital stay following video assisted thoracic surgery compared with thoracotomy have led to its increased acceptance as an alternative approach for SHP patients who are haemodynamically stable. PMID- 21690253 TI - Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. AB - Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumors. 60% of these tumors have IL-6 signal transducer (IL6ST; gp130) mutations that activate interleukin 6 (IL-6) signaling. Here, we report that 12% of IHCA subsets lacking IL6ST mutations harbor somatic signal transducer and activator of transcription 3 (STAT3) mutations (6/49). Most of these mutations are amino acid substitutions in the SH2 domain that directs STAT3 dimerization. In contrast to wild-type STAT3, IHCA STAT3 mutants constitutively activated the IL-6 signaling pathway independent of ligand in hepatocellular cells. Indeed, the IHCA STAT3 Y640 mutant homodimerized independent of IL-6 and was hypersensitive to IL-6 stimulation. This was associated with phosphorylation of tyrosine 705, a residue required for IL-6-induced STAT3 activation. Silencing or inhibiting the tyrosine kinases JAK1 or Src, which phosphorylate STAT3, impaired constitutive activity of IHCA STAT3 mutants in hepatocellular cells. Thus, we identified for the first time somatic STAT3 mutations in human tumors, revealing a new mechanism of recurrent STAT3 activation and underscoring the role of the IL-6-STAT3 pathway in benign hepatocellular tumorigenesis. PMID- 21690255 TI - Are medical graduates ready to face the challenges of Foundation training? AB - PURPOSE OF STUDY Previous research demonstrates that graduating medical students often feel unprepared for practice and that their perceptions of preparedness correlate only partially with those of their supervising consultants. This study explores the components of preparedness for practice from the perspectives of both newly qualified doctors and their educational supervisors. STUDY DESIGN A questionnaire study was undertaken at the University of Edinburgh, involving feedback on preparedness for practice over three consecutive years from 2007 to 2009, against 13 major programme outcomes, from graduates and their educational supervisors. In addition, free text responses were sought and thematically analysed. RESULTS Graduates consistently felt well prepared in consultation and communication skills but less prepared in acute care and prescribing. Educational supervisors consistently felt that graduates were well prepared in information technology and communication skills but less prepared in acute care and practical procedures. Free text analysis identified four main themes: knowledge; skills; personal attributes; and familiarity with the ward environment. CONCLUSIONS Preparedness for practice data can be enriched by repeated collection over several years, comparison of different perspectives, and incorporation of free text responses. The non-technical skills of decision-making, initiative, prioritisation, and coping with stress are important components of preparing new doctors for practice. Education for Foundation trainees should focus on the areas in which graduates are perceived to be less prepared, such as acute care, prescribing, and procedural skills. PMID- 21690256 TI - A practical guide to the differential diagnosis of tremor. AB - Tremor is, by definition, a rhythmic oscillation of a body part. It is the most prevalent movement disorder in clinical medicine, so doctors working in many specialities and in general practice can expect to encounter it. Most tremors can be classified on the basis of four observable clinical characteristics: anatomical pattern; the relative prominence of the tremor at rest, on maintaining a posture, and with action; tremor frequency; and tremor amplitude. A resting tremor suggests Parkinson's disease, and the diagnosis then depends on a judgement about whether the patient has other signs of parkinsonism. The most common causes of postural tremor are physiological tremor, essential tremor and drug-induced tremor. The differential diagnosis may also include dystonic tremor and psychogenic tremor, while metabolic tremor caused by thyrotoxicosis should be considered in any recent-onset postural tremor. Wilson's disease and fragile X associated tremor/ataxia syndrome are rarer conditions that may present with tremor and are very important to identify. There is a small but genuine diagnostic grey zone between Parkinson's disease and more benign tremor disorders such as essential tremor and dystonic tremor, in which resting and postural tremor coexist with mild or equivocal non-tremor parkinsonian signs. The authors review clinical features and investigational techniques that may help to discriminate this group of hard-to-classify tremors. PMID- 21690257 TI - Prognostic associations of clinical and histopathological features in renal amyloidosis. AB - AIM: This retrospective study was conducted to assess the relationship between renal functional parameters and histolopathological findings in patients with renal amyloidosis. METHODS: A total of 40 patients with biopsy-proven renal amyloidosis, which was diagnosed at the Department of Pathology, Hanyang University Hospital, between 1986 and 2010, were investigated. Renal biopsy specimens were evaluated in various histochemical and immunohistochemical stains using light, immunofluorescence and electron microscopes, and renal function was determined by estimated glomerular filtration rate (eGFR) (ml/min/1.73 m(2)) using the method proposed by the Modification of Diet in Renal Disease study. Glomerular amyloid deposits were classified into four groups: none, mild, segmental and diffuse types. The vascular, tubular and interstitial deposits were subdivided into the negative and positive groups. RESULTS: In simple regression analysis, 24-hour protein excretion, serum blood urea nitrogen and eGFR were found to significantly correlate with the increased extent of glomerular amyloid deposit. In multiple regression analysis, a decrease in eGFR was significantly associated with an increase in glomerular amyloid deposits (p=0.024), but there was no significant correlation with an increase in 24-hour protein excretion and blood urea nitrogen (p=0.119 and 0.184, respectively). CONCLUSION: The results of this study demonstrate that the increased extent of glomerular amyloid deposits may be associated with the decline of GFR in patients with renal amyloidosis. PMID- 21690258 TI - Unconscious priming instructions modulate activity in default and executive networks of the human brain. AB - During task executions, brain activity increases in executive networks (ENs) and decreases in default-mode networks (DMNs). Here, we examined whether these large scale network dynamics can be influenced by unconscious cognitive information processing. Volunteers saw instructions (cues) to respond either ipsilaterally or contralaterally to a subsequent lateralized target. Unbeknownst to them, each cue was preceded by a masked stimulus (prime), which could be identical (congruent), or opposite (incongruent) to the cue, or neutral (not an instruction). Behaviorally, incongruent primes interfered with performance, even though they were not consciously perceived. With functional magnetic resonance imaging, we individuated the anticorrelated ENs and DMNs involved during task execution. With effective connectivity analyses, we found that DMNs caused activity in ENs throughout the task. Unconscious interference during incongruent trials was associated with a specific activity increase in ENs and an activity drop in DMNs. Intersubject efficiency in performance during incongruent trials was correlated with functional connectivity between specific ENs and DMNs. These results indicate that unconscious instructions can prime activity in ENs and DMNs and suggest that the DMNs play a key role in unconscious monitoring of the environment in the service of efficient resource allocation for task execution. PMID- 21690260 TI - Object presence modulates activity within the somatosensory component of the action observation network. AB - In the present study, we used functional magnetic resonance imaging to investigate the influence that the presence of an object, intended as the target for an action, might have on the neural circuit underlying the observation of the movement of others (action observation network [AON]). This system entails a simulation process of the observed movement occurring via the recruitment of the motor and somatosensory cortices involved in the execution of such movement. Here, participants were requested to observe grasping actions ending behind a partition knowing in advance whether a target-object would be present (i.e., object-directed action) or absent (i.e., non object-directed action). These "action" conditions were compared with "control" conditions in which a stationary hand was presented either alone or together with the target-object hidden behind the partition. Activation within most regions of the AON was similar for observing partially occluded object-related and non object-related actions. However, within one of the regions belonging to the AON, namely in the somatosensory cortices, blood oxygen level-dependent activity was modulated by the presence of a target-object. We interpreted such modulation as demonstration of the differential involvement of the somatosensory component of the AON for the coding of these 2 types of actions. PMID- 21690259 TI - The putative visual word form area is functionally connected to the dorsal attention network. AB - The putative visual word form area (pVWFA) is the most consistently activated region in single word reading studies (i.e., Vigneau et al. 2006), yet its function remains a matter of debate. The pVWFA may be predominantly used in reading or it could be a more general visual processor used in reading but also in other visual tasks. Here, resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) is used to characterize the functional relationships of the pVWFA to help adjudicate between these possibilities. rs-fcMRI defines relationships based on correlations in slow fluctuations of blood oxygen level dependent activity occurring at rest. In this study, rs-fcMRI correlations show little relationship between the pVWFA and reading-related regions but a strong relationship between the pVWFA and dorsal attention regions thought to be related to spatial and feature attention. The rs-fcMRI correlations between the pVWFA and regions of the dorsal attention network increase with age and reading skill, while the correlations between the pVWFA and reading-related regions do not. These results argue the pVWFA is not used predominantly in reading but is a more general visual processor used in other visual tasks, as well as reading. PMID- 21690261 TI - Rac1-dependent cell cycle exit of MGE precursors and GABAergic interneuron migration to the cortex. AB - Cortical gamma-aminobutyric acid (GABA)ergic interneurons are characterized by extraordinary neurochemical and functional diversity. Although recent studies have uncovered some of the molecular components underlying interneuron development, including the cellular and molecular mechanisms guiding their migration to the cortex, the intracellular components involved are still unknown. Rac1, a member of the Rac subfamily of Rho-GTPases, has been implicated in various cellular processes such as cell cycle dynamics, axonogenesis, and migration. In this study, we have addressed the specific role of Rac1 in interneuron progenitors originating in the medial ganglionic eminence, via Cre/loxP technology. We show that ablation of Rac1 from Nkx2.1-positive progenitors, results in a migratory impairment. As a consequence, only half of GABAergic interneurons are found in the postnatal cortex. The rest remain aggregated in the ventral telencephalon and show morphological defects in their growing processes in vitro. Ablation of Rac1 from postmitotic progenitors does not result in similar defects, thus underlying a novel cell autonomous and stage specific requirement for Rac1 activity, within proliferating progenitors of cortical interneurons. Rac1 is necessary for their transition from G1 to S phase, at least in part by regulating cyclin D levels and retinoblastoma protein phosphorylation. PMID- 21690262 TI - fMRI repetition suppression: neuronal adaptation or stimulus expectation? AB - Measurements of repetition suppression with functional magnetic resonance imaging (fMRI adaptation) have been used widely to probe neuronal population response properties in human cerebral cortex. fMRI adaptation techniques assume that fMRI repetition suppression reflects neuronal adaptation, an assumption that has been challenged on the basis of evidence that repetition-related response changes may reflect unrelated factors, such as attention and stimulus expectation. Specifically, Summerfield et al. (Summerfield C, Trittschuh EH, Monti JM, Mesulam MM, Egner T. 2008. Neural repetition suppression reflects fulfilled perceptual expectations. Nat Neurosci. 11:1004-1006) reported that the relative frequency of stimulus repetitions and non-repetitions influenced the magnitude of repetition suppression in the fusiform face area, suggesting that stimulus expectation accounted for most of the effect of repetition. We confirm that stimulus expectation can significantly influence fMRI repetition suppression throughout visual cortex and show that it occurs with long as well as short adaptation durations. However, the effect was attention dependent: When attention was diverted away from the stimuli, the effects of stimulus expectation completely disappeared. Nonetheless, robust and significant repetition suppression was still evident. These results suggest that fMRI repetition suppression reflects a combination of neuronal adaptation and attention-dependent expectation effects that can be experimentally dissociated. This implies that with an appropriate experimental design, fMRI adaptation can provide valid measures of neuronal adaptation and hence response specificity. PMID- 21690263 TI - Glial D-serine gates NMDA receptors at excitatory synapses in prefrontal cortex. AB - N-methyl-D-aspartate receptors (NMDARs) subserve numerous neurophysiological and neuropathological processes in the cerebral cortex. Their activation requires the binding of glutamate and also of a coagonist. Whereas glycine and D-serine (D ser) are candidates for such a role at central synapses, the nature of the coagonist in cerebral cortex remains unknown. We first show that the glycine binding site of NMDARs is not saturated in acute slices preparations of medial prefrontal cortex (mPFC). Using enzymes that selectively degrade either D-ser or glycine, we demonstrate that under the present conditions, D-ser is the principle endogenous coagonist of synaptic NMDARs at mature excitatory synapses in layers V/VI of mPFC where it is essential for long-term potentiation (LTP) induction. Furthermore, blocking the activity of glia with the metabolic inhibitor, fluoroacetate, impairs NMDAR-mediated synaptic transmission and prevents LTP induction by reducing the extracellular levels of D-serine. Such deficits can be restored by exogenous D-ser, indicating that the D-amino acid mainly originates from glia in the mPFC, as further confirmed by double-immunostaining studies for D-ser and anti-glial fibrillary acidic protein. Our findings suggest that D-ser modulates neuronal networks in the cerebral cortex by gating the activity of NMDARs and that altering its levels is relevant to the induction and potentially treatment of psychiatric and neurological disorders. PMID- 21690264 TI - Oral absorption of clarithromycin is nearly abolished by chronic comedication of rifampicin in foals. AB - The delivery of clarithromycin (CRL) to its site of action in bronchial/alveolar epithelial cells (EC), bronchial epithelial lining fluid (ELF), and bronchoalveolar lavage cells (BALC) may be influenced by CYP3A4 and the drug transporters, ATP-binding cassette (ABC) B1 and ABCC2 and organic anion transporting polypeptides (OATPs), which can be modulated and/or up-regulated via the nuclear pregnane X receptor (PXR) by rifampicin (RIF). Therefore, we evaluated the disposition and pulmonary distribution of CLR (7.5 mg/kg b.i.d., 21 days) and expression of ABCB1, ABCC2, OATP1A2, and OATP2B1 in EC and BALC before and after comedication of RIF (10 mg/kg b.i.d., 11 days) in nine healthy foals (41-61 days, 115-159 kg) in which the genetic homology of drug transporters is close to that of their human analogs. After RIF comedication, relative bioavailability of CLR decreased by more than 90%. Concentrations in plasma (29.8 +/- 26.3 versus 462 +/- 368 ng/ml), ELF (0.69 +/- 0.66 versus 9.49 +/- 6.12 MUg/ml), and BALC (10.2 +/- 10.2 MUg/ml 264 +/- 375 MUg/ml; all P < 0.05) were lowered drastically, whereas levels of the metabolite 14-hydroxyclarithromycin were not elevated despite higher 4beta-hydroxycholesterol/cholesterol plasma concentration ratio, a surrogate for CYP3A4 induction. In the presence of CLR, ABCC2 and PXR mRNA contents were significantly and coordinately (r(2) = 0.664, P < 0.001) reduced in BALC after RIF. In EC, mRNA expression of OATP1A2 increased but that of OATP2B1 decreased (both P < 0.05). RIF interrupts oral absorption and decreases CRL plasma levels below the minimal inhibitory concentration for eradication of Rhodococcus equi. Evidence that RIF influences the cellular uptake of CLR in bronchial cells and the PXR expression in BALC in the presence of high CLR concentrations exists. PMID- 21690265 TI - Preclinical species and human disposition of PF-04971729, a selective inhibitor of the sodium-dependent glucose cotransporter 2 and clinical candidate for the treatment of type 2 diabetes mellitus. AB - (1S,2S,3S,4R,5S)-5-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-1-hydroxymethyl-6,8 dioxabicyclo[3.2.1]octane-2,3,4-triol (PF-04971729), a potent and selective inhibitor of the sodium-dependent glucose cotransporter 2, is currently in phase 2 trials for the treatment of diabetes mellitus. This article describes the preclinical species and in vitro human disposition characteristics of PF-04971729 that were used in experiments performed to support the first-in-human study. Plasma clearance was low in rats (4.04 ml . min(-1) . kg(-1)) and dogs (1.64 ml . min(-1) . kg(-1)), resulting in half-lives of 4.10 and 7.63 h, respectively. Moderate to good bioavailability in rats (69%) and dogs (94%) was observed after oral dosing. The in vitro biotransformation profile of PF-04971729 in liver microsomes and cryopreserved hepatocytes from rat, dog, and human was qualitatively similar; prominent metabolic pathways included monohydroxylation, O deethylation, and glucuronidation. No human-specific metabolites of PF-04971729 were detected in in vitro studies. Reaction phenotyping studies using recombinant enzymes indicated a role of CYP3A4/3A5, CYP2D6, and UGT1A9/2B7 in the metabolism of PF-04971729. No competitive or time-dependent inhibition of the major human cytochrome P450 enzymes was discerned with PF-04971729. Inhibitory effects against the organic cation transporter 2-mediated uptake of [(14)C]metformin by PF-04971729 also were very weak (IC(50) = ~900 MUM). Single-species allometric scaling of rat pharmacokinetics of PF-04971729 was used to predict human clearance, distribution volume, and oral bioavailability. Human pharmacokinetic predictions were consistent with the potential for a low daily dose. First-in human studies after oral administration indicated that the human pharmacokinetics/dose predictions for PF-04971729 were in the range that is likely to yield a favorable pharmacodynamic response. PMID- 21690266 TI - Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice. AB - Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver disease. Mechanisms that underlie this progression remain poorly understood, partly due to lack of good animal models that resemble human NASH. We previously showed that several metabolic syndrome features that develop in LDL receptor deficient (LDLR-/-) mice fed a diabetogenic diet are worsened by dietary cholesterol. To test whether dietary cholesterol can alter the hepatic phenotype in the metabolic syndrome, we fed LDLR-/- mice a high-fat, high-carbohydrate diabetogenic diet (DD) without or with added cholesterol (DDC). Both groups of mice developed obesity and insulin resistance. Hyperinsulinemia, dyslipidemia, hepatic triglyceride, and alanine aminotransferase (ALT) elevations were greater with DDC. Livers of DD-fed mice showed histological changes resembling NAFLD, including steatosis and modest fibrotic changes; however, DDC-fed animals developed micro- and macrovesicular steatosis, inflammatory cell foci, and fibrosis resembling human NASH. Dietary cholesterol also exacerbated hepatic macrophage infiltration, apoptosis, and oxidative stress. Thus, LDLR-/- mice fed diabetogenic diets may be useful models for studying human NASH. Dietary cholesterol appears to confer a second "hit" that results in a distinct hepatic phenotype characterized by increased inflammation and oxidative stress. PMID- 21690267 TI - Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism. AB - Activating mutations of RET, a gene encoding two isoforms of a tyrosine kinase receptor physiologically expressed in several neural crest-derived cell lineages, are associated with the inherited forms of medullary thyroid carcinoma (MTC). The identification and characterization of novel RET mutations involved in MTC is valuable, as RET gene testing plays a crucial role in the management of these patients. In an MTC patient, we have identified a germline c.1996A>G transition in heterozygosis leading to K666E substitution. In addition, the conservative S904S (c.2712C>G) and the non-conservative functional G691S (c.2071G>A) polymorphisms have been identified. Through functional studies, we demonstrate for the first time that K666E is a gain-of-function mutation with oncogenic potential, based on its ability to transform NIH3T3 cells. It was not possible to define whether K666E is a de novo or inherited RET variant in the patient, as the family history was negative for MTC, and the carrier status of family members could not be tested. Our results, together with a recent report of co-segregation of the mutation in three MTC families, suggest that K666E is a causative MTC mutation. As we have shown that the same patient allele carries both K666E and G691S variants, the latter known to increase downstream RET signaling, a possible role for the G691S polymorphism has also been investigated. We have demonstrated that, although RET-G691S is not oncogenic per se, it enhances the transforming activity of the RET-K666E mutant, thus suggesting a modifier role for this functional polymorphism. PMID- 21690268 TI - Antineoplastic effect of iodine and iodide in dimethylbenz[a]anthracene-induced mammary tumors: association between lactoperoxidase and estrogen-adduct production. AB - Several groups, including ours, have reported that iodine exhibited antiproliferative and apoptotic effects in various cancer cells only if this element is supplemented as molecular iodine, or as iodide, to cells that are able to oxidize it with the enzyme thyroperoxidase. In this study, we analyzed the effect of various concentrations of iodine and/or iodide in the dimethylbenz[a]anthracene (DMBA) mammary cancer model in rats. The results show that 0.1% iodine or iodide increases the expression of peroxisome proliferator activated receptor type gamma (PPARgamma), triggering caspase-mediated apoptosis pathways in damaged mammary tissue (DMBA-treated mammary gland) as well as in frank mammary tumors, but not in normal mammary gland. DMBA treatment induces the expression of lactoperoxidase, which participates in the antineoplastic effect of iodide and could be involved in the pro-neoplastic effect of estrogens, increasing the formation of DNA adducts. In conclusion, our results show that a supplement of 0.1% molecular iodine/potassium iodide (0.05/0.05%) exert antineoplastic effects, preventing estrogen-induced DNA adducts and inducing apoptosis through PPARgamma/caspases in pre-cancer and cancerous cells. Since this iodine concentration does not modify the cytology (histology, apoptosis rate) or physiology (triiodothyronine and thyrotropin) of the thyroid gland, we propose that it be considered as an adjuvant treatment for premenopausal mammary cancer. PMID- 21690269 TI - A technique with manipulator-assisted endoscope guidance for functional endoscopic sinus surgery: proof of concept. AB - OBJECTIVE: The goal of this study was to examine the theoretical feasibility of a new manipulator system for endoscope guidance in functional endoscopic sinus surgery. STUDY DESIGN: The accuracy of endoscope positioning and time of endoscope movement with an endoscope manipulator system were determined with an artificial sinus model. SETTING: A laboratory trial was performed. The time for 60 repetitions of manual compared to manipulator-assisted endoscope movements directed at 3 different target positions was evaluated. In addition, the alignment of the position vector for each endoscope movement was examined. SUBJECTS AND METHODS: A zero-degree Hopkins II telescope with a camera was used to head for the target positions. First, the endoscope movements were done manually, and afterward the endoscope manipulator system was used for endoscope guidance. The alignment of the position vector of the endoscope was measured with a portable measuring arm. RESULTS: There was no statistical difference between the time for manual and manipulator-assisted endoscope movements for all target positions. The alignment of the position vector of the endoscope was statistically different at 2 target positions: anterior ethmoid left side and ostium of maxillary sinus left side. There was no statistical difference at all other positions. CONCLUSION: The endoscope manipulator system has the potential to be integrated into the operating workflow without extending the time for endoscope guidance. The surgeon will be able to use both hands for the manipulation of the instruments. Less frequent endoscope movements and instrument changes may be expected after technical modification. PMID- 21690270 TI - Mantle cell lymphoma presenting as a saccular cyst. PMID- 21690271 TI - Variability in the management of idiopathic sudden sensorineural hearing loss. AB - OBJECTIVES: To evaluate current trends in the management of idiopathic sudden sensorineural hearing loss (ISSNHL), determine if variance in diagnostic and treatment protocols exists, and compare diagnostic and treatment strategies of ISSNHL between nonotologists/neurotologists (NONs) and otologists/neurotologists (ONs). STUDY DESIGN: Cross-sectional survey of practicing otolaryngologists. SETTING: Otolaryngology practices within the United States. SUBJECTS AND METHODS: In January 2010, a survey was mailed to 500 NONs and 500 ONs. Data were collected and analyzed using chi(2), standard deviations, and variance. RESULTS: A variety and distribution of responses were seen in the definition of ISSNHL, including dB loss necessary for diagnosis, number of consecutive frequencies involved, and maximum duration of hearing loss. Differences in diagnostic tools were also seen, with 50.4% of respondents (NON 34.2%, ON 66.7%; P = .0001) always using magnetic resonance imaging in their workup. Of the total respondents, 26.7% (NON 35.0%, ON 18.3%; P < .0001) preferred oral steroids alone; 22.1% (NON 11.7%, ON 32.5%; P < .0001) preferred a combination of oral and intratympanic steroids. Of the respondents, 68.6% (NON 57.5%, ON 80.0%; P = .0003) would continue with additional treatment after partial response; 20.8% (NON 33.3%, ON 8.3%; P < .005) would retreat with oral steroids alone and 46.6% (NON 35.8%, ON 57.3%; P < .05) with intratympanic injections. Overall, 69.2% (NON 45.8%, ON 92.5%; P = .0001) were very comfortable managing ISSNHL. CONCLUSION: Significant differences exist in the diagnosis and treatment of ISSNHL. Such lack of uniformity highlights the need for strong evidence-based research-ultimately leading to formalized practice guidelines and educational outreach. PMID- 21690272 TI - Riga-Fede disease: a rare sublingual traumatic ulcerative lesion in a child. PMID- 21690273 TI - Gustatory function after radiofrequency tongue base reduction in patients with obstructive sleep apnea. AB - OBJECTIVES: To investigate the changes in gustatory function as a complication after radiofrequency tongue base reduction (RTBR) in patients with obstructive sleep apnea (OSA). STUDY DESIGN: Before-and-after study. SETTING: Academic tertiary medical center. SUBJECTS AND METHODS: Thirty-four patients with suspected velopharyngeal collapse only underwent uvulopalatopharyngoplasty (UPPP group). Twenty-five patients with velopharyngeal and retrolingual collapse underwent concurrent UPPP with RTBR (RTBR group). All patients were evaluated before surgery and at 1 and 4 weeks after surgical treatment. A questionnaire was given to assess symptoms of hypogeusia, dysgeusia, hyposmia, and sensation of the tongue. Electrogustometry (EGM) in 4 areas was used to determine gustatory function. RESULTS: Postoperative values for subjective symptoms did not significantly change following surgical treatment in either group. EGM thresholds of all tested in both groups did not significantly change 1 week and 4 weeks after surgery. CONCLUSIONS: Gustatory function remained unchanged after RTBR in patients with OSA. The authors suggest that RTBR is a safe procedure in terms of taste sensation in OSA patients. PMID- 21690274 TI - A novel low-cost sinus surgery task trainer. AB - Sinus surgery simulation has proven to be a valuable teaching tool, yet the cost of many simulators limits the incorporation of this technology into training programs. The authors developed an inexpensive endoscopic sinus surgery task trainer and evaluated its value as a means of developing basic endoscopy and sinus surgery skills. For less than 5 US dollars, the training model was constructed using gelatin and embedded with reusable, recyclable, and readily available materials. Ten attending otolaryngologists performed nasal endoscopy and 5 specific tasks using this model, followed by completion of a survey evaluating the value of the model as a teaching tool. The model scored very well in promoting camera skills, instrumentation, and hand-eye coordination. This easily reproducible, highly rated sinus surgery task trainer can serve as an alternative to more expensive simulators. Studies are under way to determine its validity and effectiveness as both a teaching and assessment tool. PMID- 21690275 TI - Improved plasma free metadrenaline analysis requires mixed mode cation exchange solid-phase extraction prior to liquid chromatography tandem mass spectrometry detection. AB - BACKGROUND: The investigation and effective management of phaeochromocytoma involves biochemical measurement of either conjugated total urine or plasma free metadrenalines. Current analytical methods include enzyme-linked immunosorbent assays, high-performance liquid chromatography (HPLC) with electrochemical detection (ECD) or liquid chromatography tandem mass spectrometry (LCMS/MS). Since the first two methods are either extremely laborious, necessitate low sample run numbers, result in slow turnaround times or are subject to analytical interference, a robust, routine clinical method is not achievable. We established a novel sample preparation method to measure plasma free metadrenalines using LCMS/MS. METHODS: Three different solid-phase extraction (SPE) methods were compared: hydrophilic-lipophilic balance sorbent (HLB), weak cation exchange (WCX) and mixed mode cation exchange (MCX) and their ability to remove interfering compounds prior to LCMS/MS analysis. Maximum recovery of plasma free metadrenaline and plasma free normetadrenaline were achieved by positively charging compounds prior to SPE application. RESULTS: Compared with HLB and WCX cartridges, MCX extraction resulted in chromatography without co-eluting interference with superior assay precision and accuracy. Additionally, samples that could not be quantified because of interference using HPLC/ECD could be readily assayed using this new method. CONCLUSIONS: The use of the MCX SPE method with LCMS/MS detection provides an improved assay to measure plasma free metadrenalines in comparison to many available alternative methods. PMID- 21690276 TI - Impact of derepressed AmpC beta-lactamase ACT-9 on the clinical efficacy of ertapenem. AB - An in vivo development of Pantoea agglomerans mutants (isolates PA2 to PA4) with reduced ertapenem susceptibility from that of isolate PA1 was associated with an inadequate clinical response to ertapenem therapy. All four isolates harbored the bla(ACT-9) AmpC beta-lactamase gene. However, a loss-of-function mutation in the ampD gene in PA2 to PA4, but not PA1, led to derepressed ACT-9. The reduced ertapenem susceptibility caused by derepressed ACT-9 was confirmed with an ampD knockout mutant of PA1. PMID- 21690277 TI - Linezolid plus rifampin as a salvage therapy in prosthetic joint infections treated without removing the implant. AB - The aim of this study is to describe our experience with linezolid plus rifampin as a salvage therapy in prosthetic joint infections (PJIs) when other antibiotic regimens failed or were not tolerated. A total of 161 patients with a documented prosthetic joint infection were diagnosed with a PJI and prospectively followed up from January 2000 to April 2007. Clinical characteristics, inflammatory markers, microbiological and radiological data, and antibiotic treatment were recorded. After a 2-year follow-up, patients were classified as cured when the prosthesis was not removed, symptoms of infection disappeared, and inflammatory parameters were within the normal range. Any other outcome was considered a failure. The mean age of the entire cohort (n = 161) was 67 years. Ninety-five episodes were on a knee prosthesis (59%), and 66 were on a hip prosthesis (41%). A total of 49 patients received linezolid plus rifampin: 45 due to failure of the previous antibiotic regimen and 4 due to an adverse event associated with the prior antibiotics. In no case was the implant removed. The mean (standard deviation) duration of treatment was 80.2 (29.7) days. The success rate after 24 months of follow-up was 69.4% (34/49 patients). Three patients developed thrombocytopenia and 3 developed anemia; however, it was not necessary to stop linezolid. Linezolid plus rifampin is an alternative salvage therapy when the implant is not removed. PMID- 21690278 TI - Apoptosis-inducing activity of clofazimine in macrophages. AB - Clofazimine is a riminophenazine compound which has been used for the treatment of leprosy since the 1960s. Although the drug is effective in the management of leprosy reactions because of its anti-inflammatory activity, the mechanism leading to the cessation of inflammation is not well understood. In the present study, it was shown that clofazimine exhibits apoptosis-inducing activity in macrophages. When human monocyte-derived macrophages were cultured in vitro in the presence of clofazimine, the cells exhibited a marked decrease in metabolic activity and showed shrinkage in cell size, indicating cell death. Nuclear condensation and fragmentation were also observed by Giemsa and Hoechst 33248 stains. The endonuclease inhibitor ZnCl(2) inhibited the clofazimine-induced cell death. Significant enhancement of caspase-3 activity was observed in clofazimine treated macrophages and THP-1 cells. Collectively, these results suggest the apoptosis-inducing activity of clofazimine in macrophages, which may also be responsible for the antibacterial properties of clofazimine. PMID- 21690279 TI - Antimicrobial susceptibility to azithromycin among Salmonella enterica isolates from the United States. AB - Due to emerging resistance to traditional antimicrobial agents, such as ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol, azithromycin is increasingly used for the treatment of invasive Salmonella infections. In the present study, 696 isolates of non-Typhi Salmonella collected from humans, food animals, and retail meats in the United States were investigated for antimicrobial susceptibility to azithromycin. Seventy-two Salmonella enterica serotype Typhi isolates from humans were also tested. For each isolate, MICs of azithromycin and 15 other antimicrobial agents were determined by broth microdilution. Among the non-Typhi Salmonella isolates, azithromycin MICs among human isolates ranged from 1 to 32 MUg/ml, whereas the MICs among the animal and retail meat isolates ranged from 2 to 16 MUg/ml and 4 to 16 MUg/ml, respectively. Among Salmonella serotype Typhi isolates, the azithromycin MICs ranged from 4 to 16 MUg/ml. The highest MIC observed in the present study was 32 MUg/ml, and it was detected in three human isolates belonging to serotypes Kentucky, Montevideo, and Paratyphi A. Based on our findings, we propose an epidemiological cutoff value (ECOFF) for wild-type Salmonella of <=16 MUg/ml of azithromycin. The susceptibility data provided could be used in combination with clinical outcome data to determine tentative clinical breakpoints for azithromycin and Salmonella enterica. PMID- 21690280 TI - Self-resistance and cell wall composition in the glycopeptide producer Amycolatopsis balhimycina. AB - The prevailing resistance mechanism against glycopeptides in Gram-positive pathogens involves reprogramming the biosynthesis of peptidoglycan precursors, resulting in d-alanyl-d-lactate depsipeptide termini. Amycolatopsis balhimycina produces the vancomycin-like glycopeptide balhimycin and therefore has to protect itself from the action of the glycopeptide. We studied the roles of the accessory resistance gene orthologs vanY(b), vnlR(b), and vnlS(b), which are part of the balhimycin biosynthetic gene cluster (represented by the subscript "b"). The VanY(b) carboxypeptidase cleaved the terminal d-Ala from peptidoglycan precursors, and its heterologous expression enhanced glycopeptide resistance in Streptomyces coelicolor. The VanRS-like two component system VnlRS(b) was not involved in glycopeptide resistance or in the expression of the vanHAX glycopeptide resistance genes. Mature A. balhimycina peptidoglycan contained mainly tri- and tetrapeptides, with only traces of the d-Ala-d-Ala-ending pentapeptides that are binding sites for the antibiotic produced. The structure of the peptidoglycan precursor is consistent with the presence of vanHAX genes, which were identified outside the balhimycin synthesis cluster. Both wild-type and non-antibiotic-producing mutant strains synthesized peptidoglycan precursors ending mainly with d-Lac, indicating constitutive synthesis of a resistant cell wall. A. balhimycina could provide a model for an ancestral glycopeptide producer with constitutively expressed resistance genes. PMID- 21690281 TI - Real-time PCR for detection of NDM-1 carbapenemase genes from spiked stool samples. AB - An in-house quantitative real-time PCR (qPCR) assay using TaqMan chemistry has been developed to detect NDM-1 carbapenemase genes from bacterial isolates and directly from stool samples. The qPCR amplification of bla(NDM-1) DNA was linear over 10 log dilutions (r(2) = 0.99), and the amplification efficiency was 1.03. The qPCR detection limit was reproducibly 1 CFU, or 10 plasmid molecules, and there was no cross-reaction with DNA extracted from several multidrug-resistant bacteria harboring other beta-lactam resistance genes. Feces spiked with decreasing amounts of enterobacterial isolates producing NDM-1 were spread on ChromID ESBL and on CHROMagar KPC media and were subjected to the qPCR. The limits of carbapenem-resistant bacterial detection from stools was reproducibly 1 * 10(1) to 3 * 10(1) CFU/100 mg feces with ChromID ESBL medium. The CHROMagar KPC culture medium had higher limits of detection (1 * 10(1) to 4 * 10(3) CFU/ml), especially with bacterial isolates having low carbapenem MICs. The limits of detection with the qPCR assay were reproducibly below 1 * 10(1) CFU/100 mg of feces by qPCR assay. Samples spiked with NDM-1-negative bacteria were negative by qPCR. The sensitivity and specificity of the bla(NDM-1) qPCR assay on spiked samples were 100% in both cases. Using an automated DNA extraction system (QIAcube system), the qPCR assay was reproducible. The use of qPCR is likely to shorten the time for bla(NDM-1) detection from 48 h to 4 h and will be a valuable tool for outbreak follow-up in order to rapidly isolate colonized patients and assign them to cohorts. PMID- 21690282 TI - In vitro and in vivo synergistic effects of cryptdin 2 and ampicillin against Salmonella. AB - In view of the emergence of multidrug-resistant Salmonella strains, there is a need for therapeutic alternatives. To reduce the dose of antibiotic required in order to decrease the associated side effects, the present study was aimed at evaluating the synergism between cryptdin 2 (a Paneth cell antimicrobial peptide) and ampicillin (Amp) against Salmonella enterica serovar Typhimurium. The synergy was evaluated in terms of the fractional bactericidal concentration (FBC) index, time-kill assay results (in vitro), macrophage functions, i.e., intracellular killing, lipid peroxidation, superoxide dismutase activity, and generation of nitrite (ex vivo), and decreases in CFU of salmonellae in livers, spleens, and small intestines of infected mice treated with cryptdin 2 and/or Amp (in vivo). In vitro synergism between the two agents was observed on the basis of the FBC index and time-kill assays. When the agents were used in combination, ex vivo studies revealed an enhanced effect on macrophage functions, particularly exhibiting a synergetic effect in terms of SOD levels. In vivo synergy was indicated by larger log unit decreases in all target organs of mice treated with the combination than those for the drugs used alone. These results point toward the possible use of cryptdin 2 as an adjunct to ampicillin and may help in developing alternate strategies to combat Salmonella infections. PMID- 21690283 TI - Antimicrobial susceptibility testing of two Lawsonia intracellularis isolates associated with proliferative hemorrhagic enteropathy and porcine intestinal adenomatosis in South Korea. AB - This study represents the first published data on antimicrobial susceptibility of Asian isolates of Lawsonia intracellularis. We assessed MICs of 16 antimicrobials for two isolates of L. intracellularis recovered from diseased pigs in South Korea, one from a finisher pig with acute proliferative hemorrhagic enteropathy in 2002 and the other from a grower pig with porcine intestinal adenomatosis in 2010. Tylosin and tilmicosin were found to be the most active against L. intracellularis both intracellularly (MICs, 0.25 to 0.5 MUg/ml and 0.125 MUg/ml, respectively) and extracellularly (MICs, 0.25 to 0.5 MUg/ml and 1 MUg/ml, respectively). PMID- 21690284 TI - Population pharmacokinetics of ethambutol in South African tuberculosis patients. AB - Ethambutol, one of four drugs in the first-line antitubercular regimen, is used to protect against rifampin resistance in the event of preexisting resistance to isoniazid. The population pharmacokinetics of ethambutol in South African patients with pulmonary tuberculosis were characterized using nonlinear mixed effects modeling. Patients from 2 centers were treated with ethambutol (800 to 1,500 mg daily) combined with standard antitubercular medication. Plasma concentrations of ethambutol were measured following multiple doses at steady state and were determined using a validated high-pressure liquid chromatography tandem mass spectrometric method. The data comprised 189 patients (54% male, 12% HIV positive) weighing 47 kg, on average (range, 29 to 86 kg), and having a mean age of 36 years (range, 16 to 72 years). The estimated creatinine clearance was 79 ml/min (range, 23 to 150 ml/min). A two-compartment model with one transit compartment prior to first-order absorption and allometric scaling by body weight on clearance and volume terms was selected. HIV infection was associated with a 15% reduction in bioavailability. Renal function was not related to ethambutol clearance in this cohort. Interoccasion variability exceeded interindividual variability for oral clearance (coefficient of variation, 36 versus 20%). Typical oral clearance in this analysis (39.9 liters/h for a 50-kg individual) was lower than that previously reported, a finding partly explained by the differences in body weight between the studied populations. In summary, a population model describing the pharmacokinetics of ethambutol in South African tuberculosis patients was developed, but additional studies are needed to characterize the effects of renal function. PMID- 21690285 TI - Azole resistance in Aspergillus fumigatus isolates from the ARTEMIS global surveillance study is primarily due to the TR/L98H mutation in the cyp51A gene. AB - We surveyed 497 isolates of Aspergillus fumigatus collected from 2008 to 2009 as part of the ARTEMIS global surveillance study for elevated MIC values to itraconazole, voriconazole, and posaconazole. Sequencing of the cyp51A gene revealed that 8/29 isolates with elevated MIC values to one or more triazoles, all originating in China, contained the TR/L98H mutation associated with resistant European isolates of A. fumigatus. This is the first time the TR/L98H mutation has been identified outside Europe. PMID- 21690286 TI - Synergistic effect of antituberculosis drugs and azoles in vitro against Histoplasma capsulatum var. capsulatum. AB - This study evaluated in vitro interactions of antituberculosis drugs and triazoles against Histoplasma capsulatum. Nine drug combinations, each including an antituberculosis drug (isoniazid, pyrazinamide, or ethambutol) plus a triazole (itraconazole, fluconazole, or voriconazole), were tested against both growth forms of H. capsulatum. Stronger synergistic interactions were seen in isoniazid or pyrazinamide plus triazoles for the mold form and ethambutol plus voriconazole for the yeast-like form. Further studies should evaluate these combinations in vivo. PMID- 21690287 TI - An open-label crossover study to evaluate potential pharmacokinetic interactions between oral oseltamivir and intravenous zanamivir in healthy Thai adults. AB - There is no parenteral formulation of the neuraminidase inhibitor oseltamivir, the most widely used anti-influenza virus drug. Oseltamivir resistance is an increasing problem. Zanamivir is effective against the most prevalent oseltamivir resistant influenza viruses. A parenteral formulation of zanamivir is in development for the treatment of severe influenza. It is not known if there is any pharmacokinetic interaction between the two drugs. Sixteen healthy Thai adult volunteers were studied in an open-label, four-period, randomized two-sequence crossover pharmacokinetic study in which zanamivir was given by constant-rate infusion or slow intravenous injection either alone or together with oral oseltamivir. Plasma concentration profiles of oseltamivir, the active metabolite oseltamivir carboxylate, and zanamivir were measured by liquid chromatography mass spectrometry-mass spectrometry. Both drugs were well tolerated alone and in combination. The maximum plasma concentrations and the areas under the plasma concentration-time curves (AUC) of oseltamivir and oseltamivir carboxylate were not significantly different when oseltamivir was given separately or together with zanamivir. Maximum plasma concentrations of zanamivir were 10% (95% confidence interval, 7 to 12%) higher when zanamivir was infused concurrently with oral oseltamivir than with infusions before or after oral oseltamivir. The plasma zanamivir total AUC was positively correlated with the total oseltamivir carboxylate AUC (Pearson's correlation coefficient [r(P)] = 0.720, P = 0.002, n = 16) but not with the oseltamivir AUC (r(p) = 0.121, n = 16). There is no clinically significant pharmacokinetic interaction between oseltamivir and zanamivir. PMID- 21690288 TI - In vitro evaluation of the type of interaction obtained by the combination of terbinafine and itraconazole, voriconazole, or amphotericin B against dematiaceous molds. AB - In vitro associations using the checkerboard microdilution method indicated lower MIC ranges and MIC median values for each drug (terbinafine, itraconazole, voriconazole, and amphotericin B) in association than those obtained for each single drug. Fractional inhibitory concentration index (FIC) results showed 100% synergism in the association of terbinafine with voriconazole, 96.5% in the association of terbinafine with amphotericin B, and 75.9% in the association of terbinafine with itraconazole. Drug combinations may be useful for treatment of dematiaceous mold infections as an alternative treatment to enhance the effectiveness of each drug. PMID- 21690289 TI - The Ras inhibitors caveolin-1 and docking protein 1 activate peroxisome proliferator-activated receptor gamma through spatial relocalization at helix 7 of its ligand-binding domain. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor that promotes differentiation and cell survival in the stomach. PPARgamma upregulates and interacts with caveolin-1 (Cav1), a scaffold protein of Ras/mitogen-activated protein kinases (MAPKs). The cytoplasmic-to-nuclear localization of PPARgamma is altered in gastric cancer (GC) patients, suggesting a so-far-unknown role for Cav1 in spatial regulation of PPARgamma signaling. We show here that loss of Cav1 accelerated proliferation of normal stomach and GC cells in vitro and in vivo. Downregulation of Cav1 increased Ras/MAPK-dependent phosphorylation of serine 84 in PPARgamma and enhanced nuclear translocation and ligand-independent transcription of PPARgamma target genes. In contrast, Cav1 overexpression sequestered PPARgamma in the cytosol through interaction of the Cav1 scaffolding domain (CSD) with a conserved hydrophobic motif in helix 7 of PPARgamma's ligand-binding domain. Cav1 cooperated with the endogenous Ras/MAPK inhibitor docking protein 1 (Dok1) to promote the ligand-dependent transcriptional activity of PPARgamma and to inhibit cell proliferation. Ligand activated PPARgamma also reduced tumor growth and upregulated the Ras/MAPK inhibitors Cav1 and Dok1 in a murine model of GC. These results suggest a novel mechanism of PPARgamma regulation by which Ras/MAPK inhibitors act as scaffold proteins that sequester and sensitize PPARgamma to ligands, limiting proliferation of gastric epithelial cells. PMID- 21690290 TI - Histone occupancy in vivo at the 601 nucleosome binding element is determined by transcriptional history. AB - We report in vivo analysis of histone and RNA polymerase II (pol II) occupancy at the 601 element, which functions as a strong in vitro nucleosome-positioning element and transcriptional pause site. Surprisingly, nucleosomes were not strongly positioned over the 601 element inserted either within a yeast chromosomal open reading frame (ORF) (GAL1-YLR454W) or in an intergenic region. In fact 601 within GAL1-YLR454W was actually depleted of histones relative to flanking sequences and did not cause pol II pausing. Upstream of an inserted 601 element within GAL1-YLR454W, a positioned nucleosome was formed whose location depended on transcriptional history; it shifted after a round of activation and repression. Transcriptional activation caused histone eviction throughout the GAL1-YLR454W ORF, except at 601, where there was no loss and some net histone deposition. In contrast, a second round of activation after glucose shutoff caused histone eviction both at 601 and elsewhere in the ORF. We conclude that the intrinsic high-affinity histone-DNA interactions at 601 do not necessarily play a dominant role in establishing nucleosomes or pol II pause sites within a coding region in vivo and that transcriptional history can have an important influence on histone occupancy flanking this sequence. PMID- 21690291 TI - The BAR domain protein PICK1 regulates cell recognition and morphogenesis by interacting with Neph proteins. AB - Neph proteins are evolutionarily conserved membrane proteins of the immunoglobulin superfamily that control the formation of specific intercellular contacts. Cell recognition through these proteins is essential in diverse cellular contexts such as patterning of the compound eye in Drosophila melanogaster, neuronal connectivity in Caenorhabditis elegans, and the formation of the kidney filtration barrier in mammals. Here we identify the PDZ and BAR domain protein PICK1 (protein interacting with C-kinase 1) as a Neph-interacting protein. Binding required dimerization of PICK1, was dependent on PDZ domain protein interactions, and mediated stabilization of Neph1 at the plasma membrane. Moreover, protein kinase C (PKCalpha) activity facilitated the interaction through releasing Neph proteins from their binding to the multidomain scaffolding protein zonula occludens 1 (ZO-1), another PDZ domain protein. In Drosophila, the Neph homologue Roughest is essential for sorting of interommatidial precursor cells and patterning of the compound eye. RNA interference-mediated knockdown of PICK1 in the Drosophila eye imaginal disc caused a Roughest destabilization at the plasma membrane and a phenotype that resembled rst mutation. These data indicate that Neph proteins and PICK1 synergistically regulate cell recognition and contact formation. PMID- 21690292 TI - The duplicated deacetylases Sir2 and Hst1 subfunctionalized by acquiring complementary inactivating mutations. AB - Protein families are generated by successive rounds of gene duplication and subsequent diversification. However, the paths by which duplicated genes acquire distinct functions are not well characterized. We focused on a pair of duplicated deacetylases from Saccharomyces cerevisiae, Sir2 and Hst1, that subfunctionalized after duplication. As a proxy for the ancestral, nonduplicated deacetylase, we studied Sir2 from another yeast, Kluyveromyces lactis. We compared the interaction domains of these deacetylases for the Sir transcriptional silencing complex, which acts with ScSir2, and the Sum1 repressor, which acts with ScHst1, and found that these interaction domains have been retained over the course of evolution and can be disrupted by simple amino acid substitutions. Therefore, Sir2 and Hst1 subfunctionalized by acquiring complementary inactivating mutations in these interaction domains. PMID- 21690293 TI - Molecular chaperone Hsp90 regulates REV1-mediated mutagenesis. AB - REV1 is a Y-family polymerase that plays a central role in mutagenic translesion DNA synthesis (TLS), contributing to tumor initiation and progression. In a current model, a monoubiquitinated form of the replication accessory protein, proliferating cell nuclear antigen (PCNA), serves as a platform to recruit REV1 to damaged sites on the DNA template. Emerging evidence indicates that posttranslational mechanisms regulate REV1 in yeast; however, the regulation of REV1 in higher eukaryotes is poorly understood. Here we show that the molecular chaperone Hsp90 is a critical regulator of REV1 in human cells. Hsp90 specifically binds REV1 in vivo and in vitro. Treatment with a specific inhibitor of Hsp90 reduces REV1 protein levels in several cell types through proteasomal degradation. This is associated with suppression of UV-induced mutagenesis. Furthermore, Hsp90 inhibition disrupts the interaction between REV1 and monoubiquitinated PCNA and suppresses UV-induced focus formation. These results indicate that Hsp90 promotes folding of REV1 into a stable and/or functional form(s) to bind to monoubiquitinated PCNA. The present findings reveal a novel role of Hsp90 in the regulation of TLS-mediated mutagenesis. PMID- 21690294 TI - Prevention of transcriptional silencing by a replicator-binding complex consisting of SWI/SNF, MeCP1, and hnRNP C1/C2. AB - Transcriptional silencing selectively impedes gene expression. Silencing is often accompanied by replication delay and can be prevented by replicator sequences. Here we report a replicator-binding protein complex involved in the prevention of transcriptional silencing. The protein complex interacts with an essential asymmetric region within the human beta-globin Rep-P replicator and includes hnRNP C1/C2, SWI/SNF complex, and MeCP1, which are members of the locus control region (LCR)-associated remodeling complex (LARC). Interaction between LARC and Rep-P prevented transcriptional silencing and replication delay. Transgenes that did not contain the asymmetric LARC-binding region of Rep-P replicated late and exhibited stable silencing that could not be affected by a DNA methylation inhibitor. In contrast, transgenes that contain a mutation of the asymmetric region of Rep-P that could not bind LARC exhibited a silent state that could transiently be reactivated by DNA demethylation. The effect of DNA demethylation was transient, and prolonged exposure to a methylation inhibitor induced distinct, stable, methylation-independent silencing. These observations suggest that the interaction of LARC complex with replicators plays a role in preventing gene silencing and provides support for a novel, epigenetic mechanism of resistance to methylation inhibitors. PMID- 21690295 TI - Stochastic receptor expression determines cell fate upon interferon treatment. AB - Type I interferons trigger diverse biological effects by binding a common receptor, composed of IFNAR1 and IFNAR2. Intriguingly, while the activation of an antiviral state is common to all cells, antiproliferative activity and apoptosis affect only part of the population, even when cells are stimulated with saturating interferon concentrations. Manipulating receptor expression by different small interfering RNA (siRNA) concentrations reduced the fraction of responsive cells independent of the interferon used, including a newly generated, extremely tight-binding variant. Reduced receptor numbers increased 50% effective concentrations (EC(50)s) for alpha interferon 2 (IFN-alpha2) but not for the tight-binding variant. A correlation between receptor numbers, STAT activation, and gene induction is observed. Our data suggest that for a given cell, the response is binary (+/-) and dependent on the stochastic expression levels of the receptors on an individual cell. A low number of receptors suffices for antiviral response and is thus a robust feature common to all cells. Conversely, a high number of receptors is required for antiproliferative activity, which allows for fine-tuning on a single-cell level. PMID- 21690296 TI - c-Abl-mediated tyrosine phosphorylation of the T-bet DNA-binding domain regulates CD4+ T-cell differentiation and allergic lung inflammation. AB - The tyrosine kinase c-Abl is required for full activation of T cells, while its role in T-cell differentiation has not been characterized. We report that c-Abl deficiency skews CD4(+) T cells to type 2 helper T cell (Th2) differentiation, and c-Abl(-/-) mice are more susceptible to allergic lung inflammation. c-Abl interacts with and phosphorylates T-bet, a Th1 lineage transcription factor. c Abl-mediated phosphorylation enhances the transcriptional activation of T-bet. Interestingly, three tyrosine residues within the T-bet DNA-binding domain are the predominant sites of phosphorylation by c-Abl. Mutation of these tyrosine residues inhibits the promoter DNA-binding activity of T-bet. c-Abl regulates Th cell differentiation in a T-bet-dependent manner because genetic deletion of T bet in CD4(+) T cells abolishes c-Abl-deficiency-mediated enhancement of Th2 differentiation. Reintroduction of T-bet-null CD4(+) T cells with wild-type T bet, but not its tyrosine mutant, rescues gamma interferon (IFN-gamma) production and inhibits Th2 cytokine production. Therefore, c-Abl catalyzes tyrosine phosphorylation of the DNA-binding domain of T-bet to regulate CD4(+) T cell differentiation. PMID- 21690297 TI - Identification of heat shock factor 1 molecular and cellular targets during embryonic and adult female meiosis. AB - Heat shock factor 1 (HSF1), while recognized as the major regulator of the heat shock transcriptional response, also exerts important functions during mammalian embryonic development and gametogenesis. In particular, HSF1 is required for oocyte maturation, the adult phase of meiosis preceding fertilization. To identify HSF1 target genes implicated in this process, comparative transcriptomic analyses were performed with wild-type and HSF-deficient oocytes. This revealed a network of meiotic genes involved in cohesin and synaptonemal complex (SC) structures, DNA recombination, and the spindle assembly checkpoint (SAC). All of them were found to be regulated by HSF1 not only during adult but also in embryonic phases of female meiosis. Additional investigations showed that SC, recombination nodules, and DNA repair were affected in Hsf1(-/-) oocytes during prenatal meiotic prophase I. However, targeting Hsf1 deletion to postnatal oocytes (using Zp3 Cre; Hsf1(loxP/loxP)) did not fully rescue the chromosomal anomalies identified during meiotic maturation, which possibly caused a persistent SAC activation. This would explain the metaphase I arrest previously described in HSF1-deficient oocytes since SAC inhibition circumvented this block. This work provides new insights into meiotic gene regulation and points out potential links between cellular stress and the meiotic anomalies frequently observed in humans. PMID- 21690299 TI - The lysyl oxidase propeptide interacts with the receptor-type protein tyrosine phosphatase kappa and inhibits beta-catenin transcriptional activity in lung cancer cells. AB - The propeptide region of the lysyl oxidase proenzyme (LOX-PP) has been shown to inhibit Ras signaling in NIH 3T3 and lung cancer cells with activated RAS, but its mechanism of action is poorly understood. Here, a yeast two-hybrid assay of LOX-PP-interacting proteins identified a clone encoding the intracellular phosphatase domains of receptor-type protein tyrosine phosphatase kappa (RPTP kappa), and the interaction of the two proteins in mammalian cells was confirmed. RPTP-kappa is proteolytically processed to isoforms that have opposing effects on beta-catenin activity. The RPTP-kappa transmembrane P subunit interacts with and sequesters beta-catenin at the cell membrane, where it can associate with E cadherin and promote intercellular interactions. At high cell density, further processing of the P subunit yields a phosphatase intracellular portion (PIC) subunit, which chaperones beta-catenin to the nucleus, where it can function to activate transcription. Lung cancer cells were found to contain higher PIC levels than untransformed lung epithelial cells. In H1299 lung cancer cells, ectopic LOX PP expression reduced the nuclear levels of PIC by increasing its turnover in the lysosome, thereby decreasing the nuclear levels and transcriptional activity of beta-catenin while increasing beta-catenin membrane localization. Thus, LOX-PP is shown to negatively regulate pro-oncogenic beta-catenin signaling in lung cancer cells. PMID- 21690300 TI - Severe alterations of cerebellar cortical development after constitutive activation of Wnt signaling in granule neuron precursors. AB - The Wnt/beta-catenin signaling pathway plays crucial roles in early hindbrain formation, and its constitutive activity is associated with a subset of human medulloblastoma, a malignant childhood tumor of the posterior fossa. However, the precise function of Wnt/beta-catenin signaling during cerebellar development is still elusive. We generated Math1-cre::Apc(Fl/Fl) mice with a conditional knockout for the Adenomatosis polyposis coli (Apc) gene that displayed a constitutive activity of Wnt/beta-catenin signaling in cerebellar granule neuron precursors. Such mice showed normal survival without any tumor formation but had a significantly smaller cerebellum with a complete disruption of its cortical histoarchitecture. The activation of the Wnt/beta-catenin signaling pathway resulted in a severely inhibited proliferation and premature differentiation of cerebellar granule neuron precursors in vitro and in vivo. Mutant mice hardly developed an internal granular layer, and layering of Purkinje neurons was disorganized. Clinically, these mice presented with significantly impaired motor coordination and ataxia. In summary, we conclude that cerebellar granule neurons essentially require appropriate levels of Wnt signaling to balance their proliferation and differentiation. PMID- 21690298 TI - Posttranscriptional control of type I interferon genes by KSRP in the innate immune response against viral infection. AB - Inherently unstable mRNAs contain AU-rich elements (AREs) in the 3' untranslated regions. Expression of ARE-containing type I interferon transcripts is robustly induced upon viral infection and rapidly shut off thereafter. Their transient accumulation is partly mediated through posttranscriptional regulation. Here we show that mouse embryonic fibroblasts derived from knockout mice deficient in KH type splicing regulatory protein (KSRP), an RNA-binding protein required for ARE mediated mRNA decay, produce higher levels of Ifna and Ifnb mRNAs in response to viral infection as a result of decreased mRNA decay. Functional analysis showed that KSRP is required for the decay of Ifna4 and Ifnb mRNAs by interaction with AREs. The increased IFN expression renders Ksrp(-)(/)(-) cells refractory to herpes simplex virus type 1 and vesicular stomatitis virus infection. These findings support a role of a posttranscriptional mechanism in the control of type I IFN expression and highlight the function of KSRP in innate immunity by negatively regulating IFN production. PMID- 21690301 TI - Clinical Outcomes and Hospitalizations among Children Perinatally Infected with HIV-1 in Baja California, Mexico. AB - This study characterizes temporal trends in HIV disease progression among perinatally infected children at a clinic in Baja California, Mexico. A total of 73 children were followed, 52% were categorized under US Centers for Disease Control and Prevention (CDC) classification group C with a mean age of 2.3 years (SD +/- 3.16) at HIV diagnosis. For the years 1998 to 2001, 2002 to 2003, 2004 to 2005, and 2006 to 2007, highly active antiretroviral therapy (HAART) use increased to 60%, 75%, 83%, and 94% (P < .001) as did mean CD4 percentage of 23.4%, 23.2%, 26.9%, and 29.0%, respectively (P = .009), while HIV plasma RNA log(10) decreased significantly (4.49, 4.23, 4.00, and 3.79, respectively; P = .019). Overall mortality was 31% (23 of 73), with pneumonia being the most common cause of death (43% of all deaths) followed by tuberculosis (22%). Mortality rates declined from 30.4% to 25%, 8.9%, and 9.3% (p = 0.035) for the years 1998 to 2001, 2002 to 2003, 2004 to 2005, and 2006 to 2007, respectively. Kaplan-Meier survival analysis showed that median survival was 11.2 years; 1-, 2-, and 5-year survival was 87%, 83%, and 67%, respectively. These findings document a high but improving trend in morbidity and mortality of children perinatally infected with HIV in Tijuana, Baja California, Mexico. PMID- 21690303 TI - Randomized trial of risk information formats in direct-to-consumer prescription drug advertisements. AB - BACKGROUND: Federal regulations specify that print advertisements for prescription drugs and biological products must provide a true statement of information "in brief summary" about each advertised product's "side effects, contraindications, and effectiveness." Some of the current approaches to fulfilling the brief summary requirement, although adequate from a regulatory perspective, result in ads that may be difficult to read and understand when used in consumer-directed promotion. OBJECTIVE: . To explore ways in which the brief summary might be improved. DESIGN: . The authors conducted an experimental study that examined 300 consumers' (mall visitors ever told that they were overweight) understanding of and preference for 4 different brief summary formats: traditional (a plain-language version of the risk sections from professional labeling), question and answer (Q&A; with headings framed in the form of questions), highlights (a summary section from revised professional labeling), and prescription drug facts box (similar to the current over-the-counter drug facts label). RESULTS: . The format had several effects. For instance, participants who viewed the drug facts format were better able to recall risks (P < .01) and reported greater confidence to perform the tasks (P < .01) than those who saw the traditional format. Differences in preference were noted; for example, the drug facts format was ranked highest, followed by the Q&A format, the traditional format, and finally the highlights format, P < 0.001. CONCLUSIONS: . Taken together, these data suggest that the traditional method of conveying information in the brief summary is neither the most comprehensible nor the most preferred by consumers. These data provide policy makers and researchers with important information regarding the role of format in consumers' understanding of the brief summary. PMID- 21690304 TI - Effects of an incinerator project on a healthcare-waste management system. AB - This evaluative research study aimed to assess the effects of the central healthcare incinerator project on waste management in Yala Province. The study data were collected twice: at baseline and during the operational phase. A combination of structured interview and observation were used during data collection. The study covered 127 healthcare facilities: government hospitals, healthcare centres, and private clinics. The results showed 63% of healthcare risk waste (HCRW) handlers attended the HCRW management training. Improvements in each stage of the HCRW management system were observed in all groups of facilities. The total cost of the HCRW management system did not change, however; the costs for hospitals decreased, whereas those for clinics increased significantly. It was concluded that the central healthcare waste incinerator project positively affected HCRW management in the area, although the costs of management might increase for a particular group. However, the benefits of changing to a more appropriately managed HCRW system will outweigh the increased costs. PMID- 21690302 TI - Novel acidic sesquiterpenoids constitute a dominant class of pathogen-induced phytoalexins in maize. AB - Nonvolatile terpenoid phytoalexins occur throughout the plant kingdom, but until recently were not known constituents of chemical defense in maize (Zea mays). We describe a novel family of ubiquitous maize sesquiterpenoid phytoalexins, termed zealexins, which were discovered through characterization of Fusarium graminearum induced responses. Zealexins accumulate to levels greater than 800 MUg g-1 fresh weight in F. graminearum-infected tissue. Their production is also elicited by a wide variety of fungi, Ostrinia nubilalis herbivory, and the synergistic action of jasmonic acid and ethylene. Zealexins exhibit antifungal activity against numerous phytopathogenic fungi at physiologically relevant concentrations. Structural elucidation of four members of this complex family revealed that all are acidic sesquiterpenoids containing a hydrocarbon skeleton that resembles beta macrocarpene. Induced zealexin accumulation is preceded by increased expression of the genes encoding TERPENE SYNTHASE6 (TPS6) and TPS11, which catalyze beta macrocarpene production. Furthermore, zealexin accumulation displays direct positive relationships with the transcript levels of both genes. Microarray analysis of F. graminearum-infected tissue revealed that Tps6/Tps11 were among the most highly up-regulated genes, as was An2, an ent-copalyl diphosphate synthase associated with production of kauralexins. Transcript profiling suggests that zealexins cooccur with a number of antimicrobial proteins, including chitinases and pathogenesis-related proteins. In addition to zealexins, kauralexins and the benzoxazinoid 2-hydroxy-4,7-dimethoxy-1,4-benzoxazin-3-one glucose (HDMBOA-glucose) were produced in fungal-infected tissue. HDMBOA-glucose accumulation occurred in both wild-type and benzoxazine-deficient1 (bx1) mutant lines, indicating that Bx1 gene activity is not required for HDMBOA biosynthesis. Together these results indicate an important cooperative role of terpenoid phytoalexins in maize biochemical defense. PMID- 21690305 TI - Impact of revised Task Force Criteria: distinguishing the athlete's heart from ARVC/D using cardiac magnetic resonance imaging. AB - BACKGROUND: Cardiac magnetic resonance (CMR) evaluation of athletes for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is complicated by overlapping features such as right ventricular (RV) volume increase. The revised ARVC/D diagnostic Task Force Criteria (TFC) incorporate cut-off values for RV ejection fraction (EF) and RV end-diastolic volume (EDV) on CMR. DESIGN: To distinguish ARVC/D patients from athletes we compared CMR ventricular volumes, function, TFC cut-off values, and LV/RV ratios since athletes show proportionate, and ARVC/D patients disproportionate, changes in LV and RV. METHODS: Quantitative CMR parameters of 33 ARVC/D patients (64% male, mean age 45.4 years, diagnosed by revised TFC), 66 healthy athletes and 66 healthy non-athletes (sex and age matched) were compared using revised TFC and new cut-off values representing LV/RV balance. RESULTS AND CONCLUSIONS: Absolute values for ARVC/D patients/athletes/non-athletes were: in males, RV EDV 149/133/106 ml/m(2), ratio EDV LV/RV 0.70/0.91/0.93, RV EF 34/52/54%, LV EF 48/57/58%, ratio EF LV/RV 1.49/1.10/1.09; and in females, RV EDV 115/115/91 ml/m(2), ratio EDV LV/RV 0.86/0.94/0.97, RV EF 43/54/58%, LV EF 52/57/61%, ratio EF LV/RV 1.23/1.08/1.04 (p-values < 0.05). Areas under the ROC-curve are 0.68 (RV EDV index), 0.84 (LV/RV EDV ratio) and 0.93 (RV EF), demonstrating significantly (p < 0.001) better performance of RV EF and LV/RV EDV ratio. If a wall motion abnormality is present (observed in 30 ARVC/D patients and not in healthy subjects), RV EF can help distinguish ARVC/D from physiological cardiac adaptation in athletes on CMR whereas RV EDV index cannot. A good alternative in athletes is the LV/RV EDV ratio, representing normal proportionate adaptation of both ventricles. PMID- 21690307 TI - RA-RAR-beta counteracts myelin-dependent inhibition of neurite outgrowth via Lingo-1 repression. AB - After an acute central nervous system injury, axonal regeneration is limited as the result of a lack of neuronal intrinsic competence and the presence of extrinsic inhibitory signals. The injury fragments the myelin neuronal insulating layer, releasing extrinsic inhibitory molecules to signal through the neuronal membrane-bound Nogo receptor (NgR) complex. In this paper, we show that a neuronal transcriptional pathway can interfere with extrinsic inhibitory myelin dependent signaling, thereby promoting neurite outgrowth. Specifically, retinoic acid (RA), acting through the RA receptor beta (RAR-beta), inhibited myelin activated NgR signaling through the transcriptional repression of the NgR complex member Lingo-1. We show that suppression of Lingo-1 was required for RA-RAR-beta to counteract extrinsic inhibition of neurite outgrowth. Furthermore, we confirm in vivo that RA treatment after a dorsal column overhemisection injury inhibited Lingo-1 expression, specifically through RAR-beta. Our findings identify a novel link between RA-RAR-beta-dependent proaxonal outgrowth and inhibitory NgR complex dependent signaling, potentially allowing for the development of molecular strategies to enhance axonal regeneration after a central nervous system injury. PMID- 21690306 TI - CDK-1 inhibits meiotic spindle shortening and dynein-dependent spindle rotation in C. elegans. AB - In animals, the female meiotic spindle is positioned at the egg cortex in a perpendicular orientation to facilitate the disposal of half of the chromosomes into a polar body. In Caenorhabditis elegans, the metaphase spindle lies parallel to the cortex, dynein is dispersed on the spindle, and the dynein activators ASPM 1 and LIN-5 are concentrated at spindle poles. Anaphase-promoting complex (APC) activation results in dynein accumulation at spindle poles and dynein-dependent rotation of one spindle pole to the cortex, resulting in perpendicular orientation. To test whether the APC initiates spindle rotation through cyclin B CDK-1 inactivation, separase activation, or degradation of an unknown dynein inhibitor, CDK-1 was inhibited with purvalanol A in metaphase-I-arrested, APC depleted embryos. CDK-1 inhibition resulted in the accumulation of dynein at spindle poles and dynein-dependent spindle rotation without chromosome separation. These results suggest that CDK-1 blocks rotation by inhibiting dynein association with microtubules and with LIN-5-ASPM-1 at meiotic spindle poles and that the APC promotes spindle rotation by inhibiting CDK-1. PMID- 21690308 TI - Cdc55 coordinates spindle assembly and chromosome disjunction during meiosis. AB - During meiosis, two consecutive nuclear divisions follow a single round of deoxyribonucleic acid replication. In meiosis I, homologues are segregated, whereas in meiosis II, sister chromatids are segregated. This requires that the sequential assembly and dissolution of specialized chromosomal factors are coordinated with two rounds of spindle assembly and disassembly. How these events are coupled is unknown. In this paper, we show, in budding yeast, that the protein phosphatase 2A regulatory subunit Cdc55 couples the loss of linkages between chromosomes with nuclear division by restraining two other phosphatases, Cdc14 and PP2A(Rts1). Cdc55 maintains Cdc14 sequestration in the nucleolus during early meiosis, and this is essential for the assembly of the meiosis I spindle but not for chromosomes to separate. Cdc55 also limits the formation of PP2A holocomplexes containing the alternative regulatory subunit Rts1, which is crucial for the timely dissolution of sister chromatid cohesion. Therefore, Cdc55 orders passage through the meiotic divisions by ensuring a balance of phosphatases. PMID- 21690309 TI - Pannexin 3 functions as an ER Ca(2+) channel, hemichannel, and gap junction to promote osteoblast differentiation. AB - The pannexin proteins represent a new gap junction family. However, the cellular functions of pannexins remain largely unknown. Here, we demonstrate that pannexin 3 (Panx3) promotes differentiation of osteoblasts and ex vivo growth of metatarsals. Panx3 expression was induced during osteogenic differentiation of C2C12 cells and primary calvarial cells, and suppression of this endogenous expression inhibited differentiation. Panx3 functioned as a unique Ca(2+) channel in the endoplasmic reticulum (ER), which was activated by purinergic receptor/phosphoinositide 3-kinase (PI3K)/Akt signaling, followed by activation of calmodulin signaling for differentiation. Panx3 also formed hemichannels that allowed release of ATP into the extracellular space and activation of purinergic receptors with the subsequent activation of PI3K-Akt signaling. Panx3 also formed gap junctions and propagated Ca(2+) waves between cells. Blocking the Panx3 Ca(2+) channel and gap junction activities inhibited osteoblast differentiation. Thus, Panx3 appears to be a new regulator that promotes osteoblast differentiation by functioning as an ER Ca(2+) channel and a hemichannel, and by forming gap junctions. PMID- 21690311 TI - Meiotic nuclear divisions in budding yeast require PP2A(Cdc55)-mediated antagonism of Net1 phosphorylation by Cdk. AB - During meiosis, one round of deoxyribonucleic acid replication is followed by two rounds of nuclear division. In Saccharomyces cerevisiae, activation of the Cdc14 early anaphase release (FEAR) network is required for exit from meiosis I but does not lead to the activation of origins of replication. The precise mechanism of how FEAR regulates meiosis is not understood. In this paper, we report that premature activation of FEAR during meiosis caused by loss of protein phosphatase PP2A(Cdc55) activity blocks bipolar spindle assembly and nuclear divisions. In cdc55 meiotic null (cdc55-mn) cells, the cyclin-dependent kinase (Cdk) counteracting phosphatase Cdc14 was released prematurely from the nucleolus concomitant with hyperphosphorylation of its nucleolar anchor protein Net1. Crucially, a mutant form of Net1 that lacks six Cdk phosphorylation sites rescued the meiotic defect of cdc55-mn cells. Expression of a dominant mutant allele of CDC14 mimicked the cdc55-mn phenotype. We propose that phosphoregulation of Net1 by PP2A(Cdc55) is essential for preventing precocious exit from meiosis I. PMID- 21690310 TI - Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species. AB - Unraveling the gene regulatory networks that govern development and function of the mammalian heart is critical for the rational design of therapeutic interventions in human heart disease. Using the Drosophila heart as a platform for identifying novel gene interactions leading to heart disease, we found that the Rho-GTPase Cdc42 cooperates with the cardiac transcription factor Tinman/Nkx2 5. Compound Cdc42, tinman heterozygous mutant flies exhibited impaired cardiac output and altered myofibrillar architecture, and adult heart-specific interference with Cdc42 function is sufficient to cause these same defects. We also identified K(+) channels, encoded by dSUR and slowpoke, as potential effectors of the Cdc42-Tinman interaction. To determine whether a Cdc42-Nkx2-5 interaction is conserved in the mammalian heart, we examined compound heterozygous mutant mice and found conduction system and cardiac output defects. In exploring the mechanism of Nkx2-5 interaction with Cdc42, we demonstrated that mouse Cdc42 was a target of, and negatively regulated by miR-1, which itself was negatively regulated by Nkx2-5 in the mouse heart and by Tinman in the fly heart. We conclude that Cdc42 plays a conserved role in regulating heart function and is an indirect target of Tinman/Nkx2-5 via miR-1. PMID- 21690312 TI - Twice upon a time: multiple concurrent temporal recalibrations of audiovisual speech. AB - Audiovisual timing perception can recalibrate following prolonged exposure to asynchronous auditory and visual inputs. It has been suggested that this might contribute to achieving perceptual synchrony for auditory and visual signals despite differences in physical and neural signal times for sight and sound. However, given that people can be concurrently exposed to multiple audiovisual stimuli with variable neural signal times, a mechanism that recalibrates all audiovisual timing percepts to a single timing relationship could be dysfunctional. In the experiments reported here, we showed that audiovisual temporal recalibration can be specific for particular audiovisual pairings. Participants were shown alternating movies of male and female actors containing positive and negative temporal asynchronies between the auditory and visual streams. We found that audiovisual synchrony estimates for each actor were shifted toward the preceding audiovisual timing relationship for that actor and that such temporal recalibrations occurred in positive and negative directions concurrently. Our results show that humans can form multiple concurrent estimates of appropriate timing for audiovisual synchrony. PMID- 21690313 TI - Inside the opponent's head: perceived losses in group position predict accuracy in metaperceptions between groups. AB - Members of groups in conflict typically perceive the same reality in opposing ways. We investigated individuals' ability to accurately perceive out-group members' views of the conflict. Drawing on research on power and metaperceptions, we hypothesized that perceiving losses to in-group position would increase accuracy in predicting out-group members' views. Study 1 was conducted immediately following the Gaza flotilla incident. Israelis, who perceived the event as causing political losses to their group, were more accurate in predicting out-group members' views of the incident than were Palestinians, who perceived the event as causing political gains for their group. Moreover, Israelis' accuracy increased with their perception of political losses for Israel, whereas Palestinians' accuracy decreased with their perception of political gains for Palestinians. These effects were particularly pronounced among those participants who were highly identified with their group. Study 2 replicated the relationship between perceived losses and accuracy, and demonstrated that it could not be accounted for by factors such as education, political orientation, or empathy. PMID- 21690315 TI - Arousal increases social transmission of information. PMID- 21690314 TI - Awareness becomes necessary between adaptive pattern coding of open and closed curvatures. AB - Visual pattern processing becomes increasingly complex along the ventral pathway, from the low-level coding of local orientation in the primary visual cortex to the high-level coding of face identity in temporal visual areas. Previous research using pattern aftereffects as a psychophysical tool to measure activation of adaptive feature coding has suggested that awareness is relatively unimportant for the coding of orientation, but awareness is crucial for the coding of face identity. We investigated where along the ventral visual pathway awareness becomes crucial for pattern coding. Monoptic masking, which interferes with neural spiking activity in low-level processing while preserving awareness of the adaptor, eliminated open-curvature aftereffects but preserved closed curvature aftereffects. In contrast, dichoptic masking, which spares spiking activity in low-level processing while wiping out awareness, preserved open curvature aftereffects but eliminated closed-curvature aftereffects. This double dissociation suggests that adaptive coding of open and closed curvatures straddles the divide between weakly and strongly awareness-dependent pattern coding. PMID- 21690316 TI - Research gaps related to tobacco product marketing and sales in the Family Smoking Prevention and Tobacco Control Act. AB - This paper is part of a collection that identifies research priorities that will help guide the efforts of the U.S. Food and Drug Administration (FDA) as it regulates tobacco products. This paper examines the major provisions related to tobacco product advertising, marketing, sales, and distribution included in Public Law 111-31, the "Family Smoking Prevention and Tobacco Control Act". This paper covers 5 areas related to (a) marketing regulations (e.g., ban on color and imagery in ads, ban on nontobacco gifts with purchase); (b) granting FDA authority over the sale, distribution, accessibility, advertising, and promotion of tobacco and lifting state preemption over advertising; (c) remote tobacco sales (mail order and Internet); (d) prevention of illicit and cross-border trade; and (e) noncompliant export products. Each of the 5 sections of this paper provides a description and brief history of regulation, what is known about this regulatory strategy, and research opportunities. PMID- 21690317 TI - CHRNA3 rs1051730 genotype and short-term smoking cessation. AB - INTRODUCTION: The rs1051730 genetic variant within the CHRNA5-A3-B4 gene cluster is associated with heaviness of smoking and has recently been reported to be associated with likelihood of stopping smoking. We investigated the potential association of rs1051730 genotype with reduced likelihood of smoking cessation in 2 cohorts of treatment-seeking smokers in primary care in the United Kingdom. METHODS: Data were drawn from 2 clinical trials on which DNA was available. One sample was a randomized placebo-controlled trial of nicotine transdermal patch and the other sample an open-label trial where all participants received nicotine transdermal patch. Smoking status was biochemically verified. Logistic regression was used to assess evidence for association in each sample, and data were combined within a meta-analysis. RESULTS: There was evidence of association of rs1051730 genotype with short-term (4-week) cessation in our open-label trial sample but not our placebo-controlled trial sample. When combined in a meta analysis, this effect remained. There was no evidence of association at later follow-up intervals. Adjustment for cigarette consumption and tobacco dependence did not alter these results substantially. CONCLUSIONS: Our data, taken together with previous recent studies, provide some support for a weak association between this variant and short-term smoking cessation in treatment-seeking smokers, which does not seem to operate only among those receiving nicotine replacement therapy. Moreover, the rs1051730 variant may not merely operate as a marker for dependence or heaviness of smoking. PMID- 21690318 TI - Effects of 24 hours of tobacco withdrawal and subsequent tobacco smoking among low and high sensation seekers. AB - INTRODUCTION: Previous studies have indicated that high sensation seekers are more sensitive to the reinforcing effects of nicotine, initiate smoking at an earlier age, and smoke greater amounts of cigarettes. This study examined the influence of sensation-seeking status on tobacco smoking following deprivation in regular tobacco users. METHODS: Twenty healthy tobacco-smoking volunteers with low or high impulsive sensation-seeking subscale scores completed 2 consecutive test days per week for 3 consecutive weeks. Each week, a range of self-report, performance, and cardiovascular assessments were completed during ad libitum smoking on Day 1 and before and after the paced smoking of a tobacco cigarette containing 0.05, 0.6, or 0.9 mg of nicotine following 24 hr of tobacco deprivation on Day 2. In addition, self-administration behavior was analyzed during a 2-hr free access period after the initial tobacco administration. RESULTS: In high sensation seekers, tobacco smoking independent of nicotine yield ameliorated deprivation effects, whereas amelioration of deprivation effects was dependent on nicotine yield among low sensation seekers. However, this effect was limited to a small subset of measures. Subsequent cigarette self-administration increased in a nicotine-dependent manner for high sensation seekers only. CONCLUSIONS: Compared with low sensation seekers, high sensation seekers were more sensitive to the withdrawal relieving effects of nonnicotine components of smoking following 24 hr of deprivation on selective measures and more sensitive to nicotine yield during subsequent tobacco self-administration. These results are consistent with studies suggesting that factors driving tobacco dependence may vary as a function of sensation-seeking status. PMID- 21690319 TI - Economic effects of smoke-free laws on rural and urban counties in Kentucky and Ohio. AB - INTRODUCTION: Numerous empirical studies have examined the influence of smoke free legislation on economic activity, with most finding a null effect. The influence could possibly differ in rural areas relative to urban areas due to differing rates of smoking prevalence and access to prevention and treatment programs. Furthermore, the discussion of the effectiveness of smoke-free laws has been extended to consider local ordinances relative to statewide laws. This study examines these issues using 21 local laws in Kentucky and the Ohio statewide smoke-free law. METHODS: The number of employees, total wages paid, and number of reporting establishments in all hospitality and accommodation services in Kentucky and Ohio counties were documented, beginning the first quarter 2001 and ending the last quarter of 2009. A generalized estimating equation time-series design is used to estimate the impact of local and state smoke-free laws in Kentucky and Ohio rural and urban counties. RESULTS: There is no evidence that the economies in Kentucky counties were affected in any way from the implementation of local smoke-free laws. There was also no evidence that total employment or the number of establishments was influenced by the statewide law in Ohio, but wages increased following the implementation of the law. Furthermore, there is no evidence that either rural or urban counties experienced a loss of economic activity following smoke-free legislation. CONCLUSIONS: The study finds no evidence that local or state smoke-free legislation negatively influences local economies in either rural or urban communities. PMID- 21690320 TI - Paying women to quit smoking during pregnancy? Acceptability among pregnant women. AB - INTRODUCTION: There is growing international interest in the use of financial incentives in smoking cessation, yet little research on public opinion of the scheme. This paper reports on the acceptability of incentives for reducing smoking in pregnant women and the perceived size of incentive that would encourage smoking cessation during pregnancy. METHODS: A cross-sectional survey was conducted on a convenience sample of 213 women attending the antenatal clinic of a large public hospital in Australia. Participants completed a questionnaire on their views on the use of incentives with responses measured on a 5-point Likert scale. RESULTS: The majority of participants (60%) did not agree that paying pregnant smokers to quit is a good idea. Opinions regarding the likely effectiveness were mixed with 30% of respondents in agreement and 22% undecided. Most (62%) were not willing to pay smokers any amount to quit. Smokers were more likely to have more favorable views about incentives than nonsmokers (p < .0001) and considered payments of between $100 and >$1,000 acceptable as reward for quitting smoking. CONCLUSIONS: Acceptability for the use of financial incentives in reducing antenatal smoking is low among pregnant women. Future research should explore views of a wider audience and continue to gather stronger evidence of the efficacy of rewards for reducing smoking in pregnancy. PMID- 21690322 TI - Thymic stromal lymphopoietin is produced by dendritic cells. AB - Thymic stromal lymphopoietin (TSLP) is a type 1 cytokine that contributes to lymphopoiesis and the development of asthma and atopic dermatitis. TSLP acts on multiple lineages, including dendritic cells (DCs), T cells, NKT cells, eosinophils, and mast cells, mediating proliferation and survival and linking innate and adaptive immune responses. TSLP is produced by a range of cells, including epithelial cells, fibroblasts, stromal cells, and keratinocytes. DCs are important primary targets of TSLP, and we unexpectedly demonstrated that DCs also produce TSLP in response to TLR stimulation and that this is augmented by IL 4. Moreover, we demonstrated that when mice were challenged with house dust mite extract, lung CD11c(+) DCs expressed TSLP mRNA at an even higher level than did epithelial cells. These data suggested that DCs not only respond to TSLP but also are a source of TSLP during pathogen and/or allergen encounter. PMID- 21690321 TI - Neutrophil mobilization from the bone marrow during polymicrobial sepsis is dependent on CXCL12 signaling. AB - Neutrophils are essential for successful host eradication of bacterial pathogens and for survival to polymicrobial sepsis. During inflammation, the bone marrow provides a large reserve of neutrophils that are released into the peripheral circulation where they traverse to sites of infection. Although neutrophils are essential for survival, few studies have investigated the mechanisms responsible for neutrophil mobilization from the bone marrow during polymicrobial sepsis. Using a cecal ligation and puncture model of polymicrobial sepsis, we demonstrated that neutrophil mobilization from the bone marrow is not dependent on TLR4, MyD88, TRIF, IFNARalpha/beta, or CXCR2 pathway signaling during sepsis. In contrast, we observed that bone marrow CXCL12 mRNA abundance and specific CXCL12 levels are sharply reduced, whereas splenic CXCR4 mRNA and cell surface expression are increased during sepsis. Blocking CXCL12 activity significantly reduced blood neutrophilia by inhibiting bone marrow release of granulocytes during sepsis. However, CXCL12 inhibition had no impact on the expansion of bone marrow neutrophil precursors and hematopoietic progenitors. Bone marrow neutrophil retention by CXCL12 blockade prevented blood neutrophilia, inhibited peritoneal neutrophil accumulation, allowed significant peritoneal bacterial invasion, and increased polymicrobial sepsis mortality. We concluded that changes in the pattern of CXCL12 signaling during sepsis are essential for neutrophil bone marrow mobilization and host survival but have little impact on bone marrow granulopoiesis. PMID- 21690323 TI - A self-reactive TCR drives the development of Foxp3+ regulatory T cells that prevent autoimmune disease. AB - Although Foxp3(+) regulatory T cells (Tregs) are thought to express autoreactive TCRs, it is not clear how individual TCRs influence Treg development, phenotype, and function in vivo. We have generated TCR transgenic mice (termed SFZ70 mice) using Tcra and Tcrb genes cloned from an autoreactive CD4(+) T cell isolated from a Treg-deficient scurfy mouse. The SFZ70 TCR recognizes a cutaneous autoantigen and drives development of both conventional CD4(+) Foxp3(-) T cells (T(conv)) and Foxp3(+) Tregs. SFZ70 Tregs display an activated phenotype evidenced by robust proliferation and expression of skin-homing molecules such as CD103 and P selectin ligand. Analysis of Foxp3-deficient SFZ70 mice demonstrates that Tregs inhibit T(conv) cell expression of tissue-homing receptors and their production of proinflammatory cytokines. In addition, Treg suppression of SFZ70 T(conv) cells can be overcome by nonspecific activation of APCs. These results provide new insights into the differentiation and function of tissue-specific Tregs in vivo and provide a tractable system for analyzing the molecular requirements of Treg-mediated tolerance toward a cutaneous autoantigen. PMID- 21690324 TI - Clonally related CD8+ T cells responsible for rapid population of both diffuse nasal-associated lymphoid tissue and lung after respiratory virus infection. AB - The immune system has evolved to use sophisticated mechanisms to recruit lymphocytes to sites of pathogen exposure. Trafficking pathways are precise. For example, lymphocytes that are primed by gut pathogens can, in some cases, be imprinted with CCR9 membrane receptors, which can influence migration to the small intestine. Currently, little is known about T cell trafficking to the upper respiratory tract or the relationship between effectors that migrate to the diffuse nasal-associated lymphoid tissue (d-NALT), the lower airways, and the lung. To determine whether a T cell primed by Ag from a respiratory pathogen is imprinted for exclusive trafficking to the upper or lower respiratory tract or whether descendents from that cell have the capacity to migrate to both sites, we inoculated mice by the intranasal route with Sendai virus and conducted single cell-sequencing analyses of CD8(+) T lymphocytes responsive to a K(b)-restricted immunodominant peptide, FAPGNYPAL (Tet(+)). Cells from the d-NALT, lung airways (bronchoalveolar lavage), lung, and mediastinal lymph node were examined 10 d postinfection to determine TCR usage and clonal relationships. We discovered that 1) Tet(+) cells were heterogeneous but preferentially used TCR elements TRAV6, TRAV16, and TRBD1; 2) both N and C termini of Valpha and Vbeta TCR junctions frequently encompassed charged residues, perhaps facilitating TCR alphabeta pairing and interactions with a neutral target peptide; and 3) T cells in the d NALT were often clonally related to cells in the lower respiratory tract. PMID- 21690325 TI - FOXO3 deficiency leads to increased susceptibility to cigarette smoke-induced inflammation, airspace enlargement, and chronic obstructive pulmonary disease. AB - Forkhead box class O 3a (FOXO3) is a member of the FoxO transcription factor subfamily, which regulates the expression of target genes not only through DNA binding as a transcription factor, but also through protein-protein interaction. Although FoxO3 is a well-known transcription factor involved in diverse biological processes, the role of FoxO3 in cigarette smoke (CS)-induced lung inflammation and injury has not been studied. It is, therefore, hypothesized that deficiency of FoxO3 leads to increased susceptibility to CS-induced lung inflammatory response and airspace enlargement. In this article, we show that the levels of FOXO3 are significantly decreased in lungs of smokers and patients with chronic obstructive pulmonary disease, as well as in lungs of mice exposed to CS. Genetic ablation of FoxO3 led to pulmonary emphysema and exaggerated inflammatory response in lungs of mice exposed to CS. We further showed that CS induced the translocation of FoxO3 into the nucleus where FoxO3 interacted with NF-kappaB and disrupted NF-kappaB DNA-binding ability, leading to inhibition of its activity. Targeted disruption of FoxO3 also resulted in downregulation of antioxidant genes in mouse lungs in response to CS exposure. These results suggest that FoxO3 plays a pivotal role in regulation of lung inflammatory response and antioxidant genes, and deficiency of FoxO3 results in development of chronic obstructive pulmonary disease/emphysema. PMID- 21690326 TI - Simulations of the NK cell immune synapse reveal that activation thresholds can be established by inhibitory receptors acting locally. AB - NK cell activation is regulated by a balance between activating and inhibitory signals. To address the question of how these signals are spatially integrated, we created a computer simulation of activating and inhibitory NK cell immunological synapse (NKIS) assembly, implementing either a "quantity-based" inhibition model or a "distance-based" inhibition model. The simulations mimicked the observed molecule distributions in inhibitory and activating NKIS and yielded several new insights. First, the total signal is highly influenced by activating complex dissociation rates but not by adhesion and inhibitory complex dissociation rates. Second, concerted motion of receptors in clusters significantly accelerates NKIS maturation. Third, when the potential of a cis interaction between Ly49 receptors and MHC class I on murine NK cells was added to the model, the integrated signal as a function of receptor and ligand numbers was only slightly increased, at least up to the level of 50% cis-bound Ly49 receptors reached in the model. Fourth, and perhaps most importantly, the integrated signal behavior obtained when using the distance-based inhibition signal model was closer to the experimentally observed behavior, with an inhibition radius of the order 3-10 molecules. Microscopy to visualize Vav activation in NK cells on micropatterned surfaces of activating and inhibitory strips revealed that Vav is only locally activated where activating receptors are ligated within a single NK cell contact. Taken together, these data are consistent with a model in which inhibitory receptors act locally; that is, that every bound inhibitory receptor acts on activating receptors within a certain radius around it. PMID- 21690327 TI - Neonatal Fc receptor blockade by Fc engineering ameliorates arthritis in a murine model. AB - Multiple autoimmune diseases are characterized by the involvement of autoreactive Abs in pathogenesis. Problems associated with existing therapeutics such as the delivery of intravenous immunoglobulin have led to interest in developing alternative approaches using recombinant or synthetic methods. Toward this aim, in the current study, we demonstrate that the use of Fc-engineered Abs (Abs that enhance IgG degradation [Abdegs]) to block neonatal FcR (FcRn) through high affinity, Fc region binding is an effective strategy for the treatment of Ab mediated disease. Specifically, Abdegs can be used at low, single doses to treat disease in the K/B*N serum transfer model of arthritis using BALB/c mice as recipients. Similar therapeutic effects are induced by 25- to 50-fold higher doses of i.v. Ig. Importantly, we show that FcRn blockade is a primary contributing factor toward the observed reduction in disease severity. The levels of albumin, which is also recycled by FcRn, are not affected by Abdeg delivery. Consequently, Abdegs do not alter FcRn expression levels or subcellular trafficking behavior. The engineering of Ab Fc regions to generate potent FcRn blockers therefore holds promise for the therapy of Ab-mediated autoimmunity. PMID- 21690329 TI - Comment on "Chaperone activity of alpha B-crystallin is responsible for its incorrect assignment as an autoantigen in multiple sclerosis". PMID- 21690328 TI - Developmental arrest of T cells in Rpl22-deficient mice is dependent upon multiple p53 effectors. AB - alphabeta and gammadelta lineage T cells are thought to arise from a common CD4( )CD8(-) progenitor in the thymus. However, the molecular pathways controlling fate selection and maturation of these two lineages remain poorly understood. We demonstrated recently that a ubiquitously expressed ribosomal protein, Rpl22, is selectively required for the development of alphabeta lineage T cells. Germline ablation of Rpl22 impairs development of alphabeta lineage, but not gammadelta lineage, T cells through activation of a p53-dependent checkpoint. In this study, we investigate the downstream effectors used by p53 to impair T cell development. We found that many p53 targets were induced in Rpl22(-/-) thymocytes, including miR-34a, PUMA, p21(waf), Bax, and Noxa. Notably, the proapoptotic factor Bim, while not a direct p53 target, was also strongly induced in Rpl22(-/-) T cells. Gain-of-function analysis indicated that overexpression of miR-34a caused a developmental arrest reminiscent of that induced by p53 in Rpl22-deficient T cells; however, only a few p53 targets alleviated developmental arrest when individually ablated by gene targeting or knockdown. Co-elimination of PUMA and Bim resulted in a nearly complete restoration of development of Rpl22(-/-) thymocytes, indicating that p53-mediated arrest is enforced principally through effects on cell survival. Surprisingly, co-elimination of the primary p53 regulators of cell cycle arrest (p21(waf)) and apoptosis (PUMA) actually abrogated the partial rescue caused by loss of PUMA alone, suggesting that the G1 checkpoint protein p21(waf) facilitates thymocyte development in some contexts. PMID- 21690330 TI - The tetramer transformation. PMID- 21690331 TI - Phenotypic analysis of antigen-specific T lymphocytes. Science. 1996. 274: 94-96. PMID- 21690333 TI - Expanding the role of Drosha to the regulation of viral gene expression. AB - It is well-appreciated that viruses use host effectors for macromolecular synthesis and as regulators of viral gene expression. Viruses can encode their own regulators, but often use host-encoded factors to optimize replication. Here, we show that Drosha, an endoribonuclease best known for its role in the biogenesis of microRNAs (miRNAs), can also function to directly regulate viral gene expression. Kaposi's Sarcoma-associated Herpesvirus (KSHV) is associated with various tumors, and like all herpesviruses, has two modes of infection, latent and lytic, which are characterized by differential expression of viral gene products. Kaposin B (KapB) is a KSHV-encoded protein associated with cytokine production and cytotoxicity. We demonstrate that in addition to previously known transcriptional mechanisms, differences in Drosha levels contribute to low levels of KapB expression in latency and robust increases in expression during lytic replication. Thus, surprisingly, KSHV modulates Drosha activity differentially depending on the mode of replication. This regulation is dependent on Drosha-mediated cleavage, and KapB transcripts lacking the Drosha cleavage sites express higher levels of KapB, resulting in increased cell death. This work increases the known functions of Drosha and implies that tying viral gene expression to Drosha activity is advantageous for viruses. PMID- 21690332 TI - Variable NK cell receptors exemplified by human KIR3DL1/S1. AB - Variegated expression of variable NK cell receptors for polymorphic MHC class I broadens the range of an individual's NK cell response and the capacity for populations and species to survive disease epidemics and population bottlenecks. On evolutionary time scales, this component of immunity is exceptionally dynamic, unstable, and short-lived, being dependent on coevolution of ligands and receptors subject to varying, competing selection pressures. Consequently these systems of variable NK cell receptors are largely species specific and have recruited different classes of glycoprotein, even within the primate order of mammals. Such disparity helps to explain substantial differences in NK cell biology between humans and animal models, for which the population genetics is largely ignored. KIR3DL1/S1, which recognizes the Bw4 epitope of HLA-A and -B and is the most extensively studied of the variable NK cell receptors, exemplifies how variation in all possible parameters of function is recruited to diversify the human NK cell response. PMID- 21690334 TI - Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88. AB - Oil-in-water emulsions have been successfully used to increase the efficacy, immunogenicity, and cross-protection of human vaccines; however, their mechanism of action is still largely unknown. Nlrp3 inflammasome has been previously associated to the activity of alum, another adjuvant broadly used in human vaccines, and MyD88 adaptor protein is required for the adjuvanticity of most Toll-like receptor agonists. We compared the contribution of Nlrp3 and MyD88 to the adjuvanticity of alum, the oil-in-water emulsion MF59, and complete Freund's adjuvant in mice using a three-component vaccine against serogroup B Neisseria meningitidis (rMenB). Although the basal antibody responses to the nonadjuvanted rMenB vaccine were largely dependent on Nlrp3, the high-level antibody responses induced by alum, MF59, or complete Freund's adjuvant did not require Nlrp3. Surprisingly, we found that MF59 requires MyD88 to enhance bactericidal antibody responses to the rMenB vaccine. Because MF59 did not activate any of the Toll like receptors in vitro, we propose that MF59 requires MyD88 for a Toll-like receptor-independent signaling pathway. PMID- 21690335 TI - Neurotrophin-mediated dendrite-to-nucleus signaling revealed by microfluidic compartmentalization of dendrites. AB - Signaling from dendritic synapses to the nucleus regulates important aspects of neuronal function, including synaptic plasticity. The neurotrophin brain-derived neurotrophic factor (BDNF) can induce long-lasting strengthening of synapses in vivo and this effect is dependent on transcription. However, the mechanism of signaling to the nucleus is not well understood. Here we describe a microfluidic culture device to investigate dendrite-to-nucleus signaling. Using these microfluidic devices, we demonstrate that BDNF can act directly on dendrites to elicit an anterograde signal that induces transcription of the immediate early genes, Arc and c-Fos. Induction of Arc is dependent on dendrite- and cell body derived calcium, whereas induction of c-Fos is calcium-independent. In contrast to retrograde neurotrophin-mediated axon-to-nucleus signaling, which is MEK5 dependent, BDNF-mediated anterograde dendrite-to-nucleus signaling is dependent on MEK1/2. Intriguingly, the activity of TrkB, the BDNF receptor, is required in the cell body for the induction of Arc and c-Fos mediated by dendritically applied BDNF. These results are consistent with the involvement of a signaling endosome-like pathway that conveys BDNF signals from the dendrite to the nucleus. PMID- 21690336 TI - Diffusion model for one-choice reaction-time tasks and the cognitive effects of sleep deprivation. AB - One-choice reaction-time (RT) tasks are used in many domains, including assessments of motor vehicle driving and assessments of the cognitive/behavioral consequences of sleep deprivation. In such tasks, subjects are asked to respond when they detect the onset of a stimulus; the dependent variable is RT. We present a cognitive model for one-choice RT tasks that uses a one-boundary diffusion process to represent the accumulation of stimulus information. When the accumulated evidence reaches a decision criterion, a response is initiated. This model is distinct in accounting for the RT distributions observed for one-choice RT tasks, which can have long tails that have not been accurately captured by earlier cognitive modeling approaches. We show that the model explains performance on a brightness-detection task (a "simple RT task") and on a psychomotor vigilance test. The latter is used extensively to examine the clinical and behavioral effects of sleep deprivation. For the brightness detection task, the model explains the behavior of RT distributions as a function of brightness. For the psychomotor vigilance test, it accounts for lapses in performance under conditions of sleep deprivation and for changes in the shapes of RT distributions over the course of sleep deprivation. The model also successfully maps the rate of accumulation of stimulus information onto independently derived predictions of alertness. The model is a unified, mechanistic account of one-choice RT under conditions of sleep deprivation. PMID- 21690337 TI - A dynamical model of ommatidial crystal formation. AB - The crystalline photoreceptor lattice in the Drosophila eye is a paradigm for pattern formation during development. During eye development, activation of proneural genes at a moving front adds new columns to a regular lattice of R8 photoreceptors. We present a mathematical model of the governing activator inhibitor system, which indicates that the dynamics of positive induction play a central role in the selection of certain cells as R8s. The "switch and template" patterning mechanism we observe is mathematically very different from the well known Turing instability. Unlike a standard lateral inhibition model, our picture implies that R8s are defined before the appearance of the complete group of proneural cells. The model reproduces the full time course of proneural gene expression and accounts for specific features of the refinement of proneural groups that had resisted explanation. It moreover predicts that perturbing the normal template can lead to eyes containing stripes of R8 cells. We observed these stripes experimentally after manipulation of the Notch and scabrous genes. Our results suggest an alternative to the generally assumed mode of operation for lateral inhibition during development; more generally, they hint at a broader role for bistable switches in the initial establishment of patterns as well as in their maintenance. PMID- 21690338 TI - Evolution of cooperation and control of cheating in a social microbe. AB - Much of what we know about the evolution of altruism comes from animals. Here, we show that studying a microbe has yielded unique insights, particularly in understanding how social cheaters are controlled. The social stage of Dictylostelium discoideum occurs when the amoebae run out of their bacterial prey and aggregate into a multicellular, motile slug. This slug forms a fruiting body in which about a fifth of cells die to form a stalk that supports the remaining cells as they form hardy dispersal-ready spores. Because this social stage forms from aggregation, it is analogous to a social group, or a chimeric multicellular organism, and is vulnerable to internal conflict. Advances in cell labeling, microscopy, single-gene knockouts, and genomics, as well as the results of decades of study of D. discoideum as a model for development, allow us to explore the genetic basis of social contests and control of cheaters in unprecedented detail. Cheaters are limited from exploiting other clones by high relatedness, kin discrimination, pleiotropy, noble resistance, and lottery-like role assignment. The active nature of these limits is reflected in the elevated rates of change in social genes compared with nonsocial genes. Despite control of cheaters, some conflict is still expressed in chimeras, with slower movement of slugs, slightly decreased investment in stalk compared with spore cells, and differential contributions to stalk and spores. D. discoideum is rapidly becoming a model system of choice for molecular studies of social evolution. PMID- 21690339 TI - Evolutionary transitions in bacterial symbiosis. AB - Diverse bacterial lineages form beneficial infections with eukaryotic hosts. The origins, evolution, and breakdown of these mutualisms represent important evolutionary transitions. To examine these key events, we synthesize data from diverse interactions between bacteria and eukaryote hosts. Five evolutionary transitions are investigated, including the origins of bacterial associations with eukaryotes, the origins and subsequent stable maintenance of bacterial mutualism with hosts, the capture of beneficial symbionts via the evolution of strict vertical transmission within host lineages, and the evolutionary breakdown of bacterial mutualism. Each of these transitions has occurred many times in the history of bacterial-eukaryote symbiosis. We investigate these evolutionary events across the bacterial domain and also among a focal set of well studied bacterial mutualist lineages. Subsequently, we generate a framework for examining evolutionary transitions in bacterial symbiosis and test hypotheses about the selective, ecological, and genomic forces that shape these events. PMID- 21690340 TI - The cultural niche: why social learning is essential for human adaptation. AB - In the last 60,000 y humans have expanded across the globe and now occupy a wider range than any other terrestrial species. Our ability to successfully adapt to such a diverse range of habitats is often explained in terms of our cognitive ability. Humans have relatively bigger brains and more computing power than other animals, and this allows us to figure out how to live in a wide range of environments. Here we argue that humans may be smarter than other creatures, but none of us is nearly smart enough to acquire all of the information necessary to survive in any single habitat. In even the simplest foraging societies, people depend on a vast array of tools, detailed bodies of local knowledge, and complex social arrangements and often do not understand why these tools, beliefs, and behaviors are adaptive. We owe our success to our uniquely developed ability to learn from others. This capacity enables humans to gradually accumulate information across generations and develop well-adapted tools, beliefs, and practices that are too complex for any single individual to invent during their lifetime. PMID- 21690341 TI - Profile of B. Rosemary Grant. PMID- 21690342 TI - The HOXB7 protein renders breast cancer cells resistant to tamoxifen through activation of the EGFR pathway. AB - Multiple factors including long-term treatment with tamoxifen are involved in the development of selective estrogen receptor (ER) modulator resistance in ERalpha positive breast cancer. Many underlying molecular events that confer resistance are known but a unifying theme is yet to be revealed. In this report, we provide evidence that HOXB7 overexpression renders MCF-7 cells resistant to tamoxifen via cross-talk between receptor tyrosine kinases and ERalpha signaling. HOXB7 is an ERalpha-responsive gene. Extended treatment of MCF-7 cells with tamoxifen resulted in progressively increasing levels of HOXB7 expression, along with EGFR and EGFR ligands. Up-regulation of EGFR occurs through direct binding of HOXB7 to the EGFR promoter, enhancing transcriptional activity. Finally, higher expression levels of HOXB7 in the tumor significantly correlated with poorer disease-free survival in ERalpha-positive patients with breast cancer on adjuvant tamoxifen monotherapy. These studies suggest that HOXB7 acts as a key regulator, orchestrating a major group of target molecules in the oncogenic hierarchy. Functional antagonism of HOXB7 could circumvent tamoxifen resistance. PMID- 21690343 TI - Cooperation and competition in a cliff-dwelling people. AB - In animals that breed cooperatively, adult individuals will sometimes delay reproduction to act as helpers at the nest who raise young that are not their genetic offspring. It has been proposed that humans are also a cooperatively breeding species because older daughters, grandmothers, and other kin and nonkin may provide significant childcare. Through a prospective cohort study of children's (n = 1,700) growth and survival in the Dogon of Mali, I show that cooperative breeding theory is a poor fit to the family dynamics of this population. Rather than helping each other, siblings competed for resources, producing a tradeoff between the number of maternal siblings and growth and survival. It did not take a village to raise a child; children fared the same in nuclear as in extended families. Of critical importance was the degree of polygyny, which created conflicts associated with asymmetries in genetic relatedness. The risk of death was higher and the rate of growth was slower in polygynous than monogamous families. The hazard of death for Dogon children was twofold higher if the resident paternal grandmother was alive rather than dead. This finding may reflect the frailty of elderly grandmothers who become net consumers rather than net producers in this resource-poor society. Mothers were of overwhelming importance for child survival and could not be substituted by any category of kin or nonkin. The idea of cooperative breeding taken from animal studies is a poor fit to the complexity and diversity of kin interactions in humans. PMID- 21690344 TI - Kinship, greenbeards, and runaway social selection in the evolution of social insect cooperation. AB - Social Hymenoptera have played a leading role in development and testing of kin selection theory. Inclusive fitness models, following from Hamilton's rule, successfully predict major life history characteristics, such as biased sex investment ratios and conflict over parentage of male offspring. However, kin selection models poorly predict patterns of caste-biasing nepotism and reproductive skew within groups unless kin recognition constraints or group-level selection is also invoked. These successes and failures mirror the underlying kin recognition mechanisms. With reliable environmental cues, such as the sex of offspring or the origin of male eggs, predictions are supported. When only genetic recognition cues are potentially available, predictions are not supported. Mathematical simulations demonstrate that these differing mechanisms for determining kinship produce very different patterns of behavior. Decisions based on environmental cues for relatedness result in a robust mixture of cooperation and noncooperation depending on whether or not Hamilton's rule is met. In contrast, cooperation evolves under a wider range of conditions and to higher frequencies with genetic kin recognition as shared greenbeard traits. This "excess of niceness" matches the existing patterns in caste bias and reproductive skew; individuals often help others at an apparent cost to their inclusive fitness. The results further imply a potential for greenbeard-type kin recognition to create arbitrary runaway social selection for shared genetic traits. Suggestive examples in social evolution may be alloparental care and unicoloniality in ants. Differences in kin recognition mechanisms also can have consequences for maintenance of advantageous genetic diversity within populations. PMID- 21690345 TI - Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging. AB - Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits. Mice lacking the Cnr1 gene (Cnr1(-/-)), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated age dependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1(-/-) mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1(-/-) mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells. Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation. PMID- 21690346 TI - Rodent blood-stage Plasmodium survive in dendritic cells that infect naive mice. AB - Plasmodium spp. parasites cause malaria in 300 to 500 million individuals each year. Disease occurs during the blood-stage of the parasite's life cycle, where the parasite is thought to replicate exclusively within erythrocytes. Infected individuals can also suffer relapses after several years, from Plasmodium vivax and Plasmodium ovale surviving in hepatocytes. Plasmodium falciparum and Plasmodium malariae can also persist after the original bout of infection has apparently cleared in the blood, suggesting that host cells other than erythrocytes (but not hepatocytes) may harbor these blood-stage parasites, thereby assisting their escape from host immunity. Using blood stage transgenic Plasmodium berghei-expressing GFP (PbGFP) to track parasites in host cells, we found that the parasite had a tropism for CD317(+) dendritic cells. Other studies using confocal microscopy, in vitro cultures, and cell transfer studies showed that blood-stage parasites could infect, survive, and replicate within CD317(+) dendritic cells, and that small numbers of these cells released parasites infectious for erythrocytes in vivo. These data have identified a unique survival strategy for blood-stage Plasmodium, which has significant implications for understanding the escape of Plasmodium spp. from immune-surveillance and for vaccine development. PMID- 21690347 TI - Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. AB - Efforts to extend nanoparticle residence time in vivo have inspired many strategies in particle surface modifications to bypass macrophage uptake and systemic clearance. Here we report a top-down biomimetic approach in particle functionalization by coating biodegradable polymeric nanoparticles with natural erythrocyte membranes, including both membrane lipids and associated membrane proteins for long-circulating cargo delivery. The structure, size and surface zeta potential, and protein contents of the erythrocyte membrane-coated nanoparticles were verified using transmission electron microscopy, dynamic light scattering, and gel electrophoresis, respectively. Mice injections with fluorophore-loaded nanoparticles revealed superior circulation half-life by the erythrocyte-mimicking nanoparticles as compared to control particles coated with the state-of-the-art synthetic stealth materials. Biodistribution study revealed significant particle retention in the blood 72 h following the particle injection. The translocation of natural cellular membranes, their associated proteins, and the corresponding functionalities to the surface of synthetic particles represents a unique approach in nanoparticle functionalization. PMID- 21690348 TI - Functional motor recovery from brain ischemic insult by carbon nanotube-mediated siRNA silencing. AB - Stroke is the second cause of death worldwide with ischemic stroke accounting for 80% of all stroke insults. Caspase-3 activation contributes to brain tissue loss and downstream biochemical events that lead to programmed cell death after traumatic brain injury. Alleviation of symptoms following ischemic neuronal injury can be potentially achieved by either genetic disruption or pharmacological inhibition of caspases. Here, we studied whether silencing of Caspase-3 using carbon nanotube-mediated in vivo RNA interference (RNAi) could offer a therapeutic opportunity against stroke. Effective delivery of siRNA directly to the CNS has been shown to normalize phenotypes in animal models of several neurological diseases. It is shown here that peri-lesional stereotactic administration of a Caspase-3 siRNA (siCas 3) delivered by functionalized carbon nanotubes (f-CNT) reduced neurodegeneration and promoted functional preservation before and after focal ischemic damage of the rodent motor cortex using an endothelin-1 induced stroke model. These observations illustrate the opportunity offered by carbon nanotube-mediated siRNA delivery and gene silencing of neuronal tissue applicable to a variety of different neuropathological conditions where intervention at well localized brain foci may offer therapeutic and functional benefits. PMID- 21690350 TI - Gas uptake and chemical aging of semisolid organic aerosol particles. AB - Organic substances can adopt an amorphous solid or semisolid state, influencing the rate of heterogeneous reactions and multiphase processes in atmospheric aerosols. Here we demonstrate how molecular diffusion in the condensed phase affects the gas uptake and chemical transformation of semisolid organic particles. Flow tube experiments show that the ozone uptake and oxidative aging of amorphous protein is kinetically limited by bulk diffusion. The reactive gas uptake exhibits a pronounced increase with relative humidity, which can be explained by a decrease of viscosity and increase of diffusivity due to hygroscopic water uptake transforming the amorphous organic matrix from a glassy to a semisolid state (moisture-induced phase transition). The reaction rate depends on the condensed phase diffusion coefficients of both the oxidant and the organic reactant molecules, which can be described by a kinetic multilayer flux model but not by the traditional resistor model approach of multiphase chemistry. The chemical lifetime of reactive compounds in atmospheric particles can increase from seconds to days as the rate of diffusion in semisolid phases can decrease by multiple orders of magnitude in response to low temperature or low relative humidity. The findings demonstrate that the occurrence and properties of amorphous semisolid phases challenge traditional views and require advanced formalisms for the description of organic particle formation and transformation in atmospheric models of aerosol effects on air quality, public health, and climate. PMID- 21690349 TI - Fluid dynamics and noise in bacterial cell-cell and cell-surface scattering. AB - Bacterial processes ranging from gene expression to motility and biofilm formation are constantly challenged by internal and external noise. While the importance of stochastic fluctuations has been appreciated for chemotaxis, it is currently believed that deterministic long-range fluid dynamical effects govern cell-cell and cell-surface scattering-the elementary events that lead to swarming and collective swimming in active suspensions and to the formation of biofilms. Here, we report direct measurements of the bacterial flow field generated by individual swimming Escherichia coli both far from and near to a solid surface. These experiments allowed us to examine the relative importance of fluid dynamics and rotational diffusion for bacteria. For cell-cell interactions it is shown that thermal and intrinsic stochasticity drown the effects of long-range fluid dynamics, implying that physical interactions between bacteria are determined by steric collisions and near-field lubrication forces. This dominance of short range forces closely links collective motion in bacterial suspensions to self organization in driven granular systems, assemblages of biofilaments, and animal flocks. For the scattering of bacteria with surfaces, long-range fluid dynamical interactions are also shown to be negligible before collisions; however, once the bacterium swims along the surface within a few microns after an aligning collision, hydrodynamic effects can contribute to the experimentally observed, long residence times. Because these results are based on purely mechanical properties, they apply to a wide range of microorganisms. PMID- 21690351 TI - CD9 tetraspanin generates fusion competent sites on the egg membrane for mammalian fertilization. AB - CD9 tetraspanin is the only egg membrane protein known to be essential for fertilization. To investigate its role, we have measured, on a unique acrosome reacted sperm brought in contact with an egg, the adhesion probability and strength with a sensitivity of a single molecule attachment. Probing the binding events at different locations of wild-type egg we described different modes of interaction. Here, we show that more gamete adhesion events occur on Cd9 null eggs but that the strongest interaction mode disappears. We propose that sperm egg fusion is a direct consequence of CD9 controlled sperm-egg adhesion properties. CD9 generates adhesion sites responsible for the strongest of the observed gamete interaction. These strong adhesion sites impose, during the whole interaction lifetime, a tight proximity of the gamete membranes, which is a requirement for fusion to take place. The CD9-induced adhesion sites would be the actual location where fusion occurs. PMID- 21690352 TI - Microscopic events in beta-hairpin folding from alternative unfolded ensembles. AB - We have performed the first unbiased folding simulations of the GB1 hairpin in explicit solvent, using hundreds of microsecond-long molecular dynamics simulations (total time: 0.7 ms). Our simulations are initiated from two sets of structures. Starting from an equilibrium unfolded state, we obtain single exponential folding kinetics with rate coefficients in good agreement (T=350 K) or within an order of magnitude (T=300 K) of the experimental values. However, simulations initiated from unfolded configurations lacking secondary structure result in biexponential kinetics with an additional fast nanosecond kinetic mode. This mode can strongly bias the folding rate estimated from the mean first passage time, when the trials are much shorter than the folding time. We find that the mechanism of the hairpin folding is insensitive to the details of the initial unfolded ensemble and is initiated by correct formation of the turn of the hairpin, followed by the formation of the native hydrogen bonds and hydrophobic contacts, consistent with experimental -value analysis. Subsequent native interactions can be formed either from the turn or from the hairpin termini, helping to explain an apparent discrepancy in experimental results. From our simulations, we also obtain the transition path durations, a critical parameter for single molecule experiments aiming to resolve events along folding pathways. The lengths of transition paths span a wide range, from 50 ps to 140 ns, at 300 K. PMID- 21690353 TI - Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels. AB - The molecular basis of the thermal sensitivity of temperature-sensitive channels appears to arise from a specific protein domain rather than integration of global thermal effects. Using systematic chimeric analysis, we show that the N-terminal region that connects ankyrin repeats to the first transmembrane segment is crucial for temperature sensing in heat-activated vanilloid receptor channels. Changing this region both transformed temperature-insensitive isoforms into temperature-sensitive channels and significantly perturbed temperature sensing in temperature-sensitive wild-type channels. Swapping other domains such as the transmembrane core, the C terminus, and the rest of the N terminus had little effect on the steepness of temperature dependence. Our results support that thermal transient receptor potential channels contain modular thermal sensors that confer the unprecedentedly strong temperature dependence to these channels. PMID- 21690354 TI - Simulations of nuclear pore transport yield mechanistic insights and quantitative predictions. AB - To study transport through the nuclear pore complex, we developed a computational simulation that is based on known structural elements rather than a particular transport model. Results agree with a variety of experimental data including size cutoff for cargo transport with (30-nm diameter) and without (< 10 nm) nuclear localization signals (NLS), macroscopic transport rates (hundreds per second), and single cargo transit times (milliseconds). The recently observed bimodal cargo distribution is predicted, as is the relative invariance of single cargo transit times out to large size (even as macroscopic transport rate decreases). Additional predictions concern the effects of the number of NLS tags, the RanGTP gradient, and phenylalanine-glycine nucleopore protein (FG-Nup) structure, flexibility, and cross-linking. Results are consistent with and elucidate the molecular mechanisms of some existing hypotheses (selective phase, virtual gate, and selective gate models). A model emerges that is a hybrid of a number of preexisting models as well as a Brownian ratchet model, in which a cargo karyopherin complex remains bound to the same FG-Nups for its entire trajectory through the nuclear pore complex until RanGTP severs the cargo-Nup bonds to effect release into the nucleus. PMID- 21690355 TI - Multiscale approach to link red blood cell dynamics, shear viscosity, and ATP release. AB - RBCs are known to release ATP, which acts as a signaling molecule to cause dilation of blood vessels. A reduction in the release of ATP from RBCs has been linked to diseases such as type II diabetes and cystic fibrosis. Furthermore, reduced deformation of RBCs has been correlated with myocardial infarction and coronary heart disease. Because ATP release has been linked to cell deformation, we undertook a multiscale approach to understand the links between single RBC dynamics, ATP release, and macroscopic viscosity all at physiological shear rates. Our experimental approach included microfluidics, ATP measurements using a bioluminescent reaction, and rheology. Using microfluidics technology with high speed imaging, we visualize the deformation and dynamics of single cells, which are known to undergo motions such as tumbling, swinging, tanktreading, and deformation. We report that shear thinning is not due to cellular deformation as previously believed, but rather it is due to the tumbling-to-tanktreading transition. In addition, our results indicate that ATP release is constant at shear stresses below a threshold (3 Pa), whereas above the threshold ATP release is increased and accompanied by large cellular deformations. Finally, performing experiments with well-known inhibitors, we show that the Pannexin 1 hemichannel is the main avenue for ATP release both above and below the threshold, whereas, the cystic fibrosis transmembrane conductance regulator only contributes to deformation-dependent ATP release above the stress threshold. PMID- 21690356 TI - Protein crystallization facilitated by molecularly imprinted polymers. AB - We present a previously undescribed initiative and its application, namely the design of molecularly imprinted polymers (MIPs) for producing protein crystals that are essential for determining high-resolution 3D structures of proteins. MIPs, also referred to as "smart materials," are made to contain cavities capable of rebinding protein; thus the fingerprint of the protein created on the polymer allows it to serve as an ideal template for crystal formation. We have shown that six different MIPs induced crystallization of nine proteins, yielding crystals in conditions that do not give crystals otherwise. The incorporation of MIPs in screening experiments gave rise to crystalline hits in 8-10% of the trials for three target proteins. These hits would have been missed using other known nucleants. MIPs also facilitated the formation of large single crystals at metastable conditions for seven proteins. Moreover, the presence of MIPs has led to faster formation of crystals in all cases where crystals would appear eventually and to major improvement in diffraction in some cases. The MIPs were effective for their cognate proteins and also for other proteins, with size compatibility being a likely criterion for efficacy. Atomic force microscopy (AFM) measurements demonstrated specific affinity between the MIP cavities and a protein-functionalized AFM tip, corroborating our hypothesis that due to the recognition of proteins by the cavities, MIPs can act as nucleation-inducing substrates (nucleants) by harnessing the proteins themselves as templates. PMID- 21690357 TI - Measurement of radon and xenon binding to a cryptophane molecular host. AB - Xenon and radon have many similar properties, a difference being that all 35 isotopes of radon ((195)Rn-(229)Rn) are radioactive. Radon is a pervasive indoor air pollutant believed to cause significant incidence of lung cancer in many geographic regions, yet radon affinity for a discrete molecular species has never been determined. By comparison, the chemistry of xenon has been widely studied and applied in science and technology. Here, both noble gases were found to bind with exceptional affinity to tris-(triazole ethylamine) cryptophane, a previously unsynthesized water-soluble organic host molecule. The cryptophane-xenon association constant, K(a)=42,000 +/- 2,000 M(-1) at 293 K, was determined by isothermal titration calorimetry. This value represents the highest measured xenon affinity for a host molecule. The partitioning of radon between air and aqueous cryptophane solutions of varying concentration was determined radiometrically to give the cryptophane-radon association constant K(a)=49,000 +/ 12,000 M(-1) at 293 K. PMID- 21690358 TI - Designing super selectivity in multivalent nano-particle binding. AB - A key challenge in nano-science is to design ligand-coated nano-particles that can bind selectively to surfaces that display the cognate receptors above a threshold (surface) concentration. Nano-particles that bind monovalently to a target surface do not discriminate sharply between surfaces with high and low receptor coverage. In contrast, "multivalent" nano-particles that can bind to a larger number of ligands simultaneously, display regimes of "super selectivity" where the fraction of bound particles varies sharply with the receptor concentration. We present numerical simulations that show that multivalent nano particles can be designed such that they approach the "on-off" binding behavior ideal for receptor-concentration selective targeting. We propose a simple analytical model that accounts for the super selective behavior of multivalent nano-particles. The model shows that the super selectivity is due to the fact that the number of distinct ligand-receptor binding arrangements increases in a highly nonlinear way with receptor coverage. Somewhat counterintuitively, our study shows that selectivity can be improved by making the individual ligand receptor bonds weaker. We propose a simple rule of thumb to predict the conditions under which super selectivity can be achieved. We validate our model predictions against the Monte Carlo simulations. PMID- 21690359 TI - Kinetic design of the respiratory oxidases. AB - Energy conservation in all kingdoms of life involves electron transfer, through a number of membrane-bound proteins, associated with proton transfer across the membrane. In aerobic organisms, the last component of this electron-transfer chain is a respiratory heme-copper oxidase that catalyzes reduction of O(2) to H(2)O, linking this process to transmembrane proton pumping. So far, the molecular mechanism of proton pumping is not known for any system that is driven by electron transfer. Here, we show that this problem can be addressed and elucidated in a unique cytochrome c oxidase (cytochrome ba(3)) from a thermophilic bacterium, Thermus thermophilus. The results show that in this oxidase the electron- and proton-transfer reactions are orchestrated in time such that previously unresolved proton-transfer reactions could be directly observed. On the basis of these data we propose that loading of the proton pump occurs upon electron transfer, but before substrate proton transfer, to the catalytic site. Furthermore, the results suggest that the pump site alternates between a protonated and deprotonated state for every second electron transferred to the catalytic site, which would explain the noninteger pumping stoichiometry (0.5 H(+)/e(-)) of the ba(3) oxidase. Our studies of this variant of Nature's palette of mechanistic solutions to a basic problem offer a route toward understanding energy conservation in biological systems. PMID- 21690361 TI - Glass-liquid transition of water at high pressure. AB - The knowledge of the existence of liquid water under extreme conditions and its concomitant properties are important in many fields of science. Glassy water has previously been prepared by hyperquenching micron-sized droplets of liquid water and vapor deposition on a cold substrate (ASW), and its transformation to an ultraviscous liquid form has been reported on heating. A densified amorphous solid form of water, high-density amorphous ice (HDA), has also been made by collapsing the structure of ice at pressures above 1 GPa and temperatures below approximately 140 K, but a corresponding liquid phase has not been detected. Here we report results of heat capacity C(p) and thermal conductivity, in situ, measurements, which are consistent with a reversible transition from annealed HDA to ultraviscous high-density liquid water at 1 GPa and 140 K. On heating of HDA, the C(p) increases abruptly by (3.4 +/- 0.2) J mol(-1) K(-1) before crystallization starts at (153 +/- 1) K. This is larger than the C(p) rise at the glass to liquid transition of annealed ASW at 1 atm, which suggests the existence of liquid water under these extreme conditions. PMID- 21690360 TI - Measuring single-cell density. AB - We have used a microfluidic mass sensor to measure the density of single living cells. By weighing each cell in two fluids of different densities, our technique measures the single-cell mass, volume, and density of approximately 500 cells per hour with a density precision of 0.001 g mL(-1). We observe that the intrinsic cell-to-cell variation in density is nearly 100-fold smaller than the mass or volume variation. As a result, we can measure changes in cell density indicative of cellular processes that would be otherwise undetectable by mass or volume measurements. Here, we demonstrate this with four examples: identifying Plasmodium falciparum malaria-infected erythrocytes in a culture, distinguishing transfused blood cells from a patient's own blood, identifying irreversibly sickled cells in a sickle cell patient, and identifying leukemia cells in the early stages of responding to a drug treatment. These demonstrations suggest that the ability to measure single-cell density will provide valuable insights into cell state for a wide range of biological processes. PMID- 21690362 TI - Crystal engineering rescues a solution organic synthesis in a cocrystallization that confirms the configuration of a molecular ladder. AB - Treatment of an achiral molecular ladder of C(2h) symmetry composed of five edge sharing cyclobutane rings, or a [5]-ladderane, with acid results in cis- to trans isomerization of end pyridyl groups. Solution NMR spectroscopy and quantum chemical calculations support the isomerization to generate two diastereomers. The NMR data, however, could not lead to unambiguous configurational assignments of the two isomers. Single-crystal X-ray diffraction was employed to determine each configuration. One isomer readily crystallized as a pure form and X-ray diffraction revealed the molecule as being achiral based on C(i) symmetry. The second isomer resisted crystallization under a variety of conditions. Consequently, a strategy based on a cocrystallization was developed to generate single crystals of the second isomer. Cocrystallization of the isomer with a carboxylic acid readily afforded single crystals that confirmed a chiral ladderane based on C(2) symmetry. The chiral ladderane and acid self-assembled to generate a five-component hydrogen-bonded complex that packs to form large solvent-filled homochiral channels of nanometer-scale dimensions. Whereas cocrystallizations are frequently applied to structure determinations of proteins, our study represents the first application of a cocrystallization to confirm the relative configuration of a small-molecule diastereomer generated in a solution-phase organic synthesis. PMID- 21690363 TI - Tungsten tetraboride, an inexpensive superhard material. AB - Tungsten tetraboride (WB(4)) is an interesting candidate as a less expensive member of the growing group of superhard transition metal borides. WB(4) was successfully synthesized by arc melting from the elements. Characterization using powder X-ray diffraction (XRD) and energy-dispersive X-ray spectroscopy (EDX) indicates that the as-synthesized material is phase pure. The zero-pressure bulk modulus, as measured by high-pressure X-ray diffraction for WB(4), is 339 GPa. Mechanical testing using microindentation gives a Vickers hardness of 43.3 +/- 2.9 GPa under an applied load of 0.49 N. Various ratios of rhenium were added to WB(4) in an attempt to increase hardness. With the addition of 1 at.% Re, the Vickers hardness increased to approximately 50 GPa at 0.49 N. Powders of tungsten tetraboride with and without 1 at.% Re addition are thermally stable up to approximately 400 degrees C in air as measured by thermal gravimetric analysis. PMID- 21690364 TI - Uncertainties in climate assessment for the case of aviation NO. AB - Nitrogen oxides emitted from aircraft engines alter the chemistry of the atmosphere, perturbing the greenhouse gases methane (CH(4)) and ozone (O(3)). We quantify uncertainties in radiative forcing (RF) due to short-lived increases in O(3), long-lived decreases in CH(4) and O(3), and their net effect, using the ensemble of published models and a factor decomposition of each forcing. The decomposition captures major features of the ensemble, and also shows which processes drive the total uncertainty in several climate metrics. Aviation specific factors drive most of the uncertainty for the short-lived O(3) and long lived CH(4) RFs, but a nonaviation factor dominates for long-lived O(3). The model ensemble shows strong anticorrelation between the short-lived and long lived RF perturbations (R(2)=0.87). Uncertainty in the net RF is highly sensitive to this correlation. We reproduce the correlation and ensemble spread in one model, showing that processes controlling the background tropospheric abundance of nitrogen oxides are likely responsible for the modeling uncertainty in climate impacts from aviation. PMID- 21690365 TI - Evolution of cyclic peptide protease inhibitors. AB - We report a bacterial system for the evolution of cyclic peptides that makes use of an expanded set of amino acid building blocks. Orthogonal aminoacyl-tRNA synthetase/tRNA(CUA) pairs, together with a split intein system were used to biosynthesize a library of ribosomal peptides containing amino acids with unique structures and reactivities. This peptide library was subsequently used to evolve an inhibitor of HIV protease using a selection based on cellular viability. Two of three cyclic peptides isolated after two rounds of selection contained the keto amino acid p-benzoylphenylalanine (pBzF). The most potent peptide (G12: GIXVSL; X=pBzF) inhibited HIV protease through the formation of a covalent Schiff base adduct of the pBzF residue with the epsilon-amino group of Lys 14 on the protease. This result suggests that an expanded genetic code can confer an evolutionary advantage in response to selective pressure. Moreover, the combination of natural evolutionary processes with chemically biased building blocks provides another strategy for the generation of biologically active peptides using microbial systems. PMID- 21690366 TI - The MspJI family of modification-dependent restriction endonucleases for epigenetic studies. AB - MspJI is a novel modification-dependent restriction endonuclease that cleaves at a fixed distance away from the modification site. Here, we present the biochemical characterization of several MspJI homologs, including FspEI, LpnPI, AspBHI, RlaI, and SgrTI. All of the enzymes specifically recognize cytosine C5 modification (methylation or hydroxymethylation) in DNA and cleave at a constant distance (N(12)/N(16)) away from the modified cytosine. Each displays its own sequence context preference, favoring different nucleotides flanking the modified cytosine. By cleaving on both sides of fully modified CpG sites, they allow the extraction of 32-base long fragments around the modified sites from the genomic DNA. These enzymes provide powerful tools for direct interrogation of the epigenome. For example, we show that RlaI, an enzyme that prefers (m)CWG but not (m)CpG sites, generates digestion patterns that differ between plant and mammalian genomic DNA, highlighting the difference between their epigenomic patterns. In addition, we demonstrate that deep sequencing of the digested DNA fragments generated from these enzymes provides a feasible method to map the modified sites in the genome. Altogether, the MspJI family of enzymes represent appealing tools of choice for method development in DNA epigenetic studies. PMID- 21690367 TI - Climate related sea-level variations over the past two millennia. AB - We present new sea-level reconstructions for the past 2100 y based on salt-marsh sedimentary sequences from the US Atlantic coast. The data from North Carolina reveal four phases of persistent sea-level change after correction for glacial isostatic adjustment. Sea level was stable from at least BC 100 until AD 950. Sea level then increased for 400 y at a rate of 0.6 mm/y, followed by a further period of stable, or slightly falling, sea level that persisted until the late 19th century. Since then, sea level has risen at an average rate of 2.1 mm/y, representing the steepest century-scale increase of the past two millennia. This rate was initiated between AD 1865 and 1892. Using an extended semiempirical modeling approach, we show that these sea-level changes are consistent with global temperature for at least the past millennium. PMID- 21690368 TI - Structural contributions to multidrug recognition in the multidrug resistance (MDR) gene regulator, BmrR. AB - Current views of multidrug (MD) recognition focus on large drug-binding cavities with flexible elements. However, MD recognition in BmrR is supported by a small, rigid drug-binding pocket. Here, a detailed description of MD binding by the noncanonical BmrR protein is offered through the combined use of X-ray and solution studies. Low shape complementarity, suboptimal packing, and efficient burial of a diverse set of ligands is facilitated by an aromatic docking platform formed by a set of conformationally fixed aromatic residues, hydrophobic pincer pair that locks the different drug structures on the adaptable platform surface, and a trio of acidic residues that enables cation selectivity without much regard to ligand structure. Within the binding pocket is a set of BmrR-derived H-bonding donor and acceptors that solvate a wide range of ligand polar substituent arrangements in a manner analogous to aqueous solvent. Energetic analyses of MD binding by BmrR are consistent with structural data. A common binding orientation for the different BmrR ligands is in line with promiscuous allosteric regulation. PMID- 21690370 TI - New family of tilings of three-dimensional Euclidean space by tetrahedra and octahedra. AB - It is well known that two regular tetrahedra can be combined with a single regular octahedron to tile (complete fill) three-dimensional Euclidean space . This structure was called the "octet truss" by Buckminster Fuller. It was believed that such a tiling, which is the Delaunay tessellation of the face centered cubic (fcc) lattice, and its closely related stacking variants, are the only tessellations of that involve two different regular polyhedra. Here we identify and analyze a unique family comprised of a noncountably infinite number of periodic tilings of whose smallest repeat tiling unit consists of one regular octahedron and six smaller regular tetrahedra. We first derive an extreme member of this unique tiling family by showing that the "holes" in the optimal lattice packing of octahedra, obtained by Minkowski over a century ago, are congruent tetrahedra. This tiling has 694 distinct concave (i.e., nonconvex) repeat units, 24 of which possess central symmetry, and hence is distinctly different and combinatorically richer than the fcc tetrahedra-octahedra tiling, which only has two distinct tiling units. Then we construct a one-parameter family of octahedron packings that continuously spans from the fcc to the optimal lattice packing of octahedra. We show that the "holes" in these packings, except for the two extreme cases, are tetrahedra of two sizes, leading to a family of periodic tilings with units composed four small tetrahedra and two large tetrahedra that contact an octahedron. These tilings generally possess 2,068 distinct concave tiling units, 62 of which are centrally symmetric. PMID- 21690369 TI - Structure of Trypanosoma brucei flagellum accounts for its bihelical motion. AB - Trypanosoma brucei is a parasitic protozoan that causes African sleeping sickness. It contains a flagellum required for locomotion and viability. In addition to a microtubular axoneme, the flagellum contains a crystalline paraflagellar rod (PFR) and connecting proteins. We show here, by cryoelectron tomography, the structure of the flagellum in three bending states. The PFR lattice in straight flagella repeats every 56 nm along the length of the axoneme, matching the spacing of the connecting proteins. During flagellar bending, the PFR crystallographic unit cell lengths remain constant while the interaxial angles vary, similar to a jackscrew. The axoneme drives the expansion and compression of the PFR lattice. We propose that the PFR modifies the in-plane axoneme motion to produce the characteristic trypanosome bihelical motility as captured by high-speed light microscope videography. PMID- 21690371 TI - Evolution of restraint in a structured rock-paper-scissors community. AB - It is not immediately clear how costly behavior that benefits others evolves by natural selection. By saving on inherent costs, individuals that do not contribute socially have a selective advantage over altruists if both types receive equal benefits. Restrained consumption of a common resource is a form of altruism. The cost of this kind of prudent behavior is that restrained individuals give up resources to less-restrained individuals. The benefit of restraint is that better resource management may prolong the persistence of the group. One way to dodge the problem of defection is for altruists to interact disproportionately with other altruists. With limited dispersal, restrained individuals persist because of interaction with like types, whereas it is the unrestrained individuals that must face the negative long-term consequences of their rapacity. Here, we study the evolution of restraint in a community of three competitors exhibiting a nontransitive (rock-paper-scissors) relationship. The nontransitivity ensures a form of negative feedback, whereby improvement in growth of one competitor has the counterintuitive consequence of lowering the density of that improved player. This negative feedback generates detrimental long-term consequences for unrestrained growth. Using both computer simulations and evolution experiments with a nontransitive community of Escherichia coli, we find that restrained growth can evolve under conditions of limited dispersal in which negative feedback is present. This research, thus, highlights a set of ecological conditions sufficient for the evolution of one form of altruism. PMID- 21690372 TI - Evolutionary foundations of human prosocial sentiments. AB - A growing body of evidence shows that humans are remarkably altruistic primates. Food sharing and division of labor play an important role in all human societies, and cooperation extends beyond the bounds of close kinship and networks of reciprocating partners. In humans, altruism is motivated at least in part by empathy and concern for the welfare of others. Although altruistic behavior is well-documented in other primates, the range of altruistic behaviors in other primate species, including the great apes, is much more limited than it is in humans. Moreover, when altruism does occur among other primates, it is typically limited to familiar group members--close kin, mates, and reciprocating partners. This suggests that there may be fundamental differences in the social preferences that motivate altruism across the primate order, and there is currently considerable interest in how we came to be such unusual apes. A body of experimental studies designed to examine the phylogenetic range of prosocial sentiments and behavior is beginning to shed some light on this issue. In experimental settings, chimpanzees and tamarins do not consistently take advantage of opportunities to deliver food rewards to others, although capuchins and marmosets do deliver food rewards to others in similar kinds of tasks. Although chimpanzees do not satisfy experimental criteria for prosociality in food delivery tasks, they help others complete tasks to obtain a goal. Differences in performance across species and differences in performance across tasks are not yet fully understood and raise new questions for further study. PMID- 21690373 TI - Glycogen synthase kinase 3 beta-dependent Snail degradation directs hepatocyte proliferation in normal liver regeneration. AB - Liver regeneration proceeds under the well-orchestrated control of multiple transcription factors that lead hepatocytes to reenter the cell cycle, proliferate, and renew quiescence. Here, we found an important role of the zinc finger transcription factor Snail in liver regeneration. Snail was typically expressed in quiescent adult hepatocytes, but was rapidly degraded when the liver needed to regenerate itself. Decreased levels of Snail induced DNA synthesis in hepatocytes through up-regulation of cell cycle-related proteins. Snail degradation was dependent on phosphorylation by glycogen synthase kinase (GSK) 3beta, whose quantity and activity were immediately increased after loss of liver mass or hepatic injury. Inactivation of GSK-3beta resulted in suppression of Snail degradation and DNA synthesis in hepatocytes, leading to impaired liver growth during regeneration. This GSK-3beta-dependent Snail degradation occurred as a result of cytokine, growth factor, and bile acid signals that are known to drive liver regeneration. Thus, GSK-3beta-dependent Snail degradation acts as a fundamental cue for the initiation of hepatocyte proliferation in liver regeneration. PMID- 21690374 TI - Transcription factor Lhx2 is necessary and sufficient to suppress astrogliogenesis and promote neurogenesis in the developing hippocampus. AB - The sequential production of neurons and astrocytes from neuroepithelial precursors is a fundamental feature of central nervous system development. We report that LIM-homeodomain (LIM-HD) transcription factor Lhx2 regulates this transition in the developing hippocampus. Disrupting Lhx2 function in the embryonic hippocampus by in utero electroporation and in organotypic slice culture caused the premature production of astrocytes at stages when neurons are normally generated. Lhx2 function is therefore necessary to suppress astrogliogenesis during the neurogenic period. Furthermore, Lhx2 overexpression was sufficient to suppress astrogliogenesis and prolong the neurogenic period. We provide evidence that Lhx2 overexpression can counteract the instructive astrogliogenic effect of Notch activation. Lhx2 overexpression was also able to override and suppress the activation of the GFAP promoter by Nfia, a Notch regulated transcription factor that is required for gliogenesis. Thus, Lhx2 appears to act as a "brake" on Notch/Nfia-mediated astrogliogenesis. This critical role for Lhx2 is spatially restricted to the hippocampus, because loss of Lhx2 function in the neocortex did not result in premature astrogliogenesis at the expense of neurogenesis. Our results therefore place Lhx2 as a central regulator of the neuron-glia cell fate decision in the hippocampus and reveal a striking regional specificity of this fundamental function within the dorsal telencephalon. PMID- 21690375 TI - Neural substrates of cognitive capacity limitations. AB - Cognition has a severely limited capacity: Adult humans can retain only about four items "in mind". This limitation is fundamental to human brain function: Individual capacity is highly correlated with intelligence measures and capacity is reduced in neuropsychiatric diseases. Although human capacity limitations are well studied, their mechanisms have not been investigated at the single-neuron level. Simultaneous recordings from monkey parietal and frontal cortex revealed that visual capacity limitations occurred immediately upon stimulus encoding and in a bottom-up manner. Capacity limitations were found to reflect a dual model of working memory. The left and right halves of visual space had independent capacities and thus are discrete resources. However, within each hemifield, neural information about successfully remembered objects was reduced by adding further objects, indicating that resources are shared. Together, these results suggest visual capacity limitation is due to discrete, slot-like, resources, each containing limited pools of neural information that can be divided among objects. PMID- 21690376 TI - The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy. AB - The evolution of drug-resistant pathogens is a major challenge for 21st century medicine. Drug use practices vigorously advocated as resistance management tools by professional bodies, public health agencies, and medical schools represent some of humankind's largest attempts to manage evolution. It is our contention that these practices have poor theoretical and empirical justification for a broad spectrum of diseases. For instance, rapid elimination of pathogens can reduce the probability that de novo resistance mutations occur. This idea often motivates the medical orthodoxy that patients should complete drug courses even when they no longer feel sick. Yet "radical pathogen cure" maximizes the evolutionary advantage of any resistant pathogens that are present. It could promote the very evolution it is intended to retard. The guiding principle should be to impose no more selection than is absolutely necessary. We illustrate these arguments in the context of malaria; they likely apply to a wide range of infections as well as cancer and public health insecticides. Intuition is unreliable even in simple evolutionary contexts; in a social milieu where in-host competition can radically alter the fitness costs and benefits of resistance, expert opinion will be insufficient. An evidence-based approach to resistance management is required. PMID- 21690377 TI - Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a leading cause of visual dysfunction worldwide. Amyloid beta (Abeta) peptides, Abeta1-40 (Abeta40) and Abeta1-42 (Abeta42), have been implicated previously in the AMD disease process. Consistent with a pathogenic role for Abeta, we show here that a mouse model of AMD that invokes multiple factors that are known to modify AMD risk (aged human apolipoprotein E 4 targeted replacement mice on a high-fat, cholesterol-enriched diet) presents with Abeta-containing deposits basal to the retinal pigmented epithelium (RPE), histopathologic changes in the RPE, and a deficit in scotopic electroretinographic response, which is reflective of impaired visual function. Strikingly, these electroretinographic deficits are abrogated in a dose-dependent manner by systemic administration of an antibody targeting the C termini of Abeta40 and Abeta42. Concomitant reduction in the levels of Abeta and activated complement components in sub-RPE deposits and structural preservation of the RPE are associated with anti-Abeta40/42 antibody immunotherapy and visual protection. These observations are consistent with the reduction in amyloid plaques and improvement of cognitive function in mouse models of Alzheimer's disease treated with anti-Abeta antibodies. They also implicate Abeta in the pathogenesis of AMD and identify Abeta as a viable therapeutic target for its treatment. PMID- 21690378 TI - MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. AB - MicroRNA (miRNA) species (miR) regulate mRNA translation and are implicated as mediators of disease pathology via coordinated regulation of molecular effector pathways. Unraveling miR disease-related activities will facilitate future therapeutic interventions. miR-155 recently has been identified with critical immune regulatory functions. Although detected in articular tissues, the functional role of miR-155 in inflammatory arthritis has not been defined. We report here that miR-155 is up-regulated in synovial membrane and synovial fluid (SF) macrophages from patients with rheumatoid arthritis (RA). The increased expression of miR-155 in SF CD14(+) cells was associated with lower expression of the miR-155 target, Src homology 2-containing inositol phosphatase-1 (SHIP-1), an inhibitor of inflammation. Similarly, SHIP-1 expression was decreased in CD68(+) cells in the synovial lining layer in RA patients as compared with osteoarthritis patients. Overexpression of miR-155 in PB CD14(+) cells led to down-regulation of SHIP-1 and an increase in the production of proinflammatory cytokines. Conversely, inhibition of miR-155 in RA synovial CD14(+) cells reduced TNF-alpha production. Finally, miR-155-deficient mice are resistant to collagen-induced arthritis, with profound suppression of antigen-specific Th17 cell and autoantibody responses and markedly reduced articular inflammation. Our data therefore identify a role of miR-155 in clinical and experimental arthritis and suggest that miR-155 may be an intriguing therapeutic target. PMID- 21690379 TI - In the light of evolution V: cooperation and conflict. PMID- 21690380 TI - Social evolution in multispecies biofilms. AB - Microbial ecology is revealing the vast diversity of strains and species that coexist in many environments, ranging from free-living communities to the symbionts that compose the human microbiome. In parallel, there is growing evidence of the importance of cooperative phenotypes for the growth and behavior of microbial groups. Here we ask: How does the presence of multiple species affect the evolution of cooperative secretions? We use a computer simulation of spatially structured cellular groups that captures key features of their biology and physical environment. When nutrient competition is strong, we find that the addition of new species can inhibit cooperation by eradicating secreting strains before they can become established. When nutrients are abundant and many species mix in one environment, however, our model predicts that secretor strains of any one species will be surrounded by other species. This "social insulation" protects secretors from competition with nonsecretors of the same species and can improve the prospects of within-species cooperation. We also observe constraints on the evolution of mutualistic interactions among species, because it is difficult to find conditions that simultaneously favor both within- and among species cooperation. Although relatively simple, our model reveals the richness of interactions between the ecology and social evolution of multispecies microbial groups, which can be critical for the evolution of cooperation. PMID- 21690381 TI - Endogenous GABA(A) and GABA(B) receptor-mediated electrical suppression is critical to neuronal anoxia tolerance. AB - Anoxic insults cause hyperexcitability and cell death in mammalian neurons. Conversely, in anoxia-tolerant turtle brain, spontaneous electrical activity is suppressed by anoxia (i.e., spike arrest; SA) and cell death does not occur. The mechanism(s) of SA is unknown but likely involves GABAergic synaptic transmission, because GABA concentration increases dramatically in anoxic turtle brain. We investigated this possibility in turtle cortical neurons exposed to anoxia and/or GABA(A/B) receptor (GABAR) modulators. Anoxia increased endogenous slow phasic GABAergic activity, and both anoxia and GABA reversibly induced SA by increasing GABA(A)R-mediated postsynaptic activity and Cl(-) conductance, which eliminated the Cl(-) driving force by depolarizing membrane potential (~8 mV) to GABA receptor reversal potential (~-81 mV), and dampened excitatory potentials via shunting inhibition. In addition, both anoxia and GABA decreased excitatory postsynaptic activity, likely via GABA(B)R-mediated inhibition of presynaptic glutamate release. In combination, these mechanisms increased the stimulation required to elicit an action potential >20-fold, and excitatory activity decreased >70% despite membrane potential depolarization. In contrast, anoxic neurons cotreated with GABA(A+B)R antagonists underwent seizure-like events, deleterious Ca(2+) influx, and cell death, a phenotype consistent with excitotoxic cell death in anoxic mammalian brain. We conclude that increased endogenous GABA release during anoxia mediates SA by activating an inhibitory postsynaptic shunt and inhibiting presynaptic glutamate release. This represents a natural adaptive mechanism in which to explore strategies to protect mammalian brain from low-oxygen insults. PMID- 21690382 TI - Linkage maps from multiple genetic crosses and loci linked to growth-related virulent phenotype in Plasmodium yoelii. AB - Plasmodium yoelii is an excellent model for studying malaria pathogenesis that is often intractable to investigate using human parasites; however, genetic studies of the parasite have been hindered by lack of genome-wide linkage resources. Here, we performed 14 genetic crosses between three pairs of P. yoelii clones/subspecies, isolated 75 independent recombinant progeny from the crosses, and constructed a high-resolution linkage map for this parasite. Microsatellite genotypes from the progeny formed 14 linkage groups belonging to the 14 parasite chromosomes, allowing assignment of sequence contigs to chromosomes. Growth related virulent phenotypes from 25 progeny of one of the crosses were significantly associated with a major locus on chromosome 13 and with two secondary loci on chromosomes 7 and 10. The chromosome 10 and 13 loci are both linked to day 5 parasitemia, and their effects on parasite growth rate are independent but additive. The locus on chromosome 7 is associated with day 10 parasitemia. The chromosome 13 locus spans ~220 kb of DNA containing 51 predicted genes, including the P. yoelii erythrocyte binding ligand, in which a C741Y substitution in the R6 domain is implicated in the change of growth rate. Similarly, the chromosome 10 locus spans ~234 kb with 71 candidate genes, containing a member of the 235-kDa rhoptry proteins (Py235) that can bind to the erythrocyte surface membrane. Atypical virulent phenotypes among the progeny were also observed. This study provides critical tools and information for genetic investigations of virulence and biology of P. yoelii. PMID- 21690383 TI - Detection and avoidance of a carnivore odor by prey. AB - Predator-prey relationships provide a classic paradigm for the study of innate animal behavior. Odors from carnivores elicit stereotyped fear and avoidance responses in rodents, although sensory mechanisms involved are largely unknown. Here, we identified a chemical produced by predators that activates a mouse olfactory receptor and produces an innate behavioral response. We purified this predator cue from bobcat urine and identified it to be a biogenic amine, 2 phenylethylamine. Quantitative HPLC analysis across 38 mammalian species indicates enriched 2-phenylethylamine production by numerous carnivores, with some producing >3,000-fold more than herbivores examined. Calcium imaging of neuronal responses in mouse olfactory tissue slices identified dispersed carnivore odor-selective sensory neurons that also responded to 2 phenylethylamine. Two prey species, rat and mouse, avoid a 2-phenylethylamine odor source, and loss-of-function studies involving enzymatic depletion of 2 phenylethylamine from a carnivore odor indicate it to be required for full avoidance behavior. Thus, rodent olfactory sensory neurons and chemosensory receptors have the capacity for recognizing interspecies odors. One such cue, carnivore-derived 2-phenylethylamine, is a key component of a predator odor blend that triggers hard-wired aversion circuits in the rodent brain. These data show how a single, volatile chemical detected in the environment can drive an elaborate danger-associated behavioral response in mammals. PMID- 21690384 TI - Reduction-oxidation poise regulates the sign of phototaxis in Chlamydomonas reinhardtii. AB - In many phototrophic microorganisms and plants, chloroplasts change their positions relative to the incident light to achieve optimal photosynthesis. In the case of motile green algae, cells change their swimming direction by switching between positive and negative phototaxis, i.e., swimming toward or away from the light source, depending on environmental and internal conditions. However, little is known about the molecular signals that determine the phototactic direction. Using the green alga Chlamydomonas reinhardtii, we found that cellular reduction-oxidation (redox) poise plays a key role: Cells always exhibited positive phototaxis after treatment with reactive oxygen species (ROS) and always displayed negative phototaxis after treatment with ROS quenchers. The redox-dependent switching of the sign of phototaxis may contribute in turn to the maintenance of cellular redox homeostasis. PMID- 21690385 TI - Molecular evolutionary analyses of insect societies. AB - The social insects live in extraordinarily complex and cohesive societies, where many individuals sacrifice their personal reproduction to become helpers in the colony. Identifying adaptive molecular changes involved in eusocial evolution in insects is important for understanding the mechanisms underlying transitions from solitary to social living, as well as the maintenance and elaboration of social life. Here, we review recent advances made in this area of research in several insect groups: the ants, bees, wasps, and termites. Drawing from whole-genome comparisons, candidate gene approaches, and a genome-scale comparative analysis of protein-coding sequence, we highlight novel insights gained for five major biological processes: chemical signaling, brain development and function, immunity, reproduction, and metabolism and nutrition. Lastly, we make comparisons across these diverse approaches and social insect lineages and discuss potential common themes of eusocial evolution, as well as challenges and prospects for future research in the field. PMID- 21690387 TI - Role of IL-1 receptor-associated kinase-M (IRAK-M) in priming of immune and inflammatory responses by nitrogen bisphosphonates. AB - Nitrogen bisphosphonates (NBPs) are commonly prescribed for osteoporosis but have also been found to induce inflammatory reactions and to delay the progression of breast cancer. The inflammatory and anticancer effects of the NBPs might be associated with an ability to modulate innate immune signaling. In mice, intraperitoneal NBP administration causes a rapid influx of neutrophils and monocytes that is dependent on the myeloid differentiation primary response gene 88 (MyD88) mediator of Toll-like receptor (TLR) and IL-1 signaling. Bone marrow chimeras demonstrate that this inflammatory response is partially dependent on TLR4 expression by hematopoietic cells and the IL-1 receptor on radioresistant cells. In vitro, NBPs directly stimulate neither murine bone marrow-derived mononuclear cells nor human peripheral blood mononuclear cells, but rather prime them to produce increased amounts of cytokines when exposed to IL-1 or TLR ligands. This potentiation is mediated by a reduction in IL-1 receptor-associated kinase-M, a negative regulator of MyD88-dependent signaling. In vivo, this property renders the NBPs as effective adjuvants that enhance both cellular and antibody responses to antigens. PMID- 21690386 TI - Dispatched mediates Hedgehog basolateral release to form the long-range morphogenetic gradient in the Drosophila wing disk epithelium. AB - Hedgehog (Hh) moves from the producing cells to regulate the growth and development of distant cells in a variety of tissues. Here, we have investigated the mechanism of Hh release from the producing cells to form a morphogenetic gradient in the Drosophila wing imaginal disk epithelium. We describe that Hh reaches both apical and basolateral plasma membranes, but the apical Hh is subsequently internalized in the producing cells and routed to the basolateral surface, where Hh is released to form a long-range gradient. Functional analysis of the 12-transmembrane protein Dispatched, the glypican Dally-like (Dlp) protein, and the Ig-like and FNNIII domains of protein Interference Hh (Ihog) revealed that Dispatched could be involved in the regulation of vesicular trafficking necessary for basolateral release of Hh, Dlp, and Ihog. We also show that Dlp is needed in Hh-producing cells to allow for Hh release and that Ihog, which has been previously described as an Hh coreceptor, anchors Hh to the basolateral part of the disk epithelium. PMID- 21690388 TI - Smad inhibition by the Ste20 kinase Misshapen. AB - The level of TGF-beta/bone morphogenetic protein (BMP) signaling through Smad is tightly regulated to ensure proper embryonic patterning and homeostasis. Here we show that Smad activation by TGF-beta/BMP is blocked by a highly conserved phosphorylation event in the alpha-helix 1 region of Smad [T312 in Drosophila Smad1 (MAD)]. alpha-helix 1 phosphorylation reduces Smad interaction with TGF beta/BMP receptor kinase and affects all receptor-activated Smads except Smad3. Tissue culture and transgenic studies in Drosophila further demonstrate that the biological activity of MAD is repressed by T312 phosphorylation in vivo. Through RNAi screening of the kinome, we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for alpha helix 1 phosphorylation. Targeted expression of an active form of Msn in the wing imaginal disk disrupted activation of endogenous MAD by Dpp and expression of the Dpp/MAD target gene. Msn kinases belong to the Ste20 kinase family that has been shown to act as MAP kinase kinase kinase kinase (MAP4K). Our findings thus reveal a function of Msn independent of its impact on MAP kinase cascades. This Smad inhibition mechanism by Msn likely has important implications for development and disease. PMID- 21690389 TI - Expanded social fitness and Hamilton's rule for kin, kith, and kind. AB - Inclusive fitness theory has a combination of simplicity, generality, and accuracy that has made it an extremely successful way of thinking about and modeling effects on kin. However, there are types of social interactions that, although covered, are not illuminated. Here, I expand the inclusive fitness approach and the corresponding neighbor-modulated approach to specify two other kinds of social selection. Kind selection, which includes greenbeards and many nonadditive games, is where selection depends on an actor's trait having different effects on others depending on whether they share the trait. Kith selection includes social effects that do not require either kin or kind, such as mutualism and manipulation. It involves social effects of a trait that affect a partner, with feedback to the actor's fitness. I derive expanded versions of Hamilton's rule for kith and kind selection, generalizing Hamilton's insight that we can model social selection through a sum of fitness effects, each multiplied by an appropriate association coefficient. Kinship is, thus, only one of the important types of association, but all can be incorporated within an expanded inclusive fitness. PMID- 21690391 TI - Involvement of KDM1C histone demethylase-OTLD1 otubain-like histone deubiquitinase complexes in plant gene repression. AB - Covalent modifications of histones, such as acetylation, methylation and ubiquitination, are central for regulation of gene expression. Heterochromatic gene silencing, for example, is associated with hypoacetylation, methylation and demethylation, and deubiquitination of specific amino acid residues in histone molecules. Many of these changes can be effected by histone-modifying repressor complexes that include histone lysine demethylases, such as KDM1 in animals and KDM1C in plants. However, whereas KDM1-containing repressor complexes have been implicated in histone demethylation, methylation and deacetylation, whether or not they can also mediate histone deubiquitination remains unknown. We identify an Arabidopsis otubain-like deubiquitinase OTLD1 which directly interacts with the Arabidopsis KDM1C in planta, and use one target gene to exemplify that both OTLD1 and KDM1C are involved in transcriptional gene repression via histone deubiquitination and demethylation. We also show that OTLD1 binds plant chromatin and has enzymatic histone deubiquitinase activity, specific for the H2B histone. Thus, we suggest that, during gene repression, lysine demethylases can directly interact and function in a protein complex with histone deubiquitinases. PMID- 21690390 TI - Endemic social diversity within natural kin groups of a cooperative bacterium. AB - The spatial structure of genetic diversity underlying social variation is a critical determinant of how cooperation and conflict evolve. Here we investigated whether natural social groups of the cooperative soil bacterium Myxococcus xanthus harbor internal genetic and phenotypic variation and thus the potential for social conflict between interacting cells. Ten M. xanthus fruiting bodies isolated from soil were surveyed for variation in multiple social phenotypes and genetic loci, and patterns of diversity within and across fruiting body groups were examined. Eight of the 10 fruiting bodies were found to be internally diverse, with four exhibiting significant variation in social swarming phenotypes and five harboring large variation in the number of spores produced by member clones in pure culture. However, genetic variation within fruiting bodies was much lower than across fruiting bodies, suggesting that migration across even spatially proximate groups is limited relative to mutational generation of persisting endemic diversity. Our results simultaneously highlight the potential for social conflict within Myxococcus social groups and the possibility of social coevolution among diverse related lineages that are clustered in space and cotransmitted across generations. PMID- 21690392 TI - Selfish genetic elements, genetic conflict, and evolutionary innovation. AB - Genomes are vulnerable to selfish genetic elements (SGEs), which enhance their own transmission relative to the rest of an individual's genome but are neutral or harmful to the individual as a whole. As a result, genetic conflict occurs between SGEs and other genetic elements in the genome. There is growing evidence that SGEs, and the resulting genetic conflict, are an important motor for evolutionary change and innovation. In this review, the kinds of SGEs and their evolutionary consequences are described, including how these elements shape basic biological features, such as genome structure and gene regulation, evolution of new genes, origin of new species, and mechanisms of sex determination and development. The dynamics of SGEs are also considered, including possible "evolutionary functions" of SGEs. PMID- 21690393 TI - Structure and function of the complete internal fusion loop from Ebolavirus glycoprotein 2. AB - Ebolavirus (Ebov), an enveloped virus of the family Filoviridae, causes hemorrhagic fever in humans and nonhuman primates. The viral glycoprotein (GP) is solely responsible for virus-host membrane fusion, but how it does so remains elusive. Fusion occurs after virions reach an endosomal compartment where GP is proteolytically primed by cathepsins. Fusion by primed GP is governed by an internal fusion loop found in GP2, the fusion subunit. This fusion loop contains a stretch of hydrophobic residues, some of which have been shown to be critical for GP-mediated infection. Here we present liposome fusion data and NMR structures for a complete (54-residue) disulfide-bonded internal fusion loop (Ebov FL) in a membrane mimetic. The Ebov FL induced rapid fusion of liposomes of varying compositions at pH values at or below 5.5. Consistently, circular dichroism experiments indicated that the alpha-helical content of the Ebov FL in the presence of either lipid-mimetic micelles or small liposomes increases in samples exposed to pH <=5.5. NMR structures in dodecylphosphocholine micelles at pH 7.0 and 5.5 revealed a conformational change from a relatively flat extended loop structure at pH 7.0 to a structure with an ~90 degrees bend at pH 5.5. Induction of the bend at low pH reorients and compacts the hydrophobic patch at the tip of the FL. We propose that these changes facilitate disruption of lipids at the site of virus-host cell membrane contact and, hence, initiate Ebov fusion. PMID- 21690394 TI - Slow protein evolutionary rates are dictated by surface-core association. AB - Why do certain proteins evolve much slower than others? We compared not only rates per protein, but also rates per position within individual proteins. For ~90% of proteins, the distribution of positional rates exhibits three peaks: a peak of slow evolving residues, with average log(2)[normalized rate], log(2)MU, of ca. -2, corresponding primarily to core residues; a peak of fast evolving residues (log(2)MU ~ 0.5) largely corresponding to surface residues; and a very fast peak (log(2)MU ~ 2) associated with disordered segments. However, a unique fraction of proteins that evolve very slowly exhibit not only a negligible fast peak, but also a peak with a log(2)MU ~ -4, rather than the standard core peak of -2. Thus, a "freeze" of a protein's surface seems to stop core evolution as well. We also observed a much higher fraction of substitutions in potentially interacting residues than expected by chance, including substitutions in pairs of contacting surface-core residues. Overall, the data suggest that accumulation of surface substitutions enables the acceptance of substitutions in core positions. The underlying reason for slow evolution might therefore be a highly constrained surface due to protein-protein interactions or the need to prevent misfolding or aggregation. If the surface is inaccessible to substitutions, so becomes the core, thus resulting in very slow overall rates. PMID- 21690395 TI - Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. AB - Autophagy, a lysosome-mediated catabolic process, contributes to maintenance of intracellular homeostasis and cellular response to metabolic stress. In yeast, genes essential to the execution of autophagy have been defined, including autophagy-related gene 1 (ATG1), a kinase responsible for initiation of autophagy downstream of target of rapamycin. Here we investigate the role of the mammalian Atg1 homologs, uncoordinated family member (unc)-51-like kinase 1 and 2 (ULK1 and ULK2), in autophagy by generating mouse embryo fibroblasts (MEFs) doubly deficient for ULK1 and ULK2. We found that ULK1/2 are required in the autophagy response to amino acid deprivation but not for autophagy induced by deprivation of glucose or inhibition of glucose metabolism. This ULK1/2-independent autophagy was not the simple result of bioenergetic compromise and failed to be induced by AMP-activated protein kinase activators such as 5-aminoimidazole-4-carboxamide riboside and phenformin. Instead we found that autophagy induction upon glucose deprivation correlated with a rise in cellular ammonia levels caused by elevated amino acid catabolism. Even in complete medium, ammonia induced autophagy in WT and Ulk1/2(-/-) MEFs but not in Atg5-deficient MEFs. The autophagy response to ammonia is abrogated by a cell-permeable form of pyruvate resulting from the scavenging of excess ammonia through pyruvate conversion to alanine. Thus, although ULK1 and/or ULK2 are required for the autophagy response following deprivation of nitrogenous amino acids, the autophagy response to the enhanced amino acid catabolism induced by deprivation of glucose or direct exposure to ammonia does not require ULK1 and/or ULK2. Together, these data suggest that autophagy provides cells with a mechanism to adapt not only to nitrogen deprivation but also to nitrogen excess. PMID- 21690396 TI - Household and community poverty, biomass use, and air pollution in Accra, Ghana. AB - Many urban households in developing countries use biomass fuels for cooking. The proportion of household biomass use varies among neighborhoods, and is generally higher in low socioeconomic status (SES) communities. Little is known of how household air pollution varies by SES and how it is affected by biomass fuels and traffic sources in developing country cities. In four neighborhoods in Accra, Ghana, we collected and analyzed geo-referenced data on household and community particulate matter (PM) pollution, SES, fuel use for domestic and small commercial cooking, housing characteristics, and distance to major roads. Cooking area PM was lowest in the high-SES neighborhood, with geometric means of 25 (95% confidence interval, 21-29) and 28 (23-33) MUg/m(3) for fine and coarse PM (PM(2.5) and PM(2.5-10)), respectively; it was highest in two low-SES slums, with geometric means reaching 71 (62-80) and 131 (114-150) MUg/m(3) for fine and coarse PM. After adjustment for other factors, living in a community where all households use biomass fuels would be associated with 1.5- to 2.7-times PM levels in models with and without adjustment for ambient PM. Community biomass use had a stronger association with household PM than household's own fuel choice in crude and adjusted estimates. Lack of regular physical access to clean fuels is an obstacle to fuel switching in low-income neighborhoods and should be addressed through equitable energy infrastructure. PMID- 21690397 TI - Pathology from evolutionary conflict, with a theory of X chromosome versus autosome conflict over sexually antagonistic traits. AB - Evolutionary conflicts cause opponents to push increasingly hard and in opposite directions on the regulation of traits. One can see only the intermediate outcome from the balance of the exaggerated and opposed forces. Intermediate expression hides the underlying conflict, potentially misleading one to conclude that trait regulation is designed to achieve efficient and robust expression, rather than arising by the precarious resolution of conflict. Perturbation often reveals the underlying nature of evolutionary conflict. Upon mutation or knockout of one side in the conflict, the other previously hidden and exaggerated push on the trait may cause extreme, pathological expression. In this regard, pathology reveals hidden evolutionary design. We first review several evolutionary conflicts between males and females, including conflicts over mating, fertilization, and the growth rate of offspring. Perturbations of these conflicts lead to infertility, misregulated growth, cancer, behavioral abnormalities, and psychiatric diseases. We then turn to antagonism between the sexes over traits present in both males and females. For many traits, the different sexes favor different phenotypic values, and constraints prevent completely distinct expression in the sexes. In this case of sexual antagonism, we present a theory of conflict between X-linked genes and autosomal genes. We suggest that dysregulation of the exaggerated conflicting forces between the X chromosome and the autosomes may be associated with various pathologies caused by extreme expression along the male-female axis. Rapid evolution of conflicting X-linked and autosomal genes may cause divergence between populations and speciation. PMID- 21690398 TI - QnAs with May R. Berenbaum. [Interviewed by Prashant Nair]. PMID- 21690399 TI - Membrane fusion by the GTPase atlastin requires a conserved C-terminal cytoplasmic tail and dimerization through the middle domain. AB - The biogenesis and maintenance of the endoplasmic reticulum (ER) requires membrane fusion. ER homotypic fusion is driven by the large GTPase atlastin. Domain analysis of atlastin shows that a conserved region of the C-terminal cytoplasmic tail is absolutely required for fusion activity. Atlastin in adjacent membranes must associate to bring the ER membranes into molecular contact. Drosophila atlastin dimerizes in the presence of GTPgammaS but is monomeric with GDP or without nucleotide. Oligomerization requires the juxtamembrane middle domain three-helix bundle, as does efficient GTPase activity. A soluble version of the N-terminal cytoplasmic domain that contains the GTPase domain and the middle domain three-helix bundle serves as a potent, concentration-dependent inhibitor of membrane fusion both in vitro and in vivo. However, atlastin domains lacking the middle domain are without effect. GTP-dependent dimerization of atlastin generates an enzymatically active protein that drives membrane fusion after nucleotide hydrolysis and conformational reorganization. PMID- 21690400 TI - Female gamete competition in an ancient angiosperm lineage. AB - In Trimenia moorei, an extant member of the ancient angiosperm clade Austrobaileyales, we found a remarkable pattern of female gametophyte (egg producing structure) development that strikingly resembles that of pollen tubes and their intrasexual competition within the maternal pollen tube transmitting tissues of most flowers. In contrast with most other flowering plants, in Trimenia, multiple female gametophytes are initiated at the base (chalazal end) of each ovule. Female gametophytes grow from their tips and compete over hundreds of micrometers to reach the apex of the nucellus and the site of fertilization. Here, the successful female gametophyte will mate with a pollen tube to produce an embryo and an endosperm. Moreover, the central tissue within the ovules of Trimenia, through which the embryo sacs grow, contains starch and other carbohydrates similar to the pollen tube transmitting tissues in the styles of most flowers. The pattern of female gametophyte development found in Trimenia is rare but by no means unique in angiosperms. Importantly, it seems that multiple female gametophytes are occasionally or frequently initiated in members of other ancient angiosperm lineages. The intensification of pollen tube (male gametophyte) competition and enhanced maternal selection among competing pollen tubes are considered to have been major contributors to the rise of angiosperms. Based on insights from Trimenia, we posit that prefertilization female gametophyte (egg) competition within individual ovules in addition to male gametophyte (sperm) competition and maternal mate choice may have been key features of the earliest angiosperms. PMID- 21690401 TI - Centralized sanctioning and legitimate authority promote cooperation in humans. AB - Social sanctioning is widely considered a successful strategy to promote cooperation among humans. In situations in which individual and collective interests are at odds, incentives to free-ride induce individuals to refrain from contributing to public goods provision. Experimental evidence from public goods games shows that when endowed with sanctioning powers, conditional cooperators can discipline defectors, thus leading to greater levels of cooperation. However, extant evidence is based on peer punishment institutions, whereas in complex societies, systems of control are often centralized: for instance, we do not sanction our neighbors for driving too fast, the police do. Here we show the effect of centralized sanctioning and legitimate authority on cooperation. We designed an adaptation of the public goods game in which sanctioning power is given to a single monitor, and we experimentally manipulated the process by which the monitor is chosen. To increase the external validity of the study, we conducted lab-in-the-field experiments involving 1,543 Ugandan farmers from 50 producer cooperatives. This research provides evidence of the effectiveness of centralized sanctioning and demonstrates the causal effect of legitimacy on cooperation: participants are more responsive to the authority of an elected monitor than a randomly chosen monitor. Our essay contributes to the literature on the evolution of cooperation by introducing the idea of role differentiation. In complex societies, cooperative behavior is not only sustained by mechanisms of selection and reciprocity among peers, but also by the legitimacy that certain actors derive from their position in the social hierarchy. PMID- 21690402 TI - Majority of CD4+ T cells from peripheral blood of HIV-1-infected individuals contain only one HIV DNA molecule. AB - Neither the number of HIV-1 proviruses within individual infected cells in HIV-1 infected patients nor their genetic relatedness within individual infected cells and between cells and plasma virus are well defined. To address these issues we developed a technique to quantify and genetically characterize HIV-1 DNA from single infected cells in vivo. Analysis of peripheral blood CD4(+) T cells from nine patients revealed that the majority of infected cells contain only one copy of HIV-1 DNA, implying a limited potential for recombination in virus produced by these cells. The genetic similarity between HIV populations in CD4(+) T cells and plasma implies ongoing exchange between these compartments both early and late after infection. PMID- 21690403 TI - Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA. AB - Hepatitis A virus (HAV) is an hepatotropic human picornavirus that is associated only with acute infection. Its pathogenesis is not well understood because there are few studies in animal models using modern methodologies. We characterized HAV infections in three chimpanzees, quantifying viral RNA by quantitative RT-PCR and examining critical aspects of the innate immune response including intrahepatic IFN-stimulated gene expression. We compared these infection profiles with similar studies of chimpanzees infected with hepatitis C virus (HCV), an hepatotropic flavivirus that frequently causes persistent infection. Surprisingly, HAV infected animals exhibited very limited induction of type I IFN-stimulated genes in the liver compared with chimpanzees with acute resolving HCV infection, despite similar levels of viremia and 100-fold greater quantities of viral RNA in the liver. Minimal IFN-stimulated gene 15 and IFIT1 responses peaked 1-2 wk after HAV challenge and then subsided despite continuing high hepatic viral RNA. An acute inflammatory response at 3-4 wk correlated with the appearance of virus specific antibodies and apoptosis and proliferation of hepatocytes. Despite this, HAV RNA persisted in the liver for months, remaining present long after clearance from serum and feces and revealing dramatic differences in the kinetics of clearance in the three compartments. Viral RNA was detected in the liver for significantly longer (35 to >48 wk) than HCV RNA in animals with acute resolving HCV infection (10-20 wk). Collectively, these findings indicate that HAV is far stealthier than HCV early in the course of acute resolving infection. HAV infections represent a distinctly different paradigm in virus-host interactions within the liver. PMID- 21690404 TI - Interstitial flow influences direction of tumor cell migration through competing mechanisms. AB - Interstitial flow is the convective transport of fluid through tissue extracellular matrix. This creeping fluid flow has been shown to affect the morphology and migration of cells such as fibroblasts, cancer cells, endothelial cells, and mesenchymal stem cells. A microfluidic cell culture system was designed to apply stable pressure gradients and fluid flow and allow direct visualization of transient responses of cells seeded in a 3D collagen type I scaffold. We used this system to examine the effects of interstitial flow on cancer cell morphology and migration and to extend previous studies showing that interstitial flow increases the metastatic potential of MDA-MB-435S melanoma cells [Shields J, et al. (2007) Cancer Cell 11:526-538]. Using a breast carcinoma line (MDA-MB-231) we also observed cell migration along streamlines in the presence of flow; however, we further demonstrated that the strength of the flow as well as the cell density determined directional bias of migration along the streamline. In particular, we found that cells either at high seeding density or with the CCR-7 receptor inhibited migration against, rather than with the flow. We provide further evidence that CCR7-dependent autologous chemotaxis is the mechanism that leads to migration with the flow, but also demonstrate a competing CCR7-independent mechanism that causes migration against the flow. Data from experiments investigating the effects of cell concentration, interstitial flow rate, receptor activity, and focal adhesion kinase phosphorylation support our hypothesis that the competing stimulus is integrin mediated. This mechanism may play an important role in development of metastatic disease. PMID- 21690405 TI - Extent and limits of cooperation in animals. AB - Individuals in many animal species are strongly motivated to form close social bonds and to attend to the social interactions of others. Some animals may also recognize other individuals' intentions and simple mental states. Such curiosity appears to be adaptive, because it enables observers to learn about others' status and relationships and to anticipate future events without direct participation. However, many questions remain unresolved. In particular, it remains unclear whether animals keep track of favors given and received when interacting with others, and whether they rely on memory of past cooperative acts when anticipating future ones. Primates appear to possess many of the cognitive abilities required for human-like contingent cooperation. However, most investigations of captive primates have indicated that cooperation is seldom contingency-based, and that interactions are not influenced by inequity aversion or sensitivity to cheaters. In contrast, several experiments with nonprimates have found that animals can take into account recent interactions when supporting others, suggesting that the apparent rarity of contingent cooperation in primates may not stem from cognitive constraints. Instead, individuals may tolerate short term inequities in favors given and received because most cooperation occurs among long-term reciprocating partners. PMID- 21690406 TI - Functional genome analysis of Bifidobacterium breve UCC2003 reveals type IVb tight adherence (Tad) pili as an essential and conserved host-colonization factor. AB - Development of the human gut microbiota commences at birth, with bifidobacteria being among the first colonizers of the sterile newborn gastrointestinal tract. To date, the genetic basis of Bifidobacterium colonization and persistence remains poorly understood. Transcriptome analysis of the Bifidobacterium breve UCC2003 2.42-Mb genome in a murine colonization model revealed differential expression of a type IVb tight adherence (Tad) pilus-encoding gene cluster designated "tad(2003)." Mutational analysis demonstrated that the tad(2003) gene cluster is essential for efficient in vivo murine gut colonization, and immunogold transmission electron microscopy confirmed the presence of Tad pili at the poles of B. breve UCC2003 cells. Conservation of the Tad pilus-encoding locus among other B. breve strains and among sequenced Bifidobacterium genomes supports the notion of a ubiquitous pili-mediated host colonization and persistence mechanism for bifidobacteria. PMID- 21690407 TI - Coordinate linkage of HIV evolution reveals regions of immunological vulnerability. AB - Cellular immune control of HIV is mediated, in part, by induction of single amino acid mutations that reduce viral fitness, but compensatory mutations limit this effect. Here, we sought to determine if higher order constraints on viral evolution exist, because some coordinately linked combinations of mutations may hurt viability. Immune targeting of multiple sites in such a multidimensionally conserved region might render the virus particularly vulnerable, because viable escape pathways would be greatly restricted. We analyzed available HIV sequences using a method from physics to reveal distinct groups of amino acids whose mutations are collectively coordinated ("HIV sectors"). From the standpoint of mutations at individual sites, one such group in Gag is as conserved as other collectively coevolving groups of sites in Gag. However, it exhibits higher order conservation indicating constraints on the viability of viral strains with multiple mutations. Mapping amino acids from this group onto protein structures shows that combined mutations likely destabilize multiprotein structural interactions critical for viral function. Persons who durably control HIV without medications preferentially target the sector in Gag predicted to be most vulnerable. By sequencing circulating viruses from these individuals, we find that individual mutations occur with similar frequency in this sector as in other targeted Gag sectors. However, multiple mutations within this sector are very rare, indicating previously unrecognized multidimensional constraints on HIV evolution. Targeting such regions with higher order evolutionary constraints provides a novel approach to immunogen design for a vaccine against HIV and other rapidly mutating viruses. PMID- 21690408 TI - Bat wing sensors support flight control. AB - Bats are the only mammals capable of powered flight, and they perform impressive aerial maneuvers like tight turns, hovering, and perching upside down. The bat wing contains five digits, and its specialized membrane is covered with stiff, microscopically small, domed hairs. We provide here unique empirical evidence that the tactile receptors associated with these hairs are involved in sensorimotor flight control by providing aerodynamic feedback. We found that neurons in bat primary somatosensory cortex respond with directional sensitivity to stimulation of the wing hairs with low-speed airflow. Wing hairs mostly preferred reversed airflow, which occurs under flight conditions when the airflow separates and vortices form. This finding suggests that the hairs act as an array of sensors to monitor flight speed and/or airflow conditions that indicate stall. Depilation of different functional regions of the bats' wing membrane altered the flight behavior in obstacle avoidance tasks by reducing aerial maneuverability, as indicated by decreased turning angles and increased flight speed. PMID- 21690409 TI - Regulation of apoptosis by the circadian clock through NF-kappaB signaling. AB - In mice and humans the circadian rhythm of many biochemical reactions, physiology, and behavior is generated by a transcriptional-translation feedback loop (TTFL) made up of the so-called core clock genes/proteins. The circadian system interfaces with most signaling pathways including those involved in cell proliferation and inflammation. Cryptochrome (CRY) is a core clock protein that plays an essential role in the repressive arm of the TTFL. It was recently reported that mutation of CRY in p53-null mice delayed the onset of cancer. It was therefore suggested that CRY mutation may activate p53-independent apoptosis pathways, which eliminate premalignant and malignant cells and thus delay overt tumor formation. Here we show that CRY mutation sensitizes p53 mutant and oncogenically transformed cells to tumor necrosis factor alpha (TNFalpha) initiated apoptosis by interfacing with the NF-kappaB signaling pathway through the GSK3beta kinase and alleviating prosurvival NF-kappaB signaling. These findings provide a mechanistic foundation for the delayed onset of tumorigenesis in clock-disrupted p53 mutant mice and suggest unique therapeutic strategies for treating cancers associated with p53 mutation. PMID- 21690410 TI - Laminar differences in gamma and alpha coherence in the ventral stream. AB - Attention to a stimulus enhances both neuronal responses and gamma frequency synchrony in visual area V4, both of which should increase the impact of attended information on downstream neurons. To determine whether gamma synchrony is common throughout the ventral stream, we recorded from neurons in the superficial and deep layers of V1, V2, and V4 in two rhesus monkeys. We found an unexpected striking difference in gamma synchrony in the superficial vs. deep layers. In all three areas, spike-field coherence in the gamma (40-60 Hz) frequency range was largely confined to the superficial layers, whereas the deep layers showed maximal coherence at low frequencies (6-16 Hz), which included the alpha range. In the superficial layers of V2 and V4, gamma synchrony was enhanced by attention, whereas in the deep layers, alpha synchrony was reduced by attention. Unlike these major differences in synchrony, attentional effects on firing rates and noise correlation did not differ substantially between the superficial and deep layers. The results suggest that synchrony plays very different roles in feedback and feedforward projections. PMID- 21690412 TI - Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. AB - We describe a generic approach to assemble correctly two heavy and two light chains, derived from two existing antibodies, to form human bivalent bispecific IgG antibodies without use of artificial linkers. Based on the knobs-into-holes technology that enables heterodimerization of the heavy chains, correct association of the light chains and their cognate heavy chains is achieved by exchange of heavy-chain and light-chain domains within the antigen binding fragment (Fab) of one half of the bispecific antibody. This "crossover" retains the antigen-binding affinity but makes the two arms so different that light-chain mispairing can no longer occur. Applying the three possible "CrossMab" formats, we generated bispecific antibodies against angiopoietin-2 (Ang-2) and vascular endothelial growth factor A (VEGF-A) and show that they can be produced by standard techniques, exhibit stabilities comparable to natural antibodies, and bind both targets simultaneously with unaltered affinity. Because of its superior side-product profile, the CrossMab(CH1-CL) was selected for in vivo profiling and showed potent antiangiogenic and antitumoral activity. PMID- 21690413 TI - Regulation of microtubule-based microtubule nucleation by mammalian polo-like kinase 1. AB - Bipolar spindle formation is pivotal for accurate segregation of mitotic chromosomes during cell division. A growing body of evidence suggests that, in addition to centrosome- and chromatin-based microtubule (MT) nucleation, MT-based MT nucleation plays an important role for proper bipolar spindle formation in various eukaryotic organisms. Although a recently discovered Augmin complex appears to play a central role in this event, how Augmin is regulated remains unknown. Here we provide evidence that a mammalian polo-like kinase 1 (Plk1) localizes to mitotic spindles and promotes MT-based MT nucleation by directly regulating Augmin. Mechanistically, we demonstrated that Cdc2-dependent phosphorylation on a gamma-tubulin ring complex (gamma-TuRC) recruitment protein, Nedd1/GCP-WD, at the previously uncharacterized S460 residue induces the Nedd1 Plk1 interaction. This step appeared to be critical to allow Plk1 to phosphorylate the Hice1 subunit of the Augmin complex to promote the Augmin-MT interaction and MT-based MT nucleation from within the spindle. Loss of either the Nedd1 S460 function or the Plk1-dependent Hice1 phosphorylation impaired both the Augmin-MT interaction and gamma-tubulin recruitment to the spindles, thus resulting in improper bipolar spindle formation that ultimately leads to mitotic arrest and apoptotic cell death. Thus, via the formation of the Nedd1-Plk1 complex and subsequent Augmin phosphorylation, Plk1 regulates spindle MT-based MT nucleation to accomplish normal bipolar spindle formation and mitotic progression. PMID- 21690414 TI - Genomic imprinting and the evolutionary psychology of human kinship. AB - Genomic imprinting is predicted to influence behaviors that affect individuals to whom an actor has different degrees of matrilineal and patrilineal kinship (asymmetric kin). Effects of imprinted genes are not predicted in interactions with nonrelatives or with individuals who are equally related to the actor's maternally and paternally derived genes (unless a gene also has pleiotropic effects on fitness of asymmetric kin). Long-term mating bonds are common in most human populations, but dissolution of marriage has always affected a significant proportion of mated pairs. Children born in a new union are asymmetric kin of children born in a previous union. Therefore, the innate dispositions of children toward parents and sibs are expected to be sensitive to cues of marital stability, and these dispositions may be subject to effects of imprinted genes. PMID- 21690415 TI - Spatiotemporal environmental variation, risk aversion, and the evolution of cooperative breeding as a bet-hedging strategy. AB - In cooperatively breeding systems in which some individuals delay reproduction to help raise others' offspring, environmental variation in space and time influences individual reproductive strategies as well as interspecific patterns of sociality. Although most environmental explanations for cooperative breeding emphasize the mean fitness gains of living socially, the fittest individuals are not always those that produce on average the highest number of offspring. At times, variance in fecundity can influence fitness as much as mean fecundity, particularly in small populations like those of cooperative breeders. Cooperative breeding behavior could therefore be a risk-averse strategy to maximize fitness by reducing environmentally induced fecundity variance. Such a within-generation bet-hedging hypothesis for social evolution predicts that (i) variance in reproductive success should be related to environmental variation, (ii) variance in reproductive success should be related to the potential for cooperation in a group, and (iii) the potential for cooperation should be related to environmental variation. Using data from a 10-y study of cooperatively breeding superb starlings (Lamprotornis superbus) living in a temporally and spatially variable savanna ecosystem, I found that variance in reproductive success declined with increasing environmental quality (temporal variation), increasing territory quality (spatial variation), and increasing group size (potential for cooperation), which is itself related to environmental variation. To understand the adaptive value of cooperative breeding behavior in variable environments, researchers must consider both mean and environmentally induced variance in fecundity. Determining how spatiotemporal environmental variation drives risk averse strategies may provide insights into the evolution of complex social behavior. PMID- 21690411 TI - Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody. AB - To guide vaccine design, we assessed whether human monoclonal antibodies (MAbs) b12 and b6 against the CD4 binding site (CD4bs) on HIV-1 gp120 and F240 against an immundominant epitope on gp41 could prevent vaginal transmission of simian HIV (SHIV)-162P4 to macaques. The two anti-gp120 MAbs have similar monomeric gp120 binding properties, measured in vitro, but b12 is strongly neutralizing and b6 is not. F240 is nonneutralizing. Applied vaginally at a high dose, the strongly neutralizing MAb b12 provided sterilizing immunity in seven of seven animals, b6 in zero of five animals, and F240 in two of five animals. Compared with control animals, the protection by b12 achieved statistical significance, whereas that caused by F240 did not. For two of three unprotected F240-treated animals there was a trend toward lowered viremia. The potential protective effect of F240 may relate to the relatively strong ability of this antibody to capture infectious virions. Additional passive transfer experiments also indicated that the ability of the administered anti-gp120 MAbs to neutralize the challenge virus was a critical influence on protection. Furthermore, when data from all of the experiments were combined, there was a significant increase in the number of founder viruses establishing infection in animals receiving MAb b6, compared with other nonprotected macaques. Thus, a gp120-binding, weakly neutralizing MAb to the CD4bs was, at best, completely ineffective at protection. A nonneutralizing antibody to gp41 may have a limited capacity to protect, but the results suggest that the central focus of HIV-1 vaccine research should be on the induction of potently neutralizing antibodies. PMID- 21690416 TI - Sexually dimorphic regulation of the Wingless morphogen controls sex-specific segment number in Drosophila. AB - Sexual dimorphism is widespread throughout the metazoa and plays important roles in mate recognition and preference, sex-based niche partitioning, and sex specific coadaptation. One notable example of sex-specific differences in insect body morphology is presented by the higher diptera, such as Drosophila, in which males develop fewer abdominal segments than females. Because diversity in segment number is a distinguishing feature of major arthropod clades, it is of fundamental interest to understand how different numbers of segments can be generated within the same species. Here we show that sex-specific and segment specific regulation of the Wingless (Wg) morphogen underlies the development of sexually dimorphic adult segment number in Drosophila. Wg expression is repressed in the developing terminal male abdominal segment by the combination of the Hox protein Abdominal-B (Abd-B) and the sex-determination regulator Doublesex (Dsx). The subsequent loss of the terminal male abdominal segment during pupation occurs through a combination of developmental processes including segment compartmental transformation, apoptosis, and suppression of cell proliferation. Furthermore, we show that ectopic expression of Wg is sufficient to rescue this loss. We propose that dimorphic Wg regulation, in concert with monomorphic segment-specific programmed cell death, are the principal mechanisms of sculpting the sexually dimorphic abdomen of Drosophila. PMID- 21690417 TI - T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome. AB - The symptoms of irritable bowel syndrome (IBS) include significant abdominal pain and bloating. Current treatments are empirical and often poorly efficacious, and there is a need for the development of new and efficient analgesics aimed at IBS patients. T-type calcium channels have previously been validated as a potential target to treat certain neuropathic pain pathologies. Here we report that T-type calcium channels encoded by the Ca(V)3.2 isoform are expressed in colonic nociceptive primary afferent neurons and that they contribute to the exaggerated pain perception in a butyrate-mediated rodent model of IBS. Both the selective genetic inhibition of Ca(V)3.2 channels and pharmacological blockade with calcium channel antagonists attenuates IBS-like painful symptoms. Mechanistically, butyrate acts to promote the increased insertion of Ca(V)3.2 channels into primary sensory neuron membranes, likely via a posttranslational effect. The butyrate-mediated regulation can be recapitulated with recombinant Ca(V)3.2 channels expressed in HEK cells and may provide a convenient in vitro screening system for the identification of T-type channel blockers relevant to visceral pain. These results implicate T-type calcium channels in the pathophysiology of chronic visceral pain and suggest Ca(V)3.2 as a promising target for the development of efficient analgesics for the visceral discomfort and pain associated with IBS. PMID- 21690418 TI - Two drugs approved for chronic hepatitis C infection. PMID- 21690419 TI - Rosiglitazone REMS arrives in November. PMID- 21690420 TI - Role changes for pharmacists may involve labor-union input. PMID- 21690421 TI - Drug industry, FDA try to stay ahead of cargo thieves. PMID- 21690422 TI - Survey of drug information activities of ASHP-accredited pharmacy practice residency programs. PMID- 21690423 TI - Subarachnoid hemorrhage associated with tadalafil. PMID- 21690424 TI - A Web-based experiential rotation platform. PMID- 21690425 TI - Transition to new automated dispensing cabinets at two tertiary care hospitals. PMID- 21690426 TI - Maintaining pharmacy as a service-oriented profession. PMID- 21690427 TI - Echinocandins: addressing outstanding questions surrounding treatment of invasive fungal infections. AB - PURPOSE: Recent in vitro and clinical data addressing outstanding issues regarding the selection, dosing, and monitoring of echinocandins for the treatment of invasive fungal infections (IFIs) are reviewed. SUMMARY: The echinocandins (caspofungin, micafungin, and anidulafungin) are attractive treatment options for the treatment of select IFIs, most notably invasive candidiasis and treatment-refractory invasive aspergillosis. A literature review of English-language articles published between January 2007 and May 2010 was performed using the terms caspofungin, micafungin, anidulafungin, and echinocandin. In vitro, in vivo, and both pediatric and adult clinical studies and case reports were included. The challenges to establish meaningful interpretive criteria for in vitro testing of yeasts continue to persist, as do the establishment of the clinical relevancy of both the reduced in vitro susceptibilities to Candida parapsilosis and the paradoxical growth of Candida species at higher dosages. Despite increasing use of these agents and reports of breakthrough infections, echinocandins have continued to maintain potency against a broad spectrum of Candida and Aspergillus species. Recent in vitro studies also support the excellent activity of echinocandins against Candida biofilms. While recent published studies have better defined dosing in special populations (such as pediatric patients and those with organ dysfunction), attempts to increase efficacy by dosage intensification have been unsuccessful. Several pharmacoeconomic studies have been performed in attempts to justify the high acquisition costs of these drugs. In general, these studies found that echinocandins may be cost-effective for such indications. CONCLUSION: Available in vitro data, animal studies, and clinical studies do not clearly differentiate agents in the echinocandin class. Clinical data continue to support the use of echinocandins as a safe and well-tolerated treatment option for candidemia and invasive aspergillosis. PMID- 21690428 TI - Inhaler device selection: special considerations in elderly patients with chronic obstructive pulmonary disease. AB - PURPOSE: Special considerations in the selection of medication inhaler devices for elderly patients with chronic obstructive pulmonary disease (COPD) in the ambulatory care setting are reviewed. SUMMARY: Substantial deficiencies in inhaler device technique and medication adherence are evident in patients with COPD, leading to suboptimal health outcomes. As the prevalence of COPD rises with age, elderly patients pose special challenges with regard to inhaler device selection. In elderly patients with sufficient cognitive function, manual dexterity, and hand strength, the most influential factors in inhaler selection are cost reimbursement, device availability, device convenience, and patient preference. Cost reimbursement may be a deciding factor in device selection, as nearly all elderly patients are Medicare beneficiaries. Nebulizers provide a cost effective alternative to pressurized metered-dose inhaler (pMDI) and dry powder inhaler (DPI) devices. DPI device availability is limited to "controller" medications, while pMDI devices and nebulizers provide complete symptomatic coverage. Multiple-dose DPIs offer the convenience of rapid medication administration, ease of handling, and integral dose counters. Given the availability and expenses of medication devices, ambulatory patients may prefer combining the convenience of a hand-held inhaler (i.e., pMDI) as a rescue medication during the active hours of midday with the cost savings of a nebulized controller medication in the morning and at night. CONCLUSION: In elderly patients with sufficient cognitive function, manual dexterity, and hand strength, the most important factors in inhaler device selection are cost reimbursement issues, device availability, device convenience, and patient preference. Pharmacist knowledge of appropriate inhaler technique, competent patient education and demonstration, and follow-up assessment are instrumental in optimizing device competency and medication adherence. PMID- 21690429 TI - Dexmedetomidine for opioid and benzodiazepine withdrawal in pediatric patients. AB - PURPOSE: The published literature on the use of dexmedetomidine as an adjunct to sedation and analgesia in the management of pediatric narcotic withdrawal was reviewed. SUMMARY: Pediatric narcotic withdrawal syndromes are reported to be increasingly frequent in pediatric intensive care units. A number of tools specifically designed for assessment of withdrawal in newborns and infants are in current use, including the widely used Finnegan Scoring System. A limited number of studies and case reports suggest that dexmedetomidine, an alpha(2)-receptor agonist with a mechanism of action similar to that of clonidine but with greater alpha(2)-receptor specificity, might have a role in the treatment of pediatric withdrawal (by blunting withdrawal symptoms without causing respiratory depression and by permitting shorter narcotic tapering schedules) and also in the prevention of pediatric narcotic withdrawal (by reducing narcotic requirements). Potential adverse effects associated with dexmedetomidine use in pediatric patients are generally associated with use of bolus doses and mainly involve central nervous system effects (e.g., hypotension, bradycardia), with no hemodynamic manifestations. When bolus doses are used, strategies described in published reports entail a loading dose of 0.5-1.0 MUg/kg administered over 5-10 minutes, followed by a continuous infusion at 0.1-1.4 MUg/kg/hr for a period of 1 16 days. More research is needed to define the optimal use of dexmedetomidine in the management of pediatric narcotic withdrawal. CONCLUSION: A limited body of published evidence from retrospective studies and case reports suggests a potential role for dexmedetomidine as an adjunct therapy to provide sedation and analgesia to reduce narcotic withdrawal symptoms in pediatric patients. PMID- 21690430 TI - Anticoagulation therapy for hospitalized patients: patterns of use, compliance with national guidelines, and performance on quality measures. AB - PURPOSE: The use of anticoagulant therapy for the prevention and treatment of venous thromboembolism (VTE) and acute coronary syndrome (ACS) among hospital inpatients was evaluated. METHODS: Medication-use data were retrospectively collected on 1716 patients who received anticoagulants for VTE or ACS at 42 community hospitals during the period April-June 2009; all hospitals in the sample were members of the same large health care organization. Descriptive analyses were performed to characterize anticoagulant use, patient safety, compliance with national prescribing guidelines, and performance on relevant Joint Commission quality measures. RESULTS: The most common indications for anticoagulant use were VTE prophylaxis (67.5% of cases), ACS (13.5% of cases), and VTE treatment (11.9% of cases). The agents most commonly used for VTE prophylaxis were subcutaneous enoxaparin (70% of cases) and subcutaneous unfractionated heparin (UFH). Overall, the anticoagulant regimen used was consistent with national prescribing guidelines in 67.5% of cases; however, rates of appropriate prescribing were lower in subgroups of patients with renal impairment, obesity, or both (63.6%, 42.5%, and 63.6%, respectively). Reported anticoagulant-related adverse events during the study period mainly involved minor or major bleeding, which occurred in 36% and 32% of cases, respectively. Compliance with Joint Commission core measures ranged from 49.1% for core measure VTE-3 (warfarin overlap therapy) to 72.3% for VTE-4 (monitoring of UFH dosages and platelet counts by protocol). CONCLUSION: Among hospitals in a large national health care system, the most common use of anticoagulants in hospitalized patients was for VTE prevention, followed by ACS and VTE treatment. Enoxaparin and UFH were the most commonly used agents for each indication, and the selection and use of anticoagulants were in compliance with national guidelines in the majority of patients for whom those drugs were prescribed. PMID- 21690431 TI - Development of a Postgraduate Year 1 pharmacy residency program at a large teaching hospital. AB - PURPOSE: The development, implementation, and early evaluation of a postgraduate year 1 (PGY1) pharmacy residency program at a large tertiary care hospital are described. SUMMARY: In keeping with long-range initiatives by the American Society of Health-System Pharmacists (ASHP) and other pharmacy organizations to increase pharmacists' involvement in direct patient care and expand opportunities for advanced training, a PGY1 program was developed at Baystate Medical Center (BMC), a 653-bed hospital in Massachusetts. A residency advisory committee appointed in the fall of 2006 led the program development process, including curriculum planning, establishment of initial funding, recruitment procedures, and integration of faculty at an affiliated school of pharmacy (Massachusetts College of Pharmacy and Health Sciences). Recruitment efforts began in the fall of 2006; in the summer of 2007 the first group of PGY1 residents began a curriculum of 12 one-month core and elective learning experiences, as well as longitudinal direct-care experiences (e.g., performing medication reconciliations and related duties at an affiliated outpatient pharmacotherapy clinic) and teaching and management requirements. In the spring of 2009, the residency program received ASHP accreditation and federal funding for program expansion. The residency advisory committee's evaluation of early experience with the program guided adjustments in areas such as recruitment, applicant screening, resident selection, preceptor scheduling, monitoring of residents' progress through the program, and accreditation survey preparation. CONCLUSION: A PGY1 residency at BMC was developed to enhance the pharmacy department's clinical services. Residents were successfully recruited, and the program received accreditation within two years. PMID- 21690432 TI - Measures to improve safety of an elastomeric infusion system for pain management. AB - PURPOSE: Measures to improve the safe implementation and utilization of an elastomeric infusion system for pain management are described. SUMMARY: Due to the multiple safety concerns associated with the use of the On-Q infusion systems (I-Flow Corporation, Lake Forest, CA) in a community-based teaching institution, a multidisciplinary team of physicians, pharmacists, clinical nurses, nurse educators, and computer informatics personnel was formed to develop a standardized policy and procedure to ensure the safe use of On-Q pumps. The policy addressed several problems concerning prescribing, dispensing, administration, and monitoring of these pumps. The patient care policy for use of On-Q pumps dictates how the pumps are stocked, ordered, dispensed, administered, and monitored and the drugs approved for use in the pumps. Education bulletins, a summary of the new policy and procedure, and a formal presentation of the policy and procedure to unit-based nurse educators were provided. The focus was on a consistent message of safety by reiterating the problems described with these pumps in the literature and in the health care system itself. The physicians ordering the devices have provided positive feedback regarding the simplified ordering process and standardization of the pumps, medications, and concentrations. Both dispensing pharmacists and bedside nurses have noted that the orders are clearly communicated via the computerized system. The addition of documentation in the computer system and education regarding potential signs and symptoms of adverse events with the medication used with the pumps was greatly appreciated by the nursing staff. CONCLUSION: A health care system instituted measures to enhance the safety of using an elastomeric infusion system for pain management. PMID- 21690433 TI - Letter to a new director of pharmacy. PMID- 21690434 TI - Family inclusion in diabetes education: a nationwide survey of diabetes educators. AB - PURPOSE: The purpose of this study was to investigate perceptions about family inclusion and support in diabetes self-management education. METHODS: Surveys were mailed to certified diabetes educators (CDEs) in all 50 states and the District of Columbia, with a return of 225 surveys. Descriptive and inferential statistics (eg, t test, analysis of variance, correlation, and chi-square) were used as appropriate. RESULTS: Levels of importance placed on family involvement in diabetes education were significantly related to the emphasis placed on family during CDEs' formal or preprofessional education. CDEs' formal exposure to family theory influenced perceptions of their knowledge about family and the frequency that family support was emphasized in self-management activities but was unrelated to perceptions of their skillfulness in educating family members. Diabetes educators' personal values of family support were significantly related to how frequently family members were asked to participate in formal diabetes education classes. CDEs perceived that they were meeting individuals' self management needs significantly better than those of families. Regional differences did not appear to be a factor in how CDEs incorporated family in diabetes education. CONCLUSIONS: Diabetes educators without formal exposure to family theory may be overestimating how much they emphasize family support in diabetes education. Increasing formal education about the importance of family involvement in self-management behaviors could positively affect individual diabetes self-management outcomes. PMID- 21690435 TI - Community-based translation of the diabetes prevention program's lifestyle intervention in an underserved Latino population. AB - PURPOSE: The objective was to take prevention from the clinic to the community by including a high-risk group and working with the community to tailor, enhance, deliver, and evaluate a community-based version of the Diabetes Prevention Program's (DPP) clinic-based lifestyle intervention. METHODS: This was a nonrandomized prospective study using a single-group design. Study eligibility included a screening glucose value in the normal to prediabetes range with no current diagnosis of diabetes, overweight, not pregnant nor planning to become pregnant during study period, aged 18 to 65, Latino, living in the study target communities, and no reported medical restrictions related to the program goals. A total of 69 individuals participated. The Healthy Living Program (HLP) was based on the DPP's 1-year intensive lifestyle program, was tailored and enhanced for a Latino community, and was delivered by community health workers. Anthropometric and paper and pencil measures were administered to examine program outcome at 6 months and 12 months. RESULTS: In general, results indicate statistically significant improvements in anthropometrics and many behavioral outcomes, particularly at 6 months. Participants demonstrated forward movement through the stages of change during the program. CONCLUSIONS: Results support the effectiveness of the intervention and show that delivery of the translated version of the DPP's lifestyle intervention in the community by community residents holds promise as one strategy to reach people at increased risk of developing diabetes. Use of this translation model, including collaboration with community health workers, offers diabetes educators an opportunity to extend their reach into underserved communities. PMID- 21690436 TI - Single-port robotic cholecystectomy: results from a first human use clinical study of the new da Vinci single-site surgical platform. AB - OBJECTIVES: To report our results from a first human use clinical study with the da Vinci Surgical single-site instrumentation in patients with gallbladder disease and to perform a retrospective comparison with traditional multiport laparoscopic cholecystectomy. DESIGN: Ten patients underwent robotic single-port cholecystectomy performed with the da Vinci Si robot and novel da Vinci single site instrumentation. Outcomes and operative times were compared with patients undergoing traditional multiport laparoscopic cholecystectomy during the same period. SETTING: Tertiary care Veterans Administration hospital. PATIENTS: Outpatients older than 18 years with an American Society of Anesthesiologists class of 1 to 3, no prior upper abdominal surgery, and diagnosis of noninflammatory biliary disease. INTERVENTION: Single-site robotic cholecystectomy. MAIN OUTCOME MEASURES: Operative time, complications up to 30 days, pain scores, and overall satisfaction. RESULTS: Nine of 10 patients had completion of robotic single-site cholecystectomy. Average operating room time was 105.3 minutes compared with an average of 106.1 minutes in the standard laparoscopic group. There were no serious adverse events in the robotic surgery group, with an average follow-up of 3 or more months. CONCLUSION: Robotic single port cholecystectomy is feasible and comparable with standard laparoscopic cholecystectomy in the Veterans Administration medical center setting. PMID- 21690437 TI - Influence of chronic renal insufficiency on outcomes following carotid revascularization. AB - OBJECTIVES: To examine the perioperative and long-term outcomes of patients undergoing carotid revascularization and to determine the influence moderate or severe renal insufficiency may have on these outcomes. DESIGN: Retrospective database review. SETTING: Academic tertiary hospital. PATIENTS: Patients undergoing carotid endarterectomy and carotid angioplasty and stenting from 1996 to 2006. INTERVENTION: Carotid revascularization. MAIN OUTCOME MEASURE: Glomerular filtration rate (GFR) was calculated based on the Modification of Diet in Renal Disease equation. Groups were analyzed by stages 0 to 2 (GFR >=60 mL/min/1.73m(2)) vs stage 3 (GFR <60 and >=30 mL/min/1.73m(2)) vs stages 4 and 5 (GFR <30 mL/min/1.73m(2)). RESULTS: Nine hundred twenty-one carotid interventions were performed (750 carotid endarterectomy, 171 carotid angioplasty and stenting). The overall 30-day mortality and morbidity rates were 1.1% and 16.9%, respectively. Sixty-six percent of patients had normal renal function (stages 0 2). Twenty-eight percent of patients had moderate renal insufficiency (stage 3) and 6% of patients had severe renal insufficiency (stages 4-5). The 30-day stroke rates for groups were 2.98% (normal renal function), 2.67% (moderate renal insufficiency), and 5.45% (severe renal insufficiency) (P = .54). Thirty-day mortality rates between groups were 0.66% (normal renal function), 1.15% (moderate renal insufficiency), and 5.45% (severe renal insufficiency) (P = .005). For carotid endarterectomy, no difference in freedom from stroke existed based on level of renal function. For carotid angioplasty and stenting, patients with severe renal insufficiency exhibited significantly lower rates of freedom from stroke. CONCLUSIONS: Chronic kidney disease is prevalent among patients undergoing carotid revascularization. Overall, patients with moderate renal function have similar outcomes. However, those with severe renal insufficiency have significantly higher 30-day mortality when undergoing carotid revascularization. PMID- 21690438 TI - Laparoscopic vs open appendectomy in children: outcomes comparison based on age, sex, and perforation status. AB - HYPOTHESIS: Outcomes of laparoscopic appendectomy (LA) will be similar to open appendectomy (OA) in children of all ages. DESIGN: Retrospective cohort study using discharge abstract data. SETTING: Twelve regional hospitals in Southern California. PATIENTS: Seven thousand six hundred fifty patients underwent appendectomy for acute appendicitis (LA = 3551, OA = 4099). INTERVENTION: Laparoscopic appendectomy or OA. MAIN OUTCOME MEASURES: Thirty-day morbidity (wound infection, abscess drainage, and readmission) and length of hospitalization. RESULTS: Use of laparoscopy increased from 22% in 1998 to 70% in 2007. Overall, patients undergoing LA were older (mean [SD] age, 12.8 [3.2] vs 10.4 [3.7] years; P < .001) and had a lower perforation rate (24% vs 34%; P < .001). Multivariable logistic regression demonstrated a decreased odds ratio for wound infection (odds ratio, 0.6; 95% confidence interval, 0.5-0.8) and abscess drainage (odds ratio, 0.6; 95% confidence interval, 0.4-0.7) following LA compared with OA. Multivariable linear regression also showed decreased length of hospitalization following LA compared with OA. CONCLUSION: Now the preferred operation for children with appendicitis, LA was associated with a decreased risk of wound infection, abscess drainage, and length of hospitalization compared with OA. PMID- 21690439 TI - Receipt of appropriate surgical care for Medicare beneficiaries with cancer. AB - OBJECTIVE: To investigate receipt of appropriate surgical care in Medicare beneficiaries with cancer. DESIGN: Retrospective cohort study. SETTING: National Surveillance, Epidemiology, and End Results registry linked to Medicare claims data. PATIENTS: Fee-for-service Medicare patients aged 65 years or older who underwent a definitive surgical resection for breast, colon, gastric, rectal, or thyroid cancer diagnosed between January 2000 and December 2005. Claims data were available from January 1999 through December 2007. MAIN OUTCOME MEASURES: Receipt of care concordant with established practice guidelines in surgical oncology in the aggregate and by hospital. RESULTS: Concordance with guidelines was greater than 90% for 7 of 11 measures. All guidelines regarding adjuvant therapy had concordance rates greater than 90%. Only 2 of 5 measures for nodal management had concordance rates greater than 90%. At least 50% of hospitals provided guideline concordant care to 100% of their patients for 6 of 11 guidelines. Patients receiving appropriate care tended to be younger, healthier, white, and more affluent, to have less advanced disease, and to live in the Midwest. CONCLUSIONS: We found a high level of concordance with guidelines in some domains of surgical oncology care but far less so in others, particularly for gastric and colon nodal management. Given the current national focus on improving the quality of health care, surgeons must focus on generating data to define appropriate care and translating those data into everyday practice. PMID- 21690440 TI - PPE, OPPE, and FPPE: complying with the new alphabet soup of credentialing. PMID- 21690441 TI - Better than the lungs we are taking out. PMID- 21690442 TI - Neuronal differentiation of human adipose tissue-derived stem cells for peripheral nerve regeneration in vivo. AB - OBJECTIVE: To evaluate the ability of a tissue-engineered nerve construct composed of a nerve guidance channel and neurally differentiated human adipose tissue-derived stem cells (hASCs) to enhance peripheral nerve regeneration in a rat sciatic nerve model. DESIGN: A 13-mm sciatic nerve gap was bridged with silastic conduits in 64 athymic nude rats, and differentiated hASCs were implanted into the nerve gap. The effect of repetitive renewal of differentiation medium on days 14 and 28 was further tested. Adequate negative controls and isograft controls were used. SETTING: Academic research. PATIENTS: The hASCs were isolated from human adipose tissue of patients undergoing liposuction procedures. MAIN OUTCOME MEASURES: Direct measurements of nerve function included sciatic functional index score, extensor postural thrust, and sensory evaluation. Indirect measurements included gastrocnemius and soleus muscle atrophy. Histomorphometric evaluation included the number and diameter of axons and fibers, nerve fiber density, myelin thickness, g-ratio (axon diameter-total fiber diameter ratio), and myelin thickness-axon diameter ratio. RESULTS: The use of hASCs demonstrated significantly improved functional recovery as measured by the sciatic functional index, extensor postural thrust, sensory evaluation, and gastrocnemius and soleus muscle weight after 14 days and 1, 2, 3, and 4 months. Groups with their medium renewed also demonstrated further enhanced functional recovery compared with their counterparts that did not have their medium renewed. CONCLUSION: This tissue-engineered nerve construct using hASCs was able to improve functional recovery during the first 4 months, comparable with nerve isografts. PMID- 21690443 TI - Impact of antiviral therapy on the survival of patients after major hepatectomy for hepatitis B virus-related hepatocellular carcinoma. AB - OBJECTIVES: To assess whether commencement of antiviral therapy after hepatectomy improves the prognosis of hepatocellular carcinoma (HCC) in preoperatively antiviral-naive patients with chronic hepatitis B virus (HBV) infection. DESIGN: Retrospective analysis of a prospectively collected database. SETTING: University teaching hospital. MAIN OUTCOME MEASURES: Disease-free and overall survival rates. RESULTS: One hundred thirty-six patients received major hepatectomy for HBV-related HCC from September 1, 2003, through December 31, 2007. Among them, 42 patients received antiviral therapy (treatment group) after hepatectomy, whereas 94 did not (control group). Patient demographics, preoperative liver function, tumor characteristics, and liver function at the time of tumor recurrence were comparable between the 2 groups. Disease-free and overall survival rates were significantly prolonged in the treatment group. The 1-, 3-, and 5-year overall survival rates in the treatment group were 88.1%, 79.1%, and 71.2%, respectively; in the control group, 76.5%, 47.5%, and 43.5%, respectively (P = .005). The 1-, 3 , and 5-year disease-free survival rates in the treatment group were 66.5%, 51.4%, and 51.4%, respectively; in the control group, 48.9%, 33.8%, and 33.8%, respectively (P = .05). Subgroup analysis stratified against tumor stage and major vascular invasion showed that posthepatectomy antiviral treatment conferred a significant survival benefit in stages I and II tumors or HCCs without major venous invasion. CONCLUSIONS: Antiviral therapy improves the prognosis of HBV related HCC. It should be considered after hepatectomy for HBV-related HCC, especially in early-stage tumors. PMID- 21690444 TI - Comparative analysis of resection and liver transplantation for intrahepatic and hilar cholangiocarcinoma: a 24-year experience in a single center. AB - OBJECTIVES: To compare the survival difference between 2 surgical modalities in the treatment of locally advanced intrahepatic and hilar cholangiocarcinoma (CCA) and to identify factors that predict mortality. DESIGN: Retrospective study. SETTING: University transplant center. PATIENTS: Of the 132 patients with a diagnosis of CCA treated from February 1, 1985, through June 30, 2009, 75 had metastatic disease at presentation and were excluded from the study, whereas 57 patients were candidates for surgical therapy. Tumor type was intrahepatic in 37 patients and hilar in 20 patients. Surgical therapy included orthotopic liver transplant (OLT) in 38 patients and combined radical bile duct resection with partial hepatectomy (RR) in 19 patients. RESULTS: Tumors were locally advanced in 35 of 37 patients (95%) with intrahepatic tumors and 16 of 20 patients (80%) with hilar tumors. Adjunctive therapy was used in 35 patients (61%). The 5-year tumor recurrence-free patient survival was significantly higher in the OLT group compared with the RR group (33% vs 0%; P = .05). In the OLT group, neoadjuvant and adjuvant therapies resulted in better patient survival compared with no therapy or adjuvant therapy only (47% vs 20% vs 33%, respectively; P = .03). Multivariate factors predictive of worse survival outcomes included hilar CCA, multifocal tumors, perineural invasion, and RR as the treatment modality compared with OLT. Tumor sizes--5 cm or larger for intrahepatic and 3 cm or larger for hilar CCA--were not predictors of poor outcome. CONCLUSION: Orthotopic liver transplant in combination with neoadjuvant and adjuvant therapies is superior to RR with adjuvant therapy in locally advanced intrahepatic and hilar CCA. PMID- 21690445 TI - Endoscopic excision of large colorectal polyps as a viable alternative to surgical resection. AB - OBJECTIVE: To determine the outcome of endoscopic excision of large colorectal polyps. DESIGN: Retrospective medical record review. SETTING: Kaiser Permanente, a large health care maintenance organization. PATIENTS: One hundred four consecutive patients with large colorectal lesions deemed not amenable to endoscopic resection at initial colonoscopy and referred for surgical resection. INTERVENTION: Endoscopic excision under intravenous sedation by 2 interventional endoscopists. MAIN OUTCOMES MEASURES: Endoscopic success (the ability to completely eradicate the original or recurrent lesion endoscopically at the index procedure or at reintervention), procedure-related complications, disease recurrence, endoscopic reintervention, and surgical intervention. RESULTS: We included 48 men (46%) and 56 women (54%) with a mean age of 67 (range, 29-92) years for analysis. Anatomic distribution of the lesions included the colon (68%) and rectum (32%). Thirty-nine patients (37%) had carcinoma. The median size of the lesions was 3.0 (range, 1-9) cm. The endoscopic success rate was 83% and was highest in patients with noncarcinoma histologic findings compared with carcinoma (P < .001). The morbidity rate was 7%, and all complications occurred in the ascending colon (P = .06). Endoscopic reintervention occurred in 25 of 92 patients (27%). Surgical intervention was undertaken in 14% of all patients. During a mean follow-up of 14 (median, 12) months, recurrent disease was noted in 10 of 86 patients (12%) and occurred more frequently in rectal lesions (P = .002). All recurrences were eradicated endoscopically. CONCLUSIONS: Endoscopic excision of large colorectal polyps is a viable alternative to surgical resection in a select group of patients and can be performed safely with a good success rate. PMID- 21690446 TI - Hilar cholangiocarcinoma: tumor depth as a predictor of outcome. AB - BACKGROUND: The American Joint Committee on Cancer staging system for hilar cholangiocarcinoma may be inaccurate because the bile duct lacks discrete tissue boundaries. OBJECTIVES: To examine the accuracy of the American Joint Committee on Cancer staging schemes and to determine the prognostic implications of tumor depth. DESIGN, SETTING, AND PATIENTS: From January 1, 1987, through December 31, 2009, there were 106 patients who underwent resection of hilar cholangiocarcinoma who had pathologic slides available for re-review. MAIN OUTCOME MEASURES: Tumor depth and overall survival. RESULTS: Overall median survival was 19.9 months. The 6th and 7th editions of the T-classification criteria were unable to discriminate among T1, T2, and T3 lesions (P > .05 for all). Median survival was associated with the invasion depth of the tumor (>=5 mm vs <5 mm): 18 months vs 30 months (P = .01). On multivariate analysis, tumor depth remained predictive of disease specific death (hazard ratio, 1.70; P = .03). CONCLUSIONS: The American Joint Committee on Cancer T-classification criteria did not stratify patients with regard to prognosis. Depth of tumor invasion is a better predictor of long-term outcome. PMID- 21690447 TI - Effect of incomplete parathyroidectomy preserving entire parathyroid glands on renal graft function. AB - HYPOTHESIS: Parathyroidectomy (PT) corrects tertiary hyperparathyroidism in patients who have received renal grafts but can result in deterioration of renal function. OBJECTIVE: To compare different surgical procedures for their effect on renal function and efficacy to cure tertiary hyperparathyroidism. DESIGN: A retrospective cohort study. SETTING: University clinic. PATIENTS: Eighty-three patients with functioning renal grafts receiving PT for the first time. INTERVENTIONS: Group 1 received an incomplete PT, with at least 1 entire parathyroid gland (PG) remaining in situ (n = 12). Group 2 received an incomplete PT, with the most morphologically conserved PG partially resected (n = 22). Group 3 received a complete PT, with autotransplantation of PG tissue (n = 49). MAIN OUTCOMES MEASURES: The primary end point was the postoperative change in glomerular filtration rate. Secondary end points were rates of redialysis, hypercalcemia, and hyperparathyroidism within 5 years. RESULTS: A decrease in glomerular filtration rate occurred postoperatively in 75 patients (90%) and correlated significantly with the extent of PG resection. Recovery of renal function at month 6 was observed in group 1, but not in groups 2 and 3 (P < .001). Seven patients (8%) needed permanent dialysis (1 in group 2 and 6 in group 3). Hypercalcemia was abrogated in 78 patients (94%), without significant differences among the groups. Assessment of parathyroid hormone levels in accordance with target ranges from the Kidney Disease Outcomes Quality Initiative guidelines did not reveal significant differences in the rates of recurrent hyperparathyroidism. CONCLUSION: Incomplete PT preserving at least 1 entire PG does not cause deterioration of renal graft function and provides long-term correction of hypercalcemia and tertiary hyperparathyroidism. PMID- 21690448 TI - Minimally invasive esophagectomy provides equivalent oncologic outcomes to open esophagectomy for locally advanced (stage II or III) esophageal carcinoma. AB - BACKGROUND: Minimally invasive esophagectomy (MIE) has been performed at specialized centers for 15 years, but few studies have looked at outcomes in patients with locally advanced cancers, and few studies have provided long-term survival comparison with Ivor Lewis esophagectomy (ILE) to determine oncologic benefit or equivalence of MIE. HYPOTHESIS: Minimally invasive esophagectomy for locally advanced esophageal carcinoma has similar oncologic outcomes to traditional open ILE with less associated short-term morbidity and mortality. DESIGN: Retrospective comparison of patients with stage II or III esophageal carcinoma undergoing 3-field MIE compared with open ILE. SETTING: University medical center. PATIENTS: From 1995 to 2009, 64 patients who underwent MIE (33 patients) or ILE (31 patients) with clinical stage II or III esophageal cancer were compared. MAIN OUTCOME MEASURES: Primary end points included operative performance, morbidity, mortality, hospital stay, and survival. RESULTS: No differences were noted between the groups in demographics, neoadjuvant therapy use (P = .22), resection completeness (R0:R1) (P = .57), length of stay (P = .59), intensive care unit stay (P = .36), anastomotic leak (P = 1.0), pulmonary morbidity (P = .26), and mortality (P = 1.0). Median follow-up was 19 months for MIE and 17 months for ILE. Survival at 2 years was 55% for MIE (18 of 33 patients) and 32% for ILE (10 of 31 patients) while disease-free survival was 55% for MIE (18) and 26% for ILE (8). CONCLUSIONS: Our survival analysis shows divergent curves that favor MIE but have not yet reached statistical significance. The oncologic outcomes of MIE are comparable to that of ILE 2 years after resection. PMID- 21690449 TI - Early postoperative outcomes after pancreaticoduodenectomy in the elderly. AB - BACKGROUND: Single-institution case series suggest that elderly patients do as well as younger patients after pancreaticoduodenectomy. OBJECTIVES: To compare morbidity and mortality after pancreaticoduodenectomy in patients older than 70 years vs younger patients. HYPOTHESIS: Elderly patients have worse 30-day outcomes. DESIGN: Retrospective cohort study. SETTING: American College of Surgeons-National Surgical Quality Improvement Program hospitals. PATIENTS: All patients who had a pancreaticoduodenectomy from January 1, 2005, to December 31, 2007, were identified. METHODS: Multiple logistic regression models were developed to assess the association between age and 30-day outcomes. MAIN OUTCOME MEASURES: Thirty-day postoperative morbidity and mortality. RESULTS: Of the 2610 patients identified, 977 (37.4%) were elderly and 1633 (62.6%) were younger. Overall morbidity was 36.5%. Elderly patients had a higher likelihood of developing at least 1 morbidity (surgical site infection, wound disruption, outpatient pneumonia, unplanned intubation, pulmonary embolism, prolonged ventilation, acute renal failure, urinary tract infection, stroke, cardiac arrest, deep venous thrombosis, sepsis, or return to the operating room) compared with that of younger patients (40.7% vs 34.0%; odds ratio, 1.27; 95% confidence interval, 1.06-1.51; P = .01). Overall mortality was 2.7%. Elderly patients had a higher likelihood of mortality compared with that of younger patients (4.3% vs 1.7%; adjusted odds ratio, 2.01; 95% confidence interval, 1.18-3.43; P = .01). In patients who had at least 1 morbidity, mortality was 10.1% in the elderly compared with 4.1% in the younger patients (P = .002). CONCLUSIONS: Advanced age is independently associated with morbidity and death following pancreaticoduodenectomy. In addition, the elderly have a higher mortality after a complication compared with that of younger patients, suggesting that advanced age may have a role in "failure to rescue." PMID- 21690451 TI - Early-stage gallbladder cancer in the Surveillance, Epidemiology, and End Results database: effect of extended surgical resection. AB - HYPOTHESIS: Extended surgical resection (ESR) may improve survival in patients with early-stage primary gallbladder cancer. DESIGN: Retrospective analysis of findings in the Surveillance, Epidemiology, and End Results (SEER) database. SETTING: Academic research. PATIENTS: Individuals with potentially surgically curable gallbladder cancer (Tis, T1, or T2) who underwent a surgical procedure. MAIN OUTCOME MEASURES: Overall survival, number of lymph nodes (LNs) excised, and results of simple cholecystectomy vs ESR. RESULTS: We identified 3209 patients with early-stage gallbladder cancer (11.7% Tis, 30.1% T1, and 58.2% T2). On multivariate analysis, decreased survival was noted among patients older than 60 years (hazard ratio, 1.57; 95% confidence interval, 1.30-1.90), among patients with more advanced cancer (1.99; 1.46-2.70 for T1; 3.29; 2.45-4.43 for T2), and among patients with disease-positive LNs (1.65; 1.39-1.95 for regional; 2.58; 1.54-4.34 for distant) (P < .001 for all), while increased survival was observed among female patients (0.82; 0.70-0.96; P = .02) and among patients undergoing ESR (0.59; 0.45-0.78; P < .001). The survival advantage of ESR was seen only in patients with T2 lesions (0.49; 0.35-0.68; P < .001). Lymph node excision data were available for a subset of 2507 patients, of whom 68.2% had no LN excised, 28.2% had 1 to 4 LNs excised, and 3.6% had 5 or more LNs excised. On multivariate analysis, patients with 1 to 4 LNs excised had a survival benefit over those with no LN excised (HR, 0.55; 95% CI, 0.46-0.66; P < .001), and patients with 5 or more LNs excised had a survival benefit over patients with 1 to 4 LNs removed (0.63; 0.40-0.96; P = .03). Lymph node excision improved survival in patients with T2 lesions (0.42; 0.33-0.53; P < .001 for patients with 1-4 LNs excised). CONCLUSION: Extended surgical resection, LN excision, or both may improve survival in certain patients with incidentally discovered gallbladder cancer. PMID- 21690450 TI - Pancreatic endocrine tumors with major vascular abutment, involvement, or encasement and indication for resection. AB - BACKGROUND: Surgery for pancreatic endocrine tumors (PETs) with blood vessel involvement is controversial. HYPOTHESIS: Resection of PETs with major blood vessel involvement can be beneficial. DESIGN: The combined databases of the National Institutes of Health and Stanford University hospitals were queried. MAIN OUTCOME MEASURES: Operation, pathologic condition, complications, and disease-free and overall survival. RESULTS: Of 273 patients with PETs, 46 (17%) had preoperative computed tomography evidence of major vascular involvement. The mean size for the primary PET was 5.0 cm. The involved major vessel was as follows: portal vein (n = 20), superior mesenteric vein or superior mesenteric artery (n = 16), inferior vena cava (n = 4), splenic vein (n = 4), and heart (n = 2). Forty-two of 46 patients had a PET removed: 12 (27%) primary only, 30 (68%) with lymph nodes, and 18 (41%) with liver metastases. PETs were removed by either enucleation (n = 7) or resection (n = 35). Resections included distal or subtotal pancreatectomy in 23, Whipple in 10, and total in 2. Eighteen patients had concomitant liver resection: 10 wedge resection and 8 anatomic resections. Nine patients had vascular reconstruction: each had reconstruction of the superior mesenteric vein and portal vein, and 1 had concomitant reconstruction of the superior mesenteric artery. There were no deaths, but 12 patients had complications. Eighteen patients (41%) were immediately disease free, and 5 recurred with follow-up, leaving 13 (30%) disease-free long term. The 10-year overall survival was 60%. Functional tumors were associated with a better overall survival (P < .001), and liver metastases decreased overall survival (P < .001). CONCLUSION: These findings suggest that surgical resection of PETs with vascular abutment/invasion and nodal or distant metastases is indicated. PMID- 21690452 TI - Incidence and risk factors of venous thromboembolism in colorectal surgery: does laparoscopy impart an advantage? AB - OBJECTIVES: Laparoscopy is increasingly used in colon and rectal procedures. However, little is known regarding the incidence of venous thromboembolism (VTE) in laparoscopic colorectal (LC) compared with that in open colorectal (OC) procedures. We aimed to compare the incidences and to highlight the risk factors of developing VTE after LC and OC surgery. DESIGN: Analysis of the Nationwide Inpatient Sample data from 2002 through 2006. SETTING: National database. PATIENTS: Patients who underwent elective LC and OC surgery from 2002 through 2006. MAIN OUTCOMES MEASURE: Incidence of VTE during initial hospitalization after LC and OC surgery; VTE classified by surgical site, pathology type, and at risk patient population. RESULTS: Over a 60-month period, 149,304 patients underwent LC or OC resection. Overall, the incidence of VTE was significantly higher in OC cases (2036 of 141,456 [1.44%]) compared with the incidence in LC cases (65 of 7848 [0.83%]) (P < .001). When stratified according to pathologic condition and surgical site, the overall rate of VTE was highest in patients with inflammatory bowel disease and in those undergoing rectal resections. Patients who underwent OC surgery were almost twice as likely to develop VTE compared with patients who underwent LC surgery. We also identified malignancy, obesity, and congestive heart failure as statistically significant (P < .05) risk factors for VTE in OC and LC surgery. CONCLUSIONS: On the basis of data from a large clinical data set, the incidence of perioperative VTE is lower after LC than after OC surgery. These findings may help colorectal surgeons use appropriate VTE prophylaxis for patients undergoing colorectal procedures. PMID- 21690453 TI - Bariatric surgery as a novel treatment for type 2 diabetes mellitus: a systematic review. AB - OBJECTIVE: To systematically review the literature pertaining to the reversal of type 2 diabetes mellitus (DM2) after Roux-en-Y gastric bypass and adjustable gastric banding. DATA SOURCES: We conducted a review of the literature using PubMed and searched the reference lists of published studies to identify additional studies. STUDY SELECTION: We selected all published articles that were relevant with respect to bariatric surgery and its metabolic effects. DATA EXTRACTION: Only 9 original articles reporting on DM2 reversal rates after bariatric surgery were identified: 1 randomized controlled trial and 8 observational studies. Other referenced articles serve as background literature. DATA SYNTHESIS: Roux-en-Y gastric bypass leads to a reversal rate of DM2 of 83%. Adjustable gastric banding confers a reversal rate of 62%, and this effect is achieved later after surgery. CONCLUSIONS: Bariatric surgery leads to marked and long-lasting weight reduction. A large proportion of patients undergoing bariatric surgery have DM2. In fact, the presence of diabetes mellitus is a compelling argument to perform bariatric surgery in those who are eligible according to international criteria. Glycemic control improves in the months after laparoscopic adjustable gastric banding, but it improves more rapidly and completely after laparoscopic Roux-en-Y gastric bypass surgery. Thus, both types of surgery are capable of improving or even curing DM2, but the mechanisms may differ. PMID- 21690454 TI - An alternative pancreatic anastomosis following pancreaticoduodenectomy. AB - Pancreatic head resection and reconstruction is technically challenging. Eight patients underwent pancreaticoduodenectomy for either ductal adenocarcinoma (n = 7) or neuroendocrine tumor (n = 1) in the head of the pancreas with a dilated pancreatic duct. The pancreatic stump could not be mobilized to form a standard pancreaticogastrostomy or a pancreaticojejunostomy following resection because of a complete fixation to the splenic vein (n = 2), common hepatic artery (n = 1), or mesentery (n = 3) or inadequate length of the pancreatic remnant (n = 2). After laying open the pancreatic duct along the pancreatic transection margin in the ventral aspect of the pancreas, a longitudinal ventral pancreaticojejunostomy was performed using polydioxanone 3/0 sutures. The average time taken to create this pancreatic anastomosis was less than 10 minutes. This longitudinal ventral pancreatic anastomosis is quick, easy to perform, and a safe alternative method for pancreatic reconstruction after pancreaticoduodenectomy. PMID- 21690455 TI - Image of the month. Cystic hepatocellular carcinoma. PMID- 21690456 TI - Image of the month. Abdominoscrotal hydrocele. PMID- 21690457 TI - Image of the month. Gallstone ileus. PMID- 21690458 TI - Dynamic parietal closure: initial experience of an original parietal closure procedure for treatment of abdominal wound dehiscence. PMID- 21690459 TI - "Unnecessary" postmastectomy radiation therapy. PMID- 21690460 TI - An internally controlled, double-blind comparison of the efficacy of onabotulinumtoxinA and abobotulinumtoxinA. AB - OBJECTIVE: To compare 2 commercially available botulinum neuromodulators in a randomized, double-blind, split-face study. METHODS: Ninety patients were treated with 10 U of onabotulinumtoxinA and 30 U of abobotulinumtoxinA for the treatment of lateral orbital rhytids. Patients were assessed live with a validated 5-point photographic scale prior to treatment and at 30 days. Patients were also photographed at each visit. RESULTS: AbobotulinumtoxinA demonstrated a statistically significant advantage compared with onabotulinumtoxinA in the treatment of lateral orbital rhytids at maximal contraction, as evaluated independently by the investigator (P = .01) and patient (P = .03). AbobotulinumtoxinA was also favored by the patient over onabotulinumtoxinA 67% of the time. While abobotulinumtoxinA seemed to treat lateral orbital rhytids better at rest, as evidenced by the data and photographs, this difference was not statistically significant (P = .42). CONCLUSIONS: AbobotulinumtoxinA offers superior efficacy in the treatment of lateral orbital rhytids compared with onabotulinumtoxinA. Further studies are needed to compare the 2 products in different muscle groups and for other indications. PMID- 21690461 TI - Anterior ethmoidal artery septal flap for the management of septal perforation. AB - OBJECTIVES: To achieve long-term closure of nasal septal perforations and to describe our surgical technique for repairing septal defects. METHODS: We describe 11 patients who underwent endoscopic repair of anterior septal perforations with a unilateral septal flap pedicled by the anterior ethmoidal artery. The patients were followed up for a period of 12 to 132 months (median follow-up, 51 months). RESULTS: There were no complications after surgery. All cases of septal perforation remained closed for the duration of follow-up. CONCLUSION: Closure of a perforated nasal septum through an endonasal technique can be achieved with a unilateral mucosal flap based on the anterior ethmoidal artery. PMID- 21690462 TI - Orbicularis muscle position during lower blepharoplasty with fat repositioning. AB - OBJECTIVE: To evaluate intraoperative changes in the position of the orbicularis muscle edge, which defines the tear trough during lower eyelid blepharoplasty with supraperiosteal fat repositioning. METHODS: Thirty consecutive patients undergoing transconjunctival lower eyelid blepharoplasty with a supraperiosteal fat repositioning technique underwent intraoperative measurement of the elevation of the released orbicularis muscle edge. Using a "dipstick" method, the distance between the midinferior orbital rim and the inferior orbicularis muscle edge, which was previously located below the orbital rim, was measured after fixation of the repositioned orbital fat. Age, associated procedures, length of follow-up, and complications were noted. RESULTS: The released orbicularis muscle edge was elevated between 6 and 12 mm above the orbital rim (average elevation, 8.8 mm). All measurements were within 2 mm between the 2 sides for a given patient, with 24 of the cases being within 1 mm. No apparent difference was seen between the muscle elevation achieved with externalized suture fixation of repositioned fat (22 patients) and that achieved with internal suture fixation (8 patients). CONCLUSIONS: The orbicularis oculi muscle fusion to the maxilla below the arcus marginalis defines the junction between the eyelid and the cheek, and it provides an anchor for the tear trough. The eyelid-cheek interface is significantly elevated with our surgical technique of fat repositioning in the supraperiosteal plane. Elevation of the orbicularis muscle edge may contribute to improved blepharoplasty results in treating the aging midface. PMID- 21690463 TI - Dynamically shaped magnetic fields: initial animal validation of a new remote electrophysiology catheter guidance and control system. AB - BACKGROUND: To address some of the shortcomings of existing remote catheter navigation systems (RNS), a new magnetic RNS has been developed that provides real-time navigation of catheters within the beating heart. The initial experience using this novel RNS in animals is described. METHODS AND RESULTS: A real-time, high-speed, closed-loop, magnetic RNS system (Catheter Guidance Control and Imaging) comprises 8 electromagnets that create unique dynamically shaped ("lobed") magnetic fields around the subject's torso. The real-time reshaping of these magnetic fields produces the appropriate 3D motion or change in direction of a magnetized electrophysiology ablation catheter within the beating heart. The RNS is fully integrated with the Ensite-NavX 3D electroanatomic mapping system (St Jude Medical) and allows for both joystick and automated navigation. Conventional and remote navigational mapping of the left atrium were performed using a 4-mm-tip ablation catheter in 10 pigs. A multielectrode transseptal sheath allowed for additional motion compensation. Linear and circumferential radiofrequency lesion sets were performed; in a subset of cases, selective pulmonary vein isolation was also performed. Recording and fluoroscopic equipments were unaffected by the magnetic fields generated by Catheter Guidance Control and Imaging. Automated mode navigation was highly reproducible (96+/-8.4% of attempts), accurate (1.9+/-0.4 mm from target site), and rapid (11.6+/-3.5 seconds to reach targets). At postmortem examination, radiofrequency lesion depth was 78.5+/-12.1% of atrial wall thickness. CONCLUSIONS: A new magnetic RNS using a dynamically shaped magnetic field concept can reproducibly and effectively reach target radiofrequency ablation points within the pig left atrium. Validation of the system in clinical settings is under way. PMID- 21690464 TI - Prospective multi-institutional study evaluating the performance of prostate cancer risk calculators. AB - PURPOSE: Prostate cancer risk calculators incorporate many factors to evaluate an individual's risk for prostate cancer. We validated two common North American based, prostate cancer risk calculators. PATIENTS AND METHODS: We conducted a prospective, multi-institutional study of 2,130 patients who underwent a prostate biopsy for prostate cancer detection from five centers. We evaluated the performance of the Sunnybrook nomogram-based prostate cancer risk calculator (SRC) and the Prostate Cancer Prevention Trial (PCPT) -based risk calculator (PRC) to predict the presence of any cancer and high-grade cancer. We examined discrimination, calibration, and decision curve analysis techniques to evaluate the prediction models. RESULTS: Of the 2,130 patients, 867 men (40.7%) were found to have cancer, and 1,263 (59.3%) did not have cancer. Of the patients with cancer, 403 (46.5%) had a Gleason score of 7 or more. The area under the [concentration-time] curve (AUC) for the SRC was 0.67 (95% CI, 0.65 to 0.69); the AUC for the PRC was 0.61 (95% CI, 0.59 to 0.64). The AUC was higher for predicting aggressive disease from the SRC (0.72; 95% CI, 0.70 to 0.75) compared with that from the PRC (0.67; 95% CI, 0.64 to 0.70). Decision curve analyses showed that the SRC performed better than the PRC for risk thresholds of more than 30% for any cancer and more than 15% for aggressive cancer. CONCLUSION: The SRC performed better than the PRC, but neither one added clinical benefit for risk thresholds of less than 30%. Further research is needed to improve the AUCs of the risk calculators, particularly for higher-grade cancer. PMID- 21690465 TI - Impact of patient-reported outcomes in oncology: a longitudinal analysis of patient-physician communication. AB - PURPOSE: Regularly collecting patient-reported outcomes (PROs) of health-related quality of life with feedback to oncologists may assist in eliciting and monitoring patients' problems during cancer treatment. This study examined how PRO feedback had an impact on patient-physician communication over time to gain a better understanding of how it may influence patient care. PATIENTS AND METHODS: Exploratory analyses were performed on a data set from a previous study. Patients were randomly assigned to intervention (regular completion of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Hospital Anxiety and Depression Scale with feedback to oncologists), attention-control (completion of same questionnaires without feedback), and control (standard care) arms. The content of consultation audio recordings between 28 oncologists and 198 patients over four consecutive visits (792 consultations) was analyzed. Mixed-effects models and multivariate regressions were used to examine the longitudinal impact of the intervention on patient physician communication, dynamics of patient-physician interaction, and the association between PROs and the content of clinic discussion. RESULTS: Patients in the intervention arm discussed more symptoms over time compared with patients in the attention-control (P = .008) and control (P = .04) arms. No study arm effect was observed for function discussions. Discussion topics were predominantly raised by patients/relatives, regardless of arm allocation. Clinic discussions were associated with severity of patient-reported symptoms but not with patient-reported functional concerns. CONCLUSION: A positive longitudinal impact of the intervention on symptom discussion was observed, but not for function discussion, suggesting that potentially serious problems may remain unaddressed. Training oncologists in responding to patient-reported functional concerns may increase the impact of this intervention. PMID- 21690466 TI - Identifying circulating tumor stem cells that matter: the key to prognostication and therapeutic targeting. PMID- 21690467 TI - Malignant fibrous histiocytoma in a male breast: a case report. PMID- 21690468 TI - Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. AB - PURPOSE: Melanomas harbor aberrations in the c-Kit gene. We tested the efficiency of the tyrosine kinase inhibitor imatinib in selected patients with metastatic melanoma harboring c-Kit mutations or amplifications. PATIENTS AND METHODS: Forty three patients with metastatic melanoma harboring c-Kit aberrations were enrolled on this phase II trial. Each patient received a continuous dose of imatinib 400 mg/d unless intolerable toxicities or disease progression occurred. Fifteen patients who experienced progression of disease were allowed to escalate the dose to 800 mg/d. RESULTS: Forty-three patients were eligible for evaluation, and the median follow-up time was 12.0 months. The median progression-free survival (PFS) was 3.5 months, and the 6-month PFS rate was 36.6%. Rate of total disease control was 53.5%: 10 patients (23.3%; 95% CI, 10.2% to 36.4%) and 13 patients (30.2%; 95% CI, 16.0% to 44.4%) achieved partial response (PR) and stable disease (SD), respectively. Eighteen patients (41.9%) demonstrated regression of tumor mass. Notably, nine of the 10 PRs were observed in patients with mutations in exons 11 or 13. The 1-year overall survival (OS) rate was 51.0%. The median PFS and OS times for patients who had PR or SD versus disease progression were 9.0 months versus 1.5 months (P < .001) and 15.0 months versus 9.0 months (P = .036), respectively. Imatinib 400 mg/d was well tolerated, and only one of the 15 patients who received dose escalation to 800 mg/d achieved SD. CONCLUSION: Imatinib demonstrated significant activity in patients with metastatic melanoma harboring genetic c-Kit aberrations, with an overall response rate of 23.3%. Escalation to 800 mg/d could not restore disease control. PMID- 21690469 TI - Fatal infusion reaction to cetuximab: the need for predictive risk factors and safer patient selection. PMID- 21690470 TI - Exercise behavior, functional capacity, and survival in adults with malignant recurrent glioma. AB - PURPOSE: Identifying strong markers of prognosis are critical to optimize treatment and survival outcomes in patients with malignant recurrent glioma. We investigated the prognostic significance of exercise behavior and functional capacity in this population. PATIENTS AND METHODS: Using a prospective design, 243 patients with WHO grades 3 to 4 recurrent malignant glioma and Karnofsky performance status (KPS) >= 70 completed a self-administered questionnaire that assessed exercise behavior and performed a 6-minute walk test (6MWT) to assess functional capacity. Cox proportional models were used to estimate the risk of all-cause mortality according to 6MWT distance (6MWD; < 390 meters, 390-489 meters, > 489 meters) and exercise behavior (metabolic equivalent [MET] -h/wk) adjusted for KPS and other important clinical factors. RESULTS: Median follow-up was 27.43 months. During this period, 149 deaths were recorded (61% of the total sample). Exercise behavior was an independent predictor of survival (P = .0081). Median survival was 13.03 months for patients reporting < 9 MET-h/wk relative to 21.84 months for those reporting >= 9 MET-h/wk. Exercise behavior added incremental prognostic value beyond that provided by KPS, age, sex, grade, and number of prior progressions (P < .001). Compared with patients reporting < 9 MET h/wk, the adjusted hazard ratio for mortality was 0.64 (95% CI, 0.46 to 0.91) for patients reporting >= 9 MET-h/wk. Functional capacity was not an independent predictor of prognosis. CONCLUSION: Exercise behavior is a strong independent predictor of survival that provides incremental prognostic value to KPS as well as traditional markers of prognosis in malignant recurrent glioma. PMID- 21690472 TI - Cost-effectiveness of contralateral prophylactic mastectomy versus routine surveillance in patients with unilateral breast cancer. AB - PURPOSE: Contralateral prophylactic mastectomy (CPM) rates in women with unilateral breast cancer are increasing despite controversy regarding survival advantage. Current scrutiny of the medical costs led us to evaluate the cost effectiveness of CPM versus routine surveillance as an alternative contralateral breast cancer (CBC) risk management strategy. METHODS: Using a Markov model, we simulated patients with breast cancer from mastectomy to death. Model parameters were gathered from published literature or national databases. Base-case analysis focused on patients with average-risk breast cancer, 45 years of age at treatment. Outcomes were valued in quality-adjusted life-years (QALYs). Patients' age, risk level of breast cancer, and quality of life (QOL) were varied to assess their impact on results. RESULTS: Mean costs of treatment for women age 45 years are comparable: $36,594 for the CPM and $35,182 for surveillance. CPM provides 21.22 mean QALYs compared with 20.93 for surveillance, resulting in an incremental cost-effectiveness ratio (ICER) of $4,869/QALY gained for CPM. To prevent one CBC, six CPMs would be needed. CPM is no longer cost-effective for patients older than 70 years (ICER $62,750/QALY). For BRCA-positive patients, CPM is clearly cost-effective, providing more QALYs while being less costly. In non BRCA patients, cost-effectiveness of CPM is highly dependent on assumptions regarding QOL for CPM versus surveillance strategy. CONCLUSION: CPM is cost effective compared with surveillance for patients with breast cancer who are younger than 70 years. Results are sensitive to BRCA-positive status and assumptions of QOL differences between CPM and surveillance patients. This highlights the importance of tailoring treatment for individual patients. PMID- 21690471 TI - Phase I study of temsirolimus in pediatric patients with recurrent/refractory solid tumors. AB - PURPOSE: To determine dose-limiting toxicities, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of weekly intravenous temsirolimus, a mammalian target of rapamycin (mTOR) signaling pathway inhibitor, in pediatric patients with recurrent or refractory solid tumors. PATIENTS AND METHODS: Cohorts of three to six patients 1 to 21 years of age with recurrent or refractory solid tumors were treated with a 1-hour intravenous infusion of temsirolimus weekly for 3 weeks per course at one of four dose levels: 10, 25, 75, or 150 mg/m(2). During the first two courses, pharmacokinetic and pharmacodynamic evaluations (phosphorylation of S6, AKT, and 4EBP1 in peripheral-blood mononuclear cells) were performed. RESULTS: Dose-limiting toxicity (grade 3 anorexia) occurred in one of 18 evaluable patients at the 150 mg/m(2) level, which was determined to be tolerable, and an MTD was not identified. In 13 patients evaluable for response after two courses of therapy, one had complete response (CR; neuroblastoma) and five had stable disease (SD). Four patients (three SDs + one CR) remained on treatment for more than 4 months. The sum of temsirolimus and sirolimus areas under the concentration-time curve was comparable to values in adults. AKT and 4EBP1 phosphorylation were inhibited at all dose levels, particularly after two courses. CONCLUSION: Weekly intravenous temsirolimus is well tolerated in children with recurrent solid tumors, demonstrates antitumor activity, has pharmacokinetics similar to those in adults, and inhibits the mTOR signaling pathway in peripheral-blood mononuclear cells. Further studies are needed to define the optimal dose for use in combination with other antineoplastic agents in pediatric patients. PMID- 21690473 TI - Chronic immune stimulation might act as a trigger for the development of acute myeloid leukemia or myelodysplastic syndromes. AB - PURPOSE: Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often present with infections, but there are little data to assess whether a personal history of selected infections may act as pathogenic triggers. To additionally expand our knowledge on the role of immune stimulation in the causation of AML and MDS, we have conducted a large, population-based study to evaluate the risk of AML and MDS associated with a prior history of a broad range of infections or autoimmune diseases. PATIENTS AND METHODS: By using population based central registries in Sweden, we included 9,219 patients with AML, 1,662 patients with MDS, and 42,878 matched controls. We used logistic regression to calculate odds ratios (ORs) and 95% CIs for the association of AML or MDS with infectious and/or autoimmune diseases. RESULTS: Overall, a history of any infectious disease was associated with a significantly increased risk of both AML (OR, 1.3; 95% CI, 1.2 to 1.4) and MDS (OR, 1.3; 95% CI, 1.1 to 1.5). These associations were significant even when we limited infections to those occurring 3 or more years before AML/MDS. A previous history of any autoimmune disease was associated with a 1.7-fold (95% CI, 1.5 to 1.9) increased risk for AML and 2.1 fold (95% CI, 1.7 to 2.6) increased risk for MDS. A large range of conditions were each significantly associated with AML and MDS. CONCLUSION: Our novel findings indicate that chronic immune stimulation acts as a trigger for AML/MDS development. The underlying mechanisms may also be due to a common genetic predisposition or an effect of treatment for infections/autoimmune conditions. PMID- 21690474 TI - Prediction models: revolutionary in principle, but do they do more good than harm? PMID- 21690475 TI - Randomized multicenter trial of the effects of melanoma-associated helper peptides and cyclophosphamide on the immunogenicity of a multipeptide melanoma vaccine. AB - PURPOSE: This multicenter randomized trial was designed to test whether melanoma associated helper peptides augment CD8(+) T-cell responses to a melanoma vaccine and whether cyclophosphamide (CY) pretreatment augments CD4(+) or CD8(+) T-cell responses to that vaccine. PATIENTS AND METHODS: In all, 167 eligible patients with resected stage IIB to IV melanoma were randomly assigned to four vaccination study arms. Patients were vaccinated with 12 class I major histocompatibility complex-restricted melanoma peptides (12MP) to stimulate CD8(+) T cells and were randomly assigned to receive a tetanus helper peptide or a mixture of six melanoma-associated helper peptides (6MHP) to stimulate CD4(+) T cells. Before vaccination, patients were also randomly assigned to receive CY pretreatment or not. T-cell responses were assessed by an ex vivo interferon gamma ELISpot assay. Clinical outcomes and toxicities were recorded. RESULTS: Vaccination with 12MP plus tetanus induced CD8(+) T-cell responses in 78% of patients and CD4(+) T-cell responses to tetanus peptide in 93% of patients. Vaccination with 12MP plus 6MHP induced CD8(+) responses in 19% of patients and CD4(+) responses to 6MHP in 48% of patients. CY had no significant effect on T-cell responses. Overall 3-year survival was 79% (95% CI, 71% to 86%), with no significant differences (at this point) by study arm. CONCLUSION: Melanoma-associated helper peptides paradoxically decreased CD8(+) T-cell responses to a melanoma vaccine (P < .001), and CY pretreatment had no immunologic or clinical effect. Prior work showed immunologic and clinical activity of 6MHP alone. Possible explanations for negative effects on CD8 responses include modulation of homing receptor expression or induction of antigen-specific regulatory T cells. PMID- 21690476 TI - Angiotensin receptor blockade and risk of cancer in type 2 diabetes mellitus: a nationwide case-control study. AB - PURPOSE: The objective of this case-control study was to evaluate the risk of malignancy in diabetic patients who received angiotensin receptor blockers (ARBs). PATIENTS AND METHODS: A total of 21,750 new diabetic patients who started antihypertensive treatment were identified from the Taiwan National Health Insurance claims database during the period from July 1, 2000, to December 31, 2000. As of December 31, 2007, patients with incident cancer were included as cases and up to four age- and sex-matched controls were selected by risk-set sampling. Logistic regression models were applied to estimate the odds ratios (ORs) and 95% CIs between ARB use and cancer incidence, adjusted for other types of antihypertensive drugs, insulin, oral hypoglycemic agents, statins, and underlying diseases. RESULTS: Among the 1,281 patients with incident cancer and 5,104 controls, 333 (26.0%) and 1,341 (26.3%), respectively, received ARBs (OR, 0.98; 95% CI, 0.85 to 1.14). There was no statistically significant association between the effect of ARBs as a class and cancer incidence after adjustment for covariates (OR, 0.94; 95% CI, 0.80 to 1.10). Among the individual ARBs, losartan decreased the risk (OR, 0.78; 95% CI, 0.63 to 0.97) and candesartan (OR, 1.79; 95% CI, 1.05 to 3.06) and telmisartan (OR, 1.54; 95% CI, 0.97 to 2.43) possibly increased the risk of occurrence of malignancy. CONCLUSION: The results did not show an effect of ARBs as a class on increasing cancer incidence in patients with diabetes. However, there was a negative association of losartan but a positive one of candesartan and telmisartan with the overall occurrence of cancer. The underlying mechanism certainly requires further investigation. PMID- 21690477 TI - Levels of symptom burden during chemotherapy for advanced lung cancer: differences between public hospitals and a tertiary cancer center. AB - PURPOSE: We compared risk factors for high disease- and treatment-related symptom burden over 15 weeks of therapy in medically underserved patients with advanced non-small-cell lung cancer and in patients treated at a tertiary cancer center. PATIENTS AND METHODS: We monitored symptom severity weekly during chemotherapy. Patients were recruited from a tertiary cancer center (n=101) and three public hospitals treating the medically underserved (n=80). We used a composite symptom severity score and group-based trajectory analysis to form two groups: one with consistently more severe symptoms and another with less severe symptoms. We examined predictors of group membership. RESULTS: Seventy percent of the sample (n=126) reported low symptom-severity levels that decreased during therapy; 30% (n=55) had consistently severe symptoms throughout the study. In multivariate analysis, patients with good performance status being treated in public hospitals were significantly more likely than patients treated at the tertiary cancer center to be in the high-symptom group (odds ratio, 5.6; 95% CI, 2.1 to 14.6; P = .001) and to report significantly higher symptom interference (P = .001). Other univariate predictors of high-symptom group membership included variables associated with being medically underserved (eg, having less education, being single, and being nonwhite). No group differences by ethnicity were observed in the public hospitals. Medically underserved patients were less likely to receive adequate pain management. CONCLUSION: Patients with advanced lung cancer and good performance status treated at public hospitals were more likely than those treated at a tertiary cancer center to experience substantial symptoms during chemotherapy. PMID- 21690478 TI - Human epidermal growth factor eyedrops for cetuximab-related filamentary keratitis. PMID- 21690479 TI - Association of diagnostic radiation exposure and second abdominal-pelvic malignancies after testicular cancer. AB - PURPOSE: The evidence associating cancer risk with diagnostic radiation exposure is unclear. Men recovering from low-grade testicular cancer frequently undergo serial abdominal-pelvic computerized tomography (CT) scanning to monitor for recurrent disease. METHODS: We used population-based administrative data sets to identify every incident case of testicular cancer between 1991 and 2004 in Ontario, Canada. We excluded those with previous cancer, concurrent radiation therapy, retroperitoneal lymph node dissection, or fewer than 5 years observation. Patients were observed until the occurrences of death or development of a second abdominal-pelvic malignancy or until December 31, 2009. RESULTS: A total of 2,569 men (mean age, 34.7 years; standard deviation, 10.2) were observed for a median of 11.2 years (interquartile range [IQR], 8.3 to 14.3). During the first 5 years after diagnosis, men underwent a median of 10 computed tomography (CT) scans (IQR, 4 to 18) of the abdominal-pelvic area, and they were exposed to a median of 110 mSv of radiation from radiologic investigations (IQR, 44 to 190). After this, 14 men were diagnosed with a second abdominal-pelvic malignancy (rate, five per 10,000 patient-years observation, 95% CI, three to eight); the most common diagnoses were colorectal and kidney malignancies. Radiation exposure was not associated with an excess risk of second cancers (hazard ratio per 10 mSv increase, 0.99; 95% CI, 0.95 to 1.04). This association did not change if men observed for fewer than 5 years were included in the analysis (hazard ratio, 1.00; 95% CI, 0.96 to 1.04). CONCLUSION: Second malignancies of the abdomen pelvis are uncommon in men with low-grade testicular cancer. In this study, the risk of second cancer was not associated with the amount of diagnostic radiation exposure. PMID- 21690480 TI - Increase of ascites and pleural effusion misleading assessment of antitumor response to erlotinib in adenocarcinoma of the lung. PMID- 21690481 TI - Erythropoietin increases expression and function of transient receptor potential canonical 5 channels. AB - Hypertension is a common complication in hemodialysis patients during erythropoietin (EPO) treatment. The underlying mechanisms of EPO-induced hypertension still remain to be determined. Increased transient receptor potential canonical (TRPC) channels have been associated with hypertension. Now, TRPC gene expression was investigated using quantitative real-time RT-PCR and immunoblotting in cultured human endothelial cells and in monocytes from hemodialysis patients. EPO dose-dependently increased TRPC5 mRNA in endothelial cells. EPO increased TRPC5 mRNA stability, that is, EPO prolonged the half-life period for TRPC5 mRNA from 16 hours (control) to 24 hours (P<0.05). The poly(A) tail length was measured by rapid amplification of cDNA ends-poly(A) test. Increased TRPC5 mRNA stability was attributed to longer 3' poly(A) tail lengths after EPO administration. EPO also significantly increased TRPC5 channel protein abundance by 70% (P<0.05). Whole-cell patch clamp showed that angiotensin II induced, TRPC5-mediated currents were dramatically increased in endothelial cells treated with EPO. Fluorescent dye techniques confirmed that increased calcium influx after EPO treatment was abolished after TRPC5 knockdown (P<0.05). EPO also significantly increased intracellular reactive oxygen species production. Knockdown of TRPC5 alleviated EPO-induced reactive oxygen species generation in endothelial cells (P<0.05). In vivo, EPO-treated hemodialysis patients showed significantly increased amounts of TRPC5 mRNA in monocytes compared with EPO-free hemodialysis patients (6.0+/-2.4 [n=12] versus 1.0+/-0.5 [n=9]; P<0.01). Patients undergoing EPO treatment also showed significantly elevated systolic blood pressure (160+/-7 versus 139+/-6 mm Hg; P<0.05). Our findings suggest that upregulated functional TRPC5 gene may be one cause of EPO-induced hypertension in patients with chronic kidney disease. PMID- 21690482 TI - Heme oxygenase 1 is differentially involved in blood flow-dependent arterial remodeling: role of inflammation, oxidative stress, and nitric oxide. AB - Heme oxygenase 1 is induced by hemodynamic forces in vascular smooth muscle and endothelial cells. We investigated the involvement of heme oxygenase 1 in flow (shear stress)-dependent remodeling. Two or 14 days after ligation of mesenteric resistance arteries, vessels were isolated. In rats, at 14 days, diameter increased by 23% in high-flow arteries and decreased by 22% in low-flow arteries compared with normal flow vessels. Heme oxygenase activity inhibition using Tin protoporphyrin abolished diameter enlargement in high-flow arteries and accentuated arterial narrowing in low-flow arteries (32% diameter decrease versus 22% in control). Two days after ligation, heme oxygenase 1 expression increased in high-flow and low-flow vessels, in association with a reduced mitochondrial aconitase activity (marker of oxidative stress) in high-flow arteries only. Inhibition of macrophage infiltration (clodronate) decreased heme oxygenase 1 induction in low-flow but not in high-flow arteries. Similarly, inhibition of NADPH oxidase activity (apocynin) decreased heme oxygenase 1 induction in low flow but not high-flow arteries. However, dihydroethidium staining was higher in high-flow and low-flow compared with normal flow arteries. In arteries cannulated in an arteriograph, heme oxygenase 1 mRNA increased in a flow-dependent manner and was abolished by N(G)-nitro-l-arginine methyl ester, catalase, or mitochondrial electron transport chain inhibition. Furthermore, heme oxygenase 1 induction using cobalt-protoporphyrin restored altered high-flow remodeling in endothelial NO synthase knockout mice. Thus, in high-flow remodeling, heme oxygenase 1 induction depends on shear stress-generated NO and mitochondria derived hydrogen peroxide. In low-flow remodeling, heme oxygenase 1 induction requires macrophage infiltration and is mediated by NADPH oxidase-derived superoxide. PMID- 21690483 TI - Peroxisome proliferator-activated receptor-gamma as a potential therapeutic target in the treatment of preeclampsia. AB - Preeclampsia is a multisystemic disorder of pregnancy characterized by hypertension, proteinuria, and maternal endothelial dysfunction. It is a major cause of maternal and perinatal morbidity and mortality and is thought to be attributable, in part, to inadequate trophoblast invasion. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor expressed in trophoblasts, and the vasculature of which activation has been shown to improve endothelium-dependent vasodilatation in hypertensive conditions. We investigated the effects of the administration of a PPAR-gamma agonist using the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. The selective PPAR-gamma agonist, rosiglitazone, was administered to pregnant rats that had undergone RUPP surgery. To investigate whether any observed beneficial effects of PPAR-gamma activation were mediated by the antioxidant enzyme, heme oxygenase 1, rosiglitazone was administered in combination with the heme oxygenase 1 inhibitor tin-protoporphyrin IX. RUPP rats were characterized by hypertension, endothelial dysfunction, and elevated microalbumin:creatinine ratios. Rosiglitazone administration ameliorated hypertension, improved vascular function, and reduced the elevated microalbumin:creatinine ratio in RUPP rats. With the exception of microalbumin:creatinine ratio, these beneficial effects were abrogated in the presence of the heme oxygenase 1 inhibitor. Administration of a PPAR-gamma agonist prevented the development of several of the pathophysiological characteristics associated with the RUPP model of preeclampsia, via a heme oxygenase 1-dependent pathway. The findings from this study provide further insight into the underlying etiology of preeclampsia and a potential therapeutic target for the treatment of preeclampsia. PMID- 21690484 TI - Exercise training versus propranolol in the treatment of the postural orthostatic tachycardia syndrome. AB - We have found recently that exercise training is effective in the treatment of the postural orthostatic tachycardia syndrome (POTS). Whether this nondrug treatment is superior to "standard" drug therapies, such as beta-blockade, is unknown. We tested the hypothesis that exercise training but not beta-blockade treatment improves symptoms, hemodynamics, and renal-adrenal responses in POTS patients. Nineteen patients (18 women and 1 man) completed a double-blind drug trial (propranolol or placebo) for 4 weeks, followed by 3 months of exercise training. Fifteen age-matched healthy individuals (14 women and 1 man) served as controls. A 2-hour standing test was performed before and after drug treatment and training. Hemodynamics, catecholamines, plasma renin activity, and aldosterone were measured supine and during 2-hour standing. We found that both propranolol and training significantly lowered standing heart rate. Standing cardiac output was lowered after propranolol treatment (P=0.01) but was minimally changed after training. The aldosterone:renin ratio during 2-hour standing remained unchanged after propranolol treatment (4.1+/-1.7 [SD] before versus 3.9+/-2.0 after; P=0.46) but modestly increased after training (5.2+/-2.9 versus 6.5+/-3.0; P=0.05). Plasma catecholamines were not affected by propranolol or training. Patient quality of life, assessed using the 36-item Short-Form Health Survey, was improved after training (physical functioning score 33+/-10 before versus 50+/-9 after; social functioning score 37+/-9 versus 48+/-6; both P<0.01) but not after propranolol treatment (34+/-10 versus 36+/-11, P=0.63; 39+/-7 versus 39+/-5, P=0.73). These results suggest that, for patients with POTS, exercise training is superior to propranolol at restoring upright hemodynamics, normalizing renal-adrenal responsiveness, and improving quality of life. PMID- 21690485 TI - Exercise training in Postural Orthostatic Tachycardia syndrome: blocking the urge to block beta-receptors? PMID- 21690487 TI - Re: Comparative effectiveness of prostate cancer treatments: evaluating statistical adjustments for confounding in observational data. PMID- 21690486 TI - Impact of leptin-mediated sympatho-activation on cardiovascular function in obese mice. AB - Although the anorexic effects of leptin are lost in obesity, leptin-mediated sympatho-activation is preserved. The cardiovascular consequences of leptin mediated sympatho-activation in obesity are poorly understood. We tested the hypothesis that 32 weeks of high-fat diet (HFD) induces metabolic leptin resistance but preserves leptin-mediated sympatho-activation of the cardiovascular system. HFD in mice significantly increased body weight and plasma leptin concentrations but significantly reduced the anorexic effects of leptin. HFD increased heart rate, stroke volume, cardiac output, and plasma aldosterone levels but not blood pressure. As reflected by the contractile response to phenylephrine measured both in vivo and ex vivo, vascular adrenergic reactivity was reduced by HFD, suggesting that reductions in sympathetic tone to the periphery vasculature may mitigate sympatho-activation of the heart and the renin angiotensin-aldosterone system. Tachyphylaxis was partially restored by symptho inhibition and not present in ob/ob and db/db mice, despite obesity, arguing for a sympatho-mediated and leptin-specific mechanism. Although infusion of leptin in HFD mice had no effect on heart rate or blood pressure, it further increased aldosterone levels and further reduced vascular adrenergic tone in the absence of weight loss, indicating persistent leptin-mediated stimulation of the cardiovascular system in obesity. In conclusion, these data indicate that, despite metabolic leptin resistance, leptin-mediated stimulation of the heart, the vasculature, and aldosterone production persists in obesity. Blood pressure effects in response to leptin may be limited by a tachyphylactic response in the circulation, suggesting that failure of adrenergic desensitization may be a requisite step for hypertension in the context of obesity. PMID- 21690488 TI - Signature microRNA expression profile of essential hypertension and its novel link to human cytomegalovirus infection. AB - BACKGROUND: Essential hypertension has been recognized as a disease resulting from a combination of environmental and genetic factors. Recent studies demonstrated that microRNAs (miRNAs) are involved in cardiac hypertrophy and heart failure. However, little is known about the roles of miRNAs in essential hypertension. METHODS AND RESULTS: Using microarray-based miRNA expression profiling, we compared the miRNA expressions in plasma samples from 13 hypertensive patients and 5 healthy control subjects. Twenty-seven miRNAs were found to be differentially expressed. The expressions of selected miRNAs (miR-296 5p, let-7e, and a human cytomegalovirus [HCMV]-encoded miRNA, hcmv-miR-UL112) were validated independently in plasma samples from 24 hypertensive patients and 22 control subjects. The absolute expression levels of hcmv-miR-UL112, miR-296 5p, and let-7e were further determined in 127 patients and 67 control subjects (fold changes are 2.5, 0.5, and 1.7 respectively; all P<0.0001). Additionally, we demonstrated that interferon regulatory factor 1 is a direct target of hcmv-miR UL112. Increased HCMV seropositivity and quantitative titers were found in the hypertension group compared with the control group (52.7% versus 30.9%, P=0.0005; 1870 versus 54 copies per 1 mL plasma, P<0.0001). Seropositivity, log-transformed copies of HCMV, and hcmv-miR-UL112 were independently associated with an increased risk of hypertension (odds ratio, 2.48; 95% confidence interval, 1.48 to 4.15; P=0.0005; odds ratio, 1.97; 95% confidence interval, 1.58 to 2.46; P<0.0001; and odds ratio, 2.55; 95% confidence interval, 1.98 to 3.27; P<0.0001, respectively). CONCLUSIONS: We report for the first time a circulating miRNA profile for hypertensive patients and demonstrate a novel link between HCMV infection and essential hypertension. These findings may reveal important insights into the pathogenesis of essential hypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT00420784. PMID- 21690489 TI - Secondary prevention and mortality in peripheral artery disease: National Health and Nutrition Examination Study, 1999 to 2004. AB - BACKGROUND: Whether individuals with peripheral artery disease (PAD) identified by screening ankle-brachial index benefit from preventive therapies to reduce cardiovascular risk is unknown. We aimed to determine the number of US adults with PAD who are not receiving preventive therapies and whether treatment is associated with reduced mortality in PAD subjects without known cardiovascular disease. METHODS AND RESULTS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 with mortality follow-up through December 31, 2006. We defined PAD as an ankle-brachial index <=0.90. Of 7458 eligible participants >=40 years, weighted PAD prevalence was 5.9+/-0.3% (mean+/-SE), corresponding to ~7.1 million US adults with PAD. Statin use was reported in only 30.5+/-2.5%, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use in 24.9+/-1.9%, and aspirin use in 35.8+/-2.9%, corresponding to 5.0 million adults with PAD not taking statins, 5.4 million not taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 4.5 million not receiving aspirin. After adjustment for age, sex, and race/ethnicity, PAD was associated with all-cause mortality (hazard ratio, 2.4; 95% confidence interval, 1.9 to 2.9; P<0.0001). Even after exclusion of individuals with known cardiovascular disease, subjects with PAD had higher mortality rates (16.1+/-2.1%) than subjects without PAD or cardiovascular disease (4.1+/-0.3%), with an adjusted hazard ratio of 1.9 (95% confidence interval, 1.3 to 2.8; P=0.001). Among PAD subjects without cardiovascular disease, use of multiple preventive therapies was associated with 65% lower all-cause mortality (hazard ratio, 0.35; 95% confidence interval, 0.20 to 0.86; P=0.02). CONCLUSIONS: Millions of US adults with PAD are not receiving secondary prevention therapies. Treatment with multiple therapies is associated with reduced all-cause mortality. PMID- 21690490 TI - Dynamic changes in regulatory T cells are linked to levels of diet-induced hypercholesterolemia. AB - BACKGROUND: Regulatory T cells (Treg) are present in atherosclerotic lesions and can modulate disease. In this study we characterized changes in Treg responses associated with prolonged hypercholesterolemia and lesion progression. METHODS AND RESULTS: Low-density lipoprotein receptor null mice in which Treg express green fluorescent protein were fed a control or cholesterol-rich diet, and green fluorescent protein-positive cells were enumerated in lymphoid tissues and in aorta. Splenic Treg numbers increased after 4, 8, and 20 weeks in cholesterol diet-fed mice. However, the number of circulating and lesional Treg peaked at 4 weeks and decreased significantly at 8 and 20 weeks, concomitant with increased numbers of CD4(+) effector T cells and increased lesion size over this period. Treg expression of selectin ligands and their ability to bind to aortic endothelium decreased after prolonged hypercholesterolemia, and apoptosis of lesional Treg increased. After 4 weeks of cholesterol-rich diet, a switch to a control diet for 4 weeks reduced serum cholesterol and stopped lesion growth, and the high aortic Treg content was maintained, compared with mice fed a cholesterol diet for 8 weeks. After the diet reversal, the splenic Treg retained the phenotype of Treg after 4 weeks of cholesterol diet. CONCLUSIONS: Prolonged hypercholesterolemia impairs Treg but not effector T cell accumulation in lesions, but reversal of hypercholesterolemia can prevent loss of lesional Treg. Therefore, cholesterol-lowering therapies may induce dynamic and beneficial changes in Treg:effector T cell ratios in atherosclerotic lesions. PMID- 21690491 TI - Rhesus macaques develop metabolic syndrome with reversible vascular dysfunction responsive to pioglitazone. AB - BACKGROUND: The metabolic syndrome (MetS) is a constellation of clinical features that include central obesity, hypertension, atherogenic dyslipidemia, and insulin resistance. However, the concept remains controversial; it has been debated whether MetS represents nothing more than simultaneous co-occurrence of individual risk factors or whether there are common shared pathophysiological mechanisms that link the individual components. METHODS AND RESULTS: To investigate the emergence of metabolic and cardiovascular components during the development of MetS, we identified MetS-predisposed animals (n=35) in a large population of rhesus macaques (Macaca mulatta, 12.7+/-2.9 years old, n=408), acclimated them to standardized conditions, and monitored the progression of individual component features over 18 months. In 18 MetS animals with recently developed fasting hyperinsulinemia, central obesity, hypertension, and atherogenic dyslipidemia, we found that individual metabolic and cardiovascular components track together during the transition from pre-MetS to onset of MetS; MetS was associated with a 60% impairment of flow-mediated dilation, establishing the mechanistic link with vascular dysfunction. Pioglitazone treatment (3 mg/kg body weight/d for 6 weeks), a peroxisome proliferator-activated receptor gamma agonist, reversibly improved atherogenic dyslipidemia and insulin resistance and fully restored flow-mediated dilation with persistent benefits. CONCLUSIONS: Coemergence of metabolic and cardiovascular components during MetS progression and complete normalization of vascular dysfunction with peroxisome proliferator activated receptor gamma agonists suggest shared underlying mechanisms rather than separate processes, arguing for the benefit of early intervention of MetS components. Predictive nonhuman primate (NHP) models of MetS should be highly valuable in mechanistic and translational studies on the pathogenesis of MetS in relation to cardiovascular disease and diabetes mellitus. PMID- 21690492 TI - Increased risk for heart valve disease associated with antiphospholipid antibodies in patients with systemic lupus erythematosus: meta-analysis of echocardiographic studies. AB - BACKGROUND: Heart valve disease (HVD) is frequent in patients with systemic lupus erythematosus (SLE), and the role of antiphospholipid antibodies (aPL) is controversial. Thus, our objective was to estimate the risk of HVD, including Libman-Sacks endocarditis, associated with aPL in patients with SLE. METHODS AND RESULTS: Studies were selected if they investigated the association between aPL and HVD in SLE patients and if aPL-negative patients were included for comparison. Data sources were MEDLINE, Embase, Cochrane Library, hand search, contact with investigators, and reference lists of studies, without language restrictions. Data on study and patient characteristics, risk estimates, and study quality were independently extracted by 2 investigators. Pooled effect estimates were obtained by using the DerSimonian-Laird method. Of 234 identified abstracts, 23 primary studies (15 cross-sectional, 7 cohort, 1 case-control) met inclusion criteria, including 1656 SLE patients and 508 cases of HVD. Compared with SLE patients without aPL (n=988), the overall pooled odds ratios for HVD and Libman-Sacks endocarditis in aPL-positive patients (n=668) were 3.13 (95% confidence interval, 2.31 to 4.24) and 3.51 (95% confidence interval, 1.93 to 6.38), respectively. The risk of HVD depending on aPL subtypes was the highest for lupus anticoagulant at 5.88 (95% confidence interval, 2.92 to 11.84) and IgG anticardiolipin antibodies at 5.63 (95% confidence interval, 3.53 to 8.97). CONCLUSIONS: Overall, the presence of aPL in SLE patients is significantly associated with an increased risk for HVD including Libman-Sacks endocarditis. The risk conferred by IgG anticardiolipin antibodies is as strong as by lupus anticoagulant. Systematic echocardiographic examinations in SLE patients with aPL should be performed. PMID- 21690493 TI - Peroxisome proliferator-activated receptor-gamma agonists prevent in vivo remodeling of human artery induced by alloreactive T cells. AB - BACKGROUND: Ligands activating the transcription factor peroxisome proliferator activated receptor-gamma (PPARgamma) have antiinflammatory effects. Vascular rejection induced by allogeneic T cells can be responsible for acute and chronic graft loss. Studies in rodents suggest that PPARgamma agonists may inhibit graft vascular rejection, but human T-cell responses to allogeneic vascular cells differ from those in rodents, and the effects of PPARgamma in human transplantation are unknown. METHODS AND RESULTS: We tested the effects of PPARgamma agonists on human vascular graft rejection using a model in which human artery is interposed into the abdominal aorta of immunodeficient mice, followed by adoptive transfer of allogeneic (to the artery donor) human peripheral blood mononuclear cells. Interferon-gamma-dependent rejection ensues within 4 weeks, characterized by intimal thickening, T-cell infiltrates, and vascular cell activation, a response resembling clinical intimal arteritis. The PPARgamma agonists 15-deoxy-prostaglandin-J(2), ciglitazone, and pioglitazone reduced intimal expansion, intimal infiltration of CD45RO(+) memory T cells, and plasma levels of inflammatory cytokines. The PPARgamma antagonist GW9662 reversed the protective effects of PPARgamma agonists, confirming the involvement of PPARgamma mediated pathways. In vitro, pioglitazone inhibited both alloantigen-induced proliferation and superantigen-induced transendothelial migration of memory T cells, indicating the potential mechanisms of PPARgamma effects. CONCLUSION: Our results suggest that PPARgamma agonists inhibit allogeneic human memory T cell responses and may be useful for the treatment of vascular graft rejection. PMID- 21690494 TI - Use of emergency medical service transport among patients with ST-segment elevation myocardial infarction: findings from the National Cardiovascular Data Registry Acute Coronary Treatment Intervention Outcomes Network Registry-Get With The Guidelines. AB - BACKGROUND: Activation of emergency medical services (EMS) is critical for the early triage and treatment of patients experiencing ST-segment-elevation myocardial infarction, yet data regarding EMS use and its association with subsequent clinical care are limited. METHODS AND RESULTS: We performed an observational analysis of 37 634 ST-segment-elevation myocardial infarction patients treated at 372 US hospitals participating in the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry Get With the Guidelines between January 2007 and September 2009, and examined independent patient factors associated with EMS transportation versus patient self-transportation. We found that EMS transport was used in only 60% of ST segment-elevation myocardial infarction patients. Older patients, those living farther from the hospital, and those with hemodynamic compromise were more likely to use EMS transport. In contrast, race, income, and education level did not appear to be associated with the mode of transport. Compared with self transported patients, EMS-transported patients had significantly shorter delays in both symptom-onset-to-arrival time (median, 89 versus 120 minutes; P<0.0001) and door-to-reperfusion time (median door-to-balloon time, 63 versus 76 minutes; P<0.0001; median door-to-needle time, 23 versus 29 minutes; P<0.0001). CONCLUSIONS: Emergency medical services transportation to the hospital is underused among contemporary ST-segment-elevation myocardial infarction patients. Nevertheless, use of EMS transportation is associated with substantial reductions in ischemic time and treatment delays. Community education efforts are needed to improve the use of emergency transport as part of system-wide strategies to improve ST-segment-elevation myocardial infarction reperfusion care. PMID- 21690496 TI - Traumatic laceration of the posterior left ventricle diagnosed by transesophageal echocardiography. PMID- 21690497 TI - Letter by Benedetto et al regarding article, "Importance of refractory pain and hypertension in acute type B aortic dissection: insights from the International Registry of Acute Aortic Dissection (IRAD)". PMID- 21690495 TI - Perishock pause: an independent predictor of survival from out-of-hospital shockable cardiac arrest. AB - BACKGROUND: Perishock pauses are pauses in chest compressions before and after defibrillatory shock. We examined the relationship between perishock pauses and survival to hospital discharge. METHODS AND RESULTS: We included out-of-hospital cardiac arrest patients in the Resuscitation Outcomes Consortium Epistry-Cardiac Arrest who suffered arrest between December 2005 and June 2007, presented with a shockable rhythm (ventricular fibrillation or pulseless ventricular tachycardia), and had cardiopulmonary resuscitation process data for at least 1 shock (n=815). We used multivariable logistic regression to determine the association between survival and perishock pauses. In an analysis adjusted for Utstein predictors of survival, the odds of survival were significantly lower for patients with preshock pause >=20 seconds (odds ratio, 0.47; 95% confidence interval, 0.27 to 0.82) and perishock pause >=40 seconds (odds ratio, 0.54; 95% confidence interval, 0.31 to 0.97) compared with patients with preshock pause <10 seconds and perishock pause <20 seconds. Postshock pause was not independently associated with a significant change in the odds of survival. Log-linear modeling depicted a decrease in survival to hospital discharge of 18% and 14% for every 5-second increase in both preshock and perishock pause interval (up to 40 and 50 seconds, respectively), with no significant association noted with changes in the postshock pause interval. CONCLUSIONS: In patients with cardiac arrest presenting in a shockable rhythm, longer perishock and preshock pauses were independently associated with a decrease in survival to hospital discharge. The impact of preshock pause on survival suggests that refinement of automatic defibrillator software and paramedic education to minimize preshock pause delays may have a significant impact on survival. PMID- 21690498 TI - Letter by Yusuf regarding article, "Pacemaker reuse: an initiative to alleviate the burden of symptomatic bradyarrhythmia in impoverished nations around the world". PMID- 21690499 TI - It takes three to tango: genes complicate the association between birth weight and cardiovascular disease. PMID- 21690500 TI - Blood pressure control in diabetes mellitus: is lower always better, and how low should it go? PMID- 21690501 TI - Endovascular repair of abdominal aortic aneurysm: no cause for alarm. PMID- 21690504 TI - Hypertension: a global perspective. PMID- 21690505 TI - Chronic mitral stenosis. PMID- 21690506 TI - Effect of endoscopic sinus surgery on pulmonary function and microbial pathogens in a pediatric population with cystic fibrosis. AB - OBJECTIVE: To assess whether improvements in pulmonary function and microbial pathogenic findings can be achieved by endoscopic sinus surgery in a pediatric population with cystic fibrosis. DESIGN: Retrospective medical record review. SETTING: Academic research. PATIENTS: Forty-one patients with cystic fibrosis who had undergone endoscopic sinus surgery at a single tertiary academic pediatric otolaryngology practice. MAIN OUTCOME MEASURES: Changes in pulmonary function test values or respiratory tract microbial pathogens after endoscopic sinus surgery were examined. RESULTS: Endoscopic sinus surgery did not improve pulmonary function test results in this population. Examination of respiratory tract microbial colonization showed that endoscopic sinus surgery did not affect microbial pathogens. The most common organisms isolated were Staphylococcus aureus and Pseudomonas aeruginosa. CONCLUSION: The lack of effect of endoscopic sinus surgery on pulmonary function test results and respiratory tract microbial pathogens in our study highlights the need for prospective assessments of postoperative quality-of-life improvement and of adjunct medical therapy efficacy. PMID- 21690502 TI - Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease. PMID- 21690507 TI - Patterns of frontobasal and frontosinal fractures in children and teenagers relative to developmental stage of the facial skeleton. AB - OBJECTIVES: To clarify the patterns of frontobasal and frontosinal fractures in children and teenagers and to analyze whether the patterns relate to developmental stage of the facial skeleton. DESIGN: Retrospective study. SETTING: Level I trauma center in Bern, Switzerland. PATIENTS: Forty-three consecutive patients aged 18 years or younger with fracture of the frontal skull base. MAIN OUTCOME MEASURES: Age at the time of injury and site, type, and degree of displacement among frontobasal and frontosinal fractures. RESULTS: The orbital roof was the most common frontobasal fracture site (86.0% [37 of 43]), and a combined lateral and central frontobasal fracture was the most common fracture type (55.8% [24 of 43]). Frontosinal fractures were observed in 46.5% of patients (20 of 43). Displacement or communitation of frontobasal fractures occurred in 46.5% of patients (20 of 43) and of frontosinal fractures in 70.0% (14 of 20). Isolated central frontobasal fractures were significantly more frequent in teenagers than in children aged 6 years or younger, but isolated lateral frontobasal fractures were significantly more frequent in children aged 6 years or younger than in teenagers (P = .02 for both). Dislocation or communition of frontosinal fractures was significantly more frequent in teenagers than in children aged 6 years or younger (P = .04). CONCLUSION: Frontobasal fracture patterns are related to age, reflecting their correlation with the developmental phase of the facial skeleton, particularly size and degree of pneumatization of the paranasal sinuses. PMID- 21690508 TI - Modern technology-assisted vs conventional tonsillectomy: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To systematically review evidence regarding modern technology-assisted tonsillectomy pertaining to operative time, intraoperative and postoperative bleeding, postoperative pain, and other outcomes. DESIGN: A systematic search for randomized controlled trials comparing total tonsillectomies performed using vessel sealing systems (VSS), Harmonic Scalpel (HS), or radiofrequency ablation (ie, Coblation) with the conventional technique of cold steel and/or electrocautery dissection (CS/EC). Estimation of odds ratios and 95% confidence intervals (CIs), weighted mean differences (WMD), or standardized mean difference (SMD), as appropriate. PATIENTS: Thirty-three randomized controlled trials studying a total of 3139 patients were included in this meta-analysis. MAIN OUTCOME MEASURES: Operative time, perioperative and postoperative bleeding, and postoperative pain. RESULTS: For the VSS group compared with the CS/EC group, operative time was significantly shorter (WMD), -4.09 minutes; 95% CI, -7.43 to 0.75 minutes; 760 patients), perioperative bleeding was significantly less (SMD, 1.67; -2.80 to -0.53; 355 patients), and postoperative bleeding was significantly less (odds ratio, 0.28; 0.13 to 0.61; 792 patients). Pain on the first and seventh postoperative days was significantly less in the VSS group (SMD, -1.73; 95% CI, -3.07 to -0.39; 740 patients; and SMD, -1.46; -2.35 to -0.57; 684 patients; respectively). For the HS group compared with the CS/EC group, the only studied outcome that differed significantly was perioperative bleeding, which was significantly less in the HS group (WMD -37.71 mL; 95% CI, -52.98 to -22.43 mL; 535 cases). No difference was noted between the Coblation and CS/EC groups for any of the studied outcomes. CONCLUSIONS: For tonsillectomies, the Coblation and HS techniques do not provide any significant advantage compared with CS/EC. Synthesis of the limited and heterogeneous data regarding VSSs showed a significant benefit in all studied outcomes. PMID- 21690503 TI - Components of a cardioprotective diet: new insights. PMID- 21690509 TI - Assessment of vocal fold mobility before and after cardiothoracic surgery in children. AB - OBJECTIVES: To assess the incidence of vocal fold immobility (VFI) after cardiothoracic surgery in children and to determine the factors potentially associated with this outcome. METHODS: Flexible laryngoscopy to assess vocal fold mobility was performed before surgery and within 72 hours after extubation in 100 pediatric patients who underwent cardiothoracic procedures. The 2 operating surgeons recorded the surgical technique and their impression of possible injury to the recurrent laryngeal nerve. The presence of laryngeal symptoms, such as stridor, hoarseness, and strength of cry, after extubation was documented. RESULTS: Of 100 children included in this study, 8 had VFI after surgery. Univariate analyses showed that these 8 patients were younger and weighed less than the patients with normal vocal fold movement. Monopolar cautery was used in all patients with VFI. On univariate analysis, factors statistically significantly associated with VFI were circulatory arrest and dissection or ligation of the patent ductus arteriosus, left pulmonary artery, right pulmonary artery, or descending aorta. However, multivariate analyses failed to show these associations. CONCLUSIONS: The incidence of VFI after cardiothoracic surgery in our population of children was 8.0% (8 of 100). Of several factors found to be potentially associated with VFI on univariate analysis, none were significant on multivariate analysis. This may be a result of the few patients with VFI. A larger multicenter prospective study would be needed to definitively identify factors associated with the outcome of VFI. PMID- 21690510 TI - Effect of fluticasone furoate on interleukin 6 secretion from adenoid tissues in children with obstructive sleep apnea. AB - OBJECTIVE: To determine the effect of intranasal corticosteroid therapy on T regulatory cells and other inflammatory cytokines in adenoid tissues in children with obstructive sleep apnea syndrome. DESIGN: Randomized, prospective, exploratory study. SETTING: Academic pediatric otolaryngology practice in a tertiary care children's hospital. PATIENTS: Participants included 24 children between the ages of 2 and 12 years who were undergoing adenotonsillectomy for polysomnogram-documented obstructive sleep apnea syndrome. INTERVENTION: Children were randomized to either no treatment (n = 13) or treatment with fluticasone furoate nasal spray, 55 MUg/nostril daily (n = 11), for 2 weeks before adenotonsillectomy. Adenoid tissue was obtained at the time of the procedure. MAIN OUTCOME MEASURES: The number of tissue T-regulatory cells, as determined by staining with FOXP3, CD4, and CD25, was the primary outcome measure. Staining for interleukin (IL)-10 and transforming growth factor-beta protein by immunohistochemistry, and adenoid mononuclear cell spontaneous and induced release of cytokines (IL-10, IL-6, IL-12, IL-13, tumor necrosis factor, and transforming growth factor beta) were secondary outcomes. RESULTS: Cells isolated from fluticasone furoate nasal spray-treated adenoid tissue released significantly less IL-6 spontaneously as well as upon stimulation with anti-CD3 monoclonal antibody (P = .05) compared with nontreated adenoid tissue. There were no significant differences in the number of CD4/FOXP3-, CD25/FOXP3-, or transforming growth factor beta-positive cells. Intensity of staining for IL-10 was also comparable between the groups. CONCLUSIONS: In this study, we show reduction of IL-6, a proinflammatory cytokine, in adenoid tissue obtained from children with obstructive sleep apnea syndrome treated with fluticasone furoate nasal spray. This reduction could contribute to the clinical efficacy of this class of medications in the treatment of childhood obstructive sleep apnea syndrome. PMID- 21690511 TI - Pediatric tracheal reconstruction using cadaveric homograft. AB - OBJECTIVE: To examine the indications, risks, and surgical outcomes after tracheal reconstruction using cadaveric homograft in children. DESIGN: Retrospective medical record review. SETTING: Tertiary referral center. PATIENTS: Ten children (4 boys and 6 girls). INTERVENTION: Tracheal reconstruction using cadaveric homograft. MAIN OUTCOME MEASURES: Cause of stenosis, number and type of procedures before homograft reconstruction, severity of preoperative stenosis, surgical approach, homograft length, duration of stenting, number and type of procedures after reconstruction, and rates of decannulation and survival. RESULTS: Ten children (mean [SD] age, 8.4 [5.5] years) underwent 14 tracheal reconstructions using cadaveric homograft. Patients had an average of 7.0 (range, 1-16) procedures before homograft reconstruction, including an average of 2.8 (range, 0-6) major open airway reconstructions. Mean (SD) pretracheoplasty Myer Cotton grade of stenosis was 3.80 (0.42) (range, 3-4), and all patients were tracheotomy dependent. A cervical approach was used in 12 reconstructions (86%), and 2 (14%) required median sternotomy. Mean (SD) homograft length was 3.9 (1.7) cm (range, 2-8 cm), which was approximately 0.60 times the length of the total recipient trachea. Mean (SD) duration of stenting for all homografts was 0.67 (0.46) years (range, 0.24-1.98 years). The survival rate was 90% after a mean follow-up of 5.47 (1.52) years (range, 3.32-7.55 years). Surviving patients required an average of 7.38 (5.52) procedures (range, 1-19) after homograft transplant, including an average of 1 major open airway reconstruction (range, 0 4). The mean (SD) grade of stenosis after the final homograft placement was 1.89 (1.27) (range, 1-4). Although the operation-specific decannulation rate was only 7% (1 of 14), the overall decannulation rate eventually reached 60%. Statistical bootstrapping methods and a multivariate regression model determined that increasing patient age (odds ratio, 1.21; 95% confidence interval, 1.07-1.36), increasing number of prior procedures (1.26; 1.02-1.57), and increasing homograft length (2.42; 1.60-3.40 [P < .001]) were associated with an increased risk of no decannulation after tracheal homograft reconstruction. CONCLUSIONS: Tracheal reconstruction using cadaveric homograft is an option in children who have undergone multiple airway surgical procedures and present with long-segment stenoses that cannot be bridged using conventional methods. These patients must receive close postoperative follow-up. Subsequent procedures are almost always required before decannulation, and eventual decannulation rates are only 60%. Decannulation rates are lower in older patients who have previously undergone many procedures and require a long tracheal homograft. PMID- 21690512 TI - Long-term retention of a 3-dimensional educational computer model of the larynx: a follow-up study. AB - OBJECTIVES: To determine the long-term retention of a 3-dimentional (3-D) educational computer model of the larynx to teach laryngeal anatomy and to compare it with standard written instruction (SWI). DESIGN: Prospective randomized controlled trial. SETTING: University education program. PARTICIPANTS: One hundred health care students. INTERVENTIONS: For short-term assessment, 50 students were randomized to the 3-D model and 50 to SWI and were tested using a 20-question laryngeal test. Six months later, the same students were invited to retake the laryngeal anatomy test to examine long-term retention. MAIN OUTCOME MEASURE: The score on a 20-item Web-based test that assessed the students' level of knowledge of laryngeal anatomy approximately 6 months after their initial exposure to the laryngeal anatomy teaching intervention. RESULTS: Sixty-two students retook the test: 3-D (n = 30) and SWI (n = 32). No significant difference was noted in mean scores (P = .54) and change in scores (P = .59) between short- and long-term retention on the laryngeal anatomy test. There was a trend toward an increase in 3-D scores in both groups (P = .07) and a significant increase in 3-D scores in the 3-D group only (P = .049). CONCLUSIONS: A low fidelity model (SWI) is just as effective as a high-fidelity model (3-D) in teaching laryngeal anatomy. The acquired knowledge from either educational intervention may last up to 6 months for long-term retention. This study is one of the few in medical education to examine long-term retention. PMID- 21690513 TI - Collagen type I, collagen type III, and versican in vocal fold lamina propria. AB - OBJECTIVE: To analyze the distributions of collagen type I, collagen type III, and versican in the lamina propria of the human vocal fold. DESIGN: Cross sectional analysis of cadaveric vocal folds of adult human larynges. SETTING: Academic tertiary referral center. SUBJECTS: Larynges harvested at autopsy from 10 adult men and 10 adult women. MAIN OUTCOME MEASURES: Immunohistochemical reactions were performed using antihuman monoclonal antibodies to analyze the expression of collagen type I, collagen type III, and versican. RESULTS: Collagen type I density was lower in the intermediate layer compared with the superficial and deep layers of vocal folds. Collagen type III density was lower in the intermediate layer compared with the deep layer. Versican density was lower in the superficial layer compared with the intermediate and deep layers. Versican density was lower in the lamina propria of women compared with men; this difference was noted in the superficial layer only. There was a positive correlation between collagen type III and versican densities within the lamina propria. CONCLUSION: Collagen type I, collagen type III, and versican are distributed differently within the lamina propria layers of the adult vocal folds. PMID- 21690514 TI - Detection of oral squamous cell carcinoma and cervical lymph node metastasis using activatable near-infrared fluorescence agents. AB - OBJECTIVE: To assess the feasibility of optical imaging using activatable near infrared fluorescence (NIRF) agents to detect oral cancer and cervical lymph node metastasis in vivo. DESIGN: In vivo study. SETTING: University medical center. SUBJECTS: Female nude mice aged 4 to 6 weeks. INTERVENTION: Luciferase-expressing OSC-19-luc cells were injected into the tongues of nude mice. A control group of nude mice was injected in the tongue with a physiologic saline solution. Tumor growth was followed by bioluminescence imaging. After 3 weeks, animals were randomly allocated to intravenous administration of 1 of 2 activatable NIRF agents: ProSense680 or MMPSense680. Fluorescence imaging of the mice was performed, and the tumor to background ratio (TBR) was determined on histologic sections of the tongue and cervical lymph nodes after resection at necropsy. MAIN OUTCOME MEASURE: Fluorescence signals. RESULTS: The fluorescence signals in tongue tumor and cervical lymph node metastases were significantly higher than those in control animals. The mean (SD) TBR of ProSense680 in the tongue was 15.8 (8.1) and in the lymph nodes was 11.8 (3.6). For MMPSense680, the mean (SD) TBR in the tongue was 18.6 (9.4) and in the lymph nodes was 10.5 (4.0). CONCLUSIONS: Oral cancer and cervical lymph node metastases can be detected by targeting increased proteolytic activity at the tumor borders using NIRF optical imaging. These NIRF agents could be used for real-time image-guided surgery, which has the potential to improve the complete surgical resection of oral cancer. PMID- 21690515 TI - Hoarseness. AB - Hoarseness is the colloquial expression for dysphonia ; these terms are often used interchangeably in medicine to refer to altered voice quality. Hoarseness may be both a symptom and a sign of dysfunction of the phonatory apparatus. It is never a diagnosis, despite having a corresponding International Classification of Diseases code and sometimes serving as such for purposes of administrative convenience. The same anatomical and physiological features that make the vocal folds uniquely suited for the high-speed vibration necessary for sound production render them exquisitely sensitive to a wide range of abnormalities. The breadth of pathologic conditions that can cause hoarseness makes a unified overview a challenge; hoarseness is simply not a homogeneous category after the initial laryngoscopy. Moreover, the available literature predominantly focuses on specific diagnoses rather than on hoarseness as a whole, so scant published data exist to support an evidence-based approach. Nevertheless, certain unifying principles exist. PMID- 21690516 TI - Vacuum-assisted closure in revision free flap reconstruction. PMID- 21690517 TI - Tongue entrapment in metal drinking bottle. PMID- 21690518 TI - Radiology quiz case 1. Diagnosis: bilateral retropharyngeal carotid arteries ("kissing carotid arteries"). PMID- 21690519 TI - Radiology quiz case 2. Diagnosis: schwannoma of the masseteric nerve. PMID- 21690520 TI - Radiology quiz case 3. Diagnosis: lingual tonsillar hypertrophy (LTH). PMID- 21690521 TI - Pathology quiz case 1. Diagnosis: laryngeal rhabdomyosarcoma, embryonal subtype. PMID- 21690522 TI - Pathology quiz case 2. Diagnosis: granuloma faciale (GF), late stage. PMID- 21690523 TI - Pathology quiz case 3. Diagnosis: plexiform neurofibroma of the larynx. PMID- 21690524 TI - Completion of the Patient Scar Assessment Scale via a telephone interview. PMID- 21690525 TI - Variables predicting change in benign melanocytic nevi undergoing short-term dermoscopic imaging. AB - OBJECTIVE: To determine whether certain patient demographics are associated with poorer specificity for the diagnosis of melanoma in nevi undergoing short-term sequential digital dermoscopic imaging. DESIGN: Retrospective cohort study performed from April 1, 1998, through May 31, 2007. SETTING: Sydney Melanoma Diagnostic Centre, a tertiary referral institution. PATIENTS: A total of 2497 benign melanocytic lesions in 1765 patients undergoing short-term sequential digital dermoscopic imaging during 2.5 to 4.5 months (42.3% male; mean [SD] age, 40 [14] years; age range, 1-86 years). MAIN OUTCOME MEASURES: Proportion of changed nevi as a function of age, sex, lesion diameter, and anatomical site. RESULTS: The only variable significantly associated with nevus change was age group (P = .002). When compared with the middle-aged (aged 36-50 years) group, the odds of change were significantly increased in the child and adolescent (aged 0-18 years: odds ratio, 2.60; 95% confidence interval, 1.30-5.22), young adult (aged 19-35 years: 1.50; 1.04-2.17), and elderly (> 65 years old: 2.04; 1.04 3.99) age groups. Within the changed benign lesions, a significant association was observed between histologic subtype and age group (P = .01). The proportion of changed lesions of the banal nevi type decreased and the proportion of the dysplastic nevi type increased with age. In the elderly group, 75.9% of changed lesions were of the dysplastic nevi type compared with 35.7% in the youngest group. CONCLUSION: A poorer specificity is observed for the diagnosis of melanoma for nevi undergoing short-term sequential digital dermoscopic imaging in children and adolescents (75.7%) and elderly patients (77.9%) compared with other patients (84.6%). PMID- 21690526 TI - To biopsy or not to biopsy changing moles in children and adolescents: are we removing too many pigmented nevi in this age group?: comment on "Variables predicting change in benign melanocytic nevi undergoing short-term dermoscopic imaging". PMID- 21690528 TI - Frequency of dermoscopic nevus subtypes by age and body site: a cross-sectional study. AB - OBJECTIVE: To subclassify acquired nevi by dermoscopic pattern. DESIGN: Cross sectional study with consecutive enrollment. SETTING: Pigmented lesion clinics in referral academic medical centers. PARTICIPANTS: Individuals older than 2 years undergoing total skin examination were consecutively recruited between October 1, 2008, and May 31, 2009, and, based on their age, assigned to 1 of 8 groups. For each patient, the location and dermoscopic pattern of all nevi on the torso were recorded. Nevi were dermoscopically subclassified as globular, reticular, mixed (reticular-globular) pattern with peripheral or central globules, or unspecified pattern. MAIN OUTCOME MEASURE: Frequency of dermoscopic nevus subtypes stratified by patient age and location of the nevi. RESULTS: A total of 5481 nevi in 480 individuals were evaluated. The number of all nevus subgroups, except for unspecified pattern nevi, significantly increased before and decreased after the fourth decade of life. Globular nevi were most prevalent on the upper trunk in children and adolescents; the number decreased consistently after the second decade of life. The reticular pattern was the most common nevus pattern after the second decade of life and the most common nevus subgroup on the upper and middle back. Although uncommon, central globular nevi also showed an age-dependent trend, similar to that of reticular nevi. Nevi with the peripheral globular pattern declined rapidly after the third decade of life and were no longer observed after the sixth decade. The number of unspecified pattern nevi was stable across all age groups. CONCLUSION: Age, dermoscopic pattern, and location of nevi should be jointly considered when evaluating melanocytic lesions. PMID- 21690531 TI - Importance of providing adequate patient information to ensure good adherence and outcomes: comment on "Efficacy of an educational intervention with kidney transplant recipients to promote skin self-examination for squamous cell carcinoma detection". PMID- 21690529 TI - Surveillance of patients for early detection of melanoma: patterns in dermatologist vs patient discovery. AB - OBJECTIVE: To determine which groups of patients are most and least likely to detect their own melanomas independent of dermatologist evaluation. DESIGN: Retrospective analysis. SETTING: Academic dermatology department from January 1, 2003, through December 31, 2008. PATIENTS: One hundred sixty-seven consecutive patients with incident biopsy-confirmed melanomas. MAIN OUTCOME MEASURES: Proportion of melanomas found on dermatologist examination vs those brought to the attention of the examining dermatologist by the patient. Secondary analysis examined associations between who detected the melanoma (dermatologist vs patient) and patient age, personal history of skin cancer, family history of melanoma, and depth of lesion. RESULTS: Of the 167 melanomas, 101 (60.5%) were brought to the attention of the dermatologist by the patient. Detection by a dermatologist was significantly associated with patient age of 50 years or older (P = .002), personal skin cancer history (P < .001), and a lesion depth of less than 0.75 mm at the time of detection (P = .03). Only 3.0% of all melanomas in this study were detected by dermatologists in patients who had a low baseline risk of melanoma (age <50 years, no personal history of skin cancer, and no family history of melanoma). These patients were much more likely to detect their own melanoma (odds ratio, 7.32 [95% confidence interval, 2.69-19.90]). CONCLUSIONS: Screening for melanoma in asymptomatic patients younger than 50 years with no medical history of skin cancer or family history of melanoma yields few physician-detected melanomas because these patients are most likely to detect their melanomas themselves. Screening and surveillance efforts should focus on patients 50 years or older and those with a personal history of skin cancer or a family history of melanoma. PMID- 21690532 TI - Acute generalized exanthematous pustulosis simulating toxic epidermal necrolysis: a case report and review of the literature. AB - BACKGROUND: Both acute generalized exanthematous pustulosis (AGEP) and toxic epidermal necrolysis (TEN) are adverse cutaneous reactions. Despite the fact that these 2 cutaneous reactions differ in presentation, prognosis, pathologic features, and treatment, overlap can exist between them, creating a diagnostic challenge. OBSERVATIONS: We describe a patient who presented with clinical features of both AGEP and TEN, and we summarize overlapping cases of AGEP-TEN that have been reported in the literature. It is essential to be able to differentiate between AGEP and TEN, as these conditions are clinically and morphologically distinct entities. They also differ considerably in their prognosis and treatment. CONCLUSIONS: Because overlap exists, AGEP should be considered in the differential diagnosis of widespread blistering and erosive conditions. A greater understanding of how to differentiate AGEP and TEN can lead to quicker diagnosis as well as more effective case management and treatment. PMID- 21690533 TI - Failure of extensive extramammary Paget disease of the inguinal area to clear with imiquimod cream, 5%: possible progression to invasive disease during therapy. AB - BACKGROUND: Surgical approaches are the standard treatment for extramammary Paget disease (EMPD), but nonsurgical modalities may be preferred and more appropriate for some patients. Topical administration of imiquimod cream, 5%, has improved or resolved in situ EMPD (n = 21), but treatment failures (n = 6) have also been reported. OBSERVATIONS: We treated an elderly patient with initial biopsy-proved in situ genital EMPD with daily topical imiquimod, 5%, for 14 weeks. Midtreatment mapping biopsy specimens demonstrated invasive disease, with minimal clinical improvement. The patient subsequently underwent surgical excision. CONCLUSIONS: Of the 27 published cases that describe imiquimod treatment of EMPD, 6 report treatment failure (22%), but factors that may contribute to treatment failure are not well understood. In the present patient, treatment with imiquimod may have been complicated by variable lesion thickness, which inhibited uniform penetration of imiquimod, or the presence of invasive disease not detected on initial biopsy. The efficacy of imiquimod to treat extensive invasive EMPD has not been demonstrated, and surgical approaches remain the most appropriate treatment for invasive disease. Variable responses to topical imiquimod use among patients suggest that other factors may be important in determining response to therapy. PMID- 21690534 TI - Recognizing and managing reticular erythematous mucinosis: comment on "Clinical features and efficacy of antimalarial treatment for reticular erythematous mucinosis". PMID- 21690537 TI - Isotretinoin therapy and inflammatory bowel disease. PMID- 21690538 TI - Include discussions and review of systems regarding inflammatory bowel disease in patients starting isotretinoin therapy: comment on "Isotretinoin therapy and inflammatory bowel disease". PMID- 21690539 TI - Age-dependent differences in growth curves for distinct melanocytic nevus subsets. PMID- 21690540 TI - Erythematous shiny plaque over the glans penis. PMID- 21690541 TI - Erythema nodosum-like lesions in a renal transplant recipient. PMID- 21690542 TI - Papulopustular eruptions in a 32-year-old woman after lung cancer treatment. PMID- 21690543 TI - Multiple cafe au lait macules and Crowe sign. PMID- 21690544 TI - Revised 3-step dermoscopic algorithm for the management of acral melanocytic lesions. PMID- 21690545 TI - Cutaneous melanoma and other skin cancer screening among Hispanics in the United States: a review of the evidence, disparities, and need for expanding the intervention and research agendas. PMID- 21690546 TI - Suboptimal skin cancer screening and delayed melanoma diagnosis in Hispanics: comment on "Cutaneous melanoma and other skin cancer screening among Hispanics in the United States". PMID- 21690547 TI - Congenital hypertrichosis lanuginosa in a father and son. PMID- 21690548 TI - Finasteride-induced pseudoporphyria. PMID- 21690549 TI - A novel homozygous missense mutation in SLURP1 causing Mal de Meleda with an atypical phenotype. PMID- 21690550 TI - Ichthyosis prematurity syndrome caused by a novel fatty acid transport protein 4 gene mutation in a German infant. PMID- 21690551 TI - Writer's block: "texting" impairment as a complication of botulinum toxin type A therapy for palmar hyperhidrosis. PMID- 21690552 TI - A novel cause of economic loss due to hand dermatitis. PMID- 21690553 TI - Palmoplantar pustular psoriasis: clinical and video thermographic evaluation before and after topical tacrolimus treatment. PMID- 21690554 TI - Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses. AB - Oligo-array comparative genomic hybridization (CGH) and gene-expression profiling of natural killer (NK)-cell neoplasms were used in an effort to delineate the molecular pathogenesis involved. Oligo-array CGH identified two 6q21 regions that were most frequently deleted (14 of 39 or 36%). One of these regions included POPDC3, PREP, PRDM1, ATG5, and AIM1, whereas the other included LACE1 and FOXO3. All genes located in these regions, except for POPDC3 and AIM1, were down regulated in neoplastic samples, as determined by gene-expression analysis, and were therefore considered to be candidate tumor-suppressor genes. A20 and HACE1, the well-known tumor-suppressor genes located on 6q21-23, were included as candidate genes because they also demonstrated frequent genomic deletions and down-regulated expression. The Tet-Off NK cell line NKL was subsequently established for functional analyses. Seven candidate genes were transduced into Tet-Off NKL and forced re-expression was induced. Re-expression of FOXO3 and PRDM1 suppressed NKL proliferation, but this was not the case after re-expression of the other genes. This effect was confirmed using another NK cell line, SNK10. Furthermore, genomic analyses detected nonsense mutations of PRDM1 that led to functional inactivation in one cell line and one clinical sample. PRDM1 and FOXO3 are considered to play an important role in the pathogenesis of NK-cell neoplasms. PMID- 21690555 TI - Comparison of high-dose cytarabine and timed-sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study. AB - To assess the value of administering timed-sequential chemotherapy (TSC; 2 therapeutic sequences separated by a 4-day interval-free chemotherapy) or high dose cytarabine (HDAraC) cycles in consolidation therapy for acute myeloid leukemia (AML), 459 patients 15 to 50 years of age were enrolled in the prospective randomized Acute Leukemia French Association-9802 trial. Complete remission was achieved in 89%. A total of 237 patients were then randomized to either TSC consolidation (120 patients) or HDAraC consolidation cycles (117 patients). Overall, there was no significant difference between the 2 consolidation arms (5-year event-free survival [EFS]: 41% for HDAraC vs 35% for TSC), or cumulative incidence of relapse, or treatment-related mortality. Cytogenetically normal AML NPM1(+) or CEBPA(+) and FLT3-ITD(-) had the same outcome as those with favorable cytogenetics. When considering favorable and unfavorable risk groups, the trend was in favor of HDAraC. However, the difference became significant when considering intermediate cytogenetics (5-year EFS: 49% vs 29%; P = .02), especially cytogenetically normal AML (5-year EFS: 48% vs 31%; P = .04), which was related to lower relapse rate and less toxicity. This study demonstrates that TSC did not produce any benefit when used as consolidation therapy in younger adults compared with HDAraC. This trial was registered at www.clinicaltrials.gov as #NCT00880243. PMID- 21690556 TI - Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial. AB - To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in multiple myeloma as part of first-line treatment, we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started maintenance 1 to 6 months after nonmyeloablative allo-SCT. Lenalidomide was dosed 10 mg on days 1 to 21 of a 28-day schedule for a total of 24 cycles. Peripheral blood samples were taken to evaluate immune modulating effects. Thirty-five eligible patients were enrolled, and 30 started with lenalidomide. After 2 cycles, 14 patients (47%) had to stop treatment, mainly because of the development of acute graft versus host disease (GVHD). In total, 13 patients (43%) stopped treatment because of development of GVHD, 5 patients (17%) because of other adverse events, and 5 patients (17%) because of progression. Responses improved in 37% of patients, and the estimated 1-year progression-free survival from start of maintenance was 69% (90% confidence interval, 53%-81%). Lenalidomide increased the frequency of human leukocyte antigen-DR(+) T cells and regulatory T cells, without correlation with clinical parameters. In conclusion, lenalidomide maintenance 10 mg daily after nonmyeloablative allo-SCT with unmanipulated graft in multiple myeloma patients is not feasible, mainly because of the induction of acute GVHD. This trial was registered at www.trialregister.nl as #NTR1645. PMID- 21690557 TI - Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. AB - Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with multiple myeloma (MM). We opened 2 sequential phase 2 trials using the pomalidomide with weekly dexamethasone (Pom/dex) regimen at differing doses to study the efficacy of this regimen in patients who have failed both lenalidomide and bortezomib. Pomalidomide was given orally 2 or 4 mg daily with dexamethasone 40 mg weekly. Thirty-five patients were enrolled in each cohort. Confirmed responses in the 2-mg cohort consisted of very good partial response (VGPR) in 5 (14%), partial response (PR) in 4 (11%), minor response (MR) in 8 (23%) for an overall response rate of 49%. In the 4-mg cohort, confirmed responses consisted of complete response (CR) in 1 (3%), VGPR in 3 (9%), PR in 6 (17%), MR in 5 (14%) for an overall response rate of 43%. Overall survival at 6 months is 78% and 67% in the 2- and 4-mg cohort, respectively. Myelosuppression was the most common toxicity. This nonrandomized data suggests no advantage for 4 mg over the 2 mg daily. Pomalidomide overcomes resistance in myeloma refractory to both lenalidomide and bortezomib. This trial is registered at http://ClinicalTrials.gov, number NCT00558896. PMID- 21690558 TI - Human memory B cells originate from three distinct germinal center-dependent and independent maturation pathways. AB - Multiple distinct memory B-cell subsets have been identified in humans, but it remains unclear how their phenotypic diversity corresponds to the type of responses from which they originate. Especially, the contribution of germinal center-independent responses in humans remains controversial. We defined 6 memory B-cell subsets based on their antigen-experienced phenotype and differential expression of CD27 and IgH isotypes. Molecular characterization of their replication history, Ig somatic hypermutation, and class-switch profiles demonstrated their origin from 3 different pathways. CD27-IgG+ and CD27+IgM+ B cells are derived from primary germinal center reactions, and CD27+IgA+ and CD27+IgG+ B cells are from consecutive germinal center responses (pathway 1). In contrast, natural effector and CD27-IgA+ memory B cells have limited proliferation and are also present in CD40L-deficient patients, reflecting a germinal center-independent origin. Natural effector cells at least in part originate from systemic responses in the splenic marginal zone (pathway 2). CD27 IgA+ cells share low replication history and dominant Iglambda and IgA2 use with gut lamina propria IgA+ B cells, suggesting their common origin from local germinal center-independent responses (pathway 3). Our findings shed light on human germinal center-dependent and -independent B-cell memory formation and provide new opportunities to study these processes in immunologic diseases. PMID- 21690559 TI - Cytoskeletal remodeling mediated by WASp in dendritic cells is necessary for normal immune synapse formation and T-cell priming. AB - Rearrangement of the cytoskeleton in T cells plays a critical role in the organization of a complex signaling interface referred to as immunologic synapse (IS). Surprisingly, the contribution of antigen presenting cells, in particular dendritic cells (DCs), to the structure and function of the IS has not been investigated in as much detail. We have used a natural model of cytoskeletal dysfunction caused by deficiency of the Wiskott-Aldrich syndrome protein (WASp) to explore the contribution of the DC cytoskeleton to IS formation and to T-cell priming. In an antigen-specific system, T-DC contacts were found to be less stable when DCs alone lacked WASp, and associated with multiple defects of IS structure. As a consequence, DCs were unable to support normal IL-12 secretion, and events downstream of TCR signaling were abrogated, including increased calcium flux, microtubule organizing center (MTOC) polarization, phosphorylation of ZAP-70, and T-cell proliferation. Formation of an effective signaling interface is therefore dependent on active cytoskeletal rearrangements in DCs even when T cells are functionally competent. Deficiency of DC-mediated activities may contribute significantly to the varied immunodysregulation observed in patients with WAS, and also in those with limited myeloid reconstitution after allogeneic hematopoietic stem cell transplantation. PMID- 21690560 TI - Trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis. AB - Allogeneic hematopoietic cell transplantation in multiple myeloma is limited by prior reports of high treatment-related mortality. We analyzed outcomes after allogeneic hematopoietic cell transplantation for multiple myeloma in 1207 recipients in 3 cohorts based on the year of transplantation: 1989-1994 (n = 343), 1995-2000 (n = 376), and 2001-2005 (n = 488). The most recent cohort was significantly older (53% > 50 years) and had more recipients after prior autotransplantation. Use of unrelated donors, reduced-intensity conditioning and the blood cell grafts increased over time. Rates of acute graft-versus-host (GVHD) were similar, but chronic GVHD rates were highest in the most recent cohort. Overall survival (OS) at 1-year increased over time, reflecting a decrease in treatment-related mortality, but 5-year relapse rates increased from 39% (95% confidence interval [CI], 33%-44%) in 1989-1994 to 58% (95% CI, 51%-64%; P < .001) in the 2001-2005 cohort. Projected 5-year progression-free survival and OS are 14% (95% CI, 9%-20%) and 29% (95% CI, 23%-35%), respectively, in the latest cohort. Increasing age, longer interval from diagnosis to transplantation, and unrelated donor grafts adversely affected OS in multivariate analysis. Survival at 5 years for subjects with none, 1, 2, or 3 of these risk factors were 41% (range, 36%-47%), 32% (range, 27%-37%), 25% (range, 19%-31%), and 3% (range, 0%-11%), respectively (P < .0001). PMID- 21690561 TI - The operonic location of auto-transcriptional repressors is highly conserved in bacteria. AB - Bacterial genes are commonly encoded in clusters, known as operons, which share transcriptional regulatory control and often encode functionally related proteins that take part in certain biological pathways. Operons that are coregulated are known to colocalize in the genome, suggesting that their spatial organization is under selection for efficient expression regulation. However, the internal order of genes within operons is believed to be poorly conserved, and hence expression requirements are claimed to be too weak to oppose gene rearrangements. In light of these opposing views, we set out to investigate whether the internal location of the regulatory genes within operons is under selection. Our analysis shows that transcription factors (TFs) are preferentially encoded as either first or last in their operons, in the two diverged model bacteria Escherichia coli and Bacillus subtilis. In a higher resolution, we find that TFs that repress transcription of the operon in which they are encoded (autorepressors), contribute most of this signal by specific preference of the first operon position. We show that this trend is strikingly conserved throughout highly diverged bacterial phyla. Moreover, these autorepressors regulate operons that carry out highly diverse biological functions. We propose a model according to which autorepressors are selected to be located first in their operons in order to optimize transcription regulation. Specifically, the first operon position helps autorepressors to minimize leaky transcription of the operon structural genes, thus minimizing energy waste. Our analysis provides statistically robust evidence for a paradigm of bacterial autorepressor preferential operonic location. Corroborated with our suggested model, an additional layer of operon expression control that is common throughout the bacterial domain is revealed. PMID- 21690562 TI - Phylogenomic evidence for the presence of a flagellum and cbb(3) oxidase in the free-living mitochondrial ancestor. AB - The initiation of the intracellular symbiosis that would give rise to mitochondria and eukaryotes was a major event in the history of life on earth. Hypotheses to explain eukaryogenesis fall into two broad and competing categories: those proposing that the host was a phagocytotic proto-eukaryote that preyed upon the free-living mitochondrial ancestor (hereafter FMA), and those proposing that the host was an archaebacterium that engaged in syntrophy with the FMA. Of key importance to these hypotheses are whether the FMA was motile or nonmotile, and the atmospheric conditions under which the FMA thrived. Reconstructions of the FMA based on genome content of Rickettsiales representatives-generally considered to be the closest living relatives of mitochondria-indicate that it was nonmotile and aerobic. We have sequenced the genome of Candidatus Midichloria mitochondrii, a novel and phylogenetically divergent member of the Rickettsiales. We found that it possesses unique gene sets found in no other Rickettsiales, including 26 genes associated with flagellar assembly, and a cbb(3)-type cytochrome oxidase. Phylogenomic analyses show that these genes were inherited in a vertical fashion from an ancestral alpha-proteobacterium, and indicate that the FMA possessed a flagellum, and could undergo oxidative phosphorylation under both aerobic and microoxic conditions. These results indicate that the FMA played a more active and potentially parasitic role in eukaryogenesis than currently appreciated and provide an explanation for how the symbiosis could have evolved under low levels of oxygen. PMID- 21690564 TI - Evolutionary models accounting for layers of selection in protein-coding genes and their impact on the inference of positive selection. AB - The selective forces acting on a protein-coding gene are commonly inferred using evolutionary codon models by contrasting the rate of nonsynonymous substitutions to the rate of synonymous substitutions. These models usually assume that the synonymous substitution rate, Ks, is homogenous across all sites, which is justified if synonymous sites are free from selection. However, a growing body of evidence indicates that the DNA and RNA levels of protein-coding genes are subject to varying degrees of selective constraints due to various biological functions encoded at these levels. In this paper, we develop evolutionary models that account for these layers of selection by allowing for both among-site variability of substitution rates at the DNA/RNA level (which leads to Ks variability among protein-coding sites) and among-site variability of substitution rates at the protein level (Ka variability). These models are constructed so that positive selection is either allowed or not. This enables statistical testing of positive selection when variability at the DNA/RNA substitution rate is accounted for. Using this methodology, we show that variability of the baseline DNA/RNA substitution rate is a widespread phenomenon in coding sequence data of mammalian genomes, most likely reflecting varying degrees of selection at the DNA and RNA levels. Additionally, we use simulations to examine the impact that accounting for the variability of the baseline DNA/RNA substitution rate has on the inference of positive selection. Our results show that ignoring this variability results in a high rate of erroneous positive selection inference. Our newly developed model, which accounts for this variability, does not suffer from this problem and hence provides a likelihood framework for the inference of positive selection on a background of variability in the baseline DNA/RNA substitution rate. PMID- 21690565 TI - Effects of Streptococcus mutans on dendritic cell activation and function. AB - Despite existing preventive and therapeutic measures, caries remains a ubiquitous infectious disease. Vaccine studies suggest that an adaptive immune response, culminating in effective antibody production, may reduce an individual's susceptibility to caries. However, the efficacy of the immune response elicited by mutans streptococci in the oral cavity remains controversial. A greater understanding of the early stages of the adaptive immune response to cariogenic bacteria may potentially assist therapeutic targeting and design. We therefore sought to characterize dendritic cell (DC) activation and antigen presentation following Streptococcus mutans exposure. We found that S. mutans up-regulated DC expression of co-stimulatory molecules and MHCII in vitro and that DCs effectively processed and presented exogenously administered antigen. These DCs effectively initiated T-cell proliferation, but this was abrogated by live bacteria. The in vitro DC activation effects were not mirrored in vivo, where DCs in draining lymph nodes did not mature following oral exposure to S. mutans. Analysis of these data provides a model for studying antigen uptake from the oral cavity and evidence that, in vitro, S. mutans activates dendritic cells, a critical event for initiating adaptive immunity. PMID- 21690568 TI - Low molecular weight heparin in obstetric care: a review of the literature. AB - Low molecular weight heparins (LMWHs) are widely used during pregnancy since several randomized controlled trials have demonstrated their important role in preventing not only thromboembolic disease but also pregnancy complications associated with thrombophilia: recurrent pregnancy loss (RPL), fetal growth restriction (FGR), preeclampsia (PE), abruptio placentae and intrauterine fetal death (IUFD). LMWHs have revealed their effectiveness in reducing the recurrence of negative obstetrics events even in patients without known trombophilias, despite the mechanisms whereby LMWHs operate remain still unclear. However, in order to confirm the suggested benefits, adequately powered and properly controlled trials are needed in this area. Such trials are currently underway and their results will be important to inform evidence-based practice in this area. In our review we report the results of the most relevant trials performed to assess the efficacy of LMWHs in preventing pregnancy complications associated or not with maternal thrombophilia. This review was conducted based on a MEDLINE search for relevant articles between January 2000 and August 2010 and using the following search terms: heparin, low molecular weight heparin, thrombophilia, pregnancy complications, preeclampsia, recurrent pregnancy loss, abruptio placentae, fetal growth restriction. PMID- 21690566 TI - MicroRNA replacement therapy for miR-145 and miR-33a is efficacious in a model of colon carcinoma. AB - MicroRNAs (miRNA) aberrantly expressed in tumors may offer novel therapeutic approaches to treatment. miR-145 is downregulated in various cancers including colon carcinoma in which in vitro studies have established proapoptotic and antiproliferative roles. miR-33a was connected recently to cancer through its capacity to downregulate the oncogenic kinase Pim-1. To date, miRNA replacement therapy has been hampered by the lack of robust nonviral delivery methods for in vivo administration. Here we report a method of miRNA delivery by using polyethylenimine (PEI)-mediated delivery of unmodified miRNAs, using miR-145 and miR-33a to preclinically validate the method in a mouse model of colon carcinoma. After systemic or local application of low molecular weight PEI/miRNA complexes, intact miRNA molecules were delivered into mouse xenograft tumors, where they caused profound antitumor effects. miR-145 delivery reduced tumor proliferation and increased apoptosis, with concomitant repression of c-Myc and ERK5 as novel regulatory target of miR-145. Similarly, systemic injection of PEI-complexed miR 33a was validated as a novel therapeutic targeting method for Pim-1, with antitumor effects comparable with PEI/siRNA-mediated direct in vivo knockdown of Pim-1 in the model. Our findings show that chemically unmodified miRNAs complexed with PEI can be used in an efficient and biocompatible strategy of miRNA replacement therapy, as illustrated by efficacious delivery of PEI/miR-145 and PEI/miR-33a complexes in colon carcinoma. PMID- 21690563 TI - Unity in variety--the pan-genome of the Chlamydiae. AB - Chlamydiae are evolutionarily well-separated bacteria that live exclusively within eukaryotic host cells. They include important human pathogens such as Chlamydia trachomatis as well as symbionts of protozoa. As these bacteria are experimentally challenging and genetically intractable, our knowledge about them is still limited. In this study, we obtained the genome sequences of Simkania negevensis Z, Waddlia chondrophila 2032/99, and Parachlamydia acanthamoebae UV-7. This enabled us to perform the first comprehensive comparative and phylogenomic analysis of representative members of four major families of the Chlamydiae, including the Chlamydiaceae. We identified a surprisingly large core gene set present in all genomes and a high number of diverse accessory genes in those Chlamydiae that do not primarily infect humans or animals, including a chemosensory system in P. acanthamoebae and a type IV secretion system. In S. negevensis, the type IV secretion system is encoded on a large conjugative plasmid (pSn, 132 kb). Phylogenetic analyses suggested that a plasmid similar to the S. negevensis plasmid was originally acquired by the last common ancestor of all four families and that it was subsequently reduced, integrated into the chromosome, or lost during diversification, ultimately giving rise to the extant virulence-associated plasmid of pathogenic chlamydiae. Other virulence factors, including a type III secretion system, are conserved among the Chlamydiae to variable degrees and together with differences in the composition of the cell wall reflect adaptation to different host cells including convergent evolution among the four chlamydial families. Phylogenomic analysis focusing on chlamydial proteins with homology to plant proteins provided evidence for the acquisition of 53 chlamydial genes by a plant progenitor, lending further support for the hypothesis of an early interaction between a chlamydial ancestor and the primary photosynthetic eukaryote. PMID- 21690569 TI - Enhancement of 5-fluorouracil-induced in vitro and in vivo radiosensitization with MEK inhibition. AB - PURPOSE: Gastrointestinal cancers frequently exhibit mutational activation of the Ras/MAPK pathway, which is implicated in resistance to ionizing radiation (IR) and chemotherapy. Concurrent radiotherapy and 5-fluorouracil (5-FU) based chemotherapy is commonly used for treatment of gastrointestinal malignancies. We previously reported radiosensitization with selumetinib, an inhibitor of MEK1/2. The purpose of the current study was to evaluate if selumetinib could enhance radiosensitivity induced by 5-FU. EXPERIMENTAL DESIGN: Clonogenic survival assays were carried out with the HT29 (colorectal), HCT116 (colorectal), and MiaPaca-2 (pancreatic) cell lines using pre-IR treatment with selumetinib, 5-FU and 5 FU+selumetinib. Cell proliferation was determined using a tetrazolium conversion assay. Mitotic catastrophe and DNA repair were analyzed using immunocytochemistry. Flow cytometry was used to analyze cell cycle and apoptosis. Growth delay was used to determine effects of 5-FU+selumetinib on in vivo tumor radiosensitivity. RESULTS: Pre-IR treatment with 5-FU+selumetinib significantly decreased clonogenic survival compared with either agent alone. Dose modifying factors at a surviving fraction of 0.1 for 5-FU+selumetinib was 1.78, 1.52, and 1.3 for HT29, HCT116, and MiaPaca-2, respectively. Cell proliferation was decreased by treatment with selumetinib+5-FU as compared with single agent treatment regardless of treatment sequencing. Enhancement of 5-FU cytotoxicity and 5-FU mediated radiosensitization with selumetinib treatment was accompanied by an increase in mitotic catastrophe and apoptosis, and reductions in Stat3 phosphorylation and survivin expression. In vivo, an additive growth delay was observed with 5-FU+selumetinib+3Gy versus 5-FU+3Gy and selumetinib alone. CONCLUSION: These data suggest that selumetinib can be used with 5-FU to augment radiation response. PMID- 21690571 TI - Clinical, pharmacodynamic, and pharmacokinetic evaluation of BNC105P: a phase I trial of a novel vascular disrupting agent and inhibitor of cancer cell proliferation. AB - PURPOSE: To determine the recommended phase II dose and evaluate the safety and toxicity profile and pharmacokinetic (PK) and pharmacodynamic (PD) effects of BNC105P, an inhibitor of tubulin polymerization that has vascular disrupting and antiproliferative effects. EXPERIMENTAL DESIGN: BNC105P was administered as a 10 minute infusion on days 1 and 8 of a 21-day cycle in a first-in-human phase I study. A dynamic accelerated dose titration method was used for dose escalation. Plasma concentrations of BNC105P (phosphate prodrug) and BNC105 (active agent) were determined. PD assessments were carried out using dynamic contrast enhanced (DCE)-MRI and analysis of a blood-borne biomarker. RESULTS: Twenty-one subjects with advanced solid tumors were enrolled on 6 dose levels (range: 2.1-18.9 mg/m(2)). The recommended dose level was 16 mg/m(2) and was well tolerated. BNC105P (prodrug) rapidly converted to BNC105 with a half-life of 0.13 hours. Plasma concentrations of BNC105 generally increased in proportion to dose with a half-life of 0.57 hours. Pharmacodymanically active plasma levels were obtained with a dose dependant reduction in the levels of polymerized tubulin (on-target action) being observed in PBMCs. DCE-MRI also indicated blood flow changes in the tumor lesions of a number of subjects. CONCLUSIONS: BNC105P has a favorable toxicity profile at the recommended dose of 16 mg/m(2) and is associated with PD changes consistent with its known mechanism of action. Phase II studies in renal cancer and mesothelioma have commenced. PMID- 21690572 TI - Class III beta-tubulin in advanced NSCLC of adenocarcinoma subtype predicts superior outcome in a randomized trial. AB - PURPOSE: Platinum-based doublets are the cornerstone of treatment in advanced non small-cell lung cancer (NSCLC) and often include vinorelbine or taxanes. A predictive biomarker is greatly needed to select chemotherapy-sensitive patients for these microtubule-interfering agents. Class III beta-tubulin (TUBB3) has been shown of value in NSCLC, but evidence is not uniform. Accordingly, we explored the predictive role of TUBB3 in advanced NSCLC. EXPERIMENTAL DESIGN: Four hundred forty-three patients with advanced NSCLC were enrolled in a phase III trial and randomized to vinorelbine- or paclitaxel-containing chemotherapy. Immunohistochemical evaluation of TUBB3 status was mainly done on bioptic material and correlated to response rates, progression-free survival (PFS), overall survival (OS), quality of life (QOL), and toxicity. RESULTS: Two hundred sixty-one (58.9%) patients had representative tissue samples for TUBB3 evaluation. Patients with TUBB3-negative adenocarcinomas had a significantly prolonged PFS and OS when compared with the opposite subgroup (7.87 vs. 6.83 months, P = 0.035 and 14.17 vs. 11.17 months, P = 0.018, respectively). Multivariate analyses revealed an HR of 1.55 (95% CI, 1.04-2.31, P = 0.032) for TUBB3-positive adenocarcinoma patients. TUBB3-negative adenocarcinoma patients showed a mean QOL decline of -18.25 points (95% CI, -4.28 to -32.22, P = 0.013) as compared with -3.86 (95% CI, -7.0 to 15.52, P = 0.5). CONCLUSION: TUBB3 was of predictive value in adenocarcinoma patients in the largest, randomized advanced NSCLC population published to date. It may be clinically useful in conjunction with other biomarkers, but QOL information should be recorded during validation, as prophylactic intervention may be needed in specific subgroups at risk of toxicity. PMID- 21690570 TI - Phase I and pharmacokinetic study of sunitinib in pediatric patients with refractory solid tumors: a children's oncology group study. AB - PURPOSE: Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor. The purpose of this study was to determine the recommended phase 2 dose, pharmacokinetics, pharmacodynamic effects, and preliminary antitumor activity of sunitinib in a pediatric population. EXPERIMENTAL DESIGN: Patients who were 2 to 21 years of age with refractory solid tumors were eligible if they had measurable or evaluable disease and met baseline organ function requirements. Patients received sunitinib once daily for 28 days followed by a 14-day break between each cycle. Dose levels of 15 and 20 mg/m(2)/d were evaluated, with dose escalation based on a 3 + 3 design. Sunitinib pharmacokinetics and biomarkers of angiogenesis were also evaluated during the first cycle. RESULTS: Twenty-three patients were treated (median age 13.9 years; range, 3.9-20.6 years). The most common toxicities were neutropenia, thrombocytopenia, elevated liver transaminases, gastrointestinal symptoms, and fatigue. Two patients developed dose-limiting reductions in cardiac ejection fraction prompting a protocol amendment to exclude patients with previous exposure to anthracyclines or cardiac radiation. In patients without these cardiac risk factors, the maximum tolerated dose (MTD) was 15 mg/m(2)/d. Steady-state plasma concentrations were reached by day 7. No objective responses were observed. Four patients with sarcoma and glioma had stable disease for 2 to 9 cycles. CONCLUSIONS: Cardiac toxicity precluded determination of a recommended dose for pediatric patients with previous anthracycline or cardiac radiation exposure. The MTD of sunitinib for patients without risk factors for cardiac toxicity is 15 mg/m(2)/d for 28 days followed by a 14-day break. PMID- 21690573 TI - Adoptive transfer of tumor reactive B cells confers host T-cell immunity and tumor regression. AB - PURPOSE: We investigated the antitumor reactivity of adoptively transferred effector B cells and the mechanisms by which they may mediate tumor regression in a spontaneous metastases model. EXPERIMENTAL DESIGN: 4T1 breast cancer cells were inoculated into the flanks of syngeneic Balb/C mice to prime draining lymph nodes. Tumor-draining lymph nodes (TDLN) were harvested and B cells activated ex vivo with lipopolysaccharide and anti-CD40 monoclonal antibody. These activated B cells were adoptively transferred into mice inoculated with 4T1 tumor in the mammary fat pad. The induction of host T-cell immunity was evaluated. RESULTS: Activated 4T1 TDLN B cells secreted immunoglobulin G (IgG) in response to tumor cells which was immunologically specific. These activated B cells were capable of mediating specific lysis of tumor cells in vitro. Transfer of these activated B cells alone mediated the inhibition of spontaneous metastases to the lung. Examination of the host revealed that the transfer of these B cells resulted in the induction of tumor-specific T-cell immunity as measured by cytotoxicity and cytokine (IFNgamma and granulocyte-macrophage colony-stimulating factor) production. The combined transfer of activated T and B cells from TDLN resulted in tumor regression, which was greater than either cell population alone, with host B cells capable of producing IgG that mediated lysis of tumor in the presence of complement. CONCLUSIONS: We have found that appropriately primed B cells can mediate tumor regression by itself and confers host T-cell antitumor immunity. Furthermore, effector B cells can serve as a useful adjunct in adoptive T-cell therapy. PMID- 21690574 TI - PM02734 (elisidepsin) induces caspase-independent cell death associated with features of autophagy, inhibition of the Akt/mTOR signaling pathway, and activation of death-associated protein kinase. AB - PURPOSE: PM02734 (elisidepsin) is a synthetic marine-derived cyclic peptide of the kahalalide family currently in phase II clinical development. The mechanisms of cell death induced by PM02734 remain unknown. EXPERIMENTAL DESIGN: Human non small-cell lung cancer (NSCLC) cell lines H322 and A549 were used to evaluate PM02734-induced cytotoxicity, apoptosis, and autophagy, as well as effects on cell death-related signaling pathways. RESULTS: PM02734 at clinically achievable concentrations (0.5-1 MUmol/L) was cytotoxic to H322 and A549 cells but did not cause nuclear fragmentation, PARP cleavage, or caspase activation, suggesting that classical apoptosis is not its main mechanism of cell death. In contrast, PM02734-induced cell death was associated with several characteristics of autophagy, including an increase in acidic vesicular organelle content, levels of GFP-LC3-positive puncta, elevation of the levels of Atg-5/12 and LC3-II, and an associated compromise of the autophagic flux resulting in increased number of autophagosomes and/or autolysosomes. Cotreatment with 3-methyladenine (3-MA) and downregulation of Atg-5 gene expression by siRNA partially inhibited PM02734 induced cell death. PM02734 caused inhibition of Akt/mTOR signaling pathways and cotreatment with the Akt inhibitor wortmannin or with the mTOR inhibitor rapamycin led to a significant increase in PM02734-induced cell death. Furthermore, PM02734 caused the activation of death-associated protein kinase (DAPK) by dephosphorylation at Ser308, and downregulation of DAPK expression with siRNA caused also a partial but significant reduction of PM02734-induced cell death. In vivo, PM02734 significantly inhibited subcutaneous A549 tumor growth in nude mice (P < 0.05) in association with induction of autophagy. CONCLUSIONS: Our data indicate that PM02734 causes cell death by a complex mechanism that involves increased autophagosome content, due for the most part to impairment of autophagic flux, inhibition of the Akt/mTOR pathway, and activation of DAPK. This unique mechanism of action justifies the continued development of this agent for the treatment of NSCLC. PMID- 21690576 TI - Summaries for patients. Measuring blood pressure for decision making and quality reporting. PMID- 21690577 TI - Summaries for patients. The role of multidetector computed tomography for diagnosing acute appendicitis. PMID- 21690575 TI - Abnormal structure of frontostriatal brain systems is associated with aspects of impulsivity and compulsivity in cocaine dependence. AB - A growing body of preclinical evidence indicates that addiction to cocaine is associated with neuroadaptive changes in frontostriatal brain systems. Human studies in cocaine-dependent individuals have shown alterations in brain structure, but it is less clear how these changes may be related to the clinical phenotype of cocaine dependence characterized by impulsive behaviours and compulsive drug-taking. Here we compared self-report, behavioural and structural magnetic resonance imaging data on a relatively large sample of cocaine-dependent individuals (n = 60) with data on healthy volunteers (n = 60); and we investigated the relationships between grey matter volume variation, duration of cocaine use, and measures of impulsivity and compulsivity in the cocaine dependent group. Cocaine dependence was associated with an extensive system of abnormally decreased grey matter volume in orbitofrontal, cingulate, insular, temporoparietal and cerebellar cortex, and with a more localized increase in grey matter volume in the basal ganglia. Greater duration of cocaine dependence was correlated with greater grey matter volume reduction in orbitofrontal, cingulate and insular cortex. Greater impairment of attentional control was associated with reduced volume in insular cortex and increased volume of caudate nucleus. Greater compulsivity of drug use was associated with reduced volume in orbitofrontal cortex. Cocaine-dependent individuals had abnormal structure of corticostriatal systems, and variability in the extent of anatomical changes in orbitofrontal, insular and striatal structures was related to individual differences in duration of dependence, inattention and compulsivity of cocaine consumption. PMID- 21690578 TI - Summaries for patients. Sirolimus therapy in patients with lymphangioleiomyomatosis. PMID- 21690579 TI - Summaries for patients. Tuberous sclerosis complex in adult women. PMID- 21690580 TI - ACP Journal Club. Quadruple-drug therapy was better than triple-drug therapy for eradicating Helicobacter pylori in adults. PMID- 21690581 TI - ACP Journal Club. The Cardiovascular Health Awareness Program reduced CV hospitalizations but not mortality in older adults. PMID- 21690582 TI - ACP Journal Club. Review: Counseling and educational methods that target multiple CV risk factors do not reduce mortality in adults without CHD. PMID- 21690583 TI - ACP Journal Club. Candesartan did not improve clinical or functional outcomes in patients with acute stroke and elevated BP. PMID- 21690584 TI - ACP Journal Club. Review: Antihypertensive treatment prevents cardiovascular events and mortality in cardiovascular disease without hypertension. PMID- 21690585 TI - ACP Journal Club. Review: Adding noninvasive ventilation to standard therapy improves outcomes in patients with some causes of acute respiratory failure. PMID- 21690586 TI - ACP Journal Club. Review: Current drug treatments do not reduce mortality in idiopathic pulmonary fibrosis. PMID- 21690587 TI - ACP Journal Club. Review: Evidence on PPIs for nonspecific chronic cough in adults with gastroesophageal reflux disease is inconsistent. PMID- 21690588 TI - ACP Journal Club. Review: Insufficient evidence exists about which drugs are associated with delirium; benzodiazepines may increase risk. PMID- 21690589 TI - ACP Journal Club. PPI use in the first trimester was not associated with increased risk for birth defects; PPI use 1 to 4 weeks before conception was. PMID- 21690590 TI - ACP Journal Club. Compared with warfarin, high-dose dabigatran might be cost effective for preventing stroke in older patients with nonvalvular AF. PMID- 21690591 TI - ACP Journal Club. The Wells rule and a primary care rule were useful for ruling out deep venous thrombosis in primary care. PMID- 21690592 TI - Measuring blood pressure for decision making and quality reporting: where and how many measures? AB - BACKGROUND: The optimal setting and number of blood pressure (BP) measurements that should be used for clinical decision making and quality reporting are uncertain. OBJECTIVE: To compare strategies for home or clinic BP measurement and their effect on classifying patients as having BP that was in or out of control. DESIGN: Secondary analysis of a randomized, controlled trial of strategies to improve hypertension management. (ClinicalTrials.gov registration number: NCT00237692) SETTING: Primary care clinics affiliated with the Durham Veterans Affairs Medical Center. PATIENTS: 444 veterans with hypertension followed for 18 months. MEASUREMENTS: Blood pressure was measured repeatedly by using 3 methods: standardized research BP measurements at 6-month intervals; clinic BP measurements obtained during outpatient visits; and home BP measurements using a monitor that transmitted measurements electronically. RESULTS: Patients provided 111,181 systolic BP (SBP) measurements (3218 research, 7121 clinic, and 100,842 home measurements) over 18 months. Systolic BP control rates at baseline (mean SBP<140 mm Hg for clinic or research measurement; <135 mm Hg for home measurement) varied substantially, with 28% classified as in control by clinic measurement, 47% by home measurement, and 68% by research measurement. Short-term variability was large and similar across all 3 methods of measurement, with a mean within-patient coefficient of variation of 10% (range, 1% to 24%). Patients could not be classified as having BP that was in or out of control with 80% certainty on the basis of a single clinic SBP measurement from 120 mm Hg to 157 mm Hg. The effect of within-patient variability could be greatly reduced by averaging several measurements, with most benefit accrued at 5 to 6 measurements. LIMITATION: The sample was mostly men with a long-standing history of hypertension and was selected on the basis of previous poor BP control. CONCLUSION: Physicians who want to have 80% or more certainty that they are correctly classifying patients' BP control should use the average of several measurements. Hypertension quality metrics based on a single clinic measurement potentially misclassify a large proportion of patients. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs Health Services Research and Development Service. PMID- 21690593 TI - Diagnostic performance of multidetector computed tomography for suspected acute appendicitis. AB - BACKGROUND: Use of preoperative computed tomography for suspected acute appendicitis has dramatically increased since the introduction of multidetector CT (MDCT) scanners. OBJECTIVE: To evaluate the diagnostic performance of MDCT for suspected acute appendicitis in adults. DESIGN: Analysis of MDCT findings and clinical outcomes of consecutive adults referred for MDCT for suspected appendicitis from January 2000 to December 2009. SETTING: Single academic medical center in the United States. PATIENTS: 2871 adults. MEASUREMENTS: Interpretation of nonfocused abdominopelvic MDCT scans by radiologists who were aware of the study indication. Posttest assessment of diagnostic performance of MDCT for acute appendicitis, according to the reference standard of final combined clinical, surgical, and pathology findings. RESULTS: 675 of 2871 patients (23.5%) had confirmed acute appendicitis. The sensitivity, specificity, and negative and positive predictive values of MDCT were 98.5% (95% CI, 97.3% to 99.2%) (665 of 675 patients), 98.0% (CI, 97.4% to 98.6%) (2153 of 2196 patients), 99.5% (CI, 99.2% to 99.8%) (2153 of 2163 patients), and 93.9% (CI, 91.9% to 95.5%) (665 of 708 patients), respectively. Positive and negative likelihood ratios were 51.3 (CI, 38.1 to 69.0) and 0.015 (CI, 0.008 to 0.028), respectively. The overall rate of negative findings at appendectomy was 7.5% (CI, 5.8% to 9.7%) (54 of 716 patients), but would have decreased to 4.1% (28 of 690 patients) had surgery been avoided in 26 cases with true-negative findings on MDCT. The overall perforation rate was 17.8% (120 of 675 patients) but progressively decreased from 28.9% in 2000 to 11.5% in 2009. Multidetector computed tomography provided or suggested an alternative diagnosis in 893 of 2122 patients (42.1%) without appendicitis or appendectomy. LIMITATION: Possible referral bias, because some patients whose appendicitis was difficult to diagnose on clinical grounds may not have been referred for MDCT for evaluation of suspected appendicitis. CONCLUSION: Multidetector computed tomography is a useful test for routine evaluation of suspected appendicitis in adults. PRIMARY FUNDING SOURCE: None. PMID- 21690594 TI - Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is a disorder that affects women and is characterized by cystic lung destruction, chylous effusions, lymphangioleiomyomas, and angiomyolipomas. It is caused by proliferation of abnormal smooth muscle-like cells. Sirolimus is a mammalian target of rapamycin inhibitor that has been reported to decrease the size of neoplastic growths in animal models of tuberous sclerosis complex and to reduce the size of angiomyolipomas and stabilize lung function in humans. OBJECTIVE: To assess whether sirolimus therapy is associated with improvement in lung function and a decrease in the size of chylous effusions and lymphangioleiomyomas in patients with LAM. DESIGN: Observational study. SETTING: The National Institutes of Health Clinical Center. PATIENTS: 19 patients with rapidly progressing LAM or chylous effusions. INTERVENTION: Treatment with sirolimus. MEASUREMENTS: Lung function and the size of chylous effusions and lymphangioleiomyomas before and during sirolimus therapy. RESULTS: Over a mean of 2.5 years before beginning sirolimus therapy, the mean (+/-SE) FEV1 decreased by 2.8%+/-0.8% predicted and diffusing capacity of the lung for carbon monoxide (Dlco) decreased by 4.8%+/-0.9% predicted per year. In contrast, over a mean of 2.6 years of sirolimus therapy, the mean (+/-SE) FEV1 increased by 1.8%+/-0.5% predicted and Dlco increased by 0.8%+/-0.5% predicted per year (P<0.001). After beginning sirolimus therapy, 12 patients with chylous effusions and 11 patients with lymphangioleiomyomas experienced almost complete resolution of these conditions. In 2 of the 12 patients, sirolimus therapy enabled discontinuation of pleural fluid drainage. LIMITATIONS: This was an observational study. The resolution of effusions may have affected improvements in lung function. CONCLUSION: Sirolimus therapy is associated with improvement or stabilization of lung function and reduction in the size of chylous effusions and lymphangioleiomyomas in patients with LAM. PRIMARY FUNDING SOURCE: Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health. PMID- 21690596 TI - Assessment of thiopurine S-methyltransferase activity in patients prescribed thiopurines: a systematic review. AB - BACKGROUND: The evidence for testing thiopurine S-methyltransferase (TPMT) enzymatic activity or genotype before starting therapy with thiopurine-based drugs is unclear. PURPOSE: To examine the sensitivity and specificity of TPMT genotyping for TPMT enzymatic activity, reducing harm from thiopurine by pretesting, and the association of thiopurine toxicity with TPMT status in adults and children with chronic inflammatory diseases. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Library, and Ovid HealthSTAR (from inception to December 2010) and BIOSIS and Genetics Abstracts (to May 2009). STUDY SELECTION: Two reviewers screened records and identified relevant studies in English. DATA EXTRACTION: Data on patient characteristics, outcomes, and risk for bias were extracted by one reviewer and independently identified by another. DATA SYNTHESIS: 54 observational studies and 1 randomized, controlled trial were included. Insufficient evidence addressed the effectiveness of pretesting. Genotyping sensitivity to identify patients with low and intermediate TPMT enzymatic activity ranged from 70.33% to 86.15% (lower-bound 95% CI, 54.52% to 70.88%; upper-bound CI, 78.50% to 96.33%). Sparse data precluded estimation of genotype sensitivity to identify patients with low to absent enzymatic activity. Genotyping specificity approached 100%. Compared with noncarriers, heterozygous and homozygous genotypes were both associated with leukopenia (odds ratios, 4.29 [CI, 2.67 to 6.89] and 20.84 [CI, 3.42 to 126.89], respectively). Compared with intermediate or normal activity, low TPMT enzymatic activity was significantly associated with myelotoxicity and leukopenia. LIMITATION: Available evidence was not rigorous and was underpowered to detect a difference in outcomes. CONCLUSION: Insufficient evidence addresses the effectiveness of TPMT pretesting in patients with chronic inflammatory diseases. Estimates of the sensitivity of genotyping are imprecise. Evidence confirms the known associations of leukopenia or myelotoxicity with reduced TPMT activity or variant genotype. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 21690595 TI - Recognition of tuberous sclerosis in adult women: delayed presentation with life threatening consequences. AB - BACKGROUND: Tuberous sclerosis complex (TSC) is associated with tumor development in the brain, retina, kidney, skin, heart, and lung. Seizures, intellectual disability, and characteristic skin lesions commonly manifest in early childhood, but some findings, notably renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM), emerge later, placing adults with undiagnosed TSC at increased risk for morbidity and mortality. OBJECTIVE: To describe the clinical presentation and severity of TSC in adult women. DESIGN: Retrospective cohort study. SETTING: National Institutes of Health Clinical Center, Bethesda, Maryland, 1995 to 2010. PATIENTS: 79 women aged 18 years or older who were enrolled in an observational cohort study of TSC to evaluate disease manifestations. MEASUREMENTS: History, physical examination, pulmonary function testing, chest radiography, abdominal computed tomography, high-resolution chest computed tomography, and brain magnetic resonance imaging were used to evaluate patients. RESULTS: Among the 45 patients who received a diagnosis of TSC in adulthood, 21 presented with symptoms due to LAM, 19 with renal angiomyolipomas, and 10 with seizures. Of the 45 patients, 30 met clinical criteria for TSC in childhood that remained undiagnosed for a median of 21.5 years and 15 were older than 18 years before meeting the clinical criteria for TSC. Patients diagnosed in adulthood and those diagnosed in childhood had similar occurrences of pneumothorax, shortness of breath, hemoptysis, nephrectomy, and death. LIMITATION: No men were included in the study, and selection was biased toward patients having pulmonary LAM. CONCLUSION: Women who received a TSC diagnosis in adulthood had minimal morbidity during childhood but were still at risk for life threatening pulmonary and renal manifestations. PRIMARY FUNDING SOURCE: Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute. PMID- 21690597 TI - Talking it out: helping our patients live better while dying. AB - Although dying is an inevitable part of the life cycle, there has been extensive political debate over end-of-life care. Participating in end-of-life care conversations can be emotionally challenging for everyone involved. Messages about serious or terminal illnesses can be very hard for patients and their families to hear, and physicians frequently struggle with the burden of delivering these messages. Still, evidence shows that conversations about end-of life care options between physicians and patients can improve the quality of life of dying patients and help to relieve the emotional burden on surviving loved ones. Legislation to support these discussions by consistently reimbursing physicians for their time spent performing this service has been blocked on multiple occasions. More research on how to improve end-of-life care will enable health care providers to optimize treatment of their patients. Overcoming political divides to support end-of-life care conversations is needed to promote care that is consistent with patients' values and needs and is a key step in encouraging better quality of life for dying patients. PMID- 21690599 TI - Improving the measurement of blood pressure: is it time for regulated standards? PMID- 21690598 TI - Enhancing prescription drug innovation and adoption. AB - The adoption and use of a new drug would ideally be guided by its innovation and cost-effectiveness. However, information about the relative efficacy and safety of a drug is typically incomplete even well after market entry, and various other forces create a marketplace in which most new drugs are little better than their older counterparts. Five proposed mechanisms are considered for promoting innovation and reducing the use of therapies ultimately found to offer poor value or have unacceptable risks. These changes range from increasing the evidence required for U.S. Food and Drug Administration approval to modifying the structure of drug reimbursement. Despite the challenges of policy implementation, the United States has a long history of successfully improving the societal value and safe use of prescription medicines. PMID- 21690600 TI - Tuberous sclerosis complex and lymphangioleiomyomatosis: miles to go, promises to keep. PMID- 21690601 TI - Preemptive pharmacogenetic testing: insufficient data equal unsatisfactory guidance. PMID- 21690602 TI - Intensive insulin therapy in hospitalized patients. PMID- 21690603 TI - Intensive insulin therapy in hospitalized patients. PMID- 21690604 TI - Intensive insulin therapy in hospitalized patients. PMID- 21690605 TI - Intensive insulin therapy in hospitalized patients. PMID- 21690607 TI - Psychological well-being and reactions to multiple unemployment events: adaptation or sensitisation? AB - BACKGROUND: Unemployment has been negatively associated with psychological well being. This study examines the effect of multiple unemployment spells, specifically whether people become sensitised or adapt to unemployment if they are previously employed or economically inactive. METHODS: Data come from waves 1 17 of the British Household Panel Survey. Psychological well-being was measured using the 12-item General Health Questionnaire (GHQ-12), and employment status was self-reported. Multilevel modelling was used to examine the effects of unemployment, overall and by previous employment status, on well-being. RESULTS: Without consideration of prior employment status, psychological well-being was poorer at each unemployment spell. Previously employed persons had significantly higher GHQ-12 scores at the first and second unemployment spells but not at the third spell (p(trend)<0.0001). Previously economically inactive persons had poorer psychological well-being at all unemployment spells, with significantly higher scores at the third spell than those at the first two spells (p(trend)=0.0004). Thus, those employed prior to all unemployment spells adapted, while those previously economically inactive became more sensitised with additional unemployment spells. Pre-study unemployment and average annual household income moderated the effects of unemployment; effects varied by previous employment status and unemployment spell number. CONCLUSIONS: The findings suggest that initially employed people who experience repeated unemployment cope better psychologically if they are able to regain employment in between unemployment spells. Those who make several attempts to re-enter the labour market following economic inactivity have a more difficult time, becoming more distressed with each try. This has implications for people affected by welfare to work policies. PMID- 21690606 TI - Air pollution and asthma control in the Epidemiological study on the Genetics and Environment of Asthma. AB - BACKGROUND: The associations between exposure to air pollution and asthma control are not well known. The objective of this study was to assess the association between long-term exposure to NO(2), O(3) and PM(10) and asthma control in the follow-up of the Epidemiological study on the Genetics and Environment of Asthma (EGEA2) (2003-2007). METHODS: Modelled outdoor NO(2), O(3) and PM(10) estimates were linked to each residential address using the 4 km grid air pollutant surface developed by the French Institute of Environment in 2004. Asthma control was assessed in 481 subjects with current asthma using a multidimensional approach following the 2006-2009 Global Initiative for Asthma guidelines. Multinomial and ordinal logistic regressions were conducted adjusted for sex, age, body mass index, education, smoking and use of inhaled corticosteroids. The association between air pollution and the three domains of asthma control (symptoms, exacerbations and lung function) was assessed. ORs are reported per IQR. RESULTS: Median concentrations (in micrograms per cubic metre) were 32 (IQR 25-38) for NO(2) (n=465), 46 (41-52) for O(3) and 21 (18-21) for PM(10) (n=481). In total, 44%, 29% and 27% had controlled, partly controlled and uncontrolled asthma, respectively. The ordinal ORs for O(3) and PM(10) with asthma control were 1.69 (95% CI 1.22 to 2.34) and 1.35 (95% CI 1.13 to 1.64), respectively. When including both pollutants in the same model, both associations persisted. Associations were not modified by sex, smoking status, use of inhaled corticosteroids, atopy, season of examination or body mass index. Both pollutants were associated with each of the three main domains of control. CONCLUSIONS: The results suggest that long-term exposure to PM(10) and O(3) is associated with uncontrolled asthma in adults, defined by symptoms, exacerbations and lung function. PMID- 21690608 TI - Silent myocardial damage in cocaine addicts. AB - BACKGROUND: Cocaine addiction is associated with either ischaemic or non ischaemic cardiac complications. The prevalence of myocardial damage in asymptomatic addicts has never been evaluated by cardiovascular magnetic resonance (CMR), which allows non-invasive detection of myocardial oedema and fibrosis. OBJECTIVE: To prospectively evaluate the prevalence of myocardial damage in cocaine addicts with no history of cardiac disease by CMR. METHODS: Thirty consecutive subjects (25 men, mean age 39 +/- 7 years), with no history of cardiac symptoms/disease were evaluated 48 h after the withdrawal of cocaine by a comprehensive humoral, clinical and instrumental assessment, including B-type natriuretic peptide and troponin I assay, echocardiography, exercise stress test and 24 h ECG recording, as well as CMR examination. The CMR study was performed using a 1.5 Tesla scanner. Myocardial oedema was evaluated by a T2-weighted STIR sequence and fibrosis using the late gadolinium enhancement technique. RESULTS: Biohumoral markers of cardiac involvement were negative in all subjects except one. Fifteen subjects had subtle abnormalities at resting ECG, while exercise stress testing and Holter studies were negative for ischaemic or arrhythmic events. Echocardiography provided evidence of wall motion abnormalities in 12 subjects. At CMR evaluation, myocardial involvement was detected in 25 subjects (83%), oedema in 14 (47%) and fibrosis in 22 (73%). Eleven subjects (37%) showed both myocardial oedema and fibrosis with similar localisations in nine. Seven subjects had ischaemic patterns of fibrosis and 15 had non-ischaemic patterns of fibrosis. CONCLUSIONS: A high prevalence of cardiac damage in asymptomatic cocaine addicts can be found by CMR examination. PMID- 21690609 TI - 4-Hydroperoxy-2-nonenal is not just an intermediate but a reactive molecule that covalently modifies proteins to generate unique intramolecular oxidation products. AB - alpha,beta-Unsaturated aldehydes generated during lipid peroxidation, such as 4 oxoalkenals and 4-hydroxyalkenals, can give rise to protein degeneration in a variety of pathological states. Although the covalent modification of proteins by these end products has been well studied, the reactivity of unstable intermediates possessing a hydroperoxy group, such as 4-hydroperoxy-2-nonenal (HPNE), with protein has received little attention. We have now established a unique protein modification in which the 4-hydroperoxy group of HPNE is involved in the formation of structurally unusual lysine adducts. In addition, we showed that one of the HPNE-specific lysine adducts constitutes the epitope of a monoclonal antibody raised against the HPNE-modified protein. Upon incubation with bovine serum albumin, HPNE preferentially reacted with the lysine residues. By employing N(alpha)-benzoylglycyl-lysine, we detected two major products containing one HPNE molecule per peptide. Based on the chemical and spectroscopic evidence, the products were identified to be the N(alpha)-benzoylglycyl derivatives of N(epsilon)-4-hydroxynonanoic acid-lysine and N(epsilon)-4-hydroxy (2Z)-nonenoyllysine, both of which are suggested to be formed through mechanisms in which the initial HPNE-lysine adducts undergo Baeyer-Villiger-like reactions proceeding through an intramolecular oxidation catalyzed by the hydroperoxy group. On the other hand, using an HPNE-modified protein as the immunogen, we raised a monoclonal antibody against the HPNE-modified protein and identified one of the HPNE-specific lysine adducts, N(epsilon)-4-hydroxynonanoic acid-lysine, as an intrinsic epitope of the monoclonal antibody. Furthermore, we demonstrated that the HPNE-specific epitopes were produced not only in the oxidized low density lipoprotein in vitro but also in the atherosclerotic lesions. These results indicated that HPNE is not just an intermediate but also a reactive molecule that could covalently modify proteins in biological systems. PMID- 21690616 TI - Epidemiology, antibiotic therapy, and clinical outcomes in health care-associated pneumonia: a UK cohort study. AB - BACKGROUND: The recently introduced concept of health care-associated pneumonia (HCAP), referring to patients with frequent healthcare contacts and at higher risk of contracting resistant pathogens, is controversial. METHODS: This prospective observational study recorded the clinical features, microbiology, and outcomes in a UK cohort of hospitalized patients with pneumonia. The primary outcome was 30-day mortality. Logistic regression was used to adjust for confounders when determining the impact of HCAP on clinical outcomes. RESULTS: A total of 20.5% of patients met the HCAP criteria. HCAP patients were older than patients with community-acquired pneumonia (CAP) (median 76 y, IQR 65-83 vs 65 y, IQR 48-77; P < .0001) and more frequently had major comorbidities (62.1% vs 45.2%; P < .0001). Patients with HCAP had higher initial severity compared to CAP patients (Pneumonia Severity Index, mean 3.7 [SD 1.1] vs mean 3.1 [SD 1.3]; P < .0001) but also worse functional status using the Eastern Cooperative Oncology Group scale (mean 2.4 [SD 1.44] vs mean 1.4 [SD 1.13]; P < .0001) and more frequently had treatment restrictions such as do not resuscitate orders (59.9% vs 29.8%; P < .0001). Consequently mortality was increased (odds ratio [OR] 2.15 [1.44-3.22]; P = .002) in HCAP patients on univariate analysis. Multivariate analysis suggested this relationship was primarily due to confounders rather than a higher frequency of treatment failure due to resistant organisms (adjusted OR .97 [.61-1.55]; P = .9). The frequencies of Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus, and Gram-negative Enterobacteriaceae were low in both cohorts. CONCLUSIONS: HCAP is common in the United Kingdom and is associated with a high mortality. This increased mortality was primarily related to underlying patient-related factors rather than the presence of antibiotic resistant pathogens. This study did not establish a clear indication to change prescribing practices in a UK cohort. PMID- 21690617 TI - Incidence and severity of invasive Streptococcus pneumoniae, group A Streptococcus, and group B Streptococcus infections among pregnant and postpartum women. AB - BACKGROUND: The epidemiology of streptococcal infection in pregnant and postpartum women is poorly described in recent literature. We used data from multistate surveillance for invasive Streptococcus pneumoniae, group A Streptococcus (GAS), and group B Streptococcus (GBS) infections to estimate disease incidence and severity in these populations. METHODS: Cases were reported through the Centers for Disease Control and Prevention Active Bacterial Core surveillance, an active population- and laboratory-based system. A case was defined as illness in a woman aged 15-44 years with streptococcus isolated from a normally sterile body site during 2007-2009. Pregnant or postpartum status was recorded at the time of culture. Incidence was calculated as cases per 1000 woman years with use of national Census data; 95% confidence intervals were calculated on the basis of lambda distribution. We used multivariable logistic regression to explore associations between pregnant or postpartum status and hospital length of stay, a marker of disease severity. RESULTS: We identified 1848 cases in women; 6.0% of women were pregnant, and 7.5% were postpartum. Pregnant women had a higher mean incidence of GBS disease, compared with nonpregnant women (0.04 cases per 1000 woman-years [range, 0.03-0.05 cases per 1000 woman-years] vs 0.02 cases per 1000 woman-years [range, 0.02-0.02 cases per 1000 woman-years]). Postpartum women had elevated mean incidence of all 3 pathogens, compared with nonpregnant women (S. pneumoniae: 0.15 cases per 1000 woman-years [range, 0.09-0.25 cases per 1000 woman-years] vs 0.052 cases per 1000 woman-years [range, 0.049-0.056 cases per 1000 woman-years]; GAS: 0.56 cases per 1000 woman-years [range, 0.42-0.70 cases per 1000 woman-years] vs 0.019 cases per 1000 woman-years [range, 0.017 0.021 cases per 1000 woman-years]; GBS: 0.49 cases per 1000 woman-years [range, 0.36-0.64 cases per 1000 woman-years] vs 0.018 [range, 0.016-0.020 cases per 1000 woman-years]). Neither pregnancy nor postpartum status was associated with longer length of stay among women infected with any of the 3 pathogens. CONCLUSIONS: Although invasive streptococcal infections do not appear to be more severe in pregnant or postpartum women, postpartum women have a 20-fold increased incidence of GAS and GBS, compared with nonpregnant women. PMID- 21690618 TI - Implementation of a dose calculator for vancomycin to achieve target trough levels of 15-20 microg/mL in persons undergoing hemodialysis. AB - (See the article by Brown et al, on pages 164-166.) BACKGROUND: Vancomycin is a key antibiotic for the treatment of Gram-positive bacterial infections in patients undergoing dialysis. Vancomycin has a narrow therapeutic range. Overdosing imposes a risk of nephro- and ototoxicity, wherease underdosing predisposes to treatment failure and the emergence of drug resistance. Trough levels of 15-20 MUg/mL have been identified as the optimal target trough levels. METHODS: A multivariate model called the vancomycin dose calculator (VDC) was prospectively developed and validated to permit accurate vancomycin dosing in persons undergoing hemodialysis. RESULTS: The model identified 3 simple parameters that were responsible for 94.6% of the variance observed: predialysis vancomycin trough level, dry body weight, and period to the next dialysis session. Maintenance dosing was accurate in 77.9% of patients, whereas major over and underdosing were avoided in the remaining patients. The mean measured trough level of 16.5 MUg/mL was 5.6% lower than the mean predicted trough level of 17.5 MUg/mL. With regard to loading doses, a fixed loading dose of 20 mg/kg led to subtherapeutic trough levels in one-half of patients. CONCLUSIONS: The VDC permits accurate vancomycin maintenance dosing based on predialysis trough level, dry body weight, and period to the next dialysis session in the majority of patients undergoing hemodialysis. Higher loading doses that accounted for the period to the next dialysis may be more appropriate than fixed loading doses used in this study. PMID- 21690619 TI - Influenza vaccination of schoolchildren and influenza outbreaks in a school. AB - BACKGROUND: The objective of this retrospective descriptive study was to determine whether the universal influenza vaccination for schoolchildren was effective in controlling influenza outbreaks in a school. A universal vaccination program for schoolchildren was started in Japan in the 1960s, but the government abandoned the program in 1994 because of lack of evidence that the program was effective in preventing influenza in schoolchildren. METHODS: Influenza vaccine coverage rates, total numbers of class cancellation days, and absentee rates were reviewed in a single elementary school during the 24-year period during 1984 2007. RESULTS: The mean number of class cancellation days and the mean absentee rate in the compulsory vaccination period (1984-1987; mean vaccine coverage rate, 96.5%) were 1.3 days and 2.5%, respectively, and they increased to 8.3 days and 3.2% during the quasi-compulsory vaccination period (1988-1994; vaccine coverage, 66.4%). In the no-vaccination period (1995-1999; vaccine coverage, 2.4%), they were 20.5 days and 4.3%, respectively, and in the voluntary vaccination period (2000-2007; vaccine coverage, 38.9-78.6%), they were 7.0-9.3 days and 3.8%-3.9%. When minor epidemics were excluded, there was a significant inverse correlation between the vaccine coverage rates and both the number of class cancellation days and absentee rates. CONCLUSIONS: The universal influenza vaccination for schoolchildren was effective in reducing the number of class cancellation days and absenteeism in the school. PMID- 21690620 TI - Geographic variation in invasive pneumococcal disease following pneumococcal conjugate vaccine introduction in the United States. AB - BACKGROUND: Rates of invasive pneumococcal disease (IPD) varied among the United States before pneumococcal conjugate vaccine (PCV7) introduction. We compared trends in IPD rates among diverse US sites over 10 years since PCV7 introduction. METHODS: Patients with IPD of all ages were identified through active population and laboratory-based surveillance in 8 geographic areas under continuous surveillance during 1998-2009. Isolates were serotyped. IPD incidence rates and percent changes were calculated by site, serotype group, age, and year. RESULTS: Reductions in rates of IPD ranged, by site, from 19 to 29.9 cases per 100,000 population during 1998-1999 to 11.2-18.0 cases per 100,000 population during 2009 (rate reduction, 5.1-15.3 cases per 100,000 population). Reductions in IPD rates among children aged <5 years ranged from 35.7 to 117.2 cases per 100,000 population across the sites. Reductions in rates of IPD due to PCV7 serotypes were seen in all age groups at all sites, ranging from 12 to 21.4 cases per 100,000 population during 1998-1999 to <2 cases per 100,000 population during 2009 (92%-98% reductions). Serotype 19A rates ranged from 0.4 to 1.5 cases per 100,000 population during 1998-1999 to 1.3 to 3.4 cases per 100,000 population during 2009 (rate difference, 0.9-2.8 cases per 100,000 population); modest increases were observed for most age groups across the sites. Rates of IPD due to all other serotypes ranged from 6.3 to 10.3 cases per 100,000 population during 1998-1999 to 8.3-13.6 cases per 100,000 population during 2009 (rate difference, 0.4 to 5.7 cases per 100,000 population). Across the sites, the greatest rate increases were seen in the 50-64 and >65 year age groups. CONCLUSIONS: Reductions in IPD due to vaccine serotypes were consistent across sites. Changes in serotype 19A and all other serotypes were variable. Although relative increases in non vaccine type serotypes were large in some sites, absolute rate increases were small. PMID- 21690622 TI - Use of antistaphylococcal beta-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycin binding. AB - We used daptomycin plus antistaphylococcal beta-lactams (ASBL) to clear refractory MRSA bacteremia. In vitro studies showed enhanced daptomycin bactericidal activity, increased membrane daptomycin binding, and decrease in positive surface charge induced by ASBLs against daptomycin nonsusceptible MRSA. Addition of ASBLs to daptomycin may be of benefit in refractory MRSA bacteremia. (Although the official designation is "daptomycin nonsusceptiblity," we will use the term "daptomycin-resistance" in this paper for facility of presentation.). PMID- 21690621 TI - Comparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008. AB - BACKGROUND: In the past decade, new methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged as a predominant cause of community-associated skin and soft-tissue infections (SSTIs). Little information exists regarding trends in MRSA prevalence and molecular characteristics or regarding antimicrobial susceptibility profiles of S. aureus isolates. METHODS: We enrolled adults with acute, purulent SSTIs presenting to a US network of 12 emergency departments during August 2008. Cultures and clinical information were collected. S. aureus isolates were characterized by antimicrobial susceptibility testing, pulsed-field gel electrophoresis, and toxin genes detection. The prevalence of S. aureus and MRSA and isolate genetic characteristics and susceptibilities were compared with those from a similar study conducted in August 2004. RESULTS: The prevalence of MRSA was 59% among all SSTIs during both study periods; however, the prevalence by site varied less in 2008 (38%-84%), compared with 2004 (15%-74%). Pulsed-field type USA300 continued to account for almost all MRSA isolates (98%). Susceptibility to trimethoprim-sulfamethoxazole, clindamycin, and tetracycline among MRSA isolates remained greater than 90% in 2008. A higher proportion of MRSA infections were treated with an agent to which the infecting isolate was susceptible in vitro in 2008 (97%), compared with 2004 (57%). CONCLUSIONS: Similar to 2004, MRSA remained the most common identifiable cause of purulent SSTIs among patients presenting to a network of US emergency departments in 2008. The infecting MRSA isolates continued to be predominantly pulsed-field type USA300 and susceptible to recommended non-beta-lactam oral agents. Clinician prescribing practices have shifted from MRSA-inactive to MRSA-active empirical antimicrobial regimens. PMID- 21690623 TI - Weight-based loading of vancomycin in patients on hemodialysis. AB - We evaluated weight-based loading doses of vancomycin and resulting initial prehemodialysis concentrations. Modeling demonstrated modest correlation between dose administered, age, and initial concentration achieved. Actual body weight based loading of vancomycin predictably achieves therapeutic initial concentrations in patients who receive hemodialysis. PMID- 21690624 TI - A rash and cough in a traveler. PMID- 21690625 TI - Opportunistic infection-associated immune reconstitution syndrome in transplant recipients. AB - Reversal of pathogen-induced immunosuppression upon employment of effective antimicrobial therapy and withdrawal of iatrogenic immunosuppression has the potential to shift the host immune repertoire towards pathologic inflammatory responses conducive to immune reconstitution syndrome (IRS). Posttransplant IRS has been observed with fungi, M. tuberculosis, cytomegalovirus, and polyoma virus nephropathy. This review discusses the existing state of knowledge regarding IRS and the immune mechanisms that underlie its pathogenesis, with significant implications for developing reliable diagnostic biomarkers and optimal management strategies for post-transplant opportunistic infection-associated IRS. PMID- 21690626 TI - The challenges of antimicrobial drug resistance in Greece. AB - Antimicrobial drug resistance rates in Greece are among the highest in Europe. The prevalence of carbapenem-resistant Gram-negative species has increased considerably, including endemic strains in intensive care units. Pandrug resistant Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are sporadically reported. Methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus rates are also high in Greek hospitals. Multidrug resistance increases risk of mortality, hospitalization duration and costs, and undermines the medical system. Administrative responses initiated include action plans, monitoring systems, and guidelines. Common terminology among involved parties for defining and grading resistance is required. Multidrug resistant microorganisms challenge clinical laboratories; uniform recommendations towards detection of resistance mechanisms need to be established. Prospective multicenter outcome studies comparing antibiotic regimens and containment methods are needed. Because new antimicrobials against Gram-negative pathogens are not foreseeable, judicious use of the existing and strict adherence to infection control best practice might restrain resistance spread. Awareness of resistance patterns and organisms prevailing locally by reporting laboratories and treating physicians is important. PMID- 21690627 TI - Peripheral and central fat changes in subjects randomized to abacavir-lamivudine or tenofovir-emtricitabine with atazanavir-ritonavir or efavirenz: ACTG Study A5224s. AB - BACKGROUND: We compare the effect of 4 different antiretroviral regimens on limb and visceral fat. METHODS: A5224s was a substudy of A5202, a trial of human immunodeficiency virus type 1 (HIV-1)-infected, treatment-naive subjects randomized to blinded abacavir-lamivudine (ABC-3TC) or tenofovir DF-emtricitabine (TDF-FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV-r). The primary endpoint was the presence of lipoatrophy (>= 10% loss of limb fat) at week 96 by intent-to-treat (ITT) analysis. Secondary endpoints included changes in limb and visceral fat. Statistical tests included linear regression, binomial, two-sample t test, and Fisher's exact test. RESULTS: A5224s enrolled 269 subjects; 85% were male, and 47% were white non-Hispanic. The subjects had a median baseline HIV-1 RNA level of 4.6 log(10) copies/mL, a median age of 38 years, a median CD4+ cell count of 233 cells/MUL, median limb fat of 7.4 kg, median visceral adipose tissue (VAT) of 84.1 cm(2), and VAT: total adipose tissue (TAT) ratio of 0.31. At week 96, estimated prevalence of lipoatrophy (upper 95% confidence interval [CI]) was 18% (25%) for ABC-3TC and 15% (22%) for TDF-FTC (P = .70); this was not significantly less than the hypothesized 15% for both (P >= .55 for both). The secondary as-treated (AT) analysis showed similar results. At week 96, the estimated mean percentage change from baseline in VAT was higher for the ATV-r group than for the EFV group (26.6% vs 12.4%; P = .090 in ITT analysis and 30.0% vs 14.5%; P = .10 in AT analysis); however, the percentage change in VAT:TAT was similar by ITT and AT analysis (P >= .60 for both). Results were similar for absolute changes in VAT and VAT:TAT. CONCLUSIONS: ABC-3TC- and TDF FTC-based regimens increased limb and visceral fat at week 96, with a similar prevalence of lipoatrophy. Compared to the EFV group, subjects assigned to ATV-r had a trend towards higher mean percentage increase in VAT. CLINICAL TRIALS REGISTRATION: NCT00118898. PMID- 21690628 TI - Blood (1->3)-beta-D-glucan as a diagnostic test for HIV-related Pneumocystis jirovecii pneumonia. AB - (See the editorial commentary by Morris and Masur, on pages 203-204.) BACKGROUND: Improved noninvasive diagnostic tests for Pneumocystis jirovecii pneumonia (PCP) are needed. We evaluated the test characteristics of plasma (1 -> 3)-beta-D glucan (beta-glucan) for HIV-related PCP among a large group of patients presenting with diverse opportunistic infections (OIs). METHODS: The study population included all 282 participants in AIDS Clinical Trials Group A5164, a study of early versus deferred antiretroviral therapy in conjunction with initial therapy of acute OIs. Baseline plasma samples were assayed for beta-glucan, with standard assay reference values defining >= 80 pg/mL as positive. Before this analysis, diagnosis of PCP was independently adjudicated by 2 study investigators after reviewing reports from study sites. RESULTS: A total of 252 persons had a beta-glucan result that could be analyzed, 173 (69%) of whom had received a diagnosis of PCP. Median beta-glucan with PCP was 408 pg/mL (interquartile range [IQR], 209-500 pg/mL), compared with 37 pg/mL (IQR, 31-235 pg/mL) without PCP (P < .001). The sensitivity of beta-glucan dichotomized at 80 pg/mL for the diagnosis of PCP was 92% (95% confidence interval [CI], 87%-96%), and the specificity was 65% (95% CI, 53%-75%); positive and negative predictive values were 85% (95% CI, 79%-90%) and 80% (95% CI, 68%-89%) respectively, based on the study prevalence of 69% of patients with PCP. Rates of abnormal lactate dehyrogenase levels did not differ significantly between those with and without PCP. CONCLUSIONS: Blood (1 -> 3)-beta-D-glucan is strongly correlated with HIV related PCP. In some clinical centers, this may be a more sensitive test than the induced sputum examination and could reduce the need for both bronchoscopy and empirical therapy of PCP. PMID- 21690629 TI - A serologic test to diagnose pneumocystis pneumonia: are we there yet? PMID- 21690631 TI - Possible reduced effectiveness of the 2009 H1N1 component of live, attenuated influenza vaccine. PMID- 21690632 TI - New information on the relationship between exclusive breastfeeding and lower mother-to-child HIV transmission. PMID- 21690635 TI - Bedbugs and transmission of Trypanosoma cruzi. PMID- 21690636 TI - Vancomycin "telephone". PMID- 21690637 TI - Clostridium difficile disease and vancomycin--questionable clinical superiority. PMID- 21690639 TI - Image segmentation by probabilistic bottom-up aggregation and cue integration. AB - We present a bottom-up aggregation approach to image segmentation. Beginning with an image, we execute a sequence of steps in which pixels are gradually merged to produce larger and larger regions. In each step, we consider pairs of adjacent regions and provide a probability measure to assess whether or not they should be included in the same segment. Our probabilistic formulation takes into account intensity and texture distributions in a local area around each region. It further incorporates priors based on the geometry of the regions. Finally, posteriors based on intensity and texture cues are combined using "a mixture of experts" formulation. This probabilistic approach is integrated into a graph coarsening scheme, providing a complete hierarchical segmentation of the image. The algorithm complexity is linear in the number of the image pixels and it requires almost no user-tuned parameters. In addition, we provide a novel evaluation scheme for image segmentation algorithms, attempting to avoid human semantic considerations that are out of scope for segmentation algorithms. Using this novel evaluation scheme, we test our method and provide a comparison to several existing segmentation algorithms. PMID- 21690640 TI - EXCOL: an EXtract-and-COmplete layering approach to cartoon animation reusing. AB - We introduce the EXtract-and-COmplete Layering method (EXCOL)--a novel cartoon animation processing technique to convert a traditional animated cartoon video into multiple semantically meaningful layers. Our technique is inspired by vision based layering techniques but focuses on shape cues in both the extraction and completion steps to reflect the unique characteristics of cartoon animation. For layer extraction, we define a novel similarity measure incorporating both shape and color of automatically segmented regions within individual frames and propagate a small set of user-specified layer labels among similar regions across frames. By clustering regions with the same labels, each frame is appropriately partitioned into different layers, with each layer containing semantically meaningful content. Then, a warping-based approach is used to fill missing parts caused by occlusion within the extracted layers to achieve a complete representation. EXCOL provides a flexible way to effectively reuse traditional cartoon animations with only a small amount of user interaction. It is demonstrated that our EXCOL method is effective and robust, and the layered representation benefits a variety of applications in cartoon animation processing. PMID- 21690641 TI - Morse set classification and hierarchical refinement using Conley index. AB - Morse decomposition provides a numerically stable topological representation of vector fields that is crucial for their rigorous interpretation. However, Morse decomposition is not unique, and its granularity directly impacts its computational cost. In this paper, we propose an automatic refinement scheme to construct the Morse Connection Graph (MCG) of a given vector field in a hierarchical fashion. Our framework allows a Morse set to be refined through a local update of the flow combinatorialization graph, as well as the connection regions between Morse sets. The computation is fast because the most expensive computation is concentrated on a small portion of the domain. Furthermore, the present work allows the generation of a topologically consistent hierarchy of MCGs, which cannot be obtained using a global method. The classification of the extracted Morse sets is a crucial step for the construction of the MCG, for which the Poincare' index is inadequate. We make use of an upper bound for the Conley index, provided by the Betti numbers of an index pair for a translation along the flow, to classify the Morse sets. This upper bound is sufficiently accurate for Morse set classification and provides supportive information for the automatic refinement process. An improved visualization technique for MCG is developed to incorporate the Conley indices. Finally, we apply the proposed techniques to a number of synthetic and realworld simulation data to demonstrate their utility. PMID- 21690642 TI - Model-driven design for the visual analysis of heterogeneous data. AB - As heterogeneous data from different sources are being increasingly linked, it becomes difficult for users to understand how the data are connected, to identify what means are suitable to analyze a given data set, or to find out how to proceed for a given analysis task. We target this challenge with a new model driven design process that effectively codesigns aspects of data, view, analytics, and tasks. We achieve this by using the workflow of the analysis task as a trajectory through data, interactive views, and analytical processes. The benefits for the analysis session go well beyond the pure selection of appropriate data sets and range from providing orientation or even guidance along a preferred analysis path to a potential overall speedup, allowing data to be fetched ahead of time. We illustrate the design process for a biomedical use case that aims at determining a treatment plan for cancer patients from the visual analysis of a large, heterogeneous clinical data pool. As an example for how to apply the comprehensive design approach, we present Stack'n'flip, a sample implementation which tightly integrates visualizations of the actual data with a map of available data sets, views, and tasks, thus capturing and communicating the analytical workflow through the required data sets. PMID- 21690643 TI - An RBF-based reparameterization method for constrained texture mapping. AB - Texture mapping has long been used in computer graphics to enhance the realism of virtual scenes. However, to match the 3D model feature points with the corresponding pixels in a texture image, surface parameterization must satisfy specific positional constraints. However, despite numerous research efforts, the construction of a mathematically robust, foldover-free parameterization that is subject to positional constraints continues to be a challenge. In the present paper, this foldover problem is addressed by developing radial basis function (RBF)-based reparameterization. Given initial 2D embedding of a 3D surface, the proposed method can reparameterize 2D embedding into a foldover-free 2D mesh, satisfying a set of user-specified constraint points. In addition, this approach is mesh free. Therefore, generating smooth texture mapping results is possible without extra smoothing optimization. PMID- 21690644 TI - Hexagonal global parameterization of arbitrary surfaces. AB - We introduce hexagonal global parameterization, a new type of surface parameterization in which parameter lines respect sixfold rotational symmetries (6-RoSy). Such parameterizations enable the tiling of surfaces with nearly regular hexagonal or triangular patterns, and can be used for triangular remeshing. Our framework to construct a hexagonal parameterization, referred to as HEXCOVER, extends the QUADCOVER algorithm and formulates necessary conditions for hexagonal parameterization. We also provide an algorithm to automatically generate a 6-RoSy field that respects directional and singularity features in the surface. We demonstrate the usefulness of our geometry-aware global parameterization with applications such as surface tiling with nearly regular textures and geometry patterns, as well as triangular and hexagonal remeshing. PMID- 21690645 TI - Simple culling methods for continuous collision detection of deforming triangles. AB - We present a simple and efficient approach for continuous collision detection of deforming triangles based on conservative advancement. The efficiency of our approach is due to a sequence of simple collision-free conditions for deforming triangles. In our experiment, we show that our CCD algorithm achieves 2-30 times performance improvement over existing algorithms for triangle primitives. PMID- 21690646 TI - A 2D flow visualization user study using explicit flow synthesis and implicit task design. AB - This paper presents a 2D flow visualization user study that we conducted using new methodologies to increase the objectiveness. We evaluated grid-based variable size arrows, evenly spaced streamlines, and line integral convolution (LIC) variants (basic, oriented, and enhanced versions) coupled with a colorwheel and/or rainbow color map, which are representative of many geometry-based and texture-based techniques. To reduce data-related bias, template-based explicit flow synthesis was used to create a wide variety of symmetric flows with similar topological complexity. To suppress task-related bias, pattern-based implicit task design was employed, addressing critical point recognition, critical point classification, and symmetric pattern categorization. In addition, variable duration and fixed-duration measurement schemes were utilized for lightweight precision-critical and heavyweight judgment intensive flow analysis tasks, respectively, to record visualization effectiveness. We eliminated outliers and used the Ryan REGWQ post-hoc homogeneous subset tests in statistical analysis to obtain reliable findings. Our study shows that a texture-based dense representation with accentuated flow streaks, such as enhanced LIC, enables intuitive perception of the flow, while a geometry-based integral representation with uniform density control, such as evenly spaced streamlines, may exploit visual interpolation to facilitate mental reconstruction of the flow. It is also shown that inappropriate color mapping (e.g., colorwheel) may add distractions to a flow representation. PMID- 21690647 TI - Efficiently computing exact geodesic loops within finite steps. AB - Closed geodesics, or geodesic loops, are crucial to the study of differential topology and differential geometry. Although the existence and properties of closed geodesics on smooth surfaces have been widely studied in mathematics community, relatively little progress has been made on how to compute them on polygonal surfaces. Most existing algorithms simply consider the mesh as a graph and so the resultant loops are restricted only on mesh edges, which are far from the actual geodesics. This paper is the first to prove the existence and uniqueness of geodesic loop restricted on a closed face sequence; it contributes also with an efficient algorithm to iteratively evolve an initial closed path on a given mesh into an exact geodesic loop within finite steps. Our proposed algorithm takes only an O(k) space complexity and an O(mk) time complexity (experimentally), where m is the number of vertices in the region bounded by the initial loop and the resultant geodesic loop, and k is the average number of edges in the edge sequences that the evolving loop passes through. In contrast to the existing geodesic curvature flow methods which compute an approximate geodesic loop within a predefined threshold, our method is exact and can apply directly to triangular meshes without needing to solve any differential equation with a numerical solver; it can run at interactive speed, e.g., in the order of milliseconds, for a mesh with around 50K vertices, and hence, significantly outperforms existing algorithms. Actually, our algorithm could run at interactive speed even for larger meshes. Besides the complexity of the input mesh, the geometric shape could also affect the number of evolving steps, i.e., the performance. We motivate our algorithm with an interactive shape segmentation example shown later in the paper. PMID- 21690648 TI - Video stereolization: combining motion analysis with user interaction. AB - We present a semiautomatic system that converts conventional videos into stereoscopic videos by combining motion analysis with user interaction, aiming to transfer as much as possible labeling work from the user to the computer. In addition to the widely used structure from motion (SFM) techniques, we develop two new methods that analyze the optical flow to provide additional qualitative depth constraints. They remove the camera movement restriction imposed by SFM so that general motions can be used in scene depth estimation-the central problem in mono-to-stereo conversion. With these algorithms, the user's labeling task is significantly simplified. We further developed a quadratic programming approach to incorporate both quantitative depth and qualitative depth (such as these from user scribbling) to recover dense depth maps for all frames, from which stereoscopic view can be synthesized. In addition to visual results, we present user study results showing that our approach is more intuitive and less labor intensive, while producing 3D effect comparable to that from current state-of-the art interactive algorithms. PMID- 21690649 TI - Topology verification for isosurface extraction. AB - The broad goals of verifiable visualization rely on correct algorithmic implementations. We extend a framework for verification of isosurfacing implementations to check topological properties. Specifically, we use stratified Morse theory and digital topology to design algorithms which verify topological invariants. Our extended framework reveals unexpected behavior and coding mistakes in popular publicly available isosurface codes. PMID- 21690650 TI - A versatile optical model for hybrid rendering of volume data. AB - In volume rendering, most optical models currently in use are based on the assumptions that a volumetric object is a collection of particles and that the macro behavior of particles, when they interact with light rays, can be predicted based on the behavior of each individual particle. However, such models are not capable of characterizing the collective optical effect of a collection of particles which dominates the appearance of the boundaries of dense objects. In this paper, we propose a generalized optical model that combines particle elements and surface elements together to characterize both the behavior of individual particles and the collective effect of particles. The framework based on a new model provides a more powerful and flexible tool for hybrid rendering of isosurfaces and transparent clouds of particles in a single scene. It also provides a more rational basis for shading, so the problem of normal-based shading in homogeneous regions encountered in conventional volume rendering can be easily avoided. The model can be seen as an extension to the classical model. It can be implemented easily, and most of the advanced numerical estimation methods previously developed specifically for the particle-based optical model, such as preintegration, can be applied to the new model to achieve high-quality rendering results. PMID- 21690651 TI - Efficient optimization of common base domains for cross parameterization. AB - Given a set of corresponding user-specified anchor points on a pair of models having similar features and topologies, the cross parameterization technique can establish a bijective mapping constrained by the anchor points. In this paper, we present an efficient algorithm to optimize the complexes and the shape of common base domains in cross parameterization for reducing the distortion of the bijective mapping. The optimization is also constrained by the anchor points. We investigate a new signature, Length-Preserved Base Domain (LPBD), for measuring the level of stretch between surface patches in cross parameterization. This new signature well balances the accuracy of measurement and the computational speed. Based on LPBD, a set of metrics are studied and compared. The best ones are employed in our domain optimization algorithm that consists of two major operators, boundary swapping and patch merging. Experimental results show that our optimization algorithm can reduce the distortion in cross parameterization efficiently. PMID- 21690652 TI - Region-based line field design using harmonic functions. AB - Field design has wide applications in graphics and visualization. One of the main challenges in field design has been how to provide users with both intuitive control over the directions in the field on one hand and robust management of its topology on the other hand. In this paper, we present a design paradigm for line fields that addresses this challenge. Rather than asking users to input all singularities as in most methods that offer topology control, we let the user provide a partitioning of the domain and specify simple flow patterns within the partitions. Represented by a selected set of harmonic functions, the elementary fields within the partitions are then combined to form continuous fields with rich appearances and well-determined topology. Our method allows a user to conveniently design the flow patterns while having precise and robust control over the topological structure. Based on the method, we developed an interactive tool for designing line fields from images, and demonstrated the utility of the fields in image stylization. PMID- 21690653 TI - Transforming GIS data into functional road models for large-scale traffic simulation. AB - There exists a vast amount of geographic information system (GIS) data that model road networks around the world as polylines with attributes. In this form, the data are insufficient for applications such as simulation and 3D visualization tools which will grow in power and demand as sensor data become more pervasive and as governments try to optimize their existing physical infrastructure. In this paper, we propose an efficient method for enhancing a road map from a GIS database to create a geometrically and topologically consistent 3D model to be used in real-time traffic simulation, interactive visualization of virtual worlds, and autonomous vehicle navigation. The resulting representation provides important road features for traffic simulations, including ramps, highways, overpasses, legal merge zones, and intersections with arbitrary states, and it is independent of the simulation methodologies. We test the 3D models of road networks generated by our algorithm on real-time traffic simulation using both macroscopic and microscopic techniques. PMID- 21690654 TI - Design and evaluation of MagnetViz-a graph visualization tool. AB - MagnetViz was designed for the interactive manipulation of force-directed graph layouts, allowing the user to obtain visualizations based on the graph topology and/or the attributes of its nodes and edges. The user can introduce virtual magnets anywhere in the graph and these can be set to attract nodes and edges that fulfill user-defined criteria. When a magnet is placed, the force-directed nature of the layout forces it to reorganize itself in order to reflect the changes in the balance of forces, consequently changing the visualization into one that is more semantically relevant to the user. This paper describes MagnetViz's concepts, illustrating them with examples and a case study based on a usage scenario. We also describe how the MagnetViz has evolved since its original version and present the evaluation of its latest version. This evaluation consists of two user studies aiming at assessing generated layout quality and how well the concepts can be apprehended and employed, and a task taxonomy assessment focusing on establishing which graph visualization tasks the technique is able to handle. PMID- 21690655 TI - CASSys: an integrated software-system for the interactive analysis of ChIP-seq data. AB - The mapping of DNA-protein interactions is crucial for a full understanding of transcriptional regulation. Chromatin-immunoprecipitation followed by massively parallel sequencing (ChIP-seq) has become the standard technique for analyzing these interactions on a genome-wide scale. We have developed a software system called CASSys (ChIP-seq data Analysis Software System) spanning all steps of ChIP seq data analysis. It supersedes the laborious application of several single command line tools. CASSys provides functionality ranging from quality assessment and -control of short reads, over the mapping of reads against a reference genome (readmapping) and the detection of enriched regions (peakdetection) to various follow-up analyses. The latter are accessible via a state-of-the-art web interface and can be performed interactively by the user. The follow-up analyses allow for flexible user defined association of putative interaction sites with genes, visualization of their genomic context with an integrated genome browser, the detection of putative binding motifs, the identification of over-represented Gene Ontology-terms, pathway analysis and the visualization of interaction networks. The system is client-server based, accessible via a web browser and does not require any software installation on the client side. To demonstrate CASSys's functionality we used the system for the complete data analysis of a publicly available Chip-seq study that investigated the role of the transcription factor estrogen receptor-alpha in breast cancer cells. PMID- 21690656 TI - Estimation of electrode location in a rat motor cortex by laminar analysis of electrophysiology and intracortical electrical stimulation. AB - While the development of microelectrode arrays has enabled access to disparate regions of a cortex for neurorehabilitation, neuroprosthetic and basic neuroscience research, accurate interpretation of the signals and manipulation of the cortical neurons depend upon the anatomical placement of the electrode arrays in a layered cortex. Toward this end, this report compares two in vivo methods for identifying the placement of electrodes in a linear array spaced 100 um apart based on in situ laminar analysis of (1) ketamine-xylazine-induced field potential oscillations in a rat motor cortex and (2) an intracortical electrical stimulation-induced movement threshold. The first method is based on finding the polarity reversal in laminar oscillations which is reported to appear at the transition between layers IV and V in laminar 'high voltage spindles' of the rat cortical column. Analysis of histological images in our dataset indicates that polarity reversal is detected 150.1 +/- 104.2 um below the start of layer V. The second method compares the intracortical microstimulation currents that elicit a physical movement for anodic versus cathodic stimulation. It is based on the hypothesis that neural elements perpendicular to the electrode surface are preferentially excited by anodic stimulation while cathodic stimulation excites those with a direction component parallel to its surface. With this method, we expect to see a change in the stimulation currents that elicits a movement at the beginning of layer V when comparing anodic versus cathodic stimulation as the upper cortical layers contain neuronal structures that are primarily parallel to the cortical surface and lower layers contain structures that are primarily perpendicular. Using this method, there was a 78.7 +/- 68 um offset in the estimate of the depth of the start of layer V. The polarity reversal method estimates the beginning of layer V within +/-90 um with 95% confidence and the intracortical stimulation method estimates it within +/-69.3 um. We propose that these methods can be used to estimate the in situ location of laminar electrodes implanted in the rat motor cortex. PMID- 21690657 TI - Effect of non-magnetic impurities on the magnetic states of anatase TiO2. AB - The electronic and magnetic properties of TiO2, TiO1.75, TiO1.75N0.25, and TiO1.75F0.25 compounds have been studied by using ab initio electronic structure calculations. TiO2 is found to evolve from a wide-band-gap semiconductor to a narrow-band-gap semiconductor to a half-metallic state and finally to a metallic state with oxygen vacancy, N-doping and F-doping, respectively. The present work clearly shows the robust magnetic ground state for N-and F-doped TiO2. The N doping gives rise to a magnetic moment of ~ 0.4 MU(B) at the N site and ~ 0.1 MU(B) each at two neighboring O sites, whereas F-doping creates a magnetic moment of ~ 0.3 MU(B) at the nearest Ti atom. Here we also discuss the possible cause of the observed magnetic states in terms of the spatial electronic charge distribution of Ti, N, and F atoms responsible for bond formation. PMID- 21690658 TI - In situ observation of thermally activated domain memory and polarization memory in an aged K+-doped (Ba, Sr)TiO3 single crystal. AB - Different ferroelectric domains are degenerate states of the same ferroelectric phase; thus they are energetically equivalent and, in principle there exists no preference for a particular domain pattern. However, the existence of point defects is considered to stabilize certain preferential domain states. In order to study the temperature violation on such stabilized domains, we performed in situ observation on an aged K+-doped (Ba, Sr)TiO3 single crystal and found that both the domain configuration and polarization state can be memorized after experiencing a thermally activated ferro-para-ferro transition cycle, as manifested by a reappearance of the same domain pattern and double P-E hysteresis loop. In contrast, after the sample was aged in the paraelectric state (>10 min), these memory effects disappeared. The above memory effects are considered to originate from the interaction between point defects and the crystal symmetry driven by a symmetry-conforming tendency of point defects. Such a mechanism suggests that the memory effects are relevant to the existence of acceptor dopant and associated mobile oxygen vacancies, and they are not restricted to a particular dopant. Thus similar memory effects are expected to exist in a wide range of ferroelectric materials with acceptor doping. PMID- 21690659 TI - Scanning tunneling microscopic images and scanning tunneling spectra for coupled rectangular quantum corrals. AB - Assuming that an electron confined by double delta-function barriers lies in a quasi-stationary state, we derived eigenstates and eigenenergies of the electron. Such an electron has a complex eigenenergy, and the imaginary part naturally leads to the lifetime of the electron associated with tunneling through barriers. We applied this point of view to the electron confined in a rectangular quantum corral (QC) on a noble metal surface, and obtained scanning tunneling microscopic images and a scanning tunneling spectrum consistent with experimental ones. We investigated the electron states confined in coupled QCs and obtained the coupled states constructed with bonding and anti-bonding states. Using those energy levels and wavefunctions we specified scanning tunneling microscope (STM) images and scanning tunneling spectra (STS) for the doubly and triply coupled QCs. In addition we pointed out the feature of resonant electron states associated with the same QCs at both ends of the triply coupled QCs. PMID- 21690660 TI - Tight-binding simulation of transition-metal alloys. AB - In order to perform atomistic simulations of steel, it is necessary to have a detailed understanding of the complex interatomic interactions in transition metals and their alloys. The tight-binding approximation provides a computationally efficient, yet accurate, method to investigate such interactions. In the present work, an orthogonal tight-binding model for Fe, Mn and Cr, with the explicit inclusion of magnetism, has been parameterized from ab initio density-functional calculations. PMID- 21690661 TI - Ageing, fragility and the reversibility window in bulk alloy glasses. AB - Non-reversing relaxation enthalpies (DeltaH(nr)) at glass transitions T(g)(x) in the P(x)Ge(x)Se(1-2x) ternary display wide, sharp and deep global minima ([Formula: see text]) in the 0.090.2. In the solution phase, we do not observe any signatures of a spontaneous ordering of the cobalt spins despite a large concentration of mobile electrons (>10(20) cm(-3)). The absence of anomalous Hall resistance is consistent with this observation. The carrier concentration (n) over the entire range of x remains above the Mott limit for the insulator-to-metal transition in a doped semiconductor. However, while the Co-free samples are metallic (T>2 K), we see a resistivity (rho) minimum followed by lnT divergence of rho(T) at low temperatures with increasing x. The magnetoresistance of these samples is negative and predominantly isotropic. Moreover, the MR tends to follow a logH behaviour at high fields. These observations, including the Kondo-like minimum in the resistivity, suggest s-d exchange dominated transport in these dilute magnetic semiconductors. PMID- 21690671 TI - Coulomb drag in a longitudinal magnetic field in quantum wells. AB - The influence of a longitudinal magnetic field on the Coulomb drag current created in the ballistic transport regime in a quantum well by a ballistic current in a nearby parallel quantum well is investigated. We consider the case where the magnetic field is so strong that the magnetic length a(B) is smaller than the width of the well. Both in the ohmic and non-ohmic case, sharp peaks of the drag current as a function of the gate voltage or chemical potential are predicted. We study the dependence of the drag current on the voltage V across the driving wire, as well as on the magnetic field B. The fine structure of the peaks due to the electron spin is also considered. By studying the Coulomb drag one can make conclusions about the electron spectrum, g-factor and electron electron interaction in quantum wells. PMID- 21690672 TI - The observation of magnetic excitations in a single layered and a bilayered brownmillerite. AB - We describe the results of an inelastic neutron scattering measurement of the magnetic excitations in SrCaGaMnO(5+delta), a quasi-two-dimensional compound whose structure consists of layers of MnO(6) octahedra separated by layers of GaO(4) tetrahedra (the brownmillerite structure), and Ca(2.5)Sr(0.5)Mn(2)GaO(8), a bilayered brownmillerite. In both materials, a band of magnetic scattering appears below the magnetic ordering temperature which can be associated with magnon excitations. Our measurements allow us to provide an estimate for the intraplane exchange constant in both materials, which we find to be 3.4(4) meV for SrCaGaMnO(5+delta) and 2.2(4) meV for Ca(2.5)Sr(0.5)Mn(2)GaO(8). PMID- 21690673 TI - Lattice distortions, magnetoresistance and hopping conductivity in LaMnO(3+delta). AB - Structural and transport properties of ceramic LaMnO(3+delta) are investigated for delta = 0-0.154. According to x-ray diffraction measurements at room temperature the crystal structure of this compound varies from orthorhombic (Pbnm) for delta = 0 to rhombohedrally distorted cubic (Pm3m) for delta = 0.065 0.112 and to rhombohedral ([Formula: see text]) crystal symmetry for delta = 0.125-0.154. These structural modifications are confirmed by the Raman micro spectroscopy measurements. The resistivity displays in the range delta = 0-0.154 an activated behaviour both above and below the paramagnetic (PM) to ferromagnetic transition temperature, T(C). In the field of 8 T the relative magnetoresistance, Deltarho(B)/rho(0), reaches at delta = 0.154 the values of 88% near T(C) and -98% at [Formula: see text] K. The resistivity of the PM phase of LaMnO(3+delta) with delta = 0.100-0.154 satisfies the Shklovskii-Efros-like variable-range hopping (VRH) conductivity law between [Formula: see text] K and the VRH onset temperature [Formula: see text] K. The resistivity is governed by a complex energy dependence of the density of the localized states near the Fermi level, comprising a soft Coulomb gap [Formula: see text] eV and a rigid gap [Formula: see text] eV, the latter being connected to formation of small polarons. PMID- 21690674 TI - High magnetization and the high-temperature superparamagnetic transition with intercluster interaction in disordered zinc ferrite thin film. AB - Magnetic properties have been investigated for a zinc ferrite thin film deposited on glass at a substrate temperature close to room temperature using a sputtering method. X-ray diffraction analysis reveals that the thin film consists of nanocrystalline ZnFe(2)O(4) with the size of approximately 10 nm. The magnetization at 300 K as a function of the external magnetic field shows ferrimagnetic behaviour, and tends to be saturated to the high value of 32 emu g( 1) when the external magnetic field is higher than 30 kOe. It is considered that the preparation of the ZnFe(2)O(4) thin film by the sputtering method, which involves very rapid cooling of vapour to form the solid-state phase, causes the random distribution of Zn(2+) and Fe(3+) ions in the spinel structure. In such a situation, Fe(3+) ions occupy both octahedral and tetrahedral sites, and the strong superexchange interaction among them gives rise to ferrimagnetic properties accompanied with high magnetization. The static and dynamic magnetic responses, such as the frequency dependence of the linear ac susceptibility, the temperature dependence of the nonlinear ac susceptibility, the discrepancy between the zero-field-cooled (ZFC) and field-cooled dc magnetizations, and the relaxation of the ZFC magnetization, demonstrate that the magnetism of the present thin film is attributable to the superparamagnetism with the interaction among magnetic clusters. Spin freezing occurs at a temperature higher than room temperature ([Formula: see text] K). PMID- 21690675 TI - Coercivity of permanent magnetic thin film. AB - The coercivity of magnetic thin film having a two-dimensional easy-axis distribution is investigated within the framework of a simple micromagnetic model. It is found that the coercivity decreases from 0.14H(K) to a minimum of 0.07H(K) as thickness increases, where H(K) is the anisotropy field. It is substantially lower than that given by the Stoner-Wohlfarth model and is consistent with available experimental data. The calculated hysteresis loop and the initial magnetization curve are also in good agreement with experiments. PMID- 21690676 TI - Dielectric polarization and refractive indices of ultrathin barium titanate films on strontium titanate single crystals. AB - The electrical and optical properties of ultrathin films of tetragonal barium titanate (BaTiO(3)) on strontium titanate (SrTiO(3)) single-crystal substrates are theoretically investigated using a microscopic quantum mechanical model based on the orbital approximation in correlation with the dipole-dipole interaction. First-, second-, and third-order electronic polarizabilities had to be considered in this calculation in order to obtain accurate results for both the dielectric spontaneous polarization and the refractive indices of the BaTiO(3) overlayer. The spontaneous polarization is drastically reduced in the film as its thickness decreases. However, an electronic polarization appears within the SrTiO(3) substrate in the neighbourhood of the interface. This polarization, which vanishes far away from the interface into the SrTiO(3) bulk, is induced by the polarization of the BaTiO(3) film. Furthermore, we find the refractive index for both the BaTiO(3) film and the SrTiO(3) substrate to be deeply reduced for light polarized perpendicular to the surface. PMID- 21690677 TI - Participation of Eu-aggregates in the photoluminescence, afterglow and thermoluminescence of UV-irradiated KCl:Eu at 20 K. AB - The participation of different aggregated phases of the Eu impurity in the afterglow (AG) and thermoluminescence (TL) of KCl:Eu after UV-irradiation at 20 K is investigated. Several aggregated phases of Eu are formed by applying different thermal treatments and their formation is monitored by photoluminescence. It is shown that the treatments leading to high concentration of aggregates result in much higher AG and TL yields than the treatments leading to high concentration of dipoles. This is due to a more efficient AG and TL production for aggregates than for dipoles. Additionally, we observed a huge increase of the AG and TL production efficiency around dipoles after ageing at 200 degrees C. The results are discussed in view of a recently proposed mechanism for AG based on the migration of H centres through dislocation lines. The main conclusions are that dislocation lines trap dipoles and that precipitation occurs along dislocation lines causing a large fraction of aggregates to participate in the AG and TL. PMID- 21690678 TI - Coherence properties of the photoluminescence from CdS-ZnO nanocomposite thin films. AB - The application of semiconductor quantum dots in important new areas such as random lasing and quantum-information processing requires knowledge of the coherence of the optical emission from such systems. We report the first direct experimental estimation of the coherence in the light emitted by a nanoparticle ensemble. The photoluminescence from a two-phase nanocomposite CdS-ZnO thin film (with a characteristic grain size of 2-3 nm for both the chemical phases) possesses an appreciable degree of spatial and temporal coherence at room temperature. The degree of spatial coherence was estimated from the classical Young's double slit experiment. We also discuss a simple technique for estimating the degree of spectral coherence of the photoluminescence from thin films. PMID- 21690679 TI - Magnetism in V-doped ZnO thin films. AB - Ferromagnetism at room temperature, along with a spin-glass-like behaviour at low temperatures, has been observed in laser ablated V-doped ZnO thin films. It is found that V atoms were well substituted for Zn atoms and resulted in a very uniform distribution among the ZnO matrices. PMID- 21690680 TI - Polarization effects in the excitation and emission of Fe(3+) in orthoclase and their relevance to the determination of lattice sites of unknown defects. AB - A method was recently proposed for determining possible lattice sites of an unknown defect from polarization effects in its optical transitions. In this paper the method is tested using the optically excited 1.77 eV (700 nm) fluorescence of Fe(3+) ions which predominantly occupy the T1 sites in orthoclase feldspar. The emission intensity depended on the polarization of the exciting photons and the emission was itself polarized. Two pairs of crystal field symmetry directions were deduced from polarization data for each of the transitions at 1.77, 2.79 and 3.26 eV, and one pair was aligned with symmetry axes in the average geometry of the four anions around the T1 sites. An analysis of EPR data for Fe(3+) ions in feldspar showed that there was a symmetry axis in the crystal field similar to one of those deduced from the polarization data. Group theory calculations were used to determine if the transitions were dipolar a major assumption of the method. Three symmetries (S(4), C(2v) and C(2)) were found to lead to dipolar transitions consistent with the excitation results, and four (D(2), C(3), C(2) and C(s)) were consistent with a 1.77 eV dipolar emission. PMID- 21690681 TI - Giant volume magnetostriction and colossal magnetoresistance at room temperature in La(0.7)Ba(0.3)MnO(3). AB - Giant volume magnetostriction at room temperature is found for the first time in a La(0.7)Ba(0.3)MnO(3) single crystal, achieving 2.54 * 10(-4) in a magnetic field of 8.2 kOe. An even greater value of the volume magnetostriction, equal to 4 * 10(-4) in the same magnetic field, is observed at the Curie point T(C) = 310 K.Volume magnetostriction and magnetoresistance exhibit similar dependences on temperature and magnetic field in the T(C)-region, that is explained by the presence in this compound of a magnetic two-phase ferromagnetic-antiferromagnetic state due to strong s-d exchange. PMID- 21690682 TI - The characteristics of photon and phonon standing waves in a periodic medium. AB - The main characteristics of the spatial variation of the photon and phonon wave fields at the band gap boundaries are analysed for a one-dimensional medium with periodic optical or acoustic parameters. The derivations are based on symmetry considerations and on analytical results derived from the basic differential equation for the wave field. A simple relation is derived between the band gap width and the derivative of the field intensity at the interface between the regions of high and low wave velocity. The general field characteristics are derived for some examples. Using the analysis a remarkable asymmetric behaviour of the wave absorption near the Brillouin zone boundaries can be explained in a straightforward way. PMID- 21690683 TI - Polarization-dependent soft-x-ray absorption of a highly oriented ZnO microrod array. AB - Polarization-dependent x-ray absorption measurements were performed on a crystalline ZnO three-dimensional array consisting of highly oriented microrods as well as on particulate thin film consisting of monodisperse spherical nanoparticles. Strong anisotropic effects have been observed for the highly oriented ZnO rods, unlike for the isotropic spherical ones. Full-potential calculations of orbital-resolved x-ray absorption of a ZnO wurtzite periodic crystal, including the Zn 3d as part of the valence states, shows a very good agreement with the experimental findings. Comprehensive fundamental knowledge of the electronic structure of ZnO is obtained by probing and demonstrating the orbital symmetry of oxygen and its contribution to the conduction band of this important II-VI semiconductor. PMID- 21690684 TI - High field magnetic transitions in the mixed holmium-yttrium iron garnet Ho(0.43)Y(2.57)Fe(5)O(12). AB - High static magnetic field magnetization measurements have been performed up to 23 T on Ho(0.43)Y(2.57)Fe(5)O(12) single crystals at helium temperature (T = 4.2 K) with fields applied along the three main cubic axes: [Formula: see text], [Formula: see text] and [Formula: see text]. The change from the spontaneous ferrimagnetic structure in zero magnetic field to the fully ferromagnetic one in high field takes place through several intermediate phases separated by transitions with step-like magnetization behaviour, but without any observed hysteresis. Using the effective spin Hamiltonian approximation, we show that the general features of these transitions can be accounted for by a large magnetocristalline anisotropy of the Ho(3+) moments of the uniaxial type along the local z axis of each rare-earth site. The model is in better agreement with the experiments than its Ising limit, widely used before, but is still unsuccessful in predicting the 'umbrella' magnetic structures found by previous neutron and NMR experiments. PMID- 21690685 TI - A functional-integral formulation for polymer colloids: Pagonabarraga-Cates free energy revisited. AB - We have formulated a new functional-integral representation with respect to both polymer and monomer densities, along the lines of the current picture treating polymers as soft colloids. Comparison between the resulting form and a model free energy functional of Pagonabarraga and Cates (PC 2001 Europhys. Lett. 55 348) indicates that the PC relation between monomer and polymer concentrations is to be modified, and that further insertion of the order parameter defined by the square of monomer density is indispensable for regularizing a divergent term absent in the PC functional. Moreover, the saddle-point approximation to our functional integral leads to a self-consistent equation which efficiently preincludes the minimum of the Flory-Huggins-type local free energy as input. PMID- 21690686 TI - Ionic fluids: charge and density correlations near gas-liquid criticality. AB - The correlation functions of an ionic fluid with charge and size asymmetry are studied within the framework of the random phase approximation. The results obtained for the charge-charge correlation function demonstrate that the second moment Stillinger-Lovett (SL) rule is satisfied away from the gas-liquid critical point (CP) but not, in general, at the CP. However, in the special case of a model without size asymmetry the SL rules are satisfied even at the CP. The expressions for the density-density and charge-density correlation functions valid far from and close to the CP are obtained explicitly. PMID- 21690687 TI - Staggered magnetism in LiV(2)O(4) at low temperatures probed by means of the muon Knight shift. AB - We report on measurement of the muon Knight shift in single crystals of LiV(2)O(4). Contrary to what is anticipated for the heavy fermion state based on the Kondo mechanism, the presence of inhomogeneous local magnetic moments is demonstrated by the broad distribution of the Knight shift at temperatures well below the presumed 'Kondo temperature' ([Formula: see text] K). Moreover, a significant fraction ([Formula: see text]) of the specimen gives rise to a second component which is virtually non-magnetic. These observations strongly suggest that the anomalous properties of LiV(2)O(4) originate from frustration of local magnetic moments. PMID- 21690688 TI - Infrared spectroscopy of KTa(1-x)Nb(x)O(3) crystals. AB - Fourier-transform infrared and time-domain THz dielectric spectroscopy measurements on KTa(1-x)Nb(x)O(3) crystals for x = 0.018 and 0.022 were performed. The temperature behaviour of the soft mode frequency and damping have been determined above the ferroelectric phase transition. No dielectric dispersion in the frequency range below the polar phonon absorption is observed down to kHz frequencies at temperatures from room temperature down to 60 K. At lower temperatures the KTa(1-x)Nb(x)O(3) samples become opaque due to additional losses, which persist down to liquid helium temperatures. This supports the nanoscopic dipolar glassy state rather than macroscopic ferroelectricity at low temperatures. PMID- 21690689 TI - Viscoelastic properties of attractive and repulsive colloidal glasses. AB - We report a numerical study of the shear viscosity and the frequency dependent elastic moduli close to dynamical arrest for a model of short range attractive colloids, both for the repulsive and the attractive glass transition. Calculating the stress autocorrelation functions, we find that density fluctuations of wavevectors close to the first peak in the structure factor control the viscosity rise on approaching the repulsive glass, while fluctuations of larger wavevectors control the viscosity close to the attractive glass. On approaching the glass transition, the viscosity diverges with a power law with the same exponent as the density autocorrelation time. PMID- 21690690 TI - Microrheology of polymeric solutions using x-ray photon correlation spectroscopy. AB - We demonstrate the technique of XPCS microrheology on opaque polymeric solutions (1-20% w/w) using colloidal silica probes. The short time decay of the intensity correlation function provides the mean square displacement (MSD) of the colloidal probes. The MSDs of the probes are subsequently transformed using the generalized Stokes-Einstein equation, allowing the linear viscoelastic spectra of a biopolymer (gellan) and a synthetic polyelectrolyte (polystyrene sulfonate, PSS) to be calculated over two decades of frequency. MSDs can be measured that are two orders of magnitude smaller than those possible with video particle tracking microrheology, with a sensitivity of ~10 nm s(-1) for displacements of ~nms. The XPCS data for water, glycerol and PSS combs are in agreement with video particle tracking microrheology experiments performed at lower polymer concentrations. PMID- 21690691 TI - Nonlinear algorithm for the solution of the Kohn-Sham equations in solids. AB - We apply a nonlinear multigrid algorithm, named the full approximation storage (FAS) scheme, to the Kohn-Sham equations for pseudopotential band structure calculations. Traditionally, the nonlinear self-consistent problem is linearized into successive fixed potential eigenvalue problems with potentials updated between them. In the new method, the self-consistent problem is solved directly with the FAS scheme. First, the error of self-consistence in density is calculated; then, an FAS coarse grid problem is defined and solved; finally, a correction is interpolated to the fine grid to modify the density. The eigenvalue problem is integrated inside the FAS scheme, and evolves along with the self consistent problem within the FAS frame. Calculations are demonstrated for Si and Al. PMID- 21690692 TI - Negative refractive index metamaterials from inherently non-magnetic materials for deep infrared to terahertz frequency ranges. AB - We present a new set of artificial structures which can exhibit a negative refractive index band in excess of 6% in a broad frequency range from the deep infrared to the terahertz region. The structures are composites of two different kinds of non-overlapping spheres, one made from inherently non-magnetic polaritonic and the other from a Drude-like material. The polaritonic spheres are responsible for the existence of negative effective magnetic permeability whilst the Drude-like spheres are responsible for negative effective electric permittivity. The resulting negative refractive index structures are truly subwavelength structures with wavelength-to-structure ratio 14:1, which is almost 50% higher than has been previously achieved. Our results are explained in the context of the extended Maxwell-Garnett theory and are reproduced by calculations based on the layer Korringa-Kohn-Rostoker method, an ab initio multiple scattering theory. The role of absorption in the constituent materials is discussed. Effective medium computer F77 code is freely available at http://www.wave-scattering.com. PMID- 21690693 TI - Multiple-scattering theory for out-of-plane propagation of elastic waves in two dimensional phononic crystals. AB - We extend the multiple-scattering theory (MST) to out-of-plane propagating elastic waves in 2D periodical composites by taking into account the full vector character. The formalism for both the band structure calculation and the reflection and transmission coefficient calculation for finite slabs is presented. The latter is based on a double-layer scheme, which obtains the reflection and transmission matrix elements for the multilayer slab from those of a single layer. Being more rapid in both the band structure and the transmission coefficient calculations for out-of-plane propagating elastic waves, our approach especially shows great advantages in handling the systems with mixed solid and fluid components, for which the conventional plane wave approach fails. As the applications of the formalism, we calculate the band structure as well as the transmission coefficients through finite slabs for systems with lead rods in an epoxy host, steel rods in a water host and water rods in a PMMA host. PMID- 21690694 TI - The relationship between interface structure, conformality and perpendicular anisotropy in CoPd multilayers. AB - The relationship between the interface structure and perpendicular anisotropy in sputtered Co/Pd multilayers has been investigated using grazing incidence x-ray scattering and vibrating sample magnetometry. Using fits to a self-affine fractal model of the interfaces, the variation in in-plane correlation length, fractal parameter and conformality has been determined as a function of the number of repeats in the Co/Pd bilayers. As the number of interfaces rises, the roughness becomes predominantly non-conformal and the in-plane length scale associated with the roughness increases as a power law with multilayer thickness. It is suggested that the loss of conformality, characterized by a relatively short out-of-plane correlation length, may be the cause of the reduction in anisotropy energy per interface observed for high numbers of bilayer repeats. There is a weak association between fractal parameter and interface anisotropy; a reduction in the fractal dimension of the interface appears to result in a higher surface anisotropy. PMID- 21690695 TI - Optical study of Yb(3+)/Yb(2+) conversion in CaF(2) crystals. AB - Yb(3+) ions with various site symmetries have been observed in the absorption and emission spectra of Yb(3+):CaF(2) crystals, both gamma-irradiated and annealed in hydrogen. The absorption intensity value is found to be much higher for the gamma irradiated crystal and strongly dependent on the gamma dose. The UV absorption spectra of gamma-irradiated and H(2)-annealed CaF(2):5 at.% Yb(3+) crystals are quite similar. Yb(2+) absorption bands are observed at 360, 315, 271, 260, 227 and 214 nm, which are called A, B, C, D, F and G bands, respectively. For gamma irradiated CaF(2):30 at.% Yb(3+), an additional band at 234 nm can be seen. It is suggested that only a negligible amount of Yb(3+) ions are converted into Yb(2+) under the gamma-irradiation. The presence of Yb(2+) is confirmed by the 565 and 540 nm luminescence under 357 nm excitation. It is also suggested that the excitation in the A, C, D and F absorption bands of Yb(2+) gives rise to photo ionization of Yb(2+) ions and electrons in the conduction band to form the excited Yb(3+) ions which emit IR Yb(3+) luminescence.The UV absorption and emission spectra obtained for gamma-irradiated and H(2)-annealed crystals have different structures. This suggests that different mechanisms are responsible for the creation of Yb(2+) ions. gamma-irradiation favours Yb(2+) isolated centres by reduction of Yb(3+) ions located at Ca(2+) lattice sites, whereas annealing in hydrogen favours Yb(2+) centres neighbouring Yb(3+) ions when a Yb(3+) ion pair captures a Compton electron. Also, gamma-irradiation does not change the position of Yb(3+) ions converted into Yb(2+) in the CaF(2) lattice. In the case of H(2) annealing, a Yb(3+) ion converted to Yb(2+) is shifted to the Ca(2+) position in the lattice. PMID- 21690696 TI - Vibrational properties of nanometric AB(2) ionic clusters. AB - A broad survey of harmonic dynamics in AB(2) clusters with up to N = 3000 atoms is performed using a simple rigid ion model, with ionic radii selected to give rutile as the ground state structure for the corresponding extended crystal. The vibrational density of states is already close to its bulk counterpart for N~500, with characteristic differences due to surfaces, edges and vertices. Two methods are proposed and tested to map the cluster vibrational states onto the rutile crystal phonons. The net distinction between infrared (IR) active and Raman active modes that exists for bulk rutile becomes more and more blurred as the cluster size is reduced. It is found that, in general, the higher the IR activity of the mode, the more this is affected by the system size. IR active modes are found to spread over a wide frequency range for the finite clusters. Simple models based on either a crude confinement constraint or surface pressure arguments fail to reproduce the results of the calculations. The effects of the stoichiometry and dielectric properties of the surrounding medium on the vibrational properties of the clusters are also investigated. PMID- 21690697 TI - Gutzwiller variational theory for the Hubbard model with attractive interaction. AB - We investigate the electronic and superconducting properties of a negative-U Hubbard model. For this purpose we evaluate a recently introduced variational theory based on Gutzwiller-correlated BCS wavefunctions. We find significant differences between our approach and standard BCS theory, especially for the superconducting gap. For small values of |U|, we derive analytical expressions for the order parameter and the superconducting gap which we compare to exact results from perturbation theory. PMID- 21690698 TI - Shot noise enhancement from non-equilibrium plasmons in Luttinger liquid junctions. AB - We consider a quantum wire double junction system with each wire segment described by a spinless Luttinger model, and study theoretically shot noise in this system in the sequential tunnelling regime. We find that the non-equilibrium plasmonic excitations in the central wire segment give rise to qualitatively different behaviour compared to the case with equilibrium plasmons. In particular, shot noise is greatly enhanced by them, and exceeds the Poisson limit. We show that the enhancement can be explained by the emergence of several current-carrying processes, and that the effect disappears if the channels effectively collapse to one because of fast plasmon relaxation processes, for example. PMID- 21690699 TI - Atomic and electronic structure of carbon strings. AB - This paper presents an extensive study of various string and tubular structures formed by carbon atomic chains. Our study is based on first-principles pseudopotential plane wave and finite-temperature ab initio molecular dynamics calculations. Infinite- and finite-length carbon chains exhibit unusual mechanical and electronic properties such as large cohesive energy, axial strength, high conductance, and overall structural stability even at high temperatures. They are suitable for structural and chemical functionalizations. Owing to their flexibility and reactivity they can form linear chain, ring, helix, two-dimensional rectangular and honeycomb grids, three-dimensional cubic networks, and tubular structures. Metal-semiconductor heterostructures and various quantum structures, such as multiple quantum wells and double-barrier resonant tunnelling structures, can be formed from the junctions of metallic carbon and semiconducting BN linear chains. Analysis of atomic and electronic structures of these periodic, finite, and doped structures reveals fundamentally and technologically interesting features, such as structural instabilities and chiral currents. The double covalent bonding of carbon atoms depicted through self-consistent charge density analysis underlies the chemical, mechanical, and electronic properties. PMID- 21690700 TI - In situ observation of the generation and annealing kinetics of E ' centres induced in amorphous SiO(2) by 4.7 eV laser irradiation. AB - The kinetics of E ' centres induced in silica by 4.7 eV laser irradiation was investigated observing in situ their optical absorption band at 5.8 eV. After exposure, the defects decay due to reaction with diffusing molecular hydrogen of radiolytic origin. Hydrogen-related annealing is also active during exposure and competes with the photo-induced generation of the centres until a saturation is reached. The concentrations of E ' and H(2) at saturation are proportional, so indicating that the UV-induced generation processes of the two species are correlated. These results are consistent with a model in which E ' and hydrogen are generated from a common precursor Si-H. PMID- 21690701 TI - On the hot and cold autosolitons in dissipative semiconductor structures. AB - It is experimentally shown that in bulk InSb and Te single crystals, during the formation and excitation of the dissipative structure in the non-equilibrium electron-hole plasma, in the case of a presence of longitudinal autosolitons, the carrier concentration decreases outside the autosolitons, while it increases in the case of transverse autosolitons. The longitudinal autosolitons, forming in the non-equilibrium electron-hole plasma by Joule heating, are considered to be cold, and the transverse autosolitons to be hot. PMID- 21690702 TI - A quasiclassical approach to strongly correlated quantum dots in intense magnetic fields. AB - We present a general quasiclassical description of parabolic many-electron quantum dots in the limit of high magnetic fields. The key points of our approach are the transition to a rotating frame of reference, in order to decouple rotational and vibrational modes, as well as the recognition and inclusion of the role of potential anisotropy felt by the vibrational modes. We are able to obtain the complete wavefunction of quantum dots containing any number of electrons in the Gaussian form, and present results concerning inter-particle correlation and deformation of large quantum dots. PMID- 21690703 TI - Influence of an electric field on the spin polarization in semiconductor superlattices. AB - The influence of a quantizing electric field on the spin polarization is treated for semiconductor superlattices with a Rashba spin-orbit interaction. For weakly coupled superlattices, the quantum kinetic equation for the canonically transformed density matrix is analytically solved. The spin polarization, which is induced by a magnetic field via the Zeeman splitting, exhibits a sharp minimum at the cyclotron-Stark tunnelling resonance. This electric-field-induced resonant tunnelling mixes different spin states and leads to a strong spin depolarization. PMID- 21690704 TI - On the Mott formula for the thermopower of non-interacting electrons in quantum point contacts. AB - We calculate the linear response thermopower S of a quantum point contact using the Landauer formula and therefore assume non-interacting electrons. The purpose of the paper is to compare analytically and numerically the linear thermopower S of non-interacting electrons to the low-temperature approximation, [Formula: see text], and the so-called Mott expression, [Formula: see text], where G(MU,T) is the (temperature-dependent) conductance. This comparison is important, since the Mott formula is often used to detect deviations from single-particle behaviour in the thermopower of a point contact. PMID- 21690705 TI - The negative-U Hubbard model with long-range Coulomb interaction: metal-insulator transition far from half-filling. AB - It is shown that a metal-insulator transition can occur far from half-filling in the negative-U Hubbard model in the presence of long-range repulsive interactions. Specifically, we consider the bcc lattice at an electron concentration of 2/3 and show that a CDW insulating state exists which is energetically favoured over the relevant metallic states. The repulsive interaction plays the same role as it does in stabilizing a Wigner crystal. Despite the absence of Fermi surface nesting, the CDW insulator appears at rather small values of the interaction, preceded by a CDW semimetal at even smaller values. This places severe restrictions on the region of the parameter space where superconductivity may exist. We believe that the model will show similar behaviour for other electron densities and other lattices. PMID- 21690706 TI - Spin-wave softening and Hund's coupling in ferromagnetic manganites. AB - Using a one-orbital model of hole-doped manganites, we show with the help of the Holstein-Primakov transformation that finite Hund's coupling is responsible for the spin-wave softening in the ferromagnetic B-phase manganites. We obtain an analytical result for the spin-wave spectrum for [Formula: see text]. In the limit of infinite Hund's coupling, the spectrum is the conventional nearest neighbour Heisenberg ferromagnetic spin-wave. The o (t/J(H))-order correction is negative and thus accounts for the softening near the zone boundary. PMID- 21690707 TI - Magnetic heterogeneity in electron doped La(1-x)Ca(x)MnO(3) manganites studied by means of electron spin resonance. AB - Electron spin resonance (ESR) has been applied to investigate the magnetic heterogeneity in electron doped La(1-x)Ca(x)MnO(3) (0.80<=x<=0.95). A low field ferromagnetic resonance (FMR) mode is observed for lightly doped compounds (x = 0.90,0.95), signifying the formation of ferromagnetic (FM) spin clusters within the antiferromagnetic G-type AFM phase. The anomalous temperature variations of the resonance field, linewidth and FMR intensity, as well as the observation of thermal cycling effects below T(C), emphasize the non-trivial dynamics of the FM phase, which is attributed to the temperature dependent size evolution of the underlying spin clusters towards canted AFM and FM domains. For heavier electron doping (x = 0.80,0.85), distinct AFM behaviour is evinced in the vicinity of T(N) in the monoclinic C-type AFM phase, characterized by the absence of critical relaxation. Additional weak FMR lines are observed for x = 0.80 and 0.85, whereas a narrow superparamagnetic-like signal is detected for x = 0.95. PMID- 21690708 TI - Stability of ferromagnetism in the half-metallic pnictides and similar compounds: a first-principles study. AB - Based on first-principles electron structure calculations and employing the frozen-magnon approximation, we study the exchange interactions in a series of transition-metal binary alloys crystallizing in the zinc-blende structure and calculate the Curie temperature within both the mean-field approximation and random-phase approximation. We study two Cr compounds, CrAs and CrSe, and four Mn compounds, MnSi, MnGe, MnAs and MnC. MnC, MnSi and MnGe are isovalent to CrAs and MnAs is isoelectronic to CrSe. Ferromagnetism is particular stable for CrAs, MnSi and MnGe: all three compounds show Curie temperatures around 1000 K. On the other hand, CrSe and MnAs show a tendency to antiferromagnetism when compressing the lattice. In MnC the half-metallic gap is located in the majority-spin channel, in contrast to the other five compounds. The large half-metallic gaps, very high Curie temperatures, the stability of the ferromagnetism with respect to the variation of the lattice parameter and a coherent growth on semiconductors make MnSi and CrAs the most promising candidates for use in spintronics devices. PMID- 21690709 TI - Magnetic properties of large area cobalt nanomagnets. AB - We have investigated the magnetization reversal process of cobalt nanomagnetic dot arrays with thickness t in the range from 5 to 90 nm and diameter d in the range from 150 to 250 nm. Large area cobalt nanomagnets were fabricated on Si(100) substrate using deep ultra-violet lithography at 248 nm exposure wavelength. We observed that the magnetic properties of the nanomagnets strongly depend on the thickness and diameter of Co dots due to the effect of the demagnetizing field. The onset of the formation of a magnetization vortex at remanence was found at a phase boundary of thickness and size (e.g., t = 20 nm, d = 250 nm; t = 40 nm, d = 150 nm). Above this boundary, vortex annihilation and nucleation fields markedly varied with the thickness and diameter of the dots. Our experimental results are in good agreement with a simple micromagnetic modelling. PMID- 21690710 TI - Electron paramagnetic resonance study of ZnAl(2)S(4) spinel. AB - Single crystals of ZnAl(2)S(4) spinel doped by paramagnetic Cr(3+) and Mn(2+) ions have been studied by the electron paramagnetic resonance (EPR) technique. The crystal field symmetry around the impurity ions has been determined from the angular behaviour of X-band EPR spectra. The anisotropic EPR signal of the Cr(3+) ions shows splitting into 31 narrow lines due to the super-hyperfine interaction between unpaired electron spins of the chromium centres and nuclear spins of six neighbouring Al(27) (I = 5/2) ions. It has been established that the Cr(3+) ions are located at the octahedral sites in the spinel structure, and the super hyperfine interaction results from a weak covalent bounding with the Al atoms. The EPR signals of the Cr(3+) paramagnetic centres show no fine-structure splitting due to a perfectly cubic symmetry of the local crystal field in the octahedral sites of the ZnAl(2)S(4) spinel structure. A weak EPR signal consisting of six components has been ascribed to the transitions between hyperfine levels of the Mn(2+) (I = 5/2,S = 5/2) ions located at tetrahedral sites, while the fine-structure splitting of each component could be resolved only for special orientations of the sample in the external magnetic field. The parameters of the EPR signal of both chromium and manganese centres indicate that there is an essential covalence in the ZnAl(2)S(4) spinel crystal. Very narrow linewidths (~2 Oe) of the Cr(3+) EPR signal components point to very high homogeneity and quality of the ZnAl(2)S(4) crystals. PMID- 21690711 TI - Soft and central mode behaviour in PbMg(1/3)Nb(2/3)O(3) relaxor ferroelectric. AB - The relaxor ferroelectric PbMg(1/3)Nb(2/3)O(3) (PMN) is investigated by means of dielectric and Fourier transform far infrared transmission spectroscopy in the frequency range from 10 kHz to 15 THz at temperatures between 20 and 900 K using mostly thin films on infrared transparent sapphire substrates. While the thin film relaxors display reduced dielectric permittivity at low frequencies, their high frequency lattice response is shown to be the same as for single crystal/ceramic specimens. In contrast to the results of inelastic neutron scattering, the optic soft mode is found to be underdamped at all temperatures. On heating, the TO1 soft phonon follows the Cochran law with an extrapolated critical temperature of 670 K near to the Burns temperature. Above 450 K the soft mode frequency levels off near 50 cm(-1) and above the Burns temperature it slightly hardens. Central-mode-type dispersion assigned to the dynamics of polar nanoclusters appears below the Burns temperature at frequencies near to but below the soft mode and slows down and broadens dramatically on cooling, finally, below the freezing temperature of 200 K, giving rise to frequency independent losses from the microwave range down. A new explanation of the phonon 'waterfall' effect in inelastic neutron scattering spectra is proposed. PMID- 21690712 TI - Effects of boron addition on a-Si(90)Ge(10):H films obtained by low frequency plasma enhanced chemical vapour deposition. AB - Optical, structural and electric properties of (a-(Si(90)Ge(10))(1-y)B(y):H) thin film alloys, deposited by low frequency plasma enhanced chemical vapour deposition, are presented. The chemical bonding structure has been studied by IR spectroscopy, while the composition was investigated by Raman spectroscopy. A discussion about boron doping effects, in the composition and bonding of samples, is presented. Transport of carriers has been studied by measurement of the conductivity dependence on temperature, which increases from 10(-3) to 10(1) Omega(-1) cm(-1) when the boron content varies from 0 to 50%. Similarly, the activation energy is between 0.62 and 0.19 eV when the doping increases from 0 to 83%. The optical properties have been determined from the film's optical transmission, using Swanepoel's method. It is shown that the optical gap varies from 1.3 to 0.99 eV. PMID- 21690713 TI - Correlated electron-ion dynamics with open boundaries: formalism. AB - We extend a new formalism, which allows correlated electron-ion dynamics to be applied to the problem of open boundary conditions. We implement this at the first moment level (allowing heating of ions by electrons) and observe the expected cooling in the classical part of the ionic kinetic energy and current induced heating in the quantum contribution. The formalism for open boundaries should be easily extended to higher moments of the correlated electron-ion fluctuations. PMID- 21690714 TI - Formation of a metastable phase due to the presence of impurities. AB - Phase transitions into a new phase that is itself metastable are common; instead of the equilibrium phase nucleating, a metastable phase does so. When this occurs the system is sometimes said to be obeying Ostwald's rule. We show how this can happen when there are impurities present that reduce the barrier to heterogeneous nucleation of the metastable phase. We do so by studying a Potts lattice model using Monte Carlo simulation. Thus, which phase forms depends not only on the properties of the different phases but also on the impurities present. Understanding why systems obey Ostwald's rule may therefore require a study of the impurities present. PMID- 21690715 TI - Periodic driving controls random motion of Brownian steppers. AB - We study the motion of Brownian steppers, which are objects moving unidirectionally by discrete steps. A single step is composed of two processes. An activation process describing the random attachment of a fuel molecule is followed by a conformational change of the stepper, leading to the forward motion. Whereas activation is given by a Markovian rate process, the forward motion is defined by a gamma distribution. In this paper we propose a periodic modulation of the fuel concentration in order to control the random motion of the stepper. We show that the driving may reduce the fluctuations of the stepper. Corresponding minima of the diffusion coefficient and maxima of the Peclet number prove the regularity of the motion. PMID- 21690716 TI - Thermal Brownian motor. AB - Recently, a thermal Brownian motor was introduced (Van den Broeck et al 2004 Phys. Rev. Lett. 93 090601), for which an exact microscopic analysis is possible. The purpose of this paper is to review some further properties of this construction, and to discuss in particular specific issues including the relation with macroscopic response and the efficiency at maximum power. PMID- 21690717 TI - One-dimensional optical thermal ratchets. AB - The ability to rectify Brownian forces with spatially extended time-varying light fields creates new opportunities for studying the statistical properties of thermal ratchet models and to exploit these models' interesting and useful properties for practical applications. This paper describes experimental studies of one-dimensional thermal ratchets implemented with the holographic optical trapping technique applied to fluid-borne colloidal spheres. These studies demonstrate the complementary roles of global spatiotemporal symmetry and local dynamics in establishing the direction of ratchet-induced motion and also highlight avenues for future advances in higher-dimensional systems. PMID- 21690718 TI - Saltatory drift in a randomly driven two-wave potential. AB - The dynamics of a classical particle in a one-dimensional, randomly driven potential is analysed both analytically and numerically. The potential considered here is composed of two identical spatially periodic saw-tooth-like components, one of which is externally driven by a random force. We show that under certain conditions the particle may travel against the averaged external force, performing a saltatory unidirectional drift with a constant velocity. Such a behaviour persists also in situations when the external force averages out to zero. We demonstrate that the physics behind this phenomenon stems from a particular behaviour of fluctuations in random force: upon reaching a certain level, random fluctuations exercise a locking function creating points of irreversibility which the particle cannot overpass. Repeated (randomly) in each cycle, this results in a saltatory unidirectional drift. This mechanism resembles the work of an escapement-type device in watches. Considering the overdamped limit, we propose simple analytical estimates for the particle's terminal velocity. PMID- 21690719 TI - Transport by bi-harmonic drives: from harmonic to vibrational mixing. AB - Transport in a one-dimensional symmetric device can be activated by the combination of thermal noise and a bi-harmonic drive. The results of extensive simulations allow us to distinguish between two apparently different bi-harmonic regimes: (i) harmonic mixing, where the two drive frequencies are commensurate but not too high; (ii) vibrational mixing, where one harmonic drive component possesses a high frequency but finite amplitude-to-frequency ratio. A comparison with the earlier theoretical predictions shows that at present the analytical understanding of nonlinear frequency mixing is still not satisfactory. PMID- 21690720 TI - Chaotic dynamics and control of deterministic ratchets. AB - Deterministic ratchets, in the inertial and also in the overdamped limit, have a very complex dynamics, including chaotic motion. This deterministically induced chaos mimics, to some extent, the role of noise, changing, on the other hand, some of the basic properties of thermal ratchets; for example, inertial ratchets can exhibit multiple reversals in the current direction. The direction depends on the amount of friction and inertia, which makes it especially interesting for technological applications such as biological particle separation. We overview in this work different strategies to control the current of inertial ratchets. The control parameters analysed are the strength and frequency of the periodic external force, the strength of the quenched noise that models a non-perfectly periodic potential, and the mass of the particles. Control mechanisms are associated with the fractal nature of the basins of attraction of the mean velocity attractors. The control of the overdamped motion of noninteracting particles in a rocking periodic asymmetric potential is also reviewed. The analysis is focused on synchronization of the motion of the particles with the external sinusoidal driving force. Two cases are considered: a perfect lattice without disorder and a lattice with noncorrelated quenched noise. The amplitude of the driving force and the strength of the quenched noise are used as control parameters. PMID- 21690721 TI - Optimal strategy for controlling transport in inertial Brownian motors. AB - In order to optimize the directed motion of an inertial Brownian motor, we identify the operating conditions that both maximize the motor current and minimize its dispersion. Extensive numerical simulation of an inertial rocked ratchet displays that two quantifiers, namely the energetic efficiency and the Peclet number (or equivalently the Fano factor), suffice to determine the regimes of optimal transport. The effective diffusion of this rocked inertial Brownian motor can be expressed as a generalized fluctuation theorem of the Green-Kubo type. PMID- 21690722 TI - Biasing the random walk of a molecular motor. AB - Biomolecular motors are often described in mechanical terms, with analogy to cars, turbines, judo throws, levers, etc. It is important to remember however that because of their small size, and because of the aqueous environment in which molecular motors move, viscous drag and thermal noise dominate the inertial forces that drive macroscopic machines. The sequence of motions-conformational changes-by which a motor protein moves can best be described as a random walk, with transitions from one state to another occurring by thermal activation over energy barriers. In this paper I will address the question of how this random walk is biased by a non-equilibrium chemical reaction (ATP hydrolysis) so that the motor molecule moves preferentially (with almost unit certainty) in one direction, even when an external force is applied to drive it in the opposite direction. I will also discuss how these 'soft matter' motors can achieve thermodynamic efficiencies of nearly 100%. PMID- 21690723 TI - Optimally controlled optomechanical work cycle for a molecular locomotive. AB - This work seeks to apply the laser optimal control technique to light-driven molecular motors. Taking a recently proposed molecular locomotive as a model system, a control loop is developed specifically for it, and concrete schemes for experimentally closing the loop are devised. A list of unique control objectives is rigorously formulated from the nanomachinery perspective, and corresponding optimization is made feasible by an innovative application of the established technique of closed-loop learning control. The optimization may be pursued for individual laser operational steps as well as for the overall nanolocomotion performance of the entire work cycle. The locomotive optimal control, capable of co-adapting the laser procedure and the periodically driven molecular dynamics, essentially leads to an optimally performing optomechanical work cycle for the locomotive beyond any model-based pre-designed version. These findings reveal a great potential of laser optimally controlled nanowork cycles in the emerging field of nanomachinery. PMID- 21690724 TI - Cycle kinetics, steady state thermodynamics and motors-a paradigm for living matter physics. AB - An integration of the stochastic mathematical models for motor proteins with Hill's steady state thermodynamics yields a rather comprehensive theory for molecular motors as open systems in the nonequilibrium steady state. This theory, a natural extension of Gibbs' approach to isothermal molecular systems in equilibrium, is compared with other existing theories with dissipative structures and dynamics. The theory of molecular motors might be considered as an archetype for studying more complex open biological systems such as biochemical reaction networks inside living cells. PMID- 21690725 TI - Quantifying stochastic resonance: theory versus experiment. AB - We discuss different quantifiers of stochastic resonance (SR) and how far they are mathematically related with each other. Specifically, we address bona fide SR in terms of the areas of the hysteresis loops and of the first peaks in the residence time distributions. We demonstrate a surprisingly good agreement of these two SR quantifiers experimentally for colloidal particles in periodically modulated laser traps. A simple theoretical model is established, which reproduces the experimental observations very well. PMID- 21690726 TI - Statistical determination of the step size of molecular motors. AB - Molecular motors are enzymatic proteins that couple the consumption of chemical energy to mechanical displacement. In order to elucidate the translocation mechanisms of these enzymes, it is of fundamental importance to measure the physical step size. The step size can, in certain instances, be directly measured with single-molecule techniques; however, in the majority of cases individual steps are masked by noise. The step size can nevertheless be obtained from noisy single-molecule records through statistical methods. This analysis is analogous to determining the charge of the electron from current shot noise. We review methods for obtaining the step size based on analysing, in both the time and frequency domains, the variance in position from noisy single-molecule records of motor displacement. Additionally, we demonstrate how similar methods may be applied to measure the step size in bulk kinetic experiments. PMID- 21690727 TI - Vectorial loading of processive motor proteins: implementing a landscape picture. AB - Individual processive molecular motors, of which conventional kinesin is the most studied quantitatively, move along polar molecular tracks and, by exerting a force F = (F(x),F(y),F(z)) on a tether, drag cellular cargoes, in vivo, or spherical beads, in vitro, taking up to hundreds of nanometre-scale steps. From observations of velocities and the dispersion of displacements with time, under measured forces and controlled fuel supply (typically ATP), one may hope to obtain insight into the molecular motions undergone in the individual steps. In the simplest situation, the load force F may be regarded as a scalar resisting force, F(x)<0, acting parallel to the track: however, experiments, originally by Gittes et al (1996 Biophys. J. 70 418), have imposed perpendicular (or vertical) loads, F(z)>0, while more recently Block and co-workers (2002 Biophys. J. 83 491, 2003 Proc. Natl Acad. Sci. USA 100 2351) and Carter and Cross (2005 Nature 435 308) have studied assisting (or reverse) loads, F(x)>0, and also sideways (or transverse) loads [Formula: see text]. We extend previous mechanochemical kinetic models by explicitly implementing a free-energy landscape picture in order to allow for the full vectorial nature of the force F transmitted by the tether. The load-dependence of the various forward and reverse transition rates is embodied in load distribution vectors, [Formula: see text] and [Formula: see text], which relate to substeps of the motor, and in next order, in compliance matrices [Formula: see text] and [Formula: see text]. The approach is applied specifically to discuss the experiments of Howard and co-workers (1996 Biophys. J. 70 418) in which the buckling of partially clamped microtubules was measured under the action of bound kinesin molecules which induced determined perpendicular loads. But in the normal single-bead assay it also proves imperative to allow for F(z)>0: the appropriate analysis for kinesin, suggesting that the motor 'crouches' on binding ATP prior to stepping, is sketched. It yields an expression for the velocity, V (F(x),F(z);[ATP]), needed to address the buckling experiments. PMID- 21690728 TI - Molecular motor traffic in a half-open tube. AB - The traffic of molecular motors which interact through mutual exclusion is studied theoretically for half-open tube-like compartments. These half-open tubes mimic the shapes of axons. The mutual exclusion leads to traffic jams or density plateaus on the filaments. A phase transition is obtained when the motor velocity changes sign. We identify the relevant length scales and characterize the jamming behaviour using both analytical approximations and Monte Carlo simulations of lattice models. PMID- 21690729 TI - Velocity and processivity of helicase unwinding of double-stranded nucleic acids. AB - Helicases are molecular motors which unwind double-stranded nucleic acids (dsNA) in cells. Many helicases move with directional bias on single-stranded (ss) nucleic acids, and couple their directional translocation to strand separation. A model of the coupling between translocation and unwinding uses an interaction potential to represent passive and active helicase mechanisms. A passive helicase must wait for thermal fluctuations to open dsNA base pairs before it can advance and inhibit NA closing. An active helicase directly destabilizes dsNA base pairs, accelerating the opening rate. Here we extend this model to include helicase unbinding from the nucleic-acid strand. The helicase processivity depends on the form of the interaction potential. A passive helicase has a mean attachment time which does not change between ss translocation and ds unwinding, while an active helicase in general shows a decrease in attachment time during unwinding relative to ss translocation. In addition, we describe how helicase unwinding velocity and processivity vary if the base-pair binding free energy is changed. PMID- 21690730 TI - Sequence heterogeneity and the dynamics of molecular motors. AB - The effect of sequence heterogeneity on the dynamics of molecular motors is reviewed and analysed using a set of recently introduced lattice models. First, we review results for the influence of heterogeneous tracks such as a single strand of DNA or RNA on the dynamics of the motors. We stress how the predicted behaviour might be observed experimentally in anomalous drift and diffusion of motors over a wide range of parameters near the stall force and discuss the extreme limit of strongly biased motors with one-way hopping. We then consider the dynamics in an environment containing a variety of different fuels which supply chemical energy for the motor motion, either on a heterogeneous or on a periodic track. The results for motion along a periodic track are relevant to kinesin motors in a solution with a mixture of different nucleotide triphosphate fuel sources. PMID- 21690731 TI - Oscillations in molecular motor assemblies. AB - Autonomous oscillations in biological systems may have a biochemical origin or result from an interplay between force-generating and visco-elastic elements. In molecular motor assemblies the force-generating elements are molecular engines and the visco-elastic elements are stiff cytoskeletal polymers. The physical mechanism leading to oscillations depends on the particular architecture of the assembly. Existing models can be grouped into two distinct categories: systems with a delayed force activation and anomalous force-velocity relations. We discuss these systems within phase plane analysis known from the theory of dynamic systems and by adopting methods from control theory, the Nyquist stability criterion. PMID- 21690732 TI - Force-driven polymerization in cells: actin filaments and focal adhesions. AB - We describe a thermodynamic principle determining the phenomenon of protein self assembly controlled by elastic stresses. This principle is based on the Gibbs Duhem-like relationship between the chemical potential of the aggregated molecules and the stresses produced by forces acting on a protein aggregate. We present two biological systems whose operation can be driven by this principle: actin filament, a polymerizing processive capping by proteins of the formin family, and focal adhesions mediating a mechanical link between the cytoskeleton and extracellular substrates. We describe the major phenomenology of these systems and overview recent models, aimed at understanding the mechanisms of their functioning. PMID- 21690733 TI - Actin-based motility: cooperative symmetry-breaking and phases of motion. AB - A microscopic model is proposed for the motility of a bead driven by the polymerization of actin filaments. The model exhibits a rich spectrum of behaviours similar to those observed in biomimetic experiments, which include spontaneous symmetry-breaking, various regimes of the bead's motion and correlations between the structure of the actin tail which propels the bead and the bead dynamics. The dependences of the dynamical properties (such as symmetry breaking time, regimes of motion, mean velocity, and tail asymmetry) on the physical parameters (the bead radius and viscosity) agree well with the experimental observations. We find that most experimental observations can be reproduced taking into account only one type of filaments interacting with the bead: the detached filaments that push the bead. Our calculations suggest that the analysis of mean characteristics only (velocities, symmetry-breaking times, etc) does not always provide meaningful information about the mechanism of motility. The aim should be to obtain the corresponding distributions, which might be extremely broad and therefore not well represented by their mean only. Our findings suggest a simple coarse-grained description, which captures the main features obtained within the microscopic model. PMID- 21690734 TI - Directed motion emerging from two coupled random processes: translocation of a chain through a membrane nanopore driven by binding proteins. AB - We investigate the translocation of a stiff polymer consisting of M monomers through a nanopore in a membrane, in the presence of binding particles (chaperones) that bind onto the polymer, and partially prevent backsliding of the polymer through the pore. The process is characterized by the rates: k for the polymer to make a diffusive jump through the pore, q for unbinding of a chaperone, and the rate qkappa for binding (with a binding strength kappa); except for the case of no binding kappa = 0 the presence of the chaperones gives rise to an effective force that drives the translocation process. In more detail, we develop a dynamical description of the process in terms of a (2+1)-variable master equation for the probability of having m monomers on the target side of the membrane with n bound chaperones at time t. Emphasis is put on the calculation of the mean first passage time [Formula: see text] as a function of total chain length M. The transfer coefficients in the master equation are determined through detailed balance, and depend on the relative chaperone size lambda and binding strength kappa, as well as the two rate constants k and q. The ratio gamma = q/k between the two rates determines, together with kappa and lambda, three limiting cases, for which analytic results are derived: (i) for the case of slow binding ([Formula: see text]), the motion is purely diffusive, and [Formula: see text] for large M; (ii) for fast binding ([Formula: see text]) but slow unbinding ([Formula: see text]), the motion is, for small chaperones lambda = 1, ratchet-like, and [Formula: see text]; (iii) for the case of fast binding and unbinding dynamics ([Formula: see text] and [Formula: see text]), we perform the adiabatic elimination of the fast variable n, and find that for a very long polymer [Formula: see text], but with a smaller prefactor than for ratchet-like dynamics. We solve the general case numerically as a function of the dimensionless parameters lambda, kappa and gamma, and compare to the three limiting cases. PMID- 21690735 TI - A DNA ring acting as a thermal ratchet. AB - Several DNA nanomotors have been recently constructed in laboratories worldwide. These machines are, however, relatively slow and do not perform continuous rotations. We have recently proposed a rotary DNA nanomachine that shows a continuous rotation with a frequency of 10(2)-10(4) Hz. This motor is a closed DNA ring whose elastic features are tuned such that it can be externally driven via e.g. periodic temperature changes. As a result, the twirling ring propels itself through the fluid with a speed of tens of nanometres up to a few microns per second. The current paper gives a more detailed presentation of this motor and provides a derivation of the low- and high-frequency asymptotic behaviour of thermal ratchets in general. PMID- 21690736 TI - Molecular motors one at a time: FIONA to the rescue. AB - Processive molecular motors act as intracellular transporters of a broad range of cargoes varying from organelles to messenger RNAs. Due to the nanometre range movements and complex dynamics of these motors, highly specialized tools are required to study them, in particular at the single-molecule level. Such tools are what physicists are providing for understanding these biological systems. Fluorescence based real-time localization techniques, with 1 nm spatial resolution and down to 1 ms temporal resolution (FIONA: fluorescence imaging with one-nanometre accuracy), and their applications to a group of molecular motors (myosin V, myosin VI, kinesin, and dynein) are the topics of this paper. In addition to the well established in vitro studies, the recent applications of these techniques to the much more challenging, but also more informative, in vivo realm will be discussed. PMID- 21690737 TI - Chemical and mechanical efficiencies of molecular motors and implications for motor mechanisms. AB - Molecular motors operate in an environment dominated by viscous friction and thermal fluctuations. The chemical reaction in a motor may produce an active force at the reaction site to directly move the motor forward. Alternatively a molecular motor may generate a unidirectional motion by rectifying thermal fluctuations using free energy barriers established in the chemical reaction. The reaction cycle has many occupancy states, each having a different effect on the motor motion. The average effect of the chemical reaction on the motor motion can be characterized by the motor potential profile. The biggest advantage of studying the motor potential profile is that it can be reconstructed from the time series of motor positions measured in single-molecule experiments. In this paper, we use the motor potential profile to express the Stokes efficiency as the product of the chemical efficiency and the mechanical efficiency. We show that both the chemical and mechanical efficiencies are bounded by 100% and, thus, are properly defined efficiencies. We discuss implications of high efficiencies for motor mechanisms: a mechanical efficiency close to 100% implies that the motor potential profile is close to a constant slope; a chemical efficiency close to 100% implies that (i) the chemical transitions are not slower than the mechanical motion and (ii) the equilibrium constant of each chemical transition is close to one. PMID- 21690738 TI - Close-up view of the modifications of fluid membranes due to phospholipase A(2). AB - Phospholipases are a class of molecular machines that are involved in the active remodelling processes of biological membranes. These lipases are interfacially activated enzymes and in the specific case of phospholipase A(2) (PLA(2)) the enzyme catalyses the hydrolysis of di-acyl phospholipids into products of lysolipids and fatty acids, that dramatically change the physical properties of lipid membrane substrates. Using dissipative particle dynamics simulations on a simple coarse-grained bead-spring model of a fluid lipid bilayer in water, the mechanical and diffusive properties of the bilayer in the pure state and after the action of PLA(2) have been calculated. It is found that, in response to hydrolysis, the lipid membrane becomes mechanically softened and the various in plane and trans-bilayer diffusional modes become enhanced. The results compare favourably with available experimental data. PMID- 21690739 TI - Resolving the quantum criticality paradox in O-18 isotopic SrTiO(3). AB - Recently there has been considerable interest in the displacive ferroelectric phase transition near T = 28 K in O-18 isotopic strontium titanate. Special efforts have been made to combine the quantum criticality exponents alpha = -2 (2D) or -3 (3D), delta = 3, and gamma = 2 with the thermodynamic inequalities of Rushbrooke, Griffiths, Widom et al, which become exact equalities under the hypothesis of scaling. In particular, these have led others to the inference that gamma = 2.0 and beta = 1.2 in SrTiO(3). First we show that this is mathematically incorrect and explain why (quantum criticality is exact only at T = 0, whereas the thermodynamic (in)equalities are valid everywhere except T = 0). Second, we show that the inferred values strongly violate a new equality, gamma-2beta = nu(4 d-2eta)>0, we derive from hyperscaling. Third, we show that the existing soft mode frequency data omega(T) from Takesada et al (2006 Phys. Rev. Lett. at press) yield above T(c) (from the Lyddane-Sachs-Teller relationship) gamma = 1.0. Fourth, we remeasure beta from the polarization P(T) and find beta = 0.50 +/- 0.02. Fifth, we remeasure the electric susceptibility and find that it perfectly satisfies the Salje-Wruck-Thomas equation, which requires gamma = 1.0. The important conclusions are: (a) O-18 SrTiO(3) near T(c) is mean-field; (b) the thermodynamic scaling equalities of Rushbrooke, Griffiths et al are mathematically incompatible with quantum criticality theory; (c) a new hyperscaling relationship makes beta = 1.2 and beta>gamma/2 impossible. PMID- 21690740 TI - Dynamics of photoexcited quasiparticles in heavy electron compounds. AB - Femtosecond real-time spectroscopy is an emerging new tool for studying low energy electronic structure in correlated electron systems. Motivated by recent advances in understanding the nature of relaxation phenomena in various correlated electron systems (superconductors, density wave systems) the technique has been applied to heavy electron compounds in comparison with their non magnetic counterparts. While the dynamics in their non-magnetic analogues are similar to the dynamics observed in noble metals (only weak temperature dependences are observed) and can be treated with a simple two-temperature model, the photoexcited carrier dynamics in heavy electron systems show dramatic changes as a function of temperature and excitation level. In particular, below some characteristic temperature the relaxation rate starts to decrease, dropping by more than two orders of magnitude upon cooling down to liquid He temperatures. This behaviour has been consistently observed in various heavy fermion metals as well as Kondo insulators, and is believed to be quite general. In order to account for the experimental observations, two theoretical models have been proposed. The first treats the heavy electron systems as simple metals with very flat electron dispersion near the Fermi level. An electron-phonon thermalization scenario can account for the observed slowing down of the relaxation provided that there exists a mechanism for suppression of electron-phonon scattering when both the initial and final electronic states lie in the region of flat dispersion. An alternative scenario argues that the relaxation dynamics in heavy electron systems are governed by the Rothwarf-Taylor bottleneck, where the dynamics are governed by the presence of a narrow gap in the density of states near the Fermi level. The so-called hybridization gap results from hybridization between localized moments and the conduction electron background. Remarkable agreement with the model suggests that carrier relaxation in a broad class of heavy electron systems (both metals and insulators) is governed by the presence of a (weakly temperature dependent) indirect hybridization gap. Here we review the experimental results on a variety of heavy electron compounds, point out the common features as well as the peculiarities observed in some compounds, and compare the data with existing theoretical models. PMID- 21690741 TI - A theorist in industry: can one fall between two stools and still land on one's feet? AB - Here are reminiscences of some of my interactions with Marshall Stoneham and my career in industry, and particularly of his timely support for my work; and with some illustration of the importance of keeping a firm grasp on basic science to help see the wood from the trees in evaluating new technologies. It is interesting to see that fundamental theory established several decades ago needs to be further developed with some quite radical change of viewpoint when it is applied to new technology; and it is ironic that the impetus for such development of fundamental theory can be technological and commercial, rather than purely academic. PMID- 21690742 TI - From measurements to quantum friction. AB - We present a quantum theory of friction in which interactions with the surrounding medium are described by generalized measurements of the particle's position and momentum. The theory predicts intrinsically quantum contributions to the particle's steady-state energy and to the associated diffusion in position. We discuss the physical significance of these and demonstrate their significance in ensuring a well behaved theory. PMID- 21690743 TI - Nucleation and growth on defect sites: experiment-theory comparison for Pd/MgO(001). AB - It is well established that nucleation of metal clusters on oxide and halide surfaces is typically dominated by defect sites. Rate equation models of defect nucleation have been developed and applied to these systems. By comparing the models with nucleation density experiments, energies for defect trapping, adsorption, surface diffusion and pair binding have been deduced in favourable cases, notably for Pd deposited on Ar-cleaved MgO(001). However, the defects responsible remain largely unknown. More recently, several types of ab initio calculation have been presented of these energies for Pd and related metals on MgO(001) containing several types of surface defect; these calculated values are surveyed, and some are widely divergent. New rate equation nucleation density predictions are presented using the calculated values. Some calculations, for some defect types, are much closer to experiment than others; the singly charged F(s)(+) centre and the neutral divacancy emerge as candidate defects. In these two cases, the Pd/MgO(001) nucleation density predictions agree well with experiment, and the corresponding surface defects deserve to be taken seriously. Energy and entropy values are discussed in the light of differences in calculated charge redistribution between the metal atoms, clusters and (charged) surface defects, and (assumed or calculated) cluster geometries. PMID- 21690744 TI - Modelling the effects of molecular arrangements in polymer light-emitting diodes. AB - In order to understand how to enhance the performance of polymer light-emitting diodes (PLEDs), we used a mesoscopic hopping model, taking into account molecular properties and polymer morphology, to investigate the impact of a number of conjugated polymers and molecular arrangements on the functioning of single-layer devices. The model is applied to devices with the active polymer consisting of poly(p-phenylene vinylene) (PPV) and PPV derivatives with stiff conjugated segments having their long axis oriented parallel and perpendicular to the electrode surfaces as well as randomly oriented, which are three of the molecular arrangements that can be obtained experimentally at microscopic scale in solution processed conjugated polymer thin films. The model provides insight into current efficiency, charge distribution, internal electric field and consequently recombination throughout the polymer layer. We found that the details of molecular arrangement crucially affect the distribution of recombination events far from the electrodes and its field dependence, which has implications for the efficiency of PLEDs. In particular, we found a variation of recombination efficiency in the bulk of uniform ordered polymer films depending on the molecular alignment relative to the electrode surfaces. It turns out that molecular orientation perpendicular to the electrodes increases recombination in the centre of the polymer film as compared to the case of parallel orientation. We conclude that the orientational alignment perpendicular to the electrode surfaces might be a viable strategy towards efficient polymer-based LEDs. PMID- 21690745 TI - Why is diffusion in metals and on metal surfaces universal? AB - Recent experiments that determine mass diffusion D(s) on the close packed surfaces of vacuum compatible metals are reviewed. The results turn out to be approximately universal when scaled to homologous temperatures T/T(m), with T(m) the melting temperature. Similar behaviour for vacancy-driven diffusion in bulk metals has been recognized for decades. Remarkably, the uncertainty with which this scaling occurs is only ~10%. Possible origins of the universality are discussed. PMID- 21690746 TI - Angular-dependent matrix potentials for fast molecular-dynamics simulations of transition metals. AB - The significance of the part played by the angular-dependent components of forces associated with d-d bonding between atoms in a transition metal has long remained a subject of debate. While almost all the large-scale molecular dynamics simulations of collision cascades and radiation damage in transition metals and alloys are currently performed using spherically symmetric many-body potentials, density functional calculations exhibit a highly anisotropic pattern of charge density deformation in and around the core of interstitial atom defects. This paper describes a fast second-order matrix recursion-based algorithm for including effects of angular anisotropy of d-d bonds in a large-scale molecular dynamics simulation. PMID- 21690747 TI - Generalized gradient approximation calculations of the pressure-induced phase transition of YAlO(3) perovskite. AB - An investigation into the high-pressure behaviour of YAlO(3) perovskite was conducted using first-principles calculations based on density functional theory within the generalized gradient approximation. Five candidate phases were considered, Pbnm, Cmcm, I4/mcm, P4/mbm and Pm3m respectively. Our results demonstrate a phase transition of YAlO(3) from Pbnm to I4/mcm at 80 GPa and 0 K, and no tendency to the cubic phase or the post-perovskite phase in our pressure range. This high-pressure behaviour of YAlO(3) is similar to that of CaSiO(3). The pressure dependence of the distortion of AlO(6) octahedra is described by the octahedral tilting and rotation angles, the tolerance factor, the polyhedral volume ratio and the valence charge density. We also summarize the relations between tolerance factor, bulk modulus and radius of the A-site in Pbnm-AAlO(3) systems. PMID- 21690748 TI - Raman and x-ray diffraction investigations on BaMoO(4) under high pressures. AB - X-ray diffraction and Raman scattering studies on the scheelite structured barium molybdate show that, at ~5.8 GPa, it undergoes a first order phase transition to the fergusonite structure (I 2/a,Z = 4)-as also observed in iso-structural barium tungstate. At still higher pressures, barium molybdate transforms to another phase between ~7.2 and 9.5 GPa. On release of pressure from 15.8 GPa, the initial phase is recovered, implying that the observed structural modifications are reversible. PMID- 21690749 TI - The pseudogap and anisotropic thermal expansion in RMn(4)Al(8) (R = La,Y,Lu and Sc). AB - The temperature dependence of the magnetic susceptibility shows a broad maximum at ~550 and 630 K for LuMn(4)Al(8) and ScMn(4)Al(8), respectively, which can be interpreted as due to the presence of a pseudogap in the effective bands as in LaMn(4)Al(8) and YMn(4)Al(8). The anisotropic thermal expansion observed for RMn(4)Al(8) (R = La, Y, Lu and Sc) and the sensitive volume dependence of the gap width throughout the RMn(4)Al(8) system suggest dominant magnetic coupling in Mn spin chains along the c axis. PMID- 21690750 TI - Exciton states in cylindrical nanowires. AB - The exciton ground state and excited state energies are calculated for a model system of an infinitely long cylindrical wire. The effective Coulomb potential between the electron and the hole is studied as function of the wire radius. Within the adiabatic approximation, we obtain 'exact' numerical results for the effective exciton potential and the lowest exciton energy levels which are fitted to simple analytical expressions. Furthermore, we investigated the influence of a magnetic field parallel to the nanowire on the effective potential and the exciton energy. PMID- 21690751 TI - Femtosecond pump-probe measurements of non-radiative relaxation in LiAlO(2):V(3+). AB - We report on time-resolved studies of non-radiative relaxation of V(3+) ions in LiAlO(2) by means of a two-beam, pump-probe saturation experiment performed with the 150 fs pulsed output of a Ti-sapphire laser. Exciting into the vibronically broadened [Formula: see text] transition at 800 nm, a (3)T(1) relaxation time of 199 ps has been measured at 4 K. This value decreases to 82 ps at room temperature, representing a reduction in the lifetime of a factor of 2.5 due to internal-conversion processes. The relative probabilities for non-radiative, phonon-assisted barrier hopping and quantum mechanical tunnelling through the potential barrier to the (3)A(2) ground state have been obtained using Mott's expression, yielding best-fit parameters of W(0) = (5.2 +/- 1) * 10(9) Hz and W(1) = (7.5 +/- 1) * 10(10) Hz for a potential barrier of E(nr) = 530 +/- 50 cm( 1). PMID- 21690752 TI - Luminescence and optical absorption properties of Nd(3+) ions in K-Mg-Al phosphate and fluorophosphate glasses. AB - Absorption and emission properties and fluorescence lifetimes for the [Formula: see text] transition of Nd(3+) ions embedded in P(2)O(5)-K(2)O-MgO-Al(2)O(3) (PKMA)-based glasses modified with AlF(3) and BaF(2) are reported at room temperature. The observed energy levels of Nd(3+) ions in these glasses have been analysed through a semi-empirical free-ion Hamiltonian model. The spin-orbit interaction and net electrostatic interaction experienced by the Nd(3+) ions follow the trend as PKMA>PKMA+AlF(3)> PKMA+BaF(2) glasses. Judd-Ofelt analysis has been carried out on the absorption spectra of 1.0 mol% Nd(3+)-doped glasses to predict the radiative properties for the fluorescent levels of the Nd(3+) ion. Branching ratios and stimulated emission cross-sections show that the [Formula: see text] transition of the glasses under investigation has the potential for laser applications. The Inokuti-Hirayama model has been applied to investigate the non-radiative relaxation of the Nd(3+) ion emitting state, (4)F(3/2). Based on the decay curve analysis, concentration quenching of the (4)F(3/2) emission has been attributed to a cross-relaxation process between the Nd(3+) ions. PMID- 21690753 TI - Nonlinear dielectric properties and temperature stabilization effect near the ferroelectric phase transition in sodium trihydrogen selenite. AB - The ferroelectric phase transition of crystalline sodium trihydrogen selenite has been characterized by domain observations and measurements of electric permittivity, pyroeffect and spontaneous polarization. The first-order character of the phase transition is clearly demonstrated by the phase coexistence and temperature autostabilization. The considerable heating effect at 50 Hz ac field is described. The electric field effect on the temperature variation of the electric permittivity, in the phase transition region, shows a considerable domain structure contribution to the permittivity value. It is demonstrated that the dielectric properties of x- and y-samples can be described by classical dielectric state equations: the set of coefficients has been determined. It is concluded that the x-component of spontaneous polarization plays a predominant role in the phase transition. PMID- 21690754 TI - Paramagnetic defects induced by electron irradiation in barium hollandite ceramics for caesium storage. AB - We have studied by electron paramagnetic resonance the mechanism of defect production by electron irradiation in barium hollandite, a material used for immobilization of radioactive caesium. The irradiation conditions were the closest possible to those occurring in Cs storage waste forms. Three paramagnetic defects were observed, independently of the irradiation conditions. A hole centre (H centre) is attributed to a superoxide ion O(2)(-) originating from hole trapping by interstitial oxygen produced by electron irradiation. An electron centre (E(1) centre) is attributed to a Ti(3+) ion adjacent to the resulting oxygen vacancy. Another electron centre (E(2) centre) is attributed to a Ti(3+) ion in a cation site adjacent to an extra Ba(2+) ion in a neighbouring tunnel, originating from barium displacement by elastic collisions. Comparison of the effects of external irradiations by electrons with the beta-decay of Cs in storage waste forms is discussed. It is concluded that the latter would be dominated by E(1) and H centres rather than E(2) centres. PMID- 21690755 TI - Photoconductivity in AC-driven modulated two-dimensional electron gas in a perpendicular magnetic field. AB - In this work we study the microwave photoconductivity of a two-dimensional electron system (2DES) in the presence of a magnetic field and a two-dimensional modulation (2D). The model includes the microwave and Landau contributions in a non-perturbative exact way; the periodic potential is treated perturbatively. The Landau-Floquet states provide a convenient base with respect to which the lattice potential becomes time dependent, inducing transitions between the Landau-Floquet levels. Based on this formalism, we provide a Kubo-like formula that takes into account the oscillatory Floquet structure of the problem. The total longitudinal conductivity and resistivity exhibit strong oscillations, determined by epsilon = omega/omega(c), with omega the radiation frequency and omega(c) the cyclotron frequency. The oscillations follow a pattern with minima centred at [Formula: see text], and maxima centred at [Formula: see text], where j = 1,2,3..., delta~1/5 is a constant shift and l is the dominant multipole contribution. Negative resistance states (NRSs) develop as the electron mobility and the intensity of the microwave power are increased. These NRSs appear in a narrow window region of values of the lattice parameter (a), around a~l(B), where l(B) is the magnetic length. It is proposed that these phenomena may be observed in artificially fabricated arrays of periodic scatterers at the interface of ultraclean GaAs /Al(x)Ga(1-x)As heterostructures. PMID- 21690756 TI - Lattice instability at phase transitions near the Lifshitz point in proper monoclinic ferroelectrics. AB - The temperature dependence of acoustic properties of the Sn(2)P(2)(Se(x)S(1 x))(6) uniaxial ferroelectric in the vicinity of the Lifshitz point (LP) was investigated by Brillouin spectroscopy and analysed in the Landau-Khalatnikov approximation. An anomalous decrease of the longitudinal hypersound velocity in the paraelectric phase caused by fluctuation effects and crystal structure defects has been found near the LP. Besides this, a small softening of the transverse acoustic phonons is observed, which is due to their linear interaction with the soft optic mode found for incommensurate phase transitions in proper ferroelectrics. The lattice instability analysis of Sn(2)P(2)S(6) and Sn(2)P(2)Se(6) crystals and their solid solutions in a polarizable ion model shows that a possible reason for the absence of a soft acoustic mode is nonorthogonality of the spontaneous polarization vector and modulation wavevector which both lie in the monoclinic symmetry plane. PMID- 21690757 TI - Phonon analysis of the S = 1 quantum spin systems Ni(5)Te(4)O(12)X(2) (X = Cl and Br). AB - We report our investigations of the electrodynamic response of the S = 1 quantum spin systems Ni(5)Te(4)O(12)X(2) (X = Cl and Br), which develop a magnetic ordered state below 30 K. We measure the optical reflectivity over a broad spectral range extending from the far infrared up to the ultraviolet. Besides identifying the electronic interband transitions, we primarily focus our attention on the lattice dynamics, emphasizing the phonon modes spectrum and its temperature dependence. Our findings do not reveal any direct link between possible structural anomalies and the transition into the magnetically ordered state at low temperatures. PMID- 21690758 TI - Electronic structure and elastic properties of Y(n+1)Co(3n+5)B(2n) ([Formula: see text]). AB - We have studied the electronic structure and elastic properties of Y(n+1)Co(3n+5)B(2n) (space group P6/mmm), where n = 1, 2, 3 and [Formula: see text], using ab initio calculations. These ternary borides exhibit a bulk-modulus to-C(44) ratio from 1.6 to 1.9, which is rather unusual for ceramics. This may be understood on the basis of the electronic structure: predominantly covalent-ionic YCo(3)B(2) layers are interleaved with predominantly metallic YCo(5) layers. Covalent-ionic bonding between B and Co may give rise to a large bulk modulus, while weak coupling between the YCo(3)B(2) and YCo(5) layers may be responsible for the low C(44) value. On the basis of the similarity in electronic structure and elasticity data, it is reasonable to assume that the Y(n+1)Co(3n+5)B(2n) compounds investigated here may exhibit similar properties to the so-called MAX phases (Barsoum 2000 Prog. Solid State Chem. 28 201). PMID- 21690759 TI - Electronic structure of carbon nanotori: the roles of curvature, hybridization, and disorder. AB - An efficient and reasonable procedure is proposed for calculating the electronic structure of carbon nanotori in terms of rotational symmetry, within the tight binding formalism. It is shown that the curvature induced sigma(*)-pi(*) hybridization effects play an important role in determining the electronic structure of this novel nanostructure. The energy gap of the carbon nanotorus exhibits a well defined oscillation feature with increasing size of the torus, converging to that of the corresponding infinite nanotube, while its density of states spectrum evolves from the characteristic of a zero dimensional system to that of a quasi-one dimensional system. Effects of disorder on the electronic properties are also discussed. PMID- 21690760 TI - Angular-dependent I-V characteristics in borocarbide superconductor YNi(2)B(2)C. AB - We present angular-dependent current-voltage (I-V) measurements in borocarbide YNi(2)B(2)C single crystals near the vortex-glass irreversible line. External magnetic fields are applied along the angle theta with respect to the c-axis. The nonlinear I-V curves reveal scaling behaviour near the transition. Using the scaling analysis, the relevant critical exponents and vortex transition temperatures are determined for all orientations. The data agrees well with the vortex-glass (VG) model. No evidence was found that supports the existence of a Bose-glass (BG) type of transition. PMID- 21690761 TI - An approach to the Klein-Gordon equation for a dynamic study in ferroelectric materials. AB - Ferroelectric materials such as lithium niobate and lithium tantalate show a non linear hysteresis behaviour, which may be explained by dynamical system analysis. The behaviour of these ferroelectrics is usually explained by domains and domain wall movements. So, the spatial variation of the domain wall was studied previously in order to see its effect on the domain wall width in the context of the Landau-Ginzburg functional. In the present work, both temporal and spatial variations of polarization are considered, and by using the Euler-Lagrange dynamical equation of motion, a Klein-Gordon equation is derived by taking the ferroelectrics as a Hamiltonian system. An interaction has been considered between the nearest neighbour domains, which are stacked sideways in a parallel array with uniform polarization. This interaction term is associated with the spatial term and when this interaction is assumed to be zero, the spatial term vanishes, giving rise to a Duffing oscillator differential equation, which can be also studied by a dynamic system analysis. PMID- 21690762 TI - Spin accumulation on a one-dimensional mesoscopic Rashba ring. AB - The nonequilibrium spin accumulation on a one-dimensional (1D) mesoscopic Rashba ring is investigated with unpolarized current injected through ideal leads. Due to the Rashba spin-orbit (SO) coupling and back-scattering at the interfaces between the leads and the ring, a beating pattern is formed in the fast oscillation of spin accumulation. If every beating period is complete, a plateau is formed, where the variation of spin accumulation with the external voltage is slow, but if new incomplete periods emerge in the envelope function, a transitional region appears. This plateau structure and the beating pattern are related to the tunnelling through spin-dependent resonant states. Because of the Aharonov-Casher (AC) effect, the average spin accumulation oscillates quasi periodically with the Rashba SO coupling and has a series of zeros. In some situations, the direction of the average spin accumulation can be reversed by the external voltage in this 1D Rashba ring. PMID- 21690763 TI - Real-time coverage monitoring of initial oxidation processes on Si(001) by means of surface differential reflectance. AB - Initial oxidation processes on Si(001) have been studied by means of surface differential reflectance (SDR). The time courses of the SDR spectra measured during thermal oxidation at 820 and 920 K allowed two different growth modes, Langmuir-type adsorption and two-dimensional island growth, to be distinguished. No photon energy dependence was observed in the time course of the SDR intensity at either temperature. On the other hand, different uptake curves were observed at different photon energies for oxidation at 300 K. The difference between the oxidation mechanisms at 300 K and at high temperatures was qualitatively apparent from SDR results, because significant photon energy dependence was observed only at 300 K. Possible assignments of the spectral components in the SDR spectra are discussed. PMID- 21690764 TI - Interaction of scanning tunneling microscopy tip with mesoscopic islands at the atomic-scale. AB - Performing atomic-scale simulations, we study the interaction of the scanning tunneling microscopy (STM) tip with mesoscopic islands at zero bias voltage. Our calculations reveal tip-induced shape transitions in Co islands on Cu(100) as the tip approaches the surface. The structure of the islands and of the tip are found to depend strongly on the tip-substrate distance. A significant influence of the tip on atomic diffusion on the top and at the edges of the islands is demonstrated. The size-dependent strain relief in the islands caused by the tip and by the substrate is found to play a key role in atomistic processes on islands. Our results show that, for certain tip-surface separations, the hopping diffusion of Co adatoms on the top of Co islands and the upward mass transport at the edge of the islands can be strongly enhanced. Our findings point out the possibility of manipulating atomic motion on mesoscopic islands using the STM tip. PMID- 21690765 TI - Microscopic insight into properties and electronic instabilities of impurities in cubic and lower symmetry insulators: the influence of pressure. AB - This article reviews the microscopic origin of properties due to transition-metal (TM) impurities, M, in insulator materials. Particular attention is paid to the influence of pressure upon impurity properties. Basic concepts such as the electronic localization in an MX(N) complex, the electrostatic potential, V(R), arising from the rest of the lattice ions or the elastic coupling of the complex to the host lattice are initially exposed. The dependence of optical and magnetic parameters on the impurity-ligand distance, R, in cubic lattices is discussed in a first step. Emphasis is put on the actual origin of the R dependence of 10Dq. Examples revealing that laws for strict cubic symmetry cannot in general be transferred to lower symmetries are later given. This relevant fact is shown to come from allowed hybridizations like nd-(n+1)s as well as the influence of V(R). As a salient feature the different colour in ruby and emerald is stressed to arise from distinct V(R) potentials in Al(2)O(3) and Be(3)Si(6)Al(2)O(18). The last part of this review deals with electronic instabilities. The phenomena associated with the Jahn-Teller (JT) effect in cubic lattices, the origin of the energy barrier among equivalent minima and the existence of coherent tunnelling in systems like MgO:Cu(2+) are discussed. An increase of elastic coupling is pointed out to favour a transition from an elongated to a compressed equilibrium conformation. Interestingly the equilibrium geometry of JT ions in non-cubic lattices is shown to be controlled by mechanisms different to those in cubic systems, V(R) playing again a key role. The relevance of first principles calculations for clarifying the subtle mechanisms behind off-centre instabilities is also pointed out. Examples concern monovalent and divalent TM impurities in lattices with the CaF(2) structure. The instability due to the transition from the ground to an excited state is finally considered. For complexes with significant elastic coupling vibrational frequencies and the Stokes shift are expected to undergo bigger changes through a chemical rather than a hydrostatic pressure. The reduction of Huang-Rhys factors upon increasing the pressure is discussed as well. PMID- 21690766 TI - Nanoferroelectrics: statics and dynamics. AB - A topical review is given of the physics of submicron ferroelectrics, describing the application considerations for memory devices (both as switching memory elements for ferroelectric nonvolatile random access memories, FRAMs, and as passive capacitors for volatile dynamic random access memories, DRAMs) as well as the fundamental physics questions regarding both the thickness and lateral size of present interest. PMID- 21690767 TI - Thermal stabilization of phase and structural state in binary lamellar metallic systems. AB - The paper proposes and describes a physical model of thermally induced processes in binary lamellar systems. The model has been developed for the theoretical explanation of an experimentally revealed fact of thermal stabilization of intermetallic phases on the surface of a lamellar sample. Based on the model we developed an algorithm for calculations and a computer code that operates with three one-phase and two two-phase regions in the binary alloy state diagram. The computational model includes as inputs changes in concentration boundaries for existing phases with change in temperature, as well as arbitrary temperature-time regimes for the thermal treatment of the lamellar system under investigation. Good agreement between the theoretical calculations and Mossbauer investigations of binary lamellar Fe-Be systems has been achieved. PMID- 21690768 TI - Propagation of Nd magnetic phases in Nd/Sm(001) superlattices. AB - The propagation of Nd long range magnetic order in the hexagonal and cubic sublattices has been investigated in double hexagonal compact Nd/Sm(001) superlattices by resonant x-ray magnetic scattering at the Nd L(2) absorption edge. For a superlattice with 3.7 nm thick Sm layers, the magnetic structure of the hexagonal sublattice propagates coherently through several bilayers, whereas the order in the cubic sublattice remains confined to single Nd blocks. For a superlattice with 1.4 nm thick Sm layers, the magnetic structures of both sublattices appear to propagate coherently through the superlattice. This is the first observation (i) of the long range coherent propagation of Nd order on the cubic sites between Nd blocks and (ii) of a different thickness dependence of the propagation of the Nd magnetic phases associated with the hexagonal and cubic sublattices. The propagation of the Nd magnetic order through Sm is interpreted in terms of generalized susceptibility of the Nd conduction electrons. PMID- 21690769 TI - Raman and AFM studies of swift heavy ion irradiated InGaAs/GaAs heterostructures. AB - The effect of swift heavy ion (SHI) irradiation on InGaAs/GaAs heterostructures is studied using Raman spectroscopy and atomic force microscopy (AFM). The structures consist of molecular beam epitaxy (MBE) grown InGaAs layers on GaAs(001), having layer thicknesses of 12, 36, 60 and 96 nm. After irradiation, the GaAs type longitudinal optical (LO) mode blue shifted to higher frequency in thin samples and red shifted towards lower frequency in thick samples. These results are discussed invoking the penetration depth of the probe radiation (lambda = 514.5 nm) in InGaAs. Deconvoluting the Raman spectra of thin samples indicates a compressive strain developed in the substrate, close to the interface upon irradiation. This modification and diffusion of indium across the interface results in an increase of strain and reduction of the defect densities in the InGaAs layer. The variations in FWHM of the Raman modes are discussed in detail. The surface morphology of these heterostructures has been studied by AFM before and after SHI irradiation. These studies, combined with Raman results, help to identify different relaxation regimes. PMID- 21690770 TI - Role of surface roughness in superlubricity. AB - We study the sliding of elastic solids in adhesive contact with flat and rough interfaces. We consider the dependence of the sliding friction on the elastic modulus of the solids. For elastically hard solids with planar surfaces with incommensurate surface structures we observe extremely low friction (superlubricity), which very abruptly increases as the elastic modulus decreases. We show that even a relatively small surface roughness may completely kill the superlubricity state. PMID- 21690771 TI - The magnetic moment of NiO nanoparticles determined by Mossbauer spectroscopy. AB - We have studied the magnetic properties of (57)Fe-doped NiO nanoparticles using Mossbauer spectroscopy and magnetization measurements. Two samples with different degrees of interparticle interaction were studied. In both samples the particles were characterized by high-resolution transmission electron microscopy and x-ray diffraction and found to be plate-shaped. Computer simulations showed that high field Mossbauer data are very sensitive to the size of the uncompensated magnetic moment. From analyses of the Mossbauer spectra we have estimated that the size of the uncompensated magnetic moment is in accordance with a model based on random occupation of surface sites. The analyses of the magnetization data gave larger magnetic moments, but the difference can be explained by the different sensitivity of the two methods to a particle size distribution and by interactions between the particles, which may have a strong influence on the moments estimated from magnetization data. PMID- 21690772 TI - First-principles investigation of magnetism of U films and U(001)(1)/Fe(110)(3) multilayers. AB - The magnetism of surfaces and interfaces can differ strongly from the magnetism of corresponding bulk materials. In the case of actinide systems the study of the surfaces and interfaces is still at the very beginning. In this work, we investigated the electronic and magnetic properties of U films and U(001)(1)/Fe(110)(3) multilayers within the framework of the density functional theory. We report both scalar-relativistic and fully relativistic calculations. The exchange correlation potential was treated in the generalized gradient approximation (GGA). In agreement with previous calculation by Stojic et al (2003 Phys. Rev. B 68 094407) we obtained the surface layer of the U films to be magnetic for the bulk lattice parameter. The dependence of the magnetic properties of the U films on the lattice parameter was studied. It is shown that decreasing distances between U atoms lead to decreasing magnetic moment and finally to the nonmagnetic ground state. The variation of the magnetic moment as a function of the lattice parameter is discontinuous. Using the frozen-magnon approach we evaluated the parameters of the inter-atomic exchange interactions and estimated the Curie temperature. The calculation for U(001)(1)/Fe(110)(3) multilayers showed that the U layer is magnetic with the direction of the U moments opposite to the Fe moments. The importance of the U-Fe hybridization is revealed. Both the intra-layer (U-U, Fe-Fe) and inter-layer (U-Fe) exchange interactions were evaluated. The temperature dependence of the layer magnetizations was studied within the random-phase approximation for the Heisenberg Hamiltonian for classical spins. PMID- 21690773 TI - Interfacial electronic traps at ZnSe/GaAs heterostructures studied by photomodulation Raman scattering. AB - Photomodulation Raman scattering spectroscopy has been employed to study free charge trapping mechanisms at ZnSe-GaAs(001) heterostructure interfaces. This technique reveals that the interfacial region contains predominantly hole traps. Time dependent measurements of the photomodulated Raman scattering intensity show that interfacial charge-trap lifetime is ~30 s for both electrons and holes. PMID- 21690774 TI - First-principles study of TiB(2)(0001) surfaces. AB - The TiB(2)(0001) surfaces are calculated using the first-principles total-energy plane-wave pseudopotential method based on density functional theory. It is found that there are large relaxations within the top three layers for both termination surfaces, and the outermost and second interlayer relaxations for B-terminated surfaces are much larger than those for Ti-terminated surfaces. The charge depletion in the vacuum and the charge accumulations in the interlayer region between the first and second layers reinforces the interlayer Ti-B chemical bonds and reduces the outermost interlayer distance. Simultaneously, the charge accumulation for B-terminated surface is more than that for Ti-terminated surface, and the interlayer Ti-B bonds between the second and third layers are weakened more for the B-terminated surface. The Ti-terminated surface is thermodynamically more favourable in most of the range of MU(B)(slab). PMID- 21690775 TI - The energetics and structure of rutile TiO(2)(110). AB - Density functional theory and a pseudopotential plane wave method are applied to study electronic and structural properties of the defect-free TiO(2)(110) surface. The variations of the surface energy, work function, and atomic displacements are examined for partially and fully relaxed slabs modelling the rutile (110) surface, and consisting of up to 33 atomic layers. Relatively small relaxations of atomic positions in the outermost layers have a strong influence on the calculated surface energies and work functions. The effect of nonequivalence of the odd-even layer terminations is explored. A simple method is proposed which allows one to estimate accurate surface energies for relaxed systems from calculations for partially relaxed slabs. PMID- 21690776 TI - Mean field approach for describing thin film morphology. AB - A mean field approach is employed for determining the kinetics of two main quantities for film morphology, namely the number of islands and the film perimeter. These two quantities have been computed for both coalescence and impingement growth regimes. For each case the growth of two- and three dimensional islands has been considered. In addition, the effect of the spatial correlation among nuclei has been taken into account on the grounds of the hard core interaction. Analytic formulae have been derived for each case. PMID- 21690777 TI - Effects of the chemical bonding on the optical and mechanical properties for germanium carbide films used as antireflection and protection coating of ZnS windows. AB - Germanium carbide (Ge(1-x)C(x)) films have been prepared by RF reactive sputtering a pure Ge(111) target at different flow rate ratios of CH(4)/(CH(4)+Ar) in a CH(4)/Ar mixture discharge, and it has been found that the composition, chemical bonding, optical and mechanical properties of Ge(1-x)C(x) films are remarkably influenced by the flow rate ratio of CH(4)/(CH(4)+Ar). The effects of the chemical bonding on the optical and mechanical properties of the Ge(1-x)C(x) films have been explored. In addition, an antireflection Ge(1-x)C(x) double-layer coating deposited on both sides of the ZnS substrate wafer has been developed for application as an infrared window. It is shown that the transmittance in the wavelength region between 8 and 12 um and the hardness of the ZnS substrate have been significantly improved by the double-layer coating. PMID- 21690778 TI - Clustering of impurity atoms in Co-doped anatase TiO(2) thin films probed with soft x-ray fluorescence. AB - The electronic structure of Co-doped anatase TiO(2) epitaxial thin films grown at different partial oxygen pressures is investigated using soft x-ray emission spectroscopy. The resonantly excited Co L(2,3) x-ray emission spectra of ferromagnetic Ti(0.96)Co(0.04)O(2) samples for the oxygen-deficient regime show that the ratio of integral intensities for Co L(2) and L(3) emission lines significantly decreases with respect to nonmagnetic samples in the oxygen-rich regime. This is due to L(2)L(3)M(4,5) Coster-Kronig transitions and suggests that ferromagnetic Ti(0.96)Co(0.04)O(2) samples have n-type charge carriers and Co-Co bonds between substitutional and interstitial Co atoms are present while Co-O bonds are dominant in nonmagnetic Ti(0.96)Co(0.04)O(2) samples in the oxygen-rich regime. Electronic structure calculations show that the presence of free charge carriers and Co segregation play a crucial role in strong ferromagnetism at room temperature in Co-doped TiO(2). PMID- 21690779 TI - Surface plasmon and electron-hole structures in the excitation spectra of thin films. AB - Surface excitation spectra are calculated, including both collective and single particle modes, and examined in detail. This is achieved by calculating the non local dielectric function epsilon(p)(Q,z,z('),omega) of the thin jellium film within the random phase approximation (RPA) (using local density approximation wavefunctions which actually takes us beyond the RPA), from which we then derive the spectral function. The high precision of the calculations enables us to analyse not only the collective (surface plasmon) modes and their dependence on the film thickness, but also the intra-band electron-hole excitations, and for the first time oscillatory structures due to inter-band transitions. The spectra are then analysed with special attention to their dependence on the slab thickness, and the periodic peaks observed due to single-particle excitations in the spectra. PMID- 21690780 TI - Dynamical effects and ergodicity in the dipolar glass phase: evidence from time domain EPR and phase memory time studies of AsO(4)(4-) in Rb(1 x)(NH(4))(x)H(2)PO(4) (x = 0,0.5,1). AB - Three-pulse electron spin echo envelope modulation (ESEEM), hyperfine sublevel correlation spectroscopy (HYSCORE) investigations and two-pulse electron spin echo (ESE) measurements of phase memory time T(M), were carried out, in the 20 200 K temperature range, on an AsO(4)(4-) paramagnetic probe stabilized in RbH(2)PO(4) (RDP), NH(4)H(2)PO(4) (ADP), and dipolar glass Rb(0.5)(NH(4))(0.5)H(2)PO(4) (RADP). The results obtained on ADP revealed hyperfine interaction of the probe ion with the (14)N of the ammonium ion, the coupling constant satisfying the condition of 'cancellation' at a field of 480 mT. The ammonium ion was found to be in two different sites in ADP, which became indistinguishable on the formation of dipolar glass RADP. These results were confirmed by HYSCORE spectral measurements. The fast Fourier transform (FFT) spectra of three-pulse ESEEM decays have clearly revealed the interaction with protons in the [Formula: see text] bond both in ADP and RDP; and in RADP with an averaged coupling constant. The phase memory times in RADP exhibited strong temperature dependence and were found to be dependent on the nuclear spin quantum number m(I) of (75)As. The temperature dependence of T(M) exhibited a well defined maximum around 90 K, coinciding with the temperature of onset of 'freezing' in Rb(0.5)(NH(4))(0.5)H(2)PO(4). This is symptomatic of dynamic fluctuations in the dipolar glass phase, with onset around 150 K, going through a maximum around 90 K and slowing down on further cooling. These results suggest that in RADP, a dynamical mechanism with progressive slowing down below 90 K is operative in the glass formation. This implies that the RADP system, with x = 0.5, exists in an ergodic relaxor (R)-state in the 20-200 K temperature range wherein every fluctuating monodomain can be viewed as statistically representative of the whole sample. PMID- 21690781 TI - (31)P NMR study of Na(2)CuP(2)O(7): an S = 1/2 two dimensional Heisenberg antiferromagnetic system. AB - The magnetic properties of Na(2)CuP(2)O(7) were investigated by means of (31)P nuclear magnetic resonance (NMR), magnetic susceptibility, and heat capacity measurements. We report the (31)P NMR shift, the spin-lattice [Formula: see text], and spin-spin (1/T(2)) relaxation rate data as a function of temperature T. The temperature dependence of the NMR shift K(T) is well described by the S = 1/2 square lattice Heisenberg antiferromagnetic model with an intraplanar exchange of [Formula: see text] K and a hyperfine coupling A = 3533 +/- 185 Oe /MU(B). The (31)P NMR spectrum was found to broaden abruptly below T~10 K, signifying some kind of transition. However, no anomaly was noticed in the bulk susceptibility data down to 1.8 K. The heat capacity appears to have a weak maximum around 10 K. With decrease in temperature, the spin-lattice relaxation rate 1/T(1) decreases monotonically and appears to agree well with the high temperature series expansion expression for a S = 1/2 2D square lattice. PMID- 21690782 TI - The optimized effective potential with finite temperature. AB - The optimized effective potential (OEP) method provides an additional level of exactness in the computation of electronic structures, e.g. the exact exchange energy can be used. This extra freedom is likely to be important in moving density functional methods beyond traditional approximations such as the local density approximation. We provide a new density-matrix-based derivation of the gradient of the Kohn-Sham energy with respect to the effective potential. This gradient can be used to iteratively minimize the energy in order to find the OEP. Previous work has indicated how this can be done in the zero temperature limit. This paper generalizes the previous results to the finite temperature regime. Equating our gradient to zero gives a finite temperature version of the OEP equation. PMID- 21690783 TI - Re-entrant metallicity and magnetoresistance induced by Ce for Sr substitution in SrCoO(3-delta). AB - Cerium for strontium substitution allows an oxygen deficient perovskite Sr(1 x)Ce(x)CoO(3-delta) to be stabilized with a cerium solubility limited to x<=0.15 (Trofimenko et al 1997 Solid State Ion. 100 183). For these samples, the magnetic properties depend clearly upon the oxygen content: Sr(0.9)Ce(0.1)CoO(2.74) and Sr(0.9)Ce(0.1)CoO(2.83) are weak and strong ferromagnets (T(C) = 160 K), respectively, the maximum ac-magnetic susceptibility of the latter being larger by two orders of magnitude than that of the former. In contrast to other Sr(1 x)L(x)CoO(3-delta) series (L = lanthanide, Y(3) or Th(4+)), the electrical resistivity (rho) behaviour does not simply reflect the magnetic behaviour. For x = 0.10 the re-entrant rho feature becomes more pronounced whereas the ferromagnetic fraction and cobalt oxidation state increase. This unexpected behaviour could be related to the Ce(3+)/Ce(4+) mixed valency, the 4f localized moment of the Ce(3+) cations interacting with the conduction electrons through a Kondo-like mechanism. It is also found that the increase of oxygen vacancies favours the appearance of magnetoresistance at low T, reaching -50% at 5 K in 7 T for the Sr(0.95)Ce(0.05)CoO(2.61) sample prepared in a sealed tube. PMID- 21690784 TI - A high-temperature Raman scattering study of the phase transitions in GaPO(4) and in the AlPO(4)-GaPO(4) system. AB - Al(1-x)Ga(x)PO(4) solid solutions (x = 0.2, 0.3, 0.38, 0.7) and the pure AlPO(4) (x = 0) and GaPO(4) (x = 1) end members with the alpha-quartz-type structure were studied by Raman scattering. An investigation as a function of composition enabled the various modes to be assigned, in particular coupled and decoupled vibrations. The tetrahedral tilting modes, which have been linked to high temperature phase transitions to beta-quartz-type forms, were found to be decoupled. In addition, it is shown that Raman spectroscopy is a powerful technique for determining the gallium content of these solid solutions. Single crystals with x = 0.2, 0.38, and 1.0 (GaPO(4)) were investigated at high temperature. The composition Al(0.8)Ga(0.2)PO(4) was found to exhibit sequential transitions upon heating to the beta-quartz and beta-cristobalite forms at close to 993 K and 1073 K, respectively. Direct alpha-quartz-beta-cristobalite transitions were observed for the two other compositions at close to 1083 K and 1253 K, respectively, upon heating. The spectra of the beta-quartz and beta cristobalite forms indicate the presence of significant disorder. Back transformation to the alpha-quartz-type form occurred readily with a hysteresis of less than 100 K for the composition x = 0.38 and for pure GaPO(4). Rapid cooling was necessary to obtain the metastable alpha-cristobalite form. In contrast, for Al(0.80)Ga(0.20)PO(4), the alpha-cristobalite form was obtained even upon slow cooling. PMID- 21690785 TI - Second harmonic generation of magnetic and dielectric multilayers. AB - The second harmonic generation of antiferromagnetic and dielectric multilayers is analysed by using a conventional nonlinear optics approach and transfer matrix formalism. The theoretical modelling of the multilayers is configured in Voigt geometry in order to observe second harmonic transmission and reflection through the film system, with the assumption of weak nonlinearity and no depletion of incident waves. With these, some of the linear and second harmonic transmissions and reflections are calculated numerically and shown graphically. PMID- 21690786 TI - First-principles calculations of the structural stability and magnetic property of the metastable phases in the equilibrium immiscible Co-Au system. AB - To reveal the energetic sequence of the alloy phases in the Co-Au system, the lattice constants, cohesive energies, and bulk modulus of the fcc Au, hcp Co, the B1, B2, and L1(0) structured CoAu phases, and the D0(3), L1(2), and D0(19) structured Co(3)Au and CoAu(3) phases, respectively, are acquired by first principles calculations within the generalized-gradient approximation (GGA) as well as within the local density approximation (LDA). In addition, the magnetic moment of the Co atom in the studied phases are also calculated. To further examine the structural stability, the elastic constants of the studied phases are calculated and the results suggest that the fcc-type structures could be elastically stable at Co/Au = 1:3, 1:1, and 3:1, whereas the hcp-type structures could be stable at Co/Au = 1:3 and 3:1. Moreover, the spatial valence charge density (SVCD) and spin density of the studied phases are also calculated to clarify the physical origin of the structural stability. It turns out that, in the relatively stable phases, the high SVCDs mostly distribute between the similar atoms, thus forming the attractive covalent bonding to stabilize the respective structures, and that the spin density may also play an important role in influencing the stability of the ferromagnetic metastable phases. PMID- 21690787 TI - Photoemission studies and electronic structure of U(2)T(2)In (T = Ni, Rh, Pt) compounds. AB - The electronic structure of the tetragonal U(2)T(2)In (T = Ni, Rh, Pt) compounds in the paramagnetic phase were studied by x-ray photoelectron spectroscopy (XPS). Both valence band and core level spectra were analysed. The experimental data are compared with the calculations of the density of states using the tight-binding linear muffin-tin orbital method (TB-LMTO) and full-potential local-orbital full relativistic method (FPLO). The calculated data reveal a dominant U 5f electron character for the states near the Fermi level E(F) with a small contribution from U 5d, Ni 3d, Rh 4d, Pt 5d and In 5p states. The XPS valence bands of these compounds are characterized by a sharp peak of the U 5f states near the Fermi level (E(F)) and broad peaks of the Ni 3d, Rh 4d and Pt 5d states at about 2.6, 3.2 and 4.0 eV below E(F), respectively. The small change in the position of the U 5f peak with respect to E(F) is -0.35 eV for T = Ni and -0.15 eV for T = Rh and Pt. A satellite between the Ni 2p(1/2) and Ni 2p(3/2) peaks is visible, suggesting that the Ni 3d band is not completely filled, and the existence of a small induced magnetic moment on the Ni atoms cannot be ruled out. PMID- 21690788 TI - Superlattice induced by electron-beam irradiation in magnetic ferroelectric BiMnO(3). AB - Single-phased polycrystalline BiMnO(3) (hereinafter abbreviated as BMO) ceramic was fabricated via high-pressure solid-state reaction. Microstructure modification of selective grains, signalled by emergence of superlattice diffraction, was scrutinized by means of electron diffraction (ED) combined with high-resolution transmission electron microscopy (HRTEM). It was clearly evidenced that the well established C 2 monoclinic substructure (a = 9.53 A, b = 5.61 A, c = 9.85 A and beta = 110.67 degrees ) of BMO (Atou et al 1999 J. Solid State Chem. 145 639) is metastable and prone to be transformed to a new pseudocubic superstructure (a~b~c~15.8 A and alpha~beta~gamma~90 degrees ) (Yang et al 2006 Phys. Rev. B 73 024114) when irradiated continuously by an electron beam. Magnetization measurement unveiled a unique ferromagnetic phase transition at 103 K, which corroborated our speculation that as-prepared BMO ceramic is free of polymorphism at ambient conditions. PMID- 21690789 TI - Effect of Ga and Mn doping on structural, electrical transport and magnetic properties of Na(0.75)CoO(2). AB - The effects of doping with magnetic Mn ions or nonmagnetic Ga ions on the structural, electrical transport and magnetic properties of Na(0.75)CoO(2) have been investigated. It has been found that the lattice parameter c of the samples increases with Ga or Mn ion doping. Ga doping raises the electrical resistivity of Na(0.75)CoO(2), but the metallic conducting behaviour of the compound has not been influenced. In contrast, 5% Mn doping leads to a metal-insulator transition at low temperatures in Na(0.75)Co(1-y)Mn(y)O(2). The susceptibility of the Ga doped sample shows strong magnetic field dependence, while the susceptibility of the Mn doped samples is not very sensitive to the magnetic field. This work implies that magnetic interaction plays an important role in Na(x)CoO(2). PMID- 21690790 TI - Ab initio study of basal slip in Nb(2)AlC. AB - Using ab initio calculations, we have studied shearing in Nb(2)AlC, where NbC and Al layers are interleaved. The stress-strain analysis of this deformation mode reveals Nb-Al bond breaking, while the Nb-C bond length decreases by 4.1%. Furthermore, there is no evidence for phase transformation during deformation. This is consistent with basal slip and may be understood on the basis of the electronic structure: bands below the Fermi level are responsible for the dd bonding between NbC basal planes and only a single band with a weak dd interaction is not resistant to shearing, while all other bands are unaffected. The Al-Nb bonding character can be described as mainly metallic with weak covalent-ionic contributions. Our study demonstrates that Al layers move with relative ease under shear strain. Phase conservation upon shearing is unusual for carbides and may be due to the layered nature of the phase studied. Here, we describe the electronic origin of basal slip in Nb(2)AlC, the atomic mechanism which enables reversible plasticity in this class of materials. PMID- 21690791 TI - Heat capacity study of relaxors BaTi(0.65)Zr(0.35)O(3) and BaTi(0.60)Zr(0.40)O(3). AB - The heat capacity of two relaxors BaTi(1-x)Zr(x)O(3) (x = 0.35,0.40) was measured using adiabatic calorimetry in the temperature range 100-360 K. The C(p)(T) dependence of both compositions is characterized by the presence of two diffuse anomalies near the Burns temperature T(d) and the temperature of the maximum in permittivity T(m) in the temperature ranges 250-350 K and 120-200 K. The anomalous heat capacity near T(d) was analysed taking into account the distribution of Zr concentration in nanoregions leading to the distribution of their transition temperatures into the polar phase. Excess heat capacity near T(m) was discussed in the framework of the spherical random bond-random field model. The results are compared with the data obtained by the same procedures for PbMg(1/3)Nb(2/3)O(3) studied experimentally earlier. PMID- 21690792 TI - Superconductivity in ternary chalcogenides Bi(2)Ni(3)X(2) (X = S, Se). AB - The physical properties of parkerite and its related compound, Bi(2)Ni(3)X(2) (X = S, Se), were studied. The electrical resistivity of both compounds shows typical metallic behaviour up to 400 K. The resistivity and specific heat measurements at low temperatures reveal that these compounds are superconducting with a transition temperature of ~0.7 K. The upper critical fields at 0 K, MU(0)H(c2)(0), are 95 mT (Bi(2)Ni(3)S(2)) and 75 mT (Bi(2)Ni(3)Se(2)). In the normal state, the electronic specific heat coefficient, gamma, and the Debye temperature, Theta(D), are found to be 11.4 mJ mol(-1) K(-2) and 189 K, respectively, for Bi(2)Ni(3)S(2), and 12.2 mJ mol(-1) K(-2) and 173 K, respectively, for Bi(2)Ni(3)Se(2). From the electronic specific heat in the superconducting temperature range, it was found these compounds belong to the weak-coupling BCS superconductors. PMID- 21690793 TI - Double MITs and magnetoresistance: an intrinsic feature of Ru substituted La(0.67)Ca(0.33)MnO(3). AB - In this paper, we examine the possible influence of extrinsic factors on the electrical and magnetotransport of La(0.67)Ca(0.33)Mn(1-x)Ru(x)O(3) (x<=0.10). Ru substitution results in double metal-insulator transitions (MITs) at T(MI1) and T(MI2), both exhibiting magnetoresistance (MR). No additional magnetic signal corresponding to a second low-temperature maximum (LTM) at T(MI2) could be observed, either in ac susceptibility (chi(')) or in specific heat (C(p)). Typical grain sizes of ~18 000-20 000 nm, as estimated from the scanning electron microscope (SEM) micrographs, are not so small as to warrant an LTM. The absence of additional peaks in the high statistics powder x-ray diffraction (XRD), a linear systematic increase of the unit cell parameters, close matching of the transition temperatures in resistivity, chi(') and C(p) and their linear systematic decrease with x, and an homogeneous distribution of Mn, Ru and O at arbitrarily selected regions within and across the grains exclude chemical inhomogeneity in the samples. The insensitivity of grain boundary MR at 5 K to Ru composition indicates that the grain boundary is not altered to result in an LTM. Oxygen stoichiometry of all the compounds is close to the nominal value of 3. These results not only exclude the extrinsic factors, but also establish that double MITs, both exhibiting MR, are intrinsic to Ru substituted La(0.67)Ca(0.33)MnO(3). PMID- 21690794 TI - Spinodal decomposition in a food colloid-biopolymer mixture: evidence for a linear regime. AB - We investigate phase separation and structural evolution in a complex food colloid (casein micelles) and biopolymer (xanthan) mixture using small-angle light scattering. We demonstrate that phase separation is induced by a depletion mechanism, and that the resulting coexistence curve can be described by osmotic equilibrium theory for mixtures of colloids and polymer chains in a background solvent, taking into account interactions between the polymer chains in the excluded volume limit. We show that the light scattering pattern of an unstable mixture exhibits the typical behaviour of spinodal decomposition, and we are able to confirm the validity of dynamic similarity scaling. We find three distinct regimes (initial or linear, intermediate and transition stage) for the decomposition kinetics that differ in the time dependence of the peak position of the structure factor. In particular we find clear evidence for the existence of an initial linear regime, where the peak position remains constant and the amplitude grows. The existence of spinodal-like decomposition and the validity of universal scaling in the intermediate and transition stages have been found in previous studies of phase separation in attractive colloidal suspensions. However, to our knowledge the initial linear regime has never been observed in colloidal suspensions, and we attribute this at least partly to the effect of hydrodynamic interactions which are efficiently screened in our system due to the fact that the measurements were performed at high polymer concentrations, i.e. in the semi-dilute regime. PMID- 21690795 TI - Model for assembly and gelation of four-armed DNA dendrimers. AB - We introduce and numerically study a model designed to mimic the bulk behaviour of a system composed of single-stranded DNA dendrimers. Complementarity of the base sequences of different strands results in the formation of strong cooperative intermolecular links. We find that in an extremely narrow temperature range the system forms a large-scale, low-density disordered network via a thermo reversible gel transition. By controlling the strand length, the gel transition temperature can be made arbitrarily close to the percolation transition, in contrast with recent model systems of physical gelation. This study helps the understanding of self-assembly in this class of new biomaterials and provides a bridge between physical and chemical gels. PMID- 21690796 TI - Structured surfaces of wide band gap insulators as templates for overgrowth of adsorbates. AB - Surface structures on wide band gap insulators and their use as templates for the growth of adsorbates are reviewed. Surface structures include evaporation structures, vicinal surfaces, facetted surfaces, epitaxial structures, or structures transferred to or induced by the growth of thin films. Most structures have been realized so far on Al(2)O(3) and on alkali halide crystals. The guided growth of adsorbates is discussed, considering the examples of metallic clusters or wires and ordered films of organic molecules. PMID- 21690797 TI - Apparent diameter of carbon nanotubes in scanning tunnelling microscopy measurements. AB - Geometric effects influencing scanning tunnelling microscopy (STM) image formation of single wall carbon nanotubes (SWCNTs) were studied within the framework of a simple model potential. We focused on the geometrical effects which may influence the tunnelling probabilities and lead to discrepancies between the apparent height of the nanotubes measured by STM and their real geometrical diameter. We found that there are two main factors responsible for the underestimation of nanotubes diameter by measuring their height in STM images: (1) the curvature of the nanotube affects the cross sectional shape of the tunnelling channel; (2) the decay rate of tunnelling probabilities inside the tunnel gap increases with increasing curvature of the electrodes. For a nanotube with 1 nm diameter an apparent flattening of about 10%, due to these geometry related effects, is predicted. Furthermore these effects are found to be dependent on the diameter of the tubes and tip-sample distances: an increasing flattening of the tubes is predicted for decreasing tube diameter and increasing tip-sample distance. PMID- 21690798 TI - Local magnetic effects of interface alloying in Fe/Co superlattices. AB - Effects of interface alloying and the thickness dependence of magnetic properties of Fe/Co(001) multilayers have been investigated. The thicknesses of the Fe layers have been varied between two and 14 monolayers while the Co layers have been held constant at 7 ML. From conversion electron Mossbauer spectroscopy (CEMS) measurements and electronic structure calculations it is found that the magnitude of the Fe magnetic hyperfine field is larger close to the interface and smaller in the middle of thick (>=9 ML) Fe layers. For a thinner Fe layer (<=5 ML) the largest field is found in the centre of the Fe layer. By modelling the effects of interface alloying from earlier data for bulk Fe-Co alloys, and comparing with the experimental results, the degree of interface alloying is estimated to be 2-3 ML at each interface. PMID- 21690799 TI - Raman scattering study of GaN nanostructures obtained by bottom-up and top-down approaches. AB - GaN nanocolumnar structures were grown by plasma-assisted molecular beam epitaxy (PAMBE) and also fabricated by electron cyclotron resonance reactive ion etching (ECR-RIE) of a compact GaN film parallel to the [111] direction of the Si(111) substrates. Scanning electron microscopy shows that the nanocolumns fabricated by PAMBE have a length of about 300-500 nm with diameters ranging from 20 to 150 nm while nanowhiskers formed by RIE have diameters of 40-80 nm and a height between 1.4 and 1.7 um. A comparative study of the vibrational spectrum (including optical and interface phonons) of the nanostructures using conventional macro Raman and micro-Raman scattering as well as surface-enhanced Raman scattering is presented. PMID- 21690800 TI - Effect of oxygen content on the transport properties of LaTiO(3+beta/2) thin films. AB - The structural and transport properties of LaTiO(3+beta/2) epitaxial thin films, grown at different oxygen pressures ranging from 6.6 * 10(-4) to 5 Pa, have been investigated. X-ray diffraction peaks of the films shift to lower angles with increasing oxygen pressure, indicative of a variation of the corresponding lattice spacing. All the films show T(2) dependence of resistivity over a large temperature range of ~200 K, suggesting a band-filling-induced metallic Fermi liquid behaviour. Upturns in resistivity have been revealed at low temperatures, which could be ascribed to the Anderson-localization effect caused by the cation vacancies. Furthermore, for the thin films grown at high oxygen pressures of 0.5 and 5 Pa, the dependence of resistivity on temperature shows a maximum at high temperatures. The maximum seems to support the argument that transition between t orbital ordering and disordering plays an important role in dominating transport properties at high temperatures. Carrier density deduced from Hall coefficient increases with the decrease of oxygen content, and shows strong temperature dependence. From the experimental data, it can be asserted that in the LaTiO(3+beta/2) thin films, besides the band filling effect, localization or disorder caused by La and Ti vacancy effects controls the unique transport properties. PMID- 21690801 TI - Low-energy electronic properties of the AB-stacked few-layer graphites. AB - In the presence of a perpendicular electric field, the low-energy electronic properties of the AB-stacked N-layer graphites with layer number N = 2, 3, and 4, respectively, are examined through the tight-binding model. The interlayer interactions, the number of layers, and the field strength are closely related to them. The interlayer interactions can significantly change the energy dispersions and produce new band-edge states. Bi-layer and four-layer graphites are two dimensional semimetals due to a tiny overlap between the valence and conduction bands, while tri-layer graphite is a narrow-gap semiconductor. The electric field affects the low-energy electronic properties: the production of oscillating bands, the cause of subband (anti)crossing, the change in subband spacing, and the increase in band-edge states. Most importantly, the aforementioned effects are revealed completely in the density of states, e.g. the generation of special structures, the shift in peak position, the change in peak height, and the alteration of the band gap. PMID- 21690802 TI - Magnetic anisotropy terms in [110] MBE-grown REFe(2) films involving the strain term epsilon(xy). AB - The magnetic anisotropy parameters in [110] MBE-grown films of REFe(2) (RE, rare earth) compounds are not the same as those in the bulk. This is due to the presence of a shear strain epsilon(xy), frozen-in during crystal growth. In this paper, magnetic anisotropy parameters for [110] MBE-grown REFe(2) films, that directly involve the shear strain epsilon(xy), are presented and discussed. In addition to the usual first-order Callen and Callen term [Formula: see text], there are nine second-order terms, six of which involve cross-terms between epsilon(xy) and the cubic crystal field terms B(4) and B(6). Two of the second order cross-terms are identified as being important: [Formula: see text] and [Formula: see text]. Of these, the rank-two term [Formula: see text] dominates over a large temperature range. It has the same angular dependence as the first order term [Formula: see text], but with a more rapid temperature dependence. The correction at T = 0 K for TbFe(2), DyFe(2), HoFe(2), ErFe(2) and TmFe(2), amounts to ~+9.2%, -13.9%, -11.6%, +14.3%, and 27.1%, respectively. Similar comments are made concerning the rank-four [Formula: see text] term. PMID- 21690803 TI - Effect of the surface polarizability on electrostatic screening in semiconductors. AB - Following the Gibbs approach a general electrostatic model of heterogeneous systems with non-homogeneous interfaces is proposed. The intrinsic surface polarization is taken into account through the introduction of a surface dielectric constant and the electrostatic boundary conditions are generalized as two-dimensional Poisson equations. This model is applied to analysis of the electrostatic potential of charged defects on a semiconductor surface. As a result, a good theoretical fit of the experimental data is obtained. The fitting value of the surface dielectric constant is in good agreement with its theoretical estimation in the framework of the Gibbs approach. PMID- 21690804 TI - Potential barrier for spin-polarized electrons induced by the exchange interaction at the interface in the ferromagnet/semiconductor heterostructure. AB - We have calculated the exchange interaction between electrons in the accumulation electron layer in the semiconductor near the interface and electrons in the ferromagnet in the ferromagnet/semiconductor heterostructure. It is found that the exchange interaction forms the potential barrier for spin-polarized electrons. The barrier height strongly depends on the difference of chemical potentials between the semiconductor and the ferromagnet. The maximum of the potential barrier height on the temperature dependence is due to the existence of localized electron states in the accumulation layer. In the framework of the developed theoretical model, the injection magnetoresistance effect observed in semiconductor/granular film heterostructures with ferromagnetic metal nanoparticles is explained. A spin filter on the base of granular film/semiconductor/granular film heterostructures operated at room temperature is proposed. PMID- 21690805 TI - Characterization of initial halogen adsorption on Si(111) surface by scanning tunnelling microscopy: correlation with optical measurements. AB - Initial adsorption processes of halogen atoms on a Si(111)-(7 * 7) surface were studied by means of scanning tunnelling microscopy (STM). The adsorption sites of halogen atoms were clarified directly with STM, and the results were compared with the partial coverage at each site, estimated previously from surface differential reflectance and thermal desorption spectroscopic analyses. The microscopic geometry of the atomic structure showed a good correspondence with the optical measurements, especially in terms of the density of the reacted sites. Bromine atoms were predominantly adsorbed near already adsorbed bromine, while chlorine atoms were almost randomly adsorbed. Polybromide formation occurred at coverage levels above 0.1 ML. Bromine atoms break the back-bonds of Si adatoms at lower levels of coverage than do chlorine atoms. The reason for the difference in adsorption behaviour between chlorine and bromine is discussed. PMID- 21690806 TI - The origin of the non-monotonic field dependence of the blocking temperature in magnetic nanoparticles. AB - The dependence of the peak temperature (T(P)) of the zero-field-cooled (ZFC) magnetization curves on the field in a magnetic nanoparticle system was studied using a diluted magnetic fluid composed of FePt nanoparticles. We found that the peak temperature increases with increasing applied field below 3 kOe; it then decreases when the applied field is increased further. We attribute the non monotonic field dependence of the peak temperature to the anisotropic energy barrier distribution of the particles and to the slow decrease of high-field magnetization above the blocking temperature. Numerical simulations, based on magnetic dynamics, agree well with our experimental results. PMID- 21690807 TI - Calculation of transition probability for neutralization process of +1 ion based on the Nozieres and Dominicis theory. AB - We investigate the neutralization probability of a +1 ion moving parallel to a metal surface, mainly using the Nozieres and Dominicis theory (ND theory), which was applied to the edge singularities in x-ray absorption and emission spectra in metals. In particular, we focus on the effects due to the sudden disappearance of the image potential in the neutralization process. From the analysis, we found that the neutralization probability is given by [Formula: see text], where D and Gamma are the band width and the gamma function. The factor alpha = 2delta/pi (delta/pi)(2) is given by the phase shift (delta: phase shift on Fermi surface), and the energy difference between the initial and final states, Delta, includes the kinetic energy of the ion and various other phenomenological factors. The singularity caused from the sudden disappearance of the image potential enhances or reduces the neutralization probability depending on the symmetry of atomic orbital of the ion. When the ion velocity is too fast to form an image potential, the neutralization process would proceed without the creation of an image potential, accompanying an excitation of a surface plasmon; as a result of plasmon excitation the ion velocity becomes slower than the plasma frequency because of screening effects. In this paper, we apply the ND theory to the case of slow ion motion and discuss the dynamics. PMID- 21690808 TI - Modulation spectroscopy study of the effects of growth interruptions on the interfaces of GaAsSb/GaAs multiple quantum wells. AB - The effects of growth interruption times combined with Sb exposure of GaAsSb/GaAs multiple quantum wells (MQWs) have been investigated by using phototransmittance (PT), contactless electroreflectance (CER) and wavelength modulated surface photovoltage spectroscopy (WMSPS). The features originated from different portions of the samples, including interband transitions of MQWs, interfaces and GaAs, are observed and identified through a detailed comparison of the obtained spectra and theoretical calculation. A red-shift of the interband transitions and a broader lineshape of the fundamental transition are observed from samples grown under Sb exposure compared to the reference sample grown without interruption. The results can be interpreted in terms of both increases in Sb content and mixing of Sb in the GaAs interface layers. An additional feature has been observed below the GaAs region in the samples with Sb treatment. The probable origin of this additional feature is discussed. PMID- 21690809 TI - Quantum chemical study of the initial surface reactions in atomic layer deposition of TiN on the SiO(2) surface. AB - Cluster calculations employing hybrid density functional theory have been carried out to examine the initial surface reactions in atomic layer deposition (ALD) of TiN thin films on the SiO(2) surface using TiCl(4) and NH(3) as precursors. The potential energy surface (PES) of both half-reactions at different temperatures is presented. The first half-reaction between TiCl(4) with the SiO(2) surface is activated with an activation barrier of 0.78 eV and an exothermicity of 0.38 eV, suggesting that it is thermodynamically favourable. Also, the NH(3) half-reaction begins with the formation of amido complexes by the replacement of Cl atoms by NH(2), which is endothermic by 0.58 eV with a physisorbed HCl state (HCl-PS1). Formation of the amido complexes can be followed by an elimination reaction to form imido complexes, which has a relatively high activation barrier of 2.51 eV. In addition, the effect of the reaction temperature on the Cl impurity concentrations and film growth rate in the ALD process is also discussed. PMID- 21690810 TI - Production and characterization of thin a-C:(H) films for gas permeation barrier functionality against He, CO(2), N(2), O(2) and H(2)O. AB - This work reports on (i) the gas barrier properties of a-C:H films rf-sputtered in Ar-H(2) plasmas from a graphite target on polyethylene terephthalate (PET) and (ii) the influence of the film chemical structure and defect properties on the gas permeability. The intrinsic permeabilities of the films to He, CO(2), O(2), N(2) gases and H(2)O vapour were determined and found to be orders of magnitude lower than that of the bare PET. Indirect evidence was given to a solubility diffusion process as the more probable permeation mechanism, over a gas flow through microdefects or gas transport through nanodefects by a Knudsen diffusion mechanism. The barrier capability of the films was found to scale as the gas molecular diameter within the He, CO(2), O(2) and N(2) series, and inversely with the gas critical temperature for the CO(2), O(2), N(2) and H(2)O series. A correlation between the film Urbach energy, E(u), and the gas permeability was established, except for H(2)O. Such findings further favour a bulk diffusion contributing mechanism to permeation over the gas state transport. Conversely, this E(u)-permeability relation shed more light on the origin of the valence band tailing of the amorphous carbon electron structure. PMID- 21690811 TI - Magnetization dynamics in the normal and superconducting phases of UPd(2)Al(3): II. Inferences on the nodal gap symmetry. AB - This paper provides an analysis of neutron inelastic scattering experiments on single crystals of UPd(2)Al(3). The emphasis is on establishing robust general inferences on the joint antiferromagnetic-superconducting state that characterizes UPd(2)Al(3) at low temperatures. A distinction is drawn between these conclusions and various theoretical perspectives of a more model-sensitive nature that have been raised in the literature. PMID- 21690812 TI - A band structure analysis of the coexistence of superconductivity and magnetism in (Ho,Dy)Ni(2)B(2)C. AB - The phenomenological theory of complex interplay of superconductivity and magnetism in Ho(1-x)Dy(x)Ni(2)B(2)C by Doh et al (1999 Phys. Rev. Lett. 83 5350) is based on the multi-band picture with at least one band which is strongly dominated by Ni 3d-electron orbitals. These orbitals are insensitive to the antiferromagnetic order of the (Ho, Dy) 4f-electrons, found in these alloys. In the present study we show by detailed analysis of the band structure that indeed such a band can be identified. This provides a microscopic justification of the basic idea underlying the phenomenological discussion. PMID- 21690813 TI - Dissipative exciton transfer in donor-bridge-acceptor systems: numerical renormalization group calculation of equilibrium properties. AB - We present a detailed model study of exciton transfer processes in donor-bridge acceptor (DBA) systems. Using a model which includes the intermolecular Coulomb interaction and the coupling to a dissipative environment we calculate the phase diagram, the absorption spectrum as well as dynamic equilibrium properties with the numerical renormalization group. This method is non-perturbative and therefore allows one to cover the full parameter space, especially the case when the intermolecular Coulomb interaction is of the same order as the coupling to the environment and perturbation theory cannot be applied. For DBA systems with up to six sites we found a transition to the localized phase (self-trapping) depending on the coupling to the dissipative environment. We discuss various criteria which favour delocalized exciton transfer. PMID- 21690814 TI - Magnetic interaction in Co-doped SnO(2) nano-crystal powders. AB - Rutile-type Co-doped SnO(2) nano-crystal powders are prepared by the wet chemical method. The magnetic moment is found to decrease with increasing Co content. There is hysteresis between field cooled (FC) and zero field cooled (ZFC) magnetization when the temperature is below 70 K. These magnetic behaviours represent antiferromagnetic interaction between Co ions. By measuring the magnetization as a function of temperature, the magnetic interaction between Co ions is evaluated qualitatively using the Curie-Weiss law. The value of the effective exchange integral J(1)/k(B) is about -62 K, indicating a very strong antiferromagnetic superexchange interaction between Co ions. PMID- 21690815 TI - Improvement in electrical properties of hafnium and zirconium silicates by postnitriding. AB - Hafnium and zirconium silicate films were deposited on a silicon substrate and the effects of postannealing on their electrical properties were investigated. When the films are postannealed in nitrogen monoxide (NO), the leakage current becomes lower by more than one order of magnitude as compared with that of the as deposited films. The capacitance-voltage (C-V) hysteresis width is also decreased drastically by the NO postannealing. From electron spin resonance spectroscopy, it is indicated that paramagnetic defects at the interface between the film and the substrate are responsible for the leakage current and the C-V hysteresis. It is also indicated by x-ray photoelectron spectroscopy that the postnitridation effectively terminates these interface defects and contributes to the improvement in electrical properties. PMID- 21690816 TI - Vacuum ultraviolet spectroscopy of Ce(3+)-doped SrMgF(4) with superlattice structure. AB - X-ray diffraction of Ce(3+)-doped SrMgF(4) (SMF:Ce) crystals shows a superlattice structure, reflecting the distribution of Ce(3+) polyhedra centres observed in optical experiments. Optical absorption bands and fluorescence bands from the Ce(3+) polyhedra centres overlap in the vacuum ultraviolet (VUV) and ultraviolet (UV) regions, respectively, so that wide pumping and tuning ranges are expected for laser operation. The SMF:Ce crystals, as well as the isomorphous BaMgF(4), are candidates for a tunable laser gain material with nonlinear properties. The optical absorption, excitation, and fluorescence bands observed in the SMF:Ce crystals at low temperatures are ascribed to five distinct fluorescent centres. Three centres have well-known Ce(3+) optical characters, for example, fluorescence with double peaks separated by 2000 cm(-1) and five resolved absorption/excitation bands. These centres are assigned to Ce(3+)-polyhedra classified by weak and strong crystal fields as a consequence of the superlattice structure. The other two fluorescence bands observed in the visible region have 1.5-2 times larger linewidths than those of the former three bands. These bands are interpreted as optical transitions from complexes consisting of Ce(3+) and one or two electrons trapped at a vacancy of the nearest neighbour F(-) ligand ions. PMID- 21690817 TI - Influence of Ce-H bonding on the physical properties of the hydrides CeCoSiH(1.0) and CeCoGeH(1.0). AB - The hydrides CeCoSiH(1.0) and CeCoGeH(1.0) which crystallize like the parent antiferromagnetic compounds CeCoSi and CeCoGe in the tetragonal CeFeSi-type structure, have been investigated by specific heat and thermoelectric power measurements and (1)H nuclear magnetic resonance (NMR). CeCoSiH(1.0) is an intermediate valence compound whereas CeCoGeH(1.0) can be considered as a nearly trivalent cerium compound. This behaviour is corroborated by the occurrence of a slight broadening of the (1)H NMR signal in the sequence [Formula: see text]. The band structure calculations performed on these hydrides reveal the existence of strong bonding Ce-H interaction, found to be larger in CeCoSiH(1.0) than in CeCoGeH(1.0). PMID- 21690818 TI - Visible photoluminescence from chain Tl(4)In(3)GaSe(8) semiconductor. AB - The emission band spectra of undoped Tl(4)In(3)GaSe(8) chain crystals have been studied in the 16-300 K temperature range and the 535-740 nm wavelength range. Two visible photoluminescence bands centred at 589 and 633 nm were observed at T = 16 K. Variations of both bands have been investigated over a wide range of laser excitation intensity (3 * 10(-4)-1.2 W cm(-2)). Radiative transitions with energies of 2.10 and 1.96 eV from two upper conduction bands to two shallow acceptor levels (0.03 and 0.01 eV), respectively, were suggested as being responsible for the observed bands in Tl(4)In(3)GaSe(8) crystal, which is non transparent in the visible range. PMID- 21690819 TI - Spectral properties and energy transfer in PbWO(4) co-doped with Cr(3+) and F(-). AB - A Cr(3+), F(-)-co-doped PbWO(4) crystal was grown by the Czochralski method and its spectroscopic properties were investigated. In addition to the intrinsic luminescence of PbWO(4), the sample showed [Formula: see text] radiation of Cr(3+) excited by x-radiation or UV-vis light. This indicated that the Cr(3+) is submitted to a strong crystal field and a doping mechanism is hereby proposed that Cr(3+) replaces W(6+) with the cooperation of F(-). The reabsorption and resonant energy transfer mechanisms from host to Cr(3+) were studied. As a result, the PbWO(4) intrinsic emission was intensively suppressed and the [Formula: see text] luminescence increased when excited by x-radiation compared to excitation by UV-vis light, and the decay constants of PbWO(4) host scintillation reduce. The significant [Formula: see text] luminescence of this material may be of interest for further application. PMID- 21690820 TI - Tuning the magnetic properties of GaAs:Mn/MnAs hybrids via the MnAs cluster shape. AB - We report a systematic study of ferromagnetic resonance in granular GaAs:Mn/MnAs hybrids grown on GaAs(001) substrates by metal-organic vapour-phase epitaxy. The ferromagnetic resonance of the MnAs clusters can be resolved at all temperatures below T(c). An additional broad absorption is observed below 60 K and is ascribed to localized charge carriers of the GaAs:Mn matrix. The anisotropy of the MnAs ferromagnetic resonance field originates from the magneto-crystalline field and demagnetization effects of the ferromagnetic MnAs clusters embedded in the GaAs:Mn matrix. Its temperature dependence basically scales with magnetization. Comparison of the observed angular dependence of the resonance field with model calculations yields the preferential orientation and shape of the clusters formed in hybrid layers of different thickness (150-1000 nm) grown otherwise at the same growth conditions. The hexagonal axes of the MnAs clusters are oriented along the four cubic GaAs space diagonals. Thin layers contain lens-shaped MnAs clusters close to the surface, whereas thick layers also contain spherical clusters in the bulk of the layer. The magnetic properties of the hexagonal MnAs clusters can be tuned by a controlled variation of the cluster shape. PMID- 21690821 TI - Magnetotransport properties depending on the nanostructure of Fe(3)O(4) nanowires. AB - We have studied the magnetic behaviour of Fe(3)O(4) nanowires (NWs) with two different diameter ranges, above 150 nm and below 60 nm, made by electrodeposition techniques into a polymeric template. The nanowires were characterized using various techniques, in particular Mossbauer and thermoelectrical power measurements. The stoichiometric distribution of Fe cations showed clearly the presence of the magnetite inverse spinel electronic structure. Structural analysis performed using high-resolution transmission electron microscopy revealed two kinds of nanowire morphologies depending on the size. For nanowires above 150 nm in diameter, a contiguous network of well-bound nanoparticles was obtained. Instead, with a diameter of 60 nm, a polycrystalline structure was observed. The largest nanowires presented a magnetoresistance (MR) greater than 10%, whereas the thinner nanowires had almost none. PMID- 21690822 TI - Gradient equivalent crystal theory. AB - This paper presents an extension of the formalism of equivalent crystal theory (ECT) by introducing an electron density gradient term so that the total model density becomes a more accurate representation of the real local density. Specifically, we allow for the electron density around a lattice site to have directionality, in addition to an average value, as assumed in ECT. We propose that an atom senses its neighbouring density as a weighted sum-the weights given by the its own electronic probability. As a benchmark, the method is used to compute vacancy migration energy curves of iron. These energies are in good agreement with previously published results. PMID- 21690823 TI - Magnetic properties of epitaxial Heusler alloy (Co(2/3)Fe(1/3))(3+x)Si(1 x)/GaAs(001) hybrid structures. AB - The magnetic properties of full Heusler alloy (Co(2/3)Fe(1/3))(3+x)Si(1 x)/GaAs(001) hybrid structures grown by molecular beam epitaxy have been investigated. The magnetic moment, the coercive field and the in-plane magnetic anisotropy of (Co(2/3)Fe(1/3))(3+x)Si(1-x) films with various Si compositions ( 0.46<=x<=1) are discussed. The increase in amount of Si results in a significant reduction in the cubic magnetocrystalline anisotropy constant |K(1)(eff)|. K(1)(eff) changes sign and saturates near the stoichiometric composition of Co(2)FeSi and the easy axis of the cubic component changes from the [Formula: see text] direction to the [Formula: see text] direction accordingly. However, due to the presence of a dominating uniaxial magnetic anisotropy component, the easy axis of magnetization in total is shifted to the [110] direction. The saturation magnetization of stoichiometric Co(2)FeSi films turned out to be 1250 +/- 120 emu cm(-3), being equivalent to 6.1 +/- 0.57 (MU(B)/formula unit (fu)). The relatively close value of magnetic moment to the theoretically expected integer value (6 MU(B)) suggests that Co(2)FeSi films could be half-metallic ferromagnets. PMID- 21690824 TI - Direct observation of the microstructure in cluster glass compound U(2)IrSi(3). AB - We have examined the structure of a U(2)IrSi(3) compound exhibiting ferromagnetic cluster glass behaviour by means of electron diffraction observation and high resolution electron microscopy. The structure of U(2)IrSi(3) has been proposed as a new one of the U(2)RuSi(3)-type with a short-range ordered double stacking sequence of the U(2)RuSi(3)-type structure along the c-axis, and long-range ordered atomic arrangements in the a-b plane. The calculated patterns reproduce the characteristic features of observed electron patterns well. The Fourier filtered high-resolution image clearly exhibits a micro-domain structure, which is considered to relate directly to the origin of the observed cluster glass behaviour in U(2)IrSi(3). PMID- 21690825 TI - Metal-insulator transition in Nd(1-x)Eu(x)NiO(3) compounds. AB - Polycrystalline Nd(1-x)Eu(x)NiO(3) (0<=x<=0.5) compounds were synthesized in order to investigate the character of the metal-insulator (MI) phase transition in this series. Samples were prepared through the sol-gel route and subjected to heat treatments at ~1000 degrees C under oxygen pressures as high as 80 bar. X ray diffraction (XRD) and neutron powder diffraction (NPD), electrical resistivity rho(T), and magnetization M(T) measurements were performed on these compounds. The NPD and XRD results indicated that the samples crystallize in an orthorhombic distorted perovskite structure, space group Pbnm. The analysis of the structural parameters revealed a sudden and small expansion of ~0.2% of the unit cell volume when electronic localization occurs. This expansion was attributed to a small increase of ~0.003 A of the average Ni-O distance and a simultaneous decrease of ~-0.5 degrees of the Ni-O-Ni superexchange angle. The rho(T) measurements revealed a MI transition occurring at temperatures ranging from T(MI)~193 to 336 K for samples with x = 0 and 0.50, respectively. These measurements also show a large thermal hysteresis in NdNiO(3) during heating and cooling processes, suggesting a first-order character of the phase transition at T(MI). The width of this thermal hysteresis was found to decrease appreciably for the sample Nd(0.7)Eu(0.3)NiO(3). The results indicate that cation disorder associated with increasing substitution of Nd by Eu is responsible for changing the first-order character of the transition in NdNiO(3). PMID- 21690826 TI - Scintillation properties and anomalous Ce(3+) emission of Cs(2)NaREBr(6):Ce(3+) (RE = La,Y,Lu). AB - We report the optical and scintillation properties of the Ce(3+)-doped bromoelpasolites Cs(2)NaREBr(6) (RE = La,Y,Lu). The gamma-ray scintillation light yield of these materials varies from 6000 to 17 000 photons per MeV absorbed gamma-ray energy. At room temperature (RT), the gamma-ray scintillation decay curves for all compounds show a fast component of 61 ns, whereas the intrinsic Ce(3+) decay time is 30 ns. The scintillation mechanism in elpasolites is addressed. In Cs(2)NaLuBr(6):Ce(3+) and Cs(2)NaYBr(6):Ce(3+), we observe for the first time the so-called Ce(3+) anomalous emission in bromide compounds. This emission previously observed for chloride compounds is an ultrafast Ce(3+) emission with a selective excitation mechanism. The decay time of the anomalous emission at 10 K in bromide compounds (~7.80 ns) is faster than that in chloride compounds (~9.90 ns). Two bands of the anomalous emission are resolved for the first time. The mechanism behind this emission is discussed. PMID- 21690827 TI - Angular momentum of sound pulses. AB - Three-dimensionally localized acoustic pulses in an isotropic fluid medium necessarily have transverse components of momentum density. Those with an azimuthal component of momentum density can carry angular momentum. The component of total pulse angular momentum along the direction of the total momentum is an invariant (constant in time and independent of choice of origin). The pulse energy, momentum and angular momentum are evaluated analytically for a family of localized solutions of the wave equation. In the limit where the pulses have many oscillations within their spatial extent ([Formula: see text], where k is the wavenumber and a determines the size of a pulse), the energy, momentum and angular momentum are consistent with a multiphonon representation of the pulse, each phonon having energy [Formula: see text], momentum [Formula: see text] and angular momentum [Formula: see text] (with integer m). PMID- 21690828 TI - Electron spin echo of Cu(2+) in the triglycine sulfate crystal family (TGS, TGSe, TGFB): electron spin-lattice relaxation, Debye temperature and spin-phonon coupling. AB - The electron spin-lattice relaxation of Cu(2+) has been studied by the electron spin echo technique in the temperature range 4.2-115 K in triglycine sulfate (TGS) family crystals. Assuming that the relaxation is due to Raman relaxation processes the Debye temperature Theta(D) was determined as 190 K for TGS, 168 K for triglycine selenate (TGSe) and 179 K for triglycine fluoroberyllate (TGFB). We also calculated the Theta(D) values from the sound velocities derived from available elastic constants. The elastic Debye temperatures were found as 348 K for TGS, 288 K for TGSe and 372 K for TGFB. The results shown good agreement with specific heat data for TGS. The elastic Theta(D) are considerably larger than those determined from the Raman spin-lattice relaxation. The possible reasons for this discrepancy are discussed. We propose to use a modified expression describing two-phonon Raman relaxation with a single variable only (Theta(D)) after elimination of the sound velocity. Moreover, we show that the relaxation data can be fitted using the elastic Debye temperature value as a constant with an additional relaxation process contributing at low temperatures. This mechanism can be related to a local mode of the Cu(2+) defect in the host lattice. Electron paramagnetic resonance g-factors and hyperfine splitting were analysed in terms of the molecular orbital theory and the d-orbital energies and covalency factors of the Cu(gly)(2) complexes were found. Using the structural data and calculated orbital energies the spin-phonon coupling matrix element of the second-order Raman process was calculated as 553 cm(-1) for TGS, 742 cm(-1) for TGSe and 569 cm(-1) for TGFB. PMID- 21690829 TI - Renormalization in charged colloids: non-monotonic behaviour with the surface charge. AB - The static structure factor S(q) is measured for a set of deionized latex dispersions with different numbers of ionizable surface groups per particle and similar diameters. For a given volume fraction, the height of the main peak of S(q), which is a direct measure of the spatial ordering of latex particles, does not increase monotonically with the number of ionizable groups. This behaviour cannot be described using the classical renormalization scheme based on the cell model. We analyse our experimental data using a renormalization model based on the jellium approximation, which predicts the weakening of the spatial order for moderate and large particle charges. PMID- 21690830 TI - Phase behaviour of hard spheres confined between parallel hard plates: manipulation of colloidal crystal structures by confinement. AB - We study the phase behaviour of hard spheres confined between two parallel hard plates using extensive computer simulations. We determine the full equilibrium phase diagram for arbitrary densities and plate separations from one to five hard sphere diameters using free energy calculations. We find a first-order fluid solid transition, which corresponds to either capillary freezing or melting depending on the plate separation. The coexisting solid phase consists of crystalline layers with either triangular ([Formula: see text]) or square ([Formula: see text]) symmetry. Increasing the plate separation, we find a sequence of crystal structures from [Formula: see text], where n is the number of crystal layers, in agreement with experiments on colloids. At high densities, the transition between square to triangular phases is interrupted by intermediate structures, e.g., prism, buckled, and rhombic phases. PMID- 21690831 TI - Compaction of DNA on nanoscale three-dimensional templates. AB - There exist several important in vivo examples, where a DNA chain is compacted on interacting with nanoscale objects such as proteins, thereby forming complexes with a well defined molecular architecture. One of the well known manifestations of such a natural organization of a semi-flexible DNA chain on nanoscale objects is hierarchical DNA molecule assembly into a chromosome, which is mediated by cationic histone proteins at the first stages of compaction. The biological importance of this and other natural nanostructural organizations of the DNA molecule has inspired many theoretical and numerical studies to gain physical insight into this problem. On the other hand, the experimental model systems containing DNA and nanoobjects, which are important to extend our knowledge beyond natural systems, were almost unavailable until the last decade. Accelerating progress in nanoscale chemistry and materials science has brought about various nanoscale three-dimensional structures such as dendrimers, nanoparticles, and nanotubes, and thus has provided a basis for the next important step in creating novel DNA-containing nanostructures, modelling of natural DNA compaction, and verification of accumulated theoretical predictions on the interaction between DNA and nanoscale templates. This review is written to highlight this early stage of nano-inspired progress and it is focused on physico chemical and biophysical experimental investigations as well as theoretical and numerical studies dedicated to the compaction of DNA on nanoscale three dimensional templates. PMID- 21690832 TI - Inverse lyotropic phases of lipids and membrane curvature. AB - In recent years it has become evident that many biological functions and processes are associated with the adoption by cellular membranes of complex geometries, at least locally. In this paper, we initially discuss the range of self-assembled structures that lipids, the building blocks of biological membranes, may form, focusing specifically on the inverse lyotropic phases of negative interfacial mean curvature. We describe the roles of curvature elasticity and packing frustration in controlling the stability of these inverse phases, and the experimental determination of the spontaneous curvature and the curvature elastic parameters. We discuss how the lyotropic phase behaviour can be tuned by the addition of compounds such as long-chain alkanes, which can relieve packing frustration. The latter section of the paper elaborates further on the structure, geometric properties, and stability of the inverse bicontinuous cubic phases. PMID- 21690833 TI - Nonideal mixing in multicomponent lipid/detergent systems. AB - A detailed understanding of the mixing properties of membranes to which detergents are added is mandatory for improving the application and interpretation of detergent based protein or lipid extraction assays. For Triton X-100 (TX-100), a nonionic detergent frequently used in the process of solubilizing and purifying membrane proteins and lipids, we present here a detailed study of the mixing properties of binary and ternary lipid mixtures by means of high-sensitivity isothermal titration calorimetry (ITC). To this end the partitioning thermodynamics of TX-100 molecules from the aqueous phase to lipid bilayers composed of various mixtures of 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC), egg-sphingomyelin (SM), and cholesterol (cho) are characterized. Composition-dependent partition coefficients K are analysed within the frame of a thermodynamic model developed to describe nonideal mixing in multicomponent lipid/detergent systems. The results imply that POPC, fluid SM, and TX-100 mix almost ideally (nonideality parameters |rho(alpha/beta)|3.8). This is by no means a rare case in the studies of real fluids and colloidal suspensions. We show that the deficiency is resolved in the modified version of the SCOZA with multi-SCPPS tails. As a demonstration, we present some numerical results for z(2) = 8.0. PMID- 21690871 TI - Atomic structure of Al(89)La(6)Ni(5) metallic glass. AB - Atomic structures of amorphous Al(89)La(6)Ni(5), prepared by single-roller melt spinning, and pre-annealed at 493 and 588 K for 1 h, were characterized by differential scanning calorimetry, x-ray diffraction with a large wavevector transfer value, La L(3)-edge and Ni K-edge x-ray absorption fine structure and the reverse Monte Carlo technique. In the as-prepared amorphous alloy, our study reveals that the Ni-Al distance is 2.38 +/- 0.02 A coupled with a coordination number as low as 6.2. The Al-Al distance was found to be ~4.5% shorter than the nominal atomic diameter of aluminium and the coordination number to be ~39% less than expected from the dense random packing model. Crystallization of the Al(89)La(6)Ni(5) glassy alloy at high temperatures can be described as follows: [amorphous alloy] [Formula: see text] [fcc-Al] + [bcc-(AlLa)] + residual amorphous [Formula: see text] [fcc-Al] + [o-Al(3)Ni ] + [o-La(3)Al(11) ]. PMID- 21690872 TI - Probing field-induced submolecular motions in a ferroelectric liquid crystal mixture with time-resolved two-dimensional infrared spectroscopy. AB - Time-resolved two-dimensional infrared (2D IR) spectroscopy has been applied to analyse an electro-optic switching ferroelectric liquid crystal (FLC) mixture. The 2D IR correlation technique clearly shows that the Goldstone mode in the SmC* phase is suppressed by an applied electric field. The field-induced reorientation process initiates from intramolecular motions in about 10 us. The intramolecular motions then propagate from the molecular segments attached to the same molecule to those fragments on other surrounding molecules. During the field-induced switching, the IR dipoles undergo a collective reorientation but with hindered rotation about the molecular long axis. PMID- 21690873 TI - Oscillating bubble as a sensor of low frequency electro-acoustic signals in electrolytes. AB - Small air-bubble deformations, caused by electro-acoustic signals generated in electrolytic solutions have been detected by angle-modulation of a refracted He Ne laser beam. The observed electromechanical resonance at low frequency, below 100 Hz, has proved to be directly related to the oscillations of characteristic ion-doped water structures when driven by an external electric field. The presence of structure-breaking or structure-making ions modifies the water structure, which varies the mechanical losses of the oscillating system and can be registered as changes in the width of the observed resonance curves. PMID- 21690874 TI - A study of the magnetic resonance in a single-crystal Ni(50.47)Mn(28.17)Ga(21.36) alloy. AB - The single-crystal non-stoichiometric magnetic shape memory alloy Ni(1-x y)Mn(x)Ga(y) with x = 0.2817, y = 0.2136 is studied using magnetic resonance spectroscopy: ferromagnetic resonance (FMR) and conduction electron spin resonance (CESR). The temperature dependence of the integral intensity, the resonance field and the line-width are measured across the wide temperature interval from 4.2 to 570 K. Three phase transformations are found in this alloy: [Formula: see text] with a Curie temperature of 360 K, austenite-to-martensite (direct with T(ms) = 312 K and reverse with T(as) = 313 K), and a transformation at T = 45 K, suggestive of the spin-glass state. The angular dependence of the FMR signals is measured in the martensitic and austenitic states before and after the martensite-to-austenite transition. The experimental data are used for determination of the magnetization M(m) and anisotropy parameters K(1) and K(2) in the martensitic state. The obtained coefficient K(2) is determined to be not small and, moreover, it is comparable with K(1). The temperature dependence of the resonance signals is also investigated at temperatures significantly higher than T(C), where FMR was transformed to CESR. In the paramagnetic austenitic state (above T(C)) the alloy reveals an extremely intensive signal of CESR, which suggests a high concentration of conduction electrons and correlates with the large value of the magnetic-field-induced strain observed in the alloys of such composition. The temperature dependence of the skin layer depth is found from the sharp decay of the CESR signal with temperature, which is related to the disappearing large magnetic resistance after transformation to the paramagnetic state. PMID- 21690875 TI - Magnetocaloric effect in potassium doped lanthanum manganite perovskites prepared by a pyrophoric method. AB - The magnetocaloric effect (MCE) in fine grained perovskite manganites of the type La(1-x)K(x)MnO(3) (0T>T(c2) = 79 K), the dynamics of the lattice change considerably and the parameters characterizing several vibrational modes display anomalous temperature dependences. The second phase transition occurring at T(c2) is marked by an important and discontinuous change of the spectral shape, indicating that a considerable lattice distortion is involved. PMID- 21690887 TI - Raman scattering study of beta-Sr(0.33)V(2)O(5) in charge disordered and ordered phase. AB - Polarized Raman spectra of the strontium vanadium oxide bronze beta Sr(0.33)V(2)O(5) are measured in the temperature range between 300 and 77 K. The charge ordering phase transition at about 165 K is characterized by the appearance of new Raman-active modes in the spectra, as well as through an abrupt change of the phonon frequencies and dampings. The Raman scattering spectra of beta-Sr(0.33)V(2)O(5) in the charge disordered phase are in apparent resemblance with those of alpha'-NaV(2)O(5), which suggests that there is a similar charge phonon dynamics in both compounds. We also suggest that the electrons are delocalized into V(1)-O(5)-V(3) orbitals in the mixed valence state of beta Sr(0.33)V(2)O(5). PMID- 21690888 TI - Rubber friction: role of the flash temperature. AB - When a rubber block is sliding on a hard rough substrate, the substrate asperities will exert time-dependent deformations of the rubber surface resulting in viscoelastic energy dissipation in the rubber, which gives a contribution to the sliding friction. Most surfaces of solids have roughness on many different length scales, and when calculating the friction force it is necessary to include the viscoelastic deformations on all length scales. The energy dissipation will result in local heating of the rubber. Since the viscoelastic properties of rubber-like materials are extremely strongly temperature dependent, it is necessary to include the local temperature increase in the analysis. At very low sliding velocity the temperature increase is negligible because of heat diffusion, but already for velocities of order 10(-2) m s(-1) the local heating may be very important. Here I study the influence of the local heating on the rubber friction, and I show that in a typical case the temperature increase results in a decrease in rubber friction with increasing sliding velocity for v>0.01 m s(-1). This may result in stick-slip instabilities, and is of crucial importance in many practical applications, e.g. for tyre-road friction and in particular for ABS braking systems. PMID- 21690889 TI - Dendritic solidification and characterization of a succinonitrile-acetone alloy. AB - A succinonitrile (SCN)-3.6 wt% acetone (ACE) alloy was unidirectionally solidified with a constant temperature gradient G = 5.7 K mm(-1) in the growth rate ranges V = 6.5-113 um s(-1) and a constant growth rate V = 6.5 um s(-1) in the temperature gradient ranges G = 3.5-5.7 K mm(-1). The primary dendrite arm spacings, secondary dendrite arm spacings, dendrite tip radius and mushy zone depth were measured as a function of growth rate and temperature gradient. Theoretical models for the dendrite arm spacing and tip radius have been compared with the experimental observations, and a comparison of our results with the current theoretical models and previous experimental results has also been made. The stability constant (sigma) for this alloy system was measured and this result was compared with various similar organic transparent alloys. PMID- 21690890 TI - Voltage noise of current-driven vortices in disordered Josephson junction arrays. AB - Dynamical phenomena of moving vortices and voltage noise spectra are studied in disordered Josephson junction arrays (JJAs). The plastic motion of vortices, smectic flow, and moving Bragg glass phases are separated by two dynamic melting transitions driven by current. From the voltage noise spectra of moving vortices, it is found that the driving current plays an important role in the melting of pinning vortices glass and ordering of moving vortices. The features of noise spectra obtained in the disordered JJA model have been observed recently in the high-temperature superconductor Bi(2)Sr(2)CaCu(2)O(y) near the first-order melting transition, indicating that both of them are related to each other. PMID- 21690891 TI - Determination of the absorption cross section of dopants in lithium niobate crystals. AB - A method is presented to acquire the absorption cross sections of dopants in photorefractive lithium niobate crystals utilizing doubly doped samples. The absorption cross section of one dopant must be well known. By illumination with ultraviolet light, electrons are transferred from one centre to the other. From the changes of the absorption spectra, the absorption cross section of the centre under investigation is deduced. For a wavelength of lambda = 577 nm the absorption cross section of Mn(3+) is determined by this method to be sigma(Mn(3+),577 nm)(o) = (9.2 +/- 1.3) * 10(-19) cm(2) for ordinarily polarized light. The described method can be adapted to other dopants and host materials. PMID- 21690892 TI - Absolute rate of thermal desorption from first-principles simulation. AB - We present a technique for computing by first-principles simulation the absolute desorption rate gamma of adsorbate molecules from a surface for any coverage and temperature. The technique is valid when the thermal equilibration rate on the surface is faster than gamma, and is based on an exact expression for gamma in terms of the difference of non-configurational chemical potentials of gas-phase and adsorbed molecules. This difference is expressed in terms of a potential of mean force, which is computed by constrained first-principles molecular dynamics. The technique is applied to D(2)O on the MgO(001) surface at low coverage, using the generalized gradient approximation (GGA) for exchange-correlation energy. Comparisons with experimental temperature programmed desorption data allow an assessment of the accuracy of the GGA for the adsorption of D(2)O on MgO(001). PMID- 21690893 TI - Observations of distinct atomic packings in Cu-Nb metallic glasses synthesized by ion beam mixing. AB - The structural transformation and disordered atomic packing of metallic glasses in a selected immiscible system at equilibrium, i.e. the Cu-Nb system characterized by a positive heat of formation, are studied using ion beam mixing far from equilibrium. The experimental results indicate that the Cu-Nb metallic glasses could be formed in a composition range from 30 to 85 at.% of Nb and that the Cu-Nb metallic glasses are formed through two different structural phase transition routes, i.e. from the Nb-based body centred cubic and face centred cubic solid solutions, in which the two distinct predominant atomic packings have icosahedral and icositetrahedral orderings, respectively, revealed by the respective diffraction patterns. These observations not only help in formulating a general atomic structural spectrum for the binary metallic glasses, but also suggest an important concept of structural heredity: that the crystalline structure of the constituent metals plays a decisive role in determining the atomic structure of the resultant metallic glasses. PMID- 21690894 TI - Glasses under high pressure: a link to colloidal science? AB - Whether glass formation is mainly driven by temperature or by pressure is an open question that is now being addressed in high-pressure experiments. Here we propose that some insight into these questions could be gained by comparing in a suitable manner with colloidal glass-transition data. Based on such a comparison, a cross-over is found from the usual regime of molecular glasses (where temperature effects tend to be important) to a very-high-pressure regime (where density effects eventually take over). This regime is found to be located at pressures higher than commonly studied in today's glass-transition experiments. PMID- 21690895 TI - State dependent particle dynamics in liquid alkali metals. AB - This paper gives a survey of the particle dynamics in the liquid alkali metals observed with inelastic x-ray and neutron scattering experiments. Liquid rubidium and sodium are chosen as model fluids to represent the behaviour of this group of fluids. In the dense metallic monatomic melt the microscopic dynamics is characterized by collective excitations similar to those in the corresponding solids. The collective particle behaviour is appropriately described using a memory function formalism with two relaxation channels for the density correlation. A similar behaviour is found for the single particle motion where again two relaxation mechanisms are needed to accurately reproduce the experimental findings. Special emphasis is given to the density dependence of the particle dynamics. An interesting issue in liquid metals is the metal to non metal transition, which is observed if the fluid is sufficiently expanded with increasing temperature and pressure. This causes distinct variations in the interparticle interactions, which feed back onto the motional behaviour. The associated variations in structure and dynamics are reflected in the shape of the scattering laws. The experimentally observed features are discussed and compared with simple models and with the results from computer simulations. PMID- 21690896 TI - Measurement of solid-liquid interfacial energy in the pyrene succinonitrile monotectic system. AB - The equilibrated grain boundary groove shapes for solid pyrene (PY) in equilibrium with the PY succinonitrile (SCN) monotectic liquid were directly observed. From the observed grain boundary groove shapes, the Gibbs-Thomson coefficient and solid-liquid interfacial energy for solid PY in equilibrium with the PY SCN monotectic liquid have been determined to be (8.72 +/- 0.87) * 10(-8) K m and (21.9 +/- 3.28) * 10(-3) J m(-2) with the present numerical method and Gibbs-Thomson equation, respectively. The grain boundary energy of the solid PY phase has been determined to be (42.84 +/- 7.28) * 10(-3) J m(-2) from the observed grain boundary groove shapes. Thermal conductivities of solid and liquid phases for PY-2.5 mol% SCN alloy and pure PY have also been measured. PMID- 21690897 TI - Density functional theory for hard-sphere mixtures: the White Bear version mark II. AB - In the spirit of the White Bear version of fundamental measure theory we derive a new density functional for hard-sphere mixtures which is based on a recent mixture extension of the Carnahan-Starling equation of state. In addition to the capability to predict inhomogeneous density distributions very accurately, like the original White Bear version, the new functional improves upon consistency with an exact scaled-particle theory relation in the case of the pure fluid. We examine consistency in detail within the context of morphological thermodynamics. Interestingly, for the pure fluid the degree of consistency of the new version is not only higher than for the original White Bear version but also higher than for Rosenfeld's original fundamental measure theory. PMID- 21690898 TI - Glass transition on the development of a hydrogen-bond network in nano-channel ice, and subsequent phase transitions of the ordering of hydrogen atom positions within the network in [Co(H(2)bim)(3)](TMA).20H(2)O. AB - Low-temperature thermal properties of crystalline [Co(H(2)bim)(3)](TMA).20H(2)O were studied by adiabatic calorimetry, where H(2)bim is 2,2'-biimidazole, TMA is 1,3,5-benzene tricarboxylic acid, and 20H(2)O represents the water forming nano channel in the crystal. A glass transition was observed at T(g) = 107 K. It was discussed as a freezing-in phenomenon of a small number of water molecules remaining partially disordered in their positional arrangement. The possibility that some defects really remain in the hydrogen-bond network of channel water was mentioned. Two subsequent phase transitions were observed at 54.8 and 59 K. These were interpreted as being of a (super-structural commensurate)-incommensurate (normal commensurate) type in the heating direction with respect to the hydrogen atom positions as referred to the periodicity of the hydrogen-bond network. The transition entropy was evaluated to be 0.65 J K(-1)(H(2)O-mol)(-1) as a total of the two, indicating that the disorder of the hydrogen atoms is present only in part of the water molecules of the channel. Based on the fact that the excess heat capacity due to the equilibrium phase transition is observed down to 35-40 K, the relaxation time for the rearrangement of the hydrogen-atom positions was assumed at the longest to be 1 ks at 35 K. This indicates that the activation energy of the rearrangement amounts to at most 13 kJ mol(-1) and that the transfer of Bjerrum defects is attributed to the rearrangement. PMID- 21690899 TI - Neutron diffraction studies of electrolytes in null water: a direct determination of the first hydration zone of ions. AB - A method of neutron diffraction is described which enables the first hydration zone of small cations to be investigated at atomic resolution. It is shown that the cation structures of aqueous electrolyte solutions dissolved in a 'null' mixture of water (H(2)O) and heavy water (D(2)O), can be calculated directly from the neutron scattering patterns. The hitherto unresolved structure around Na(+) is used to illustrate the power of this method, the accuracy of which is discussed formally with reference to standard nickel chloride solutions. Possible applications to a variety of other systems and at different thermodynamic states are proposed. PMID- 21690900 TI - Critical point dewetting observed in the liquid Se-Tl system on a quartz substrate. AB - We have studied the wetting phenomena of the liquid Se-Tl system on a quartz substrate by photography and ellipsometry, and found that a thin layer of the Se rich liquid phase intrudes between the Tl-rich liquid phase and the quartz substrate in the temperature region far below the critical temperature. Surprisingly, neither the Se-rich nor the Tl-rich wetting film is formed near the critical temperature, indicating the critical point dewetting. In addition, we found that the temperature difference between the surface and the bulk liquid induces the transition between the wetting and non-wetting states. In order to interpret the observation, we constructed a model grand potential, incorporating the long-range interaction, the temperature difference and gravity. From this analysis, it is suggested that the combination of the long-range force and gravity plays an important role in overcoming the critical point wetting phenomena. PMID- 21690901 TI - The existence of a plastic phase and a solid-liquid dynamical bistability region in small fullerene cluster (C(60))(7): molecular dynamics simulation. AB - We have simulated (by the molecular dymanics (MD) method) the dynamics of fullerenes (C(60)) in an extremely small cluster composed of only as many as seven C(60) molecules. The interaction is taken to be the full 60-site pairwise additive Lennard-Jones (LJ) potential which generates both translational and anisotropic rotational motions of each molecule. Our atomically detailed MD simulations discover the plastic phase (no translations but active reorientations of fullerenes) at low energies (temperatures) of the (C(60))(7) cluster. We provide the in-depth evidence of the dynamical solid-liquid bistability region in the investigated cluster. Moreover, we confirm the existence of the liquid phase in (C(60))(7), the finding of Gallego et al (1999 Phys. Rev. Lett. 83 5258) obtained earlier on the basis of Girifalco's model, which assumes single-site only and spherically symmetrical interaction between C(60) molecules. We have calculated the translational and angular velocity autocorrelation functions and estimated the diffusion coefficient of fullerene in the liquid phase. PMID- 21690902 TI - Universal and non-universal features of the dynamic susceptibility of supercooled liquids. AB - We discuss the dynamics of the glass-forming liquids glycerol, propylene carbonate, and benzophenone, as revealed in their dielectric behaviour and in depolarized light scattering (DLS) data. Above the melting point, the liquids exhibit two-step stretched relaxation behaviour typical of 'glassy dynamics' at all attainable temperatures [Formula: see text]. There is no sign of a transition to exponential relaxation; rather, the stretching depends only weakly on the temperature. The spectral change, in first approximation, amounts to shifting the alpha-relaxation peak with the temperature. This behaviour is in contrast with the temperature-dependent spectral shapes observed in the low-temperature state close to T(g). Analysing corresponding dielectric spectroscopic (DS) data for comparisons, similar tendencies are observed, except that the stretching parameters are different. Below a certain temperature in glycerol, the tail of the excess wing, which is clearly pronounced in the DS data, appears also in the DLS spectra, with the same ratio of the wing exponents in DLS versus DS as of the stretching exponents at higher T. In propylene carbonate, the presence of a wing in the DLS data is not immediately obvious. However, its low-temperature DLS spectra are fully compatible with an empirical model for the temperature dependent spectral shape that adequately describes the DS data of both materials and includes the wing. We were however unable to reconcile the DLS results of glycerol with this model. This, together with the pronounced difference in DLS and DS spectral widths of glycerol, cast doubts over the general validity of universal scaling procedures for different techniques. PMID- 21690903 TI - Study of damage in ion-irradiated alpha-SiC by optical spectroscopy. AB - UV-visible absorption and Raman scattering spectroscopy were used to investigate the effects of 4 MeV Xe-ion and 4 MeV Au-ion irradiations on alpha-SiC single crystals. The evolution of transmission spectra upon irradiation evidences an increase of the optical absorption. The optical band-gap energy decreases versus fluence, which is linked to band-gap closure attributed to the creation of localized states into the forbidden energy band. A strong effect of the irradiation temperature is observed as a result of dynamic annealing enhanced by the temperature increase. The Urbach energy increases versus fluence due to disorder accumulation in the damaged layer. Comparison of Urbach energy and disorder parameters extracted from Raman spectra shows that the Urbach energy is sensitive to the disorder induced by the accumulation of point defects. PMID- 21690904 TI - Energy levels and hypersensitivity of samarium(III) in the elpasolite Cs(2)NaSmCl(6). AB - Electronic absorption spectra of neat Cs(2)NaSmCl(6) between 300 and 10 K are reported for the spectral region between 900 and 40 000 cm(-1). Interpretation of the intricate vibronic structure enables 91 conclusive and 45 tentative Kramers doublet and quartet energy levels of the 4f(5) ion Sm(3+) in this system to be assigned. Configuration interaction assisted crystal field calculations employing the diagonalization of the combined 4f(5) and 4f(4)6p(1) matrices fit the energy levels better than the conventional 4f(5) crystal field calculation. The 4f(5) calculation is more accurate, however, than for the Pr(3+) and Nd(3+) elpasolite systems, showing the greater importance of intra- rather than inter-configuration interaction for the more complex electronic structure of Sm(3+). The experimental dataset generally shows agreement with that from two-photon excitation spectroscopy and the differences are highlighted. The intensity of structure at and near the zero phonon line of the hypersensitive infrared [Formula: see text] absorption transition increases relative to the intensity of the vibronic sideband when z is increased in Cs(2)NaSm(Cl(1-z)Br(z))(6). This is attributed to the introduction of electric dipole transition intensity into the pure electronic transition by lowering the site-symmetry of SmCl(6)(3-), or by the presence of SmCl(5)Br(3-). PMID- 21690905 TI - Electronic topological and structural transitions in AuGa(2) under pressure. AB - Results of electronic band structure calculations, electrical resistance, thermoelectric power (TEP), and x-ray diffraction measurements, under pressure carried out on AuGa(2) to investigate its anomalous behaviour are reported. The first principles electronic band structure calculations confirm that a flat band close to the Fermi level along the Gamma-X direction of the Brillouin zone is responsible for the unusual behaviour of AuGa(2). In synchrotron-based high pressure x-ray diffraction measurements, it is observed to undergo a structural phase transition above 7 GPa. The TEP variation with pressure and the P-V data up to 7 GPa transformed to the universal equation of state (UEOS) indicate the existence of an electronic topological transition (ETT) near 3.2 GPa. Consistent with this, in electronic structure calculations carried out at reduced sample volume corresponding to 4 GPa, it is seen that the flat band crosses the Fermi level. The structure above 7 GPa is a distortion of the CaF(2) phase. This structure continuously evolves with increasing pressure. The continuous variation of electrical resistance across the transition is consistent with this. PMID- 21690906 TI - Reentrant behaviour in Y-doped Ho(0.75)Y(0.25)Ni(2)B(2)C single crystal. AB - The transport and superconducting properties of Ho(0.75)Y(0.25)Ni(2)B(2)C single crystals were investigated to study the competing effects between superconductivity and magnetism. The superconducting transition temperature T(c) is 7.6 K, determined from the resistivity transition; meanwhile, the commensurate antiferromagnetic (AFM) transition occurs at T(N) of 3.9 K, which is lower than that of pure HoNi(2)B(2)C (T(N)~5 K). Ho(0.75)Y(0.25)Ni(2)B(2)C reentered into the normal state at T(m) (T(N)rho(b)(T), exhibit an activated dependence, similar in both directions and characterized by a nearest-neighbour hopping followed by a variable-range hopping (VRH) regime when T is decreased. A detailed analysis of rho(T) demonstrates that conventional d-dimensional models of the hopping conductivity, based on the electron localization in disordered systems, cannot interpret the experimental data at any d = 1, 2 or 3, leading to the mismatch of the characteristic energies and/or unphysical values of the characteristic length scales. The observed VRH conductivity law on the low-temperature interval, lnrho~T(-3/4), contradicts the models above, too. Instead, it is found that this law can be substantiated and the correct matching of the energy and length scales can be found within a model of Fogler et al (2004 Phys. Rev. B 69 035413) by treating CaCu(2)O(3) as a three-dimensional array of quasi-one-dimensional electron crystals. PMID- 21690908 TI - The physical properties of oxygen-deficient perovskite SrPbO(3-delta). AB - The transport properties of oxygen-deficient perovskite SrPbO(3-delta) with mixed lead valency were investigated down to 4.2 K. The small delta-value (0.059), determined from iodometry, is due to the inert lone pair Pb(2+) that does not enjoy regular octahedral coordination in spite of collective electron behaviour. The oxide exhibits a temperature-independent magnetic susceptibility consistent with itinerant electrons. The sign of carriers like polarons is that of n-type conductivity coming from the balance charge via oxygen extraction. The thermal variation of conductivity and thermopower reveal the existence of an energy gap. The conduction mechanism occurs by polaron hopping in conformity with small activation energy. The metal-insulating transition seems to be of Anderson type, resulting from the disorder of oxygen vacancies. At low temperature, the conductivity was fitted to a variable range hopping [Formula: see text]. A comparison with SrSnO(3) will be reported. The covalency of Sn-O raises the antibonding conduction state of 5s parentage and increases the forbidden gap from 1.78 to 3.30 eV. PMID- 21690909 TI - Ultrasonic study of the charge mismatch effect in charge-ordered (Nd(0.75)Na(0.25))(x)(Nd(0.5)Ca(0.5))(1-x)MnO(3). AB - The resistivity, magnetization and ultrasonic properties of charge-ordered polycrystalline (Nd(0.75)Na(0.25))(x)(Nd(0.5)Ca(0.5))(1-x)MnO(3) have been investigated from 50 to 300 K. A considerable velocity softening accompanied by an attenuation peak was observed around the charge-ordering transition temperature (T(CO)) upon cooling. The simultaneous occurrence of the charge ordering (CO) and the ultrasonic anomaly implies strong electron-phonon coupling, which originates from the cooperative Jahn-Teller effect. At very low temperature, another broad attenuation peak was observed, which is attributed to the phase separation (PS) and gives a direct evidence of spin-phonon coupling in the compound. With increasing x, T(CO) shifts to lower temperature, the magnetization of the system is strengthened and the PS is enhanced. The temperature dependence of the longitudinal modulus shows that the Jahn-Teller coupling energy E(JT) decreases with increasing Na content. The analysis suggests that the charge mismatch effect may be the main reason for the suppression of the CO and enhancement of the PS. PMID- 21690910 TI - High pressure studies on silane to 210 GPa at 300 K: optical evidence of an insulator-semiconductor transition. AB - Silane (SiH(4)) has been studied in a diamond anvil cell from 7-210 GPa by using optical reflection and absorption techniques at 300 K. The reflectivity and transmission measurements showed a dramatic change in the neighbourhood of 100 GPa. On the basis of reflectivity and absorption experimental data, the pressure dependence of the refractive index (n) of solid SiH(4) was derived, which was then used to determine the ratio of the molar refraction (R) to the molar volume (V). There is a large jump in the ratio R/V between 92 and 109 GPa. At 109 GPa and 1.6 eV, n(*)(SiH(4)) = 3.62 (the real part of refractive index) and R/V (SiH(4)) = 0.79, which are similar to the values for silicon at one atmosphere at the same energy. The results indicated that an insulator-semiconductor phase transition might have occurred in solid SiH(4) between 92 and 109 GPa. Comparing values of the real part of n, n(*), and the extinction coefficient k(*) with that of metals, we conclude that SiH(4) is not yet a metal at the maximum pressure investigated (210 GPa), suggesting that a higher pressure is needed for its metallization. PMID- 21690911 TI - Theoretical study of dilute GaN-4d transition metal alloys. AB - Electronic calculations were carried out for the dilute ordered alloys Ga(0.94) (TM)(0.06)N (TM = Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, and Ag) in the zinc-blende structure. The theoretical framework used was the density functional theory, using the local spin density approximation, as implemented in the full-potential linearized augmented plane wave method. We examine energy band structures, densities of states, charge distributions, and local magnetic moments and anticipate the properties of these promising systems for applications in spin electronic devices. PMID- 21690912 TI - Correlation between ionic charge and ground-state properties in rocksalt and zinc blende structured solids. AB - In this paper we have evaluated the ground-state properties (i.e., bulk modulus and cohesive energy) of rocksalt and zinc blende structured solids. We have presented two expressions relating the bulk modulus B (GPa) for the alkali halides, alkaline-earth chalcogenides, transition metal nitrides, rare-earth {divalent (R(2+)X) and trivalent (R(3+)X) } monochalcogenides, group IV, III-V and II-VI semiconductors and the cohesive energy E(coh) (kcal mol(-1)) for the alkali halides and alkaline-earth chalcogenides with the product of ionic charges (Z(1)Z(2)) and nearest-neighbour distance d (A). The bulk moduli and cohesive energy of rocksalt and zinc blende type structure compounds exhibit a linear relationship when plotted on a log-log scale against the nearest-neighbour distance d (A), but fall on different straight lines according to the ionic charge product of the compounds. We have applied the modified relation on rocksalt and zinc blende structured solids and found a better agreement with experimental data as compared to the values evaluated by earlier researchers. The results for bulk modulus differ from experimental values by the following amounts: BaO-0%, LiCl-0%, LaS-0%, SmSe-0%, ZnS-0%, CdS-0%, GaP-0%, InP-0%, MgO 0.61%, CaO-0.89%, SmS-1.7%, YbSe-1.6%, UP-1.9%, EuSe-1.9%; and the results for cohesive energy differ from experimental values by the following amounts: LiCl 0.49%, KF-0.51%, RbF-0.54%, SrO-1.2%, NaCl-1.6%, NaF-1.8%, MgSe-1.9%. PMID- 21690914 TI - Vorticity and magnetic shielding in a type-II superconductor. AB - We study in detail, solving the Bogoliubov-de Gennes equations, the magnetic field, supercurrent and order parameter profiles originated by a solenoid or magnetic whisker inserted in a type-II superconductor. We consider solutions of different vorticities, n, in the various cases. The results confirm the connection between the vorticity, the internal currents and the boundstates in a self-consistent way. The number of boundstates is given by the vorticity of the phase of the gap function as in the case with no external solenoid. In the limiting case of an infinitely thin solenoid, like a Dirac string, the solution is qualitatively different. The quasiparticle spectrum and wavefunctions are a function of n-n(ext), where n(ext) is the vorticity of the solenoid. The flux is in all cases determined by the vorticity of the gap function. PMID- 21690913 TI - Mechanical alloying: a pressure induced reaction for obtaining zinc blende GaSb and multiphase states. AB - The cubic zinc blende GaSb phase was produced by a mechanical alloying technique, which is a solid state route based on the action of non-hydrostatic pressures. The thermal stability of this phase was tested using the differential scanning calorimetry technique and, in order to clarify the results, an annealing process was performed. Comparing x-ray diffraction patterns for as-prepared and annealed samples, the improvement in crystallinity of the cubic phase and Sb segregation and/or crystallization can be easily seen. Optical phonons frequencies were measured for both as-milled and annealed samples by means of the Raman spectroscopy technique. Raman profiles of as-milled samples showed typical zinc blende GaSb optical modes and revealed new features that can be associated with multiphase states. PMID- 21690915 TI - Synthesis of hexagonal Ni(3)N using high pressures and temperatures. AB - The only known bulk ambient pressure nickel nitride phase is hexagonal Ni(3)N (space group P6(3)22). Multianvil synthesis experiments at 20 GPa and 2000 K using nickel (Ni) and sodium azide (NaN(3)) starting materials, and ex situ analysis using transmission electron microscopy and scanning electron microscopy measurements show that this phase can be recovered at ambient pressure (space group P6(3)22, a = 4.62 A, c = 4.30 A, Z = 2). Formation of this phase is correlated with the repulsive interactions between closely spaced nitrogen ions and with the extent of thermal stability of nickel nitride at ambient and at high densities. These two factors are also important in relating the high temperature and pressure behaviour of nickel nitride to those of several other interstitial nitrides recovered from similar pressures after heating. Further, we report formation of a sodium rhenium nitride phase by reaction of the azide with the rhenium capsule in which the reactants were contained. PMID- 21690916 TI - Structural study of La(0.75)Sr(0.25)CrO(3) at high temperatures. AB - A high-temperature neutron diffraction study has been carried out on La(0.75)Sr(0.25)CrO(3) compound in the temperature range 300-1400 K. On doping the parent compound LaCrO(3) with Sr at the La site, the orthorhombic (Pbnm) to rhombohedral ([Formula: see text]) structural transition shifts to lower temperatures. From quantitative Rietveld analysis it is found unequivocally that there is a two-phase coexistence (orthorhombic and rhombohedral phases with ~89 and 11 weight%, respectively) in the temperature range 300-470 K and a three phase coexistence (with a new cubic phase with space group Pm3m) in the temperature range 480-1400 K. The weight percentages of the orthorhombic, rhombohedral and cubic phases were found to be ~49%, 37% and 14%, respectively, in the temperature range 480-1300 K, while over 1350-1400 K, the average weight percentages of orthorhombic, rhombohedral and cubic phases were found to be ~41%, 41% and 18%, respectively. The coefficients of volume thermal expansion and linear thermal expansion have been determined for all three phases. The importance of the present study has been discussed for practical applications of the studied compound in solid oxide fuel cells. PMID- 21690917 TI - Structural and electronic properties of the triangular lattice system Na(x)CoO(2). AB - The structural and electronic properties of the triangular lattice system Na(x)CoO(2) with nominal compositions of [Formula: see text] annealed at temperatures from 923 to 1123 K have been explored by means of x-ray diffraction and through measurements of electrical resistivity, thermoelectric power and magnetization. All of the properties for the single-phase specimens are classified into two groups according to the annealing temperature, and a significant correlation exists between the transport and magnetic properties. The first-order phase transition and the irreversible transition for the transport properties, likely due to the ordering of Na ions and to the metastability in the local structure for the polycrystalline specimens, respectively, are also pointed out. PMID- 21690918 TI - Mixed order parameters, accidental nodes and broken time reversal symmetry in organic superconductors: a group theoretical analysis. AB - We present a group theoretical analysis of several classes of organic superconductor. We predict that highly frustrated organic superconductors, such as kappa-(ET)(2)Cu(2)(CN)(3) (where ET is BEDT-TTF, bis(ethylene dithio)tetrathiafulvalene) and beta'-[Pd(dmit)(2)](2)X, undergo two superconducting phase transitions, the first from the normal state to a d-wave superconductor and the second to a d+id state. We show that the monoclinic distortion of kappa-(ET)(2)Cu(NCS)(2) means that the symmetry of its superconducting order parameter is different from that of orthorhombic kappa (ET)(2)Cu[N(CN)(2)]Br. We propose that beta'' and theta phase organic superconductors have d(xy)+s order parameters. PMID- 21690919 TI - Conductance modulation of a nonballistic Datta-Das spin field effect transistor. AB - A Datta-Das spin field effect transistor (FET) made of a nonballistic quantum wire with a single transport channel is considered. Although there is no spin relaxation and the spin precession is not influenced by elastic scattering, successful spin FET operation can still be prevented by the conductance fluctuations. The necessary condition for the desired spin FET operation is obtained. PMID- 21690920 TI - Electronic structure, magnetic properties and electrical resistivity of the Fe(2)V(1-x)Ti(x)Al Heusler alloys: experiment and calculation. AB - The aim of this work is to investigate electronic structure, magnetic properties and electrical resistivity of Fe(2)V(1-x)Ti(x)Al Heusler alloys. Numerical calculations give a pseudogap at the Fermi level for the majority-spin band of Fe(2)TiAl and a magnetic moment larger than 0.9 MU(B), whereas the ground state of Fe(2)VAl is calculated as a nonmagnetic semimetal with a very low total density of states at the Fermi level. In our calculations the remaining alloys of the Fe(2)V(1-x)Ti(x)Al series are nonmagnetic for x<0.1 and weakly magnetic for 0.1=0.2, leading to changes in the magnetic hysteresis loops measured at low temperatures. These hysteresis loops can be explained as a result of the contribution of two distinct magnetic phases: the canted AFM phase and embedded Ru(4+)-rich clusters which order as a CG in low temperatures. Interestingly, the significant changes in the magnetic response of the material do affect the superconducting transition temperature T(c). It was found that both T(c) and the superconducting fraction are reduced in samples which present the spin glass phase. Therefore, our results point to some coupling between magnetism and superconductivity in this ruthenocuprate family, the presence of the magnetic moment being deleterious for the superconductivity. PMID- 21691007 TI - Phase diagram of La(5/8-y)Nd(y)Ca(3/8)MnO(3) manganites. AB - We report a detailed study of the electric transport and magnetic properties of the La(5/8-y)Nd(y)Ca(3/8)MnO(3) manganite system. Substitution of La(3+) by smaller Nd(3+) ions reduces the mean ionic radius of the A-site ion. We have studied samples in the entire range between La-rich and Nd-rich compounds (0.1=70 years and majority (84.2%) of them were in low socioeconomic class. The mean hospital stay for stroke treatment was 12 +/- 9 days, Glasgow coma score on admission was 11 +/- 4. Ischemic stroke was 64.4%; hemorrhagic stroke, 34.7%; and indeterminate, 1.0%. Hypertension (85.2%), diabetes mellitus (23.8%), and tobacco smoking (22.8%) were the common identifiable risk factors for stroke. Of all the patients, 69% had >=2 risk factors for stroke. Thirty-day case fatality was 23.8%; it increases with age and was higher among men than women (29.2 vs 18.9%) and in patients with diagnosis of hemorrhagic stroke (34.3 vs 18.5%). The numbers of identifiable risk factors of stroke has no effect on the 30-day case fatality. When compared with stroke in urban areas of Nigeria, we found no differences in frequency of hospitalization (1.3 vs 0.9 - 4%) and the major risk factor (hypertension). Hemorrhagic stroke was more common in urban than in the rural community (45.2 - 51 vs 34.7%) and the 30-day case fatality was lower in the rural community (23.8 vs 37.6 - 41.2%). CONCLUSION: Stroke is also a common neurological condition in rural Nigeria, in view of the fact that almost 70% of the patients had >=2 risk factors of stroke. We recommend that, sustainable, community-friendly intervention programmes are incorporated into the health care system for the early prevention, recognition, and modification of the risk factors in persons prone to the disease. PMID- 21691012 TI - Profile and outcome of non-traumatic paraplegia in Kano, northwestern Nigeria. AB - AIM: This study was aimed to identify the clinical and radiological profile of non-traumatic paraplegia and the various etiologies associated with the condition. MATERIALS AND METHODS: A review of the clinical and radiological presentations of adult patients presenting with non-traumatic paraplegia managed at the Aminu Kano Teaching Hospital (AKTH) and Murtala Specialist Hospital (MMSH), Kano, from June 2006 to November 2009 was carried out. Patients underwent a detailed clinical evaluation followed by laboratory investigation and neuroimaging studies and were followed up for 9 months to asses outcome and complications. RESULTS: 98 patients with non-traumatic paraplegia consisting of 71 males and 27 females (M:F: 5:2) were seen. The age range of the patients was between 16 and 76 years, with a mean age of 40 years (SD = 15.3) years; 54 (55%) of the patients presented after 2 months of the onset of paraplegia. The commonest symptoms were weakness of the lower limbs (100%), loss of sensation (55%), sphincteric disturbance (50%) radicular pain and paresthesia (38.4%), back pain (21.4%) and erectile dysfunction (40%). All the patients had X-ray of the spine; 26.3% had Magnetic Resonance Imaging (MRI) spine. The commonest etiological factors were tuberculosis (TB) (44.4%), transverse myelitis (13.1%), Guillain-Barre syndrome (9.1%), metastatic spinal disease (4%), and HIV myelopathy (4%). However, the cause could not be identified in 14 (14%) of the patients. The commonest site of affectation in those with TB spine was lower thoracic (53.8%) and upper lumbar (23.1%) vertebrae. CONCLUSION: Clinical profile of non-traumatic paraplegia in Kano, northwestern Nigeria, is similar to that reported elsewhere in Africa, with spinal tuberculosis and transverse myelitis accounting for over half the cases. PMID- 21691013 TI - Community survey of attention-deficit/hyperactivity disorder among primary school pupils in Benin City, Nigeria. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common childhood neuro-developmental condition with early onset. ADHD affects children worldwide. However, there is a variation in the prevalence across different countries. In Nigeria, there is paucity of information on the prevalence. To provide the relevant information, a cross-sectional study was conducted between February and August 2006 among 1473 public primary school pupils aged 6-12 years selected systematically among pupils in Egor Local Government Area of Edo State. MATERIALS AND METHODS: All the 1473 pupils were screened with the Disruptive Behavior Disorder (DBD) Rating Scale to identify children who had ADHD symptoms as contained in the DSM -IV. Such children were compared with randomly selected controls. The academic records of both the groups were also compared. RESULTS: The prevalence of ADHD was 7.6%. The prevalence was higher in boys (9.4%) when compared to girls (5.5%) (P = 0.003). Of the three different subtypes of ADHD, the predominantly inattentive subtype (ADHD-I) was the most prevalent (47.3% of the ADHD population) followed by the combined type (ADHD-C; 31.3%), while the least prevalent was the hyperactive/impulsive subtype (ADHD-HI; 21.4%). There was no statistically significant difference in the prevalence of ADHD amongst the different age cohorts. CONCLUSION: The prevalence of ADHD was relatively high when compared to the figures available for other countries. For this reason, there is a need to pay increased attention to this condition in Nigeria. Community screening under the umbrella of the School Health Program could be of assistance. PMID- 21691014 TI - Socio-demographic characteristics of alcohol abusers in a rural Ijaw community in Bayelsa State, South-South Nigeria. AB - BACKGROUND: Causal relationship has been established between alcohol and more than 60 types of disease and injury. Despite this, alcohol is still widely consumed in several communities in Nigeria, and sometimes considered a health tonic. This study described the pattern, prevalence, and factors associated with alcohol abuse in a typical Ijaw community, where alcohol is produced and consumed in large quantities. MATERIALS AND METHODS: The study was carried out in Okoloba, a rural community in Bayelsa State, South-South Nigeria using an analytical cross sectional study design. The data were collected from members of the community aged 16 to 65 years, using the Alcohol Use Disorders Identification Test questionnaire and clinical examination for hepatomegaly, tongue tremor, and hand tremor. RESULTS: A total of 322 subjects, comprising 166 men and 156 women were studied. They had an average age of 41.4 +/- 2.5 years, were mostly farmers (43.17%), married (66.15%), and had at most primary school education (62.42%). More than 90% of the subjects took alcohol in the preceding year, with more of them (43%) preferring the locally produced drinks. About 33% of the subjects had harmful drinking, while 12.73% had alcohol dependence problem. There is no significant age difference between the alcohol abusers and abstainers/social drinkers (P > 0.05), but alcohol abusers were significantly more likely to be males (P < 0.001), in polygamous marriages (P < 0.00001), had lower educational status (P < 0.0001), likely to be practitioners of the traditional religion (P < 0.0001), and more likely to be engaged in palm wine tapping. CONCLUSION: Alcohol is widely consumed in the community, but the prevalence of abuse was moderate, mainly due to cultural restrictions. Sales restrictions might be needed as the drinking habits of members of the community change with urbanization. PMID- 21691015 TI - Secondhand smoke exposure among nonsmoking adults in two Nigerian cities. AB - BACKGROUND: Tobacco control policy can only succeed if the burdens of smoking are known. The objective of this study was to determine the prevalence and correlates of secondhand smoke (SHS) exposure among nonsmoking adults in two Nigerian cities. MATERIALS AND METHODS: We carried out a cross-sectional study from October 2009 to April 2010 among adult population of two Nigerian cities: Enugu and Ilorin. A semi-structured questionnaire was administered by interviewers to obtain socio-demographic information; and information regarding pattern of SHS exposure, awareness of tobacco control policy and the harmful effects of SHS. SHS exposure was defined as regular exposure to tobacco smoke in the previous 30 days in a nonsmoking adult. RESULTS: Of the 585 nonsmoking adults that completed the study, 38.8% had regular exposure to SHS; mostly, in public places (24.4%). More men were exposed at public places when compared with women (27.0% vs. 19.5%). The strongest factor associated with exposure to SHS in women was having a smoking spouse [prevalence rate (PR) ratio-7.76; 95% confidence interval (CI), 3.08 9.42]; and in men, it was lack of home smoking restriction (PR ratio-6.35; 95% CI, 4.51-8.93). Among men, SHS exposure at any location was associated with lack of secondary school education, residing in slum apartment (house with many households), living with a smoking family member (non-spouse), lack of home smoking restriction, and alcohol intake. Among women, SHS exposure at any location was associated with having a smoking spouse, residing in slum apartment and lack of home smoking restriction. Seventy-two percent of respondents were aware of the harmful effects of SHS on their health. Lack of awareness of the harmful effects was significantly associated with increasing age (r = +0.45; P = <0.01), lack of secondary school education (r = -0.10; P = 0.04), residing in slum apartment (r = -0.12; P = 0.03) and being a widow/widower (r = +0.24; P < 0.01). Only 17.4% of the employees reported availability of outdoor smoking area at their workplaces. CONCLUSION: Our results show that prevalence of SHS exposure was the highest in public places. These findings underscore the need for enactment of comprehensive smoke-free legislation and implementation of educational strategies to reduce SHS exposure in homes. PMID- 21691016 TI - Incidence of bladder cancer in a one-stop clinic. AB - OBJECTIVE: The aim of this study is to demonstrate the importance of transvaginal scan (TVS) in the detection of bladder tumors in patients presenting with postmenopausal bleeding. MATERIALS AND METHODS: We examined the case records of all patients that attended a one-stop clinic between September 2001 and May 2004. Those presenting with postmenopausal bleeding (PMB) underwent transvaginal scan and endometrial pipelle sampling. Where bladder pathology was detected, urine cytology was done before referral to the urologist. RESULTS: In all, 753 women were referred. There were 17 cases of endometrial cancer detected. Three cases of bladder tumor (malignant transitional cell cancer) were found. CONCLUSION: We recommend careful assessment of all pelvic organs in women presenting with PMB. PMID- 21691017 TI - Duration of labor with spontaneous onset at the University of Ilorin Teaching Hospital, Ilorin, Nigeria. AB - BACKGROUND/OBJECTIVE: Duration of labor varies from one pregnancy to another and a period of less than 12 hours is regarded as normal. Modern obstetric practice involves active management of labor with the aim of preventing prolonged labor and its sequelae. The main objective of this study was to determine and compare the average duration of labor of spontaneous onset between nulliparas (Po) and multiparas (P >= 1) and to determine factors affecting duration of labor. MATERIALS AND METHODS: This study was a prospective study carried out between 15 May and 14 June 2004 at the Labor Ward of the University of Ilorin Teaching Hospital, Ilorin, Nigeria. Two hundred and thirty-eight women who satisfied the inclusion criteria were studied. The inclusion criteria were term pregnancy with vertex presentation, labor with spontaneous onset, live fetus at presentation and spontaneous vertex delivery. RESULTS: The mean +/- SD admission-delivery interval in labor ward was shorter (3.77 +/- 2.88 hours) among multiparas than that of nulliparas (5.00 +/- 3.17 hours) (P = 0.235). The mean +/- SD duration of labor (from the onset of labor to delivery) was shorter among multiparas (8.73 +/- 4.17 hours) than that of nulliparas (11.23 +/- 4.29 hours) (P = 0.426). The differences were not significant (t-test, P > 0.05). Maternal age and individual parity had significant correlation with the duration of labor in this study (Pearson correlation = -0.019, -0.027, respectively, P < 0.05). CONCLUSION: Interestingly, duration of labor was not significantly different among multiparas and nulliparas although it was shorter. Correlation existed between duration of labor and maternal age and individual parity. PMID- 21691018 TI - Evaluation of blood pressure and indices of obesity in a typical rural community in eastern Nigeria. AB - AIM: With increasing urbanization of lifestyle, cardiovascular morbidity and mortality have been on the increase in Africans. Studies on cardiovascular risk factors in rural communities in South East Nigeria are scarce. This study focused on hypertension and obesity in adult Nigerians dwelling in a rural setting in Eastern Nigeria. MATERIALS AND METHODS: A total of 218 participants from the rural community were recruited into the study. A questionnaire was used to assess prior knowledge of their weight and blood pressure status as well as drug history for those found to have hypertension. Each participant's blood pressure was measured and any value >=140/90 mmHg was regarded as high blood pressure (HBP). Their heights and weights were measured and their body mass indices (BMI) calculated using the standard formula of BMI = Weight in Kg/Height in m 2 ; BMI >=30 Kg/m 2 was referred to as global obesity. Their waist circumferences (WC) were also measured and any value >=102 cm for males and >=88 cm for females was regarded as abdominal obesity. RESULTS: The general prevalence of HBP in the rural community was 44.5%. The prevalence of HBP increased as age increased and awareness about HBP was low (15.2%). Females were more aware than the males. The prevalence of HBP was higher in males (49.3%) compared with their female counterparts (42.3%), whereas the females had a higher prevalence of all forms of obesity (abdominal: 36.2%, global: 14.8%) compared with the males (abdominal: 14.5%, global: 10.1%). Higher BMI was associated with higher systolic and diastolic BP values. Hypertensive participants had higher BMI and WC than those who had normal BP. CONCLUSION: The prevalence of both hypertension and obesity seems to be increasing in rural communities in Nigeria and thus, the available prevalence documented in previous studies for rural communities may no longer represent the current trend. Awareness of the participants about these major cardiovascular risk factors is still very low. Higher BMI was associated with higher values of both systolic and diastolic BP. PMID- 21691019 TI - Living kidney donor transplants over a 16-year period in South Africa: a single center experience. AB - BACKGROUND: Kidney transplantation is the treatment of choice for end-stage renal disease (ESRD). The number of patients on the waiting list is increasing due to an imbalance between organ supply and demand. This has led to an increase in the number of living donor transplants in most parts of the world. The benefits to the recipients must, however, be weighed against the risks to the donors. Long term follow-up of the donors is therefore imperative to ascertain the risks of living kidney donation. MATERIALS AND METHODS: We reviewed the records of 571 potential living kidney donors (PLDs) in Johannesburg hospital over a 16-year period between 1990 and 2005. RESULTS: There were 1030 kidney transplants during this period, with 800 cadaveric and 230 actual living donor (ALD) transplants. There were 571 PLDs; however, 341 (59.7%) withdrew or were withdrawn because of medical and non-medical reasons. Among the 230 ALDs, the mean age of the donors was 35.2 +/- 8.3 years; 55% were females; 24% were Blacks. Eighty-five percent were related to the recipients while 15% were unrelated. Mean duration of follow up was 8.6 +/- 6.4 years. The pattern of post-donation follow-up was excellent in 29.7%, adequate in 34% and unacceptable/poor in 36.3%, based on the number of clinic visits post-donation. Hypertension was noted in 24% of the donors during long-term follow-up. Three of the donors also developed significant microalbuminuria. CONCLUSION: There is a need to encourage living kidney donation, especially amongst the Black populations, and to emphasize the value and significance of post-donation follow-up visits to all potential donors. PMID- 21691020 TI - Ultrasound guided percutaneous fine needle aspiration biopsy/automated needle core biopsy of abdominal lesions: effect on management and cost effectiveness. AB - AIMS: This prospective study was designed to determine whether ultrasound (US) guided percutaneous fine needle aspiration biopsy (PFNAB)/US-guided percutaneous needle core biopsy (PNCB) of abdominal lesions is efficacious in diagnosis, is helpful in treatment choice, to evaluate whether various other investigations can be avoided, especially invasive ones, its time (shortening hospitalization) and cost-effectiveness. MATERIALS AND METHODS: A total 159 US-guided PFNAB (67) and US-guided automated PNCB (92) of abdominal lesions were performed percutaneously in 150 patients; the youngest patient was a 3-month-old female and eldest was a 75-year-old female. The patient selection was irrespective of age, sex, or location of the abdominal lesion. These patients presented with abdominal mass/lesions, suspected malignancy, jaundice, and in some cases, however, biopsy was performed to determine the nature of indeterminate lesion (malignant / benign versus abscesses). They were 47 hepatobiliary, 6 pancreas, 24 gastrointestinal tract (GIT), 20 kidneys and urinary bladder, 20 prostate, 3 lymph nodes, 4 adrenals, 8 retroperitoneal, 13 ovaries, and 9 other types of lesions. We used free-hand technique (without biopsy attachment) in 129 cases, and transrectal and transvaginal with biopsy attachment was used in 30 cases. RESULTS: In 91.99% of cases, US-guided PFNAB/US-guided PNCB contributed significantly to diagnosis in which US-guided PFNAB/US-guided PNCB was the diagnostic test in 23.33% cases. It confirmed a highly suspected diagnosis in 64% patients, and indicated a specific diagnosis that was not suspected in the remaining 36%. In 57.33% cases, the results of US-guided PFNAB/US-guided PNCB, did not alter treatment choice but increased physician confidence in the choice. US-guided PFNAB/US-guided PNCB was responsible in avoiding 107 planned investigations, including 8 laparotomies, with no significant complications and decreasing length of stay and resulting in 20% cost savings. CONCLUSIONS: Thus, the US-guided PFNAB/US-guided PNCB contributed significantly in diagnosis, and in most of the cases it did not change treatment choice but increased clinicians confidence in the choice. We can avoid the number of investigations, decrease morbidity and mortality, shorten hospitalization and cost by using these methods. PMID- 21691021 TI - Underweight, overweight and obesity in adults Nigerians living in rural and urban communities of Benue State. AB - OBJECTIVE: To assess the prevalence of underweight, overweight and obesity among Nigerians aged 18-45 years, living in urban and rural settlements in one state in Nigeria. MATERIALS AND METHODS: Four hundred and thirty-five subjects between 18 and 45 years of age were recruited for height, weight and waist circumference (WC) measurements. Body mass index (BMI) was calculated (weight/height 2, kg/m 2 ); WHO criteria determined BMI and WC categories. RESULTS: Based on BMI, about 2% of the study population was underweight, 22% was overweight and 4% was obese. There were more normal weight persons in rural than in urban settlement. About 40 and 30% of females in urban and rural settlement, respectively, were either overweight or obese. Based on WC of the sample population, 10.34% had increased risk for metabolic syndrome [action level I (defi ned as WC >=94 cm in men and >=80 cm in women)] and 2.8% had substantially increased risk [action level II (defi ned as WC >=102 cm in men and >=88 cm in women)]. At action level II, there was no obese male. CONCLUSION: This study revealed that underweight, overweight and obesity exist in young adults, but overweight and obesity are more prevalent. Therefore, concerted efforts should be made to control this in young adults for their present well-being and to possibly avoid the risk of disease later in life. PMID- 21691022 TI - Survey of medical specialists on their attitudes to and resources for health research in Nigeria. AB - AIM: To study the views of medical specialists on their attitude to and the resources for health research in Nigeria and draw appropriate policy implications. MATERIALS AND METHODS: Structured questionnaires were distributed to consenting 90 randomly selected medical specialists practising in six Nigerian tertiary health institutions. Participants' background information, importance attached to research, motivations for conducting research, funding, ethical oversight, literature search, and statistical support were probed. The coded responses were stored and analyzed using the statistical SPSS software. RESULTS: Fifty-one out of the 90 questionnaires distributed were returned, giving a response rate of 63.3%. Research function was rated third by 64.7% of the respondents after hospital service (72.5%) and teaching (66.0%). Advancement of knowledge was the strongest motivating factor for conducting research (78.4%). Securing funding (94%) and finding time (80%) were their major constraints. Only a minority of the respondents, 20% and 14%, respectfully, positively rated the quality and promptness of the decisions of their institutions' ethical organs in the highest category. Most of their literature search was conducted on the internet (96.1%) and they stored and analyzed their research data with commonly available statistical software. CONCLUSION: Our study respondents regarded research highly but were severely constrained in conducting research by lack of access to sources of funding from within and outside Nigeria and finding time from core hospital functions. We recommend periodic (re)training in research particularly on how to apply for research grants and giving some protected research time for Nigerian medical specialists in order to boost their research function. PMID- 21691023 TI - Observations of teachers in Ilorin, Nigeria on their practices of corporal punishment that are potentially injurious to their pupils' eyes. AB - OBJECTIVE: To document the observations of elementary school teachers (ESTs) in Ilorin, Nigeria on their practice of some types of corporal punishment (CP) that could result in eye injuries among their pupils. MATERIALS AND METHODS: A short battery of questions that explored ESTs' observations on attitudes to, and knowledge of some commonly used CP practices was self-administered on 172 consenting teachers from six sampled schools. The potentials for their pupils to sustain eye injuries while receiving such CP practices were inferred from the usage of items with sharp and protruding ends to administer CP, and the application of CP onto pupils' body parts that are in close proximity to the eye such as the head and face. RESULTS: Only 50 of the 172 ESTs favored the practice of CP of pupils by their teachers. Analyses of several potentially moderating variables on this response such as ESTs' ages, years of EST teaching experience, school, and class or grade that EST teaches did not prove significant. Over three quarters of ESTs (80.2%) had ever observed that pupils were being disciplined by ESTs with a cane. About a fifth of them had also observed that ESTs applied CP to the head (19.8%) and the face (16.3%) of pupils. CONCLUSION: Findings suggest that ESTs' commonly employed CP practices have significant injurious potential to their pupils' eyes. It is recommended that CP be abolished in elementary schools, and instead alternative nonabusive methods of disciplining erring pupils by teachers be introduced. PMID- 21691024 TI - Psychological and social adjustment to blindness: understanding from two groups of blind people in Ilorin, Nigeria. AB - BACKGROUND: Blindness can cause psychosocial distress leading to maladjustment if not mitigated. Maladjustment is a secondary burden that further reduces quality of life of the blind. Adjustment is often personalized and depends on nature and quality of prevailing psychosocial support and rehabilitation opportunities. This study was aimed at identifying the pattern of psychosocial adjustment in a group of relatively secluded and under-reached totally blind people in Ilorin, thus sensitizing eye doctors to psychosocial morbidity and care in the blind. MATERIALS AND METHODS: A cross-sectional descriptive study using 20-item Self Reporting Questionnaire (SRQ) and a pro forma designed by the authors to assess the psychosocial problems and risk factors in some blind people in Ilorin metropolis. RESULT: The study revealed that most of the blind people were reasonably adjusted in key areas of social interaction, marriage, and family. Majority were considered to be poorly adjusted in the areas of education, vocational training, employment, and mobility. Many were also considered to be psychologically maladjusted based on the high rate of probable psychological disorder of 51%, as determined by SRQ. Factors identified as risk factors of probable psychological disorder were poor educational background and the presence of another medical disorder. CONCLUSION: Most of the blind had no access to formal education or rehabilitation system, which may have contributed to their maladjustment in the domains identified. Although their prevailing psychosocial situation would have been better prevented yet, real opportunity still exists to help this group of people in the area of social and physical rehabilitation, meeting medical needs, preventive psychiatry, preventive ophthalmology, and community health. This will require the joint efforts of medical community, government and nongovernment organizations to provide the framework for delivery of these services directly to the communities. PMID- 21691025 TI - Acute abdominal conditions in people with sickle cell disease: a 10-year experience in Port Harcourt, Nigeria. AB - BACKGROUND: Abdominal crises (vaso-occlusive) are not infrequent in patients with sickle cell anemia. They usually present as acute abdomen. These patients none the less present with other causes of acute abdomen like others without hemoglobinopathy. Six cases of surgical acute abdomen in sickle cell disease patients treated in the University of Port Harcourt Teaching Hospital (UPTH) are presented. MATERIALS AND METHODS: Six sickle cell anaemia patients presenting with acute abdominal conditions from 1999 to 2008 (inclusive) in the University of Port Harcourt Teaching Hospital were studied retrospectively (two patients) and prospectively (four patients). After initial resuscitation, appropriate surgical procedures, namely, appendicectomy (2), cholecystectomy (1), open drainage of splenic abscess (1), and release of adhesive band (1) were performed. RESULTS: Six cases were treated (female/male ratio 2:1). Four patients were in the 11-20 year age group. Two patients had appendicectomy and two presented with acute cholecystitis/cholelithiasis, one of whom had open cholecystectomy. One young girl had drainage of splenic abscess and a 42-year-old male had division of obstructive adhesive band at laparotomy. There were two complications, namely, postoperative haemorrhage (in cholecystectomy patient) and acute chest syndrome (in one appendicectomy patient). These were successfully managed with blood transfusion and antibiotic/oxygen therapy, respectively. There was no mortality. CONCLUSION: Sickle cell anaemia patients are not exempt from acute abdominal conditions requiring surgery. A high index of suspicion coupled with repeated clinical examination is needed for early diagnosis and appropriate treatment. PMID- 21691027 TI - Inflammatory bowel disease in Nigerians: still a rare diagnosis? AB - Inflammatory bowel disease (IBD) has been thought to have a low incidence among subSaharan Africans mainly because of the sporadic cases reported from the continent in comparison with the larger numbers reported from North America and Western European countries. Is this difference based on real demographic susceptibilities or a reflection of lower level of healthcare delivery? Three cases of ulcerative colitis and one case of Crohn's disease diagnosed in a tertiary institution in northern Nigeria in the span of three years are reported. Their presentation coincided with the creation of the Gastrointestinal Surgery Unit of our hospital and with it the availability of endoscopic diagnostic procedures. All four patients were indigenous Nigerians. Our findings suggest that IBD may be more common in this part of the world than previously thought. With an increased awareness of the disease in our population, a greater utilization of modern medicine as against alternative medicine and with wider availability of diagnostic tools in our hospitals, it is our guess that more cases may be found in the future to dispel the belief that Africans are somewhat immune to this affliction. PMID- 21691026 TI - Prevalence of malaria parasitemia amongst asymptomatic pregnant women attending a Nigerian teaching hospital. AB - BACKGROUND: Malaria parasitemia among pregnant women is associated with complications to mother and the unborn fetus. There is paucity of data on asymptomatic malaria parasitemia, particularly in the northwest region of Nigeria. The objectives of this study were to determine the prevalence of malaria parasitemia in asymptomatic pregnant women and to estimate the packed cell volume (PCV) of this group of pregnant women. MATERIALS AND METHODS: This was a cross sectional, descriptive study of only well pregnant women recruited consecutively at the time of booking for antenatal care. Thick film microscopy and qualitative immunoassay test for malaria parasite (MP) were performed for all the women. PCV estimation was also done using the micro-centrifuge method and comparison was made for women with parasitemia with those without MP. Some socio-demographic variables were also analyzed. Chi-square test was used to test for significance and a P-value less than 0.05 was considered statistically significant. RESULTS: Two hundred and twenty-five healthy pregnant women were studied. Seven women (3.1%) had MP by direct microscopy while 11 (4.8%) were MP positive with the qualitative immunoassay test. One hundred and eighty-five (82%) of the women were literate while 128 (57%) used insecticide treated mosquito nets in their homes. The mean PCV of the women with positive MP was 30.57 +/- 2.26 as against 32.89 +/ 2.45 for those without parasitemia (P < 0.05). CONCLUSION: The prevalence of asymptomatic malaria parasitemia in the study group was low but there was associated anemia in those with parasitemia. The use of intermittent preventive treatment is recommended for all pregnant women including those who are asymptomatic to forestall complications like maternal anemia. PMID- 21691028 TI - Penile gangrene due to calcific uremic arteriopathy. AB - Calcific uremic arteriopathy (CUA) is a rare but potentially life-threatening complication of end-stage renal disease (ESRD) and secondary hyperparathyroidism. It typically presents with ischemic necrosis involving areas of adiposity in the body mainly the trunk, buttocks, or proximal extremity. Patients can also present with digital ischemia and more rarely penile gangrene. The pathogenesis of CUA is not yet clear but several putative factors, mainly hyperparathyroidism and related metabolic abnormalities are implicated. A number of conditions can mimic CUA clinically and should be differentiated from it. We present in the current study, a patient who presented with progressive penile gangrene and skin necrosis due to CUA. We review the current understanding of the pathogenesis, diagnosis/differential diagnosis, and management of this rare but potentially life-threatening complication of ESRD. PMID- 21691029 TI - Interscalene block for shoulder surgery. AB - Fracture dislocation of the shoulder is a common musculoskeletal injury following road traffic accident. Peripheral nerve block has become a recognized anesthetic technique due to the rapid onset of prolonged analgesia, sufficient for both pain and surgical management. However, interscalene block for shoulder surgery has not been reported as a primary anesthetic technique in our environment. We report its successful use in open reduction and internal fixation of left humeral surgical neck fracture dislocation. The interscalene brachial plexus were localized by a Polystim II nerve stimulator (te me na, Bondy, France) with sustained biceps motor response at 0.2 mA and 40 ml of local anesthetic, comprising 0.25% bupivacaine and 1.0% of lidocaine with 1 : 200,000 epinephrine in equal parts was administered to establish the block. Surgical anesthesia was achieved 18 minutes after instituting the block and surgery lasted 70 minutes without complications. This technique may obviate the use of general anesthesia with its risks. PMID- 21691030 TI - Absence seizure in the elderly. AB - Absence seizure is most common in children. It commonly occurs between 5 and 18 years of age; it is not common before the age of 2 years or after adolescence and it is relatively rare in adults over the age of 50. We report a case of electroencephalography confirmed absence seizure and absence status successfully treated with sodium valproate in an elderly patient with dementia. Differential diagnosis between absence status and complex partial seizure is emphasized. PMID- 21691031 TI - Peculiarities of genital ulcer diseases in HIV-infected patients: report of four cases from Zaria, Nigeria. PMID- 21691032 TI - Acute acalculous cholecystitis due to hepatitis A infection in a child: a rare cause of acute abdomen. PMID- 21691033 TI - Our response in the aftermath of the great Tohoku-Kanto Earthquake and Tsunami. PMID- 21691034 TI - Reliability and validity of Wisconsin Upper Respiratory Symptom Survey, Korean version. AB - BACKGROUND: The Wisconsin Upper Respiratory Symptom Survey (WURSS) is a self administered questionnaire developed in the United States to evaluate the severity of the common cold and its reliability has been validated. We developed a Korean language version of this questionnaire by using a sequential forward and backward translation approach. The purpose of this study was to validate the Korean version of the Wisconsin Upper Respiratory Symptom Survey (WURSS-K) in Korean patients with common cold. METHODS: This multicenter prospective study enrolled 107 participants who were diagnosed with common cold and consented to participate in the study. The WURSS-K includes 1 global illness severity item, 32 symptom-based items, 10 functional quality-of-life (QOL) items, and 1 item assessing global change. The SF-8 was used as an external comparator. RESULTS: The participants were 54 women and 53 men aged 18 to 42 years. The WURSS-K showed good reliability in 10 domains, with Cronbach's alphas ranging from 0.67 to 0.96 (mean: 0.84). Comparison of the reliability coefficients of the WURSS-K and WURSS yielded a Pearson correlation coefficient of 0.71 (P = 0.02). Validity of the WURSS-K was evaluated by comparing it with the SF-8, which yielded a Pearson correlation coefficient of -0.267 (P < 0.001). The Guyatt's responsiveness index of the WURSS-K ranged from 0.13 to 0.46, and the correlation coefficient with the WURSS was 0.534 (P < 0.001), indicating that there was close correlation between the WURSS-K and WURSS. CONCLUSIONS: The WURSS-K is a reliable, valid, and responsive disease-specific questionnaire for assessing symptoms and QOL in Korean patients with common cold. PMID- 21691035 TI - Kawasaki disease in Mongolia: results from 2 nationwide retrospective surveys, 1996-2008. AB - BACKGROUND: Kawasaki disease (KD) has been reported in many countries. However, the incidence of KD in Mongolia is not known. This is the first report of incident cases of KD in Mongolia, which were identified using data from 2 nationwide surveys. METHODS: Two nationwide retrospective surveys were conducted: medical histories were collected from patients aged 0 to 16 years who were hospitalized countrywide between 1996 and 2008. Hospital records for these patients were also reviewed. Nationwide training seminars on KD were conducted before each survey. RESULTS: For the nationwide surveys, the participation rates among all hospitals with pediatric wards were 97% and 94%. Inpatient medical histories from 1996 through 2008 were reviewed, and, among children younger than 16 years, 9 patients with KD were investigated. The age of KD patients ranged from 1.4 to 14 years; 7 of 9 patients were male. Six (67%) patients fulfilled all 6 clinical diagnostic criteria; the other 3 (33%) were defined as having KD based on the presence of 5 such criteria. Fever persisting 5 or more days, bilateral conjunctival congestion, and changes of the lips and oral cavity were the most common symptoms, and cervical lymphadenopathy was the least common symptom. Cardiac sequelae developed in 5 of the patients, 4 of whom were older than 10 years. CONCLUSIONS: The results of these nationwide surveys reveal that KD cases do exist in Mongolia. However, knowledge of KD among Mongolian pediatricians is likely to be poor. Thus, there is a need to augment their understanding to improve management of KD patients. Further studies are crucial to clarify the epidemiologic characteristics of KD in Mongolia. PMID- 21691036 TI - Occupational stress and its related factors among university teachers in China. AB - OBJECTIVES: University teachers in China are expected to suffer serious occupational stress due to the expanding enrollment in universities without a proportional increase in teacher resources and the fact that all promotions for university teachers are determined based on not only teaching but also the outcome of scientific research. This study was designed to assess the occupational stress among university teachers in China and clarify its risk factors. METHODS: A cross-sectional study was performed in Liaoning Province, the centralized area of higher education in Northeast China. Eight universities (2 multidiscipline and 6 specialized) and 10% of academic staff each were randomly sampled. Questionnaires pertaining to occupational stress indicated by the Chinese Version Personal Strain Questionnaire (PSQ) and demographic characteristics, health status, work situations, and personal and social resources were distributed in October 2008. A total of 827 effective respondents (response rate 76.4%) became our participants. RESULTS: The average raw score of PSQ was 91.0 among the university teachers. General linear model analysis showed that the factors significantly associated with the PSQ score were, in standardized estimate (beta) sequence, mental health, role overload, role insufficiency, social support, monthly income, role limitations due to physical problems, research finance and self-rated disease with adjustment for age and sex. CONCLUSION: We concluded that, in comparison to work-related factors and social support, mental health is a prominent risk factor for occupational stress in university teachers in China. Improvement of mental health and organizational climate should be considered to lessen the occupational stress of university teachers. PMID- 21691037 TI - Irbesartan prevents metabolic syndrome in rats via activation of peroxisome proliferator-activated receptor gamma. AB - Irbesartan, an angiotensin-receptor blocker, is a known agonist of peroxisome proliferator-activated receptor (PPAR) gamma. In this study, thirteen-week-old spontaneously hypertensive (SHR)/NDmcr-cp rats, representing a genetic model of metabolic syndrome, were treated daily with placebo, irbesartan (30 mg/kg), valsartan (10 mg/kg), or pioglitazone (10 mg/kg) for 4 weeks. Significant reductions in systolic blood pressure were seen in the irbesartan- and valsartan treated groups, but not in the pioglitazone-treated group. Compared with the placebo group, plasma insulin, homeostasis model assessment of insulin resistance index, and plasma triglyceride levels were significantly lower while plasma adiponectin levels were significantly higher in the pioglitazone- and irbesartan treated groups, but not in the valsartan-treated group. Significant increases in the gene expression of adiponectin and GLUT4 within adipose tissue were also observed in the pioglitazone- and irbesartan-treated groups, but not in the valsartan-treated group. These findings suggest that through PPARgamma stimulation along with angiotensin II inhibition, irbesartan may be an optimal treatment option in the prevention of metabolic syndrome as well as hypertension. PMID- 21691038 TI - Yokukansan Enhances Pentobarbital-Induced Sleep in Socially Isolated Mice: Possible Involvement of GABA(A) - Benzodiazepine Receptor Complex. AB - In the present study, we investigated the effect of the Kampo medicine Yokukansan (YKS) on pentobarbital-induced sleep in group-housed and socially isolated mice. Socially isolated mice showed shorter sleeping time than the group-housed mice. YKS (300 mg/kg, p.o.) prolonged the pentobarbital-induced sleeping time in socially isolated mice without affecting pentobarbital sleep in group-housed mice. The prolongation of sleeping time by YKS was reversed by bicuculline (3 mg/kg, i.p.) and flumazenil (3 mg/kg, i.p.), but not WAY100635. These findings suggest that the GABA(A) - benzodiazepine receptor complex, but not 5-HT(1A) receptors, is involved in the reversal effect of YKS on the decrease of pentobarbital sleep by social isolation. PMID- 21691039 TI - Dopamine D2-receptor antagonists ameliorate indomethacin-induced small intestinal ulceration in mice by activating alpha7 nicotinic acetylcholine receptors. AB - We have reported that nicotine and the specific alpha7AChR agonist ameliorate indomethacin-induced intestinal lesions in mice by activating alpha7 nicotinic acetylcholine receptors (alpha7nAChR). Dopamine D2-receptor antagonists, such as domperidone and metoclopramide, enhance the release of ACh from vagal efferent nerves. The present study examined the effects of domperidone and metoclopramide on indomethacin-induced small intestinal ulceration in mice, focusing on the alpha7AChR. Male C57BL/6 mice were administered indomethacin (10 mg/kg, s.c.) and sacrificed 24 h later. Domperidone (0.1-10 mg/kg) and metoclopramide (0.03-0.3 mg/kg) were administered i.p. twice, at 0.5 h before and 8 h after indomethacin treatment, while methyllycaconitine (a selective antagonist of alpha7nAChR, 30 mg/kg) was administered twice, at 0.5 h before each domperidone treatment. Indomethacin caused severe hemorrhagic lesions in the small intestine, mostly to the jejunum and ileum, with a concomitant increase in myeloperoxidase (MPO) activity. Domperidone suppressed the severity of lesions and the increase in MPO activity at low doses (0.1-3 mg/kg), but not at a high dose (10 mg/kg). Similar effects were also observed by metoclopramide. The protective effects of domperidone and metoclopramide were totally abolished by prior administration of methyllycaconitine. Indomethacin treatment markedly enhanced inducible nitric oxide synthase and chemokine mRNA expression in the small intestine, but these responses were all significantly attenuated by either domperidone or metoclopramide. These findings suggest that dopamine D2-receptor antagonists ameliorate indomethacin-induced small intestinal ulceration through the activation of endogenous anti-inflammatory pathways mediated by alpha7nAChR. PMID- 21691040 TI - Dosing time-dependency of the arthritis-inhibiting effect of tacrolimus in mice. AB - Stiffness and cytokine in blood levels show 24-h rhythms in rheumatoid arthritis (RA) patients. We previously revealed that higher therapeutic effects were obtained in RA patients and RA model animals when the dosing time of methotrexate was chosen according to the 24-h rhythms to cytokine. In this study, we examined whether a dosing time-dependency of the therapeutic effect of tacrolimus (TAC) could be detected in collagen-induced arthritis (CIA) and MRL/lpr mice. To measure the levels of cytokines and serum amyloid A (SAA), blood was collected from CIA mice at different times. TAC was administered at two different dosing times based on these findings and its effects on arthritis and toxicity were examined. Plasma tumor necrosis factor (TNF)-alpha, interleukin-6 (IL-6), and SAA concentrations showed obvious 24-h rhythms with higher levels during the light phase and lower levels during the dark phase after RA crisis. The arthritis score and leukocyte counts were significantly lower in the group treated at 2 h after the light was turned on (HALO) than in the control and 14 HALO-treated groups. Our findings suggest that choosing an optimal dosing time could lead to the effective treatment of RA by TAC. PMID- 21691042 TI - Identification of the modifier locus that suppresses neonatal lethality in (?DDD * ?DH- Dh/+) F1-Dh/+ male mice. AB - Most F(1)-Dh/+ male mice resulting from a cross between inbred DDD strain females and DH-Dh/+ strain males exhibit growth retardation and die during the neonatal period. The lethality is caused by a combination of three independent gene loci, namely the Dh locus on chromosome 1, Grdhq1 locus on the X chromosome, and a putative Y chromosome-linked locus in some strains. Among these loci, Grdhq1 was previously mapped to a distal region of the X chromosome using progeny from?(?DDD * ?DH-+/+) F(1) * ?DH-Dh/+ mice. In this study, fine mapping of Grdhq1 was performed using progeny of ?(?DDD * ?CAST/EiJ) F(1) ?DH-Dh/+ mice. Contrary to expectation, Dh/+ male pups carrying the DDD allele at DXMit135 (genetic marker nearest to Grdhq1) survived to weaning. The presence of modifier loci that suppressed the lethality by impeding the action of Grdhq1 was suggested; therefore, a genome-wide scan was performed in the surviving Dh/+ males. As a result, a significant modifier locus was identified on proximal chromosome 11. This in turn suggested that Grdhq1 was located more distally than we had expected; that is, the actual location of Grdhq1 appeared to be near and/or distal to the Mid1 locus. Thus, the results revealed that the neonatal lethality in (DDD * DH-Dh/+) F(1)-Dh/+ males was caused by the fourth gene locus on chromosome 11 in addition to the above-mentioned three gene loci on chromosomes 1, X, and Y. PMID- 21691041 TI - Ethanol production efficiency of an anaerobic hemicellulolytic thermophilic bacterium, strain NTOU1, isolated from a marine shallow hydrothermal vent in Taiwan. AB - A new extremely thermophilic, anaerobic, gram-negative bacterium, strain NTOU1, was enriched and isolated from acidic marine hydrothermal fluids off Gueishandao island in Taiwan with 0.5% starch and 0.5% maltose as carbon sources. This strain was capable of growth utilizing various sugars found in lignocellulosic biomass as well as xylan and cellulose, and produced ethanol, lactate, acetate, and CO(2) as fermentation products. The results of a 16S rRNA gene sequence analysis (1,520 bp) revealed NTOU1 to belong to the genus Thermoanaerobacterium. When tested for the ability to grow and produce ethanol from xylose or rice straw hemicellulosic hydrolysate at 70 degrees C, the strain showed the highest levels of ethanol production (1.65 mol ethanol mol xylose(-1)) in a medium containing 0.5% xylose plus 0.5% yeast extract. Maximum ethanol production from the rice straw hemicellulose was 0.509 g g(-1), equivalent to 98.8% theoretical conversion efficiency. Low concentrations of inhibitors (derived from dilute acid hydrolysis) in the rice straw hemicellulose hydrolysate did not affect the ethanol yield. Thus, Thermoanaerobacterium strain NTOU1 has the potential to be used for ethanol production from hemicellulose. PMID- 21691043 TI - Estrogen receptor-alpha gene polymorphisms and body composition in children and adolescents. AB - BACKGROUND/AIMS: Gender differences in body composition are largely explained by differences in sex hormones, such as estrogens. Associations between 2 polymorphisms in the estrogen receptor-alpha gene (ESR1) and body composition in children and adolescents were investigated. METHODS: Two comparable Dutch cohorts with a generational difference of about 20 years were investigated. The first consisted of 350 subjects (184 girls) and the second of 316 subjects (155 girls). Associations between height, weight, BMI, fat mass (FM) and fat-free mass and two polymorphisms in the ESR1 gene were investigated. RESULTS: In girls in the recent cohort, the PvuII-XbaI haplotype 2 polymorphism in the ESR1 gene was associated with a lower body weight, BMI, and FM. These associations were not observed in the older cohort. The younger cohort had a significantly higher total FM, body weight and BMI compared to the older cohort. CONCLUSION: Because the associations between the PvuII-XbaI haplotype 2 polymorphism and body FM in girls were only found in the recent cohort, but not in a comparable, generally leaner cohort from an older generation, it is suggested that non-carriers of this polymorphism are likely to be more vulnerable to fat accumulation in today's obesity promoting environment, than carriers. PMID- 21691044 TI - Reconstructing the areal organization of the neocortex of the first mammals. AB - The fossil record indicates that early mammals had small brains with proportionately little neocortex. Here we consider what is known about the organization of the neocortex in species with the least expanded neocortex from 6 major clades of the mammalian radiation. Common features of the neocortex across these clades include primary and secondary sensory areas, retrosplenial and cingulate cortex, and frontal cortex. Overall, early mammals likely had a core of 15-20 cortical areas that have been retained in most present-day mammals. PMID- 21691045 TI - Not all brains are made the same: new views on brain scaling in evolution. AB - Evolution has generated mammalian brains that vary by a factor of over 100,000 in mass. Despite such tremendous diversity, brain scaling in mammalian evolution has tacitly been considered a homogeneous phenomenon in terms of numbers of neurons, neuronal density, and the ratio between glial and neuronal cells, with brains of different sizes viewed as similarly scaled-up or scaled-down versions of a shared basic plan. According to this traditional view, larger brains would have more neurons, smaller neuronal densities (and, hence, larger neurons), and larger glia/neuron ratios than smaller brains. Larger brains would also have a cerebellum that maintains its relative size constant and a cerebral cortex that becomes relatively larger to the point that brain evolution is often equated with cerebral cortical expansion. Here I review our recent data on the numbers of neuronal and nonneuronal cells that compose the brains of 28 mammalian species belonging to 3 large clades (Eulipotyphla, Glires, and Primata, plus the related Scandentia) and show that, contrary to the traditional notion of shared brain scaling, both the cerebral cortex and the cerebellum scale in size as clade specific functions of their numbers of neurons. As a consequence, neuronal density and the glia/neuron ratio do not scale universally with structure mass and, most importantly, mammalian brains of a similar size can hold very different numbers of neurons. Remarkably, the increased relative size of the cerebral cortex in larger brains does not reflect an increased relative concentration of neurons in the structure. Instead, the cerebral cortex and cerebellum appear to gain neurons coordinately across mammalian species. Brain scaling in evolution, hence, should no longer be equated with an increasing dominance of the cerebral cortex but rather with the concerted addition of neurons to both the cerebral cortex and the cerebellum. Strikingly, all brains appear to gain nonneuronal cells in a similar fashion, with relatively constant nonneuronal cell densities. As a result, while brain size can no longer be considered a proxy for the number of brain neurons across mammalian brains in general, it is actually a very good proxy for the number of nonneuronal cells in the brain. Together, these data point to developmental mechanisms that underlie evolutionary changes in brain size in mammals: while the rules that determine how neurons are added to the brain during development have been largely free to vary in mammalian evolution across clades, the rules that determine how other cells are added in development have been mostly constrained and to this day remain largely similar both across brain structures and across mammalian groups. PMID- 21691046 TI - Variability in neuron densities across the cortical sheet in primates. AB - The function of any area of the brain is a product of its unique population of neurons and nonneurons and their local and long-range connectional architecture. At the present time, we have inadequate data about numbers of neurons and the distribution patterns of neurons in the cortex and other parts of the brain. Numbers and densities of neurons and nonneurons provide the foundation for the assembly of a cortical and whole-brain neuronal network, yet the majority of studies reporting neuron densities for the primate cortex estimate the number of neurons in the cortex as a whole or in specific areas for comparisons between treatment groups or species. While this is valuable information for studies of scaling or comparative studies of specific pathways or functions, a more detailed examination of cell and neuron number distribution across the entire cortical expanse is needed. Two studies reviewed here use the isotropic fractionator method for the determination of cell and neuron numbers to investigate the distribution of cells and neurons across the entire cortical sheet of 4 primate species, taking into consideration cortical areal boundaries. Neuron and total cell numbers were found to vary as much as 5 times between different functional areas across the cortical sheet. Numbers were also variable across representational zones within cortical areas like V1 and S1. The overall distribution of cells and neurons appears to be conserved across the species examined, suggesting a common plan for cell distribution in primates, with more areas of high neuron density in macaques and baboons compared to the smaller and less differentiated cortex of prosimian galagos and the New World owl monkey. PMID- 21691047 TI - Evolution of cerebral cortical development. AB - Understanding how the human cerebral cortex evolved to its present complex state is a fascinating topic for neuroscience, genetics, bioinformatics and comparative biology. To gain further insights into the origins of the mammalian neocortex and to understand how the cortex evolved to be able to serve more complex cognitive functions, we study the development of various extant species. Our aim is to correlate cortical cell numbers and neuronal cell types with the elaboration of cortical progenitor populations and their modes of proliferation in different species. There are several progenitors, i.e. the ventricular radial glia, the subventricular intermediate progenitors and subventricular (outer) radial glia types, but the contribution of each to cortical layers and cell types through specific lineages is not fully understood. Recent comparisons of the proportions of these progenitors in various species during embryonic neurogenesis have revealed the elaboration and cytoarchitectonic compartmentalization of the germinal zone, with alterations in the proportions of various types that can be included among the intermediate progenitors. Across species, larger and more diverse intermediate progenitor populations correlate with brain size and cortical cell diversity. Understanding the molecular and cellular interactions regulating the divisions of these intermediate progenitors not only has implications for cortical evolution but also relates to stem cell biology and illuminates the pathomechanisms of several cortical developmental disorders. PMID- 21691048 TI - Endocrine outcome in long-term survivors of childhood brain tumors. AB - AIM: To evaluate the rates of endocrine abnormalities in survivors of childhood brain tumors and identify risk factors. METHODS: The medical charts of patients were reviewed for background, disease-related and treatment-related data. Endocrine dysfunction was determined by clinical and laboratory evaluation. RESULTS: The study group included 114 patients with a mean age of 15.57 +/- 5.93 years. Mean age at brain tumor diagnosis was 7.07 +/- 5.42 years, and mean follow up was 12.8 +/- 6.25 years. Fifty-seven patients (50%) had an endocrine abnormality. The occurrence of several endocrine abnormalities was significantly associated with cranial irradiation and age <16 years at tumor diagnosis. The presence of growth hormone deficiency (n = 40) was associated with cranial or spinal irradiation, younger age and prepubertal stage at tumor diagnosis; the presence of hypogonadotropic hypogonadism (n = 9) was associated with prepubertal stage at diagnosis, and hypothyroidism (n = 23) was associated with cranial irradiation. Hypocortisolism was diagnosed in 9 patients, short stature in 20 patients and obesity in 8 male patients. Patients with early puberty (n = 19) and an abnormal lipid profile (n = 15) were significantly younger at tumor diagnosis than patients without these disorders. CONCLUSIONS: Childhood brain tumor survivors are at increased risk of late endocrine effects, particularly those treated with cranial radiation and diagnosed at a younger age. The frequency of hormonal deficits increases with time, warranting lifelong surveillance. PMID- 21691049 TI - Characterization of Fpr-rs8, an atypical member of the mouse formyl peptide receptor gene family. AB - The formyl peptide receptor gene family encodes G protein-coupled receptors for phagocyte chemoattractants, including bacteria- and mitochondria-derived N formylpeptides. The human family has 3 functional genes, whereas the mouse family has 7 functional genes and 2 possible pseudogenes (PsiFpr-rs2 and PsiFpr-rs3). Here we characterize PsiFpr-rs2, a duplication of Fpr-rs2. Compared to Fpr-rs2, the PsiFpr-rs2 ORF is 186 nucleotides shorter but 98% identical. Due to a deletion and frame shift, the sequences lack homology from amino acid 219-289. Both transcripts were detected constitutively in multiple immune organs; however, PsiFpr-rs2 was consistently less abundant than Fpr-rs2. LPS induced expression of PsiFpr-rs2, but not Fpr-rs2, in spleen and bone marrow. Both transcripts were detected constitutively in thioglycollate-elicited peritoneal neutrophils, whereas only Fpr-rs2 was detected in thioglycollate-elicited peritoneal macrophages. Both transcripts were induced in LPS-stimulated macrophages. PsiFpr rs2-GFP fusion protein appeared in cytoplasm but not plasma membrane of transfected HEK 293 cells, whereas Fpr-rs2-GFP labeled only plasma membrane. Survival of PsiFpr-rs2(-/-) mice was 33% shorter than that of wild-type and heterozygous littermates (p < 0.05), but no signature pathology was identified. Since PsiFpr-rs2 is expressed in phagocytes and regulated by bacterial products, and may affect longevity, we propose renaming it Fpr-rs8, an atypical member of the formyl peptide receptor gene family. PMID- 21691050 TI - Clinical characteristics of molluscum contagiosum in children in a private dermatology practice in the greater Paris area, France: a prospective study in 661 patients. AB - BACKGROUND: Series regarding the clinical characteristics of molluscum contagiosum (MC) are retrospective and concern small defined populations seen in a hospital setting. METHODS: We prospectively studied patients under 15 years of age with MC seen in 25 private dermatology practices in the greater Paris area during 1 year. RESULTS: Six hundred fifty patients were included. The mean age was 6 years. Of the patients, 30.5% had had MC in the past, 53% had 5-20 MC, 43% had a history of atopic dermatitis (AD), 5% were using topical steroids, 25.5% had coexistent AD, 13% had giant MC (>5 mm), 21% had inflammatory MC, and 19% had MC surrounded by eczema. Bathing with siblings was associated with a higher number of MC. A history of AD was associated with the presence of MC surrounded by eczema. The use of topical steroids was associated with a higher risk of relapse. There was no relation between environmental factors (MC in surrounding people, going to the swimming pool, sports practice) and the number of lesions or between environmental factors and the number of recurrences. CONCLUSION: Atypical lesions are frequent. Bathing with siblings is associated with a higher number of MC. Topical steroid use increases the risk of relapses. AD prevalence is higher than in the general population. PMID- 21691051 TI - Preface: 'Diversity in Cortical Organization'. PMID- 21691052 TI - Age differences in brain activity during emotion processing: reflections of age related decline or increased emotion regulation? AB - Despite the fact that physical health and cognitive abilities decline with aging, the ability to regulate emotion remains stable and in some aspects improves across the adult life span. Older adults also show a positivity effect in their attention and memory, with diminished processing of negative stimuli relative to positive stimuli compared with younger adults. The current paper reviews functional magnetic resonance imaging studies investigating age-related differences in emotional processing and discusses how this evidence relates to two opposing theoretical accounts of older adults' positivity effect. The aging brain model [Cacioppo et al. in: Social Neuroscience: Toward Understanding the Underpinnings of the Social Mind. New York, Oxford University Press, 2011] proposes that older adults' positivity effect is a consequence of age-related decline in the amygdala, whereas the cognitive control hypothesis [Kryla Lighthall and Mather in: Handbook of Theories of Aging, ed 2. New York, Springer, 2009; Mather and Carstensen: Trends Cogn Sci 2005;9:496-502; Mather and Knight: Psychol Aging 2005;20:554-570] argues that the positivity effect is a result of older adults' greater focus on regulating emotion. Based on evidence for structural and functional preservation of the amygdala in older adults and findings that older adults show greater prefrontal cortex activity than younger adults while engaging in emotion-processing tasks, we argue that the cognitive control hypothesis is a more likely explanation for older adults' positivity effect than the aging-brain model. PMID- 21691053 TI - Viral stimuli trigger exaggerated thymic stromal lymphopoietin expression by chronic obstructive pulmonary disease epithelium: role of endosomal TLR3 and cytosolic RIG-I-like helicases. AB - BACKGROUND: Rhinovirus (RV)-induced chronic obstructive pulmonary disease (COPD) exacerbations exhibit TH(2)-like inflammation. We hypothesized that RV-infected bronchial epithelial cells (BEC) overproduce TH(2)-switching hub cytokine, thymic stromal lymphopoietin (TSLP) in COPD. METHODS: Primary BEC from healthy (HBEC) and from COPD donors (COPD-BEC) were grown in 12-well plates, infected with RV16 (0.5-5 MOI) or stimulated with agonists for either toll-like receptor (TLR) 3 (dsRNA, 0.1-10 MUg/ml) or RIG-I-like helicases (dsRNA-LyoVec, 0.1-10 MUg/ml). Cytokine mRNA and protein were determined (RTqPCR; ELISA). RESULTS: dsRNA dose dependently evoked cytokine gene overproduction of TSLP, CXCL8 and TNF-alpha in COPD-BEC compared to HBEC. This was confirmed using RV16 infection. IFN-beta induction did not differ between COPD-BEC and HBEC. Endosomal TLR3 inhibition by chloroquine dose-dependently inhibited dsRNA-induced TSLP generation and reduced generation of CXCL8, TNF-alpha, and IFN-beta. Stimulation of cytosolic viral sensors (RIG-I-like helicases) with dsRNA-LyoVec increased production of CXCL8, TNF-alpha, and IFN-beta, but not TSLP. CONCLUSIONS: Endosomal TLR3-stimulation, by dsRNA or RV16, induces overproduction of TSLP in COPD-BEC. dsRNA- and RV induced overproduction of TNF-alpha and CXCL8 involves endosomal TLR3 and cytosolic RIG-I-like helicases and so does the generation of IFN-beta in COPD BEC. RV16 and dsRNA-induced epithelial TSLP may contribute to pathogenic effects at exacerbations and development of COPD. PMID- 21691054 TI - The use of bone age in clinical practice - part 1. AB - This review examines the role of skeletal maturity ('bone age', BA) assessment in clinical practice. BA is mainly used in children with the following conditions: short stature (addressed in part 1 of this review), tall stature, early or late puberty, and congenital adrenal hyperplasia (all addressed in part 2). Various manual and automatic methods of BA assessment have been developed. Healthy tall children tend to have advanced BA and healthy short children tend to have delayed BA in comparison to chronological age. Growth hormone (GH) treatment of children with GH deficiency leads to a catch-up in BA that is usually appropriate for the height of the child. Response to GH is dependent on BA delay in young children with idiopathic short stature, and GH dosage appears to affect BA acceleration. In chronic renal failure, BA is delayed until puberty but then increases due to increased sensitivity of the growth plate to sex steroids, thus further impairing adult height. The assessment of BA provides an important contribution to the diagnostic workup and management of children with short stature. PMID- 21691055 TI - The use of bone age in clinical practice - part 2. AB - If height-limiting treatment is being considered for a child with tall stature, skeletal maturity is invaluable in the selection of appropriate patients for treatment, determining appropriate age of treatment commencement, monitoring progress of treatment, and determining the expected treatment effect on adult height. In precocious puberty, bone maturation can be usefully assessed at initial diagnosis and start of treatment and at regular intervals thereafter during treatment monitoring. Together with height, bone maturation is an essential parameter for long-term treatment monitoring in congenital adrenal hyperplasia. Bone age (BA) determination in children with skeletal dysplasia is only feasible in a few disorders and estimations should be treated with caution. Radiographs of the left hand and wrist are, however, essential in the diagnosis of many skeletal disorders. Bone mineralization and measures of bone lengths, width, thickness and cortical thickness should always be evaluated in relation to a child's height and BA, especially around puberty. The use of skeletal maturity, assessed on a radiograph alone to estimate chronological age for immigration authorities or criminal courts is not recommended. PMID- 21691056 TI - Effects of cyclosporine, tacrolimus and rapamycin on renal calcium transport and vitamin D metabolism. AB - BACKGROUND: Abnormalities in mineral metabolism are common complications of organ transplantation. The role of immunosuppressive agents in alteration of mineral metabolism is not clear. METHODS: We conducted an animal study to investigate the effects of cyclosporine A (CsA), tacrolimus, and sirolimus on renal calcium, magnesium and vitamin D metabolism. RESULTS: CsA and tacrolimus induced a 2- to 3 fold and 1.6- to 1.8-fold increase in urinary calcium and magnesium excretion, respectively, while rapamycin had no effects on calcium, but doubled the urinary magnesium excretion. CsA and tacrolimus, but not rapamycin, elevated serum 1,25(OH)(2) vitamin D without affecting the parathyroid hormone level. CsA and tacrolimus reduced mRNA abundance in TRPV5 (CsA: 64 +/- 3% of control; tacrolimus: 50 +/- 3%) calbindin-D28k (CsA: 62 +/- 4%; tacrolimus: 43 +/- 3%), and vitamin D receptor (CsA: 52 +/- 3%; tacrolimus: 58 +/- 2%, all p < 0.05). Rapamycin did not affect gene expression in any of studied proteins. The immunofluorescence staining study demonstrated a 50% reduction of TRPV5 and calbindin-D28k by CsA and tacrolimus. CONCLUSION: The suppression of VDR by calcineurin inhibitors is probably the underlying mechanism of renal calcium wasting. In spite of an increased 1,25(OH)(2) vitamin D level, the kidney is not able to reserve calcium, suggesting a role of vitamin D resistance that may be related to bone loss. PMID- 21691057 TI - Outcomes following dialysis for acute kidney injury among different stages of chronic kidney disease. AB - BACKGROUND: Information is limited regarding the outcomes of patients with preexisting chronic kidney disease (CKD) who develop dialysis-requiring acute kidney injury. METHODS: 131 adult patients with advanced CKD who received emergent hemodialysis from January to June in 2002 were recruited and monitored for all-cause mortality and end-stage renal disease until the end of 2007. RESULTS: Among patients investigated, 21 (16%) were successfully withdrawn from acute hemodialysis after an average of 8 sessions of dialysis therapy (range: 1 44). Multivariate analysis revealed that larger kidney size (odds ratio, OR = 1.755, p = 0.018), lower predialysis creatinine (OR = 0.722, p = 0.002), and non diabetes (OR = 0.271, p = 0.037) were predictors for withdrawal. After 5 years, all patients in the non-withdrawal group remained on chronic dialysis, whereas only 8/21 (38%) patients in the withdrawal group developed end-stage renal disease. Cox's analysis showed that age (hazard ratio, HR = 1.043, p < 0.0001), prerenal azotemia (HR = 1.040, p = 0.002), and adjusted propensity score for assigning to dialysis withdrawal (HR = 6.819, p = 0.008) were associated with mortality. Withdrawal from acute dialysis was not related to long-term mortality (p = 0.34). CONCLUSIONS: Among the advanced CKD patients, predictors of the successful weaning from acute dialysis were non-diabetes, larger kidney size and lower serum creatinine levels. The strategy of removal from emergent dialysis was not related to long-term mortality. PMID- 21691058 TI - Management of vagal paragangliomas including application of internal carotid artery stenting. AB - BACKGROUND: The primary treatment of vagal paraganglioma (VP) includes 'wait and scan', surgery and radiotherapy. OBJECTIVES: To present the clinical findings, surgical treatment including application of internal carotid artery (ICA) stenting to facilitate surgery, and complications, as well as to review the literature and to discuss the decision-making process in the management of VP cases based on our experience and the literature. DESIGN: A retrospective case review of 22 cases with VP. SETTING: Quaternary neurotologic and skull base referral center. MATERIAL AND METHODS: The retrospective chart review identified 22 patients presenting with VP. Our indication for surgery was VP in younger patients, irrespective of the existence of vocal cord paralysis. Preoperative endovascular management of the ICA included permanent balloon occlusion (PBO) and stenting. The transcervical approach and the infratemporal fossa approach type A (ITFA) were used. RESULTS: Fifteen cases had multicentric paragangliomas, 5 cases bilateral tumors, 3 cases a genetic mutation, and 2 cases a positive family history. The most common symptoms were hoarseness, tinnitus and hearing loss. The surgical approaches commonly employed for excision were the transcervical approach (9 cases) and the ITFA (12 cases), whereas 1 case did not have surgery. Three cases had PBO and 7 had intracarotid stent insertion. Gross total removal was achieved in 19 cases, and 1 case had a recurrence. Eighteen cases had no dysphagia or were well compensated after surgery. There were no significant complications noted in our series. CONCLUSIONS: In younger patients with VP, surgery should be recommended. The proper preoperative endovascular intervention and surgical approach facilitates gross total tumor removal. In the management of bilateral or familial paragangliomas, careful and appropriate decision making is essential. PMID- 21691059 TI - Ca(v)2.3 Ca2+ channel interacts with the G1-subunit of V-ATPase. AB - BACKGROUND: Calcium channels are essential in coupling action potential to signal transduction in cells. There are several types of calcium channels, which can be pharmacologically classified as L-, N-, P/Q-, R- and T-type. But molecular basis of R-type channels is less clearly understood compared the other channel types. Therefore the current study aims at understanding the molecular functions of R type calcium channels by identifying interaction partners of the channel. METHODS: In order to do so, a yeast two hybrid (Y2H) screen, with carboxy terminus of alpha1 subunit of the channel, as the bait, was performed. G1 subunit of v-ATPase was identified as a putative interaction partner of human Ca(v)2.3 by using the Y2H screening. The interaction was confirmed by immunoprecipitation. To study the functional importance of the interaction, bafilomycin A(1), a potent and specific inhibitor of v-ATPase was used in patch-clamp recordings in Ca(v)2.3 stably-transfected HEK-293 cells (2C6) as well as in electroretinography of the isolated bovine retina expressing R-type Ca(2+) channels. RESULTS: G1 subunit of v-ATPase interacts with C-terminal tail of Ca(v)2.3 and bafilomycin A(1) reduces Ca(v)2.3 mediated calcium currents. Additionally peak I(Ca) is inhibited in retinal signal transduction when recorded as ERG b-wave. CONCLUSIONS: The results suggest that v-ATPase interacts physically and also functionally with Ca(v)2.3. This is the first demonstration of association of Ca(v)2.3 C-terminus with a protein complex which is involved in transmembrane signalling. PMID- 21691060 TI - N-n-butyl haloperidol iodide preserves cardiomyocyte calcium homeostasis during hypoxia/ischemia. AB - AIMS: N-n-Butyl haloperidol iodide (F(2)) is a novel compound derived from haloperidol. In our previous work, F(2) was found to be an L-type calcium channel blocker which played a protective role in rat heart ischemic-reperfusion injury in a dose-dependent manner. In the current study, we aimed to investigate the effects and some possible mechanisms of F(2) on calcium transients in hypoxic/ischemic rat cardiac myocytes. METHODS AND RESULTS: Calcium transients' images of rat cardiac myocytes were recorded during simulated hypoxia, using a confocal calcium imaging system. The amplitude, rising time from 25% to 75% (RT25 75), decay time from 75% to 25% (DT75-25) of calcium transients, and resting [Ca(2+)](i) were extracted from the images by self-coding programs. In this study, hypoxia produced a substantial increase in diastolic [Ca(2+)](i) and reduced the amplitude of calcium transients. Both RT25-75 and DT75-25 of Ca(2+) transients were significantly prolonged. And F(2) could reduce the increase in resting [Ca(2+)](i)and the prolongation of RT25-75 and DT75-25 of Ca(2+) transients during hypoxia. F(2) also inhibited the reduction in amplitude of calcium transients which was caused by 30-min hypoxia. The activity of SERCA2a (sarcoplasmic reticulum Ca(2+)-ATPase, determined by test kits) decreased after 30-min ischemia, and intravenous F(2) in rats could ameliorate the decreased activity of SERCA2a. The inward and outward currents of NCX (recorded by whole cell patch-clamp analysis) were reduced during 10-min hypoxia, and F(2) further inhibited the outward currents of NCX during 10-min hypoxia. All these data of SERCA2a and NCX might be responsible for the changes in calcium transients during hypoxia. CONCLUSION: Our data suggest that F(2) reduced changes in calcium transients that caused by hypoxia/ischemia, which was regarded to be a protective role in calcium homeostasis of ventricular myocytes, probably via changing the function of SERCA2a. PMID- 21691061 TI - Structural basis of slow activation gating in the cardiac I Ks channel complex. AB - Accessory beta-subunits of the KCNE gene family modulate the function of various cation channel alpha-subunits by the formation of heteromultimers. Among the most dramatic changes of biophysical properties of a voltage-gated channel by KCNEs are the effects of KCNE1 on KCNQ1 channels. KCNQ1 and KCNE1 are believed to form nativeI(Ks) channels. Here, we characterize molecular determinants of KCNE1 interaction with KCNQ1 channels by scanning mutagenesis, double mutant cycle analysis, and molecular dynamics simulations. Our findings suggest that KCNE1 binds to the outer face of the KCNQ1 channel pore domain, modifies interactions between voltage sensor, S4-S5 linker and the pore domain, leading to structural modifications of the selectivity filter and voltage sensor domain. Molecular dynamics simulations suggest a stable interaction of the KCNE1 transmembrane alpha-helix with the pore domain S5/S6 and part of the voltage sensor domain S4 of KCNQ1 in a putative pre-open channel state. Formation of this state may induce slow activation gating, the pivotal characteristic of native cardiac I(Ks) channels. This new KCNQ1-KCNE1 model may become useful for dynamic modeling of disease-associated mutant I(Ks) channels. PMID- 21691062 TI - The electrophysiological effects of cardiac glycosides in human iPSC-derived cardiomyocytes and in guinea pig isolated hearts. AB - BACKGROUND/AIMS: Monitoring changes in the field potential (FP) of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) following compound administration has been proposed as a novel screening tool to evaluate cardiac ion channel interactions and QT liability. Here we extended the use of FP to evaluate the pharmacological and toxicological properties of cardiac glycosides. METHODS: FPs were recorded using microelectrode arrays (MEAs) in spontaneously beating hiPSC-CMs. The in vitro effects of ouabain and digoxin on FPs were compared with data generated on hemodynamic and ECG parameters in guinea pig Langendorff hearts. RESULTS: In hiPSC-CMs, ouabain and digoxin reduced Na(+) spike amplitude, shortened FP duration (FPD), increased Ca(2+)-wave amplitude, and dose-dependently induced arrhythmic beats. The ouabain-induced changes observed in hiPSC-CMs correlated well with the effects seen in isolated hearts which revealed QT shortening, enhancement of contractility, and arrhythmogenesis. Nifedipine, an L-type Ca(2+) channel blocker, reduced Ca(2+)-wave amplitude and FPD in hiPSC-CMs, and led to parallel effects of decreased ventricular contractility and shortened QT interval in isolated hearts. Further, nifedipine attenuated the Ca(2+)-peak amplitude and proarrhythmic effect of both glycosides. These results suggested that FPD and Ca(2+)-wave amplitude are comparable surrogates of QT interval and contractility of intact hearts, respectively. CONCLUSION: hiPSC-CMs reflect similar cardiac pharmacology as seen in isolated cardiac preparations and thus are a suitable model in study of the pharmacology and toxicology of cardioactive ion channel and transporter modulators. PMID- 21691063 TI - Stability of F-box protein atrogin-1 is regulated by p38 mitogen-activated protein kinase pathway in cardiac H9c2 cells. AB - BACKGROUND: Atrogin-1/MAFbx is a major atrophy-related E3 ubiquitin ligase that functions as a negative regulator of cardiac hypertrophy. The mRNA expression of atrogin-1 is induced by oxidative stress via p38 mitogen-activated protein kinase (p38 MAPK). However, the molecular mechanisms that regulate the stability of atrogin-1 protein remain unclear. METHODS: 293T and cardiac H9c2 cells were transfected with plasmids as indicated. The in vivo and in vitro ubiquitination assay and pulse-chase analysis were performed to detect the ubiquitination and stability of atrogin-1. The protein levels were measured by Western blot analysis. RESULTS: We found that atrogin-1 underwent ubiquitin-mediated degradation by proteasome. The F-box motif of atrogin-1 and Skp1-Cul1-Roc1-F-box (SCF) complex are required for ubiquitination and degradation of atrogin-1. Furthermore, p38 MAPK signaling plays critical roles in regulating the ubiquitination and degradation of atrogin-1 as well as serum starvation-induced expression of atrogin-1 and reduction of H9c2 cell size. CONCLUSION: These findings may define a new mechanism for regulating the stability of atrogin-1 partially by p38 MAPK signaling. PMID- 21691064 TI - NOX2, p22phox and p47phox are targeted to the nuclear pore complex in ischemic cardiomyocytes colocalizing with local reactive oxygen species. AB - BACKGROUND: NADPH oxidases play an essential role in reactive oxygen species (ROS)-based signaling in the heart. Previously, we have demonstrated that (peri)nuclear expression of the catalytic NADPH oxidase subunit NOX2 in stressed cardiomyocytes, e.g. under ischemia or high concentrations of homocysteine, is an important step in the induction of apoptosis in these cells. Here this ischemia induced nuclear targeting and activation of NOX2 was specified in cardiomyocytes. METHODS: The effect of ischemia, mimicked by metabolic inhibition, on nuclear localization of NOX2 and the NADPH oxidase subunits p22(phox) and p47(phox), was analyzed in rat neonatal cardiomyoblasts (H9c2 cells) using Western blot, immuno electron microscopy and digital-imaging microscopy. RESULTS: NOX2 expression significantly increased in nuclear fractions of ischemic H9c2 cells. In addition, in these cells NOX2 was found to colocalize in the nuclear envelope with nuclear pore complexes, p22(phox), p47(phox) and nitrotyrosine residues, a marker for the generation of ROS. Inhibition of NADPH oxidase activity, with apocynin and DPI, significantly reduced (peri)nuclear expression of nitrotyrosine. CONCLUSION: We for the first time show that NOX2, p22(phox) and p47(phox) are targeted to and produce ROS at the nuclear pore complex in ischemic cardiomyocytes. PMID- 21691065 TI - L-NAME treatment enhances exercise-induced content of myocardial heat shock protein 72 (Hsp72) in rats. AB - BACKGROUND/AIM: Nitric oxide (NO) modulates the expression of the chaperone Hsp72 in the heart, and exercise stimulates both NO production and myocardial Hsp72 expression. The main purpose of the study was to investigate whether NO interferes with an exercise-induced myocardial Hsp72 expression. METHODS: Male Wistar rats (70-100 days) were divided into control (C, n=12), L-NAME-treated (L, n=12), exercise (E, n=13) and exercise plus L-NAME-treated (EL, n=20) groups. L NAME was given in drinking water (700 mg.L(-1)) and the exercise was performed on a treadmill (15-25 m.min(-1), 40-60 min.day(-1)) for seven days. Left ventricle (LV) protein Hsp content, NOS and phosphorylated-NOS (p-NOS) isoforms were measured using Western blotting. The activity of NOS was assayed in LV homogenates by the conversion of [(3)H]L-arginine to [(3)H]L-citrulline. RESULTS: Hsp72 content was increased significantly (223%; p < 0.05) in the E group compared to the C group, but exercise alone did not alter the NOS content, p-NOS isoforms or NOS activity. Contrary to our expectation, L-NAME enhanced (p < 0.05) the exercise-induced Hsp72 content (EL vs. C, L and E groups = 1019%, 548% and 457%, respectively). Although the EL group had increased stimulatory p eNOS(Ser1177) (over 200%) and decreased inhibitory p-nNOS(Ser852) (n50%) compared to both the E and L groups (p < 0.05), NOS activity was similar in all groups. CONCLUSIONS: Our results suggest that exercise-induced cardiac Hsp72 expression does not depend on NO. Conversely, the in vivo L-NAME treatment enhances exercise induced Hsp72 production. This effect may be due to an increase in cardiac stress. PMID- 21691066 TI - Attenuation of CHOP-mediated myocardial apoptosis in pressure-overloaded dominant negative p38alpha mitogen-activated protein kinase mice. AB - BACKGROUND/AIMS: Pressure overload stimulation is known to elicit disturbances in the endoplasmic reticulum (ER), which leads to ER stress (ERS). p38 mitogen activated protein kinase (MAPK) plays an important role in mediating apoptotic processes, however, the roles of this kinase in activating ERS-initiated apoptosis in pressure-overloaded hearts are largely unknown. METHODS: We clarified the role of p38alpha MAPK in ERS-associated apoptosis by subjecting transgenic mice displaying cardiac specific dominant negative (DN) mutant p38alpha MAPK over-expression to seven day pressure overload. RESULTS: Seven days pressure overload resulted in the same extent of cardiac hypertrophy and ERS in the wild-type (WT) and DN p38alpha mice compared with the sham mice. It also activated inositol-requiring enzyme (Ire)-1alpha and its downstream molecule, tumor necrosis factor receptor (TNFR)-associated factor (TRAF)2 in the WT and DN p38alpha mice compared with the sham mice. Interestingly, increased myocardial apoptosis and the up-regulation of CCAAT/enhancer binding protein homology protein (CHOP) expression compared with those in the sham mice were found in the aortic-banded WT mice, but not in the DN p38alpha mice. CONCLUSION: Partial inhibition of p38alpha protein blocked the activation of CHOP-mediated apoptotic processes during pressure overload by partially inhibiting signaling from the Ire 1alpha/TRAF2 to its down-stream molecule, CHOP. PMID- 21691067 TI - Atrial and vascular oxidative stress in patients with heart failure. AB - Heart failure is characterized by a great number of metabolic and histological defects, however, previous studies did not provide strong evidence of a correlation between the antioxidant status of myocardial tissue itself and cardiac function. The goal of our study was to assess, in patients with heart failure consecutive to dilated cardiomyopathy (DCM), alterations in norepinephrine (NE), lipid peroxidation (malonedialdehyde: MDA) and iron levels in different parts of the myocardium and aorta, in relation to functional parameters. Biopsied heart samples were obtained from 12 DCM patients and from 4 brain-dead organ donors (Controls). The left ventricular ejection fraction (LVEF) was reduced to 19.1+/-2.6% in DCM. For all patients, the distribution of NE in the atria, ventricles and vessels was different, but NE content in control hearts was systematically higher than in cardiomyopathy patients. MDA levels tended to be higher in the different samples from the DCM group in comparison with the values obtained in the C group; the values were significantly decreased (p<0.05) in endocardium and the aortic samples. In the right atrium there was a significant correlation between NE content and LVEF and between MDA and iron concentrations. These findings could give further insights into the relationship between iron metabolism disturbances and the severity of cardiovascular diseases. PMID- 21691068 TI - GABARAPL1 negatively regulates Wnt/beta-catenin signaling by mediating Dvl2 degradation through the autophagy pathway. AB - Wnt signaling is critical for many biological processes and is tightly regulated. In this study, we found that GABARAPL1 (GABA(A) receptor-associated protein like 1, GABARAPL1) interacts with Dvl2 by both yeast two-hybrid screening and immunoprecipitation experiments. Furthermore, we observed that p62 is required for the interaction of Dvl2 and GABARAPL1. Luciferase assays indicated that GABARAPL1 represses Wnt/beta-catenin signaling stimulated by Wnt1, Dvl2 and beta catenin. We further demonstrated that GABARAPL1 mediates degradation of Dvl2 and the effect is blocked by addition of 3-MA, a specific inhibitor of autophagy. Finally, we provided evidence that over-expression of GABARAPL1 inhibits proliferation and tumor growth of MCF7 cells in vitro and in nude mice. Taken together, our results suggested that GABARAPL1 as a tumor repressor inhibits Wnt signaling via mediating Dvl2 degradation through the autophagy pathway. PMID- 21691069 TI - Cytoprotective effect of eriodictyol in UV-irradiated keratinocytes via phosphatase-dependent modulation of both the p38 MAPK and Akt signaling pathways. AB - Although flavonoids exhibit a variety of beneficial biological activities, the exact molecular mechanism of the cellular effects is still not fully explained. In this study, we investigated the molecular mechanism of cytoprotective effect of eriodictyol in UV-irradiated keratinocytes. We found that treatment with eriodictyol effectively suppressed the UV-induced cell death of the keratinocytes, concomitant with the inhibition of pro-caspase-3 or pro-caspase-9 cleavage and the suppression of cytochrome C release. The phosphorylation of p38 MAPK was suppressed during UV-induced apoptosis of the keratinocytes and eriodictyol could reverse the down-regulation of p38 MAPK upon UV irradiation. Inhibition of p38 MAPK activity by SB202190, or over-expression of dominant negative mutant form of p38 MAPK resulted in suppression of cytoprotective effect of the flavonoid. PP2A appeared to participate in the regulation of both p38 MAPK and Akt activities by directly associating with the kinases. UV treatment stimulated not only the phosphatase activity, but also its association with p38 MAPK or Akt. Interestingly, eriodictyol reversed the increase in PP2A activity and the association between the proteins. Taken together, these findings suggest that eriodictyol may lead to protection of keratinocytes from UV-induced cytotoxicity by modulating both the p38 MAPK and Akt signaling pathways in a phosphatase-dependent manner. PMID- 21691070 TI - Inhibitory effect of unsaturated fatty acids on saturated fatty acid-induced apoptosis in human pancreatic beta-cells: activation of caspases and ER stress induction. AB - AIMS: In this study we have tested the effect of unsaturated fatty acids on the proapoptotic effects of saturated fatty acids in the human pancreatic beta-cells NES2Y. RESULTS: We found that unsaturated palmitoleic and oleic acid at a concentration of 0.2 mM and higher are able to completely inhibit the proapoptotic effect of their counterpart saturated palmitic and stearic acid at a concentration of 1 mM. Apoptosis induced by stearic acid was associated with significant activation of caspase-6, -7, -9, -2 and -8, but not with significant activation of caspase-3. The activation of caspases was blocked by coincubation with oleic acid. Stearic acid treatment was not associated with a significant change in mitochondrial membrane potential, reactive oxygen species level and with cytochrome c release from mitochondria. Furthermore, stearic acid treatment was not associated with changes in p21(WAF1/CIP1), PIDD, Fas receptor and Fas ligand expression. However, we detected endoplasmic reticulum (ER) stress markers, i. e. a significant upregulation of BiP and CHOP expression as well as XBP1 mRNA splicing. These changes were inhibited by coincubation with oleic acid. CONCLUSION: Presented data indicate that oleic acid inhibits apoptosis induction by stearic acid in NES2Y cells upstream of caspase activation and ER stress induction. It does not involve an interference with the mitochondrial pathway of apoptosis induction, with p53 activation and PIDD expression as well as with Fas receptor and Fas ligand expression. PMID- 21691071 TI - Caspase 3 is activated through caspase 8 instead of caspase 9 during H2O2-induced apoptosis in HeLa cells. AB - Oxidative stress is known to be involved in a variety of pathological processes including atherosclerosis, diabetes, and neurodegenerative diseases. Understanding how intracellular signaling pathways respond to oxidative stress will have a significant implication in the therapy of these diseases. In this study, we applied hydrogen peroxide (H(2)O(2)) to trigger apoptosis and investigated the dynamic activation of various caspases using a FRET technique. We measured the activation dynamics of caspase 3 and caspase 9 based on two reporter systems, SCAT 3 and SCAT 9. We found that caspase 3 activation was earlier than that of caspase 9 following H(2)O(2) treatment. Caspase 3 was activated rapidly, reaching a maximum in 12+/-3 min, while the average duration of caspase 9 activation was 21+/-3 min. When cells were pretreated with Z-LEHD fmk, a caspase 9 specific inhibitor, caspase 3 activation and apoptosis by H(2)O(2) treatment were little affected, although the caspase 9 activation was completely inhibited. When cells were pretreated with Z-DEVD-fmk, a caspase 3 specific inhibitor, the activation of both caspase 3 and caspase 9, as well as apoptosis, were inhibited. When cells were pretreated with Z-IETD-fmk, a caspase 8 specific inhibitor, the activation of caspase 3 and caspase 9 were significantly delayed. Finally, we found that Bax did not translocate from the cytosol to the mitochondrial membrane during H(2)O(2)-induced apoptosis. Our results suggest that, during H H(2)O(2)-induced apoptosis, caspase 3 is activated directly through caspase 8 and is not through the mitochondria-dependent caspase 9 activation. PMID- 21691073 TI - Hemotrophic mycoplasmas induce programmed cell death in red blood cells. AB - Hemotrophic mycoplasmas (HM) are uncultivable bacteria found on and in the red blood cells (RBCs). The main clinical sign of HM infections is the hemolytic anemia. However, anemia-inducing pathogenesis has not been totally clarified. In this work we used the splenectomized pig as animal model and Mycoplasma suis as a representative for hemotrophic mycoplasmas to study anemia pathogenesis. Eryptosis, i.e. programmed cell death of RBCs, is characterized by cell shrinkage, microvesiculation and phosphatidylserine (PS) exposure on the outer membrane. The eryptosis occurrence and its influence on anemia pathogenesis was observed over the time-course of M. suis infections in pigs using 3 M. suis isolates of differing virulence. All 3 isolates induced eryptosis, but with different characteristics. The occurrence of eryptosis could as well be confirmed in vitro: serum and plasma of an acutely ill pig induced PS exposure on erythrocytes drawn from healthy pigs. Since M. suis is able to induce eryptotic processes it is concluded that eryptosis is one anemia-inducing factor during M. suis infections and, therefore, plays a significant role in the pathogenesis of infectious anemia due to HM infection. PMID- 21691072 TI - Janus kinase 3 is expressed in erythrocytes, phosphorylated upon energy depletion and involved in the regulation of suicidal erythrocyte death. AB - Janus kinase 3, a tyrosine kinase expressed in haematopoetic tissues, plays a decisive role in T-lymphocyte survival. JAK3 deficiency leads to (Severe) Combined Immunodeficiency (SCID) resulting from enhanced lymphocyte apoptosis. JAK3 is activated by phosphorylation. Nothing is known about expression of JAK3 in erythrocytes, which may undergo apoptosis-like cell death (eryptosis) characterized by cell membrane scrambling with phosphatidylserine exposure and cell shrinkage. Triggers of eryptosis include energy depletion. The present study utilized immunohistochemistry and confocal microscopy to test for JAK3 expression and phosphorylation, and FACS analysis to determine phosphatidylserine exposure (annexin binding) and cell volume (forward scatter). As a result, JAK3 was expressed in erythrocytes and phosphorylated following 24h and 48h glucose depletion. Forward scatter was slightly but significantly smaller in erythrocytes from JAK3-deficient mice (jak3(-/-)) than in erythrocytes from wild type mice (jak3(+/+)). Annexin V binding was similarly low in both genotypes. The JAK3 inhibitors WHI-P131/JANEX-1 (4-(4'-Hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 156MUM) and WHI-P154 (4-[(3'-Bromo-4'-hydroxyphenyl)amino]-6,7 dimethoxyquinazoline, 11.2MUM) did not significantly modify annexin V binding or forward scatter. Glucose depletion increased annexin V binding, an effect significantly blunted in jak3(-/-) erythrocytes and in the presence of the JAK3 inhibitors. The observations disclose a completely novel role of Janus kinase 3, i.e. the triggering of cell membrane scrambling in energy depleted erythrocytes. PMID- 21691074 TI - SKLB610: a novel potential inhibitor of vascular endothelial growth factor receptor tyrosine kinases inhibits angiogenesis and tumor growth in vivo. AB - Antagonizing angiogenesis-related receptor tyrosine kinase is a promising therapeutic strategy in oncology. In present study, we designed and synthesized a novel vascular endothelial growth factor receptor (VEGFR) inhibitor N-methyl-4-(4 (3-(trifluoromethyl) benzamido) phenoxy) picolinamide SKLB610 that potently suppresses human tumor angiogenesis. SKLB610 inhibited angiogenesis-related tyrosine kinase VEGFR2, fibroblast growth factor receptor 2 (FGFR2) and platelet derived growth factor receptor (PDGFR) at rate of 97%, 65% and 55%, respectively, at concentration of 10MUM in biochemical kinase assays. In vitro, SKLB610 showed more selective inhibition of VEGF-stimulated human umbilical vein endothelial cells (HUVECs) proliferation, and this proliferation inhibitory effect was associated with decreased phosphorylation of VEGFR2 and p42/44 mitogen-activated protein kinase (p42/44 MAPK). Antiangiogenic evaluation showed that SKLB610 inhibited the HUVECs capillary-tube formation on Matrigel in vitro and the sub intestinal vein formation of zebrafish in vivo. Moreover, SKLB610 inhibited a panel of human cancer cells proliferation in a concentration-dependent manner and human non-small cell lung cancer cell line A549 and human colorectal cancer cell line HCT116 were most sensitive to SKLB610 treatment. In vivo, chronic intraperitoneally administration of SKLB610 at dose of 50mg/kg/d resulted in significant inhibition in the growth of established human A549 and HCT116 tumor xenografts in nude mice without exhibit toxicity. Histological analysis showed significant reductions in intratumoral microvessel density (CD31 staining) of 43 55% relative to controls depending on the specific tumor xenografts. In conclusion, the present study demonstrated that SKLB610 exhibited its antitumor activity as a multi-targeted inhibitor with more potent inhibition of VEGFR2 activity. Its potential to be a candidate of anticancer agent is worth being further investigated. PMID- 21691075 TI - Metastasis suppressor KAI1/CD82 attenuates the matrix adhesion of human prostate cancer cells by suppressing fibronectin expression and beta1 integrin activation. AB - KAI1/CD82, a tetraspanin membrane protein functions as a metastasis suppressor in many types of human cancers and has been shown to regulate cell adhesion properties. In the present study, we investigated the underlying mechanism of KAI1/CD82-mediated changes in cell adhesion to the extracellular matrix using human prostate cancer cells. We found that high KAI1/CD82 expression attenuated short-term cell adhesion to uncoated- or fibronectin-coated plates. Moreover, high KAI1/CD82 expression generated an extracellular environment unfavorable for cell adhesion as compared to low KAI1/CD82 expression, suggesting KAI1/CD82 dependent regulation of extracellular matrix (ECM) molecule(s) expression and/or secretion. Among ECM components examined, fibronectin exhibited decreased expression and secretion in high KAI1/CD82-expressing cells. Furthermore, high KAI1/CD82 expression interfered with the activation of beta (1) integrin at the cell surface while total beta (1) integrin levels remained unchanged, concomitant with reduced formation of focal adhesion complex and decreased bundling of actin filaments. Finally, high KAI1/CD82 expression significantly retarded cell motility in a scratch wound assay. Taken together, our results strongly suggest that KAI1/CD82 attenuates the activation of beta (1) integrin, and thereby down regulates outside-in signaling of beta (1) integrin, leading to the reduction of focal adhesion formation and fibronectin expression/secretion, which subsequently interferes with cell adhesion properties and motility. PMID- 21691076 TI - Intrapulmonary delivery of human umbilical cord mesenchymal stem cells attenuates acute lung injury by expanding CD4+CD25+ Forkhead Boxp3 (FOXP3)+ regulatory T cells and balancing anti- and pro-inflammatory factors. AB - BACKGROUND: Systemic and local inflammatory processes play key, mainly detrimental roles in the pathophysiology of acute lung injury (ALI). The present study was designed to determine whether human umbilical cord mesenchymal stem cells (UCMSC) are able to act on CD4(+)CD25(+) Foxp3(+)Treg cells and lead to an improvement in ALI. METHODS: Mice were administered intratracheally endotoxin (lipopolysaccharide [LPS]) and received intrapulmonary 1*10(6) UCMSC 4 hours after challenge. The CD4(+)CD25(+) Foxp3(+)Treg, survival time, body weight, histology and lung injury scores were assessed after transplantation of UCMSC. In addition, anti-inflammatory factor IL10 and pro-inflammatory mediators production including tumor necrosis factor-a (TNF-alpha), macrophage inflammatory protein 2(MIP-2) and interferon-gamma (IFN-gamma) were detected. RESULTS: Transplantation of UCMSC resulted in significant increase in the level of CD4(+)CD25(+) Foxp3(+)Treg in ALI. Increased level of anti-inflammatory factor IL-10 and reduced levels of TNF-alpha, MIP-2 and IFN-gamma were simultaneously observed in ALI in comparison with control mice. CONCLUSION: Our data demonstrate for the first time that transplantation of UCMSC ameliorates ALI by enhancing the diminished levels of alveolar CD4(+)CD25(+) Foxp3(+)Treg and balancing anti- and pro-inflammatory factors in ALI mice. PMID- 21691077 TI - Ca2+ activated K+ channel Kca3.1 as a determinant of gastric acid secretion. AB - The Ca(2+) activated K(+) channel K(ca)3.1 is expressed in a variety of tissues. In the gastric gland it is expressed in the basolateral cell membrane. To determine the functional significance of K(ca)3.1 activity for gastric acid secretion, gastric acid secretion was determined in isolated glands from gene targeted mice lacking functional K(ca)3.1 (K(ca)3.1(-/-)) and from their wild type littermates (K(ca)3.1(+/+)). According to BCECF-fluorescence cytosolic pH in isolated gastric glands was similar in K(ca)3.1(-/-) and K(ca)3.1(+/+) mice. Na(ca)-independent pH recovery (DeltapH/min) following an ammonium pulse, a measure of H(ca)/K(ca) ATPase activity, was, however, significantly faster in K(ca)3.1(-/-) than in K(ca)3.1(+/+) mice. Accordingly, the luminal pH was significantly lower and the acid content significantly higher in K(ca)3.1(-/-) than in K(ca)3.1(+/+) mice. The abundance of mRNA encoding H(ca)/K(ca) ATPase and KCNQ1 was similar in both genotypes. Increase of extracellular K(ca) concentrations to 35 mM (replacing Na(ca)/NMDG) and treatment with histamine (100 MUM) significantly increased DeltapH/min to a larger extent in K(ca)3.1(+/+) than in K(ca)3.1(-/-) mice and dissipated the differences between the genotypes. Carbachol (100 MUM) increased DeltapH/min in both genotypes but did not abolish the difference between K(ca)3.1(-/-) and K(ca)3.1(+/+) mice. In K(ca)3.1(+/+) mice the K(ca)3.1 opener DCEBIO (100 MUM) did not significantly alter basal DeltapH/min but significantly blunted DeltapH/min in the presence of carbachol. In conclusion, K(ca)3.1 activity suppresses carbachol stimulated gastric acid secretion. PMID- 21691079 TI - Activation of growth hormone secretagogue type 1a receptor inhibits T-type Ca2+ channel currents through pertussis toxin-sensitive novel protein kinase C pathway in mouse spermatogenic cells. AB - Ghrelin, a newly isolated brain-gut peptide, has been found to play important roles in the male reproduction. However, to date, the detailed mechanisms still remain unknown. In this study, we identified a novel functional role of ghrelin in modulating T-type Ca(2+) channel currents (T-currents) in mouse spermatogenic cells. We found that ghrelin inhibited T-currents in a dose-dependent manner. Ghrelin at 0.1 MUM reversibly inhibited T-currents by ~31.7%. This inhibitory effect was blocked by D-Lys3-GHRP-6, a selective growth hormone secretagogue receptor 1a (GHS-R1a) antagonist. Intracellular infusion of GDP-b-S or pretreatment of the cells with pertussis toxin (PTX) completely blocked the inhibitory effects of ghrelin. Furthermore, ghrelin responses were abolished by the phospholipase C inhibitor U73122, but not the inactive analogue U73343. The classical and novel protein kinase C antagonist chelerythrine chlorid or GF109203X abolished ghrelin responses, whereas Ro31-8820, a classical PKC antagonist or PKI 6-22, a PKA antagonist, elicited no such effects. Taken together, these results suggest that ghrelin acting through GSH-R1a inhibits T currents via a PTX-sensitive novel PKC pathway in mouse spermatogenic cells, which could contribute to its male reproductive functions such as acrosome reactions. PMID- 21691078 TI - Nicotine reduces TNF-alpha expression through a alpha7 nAChR/MyD88/NF-KB pathway in HBE16 airway epithelial cells. AB - AIMS: To explore the signaling mechanism associated with the inhibitory effect of nicotine on tumor necrosis factor (TNF)- alpha expression in human airway epithelial cells. METHODS: HBE16 airway epithelial cells were cultured and incubated with either nicotine or cigarette smoke extract (CE). Cells were then transfected with alpha1, alpha5, or alpha7 nicotinic acetylcholine receptor (nAChR)-specific small interfering RNAs (siRNAs). The effects of nicotine on the production of proinflammatory factors TNF-alpha, in transfected cells were analyzed. Furthermore, we assayed the expression levels of myeloid differentiation primary response gene 88 (MyD88) protein, nuclear factor kappa light-chain-enhancer of activated B cells (NF-kappaB) p65 protein, NF-kappaB activity and NF-kappaB inhibitor alpha (I-kappaBalpha) expression in cells after treatment with nicotine or alpha7 nAChR inhibitor, alpha -bungarotoxin (alpha BTX). RESULTS: The production of TNF-alpha was lower in cells pretreated with nicotine before lipopolysaccharide (LPS) stimulation, compared with LPS-only treated cells. In contrast, in alpha7 siRNA-transfected cells incubated with nicotine and LPS, TNF-alpha expression was higher than that in non-transfected cells or in alpha1 or alpha5 siRNA-transfected cells. Addition of MyD88 siRNA or the NF-kappaB inhibitor pyridine-2,6-dithiocarboxylic acid (PDTC) also reduced TNF-alpha expression. Furthermore, we found that nicotine decreased MyD88 protein, NF-kappaB p65 protein, NF-kappaB activity and phospho-I-kappaBalpha expression induced by CE or LPS. The inhibitor alpha-BTX could reverse these effects. CONCLUSION: Nicotine reduces TNF-alpha expression in HBE16 airway epithelial cells, mainly through an alpha7 nAChR/MyD88/NF-kappaB pathway. PMID- 21691080 TI - A semi-automated programme for tracking myoblast migration following mechanical damage: manipulation by chemical inhibitors. AB - BACKGROUND: Potential roles for undifferentiated skeletal muscle stem cells or satellite cells in muscle hypertrophy and repair have been reported, however, the capacity, the mode and the mechanisms underpinning migration have not been investigated. We hypothesised that damaged skeletal myoblasts would elicit a mesenchymal-like migratory response, which could be precisely tracked and subsequently manipulated. METHODS: We therefore established a model of mechanical damage and developed a MATLAB(TM) tool to measure the migratory capacity of myoblasts in a non-subjective manner. RESULTS: Basal migration following damage was highly directional, with total migration distances of 948MUm +/- 239MUm being recorded (average 0-24 hour distances: 491MUm +/- 113MUm and 24-48 hour distances: 460MUm +/- 218MUm). Pharmacological inhibition of MEK or PI3-K using PD98059 (20MUM) or LY294002 (5MUm), resulted in significant reduction of overall cell migration distances of 38% (p<0.001) and 39.5% (p<0.0004), respectively. Using the semi-automated cell tracking using MATLAB(TM) program we validated that not only was migration distance reduced as a consequence of reduced cell velocity, but critically also as a result of altered directionality of migration. CONCLUSION: These studies demonstrate that murine myoblasts in culture migrate and provide a good model for studying responsiveness to damage in vitro. They illustrate for the first time the powerful tool that MATLAB(TM) provides in determining that both velocity and directional capacity influence the migratory potential of cellular movement with obvious implications for homing and for metastases. PMID- 21691081 TI - High insulin concentrations repress insulin receptor gene expression in calf hepatocytes cultured in vitro. AB - The major role of insulin and the insulin receptor (InsR) in the liver is to mediate glucose uptake into hepatocytes to synthesize glycogen and to maintain blood glucose homeostasis. In this study, we investigated the effects of high insulin concentrations on InsR gene expression in calf hepatocytes cultured in vitro. After the cells were cultured for 72 h, insulin was added to the culture solution at final concentrations of 0, 1, 10, 100 or 1000 nM. InsR mRNA expression was determined by semi-quantitative RT-PCR. The results showed that InsR mRNA expression in hepatocytes, adjusted for beta-actin expression, decreased dose dependently with increasing insulin concentration. InsR mRNA expression was similar at 1 and 10 nM insulin, but was significantly lower than that in the control. InsR expression was similar at 100 and 1000 nM insulin, but was significantly lower than that in the control, 1 and 10 nM insulin groups. These data suggest that high concentrations of insulin significantly repress InsR mRNA expression in calf hepatocytes, and this inhibition occurs in a dose dependent manner. Further studies are needed to investigate the mechanisms underlying these effects of insulin. PMID- 21691082 TI - Expression and function of fibroblast growth factor (FGF) 7 during liver regeneration. AB - BACKGROUND/AIM: Previous studies have shown that fibroblast growth factors (FGFs) are involved in the process of liver injury repair. Liver regeneration after partial hepatectomy (PH) is impaired in transgenic mice expressing dominant negative FGFR2b in hepatocytes. Although FGF7, a ligand specifically bound to FGFR2b, is expressed by activated hepatic stellate cells (HSCs) in fibrotic livers, the expressions and functions of FGF7 and FGFR2b after PH remain unexplored. Therefore, this study sought to examine the potential role of FGF7 signaling during liver regeneration. METHODS: We examined the expression of FGF7 and FGFR2b in normal and regenerating livers. Effects of FGF7 on hepatocytes were examined in vitro using primary hepatocyte culture with FGF7 recombinant protein and in vivo by hydrodynamic-based gene transfer method. RESULTS: We found that FGF7 expression was increased according to the activation status of HSCs after PH. The receptor, FGFR2b, was also increased in hepatocytes during liver regeneration. In vitro treatment with FGF7 protein activated ERK1/2 and promoted proliferation of hepatocytes isolated from regenerating livers. In vivo overexpression of exogenous FGF7 could notably promote hepatic proliferation and activate MAPKs after PH. CONCLUSION: This study suggests a role for activated HSC expressed FGF7 in stimulating FGF signaling pathways in hepatocytes and regulating liver regeneration. PMID- 21691083 TI - Disruption of the actin cytoskeleton induces fluorescent glucose accumulation on the rat hepatocytes Clone 9. AB - BACKGROUND: Glucose transport and metabolism are highly specialized in hepatocytes. Actin cytoskeleton is fundamental to the maintenance of their morphology as well as to ensure their functionality. Here we study the effect of the actin disrupting natural compounds cytochalasin B and latrunculin A on the glucose metabolism of the Clone 9 rat hepatocytes once the glucose molecule is inside them and the effects of two hormones which main function is regulating the glucose metabolism on the actin cytoskeleton of Clone 9 cells. METHODS: F-actin was labeled by using Oregon Green 514 (r) phalloidin and glucose inside cells was monitored with the fluorescent D-glucose derivative; 2-NBDG. Observations and measurements were carried out by using a confocal microscope. RESULTS: Nor insulin neither glucagon was able to induce any significant effect in the quantity of F-actin present on Clone 9 cells. But insulin triggers a strong reorganization on the pattern of distribution of F-actin. However, the actin cytoskeleton disruption induced by CB and more efficiently by Lat A caused accumulation of 2-NBDG in cells. CONCLUSION: These results state that disruption of the actin cytoskeleton induces fluorescent glucose accumulation on the rat hepatocytes Clone 9 suggesting that actin disrupting agents cause a blockage in the glycolytic pathway of Clone 9 hepatocytes. PMID- 21691084 TI - 1alpha,25-dihydroxycholecalciferol induces nitric oxide production in cultured endothelial cells. AB - BACKGROUND: Recently, 1alpha,25-dihydroxycholecalciferol (vitD) has received increasing interest for its effects on many tissues and organs other than bone. A number of experimental studies have shown that vitD may have an important role in modifying risk for cardiovascular disease. AIMS: This study was planned to test the effects of vitD on endothelial nitric oxide (NO) production and to study the intracellular pathways leading to NO release. METHODS: In human umbilical vein endothelial cells (HUVEC) cultures the effects of vitD on NO production and p38, Akt, ERK and eNOS phosphorylations were examined in absence or in presence of the NO synthase inhibitor L-NAME and protein kinases specific inhibitors SB203580, wortmannin and UO126. RESULTS: VitD caused a concentration-dependent increase in NO production. The maximum effect was observed at a concentration of 1 nM and the optimal time of stimulation was 1 min. Effects induced by vitD were abolished by L-NAME and by pre-treatment with protein kinases inhibitors. To verify the effective involvement of vitD receptor (VDR) in the action mechanism of vitD, experiments were repeated in presence of the specific VDR ligands ZK159222 and ZK191784. CONCLUSIONS: The results of this study demonstrate that vitD can induce a significant increase in endothelial NO production. VitD interaction with VDR caused the phosphorylation of p38, AKT and ERK leading to eNOS activation. PMID- 21691085 TI - Degradation of filamin induces contraction of vascular smooth muscle cells in type-I collagen matrix honeycombs. AB - BACKGROUND: Dedifferentiated rabbit vascular smooth muscle cells (SMCs) exhibit similar features to differentiated SMCs when cultured in three-dimensional matrices of type-I collagen called "honeycombs," but the mechanism is unknown. The role of filamin, an actin-binding protein that links actin filaments in SMCs, was investigated. METHODS: Filamin and other related proteins were detected by western blot analysis and immunofluorescence staining. Honeycomb size was measured to confirm the contraction of SMCs. RESULTS: Full-length filamin was expressed in subconfluent SMCs cultured on plates; however, degradation of filamin, which might be regulated by calpain, was observed in confluent SMCs cultured on plates and in honeycombs. While filamin was co-localized with beta actin in subconfluent SMCs grown on plates, filamin was detected in the cytoplasm in SMCs cultured in honeycombs, and degraded filamin was mainly detected in the cytoplasmic fraction of these cells. In addition, beta-actin expression was low in the cytoskeletal fraction of SMCs cultured in honeycombs compared with cells cultured on plates, and the size of the honeycombs used for culturing SMCs was significantly reduced. CONCLUSION: These data suggest that degradation of filamin in SMCs cultured in honeycombs induces structural weakness of beta-non-muscle actin filaments, thereby permitting SMCs in honeycombs to achieve contractility. PMID- 21691086 TI - NAD blocks high glucose induced mesangial hypertrophy via activation of the sirtuins-AMPK-mTOR pathway. AB - BACKGROUND/AIMS: Since the discovery of NAD-dependent deacetylases, Sirtuins, it has been recognized that maintaining intracellular levels of NAD is crucial for the management of stress-response of cells. Here we show that high glucose(HG) induced mesangial hypertrophy is associated with loss of intracellular levels of NAD. This study was designed to investigate the effect of NAD on HG-induced mesangial hypertrophy. METHODS: The rat glomerular mesangial cells (MCs) were incubated in HG medium with or without NAD. Afterwards, NAD(+)/NADH ratio and enzyme activity of Sirtuins was determined. In addition, the expression analyses of AMPK-mTOR signaling were evaluated by Western blot analysis. RESULTS: We showed that HG induced the NAD(+)/NADH ratio and the levels of SIRT1 and SIRT3 activity decreased as well as mesangial hypertrophy, but NAD was capable of maintaining intracellular NAD(+)/NADH ratio and levels of SIRT1 and SIRT3 activity as well as of blocking the HG-induced mesangial hypertrophy in vitro. Activating Sirtuins by NAD blocked the activation of pro-hypertrophic Akt signaling, and augmented the activity of the antihypertrophic AMPK signaling in MCs, which prevented the subsequent induction of mTOR-mediated protein synthesis. By AMPK knockdown, we showed it upregulated phosphorylation of mTOR. In such, the NAD inhibited HG-induced mesangial hypertrophy whereas NAD lost its inhibitory effect in the presence of AMPK siRNA. CONCLUSION: These results reveal a novel role of NAD as an inhibitor of mesangial hypertrophic signaling, and suggest that prevention of NAD depletion may be critical in the treatment of mesangial hypertrophy. PMID- 21691087 TI - Reversal by growth hormone of homocysteine-induced epithelial-to-mesenchymal transition through membrane raft-redox signaling in podocytes. AB - Epithelial-to-Mesenchymal Transition (EMT) is an important pathogenic mechanism mediating glomerular injury or sclerosis in a variety of renal and systemic diseases such as hyperhomocysteinemia (hHcys). The present study was designed to test whether Hcys-induced EMT in podocytes is reversed by growth hormone (GH), a hormone regulating cell differentiation and growth and to explore the cellular and molecular mechanism mediating its action. It was found that Hcys induced significant EMT in podocytes, as shown by marked decreases in slit diaphragm associated protein P-cadherin and zonula occludens-1 as epithelial markers and by dramatic increases in the expression of mesenchymal markers, fibroblast specific protein-1 and alpha-smooth muscle actin, which were detected by all examinations via immunocytochemistry, real time RT-PCR and Western blot analysis. When podocytes were treated with GH at 25 ng/mL, however, Hcys failed to induce podocyte EMT. Using electromagnetic spin resonance spectrometry, Hcys-induced superoxide (O(2).(-)) production via NADPH oxidase was found to be significantly inhibited by GH (66%). Functionally, GH was shown to substantially inhibit Hcys induced increases in the permeability of podocyte monolayers and to block the decrease in podocin expression in these cells. In addition, NADPH oxidase subunit, gp91(phox) and GH receptors aggregated in membrane raft clusters, which produced O(2).(-) in response to Hcys and could be blocked by GH, membrane raft disruptors filipin and MCD or NADPH oxidase inhibitor, apocynin. It is concluded that Hcys-induced podocyte EMT is associated with transmembrane membrane raft redox signaling and that GH reverses this Hcys-induced EMT protecting podocytes from functional disturbance. PMID- 21691088 TI - Role of vacuolar ATPase in the trafficking of renal type IIa sodium-phosphate cotransporter. AB - BACKGROUND/AIMS: Total body phosphate homeostasis is regulated by expression of type IIa sodium phosphate cotransporter (NpT2a) in the apical membrane (BBM) of renal proximal tubule cells. NpT2a expression is regulated by dietary phosphate and PTH but the mechanisms for trafficking of the protein are unknown. Based on 2D gel electrophoresis and mass spectroscopy data that changes in dietary phosphate stimulated changes in BBM expression of vacuolar H(+)-ATPase, we hypothesized that vacuolar H(+)-ATPase plays a significant role in regulation of NpT2a in opossum kidney (OK) cells, a model for renal proximal tubule transport. METHODS: Role of vacuolar H(+)-ATPase was studied in opossum kidney (OK) cells by examining the effect of inhibition of vacuolar H(+)-ATPase on Pi uptake and NpT2a expression. RESULTS: Pretreatment of OK cells with bafilomycin A(1) and concanamycin A, inhibitors of vacuolar H(+)-ATPases, blocked high phosphate- and PTH-induced degradation of NpT2a, but had no effect on high phosphate or PTH induced inhibition of sodium-dependent phosphate transport. Exposure of the cells to bafilomycin A(1) significantly decreased phosphate transport and apical membrane expression of NpT2a. Treatment with brefeldin A, an inhibitor of Golgi transport, decreased phosphate transport and apical membrane expression of NpT2a while treatment of cells with both brefeldin A and bafilomycin A(1) had no additive effect. CONCLUSION: We conclude that vacuolar H(+)-ATPase plays a significant role in exocytosis of NpT2a into the apical membrane and in degradation of NpT2a but has no role in endocytosis. PMID- 21691090 TI - Gender differences in serum and glucocorticoid regulated kinase-1 (SGK-1) expression during renal ischemia/reperfusion injury. AB - Several studies reported sexual dimorphism in the signaling mechanisms of renal ischemia/reperfusion (I/R). The anti-apoptotic serum and glucocorticoid-regulated kinase-1 (SGK-1) is up-regulated and has a significant protective role in renal I/R. SGK-1 has several target molecules, and inhibition of the inducible nitric oxide synthase (iNOS) transcription is one of its effector mechanisms. The objective of the present study was to examine if there is a gender-specific expression and activation of SGK-1 during renal I/R injury. In vitro, treatment of HK-2 kidney proximal tubular cells with different concentrations of 17-beta estradiol had no effect, whereas testosterone increased SGK-1 abundance in a dose dependent manner. In vivo, in a rat model of unilateral renal I/R injury, there was a higher SGK-1 expression and phosphorylation in males 2 and 24 h after ischemia paralleled by reduction in the mRNA expression of iNOS compared to females. Deprivation of testosterone by castration of males resulted in decreased SGK-1 protein level at all time-points and reduced phosphorylation 2 and 24 h after reperfusion. Our results suggest that testosterone up-regulates SGK-1 in the kidney contributing to sexual dimorphisms in the cell signalling machinery. The significance of the testosterone-regulated SGK-1 level and activity in the kidney needs further investigations. PMID- 21691089 TI - Polycystin-1, 2, and STIM1 interact with IP(3)R to modulate ER Ca release through the PI3K/Akt pathway. AB - Dysregulation of Ca(2+) signaling and homeostasis has been linked to the development of ADPKD through aberrant functioning of the polycystins. In this study, we investigated the role of the polycystins in modulating Ca(2+) signaling. Expression of full-length PC1 in MDCK cells inhibited intracellular Ca(2+) release in response to ATP when compared to control cells. This phenotype correlated with reduced interaction of endogenous PC2 and IP(3)R in PC1 containing cells. We also found that endogenous STIM1 also interacted with the IP(3)R, and this interaction was enhanced by PC1 expression. Increased interaction between STIM1 and IP(3)R inhibited Ca(2+) release. PC1 regulates intracellular Ca(2+) release and the interaction of PC2-IP(3)R-STIM1 through the PI3K/Akt signaling pathway. Inhibition of the PI3K/Akt pathway in PC1 containing cells restored intracellular Ca(2+) release, increased the interaction between PC2 and IP(3)R and disrupted the STIM1-IP(3)R complex. Conversely, activation of the PI3K/Akt signaling pathway by HGF in control MDCK cells gave the reverse effects. It reduced the release of Ca(2+) to levels comparable to the PC1 cells, inhibited the association PC2 and IP(3)R, and increased the interaction between STIM and IP(3)R. Overall, our studies provide a potential mechanism for the modulation of intracellular Ca(2+) signaling by the polycystins. PMID- 21691091 TI - Integrin signaling modulates AQP2 trafficking via Arg-Gly-Asp (RGD) motif. AB - Aquaporin-2 (AQP2) increases the water permeability of renal collecting ducts in response to vasopressin. Vasopressin stimulation is accompanied by a profound remodeling of actin cytoskeleton whose dynamics are regulated by crosstalk between intracellular and extracellular signals. Here, we report that AQP2 contains a conserved RGD domain in its external C-loop. Co-immunoprecipitation experiments demonstrated that AQP2 binds integrin beta1 in renal tissue and in MCD4 cells. To investigate the role of this interaction on AQP2 trafficking, cells were exposed to synthetic RGD-containing peptides, GRGDNP or GRGDSP, able to bind certain integrins. Incubation with these peptides increased the membrane expression of AQP2 in the absence of hormonal stimulation as assessed by confocal analysis and cell surface biotinylation. To identify the signals underlying the effects of peptides on AQP2 trafficking, some possible intracellular messengers were evaluated. Exposure of MCD4 cells to GRGDNP increased intracellular cAMP as assessed by FRET studies while GRGDSP increased intracellular calcium concentration. Taken together, these data propose integrins as new players controlling the cellular localization of AQP2, via two distinct signal transduction pathways dependent on cAMP and calcium respectively. PMID- 21691092 TI - Dual functional characteristic of human aquaporin 10 for solute transport. AB - BACKGROUND/AIMS: Although aquaglyceroporins have been generally believed to operate in a channel mode, which is of nonsaturable nature, for glycerol as well as for water, we recently found that human aquaporin 9 (hAQP9) operates in a carrier-mediated mode, which is of saturable nature, for glycerol. Based on the finding, we assumed that such a characteristic might be shared by the other aquaglyceroporins and examined the functional characteristics of hAQP10, which is an intestine-specific aquaglyceroporin. METHODS: Transport assays were conducted using Xenopus laevis oocytes expressing hAQP10 derived from the microinjected cRNA. RESULTS: The transport of glycerol by hAQP10 was found to be highly saturable with a Michaelis constant of 10.4 MUM and specifically inhibited by several glycerol analogs such as monoacetin. Furthermore, when glycerol was preloaded in hAQP10-expressing oocytes, its efflux was trans-stimulated by extracellular glycerol. These results indicate the involvement of a carrier mediated mechanism in glycerol transport by hAQP10. Interestingly, a channel mechanism was also found to be involved in part in hAQP10-mediated glycerol transport. CONCLUSION: The present study unveiled the uniquely dual functional characteristic of hAQP10 as a carrier/channel for solute transport, providing a novel insight into its operation mechanism, which would help further elucidate its physiological role. PMID- 21691093 TI - Hydration-sensitive gene expression in brain. AB - Dehydration has a profound influence on neuroexcitability. The mechanisms remained, however, incompletely understood. The present study addressed the effect of water deprivation on gene expression in the brain. To this end, animals were exposed to a 24 hours deprivation of drinking water and neuronal gene expression was determined by microarray technology with subsequent confirmation by RT-PCR. As a result, water deprivation was followed by significant upregulation of clathrin (light polypeptide Lcb), serum/glucocorticoid-regulated kinase (SGK) 1, and protein kinase A (PRKA) anchor protein 8-like. Water deprivation led to downregulation of janus kinase and microtubule interacting protein 1, neuronal PAS domain protein 4, thrombomodulin, purinergic receptor P2Y - G-protein coupled 13 gene, gap junction protein beta 1, neurotrophin 3, hyaluronan and proteoglycan link protein 1, G protein-coupled receptor 19, CD93 antigen, forkhead box P1, suppressor of cytokine signaling 3, apelin, immunity related GTPase family M, serine (or cysteine) peptidase inhibitor clade B member 1a, serine (or cysteine) peptidase inhibitor clade H member 1, glutathion peroxidase 8 (putative), discs large (Drosophila) homolog-associated protein 1, zinc finger and BTB domain containing 3, and H2A histone family member V. Western blotting revealed the downregulation of forkhead box P1, serine (or cysteine) peptidase inhibitor clade H member 1, and gap junction protein beta 1 protein abundance paralleling the respective alterations of transcript levels. In conclusion, water deprivation influences the transcription of a wide variety of genes in the brain, which may participate in the orchestration of brain responses to water deprivation. PMID- 21691094 TI - Long-term treatment with suberythropoietic Epo is vaso- and neuroprotective in experimental diabetic retinopathy. AB - BACKGROUND/AIMS: Diabetic retinopathy is characterized by pericyte loss and vasoregression both in the clinic and in animal models. A mild neurodegeneration with loss of ganglion cells is also described in the diabetic retina. Like VEGF A, Epo is angioprotective and, in high doses, neuroprotective, however, without affecting vessel permeability. This study was to investigate the effect of a long term suberythropoietic dose of Epo on vascular damage and neurodegeneration in a rat model of diabetic retinopathy. METHODS: We administered Epo 3x256 IU/kg body weight/week to streptozotocin-diabetic Wistar rats for up to 6 months. Leukostasis was analyzed by quantitation of CD45 positive cells adherent to the retinal microvasculature. VEGF-A levels were assessed by Elisa at 3 months of treatment. Vasoregression was quantified in retinal digest preparations after 6 months of Epo treatment. Neurodegeneration was analyzed from PAS stained retinal paraffin preparations. RESULTS: Leukostasis was unaffected by treatment with Epo which significantly inhibited the loss of pericyte and the formation of acellular capillaries. Neurodegeneration in the diabetic retina was significantly reduced by Epo treatment. Increased VEGF-A levels in the diabetic retina were normalized by Epo treatment. CONCLUSIONS: Suberythropoietic Epo is effective to protect microvascular and neuronal damage in the experimental diabetic retina. PMID- 21691096 TI - Heritable cardiac conduction and myocardial disease: from the clinic to the basic science laboratory and back to the clinic. AB - A close collaboration between the physicians-scientists of the Division of Cardiology, The Ohio State University and the basic scientists of the Department of Genetics, Harvard Medical School was essential to define the multiple phenotypic expressions and the genetic abnormalities in the heritable conduction and myocardial disease in a family from central Ohio (Family OSU). The Family OSU presents evidence of sequential hierarchical progression through multiple cardiac phenotypes (sinus bradycardia, atrioventricular conduction defects requiring pacemaker, supraventricular arrhythmias including atrial fibrillation, heart failure, and sudden cardiac death) on a decade-to-decade basis. In this setting, each phenotype may be mistakenly considered as a specific diagnosis by physicians working without a pedigree or long-term follow-up. Genetic analysis, however, confirms lamin A/C mutation. The role of the physician-scientist and the basic scientist for the study of heritable disorders is equally important but different. Only the physician-scientist, however, who is in constant contact with the patient understands the complexity of the disease. The physician-scientist with an interest in a particular disease can guide the basic scientist to define molecular mechanisms of that disease and by extension learn important lessons for other diseases. PMID- 21691095 TI - The cholinergic antagonist gymnodimine improves Abeta and tau neuropathology in an in vitro model of Alzheimer disease. AB - Gymnodimine (GYM) is a marine phycotoxin with a macrocyclic imine structure, isolated from extracts of the dinoflagellate Karenia selliformis known to act as a cholinergic antagonist with subtype selectivity. However, no data on the chronic effects of this compound has been reported so far. In this work, we evaluated the effect of long term exposure of cortical neurons to gymnodimine in the progress of Alzheimer disease (AD) pathology in vitro. Treatment of cortical neurons with 50 nM gymnodimine decreased the intracellular amyloid beta (Abeta) accumulation and the levels of the hyperphosphorylated isoforms of tau protein recognized by AT8 and AT100 antibodies. These results are suggested to be mediated by the increase in the inactive isoform of the glycogen synthase kinase 3 (phospho GSK-3 Ser9), the decrease in the levels of the active isoform of the ERK1/2 kinase and the increase in acetylcholine (Ach) synthesis elicited by long term exposure of cortical neurons to the toxin. Moreover, gymnodimine decreased glutamate-induced neurotoxicity in vitro. Altogether these results indicate that the marine phycotoxin gymnodimine may constitute a valuable tool for the development of drugs to treat neurodegenerative diseases. PMID- 21691097 TI - 21st International Bile Acid Meeting. Preface. PMID- 21691098 TI - The role of cilia in the regulation of bile flow. AB - Cholangiocytes, the epithelial cells lining intrahepatic bile ducts, are ciliated cells. Each cholangiocyte has a primary cilium consisting of (i) a microtubule based axoneme and (ii) the basal body, centriole-derived, microtubule-organizing center from which the axoneme emerges. Primary cilia in cholangiocytes were described decades ago, but their physiological and pathophysiological significance remained unclear until recently. We now recognize that cholangiocyte cilia extend from the apical plasma membrane into the bile duct lumen and, as such, are ideally positioned to detect changes in bile flow, bile composition and bile osmolality. These sensory organelles act as cellular antennae that can detect and transmit signals that influence cholangiocyte function. Indeed, recent data show that cholangiocyte primary cilia can activate intracellular signaling pathways when they sense modifications in the flow, molecular constituents and osmolarity of bile. Their ability to sense and transmit signals depends on the participation of a growing number of specific ciliary-associated proteins that act as receptors, channels and transporters. Cholangiocyte cilia, in addition to being important in normal biliary physiology, likely contribute to the cholangiopathies when their normal structure or function is disturbed. Indeed, the polycystic liver diseases that occur in combination with autosomal dominant and recessive polycystic kidney disease (i.e. ADPKD and ARPKD) are two important examples of such conditions. Recent insights into the role of cholangiocyte cilia in cystic liver disease using in vitro and animal models have already resulted in clinical trials that have influenced the management of cystic liver disease. PMID- 21691099 TI - Pleiotropic functions of the organic solute transporter Ostalpha-Ostbeta. AB - The heteromeric organic solute transporter alpha-beta (Ostalpha-Ostbeta) is expressed at relatively high levels on the basolateral membrane of enterocytes, where it plays a critical role in the intestinal absorption of bile acids and the enterohepatic circulation. However, this transporter is also expressed in nearly all human tissues, including those that are not normally thought to be involved in bile acid homeostasis, indicating that Ostalpha-Ostbeta may have additional roles beyond bile acid transport in these other tissues, or that bile acids and their derivatives are more pervasive than currently envisioned. Emerging data from different laboratories provide support for both of these hypotheses. In particular, recent studies indicate that tissues such as brain and ovary have the capacity to synthesize bile acids or bile acid precursors. In addition, studies examining Ostalpha-Ostbeta substrate specificity have revealed that this transporter can also accept conjugated steroids, including some neurosteroids, and that the transporter is selectively expressed in steroidogenic cells of the brain and adrenal gland, suggesting a novel function for Ostalpha-Ostbeta. The broad tissue expression of Ostalpha-Ostbeta is also consistent with the emerging concept that bile acids and their derivatives act as signaling molecules in diverse tissues. Bile acids activate nuclear receptors such as the farnesoid X receptor (FXR/NR1H4), the pregnane X receptor and the vitamin D receptor, are ligands for a G-protein-coupled bile acid receptor (GPBAR1/TGR5), and can also activate protein kinases A and C as well as mitogen-activated protein kinase pathways. These signaling pathways are present in many tissues and regulate processes such as triglyceride, glucose and energy homeostasis. Note that although FXR and TGR5 are thought to function primarily as bile acid receptors, they are modulated by some other sterols and select lipid metabolites, and are also widely expressed in tissues, indicating a complex interplay among diverse regulatory networks that impact critical cell and organ functions. The present report summarizes the evidence for a pleiotropic role of Ostalpha-Ostbeta in different tissues. PMID- 21691100 TI - Molecular mechanisms of altered bile acid homeostasis in organic solute transporter-alpha knockout mice. AB - BACKGROUND/AIMS: Mutations in the apical sodium-dependent bile acid transporter (SLC10A2) block intestinal bile acid absorption, resulting in a compensatory increase in hepatic bile acid synthesis. Inactivation of the basolateral membrane bile acid transporter (OSTalpha-OSTbeta) also impairs intestinal bile acid absorption, but hepatic bile acid synthesis was paradoxically repressed. We hypothesized that the altered bile acid homeostasis resulted from ileal trapping of bile acids that act via the farnesoid X receptor (FXR) to induce overexpression of FGF15. To test this hypothesis, we investigated whether blocking FXR signaling would reverse the bile acid synthesis phenotype in Ostalpha null mice. METHODS: The corresponding null mice were crossbred to generate OstalphaFxr double-null mice. All experiments compared wild-type, Ostalpha, Fxr and OstalphaFxr null littermates. Analysis of the in vivo phenotype included measurements of bile acid fecal excretion, pool size and composition. Hepatic and intestinal gene and protein expression were also examined. RESULTS: OstalphaFxr null mice exhibited increased bile acid fecal excretion and pool size, and decreased bile acid pool hydrophobicity, as compared with Ostalpha null mice. Inactivation of FXR reversed the increase in ileal total FGF15 expression, which was associated with a significant increase in hepatic Cyp7a1 expression. CONCLUSIONS: Inactivation of FXR largely unmasked the bile acid malabsorption phenotype and corrected the bile acid homeostasis defect in Ostalpha null mice, suggesting that inappropriate activation of the FXR-FGF15-FGFR4 pathway partially underlies this phenotype. Intestinal morphological changes and reduced apical sodium-dependent bile acid transporter expression were maintained in Ostalpha(-/ )Fxr(-/-) mice, indicating that FXR is not required for these adaptive responses. PMID- 21691101 TI - Herbert Falk: a vital force in the renaissance of bile acid research and bile acid therapy. AB - Herbert Falk died on August 8, 2008, after a long illness. It was his vision that initiated the Bile Acid Meetings and brought to market chenodeoxycholic acid and ursodeoxycholic acid for the dissolution of cholesterol gallstones as well as the successful treatment of cholestatic liver disease. The 1st Bile Acid Meeting was a small workshop held at the University Hospital of Freiburg in 1970. Great interest in the topic was evident at that small meeting and led to a larger meeting in 1972, whose scope included both the basic and clinical aspects of bile acids. These meetings have continued at biennial intervals, the 2010 meeting being the 21st. The program has always included discussions of the most fundamental aspects of bile acid biosynthesis and metabolism as well as clinical applications of bile acid therapy. The meetings featured brief presentations, ample time for discussion, and imaginative social programs. They have always been flawlessly organized. Social programs usually included a hike through the beautiful countryside of the Black Forest followed by dinner in a rustic restaurant. Herbert Falk took part in these programs, personally welcoming every participant. In the warm glow of the 'Badische' hospitality, friendships developed, and scientific collaborations were often arranged. From a scientific standpoint, there has been enormous progress in understanding the chemistry and biology of bile acids. Herbert Falk established the Windaus Prize in 1978, and the prize has been given to individuals whose contributions moved the field forward. These bile acid meetings have been marvelous, rewarding experiences. We must all be grateful to Herbert Falk's vision in establishing the Falk Foundation that has so generously sponsored these meetings. We also express our gratitude to his widow, Ursula Falk, who continues this worthy tradition. PMID- 21691102 TI - The bile acid membrane receptor TGR5: a valuable metabolic target. AB - Bile acids (BAs) are amphipathic molecules that facilitate the uptake of lipids, and their levels fluctuate in the intestines as well as in the circulation depending on food intake. Besides their role in dietary lipid absorption, BAs function as signaling molecules that activate specific BA receptors and trigger downstream signaling cascades. The BA receptors and the signaling pathways they control are not only important in the regulation of BA synthesis and their metabolism, but they also regulate glucose homeostasis, lipid metabolism and energy expenditure - processes relevant in the context of the metabolic syndrome. In addition to the function of the nuclear receptor FXRalpha in regulating local effects of BAs in the organs of the enterohepatic axis, increasing evidence points to a crucial role of the G-protein-coupled receptor TGR5 in mediating systemic actions of BAs. Here we review the current knowledge on BA receptors, with a strong focus on the cell membrane receptor TGR5, which has emerged as a promising target for intervention in metabolic diseases. PMID- 21691103 TI - TGR5 in the biliary tree. AB - BACKGROUND/AIMS: TGR5 is a plasma membrane-bound, G-protein-coupled receptor for bile acids. TGR5 mRNA has been detected in a variety of tissues, including liver. The aim of the present study was to determine the localization and function of the receptor in biliary epithelial cells. METHODS: Liver and gallbladder tissue from humans and rodents were analyzed for TGR5 expression and localization by real-time PCR, Western blot and immunofluorescence microscopy. Cholangiocytes and gallbladder epithelial cells were isolated from wild-type and TGR5 knockout mice. Cyclic AMP (cAMP) was measured using a radioimmunoassay and chloride concentrations were analyzed using the chloride-sensitive dye N (ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE). Cell proliferation was determined by bromodeoxyuridine incorporation. RESULTS: TGR5 is localized in the apical membrane and the primary cilium of cholangiocytes and gallbladder epithelial cells. Activation of the receptor by bile acids led to a rise in intracellular cAMP concentrations and a decrease in intracellular chloride concentrations as measured by MQAE fluorescence, indicating increased chloride secretion. This effect could be abolished in the presence of an inhibitor of the cAMP-dependent chloride channel cystic fibrosis transmembrane conductance regulator. Furthermore, activation of TGR5 by bile acids induced cholangiocyte proliferation, which was not observed in cells derived from TGR5 knockout mice. CONCLUSION: In biliary epithelial cells, TGR5 acts as a bile acid sensor coupling biliary bile acid concentrations to bile formation. Furthermore, the receptor may play a role in bile acid-dependent cholangiocyte proliferation and may protect biliary epithelial cells from bile acid-induced cell death. PMID- 21691104 TI - Alterations of hormonally active fibroblast growth factors after Roux-en-Y gastric bypass surgery. AB - Thirty-five morbidly obese patients underwent Roux-en-Y gastric bypass surgery (RYGB). In addition to weight loss, these patients showed significant improvement of insulin resistance and a reduction of hepatic fat content. Three months after surgery, the serum bile salts were slightly but significantly elevated, and the levels of the endocrine-acting fibroblast growth factor 19 (FGF19) and FGF21 were increased. FGF19 and FGF21 play a role as regulators of hepatic lipid and glucose metabolism. These results show that RYGB surgery improves metabolism and that this improvement is still apparent 3 months after surgery. Bile salts may play a key role in the improvement of metabolism after RYGB. Why serum bile salt concentrations are elevated after RYGB needs to be investigated. PMID- 21691105 TI - Role of nuclear receptors in the biliary epithelium. AB - The biliary epithelium is organized as a single layer of biliary epithelial cells lining the biliary tree. Biliary epithelial cells have three major biological functions: protection, secretion and proliferation. These functions are all controlled by nuclear receptors. The biliary tree conveys bile, a complex fluid containing toxics such as endotoxins, from the liver to the duodenum. Active protection against endotoxins can be elicited by the vitamin D receptor or the farnesoid X receptor (FXR), thus avoiding constant inflammation of the biliary epithelium. Anti-inflammatory activities may be triggered by PPAR-alpha and gamma, which are also able to inhibit the deleterious effect of bacterial products. Secretion, a major function of biliary epithelial cells, is mainly regulated by circulating factors. Luminal factors, such as bile salts, may also control fluid secretion by classical intracellular pathways, membrane receptors or nuclear receptors. FXR or the glucocorticoid receptor have indeed been shown to increase the expression of genes encoding membrane-bound proteins that participate in biliary epithelial cell secretion. Biliary epithelial cells are quiescent cells that are able to proliferate in pathophysiological settings. Inhibition of estrogen receptor signaling decreases pathological biliary epithelial cell proliferation. Furthermore, progesterone, through the progesterone receptor, increases biliary epithelial cells proliferation. Taken together these observations suggest that nuclear receptors are involved in the control of biliary epithelial cell biology. A better delineation of the specific biliary epithelial cell functions controlled by nuclear receptors may shed light on potential therapeutic molecular targets of cholangiopathies. PMID- 21691106 TI - Bile acid signaling in fetal tissues: implications for intrahepatic cholestasis of pregnancy. AB - BACKGROUND/AIMS: Intrahepatic cholestasis of pregnancy (ICP) is complicated by spontaneous preterm labor, fetal anoxia and unexplained fetal death. We aim to evaluate the mechanisms by which raised fetal bile acids cause placental abnormalities and fetal cardiac pathology. METHODS: The study was performed using placental samples taken from ICP pregnancies, placental explant culture, neonatal and adult cardiomyocytes, and murine and human embryonic stem cell-derived cardiomyocytes. RESULTS: Maternal cholestasis causes a placental phenotype with histological abnormalities. This can be evaluated using placental explant cultures. Taurocholate, the principal bile acid raised in the fetal compartment in ICP, causes abnormal cardiomyocyte contraction, rhythm and desynchronization of calcium dynamics. To extend our observations that the muscarinic M2 receptor plays a role in bile acid-induced arrhythmia in cardiomyocytes, we are developing a model containing mixed cell populations to represent the fetal and maternal hearts. This will be used to evaluate the underlying mechanisms to explain fetal arrhythmia in the presence of cholestasis. CONCLUSION: Bile acids signal via a spectrum of pathways in the placenta and the fetal heart. PMID- 21691107 TI - Biliary bicarbonate secretion constitutes a protective mechanism against bile acid-induced injury in man. AB - BACKGROUND: Cholangiocytes expose a striking resistance against bile acids: while other cell types, such as hepatocytes, are susceptible to bile acid-induced toxicity and apoptosis already at micromolar concentrations, cholangiocytes are continuously exposed to millimolar concentrations as present in bile. We present a hypothesis suggesting that biliary secretion of HCO(3)(-) in man serves to protect cholangiocytes against bile acid-induced damage by fostering the deprotonation of apolar bile acids to more polar bile salts. Here, we tested if bile acid-induced toxicity is pH-dependent and if anion exchanger 2 (AE2) protects against bile acid-induced damage. METHODS: A human cholangiocyte cell line was exposed to chenodeoxycholate (CDC), or its glycine conjugate, from 0.5 mM to 2.0 mM at pH 7.4, 7.1, 6.7 or 6.4, or after knockdown of AE2. Cell viability and apoptosis were determined by WST and caspase-3/-7 assays, respectively. RESULTS: Glycochenodeoxycholate (GCDC) uptake in cholangiocytes is pH-dependent. Furthermore, CDC and GCDC (pK(a) 4-5) induce cholangiocyte toxicity in a pH-dependent manner: 0.5 mM CDC and 1 mM GCDC at pH 7.4 had no effect on cell viability, but at pH 6.4 decreased viability by >80% and increased caspase activity almost 10- and 30-fold, respectively. Acidification alone had no effect. AE2 knockdown led to 3- and 2-fold enhanced apoptosis induced by 0.75 mM CDC or 2 mM GCDC at pH 7.4. DISCUSSION: These data support our hypothesis of a biliary HCO(3)(-) umbrella serving to protect human cholangiocytes against bile acid induced injury. AE2 is a key contributor to this protective mechanism. The development and progression of cholangiopathies, such as primary biliary cirrhosis, may be a consequence of genetic and acquired functional defects of genes involved in maintaining the biliary HCO(3)(-) umbrella. PMID- 21691108 TI - The molecular mechanism of cholestatic pruritus. AB - Pruritus is a frequent symptom in patients with cholestatic liver diseases. Pruritus can be excruciating and, in rare cases, become a primary indication for liver transplantation. The molecular mechanism of itch signal transduction is largely unclear. It was our hypothesis that compounds which accumulate in the circulation during cholestasis act as direct or indirect pruritogens by affecting signaling in itch fibers. To test this, we screened plasma samples of a large group of patients with various cholestatic conditions for their capacity to activate neuroblastoma cells. Quite strikingly, we found that samples from itchy cholestatic patients caused a significantly higher activation than samples from non-itchy cholestatic patients and healthy controls. Purification revealed lysophosphatidic acid (LPA) as the active compound. LPA is a very potent signaling lipid that can activate cells through various LPA receptors. Subsequently, we could demonstrate that cholestatic patients with pruritus have highly elevated levels of serum autotaxin (ATX), the enzyme that converts lysophosphatidylcholine into LPA. This is a striking finding as ATX has never been connected to itch perception thus far. We have also shown that LPA, when injected intradermally, causes itching in mice. On the basis of our results, we hypothesize that during cholestasis, expression of ATX is induced and gives rise to increased local formation of LPA near unmyelinated nerve endings of itch fibers. LPA then activates these neurons through one of the LPA receptors, which in turn potentiates action potentials along itch fibers. PMID- 21691109 TI - An update on genetic analysis of cholestatic liver diseases: digging deeper. AB - Investigations into the molecular mechanisms of cholestasis have revealed intricate and intriguing details of bile salt metabolism as well as its regulatory mechanisms in health and disease. Extensive studies on genotype phenotype correlations in monogenic diseases, such as progressive familial and benign recurrent intrahepatic cholestasis, facilitate diagnostics and improve the risk assessment of hepatobiliary transporter gene variants in bile transport pathophysiology. While the comparatively easy targets in monogenic cholestasis have been identified for some time now, progress in complex liver disease is rather laborious but steady. Genome-wide association scans are the next step in gathering information about common contributors towards polygenic (multifactorial) cholestatic diseases. New determinants of bile salt metabolism affecting feedback loops within the liver or the enterohepatic circulation are presently under investigation for their contribution towards complex cholestatic syndromes. PMID- 21691110 TI - TGR5 sequence variation in primary sclerosing cholangitis. AB - TGR5, the G-protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways and homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC), a chronic inflammatory bile duct disease associated with ulcerative colitis (UC). In addition, the TGR5 gene is localized at chromosome 2q35, close to a genetic variant associated with both PSC and UC in recent genome-wide association studies. This provided a strong rationale for a recent study searching for novel genetic variants of TGR5 in PSC. In the study, resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single nucleotide polymorphisms. In experimental studies, five of the nonsynonymous mutations were found to reduce or abolish TGR5 function by affecting localization or activity. Fine-mapping of the chromosome 2q35 locus in large patient panels revealed an overall association between a common TGR5 single-nucleotide polymorphism and PSC and UC, but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes. In conclusion, the data from the experimental evaluation of novel nonsynonymous mutations represent an important insight into the structural biology of TGR5. In addition, the combination of the known roles of the receptor, the genetic associations and the mutations which affect receptor function, suggests that TGR5 variation may contribute to PSC and UC susceptibility. However, this conclusion needs to be strengthened in further research. PMID- 21691111 TI - Treatment of primary biliary cirrhosis with ursodeoxycholic acid, budesonide and fibrates. AB - Long-term treatment with ursodeoxycholic acid (UDCA; 13-15 mg/kg/day) in patients with primary biliary cirrhosis (PBC) improves biochemical liver tests, delays histological progression and prolongs survival without liver transplantation. UDCA monotherapy appears sufficient for many patients as suggested by long-term observational data. However, the transplant-free survival rate of UDCA-treated patients remains significantly lower than that of an age- and sex-matched control population. Therefore, there is a continued need for new therapeutic options in PBC. In this article we review and discuss the following issues: the appropriate selection of patients requiring new therapeutic options, the role of budesonide in the management of these patients, and the emerging place of peroxisome proliferator-activated receptor-alpha ligands as anti-inflammatory and immunomodulating agents in PBC. PMID- 21691112 TI - Genetic variants of the bile salt export pump: inducers and modifiers of liver diseases. AB - The bile salt export pump (BSEP, ABCB11) is the major transporter protein for the excretion of bile salts into bile. Here we describe a spectrum of BSEP-dependent effects on the course of liver diseases, and present two mutations that differentially affect total bile acid output and the biliary bile acid profile. According to the clinical course of affected children, low bile acid output but a normal profile was less harmful than higher output in combination with changes in the ratio of chenodeoxycholic acid to cholic acid. On the other hand, the common BSEP polymorphism V444A (c.1331T>C; allele frequency 65%) emerged as an independent predictor of the success rate in patients with chronic hepatitis C treated with pegylated interferon/ribavirin. This association between bile acid transport and hepatitis C may be due to interference of bile acids with viral replication, interferon signaling or antiviral proteins. PMID- 21691113 TI - Genetic factors in the pathogenesis of cholangiocarcinoma. AB - BACKGROUND: Cholangiocarcinoma (CC) is increasing in incidence, but its pathogenesis remains poorly understood. Chronic inflammation of the bile duct and cholestasis are major risk factors, but most cases in the West are sporadic. Genetic polymorphisms in biliary transporter proteins have been implicated in benign biliary disease and, in the case of progressive familial cholestasis, have been associated with childhood onset of CC. In the current study, five biologically plausible candidate genes were investigated: ABCB11 (BSEP), ABCB4 (MDR3), ABCC2 (MRP2), ATP8B1 (FIC1) and NR1H4 (FXR). METHODS: DNA was collected from 172 Caucasian individuals with confirmed CC. A control cohort of healthy Caucasians was formed. Seventy-three SNPs were selected using the HapMap database to capture genetic variation around the five candidate loci. Genotyping was undertaken with a competitive PCR-based system. Confirmation of Hardy-Weinberg equilibrium and Cochran-Armitage trend testing were performed using PLINK. Haplotype frequencies were compared using haplo.stats. RESULTS: All 73 SNPs were in Hardy-Weinberg equilibrium. Four SNPs in ABCB11 were associated with altered susceptibility to CC, including the V444A polymorphism, but these associations did not retain statistical significance after Bonferroni correction for multiple testing. Haplotype analysis of the genotyped SNPs in ATP8B1 identified significant differences in frequencies between cases and controls (global p value of 0.005). CONCLUSION: Haplotypes in ATP8B1 demonstrated a significant difference between CC and control groups. There was a trend towards significant association of V444A with CC. Given the biological plausibility of polymorphisms in ABCB11 and ATP8B1 as risk modifiers for CC, further study in a validation cohort is required. PMID- 21691114 TI - Targeting nuclear bile acid receptors for liver disease. AB - Bile acids (BAs) are able to activate a range of dedicated nuclear receptors (NRs) which play a key role in the transcriptional control of critical steps of a wide range of hepatic functions ranging from BA homeostasis and bile formation, phase I/II metabolism of endo- and xenobiotics such as BAs and drugs, respectively, to hepatic lipids and glucose metabolism. Apart from these metabolic roles, BA-activated nuclear receptors also play a key role in the control of hepatic inflammation, fibrogenesis, replication of hepatitis B and C virus, liver regeneration and carcinogenesis. As such, several physiological and pathophysiological effects of BAs can now be explained through activation of regulatory NR networks. Moreover, BA-activated NRs are key for understanding the pathogenesis of several liver diseases and represent attractive drug targets. This article will provide a brief overview on the role of BA-activated NRs in cholestatic and fatty liver disease. PMID- 21691115 TI - Role of the anion exchanger 2 in the pathogenesis and treatment of primary biliary cirrhosis. AB - The essential anion exchanger (AE) involved in biliary bicarbonate secretion is AE2/SLC4A2, a membrane protein which has also been recognized to be relevant for the regulation of the intracellular pH (pH(i)) in several cell types. Previously, we reported that the expression of AE2 mRNA is diminished in liver biopsies and peripheral blood mononuclear cells from patients with primary biliary cirrhosis (PBC). Immunohistochemical studies indicated that the expression of the AE2 protein is decreased in the bile ducts and hepatocytes in PBC livers. Moreover, we found that bile duct cells isolated from PBC patients and cultured for a few passages exhibit defective Na(+)-independent Cl(-)/HCO(3)(-) exchange. Interestingly, positron emission tomography studies have shown that PBC patients, even at early stages of the disease, fail to secrete bicarbonate to bile in response to secretin, a defect that can be partially reversed after several months of treatment with ursodeoxycholic acid. Altogether, these findings sustain our hypothesis that dysfunctions related to AE2 might have a role in the pathogenesis of PBC. Inadequate AE2 function in lymphocytes may disturb pH(i) regulation in these cells and alter immune homeostasis leading to autoimmunity. On the other hand, reduced AE2 in cholangiocytes could cause cholestasis and oxidative stress of bile duct cells. Cholangiocyte changes, together with altered immune homeostasis, could favor the development of antimitochondrial antibodies and the autoimmune attack on biliary ducts. Our recent findings that Ae2(a,b) deficient mice indeed display most of these features strongly support the notion that AE2 abnormalities may be involved in the pathogenesis of PBC. PMID- 21691116 TI - New treatment strategies for primary sclerosing cholangitis. AB - Primary sclerosing cholangitis (PSC) is a progressive liver disease without adequate treatment. Because the pathogenesis of PSC is not well understood, specific therapies designed to alter the pathogenesis are not available. Animal models suggest a link between bacterial overgrowth, lipopolysaccharides from the bacterial cell walls and stimulation of endogenous TNF formation which can be inhibited by pentoxifylline. Unfortunately, in humans treated with pentoxifylline, little effect was seen. Antibiotics such as metronidazole, vancomycin, tetracycline and azithromycin in small studies show biochemical improvement. Docosahexanoic acid has been used for treating patients in a small pilot study and led to some improvement in liver biochemistries. Immunologic abnormalities have been considered to be potentially important. Attempts to treat PSC with mycophenolate mofetil and tacrolimus have been largely unsuccessful. Budesonide has shown a limited benefit, but perhaps more so in patients with elevated IgG4 levels. PSC is characterized by marked fibrosis. Modulation of the renin-angiotensin system as well as use of rapamycin may reduce fibrosis, but data from this approach has been scant. Bile acids have been tested, but initial doses used in primary biliary cirrhosis led only to biochemical improvement. Higher doses of ursodeoxycholic acid (28-30 mg/kg/day) seemed to be associated with a worsening outcome. Intermediate doses have been tested in a study where biochemical improvement was seen and trends towards enhanced survival were found, but only about two thirds of the anticipated enrollment occurred. Currently, there are multiple potential therapeutic avenues to explore for patients with PSC, and it is hoped that one of these will lead to identification of a proven therapy for this disease. PMID- 21691117 TI - Ursodeoxycholic acid for treatment of fatty liver disease and dyslipidemia in morbidly obese patients. AB - Bile acids have recently been identified as major integrators of hepatic fatty acid and triglyceride metabolism. We explored potential mechanism(s) of action of ursodeoxycholic acid (20 mg/kg/day in 3 weeks) in 40 morbidly obese patients (mean BMI >40 kg/m(2)) with suggested fatty liver disease awaiting bariatric surgery. At follow-up half a year after surgery, patients had decreased their BMI by approximately 10 kg/m(2), which resulted in significant improvements of liver function tests, insulin sensitivity and glucose tolerance. PMID- 21691118 TI - Drinking motives in clinical and general populations. AB - AIMS: This paper had three aims: (1) to validate a Spanish adaptation of the Modified Drinking Motives Questionnaire-Revised (M DMQ-R), (2) to explore the relationship of each drinking motive with different patterns of alcohol use, and (3) to compare the drinking motives of moderate drinkers, heavy drinkers, and alcohol abusing/dependent individuals. METHODS: Two studies were carried out. In Study 1, a sample of 488 participants completed the M DMQ-R and a self-report scale of alcohol consumption in order to study the factor structure and different indices of reliability and validity of the Spanish M DMQ-R. In Study 2, we compared the drinking motives of moderate and heavy drinkers from Study 1 and an additional sample of 59 clinical drinkers. RESULTS: The M DMQ-R demonstrated sound reliability and validity indices. Coping-with-anxiety, social, and enhancement motives predicted higher alcohol use on weekends, but only coping with-anxiety and social motives were related to consumption on weekdays. Furthermore, moderate drinkers had the lowest scores for all motives, whereas alcohol-dependent participants obtained the highest scores for negative reinforcement drinking motives. CONCLUSION: The Spanish M DMQ-R is a reliable and valid measure of drinking motives and has potential for assisting with treatment planning for problem drinkers. PMID- 21691119 TI - Shear stress induces the release of an endothelial elastase: role in integrin alpha(v)beta(3)-mediated FGF-2 release. AB - BACKGROUND/AIMS: Laminar shear stress is an important stimulus in the endothelium dependent control of vascular tone and of vascular remodeling processes. Based on previous studies demonstrating integrin-mediated release of fibroblast growth factor 2 (FGF-2), we investigated whether shear stress-induced integrin activation requires the involvement of an extracellular protease. METHODS: Cultured porcine aortic endothelial cells (PAEC) were exposed to laminar shear stress (16 dyn/cm(2)), whereas static cells served as controls. RESULTS: Exposure of PAEC to shear stress led to an increased activity of a protease in supernatants. This protease could be characterized as elastase but was different from neutrophil and pancreatic elastases. The enhanced activity was accompanied by the activation of integrin alpha(v)beta(3) and p38 MAPK, and followed by an increased FGF-2 concentration in the supernatant. Pretreatment with inhibitors of either elastase or integrin alpha(v)beta(3) resulted in a reduction of FGF-2 release. The observed effects of shear stress on integrin alpha(v)beta(3) and p38 MAPK activation, as well as on FGF-2 release could be mimicked by application of pancreatic elastase to static endothelial cells. CONCLUSION: By inducing the release of an endothelial elastase, shear stress induces an integrin-dependent release of FGF-2 from endothelial cells. PMID- 21691121 TI - Chronic renal failure and its complications. PMID- 21691120 TI - Hypoxia does neither stimulate pulmonary artery endothelial cell proliferation in mice and rats with pulmonary hypertension and vascular remodeling nor in human pulmonary artery endothelial cells. AB - BACKGROUND: Hypoxia results in pulmonary hypertension and vascular remodeling due to induction of pulmonary artery cell proliferation. Besides pulmonary artery smooth muscle cells, pulmonary artery endothelial cells (PAECs) are also involved in the development of pulmonary hypertension, but the effect of hypoxia on PAEC proliferation has not been completely understood. METHODS: We investigated PAEC proliferation in mice and rats with hypoxia-induced pulmonary hypertension and vascular remodeling as well as in human PAECs under hypoxia. RESULTS AND CONCLUSION: We did not find significant PAEC proliferation in chronically hypoxic rats or mice. There was a slight decrease in proliferation in mice and rats with pulmonary hypertension and vascular remodeling. We also did not find significant human PAEC proliferation and cell cycle progression under different levels of oxygen (1, 2, 3, 5 and 10%) for one day, although the same conditions of hypoxia induced significant proliferation and cell cycle progression in pulmonary artery smooth muscle cells and pulmonary artery fibroblasts. Exposure to hypoxia for 7 days also did not increase PAEC proliferation. These results demonstrated that hypoxia alone is not a stimulus to PAEC proliferation in vivo and in vitro. The present study provides a novel role for PAECs in hypoxia-induced pulmonary hypertension and vascular remodeling. PMID- 21691122 TI - Soft bone - hard arteries: a link? AB - Chronic kidney disease is characterized by mineral and various bone disorders associated with extraosseous and cardiovascular calcifications. Experimental studies and clinical observations in the general population and in chronic kidney disease patients show an inverse relationship between the extent of cardiovascular calcifications and bone mineral density or bone metabolic activity. Arterial calcification and osteoporosis are frequently observed in the same subjects and progress in parallel in postmenopausal women, and associations between histomorphometric indices of bone activity and vascular calcifications were also observed in patients with chronic and end-stage kidney diseases. The biological linkage between vascular calcifications and bone changes is certainly a part of the aging process, but in many studies these bone-vascular associations remained significant after adjustment for age, which suggests an age-independent causal relationship. Based on clinical and experimental evidence showing an association between bone disorders and functional and structural changes of the arterial system the concept of a bone-vascular axis was established complementary to the classical kidney-bone axis. Nevertheless, the factors or mechanisms accounting for these associations are not well understood, and could result from (1) arterial disease responsible for bone abnormalities; (2) action of common dysmetabolic or 'toxic' factors and mechanisms acting on bones and vessels, or (3) direct or indirect influence of bone cells and metabolism on the arterial system. This short review aims to illustrate these possible mechanisms. PMID- 21691123 TI - Recent advances in the treatment of atherogenic dyslipidemia in type 2 diabetes mellitus. AB - Despite best treatment efforts reducing low-density lipoprotein cholesterol, a substantial number of type 2 diabetes mellitus patients still experience progression of cardiovascular risk. Even with intensification of statin therapy, a substantial residual cardiovascular risk remains and atherogenic dyslipidemia is an important driver of this so-called residual risk. Besides statin therapy, new strategies evaluate the role of intensive combination lipid treatment for the entire type 2 diabetic population. The results from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Lipid trial suggest that there is a lipid related modifiable component to cardiovascular residual risk in statin-treated type 2 diabetic patients, and that further research should address patients with triglycerides above 204 mg/dl and high-density lipoprotein cholesterol below 34 mg/dl. Based on their respective lipid-modifying activity, the combination of a fibrate and statin is a logical approach to improving achievement of lipid targets in statin-treated patients with a glomerular filtration rate of >60 ml/min/1.73 m(2) and with residual atherogenic dyslipidemia. The link between dyslipidemia treatment and diabetic retinopathy, nephropathy and neuropathy is an emerging new field and microvascular complications are targets for new treatments. PMID- 21691124 TI - Dialytic treatment for septic patients with acute kidney injury. AB - BACKGROUND: Sepsis is the commonest precipitating factor for acute kidney injury in hospitalised patients, and similarly patients with acute kidney injury are predisposed to sepsis. Mortality remains high despite improvements in supportive care. METHODS: Literature search of Medline and Web of Science. RESULTS: Above a threshold dialytic dose of 20 ml/kg/h for continuous renal replacement therapy and a sessional Kt/V of 1.2 for intermittent dialysis, further increases in dose do not appear to impact on survival. Similarly, no treatment mode offers survival advantage, and renal support should be targeted to maintain electrolyte homeostasis and correct volume overload. Additional therapies designed to reduce the inflammatory milieu associated with sepsis have been studied, including increased permeability dialysers, plasma filtration and adsorption techniques, endotoxin filters, selective leucapheresis and bio-artificial renal devices. Antibiotic-coated catheters have been shown to reduce catheter-associated bacteraemia. CONCLUSIONS: Although no modality confers survival advantage, prevention of intratreatment hypotension may result in increased dialysis independence in the survivors, and as such treatments should be designed to minimise the risk of hypotension. As patients with acute kidney injury are at risk of sepsis, catheter-associated bacteraemia should be minimised by using antibiotic- or antiseptic-coated catheters, and hub colonisation reduced with appropriate catheter locks. Further trials of adjunct therapies designed to reduce the inflammatory milieu are required before these potential advances can be recommended for clinical practice. PMID- 21691125 TI - Chronic kidney disease: novel insights from genome-wide association studies. AB - Chronic kidney disease (CKD) is common, affecting about 10% of the general population, and causing significant morbidity and mortality. Apart from the risk conferred by traditional cardiovascular risk factors, there is a strong genetic component. The method of a genome-wide association study (GWAS) is a powerful hypothesis-free approach to unravel this component by association analyses of CKD with several million genetic variants distributed across the genome. Since the publication of the first GWAS in 2005, this method has led to the discovery of novel loci for numerous human common diseases and phenotypes. Here, we review the recent successes of meta-analyses of GWAS on renal phenotypes. UMOD, SHROOM3, STC1, LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2/SH2B3, DACH1, UBE2Q2, and SLC7A9 were uncovered as loci associated with estimated glomerular filtration rate (eGFR) and CKD, and CUBN as a locus for albuminuria in cross-sectional data of general population studies. However, less than 1.5% of the total variance of eGFR and albuminuria is explained by the identified variants, and the relative risk for CKD is modified by at most 20% per locus. In African Americans, much of the risk for end-stage nondiabetic kidney disease is explained by common variants in the MYH9/APOL1 locus, and in individuals of European descent, variants in HLA-DQA1 and PLA(2)R1 implicate most of the risk for idiopathic membranous nephropathy. In contrast, genetic findings in the analysis of diabetic nephropathy are inconsistent. Uncovering variants explaining more of the genetically determined variability of kidney function is hampered by the multifactorial nature of CKD and different mechanisms involved in progressive CKD stages, and by the challenges in elucidating the role of low frequency variants. Meta-analyses with larger sample sizes and analyses of longitudinal renal phenotypes using higher-resolution genotyping data are required to uncover novel loci associated with severe renal phenotypes. PMID- 21691126 TI - Potential deleterious effects of vasopressin in chronic kidney disease and particularly autosomal dominant polycystic kidney disease. AB - The antidiuretic hormone vasopressin is crucial for regulating free water clearance in normal physiology. However, it has also been hypothesized that vasopressin has deleterious effects on the kidney. Vasopressin is elevated in animals and patients with chronic kidney disease. Suppression of vasopressin activity reduces proteinuria, renal hypertrophy, glomerulosclerosis and tubulointerstitial fibrosis in animal models. The potential detrimental influence of vasopressin is probably mediated by its effects on mesangial cell proliferation, renin secretion, renal hemodynamics, and blood pressure. In this review, we discuss the increasing body of evidence pointing towards the contribution of vasopressin to chronic kidney disease progression in general and to autosomal dominant polycystic kidney disease in particular. These data allude to the possibility that interventions directed at lowering vasopressin activity, for example by the administration of vasopressin receptor antagonists or by drinking more water, may be beneficial in chronic kidney disease. PMID- 21691127 TI - Angiogenesis in peritoneal dialysis. AB - Long-term exposure to peritoneal dialysis fluid induces morphological alterations, including angiogenesis, leading to a loss of ultrafiltration (UF) capacity. We discuss the effect of different factors in peritoneal dialysis (PD) on angiogenesis. In addition, we describe the process of angiogenesis and the possible role of different cell types in the peritoneum upon PD contributing to new blood vessel formation. Furthermore, we review several interventions used in our rat PD exposure model to decrease angiogenesis in PD. Moreover, we show new data on the use of sunitinib to inhibit angiogenesis in this rat model. Although various interventions seem to be promising, well-randomised clinical trials showing absolute prevention of angiogenesis and UF failure are, yet, still missing. To make real progress in PD treatment, the aim should be to prevent angiogenesis as well as peritoneal fibrosis and PD-induced inflammation. PMID- 21691128 TI - Update on pregnancy in chronic kidney disease. AB - The occurrence of pregnancy in patients with chronic kidney disease (CKD) has been considered a dangerous event both for the mother and for the fetus. However, increasing evidence shows that the stage of CKD is the leading factor that can predict possible acceleration in the declining of renal function and complications of pregnancy. This review summarizes recent data on pregnancy in patients with CKD, dialysis and kidney transplantation. PMID- 21691129 TI - Vitamin D and vascular calcification in chronic kidney disease. AB - Vascular calcification is common in patients with chronic kidney disease (CKD) and contributes to the increased rate of cardiovascular morbidity and mortality. The mechanisms regulating vascular calcification are under investigation; it is accepted that vascular calcification is an active and complex process involving many factors that promote or inhibit calcification. Vascular smooth muscle cells undergo transformation into osteogenic cells. This transformation is being stimulated by high phosphate, and more recently the role of the calcium phosphate nanocrystals has gained attention. Experimental models of uremia and in vitro studies have shown that an excess of calcitriol accelerates vascular calcification. However, observational studies suggest that vitamin D provides a survival advantage for patients with CKD. Experimental work shows that for similar serum concentrations of calcium and phosphate paricalcitol produces less vascular calcification than calcitriol suggesting a differential effect at the cellular level. Important issues regarding the role of vitamin D compounds on vascular calcification will be commented in this review. PMID- 21691130 TI - Sudden cardiac death in patients with chronic kidney disease: prevention is the sine qua non. AB - Despite developments in the technology of dialysis procedures and improvements in the understanding of systemic derangements related to chronic kidney disease (CKD), cardiovascular disease is the major cause of death. Unfortunately, the leading subset of cardiovascular disease death is sudden cardiac death (SCD). To date much effort has been exerted to figure out the clues pointing to the risk of future development of SCD in patients with CKD. However, none of these factors satisfactorily detects a truly vulnerable dialysis patient. Thus, recently, it has been advocated that a combination of noninvasive risk assessment methods, carefully chosen to reflect the different aspects of the underlying pathology and changes in the myocardial substrate in CKD, could help to identify patients at high risk of SCD within the CKD. In this review, we aimed to summarize what is known about risk stratification of patients with CKD and appropriate prevention strategies with a special emphasis on recent developments and the use of complimentary tests perhaps as a risk prediction rule. PMID- 21691131 TI - The management of atherosclerotic renovascular disease. AB - Atherosclerotic renovascular disease (ARVD) seems to be a common clinical condition. ARVD is clinically presented as: 'silent' renal artery stenosis, renovascular hypertension, ischemic nephropathy leading to deterioration of renal function and recurrent 'flash' pulmonary edema. Management of ARVD involves both revascularization and medical treatment. However, the impact of revascularization on kidney function and blood pressure control is a matter of great controversy in view of the results of recent randomized clinical trials. At present, concerted medical management (includes lifestyle modifications, such as smoking cessation) remains the main treatment option for patients with ARVD. However, there is a need to accurately identify individuals who may benefit from renal revascularization. PMID- 21691132 TI - Does uremia cause vascular dysfunction? AB - Vascular dysfunction induced by uremia has 4 main aspects. (1) Atherosclerosis is increased. Intima-media thickness is increased, and animal studies have established that uremia accelerates atherosclerosis. Uremic toxins are involved in several steps of atherosclerosis. Leukocyte activation is stimulated by guanidines, advanced glycation end products (AGE), p-cresyl sulfate, platelet diadenosine polyphosphates, and indoxyl sulfate. Endothelial adhesion molecules are stimulated by indoxyl sulfate. Migration and proliferation of vascular smooth muscle cells (VSMC) are stimulated by local inflammation which could be triggered by indoxyl sulfate and AGE. Uremia is associated with an increase in von Willebrand factor, thrombomodulin, plasminogen activator inhibitor 1, and matrix metalloproteinases. These factors contribute to thrombosis and plaque destabilization. There is also a decrease in nitric oxide (NO) availability, due to asymmetric dimethylarginine (ADMA), AGE, and oxidative stress. Moreover, circulating endothelial microparticles (EMP) are increased in uremia, and inhibit the NO pathway. EMP are induced in vitro by indoxyl sulfate and p-cresyl sulfate. (2) Arterial stiffness occurs due to the loss of compliance of the vascular wall which induces an increase in pulse pressure leading to left ventricular hypertrophy and a decrease in coronary perfusion. Implicated uremic toxins are ADMA, AGE, and oxidative stress. (3) Vascular calcifications are increased in uremia. Their formation involves a transdifferentiation process of VSMC into osteoblast-like cells. Implicated uremic toxins are mainly inorganic phosphate, as well as reactive oxygen species, tumor necrosis factor and leptin. (4) Abnormalities of vascular repair and neointimal hyperplasia are due to VSMC proliferation and lead to severe reduction of vascular lumen. Restenosis after coronary angioplasty is higher in dialysis than in nondialysis patients. Arteriovenous fistula stenosis is the most common cause of thrombosis. Uremic toxins such as indoxyl sulfate and some guanidine compounds inhibit endothelial proliferation and wound repair. Endothelial progenitor cells which contribute to vessel repair are decreased and impaired in uremia, related to high serum levels of beta(2)-microglobulin and indole-3 acetic acid. Overall, there is a link between kidney function and cardiovascular risk, as emphasized by recent meta analyses. Moreover, an association has been reported between cardiovascular mortality and uremic toxins such as indoxyl sulfate, p-cresol and p-cresyl sulfate. PMID- 21691133 TI - Molecular phenotypes of kidney graft rejection. AB - In the last decade, gene expression studies of kidney transplants provided an opportunity to better understand the development and regulation of kidney graft rejection. This review outlines the progress in the definition of biomarkers of rejection and, above all, concentrates on studies of the molecular phenotype of rejection. This phenotype, rather than morphological characterization, may be critical for assessing the ongoing processes in the graft and for the outcome prediction. PMID- 21691134 TI - Contribution of Jan Brod to nephrology. AB - Jan Brod (1912-1985), Professor of Medicine of Charles University, Prague, was one of the outstanding personalities of the Czechoslovak medicine and European nephrology of the 20th century. He was an eminent clinician, teacher and scientist who belonged among the founders of renal medicine in Europe. He grew up in the scientific tradition of Prague and Vienna and he was trained by some outstanding personalities, particularly Paul Wood. He became famous due to his pathophysiological-clinical approach to hypertension, heart and kidney diseases. He was not only interested in renal and cardiac physiology but in the entire clinical nephrology. He was among the first clinicians who started to use creatinine clearance in routine practice. His early work was also performed in the field of acute glomerulonephritis and in interstitial nephritis. Later he was interested in water and electrolytes in heart failure and the pathogenesis of edema, and he published priority data on the hemodynamic pattern in emotional stress. Furthermore, it is for sure that he was one of the first cardionephrologists, too. As early as in 1950, he studied diurnal variation in renal perfusion and urinary output in heart failure and later the effect of the adrenergic blockade on the renal hemodynamics in heart failure. Up to his exile in 1968, he served as the head of the Institute for Cardiovascular Research based in Prague and later on, up to his retirement, as the head of the Department of Nephrology in Hannover. He was a founding member of the International Society of Nephrology and president of its 2nd congress held in Prague in 1963. Throughout his life, Jan Brod remained a political man who voiced his opinions. Despite two exiles, he was always the Czech patriot. He holds a special place in the history of Czechoslovak and European nephrology. PMID- 21691135 TI - Role of inferior orbital wall morphologic properties in isolated orbital blow-out fracture. AB - PURPOSE: To compare inferior orbital wall morphology between isolated inferior and medial orbital wall fracture patients. METHODS: The morphologic properties of patients with isolated blow-out fractures involving the medial wall or inferior wall treated from August 2004 to August 2009 were reviewed. The cross-sectional area, thickness, gradient, and curvature of the inferior wall were measured via orbital CT in the opposite non-traumatized eye. RESULTS: Patients with isolated inferior wall fractures (n = 77) and isolated medial wall fractures (n = 78) evidenced no differences in sex, age, etiology of trauma, laterality of trauma, and associated concomitant intraocular injuries. The cross-sectional area, thickness, and gradient of the inferior wall did not differ significantly between the 2 groups. However, the coefficient of curvature was significantly greater in patients with inferior wall fracture than in patients with medial wall fracture (0.016 +/- 0.006 vs. 0.006 +/- 0.002, respectively; p = 0.000). CONCLUSION: Patients with more convex and steep inferior walls are more likely to incur isolated inferior wall fractures than isolated medial wall fractures. PMID- 21691136 TI - Vitreous vascular endothelial growth factor concentrations in proliferative diabetic retinopathy versus proliferative vitreoretinopathy. AB - PURPOSE: To assess vitreous vascular endothelial growth factor (VEGF) concentrations in proliferative diabetic retinopathy (PDR) in comparison to proliferative vitreoretinopathy (PVR). PATIENTS AND METHODS: Vitreous samples were collected from 69 eyes of 69 patients with traumatic lens dislocation (n = 10), grade B PVR with rhegmatogenous retinal detachment (n = 13), grade C PVR with rhegmatogenous retinal detachment (n = 14), PDR with vitreous hemorrhage (n = 18), and PDR with vitreous hemorrhage and tractional retinal detachment (n = 14). Vitreous fluid samples were obtained at vitrectomy, and the levels of VEGF were measured by enzyme-linked immunosorbent assay. RESULTS: The mean vitreous level of VEGF was 15.14 +/- 5.22 pg/ml in eyes with grade B PVR, 99.15 +/- 38.58 pg/ml in eyes with grade C PVR, 4,534.01 +/- 1,193.28 pg/ml in eyes with vitreous hemorrhage secondary to PDR, 5,157.29 +/- 969.44 pg/ml in eyes with vitreous hemorrhage and tractional retinal detachment secondary to PDR, and 16.19 +/- 5.76 pg/ml in eyes of the control group with traumatic lens dislocation. Vitreous VEGF concentrations were significantly higher in the patients with grade C PVR, PDR with vitreous hemorrhage and PDR with vitreous hemorrhage and tractional retinal detachment in comparison to the control patients (p < 0.05). A significant alteration was not observed in patients with grade B PVR (p = 0.55). CONCLUSIONS: Vitreous VEGF concentrations are increased in PDR and grade C PVR. The high VEGF concentrations could suggest a possible effect of VEGF on advanced PVR. PMID- 21691137 TI - Inhibitory effects of SU5416, a selective vascular endothelial growth factor receptor tyrosine kinase inhibitor, on experimental corneal neovascularization. AB - PURPOSE: Treatment of neovascularization in ocular diseases with vascular endothelial growth factor (VEGF) inhibition shows promising results. SU5416 is a low-molecular-weight tyrosine kinase inhibitor. It selectively inhibits the membrane-bound tyrosine kinase activity of VEGF-2 receptor (Flk-1/KDR) and blocks the intracellular signaling process. The aim of this study was to evaluate the effect of SU5416 on corneal neovascularization. METHODS: Corneas were cauterized with silver nitrate/potassium nitrate sticks in 20 eyes of 20 BALB/C mice. In the study group (n = 10), SU5416 (25 mg/kg) dissolved in dimethyl sulfoxide was given as an intraperitoneal injection in a single daily dose for 7 days. The other group of 10 mice given intraperitoneal dimethyl sulfoxide alone served as a control group. After 7 days, corneal neovascularization was evaluated using photographs captured by fluorescein angiography. Colored photographs were taken by a biomicroscope with a digital camera. Data were expressed as mean neovascular length and mean number of new vessels for each animal. The values were computed and compared between the groups. RESULTS: The mean burn stimulus intensities were not different between the groups. In the study group, the mean length of the vessels and the mean number of vessels were 0.49 +/- 0.05 and 11.20 +/- 1.69 mm, respectively. In the control group, the mean length of the vessels and the mean number of the vessels were 0.89 +/- 0.11 and 17.80 +/- 1.03 mm, respectively. There is a statistically significant difference in the mean length and the mean number of new vessels between the study and control groups (p < 0.001). CONCLUSION: Selective inhibition of VEGFR-2 (Flk-1/KDR) tyrosine kinase with SU5416 was shown to have an inhibitory effect on corneal neovascularization in this animal model. VEGFR-2 (Flk-1/KDR) tyrosine kinase inhibition may represent a different pathway for treatment of the neovascularization process in ocular pathologies. Fluorescein angiography photographs of new vessels on the cornea may provide a better evaluation of neovascularization than colored images in animal models. PMID- 21691138 TI - Influence of hyperbaric oxygen therapy on central corneal thickness. AB - BACKGROUND/AIMS: Hyperbaric oxygen (HBO) therapy is used in the treatment of several disorders. Little is known about the effects of HBO treatment on corneal thickness. The aim of this study was to investigate the effect of HBO treatment on central corneal thickness. METHODS: Thirty-two subjects (18 males and 14 females, mean age 57.3 +/- 16.7 years) undergoing HBO treatment were consecutively enrolled. The subjects were assigned into diabetic (n = 16) and nondiabetic groups (n = 16). Best-corrected visual acuity was recorded before HBO treatment, and anterior and posterior segment examinations were performed on a slit lamp biomicrosope. Central corneal thickness was measured with an ultrasonic pachymeter before and immediately after HBO treatment, which lasted 120 min at 2.4 atmospheres absolute with three 30-min oxygen and two 5-min air breathing periods. RESULTS: HBO treatment did not change the central corneal thickness in diabetic subjects (547.6 +/- 34.5 vs. 548.6 +/- 34.6 MUm; p = 0.606). In nondiabetic subjects, however, the central corneal thickness was significantly reduced after HBO treatment (576.5 +/- 34.8 vs. 569.0 +/- 34.8 MUm; p < 0.001). CONCLUSION: A single exposure to HBO treatment reduced the central corneal thickness in nondiabetic subjects but not in diabetic subjects. However, the change in central corneal thickness was minor. PMID- 21691139 TI - Safety and efficacy of fibrin glue versus vicryl sutures in recurrent pterygium with amniotic membrane grafting. AB - PURPOSE: The study aimed to compare surgical outcomes with likely toxic side effects when using pterygium excision and amniotic membrane grafting with fibrin glue versus Vicryl sutures. METHOD: This is a prospective randomized study. Patients were classified into two groups: group 1 consisted of 20 patients with Vicryl-sutured grafts, and group 2 consisted of 20 patients with fibrin-glued grafts that were prepared from autologous blood. Results including surgery time, patient discomfort, complications and recurrence rates within 1, 6 and 12 months were analyzed. RESULTS: The study demonstrated that there was a statistically significant decrease in surgery time in the fibrin glue group (the procedure took 17 min) relative to the sutured group (28 min; p < 0.05). Additionally, both postoperative pain and discomfort were noted significantly less often in the fibrin glue group. Complications were also decreased in the fibrin glue group. CONCLUSION: The study revealed that the use of fibrin glue in pterygium surgery with amniotic membrane grafting was safer, less toxic and less time-consuming, and resulted in fewer complications than graft surgery with sutures. PMID- 21691140 TI - Mutation analysis of PAX6 in a Chinese family and a patient with a presumed sporadic case of congenital aniridia. AB - AIMS: Mutations in the PAX6 are the major cause of congenital aniridia. The objective of this study was to analyze genetic mutations in PAX6 in Chinese patients with congenital aniridia. METHODS: Total genomic DNA was isolated from the peripheral blood of the aniridia patients, all healthy family members and 100 healthy volunteers. The 14 exons (including alternatively spliced exon 5a) of the PAX6 gene were amplified by polymerase chain reaction, and the products were sequenced to identify the mutation. RESULTS: Two mutations of PAX6 were detected in exon 11 in the congenital aniridia patients. One mutation was caused by the duplication of the 4 nucleic acids CTCC (c.1286insCTCC), which would lead to a frameshift. The other mutation was caused by a transition from C to T (c.1311C -> T), which would generate a stop codon. Neither mutation was present in the healthy family members or 100 healthy volunteers. CONCLUSION: We examined the exon sequence of the PAX6 gene in a Chinese family and an unrelated individual with aniridia. The predicted outcome of both mutations is premature termination. The mutation found in the unrelated individual has not previously been reported and represents a new addition to the spectrum of mutations in PAX6. PMID- 21691141 TI - Pharmacological enhancement of ex vivo gene therapy neuroprotection in a rodent model of retinal degeneration. AB - AIMS: We have previously shown the benefits of cell-based delivery of neuroprotection in a rodent model of retinitis pigmentosa (RP). In order to maximise the effectiveness of this approach, we hypothesised that this could be augmented by combination with an aminoglycoside known to limit the abnormal RNA translation seen in this model. METHODS: A rhodopsin TgN S334ter-4 rat model of RP underwent daily subcutaneous injection of 12.5 MUg/g gentamicin from postnatal day 5 (P5). At P21, selected rats also underwent intravitreal injection of cells genetically engineered to oversecrete glial cell-derived neurotrophic factor. Histological imaging was undertaken to evaluate photoreceptor survival at P70 and compared with images from untreated TgN S334ter-4 rats and control Sprague-Dawley rats. RESULTS: Statistically significant (p < 0.05) improvements in outer retinal indices were seen with this combination strategy when compared with results in rats treated with individual therapies alone. This improvement was most apparent in the peripheral retina, where the greatest degeneration was observed. CONCLUSIONS: We have shown that the combination of neuroprotection plus aminoglycoside read-through in an animal model of retinal degeneration improved the histological appearance of the retina such that it was statistically indistinguishable from unaffected controls. Further functional and longitudinal studies of this approach are warranted. PMID- 21691143 TI - Cognitive Reserve Index questionnaire (CRIq): a new instrument for measuring cognitive reserve. AB - BACKGROUND AND AIMS: The concept of "reserve" has been used to explain the difference between individuals in their capacity to cope with or compensate for pathology. Brain reserve refers to structural aspects of the brain, such as brain size and synapse count. Cognitive reserve is the ability to optimize and maximize performance through two mechanisms: recruitment of brain networks, and/or compensation by alternative cognitive strategies. The aim of the present research was to devise an instrument for comprehensive assessment and measurement of the quantity of cognitive reserve accumulated by individuals throughout their lifespan. METHODS: A new approach using the Cognitive Reserve Index questionnaire (CRIq) was developed and tested in a sample of 588 healthy individuals, from 18 to 102 years old, stratified by age (Young, Adults, Elderly) and gender. The CRIq includes demographic data and items grouped into three sections: education, working activity and leisure time, each of which returns a subscore. The WAIS Vocabulary test and TIB were also administered. RESULTS: The main descriptive features and some inferential results are described. Intelligence was only moderately correlated with cognitive reserve, stressing the distinction between these two concepts. Age and gender significantly affected CRIq scores, whereas no effect emerged from their interaction. Adults showed a higher score than Young and Elderly. CONCLUSIONS: This study provides a new instrument for a standardized measure of the cognitive reserve accumulated by individuals through their lifespan. The potential use of the CRIq in both experimental research and clinical practice is discussed. PMID- 21691142 TI - 5-(4-Hydroxy-2,3,5-trimethylbenzylidene) thiazolidine-2,4-dione attenuates atherosclerosis possibly by reducing monocyte recruitment to the lesion. AB - A variety of benzylidenethiazole analogs have been demonstrated to inhibit 5 lipoxygenase (5-LOX). Here we report the anti-atherogenic potential of 5-(4 hydroxy- 2,3,5-trimethylbenzylidene) thiazolidin-2,4-dione (HMB-TZD), a benzylidenethiazole analog, and its potential mechanism of action in LDL receptor deficient (Ldlr-/-) mice. HMB-TZD Treatment reduced leukotriene B4 (LTB4) production significantly in RAW264.7 macrophages and SVEC4-10 endothelial cells. Macrophages or endothelial cells pre-incubated with HMB-TZD for 2 h and then stimulated with lipopolysaccharide or tumor necrosis factor-alpha (TNF-alpha) displayed reduced cytokine production. Also, HMB-TZD reduced cell migration and adhesion in accordance with decreased proinflammatory molecule production in vitro and ex vivo. HMB-TZD treatment of 8-week-old male Ldlr-/- mice resulted in significantly reduced atherosclerotic lesions without a change to plasma lipid profiles. Moreover, aortic expression of pro-atherogenic molecules involved in the recruitment of monocytes to the aortic wall, including TNF-alpha , MCP-1, and VCAM-1, was downregulated. HMB-TZD also reduced macrophage infiltration into atherosclerotic lesions. In conclusion, HMB-TZD ameliorates atherosclerotic lesion formation possibly by reducing the expression of proinflammatory molecules and monocyte/macrophage recruitment to the lesion. These results suggest that HMB TZD, and benzylidenethiazole analogs in general, may have therapeutic potential as treatments for atherosclerosis. PMID- 21691144 TI - World Antibody Drug Conjugate Summit Europe: February 21-23, 2011; Frankfurt, Germany. AB - The World Antibody Drug Conjugate Summit Europe, organized by Biorbis/ Hanson Wade was held in Frankfurt, Germany on February 21-23, 2011. Antibody drug conjugates (ADCs), also called immunoconjugates, are becoming an increasingly important class of therapeutics as demonstrated by the attendance of nearly 100 delegates at this highly focused meeting. Updates on three ADCs that are in late stage clinical development, trastuzumab emtansine (T-DM1), brentuximab vedotin (SGN-35) and inotuzumab ozogamicin (CMC-544), were presented by speakers from ImmunoGen, Genentech, Roche, Seattle Genetics and Pfizer. These ADCs have shown encouraging therapeutic effects against solid tumors (T-DM1) and hematological malignancies (SGN-35, CMC-544). The key feature of the new generation of ADCs is the effective combination of the cytotoxicity of natural or synthetic highly potent antineoplastic agents, tumor selective monoclonal antibodies and blood stable optimized linkers. Early clinical data for ADCs were showcased by Progenics Pharmaceuticals (PSMA ADC), Celldex (CDX-011) and Biotest (BT-062). Takeda, MedImmune and sanofi-aventis outlined their strategies for process development and analytical characterization. In addition, presentations on duocarmycin based-ADCs, alpha emitting immunoconjugates and antibody-conjugated nanoparticles were given by representatives from Syntarga, Algeta and the University of Stuttgart, respectively. PMID- 21691146 TI - Metabolic regulation by HMGB1-mediated autophagy and mitophagy. AB - Autophagy is a dynamic process for degradation of cytosolic components such as dysfunctional organelles and proteins and a means for generating metabolic substrates during periods of starvation. Mitochondrial autophagy ("mitophagy") is a selective form of autophagy, which is important in maintaining mitochondrial homeostasis. High mobility group box 1 (HMGB1) plays important intranuclear, cytosolic and extracellular roles in the regulation of autophagy. Cytoplasmic HMGB1 is a novel Beclin 1-binding protein active in autophagy. Extracellular HMGB1 induces autophagy, and this role is dependent on its redox state and receptor (Receptor for Advanced Glycation End products, RAGE) expression. Nuclear HMGB1 modulates the expression of heat shock protein beta-1 (HSPB1/HSP27). As a cytoskeleton regulator, HSPB1 is critical for dynamic intracellular trafficking during autophagy and mitophagy. Loss of either HMGB1 or HSPB1 results in a phenotypically similar deficiency in mitophagy typified by mitochondrial fragmentation with decreased aerobic respiration and adenosine triphosphate (ATP) production. These findings reveal a novel pathway coupling autophagy and cellular energy metabolism. PMID- 21691147 TI - Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. AB - Sorafenib, a potent multikinase inhibitor, has been recognized as the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). However, the direct functional mechanism of tumor lethality mediated by sorafenib remains to be fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, we showed sorafenib induced both apoptosis and autophagy in human HCC cells through a mechanism that involved endoplasmic reticulum (ER) stress and was independent of the MEK1/2-ERK1/2 pathway. Upregulation of IRE1 signals from sorafenib-induced ER stress was critical for the induction of autophagy. Moreover, autophagy activation alleviated the ER stress-induced cell death. Inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown enhanced cell death in sorafenib treated HCC cell lines. Critically, the combination of sorafenib with the autophagy inhibitor chloroquine produced more pronounced tumor suppression in HCC both in vivo and in vitro. These findings indicated that both ER stress and autophagy were involved in the cell death evoked by sorafenib in HCC cells. The combination of autophagy modulation and molecular targeted therapy is a promising therapeutic strategy in treatment of HCC. PMID- 21691145 TI - Immunoglobulin A: A next generation of therapeutic antibodies? AB - Although immunoglobulin (Ig) A is commonly recognized as the most prevalent antibody subclass at mucosal sites with an important role in mucosal defense, its potential as a therapeutic monoclonal antibody is less well known. However, IgA has multifaceted anti-, non-, and pro-inflammatory functions that can be exploited for different immunotherapeutical strategies, which will be the focus of this review. PMID- 21691148 TI - ATRA-induced upregulation of Beclin 1 prolongs the life span of differentiated acute promyelocytic leukemia cells. AB - Acute promyelocytic leukemia (APL) results from a blockade of granulocyte differentiation at the promyelocytic stage. All-trans retinoic acid (ATRA) induces clinical remission in APL patients by enhancing the rapid differentiation of APL cells and the clearance of PML-RARalpha, APL's hallmark oncoprotein. In the present study, we demonstrated that both autophagy and Beclin 1, an autophagic protein, are upregulated during the course of ATRA-induced neutrophil/granulocyte differentiation of an APL-derived cell line named NB4 cells. This induction of autophagy is associated with downregulation of Bcl-2 and inhibition of mTOR activity. Small interfering RNA-mediated knockdown of BECN1 expression enhances apoptosis triggered by ATRA in NB4 cells but does not affect the differentiation process. These results provide evidence that the upregulation of Beclin 1 by ATRA constitutes an anti-apoptotic signal for maintaining the viability of mature APL cells, but has no crucial effect on the granulocytic differentiation. This finding may help to elucidate the mechanisms involved in ATRA resistance of APL patients, and in the ATRA syndrome caused by an accumulation of mature APL cells. PMID- 21691149 TI - Regulation of stomatal density by the GTL1 transcription factor for improving water use efficiency. AB - A stoma (pl. stomata) is the pore formed by two guard cells found predominantly in the leaf epidermis. Plants control stomatal aperture (opening and closing) and/or number (density) to regulate carbon dioxide (CO2) uptake and water loss (transpiration), which is necessary to optimize plant growth, development, and fitness in response to various environmental conditions. Recently, we identified Arabidopsis GT2-LIKE 1 (GTL1) as a transcriptional repressor of STOMATAL DENSITY AND DISTRIBUTION 1 (SDD1), a negative regulator of stomatal density. GTL1 directly interacts with the SDD1 promoter regulating stomatal density, transpiration, and water use efficiency (WUE). Here we discuss potential GTL1 orthologs in other plant species. PMID- 21691150 TI - Population differences in microRNA expression and biological implications. AB - Population differences observed for complex traits may be attributed to the combined effect of socioeconomic, environmental, genetic and epigenetic factors. To better understand population differences in complex traits, genome-wide genetic and gene expression differences among ethnic populations have been studied. Here we set out to evaluate population differences in small non-coding RNAs through an evaluation of microRNA (miRNA) baseline expression in HapMap lymphoblastoid cell lines (LCLs) derived from 53 CEU (Utah residents with northern and western European ancestry) and 54 YRI (African from Ibadan, Nigeria). Using the Exiqon miRCURYTM LNA arrays, we found that 16% of all miRNAs evaluated in our study differ significantly between these 2 ethnic groups (pBonferroni corrected< 0.05). Furthermore, we explored the potential biological function of these observed differentially expressed miRNAs by comprehensively examining their effect on the transcriptome and their relationship with cellular sensitivity drug phenotypes. After multiple testing adjustment (false discovery rate (FDR)< 0.1), we found that 55% and 88% of the differentially expressed miRNAs were significantly and inversely correlated with an mRNA expression phenotype in the CEU and YRI samples, respectively. Interestingly, a substantial proportion (64%) of these miRNAs correlated with cellular sensitivity to chemotherapeutic agents (FDR< 0.05). Lastly, upon performing a genome-wide association study between SNPs and miRNA expression, we identified a large number of SNPs exhibiting different allele frequencies that affect the expression of these differentially expressed miRNAs, suggesting the role of genetic variants in mediating the observed population differences. PMID- 21691151 TI - Cell biology of retroviral RNA packaging. AB - Generation of infectious retroviral particles rely on the targeting of all structural components to the correct cellular sites at the correct time. Gag, the main structural protein, orchestrates the assembly process and the mechanisms that trigger its targeting to assembly sites are well described. Gag is also responsible for the packaging of the viral genome and the molecular details of the Gag/RNA interaction are well characterized. Until recently, much less was understood about the cell biology of retrovirus RNA packaging. However, novel biochemical and live-cell microscopic approaches have identified where in the cell the initial events of genome recognition by Gag occur. These recent developments have shed light on the role played by the viral genome during virion assembly. Other central issues of the cell biology of RNA packaging, such as how the Gag-RNA complex traffics through the cytoplasm towards assembly sites, await characterization. PMID- 21691152 TI - Global assessment of GU-rich regulatory content and function in the human transcriptome. AB - Unlike AU-rich elements (AREs) that are largely present in the 3'UTRs of many unstable mammalian mRNAs, the function and abundance of GU-rich elements (GREs) are poorly understood. We performed a genome-wide analysis and found that at least 5% of human genes contain GREs in their 3'UTRs with functional over representation in genes involved in transcription, nucleic acid metabolism, developmental processes, and neurogenesis. GREs have similar sequence clustering patterns with AREs such as overlapping GUUUG pentamers and enrichment in 3'UTRs. Functional analysis using T-cell mRNA expression microarray data confirms correlation with mRNA destabilization. Reporter assays show that compared to AREs the ability of GREs to destabilize mRNA is modest and does not increase with the increasing number of overlapping pentamers. Naturally occurring GREs within U rich contexts were more potent in destabilizing GFP reporter mRNAs than synthetic GREs with perfectly overlapping pentamers. Overall, we find that GREs bear a resemblance to AREs in sequence patterns but they regulate a different repertoire of genes and have different dynamics of mRNA decay. A dedicated resource on all GRE-containing genes of the human, mouse and rat genomes can be found at brp.kfshrc.edu.sa/GredOrg. PMID- 21691153 TI - Mutations in leaf starch metabolism modulate the diurnal root growth profiles of Arabidopsis thaliana. AB - Roots of Arabidopsis thaliana exhibit stable diurnal growth profiles that are controlled by the circadian clock. Here we describe the effects of mutations in leaf starch metabolism on the diurnal root growth characteristics of Arabidopsis thaliana. High temporal and spatial resolution video imaging was performed to quantify the growth kinetics of Arabidopsis wild-type as well as pgm, sex1, mex1, dpe1 and dpe2 starch metabolism mutants grown in three different photoperiods. As a result, root growth patterns of all genotypes displayed characteristic modifications in their diurnal kinetics that were also affected by the photoperiod. To further investigate the role of starch derived substrate deficiency on root growth, the effect of 0.05% extracellular sucrose was studied in 12 h-12 h light-dark cycles. PMID- 21691154 TI - Geminivirus C2 protein might be the key player for geminiviral co- option of SCF mediated ubiquitination. AB - Viruses are obligate intracellular parasites, and need to create a suitable cell environment for viral propagation to complete their life cycle. In order to achieve this, viruses must usurp or interfere with the cellular machinery. Ubiquitination, a post-translational modification that controls numerous cellular processes, has proven to be a common target for viruses. Recently, geminivirus C2 protein has been shown to interact with the CSN complex and disrupt its activity over CULLIN1, interfering with the function of the CULLIN1-based SCF ubiquitin E3 ligases. Interestingly, overexpression of a given F-box protein may circumvent the general SCF malfunction caused by C2. This result raises the tantalizing idea that geminiviruses might be not only hampering, but also redirecting the activity of SCF complexes, thus co-opting the SCF-mediated ubiquitination pathway. We hypothesize that the mechanism of C2-facilitated co-option of SCF-mediated ubiquitination might not be exclusive for geminiviruses, but rather a common strategy for viruses. PMID- 21691155 TI - Promoter of a salinity and cold stress-induced MCM6 DNA helicase from pea. AB - The eukaryotic hetrohexameric mini-chromosome maintenance (MCM2-7) proteins complex provides DNA unwinding function during the DNA replication. The complex also functions as DNA replication licensing factor which ensures that the DNA in genome is replicated only once per cell division cycle. Recently, a single subunit MCM6 from pea has been shown to contain helicase and ATPase activities in vitro. Recently, the transcript of a single subunit was reported to be upregulated in pea plant in response to high salinity and cold stress and not with ABA, drought and heat stress. The first direct evidence that overexpression of single subunit MCM6 confers salinity stress tolerance without yield loss has also been reported. Here we report the promoter of the pea MCM6 single subunit that contains stress responsive elements which may be responsible for regulating the MCM6 under abiotic stress conditions. PMID- 21691156 TI - Abuses in human papillomavirus DNA testing. PMID- 21691157 TI - Low-risk human papillomavirus testing and other nonrecommended human papillomavirus testing practices among U.S. health care providers. AB - OBJECTIVE: To assess self-reported human papillomavirus (HPV) DNA testing practices by health care providers and clinics, including nonrecommended practices such as low-risk HPV testing, HPV cotesting in women younger than age 30 years, and HPV reflex testing for high-grade abnormal Pap test results. METHODS: We analyzed responses to a cross-sectional survey of a nationally representative sample of Papanicolaou test providers administered in conjunction with the 2006 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey. Data analysis was performed on responses from 376 office-based health care providers and 216 outpatient clinics. RESULTS: Overall, 75.5% (95% confidence interval [CI] 68.7-81.2%) of health care providers and 77.2% (95% CI 60.3-88.3%) of clinics reported ever using the HPV DNA test. Of health care providers who used HPV testing, 28.5% (95% CI 21.6-36.6%) used both high-risk and low-risk HPV tests. Most health care providers (59.6%, 95% CI 48.5 69.7%) and clinics (66.0%, 95% CI 48.0-80.3%) used HPV cotesting in women younger than age 30 years. A high percentage of health care providers and clinics performed reflex HPV testing after Pap test results of atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions (71.4%, 95% CI 63.5 78.3% and 62.8%, 95% CI 49.0-74.9%, respectively) and high-grade squamous intraepithelial lesions (50.7%, 95% CI 42.4-58.9% and 49.0%, 95% CI 33.1-65.2%, respectively), results for which HPV testing is not recommended. CONCLUSION: Many health care providers reported inappropriate uses of HPV testing, which may lead to unnecessary follow-up and increased medical costs without added benefits. Interventions such as eliminating the low-risk HPV test from the U.S. market and educating health care providers and patients on appropriate indications for HPV testing are needed to discourage health care providers from such practices. PMID- 21691158 TI - Disparities in human papillomavirus vaccine completion among vaccine initiators. AB - OBJECTIVE: To estimate rates of completing the full three-dose prophylactic human papillomavirus (HPV) vaccination regimen in patients who initiated the series and to identify variables associated with not completing vaccination. METHODS: This single-institution review identified all patients initiating HPV vaccination at one of four affiliated clinics between January 2007 and June 2008. Vaccination "completers" were defined as patients who had completed all three vaccinations within 12 months of initiating the vaccination series. Logistic regression was used to identify factors associated with vaccine completion. Variables analyzed included age, type of insurance (private compared with public), practice location (urban compared with suburban), practice type (pediatrics, gynecology, or family practice), and race or ethnicity (white or African American and Hispanic). RESULTS: Of the 1,413 girls and young women who initiated HPV vaccination, 469 (33.2%) completed the vaccine series. Overall, private insurances (odds ratio 1.87, 95% confidence interval 1.26-2.76) and suburban practice locations (odds ratio 1.44, 95% confidence interval 1.04-1.98) were associated with higher vaccine completion rates. African American race was associated with lower completion rates (odds ratio 0.50, 95% confidence interval 0.38-0.65). In multivariable analyses, the combination of younger age (11-17 years) and urban practice location was associated with very low likelihood of completing HPV vaccination (22%; P=.023). CONCLUSION: The HPV vaccine completion rate is low. When resources are limited, disparities in HPV vaccine completion should be considered when developing programs to improve vaccine utilization. Urban girls and young women should be targeted as an at-risk population. PMID- 21691160 TI - Interbirth interval with frequency of cesarean delivery. AB - OBJECTIVE: To estimate whether and to what extent interbirth interval is associated with cesarean delivery. METHODS: This is a retrospective cohort study of 2,528 multiparous women who presented to labor and delivery at a single tertiary care obstetric hospital during an 18-month period. Women were grouped by their interdelivery interval in 5-year increments, and the rate of cesarean delivery was determined for these groups. The independent association of interdelivery interval with cesarean delivery was further estimated after controlling for potential confounding factors in logistic regression. RESULTS: Women with an interbirth interval of less than 5 years had a cesarean delivery rate of 1.9%. Women with interbirth intervals of 5-9 years, 10-14 years, and 15 or more years had cesarean delivery rates of 5.0%, 7.7%, and 13.3%, respectively (P<.001). After controlling for potential confounding factors, the corresponding odds ratio (and 95% confidence intervals) for cesarean delivery for each respective interdelivery interval group, in reference to the "less than 5 years" group, was 2.1 (1.12-3.92), 3.2 (1.17-8.63), and 7.2 (1.47-35.53). CONCLUSION: A longer interbirth interval is independently associated with an increased risk of cesarean delivery. PMID- 21691159 TI - Endometrial intraepithelial neoplasia: clinical correlates and outcomes. AB - OBJECTIVE: To estimate cancer outcome and outcome predictors of women with endometrial intraepithelial neoplasia (EIN). METHODS: Outcomes of women with first diagnosis of EIN ("index biopsy") were determined by follow-up pathology. Patient characteristics were correlated with EIN regression, EIN persistence, and progression to cancer. RESULTS: Fifteen percent (95% confidence interval [CI] 9.8 20.8%, 26 of 177) of index EIN biopsy samples had concurrent cancer. Of the women with cancer-free index EIN biopsy samples and follow-up by hysterectomy or more than 18 months of surveillance, 25% (95% CI 18.4-33.3%, 36 of 142) showed regression, 35% (95% CI 27.4-43.7%, 50 of 142) showed persistence, and 39% (95% CI 31.3-48.0%, 56 of 142) showed progression. Nonwhite ethnicity and progestin treatment reduced cancer outcomes (odds ratio [OR] 0.16, 95% CI 0.03-0.84 and OR 0.24, 95% CI 0.08-0.70, respectively), whereas body mass index greater than 25 increased malignant outcomes (body mass index 25 or higher, OR 3.05, 95% CI 1.10 8.45). CONCLUSION: Endometrial intraepithelial neoplasia confers a high risk of cancer, but individual patient outcomes cannot be predicted. Management should include exclusion of concurrent carcinoma and consideration of hysterectomy. PMID- 21691161 TI - Extremely preterm infant mortality rates and cesarean deliveries in the United States. AB - OBJECTIVES: To estimate trends in infant mortality rates and cesarean delivery rates for extremely preterm infants born in the United States. METHODS: This national population-based study used public data from the Centers for Disease Control and Prevention to investigate extremely preterm infants born alive between 22 0/7 and 27 6/7 weeks of gestational age from 1999 to 2005. RESULTS: There were 177,552 extremely preterm infant births (fewer than 1% of all births) from 1999 to 2005. The number of annual extremely preterm births increased by 7% compared with a 4.5% increase for births at all gestations. During the study years, the extremely preterm infant mortality rate (percentage of infants who died in the first year) remained steady (range 33-34%; P=.22), whereas the cesarean delivery rate increased from 43% to 54% (P<.001). The infant mortality rate after cesarean delivery increased from 24% to 26% (P=.012). At each gestational age, the annual cesarean delivery rate increased over time (P<.001 for each), whereas gestational age-specific infant mortality rates were unchanged except for a 2% decline from 2004 to 2005 for infants born at 24 weeks of gestation (P=.01). CONCLUSION: A significant rise in the cesarean delivery rate in the United States from 1999 to 2005 for infants born at less than 28 weeks of gestation was not associated with an improvement in the infant mortality rate. PMID- 21691163 TI - Factors influencing the use of frozen section analysis in adnexal masses. AB - OBJECTIVE: To determine the factors that influence the use of frozen section analysis in adnexal masses and the factors that predict malignancy. METHODS: The study participants were women scheduled for adnexal mass surgery in 11 hospitals between 2005 and 2009. Factors that potentially influenced the use of frozen section analysis and potentially predicted malignancy were studied, such as menopausal status, CA 125 level, ultrasound characteristics, presence of adhesions, and tumor size. We used univariable and multivariable analyses to assess the factors. RESULTS: A total of 670 patients were included in the study. The frozen section analyses for 323 patients (48%) showed 206 benign, 55 borderline, and 62 malignant adnexal masses. The CA 125 level, locularity of the tumor, and presence of solid areas predicted both the use of frozen section analysis and the presence of malignancy. The presence of adhesions predicted malignancy, but not the use of frozen section analysis. Menopausal status and tumor size predicted the use of frozen section analysis, but not malignancy. CONCLUSION: Menopausal status and tumor size are associated with more use of frozen section analysis, but they have not been identified as factors associated with malignancy. Frozen section analysis is useful when the CA 125 levels are greater than 35 units/mL and when there are multilocular tumors, solid areas on ultrasonography, and adhesions revealed during surgery. PMID- 21691162 TI - Predictors of cesarean delivery for periviable neonates. AB - OBJECTIVE: To test for racial or ethnic disparities or both in periviable cesarean delivery and describe sociodemographic and clinical characteristics associated with periviable cesarean delivery. METHODS: This was a retrospective cohort study of state-level maternal and neonatal hospital discharge data linked to vital statistics data for deliveries occurring between 23 0/7 and 24 6/7 [corrected] weeks of gestation in California, Missouri, and Pennsylvania from 1995 to 2005 (N=8,290). RESULTS: Approximately 79% of the population was aged 18 35 years, and almost half were nulliparous. Almost 20% of the women were African American, 36.4% were Hispanic, and 33.6% were white. Overall, 33.6% of periviable neonates were delivered by cesarean. In multivariable analyses adjusting for sociodemographic and clinical characteristics, cesarean delivery did not differ among African American and Hispanic women compared with white women (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.76-1.05; and OR 0.95, 95% CI 0.83-1.09, respectively). Women presenting with preterm labor were significantly less likely to undergo cesarean delivery (OR 0.84, 95% CI 0.73-0.96), whereas women presenting with preterm premature rupture of membranes (OR 1.29, 95% CI 1.14 1.45) or abruption (OR 2.43, 95% CI 2.09-2.81) were more likely to have cesarean deliveries. The strongest predictor of periviable cesarean delivery was pregnancy induced hypertension (OR 15.6.4, 95% CI 12.3-19.7). CONCLUSION: Unlike disparities observed at later gestational ages, cesarean delivery did not differ by race and ethnicity among this periviable cohort. Instead, medical indications such as pregnancy-induced hypertension, preterm premature rupture of membranes, or abruption were associated with a higher likelihood of cesarean delivery. Periviable deliveries represent a subset of deliveries, wherein race and ethnicity do not influence mode of delivery; the acuity of the clinical encounter dictates the course of care. PMID- 21691164 TI - Effect of obesity on oocyte and embryo quality in women undergoing in vitro fertilization. AB - OBJECTIVE: To estimate the effect of body mass index (BMI) on oocyte and embryo parameters and cycle outcomes in women undergoing in vitro fertilization (IVF). METHODS: We evaluated a retrospective cohort of 1,721 women undergoing a first IVF cycle with fresh, autologous embryos between 2007 and 2010 in an academic infertility practice. Main outcome measures included number of mature and normally fertilized oocytes, embryo morphology, estradiol on the day of human chorionic gonadotropin administration, clinical pregnancy, spontaneous abortion, and live birth. We performed multivariable analyses, adjusting for potential confounders, including age at cycle start, infertility diagnosis, type of stimulation, total gonadotropin dose, use of intracytoplasmic sperm injection, and number of embryos transferred. RESULTS: Compared with women of normal BMI, women with class II (BMI 35-39.9) and III (BMI 40 or higher) obesity had fewer normally fertilized oocytes (9.3 compared with 7.6 and 7.7, P<.03) and lower estradiol levels (2,047 pg/mL compared with 1,498 and 1,361, P<.001) adjusting for age and despite similar numbers of mature oocytes. Odds of clinical pregnancy (odds ratio [OR] 0.50, 95% confidence interval [CI] 0.31-0.82) and live birth (OR 0.51, 95% CI 0.29-0.87) were 50% lower in women with class III obesity as compared with women of normal BMI. CONCLUSION: Obesity was associated with fewer normally fertilized oocytes, lower estradiol levels, and lower pregnancy and live birth rates. Infertile women requiring IVF should be encouraged to maintain a normal weight during treatment. PMID- 21691165 TI - Early possible risk factors for overt diabetes after gestational diabetes mellitus. AB - OBJECTIVE: To assess a cluster of risk factors, including parameters of the metabolic syndrome, in women with gestational diabetes mellitus (GDM) early after delivery, that features the best prediction for developing diabetes. METHODS: Women with GDM 3-6 months after delivery received a complete metabolic characterization at baseline as well as annually for up to 10 years of follow-up (N=110). We used parameters characterizing the metabolic syndrome as well as demographic variables at baseline to predict diabetes manifestation. RESULTS: Metabolic disturbances and insulin treatment during pregnancy were significantly associated with overt diabetes. Waist circumference of 80 cm or higher failed to show a significant effect on later development of the disease; however, it was significant when 88 cm or more was used as a cutoff value. We identified impaired glucose tolerance (13 [56.5%]; hazard ratio 6.77, confidence interval [CI] 2.96 15.45, P<.001) as well as high-density lipoprotein (HDL) cholesterol less than 50 mg/dL (14 [60.9%]; hazard ratio 2.88, CI 1.24-6.67, P=.010) and age older than 35 years (12 [52.2%]; hazard ratio 3.06, CI 1.32-7.12, P=.006) as the best predictors with additive effects. Women with at least two risk factors had a higher risk to develop the disease as compared with those women who showed only one risk factor (hazard ratio 3.2, CI 1.4-7.7, P=.008). CONCLUSION: Impaired glucose tolerance, HDL cholesterol less than 50 mg/dL, and age older than 35 years were identified as the best predictors of developing diabetes after GDM. PMID- 21691166 TI - Single-balloon compared with double-balloon catheters for induction of labor: a randomized controlled trial. AB - OBJECTIVE: To estimate the efficacy of a single-balloon catheter compared with a double-balloon catheter among women with unfavorable cervices undergoing induction of labor. METHODS: This prospective randomized study was conducted at a university teaching medical center between June 2008 and December 2010. Pregnant women admitted for induction of labor with a live singleton gestation in cephalic presentation with intact membranes and a Bishop score of 6 or less were randomly assigned for cervical ripening by a single-balloon catheter or a double-balloon catheter. The primary outcome was the length of time from catheter insertion until delivery. The secondary outcome was mode of delivery. RESULTS: Of 368 eligible women screened during the study period, 293 were included in the final analysis; 145 were randomly assigned to receive a single-balloon catheter and 148 received a double-balloon catheter. Demographic and obstetric parameters were comparable between the two groups. Length of time from catheter insertion until delivery was 19.4 (+/-6.0) and 19.1 (+/-6.8) hours among the single-balloon and the double-balloon catheter groups, respectively (P=.80). Length of time did not differ when primiparous women were analyzed separately. Incidence of cesarean delivery was 10.3% and 17.6% among the single-balloon and double-balloon catheter groups, respectively (P=.09). The incidence of either vacuum deliveries or cesarean deliveries was significantly lower among the single-balloon group (14.4%) compared with the double-balloon catheter group (25.7%; odds ratio 0.49, 95% confidence interval 0.26-0.92; P=.02). CONCLUSION: Both the single-balloon and double-balloon catheters are equally efficacious for inducing labor. The double-balloon catheter may be associated with more operative deliveries. PMID- 21691167 TI - Preterm nonstress testing: 10-beat compared with 15-beat criteria. AB - OBJECTIVE: To evaluate the relation of different acceleration criteria to perinatal outcome for interpretation of nonstress test (NST) at 32 weeks of gestation or earlier. METHODS: Nonstress tests within 1 week of delivery for women at 32 weeks of gestation or earlier were classified as reactive by 10-beat criteria, reactive by 15-beat criteria, or nonreactive. In women with three NSTs within 1 week of delivery, patterns were categorized into decreasing, increasing, irregular, or consistent reactivity. Perinatal outcomes included perinatal death, intensive delivery room resuscitation, 5-minute Apgar score less than 7, mechanical ventilation, necrotizing enterocolitis, intraventricular hemorrhage, and hypotension. Analysis included chi and logistic regression. RESULTS: Seven hundred fifty-one NSTs from 488 women were assessed. Of the final NSTs before delivery, 105 (21.5%) were nonreactive, 151 (30.9%) were reactive by 10-beat criteria, 232 (47.5%) were reactive by 15-beat criteria, and 274 (56.1%) had decelerations. Unadjusted data consistently associated degree of reactivity with outcome and also associated gestational age with degree of reactivity. After adjustment for gestational age and birth weight, there was no association between NST criterion (or decelerations) and outcomes except between nonreactivity and perinatal death (odds ratio 6.1, 95% confidence interval 2.3-16.5). For 97 women who underwent three tests, all patterns were common (range 16.5-37.1%) and none was significantly associated with any outcome. CONCLUSION: In preterm pregnancies, the criterion used for NST interpretation is much less important than the gestational age at delivery. There was no appreciable difference between the 10-beat criteria and 15-beat criteria in predicting outcome. When tested repeatedly, fetuses frequently had varying degrees of reactivity without relation to outcome. PMID- 21691168 TI - Definition of intertwin birth weight discordance. AB - OBJECTIVE: To establish the level of birth weight discordance at which perinatal morbidity increases in monochorionic and dichorionic twin pregnancy. METHODS: This prospective multicenter cohort study included 1,028 unselected twin pairs recruited over a 2-year period. Participants underwent two weekly ultrasonographic surveillance from 24 weeks of gestation with surveillance of monochorionic twins two-weekly from 16 weeks. Analysis using Cox proportional hazards compared a composite measure of perinatal morbidity (including any of the following: mortality, respiratory distress syndrome, hypoxic-ischemic encephalopathy, periventricular leukomalacia, necrotizing enterocolitis, or sepsis) at different degrees of birth weight discordance with adjustment for chorionicity, gestational age, twin-twin transfusion syndrome, birth order, gender, and growth restriction. RESULTS: Perinatal outcome data were recorded for 977 patients (100%) who continued the study with both fetuses alive beyond 24 weeks, including 14 cases of twin-twin transfusion syndrome. Adjusting for gestation at delivery, twin order, gender, and growth restriction, perinatal mortality, individual morbidity, and composite perinatal morbidity were all seen to increase with birth weight discordance exceeding 18% for dichorionic pairs (hazard ratio 2.2, 95% confidence interval [CI] 1.6-2.9, P<.001) and 18% for monochorionic twins without twin-twin transfusion syndrome (hazard ratio 2.6, 95% CI 1.6-4.3, P<.001). A minimum twofold increase in risk of perinatal morbidity persisted even when both twin birth weights were appropriate for gestational age. CONCLUSION: : The threshold for birth weight discordance established by this prospective study is 18% both for dichorionic twin pairs and for monochorionic twins without twin-twin transfusion syndrome. This threshold is considerably lower than that defined by many retrospective series as pathologic. We suggest that an anticipated difference of 18% in birth weight should prompt more intensive fetal monitoring. PMID- 21691169 TI - Changes in pregnancy mortality ascertainment: United States, 1999-2005. AB - OBJECTIVE: To estimate mortality ratios for all reported pregnancy deaths in the United States, 1999-2005, and to estimate the effect of the 1999 implementation of International Classification of Diseases, Tenth Revision (ICD-10) and adoption of the U.S. Standard Certificate of Death, 2003 Revision, on the ascertainment of deaths resulting from pregnancy. METHODS: We combined information on pregnancy deaths from the National Vital Statistics System and the Pregnancy Mortality Surveillance System to estimate maternal (during or within 42 days of pregnancy) and pregnancy-related (during or within 1 year of pregnancy) mortality ratios (deaths per 100,000 live births). Data for 1995-1997, 1999-2002, and 2003-2005 were compared in order to estimate the effects of the change to ICD-10 and the inclusion of a pregnancy checkbox on the death certificate. RESULTS: The maternal mortality ratio increased significantly from 11.6 in 1995-1997 to 13.1 for 1999 2002 and 15.3 in 2003-2005; the pregnancy-related mortality ratio increased significantly from 12.6 to 14.7 and 18.1 during the same periods. Vital statistics identified significantly more indirect maternal deaths in 2002-2005 than in 1999-2002. Between 2002 and 2005, mortality ratios increased significantly among 19 states using the revised death certificate with a pregnancy checkbox; ratios did not increase in states without a checkbox. CONCLUSION: Changes in ICD-10 and the 2003 revision of the death certificate increased ascertainment of pregnancy deaths. The changes may also have contributed to misclassification of some deaths as maternal in the vital statistics system. Combining data from both systems estimates higher pregnancy mortality ratios than from either system individually. PMID- 21691170 TI - Amniotic fluid eicosanoids in preterm and term births: effects of risk factors for spontaneous preterm labor. AB - OBJECTIVE: To evaluate amniotic fluid arachidonic acid metabolites using enzymatic and nonenzymatic (lipid peroxidation) pathways in spontaneous preterm birth and term births, and to estimate whether prostanoid concentrations correlate with risk factors (race, cigarette smoking, and microbial invasion of amniotic cavity) associated with preterm birth. METHODS: In a case-control study, amniotic fluid was collected at the time of labor or during cesarean delivery. Amniotic fluid samples were subjected to gas chromatography, negative ion chemical ionization, and mass spectrometry for prostaglandin (PG) E2, PGF2alpha, and PGD2 and for 6-keto-PGF1alpha (thromboxane 2 and F2-isoprostane). Primary analysis examined differences between prostanoid concentrations in preterm birth (n=133) compared with term births (n=189). Secondary stratified analyses (by race, cigarette smoking, and microbial invasion of amniotic cavity) compared eicosanoid concentrations in three epidemiological risk factors. RESULTS: Amniotic fluid F2-isoprostane, PGE2, and PGD2 were significantly higher at term than in preterm birth, whereas PGF2alpha was higher in preterm birth 6-keto PGF1alpha and thromboxane 2 concentrations were not different. Data stratified by race (African American or white) showed no significant disparity among prostanoid concentrations. Regardless of gestational age status, F2-isoprostane was threefold higher in smokers, and other eicosanoids were also higher in smokers compared with nonsmokers. Preterm birth with microbial invasion of amniotic cavity had significantly higher F2-isoprostane compared with preterm birth without microbial invasion of amniotic cavity. CONCLUSION: Most amniotic fluid eicosanoid concentrations (F2-isoprostane, PGE2, and PGD2), are higher at term than in preterm births. The only amniotic fluid eicosanoid that is not higher at term is PGF2alpha. PMID- 21691171 TI - Association between adverse neonatal outcome and lactate concentration in amniotic fluid. AB - OBJECTIVE: To estimate whether a high lactate concentration in amniotic fluid, together with cardiotocography, can be used as an indicator for an increased risk of adverse neonatal outcome at delivery. METHOD: A prospective cohort study was performed at two tertiary center labor wards in Sweden. Healthy women with full term, singleton pregnancies and cephalic presentation in spontaneous active labor were included in the study (N=825). Lactate concentration in samples of amniotic fluid collected in the course of vaginal examinations during labor were correlated with cardiotocography 30 minutes before delivery and a composite score for adverse neonatal outcome. RESULTS: High lactate concentration in amniotic fluid (greater than 10.1 mmol/L) was associated with an adverse neonatal outcome (odds ratio [OR] 4.4, 95% confidence interval [CI] 2.3-8.2). Fetal bradycardia within 30 minutes before delivery was also associated with an increased risk of adverse neonatal outcome (OR 7.4, 95% CI 3.04-18.11). If lactate in amniotic fluid was greater than 10.1 mmol/L and bradycardia was seen together, the risk of delivering a neonate with an adverse neonatal outcome was increased 11-fold (OR 10.7, 95% CI 3.7-31.7). CONCLUSION: High lactate concentration in amniotic fluid and fetal bradycardia during the last 30 minutes before delivery indicate an increased risk of adverse neonatal outcome at delivery. PMID- 21691172 TI - Postpartum sterilization with the titanium clip: a systematic review. AB - OBJECTIVE: To estimate the efficacy of the titanium clip in postpartum sterilization. DATA SOURCES: We searched the Medline and Cochrane databases from their inception through January 2011 for all articles in any language pertaining to the titanium clip use in postpartum sterilization. Reference lists and device registration files were also searched. METHODS OF STUDY SELECTION: We identified 13 articles for this review, 10 observational trials and three reports from one single randomized controlled trial. Studies were included if they used the titanium clip for sterilization during the postpartum period and reported subsequent pregnancy as an outcome. Studies of the Hulka clip (spring-loaded) without a titanium comparison group or of the postabortion population were excluded. TABULATION, INTEGRATION, AND RESULTS: Data abstraction was independently performed by two authors. Standard data abstraction templates were used to systematically assess and summarize the data. Quality of the evidence was rated with the U.S. Preventive Task Force System. Efficacy of the titanium clip was estimated from the only randomized controlled trial identified. This trial found a significantly increased risk of pregnancy at 24 months with clip sterilization postpartum (cumulative rate 1.7 compared with 0.04, P=.04) compared with postpartum partial salpingectomy. CONCLUSION: Based on limited data, the titanium clip has decreased efficacy than partial salpingectomy in the postpartum population. Routine use of the titanium clip during the postpartum period should not be recommended. PMID- 21691173 TI - Cervical length screening with ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth: a meta-analysis. AB - OBJECTIVE: To compare pregnancy outcomes in singleton gestations with prior preterm birth that were managed either by cervical length screening with cerclage for short cervical length or history-indicated cerclage. DATA SOURCES AND METHODS OF STUDY SELECTION: Medline, Scopus, and the Cochrane Central Register of Controlled Trials were searched for the terms "cerclage," "randomized trial," and "clinical trial" from 1966 until January 2011. No restrictions for language were applied. We performed a meta-analysis of randomized trials of singleton gestations with prior preterm birth. Management by policy of transvaginal ultrasonography cervical length screening with cerclage placement for cervical shortening was compared with history-indicated cerclage. TABULATION, INTEGRATION, AND RESULTS: Four randomized trials met inclusion criteria, including 467 women. In women with a singleton gestation and prior preterm birth, cervical length screening with cerclage for short cervical length was associated with similar incidences of preterm birth before 37 weeks (31% compared with 32%, relative risk 0.97, 95% confidence interval [CI] 0.73-1.29), preterm birth before 34 weeks (17% compared with 23%, relative risk 0.76, 95% CI 0.48-1.20), and perinatal mortality (5% compared with 3%, relative risk 1.77, 95% CI 0.58-5.35) compared with history indicated cerclage. In the transvaginal ultrasound cervical length screening group, 42% developed a short cervical length and received cerclage. CONCLUSION: Singleton gestations in women with prior preterm birth may be monitored safely with a policy of transvaginal ultrasound cervical length screening as compared with a policy of routine history-indicated cerclage. Cerclage can be reserved for the minority of women who develop a short cervical length. PMID- 21691174 TI - Adhesion barriers at cesarean delivery: advertising compared with the evidence. AB - Cesarean delivery, the most common surgery performed in the United States, is complicated by adhesion formation in 24-73% of cases. Because adhesions have potential sequelae, different synthetic adhesion barriers are currently heavily marketed as a means of reducing adhesion formation resultant from cesarean delivery. However, their use for this purpose has been studied in only two small, nonblinded and nonrandomized trials, both of which were underpowered and subject to bias. Neither demonstrated improvement in meaningful clinical outcomes. In the only cost-effectiveness analysis of adhesion barriers to date, the use of synthetic adhesion barriers was cost-effective only when the subsequent rate of small bowel obstruction was at least 2.4%, a rate far higher than that associated with cesarean delivery. In fact, intra-abdominal adhesions from prior cesarean delivery rarely cause maternal harm and have not been demonstrated to adversely affect perinatal outcome. Based on our review of the available literature, we think the use of adhesion barriers at the time of cesarean delivery would be ill advised at the present time. PMID- 21691175 TI - Mobilizing faculty for simulation. AB - Faculty involvement in simulation training is essential for curriculum development, utilization of their clinical expertise in teaching, and ultimately for validating the importance of the training program. Several barriers to faculty involvement exist, including competing demands on time, the challenges in developing curriculum, and teaching using simulation. Through our experiences in implementing a widely expansive program, we have identified several areas to encourage and engage faculty. Further discussion as a medical education community is needed to support the interaction and involvement of our faculty to support and promote ongoing simulation education. PMID- 21691176 TI - Pacifier use compared with no pacifier use in breastfeeding term infants for increasing duration of breastfeeding. PMID- 21691177 TI - Staples compared with subcuticular suture for skin closure after cesarean delivery: a systematic review and meta-analysis. PMID- 21691179 TI - Clearance of human papillomavirus in women treated for cervical dysplasia. PMID- 21691183 TI - ACOG Practice Bulletin No. 121: Long-acting reversible contraception: Implants and intrauterine devices. PMID- 21691184 TI - ACOG Committee Opinion No. 495: Vitamin D: Screening and supplementation during pregnancy. AB - During pregnancy, severe maternal vitamin D deficiency has been associated with biochemical evidence of disordered skeletal homeostasis, congenital rickets, and fractures in the newborn. At this time, there is insufficient evidence to support a recommendation for screening all pregnant women for vitamin D deficiency. For pregnant women thought to be at increased risk of vitamin D deficiency, maternal serum 25-hydroxyvitamin D levels can be considered and should be interpreted in the context of the individual clinical circumstance. When vitamin D deficiency is identified during pregnancy, most experts agree that 1,000-2,000 international units per day of vitamin D is safe. Higher dose regimens used for treatment of vitamin D deficiency have not been studied during pregnancy. Recommendations concerning routine vitamin D supplementation during pregnancy beyond that contained in a prenatal vitamin should await the completion of ongoing randomized clinical trials. PMID- 21691188 TI - Re: Ward K, Ogilvie JW, Singleton MV, et al. Validation of DNA-based prognostic testing to predict spinal curve progression in adolescent idiopathic scoliosis. Spine 2010;35:E1455-64. PMID- 21691191 TI - Soluble human leukocyte antigen-G in pediatric renal transplantation. PMID- 21691192 TI - The risk to human islet cell transplant recipients of acquiring variant Creutzfeldt-Jakob disease: a provisional quantitative risk assessment. PMID- 21691193 TI - Oxidative stress in chronic liver disease: relationship between peripheral and hepatic measurements. AB - INTRODUCTION: Oxidative stress plays an important role in the pathogenesis of many liver diseases. Investigators often measure markers of oxidative stress in peripheral veins as a reflection of hepatic oxidative stress as it is not always feasible to measure oxidative stress in liver tissue. However, it is unknown whether markers of oxidative stress measured from peripheral sites accurately reflect hepatic tissue oxidative stress. The aim of this study is to examine the relationship of oxidative stress marker among hepatic tissue, hepatic and peripheral veins and urine. METHODS: Malondialdehyde (MDA), a marker of oxidative stress was measured in hepatic vein, peripheral vein and urine samples from 26 consecutive patients undergoing transjugular liver procedures. In 19 patients undergoing liver biopsies, we measured MDA by immunohistochemical staining of paraffin-embedded liver tissue. RESULTS: Peripheral venous MDA levels showed significant correlation with hepatic venous MDA levels (r = 0.62, P = 0.02), but they did not correlate with hepatic tissue MDA content (r = 0.22, P = 0.4). Hepatic venous MDA levels did not correlate with hepatic tissue MDA content (r = 0.01, P = 0.9). Subgroup analysis of patients without portal hypertension showed a positive correlation between hepatic venous and hepatic tissue MDA levels, but this was not statistically significant (r = 0.45, P = 0.22). Urinary MDA did not correlate with MDA from any other sampling location. CONCLUSION: Oxidative stress measured from the peripheral venous samples is poorly reflective of hepatic tissue oxidative stress. Hepatic venous sampling might be suitable for assessing hepatic tissue oxidative stress in patients without portal hypertension, but a larger study is needed to examine this possibility. PMID- 21691194 TI - Assessment of fluid responsiveness: insights in a "gray zone". PMID- 21691195 TI - Phosphorylation of GSK-3beta mediates intralipid-induced cardioprotection against ischemia/reperfusion injury. AB - BACKGROUND: Intralipid (Sigma, St. Louis, MO), a brand name for the first safe fat emulsion for human use, has been shown to be cardioprotective. However, the mechanism of this protection is not known. The authors investigated the molecular mechanism(s) of Intralipid-induced cardioprotection against ischemia/reperfusion injury, particularly the role of glycogen synthase kinase-3beta (GSK-3beta) and mitochondrial permeability transition pore in this protective action. METHODS: In vivo rat hearts or isolated Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion with Intralipid (1% in ex vivo and one bolus of 20% in in vivo) or vehicle. The hemodynamic function, infarct size, threshold for the opening of mitochondrial permeability transition pore, and phosphorylation levels of protein kinase B (Akt)/extracellular signal regulating kinase (ERK)/GSK 3beta were measured. RESULTS: Administration of Intralipid at the onset of reperfusion resulted in approximately 70% reduction in infarct size in the in vivo rat model. Intralipid also significantly improved functional recovery of isolated Langendorff-perfused mouse hearts as the rate pressure product was increased from 2,999 +/- 863 mmHg*beats/min in the control group to 13,676 +/- 611 mmHg*beats/min (mean+/-SEM) and the infarct size was markedly smaller (18.3 +/- 2.4% vs. 54.8 +/- 2.9% in the control group, P < 0.01). The Intralipid induced cardioprotection was fully abolished by LY294002, a specific inhibitor of PI3K, but only partially by PD98059, a specific ERK inhibitor. Intralipid also increased the phosphorylation levels of Akt/ERK1/glycogen synthase kinase-3beta by eightfold, threefold, and ninefold, respectively. The opening of mitochondrial permeability transition pore was inhibited by Intralipid because calcium retention capacity was higher in the Intralipid group (274.3 +/- 8.4 nM/mg vs. 168.6 +/- 9.6 nM/mg in the control group). CONCLUSIONS: Postischemic treatment with Intralipid inhibits the opening of mitochondiral permeability transition pore and protects the heart through glycogen synthase kinase-3beta via PI3K/Akt/ERK pathways. PMID- 21691196 TI - Diagnostic performance and therapeutic consequence of thromboelastometry activated by kaolin versus a panel of specific reagents. AB - BACKGROUND: Thromboelastography/metry (TEG(r); Haemoscope, Niles, IL/ROTEM(r); Tem International GmbH, Munich, Germany) is increasingly used to guide transfusion therapy. This study investigated the diagnostic performance and therapeutic consequence of using kaolin-activated whole blood compared with a panel of specific TEM(r)-reagents to distinguish: dilutional coagulopathy, thrombocytopenia, hyperfibrinolysis, and heparinization. METHODS: Blood was drawn from 11 healthy volunteers. Dilutional coagulopathy was generated by 50% dilution with hydroxyethyl starch 130/0.4 whereas thrombocytopenia (mean platelet count 20 *109/l) was induced using a validated model. Hyperfibrinolysis and heparin contamination were generated by tissue plasminogen activator 2 nM and unfractionated heparin 0.1U/ml, respectively. Coagulation tests were run on ROTEM(r) delta. RESULTS: Kaolin-activated whole blood showed no differences between dilutional coagulopathy and thrombocytopenia (mean clotting time 450 s vs. 516 s, alpha-angle 47.1 degrees vs. 41.5 degrees , maximum clot firmness 35.0 mm vs. 34.2 mm, all P values >=0.14). Hyperfibrinolysis specifically disclosed an increased maximum lysis (median: 100%, all P values less than 0.001), and heparin induced a distinctly prolonged clotting time (2283 s, all P values less than 0.02). The coagulopathies were readily distinguishable using a panel of TEM-reagents. In particular, dilutional coagulopathy was separated from thrombocytopenia using FIBTEM (maximum clot firmness 1.9 mm vs. 11.2 mm, P < 0.001). The run time of analysis to achieve diagnostic data was shorter applying a panel of TEM-reagents. A transfusion algorithm based on kaolin suggested platelets in case of dilutional coagulopathy, whereas an algorithm applying TEM reagents suggested fibrinogen. CONCLUSION: Monoanalysis with kaolin was unable to distinguish coagulopathies caused by dilution from that of thrombocytopenia. Algorithms based on the use of kaolin may lead to unnecessary transfusion with platelets, whereas the application of TEM-reagents may result in goal-directed fibrinogen substitution. PMID- 21691197 TI - Orientation strategies in natural orifice translumenal endoscopic surgery. AB - OBJECTIVE: The aims of this study were to (1) describe the visual attention strategies employed by surgeons that are associated with high performance in reorientation and (2) identify key structures guiding attention deployment of the surgeon in the process of self-orientation in common clinical natural orifice translumenal endoscopic surgery (NOTES) scenarios. BACKGROUND: Disorientation has been identified as one of the major barriers to be overcome before widespread clinical NOTES uptake. Understanding disorientation requires description of key perceptual-motor factors leading to disorientation, assessment of their relative impact, and quantification of navigation performance. METHODS: Twenty-one surgeons were shown a series of 8 images acquired during human NOTES operations from the flexible endoscope from different perspectives to induce disorientation. Gaze behavior was recorded using an eye tracker as the subjects were asked to establish the image orientation. Main outcome measures were times taken to establish orientation, eye-tracking parameters, and fixation sequences on organs and structures/regions of interest (ROI). RESULTS: High-performance subjects had a lower number of fixations and normalized dwell time per ROI compared with others, suggesting a more structured and focused approach to orientation. Orientation strategies associated with high performance were described using a validated algorithm for comparing visual reorientation behavior and amount of visual attention on individual ROIs in each scenario were quantified. Key areas of organs and structures during reorientation were illustrated using dwell time normalized visual maps. CONCLUSIONS: Targeted orientation strategies revealed in this study are expected to aid in decreasing the learning curve associated with NOTES and increase performance even for experienced surgeons and gastroenterologists. Crucially, these data can provide guidance for designing orientation friendly NOTES platforms. PMID- 21691198 TI - Do indeterminate cells follow the footsteps of Langerhans cells and migrate from the skin to the lymph node? AB - Indeterminate cells are considered by many to be pre-Langerhans cells as they mimic Langerhans cells in certain morphologic and immunophenotypic aspects. Indeterminate cells express CD1a and S-100 but lack Langerin expression (Langerin is used as an immunohistochemical substitute for electron microscopy for the detection of Birbeck granules). Migration of Langerhans cells to the lymph nodes through the dermal lymphatics to present skin antigens to T lymphocytes has been well defined before; however, the migration and the identification of indeterminate cells in lymph node has not been investigated before. In our study, we attempt to investigate the presence of indeterminate cells in normal lymph nodes and in lymph nodes with dermatopathic lymphadenitis and analyze their possible coexistence with Langerhans cells. We examined 9 cases of normal skin, 7 cases of normal lymph nodes (both normal skin and normal lymph nodes are obtained from mastectomy specimens), and 5 cases of reactive lymph nodes with dermatopathic lymphadenitis, for the presence of indeterminate cells. A set panel of immunostains was used that included CD1a, S-100, Langerin, CD3, and CD20. Indeterminate cells were defined as CD1a+, S-100+, and Langerin-, whereas Langerhans cells were defined as CD1a+, S-100+, and Langerin+. Scattered indeterminate cells were identified in most lymph nodes with dermatopathic lymphadenitis, but only in those normal lymph nodes that showed paracortical hyperplasia or expansion, whereas Langerhans cells were identified in both. PMID- 21691199 TI - Image cytometry of fine needle aspiration of thyroid epithelial lesions. AB - Fine needle aspiration (FNA) biopsy has been documented as a reliable, cost effective test, diagnosing different thyroid lesions. However, its sensitivity declines much in some settings. This study aimed to investigate the value of computerized morphometry and DNA ploidy in differential diagnosis of different thyroid epithelial follicular lesions diagnosed on FNA smears. In this study, 68 cases of thyroid FNA were cytologically examined, and classified according to their postthyroidectomy histopathologic diagnosis as follow: 10 cases of nodular goiter, 14 cases of adenomas, 10 cases of follicular carcinoma, 20 cases of papillary carcinoma, 10 cases of anaplastic carcinoma, and 4 cases of poorly differentiated carcinoma. Using Leica Qwin 500 image analysis system, nuclear area as a morphologic variable, and the DNA ploidy, DNA index, and proliferation indices were measured for each case. Sensitivity of FNA in the studied cases was optimum (100%) in papillary carcinomas and anaplastic carcinomas. However, the sensitivity declined sharply in discriminating nodular goiter and follicular adenoma from well-differentiated follicular carcinoma, thus, most of these cases were diagnosed as follicular lesions. A significant difference in mean values of nuclear area was found between benign and malignant lesions, with no statistical differences within the benign group. Aneuploidy was significantly associated with malignancy. Therefore, image analysis may become an important ancillary test in the initial evaluation of patients with thyroid epithelial lesions. PMID- 21691200 TI - Expression of S100A4 in renal epithelial neoplasms. AB - Expression of S100A4 has been associated with progression and poor clinical outcome in a variety of malignancies including those of the breast, pancreas, bladder, and thyroid. To date, the expression of S100A4 protein in renal epithelial neoplasms is poorly understood. In this study, we evaluated the expression of S100A4 protein and mRNA in the nontumoral kidney and renal epithelial neoplasms of different types and correlated its expression with patient outcome. The study population included 155 clear cell renal cell carcinomas (cRCC), 22 papillary renal cell carcinomas (pRCC), 13 chromophobe renal cell carcinomas and 13 oncocytomas. In nontumoral kidney, nuclear and cytoplasmic S100A4 staining was detected in the glomerular epithelium and endothelium, distal tubules and collecting ducts, and loops of Henle. A different expression pattern was noted in the various neoplasms. S100A4 expression was significantly increased in the stromal cells in cRCC (83%) and pRCC (73%) compared with paired nontumoral kidney tissue (P<0.001). There was no increased stromal cell expression of S100A4 in oncocytomas and chromophobe carcinomas. Positive epithelial staining was more common in pRCC (58%) than cRCC (11%) (P=0.01). The level of mRNA detected by reverse transcription-polymerase chain reaction was significantly higher in the tumor as opposed to normal tissue in cRCC but not in the other neoplasms (P=0.03). Multivariate analysis revealed that epithelial S100A4 protein expression is an independent poor prognostic factor along with grade and stage only in cRCC (P<0.01). Although S100A4 protein was expressed in a minority of cRCC, its expression was associated with shorter overall patient survival. PMID- 21691201 TI - Methodology and technical requirements of the galectin-3 test for the preoperative characterization of thyroid nodules. AB - In the last decade, the beta-galactosyl binding protein galectin-3 has been the object of extensive molecular, structural, and functional studies aimed to clarify its biological role in cancer. Multicenter studies also contributed to discover the potential clinical value of galectin-3 expression analysis in distinguishing, preoperatively, benign from malignant thyroid nodules. As a consequence galectin-3 is receiving significant attention as tumor marker for thyroid cancer diagnosis, but some conflicting results mostly owing to methodological problems have been published. The possibility to apply preoperatively a reliable galectin-3 test method on fine needle aspiration biopsy (FNA)-derived thyroid cells represents an important achievement. When correctly applied, the method reduces consistently the gray area of thyroid FNA cytology, contributing to avoid unnecessary thyroid surgery. Although the efficacy and reliability of the galectin-3 test method have been extensively proved in several studies, its translation in the clinical setting requires well-standardized reagents and procedures. After a decade of experimental work on galectin-3 related basic and translational research projects, the major methodological problems that may potentially impair the diagnostic performance of galectin-3 immunotargeting are highlighted and discussed in detail. A standardized protocol for a reliable galectin-3 expression analysis is finally provided. The aim of this contribution is to improve the clinical management of patients with thyroid nodules, promoting the preoperative use of a reliable galectin-3 test method as ancillary technique to conventional thyroid FNA cytology. The final goal is to decrease unnecessary thyroid surgery and its related social costs. PMID- 21691202 TI - Analgesic synergy of neurotensin receptor subtype 2 agonist NT79 and morphine. AB - Neurotensin (NT) is a tridecapeptide with naloxone-independent analgesic action. NT exerts its effects through three molecularly cloned receptor subtypes, NTS1, NTS2, and NTS3. The analgesic efficacy of NT agonists depends on their activation of NTS1 and/or NTS2. NT79 is an NTS2-selective agonist without hypothermic and hypotensive effects, produces analgesic effects in animal models of visceral (writhing), but not thermal (hot plate) pain. This study extends previous study with NT79 to test its efficacy in an animal model of persistent pain (formalin test) and to determine whether there is analgesic synergy between NT79 and morphine on visceral and persistent pain. NT79 enhanced the analgesic potency of morphine in the writhing test. In the persistent pain model, NT79 and morphine attenuated formalin-induced lifting and biting during the inflammatory phase. NT79 and morphine alone significantly blocked the lifting but not the biting response, which involves the activity of spinal nociceptive circuits. However, the combination of NT79 and morphine attenuated both lifting and biting responses, results indicating both spinal and supraspinal modulation of persistent nociception. Isobolographic analyses show analgesic synergism between NT79 and morphine in persistent pain, thus providing a promise of therapy for pain while minimizing adverse effects associated with morphine use. PMID- 21691203 TI - Homozygous mutation of CRLF-1 gene in a Turkish newborn with Crisponi syndrome. AB - Crisponi syndrome is a recently described rare autosomal recessive disorder. The main clinical features of the syndrome are neonatal onset of episodic contractions of the facial muscles with trismus and abundant salivation resembling a tetanic spasm. Herein, we report a case of 3-day-old male neonate presenting with trismus, abundant salivation, feeding difficulties, camptodactyly, and hyperthermia, which are consistent with the diagnostic criteria of Crisponi syndrome. The parents of the patient were consanguineous, supporting autosomal recessive inheritance. Molecular analysis revealed a homozygous mutation in cytokine receptor-like factor-1 gene in the patient. PMID- 21691204 TI - Impact of renal dysfunction on the prognostic value of the TIMI risk score in patients with non-ST elevation acute coronary syndrome. AB - BACKGROUND: The thrombolysis-in-myocardial-infarction risk score (TRS) is a validated risk-assessment tool based on randomized clinical trials. Its applicability to an unselected group of patients seen in general clinical practice may be limited as renal dysfunction was an exclusion criteria in the original trials upon which the TRS was determined. MATERIALS AND METHODS: Consecutive patients with non-ST elevation acute coronary syndrome were stratified based on renal function. Normal renal function was defined as a creatinine clearance (CrCl) of more than 60 ml/min, moderate renal dysfunction was defined as a CrCl of at least 30 ml/min but 60 ml/min or less, and severe renal dysfunction was defined as a CrCl of less than 30 ml/min. A TRS was calculated using the original seven criteria (TRS-7) which did not consider renal function. A second TRS was calculated using the original seven criteria plus the addition of renal dysfunction if the CrCl was 60 ml/min or less (TRS-8 <= 60). A third TRS was calculated using the original seven criteria plus renal dysfunction if the CrCl was less than 30 ml/min (TRS-8<30). In the calculation of both of the TRS-8, the presence of renal dysfunction was given weight equal to each of the original seven criteria. Comparisons between groups stratified by renal function were made using Pearson's chi2 test or Fisher's exact test for categorical variables (presented as counts and percentages) and the unpaired t-test for continuous variables (presented as the mean +/- standard deviation). The chi2 test was used to compare the statistical differences between each of the three TRS and the percentage of patients achieving the primary composite outcome during the index hospitalization. The primary outcome was the composite of cardiovascular death, nonfatal myocardial infarction, or urgent coronary revascularization for documented myocardial ischemia. RESULTS: Of the 798 patients included in the analysis, 281 (35%) patients had renal dysfunction (26% had moderate dysfunction and 9% had severe dysfunction). When considered categorically, patients with moderate or severe renal dysfunction had significantly higher rates of the primary composite outcome. The three TRS (TRS 7, TRS-8 <= 60, and TRS-8<30) were significantly correlated with the primary composite outcome. With a calculated TRS of 5 or less, the TRS-8 <= 60 and the TRS<30 were not associated with a significantly higher prevalence of the composite outcome (all comparisons P>0.05). At a calculated TRS of 6 or 7, the TRS-8<30 was associated with a significantly greater prevalence of the composite outcome compared with the TRS-7 (P=0.02) and the TRS-8 <= 60 (P=0.02). There was no significant difference in the frequency of the composite outcome with a calculated TRS of 6 or 7 using the TRS-7 compared with the TRS-8 <= 60 (P=0.79). At a calculated TRS of 8, both the TRS-8<30 and TRS-8 <= 60 had a significantly higher prevalence of the composite outcome compared with a calculated TRS of 7 using the TRS-7 (P=0.002 for the TRS-8<30 and P=0.045 for the TRS-8 <= 60). At a TRS of 8, the TRS-8<30 was associated with a significantly higher composite outcome compared with the TRS-8 <= 60 (P=0.035). CONCLUSION: The addition of renal dysfunction to the TRS-7 as an eighth clinical criterion was associated with a higher prevalence of the primary composite outcome primarily at scores of 6 or more. When considered in the context of clinical practice, the use of the TRS-8 <= 60 and TRS-8<30 rather than the TRS-7 would not be expected to substantially change the management strategy for patients presenting with non-ST elevation acute coronary syndrome. PMID- 21691205 TI - Relationship between serum thymosin beta4 levels and coronary collateral development. AB - BACKGROUND: Thymosin beta4 was recently demonstrated to be a potential stimulator of angiogenesis and arteriogenesis in both in-vivo and in-vitro studies. Little is known about the relationship between serum thymosin beta4 levels and the extent of coronary collaterals in patients with coronary artery disease. HYPOTHESIS: Serum thymosin beta4 independently predicts the formation of coronary collaterals in patients with coronary artery disease. MATERIALS AND METHODS: A total of 190 consecutive patients who underwent coronary angiography were divided into two groups according to coronary angiograms and collateral formation: the poor collateral group consisting of 103 patients with at least more than or equal to one coronary stenosis of greater than or equal to 75% without visible collateral circulation, and the good collateral group consisting of 87 patients with at least more than or equal to one coronary stenosis of greater than or equal to 75% with well-developed collateral circulation. Collateral score was analyzed using the Cohen-Rentrop classification. RESULTS: Serum thymosin beta4 levels were 1024.50 +/- 516.92 ng/ml and 1373.00 +/- 1082.88 ng/ml for patients in the poor collateral group and the good collateral group, respectively. Serum thymosin beta4 levels in the good collateral group were significantly higher than those in the poor collateral group (P<0.01). After adjustment in the multiple ordinal logistic regression model, serum thymosin beta4 levels showed a strong independent association with the collateral Cohen-Rentrop score (chi(2)=4.45, odds ratio=1.00, 95% confidence interval: 1.000-1.002, P=0.035). CONCLUSION: Elevated serum thymosin beta4 level is independently associated with a significant enhancement in coronary collateralization and patients in the good collateral tend to have a higher thymosin beta4 level. PMID- 21691206 TI - Pregnancy history and risk of endometrial cancer. AB - BACKGROUND: Epidemiologic studies are consistent in finding that women who have had at least one birth are less likely to develop endometrial cancer. Less clear is whether timing of pregnancies during reproductive life influences risk, and the degree to which incomplete pregnancies are associated with a reduced risk. METHODS: We evaluated pregnancy history in relation to endometrial cancer risk using data from a series of 4 population-based endometrial cancer case-control studies of women 45-74 years of age (1712 cases and 2134 controls) during 1985 2005 in western Washington State. Pregnancy history and information on other potential risk factors were collected by in-person interviews. RESULTS: Older age at first birth was associated with a reduced risk of endometrial cancer after adjustment for number of births and age at last birth (test for trend P = 0.004). The odds ratio comparing women at least 35 years of age at their first birth with those younger than 20 years was 0.34 (95% confidence interval = 0.14-0.84). Age at last birth was not associated with risk after adjustment for number of births and age at first birth (test for trend P = 0.830). Overall, a history of incomplete pregnancies was not associated with endometrial cancer risk to any appreciable degree. CONCLUSIONS: In this study, older age at first birth was more strongly associated with endometrial cancer risk than was older age at last birth. To date, there remains some uncertainty in the literature on this issue. PMID- 21691207 TI - Adherence to breast and ovarian cancer screening recommendations for female relatives from the Ontario site of the Breast Cancer Family Registry. AB - This study compares adherence to breast and ovarian cancer screening recommendations among a population cohort of women at familial risk of breast and/or ovarian cancer. This cross-sectional study included 1039 first-degree female relatives without breast cancer identified from the Ontario site of the Breast Cancer Family Registry. We compared breast and ovarian cancer screening behaviors, using a telephone-administered questionnaire among three groups of women defined by their familial risk (high, moderate, and low) of breast and/or ovarian cancer. Associations between screening behaviors and familial risk were assessed using multinomial regression models adjusted by familial clustering. Women, 40-49 years of age, at moderate or high familial risk were significantly more likely to have had a screening mammogram within the past 12 months [odds ratio (OR): 2.80; 95% confidence interval (CI): 1.40-5.58], and women of less than 50 years of age were more likely to have a clinical breast examination (OR: 1.84; 95% CI: 1.02-3.31) compared with women at low familial risk. Compared with women at low or moderate familial risk, women at high familial risk were significantly more likely to have ever had a genetic test for the BRCA 1/2 genes (OR: 2.67; 95% CI: 1.76-4.05). Although the overall level of adherence among high risk women is suboptimal in the community, women at a higher familial risk are adhering more often to cancer screening recommendations than women at a lower familial risk. PMID- 21691208 TI - Response to antiviral therapy in patients with genotype 3 chronic hepatitis C: fibrosis but not race encourages relapse. AB - BACKGROUND AND AIMS: We completed a retrospective analysis of patients with genotype 3 hepatitis C virus (HCV) undergoing therapy in four UK centres with large populations of patients from the Indian subcontinent. MATERIALS AND METHODS: Notes on all patients treated with pegylated interferon and ribavirin were reviewed and factors that influenced the response were examined. RESULTS: Six hundred and four patients with genotype 3 HCV were studied, of whom 299 were Asians. Median age was 43 years, 65% were men and 24% had cirrhosis. Overall, 457 (76%) patients achieved sustained virological response (SVR). By multivariable analysis it was found that ethnicity was not associated with an impaired response but age, cirrhosis and diabetes were significantly associated with a reduced SVR, the likelihood of a response was reduced by 25% per 10-year increment in age, by 59% among individuals with cirrhosis and by 62% among individuals with diabetes mellitus. Most patients who did not achieve an SVR relapsed (15%) rather than failing to achieve an end of treatment response. CONCLUSION: The response to antiviral therapy in genotype 3 HCV is not affected by South Asian (vs. Caucasian) ethnicity, but age, cirrhosis and diabetes reduce the response. Treatment failure most often is due to relapse. PMID- 21691209 TI - Prediction of esophageal varices in hepatic cirrhosis by noninvasive markers. AB - OBJECTIVE: To determine whether Model for End-stage Liver Disease (MELD) Child Turcotte-Pugh (CTP) classification, AST to platelet ratio index (APRI), and laboratory tests could predict the presence of esophageal varices (EV) or varices which need prophylactic therapy (medium or large size EV). METHODS: Three hundred patients with cirrhosis (193 men; mean age 53.1 years; majority with chronic C hepatitis) were prospectively analyzed. The presence of EV (any size and medium or large EV) was correlated with patients' characteristics (MELD, CTP classification, APRI, platelets count, and liver tests). RESULTS: One hundred and seventy-one patients (57%) had EV, of whom 35% (105) had varices which need prophylactic therapy (VPT). The distribution of EV according to CTP classification was as follows: A, 49%; B, 75.3% and C, 80%. Independent predictors of EV were: MELD higher than 8 (P=0.02); APRI higher than 1.64 (P=0.01); platelet count lower than 93,000/mm3 (P<0.01); aspartate aminotransferase higher than 1.34 * UNL (P=0.01), and total bilirubin higher than 1 mg/dl (P=0.04). MELD higher than 8 had the highest discriminative value for presence of EV (sensitivity=80.1%; specificity=51.2%; area under receiver operating characteristics=0.68). Factors independently associated with VPT were: thrombocytopenia (<92,000/mm3; P<0.01) and aspartate aminotransferase higher than 1.47 * UNL (P=0.03). Platelet count lower than 92,000/mm3 had sensitivity of 65.7%, specificity of 57.9%, and an area under receiver operating characteristics of 0.62 for the presence of VPT. CONCLUSION: High values on MELD are associated with EV and thrombocytopenia, with varices which need prophylactic therapy. As a result of their low sensitivity and specificity, it is suggested to maintain the recommendation of upper gastrointestinal endoscopy for all patients with cirhosis. PMID- 21691210 TI - Beyond service quality: the mediating role of patient safety perceptions in the patient experience-satisfaction relationship. AB - BACKGROUND: Although the extant literature on patient safety is rich, few studies have specifically examined safety from the patient perspective. In addition, little is known about how patients decide whether they are safe or satisfied with their care. From a foundation of attribution theory, we suggest that patients may interpret service quality lapses as risks to their safety, and this will influence their evaluations of their care. PURPOSE: The aim of this study was to examine the relationships among service quality, patient safety perceptions, and patient satisfaction by testing a model that hypothesized a mediating role for patient safety perceptions. METHODOLOGY: Acute care patients with recent inpatient visits at three hospitals were surveyed (Hospital 1, n = 486; Hospital 2, n = 279; Hospital 3, n = 231) to examine the relationships among service quality, safety, and satisfaction. FINDINGS: Analysis found that patient safety perceptions partially mediated the relationship between service quality and satisfaction in Hospital 1 and fully mediated the relationship in the Hospitals 2 and 3. Thus, patient safety perceptions explained the relationship between service quality and satisfaction. Consistent with previous research, patients who reported service quality problems perceived risks to their safety. PRACTICE IMPLICATIONS: Although practitioners focus heavily on the technical aspects of care, this study suggests that it would be worthwhile to pay closer attention to how patients evaluate processes of care, in particular, the processes they may use to infer their safety in the hospital. PMID- 21691211 TI - The diffusion of Magnet hospital recognition. AB - BACKGROUND: Magnet recognition is promoted by many in the practice community as the gold standard of nursing care quality. The Magnet hospital population has exploded in recent years, with about 8% of U.S. general hospitals now recognized. PURPOSE: The purpose of this study was to identify the characteristics that distinguish Magnet-recognized hospitals from other hospitals within the framework of diffusion theory. METHODOLOGY/APPROACH: We conceptualize Magnet recognition as an organizational innovation and Magnet-recognized hospitals as adopters of the innovation. We hypothesize that adoption is associated with selected characteristics of hospitals and their markets. The study population consists of the 3,657 general hospitals in the United States in 2008 located in metropolitan or micropolitan areas. We used logistic regression analysis to estimate the association of Magnet recognition with organizational and market characteristics. FINDINGS: Empirical results support hypotheses that adoption is positively associated with hospital complexity and specialization, as measured by teaching affiliation, and with hospital size, slack resources, and not-for-profit or public ownership (vs. for-profit). Adopters also are more likely to be located in markets that are experiencing population growth and are more likely to have competitor hospitals within the market that also have adopted Magnet status. A positive association of adoption with baccalaureate nursing school supply is contrary to the hypothesized relationship. PRACTICE IMPLICATIONS: Because of its rapid recent growth, consideration of Magnet program recognition should be on the strategic planning agenda of hospitals and hospital systems. Hospital administrators, particularly in smaller, for-profit hospitals, may expect more of their larger not-for-profit competitors, particularly teaching hospitals, to adopt Magnet recognition, increasing competition for baccalaureate-prepared registered nurses in the labor market. PMID- 21691212 TI - Implementing complex innovations: factors influencing middle manager support. AB - BACKGROUND: Middle manager resistance is often described as a major challenge for upper-level administrators seeking to implement complex innovations such as evidence-based protocols or new skills training. However, factors influencing middle manager support for innovation implementation are currently understudied in the U.S. health care literature. PURPOSE: This article examined the factors that influence middle managers' support for and participation in the implementation of work-based learning, a complex innovation adopted by health care organizations to improve the jobs, educational pathways, skills, and/or credentials of their frontline workers. METHODS: We conducted semistructured interviews and focus groups with 92 middle managers in 17 health care organizations. Questions focused on understanding middle managers' support for work-based learning as a complex innovation, facilitators and barriers to the implementation process, and the systems changes needed to support the implementation of this innovation. FINDINGS: Factors that emerged as influential to middle manager support were similar to those found in broader models of innovation implementation within the health care literature. However, our findings extend previous research by developing an understanding about how middle managers perceived these constructs and by identifying specific strategies for how to influence middle manager support for the innovation implementation process. These findings were generally consistent across different types of health care organizations. PRACTICE IMPLICATIONS: Study findings suggest that middle manager support was highest when managers felt the innovation fit their workplace needs and priorities and when they had more discretion and control over how it was implemented. Leaders seeking to implement innovations should consider the interplay between middle managers' control and discretion, their narrow focus on the performance of their own departments or units, and the dedication of staff and other resources for empowering their managers to implement these complex innovations. PMID- 21691213 TI - Low b-value diffusion-weighted cardiac magnetic resonance imaging: initial results in humans using an optimal time-window imaging approach. AB - OBJECTIVES: Diffusion-weighted imaging (DWI) using low b-values permits imaging of intravoxel incoherent motion in tissues. However, low b-value DWI of the human heart has been considered too challenging because of additional signal loss due to physiological motion, which reduces both signal intensity and the signal-to noise ratio (SNR). We address these signal loss concerns by analyzing cardiac motion during a heartbeat to determine the time-window during which cardiac bulk motion is minimal. Using this information to optimize the acquisition of DWI data and combining it with a dedicated image processing approach has enabled us to develop a novel low b-value diffusion-weighted cardiac magnetic resonance imaging approach, which significantly reduces intravoxel incoherent motion measurement bias introduced by motion. MATERIALS AND METHODS: Simulations from displacement encoded motion data sets permitted the delineation of an optimal time-window with minimal cardiac motion. A number of single-shot repetitions of low b-value DWI cardiac magnetic resonance imaging data were acquired during this time-window under free-breathing conditions with bulk physiological motion corrected for by using nonrigid registration. Principal component analysis (PCA) was performed on the registered images to improve the SNR, and temporal maximum intensity projection (TMIP) was applied to recover signal intensity from time-fluctuant motion-induced signal loss. This PCATMIP method was validated with experimental data, and its benefits were evaluated in volunteers before being applied to patients. RESULTS: Optimal time-window cardiac DWI in combination with PCATMIP postprocessing yielded significant benefits for signal recovery, contrast-to noise ratio, and SNR in the presence of bulk motion for both numerical simulations and human volunteer studies. Analysis of mean apparent diffusion coefficient (ADC) maps showed homogeneous values among volunteers and good reproducibility between free-breathing and breath-hold acquisitions. The PCATMIP DWI approach also indicated its potential utility by detecting ADC variations in acute myocardial infarction patients. CONCLUSIONS: Studying cardiac motion may provide an appropriate strategy for minimizing the impact of bulk motion on cardiac DWI. Applying PCATMIP image processing improves low b-value DWI and enables reliable analysis of ADC in the myocardium. The use of a limited number of repetitions in a free-breathing mode also enables easier application in clinical conditions. PMID- 21691214 TI - Early attention impairment and recovery profiles after childhood traumatic brain injury. AB - OBJECTIVES: To examine recovery of attention from 3 to 6 months postinjury; to identify effects of injury severity and time since injury on performance; to explore whether complex attention skills (eg, shifting, divided attention, attentional control) are more vulnerable to traumatic brain injury (TBI), and slower to recover than simple attention skills (eg, attentional capacity, selective attention, sustained attention). DESIGN: Prospective longitudinal investigation. PARTICIPANTS: A total of 205 school-aged children with TBI were divided into groups according to injury severity (mild = 63%, moderate = 27%, severe = 10%). SETTING: Emergency departments of 3 metropolitan children's hospitals across Australia. MAIN MEASURES: Standardized clinical measures of both simple and complex attention were administered at 3 months and 6 months postinjury. RESULTS: Attention skills were vulnerable to the impact of TBI. More severe injury affected attention skills most negatively. Significant recovery was observed over time. There were few interaction effects, with severity groups exhibiting similar levels of recovery over the 6 months post-TBI. No differences in recovery trajectories were detected for simple and complex attention. CONCLUSIONS: These findings have important clinical and educational implications, suggesting that children with TBI, and particularly those with more serious injuries, are most vulnerable to attention deficits in the acute stages postinjury. It is important that schools and families are aware of these limitations and structure expectations accordingly. For example, gradual return to school should be considered, and in the early stages of recovery, children should be provided with sufficient rest time, with reduced expectations for tasks such as homework. PMID- 21691216 TI - Measuring preoperative anxiety in patients with intracranial tumors: the Amsterdam preoperative anxiety and information scale. AB - BACKGROUND: Preoperative anxiety is a major problem in patients with brain tumors and is of high clinical relevance. However, to date no instruments have been validated for the assessment of preoperative anxiety for this patient group. The Amsterdam Preoperative Anxiety and Information Scale (APAIS) has shown promising results for the assessment of preoperative anxiety. The aim of this study was to determine its psychometric properties and the optimal cutoff score for patients with intracranial tumors to make it applicable in the neurosurgical setting. METHODS: The sample totaled 180 neurosurgical patients with intracranial tumors. Patients were administered the APAIS along with the Hospital Anxiety and Depression Scale as the gold standard against which the APAIS was compared. Patients scoring 11 or above in the anxiety subscale of the Hospital Anxiety and Depression Scale were defined as clinical cases having anxiety. The psychometric properties of the APAIS were evaluated for a postulated 2-factor structure, Cronbach alpha, and correlations. RESULTS: The postulated 2-factor structure could not be replicated. Instead, we found a 3-factor solution (anxiety about the operation, anxiety about the anesthesia, information requirement). The area under the receiver operating characteristics curve ranged from >=0.65 to >=0.77. Optimal cutoff scores were calculated. The cutoff score for the anxiety scale was >=10 for the whole sample and men only, and was >=11 for women only. Analysis of the psychometric properties yielded satisfactory results (eg. Cronbach alpha for the anxiety scale >0.84). CONCLUSIONS: Despite its brevity, the APAIS is valid and recommendable for the assessment of preoperative anxiety in patients with intracranial tumors. As this is the first validation study focusing on patients with severe diseases and major surgeries, we recommend the application of our cutoff scores also for patients similar to our study population with regard to disease and surgery severity. PMID- 21691217 TI - Glycine N-methyltransferase affects urinary 1-hydroxypyrene and 8-hydroxy-2' deoxyguanosine levels after PAH exposure. AB - OBJECTIVES: The object of this study was to assess the modulating effects of genetic polymorphisms of glycine N-methyltransferase (GNMT) genotypes on 1 hydroxypyrene (1-OHP) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine from coke oven workers, consistently exposed to polycyclic aromatic hydrocarbons (PAHs). METHODS: The study participants included 289 coke-oven workers from a steel company in Taiwan. Personal air samples, spot urine samples, peripheral blood samples, and questionnaires were used to quantify PAH exposure, oxidative DNA damage, GNMT gene polymorphisms, demographic data, and environmental pollutants. RESULTS: Urinary 1-OHP level, GNMT STRP1 genotype, and worksite were significant predictors of urinary 8-OHdG levels after adjustments were made for covariates. CONCLUSIONS: This study suggests that GNMT STRP1 could modulate urinary 1-OHP and 8-OHdG levels in coke-oven workers exposed to PAHs. PMID- 21691218 TI - Burnout levels and self-rated health prospectively predict future long-term sickness absence: a study among female health professionals. AB - OBJECTIVE: This study investigates the predictive validity of the Oldenburg Burnout Inventory (OLBI), and of three health indicators (depression, anxiety, and self-rated health), for long-term sickness absence (LTSA). METHODS: Questionnaires were sent to all employees in a Swedish County Council (N = 6118), and the overall response rate was 65% (N = 3976). As 82% were women, only women were included in the study. Certified LTSA data were collected. RESULTS: Logistic regression analyses showed that high scores on exhaustion, depression, and poor self-rated health increased the risk of future LTSA (>=90 days). Support for the proposed two-factorial structure of the OLBI was found, including the dimensions of exhaustion and disengagement from work. CONCLUSION: Using burnout measures might be useful to identify those at risk for LTSA, and to enable preventive solutions in organizations. PMID- 21691219 TI - The Healthy LifeWorks Project: a pilot study of the economic analysis of a comprehensive workplace wellness program in a Canadian government department. AB - OBJECTIVE: To examine the relationship between health risks and absenteeism and drug costs vis-a-vis comprehensive workplace wellness. METHODS: Eleven health risks, and change in drug claims, short-term and general illness calculated across four risk change groups. Wellness score examined using Wilcoxon test and regression model for cost change. RESULTS: The results showed 31% at risk; 9 of 11 risks associated with higher drug costs. Employees moving from low to high risk showed highest relative increase (81%) in drug costs; moving from high to low had lowest (24%). Low-high had highest increase in absenteeism costs (160%). With each risk increase, absenteeism costs increased by $CDN248 per year (P < 0.05) with average decrease of 0.07 risk factors and savings $CDN6979 per year. CONCLUSIONS: Both high-risk reduction and low-risk maintenance are important to contain drug costs. Only low-risk maintenance also avoids absenteeism costs associated with high risks. PMID- 21691220 TI - The well-being assessment for productivity: a well-being approach to presenteeism. AB - OBJECTIVE: To develop a presenteeism assessment, the Well-Being Assessment for Productivity (WBA-P), that provides an informative evaluation of job performance loss due to well-being related barriers. METHOD: The WBA-P was developed using exploratory and confirmatory factor analysis using survey data from 1827 employed individuals. Evidence of criterion-related validity was established using multivariate analysis of variance across measures of health and well-being. RESULTS: A hierarchical, two-factor model demonstrated good fit and included factors capturing productivity loss from personal reasons (WBA-PP) and work environment (WBA-PW). Significant interactions existed between these and previously validated presenteeism measures with respect to physical and emotional health, risk factors, and life evaluation. CONCLUSIONS: This initial psychometric evidence suggests that the WBA-P and its subscales are valid measures of presenteeism that capture actionable well-being-related performance barriers. PMID- 21691215 TI - Noninvasive brain stimulation in traumatic brain injury. AB - OBJECTIVE: To review novel techniques of noninvasive brain stimulation (NBS), which may have value in assessment and treatment of traumatic brain injury (TBI). METHODS: Review of the following techniques: transcranial magnetic stimulation, transcranial direct current stimulation, low-level laser therapy, and transcranial Doppler sonography. Furthermore, we provide a brief overview of TMS studies to date. MAIN FINDINGS: We describe the rationale for the use of these techniques in TBI, discuss their possible mechanisms of action, and raise a number of considerations relevant to translation of these methods to clinical use. Depending on the stimulation parameters, NBS may enable suppression of the acute glutamatergic hyperexcitability following TBI and/or counter the excessive GABAergic effects in the subacute stage. In the chronic stage, brain stimulation coupled to rehabilitation may enhance behavioral recovery, learning of new skills, and cortical plasticity. Correlative animal models and comprehensive safety trials seem critical to establish the use of these modalities in TBI. CONCLUSIONS: Different forms of NBS techniques harbor the promise of diagnostic and therapeutic utility, particularly to guide processes of cortical reorganization and enable functional restoration in TBI. Future lines of safety research and well-designed clinical trials in TBI are warranted to determine the capability of NBS to promote recovery and minimize disability. PMID- 21691221 TI - Traumatic floating clavicle: a case report. AB - Most published reports of a floating clavicle consist of a dislocation of both ends of the clavicle and are associated with a high-energy injury. We report a 71 year old patient with a fracture of the medial end of the clavicle with anterior sternoclavicular dislocation and a nondisplaced fracture of the lateral end of the same clavicle distal to the insertion of coracoclavicular ligaments due to a low velocity fall. PMID- 21691222 TI - Neonatal cholestasis caused by hyperthyroidism. PMID- 21691223 TI - Delayed diagnosis of glycogen storage disease type III. PMID- 21691224 TI - Acute on chronic liver disease in children from the developing world: recognition and prognosis. AB - OBJECTIVES: A subset of children with chronic liver disease (CLD) decompensate following an acute insult; however, data for children are not readily available. The present study aims to characterize the clinical presentation, etiology, outcome, and determinants of short-term mortality in children with an acute hepatic insult superimposed over CLD. PATIENTS AND METHODS: Children of acute on chronic liver disease (ACLD) were grouped as acute on chronic liver failure (ACLF) and non-ACLF. ACLF was defined as per the definition proposed by Asian Pacific Association for the Study of Liver. The acute insult, etiology of CLD, and clinical and laboratory parameters at admission along with 3-month outcome were assessed. Receiver operating curve (ROC) was plotted to measure the performance of pediatric end-stage liver disease (PELD) score in predicting the 3 month mortality. RESULTS: Of the 36 children with ACLD (median age 9.5; range 3 15 years), 17 fulfilled ACLF criteria and 19 non-ACLF. CLD was diagnosed for the first time in 86% children during their presentation with a superimposed acute insult. Wilson disease and autoimmune liver disease were the most common underlying etiology. Acute insult was caused by hepatitis E virus (HEV) in 27 (75%) children and hepatitis A virus (HAV) in 10 (28%). The 3-month mortality of ACLF group was significantly higher than that of non-ACLF group (59% vs 11%, P = 0.001). PELD score of >25.5 predicted death, with a sensitivity of 100% and specificity of 83.3%. CONCLUSIONS: Superinfection with hepatotropic viruses on CLD in children manifests as ACLD: ACLF and non-ACLF. Hepatitis E virus is the most common superinfection in the population studied. The mortality in ACLF is 5 times higher than that in the non-ACLF group. PELD score is useful in differentiating likely survivors and nonsurvivors. PMID- 21691225 TI - Congenital tufting enteropathy in the era of molecular genetics. PMID- 21691226 TI - Spectrum of intra-articular findings of the acute and subacute painful hip with multiple epiphyseal dysplasia/spondyloepiphyseal dysplasia. AB - Seven patients (10 hips), five with multiple epiphyseal dysplasia and two with spondyloepiphyseal dysplasia, were studied as to the etiology of a significant change in their baseline symptoms. Patients presented with decreased activity due to increased pain and mechanical symptoms and had a positive impingement test on physical examination. Three patients had a sudden increase in pain during normal walking and had subsequent difficulty with weight bearing. Arthrotomy or arthroscopy was used to identify the intra-articular pathology. Findings included loose bodies, chondromalacia, and labral pathology. Chondral avulsion fractures were found in the three patients who had a sudden increase in symptoms. Significant intra-articular pathology can develop in patients with multiple epiphyseal dysplasia or spondyloepiphyseal dysplasia. PMID- 21691227 TI - Congenital pseudoarthrosis of the tibia - results of treatment by free fibular transfer and associated procedures - preliminary study. AB - We evaluated 16 children with congenital pseudoarthrosis of the tibia treated with contralateral fibular graft, with the aim to report the difficulties and clinical results in the affected limb after consolidation. Sixty-three percent of the children had characteristics of neurofibromatosis. Consolidation was achieved after the main surgery in 37%of patients, and the remainder, after multiple procedures. Consolidation time was longer for male patients. Refracture was observed in six patients and recurrence of the anterior bowing in six; four of these patients were submitted to correction. Four patients presented femur overgrowth. The average shortening of the affected leg was 3.6 cm. The proposed procedure leads to a long treatment course with many reoperations for correction of possible complications. PMID- 21691228 TI - Comparisons of age-predicted maximum heart rate equations in college-aged subjects. AB - This study investigated the accuracy of age-predicted equations to predict heart rate maximum (HRmax) in a college-age sample and establish efficacy of short duration anaerobic capacity tests to determine the actual HRmax. A criterion HRmax (CHRmax) was obtained from 96 (52 men and 44 women, age = 22.0 +/- 2.8 years, height = 163.9 +/- 9.5 cm, 70.6 +/- 14.7 kg, resting HR = 68.9 +/- 11.2 b.min) healthy volunteers during 2 200-m sprint trials on a standard track. Maximal effort was confirmed via plasma lactate >=7 mmol.L(-1) and rating of perceived exertion >=17 points. The CHRmax was compared to 7 age-predicted HRmax equations: Fox et al., 3 equations from Gellish et al., Tanaka et al., and gender specific equations from Fairbarn et al., and Hossack et al. Descriptive statistics and standard errors of estimate (SEEs) were calculated. One-way analysis of variance was used to assess differences between the criterion HRmax and the age-predicted HRmax from the 7 equations. The predicted HRmax from the Fox equation and those of Gellish(3), Tanaka, and Hossack were all significantly higher (p <= 0.05) than the CHRmax. The Fox equation resulted in overpredicting HRmax in 88.5% of the cases compared to the CHRmax. Compared to the CHRmax, the age-predicted HRmax equations resulted in the following percentages of the CHRmax: Fox = 104.8%, SEE = 12.7; Gellish(1) = 95.2%, SEE = 12.2; Gellish(2) = 99.6%, SEE = 8.3; Gellish(3) = 101.8%, SEE = 9.1; Tanaka = 102.0%, SEE = 9.3; Fairbarn = 100.1%, SEE = 8.5; and Hossack = 105.2%, SEE = 13.9 of CHRmax. It was concluded that the Gellish(2) and Fairbarn equations were the most accurate of the age-predicted HRmax equations in a college-age population. In practical application, 2 200-m sprint trials provide a reasonable estimate of HRmax compared to a graded exercise test. PMID- 21691229 TI - The effect of muscular endurance on running economy. AB - The purpose of this study was to examine the relationship between fatigue-induced changes in running economy (RE) and muscular strength endurance (MSE). Ten well trained male runners completed 2 runs of the same energy expenditure at 20%Delta VO(2) below LT. In the middle of the experimental condition (high intensity exercise [HIE]), there was a 4-minute block at sVO(2)max. The aim of the 4-minute block was to increase RE through fatigue, without inducing exhaustion. The MSE of hip extensors (HEs) and knee flexors (KFs) was assessed by 2 20-second eccentric bouts on an isokinetic dynamometer at 180 degrees .s(-1). The RE increased after HIE compared to the control condition. Partial correlations found the increase in RE was strongly related with KF MSE (r = -0.709-0.798; p = 0.03-0.01). Greater MSE appeared to confer a fatigue resistant effect, resulting in a smaller increase in RE. The underlying mechanism of the fatigue resistant effect remains to be elucidated. Conditioning work focusing on augmenting eccentric muscular endurance of the legs may offer beneficial adaptations that promote fatigue resistance. PMID- 21691230 TI - Skinfold thickness is related to cardiovascular autonomic control as assessed by heart rate variability and heart rate recovery. AB - The purpose of this study was to determine if heart rate recovery (HRR) and heart rate variability (HRV) are related to maximal aerobic fitness and selected body composition measurements. Fifty men (age = 21.9 +/- 3.0 years, height = 180.8 +/- 7.2 cm, weight = 80.4 +/- 9.1 kg, volunteered to participate in this study. For each subject, body mass index (BMI), waist circumference (WC), and the sum of skinfolds across the chest, abdomen, and thigh regions (SUMSF) were recorded. Heart rate variability (HRV) was assessed during a 5-minute period while the subjects rested in a supine position. The following frequency domain parameters of HRV were recorded: normalized high-frequency power (HFnu), and low-frequency to high-frequency power ratio (LF:HF). To determine maximal aerobic fitness (i.e., VO2max), each subject performed a maximal graded exercise test on a treadmill. Heart rate recovery was recorded 1 (HRR1) and 2 (HRR2) minutes during a cool-down period. Mean VO2max and BMI for all the subjects were 49.5 +/- 7.5 ml.kg(-1).min(-1) and 24.7 +/- 2.2 kg.m(-2), respectively. Although VO2max, WC, and SUMSF was each significantly correlated to HRR and HRV, only SUMSF had a significant independent correlation to HRR1, HRR2, HFnu, LF:HF (p < 0.01). The results of the regression procedure showed that SUMSF accounted for the greatest variance in HRR1, HRR2, HFnu, and LF:HF (p < 0.01). The results of this study suggest that cardiovascular autonomic modulation is significantly related to maximal aerobic fitness and body composition. However, SUMSF appears to have the strongest independent relationship with HRR and HRV, compared to other body composition parameters and VO2max. PMID- 21691231 TI - Role of H4 receptor in histamine-mediated responses in human melanoma. AB - We have previously reported that histamine at micromolar concentrations reduces the proliferation of melanoma cell lines. It is also known that melanoma cells express histamine H1, H2, and H3 receptors. The aim of this study was to investigate the presence of histamine H4 receptor (H4R) in human melanoma cells and its associated biological processes. To better understand the importance of histamine in tumor development, we explored the expression of H4R in human melanoma tissue biopsies. The expression of H4R in WM35 and M1/15 cells was analyzed by reverse-transcription-PCR, western blot, and immunocytochemistry. To characterize the biological responses we evaluated cell proliferation by clonogenic assay and 5-bromo-2'-deoxyuridine incorporation. In addition, cell senescence and differentiation were determined by beta-galactosidase enzyme assay and dopa oxidase activity, respectively. The expression levels of H4R were determined by immunohistochemistry in 19 samples of human malignant lesions. Results indicate that melanoma cells express H4R at the messenger RNA and protein levels. By using histamine agonists, antagonists, and H4R small-interfering RNA we showed that the inhibitory effect of histamine on proliferation was in part mediated through the stimulation of the H4R. The decrease in proliferation was associated with an induction of cell senescence and an increase in melanogenesis, which is a differentiation marker of these cells. Furthermore, H4R was expressed in 42% of human melanoma biopsies. To our knowledge, this is the first report that describes the presence of the H4R in melanoma cells and tissue, suggesting a potential therapeutic application of H4R ligands. PMID- 21691232 TI - Analysis of the functional integrity of the p53 tumor-suppressor gene in malignant melanoma. AB - Derogation of the p53 pathway is a hallmark in human malignancies but its implication in melanomas remains unclear. p53 is frequently accumulated in melanomas despite protein stabilizing mutations being rare. For a panel of six melanoma cell lines we performed transcript sequence analysis of the entire coding region and determined p53 protein stability and messenger RNA stability by western blot experiments and quantitative reverse-transcription-PCR, respectively. Transcript levels of p53 modifying genes as well as p53 target genes were investigated after ultraviolet irradiation, interferon-alpha-2b, and chemotherapy (cisplatin or dacarbazine) by quantitative reverse-transcription PCR. Transcript sequence analysis identified three aberrations in three of six melanomas. Four of six melanomas showed high-constitutive p53 protein levels. p53 transcripts remained stable in four of six melanomas. All p53-expressing melanomas displayed high p53 protein stability. Constitutively, and after ultraviolet irradiation, mouse double min-2 expression was reduced in melanomas. We detected high homeodomain-interacting protein kinase-2 level in melanomas expressing mutant p53. Most experimental conditions resulted in lower expression of p21, GADD45A, and PUMA, and a higher expression of CDC2 in melanomas. Altogether, accumulation of p53 protein is due to posttranslational modification or aberrant expression of p53 modifiers. p53 is functionally disrupted although the p53 upstream signaling pathway remains inducible. PMID- 21691233 TI - Audiovisual temporal discrimination is less efficient with aging: an event related potential study. AB - We investigated the crossmodal temporal discrimination deficit characterizing older adults and its event-related potential (electroencephalogram) correlates using an audiovisual temporal order judgment task. Audiovisual stimuli were presented at stimulus onset asynchronies (SOA) of 70 or 270 ms. Older were less accurate than younger adults with an SOA of 270 ms but not 70 ms. With an SOA of 270 ms only, older adults had smaller posterior P1 and frontocentral N1 amplitudes for visual stimuli in auditory-visual trials and auditory stimuli in visual-auditory trials, respectively. These results suggest a deficit in cross sensory processing with aging reflected at the behavioural and neural level, and suggest an impairment in switching between modalities even when the inputs are separated by long temporal intervals. PMID- 21691234 TI - Short-term meditation increases network efficiency of the anterior cingulate cortex. AB - Previous studies have found that short-term integrative body-mind training (IBMT) has positive effects on the brain structure and function in the anterior cingulate cortex. Here, we determined whether 11 h of IBMT alters topological properties of the anterior cingulate cortex in brain functional networks. We applied network analysis to resting-state functional connectivity between 90 cortical and subcortical regions before and after IBMT and relaxation training. The results demonstrated a significant increase in the network efficiency and connectivity of the anterior cingulate cortex after IBMT, but not after relaxation training. These findings indicated that the change in network topology might occur by altering the brain or psychological state. IBMT might be an intervention tool for improvement of self-regulation. PMID- 21691235 TI - Matrix metalloproteinase-9 is associated with acute inflammation after olfactory injury. AB - We previously reported an increase in matrix metalloproteinase-9 (MMP-9) levels in the olfactory bulb immediately after nerve transection; however, its role remains unknown. In this study, we determined the source of MMP-9 by monitoring the infiltration of inflammatory leukocytes in the olfactory bulb after nerve transection. We used myeloperoxidase to identify neutrophils and CD68 to identify macrophages at days 1, 7, and 10. MMP-9 colocalized with neutrophils at all three time points but was not contained in macrophages. This is the first study to demonstrate that MMP-9 is associated with early inflammatory response after olfactory injury, and provides insight into mechanisms underlying olfactory injury and recovery processes. PMID- 21691237 TI - Treatment room length-of-stay and patient throughput with radioiodine thyroid remnant ablation in differentiated thyroid cancer: comparison of thyroid stimulating hormone stimulation methods. AB - OBJECTIVES: We sought to empirically compare treatment room length-of-stay and patient throughput for recombinant human thyroid-stimulating hormone (rhTSH) aided thyroid remnant ablation with thyroid hormone withdrawal (THW)-aided ablation in patients with differentiated thyroid carcinoma (DTC). METHODS: We retrospectively reviewed charts of all eligible (near) totally thyroidectomized patients with DTC undergoing ablation and 1-year ablation success evaluation at our tertiary referral centre from January 2003 to February 2009 (N=274). M1 disease caused exclusion unless discovered by a postablation scan or present when rhTSH was the only tolerable stimulation method. We extracted data on the length of-stay, defined as the time between treatment room admission and discharge, and patient throughput, defined as patients ablated per treatment room per week. The treatment room discharge criterion was a whole-body dose rate of less than 60 MUSv/h at 50 cm. RESULTS: The treatment groups (rhTSH, n=187; THW, n=87) had mostly statistically similar characteristics, but differed in primary tumour status distribution. In addition, at ablation, the rhTSH patients had a greater prevalence of prior diagnostic scintigraphy, higher mean serum TSH, and shorter interval since surgery, and received a 5.6% larger mean ablation activity. On average, rhTSH patients had a significantly lower peak whole-body dose rate (57.1 vs. 83.4 MUSv/h at 50 cm; P<0.0001) and a significantly shorter treatment room stay than did the THW patients (1.41 vs. 2.02 days; P<0.001). rhTSH use allowed significantly more patients to be ablated per room per week (2.7 vs. 1.2; P<0.001). CONCLUSION: Relative to THW, rhTSH use to aid ablation reduced mean treatment room length-of-stay by almost one-third and more than doubled the average weekly patient throughput, both of which were significant differences. PMID- 21691238 TI - Chinese version of the Postpartum Depression Screening Scale: translation and validation. AB - BACKGROUND: Postpartum depression is an important public health problem in China. Although 10%-20% of Chinese women having recently given birth are affected by postpartum depression, only 10% receive treatment due to the lack of proper screening. OBJECTIVES: The aims of this study were to translate the Postpartum Depression Screening Scale into Chinese (C-PDSS) and establish the psychometric properties of the C-PDSS. METHOD: The study was undertaken in three phases, composed of forward and backward translation of the Postpartum Depression Screening Scale into Chinese, examination of content validity, and field testing to establish the reliability, validity, and optimal cutoff score of the C-PDSS along with its sensitivity, specificity, and predictive values. A total sample of 387 mothers within 12 weeks postpartum participated in the study. Each mother was asked to complete the C-PDSS and the Chinese version of the Edinburgh Postnatal Depression Scale and then was interviewed by an experienced researcher using the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. RESULTS: The Cronbach's alpha coefficient was .96 for the total C-PDSS, and the overall intraclass correlation was .79. Factor analysis of the scale revealed that it was composed of 7 factors with eigenvalues >1, accounting for 74.25% of the total variance. There was a significantly positive correlation between the C-PDSS and the Chinese version of the Edinburgh Postnatal Depression Scale (r = .66, p < .001). Discriminant validity suggested a statistically significant difference in the C-PDSS scores among the nondepressed, minor depressed, and major-depressed participants. A cutoff score of 76.5 (sensitivity = 97.3% and specificity = 87.0%) was recommended for major and minor postpartum depression, and a cutoff score of 98 (sensitivity = 87.5% and specificity = 96.9%) was recommended for major postpartum depression. The area under the curve was 0.98 (95% confidence interval = 0.96-1.00) for major and minor postpartum depression and 0.99 (95% confidence interval = 0.98-1.01) for major postpartum depression. DISCUSSION: The C-PDSS has satisfactory psychometric properties in screening postpartum depression among Chinese mothers. Future research would provide data for further validation using confirmatory factor analysis and generalization of the C-PDSS to a different sample in China. PMID- 21691239 TI - Nurse dose: linking staffing variables to adverse patient outcomes. AB - BACKGROUND: Inconsistent findings in more than 100 studies have made it difficult to explain how variation in nurse staffing affects patient outcomes. Nurse dose, defined as the level of nurses required to provide patient care in hospital settings, draws on variables used in staffing studies to describe the influence of many staffing variables on outcomes. OBJECTIVES: The aim of this study was to examine the construct validity of nurse dose by determining its association with methicillin-resistant Staphylococcus aureus (MRSA) infections and reported patient falls on a sample of inpatient adult acute care units. METHODS: Staffing data came from 26 units in Ontario, Canada, and Michigan. Financial and human resource data were data sources for staffing variables. Sources of data for MRSA came from infection control departments. Incident reports were the data source for patient falls. Data analysis consisted of bivariate correlations and Poisson regression. RESULTS: Bivariate correlations revealed that nurse dose attributes (active ingredient and intensity) were associated significantly with both outcomes. Active ingredient (education, experience, skill mix) and intensity (full-time employees, registered nurse [RN]:patient ratio, RN hours per patient day) were significant predictors of MRSA. Coefficients for both attributes were negative and almost identical. Both attributes were significant predictors of reported patient falls, and coefficients were again negative, but coefficient sizes differed. DISCUSSION: By conceptualizing nurse and staffing variables (education, experience, skill mix, full-time employees, RN:patient ratio, RN hours per patient day) as attributes of nurse dose and by including these in the same analysis, it is possible to determine their relative influence on MRSA infections and reported patient falls. PMID- 21691240 TI - Use of Rasch analysis in the evaluation of the Oropharyngeal Mucositis Quality Of Life Scale. AB - BACKGROUND: Oropharyngeal mucositis (OM) is a significant clinical problem causing profound impairment of health-related quality of life (HQoL) for patients undergoing cancer therapy. The Oropharyngeal Mucositis-Specific Health-Related Quality of Life Measure (OMQoL) was developed using classical test theory to measure the self-perceived HQoL of patients with mucositis. OBJECTIVES: The aim of this study was to analyze the OMQoL according to the Rasch model and, on the basis of results, determine whether improvements could be made. METHOD: A multicenter approach was used, and 210 patients treated with stomatotoxic chemotherapy (36%), high-dose myeloablative chemotherapy +/- total body irradiation (10%), or head and neck irradiation +/- chemotherapy (54%) completed the OMQoL. The Partial Credit Model of Rasch analysis was applied to evaluate the 31-item OMQoL using WINSTEPS and R software. Unidimensionality (measurement of a single construct), item fit, response category performance, person separation reliability, targeting of item difficulty to person ability, and differential item functioning (DIF) were examined. RESULTS: Of 31 items, 5 were removed due to misfit; the OMQoL was reduced to 26 items with acceptable information weighted fit/outlier-sensitive fit indices (within 0.7-1.3) and eigenvalue units (<=2.0), confirming the unidimensionality of the reduced OMQoL. The OMQoL and its four subscales showed ordered category thresholds, and the person separation reliability was high (person separation index >0.2 with reliability >.8). Nevertheless, some of the items in the OMQoL might not be targeted effectively to patients with low levels of OM. Significant uniform and nonuniform DIFs were not found for gender (uniform DIF, p = .26; nonuniform DIF, p= .24) and age (uniform DIF, p = .95; nonuniform DIF, p = .65). DISCUSSION: Rasch analysis reveals that the reduced 26-item OMQoL is unidimensional and is adequate to measure HQoL for patients with OM regardless of gender and age group. This improved version can provide a common platform for nurses to use in their assessment, caring, and treatment of patients with OM. PMID- 21691241 TI - Feasibility and impact of a function focused care intervention for Parkinson's disease in the community. AB - BACKGROUND: Parkinson's disease (PD) results in a progressive loss of function such that family caregivers provide a large percentage of the personal care to PD patients living in the home setting. OBJECTIVES: The aim of this study was to test the feasibility and impact of function-focused care for PD (FFC-PD) developed to optimize function and physical activity among people with PD who live in the community. METHODS: This pilot study was a single-group, 2 pretest, 3 posttest repeated-measures design to investigate the impact of the FFC-PD intervention over a 12-month period. Measurements included the Self-Efficacy and Outcome Expectations for Exercise and Functional Activities, Yale Physical Activity Scale, Unified Parkinson's Disease Rating Scale, Barthel Index, Schwab & England, Timed Chair Rise, Parkinson's Disease Questionnaire-39, and Geriatric Depression Scale. RESULTS: The impact of FFC-PD on a person with PD showed a statistically significant increase in outcome expectations for exercise, F(3, 60) = 3.09, p = .034; hours a week exercising, F(1, 24) = 4.95, p = .004; mean weekly energy expenditure, F(2,43) = 4.32, p = .017; hours spent in overall activities, F(3, 60) = 6.06, p = .001; decreased disability based on the Unified Parkinson's Disease Rating Scale, F(2, 40) = 9.48, p < .001; improved Parkinson's Disease Questionnaire-39 score, F(3, 60) = 3.81, p = .014; and a trend toward significance on Barthel Index, F(1.6, 31) = 3.47, p = .055. DISCUSSION: Function focused care for PD has a significant effect on increasing and on strengthening outcome expectations related to exercise, time spent in exercise, and physical activity and in improving functional performance in people with PD. Further research is needed to explore the use of objective measurements of functional performance and activity and to test FFC-PD in a randomized controlled trial. PMID- 21691242 TI - Registered nurses' job demands in relation to sitter use: nested case-control study. AB - BACKGROUND: Increases in overtime and absenteeism among registered nurses (RNs), in conjunction with a workforce having less experience, have resulted in high RN job demands. At the same time, there has been an increase in hospitals' use of patient sitters (i.e., unskilled attendants), but it is not known if these two changes are correlated. OBJECTIVE: The aim of this study was to determine if indicators of RN job demands, specifically overtime, absenteeism, and experience, are related to greater sitter use. METHOD: A nested case-control study design was used. All patients who were assigned a sitter (cases) were selected from a cohort of 43,212 medical and surgical patients who had been admitted to an academic health center in Montreal (Canada) in 2007 and 2008. For each case (n = 1,179), up to four controls (n = 4,167) were selected randomly among patients who did not receive a sitter. Multivariate logistic regression, within a generalized estimating equation framework, was used to assess the association between RN job demand indicators and sitter use, while controlling for other risk factors for sitter use. RESULTS: Compared with controls, patients who were assigned sitters had been subject to high rates of RN overtime and absenteeism and lower RN cumulative experience in the period prior to sitter use. Each additional hour of RN overtime increased the likelihood of sitter use by 108% (odds ratio = 2.08, 95% confidence interval = 1.32-3.29). Every 5 years of collective RN experience reduced the odds of sitter use by 23% (odds ratio = 0.77, 95% confidence interval = 0.66-0.89). Absenteeism was not associated with sitter use. DISCUSSION: High RN overtime and collective inexperience are associated with greater sitter use. A possible explanation is that sitters are used to palliate failures to meet high job demands. Further research is required to assess the impact of sitter use on patient outcomes. PMID- 21691243 TI - Tuberculosis and profound hypovitaminosis D in an infant. AB - A young infant presented with a febrile respiratory illness, irritability, and failure to thrive. Clinical evaluation identified that he had profound hypovitaminosis D with severe hypocalcemia and active pulmonary tuberculosis. We review the literature and discuss the current state of knowledge of the interrelationship between Mycobacterium infection and vitamin D status, and its implication to pediatricians. PMID- 21691244 TI - Baseline estimates of diarrhea-associated mortality among United States children before rotavirus vaccine introduction. AB - OBJECTIVES: Deaths due to diarrhea among US children declined substantially from the 1960s through the 1980s, but have not been recently assessed. We examined diarrhea-associated mortality among young US children from 1992 to 2006 to establish baseline estimates through which the effect of rotavirus vaccines, introduced in 2006, can be assessed. METHODS: National Center for Health Statistics multiple cause-of-death mortality data were used to examine diarrhea associated deaths and death rates among US children 1 to 59 months of age during 1992-2006. The winter residual method was used to indirectly estimate the annual number of diarrhea-associated deaths attributable to rotavirus. RESULTS: An average of 369 diarrhea-associated deaths/year (3320 total deaths) occurred among US children 1 to 59 months of age during 1992-1998 and 2005-2006. The diarrhea associated death rate increased 40% between the first 3 and last 2 years of the study period, from an average of 1.6 deaths per 100,000 to 2.3 deaths per 100,000. Black children died at almost 4 times the rate of white children. Diarrhea-associated deaths showed a winter seasonal pattern similar to that of rotavirus, particularly among children 4 to 23 months of age. Using indirect methods, we estimated 25 yearly rotavirus-associated deaths during the study period. Rotavirus vaccination could potentially prevent 21 of these deaths annually. CONCLUSIONS: Diarrhea-associated mortality among US children stabilized but appears to be increasing in recent years. Rotavirus was associated with a small but significant number of preventable deaths. The national multiple cause of-death data should prove useful for assessing mortality impact of rotavirus vaccination in the United States. PMID- 21691245 TI - Reduction in the incidence of influenza A but not influenza B associated with use of hand sanitizer and cough hygiene in schools: a randomized controlled trial. AB - BACKGROUND: Laboratory-based evidence is lacking regarding the efficacy of nonpharmaceutical interventions (NPIs) such as alcohol-based hand sanitizer and respiratory hygiene to reduce the spread of influenza. METHODS: The Pittsburgh Influenza Prevention Project was a cluster-randomized trial conducted in 10 elementary schools in Pittsburgh, PA, during the 2007 to 2008 influenza season. Children in 5 intervention schools received training in hand and respiratory hygiene, and were provided and encouraged to use hand sanitizer regularly. Children in 5 schools acted as controls. Children with influenza-like illness were tested for influenza A and B by reverse-transcriptase polymerase chain reaction. RESULTS: A total of 3360 children participated in this study. Using reverse-transcriptase polymerase chain reaction, 54 cases of influenza A and 50 cases of influenza B were detected. We found no significant effect of the intervention on the primary study outcome of all laboratory-confirmed influenza cases (incidence rate ratio [IRR]: 0.81; 95% confidence interval [CI]: 0.54, 1.23). However, we did find statistically significant differences in protocol specified ancillary outcomes. Children in intervention schools had significantly fewer laboratory-confirmed influenza A infections than children in control schools, with an adjusted IRR of 0.48 (95% CI: 0.26, 0.87). Total absent episodes were also significantly lower among the intervention group than among the control group; adjusted IRR 0.74 (95% CI: 0.56, 0.97). CONCLUSIONS: NPIs (respiratory hygiene education and the regular use of hand sanitizer) did not reduce total laboratory-confirmed influenza. However, the interventions did reduce school total absence episodes by 26% and laboratory-confirmed influenza A infections by 52%. Our results suggest that NPIs can be an important adjunct to influenza vaccination programs to reduce the number of influenza A infections among children. PMID- 21691246 TI - Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation: analysis of hypothalamic and autonomic candidate genes. AB - Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is a rare and complex pediatric disorder. Despite increased identification and advancing knowledge of the disease course, the variable onset and timing of phenotypic features in ROHHAD often result in delayed or missed diagnosis, potentially leading to fatal central hypoventilation, cardiorespiratory arrest, and impaired neurocognitive development. The 5-hydroxytryptamine receptor 1A (HTR1A), orthopedia (OTP), and pituitary adenylate cyclase activating polypeptide (PACAP) genes were targeted in the etiology of ROHHAD based on their roles in the embryologic development of the hypothalamus and autonomic nervous system. We hypothesized that variations of HTR1A, OTP, and/or PACAP would be associated with ROHHAD. All coding regions and intron-exon boundaries of the HTR1A, OTP, and PACAP genes, in addition to the promoter region of the HTR1A gene, were analyzed by standard sequencing in 25 ROHHAD cases and 25 matched controls. Thirteen variations, including six protein changing mutations, were identified. None of these variations were significantly correlated with ROHHAD. This report provides evidence that variation of the HTR1A, OTP, and PACAP genes are not responsible for ROHHAD. These results represent a further step in the investigation of the genetic determinants of ROHHAD. PMID- 21691247 TI - The relationship between electrocerebral activity and cerebral fractional tissue oxygen extraction in preterm infants. AB - Impaired cerebral oxygen delivery may cause cerebral damage in preterm infants. At lower levels of cerebral perfusion and oxygen concentration, electrocerebral activity is disturbed. The balance between cerebral oxygen delivery and oxygen use can be measured by near-infrared spectroscopy (NIRS), and electrocerebral activity can be measured by amplitude-integrated EEG (aEEG). Our aim was to determine the relationship between regional cerebral tissue oxygen saturation (rcSO2), fractional tissue oxygen extraction (FTOE), and aEEG. We recorded longitudinal digital aEEG and rcSO2 prospectively in 46 preterm infants (mean GA 29.5 wk, SD 1.7) for 2 hr on the 1st to 5th, 8th, and 15th d after birth. We excluded infants with germinal matrix hemorrhage exceeding grade I and recordings of infants receiving inotropes. FTOE was calculated using transcutaneous arterial oxygen saturation (tcSaO2) and rcSO2 values: (tcSaO2 - rcSO2)/tcSaO2. aEEG was assessed by calculating the mean values of the 5th, 50th, and 95th centiles of the aEEG amplitudes. The aEEG amplitude centiles changed with increasing GA. FTOE and aEEG amplitude centiles increased significantly with postnatal age. More mature electrocerebral activity was accompanied by increased FTOE. FTOE also increased with increasing postnatal age and decreasing Hb levels. PMID- 21691248 TI - Genetic contribution of catechol-O-methyltransferase polymorphism (Val158Met) in children with chronic tension-type headache. AB - Our aim was to investigate the relationship between Val158Met polymorphisms, headache, and pressure hypersensitivity in children with chronic tension-type headache (CTTH). A case-control study with blinded assessor was conducted. Seventy children with CTTH associated with pericranial tenderness and 70 healthy children participated. After amplifying Val158Met polymorphism by polymerase chain reactions, we assessed genotype frequencies and allele distributions. We classified children according to their Val158Met polymorphism: Val/Val, Val/Met, Met/Met. Pressure pain thresholds (PPT) were bilaterally assessed over the temporalis, upper trapezius, second metacarpal, and tibialis anterior muscles. The distribution of Val158Met genotypes was not significantly different (p = 0.335), between children with CTTH and healthy children, and between boys and girls (p = 0.872). Children with CTTH with the Met/Met genotype showed a longer headache history compared with those with Met/Val (p = 0.001) or Val/Val (p = 0.002) genotype. Children with CTTH with Met/Met genotype showed lower PPT over upper trapezius and temporalis muscles than children with CTTH with Met/Val or Val/Val genotype (p < 0.01). The Val158Met catechol-O-methyltransferase (COMT) polymorphism does not appear to be involved in predisposition to suffer from CTTH in children; nevertheless, this genetic factor may be involved in the phenotypic expression, as pressure hypersensitivity was greater in those CTTH children with the Met/Met genotype. PMID- 21691249 TI - Anatomic closure of the premature patent ductus arteriosus: The role of CD14+/CD163+ mononuclear cells and VEGF in neointimal mound formation. AB - Permanent closure of the newborn ductus arteriosus requires the development of neointimal mounds to completely occlude its lumen. VEGF is required for neointimal mound formation. The size of the neointimal mounds (composed of proliferating endothelial and migrating smooth muscle cells) is directly related to the number of VLA4 mononuclear cells that adhere to the ductus lumen after birth. We hypothesized that VEGF plays a crucial role in attracting CD14/CD163 mononuclear cells (expressing VLA4) to the ductus lumen and that CD14/CD163 cell adhesion to the ductus lumen is important for neointimal growth. We used neutralizing antibodies against VEGF and VLA-4 to determine their respective roles in remodeling the ductus of premature newborn baboons. Anti-VEGF treatment blocked CD14/CD163 cell adhesion to the ductus lumen and prevented neointimal growth. Anti-VLA-4 treatment blocked CD14/CD163 cell adhesion to the ductus lumen, decreased the expression of PDGF-B (which promotes smooth muscle migration), and blocked smooth muscle influx into the neointimal subendothelial space (despite the presence of increased VEGF in the ductus wall). We conclude that VEGF is necessary for CD14/CD163 cell adhesion to the ductus lumen and that CD14/CD163 cell adhesion is essential for VEGF-induced expansion of the neointimal subendothelial zone. PMID- 21691250 TI - Immediate hypothermia reduces cardiac troponin I after hypoxic-ischemic encephalopathy in newborn pigs. AB - Neonatal hypoxic-ischemic encephalopathy (HIE) is a clinically defined neurological condition after lack of oxygen and often associated with cardiac dysfunction in term infants. Therapeutic hypothermia (HT) after birth is neuroprotective in infants with HIE. However, it is not known whether HT is also cardioprotective. Four newborn pigs were used in the pilot study and a further 18 newborn pigs [randomly assigned to 72 h normothermia (NT) or 24 h HT followed by 48 h NT] were subjected to global HIE insults. Serum cTnI was measured before and post the HIE insult. Blood pressure, inotropic support, blood gases, and heart rate (HR) were recorded throughout. Cardiac pathology was assessed from histological sections. Cooling reduced serum cTnI levels significantly in HT pigs by 6 h (NT, 1.36 +/- 0.67; HT, 0.34 +/- 0.23 ng/mL; p = 0.0009). After rewarming, from 24 to 30 h postinsult, HR and cTnI increased in the HT group; from HR[24 h] = 117 +/- 22 to HR[30 h] = 218 +/- 32 beats/min (p = 0.0002) and from cTnI[24 h] = 0.23 +/- 0.12 to cTnI[30 h] = 0.65 +/- 0.53 ng/mL, (p = 0.05). There were fewer ischemic lesions on cardiac examination (37%) in the HT group compared with the NT group (70%). HT (24 h) pigs did not have the postinsult cTnI increase seen in NT-treated pigs. There was a trend that HT improved cardiac pathology in this 3-d survival model. PMID- 21691251 TI - Urinary neutrophil gelatinase-associated lipocalin at birth predicts early renal function in very low birth weight infants. AB - Preterm infants are exposed to conditions that can impair renal function. We evaluated the ability of serum and urinary neutrophil gelatinase-associated lipocalin (sNGAL and uNGAL) to predict renal function in the first weeks of life. From September 2008 to July 2009, infants weighing <=1500 g at birth with no major congenital anomalies or sepsis were eligible. We measured sNGAL and uNGAL levels at birth. To evaluate renal function, we determined changes in serum creatinine (sCreat) and estimated GFR (eGFR) from birth to d 21. Forty neonates (mean GA, 27 +/- 2 wk) completed the study. Renal function improved in 32 of 40 (80%) infants (normal renal function, NRF group) (sCreat, from 0.97 +/- 0.2 to 0.53 +/- 0.13 mg/dL; eGFR, from 15.3 +/- 4.1 to 28.6 +/- 7.9 mL/min), whereas renal function worsened in 8 of 40 (20%) infants (impaired renal function, IRF group) (sCreat, from 0.71 +/- 0.27 to 0.98 +/- 0.43 mg/dL; eGFR from 23 +/- 14.7 to 16.4 +/- 9.1 mL/min). The uNGAL/urinary creatinine (uCreat) ratio at birth was higher in the IRF group (31.05 ng/mg) than the NRF group (6.0 ng/mg), and uNGAL was significantly higher in IRF group, detecting IRF with a cutoff of 100 ng/mL. uNGAL levels at birth may have a predictive role in very LBW (VLBW) infants. PMID- 21691252 TI - Longitudinal myocardial contribution to peak systolic flow and stroke volume in the neonatal heart. AB - Systolic longitudinal myocardial function is important for cardiac ejection. Data describing hemodynamic determinants and the time course of myocardial longitudinal contraction as measured by tissue Doppler are lacking. Ten newborn pigs were used for invasive hemodynamic investigation. Tissue Doppler assessment of the lateral part of the mitral valve annulus during systole was performed during pharmacological modulation of inotropy, cardiac pacing, and modulations of loading conditions. The strongest association was found between peak systolic velocity (S') and peak systolic flow (PSF) and end-systolic pressure (ESP), respectively (beta = 0.09 cm/mL, p < 0.001 and beta = -0.07 cm/mL, p = 0.003). Displacement (D) was mostly influenced by stroke volume (SV) (beta = 0.05 cm/mL, p < 0.001). Ejection time, SV, ESP, maximum first derivative of pressure (dP/dtmax), and PSF were all associated with S' and D under different states of hemodynamic modulation; however, the ratio between PSF and S', SV, and D were stable during hemodynamic modulations. Normalized cross correlations indicate that S' and D follow the same trajectory as flow and SV, respectively. In conclusion, this study provides validity of accounting systolic D in the long axis as the longitudinal contribution to SV and peak systolic tissue velocity as the longitudinal contribution to PSF. PMID- 21691253 TI - A randomized controlled intervention with fish oil versus sunflower oil from 9 to 18 months of age: exploring changes in growth and skinfold thicknesses. AB - n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA), from fish oil (FO), in rodents have been shown to reduce adipogenesis. Evidence of an effect on adipose tissue mass in humans is limited, and no studies have specifically aimed to elucidate this in infancy. To explore whether n-3 LCPUFA intake affects adipose tissue growth, we randomly allocated 154 healthy infants to daily supplementation with FO or sunflower oil (SO) from 9 to 18 mo of age and measured z-score changes in various anthropometric assessments of body size and skinfold thicknesses and plasma adipokine concentrations. Among the 133 completing infants, erythrocyte n 3 PUFA increased more in those receiving FO than in infants receiving SO [12.2 +/ 0.7 (mean +/- SE) versus 2.0 +/- 0.4 fatty acid percentage (FA%), p < 0.001] with a concomitant larger decrease in n-6 PUFA (-8.9 +/- 0.7 versus -0.9 +/- 0.6 FA%, p < 0.001). We found no association between FO consumption relative to SO consumption and any of the anthropometric measures related to the size of the fat mass, but infants in the FO group had a lower skinfold ratio (triceps/subscapular) at 18 mo than those in SO group (p = 0.02). Our findings do not support the hypothesis that dietary n-3 LCPUFA is important for infant fat mass, but future studies testing this specifically are warranted. PMID- 21691254 TI - Flice inhibitory protein is associated with the survival of neonatal neutrophils. AB - Neonatal polymorphonuclear leukocytes (PMN) exhibit delayed apoptosis both constitutively and under inflammatory conditions, and evidence has linked PMN longevity to the presence of antiapoptotic proteins. Activation of the survival associated transcription factor, nuclear factor kappa B (NF-kappaB), promotes the synthesis of several antiapoptotic proteins including Flice inhibitory protein (FLIP). Neonatal and adult PMN were compared in this study to test the hypothesis that FLIP modulates age-related apoptosis. Expression of the short isoform, FLIP S, was prominent at baseline and persisted during spontaneous apoptosis in neonatal PMN, whereas basal expression was lower and decreased under the same conditions in adult PMN. Stable FLIP-S expression in neonatal PMN was associated with a relative resistance to apoptosis in response to the protein synthesis inhibitor, cycloheximide (CHX), or the NF-kappaB inhibitor, gliotoxin. In contrast, similar treatment of adult PMN promoted greater overall apoptosis accompanied by FLIP degradation. Nuclear levels of phosphorylated p65, a critical NF-kappaB dimer, were relatively robust in neonatal PMN under basal conditions or after stimulation with TNF-alpha, a cytokine that induces FLIP. In conclusion, persistent FLIP-S expression is involved in the longevity of neonatal PMN, and our data suggest a contribution of NF-kappaB signaling and related survival mechanisms. PMID- 21691255 TI - Functional analysis of nonsynonymous single nucleotide polymorphisms of multidrug resistance-associated protein 2 (ABCC2). AB - BACKGROUND: Multidrug resistance-associated protein 2 (MRP2; ABCC2) mediates the biliary excretion of glutathione, glucuronide, and sulfate conjugates of endobiotics and xenobiotics. Single nucleotide polymorphisms (SNPs) of MRP2 contribute to interindividual variability in drug disposition and ultimately in drug response. OBJECTIVES: To characterize the transport function of human wild type (WT) MRP2 and four SNP variants, S789F, A1450T, V417I, and T1477M. METHODS: The four SNP variants were expressed in Sf9 cells using recombinant baculovirus infection. The kinetic parameters [Km, (MUmol/l); V(max), (pmol/mg/min); the Hill coefficient] of ATP-dependent transport of leukotriene C(4) (LTC(4)), estradiol-3 glucuronide (E(2)3G), estradiol-17beta-glucuronide (E(2)17G), and tauroursodeoxycholic acid (TUDC) were determined in Sf9-derived plasma membrane vesicles. Transport activity was normalized for expression level. RESULTS: The V(max) for transport activity was decreased for all substrates for S789F, and for all substrates except E(2)17G for A1450T. V417I showed decreased apparent affinity for LTC(4), E(2)3G, and E(2)17G, whereas transport was similar between wild-type (WT) and T1477M, except for a modest increase in TUDC transport. Examination of substrate-stimulated MRP2-dependent ATPase activity of S789F and A1450T, SNPs located in MRP2 nucleotide-binding domains (NBDs), demonstrated significantly decreased ATPase activity and only modestly decreased affinity for ATP compared with WT. CONCLUSION: SNPs in the NBDs (S789F in the D-loop of NBD1, or A1450T near the ABC signature motif of NBD2) variably decreased the transport of all substrates. V417I in membrane spanning domain 1 selectively decreased the apparent affinity for the glutathione and glucuronide conjugated substrates, whereas the T1477M SNP in the carboxyl terminus altered only TUDC transport. PMID- 21691257 TI - Focal retinal phlebitis. AB - PURPOSE: To report three cases of solitary, focal retinal phlebitis. METHODS: An observational case series. RESULTS: Three eyes in three patients were noted to have unilateral decreased vision, macular edema, and a focal retinal phlebitis, which was not at an arteriovenous crossing. All three patients developed a branch retinal vein occlusion at the site of inflammation. These patients had no other evidence of intraocular inflammation, including vitritis, retinitis, retinal vasculitis, or choroiditis, nor was there any systemic disorder associated with inflammation, infection, or coagulation identified. CONCLUSION: Focal retinal phlebitis appears to be an uncommon and unique entity that produces macular edema and ultimately branch retinal vein occlusion. In our patients, the focal phlebitis and venous occlusion did not occur at an arteriovenous crossing, which is the typical site for branch retinal venous occlusive disease. This suggests that our cases represent a distinct clinical entity, which starts with a focal abnormality in the wall of a retinal venule, resulting in surrounding exudation and, ultimately, ends with branch retinal vein occlusion. PMID- 21691256 TI - Pharmacokinetic and pharmacogenomic profiles of telmisartan after the oral microdose and therapeutic dose. AB - OBJECTIVES: In this study, we evaluated (a) the contribution of SLCO1B3 and UGT1A polymorphisms to the pharmacokinetics of telmisartan in two forms, a microdose (MD) and a therapeutic dose (TD); (b) linkage disequilibrium (LD) between UGT1A1 and UGT1A3; and (c) linearity in the pharmacokinetics of telmisartan between the two forms. METHODS: Telmisartan was orally administered at MD condition (100 MUg), and then at TD condition (80 mg) to 33 healthy volunteers whose genotypes were prescreened by DMET Plus. Plasma concentrations of telmisartan and its glucuronide were measured by LC-MS/MS, and population pharmacokinetic analysis was performed. RESULTS: No obvious effect of SLCO1B3 polymorphisms (334T>G, 699G>A, and rs11045585) on the pharmacokinetics of telmisartan was observed. The strong LD between UGT1A1*6 and UGT1A3*4a, and between UGT1A1*28 and UGT1A3*2a were observed. After both MD and TD administration, the mean area under the curve0-24 (+/-standard deviation) of telmisartan was significantly lower and higher in individuals with the UGT1A3*2a (TD, 1701+/-970 ng hr/ml; MD, 978+/-537 pg hr/ml) and *4a variants (TD, 5340+/-1168; MD, 3145+/-1093), respectively, compared with those in individuals with UGT1A3*1/*1 (TD, 2969+/-1456; MD, 1669+/ 726). These results were quantitatively confirmed by population pharmacokinetic analysis. Nonlinearity of the dose-exposure relationship was observed between the MD and TD. CONCLUSION: The haplotypes of UGT1A3 significantly influenced pharmacokinetics of telmisartan and a strong LD between UGT1A1 genotype and UGT1A3 haplotype was observed. These findings are potentially of pharmacological and toxicological importance to the development and clinical use of drugs. PMID- 21691259 TI - Recurrence of Clostridium difficile infection after total colectomy in an allogeneic stem cell transplant patient. PMID- 21691258 TI - Anti-vascular endothelial growth factor monotherapy versus combination treatment with photodynamic therapy for subfoveal choroidal neovascularization secondary to causes other than age-related macular degeneration. AB - PURPOSE: To compare the visual outcomes and retreatment rates of monotherapy with intravitreal bevacizumab versus combination with photodynamic therapy for choroidal neovascularization secondary to causes other than age-related macular degeneration. METHODS: Seventeen patients received intravitreal bevacizumab, and 6 patients underwent intravitreal bevacizumab combined with verteporfin photodynamic therapy within 3 days. Additional bevacizumab was administrated if there was persistent fluorescein leakage or subretinal fluid on optical coherence tomography. RESULTS: The mean change in visual acuity was vision gain of 1.7 lines in the monotherapy group compared with 2.8 lines in the combination therapy group at 12-month follow-up (P = 0.45). At 12 months, 93% in the monotherapy group and 100% in the combination group lost <2 lines of vision (P = 1.0); 36% gained >3 lines of vision in the monotherapy compared with 60% in the combination therapy group (P = 0.60). The monotherapy group received a mean of 4.8 reinjections, while the combination group received 2.6 reinjections over 12 months (P = 0.11). Subgroup analysis of cases of choroidal neovascularization caused by pathologic myopia demonstrated a mean change in visual acuity of vision gain of +2.0 lines in the monotherapy group versus +2.3 lines in the combination therapy group (P = 0.82) and a mean of 7.2 reinjections versus 2 in monotherapy and combination group, respectively (P = 0.0498) at 12 months. CONCLUSION: The majority of patients had stabilization or improvement in vision in both treatment groups. Combination therapy with bevacizumab plus photodynamic therapy showed lower retreatment rates in patients with myopia. Randomized clinical trials are necessary to confirm these findings. PMID- 21691260 TI - Predictors of non-compliance in autologous hematopoietic SCT patients undergoing out-patient transplants. AB - Non-compliance has received significant attention in medicine, yet few studies have examined its correlates in autologous hematopoietic SCT (AHSCT) patients. This study examined predictors of non-compliance in a sample of 151 AHSCT patients treated in an outpatient setting. Before AHSCT, participants completed a validated measure of mood and retrospective chart reviews were conducted to assess non-compliance during AHSCT, defined as refusal of oral hygiene, prescribed exercise programs, oral nutrition and/or prescribed medications. We found 121 patients (80%) were non-compliant with an aspect of the AHSCT regimen on 1 or more days; mean percentage of non-compliant days was 16.6 (s.d. 15.6). Men were more likely than women to be non-compliant (P<0.05); as were participants with an elevated depression score (P<0.05). Stepwise regression models identified significant predictors of non-compliance: gender, depression, global distress and nausea and vomiting severity (P-values all <0.01). Further analysis revealed that the interaction of the psychological variables with gender was a more robust predictor of non-compliance (P<0.001). For outpatient AHSCT, our findings suggest the need to broaden conceptualizations of risk factors for non-compliance and the importance of assessing patient barriers to compliance to ensure optimal treatment outcome. PMID- 21691261 TI - Risk and prevention of graft failure in patients with preexisting donor-specific HLA antibodies undergoing unmanipulated haploidentical SCT. AB - A role of donor-specific HLA antibodies (DSA) in graft failure after SCT has been suggested, but the relevance of DSA in unmanipulated haploidentical SCT (haplo SCT) remains unknown. We prospectively examined HLA antibodies using the Luminex based single Ag assay for 79 adult patients undergoing unmanipulated haplo-SCT. Among them, 16 (20.2%) were HLA Ab-positive, including five patients with antibodies not corresponding to donor HLA Ags and 11 DSA-positive patients. Of the 11 DSA-positive patients, five received treatments to decrease DSA levels, including two, who received plasma exchange and rituximab, two who received platelet transfusions from healthy-related donors having DSA-corresponding HLA Ags and one who received bortezomib. Platelet transfusion was the most simple and effective treatment option for class I DSA. The cumulative incidence of neutrophil recovery was significantly lower in pretransplant (post-treatment) DSA positive patients than in DSA-negative patients (61.9 vs 94.4%, P=0.026). Notably, three of five patients with high levels of DSA had graft failure. Donors should be selected on the basis of an evaluation of HLA antibodies. If haplo-SCT from donors with HLA Ags that correspond to high levels of DSA must be performed, then recipients should be treated for DSA to improve the chances of successful donor engraftment. PMID- 21691263 TI - Induction of metastatic cancer stem cells from the NK/LAK-resistant floating, but not adherent, subset of the UP-LN1 carcinoma cell line by IFN-gamma. AB - As an advanced status of cancer stem cells (CSCs), metastatic CSCs (mCSCs) have been proposed to be the essential seeds that initiate tumor metastasis. However, the biology of mCSCs is poorly understood. In this study, we used a lymph node (LN) metastatic CEA-producing carcinoma cell line, UP-LN1, characterized by the persistent appearance of adherent (A) and floating (F) cells in culture, to determine the distribution of CSCs and mechanisms for the induction of mCSCs. F and A cells displayed distinct phenotypes, CD44(high)/CD24(low) and CD44(low)/CD24(high), respectively. The CSC-rich nature of F cells was typified by stronger expression of multiple drug resistance genes and a 7.8-fold higher frequency of tumor-initiating cells in NOD/SCID mice when compared with A cells. F cells showed a greater depression in HLA class I expression and an extreme resistance to NK/LAK-mediated cytolysis. Moreover, the NK/LAK-resistant F cells were highly susceptible to IFN-gamma-mediated induction of surface CXCR4, with concomitant downregulation of cytoplasmic CXCL12 expression, whereas these two parameters remained essentially unchanged in NK/LAK-sensitive A cells. Following the induction of surface CXCR4, enhanced migratory/invasive potential of F cells was demonstrated by in vitro assays. Confocal immunofluorescence microscopy showed the two distinct phenotypes of F and A cells could be correspondingly identified in monodispersed and compact tumor cell areas within the patient's LN tumor lesion. In response to IFN-gamma or activated NK/LAK cells, the CXCR4(+) mCSCs could be only induced from the CSCs, which were harbored in the highly tumorigenic CD44(high)/CD24(low) F subset. Our results revealed the complexity and heterogeneity of the CSC of this cell line/tumor and the differential immunomodulatory roles of F and A cells. A better understanding of the interactions among different classes of CSCs and their niches may assist us in eradicating the CSCs/mCSCs through targeted immunotherapy, chemotherapy, or both. PMID- 21691265 TI - The paradox of obesity and cardiovascular disease risk: time to change labels. PMID- 21691266 TI - Clinical pharmacology as a foundation for translational science. PMID- 21691262 TI - A polymeric nanoparticle formulation of curcumin (NanoCurcTM) ameliorates CCl4 induced hepatic injury and fibrosis through reduction of pro-inflammatory cytokines and stellate cell activation. AB - Plant-derived polyphenols such as curcumin hold promise as a therapeutic agent in the treatment of chronic liver diseases. However, its development is plagued by poor aqueous solubility resulting in poor bioavailability. To circumvent the suboptimal bioavailability of free curcumin, we have developed a polymeric nanoparticle formulation of curcumin (NanoCurcTM) that overcomes this major pitfall of the free compound. In this study, we show that NanoCurcTM results in sustained intrahepatic curcumin levels that can be found in both hepatocytes and non-parenchymal cells. NanoCurcTM markedly inhibits carbon tetrachloride-induced liver injury, production of pro-inflammatory cytokines and fibrosis. It also enhances antioxidant levels in the liver and inhibits pro-fibrogenic transcripts associated with activated myofibroblasts. Finally, we show that NanoCurcTM directly induces stellate cell apoptosis in vitro. Our results suggest that NanoCurcTM might be an effective therapy for patients with chronic liver disease. PMID- 21691269 TI - The metabolic syndrome: looking beyond the debates. PMID- 21691270 TI - Obesity and the "obesity paradox" in cardiovascular diseases. AB - Obesity adversely affects most cardiovascular (CV) risk factors and is strongly associated, probably as an independent risk factor, with most CV diseases. However, substantial evidence points to the existence of an "obesity paradox," in that overweight and obese patients with established CV diseases typically have a better prognosis than leaner patients with the same CV disease. Despite this paradox, we believe that the "weight" of evidence still supports efforts at purposeful weight loss in both primary and secondary CV prevention. PMID- 21691271 TI - Practical ethics: establishing a pathway to benefit for complex pharmacogenomic tests. AB - Pharmacogenomic tests offer a promising strategy to improve the safety and efficacy of drug treatment. Compelling examples, such as HLA-B*5701 testing to identify patients at risk for abacavir-associated hypersensitivity, are already changing clinical care. However, the level of evidence required to establish clinical utility is often the subject of debate. Determining the most efficient and effective pathway to benefit for a given test is therefore both a practical and an ethical concern. PMID- 21691272 TI - The importance of high-quality evidence of the long-term impact of nonfatal events used in randomized controlled trials: a case study of prasugrel. AB - Randomized controlled trials (RCTs) are the centerpiece of evidence-based medicine. However, because of the limited follow-up, additional evidence on the long-term consequences of the outcomes used in trials is commonly required for clinical and policy decision making. This article provides insights into the importance and challenges of using such evidence through the case study of nonfatal myocardial infarction (MI) and nonfatal bleeding with prasugrel. PMID- 21691273 TI - Regulatory science as a bridge between science and society. AB - Development of innovative drugs has recently become more difficult. The case of rosiglitazone shows the extreme difficulty of making the regulatory decision that will best balance the benefits and risks of a drug. There is a high expectation that regulatory science (RS) can improve the situation. However, without user understanding of its basic characteristics, RS will not deliver what is expected. PMID- 21691274 TI - Association of a polymorphism in the indoleamine- 2,3-dioxygenase gene and interferon-alpha-induced depression in patients with chronic hepatitis C. AB - Interferon (IFN)-alpha treatment for infectious diseases and cancer is associated with significant depressive symptoms that can limit therapeutic efficacy. Multiple mechanisms have been implicated in IFN-alpha-induced depression including immune, neuroendocrine and neurotransmitter pathways. To further explore mechanisms of IFN-alpha-induced depression and establish associated genetic risk factors, single nucleotide polymorphisms in genes encoding proteins previously implicated in IFN-alpha-induced depression were explored in two self reported ethnic groups, Caucasians (n=800) and African Americans (n=232), participating in a clinical trial on the impact of three pegylated IFN-alpha treatment regimens on sustained viral response in patients with chronic hepatitis C. Before treatment, all subjects were free of psychotropic medications and had a score <=20 on the Center for Epidemiologic Studies Depression Scale (CES-D), which was used to assess depressive symptom severity throughout the study. In Caucasians, a polymorphism (rs9657182) in the promoter region of the gene encoding indoleamine-2,3-dioxygenase (IDO1) was found to be associated with moderate or severe IFN-alpha-induced depressive symptoms (CES-D>20) at 12 weeks of IFN-alpha treatment (P=0.0012, P<0.05 corrected). Similar results were obtained for treatment weeks 24, 36 and 48. In subjects homozygous for the risk allele (CC, n=150), the odds ratio for developing moderate or severe depressive symptoms at treatment week 12 was 2.91 (confidence interval: 1.48-5.73) compared with TT homozygotes (n=270). rs9657182 did not predict depression in African Americans, who exhibited a markedly lower frequency of the risk allele at this locus. The findings in Caucasians further support the notion that IDO has an important role in cytokine-induced behavioral changes. PMID- 21691276 TI - Primary myelofibrosis with or without mutant MPL: comparison of survival and clinical features involving 603 patients. AB - MPL and JAK2V617F mutation analysis was performed in 603 patients with primary myelofibrosis (PMF) seen at the Mayo Clinic, USA (n=329) or University of Florence, Italy (n=274). Mutant MPL was detected in 49 (8.1%) patients and JAK2V617F in 350 (58%); 4 patients showed both mutations. MPLW515L/K was the commonest mutation; 2 patients showed novel mutations (L513ins and Q516 P518insAAAA). The US and Italy patient cohorts were separately analyzed for comparison of survival and clinical features between MPL-mutated, JAK2-mutated and JAK2/MPL-unmutated cases. JAK2/MPL-unmutated patients were significantly younger than their JAK2-mutated counterparts, in both patient cohorts (P<0.01). In the Florence only cohort, the presence of mutant MPL was associated with older age (P<0.01) and constitutional symptoms (P=0.04) and JAK2V617F with higher hemoglobin (P<0.01) and leukocyte (P=0.03) count; neither patient cohort showed significant associations with platelet count, hemoglobin <10 g/dl, abnormal/unfavorable karyotype, spleen size or prognostic score distribution. To date, 240 deaths and 79 leukemic transformations have been documented among all 603 study patients. Multivariable analysis disclosed no significant difference in overall or leukemia-free survival between the three molecular subgroups. We conclude that the presence of mutant MPL has narrow and inconsistent phenotypic effect in PMF and does not influence overall or leukemia-free survival. PMID- 21691275 TI - SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. AB - SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC50=23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) within the JAK family (IC50=1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC50=22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2(V617F)-driven disease model. SB1518 dose dependently inhibits intra-tumor JAK2/STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2(V617F) patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma. PMID- 21691277 TI - Response to Boswell-Ruys et al. PMID- 21691278 TI - A cost analysis of conservative management of spinal cord-injured patients in Nigeria. AB - STUDY DESIGN: A prospective study. OBJECTIVES: To determine the cost of acute phase of injury (ASCI) among spinal cord-injured patients managed conservatively in Nigeria. SETTINGS: Gwagwalada, Abuja. METHODS: Over a 1-year period (1 January 2009 to 31 December 2009), the cost of ASCI of consecutive spinal cord-injured patients, gainfully employed preinjury, who paid the hospital bill directly from their purses and could estimate their daily income, and who were managed conservatively for 6 weeks before discharge to rehabilitation, was prospectively examined. RESULTS: A total of 34 cases of spinal cord-injured patients with a mean age of 35.4 +/- 12.8 years were included in this study. The mean cost of ASCI over 6 weeks was $1598.29, an average of 6.4-232.8% of patients' annual income where >50% of the people live on less than a dollar a day. The mean cost of hospitalization was 14.9% of the total cost of ASCI in this study. It was significantly more expensive to treat tetraplegics compared with paraplegics. CONCLUSION: This study identified the cost of acute phase of spinal cord injury in Nigeria to assist clinicians in planning treatment that could reduce financial burden on the patients but optimize patients' care. PMID- 21691279 TI - Predicting the long-term impact of acquired severe injuries on functional health status: the role of optimism, emotional distress and pain. AB - STUDY DESIGN: Longitudinal. OBJECTIVE: To investigate the relative importance of personality traits, emotional distress and pain as predictors of functional health status in patients with spinal cord injury (SCI) or multiple traumas (MTs). SETTING: Sunnaas Rehabilitation Hospital, Norway. METHODS: Data were obtained from SCI and MT patients at admission (n=101) and at discharge (n=87) from rehabilitation, as well as 4 years post injury (n=75). The primary outcome measure was the sickness impact profile (SIP). Personality traits, that is, dispositional optimism and positive/negative affectivity, were measured using the Life Orientation Test-Revised and the Positive Affect and Negative Affect Schedule, respectively. RESULTS: Using hierarchical regression analysis, dispositional optimism and pain emerged as the most robust predictors of functional health status. Generally, these two variables accounted for a substantial part of the variance (that is, 20-40%) in the SIP scales. Significant correlations between pain and anxiety/depression were found in all phases of the study, and at follow-up depression level appeared as an independent predictor of functional health. CONCLUSION: The substantial predictive power, in terms of explained variance, of dispositional optimism, pain and depression/anxiety, indicates that these variables may be of practical-clinical importance in a rehabilitation setting. Specifically, patients characterized by low optimism, combined with presence of pain and depression/anxiety, may constitute a high-risk group for disability and reduced quality of life. On the other hand, high optimism should be regarded as a resilience characteristic, protecting the individual against long-term sequelae of severe physical injury. PMID- 21691280 TI - Critical role of interleukin-17/interleukin-17 receptor axis in mediating Con A induced hepatitis. AB - Concanavalin A (Con A)-induced hepatitis is thought to be a T-cell-mediated disease with active destruction of liver cells. Interleukin (IL)-17 is a cytokine produced principally by CD4(+) T cells. However, whether IL-17/IL-17 receptor (IL 17/IL-17R)-mediated responses are involved in T-cell-mediated Con A-induced liver injury remains unclear. In this study, we found that IL-17 expression was highly elevated in liver tissues during Con A-induced hepatitis. The increased levels of IL-17 were paralleled with the severity of liver injury reflected by Alanine aminotransaminase and histological assay as well as the secretion of tumor necrosis factor (TNF)-alpha and IL-6. Blockage of IL-17 significantly ameliorated Con A-induced hepatitis, while overexpression of IL-17 systemically resulted in massive hepatocyte necrosis in mice. Furthermore, overexpression of an IL-17R immunoglobulin G1 fusion protein significantly attenuated liver inflammation after acute Con A treatment. High expression of IL-17R on Kupffer cells was also observed along with the production of cytokines including TNF-alpha and IL-6. Inhibition of Kupffer cells by gadolinium chloride completely prevented Con A induced liver injury and cytokine release. Finally, IL-17-expressing CD4(+) T and natural killer T cells were greatly increased in Con A-injected mice compared with that in controls. Overall, our results indicate that IL-17R signaling is critically involved in the pathogenesis in Con A-induced hepatitis, and blockade of IL-17/IL-17R signaling pathway may represent a novel therapeutic intervention in human autoimmune-related hepatitis. PMID- 21691281 TI - Projecting the clinical benefits of adjuvant radiotherapy versus observation and selective salvage radiotherapy after radical prostatectomy: a decision analysis. AB - Our purpose was to project and compare clinical and quality-adjusted life year (QALY) outcomes of adjuvant radiotherapy (ART) versus salvage RT (SRT) after radical prostatectomy for men with locally advanced prostate cancer. We constructed a Markov model to simulate the randomized studies of observation versus ART, assuming 75% of observation patients would receive SRT at PSA recurrence. Transition probabilities and utility inputs were drawn from randomized trials of ART and cohort studies of SRT. We projected 10-year PSA recurrence-free survival, metastasis-free survival and overall survival. We found that observation with selective SRT yielded slightly worse outcomes than ART for post-RT PSA recurrence-free survival (47 and 52%), metastasis-free survival (69 and 70%) and overall survival (72 and 73%). Findings were robust to sensitivity analyses. After adjusting for the disutility of RT, observation plus SRT yielded better QALYs at 10 years than ART (6.80 and 6.13 QALYs). Thus, observation plus SRT may be optimal for men likely to comply with surveillance who wish to minimize side effects of the treatment. These findings reflect outcomes for the average patient given the current level of evidence and are meant to help inform current decision-making as we await future clinical studies of comparative effectiveness. PMID- 21691287 TI - Surgical management of the goat. PMID- 21691288 TI - Surgical management of the goat. PMID- 21691290 TI - 'Doubling up' procedures in a protocol amendment. PMID- 21691291 TI - 'Doubling up' procedures in a protocol amendment. One size does not fit all. PMID- 21691292 TI - 'Doubling up' procedures in a protocol amendment. Flawed reasoning. PMID- 21691293 TI - 'Doubling up' procedures in a protocol amendment. Too many problems. PMID- 21691294 TI - Sudden hind limb injuries in two rabbits. Self-mutilation after intramuscular ketamine-related neuronal injury. PMID- 21691296 TI - The effect of housing and environmental enrichment on stereotyped behavior of adult vervet monkeys (Chlorocebus aethiops). AB - Little information is available on the response of vervet monkeys to different housing conditions or on the suitability of enrichment devices or methods for vervet monkeys. In this study, the authors evaluated the occurrence of stereotyped behavior in adult vervet monkeys under various conditions of housing and enrichment. The variables included cage size, cage level (upper or lower), enrichment with a foraging log, enrichment with an exercise cage and presence of a mate. The authors first determined the incidence of stereotyped behavior in captive-bred, singly housed adult female and male vervet monkeys. They then exposed monkeys to different housing and enrichment situations and compared the incidence of stereotyped behavior among the monkeys. The authors found that more females than males engaged in stereotyped behavior and that females, on average, engaged in such behavior for longer periods of time than males. Stereotyped behavior was most often associated with a small, single cage. The average amount of observed stereotyped activity in monkeys housed in a small cage was significantly lower when the monkeys had access to either a foraging log or an exercise cage. Stereotyped behavior was also lower in female monkeys that were housed (either with a male or without a male) in a larger cage. The least amount of abnormal behavior was associated with the largest, most complex and enriched housing situation. Males and females housed in cages on the lower level of two level housing engaged in more stereotyped behavior than did monkeys housed in the upper level, regardless of the presence or type of enrichment provided. PMID- 21691297 TI - Cage-change interval preference in mice. AB - Before animal research facilities began using individually ventilated cage (IVC) systems for mice, cages were often changed one or more times per week. When using IVC systems, however, it is standard practice to change cages only once every 2-3 weeks. When deciding how often to change cages, personnel may consider the cost of labor needed to change the cage, as well as the cage type and bedding type, rather than animal preference or concern for animal well-being. The authors carried out a simple preference test in groups of mice. Mice were allowed to choose between an unsoiled cage and cages that had not been changed for 1 d, 7 d or 14 d. When evaluating where mice positioned their nests and the amount of time mice spent in the various cages, the authors found that the mice preferred the unsoiled cage. Younger mice (<150 d old) showed a stronger preference for the unsoiled cage than did older mice (>150 d old). Further studies are warranted to evaluate mice's preferences for cages changed at different intervals and to determine whether prolonging the interval between cage changes has any negative effects on mice. PMID- 21691298 TI - Serum inducible kinase is a positive regulator of cortical dendrite development and is required for BDNF-promoted dendritic arborization. AB - Serum inducible kinase (SNK), also known as polo-like kinase 2 (PLK2), is a known regulator of mitosis, synaptogenesis and synaptic homeostasis. However, its role in early cortical development is unknown. Herein, we show that snk is expressed in the cortical plate from embryonic day 14, but not in the ventricular/subventricular zones (VZ/SVZ), and SNK protein localizes to the soma and dendrites of cultured immature cortical neurons. Loss of SNK impaired dendritic but not axonal arborization in a dose-dependent manner and overexpression had opposite effects, both in vitro and in vivo. Overexpression of SNK also caused abnormal branching of the leading process of migrating cortical neurons in electroporated cortices. The kinase activity was necessary for these effects. Extracellular signal-regulated kinase (ERK) pathway activity downstream of brain-derived neurotrophic factor (BDNF) stimulation led to increases in SNK protein expression via transcriptional regulation, and this upregulation was necessary for the growth-promoting effect of BDNF on dendritic arborization. Taken together, our results indicate that SNK is essential for dendrite morphogenesis in cortical neurons. PMID- 21691299 TI - The oncoprotein p28GANK establishes a positive feedback loop in beta-catenin signaling. AB - p28(GANK) (also known as PSMD10 or gankyrin) is a novel oncoprotein that is highly expressed in hepatocellular carcinoma (HCC). Through its interaction with various proteins, p28(GANK) mediates the degradation of the tumor suppressor proteins Rb and p53. Although p53 was reported to downregulate beta-catenin, whether p28(GANK) is involved in the regulation of beta-catenin remains uncertain. Here we report that both growth factors and Ras upregulate p28(GANK) expression through the activation of the phosphoinositide 3-kinase-AKT pathway. Upregulation of p28(GANK) expression subsequently enhanced the transcription activity of beta-catenin. This effect was observed in p53-deficient cells, suggesting a p53-independent mechanism for the p28(GANK)-mediated activation of beta-catenin. p28(GANK) overexpression also reduced E-cadherin protein levels, leading to increased release of free beta-catenin into the cytoplasm from the cadherin-bound pool. Interestingly, exogenous expression of p28(GANK) resulted in elevated expression of the endogenous protein. We also observed that both beta catenin and c-Myc were transcriptional activators of p28(GANK), and a correlation between p28(GANK) overexpression and c-Myc, cyclin D1 and beta-catenin activation in primary human HCC. Together, these results suggest that p28(GANK) expression is regulated by a positive feedback loop involving beta-catenin, which may play a critical role in tumorigenesis and the progression of HCC. PMID- 21691300 TI - Migrating neuroblasts in the adult human brain: a stream reduced to a trickle. PMID- 21691301 TI - Regulation of the histone acetyltransferase activity of hMOF via autoacetylation of Lys274. PMID- 21691302 TI - Two transposable element insertions are causative mutations for the major domestication gene teosinte branched 1 in modern maize. PMID- 21691303 TI - mir-35 is involved in intestine cell G1/S transition and germ cell proliferation in C. elegans. AB - MicroRNA (miRNA) regulates gene expression in many cellular events, yet functions of only a few miRNAs are known in C. elegans. We analyzed the function of mir-35 41 unique to the worm, and show here that mir-35 regulates the G1/S transition of intestinal cells and germ cell proliferation. Loss of mir-35 leads to a decrease of nuclei numbers in intestine and distal mitotic gonad, while re-introduction of mir-35 rescues the mutant phenotypes. Genetic analysis indicates that mir-35 may act through Rb/E2F and SCF pathways. Further bioinformatic and functional analyses demonstrate that mir-35 targets evolutionally conserved lin-23 and gld 1. Together, our study reveals a novel function of mir-35 family in cell division regulation. PMID- 21691306 TI - Diagnosis: 18-Oxocortisol-a biomarker in adrenal vein sampling. PMID- 21691305 TI - Obesity: childhood obesity--methylate now, pay later? PMID- 21691304 TI - Epithelial-to-mesenchymal transition in prostate cancer: paradigm or puzzle? AB - The lethal consequences of prostate cancer are related to its metastasis to other organ sites. Epithelial-to-mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm to explain invasive and metastatic behavior during cancer progression. EMT is a normal physiologic process by which cells of epithelial origin convert into cells bearing mesenchymal characteristics. It has been proposed that EMT is co-opted by cancer cells during their metastatic dissemination from a primary organ to secondary sites, but the extent to which this recapitulates physiologic EMT remains uncertain. However, there is ample evidence that EMT-like states occur in, and may contribute to, prostate cancer progression and metastasis, and so has become a very active area of research. Here we review this evidence and explore recent studies that have aimed to better define the role and mechanisms of EMT in prostate cancer. While definitive evidence of something akin to physiologic EMT is still lacking in human prostate cancer, this area of research has nonetheless provided new avenues of investigation into the longstanding puzzles of metastasis, therapeutic resistance, and prognostic biomarkers. PMID- 21691307 TI - Therapy: HIV-associated dyslipidemia: the heart positive study. PMID- 21691308 TI - Diabetes: Hypertension after gestational diabetes mellitus. PMID- 21691309 TI - Adrenal gland: uncertainty in the selective use of adrenal vein sampling. PMID- 21691311 TI - Vascular disease: gene therapy for CLI disappoints. PMID- 21691312 TI - Valvular disease: PARTNER cohort A-TAVR is an option for operable severe aortic stenosis. PMID- 21691310 TI - The therapeutic potential of ischemic conditioning: an update. AB - Novel approaches are required to improve clinical outcomes in patients with coronary heart disease (CHD). Ischemic conditioning--the practice of applying brief episodes of nonlethal ischemia and reperfusion to confer protection against a sustained episode of lethal ischemia and reperfusion injury--is one potential therapeutic strategy. Importantly, the protective stimulus can be applied before (ischemic preconditioning) or after (ischemic perconditioning) onset of the sustained episode of lethal ischemia, or even at the onset of myocardial reperfusion (ischemic postconditioning). Furthermore, the protective stimulus can be applied noninvasively by placing a blood-pressure cuff on an upper or lower limb to induce brief episodes of nonlethal ischemia and reperfusion (remote ischemic conditioning), a finding that has greatly facilitated the translation of ischemic conditioning to various clinical settings. In addition to mechanical approaches, elucidation of the signal-transduction pathways underlying ischemic conditioning has identified several novel targets for pharmacological conditioning. This Review highlights findings from proof-of-concept clinical studies conducted in the past 5-6 years, in which the therapeutic potential of ischemic and pharmacological conditioning has been realized. Large, randomized, controlled trials are now required to determine whether pharmacological and ischemic conditioning improve clinical end points and outcomes in patients with CHD. PMID- 21691313 TI - Antiplatelet therapy: terutroban does not out-PERFORM aspirin in secondary prevention. PMID- 21691315 TI - Transplantation: Prolonged agonal time--not a contraindication for transplantation. PMID- 21691316 TI - Nephrotic syndrome: Genetic testing in steroid-resistant nephrotic syndrome. PMID- 21691317 TI - Transplantation: Prophylactic fenestration: prevention is better than cure. PMID- 21691319 TI - Genetics: DRB1*15 allele associated with PR3-ANCA disease. PMID- 21691314 TI - Mechanisms of disease: pulmonary arterial hypertension. AB - Our understanding of, and approach to, pulmonary arterial hypertension has undergone a paradigm shift in the past decade. Once a condition thought to be dominated by increased vasoconstrictor tone and thrombosis, pulmonary arterial hypertension is now seen as a vasculopathy in which structural changes driven by excessive vascular cell growth and inflammation, with recruitment and infiltration of circulating cells, play a major role. Perturbations of a number of molecular mechanisms have been described, including pathways involving growth factors, cytokines, metabolic signaling, elastases, and proteases, that may underlie the pathogenesis of the disease. Elucidating their contribution to the pathophysiology of pulmonary arterial hypertension could offer new drug targets. The role of progenitor cells in vascular repair is also under active investigation. The right ventricular response to increased pressure load is recognized as critical to survival and the molecular mechanisms involved are attracting increasing interest. The challenge now is to integrate this new knowledge and explore how it can be used to categorize patients by molecular phenotype and tailor treatment more effectively. PMID- 21691318 TI - Managing kidney disease with blood-pressure control. AB - The progression of chronic kidney disease (CKD) is largely independent of the underlying kidney disorder once renal function has fallen below a critical level. Hypertension is an independent risk factor for disease progression in both adult and pediatric patients with kidney disorders. Increasing evidence from clinical trials indicates that the rate of CKD progression can be lowered by pharmacological interventions. Nephroprotective strategies currently focus on the blockade of the renin-angiotensin system. Angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers provide efficient control not only of blood pressure, but also of proteinuria, an effect associated with improved long-term nephroprotection compared with other antihypertensive drug classes. In addition, evidence for an additional nephroprotective advantage of tight blood pressure control towards the low-normal range in young patients and patients with proteinuria is emerging. In this Review, we describe the role of hypertension in CKD and discuss the therapeutic principle of the prevention of CKD progression with antihypertensive agents. PMID- 21691320 TI - Genetics: Clues for targeting leukemia. PMID- 21691323 TI - Experimental arthritis: NKG2D: a potential therapeutic target in RA? PMID- 21691321 TI - Novel strategies for the treatment of small-cell lung carcinoma. AB - Small-cell lung cancer (SCLC) is a disease with a poor prognosis and limited treatment options. Over the past 30 years, basic and clinical research have translated to little innovation in the treatment of this disease. The Study of Picoplatin Efficacy After Relapse (SPEAR) evaluated best supportive care with or without picoplatin for second-line SCLC treatment and failed to meet its primary end point of overall survival. As the largest second-line, randomized study in patients with SCLC, SPEAR provides an opportunity to critically examine the drug development model in this disease. In this Review, we discuss the current standard approach for the management of SCLC that progresses after first-line therapy, analyze the preliminary data that supported the evaluation of picoplatin in this setting, and critically evaluate the SPEAR trial design and results. Lastly, we present advances in the understanding of the molecular biology of SCLC that could potentially inform future clinical trials and hopefully lead to the successful development of molecular targeted agents for the treatment of this disease. PMID- 21691324 TI - Experimental arthritis: Dendrimer drug mends monocytes. PMID- 21691322 TI - Stress and resilience in rheumatic diseases: a review and glimpse into the future. AB - Stress resilience factors, and interventions to ease stress and enhance resilience, are gaining increasing attention for the treatment of rheumatic conditions. This Review presents a digest of empirical work on the factors that determine the risk of adapting poorly to a rheumatic condition, and on the resilience factors that counteract such risks. We consider the types of stress management and resilience treatments that are most effective in promoting the physical and psychological functioning of patients at risk of long-term adjustment problems. Prospective research shows that cognitive-behavioral and social risk and resilience factors predict the long-term physical and psychological functioning of patients with rheumatic conditions. Furthermore, validated screening instruments are becoming increasingly useful in clinical practice to identify and select patients at risk. Stress-management and resilience interventions offer promising ways to improve the long-term functioning of patients. These treatment methods might be especially useful when they are tailored to the specific risk and resilience factors of patients, and when they incorporate innovative approaches to the delivery of services, including internet applications such as eHealth, to increase efficiency and availability of treatments, and to optimize patient empowerment in rheumatic conditions. PMID- 21691326 TI - Osteoarthritis: Local antagonism of endothelin-1 and bradykinin receptors improves OA pain and joint morphology in rats. PMID- 21691325 TI - Inflammation: Cadherin 11: a key mediator of fibroblast inflammation. PMID- 21691327 TI - Bone: Evidence for local effects of LRP5 on bone mass. PMID- 21691329 TI - Connective tissue diseases: Lupus nephritis-winning a few battles but not the war. PMID- 21691330 TI - The role of bioinformatics in studying rheumatic and autoimmune disorders. AB - In the past decade, the availability and abundance of individual-level molecular data, such as gene expression, proteomics and sequence data, has enabled the use of integrative computational approaches to pose and answer novel questions about disease. In this article, we discuss several examples of applications of bioinformatics techniques to study autoimmune and rheumatic disorders. We focus our discussion on how integrative techniques can be applied to analyze gene expression and genetic variation data across different diseases, and discuss the implications of such analyses. We also outline current challenges and future directions of these approaches. We show that integrative computational methods are essential for translational research and provide a powerful opportunity to improve human health by refining the current knowledge about diagnostics, therapeutics and mechanisms of disease pathogenesis. PMID- 21691331 TI - Peripheral neuropathy: discovering the 'Bumps': a new method to measure symptoms of peripheral neuropathy. PMID- 21691332 TI - Parkinson disease: sniffing out dementia. PMID- 21691333 TI - Neuroimmunology: estrogen receptor ligands suppress inflammatory responses in astrocytes and microglia. PMID- 21691334 TI - Peripheral neuropathies: clinical prognostic scales in Guillain-Barre syndrome. PMID- 21691335 TI - Stroke: CT angiography offers improved prediction of outcome. PMID- 21691336 TI - Alzheimer disease: bifunctional therapeutic antibody. PMID- 21691338 TI - The collagen VI-related myopathies: muscle meets its matrix. AB - The collagen VI-related myopathy known as Ullrich congenital muscular dystrophy is an early-onset disease that combines substantial muscle weakness with striking joint laxity and progressive contractures. Patients might learn to walk in early childhood; however, this ability is subsequently lost, concomitant with the development of frequent nocturnal respiratory failure. Patients with intermediate phenotypes of collagen VI-related myopathy display a lesser degree of weakness and a longer period of ambulation than do individuals with Ullrich congenital muscular dystrophy, and the spectrum of disease finally encompasses mild Bethlem myopathy, in which ambulation persists into adulthood. Dominant and recessive autosomal mutations in the three major collagen VI genes-COL6A1, COL6A2, and COL6A3-can underlie this entire clinical spectrum, and result in deficient or dysfunctional microfibrillar collagen VI in the extracellular matrix of muscle and other connective tissues, such as skin and tendons. The potential effects on muscle include progressive dystrophic changes, fibrosis and evidence for increased apoptosis, which potentially open avenues for pharmacological intervention. Optimized respiratory management, including noninvasive nocturnal ventilation together with careful orthopedic management, are the current mainstays of treatment and have already led to a considerable improvement in life expectancy for children with Ullrich congenital muscular dystrophy. PMID- 21691339 TI - Risk assessment of esophageal variceal bleeding in B-viral liver cirrhosis by a liver stiffness measurement-based model. AB - OBJECTIVES: Periodic endoscopic screening for esophageal varices (EVs) and prophylactic treatment for high-risk EVs (HEVs; (i) medium/large EVs and (ii) small EVs with red sign or decompensated cirrhosis) are recommended for cirrhotic patients. We assessed cumulative risks of future EV bleeding (EVB) using the liver stiffness measurement (LSM)-based model, LSM-spleen diameter to platelet ratio score (LSPS=LSM*spleen diameter/platelet count). METHODS: We prospectively enrolled 577 consecutive B-viral cirrhosis patients from 2005 to 2009, none of whom experienced EVB. All underwent laboratory workups, endoscopy, LSM, and ultrasonography. Those with HEVs took nonselective beta-blockers as prophylaxis for EVB after diagnosis, if not contraindicated. The major end point was the first EVB event, examined using Kaplan-Meier and Cox-regression methods. RESULTS: Among whole population, 95.9% negative- /93.5% positive-predictive value by LSPS<3.5/LSPS>=5.5 were provided for predicting the presence of HEV at enrollment, respectively. Among patients with HEV (n=150), 25 experienced their first EVBs during follow-up (median, 29 months). To differentiate EVB risk, we divided them into subgroup 1 (LSPS<6.5) and 2 (LSPS>=6.5) according to LSPS 6.5, a point with maximum sum of sensitivity and specificity from time-dependent receiver-operating characteristic (ROC) curves (area under ROC curve=0.929). EVB risk was higher in subgroup 2 than subgroup 1 (P<0.001). Multivariate analysis found higher LSPS (P=0.003) a significant predictor, alongside large variceal sizes (P=0.004) and Child-Pugh classifications B/C (P=0.001). Notably, EVB risk of subgroup 1 was as low as that of low-risk EVs (P=0.507). CONCLUSIONS: LSPS is a reliable predictor for EVB risk. According to risk stratification, different prophylactic treatments should be considered for subgroups with LSPS>=6.5. PMID- 21691340 TI - Prevalence of celiac disease in healthy Turkish school children. AB - OBJECTIVES: Epidemiological studies of celiac disease (CD) in Turkey have been performed only within some regions of the country. The aim of this study was to determine the prevalence of CD in Turkish school children. METHODS: Between 2006 and 2008, serum samples were collected from 20,190 students (age range, 6-17 years) in 139 schools in 62 cities from different regions of Turkey. CD was screened using IgA antitissue transglutaminase (IgA-tTG) and total serum IgA. Subjects with selective IgA deficiency were further tested for IgG-tTG. Serum samples positive for IgA or IgG-tTG were further tested for IgA antiendomysial antibodies (IgA-EMAs) using an indirect immunofluorescence method. Small intestinal biopsy was offered to all subjects with tTG antibody positivity. RESULTS: Of the 20,190 subjects, 489 were antibody positive (IgA-tTG only in 270, both IgA-tTG and IgA-EMA in 215, and IgG-tTG in 4). Selective IgA deficiency was detected in 108 patients, and 4 of them were positive for IgG-tTG. An intestinal biopsy was conducted in 215 subjects (IgA-tTG positive in 110, IgA-tTG and IgA EMA positive in 104, and IgG-tTG positive in 1). The biopsy findings of 95 children were consistent with CD. Thus, the estimated biopsy-proven prevalence was 1:212 children. The positive predictive value (PPV) for IgA-tTG plus EMA was 75.9%. PPV was 44.3% when only IgA-tTG was used. CONCLUSIONS: We estimate that the prevalence of CD is at least 0.47% in healthy Turkish school children. Screening for IgA-tTG plus EMA provided better results for diagnosis when compared with testing for IgA-tTG alone. PMID- 21691341 TI - Mindfulness training reduces the severity of irritable bowel syndrome in women: results of a randomized controlled trial. AB - OBJECTIVES: This prospective, randomized controlled trial explored the feasibility and efficacy of a group program of mindfulness training, a cognitive behavioral technique, for women with irritable bowel syndrome (IBS). The technique involves training in intentionally attending to present-moment experience and non-judgmental awareness of body sensations and emotions. METHODS: Seventy-five female IBS patients were randomly assigned to eight weekly and one half-day intensive sessions of either mindfulness group (MG) training or a support group (SG). Participants completed the IBS severity scale (primary outcome), IBS-quality of life, brief symptom inventory-18, visceral sensitivity index, treatment credibility scale, and five-facet mindfulness questionnaire before and after treatment and at 3-month follow-up. RESULTS: Women in the MG showed greater reductions in IBS symptom severity immediately after training (26.4% vs. 6.2% reduction; P=0.006) and at 3-month follow-up (38.2% vs. 11.8%; P=0.001) relative to SG. Changes in quality of life, psychological distress, and visceral anxiety were not significantly different between groups immediately after treatment, but evidenced significantly greater improvements in the MG than in the SG at the 3-month follow-up. Mindfulness scores increased significantly more in the MG after treatment, confirming effective learning of mindfulness skills. Participants' ratings of the credibility of their assigned interventions, measured after the first group session, were not different between groups. CONCLUSIONS: This randomized controlled trial demonstrated that mindfulness training has a substantial therapeutic effect on bowel symptom severity, improves health-related quality of life, and reduces distress. The beneficial effects persist for at least 3 months after group training. PMID- 21691342 TI - A prospective study to compare a symptom-based reflux disease questionnaire to 48 h wireless pH monitoring for the identification of gastroesophageal reflux (revised 2-26-11). AB - OBJECTIVES: The gastroesophageal reflux disease questionnaire (GerdQ) is a validated questionnaire that identifies patients with gastroesophageal reflux disease (GERD). The aim of this study was to prospectively evaluate the association between GerdQ scores and 48-h wireless pH recording in patients studied either on or off acid suppression. METHODS: Demographics, symptoms, acid suppressant use, and GerdQ scores were obtained from consecutive patients referred for wireless pH testing; 48-h pH data and endoscopic findings were recorded. Multivariate logistic regression models controlling for age, gender, and body mass index (BMI) were used to evaluate the association between GerdQ scores, acid reflux, and symptom association probability (SAP) scores. RESULTS: Wireless pH-metry was completed in 180 patients off proton pump inhibitor (PPI) (mean (s.d.) age, 50 (14) years; BMI, 28.08 (6.87) kg/m(2)) and 178 patients on PPI (mean (s.d.) age, 52 (14) years; BMI, 29.00 (6.90) kg/m(2)). Abnormal acid exposure was noted in 26% of patients on and 61% off PPI therapy. The odds of an abnormal study were 5.04 (95% confidence interval (CI), 3.14-8.11) times greater in patients studied off PPI therapy compared with patients studied on PPI therapy. The odds ratio of the SAP being >95% was 5.69 (95% CI, 3.36-9.64; P<0.001) for patients studied off PPI therapy compared with on PPI therapy. The mean (s.d.) GerdQ score was 7.48 (4.53) in patients on PPI therapy and 9.11 (1.25) in patients off PPI therapy (P<0.001). The odds of having an abnormal pH study was 1.08 (95% CI, 0.99-1.16; P=0.07) in patients studied off PPI therapy and 1.00 (95% CI, 0.92-1.08; P=0.94) in patients on PPI therapy for each point increase on the GerdQ. The odds of an abnormal SAP 95% in patients studied off PPI therapy was 1.18 (95% CI, 1.09-1.28; P<0.001) and 1.10 (95% CI, 1.01-1.21; P<0.03) in patients studied on PPI therapy for each point increase in the GerdQ score. CONCLUSIONS: Higher GerdQ scores were predictive of an abnormal pH study in patients studied off PPI therapy. Compared with wireless pH capsule monitoring, the GerdQ has only modest sensitivity and specificity at diagnosing acid reflux and thus cannot be recommended as a screening tool for GERD. PMID- 21691343 TI - Method for designing phase-calculation algorithms for two-dimensional grating phase-shifting interferometry. AB - We propose a design method of phase-analysis algorithms based on two-dimensional grating phase shifting for Talbot interferometry, Talbot-Lau imaging, or the Ronchi test. These algorithms are designed to separate the two orthogonal shearing wavefronts and eliminate error effects of unwanted diffraction orders, simultaneously. Taking the effect of multidiffraction into account, moving the two-dimensional grating along a certain pass leads to a series of phase-shifted interfrograms, from which two orthogonal shearing wavefronts are derived, for the tested wavefront to be retrieved. The designing process is demonstrated, and the residual errors are analyzed via simulation works and experimental comparison. PMID- 21691344 TI - Measurement of the surface profile of a curved optical surface with rotation phase-shifting lateral shear cyclic path optical configuration. AB - We present a new (to our knowledge) technique for introducing phase shifts between the laterally sheared emergent beam components of a cyclic path optical configuration (CPOC). The phase shifts are introduced by applying a small change in the angle of incidence of the incident beam due to the small angular rotation of the CPOC setup. Phase-shifting interferometry has been applied along with this phase-shifting technique for a CPOC with lateral shear to find the surface slope/profile of curved optical surfaces. Results for a spherical optical surface have been discussed. An optical setup for measurement of the surface profile of toroidal beam line mirrors of synchrotron radiation sources is proposed. PMID- 21691345 TI - Multiwavelength picosecond and single wavelength femtosecond pulses emission in a passively mode-locked fiber laser using a semiconductor saturable absorber mirror and a contrast ratio tunable comb filter. AB - We propose and demonstrate a highly flexible fiber laser capable of generating stable multiwavelength picosecond and single wavelength femtosecond pulses by using a semiconductor saturable absorber mirror and a contrast ratio tunable comb filter. In the multiwavelength lasing regime, up to 11-wavelength stable mode locked pulses in 3 dB bandwidth with a channel spacing of 0.8 nm were obtained. While in the single wavelength with broadband spectrum lasing regime, the fiber laser emitted 576 fs soliton pulse. Through changing the contrast ratio of the comb filter, the conversion between the multiwavelength picosecond and single wavelength femtosecond pulsed operations could be efficiently achieved. PMID- 21691346 TI - Method for studying the effects of thermal deformations on optical systems for space application. AB - In this paper, the results of the thermo-elastic analysis performed on the stereo channel of the imaging system Integrated Observatory System for the BepiColombo European Space Agency mission to Mercury are presented. The aim of the work is to determine the effects of ambient parameter variations on the equipment performance; the optical performance is changing during the mission lifetime primarily because of the optics misalignments and deformations induced by temperature variations. The camera optics and their mountings are modeled and processed by a thermo-mechanical finite element model (FEM) program, which reproduces the expected optics and structure thermo-elastic deformations in the instrument foreseen operative temperature range, i.e., between -20 degrees C and 30 degrees C. The FEM outputs are elaborated using a MATLAB optimization routine: an algorithm based on nonlinear least square data fitting is adopted to determine the surface equation (plane, spherical, nth polynomial) which best fits the deformed optical surfaces. The obtained surfaces are then directly imported into a ZEMAX code for sequential ray-tracing analysis. Variations of the optical spot diagrams, modulation transfer function curves, and ensquared energy are then computed. The overall analysis shows that the preferred solution for mounting the optical elements is adopting the kinematic constraints instead of using the classical glue solution. PMID- 21691347 TI - Enhancement of localized surface plasmon resonance detection by incorporating metal-dielectric double-layered subwavelength gratings. AB - In this study, we investigated the enhanced sensing performance of a localized surface plasmon resonance (LSPR) biosensor by employing metal-dielectric double layered subwavelength grating structures. The numerical results showed that the LSPR substrate with a dielectric spacer can provide not only a better sensitivity but also a significantly improved reflectance characteristic. While the presence of metallic gratings leads to a broad and shallow reflectance curve inevitably, the dielectric spacer can prevent the propagating surface plasmons from being interfered by the locally enhanced fields excited at the gold gratings, finally resulting in a strong and deep absorption band at resonance. Therefore, the proposed structure could potentially open a new possibility of the enhanced LSPR detection for monitoring biomolecular interactions of low molecular weights. PMID- 21691348 TI - Three-dimensional polarization ray-tracing calculus I: definition and diattenuation. AB - A three-by-three polarization ray-tracing matrix method for polarization ray tracing in optical systems is presented for calculating the polarization transformations associated with ray paths through optical systems. The method is a three-dimensional generalization of the Jones calculus. Reflection and refraction algorithms are provided. Diattenuation of the optical system is calculated via singular value decomposition. Two numerical examples, a three fold mirror system and a hollow corner cube, demonstrate the method. PMID- 21691349 TI - Three-dimensional polarization ray-tracing calculus II: retardance. AB - The concept of retardance is critically analyzed for ray paths through optical systems described by a three-by-three polarization ray-tracing matrix. Algorithms are presented to separate the effects of retardance from geometric transformations. The geometric transformation described by a "parallel transport matrix" characterizes nonpolarizing propagation through an optical system, and also provides a proper relationship between sets of local coordinates along the ray path. The proper retardance is calculated by removing this geometric transformation from the three-by-three polarization ray-tracing matrix. Two rays with different ray paths through an optical system can have the same polarization ray-tracing matrix but different retardances. The retardance and diattenuation of an aluminum-coated three fold-mirror system are analyzed as an example. PMID- 21691350 TI - Level crossing statistics for optical beam wander in a turbulent atmosphere with applications to ground-to-space laser communications. AB - Level crossing statistics is applied to the complex problem of atmospheric turbulence-induced beam wander for laser propagation from ground to space. A comprehensive estimate of the single-axis wander angle temporal autocorrelation function and the corresponding power spectrum is used to develop, for the first time to our knowledge, analytic expressions for the mean angular level crossing rate and the mean duration of such crossings. These results are based on an extension and generalization of a previous seminal analysis of the beam wander variance by Klyatskin and Kon. In the geometrical optics limit, we obtain an expression for the beam wander variance that is valid for both an arbitrarily shaped initial beam profile and transmitting aperture. It is shown that beam wander can disrupt bidirectional ground-to-space laser communication systems whose small apertures do not require adaptive optics to deliver uniform beams at their intended target receivers in space. The magnitude and rate of beam wander is estimated for turbulence profiles enveloping some practical laser communication deployment options and suggesting what level of beam wander effects must be mitigated to demonstrate effective bidirectional laser communication systems. PMID- 21691351 TI - Investigation on the panchromaticity of silver-doped poly(vinyl alcohol)/acrylamide photopolymer. AB - An investigation on the panchromaticity of a silver-doped poly(vinyl alcohol)/acrylamide photopolymer system is presented in this paper. Frequency doubled Nd:YAG (532 nm) and Ar+ (488 nm) lasers were used for the characterization of the films. Previous studies using an He-Ne laser (632.8 nm) showed that plane-wave transmission grating with a high diffraction efficiency of 75% could be stored in the optimized film. From the present study, it was noted that transmission gratings with 70% diffraction efficiency could be recorded using Ar+ and Nd:YAG lasers, thereby elucidating the possibility of using the developed photopolymer system as a competent panchromatic recording medium. PMID- 21691352 TI - Reconstruction dynamics of recorded holograms in photochromic glass. AB - We have investigated the dynamics of the record-erase process of holograms in photochromic glass using continuum Nd:YVO4 laser radiation (lambda=532 nm). A bidimensional microgrid pattern was formed and visualized in photochromic glass, and its diffraction efficiency decay versus time (during reconstruction step) gave us information (D, Deltan) about the diffusion process inside the material. The recording and reconstruction processes were carried out in an off-axis setup, and the images of the reconstructed object were recorded by a CCD camera. Measurements realized on reconstructed object images using holograms recorded at a different incident power laser have shown a two-stage process involved in silver atom kinetics. PMID- 21691353 TI - Compensation for time fluctuations of phase modulation in a liquid-crystal-on silicon display by process synchronization in laser materials processing. AB - We demonstrate the adverse influence of temporal fluctuations of the phase modulation of a spatial light modulator (SLM) display device on nanosecond laser micromachining. We show that active cooling of the display reduces the amplitude of these fluctuations, and we demonstrate a process synchronization technique developed to compensate for these fluctuations when applying the SLM to laser materials processing. For alternative SLM devices developed specifically for laser wavefront control (which do not exhibit such flickering problems), we show that our process synchronization approach is also beneficial to avoid machining glitches when switching quickly between different phase profiles (and hence beam patterns). PMID- 21691354 TI - Investigation of THz birefringence measurement and calculation in Al2O3 and LiNbO3. AB - Based on the polarization-sensitive terahertz time-domain spectroscopy, we measured the birefringence for Al2O3 and LiNbO3 single crystals, which correspond to trigonal structures that have an uniaxial birefringence, in the THz frequency range of 0.25 to 1.4 THz. For more comprehensive understanding of the THz birefringence, the measured birefringence is compared with the results of ab initio calculations. The measured birefringence shows good agreement with the calculated value. PMID- 21691356 TI - Mesopause-region temperature and wind measurements with pseudorandom modulation continuous-wave (PMCW) lidar at 589 nm. AB - A study on the feasibility of using pseudorandom modulation continuous-wave (PMCW) Na lidar for mesopause-region temperature and horizontal wind measurements is presented with a number of specific geometries and associated beam-telescope overlap functions, suitable for ground-based and airborne deployments. The performance of these deployment scenarios is analyzed by scaling from the received signal and sky background and the measurement uncertainties in temperature and horizontal wind of the well-tested Colorado State University pulsed Na lidar. Using currently available high-power (~20 W) continuous-wave Na narrowband lasers, a compact PMCW bistatic Na lidar system can indeed be deployed to simultaneously measure mesopause-region temperature and horizontal winds on a 24 h continuous basis, weather permitting. PMID- 21691355 TI - Autostereoscopic three-dimensional display based on two parallax barriers. AB - An autostereoscopic three-dimensional (3D) display composed of a flat-panel display, two parallax barriers, and a backlight panel is proposed. Parallax barrier 1, located between the backlight panel and the flat-panel display, divides the lights to create the perception of stereoscopic images. Parallax barrier 2, located between the flat-panel display and the viewers, acts as the function of decreasing the cross talk of the stereoscopic images. The operation principle of the display and the calculation equations for the parallax barriers are described in detail. An autostereoscopic 3D display prototype is developed. The prototype presents high-quality stereoscopic images. At the optimal viewing distance, it presents stereoscopic images without cross talk. At other viewing distances, it has less cross talk than a conventional autostereoscopic 3D display based on one parallax. PMID- 21691357 TI - Beam shaping design for coupling high power diode laser stack to fiber. AB - A beam shaping technique that rearranges the beam for improving the beam symmetry and power density of a ten-bar high power diode laser stack is simulated considering a stripe mirror plate and a V-Stack mirror in the beam shaping system. In this technique, the beam of a high power diode laser stack is effectively coupled into a standard 550 MUm core diameter and a NA=0.22 fiber. By this technique, compactness, higher efficiency, and lower cost production of the diode are possible. PMID- 21691358 TI - Incorrect depth sense due to focused object distance. AB - In stereoscopy, stereoscopic depth distortion is a serious problem in terms of determining the correct depth sense. There have been few studies pertaining to the problem in terms of the focused object distance (FOD). In this investigation, we discuss the FOD as one of the factors inducing an incorrect depth sense in using common stereo camera systems and propose a method for compensating the incorrect depth sense, which is strongly related to the process of demagnifying the size of displayed stereo image on the screen. The incorrect depth sense increases when the FOD becomes shortened. Our method illustrates that the depth sense difference between a correct depth sense and an induced depth error is compensated completely. We verified the validation of our concerns by both a theoretical simulation and a practical experiment. PMID- 21691359 TI - Switchable and tunable multiple-channel erbium-doped fiber laser using graphene polymer nanocomposite and asymmetric two-stage fiber Sagnac loop filter. AB - A high-performance multiple-channel erbium-doped fiber laser (EDFL) is proposed and experimentally demonstrated, using graphene-polymer nanocomposite as a multiwavelength equalizer and an asymmetric two-stage polarization-maintaining fiber (PMF) Sagnac loop as a flexible comb filter. At first, the filtering characteristics of the PMF Sagnac loop filter (SLF) are investigated. Both theoretical and experimental results show that it can provide a flexibly switchable and tunable comblike filtering. Then, the two-stage PMF SLF is inserted into a graphene-assisted EDFL cavity for generating multiwavelength oscillation. The extreme-high third-order optical nonlinearity of graphene is exploited to suppress the mode competition of the EDFL, and a stable multiple channel lasing is observed. By carefully adjusting the polarization controllers in the two-stage PMF SLF, not only can the lasing-line number per channel be switchable between single and multiple wavelengths, but also the wavelength spacing in the triple-wavelength condition can be tunable. In the case of triple wavelengths per channel, up to 12 wavelengths with four channels stable oscillations can be achieved. The multiple-channel EDFL can keep a high extinction ratio of >40 dB and a narrow linewidth of <0.01 nm. PMID- 21691360 TI - Influence of altitude on aero-optic imaging deviation. AB - Aero-optic imaging deviation is a kind of aero-optic effect. It characterizes the image position displacement on an imaging plane. This paper studies the influence of altitude on aero-optic imaging deviation. The Reynolds-averaged Navier-Stokes solver provided in FLUENT was used for flow computations. The Runge-Kutta method based ray tracing was adopted for optics calculations. The orthogonal array was brought in for the experiment arrangement. Four representative suites of imaging deviations and imaging deviation slopes were obtained in the altitude range of 10 60 km. The results show that as altitude increases, the imaging deviation decreases, and the imaging deviation slope approaches zero from a negative value. PMID- 21691361 TI - Slope measurement of bent plates using double grating shearing interferometry. AB - A grating-based shearing interferometeric setup for slope measurement of bent plates has been proposed. The specimen under test is illuminated by a collimated beam from the laser. Light reflected from the specimen passes through two identical holographic gratings placed in tandem. The grating frequency has been so chosen that the diffracted orders from each grating are separated out distinctly. Two first-order beams diffracted from each of the gratings superpose in space. In the resulting interferogram, the fringes due to slope information of the object are visualized. Mathematical formulation for experimental determination of slope values has been undertaken. Validation of the experimental results with theoretical predictions in case of cantilever beam provides good correlation. The main advantage of the technique has been the realization of very compact geometry without the need for spatial filtering arrangement commonly associated with the grating-based techniques used to date. PMID- 21691362 TI - Ion-exchanged silica-on-silicon structured channel erbium-doped waveguide amplifiers. AB - Silica-on-silicon structured channel erbium-doped waveguide amplifiers (EDWAs) were fabricated by a combination of the ion-exchange and sol-gel techniques. A small signal fiber-device-fiber net gain of 0.5 dB at 1531 nm was obtained for a 4 cm long EDWA with an optimized waveguide structure. The low noise figure of 4.0 dB was also achieved. Samples of different waveguide structures and rare-earth ion doping levels were fabricated to compare the EDWA gain properties. The results demonstrate that a better gain spectrum can be obtained by maximizing the distribution overlap of pump and signal mode intensity. The gain performance can be further improved by reducing upconversion efficiency of the EDWA. This work demonstrates that the ion-exchanged silica-on-silicon waveguide structure is an alternative approach for EDWA fabrication. PMID- 21691363 TI - Spectroscopic ellipsometer based on direct measurement of polarization ellipticity. AB - A polarizer-sample-Wollaston prism analyzer ellipsometer is described in which the ellipsometric angles psi and Delta are determined by direct measurement of the elliptically polarized light reflected from the sample. With the Wollaston prism initially set to transmit p- and s-polarized light, the azimuthal angle P of the polarizer is adjusted until the two beams have equal intensity. This condition yields psi=+/-P and ensures that the reflected elliptically polarized light has an azimuthal angle of +/-45 degrees and maximum ellipticity. Rotating the Wollaston prism through 45 degrees and adjusting the analyzer azimuth until the two beams again have equal intensity yields the ellipticity that allows Delta to be determined via a simple linear relationship. The errors produced by nonideal components are analyzed. We show that the polarizer dominates these errors but that for most practical purposes, the error in psi is negligible and the error in Delta may be corrected exactly. A native oxide layer on a silicon substrate was measured at a single wavelength and multiple angles of incidence and spectroscopically at a single angle of incidence. The best fit film thicknesses obtained were in excellent agreement with those determined using a traditional null ellipsometer. PMID- 21691364 TI - Hole-assisted dual concentric core fiber with ultralarge negative dispersion coefficient of -13,200 ps/nm/km. AB - We propose a dual concentric core fiber (DCCF) with six homogeneous air holes, designed to realize a large negative dispersion coefficient. We clarify numerically that the dispersion property of the proposed DCCF can be controlled flexibly by adjusting the air-hole structure, and we realize the largest reported negative dispersion of -13,200 ps/nm/km experimentally. PMID- 21691365 TI - Depth fingerprint map of active range-gated imaging for real-time three dimensional measurement of foreground objects. AB - We present a depth fingerprint map to obtain three-dimensional (3D) spatial information from objects in a large deterministic background by active range gated imaging, for night remote surveillance. This method first gives the depth fingerprint map of the region of interest in the background by gate viewing in the form of contour bands in range. The map is then embedded in the range-gated laser surveillance system. Finally, 3D spatial information such as target scale and location can be estimated by segmenting the target from the background and matching them with the depth fingerprint map. The measurement is performed by computer background processing. Therefore, the method has no influence on the frame rate of surveillance systems and can realize real-time surveillance. In this paper, the approach to acquisition of the depth fingerprint map is also demonstrated without an echo-broadening effect. PMID- 21691366 TI - Relationships between water attenuation coefficients derived from active and passive remote sensing: a case study from two coastal environments. AB - Relationships between the satellite-derived diffuse attenuation coefficient of downwelling irradiance (K(d)) and airborne-based vertical attenuation of lidar volume backscattering (alpha) were examined in two coastal environments. At 1.1 km resolution and a wavelength of 532 nm, we found a greater connection between alpha and K(d) when alpha was computed below 2 m depth (Spearman rank correlation coefficient up to 0.96), and a larger contribution of K(d) to alpha with respect to the beam attenuation coefficient as estimated from lidar measurements and K(d) models. Our results suggest that concurrent passive and active optical measurements can be used to estimate total scattering coefficient and backscattering efficiency in waters without optical vertical structure. PMID- 21691367 TI - Analysis of the improvement in sky coverage for multiconjugate adaptive optics systems obtained using minimum variance split tomography. AB - The scientific utility of laser-guide-star-based multiconjugate adaptive optics systems depends upon high sky coverage. Previously we reported a high-fidelity sky coverage analysis of an ad hoc split tomography control algorithm and a postprocessing simulation technique. In this paper, we present the performance of a newer minimum variance split tomography algorithm, and we show that it brings a median improvement at zenith of 21 nm rms optical path difference error over the ad hoc split tomography control algorithm for our system, the Narrow Field Infrared Adaptive Optics System for the Thirty Meter Telescope. In order to make the comparison, we also validated our previously developed sky coverage postprocessing software using an integrated simulation of both high- (laser guide star) and low-order (natural guide star) loops. A new term in the noise model is also identified that improves the performance of both algorithms by more properly regularizing the reconstructor. PMID- 21691368 TI - Core-offset hollow core photonic bandgap fiber-based intermodal interferometer for strain and temperature measurements. AB - A novel core-offset hollow core photonic bandgap fiber (HCPBF) based intermodal interferometer is presented. It is fabricated by splicing a section of HCPBF between two single mode fibers with a slight core offset at one splice joint. The fabrication process only involves splicing and cleaving. Its applications for strain and temperature measurements are also demonstrated. Its strain and temperature sensitivities are -1.17 pm/MUepsilon and 6.66 pm/ degrees C, respectively. PMID- 21691369 TI - Characterization of zone plate properties using monochromatic synchrotron radiation in the 2 to 20 nm wavelength range. AB - A zone plate composed of Mo zones having 4 mm outermost zone diameter, 100 nm outermost zone width, and supported on a silicon nitride membrane was characterized using monochromatic synchrotron radiation in the 2 to 20 nm wavelength range. The zero and first order efficiencies were measured and compared to ab initio calculations that account for the optical properties of the materials, the width and shape of the zones, and multiple-layer thin-film effects. It is shown that the thicknesses of the Mo zones and the membrane and the ratio of the zone width to zone period can be independently determined from the measured diffraction efficiencies in the zero and first orders and that the computational code can be used to reliably design zone plates that are optimized for applications such as solar irradiance monitors in the extreme ultraviolet region. PMID- 21691370 TI - Spatial coherence effect on layer thickness determination in narrowband full field optical coherence tomography. AB - Longitudinal spatial coherence (LSC) is determined by the spatial frequency content of an optical beam. The use of lenses with a high numerical aperture (NA) in full-field optical coherence tomography and a narrowband light source makes the LSC length much shorter than the temporal coherence length, hence suggesting that high-resolution 3D images of biological and multilayered samples can be obtained based on the low LSC. A simplified model is derived, supported by experimental results, which describes the expected interference output signal of multilayered samples when high-NA lenses are used together with a narrowband light source. An expression for the correction factor for the layer thickness determination is found valid for high-NA objectives. Additionally, the method was applied to a strongly scattering layer, demonstrating the potential of this method for high-resolution imaging of scattering media. PMID- 21691371 TI - Impact of atmospheric clutter on Doppler-limited gas sensors in the submillimeter/terahertz. AB - It is well known that clutter (spectral interference) from atmospheric constituents can be a severe limit for spectroscopic point sensors, especially where high sensitivity and specificity are required. In this paper, we will show for submillimeter/terahertz (SMM/THz) sensors that use cw electronic techniques the clutter limit for the detection of common target gases with absolute specificity (probability of false alarm ? 10-10) is in the ppt (1 part in 1012) range or lower. This is because the most abundant atmospheric gases are either transparent to SMM/THz radiation (e.g., CO2) or have spectra that are very sparse relative to the 105 Doppler-limited resolution elements available (e.g., H2O). Moreover, the low clutter limit demonstrated for cw electronic systems in the SMM/THz is independent of system size and complexity. PMID- 21691372 TI - Midwave infrared optical zooming design and kinoform degrading evaluation methods. AB - In this study, an optical zooming design method is constructed by ray tracing. The loci of each thin lens is determined utilizing algebraic relationships. A mechanical compensation structure is adapted to stabilize the position of the focal plane. The Gaussian design result is applied for the midwave infrared spectrum, and aberrations can be reduced by controlling the geometric parameters of the thick lens. One hybrid achromatic singlet is introduced utilizing a diffraction optical element. The kinoform surface relief is calculated being the same as its microfabrication process. The effects of the discontinuous zonal profile and the thermal degradation are evaluated. PMID- 21691373 TI - Off-axis detection and characterization of laser beams in the maritime atmosphere. AB - Remote detection and characterization of laser beams propagating in maritime atmospheres is discussed. A model for off-axis scattered laser light based on Mie scattering from maritime aerosols is presented and compared with angle and time resolved measurements from a pulsed laser source. We demonstrate that the direction of the source can be determined from the angle-resolved intensity and that the beam direction can be determined from arrival times of the scattered signals if the position of the laser source is known. PMID- 21691374 TI - Analysis on the polarization property of the eigenmodes in a nonplanar ring resonator. AB - Based on the theory of the Abeles matrix, the reflections from the multilayer dielectric mirrors in a nonplanar ring resonator are discussed in detail considering the imperfect layer thickness and the incident angle errors. The polarization of Gaussian beams in nonplanar ring resonators are analyzed by using a statistical method and the way to analyze the stability of a nonplanar ring resonator in the perspective of polarization is also presented. The results show that a nonlanar ring resonator with a finite mode size may not have the reasonable polarization performances sometimes; the eigenmodes might be right- and left-handed elliptically polarized instead of circularly polarized, and they also have different ellipticity and round trip losses, which are critical for a nonplanar ring resonator. These interesting findings are important to the cavity designs of ring resonators with a nonplanar structure. PMID- 21691375 TI - [The PARTNER study]. PMID- 21691376 TI - [Risk stratification in Brugada syndrome]. AB - Individuals with type 1 Brugada ECG pattern may suffer from malignant ventricular arrhythmias (Brugada syndrome). Patients with Brugada syndrome and documented cardiac arrest should receive an implantable cardioverter-defibrillator. In the remaining subjects, the best management is controversial. Many data suggest that patients with syncope, particularly if they have a spontaneous type 1 ECG pattern, have a significant risk. In the remaining population of asymptomatic subjects, the risk is lower but not negligible. How to manage these latter cases is an unsolved issue. The usefulness of the electrophysiological study (EPS) in risk stratification, i.e. inducibility of sustained ventricular tachycardia/fibrillation, is controversial. Indeed, some authors strongly support the prognostic value of EPS, while others completely deny its usefulness. We recently published our experience concerning the usefulness of a combined approach that considered both clinical data and EPS results; 320 patients (258 males, mean age 43 years) with type 1 ECG were enrolled. No patient had previous cardiac arrest; 54% of patients had a spontaneous and 46% a drug-induced type 1 ECG. One third had syncope, two thirds were asymptomatic; 245 patients underwent EPS; 110 patients received an implantable defibrillator. Patients were followed up for 40 months. During follow-up, 17 patients had major arrhythmic events (MAE) (14 resuscitated ventricular fibrillations and 3 sudden deaths). Both spontaneous type 1 ECG and syncope significantly increased the risk (8.6% and 10.4% event rates vs 2.8% and 1.3%). MAE occurred in 14% of subjects with positive EPS, in no subjects with negative EPS, and in 5.3% of subjects without EPS. All MAE occurred in subjects who had >= 2 risk factors (syncope, family history of sudden death and positive EPS). Among these patients, those with spontaneous type 1 ECG had a 30% event rate. In subjects with drug-induced type 1 MAE were rare. In conclusion, 1) in subjects with the Brugada type 1 ECG neither a single clinical risk factor nor EPS alone are able to identify subjects at the highest risk; 2) a multiparametric approach (including syncope, family history of sudden death and positive EPS) helps to identify populations at the highest risk; 3) subjects at the highest risk are those with a spontaneous type 1 ECG and >= 2 risk factors; 4) the remainder is at low risk. PMID- 21691377 TI - [The ECG in pediatric patients: what the cardiologist needs to know]. AB - During life ECG is always changing according to postnatal circulation adaptation, position of the heart in the chest, and body mass. Reference values and normal morphologies of P wave, PR interval, QRS complex, ST segment, T wave, and QTc interval are reported. Some clues to detect congenital and acquired heart diseases are also provided. Finally, a brief look at the most common diseases and arrhythmias in the neonatal and pediatric period is reported. When the pediatric ECG is too "young" for a cardiologist? When we need to stop doing the report? ... never! The baby is the father of the adult. The heart is made of signs: we have to decipher them. PMID- 21691378 TI - [Transradial access for percutaneous coronary and non-coronary interventions]. AB - The transfemoral access is still the most widely used approach for percutaneous coronary and non-coronary interventions. However, the transradial access has been increasingly used, mostly because it is associated with less hemorrhagic complications. The present review is aimed at evaluating the use of the transradial access for percutaneous vascular interventions. In many institutions, the radial artery is already the preferred vascular access for coronary procedures for routine coronary angiography but also for complex interventions such as primary angioplasty and angioplasty for stenosis at coronary bifurcations or coronary bypass grafts, or for treating chronic coronary occlusions. The radial artery can be used also as a vascular access for percutaneous peripheral interventions. Supra-aortic vessels (carotid, subclavian and vertebral arteries) can be treated via the radial route when obstructions of the femoro-iliac tract preclude groin access or also to circumvent anatomic variations such as bovine aortic arch. For renal artery angioplasty, the transradial access can be considered ideal for anatomic reasons, at least for those operators who use this access routinely for coronary interventions. At present, the transradial access can also be used, although in specific cases, to treat stenosis of the lower limb arteries in above the knee segments. PMID- 21691379 TI - [The heart and its unparalleled symbolism in faith, art and science]. PMID- 21691380 TI - [Extensive disease of the thoracic aorta: hybrid treatment with the frozen elephant trunk technique]. AB - BACKGROUND: Aneurysms of the aortic arch extending beyond the origin of the left subclavian artery represent a challenging pathology in aortic surgery and, most commonly, are treated with different surgical, endovascular or hybrid two-staged procedures. In 2006, we initiated an intense surgical program with the frozen elephant trunk procedure that, combining together conventional surgery with endovascular techniques, allows single-stage treatment of patients with extended disease of the thoracic aorta. We here describe our surgical technique and the results with the single-stage frozen elephant trunk procedure. METHODS: Between January 2007 and August 2010, 87 patients were treated with the frozen elephant trunk procedure in our institution. The mean age was 62 +/- 10 years. Indications for surgery included: chronic aneurysm (n=28; 32.2%), acute type A dissection (n=5; 5.7%), acute type B dissection (n=2; 2.3%), chronic type A dissection (n=41; 47.2%), chronic type B dissection (n=11; 12.6%). Forty-nine patients (56.4%) had undergone previous cardiac/aortic operations. Sixty-four associated aortic/cardiac operations were performed. RESULTS: Hospital mortality was 12.6%. Postoperatively, major neurological complications occurred in 4 patients (4.5%) and paraplegia in 6 (6.9%). Follow-up was 100% completed at a mean time of 15.0 +/- 12.4 months. Estimated 3-year survival was 72.7 +/- 8.3%. Endovascular extension was required in 14 patients (16.0%) with a technical/procedural success of 100%. CONCLUSIONS: Our preliminary results with the frozen elephant trunk in the above-mentioned high-risk group of patients were encouraging. The frozen elephant trunk, as a single-stage hybrid procedure, avoids peculiar drawbacks of staged procedures such as cumulative mortality of two major aortic procedures, interval mortality and failure to complete the final stage. PMID- 21691381 TI - [The Mattone Outcome-BYPASS study: short-term outcome in patients undergoing coronary artery bypass graft surgery in Italian hospitals. Final results]. AB - BACKGROUND: In early 2008, a new national prospective study on short-term outcomes of coronary artery bypass graft (CABG) procedures started in Italy. The aim was to describe short-term results in patients undergoing CABG and improve methodologies for comparative outcome evaluation. METHODS: Only 26 Italian cardiac surgery centers participated in this survey. For each patient undergoing a CABG procedure, all centers were requested to provide specific data (type of procedure, hemodynamic conditions, comorbidities, recent myocardial infarction and unstable angina, ventricular function, emergency conditions, vital status at 30 days). Representativeness was tested by comparing characteristics of the enrolled population with information derived from national hospital discharge records. A multiple logistic regression analysis was used to perform indirect standardization; the mortality rate of the whole population was used as a reference standard. Comparison with the CABG model built on 34 310 patients in 2002-2004 was performed as well. RESULTS: The analysis of 7436 isolated CABG procedures showed a 30-day mortality of approximately 2%. The study population seemed to be representative of the Italian population of CABG patients. Using the new estimate model, two cardiac surgery centers showed significantly better risk adjusted mortality rates than the national reference standard, and two others showed significantly worse rates. The application of the "CABG model" yielded similar results. CONCLUSIONS: Our study shows a high-quality level of Italian cardiac surgery centers and confirms the good applicability of the CABG model to the Italian CABG population. Comparison between results from the two models highlights the usefulness of regular outcome studies either for updating risk adjustment procedures and monitoring quality of care in Italian hospitals. PMID- 21691382 TI - [Consensus document on remote monitoring of cardiac implantable electronic devices: technology, indications, organizational models, acceptability, responsibility, and economic issues]. PMID- 21691384 TI - Unusual stab wound of the spinal cervical cord caused by a screw driver. AB - We present a case of dorsal cervical spinal cord injury in a 16-year-old boy caused by a screwdriver. Neurological deficits were hypaesthesia of the right body and neurovegetative functional deficits. Magnetic resonance imaging showed significant myelopathy and a subdural haematoma of the cervical spine. Surgical treatment was not necessary. Rheological infusions, lumbar puncture and rehabilitation resulted in full neurological recovery. PMID- 21691386 TI - Acute haemorrhagic rectal ulcer in fulminant hepatitis. PMID- 21691385 TI - Acquired von Willebrand syndrome in a 10-year-old girl with acute lymphoblastic leukaemia. AB - Following diagnosis of acute lymphoblastic leukaemia (ALL) in a 10-year-old girl, routine coagulation screening including von Willebrand factor antigen (VWF:Ag), ristocetin cofactor activity (VWF:RCo) and factor VIIIC (FVIII:C) detected no pathological findings. After the first HR2' element of the high-risk group of the ALL-BFM 2000 protocol, the patient demonstrated extensive bleeding symptoms and acquired von Willebrand syndrome was diagnosed. VWF:Ag (13%), VWF:RCo (13%) and FVIII:C (27%) were decreased. Multimer analysis showed a loss of large multimers and a loss in triplet structures. The observed pattern was thought to be typical for monoclonal IgG gammopathy; however, in this case, unexpectedly, biclonal IgM gammopathy (kappa and lambda) was detected. After treatment with intravenous immunoglobulin over 5 days, coagulation factors increased to normal levels. Although this effect was assumed to be at best only temporary, especially in a case of IgM gammopathy, no further bleeding symptoms have been observed. TRIAL REGISTRATION NUMBER: M208. PMID- 21691387 TI - Mycobacterium marinum infection. PMID- 21691388 TI - Modified Giemsa method for confirmation of Pneumocystis pneumonia in low-income countries. AB - An HIV-seropositive man who presented with cough, low-grade fever and difficulty in breathing was admitted to the pulmonology unit at Mulago Hospital in Kampala, Uganda. He was initially diagnosed with bacterial pneumonia and treated with ceftriaxone without significant improvement. Induced sputum and bronchoalveolar lavage specimens were collected and stained using a modified Giemsa stain (Diff Quik). With this technique, it was possible to demonstrate cystic and trophic forms of Pneumocystis jirovecii and confirm the diagnosis of Pneumocystis pneumonia in this patient. PMID- 21691389 TI - Transient hypopituitarism in a patient with nephropathia epidemica. AB - Involvement of the pituitary gland is only rarely observed in hantavirus infection. This report describes the case of a patient who had transient hypopituitarism requiring hormonal replacement therapy due to hypophysitis as a result of Puumala virus infection. MRI studies revealed oedematous swelling of the gland as a morphological correlate. This report provides new evidence that hypopituitarism can be a serious complication in Puumala virus infection and highlights the clinical implications of this disorder. PMID- 21691391 TI - Intrahepatic splenosis mimicking hepatoma. AB - A 54-year-old man with a past history of splenectomy some 20 years previously presented with a hepatic mass. Subsequent histopathology revealed that the mass was due to intrahepatic splenosis. The presentation of this case is discussed together with a literature review of splenosis. PMID- 21691390 TI - Bilateral vertebral artery occlusion with retrograde basilary flow in three cases of giant cell arteritis. AB - Vertebrobasilar ischaemia is a rare life-threatening complication in giant cell arteritis (GCA). We report three patients with bilateral vertebral artery occlusion. Neurovascular imaging, including CT-angiography, MR-angiography and colour-coded duplex sonography revealed flow reversal in the basilar artery as well as inflammation of the vertebral vessel wall. The first patient died from massive brainstem infarction, the other two patients survived the initial inflammatory phase of GCA. No stroke recurrence at 12 months' follow-up on warfarin and steroid treatment was observed. Bilateral distal vertebral artery occlusion and retrograde basilar artery flow persisted.Outcome in these patients is dependant on potent immunosuppression, concurrent atherosclerotic steno occlusive disease and presence and/or rapid development of sufficient collateral pathways into the vertebrobasilar circulation. The identification of patients with high risk of ischaemia due to compromised vertebrobasilar flow may be important to select adjunct treatment to immunosuppression, such as anticoagulation in GCA. PMID- 21691392 TI - Effect of high-intensity statin treatment in rheumatoid arthritis: a case with possible coronary atheroma regression and progression of rheumatoid valve degeneration. AB - Rheumatoid arthritis (RA) is complicated by high mortality from cardiovascular disease. Statins have been shown to reduce cardiovascular disease events by approximately 30% and to induce coronary atheroma regression. There is no such documentation in patients with RA. This report describes a 49-year-old patient with RA who developed coronary atherosclerosis and rheumatoid valve disease. She underwent coronary artery bypass graft operation with two bypasses and a biological aortic valve replacement. Simultaneously, she was started on atorvastatin 80 mg, and low-density lipoprotein cholesterol reached 1.79 mmol/l and high-density lipoprotein cholesterol reached 1.59 mmol/l. One year after the heart surgery, she developed rheumatoid disease of the mitral valve. Coronary angiography revealed no signs of filling defect in her native coronary arteries. This case indicates that high-dose statin treatment may induce coronary atheroma regression in RA patients and that the rheumatoid valve disease process is not modulated by statins. PMID- 21691393 TI - An unusual complication of endoscopic retrograde cholangiopancreatography (ERCP). PMID- 21691394 TI - Two generations of identical twins with ELN deletion. AB - We report a family with three generations of an ELN deletion. The grandfather was normal except for two inguinal herniotomies. The first generation identical twins had supravalvular aortic and multiple peripheral pulmonary artery stenoses. The second generation twins died during the neonatal period of myocardial infarcts. PMID- 21691395 TI - Acquired syndactyly in epidermolysis bullosa dystrophica. PMID- 21691396 TI - PNET/Ewing's sarcoma of the rectum: a case report and review of the literature. AB - A 34-year-old female presented with anorectal pain and rectal bleeding due to an extensive rectal tumour. A trephine loop ileostomy was fashioned and biopsies were initially reported to show a poorly differentiated cloacogenic carcinoma. CT revealed numerous liver metastases. A histological review and immunohistochemical studies subsequently favoured a primitive neuroectodermal tumour (PNET). Stem cell supported chemoradiotherapy resulted in complete resolution of her primary tumour and liver metastases. Serial CT scanning and endoscopy revealed no recurrence after 7 years of follow-up, when she presented with a malignant anal fissure. Imaging and subsequently abdominoperineal resection revealed no evidence of metastases from either the anal cancer or the PNET tumour. Histopathology showed a T1N0R0 basaloid squamous carcinoma originating from grade III squamous intraepithelial neoplasia with no obvious wart viral infection. PMID- 21691397 TI - Little old ladies' hernia: a clinical diagnostic conundrum. PMID- 21691398 TI - An unusual case of bilateral myositis ossificans in a young athlete. AB - This case report describes the occurrence of bilateral myositis ossificans in the rectus femoris muscles of a young Gaelic football player with a long history of recurrent bilateral thigh strain. In each case, clinical diagnosis was followed up with biochemical profiling and sonographic investigations. Management consisted of rest from elite level competition and intense rehabilitation to address any potential risk factors for rectus femoris strain. A 4-week course of acetic acid iontophoresis was administered to the first myositis ossificans lesion on the left thigh; however, as this did not result in any significant changes to the lesion's dimensions, it was not used on the contralateral lesion. The athlete returned to full sporting capacity 4 months after the first lesion was diagnosed. A 13-month follow-up showed that the athlete continued to play to full capacity with no recurrence of injury. PMID- 21691399 TI - Molecular identification of Borrelia crocidurae in a patient returning from Senegal. AB - Borrelia spp. are pathogens responsible for worldwide tickborne relapsing fever (TBRF). In West Africa, TBRF is due to a single species, Borrelia crocidurae, transmitted by the soft-body tick Ornithodoros sonrai. We report a case of B crocidurae infection in a French tourist in Senegal, diagnosed by molecular biology using 16S rDNA, flaB, and the 16S-23S intergenic spacer. We found six imported cases reported in travellers (since 1999). We review here clinical and molecular aspects and pathophysiology, and discuss diagnostic methods and therapeutic regimens. In the coming years, this emerging disease will be of concern to more and more travellers returning from disease-endemic regions. Thus, physicians must be aware of its presentation and diagnosis, since the spontaneous outcome can be severe, and a simple treatment is effective. PMID- 21691400 TI - Faecal peritonitis secondary to perforated recto sigmoid colon by a large gallstone: a case report. AB - Large bowel obstruction is an important surgical emergency. The cause of obstruction may be benign or malignant, and include large bowel volvulus, polyps, intraperitoneal adhesions, strictures and neoplastic growths. Large bowel obstruction caused by gallstone(s) is a very rare phenomenon and not many cases are reported in the English literature. The present report describes a case of large bowel obstruction and faecal peritonitis caused by a gallstone perforating sigmoid colon. A database search (PubMed) did not locate any cases of large bowel perforation by a gallstone in the English literature, and hence this case report may be the first on this subject. PMID- 21691401 TI - Cardiac arrhythmias associated with umbilical venous catheterisation in neonates. AB - Umbilical venous catheters (UVCs) are commonly used in the management of severely ill neonates. Several life-threatening complications have been described, including catheter-related infections, myocardial perforation, pericardial effusion and cardiac arrhythmias. This report describe two neonates with cardiac arrhythmias due to umbilical venous catheterisation. One neonate had a supraventricular tachycardia requiring treatment with intravenous adenosine administration. Another neonate had an atrial flutter and was managed successfully with synchronised cardioversion. The primary cause of cardiac arrhythmias after umbilical venous catheterisation is inappropriate position of the UVC within the heart and the first step to treat them should be to pull back or even remove the catheter. Cardiac arrhythmia is a rare but potentially severe complication of umbilical venous catheterisation in neonates. PMID- 21691402 TI - Cytomegalovirus retinitis in Good syndrome: case report and review of literature. AB - This report describes the case of a 59-year-old woman diagnosed with cytomegalovirus (CMV) retinitis. The diagnosis was suggested by a typical fundus appearance, and confirmed by a positive PCR for CMV of both serum and vitreous biopsy. HIV status was negative. The patient's medical history included thymoma followed by a thymectomy, recent multiple oral thrush infections, lower respiratory tract infections, urinary tract infections and severe weight loss. She had previously been treated for toxoplasma chorioretinitis and had vitrectomies for retinal detachment in the right eye. Immunological investigations revealed low T cells, almost absent B cells with reduced immunoglobulins consistent with the diagnosis of Good syndrome. The patient received treatment with intravenous ganciclovir, followed by maintenance valganciclovir, resulting in resolution of the ocular pathology. Immunoglobulin replacement therapy to boost the humoral immunity has been commenced. PMID- 21691403 TI - Bilateral pulmonary nodules in an adult patient with bronchiolitis obliterans organising pneumonia. AB - A 58-year-old male ex-smoker was admitted to hospital because of nodular infiltrates on chest x rays. He was complaining of fatigue, dyspnoea with exertion, low grade fever and weight loss. Physical examination was unremarkable. Bronchoscopy was inconclusive but revealed endobronchial lesions of chronic active inflammation. The diagnosis of cryptogenic organising pneumonitis bronchiolitis obliterans-organising pneumonia (COP-BOOP) was established by open lung biopsy. Proliferative bronchiolitis with regions of organising pneumonia is the characteristic feature of COP. The radiological picture of bilateral pulmonary nodules is an infrequent manifestation of COP. Lung biopsy, open or with video assistance thoracic surgery, is recommended to confirm the diagnosis. PMID- 21691404 TI - Sub-acute blindness in a patient with a temporal lobe astrocytoma. AB - This report describes an unusual case of a middle-aged man who suffered sub-acute visual loss rendering him blind over a period of 4 weeks, associated with the diagnosis of a right temporal lobe World Health Organization grade 4 astrocytoma (glioblastoma multiforme). Chronic papilloedema had been diagnosed at presentation, and this persisted after his debulking surgery, but there was no radiological evidence of direct involvement (by compression or infiltration) of the visual pathways. This case report describes the sub-acute on chronic nature of his visual loss, and suggests possible causes and preventative measures for visual loss in these patients. PMID- 21691412 TI - Racial Diversity and Change in Metropolitan Neighborhoods. AB - This study investigates the changing racial diversity and structure of metropolitan neighborhoods. We consider three alternative perspectives about localized racial change: that neighborhoods are bifurcating along a white/nonwhite color line, fragmenting into homogeneous enclaves, or integrating white, black, Latino, and Asian residents into diverse residential environments. To assess hypotheses drawn from these perspectives, we develop a hybrid methodology (incorporating the entropy index and majority-rule criteria) that offers advantages over previous typological efforts. Our analysis of 1990-2000 census tract data for the 100 largest U.S. metropolitan areas finds that most neighborhoods are becoming more diverse and that members of all groups have experienced increasing exposure to neighborhood diversity. However, white populations tend to diminish rapidly in the presence of multiple minority groups and there has been concomitant white growth in low-diversity neighborhoods. Latino population dynamics have emerged as a primary force driving neighborhood change in a multi-group context. PMID- 21691413 TI - On the use of a PM(2.5) exposure simulator to explain birthweight. AB - In relating pollution to birth outcomes, maternal exposure has usually been described using monitoring data. Such characterization provides a misrepresentation of exposure as it (i) does not take into account the spatial misalignment between an individual's residence and monitoring sites, and (ii) it ignores the fact that individuals spend most of their time indoors and typically in more than one location. In this paper, we break with previous studies by using a stochastic simulator to describe personal exposure (to particulate matter) and then relate simulated exposures at the individual level to the health outcome (birthweight) rather than aggregating to a selected spatial unit.We propose a hierarchical model that, at the first stage, specifies a linear relationship between birthweight and personal exposure, adjusting for individual risk factors and introduces random spatial effects for the census tract of maternal residence. At the second stage, our hierarchical model specifies the distribution of each individual's personal exposure using the empirical distribution yielded by the stochastic simulator as well as a model for the spatial random effects.We have applied our framework to analyze birthweight data from 14 counties in North Carolina in years 2001 and 2002. We investigate whether there are certain aspects and time windows of exposure that are more detrimental to birthweight by building different exposure metrics which we incorporate, one by one, in our hierarchical model. To assess the difference in relating ambient exposure to birthweight versus personal exposure to birthweight, we compare estimates of the effect of air pollution obtained from hierarchical models that linearly relate ambient exposure and birthweight versus those obtained from our modeling framework.Our analysis does not show a significant effect of PM(2.5) on birthweight for reasons which we discuss. However, our modeling framework serves as a template for analyzing the relationship between personal exposure and longer term health endpoints. PMID- 21691414 TI - Economic Factors and Relationship Quality Among Young Couples: Comparing Cohabitation and Marriage. AB - Are economic resources related to relationship quality among young couples, and to what extent does this vary by relationship type? To answer these questions, we estimated regression models predicting respondent reports of conflict and affection in cohabiting and married partner relationships using the National Longitudinal Study of Youth, 1997 (NLSY97, N = 2,841) and the National Longitudinal Study of Adolescent Health (Add Health, N = 1,702). We found that economic factors are an important predictor of conflict for both married and cohabiting couples. Affection was particularly responsive to human capital rather than short-term economic indicators. Economic hardship was associated with more conflict among married and cohabiting couples. PMID- 21691417 TI - Padlock probe-mediated qRT-PCR for DNA computing answer determination. AB - Padlock probe-mediated quantitative real time PCR (PLP-qRT-PCR) was adapted to quantify the abundance of sequential 10mer DNA sequences for use in DNA computing to identify optimal answers of traveling salesman problems. The protocol involves: (i) hybridization of a linear PLP with a target DNA sequence; (ii) PLP circularization through enzymatic ligation; and (iii) qRT-PCR amplification of the circularized PLP after removal of non-circularized templates. The linear PLP was designed to consist of two 10-mer sequence-detection arms at the 5' and 3' ends separated by a core sequence composed of universal PCR primers, and a qRT PCR reporter binding site. Circularization of each PLP molecule is dependent upon hybridization with target sequence and high-fidelity ligation. Thus, the number of PLP circularized is determined by the abundance of target in solution. The amplification efficiency of the PLP was 98.7% within a 0.2 pg-20 ng linear detection range between thermal cycle threshold (C(t) value) and target content. The C(t) values derived from multiplex qRT-PCR upon three targets did not differ significantly from those obtained with singleplex assays. The protocol provides a highly sensitive and efficient means for the simultaneous quantification of multiple short nucleic acid sequences that has a wide range of applications in biotechnology. PMID- 21691415 TI - WORKPLACE SOCIAL SUPPORT AND WORK-FAMILY CONFLICT: A META-ANALYSIS CLARIFYING THE INFLUENCE OF GENERAL AND WORK-FAMILY-SPECIFIC SUPERVISOR AND ORGANIZATIONAL SUPPORT. AB - This article uses meta-analysis to develop a model integrating research on relationships between employee perceptions of general and work-family-specific supervisor and organizational support and work-family conflict. Drawing on 115 samples from 85 studies comprising 72,507 employees, we compared the relative influence of 4 types of workplace social support to work-family conflict: perceived organizational support (POS); supervisor support; perceived organizational work-family support, also known as family-supportive organizational perceptions (FSOP); and supervisor work-family support. Results show work-family-specific constructs of supervisor support and organization support are more strongly related to work-family conflict than general supervisor support and organization support, respectively. We then test a mediation model assessing the effects of all measures at once and show positive perceptions of general and work-family-specific supervisor indirectly relate to work-family conflict via organizational work-family support. These results demonstrate that work-family-specific support plays a central role in individuals' work-family conflict experiences. PMID- 21691416 TI - A Technical Assessment of the Utility of Reverse Phase Protein Arrays for the Study of the Functional Proteome in Non-microdissected Human Breast Cancers. AB - INTRODUCTION: The lack of large panels of validated antibodies, tissue handling variability, and intratumoral heterogeneity potentially hamper comprehensive study of the functional proteome in non-microdissected solid tumors. The purpose of this study was to address these concerns and to demonstrate clinical utility for the functional analysis of proteins in non-microdissected breast tumors using reverse phase protein arrays (RPPA). METHODS: Herein, 82 antibodies that recognize kinase and steroid signaling proteins and effectors were validated for RPPA. Intraslide and interslide coefficients of variability were <15%. Multiple sites in non-microdissected breast tumors were analyzed using RPPA after intervals of up to 24 h on the benchtop at room temperature following surgical resection. RESULTS: Twenty-one of 82 total and phosphoproteins demonstrated time dependent instability at room temperature with most variability occurring at later time points between 6 and 24 h. However, the 82-protein functional proteomic "fingerprint" was robust in most tumors even when maintained at room temperature for 24 h before freezing. In repeat samples from each tumor, intratumoral protein levels were markedly less variable than intertumoral levels. Indeed, an independent analysis of prognostic biomarkers in tissue from multiple tumor sites accurately and reproducibly predicted patient outcomes. Significant correlations were observed between RPPA and immunohistochemistry. However, RPPA demonstrated a superior dynamic range. Classification of 128 breast cancers using RPPA identified six subgroups with markedly different patient outcomes that demonstrated a significant correlation with breast cancer subtypes identified by transcriptional profiling. CONCLUSION: Thus, the robustness of RPPA and stability of the functional proteomic "fingerprint" facilitate the study of the functional proteome in non-microdissected breast tumors. PMID- 21691418 TI - Exploring the Requirements for the Hydrophobic Scaffold and Polar Amine in inhibitors of M2 from Influenza A Virus. AB - Inhibitors targeting the influenza A virus M2 (A/M2) proton channel, have lost their effectiveness due to widespread resistance. As a first step in the development of new inhibitors that address this problem, we have screened several focused collections of small molecules using two electrode voltage patch clamp assays (TEVC) on Xenopus laevis Oocyte. Diverse head groups and scaffolds of A/M2 inhibitors have been explored. It has been found that not only amine, but also hydroxyl, aminooxyl, guanidine and amidine compounds are active against the A/M2 proton channel. Moreover, the channel is able to accommodate a wide range of structural variation in the apolar scaffold. This study offers information to guide the next generation of A/M2 proton channel inhibitor design. PMID- 21691419 TI - Biobanking in pediatrics: the human nonsubjects approach. AB - Pediatric biobanks are an indispensible resource for the research that will be needed to bring advances in personalized medicine into pediatric medical care. Investigators developing pediatric biobanks have struggled with the ethical and legal challenges that arise in pediatric research. This article explores how one biobank model, the 'human nonsubjects models', is able to respond to such common challenges as the role of the parent and the child in agreeing to research participation, reconsent at the age of majority, data sharing and return of research results. Although this approach does not involve formal informed consent, it is well-suited to pediatric biobanking owing to its potential to reduce risk to children through a combination of advanced deidentification techniques and extensive oversight. PMID- 21691420 TI - Apparent Linear Attenuation Coefficients in Phase Contrast X-Ray Tomography. AB - In the inline phase contrast x-ray tomography the reconstructed apparent linear attenuation coefficient values may be greatly larger than sample's linear attenuation coefficients or even be negative. In this work we present a general formula to quantitatively relate the apparent linear attenuation coefficient values in cone-beam phase contrast tomography to sample's linear attenuation coefficients and refractive indices. This formula overcomes the gross inaccuracy of the existing formula in the literature in analyzing high-resolution phase contrast tomography, and it will be useful for correctly interpreting and quantifying the apparent linear attenuation coefficients in cone-beam x-ray phase contrast tomography. PMID- 21691421 TI - Recent History Functional Linear Models for Sparse Longitudinal Data. AB - We consider the recent history functional linear models, relating a longitudinal response to a longitudinal predictor where the predictor process only in a sliding window into the recent past has an effect on the response value at the current time. We propose an estimation procedure for recent history functional linear models that is geared towards sparse longitudinal data, where the observation times across subjects are irregular and total number of measurements per subject is small. The proposed estimation procedure builds upon recent developments in literature for estimation of functional linear models with sparse data and utilizes connections between the recent history functional linear models and varying coefficient models. We establish uniform consistency of the proposed estimators, propose prediction of the response trajectories and derive their asymptotic distribution leading to asymptotic point-wise confidence bands. We include a real data application and simulation studies to demonstrate the efficacy of the proposed methodology. PMID- 21691423 TI - Influence of Nanoparticle Size and Shape on Oligomer Formation of an Amyloidogenic Peptide. AB - Understanding the influence of macromolecular crowding and nanoparticles on the formation of in-register beta-sheets, the primary structural component of amyloid fibrils, is a first step towards describing in vivo protein aggregation and interactions between synthetic materials and proteins. Using all atom molecular simulations in implicit solvent we illustrate the effects of nanoparticle size, shape, and volume fraction on oligomer formation of an amyloidogenic peptide from the transthyretin protein. Surprisingly, we find that inert spherical crowding particles destabilize in-register beta-sheets formed by dimers while stabilizing beta-sheets comprised of trimers and tetramers. As the radius of the nanoparticle increases crowding effects decrease, implying smaller crowding particles have the largest influence on the earliest amyloid species. We explain these results using a theory based on the depletion effect. Finally, we show that spherocylindrical crowders destabilize the ordered beta-sheet dimer to a greater extent than spherical crowders, which underscores the influence of nanoparticle shape on protein aggregation. PMID- 21691422 TI - Diving Into the Lipid Bilayer to Investigate the Transmembrane Organization and Conformational State Transitions of P-type Ion ATPases. AB - Although membrane proteins constitute more than 20% of the total proteins, the structures of only a few are known in detail. An important group of integral membrane proteins are ion-transporting ATPases of the P-type family, which share the formation of an acid-stable phosphorylated intermediate as part of their reaction cycle. There are several crystal structures of the sarcoplasmic reticulum Ca(2+) pump (SERCA) revealing different conformations, and recently, crystal structures of the H(+)-ATPase and the Na(+)/K(+)-ATPase were reported as well. However, there are no atomic resolution structures for other P-type ATPases including the plasma membrane calcium pump (PMCA), which is integral to cellular Ca(2+) signaling. Crystallization of these proteins is challenging because there is often no natural source from which the protein can be obtained in large quantities, and the presence of multiple isoforms in the same tissue further complicates efforts to obtain homogeneous samples suitable for crystallization. Alternative techniques to study structural aspects and conformational transitions in the PMCAs (and other P-type ATPases) have therefore been developed. Specifically, information about the structure and assembly of the transmembrane domain of an integral membrane protein can be obtained from an analysis of the lipid-protein interactions. Here, we review recent efforts using different hydrophobic photo-labeling methods to study the non-covalent interactions between the PMCA and surrounding phospholipids under different experimental conditions, and discuss how the use of these lipid probes can reveal valuable information on the membrane organization and conformational state transitions in the PMCA, Na(+)/K(+)-ATPase, and other P-type ATPases. PMID- 21691424 TI - Adjusting for Network Size and Composition Effects in Exponential-Family Random Graph Models. AB - Exponential-family random graph models (ERGMs) provide a principled way to model and simulate features common in human social networks, such as propensities for homophily and friend-of-a-friend triad closure. We show that, without adjustment, ERGMs preserve density as network size increases. Density invariance is often not appropriate for social networks. We suggest a simple modification based on an offset which instead preserves the mean degree and accommodates changes in network composition asymptotically. We demonstrate that this approach allows ERGMs to be applied to the important situation of egocentrically sampled data. We analyze data from the National Health and Social Life Survey (NHSLS). PMID- 21691425 TI - MSCALE: A General Utility for Multiscale Modeling. AB - The combination of theoretical models of macromolecules that exist at different spatial and temporal scales has become increasingly important for addressing complex biochemical problems. This work describes the extension of concurrent multiscale approaches, introduces a general framework for carrying out calculations, and describes its implementation into the CHARMM macromolecular modeling package. This functionality, termed MSCALE, generalizes both the additive and subtractive multiscale scheme (e.g. QM/MM ONIOM-type), and extends its support to classical force fields, coarse grained modeling (e.g. ENM, GNM, etc.), and a mixture of them all. The MSCALE scheme is completely parallelized with each subsystem running as an independent, but connected calculation. One of the most attractive features of MSCALE is the relative ease of implementation using the standard MPI communication protocol. This allows external access to the framework and facilitates the combination of functionality previously isolated in separate programs. This new facility is fully integrated with free energy perturbation methods, Hessian based methods, and the use of periodicity and symmetry, which allows the calculation of accurate pressures. We demonstrate the utility of this new technique with four examples; (1) subtractive QM/MM and QM/QM calculations; (2) multi-force field alchemical free energy perturbation; (3) integration with the SANDER module of AMBER and the TINKER package to gain access to potentials not available in CHARMM; and (4) mixed resolution (i.e. coarse grain / all-atom) normal mode analysis. The potential of this new tool is clearly established and in conclusion an interesting mathematical problem is highlighted and future improvements are proposed. PMID- 21691426 TI - Convection-enhanced delivery of camptothecin-loaded polymer nanoparticles for treatment of intracranial tumors. AB - Direct delivery of chemotherapy agents to the brain via degradable polymer delivery systems-such as Gliadel(r)-is a clinically proven method for treatment of glioblastoma multiforme, but there are important limitations with the current technology-including the requirement for surgery, profound local tissue toxicity, and limitations in diffusional penetration of agents-that limit its application and effectiveness. Here, we demonstrate another technique for direct, controlled delivery of chemotherapy to the brain that provides therapeutic benefit with fewer limitations. In our new approach, camptothecin (CPT)-loaded poly(lacticco glycolic acid) (PLGA) nanoparticles are infused via convection-enhanced delivery (CED) to a stereotactically defined location in the brain, allowing simultaneous control of location, spread, and duration of drug release. To test this approach, CPT-PLGA nanoparticles (~100 nm in diameter) were synthesized with 25% drug loading. When these nanoparticles were incubated in culture with 9L gliosarcoma cells, the IC50 of CPT-PLGA nanoparticles was 0.04 uM, compared to 0.3 uM for CPT alone. CPT-PLGA nanoparticles stereotactically delivered by CED improved survival in rats with intracranial 9L tumors: the median survival for rats treated with CPT-PLGA nanoparticles (22 days) was significantly longer than unloaded nanoparticles (15 days) and free CPT infusion (17 days). CPT-PLGA nanoparticle treatment also produced significantly more long-term survivors (30% of animals were free of disease at 60 days) than any other treatment. CPT was present in tissues harvested up to 53 days post-infusion, indicating prolonged residence at the local site of administration. These are the first results to demonstrate the effectiveness of combining polymer-controlled release nanoparticles with CED in treating fatal intracranial tumors. PMID- 21691427 TI - Characterization and Quantification of Nanoparticle-Antibody Conjugates on Cells Using C(60) ToF SIMS in the Event-By-Event Bombardment/Detection Mode. AB - Cluster C(60) ToF-SIMS (time-of-flight secondary ion mass spectrometry) operated in the event-by-event bombardment-detection method has been applied to: a) quantify the binding density of Au nanoparticles (AuNPs)-antiCD4 conjugates on the cell surface; b) identify the binding sites between AuNPs and antibody. Briefly, our method consists of recording the secondary ions, SIs, individually emitted from a single C(60) (1,2+) impact. From the cumulative mass spectral data we selected events where a specific SI was detected. The selected records revealed the SIs co-ejected from the nanovolume impacted by an individual C(60) with an emission area of ~ 10nm in diameter as an emission depth of 5-10 nm. The fractional coverage is obtained as the ratio of the effective number of projectile impacts on a specified sampling area (N(e)) to the total number of impacts (N(0)). In the negative ion mass spectrum, the palmitate (C(16)H(31)O(2) (-)) and oletate (C(18)H(33)O(2) (-)) fatty acid ions present signals from lipid membrane of the cells. The signals at m/z 197 (Au(-)) and 223 (AuCN(-)) originate from the AuNPs labeled antibodies (antiCD4) bound to the cell surface antigens. The characteristic amino acid ions validate the presence of antiCD4. A coincidence mass spectrum extracted with ion at m/z 223 (AuCN(-)) reveals the presence of cysteine at m/z 120, documenting the closeness of cysteine and the AuNP. Their proximity suggests that the binding site for AuNP on the antibody is the sulfur-terminal cysteine. The fractional coverage of membrane lipid was determined to be ~23% of the cell surfaces while the AuNPs was found to be ~21%. The novel method can be implemented on smaller size NPs, it should thus be applicable for studies on size dependent binding of NP-antibody conjugates. PMID- 21691428 TI - Preparative Protein Production from Inclusion Bodies and Crystallization: A Seven Week Biochemistry Sequence. AB - We describe how to produce and purify proteins from E. coli inclusion bodies by adapting versatile, preparative-scale techniques to the undergraduate laboratory schedule. This seven-week sequence of experiments fits into an annual cycle of research activity in biochemistry courses. Recombinant proteins are expressed as inclusion bodies, which are collected, washed, then solubilized in urea. Stepwise dialysis to dilute urea over the course of a week produces refolded protein. Column chromatography is used to purify protein into fractions, which are then analyzed with gel electrophoresis and concentration assays. Students culminate the project by designing crystallization trials in sitting-drop trays. Student evaluation of the experience has been positive, listing 5-12 new techniques learned, which are transferrable to graduate research in academia and industry. PMID- 21691430 TI - Synthetic and Immunological Studies of sTn Derivatives Carrying 5-N-(p Substituted Phenylacetyl)Sialic Acid for the Development of Effective Cancer Vaccines. AB - To search for effective cancer vaccines based on sTn, a sialylated tumor associated carbohydrate antigen (sialo-TACA) expressed by a number of tumors, four unnatural N-acyl sTn derivatives, including 5'-N-p-methylphenylacetyl sTn (sTnNMePhAc), 5'-N-p-methoxylphenylacetyl sTn (sTnNMeOPhAc), 5'-N-p acetylphenylacetyl sTn (sTnNAcPhAc) and 5'-N-p-chlorophenylacetyl sTn (sTnNClPhAc), as well as their protein conjugates, were synthesized by a highly convergent procedure. The immunological properties of these sTn derivatives in the form of keyhole limpet hemocyanin conjugate were evaluated in mice and compared to that of sTnNPhAc, a sTn derivative previously investigated as a vaccine candidate. It was shown that sTnNMePhAc, sTnNMeOPhAc, sTnNAcPhAc and sTnNClPhAc are all much more immunogenic than sTnNPhAc and that they provoked strong T cell-dependent IgG1 immune responses useful for cancer immunotherapy. It was concluded that sTnNClPhAc is a promising candidate for cancer vaccine development and is worthy further investigation. PMID- 21691431 TI - Predicting Fixation Tendencies of the H3N2 Influenza Virus by Free Energy Calculation. AB - Influenza virus evolves to escape from immune system antibodies that bind to it. We used free energy calculations with Einstein crystals as reference states to calculate the difference of antibody binding free energy (DeltaDeltaG) induced by amino acid substitution at each position in epitope B of the H3N2 influenza hemagglutinin, the key target for antibody. A substitution with positive DeltaDeltaG value decreases the antibody binding constant. On average an uncharged to charged amino acid substitution generates the highest DeltaDeltaG values. Also on average, substitutions between small amino acids generate DeltaDeltaG values near to zero. The 21 sites in epitope B have varying expected free energy differences for a random substitution. Historical amino acid substitutions in epitope B for the A/Aichi/2/1968 strain of influenza A show that most fixed and temporarily circulating substitutions generate positive DeltaDeltaG values. We propose that the observed pattern of H3N2 virus evolution is affected by the free energy landscape, the mapping from the free energy landscape to virus fitness landscape, and random genetic drift of the virus. Monte Carlo simulations of virus evolution are presented to support this view. PMID- 21691432 TI - Generalized Detectability for Discrete Event Systems. AB - In our previous work, we investigated detectability of discrete event systems, which is defined as the ability to determine the current and subsequent states of a system based on observation. For different applications, we defined four types of detectabilities: (weak) detectability, strong detectability, (weak) periodic detectability, and strong periodic detectability. In this paper, we extend our results in three aspects. (1) We extend detectability from deterministic systems to nondeterministic systems. Such a generalization is necessary because there are many systems that need to be modeled as nondeterministic discrete event systems. (2) We develop polynomial algorithms to check strong detectability. The previous algorithms are based on observer whose construction is of exponential complexity, while the new algorithms are based on a new automaton called detector. (3) We extend detectability to D-detectability. While detectability requires determining the exact state of a system, D-detectability relaxes this requirement by asking only to distinguish certain pairs of states. With these extensions, the theory on detectability of discrete event systems becomes more applicable in solving many practical problems. PMID- 21691429 TI - Duchenne muscular dystrophy gene therapy: Lost in translation? AB - A milestone of molecular medicine is the identification of dystrophin gene mutation as the cause of Duchenne muscular dystrophy (DMD). Over the last 2 decades, major advances in dystrophin biology and gene delivery technology have created an opportunity to treat DMD with gene therapy. Remarkable success has been achieved in treating dystrophic mice. Several gene therapy strategies, including plasmid transfer, exon skipping, and adeno-associated virus-mediated microdystrophin therapy, have entered clinical trials. However, therapeutic benefit has not been realized in DMD patients. Bridging the gap between mice and humans is no doubt the most pressing issue facing DMD gene therapy now. In contrast to mice, dystrophin-deficient dogs are genetically and phenotypically similar to human patients. Preliminary gene therapy studies in the canine model may offer critical insights that cannot be obtained from murine studies. It is clear that the canine DMD model may represent an important link between mice and humans. Unfortunately, our current knowledge of dystrophic dogs is limited, and the full picture of disease progression remains to be clearly defined. We also lack rigorous outcome measures (such as in situ force measurement) to monitor therapeutic efficacy in dystrophic dogs. Undoubtedly, maintaining a dystrophic dog colony is technically demanding, and the cost of dog studies cannot be underestimated. A carefully coordinated effort from the entire DMD community is needed to make the best use of the precious dog resource. Successful DMD gene therapy may depend on valid translational studies in dystrophin-deficient dogs. PMID- 21691433 TI - MIB method for elliptic equations with multi-material interfaces. AB - Elliptic partial differential equations (PDEs) are widely used to model real world problems. Due to the heterogeneous characteristics of many naturally occurring materials and man-made structures, devices, and equipments, one frequently needs to solve elliptic PDEs with discontinuous coefficients and singular sources. The development of high-order elliptic interface schemes has been an active research field for decades. However, challenges remain in the construction of high-order schemes and particularly, for nonsmooth interfaces, i.e., interfaces with geometric singularities. The challenge of geometric singularities is amplified when they are originated from two or more material interfaces joining together or crossing each other. High-order methods for elliptic equations with multi-material interfaces have not been reported in the literature to our knowledge. The present work develops matched interface and boundary (MIB) method based schemes for solving two-dimensional (2D) elliptic PDEs with geometric singularities of multi-material interfaces. A number of new MIB schemes are constructed to account for all possible topological variations due to two-material interfaces. The geometric singularities of three-material interfaces are significantly more difficult to handle. Three new MIB schemes are designed to handle a variety of geometric situations and topological variations, although not all of them. The performance of the proposed new MIB schemes is validated by numerical experiments with a wide range of coefficient contrasts, geometric singularities, and solution types. Extensive numerical studies confirm the designed second order accuracy of the MIB method for multi-material interfaces, including a case where the derivative of the solution diverges. PMID- 21691434 TI - The Heart in Friedreich's Ataxia: Basic Findings and Clinical Implications. AB - Friedreich's Ataxia is the most common inherited ataxia in man. It is a mitochondrial disease caused by severely reduced expression of the iron binding protein, frataxin. A large GAA triplet expansion in the human FRDA gene encoding this protein inhibits expression of this gene. It is inherited in an autosomal recessive pattern and typically diagnosed in childhood. The primary symptoms include severe and progressive neuropathy, and a hypertrophic cardiomyopathy that may cause death. The cardiomyopathy is difficult to treat and is frequently associated with arrhythmias, heart failure, and intolerance of cardiovascular stress, such as surgeries. Innovative approaches to therapy, such as histone deacetylase inhibitors, and enzyme replacement with cell penetrant peptide fusion proteins, hold promise for this and other similar mitochondrial disorders. This review will focus on the basic findings of this disease, and the cardiomyopathy associated with its diagnosis. PMID- 21691436 TI - Silver-mediated fluorination of aryl silanes. AB - A regiospecific silver-mediated fluorination of aryl silanes is reported. The reaction is operationally simple, and employs Ag(2)O as readily available, inexpensive silver source, which can be recovered. PMID- 21691435 TI - Exploiting PubChem for Virtual Screening. AB - IMPORTANCE OF THE FIELD: PubChem is a public molecular information repository, a scientific showcase of the NIH Roadmap Initiative. The PubChem database holds over 27 million records of unique chemical structures of compounds (CID) derived from nearly 70 million substance depositions (SID), and contains more than 449,000 bioassay records with over thousands of in vitro biochemical and cell based screening bioassays established, with targeting more than 7000 proteins and genes linking to over 1.8 million of substances. AREAS COVERED IN THIS REVIEW: This review builds on recent PubChem-related computational chemistry research reported by other authors while providing readers with an overview of the PubChem database, focusing on its increasing role in cheminformatics, virtual screening and toxicity prediction modeling. WHAT THE READER WILL GAIN: These publicly available datasets in PubChem provide great opportunities for scientists to perform cheminformatics and virtual screening research for computer-aided drug design. However, the high volume and complexity of the datasets, in particular the bioassay-associated false positives/negatives and highly imbalanced datasets in PubChem, also creates major challenges. Several approaches regarding the modeling of PubChem datasets and development of virtual screening models for bioactivity and toxicity predictions are also reviewed. TAKE HOME MESSAGE: Novel data-mining cheminformatics tools and virtual screening algorithms are being developed and used to retrieve, annotate and analyze the large-scale and highly complex PubChem biological screening data for drug design. PMID- 21691437 TI - Contextual Variation in Automatic Evaluative Bias to Racially-Ambiguous Faces. AB - Three studies examined the implicit evaluative associations activated by racially ambiguous Black-White faces. In the context of both Black and White faces, Study 1 revealed a graded pattern of bias against racially-ambiguous faces that was weaker than the bias to Black faces but stronger than that to White faces. Study 2 showed that significant bias was present when racially-ambiguous faces appeared in the context of only White faces, but not in the context of only Black faces. Study 3 demonstrated that context produces perceptual contrast effects on racial prototypicality judgments. Racially-ambiguous faces were perceived as more prototypically Black in a White-only than mixed-race context, and less prototypically Black in a Black-only context. Conversely, they were seen as more prototypically White in a Black-only than mixed context, and less prototypically White in a White-only context. The studies suggest that both race-related featural properties within a face (i.e., racial ambiguity) and external contextual factors affect automatic evaluative associations. PMID- 21691438 TI - Advent of Imidazo[1,2-a]pyridine-3-carboxamides with Potent Multi- and Extended Drug Resistant Antituberculosis Activity. AB - A set of nine 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamides and one 2,6 dimethylimidazo[1,2-a]pyrimidine-3-carboxamide were synthesized. The compounds were evaluated for their in vitro anti-tuberculosis activity versus replicating, non-replicating, multi- and extensive drug resistant Mtb strains. The MIC(90) values of seven of these agents were <= 1 MUM against the various tuberculosis strains tested. A representative compound of this class (1) was screened against seven non-tubercular strains as well as other non-mycobacteria organisms and demonstrated remarkable microbe selectivity. A transcriptional profiling experiment of Mtb treated with compound 1 was performed to give a preliminary indication of the mode of action. Lastly, the in vivo ADME properties of compounds 1, 3, 4, and 6 were assessed. The 2,7-dimethylimidazo[1,2-a]pyridine-3 carboxamides are a drug-like and synthetically accessible class of anti-TB agents that have excellent selective potency against multi- and extensive drug resistant TB and encouraging pharmacokinetics. PMID- 21691439 TI - It's a Bird, It's A Plane, It's ... Fidelity Measurement In the Real World. AB - In psychotherapy research, fidelity instruments were originally developed as manipulation checks in experimental tests of treatment efficacy. The purposes of fidelity measurement are expanding as consumers, administrators, and payers seek to determine the extent to which the interventions purchased are actually received. Emerging purposes for fidelity measurement are described, as are challenges to developing a single instrument that can adequately meet multiple purposes, and that is both effective (psychometrically sound) and efficient (feasibly used in routine care). Examples are provided of efforts to balance these attributes of fidelity measurement, to measure fidelity at multiple levels of the practice context, and to index and evaluate the effects of additional program parameters on client outcomes in routine care. PMID- 21691440 TI - A carbon nanotube field emission multipixel x-ray array source for microradiotherapy application. AB - The authors report a carbon nanotube (CNT) field emission multipixel x-ray array source for microradiotherapy for cancer research. The developed multipixel x-ray array source has 50 individually controllable pixels and it has several distinct advantages over other irradiation source including high-temporal resolution (millisecond level), the ability to electronically shape the form, and intensity distribution of the radiation fields. The x-ray array was generated by a CNT cathode array (5*10) chip with electron field emission. A dose rate on the order of >1.2 Gy/min per x-ray pixel beam is achieved at the center of the irradiated volume. The measured dose rate is in good agreement with the Monte Carlo simulation result. PMID- 21691442 TI - Pulmonary arterial hypertension in children: Diagnostic work-up and challenges. AB - The diagnostic evaluation of a pediatric patient with suspected pulmonary arterial hypertension (PAH) is extensive but essential, given the rapid progression of the disease if left undiagnosed and untreated. The major goals of performing a complete diagnostic work-up are to confirm the diagnosis of PAH, assess disease severity, rule out associated diseases, and begin to formulate an individualized treatment plan for the pediatric patient with pulmonary hypertension. This article will provide a comprehensive review of the diagnostic work-up of the child with suspected PAH as well as a review of some of the challenges faced when assessing a child for PAH. PMID- 21691441 TI - Functional polymers in protein detection platforms: optical, electrochemical, electrical, mass-sensitive, and magnetic biosensors. AB - The rapidly growing field of proteomics and related applied sectors in the life sciences demands convenient methodologies for detecting and measuring the levels of specific proteins as well as for screening and analyzing for interacting protein systems. Materials utilized for such protein detection and measurement platforms should meet particular specifications which include ease-of-mass manufacture, biological stability, chemical functionality, cost effectiveness, and portability. Polymers can satisfy many of these requirements and are often considered as choice materials in various biological detection platforms. Therefore, tremendous research efforts have been made for developing new polymers both in macroscopic and nanoscopic length scales as well as applying existing polymeric materials for protein measurements. In this review article, both conventional and alternative techniques for protein detection are overviewed while focusing on the use of various polymeric materials in different protein sensing technologies. Among many available detection mechanisms, most common approaches such as optical, electrochemical, electrical, mass-sensitive, and magnetic methods are comprehensively discussed in this article. Desired properties of polymers exploited for each type of protein detection approach are summarized. Current challenges associated with the application of polymeric materials are examined in each protein detection category. Difficulties facing both quantitative and qualitative protein measurements are also identified. The latest efforts on the development and evaluation of nanoscale polymeric systems for improved protein detection are also discussed from the standpoint of quantitative and qualitative measurements. Finally, future research directions towards further advancements in the field are considered. PMID- 21691443 TI - Norms About Nonmarital Pregnancy and Willingness to Provide Resources to Unwed Parents. AB - Contested social norms underlie public concern about adults' and teenagers' nonmarital pregnancy. The original, vignette-based National Pregnancy Norms Survey (N = 812) measures these norms and related sanctions. Descriptive analyses report embarrassment at the prospect of a nonmarital pregnancy by age and gender of hypothetical prospective parents and age, race or ethnicity, and socioeconomic status of respondents. Multivariate analyses show that embarrassment about nonmarital pregnancy is frequently weak but much stronger when prospective parents are teenagers. Embarrassment predicts respondents' hypothetical sanctions of a new parent in their family by withholding several types of needed material resources. Because research has shown that such resources affect education and income, this study helps explain how violating norms might lead to negative outcomes among unmarried parents. PMID- 21691444 TI - Information and Communication Technologies in Social Work. AB - Information and communication technologies (ICTs) are electronic tools used to convey, manipulate and store information. The exponential growth of Internet access and ICTs greatly influenced social, political, and economic processes in the United States, and worldwide. Regardless of the level of practice, ICTs will continue influencing the careers of social workers and the clients they serve. ICTs have received some attention in the social work literature and curriculum, but we argue that this level of attention is not adequate given their ubiquity, growth and influence, specifically as it relates to upholding social work ethics. Significant attention is needed to help ensure social workers are responsive to the technological changes in the health care system, including the health care infrastructure and use of technology among clients. Social workers also need ICT competencies in order to effectively lead different types of social change initiatives or collaborate with professionals of other disciplines who are using ICTs as part of existing strategies. This paper also identifies potential pitfalls and challenges with respect to the adoption of ICTs, with recommendations for advancing their use in practice, education, and research. PMID- 21691445 TI - Longitudinal fMRI analysis: A review of methods. AB - Functional magnetic resonance imaging (fMRI) investigations of a longitudinal nature, where participants are scanned repeatedly over time and imaging data are obtained at more than one time-point, are essential to understanding functional changes and development in healthy and pathological brains. The main objective of this paper is to provide a brief summary of common longitudinal analysis approaches, develop an overview of fMRI by introducing how such data manifest, and explore the statistical challenges that arise at the intersection of these two techniques. PMID- 21691446 TI - UNEQUAL RISK: COMBAT OCCUPATIONS IN THE VOLUNTEER MILITARY. AB - This study evaluates the characteristics of the men who served in the volunteer military in combat occupations. It examines whether these characteristics stem from supply-side or demand-side decisions, or reflect class bias. The findings suggest that, on the supply side, men who had greater academic abilities were more likely to go to college, thereby avoiding military service and the possibility of serving in a combat occupation. On the demand side, the armed forces were more likely to exclude men with lower academic abilities but were more likely to assign such men in the military to combat occupations. Net of the impacts of these supply-side and demand-side decisions, men who served in combat occupations still differed from those who did not in terms of their family background. The impact of family background was stronger on entering the military than on being assigned to combat occupations once in the military. PMID- 21691447 TI - Single Mothers, Single Fathers: Gender Differences in Fertility after a Nonmarital Birth. AB - Research on nonmarital fertility has focused almost exclusively on unmarried mothers, due in part to a lack of fertility information for men. Cycle 6 of the National Survey of Family Growth allows exploration of nonmarital fertility for both genders. We compare the characteristics of unmarried first-time mothers (n = 2,455) and fathers (n = 797), use event history techniques to model second birth hazards, and examine the distribution of men's and women's second births across types of relationships. Our analysis is motivated by questions about how selection into nonmarital fertility relates to subsequent fertility behavior and by theories of mate selection and the "relationship" market. We find that unmarried mothers are more likely to have a second birth than unmarried fathers, driven largely by a higher hazard of having a noncoresidential second birth. PMID- 21691448 TI - Obese Adolescents with Type 2 Diabetes Mellitus Have Hippocampal and Frontal Lobe Volume Reductions. AB - The rates of type 2 diabetes (T2DM) continue to parallel the rising rates of obesity in the United States, increasingly affecting adolescents as well as adults. Hippocampal and frontal lobe reductions have been found in older adults with type 2 diabetes, and we sought to ascertain if these brain alterations were also present in obese adolescents with T2DM. In a cross-sectional study we compared MRI-based regional brain volumes of 18 obese adolescents with T2DM and 18 obese controls without evidence of marked insulin resistance. Groups were matched on age, sex, school grade, ethnicity, socioeconomic status, body mass index, and waist circumference. Relative to obese controls, adolescents with T2DM had significantly reduced hippocampal and prefrontal volumes, and higher rates of global cerebral atrophy. Hemoglobin A1c, an index of long-term glycemic control, was inversely associated with prefrontal volume and positively associated with global cerebral atrophy (both p < 0.05). Brain integrity is negatively impacted by T2DM already during adolescence, long before the onset of overt macrovascular disease. Paralleling the findings of greater vascular and renal complications among obese adolescents with severe insulin resistance and T2DM relative to their age-matched peers with type 1 diabetes, we find clear evidence of possible brain complications. Our findings call for aggressive and early intervention to limit the negative impact of obesity-associated insulin resistance leading to T2DM on the developing brains of adolescents. PMID- 21691449 TI - The Effects of Consultation on Individualized Education Program Outcomes for Young Children With Autism: The Collaborative Model for Promoting Competence and Success. AB - The effects of a teacher consultation intervention were examined-namely, the collaborative model for promoting competence and success (COMPASS), which was designed to improve objectives of individualized education programs for children with autism. The intervention consists of an initial parent-teacher consultation, followed by four teacher consultations across the school year. Thirty-five teachers and a randomly selected child with autism (M age = 6.1 years) from each classroom participated. Compared to the nonintervention teacher-child dyads, the intervention teacher-child dyads showed improvements in individualized education program objectives, with a large effect size (d = 1.51). PMID- 21691450 TI - Multiclass discrimination of cervical precancers using Raman spectroscopy. AB - Raman spectroscopy has the potential to differentiate among the various stages leading to high-grade cervical cancer such as normal, squamous metaplasia, and low-grade cancer. For Raman spectroscopy to successfully differentiate among the stages, an applicable statistical method must be developed. Algorithms like linear discriminant analysis (LDA) are incapable of differentiating among three or more types of tissues. We developed a novel statistical method combining the method of maximum representation and discrimination feature (MRDF) to extract diagnostic information with sparse multinomial logistic regression (SMLR) to classify spectra based on nonlinear features for multiclass analysis of Raman spectra. We found that high-grade spectra classified correctly 95% of the time; low-grade data classified correctly 74% of the time, improving sensitivity from 92 to 98% and specificity from 81 to 96% suggesting that MRDF with SMLR is a more appropriate technique for categorizing Raman spectra. SMLR also outputs a posterior probability to evaluate the algorithm's accuracy. This combined method holds promise to diagnose subtle changes leading to cervical cancer. PMID- 21691451 TI - Boosting The Late Blooming Male: Use of growth promoting agents in the athlete with constitutional delay of growth and puberty. AB - CONTEXT: The indications for use of growth hormone (GH) have broadened with the availability of unlimited recombinant human growth hormone (rhGH). The FDA's approval for use of growth hormone in GH-sufficient patients with idiopathic short stature includes some children with constitutional delay of growth and puberty (CGD), a normal growth pattern variation which includes delayed puberty and prolonged linear growth, usually leading to normal adult height. Use of rhGH to increase growth in short-statured children with CGD has been challenged for its modest efficacy in increasing ultimate height, high cost, limited evidence for psychosocial benefit, and some unresolved concerns about long-term post treatment safety. An additional controversy for the young athlete with CGD is the concern for fairness in competition. EVIDENCE ACQUISITION: Data sources were limited to peer-reviewed publications. RESULTS: RhGH is a safe and effective therapy for increasing growth rate in very short children with CGD, but does not markedly increase ultimate stature nor confer a clear benefit in athletic performance. (SORT A) CONCLUSIONS: Prescribing physicians should use rhGH treatment responsibly to bring children disabled by short stature just into the "normal" range. (SORT C). PMID- 21691452 TI - An examination of the relationship between reading comprehension, higher-level and lower-level reading sub-skills in adults. PMID- 21691453 TI - Preliminary Investigation of the Sources of Self-Efficacy Among Teachers of Students with Autism. AB - Teacher self-efficacy refers to the beliefs teachers hold regarding their capability to bring about desired instructional outcomes and may be helpful for understanding and addressing critical issues such as teacher attrition and teacher use of research-supported practices. Educating students with autism likely presents teachers with some of the most significant instructional challenges. The self-efficacy of 35 special education teachers of students with autism between the ages of 3 to 9 years was evaluated. Teachers completed rating scales that represented self-efficacy and aspects of the following 3 of Bandura's 4 sources of self-efficacy: (1) sense of mastery, (2) social persuasions, and (3) physiological/affective states. Significant associations were observed between physiological/affective states and self-efficacy, but no associations were observed for the other sources. PMID- 21691454 TI - Progress in the Prospective Study of the Schizophrenia Prodrome. AB - Further understanding of the schizophrenia spectrum has helped to define the prodrome of the illness, leading to hopes of earlier identification and intervention in susceptible, at-risk individuals. Given the heterogeneity and comorbidity observed in the clinically and demographically identified prodromal sample, it is essential that neurobiological markers that are more closely linked to brain function, and perhaps the ability to predict evolution of psychosis, be identified. Ultimately, it may be possible to identify an algorithm of risk factors that will combine clinical and demographic risk factors with vulnerability markers associated with later development of schizophrenia to better target at-risk individuals or preventative treatment. PMID- 21691455 TI - Criticism of drinking as informal social control: a study in 18 countries. AB - The focus of this paper is on informal control of drinking, indicated by criticism of people in the social network on someone's alcohol consumption. It studies country and gender differences in the extent drinkers suffering from typical symptoms of heavy or prolonged alcohol use report informal control from others (reactive informal control), and country and gender differences in the extent comments on someone's drinking are (also) directed at those who do not suffer from these symptoms (pro-active informal control). The data come from eighteen general population surveys, selected from an integrated dataset on drinking and drinking-related factors including more than 35 countries. The criteria for inclusion were that data for both men and women were available and that at least 3 items about symptoms of severe physiological consequences and about criticism of drinking had valid responses. The results show that men suffering from typical symptoms of heavy or prolonged alcohol use are more likely to be criticized than equivalent women (reactive control). Irrespective of gender, reactive informal control is more prevalent in poorer countries and in countries with a high proportion of abstainers. Concerning pro-active control, among women a larger part of criticism appeared to be directed at those who (as yet) do not suffer from symptoms typical for heavy or prolonged alcohol use. There is a lot of variation between countries in pro-active informal control. This variation is only weakly related to prosperity of a country but not to its proportion of abstainers. PMID- 21691456 TI - One-, two- and three-phase viscosity treatments for basaltic lava flows. AB - Lava flows comprise three-phase mixtures of melt, crystals, and bubbles. While existing one-phase treatments allow melt phase viscosity to be assessed on the basis of composition, water content, and/or temperature, two-phase treatments constrain the effects of crystallinity or vesicularity on mixture viscosity. However, three-phase treatments, allowing for the effects of coexisting crystallinity and vesicularity, are not well understood. We investigate existing one- and two-phase treatments using lava flow case studies from Mauna Loa (Hawaii) and Mount Etna (Italy) and compare these with a three-phase treatment that has not been applied previously to basaltic mixtures. At Etna, melt viscosities of 425 +/- 30 Pa s are expected for well-degassed (0.1 w. % H(2)O), and 135 +/- 10 Pa s for less well-degassed (0.4 wt % H(2)O), melt at 1080 degrees C. Application of a three-phase model yields mixture viscosities (45% crystals, 25-35% vesicles) in the range 5600-12,500 Pa s. This compares with a measured value for Etnean lava of 9400 +/- 1500 Pa s. At Mauna Loa, the three-phase treatment provides a fit with the full range of field measured viscosities, giving three-phase mixture viscosities, upon eruption, of 110-140 Pa s (5% crystals, no bubble effect due to sheared vesicles) to 850-1400 Pa s (25-30% crystals, 40-60% spherical vesicles). The ability of the three-phase treatment to characterize the full range of melt-crystal-bubble mixture viscosities in both settings indicates the potential of this method in characterizing basaltic lava mixture viscosity. PMID- 21691457 TI - Parental Agreement on ADHD Symptom-Specific and Broadband Externalizing Ratings of Child Behavior. AB - Mothers and fathers often disagree in their ratings of child behavior as evidenced clinically and supported by a substantial literature examining parental agreement on broadband rating scales. The present study examined mother-father agreement on DSM-based, ADHD symptom-specific ratings, as compared to agreement on broadband ratings of externalizing behavior. Using mother and father ratings from 324 children who participated in the Multimodal Treatment Study of Children with ADHD, parental agreement was computed and patterns of disagreement were examined. Mother-father ratings were significantly correlated. However, a clear pattern of higher ratings by mothers compared to fathers was present across ratings. Agreement on ADHD symptom-specific ratings was significantly lower than agreement for broadband externalizing behaviors or ODD symptoms. Of several moderator variables tested, parental stress was the only variable that predicted the discrepancy in ratings. Disagreement between parents is clinically significant and may pose complications to the diagnostic process. PMID- 21691459 TI - Patients' and caregivers' experiences of the impact of Parkinson's disease on health status. AB - BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease that significantly affects patients' quality of life. The myriad complexities of the disease, including its nonmotor manifestations, are beginning to be more fully appreciated, particularly in regard to the emotional and social effects of PD. Considering that both motor and nonmotor manifestations of PD significantly influence the health outcomes and conditions of patients, and their health related quality of life (HRQOL), we collected qualitative data from patients with PD, as well as caregivers of persons with PD having cognitive impairment, to assess their perceptions of the impact of PD on HRQOL. METHODS: We conducted eight focus groups and five one-on-one interviews in English and in Spanish between March 2007 and February 2008. Three of the focus groups were conducted with a total of 15 caregivers; the remaining focus groups and all interviews were conducted with 48 PD patients. Study participants were asked about the challenges that PD patients may experience, particularly pertaining to physical functioning, the impact of PD on their emotional status, and social functioning. RESULTS: Based on analysis of the transcripts, we identified seven overarching domains or themes that reflect patients' perspectives on living with PD, ie, physical functioning, social and role functioning, emotional impact, fears and uncertainty about the future, stigma and other feelings about PD, coping mechanisms, and benefits of having PD. CONCLUSION: We underscore the salient aspects regarding the physical effects of PD along with its nonphysical ramifications, offering perspectives into the experience of PD and suggestions on how PD patients and their caregivers may cope with the disease. PMID- 21691458 TI - Evaluation of an enzyme-linked immunosorbent assay using purified, deglycosylated histoplasmin for different clinical manifestations of histoplasmosis. AB - Diagnosis of invasive fungal diseases remains problematic, especially in undeveloped countries. We have developed an enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies to Histoplasma capsulatum using metaperiodate treated purified histoplasmin (ptHMIN). Our ELISA was validated comparing sera from patients with histoplasmosis, related mycoses, and healthy individuals. The overall test specificity was 96%, with sensitivities of 100% (8/8) in acute disease, 90% (9/10) in chronic disease, 89% (8/9) in disseminated infection in individuals without HIV infection, 86% (12/14) in disseminated disease in the setting of HIV infection and 100% (3/3) in mediastinal histoplasmosis. These parameters are superior to the use of untreated histoplasmin in diagnostic ELISAs. The high specificities, sensitivities, and simplicity of our ELISA support further development of a deglycosylated HMIN ELISA for clinical use and for monitoring the humoral immune response during therapy in patients with chronic and disseminated histoplasmosis. PMID- 21691460 TI - Nice to know you: Positive emotions, self-other overlap, and complex understanding in the formation of a new relationship. AB - Based on Fredrickson's ((1998). What good are positive emotions? Review of General Psychology, 2, 300-319.; (2001). The role of positive emotions in positive psychology: The broaden-and-build theory of positive emotions. American Psychologist, 56, 218-226) broaden-and-build theory and Aron and Aron's ((1986). Love as expansion of the self: Understanding attraction and satisfaction. New York: Hemisphere) self-expansion theory, it was hypothesized that positive emotions broaden people's feelings of self-other overlap in the beginning of a new relationship. In a prospective study of first-year college students, we found that, after 1 week in college, positive emotions predicted increased self-other overlap with new roommates, which in turn predicted a more complex understanding of the roommate. In addition, participants who experienced a high ratio of positive to negative emotions throughout the first month of college reported a greater increase in self-other overlap and complex understanding than participants with a low positivity ratio. Implications for the role of positive emotions in the formation of new relationships are discussed. PMID- 21691461 TI - Determination of lipid oxidation products in vegetable oils and marine omega-3 supplements. AB - BACKGROUND: There is convincing evidence that replacing dietary saturated fats with polyunsaturated fats (PUFA) decreases risk of cardiovascular diseases. Therefore, PUFA rich foods such as vegetable oils, fatty fish, and marine omega-3 supplements are recommended. However, PUFA are easily oxidizable and there is concern about possible negative health effects from intake of oxidized lipids. Little is known about the degree of lipid oxidation in such products. OBJECTIVE: To assess the content of lipid oxidation products in a large selection of vegetable oils and marine omega-3 supplements available in Norway. Both fresh and heated vegetable oils were studied. DESIGN: A large selection of commercially available vegetable oils and marine omega-3 supplements was purchased from grocery stores, pharmacies, and health food stores in Norway. The content of lipid oxidation products were measured as peroxide value and alkenal concentration. Twelve different vegetable oils were heated for a temperature (225 degrees C) and time (25 minutes) resembling conditions typically used during cooking. RESULTS: The peroxide values were in the range 1.04-10.38 meq/kg for omega-3 supplements and in the range 0.60-5.33 meq/kg for fresh vegetable oils. The concentration range of alkenals was 158.23-932.19 nmol/mL for omega-3 supplements and 33.24-119.04 nmol/mL for vegetable oils. After heating, a 2.9 11.2 fold increase in alkenal concentration was observed for vegetable oils. CONCLUSIONS: The contents of hydroperoxides and alkenals in omega-3 supplements are higher than in vegetable oils. After heating vegetable oils, a large increase in alkenal concentration was observed. PMID- 21691462 TI - Association of candy consumption with body weight measures, other health risk factors for cardiovascular disease, and diet quality in US children and adolescents: NHANES 1999-2004. AB - OBJECTIVE: The purpose of this study was to determine the effects of total, chocolate, or sugar candy consumption on intakes of total energy, fat, and added sugars; diet quality; weight/adiposity parameters; and risk factors for cardiovascular disease in children 2-13 years of age (n=7,049) and adolescents 14 18 years (n=4,132) participating in the 1999-2004 National Health and Nutrition Examination Survey. METHODS: Twenty-four hour dietary recalls were used to determine intake. Diet quality was determined using the Healthy Eating Index-2005 (HEI-2005). Covariate-adjusted means, standard errors, and prevalence rates were determined for each candy consumption group. Odds ratios were used to determine the likelihood of associations with weight status and diet quality. RESULTS: In younger children, total, chocolate, and sugar candy consumption was 11.4 g+/ 1.61, 4.8 g+/-0.35, and 6.6 g+/-0.46, respectively. In adolescents, total, chocolate, and sugar candy consumption was 13.0 g+/-0.87, 7.0 g+/-0.56, and 5.9 g+/-0.56, respectively. Total candy consumers had higher intakes of total energy (2248.9 kcals+/-26.8 vs 1993.1 kcals+/-15.1, p<0.0001) and added sugars (27.7 g+/ 0.44 vs 23.4 g+/-0.38, p<0.0001) than non-consumers. Mean HEI-2005 score was not different in total candy and sugar candy consumers as compared to non-consumers, but was significantly lower in chocolate candy consumers (46.7+/-0.8 vs 48.3+/ 0.4, p=0.0337). Weight, body mass index (BMI), waist circumference, percentiles/z score for weight-for-age and BMI-for-age were lower for candy consumers as compared to non-consumers. Candy consumers were 22 and 26%, respectively, less likely to be overweight and obese than non-candy consumers. Blood pressure, blood lipid levels, and cardiovascular risk factors were not different between total, chocolate, and sugar candy consumers and non-consumers (except that sugar candy consumers had lower C-reactive protein levels than non-consumers). CONCLUSION: This study suggests that candy consumption did not adversely affect health risk markers in children and adolescents. PMID- 21691463 TI - Racial Differences in the Time-Course Oxidative Stress Responses to Acute Exercise. AB - African Americans have disproportionate levels of cardiovascular disease and oxidative stress. The purpose of our study was to examine racial differences between African American and Caucasian adults in time-course oxidative stress responses to a treadmill test. After a 12-hr fast, 18 participants (9 of each ethnic group; 21 +/- 0.4 yrs) completed a submaximal treadmill test and underwent serial blood draws: Pre, Post (within 2 min), 30, 60, and 120 min after exercise. At each time-point, superoxide dismutase (SOD, U/mL), total antioxidant capacity (TAC, mM), protein carbonyls (PC, nmol/mg), and thiobarbituric acid-reactive substance (TBARs, MUmol/L) were measured. We found no difference between groups for blood pressure, BMI, or exercise capacity (as measured by volume of oxygen consumed, VO(2) max). African Americans had significantly (p < 0.05) higher SOD (Pre: 5.45 +/- 0.4 vs. 3.69 +/- 0.69; 60 min: 8.99 +/- 0.7 vs. 4.23 +/- 0.6; 120 min: 9.69 +/- 1.6 vs. 3.52 +/- 0.7), TAC (Pre: 2.31 +/- 0.25 vs. 1.16 +/- 0.3; Post: 2.39 +/- 0.2 vs. 1.34 +/- 0.2; 30 min: 2.29 +/- 0.2 vs. 1.09 +/- 0.2), and PC (Pre: 1.09 +/- 0.1 vs. 0.82 +/- 0.1; Post: 1.14 +/- 0.1 vs. 0.81 +/- 0.1; 30 min: 1.13 +/- 0.1 vs. 0.85 +/- 0.1; 60 min: 1.06 +/- 0.1 vs. 0.81 +/- 0.05), but not TBARs. Between groups, only SOD exhibited a different time-course response: levels for African Americans rose steadily throughout the 120 min, while levels for Caucasians peaked at 30 min and by 120 min had returned to pre-exercise levels. Race had a greater effect on oxidative stress responses than submaximal exercise did. African Americans had significantly higher TAC, SOD, and PC levels compared to Caucasians. PMID- 21691464 TI - Randomized Controlled Trial of Ondansetron vs. Prochlorperazine in Adults in the Emergency Department. AB - OBJECTIVE: To compare the effectiveness of ondansetron and prochlorperazine to treat vomiting. Secondary objectives were the effectiveness of ondansetron and prochlorperazine to treat nausea and their tolerability. METHODS: This was a prospective, randomized, active controlled, double-blinded study. Using a convenience sample, patients were randomized to either intravenous ondansetron 4mg (n=32) or prochlorperazine 10mg (n=32). The primary outcome was the percentage of patients with vomiting at 0-30, 31-60, and 61-120 minutes after the administration of ondansetron or prochlorperazine. Secondary outcomes were nausea assessed by a visual analog scale (VAS) at baseline, 0-30, 31-60, and 61-120 minutes after the administration of ondansetron or prochlorperazine and the percentage of patients with adverse effects (sedation, headache, akathisia, dystonia) to either drug. We performed statistical analyses on the VAS scales at each time point and did a subgroup analysis to examine if nausea scores were affected if the patient had vomited at baseline. RESULTS: The primary identified cause for nausea and vomiting was flu-like illness or gastroenteritis (19%). The number of patients experiencing breakthrough vomiting at 0-30, 31-60, and 61-120 minutes was similar between groups for these time periods; however, more patients receiving ondansetron experienced vomiting overall (7 [22%] vs. 2[3.2%] patients, p=not significant). Nausea scores at baseline and 0-30 minutes were severe and similar between groups; however, at 31-60 and 61-120 minutes, patients receiving prochlorperazine had better control of nausea (24.9 vs. 43.7 mm, p=0.03; 16.8 vs. 34.3 mm, p=0.05). Sedation scores were similar between groups. There were no cases of extrapyramidal symptoms as assessed by the treating physician and there were four cases of akathisia (prochlorperazine=3 [9%], ondansetron=1[3%]). CONCLUSION: Prochlorperazine and ondansetron appear to be equally effective at treating vomiting in the emergency department. PMID- 21691465 TI - Punch injuries: insights into intentional closed fist injuries. AB - OBJECTIVES: This study sought to investigate the patterns of injury resulting from a punch mechanism and to investigate the associated psychopathology present in patients with these injuries. METHODS: Retrospective analysis of patients with hand radiographs ordered from the emergency department allowed for identification of patients with a punch mechanism. We recorded injury patterns and queried patients' medical records for associated psychopathology. RESULTS: 1,292 patients underwent hand radiographs during a one-year time period; 172 patients (13%) were radiographed following an intentional punch injury, identifying 76 fractures in 70 patients. Males contributed a greater proportion of patients presenting with punch injury when compared to females (80% vs. 20%). Males were more likely to sustain fracture from a punch mechanism (48% vs. 11%, OR 7 [95% CI 2.3-20.9]), but were less likely to have preexisting documented psychiatric disease (23% vs. 49%, OR 3.1 [95% CI 1.4-6.7]). Of all fractures, 61% were to the fifth metacarpal, 21% were to the remainder of the metacarpals, and the remaining were fractures to phalanges and bones of the wrist. CONCLUSION: Women are less likely to present with punch injury and are less likely to sustain a fracture when they do present but have more associated psychiatric disease. Both men and women presenting with punch injuries have a higher prevalence of psychiatric disease than the background incidence in the population as a whole. Although punch injuries result in a significant number of boxer fractures, a number of other injuries are associated with punch mechanisms. PMID- 21691466 TI - Genetics of warfarin sensitivity in an emergency department population with thromboembolic. AB - BACKGROUND: Emergency department (ED) patients with venous thromboembolism (VTE) are eventually treated with a standard dose of warfarin despite the fact that a number of patients are known to be sensitive to warfarin and may experience supra therapeutic INRs and adverse bleeding events. Pharmacogenetics is an emerging field of medical practice that seeks to improve drug safety and efficacy in an individual patient by tailoring treatment to the patient's known genetic makeup. OBJECTIVE: To identify patients with risk for warfarin sensitivity among an ED population with VTE and to assess if the warfarin sensitivity mutations were of significant enough prevalence to be of clinical significance in customizing treatment of VTE. We sought in a pilot study to identify if testing for common CYP2C9 and VKORC1 single nucleotide polymorphisms (SNPs) in patients who were likely to begin warfarin treatment was feasible in an ED setting. METHODS: A prospective study that identified and enrolled patients presenting to our ED with high clinical suspicion of VTE. Those with high clinical suspicion of VTE were defined as those who had a Doppler ultrasound or computed tomography pulmonary angiography (CTPA) ordered by the primary emergency physician. Blood was taken and processed to ascertain the following SNPs: CYP2C9*2, CYP2C9*3, and VKORC1 3673. RESULTS: Of the 194 patients enrolled, 132 (68.0%) had at least one known warfarin sensitivity mutation and 114 (58.8%) had the most clinically significant VKORC1 3673 mutation. CONCLUSION: A majority of our patients had at least one mutation associated with the atypical metabolism of warfarin. Over half of our population had the most clinically significant VKORC1 3673 mutation. They would likely benefit from individualized warfarin dosing if ever needing anticoagulation. Our initial pilot study shows that allele frequencies of target warfarin sensitivity SNPs in our patient population are frequent enough to make initiation of personalized warfarin dosing feasible. PMID- 21691467 TI - New Functional Imaging Technology to Differentiate between Chronic Obstructive Pulmonary Disease and Heart Failure. PMID- 21691468 TI - Detailed analysis of prehospital interventions in medical priority dispatch system determinants. AB - BACKGROUND: Medical Priority Dispatch System (MPDS) is a type of Emergency Medical Dispatch (EMD) system used to prioritize 9-1-1 calls and optimize resource allocation. Dispatchers use a series of scripted questions to assign determinants to calls based on chief complaint and acuity. OBJECTIVE: We analyzed the prehospital interventions performed on patients with MPDS determinants for breathing problems, chest pain, unknown problem (man down), seizures, fainting (unconscious) and falls for transport status and interventions. METHODS: We matched all prehospital patients in complaint-based categories for breathing problems, chest pain, unknown problem (man down), seizures, fainting (unconscious) and falls from January 1, 2004, to December 31, 2006, with their prehospital record. Calls were queried for the following prehospital interventions: Basic Life Support care only, intravenous line placement only, medication given, procedures or non-transport. We defined Advanced Life Support (ALS) interventions as the administration of a medication or a procedure. RESULTS: Of the 77,394 MPDS calls during this period, 31,318 (40%) patients met inclusion criteria. Breathing problems made up 12.2%, chest pain 6%, unknown problem 1.4%, seizures 3%, falls 9% and unconscious/fainting 9% of the total number of MPDS calls. Patients with breathing problem had a low rate of procedures (0.7%) and cardiac arrest medications (1.6%) with 38% receiving some medication. Chest pain patients had a similar distribution; procedures (0.5%), cardiac arrest medication (1.5%) and any medication (64%). Unknown problem: procedures (1%), cardiac arrest medication (1.3%), any medication (18%). Patients with Seizures had a low rate of procedures (1.1%) and cardiac arrest medications (0.6%) with 20% receiving some medication. Fall patients had a lower rate of severe illness with more medication, mostly morphine: procedures (0.2%), cardiac arrest medication (0.2%), all medications (28%). Unconscious/fainting patients received the following interventions: procedures (0.3%), cardiac arrest medication (1.9%), all medications (32%). Few stepwise increases in the rate of procedures or medications were seen as determinants increased in acuity. CONCLUSION: Among these common MPDS complaint-based categories, the rates of advanced procedures and cardiac arrest medications were low. ALS medications were common in all categories and most determinants. Multiple determinants were rarely used and did not show higher rates of interventions with increasing acuity. Many MPDS determinants are of modest use to predict ALS intervention. PMID- 21691469 TI - Characteristics of patients with an abnormal glasgow coma scale score in the prehospital setting. AB - OBJECTIVE: This cross-sectional study describes the characteristics of patients with an abnormal Glasgow Coma Scale (GCS) in the prehospital setting. METHODS: We reviewed existing prehospital care reports (PCRs) in the San Mateo County, California, emergency medical services (EMS) database from January 1 to December 31, 2007. Adults age 18 or greater with a documented GCS fit inclusion criteria. We excluded single and multisystem trauma patients, as well as patients in cardiac arrest, respiratory arrest, or listed as deceased from the study. We classified the remaining patients as a normal GCS of 15 or abnormal (defined as less than 15 at any time during paramedic contact), and then further sub classified into mild (GCS 13-14), moderate (GCS 9-12) or severe (GCS 3-8). RESULTS: Of the 12,235 unique prehospital care record in the database, 9,044 (73.9%) met inclusion criteria, comprised of 2,404 (26.6%) abnormal GCS patients and 6,640 (73.4%) normal GCS patients. In the abnormal GCS category, we classified 1,361 (56.6%) patients as mild, 628 (26.1%) as moderate, and 415 (17.3%) as severe. Where sex was recorded, we identified 1,214 (50.5%) abnormal GCS patients and 2,904 (43.7%) normal GCS patients as male. Mean age was 65.6 years in the abnormal GCS group and 61.4 in the normal GCS group (p<0.0001). Abnormal GCS patients were more likely to have a history of conditions known to be associated, such as alcohol abuse (odds ratio [OR] 2.3, 95% confidence interval [CI]=2.75-3.00), diabetes (OR 1.34, 95% CI=1.17-1.54), substance abuse (OR 1.6, CI=1.09-2.3), stroke/transient ischemic attack (OR 2.0, CI=1.64-2.5), and seizures (OR 3.0, CI=1.64-2.5). Paramedics established intravenous (IV) access on 1,821 (75.7%, OR 1.94, CI=1.74-2.2) abnormal GCS patients and administered medications to 777 (32.3%, OR 1.01, CI=0.92-1.12). Compared to patients with normal GCS, patients with a mildly abnormal GCS were less likely to receive medications (OR 0.61, CI=0.53-0.70) while those with a moderately or severely abnormal GCS were more likely (OR 1.27, CI=1.07-1.50 and OR 2.86, CI=2.34-3.49, respectively). Of the normal GCS patients, 4,097 (61.7%) received an IV and 2,125 (32.0%) received medications by any route. CONCLUSION: Twenty seven percent of all prehospital patients in our study presented with an abnormal GCS. Prehospital patients with an abnormal GCS are more likely to be male, slightly older, and have higher rates of history of alcohol use or seizure. This group of patients had a higher rate of IV placement. Patients with a mildly abnormal GCS were less likely to receive medications while those with a moderately or severely abnormal GCS were more likely. PMID- 21691470 TI - Mass casualty incident response and aeromedical evacuation in antarctica. AB - Antarctica is one of the most remote regions on Earth. Mass casualty incident (MCI) responses in Antarctica are prone to complications from multiple environmental and operational challenges. This review of the current status of MCI risks and response strategies for Antarctica focuses on aeromedical evacuation, a critical component of many possible MCI scenarios. Extreme cold and weather, a lack of medical resources and a multitude of disparate international bases all exert unique demands on MCI response planning. Increasing cruise ship traffic is also escalating the risk of MCI occurrence. To be successful, MCI response must be well coordinated and undertaken by trained rescuers, especially in the setting of Antarctica. Helicopter rescue or aeromedical evacuation of victims to off-continent facilities may be necessary. Currently, military forces have the greatest capacity for mass air evacuation. Specific risks that are likely to occur include structure collapses, vehicle incapacitations, vehicle crashes and fires. All of these events pose concomitant risks of hypothermia among both victims and rescuers. Antarctica's unique environment requires flexible yet robust MCI response planning among the many entities in operation on the continent. PMID- 21691471 TI - Analgesia for older adults with abdominal or back pain in emergency department. AB - OBJECTIVE: To determine the association between age and analgesia for emergency department (ED) patients with abdominal or back pain. METHODS: Using a fully electronic medical record, we performed a retrospective cohort study of adults presenting with abdominal or back pain to two urban EDs. To assess differences in analgesia administration and time to analgesia between age groups, we used chi square and Kruskal-Wallis test respectively. To adjust for potential confounders, we used a generalized linear model with log link and Gaussian error. RESULTS: Of 24,752 subjects (mean age 42 years, 65% female, 69% black, mean triage pain score 7.5), the majority (76%) had abdominal pain and 61% received analgesia. The >=80 years group (n=722; 3%), compared to the 65-79 years group (n=2,080; 8%) and to the <65 years group (n=21,950; 89%), was more often female (71 vs. 61 vs. 65%), black (72 vs. 65 vs. 69%), and had a lower mean pain score (6.6 vs. 7.1 vs. 7.6). Both older groups were less likely to receive any analgesia (48 vs. 59 vs. 62%, p<0.0001) and the oldest group less likely to receive opiates (35 vs. 47 vs. 44%, p<0.0001). Of those who received analgesia, both older groups waited longer for their medication (123 vs. 113 vs. 94 minutes; p<0.0001). After controlling for potential confounders, patients >=80 years were 17% less likely than the <65 years group to receive analgesia (95% CI 14-20%). CONCLUSION: Older adults who present to the ED for abdominal or back pain are less likely to receive analgesia and wait significantly longer for pain medication compared to younger adults. PMID- 21691472 TI - Older emergency department drivers: patterns, behaviors, and willingness to enroll in a safe driver program. AB - OBJECTIVE: Our objective was to assess the reported driving patterns of older emergency department (ED) drivers and the factors that might lead them to enroll in a safe driving program. METHODS: We conducted a prospective, cross-sectional survey of a convenience sample of ED patients 65-years-old and up regarding their driving patterns, behaviors and willingness to enroll in a safe driving program. RESULTS: We surveyed 138 patients. Most (73%) reported driving within the last year, and 88% of these believe they could not manage without driving. Eleven percent of ED older drivers have been in a motor vehicle crash (MVC) in the past year (95% CI 6-20%), compared to 2.5% of all seniors. Our survey findings suggest that 88% of older ED drivers avoid at least some high-risk driving situations and 65% are unwilling to enroll in a safe driver program unless it lowers their automobile insurance rates. At the same time, most older ED drivers underestimate their risk of being involved in (75%) or dying from (74%) a MVC. CONCLUSION: Overall, there are a significant number of older people for whom driving remains a vital yet risky daily function. Most of these drivers have little interest in information regarding safe driving programs while in the ED. Those willing to learn about such programs would prefer to take home the information regarding the program rather than have any staff member discuss it while in the ED. PMID- 21691473 TI - Cognitive Impairment among Older Adults in the Emergency Department. AB - BACKGROUND: Within the next 30 years, the number of visits older adults will make to emergency departments (EDs) is expected to double from 16 million, or 14% of all visits, to 34 million and comprise nearly a quarter of all visits. OBJECTIVE: The objectives of this study were to determine prevalence rates of cognitive impairment among older adults in the ED and to identify associations, if any, between environmental factors unique to the ED and rates of cognitive impairment. METHODS: A cross-sectional observational study of adults 65 and older admitted to the ED of a large, urban, tertiary academic health center was conducted between September 2007 and May 2008. Patients were screened for cognitive impairment in orientation, recall and executive function using the Six-Item Screen (SIS) and the CLOX1, clock drawing task. Cognitive impairment among this ED population was assessed and both patient demographics and ED characteristics (crowding, triage time, location of assessment, triage class) were compared through adjusted generalized linear models. RESULTS: Forty-two percent (350/829) of elderly patients presented with deficits in orientation and recall as assessed by the SIS. An additional 36% of elderly patients with no impairment in orientation or recall had deficits in executive function as assessed by the CLOX1. In full model adjusted analyses patients were more likely to screen deficits in orientation and recall (SIS) if they were 85 years or older (Relative Risk [RR]=1.63, 95% Confidence Interval [95% CI]=1.3-2.07), black (RR=1.85, 95% CI=1.5-2.4) and male (RR=1.42, 95% CI=1.2-1.7). Only age was significantly associated with executive functioning deficits in the ED screened using the clock drawing task (CLOX1) (75 84 years: RR=1.35, 95% CI= 1.2-1.6; 85+ years: RR=1.69, 95% CI= 1.5-2.0). CONCLUSION: These findings have several implications for patients seen in the ED. The SIS coupled with a clock drawing task (CLOX1) provide a rapid and simple method for assessing and documenting cognition when lengthier assessment tools are not feasible and add to the literature on the use of these tools in the ED. Further research on provider use of these tools and potential implication for quality improvement is needed. PMID- 21691474 TI - Urine test strips to exclude cerebral spinal fluid blood. AB - INTRODUCTION: Determining the presence or absence of red blood cells (RBC) or their breakdown products in cerebrospinal fluid (CSF) is essential for the evaluation of subarachnoid hemorrhage (SAH) in headache patients. Current methodology for finding blood in the CSF is either spectrophotometric detection of pigment, which is time consuming and labor intensive, or visual assesment of samples for color change (xanthochromia), which is inaccurate. Bayer Multistix((r)) urine test strips are designed to test urine for RBC by detecting the presence of hemoglobin. The aim of this pilot study was to evaluate the perfomance of urine reagent test strips for ruling out the presence of RBC in CSF. METHODS: We compared color changes on Multistix((r)) urine test strips to the standard of spectrophotometric absorbtion at 415nm and initial RBC counts in 138 visually clear CSF samples. RESULTS: We performed Pearson Chi-Square and likelihood ratios on the results and found a correlation between a negative result on the urine test strip and less than 5 RBC per high power field and a spectrophotometric absorbance of less than 0.02% at 415nm in a CSF sample. CONCLUSION: These results warrant further investigation in the form of a prospective clinical validation as it may alter the emergency department evaluation for SAH. PMID- 21691476 TI - Primary cardiac tumor identified as the cause of seizure. AB - A 65-year-old woman presented to the emergency department after a seizure. An unexplained bradycardia and heart murmur were detected and an emergency bedside echocardiography was performed. This revealed a mass in the left atrium. The provisional diagnosis of left atrial tumor was later confirmed by formal echocardiography and ultimately by histology. The first presentation of primary cardiac tumors can be misleading and sometimes presents with neurological manifestations. An early echocardiography can be diagnostic and could lead to early surgical intervention with better prognosis. PMID- 21691475 TI - Excited delirium. AB - Excited (or agitated) delirium is characterized by agitation, aggression, acute distress and sudden death, often in the pre-hospital care setting. It is typically associated with the use of drugs that alter dopamine processing, hyperthermia, and, most notably, sometimes with death of the affected person in the custody of law enforcement. Subjects typically die from cardiopulmonary arrest, although the cause is debated. Unfortunately an adequate treatment plan has yet to be established, in part due to the fact that most patients die before hospital arrival. While there is still much to be discovered about the pathophysiology and treatment, it is hoped that this extensive review will provide both police and medical personnel with the information necessary to recognize and respond appropriately to excited delirium. PMID- 21691477 TI - Contagious weakness in an elderly couple with neurologic emergencies. AB - We present an unusual neurologic emergency in an elderly male patient. Given his presentation and risk factors, we presumed the initial symptoms to be secondary to a cerebrovascular accident. As the case evolved, however, it became apparent that a more unusual pathology was present. This case report showcases a rare condition masquerading as a common neurologic emergency. PMID- 21691479 TI - Variable access to immediate bedside ultrasound in the emergency department. AB - OBJECTIVE: Use of bedside emergency department (ED) ultrasound has become increasingly important for the clinical practice of emergency medicine (EM). We sought to evaluate differences in the availability of immediate bedside ultrasound based on basic ED characteristics and physician staffing. METHODS: We surveyed ED directors in all 351 EDs in Colorado, Georgia, Massachusetts, and Oregon between January and April 2009. We assessed access to bedside ED ultrasound by the question: "Is bedside ultrasound available immediately in the ED?" ED characteristics included location, visit volume, admission rate, percent uninsured, total emergency physician full-time equivalents and proportion of EM board-certified (BC) or EM board-eligible (BE) physicians. Data analysis used chi square tests and multivariable logistical regression to compare differences in access to bedside ED ultrasound by ED characteristics and staffing. RESULTS: We received complete responses from 298 (85%) EDs. Immediate access to bedside ultrasound was available in 175 (59%) EDs. ED characteristics associated with access to bedside ultrasound were: location (39% for rural vs. 71% for urban, P<0.001); visit volume (34% for EDs with low volume [<1 patient/hour] vs. 79% for EDs with high volume [>=3 patients/hour], P<0.001); admission rate (39% for EDs with low [0-10%] admission rates vs. 84% for EDs with high [>20%] rates, P<0.001); and EM BC/BE physicians (26% for EDs with a low percentage [0-20%] vs.74% for EDs with a high percentage [>=80%], P<0.001). CONCLUSION: U.S. EDs differ significantly in their access to immediate bedside ultrasound. Smaller, rural EDs and those staffed by fewer EM BC/BE physicians more frequently lacked access to immediate bedside ultrasound in the ED. PMID- 21691478 TI - Differential use of diagnostic ultrasound in u.s. Emergency departments by time of day. AB - BACKGROUND: Survey data over the last several decades suggests that emergency department (ED) access to diagnostic ultrasound performed by the radiology department is unreliable, particularly outside of regular business hours. OBJECTIVE: To evaluate the association between the time of day of patient presentation and the use of diagnostic ultrasound services in United States (U.S.) EDs. METHODS: This was a cross-sectional study of ED patient visits using the National Hospital Ambulatory Medical Care Survey for the years 2003 to 2005. Our main outcome measure was the use of diagnostic ultrasound during the ED patient visit as abstracted from the medical record. We performed multivariate analyses to identify any association between ultrasound use and time of presentation for all patients, as well as for two subgroups who are more likely to need ultrasound as part of their routine workup: patients at risk of deep venous thrombosis, and patients at risk for ectopic pregnancy. RESULTS: During the three-year period, we analyzed 110,447 patient encounters, representing 39 million national visits. Of all ED visits, 2.6% received diagnostic ultrasound. Presenting to the ED "off hours" (defined as Monday through Friday 7pm to 7am and weekends) was associated with a lower rate of ultrasound use independent of potential confounders (odds ratio [OR] 0.73, 95% confidence interval [CI]: 0.65 - 0.82). Patients at increased risk of deep venous thrombosis who presented to the ED during "off hours" were also less likely to undergo diagnostic ultrasound (OR 0.34, 95% CI: 0.15 - 0.79). Similarly, patients at increased risk of ectopic pregnancy received fewer diagnostic ultrasounds during "off hours" (OR 0.56, 95% CI 0.35 - 0.91). CONCLUSION: In U.S. EDs, ultrasound use was lower during "off hours," even among patient populations where its use would be strongly indicated. PMID- 21691480 TI - Accidental carotid artery cannulation detected by bedside ultrasound. AB - This report highlights the importance of using bedside ultrasound in the emergency department to confirm guide-wire placement when performing central venous catheter placement prior to dilating and cannulating the vessel. PMID- 21691482 TI - Great tool or gold standard? B-type natriuretic Peptide and congestive heart failure. PMID- 21691481 TI - Identification of Sonographic B-lines with Linear Transducer Predicts Elevated B Type Natriuretic Peptide Level. AB - OBJECTIVE: This study sought to correlate the presence of pleural-based B-lines seen by emergency department ultrasound performed with the linear transducer with B-type natriuretic peptide (BNP) level in patients with suspected congestive heart failure. METHODS: The study was a prospective convenience sample on adult patients in an academic, urban emergency department with over 100,000 annual patient visits. Adult patients with a BNP level ordered by the treating physician were prospectively enrolled by one of four physicians, blinded to the BNP level. The enrolling physicians included an emergency ultrasound director, two emergency ultrasound fellows, and a senior emergency medicine resident. Bedside ultrasound was performed using a 3-12 MHz linear broadband transducer in four lung fields. The serum BNP level was correlated with bilateral B-lines, defined as three or more comet-tail artifacts arising from the pleural line extending to the far field without a decrease in intensity on the right and left thorax. RESULTS: Sixty three patients were consented and enrolled during a four-month period. Fifteen patients had the presence of bilateral B-lines. The median BNP in patients with bilateral B-lines was 1560 pg/mL (95% confidence interval (CI) 1141 3706 pg/mL), compared with 538 pg/mL (95% confidence interval 310-1917 pg/mL) in patients without B-lines. The distributions in the two groups differed significantly (p=0.0006). Based on the threshold level of BNP 500 pg/mL, the sensitivity of finding bilateral B-lines on ultrasound was 33.3% (95% CI: 0.19 0.50), and the specificity was 91.7% (95% CI: 0.73-0.99). In addition, bilateral B-lines were absent in all patients with a BNP<100 pg/mL. CONCLUSION: The presence of bilateral B-lines identified with the linear probe is associated with significantly higher BNP levels than patients without B-lines. In our patient population, the presence of B-lines was specific but not sensitive for BNP>500. Further research may show that it can be applied to quickly assess patients with undifferentiated dyspnea. PMID- 21691483 TI - The standard of care: legal history and definitions: the bad and good news. AB - The true meaning of the term "the standard of care" is a frequent topic of discussion among emergency physicians as they evaluate and perform care on patients. This article, using legal cases and dictums, reviews the legal history and definitions of the standard of care. The goal is to provide the working physician with a practical and useful model of the standard of care to help guide daily practice. PMID- 21691484 TI - Cardiac tamponade after minimally invasive coronary artery bypass graft. PMID- 21691485 TI - Plastic bronchitis. PMID- 21691486 TI - Akathisia after cyclic antidepressants poisoning. PMID- 21691487 TI - Symptomatic morgagni hernia misdiagnosed as chilaiditi syndrome. AB - Chilaiditi syndrome, symptomatic interposition of bowel beneath the right hemidiaphragm, is uncommon and usually managed without surgery. Morgagni hernia is an uncommon diaphragmatic hernia that generally requires surgery. In this case a patient with a longstanding diagnosis of bowel interposition (Chilaiditi sign) presented with presumed Chilaiditi syndrome. Abdominal computed tomography was performed and revealed no bowel interposition; instead, a Morgagni hernia was found and surgically repaired. Review of the literature did not reveal similar misdiagnosis or recommendations for advanced imaging in patients with Chilaiditi sign or syndrome to confirm the diagnosis or rule out other potential diagnoses. PMID- 21691488 TI - Lingual ischemia from prolonged insertion of a fastrach laryngeal mask airway. AB - We report a case of lingual ischemia and swelling in an elderly stroke patient from prolonged insertion of a FastrachTM Laryngeal Mask Airway (r) following a failed Emergency Department intubation. Simple suggestions to mitigate such injury are provided. PMID- 21691489 TI - Delayed duodenal hematoma and pancreatitis from a seatbelt injury. AB - Traumatic duodenal hematoma is a rare condition that is encountered in the paediatric age group following blunt abdominal trauma. It poses both a diagnostic and therapeutic challenge. The main concern is increased morbidity secondary to delayed diagnosis and associated occult injuries to the adjacent structures. Most of these hematomas resolve spontaneously with conservative management, and the prognosis is good. We present a case of a 15-year-old boy who had a delayed presentation of duodenal hematoma and acute pancreatitis, which was treated conservatively with complete resolution. PMID- 21691490 TI - Fracture blisters. AB - Fracture blisters are a relatively uncommon complication of fractures in locations of the body, such as the ankle, wrist elbow and foot, where skin adheres tightly to bone with little subcutaneous fat cushioning. The blister that results resembles that of a second degree burn.These blisters significantly alter treatment, making it difficult to splint or cast and often overlying ideal surgical incision sites. Review of the literature reveals no consensus on management; however, most authors agree on early treatment prior to blister formation or delay until blister resolution before attempting surgical correction or stabilization. PMID- 21691491 TI - Spontaneous thigh compartment syndrome. AB - A young man presented with a painful and swollen thigh, without any history of trauma, illness, coagulopathic medication or recent exertional exercise. Preliminary imaging delineated a haematoma in the anterior thigh, without any fractures or muscle trauma. Emergent fasciotomies were performed. No pathology could be identified intra-operatively, or on follow-up imaging. A review of thigh compartment syndromes described in literature is presented in a table. Emergency physicians and traumatologists should be cognisant of spontaneous atraumatic presentations of thigh compartment syndrome, to ensure prompt referral and definitive management of this limb-threatening condition. PMID- 21691492 TI - Patellar tendonitis. PMID- 21691493 TI - Isolated traumatic expressive aphasia. PMID- 21691494 TI - Neurologically intact lumbar spine displaced fracture with ankylosing spondylitis. PMID- 21691495 TI - Dear friends in FODI. PMID- 21691496 TI - An evaluation of antibacterial efficacy of 3% sodium hypochlorite, high-frequency alternating current and 2% chlorhexidine on Enterococcus faecalis: An in vitro study. AB - AIM: The purpose of this study was to evaluate the antibacterial efficacy of 3% sodium hypochlorite (NaOCl), high-frequency alternating current (HFAC) (Endox Endodontic System), 2% chlorhexidine (CHX) in elimination of Enterococcus faecalis from experimentally infected root canals, in vitro. MATERIALS AND METHODS: Eighty extracted, single rooted permanent upper anterior teeth were instrumented up to size 50, teeth were sterilized and inoculated with E. faecalis, subcultured in BHI broth which had its optical density adjusted to approximately 1.5Chi10(8) colony forming units (CFUs) ml(-1) by comparing its turbidity to a McFarland 0.5 BaSO(4) standard solution. After incubation for 24 h, the contaminated root canals were divided into four groups and subjected to action of NaOCl 3%, CHX 2%, and HFAC with physiological saline as a positive control. Sterile paper points were selected to take the sample of the bacteria and transferred to tubes containing 5ml of BHI broth and then incubated for 24 and 48 h, followed by agar plating of the resultant broth turbidity on Enterococcus confirmatory agar. RESULTS: Data obtained were analyzed statistically for differences using chi-squared test, comparing different groups, with a significance level established at P<0.05 and 3% NaOCl showed no growth postoperatively, CHX and HFAC showed reduction of postoperative growth compared to physiological saline and, were statistically significant (P<0.05). CONCLUSION: In the present study, sodium hypochlorite, CHX, HFAC all were significantly effective in eliminating E. faecalis and sodium hypochlorite showed the maximum anti-bacterial activity against E. faecalis. PMID- 21691497 TI - Effect of internal matrices of hydroxyapatite and calcium sulfate on the sealing ability of mineral trioxide aggregate and light cured glass ionomer cement. AB - OBJECTIVE: The present study was undertaken to evaluate the effect of hydroxyapatite (HA) and calcium sulfate (CS) on the sealing ability of mineral trioxide aggregate (MTA) and light cured glass ionomer cement (LC GIC) when used to repair furcation perforations. MATERIALS AND METHODS: The study was conducted on 70 human molars. Sixty teeth with furcal perforations were randomly divided into six groups of 10 teeth each and repaired with MTA or LC GIC either alone or over an internal matrix, i.e., CS or HA. Access openings were filled with composite resin. Five teeth with unrepaired perforations were used as positive controls and five teeth without perforations were used as negative controls. The teeth were immersed in a solution of 2% methylene blue dye for 2 weeks. The samples were then sectioned and evaluated for linear dye leakage and analyzed statistically. RESULTS: MTA showed the best sealing ability followed by LC GIC, MTA + CS, MTA + HA, LC GIC + CS and LC GIC + HA. CONCLUSION: Neither of the two internal matrices improved the sealing ability of the repair materials used. PMID- 21691499 TI - Comparative evaluation of the apical sealing ability and adaptation to dentine of three resin-based sealers: An in vitro study. AB - OBJECTIVE: To evaluate the apical sealing ability and adaptation of three resin based sealers to the dentine. MATERIALS AND METHODS: A total of 66 recently extracted human maxillary anterior teeth were subjected for the study. The teeth were prepared and obturated with gutta-percha by a lateral condensation using AH Plus, Endorez and Epiphany sealers. Fifteen teeth from each group were used for the apical leakage test and the remaining five teeth from each group were used for examination under the scanning electron microscope. Data were analyzed using one-way ANOVA and the Student Newman-Keuls test. RESULTS: Epiphany sealer showed better sealing ability and adaptation to dentine. CONCLUSION: The Epiphany sealer has a better apical sealing ability and adaptation to dentine than the AH Plus and Endorez sealers. PMID- 21691498 TI - Survival rates of porcelain laminate restoration based on different incisal preparation designs: An analysis. AB - BACKGROUND: Veneer restorations provide a valid conservative alternative to complete coverage as they avoid aggressive dental preparation; thus, maintaining tooth structure. Initially, laminates were placed on the unprepared tooth surface. Although there is as yet no consensus as to whether or not teeth should be prepared for laminate veneers, currently, more conservative preparations have been advocated. Because of their esthetic appeal, biocompatibility and adherence to the physiology of minimal-invasive dentistry, porcelain laminate veneers have now become a restoration of choice. Currently, there is a lack of clinical consensus regarding the type of design preferred for laminates. Widely varying survival rates and methods for its estimation have been reported for porcelain veneers over approximately 2-10 years. Relatively few studies have been reported in the literature that use survival estimates, which allow for valid study comparisons between the types of preparation designs used. No survival analysis has been undertaken for the designs used. The purpose of this article is to attempt to review the survival rates of veneers based on different incisal preparation designs from both clinical and non-clinical studies. AIMS AND OBJECTIVES: The purpose of this study is to review both clinical and non-clinical studies to determine the survival rates of veneers based on different incisal preparation designs. A further objective of the study is to understand which is the most successful design in terms of preparation. MATERIALS AND METHODS: This study evaluated the existing literature - survival rates of veneers based on incisal preparation designs. The search strategy involved MEDLINE, BITTORRENT and other databases. STATISTICAL ANALYSIS: Data were tabulated. Because of variability in the follow-up period in different studies, the follow-up period was extrapolated to 10 years in common for all of them. Accordingly, the failure rate was then estimated and The weighted mean was computed. CONCLUSIONS: The study found that the window preparation was of the most conservative type. Incisal coverage was better than no incisal coverage and, in incisal coverage, two predictable designs - incisal overlap and butt were reported. In butt preparation, no long-term follow-up studies have been performed as yet. In general, incisal overlap was preferred for healthy normal tooth with sufficient thickness and incisal butt preparation was preferred for worn tooth and fractured teeth. PMID- 21691500 TI - The comparison of microbial leakage in roots filled with resilon and gutta percha: An in vitro study. AB - BACKGROUND AND OBJECTIVE: The objective of this study was to compare bacterial leakage using streptococcus mutans through gutta-percha and a thermoplastic synthetic polymer based root canal filling material (Resilon) using two filling techniques. MATERIALS AND METHODS: A total of 90 single-rooted extracted human teeth were subjected for the study. Teeth were divided into 6 groups of 10 and 3 control groups of 10 teeth each. All the samples were decoronated and the coronal surfaces of the roots were prepared perpendicular to the long axis of the root with a high-speed handpiece and a multipurpose bur using air water spray. The length of all the roots was prepared approximately 16 mm from the coronal surface to the apex of the root. Roots were filled using lateral and vertical condensation techniques with gutta-percha and AH26 sealer (Group 1 and 2) or with gutta-percha and epiphany sealer (Group 3 and 4). Group 5 and 6 were filled with Resilon and epiphany sealer using the lateral and vertical condensation techniques. A split chamber microbial leakage model was used in which S. mutans placed in the upper chamber could reach the lower chamber only through the filled root canal. Group 7 and 8 (positive control) were filled with Resilon and gutta percha without sealer and tested with bacteria, whereas Group 7 (negative control) was sealed with wax to test the seal between the chambers. Data were analyzed using Kruskal-Wallis test and Mann-Whitney U test. RESULTS: All positive groups (Group 7 and 8) showed leakage within 1 hour of the start of the study (100%), whereas none of the negative control (Group 9) leaked. The roots obturated with Resilon and epiphany (Group 5 and 6) showed minimal leakage, i.e., each with 6 leakages, which was significantly less than gutta-percha (Group 1-4), in which approximately 80% of specimens with either sealer or techniques leaked. Kruskal-Wallis test showed statistical significance when all groups were compared (P<0.05). Mann-Whitney U test compared the respective groups and found Resilon groups superior to gutta-percha groups (P<0.05). INTERPRETATION AND CONCLUSION: This study demonstrated that the new polymer-based Resilon and epiphany sealer using two obturating techniques, i.e., lateral as well as vertical condensation found to be significantly better than the gutta-percha. PMID- 21691501 TI - Evaluation of post-surface conditioning to improve interfacial adhesion in post core restorations. AB - AIM: To examine the influence of different post-surface treatments on the interfacial strength between epoxy resin-based fiber posts and methacrylate-based resin composites that are employed as core build-up materials. MATERIALS AND METHODS: Forty clear posts were divided into four groups of 10 each. The different surface treatments used were etching with alkaline potassium permanganate, 10% hydrogen peroxide, 37% phosphoric acid, and silanization alone. After etching and thorough rinsing, a single layer of silane was applied to the post surface. Then the post was placed in a rectangular plastic matrix and core bulid-up was done using Multi Core, a dual cured composite resin. A slab of uniform thickness, with the post in the center and the core build-up composite on either side was created. The specimens were cut so as to obtain microtensile sticks that were loaded in tension at a cross-head speed of 1 mm/min until failure. The statistical analysis was performed using two-way ANOVA and the paired T test for post-hoc comparisons. RESULTS: The results achieved with potassium permanganate had a significant influence on microtensile interfacial bond strength values with the tested material. CONCLUSION: Surface chemical treatments of the resin phase of fiber posts enhance the silanization efficiency of the quartz fiber phase, so that the adhesion in the post/core unit may be considered as a net sum of chemical and micromechanical retention. PMID- 21691502 TI - Influence of caries detection dye on bond strength of sound and carious affected dentin: An in-vitro study. AB - OBJECTIVES: The objective of this study was to evaluate the influence of caries detection dye on the in-vitro tensile bond strength of adhesive materials to sound and carious affected dentin. MATERIALS AND METHODS: Forty healthy and carious human molars were ground to expose superficial sound dentin and carious affected dentin. Caries Detector dye was applied to sound and carious affected dentin and rinsed. Subsequently the dentin was etched with 37% phosphoric acid and rinsed leaving a moist dentin surface. The adhesive (Single bond) was applied in single layers and light cured. A posterior composite (Filtek Z 250) were used to prepare the bond strength specimens with a 3 mm in diameter bonding area. Control and experimental groups were made with and without application of dye respectively. Each group includes both sound and carious affected dentin. After 24 hour immersion in distilled water, tensile bond strength (MPa) was measured using an Instron testing machine. RESULTS: Analysis of variance (ANOVA) was used to evaluate the data. The tensile bond strength were significantly less in experimental subgroup than control subgroups. CONCLUSION: The tensile bond strengths were higher in sound and carious affected dentin without application of caries detection dyes. PMID- 21691503 TI - An evalution of compressive strength of newer nanocomposite: An in vitro study. AB - AIM: The purpose of the study is to assess and compare compressive strength of newer nanocomposites (FiltekZ350, Ceram X Mono, Ceram X Duo) with microhybrid (Tetric Ceram) and to compare difference in compressive strength of newer nanocomposites. MATERIALS AND METHODS: Forty eight specimens of composite were fabricated using customized biparpite brass mold measuring 5mm x 5mm and were grouped with twelve specimens in each Group I : Tetric Ceram, Group II: Filtek Z 350, Group III : Ceram X Mono, Group IV : Ceram X Duo. Composite resins are placed in cylindrical recesses and covered with mylar strip and are cured using QHL light curing unit. Compressive strength is evaluated using Instron machine. Results are statistically analyzed using One way Anova and Student t test. Analysis demonstrated that nanocomposites have better compressive strength than micro hybrid (P<0.001). RESULTS: Within the limitations of the study, it can be concluded that nanocomposites have better compressive strength than microhybrid composite and nanocomposite showed optimal compressive strength of 312 - 417 Mpa. PMID- 21691504 TI - Effects of various final irrigants on the shear bond strength of resin-based sealer to dentin. AB - AIM: This study has been designed to evaluate the effect of strong (MTAD) or soft (1- hydroxyethylidene - 1, 1-bisphosphonate (HEBP) final irrigating solution on the shear bond strength of AH plus sealer to coronal dentin. 17% EDTA was used as the reference. MATERIALS AND METHODS: Forty freshly extracted human maxillary first premolars were prepared using different irrigation protocols (n=10). All the test groups had 1.3% NaOCl as initial rinse and followed by specific final rinse for each group: G1 - distilled water(control), G2 - 17% EDTA, G3- 18% HEBP and G4 - MTAD. Sections of polyethylene tubes that are 3mm long were filled with freshly mixed sealer and placed on the dentin surfaces. The bonding between the sealer and dentine surface was evaluated using shear bond testing. The values were statistically evaluated using one-way ANOVA followed by Tukey's test. RESULT: Significant difference was found among the irrigating regimes. EDTA showed highest bond strength followed by HEBP and MTAD. PMID- 21691505 TI - Effect of 4% titanium tetrafluoride application on shear bond strength of composite resin: An in vitro study. AB - AIMS: The objective of thisstudy is to evaluate and compare 4% titanium tetrafluoride with 2% Sodium fluoride, and the bond strength of composite resin with dentin and their effects on the smear layer. MATERIALS AND METHODS: Fifty freshly extracted non-carious molar and premolar teeth were selected. The occlusal surfaces of the teeth were ground, to prepare flat dentin surfaces at a depth of 2 mm and were randomly grouped with 10 specimens in each. Group I (Etching + Adhesive + Composite resin) was taken as a control group. In Group II, 4% titanium tetrafluoride was applied before etching and in Group III, 4% titanium tetrafluoride was applied after etching. In Group IV, 2% Sodium fluoride was applied before etching and in Group V, 2% Sodium fluoride was applied after etching. Shear bond strength was tested using the Lloyds Universal testing machine and was recorded in MPa. RESULTS: The results were statistically analyzed using the one-way Anova test. Group III showed the highest bond strength among the experimental groups, but less than the control group. CONCLUSIONS: Under the conditions of this in vitro study, titanium tetrafluoride did not significantly affect the bond strength of the composite. Sodium fluoride was found to deleteriously affect the bond strength of the composite. PMID- 21691506 TI - Comparative evaluation of combined amalgam and composite resin restorations in extensively carious vital posterior teeth: An in vivo study. AB - AIM: The clinical performance of the combined composite - amalgam restorations in posterior teeth was evaluated. MATERIALS AND METHODS: One hundred carious posterior teeth were randomly divided into four groups of 25 teeth each. In Group A, the teeth were restored with composite Z250 and amalgam FusionAlloy. In Group B, composite Surefil and amalgam were used. In Groups C and D, the teeth were restored with composite Surefil and amalgam FusionAlloy, respectively. The restorations were evaluated at 3, 6, 12, and 15 months, using the Ryge criteria. RESULTS: Combined restorations and amalgam restorations showed better contact and contour than the composite restorations. No statistically significant difference was observed among the groups. Three amalgam restorations exhibited loss of retention. CONCLUSION: The combined composite-amalgam restorations performed better for contact and contour and retention than composite and amalgam restorations, respectively. PMID- 21691507 TI - Effect of thermal and mechanical loading on marginal adaptation and microtensile bond strength of a self-etching adhesive with caries-affected dentin. AB - AIM: This study evaluated the effect of thermal and mechanical loading on marginal adaptation and microtensile bond strength in total-etch versus self-etch adhesive systems in caries-affected dentin. MATERIALS AND METHODS: FORTY CLASS II CAVITIES WERE PREPARED ON EXTRACTED PROXIMALLY CARIOUS HUMAN MANDIBULAR FIRST MOLARS AND WERE DIVIDED INTO TWO GROUPS: Group I - self-etch adhesive system restorations and Group II - total-etch adhesive system restorations. Group I and II were further divided into sub-groups A (Without thermal and mechanical loading) and B (With thermal and mechanical loading of 5000 cycles, 5 +/- 2 degrees C to 55 +/- 2 degrees C, dwell time 30 seconds, and 150,000 cycles at 60N). The gingival margin of the proximal box was evaluated at 200X magnification for marginal adaptation in a low vacuum scanning electron microscope. The restorations were sectioned, perpendicular to the bonded surface, into 0.8 mm thick slabs. All the specimens were subjected to microtensile bond strength testing. The marginal adaptation was analyzed using descriptive studies, and the bond strength data was analyzed using the one-way analysis of variance (ANOVA) test. RESULTS AND CONCLUSIONS: The total-etch system performed better under thermomechanical loading. PMID- 21691508 TI - Evaluation and comparison of sealing ability of three different obturation techniques - Lateral condensation, Obtura II, and GuttaFlow: An in vitro study. AB - AIM: To evaluate and compare the sealing ability between the conventional cold lateral condensation technique and two different obturating techniques - Obtura II and GuttaFlow under a stereomicroscope at 40* magnification. MATERIALS AND METHODS: Sixty single-rooted teeth were selected and the canals were shaped with ProTaper rotary files. Irrigation was performed with 5% sodium hypochlorite and 17% EDTA. The teeth were then separated into three groups depending on the type of obturation technique. Group A (n = 20) - obturated using the Lateral condensation technique and AHplus sealer, Group B (n = 20) - obturated with Obtura II injection-molded thermoplasticized technique and AHplus sealer, and Group C (n = 20) obturated using GuttaFlow. After storing the teeth in 100% humidity for seven days at 37 degrees C, the roots of the teeth were sectioned at five levels. The sections were then observed under a stereomicroscope at 40 * magnification and the images were analyzed for area of voids (AV) and frequency of voids. STATISTICAL ANALYSIS USED: The data was statistically analyzed using the SPSS version 17 software. The 95% confidence intervals (CI) were calculated. One-way analysis of variance with post-hoc test and non-parametric Mann-Whitney U test was carried out, to compare the means. RESULTS: The lowest mean of AV was recorded in the Obtura II group, 1.0% (95% CI = 0.5 - 1.5). This was statistically and significantly different from the GuttaFlow group, 3.0% (95% CI = 2.1 - 3.9). There was no significant difference between the Obtura II group and the lateral condensation group, 1.6% (95% CI= 1.0 - 2.2) with regard to the area of voids, but there was a statistically significant difference between the Lateral condensation and GuttaFlow groups. The GuttaFlow group showed the maximum number of voids, 56% (95% CI = 48 - 64), which was significantly higher than those in the lateral condensation, 26% (95% CI= 19 - 34), and Obtura II, 15% (95% CI= 10 - 21) groups. CONCLUSION: The Obtura II technique utilizing the injection molded thermoplasticized gutta-percha had better adaptability to the canal walls when compared to the GuttaFlow obturation and lateral condensation techniques. PMID- 21691510 TI - Prognosis of periapical surgery using bonegrafts: A clinical study. AB - AIM: to evaluate and compares the healing clinically and radiographically following periapical surgery with and without using hydroxyapatite graules. MATERIALS AND METHODS: Twenty patients were selected for the study & the nature of healing is compared with that of conventional periapical surgery. In the present clinical study chitra hydroxyapatite granules, a freeze-dried hydroxyapatite, is used to fill the osseous defects following periapical surgery. Following surgery all patients were assessed both clinically & radiographically for a period of nine months. RESULTS: On clinical evaluation the test group did not show any significant immediate or delayed local tissue reactions. Radiographically in the follow up period of 6 - 9 months the bone graft became indistinguishable from the surrounding bone which indicates complete bone regeneration. Where as in the control group ever after 9 months the radiographs showed inadequate bone fills. CONCLUSION: The bone regeneration following periapical surgery can be facilitated by using bone graft. Hydroxyapatite is found to be very effective alloplastic material. Based on this study it might be concluded that in large bone destruction caused by periradicular lesion bone regeneration can be facilitated by effective bone replacing materials like hydroxyapatite. PMID- 21691509 TI - Factors affecting the bond strength of self-etch adhesives: A meta-analysis of literature. AB - AIM: The purpose of this study is to critically evaluate the factors that affect the bond strength of one-step and two-step self-etch adhesives by using meta analysis. MATERIALS AND METHODS: Potential papers that were selected according to inclusion and exclusion criteria from articles were published in 13 peer-reviewed journals using "PubMed data base". From each report, means and standard deviations of bond strengths were extracted and tabulated with corresponding experimental conditions. RESULTS: All the studied parameters showed no significant difference, except for dentin origin/site and bonding area. In addition, statistical analysis done with ANOVA showed statistical significance between the one-step and two-step self-etch adhesives. CONCLUSIONS: Our analysis has showed that two-step self-etch adhesive system showed a superior in vitro performance in comparison to one-step self-etch system. Nevertheless, certain factors such as dentin origin, site and area of bonding affect the bond strength of adhesives. PMID- 21691511 TI - Effects of different bleaching time intervals on fracture toughness of enamel. AB - AIM: This study was designed to evaluate the influence of different time intervals of a vital home bleaching procedure on the fracture toughness of bovine enamel. MATERIALS AND METHODS: Labial aspects of 48 bovine incisors were prepared and stored in artificial saliva. The samples were divided into four groups (n = 12) according to the different time intervals of the bleaching procedure: 0, 2, 4, and 6 weeks. The experimental groups were subjected to the bleaching agent; 15% Opalescence PF according to manufacturer's instructions. The fracture toughness (FT) of enamel was assessed using Vickers hardness indentation. Then, FTs were compared statistically by one-way ANOVA (alpha = 0.05). RESULTS AND DISCUSSION: Different tested time intervals did not significantly influence the fracture toughness of bovine enamel following treatment with 15% carbamide peroxide (P = 0.05) CONCLUSION: 15% Opalescence PF after 6 weeks did not reduce the fracture toughness of human enamel compared with the baseline, 2 and 4-week values. PMID- 21691512 TI - Postoperative sensitivity in Class V composite restorations: Comparing soft start vs. constant curing modes of LED. AB - BACKGROUND: One of the major disadvantages associated with using composites is polymerization shrinkage; stresses are generated at the margins, and if these stresses exceed the bond strength, microleakage occurs at the tooth restoration interface which causes ingress of cariogenic bacteria, post-operative sensitivity, and secondary caries. LED offers several curing modes: constant cure, ramped cure, and soft start cure. It is claimed that soft start polymerization mode produces less polymerization shrinkage and consequently less postoperative sensitivity. OBJECTIVE: To compare the postoperative sensitivity in Class V composite restorations using soft start and constant LED curing modes. MATERIALS AND METHODS: Using the appropriate burrs cavity was prepared and filled with composite Z 100(3M-ESPE) using a incremental technique. Each increment of 2 mm was cured either with soft start or constant cure. All patients were evaluated at day 2 for postoperative sensitivity. RESULTS AND DISCUSSION: Out of 124 restorations that were placed, only three restorations presented with postoperative sensitivity, each one being in mild, moderate, and severe categories, respectively. No relationship was seen between the sensitivity and tooth type. There was no statistically significant difference in postoperative sensitivity in either of the treatment modalities (constant or soft start). CONCLUSION: We conclude that restorations placed with the soft start curing technique did not show significant changes in postoperative sensitivity when compared to the constant curing technique. PMID- 21691513 TI - Maxillary canine with two root canals. AB - To report a rare case of maxillary canine with two root canals. The case describes the treatment of a maxillary canine with two root canals which was referred from department of prosthodontia for intentional root canal treatment for prosthetic rehabilitation. Clinical examination revealed a maxillary canine with carious lesion and responded within normal limits to electric pulp test. Radiographic examination revealed a distal carious lesion (close proximity to pulp) and also appeared to be an additional canal in this permanent maxillary canine. PMID- 21691514 TI - Non surgical perforation repair by mineral trioxide aggregate under dental operating microscope. AB - Root perforation repair has historically been an unpredictable treatment modality, with an unacceptably high rate of clinical failure. Recent developments in the techniques and materials utilized in root perforation repair have dramatically enhanced the prognosis of both surgical and nonsurgical procedures. Mineral Trioxide Aggregate is a relatively new material that is being successfully used to repair perforations. Technological advancements such as the use of a Dental Operating Microscope for correction of these inevitable procedural errors are a major breakthrough in dentistry today. This article presents one clinical case of nonsurgical root perforation repair by Mineral Trioxide Aggregate, using the Dental Operating Microscope. PMID- 21691515 TI - CAD/CAM fabricated single-unit all-ceramic post-core-crown restoration. AB - This case report explains about an innovative treatment strategy for the management of damaged anterior teeth with reduced incisal clearance by means of a single-unit all-ceramic post-core-crown zirconia ceramic restoration fabricated by Computer-aided designing and computer-aided manufacturing (CAD/CAM) technology. The reinforced zirconia ceramics allow fabrication of durable esthetic restorations in cases with high functional loading and the unification of the post, core, and crown in a single unit decreases the frequency of failure by creating a monobloc effect. In addition, the use of CAD/CAM technology for designing and fabricating ceramic restorations offers the option of expeditiously preparing these high-strength all-ceramic restorations. PMID- 21691517 TI - The XXV FODI and XVIII National Conference, Chennai, TamilNadu. PMID- 21691516 TI - Calcium-enriched mixture pulpotomy of a human permanent molar with irreversible pulpitis and condensing apical periodontitis. AB - This case report describes a pulpotomy treatment of a permanent mature molar tooth with established irreversible pulpitis and condensing apical periodontitis, using calcium-enriched mixture (CEM) cement. Clinical examination revealed that the first right lower molar had a large carious lesion with history of spontaneous/lingering pain; radiographic examination showed condensing apical periodontitis. Pulpotomy was opted as the treatment; cervical pulpotomy was carried out. Following hemostasis, the radicular pulp stumps were covered with ~2 mm-thick layer of the prepared CEM cement; the tooth was restored with amalgam. Two-year follow-up showed that the treated tooth had been symptomless, and there were no clinical signs/symptoms of either inflammation or infection. Radiographically, the periradicular lesion was completely healed with reconstruction of bone structures to normal appearance; the root canals were not calcified. According to chemical, physical, and biological properties of the CEM cement, this novel biomaterial may be suitable for endodontic treatment. PMID- 21691518 TI - Challenging the Pathophysiologic Connection between Subdural Hematoma, Retinal Hemorrhage and Shaken Baby Syndrome. AB - Child abuse experts use diagnostic findings of subdural hematoma and retinal hemorrhages as near-pathognomonic findings to diagnose shaken baby syndrome. This article reviews the origin of this link and casts serious doubt on the specificity of the pathophysiologic connection. The forces required to cause brain injury were derived from an experiment of high velocity impacts on monkeys, that generated forces far above those which might occur with a shaking mechanism. These forces, if present, would invariably cause neck trauma, which is conspicuously absent in most babies allegedly injured by shaking. Subdural hematoma may also be the result of common birth trauma, complicated by prenatal vitamin D deficiency, which also contributes to the appearance of long bone fractures commonly associated with child abuse. Retinal hemorrhage is a non specific finding that occurs with many causes of increased intracranial pressure, including infection and hypoxic brain injury. The evidence challenging these connections should prompt emergency physicians and others who care for children to consider a broad differential diagnosis before settling on occult shaking as the de-facto cause. While childhood non-accidental trauma is certainly a serious problem, the wide exposure of this information may have the potential to exonerate some innocent care-givers who have been convicted, or may be accused, of child abuse. PMID- 21691519 TI - Management of pediatric skin abscesses in pediatric, general academic and community emergency departments. AB - OBJECTIVES: To compare the evaluation and management of pediatric cutaneous abscess patients at three different emergency department (ED) settings. METHOD: We conducted a retrospective cohort study at two academic pediatric hospital EDs, a general academic ED and a community ED in 2007, with random sampling of 100 patients at the three academic EDs and inclusion of 92 patients from the community ED. Eligible patients were <=18 years who had a cutaneous abscess. We recorded demographics, predisposing conditions, physical exam findings, incision and drainage procedures, therapeutics and final disposition. Laboratory data were reviewed for culture results and antimicrobial sensitivities. For subjects managed as outpatients from the ED, we determined where patients were instructed to follow up and, using electronic medical records, ascertained the proportion of patients who returned to the ED for further management. RESULT: Of 392 subjects, 59% were female and the median age was 7.7 years. Children at academic sites had larger abscesses compared to community patients, (3.5 versus 2.5 cm, p=0.02). Abscess incision and drainage occurred in 225 (57%) children, with the lowest rate at the academic pediatric hospital EDs (51%) despite the relatively larger abscess size. Procedural sedation and the collection of wound cultures were more frequent at the academic pediatric hospital and the general academic EDs. Methicillin-resistant Staphylococcus aureus (MRSA) prevalence did not differ among sites; however, practitioners at the academic pediatric hospital EDs (92%) and the general academic ED (86%) were more likely to initiate empiric MRSA antibiotic therapy than the community site (71%), (p<0.0001). At discharge, children who received care at the community ED were more likely to be given a prescription for a narcotic (23%) and told to return to the ED for ongoing wound care (65%). Of all sites, the community ED also had the highest percentage of follow-up visits (37%). CONCLUSION: Abscess management varied among the three settings, with more conservative antibiotic selection and greater implementation of procedural sedation at academic centers and higher prescription rates for narcotics, self-referrals for ongoing care and patient follow-up visits at the community ED. PMID- 21691520 TI - Test characteristics of urinalysis to predict urologic injury in children. AB - OBJECTIVE: To use receiver operator characteristic curve methodology to determine the test characteristics of microscopic hematuria for identifying urologic injuries in children who underwent computed tomography (CT) of the abdomen and pelvis as part of a trauma evaluation. METHODS: We performed a retrospective medical record review of all children from 0 to 12 years of age who presented to our pediatric emergency department within a Level 1 trauma center, had an abdominal and pelvic CT and a microscopic urinalysis as part of an initial evaluation for trauma. Urologic injury was defined as any injury to the kidneys, ureters or bladder. We defined hematuria from the microscopic urinalysis and reported by the clinical laboratory as the exact number of red blood cells per high power field (RBC/hpf). RESULTS: Of the 502 children in the study group, 17 (3%; 95% CI [2%-5.4%]) had evidence of urologic injury on the abdominal or pelvic CT. Microscopic urinalysis for those children with urologic injury ranged from 0 to15,544 RBC/hpf. The remaining 485 children without urologic injury had a range of hematuria from 0 to 20,596 RBC/hpf. A receiver operating characteristic curve was generated and the area under the curve is 0.796 (95% CI [0.666-0.925]). CONCLUSION: If the abdominal and pelvic CT is used as the criterion standard for identifying urologic trauma, the microscopic urinalysis has moderate discriminatory power to predict urologic injury. PMID- 21691521 TI - Transphyseal fracture of the distal humerus in a neonate. PMID- 21691522 TI - Online health information impacts patients' decisions to seek emergency department care. AB - OBJECTIVE: To investigate the impact of online health information (OHI) and patients' decisions to seek emergency department (ED) care. METHODS: We conducted a survey of a convenience sample of 489 ambulatory patients at an academic ED between February and September 2006. The primary measure was the prevalence of Internet use, and the secondary outcome was the impact of OHI on patients' decision to seek ED care. RESULTS: The study group comprised 175 (38%) males. Mean age was 33 years old; 222 (45.4%) patients were white, 189 (38.7%) patients were African American, and 33 (6.7%) were Hispanic. 92.6% had Internet access, and 94.5% used email; 58.7% reported that OHI was easy to locate, while 49.7% felt that it was also easy to understand. Of the subjects who had Internet access, 15.1% (1.6, 95% CI 1.3-2.0) stated that they had changed their decision to seek care in the ED. CONCLUSION: This study suggests that Internet access in an urban adult ED population may mirror reported Internet use among American adults. Many ED patients report that they are able to access and understand online health information, as well as use it to make decisions about seeking emergency care. PMID- 21691523 TI - Rural-urban disparities in emergency department intimate partner violence resources. AB - OBJECTIVE: Little is known about availability of resources for managing intimate partner violence (IPV) at rural hospitals. We assessed differences in availability of resources for IPV screening and management between rural and urban emergency departments (EDs) in Oregon. METHODS: We conducted a standardized telephone interview of Oregon ED directors and nurse managers on six IPV-related resources: official screening policies, standardized screening tools, public displays regarding IPV, on-site advocacy, intervention checklists and regular clinician education. We used chi-square analysis to test differences in reported resource availability between urban and rural EDs. RESULTS: Of 57 Oregon EDs, 55 (96%) completed the survey. A smaller proportion of rural EDs, compared to urban EDs, reported official screening policies (74% vs. 100%, p=0.01), standardized screening instruments (21% vs. 55%, p=0.01), clinician education (38% vs. 70%, p=0.02) or on-site violence advocacy (44% vs. 95%, p<0.001). Twenty-seven percent of rural EDs had none or one of the studied resources, 50% had two or three, and 24% had four or more (vs. 0%, 35%, and 65% in urban EDs, p=0.003). Small, remote rural hospitals had fewer resources than larger, less remote rural hospitals or urban hospitals. CONCLUSION: Rural EDs have fewer resources for addressing IPV. Further work is needed to identify specific barriers to obtaining resources for IPV management that can be used in all hospital settings. PMID- 21691524 TI - Applying lean: implementation of a rapid triage and treatment system. AB - OBJECTIVE: Emergency department (ED) crowding creates issues with patient satisfaction, long wait times and leaving the ED without being seen by a doctor (LWBS). Our objective was to evaluate how applying Lean principles to develop a Rapid Triage and Treatment (RTT) system affected ED metrics in our community hospital. METHODS: Using Lean principles, we made ED process improvements that led to the RTT system. Using this system, patients undergo a rapid triage with low-acuity patients seen and treated by a physician in the triage area. No changes in staffing, physical space or hospital resources occurred during the study period. We then performed a retrospective, observational study comparing hospital electronic medical record data six months before and six months after implementation of the RTT system. RESULTS: ED census was 30,981 in the six months prior to RTT and 33,926 after. Ambulance arrivals, ED patient acuity and hospital admission rates were unchanged throughout the study periods. Mean ED length of stay was longer in the period before RTT (4.2 hours, 95% confidence interval [CI] = 4.2-4.3; standard deviation [SD] = 3.9) than after (3.6 hours, 95% CI = 3.6 3.7; SD = 3.7). Mean ED arrival to physician start time was 62.2 minutes (95% CI = 61.5-63.0; SD = 58.9) prior to RTT and 41.9 minutes (95% CI = 41.5-42.4; SD = 30.9) after. The LWBS rate for the six months prior to RTT was 4.5% (95% CI = 3.1 5.5) and 1.5% (95% CI = 0.6-1.8) after RTT initiation. CONCLUSION: Our experience shows that changes in ED processes using Lean thinking and available resources can improve efficiency. In this community hospital ED, use of an RTT system decreased patient wait times and LWBS rates. PMID- 21691525 TI - Financial impact of emergency department crowding. AB - OBJECTIVE: The economic benefits of reducing emergency department (ED) crowding are potentially substantial as they may decrease hospital length of stay. Hospital administrators and public officials may therefore be motivated to implement crowding protocols. We sought to identify a potential cost of ED crowding by evaluating the contribution of excess ED length of stay (LOS) to overall hospital length of stay. METHODS: We performed a retrospective review of administrative data of adult patients from two urban hospitals (one county and one university) in Brooklyn, New York from 2006-2007. Data was provided by each facility. Extrapolating from prior research (Krochmal and Riley, 2005), we determined the increase in total hospital LOS due to extended ED lengths of stay, and applied cost and charge analyses for the two separate facilities. RESULTS: We determined that 6,205 (5.0%) admitted adult patients from the county facility and 3,017 (3.4%) patients from the university facility were held in the ED greater than one day over a one-year period. From prior research, it has been estimated that each of these patient's total hospital length of stay was increased on average by 11.7% (0.61 days at the county facility, and 0.71 days at the university facility). The increased charges over one year at the county facility due to the extended ED LOS was therefore approximately $9.8 million, while the increased costs at the university facility were approximately $3.9 million. CONCLUSION: Based on extrapolations from Krochmal and Riley applied to two New York urban hospitals, the county hospital could potentially save $9.8 million in charges and the university hospital $3.9 million in costs per year if they eliminate ED boarding of adult admitted patients by improving movement to the inpatient setting. PMID- 21691526 TI - Impact of an expeditor on emergency department patient throughput. AB - OBJECTIVE: Our hypothesis was that an individual whose primary role was to assist with patient throughput would decrease emergency department (ED) length of stay (LOS), elopements and ambulance diversion. The objective of this study was to measure how the use of an expeditor affected these throughput metrics. METHODS: This pre-and post-intervention study analyzed ED patients >= 21-years-old between June 2008 and June 2009, at a level one trauma center in an academic medical center with an annual ED census of 40,000 patients. We created the expeditor position as our study intervention in December 2008, by modifying the job responsibilities of an existing paramedic position. An expeditor was on duty from 1PM-1AM daily. The pre-intervention period was June to November 2008, and the post-intervention period was January to June 2009. We used multivariable to assess the impact of the expeditor on throughput metrics after adjusting for confounding variables. RESULTS: We included a total of 13,680 visits in the analysis. There was a significant decrease in LOS after expeditor implementation by 0.4 hours, despite an increased average daily census (109 vs. 121, p<0.001). The expeditor had no impact on elopements. The probability that the ED experienced complete ambulance diversion during a 24-hour period decreased from 55.2% to 16.0% (OR:0.17, 95%CI:0.05-0.67). CONCLUSION: The use of an expeditor was associated with a decreased LOS and ambulance diversion. These findings suggest that EDs may be able to improve patient flow by using expeditors. This tool is under the control of the ED and does not require larger buy-in, resources, or overall hospital changes. PMID- 21691527 TI - Predicting patient patterns in veterans administration emergency departments. AB - Veteran's Affairs (VA) hospitals represent a unique patient population within the healthcare system; for example, they have few female and pediatric patients, typically do not see many trauma cases and often do not accept ambulance runs. As such, veteran-specific studies are required to understand the particular needs and stumbling blocks of VA emergency department (ED) care. The purpose of this paper is to analyze the demographics of patients served at VA EDs and compare them to the national ED population at large. Our analysis reveals that the VA population exhibits a similar set of common chief complaints to the national ED population (and in similar proportions) and yet differs from the general population in many ways. For example, the VA treats an older, predominantly male population, and encounters a much lower incidence of trauma. Perhaps most significantly, the incidence of psychiatric disease at the VA is more than double that of the general population (10% vs. 4%) and accounts for a significant proportion of admissions (23%). Furthermore, the overall admission percentage at the VA hospital is nearly three times that of the ED population at large (36% versus 13%). This paper provides valuable insight into the make-up of a veteran's population and can guide staffing and resource allocation accordingly. PMID- 21691528 TI - Does pelvic exam in the emergency department add useful information? AB - OBJECTIVE: Physicians are taught that the pelvic exam is a key part of the evaluation of a woman presenting with abdominal pain or vaginal bleeding. However, the exam is time consuming and invasive, and its use in the emergency department (ED) has not been prospectively evaluated. We evaluated how often the findings of the pelvic exam changed management in a cohort of consecutive female patients presenting with acute abdominal pain or vaginal bleeding. METHODS: We enrolled women who required a pelvic exam together with the providers caring for them in an academic ED from September 2004 to August 2005. We collected the results of the general history and physical exam. The provider was asked to predict the findings of the pelvic exam, and these were compared with the actual findings of the exam. RESULTS: One hundred eighty-three patients were prospectively entered into the study. When compared with predicted findings, the pelvic exam was as expected in 131 patients (72%). In a further 40 patients (22%), the findings of the pelvic exam were not as predicted, but resulted in no change in the clinical plan. In 12 cases (6%) the exam revealed a finding that was both unexpected and changed the clinical plan. Only one of these patients was admitted. Of the 24 patients who were admitted, four had a pelvic exam that revealed unexpected results, but only one of these cases caused the physician to change the care planned for the patient. CONCLUSION: In 94% of women with acute abdominal pain or vaginal bleeding, the results of the pelvic exam were either predictable or had no effect on the clinical plan. This suggests that there may be a subset of women with abdominal pain or vaginal bleeding in whom a pelvic exam may safely be deferred. PMID- 21691529 TI - Molar Pregnancy with False Negative beta-hCG Urine in the Emergency Department. AB - This case describes an atypical presentation of molar pregnancy in an emergency department patient with abdominal pain and vaginal bleeding. The patient demonstrated clinical features of hydatidiform mole, including acute discharge of a large, grape-like vesicular mass, despite multiple negative urine pregnancy tests. These false-negative qualitative human chorionic gonadotropin assays were likely caused by the "high-dose hook effect" and may have delayed proper care of the patient, who displayed pulmonary choriocarcinoma at the time of diagnosis. PMID- 21691530 TI - Warfarin Overdose in a Breast-feeding Woman. AB - We describe a case of a breastfeeding woman with an accidental warfarin overdose resulting in a markedly elevated prothrombin time. The breast-fed infant was evaluated and tested for ill effects. We discuss the use of warfarin while breast feeding. PMID- 21691531 TI - Takotsubo Syndrome in African American vs. Non-African American Women. AB - OBJECTIVES: Takotsubo syndrome (TTS) is a reversible cause of heart failure rarely described in African-American patients. This study aimed to compare and contrast the clinical characteristics of TTS in African-American (AA) and non African-American (NAA) patients. METHODS: We retrospectively reviewed the charts of eight patients (four AA and four NAA) diagnosed with TTS, between June 2006 and August 2008, in four different teaching hospitals: St Michael's Medical Center, St Joseph's Medical Center, Trinitas hospital and St Louis' University Hospital. We compared the patients with regard to presenting symptoms, precipitating stressors, electrocardiographic findings, troponin levels, ejection fraction and in-hospital course. RESULTS: All patients were females (mean age 64 for AA and 67 for NAA). All patients experienced chest pain and had elevated troponin levels. Two AA and three NAA patients had associated shortness of breath and one NAA had syncope. All AA and three NAA had T-wave inversions. Three NAA and one AA had ST segment elevation. Three patients in both groups developed prolongation of the QT interval. Coronary angiograms did not reveal any significant obstructive coronary artery disease. Three patients, all NAA, needed hemodynamic support during their hospital stay but none died. CONCLUSION: AA and NAA women with TTS have similar presenting symptoms but may differ in the electrocardiographic findings and in-hospital course of the disease. PMID- 21691532 TI - Myocardial ischemia with penetrating thoracic trauma. AB - Penetrating trauma is a rare cause of myocardial infarction. Our report describes a 47-year-old female who presented with a gunshot wound from a shotgun and had an ST-elevation myocardial infarction. The patient received emergent coronary angiography, which demonstrated no evidence of coronary atherosclerotic disease but did show occlusion of a marginal vessel secondary to a pellet. The patient was managed medically for the myocardial infarction without cardiac sequelae. Patients with penetrating trauma to the chest should be evaluated for myocardial ischemia. Electrocardiography, echocardiography and cardiac angiography play vital roles in evaluating these patients and helping to guide management. PMID- 21691533 TI - The impact of cardiac contractility on cerebral blood flow in ischemia. AB - OBJECTIVE: In cerebral regions affected by ischemia, intrinsic vascular autoregulation is often lost. Blood flow delivery depends upon cardiac function and may be influenced by neuro-endocrine mediated myocardial suppression. Our objective is to evaluate the relation between ejection fraction (EF) and transcranial doppler (TCD) peak systolic velocities (PSV) in patients with cerebral ischemic events. METHODS: We conducted a retrospective cohort study from an existing TCD registry. We evaluated patients admitted within 24 hours of onset of a focal neurological deficit who had an echocardiogram and TCD performed within 72 hours of admission. RESULTS: We identified 58 patients from March to October 2003. Eighty-one percent (n=47) had a hospital discharge diagnosis of ischemic stroke and 18.9% (n=11) had a diagnosis of transient ischemic attack. Fourteen patients had systolic dysfunction (EF<50%). The mean PSV in patients with normal systolic function (EF>=50%) compared to those with systolic dysfunction (EF<50%) was as follows: middle cerebral artery 62.0 +/- 28.6 cm/s vs. 51.0 +/- 23.3 cm/s, p=0.11; anterior cerebral artery 52.1 +/- 21.6 cm/s vs. 45.9 +/- 22.7 cm/s, p=0.28; internal carotid artery 56.5 +/- 20.1 cm/s vs. 46.4 +/- 18.4 cm/s, p=0.04; ophthalmic artery 18.6 +/- 7.2 cm/s vs. 15.3 +/- 5.2 cm/s, p=0.11; vertebral artery 34.0 +/- 13.9 cm/s vs. 31.6 +/- 15.0 cm/s, p=0.44. CONCLUSION: Cerebral blood flow in the internal carotid artery territory appears to be higher in cerebral ischemia patients with preserved left ventricular contractility. Our study was unable to differentiate pre-existing cardiac dysfunction from neuro-endocrine mediated myocardial stunning. Future research is necessary to better understand heart-brain interactions in this setting and to further explore the underlying mechanisms and consequences of neuro-endocrine mediated cardiac dysfunction. PMID- 21691534 TI - Vertebrobasilar artery occlusion. AB - The presentation of vertebrobasilar artery occlusion varies with the cause of occlusion and location of ischemia. This often results in delay in diagnosis. Areas of the brain supplied by the posterior circulation are difficult to visualize and usually require angiography or magnetic resonance imaging. Intravenous thrombolysis and local-intra arterial thrombolysis are the most common treatment approaches used. Recanalization of the occluded vessel significantly improves morbidity and mortality. Here we present a review of the literature and a case of a patient with altered mental status caused by vertebrobasilar artery occlusion. PMID- 21691535 TI - Artifact simulating fracture on cervical spine computed tomography. AB - We present the case of a 31-year-old trauma patient with computed tomography concerning significant C3-C4 subluxation. The abnormality is due to an artifact with which emergency physicians should be aware. PMID- 21691536 TI - Comparison of pressures applied by digital tourniquets in the emergency department. AB - BACKGROUND: Digital tourniquets used in the emergency department have been scrutinized due to complications associated with their use, including neurovascular injury secondary to excessive tourniquet pressure and digital ischemia caused by a forgotten tourniquet. To minimize these risks, a conspicuous tourniquet that applies the least amount of pressure necessary to maintain hemostasis is recommended. OBJECTIVE: To evaluate the commonly used tourniquet methods, the Penrose drain, rolled glove, the Tourni-cot and the T-Ring, to determine which applies the lowest pressure while consistently preventing digital perfusion. METHODS: We measured the circumference of selected digits of 200 adult males and 200 adult females to determine the adult finger size range. We then measured the pressure applied to four representative finger sizes using a pressure monitor and assessed the ability of each method to prevent digital blood flow with a pulse oximeter. RESULTS: WE SELECTED FOUR REPRESENTATIVE FINGER SIZES: 45mm, 65mm, 70mm, and 85mm to test the different tourniquet methods. All methods consistently prevented digital perfusion. The highest pressure recorded for the Penrose drain was 727 mmHg, the clamped rolled glove 439, the unclamped rolled glove 267, Tourni-cot 246, while the T-Ring had the lowest at 151 mmHg and least variable pressures of all methods. CONCLUSION: All tested methods provided adequate hemostasis. Only the Tourni-cot and T-Ring provided hemostasis at safe pressures across all digit sizes with the T-Ring having a lower overall average pressure. PMID- 21691537 TI - Test characteristics of urine dipstick for identifying renal insufficiency in patients with diabetes. AB - OBJECTIVE: To evaluate the test characteristics of the urine dipstick as a screening tool for elevated serum creatinine in patients with uncontrolled diabetes mellitus in the emergency department (ED). METHODS: Patients with diabetes over the age of 18 who presented to the ED for any complaint over a three-month study period were considered eligible for participation in this study. A finger-stick blood glucose of >=250 mg/dL at triage was used to confirm the diagnosis of uncontrolled diabetes. After obtaining written consent, each patient had a urine dip performed and a chemistry panel drawn. Any level of proteinuria on the urine dip was considered to be a positive test. Based on the laboratory and clinical guidelines at our institution, renal insufficiency was defined as creatinine concentration of greater than 1.3 mg/dL. RESULTS: Three Hundred ninety-three confirmed patients with uncontrolled diabetes were enrolled in this study, and 49 of these (12.5%) were found to have renal insufficiency. The sensitivity and specificity of the urine dip for predicting renal insufficiency were 69.4% (95% confidence interval [CI] 54.6-81.7%) and 57.8% (95%CI 52.4-63.1%) respectively. The positive predictive value was 19% (95%CI 13.5-25.5%), and the negative predictive value was 93% (95%CI 88.7-96%). The positive likelihood ratio was 1.65 (95%CI 1.32-2.06) and the negative likelihood ratio was 0.53 (95%CI 0.34-0.81). CONCLUSION: In this cohort of patients with uncontrolled diabetes, the test characteristics of the urine dipstick make it a poor screening tool for renal insufficiency in the ED. PMID- 21691538 TI - Those who can, do and they teach too: faculty clinical productivity and teaching. AB - OBJECTIVE: Academic emergency physicians (EPs) often feel that the demands of clinical productivity, income generation, and patient satisfaction conflict with educational objectives. The objective of this study was to explore whether the quality of faculty bedside teaching of residents correlated with high clinical productivity, measured by relative value units (RVUs). We also explored the strategies of high-performing faculty for optimal RVU generation and teaching performance. METHODS: We performed a mixed method study using quantitative and qualitative methods to analyze the relationship between RVUs, patient satisfaction, and teaching performance. We examined the relationship between teaching performance ratings, patient satisfaction, and RVUs per hour using correlations. Following this initial analysis, we conducted semi-structured interviews with the eight faculty members who have the highest clinical (RVU) and educational productivity ratings to learn more about their strategies for success. Our Institutional Review Board approved this study. RESULTS: We correlated resident evaluations of faculty with RVUs billed per hour. We conducted semi-structured interviews of faculty who led in both RVU productivity and resident evaluations. From these interviews, several themes emerged. When asked about how they excel in billing, most said that they pay attention to dictating a thorough chart on every patient and try to "stay busy" throughout their entire shift. When asked how they excel at resident education, most leading faculty said that they try to find a "teaching moment" and find small "clinical pearls" to pass along. Nevertheless, all eight leading faculty members believe that as the emphasis on billing productivity increases, resident and student education will suffer. CONCLUSION: Contrary to the opinion of some physicians, faculty can excel at both clinical productivity and resident education. This study found that highly efficient clinical productivity correlated with excellent resident teaching. This high level of performance did not appear to be at the expense of other important measures such as patient satisfaction or student teaching. PMID- 21691539 TI - Extra-adrenal Pheochromocytoma in an Adolescent. AB - A 17-year-old male with symptoms of headache and diaphoresis presented to the emergency department. He had eight months of noted hypertension attributed to medications. On arrival his blood pressure was 229/117mmHg, and he was ill appearing. His blood pressure was managed aggressively, and he was diagnosed with extra-adrenal pheochromocytoma by computed tomography. He eventually underwent resection of the mass. Children with severe, symptomatic hypertension should be evaluated for pheochromocytoma. Although rare, it is curable. Failure to diagnose carries a high risk of morbidity and mortality. PMID- 21691540 TI - Superior mesenteric vein thrombosis mimicking acute appendicitis. AB - Abdominal pain is one of the most common presenting complaints to the emergency department. Mesenteric venous thrombosis represents an important cause to consider in patients with acute abdominal pain. The diagnosis is often delayed, and cases traditionally have been identified either at laparotomy or at autopsy. In this case, we describe a 21-year-old female with acute onset of right lower quadrant pain attributable to a hyperhomocysteinemia related non-occlusive superior mesenteric vein thrombosis. This case highlights how the use of computed tomography in select cases can lead to earlier recognition of this condition and increasingly allow for non-surgical treatment. PMID- 21691541 TI - Self-knotting of a nasogastric tube. PMID- 21691542 TI - Are we still here? PMID- 21691543 TI - www.jisponline.com. PMID- 21691544 TI - The need of the hour - To make periodontics more interesting for undergraduate students! PMID- 21691545 TI - Obesity and periodontal disease. AB - Obesity is characterized by the abnormal or excessive deposition of fat in the adipose tissue. Its consequences go far beyond adverse metabolic effects on health, causing an increase in oxidative stress, which leads not only to endothelial dysfunction but also to negative effects in relation to periodontitis, because of the increase in proinflammatory cytokines. Thus obesity appears to participate in the multifactorial phenomenon of causality of periodontitis through the increased production of reactive oxygen species. The possible causal relationship between obesity and periodontitis and potential underlying biological mechanisms remain to be established; however, the adipose tissue actively secretes a variety of cytokines and hormones that are involved in inflammatory processes, pointing toward similar pathways involved in the pathophysiology of obesity, periodontitis and related inflammatory diseases. So the aim of this article is to get an overview of the association between obesity and periodontitis and to review adipose-tissue - derived hormones and cytokines that are involved in inflammatory processes and their relationship to periodontitis. PMID- 21691546 TI - Duration of reappearance of gingival melanin pigmentation after surgical removal A clinical study. AB - BACKGROUND: In dentistry, esthetics has a special place. Although gingival melanin pigmentation does not present a medical problem, clinicians are often faced with a challenge of achieving gingival esthetics. MATERIALS AND METHODS: A method of de-epithelialization of the pigmented gingiva using Kirkland's gingivectomy knife is described. Twenty patients who were conscious about their gingival melanin pigmentation were selected. The gingiva of the whole of the arch was abraded until the entire visible pigmentation was removed. Clinical observations for intensity of pigmentation were recorded at baseline and then after surgery at monthly intervals over a period of 9 months according to Dummett Gupta Oral Pigmentation Index scoring criteria proposed by Dummett C. O. in 1964. RESULTS: The mean gingival melanin pigmentation score came down to 0.407 after 9 months as compared to preoperative score, which was 2.24. No repigmentation occurred in fair-complexioned persons. In persons with wheatish complexion, repigmentation was seen in 85.71% of the cases, but scores came down to 0.38 postoperatively as compared to 2.27 preoperatively. In dark-complexioned persons, repigmentation occurred in all cases, but the mean scores were 0.93 as compared to 2.40 preoperatively. The difference between preoperative and postoperative mean scores for each segment was put to statistical analysis by applying paired t test and was found to be significant. CONCLUSION: As this method has shown statistically significant results, it can be used in patients who are conscious of pigmented gingiva and want an esthetically satisfactory color. PMID- 21691547 TI - Compliance to recall visits by patients with periodontitis - Is the practitioner responsible? AB - CONTEXT: Compliance to recall visit is directly related to the medium and long term success of active periodontal therapy. AIMS: To determine the percentage of patients who were compliant to recall visits by the practitioner and to find out the reasons for noncompliance by noncompliant patients. SETTINGS AND DESIGN: Cross-sectional study was carried out in the Department of Periodontology, Amrita School of Dentistry. The study participants were former patients of the Department of Periodontology. PATIENTS AND METHODS: A total of 216 patients were selected for the study - 116 males and 100 females. They were divided according to their socioeconomic status - professionals and nonprofessionals. Nonprofessionals were divided into those who had completed high school education and those who had not. They were followed up to find out how many were compliant to recall visits and the reasons for noncompliance by noncompliant patients. STATISTICAL ANALYSIS: The data was entered into SPSS version 11.5. Descriptive statistics were used. The frequencies of responses were calculated. RESULT: Of the total study population, 48.1% was compliant, of which 58.6% and 37.6% of males and females were compliant, respectively. In terms of percentage, 60.6% of professionals, 52.4% of those who had completed high school education and 31.3% of those who had not completed high school education were compliant. CONCLUSION: Compliance to recall visits by the periodontitis patients depends largely on the practitioner. Inadequate motivation by the practitioner and inadequate education in general are responsible for noncompliance to periodontal treatment. PMID- 21691548 TI - Role of salivary leukocyte protease inhibitor in periodontal disease progression. AB - CONTEXT: Proteases play a major role in the tissue destruction involved in periodontal disease. It is known that the balance between proteases and their inhibitors is a major determinant in maintaining tissue integrity. The association between the proteases and periodontitis is well established, but not many studies have been carried out to know the role played by a protease inhibitor like salivary leukocyte protease inhibitor (SLPI) in periodontitis. AIM: The aim of the present study was to correlate SLPI with periodontitis. SETTINGS AND DESIGN: Case-control study. MATERIALS AND METHODS: Seventy-five clinically confirmed cases of periodontitis and 20 controls were included in the study. A detailed case history and periodontal index (PI) were recorded. Two milliliters of unstimulated saliva samples was obtained and subjected to quantification of SLPI leaves using SLPI in enzyme-linked immunosorbent assay (ELISA) kit. Based on the periodontal index score of the individuals, the cases and controls were divided into groups A, B and C, and the obtained SLPI levels were compared among the groups. STATISTICAL ANALYSIS: Mann-Whitney U test and correlation coefficient test. RESULTS: The results showed that in the initial stages of periodontitis there is a tendency of SLPI levels to be raised. The SLPI levels were found to be reduced in the terminal stages of periodontitis. CONCLUSION: It appears that SLPI accumulates in the local environment, at least in the initial stages of the periodontal disease, probably to inhibit the action of increased elastic activity. PMID- 21691549 TI - Periodontal infection as a risk factor for preterm low birth weight. AB - INTRODUCTION: There is an overwhelming body of evidence strongly suggesting that periodontal infection may have a significant negative impact on pregnancy outcome in some women. The aim of this study was to determine the association, if any, between periodontal disease and preterm low birth weight. MATERIALS AND METHODS: A total of 211 mothers between the ages of 17 and 35 were grouped into two categories based on the gestational age and weight of the baby as cases (< 37 weeks, < 2500 g) and controls (>37 weeks, >2500 g). Relevant obstetric history and information on other primary risk factors for preterm low birth weight were obtained. Investigation reports on blood group, Rh factor and hemoglobin (Hb) were also gathered. Oral assessments included: simplified oral hygiene index (OHI S), gingival bleeding index, probing pocket depth and clinical attachment level (CAL). RESULTS: Cases had significantly more attachment loss and probing pocket depth, poor oral hygiene, more percentage of sites with attachment loss (Extent) and more mean attachment loss per site (Severity) and less Hb than controls. The number of visits for prenatal care and the percentage of sites with CAL>=2mm (Extent 2) remained significant when compared to other variables. CONCLUSIONS: The study indicated that periodontal disease is a contributing factor for preterm low birth weight. PMID- 21691550 TI - A Radiographic comparison of mandibular bone quality in pre- and post-menopausal women in Indian population. AB - AIM AND OBJECTIVES: The main objective of the study is to assess mandibular bone changes in pre and postmenopausal women with chronic generalized periodontitis using different radiomorphometric indices, mandibular cortical index (MCI), mental index (MI), and panoramic mandibular index (PMI) in Indian population. MATERIALS AND METHODS: Panoramic radiographs of 60 patients visiting the Department of Periodontology were taken and divided in two groups - pre and post menopausal. Detailed medical and menopausal history was recorded for each patient. All the radiographs were assessed for PMI, MI and MCI and presence of periodontitis. The destructive periodontitis was assessed as distance from the cementoenamel junction to the alveolar crest greater than 2mm. STATISTICAL ANALYSIS: Student-t test was applied to compare mean values of MI and PMI. Intra and inter group comparison of MCI were made using chi-square test. Correlation of age and MI and PMI was found by Pearson's correlation coefficient. RESULTS: MCI, PMI and MI were related to the menopausal status. Patients with C3 category were seen only in post-menopausal group after 54 years of age. Higher mean values for both MI (p<0.05) and PMI (p<0.05) were observed in pre-menopausal group with statistically significant differences. MI showed negative correlation with age in both the groups; however PMI was positively correlated with age. CONCLUSIONS: Radiomorphometric indices could be used by general dentists after a little training to detect post-menopausal women at higher risk of osteoporosis. PMID- 21691551 TI - Comparative evaluation of bovine porous bone mineral. AB - BACKGROUND: The aim of the present clinical study was to compare the efficacy of bovine porous bone mineral (BPBM) with and without platelet-rich plasma (PRP) for the treatment of periodontal intrabony defects. MATERIALS AND METHODS: Twenty eight identical bilateral periodontal intrabony defects were selected from 14 chronic periodontitis patients. The subjects were randomly assigned to test group (BPBM+PRP) or the control group (BPBM). The clinical, radiographic, and intrasurgical (re-entry) measurements were made at baseline and at 9 months postoperatively. RESULTS: Both treatment modalities resulted in significant reduction in probing depth and gain in clinical attachment level as compared to baseline values. The probing depth reduction was 6.20+/-1.40 mm in BPBM and 6.60+/-1.43 mm for the BPBM/PRP-treated sites. The gain in clinical attachment level observed was 4.16+/-1.05 mm for BPBM and 4.70+/-0.76 mm for the BPBM/PRP group. Radiographically, there was a significant defect fill (3.83+/-1.01 mm) for the BPBM group and (4.04+/-1.77 mm) in the BPBM/PRP group. Similar trend was observed between the two groups in relation to intrasurgical parameters. CONCLUSIONS: The combination therapy (BPBM+PRP) showed more favorable clinical outcome in the treatment of intrabony defects than the BPBM alone group, although the mean difference between the two groups was statistically nonsignificant. PMID- 21691552 TI - Management of recalcitrant oral pemphigus vulgaris with CO(2) laser - Report of two cases. AB - Laser has been used efficiently for treatment of oral lichen planus, leukoplakia, aphthous ulcers and oral manifestations of HIV. Two cases of recalcitrant oral pemphigus vulgaris that were successfully treated with CO(2) laser are described. The patients had been treated by a dermatologist with pulse therapy of methyl prednisolone and cyclophosphamide over a period of 6 to 8 months, but the clinical course was characterized by episodes of painful flare-ups and nonresponsiveness. The patients were extremely uncomfortable with recurrent oral lesions. CO(2) laser at low power was used to irradiate the lesions. It was shown to be effective in relieving pain and healing of lesions, with nonrecurrence. To the best of our knowledge, this is the first case report of such a treatment of oral pemphigus vulgaris. Further clinical studies are warranted to confirm efficacy and to optimize the treatment protocol. PMID- 21691553 TI - Supernumerary eumorphic mandibular incisor in association with aggressive periodontitis. AB - According to the literature, the prevalence of supernumerary teeth is 1% to 4% of permanent dentitions; and among these, the presence of fifth mandibular incisor - a supernumerary eumorphic tooth - has rarely been described in literature, and its association with localized aggressive periodontitis is an even more rare entity. This paper reports a very rare case of unusual association of supernumerary eumorphic fifth mandibular incisor with aggressive periodontitis in a Muslim individual, so that these findings generate curiosity and inspire others to carry out further studies and investigations. PMID- 21691554 TI - Combined periodontic-orthodonticendodontic interdisciplinary approach in the treatment of periodontally compromised tooth. AB - Orthodontic treatment in adult patients is one of the most frequently encountered components involving multidisciplinary approaches. In the present report, a 28 year-old male patient was treated for localized chronic periodontitis with pocket formation, mobility, pathologic migration and malalignment of maxillary left lateral incisor tooth #22. The periodontal therapy included motivation, education and oral-hygiene instructions (O.H.I.), scaling and root planing and periodontal flap surgery. Subsequently on resolution of periodontal inflammation, orthodontic therapy was carried out using the orthodontic aligner for a period of 6 months. Post-treatment (3 years) results showed complete resolution of infrabony pocket with significant bone fill, reduced tooth mobility and complete alignment of the affected maxillary left lateral incisor, thus restoring the esthetics and function. PMID- 21691555 TI - Trauma from occlusion - An orthodontist's perspective. AB - Orthodontic therapy has a big role in the treatment and prevention of malpositions. The signs and symptoms experienced by patients with occlusal trauma are mobility of teeth, temperomandibular joint pain, pain on mastication and periodontal disease. Early diagnosis, proper treatment plan and correction of malocclusion can lead to a successful outcome. Lack of awareness of orthodontic treatment in patients with occlusal trauma can even lead to loss of tooth structure. PMID- 21691556 TI - Charcot osteoarthropathy in diabetes: A brief review with an emphasis on clinical practice. AB - Charcot osteoarthropathy (COA) is a potentially limbthreatening condition that mainly affects diabetic patients with neuropathy. In everyday practice, it presents as a red, hot, swollen foot, usually painless, and is frequently triggered by trivial injury. Its etiology is traditionally attributed to impairment of either the autonomic nervous system, leading to increased blood flow and bone resorption, or of the peripheral nervous system, whereby loss of pain and protective sensation render the foot susceptible to repeated injury. More recently, excessive local inflammation is thought to play a decisive role. Diagnosis is based on clinical manifestation and imaging studies (plain X-rays, bone scan, Magnetic Resonance Imaging). The mainstay of management is immediate off-loading, while surgery is usually reserved for chronic cases with irreversible deformities and/or joint instability. The aim of this review is to provide an overview of COA in terms of pathogenesis, classification and clinical presentation, diagnosis and treatment, with an emphasis on the high suspicion required by clinicians for timely recognition to avoid further complications. PMID- 21691557 TI - Nkx6.2 synergizes with Cdx-2 in stimulating proglucagon gene expression. AB - AIM: To investigate whether the transactivator of the proglucagon gene (Gcg), Cdx 2, synergizes with other transcription factors in stimulating Gcg expression and the trans-differentiation of Gcg-expressing cells. METHODS: We conducted affinity chromatography to identify proteins that interact with Cdx-2, using GST-tagged Cdx-2 against cell lysates from pancreatic InR1-G9 and intestinal GLUTag cell lines. This was followed by a mass-spectrometry analysis. From a potential Cdx-2 interaction protein identified, we examined its expression in pancreatic and gut endocrine cells, confirmed its interaction with Cdx-2 by GST-pull down and determined its effect in provoking Gcg expression in cell lines that do not express endogenous Gcg. RESULTS: We identified 18 potential Cdx-2 interacting proteins. One of them is Nkx6.2. This homeodomain (HD) protein is expressed in pancreatic alpha and intestinal endocrine L cells but not in insulin producing cell lines, including In111. Nkx6.2, but not Nkx6.1, was shown to interact with Cdx-2, detected by GST-pull down. Furthermore, Nkx6.2 was found to synergize with Cdx-2 in provoking Gcg expression when they were ectopically expressed in the In111 cell line. Finally, when Cdx-2 and Nkx6.2 were co-transfected into the undifferentiated rat intestinal IEC-6 cell line, it produced detectable amount of Gcg mRNA. CONCLUSION: Cdx-2 recruits Nkx6.2 in exerting its effect in stimulating Gcg expression. Our observations further support the notion that multiple HD proteins, including Cdx-2 and Nkx6.2, are involved in the regulation of Gcg expression and the genesis of Gcg-producing cells. PMID- 21691558 TI - Elevated pancreatic enzymes, IgM, soluble interleukin-2 receptor in anti-GADab(+) type 1 diabetes. AB - Type 1 diabetes can be classified into immune-mediated diabetes (type 1A) and idiopathic diabetes, which lacks immunological evidence for beta cell autoimmunity (type 1B). Type 1A diabetes is characterized by the presence of the anti-glutamic acid decarboxylase antibody (anti-GADab). Fulminant type 1 diabetes is classified as type 1B diabetes, and characterized by the absence of anti GADab, flu-like symptoms, and elevated serum exocrine pancreatic enzymes. We report a type 1 diabetic patient who showed flu-like symptoms, elevated serum exocrine pancreatic enzymes, and an extremely high-titer of anti-GADab, manifesting the characteristics of both type 1A and fulminant type 1 diabetes. PMID- 21691559 TI - The intensity and effects of strength training in the elderly. AB - BACKGROUND: The elderly need strength training more and more as they grow older to stay mobile for their everyday activities. The goal of training is to reduce the loss of muscle mass and the resulting loss of motor function. The dose response relationship of training intensity to training effect has not yet been fully elucidated. METHODS: PubMed was selectively searched for articles that appeared in the past 5 years about the effects and dose-response relationship of strength training in the elderly. RESULTS: Strength training in the elderly (>60 years) increases muscle strength by increasing muscle mass, and by improving the recruitment of motor units, and increasing their firing rate. Muscle mass can be increased through training at an intensity corresponding to 60% to 85% of the individual maximum voluntary strength. Improving the rate of force development requires training at a higher intensity (above 85%), in the elderly just as in younger persons. It is now recommended that healthy old people should train 3 or 4 times weekly for the best results; persons with poor performance at the outset can achieve improvement even with less frequent training. Side effects are rare. CONCLUSION: Progressive strength training in the elderly is efficient, even with higher intensities, to reduce sarcopenia, and to retain motor function. PMID- 21691560 TI - Adjuvant therapy for women over age 65 with breast cancer. AB - BACKGROUND: Women over age 65 with breast cancer are often not treated in accordance with current guidelines as far as adjuvant therapy is concerned, because of the lack of adequate scientific evidence. METHODS: This article is based on a selective review of pertinent literature retrieved by a PubMed search, as well as on the German S3 guidelines for the diagnosis, treatment, and follow up care of breast cancer, the treatment recommendations of the German Working Group on Gynecological Oncology (Arbeitsgemeinschaft Gynakologische Onkologie, AGO) and the German Society of Radiation Oncology (Deutsche Gesellschaft fur Radioonkologie), US National Comprehensive Cancer Network, and the Cochrane database. RESULTS: Women over age 65 are underrepresented in randomized trials of treatments for breast cancer. Geriatric assessment is essential for therapeutic decision-making. Endocrine treatment is feasible for nearly all patients with hormone-sensitive tumors. In selected patients over age 65, chemotherapy significantly improves overall survival. The best evidence regarding toxicity is available for anthracycline monotherapy and for combined therapy with doxorubicin/cyclophosphamide or taxane/doxorubicin. Women without cardiac disease can be given trastuzumab, which may lead to reversible cardiotoxicity. Adjuvant radiotherapy significantly improves local tumor control and survival. Adjuvant radiotherapy that is carried out with modern treatment planning, as recommended by the current guidelines, is no more toxic to older patients than to younger ones; thus, it should always be given, unless there is a special reason not to. CONCLUSION: Women with breast cancer over age 65 whose life expectancy is greater than 5 years, and who are not otherwise too ill, should be given chemotherapy, trastuzumab, and radiotherapy as standard adjuvant treatment. Adjuvant therapy can be reduced or omitted in frail patients. Patients over age 65 should be given the opportunity to enroll in clinical trials. PMID- 21691561 TI - Current pacemaker and defibrillator therapy. AB - BACKGROUND: Pacemakers have been available for 50 years, and implantable cardiac defibrillators for 25. Clear indications for each have been established on the basis of data from randomized clinical trials (RCTs). METHODS: This review article is the product of a collaborative effort by a cardiologist and a cardiac surgeon. The authors arrived at a consensus through a selective review of the literature, with special attention to randomized controlled trials and registry data. RESULTS: Atrioventricular (AV) block only rarely necessitates permanent pacemaker stimulation after inferior myocardial infarction, of which it is a rare (12% to 20%) and often transient accompaniment. AV block is more common, however, in anterior wall infarction (frequency ca. 5%), and often necessitates permanent pacemaker therapy in such cases. Pacemaker complications are rare; they include oversensing (the detection of impulse noise) (0.7%), undersensing (the failure to detect impulses) (3.8%), electrode fractures (3.8%), isolation defects (3.4%), perforation (<1%), dislocation (<1%), and infection (<1% to 12%). Many RCTs have confirmed that defibrillators are effective in the prevention of sudden cardiac death (SCD): they lower the risk of SCD by 20% to 30% in primary prevention and by 20% to 40% in secondary prevention. Cardiac resynchronization therapy improves the clinical manifestations and outcome of patients with congestive heart failure, with a relative risk reduction (RR) of 20% to 40%, even among patients in NYHA classes I and II (RR ca. 40%). Implantable defibrillators only rarely cause problems or complications in either the short or the long term. Emotional disturbances, including anxiety, are a rare side effect, occurring in less than 1% of cases. CONCLUSION: Pacemakers and implantable defibrillators are well established electrotherapeutic devices that are highly effective and have only rare complications. PMID- 21691562 TI - Requests, Blocking Moves, and Rational (Inter)action in Survey Introductions. AB - We draw on conversation analytic methods and research to explicate the interactional phenomenon of requesting in general and the specific case of requesting participation in survey interviews. Recent work on survey participation has given much attention to leverage-saliency theory, but has not engaged how the key concepts of this theory are exhibited in the actual unfolding interaction of interviewers and potential respondents. We do so using digitally recorded and transcribed calls to recruit participation in the 2004 Wisconsin Longitudinal Study. We describe how potential respondents present interactional environments that are relatively discouraging or encouraging, and how, in response, interviewers may be relatively cautious or presumptive in their requesting actions. We consider how the ability of interviewers to tailor their behavior to their interactional environment can affect whether the introduction reaches the point at which a request to participate is made, the form that this request takes, and the sample person's response. Our analysis contributes to understanding how we might use insights from the analysis of interaction to increase cooperation with requests to participate in surveys. PMID- 21691565 TI - Safety, efficacy, and patient acceptability of imiquimod for topical treatment of actinic keratoses. AB - Imiquimod, an immune-modulating imidazoquinoline compound, has been approved in topical formulation for the treatment of actinic keratoses, superficial basal cell carcinomas, and external genital warts. Its use in the treatment of field cancerization, in particular, has been rapidly evolving. With the recent approval of a new drug application for a new concentration, as well as generic formulations, this drug has emerged at the forefront of treatment for actinic keratoses, with improved dosage scheduling and more patients having access to generic options. In the nearly 15 years since its original approval by the Food and Drug Administration for the treatment of actinic keratoses in 1997, topical imiquimod has been reviewed and studied extensively, not only for its safety and efficacy, but also for its tolerability in patients. This paper provides an indepth review of the literature, and provides clinical evidence for its inclusion in the arsenal of treatment options for patients with actinic keratoses. PMID- 21691566 TI - Management strategies for acne vulgaris. AB - CLINICAL QUESTION: What are the most effective treatment(s) for mild, moderate, severe, and hormonally driven acne? RESULTS: Mild acne responds favorably to topical treatments such as benzoyl peroxide, salicylic acid, and a low-dose retinoid. Moderate acne responds well to combination therapy comprising-topical benzoyl peroxide, antibiotics, and/or retinoids, as well as oral antibiotics in refractory cases and oral contraceptive pills for female acne patients. Severe nodulocystic acne vulgaris responds best to oral isotretinoin therapy. In female patients with moderate to severe acne, facial hair, loss of scalp hair and irregular periods, polycystic ovarian syndrome should be considered and appropriate treatment with hormonal modulation given. Adjunctive procedures can also be considered for all acne patients. IMPLEMENTATION: PITFALLS TO AVOID WHEN TREATING ACNE: treatment of acne in women of child-bearing age; familiarization of all acne treatments in order to individualize management for patients; indications for specialist referral. PMID- 21691567 TI - Treatment of cellulite based on the hypothesis of a novel physiopathology. AB - BACKGROUND: The aim of the current study is to report on a new form of treatment for cellulite based on a novel physiological hypothesis. METHODS: A novel treatment for cellulite was evaluated in 14 patients aged 19-36 (mean 27.5) years. The only inclusion criterion was clinically diagnosed cellulite, and the exclusion criteria were history of edema, obesity, or any other disease diagnosed during the physical examination. Perimetry was performed at the gluteal fold, at 5 cm and 10 cm below the gluteal fold for both legs, and 5 cm and 10 cm below the navel. Additionally, standard photographs were taken and a questionnaire of satisfaction was applied. The patients were submitted to a treatment regimen of 1.5 hours per day adapted for the treatment of cellulite, consisting of manual and mechanical lymph drainage and cervical stimulation using the Godoy and Godoy technique. After 10 sessions over two weeks, the patients were evaluated again. RESULTS: Reductions were identified at both points below the navel, the points on the thighs, and at the gluteal fold (P < 0.0001). CONCLUSION: This technique of lymphatic system stimulation is efficacious in the treatment of cellulite. PMID- 21691568 TI - Burned-out testicular tumor: a case report. AB - Germ cell tumors constitute the majority of all testicular tumors, which are relatively rare overall and are mainly encountered in young adults and teenagers. The term 'burnedout' germ cell tumor refers to the presence of a metastatic germ cell tumor with histological regression of the primary testicular lesion. Clinical examination of the testes and scrotal sonography is pivotal in the initial diagnosis of such neoplasms. We present a case of a 31-year-old male with a retroperitoneal mass and no palpable lesion on testicular examination. PMID- 21691569 TI - Anti-angiogenic treatment (sunitinib) for disseminated malignant haemangiopericytoma: a case study and review of the literature. AB - INTRODUCTION: A meningeal haemangiopericytoma (HP) is a mesenchymal tumour that makes up less than 1% of all CNS tumours. HPs arise from pericytes and present high rates of recurrence and distant metastasis. The primary treatment option is surgery. When the disease is disseminated, chemotherapy produces a weak and short lived response; therefore, new drugs are needed. CASE PRESENTATION: We describe the case of a 65-year-old woman with a 13-year history of recurrent HP. After local treatment with radiotherapy, she developed metastases that required systemic treatment, and treatment with sunitinib, an oral inhibitor of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor, was initiated. As a result, radiological stabilisation of the systemic disease was maintained for over 12 months. CONCLUSIONS: Anti-angiogenic agents can be useful for treating disseminated HP, but further studies are needed to confirm their possible role in controlling metastatic disease. PMID- 21691570 TI - Solitary Internal Mammary Lymph Node Metastases Detected by F-FDG-PET/CT in Ovarian Cancer. AB - Internal mammary lymph nodes as solitary site of recurrent ovarian cancer have not been previously described. In this case report, 3 cases of late and very late isolated recurrence in internal mammary lymph nodes are presented. (18)F-FDG PET/CT allowed the diagnosis which was suspected by the increase of the serum CA 125 level in 2 out of 3 cases. Local treatment, consisting of surgery (in 2 patients) and radiation therapy (in 1 patient), permitted an optimal long-term disease control. PMID- 21691571 TI - An unusual case of unilateral malignant leydig cell tumour of the testis. AB - Leydig cell tumour is a benign testicular non-germ cell tumour, and malignant transformation is rare. We report a case of a 35-year-old man who came to our hospital with a painless left testicular mass measuring 1.2 * 1 cm. Histological evaluation of the tumour showed features of a malignant Leydig cell tumour but no infiltration beyond the capsule or metastasis. The small size of the tumour was remarkable. PMID- 21691572 TI - Progressive Multifocal Leukoencephalopathy in a HIV-Negative Patient with Small Lymphocytic Leukemia following Treatment with Rituximab. AB - We describe a case of progressive multifocal leukoencephalopathy (PML) caused by infection with the human polyomavirus JC virus in a patient with B-cell small lymphocytic leukemia who was treated with rituximab. The first symptoms of PML appeared immediately following the last of five cycles of rituximab, cyclophosphamide and pentostatin. Magnetic resonance imaging revealed changes consistent with PML, although JC virus DNA was not detected by polymerase chain reaction assay of the cerebrospinal fluid. A stereotactic biopsy of the brain showed histological changes consistent with PML, while electron microscopy revealed JC virus particles attached to the nuclei of astrocytes. The patient was treated supportively but died 53 days after the initial onset of symptoms. PMID- 21691573 TI - Thrombotic thrombocytopenic purpura and gemcitabine. AB - Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening complication of gemcitabine treatment. Since the approval of this nucleoside analog for the treatment of pancreatic cancer by the FDA in 1996, reported incidence varies from 0.015 to 1.4%. The classic 'pentad' describing the disease process (fever, hemolytic anemia, thrombocytopenia, neurological complications and renal impairment) is not always present to the same extent in every patient. Here, we present a rare case of TTP associated specifically with gemcitabine treatment, and further, we briefly discuss the manifestations, treatment options and outcomes related to the complication. In our opinion, it is important to realize that as the indications for the use of gemcitabine increase and its use becomes more widespread, TTP and other disorders on the spectrum of thrombotic microangiopathies are important considerations to remember in patients with worsening anemia and thrombocytopenia. New onset or exacerbation of underlying hypertension may provide a clue to diagnose the disease entity earlier in this subgroup of patients. PMID- 21691574 TI - Mixed adenocarcinoma of the rectovaginal septum associated with endometriosis and endometrial carcinoma: a case report. AB - PURPOSE: To present a case of primary mixed (clear cell and endometrioid type) adenocarcinoma of the rectovaginal septum, probably arising from endometriosis and associated with a highly differentiated, early-stage endometrioid endometrial carcinoma. The case was managed by a minimally invasive approach and postoperative adjuvant chemotherapy. RESULTS: The patient underwent clinical/instrumental follow-up and a second-look laparoscopy after the primary surgery as well as adjuvant chemotherapy. No evidence of disease could be observed after the treatment. CONCLUSION: Surgery with postoperative chemotherapy can be recommended for the treatment of mixed adenocarcinoma of the rectovaginal septum. PMID- 21691575 TI - Mitochondrial complex 1 gene analysis in keratoconus. AB - PURPOSE: Keratoconus is characterized by the thinning of corneal stroma, resulting in reduced vision. The exact etiology of keratoconus (KC) is still unknown. The involvement of oxidative stress (OS) in this disease has been reported. However, the exact mechanism of OS in keratoconus is still unknown. Thus we planned this study to screen mitochondrial complex I genes for sequence changes in keratoconus patients and controls, as mitochondrial complex I is the chief source of reactive oxygen species (ROS) production. METHODS: A total of 20 keratoconus cases and 20 healthy controls without any ocular disorder were enrolled in this study. Mitochondrial complex I genes (ND1, 2, 3, 4, 4L, 5, and 6) were amplified in all patients and controls using 12 pairs of primers by PCR. After sequencing, DNA sequences were analyzed against the mitochondrial reference sequence NC_012920. Haplogroup frequency based Principle Component Analysis (PCA) was constructed to determine whether the gene pool of keratoconus patients is closer to major populations in India. RESULTS: DNA sequencing revealed a total 84 nucleotide variations in patients and 29 in controls. Of 84 nucleotide changes, 18 variations were non-synonymous and two novel frame-shift mutations were detected in cases. Non-synonymous mtDNA sequence variations may account for increased ROS and decreased ATP production. This ultimately leads to OS; which is a known cause for variety of corneal abnormalities. Haplotype analysis showed that most of the patients were clustered under the haplogroups: T, C4a2a, R2'TJ, M21'Q1a, M12'G2a2a, M8'CZ and M7a2a, which are present as negligible frequency in normal Indian population, whereas only few patients were found to be a part of the other haplogroups like U7 (Indo-European), R2 and R31, whose origin is contentious. CONCLUSIONS: Mt complex I sequence variations are the main cause of elevated ROS production which leads oxidative stress. This oxidative stress then starts a cascade of events which ultimately can lead to keratoconus. Prompt antioxidant therapy should be initiated in keratoconus patients to minimize ROS related damage. PMID- 21691576 TI - An update on TroVax for the treatment of progressive castration-resistant prostate cancer. AB - Prostate cancer is a common human malignancy with few effective therapeutic options for treating advanced castration-resistant disease. The potential therapeutic effectiveness of immunotherapy and vaccines, in particular, has gained popularity based on the identification of prostate-associated antigens, potent expression vectors for vaccination, and data from recent clinical trials. A modified vaccinia Ankara (MVA) virus expressing 5T4, a tumor-associated glycoprotein, has shown promise in preclinical studies and clinical trials in patients with colorectal and renal cell carcinoma. This review will discuss the rationale for immunotherapy in prostate cancer and describe preclinical and limited clinical data in prostate cancer for the MVA-5T4 (TroVax((r))) vaccine. PMID- 21691577 TI - Rationale for targeting VEGF, FGF, and PDGF for the treatment of NSCLC. AB - Lung cancer remains a leading cause of death globally, with the most frequent type, nonsmall cell lung cancer (NSCLC), having a 5-year survival rate of less than 20%. While platinum-based doublet chemotherapy is currently first-line therapy for advanced disease, it is associated with only modest clinical benefits at the cost of significant toxicities. In an effort to overcome these limitations, recent research has focused on targeted therapies, with recently approved agents targeting the epidermal growth factor receptor and vascular endothelial growth factor (VEGF) signaling pathways. However, these agents (gefitinib, erlotinib, and bevacizumab) provide antitumor activity for only a small proportion of patients, and patients whose tumors respond inevitably develop resistance to treatment. As angiogenesis is a crucial step in tumor growth and metastasis, antiangiogenic treatments might be expected to have antitumor activity. Important targets for the development of novel antiangiogenic therapies include VEGF, fibroblast growth factor, platelet-derived growth factor, and their receptors. It is hypothesized that targeting multiple angiogenic pathways may not only improve antitumor activity but also reduce the risk of resistance. Several novel agents, such as BIBF 1120, sorafenib, sunitinib, and cediranib have shown promising preliminary activity and tolerability in Phase II studies, and results of ongoing Phase III randomized studies will be necessary to establish the potential place of these new therapies in the management of individual patients with NSCLC. PMID- 21691578 TI - Antioxidant oils and Salmonella enterica Typhimurium reduce tumor in an experimental model of hepatic metastasis. AB - Fruit seeds high in antioxidants have been shown to have anticancer properties and enhance host protection against microbial infection. Recently we showed that a single oral dose of Salmonella enterica serovar Typhimurium expressing a truncated human interleukin-2 gene (SalpIL2) is avirulent, immunogenic, and reduces hepatic metastases through increased natural killer cell populations in mice. To determine whether antioxidant compounds enhance the antitumor effect seen in SalpIL2-treated animals, we assayed black cumin (BC), black raspberry (BR), and milk thistle (MT) seed oils for the ability to reduce experimental hepatic metastases in mice. In animals without tumor, BC and BR oil diets altered the kinetics of the splenic lymphocyte response to SalpIL2. Consistent with previous reports, BR and BC seed oils demonstrated independent antitumor properties and moderate adjuvant potential with SalpIL2. MT oil, however, inhibited the efficacy of SalpIL2 in our model. Based on these data, we conclude that a diet high in antioxidant oils promoted a more robust immune response to SalpIL2, thus enhancing its antitumor efficacy. PMID- 21691579 TI - Acute endothelial failure after cosmetic iris implants (NewIris(r)). AB - We report a case of an acute endothelial failure after the implantation of a new cosmetic, colored, artificial iris diaphragm implant called NewIris((r)). A 21 year-old woman came to us complaining of progressive loss of vision and pain after NewIris lenses had been implanted. Decreased visual acuity, corneal edema, and increased intraocular pressure in both eyes appeared only 3 weeks after the surgery. The lenses were removed as soon as possible but had already severely affected the endothelial cell count. NewIris implants are an alternative to cosmetic contact lenses, but they are not as safe as other phakic anterior chamber intraocular lenses, nor are they a good option for the patient. PMID- 21691580 TI - Profile of Xeomin(r) (incobotulinumtoxinA) for the treatment of blepharospasm. AB - Even though conventional botulinum neurotoxin (BoNT) products have shown successful treatment results in patients with benign blepharospasm (BEB), the main, potential long-term side effect of BoNT use is the development of immunologic resistance due to the production of neutralizing antibody to the neurotoxin after repeated injections. Xeomin((r)) (incobotulinumtoxinA), a unique botulinum neurotoxin type A (BoNT/A) drug free of complexing proteins otherwise contained in all conventional BoNT/A drugs, was recently approved by US Food and Drug Administration for the treatment of cervical dystonia or blepharospasm in adults. The newly approved BoNT/A drug may overcome this limitation of previous conventional products, since it contains pure neurotoxin (150 kDa) through a manufacturing process that separates it from complexing proteins such as hemagglutinins produced by fermentation of Clostridium botulinum. Many studies have also shown that Xeomin((r)) has the same efficacy and safety profile as complexing protein-containing products such as Botox((r)) and is exchangeable with Botox((r)) using a simple 1:1 conversion ratio. Xeomin((r)) represents a new treatment option for the repeated treatment of patients with blepharospasm in that it may reduce antibody-induced therapy failure. But, long-term comparative trials in naive patients between Xeomin((r)) and conventional BoNT/A drugs are required to confirm the low immunogenicity of Xeomin((r)). PMID- 21691581 TI - Evaluation of a partial retinal surface tear by optical coherence tomography. AB - Differential diagnosis of retinal hemorrhage and partial tear of the retinal surface may be difficult in some cases. A 62-year-old woman was mistakenly followed-up for small retinal hemorrhages for more than 1 year. Blocked fluorescence specific to retinal hemorrhage was not observed by fluorescein angiography (FAG). Optical coherence tomography (OCT) clearly showed defects of the retinal surface indicating partial tears of the surface at the vitreo-retinal juncture and not hemorrhage. OCT is a useful and noninvasive device for the differential diagnosis of retinal hemorrhage and partial tear of the retinal surface. PMID- 21691582 TI - Cataract surgery in Knobloch syndrome: a case report. AB - Knobloch syndrome is an autosomal recessive disorder associated with early-onset ocular abnormalities and central nervous system malformations. Ocular abnormalities are usually severe, and include high myopia, vitreoretinal degeneration, retinal detachment, macular abnormalities, and cataract. The most frequent systemic changes are midline malformations of the brain, ventricular dilation, and occipital encephalocele. Cognitive delay may occur. We report a case of cataract in a child with Knobloch syndrome. Cataract surgery and follow up are described. PMID- 21691583 TI - Delayed-onset bleb-associated endophthalmitis: presentation and outcome by culture result. AB - PURPOSE: To determine how culture results are associated with clinical presentations and outcomes in delayed-onset bleb-associated endophthalmitis (BAE). METHODS: Retrospective consecutive case series of BAE at Bascom Palmer Eye Institute between January 1, 1996 and December 31, 2009. All patients had prior glaucoma filtering surgery. BAE was defined as intraocular infection with vitreous involvement receiving treatment with intravitreal antibiotics. Visual acuity (VA) outcomes and other clinical data were grouped by culture result and compared using the 2-sided Student's t-test. MAIN OUTCOME MEASURE: Mean logMAR change at 3 months after treatment (3-month logMARDelta). RESULTS: Eighty-six eyes of 85 patients were identified. Two eyes were primarily eviscerated. Fifty three (63%) eyes were culture-positive with the following organisms: Streptococcus, 21 (25%); coagulase-negative Staphylococcus, 9 (11%); Enterococcus, 6 (7%); Gram-negative, 15 (18%); Moraxella, 8 (10%); Pseudomonas, 3 (4%); and Serratia, 3 (4%). Presenting logMAR VA: culture-positive worse than culture-negative cases (2.45 vs 2.19, P = 0.05). Presenting intraocular pressure (IOP): culture-positive higher than culture-negative cases (24 mmHg vs 14 mmHg, P = 0.002). Poor presenting view of the fundus: Streptococcus worse than coagulase negative Staphylococcus cases (90% vs 44%, P = 0.006), Pseudomonas and Serratia worse than Moraxella cases (100% vs 50%, P = 0.04). Three month logMARDelta: culture-positive worse than culture-negative cases (1.03 vs 0.43, P = 0.02), Streptococcus worse than coagulase-negative Staphylococcus cases (1.44 vs 0.31, P = 0.004), Pseudomonas and Serratia worse than coagulase-negative Staphylococcus cases (2.41 vs 0.31, P = 0.001), Pseudomonas and Serratia worse than Moraxella cases (2.41 vs 0.04, P = 0.001). A culture result of Streptococcus or Serratia was present in 6 of 7 eyes that received an additional treatment of enucleation or evisceration (P = 0.01). CONCLUSION: Culture-positive cases were associated with worse presenting VA, higher presenting IOP, and worse VA outcomes than culture-negative cases. Streptococcus, Pseudomonas, and Serratia cases were associated with poor presenting view of the fundus and worse VA outcomes than coagulase-negative Staphylococcus and Moraxella cases. PMID- 21691584 TI - Long-term safety evaluation of bimatoprost ophthalmic solution 0.03%: a pooled analysis of six double-masked, randomized, active-controlled clinical trials. AB - BACKGROUND: Bimatoprost ophthalmic solution 0.03% was approved in the US for reducing intraoccular pressure (IOP) based on two double-masked, active controlled clinical trials. Four additional long-term studies (>=12 months) were conducted; however, the aggregate safety profile of the six studies has not been reported. METHODS: Adverse events (AEs) were pooled from six double-masked, active-controlled, long-term clinical trials in which subjects received bimatoprost 0.03% once daily (QD) or twice daily (BID) as an eyedrop. AE terms were converted to MedDRA (V.11.0) Preferred Terms and analyzed. RESULTS: In total, 1409 patients received more than one dose of bimatoprost 0.03% QD or BID. Most AEs were mild in severity and reported by 86.7% (QD) and 94.8% (BID) of subjects (<=12 months of treatment). AEs reported through month 12 (aggregate incidence of >=5%) were conjunctival hyperemia, increased eyelash growth, eye pruritus, periocular skin hyperpigmentation, eye irritation, dry eye, and hypertrichosis. AE onset was generally reported within four months of treatment. The cumulative incidence of common AEs in the QD treatment group at 24-48 months was similar to that measured at 12 months of treatment. CONCLUSION: Bimatoprost 0.03% has a favorable safety and tolerability profile as characterized by six long-term studies. Common AEs were due to the known pharmacological activity of bimatoprost and reversible with treatment cessation. PMID- 21691585 TI - Quantifying the impact of nonadherence patterns on exposure to oral immunosuppressants. AB - BACKGROUND AND OBJECTIVES: Nonadherence to oral immunosuppressive drugs in renal transplant patients remains a major challenge. The objective of this study was to develop an adherence-exposure model that 1) quantifies the impact of nonadherence patterns on cyclosporine levels and 2) identifies nonadherence patterns that are associated with unfavorable transplantation outcomes. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This model quantified variability in drug exposure, expressed as the coefficient of variation (CV%), for time-averaged and trough cyclosporine levels (C(avg) and C(min), respectively), and percentage of days spent below the therapeutic C(min) target. Simulated patterns of nonadherence closely matched those observed in clinical practice for four nonadherence clusters and an "Others" category. RESULTS: Patients in simulated nonadherence clusters 1-3 spent a mean (standard deviation) 5.8% (4.9), 9.0% (5.0), and 6.5% (3.4) of days below the C(min) target, compared with 76.8% (6.5) for cluster 4 and 38.3% (6.4) for the "Others" category. Mean (standard deviation) CV% values for C(min) were 24.1 (7.9), 35.4 (11.7), and 34.1 (10.6) for clusters 1-3, compared with 136.4 (23.6) for cluster 4 and 64.8 (10.3) for the "Others" category. Findings for C(avg) were similar. CONCLUSION: Based on nonadherence patterns and known relationships between CV% for C(min) and C(avg), and transplantation outcomes, patients in cluster 4 and the "Others" category are expected to be at high risk of allograft rejection. The proposed drug adherence exposure model is useful to identify high-risk patients who can be targeted for interventions aimed at enhancing drug adherence to optimize clinical long-term outcomes. PMID- 21691586 TI - Fracture risk associated with continuation versus discontinuation of bisphosphonates after 5 years of therapy in patients with primary osteoporosis: a systematic review and meta-analysis. AB - PURPOSE: The risks and benefits of continuing bisphosphonate therapy beyond 5 years in patients with primary osteoporosis have not been well established. METHODS: We searched MedLine, EMBase, CENTRAL, CINAHL, and AgeLine prior to February 2010. Bibliographies were also searched and experts in the field contacted. The ProQuest Dissertations and Theses database and relevant conference proceedings were searched to identify unpublished or ongoing studies. Two authors independently reviewed search results. Randomized controlled trials and comparative nonrandomized controlled trials examining post-menopausal women or men >=50 years of age with primary osteoporosis assigned to continue versus discontinue bisphosphonate therapy after >=5 years of therapy were included. Of 1188 identified articles, three studies (n = 1443) met criteria for inclusion in data synthesis. Data were extracted and risk of bias assessed by two independent reviewers using predefined criteria. RESULTS: No statistically significant association was found between fracture incidence and the discontinuation of therapy beyond 5 years for any type of fracture: clinical nonvertebral fracture (relative risk [RR] = 0.97; 95% confidence interval [CI] 0.77-1.23), clinical vertebral fracture (RR = 0.61; 95% CI 0.32-1.19), or morphometric vertebral fracture (RR = 0.90; 95% CI 0.5-1.64). No differences in adverse events were identified between the two groups. CONCLUSION: We found no significant difference in fracture risk or adverse events between postmenopausal women with primary osteoporosis who continued bisphosphonate therapy versus those who discontinued bisphosphonate therapy after 5 years of treatment. However, given the small number and limited quality of available studies, no firm conclusions or recommendations can be made. PMID- 21691587 TI - Steroid response pattern and outcome of pediatric idiopathic nephrotic syndrome: a single-center experience in northwest Iran. AB - AIMS: Characteristics of nephrotic syndrome (NS) in children varies in different geographical areas based on genetic and environmental factors. The aim of this study is to evaluate the steroid response pattern and outcome of idiopathic NS (INS) in a pediatric referral hospital in northwest Iran. METHODS: Medical records of all admitted children under 14 years of age with INS in the Children's Hospital of Tabriz, Iran, from 1999 to 2010 were studied retrospectively. Demographics, pattern of response to medications, recurrence rate, histopathology, and outcome were documented. RESULTS: A total of 165 patients with INS, with a mean age of 4.98 +/- 2.61 years were studied. Male to female ratio was 2:1. Duration of follow-up was 5.36 +/- 2.2 years (1-10 years). A total of 124 patients (75.2%) responded to steroids, and 41 patients (24.8%) were steroid resistant. Frequency of hematuria (P = 0.01) and steroid resistance (P = 0.005) in girls was significantly higher than boys. Patients with steroid resistance had a higher frequency of hematuria (P = 0.001) and a higher mean age (P = 0.017) in comparison with steroid responders. Renal biopsy carried out in 49 patients (29.7%) revealed minimal change in NS in 20 (40.8%), focal segmental glomerulosclerosis in 16 (32.7%), and mesangial proliferation in 11 (22.5%) patients. Twenty-two steroid resistant patients (13%) achieved remission with other immunosupressives. Nineteen patients (11.5%) were resistant to all treatment modalities; of these, nine (5.4%) progressed to end-stage renal disease, and 10 (6%) continued nephrotic range proteinuria. Seven patients (4.2%) died. Of the 146 patients who achieved remission with any one of the treatment modalities, 91 patients (62.3%) experienced at least one recurrence episode, 15 patients (10.3%) were frequent relapsers, and 12 patients (8.2%) were steroid dependent. Higher age at onset of NS was associated with lower relapse rate (P = 0.04). CONCLUSION: Demographics, histological features, and outcome of INS in our area were similar to western countries. In the present study, risk of steroid resistance was higher in girls than boys. PMID- 21691588 TI - Accidental ingestion of BiTine ring and a note on inefficient ring separation forceps. AB - BACKGROUND: Accidental ingestion of medium-to-large instruments is relatively uncommon during dental treatment but can be potentially dangerous. A case of BiTine ring ingestion is presented with a note on inefficient ring separation forceps. CASE DESCRIPTION: A 28-year-old male patient accidentally ingested the BiTine ring (2 cm diameter, 0.5 cm outward projections) while it was being applied to a distoproximal cavity in tooth # 19. The ring placement forceps were excessively flexible; bending of the beaks towards the ring combined with a poor no-slippage mechanism led to sudden disengagement of the ring and accelerated movement towards the pharynx. We followed the patient with bulk forming agents and radiographs. Fortunately the ring passed out without any complications. CLINICAL IMPLICATIONS: Checking equipment and methods is as important as taking precautions against any preventable medical emergency. It is the responsibility of the clinician to check, verify and then use any instrument/equipment. PMID- 21691589 TI - If you don't take it - it can't work: the consequences of not being treated or nonadherence to osteoporosis therapy. AB - Osteoporosis is a growing problem worldwide, linked to an increasingly aging population. Despite the availability of a wide variety of treatments for osteoporosis, a significant number of patients are either not being prescribed treatment or discontinue therapy as early as 6 months after initiation. The reasons for a lack of adherence are many but poor adherence increases the risk of fracture and, therefore, the disease burden to the patient and society. Results from large-scale, randomized clinical studies have shown that different osteoporosis treatments are efficacious in reducing the risk of fracture. Studies assessing the effects of discontinuing osteoporosis therapies show that some treatments appear to continue to protect patients from the risk of future fracture even when treatment is stopped. However, these trials involve patients who have been compliant with treatment for between 2 and 5 years, a situation not reflective of real-world clinical practice. In reality, patients who discontinue therapy within the first 6 months may never achieve the optimum protection from fracture regardless of which treatment they have been prescribed. Clinicians need to develop management strategies to enable patients to adhere to their treatment. This will ultimately result in better prevention of fracture and a lower burden of disease to society and patients. PMID- 21691591 TI - The Use of Sample Weights in Hot Deck Imputation. AB - A common strategy for handling item nonresponse in survey sampling is hot deck imputation, where each missing value is replaced with an observed response from a "similar" unit. We discuss here the use of sampling weights in the hot deck. The naive approach is to ignore sample weights in creation of adjustment cells, which effectively imputes the unweighted sample distribution of respondents in an adjustment cell, potentially causing bias. Alternative approaches have been proposed that use weights in the imputation by incorporating them into the probabilities of selection for each donor. We show by simulation that these weighted hot decks do not correct for bias when the outcome is related to the sampling weight and the response propensity. The correct approach is to use the sampling weight as a stratifying variable alongside additional adjustment variables when forming adjustment cells. PMID- 21691590 TI - Effects of recombinant growth hormone (GH) replacement and psychomotor and cognitive stimulation in the neurodevelopment of GH-deficient (GHD) children with cerebral palsy: a pilot study. AB - Cerebral palsy (CP) is the main cause of physical disability in childhood and is an important health issue that has a strong socioeconomic impact. There is no effective treatment for CP and therapeutic approaches report only partial benefits for affected people. In this study we assessed the effects of growth hormone (GH) treatment combined with psychomotor and cognitive stimulation in the neurodevelopment of children with CP and GH deficiency (GHD). The study was carried out in 11 patients (7 boys and 4 girls; 4.12 +/- 1.31 years) with GHD and CP who were treated with recombinant GH (rGH) and psychomotor and cognitive stimulation during 2 months. Battelle Developmental Inventory Screening Test (BDIST) was performed 2 months before commencing GH treatment, just before commencing GH administration, and after 2 months of combined treatment involving GH and cognitive stimulation. Psychomotor and cognitive status did not change during the period in which only cognitive stimulation was performed; however, significant improvements in personal and social skills, adaptive behavior, gross motor skills and total psychomotor abilities, receptive and total communication, cognitive skills and in the total score of the test (P < 0.01), and in fine motor skills and expressive communication (P < 0.02) were observed after the combined treatment period. Therefore, GH replacement together with psychomotor and cognitive stimulation seem to be useful for the appropriate neurodevelopment of children with GHD and CP. PMID- 21691592 TI - P-SPLINES USING DERIVATIVE INFORMATION. AB - Time series associated with single-molecule experiments and/or simulations contain a wealth of multiscale information about complex biomolecular systems. We demonstrate how a collection of Penalized-splines (P-splines) can be useful in quantitatively summarizing such data. In this work, functions estimated using P splines are associated with stochastic differential equations (SDEs). It is shown how quantities estimated in a single SDE summarize fast-scale phenomena, whereas variation between curves associated with different SDEs partially reflects noise induced by motion evolving on a slower time scale. P-splines assist in "semiparametrically" estimating nonlinear SDEs in situations where a time dependent external force is applied to a single-molecule system. The P-splines introduced simultaneously use function and derivative scatterplot information to refine curve estimates. We refer to the approach as the PuDI (P-splines using Derivative Information) method. It is shown how generalized least squares ideas fit seamlessly into the PuDI method. Applications demonstrating how utilizing uncertainty information/approximations along with generalized least squares techniques improve PuDI fits are presented. Although the primary application here is in estimating nonlinear SDEs, the PuDI method is applicable to situations where both unbiased function and derivative estimates are available. PMID- 21691593 TI - Osteoblast-like cell attachment and proliferation on turned, blasted, and anodized titanium surfaces. AB - PURPOSE: The purpose of this study was to investigate the cellular activities of MG63 osteoblast-like cells on modified titanium surfaces. MATERIALS AND METHODS: MG63 osteoblast-like cells were cultured on titanium disks (n = 20 in each group) with turned, resorbable blast media (RBM)-treated, or anodized surfaces. The surfaces of commercially available implants of Osstem (Osstem Implant) were reproduced for the titanium disks. The morphology of cells cultured on these disks was examined using scanning electron microscopy. X-ray photoelectron spectroscopy (XPS) was employed for the analysis of surface chemistry. Specimens were also evaluated with an initial cell adhesion assay to compare initial adhesion, with a methyl tetrazol sulfate (MTS) assay to compare the proliferation ability, and with an alkaline phosphatase (ALP) assay to compare the differentiation ability. Statistical significance of the differences was determined using the Kruskal-Wallis test for the cell adhesion assay and analysis of variance for the MTS and ALP assays. RESULTS: Attached cells with more defined lamellopodia and flattened morphology were observed on the anodized and RBM surfaces than on the turned surfaces. The titanium surfaces were all oxidized as titanium oxide and polluted by carbon determinants, as determined by XPS. Anodized titanium surfaces exhibited calcium and phosphorus peaks. Initial cell attachment activity, cell proliferation activity, and ALP activity were higher on the anodized surfaces than on the other surfaces. Cell differentiation on the anodized surfaces at culture day 10 was significantly higher (P < .05) than on the other surfaces. CONCLUSIONS: Surface treatment by anodization may improve initial attachment of cells, proliferation ability, and differentiation activity, which play important roles in providing better osseointegration of implants. More rapid and stronger osseointegration of implants may make it possible to offer the best anchorage and shorten the healing time required prior to functional loading. PMID- 21691594 TI - Platform switching: biomechanical evaluation using three-dimensional finite element analysis. AB - PURPOSE: The objective of this study was to evaluate, using three-dimensional finite element analysis (3D FEA), the stress distribution in peri-implant bone tissue, implants, and prosthetic components of implant-supported single crowns with the use of the platform-switching concept. MATERIALS AND METHODS: Three 3D finite element models were created to replicate an external-hexagonal implant system with peri-implant bone tissue in which three different implant-abutment configurations were represented. In the regular platform (RP) group, a regular 4.1-mm-diameter abutment (UCLA) was connected to regular 4.1-mm-diameter implant. The platform-switching (PS) group was simulated by the connection of a wide implant (5.0 mm diameter) to a regular 4.1-mm-diameter UCLA abutment. In the wide platform (WP) group, a 5.0-mm-diameter UCLA abutment was connected to a 5.0-mm diameter implant. An occlusal load of 100 N was applied either axially or obliquely on the models using ANSYS software. RESULTS: Both the increase in implant diameter and the use of platform switching played roles in stress reduction. The PS group presented lower stress values than the RP and WP groups for bone and implant. In the peri-implant area, cortical bone exhibited a higher stress concentration than the trabecular bone in all models and both loading situations. Under oblique loading, higher intensity and greater distribution of stress were observed than under axial loading. Platform switching reduced von Mises (17.5% and 9.3% for axial and oblique loads, respectively), minimum (compressive) (19.4% for axial load and 21.9% for oblique load), and maximum (tensile) principal stress values (46.6% for axial load and 26.7% for oblique load) in the peri-implant bone tissue. CONCLUSION: Platform switching led to improved biomechanical stress distribution in peri-implant bone tissue. Oblique loads resulted in higher stress concentrations than axial loads for all models. Wide-diameter implants had a large influence in reducing stress values in the implant system. PMID- 21691596 TI - Influence of tissue biotype on implant esthetics. AB - Implant dentistry has come a long way since 1981, with great improvements made to achieve primary implant stability and improve bone-to-implant contact. The focus has since shifted toward creating an esthetic restoration that is indistinguishable from natural teeth and is stable over time. This paper proposes a management triad that enhances soft tissue thickness around implant-supported restorations while discussing distinct differences between thin and thick tissue biotypes. In addition, the effect of tissue biotype on implant esthetics is highlighted. PMID- 21691595 TI - The effects of laser microtexturing of the dental implant collar on crestal bone levels and peri-implant health. AB - PURPOSE: Polished and machined collars have been advocated for dental implants to reduce plaque accumulation and crestal bone loss. More recent research has suggested that a roughened titanium surface promotes osseointegration and connective tissue attachment. The purpose of this research was to compare crestal bone height adjacent to implants with laser-microtextured and machined collars from two different implant systems. MATERIALS AND METHODS: Four implants, two with laser-microtextured collars and two with machined collars, were placed in the anterior mandible to serve as overdenture abutments. They were placed in alternating order, and the distal microtextured- and machined-collar implants were loaded with ball abutments. The mesial implants were left unloaded. The distal implants were immediately loaded with prefabricated dentures. Plaque Index, Bleeding Index, and probing depths (PDs) were measured after 6 and 12 months for the loaded implants. Bone loss for both groups (loaded and unloaded) was evaluated via standardized radiographs. RESULTS: Plaque and bleeding values were similar for both implant types. The microtextured-collar implants showed shallower PDs (0.36 +/- 0.5 mm and 0.43 +/- 0.51 mm) than those with machined collars (1.14 +/- 0.77 mm and 1.64 +/- 0.93 mm; < .05 for 6 and 12 months, respectively). At 6 and 12 months, respectively, the microtextured implants showed less crestal bone loss for both loaded (0.19 +/- 0.15 mm and 0.42 +/- 0.34 mm) and unloaded groups (0.15 +/- 0.15 mm and 0.29 +/- 0.20 mm) than the machined implants for both the loaded (0.72 +/- 0.5 mm and 1.13 +/- 0.61 mm) and unloaded groups (0.29 +/- 0.28 mm and 0.55 +/- 0.32 mm). CONCLUSION: Application of laser microtextured grooves to the implant collar resulted in shallower PDs and less peri-implant crestal bone loss than that seen around implants with machined collars. PMID- 21691597 TI - Attachment and proliferation of human osteoblast-like cells on guided bone regeneration (GBR) membranes in the absence or presence of nicotine: an in vitro study. AB - PURPOSE: To compare in vitro the attachment and proliferation of human osteoblast like cells (MG63) on tissue culture plates and guided bone regeneration (GBR) membranes in the absence or presence of nicotine. MATERIALS AND METHODS: Membrane samples were fixed to wells and the cell number (CN) was counted after 24 hours (attachment assay) or 5 days (proliferation assay). The ratio of cell count (RCC) (CN at 5 days/CN at 24 hours) was calculated. The study had three parts: First, five different resorbable GBR membranes were compared (Resolut Adapt LT [RALT], Biocollagen [BC], Bio-Gide [BG], OsseoGuard [OG], and Demokritos Human Tissue Bank [DEM]). Next, cells were cultured on tissue culture plates with five different concentrations of nicotine. Finally, cells were cultured on the membrane that had demonstrated the highest RCC and CN in part 1 with four different concentrations of nicotine. RESULTS: At 24 hours, BG showed the highest CN and OG showed the lowest CN. At 5 days, BG showed the highest CN. The order of RCC was BG > OG > DEM > RALT ~ BC. At 24 hours, lower nicotine concentrations (0.3 and 3 MUg/mL) showed higher CNs versus the control, whereas CNs for high nicotine concentrations (30 and 300 MUg/mL) were lower than for the control. CN at 5 days and RCC were lowest with 300 MUg/mL nicotine. At 24 hours and 5 days, all differences among wells with membrane were statistically insignificant. Nevertheless, CN at 5 days and RCC were highest with the lowest nicotine concentration (3 MUg/mL) and lowest with high concentrations. CONCLUSIONS: Membrane materials influence attachment and proliferation of bone cells and, therefore, could affect the outcomes of GBR. On both tissue culture plates and membranes, there is a tendency toward a biphasic effect of nicotine, with stimulatory effects at low concentrations and inhibitory effects at high concentrations. PMID- 21691598 TI - Accuracy of implant placement using a CAD/CAM surgical guide: an in vitro study. AB - PURPOSE: To determine and compare the accuracy of an advanced surgical template based on computer-aided design/computer-assisted manufacture (CAD/CAM) with the conventional surgical template in different respects such as entry point, length, and osteotomy angle. MATERIALS AND METHODS: Computed tomography (CT) scanning of a dentate epoxy mandible was performed and its three-dimensional computerized model was simulated. Sixteen rapid-prototyped models were fabricated and divided into two groups. In the first group, a radiographic template was fabricated and placed on the model during CT scanning and then was modified to the conventional surgical template form. In the second group, a coordinate measuring machine was used to reformat a nonanatomic radiographic template fabricated by a stereolithographic machine, and four implants were planned and then placed in the jaw. The differences between planned and actual mesiodistal and buccolingual entry points, lengths, and angles of the implants were measured. Statistical analysis was performed with the Mann-Whitney and Friedman tests to detect differences between groups. RESULTS: The average differences between the planned and actual entry points in the mesiodistal and buccolingual directions, lengths, and angles of the implants and the osteotomy showed a considerable reduction in the CAD/CAM group versus the conventional group (P < .005). CONCLUSION: The accuracy of implant placement was improved using an innovative CAD/CAM surgical template. PMID- 21691599 TI - Effects of occlusal inclination and loading on mandibular bone remodeling: a finite element study. AB - PURPOSE: To provide a preliminary understanding of the biomechanics with respect to the effect of cusp inclination and occlusal loading on the mandibular bone remodeling. MATERIALS AND METHODS: Three different cusp inclinations (0, 10, and 30 degrees) of a ceramic crown and different occlusal loading locations (central fossa and 1- and 2-mm offsets horizontally) were taken into account to explore the stresses and strains transferred from the crown to the surrounding dental bone through the implant. A strain energy density obtained from two-dimensional plane-strain finite element analysis was used as the mechanical stimulus to drive cancellous and cortical bone remodeling in a buccolingual mandibular section. RESULTS: Different ceramic cusp inclinations had a significant effect on bone remodeling responses in terms of the change in the average peri-implant bone density and overall stability. The remodeling rate was relatively high in the first few months of loading and gradually decreased until reaching its equilibrium. A larger cusp inclination and horizontal offset (eg, 30 degrees and 2-mm offset) led to a higher bone remodeling rate and greater interfacial stress. CONCLUSIONS: The dental implant superstructure design (in terms of cusp inclination and loading location) determines the load transmission pattern and thus largely affects bone remodeling activities. Although the design with a lower cusp inclination recommended in previous studies may reduce damage and fracture failure, it could, to a certain extent, compromise bone engagement and long-term stability. PMID- 21691600 TI - Dimensional accuracy of pickup implant impression: an in vitro comparison of novel modular versus standard custom trays. AB - PURPOSE: The purpose of this in vitro study was to compare the dimensional accuracy of the pickup impression technique using a modular individual tray (MIT) and using a standard individual tray (ST) for multiple internal-connection implants. The roles of both materials and geometric misfits were considered. MATERIALS AND METHODS: First, because the MIT relies on the stiffness and elasticity of acrylic resin material, a preliminary investigation of the resin volume contraction during curing and polymerization was done. Then, two sets of specimens were tested to compare the accuracy of the MIT (test group) to that of the ST (control group). The linear and angular displacements of the transfer copings were measured and compared during three different stages of the impression procedure. Experimental measurements were performed with a computerized coordinate measuring machine. RESULTS: The curing dynamic of the acrylic resin was strongly dependent on the physical properties of the acrylic material and the powder/liquid ratio. Specifically, an increase in the powder/liquid ratio accelerated resin polymerization (curing time decreases by 70%) and reduced the final volume contraction by 45%. However, the total shrinkage never exceeded the elastic limits of the material; hence, it did not affect the coping's stability. In the test group, linear errors were reduced by 55% and angular errors were reduced by 65%. CONCLUSIONS: Linear and angular displacements of the transfer copings were significantly reduced with the MIT technique, which led to higher dimensional accuracy versus the ST group. The MIT approach, in combination with a thin and uniform amount of acrylic resin in the pickup impression technique, showed no significant permanent distortions in multiple misalignment internal-connection implants compared to the ST technique. PMID- 21691601 TI - Argon ion beam polishing: a preparation technique for evaluating the interface of osseointegrated implants with high resolution. AB - PURPOSE: The objective of this study was to assess the use of ion beam polishing for preparing cross sections suitable for high-resolution scanning electron microscope (SEM) investigation of dental implants with a brittle porous oxide layer and of bone/implant interfaces. MATERIALS AND METHODS: Thirteen Nobel Biocare TiUnite implants were placed in minipigs. After 4 weeks, the implant and surrounding bone were removed en bloc and the implant was cut axially into two halves. The cross section was then polished with an argon ion beam. Additionally, ion beam-polished cross sections were prepared from four as-received implants. Ion beam-polished surfaces were studied with a field emission SEM (FE-SEM). RESULTS: With FE-SEM, up to 1 mm along the interface of ion beam-polished implant surfaces can be studied with a resolution of a few nanometers. Filled and unfilled pores of the porous TiUnite coating can be distinguished, providing information on pore accessibility. Implant-bone interfaces can be analyzed using backscattered electron images, where titanium, the oxide layer, mineralized extracellular matrix, and osteocyte lacunae/resin/soft tissue can easily be distinguished as a result of atomic number contrast and the sharp boundaries between the different materials. Filled and unfilled pores can be distinguished. Characterization of local chemistry is possible with energy dispersive X-ray spectrometry, and bone growth into small pores (< 1 MUm) can be unambiguously confirmed. CONCLUSION: FE-SEM complements the established methods for the characterization of interfaces and bridges the wide gap in accessible length scale and resolution between the observations of mechanically polished interfaces by optical or scanning electron microscopes and the observation of focused ion beam-milled sections in a transmission electron microscope. PMID- 21691602 TI - Emerging antibacterial biomaterial strategies for the prevention of peri-implant inflammatory diseases. AB - PURPOSE: Peri-implantitis is an inflammatory disease due to bacteria and plaque formation on implant surfaces which can lead to bone resorption and loss of osseointegration. Biomaterial strategies to prevent or eliminate initial bacterial attachment, in favor of host tissue attachment may have a positive effect on decreasing peri-implantitis, particularly for at risk patient groups. This study provides a brief overview of some of the experimental biomaterial strategies aimed at suppressing or inhibiting bacterial colonization of implant surfaces in favor or host cells and tissues. MATERIALS AND METHODS: These biomaterial strategies have different mechanisms of action from interfering with bacterial adhesion by modifying surface energies, immobilizing antimicrobials on implant surfaces, creating photocatalytic surfaces, as well as modifying surfaces to deliver antimicrobial agents either prophylactically or in response to bacterial challenge. This is not a comprehensive review, rather a review of studies that serve to illustrate many of the different approaches being investigated. RESULTS: While many of these strategies have demonstrated the potential to significantly reduce bacterial attachment on implant surfaces in vitro, it is unclear if these same reductions will be adequate clinically since even a few adhering bacteria may over time develop into inflammatory inducing biofilms or plaque. Also, data on the ability of the antibacterial modified biomaterials to support osseointegration and permuosal seal formation is still needed. CONCLUSION: Given the complex and multivariate causes of peri-implant disease, it is likely that combinations of these strategies (eg, antimicrobial surfaces and or delivery mechanisms coupled with methods to favor stable osseointegration and permucosal seal) will be most effective in developing implants resistant to peri-implant disease. PMID- 21691603 TI - Microcomputed tomographic and histologic analysis of anorganic bone matrix coupled with cell-binding peptide suspended in sodium hyaluronate carrier after sinus augmentation: a clinical study. AB - PURPOSE: Anorganic bovine hydroxyapatite matrix (ABM), when coupled with synthetic cell-binding peptide (P15), mimics the cell-binding region of type 1 collagen and is commercially available suspended in a sodium hyaluronate carrier. The aim of the present study, therefore, was to test the efficacy of ABM/P-15 Putty (DENTSPLY Friadent CeraMed) as a sole graft material for sinus augmentation in patients with severely resorbed posterior maxillae. MATERIALS AND METHODS: Sinus augmentation was performed in 10 patients using ABM/P-15 Putty and two provisional dental implants (3.0 mm in diameter). The graft and implants were placed simultaneously with the aid of a surgical stent. After 8 or 16 weeks, the implants were removed using a 4.25-mm trephine bur; this was followed by immediate placement of wider-diameter (5.5-mm) implants. All 20 implants were scanned by microcomputed tomography to determine bone mineral density (BMD), percent bone volume (PBV), and percent bone contact (PBC). RESULTS: There was a significant increase in the BMD of bone around the implants at 8 weeks and 16 weeks compared to native residual (control) bone. There was no significant difference in PBV or PBC between 8 weeks and 16 weeks. The average increase in bone height at 16 weeks was 9.63 +/- 1 mm. Microcomputed tomographic images and histologic sections showed dense graft particles surrounded by vital trabecular bone. CONCLUSION: BMD increases as early as 8 weeks and does not show an additional increase after 16 weeks. PepGen P-15 Putty was found to be a promising osteoconductive graft for sinus augmentation, supporting immediate placement of implants. PMID- 21691604 TI - Change in subjective oral health after single dental implant treatment. AB - PURPOSE: The aim of this study was to evaluate changes in subjective oral health among patients receiving single dental implants in different anatomic locations. MATERIALS AND METHODS: Subjective oral health was surveyed with the Oral Health Impact Profile 14 (OHIP-14) questionnaire after implant placement but prior to uncovering and 3 months after the completion of treatment. The locations of the implants and age and gender of the patients were recorded. Mean OHIP-14 severity scores were compared before and after treatment (paired t test). RESULTS: Ninety consecutive self-referred patients were enrolled in the study, and 80 of them (28 men and 52 women) completed the OHIP-14 both before and after treatment. The mean age of the patients at the time of surgery was 52 years (range, 24 to 75 years). The patients received a total of 131 commercially available dental implants (Astra Tech) and appropriate prosthetic constructions. The mean OHIP-14 severity score decreased significantly, from 10.4 before treatment to 3.1 after treatment (P < .001). The drop was from 13.4 to 1.5 (P < .001) if the missing tooth was replaced with an implant in the anterior area, from 11.2 to 4.3 (P < .001) if it was replaced in the premolar area, and from 6.5 to 3.0 (P = .085) if it was replaced in the molar area. In general, both before and after treatment, women reported subjective oral impacts approximately three times more often than men did. CONCLUSION: Replacement of missing teeth with single dental implants in anterior and premolar areas, but not necessarily in molar areas, may significantly improve subjective oral health, especially among women. PMID- 21691605 TI - Single implants in the esthetic zone: analysis of recent peri-implant soft tissue alterations and patient satisfaction. A photographic study. AB - PURPOSE: The appearance of the peri-implant soft tissue is a crucial factor in the success of implant therapy. However, no effective objective method exists to observe and document this factor over the long term. The aim of this clinical trial was to determine whether oral photographs can be used for peri-implant soft tissue data collection by observing peri-implant soft tissue alterations after placement of a single-tooth implant in the esthetic zone and to determine whether the pink esthetic score (PES) reflects patient satisfaction with the peri-implant soft tissue esthetic result. MATERIALS AND METHODS: Twenty-eight consecutive patients received single implants in the esthetic zone. Clinical photographs were taken to collect data on the peri-implant soft tissue at baseline (crown placement) and again 3 months later. Two observers assigned PES values to the peri-implant soft tissue in the photographs. Changes in the PES value from baseline to the 3-month follow-up were calculated. Patient satisfaction was measured using a visual analog scale (VAS) at the 3-month follow-up appointment. The correlation between the VAS and PES scores was calculated. RESULTS: The mean PES value (+/- SD) was 8.68 +/- 2.69 at baseline and 10.37 +/- 2.13 at follow-up (P < .01). VAS values ranged from 72.5 to 100. A significant correlation was found between VAS and PES values. The linear regression of patient satisfaction and PES values was significant. CONCLUSIONS: Oral photographs can be used to collect PES data on peri-implant soft tissue. The esthetic result of peri-implant soft tissue is markedly improved 3 months after restoration of the implant with a porcelain-fused-to-metal crown. The PES value generally reflects the degree of patient satisfaction with the peri-implant soft tissue esthetic result. PMID- 21691606 TI - Radiographic evaluation of marginal bone level around internal-hex implants with switched platform: a clinical case report series. AB - PURPOSE: The purpose of this retrospective investigation was to evaluate the influence on the adjacent cervical bone of moving the implant-abutment microgap inward from the outer edge of an internal-hex implant platform (ie, a platform switched configuration). MATERIALS AND METHODS: A convenience sample of 26 patients received 42 Frialit-2 (Dentsply-Friadent) implants for single tooth replacement and were divided into two groups. One group followed the original protocol (control group), and the other (study group) received narrower replaceable components. Follow-up time varied between 6 and 60 months (mean, 33.45 months). RESULTS: The control group showed noticeable bone remodeling (mean bone loss = 2.30 mm), and all the remodeled crests were apical to the implant platform. In contrast, all patients in the study (platform-switched) group showed stable levels (mean bone loss = 0.27) of the peri-implant crestal bone, coronal to the implant platform. CONCLUSION: The relocation of the implant-abutment microgap through platform switching with Frialit-2 System implants seems to be an effective means to minimize marginal bone loss in all circumstances employed. PMID- 21691607 TI - Treatment concept of the edentulous mandible with prefabricated telescopic abutments and immediate functional loading. AB - PURPOSE: The present paper demonstrates a new technique and long-term results of a treatment concept that uses four implants placed in the anterior mandible that are connected to prefabricated telescopic abutments and immediately loaded with removable restorations. MATERIALS AND METHODS: The present retrospective study included 488 implants (Ankylos, Dentsply) placed in 122 patients (mean age: 65.2 +/- 9.8 years) with clinical and radiographic evaluation for a period of at least 1 year. Eighty-four implants were placed in fresh extraction sockets and combined in the restorations with implants placed in healed ridges. All implants were placed 2 mm subcrestally (based on chart documentation, measured from the midfacial bone level). The implants were connected immediately after surgery to conical prefabricated abutments (angle of 4 to 6 degrees) using a final torque of 15 Ncm. Secondary prefabricated copings that fit the abutments were placed over the abutments after abutment connection, and the complete denture of each patient was relined chairside with methyl methacrylate resin. The prosthetic restorations were to remain in place for 10 days to ensure that the implants remained immobile. RESULTS: After a mean of 79 +/- 29.8 months (range, 17 to 129 months) only eight implants failed (1.6%). Twenty-one implants (4.3%) showed crestal bone loss greater than 2 mm relative to the implant position at the time of implant insertion. Therefore, the failure rate was 5.94% for the entire observation period. The success rate for the evaluated implants was 94.06%. The patients were satisfied with the stability of their prostheses, and no prosthetic or peri implant problems were observed. CONCLUSIONS: These telescopic implant-supported restorations with immediate loading seem to be an alternative prosthetic solution for the edentulous patient, providing long-term implant stability. PMID- 21691608 TI - Comparison of ball and telescopic crown attachments in implant-retained mandibular overdentures: a 5-year prospective study. AB - PURPOSE: Implant success, peri-implant conditions, and prosthodontic maintenance requirements were evaluated and compared for mandibular overdentures supported by two implants and retained with ball or resilient telescopic crown attachments during a 5-year period. MATERIALS AND METHODS: Twenty-five patients with an edentulous mandible each received two root-form dental implants in the mandibular interforaminal (canine) region. The type of denture attachment was chosen randomly; 13 patients received ball attachments and 12 patients received resilient telescopic crowns. Implant success and peri-implant conditions (bone resorption, pocket depth, Plaque Index, Gingival Index, Bleeding Index) as well as prosthodontic maintenance and patient satisfaction were evaluated annually during a 5-year follow-up period and compared with respect to the two retention modalities used. RESULTS: Implant success, peri-implant conditions, and subjective patient satisfaction scores did not differ between the two retention modalities used. However, during the 5-year observation period, significantly more postinsertion complications/interventions for maintenance purposes were registered in the ball group (87 interventions, 61.1%) than in the telescopic crown group (53 interventions, 37.9%; P < .01). Differences in prosthodontic maintenance efforts were most significant in the second and third years (P < .05) of the follow-up period but were similar at the end of the study for both anchorage systems. CONCLUSION: Both ball attachments and resilient telescopic crowns on isolated implants in the atrophic mandible are viable treatment options for implant-supported overdentures. No implant losses, good peri-implant conditions, and general patient satisfaction were noted. Although the frequency of technical complications was initially higher with ball attachments than with resilient telescopic crowns over a 5-year period, similar frequencies of maintenance efforts may be anticipated for both retention modalities. PMID- 21691609 TI - Addressing the atrophied mandible: a proposal for a treatment approach involving endosseous implants. AB - PURPOSE: Since the introduction of endosseous dental implants, the treatment concepts for management of the edentulous mandible have changed drastically. Reconstructive, preprosthetic surgery has changed from surgery aimed to provide a sufficient osseous and mucosal support for a conventional denture into surgery aimed to provide a sufficient bone volume enabling placement of dental implants at the, from a prosthetic point of view, optimal position. Moreover, the currently applied implant based prosthodontic concepts for the edentulous mandible are based on prospective randomized clinical trials comparing the treatment outcome of a variety of treatment modalities. This study reviews the various treatment concepts that are currently in use to rehabilitate the extremely atrophied mandible. MATERIALS AND METHODS: A comprehensive review of human studies published in the international peer-reviewed literature up to March 2010 regarding procedures related to implant treatment in the extremely atrophied edentulous mandible was made. A MEDLINE search was completed, along with a manual search, to locate relevant literature. RESULTS: There are advantages and disadvantages that are specific to removable implant-supported overdentures and fixed implant-supported full prostheses. The choice of an overdenture or a fixed full-arch prosthesis should be made on an individual basis. Once this choice has been made, the surgical procedure and the number of implants to be placed have to be determined. CONCLUSION: On the basis of the best evidence currently available, a treatment concept is proposed on how to deal with the edentulous mandible in order to provide patients with a mandibular overdenture supported by endosseous implants. PMID- 21691610 TI - The influence of individual bone patterns on peri-implant bone loss: preliminary report from a 3-year randomized clinical and histologic trial in patients treated with implants restored with matching-diameter abutments or the platform-switching concept. AB - PURPOSE: This study sought to determine whether there was a correlation between bone resorption and individual bone patterns in patients treated with implants restored conventionally or using the platform-switching concept. MATERIALS AND METHODS: Ten patients (24 implants) were randomly assigned to receive implants with different platform diameters (3.8, 4.3, 4.8, or 5.5 mm), all of which were restored with standard 3.8-mm-diameter abutments. Biopsy specimens were obtained prior to implant placement, and histologic and immunohistochemical analyses were performed. Standardized radiographs were made at each site after implant placement and at 36 months after prosthetic loading and bone levels were determined. RESULTS: One patient dropped out, resulting in a total of 9 patients and 22 implants. Mean bone resorption was 1.358 mm for non-platform-switched implants; mean resorption was 0.832, 0.486, and 0.375 mm for implant platforms of 4.3, 4.8, and 5.5 mm, respectively. After standardization of peri-implant bone remodeling values, a borderline direct correlation between peri-implant bone changes and levels of biglycans was found. At the same time, a borderline indirect correlation between bone changes and levels of tumor necrosis factor-a was found. CONCLUSIONS: Within the limit of this study, which was conducted in a small patient sample over a short observation period, an individual resorption trend was detected and paralleled by immunohistochemical findings. Individual local bone structure and quality seemed to be correlated to peri-implant bone resorption. Correlations between biglycan and tumor necrosis factor-a and bone resorption should be confirmed by a larger patient sample. PMID- 21691611 TI - A 36-month randomized controlled split-mouth trial comparing immediately loaded titanium oxide-anodized and machined implants supporting fixed partial dentures in the posterior mandible. AB - PURPOSE: A single-blind randomized controlled split-mouth trial was performed to compare the 36-month outcomes of machined and titanium oxide-anodized (ADZ) dental implant surfaces immediately loaded with fixed partial dentures in the posterior mandible. MATERIALS AND METHODS: Ten patients with bilateral partial edentulism in the posterior mandible received 42 implants; 20 were placed on the test side (ADZ) and 22 were placed on the control (machined) side. The implants were loaded within 24 hours after placement. Changes in the radiographic bone level (RBL) were measured on standardized periapical films at baseline, 12 months, and 36 months. The mean changes in RBL were compared using a paired t test, and the mean changes in RBL with regard to implant position and implant surface type were compared via two-way analysis of variance. RESULTS: After 36 months of functional loading, the overall cumulative success rate for all implants was 95%. The mean change in RBL at 36 months was 0.35 mm and 0.32 mm for ADZ and machined implants, respectively (not statistically significantly different between groups; P = .88). A reduction in RBL was observed for both machined and ADZ implants between 12 and 36 months, but only the machined implants demonstrated a statistically significant decrease in RBL during the observation period. CONCLUSIONS: No statistically significant differences in RBL change were found between machined and ADZ implant surfaces after 36 months in function, and both surfaces demonstrated minimal marginal bone remodeling. As such, immediate loading of ADZ and machined dental implants supporting fixed partial dentures may be a suitable long-term treatment option in the posterior mandible. PMID- 21691612 TI - Five-year treatment outcomes with four types of implants in the posterior maxilla and mandible in partially edentulous patients: a retrospective study. AB - PURPOSE: The aim of this retrospective study was to evaluate the outcomes, after 5 years of functional loading, of four different types of implants supporting prostheses in the posterior maxilla and mandible. MATERIALS AND METHODS: Patients missing posterior teeth were treated with implants between 1998 and 2004. The implants were evaluated by clinical and radiographic parameters and Plaque Index, Sulcus Bleeding Index (BI), peri-implant probing depths (PD), and marginal bone loss (MBL) were recorded. Repeated-measures analysis of variance, Kruskal-Wallis, and Wilcoxon signed rank tests were used for statistical analysis. RESULTS: In all, 244 implants were placed in 83 patients: 86 Straumann implants, 35 Swiss Plus implants, 90 Camlog implants, and 33 Frialit implants. Patients received 93 single crowns and 71 fixed partial dentures (FPDs). Nine FPDs were cemented to both implants and natural teeth, and 62 FPDs were supported by implants only. At the 5-year recall, plaque accumulation was significantly higher than at baseline for all groups (P = .01). Mean PD was 1.8 mm in the maxilla and 1.6 mm in the mandible. The mean PD values were 1.77 +/- 0.52 mm for Straumann, 1.87 +/- 0.64 mm for Swiss Plus, 2.33 +/- 0.58 mm for Camlog, and 2.29 +/- 0.46 mm for Frialit. MBL was 0.19 +/- 0.07 mm for Straumann, 0.27 +/- 0.06 mm for Camlog, 0.26 +/- 0.07 mm for Swiss Plus, and 0.24 +/- 0.07 mm for Frialit. The mean MBL of Straumann implants was significantly lower than that seen in the other groups (P = .001). CONCLUSION: The four types of implants resulted in similar clinical success after 5 years. PMID- 21691613 TI - Maintenance of implant-supported maxillary prostheses: a 2-year controlled clinical trial. AB - PURPOSE: To analyze maintenance service of fixed maxillary prostheses and overdentures based on conventional gold bars or titanium bars and frameworks fabricated with computer-aided design/computer-assisted manufacture (CAD/CAM) technology. MATERIALS AND METHODS: Forty-one patients participated; 16 received an implant overdenture with a gold bar (gold OD), 12 received a CAD/CAM fabricated implant OD with a titanium bar (Ti OD), and 13 received a CAD/CAM implant-supported fixed prosthesis (IFP). The bars and frameworks were screw retained at the implant level. Maintenance service performed during the first 2 years was recorded and compared between the three groups. After this 2-year period, the Oral Health Impact Profile (OHIP) was administered. RESULTS: For ODs (gold, Ti) most service consisted of activation of the matrices. Fractures of matrices and bar extensions occurred only in the gold OD group, and 65% of these patients exhibited hyperplasia of the peri-implant mucosa. The maintenance rates were 1.24 (gold OD), 1.36 (Ti OD), and 0.98 (IFP). These differences were not statistically significant. Retightening of occlusal screws was not necessary in any group. The probability that a complication occurred in the first year was high (60% to 70%) and statistically not different between the three groups. The probability that a second complication occurred was significantly lower for the IFP group versus the gold OD group. The mean OHIP values were 1.7 (IFP), 6.7 (gold OD), and 7.3 (Ti OD); ratings in the IFP group were significantly better. CONCLUSIONS: Maintenance service was typical for implant prostheses in the edentulous maxilla. Direct screw retention at the implant level without abutments had a favorable effect in all groups. A trend toward a reduction in problems was observed with the CAD/CAM superstructures. The OHIP confirmed high satisfaction, but quality of life appeared to be slightly higher with fixed prostheses. PMID- 21691614 TI - Telescopic magnetic attachment for implant-supported denture: evaluation of splint effect. AB - PURPOSE: Retrievability, connecting strength, and ease of laboratory work are important but conflicting prerequisites for the success of an implant superstructure, particularly with regard to immediate function. To resolve this issue, a telescopic magnetic attachment system has been developed for implant supported removable dentures. The splinting effect of the attachment was evaluated for stress distribution and elevation with an in vitro model of three implants in an edentulous mandible. MATERIALS AND METHODS: Two types of telescopic magnetic attachments were prepared; the inclination angles of the axial wall of the abutment were 2.5 and 6.0 degrees. Three types of three-unit superstructures--a screw-retained superstructure and two telescopic magnet retained superstructures--were fabricated. Static loads of 24.5, 49, and 98 N were applied vertically at three loading points on one side of each occlusal table. The elevation was measured as the height at which the magnet-retained superstructure detached from the abutment (on the other side of the prosthesis). In addition, by means of strain gauges, the stress distribution around the implants was evaluated and compared among the superstructures with the same three loads applied at six different points. RESULTS: The magnet-retained superstructure with the axial wall inclined at 2.5 degrees did not detach from the abutment. The differences in stress distribution between the screw-retained and magnet-retained superstructures with a 2.5-degree inclination were found to be statistically insignificant. The magnet-retained superstructure with a 6 degree inclination detached from the abutment, and the stress was concentrated during loading to a cantilever site. CONCLUSION: Because of its stress distribution and elevation, the new telescopic magnetic attachment, which has properties such as splinting the implants, ease of fabrication, and retrievability, is expected to be a viable alternative for the retention of implant-supported removable dentures. PMID- 21691616 TI - Direct synthesis of nanoporous carbon nitride fibers using Al-based porous coordination polymers (Al-PCPs). AB - We report a new synthetic route for preparation of nanoporous carbon nitride fibers with graphitic carbon nitride polymers, by calcination of Al-based porous coordination polymers (Al-PCPs) with dicyandiamide (DCDA) under a nitrogen atmosphere. PMID- 21691615 TI - Restoration of the edentulous maxilla using extrasinus zygomatic implants combined with anterior conventional implants: a retrospective study. AB - PURPOSE: To report on the clinical outcome of 150 extrasinus zygomatic implants placed lateral to the maxillary sinus and combined with conventional implants in the anterior maxilla for the implant-supported rehabilitation of the edentulous maxilla. MATERIALS AND METHODS: All patients included in this study presented with completely or partially edentulous maxillae with any remaining teeth indicated for extraction. Indications for extractions in partially edentulous patients included longitudinal fractures, periodontal disease, endodontic failure, perforated roots, and prosthetic convenience. All patients showed severe resorption of the posterior maxilla. Each patient was treated with at least four implants, with a minimum of one zygomatic implant. No bone grafting was performed. The zygomatic implants were placed outside the sinus, lateral to the maxillary sinus. The patients were followed with standardized clinical and radiographic examinations. RESULTS: Seventy-five patients with severely atrophic maxillae (mean age, 52 years) were treated between 2003 and 2006. In all, 436 implants (150 zygomatic implants and 286 conventional implants) were placed. Two conventional implants failed during the study period, and two zygomatic implants were removed. All the prostheses were successful. No patients presented sinusitis. No loosened or fractured screws on any implants were recorded. CONCLUSION: Extrasinus zygomatic implants, when combined with conventional implants in the anterior maxilla, represent a predictable treatment option for the atrophic edentulous maxilla. Further studies are necessary to evaluate the long-term prognosis of these implants. PMID- 21691617 TI - Terbium(III) complex as a luminescent sensor for human serum albumin in aqueous solution. AB - A terbium(III) complex gives off strong luminescence upon reacting with human serum albumin in aqueous solution, which can be used to detect the presence and structural modifications of this protein. PMID- 21691618 TI - Surface-assisted bowl-in-bowl stacking of nonplanar aromatic hydrocarbons. AB - Bowl-in-bowl stacking of buckybowls on a copper surface is observed via scanning tunneling microscopy (STM) at low temperatures and characterized by density functional theory (DFT) calculations. PMID- 21691619 TI - Control of DNA hybridization by photoswitchable molecular glue. AB - Hybridization of DNA is one of the most intriguing events in molecular recognition and is essential for living matter to inherit life beyond generations. In addition to the function of DNA as genetic material, DNA hybridization is a key to control the function of DNA-based materials in nanoscience. Since the hybridization of two single stranded DNAs is a thermodynamically favorable process, dissociation of the once formed DNA duplex is normally unattainable under isothermal conditions. As the progress of DNA based nanoscience, methodology to control the DNA hybridization process has become increasingly important. Besides many reports using the chemically modified DNA for the regulation of hybridization, we focused our attention on the use of a small ligand as the molecular glue for the DNA. In 2001, we reported the first designed molecule that strongly and specifically bound to the mismatched base pairs in double stranded DNA. Further studies on the mismatch binding molecules provided us a key discovery of a novel mode of the binding of a mismatch binding ligand that induced the base flipping. With these findings we proposed the concept of molecular glue for DNA for the unidirectional control of DNA hybridization and, eventually photoswitchable molecular glue for DNA, which enabled the bidirectional control of hybridization under photoirradiation. In this tutorial review, we describe in detail how we integrated the mismatch binding ligand into photoswitchable molecular glue for DNA, and the application and perspective in DNA-based nanoscience. PMID- 21691620 TI - The fluorous effect in biomolecular applications. AB - From being a niche area only a few decades ago, fluorous chemistry has gained momentum and is, nowadays, a fervent area of research. It has brought forth, in fact, numerous applicative innovations that stretch among different fields: from catalysis to separation science, from supramolecular to materials and analytical chemistry. Recently, the unique features of perfluorinated compounds have reached the attention of the biochemists' audience. This tutorial review introduces the basic concepts of fluorous chemistry and illustrates its main biomolecular applications. Special attention has been given to fluorous microarrays and their combination with Mass-Spectroscopy (MS) techniques, to protein properties modification by the introduction of local fluorous domains, and to the most recent applications of (19)F-Magnetic Resonance Imaging ((19)F-MRI). PMID- 21691621 TI - The effects of protein crowding in bacterial photosynthetic membranes on the flow of quinone redox species between the photochemical reaction center and the ubiquinol-cytochrome c2 oxidoreductase. AB - Atomic force microscopy (AFM) of the native architecture of the intracytoplasmic membrane (ICM) of a variety of species of purple photosynthetic bacteria, obtained at submolecular resolution, shows a tightly packed arrangement of light harvesting (LH) and reaction center (RC) complexes. Since there are no unattributed structures or gaps with space sufficient for the cytochrome bc(1) or ATPase complexes, they are localized in membrane domains distinct from the flat regions imaged by AFM. This has generated a renewed interest in possible long range pathways for lateral diffusion of UQ redox species that functionally link the RC and the bc(1) complexes. Recent proposals to account for UQ flow in the membrane bilayer are reviewed, along with new experimental evidence provided from an analysis of intrinsic near-IR fluorescence emission that has served to test these hypotheses. The results suggest that different mechanism of UQ flow exist between species such as Rhodobacter sphaeroides, with a highly organized arrangement of LH and RC complexes and fast RC electron transfer turnover, and Phaeospirillum molischianum with a more random organization and slower RC turnover. It is concluded that packing density of the peripheral LH2 antenna in the Rba. sphaeroides ICM imposes constraints that significantly slow the diffusion of UQ redox species between the RC and cytochrome bc(1) complex, while in Phs. molischianum, the crowding of the ICM with LH3 has little effect upon UQ diffusion. This supports the proposal that in this type of ICM, a network of RC LH1 core complexes observed in AFM provides a pathway for long-range quinone diffusion that is unaffected by differences in LH complex composition or organization. PMID- 21691622 TI - Highly porous and robust scandium-based metal-organic frameworks for hydrogen storage. AB - The metal-organic frameworks NOTT-400 and NOTT-401, based on a binuclear [Sc(2)(MU(2)-OH)(O(2)CR)(4)] building block, have been synthesised and characterised; the desolvated framework NOTT-401a shows a BET surface area of 1514 m(2) g(-1) with a total H(2) uptake of 4.44 wt% at 77 K and 20 bar. PMID- 21691623 TI - Promoting peptide alpha-helix formation with dynamic covalent oxime side-chain cross-links. AB - Covalent side-chain cross-linking has been shown to be a viable strategy to control peptide folding. We report here that an oxime side-chain linkage can elicit alpha-helical folds from peptides in aqueous solution. The bio-orthogonal bridge is formed rapidly under neutral buffered conditions, and the resulting cyclic oximes are capable of dynamic covalent exchange. PMID- 21691624 TI - Highly diastereo- and enantioselective one-pot Michael-Aldol reactions of alpha,beta-unsaturated aldehydes with imidazole derivatives. AB - Highly diastereo- and enantioselective one-pot Michael-Aldol reactions of alpha,beta-unsaturated aldehydes with imidazole derivatives have been developed. The cascade reactions products could be obtained with three stereocenters in high yields and excellent diastereo- and enantioselectivities. PMID- 21691625 TI - Selective opening of nanoscopic capped mesoporous inorganic materials with nerve agent simulants; an application to design chromo-fluorogenic probes. AB - A hybrid nanoscopic capped mesoporous material, that is selectively opened in the presence of nerve agent simulants, has been prepared and used as a probe for the chromo-fluorogenic detection of these chemicals. PMID- 21691626 TI - Semi-synthesis of a protease-activatable collagen targeting probe. AB - A protease-activatable collagen targeting probe (proCNA35) is synthesized by conjugation of a synthetic collagen fragment to the collagen binding protein CNA35 via a protease-cleavable linker. Cleavage of the linker by MMP1 releases the intramolecular inhibition of the collagen binding site and restores its collagen binding capacity. PMID- 21691635 TI - A quantum description of the proton movement in an idealized NHN+ bridge. AB - A series of model calculations was done to analyze the delocalization of the proton in the linking hydrogen bond of the (Dih)(2)H(+) cation (Dih: 4,5-dihydro 1H-imidazole). Standard quantum chemical calculations (B3LYP/D95+(d,p)) predict a low barrier hydrogen bond (LBHB) and thereby a delocalized proton in the NHN(+) hydrogen bridge. Explicit quantum calculations on the proton indicate that the delocalization of the proton does not provide enough energy to stabilize a permanent LBHB. Additional Born-Oppenheimer Molecular Dynamics (BOMD) simulations indicate further that the proton is localized at either side of the NHN(+) bridge and that a central proton position is the result of temporal averaging. The possibility of the proton to tunnel from one side to the other side of the NHN(+) bridge increases with the temperature as the trajectory of the (Dih)(2)H(+) cation runs through regions where the thermal excitation of Dih ring vibrations creates equal bonding opportunities for the proton on both sides of the bridge (vibrationally assisted proton tunneling). The quantum calculations for the proton in (Dih)(2)H(+) suggest further a broad peak for the 1 <- 0 transition with a maximum at 938 cm(-1) similar to that observed for LBHBs. Moreover, the asymmetric NHN(+) bridge in a thermally fluctuating environment is strong enough to create a significant peak at 1828 cm(-1) for the 2 <- 0 transition, while contributions from the 2 <- 1 are expected to be weak for the same reason. PMID- 21691636 TI - Molecular dynamics simulation studies of absorption in piperazine activated MDEA solution. AB - Development of more efficient solvent solutions for removal of CO(2) from natural gas and flue gases is a major task, which contributes to improved design of process plants and leads to decreased costs for its removal. Understanding the mechanisms of CO(2) absorption as well as analysis of undesired simultaneous processes is crucially important in this regard. In this work, we have applied Molecular Dynamics (MD) to investigate the absorption of CO(2) from a binary mixture of CO(2) and CH(4) into aqueous piperazine activated MDEA solution. The MD simulations were performed at a constant temperature of 298 K for five different systems with a loading factor of 0.07 to provide insight into molecular distribution in the amine solution and to enhance understanding of absorption mechanisms on the molecular scale. Force field parameters that were missing from the OPLS-AA force field, as well as charge distribution of piperazine (PZ), protonated piperazine (PZH(+)), piperazine carbamate (PZCOO(-)) and MDEA were obtained by QM calculations. The results of our simulations emphasize the importance of piperazine and piperazine carbamate in accelerating the absorption process. For the first time, we have shown the undesirable trapping of CH(4) by the amine solution and revealed that amine groups are mainly responsible for both absorption of CO(2) and the undesired trapping of CH(4). PMID- 21691637 TI - A water-soluble perylene dye functionalised with a 17beta-estradiol: a new fluorescent tool for steroid hormones. AB - We have successfully been able to synthesise a specific estrogen receptor directed biolabel based on a fluorescent water-soluble perylenebisimide, thus offering great potential for determining the presence of estrogen receptors in any kind of cell. Moreover, this synthetic strategy allows the preparation of other conjugates involved in the study of any kind of receptor, simply by selecting the appropriate agonist or antagonist. PMID- 21691638 TI - A rapid and highly selective colorimetric method for direct detection of tryptophan in proteins via DMSO acceleration. AB - A simple, rapid and highly selective method has been developed for the direct visual detection of tryptophan in a mixture of amino acids or in a protein based on DMSO acceleration. PMID- 21691639 TI - Templated assembling of phthalocyanine arrays along a polymer chain. AB - Copper phthalocyanine can assemble along PPE backbones into molecular arrays and 2D assemblies with structural parameters different from its intrinsic 2D crystal. The template effect depends on the match between the size of phthalocyanine and the repeating period of the PPE backbone. PMID- 21691640 TI - Electrophoretic deposition of mesoporous TiO2 nanoparticles consisting of primary anatase nanocrystallites on a plastic substrate for flexible dye-sensitized solar cells. AB - A film of mesoporous TiO(2) nanoparticles (MTNs) consisting of anatase nanocrystallites was electrophoretically deposited and compressed on a plastic substrate for the corresponding DSSC that gave an excellent conversion efficiency (eta) of 5.25% under illumination of 100 mW cm(-2). PMID- 21691641 TI - A new insight into ortho-(dimesitylboryl)diphenylphosphines: applications in Pd catalyzed Suzuki-Miyaura couplings and evidence for secondary pi-interaction. AB - ortho-(Dimesitylboryl)phenylphosphines 1 and 2 were applied in Pd-catalyzed Suzuki-Miyaura C-C couplings. Coordination studies were performed in order to rationalize the relationship between structure and reactivity. Full characterization of a Pd(0) complex derived from 1 has evidenced a new coordination mode for phosphine-arylboranes involving secondary pi-interaction between one of the mesityl groups at boron and the metal centre. PMID- 21691642 TI - Electrochemically induced oxygen spillover and diffusion on Pt(111): PEEM imaging and kinetic modelling. AB - Electrochemically induced oxygen spillover and diffusion in the Pt(O(2))|YSZ system is investigated in a combined experimental and theoretical study. The spreading of spillover oxygen is imaged by photoelectron emission microscopy (PEEM) on dense and epitaxial Pt(111) thin film electrodes prepared by pulsed laser deposition (PLD). Two different models are used to obtain surface diffusion coefficients from the experimental data, (i) an analytical solution of Fick's 2nd law of diffusion, and (ii) a numerical reaction-diffusion model that includes recombinative desorption of O(2) into the gas phase. The resulting diffusion coefficient has an activation energy of 50 kJ mol(-1) and a preexponential factor of 0.129 cm(2) s(-1) with an estimated uncertainty of +/-20% for the activation energy and +/-50% for the absolute value. The Fickian model slightly overpredicts diffusion coefficients due to the neglect of oxygen desorption. Experimental and theoretical results and limitations are discussed and compared to previous work. PMID- 21691643 TI - Simulating electron spin resonance spectra of macromolecules labeled with two dipolar-coupled nitroxide spin labels from trajectories. AB - An efficient method for simulating continuous-wave electron spin resonance spectra (ESR) of molecules labeled with two dipolar-coupled nitroxides from trajectories of the molecular motion is presented. Two approximate treatments of the dipolar spin evolution, resulting in significantly shorter simulation times, are examined in order to determine their range of applicability. The approach is illustrated in the context of a double-helical B-DNA. ESR spectra for DNA undergoing anisotropic global diffusion and internal stretching dynamics are calculated for three different labeling geometries with the spin labels bracketing, respectively, three, two and one base pairs. While multifrequency spectra of all three labeling schemes are very sensitive to DNA tumbling, the last one is found to be most informative about the local DNA dynamics. PMID- 21691644 TI - Supramolecular assembly of Hoechst-33258 with cucurbit[7]uril macrocycle. AB - Molecular assemblies of potential guest molecules through non-covalent host-guest interactions have found immense use in many applied areas. In this study supramolecular interaction of a biologically important dye Hoechst-33258 (H33258) has been investigated in aqueous solutions at different pHs, in the presence of a macrocyclic host, namely, cucurbit[7]uril (CB7). The pH dependent emission behaviour of H33258 is inherently connected with its protolytic equilibria which allow the dye in different geometrical conformations. This pH dependent structural orientation is greatly affected by the complexation with CB7. The significant structural changes in the monocationic H33258 brought out by CB7 at pH 7 have been documented in the fluorescence emission and lifetime data, which are comparatively less affected in case of the dicationic form, which is prominent in dye solutions at pH 4.5. The strong ion-dipole interactions provided by the carbonyl portals of the CB7 host adequately stabilize the CB7-H33258 complex, both in 1:1 and 2:1 stoichiometries at both the pH conditions. The Job's plot method, fluorescence anisotropy, NMR measurements and geometry optimization calculations confirm the stoichiometric arrangement and are found to be tunable with the addition of metal ions. The non-covalently stabilized assembly brings out large enhancement in the fluorescence emission due to the unique structural orientation attained by H33258, which reduces the non-radiative relaxation pathways. Comparison of the spectral data of the dye at different pH conditions in the absence and presence of CB7 proposes a large upward pK(a) shift due to CB7 encapsulation, thus providing a handy tool to modulate the photophysical characteristics of the guest molecules. PMID- 21691645 TI - Surface abundance change in vacuum ultraviolet photodissociation of CO2 and H2O mixture ices. AB - Photodissociation of amorphous ice films of carbon dioxide and water co-adsorbed at 90 K was carried out at 157 nm using oxygen-16 and -18 isotopomers with a time of-flight photofragment mass spectrometer. O((3)P(J)) atoms, OH (v = 0) radicals, and CO (v = 0,1) molecules were detected as photofragments. CO is produced directly from the photodissociation of CO(2). Two different adsorption states of CO(2), i.e., physisorbed CO(2) on the surface of amorphous solid water and trapped CO(2) in the pores of the film, are clearly distinguished by the translational and internal energy distributions of the CO molecules. The O atom and OH radical are produced from the photodissociation of H(2)O. Since the absorption cross section of CO(2) is smaller than that of H(2)O at 157 nm, the CO(2) surface abundance is relatively increased after prolonged photoirradiation of the mixed ice film, resulting in the formation of a heterogeneously layered structure in the mixed ice at low temperatures. Astrophysical implications are discussed. PMID- 21691646 TI - Self-localization of polyacrylic acid molecules on polar ZnO(0001)-Zn surfaces. AB - The adsorption of single polyacrylic acid (PAAc) molecules was investigated on stepped hydroxide-stabilized polar ZnO(0001)-Zn surfaces using atomic force microscope (AFM) topography and force distance spectroscopy. Stepped surfaces of ZnO(0001)-Zn were prepared by a wet chemical etching procedure and PAAc molecules were adsorbed from aqueous NaClO(4) solutions. AFM single molecule topography studies could be utilized to show that polyacrylic acid molecules specifically adsorb on the non-polar (10-10) step edge faces at low ionic strengths. The radius of gyration of the dissolved PAAc in aqueous solution was measured by means of static light scattering experiments yielding a radius of gyration of R(g)=136 nm at pH 7.4 in 50 mM NaClO(4)/NaOH solution, which is in good agreement with the size of the adsorbed PAAc molecules as measured using AFM. The obtained results could be rationalized in terms of binding-site configurations at step edges and the effect of the chemical environment on both local electric double layer charge and molecular conformation of the PAAc molecules. The point of zero charge of the ZnO(10-10) surface was measured with chemical force microscopy to be pH(PZC)=10.2 +/- 0.2. The specific adsorption of polyacrylic acid at non-polar ZnO step-edges can be explained by coordinative bonds formed between the carboxylic acid group and the Zn-surface atoms. On the hydroxide stabilized polar surface only weak hydrogen bonds can be formed in addition to van-der-Waals forces. Thus a "diffusion and trapping" mechanism keeps the adsorbed PAAc molecules mobile on the ZnO(0001)-Zn surface terraces due to small interaction forces until they are trapped at the (10-10) step faces by stronger coordinative bonds from the carboxylic groups to zinc atoms located in the first atomic layer of the crystal structure. PMID- 21691647 TI - Neutral and cationic chiral NCN pincer nickel(II) complexes with 1,3-bis(2' imidazolinyl)benzenes: synthesis and characterization. AB - Chiral 1,3-bis(2'-imidazolinyl)benzenes 1a-e easily undergo direct nickelation at the C2 position of the central benzene ring via the C-H bond activation in the reaction with anhydrous NiCl(2) giving neutral NCN pincer nickel(II) complexes 2a e in 40-87% yields. Treatment of the nickel pincers 2a or 2c with AgBF(4) in CH(3)CN-CH(2)Cl(2) afforded the cationic nickel pincers 3a or 3c in good yields. All the complexes were characterized by elemental analysis, (1)H, (13)C NMR, and IR spectra. Molecular structures of the neutral complexes 2a, 2b and 2c as well as the cationic complex 3c have been determined by X-ray single-crystal diffraction. The cationic nickel pincers 3 are found to be effective catalysts for the Michael addition of ethyl 2-cyanopropionate to methyl vinyl ketone in the presence of i-Pr(2)NEt base with a catalyst loading of 5 mol% even at -78 degrees C, producing the adduct in >99% yield after 24 h albeit with no ee. PMID- 21691648 TI - Negishi cross-coupling reaction catalyzed by an aliphatic, phosphine based pincer complex of palladium. biaryl formation via cationic pincer-type Pd(IV) intermediates. AB - The aliphatic, phosphine-based pincer complex [(C(10)H(13)-1,3 (CH(2)P(Cy(2))(2))Pd(Cl)] (1) is a highly active Negishi catalyst, enable to quantitatively couple various electronically activated, non-activated, deactivated, sterically hindered and functionalized aryl bromides with various diarylzinc reagents within short reaction times and low catalyst loadings. Experimental observations strongly indicate that a molecular mechanism is operative with initial chloride dissociation of 1 and formation of the cationic T shaped 14e(-) complex [(C(10)H(13)-1,3-(CH(2)P(C(6)H(11))(2))(2))Pd](+) (B), which undergoes oxidative addition of an aryl bromide (Ar'Br) to yield the cationic, penta-coordinated aryl bromide pincer complexes of type [(C(10)H(13) 1,3-(CH(2)P(Cy(2))(2))Pd(Br)(aryl')](+) (C) with the metal center in the oxidation state of +IV and the aryl unit in cis position relative to the aliphatic pincer core. Subsequent transmetalation with Zn(aryl)(2) result in the cationic diaryl pincer complexes of type [(C(10)H(13)-1,3 (CH(2)P(Cy(2))(2))Pd(aryl)(aryl')](+) (D), which reductively eliminate the coupling products, thereby regenerating the catalyst. The neutral square planar aryl pincer complex--a possible key intermediate in the catalytic cycle--was found to be reversibly formed in the reaction mixture but is not involved in the catalytic mechanism. Similarly, palladium nanoparticles as the catalytically active form of 1 could have been excluded. PMID- 21691649 TI - Pincer Ru and Os complexes as efficient catalysts for racemization and deuteration of alcohols. AB - The pincer complexes [MX(CNN)(PP)] (M = Ru, Os; X = Cl, OTf; HCNN = 1-(6 arylpyridin-2-yl)methanamine; PP = diphosphine) have proven to efficiently catalyze both racemization and deuteration of alcohols in the presence of a base. Chiral alcohols have been racemized at 30-50 degrees C using 1 mol% of Ru or Os pincer complexes and 5 mol% of KOtBu in 2-propanol. Primary and secondary alcohols are efficiently deuterated at the alpha position, with respect to the OH group, using 2-propanol-d(8) as solvent with Ru or Os pincer complexes and KOtBu at 30-50 degrees C. For secondary alcohols incorporation of deuterium at the beta position has also been observed. In 2-propanol-d(8) the pincer complexes catalyze the simultaneous deuteration and racemization of (S)-1-phenylethanol, the two processes being strictly correlated. For both reactions much the same activity has been observed with the Ru and Os complexes. The pincer complexes display a superior activity with respect to the related compounds [MCl(2)(NN)(PP)] (NN = bidentate amine or pyridine ligand). The synthesis of the new complexes [MCl(CNN)(PP)] (M = Ru, 2, 4 and Os, 6, 7; PP = dppb, dppf) and [Ru(OTf)(CNN)(dppb)] (3) is also reported. PMID- 21691651 TI - Regiospecific [2 + 2] photocyclodimerization of trans-4-styrylpyridines templated by cucurbit[8]uril. AB - Addition of HCl accelerated the photocyclodimerization of trans-4-styrylpyridine 1a in methanol and increased the yield of syn-head-to-tail (syn-HT) dimer 2a through the effect of cation-pi interactions between the pyridinium ion of one molecule and the phenyl group of the other. We examined the photoirradiation products of derivatives of 1a having alkyl substituents on the phenyl group (1b 1f). The effect of the alkyl substituent on product distribution was rather limited for the photoreaction in MeOH solutions. However, the substituents had a distinct effect on the product distribution for the photoreaction of the inclusion complexes of hydrochloride salts of trans-4-styrylpyridines with cucurbit[8]uril in aqueous solutions. Introducing an alkyl group at the 2- or 3 position of the phenyl group completely shifted the major product from the syn-HT dimer to the syn-head-to-head (syn-HH) dimer. By adjusting the balance of host guest interactions and cation-pi interactions between guest molecules through systematic changes in the substituents on the phenyl ring of trans-4 styrylpyridine, we could change the orientation of the reactant molecules in the host cavity, resulting in a change of the major regioisomer of the photocyclodimerization products. PMID- 21691650 TI - Synthesis of dimeric Re(I) amino acid conjugate complexes. AB - The aqueous one-step reaction of Re(CO)(3)(H(2)O)(3)(+) with pyridine-2 carboxyaldehyde and glycine or alanine produces a new class of cyclic dimeric products. The ligands of the chiral C(2)-symmetric products are bound via the diimine at one rhenium centre and via the pendant carboxylate to a second rhenium center. PMID- 21691652 TI - Redox mediated electron transfer behaviors at azobenzene functionalized electrode. AB - Three kinds of redox-mediated behavior were realized at an azobenzene functionalized electrode, which has great potential for application in the field of molecular devices. According to these results, the functionalized electrode could act as either a cathodic molecular rectifier or anodic molecular rectifier. PMID- 21691653 TI - Synthesis, surface morphology, and photoluminescence properties of anatase iron doped titanium dioxide nano-crystalline films. AB - Iron (Fe)-doped (0 to 4%) TiO(2) nano-crystalline (nc) films with the grain size of about 25 nm have been deposited on n-type Si (100) substrates by a facile nonhydrolytic sol-gel processing. X-ray diffraction measurements prove that the films are polycrystalline and present the pure anatase phase. X-ray photoelectron spectroscopy spectra indicate that the chemical valent state of Fe element is +3 and the Fe(3+) ions replace the Ti(4+) sites. The Fe dopant effects on the surface morphology, microstructure, and dielectric functions of the nc-Fe/TiO(2) films have been studied by atomic force microscope, ultraviolet Raman scattering and spectroscopic ellipsometry. With increasing Fe composition, the intensity of Raman-active mode B(1g) increases, while that of the A(1g) phonon mode decreases. The dielectric functions have been uniquely extracted by fitting ellipsometric spectra with the Adachi's dielectric function model and a four-phase layered model. It is found that the real part of dielectric functions in the transparent region and the optical band gap slightly decrease with the Fe composition due to the introduction of acceptor level Fe t(2g). Finally, the composition and temperature dependence of the surface and lattice defects in the Fe/TiO(2) films have been investigated by photoluminescence spectra in detail. At room temperature, the emission intensities decrease with increasing Fe compositions since the Fe incorporation could prolong the radiative lifetime and/or shorten the non-radiative lifetime. By analyzing the low temperature photoluminescence spectra, the intensities and positions of five emission peaks and shoulder structure can be unambiguously assigned. The phenomena could be reasonably explained by the physical mechanisms such as oxygen vacancies, localized excitons, self-trapped excitons, and indirect transitions, which are strongly related to the electronic band structure perturbed by the Fe doping. PMID- 21691654 TI - Label-free imaging of cell attachment with photonic crystal enhanced microscopy. AB - We introduce photonic crystal enhanced microscopy (PCEM) as a label-free biosensor imaging technique capable of measuring cell surface attachment and attachment modulation. The approach uses a photonic crystal optical resonator surface incorporated into conventional microplate wells and a microscope-based detection instrument that measures shifts in the resonant coupling conditions caused by localized changes in dielectric permittivity at the cell-sensor interface. Four model systems are demonstrated for studying cancer cells, primary cardiac muscle cells, and stem cells. First, HepG2/C3 hepatic carcinoma cells were cultured and observed via PCEM in order to characterize cell adhesion in the context of growth and locomotion. Second, Panc-1 pancreatic cancer cells were used to verify that cell attachment density decreases in response to staurosporine, a drug that induces apoptosis. Third, we used PCEM to confirm the influence of integrin-mediated signaling on primary neonatal cardiomyocyte growth and development. Rounded cardiomyocytes consistently showed decreased cell attachment density as recorded via PCEM, while spreading cells exhibited greater attachment strength as well as increased contractility. Finally, PCEM was used to monitor the morphological changes and extracellular matrix remodeling of porcine adipose-derived stem cells subjected to a forced differentiation protocol. Each of these experiments yielded information regarding cell attachment density without the use of potentially cytotoxic labels, enabling study of the same cells for up to several days. PMID- 21691655 TI - Improved accuracy for Raman spectroscopic determination of polyethylene property by optimization of measurement temperature and elucidation of its origin by multiple perturbation two-dimensional correlation spectroscopy. AB - A novel strategy is demonstrated to improve the accuracy for determination of polyethylene (PE) density using Raman spectroscopy by optimizing the temperature of sample measurement. Spectral features associated with the conformation change of the polymer induced by temperature may provide valuable information to quantify important polymer properties such as density. To evaluate possible existence of an optimal temperature providing improved quantitative accuracy, Raman spectra of PE pellets with different densities were collected at eight different temperatures from 30 to 100 degrees C at 10 degrees C intervals. Using the spectral datasets collected at each temperature, partial least squares (PLS) models were developed using the reference PE density values determined by a standard density gradient method at 23 degrees C. Interestingly, the most accurate determination of density was realized at 70 degrees C. Multiple perturbation two-dimensional (MP2D) correlation analysis and differential scanning calorimetry (DSC) were used to examine the origin of improved accuracy at 70 degrees C. From these analyses, the pre-melt behavior of the PE samples was identified below their melting temperatures. Structural variations induced at the pre-melt stages enhance Raman spectral selectivity among the samples, thereby providing more accurate determination of PE density. The MP2D correlation analysis revealed the unforeseen thermal behavior of PE samples and successfully explained the improved accuracy at 70 degrees C. PMID- 21691657 TI - High-yield synthesis of single-crystalline zinc oxide nanobelts and their applications in novel Schottky solar cells. AB - High-quality ZnO nanobelts were synthesized through introducing an unsteady state in the vapour transport process and their applications in novel Schottky solar cells were demonstrated by contact-printing the ZnO nanobelt network onto a pre patterned Pt electrode followed by the deposition of a Ti/Au electrode. PMID- 21691656 TI - Branched RNA nanostructures for RNA interference. AB - Branched RNAs with three- or four-way junctions were designed by assembling single-stranded RNA for RNA interference. Human Dicer transformed branched RNAs into about 20 base pairs of double-stranded RNA, which is a standard siRNA species. Our tetramer design provides a potent silencing effect over a period of 5 days. PMID- 21691658 TI - Evolution of cobalt spin states and magnetic coupling along the SrCo(1-x)Sb(x)O(3 delta) system: correlation with the crystal structure. AB - The oxides of the SrCo(1-x)Sb(x)O(3-delta) perovskite family have been recently designed, characterized and described as cathode materials for solid-oxide fuel cells with competitive power performance in the temperature range 750-850 degrees C. They feature a number of interesting properties including a good electronic conductivity, low electrode polarization resistance and adequate thermal expansion; the crystal structure adopts a 3C corner-linked perovskite network with a considerable number of oxygen vacancies. This paper reports on the effects of Sb-doping on the crystal structure features, the Co oxidation state and magnetic properties related to the presence of spin-state transitions in the Co cations. A phase transition was observed from the tetragonal P4/mmm space group for x<= 0.15 to the cubic Pm 3m space group in the x = 0.2 composition from neutron powder diffraction data. For the tetragonal phases the oxygen vacancies were found to be ordered and localized in the axial O2 and equatorial O3 atoms surrounding the Co2 positions. A noticeable distortion of CoO(6) octahedra is observed for x = 0.05 and 0.1, exhibiting a charge-ordering with a mixed oxidation state of Co(3+/4+) at Co1 sites and Co(3+) at Co2 positions: the Jahn Teller Co(3+) in an intermediate-spin configuration is responsible for the octahedral distortion. Increasing Sb contents promotes a higher average oxidation state of cobalt, from a valence of 3.2+ for x = 0.05 to 3.4+ for x = 0.2, inducing a decrease of the oxygen vacancies and favouring a random distribution over a Pm 3m cubic symmetry. All the samples present an antiferromagnetic behaviour with a G-type (k = 0) magnetic structure. The increase of the Sb content induces the weakening of the crystal field (Delta(cf)) in the octahedral environment promoting the Co spin-transition from the intermediate-spin to the high-spin configuration, as evidenced by the decrease of the octahedral distortion, increment of the unit-cell volume and enhancement of the ordered magnetic moment. PMID- 21691659 TI - Development of excellent long-wavelength BODIPY laser dyes with a strategy that combines extending pi-conjugation and tuning ICT effect. AB - By comparison and combination of two strategies, extending pi-conjugation and tuning Intramolecular Charge Transfer (ICT) effect, new long-wavelength BODIPY dyes have been efficiently synthesized. The new chromophores exhibit good optical properties: high fluorescence quantum yields, exceptionally large molar extinction coefficients, narrow red-emission bands, and relatively large Stokes shifts etc., in polar or apolar solvents. Besides, the new dyes, under transversal pumping at 532 nm, exhibit highly efficient and stable laser emission tunable from the green to NIR spectral region (570-725 nm). Moreover, one of these new BODIPY derivatives shows cell membrane permeability and bright intracellular red fluorescence. These advantageous characteristics assure the potential of these dyes for biophotonic applications. PMID- 21691660 TI - Synthesis, structural characterization, photophysical properties and theoretical analysis of gold(I) thiolate-phosphine complexes. AB - A series of luminescent dinuclear neutral complexes of stoichiometry [(AuSPh)(2)(PPh(2)-(C(6)H(4))(n)-PPh(2))] (n = 1, 2, 3) as well as their tetranuclear cationic derivatives [(Au(2)SPh)(2)(PPh(2)-(C(6)H(4))(n) PPh(2))(2)](PF(6))(2) are reported. Their crystal structures have been elucidated by X-ray studies. These studies indicate that, for the dinuclear species, only when n = 1 the molecules exhibit intermolecular aurophilic interactions. None of the tetranuclear species crystallizes in their molecular form, due to the formation of aggregates through Au...Au interactions. The origin of the luminescence has been analyzed by computational studies indicating that the presence or absence of aurophilic interactions does not affect the luminescent behavior and that intraligand charge transfer processes which involve the thiolate and the diphosphine are responsible for the emissions. The result is in contrast with the thiolate-gold charge transfer processes which dominate the photophysics of gold-thiolate compounds and reveals the influence of the phenylene spacers in the emissive behavior of these compounds. PMID- 21691661 TI - Rapid liposome quality assessment using a lab-on-a-chip. AB - Although liposomes have many outstanding features such as biocompatibility, biodegradability, low toxicity and structural diversity, and are successfully applied in many areas of chemistry and biotechnology, a lack of characterization standards and quality control tools are still inhibiting the translation of liposome technology into clinical routine. The greatest obstacle to clinical scale commercialization is the inability to ensure liposome formulation stability because small size variations or altered surface chemistries can significantly influence in vivo distribution and excretion kinetics that could in turn lead to unpredictable therapy outcomes. To enhance the product development process we have developed a microfluidic biochip containing embedded dielectric microsensors capable of providing quantitative results on formulation composition and stability based on the monitoring of the unique electric properties of liposomes. Computational fluid dynamic (CFD) simulations confirmed that microfluidics offer reproducible and well-defined measurement conditions where a moving liposome suspension within a microchannel behaves like a bulk material. Results of this study demonstrate the ability of microfluidics, in combination with dielectric spectroscopy and multivariate data analysis methods, to identify nine different liposomes. We also show that various liposome modifications such as membrane bound surface proteins, lipid bilayer soluble drugs, as well as protein and dye encapsulations, can be detected in the absence of any labels or indicators. Since shelf-life stability of a liposome formulation is regarded of prime importance for regulatory approval and clinical application, we further provide a possible practical application of the developed liposome analysis platform as a high throughput tool for industrial quality insurance purposes. PMID- 21691662 TI - A flexible microfluidic processor for molecular biology: application to microarray sample preparation. AB - We describe a programmable microfluidic system with onboard pumps and valves that has the ability to process reaction volumes in the sub-microlitre to hundred microlitre range. The flexibility of the architecture is demonstrated with a commercial molecular biology protocol for mRNA amplification, implemented without significant modification. The performance of the microchip system is compared to conventional bench processing at each stage of the multistep protocol, and DNA microarrays are used to assess the quality and performance of bench- and microchip-amplified RNA. The results show that the microchip system reactions are similar to bench control reactions at each step, and that the microchip- and bench-derived amplified RNAs are virtually indistinguishable in differential microarray analyses. PMID- 21691663 TI - Soft-lithography fabrication of microfluidic features using thiol-ene formulations. AB - In this work, a novel thiol-ene based photopolymerizable resin formulation was shown to exhibit highly desirable characteristics, such as low cure time and the ability to overcome oxygen inhibition, for the photolithographic fabrication of microfluidic devices. The feature fidelity, as well as various aspects of the feature shape and quality, were assessed as functions of various resin attributes, particularly the exposure conditions, initiator concentration and inhibitor to initiator ratio. An optical technique was utilized to evaluate the feature fidelity as well as the feature shape and quality. These results were used to optimize the thiol-ene resin formulation to produce high fidelity, high aspect ratio features without significant reductions in feature quality. For structures with aspect ratios below 2, little difference (<3%) in feature quality was observed between thiol-ene and acrylate based formulations. However, at higher aspect ratios, the thiol-ene resin exhibited significantly improved feature quality. At an aspect ratio of 8, raised feature quality for the thiol ene resin was dramatically better than that achieved by using the acrylate resin. The use of the thiol-ene based resin enabled fabrication of a pinched-flow microfluidic device that has complex channel geometry, small (50 MUm) channel dimensions, and high aspect ratio (14) features. PMID- 21691664 TI - Target-selective fluorescent "switch-on" protein labeling by 6pi azaelectrocyclization. AB - Application of azaelectrocyclization and FRET techniques to lysine groups enabled the selective and sensitive detection of a target protein from a mixture, with high fluorescence contrast. PMID- 21691665 TI - Regioselective enzymatic acylation of complex natural products: expanding molecular diversity. AB - Enzymatic catalysis has become a common tool in both academia and industrial chemistry. The efforts of chemists over recent decades have led to the rationalization of the mechanism of action of biocatalysts, which have been routinely incorporated into many synthetic sequences. Nowadays, a further step consists in expanding the application of enzymes to the modification of complex molecular scaffolds common to many pharmaceutical leads isolated from nature. Regioselective enzymatic acylation is a process which has been profitably applied for this purpose in recent times, leading to new drugs with improved activity, stability and pharmacokinetic properties. This tutorial review provides an overview of this subject employing two classes of enzymes, hydrolases and acyltransferases, in the recently concluded decade although some representative older studies are commented upon, if required. We shall place special emphasis on those examples in which the novel acylated derivatives have improved the activity or properties of the parental molecules. PMID- 21691667 TI - Chemical strategies for tagging and imaging the proteome. AB - Proteomic visualization serves as a complement to proteomic identification. In recent years, chemical biologists have made rapid progress developing new methods to tag and image defined sets of proteins. These researchers have requisitioned cellular machinery to place small, reactive analogues into biomolecules. The analogue has been labeled subsequently using a selective ligation reaction. Many groups have demonstrated the efficacy of the copper-catalyzed or strain-promoted azide-alkyne ligation; both enable rapid and precise labeling in complex biological mixtures. This review provides an overview of the methods which have been optimized to tag and fluorophore-label biomolecules for imaging subsets of the proteome in bacterial and mammalian cells. With the approaches described herein, it should be possible to image cells as they undergo changes over time. PMID- 21691666 TI - Dynamic physical properties of dissociated tumor cells revealed by dielectrophoretic field-flow fractionation. AB - Metastatic disease results from the shedding of cancer cells from a solid primary tumor, their transport through the cardiovascular system as circulating tumor cells (CTCs) and their engraftment and growth at distant sites. Little is known about the properties and fate of tumor cells as they leave their growth site and travel as single cells. We applied analytical dielectrophoretic field-flow fractionation (dFFF) to study the membrane capacitance, density and hydrodynamic properties together with the size and morphology of cultured tumor cells after they were harvested and placed into single cell suspensions. After detachment, the tumor cells exhibited biophysical properties that changed with time through a process of cytoplasmic shedding whereby membrane and cytoplasm were lost. This process appeared to be distinct from the cell death mechanisms of apoptosis, anoikis and necrosis and it may explain why multiple phenotypes are seen among CTCs isolated from patients and among the tumor cells obtained from ascitic fluid of patients. The implications of dynamic biophysical properties and cytoplasmic loss for CTC migration into small blood vessels in the circulatory system, survival and gene expression are discussed. Because the total capacitance of tumor cells remained higher than blood cells even after they had shed cytoplasm, dFFF offers a compelling, antibody-independent technology for isolating viable CTCs from blood even when they are no larger than peripheral blood mononuclear cells. PMID- 21691668 TI - A naphthalene-based Al3+ selective fluorescent sensor for living cell imaging. AB - An efficient fluorescent Al(3+) receptor, N-(2-hydroxy-1-naphthalene)-N'-(2-(2 hydroxy-1-naphthalene)amino-ethyl)-ethane-1,2-diamine (L) has been synthesized by the condensation reaction between 2-hydroxy naphthaldehyde and diethylenetriamine. High selectivity and affinity of L towards Al(3+) in ethanol (EtOH) as well as in HEPES buffer at pH 7.4, makes it suitable to detect intracellular Al(3+) with fluorescence microscopy. Metal ions, viz. Li(+), Na(+), K(+), Mg(2+), Ca(2+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Ag(+), Cd(2+), Hg(2+) and Pb(2+) do not interfere. The lowest detection limit for Al(3+) is 3.0 * 10(-7) M and 1.0 * 10(-7) M in EtOH and HEPES buffer respectively. PMID- 21691669 TI - Self-sorting self-complementary assemblies of pi-conjugated acyclic anion receptors. AB - Pyrrole-based pi-conjugated anion-responsive molecules bearing an anionic moiety form self-complementary dimers, which exhibit self-sorting behaviours depending on the substituted positions of anionic sites. PMID- 21691670 TI - Energetics of Ce and Pu incorporation into zirconolite waste-forms. AB - The General Utility Lattice Program (GULP) has been used to model the zirconolite lattice, calculate the energies of substituting Ce(3+), Ce(4+), Pu(3+), Pu(4+) and Fe(3+) into the lattice both as single and multi-defect systems and model the formation of Ce(3+), Ce(4+), Pu(3+) and Pu(4+) doped zirconolite lattices. These results have been compared against experimental observations, with particular emphasis on those Ce containing solid solutions that exhibit Ce(3+)/Ce(4+) mixed valence characteristics. It is found that the Ce(3+)/Ce(4+) mixed valence is as a result of reduction within the lattice, with the Ce(3+) being stabilised on the Ca site, and that this behaviour would not be expected for the corresponding Pu solid solutions. PMID- 21691671 TI - Ionic conductance of synthetic channels: analysis, lessons, and recommendations. AB - Synthetic ion channels have been known for nearly three decades, but it is only in the past decade that analysis of the currents these ionic conductors carry has become a standard technique. A broad range of structural types have been explored and these reports have produced a very diverse collection of ion channel conductance behaviours. In this critical review we describe a notational method to extract salient information from reported ion channel experiments. We use an activity grid to represent quantitative information on conductance and opening duration with a five-level colour code to represent qualitative information on the nature of the conductance-time profile. Analysis of the cumulative dataset suggests that the reported conductance data can reflect the structural features of the compounds prepared, but does also reflect the energetic landscape of the bilayer membrane in which synthetic ion channels function (143 references). PMID- 21691672 TI - The evolving plasticity of coagulation protease-dependent cytoprotective signalling. AB - Coagulation proteases control cellular homeostasis beyond haemostasis. While the role of coagulation proteases in regulating vascular healing and thrombosis is well established, the mechanism underlying the receptor-dependent regulation of cellular function remain incompletely understood. In particular, the opposing effects of the protease-activated receptor 1 (PAR-1), dependent on the activating proteases thrombin or activated protein C generated a conundrum researchers only recently have begun to decipher. The net-effect (cellular perturbation vs. cellular protection) depends on co-receptors involved, the concentration of the activating protease, the temporal context of receptor activation, and a dynamic process of receptor rearrangement upon receptor activation. The latter scenario recruits receptors to a cytoprotective signalling pathways. Recent insights into these mechanisms are summarized in this article. PMID- 21691673 TI - The protein Z/protein Z-dependent protease inhibitor complex. Systemic or local control of coagulation? AB - Protein Z (PZ) is a vitamin K-dependent factor identified in human plasma in 1984 but it has no enzymatic activity. It is a cofactor of a serpin, the protein Z dependent protease inhibitor (ZPI), and the complex PZ/ZPI inhibits activated factor X on phospholipid surfaces. In mice, the disruption of PZ or ZPI gene is asymptomatic, but enhances the thrombotic phenotype and mortality of other thrombotic risk factors. Most of the clinical studies focused on PZ. Despite conflicting results, a recent meta-analysis indicated that PZ deficiency could be a risk for venous and arterial thrombosis and early fetal loss. However, these conclusions are drawn from case-control studies of small size, constituting an important limitation. Recently, it was shown that PZ and/or ZPI are synthesised by normal kidney and different cancer cells, suggesting that the complex PZ/ZPI could play a role in inhibiting the tissue deposition of fibrin. The physiopathological consequences of these observations remain to be established. At this time, the measurement of plasma PZ and ZPI or analysis of their gene polymorphisms should not be performed routinely for the exploration of thrombophilia. PMID- 21691674 TI - Lessons learned from data mining of WHO mortality database. AB - OBJECTIVES: The objectives of this research were to test the ability of classification algorithms to predict the cause of death in the mortality data with unknown causes, to find association between common causes of death, to identify groups of countries based on their common causes of death, and to extract knowledge gained from data mining of the World Health Organization mortality database. METHODS: The WEKA software version 3.5.3 was used for classification, clustering and association analysis of the World Health Organization mortality database which contained 1,109,537 records. Three major steps were performed: Step 1 - preprocessing of data to convert all records into suitable formats for each type of analysis algorithm; Step 2 - analyzing data using the C4.5 decision tree and Naive Bayes classification algorithm, K-means clustering algorithm and Apriori association analysis algorithm; Step 3 - interpretation of results and hypothesis testing after clustering analysis. RESULTS: Using a C4.5 decision tree classifier to predict cause of death, we obtained 440 leaf nodes that correctly classify death instances with an accuracy of 40.06%. Naive Bayes classification algorithm calculated probability of death from each disease that correctly classify death instances with an accuracy of 28.13%. K means clustering divided the data into four clusters with 189, 59, 65, 144 country-years in each cluster. A Chi-square was used to test discriminate disease differences found in each cluster which had different diseases as predominant causes of death. Apriori association analysis produced association rules of linkage among cancer of the lung, hypertension and cerebrovascular diseases. These were found in the top five leading causes of death with 99-100% confidence level. CONCLUSION: Classification tools produced the poorest results in predicting cause of death. Given the inadequacy of variables in the WHO database, creation of a classification model to predict specific cause of death was impossible. Clustering and association tools yielded interesting results that could be used to identify new areas of interest in mortality data analysis. This can be used in data mining analysis to help solve some quality problems in mortality data. PMID- 21691675 TI - Multidimensional point transform for public health practice. AB - BACKGROUND: With increases in spatial information and enabling technologies, location-privacy concerns have been on the rise. A commonly proposed solution in public health involves random perturbation, however consideration for individual dimensions (attributes) has been weak. OBJECTIVES: The current study proposes a multidimensional point transform (MPT) that integrates the spatial dimension with other dimensions of interest to comprehensively anonymise data. METHODS: The MPT relies on the availability of a base population, a subset patient dataset, and shared dimensions of interest. Perturbation distance and anonymity thresholds are defined, as are allowable dimensional perturbations. A preliminary implementation is presented using sex, age and location as the three dimensions of interest, with a maximum perturbation distance of 1 kilometre and an anonymity threshold of 20%. A synthesised New York county population is used for testing with 1000 iterations for each of 25, 50, 100, 200 and 400 patient dataset sizes. RESULTS: The MPT consistently yielded a mean perturbation distance of 46 metres with no sex or age perturbation required. Displacement of the spatial mean decreased with patient dataset size and averaged 5.6 metres overall. CONCLUSIONS: The MPT presents a flexible, customisable and adaptive algorithm for perturbing datasets for public health, allowing tweaking and optimisation of the trade-offs for different datasets and purposes. It is not, however, a substitute for secure and ethical conduct, and a public health framework for the appropriate disclosure, use and dissemination of data containing personal identifiable information is required. The MPT presents an important component of such a framework. PMID- 21691676 TI - Visual clustering analysis of CIS logs to inform creation of a user-configurable Web CIS interface. AB - BACKGROUND: In this paper, we describe a new method for the study of clinical information system (CIS) logfiles joined with information in the clinical data warehouse. This method uses heatmap representations and clustering techniques to examine clinicians' viewing patterns of laboratory test results. The context of our application of these techniques is to inform the creation of a widget-based interface to the CIS. OBJECTIVES: We address the rationale, feasibility, and usefulness of our method through examination of three hypotheses: 1) The frequency distribution of laboratory test viewing will follow a 'long tail' pattern, indicating that patterns are highly variable and supporting the rationale for a widget-based configurable system. 2) Patterns of laboratory testing viewing (by clinician, specialty, clinician/patient/day, and ICD-9-CM codes) can be distinguished by our methods. 3) The identified clusters will include more than 80% of the laboratory test elements found in 30 randomly selected patient records for one day. METHODS: The data were plotted as heatmaps and clustered using hierarchical clustering software. Various parameters were tested to give the optimal clusters. RESULTS: All the hypotheses were supported. For Hypothesis 3, 91.4% of information elements in the records were covered by the generated clusters. CONCLUSIONS: Study findings support the rationale, feasibility, and usefulness of our methods to examine patterns of information access among clinicians and to inform the creation of widget-based interfaces. The results also contribute to our general understanding of clinicians' CIS use. PMID- 21691677 TI - Comparison and correlation between self-measured blood pressure, casual blood pressure measurement and ambulatory blood pressure monitoring. AB - BACKGROUND: Casual blood pressure (BP) measurement by healthcare professionals is subject to great variability and new methods are necessary to overcome this limitation. OBJECTIVE: To compare and assess the correlation between the BP levels obtained by self-measured BP (SMBP), casual BP measurement and ambulatory blood pressure monitoring (ABPM). METHODS: We assessed hypertensive individuals submitted to the three methods of BP measurement at an interval < 30 days; the BP means were used for comparison and correlation. The following devices were used: OMRON 705 CP (casual measurement), OMRON HEM 714 (SMBP) and SPACELABS 9002 (ABPM). RESULTS: A total of 32 patients were assessed, of which 50.09% were females, with a mean age of 59.7 (+/- 11.2), BMI mean of 26.04 (+/- 3.3) kg/m(2). Mean systolic (SBP) and diastolic blood pressure (DBP) for SMBP were 134 (+/- 15.71) mmHg and 79.32 (+/- 12.38) mmHg. The casual measurement means of SBP and DBP were, respectively, 140.84 (+/- 16.15) mmHg and 85 (+/- 9.68) mmHg. The mean values of ABPM during the wakefulness period were 130.47 (+/- 13.26) mmHg and 79.84 (+/- 9.82) mmHg for SBP and DBP, respectively. At the comparative analysis, the SMBP had similar results to those obtained at ABPM (p > 0.05) and different from the casual measurement (p < 0.05). At the analysis of correlation, SMBP values were higher than the casual measurements, considering ABPM as the reference standard in BP measurements. CONCLUSION: SMBP showed a better correlation with ABPM than the casual measurement and was also better correlated with the latter, especially regarding the DBP and should be considered as a low cost alternative for the follow-up of the hypertensive patient. PMID- 21691678 TI - Impact of renal failure on in-hospital outcomes after coronary artery bypass surgery. AB - BACKGROUND: Chronic kidney disease (CKD) is a predictor of increased mortality in patients undergoing coronary artery bypass surgery (CABG). OBJECTIVE: To evaluate the characteristics and predictors of increased mortality in the CKD population submitted to CABG. To compare in-hospital outcomes between patients with and without CKD, and with and without development of acute renal failure (ARF). METHODS: Retrospective analysis of a prospective database of all isolated CABG performed in a single public tertiary hospital from 1999 to 2007. CKD was considered when creatinine > 1.5 mg/dl. Clinical characteristics, mortality and post-operative complications were evaluated according to renal function. RESULTS: Of 3,890 patients, 362 (9.3%) had CKD. This population was older, presented grater prevalence of hypertension, left ventricular dysfunction, previous stroke, peripheral vascular disease and three-vessel disease. In-hospital outcomes revealed greater incidence of stroke (5.5% vs 2.1%), atrial fibrillation (16 vs 8.3%), low cardiac ouput syndrome (14.4% vs 8.5%), longer stay in intensive care unit (4.04 vs 2.83 days), and greater mortality (10.5% vs 3.8%). Logistic regression: female gender, smoking, diabetes and peripheral vascular disease were associated with higher in-hospital mortality within the CKD group. Patients who did not develop post-operative ARF presented 3.5% mortality; non-dialytic ARF: 35.4%; dialytic ARF: 66.7% mortality. Mortality was directly related to the stage of CKD, according to glomerular filtration rate. CONCLUSION: CKD patients submitted to CABG represent a high risk population, with increased incidence of complications and mortality. Post-operative ARF is a strong in-hospital mortality predictor. Glomerular filtration rate was inversely related to mortality. PMID- 21691679 TI - Left ventricular end diastolic pressure and acute coronary syndromes. AB - BACKGROUND: Data is lacking in the literature regarding the prognostic impact of left ventricular-end diastolic pressure (LVEDP) across acute coronary syndromes (ACS). OBJECTIVE: To assess LVEDP and its prognostic implications in ACS patients. METHODS: Prospective, longitudinal and continuous study of 1329 ACS patients from a single center between 2004 and 2006. Diastolic function was determined by LVEDP. Population was divided in two groups: A - LVEDP < 26.5 mmHg (n = 449); group B - LVEDP >= 26.5 mmHg (n = 226). RESULTS: There were no significant differences between groups with respect to risk factors for cardiovascular disease, medical history and medical therapy during admission. In group A, patients with non-ST elevation ACS were more frequent, as well as normal coronary angiograms. In-hospital mortality was similar between groups, but one year survival was higher in group A patients (96.9 vs 91.2%, log rank p = 0.002). On a multivariate Cox regression model, a LVEDP >= 26.5 mmHg (HR 2.45, 95%CI 1.05 - 5.74) remained an independent predictor for one-year mortality, when adjusted for age, LV systolic ejection fraction, ST elevation ACS, peak troponin, admission glycemia, and diuretics at 24 hours. Also, a LVEDP >= 26.5 mmHg was an independent predictor for a future readmission due to congestive HF (HR 6.65 95%CI 1.74 - 25.5). CONCLUSION: In our selected population, LVEDP had a significant prognostic influence. PMID- 21691680 TI - Comparison between 2D and 3D echocardiography in the evaluation of reverse remodeling after CRT. AB - BACKGROUND: Echocardiography is a useful method for screening and assessing response to cardiac resynchronization therapy (CRT). 3D echocardiography has already established its role in the evaluation of ventricular volumes and ejection fraction (LVEF) with excellent correlation of results when compared with MRI. OBJECTIVE: To compare the evaluation of ventricular volumes (LVDV, LVSV), LVEF, and LV mass before and after CRT by 2D echocardiography and three dimensional echocardiography. METHODS: We evaluated 24 patients with heart failure (HF), functional class (FC) III or IV (NYHA), sinus rhythm QRS >= 120 ms, during an optimized therapy for HF undergoing CRT. We conducted electrocardiogram (ECG), clinical evaluation, 2D and 3D echocardiography before, three and six months after CRT. The comparison between the techniques was performed using Pearson's correlation (r). RESULTS: At baseline, the correlation between methods was 0.96 for evaluation of LVDV, 0.95 for evaluation of LVSV, 0.87 for LVEF and 0.72 for LV mass. After three months of CRT, the correlation between methods for analysis of LVDV was 0.96, 0.95 for LVSV, 0.95 for LVEF, and 0.77 for LV mass. After six months of CRT, the correlation between 2D and 3D echocardiography for analysis of LVDV was 0.98, 0.91 for LVSV, 0.96 for LVEF, and 0.85 for LV mass. CONCLUSION: This study reported was a reduction of LVDV, LVSV, besides improvement in LVEF after CRT. There was an excellent correlation between the 2D and 3D echocardiography for evaluation of ventricular volumes and LVEF, and a good correlation between methods for evaluation of left ventricular mass before and after CRT. PMID- 21691682 TI - The Athlete's heart and the endless pursuit of prediction factors. PMID- 21691683 TI - Ethical considerations in collective health. PMID- 21691684 TI - Is inhaled nitric oxide therapy more effective or safer than the conventional treatment for the treatment of vaso-occlusive crises in sickle-cell anemia? PMID- 21691685 TI - Uncomplicated urinary infection in women: diagnosis. PMID- 21691686 TI - Renal replacement lipomatosis and xanthogranulomatous pyelonephritis: differential diagnosis. PMID- 21691688 TI - Ethical standards adopted by Brazilian journals of medical specialties. AB - OBJECTIVE: To review ethical standards contained in guidelines to authors of Brazilian scientific journals in several medical specialties and see if there is any standardization available. METHODS: This is an exploratory study evaluating Brazilian scientific journals classified on the Portal of Journals on Health Sciences of the Virtual Health Library in all medical specialties regarding guidelines to authors submitting manuscripts and concerning ethical standards for research in humans. Data was collected and categorized for the presence of the following variables: Ethics Committee approval; Helsinki Declaration and/or Resolution 196/96, informed consent; ethical standards; uniform requirements; patients' confidentiality and no ethical references. The association among the variables was also examined. RESULTS: Out of a total of 8,701 journals, 95 were included in the current study. The variables were investigated, with each one's frequency being verified. Eighty per cent were referred for an Ethics Committee approval; 43.15% of Helsinki Declaration; 43.15% of informed consent; 9.47% of ethical standards; 32.63% of uniform requirements and 15.78% of patients' confidentiality were referenced. In the whole sampling, 9.47% of journals do not mention any ethical reference as a guide to authors submitting manuscripts. An association among variables occurred in 61% of the sample. CONCLUSION: Ethical aspects of submitting manuscripts were mentioned in over 90% of the guides to authors of national scientific journals and no standardization at all is available. PMID- 21691689 TI - Impact of perinatal factors on growth deficits of preterm infants. AB - OBJECTIVE: To review perinatal factors associated with a growth deficit in preterm infants at a corrected age of one year. METHODS: Cohort study of preterm infants with a birth weight < 2,000 g. Percentiles and Z scores of body weight (W/A), length (L/A) and head circumference (HC/A) at one year of corrected age were calculated by using the Centers for Disease Control and Prevention curves. RESULTS: Among 303 preterm infants, the frequencies of measures below the 10th percentile (P10) and Z scores -2 were 43.2% and 24.4% for W/A, 22.1% and 8.6% for L/A and 15.8% and 4.6% for HC/A, respectively. Logistic regression analyses showed factors associated with higher odds for W/A < P10 were resuscitation at birth (1.8 times) and small for gestational age infants (3.0 times). In infants rated as small at full-term postconceptual age, the odds for W/A < P10 were 4.0 times as high in those with a birth weight between 1,000 and 1,499 g and 3.5 times as high in those > 1,500 g. As birth length was reduced, the odds for L/A < P10 increased, but this was not associated with birth weight. The odds for HC/A < P10 were 2.5 times as high in small for gestational age infants. In infants with a body weight < 1,000 g, the odds for HC/A < P10 were 4.4 times higher, compared with those between 1,000 g and 1,499 g and 5.3 times higher if compared with those > 1,500 g. CONCLUSION: At a corrected age of one year, preterm infants with a birth weight < 2,000 g were found with high growth deficits frequencies, and associated factors were variable, depending on the analyzed deficit, with intrauterine and postnatal growth restriction being outstanding predictors. PMID- 21691690 TI - Aortic properties and atrial electrophysiology in the young and old football players. AB - OBJECTIVE: The purpose of this study was to investigate the differences between P wave dispersion, aortic elastic properties and transthoracic echocardiographic findings in the young and old football players compared to control groups in order to asses the influence of regular sportive activity on aortic distensibility and its potential effect on atrial electrophysiology. METHODS: We recruited 42 young football players with a training history of many years. The control group was formed by 27 healthy sedentary men. Twenty-three healthy retired football players of a professional football club aged over 50 years were included in the study as old group and 18 subjects over 50 year old who did not perform regular exercise when they were young were included in the control group of old subjects. RESULTS: The heart rate and ejection fraction were decreased in the young football players. There were no significant differences in the aortic elastic parameters and P wave dispersion between young football players and control group. But in old subjects with sustained participation in regular sportive activity, the significant difference of left ventricular dimension, wall thickness and systolic functions detected in the young group disappeared while increase in the left atrial diameter became significant. CONCLUSION: Potential effect of aortic elastic properties which changes with age, on atrial electrophysiology through increasing P wave dispersion was shown. PMID- 21691692 TI - Thoracic surgery: risk factors for postoperative complications of lung resection. AB - OBJECTIVE: To identify preoperative and transoperative risks factors for postoperative complications developed in lung resection surgery. METHODS: During 14 months; 189 patients underwent pulmonary resection and were enrolled to the study. After a clinical interview, patients were evaluated by laboratory, pulmonary function tests and radiography, submitted to a surgical procedure, and were followed during their stay in the ICU and hospital, evaluating postoperatory complications and death. RESULTS: The postoperative rate of complications was 52.9%: respiratory (34.3%), infectious (31%), and cardiovascular (21.4%). Respiratory complications were related to smoking (p < 0.01, RR 2.31), airway obstruction by spirometry (p = 0.01, RR 2.60), presence of anemia (p < 0.01, RR 2.13), and prolonged protrombine time [PT] (p = 0.03, RR 1.77). Infection complications were related to smoking (p < 0.01, RR 2.69), airway obstruction by spirometry (p = 0.01, RR 3.31), presence of anemia (p < 0.01, RR 2.10), and prolonged PT (p = 0.03, RR 2.29). Cardiovascular problems were related with older age (p < 0.01, RR 2.66), cigarette smoking (p < 0.01, RR 4.55), and hypoxemia (p = 0.03, RR 2.43). The postoperative mortality rate was 7.1%. CONCLUSION: A preoperative evaluation can provide a suitable and safe postoperative prediction of complications in patients submitted to lung resection. Patients with COPD, hypoxemic, older, and anemic patients must be classified as high-risk for developing these complications. PMID- 21691691 TI - Failed back surgery pain syndrome: therapeutic approach descriptive study in 56 patients. AB - OBJECTIVE: The authors show the clinical evaluation and follow-up results in 56 patients diagnosed with a failed back surgery pain syndrome. METHODS: Descriptive and prospective study conducted over a one-year period. In this study, 56 patients with a failed back surgery pain syndrome were assessed in our facility. The age ranged from 28 to 76 years (mean, 48.8 +/- 13.9 years). The pain was assessed through a Visual Analog Scale (VAS). RESULTS: Postoperative pain was more severe (mean VAS score 8.3) than preoperative pain (7.2). Myofascial pain syndromes (MPS) were diagnosed in 85.7% of patients; neuropathic abnormalities associated or not with MPS were found in 73.3%. Drug therapy associated with physical medicine treatment provided > 50% pain improvement in 57.2% of cases; trigger point injection in 60.1%, and epidural infusion of morphine with lidocaina in 69.3% of refractory cases. CONCLUSION: In patients with a post laminectomy syndrome, postoperative pain was more severe than preoperative pain from a herniated disk. A miofascial component was found in most patients. PMID- 21691693 TI - Prospective study of Kawasaki disease complications: review of 115 cases. AB - OBJECTIVE: To draw attention to complications that might arise in any Kawasaki disease (KD) stage, risk factors contributing to the onset of complications and possible transient or permanent disease sequelae. METHODS: Prospective study (clinical cohort) conducted between April 2002 and April 2009 of 115 patients with KD admitted to the Pediatric Rheumatology Clinic of the General Hospital of the Federal District, Brazil. All patients were sequentially assessed with clinical and laboratory examinations, Doppler echocardiography, imitanciometry, auditory evoked potentials, psychological evaluation, ophthalmologic examination and, in one patient with chorea, cerebral magnetic resonance angiography. In all patients, a questionnaire assessing the possible presence of cognitive, emotional, behavioral and social disorders was applied. RESULTS: Twenty-five patients (21.7%) had coronary aneurisms. Thirty eight patients (33%) had a sensorineural auditory loss during the acute and subacute phases of the disease and 13 patients (11.3%) maintained the auditory loss six months after the first assessment. Other complications observed were as follows: facial palsy in one patient (0.9%), ataxia in acute and subacute phases in 11 (9.5%); 15 patients had ophthalmologic complications (13.2%), with uveitis in 13, papilledema in one patient, and conjunctival hemorrhage in another patient. One patient experienced chorea (0.9%), with a magnetic resonance angiography showing changes consistent with cerebral ischemia. In one patient, a thoracic aorta aneurism was found (0.9%) and another patient had a necrotizing vasculitis progressing to peripheral gangrene and tongue tip loss (0.9%). Behavioral changes over convalescence were observed in 23 children. CONCLUSION: KD may progress with several complications even within months of the disease acute phase, eventually resulting in permanent sequelae. The earlier the diagnosis and therapeutic intervention with IV IgG administration are, the lower will be the occurrence of complications; the presence of thrombocytosis, anemia and elevated and extended inflammatory activity are risk factors for complication arising. PMID- 21691695 TI - HTLV-II in blood donors at the Blood Center Net of Ceara - HEMOCE. AB - OBJECTIVE: To identify HTLV-II revalence in blood donors at the Blood Center Net of Ceara (Hemorrede do Ceara - HEMOCE) and epidemiological aspects of positive cases. METHODS: Cases considered positive were surveyed from data bases through the immunoenzymatic method ELISA and confirmed by Western Blot from 2001 to 2008. In this period, 679,610 blood samples from voluntary donors were tested. RESULTS: From all donors, 164 samples were actually positive in both tests; of these, 33 (20.1%) were typed as HTLV-II, showing a prevalence of 0.006%. In positive cases, a mean age 28.2 years, and a predominantly male gender (54.5%) were observed, the race was mixed in 78.8%, most donors had Fortaleza as hometown (72.7%), with 51.5% being married/consensual union, and 33.3% reported to have completed high school education. CONCLUSION: Although HTLV-II infection is low, its presence is universal, being similar in males and females mostly in urban centers. The need of preventive measures as a way of avoiding infection spread is stressed. PMID- 21691694 TI - Drug prescription errors in a Brazilian hospital. AB - OBJECTIVE: To identify the prevalence of clinically significant prescription errors in a Brazilian university hospital compared with their occurrence in 2003 and 2007. METHODS: Variables and group of variables, such as readability, compliance with legal and institutional procedures of prescription, and prescription errors analysis were analyzed. RESULTS: When the prevalence rates of clinically significant prescription errors were calculated, a statistically significant decrease was shown [year of 2003 (29.25%), year of 2007 (24.20%); (z = 2.99; p = 0.03)], reflecting on the safety rate [year of 2003 (70.75%), year of 2007 (75.80%); (z = 3.30; p =0.0001)]. CONCLUSION: Despite significant, the increased safety rate reflected the quantitative reduction of errors, with no observed difference in severity between the studied periods. Our results suggest the institutional steps taken could reduce the number of errors, but they were ineffective in reducing the severity of the errors. PMID- 21691696 TI - Secondary Sjogren's syndrome and disease activity of rheumatoid arthritis. AB - OBJECTIVE: To study the relationship of the presence of secondary SS with disease activity, duration in RA. METHODS: Eighty two patients with RA were submitted to Schirmer test, minor salivary gland biopsy, questionnaire on sicca symptoms, DAS 28 4v determination. RESULTS: In this population, 20 (24.3%) patients fulfilled the American-European classification criteria for secondary SS. No relation could be found between the presence of secondary SS and disease activity (p = 0.31) and RA duration (p = 0.95). CONCLUSION: Appearance of Secondary SS in RA patients is independent of RA duration or activity. PMID- 21691697 TI - Carotid stenosis and coronary artery bypass grafting. AB - OBJECTIVE: To identify carotid stenosis (CS) prevalence and potential mortality predictors in individuals undergoing elective coronary artery bypass grafting (CABG). METHODS: Cohort study including 393 scheduled for CABG. All patients underwent a color Doppler ultrasound study of the carotid arteries prior to CABG and were assessed for morbidity and mortality over the hospitalization. CS was considered clinically relevant when if > 50%. Significance was set at p < 0.05. Logistic regression was used to define mortality independent predictors. RESULTS: CS prevalence was 17.4%. Following logistic regression analysis, CS > 50% (p = 0.001) and chronic renal failure (CRF) (p = 0.03) remained as mortality independent predictors. CONCLUSION: CS showed a high prevalence in the study sample and together with CRF was a mortality independent factor. PMID- 21691698 TI - Heparin pharmacovigilance in Brazil. AB - OBJECTIVE: To investigate the biological origin of injectable unfractioned heparin available in Brazilian market by discussing the impact of the profile of commercial products and the changes in heparin monograph on the drug safety. METHODS: The Anvisa data base for the Registered Products of Pharmaceutical Companies and the Dictionary of Pharmaceutical Specialties (DEF 2008/2009) were searched. A survey with industries having an active permission for marketing the drug in Brazil was conducted. RESULTS: Five companies were granted a permission to market unfractioned heparin in Brazil. Three of them are porcine in origin and two of them are bovine in origin, with only one explicitly showing this information in the package insert. The effectiveness and safety of heparin studied in non-Brazilian populations may not represent the Brazilian reality, since most countries no longer produce bovine heparin. The currently marketed heparin has approximately 10% less anticoagulant activity than that previously produced and this change may have clinical implications. CONCLUSIONS: Evidence about the lack of dose interchangeability between bovine and porcine heparins and the unique safety profile of these drugs indicates the need to follow the treatment and the patients' response. Events threatening the patient's safety must be reported to the pharmacovigilance system in each particular country. PMID- 21691699 TI - Deaths in nursing homes. AB - OBJECTIVE: To define the causes of death in a nursing home population. METHODS: The study selected a 508-bed nursing home with standard medical records, regular meetings concerning death certificates and 12 medical doctors in charge of supervising or issuing death certificates. The procedure standard (2006 death certificates) was considered consistent enough to undergo the analysis. The collected data were gender, age, cause(s) of death and underlying disease(s). The statistical analysis compared data between the two genders and two age ranges (< 75 years and > 75 years). RESULTS: There were 118 deaths in 2006 (mean age: 74.5 +/- 15.2 years) - 64 women (mean age: 78.4 +/- 14.4 years old) and 54 men (mean age: 69.8 +/- 15.0 years old). Causes of death were sepsis (41 deaths), septic shock (25), bronchopneumonia (16), sudden death (11), multiple-organ failure (9) and other causes (16 deaths). The main underlying diseases were infections (63 deaths) - bronchopneumonia (34), sepsis (12), urinary tract infection (7) infected pressure ulcers (7), osteomyelitis (2) and bile duct infection (1); immobility syndrome (42 deaths). The proportion of women older than 75 years showed statistical significance concerning the number of deaths. The sample did not show statistical significance regarding seasonality, causes of death or underlying disease(s) when comparing infectious and noninfectious causes of death vs. men and women, aged older or younger than 75 years. CONCLUSION: Deaths in nursing homes were basically caused by a combination of immobility and infections that developed into sepsis. PMID- 21691700 TI - Trends of mortality from ill-defined causes in the Northeast region of Brazil, 1979-2009. AB - OBJECTIVE: This study aimed to analyze the trends of mortality from symptoms, signs and ill-defined causes (SSIDC) in the Northeast region of Brazil, during the period of 1979- 2009. METHODS: The study used secondary data provided by the Mortality Information System SIM/Datasus/Ministry of Health. RESULTS: There was a reduction in the proportion of this type of death (y = -1.3751x + 55.953 R2 = 0.9035), from 45.7% in 1979 to 8.1% in 2009, as well as according to sex: males (y = -1.3716x + 54.559 R2 = 0.9197) and females (y = -1.3828x + 57.932 R2 = 0.8771). The proportion of deaths due to ill-defined causes showed a decreasing tendency in all age groups. The highest reduction was observed in the upper and lower age ranges, < 1 and 1 to 4 year and elderly group, namely 60 years old and older. Capitals and countryside also showed a decreasing tendency in proportional mortality due to IDC, (y = -0.1118x + 9.4275 R2 = 0.3087) and (y = -1.7908x + 71.178 R2 = 0.9151) respectively, but with different temporal patterns. The capital cities had the lower rates since the beginning of the series regardless of the age groups, but the great reduction in rates was observed in the countryside, being 7.1 times higher among adults (20 to 59 years old). CONCLUSION: Decreased trends were observed, but it is necessary to reinforce the actions to improve the capacity of health service assistance and coverage and data registration in order to maintain this trend. PMID- 21691701 TI - Cystatin C and inflammatory markers in kidney transplant recipients. AB - OBJECTIVE: Kidney transplantation is the best option for patients with end-stage renal disease. This study evaluated the profile of cystatin C (CysC), interleukin 2 (IL-2), IL-6, and tumor necrosis factor-alpha (TNF-alpha) as inflammatory markers in 23 living donor kidney transplant recipients. METHODS: A descriptive, analytical and prospective study was conducted between January 1st, 2007 and June 30th, 2008 on 23 living donor kidney transplant recipients. The biomarkers were evaluated before and 30 and 180 days after transplantation. RESULTS: The mean age of the patients was 34.3 years (+/- 11.7), females (52%) and non-whites (61%). Significant difference was found in cystatin C and creatinine before and 30 days after transplantation (p < 0.0001) and before and 180 days after transplantation (p < 0.0001). There was a significant difference in IL-2 between 30 and 180 days post-transplant (p = 0.0418) and in TNF-alpha between pre-transplant and 30 days post-transplant (p = 0.0001). A negative correlation was observed between cystatin C and TNF-alpha at pre-transplant and between cystatin C and IL-6 at 180 days post-transplant. Comparison of biopsied and non-biopsied patients showed a significant difference in creatinine and cystatin C at 30 and 180 days post transplant in biopsied patients. CONCLUSION: Our results showed no significant correlations between CysC, IL-2, IL-6 and TNF-alpha levels in kidney transplant recipients at short-term follow-up. Moreover, CysC levels were very similar to creatinine levels in contrast to other inflammatory markers studied in biopsied and non-biopsied patients. Further studies are important to evaluate the long term profile of these markers. PMID- 21691702 TI - Transcriptional profile and response to neoadjuvante chemotherapy in breast cancer. AB - OBJECTIVE: To improve the accuracy predictive models of response to neoadjuvante chemotherapy in breast cancer, cDNA microarray technology was used to study tumor transcriptional profile. Gene signatures associated with predicting the response to neoadjuvante chemotherapy are the subject of this review. METHODS: The data base http://www.ncbi.nlm.nih.gov/pubmed/ search was conducted by using the words "breast cancer" AND "neoadjuvante/primary chemotherapy" AND "gene expression profile/microarray". After excluding the repeats and selecting the publications considered most relevant by the authors to be presented, 279 publications were retrieved. RESULTS: The number of publications regarding this subject has been increasing over the years, reaching over 50 in 2010, including the response to different chemotherapeutic drugs, such as anthracyclines and taxanes either alone or in combination. The first studies are from early last decade and used microarray platforms produced by the investigators. Recent studies have used commercial microarray platforms whose data have been stored in public databases, allowing for the analysis of a higher number of samples. Several transcriptional profiles associated with the complete pathological response were identified. Other authors used the clinical response to treatment as an endpoint, and, in this case, a predictive panel of resistance to the chemotherapeutic regimen at issue was determined. This is also a key issue, as it can contribute to individualize treatment, allowing patients resistant to a certain chemotherapeutic agent to be offered another therapeutic regimen. CONCLUSION: Identifying patients responsive to chemotherapy is of essential interest and despite major steps have been taken, the issue warrants further studies in view of its complexity. PMID- 21691703 TI - Acquired angioedema responding to rituximab. PMID- 21691704 TI - In vivo study of hepatitis B vaccine effects on inflammation and metabolism gene expression. AB - Pharmaceutical companies usually perform safety testing of vaccines, but all requirements of the World Health Organization and drug pharmacopoeias depend on general toxicity testing, and the gene expression study of hepatitis B vaccine is not done routinely to test vaccine quality. In this study, we applied a new technique of gene expression analysis to detect the inflammation and metabolism genes that might be affected by hepatitis B vaccine in mouse liver. Mice were used and divided into three groups: the first and second groups were treated with one or two human doses of vaccine, respectively, and the third group was used as a control. A microarray test showed that expression of 144 genes in the liver was significantly changed after 1 day of vaccination. Seven of these genes, which were related to inflammation and metabolism, were chosen and confirmed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) at 1, 4 and 7 days. The expression level of these genes can be considered as a biomarker for the effects of the vaccine. PMID- 21691705 TI - The effect of mutation at M307 in FUT1 gene on susceptibility of Escherichia coli F18 and gene expression in Sutai piglets. AB - Escherichia coli F18 (ECF18) is a common porcine enteric pathogen. The pathogenicity of ECF18 bacteria depends on the existence of ECF18 receptor in the brush border membranes of piglet's small intestinal mucosa. Alpha (1) fucosyltransferase gene (FUT1) has been identified as the candidate gene controlling the adhesion to ECF18 receptor. The genetic variations in the position of M307 nucleotide in open reading frame of FUT1 have been proposed as a marker for selecting resistant pigs. The piglets were divided into three groups, AA, AG and GG, according to the genotypes present at M307 of FUT1. Small intestinal epithelium cells of piglets with AA, AG and GG genotypes were selected to test the adhesion capability of the wild type E.coli expressing F18ab fimbriae, the recombinant E. coli expressing F18ac fimbriae or the recombinant E. coli secreting and surface-displaying the FedF subunit of F18ab fimbriae, respectively. Here, we examined the distribution and expression of porcine FUT1 mRNA in different tissues in Sutai pigs using real-time PCR. The results showed that piglets with AA genotype show resistance, whereas piglets with GG or AG genotypes are sensitive to the pathogenic E. coli F18 in Sutai piglets. FUT1 was expressed in all the tissues that were examined, and the gene's expression was highest in the lungs. There was no significant difference in expression level among the three genotypes in the liver, lung, stomach and duodenum, where the gene expression was relatively high. The present analysis suggested that mutation at M307 in FUT1 gene determines susceptibility of small intestinal epithelium to E. coli F18 adhesion in Sutai piglet and the expression of FUT1 gene may be regulated by other factors or the mutation was likely to be in linkage disequilibrium with some cis-regulatory variants. PMID- 21691706 TI - Clinical implications for BRCA gene mutation in breast cancer. AB - To investigate the mutations of BRCA1 and BRCA2 and determine whether clinic pathological factors related to BRCA gene mutation. Mastectomy specimens from 360 breast cancers were enrolled and examined in the study. The relationship between BRCA gene mutation and clinic-pathological factors was evaluated. Overall, 280 patients were BRCA negative and 80 got BRCA gene mutation. Triple-negative breast cancers--i.e., breast cancers that do not express estrogen receptors (ER), progesterone receptors (PR) or human epidermal growth factor receptor 2 (HER2/neu)--was observed in 53.85% of the BRCA1 mutation patients, in 28.57% of the BRCA2 mutation cases, while 14.29% of BRCA negative patients. BRCA1 mutation patients got a heavy lymph node metastasis and higher nuclear grade tumors than the others (P = 0.004, 0.007). Furthermore, BRCA mutation was also found to be significantly related to ER, PR and HER2/neu status (P < 0.05). BRCA1 expression was not associated with breast cancer-specific survival in the triple-negative breast cancers (P = 0.742). After Cox regression, BRCA1 mutation was not shown to be an independent prognostic factor for breast cancer. These findings substantiated the possibility of tumors associated with BRCA1 mutations divided into two distinct groups, triple-negative and non-triple-negative groups requires further investigation. PMID- 21691707 TI - Identification of differentially expressed genes in ovaries of chicken attaining sexual maturity at different ages. AB - In poultry as well as in other birds, sexual maturity is one of the important factors influencing female reproduction and egg production. In this study, cDNA amplified fragment length polymorphism (cDNA-AFLP) differential display approach was used to identify genes related to sexual maturity. Using 54 EcoR I/Mse I selective primer combinations, totally 403 differentially expressed transcript derived fragments (TDFs) were isolated, 27 of which belong to 25 unigenes. By real-time quantitative PCR (qPCR), the expression pattern of 13 genes was confirmed; among them, four genes including ZNF183 (P < 0.01), KIAA0700, CCT6A, and 23e 15 (P < 0.05) are significantly up-regulated and one gene (Loc418883) is significantly down-regulated (P < 0.01) in sexually mature ovaries compared to immature ones. The mRNA expression dynamics of ZNF183, CCT6A, 23e 15 and Loc418883 were further investigated in ovaries of 70-, 300- and 500-day-old commercial egg-laying hens: the expression level of CCT6A was the highest in 300 day-old hens (P < 0.05), while that of Loc418883 in 500-day-old hens was significantly higher than the other two stages (P < 0.01). The expression levels of ZNF183 and 23e 15 in ovary increase significantly from 70-day-old hens (P < 0.01) and 300-day-old (P < 0.05) to 500-day-old hens, respectively. The consistence of CCT6A expression and egg-laying performance suggests that CCT6A likely plays important role in sexual maturity in hens. PMID- 21691708 TI - Catechol-O-methyltransferase (COMT) Val158Met polymorphism and risk of osteoporotic fracture. AB - Catechol-O-methyltransferase (COMT) is an estrogen degrading enzyme. The COMT Val158Met polymorphism is associated with bone mineral density. The aim of this study was to investigate associations between COMT Val158Met and osteoporotic fractures in Chinese Han patients. Case-control study of 320 patients with osteoporotic fractures and 320 healthy controls were conducted. The COMT Val158Met polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism assay. Patients with osteoporotic fracture had a significantly lower frequency of Val/Val genotype [odds ratio (OR) = 0.62, 95% confidence interval (CI) 0.39-0.99, P = 0.04] than controls. When stratified by the fracture type, there was a significantly lower frequency of Val/Val genotype in patients with vertebral fracture (OR = 0.58, 95% CI 0.36-0.94, P = 0.03) than controls. There was no significant difference in the distribution of each genotype between patients with hip fracture and the control group. Our findings suggest that COMT Val/Val genotype was associated with a lower risk of osteoporotic fracture in Chinese population, especially to vertebral fracture. PMID- 21691709 TI - Maize ZmMEK1 is a single-copy gene. AB - Mitogen-activated protein kinase (MAPK) cascade constitutes a conserved signaling module in eukaryotes. MAPK kinase (MAPKK) plays a crucial role in a MAPK cascade. ZmMEK1 is the first characterized MAPKK gene in maize. Although ZmMEK1 has been studied in detail in biochemical level, the genomic organization of ZmMEK1 gene is obscure. In this research, we clarified ZmMEK1 is a single-copy gene in the maize genome. Southern blot analysis using 3' specific region of ZmMEK1 cDNA as a probe revealed the presence of distinct single bands in each lane of EcoRI and HindIII. Although previous Southern blot analysis using full-length ZmMEK1 cDNA as a probe revealed several hybridizing bands, we showed here that all bands come from one genomic fragment corresponding to ZmMEK1 gene. Furthermore, ZmMEK1 was induced by PEG, abscisic acid (ABA), and salicylic acid (SA) and was down regulated by NaCl. PMID- 21691711 TI - Polymorphisms in chicken extracellular fatty acid binding protein gene. AB - In this study, we report the investigation of extracellular fatty acid binding protein gene (Ex-FABP) genetic polymorphism in a sample of 360 chicken individuals. The screening of the coding regions with their intron-exon boundaries and the proximal flanking regions was performed through a PCR-SSCP strategy. Following sequence analysis revealed 35 novel single nucleotide polymorphisms (SNPs) of chicken Ex-FABP gene. Among the 35 SNPs, twenty-five were found in the introns. And the remaining seven and three SNPs were in the coding region and the 5'UTR, respectively. Two SNPs in the coding region caused two missense mutants and the other five did not result in any amino acid changes. The nature and the distribution of Ex-FABP mutations in three chicken breeds were analyzed. Variations detected here might have an impact on Ex-FABP activity and function and underpin the development of gene markers for chicken fatty deposition and metabolism. The polymorphism, generated by C4715T mutation in exon5, was significantly associated with thickness of subcutaneous fat plus skin in cocks. Subcutaneous fat plus skin of cocks was more thick in TT genotype than in CC genotype (P < 0.05). The Ex-FABP gene could be a candidate locus or linked to a QTL that significantly affects fatty deposition and metabolism in chicken. PMID- 21691712 TI - Over-expression of Nkx2.5 and/or cardiac alpha-actin inhibit the contraction ability of ADSCs-derived cardiomyocytes. AB - Adipose tissue-derived stromal cells (ADSCs) can differentiate into cardiomyocytes, which provide a source of new cardiomyocyte progenitors for tissue engineering. Here, we showed that ADSCs isolated from subcutaneous adipose tissues of mouse were largely negative for CD31, CD34, but positive for CD105. About 1.62% cells in these cells can spontaneously differentiate into cardiac like cells (cells expressing cardiac marker proteins) when cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented only with penicillin, streptomycin, and 20% newborn bovine serum (NBS), expressed cardiac markers such as MF20, Connexin45, cMHC, cTnT, a-actin, Nkx2.5, and GATA4, and part of these cells (account for about 0.47% of inoculated cells) showed spontaneous contractions accompanied by transient Ca(2+) activity in culture. In vitro, although over expression of Nkx2.5 and/or cardiac alpha-actin increased the number of cardiac like cells expressing cardiac-specific proteins, but while inhibited the contraction function of ADSCs-derived cardiomyocytes. PMID- 21691713 TI - The mitochondrial aspartate/glutamate carrier AGC1 and calcium homeostasis: physiological links and abnormalities in autism. AB - Autism spectrum disorder (ASD) is a severe, complex neurodevelopmental disorder characterized by impairments in reciprocal social interaction and communication, and restricted and stereotyped patterns of interests and behaviors. Recent evidence has unveiled an important role for calcium (Ca(2+)) signaling in the pathogenesis of ASD. Post-mortem studies of autistic brains have pointed toward abnormalities in mitochondrial function as possible downstream consequences of altered Ca(2+) signaling, abnormal synapse formation, and dysreactive immunity. SLC25A12, an ASD susceptibility gene, encodes the Ca(2+)-regulated mitochondrial aspartate-glutamate carrier, isoform 1 (AGC1). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and adenosine triphosphate (ATP) production. Here, we review the physiological roles of AGC1, its links to calcium homeostasis, and its involvement in autism pathogenesis. PMID- 21691716 TI - Finite element analysis to compare stress distribution of connector of lithia disilicate-reinforced glass-ceramic and zirconia-based fixed partial denture. AB - This study used finite element method to analyze the stress distribution in connector of ceramic-based bilayer structures, in simulation of dental crown-like structures with a functional but weak veneer layer bonded onto a strong core layer. The purpose of this study was to evaluate the stress distribution at veneer/core interface of 2 different core materials [Yttria-stabilized tetragonal zirconia polycrystals (Y-TZP) and lithia disilicate-reinforced glass-ceramic] using three-dimensional finite element analysis. Within the limitations of this study, finite element analysis showed that stress concentrations were located at the veneer/core interface of the connector in Y-TZP core models. The general observation was that compared with Y-TZP, lithia disilicate-reinforced glass ceramic showed a relatively stable stress value and had a minor effect on the stress concentration susceptibility. PMID- 21691715 TI - The difference of fibroblast behavior on titanium substrata with different surface characteristics. AB - Connective tissue, one of the main components of peri-implant soft tissue, is key to the formation of the peri-implant mucosal seal and helping to prevent epithelial ingrowth. Rough surfaces (Rs), machined surfaces (Ms) or microgrooved surface (MG) are used in the neck area of commercially available titanium implants. In this paper, we aimed to evaluate the influence of surface topography of titanium substratum on connective tissue fibroblasts to gain a better understanding of this effect. Fibroblasts were cultured on titanium plates with Rs, Ms and MG. Adhesion cell number at day 3 was compared and protein distribution of both F-actin and vinculin was determined to observe cellular structure and adhesion. Cell adhesion strength was compared on each surface. At day 3, the number of fibroblasts attached on each substratum was in the order of MG ~ Ms > Rs. Fibroblasts strongly expressed vinculin in the peripheral area on Ms and MG, and showed strong F-actin architecture. Decreased expression of vinculin and weaker continuity of F-actin were observed on Rs. Fibroblasts on MG were aligned along the grooves, with a significantly higher cell density, whereas cells on Ms and Rs had no clear orientation. The cell adhesion strength was significantly lower on Rs, and no significant difference was seen between MG and Ms. Both MG and Ms showed greater adhesion cell numbers and adhesion strength of fibroblasts when compared with Rs at day 3. The cell density on MG was greater than those on other substrata. PMID- 21691717 TI - Protective effects of green tea against hepatic injury induced by high cholesterol diet in rats: histopathological analysis, oxidative DNA damage and COX-2 expression. AB - PURPOSE: The goal of this study was to investigate whether daily administration of green tea is able to protect the liver injury induced by cholesterol. METHODS: Male Wistar rats (n = 24) were distributed into four groups: group 1, negative control; group 2, cholesterol at 1% (w/w) in the diet treated for 5 weeks; group 3, cholesterol at 1% treated for 5 weeks and green tea at 1% (w/v) in drinking water in the last week only and group 4, cholesterol and green tea at 1% in drinking water for 5 weeks. RESULTS: The results pointed out that treatment with green tea in the last week (group 3) showed mild degenerative changes of liver tissue in cholesterol exposed group when compared to group 2. Green tea aqueous extract was not able to reduce cholesterol levels, that is, no significant statistical differences (p > 0.05) were noticed when compared to positive control group. Nevertheless, green tea was able to decrease oxidative deoxyribonucleic acid (DNA) damage either to peripheral blood or to liver cells as depicted by significant statistical differences (p < 0.05) in the mean tail moment between groups treated with green tea and cholesterol and cholesterol only. Furthermore, histomorphometric analysis of COX-2 expression revealed that in groups exposed to green tea they were significantly decreased (p < 0.05), regardless of time exposure adopted. CONCLUSION: Taken together, our results suggest that daily administration of green tea for at least 7 days displays some preventive properties as indicated by COX-2 downregulation and decreased oxidative DNA damage. PMID- 21691719 TI - Exploring the knowledge of nasopharyngeal carcinoma among medical doctors at primary health care level in Perak state, Malaysia. AB - Nasopharyngeal carcinoma (NPC) is among the commonest cancers in Malaysia. The prognosis for NPC like most other head and neck cancer is dependent on its staging. Majority of patients in Malaysia at the time of diagnosis are either at stage III or IV (27 and 47%, respectively). The lack of knowledge among primary care medical doctors regarding NPC may contribute to this delay in diagnosis. The aim of this study was to assess the knowledge of the primary care doctors in the state of Perak on the various aspects of NPC. The doctors at the primary care level in the state of Perak were recruited to take part in this study on a voluntary basis. A total number of 154 out of 198 doctors participated in this survey. They were given a questionnaire to fill in to test their knowledge on different aspects of NPC and its treatment. The overall respondents' score was poor with a score of 67.5% on all sections. The doctors appear to be able to identify common presenting features of NPC with a mean score of 85.3% but for the uncommon presentations of NPC, the scores were poorer with 61.8%. In addition, 54.1% of the participants answered that they would refer a patient with symptoms suspicious of NPC after a period of 1 month from the onset of symptom. However, only 34% would refer within 2 weeks. Based on the results of this study, the authors feel that it is clear that the doctors posted in the primary care hospitals and clinics appear to have inadequate knowledge to diagnose and refer patients with suspected NPC. As early diagnosis can often lead to a better prognostic outcome, steps must be taken to raise the awareness among these doctors. PMID- 21691720 TI - Pathologic evaluation of non-neoplastic renal parenchyma in partial nephrectomy specimens. AB - PURPOSE: This study aimed to identify non-neoplastic pathologic changes in partial nephrectomy specimens of patients without a known history of medical comorbidities. Routine analysis of this tissue may allow the clinician to identify subclinical renal disease. METHODS: We retrospectively reviewed our database of patients who underwent open partial nephrectomy for a small renal mass. Non-neoplastic tissue of partial nephrectomy specimens of patients without a known history of chronic kidney disease, diabetes mellitus, hypertension, or coronary artery disease was evaluated for glomerular, interstitial, and vascular pathologic changes. RESULTS: A rim of non-neoplastic tissue was adequate for pathologic evaluation in 91.8% of specimens. A total of 45 patients were studied with a median age of 52.0 years. Atherosclerosis was the most commonly identified pathologic finding in 9 (20%) patients, followed by mesangial expansion and interstitial fibrosis, each found in 8 (17.8%) patients. Linear regression found interstitial fibrosis to be the only pathologic lesion associated with preoperative serum creatinine (coefficient = 0.697, P = 0.001). Male gender was also associated with a higher preoperative creatinine (coefficient = 0.270, P = 0.034). Postoperative serum creatinine was not associated with any of the examined lesions. CONCLUSIONS: Current surgical techniques provide adequate non neoplastic tissue for pathologic evaluation. We observed a striking degree of pathologic disease in patients without a known history of medical comorbidities. Routine inspection of the non-neoplastic parenchyma of partial nephrectomy specimens should be performed as it can alert the clinician to presence subclinical renal disease allowing for medical intervention. PMID- 21691718 TI - Deconstructing the mechanisms and consequences of TGF-beta-induced EMT during cancer progression. AB - Transforming growth factor-beta (TGF-beta) is a potent pleiotropic cytokine that regulates mammalian development, differentiation, and homeostasis in essentially all cell types and tissues. TGF-beta normally exerts anticancer activities by prohibiting cell proliferation and by creating cell microenvironments that inhibit cell motility, invasion, and metastasis. However, accumulating evidence indicates that the process of tumorigenesis, particularly that associated with metastatic progression, confers TGF-beta with oncogenic activities, a functional switch known as the "TGF-beta paradox." The molecular determinants governing the TGF-beta paradox are complex and represent an intense area of investigation by researchers in academic and industrial settings. Recent findings link genetic and epigenetic events in mediating the acquisition of oncogenic activity by TGF-beta, as do aberrant alterations within tumor microenvironments. These events coalesce to enable TGF-beta to direct metastatic progression via the stimulation of epithelial-mesenchymal transition (EMT), which permits carcinoma cells to abandon polarized epithelial phenotypes in favor of apolar mesenchymal-like phenotypes. Attempts to deconstruct the EMT process induced by TGF-beta have identified numerous signaling molecules, transcription factors, and microRNAs operant in mediating the initiation and resolution of this complex transdifferentiation event. In addition to its ability to enhance carcinoma cell invasion and metastasis, EMT also endows transitioned cells with stem-like properties, including the acquisition of self-renewal and tumor-initiating capabilities coupled to chemoresistance. Here, we review recent findings that delineate the pathophysiological mechanisms whereby EMT stimulated by TGF-beta promotes metastatic progression and disease recurrence in human carcinomas. PMID- 21691721 TI - Nephrolithiasis during pregnancy: characteristics, complications, and pregnancy outcome. AB - PURPOSE: To evaluate obstetric complications and birth outcome in pregnant women with nephrolithiasis. METHODS: A retrospective population-based study comparing all pregnancies of women with and without nephrolithiasis between 1989 and 2010 was conducted. Clinical characteristics were compared, and the obstetric risk factors and labor complication were analyzed. Multivariable logistic regression models were constructed in order to identify independent risk factors for nephrolithiasis. RESULTS: During the study period, there were 219,656 deliveries, of which 195 women with nephrolithiasis were identified. Nephrolithiasis in pregnant women was significantly associated with recurrent abortions, mild preeclampsia, chronic hypertension, gestational diabetes mellitus, and cesarean deliveries. Nephrolithiasis was also significantly associated with urinary tract infections, pyelonephritis, hydronephrosis, and hydroureter. Nevertheless, no higher rates of premature rupture of membranes, preterm deliveries, or adverse perinatal outcomes (birth weight, Apgar scores or perinatal mortality) were noted in patients with nephrolithisais. Using a multiple logistic regression model, obesity (odds ratio 4.4, 95% confidence interval 2.1-9.0) and hypertensive disorders (odds ratio 2.8, 95% confidence interval 1.9-4.1) were independently associated with nephrolithiasis. CONCLUSION: Maternal kidney stones are significantly associated with several pregnancy complications, including recurrent abortions, hypertensive disorders, gestational diabetes, and cesarean deliveries. Nevertheless, it is not associated with adverse perinatal outcomes. These findings raise the question regarding the proper management of small asymptomatic kidney stone in a pregnant woman. PMID- 21691722 TI - Computerized transrectal ultrasound of the prostate in a multicenter setup (C TRUS-MS): detection of cancer after multiple negative systematic random and in primary biopsies. AB - OBJECTIVE: To improve prostate cancer diagnostic imaging, a computer-based analysis of the transrectal ultrasound signal (C-TRUS) was developed. Until recently, the C-TRUS existed only as a stand-alone device. Now, C-TRUS was developed into a network-compatible module (C-TRUS-MS). This new technology allows users to transmit C-TRUS images from any internet platform to C-TRUS-MS investigation. After analysis, the cancer-suspicious marked images are then retransmitted via internet. Targeted biopsies can then be taken at the urologists' office remotely. MATERIALS AND METHODS: This prospective study investigates whether the rates of prostate cancer detection with C-TRUS-MS "multicenter online" are comparable with those achieved by the stand-alone unit. In addition to patients with a history of multiple systematic random biopsies, a group of patients who had not undergone systematic random biopsies were analyzed. RESULTS: A total of 1,545 digital images (2-23 per patient, median 6) from 57 urologists were transmitted to the analysis center. After analysis, the color coded images were sent back electronically and utilized for a maximum of six targeted biopsies. C-TRUS-MS was able to detect prostate cancer in 91 patients. In addition, we evaluated 75 patients without any previous random biopsies. In this group, C-TRUS-MS was able to detect prostate cancer in 31 out of 75 patients (41%). CONCLUSION: The results indicate that C-TRUS-MS "online" achieves similar results as the stand-alone system, independent of the user even with little experience in the method. Furthermore, C-TRUS-MS for the first time is able to detect carcinomas in patients without prior biopsies in a high number by taking only six targeted biopsies. PMID- 21691723 TI - Vaccination with CD133(+) melanoma induces specific Th17 and Th1 cell-mediated antitumor reactivity against parental tumor. AB - Accumulating evidence suggests that cancer cells possess a small subpopulation that survives during potentially lethal stresses, including chemotherapy, radiation treatment, and molecular-targeting therapy. CD133 is a putative marker that distinguishes a minor subpopulation from normal differentiated tumor cells in many cancers. Although it is necessary to eradicate all cancer cells to obtain a cure, effective treatment to eliminate the CD133(+) treatment-tolerant cells has not been elucidated. In this study, we demonstrated that a CD133(+) subpopulation in murine melanoma is immunogenic and that effector T cells specific for the CD133(+) melanoma cells mediated potent antitumor reactivity, curing the mice of the parental melanoma. CD133(+) melanoma antigens preferentially induced type 17 T helper (Th17) cells and Th1 cells but not Th2 cells. CD133(+) melanoma cell-specific CD4(+) T-cell treatment eradicated not only CD133(+) tumor cells but also CD133(-) tumor cells while inducing long lasting accumulation of lymphocytes and dendritic cells with upregulated MHC class II in tumor tissues. Further, the treatment prevented regulatory T-cell induction. These results indicate that T-cell immunotherapy is a promising treatment option to eradicate CD133(+) drug-tolerant cells to obtain a cure for cancer. PMID- 21691724 TI - Poly(I:C)-induced tumour cell death leads to DC maturation and Th1 activation. AB - Dendritic cells (DCs) have the ability to generate peptide epitopes for MHC class I molecules derived from apoptotic tumour cells for direct recognition by cytotoxic T cells. This function has lead to DCs being used in vaccine strategies. In this study, we investigate the effect of inducing apoptosis in tumour cell lines using IFN-gamma and poly(I:C), the subsequent maturation of the endocytosing DC and its ability to direct the resulting T cell response. We show that uptake of poly(I:C)-induced apoptotic tumour cells leads to DC maturation and activation with a Th1 cell polarising capacity. In contrast, these effects are not seen by DCs loaded with gamma-irradiated apoptotic tumour cells. We propose that the manner in which tumour cells are induced to die can have a profound effect on the endocytosing DC and the resulting T cell response. PMID- 21691725 TI - Fragment of pubis through the urinary bladder wall causing urinary bladder calculus. AB - Bladder calculi can result from various types of foreign bodies. A number of intra-vesical foreign bodies have been described in the literature. However, there is no report on the bladder calculi resulting from the fracture of pubis; we present one unique case of bladder calculus caused by the fracture of pubis for 10 years that was succeeded by successive surgical procedures. PMID- 21691726 TI - Efficacy of clove solution on blood sampling and hematological study in Beluga, Huso huso (L.). AB - Two experiments were conducted to evaluate the efficacy of clove solution on anesthesia and hematological parameters in Beluga, Huso huso (L.). In the experiment 1, fish were exposed to concentrations of 300, 500, 700, 1,800 and 3,000 ppm clove solution and induction (stage 3 and 4) as well as recovery period lengths were recorded. These concentrations were led to induction and recovery time between 42-365 and 125-235 s, respectively, in dose-dependent manner. There was negative correlation between induction and recovery time (R(2) = 0.92). In the experiment 2, fish were exposed to each aforementioned concentrations and let to reach stage 4 anesthesia and then blood-sampled. Control group was sampled without anesthesia. Hematological studies between groups showed no significant changes in white blood cell (WBC) and differential leukocyte count (P > 0.05). Hematocrit (Hct), hemoglobin (Hb), red blood cell (RBC) and mean corpuscular hemoglobin concentration levels were significantly high in concentrations of 300 700 ppm compared to control, 1,800 and 3,000 ppm. Control and 500-3,000 ppm groups have similar mean corpuscular volume values and significantly higher than 300 ppm. Lower values of mean corpuscular hemoglobin were related to control, 3,000 and 1,800 ppm and higher values were observed in the others. Strong positive correlation were observed between induction periods and Hct, Hb and RBC levels (R(2) = 0.095, 0.99 and 0.92, respectively). Results suggested that anesthesia with low concentrations of clove solution over a long period is stressful compared to high concentrations over short period. PMID- 21691727 TI - Assessment of tissue-specific effect of cadmium on antioxidant defense system and lipid peroxidation in freshwater murrel, Channa punctatus. AB - The effects of different concentrations of cadmium chloride on the extent of lipid peroxidation (LPO) and alterations in the antioxidant enzyme activities were studied in liver, kidney and gill tissues of freshwater murrel, Channa punctatus. The fish specimens were exposed to 6.7, 13.4 and 20.1 mg l(-1) sublethal concentrations of cadmium chloride and the oxidative stress was assessed after 24, 48, 72 and 96 h post-exposure. The biomarkers selected for the study were thiobarbituric acid reactive substances for assessing the extent of lipid peroxidation and antioxidant defense system such as reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GP(X)), glutathione-S transferase (GST), catalase (CAT) and superoxide dismutase (SOD) activities. In general, the cadmium exposure elevated the LPO in subject tissues of treated group and modulated the activities of GPx, GST, SOD, CAT, GR and level of GSH after given exposure as compared to the control. All enzymes activities, except CAT (in kidney and gills), and amount of LPO elevated significantly (P < 0.05) in treated group with respect to control in all tissues, while significant difference was not observed between the exposed concentrations and within exposure duration. The results indicated that increase in LPO level and the fluctuation in antioxidant defense system in fish could be due to cadmium-induced increase in the production of reactive oxygen species (ROS). The potential role of these parameters as biomarkers of heavy metal pollution in aquatic system is discussed. PMID- 21691728 TI - The clinical importance of bone metabolic markers in detecting bone metastasis of lung cancer. AB - AIM: The aim of this study was to evaluate the role of bone metabolic markers in clinical evaluation of bone metastasis of lung cancer. MATERIALS AND METHODS: Sixty-five male patients with lung cancer were included in this trial, 77% of whom were diagnosed as having non-small cell lung cancer and 20% were small cell lung cancer. The presence of bone metastasis was investigated by whole-body bone scintigraphy via Tc-99m mostly (80%) and, in some cases, PET/CT (positron emission tomography and computerized tomography) which was performed for staging. Bone-specific alkaline phosphatase (BALP) and osteocalcin were measured in serum of the patients as markers of bone formation. N-terminal telopeptide (NTX) and beta-form of C terminal telopeptide (beta-CTX) were studied as bone destruction markers. RESULTS: The cases were divided into two groups according to the presence of bone metastasis. Twenty-three patients (35%) had bone metastasis. Serum levels of total ALP, BALP and NTX were significantly higher in the group with bone metastasis (p < 0.05). Osteocalcin and beta-CTX levels were not significantly different between two groups. According to ROC-curve analysis, at the threshold value of 22.38 MUg/L, the sensitivity of BALP was 60.87% and the specificity was 69.05%. Similarly, at the threshold value of 25.69 nmol BCE, the sensitivity of NTX was 90.24% and the specificity was 43.4%. CONCLUSION: Bone metabolic markers are considered noninvasive, useful and cost-effective. However, more prospective studies are needed in order to use them for evaluation of bone metastasis in lung cancer. PMID- 21691729 TI - Detection methods of ZAP-70 in chronic lymphocytic leukemia. AB - The clinical course of patients with chronic lymphocytic leukemia (CLL) is highly heterogeneous, with some patients experiencing rapid disease progression and others living for decades without requiring treatment. Immunoglobulin heavy chain variable region (IGHV) mutation status is a powerful prognostic factor in patients with CLL. The presence or absence of IGHV mutation status is currently the gold-standard prognostic factor, but this technique is labor-intensive and costly. The expression of zeta-chain-associated protein kinase 70 kDa (ZAP-70), detected by flow cytometry, has been served as a potential surrogate for the absence of IGHV mutation status since 2003. Given the current problems with the standardization of ZAP-70 assessment by flow cytometry, this chapter reviews the analysis of ZAP-70 expression by flow cytometry and the relative experimental conditions using the associated publications for "ZAP-70" and "detection method" on Medline since 2003. Thus, mean fluorescence intensity (MFI) ratio method yielded a more reproducible and easily adaptable method to routine use in the clinical diagnostic laboratory. In conclusion, though ZAP-70 is a valuable prognostic factor in CLL, detection methods of ZAP-70 remain to be fully standardized. PMID- 21691730 TI - Psychiatric symptoms screening in the early stages of Parkinson's disease. AB - Psychiatric complaints are common in Parkinson's disease (PD), and have a significant influence in disease outcome and quality of life. Little attention has been paid to psychiatric symptoms at early stage disease. We aimed to screen a population of early stage PD patients for psychiatric symptoms and to study the relation with motor and cognitive function. Thirty-six early stage PD patients underwent motor [Hoehn and Yahr (HY), Unified Parkinson's Disease Rating Scale] and cognitive [Frontal Assessment Battery, Mini-Mental State Examination (MMSE)] assessment as well as general psychiatric [Symptom Check-List 90 (SCL-90-R)] and psychosis [Brief Psychiatric Rating Scale (BPRS)] screening. Relation between psychiatric domains scores was studied with principal component analysis. Relation between psychiatric, disease related, cognitive and motor function was assessed with bivariate correlation (Pearson). SCL-90-R scores were higher for somatization (significant scores in 66.7% of patients), depression (36.1%), anxiety (27%) and obsessive-compulsive symptoms (OCS) (52.8%). Scores were highly correlated, except for psychosis and phobia. Depression and anxiety were negatively correlated to MMSE score and dopaminergic doses, respectively. BPRS scores were higher for somatic concern, depression, anxiety and hallucinations. There was segregation between depression, anxiety, hallucinations, other positive psychotic symptoms and negative psychotic symptoms. Depression was related to MMSE score. We found a high prevalence of psychiatric complaints in PD patients, mostly related to depression, anxiety, somatization and OCS. Hallucinations were also frequent, but not associated to cognitive function or dopaminergic doses, suggesting a different physiopathological background. PMID- 21691731 TI - Acute myocardial infarction and heart failure in acute stroke patients: frequency and influence on clinical outcome. AB - In patients admitted for acute stroke, the clinical burden of acute myocardial infarction (AMI) and acute heart failure (AHF) is unclear. In these patients we evaluated: (1) the prevalence of AMI and AHF; (2) the effect of AMI and/or AHF on mortality at 3 months; (3) the risk factors for AMI and/or AHF. Consecutive patients admitted for acute stroke were prospectively assessed for the occurrence of AMI and AHF during the hospital stay. Mortality at 3 months was also assessed. Multiple logistic regression analysis was used to identify independent predictors for cardiovascular events and death. Eight hundred fourteen patients were included in the study, 685 of which had an ischemic stroke (84.2%). Fifty-three patients (6.5%) had an AMI and/or an AHF (13 AMI alone, 28 AHF alone and 12 AMI and AHF); all these events occurred in patients with ischemic stroke. At 3 months, 151 patients had died (18.8%). Among patients who had an AMI and/or AHF, 60.4% died as compared with 119 of the 750 patients who did not have these events (15.9%) (p < 0.0001). At logistic regression analysis, AMI and/or AHF were associated with increased mortality at 3 months (p = 0.001). History of angina (p = 0.003), AMI in the 3 months before admission (p < 0.0001), hyperglycemia (p = 0.047), and high NIHSS on admission (p < 0.0001) were associated with in hospital AMI and/or AHF. In acute stroke patients, AMI and AHF are common and associated with increased mortality at 3 months. Whether a timely and more careful management of these complications may improve clinical outcome should be further explored. PMID- 21691732 TI - Maternal exposure to household chemicals and risk of infant leukemia: a report from the Children's Oncology Group. AB - OBJECTIVE: Utilizing data from the largest study to date, we examined associations between maternal preconception/prenatal exposure to household chemicals and infant acute leukemia. METHODS: We present data from a Children's Oncology Group case-control study of 443 infants (<1 year of age) diagnosed with acute leukemia [including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)] between 1996 and 2006 and 324 population controls. Mothers recalled household chemical use 1 month before and throughout pregnancy. We used unconditional logistic regression adjusted for birth year, maternal age, and race/ethnicity to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We did not find evidence for an association between infant leukemia and eight of nine chemical categories. However, exposure to petroleum products during pregnancy was associated with AML (OR = 2.54; 95% CI:1.40-4.62) and leukemia without mixed lineage leukemia (MLL) gene rearrangements ("MLL-") (OR = 2.69; 95% CI: 1.47-4.93). No associations were observed for exposure in the month before pregnancy. CONCLUSIONS: Gestational exposure to petroleum products was associated with infant leukemia, particularly AML, and MLL- cases. Benzene is implicated as a potential carcinogen within this exposure category, but a clear biological mechanism has yet to be elucidated. PMID- 21691733 TI - Expression of stem cell marker and receptor kinase genes in glioblastoma tissue quantified by real-time RT-PCR. AB - Glioblastoma is dependent on a specific signaling pathway to maintain its tumor phenotype. The receptor tyrosine kinase (RTK) family mediates the multiple oncogenic growth factor receptor signaling and contributes to the pathogenesis of glioblastoma. Recently, many studies have shown that the expression of stem cell marker in glioblastoma tissue has prognostic significance, which indicates that the quantification of stem cell markers and RTK genes yields biological information about glioblastoma. In this study, we quantified RNA expression levels of stem cell markers [CD133, Nestin, BMI-1, maternal embryonic leucine zipper kinase (MELK), and Notch1-4] as well as RTKs (EGFR, ErbB4, VEGFR1-3, FGFR1, -2, PDGFRAlpha, and PDGFRBeta) in 42 clinical samples of glioblastoma by the real-time RT-PCR method. We demonstrated that the expression of MELK is exclusively upregulated in glioblastoma tissue. Notch receptor expression is moderately upregulated and is correlated with that of VEGFR2, VEGFR3, and PDGFRbeta. Unsupervised clustering identified one unique sample group that showed high expression of most of the genes analyzed. Our results suggest that quantification of these stem cell markers and RTK genes can stratify patients based on the expression profile, which might provide insight into the glioma biology in each cluster. PMID- 21691734 TI - The effect of open Bristow-Latarjet procedure for anterior shoulder instability: a 10-year study. AB - Operative procedures are the usual treatment for patients with anterior traumatic shoulder instabilities. Soft tissue procedures, Bankart repair, cannot be performed in some patients. They need Bristow-Latarjet one. We decided to determine midterm results of this procedure in almost all types of anterior shoulder instability, even shoulders with Bankart lesion in non-athletic cases. Thirty patients after Bristow-Latarjet procedure from 1997 to 2007 were followed 2-8 years. Clinical outcomes, consisted of muscle strength, range of motion (mean 8.66 degrees decreased in external rotation with arm in neutral position and 18.33 with arm in 90 degrees of abduction), recurrent instability (no relapse), and Rowe score (mean 77.66) showed good to excellent results. We had no screw related or neurovascular complications. Thirty percent of cases had signs of mild arthropathy. Although Bankart procedure is the preferred method in patients with isolated Bankart lesion, but we can perform Bristow-Latarjet for all types of anterior traumatic shoulder instability in non-athletics cases with acceptable results. PMID- 21691735 TI - Human dermal matrix scaffold augmentation for large and massive rotator cuff repairs: preliminary clinical and MRI results at 1-year follow-up. AB - The high incidence of recurrent tendon tears after repair of massive cuff lesions is prompting the research of materials aimed at mechanically or biologically reinforcing the tendon. Among the materials studied upto now, the extracellular matrix (ECM) scaffolds of human origin have proved to be the safest and most efficient, but the current laws about grafts and transplants preclude their use in Europe. In order to overcome this condition in 2006, we started a project regarding the production of an ECM scaffold of human origin which could be implanted in Europe too. In 2009, the clinical study began with the implantation of dermal matrix scaffolds in 7 middle-aged patients affected with large/massive cuff lesions and tendon degeneration. Out of 5 cases, followed for at least 1 year in which the scaffold was employed as an augmentation device, there were 3 patients with complete healing, 1 partial re-tear, and 1 total recurrence. The absence of adverse inflammatory or septic complications allows to continue this line of research with a prospective controlled study in order to define the real advantages and correct indications offered by scaffold application. PMID- 21691736 TI - Laparoscopic versus open inguinal hernia repair in octogenarians. AB - PURPOSE: This retrospective chart review was designed to compare outcomes for open and laparoscopic repair of inguinal hernias in the population over the age of 80. METHODS: A retrospective chart review was conducted for 104 patients over 80 years old who underwent inguinal hernia repair (2005-2008) at The Mount Sinai Medical Center. Patients were grouped into laparoscopic or open repair cohorts and compared accordingly. RESULTS: The open group (n = 73) and the laparoscopic group (n = 31) had mean ages of 84 and 83 years, respectively. The mean American Society of Anesthesiologists score was 2.6 for the open cohort and 2.3 for the laparoscopic group (P < 0.05). Peri-operative complications in the open and laparoscopic groups were not found to be statistically significant. There was no mortality in either group. CONCLUSIONS: With octogenarians, laparoscopic inguinal hernia repair can be performed as a safe alternative to open repair with comparable rates of morbidity and mortality. PMID- 21691737 TI - Laparoscopic repair of extraction site ventral hernia after robotic prostatectomy: institutional experience with 42 consecutive cases. AB - INTRODUCTION: Robotic-assisted laparoscopic prostatectomy (RALP) has become one of the most common laparoscopic procedures in the United States, with over 80,000 cases performed yearly. There is increasing awareness that extraction site ventral hernias (ESVH) are an important cause of morbidity after laparoscopic resective surgery. However, there is no data in the literature concerning ESVH after RALP. The purpose of this study is to report our experience with this novel ESVH and our results with its laparoscopic (LAP) repair. METHODS: The charts of all patients subjected to LAP VH repair at the City of Hope National Medical Center between 2005 and 2009 were retrospectively reviewed. Only patients undergoing LAP ESVH after RALP were included in the study. Relevant data analyzed included patient demographics, operative parameters, complications, and recurrence. RESULTS: A total of 42 consecutive male patients were identified, with a median age of 65 years (range 46-81). The median time from RALP to ESVH repair was 10 months (range 1-43). All hernias were periumbilical and all were symptomatic. A laparoscopic left lateral approach was used in all cases. The median operative time was 91 min (range 61-162). The median defect area was 64 cm(2) (range 4-176), which was repaired with polytetrafluoroethylene (PTFE) (18 cases) or Marlex composite mesh (24 cases) with a 5-cm overlap. The estimated blood loss (EBL) was minimal in all cases. The median hospital stay was 1 day (range 0-4). Minor complications occurred in 14% of cases. There was no mortality and the recurrence rate was 0%. CONCLUSIONS: ESVH after RALP are likely to become a common cause of abdominal wall morbidity in the near future. A laparoscopic repair is safe and effective. Prospective studies are needed in order to further investigate ESVH and ways to reduce its incidence. PMID- 21691739 TI - Reliability, validity, and responsiveness of the Japanese version of the Neck Pain and Disability Scale. AB - BACKGROUND: Until recently, no Japanese versions have existed of the more popular, patient-reported disability questionnaires for neck pain. This study aimed to test the reliability, validity, and responsiveness of the Japanese version of the Neck Pain and Disability Scale (NPDS), one of the most widely used questionnaires in patients with neck pain. METHODS: In this validation study, 167 outpatients with neck pain participated. Patients received the NPDS and the Medical Outcome Study Short Form 36-item Health Survey (SF-36), and used Visual Analog Scales (VASs) to assess pain and global health. To examine test-retest reliability, patients who were considered stable by clinicians were given the NPDS 2 weeks after baseline. To examine responsiveness, patients who had not undergone treatment at the time of the first data collection or had no change in treatment over 3 months were studied again 2 weeks after starting a new medication or physical therapy. RESULTS: Of the 167 participants, 143 completed the questionnaires (85.6%). Factor analysis showed two factors, defined as neck pain-related disability (factor 1) and neck-related pain (factor 2). Cronbach's alpha coefficient for factor 1, factor 2, and total score was 0.94, 0.93, and 0.96. The intra-class correlation coefficients for the 19 more stable patients were 0.79, 0.88, and 0.87. For concurrent validity, the correlation between NPDS subscales and total score and SF-36 subscale scores ranged from r = -0.54 to 0.22 (p < 0.01). Correlations between the NPDS subscales and total score and VAS of pain ranged from 0.56 to 0.77 (p < 0.01) and those for VAS of global health ranged from 0.48 to 0.63 (p < 0.01). The NPDS subscales and total scores of the 41 patients retested after treatment were significantly improved. CONCLUSIONS: The Japanese version of the NPDS is a useful scale with reliability, validity, and responsiveness in assessing patients suffering from neck pain. PMID- 21691738 TI - Peritonitis is still an important factor for withdrawal from peritoneal dialysis therapy in the Tokai area of Japan. AB - BACKGROUND: In Japan, the population of patients on peritoneal dialysis (PD) is <4% of the total number of patients with end-stage renal disease. Few systemic analyses have examined why the number of PD patients has not increased in Japan. We organized a registry to analyze PD patients and retrospectively investigated 561 PD patients (about 5% of all Japanese PD patients) from 13 hospitals in the Tokai area for 3 years from 2005. METHODS: We investigated background, physical status, laboratory data, status of PD therapy, and the occurrence of PD-related complications, and analyzed reasons for withdrawal from PD. RESULTS: Nutrition did not change significantly during our observation. Urinary volume showed continued decreases after the introduction period. In contrast, PD fluid demand and ultrafiltration volume were significantly increased. For calcium metabolism, multiple phosphate binders were required after the second year of PD therapy. Early drop-out within 3 years after starting PD therapy comprised 50.9% of total withdrawals, with PD-related peritonitis as the most common reason, mainly caused by Gram-positive organisms. Incidence of peritonitis was 42.8 months/patient. Culture-negative results were obtained for 32% of peritonitis cultures. Diabetes affects the prognosis of PD therapy, but not the incidence of peritonitis. CONCLUSION: We examined clinical status over 3 years in the Tokai area. The results suggest that the incidence of peritonitis needs to be decreased to prevent early withdrawal of PD patients. Education systems to decrease the incidence of peritonitis and techniques to decrease culture-negative results might be important for improving the prognosis of peritonitis. PMID- 21691740 TI - Insights on PRAME and osteosarcoma by means of gene expression profiling. AB - BACKGROUND: Osteosarcoma (OS) is the most frequent bone tumor in children and adolescents. Tumor antigens are encoded by genes that are expressed in many types of solid tumors but are silent in normal tissues, with the exception of placenta and male germ-line cells. It has been proposed that antigen tumors are potential tumor markers. OBJECTIVES: The premise of this study is that the identification of novel OS-associated transcripts will lead to a better understanding of the events involved in OS pathogenesis and biology. METHODS: We analyzed the expression of a panel of seven tumor antigens in OS samples to identify possible tumor markers. After selecting the tumor antigen expressed in most samples of the panel, gene expression profiling was used to identify osteosarcoma-associated molecular alterations. A microarray was employed because of its ability to accurately produce comprehensive expression profiles. RESULTS: PRAME was identified as the tumor antigen expressed in most OS samples; it was detected in 68% of the cases. Microarray results showed differences in expression for genes functioning in cell signaling and adhesion as well as extracellular matrix related genes, implying that such tumors could indeed differ in regard to distinct patterns of tumorigenesis. CONCLUSIONS: The hypothesis inferred in this study was gathered mostly from available data concerning other kinds of tumors. There is circumstantial evidence that PRAME expression might be related to distinct patterns of tumorigenesis. Further investigation is needed to validate the differential expression of genes belonging to tumorigenesis-related pathways in PRAME-positive and PRAME-negative tumors. PMID- 21691741 TI - Assessment of simple marker-free genetic transformation techniques in alfalfa. AB - Methods to avoid the presence of selectable marker genes (SMG) in transgenic plants are available but not implemented in many crop species. We assessed the efficiency of simple marker-free Agrobacterium-mediated transformation techniques in alfalfa: regeneration without selection, or marker-less, and co-transformation with two vectors, one containing the SMG and one containing a non-selected gene. To easily estimate the efficiency of marker-less transformation, the nptII and the GUS markers were used as non-selected genes. After Agrobacterium treatment, somatic embryos were regenerated without selection. The percentage of transgenic embryos was determined by a second cycle of regeneration using the embryos as starting material, in the presence of kanamycin, by PCR screening of T1 progenies, and by the GUS test. In two experiments, from 0 to 1.7% of the somatic embryos were transgenic. Co-transformation was performed with two vectors, one with the hemL SMG and one with the unselected nptII gene, each carried by a different culture of Agrobacterium. Only 15 putative co-transformed plants were regenerated from two experiments, with an average co-transformation percentage of 3.7. Southern blot hybridizations and/or T(1) progeny segregation were used to confirm transgene integration, and qPCR was also used to estimate the T-DNA copy number. In the T(1) progenies obtained by crossing with a non-transgenic pollinator, marker-free segregants were obtained. Both marker-free approaches showed very low efficiency. PMID- 21691742 TI - Bilirubin levels in patients with systemic lupus erythematosus: increased or decreased? AB - The aim of this study was to investigate the serum bilirubin levels in SLE patients and their associations with clinical and laboratory characteristics of SLE. There were 198 SLE patients in this study, of whom 7 cases with tobacco smoking or alcohol intake were excluded. Some clinical and laboratory characteristics of the patients were obtained by medical record review. In addition, 154 age- and sex- matched healthy volunteers with no histories of SLE, liver diseases, and other autoimmune or inflammatory diseases were randomly recruited into this study. The serum bilirubin levels were lower in SLE patients without liver diseases than in healthy controls (P = 0.000). Univariate logistic analysis demonstrated that hypertension, lupus renal involvement, positive anti dsDNA antibody, C3, C4, hsCRP, and albumin remained as impact factors of total bilirubins; lupus renal involvement, ESR, IgG, globulin, and ALT, as impact factors of direct bilirubins; and lupus renal involvement, positive anti-dsDNA antibody, C3, C4, hsCRP, and albumin, as impact factors of indirect bilirubins. However, multivariate logistic analysis showed that only hsCRP remained as an independent positive impact factor of total bilirubins, lupus renal involvement as an independent negative impact factor of direct bilirubins, and hsCRP and albumin as independent positive impact factors of indirect bilirubins. In conclusion, serum bilirubin levels are decreased in SLE and the decreased bilirubin levels could be associated with inflammatory process and lupus renal involvement of SLE. PMID- 21691743 TI - Cyclophosphamide for scleroderma lung disease: a systematic review and meta analysis. AB - To assess the effectiveness of cyclophosphamide in the management of scleroderma related interstitial lung disease (ILD). In this systematic review study, the primary outcome measures were change in forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (D(L)CO) of the patients after 6 and 12 months. To assess the effect of cyclophosphamide on early stage of ILD, alveolitis, in SSc patients, we selected the studies that used the BAL findings or HRCT or recent deterioration of PFT with minimal chest X-ray finding in early stage of disease as diagnosis of alveolitis. A sensitive systematic search strategy was used to find all relevant studies. Finally, 17 trials were included in the analysis that was performed using STATA. (Version 8) and Review Manager (version 4.1; MetaView version 4.1) softwares. Results from 10 studies were pooled for the outcome variable of FVC after 12 months. The summary WMD (random effects) was 2.45 (95% CI, 0.760-4.149 P = 0.005), which means that cyclophosphamide was able to prevent deterioration of FVC after 12 months. In pooled data of 13 studies, about DLCO after 12 months WMD (random effects) was 2.003 2.96 (95% CI, -0.228 to 6.159 P = 0.069), which means that cyclophosphamide was not able to prevent deterioration of D(L)CO after 12 months. If we considered clinically sensible improvement as absolute value >=10% in DLCO and VC, then result of treatment with cyclophosphamide treatment in scleroderma patients with ILD was not significant. PMID- 21691744 TI - Methotrexate attenuates the Th17/IL-17 levels in peripheral blood mononuclear cells from healthy individuals and RA patients. AB - To investigate whether the inhibition of Th17/interleukin (IL)-17 contributes to the beneficial effects of methotrexate (MTX) in the treatment of rheumatoid arthritis (RA). Peripheral blood mononuclear cells (PBMCs) from healthy donors and RA patients were collected. The cells were stimulated with monoclonal antibodies to CD3 and CD28 in the absence or presence of MTX. After coincubation, IL-17 production was detected at both the mRNA and protein levels, and the percentage of cells positive for both CD4 and IL-17 in PBMCs was analyzed by flow cytometry. PBMCs of healthy donors and RA patients were stimulated with CD3 and CD28 monoclonal antibodies to produce high levels of IL-17. The augmentation of IL-17 at the mRNA and protein levels was significantly inhibited when PBMC cultures were preincubated with MTX. Compared with PBMCs of healthy donors, PBMCs of RA patients produced higher levels of IL-17, and this increase in IL-17 levels was more inhibited by MTX pretreatment. MTX inhibited IL-17 at the mRNA level in a dose-dependent manner, but not at the protein level, in both PBMCs of healthy donors and RA patients. MTX did not affect the percentage of CD4- and IL-17 positive cells in PBMCs. MTX dose dependently suppressed the production of IL-17 at the mRNA level by PBMCs from healthy donors and RA patients. Suppression of IL 17 by MTX may contribute to its potent anti-inflammatory role in RA therapy. PMID- 21691745 TI - Phase II study of combined belotecan and cisplatin as first-line chemotherapy in patients with extensive disease of small cell lung cancer. AB - PURPOSE: To determine the efficacy and safety of belotecan in combination with cisplatin as first-line chemotherapy for extensive disease of small cell lung cancer (ED SCLC). METHODS: Patients with chemotherapy-naive ED SCLC were eligible if the following criteria were met: age >=18 years; a measurable lesion; Eastern Cooperative Oncology Group Performance Status (PS) 0-2; and adequate organ function. Each cycle consisted of belotecan (0.5 mg/m(2)/day) on days 1-4 and cisplatin (60 mg/m(2)) intravenously on day 1. The cycle was repeated every 3 weeks until the completion of the 6th cycle, disease progression, or intolerable toxicity. RESULTS: Thirty-five patients (median age, 68 years) were enrolled: 32 males (91.4%); and PS = 0 (n = 3), PS = 1 (n = 18), and PS = 2 (n = 14). The median number of cycles delivered was 5 (range, 1-6). The relative dose intensity was 70.1% for belotecan and 83.0% for cisplatin. Of 30 evaluable patients, objective response rate was 71.4% (95% confidence interval [CI], 55.7-87.2) by the intent-to-treat principle. The median duration of follow-up was 14.3 months. The median progression-free survival was 5.7 months (95% CI, 3.9-7.5) and the median overall survival was 10.2 months (95% CI, 9.3-11.1). The frequently reported grade 3 or 4 toxicities included neutropenia in 24 patients (68.6%), thrombocytopenia in 10 (28.6%), and anemia in 7 (20.0%). There was no grade 3 or 4 non-hematologic toxicity except three patients (8.6%) with fatigue. CONCLUSIONS: Belotecan and cisplatin combination therapy showed significant efficacy in ED SCLC with improved non-hematologic toxicities. PMID- 21691746 TI - A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects. AB - PURPOSE: Bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor, is in clinical development for the treatment of patients with chronic myelogenous leukemia (CML). To support clinical development, we conducted a dose-escalation and food-effect evaluation of safety, tolerability, and pharmacokinetics (PK) of bosutinib in healthy adults. METHODS: This was a randomized, double-blind, placebo-controlled, single-ascending dose, sequential-group study of oral bosutinib. Subjects randomly received bosutinib 200, 400, 600, and 800 mg with food; 200 and 400 mg without food; or placebo. Plasma concentrations were determined by a liquid chromatography-tandem mass spectrometry assay. Non compartmental PK analyses were performed, and power models assessed dose linearity. RESULTS: Of 55 enrolled subjects, 33 (81%) subjects had adverse events (AEs) after receiving bosutinib. Common AEs included diarrhea (39%), nausea (29%), and headache (22%). Bosutinib 200-600 mg with food was safe and well tolerated. Bosutinib exposures (C (max) and AUC) were linear and dose proportional from 200 to 800 mg with food. Absorption was relatively slow; median time to C (max) was 6 h. Apparent volume of distribution (V (z)/F) was 131-214 L/kg, mean apparent clearance (CL/F) was 2.25-3.81 L/h/kg, and mean terminal elimination half-life (t (1/2)) was 32-39 h. Preliminary food effect assessment showed that exposure to bosutinib increased by ~2.52-fold (P = 0.002) for C (max) and ~2.28-fold (P = 0.002) for AUC when 200 mg bosutinib was administered with food compared with administration under fasting conditions; administration of 400 mg bosutinib with food increased AUC by ~1.5-fold (P = 0.037). Approximately 1% of administered dose was excreted in urine. CONCLUSIONS: Bosutinib 200-600 mg with food was safe and well tolerated. Under fed conditions, bosutinib exposures were linear and dose proportional, and C (max) increased by ~1.5-fold. The t (1/2) supported a once-daily dosing regimen. PMID- 21691747 TI - DHEA and estradiol levels in brain, gonads, adrenal glands, and plasma of developing male and female European starlings. AB - Traditionally, sexual differentiation of the brain was thought to be driven by gonadal hormones, particularly testosterone (T). However, recent studies in songbirds suggest that other steroids may also be important. For example, dehydroepiandrosterone (DHEA) can be synthesized by the gonads, adrenal glands, and/or brain and locally metabolized into T and 17beta-estradiol (E(2)). Here, we examined DHEA and E(2) levels in the brain, peripheral tissues, and plasma of wild European starlings (Sturnus vulgaris). In Study 1, samples were collected from males and females at P0 (day of hatch), P6, and P8. In Study 2, samples were collected at P4. At P0, DHEA levels in the diencephalon were higher in males than females. DHEA levels were generally high in the gonads and adrenals, and they were higher in testes than ovaries at P8. Further, E(2) levels were non detectable in most brain samples, suggesting that DHEA was not metabolized to E(2) or that locally produced E(2) was rapidly inactivated. At P4, DHEA levels in telencephalic regions were lower in males than females. Taken together, these data suggest that sex differences in peripheral DHEA secretion and neural DHEA metabolism at specific ages during development might play a role in sexual differentiation of the songbird brain. PMID- 21691748 TI - Type 1 diabetes mellitus and celiac disease: endothelial dysfunction. AB - Many reports indicate a hypercoagulative state in diabetes mellitus as result of endothelial damage. Experimental evidence suggests that a metabolic derangement triggers a cascade of biochemical events that lead to vascular dysfunction. The net effect is to convert the endothelium from thromboresistant to thrombogenic surface. In literature, a strong association between type 1 diabetes mellitus (DM1) and celiac disease (CD) has been reported. We do not have information about the hemostatic system in these associated conditions. Our study aims at evaluating whether the presence of CD in a group of DM1 patients is associated with a different expression of some hemostatic factors and with a different manifestation and/or progression of microvascular complications of DM1 in comparison with patients with only diabetes. Ninety-four adult DM1 patients were enrolled in the study and subsequently screened for CD. Anti-endomysial antibodies (EMA) were positive in 13 of 94 DM1 patients (13.8%). CD diagnosis was confirmed by histology and organ culture. The mean age and duration of DM1 of patients also affected by CD were similar to those of only diabetic patients, but the metabolic control and the hemocoagulative parameters were significantly different between the two groups: DM1 patients also affected by CD presented significantly lower concentrations of glycosylated hemoglobin (HbA1c) (P < 0.05), cholesterol (P < 0.001), triglycerides (P < 0.001), factor VII antigen (FVII:ag) (P < 0.005), factor VII coagulant activity (FVII:c) (P < 0.05), and prothrombin degradation fragments (F1+2) (P < 0.001), as well as higher values of activated C protein (APC) (<0.001). No retinal abnormalities and no signs of renal damage were observed in DM1 patients also affected by CD. Our results suggest a potential protective role of CD in the prothrombotic state of DM1. PMID- 21691749 TI - Elevated expression of USP22 in correlation with poor prognosis in patients with invasive breast cancer. AB - PURPOSE: Ubiquitin-specific protease 22 (USP22), a novel deubiquitinating enzyme, has been associated with metastasis, therapy resistance, and cell-cycle progression. The purpose of this study was to investigate the expression level of USP22 in breast samples and to evaluate its clinical significance in breast cancer patients. METHODS: Immunohistochemistry was used to determine the expression of USP22 protein in 31 breast fibroadenoma and 100 breast cancer patients in comparison with 34 normal breast specimens. Furthermore, we analyzed the correlation between the expression of the USP22 protein and various clinicopathologic factors including survival status of patients with breast cancer. RESULTS: The immunohistochemistry results showed that the expression level of USP22 protein in breast cancer samples was significantly higher than that in breast fibroadenoma and normal breast tissues (P = 0.003 and P = 0.021). Moreover, statistical analysis showed that high USP22 expression was positively related to lymph node metastasis, Her-2, Ki67, and recurrence. Furthermore, it was shown that patients with high USP22 expression had significantly poorer outcome compared with patients with low expression of USP22 for patients with positive lymph nodes. Multivariate Cox regression analysis revealed that USP22 expression level was an independent prognostic factor for both overall survival and disease-free survival (P = 0.039 and P = 0.041, respectively). CONCLUSION: Overexpression of USP22 may contribute to the progression of breast cancer and thus may serve as a new molecular marker to predict the prognosis of breast cancer patients. PMID- 21691751 TI - Assessing the value of CAN-gene mutations using MALDI-TOF MS. AB - PURPOSE: To identify cancer-linked genes, Sjoblom et al. and Wood et al. performed a genome-wide mutation screening in human breast and colorectal cancers. 140 CAN-genes were found in breast cancer, which in turn contained overall 334 mutations. These mutations could prove useful for diagnostic and therapeutic purposes. METHODS: We used a MALDI-TOF MS 40-plex assay for testing 40 loci within 21 high-ranking breast cancer CAN-genes. To confirm mutations, we performed single-plex assays and sequencing. RESULTS: In general, the mutation rate of the analyzed loci in our sample cohort was very low. No mutation from the 40 loci analyzed could be found in the 6 cell lines. In tissue samples, a single breast cancer tissue sample showed heterozygosity at locus c.5834G>A within the ZFYVE26 gene (Zinc finger FYVE domain-containing gene 26). CONCLUSIONS: Sjoblom et al./Wood et al. already showed that the vast majority of CAN-genes are mutated at very low frequency. Due to the fact that we only found one mutation in our cohort, we therefore assume that at the selected loci, mutations might be low frequency events and therefore, more rarely detectable. However, further evaluation of the CAN-gene mutations in larger cohorts should be the aim of further studies. PMID- 21691750 TI - Proteomic analysis of pancreatic juice for the identification of biomarkers of pancreatic cancer. AB - INTRODUCTION: Protein profiles of endoscopically collected pancreatic juice from normal, chronic pancreatitis patients and pancreatic cancer patients were compared to identify diagnostic biomarkers of pancreatic cancer. METHODS: Secretin was injected intravenously and pancreatic juice was collected via selective cannulation of the pancreatic duct during endoscopic retrograde cholangiopancreatography. Pancreatic juices consisting of three pooled samples for normal control, chronic pancreatitis, and pancreatic cancer patients were compared using two-dimensional gel electrophoresis, and the proteins were subsequently identified using MALDI-TOF-MS. RESULTS: Thirty-five protein spots were up-regulated twofold in pancreatic cancer compared with the levels in the normal controls, and 85 protein spots were present in pancreatic cancer samples but not in normal controls. After excluding spots that were also expressed in chronic pancreatitis, 26 protein spots that were up-regulated or only expressed in pancreatic cancer samples were identified. Among the identified proteins, we confirmed the expressions of BIG2, PRDX6, and REG1alpha in pancreatic cancer tissue using immunohistochemistry. ELISA showed that the serum level of REG1alpha was significantly higher in patients with pancreatic cancer than it was in the normal controls (P = 0.023). With the best cut-off value, the sensitivity and specificity of REG1alpha to differentiate normal and pancreatic cancer were 82.6 and 81.8%, compared with 69.6 and 100% for CA19-9. CONCLUSIONS: We have shown that pancreatic juice is a good source of pancreatic cancer tumor markers. Further studies are needed to determine the clinical implications of REG1alpha and other markers. PMID- 21691752 TI - Mechanism underlying the antioxidant activity of taurine: prevention of mitochondrial oxidant production. AB - An important function of the beta-amino acid, taurine, is the regulation of oxidative stress. However, taurine is neither a classical scavenger nor a regulator of the antioxidative defenses, leaving uncertain the mechanism underlying the antioxidant activity of taurine. In the present study, the taurine antagonist and taurine transport inhibitor, beta-alanine, was used to examine the mechanism underlying the antioxidant activity of taurine. Exposure of isolated cardiomyocytes to medium containing beta-alanine for a period of 48 h led to a 45% decrease in taurine content and an increase in mitochondrial oxidative stress, as evidenced by enhanced superoxide generation, the inactivation of the oxidant sensitive enzyme, aconitase, and the oxidation of glutathione. Associated with the increase in oxidative stress was a decline in electron transport activity, with the activities of respiratory chain complexes I and III declining 50-65% and oxygen consumption falling 30%. A reduction in respiratory chain activity coupled with an increase in oxidative stress is commonly caused by the development of a bottleneck in electron transport that leads to the diversion of electrons from the respiratory chain to the acceptor oxygen forming in the process superoxide. Because beta-alanine exposure significantly reduces the levels of respiratory chain complex subunits, ND5 and ND6, the bottleneck in electron transport appears to be caused by impaired synthesis of key subunits of the electron transport chain complexes. Co-administration of taurine with beta alanine largely prevents the mitochondrial effects of beta-alanine, but treatment of the cells with 5 mM taurine in the absence of beta-alanine has no effect on the mitochondria, likely because taurine treatment has little effect on cellular taurine levels. Thus, taurine serves as a regulator of mitochondrial protein synthesis, thereby enhancing electron transport chain activity and protecting the mitochondria against excessive superoxide generation. PMID- 21691753 TI - Dietary L-arginine supplementation enhances placental growth and reproductive performance in sows. AB - Suboptimal embryonic/fetal survival and growth remains a significant problem in mammals. Using a swine model, we tested the hypothesis that dietary L-arginine supplementation during gestation may improve pregnancy outcomes through enhancing placental growth and modulating hormonal secretions. Gestating pigs (Yorkshire*Landrace, n=108) were assigned randomly into two groups based on parity and body weight, representing dietary supplementation with 1.0% L-arginine HCl or 1.7% L-alanine (isonitrogenous control) between days 22 and 114 of gestation. Blood samples were obtained from the ear vein on days 22, 40, 70 and 90 of gestation. On days 40, 70 and 90 of gestation, concentrations of estradiol in plasma were higher (P<0.05) in arginine-supplemented than in control sows. Moreover, arginine supplementation increased (P<0.05) the concentrations of arginine, proline and ornithine in plasma, but concentrations of urea or progesterone in plasma did not differ between the two groups of sows. Compared with the control, arginine supplementation increased (P<0.05) the total number of piglets by 1.31 per litter, the number of live-born piglets by 1.10 per litter, the litter birth weight for all piglets by 1.36 kg, and the litter birth weight for live-born piglets by 1.70 kg. Furthermore, arginine supplementation enhanced (P<0.05) placental weight by 16.2%. The weaning-to-estrus interval of sows was not affected by arginine supplementation during gestation. These results indicate that dietary arginine supplementation beneficially enhances placental growth and the reproductive performance of sows. PMID- 21691754 TI - Synthesis and properties of optically active nanostructured polymers bearing amino acid moieties by direct polycondensation of 4,4'-thiobis(2-tert-butyl-5 methylphenol) with chiral diacids. AB - Four derivatives of N-trimellitylimido-L-amino acid (4a-4d) were prepared by the reaction of trimellitic anhydride (1) with the L-amino acids (2a-2d) in acetic acid as diacid monomers and were used with the aim to obtain a new family of amino acid based poly(ester-imide)s (PEI)s. The polymerization was performed by direct polycondensation of chiral diacids (4a-4d) with 4,4'-thiobis(2-tert-butyl 5-methylphenol) (5) in the presence of tosyl chloride (TsCl), pyridine and N,N dimethyl formamide (DMF). Step-growth polymerization was carried out by varying the time of heating and the molar ratio of TsCl/diacid and the optimum conditions were achieved. The synthesized polymers were characterized by means of specific rotation experiments, FT-IR, 1H-NMR, X-ray diffraction techniques and elemental analysis. The surface morphology of the obtained polymers was studied by field emission scanning electron microscopy. The result showed nanostructure morphology of the resulting polymers. The obtained PEIs were soluble in polar aprotic solvents such as DMF, N,N-dimethyl acetamide, dimethyl sulfoxide, N-methyl-2 pyrrolidone and protic solvents such as sulfuric acid. Thermal stability and the weight-loss behavior of the PEIs were studied by thermal gravimetric analysis (TGA) techniques. TGA showed that the 10% weight loss temperature in a nitrogen atmosphere was more than 402 degrees C, therefore they had useful levels of thermal stability associated with excellent solubility. PMID- 21691755 TI - Prehospital pediatric emergencies in Austrian helicopter emergency medical service - a nationwide, population-based cohort study. AB - INTRODUCTION: Arguably, the most challenging emergencies encountered by emergency medical service crews involve children. Because only scant data exist about the epidemiology of pediatric emergencies in helicopter emergency medical service (HEMS) on a population level, we sought to determine the epidemiological characteristics stratified by responding area in a large nationwide sample. METHODS: This was a retrospective cohort study including all pediatric patients (0-14 years of age) who were treated by HEMS in Austria from January 2006 to June 2007 (18 months). RESULTS: Pediatric emergencies accounted for 2207 (8.2%) of a total of 26.850 helicopter rescue missions. Of those, 69.9% (n = 1543) were not involved in life-threatening emergencies. The rate of critical pediatric emergencies was higher in urban than in rural or alpine environment (45.2%, 38.2% and 20.3%, respectively). The most common chief complaint was trauma; the frequency of injuries ranged from 54.2% (582/1074) in rural area and 60.3% (44/73) in urban area to 91.4% (969/1060) in alpine environment. Fracture and head trauma (34.9%; 557/1595 and 26.3%; 419/1595, respectively) were the most common injuries. Advanced life support measures like tracheal intubation, cardiopulmonary resuscitation and intraosseous access were rarely performed (3.7%; n = 82, 1.9%; n = 42 and 0.9%; n = 19, respectively). CONCLUSIONS: Pediatric emergencies in Austrian HEMS show different epidemiological characteristics in alpine, urban and rural operational environments. Because of challenges and infrequency of prehospital pediatric emergencies, HEMS crews need to maintain their skills in pediatric advanced life support and trauma care. PMID- 21691756 TI - Quality of diabetes care in Austrian diabetic patients willing to participate in a DMP - at baseline. AB - INTRODUCTION: Diabetes mellitus type 2 plays an important role in population health worldwide, and diabetes care has been shown to be insufficient. Disease management programmes (DMPs) have been designed to overcome these deficiencies, but data on their effectiveness are inconclusive. One reason for the inconsistent extent of effects may be selection bias. Voluntary programmes might recruit preferably highly motivated patients who are already quite successful in managing diabetes. Other programmes enrol primarily patients with poor metabolic control which may lead to the demonstration of fairly large effects due to regression to the mean. We therefore investigated the baseline characteristics of patients willing to enrol in the Austrian DMP for diabetes mellitus type 2 ("Therapie aktiv"), and their quality of care. METHODS: We offered the study to all GPs and internists in the province of Salzburg. The physicians were asked to recruit all patients with type 2 diabetes according to WHO/ADA-criteria willing to participate in the Austrian DMP "Therapie aktiv". For all patients, data regarding metabolic control, medication, cardiovascular risk factors and diabetes complications were recorded and then analysed to detect deficiencies in care. RESULTS: One thousand Four hundred and eighty-nine patients (mean age 65.4 +/- 10.4 years; 47.8% women) were recruited by 92 physicians. 24.3% of all participants (28.3% of the men and 20.1% of the women) had at least one diabetes related complication with a significantly higher rate of cardiovascular complications in the male study population. 80.7% of all patients were treated with oral antidiabetics, insulin or both. With regards to quality of care 5% of all patients with an HbA1c above 7.5% did not receive any antidiabetic medication at all. 15.3% of the study population with high blood pressure was not supplied with any antihypertensive medication and 36.6% of the study participants with cardiovascular disease were not treated with a statin. CONCLUSION: Our results indicate that the majority of the patients receive treatment in adherence to current guidelines. Nevertheless there are deficits in care and hence room for improvement by implementation of the DMP. PMID- 21691757 TI - Aneurysmatic subarachnoidal haemorrhage: incidence and location of small ruptured cerebral aneurysms - a retrospective population-based study. AB - BACKGROUND: The purpose of this retrospective population-based study was to investigate the incidence of subarachnoid haemorrhage from small (5 mm and below) cerebral aneurysms and their localisation in consecutive patients surgically treated in the State of Vorarlberg/Austria. METHODS: Altogether, during the last 4 years, 82 patients after spontaneous subarachnoid haemorrhage (mean age 53.7 years, range 21-84 years, 47 females and 35 males) were referred to the Neurosurgical Department of the Academic Teaching Hospital Feldkirch, serving for all 360,000 inhabitants of the State (corresponding to a subarachnoid haemorrhage incidence of 5.7/100,000/year). In 70 patients (85.4%), a cerebral aneurysm was detected by computed tomography angiography and/or digital cerebral angiography. Out of these, 47 patients (66.2%, mean age 52.1 years, range 24-77 years) were treated with aneurysm clipping and included in the study. Preoperatively, computed tomography, computed tomography angiography and/or digital cerebral angiography were assessed for amount of blood, aneurysm size and localisation, respectively. Clinical status was graded according to the Hunt and Hess classification at admission and according to the Glasgow Outcome Scale at discharge. FINDINGS: According to Koivisto categories, 18 aneurysms were localised at the anterior cerebral artery, 17 aneurysms at the middle cerebral artery, 11 at the internal carotid artery, and 1 at the vertebrobasilar artery. The mean aneurysm diameter was 7.7 mm (range 3-30 mm). In 34% of the aneurysms the diameter was 5 mm or smaller (n = 16), in 51% between 6 and 10 mm (n = 24) and in 15% between 11 and 30 mm (n = 7). Only 1/17 ruptured middle cerebral artery aneurysms (5.9%), 4/11 internal carotid artery aneurysms (36.4%) and the vertebrobasilar artery aneurysm were small. However, in 10/18 anterior cerebral artery aneurysms (55.6%) the diameter was 5 mm or below. CONCLUSIONS: In conclusion, in our consecutive patient series with clipped cerebral aneurysms after subarachnoid haemorrhage, one third had small ruptured aneurysms, with the anterior cerebral artery complex as the main predilection site. Therefore, despite the previously reported low rupture risk, incidental small aneurysms should also be considered for therapy, depending on localisation and individual risk factors. PMID- 21691759 TI - Isoliquiritigenin is a novel NMDA receptor antagonist in kampo medicine yokukansan. AB - Effects of a traditional Japanese medicine, yokukansan, which is composed of seven medicinal herbs, on glutamate-induced cell death were examined using primary cultured rat cortical neurons. Yokukansan (10-300 MUg/ml) inhibited the 100 MUM glutamate-induced neuronal death in a concentration-dependent manner. Among seven constituent herbs, higher potency of protection was found in Uncaria thorn (UT) and Glycyrrhiza root (GR). A similar neuroprotective effect was found in four components (geissoschizine methyl ether, hirsuteine, hirsutine, and rhynchophylline) in UT and four components (glycycoumarin, isoliquiritigenin, liquiritin, and 18beta-glycyrrhetinic acid) in GR. In the NMDA receptor binding and receptor-linked Ca(2+) influx assays, only isoliquiritigenin bound to NMDA receptors and inhibited the glutamate-induced increase in Ca(2+) influx. Glycycoumarin and 18beta-glycyrrhetinic acid bound to NMDA receptors, but did not inhibit the Ca(2+) influx. The four UT-derived components did not bind to NMDA receptors. The present results suggest that neuroprotective components (isoliquiritigenin, glycycoumarin, liquiritin, and 18beta-glycyrrhetinic acid in GR and geissoschizine methyl ether, hirsuteine, hirsutine, and rhynchophylline in UT) are contained in yokukansan, and isoliquiritigenin, which is one of them, is a novel NMDA receptor antagonist. PMID- 21691760 TI - Results from two online surveys comparing sexual risk behaviors in Hispanic, black, and white men who have sex with men. AB - Many men who have sex with men (MSM) are among those who increasingly use the internet to find sexual partners. Few studies have compared behavior by race/ethnicity in internet-based samples of MSM. We examined the association of race/ethnicity with HIV risk-related behavior among 10,979 Hispanic, black, and white MSM recruited online. Significant variations by race/ethnicity were found in: age, income level, sexual orientation, number of lifetime male and female sexual partners, and rates of unprotected anal intercourse (UAI). Black and Hispanic men were more likely to report anal intercourse during the last sexual encounter, but white men were more likely to report UAI. In multivariate analysis, UAI was associated with HIV infection and sex with a main partner. Significant risk behavior variations by race/ethnicity were found. Research is needed to better target online interventions to MSM who engage in UAI or have other risk factors for transmitting or acquiring HIV. PMID- 21691761 TI - Variations in patterns of sexual risk behavior among Seattle-area MSM based on their HIV status, the HIV status of their partner and partner type. AB - We evaluated sexual risk behavior in 368 Seattle-area MSM recruited in the 2008 National HIV Behavioral Surveillance survey. We found significant concordance between participants' self-reported HIV status and that of their sexual partners. Persons unaware of partners' HIV status were more likely to report only oral sex. Those aware were less likely to report non-concordant unprotected anal intercourse (UAI). Participants reporting themselves HIV-positive were more likely than those self-reporting HIV-negative status to report non-concordant UAI and several other sexual risk behaviors. The level of non-concordant UAI did not materially differ by whether their partner was a main or casual partner. PMID- 21691758 TI - Minimizing cardiac risk in perioperative practice - interdisciplinary pharmacological approaches. AB - BACKGROUND: In an aging population, major surgery is often performed in patients with complex co-morbidities. These patients present new risk constellations so that cardiac and respiratory complications mainly contribute to perioperative morbidity. METHODS: We composed a narrative review on pharmacological approaches to cardiovascular protection in the perioperative period including effects of central neuraxial blocks and hypothermia on cardiovascular outcome. The single chapters are structured as follows: pathophysiology-early studies-recent evidence recommendations. RESULTS: In coping with this challenge, innovative concepts like fast track surgery and pharmacological treatment are being utilized with increasing frequency including perioperative cardioprotection, novel strategies of anticoagulation or antiplatelet therapy, and protocols for postoperative pain therapy. CONCLUSION: All the concepts described require an interdisciplinary approach in collaboration between operative physicians and physicians working in non-surgical disciplines like internal medicine, cardiology, and clinical pharmacology. The perioperative continuation of a pre-existing therapy with beta blockers and other potentially cardioprotective agents like alpha(2)-agonists and statines is recommended. In the management of patients presenting for major surgery stratification of the perioperative risk is essential which considers both, invasiveness of the surgical procedure and conditions of the patient. Otherwise, side-effects might outweigh benefits of a potentially effective therapy as recently shown for the perioperative administration of beta-blockers that should be restricted to high-risk patients. PMID- 21691762 TI - The postoperative occurrence of cardio-respiratory adverse events in small infants undergoing gastrointestinal surgery: a prospective comparison of general anesthesia and combined spinal-epidural anesthesia. AB - INTRODUCTION: This study was designed to compare the occurrences of postoperative cardio-respiratory adverse events during an 8-day follow-up period in the neonatal intensive care unit in small infants who underwent elective gastrointestinal surgery under general and combined spinal epidural anesthesia. METHODS: Fifty infants who underwent elective primary gastrointestinal surgery were randomly divided into two anesthetic techniques. General anesthesia (25 patients) and combined spinal-epidural anesthesia (25 patients). The frequency and types of postoperative cardiovascular and respiratory adverse events in the two groups were recorded and compared during an 8-day follow-up period in the neonatal intensive care unit. RESULTS: The total number of postoperative respiratory adverse events and the number of infants who experienced at least one respiratory adverse event were statistically more in infants anesthetised by general anesthesia than in infants who were anesthetised by combined spinal epidural anesthesia, respectively (p < 0.0001) and (RR = 2.5; 95% CI 1.2-5.3). There were significantly more cardiovascular adverse events in the general anesthesia infants than in the combined spinal-epidural anesthesia (p = 0.005). These adverse cardiovascular events were also more resistant to treatment in the general anesthesia infants than in the combined spinal-epidural anesthesia infants (p = 0.001). CONCLUSION: Compared to general anesthesia, combined spinal epidural anesthesia reduces the frequency of postoperative respiratory adverse events and improves the postoperative cardiovascular stability in small infants who undergo elective gastrointestinal surgery. PMID- 21691763 TI - Protective effects of Radix Codonopsis on ischemia-reperfusion injury in rats after kidney transplantation. AB - PURPOSE: Kidney ischemia-reperfusion injury (IRI) after kidney transplant remains a major problem, separate from immune rejection that can lead to kidney transplant failure and graft function loss. Free radicals, disturbance of microcirculation and the inflammatory cascade appear to be the main contributors. Radix Codonopsis, a traditional Chinese drug used in vascular diseases, is an antioxidant and free radical scavenger. This study investigates the protective effect and underlying mechanisms of Radix Codonopsis extract saponins on kidney transplantation. METHODS: Renal transplantation was performed after rat kidneys had been stored for 1 h at 4 degrees C. Blood urea nitrogen (BUN), serum creatinine (Scr), superoxide dismutase (SOD) and malondialdehyde (MDA) were assayed; bcl-2 and bax mRNA expression was detected using RT-PCR; bcl-2 and bax protein expression was detected by immunohistochemistry (IHC). Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) was used to detect apoptotic cells and determine the apoptosis index (AI). Analysis of variance (ANOVA) followed by Dunnett's test was used when more than two groups were compared. RESULTS: Saponin-treated animals showed increased SOD levels accompanied by decreased MDA, Scr and BUN levels (p < 0.05 vs. untreated controls); bcl-2 mRNA and protein levels were increased in transplanted kidney from treated animals, while bax mRNA and protein levels were decreased (p < 0.05 vs. untreated controls). AI was significantly decreased in transplanted kidneys from treated animals relative to untreated controls (p < 0.05 vs. untreated controls). CONCLUSION: This study clearly demonstrates the protective effects on IRI after kidney transplantation, which may be explained by decreased lipid peroxidation and inhibition of apoptosis. PMID- 21691764 TI - Misregulation of phosphoinositides in Arabidopsis thaliana decreases pollen hydration and maternal fertility. AB - Phosphoinositides are important lipids involved in membrane identity, vesicle trafficking, and intracellular signaling. In recent years, phosphoinositides have been shown to play a critical role in polarized secretion in plants, as perturbations of phosphoinositide metabolism, through loss of function mutants, result in defects in root hair elongation and pollen tube growth, where polarized secretion occurs rapidly. In the Brassicaceae, responses of stigmatic papillae to compatible pollen are also thought to involve highly regulated secretory events to facilitate pollen hydration and penetration of the pollen tube through the stigmatic surface. We therefore sought to analyze the female sporophyte fertility of the root hair defective4-1 mutant and the PI 4-kinase beta1/beta2 double mutant, which differentially affect phosphatidylinositol-4-phosphate (PI4P) levels. Stigmas from both mutants supported slower rates of pollen grain hydration, and the fecundity of these mutants was also diminished as a result of failed pollination events. This study therefore concludes that PI4P is integral to appropriate pistil responses to compatible pollen. PMID- 21691765 TI - Cholinergic imbalance in the multiple sclerosis hippocampus. AB - Hippocampal pathology was shown to be extensive in multiple sclerosis (MS) and is associated with memory impairment. In this post-mortem study, we investigated hippocampal tissue from MS and Alzheimer's disease (AD) patients and compared these to non-neurological controls. By means of biochemical assessment, (immuno)histochemistry and western blot analyses, we detected substantial alterations in the cholinergic neurotransmitter system in the MS hippocampus, which were different from those in AD hippocampus. In MS hippocampus, activity and protein expression of choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, was decreased, while the activity and protein expression of acetylcholinesterase (AChE), the acetylcholine degrading enzyme, was found to be unaltered. In contrast, in AD hippocampus both ChAT and AChE enzyme activity and protein expression was decreased. Our findings reveal an MS-specific cholinergic imbalance in the hippocampus, which may be instrumental in terms of future treatment options for memory problems in this disease. PMID- 21691766 TI - Tracking pigeons in a magnetic anomaly and in magnetically "quiet" terrain. AB - Pigeons were released at two sites of equal distance from the loft, one within a magnetic anomaly, the other in magnetically quiet terrain, and their tracks were recorded with the help of GPS receivers. A comparison of the beginning of the tracks revealed striking differences: within the anomaly, the initial phase lasted longer, and the distance flown was longer, with the pigeons' headings considerably farther from the home direction. During the following departure phase, the birds were well homeward oriented at the magnetically quiet site, whereas they continued to be disoriented within the anomaly. Comparing the tracks in the anomaly with the underlying magnetic contours shows considerable differences between individuals, without a common pattern emerging. The differences in magnetic intensity along the pigeons' path do not differ from a random distribution of intensity differences around the release site, indicating that the magnetic contours do not directly affect the pigeons' routes. Within the anomaly, pigeons take longer until their flights are oriented, but 5 km from the release point, the birds, still within the anomaly, are also significantly oriented in the home direction. These findings support the assumption that magnetically anomalous conditions initially interfere with the pigeons' navigational processes, with birds showing rather individual responses in their attempts to overcome these problems. PMID- 21691768 TI - Neoadjuvant chemotherapy with paclitaxel plus platinum for invasive cervical cancer in pregnancy: two case report and literature review. AB - BACKGROUND: Cervical cancer (including carcinoma in situ) is the most common malignancy during pregnancy. Neoadjuvant chemotherapy (NACT) with paclitaxel plus cisplatin has been used in patients with cervical cancer successfully, but experience of its prenatal treatment is limited. CASE REPORT: We report two pregnant women with locally advanced cervical cancer. They were treated with cisplatin plus paclitaxel NACT until fetal pulmonary maturity was achieved, and then accepted cesarean section followed by radical hysterectomy. To minimize the chemo-resistant/radio-resistant tumor cell clones and increase the potencies of NACT, we modified the dose of the chemotherapeutic agents and the treatment interval using cisplatin (50 mg/m(2)) and paclitaxel (75 mg/m(2)) every 2 weeks. Evaluation for clinical response to chemotherapy displayed a partial and complete response, respectively. Both patients had not had any evidence of recurrence for 21 and 13 months. Their children did not have any evidence of malformations and showed normal development at 21 and 13 months of follow-up, respectively. CONCLUSION: Neoadjuvant chemotherapy with paclitaxel plus cisplatin appears to be feasible and safe for pregnant patients with invasive cervical cancer and infants. PMID- 21691767 TI - Can we predict shoulder dystocia? AB - PURPOSE: To analyse the significance of risk factors and the possibility of prediction of shoulder dystocia. METHODS: This was a retrospective cohort study. There were 9,767 vaginal deliveries at 37 and more weeks of gestation analysed during 2005-2007. Studied population included 234 deliveries complicated by shoulder dystocia. Shoulder dystocia was defined as a delivery that required additional obstetric manoeuvres to release the shoulders after gentle downward traction has failed. First, a univariate analysis was done to identify the factors that had a significant association with shoulder dystocia. Parity, age, gestation, induction of labour, epidural analgesia, birth weight, duration of second stage of labour and mode of delivery were studied factors. All factors were then combined in a multivariate logistic regression analysis. Adjusted odds ratios (Adj. OR) with 95% confidence intervals (CI) were calculated. RESULTS: The incidence of shoulder dystocia was 2.4% (234/9,767). Only mode of delivery and birth weight were independent risk factors for shoulder dystocia. Parity, age, gestation, induction of labour, epidural analgesia and duration of second stage of labour were not independent risk factors. Ventouse delivery increases the risk of shoulder dystocia almost 3 times, forceps delivery comparing to the ventouse delivery increases risk almost 3.4 times. Risk of shoulder dystocia is minimal with the birth weight of 3,000 g or less. CONCLUSION: It is difficult to foretell the exact birth weight and the mode of delivery, therefore occurrence of shoulder dystocia is highly unpredictable. Regular drills for shoulder dystocia and awareness of increased incidence with instrumental deliveries are important to reduce fetal and maternal morbidity and mortality. PMID- 21691769 TI - Drought tolerance in eggs and juveniles of the Iberian slug, Arion lusitanicus. AB - The spread of invasive species is an increasing problem world wide. The invasive slug Arion lusitanicus has spread to most parts of Europe, where it often is considered as a serious pest. There is a need for better knowledge of its ecophysiology to be able to predict the effect of climatic factors, such as temperature and humidity on the population dynamics and abundance. The aim of the present study was to assemble data on the water balance and drought tolerance of eggs and juveniles of A. lusitanicus. Both eggs and juveniles had little capacity to prevent evaporative water loss and lost water when the ambient humidity fell below 99.8 and 99.5%, respectively. The water conductance of the cuticle of juveniles was 242 MUg cm(-2) h(-1) mmHg(-1) and resembles that of other slug species. Both eggs and juveniles of A. lusitanicus tolerate a substantial water loss. There was no difference in water loss resistance between eggs and juveniles, but the eggs were slightly more tolerant to water loss than the juveniles. The percent water loss causing 50% mortality was 72% for the juveniles and 81% for the eggs. Despite A. lusitanicus' tolerance of substantial water loss, its survival depends on humid habitats. PMID- 21691770 TI - Data logging of body temperatures provides precise information on phenology of reproductive events in a free-living Arctic hibernator. AB - Precise measures of phenology are critical to understanding how animals organize their annual cycles and how individuals and populations respond to climate induced changes in physical and ecological stressors. We show that patterns of core body temperature (T (b)) can be used to precisely determine the timing of key seasonal events including hibernation, mating and parturition, and immergence and emergence from the hibernacula in free-living arctic ground squirrels (Urocitellus parryii). Using temperature loggers that recorded T (b) every 20 min for up to 18 months, we monitored core T (b) from three females that subsequently gave birth in captivity and from 66 female and 57 male ground squirrels free living in the northern foothills of the Brooks Range Alaska. In addition, dates of emergence from hibernation were visually confirmed for four free-living male squirrels. Average T (b) in captive females decreased by 0.5-1.0 degrees C during gestation and abruptly increased by 1-1.5 degrees C on the day of parturition. In free-living females, similar shifts in T (b) were observed in 78% (n = 9) of yearlings and 94% (n = 31) of adults; females without the shift are assumed not to have given birth. Three of four ground squirrels for which dates of emergence from hibernation were visually confirmed did not exhibit obvious diurnal rhythms in T (b) until they first emerged onto the surface when T (b) patterns became diurnal. In free-living males undergoing reproductive maturation, this pre emergence euthermic interval averaged 20.4 days (n = 56). T (b)-loggers represent a cost-effective and logistically feasible method to precisely investigate the phenology of reproduction and hibernation in ground squirrels. PMID- 21691771 TI - Bactericidal activity identified in 2S Albumin from sesame seeds and in silico studies of structure-function relations. AB - Pathogenic bacteria constitute an important cause of hospital-acquired infections. However, the misuse of available bactericidal agents has led to the appearance of antibiotic-resistant strains. Thus, efforts to seek new antimicrobials with different action mechanisms would have an enormous impact. Here, a novel antimicrobial protein (SiAMP2) belonging to the 2S albumin family was isolated from Sesamum indicum kernels and evaluated against several bacteria and fungi. Furthermore, in silico analysis was conducted in order to identify conserved residues through other 2S albumin antimicrobial proteins (2S-AMPs). SiAMP2 specifically inhibited Klebsiella sp. Specific regions in the molecule surface where cationic (RR/RRRK) and hydrophobic (MEYWPR) residues are exposed and conserved were proposed as being involved in antimicrobial activity. This study reinforces the hypothesis that plant storage proteins might also play as pathogen protection providing an insight into the mechanism of action for this novel 2S-AMP and evolutionary relations between antimicrobial activity and 2S albumins. PMID- 21691772 TI - Escherichia coli induces apoptosis in human monocytic U937 cells through the Fas/FasL signaling pathway. AB - Apoptosis is a genetically regulated cellular suicide mechanism that plays an essential role in development and in defense of multicellular organism. Escherichia coli (E. coli) can induce monocyte apoptosis; however, the mechanism is not clear. This study determines if Fas/FasL regulates E. coli-induced human monocyte line U937 cell apoptosis. We found that infection of U937 cells with E. coli induced rapid cell death in a dose- and time-dependent manner displaying the characteristic features of apoptosis. Moreover, opsonized E. coli induced U937 apoptosis with a higher apoptotic rate (53.29 +/- 5.83%) than non-opsonized E. coli (19.37 +/- 2.56%). Studying the underlying mechanisms we found that the E. coli-induced apoptosis was associated with a more prominent induction expression of Fas/FasL in a time- and dose-dependent manner. Furthermore, E. coli treatment resulted in a significant increase in the levels of DR5, TRAIL, and FADD, but exerted no statistically significant effects on the levels of DR4. The activity of caspase-8 enzyme increased in infection groups, positively correlated with apoptosis rate. Taken together, these results clearly indicate that receptor mediated phagocytosis of E. coli induces apoptosis. Moreover, our findings suggest a possible regulatory role of Fas/FasL in the pathway of E. coli infection. PMID- 21691775 TI - The co-culture of Acidithiobacillus ferrooxidans and Acidiphilium acidophilum enhances the growth, iron oxidation, and CO2 fixation. AB - Although the synergetic interactions between chemolithoautotroph Acidithiobacillus ferrooxidans and heterotroph Acidiphilium acidophilum have drawn a share of attention, the influence of Aph. acidophilum on growth and metabolic functions of At. ferrooxidans is still unknown on transcriptional level. To assess this influence, a co-culture composed by At. ferrooxidans and Aph. acidophilum was successfully acclimated in this study. Depending on the growth dynamics, At. ferrooxidans in co-culture had 2 days longer exponential phase and 5 times more cell number than that in pure culture. The ferrous iron concentration in culture medium and the expression of iron oxidation-related genes revealed that the energy acquisition of At. ferrooxidans in co-culture was more efficient than that in pure culture. Besides, the analysis of CO2 fixation related genes in At. ferrooxidans indicated that the second copy of RuBisCO encoding genes cbbLS-2 and the positive regulator-encoding gene cbbR were up regulated in co-culture system. All of these results verified that Aph. acidophilum could heterotrophically grow with At. ferrooxidans and promote the growth of it. By means of activating iron oxidation-related genes and the second set of cbbLS genes in At. ferrooxidans, the Aph. acidophilum facilitated the iron oxidation and CO2 fixation by At. ferrooxidans. PMID- 21691776 TI - Streptomyces fildesensis sp. nov., a novel streptomycete isolated from Antarctic soil. AB - A novel actinomycete strain, GW25-5(T), was isolated from a soil sample collected from the Fildes Peninsula, King George Island, West Antarctica. The strain was characterized by white to grey aerial mycelia, which were differentiated to straight to flexuous spore chains, with rod-shaped smooth spores. The cell wall of strain GW25-5(T) contained LL-diaminopimelic acid (A(2)pm) and traces of meso A(2)pm. Whole-cell sugars were galactose and minor amounts of mannose and glucose. The predominant menaquinones were MK-9(H(6)) (49%), MK-9(H(8)) (24%) and MK-9(H(4)) (12%). The phospholipids contained DPG, PE, PI, PIM and PL(s). The major cellular fatty acids were iso-C(16:0) and anteiso-C(15:0). Genomic DNA G+C content of strain GW25-5(T) was 70.0 mol%. BLAST result showed that strain GW25-5 has the 16S rRNA gene sequence highest similarity of 97.5% with members of genus Streptomyces and phylogenetic analysis indicated that this strain belongs to the genus Streptomyces. DNA-DNA relatedness values of strain GW25-5(T) with the closest species of Streptomyces purpureus LMG 19368(T) and Streptomyces beijiangensis YIM 6(T) were significantly lower than 70% of the threshold value for the delineation of genomic species. A polyphasic taxonomic investigation based on a judicious combination of genotypic and phenotypic characteristics revealed that the organism represents a novel species of the genus Streptomyces. Thus, we propose strain GW25-5(T) as the type strain of this novel species, Streptomyces fildesensis (=CGMCC 4.5735(T) = YIM 93602(T) = DSM 41987(T) = NRRL B 24828(T)). PMID- 21691774 TI - Genomewide linkage analysis in Costa Rican families implicates chromosome 15q14 as a candidate region for OCD. AB - Obsessive compulsive disorder (OCD) has a complex etiology that encompasses both genetic and environmental factors. However, to date, despite the identification of several promising candidate genes and linkage regions, the genetic causes of OCD are largely unknown. The objective of this study was to conduct linkage studies of childhood-onset OCD, which is thought to have the strongest genetic etiology, in several OCD-affected families from the genetically isolated population of the Central Valley of Costa Rica (CVCR). The authors used parametric and non-parametric approaches to conduct genome-wide linkage analyses using 5,786 single nucleotide repeat polymorphisms (SNPs) in three CVCR families with multiple childhood-onset OCD-affected individuals. We identified areas of suggestive linkage (LOD score >= 2) on chromosomes 1p21, 15q14, 16q24, and 17p12. The strongest evidence for linkage was on chromosome 15q14 (LOD = 3.13), identified using parametric linkage analysis with a recessive model, and overlapping a region identified in a prior linkage study using a Caucasian population. Each CVCR family had a haplotype that co-segregated with OCD across a ~7 Mbp interval within this region, which contains 18 identified brain expressed genes, several of which are potentially relevant to OCD. Exonic sequencing of the strongest candidate gene in this region, the ryanodine receptor 3 (RYR3), identified several genetic variants of potential interest, although none co segregated with OCD in all three families. These findings provide evidence that chromosome 15q14 is linked to OCD in families from the CVCR, and supports previous findings to suggest that this region may contain one or more OCD susceptibility loci. PMID- 21691773 TI - Integrative computational biology for cancer research. AB - Over the past two decades, high-throughput (HTP) technologies such as microarrays and mass spectrometry have fundamentally changed clinical cancer research. They have revealed novel molecular markers of cancer subtypes, metastasis, and drug sensitivity and resistance. Some have been translated into the clinic as tools for early disease diagnosis, prognosis, and individualized treatment and response monitoring. Despite these successes, many challenges remain: HTP platforms are often noisy and suffer from false positives and false negatives; optimal analysis and successful validation require complex workflows; and great volumes of data are accumulating at a rapid pace. Here we discuss these challenges, and show how integrative computational biology can help diminish them by creating new software tools, analytical methods, and data standards. PMID- 21691777 TI - Pseudonocardia serianimatus sp. nov., a novel actinomycete isolated from the surface-sterilized leaves of Artemisia annua L. AB - An aerobic, non-motile, catalase-positive, Gram-stain positive actinomycete designated YIM 63233(T) was isolated from the surface-sterilized leaves of Artemisia annua L. and characterized using a polyphasic taxonomic approach. Optimal growth occurred at 20-28 degrees C, pH 6.0-7.0 and in the presence of 0 3% (w/v) NaCl. 16S rRNA gene sequence-based phylogenetic analysis showed that strain YIM 63233(T) clustered with species of the genus Pseudonocardia, displaying >=1.2% sequence divergence with recognized species of this genus (from 98.8 to 94.0%). Relatively low levels of DNA-DNA relatedness were found between strain YIM 63233(T) and Pseudonocardia petroleophila IMSNU 22072(T), which supported the classification of strain YIM 63233(T) within a novel species of the genus Pseudonocardia. The G + C content of genomic DNA was 72.0 mol%. Strain YIM 63233(T) possessed chemotaxonomic markers that were consistent with classification in the genus Pseudonocardia, i.e. the predominant fatty acids were iso-C16:0 (32.27%), C16:0 10-methyl (8.73%) and C17:1omega8c (8.30%), whilst the predominant menaquinone was MK-8(H(4)). The diagnostic diamino acid of the cell wall peptidoglycan was meso-diaminopimelic acid. The major cell wall sugars were glucose, arabinose, galactose, mannose and rhamnose. The results of physiological and biochemical tests and DNA-DNA hybridization allowed the phenotypic and genotypic differentiation of strain YIM 63233(T) from its closest phylogenetic neighbours. Therefore, the new isolate YIM 63233(T) represents a novel species of the genus Pseudonocardia, for which the name Pseudonocardia serianimatus sp. nov. is proposed. The type strain is YIM 63233(T) (=DSM 45302(T) = CCTCC AA 208079(T)). PMID- 21691778 TI - Systematic analysis of potato acid invertase genes reveals that a cold-responsive member, StvacINV1, regulates cold-induced sweetening of tubers. AB - Acid invertase is believed to play a regulatory role during plant developmental processes and to respond to environmental stimuli. The expression profiles of the entire acid invertase family are not yet available for potato. By searching existing databases, it was determined that there are at least six acid invertase genes in potato, including four cell-wall invertase genes and two vacuolar invertase genes. They were subjected to comparative expression profiling in various organs of potato plants and in stored tubers to exploit their potential functions. The results revealed that each gene exhibited a unique expression pattern, which differed in transcript abundance or showed organ-specific features, pointing to the possible involvement of individual genes in plant development. The vacuolar invertase gene StvacINV1 had the highest expression level among three genes detected in the potato tubers. Further storage experiments showed that StvacINV1 was strongly induced by low temperatures, which is consistent with glucose accumulation in cold-stored tubers. Suppression of StvacINV1 by the antisense transformation in potato confirmed that lower StvacINV1 transcript abundance in transgenic tubers is related to lower reducing sugar content and lighter chip color in comparison with the wild type. The evidence strongly suggests that StvacINV1 is a gene involved in regulation of cold-induced sweetening of potato tubers. This provides an avenue for studying the mechanism involved in the regulation of the cold-induced sweetening trait and for agronomic enhancement. PMID- 21691779 TI - [Nonunion of the femoral neck and artificial heart. How far may we go?]. AB - Due to medical improvements surgeons are increasingly confronted with conditions associated with severe medical comorbidities. Fracture or nonunion of the femoral neck would have been classified as "inoperable" in the past. We report the successful operative treatment of a patient with femoral neck nonunion after screw osteosynthesis and associated existence of a left ventricular assist device for dilated cardiomyopathy. PMID- 21691780 TI - [Elastic stable intramedullary nailing of clavicular midshaft fractures: comparison of open vs closed fracture reduction]. AB - BACKGROUND: The aim of this study was to compare the outcome of open reduction versus closed reduction of midclavicular fractures using elastic stable intramedullary nailing (ESIN) in both groups. METHODS: Titanium elastic nails were used to treat 40 patients undergoing minimally invasive ESIN between December 2006 and July 2009. A total of 19 patients were treated with a closed reduction and 21 patients required open reduction. RESULTS: The Constant Score revealed no significant differences between the two groups (closed 87.4+/-9.0; open 85.3+/-7.1) nor did the DASH Score (closed: 5.0+/-6.5; open 5.8+/-7.3). The strength measurement of shoulder abduction was consistent in each group: 75.7+/ 22.0 N in the closed reduction group and 74.2+/-26.0 N in the group with open treatment. CONCLUSION: There was no difference comparing right- and left-sided injuries and the outcomes were consistent irrespective of the treatment method. When appropriately indicated open and closed intramedullary nailing are very successful modalities of treatment. There were no significant differences in shoulder function after either procedure. PMID- 21691781 TI - [Benchmarking of university trauma centers in Germany. Research and teaching]. AB - Benchmarking is a very popular business process and meanwhile is used in research as well. The aim of the present study is to elucidate key numbers of German university trauma departments regarding research and teaching. The data set is based upon the monthly reports given by the administration in each university. As a result the study shows that only well-known parameters such as fund-raising and impact factors can be used to benchmark university-based trauma centers. The German federal system does not allow a nationwide benchmarking. PMID- 21691782 TI - [Extended lateral gastrocnemius transposition flap for reconstruction of open knee extensor disruption]. AB - We describe a modified technique to reconstruct a damaged knee extensor mechanism after infected patellar fracture. After resection of infected soft tissue and quadriceps tendon a compound suprapatellar defect existed. Due to compromised tissue on the medial aspect of the calf, we used this flap, which consists of the lateral gastrocnemius muscle with parts of the adjacent Achilles tendon. After a follow-up period of several months the range of movement is 0-0-120 degrees . PMID- 21691783 TI - Biocatalytic synthesis of optically active tertiary alcohols. AB - The enzymatic preparation of optically pure tertiary alcohols under sustainable conditions has received much attention. The conventional chemical synthesis of these valuable building blocks is still hampered by the use of harmful reagents such as heavy metal catalysts. Successful examples in biocatalysis used esterases, lipases, epoxide hydrolases, halohydrin dehalogenases, thiamine diphosphate-dependent enzymes, terpene cyclases, -acetylases, and -dehydratases. This mini-review provides an overview on recent developments in the discovery of new enzymes, their functional improvement by protein engineering, the design of chemoenzymatic routes leading to tertiary alcohols, and the discovery of entirely new biotransformations. PMID- 21691784 TI - Modelling as a tool of enzyme reaction engineering for enzyme reactor development. AB - Strategy of the development of model for enzyme reactor at laboratory scale with respect to the modelling of kinetics is presented. The recent literature on the mathematic modelling on enzyme reaction rate is emphasized. PMID- 21691785 TI - Peptide derived from anti-idiotypic single-chain antibody is a potent antifungal agent compared to its parent fungicide HM-1 killer toxin peptide. AB - Based on anti-idiotypic network theory in light of the need for new antifungal drugs, we attempted to identify biologically active fragments from HM-1 yeast killer toxin and its anti-idiotypic antibody and to compare their potency as an antifungal agent. Thirteen overlapping peptides from HM-1 killer toxin and six peptides from its anti-idiotypic single-chain variable fragment (scFv) antibodies representing the complementarity determining regions were synthesized. The binding affinities of these peptides were investigated and measured by Dot blot and surface plasmon resonance analysis and finally their antifungal activities were investigated by inhibition of growth, colony forming unit assay. Peptide P6, containing the potential active site of HM-1 was highly capable of inhibiting the growth of Saccharomyces cerevisiae but was less effective on pathogenic fungi. However, peptide fragments derived from scFv antibody exerted remarkable inhibitory effect on the growth of pathogenic strains of Candida and Cryptococcus species in vitro. One scFv-derived decapeptide (SP6) was selected as the strongest killer peptide for its high binding affinity and antifungal abilities on both Candida and Cryptococcus species with IC(50) values from 2.33 * 10(-7) M to 36.0 * 10(-7) M. SP6 peptide activity was neutralized by laminarin, a beta-1,3 glucan molecule, indicating this peptide derived from scFv anti-idiotypic antibody retains antifungal activity through interaction with cell wall beta glucan of their target fungal cells. Experimental evidence strongly suggested the possibility of development of anti-idiotypic scFv peptide-based antifungal agents which may lead to improve therapeutics for the management of varieties of fungal infections. PMID- 21691786 TI - Analysis of ammonia-oxidizing bacteria dominating in lab-scale bioreactors with high ammonium bicarbonate loading. AB - The ammonia-oxidizing bacterial community (AOB) was investigated in two types of laboratory-scale bioreactors performing partial oxidation of ammonia to nitrite or nitrate at high (80 mM) to extremely high (428 mM) concentrations of ammonium bicarbonate. At all conditions, the dominant AOB was affiliated to the Nitrosomonas europaea lineage as was determined by fluorescence in situ hybridization and polymerase chain reaction in combination with denaturing gradient gel electrophoresis. Molecular analysis of the mixed populations, based on the 16S rRNA and cbbL genes, demonstrated the presence of two different phylotypes of Nitrosomonas, while microbiological analysis produced a single phylotype, represented by three different morphotypes. One of the most striking features of the AOB populations encountered in the bioreactors was the domination of highly aggregated obligate microaerophilic Nitrosomonas, with unusual cellular and colony morphology, commonly observed in nitrifying bioreactors but rarely investigated by cultural methods. The latter is probably not an adaptation to stressful conditions created by high ammonia or nitrite concentrations, but oxygen seems to be a stressful factor in these bioreactors. PMID- 21691787 TI - The purification and characterization of a novel hypersensitive-like response inducing elicitor from Verticillium dahliae that induces resistance responses in tobacco. AB - PevD1, a novel protein elicitor from the pathogenic cotton verticillium wilt fungus, Verticillium dahliae, induced a hypersensitive response in tobacco plants. In this paper, the elicitor was purified and analyzed using de novo sequencing. The protein-encoding pevD1 gene consists of a 468-bp open reading frame that produces a polypeptide of 155 amino acids, with a theoretical molecular weight of 16.23 kDa. The sequence of elicitor protein PevD1 was matched to the genomic sequence (GenBank accession no. ABJE 01000445.1) of a putative protein from V. dahliae strain vdls.17, but a function had not yet been reported. The pevD1 gene was expressed in Escherichia coli, and the recombinant protein was characterized for its ability to confer systemic acquired resistance to tobacco mosaic virus (TMV). Recombinant PevD1-treated plants exhibited enhanced systemic resistance compared to control, including a significant reduction in the number and size of TMV lesions on tobacco leaves. The elicitor protein-induced hydrogen peroxide production, extracellular-medium alkalization, callose deposition, phenolics metabolism, and lignin synthesis in tobacco. Our results demonstrate that elicitor-PevD1 triggers defense responses in intact tobacco plants. PMID- 21691788 TI - Characterization of a recombinant cellobiose 2-epimerase from Caldicellulosiruptor saccharolyticus and its application in the production of mannose from glucose. AB - A putative N-acyl-D-glucosamine 2-epimerase from Caldicellulosiruptor saccharolyticus was cloned and expressed in Escherichia coli. The recombinant enzyme was identified as a cellobiose 2-epimerase by the analysis of the activity for substrates, acid-hydrolyzed products, and amino acid sequence. The cellobiose 2-epimerase was purified with a specific activity of 35 nmol min(-1) mg(-1) for D glucose with a 47-kDa monomer. The epimerization activity for D-glucose was maximal at pH 7.5 and 75 degrees C. The half-lives of the enzyme at 60 degrees C, 65 degrees C, 70 degrees C, 75 degrees C, and 80 degrees C were 142, 71, 35, 18, and 4.6 h, respectively. The enzyme catalyzed the epimerization reactions of the aldoses harboring hydroxyl groups oriented in the right-hand configuration at the C2 position and the left-hand configuration at the C3 position, such as D glucose, D-xylose, L-altrose, L-idose, and L-arabinose, to their C2 epimers, such as D-mannose, D-lyxose, L-allose, L-gulose, and L-ribose, respectively. The enzyme catalyzed also the isomerization reactions. The enzyme exhibited the highest activity for mannose among monosaccharides. Thus, mannose at 75 g l(-1) and fructose at 47.5 g l(-1) were produced from 500 g l(-1) glucose at pH 7.5 and 75 degrees C over 3 h by the enzyme. PMID- 21691790 TI - Regulation of trichothecene biosynthesis in Fusarium: recent advances and new insights. AB - Trichothecenes are toxic secondary metabolites produced by filamentous fungi mainly belonging to the Fusarium genus. Production of these mycotoxins occurs during infection of crops and is a threat to human and animal health. Although the pathway for biosynthesis of trichothecenes is well established, the regulation of the Tri genes implicated in the pathway remains poorly understood. Most of the Tri genes are gathered in a cluster which contains two transcriptional regulators controlling the expression of the other Tri genes. The regulation of secondary metabolites biosynthesis in most fungal genera has been recently shown to be controlled by various regulatory systems in response to external environment. The control of the "Tri cluster" by non-cluster regulators in Fusarium was not clearly demonstrated until recently. This review covers the recent advances concerning the regulation of trichothecene biosynthesis in Fusarium and highlights the potential implication of various general regulatory circuits. Further studies on the role of these regulatory systems in the control of trichothecene biosynthesis might be useful in designing new strategies to reduce mycotoxin accumulation. PMID- 21691789 TI - Biological detoxification of the mycotoxin deoxynivalenol and its use in genetically engineered crops and feed additives. AB - Deoxynivalenol (DON) is the major mycotoxin produced by Fusarium fungi in grains. Food and feed contaminated with DON pose a health risk to humans and livestock. The risk can be reduced by enzymatic detoxification. Complete mineralization of DON by microbial cultures has rarely been observed and the activities turned out to be unstable. The detoxification of DON by reactions targeting its epoxide group or hydroxyl on carbon 3 is more feasible. Microbial strains that de epoxidize DON under anaerobic conditions have been isolated from animal digestive system. Feed additives claimed to de-epoxidize trichothecenes enzymatically are on the market but their efficacy has been disputed. A new detoxification pathway leading to 3-oxo-DON and 3-epi-DON was discovered in taxonomically unrelated soil bacteria from three continents; the enzymes involved remain to be identified. Arabidopsis, tobacco, wheat, barley, and rice were engineered to acetylate DON on carbon 3. In wheat expressing DON acetylation activity, the increase in resistance against Fusarium head blight was only moderate. The Tri101 gene from Fusarium sporotrichioides was used; Fusarium graminearum enzyme which possesses higher activity towards DON would presumably be a better choice. Glycosylation of trichothecenes occurs in plants, contributing to the resistance of wheat to F. graminearum infection. Marker-assisted selection based on the trichothecene-3-O glucosyltransferase gene can be used in breeding for resistance. Fungal acetyltransferases and plant glucosyltransferases targeting carbon 3 of trichothecenes remain promising candidates for engineering resistance against Fusarium head blight. Bacterial enzymes catalyzing oxidation, epimerization, and less likely de-epoxidation of DON may extend this list in future. PMID- 21691791 TI - Characterization of two beta-xylosidases from Bifidobacterium adolescentis and their contribution to the hydrolysis of prebiotic xylooligosaccharides. AB - Xylooligosaccharides have strong bifidogenic properties and are increasingly used as a prebiotic. Nonetheless, little is known about the degradation of these substrates by bifidobacteria. We characterized two recombinant beta-xylosidases, XylB and XylC, with different substrate specificities from Bifidobacterium adolescentis. XylB is a novel beta-xylosidase that belongs to the recently introduced glycoside hydrolase family 120. In contrast to most reported beta xylosidases, it shows only weak activity on xylobiose and prefers xylooligosaccharides with a degree of polymerization above two. The remaining xylobiose is efficiently hydrolyzed by the second B. adolescentis beta xylosidase, XylC, a glycoside hydrolase of family 43. Furthermore, XylB releases more xylose from arabinose-substituted xylooligosaccharides than XylC (30% and 20%, respectively). The different specificities of XylB, XylC, and the recently described reducing-end xylose-releasing exo-oligoxylanase RexA show how B. adolescentis can efficiently degrade prebiotic xylooligosaccharides. PMID- 21691793 TI - Evaluation of cell damage caused by cold sampling and quenching for metabolome analysis. AB - Cell damage during sampling and quenching for metabolome analysis have been investigated at whole sample level using an OD-based method and ATP loss investigation, and at single cell level by means of flow cytometry. Escherichia coli was cultivated in shake flasks and sampled into several cold quenching solutions during exponential growth phase varying quenching solution composition and sampling temperature. For single cell analysis, the samples were incubated with selective propidium iodide dye and analysed via flow cytometry to differentiate between intact and damaged cells. It was found that every combination of quenching solution, temperature, or cooling rate tested influenced the E. coli cell membrane integrity indicating rupture which will not only let the dye in, but also intracellular ATP out of the cells, which is not desired in in vivo metabolome analysis. PMID- 21691792 TI - Renewable energy from Cyanobacteria: energy production optimization by metabolic pathway engineering. AB - The need to develop and improve sustainable energy resources is of eminent importance due to the finite nature of our fossil fuels. This review paper deals with a third generation renewable energy resource which does not compete with our food resources, cyanobacteria. We discuss the current state of the art in developing different types of bioenergy (ethanol, biodiesel, hydrogen, etc.) from cyanobacteria. The major important biochemical pathways in cyanobacteria are highlighted, and the possibility to influence these pathways to improve the production of specific types of energy forms the major part of this review. PMID- 21691794 TI - Enhanced production of alkaline thermostable keratinolytic protease from calcium alginate immobilized cells of thermoalkalophilic Bacillus halodurans JB 99 exhibiting dehairing activity. AB - The thermoalkalophilic Bacillus halodurans JB 99 cells known for production of novel thermostable alkaline keratinolytic protease were immobilized in calcium alginate matrix. Batch and repeated batch cultivation using calcium alginate immobilized cells were studied for alkaline protease production in submerged fermentation. Immobilized cells with 2.5% alginate and 350 beads/flask of initial cell loading showed enhanced production of alkaline protease by 23.2% (5,275 +/- 39.4 U/ml) as compared to free cells (4,280 +/- 35.4 U/ml) after 24 h. In the semicontinuous mode of cultivation, immobilized cells under optimized conditions produced an appreciable level of alkaline protease in up to nine cycles and reached a maximal value of 5,975 U/ml after the seventh cycle. The enzyme produced from immobilized cells efficiently degraded chicken feathers in the presence of a reducing agent which can help the poultry industry in the management of keratin-rich waste and obtaining value-added products. PMID- 21691795 TI - Autochthonous fermentation starters for the industrial production of Negroamaro wines. AB - The aim of the present study was to establish a new procedure for the oenological selection of Saccharomyces cerevisiae strains isolated from natural must fermentations of an important Italian grape cultivar, denoted as "Negroamaro". For this purpose, 108 S. cerevisiae strains were selected as they did not produce H(2)S and then assayed by microfermentation tests. The adopted procedure made it possible to identify 10 strains that were low producers of acetic acid and hydrogen sulphide and showed that they completed sugar consumption during fermentation. These strains were characterized for their specific oenological and technological properties and, two of them, strains 6993 and 6920, are good candidates as industrial starter cultures. A novel protocol was set up for their biomass production and they were employed for industrial-scale fermentation in two industrial cellars. The two strains successfully dominated the fermentation process and contributed to increasing the wines' organoleptic quality. The proposed procedure could be very effective for selecting "company-specific" yeast strains, ideal for the production of typical regional wines. "Winery" starter cultures could be produced on request in a small plant just before or during the vintage season and distributed as a fresh liquid concentrate culture. PMID- 21691796 TI - The effect of different levels of organic and inorganic chromium supplementation on production performance, carcass traits and some blood parameters of broiler chicken under heat stress condition. AB - A total of 250 broilers in a completely randomized design selected to evaluate the effect of different levels of chromium (Cr) supplementation on performance, carcass traits and some blood parameters of heat-stressed broiler chicks. All birds were kept under heat stress temperature (33 +/- 3 degrees C) and divided into five treatments groups. Each treatment consisted of five pens with 10 birds in each pen. The basal diets were supplemented with 0 ppb (control), 800 ppb Cr-L Met (T(1)), 1,200 ppb Cr-L-Met (T(2)) or 800 ppb CrCl(3) (T(3)), and 1,200 ppb CrCl(3) (T(4)). The feed intake and body mass were measured at 10, 21, and 42 days of age. Blood samples were collected from two birds in each replicates to determine biological and hematological values at 28 and 42 days of age. There were no significant difference in mass gain and feed conversion of broilers that received Cr supplementations compared with controls. The serum glucose concentration decreased in broilers received organic chromium methionine supplements compared with other treatments groups. Slight but not significant increases were observed in serum high-density lipoprotein (HDL) concentration of treated groups than controls while the mean serum HDL concentration was significantly higher in T(2) group compared with control group. Serum low-density lipoprotein level decreased in broiler received organic Cr supplements (p < 0.05). PMID- 21691797 TI - In vitro gas production and dry matter degradability of diets consumed by goats with or without copper and zinc supplementation. AB - An in vitro gas production technique was used to evaluate the effects of copper and zinc supplementation on the amount and rate of gas production, dry matter degradability (IVDMD), utilization of metabolizable energy (ME), and ruminal fermentation patterns using rumen fluid from four Boer male goats as inoculum. The goats were fed twice daily at 07:00 and 19:00 h a total mixed ration containing 10.3 and 22.5 mg/kg DM of Cu and Zn, respectively. This diet was incubated in vitro for 96 h with four treatments being: control, Cu (21.7), Zn (5.6), and Cu-Zn (21.7 and 5.6) which was provided as a mineral premix. Data were analyzed as a completely randomized design. Rates of gas production (RGP) at 4 (RGP(4h)) and 6 h (RGP(6h)) and gas production (GP) at 24 (GP(24h)) and 48 h (GP(48h)) differed (p < 0.01) among treatments. An addition of Cu increased the RGP(4h), RGP(6h), GP(24h), and GP(48h) (p < 0.0001). The Cu treatment had the highest IVDMD and control the lowest (p < 0.05), and the Cu treatment was the highest values of ME and SCFA. The addition of Cu to the in vitro ruminal fermentation increased gas production and efficiency of energy use. PMID- 21691798 TI - Effect of copper on morphology, weight, and chromosomal aberrations in the spiny lobster, Panulirus homarus (Linnaeus, 1758). AB - Spiny lobster Panulirus homarus which had been exposed to cupric ion at 9.55 and 19.1 MUg/l for 28 days was examined for sub-lethal effects including morphology, wet weight, and induced genotoxic effect on the chromosome. Following cupric exposure, the color of lobster P. homarus changed from yellowish-brown to greenish black in the hepatopancreas, changed from normal creamy white to yellowish white in the muscle, and changed to greenish black in the gill. A significant change in the percentage of wet weight of muscle (28.70 +/- 0.41 23.47 +/- 0.45), hepatopancreas (4.03 +/- 0.12-2.63 +/- 0.17), and gills (3.63 +/ 0.45-3.87 +/- 0.12) were observed in the copper-treated lobsters. The diploid number of chromosomes of P. homarus was over 200 metaphases from ten lobsters, as 2n = 58, and consisted of 16 acrocentric, seven metacentric, and six sub metacentric chromosomes. The lobsters exposed to cupric ion at 9.55 and 19.1 MUg/l showed different types of chromosomal aberrations such as centromeric gaps, chromatid breaks, centromeric fusion, stickiness, ring chromosomes, and acrocentric association region. The frequency of aberrations increased with duration of exposure. In conclusion, it was suggested that cupric ion interacts with the spindle formation and consequently distorts the normal karyomorphology, indicating cytogenetic effect on lobster. PMID- 21691799 TI - The relationship between serum selenium concentration and neutrophil function in peripheral blood. AB - We evaluated the relationships between neutrophil-related functions and serum selenium (Se) concentration in the general population. We examined 800 subjects who had participated in the Iwaki Health Promotion Project in 2005 to determine the relationships between serum Se concentration and neutrophil-related functions such as the production capability of reactive oxygen species (ROS), phagocytic activity, and serum opsonic activity (SOA). In nonstimulated neutrophils, i.e., in neutrophils at their baseline condition before the application of the phagocytic stimulus, the serum Se concentration tends to be high and the ROS production tends to be low. With regard to SOA, there was a significant negative correlation between lucigenin-dependent chemiluminescence and serum Se concentration in both men and women. Moreover, in women, a significant negative correlation was observed between luminol-dependent chemiluminescence and serum Se concentration. These results suggest that subjects with a lower serum Se concentration may be exposed to a greater chronic oxidative stress due to neutrophil ROS production. In addition, the findings of our study suggest that women rather than men benefit more from Se against oxidative stress. PMID- 21691800 TI - Selective interaction of amyloid precursor protein with different isoforms of neural cell adhesion molecule. AB - Compare to the thoroughly studied beta-amyloid, the physiological function of amyloid precursor protein (APP) is not well understood. We now had identified neural cell adhesion molecule (NCAM)-140 as a potential interaction partner of APP. Our data indicated that NCAM-140, but not NCAM-180, binds to the conserved central extracellular domain of APP. We also found that the phosphorylation levels of ERK1 and ERK2 were increased when cells were co-transfected with NCAM 140 and APP indicate that the interaction between NCAM-140 and APP may involve the MAPK pathway. These findings demonstrated that NCAM-140 interacts with APP, potentially playing a role in neurite outgrowth and neural development. PMID- 21691801 TI - The small chaperone protein p23 and its cleaved product p19 in cellular stress. AB - The presence of misfolded proteins elicits cellular responses including an endoplasmic reticulum (ER) stress response that may protect cells against the toxic buildup of misfolded proteins. Accumulation of these proteins in excessive amounts, however, overwhelms the "cellular quality control" system and impairs the protective mechanisms designed to promote correct folding and degrade misfolded proteins, ultimately leading to organelle dysfunction and cell death. Studies from multiple laboratories have identified the roles of several ER stress induced cell death modulators and effectors. Earlier, we reported the role of the small co-chaperone protein p23 in preventing ER stress-induced cell death. p23 undergoes caspase-dependent cleavage to yield a 19-kD product (p19), and mutation of this caspase cleavage site not only blocks the formation of the 19-kD product but also attenuates the ER stress-induced cell death process triggered by various stressors. Thus, a critical question is whether p23 and/or p19 could serve as an in vivo marker for neurodegenerative diseases featuring misfolded proteins and cellular stress. In the present study, we used an antibody that recognizes both p23 and p19 as well as a specific neo-epitope antibody that detects only the p19 fragment. These antibodies were used to detect the presence of both these proteins in cells, primary neurons, brain samples from a mouse model of Alzheimer's disease (AD), and fixed human AD brain samples. While patients with severe AD did display a consistent reduction in p23 levels, our inability to observe p19 in mouse or human AD brain samples suggests that the usefulness of the p23 neo-epitope antibody is restricted to cells and primary neurons undergoing cellular stress. PMID- 21691803 TI - Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer. AB - BACKGROUND: Tramadol is a synthetic, centrally acting analgesic for the treatment of moderate to severe pain. The marketed tramadol is a racemic mixture containing 50% (+)tramadol and 50% (-)tramadol and is mainly metabolized to O desmethyltramadol (M1) by the cytochrome P450 CYP2D6. Tramadol is generally considered to be devoid of any serious adverse effects of traditional opioid receptor agonists, such as respiratory depression and drug dependence. CASE REPORT: A 22-year-old Caucasian female patient was admitted to our ICU in refractory cardiac arrest requiring extracorporeal membrane oxygenation. This aggressive support allowed resolution of multi-organ dysfunction syndrome. Repeated blood analyses using liquid chromatography-tandem mass spectrometry confirmed high concentrations of both tramadol and its main metabolite O desmethyltramadol. Genotyping of CYP2D6 revealed the patient to be heterozygous for a duplicated wild-type allele, predictive of a CYP2D6 ultrarapid metabolizer (UM) phenotype, confirmed by calculation of the tramadol/M1 (MR1) metabolic ratio at all time points. DISCUSSION: We here report a case of near-fatal isolated tramadol cardiotoxicity. Because of the inhibition of norepinephrine reuptake, excessive blood epinephrine levels in this CYP2D6R UM patient following excessive tramadol ingestion could explain the observed strong myocardial stunning. This patient admitted intermittent tramadol consumption to gain a "high" sensation. In patients with excessive morphinomimetic effects, levels of tramadol and its main metabolite M1could be measured, ideally combined with CYP2D6 genotyping, to identify individuals at risk of tramadol-related cardiotoxicity. Tramadol treatment could be optimized in these at-risk individuals, consequently improving patient outcome and safety. PMID- 21691804 TI - A meta-analysis of the therapeutic effects of tumor necrosis factor-alpha blockers on ulcerative colitis. AB - PURPOSE: To evaluate the therapeutic effects of TNF-alpha blockers on ulcerative colitis (UC) and their safety. METHODS: Randomized controlled trials (RCTs) of TNF-alpha blockers for treatment of UC were retrieved from databases. Heterogeneity test was performed on all data to select effects models. Finally, sensitivity analysis was carried out, and a funnel plot was drawn to evaluate publication bias. RESULTS: A total of nine RCTs conformed to the inclusion criteria. Of 1,226 patients with UC, 806 were given a TNF-alpha blocker, and 420 were given placebo or other drugs as control. Infliximab was used in eight papers and adalimumab in one paper. Placebo was used in seven papers and hormones in two papers. Short-term response, short-term relief, long-term response, and long-term relief were better in the TNF-alpha blocker group than in the control group (P < 0.05). TNF-alpha blockers decreased the colectomy rate (P < 0.05). There were no significant differences in mucosal healing and quality of life between the two groups (P > 0.05). The rates of adverse reactions were similar in the two groups (P > 0.05), but the rate of severe adverse reactions was significantly lower in the TNF-alpha blocker group than in the control group (P < 0.05). The funnel plot of each parameter was symmetrical with the lower part broader than the upper. CONCLUSIONS: TNF-alpha blockers have better therapeutic effects on moderate or severe UC, which shows little response to conventional therapy. TNF-alpha blockers can induce short-term response, maintain long-term clinical response and clinical relief, and decrease the colectomy rate and the severe adverse reaction rate, but they fail to improve quality of life and mucosal healing. PMID- 21691802 TI - Structure, function, and mechanism of progranulin; the brain and beyond. AB - Mutation of human GRN, the gene encoding the secreted glycoprotein progranulin, results in a form of frontotemporal lobar degeneration that is characterized by the presence of ubiquitinated inclusions containing phosphorylated and cleaved fragments of the transactivation response element DNA-binding protein-43. This has stimulated interest in understanding the role of progranulin in the central nervous system, and in particular, how this relates to neurodegeneration. Progranulin has many roles outside the brain, including regulation of cellular proliferation, survival, and migration, in cancer, including cancers of the brain, in wound repair, and inflammation. It often acts through the extracellular signal-regulated kinase and phopshatidylinositol-3-kinases pathways. The neurobiology of progranulin has followed a similar pattern with proposed roles for progranulin (PGRN) in the central nervous system as a neuroprotective agent and in neuroinflammation. Here we review the structure, biology, and mechanism of progranulin action. By understanding PGRN in a wider context, we may be better able to delineate its roles in the normal brain and in neurodegenerative disease. PMID- 21691805 TI - Mild hypoglycaemic attacks induced by sulphonylureas related to CYP2C9, CYP2C19 and CYP2C8 polymorphisms in routine clinical setting. AB - AIM: To evaluate the impact of polymorphisms in the cytochrome P450 (CYP) 2C9, 2C19 and 2C8 genes on the risk of mild hypoglycaemic attacks in patients treated with sulphonylureas. METHODS: One hundred and eight type 2 diabetic patients (50 men, 58 women), treated with oral antidiabetics, including at least one from the sulphonylurea group (glimepiride n = 50, gliclazide n = 46, or glipizide n = 12) for 3 months or longer, were included in the study. Symptoms of hypoglycaemia (sweating, tremor, anxiety and palpitations) during a 3 month period were recorded and confirmed by home glucose measurements. Gender, age, body mass index, creatinine clearance, HbA1c, oral antidiabetic dose and concomitant medication were assessed together with functional CYP2C9, CYP2C19 and CYP2C8 polymorphisms, analysed by real-time PCR methods. RESULTS: Fifteen patients (eight men, seven women) reported hypoglycaemia symptoms which were validated by their home glucose measurements (< 70 mg/dl). Heterozygosity and homozygosity for CYP2C9 variant alleles (*2 or *3) tended to be more frequent among patients who reported hypoglycaemic attacks (60 and 7%) than those who did not (39 and 3%). Similarly, the CYP2C8*1/*3 genotype tended to be more frequent in patients with (47%) than without (27%) hypoglycaemia, while no such trend was observed for CYP2C19 variants. However, only in the gliclazide group a significant association between CYP2C9 genotype and hypoglycaemic attacks was observed (P = 0.035). None of the other covariates showed any significant association with the risk of hypoglycaemic attacks. CONCLUSIONS: CYP2C9 polymorphisms leading to decreased enzyme activity show a modest impact on the risk of mild hypoglycaemia attacks during oral antidiabetic treatment, with a significant association in patients treated with gliclazide. PMID- 21691806 TI - Potentially inappropriate drug prescription in the elderly in France: a population-based study from the French National Insurance Healthcare system. AB - BACKGROUND: Inappropriate prescribing is a known risk factor for adverse drug event occurrence in the elderly. In various countries, several studies have used insurance healthcare databases to estimate the national prevalence of potentially inappropriate medications (PIM) in the elderly, as defined by explicit PIM lists. Recently, a representative sample of the French National Insurance Healthcare database, known as the "Echantillon Generaliste des Beneficiaires" (EGB), was created, making it possible to assess the quality of drug prescription in France. Our objective was to evaluate the prevalence and the regional distribution of PIM prescription in the elderly aged 75 years and over in France, using the French PIM list and the EGB database. METHODS: The list of drugs reimbursed to patients aged 75 years and over from 1 March 2007 to 29 February 2008 was extracted from the EGB. Drugs were classified as inappropriate using the French PIM list. A PIM user was defined as a person receiving at least one PIM reimbursement during the study period. Interregion variability was estimated from logistic regression. RESULTS: In 53.6% (95% CI: 53.0-54.1) of the elderly aged 75 years and over, at least one PIM was given during the study period. The three main drug groups identified were cerebral vasodilators (19.4%), drugs with antimuscarinic properties (19.3%), and long half-life benzodiazepines (17.8%). There was an important disparity in PIM prescription among the French regions. In 14 out of 22 regions, the risk of PIM prescription was significantly elevated. This geographical variation differed for the different drug groups. CONCLUSION: PIM prescription in the elderly is a major and worrying problem in France. As in other countries, recent accessibility of the National Insurance Healthcare database makes it possible to create local indicators that the regional health agencies could use to manage public health policy in closer alignment to the needs of the patients within each French region. PMID- 21691807 TI - Palatability and chemical defense of Phragmites australis to the marsh periwinkle snail Littoraria irrorata. AB - Coastal marsh habitats are impacted by many disturbances, including habitat destruction, pollution, and the introduction of invasive species. The common reed, Phragmites australis, has been particularly invasive in the mesohaline regions of the Chesapeake Bay, but few studies have investigated its role in trophic interactions with North American marsh consumers. The marsh periwinkle snail Littoraria irrorata is a common grazer in marshes and grazes on the native grass Spartina alterniflora. Whether this snail grazes on Phragmites has not been addressed. We found Spartina leaves to be tougher than those of Phragmites, but despite this, snails consumed significantly more Spartina than Phragmites. Subsequent experiments demonstrated that Phragmites is chemically deterrent to snails by an unknown, moderately polar, compound. Further studies are required to more fully understand the interactions between Phragmites, herbivores, and Spartina, and how they may impact marsh ecosystems. PMID- 21691808 TI - Production of induced volatiles by Datura wrightii in response to damage by insects: effect of herbivore species and time. AB - Natural enemies of herbivorous insects utilize numerous chemical cues to locate and identify their prey. Among these, volatile plant compounds produced after attack by herbivores may play a significant role (hereafter herbivore-induced plant volatiles or HIPVs). One unresolved question is whether the composition of the volatile cue blends induced by different herbivore species differ consistently enough to indicate not only that the plants are damaged by herbivores but also the identity of the herbivore species causing the damage. We studied HIPV production in the undomesticated plant species Datura wrightii in the laboratory when damaged by either of two leaf-chewing herbivore species, Lema daturaphila or Manduca sexta, or when damaged by L. daturaphila and the piercing sucking bug, Tupiocoris notatus, or both L. daturaphila and T. notatus, for 24 hr. HIPV production was monitored 1 d before induction, the day of induction, and for 7 d after induction. In all experiments, both the quantities and composition of the HIPV blends varied with the time since induction as different components reached peak production at different times after induction. HIPV blends did not differ consistently with the herbivore species causing the damage. For plants damaged by both L. daturaphila and T. notatus, greater amounts of HIPVs were produced than by plants damaged by either species alone, but the amounts did not differ from that predicted as the sum from damage inflicted by each herbivore species independently. The HIPVs of D. wrightii are a general rather than specific indicator of damage by herbivores. Because generalist predators are the most abundant natural enemies in this system, general cues of herbivore damage may be all that are required to facilitate the discovery by predators of plants damaged by any of several suitable prey species. PMID- 21691809 TI - Silencing defense pathways in Arabidopsis by heterologous gene sequences from Brassica oleracea enhances the performance of a specialist and a generalist herbivorous insect. AB - The jasmonic acid (JA) signaling pathway and defensive secondary metabolites such as glucosinolates are generally considered to play central roles in the defense of brassicaceous plants against herbivorous insects. To determine the function of specific plant genes in plant-insect interactions, signaling or biosynthetic mutants are needed. However, mutants are not yet available for brassicaceous plants other than Arabidopsis thaliana, e.g., cabbage (Brassica oleracea). We employed virus-induced gene silencing (VIGS) by using tobacco rattle virus (TRV) to knock down the endogenous expression of lipoxygenase (LOX), an upstream enzyme of the JA pathway and thioglucoside glucohydrolase: myrosinase (TGG1/TGG2), a hydrolytic enzyme that catalyzes the release of defensive volatile products originating from glucosinolates, in Arabidopsis thaliana. This was done by using the heterologous gene sequences from B. oleracea. Silencing these genes in A. thaliana plants is efficient and specific. Only 18 nucleotides with 100% identity between the trigger (BoMYR) and the target (AtTGG1/2) sequence are sufficient to achieve gene silencing. LOX-silenced plants showed significantly reduced AtLOX2 transcript accumulation after Pieris rapae larval feeding. TGG-silenced plants exhibited significantly lower TGG1/TGG2 transcript levels only after shorter larval feeding. The inhibition of TGG1/TGG2 transcript accumulation via gene silencing may be overruled by longer larval feeding. Specialist P. rapae larvae developed significantly better on both types of silenced plants than on empty vector (EV) control plants, while generalist Mamestra brassicae larvae developed significantly better on the TGG1/TGG2 silenced plants than on EV control plants. This shows that not only the generalist herbivore but also the Brassicaceae specialist P. rapae is negatively affected by the ability of brassicaceous plants to produce their specific secondary metabolites, i.e., glucosinolates. Our results demonstrate the important roles of AtLOX2 and AtTGG1/TGG2 genes, which were silenced by heterologous gene sequences from B. oleracea BoLOX and BoMYR, in A. thaliana resistance to the specialist P. rapae and the generalist M. brassicae. PMID- 21691810 TI - Differential performance of a specialist and two generalist herbivores and their parasitoids on Plantago lanceolata. AB - The ability to cope with plant defense chemicals differs between specialist and generalist species. In this study, we examined the effects of the concentration of the two main iridoid glycosides (IGs) in Plantago lanceolata, aucubin and catalpol, on the performance of a specialist and two generalist herbivores and their respective endoparasitoids. Development of the specialist herbivore Melitaea cinxia was unaffected by the total leaf IG concentration in its host plant. By contrast, the generalist herbivores Spodoptera exigua and Chrysodeixis chalcites showed delayed larval and pupal development on plant genotypes with high leaf IG concentrations, respectively. This result is in line with the idea that specialist herbivores are better adapted to allelochemicals in host plants on which they are specialized. Melitaea cinxia experienced less post-diapause larval and pupal mortality on its local Finnish P. lanceolata than on Dutch genotypes. This could not be explained by differences in IG profiles, suggesting that M. cinxia has adapted in response to attributes of its local host plants other than to IG chemistry. Development of the specialist parasitoid Cotesia melitaearum was unaffected by IG variation in the diet of its host M. cinxia, a response that was concordant with that of its host. By contrast, the development time responses of the generalist parasitoids Hyposoter didymator and Cotesia marginiventris differed from those of their generalist hosts, S. exigua and C. chalcites. While their hosts developed slowly on high-IG genotypes, development time of H. didymator was unaffected. Cotesia marginiventris actually developed faster on hosts fed high-IG genotypes, although they then had short adult longevity. The faster development of C. marginiventris on hosts that ate high-IG genotypes is in line with the "immunocompromized host" hypothesis, emphasizing the potential negative effects of toxic allelochemicals on the host's immune response. PMID- 21691811 TI - Structural insights for the design of new PPARgamma partial agonists with high binding affinity and low transactivation activity. AB - Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) full agonists are molecules with powerful insulin-sensitizing action that are used as antidiabetic drugs. Unfortunately, these compounds also present various side effects. Recent results suggest that effective PPARgamma agonists should show a low transactivation activity but a high binding affinity to inhibit phosphorylation at Ser273. We use several structure activity relationship studies of synthetic PPARgamma agonists to explore the different binding features of full and partial PPARgamma agonists with the aim of differentiating the features needed for binding and those needed for the transactivation activity of PPARgamma. Our results suggest that effective partial agonists should have a hydrophobic moiety and an acceptor site with an appropriate conformation to interact with arm II and establish a hydrogen bond with Ser342 or an equivalent residue at arm III. Despite the fact that interactions with arm I increase the binding affinity, this region should be avoided in order to not increase the transactivation activity of potential PPARgamma partial agonists. PMID- 21691812 TI - Obituary: Corwin H. Hansch. AB - This is the obituary for Corwin Hansch, pioneer of the quantitative structure activity relationship (QSAR) paradigm. PMID- 21691813 TI - Quantum mechanics study of the hydroxyethylamines-BACE-1 active site interaction energies. AB - The identification of BACE-1, a key enzyme in the production of Amyloid-beta (Abeta) peptides, generated by the proteolytic processing of amyloid precursor protein, was a major advance in the field of Alzheimer's disease as this pathology is characterized by the presence of extracellular senile plaques, mainly comprised of Abeta peptides. Hydroxyethylamines have demonstrated a remarkable potential, like candidate drugs, for this disease using BACE-1 as target. Density Functional Theory calculations were employed to estimate interaction energies for the complexes formed between the hydroxyethylamine derivated inhibitors and 24 residues in the BACE-1 active site. The collected data offered not only a general but a particular quantitative description that gives a deep insight of the interactions in the active site, showing at the same time how ligand structural variations affect them. Polar interactions are the major energetic contributors for complex stabilization and those ones with charged aspartate residues are highlighted, as they contribute over 90% of the total attractive interaction energy. Ligand-ARG296 residue interaction reports the most repulsive value and decreasing of the magnitude of this repulsion can be a key feature for the design of novel and more potent BACE-1 inhibitors. Also it was explained why sultam derivated BACE-1 inhibitors are better ones than lactam based. Hydrophobic interactions concentrated at S1 zone and other relevant repulsions and attractions were also evaluated. The comparison of two different theory levels (X3LYP and M062X) allowed to confirm the relevance of the detected interactions as each theory level has its own strength to depict the forces involved, as is the case of M062X which is better describing the hydrophobic interactions. Those facts were also evaluated and confirmed by comparing the quantitative trend, of selected ligand-residue interactions, with MP2 theory level as reference standard method for electrostatic plus dispersion energies. PMID- 21691814 TI - Multichannel oscillatory-flow multiplex PCR microfluidics for high-throughput and fast detection of foodborne bacterial pathogens. AB - In the field of continuous-flow PCR, the amplification throughput in a single reaction solution is low and the single-plex PCR is often used. In this work, we reported a flow-based multiplex PCR microfluidic system capable of performing high-throughput and fast DNA amplification for detection of foodborne bacterial pathogens. As a demonstration, the mixture of DNA targets associated with three different foodborne pathogens was included in a single PCR solution. Then, the solution flowed through microchannels incorporated onto three temperature zones in an oscillatory manner. The effect factors of this oscillatory-flow multiplex PCR thermocycling have been demonstrated, including effects of polymerase concentration, cycling times, number of cycles, and DNA template concentration. The experimental results have shown that the oscillatory-flow multiplex PCR, with a volume of only 5 MUl, could be completed in about 13 min after 35 cycles (25 cycles) at 100 MUl/min (70 MUl/min), which is about one-sixth of the time required on the conventional machine (70 min). By using the presently designed DNA sample model, the minimum target concentration that could be detected at 30 MUl/min was 9.8 * 10(-2) ng/MUl (278-bp, S. enterica), 11.2 * 10(-2) ng/MUl (168 bp, E. coli O157: H7), and 2.88 * 10(-2) ng/MUl (106-bp, L. monocytogenes), which corresponds to approximately 3.72 * 10(4) copies/MUl, 3.58 * 10(4) copies/MUl, and 1.79 * 10(4) copies/MUl, respectively. This level of speed and sensitivity is comparable to that achievable in most other continuous-flow PCR systems. In addition, the four individual channels were used to achieve multi-target PCR analysis of three different DNA samples from different food sources in parallel, thereby achieving another level of multiplexing. PMID- 21691815 TI - Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer. AB - Carbonic anhydrase IX (CAIX) is a strictly membranous expressed metalloenzyme involved in cell adhesion, pH homeostasis, and cancer progression. This study was designed to assess the role of CAIX in primary ovarian cancer. Two hundred five well-characterized primary ovarian carcinomas were analyzed on a tissue microarray. CAIX expression was determined by immunohistochemistry using a four step scoring system. Moderate and strong membranous CAIX expression was found in 37 out of 205 (18%) of all assessable ovarian cancer specimens. High levels of CAIX expression were related to mucinous and endometrioid phenotype of ovarian carcinomas (p < 0.05). There was no association between CAIX overexpression and tumor stage, grading, and mitotic count of ovarian carcinomas (p > 0.05). In univariate Cox regression analysis, advanced tumor stage (p < 0.01), high tumor grade (p = 0.017), high mitotic count (p = 0.025), and high CAIX expression levels (p = 0.031) were correlated to shorter overall patient survival. High pT stage (p = 0.036) and CAIX overexpression were connected to poor clinical outcome in endometrioid ovarian carcinomas. Multivariate Cox regression hazard analysis comprising tumor stage, tumor grade, mitotic count, and CAIX expression revealed pT2/3 stage and CAIX overexpression (scores 2 and 3) as independent prognostic markers in ovarian cancer (p < 0.01, each) as well as in the subgroup of endometrioid carcinomas (p < 0.05, each). In conclusion, CAIX is overexpressed in a substantial proportion of mucinous and endometrioid ovarian carcinomas and connected to poor patient outcome. Our data support the potential therapeutic benefit of newly developed targeting antibodies in advanced ovarian cancer. PMID- 21691816 TI - OATP 1B1/1B3 expression in hepatocellular carcinomas treated with orthotopic liver transplantation. AB - The organic anion transporter peptides (OATP) 1B1 and 1B3 are hepatocytic specific transporters determinant for the uptake of the contrast media Gd-EOB DTPA during magnetic resonance, but variably lost in hepatocellular carcinoma (HCC). Here, we studied a series of HCCs from livers that underwent liver transplantation (OLT) and correlated the expression of OATP 1B1/1B3 with HCC morphological features and the expression of the biliary-type keratins K7 and K19, the latter previously correlated with a worse prognosis after OLT. Seventy five HCCs from 69 OLT patients were evaluated by histology and immunohistochemistry with monoclonal antibodies against OATP 1B1/1B3, K7, and K19. Histopathological and immunohistochemical features were therefore compared to recipient follow-up data. Thirty-four (45%) HCCs were completely OATP-, and 18 (24%) showed positivity for K7 and/or K19. We observed a significant inverse correlation between OATP and K7/19 expression (P < 0.001): all OATP+ cases were K7/19-, while all K7+ and/or K19+ cases were OATP-. Sixteen cases were negative for all antibodies. No correlation was found between histopathological features and immunohistochemistry. Twenty-five recipients experienced HCC recurrence, and ten died from neoplastic recurrence. Neither OATP nor keratin expressions were correlated with HCC recurrence, while OATP negativity significantly correlated with HCC-related death after recurrence (P = 0.036). In conclusion, HCCs show a progressive loss in OATP immunoreactivity that correlates with the gain of a biliary phenotype. Although further studies are required to define these findings better, our results support the idea that OATP could be used together with K7/19 to identify a phenotypical "spectrum" in HCC progression. PMID- 21691818 TI - Detection of circulating tumor cells by RT-PCR significantly associated with poor prognosis in breast cancer. PMID- 21691817 TI - Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial. AB - A double-blind placebo-controlled randomized phase II trial was performed to determine whether High Dose Vitamin D2 supplementation (HDD) in women receiving adjuvant anastrozole improves aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) and bone loss. Patients with early breast cancer and AIMSS were stratified according to their baseline 25-hydroxy vitamin D (25OHD) level. Stratum A (20-29 ng/ml) received either HDD 50,000 IU capsules weekly for 8 weeks then monthly for 4 months or placebo. Stratum B (10-19 ng/ml) received either HDD for 16 weeks and then monthly for 2 months, or placebo. AIMSS was assessed by the Brief Pain Inventory-Short Form (BPI-SF), the Fibromyalgia Impact Questionnaire (FIQ), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at baseline, 2, 4, and 6 months. Bone Mineral Density (BMD) was measured at baseline and at 6 months. The primary endpoint of the study was the change-from-baseline musculoskeletal pain. The secondary endpoint was the percent change in BMD at 6 months. Sixty women were enrolled. Baseline characteristics were comparable between the groups. At 2 months, FIQ pain (P = 0.0045), BPI worst-pain (P = 0.04), BPI average-pain (P = 0.0067), BPI pain-severity (P = 0.04), and BPI interference (P = 0.034) scores were better in the HDD than placebo group. The positive effect of HDD on AIMSS was stronger across all time points in Stratum B than Stratum A (FIQ pain, P = 0.04; BPI average, P = 0.03; BPI severity, P = 0.03; BPI interference, P = 0.04). BMD at the femoral neck decreased in the placebo and did not change in the HDD group (P = 0.06). Weekly HDD improves AIMSS and may have a positive effect on bone health. Vitamin D supplementation strategies for breast cancer patients on AI should be further investigated. PMID- 21691819 TI - A nutritional intervention to reduce the calorie content of meals served at psychiatric rehabilitation programs. AB - To assess the effectiveness of an intervention to reduce the calorie content of meals served at two psychiatric rehabilitation programs. Intervention staff assisted kitchen staff with ways to reduce calories and improve the nutritional quality of meals. Breakfast and lunch menus were collected before and after a 6 month intervention period. ESHA software was used to determine total energy and nutrient profiles of meals. Total energy of served meals significantly decreased by 28% at breakfast and 29% at lunch for site 1 (P < 0.05); total energy significantly decreased by 41% at breakfast for site 2 (P = 0.018). Total sugars significantly decreased at breakfast for both sites (P <= 0.001). In general, sodium levels were high before and after the intervention period. The nutrition intervention was effective in decreasing the total energy and altering the composition of macro-nutrients of meals. These results highlight an unappreciated opportunity to improve diet quality in patients attending psychiatric rehabilitation programs. PMID- 21691820 TI - Self-rated assessment of needs for mental health care: a qualitative analysis. AB - This study explored perceived mental health-related needs and barriers to meeting them in primary and mental health care settings. Fifty-one participants completed the Perceived Need for Care Questionnaire and an interview to qualitatively explore the meanings behind self-identified needs for medication, information, counselling, practical help, and skills development. Qualitative content analysis indicated perceived needs for care are multifaceted. Dissatisfaction with taking medication may coexist with perceiving medication needs as met; information needs predominantly concerned wanting to better understand one's illness; and communication was the main perceived barrier to meeting these needs. Counselling related needs included being listened to, supported or assisted with problem solving, with service attitudes, staff expertise or cost seen as limiting access. Needs for practical help and skills development were described as unmet or addressed by family, and help-seeking for these needs constrained by efforts to self-manage, insufficient information, and affordability. Collaborative care and information-sharing appear important to better meet mental health-related perceived needs. PMID- 21691821 TI - The parental attitudes toward psychological services inventory: adaptation and development of an attitude scale. AB - The purpose of this paper is to provide psychometric data on the Parental Attitudes Toward Psychological Services Inventory (PATPSI), which is a revised measure to assess parents' attitudes toward outpatient mental health services. Using a sample of adults (N = 250), Study 1 supported a 3-factor structure (RMSEA = .05, NNFI = .94, and CFI = .94), adequate internal consistency (ranging from .72 to .92), and test-retest reliability (ranging from .66 to .84). Additionally, results indicated that individuals with previous use of mental health services reported more positive views toward child mental health services. Study 2 provided confirming evidence of the 3-factor structure (NNFI = .94, RMSEA = .08, and the CFI = .95) and adequate reliability (ranging from .70 to .90) using a parent-sample (N = 260). Additionally, discriminate validity of the PATPSI was supported. Implications for research and clinical practice are discussed. PMID- 21691822 TI - Quality assessment of physical activity recommendations within clinical practice guidelines for the prevention and treatment of cardio-metabolic risk factors in people with schizophrenia. AB - The aim of this review was to assess the quality of physical activity recommendations within clinical practice guidelines for the prevention and treatment of the cardio-metabolic risk factors in schizophrenia. Several databases were searched from their inception through July 2010. The Appraisal of Guidelines for Research and Evaluation instrument was used for the quality assessment. Twelve recommendations met all the in- and exclusion criteria. The overall agreement of the quality assessment using the intraclass correlation coefficient was 0.90. Comparison identified considerable variation in the quality of the content. Based on quality assurance standards, only one of 12 guidelines was recommended. Differences on in-depth analysis suggest a lack of consistency in relation to information about the potential role of physical activity in reducing cardiometabolic risks in schizophrenia. High quality recommendations are highly needed along with specific practical advice for persons with schizophrenia, family members and health care professionals. PMID- 21691823 TI - Age-specific eNOS polymorphisms in moyamoya disease. AB - OBJECTIVE: We conducted a case-control study to investigate whether polymorphisms in eNOS are related to the age-specific onset of moyamoya disease. MATERIALS AND METHODS: Ninety-three Korean patients [mean age, 23.0 +/- 16.1 years; 59 female (63.4%) and 34 male (36.6%)] with moyamoya disease were consecutively recruited for this study. Three hundred twenty-eight healthy subjects [mean age, 27.7 +/- 16.2 years; 217 female (66.2%), 111 male (33.8%)] were consecutively included in the control group. The subjects were divided into pediatric (< 20 years) and adult (>= 20 years) groups. We further divided the moyamoya group into ischemic and hemorrhagic groups based on clinical and MRI findings. The frequencies and distributions of four eNOS polymorphisms (eNOS -922A>G, -786T>C, 4a4b, and 894G>T) were assessed in pediatric and adult patients with moyamoya disease and compared to the frequencies and distribution in the control group. RESULTS: No differences in eNOS polymorphisms were observed between control and moyamoya disease group. However, we found that the 4a4b sequences was less frequent in the adult group (p = 0.029). Compared to the control group, there were differences in the haplotype distribution of the study group, specifically the A-4b-G haplotype, which was seen more frequently in the adult patient group. CONCLUSION: Our results suggest that pediatric and adult-onset moyamoya disease have different genetic backgrounds. These genetic differences can affect age-specific clinical characteristics, such as cerebral ischemia and hemorrhage. PMID- 21691824 TI - Endovascular treatment of a traumatic carotid artery aneurysm after endoscopic arachnoid cyst fenestration. PMID- 21691825 TI - Pediatric temporal low-grade glial tumors: epilepsy outcome following resection in 48 children. AB - PURPOSE: This paper summarizes our experience with surgical treatment of pediatric low-grade glial temporal lobe tumors focusing on the long-term outcome of seizures and identifying factors associated with seizure control and failure. METHODS: We reviewed all medical records of pediatric patients that underwent temporal lobe surgery due to seizures at our institution between 1997 and 2009. Only patients with temporal lobe tumors were included in this series. The files were retrospectively reviewed for seizure history. All children had undergone pre and postoperative evaluation, neurological examination, EEG, and MRI. RESULTS: The cohort includes 48 children with mean follow-up time of 5.15 years (1-12 years). The mean age at surgery was 8.2 years (1-18.1) and the mean seizure duration until surgery was 2.6 years. All lesions in the cohort were low-grade tumors; pilocytic astrocytoma was the most common (41%). Eighty-three percent of the patients were classified as Engel class I following surgery. There was no correlation between Engel score and the preoperative epilepsy duration, age of seizure onset or type of seizures, and pathology. The surgical complication rate was 4.1% (2/48). CONCLUSIONS: Surgical treatment for seizure control in children and adolescents with low-grade temporal tumors provides excellent long-term results. PMID- 21691826 TI - In vitro inactivation of endodontic pathogens with Nd:YAG and Er:YAG lasers. AB - Both Nd:YAG and Er:YAG lasers have been suggested as root canal disinfection aids. The aim of this in vitro study is to compare both wavelengths in terms of irradiation dose required for microbial inactivation, to quantify these irradiation doses and to investigate the influence of certain (laser) parameters on the antimicrobial efficacy. Agar plates containing a uniform layer of Enterococcus faecalis, Candida albicans or Propionibacterium acnes were mounted perpendicularly underneath the laser handpieces (5 mm spot). The Er:YAG laser was operated in single-pulse mode. Pulse energies of 40-400 mJ and pulse lengths of 100, 300, 600, and 1,000 MUs were tested. After incubation at 37 degrees C for 48 h, growth on the plates was scored. The pulse energy yielding complete absence of growth over the entire spot area was taken as the total inhibition threshold (TIT). TITs were determined for every species and pulse length. The Nd:YAG laser was operated with pulse trains because single pulses were ineffective. Output power was 15 W and frequency was 100 Hz. Spots were irradiated for 5-120 s. After incubation, the diameters of the inhibition zones were measured. For the Er:YAG laser, TITs varied between 100 and 210 mJ, and differed significantly between species and pulse lengths. Using Nd:YAG irradiation, TITs were around 5,300 J/cm(2) for C. albicans and 7,100 J/cm(2) for P. acnes. No inhibition was observed for E. faecalis. Er:YAG irradiation was superior to Nd:YAG in inactivating microorganisms on agar surfaces. PMID- 21691827 TI - Sclerosing epithelioid fibrosarcoma of the oral cavity. AB - Sclerosing epithelioid fibrosarcoma (SEF) rarely occurs outside the somatic soft tissue. Until recently no consistently specific genetic alteration had been associated with SEF. Molecular testing of the FUS gene rearrangement involving chromosome 16 [at one time considered specific for low-grade fibromyxoid sarcoma (LGFMS) and its variant, LGFMS with giant collagen rosettes), may be a nonrandom abnormality in some cases of SEF.We present an example of a rare FUS-positive SEF that arose in the floor of mouth of a 56 year old male. Light microscopy, exhaustive immunohistology, and FISH examination showing chromosome rearrangement using the FUS break-apart probe led to an erroneous diagnosis of LGFMS with giant collagen rosettes. An outside expert agreed with that diagnosis citing the FISH results as confirmatory. Upon review almost 2 years later after local recurrence, the classic histopathologic features of SEF were noted instead. This example suggests that at least a subset if not most examples of SEF are part of the LGFMS "family" of neoplasms, and reiterates the value of careful histologic examination in an age of increasingly sophisticated and presumably specific molecular results. PMID- 21691828 TI - Chondromyxoid fibroma of the ethmoid sinus. PMID- 21691829 TI - Antibacterial coatings on haemodialysis catheters by photochemical deposition of silver nanoparticles. AB - Antibacterial coatings on catheters for acute dialysis were obtained by an innovative and patented silver deposition technique based on the photo-reduction of the silver solution on the surface of catheter, with consequent formation of antibacterial silver nanoparticles. Aim of this work is the structural and morphological characterization of these medical devices in order to analyze the distribution and the size of clusters on the polymeric surface, and to verify the antibacterial capability of the devices treated by this technique against bacterial proliferation. The structure and morphology of the silver nanoparticles were investigated by using scanning and transmission electron microscopy. The antimicrobial capability of the catheters after silver deposition was confirmed by antibacterial tests with Escherichia coli. Both scanning electron microscopy analysis and antibacterial tests were performed also after washing catheters for 30 days in deionized water at 37 degrees C, relating these data to thermogravimetric analysis and to energy dispersive spectroscopy, in order to check the resistance of coating and its antimicrobial capability after the maximum time of life of these devices. PMID- 21691830 TI - Osteopenic bone cell response to strontium-substituted hydroxyapatite. AB - Ionic substitution is a powerful tool to improve the biological performance of calcium phosphate based materials. In this work, we investigated the response of primary cultures of rat osteoblasts derived from osteopenic (O-OB) bone to strontium substituted hydroxyapatite (SrHA), and to hydroxyapatite (HA) as reference material, compared to normal (N-OB) bone cells. Strontium (Sr) and calcium (Ca) cumulative releases in physiological solution are in agreement with the greater solubility of SrHA than HA, whereas the differences between the two materials are levelled off in DMEM, which significantly reduced ion release. O-OB cells grown on SrHA exhibited higher proliferation and increased values of the differentiation parameters. In particular, Sr substitution increased the levels of proliferation, alkaline phosphatase, and collagen type I, and down-regulated the production of interleukin-6 of O-OB cells, demonstrating a promising future of SrHA in the treatment of bone lesions and defects in the presence of osteoporotic bone. PMID- 21691831 TI - Triglyceride level-influencing functional variants of the ANGPTL3, CILP2, and TRIB1 loci in ischemic stroke. AB - Stroke is a common multifactorial disease, and the third leading cause of death worldwide, which results in serious long-term mental and physical disability among survivors. The role of affected triglyceride metabolism in the development of ischemic stroke is under extensive investigations. Here, we examined three SNPs, rs12130333 located within the ANGPTL3 locus; rs16996148 residing at the CILP2 gene locus; and rs17321515 at the TRIB1 locus, which were originally reported in association with decreased triglyceride levels; therefore, we investigated their possible protective effect against the development of ischemic stroke. A total of 459 Caucasian stroke patients, stratified as large-vessel, small-vessel, and mixed stroke groups, and 168 control subjects were genotyped using PCR-RFLP methods. As a result, we could not detect any differences in triglyceride or total cholesterol levels in relation to any allelic variants of rs16996148, rs17321515, or rs12130333 SNPs. No correlation was found between the minor alleles rs16996148-T (P = 0.881), rs17321515-G (P = 0.070), or rs12130333-T allele (P = 0.757) and the risk for development of stroke. The data presented here suggest different scale of effect of triglyceride modifier alleles and also their variable susceptibility or protective nature. PMID- 21691832 TI - Coronary angiography and intervention during hypothermia can be performed safely without cardiac arrhythmia or vasospasm. AB - PURPOSE: Mild therapeutic hypothermia is a neuroprotective procedure after cardiac arrest. Therefore, it is increasingly used. Likewise, there is a growing demand for coronary angiography and percutaneous coronary interventions under hypothermia. Case studies suggested that hypothermia may be associated with coronary vasospasm, heart rhythm events and platelet dysfunction. In this study, it was evaluated whether vasospasm, arrhythmia or bleeding occur to a relevant degree during cardiac catheterization under concomitant hypothermia. METHODS: In this prospective, single-center, open-label, non-interventional study, 29 patients after resuscitation for cardiac arrest were treated with mild hypothermia and underwent cardiac catheterization (coronary angiography n = 11, coronary angiography plus percutaneous intervention n = 18). The incidence of vasospasm, cardiac arrhythmia and relevant bleeding at the puncture site were evaluated. RESULTS: Mean temperature at cardiac catheterization was 33.9 +/- 0.76 degrees C. The mean heart rate was 82 +/- 26 bpm at hospital admission and 67 +/- 17 bpm under hypothermia (p < 0.05). There was no patient with relevant bradycardia beyond the expected hypothermia-induced rate reduction during the procedure. There were no unexpected ventricular tachycardias or episodes of ventricular fibrillation which might have been attributed to hypothermia. Twenty nine of 29 patients (100%) were free from coronary vasospasm. There was no patient with a relevant bleeding at the puncture site. Potassium levels were low in 52% of the patients, even after resuscitation, which was partially attributed to hypothermia. CONCLUSION: Coronary angiography and percutaneous coronary interventions under mild therapeutic hypothermia were safe in this small cohort and were performed without hypothermia-induced vasospasm, relevant rhythm events or bleeding complications. This result has to be confirmed in a large series of patients. PMID- 21691833 TI - Complexation- and ligand-induced metal release from 316L particles: importance of particle size and crystallographic structure. AB - Iron, chromium, nickel, and manganese released from gas-atomized AISI 316L stainless steel powders (sized <45 and <4 MUm) were investigated in artificial lysosomal fluid (ALF, pH 4.5) and in solutions of its individual inorganic and organic components to determine its most aggressive component, elucidate synergistic effects, and assess release mechanisms, in dependence of surface changes using atomic absorption spectroscopy, Raman, XPS, and voltammetry. Complexation is the main reason for metal release from 316L particles immersed in ALF. Iron was mainly released, while manganese was preferentially released as a consequence of the reduction of manganese oxide on the surface. These processes resulted in highly complexing media in a partial oxidation of trivalent chromium to hexavalent chromium on the surface. The extent of metal release was partially controlled by surface properties (e.g., availability of elements on the surface and structure of the outermost surface) and partially by the complexation capacity of the different metals with the complexing agents of the different media. In general, compared to the coarse powder (<45 MUm), the fine (<4 MUm) powder displayed significantly higher released amounts of metals per surface area, increased with increased solution complexation capacity, while less amounts of metals were released into non-complexing solutions. Due to the ferritic structure of lower solubility for nickel of the fine powder, more nickel was released into all solutions compared with the coarser powder. PMID- 21691835 TI - Non-invasive cardiac output and oxygen delivery measurement in an infant with critical anemia. AB - OBJECTIVE: To assess the combination of a non-invasive blood oxygen content (CaO(2)) monitor and a non-invasive cardiac output (CO) monitor to continuously measure oxygen delivery (DO(2); DO(2) = CaO(2) * CO). METHODS: DO(2) was assessed during blood transfusions in an infant with acute hemolytic anemia following admission (~48 h). CaO(2) was measured by Pulse Co-Oximetry, which also provides estimates of hemoglobin (Hgb) concentration and percent oxygen saturation. CO was measured by Electrical Velocimetry, which also provides an estimate of stroke volume (SV). Lactate levels, an indirect measure of adequate DO(2), were assessed during the initial 8 h following admission. RESULTS: Incremental blood transfusions during the first 36 h increased Hgb from 2.7 to 9.5 g/dL during which time heart rate (HR) normalized from 156 to 115 beats/min. Lactate levels decreased from 20 to 0.8 mmol/L in the first 7 h. Non-invasive Hgb and CaO(2) measurements were well correlated with invasive Hgb and CaO(2) measures (r (2) = 0.88; P = 0.019; r (2) = 0.86; P = 0.0074, respectively). CO decreased from 2.47 +/- 0.06 to 1.28 +/- 0.02 L/min and SV decreased from 15.9 +/- 0.4 to 11.1 +/- 0.2 mL/beat. Mean arterial blood pressure was stable throughout the admission with systemic vascular resistance increasing from 407.6 +/- 15.2 to 887.7 +/- 30.1 dynes-s/cm(5). DO(2) was estimated to increase from 120.2 +/- 18.9 to 182.4 +/- 5.6 mL O(2)/min. CONCLUSIONS: Non-invasive continuous CO and CaO(2) monitors are shown in this single case to provide continuous DO(2) measurement. The ability to assess DO(2) may improve hemodynamic monitoring during goal directed therapies. PMID- 21691837 TI - Limited impact on self-concept in individuals with Lynch syndrome; results from a national cohort study. AB - An increasing number of individuals seek genetic counseling and hereby learn about hereditary cancer in the family. Lynch syndrome is associated with an inherited high risk for colorectal and gynecological cancer, but knowledge about how family members at risk perceive their situation is limited. We used the national Danish HNPCC register to collect data on self-concept from 413 individuals with Lynch syndrome. The recently developed Lynch syndrome self concept scale contains 20 items within two subscales related to stigma vulnerability and bowel symptom-related anxiety. Significantly higher total scores, indicating a greater impact on self-concept, were reported by females and by individuals with experience from cancer in close relatives, whereas individuals with less formal education scored significantly higher on the stigma and vulnerability subscale. Scores in the upper quartile were more often reported by women (odds ratio 1.8) and by individuals with less education (OR 1.8). This study provides the first extended use of the Lynch syndrome self-concept scale and suggests that the majority of the Danish mutation carriers adapt well to the situation, though knowledge about the increased risk of cancer seem to have a greater impact in females, individuals with less education and those with experience of cancer in close relatives. PMID- 21691836 TI - Growth inhibition and apoptotic effect of alpha-eleostearic acid on human breast cancer cells. AB - Alpha-eleostearic acid (alpha-ESA) is a natural and biologically active compound which possesses potent antioxidant and anti-tumor activity. The purpose of this study was to confirm the anticancer activity of alpha-ESA against human breast cancer cells and to further elucidate its mechanism of activity. Human breast cancer cells and normal liver cells were used for in-vitro tests of the anticancer activity of alpha-ESA, including cytotoxicity, colony formation inhibition, EdU incorporation, AO/EB staining of apoptotic cells, cell cycle distribution through flow cytometry, and PPARgamma, p21, Bax, p53, and caspase-3 mRNA expressions through RT-PCR. After alpha-ESA treatment, the proliferation, colony formation, and EdU labeling indices of cancer cells decreased (p < 0.05), while the AO/EB-stained apoptotic cells increased (p < 0.05). By FCM analysis, the apoptotic indices increased (p < 0.01), and the cell population decreased in S phase (p < 0.01) and increased in G(2)/M phase (p < 0.05) in alpha-ESA treated cancer cells. RT-RCR showed that alpha-ESA significantly increased the expression levels of PPARgamma, p21, Bax, p53, and caspase-3 mRNA. The findings in these studies suggested that alpha-ESA exhibited a potential cytotoxicity and apoptosis induction effect on human breast cancer cells, with little effect on normal cells at certain concentrations. The mechanism for such effects might be associated with the inhibition of DNA synthesis, induction of apoptosis, and cell cycle arrest of cancer cells through up-regulation of PPARgamma, p21, Bax, p53, and caspase-3 expressions. PMID- 21691838 TI - Inactivation of the extracytoplasmic function sigma factor Sig6 stimulates avermectin production in Streptomyces avermitilis. AB - The role of the extracytoplasmic function (ECF) sigma factor Sig6 (SAV663) in avermectin production by Streptomyces avermitilis was investigated by gene deletion, complementation and over-expression experiments. Inactivation of Sig6 had no major effect on growth, stress responses, or morphology. Avermectin yield was increased 2- to 2.7-fold (~680 MUg/ml) relative to the wild-type strain by deletion of the sig6 gene, and was restored to the wild-type level by introduction of a single copy of sig6. Introduction of extra multi-copy or integrative sig6 vectors into the wild-type decreased avermectin yield by 56-63%. Taken together, these findings indicate that Sig6 plays a negative regulatory role in avermectin production in S. avermitilis. RT-PCR analysis demonstrated that this role of Sig6 is mediated by the pathway-specific activator gene aveR. PMID- 21691839 TI - Biomass and lipid production of heterotrophic microalgae Chlorella protothecoides by using biodiesel-derived crude glycerol. AB - Microalgal lipids may be a more sustainable biodiesel feedstock than crop oils. We have investigated the potential for using the crude glycerol as a carbon substrate. In batch mode, the biomass and lipid concentration of Chlorella protothecoides cultivated in a crude glycerol medium were, respectively, 23.5 and 14.6 g/l in a 6-day cultivation. In the fed-batch mode, the biomass and lipid concentration improved to 45.2 and 24.6 g/l after 8.2 days of cultivation, respectively. The maximum lipid productivity of 3 g/l day in the fed-batch mode was higher than that produced by batch cultivation. This work demonstrates the feasibility of crude biodiesel glycerol as an alternative carbon substrate to glucose for microalgal cultivation and a cost reduction of carbon substrate feed in microalgal lipid production may be expected. PMID- 21691840 TI - Delta6-Desaturase from Mortierella alpina: cDNA cloning, expression, and phylogenetic analysis. AB - The open reading frame of the Delta(6)-desaturase gene was isolated from Mortierella alpina W15 and the gene was cloned into a pPIC3.5K vector. The vector was transformed into Pichia pastoris GS115 and expression was induced with methanol. The Delta(6)-desaturase expressed in P. pastoris GS115 catalyzed the conversion of linoleic acid to gamma-linolenic acid but not the conversion of alpha-linolenic acid to octadecatetraenoic acid. The results indicate that the Delta(6)-desaturase gene from M. alpina W15 has substrate specificity in different organisms. Phylogenetic analysis revealed that Delta(6)-desaturase genes can be divided into four monophyletic groups. This work paves the way for further study of the functions of Delta(6)-desaturase in fatty acid metabolism and its three-dimensional structure. PMID- 21691841 TI - The cost-effectiveness of cash versus lottery incentives for a web-based, stated preference community survey. AB - We present the results of a randomized experiment to test the effectiveness and cost-effectiveness of response incentives for a stated-preference survey of a general community population. The survey was administered using a mixed-mode approach, in which community members were invited to participate using a traditional mailed letter using contact information for a representative sample of the community; but individuals completed the survey via the web, which exploited the advantages of electronic capture. Individuals were randomized to four incentive groups: (a) no incentive, (b) prepaid cash incentive ($2), (c) a low lottery (10 prizes of $25) and (d) a high lottery (2 prizes of $250). Letters of invitation were mailed to 3,000 individuals. In total, 405 individuals (14.4%) contacted the website and 277 (9.8%) provided complete responses. The prepaid cash incentive generated the highest contact and response rates (23.3 and 17.3%, respectively), and no incentive generated the lowest (9.1 and 5.7%, respectively). The high lottery, however, was the most cost-effective incentive for obtaining completed surveys: compared with no incentive, the incremental cost effectiveness ratio (ICER) per completed survey for high lottery was $13.89; for prepaid cash, the ICER was $18.29. This finding suggests that the preferred response incentive for community-based, stated-preference surveys is a lottery with a small number of large prizes. PMID- 21691842 TI - Paying informally in the Albanian health care sector: a two-tiered stochastic frontier model. AB - Informal payments are deeply ingrained in the health care sector of most Central, Eastern and Southern European countries. Evidence suggests that the price paid informally to medical staff is negotiated either directly or indirectly between patients and medical staff. The aim of this paper is to measure the imperfect information that exists on the amount that has to be paid informally to medical staff. We measure the extent to which patients pay more than the amount medical staff expect informally and the extent to which medical staff request less than patients are willing to pay informally. A two-tiered stochastic frontier model is developed to estimate indicators of patients' and medical staff's imperfect information on informal payments and the effects on the amount the other party is minimally expecting or maximally willing to pay informally. The estimates are based on informal payments to medical staff in the inpatient health care sector in Albania. We use data from the Albania Living Standards Measurement Survey 2002 and 2005. The pooled samples include 707 individuals who have visited inpatient health care services in these 2 years. Our results show that medical staff has less information on the patients' maximum willingness to pay informally than patients have on medical staff's minimum expected amount. These estimates do not depend on categories of illnesses but on certain socio-demographic characteristics. PMID- 21691843 TI - Predictors of new and severe vertebral fractures: results from the HORIZON Pivotal Fracture Trial. AB - We examined prevalent and recent vertebral fractures in 1 year as predictors of new vertebral fractures over subsequent 2 years using data from RCT placebo patients. We found that prevalent and recent vertebral fractures strongly and independently predicted subsequent vertebral fractures including those which were severe. INTRODUCTION: While several studies have shown that prevalent vertebral fractures (pVFx) increase the risk of new vertebral fractures (VFx), the impact of recent vertebral fractures on future fractures is less studied. METHODS: Data from the placebo arm of the HORIZON Pivotal Fracture Trial, an international trial of zoledronic acid in postmenopausal, osteoporotic women between 65 and 85 years, were used. We included the subset of 2677 women with annual spinal radiographs to study the impact of vertebral fractures in year 1 (Y1 VF) on those occurring in years 2 and 3 using morphometric and semiquantitative (SQ) criteria. In addition, a subset of severe VFx was defined using SQ criteria. Logistic regression examined the impact of pVFx and Y1 VF on all incident VFx and on severe incident VFx. RESULTS: Two hundred fourty-five (9.1%) women sustained a new VFx in years 2-3. VFx risk in years 2-3 was 3.9% in those without pVFx or VFy1 and 29.8% in those with both risk factors. Both pVF and VFy1 remained independent predictors for future VF when they were both entered into a logistic regression model (odds ratio (OR) = 3.3; 95% confidence interval (CI), 2.3-4.7; OR = 3.7, 95% CI, 2.3, 5.8, respectively). ORs were similar after adjustment. Of the total number of women, 4.1% had severe VFx. PVFx and Y1 VF were also significant predictors of severe VFx; however, Y1 VF appeared more strongly predictive of severe VFx. CONCLUSIONS: Prevalent and incident vertebral fractures are highly predictive of subsequent new and severe vertebral fractures. Women with both of these risk factors are likely to benefit from anti-osteoporosis treatment. PMID- 21691844 TI - Improvement in glycemic control following a diabetes education intervention is associated with change in diabetes distress but not change in depressive symptoms. AB - In diabetes patients, depression is correlated with diabetes-specific emotional distress, and observational studies have suggested that diabetes distress may have a greater impact on diabetes outcomes than depression itself. To examine the relative effects of change in depressive symptoms and change in diabetes distress on change in glycemic control, we conducted a diabetes self-management education intervention in 234 type 2 diabetes (T2DM) patients, and measured glycemic control (HbA1c), depressive symptoms (CES-D), and diabetes distress (PAID) at baseline and 6 months. In multiple linear regression, change in depressive symptoms was not associated with change in HbA1c (P=0.23). Change in diabetes distress was significantly associated with change in HbA1c (P<0.01), such that a 10-point decrease in diabetes distress (which corresponds to the average change in distress in this study population) was associated with a 0.25% reduction in HbA1c. Change in diabetes distress, and not change in depressive symptoms, was associated with both short- and long-term change in glycemic control for patients with poorly controlled T2DM. PMID- 21691846 TI - Epidural spinal tumor and periaortitis as rare complications of Wegener's granulomatosis. AB - This case report describes findings in a 61-year-old woman who manifested scleritis, small pulmonary nodules, otitis media, periaortitis, and progressive epidural spinal tumor, associated with elevated serum myeloperoxidase anti neutrophil cytoplasmic antibody (MPO-ANCA) levels. She was clinically diagnosed with Wegener's granulomatosis, although vasculitis was not diagnosed due to the lack of typical histological findings. We discuss the differential diagnosis in this patient, and the association of MPO-ANCA with periaortitis or epidural spinal tumor. PMID- 21691845 TI - The impact of family behaviors and communication patterns on chronic illness outcomes: a systematic review. AB - In general, social support from family members affects chronic illness outcomes, but evidence on which specific family behaviors are most important to adult patient outcomes has not been summarized. We systematically reviewed studies examining the effect of specific family member behaviors and communication patterns on adult chronic illness self-management and clinical outcomes. Thirty studies meeting inclusion criteria were identified, representing 22 participant cohorts, and including adults with arthritis, chronic cardiovascular disease, diabetes, and/or end stage renal disease. Family emphasis on self-reliance and personal achievement, family cohesion, and attentive responses to symptoms were associated with better patient outcomes. Critical, overprotective, controlling, and distracting family responses to illness management were associated with negative patient outcomes. Study limitations included cross-sectional designs (11 cohorts); however results from longitudinal studies were similar. Findings suggest that future interventions aiming to improve chronic illness outcomes should emphasize increased family use of attentive coping techniques and family support for the patient's autonomous motivation. PMID- 21691847 TI - Unmet supportive care needs in colorectal cancer: differences by age. AB - PURPOSE: Cancer is primarily a disease of ageing, yet the unmet supportive care needs of older cancer patients are not well understood. This study aims to explore how unmet needs differ by age over the 3 months following colorectal cancer surgery. METHODS: Control groups from pilot phases of an ongoing randomised trial completed the Supportive Care Needs Survey-Short Form 34 (SCNS SF34) at 1 and 3 months following hospital discharge (n = 57). Multiple regression was used to investigate whether age was an independent predictor of unmet needs in each of the five SCNS-SF34 domains. The proportion of patients with unmet needs and the pattern of item responses were compared between patients aged <65 and >= 65 years at both time points. RESULTS: Older age independently predicted significantly lower levels of unmet need than younger age in nearly all SCNS-SF34 domains. However, more than half of all older patients had unmet needs at both time points (56% and 65%), and age differences in unmet needs were less apparent by 3 months. Older patients were less likely than younger patients to report 'satisfied' needs, as older patients were significantly more likely to report items were 'not applicable' at both 1 month (mean difference 29%, p < 0.001) and 3 months (mean difference 23%, p = 0.01). CONCLUSIONS: While older patients reported lower levels of unmet need than younger patients, the high prevalence of unmet needs and age differences in item response patterns indicate that further research is needed to determine whether older patients' needs are being accurately captured. PMID- 21691848 TI - Histological and molecular studies of the non-host interaction between wheat and Uromyces fabae. AB - Non-host resistance (NHR) confers plant species immunity against the majority of microbes. As an important crop, wheat can be damaged by several Puccinia species but is immune to all Uromyces species. Here, we studied the basis of NHR in wheat against the broad bean rust pathogen Uromyces fabae (Uf). In the wheat-Uf interaction, microscopic observations showed that urediospores germinated efficiently on wheat leaves. However, over 98% of the germ tubes failed to form appressoria over stomata. For the few that invaded through stomata, the majority of them failed to penetrate wheat mesophyll cells. At 96 hours after inoculation, less than 4% of the Uf infection units that had entered the mesophyll tissue formed haustoria. Attempted penetration by haustorium mother cells induced the thickening of cell wall and the formation of papillae in plant cells, which arrested the development or growth of Uf penetration pegs. For the Uf haustoria formed in wheat cells, they were encased in callose-like materials and did not elicit hypersensitive response. Localized accumulation of H(2)O(2) were observed in plant cell walls, papillae and encasement of haustoria during the wheat-Uf interaction. Furthermore, quantitative RT-PCR analysis showed that several genes involved in basal resistance and oxidative stress responses were up-regulated during Uf infection. In conclusion, our study revealed the cytological and molecular bases of NHR in wheat against the non-adapted rust fungus Uf, and highlighted the significance of papilla production in the prehaustorial NHR. PMID- 21691849 TI - The dynamics of vein graft remodeling induced by hemodynamic forces: a mathematical model. AB - Although vein bypass grafting is one of the primary options for the treatment of arterial occlusive disease and provides satisfactory results at an early stage of the treatment, the patency is limited to a few months in many patients. When the vein is implanted in the arterial system, it adapts to the high flow rate and high pressure of the arterial environment by changing the sizes of its layers, and this remodeling is believed to be a precursor of future graft failure. Hemodynamic forces, such as wall shear stress (WSS) and wall tension, have been recognized as major factors impacting vein graft remodeling. Although a wide range of experimental evidence relating hemodynamic forces to vein graft remodeling has been reported, a comprehensive mathematical model describing the relationship among WSS, wall tension, and the structural adaptation of each individual layer of the vein graft wall is lacking. The current manuscript presents a comprehensive and robust framework for treating the complex interaction between the WSS, wall tension, and the structural adaptation of each individual layer of the vein graft wall. We modeled the intimal and medial area and the radius of external elastic lamina, which in combination dictate luminal narrowing and the propensity for graft occlusion. Central to our model is a logistic relationship between independent and dependent variables to describe the initial increase and later decrease in the growth rate. The detailed understanding of the temporal changes in vein graft morphology that can be extracted from the current model is critical in identifying the dominant contributions to vein graft failure and the further development of strategies to improve their longevity. PMID- 21691850 TI - Prevalence and comorbidity of prolonged grief disorder in a sample of caregivers of patients in a vegetative state. AB - Previous studies have shown that Prolonged Grief Disorder (PGD), Post-traumatic Stress Disorder (PTSD) and major depression are autonomous nosological entities. The present study aims at further analyzing the relationship among them in a sample of caregivers of patients in Vegetative State (VS) or Minimally Conscious State (MCS). We also investigated factors predicting the development of PGD. We sampled 40 Caregivers of patients in VS or MCS consecutively admitted to long term care units. Caregivers were administered the PG-12, the Depression Questionnaire, the SCID I and the Davidson Trauma Scale. Six participants (15%) fulfilled the criteria for PGD, 25% (N = 10) for depression and 25% (N = 10) for PTSD. Although significant correlations emerged among symptom domains of the three disorders, no relevant association was found between a diagnosis of PGD, depression and PTSD. The severity of PTSD symptoms was found to be predictive of PGD. Clinical implications are discussed. PMID- 21691851 TI - Hidden stressors in the clonogenic assay used in radiobiology experiments. AB - While clonogenic assays are extensively used in radiobiology, there is no widely accepted procedure for choosing the composition of the cell culture media. Cell line suppliers recommend a specific culture medium for each cell line, however a researcher will frequently customize this aspect of the protocol by supplementing the recommended support medium with additives. For example, many researchers add antibiotics, in order to avoid contamination of cells and the consequent loss of data, with little discussion of the influence of the antibiotics on the clonogenic survival of the cells. It is assumed that the effect of any variables in the growth medium on cell survival is taken into consideration by comparing the survival fraction relative to that of controls grown under the same conditions. In the search for better cancer treatment, the effect of various stressors on clonogenic cell survival is under investigation. This study seeks to identify and test potential stressors commonly introduced into the cell culture medium, which may confound the response to radiation. PMID- 21691853 TI - Detection of dengue virus type 4 in Easter Island, Chile. AB - We report the detection of dengue virus type 4 (DENV-4) for the first time in Easter Island, Chile. The virus was detected in serum samples of two patients treated at the Hospital in Easter Island. The two samples were IgM positive, and the infection was confirmed by RT-PCR and genetic sequencing; viral isolation was possible with one of them. The Easter Island isolates were most closely related to genotype II of dengue type 4. PMID- 21691854 TI - Small mammals cause non-trophic effects on habitat and associated snails in a native system. AB - Legacy effects occur when particular species or their interactions with others have long-lasting impacts, and they are increasingly recognized as important determinants of ecological processes. However, when such legacy effects have been explicitly explored, they most often involve the long-term direct effects of species on systems, as opposed to the indirect effects. Here, we explore how a legacy of small mammal exclusion on the abundance of a shrub, bush lupine (Lupinus arboreus), influences the abundance of a native land snail (Helminthoglypta arrosa) in coastal prairie and dune habitats in central California. The factors that limit populations of land snails are very poorly known despite the threats to the persistence of this group of species. In grasslands, prior vole (Microtus californicus) exclusion created long-lasting gains in bush lupine abundance, mediated through the seedbank, and was associated with increased snail numbers (10*) compared to control plots where mammals were never excluded. Similar plots in dune habitat showed no difference in snail numbers due to previous mammal exclusion. We tested whether increased competition for food, increased predation, and/or lower desiccation explained the decline in snail numbers in plots with reduced lupine cover. Tethering experiments supported the hypothesis that voles can have long-lasting impacts as ecosystem engineers, reducing woody lupine habitat required for successful aestivation by snails. These results add to a growing list of studies that have found that non-trophic interactions can be limiting to invertebrate consumers. PMID- 21691855 TI - Tree species identity and interactions with neighbors determine nutrient leaching in model tropical forests. AB - An ecosystem containing a mixture of species that differ in phenology, morphology, and physiology might be expected to resist leaching of soil nutrients to a greater extent than one composed of a single species. We tested the effects of species identity and plant-life-form richness on nutrient leaching at a lowland tropical site where deep infiltration averages >2 m year(-1). Three indigenous tree species with contrasting leafing phenologies (evergreen, dry season deciduous, and wet-season deciduous) were grown in monoculture and together with two other life-forms with which they commonly occur in tropical forests: a palm and a giant, perennial herb. To calculate nutrient leaching over an 11-year period, concentrations of nutrients in soil water were multiplied by drainage rates estimated from a water balance. The effect of plant-life-form richness on retention differed according to tree species identity and nutrient. Nitrate retention was greater in polycultures of the dry-season deciduous tree species (mean of 7.4 kg ha(-1) year(-1) of NO(3)-N lost compared to 12.7 in monoculture), and calcium and magnesium retention were greater in polycultures of the evergreen and wet-season deciduous tree species. Complementary use of light led to intensification of soil exploitation by roots, the main agent responsible for enhanced nutrient retention in some polycultures. Other mechanisms included differences in nutrient demand among species, and avoidance of catastrophic failure due to episodic weather events or pest outbreaks. Even unrealistically simple multi-life-form mimics of tropical forest can safeguard a site's nutrient capital if careful attention is paid to species' characteristics and temporal changes in interspecific interactions. PMID- 21691856 TI - Detecting bimodality in plant size distributions and its significance for stand development and competition. AB - Bimodal distributions in plant size, with a major mode of small and minor mode of large-size plants, have been reported for a range of single species stands in different growing conditions. The occurrence of bimodality has implications for the dynamics of competition within a stand and potentially for stand productivity. However, deduction of the existence of bimodality has been by visual assessment of histograms of a single measure of plant size which can lead to differences of opinion about its existence. We show that the bivariate distribution of plant height and weight is more informative about stand structure than univariate distributions. We demonstrate how sub-populations of small- and large-size plants can be identified using a bivariate mixture distribution fitted using evolutionary computation. For the multiple datasets we analyse, a bimodal distribution fits in preference to unimodal or trimodal distributions. Small- and large-plant sub-populations, respectively, form a lower and upper canopy. The numbers of plants in these canopies change during stand development and vary with initial spacing, contrary to reports for other species. Early in stand development, large plants show spatial separation between themselves but spatial association with small plants, and as stands develop the number of large plants declines markedly but they remain spatially separated between each other. Bivariate analysis of height and weight, and spatial analysis of individuals of different sizes, provides a more comprehensive description of stand structure than that obtained in previous studies. PMID- 21691857 TI - Adelie penguin survival: age structure, temporal variability and environmental influences. AB - The driving factors of survival, a key demographic process, have been particularly challenging to study, especially for winter migratory species such as the Adelie penguin (Pygoscelis adeliae). While winter environmental conditions clearly influence Antarctic seabird survival, it has been unclear to which environmental features they are most likely to respond. Here, we examine the influence of environmental fluctuations, broad climatic conditions and the success of the breeding season prior to winter on annual survival of an Adelie penguin population using mark-recapture models based on penguin tag and resight data over a 16-year period. This analysis required an extension to the basic Cormack-Jolly-Seber model by incorporating age structure in recapture and survival sub-models. By including model covariates, we show that survival of older penguins is primarily related to the amount and concentration of ice present in their winter foraging grounds. In contrast, fledgling and yearling survival depended on other factors in addition to the physical marine environment and outcomes of the previous breeding season, but we were unable to determine what these were. The relationship between sea-ice and survival differed with penguin age: extensive ice during the return journey to breeding colonies was detrimental to survival for the younger penguins, whereas either too little or too much ice (between 15 and 80% cover) in the winter foraging grounds was detrimental for adults. Our results demonstrate that predictions of Adelie penguin survival can be improved by taking into account penguin age, prior breeding conditions and environmental features. PMID- 21691858 TI - Spatial patterns of mercury in biota of Adirondack, New York lakes. AB - We studied the spatial distribution patterns of mercury (Hg) in lake water, littoral sediments, zooplankton, crayfish, fish, and common loons in 44 lakes of the Adirondacks of New York State, USA, a region that has been characterized as a "biological Hg hotspot". Our study confirmed this pattern, finding that a substantial fraction of the lakes studied had fish and loon samples exceeding established criteria for human and wildlife health. Factors accounting for the spatial variability of Hg in lake water and biota were lake chemistry (pH, acid neutralizing capacity (ANC), percent carbon in sediments), biology (taxa presence, trophic status) and landscape characteristics (land cover class, lake elevation). Hg concentrations in zooplankton, fish and common loons were negatively associated with the lake water acid-base status (pH, ANC). Bioaccumulation factors (BAF) for methyl Hg (MeHg) increased from crayfish (mean log(10) BAF = 5.7), to zooplankton (5.9), to prey fish (6.2), to larger fish (6.3), to common loons (7.2). MeHg BAF values in zooplankton, crayfish, and fish (yellow perch equivalent) all increased with increasing lake elevation. Our findings support the hypothesis that bioaccumulation of MeHg at the base of the food chain is an important controller of Hg concentrations in taxa at higher trophic levels. The characteristics of Adirondack lake-watersheds (sensitivity to acidic deposition; significant forest and wetland land cover; and low nutrient inputs) contribute to elevated Hg concentrations in aquatic biota. PMID- 21691859 TI - Ecological risk of methylmercury to piscivorous fish of the Great Lakes region. AB - Contamination of fish populations with methylmercury is common in the region of the Laurentian Great Lakes as a result of atmospheric deposition and methylation of inorganic mercury. Using fish mercury monitoring data from natural resource agencies and information on tissue concentrations injurious to fish, we conducted a screening-level risk assessment of mercury to sexually mature female walleye (Sander vitreus), northern pike (Esox lucius), smallmouth bass (Micropterus dolomieu), and largemouth bass (Micropterus salmoides) in the Great Lakes and in interior lakes, impoundments, and rivers of the Great Lakes region. The assessment included more than 43,000 measurements of mercury in fish from more than 2000 locations. Sexually mature female fish that exceeded threshold-effect tissue concentrations of 0.20 MUg g(-1) wet weight in the whole body occurred at 8% (largemouth bass) to 43% (walleye) of sites. Fish at 3% to 18% of sites were at risk of injury and exceeded 0.30 MUg g(-1) where an alteration in reproduction or survival is predicted to occur. Most fish at increased risk were from interior lakes and impoundments. In the Great Lakes, no sites had sexually mature fish that exceeded threshold-effect concentrations. Results of this screening-level assessment indicate that fish at a substantive number of locations within the Great Lakes region are potentially at risk from methylmercury contamination and would benefit from reduction in mercury concentrations. PMID- 21691860 TI - PAH composition of Water Based Drilling Mud and drill cuttings in the offshore region, east coast of India. AB - As a consequence of offshore drilling, used Water Based Drilling Muds (WBMs) are typically disposed off, by discharging into the sea; such a disposal does not fully eliminate the environmental hazards. Hence, in this study, 2, 3, 4 and 5 ringed polycyclic aromatic hydrocarbons (PAHs i.e. naphthalene, fluorene, phenanthrene, fluoranthene, chrysene and benzo (a) pyrene) were determined from the WBMs and associated drill cuttings obtained from varying depths(viz. 150, 300 and 600 m) from three offshore wells present in East coast of India. In both WBMs and drill cuttings, concentration of naphthalene was maximum i.e. 81.59 +/- 2.73 and 39.87 +/- 2.40 mg/kg respectively, while benzo (a) pyrene was minimum i.e. 0.19 +/- 0.07 and 0.12 +/- 0.03 mg/kg respectively. The WBMs contained significantly (p < 0.05) higher PAH concentration than drill cuttings. The individual PAH concentration significantly (p < 0.01) increased with increasing depth in each well. PMID- 21691861 TI - Comparative cytogenetic mapping of Sox2 and Sox14 in cichlid fishes and inferences on the genomic organization of both genes in vertebrates. AB - To better understand the genomic organization and evolution of Sox genes in vertebrates, we cytogenetically mapped Sox2 and Sox14 genes in cichlid fishes and performed comparative analyses of their orthologs in several vertebrate species. The genomic regions neighboring Sox2 and Sox14 have been conserved during vertebrate diversification. Although cichlids seem to have undergone high rates of genomic rearrangements, Sox2 and Sox14 are linked in the same chromosome in the Etroplinae Etroplus maculatus that represents the sister group of all remaining cichlids. However, these genes are located on different chromosomes in several species of the sister group Pseudocrenilabrinae. Similarly, the ancestral synteny of Sox2 and Sox14 has been maintained in several vertebrates, but this synteny has been broken independently in all major groups as a consequence of karyotype rearrangements that took place during the vertebrate evolution. PMID- 21691863 TI - Poor housing, good health: a comparison of formal and informal housing in Johannesburg, South Africa. AB - OBJECTIVES: This study aimed to investigate the relationship between housing, demographic, socio-economic, social factors and health, in poor urban communities in Johannesburg, South Africa. METHODS: Data were drawn from a survey of 1,427 households in Johannesburg. The outcome health variable was a composite measure of chronic ill-health. Housing variables included type of housing, tenure and access to services. Multivariate regression analysis assessed the relationship between housing and health, after adjustment for demographic, socio-economic and social factors. RESULTS: The prevalence of chronic health problems was 25.1% (95% CI 22.8-27.6%). Factors independently associated with the risk of chronic ill health among household heads included older age (OR, 3.06 [2.37-3.95]), female gender (OR, 2.83 [2.01-3.97]), long-term residence (OR, 2.01 [1.10-3.67]), unemployment (OR, 0.49 [0.36-0.67]), and living in formal housing (OR, 0.66 [0.45 0.98]). CONCLUSIONS: The health of the household heads residing in informal housing was significantly better than in formal housing. Explanations for this counter-intuitive finding include the fact that the informal housing dwellers were younger and recent migrants (the 'healthy migrant' phenomenon). Policy implications of the results are identified. PMID- 21691864 TI - Brief report: the dopamine-3-receptor gene (DRD3) is associated with specific repetitive behavior in autism spectrum disorder (ASD). AB - Recently the DRD3 gene has been associated with ASD in two independent samples. Follow up analysis of the risk allele of the SNP rs167771 in 91 subjects revealed a significant association with a specific type of repetitive behavior: the factor "insistence on sameness" (IS) derived from the Autism Diagnostic Interview. This risk allele was associated with a decreased risk for IS, but not with any other symptomatology. Further study and replication of this finding is necessary, bearing in mind that these results would not be statistically significant if corrected for multiple testing. PMID- 21691865 TI - The interplay between attentional strategies and language processing in high functioning adults with autism spectrum disorder. AB - This study examined the hypothesis of an atypical interaction between attention and language in ASD. A dual-task experiment with three conditions was designed, in which sentences were presented that contained errors requiring attentional focus either at (a) low level, or (b) high level, or (c) both levels of language. Speed and accuracy for error detection were measured from 16 high-functioning adults with ASD, and 16 matched controls. For controls, there was an attentional cost of dual level processing for low level performance but not for high level performance. For participants with ASD, there was an attentional cost both for low level and for high level performance. These results suggest a compensatory strategic use of attention during language processing in ASD. PMID- 21691866 TI - Can child care workers contribute to the early detection of autism spectrum disorders? A comparison between screening instruments with child care workers versus parents as informants. AB - Several screening instruments for ASD in young children were developed during the last decades. Only few studies compare the discriminative power of these instruments in the same sample. In particular comparisons of instruments that use different informants are scarce in young children. The current study compared the discriminant ability of the Checklist for Early Signs of Developmental Disorders (CESDD) filled out by child care workers with that of frequently used parent questionnaires in a sample of 357 children between 5.57 and 48.13 months old who showed signs of ASD or language delay. The discriminant power of the CESDD was as good as that of parent questionnaires. Therefore, inclusion of child care workers in the early detection of ASD seems promising. PMID- 21691867 TI - Applying technology to visually support language and communication in individuals with autism spectrum disorders. AB - The burgeoning role of technology in society has provided opportunities for the development of new means of communication for individuals with Autism Spectrum Disorders (ASD). This paper offers an organizational framework for describing traditional and emerging augmentative and alternative communication (AAC) technology, and highlights how tools within this framework can support a visual approach to everyday communication and improve language instruction. The growing adoption of handheld media devices along with applications acquired via a consumer-oriented delivery model suggests a potential paradigm shift in AAC for people with ASD. PMID- 21691868 TI - [Functional anatomy of the female pelvic floor: interdisciplinary continence and pelvic floor surgery]. AB - Knowledge of functional anatomy is a prerequisite for the safe and targeted reconstructive therapy of incontinence and the prolapse syndrome of the female pelvic floor. We illustrate the interaction of muscles and connective tissue of the pelvic floor with anatomical illustrations and demonstrate their impact on the function of the urethra, bladder, vagina, uterus and rectum. Examples for the therapeutic rationale for a surgical reconstruction of the pelvic floor are defined and justified from their functional anatomy. PMID- 21691869 TI - Zinc deficiency in patients undergoing pancreatoduodenectomy for periampullary tumors is associated with pancreatic exocrine insufficiency. AB - BACKGROUND AND PURPOSE: The present study was done to investigate the prevalence of zinc deficiency after pancreatoduodenectomy (PD) and its correlation with pancreatic exocrine insufficiency. MATERIALS AND METHODS: Patients were included in this study if they had undergone PD for periampullary tumors without recurrence and had received follow-up for more than 6 months between February 2006 and June 2007. Serum levels of zinc, fasting glucose, albumin, and iron were obtained. The pancreatic exocrine function was evaluated by a fecal elastase-1 assay, stool fat assessment, and a pancreatic duct-parenchymal ratio (DPR) at the L1 level using abdominal computed tomography (CT). The quality of life was estimated with a questionnaire of EORTC QLQ-C30 and PAN26. All of these patients were then supplemented with oral pancreatic enzymes for 4 weeks to evaluate the effect of these enzymes on zinc deficiency. RESULTS: Forty-eight eligible patients, 27 men and 21 women, were included. The mean age was 61.3 +/- 1.7 years. Thirty-three (68%) patients had a zinc deficiency with a mean zinc level of 72.3 +/- 2.9 mcg/dl (normal range: 80-120 mcg/dl). Patients with lower serum zinc levels tended to have typical presentations of zinc deficiency (P = 0.039, chi(2)). The serum zinc level was significantly negatively correlated with pancreatic duct diameter, DPR, and positive stool fat during the late follow-up period. The most common presentations of patients with lower serum zinc levels were skin rash, photophobia, and glossitis. These gastrointestinal disorders, as well as symptoms of zinc deficiency, improved after pancreatic enzyme supplementation. CONCLUSIONS: Zinc deficiency after PD was a common phenomenon and correlated with pancreatic exocrine insufficiency. PMID- 21691870 TI - Changes in metabolic profile and adipoinsular axis in morbidly obese premenopausal females treated with restrictive bariatric surgery. AB - BACKGROUND: The aim of the present study was to evaluate the effects of surgically induced weight loss on the metabolic profile and adipocytokine levels in premenopausal morbidly obese females. METHODS: Twenty premenopausal morbidly obese (MO) women with a median age of 34 years (range: 24-48 years) and a median body mass index (BMI) of 41.47 kg/m(2) (range: 38.0-56.73 kg/m(2)) were studied (13 women underwent gastric banding and 7 women underwent sleeve gastrectomy). In addition, 20 lean premenopausal women with a median age of 32 years (range: 22-44 years) and a median BMI of 20.0 kg/m(2) (range: 18.5-24.7 kg/m(2)) were also studied. Anthropometric measurements and metabolic parameters were analyzed in each patient, along with changes in leptin, adiponectin, resistin, and interleukin-6 (IL-6) before surgery, 6 months after surgery, and 12 months after surgery. Comparisons with the reference normal-weight subjects were also performed. RESULTS: Both weight and BMI were found to be significantly decreased postoperatively. A 54.5% loss of excess BMI was observed 12 months after surgery, and was associated with significant improvement in all anthropometric and metabolic parameters. Twelve months after surgery we also observed decreased levels of serum leptin, resistin, and IL-6; increased levels of serum adiponectin; and a remarkable improvement in metabolic syndrome markers. Furthermore, postoperative serum resistin and IL-6 levels were found to reach those of normal-weight volunteers. CONCLUSIONS: The results of this study suggest that weight loss through restrictive bariatric surgery results in a significant reduction in leptin, resistin, and IL-6 levels, and an increase in adiponectin levels, in addition to improving insulin sensitivity and glucose and lipid homeostasis in young morbidly obese female patients. These changes were significantly correlated with the magnitude of weight loss. PMID- 21691872 TI - Stroke. Introduction. PMID- 21691871 TI - [Gastric neuroendocrine tumors. Endoscopic and surgical treatment]. AB - Neuroendocrine tumors (NETs) of the stomach are the most frequent among all neuroendocrine neoplasms in the digestive tract. The diagnosis and classification are complicated by the fact that these tumors have to be categorized not only by common staging and grading but also according to their pathophysiological background (types). The types differ in their biological behaviour (aggressiveness) which influences therapeutic concepts. This article explains and summarizes the etiology and classification of gastric NETs and offers a precise concept for diagnosis and treatment to improve clinical outcome. PMID- 21691873 TI - Stroke epidemiology: advancing our understanding of disease mechanism and therapy. AB - Stroke is the fourth killer and number one cause of adult disability in the United States. The estimated direct and indirect costs of stroke care in this country are $68.9 billion for 2009. The prevalence of stroke and its cost will undoubtedly rise as the aging population increases. In addition, stroke incidence and mortality are increasing in less developed countries in which the lifestyles and population restructuring are rapidly changing. More population-based research to assess incidence, risk factors, and outcomes are needed in these countries. Epidemiologic studies can help identify groups of individuals or regions at higher risk for stroke. They can also help us better understand the natural history of certain conditions and therefore push the direction of therapeutic investigations. Furthermore, the study of trends across different time periods and different populations can help investigators evaluate the effects of stroke care programs and treatment options. PMID- 21691874 TI - Vascular imaging in stroke: comparative analysis. AB - Advances in stroke treatment have mirrored advances in vascular imaging. Understanding and advances in reperfusion therapies were made possible by improvements in computed tomographic angiography, magnetic resonance angiography, neurovascular ultrasound, and renewed interest in catheter angiography. As technology allows better noninvasive vascular diagnosis, digital subtraction angiography (the remaining gold standard for vascular imaging) is increasingly used for rescue procedures and elective interventions. This review will examine specific advantages and disadvantages of different vascular imaging modalities as related to stroke diagnosis. PMID- 21691875 TI - Development of customized fire behavior fuel models for boreal forests of northeastern China. AB - Knowledge of forest fuels and their potential fire behavior across a landscape is essential in fire management. Four customized fire behavior fuel models that differed significantly in fuels characteristics and environmental conditions were identified using hierarchical cluster analysis based on fuels data collected across a boreal forest landscape in northeastern China. Fuel model I represented the dense and heavily branched Pinus pumila shrubland which has significant fine live woody fuels. These forests occur mainly at higher mountain elevations. Fuel model II is applicable to forests dominated by Betula platyphylla and Populus davidiana occurring in native forests on hill slopes or at low mountain elevations. This fuel model was differentiated from other fuel models by higher herbaceous cover and lower fine live woody loading. The primary coniferous forests dominated by Larix gmelini and Pinus sylvestris L. var. mongolica were classified as fuel model III and fuel model IV. Those fuel models differed from one another in average cover and height of understory shrub and herbaceous layers as well as in aspect. The potential fire behavior for each fuel model was simulated with the BehavePlus5.0 fire behavior prediction system. The simulation results indicated that the Pinus pumila shrubland fuels had the most severe fire behavior for the 97th percentile weather condition, and had the least severe fire behavior under 90th percentile weather condition. Fuel model II presented the least severe fire potential across weather conditions. Fuel model IV resulted in greater fire severity than Fuel model III across the two weather scenarios that were examined. PMID- 21691876 TI - Multitasking: multiple, domain-specific cognitive functions in a virtual environment. AB - Multitasking among three or more different tasks is a ubiquitous requirement of everyday cognition, yet rarely is it addressed in research on healthy adults who have had no specific training in multitasking skills. Participants completed a set of diverse subtasks within a simulated shopping mall and office environment, the Edinburgh Virtual Errands Test (EVET). The aim was to investigate how different cognitive functions, such as planning, retrospective and prospective memory, and visuospatial and verbal working memory, contribute to everyday multitasking. Subtasks were chosen to be diverse, and predictions were derived from a statistical model of everyday multitasking impairments associated with frontal-lobe lesions (Burgess, Veitch, de Lacy Costello, & Shallice, 2000b). Multiple regression indicated significant independent contributions from measures of retrospective memory, visuospatial working memory, and online planning, but not from independent measures of prospective memory or verbal working memory. Structural equation modelling showed that the best fit to the data arose from three underlying constructs, with Memory and Planning having a weak link, but with both having a strong directional pathway to an Intent construct that reflected implementation of intentions. Participants who followed their preprepared plan achieved higher scores than those who altered their plan during multitask performance. This was true regardless of whether the plan was efficient or poor. These results substantially develop and extend the Burgess et al. (2000b) model to healthy adults and yield new insight into the poorly understood area of everyday multitasking. The findings also point to the utility of using virtual environments for investigating this form of complex human cognition. PMID- 21691877 TI - Slow progress in predicting and preventing fatal gastric cancer peritoneal recurrence. PMID- 21691878 TI - Assessment of oncologic control obtained after open versus laparoscopic nephroureterectomy for upper urinary tract urothelial carcinomas (UUT-UCs): results from a large French multicenter collaborative study. AB - BACKGROUND: The purpose of this study was to compare the postsurgical survival of UUT-UC patients treated with ONU and LNU. METHODS: Using a multi-institutional, national, retrospective database, we identified patients with UUT-UC who underwent radical nephroureterectomy by open access (ONU) or by the minimally invasive alternative (LNU). Survival curves were estimated using Kaplan-Meier method. A multivariate Cox model was used to evaluate the association between surgical approach and disease recurrence. RESULTS: Overall, 609 patients were included (ONU = 459 and LNU = 150). The median age was 69.8 years (range 61.9 76), and the male-to-female ratio was 2:1. Postoperative complications occurred in 80 patients, with no significant difference between ONU and LNU on the whole (P = 0.64). The median follow-up was 27 months. There was no difference between the 2 procedures in the 5-year CSS or 5-year RFS. Moreover, the 5-year CSS (P = 0.053) and 5-year RFS (P = 0.9) for cases with locally advanced disease (pT3/pT4) were similar between ONU and LNU. In the multivariate analysis, the surgical procedure used was not found to be associated with survival. The main limitation of the study is its retrospective design, which is the result of the rarity of the disease. CONCLUSIONS: There is no evidence that oncological outcomes for LNU are inferior to those for open surgery, provided that the appropriate precautionary measures are taken. PMID- 21691879 TI - Is neo-adjuvant chemotherapy a "waiver" of extensive upper abdominal surgery in advanced epithelial ovarian cancer? AB - BACKGROUND: The goal of this study was to explore the necessity of extensive surgical procedures in patients who received neoadjuvant chemotherapy (NAC). METHODS: We analyzed the surgical outcomes and frequency of extensive procedures required for maximal cytoreductive surgery after NAC and primary debulking surgery (PDS) in 256 women with advanced epithelial ovarian cancer. RESULTS: NAC was performed in 116 of 256 women (45.3%). In NAC group, complete cytoreduction rate and optimal cytoreduction rate were 60.3 and 92.2%, respectively. Although the NAC group comprised patients with higher risk of suboptimal cytoreduction, complete cytoreduction rate was similar to that of PDS group (57.9%, P = .69). Moreover, blood loss and surgical complexity significantly reduced in NAC group (P = .011 and .017). Extensive upper abdominal surgery (EUAS) was performed in 70 of 116 patients (60.3%) in the NAC group. The frequency of EUAS was similar between NAC and PDS group (P = .60). Among NAC group, gross upper abdominal metastasis requiring EUAS was found in 51 patients (44%, 95% confidence interval = 35.3-53.1%). CONCLUSIONS: A significant proportion of patients who received NAC still have gross metastatic tumors requiring EUAS. Gynecologic oncologists should be familiar with EUAS and be ready to perform any required procedures together with multidisciplinary teams, even in the patients who have received NAC. PMID- 21691880 TI - Long-term outcome of patients with complete pathologic response after neoadjuvant chemoradiation for cT3 rectal cancer: implications for local excision surgical strategies. AB - BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) followed by radical surgery including total mesorectal excision (TME) is standard treatment in patients with locally advanced rectal cancer. Emerging data indicate that patients with complete pathologic response (ypCR) after CRT have favorable outcome, suggesting the possibility of less invasive surgical treatment. We analyzed long-term outcome of cT3 rectal cancer treated by neoadjuvant CRT in relation to ypCR and type of surgery. METHODS: The study population comprised 139 patients (93 men, 46 women; median age 62 years) with cT3N0-1M0 mid and distal rectal adenocarcinoma treated by CRT and surgery (110 TME and 29 local excision) at our institution between 1996 and 2008. At pathology, ypCR was defined as no residual cancer cells in the primary tumor. RESULTS: Tumors of 42 patients (30.2%) were classified as ypCR. After a median follow-up of 55.4 months, comparing patients with ypCR to patients with no ypCR, 5-year disease-specific survival was 95.8% versus 78.0% (P = 0.004), and 5-year disease-free survival was 90.1% vs. 64.0% (P = 0.004). In patients with ypCR, no statistically significant outcome difference was observed between TME and local excision. In patients treated by local excision, comparing patients with ypCR to patients with no ypCR, 5-year disease-free survival was 100% vs. 65.5% (P = 0.024), and 5-year local recurrence-free survival was 92.9% vs. 66.7% (P = 0.047). CONCLUSIONS: With retrospective analysis limitations, our data confirm favorable long-term outcome of cT3 rectal cancer with ypCR after CRT and warrant clinical trials exploring local excision surgical strategies. PMID- 21691881 TI - On invasion boundaries and the unprotected coexistence of two strategies. AB - In this paper we present, in terms of invasion fitness functions, a sufficient condition for a coexistence of two strategies which are not protected from extinction when rare. In addition, we connect the result to the local characterization of singular strategies in the theory of adaptive dynamics. We conclude with some illustrative examples. PMID- 21691882 TI - Optimal recall period in assessing the adherence to antihypertensive therapy: a pilot study. AB - OBJECTIVE: To evaluate the validity of patient self-reported adherence, and to find the optimal length of recall period which best reflects the long-term adherence pattern of the patient. SETTING: Patients were recruited from a general practitioner's practice in a Hungarian town. METHOD: In this prospective study 30 patients, who had already been on antihypertensive treatment, were involved. The study was designed to monitor one antihypertensive medication per patient for 3 months. Patients received a 3-month supply of one antihypertensive medication in an electronic Medication Event Monitoring System (MEMS). At the end of the study period patients completed a structured questionnaire regarding their medication taking behavior during the last 7, 14 and 30 days. The results measured with MEMS were considered as the reference value, and other measures were compared using the Bland-Altman method. MAIN OUTCOME MEASURES: Self-reported adherence, length of recall period, taking adherence and timing adherence measured by MEMS. RESULTS: Of the 30 patients included, 29 patients (13 males and 16 females) completed the study. The mean age of the patients was 60.6 years, ranging between 36 and 86 years. Patients were monitored for an average of 89 days (ranging between 49 and 106 days). Fifteen patients were on once daily, 9 patients were on twice daily, and 5 patients were on 3 times daily dosing schedule. The total expected number of medication taking events was 4,281. The MEMS caps recorded a total of 4,071 openings, which showed only a 3.56% deviation from the pill counts of the remaining tablets. The overall taking adherence was 95.1%, timing adherence was 75.2%. Patients' adherence report using a visual analog scale and reporting the number of missed doses became more accurate as the length of the recall period increased. Increased number of chronically taken medications was associated with better adherence. Increased dosing frequency of the observed antihypertensive medication resulted in decreased adherence. CONCLUSION: The results showed that the length of the recall period influences the accuracy of self-reported adherence. Patients seem to be able to report more precisely their medication taking behavior regarding a 30 day period than a 7 day period. PMID- 21691885 TI - Early steroid therapy for patients with H1N1 influenza A virus infection. PMID- 21691887 TI - The use of the Boussignac CPAP device during cardiogenic pulmonary edema (CPE): why add air to the oxygen gas source? PMID- 21691888 TI - Unblinding plan of PROWESS-SHOCK trial. PMID- 21691890 TI - Report from the 1st annual RICiFA meeting (International Meeting on Pharmaceutical Sciences 2010). PMID- 21691889 TI - The educational value of Disaster Victim Identification (DVI) missions-transfer of knowledge. AB - Transfer of knowledge is the cornerstone of any educational organisation, with senior staff expected to participate in the training of less experienced colleagues and students. Teaching in the field is, however, slightly different, and a less theoretical approach is usually recommended. In terms of Disaster Victim Identification (DVI) activities, practical work under supervision of a field team stimulates tactile memory. A more practical approach is also useful when multiple organizations from a variety of countries are involved, as language barriers make it easier to manually show someone how to solve a problem, instead of attempting to explain complex concepts verbally. "See one, do one, teach one" is an approach that can be used to ensure that teaching is undertaken with the teacher grasping the essentials of a situation before passing on the information to someone else. The key principles of adult learning that need to be applied to DVI situations include the following: participants need to know why they are learning and to be motivated to learn by the need to solve problems; previous experience must be respected and built upon and learning approaches should match participants' background and diversity; and finally participants need to be actively involved in the learning process. Active learning involves the active acquisition of knowledge and/or skills during the performance of a task and characterizes DVI activities. Learning about DVI structure, activities and responsibilities incorporates both the learning of facts ("declarative knowledge") and practical skills ("procedural knowledge"). A fundamental requirement of all DVI exercises should be succession planning with involvement of less experienced colleagues at every opportunity so that essential teaching and learning opportunities are maximized. DVI missions provide excellent teaching opportunities and international agencies have a responsibility to teach less experienced colleagues and local staff during deployment. PMID- 21691891 TI - Ocular pharmacokinetic study using T1 mapping and Gd-chelate- labeled polymers. AB - PURPOSE: Recent advances in drug discovery have led to the development of a number of therapeutic macromolecules for treatment of posterior eye diseases. We aimed to investigate the clearance of macromolecular contrast probes (polymers conjugated with Gd-chelate) in the vitreous after intravitreal injections with the recently developed ms-DSEPI-T12 MRI and to examine the degradation of disulfide-containing biodegradable polymers in the vitreous humor in vivo. METHODS: Intravitreal injections of model contrast agents poly[N-(2 hydroxypropyl)methacrylamide]-GG-1,6-hexanediamine-(Gd-DO3A), biodegradable (Gd DTPA)-cystine copolymers, and MultiHance were performed in rabbits; their distribution and elimination from the vitreous after injections were determined by MRI. RESULTS: Times for macromolecular contrast agents to decrease to half their initial concentrations in the vitreous ranged from 0.4-1.3 days post injection. Non-biodegradable polymers demonstrated slower vitreal clearance than those of disulfide-biodegradable polymers. Biodegradable polymers had similar clearance as MultiHance. CONCLUSIONS: Usefulness of T(1) mapping and ms-DSEPI-T12 MRI to study ocular pharmacokinetics was demonstrated. Results suggest an enzymatic degradation mechanism for the disulfide linkage in polymers in the vitreous leading to breakup of polymers in vitreous humor over time. PMID- 21691892 TI - Treatment of 9L gliosarcoma in rats by ferrociphenol-loaded lipid nanocapsules based on a passive targeting strategy via the EPR effect. AB - PURPOSE: To study a passive targeting strategy, via the enhanced permeability and retention effect following systemic administration of lipid nanocapsules (LNCs) loaded with ferrociphenol, FcdiOH. METHODS: Long chains of polyethylene glycol (DSPE-mPEG2000) were incorporated onto the surface of LNCs by post-insertion technique. Stealth properties of LNCs were investigated by in vitro complement consumption and macrophage uptake, and in vivo pharmacokinetics in healthy rats. Antitumour effect of FcdiOH-loaded LNCs was evaluated in subcutaneous and intracranial 9L gliosarcoma rat models. RESULTS: LNCs and DSPE-mPEG2000-LNCs presented low complement activation and weak macrophage uptake. DSPE-mPEG2000 LNCs exhibited prolonged half-life and extended area under the curve in healthy rats. In a subcutaneous gliosarcoma model, a single intravenous injection of FcdiOH-LNCs (400 MUL, 2.4 mg/rat) considerably inhibited tumour growth when compared to the control. DSPE-mPEG2000-FcdiOH-LNCs exhibited a strong antitumour effect by nearly eradicating the tumour by the end of the study. In intracranial gliosarcoma model, treatment with DSPE-mPEG2000-FcdiOH-LNCs and FcdiOH-LNCs statistically improved median survival time (28 and 27.5 days, respectively) compared to the control (25 days). CONCLUSION: These results demonstrate the interesting perspectives for the systemic treatment of glioma thanks to bio organometallic chemotherapy via lipid nanocapsules. PMID- 21691893 TI - Functional and clinical evidence of the influence of sorafenib binding to albumin on sorafenib disposition in adult cancer patients. AB - PURPOSE: Sorafenib, an oral multitargeted tyrosine kinase inhibitor, is highly bound to plasma proteins (>99.5%). Little is known about the influence of variations in sorafenib protein binding on its disposition. The aims of this study were to characterize in vitro sorafenib binding properties to albumin using the quenching fluorescence method and investigate the influence of albuminemia and bilirubinemia on sorafenib disposition in 54 adult cancer patients. RESULTS: In vitro estimate of sorafenib dissociation constant (Kd) for albumin was 0.22 MUM [CI95 0.20-0.23]. In physiological conditions, sorafenib unbound fraction would increase 1.7-fold as albuminemia decreased from 45 g/L (680 MUM) to 30 g/L (453 MUM). In presence of bilirubin, apparent Kd of sorafenib was ~1.5-fold greater for bilirubin/albumin molar ratio of 1:4. In clinical settings, median sorafenib clearance (CL) was 1.42 L/h (0.75-2.13 L/h). In univariate analysis, sex, body mass index, and albuminemia were associated with CL (p = 0.04, 0.048, and 0.008, respectively). In multivariate analysis, albuminemia (p = 0.0036) was the single parameter independently associated with CL. CONCLUSION: These findings highlight the major influence of albuminemia on sorafenib clearance and its disposition in cancer patients. PMID- 21691895 TI - Monitoring cerebral autoregulation after head injury. Which component of transcranial Doppler flow velocity is optimal? AB - BACKGROUND: Cerebral autoregulation assessed using transcranial Doppler (TCD) mean flow velocity (FV) in response to various physiological challenges is predictive of outcome after traumatic brain injury (TBI). Systolic and diastolic FV have been explored in other diseases. This study aims to evaluate the systolic, mean and diastolic FV for monitoring autoregulation and predicting outcome after TBI. METHODS: 300 head-injured patients with blood pressure (ABP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), and FV recordings were studied. Autoregulation was calculated as a correlation of slow changes in diastolic, mean and systolic components of FV with CPP (Dx, Mx, Sx, respectively) and ABP (Dxa, Mxa, Sxa, respectively) from 30 consecutive 10 s averaged values. The relationship with age, severity of injury, and dichotomized 6 months outcome was examined. RESULTS: Association with outcome was significant for Mx and Sx. For favorable/unfavorable and death/survival outcomes Sx showed the strongest association (F = 20.11; P = 0.00001 and F = 13.10; P = 0.0003, respectively). Similarly, indices derived from ABP demonstrated the highest discriminatory value when systolic FV was used (F = 12.49; P = 0.0005 and F = 5.32; P = 0.02, respectively). Indices derived from diastolic FV demonstrated significant differences (when calculated using CPP) only when comparing between fatal and non fatal outcome. CONCLUSIONS: Systolic flow indices (Sx and Sxa) demonstrated a stronger association with outcome than the mean flow indices (Mx and Mxa), irrespective of whether CPP or ABP was used for calculation. PMID- 21691894 TI - Quantitative glucose and ATP sensing in mammalian cells. AB - The functioning and survival of mammalian cells requires an active energy metabolism. Metabolic dysfunction plays an important role in many human diseases, including diabetes, cancer, inherited mitochondrial disorders, and metabolic syndrome. The monosaccharide glucose constitutes a key source of cellular energy. Following its import across the plasma membrane, glucose is converted into pyruvate by the glycolysis pathway. Pyruvate oxidation supplies substrates for the ATP-generating mitochondrial oxidative phosphorylation (OXPHOS) system. To gain cell-biochemical knowledge about the operation and regulation of the cellular energy metabolism in the healthy and diseased state, quantitative knowledge is required about (changes in) metabolite concentrations under (non) steady-state conditions. This information can, for instance, be used to construct more realistic in silico models of cell metabolism, which facilitates understanding the consequences of metabolic dysfunction as well as on- and off target effects of mitochondrial drugs. Here we review the current state-of-the art live-cell quantification of two key cellular metabolites, glucose and ATP, using protein-based sensors. The latter apply the principle of FRET (fluorescence resonance energy transfer) and allow measurements in different cell compartments by fluorescence microscopy. We further summarize the properties and applications of the FRET-based sensors, their calibration, pitfalls, and future perspectives. PMID- 21691896 TI - Strategic placement of bedside ventriculostomies using ultrasound image guidance: report of three cases. AB - BACKGROUND: The blind free-hand technique for external ventricular drain (EVD) placement sometimes requires multiple attempts, and catheter location is often less than ideal. Our institution has adapted an intraoperative ultrasound-guided ventriculostomy technique for the placement of EVDs at the bedside. Our experience with ultrasound at the bedside has proven to be invaluable in certain circumstances. We present three cases of strategic EVD catheter trajectories that were made possible at the bedside with the use of ultrasound. METHODS: Illustrative cases were chosen from a larger prospective study investigating the ultrasound-guided EVD technique. A portable ultrasound with a "burr hole" probe was used with modification of the standard surgical technique for placement of EVDs at the bedside. RESULTS: Case 1 describes an unexpected re-hemorrhage that was first realized by the ultrasound image obtained during the bedside EVD placement procedure. The catheter was purposefully directed across midline to the more prominent ventricle on the contralateral side based on this real-time finding. Case 2 describes how ultrasound was used to salvage the failed free-hand procedure and cannulate an extremely small ventricular space at the bedside. Case 3 describes an unconventionally placed burr hole that provided a customized trajectory in which the EVD catheter was placed just laterally and inferior to a large frontal hematoma. CONCLUSION: Ultrasound-guided bedside EVD placement allows EVD trajectories to be customized based on real-time information to accommodate for distorted and dynamic anatomy of the brain and its ventricles. PMID- 21691897 TI - Religion, forgiveness, hostility and health: a structural equation analysis. AB - Religious participation has been shown to increase certain factors thought to be protective of health, including social support and positive health habits. The current study considers whether religious participation may likewise have a positive influence on health by increasing forgiveness and diminishing hostility. A structural equation analysis of data collected from a national survey of 1,629 participants supported the hypothesized model that (a) religiosity is related to greater forgiveness, (b) greater forgiveness, in turn, is related to reduced hostility and finally, (c) reduced hostility is related to better subjective health. PMID- 21691898 TI - Circulating microparticles: new insights into the biochemical basis of microparticle release and activity. AB - Circulating microparticles released from various cell types are present in healthy individuals and the number and composition of their membrane vary in different disorders. Long considered to be cellular debris, microparticles have been recently identified as regulatory vectors of intercellular cross-talk. Indeed, circulating microparticles represent a heterogeneous mixture of spheroids of diverse surface membrane glycoproteins and lipids, with diverse cytoplasm components, the pattern of which depends on the type of stimulation and pathophysiology of parental cells. Despite extensive research into the procoagulant and proinflammatory properties of microparticles, there are few data that can provide information on the mechanism(s) of their formation and biological effects. Although several mechanisms of microparticle release have been suggested, the precise order of the events associated with key features of microparticle formation, transmembrane phosphatidylserine redistribution and cytoskeleton disruption remain to be clarified. In this review, we provide an overview of the molecular mechanisms involved in microparticle formation, as well as the diverse physiological and pathological roles they are able to undertake. Understanding the mechanism(s) governing microparticle release processes may be critical to understanding their precise role in various pathophysiological processes and thus indicate new potential routes to therapy. PMID- 21691899 TI - Tumor necrosis factor receptor 2 signaling limits beta-adrenergic receptor mediated cardiac hypertrophy in vivo. AB - The in vivo role of TNF signaling in the genesis of beta-adrenergic receptor (beta-AR)-mediated cardiac hypertrophy is unknown. Wild-type (WT), TNF receptor 1 (TNFR1)-/- and TNFR2-/- mice were given isoproterenol (ISO, 12.5 MUg/kg/h) or saline (SAL) for 1 or 7 days. In WT mice, 7 days of ISO yielded chamber/myocyte hypertrophy and hyperdynamic function without hypertension or fibrosis. WT ISO hearts exhibited an early (1 day) pro-inflammatory response with significant (p < 0.05) activation of nuclear factor (NF)-kappaB and activator protein 1 (AP-1) and upregulation of TNF, interleukin (IL)-1beta and IL-6, inducible nitric oxide synthase (iNOS) and monocyte chemotactic protein-1 (MCP-1), together with increased anti-inflammatory IL-10. This response diminished markedly by 7 days. As compared with WT ISO mice, TNFR1-/- ISO mice exhibited significantly (p < 0.05) less NF-kappaB and AP-1 activation, less IL-1beta, TNF, iNOS and MCP-1 upregulation, but greater IL-10 at 1 day. However, there were no differences in hypertrophy or contractility at 7 days. In contrast, TNFR2-/- ISO mice exhibited augmented NF-kappaB and AP-1 activation, increased IL-1beta and diminished IL-10 expression at 1 day, and significant exaggeration of hypertrophy and less contractile augmentation at 7 days. Moreover, TNFR2-/- mice exposed to tenfold higher ISO doses displayed significant mortality. TNF signaling contributes to beta-AR-mediated cardiac remodeling in vivo in a receptor-specific manner. Unopposed TNFR1 activation is pro-inflammatory, pro-hypertrophic and promotes functional decline. However, co-activation of TNFR2 during beta-AR stress is anti inflammatory and counterbalances these deleterious effects. TNF modulatory strategies that maintain TNFR2 signaling may help prevent the detrimental long term effects of beta-AR stimulation in the heart. PMID- 21691900 TI - Computed tomographic evaluation of odontoid process: implications for anterior screw fixation of odontoid fractures in an adult population. AB - INTRODUCTION: Odontoid diameter in some individuals may not be large enough to accommodate two 3.5-mm cortical screws for anterior odontoid fracture fixation. The study was performed to evaluate, in a Brazilian population, the diameter of the odontoid process and the feasibility of using two 3.5-mm cortical screws for anterior odontoid fracture fixation. MATERIALS AND METHODS: Computed tomographic (CT) scans of 88 adult patients (aged 18-78 years) were analyzed; 40 patients (45%) were male (mean age: 43.08 years) and 48 (55%) were female (mean age: 43.39 years). The minimum external and internal anteroposterior and transverse diameters of the odontoid process on sagittal and coronal planes were measured on CT multiplanar reconstructions of the cervical spine. RESULTS: The mean value of the minimum external anteroposterior diameter was 10.83 +/- 1.08 and 7.53 +/- 1.10 mm for the minimum internal anteroposterior diameter. The mean value of the minimum external transverse diameter was 9.19 +/- 0.91 and 6.07 +/- 1.08 mm for the minimum internal transverse diameter. The mean AP diameter was significantly larger than the mean transverse diameter; 57 (65%) individuals had the minimum external transverse diameter >9.0 mm that would allow the insertion of two 3.5-mm cortical screws with tapping, and five (6%) individuals had the minimum internal transverse diameter >8.0 mm that would allow the insertion of two 3.5-mm cortical screws without tapping. CONCLUSIONS: The insertion of two 3.5-mm cortical screws was possible for anterior fixation of odontoid fracture in 57 (65%) individuals of our study, and there was no statistical difference between males and females. PMID- 21691901 TI - Potential genetic markers predicting the outcome of brace treatment in patients with adolescent idiopathic scoliosis. AB - PURPOSE: To investigate whether the predisposition genes previously reported to be associated with the occurrence or curve severity of adolescent idiopathic scoliosis (AIS) play a role in the effectiveness of brace treatment. METHOD: A total of 312 AIS patients treated with bracing were enrolled in this study. The Cobb angle of the main curve was recorded at the beginning of brace treatment as well as at each follow-up. The patients were divided into two groups according to the outcome of brace treatment (success/failure). The failure of brace treatment was defined as a curve progression of more than 5 degrees compared to the initial Cobb angle or surgical intervention because of curve progression. Single nucleotide polymorphism (SNP) sites in the genes for estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), tryptophan hydroxylase 1 (TPH-1), melatonin receptor 1B (MTNR1B) and matrillin-1 (MATN1), which were previously identified to be predisposition genes for AIS, were selected for genotyping by the PCR-RFLP method. Differences of genotype and allele distribution between the two groups were compared by the chi(2) test. A logistic regression analysis was used to figure out the independent predictors of the outcome of brace treatment. RESULTS: There were 90 cases (28.8%) in the failure group and 222 cases (71.2%) in the success group. Patients in the failure group were associated with the genotype GA (50.9 vs. 17.9% p < 0.001) and the G allele (27.1 vs. 12.0%, p < 0.001) at SNP rs9340799 of the ERalpha gene. Similarly, they were also associated with the genotype AT (33.3 vs. 13.0%, p = 0.002) and the A allele (16.7 vs. 9.6%, p = 0.033) at SNP rs10488682 of the TPH-1 gene. For MTNR1B, the difference of genotype distribution between the two groups was found to be statistically significant, while the difference of allele distribution between the two groups was found to be marginally statistically significant; for the MATN1 and ERbeta genes, we found no significant differences of the genotype or allele distribution between the two groups. In the logistic regression analysis, ERalpha and TPH-1 were demonstrated to be independent factors predictive of bracing effectiveness. CONCLUSIONS: ERalpha and TPH-1 might be potential genetic markers that could predict the outcome of brace treatment. Patients with the G allele at the rs9340799 site of the ERalpha gene and the A allele at the rs10488682 site of the TPH-1 gene are prone to be resistant to brace treatment. PMID- 21691903 TI - Mystery of the anti-McCollough effect. AB - The McCollough Effect (ME) is a complex perceptual aftereffect that remains of interest half a century after its discovery. It is argued that a recently reported variant, dubbed the anti-McCollough effect, is not the reverse of the ME, with aftereffect colors in the same direction as the inducing stimuli. A red horizontal stimulus leads to a reddish aftereffect not because of red-horizontal parings, but despite them. The anti-ME is a weak standard-direction ME produced by complementary afterimage colors (afterimage green with horizontal), rather than by environmental colors, first shown decades ago. It is not a new type of contingent aftereffect. The red-horizontal pair does not interfere with the afterimage green-horizontal pair it produces because a single color-orientation pairing provides more ambiguous input than does the standard two orientation color pairings (red-horizontal, green-vertical) of the ME. It is also argued that not even one orientation-contingent color aftereffect is convincingly shown in the "anti"-ME, let alone, as has previously been suggested, two simultaneous orientation-contingent color aftereffects in opposite directions at different levels of the visual system, in which the higher-level effect suppresses the downstream effect from reaching consciousness. The "anti"-ME can be explained by existing theories of contingent aftereffects, including perceptual-learning theory. PMID- 21691902 TI - Target absent trials in configural contextual cuing. AB - In contextual cuing (CC), reaction times for finding targets are faster in repeated displays than in displays that have never been seen before. This has been demonstrated using target-distractor configurations, global background colors, naturalistic scenes, and covariation of targets with distractors. The majority of CC studies have used displays in which the target is always present. This study investigated what happens when the target is sometimes absent. Experiment 1 showed that, although configural CC occurs in displays when the target is always present, there is no CC when the target is always absent. Experiment 2 showed that there is no CC when the same spatial layout can be both target present and target absent on different trials. The presence of distractors in locations that had contained targets on other trials appeared to interfere with CC, and even disrupted the expression of CC in previously learned contexts (Exps. 3-5). These results show that target-distractor associations are the important element in producing CC and that, consistent with a response selection account, changing the response type from an orientation task to a detection task removes the CC effect. PMID- 21691904 TI - Behavioral dynamics of the affordance "graspable". AB - On a daily basis, one perceives whether an object affords grasping with one hand or with both hands. In experiments in which differently sized objects of a fixed type have been presented, the transition from using one manual mode to the other has depended on both the ratio of object size to hand span and the presentation sequence-that is, size increasing versus decreasing. The transitions and their observed hysteresis (i.e., a transition ratio larger for the increasing sequence) can be accommodated by the order parameter dynamics typifying self-organizing systems. Here, we show that hysteresis magnitude depends on (a) the interaction between the attractors (one hand vs. two hands) and (b) the strength of the two hands attractor. Through modeling and experimental results, we extend the investigation of affordance perception within dynamical-systems theory. PMID- 21691905 TI - Letter to the editor: Unexplained fractures: child abuse or bone disease: a systematic review. PMID- 21691906 TI - Intercalary femur allografts are an acceptable alternative after tumor resection. AB - BACKGROUND: With the improved survival for patients with malignant bone tumors, there is a trend to reconstruct defects using biologic techniques. While the use of an intercalary allograft is an option, the procedures are technically demanding and it is unclear whether the complication rates and survival are similar to other approaches. QUESTIONS/PURPOSES: We evaluated survivorship, complications, and functional scores of patients after receiving intercalary femur segmental allografts. PATIENTS AND METHODS: We retrospectively reviewed 83 patients who underwent an intercalary femur segmental allograft reconstruction. We determined allograft survival using the Kaplan-Meier method. We evaluated patient function with the Musculoskeletal Tumor Society scoring system. Minimum followup was 24 months (median, 61 months; range, 24-182 months). RESULTS: Survivorship was 85% (95% confidence interval: 93%-77%) at 5 years and 76% (95% confidence interval: 89%-63%) at 10 years. Allografts were removed in 15 of the 83 patients: one with infection, one with local recurrence, and 13 with fractures. Of the 166 host-donor junctions, 22 (13%) did not initially heal. Nonunion rate was 19% for diaphyseal junctions and 3% for metaphyseal junctions. We observed an increase in the diaphysis nonunion rate in patients fixed with nails (28%) compared to those fixed with plates (15%). Fracture rate was 17% and related to areas of the allograft not adequately protected with internal fixation. All patients without complications had mainly good or excellent Musculoskeletal Tumor Society functional results. CONCLUSIONS: Diaphyseal junctions have higher nonunion rates than metaphyseal junctions. The internal fixation should span the entire allograft to avoid the risk of fracture. Our observations suggest segmental allograft of the femur provides an acceptable alternative in reconstructing tumor resections. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 21691907 TI - Preoperative patient education reduces in-hospital falls after total knee arthroplasty. AB - BACKGROUND: Inpatient hospital falls after orthopaedic surgery represent a major problem, with rates of about one to three falls per 1000 patient days. These falls result in substantial morbidity for the patient and liability for the institution. QUESTIONS/PURPOSES: We determined whether preoperative patient education reduced the rate of in-hospital falls after primary TKA and documented the circumstances and the injuries resulting from the falls. PATIENTS AND METHODS: We reviewed data from all 244 patients who underwent primary TKA at a single institution between March and November 2009. Seventy-two patients of one surgeon were enrolled in a preoperative nurse-led education program. This group was compared with a control group of 172 patients who concurrently underwent TKA at the same institution but did not receive preoperative education. RESULTS: More control patients had in-hospital falls than those in the education group: seven (one of whom had two falls) of 172 (4%) versus none of 72 (0%), respectively. Three of the eight falls resulted in a serious injury, including one wound dehiscence and one wound hematoma that both required repeat surgery and one clavicle fracture. CONCLUSIONS: Inpatient falls after TKA may be associated with major complications. Our preoperative patient education reduced these falls and is now mandatory for patients undergoing TKA at our institution. PMID- 21691908 TI - Second-generation modular acetabular components provide fixation at 10 to 16 years. AB - BACKGROUND: First-generation modular titanium fiber-metal-coated acetabular components had high rates of wear, pelvic osteolysis, and liner dissociation. Second-generation components were designed to reduce the incidence of these problems but it is unclear whether the changes achieved these goals. QUESTIONS/PURPOSES: We asked the following questions: (1) Is the risk of revision surgery for loosening, wear, or liner dissociation low with the second-generation acetabular component? (2) Is the rate of pelvic osteolysis low? (3) Can the liner be exchanged without bone cement? METHODS: We retrospectively reviewed prospectively collected data from 99 patients (118 hips) undergoing THAs with one second-generation modular titanium acetabular component with routine screw fixation and conventional polyethylene. The minimum followup was 10 years (mean, 12 years; range, 10-16 years). We obtained Harris hip scores and examined radiographs for loosening and osteolysis. RESULTS: At last followup, all acetabular components were well fixed and no titanium shell had been revised or removed. No liner had dissociation. At most recent followup, the mean Harris hip score was 89. We observed pelvic osteolysis in eight hips (7%). There were three reoperations for dislocation (head-liner exchange only) and three loose femoral components revised. Two liners (at 11 and 14 years) were exchanged for wear pelvic osteolysis. CONCLUSIONS: This second-generation modular titanium fiber metal-coated acetabular component with screw fixation had no loosening, no liner dissociation, and a low rate of pelvic osteolysis at 10 to 16 years. Liner exchange is practical without use of cement. We continue to use this component with highly crosslinked polyethylene liners. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21691909 TI - Endosteal strut augment reduces complications associated with proximal humeral locking plates. AB - BACKGROUND: Locking-plate technology has renewed interest in plate fixation for treating proximal humerus fractures. Complications associated with these devices, including loss of reduction, screw cutout, and intra-articular penetration, are frequent. Establishing a second column of support may reduce complications and improve clinical outcome scores. QUESTIONS/PURPOSES: We asked whether addition of an endosteal cortical allograft strut, used as an augment to locking-plate fixation for displaced proximal humerus fractures, would reduce complications and improve clinical outcome scores. PATIENTS AND METHODS: We retrospectively reviewed the charts and radiographs of 38 patients treated by this method. All patients were evaluated with serial radiographs, as well as the Disabilities of the Arm, Shoulder, and Hand and Constant-Murley scores. There were seven two part, 19 three-part, and 12 four-part fractures. The minimum followup was 49 weeks (average, 75 weeks; range, 49-155 weeks). RESULTS: No patient had intra articular screw penetration or cutout. No patient had complete osteonecrosis, but one had partial osteonecrosis. The reduction was lost in one patient. The mean Disabilities of the Arm, Shoulder, and Hand score was 15 (range, 0-66.4). The mean Constant-Murley score was 87 (range, 51-95). CONCLUSIONS: Low rates of complication and high clinical outcome scores can be achieved when treating complex proximal humerus fractures with locking-plate fixation and an endosteal strut augment. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21691910 TI - Locked plating of proximal humeral fractures: is function affected by age, time, and fracture patterns? AB - BACKGROUND: Locking plate fixation of proximal humeral fractures improves biomechanical stability. It has expanded the indications of traditional open reduction internal fixation and become increasingly common for treating unstable, displaced proximal humeral fractures. Despite improved stability it is unclear whether these improve function and if so for which patients. QUESTIONS/PURPOSES: We therefore determined patient function after a locked plating technique for the treatment of unstable proximal humeral fractures based on age, time, fracture pattern, and associated injures. PATIENTS AND METHODS: We retrospectively reviewed 66 patients with 69 proximal humeral fractures treated with a locked proximal humeral plating technique from 2002-2006 using prospectively gathered data. Function was measured using the Short Musculoskeletal Function Assessment (SMFA), Disability of the Arm, Shoulder, and Hand (DASH), and SF-36 at 6, 12, and 24 months. Fracture healing was determined radiographically and complication rates were determined from the medical records. RESULTS: At 2 years, DASH scores were 26.5 and 37.4 for isolated and polytrauma patients, respectively. For age differences, DASH scores were 33.1 and 28.9 for ages younger than 60 and 60 years old or older, respectively. At 2 years, SMFA scores were higher (worse) in older compared with younger patients. Function, but not bother continues to improve in younger patients up to 2 years. More severe fracture patterns performed worse in all SMFA indices at 2 years. Polytrauma patients consistently experienced worse mobility than isolated injury patients at each time interval. CONCLUSIONS: With locked plating of unstable proximal humeral fractures, older patients function as well as younger patients; improvement continues until 1 year postoperatively, the Neer fracture classification differentiates function, and polytrauma patients perform worse clinically. Long-term functional deficits persist. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21691911 TI - An intervention to help community-based organizations implement an evidence-based HIV prevention intervention: the Mpowerment Project technology exchange system. AB - Considerable resources have been spent developing and rigorously testing HIV prevention intervention models, but such models do not impact the AIDS pandemic unless they are implemented effectively by community-based organizations (CBOs) and health departments. The Mpowerment Project (MP) is being implemented by CBOs around the U.S. It is a multilevel, evidence-based HIV prevention program for young gay/bisexual men that targets individual, interpersonal, social, and structural issues by using empowerment and community mobilization methods. This paper discusses the development of an intervention to help CBOs implement the MP called the Mpowerment Project Technology Exchange System (MPTES); CBOs' uptake, utilization and perceptions of the MPTES components; and issues that arose during technical assistance. The seven-component MPTES was provided to 49 CBOs implementing the MP that were followed longitudinally for up to two years. Except for the widely used program manual, other program materials were used early in implementing the MP and then their use declined. In contrast, once technical assistance was proactively provided, its usage remained constant over time, as did requests for technical assistance. CBOs expressed substantial positive feedback about the MPTES, but felt that it needs more focus on diversity issues, describing real world implementation approaches, and providing guidance on how to adapt the MP to diverse populations. PMID- 21691912 TI - [Total ankle arthroplasty for rheumatoid arthritis]. AB - Modern second generation total ankle arthroplasty is now a serious alternative to ankle fusion in patients with rheumatoid arthritis after careful assessment of the indications. The midterm results with 10-year survival rates between 70% and 90% and the possible revision for implant exchange or arthrodesis are the reasons for the increasing importance of ankle arthroplasty. Patients with rheumatoid arthritis in particular with generally lower physical requirements can expect a pain-free function of the operated ankle for 8-10 years. In comparison to fusion ankle arthroplasty allows a significantly faster remobilization and reserves the correction capabilities of the ankle. Arthrodesis remains a valuable therapeutic alternative for severe bony destruction and instability as well as a possible fallback for failure of arthroplasty. PMID- 21691913 TI - [Endoprosthetic replacement of the rheumatoid wrist]. AB - For patients with rheumatoid arthritis preventive and reconstructive surgery of the hand provide better functional results and higher patient satisfaction when surgery is done adequately before the inflammatory stage, especially when multiple joints are affected. Synovectomy, arthrodesis and prosthetic reconstruction are able to guarantee maintenance of function even in late stages and severe destruction, when modern drug therapy cannot prevent further inflammatory attacks and increasing destruction. PMID- 21691914 TI - ASNC model coverage policy: single photon myocardial perfusion imaging. PMID- 21691915 TI - Multinomial logistic functions in markov chain models of sleep architecture: internal and external validation and covariate analysis. AB - Mixed-effect Markov chain models have been recently proposed to characterize the time course of transition probabilities between sleep stages in insomniac patients. The most recent one, based on multinomial logistic functions, was used as a base to develop a final model combining the strengths of the existing ones. This final model was validated on placebo data applying also new diagnostic methods and then used for the inclusion of potential age, gender, and BMI effects. Internal validation was performed through simplified posterior predictive check (sPPC), visual predictive check (VPC) for categorical data, and new visual methods based on stochastic simulation and estimation and called visual estimation check (VEC). External validation mainly relied on the evaluation of the objective function value and sPPC. Covariate effects were identified through stepwise covariate modeling within NONMEM VI. New model features were introduced in the model, providing significant sPPC improvements. Outcomes from VPC, VEC, and external validation were generally very good. Age, gender, and BMI were found to be statistically significant covariates, but their inclusion did not improve substantially the model's predictive performance. In summary, an improved model for sleep internal architecture has been developed and suitably validated in insomniac patients treated with placebo. Thereafter, covariate effects have been included into the final model. PMID- 21691916 TI - Laparoscopic resection of small bowel lipoma causing obscure gastrointestinal bleeding. AB - Small bowel lipomas are rare gastrointestinal benign neoplasms, whose signs and symptoms are often obscure. When symptoms are clinically present, one of the most common is usually gastrointestinal (GI) bleeding. It is very difficult to make a precise preoperative diagnosis in the absence of evident signs. Definitive diagnosis can only be made through histopathological examination, after the surgical resection. We report a case of obscure and persistent GI bleeding in a 78-year-old woman. Through the combination of endoscopy and computed tomography (CT), it was possible to identify a small bowel lesion, being its direct cause. CT showed a certain fat component within the mass pinpointing the hypothesis of a lipoma. We then performed a laparoscopic resection of 21 cm of the middle jejunum, including the mass and an intussusception. The results of the subsequent histopathological examination of the resected specimen allowed us to conclude that the lesion was an intestinal lipoma. Surgical resection appears to be the most successful approach as good short- and long-term results are achieved. PMID- 21691917 TI - Embolisation of the gastroduodenal artery is not necessary in the presence of reversed flow before yttrium-90 radioembolisation. AB - INTRODUCTION: The gastroduodenal artery (GDA) is usually embolised to avoid nontarget dispersal before yttrium-90 (Y(90)) radioembolisation to treat liver metastases. In a minority of patients, there is retrograde flow in the GDA. The purpose of this study was to determine if there is any increased risk from maintaining a patent GDA in patients with reversed flow. MATERIALS AND METHODS: A retrospective review was performed of all patients undergoing Y(90) radioembolisation at our institution. The incidence of toxicities arising from nontarget radioembolisation by way of the GDA (gastric/duodenal ulceration, gastric/duodenal bleeding, and pancreatitis) and death occurring within 2 months of treatment were compared between the reversed and the antegrade GDA groups. RESULTS: Ninety-two patients underwent preliminary angiography. Reversed GDA flow was found on angiography in 14.1% of cases; the GDA was not embolised in these patients. The GDA was coiled in 55.7% of patients with antegrade GDA flow to prevent inadvertent dispersal of radioembolic material. There was no increased toxicity related to nontarget dispersal by way of the GDA, or increased early mortality, in patients with reversed GDA flow (P > 0.05). CONCLUSION: In patients with reversed GDA flow, maintenance of a patent GDA before administration of Y(90) radioembolisation does not increase the risk of toxicity from nontarget dispersal. Therapeutic injection, with careful monitoring to identify early vascular stasis, may be safely performed beyond the origin of the patent GDA. A patent GDA with reversed flow provides forward drive for infused particles and may allow alternative access to the hepatic circulation. PMID- 21691918 TI - Endovascular treatment in emergency setting of acute arterial injuries after orthopedic surgery. AB - PURPOSE: To assess the feasibility and effectiveness of emergency endovascular treatment of acute arterial injuries after orthopedic surgery. MATERIALS AND METHODS: Fifteen patients (mean age 68.3 years) with acute arterial injuries after orthopedic surgery were observed, in particular, 5 patients with pseudoaneurysm, 9 patients with active bleeding, and 1 patient with arterial dissection. Transarterial embolization (TAE) and positioning of covered and noncovered stents were the treatments performed. Follow-up after stent implantation (mean 36 months) was performed with color Doppler US (CDU) at 1, 3, 6, and 12 months and yearly thereafter. Plain X-ray was performed to evidence dislodgment or fracture of the graft. A minimum of 12 months' follow-up is available after TAE. RESULTS: Immediate technical success was obtained in all cases. No major complications occurred. Overall clinical success rate was 100%. During mean follow-up, stent-graft occlusions did not occurred. No recurrence and/or consequence of TAE was registered during a minimum follow-up of 12 months. CONCLUSIONS: Percutaneous treatment is a feasible and safe tool for treating arterial injuries because it can provide fast and definitive resolution of the damage. This low-invasiveness approach can be proposed as first-line treatment in patients with acute injuries after orthopedic surgery. PMID- 21691920 TI - Rapid isolation of muscle-derived stem cells by discontinuous Percoll density gradient centrifugation. AB - We investigated relationship between the maturity and density of muscle cells and developed a rapid isolation method to acquire stem cells from skeletal muscle. Mononuclear cells were isolated from the lower hind-limb muscles of 7-d-old male Sprague-Dawley rats and separated by Percoll density gradient centrifugation. After centrifugation, the cells were layered in the interfaces between each Percoll density layer. Flow cytometry was used to investigate the Sca-1, Pax7, CD34, CD45, M-cadherin, and myosin expression of the cells in each density layer. We found that CD45-positive cells were not present in freshly isolated muscle cells. CD34-, Pax7-positive cells were mainly observed at the interface between the 15% and 25% Percoll layers and had a density of 1.0235-1.0355 g/ml. Cells positive for M-cadherin were at the 25-35% Percoll density interface and had a density of 1.0355-1.0492 g/ml. We conclude that because there appears to be a correlation between maturity and density, muscle-derived stem cells may be isolated successfully from the 15-25% Percoll interface. PMID- 21691919 TI - Impaired cardiac sympathetic innervation in symptomatic patients with long QT syndrome. AB - PURPOSE: Increased sympathetic activation is a key modifier for arrhythmogenesis in patients with long QT syndrome (LQTS), a congenital channelopathy. Therefore, we investigated cardiac sympathetic function using 123I-metaiodobenzylguanidine (MIBG) single photon emission computed tomography (SPECT) in a cohort of symptomatic LQTS patients and correlated these findings with the underlying genotype. METHODS: [123I]MIBG SPECT was performed in 28 LQTS patients. Among these, 18 patients (64%) had a previous syncope and 10 patients (36%) survived sudden cardiac arrest. Patients were characterized in terms of genetic subtypes and QTc interval on surface ECGs. SPECT images were analysed for regional [123I]MIBG uptake in a 33-segment bullseye scheme and compared to those obtained from 10 age-matched healthy control subjects (43+/-12 years). RESULTS: An abnormal 123I-MIBG scan was found in 17 of 28 LQTS patients (61%) with a tracer reduction mainly located in the anteroseptal segments of the left ventricle. This finding was independent of the genetic LQTS subtype. In addition, no differences were found between LQTS patients with a QTc>500 ms vs <500 ms or those suffering from syncope vs VF (p>0.05). CONCLUSION: A distinct regional pattern of impaired cardiac sympathetic function was identified in the majority of symptomatic LQTS patients. This innervation defect was independent of the underlying genotype and clinical disease expression. PMID- 21691921 TI - FGFR3-expressing smooth muscle-like stromal cells differentiate in response to FGFR2IIIb-expressing prostate tumor cells and delay tumor progression. AB - Evolution of unresponsiveness to homeostasis-promoting signals from the microenvironment is a hallmark of malignant tumor cells. In Dunning R3327 model rat prostate tumors that are comprised of distinct stromal and epithelial compartments, progression from non-malignant, androgen-responsive tumors to malignancy is characterized by loss of compartmentation coincident with a loss of resident epithelial cell FGFR2IIIb that receives instructive signals from stromal FGF7 and FGF10. Restoration of FGFR2IIIb to malignant tumor cells restores responsiveness to stromal cells, restores distinct stromal and epithelial compartments, and retards malignant progression. Cultured stromal cells from two compartment tumors are comprised of smooth muscle alpha-actin-positive cells that express predominantly FGFR3 and fibroblast-like cells devoid of alpha-actin and FGFR3. Here, we show that it is primarily the smooth muscle cell-like alpha-actin expressing stromal cells that survive, morphologically differentiate, and delay tumor incidence and size in the presence of malignant cells in which FGFR2IIIb has been restored. Expression of FGFR3 by transfection in the fibroblast-like stromal cells conferred ability to respond similar to the smooth muscle cell-like stromal cells in which FGFR3 is normally resident. These results highlight the importance of the two-way communication back and forth between stroma and epithelium that is mediated by signaling within the FGFR family during progression to malignancy. PMID- 21691922 TI - Reply to Dr. Viroj Wiwanikit. PMID- 21691923 TI - Suspected recurrent anaphylaxis in different forms during general anesthesia: implications for Kounis syndrome. PMID- 21691925 TI - Green Carts (mobile produce vendors) in the Bronx--optimally positioned to meet neighborhood fruit-and-vegetable needs? AB - Poor access to fresh produce likely contributes to disparities in obesity and diet-related diseases in the Bronx. New York City's Green Cart program is a partial response to the problem. We evaluated this program (permitting street vendors to sell fresh produce) by canvassing the Bronx for carts, interviewing vendors, and analyzing their locations and food offerings. Green Carts were clustered in areas of probable high pedestrian traffic, covering only about 57% of needy areas by liberal estimates. Some carts sold outside allowed boundaries; a few sold sugary snacks. Vendor locations and their food offerings suggest possible areas for program improvement. PMID- 21691924 TI - Post-operative pharmacologic thromboprophylaxis after major hepatectomy: does peripheral venous thromboembolism prevention outweigh bleeding risks? AB - BACKGROUND: Although standard of care after most abdominal surgeries, post operative pharmacologic thromboprophylaxis after major hepatectomy is commonly withheld due to bleeding risks. The objective of this retrospective study is to evaluate the benefits and risks of post-operative pharmacologic thromboprophylaxis after major hepatectomy at two high volume academic centers. METHODS: Demographics, clinicopathologic data, treatments, and post-operative outcomes from patients who underwent major hepatectomy were reviewed. RESULTS: From 2005 to 2010, 419 patients underwent major hepatectomy; 275 (65.6%) were treated with pharmacologicthromboprophylaxis beginning a median of 1 day after resection. Post-operative symptomatic venous thromboembolism (VTE) occurred in 15 (3.6%) patients. Patients treated with pharmacologic thromboprophylaxis had lower rates of symptomatic VTE (2.2% vs. 6.3%, p = 0.03) and post-operative red blood cell (RBC) transfusion (16.7% vs. 26.4%, p = 0.02) with similar rates of overall RBC transfusion (35.0% vs. 30.6%, p = 0.36) compared to untreated patients. Specifically, isolated deep venous thrombosis (0% vs. 2.1%, p = 0.04) and pulmonary embolism (2.2% vs. 4.2%, p = 0.35) occurred less often in treated patients. Analysis of demographics, clinicopathologic data, and treatment factors revealed that pharmacologic thromboprophylaxis was the only variable associated with post-operative VTE. CONCLUSIONS: Post-operative pharmacologic thromboprophylaxis lowers the incidence of symptomatic VTE after major hepatectomy without increasing the rate of RBC transfusion. PMID- 21691926 TI - Trial-by-trial adjustments of top-down set modulate oculomotor capture. AB - The role of top-down control in visual search has been a subject of much debate. Recent research has focused on whether attentional and oculomotor capture by irrelevant salient distractors can be modulated through top-down control, and if so, whether top-down control can be rapidly initiated based on current task goals. In the present study, participants searched for a unique shape in an array containing otherwise homogeneous shapes. A cue prior to each trial indicated the probability that an irrelevant color singleton distractor would appear on that trial. Initial saccades were less likely to land on the target and participants took longer to initiate a saccade to the target when a color distractor was present than when it was absent; this cost was greatly reduced on trials in which the probability that a distractor would appear was high, as compared to when the probability was low. These results suggest that top-down control can modulate oculomotor capture in visual search, even in a singleton search task in which distractors are known to readily capture both attention and the eyes. Furthermore, the results show that top-down distractor suppression mechanisms can be initiated quickly in anticipation of irrelevant salient distractors and can be adjusted on a trial-by-trial basis. PMID- 21691928 TI - Dyadic effects of fear of recurrence on the quality of life of cancer survivors and their caregivers. AB - BACKGROUND: Although the 5 years cancer survival rate has increased to 66%, fear of cancer recurrence (FOR) continues to be a major concern for both cancer survivors and their family caregivers. It remains unknown, however, to what extent cancer severity is associated with the level of FOR reported by each individual in the survivor-caregiver dyad, which, in turn, is also associated with their quality of life (QOL). METHOD: A total of 455 cancer survivor caregiver dyads, who participated in national surveys targeting 2 years post diagnosis, provided complete data for variables studied. RESULTS: Results of the Actor Partner Interdependence Model suggested that higher cancer severity was related to greater levels of FOR among both survivors and caregivers, which, in turn, was related to poorer QOL. Caregivers' FOR was related to survivors' poorer physical health. The associations between FOR and QOL were significant, above and beyond those of general anxiety. CONCLUSION: Findings suggest that as expected, cancer severity was significantly related to individuals' FOR, which, in turn, played a key role in their mental health. Caregivers' FOR was also related to survivors' physical health, which suggests that programs aimed to manage FOR effectively should be provided not only to survivors but also caregivers, thereby improving the QOL of each person. PMID- 21691929 TI - Divorced fathers' proximity and children's long-run outcomes: evidence from Norwegian registry data. AB - This study examines the link between divorced nonresident fathers' proximity and children's long-run outcomes, using high-quality data from Norwegian population registers. We follow (from birth to young adulthood) each of 15,992 children born into married households in Norway in the years 1975-1979 whose parents divorced during his or her childhood. We observe the proximity of the child to his or her father in each year following the divorce and link proximity to educational and economic outcomes for the child in young adulthood, controlling for a wide range of observable characteristics of the parents and the child. Our results show that closer proximity to the father following a divorce has, on average, a modest negative association with offspring's outcomes in young adulthood. The negative associations are stronger among children of highly educated fathers. Complementary Norwegian survey data show that highly educated fathers report more post-divorce conflict with their ex-wives as well as more contact with their children (measured in terms of the number of nights that the child spends at the father's house). Consequently, the father's relocation to a more distant location following the divorce may shelter the child from disruptions in the structure of the child's life as they split time between households and/or from post-divorce interparental conflict. PMID- 21691927 TI - Modern management of rare brain metastases in adults. AB - Brain metastases (BM) represent the main cause of intracranial neoplasms in adults, while being relatively less common in children. Today, better treatment options of the primary malignancy lead to higher remission rates as well as prolonged stable clinical conditions. This may in part explain the increased incidence of BM. Morbidity and mortality rates in patients with malignancies deteriorate significantly in cases of metastatic involvement of the central nervous system. Nowadays, especially modern management using surgical, medical, and radiotherapeutic options for treatment of BM tends to improve survival rates and enhance quality of life. Nonetheless, almost all treatment options are considered as palliative. In this review, we outline current knowledge of the incidence, diagnostic facilities, and therapeutic management of rare BM, with consideration of the basic aspects of the primary malignancy. PMID- 21691930 TI - Cohabitation history, marriage, and wealth accumulation. AB - This study extends research on the relationship between wealth accumulation and union experiences, such as marriage and cohabitation. Using data from the National Longitudinal Survey of Youth 1979, we explore the wealth trajectories of married individuals in light of their premarital cohabitation histories. Over time, marriage positively correlates with wealth accumulation. Most married persons with a premarital cohabitation history have wealth trajectories that are indistinguishable from those without cohabitation experience, with one exception: individuals who marry their one and only cohabiting partner experience a wealth premium that is twice as large as that for married individuals who never cohabited prior to marrying. Results remain robust over time despite cohabiters' selection out of marriage, yet vary by race/ethnicity. We conclude that relationship history may shape long-term wealth accumulation, and contrary to existing literature, individuals who marry their only cohabiting partners experience a beneficial marital outcome. It is therefore important to understand the diversity of cohabitation experiences among the married. PMID- 21691931 TI - Men's migration and women's fertility in rural Mozambique. AB - Labor migration profoundly affects households throughout rural Africa. This study looks at how men's labor migration influences marital fertility in a context where such migration has been massive while its economic returns are increasingly uncertain. Using data from a survey of married women in southern Mozambique, we start with an event-history analysis of birth rates among women married to migrants and those married to nonmigrants. The model detects a lower birth rate among migrants' wives, which tends to be partially compensated for by an increased birth rate upon cessation of migration. An analysis of women's lifetime fertility shows that it decreases as the time spent in migration by their husbands accrues. When we compare reproductive intentions stated by respondents with migrant and nonmigrant husbands, we find that migrants' wives are more likely to want another child regardless of the number of living children, but the difference is significant only for women who see migration as economically benefiting their households. Yet, such women are also significantly more likely to use modern contraception than other women. We interpret these results in light of the debate on enhancing versus disrupting effects of labor migration on families and households in contemporary developing settings. PMID- 21691932 TI - MicroRNA expression profiling in archival tissue specimens: methods and data processing. AB - The discovery that the human genome codes for thousands (if not millions) of previously unrecognized non-protein coding RNAs with regulatory functions has changed our understanding of many physiological and pathological processes. A prominent class of non-coding RNAs with important functions in cancer initiation and progression comprised by very short single-stranded, mRNA translation modulating RNAs, termed microRNAs. The determination of microRNA expression profiles is now widely used in biology and pathology, employing a range of methodologies. A steadily growing number of studies describe the analysis of formalin-fixed paraffin-embedded, so-called "archival" specimens. However, procedures for data processing and calculations are far from standardized and differ considerably between published studies, making comparisons and meta analyses still quite difficult. In this review, we provide a short overview of profiling methods used for archival samples and describe in detail a modified method for normalization and processing of raw data obtained by fluorescence labeled bead technology from Luminex.Inc. PMID- 21691933 TI - Positive attitudes and self-harming behavior of adolescents in a juvenile detention house in Taiwan. AB - This study aimed to evaluate the less stigmatizing positivity construct screening measurement and its association with recent self-harming behaviors among adolescents. Participants were 193 detained Taiwanese adolescents. Questionnaires consisted of a deliberate self-harm inventory, a positivity construct measurement, a depression scale, data concerning risky health behaviors and demographics. The prevalence rate of recent self-harming behavior among adolescents in the detention house was 43.5%. The logistic model showed that age, gender and level of positivity demonstrated significant odds ratios for self-harm behavior. Results showed that younger age and female gender increased self harming behavior. In addition, low score on positivity construct screening measurement increased the probability of self-harming behavior. Furthermore, these adolescents also engaged in risky health behaviors and were more depressed. Parental and school awareness for these risky behaviors should be enhanced and appropriate early interventions implemented to prevent negative health outcomes. PMID- 21691934 TI - Cricoid pressure with the Truview Evo2TM laryngoscope improves the glottic view. AB - OBJECTIVE: The Truview Evo2TM laryngoscope blade is designed to improve glottic view. This study was designed to evaluate the effect of cricoid pressure (CP) on laryngeal view and the ease of orotracheal intubation with the Truview Evo2 laryngoscope. METHODS: In this randomized controlled trial, 50 patients (American Society of Anesthesiologists physical status I-II, aged 18 to 60 yr) scheduled for elective surgery were enrolled. After induction of anesthesia and muscle paralysis, laryngoscopy was performed using the Truview Evo2TM laryngoscope with the patient's head in the neutral position. In Group 1, the percentage of glottic opening (POGO) score was evaluated first without CP, then with CP, and CP was applied for intubation. In Group 2, the POGO score was evaluated first with CP, then without CP, and no CP was applied for intubation. Time to intubation and number of attempts required for intubation were also recorded. RESULTS: In 50 patients, the mean (standard deviation) POGO view obtained with the application of CP was 93% (10%) compared with 81% (19%) in patients without CP (P < 0.01). Times to intubation were similar in the two groups: 14.2 (6.6) sec vs 14.0 (9.3) sec in Groups 1 and 2, respectively (P = 0.924). Sixteen percent of patients in Group 1 required a second attempt at tracheal intubation, while only 4% of patients in Group 2 required a second attempt (P = 0.162). CONCLUSION: When using the Truview Evo2TM laryngoscope with the patient's head in the neutral position, application of CP improves the glottic view. This approach is not associated with increased difficulty in intubation. PMID- 21691935 TI - The McIvor blade improves insertion of the LMA ProSealTM in children. AB - BACKGROUND: The McIvor blade, a tongue retractor with a thin curved blade, is used to improve the operating field during a tonsillectomy. We compared the success rate and incidence of complications between digital insertion and McIvor blade-guided insertion of the laryngeal mask airway (LMATM) ProSealTM when performed by anesthesia residents in children. METHODS: A total of 134 anesthetized non-paralyzed pediatric patients were included in the study. Patients were allocated randomly to one of two groups, i.e., Digital group (LMA ProSeal insertion using the digital insertion technique) or McIvor group (LMA ProSeal insertion using the Mclvor blade-guided technique). All patients were managed by anesthesia residents who were unskilled in using each technique. We assessed success rates of insertion at the first attempt, insertion time for an effective airway, and postoperative blood staining. RESULTS: The success rate of insertion at the first attempt was higher in the McIvor group than in the Digital group (97% vs 78%, respectively; P = 0.003), and insertion time with a successful first attempt was shorter in the McIvor group than in the Digital group (20.5 [4.5] sec vs 22.8 [6.7] sec, respectively; P = 0.021). The overall insertion time for an effective airway was also shorter in the McIvor group than in the Digital group (20.9 [5.7] sec vs 26.0 [9.8] sec, respectively; P < 0.001). Blood staining was more frequent in the Digital group than in the McIvor group (23% vs 6%, respectively; P = 0.035). CONCLUSION: When inserting the LMA ProSeal in children, anesthesia residents were more successful using the McIvor blade-guided insertion technique than using the digital insertion technique. (ClinicalTrials.gov number, NCT01191619). PMID- 21691936 TI - Dectin1 activation of beta-(1-3)/(1-6)-D-glucan produces an anti-mastitis effect in rats. AB - OBJECTIVE: A lipopolysaccharide (LPS)-induced mastitis model in rats was used to study the protective effect of beta-glucan. MATERIALS AND METHODS: On gestation day 10, beta-glucan was administered to rats daily by gavage at either 0 (control), 0.1 mg/kg BW, 1 mg/kg BW and 10 mg/kg BW until parturition. LPS or pyrogen-free physiological saline was inoculated into the mammary gland 72 h after parturition and the rats were euthanized at 12 h post-infection. RESULTS: LPS increased dectin1 and toll-like receptor 4 (TLR4) mRNA and protein expression significantly in mammary tissues. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, N-acetyl-beta-D-glucosaminidase (NAGase), inducible nitric oxide synthase (iNOs) in mammary tissues and serum, and myeloperoxidase (MPO) in mammary tissues were significantly increased 12 h after LPS infusion. beta-glucan administration could enhance dectin1 mRNA and protein expression while downregulating the expression of TLR4. Level of TNF-alpha, IL-1beta in mammary tissues and serum, MPO, NAGase and iNOs activity in mammary tissues was decreased, but the level of IL-2 in serum was increased by beta-glucan. CONCLUSION: The results indicate that beta-glucan may protect mammary tissue against LPS-induced rat acute mastitis. PMID- 21691937 TI - Correlations of urinary biomarkers, TNF-like weak inducer of apoptosis (TWEAK), osteoprotegerin (OPG), monocyte chemoattractant protein-1 (MCP-1), and IL-8 with lupus nephritis. AB - OBJECTIVE: This case-controlled study was designed to correlate urinary biomarkers, TNF-like weak inducer of apoptosis (TWEAK), osteoprotegerin (OPG), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) levels, with renal involvement in a cohort of systemic lupus erythematosus (SLE) patients to examine their diagnostic performance. PATIENTS AND METHODS: In 73 SLE patients, and in 23 healthy volunteers, urinary levels of TWEAK, OPG, MCP-1, and IL-8 levels were measured. Disease activity was assessed by total SLE disease activity index, and renal activity by renal activity index (rSLEDAI), and both were correlated with urinary biomarkers. Sensitivity, specificity, and predictive values of individual biomarkers to predict lupus nephritis were also calculated. RESULTS: Significantly higher levels of urinary biomarkers were observed in SLE patients with lupus nephritis (LN) compared with those without LN (TWEAK, p < 0.001; MCP-1, p < 0.001; OPG, p < 0.001; IL-8, p < 0.032). Other significantly higher levels were observed in SLE patients with LN compared with control subjects (TWEAK, MCP-1, OPG, and IL-8 p < 0.001). Positive correlations were observed between rSLEDAI and TWEAK (r = 0.612 and p < 0.001), MCP-1 (r = 0.635 and p < 0.001), and OPG (r = 0.505 and p < 0.001). CONCLUSIONS: Urinary levels of TWEAK, OPG, and MCP-1 positively correlate with renal involvement as assessed by rSLEDAI with reasonable sensitivity, specificity, and predictive values to detect lupus nephritis while IL-8 was not significantly associated with global or rSLEDAI. PMID- 21691938 TI - Altered peripheral invariant natural killer T cells in atopic dermatitis. AB - BACKGROUND: Conflicting data exist on the number of invariant NKT (iNKT) cells in atopic dermatitis (AD); furthermore, no data have been published on their functional capacity. METHODS: The frequency and number of circulating CD3+6B11+ iNKT cells and their CD4+ and CD4- subpopulations were evaluated in peripheral blood obtained from 41 patients with AD by four-color flow cytometry. Likewise, functional properties of iNKT cells were measured by five-color intracellular cytokine staining. RESULTS: The number and percentage of total iNKT cells and their CD4/CD8 subpopulations were significantly lower than the controls. Of further importance, the CD4-CD8- (double negative, DN) iNKT subgroup showed the strongest positive correlation with total iNKT cells. In addition, the DN subgroup exhibited the most pronounced functional alteration with significantly decreased levels of intracellular IFNgamma and significantly increased levels of intracellular IL-4 in AD patients compared with the controls. CONCLUSION: The significantly altered number and cytokine production of iNKT cells from AD patients suggests that these cells may play an important role in the pathogenesis of AD. PMID- 21691940 TI - Protective effect of oxymatrine on chronic rat heart failure. AB - Oxymatrine is one of the alkaloids extracted from the Chinese herb Sophora japonica (Sophora flavescens Ait.) with anti-inflammatory, immune reaction inhibiting, antiviral, and hepatocyte and antihepatic fibrosis protective activities. However, the effect of oxymatrine on heart failure is not yet known. In this study, the effect of oxymatrine on heart failure was investigated using a Sprague-Dawley rat model of chronic heart failure. Morphological findings showed that in the group treated with 50 and 100 mg/kg of oxymatrine; intermyofibrillar lysis disappeared, myofilaments were orderly, closely and evenly arranged; and mitochondria contained tightly packed cristae compared with the heart failure group. We investigated the cytosolic Ca(2+) transients and sarcoplasmic reticulum (SR) Ca(2+) content, and assessed the expression of ryanodine receptor (RyR2), SR Ca(2+) ATPase (SERCA2a), and L-type Ca(2+) channel (dihydropyridine receptor, DHPR). We found that the cytosolic Ca(2+) transients were markedly increased in amplitude in the medium- (DeltaF/F (0) = 26.22 +/- 2.01) and high-dose groups (DeltaF/F (0) = 29.49 +/- 1.17) compared to the heart failure group (DeltaF/F (0) = 12.12 +/- 1.35, P < 0.01), with changes paralleled by a significant increase in the SR Ca(2+) content (medium-dose group: DeltaF/F (0) = 32.20 +/- 1.67, high dose group: DeltaF/F (0) = 32.57 +/- 1.29, HF: DeltaF/F (0) = 17.26 +/- 1.05, P < 0.01). Moreover, we demonstrated that the expression of SERCA2a and cardiac DHPR was significantly increased in the medium- and high-dose group compared with the heart failure rats. These findings suggest that oxymatrine could improve heart failure by improving the cardiac function and that this amelioration is associated with upregulation of SERCA2a and DHPR. PMID- 21691939 TI - Awareness and preferences regarding BRCA1/2 genetic counseling and testing among Latinas and non-Latina white women at increased risk for hereditary breast and ovarian cancer. AB - This study was an investigation of awareness, cognitions, and psychosocial and educational needs related to genetic counseling and testing among Latinas and non Latina whites at increased risk for having a BRCA1/2 mutation. Sixty-three Latina and eighty-four non-Latina white women completed telephone surveys employing a mixture of quantitative and qualitative questions assessing awareness, benefits, risks, barriers, and genetic counseling communication preferences regarding BRCA1/2 testing. Among participants who had not previously had genetic counseling/testing, 56.9% of Latinas (29/51) and 34.8% of non-Latina white participants (24/69) were unaware of the availability of BRCA1/2 testing. In multivariate logistic regression analysis, Latina ethnicity was the only statistically significant independent factor associated with lack of awareness (OR = 0.42; 95% CI = 0.19-0.35). No appreciable differences were noted between ethnic groups regarding perceived benefits of BRCA1/2 testing or desired genetic counseling topics. These findings underscore the importance of increasing awareness of cancer genetic counseling and genetic testing among both Latina and non-Latina white populations. PMID- 21691942 TI - Elevated gray and white matter densities in cocaine abstainers compared to current users. AB - RATIONALE: Numerous neuroimaging studies have demonstrated lower neural tissue density in chronic cocaine users, which may be linked to cognitive dysfunction. OBJECTIVES: The goal of this study was to determine whether neural tissue density was also impaired in individuals abstinent from cocaine and whether any observed changes were associated with cognitive performance. METHODS: A total of 73 participants were included: 24 active cocaine users, 24 abstainers (abstinent for at least 1 month), and 25 nondrug-abusing controls rigorously matched for age, gender, and IQ. All participants performed a cognitive assessment battery and received an MRI which was analyzed using voxel-based morphometry. RESULTS: The abstainers had significantly higher gray matter density than the current cocaine users in neocortical areas including the frontal and temporal cortex. In contrast to the users, there was no difference in white matter density in the abstainers relative to the controls. The abstainers performed better than current users on several behavioral tasks. Within users and abstainers, cortical density was correlated with performance on memory and reaction time tasks. Subcortical gray matter density was lower in both the users and abstainers relative to the controls. Within abstainers, subcortical tissue density was correlated with the ability to set-shift. CONCLUSIONS: These data suggest that individuals able to remain abstinent from cocaine for at least 1 month have elevated neocortical tissue density and perform better on multiple cognitive tests, relative to current cocaine users. Larger, longitudinal studies are needed to address this interaction between abstinence, cognition, and cortical tissue density directly. PMID- 21691943 TI - Congenital adrenal hyperplasia owing to 17alpha-hydroxylase/17,20 lyase and p450 oxidoreductase deficiencies. PMID- 21691941 TI - Stressful life events in childhood and risk of infectious disease hospitalization. AB - Individuals exposed to high levels of stress might have an increased risk of infectious diseases. However, most of the previous studies have been conducted among adults. To examine the effect of childhood stress, we conducted a nationwide cohort study including all Danish children born from 1977 to 2004. Stressful life events (SFLE) included parental death, death of sibling or parental divorce. Outcome was defined as hospitalizations due to less severe (LSID) or severe infectious diseases (SID). Children were followed until the age of 15 years. The association between SFLE and risk of infections was evaluated through rate ratios (RR) comparing infectious disease incidence ratios in children with and without a history of SFLE. Overall, children exposed to SFLE were at 13% increased risk of LSID (RR = 1.13 (1.10-1.15)), but at no increased risk of SID hospitalization (RR = 1.05 (0.97-1.14)). Looking at the specific type of SFLE, parental divorce increased the risk of LSID (RR = 1.11 (1.09-1.14)) and SID hospitalization (1.11 (1.02-1.21)) by 11%, whereas no increased risk of LSID and SID hospitalization was observed following parental death. Finally, a 34% increased risk of LSID hospitalization (RR = 1.34 (1.23-1.45)) was observed following death of sibling, in contrast to no increased risk of SID hospitalization. CONCLUSION: Childhood exposure to SFLE, especially parental divorce seems to increase the risk of infectious disease hospitalization. Although we cannot determine whether our observations are the result of a biological effect of stress, adoption of unhealthy behaviours or increased likelihood of hospitalization, our findings do have public health relevance as a considerable proportion of the children today will be exposed to SFLE, the majority to parental divorce. PMID- 21691944 TI - Congenital adrenal hyperplasia owing to 11beta-hydroxylase deficiency. PMID- 21691945 TI - 46,XY DSD due to 17beta-HSD3 deficiency and 5alpha-reductase type 2 deficiency. PMID- 21691946 TI - Studies of a cohort of 46,XY with DSD including steroid biosynthesis deficiencies. PMID- 21691948 TI - Gonadotropin-regulated testicular helicase (GRTH/DDX25): a master post transcriptional regulator of spermatogenesis. PMID- 21691947 TI - Aromatase deficiency and its consequences. PMID- 21691949 TI - Long range outcome of prenatal treatment. PMID- 21691950 TI - Novel non-invasive prenatal diagnosis as related to congenital adrenal hyperplasia. PMID- 21691951 TI - Medical treatment of classic and nonclassic congenital adrenal hyperplasia. PMID- 21691952 TI - Apparent mineralocorticoid excess - update. PMID- 21691953 TI - Clitoroplasty in congenital adrenal hyperplasia: description of technique. PMID- 21691954 TI - Genitoplasty/Vaginoplasty. PMID- 21691955 TI - Insights into the aetiology of ovotesticular DSD from studies of mouse ovotestes. PMID- 21691956 TI - 46,XY disorders of sex development (46,XY DSD) due to androgen receptor defects: androgen insensitivity syndrome. PMID- 21691957 TI - Androgen receptor mutations associated with androgen insensitivity syndrome: a high content analysis approach leading to personalized medicine. PMID- 21691958 TI - Phenotypic variation of SF1 gene mutations. PMID- 21691959 TI - Transsexualism ("gender identity disorder") - a CNS-limited form of intersexuality? PMID- 21691960 TI - Biology and genetics of anti-mullerian hormone. PMID- 21691961 TI - Genetic mechanisms underlying 46,XY DSD with gonadal dysgenesis. PMID- 21691962 TI - Genetic disorders of sex differentiation. PMID- 21691963 TI - The clinical spectrum and treatment of ovotesticular disorder of sexual development. PMID- 21691964 TI - The genetics of ovotesticular disorders of sex development. PMID- 21691965 TI - Growth hormone treatment in children with congenital adrenal hyperplasia. PMID- 21691966 TI - Genetic modifications of corticosteroid receptors in hypertension. PMID- 21691967 TI - Angiotensin AT2 receptors: control of renal sodium excretion and blood pressure. PMID- 21691968 TI - The pituitary-bone axis. PMID- 21691969 TI - Genetic impact of both sex hormones in male-typical behaviors. PMID- 21691970 TI - MAMLD1 (mastermind-like domain containing 1) homozygous gain-of-function missense mutation causing 46,XX disorder of sex development in a virilized female. PMID- 21691971 TI - Atypical presentation and novel star protein gene mutation in a 46,XY female with lipoid congenital adrenal hyperplasia. PMID- 21691972 TI - Patient-centered care: caring for families affected by disorders of sex development. PMID- 21691973 TI - Assessing health-related quality of life in disorders of sex development: phase I - item generation. PMID- 21691974 TI - Leydig cell hypoplasia due to inactivating luteinizing hormone/chorionic gonadotropin receptor gene mutation presenting as a 46,XY DSD. PMID- 21691975 TI - Inguinal hernia in a phenotypic female infant may reveal a 46XY sex reversal, supported by the identification of a novel SF1 gene mutation. PMID- 21691976 TI - University of Michigan disorders of sex development (DSD) research and quality improvement symposium. PMID- 21691977 TI - The challenge of mistaken sex assignment in an 11-year-old with virilizing CAH. PMID- 21691978 TI - Report of fertility in a woman with a predominantly 46,XY karyotype in a family with multiple disorders of sexual development. PMID- 21691979 TI - Endoscopic intra-hematomal evacuation of intracerebral hematomas - a suitable technique for patients with coagulopathies. AB - OBJECTIVES: To describe an endoscopic technique to evacuate acute intracerebral hemorrhage (ICH) using the balanced suction-irrigation method in patients with intrinsic or iatrogenic coagulopathies. METHODS: We report on our early experience with four patients with atypical ICH related to intrinsic and iatrogenic coagulopathies. In all patients, an endoscopic hematoma evacuation was performed using a navigated burrhole approach. The entry site and trajectory were planned according to the long axis of the hematoma. RESULTS: Every operation was carried out with the aid of neuronavigation. Gross total removal of the hematoma was not intended as first line, especially if eloquent areas could be avoided. Intra-hematomal evacuation leaving minimal hematoma remnants was performed in three of four patients. We report hematoma removal rates of approximately 90%. In all patients, a significant hematoma reduction was achieved, although residues were tolerated to limit neurological damage. No re-hemorrhage was observed. CONCLUSION: The endoscopic technique with the aid of neuronavigation may be an appropriate method to safely evacuate ICH in the acute stage in patients with intrinsic or iatrogenic coagulopathies. PMID- 21691980 TI - The prediction of 30-day mortality and functional outcome in spontaneous intracerebral hemorrhage with secondary ventricular hemorrhage: a score comparison. AB - The original ICH (oICH) score was tested in different populations and showed good accuracy in the prediction of outcome and 30-day mortality after spontaneous ICH. The oICH was developed to stratify patients with all types of spontaneous intracerebral hemorrhage (SICH). Several modifications of the oICH score exist in the literature.In the current study, we tested the oICH score, two modified ICH scores, and the IVH score on a cohort of 171 patients with SICH and mandatory secondary intraventricular hemorrhage (IVH). Receiver-operating characteristic (ROC) curves were plotted, and the areas under the curves (AUC) were calculated for each score.The calculated AUCs for the prediction of 30-day mortality in the cohort were 0.736, 0.816, 0.805, and 0.836 for the original ICH, the mICH-A, the mICH-B, and the new IVH score, respectively. The best AUC for functional outcome was observed for the mICH-B score (0.823). For the mICH-A and the IVH score, an AUC of 0.811 was calculated.The scores that include the quantification of IVH or the grading of hydrocephalus show good accuracy in the prediction of 30-day mortality and functional outcome at 6 months in SICH with secondary IVH. PMID- 21691981 TI - Characteristics of carotid plaque findings on ultrasonography and black blood magnetic resonance imaging in comparison with pathological findings. AB - BACKGROUND: Criteria to decide whether carotid endarterectomy (CEA) or carotid artery stenting (CAS) is the best mode of therapy in a specific case of cervical carotid stenosis have not been established. Overall, recent randomized clinical trials have reported that the effect on the prevention of stroke is not significantly different between CEA and CAS. CEA is more appropriate than CAS for soft atherosclerotic plaques, since such soft plaques are associated with a high incidence of ischemic complications during CAS. Therefore identification of the plaque type with noninvasive preoperative examinations plays an important role for selecting the suitable surgical method, CEA or CAS. OBJECTIVE: The objective of this study was to evaluate the association among findings of carotid ultrasonography (carotid US), black blood magnetic resonance imaging (BB-MRI), and the histopathological findings of plaque specimens removed during CEA, and secondly to consider whether these diagnostic tools are useful to predict the characteristics of carotid plaques. METHOD: We investigated a total of 25 consecutive patients who underwent CEA from November 2008 to June 2010 at Kyoto Medical Center. We examined carotid plaque in 17 patients employing both carotid US and BB-MRI, 7 patients by carotid US, and 1 patient by BB-MRI. The plaque echogenicity was qualitatively assessed as low, intermediate, or high, and the MR signal intensity of the carotid plaque was classified as low or high compared with the intensity of the ipsilateral sternocleidomastoid muscle. The plaque specimens were macroscopically and pathophysiologically classified as soft or hard plaque. RESULTS: All low-echogenic plaques on carotid US were histologically soft plaques. The high-intensity plaques on T1-weighted imaging (T1WI) showed a tendency toward soft plaque. Thirteen of 14 plaques with high signal intensity on T1WI were morphologically soft. Eleven of 14 plaques with an intermediate echogenicity on carotid US were also morphologically soft. CONCLUSION: The findings of carotid ultrasonography and BB-MRI are closely associated with the CEA specimen's morphology. Ultrasonography alone is insufficient to diagnose the plaque type accurately in some patients. Employing both carotid US and BB-MRI is useful for evaluating the characteristics of carotid plaque. PMID- 21691982 TI - Indication for surgical treatment of carotid arterial stenosis in high-risk patients. AB - The indication for carotid endarterectomy (CEA) or carotid artery stenting (CAS) has not been established, although the beneficial effects of these surgical treatments for severe cervical carotid stenosis have been confirmed by clinical trial studies. We report our clinical results of CAS and CEA and suggest an appropriate treatment strategy, especially for high-risk patients. From January 2001 to December 2009, we treated 171 carotid lesions by CEA and 251 lesions by CAS. Stenosis was symptomatic in 68%, and the average stenotic rate was 83% in the CEA group. In the CAS group, stenosis was symptomatic in 62%, and the average stenotic rate was 65%. Stenosis was relieved in all cases after CEA or CAS. Surgical mortality with CEA and CAS was 0.6% (1/171) and 0.4% (1/251), respectively. Surgical morbidity by ischemic stroke with CEA and CAS was 2.9% (5/171) and 1.2% (3/251), respectively. Surgical morbidity was not increased in patients with medical risk factors. The long-term outcome after CAS was not inferior to that after CEA. In conclusion, carotid stenosis can be treated with comparably low morbidity and mortality rates using CEA or CAS even in high-risk patients when the method is appropriately selected considering the characteristics of the carotid stenosis. PMID- 21691983 TI - The impact of early perfusion CT measurement after extracranial-intracranial bypass surgery: results of a pilot study. AB - OBJECTIVE: The early postoperative period after extracranial-intracranial bypass surgery carries the risk of hypo- as well as hyperperfusion. The purpose of this study is to evaluate early perfusion computerized tomography (PCT) after revascularization to assess the hemodynamic balance. METHODS: Standard cerebral bypass surgery was performed on ten patients, and PCT measurement within 6 h after surgery was performed and analyzed. RESULTS: The hemisphere with reduced cerebral vascular reserve (CVR) showed a regional cerebral baseline blood flow (CBF) of 5.58 +/- 1.69 and a regional cerebral baseline blood volume (CBV) of 2.41 +/- 0.76 before surgery. Mean transit time (MTT) was 4.16 +/- 0.9 s and time to peak (TTP) 3.25 +/- 1.62 s. After the procedure values changed significantly (p < 0.05) in eight patients who had no complications. Patency rate was documented in all patients by angiography. One patient showed a decrease of CBF and CBV and an increase of MTT and TTP. Clinically the patient developed a transient hemiparesis immediately after surgery. Another patient showed the expected increase in CBF and CBV; however, MTT and TTP also increased. A delayed hemiparesis probably related to hyperperfusion occurred with improvement in the follow-up. CONCLUSION: This pilot study demonstrates that early PCT parameters can provide immediate and detailed information about hemodynamic parameters and seems to have a predictive value regarding the morbidity of hypo- or hyperperfusion in patients after cerebral bypass surgery. PMID- 21691984 TI - Genetic and clinical characteristics of Moyamoya disease in Europeans. AB - The European form of Moyamoya disease clearly differs from the Asian form. Clinically the timing of vasculopathy onset and a lower rate of hemorrhage are striking as compared to the Asian Moyamoya disease.Single nucleotide polymorphisms that play a role in atherosclerosis, vascular growth and transformation processes have been found to be associated with the European form. Candidate gene associations found in Asian patients could not be replicated in European patients.To elucidate the characteristics, we describe the clinical features as well as the genetic findings that we have found in our combined cohorts of European patients. PMID- 21691985 TI - Effect of mouth opening on bypass function after combined revascularization for Moyamoya disease. AB - Moyamoya disease represents a rare steno-occlusive disease of the internal carotid artery (ICA) with a reactive and pathological basal network of collateral vessels. It may lead to ischemic stroke or intracerebral hemorrhage. Treatment options are either direct or indirect revascularization procedures or a combination thereof. Specialized centers report sufficient revascularization in most patients and low complication rates.Between 2005 and 2008, direct extra intracranial bypass surgery in combination with encephalomyosynangiosis (EMS) was performed in 71 Moyamoya patients at the Mannheim University Medical Center.Following one case of reversible neurological deficits associated with mouth opening, we prospectively evaluated the effect of mouth opening on bypass function in this patient and four further consecutive patients by digital subtraction angiography.Three out of five patients showed alterations in bypass patency upon mouth opening. The obstruction was located at the junction of the bypass and the temporal muscle. Two temporary occlusions and one case of decreased flow were observed. One patient demonstrated reversible hemiparesis and aphasia. PMID- 21691986 TI - Revascularisation surgery and long-term follow-up in juvenile Moyamoya syndrome: a retrospective analysis. AB - Due to its low incidence in Western countries, physician awareness of juvenile Moyamoya disease should be improved. The benefits of revascularisation surgery have only been proven in the juvenile version of the disease. Therefore, early revascularisation may prevent irreversible ischaemic deficits and rapidly progressive mental retardation in young patients.From 1984 to 2009, a total of 19 children (mean age 8 years, range 1-18 years, female predominance 2:1, 17/19 European white patients, 2/19 Asian origin of at least one parent) were treated for juvenile Moyamoya disease by surgical revascularisation. The leading symptoms were epilepsy (17/19), followed by transient ischaemic attacks (TIA) or prolonged reversible ischaemic neurologic deficits (PRIND) (15/19) and mental retardation (11/19). Angiography showed a clear neovascularisation in the majority of patients after indirect bypasses after 6 months. The mean follow-up was 17 years and 3 months (maximum 25 years, minimum 2 years). Two patients were lost to follow-up. In accordance with the literature, ischaemic symptoms were eliminated by the revascularisation operation in 94% of our patients with a very low rate of complications, and no lasting morbidity and mortality in any of the patients.Early diagnosis and surgical treatment seem to potentiate the benefits independently of the type of revascularisation procedure. PMID- 21691987 TI - Tissue fusion, a new opportunity for sutureless bypass surgery. AB - Microsurgical suturing is the standard for cerebral bypass surgery, a technique where temporary occlusion is usually necessary. Non-occlusive techniques such as excimer laser-assisted non-occlusive anastomosis (ELANA) have certainly widened the spectrum of treatment of complex cerebrovascular situations, such as giant cerebral aneurysms, that were otherwise non-treatable. Nevertheless, the reduction of surgical risks while widening the spectrum of indications, such as a prophylactic cerebral bypass, is still a main aim, that we would like to pursue with our sutureless tissue fusion research. The primary concern in sutureless tissue fusion- and especially in tissue fusion of cerebral vessels- is the lack of reproducibility, often caused by variations in the thermal damage of the vessel. This has prevented this novel fusion technique from being applicable in daily surgical use. In this overview, we present three ways to further improve the laser tissue soldering technique.In the first section entitled "Laser Tissue Soldering Using a Biodegradable Polymer," a porous polymer scaffold doped with albumin (BSA) and indocyanine green (ICG) is presented, leading to strong and reproducible tensile strengths in tissue soldering. Histologies and future developments are discussed.In the section "Numerical Simulation for Improvement of Laser Tissue Soldering," a powerful theoretical simulation model is used to calculate temperature distribution during soldering. The goal of this research is to have a tool in hand that allows us to determine laser irradiation parameters that guarantee strong vessel fusion without thermally damaging the inner structures such as the intima and endothelium.In a third section, "Nanoparticles in Laser Tissue Soldering," we demonstrate that nanoparticles can be used to produce a stable and well-defined spatial absorption profile in the scaffold, which is an important step towards increasing the reproducibility. The risks of implanting nanoparticles into a biodegradable scaffold are discussed.Step by step, these developments in sutureless tissue fusion have improved the tensile strength and the reproducibility, and are constantly evolving towards a clinically applicable anastomosis technique. PMID- 21691988 TI - STA-MCA bypass for the treatment of ischemic stroke. AB - It is considered controversial whether superficial temporal artery (STA)-middle cerebral artery (MCA) bypass affects the outcome of patients with ischemic stroke. This prospective study was undertaken to demonstrate the effect of STA MCA bypass on the cerebral blood flow and neurological status of the patients with ischemic stroke. Seventy-five patients underwent unilateral or bilateral STA MCA bypass surgery. The selection of the patients closely adhered to the criteria of the Japan EC-IC Bypass Trial (JET). Cerebral blood flow (CBF) before and after Diamox administration was measured by single photon emission computed tomography (SPECT) using iodine-123-N-isopropyl-p-iodoamphetamine (IMP). MRI, contrast enhanced 3D CT scans, and angiography were performed on each patient pre- and postoperatively. Bypass surgery was successfully done in all patients. CBF was significantly increased after STA-MCA bypass (P < 0.05). In addition, reservation of CBF was significantly improved after STA-MCA bypass (P < 0.05). Patients with transient ischemic attack (TIA) did not experience recurrence of such episodes after STA-MCA bypass. The neurological deficit was unchanged in patients with complete stroke after bypass surgery. However, the NIH stroke scale was significantly improved after bypass surgery (P < 0.01). In addition, the satisfaction rate of treatment as assessed by the patients themselves was very high after STA-MCA bypass (>90%) compared to the conservative treatment group (<50%). STA-MCA bypass still plays a limited role in the treatment of ischemic stroke, but may become a bright hope in depressed patients after cerebral ischemia. PMID- 21691989 TI - The new MRI modalities "BPAS and VISTA" for the diagnosis of VA dissection. AB - OBJECTIVE: Recently VA dissection has drawn attention as a relatively common cause of stroke because of the introduction of MRI as a diagnostic technique. Basiparallel anatomic scanning (BPAS) was designed to visualize the surface appearance of the vertebrobasilar artery within the cistern. Volumetric isotropic TSE acquisition (VISTA) is a sort of black blood imaging method to evaluate the arterial wall and lumen. In this study, we aimed to evaluate the efficacy of the new MRI modalities "BPAS and VISTA," and to present a retrospective analysis of our experience with the diagnosis. MATERIALS AND METHODS: Between1995 and 2010, we experienced 24 cases of VA dissection at our institution. In our cases, we could obtain images of 15 in BPAS and VISTA in addition to MRA. The mean age of the 15 patients (12 male and 3 female) was 51 years old (range 18-80). Ten of fifteen patients presented with ischemia, and 5/15 with only headache. There were no cases of SAH. In BPAS, we evaluated dilatation of the external diameter of the affected artery. We compared the findings in BPAS with MRA to evaluate the discrepancy. In VISTA, we evaluated its capability to distinguish intramural hematoma. RESULT: Thirteen of fifteen patients presented with dilatation of the external diameter on BPAS. By comparing the findings in BPAS with MRA, we found a discrepancy in 8/15 cases (53%). We could detect intramural hematoma by using VISTA in 9/15 cases (60%). Thirteen of fifteen patients received follow-up MRI. Temporal change of the arterial shape was confirmed in 7/13 cases (53.8%). CONCLUSION: Dilatation of the external diameter was shown highly frequently in VA dissections. In addition, a discrepancy between BPAS and MRA as well as the intramural hematoma on VISTA was found comparatively frequently. BPAS and VISTA are minimally invasive and useful methods as screening tests. PMID- 21691990 TI - Intracranial stenting in arterial occlusive disease. AB - The results of endovascular treatment of symptomatic intracranial arteriosclerotic stenosis with stenosis grades exceeding 70% show a mortality rate of 2% and severe morbidity of 8.3%. This justifies treatment being performed by experienced interventionalists only in selected cases, if the prospective outcome of pharmacotherapy alone indicates a higher risk (i.e., symptomatic stenosis, severe perfusion disturbances). PMID- 21691991 TI - A view on the current and future therapy of brain aneurysms. AB - While in clinical practice the use of endovascular and microsurgical methods retained relative levels by 2010, since 2008 the research activity has lagged behind that in other medical disciplines. Particularly research on neuroprotection, such as hypothermia and pharmacological measures, has lost impetus, and clinical applications of specific neuroprotective interventions have been largely abandoned. The last substantial advancement for aneurysm surgery was the introduction of intraoperative indocyanine green (ICG) angiography. The technical evolution of endovascular therapy has been somewhat more active than that of microsurgery. It is our conviction that microsurgical methods need to develop a focus particularly on minimal invasiveness and also cosmetic aspects. Teaching remains an important consideration. It appears that an explicit framework is necessary in order to communicate the specific do's, don'ts and hows of aneurysm surgery, i.e., a set of rules addressing general perioperative management, principles of exposure and dissection of the typical configurations, clipping technique and the specific issues concerning very small and very large aneurysms. Quality management has become an unconditional requirement also in neurovascular surgery. At our department we have established a system of identification of complications and monthly case analysis. Despite these efforts combined management morbidity and mortality for ruptured and unruptured aneurysms remains around 10%, which appears to be the achievable degree of safety in unselected patients with the current technology. PMID- 21691992 TI - Surgical treatment for aneurysms in the cavernous-petrous portion of the internal carotid artery. AB - BACKGROUND: As direct surgery to treat aneurysms in the cavernous-petrous portion of the ICA is difficult, proximal ligation of the ICA with or without bypass surgery is still the conventional treatment. Some patients have an ECA-ICA collateral pathway distal to the ligation site. This is related to the recanalization of the aneurysm. We describe the treatment strategy of these aneurysms and the surgical pitfalls of the treatment. METHODS: We analyzed 30 cases of symptomatic aneurysms in the cavernous-petrous portion of the ICA. In all cases, proximal ligation of the ICA was performed with bypass surgery followed by BTO. RESULTS: In 21 patients who could tolerate BTO, we performed a low-flow bypass. In nine patients who could not tolerate BTO, we performed a high flow bypass. In four patients with ECA-ICA collateral pathways distal to the ligation site, we performed endovascular parent artery occlusion using detachable coils. In four patients without endovascular parent artery occlusion, we experienced recanalization of the aneurysm. CONCLUSION: Based on our experience and in view of the late recanalization of aneurysms that have an ECA-ICA collateral pathway, we recommend that intraoperative angiography should be performed to detect the ECA-ICA collateral pathway in proximal ligation of the ICA. PMID- 21691994 TI - Resistant vasospasm in subarachnoid hemorrhage treated with continuous intraarterial nimodipine infusion. AB - Cerebral vasospasm complicating aneurysmal subarachnoid hemorrhage is a well known medical entity. The delayed ischemic neurological deficits (DIND) as a result of vasospasm remain the main cause of morbidity among patients who manage to survive this severe disease pattern. When the traditional treatment options, either medical or interventional, fail to reverse vasospasm, continuous intraarterial infusion of nimodipine through catheters directly into the spastic arteries presents a promising treatment modality. Of 73 patients with aneurysmal subarachnoid hemorrhage between 2008 and 2009, a total of 27 had Hunt and Hess grades of 4 and 5. Fifteen percent of them showed refractory vasospasms and were treated with continuous nimodipine infusion via catheters in both internal carotid arteries. We present the method's indications and possible complications. PMID- 21691993 TI - Aneurysms of the posterior cerebral artery and approach selection in their microsurgical treatment: emphasis on the approaches: SAHEA and SCTTA. AB - Aneurysms of the posterior cerebral artery (PCA) are infrequent and located in the central depth of the brain. Hence their optimal microsurgical management has not been discussed systematically, as institutions and/or neurosurgeons have only limited experience. The purpose of this communication is to report our considerations on this topic with emphasis on the selection of approaches by reviewing our 20 consecutive cases of PCA aneurysms out of more than 1,000 aneurysm patients seen over the past 15 years. Although the subtemporal approach appears to be prevalent in the literature, in our series we applied the pterional approach with or without selective extradural anterior clinoidectomy (SEAC) for P1, P1-P2 aneurysms, and either a selective amygdalohippocampectomy approach (SAHEA) or supracerebellar transtentorial approach (SCTTA) for P2 and P2-P3 aneurysms. Construction of an extracranial-intracranial EC-IC bypass, when necessary, in conjunction with parent artery occlusion or with trapping of aneurysms was adapted to selected approaches. PMID- 21691995 TI - Neck clipping of paraclinoid small aneurysms. AB - Paraclinoid small aneurysms with a diameter less than 5 mm may be difficult to handle intraoperatively. We have encountered 9 such aneurysms among 375 cases. The most frequent location was the ophthalmic segment (n = 6) followed by the anterior wall (n = 3) of the internal carotid artery (ICA). The endovascular procedure was not suitable for this particular lesion because of the difficulty in deploying the coil across such small aneurysms. One patient with an ophthalmic segment aneurysm underwent endovascular treatment first; however, the procedure was aborted because of mechanical vasospasm. Finally the patient underwent craniotomy, and the aneurysm was successfully clipped. Two patients with anterior wall aneurysms presented with subarachnoid hemorrhage, and the blood blister-like aneurysms were clipped without sacrifice of the ICA. Five patients with unruptured aneurysms of the ophthalmic segment and one such case of the anterior wall of ICA were all clipped uneventfully. The operative procedure for these small aneurysms is deemed straightforward: (1) high attention should be paid to avoid premature rupture; (2) both the internal carotid artery and optic nerve are mobilized and the anterior clinoid process and falciform ligament are removed, then the aneurysmal neck is created; (3) the neck of the aneurysm is created by pushing the wall of the ICA slightly away during clip application; this is called the "nip on method." Although neck clipping of small aneurysms can be difficult, no efforts should be spared to accomplish direct neck clipping. PMID- 21691996 TI - Deferoxamine reduces early brain injury following subarachnoid hemorrhage. AB - The effect of subarachnoid hemoglobin on neuroglial cells contributing to early brain injury is unclear. Several intracerebral hemorrhage studies indicated that pathological iron deposition in the brain contributes to secondary brain injury. Therefore, the purpose of this study was to investigate the relationship between iron and neuroglial cell changes following SAH, and examine the effect of deferoxamine (DFX). SAH was induced in male Sprague-Dawley rats (n = 56) using an endovascular perforation technique. Animals were treated with DFX (100 mg/kg) or vehicle for 3 days. Rats were sacrificed at 6 h, days 1 and 3 to determine non heme iron and heme oxygenase (HO)-1 expression using Western blot and immunohistochemistry analysis. To assess neuronal cell death, Fluoro-Jade- and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) stainings were performed. Marked HO-1 upregulation at day 3 (P < 0.01) was accompanied by elevated non-heme iron (P < 0.01) and ferritin levels (P < 0.01). DFX treatment reduced brain non-heme iron concentration, ferritin expression and neuronal cell death at day 3 (P < 0.01) following SAH. These results suggest that excessive hemoglobin and iron overload play an important role in early brain injury following SAH. Acute treatment with DFX significantly ameliorates neuronal cell death and may be a potential therapeutic agent for SAH. PMID- 21691997 TI - Does magnetic resonance imaging produce further benefit for detecting a bleeding source in subarachnoid hemorrhage of unknown origin? AB - BACKGROUND: Spontaneous subarachnoid hemorrhage (SAH) without evidence of a bleeding source on the first digital subtraction angiogram (DSA) - also called SAH of unknown origin - is observed in up to 27% of all cases. Depending on the bleeding pattern on CT scanning, SAH can be differentiated into perimesencephalic (PM-SAH) and non-perimesencephalic SAH (NON-PM-SAH). The aim of our study was to investigate the effectiveness of magnetic resonance imaging (MRI) for detecting a bleeding source in SAH of unknown origin. METHODS: We retrospectively reviewed 1,226 patients with spontaneous SAH between January 1991 and December 2008 in our department. DSA was performed in 1,068 patients, with negative results in 179 patients. RESULTS: Forty-seven patients were categorized as having PM-SAH and 132 patients as having NON-PM-SAH. MRI of the brain and the craniocervical region was performed within 72 h after diagnosis of SAH and demonstrated no bleeding sources in any of the PM-SAH and NON-PM-SAH patients (100% negative). CONCLUSIONS: In our experience MRI did not produce any additional benefit for detecting a bleeding source after SAH with a negative angiogram. The costs of this examination exceeded the clinical value. Despite our results MRI should be discussed on a case-by-case basis because rare bleeding sources are periodically diagnosed in cases of NON-PM-SAH. PMID- 21691998 TI - Treatment of experimental cerebral vasospasm by protein transduction of heme oxygenase 1 (HO-1) conjugated to a residue of 11 arginines. AB - BACKGROUND: Many kinds of proteins can be transduced into various cells by conjugation with 10-20 amino acid peptides. A sequence of 11 consecutive arginine groups (11R) is one of the most efficient protein transduction domains (PTD). We used the 32-kDa heat shock protein heme oxygenase-1 (HO-1) as a therapeutic protein for experimental cerebral vasospasm. This protein is an enzyme of the heme-catabolism and cleaves heme to form biliverdin and carbon monoxide (CO). HO 1 has known vascular relaxing properties. We examined the transduction efficacy and antispastic therapeutic effect of 11R fused HO-1 protein in cerebral arteries. METHODS: 11R fused HO-1 protein was expressed purified. An MTT assay was used to evaluate the cytotoxicity of 11R-HO-1. An antispastic effect was investigated in a rat model of experimental subarachnoid hemorrhage by measuring basilar artery diameters 4 h after the injection of 11R-HO-1 into the cisterna. FINDINGS: Expression and purification of 11R-HO-1 could be successfully effected. Transduction into the basilar artery was also successful. 11R-HO-1 protein has the positive effect of attenuating cerebral vasospasm. CONCLUSION: These results suggest that the 11R-HO-1 protein transduction method has a potential to treat cerebral vasospasm. PMID- 21691999 TI - Training models for vascular microneurosurgery. AB - INTRODUCTION: The number of microsurgical clippings of cerebral aneurysms is continuously decreasing. This will lead to fewer possibilities for practical training in aneurysm surgery, especially for the younger generation. Accordingly, realistic models for microsurgical training are mandatory. METHODS: We present a microsurgical setup for training on a PVC rat and on a lifelike vascular training model with specific plastic vessels (PVA), and an anatomical head as well as an experimental animal model (rabbit carotid artery bifurcation model). End-to-end and end-to-side anastomoses were performed with three different levels of difficulty and three different levels of expertise on the PVC rat model. The results of the animal bifurcation aneurysm model are also described. RESULTS: With increasing surgical complexity, the duration of surgery and rate of incorrect sutures of the vessel wall rise significantly. The overall patency rate of anastomosis is clearly reduced in the setup with increasing complexity grades. CONCLUSION: The PVC rat model as well as the PVA vascular kit with realistic skull and craniotomy sites is a perfect tool for advanced microvascular anastomosis training. The experimental animal model represents a higher level of vascular surgery expertise and additionally is a perfect model for practicing appropriate clip application and clip occlusion of aneurysms. PMID- 21692000 TI - How to deal with incompletely treated AVMs: experience of 67 cases and review of the literature. AB - INTRODUCTION: Despite the availability of multimodal treatment options, some arteriovenous malformations remain difficult to treat, either for intrinsic reasons at initial presentation or for reasons evolving during the course of treatment. Frequently, such cases can be easily resolved with further therapy, but some become a continuously growing treatment dilemma while exhausting dwindling therapeutic options. PATIENTS AND METHODS: A retrospective analysis was performed to identify patients with cerebral AVM who were treated unsuccessfully. Treatment was termed "not successful" if (1) postoperative angiography showed a residual AVM or missing flow reduction after palliative embolization, (2) therapy was associated with a substantial deterioration of existing neurological deficits or death, or (3) rebleeding from residual AVM occurred after therapy. Special interest was focused on the angiographic appearance of residual AVMs, their characteristic features, and their follow-up regarding second and third therapies. RESULTS: According to these criteria we identified 46 internal patients from our own series of 474 patients and 21 external patients who were referred from other institutions or sought a second opinion after incomplete treatment elsewhere. Out of those 67 cases, 50 patients (74.6%) were diagnosed with a residual AVM. Eleven patients (16.4%) experienced a deterioration of their clinical condition under therapy. Six patients did not show a flow reduction after palliative embolization. Twenty-five of the 67 patients were readmitted because of an ICH, either originating from an AVM residual or under palliative embolization. Thus, an increased risk of re-hemorrhage was found for palliative embolization (n = 16) in partially treated lesions (n = 10) and in patients with AVM grade IV and V located in eloquent regions (n = 22). In dealing with residual AVMs, microsurgical resection alone or in combination was found to be the most efficient therapeutic option, being successful in 58.9% of cases. CONCLUSION: An estimated 10% of AVM treatments may fail because of inadequate selection of either patients or management. Besides, for thorough decision-making, angiographic follow-up in all AVM patients is mandatory to allow an early identification of patients with an incompletely treated AVM requiring a second attempt. Major attention should be focused especially on high-risk subgroups with complex AVMs, partially treated AVMs, or those treated by only a palliative regimen. PMID- 21692001 TI - Clinical relevance of associated aneurysms with arteriovenous malformations of the posterior fossa. AB - The aim of this study was to determine the frequency of aneurysms associated with arteriovenous malformations (AVMs) of the posterior fossa and their relation to hemorrhagic presentation in comparison to supratentorial AVMs. We performed a retrospective analysis of 474 patients with intracranial AVMs treated in our center from 1990 to 2010. Patients were analyzed for AVM size, drainage type and their clinical course with focus on vessel anomalies including AVM-associated aneurysms. Seventeen (30%) of 57 posterior fossa AVMs versus 46 (11%) of 417 supratentorial AVMs were associated with aneurysms. In six (10.5%) versus seven (1.7%) patients, respectively, flow-associated aneurysms were the source of hemorrhage. Infratentorial location of an AVM was a significant risk factor for the incidence (p < 0.001) and rupture (p < 0.001) of AVM-associated aneurysms. Feeding artery aneurysms in particular represented a risk factor for hemorrhage in the overall group of AVM patients, independently of the location (p < 0.001). The majority of patients with a posterior fossa AVM were treated by combined embolization and surgical removal within one procedure (n = 33, 58%). Feeding artery aneurysms were excluded by endovascular coiling or surgical clipping whenever feasible. Overall treatment-associated permanent morbidity in the subgroup of posterior fossa AVMs was 11% (n = 6) and mortality 4% (n = 2). Posterior fossa AVMs display a significantly higher frequency of associated aneurysms of the adjacent vessels that are correlated to the high bleeding rate compared to AVMs of the supratentorial compartment. We therefore recommend aggressive AVM treatment including the exclusion of associated aneurysms as a minimal therapeutic goal whenever possible. PMID- 21692002 TI - Regulation of osteogenetic differentiation of mesenchymal stem cells by two axial rotational culture. AB - It is crucial to understand how gravitational force affects the osteogenic differentiation of mesenchymal stem cells (MSCs), and these fundamental aspects hold promise for the development of a novel model of MSC regulation for cell proliferation and differentiation. The objective of this study was to investigate how significantly gravitational dispersion affects the spontaneously induced osteogenic differentiation of MSCs. Expression of surface antigen was measured by flow cytometry prior to two axial rotational cultures. About 12,500 hMSC cells were spread on culture wells of 1.8 cm(2) surface area and incubated for 7 days at 5% CO(2). The culture medium, 10% FCS/DMEM containing 3 ng/ml bFGF, was replaced every 3 days. Four wells then were placed in a 50-ml centrifugal tube filled with 10% FCS/DMEM without bFGF. The centrifugal tube was attached to the center of the rotor, and two axial rotational cultures were started at 10 rpm each of both rotational speeds. It was confirmed that the hMSCs used in this study expressed typical surface antigens as well as a multipotent differentiation ability for either osteogenic or adipogenic differentiation. Spontaneous expression of alkaline phosphatase (Alp) mRNA following the conventional static culture (1G condition) was suppressed by two axial rotational cultures for 7 days (p < 0.05). A separate study indicated that the cell count number eventually increased from 24,700 +/- 6,400 to 78,400 +/- 18,700 (p < 0.05). In addition, suppressed Alp mRNA was recovered after an additional 7-day culture under static conditions. This result indicated that dispersion of gravity is a promising modality to regulate osteogenic differentiation of hMSCs. PMID- 21692003 TI - New design bioprosthesis: early outcome of Carpentier-Edwards PERIMOUNT Magna in the small annular aortic position. AB - The Carpentier-Edwards PERIMOUNT (CEP) Magna (Edwards Lifesciences, Irvine, CA, USA) is a newly developed bioprosthesis with an improved cuff design that allows its implantation into the smaller aortic annulus. We evaluated the hemodynamic performance of the CEP Magna for smaller aortic annulus cases. Patients who underwent aortic valve replacement for aortic stenosis receiving a Magna 19 mm (n = 13), were compared with a standard CEP (n = 19). In the 19-mm series, the real annular size was significantly smaller in the Magna than the standard (21.1 +/- 0.8 vs. 19.8 +/- 0.8 mm, p = 0.007). The Magna was significantly superior with respect to effective orifice area index (EOAI) at postoperative 3 months; however, no significant difference was seen in other factors (peak pressure gradient, left ventricular mass index, ejection fraction). At postoperative 3 months, despite the lack of statistical significance, the incidence of patient prosthesis mismatch (PPM) was lower with the Magna. Using the same label size, the Magna can be implanted in a smaller aortic annulus with performance comparable with or better than hemodynamic performance with the standard CEP. The Magna is a useful prosthesis for the small aortic annular patient. PMID- 21692004 TI - Combined in vivo/in silico study of mechanobiological mechanisms during endochondral ossification in bone healing. AB - Mechanobiological theories have been introduced to illustrate the interaction between biology and the local mechanical environment during bone healing. Although several theories have been proposed, a quantitative validation using histomorphometric data is still missing. In this study, in vivo histological data based on an ovine animal experiment was quantified and used to validate bone healing simulations focussing on the endochondral ossification process. The bone formation at different callus regions (periosteal and endosteal bone at the medial and lateral side) was analyzed from in vivo data and quantitatively compared with in silico results. A histomorphometric difference was found in medial and lateral hard callus formation 3 weeks after osteotomy. However, the same amount of new bone was formed on both sides between week 3 and 6. Using a parametric approach, distinct ranges for mechanical strain levels regulating tissue formation were found, for which the in silico prediction agrees with the in vivo endochondral ossification both in pattern and quantity. According to this finding, a strain range of 1 to 8% seems to be conducive for cartilage formation while bone formation may be facilitated by strains up to 4%. This study demonstrates the potential of a thorough validation of in silico results for gaining a better understanding of mechanobiological mechanisms during bone healing. PMID- 21692005 TI - [Multimodal therapy--who profits?: chances and risks of predicting treatment success]. PMID- 21692007 TI - [Postoperative pain assessment in special patient groups: part II. Children with cognitive impairment]. AB - Postoperative pain assessment in children with cognitive impairment poses major challenges to healthcare professionals.Children with moderate to severe cognitive impairment are generally unable to communicate effectively and to self-report the level of pain. Difficulties assessing pain have led to their exclusion from clinical trials and rendered them vulnerable to insufficient treatment of pain.The realization of pain is a particularly important step forward for a better care of children with cognitive impairment.Scales based on a child's own perception of pain and its severity play a limited role in this vulnerable population and pain assessment tools which rely on observing pain behavior are essential. The r-FLACC, which is reliable and valid, includes specific behavioral descriptors and can be used simply and effectively postoperatively in clinical practice. Our task has to be assessing pain as a routine procedure in cognitively impaired children as a keystone for an improved and successful pain management in this very sensitive patient population. PMID- 21692006 TI - [Postoperative pain assessment in special patient groups: part I: children without cognitive impairment]. AB - The intensity of pain cannot be measured directly but can only be described subjectively. This obviously complicates the assessment especially in the younger age group. Pain evaluation and documentation are essential for good results in pain therapy. Pain can be measured by pain scales which should fulfill the requirements of practicability, reliability and validity. In neonates and children up to 4 years of age, standardized scales have been developed for observation of their activities. Children in the age group 4-6 years old are able to communicate about pain. At this age self-report scales can be used to assess pain sensations."Quality Improvement in Postoperative Pain Management in Infants" (QUIPSInfant) represents a new tool for pediatric outcome evaluation, consisting of standardized data acquisition of outcome and process quality indicators. PMID- 21692008 TI - [Pain words activate pain-processing neural structures]. AB - Previous studies suggested that areas of the neural"pain matrix" are activated by the processing of pain-related environmental cues such as pain-related pictures or descriptors of pain. However, it is still sketchy whether these activations are specific to the pain-relevant content of the stimuli or simply reflect a general effect of negative emotional valence or increased arousal. The present study addressed this question by investigating the neural mechanisms underlying the processing of pain-related, negative (non-pain-related), positive and neutral words. When subjects were instructed to image a situation associated with the word presented (imagination task), we found increased activation within the dorsolateral prefrontal cortex (DLPFC) and inferior parietal cortex (IPC) when processing pain-related words compared to other words. When attention was focused on a distracting task (distraction task), we found a decrease in activation within the dorsal anterior cingulum (dACC) and a relative increase in activation within the subgenual anterior cingulum (sACC) when processing pain-related words compared to other words. These results indicate that the differences in processing pain-related words compared to non-pain-related words are specific to the content of the words and cannot simply be explained by emotional valence or arousal. Additionally, we showed that the specific activations to pain-related words are substantially modulated by the attention demands of the task. PMID- 21692012 TI - [Societal Impact of Pain (SIP) 2011]. PMID- 21692009 TI - [Placebo response: in studies on pain and under other clinical conditions]. AB - This contribution compares unexplained essential questions regarding the placebo response with current empirical evidence: (1) Are the placebo response rates equivalent in the groups treated with medication or placebo? Very little evidence has been gathered to support this generally accepted additivity while some findings negate its validity. (2) Is the placebo response a function of the probability of receiving medication or placebo? There are indications that the number of study groups included in a trial determines the level of placebo and medication response. (3) How great is the placebo response in trials that directly compare a (new) medication with one that for example is already on the market? There are indications that such comparative studies produce higher placebo response rates. (4) How high is the placebo response rate in everyday clinical practice--or does the response to a medication in trials substantiate the effect of the medication in everyday clinical practice? PMID- 21692014 TI - Genetic assessment of cortical malformations. AB - Malformations of cortical development comprise a clinically and etiologically heterogeneous group of distinct structural abnormalities of the cerebral cortex, commonly identified during MR imaging of patients with seizure disorders and/or developmental delay. MR imaging is crucial for further classification and together with additional clinical information and family history guiding specific genetic testing, which today is an integral part of the interdisciplinary diagnostic work-up and allows identification of an underlying genetic alteration in a significant subset of patients. Results of genetic testing may provide important prognostic information and subsequently support prospective therapeutic decisions. Furthermore, genetic forms of cortical malformations may be associated with a significantly increased recurrence risk for further siblings or other relatives and require genetic counselling of the family on individual risks and the options of prenatal or even preimplantation genetic diagnosis. PMID- 21692015 TI - Spontaneous hemorrhage into a neurenteric cyst of the cerebellar vermis. AB - Neurenteric cysts are rare benign developmental lesions of the central nervous system which are lined by endodermal cell-derived epithelium. Here we present a 17-year-old male who presented with acute onset headache and cerebellar ataxia. He was found to have a hyperdense lesion of the cerebellar vermis on CT scan. The lesion was hyperintense on T1-weighted and hypointense on T2-weighted MR images. Surgical resection of the cyst revealed hemorrhage into the neurenteric cyst. PMID- 21692016 TI - [Cannabis hyperemesis syndrome]. AB - We present the course of cyclical hyperemesis most likely induced by cannabis in a young cannabis-dependent, but otherwise healthy female adult. Cyclical hyperemesis developed in parallel to increasing cannabis inhalation, and remitted completely within a few days of abstinence in a protective inpatient setting. Just as in those increasing cases which can be found in literature, the hyperemesis improved by taking a hot shower or bath at the beginning of the detoxification. This thermosensitivity, along with the detection of a central disturbance of the thyroid axis, points to the hypothalamic cannabinoid system being involved in cannabis-induced cyclical hyperemesis. The patient was followed up for 4 months without any re-occurrence of the syndrome during controlled cannabis abstinence. PMID- 21692017 TI - Bicameral repair of right pulmonary artery to left atrial communication. AB - A right pulmonary artery to left atrial communication is a very rare vascular congenital anomaly. Patients most commonly present in the neonatal period with congestive cardiac failure or at a later stage with central cyanosis and its complications. Various diagnostic modalities are available but angiography is the most important decision-making tool for the management of this lesion. We present an unusual case of right pulmonary artery to left atrial communication in a 14 year-old patient, who underwent successful surgical repair through a bicameral approach. PMID- 21692018 TI - Chylomediastinum following mitral valve replacement. AB - Chylomediastinum is a rare but potentially serious complication. There is as yet no definitive treatment. We present an exceptional case of chylomediastinum due to mitral valve replacement. The patient was successfully treated using a conservative approach with total parenteral nutrition, nothing by mouth, and mediastinal tube drainage. PMID- 21692019 TI - Is mediastinoscopy still the gold standard to evaluate mediastinal lymph nodes in patients with non-small cell lung carcinoma? AB - OBJECTIVES: In this study, we aimed to define the efficacy of F-18 FDG PET/CT for the detection of mediastinal lymph node metastases by comparing the mediastinal findings of F-18 FDG PET/CT with the histopathological results obtained either by mediastinoscopy or thoracotomy in patients with clinically operable non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: This is a prospective, single institution study of 68 consecutive patients with suspected or pathologically proven, localized, clinically resectable NSCLC (8 females and 60 males; mean age: 60.36 +/- 1.01 years, range: 43-78 years). The patients underwent integrated PET/CT scanning at the same PET center. Standard cervical mediastinoscopy and extended mediastinoscopy were performed to sample the lymph nodes. During thoracotomy, complete mediastinal lymph node dissection was routinely performed. RESULTS: Mediastinoscopy gave true positive results in 9 patients and true negative results in 57 patients. There were two false negative results. Mediastinoscopy had a sensitivity of 81.8% (95% CI: 63-82), a specificity of 100% (95% CI: 96-100), a PPV of 100% (95% CI: 77-100), a NPV of 96.6% (95% CI: 93-96), and an accuracy of 97% for the detection of mediastinal lymph node metastases. When PET/CT results were compared with postoperative pathological examination results, PET/CT correctly identified 48 out of 50 patients (96%) who did not have metastatic lymph node involvement. N2/N3 disease was correctly determined by PET/CT in 8 of 11 patients (72.7%) who had positive results on histological analysis. When only N2 and N3 nodal diseases were included in the calculation with the aim of making a comparison with mediastinoscopy (for mediastinal nodes), integrated PET/CT had a sensitivity of 72.7% (95% CI: 51-80), a specificity of 97.7% (95% CI: 92-99), a PPV of 88.9% (95% CI: 62-97), a NPV of 93.3% (95% CI: 88 95) and an accuracy of 92.6% (95% 83-95) for the detection of intrathoracic N2 and N3 nodal metastases. CONCLUSION: Our data shows that due to its high sensitivity and accuracy, mediastinoscopy is still the most reliable method to evaluate mediastinal lymph nodes in patients with NSCLC. PMID- 21692020 TI - Surgical resection of thymoma still represents the first choice of treatment. AB - OBJECTIVE: The aim of this study was to analyze the clinicopathological factors, treatment strategies and survival rates after surgical resection of thymoma. METHODS: Between 12/1997 and 5/2010, 42 patients underwent surgical resection of the thymus. The presence of a thymoma was determined by histological examination in 23 patients, while patients with hyperplasia of the thymus (n = 19) were excluded from further analysis. RESULTS: Myasthenia gravis coexisted in 9/23 (39.1%) patients. Thymomas were classified according to the Masaoka staging system (I: n = 6 [26.1%], IIa: n = 7 [30.4%], IIb: n = 2 [8.7%], III: n = 1 [4.4%], IVa: n = 7 [30.4%]) and the WHO histological classification (A: n = 4 [17.4%], AB: n = 5 [21.7%], B1: n = 1 [4.4%], B2: n = 8 [34.8%], B3: n = 3 [13%], C: n = 2 [8.7%]). Recurrence of thymoma was documented in three (13%) patients. After a mean follow-up of 58.4 months, 21 (91.3%) patients are alive. The overall survival rate was 95% and 87.8%, at 2 and 5 years, respectively. The disease-free interval at 5 years was 85% for the 17 (73.9%) patients with complete resection. CONCLUSIONS: Surgical resection of thymoma is the preferred treatment, because it is safe and effective with a low rate of recurrence and a good long-term survival. Advanced and invasive thymomas require a multimodal approach for better local tumor control and further improvement of prognosis. PMID- 21692021 TI - The effect of microwave and bipolar radio-frequency ablation in the surgical treatment of permanent atrial fibrillation during valve surgery. AB - BACKGROUND: Atrial fibrillation (AF) is a frequent problem in patients undergoing valve surgery. This study compared microwave and bipolar radio-frequency ablation of the left atrium in AF patients undergoing valve surgery. METHODS: Patients who required left atrial ablation for permanent AF (duration > 6 months) during valve surgery were randomized to a microwave group (n = 94) or a radio-frequency group (n = 93). Regular follow-up was carried out at 3, 6, 9 and 12 months post procedure and annually thereafter. RESULTS: There were 4 postoperative deaths in the microwave group and 2 in the radio-frequency group. The median follow-up for all patients was 24.0 months (range: 12-36.0 months). Freedom from AF recurrence was significantly higher in the radio-frequency group than in the microwave group at 3 months (85.7 vs. 72.2 %, P = 0.026), 6 months (87.9 vs. 73.3 %%, P = 0.013), 9 months (84.6 vs. 68.9 %, P = 0.012), 12 months (84.6 vs. 67.8 %%, P = 0.008), and 24 months (88.7 vs. 71.2 %, P = 0.022) and at the latest follow-up (81.3 vs. 65.6 %, P = 0.016). CONCLUSION: Bipolar radio-frequency ablation is superior to microwave ablation for the treatment of permanent AF in patients undergoing valve surgery. PMID- 21692022 TI - Histological evaluation of skeletonized internal thoracic artery using ForceTriadTM. AB - BACKGROUND: The internal thoracic artery (ITA) is a useful graft for coronary artery bypass grafting. Skeletonization, a technique that uses an ultrasonic scalpel, is increasingly used. However, the cost of an ultrasonic scalpel is extremely high. The purpose of this study was to determine whether a new electrosurgical cautery device (ForceTriadTM) is as effective as an ultrasonic scalpel. METHODS: Bilateral ITAs were harvested from eight pigs using the skeletonizing technique. The ITA on one side was harvested with an ultrasonic scalpel and on the other side using the ForceTriadTM. Macroscopic and histological examinations were performed in sixteen ITAs. RESULTS: No significant differences in the time required for harvesting were observed. The macroscopic findings revealed no significant change in any of the samples. The histological findings showed that the degree of thermal injury was similar. The normal structure was maintained in all samples. The ForceTriadTM costs US$ 226.82 less per patient than the ultrasonic scalpel. CONCLUSION: The new electrosurgical cautery device ForceTriadTM was less expensive, but it was equally effective. It appears that skeletonization performed with the new device is equivalent to that performed with an ultrasonic scalpel. PMID- 21692023 TI - Transfection of short-interfering RNA silences adhesion molecule expression on cardiac microvascular cells. AB - BACKGROUND: Acute rejection reactions and the development of graft arterial disease are serious limitations after transplantation. Both are connected to the expression of adhesion molecules on the activated microvascular endothelium of the allograft. METHODS: siRNA-mediated silencing of ESELE, ICAM-1, and VCAM-1 on human cardiac microvascular cells (HCMEC) was investigated in order to inhibit leukocyte-endothelial interactions. HCMEC were investigated for the time dependent expression of ESELE, ICAM-1, and VCAM-1 after TNF-alpha stimulation and for siRNA mediated suppression using a nonviral transfecting approach. Furthermore, the effects of siRNA transfection on leukocyte binding to the endothelium were analyzed. RESULTS: Transfection with siRNA induced a significant suppression of adhesion molecule expression, regardless of whether there had been a prior single or cocktail transfection of the sequences ( P < 0.05). The quantity of attaching leukocytes was significantly reduced after an equal silencing of adhesion molecules ( P < 0.05). CONCLUSIONS: This investigation demonstrates that liposomal transfection of HCMEC with specific siRNA sequences is capable of both repressing adhesion molecule expression and of reducing subsequent leukocyte-endothelial actions. PMID- 21692024 TI - Late diagnosis of extralobar pulmonary sequestration: two cases with an uncommon malformation. AB - Pulmonary sequestration is a congenital bronchopulmonary malformation, characterized by a mass of nonfunctioning lung tissue which receives its blood supply from a systemic artery. This increased blood flow and the inflammation in the sequestrated segments are positive on PET imaging, arousing the suspicion of malignancy. We report two cases of PET-positive extralobar sequestration that presented in patients of middle age and were successfully treated with surgical resection, indicating the role of surgery and the false-positive PET-CT appearance of sequestration cases. PMID- 21692027 TI - [Intraoperative neuromonitoring: necessary - desirable - dispensable?]. PMID- 21692026 TI - [Management of complications - bile leak after cholecystectomy]. PMID- 21692028 TI - [Misunderstandings - a human being has 4 ears]. PMID- 21692029 TI - Distribution of Kiaa0319-like immunoreactivity in the adult mouse brain--a novel protein encoded by the putative dyslexia susceptibility gene KIAA0319-like. AB - Kiaa0319L is a novel protein encoded by a recently discovered gene KIAA0319 like(L) that may be associated with reading disability. Little is known about the characteristics of this protein and its distribution in the brain. We investigated here expression of this protein in adult mice, using an antibody specific for human and rodent Kiaa0319L. In the brain, Kiaa0319L was localized strongly in the olfactory bulb, and strong expression was found in other regions, including hippocampus, cerebellum, diencephalon and the cerebral cortex. Immunohistochemistry confirmed expression in these brain regions, and showed further that the protein was expressed preferentially in neurons in layer IV and VI of the neocortex, CA1 and CA2 subfields of the hippocampus and a subpopulation of neurons in CA3 and dentate gyrus. Furthermore, the protein was confined to dendrites of CA1 neurons in the stratum radiatum, but not those in the stratum oriens, and in astrocytes within the hippocampus. In the cerebellum, the protein was observed in the molecular layer and a fraction of Purkinje neurons. These findings confirmed expression of Kiaa0319L in brain regions that are involved in reading performance, supporting its possible involvement in reading disability. The specific patterns of localization in the neocortex, hippocampus and cerebellum suggest further that this protein may be related to other biological processes in a subpopulation of neurons within these regions, eg. formation and maintenance of polarity in the neuron. PMID- 21692031 TI - Phenotypic changes and possible angiogenic roles of pericytes during wound healing in the mouse skin. AB - Pericytes (PCs) are attracting increasing attention as a crucial target for anti angiogenic therapy. In this study, we sought to determine the functional significance of PCs during angiogenesis by using a skin wound healing model in which different angiogenic stages are identifiable. Angiogenesis was first observed on Day 3 after wounding and increased greatly on Day 5. On Day 5, the leading edge of the regenerating vessels (vascular advancing front; VAF) appeared to be composed of immature vessels, and was further divided into "tip" and "following" regions according to maturational differences. PCs distributed in regenerating vessels showed phenotypic differences according to different regions. PCs that expressed PDGFR-beta alone and lacked vascular basement membrane (BM) were predominant in the tip region of the VAF, while PCs that expressed both PDGFR-beta and NG2 with their BM coating were numerous in the following regions toward the rear of the VAF. Moreover, PCs in the VAF expressed VEGF-A and associated with most proliferating endothelial cells (ECs). VEGF-A expression of PCs and the proliferating ECs totally disappeared in the region toward the rear of the VAF. We conclude that PCs can differ in their phenotype according to the stage of angiogenesis during wound healing. They may promote angiogenesis at the initial stage but might in turn stabilize the newly formed vessels at the later stage. PMID- 21692030 TI - Molecular and morphological characterization of neural tube defects in embryos of diabetic Swiss Albino mice. AB - BACKGROUND AND RESULTS: Embryos from diabetic mice exhibit several forms of neural tube defects, including non-closure of the neural tube. In the present study, embryos collected at embryonic day 11.5 from diabetic pregnancies displayed open neural tube with architectural disruption of the surrounding tissues. The percentage of proliferating cells was found to be increased in the dorsal and ventral domains of the spinal neural tube of embryos from diabetic mice, indicating a defect in the proliferation index. We have analyzed the development of various cell types, including motoneurons, interneurons, oligodendrocytes and migrating neurons, as well as radial glial cells in the open neural tube using specific molecular markers. Immunofluorescence results revealed a significantly reduced number of Pax2+ interneurons and increased number of Isl 1+ motoneurons, as well as Olig2+ oligodendrocytes in the neural tube of embryos from diabetic mice as compared to controls. In addition, these embryos exhibited a decreased number of doublecortin positive migrating neurons and Glast/Blbp positive radial glial cells with shortened processes in the neural tube. Expression levels of several developmental control genes involved in the generation of different neuronal cell types (such as Shh, Ngn, Ngn2, Ascl1) were also found to be altered in the neural tube of embryos from diabetic mice. CONCLUSIONS: Overall, the open neural tube in embryos of diabetic mice exhibits defects in the specification of different cell types, including motoneurons and interneurons, as well as glial cells along the dorsoventral axis of the developing spinal cord. Although these defects are associated with altered expression of several development control genes, the exact mechanisms by which maternal diabetes contributes to these changes remain to be investigated. PMID- 21692032 TI - Myeloid CD11c+ S100+ dendritic cells express indoleamine 2,3-dioxygenase at the inflammatory border to invasive lower lip squamous cell carcinoma. AB - The prevalence of squamous cell carcinoma of the lower lip (SCC-LL) is increasing worlwide. The expression of the enzyme indoleamine 2,3-dioxygenase (IDO) by antigen-presenting cells and/or tumor cells leads to tumor escape by inhibiting T cell-mediated rejection responses. The aim of this study was to determine the expression of IDO in SCC-LL. IDO-expression was analyzed in 47 SCC-LL, together with the expression of markers of T-cells (CD3), myeloid DCs (S100, CD11c), macrophages (CD68, CD11c), Langerhans cells (CD1a, Langerin (CD207)), plasmacytoid DCs (CD123), and regulatory T cells (Foxp3) by immunohistochemistry and immunofluorescence analysis. Twelve specimens out of 47 LL-SCCs contained cells that expressed IDO. IDO-positivity was strongly associated with the intensity of the cancer-associated infiltrate (P=0.0007). IDO-positive cells are located right along the border between the developing tumor and the inflammatory infiltrate. Immunofluorescence stainings showed that CD11c+S100+CD68- dendritic cells (DCs) express IDO in SCC-LL. IDO expression in LL-SCC may aid immune escape and chronic inflammation to promote cancer progression. Inhibition of IDO might be a therapeutic strategy to increase the anti-tumor immune response in SCC-LL. PMID- 21692033 TI - De novo expression of the hemoglobin scavenger receptor CD163 by activated microglia is not associated with hemorrhages in human brain lesions. AB - The main function of CD163 (hemoglobin scavenger receptor) is to bind the hemoglobin-haptoglobin complex, thereby mediating extravasal hemolysis. However, CD163 also has an antiinflammatory function. After CD163-mediated endocytosis, hemoglobin is catabolized further by hemeoxygenase 1 (HO-1). Previously, we found expression of HO-1 to be restricted to microglia/macrophages at sites of hemorrhages in human traumatic and ischemic brain lesions. We now investigated if CD163 expression is also correlated with hemorrhages in brain lesions. Methods. Autopsy brain tissue from 44 cases with hemorrhagic brain lesions (32 traumatic brain injuries/TBI, 12 intracerebral bleedings/ICB), 56 non-hemorrhagic brain lesions (30 ischemias, 26 hypoxias) and 6 control brains were investigated. The post injury survival times ranged from a few minutes to 60 months. Results. In controls, single perivascular monocytes expressed CD163, but only single CD163+ microglia were found in 3/6 cases. CD163+ cells in the parenchyma (activated microglia/macrophages) increased significantly within 24 hours after trauma and ischemia and within 1-7 days following ICB or hypoxia. Overall, significantly lower and higher levels of parenchymal CD163+ cells occurred in hypoxia and ischemia, respectively. Perivascular CD163+ cells also increased significantly in all pathological conditions. In areas remote from circumscribed brain lesions (TBI, ICB, ischemia), significant changes were only found in ICB and ischemia. Conclusions. De novo expression of CD163 by activated microglia/macrophages and CD163+ infiltrating monocytes are neither restricted to nor predominant in hemorrhagic brain lesions. Thus, the antiinflammatory function of CD163 probably predominates, both in hemorrhagic and non-hemorrhagic brain lesions and points to possible immunomodulatory treatment strategies targeting CD163. PMID- 21692034 TI - Sperm ultrastructure of Helicometra epinepheli (Platyhelminthes, Digenea, Opecoelidae), parasite of Epinephelus fasciatus (Pisces, Teleostei). AB - This paper describes the ultrastructure of the mature spermatozoon of the digenean Helicometra epinepheli. The ultrastructural elements observed are: two axonemes with a 9+"1" pattern of Trepaxonemata, four attachment zones, a nucleus, two mitochondria, external ornamentation of the plasma membrane, spine-like bodies and cortical microtubules. A particularity of this spermatozoon is the presence of an apical cone. However, the spermatozoon presents the general pattern of the Opecoelidae and thus differs from Helicometra fasciata (which appears as an exception in this family) by several ultrastructural features: the presence of external ornamentation and spine-like bodies and the arrangement of cortical microtubules around the first mitochondrion in the region of the ornamentation. Each ultrastructural feature is discussed and compared with the literature to highlight characters which could be useful for phylogeny. PMID- 21692035 TI - Upregulation of the high mobility group AT-hook 2 gene in acute aortic dissection is potentially associated with endothelial-mesenchymal transition. AB - The high mobility group AT-hook 2 (HMGA2) gene is proposed to regulate the genes involved in the epithelial-mesenchymal transition (EMT). One form of EMT is endothelial-mesenchymal transition (EndMT). We analyzed the expression profile of the HMGA2 gene in different human aortic diseases. Aortic specimens were collected from 51 patients, including 19 with acute aortic dissection, 26 with aortic aneurysm, two with Marfan syndrome and four aortic valves. Quantitative real-time polymerase chain reaction was carried out for HMGA2 and immunohistochemical analyses were performed for HMGA2, SNAI1, Vimentin, CD34, MKI 67 and TGFB1. The expression of let-7d microRNA, which is assumed to play a role in the regulation of HMGA2, was also quantified. The level of HMGA2 gene expression was significantly higher in acute aortic dissection compared with all the other samples (193.1 vs. 8.1 fold normalized to calibrator, P<0.001). The immunohistochemical investigation showed that HMGA2, SNAI1, and Vimentin proteins were mainly detected in the endothelial cells of the vasa vasorum. The HMGA2 gene is upregulated in acute aortic dissection. This is the first report describing a link between HMGA2 and acute aortic dissection. The HMGA2, SNAI1 and Vimentin proteins were mainly detected in the endothelium of the vasa vasorum. It seems that HMGA2 overexpression in acute aortic dissection occurs in a let-7d independent manner and is associated with EndMT of the vasa vasorum. PMID- 21692036 TI - Parafibromin expression in lung normal tissue and carcinoma: its comparison with clinicopathological parameters of carcinoma. AB - Parafibromin is a protein encoded by the hyperparathyroidism 2 oncosuppressor gene and its down-regulated expression is involved in the pathogenesis of parathyroid, gastric and colorectal carcinomas. To clarify the roles of parafibromin expression in lung carcinomas, it was examined by immunohistochemistry and in situ hybridization on tissue microarray containing lung carcinomas (n=144) and normal lung tissue (n=20), with a comparison to clinicopathological parameters of carcinomas. Lung carcinoma cell lines and tissues were studied for parafibromin expression by Western blot and RT-PCR. Down regulated expression of parafibromin mRNA was found in lung carcinoma in comparison with matched normal tissue (p<0.05). Parafibromin protein was found in the cilia and nuclei of pseudo-stratified columnar epithelium, and the nuclei of lung carcinoma. According to immunostaining and in situ hybridization, there was no difference in parafibromin expression between histological subtypes of lung carcinoma (p>0.05). The Kaplan-Meier method indicated that nuclear parafibromin expression was positively correlated with adenocarcinoma patients (p<0.05). Down regulated parafibromin mRNA expression might play an important role in lung carcinogenesis, but not in its histogenesis. Strong parafibromin expression in cilia of the pseudo-stratified columnar epithelium indicated its possible involvement in cell mobility. Parafibromin expression could be employed to indicate the favorable prognosis of patients with adenocarcinoma. PMID- 21692037 TI - Maternal diabetes affects cell proliferation in developing rat placenta. AB - Placentation starts with the formation of a spheroidal trophoblastic shell surrounding the embryo, thus facilitating both implantation into the uterine stroma and contact with maternal blood. Although it is known that diabetes increases the placental size and weight, the mechanisms responsible for this alteration are still poorly understood. In mammals, cellular proliferation occurs in parallel to placental development and it is possible that diabetes induces abnormal uncontrolled cell proliferation in the placenta similar to that seen in other organs (e.g. retina). To test this hypothesis, the objective of this work was to determine cell proliferation in different regions of the placenta during its development in a diabetic rat model. Accordingly, diabetes was induced on day 2 of pregnancy in Wistar rats by a single injection of alloxan (40 mg/kg i.v.). Placentas were collected on days 14, 17, and 20 postcoitum. Immunoperoxidase was used to identify Ki67 nuclear antigen in placental sections. The number of proliferating cells was determined in the total placental area as well as in the labyrinth, spongiotrophoblast and giant trophoblast cell regions. During the course of pregnancy, the number of Ki67 positive cells decreased in both control and diabetic rat placentas. However, starting from day 17 of pregnancy, the number of Ki67 positive cells in the labyrinth and spongiotrophoblast regions was higher in diabetic rat placentas as compared to control. The present results demonstrate that placentas from the diabetic rat model have a significantly higher number of proliferating cells in specific regions of the placenta and at defined developmental stages. It is possible that this increased cell proliferation promotes thickness of the placental barrier consequently affecting the normal maternal-fetal exchanges. PMID- 21692038 TI - Isolation of pluripotent stem cells from human third molar dental pulp. AB - Potent stem/progenitor cells have been isolated from normal human dental pulps, termed dental pulp stem cells (DPSCs). However, no study has described the presence of stem cell populations in human dental pulp from the third molar with embryonic phenotypes. The dental pulp tissue was cultured in media with the presence of LIF, EGF, and PDGF. In the present study, we describe a new population of pluripotent stem cells that were isolated from dental pulp (DPPSC). These cells are SSEA-4(+), Oct4(+), Nanog(+), FLK-1(+), HNF3beta(+), Nestin(+), Sox2(+), Lin28(+), c-Myc(+), CD13(+), CD105(+), CD3(-), CD45(-), CD90(low), CD29(+), CD73(low), STRO-1(low) and CD146(-). We have investigated by SEM analysis and q-RT-PCR the capacity of DPPSCs to 3D differentiate in vitro using the Cell Carrier 3D glass scaffold into tissues that have similar characteristics to embryonic mesoderm and endoderm layers. These data would support the use of these cells, which are derived from an easily accessible source and can be used in future regeneration protocols for many tissue types that differentiate from the three embryonic layers. PMID- 21692039 TI - Ovarian pluripotent/multipotent stem cells and in vitro oogenesis in mammals. AB - There has been a long persisting dilemma about potential ovarian stem cells in adult mammalian ovaries, including human, and now there is steadily increasing experimental evidence on their existence. After some previous indirect evidence about the presence of stem cells in adult mouse ovaries, an important breakthrough was made by Zou and his co-workers who successfully established long persisting pluripotent/multipotent ovarian stem cell lines in neonatal and adult mice, and were followed by some other important studies in mouse and human. Moreover, oocyte-like cells can be developed in vitro from pluripotent stem cells of different origins (embryonic stem cells, induced pluripotent stem cells, fetal skin stem cells, pancreatic stem cells). The aim of this article is to elucidate the fast growing new knowledge on the ovarian stem cells and potential in vitro oogenesis in mammals. PMID- 21692040 TI - Insights into iron and nuclear factor-kappa B (NF-kappaB) involvement in chronic inflammatory processes in peritoneal endometriosis. AB - Endometriosis is a chronic pelvic inflammatory process. Local inflammation is known to play a role in pain and infertility associated with the disease, and may be extensively involved in molecular and cellular processes leading to endometriosis development. In this review, we focus on two inflammatory mediators clearly implicated in the pathogenesis of endometriosis, iron and NF-kappaB, and their potential association. Iron is essential for all living organisms, but excess iron results in toxicity and is linked to pathological disorders. In endometriosis patients, iron overload has been demonstrated in the different compartments of the peritoneal cavity (peritoneal fluid, endometriotic lesions, peritoneum and macrophages). This iron overload affects numerous mechanisms involved in endometriosis development. Moreover, iron can generate free radical species able to react with a wide range of cellular constituents, inducing cellular damage. Overproduction of reactive oxygen species also impairs cellular function by altering gene expression via regulation of redox-sensitive transcription factors such as NF-kappaB, which is clearly implicated in endometriosis. Indeed, NF-kappaB is activated in endometriotic lesions and peritoneal macrophages of endometriosis patients, which stimulates synthesis of proinflammatory cytokines, generating a positive feedback loop in the NF-kappaB pathway. NF-kappaB-mediated gene transcription promotes a variety of processes, including endometriotic lesion establishment, maintenance and development. In conclusion, iron and NF-kappaB appear to be linked and both are clearly involved in endometriosis development, making these pathways an attractive target for future treatment and prevention of this disease. PMID- 21692041 TI - Neural stem cell-mediated therapy for rare brain diseases: perspectives in the near future for LSDs and MNDs. AB - Lysosomal storage diseases (LSDs) are genetically inherited disorders affecting most patients in pediatric age and progressively lead to severe, even lethal, multiorgan dysfunction and brain neurodegeneration. Motor neuron diseases (MNDs) or Amyotrophic Lateral Sclerosis (ALS)-related syndromes are neurodegenerative disorders occurring in the majority of cases sporadically and affect adult middle aged patients. Despite being divergent in most pathological and physiological hallmarks, both MNDs and LSDs are characterized by tremendous clinical heterogeneity due to poor prognosis and variable onset of the symptoms. Moreover, both LSDs and MNDs are characterized by the concurrence of multiple pathogenetic processes, such as the development of inflammatory and excitotoxic environments. Furthermore, pharmacological, enzyme or genetic therapies have proven to be ineffective and no cure is currently available for the neurodegeneration in either LSD or ALS affected patients. Recent studies have identified non-neuronal cell types, such as astrocytes and microglia, as being involved in non cell autonomous effects on MND or LSD progression. These findings have prompted the use of neural stem cells for the replacement of non-neuronal cells rather than neuronal cells, which may result in neuroprotection and immunomodulation. The choice of an appropriate tissue source and the establishment of standardized paradigms to culture human neural stem cells (hNSC) will allow their use for future clinical trials on both ALS and LSD affected patients and parallel drug screening studies with novel breakthroughs in the knowledge of neurodegenerative diseases. PMID- 21692042 TI - Scientist honored for work with paclitaxel: Interest in a unique chemical structure leads to drug that helps millions. PMID- 21692043 TI - Smoking studies produce new findings regarding breast and lung cancer link. PMID- 21692044 TI - Molecular predicator of metastatic cancer identified. PMID- 21692045 TI - miR-340 inhibition of breast cancer cell migration and invasion through targeting of oncoprotein c-Met. AB - BACKGROUND: Different microRNAs have been shown to have oncogenic and tumor suppressive functions in human cancers. Detection of their expression may lead to identifying novel markers for breast cancer. METHODS: The authors detected miR 340 expression in 4 human breast cell lines and then focused on its role in regulation of tumor cell growth, migration, and invasion and target gene expression. They then analyzed miR-340 expression in benign and cancerous breast tissue specimens. RESULTS: Endogenous miR-340 expression was down-regulated in the more aggressive breast cancer cell lines, which was confirmed in breast cancer tissue specimens by using quantitative real-time polymerase chain reaction. Further studies showed that induction of miR-340 expression was able to suppress tumor cell migration and invasion, whereas knockdown of miR-340 expression induced breast cancer cell migration and invasion. At the gene level, the authors identified c-Met as a direct miR-340 target to mediate cell migration and invasion through regulation of MMP-2 and MMP-9 expression. Ex vivo, loss of miR-340 expression was associated with lymph node metastasis, high tumor histological grade, clinical stage, and shorter overall survival of breast cancer as well as increased c-Met expression in breast cancer tissue specimens. CONCLUSIONS: miR-340 may play an important role in breast cancer progression, suggesting that miR-340 should be further evaluated as a novel biomarker for breast cancer metastasis and prognosis, and potentially a therapeutic target. PMID- 21692046 TI - Do patients consider preoperative chemoradiation for primary rectal cancer worthwhile? AB - BACKGROUND: The objective of this study was to elicit future patients' preferences for preoperative chemoradiation (pre-CRT) for rectal cancer to determine whether patients' preferences are consistent with current treatment guidelines. METHODS: During a standardized interview, the treatment protocol, risks, benefits, and long-term outcomes associated with 1) surgery alone (SA) and 2) pre-CRT followed by surgery (CR + S) were described to healthy individuals, and a threshold task was performed. Each participant was asked which treatment option they would prefer when the risk of local recurrence was set initially at 15% for both options. If the participant indicated SA (which was expected), then the risk of local recurrence for CR + S was lowered systematically until the participant's preference changed from SA to CR + S. This threshold point represented the risk of local recurrence for pre-CRT that the participant would require before they would choose treatment with pre-CRT. RESULTS: Fifty individuals participated in the study, and the majority were well educated. Twenty-seven of 50 participants (54%) required a risk of local recurrence with CR + S of <= 5% (ie, equivalent to an absolute risk reduction >= 10%) before they would choose treatment with pre-CRT. Regression analysis did not identify any variables that were predictive of the participants' preferences. CONCLUSIONS: Participants seemed to highly value functional outcomes and seemed willing to accept a higher risk of local recurrence to achieve this. Therefore, developers of future guidelines may need to downgrade the use of pre-CRT for all patients with stage II/III tumors from a guideline to an option. PMID- 21692047 TI - Association between somatostatin receptor 5 gene polymorphisms and pancreatic cancer risk and survival. AB - BACKGROUND: Somatostatin (SST) inhibited cell proliferation and negatively regulated the release of growth hormones by means of specific receptors (SSTR). Genetic variation in SSTR had been associated with risk of human cancers but had never been investigated in pancreatic cancer. METHODS: In this retrospective study the SSTR5 gene in paired tumor and blood samples from 33 pancreatic adenocarcinoma patients using the Sanger method were sequenced. Three single nucleotide polymorphisms (SNPs) in samples from 863 patients with pancreatic ductal adenocarcinoma and 876 healthy controls using the TaqMan method were analyzed. The associations between gene polymorphisms and pancreatic cancer risk and survival were analyzed by multivariate logistic regression and Cox proportional hazard models, respectively. RESULTS: No somatic mutations were identified, but 3 nonsynonymous SSTR5 SNPs (P109S, L48M, and P335L) in pancreatic tumors were identified. The SSTR5 P109S variant allele was associated with a 1.62 fold increased risk of pancreatic cancer (95% confidence interval [CI]: 1.08 2.43, P = 0.019). Furthermore, the SSTR5 L48M AC variant and smoking had a joint effect on pancreatic cancer risk (p(interaction) = 0.035). The odds ratios (95% confidence intervals) were 0.58 (0.34-0.97), 1.49 (1.18-1.89), and 2.27 (1.35 3.83) for the variant genotype alone, smoking alone, and both factors, respectively, compared with no factors. Finally, SSTR5 P335L CC and P109S CC combined were associated with lower overall survival durations in patients with resectable disease. CONCLUSIONS: These data suggest that SSTR5 genetic variants play a role in pancreatic cancer development and progression. PMID- 21692048 TI - Survival after complete surgical resection of multiple metastases from renal cell carcinoma. AB - BACKGROUND: Although a role for resection of solitary metastases from renal cell carcinoma (RCC) has been described, the utility of surgery in patients with multiple sites of disease has been less well defined. The authors report the survival of patients who underwent complete metastasectomy for multiple RCC metastases. METHODS: The authors identified 887 patients who underwent nephrectomy for RCC between 1976 and 2006 who developed multiple metastatic lesions. The impact of complete metastasectomy on survival was evaluated controlling for the timing, location, and number of metastases and for patient performance status. RESULTS: Of 887 patients, 125 (14%) underwent complete surgical resection of all metastases. Complete metastasectomy was associated with a significant prolongation of median cancer-specific survival (CSS) (4.8 years vs 1.3 years; P < .001). Patients who had lung-only metastases had a 5-year CSS rate of 73.6% with complete resection versus 19% without complete resection (P < .001). A survival advantage from complete metastasectomy also was observed among patients with multiple, nonlung-only metastases, who had a 5-year CSS rate of 32.5% with complete resection versus 12.4% without complete resection (P < .001). Complete resection remained predictive of improved CSS for patients who had >= 3 metastatic lesions (P < .001) and for patients who had synchronous (P < .001) and asynchronous (P = .002) multiple metastases. Moreover, on multivariate analysis, the absence of complete metastasectomy was associated significantly with an increased risk of death from RCC (hazard ratio, 2.91; 95% confidence interval, 2.17-3.90; P < .001). CONCLUSIONS: The current results indicated that complete resection of multiple RCC metastases may be associated with long-term survival and should be considered when technically feasible in appropriate surgical candidates. PMID- 21692049 TI - Long-term survival after radical prostatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer. AB - BACKGROUND: The long-term survival of patients with high-risk prostate cancer was compared after radical prostatectomy (RRP) and after external beam radiation therapy (EBRT) with or without adjuvant androgen-deprivation therapy (ADT). METHODS: In total, 1238 patients underwent RRP, and 609 patients received with EBRT (344 received EBRT plus ADT, and 265 received EBRT alone) between 1988 and 2004 who had a pretreatment prostate-specific antigen (PSA) level >= 20 ng/mL, a biopsy Gleason score between 8 and 10, or clinical tumor classification >= T3. The median follow-up was 10.2 years, 6.0 years, and 7.2 years after RRP, EBRT plus ADT, and EBRT alone, respectively. The impact of treatment modality on systemic progression, cancer-specific survival, and overall survival was evaluated using multivariate Cox proportional hazard regression analysis and a competing risk-regression model. RESULTS: The 10-year cancer-specific survival rate was 92%, 92%, and 88% after RRP, EBRT plus ADT, and EBRT alone, respectively (P = .06). After adjustment for case mix, no significant differences in the risks of systemic progression (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.51-1.18; P = .23) or prostate cancer death (HR, 1.14; 95% CI, 0.68-1.91; P = .61) were observed between patients who received EBRT plus ADT and patients who underwent RRP. The risk of all-cause mortality, however, was greater after EBRT plus ADT than after RRP (HR, 1.60; 95% CI, 1.25-2.05; P = .0002). CONCLUSIONS: RRP alone and EBRT plus ADT provided similar long-term cancer control for patients with high-risk prostate cancer. The authors concluded that continued investigation into the differing impact of treatments on quality-of-life and noncancer mortality will be necessary to determine the optimal management approach for these patients. PMID- 21692050 TI - Assessing the clinical benefit of nuclear matrix protein 22 in the surveillance of patients with nonmuscle-invasive bladder cancer and negative cytology: a decision-curve analysis. AB - BACKGROUND: Several studies have demonstrated that abnormal levels of nuclear matrix protein 22 (NMP22) are associated with bladder cancer and have led to the approval of NMP22 as a urinary biomarker by the US Food and Drug Administration. Nonetheless, the clinical significance of NMP22 remains unclear. The objective of this study was to use decision analysis to determine whether NMP22 improves medical decision-making. METHODS: The current study included 2222 patients who had a history of nonmuscle-invasive bladder cancer and current negative cytology. The authors developed models to predict cancer recurrence or progression to muscle-invasive disease using voided NMP22 levels, cystoscopy, age, and sex. Clinical net benefit was calculated by summing the benefits (true-positives), subtracting the harms (false-positives), and weighting these values by the threshold probability at which a patient or clinician would opt for cytoscopy. RESULTS: After cystoscopy, 581 patients (26%) had cancer identified. The NMP22 level was associated significantly with bladder cancer recurrence and progression (P < .001 for both). The use of NMP22 in a model with age and sex was associated with better patient outcomes than performing cystoscopy on everyone and produced threshold probabilities > 8% for recurrence and > 3% for progression. Only offering cystoscopy to those who had a risk > 15% reduced the number of cystoscopies by 229 while missing only 25 cancer recurrences per 1000 men with negative cytology. The current study was limited by its multicenter design. CONCLUSIONS: For clinicians who would perform a cystoscopy at a threshold of 5% for recurrence or 1% for progression, NMP22 did not aid clinical decision-making. For less risk-averse clinicians who would only perform a cystoscopy at a threshold probability >thinsp;8% for recurrence or > 3% for progression, NMP22 helped to indicate which patients required cystoscopy and which could be spared this procedure. PMID- 21692051 TI - CpG island methylation profiling in human salivary gland adenoid cystic carcinoma. AB - BACKGROUND: DNA methylation is a fundamental epigenetic event associated with physiologic and pathologic conditions, including cancer. Hypermethylation of CpG islands at active gene promoters leads to transcriptional repression, whereas hypomethylation is associated with gene overexpression. The aim of this study was to identify genes in adenoid cystic carcinoma (ACC) of salivary gland strongly deregulated by epigenetic CpG island methylation, to validate selected genes by conventional techniques, and to correlate the findings with clinicopathologic factors. METHODS: The authors analyzed 16 matched normal and tumor tissues for aberrant DNA methylation using the methylated CpG island amplification and microarray method and the pyrosequencing technique. RESULTS: Microarray analysis showed hypomethylation in 7 and hypermethylation in 32 CpG islands. Hypomethylation was identified in CpG islands near FBXO17, PHKG1, LOXL1, DOCK1, and PARVG. Hypermethylation was identified near genes encoding predominantly transcription factors (EN1, FOXE1, GBX2, FOXL1, TBX4, MEIS1, LBX2, NR2F2, POU3F3, IRX3, TFAP2C, NKX2-4, PITX1, NKX2-5), and 13 genes with different functions (MT1H, EPHX3, AQPEP, BCL2L11, SLC35D3, S1PR5, PNLIPRP1, CLIC6, RASAL, XRN2, GSTM5, FNDC1, INSRR). Four CpG islands by EN1, FOXE1, TBX4, and PITX1 were validated by pyrosequencing. CONCLUSIONS: The highly methylated genes in tumor versus normal tissue are linked to developmental, apoptotic, and other fundamental cellular pathways, suggesting that down-regulation of these genes is associated with ACC development and progression. With EN1 hypermethylation showing potential as a possible biomarker for ACC in salivary gland, the biological and therapeutic implications of these findings require further preclinical investigations. PMID- 21692052 TI - Glucose, not glutamine, is the dominant energy source required for proliferation and survival of head and neck squamous carcinoma cells. AB - BACKGROUND: Tumor metabolism is an essential contributor to disease progression and response to treatment. An understanding of the metabolic phenotype of head and neck squamous cell carcinoma (HNSCC) will allow the development of appropriate antimetabolic strategies for this tumor type. METHODS: A panel of 15 HNSCC cell lines was assayed for glucose and glutamine dependence and sensitivity to metabolic inhibitors. In addition, broad-spectrum metabolomic analysis using mass spectrometry/liquid chromatography was combined with individual measurements of reducing potential, adenosine triphosphate, and lactate production to characterize cellular metabolic phenotypes. RESULTS: HNSCC energy and reducing potential levels closely mirrored extracellular glucose concentrations. Glucose starvation induced cell death despite the activation of secondary energetic pathways. Conversely, glutamine was not required for HNSCC survival and did not serve as a significant source of energy. 2-deoxyglucose (2-DG) and its fluorinated derivative decreased glycolytic and Krebs cycle activity, cellular energy, and reducing potential and inhibited HNSCC cell proliferation. 2-DG effects were potentiated by the addition of metformin, but not by inhibitors of the pentose phosphate pathway or glutaminolysis. Despite dependence on glucose catabolism, the authors identified a subset of cell lines with relative resistance to starvation. Exploration of 1 such cell line (HN30) suggested that the presence of wild-type p53 can partially protect tumor cells from glucose starvation. CONCLUSIONS: HNSCC tumor cells are dependent on glucose, not glutamine, for energy production and survival, providing a rationale for treatment strategies that target glucose catabolism. However, antimetabolic strategies may need to be tailored to the tumor background, more specifically, p53 status. PMID- 21692053 TI - Loss of MTBP expression is associated with reduced survival in a biomarker defined subset of patients with squamous cell carcinoma of the head and neck. AB - BACKGROUND: Recent genetic studies have implicated p53 mutation as a significant risk factor for therapeutic failure in squamous cell carcinoma of the head and neck (SCCHN). However, in a recent meta-analysis in the literature of p53 from major anatomical subsites (larynx, oral cavity, oropharynx/hypopharynx), associations between patient survival and p53 status were ambiguous. METHODS: The authors examined a cohort of SCCHNs using a previously developed biomarker combination that likely predicts p53 status based on p53/MDM2 expression levels determined by immunohistochemistry (IHC). In addition, the authors generated and validated an antibody to MTBP (an MDM2 binding protein that alters p53/MDM2 homeostasis and may contribute to metastatic suppression) and have incorporated data for MTBP expression into the current analyses. RESULTS: Analysis of expression data for p53 and MDM2 in 198 SCCHN patient samples revealed that the biomarker combination p53 + ve/MDM2-low (likely indicative of p53 mutation) was significantly associated with reduced overall survival (log-rank P = .035) and was an independent prognostic factor (P = .013; HR, 1.705; 95% CI, 1.12-2.60); thus, these data were compatible with earlier genetic analyses. By using IHC for p53 and MDM2 to dichotomize patients, the authors found that loss of MTBP expression was significantly associated with reduced survival (log-rank P = .004) and was an independent prognostic factor (P = .004; HR, 2.78; 95% CI, 1.39-5.54) in p53 + ve/MDM2-low patients. CONCLUSIONS: These results represent the first examination of MTBP expression in human tissues and provide evidence for a p53 status-dependent role for MTBP in suppressing disease progression in SCCHN patients as well as confirming a role for p53 pathway function in delaying disease progression. PMID- 21692054 TI - A clustered ground-glass hepatocyte pattern represents a new prognostic marker for the recurrence of hepatocellular carcinoma after surgery. AB - BACKGROUND: The recurrence of hepatocellular carcinoma (HCC) after hepatectomy is a serious event. It has been demonstrated that different ground-glass hepatocyte (GGH) patterns harbor specific hepatitis B virus (HBV) pre-S deletion mutants and represent preneoplastic lesions in chronic HBV infection. In the current study, the authors investigated whether a specific GGH pattern in nontumorous liver tissues was associated with the recurrence of HBV-related HCC after surgery. METHODS: Clinicopathologic data from 82 patients with HBV-related HCC were reviewed. GGH patterns were assessed on hematoxylin and eosin-stained sections. Tissue hepatitis B surface antigen (HBsAg) expression was evaluated by immunohistochemical staining. Serum profiles of pre-S status, viral load, and HBV genotype were determined and correlated with clinical recurrence and survival after surgery. RESULTS: The results indicated that the clustered pattern of GGHs or HBsAg expression was associated significantly with decreased local recurrence free survival (LRFS) during a mean follow-up of 46.4 months (P<.001). This biomarker was comparable to or better than the prognostic value of other parameters, such as multifocal tumors (P = .022), satellite nodules (P = .005), small cell dysplasia (P = .045), or elevated viral load (P = .027), to predict recurrent HCC. Multivariate analysis also revealed that type II GGHs, which expressed marginal HBsAg and consistently clustered in nodules, were independent variables associated with LRFS (P<.001) and overall survival (P = .003). CONCLUSIONS: The current results indicated that the assessment of GGH patterns or HBsAg expression in nontumorous liver tissues provides an easily recognized, new risk marker for the recurrence of HBV-related HCC after hepatic resection. PMID- 21692055 TI - Patient-reported receipt of and interest in smoking-cessation interventions after a diagnosis of cancer. AB - BACKGROUND: Smoking cessation is essential after the diagnosis of cancer to enhance clinical outcomes. Although effective smoking-cessation treatments are available, <50% of smokers with cancer report receiving treatment. Reasons for the low dissemination of such treatment are unclear. METHODS: Data were collected from questionnaires and medical record reviews from 160 smokers or recent quitters with lung or head and neck cancer. Descriptive statistics, Cronbach alpha coefficients, and logistic regression were used in the analyses. The median age of participants was 57 years, 63% (n = 101) were men, 93% (n = 149) were white, and 57% (n = 91) had lung cancer. RESULTS: Eight-six percent (n = 44) of smokers and 75% (n = 82) of recent quitters reported that healthcare providers gave advice to quit smoking. Sixty-five percent (n = 33) of smokers and 47% (n = 51) of recent quitters reported that they were offered assistance from their healthcare providers to quit smoking. Fifty-one percent (n = 26) of smokers and 20% (n = 22) of recent quitters expressed an interest in a smoking-cessation program. An individualized smoking-cessation program was the preferred type of program. Among smokers, younger patients with early stage disease and those with partners who were smokers were more interested in programs. CONCLUSIONS: Although the majority of patients received advice and were offered assistance to quit smoking, approximately 50% of smokers were interested in cessation programs. Innovative approaches to increase interest in cessation programs need to be developed and tested in this population. PMID- 21692056 TI - Clinical prognostic factors in patients with locally advanced (stage III) nonsmall cell lung cancer treated with hyperfractionated radiation therapy with and without concurrent chemotherapy: single-Institution Experience in 600 Patients. AB - BACKGROUND: Influence of potential clinical prognostic factors on overall survival (OS), local progression-free survival (PFS), and distant metastasis-free survival (MFS) in patients with locally advanced nonsmall cell lung cancer treated with hyperfractionated radiation therapy (HFX RT) with or without concurrent chemotherapy was investigated. METHODS: Three phase 3 and 2 phase 2 studies have been designed and executed with a total of 600 patients. HFX RT alone was given in 127 and HFX RT-chemotherapy was given in 473 patients. HFX RT doses were either 64.8 grays (Gy) or 69.6 Gy using 1.2 Gy twice daily, or 67.6 Gy using 1.3 Gy twice daily. Chemotherapy consisted of concurrent carboplatin and etoposide in 409 patients and concurrent carboplatin and paclitaxel in 64 patients. Sex, age, Karnofsky performance score (KPS), weight loss (>5%), stage, histology, interfraction interval, and treatment (the addition of concurrent chemotherapy) were investigated as potential prognostic factors. RESULTS: The median OS, median local PFS, and median distant MFS times were 19, 21, and 23 months, respectively. Five-year OS, local PFS, and distant MFS rates were 19%, 29%, and 35%, respectively. Univariate and multivariate analysis showed that only age did not influence OS and local PFS, whereas female sex, lower KPS, less pronounced weight loss, lower stage, squamous histology, shorter interfraction interval, and treatment independently predicted better OS and local PFS. Only age and treatment did not influence distant MFS, whereas histology was of borderline significance. CONCLUSIONS: This study identified independent prognosticators of treatment outcome. These results may have implications for future studies in this disease. PMID- 21692058 TI - Impact of race on biochemical disease recurrence after prostate brachytherapy. AB - BACKGROUND: Understanding racial differences in disease presentation and response to therapy is necessary for the effective treatment and control of prostate cancer. In this study, the authors examined the influence of race on biochemical disease-free survival (BDFS) among men who received prostate brachytherapy. METHODS: In total, 2301 men were identified who had a minimum follow-up of 24 months and had received low-dose-rate brachytherapy for prostate cancer at the Mount Sinai Medical Center from June 1990 to October 2008. Patient factors, with specific emphasis on patient race, were analyzed with respect to freedom from biochemical failure (FFbF). Kaplan-Meier analyses, life-tables, and log-rank tests were used to identify variables that were predictive of 10-year FFbF. RESULTS: In this series, a total of 2268 patients included 81% Caucasians, 12% African Americans, 6% Hispanics, and 1% Asians. The 10-year actuarial FFbF rate was 70% for AA men and 84% for all others (P = .002). Between Caucasian men and AA men, the 10-year FFbF rate was 83% versus 70%, respectively (P = .001).There was no significant difference in 10-year FFbF between Caucasian men and Hispanic men (83% vs 86%, respectively; P = .6). The 10-year FFbF rate for Hispanic men and AA men was 86% versus 70%, respectively (P = .062). A greater percentage of AA men presented with higher prostate-specific antigen levels (PSA) (>10 ng/mL; 44% vs 21%; P < .001) and, thus, with higher risk disease (24% vs 15%; P < .001) compared with Caucasian men. Among the men with low-risk disease, the 10-year FFbF rate was 90% for Caucasian men and 76% for AA men (P = .041). The 10-year BDFS rate for patients who received brachytherapy alone was 86% for Caucasian men and 61% for AA men (P = .001); however, this difference was not observed when brachytherapy was combined with androgen-deprivation therapy(ADT) with or without supplemental external-beam radiotherapy (EBRT). Multivariate analysis revealed that PSA (P = .024), Gleason score (P < .001), the biologic effective dose (P < .001), EBRT (P = .002), ADT (P = .03), and AA race (P = .037) were significant predictors of 10-year FFbF. No significant differences was observed in overall survival, cause-specific survival, or distant metastasis-free survival between racial groups. CONCLUSIONS: AA race appeared to be an independent negative predictor of BDFS after prostate brachytherapy, and this result may highlight the need for more aggressive therapy in this patient population. PMID- 21692057 TI - Clinical features and outcomes in patients with extraskeletal Ewing sarcoma. AB - BACKGROUND: Ewing sarcoma can arise in either bone or soft tissue. The purpose of this study was to investigate whether patient characteristics, treatment strategies, and outcomes differ between skeletal Ewing sarcoma and extraskeletal Ewing sarcoma (EES). METHODS: Patients <40 years of age with Ewing sarcoma or peripheral primitive neuroectodermal tumor reported to the United States Surveillance, Epidemiology, and End Results Program database from 1973 to 2007 were evaluated based on skeletal (n = 1519) versus extraskeletal (n = 683) site of origin. Patient characteristics were compared using Fisher exact tests. Overall survival was estimated via the Kaplan-Meier method and compared using log rank tests and Cox proportional hazard models. RESULTS: Patients with EES had a higher mean age (19.5 vs 16.3 years; P < .001) and were less likely to be male (53.4% vs 63.3%; P < .001) or white (84.8% vs 92.5%; P < .001) compared with patients with skeletal tumors. Extraskeletal tumors were more likely to arise in axial locations (72.9% vs 54.2%; P = .001) but were less likely to arise specifically in the pelvis (19.8% vs 26.6%; P < .001). Metastatic status or tumor size did not differ by group. Five-year overall survival was superior for localized EES compared with localized skeletal tumors (69.7% vs 62.6%; P = .02). The hazard ratio for death in patients with localized skeletal tumors compared with localized EES was 2.36 (95% confidence interval, 1.61-3.44) beyond 24 months from initial diagnosis. CONCLUSIONS: Patient characteristics and outcomes differ among patients with EES compared with patients with skeletal Ewing sarcoma. These findings may have important implications for patient care. PMID- 21692059 TI - Treatment adherence and outcome in women with inflammatory breast cancer: does race matter? AB - BACKGROUND: The authors compared treatment adherence rates and outcome in Caucasian and African American patients with inflammatory breast cancer (IBC). METHODS: The records of 55 (25 Caucasian and 30 African American) IBC patients treated with curative intent from 1995 to 2009 were reviewed. All patients received neoadjuvant doxorubicin (Adriamycin) and/or taxane-based chemotherapy, and mastectomy with or without radiotherapy. The median follow-up period for Caucasian and African American patients was similar (39.5 months and 36.1 months, respectively). RESULTS: There was no difference between races in median age, tumor size, grade, and receptor status at diagnosis. The number of patients who completed neoadjuvant chemotherapy, surgery, and radiotherapy did not differ by race (84% of Caucasians vs 86.7% of African Americans) nor did the median length of time to complete trimodality treatment (263 [range, 207-422] days for Caucasians vs 262 [range, 165-371] days for African Americans). There was a trend toward slightly higher pathological complete response rates in Caucasian than African American women (20% in Caucasians vs 6.7% in African Americans, P = .23). Despite slightly better response rates to neoadjuvant chemotherapy, Caucasian patients did not have higher 3-year local control rates (70% in Caucasians vs 64% in African Americans, P = .73). However, there was a trend toward higher 3-year overall survival in Caucasian versus African American patients (73% in Caucasians vs 55% in African Americans, P = .09) and higher distant metastasis-free survival (60% in Caucasians vs 40% in African Americans, P = .19). CONCLUSIONS: This study is among the largest to examine patients with IBC by race. Being Caucasian or African American did not appear to impact treatment adherence. However, African American patients tended to have poorer response to standard treatment and worse outcome than Caucasian patients. PMID- 21692060 TI - Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia chromosome negative myeloproliferative neoplasms: the Mister Hyde face of a safe drug. AB - BACKGROUND: The current study was conducted to evaluate severe mucocutaneous toxicity during treatment with hydroxyurea (HU) in a large cohort of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). METHODS: Among 993 consecutive patients newly diagnosed with MPN at 4 centers in Rome between January 1980 and December 2009, 614 patients (277 men and 337 women with a median age of 64.4 years [interquartile range (IR), 54.4 years-72.7 years]) received HU. HU was administered as first-line treatment in 523 patients (85.2%) and as >= second-line treatment in 91 patients (14.8%). RESULTS: Mucocutaneous toxicity was reported in 51 patients (8.3%) after a median period from the initiation of HU treatment of 32.1 months (IR, 10.5 months-74.6 months) and a mean HU dose of 1085 mg (+/- 390 mg); 30 patients (58.8%) developed a painful ulcerative skin toxicity, mainly located in the perimalleolar area; 11 patients (21.6%) had oral aphthous ulcers; and 10 patients (19.6%) developed a nonulcerative skin toxicity with erythema and skin infiltration. After the mucocutaneous toxicity occurred, HU treatment was continued at the same dose in 5 patients (9.8%), reduced in 12 patients (23.5%), and temporarily discontinued in 7 patients (13.7%); the remaining 27 patients (52.9%) required a permanent drug discontinuation. After a median period of 4.3 months (IR, 2.4 months-9.0 months) from the onset of the skin toxicity, 39 patients (76.5%) had a complete resolution and 12 patients (23.5%) had improvement without complete resolution. CONCLUSIONS: Mucocutaneous toxicity during HU treatment is more common than expected and may present with different clinical features. Moreover, it often requires a permanent drug discontinuation and only a partial resolution is reported to occur in approximately 25% of patients. PMID- 21692061 TI - Eradication of chemotherapy-resistant CD44+ human ovarian cancer stem cells in mice by intraperitoneal administration of Clostridium perfringens enterotoxin. AB - BACKGROUND: Emerging evidence has suggested that the capability to sustain tumor formation, growth, and chemotherapy resistance in ovarian as well as other human malignancies exclusively resides in a small proportion of tumor cells termed cancer stem cells. During the characterization of CD44(+) ovarian cancer stem cells, we found a high expression of the genes encoding for claudin-4. Because this tight junction protein is the natural high-affinity receptor for Clostridium perfringens enterotoxin (CPE), we have extensively investigated the sensitivity of ovarian cancer stem cells to CPE treatment in vitro and in vivo. METHODS: Real time polymerase chain reaction and flow cytometry were used to evaluate claudin 3/-4 expression in ovarian cancer stem cells. Small interfering RNA knockdown experiments and MTS assays were used to evaluate CPE-induced cytotoxicity against ovarian cancer stem cell lines in vitro. C.B-17/SCID mice harboring ovarian cancer stem cell xenografts were used to evaluate CPE therapeutic activity in vivo. RESULTS: CD44(+) ovarian cancer stem cells expressed claudin-4 gene at significantly higher levels than matched autologous CD44(-) ovarian cancer cells, and regardless of their higher resistance to chemotherapeutic agents died within 1 hour after exposure to 1.0 MUg/mL of CPE in vitro. Conversely, small interfering RNA-mediated knockdown of claudin-3/-4 expression in CD44(+) cancer stem cells significantly protected cancer stem cells from CPE-induced cytotoxicity. Importantly, multiple intraperitoneal administrations of sublethal doses of CPE in mice harboring xenografts of chemotherapy-resistant CD44(+) ovarian cancer stem cells had a significant inhibitory effect on tumor progression leading to the cure and/or long-term survival of all treated animals (ie, 100% reduction in tumor burden in 50% of treated mice; P < .0001). CONCLUSIONS: CPE may represent an unconventional, potentially highly effective strategy to eradicate chemotherapy-resistant cancer stem cells. PMID- 21692062 TI - Nativity and papillary thyroid cancer incidence rates among Hispanic women in California. AB - BACKGROUND: Overall, the incidence of papillary thyroid cancer in Hispanic women residing in the United States (US) is similar to that of non-Hispanic white women. However, little is known as to whether rates in Hispanic women vary by nativity, which may influence exposure to important risk factors. METHODS: Nativity-specific incidence rates among Hispanic women were calculated for papillary thyroid cancer using data from the California Cancer Registry (CCR) for the period 1988-2004. For the 35% of cases for whom birthplace information was not available from the CCR, nativity was statistically imputed based on age at Social Security number issuance. Population estimates were extracted based on US Census data. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were also estimated. RESULTS: In young (age <55 years) Hispanic women, the incidence of papillary thyroid cancer among US-born women (10.65 per 100,000) was significantly greater than that for foreign-born women (6.67 per 100,000; IRR, 1.60 [95% CI, 1.44-1.77]). The opposite pattern was observed in older women. The age-specific patterns showed marked differences by nativity: among foreign-born women, rates increased slowly until age 70 years, whereas among US-born women, incidence rates peaked during the reproductive years. Incidence rates increased over the study period in all subgroups. CONCLUSION: Incidence rates of papillary thyroid cancer vary by nativity and age among Hispanic women residing in California. These patterns can provide insight for future etiologic investigations of modifiable risk factors for this increasingly common and understudied cancer. PMID- 21692064 TI - Associations of human leukocyte antigen class II genotypes with human papillomavirus 18 infection and cervical intraepithelial neoplasia risk. AB - BACKGROUND: Only a small proportion of women infected with human papillomavirus type 18 (HPV18) may progress to persistent infection and cervical neoplasia. This community-based cohort study aimed to assess associations with human leukocyte antigen (HLA) class II genotypes for natural infection of HPV18 and subsequent risk of cervical neoplasia. METHODS: Among 10,190 cytologically normal participants, 125 with HPV18 infection were identified by HPV blot kit. HPV18 viral load at study entry was examined by real-time polymerase chain reaction; persistent infection was defined as HPV18 infection at 2 consecutive examinations. RESULTS: There was a significant association between HLA-DRB1*0403 allele and high HPV18 viral load (>1000 copies in 50 ng of total DNA) at study entry (odds ratio [OR], 7.2; 95% confidence interval [CI], 2.0-25.2). After adjustment for age and viral load at study entry, haplotype HLA-DRB1*0405 DQA1*0301-DQB1*0302 was significantly associated with persistent HPV18 infection (OR, 13.3; 95% CI, 1.7-105.9). HLA-DRB1*0403 allele was also associated with a significantly increased risk of high-grade squamous intraepithelial lesion or cancer, showing a multivariate-adjusted hazard ratio (95% CI) of 18.1 (2.6 128.5). CONCLUSIONS: HLA-DRB1*0403 allele and HLA-DRB1*0405-DQA1*0301-DQB1*0302 haplotype may play important roles in determination of high viral load and persistent infection of HPV18 and subsequent cervical neoplasia risk. PMID- 21692063 TI - Comprehensive pathway-based interrogation of genetic variations in the nucleotide excision DNA repair pathway and risk of bladder cancer. AB - BACKGROUND: Growing evidence suggests that single nucleotide polymorphisms (SNPs) in nucleotide excision repair (NER) pathway genes play an important role in bladder cancer etiology. However, only a limited number of genes and variations in this pathway have been evaluated to date. METHODS: In this study, the authors applied a comprehensive pathway-based approach to assess the effects of 207 tagging and potentially functional SNPs in 26 NER genes on bladder cancer risk using a large case-control study that included 803 bladder cancer cases and 803 controls. RESULTS: In total, 17 SNPs were associated significantly with altered bladder cancer risk (P < .05), of which, 7 SNPs retained noteworthiness after they were assessed with a Bayesian approach for the probability of false discovery. The most noteworthy SNP was reference SNP 11132186 (rs11132186) in the inhibitor of growth family, member 2 (ING2) gene. Compared with the major allele containing genotypes, the odds ratio was 0.52 (95% confidence interval, 0.32 0.83; P = .005) for the homozygous variant genotype. Three additional ING2 variants also exhibited significant associations with bladder cancer risk. Significant gene-smoking interactions were observed for 3 of the top 17 SNPs. Furthermore, through an exploratory classification and regression tree (CART) analysis, potential gene-gene interactions were identified. CONCLUSIONS: In this a large association study of the NER pathway and the risk of bladder cancer, several novel predisposition variants were identified along with potential gene gene and gene-environment interactions in modulating bladder cancer risk. The results reinforce the importance of a comprehensive, pathway-focused, and tagging SNP-based candidate gene approach to identify low-penetrance cancer susceptibility loci. PMID- 21692065 TI - Pilot study of duloxetine for treatment of aromatase inhibitor-associated musculoskeletal symptoms. AB - BACKGROUND: Approximately 50% of postmenopausal women with hormone receptor positive early stage breast cancer treated with an aromatase inhibitor (AI) develop musculoskeletal symptoms. Standard analgesics are relatively ineffective. Duloxetine is a serotonin norepinephrine reuptake inhibitor with proven efficacy for treatment of multiple chronic pain states. The authors investigated the hypothesis that duloxetine is efficacious for treatment of AI-associated musculoskeletal symptoms. METHODS: The authors performed a single-arm, open-label phase 2 study of duloxetine in postmenopausal women with breast cancer who developed new or worsening pain after treatment with an AI for at least 2 weeks. Patients were treated with duloxetine for 8 weeks (30 mg for 7 days, then 60 mg daily). The primary endpoint was a 30% decrease in average pain score over 8 weeks, and secondary outcomes included change in average and worst pain, pain interference, depression, sleep quality, and hot flashes. Statistical analysis was done with t tests for paired data. RESULTS: Twenty-one of 29 evaluable patients (72.4%) achieved at least a 30% decrease in average pain, and 18 of 23 patients (78.3%) who completed protocol-directed treatment continued duloxetine. The mean percentage reduction in average pain severity between baseline and 8 weeks was 60.9% (95% confidence interval [CI], 48.6%-73.1%), and in maximum pain severity it was 59.9% (95% CI, 47.0-72.7%). The most common adverse events were grade 1 or 2 fatigue, xerostomia, nausea, and headache. CONCLUSIONS: Duloxetine appears to be effective and well tolerated for treatment of AI-associated musculoskeletal symptoms. Future randomized, placebo-controlled studies are warranted. PMID- 21692066 TI - Do radiation use disparities influence survival in patients with advanced breast cancer? AB - BACKGROUND: The authors previously identified racial/ethnic disparities in the use of radiation therapy (RT) in patients with advanced breast cancer (BC). They hypothesized that disparities in the use of RT were associated with survival differences favoring white patients. METHODS: The authors used the Surveillance, Epidemiology, and End Results database to identify white, black, Hispanic, and Asian patients with BC associated with >= 10 metastatic lymph nodes diagnosed between 1988 and 2005. Multivariate analyses of overall survival (OS) and disease specific survival (DSS) assessed age, sex, race, tumor size, histology, estrogen receptor status, progesterone receptor status, RT, and type of surgery. The authors further stratified for use of RT and type of surgery. Risk of mortality was reported as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Of 15,895 patients with advanced BC, 12,653 met entry criteria. On multivariate analysis, RT was associated with a decreased risk of all-cause (HR, 0.78; 95% CI 0.74-0.83; P < .001) and disease-specific (HR, 0.81; 95% CI, 0.76-0.86; P < .001) mortality; black race was associated with an increased risk of all-cause (HR, 1.54; 95% CI, 1.42-1.68; P < .001) and disease-specific (HR, 1.53; 95% CI, 1.39 1.68; P < .001) mortality. After stratifying by type of surgery and use of RT, blacks demonstrated poorer survival than their white counterparts, regardless of surgery type or receipt of RT. CONCLUSIONS: Only black patients had poorer OS and DSS relative to whites. When stratified by type of surgery and use of RT, blacks continued to demonstrate poorer survival. This survival disparity is unlikely to be because of lack of RT. PMID- 21692068 TI - Adjuvant chemotherapy improves survival in patients with American Joint Committee on Cancer stage II colon cancer. AB - BACKGROUND: It is unclear whether the administration of adjuvant chemotherapy improves survival in patients with American Joint Committee on Cancer (AJCC) stage II colon cancer. METHODS: The authors used the State of California Cancer Surveillance Program (CSP) to assess patients ages 18 to 80 years with AJCC stage II colon cancer (ie, T3 or T4 and N0) who underwent surgical resection during 1991 and 2006. Patients who had rectal and rectosigmoid cancers were excluded. The cohort was stratified according to the receipt of adjuvant chemotherapy, and clinical and pathologic characteristics and outcomes were assessed. RESULTS: From the CSP data, 3716 patients were identified who underwent curative-intent surgical resection for stage II colon cancer. When the 2 treatment groups (surgery plus adjuvant chemotherapy [n = 916] and surgery alone [n = 2800]) were compared, patients who received adjuvant chemotherapy were more likely to be younger and to have left-sided lesions with >= 12 lymph nodes examined. There was no difference in sex or tumor differentiation between the 2 groups. According to a Kaplan-Meier analysis, patients who received adjuvant chemotherapy had improved overall survival compared with patients who underwent surgery alone (median survival, 12 years vs 9.2 years, respectively; P < .001). In multivariate analysis, adjuvant chemotherapy was identified as an independent predictor of improved survival (hazard ratio, 0.88; 95% confidence interval, 0.78-0.99; P = .031). CONCLUSIONS: To the authors' knowledge, this is the first population-based analysis to identify a survival advantage for adjuvant chemotherapy in patients with AJCC stage II colon cancer. On the basis of the current findings, the authors concluded that the administration of adjuvant chemotherapy improves survival in select patients with stage II disease. PMID- 21692067 TI - Hospital racial composition and the treatment of localized prostate cancer. AB - BACKGROUND: Racial differences in the treatment of men with localized prostate cancer remain poorly understood. This study examines whether hospital racial composition is associated with the type of treatment black and white men receive. METHODS: The authors performed a retrospective cohort study of men in Surveillance, Epidemiology, and End Results-Medicare diagnosed with localized prostate cancer from 1995 to 2005 linked to hospital and census data. A total of 134,291 men were assigned to the hospital where they received care. Generalized estimating equations were used to determine whether hospital racial composition was associated with the receipt of definitive therapy and type of treatment. RESULTS: Black men were less likely to receive radiation and/or prostatectomy compared with white men (55.5% vs 63.7%, P < .001) and, among those who received definitive therapy, were less likely to undergo prostatectomy (27.5% vs 31.9%, P < .001). The percentage of black men who received their care at hospitals with a high proportion of black patients was 48.0%, compared with only 5.2% of white patients who received care in this subset of hospitals. Men were significantly less likely to receive definitive treatment (odds ratio, 0.81; 95% confidence interval, 0.74-0.90) in hospitals with a high proportion of black patients compared with men seen at hospitals with fewer black patients. The association between hospital racial composition and treatment did not significantly differ by patient race. CONCLUSIONS: Hospital racial composition is consistently associated with the care that men receive for localized prostate cancer. Better understanding of the factors that determine where men receive care is an important component in reducing variation in treatment. PMID- 21692069 TI - Human papillomavirus vaccine uptake among 9- to 17-year-old girls: National Health Interview Survey, 2008. AB - BACKGROUND: Since 2006, the human papillomavirus (HPV) vaccine has been routinely recommended for preadolescent and adolescent girls in the United States. Depending on uptake patterns, HPV vaccine could reduce existing disparities in cervical cancer. METHODS: HPV vaccination status and reasons for not vaccinating were assessed using data from the 2008 National Health Interview Survey. Households with a girl aged 9-17 years were included (N = 2205). Sociodemographic factors and health behaviors associated with vaccine uptake were assessed using multivariate logistic regression. RESULTS: Overall, 2.8% of 9- to 10-year-olds, 14.7% of 11- to 12-year-olds, and 25.4% of 13- to 17-year-olds received at least 1 dose of HPV vaccine; 5.5% of 11- to 12-year-olds and 10.7% of 13- to 17-year olds received all 3 doses. Factors associated with higher uptake in multivariate analysis included less than high school parental education, well-child check and influenza shot in the past year, and parental familiarity with HPV vaccine. Parents' primary reasons for not vaccinating were beliefs that their daughters did not need vaccination, that their daughters were not sexually active, or had insufficient vaccine knowledge. More parents with private insurance (58.0%) than public (39.8%) or no insurance (39.5%) would pay $360-$500 to vaccinate their daughters. CONCLUSIONS: Less than one quarter of girls aged 9-17 years had initiated HPV vaccination by the end of 2008. Efforts to increase HPV uptake should focus on girls in the target age group, encourage providers to educate parents, and promote access to reduced-cost vaccines. PMID- 21692070 TI - Colorectal carcinoma cell production of transforming growth factor beta decreases expression of endothelial cell vascular endothelial growth factor receptor 2. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) signaling is a target for antiangiogenic cancer therapy. The authors have previously observed that up to 40% of vessels in colorectal carcinoma (CRC) tumors are negative for VEGF receptor 2 (VEGFR2) expression. Differential activity of transforming growth factor beta (TGF-beta) is a potential contributor to this receptor heterogeneity because TGF-beta contributes to both angiogenesis and CRC tumor progression. METHODS: The authors analyzed VEGFR2 expression by Western blotting, and TGF-beta expression in endothelial and CRC cell lines, respectively. In addition, they immunostained endothelial cells in CRC xenografts to find an association between VEGFR2 and TGF-beta levels or activity. RESULTS: In bovine aortic endothelial cells (BAECs), TGF-beta1 significantly repressed VEGFR2 protein in a time dependent and dose-dependent fashion (P < .05). Serum-free conditioned media from various malignant human CRC cell lines (HCT116, 379.2, Dks8, and DLD1) induced down-regulation of VEGFR2 in BAECs. This effect was proportional to the total levels of TGF-beta1 and TGF-beta2 and was blocked by SB-431542 and SD-208, TGF beta receptor I inhibitors. Immunofluorescence staining of subcutaneous mouse xenografts of HCT116, 379.2, Dks8, and SW480 cells revealed vessels with an inverse relationship between TGF-beta activity and VEGFR2 expression. Oxygen and bone morphogenetic protein 9 levels were shown to modulate TGF-beta-induced VEGFR2 down-regulation. CONCLUSIONS: In combination with other factors, TGF-beta may contribute to the vascular heterogeneity in human colorectal tumors. PMID- 21692071 TI - Adjuvant therapy for elderly patients with resected gastric adenocarcinoma: population-based practices and treatment effectiveness. AB - BACKGROUND: A study was undertaken to determine the survival benefit of postoperative chemoradiation therapy for elderly patients with resected gastric adenocarcinoma. METHODS: The authors identified 1023 individuals aged 65 years and older (median = 76) who underwent gastrectomy for nonmetastatic stage IB-IV gastric adenocarcinoma diagnosed between 2000 and 2002 in the linked Surveillance, Epidemiology, and End Results-Medicare database. They examined factors associated with receiving postoperative chemoradiation and analyzed the survival benefit associated with receiving postoperative chemoradiation. RESULTS: Thirty percent of patients received adjuvant chemoradiation. On multivariate analysis, younger age (P < .0001), lymph node involvement (P < .0001), and more recent diagnosis (P = .0284) were associated with receiving chemoradiation. There was a trend toward increased use among patients with less comorbidity (P = .0515). The median follow-up was 25.5 months, and 62% died. On multivariate survival analysis, older patients (P < .0001) and those with lymph node involvement (P < .0001), T3 or T4 disease (P = .0472), higher grade disease (P = .0355), and more comorbidity (P = .0411) were more likely to die. After adjustment for other factors, receipt of adjuvant chemoradiation therapy did not significantly increase survival (hazard ratio, 0.90; 95% confidence interval, 0.72-1.12; P = .3453) and did not increase survival in a multivariate analysis that included propensity scores (P = .2090). CONCLUSIONS: The authors did not detect a survival benefit, suggesting that some elderly patients with resected gastric adenocarcinoma may not gain a survival benefit from the administration of adjuvant chemoradiation. The analysis had limitations, and the results are hypothesis generating. Future gastric cancer trials should enroll more elderly patients and stratify patients by age to better understand the impact of treatment regimens on older patients. PMID- 21692072 TI - Cytogenetic profile of patients with acute myeloid leukemia and central nervous system disease. AB - BACKGROUND: Acute myeloid leukemia (AML) infrequently involves the central nervous system (CNS). This study was undertaken in patients with AML to determine whether cytogenetic findings predict CNS involvement. METHODS: The medical records of 1354 patients with AML who were treated at The University of Texas MD Anderson Cancer Center between January 2000 and December 2008 were reviewed. Forty patients (3%) had CNS involvement at time of presentation or disease recurrence, of whom 37 had conventional cytogenetics performed on bone marrow aspirate material. Demographics, treatment, and status at last follow-up were collected. RESULTS: Eleven patients (30%) had a diploid karyotype, and 14 patients (38%) had complex cytogenetics. Only 5 of the 40 patients had CNS disease at diagnosis, and the remaining patients had CNS disease at relapse. Patients who developed CNS disease were younger (P = .019), had a higher white blood cell (WBC) count at diagnosis (P = .001), had higher lactate dehydrogenase level (LDH) levels (P < .0001), and had higher percentages peripheral blast cells (P = .024) at diagnosis compared with the rest of the population. In addition, patients with CNS disease had higher rates of chromosome 16 inversion (P < .001), chromosome 11 abnormality (P = .005), and trisomy 8 (P = .02) and had a tendency toward complex cytogenetics (P = .2) compared with the control group (patients who had AML with no CNS involvement). CONCLUSIONS: Patients with AML and CNS disease often had higher LDH levels and WBC counts at diagnosis, and they often presented with chromosome 16 inversion and chromosome 11 abnormalities. The current study indicated that the overall survival of patients with AML who had CNS involvement is poor. PMID- 21692074 TI - Survival after second primary lung cancer: a population-based study of 187 Hodgkin lymphoma patients. AB - BACKGROUND: Lung cancer accounts for the largest absolute risk of second malignancies among Hodgkin lymphoma (HL) survivors. However, no population-based studies have compared overall survival (OS) between HL survivors who developed nonsmall cell lung cancer (HL-NSCLC) versus patients with first primary NSCLC (NSCLC-1). METHODS: The authors compared the OS of 178,431 patients who had NSCLC 1 and 187 patients who had HL-NSCLC (among 22,648 HL survivors), accounting for sex, race, sociodemographic status, calendar year, and age at NSCLC diagnosis, and NSCLC histology and stage. All patients were reported to the population-based Surveillance, Epidemiology, and End Results Program. Hazard ratios (HRs) were derived from a Cox proportional hazards model. RESULTS: Although the NSCLC stage distribution was similar in both groups (20% localized, 30% regional, and 50% distant), HL survivors experienced significantly inferior stage-specific OS. For patients with localized, regional, and distant stage NSCLC, the HRs (95% confidence interval [CI]) for death among HL survivors were 1.60 (95% CI, 1.08 2.37; P < .0001), 1.67 (95% CI, 1.26-2.22; P = .0004), and 1.31 (95% CI, 1.06 1.61; P = .013), respectively. Among HL-NSCLC patients, significant associations were observed between more advanced NSCLC stage and the following variables: younger age at HL diagnosis (P = .003), younger age at NSCLC diagnosis (P = .048), and longer latency between HL and NSCLC diagnoses (P = .015). CONCLUSIONS: Compared with patients who had de novo NSCLC, HL survivors experienced a significant 30% to 60% decrease in OS after an NSCLC diagnosis. Further research is needed to not only elucidate the clinical-biologic underpinnings of NSCLC after HL, including the influence of previous HL treatment, but also to define the role of lung cancer screening in selected patients. PMID- 21692073 TI - Advances and controversies in the diagnosis, pathogenesis, and treatment of systemic mastocytosis. AB - The term systemic mastocytosis (SM) encompasses a group of hematopoietic malignancies characterized by excessive proliferation of neoplastic mast cells that accumulate in the bone marrow and visceral organs. Most patients with SM, particularly those who present with aggressive clinical courses, carry somatic mutations of the v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) gene. KIT mutations are considered central events in the pathogenesis of SM and serve as diagnostic markers and putative therapeutic targets. The heterogeneity in the clinical course of patients with SM and recent advances in the genetic and immunophenotypic characterization of neoplastic mast cells may help to improve current diagnostic, taxonomic, and therapeutic approaches in SM. PMID- 21692075 TI - Robotic facelift thyroidectomy: I. Preclinical simulation and morphometric assessment. AB - OBJECTIVES: Robotic thyroidectomy was introduced in the United States despite scant preclinical data. We pursued a systematic preclinical investigation of a new remote access, robotic thyroidectomy technique via a facelift incision, and sought to define differences in extent of dissection associated with this approach and a second, popular robotic thyroidectomy technique. DESIGN: Surgical simulation and morphometric analysis in fresh human cadavers. METHODS: Eleven specimens were obtained to complete four experiments designed to address two specific aims: to develop a reproducible surgical protocol for robotic removal of the thyroid through a facelift incision, and to quantify the extent of dissection required with two robotic thyroidectomy techniques. RESULTS: The feasibility of the facelift approach was determined using an endoscopic technique, and two lobectomies were accomplished. Inanimate study of the optimal robotic positioning to facilitate resection was then completed. Three additional cadavers were used to develop a reproducible surgical protocol and define a stepwise algorithm of dissection. Seven specimens were used to simulate 28 robotic thyroidectomy dissection pockets. The mean area of dissection required for robotic facelift thyroidectomy was 39.2 +/- 6.6 cm(2) compared with 63.5 +/- 9.6 cm(2) for robotic axillary thyroidectomy, representing a difference of 38.3% (P < .0001). CONCLUSIONS: We have described and refined a reproducible surgical protocol for accomplishing a new robotic facelift thyroidectomy, and then quantified the reduced dissection required when comparing it with a transaxillary technique. Cautious clinical implementation to explore safety and feasibility appears to be justified. PMID- 21692076 TI - Simplified technique of tracheoesophageal prosthesis placement at the time of secondary tracheoesophageal puncture (TEP). AB - OBJECTIVES: Secondary tracheoesophageal (TE) puncture standardly involves placement of a catheter at time of TE fistula creation. We explore the feasibility of placement of the prosthesis at the time of TE puncture (TEP) obviating the need for a subsequent procedure to place the prosthesis. We describe the technique and evaluate the success and potential advantages. STUDY DESIGN: Retrospective chart review of consecutive patients who underwent TE prosthesis placement at the time of secondary TEP from 3/2009 to 1/2011. METHODS: Fourteen patients underwent the primary TE prosthesis placement at the time of secondary puncture and were evaluated. Assessed outcomes included patient demographics, success of prosthesis placement, need for repeat procedure, early or late prosthesis dislodgement, complications, and specific voice outcomes. RESULTS: Patient cohort included nine males, five females, with average age of 64 years. All TE prosthesis placements were successful. The 12-mm 20 F Blom-Singer Indwelling prosthesis was used in all cases. No complications occurred during prosthesis placement. Two perioperative complications occurred: one case of transient pulmonary edema from general anesthesia, one case of posterior tracheal wall swelling. The second was addressed with placement of a larger prosthesis. All patients successfully achieved good voice at an average of 4 days after the procedure (range: 1-9 days). CONCLUSIONS: This initial series of 14 consecutive patients demonstrates successful TE prosthesis placement at the time of secondary TE puncture. Functional voice was achieved in all patients with no significant immediate complications. No dislodgements occurred and no repeat procedures were required. Voice acquisition was achieved at an earlier time (4 days on average) than with traditional techniques and without the necessity of a subsequent procedure. Primary prosthesis placement at the time of secondary TE puncture is a successful option for surgical voice restoration with distinct advantages and minimal complications. PMID- 21692079 TI - Design and synthesis of new fluorescent probe for rapid and highly sensitive detection of proteins via electrophoretic gel stain. AB - A new fluorescent molecular probe, 2,2'-(1E,1'E)-2,2'-(4-(dicyanomethylene)-4H pyrane-2,6-diyl)bis(ethene-2,1-diyl)bis(sodium benzenesulfonate) salt (1), possessing the cyanopyranyl moieties and two benzene sulfonic acid groups was designed and synthesized to detect proteins in solution and for high-throughput SDS-PAGE. Compound 1 exhibited no fluorescence in the absence of proteins; however, it exhibited strong fluorescence on the addition of bovine serum albumin as a result of intramolecular charge transfer. Compared with the conventional protocols for in-gel protein staining, such as SYPRO Ruby and silver staining, 1 achieves higher sensitivity, even though it offers a simplified, higher throughput protocol. In fact, the total time required for protein staining was 60 90 min under optimum conditions much shorter than that required by the less sensitive silver staining or SYPRO Ruby staining protocols. Moreover, 1 was successfully applied to protein identification by mass spectrometry via in-gel tryptic digestion, Western blotting, and native PAGE together with protein staining by 1, which is a modified protocol of blue native PAGE (BN-PAGE). Thus, 1 may facilitate high-sensitivity protein detection, and it may be widely applicable as a convenient tool in various scientific and medical fields. PMID- 21692080 TI - Glycoproteomic analysis and molecular modeling of haptoglobin multimers. AB - Extra-thiol groups on the alpha-subunit allow haptoglobin (Hp) to form a variety of native multimers which influence the biophysical and biological properties of Hp. In this work, we demonstrated how differences of multimeric conformation alter the glycosylation of Hp. The isoform distributions of different multimers were examined by an alternative approach, i.e. 3-D-(Native/IEF/SDS)-PAGE, which revealed differences in N-glycosylation among individual multimers of the same Hp sample. Glycomic mapping of permethylated N-glycan indicated that the assembled monomer and multimeric conformation modulate the degree of glycosylation, especially the reduction in terminal sialic acid residues on the bi-antennary glycan. Loss of the terminal sialic acid in the higher order multimers increases the number of terminal galactose residues, which may contribute to conformation of Hp. A molecular model of the glycosylated Hp multimer was constructed, suggesting that the effect of steric hindrance on multimeric formation is critical for the enlargement of the glycan moieties on either side of the monomer. In addition, N241 of Hp was partially glycosylated, even though this site is unaffected by steric consideration. Thus, the present study provides evidence for the alteration of glycan structures on different multimeric conformations of Hp, improving our knowledge of conformation-dependent function of this glycoprotein. PMID- 21692081 TI - Global genetic analysis of all single nucleotide polymorphisms in exons of the human deoxyribonuclease I-like 3 gene and their effect on its catalytic activity. AB - Deoxyribonucleases (DNases) have been suggested to be implicated in the pathophysiology of autoimmune diseases. In the DNASE1L3 gene encoding human DNase I-like 3 (DNase 1L3), a member of the DNase I family, only two non-synonymous (R178 H and R206C) single nucleotide polymorphisms (SNPs) have been examined [Ueki et al., Clin. Chim. Acta 2009, 407, 20-24]. Three other non-synonymous (G82R, K96N, and I243M) and four synonymous (S17S, T84T, R92R, and A181A) SNPs, in addition to R206C and R178H, have been identified in DNASE1L3. We investigated the distribution of all these SNPs in exons of the gene in eight Asian, three African, and three Caucasian populations worldwide using newly devised genotyping methods. SNP T84T showed polymorphism in all the populations, and R92R was polymorphic in the three African and three Caucasian populations; R206C was distributed only in Caucasian populations. In contrast, no minor allele was found in five SNPs (S17S, G82R, K96N, A181A, and I243M) in DNASE1L3. Generally, the DNase 1L3 gene shows relatively low genetic diversity with regard to exonic SNPs. When the effect of amino acid/nucleotide substitutions resulting from the SNPs on DNase 1L3 activity was examined, none of the synonymous SNPs had any effect on the DNase 1L3 activity, whereas among non-synonymous SNPs, SNP G82R diminished the activity of the enzyme, being similar to R206C. These findings permit us to assume that, although only R206 exhibits polymorphisms in a Caucasian-specific manner, at least SNPs G82R and R206C in DNASE1L3 might be potential risk factors for autoimmune disease. PMID- 21692082 TI - CE-electrochemiluminescence with ionic liquid for the facile separation and determination of diester-diterpenoid aconitum alkaloids in traditional Chinese herbal medicine. AB - A CE-electrochemiluminescence(CE-ECL) detection system, CE/tris(2,2'-bipyridyl) ruthenium(II)ECL with ionic liquid, was established for the determination of diester-diterpenoid aconitum alkaloids (aconitine (AC), mesaconitine (MA) and hypaconitine (HA)) in traditional Chinese herbal medicine. Running buffer containing 25 mM borax-20 mM 1-ethyl-3-methylimidazolium tetrafluoroborate at pH 9.15 was used, which resulted in significant changes in separation and obvious enhancement in ECL intensity for AC, MA and HA with similar structures. End column detection was achieved in 50 mM phosphate buffer with 5 mM Ru(bpy)32+ (pH 9.15) at applied detection voltage of 1.20 V when the distance between the Pt working electrode and outlet of capillary (50 cm * 25 MUm id) was set at 150 MUm. One single quantitative analysis of three alkaloids was achieved at a separation voltage of 15 kV within 10 min. Moreover, two extraction processes (ethanol extraction and ethyl ether extraction after basification) were investigated. The result showed that ethanol extraction process has higher extraction efficiency than ethyl ether extraction process. Under the optimized conditions, the detection limits of AC, MA and HA were 5.62 * 10(-8) , 2.78 * 10(-8) and 3.50 * 10(-9) mol/L (S/N=3), respectively. The method was successfully applied to determine the amounts of AC, MA and HA in the aconitum herbal samples. PMID- 21692083 TI - First-trimester ultrasonographic diagnosis of Langer mesomelic dysplasia in a previously affected family. PMID- 21692084 TI - Trends in the utilization of invasive prenatal diagnosis in The Netherlands during 2000-2009. AB - OBJECTIVE: To analyze trends in the number and type of invasive procedure, reasons for referral, maternal age and chromosomal abnormalities over a 10-year period and correlate the trends to changes in the national prenatal screening policy. METHODS: Data from 10 706 invasive prenatal procedures yielding a full karyotype, performed between 2000 and 2009 were extracted from the cytogenetic database in the central region of The Netherlands. Trends were analyzed. RESULTS: Over a 10-year period, the number of invasive procedures halved and the percentage of chromosomal abnormalities detected, increased from 5.5 to 9.4%. After 2007, however, 5.7% of karyotypes in women over 36 years were found to be abnormal, versus 18.1% in women below 36 years. In 2009, 71.5% of women over 36 are still referred for invasive prenatal diagnosis on the indication advanced maternal age. CONCLUSIONS: Changes in prenatal screening policy significantly increased referral after screening and improved the efficacy of invasive prenatal diagnosis. We show the continuing effect of the different policies applied in the past to women below and above the age of 36. To further improve efficacy of invasive prenatal diagnosis, first trimester combination screening should be actively offered to women of all ages. PMID- 21692085 TI - Adrenal gland length in euploid and trisomy 18 fetuses at 11-13 weeks. AB - OBJECTIVES: To establish a normal range for fetal adrenal gland length at 11-13 weeks' gestation and to investigate whether the length is altered in fetal trisomy 18. METHODS: Fetal adrenal gland length was measured by three-dimensional ultrasound in fetuses at low risk of aneuploidies (n = 400) and another group at high risk, including 380 euploid fetuses and 41 with trisomy 18. The data of the low-risk group were used to establish a reference range of adrenal gland length with crown-rump length (CRL). In the high-risk group, adrenal gland length in the euploid and trisomy 18 groups was compared. RESULTS: In the low-risk group, fetal adrenal gland size increased exponentially with fetal CRL from a median of 2.3 mm at CRL of 45 mm to about 4.4 cm at CRL of 84 mm. In trisomy 18, the median adrenal gland length for CRL was significantly lower than the median in the low risk group (-1.37 mm; interquartile range: - 1.67 to - 0.99 mm, p < 0.0001). In euploid fetuses, the adrenal gland size was not significantly from the low-risk group (p = 0.100). CONCLUSION: Trisomy 18 is associated with adrenal gland hypoplasia which is apparent at 11-13 weeks' gestation. PMID- 21692086 TI - The development of a rapid assay for prenatal testing of common aneuploidies and microdeletion syndromes. AB - OBJECTIVE: To develop a novel, rapid prenatal assay for pregnancies with high likelihood of normal karyotypes, using BACs-on-Beads(TM) technology, a suspension array-based multiplex assay that employs Luminex((r)) xMAP((r)) technology, for the detection of gains and losses in chromosomal DNA. METHODS: Fifteen relatively common microdeletions were selected that are not detectable, or may be missed, by karyotyping and usually do not present with abnormal ultrasound findings. Chromosomes 13, 18, 21, X, and Y were included. We validated the assay with 430 samples. RESULTS: All microdeletions and aneuploidies were correctly identified, except for a 69,XXX incorrectly identified as a normal female and a male with ~20% maternal cell contamination (MCC) that could not be distinguished from 69,XXY. MCC became apparent at 20 to 30%. Mosaicism was identified at 30 to 35% abnormal cells. CONCLUSION: We have developed an alternative to fluorescence in situ hybridization (FISH) aneuploidy screening and microarray analysis in otherwise normal pregnancies undergoing invasive testing. We demonstrated that the assay will detect all microdeletions and aneuploidies of regions covered on the assay. We developed analytical software that displays results for well characterized syndromes but not abnormalities of unclear clinical significance. This assay is likely to be preferred by women seeking testing beyond routine karyotyping but who desire more information than provided by aneuploidy FISH. PMID- 21692087 TI - Molecular basis and prenatal diagnosis of beta-thalassemia among Balouch population in Iran. AB - OBJECTIVE: To determine the molecular spectrum of beta-thalassemia mutations among at-risk Balouch couples in Iran. METHODS: Mutations' detection in DNAs extracted from the blood of partners of at-risk couples was characterized, and chorion villus sampling by amplification refractory mutation system and DNA sequencing was performed. Fetal diagnosis was also confirmed by linkage analysis. RESULTS: Out of a total of 1234 at-risk Balouch couples referred to the center for prenatal diagnosis (PND) from June 2002 to June 2010, a high percentage of '67.4%' were from consanguineous marriages and 37.4% had between one and four affected children. The trend in referring gradually increased from 34 cases in 2002 to 357 cases in 2010. The astonishing finding was that, unlike most previous studies, only IVS 1-5 with an unusual frequency of 87.20% along with codon 8/9 (+G) with 4% constitutes about 91% of mutations. Altogether, 729 PNDs were made in 583 couples, 25% of whom had over one PND, and surprisingly five PNDs were made in the same woman within just 8 years. CONCLUSION: Regarding the limited types of frequent mutations among Balouch population, it is hopefully believed that the incidence of beta-thalassemia could be controlled by a correct diagnosis in the due time. PMID- 21692088 TI - Heavy metals in human amniotic fluid: a pilot study. AB - OBJECTIVE: Many heavy metals are essential nutrients for a healthy life. However, significant evidence supports prolonged prenatal exposure as a risk factor for several adverse health effects. The aim of this study is to evaluate the presence of heavy metals in human amniotic fluid (AF) to demonstrate that there is an early fetal in utero exposure. METHODS: The concentrations of a variety of heavy metals, including Be, Ag, Ba, Pb, U, Hg, Sr, Cu, Mn, V, Pd, Sn, Sb, Te, Pt, Sc, Tl, Ni, As, Co, Zn and Se, were measured in 25 AF samples obtained from amniocentesis between 15 and 18 weeks of gestational, after informed consent. RESULTS: Be, Ag, Ba, Pb, U, Cu, Sr, Mn, V, Sn, Te, Pt, As, Tl, Sb, Co, Se and Zn concentrations were detected in measurable amounts in second trimester AF. Mg levels are elevated in all samples. Pd, Ni, Sc and Hg concentrations are below the detection limits in all samples. CONCLUSION: This study demonstrates that heavy metals pass into and accumulate in AF from a very early stage of gestation. Other studies are needed to evaluate the long-term health effects of this early exposure. PMID- 21692089 TI - Performance adjusted risks: a method to improve the quality of algorithm performance while allowing all to play. AB - OBJECTIVE: Differences in quality among ultrasound nuchal translucency providers or laboratories can profoundly affect Down syndrome screening results. A new method, performance adjusted risks (PAR), is developed to allow for such differences and improve performance. METHODS: Individual provider and laboratory marker distribution parameters are compared with national expectations. The maximum absolute deviation over the operating range is used to derive a handicap and weighting factors. Down syndrome risks obtained from commercial software for individual women can be corrected using the weights. Those with the biggest handicap will have the greatest correction. Five theoretical examples are used to illustrate handicap calculation and prospective combined test results on 32 Down syndrome and 7205 unaffected pregnancies are used to indicate the influence of weighting on performance. RESULTS: In the theoretical examples, a 10% systematic change (inaccuracy) in one or more markers or a similar change in the standard deviation (imprecision) yielded a handicap ranging from 4 to 11. Over the operating range, the individual risk reduced 40% or increased 250%. When the prospective combined test results were artificially adjusted to create 10% inaccurracy in all three markers, the detection rate was only 59% but after PAR weighting this increased to 75%. CONCLUSIONS: PAR recognizes that not all providers are equal, and perfection is unrealistic. Using this approach all 'can play' while patients are protected from poor performance. PMID- 21692090 TI - Overcoming number numbness in prenatal risk communication. AB - OBJECTIVE: Efficient prenatal risk communication hinges upon parents' grasp of statistical information. When forming their subjective representation of a probability, pregnant women may focus on inappropriate factors and ignore the appropriate factors. METHOD: The present research investigates the subjective probability that pregnant women derive from statements of the form 'There is a 1 in X chance that the baby will have condition Y,' where the number X and the severity of the condition Y were orthogonally manipulated. RESULTS: Study 1 showed that when judging how big is a 1 in X chance that a child will be affected by condition Y, pregnant women (n = 336) were sensitive to the severity of Y, but selectively numb to the objective number X. Study 2 (n = 461) replicated this pattern, but also showed that numerical numbness could be overcome by a simple intervention, namely, a quick comment that 1 in X was 'above average.' CONCLUSION: Practitioners must be aware that when forming a subjective probability assessment, pregnant women might be inappropriately sensitive to the severity of Y, and inappropriately numb to the number X, and that a simple communicative intervention can help in overcoming this selective number numbness. PMID- 21692091 TI - Erroneous production of PAPP-A kits: the impact of a downward shift in PAPP-A concentration on the test performance of first-trimester combined screening for Down syndrome. AB - OBJECTIVE: To evaluate a 20% downward shift in the pregnancy-associated plasma protein A (PAPP-A) concentration on the test performance of first-trimester combined screening (FTS) for Down syndrome (DS) following a flaw in the production of PAPP-A kits on FTS for DS. METHODS: A retrospective re-evaluation of PAPP-A in stored sera. Inclusion criteria were a maternal weight-corrected PAPP-A multiple of the median value >= 0.9 and a biochemical risk of DS <= 1:200 at the time of testing. RESULTS: Of the 3100 women, 473 (15%) fulfilled the inclusion criteria. After combining the biochemical risk based on the incorrect PAPP-A values with nuchal translucency findings, an increased risk for DS was initially found in 107 women [false positive rate (FPR): 3.1]. Eighty-two (77%) of the 107 women opted for invasive testing. Following re-analysis of PAPP-A, the biochemical risk and the combined risk were statistically significantly different from the initial risk estimates (p < 0.001.). We noticed that 25 women (30%) had invasive testing, while this was unjustified given the re-analysed PAPP-A. CONCLUSION: Erroneous PAPP-A kits resulted in an increase in the FPR by 1.2%. There were no reports of iatrogenic miscarriage. The occurrence of this problem reaffirms the importance of continuous monitoring of quality in FTS. PMID- 21692092 TI - First trimester Down syndrome screening with dried blood spots using a dual analyte free beta hCG and PAPP-A immunofluorometric assay. AB - OBJECTIVE: To determine the effectiveness of first trimester Down syndrome screening with dried blood spots using a dual analyte free beta human chorionic gonadotrophin (hCG)/pregnancy-associated plasma protein A (PAPP-A) immunofluorometric assay. METHOD: An initial retrospective study of 54 Down syndrome cases and 1064 control specimens was performed followed by a series of 146,513 specimens from routine screening. Detection rates at a fixed 5% false positive rate were determined separately based on reference data from the retrospective study set and then adjusted based on the routine screening study set. RESULTS: On the basis of the retrospective analysis, the estimated detection rate using free beta hCG, PAPP-A and maternal age varied from 78% at 9 weeks of pregnancy to 70% at 13 weeks of pregnancy. Using a combined protocol, including NT, the detection rate varied from 92 to 90% between 9 and 13 weeks of gestation. Adjusting distribution parameters based on the routine screening dataset reduced the detection rate by at most 1%. CONCLUSION: Analysis of free beta hCG and PAPP A using a dual analyte dried blood spot assay is an effective tool in Down syndrome screening, adding an important option for those considering implementation or modification of existing prenatal screening programs. PMID- 21692093 TI - First-trimester screening and its impact on uptake of diagnostic testing. AB - OBJECTIVE: To determine the influence of first-trimester screening (FTS) on a patient's decision regarding prenatal diagnostic testing (PDT) and if the uptake rate of PDT has changed among women with advanced maternal age (AMA) following the January 2007 American College of Obstetricians and Gynecologists statement regarding FTS. METHODS: A database review was performed for the 2 years before and the 2 years after the January statement. A total of 7424 patient records were evaluated to determine the number of AMA women who obtained PDT, the number of positive and negative FTS results, and how many of those women had PDT. We then surveyed 53 patients and 23 referring physicians to determine what the patient understands about FTS, how patients utilize their FTS results, and how physicians educate their patients about FTS. RESULTS: We determined that there was a 19.6% decrease in the uptake of PDT since that statement. Prior to their counseling session (2009-2010), 43% of those surveyed were against having PDT. After counseling, only 9% were against PDT. Overall, 91% were either open to or wanted PDT after counseling. CONCLUSIONS: In addition to FTS results, we found that genetic counseling may be an influential factor in the patient's decision regarding PDT. PMID- 21692094 TI - Vocational training courses as an intervention on change of work practice among immigrant cleaners. AB - BACKGROUND: The aim of the study was to examine how knowledge and skills from vocational training courses on working techniques modified for immigrant cleaners are applied in practice and to identify factors that influence the implementation. The modifications of the standard course included language support with possibilities for translation and an extension of the duration of the course. METHODS: The study is a prospective intervention study based on qualitative data. Data were collected as structured interviews and observations were carried out at the workplaces before and after the course. The study population included 31 immigrant cleaners from five different workplaces. RESULTS: Changes were observed in the use of working techniques (i.e., positioning of hands when using the floor mop). In some cases the use of the taught techniques was incorrect, partial, or only used part of the time. Interactions between individual factors (i.e., knowledge, awareness, capability, or work orientation) and environmental factors (i.e., equipment, time, workload, or physical surroundings) influenced the use of the techniques in practice. CONCLUSIONS: The course provided the participants with new working techniques through which some were able to reduce work related pain. However, with regard to incorrect and partial use of the working techniques, follow-up and post-training support is recommended. PMID- 21692095 TI - An analysis of the respiratory health status among seafarers in the Russian trawler and merchant fleets. AB - OBJECTIVES: Trawler fishermen and merchant seafarers have tough working conditions. While workers in both occupations are exposed to a challenging environment, trawler fishermen are also engaged in onboard fish processing, which is considered to be additional exposure. The aim of the present study was to characterize respiratory health status in both groups of seamen. METHODS: In total 127 trawler fishermen and 118 merchant seafarers were enrolled during their regular medical health examinations. The study protocol comprised a standardized questionnaire, lung function test and measurements of fractional nitric oxide concentrations (FE(NO) ) in exhaled air. RESULTS: Doctor-diagnosed asthma was reported only by trawler fishermen (3.9%, P < 0.05, Pearson Chi-square test). Adjusted odds ratios (OR) of respiratory symptoms were more often elevated in trawler fishermen compared to merchant seafarers. Trawler fishermen had reduced spirometric parameters: FEV(1) % of predicted values (adjusted beta: -5.28, 95%CI: -9.28 to -1.27), FVC % of predicted values (adjusted beta: -5.21, 95%CI: 9.25 to -1.17). Increased OR of the work-related cough with phlegm (OR: 6.6, 95% CI: 1.8-21.9), running nose (OR: 3.0, 95%CI: 1.2-7.7), and frequent sneezing (OR: 3.4, 95%CI: 1.0-12.7) were found among those trawler workers whose work tasks included filleting of fish. FE(NO) levels were not significantly different between trawler and merchant seamen. CONCLUSIONS: The present study indicated that trawler fishermen exhibited impaired lung function and were more likely to have asthma. The environment of the onboard factories where fishermen fillet fish is suggested as a risk factor for work-related respiratory symptoms. PMID- 21692096 TI - Hypothyroidism among former workers of a nuclear weapons facility. AB - BACKGROUND: Ionizing radiation alters thyroid function, and workers at a nuclear weapons facility may be exposed to above environmental levels of radiation. METHODS: Hypothyroid status was determined for 622 former workers of a nuclear weapons facility located in Texas, using a combination of measured thyroid stimulating hormone (TSH) levels and thyroid medication history, as part of an on going health surveillance program. We classified 916 unique job titles into 35 job categories. RESULTS: According to the most stringent TSH definition used in this study (0.3-3.0 IU/ml), 174 (28.0%) former workers were considered to be hypothyroid; of these 66 (41.8%) were females and 108 (23.3%) were males. In logistic regression analysis adjusted for age, gender, and smoking status, only having worked as a material handler (n = 18) exhibited an elevated risk of developing hypothyroidism compared to other jobs (OR 3.88, 95% CI 1.43-11.07). This is one of the jobs with suspected exposure to radiation. No excess risk of hypothyroidism was observed for any of the other job categories. CONCLUSIONS: There is suggestive evidence that only material handlers at this nuclear weapons facility may have elevated risk of hypothyroidism; further evaluation of thyroid health in this population is warranted. PMID- 21692097 TI - Injuries to hired crop workers in the United States: a descriptive analysis of a national probability survey. AB - BACKGROUND: Little empirical data are available examining the injury experience of hired crop workers in the United States (US). This study analyzed work-related injury data collected on these workers from a national survey. METHODS: Data were collected through the National Agricultural Workers Survey (NAWS) for the federal fiscal years 1999, 2002, 2003, and 2004. These data provided descriptive injury characteristics and rate estimates from a sample of 13,604 crop farm workers. RESULTS: The injury rate was 4.3 injuries per 100 week-based full-time equivalents (FTE(WB) ). The majority of the injuries occurred to male (84%) and Mexican born (72%) workers. Shuttle migrants had the highest injury rate at 7.2 injuries/100 FTE(WB) . Workers reporting one or more health conditions and workers reporting one or more musculoskeletal complaints had higher injury. The most common injury events were overexertion from lifting (20%), being struck by hand held objects (13%), and falls to a lower level (10%). Injuries due to falls to a lower level accounted for the highest average number of restricted workdays (45 days). CONCLUSIONS: The use of hand tools, falls, and lifting overexertion injuries were identified as significant causes of injury among hired crop workers. Increased injury risk was also seen for crop workers with existing health or musculoskeletal complaints. These results are useful for targeting injury prevention efforts and future research needs for this unique worker population. Am. J. Ind. Med. 54:734-747, 2011. (c) 2011 Wiley-Liss, Inc. PMID- 21692098 TI - Exploring the interplay between work stress and socioeconomic position in relation to common health complaints: the role of interaction. AB - BACKGROUND: This study explored the interplay between work stress and socioeconomic position and investigated if the interaction of work stress and low socioeconomic position is associated with poorer health. METHODS: A representative sample of the Swedish working population, including 2,613 employees (48.7% women) aged 19-64 years, was analyzed. The health outcomes were poor self-rated health, psychological distress, and musculoskeletal pain. Work stress was operationalized as job strain and effort-reward imbalance, and socioeconomic position as occupational class. Interaction analysis was based on departure from additivity as criterion, and a synergy index (SI) was applied, using odds ratios (ORs) from logistic regressions for women and men. RESULTS/CONCLUSIONS: In fully adjusted models, work stress, and in a lesser extent also socioeconomic position, was associated with higher odds for the three health complaints. The prevalence of poorer health was highest among those individuals jointly exposed to high work stress and low occupational class, with ORs ranging from 1.94 to 6.77 (95%CI 1.01-18.65) for poor self-rated health, 2.42 8.44 (95%CI 1.28-27.06) for psychological distress and 1.93-3.93 (95%CI 1.11 6.78) for musculoskeletal pain. The joint influence of work stress and low socioeconomic position on health was additive rather than multiplicative. PMID- 21692099 TI - Clinical course of patients with aplastic anemia or myelodysplastic syndrome associated with persistent neutropenia. AB - Patients with aplastic anemia (AA) or myelodysplastic syndrome (MDS) often have persistent severe neutropenia and are susceptible to infectious complications. We retrospectively reviewed the clinical course of patients with AA or MDS who had neutropenia (neutrophil count < 500/ul) for more than 25 days. A total of 46 patients, 11 with AA and 35 with MDS, were included. Twenty-three patients had infectious events (IE), and the cumulative incidence of IE was 30% at 6 months and 51% at 1 year. The cumulative incidence of IE was 67% at 1 year in 30 patients who experienced very severe neutropenia of less than 200/ul. Overall survival in all patients was 76% at 6 months and 65% at 1 year. In a multivariate analysis, male sex, underlying diseases, and a neutrophil count of less than 200/ul as a time-dependent covariate significantly affected IE. In analyses that excluded patients with AA, male sex was the only factor. In conclusion, severe neutropenia was significantly associated with IE in patients with AA or MDS, and IE might be lethal. When we only considered patients with MDS, the neutrophil count alone could not be used to predict the prognosis. PMID- 21692100 TI - Clinical significance and prognosis of MYC translocation in diffuse large B-cell lymphoma. AB - Recent studies have suggested that chromosomal aberrations of the MYC gene locus indicate an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL). However, there have been few reports on MYC translocation in Chinese patients. One hundred and six cases of DLBCLs were analyzed using interphase fluorescent in situ hybridization. Immunophenotyping analysis (CD20, CD3, CD10, Bcl-6, Mum-1) was also performed. MYC translocation was identified in 13 (12.3%) out of 106 cases. All MYC(+) DLBCLs showed a non-germinal center B-cell type. MYC(+) DLBCLs showed significantly poorer overall survival (OS) and progression-free survival, with a median OS and progression-free survival time of 4.7 and 3.2 months, respectively (p < 0.001). Multivariate analysis using a Cox proportional hazard model confirmed that MYC(+) (for OS, Hazards ratio 5.254; 95% CI, 2.354-11.723, p < 0.001) was the strongest independent predictor. DLBCL with MYC translocation is a subgroup of non-germinal center B-cell DLBCL with poor outcome. This may be a clinical characteristic that is specific to Chinese patients. Because only a few patients received rituximab, its usefulness could not be assessed. Future studies with larger numbers of patients are required. PMID- 21692101 TI - The effect of zinc sulfate in the prevention of high-dose chemotherapy-induced mucositis: a double-blind, randomized, placebo-controlled study. AB - The purpose of this study was to evaluate the effect of oral zinc sulfate in the prevention of chemotherapy-induced mucositis in patients undergoing hematopoietic stem-cell transplantation (HSCT). This study was a double-blind, randomized, placebo-controlled design, with 60 patients undergoing HSCT, divided proportionally in experimental group who received zinc sulfate, and in placebo group. They all had received high-dose chemotherapy conditioning regimen for allogenic transplantation. Oral mucositis assessed was based on World Health Organization (WHO) oral mucositis scale. There were no significant differences in the development of mucositis between the two groups. Severity of mucositis was not significantly different between the two groups either. The same result was obtained regarding the duration of mucositis. Zinc sulfate did not show any significant adverse effects in experimental group. In conclusion, Zinc sulfate did not have any clinical benefits in prevention or reduction of severity, and duration of high-dose chemotherapy-induced mucositis in patients undergoing HSCT. PMID- 21692102 TI - Sorption of acetochlor, S-metolachlor, and atrazine in surface and subsurface soil horizons of Argentina. AB - Understanding herbicide sorption within soil profiles is the first step to predicting their behavior and leaching potential. Laboratory studies were conducted to determine the influence of surface and subsurface soil properties on acetochlor, atrazine, and S-metolachlor sorption. Soil samples were taken from horizons A, B, and C of two loamy soils of the humid pampas of Argentina under no till management; horizon A was divided into two layers, A(0) (0-5 cm) and A(1) (5 cm to the full thickness of an A horizon). Sorption isotherms were determined from each sampled horizon using the batch equilibrium method and seven concentrations (0, 0.1, 0.5, 2.0, 5.0, 10.0, and 20.0 mg L(-1)). Sorption affinity of herbicides was approximated by the Freundlich equation. The sorption strength K(f) (mg(1 - 1/n) kg(-1) L(1/n) ) over the soils and horizons studied followed the order S-metolachlor (16.51-29.19) > atrazine (4.85-12.34) >= acetochlor (5.17-11.97), which was closely related to the hydrophobicity of herbicides expressed as octanol-water partition coefficient (K(OW) ). The K(f) values of the three herbicides were positively correlated with soil organic carbon, with a significance of p < 0.01. Values of K(f) for the three herbicides decreased with depth in the two soils, indicating greater sorption onto surficial soil horizons and possibly a delayed transport toward subsurface soils and subsequent pollution of groundwater. PMID- 21692104 TI - Movement disorders 2011--the state of the journal. PMID- 21692103 TI - Comparative toxicology of mercurials in Caenorhabditis elegans. AB - Mercury (Hg) is a toxic metal that can exist in multiple chemical species. Humans are commonly exposed to methylmercury and Hg vapor, which are converted to mercuric species in the body. Despite years of research, little information exists on the similarities and differences in the mechanisms of Hg toxicity. The relative toxicity of mercuric chloride (HgCl(2)) and methylmercury chloride (MeHgCl) in Caenorhabditis elegans was determined in assays that measured growth, feeding, reproduction, and locomotion. The effect of HgCl(2) and MeHgCl on the expression of several archetypal stress-response genes was also determined. There was no significant difference between the EC50s of the two mercurials in terms of C. elegans growth. However, MeHgCl was more toxic to C. elegans than HgCl(2) when assessing feeding, movement, and reproduction, all of which require proper neuromuscular activity. Methylmercury chloride exposure resulted in increased steady-state levels of the stress response genes at lower concentrations than HgCl(2). In general, MeHgCl was more toxic to C. elegans than HgCl(2), particularly when assaying behaviors that require neuromuscular function. PMID- 21692105 TI - Pathology of vessels supplying the brain in patients with Parkinson's disease. PMID- 21692106 TI - Guest editors' introduction. PMID- 21692107 TI - Pre-operative evaluations for DBS in dystonia. AB - BACKGROUND: The preoperative evaluation in dystonia aims at characterizing the severity and topography of motor symptoms in patients, who have previously been selected for deep brain stimulation (DBS). METHODS: The literature search was performed using PubMed, CINAHL, and the Cochrane Collaborative databases. RESULTS: Commonly used scales for clinical assessment are the Burke-Fahn-Marsden dystonia rating scale for generalized dystonia and the Toronto Western Spasmodic Torticollis Scale for cervical dystonia. Motor assessment is completed by quality of life and functional scales, such as the Short-Form Health Survey (SF-36) or the Parkinson's Disease Questionnaire 39. Validated rating scales for cranial or upper limb dystonia are lacking. DISCUSSION: In common clinical practice, these outcome measures can be administered in an open-label fashion because double blind assessment is only required for ascertaining new treatment indications or research purposes. The same measures are to be used postoperatively to revaluate outcome after DBS. Brain MRI is required to confirm diagnosis and assess structural abnormalities. Other imaging techniques, particularly functional imaging, are used for research purposes. PMID- 21692108 TI - Stereotactic techniques and perioperative management of DBS in dystonia. AB - This article reviews the available literature related to the surgical technique for implantation of deep brain stimulation (DBS) hardware for the treatment of dystonia. Topics covered include stereotactic targeting, selection of specific hardware components, site of placement of the cable connectors and pulse generators, and postoperative documentation of electrode location. Techniques in stereotactic neurosurgery are rapidly evolving, and there is no Class I evidence to unequivocally validate any specific technique described. Nevertheless, the guidelines provided may assist surgical teams in tailoring a rational approach to DBS implantation in dystonia. PMID- 21692109 TI - Deep brain stimulation for dystonia. PMID- 21692110 TI - Intraoperative neurophysiology in DBS for dystonia. AB - Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) has been demonstrated to be an effective therapy for the treatment of primary dystonia as well as tardive dystonia. Results for other forms of secondary dystonia have been less consistent. Although a number of target sites have been explored for the treatment of dystonia, most notably the motor thalamus, the target of choice remains the sensorimotor portion of the GPi. Although the optimal site within the GPi has not been determined, most centers agree that the optimal site involves the posteroventral lateral "sensorimotor" portion of the GPi. Microelectrode recording (MER) can be used to identify boundaries of the GPi and nearby white matter tracts, including the corticospinal tract and optic tract, and the sensorimotor GPi. However, whether or not the use of MER leads to improved outcomes compared with procedures performed without MER has not been determined. Currently, there is no evidence to support or refute the hypothesis that mapping structures with MER provides better short- or long-term outcomes. Centers using MER do not report a preference of one system over another, but there have not been any studies to compare the relative benefits or risks of using more than 1 electrode simultaneously. Comparison studies of different target structures and targeting techniques in dystonia have not been performed. Additional research, which includes comparative studies, is needed to advance our understanding and optimization of DBS targets, techniques, and approaches along with their relative benefits and risks in dystonia. PMID- 21692111 TI - Early postoperative management of DBS in dystonia: programming, response to stimulation, adverse events, medication changes, evaluations, and troubleshooting. AB - Early postoperative management in deep brain stimulation-treated patients with dystonia differs from that of patients with essential tremor and Parkinson's disease, mainly due to the usually delayed effects of deep brain stimulation and the heterogenous clinical manifestation and etiologies of dystonia. The present chapter summarizes the available data about and concentrates on practical clinical aspects of early postoperative management in deep brain stimulation treated patients with dystonia. PMID- 21692112 TI - Inclusion and exclusion criteria for DBS in dystonia. AB - When considering a patient with dystonia for deep brain stimulation (DBS) surgery several factors need to be considered. Level B evidence has shown that all motor features and associated pain in primary generalized and segmental dystonia are potentially responsive to globus pallidus internus (GPi) DBS. However, improvements in clinical series of >= 90% may reflect methods that need improvement, and larger prospective studies are needed to address these factors. Nevertheless, to date the selection criteria for DBS-specifically in terms of patient features (severity and nature of symptoms, age, time of evolution, or any other demographic or disease aspects)--have not been assessed in a systematic fashion. In general, dystonia patients are not considered for DBS unless medical therapies have been previously and extensively tested. The vast majority of reported patients have had DBS surgery when the disease was provoking important disability, with loss of independence and impaired quality of life. There does not appear to be an upper age limit or a minimum age limit, although there are no published data regarding the outcome of GPi DBS for dystonia in children younger than 7 years of age. There is currently no enough evidence to prove that subjects with primary--generalized dystonia who undergo DBS at an early age and sooner rather than later after disease onset may gain more benefit from DBS than those undergoing DBS after the development of fixed skeletal deformities. There is no enough evidence to refuse or support consideration of DBS in patients with previous ablative procedures. PMID- 21692113 TI - Long-Term management of DBS in dystonia: response to stimulation, adverse events, battery changes, and special considerations. AB - Multiple independent case series have documented sustained benefit of bilateral pallidal deep brain stimulation (DBS) up to 3 years in patients with primary dystonia. Growing evidence exists for positive outcomes extending up to 10 years. The beneficial effects from DBS are usually reported to be stable, thus requiring little long-term modifications of the parameters of stimulation. Speech and swallowing abnormalities are less responsive than other dystonic symptoms. Symptom exacerbation after initial benefit has been reported in a few cases. It is not known whether this is related to potential tolerance or habituation to stimulation or to progression of the underlying disease. Failures of pallidal DBS, at least in primary dystonia patients, should not be accepted without further re-evaluation of each individual case, including possible revisions of the electrode location. Both hardware- and stimulation-related adverse effects, including insufficient relief of speech function, have been reported in the long term. Despite early reports suggesting that hardware problems might be more frequent in dystonia, more recent studies did not confirm these observations. In patients with severe segmental (e.g., axial) or generalized dystonia, sudden cessation of stimulation may become a medical emergency and should be anticipated changing the neurostimulator before its natural end of life. PMID- 21692114 TI - Neuropsychological, neuropsychiatric, and quality of life issues in DBS for dystonia. AB - We review the impact of dystonia and its surgical treatment with deep brain stimulation (DBS) on cognitive function, psychiatric morbidity, and health related quality of life. The current evidence suggests that globus pallidus internus (GPi) DBS does not cause cognitive decline in primary dystonia. However, we recommend general preoperative screening of cognition in patients with dystonia to evaluate baseline cognitive status and monitor for possible postoperative changes. Patients with mild to moderate depression appear to do well postoperatively; however, there are scant data about those with severe depression. This is particularly problematic given reports of postoperative suicide. Patients with tardive dystonia seem to do well post-GPi DBS despite often having a history of depression or even having active severe depression. We make recommendations for screening and basic management strategies of patients identified as having a major psychiatric illness pre- or postoperatively. Quality of life in dystonia patients quantified by generic measures such as the SF36 showed improvement in both mental and physical categories following DBS surgery. PMID- 21692115 TI - Correlation of frataxin content in blood and skeletal muscle endorses frataxin as a biomarker in Friedreich ataxia. AB - BACKGROUND: Friedreich ataxia is an autosomal recessive disorder caused by mutations in the frataxin gene, leading to reduced levels of the mitochondrial protein frataxin. Assays to quantitatively measure frataxin in peripheral blood have been established. To determine the validity of frataxin as a biomarker for clinical trials, we assessed frataxin in clinically affected tissue. METHODS: In 7 patients with Friedreich ataxia, frataxin content was measured in blood and skeletal muscle before and after treatment with recombinant human erythropoietin, applying the electrochemiluminescence immunoassay. RESULTS: We found frataxin content to be correlated in peripheral blood mononuclear cells and skeletal muscle in drug-naive patients with Friedreich ataxia. The correlation of frataxin content in both compartments remained significant after 8 weeks of treatment. Skeletal-muscle frataxin values correlated with ataxia using the Scale for the Assessment and Rating of Ataxia score. CONCLUSIONS: Our results endorse frataxin measurements in peripheral blood cells as a valid biomarker in Friedreich ataxia. PMID- 21692117 TI - Rapid identification of cyclic tetrapyrrolic photosensitisers for photodynamic therapy using on-line hyphenated LC-PDA-MS coupled with photo-cytotoxicity assay. AB - INTRODUCTION: Photodynamic therapy is a treatment modality that involves site directed generation of cytotoxic reactive oxygen species by light-activated photosensitisers. OBJECTIVE: In order to rapidly identify new photosensitisers from natural extracts, we developed a liquid chromatography-photodiode array-mass spectrometry (LC-PDA-MS) method to rapidly identify plant extracts that contain photosensitisers, particularly those possessing a cyclic tetrapyrrole structure. METHOD: Six previously isolated compounds (1-6) were identified in bioactive fractions derived from 15 plant extracts on the basis of their chromatographic retention times, UV-visible profiles, accurate mass and fragmentation patterns. RESULTS: Samples containing uncommon photosensitisers were rapidly identified using this method, and subsequent scale-up isolation efforts led to two new compounds (7 and 8) which were confirmed to be active photosensitisers in a photo cytotoxicity assay. CONCLUSION: This method serves as a useful tool in prioritising samples that may contain new photosensitisers out of a larger group of photo-cytotoxic natural products extracts. PMID- 21692116 TI - MRI in breast cancer therapy monitoring. AB - Breast MRI has several roles in the clinical management of breast cancer, including as a screening method for high-risk women, as a diagnostic tool used as an adjunct to mammography and ultrasound, and for the staging of disease extent prior to treatment. In addition to these uses, MRI is also employed to track small changes in tumor size and microenvironment. MRI has produced several early indicators of treatment response in clinical trials over the last 10 years, including initial lesion pattern, changes in lesion size, kinetic parameters, apparent diffusion coefficient and T(2) value; the related technique of (1) H MRS has also shown that choline concentration, T(2) value and water-to-fat ratio are response indicators. In addition to measuring anatomical changes in the lesion size, as performed in traditional radiology, MRI has the ability to track vascular and cellular changes using dynamic contrast-enhanced MRI and diffusion weighted MRI, respectively. By adding (1) H MRS to MRI examinations, metabolic changes can also be determined. These functional imaging techniques allow studies to focus on early time points relative to neoadjuvant treatment. Early treatment response predictors may allow therapy to be tailored to individual patients and thus aid in the realization of the goal of personalized medicine. PMID- 21692118 TI - Investigations into the phenolic constituents of dog's mercury (Mercurialis perennis L.) by LC-MS/MS and GC-MS analyses. AB - INTRODUCTION: Dog's mercury (Mercurialis perennis L.) is a traditional European medicinal plant considered as a rich source of bioactive natural products. Yet phytochemical data of the plant are scant. OBJECTIVE: This study aimed to identify the hydrophilic phenolic constituents from M. perennis by aqueous and hydroalcoholic extraction. METHODOLOGY: Extracts of herbal parts were investigated in-depth by HPLC(DAD)-MS/MS and GC/MS analyses. In addition, a novel compound was isolated and fully characterised by 1- and 2D-NMR experiments. RESULTS: Several conjugates of caffeic, p-coumaric and ferulic acids together with glucaric or 2-hydroxyglutaric acids (depsides) were detected in the aqueous extracts from aerial plant parts by use of LC-MS/MS techniques as well UV spectral data. By implementation of preparative chromatography on polyamide pretreated with formic acid followed by vacuum liquid chromatography on reversed phase C(18) -silica, one of the predominant depsides was isolated as a pure compound. The NMR spectra ((1) H and (13) C NMR) together with 2D-hetereonuclear multiple bond correlation NMR experiments (gHMBC and gHSQC) and chiral GC investigation, allowed identification of this compound as (-)-(E)-caffeoyl-2-(R) oxoglutarate. This structure was additionally supported by GC/MS data after silylation and methylation reactions. The hydroalcoholic extract from aerial parts was separated by solvent partition between ethyl acetate and n-butanol. The latter fraction (n-butanol) yielded a mixture of mono- and oligo-glycosides of kaempferol and quercetin, all of them being assigned by LC-MS/MS. CONCLUSIONS: The present investigation constitutes the first comprehensive report on the hydrophilic constituents of the rarely studied plant Mercurialis and thus completes the phytochemical knowledge on M. perennis. PMID- 21692119 TI - Characterisation of the degradation of salvianolic acid B using an on-line spectroscopic analysis system and multivariate curve resolution. AB - INTRODUCTION: Chinese herbal medicines contain complex ingredients that are unstable during the manufacturing process. Current off-line methods are usually time-consuming and inaccurate. OBJECTIVE: The aim of this study was to develop a continuous-flow-based on-line spectroscopic system for monitoring the degradation of unstable compounds in Chinese herbal medicines. METHODOLOGY: An on-line spectroscopic analysis system in the evaluation of the degradation of unstable compounds was implemented, using salvianolic acid B from Danshen (Radix Salviae Miltiorrhizae) as a model compound. Resolution of the mixture spectra obtained during the reaction was performed with multivariate curve resolution (MCR), and the pure spectra and kinetic profiles of reactant species were reconstructed. RESULTS: The degradation process of salvianolic acid B is probably a consecutive two-step reaction of the form A -> B -> C, where A is salvianolic acid B, and B and C are the intermediate and final products, respectively. The intermediate and final products were suggested to be a mixture of lithospermic acid and danshensu [3-(3, 4-dihydroxyphenyl) lactic acid], and a mixture of danshensu and salvianolic acid A, respectively. CONCLUSION: The findings suggested that the combined use of on-line spectroscopic analysis and MCR might be a cheap, readily available, sensitive tool to monitor the transformation of unstable components of Chinese herbal medicines. PMID- 21692120 TI - Lipid composition influences the release of Alzheimer's amyloid beta-peptide from membranes. AB - The behavior of the amyloid beta-peptide (Abeta) within a membrane environment is integral to its toxicity and the progression of Alzheimer's disease. Ganglioside GM1 has been shown to enhance the aggregation of Abeta, but the underlying mechanism is unknown. Using atomistic molecular dynamics simulations, we explored the interactions between the 40-residue alloform of Abeta (Abeta(40) ) and several model membranes, including pure palmitoyloleoylphosphatidylcholine (POPC) and palmitoyloleoylphosphatidylserine (POPS), an equimolar mixture of POPC and palmitoyloleoylphosphatidylethanolamine (POPE), and lipid rafts, both with and without GM1, to understand the behavior of Abeta(40) in various membrane microenvironments. Abeta(40) remained inserted in POPC, POPS, POPC/POPE, and raft membranes, but in several instances exited the raft containing GM1. Abeta(40) interacted with GM1 largely through hydrogen bonding, producing configurations containing beta-strands with C-termini that, in some cases, exited the membrane and became exposed to solvent. These observations provide insight into the release of Abeta from the membrane, a previously uncharacterized process of the Abeta aggregation pathway. PMID- 21692121 TI - Impact of structure and functionality of core polyol in highly functional biobased epoxy resins. AB - Highly functional biobased epoxy resins were prepared using dipentaerythritol (DPE), tripentaerythritol (TPE), and sucrose as core polyols that were substituted with epoxidized soybean oil fatty acids, and the impact of structure and functionality of the core polyol on the properties of the macromolecular resins and their epoxy-anhydride thermosets was explored. The chemical structures, functional groups, molecular weights, and compositions of epoxies were characterized using nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, gel permeation chromatography (GPC), and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI MS). The epoxies were also studied for their bulk viscosity, intrinsic viscosity, and density. Crosslinked with dodecenyl succinic anhydride (DDSA), epoxy-anhydride thermosets were evaluated using differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), tensile tests, and tests of coating properties. Epoxidized soybean oil (ESO) was used as a control. Overall, the sucrose-based thermosets exhibited the highest moduli, having the most rigid and ductile performance while maintaining the highest biobased content. DPE/TPE-based thermosets showed modestly better thermosetting performance than the control ESO thermoset. PMID- 21692122 TI - Synthesis of poly(anilineboronic acid) nanofibers for electrochemical detection of glucose. AB - Poly(anilineboronic acid) (PABA) nanofibers with U-shaped and ring-shaped morphologies have been synthesized successfully by chemical polymerization of 3 aminophenylboronic acid (APBA) in the presence of cetyltrimethylammonium bromide (CTAB) and NaF. The morphologies and sizes of PABA nanofibers can be controlled by adjusting the synthetic parameters, such as the concentrations of CTAB and APBA. The U-shaped PABA nanofibers exhibit excellent electrochemical redox activity and high sensitive detection of D-glucose in phosphate-buffered saline stock solution (pH 7.4) because of their high effective surface area as well as the high density of boronic acid groups. PMID- 21692123 TI - Patterned hydrophilization of nanoporous 1,2-PB by thiol-ene photochemistry. AB - We present an efficient method for functionalizing the large polymer-air interface of a gyroid nanoporous polymer. The hydrophilicity of nanoporous cross linked 1,2-polybutadiene is tuned by thiol-ene photo-grafting of mercaptosuccinic acid or sodium 2-mercaptoethanesulfonate. The reaction is monitored by FT-IR, UV Vis, contact angle, and gravimetry. Overall quantum yields are calculated for the two thiol-ene "click" reactions in nano-confinement, neatly revealing their chain like nature. Top-down photolithographic patterning is demonstrated, realizing hydrophilic nanoporous "corridors" exclusively hosting water. The presented approach can be relevant for many applications where, e.g., high control and contrast in hydrophilicity, chemical functionality or refractive index are needed. PMID- 21692124 TI - Thermoreversibly crosslinked poly(epsilon-caprolactone) as recyclable shape memory polymer network. AB - A new concept to build shape memory polymers (SMP) combining outstanding fixity and recovery ratios (both above 99% after only one training cycle) typical of chemically crosslinked SMPs with reprocessability restricted to physically crosslinked SMPs is demonstrated by covalently bonding, through thermoreversible Diels-Alder (DA) adducts, star-shaped poly(epsilon-caprolactones) (PCL) end functionalized by furan and maleimide moieties. A PCL network is easily prepared by melt-blending complementary end-functional star polymers in retro DA regime, then by curing at lower temperature to favour the DA cycloaddition. Such covalent network can be reprocessed when heated again at the retro DA temperature. The resulting SMP shows still excellent shape memory properties attesting for its good recyclability. PMID- 21692128 TI - Egg jelly proteins stimulate directed motility in Xenopus laevis sperm. AB - Previously we have shown that extracts from Xenopus egg jelly (egg water) increase the passage of sperm through a porous membrane in a dose-dependent manner. Although this assay has shown that sperm accumulation occurs only in the presence of an egg water gradient, it has not revealed the dynamic features of how Xenopus sperm swim in such gradients. Here, we use video microscopic observations to trace sperm trajectories in a Zigmond chamber. Our results show that Xenopus sperm swim in linear and gently curving paths and only infrequently perform turns. In the presence of an egg water gradient, however, the percent of sperm swimming up the gradient axis and the net distance traveled by each sperm along this axis was increased significantly. There was no change in curvilinear velocity. Rather, the orientation of sperm travel was shifted to more closely match that of the gradient axis. In addition, using a porous filter assay, we demonstrate that the egg water protein allurin, in both purified and recombinant forms, stimulates directed motility of sperm. Finally, we use Oregon Green 488 conjugated allurin to show that this protein binds primarily to the sperm midpiece; binding of allurin to the entire head was observed in a minor subpopulation of sperm. Dose dependence of allurin binding occurred over the 0-1 ug/ml range and correlated well with previously published dose-dependent sperm attraction data. Binding was rapid with a half-time of about 10 sec. These data suggest that egg water proteins bind to sperm and modify sperm-orienting behavior. PMID- 21692129 TI - Multivariable analysis of risk factors for enlargement of the tracheoesophageal puncture after total laryngectomy. AB - BACKGROUND: Enlarged tracheoesophageal puncture (TEP) is a challenging complication of surgical prosthetic voice restoration. Prevention of this complication requires identification of high-risk individuals, and surgical and prosthetic correlates of TEP enlargement. METHODS: Multivariable logistic regression methods were used to analyze preoperative, perioperative, and postoperative risk factors for enlarged TEP in a 5-year retrospective cohort. RESULTS: Enlarged TEP only occurred in irradiated patients. Adjusting for length of follow-up and timing of TEP, advanced (N2 or N3) nodal disease (odds ratio [OR](adjusted) , 4.3; 95% confidence interval [CI], 1.0-19.1), postoperative stricture (OR(adjusted) , 3.2; 95% CI, 1.2-8.6), and diagnosis of locoregional recurrence or distant metastasis after laryngectomy (OR(adjusted) , 6.2; 95% CI, 2.3-16.4) increased risk of enlarged TEP. Extended resection and preoperative nutritional status were also significantly associated with enlarged TEP. Prosthetic parameters did not significantly correlate with enlargement. CONCLUSION: Development of enlarged TEP is a multifactorial process related to both baseline and postoperative factors. PMID- 21692130 TI - Oncologic outcomes in advanced laryngeal squamous cell carcinomas treated with different modalities in a single institution: a retrospective analysis of 65 cases. AB - BACKGROUND: Treatment for laryngeal squamous cell carcinoma (SCC) has been predominantly surgical for decades, but in the last 20 years nonsurgical modalities (radiotherapy), with the aim of organ preservation, also became predominant among advanced stages. Retrospectively evaluating our series of stage III and stage IV laryngeal SCCs, we compared the 2 main therapeutic modalities. METHODS: Medical records of 65 consecutive patients with advanced laryngeal SCC, from November 2005 to January 2009, were reviewed. RESULTS: Among irradiated patients 2-year organ preservation was 86% for cT2, 43% for cT3, and 17% for cT4a (p = .037, Wilcoxon test). With respect to survival, the only significant differences between surgery and radiotherapy were detected among cT4a SCCs (p = .03, Wilcoxon test), in favor of surgery. CONCLUSIONS: The present results confirm the surgical recommendation for cT4a laryngeal SCCs. On the other hand, for T < 4, our results confirm that radiochemotherapy warrants a survival similar to that of total laryngectomy, thus allowing us to preserve the larynx in a relevant number of cases. PMID- 21692131 TI - Merkel cell carcinoma of the head and neck. AB - Merkel cell carcinomas are uncommon, but aggressive, cutaneous malignancies of neuroendocrine differentiation. To the pathologist, these lesions appear as sheets of undifferentiated tumor cells with little cytoplasm and dense nuclear chromatin. They are members of the group of "small round blue cell tumors," which includes small cell carcinomas of the lung, lymphomas, and neuroblastomas. Analogous to other skin malignancies, Merkel cell carcinomas frequently arise in the head and neck region and are commonly found in the elderly population. Merkel cell carcinomas have a high propensity for regional and distant metastases, and recurrences are frequently seen. Surgical excision is the recommended first-line treatment followed by adjuvant radiation therapy. Because of the high incidence of occult regional metastasis, patients with clinical and radioghaphically negative necks should undergo elective dissection, irradiation, or preferably sentinel lymph node biopsy. PMID- 21692132 TI - Head and neck paragangliomas: Report of 175 patients (1989-2010). AB - BACKGROUND: Attention of the otorhinolaryngologist needs to be drawn to the versatile aspects of head and neck paragangliomas (PGLs). METHODS: This study is a retrospective, nonrandomized clinical study of all 175 individuals with PGLs treated in our department between 1989 and 2010. A genetic analysis was performed on 86 patients. RESULTS: The 175 patients presented 224 head and neck PGLs as well as 2 thyroid papillary carcinomas. Genetic analysis resulted in 1 patient positive for a von Hippel-Lindau (VHL) gene mutation and 34 for succinate dehydrogenase (SDH) gene mutations (22 SDHD, 7 SDHC, and 5 SDHB), 12 of the latter carrying a novel mutation. Thirty-three patients (18.9%) had multiple PGLs and 11 patients (6.3%) had a malignant paraganglioma. SDH-mutation carriers had multiple tumors in 64.7% and malignant paragangliomas in 20.6%. CONCLUSIONS: Multifocal occurrence, potential malignancy, genetic aspects, possible coincidence of thyroid carcinoma, and hormone production have to be considered in patients with head and neck PGLs. PMID- 21692133 TI - Neck ultrasonography for the evaluation of the etiology of adult unilateral vocal fold paralysis. AB - BACKGROUND: An extralaryngeal neoplasm involving the vagus nerve and recurrent laryngeal nerve must be excluded when adult unilateral vocal fold paralysis is diagnosed. METHODS: Between 2004 and 2009, 53 adult patients with unilateral vocal fold paralysis received neck ultrasonography. Patients with laryngeal/hypopharyngeal cancer or with previously known cancers of the head and neck, thyroid, esophagus or lung, or with known etiology or trauma were excluded from this study. RESULTS: We included 26 men and 27 women. Ultrasonography revealed 16 patients (30%) having subclinical tumors, including thyroid papillary carcinoma in 7 patients, vagus nerve schwannoma in 2 patients, nodular goiter in 2 patients, malignant nodes in the lower neck in 4 patients, which were metastasized from lung cancer in 3 patients, esophageal cancer in 1 patient, and cervical esophageal cancer in 1 patient. CONCLUSION: Neck ultrasonography is useful to detect subclinical neoplasia, causing unilateral vocal fold paralysis. Thyroid cancer is the most common neoplastic etiology of adult unilateral vocal fold paralysis. PMID- 21692134 TI - Relationship of protein and calorie intake to the severity of oral mucositis in patients with head and neck cancer receiving radiation therapy. AB - BACKGROUND: The purpose of this study was to evaluate the relationship of calorie and protein intake to the severity of oral mucositis in patients with head and neck cancer receiving radiation therapy. METHODS: Patients with head and neck cancer undergoing >=60 Gy of radiation were eligible. Weekly data were collected for oral mucositis grade and protein and calorie intake. Proportional odds models examined the association of oral mucositis severity with nutritional predictors. RESULTS: During a 24-month period, 40 evaluable patients met criteria for inclusion. In a multivariate backward selection model, the sole significant nutritional predictor of reduced oral mucositis severity was meeting the protein goal for the current week (p = .01; adjusted odds ratio [OR], 2.30). CONCLUSION: Patients who met protein-related goals during radiotherapy for head and neck cancer had less severe oral mucositis. Nutritional counseling during radiotherapy, with emphasis on protein goals, may reduce oral mucositis severity. PMID- 21692135 TI - Thyroglobulin measurement in fine-needle aspiration biopsy of metastatic lymph nodes after rhTSH stimulation. AB - BACKGROUND: Thyroglobulin measurement in the washout of the needle used in fine needle aspiration cytology (FNAC) has been proposed for the early detection of lymph node metastasis both in patients with or without serum thyroglobulin antibodies; however, up to now, there have been no reports that recombinant human thyrotropin (rhTSH) stimulation modifies thyroglobulin measurement in lymph node aspirates. METHODS: We described, after rhTSH stimulation, the switching from undetectable to detectable levels of thyroglobulin in fine-needle aspiration fluid from a suspected metastatic lymph node in 2 patients. RESULTS: We hypothesized that thyroglobulin levels in the lymph node increased after rhTSH stimulation. The excess thyroglobulin saturates all thyroglobulin antibody binding sites and becomes detectable, explaining why it was undetectable when TSH was suppressed. CONCLUSION: On the basis of our experience, we suggest submitting to thyroglobulin measurement in the washout of the needle used in FNAC all patients with detectable serum thyroglobulin antibody after rhTSH stimulation. PMID- 21692137 TI - Effect of scanner in longitudinal studies of brain volume changes. AB - PURPOSE: To evaluate the effects of drift in scanner hardware and inter-scanner variability on global and regional brain volume changes using longitudinal data obtained on two scanners of the exact same model. MATERIALS AND METHODS: A total of 208 subjects (70 females and 138 males, mean age = 56.5 +/- 10.1 years) were scanned twice, at an interval of approximately 2 years (mean interval = 1.9 +/- 0.15 years), using two 3.0 Tesla (T) scanners of the exact same model. The subjects were divided into four groups according to the combination of scanners used. The effects of scanner drift and inter-scanner variability on global and regional brain volume changes were evaluated using voxel-based morphometry (VBM) and structural image evaluation using normalization of atrophy (SIENA). RESULTS: The mean whole brain volume calculated using VBM increased by 17.2 +/- 29.3 mL, and the changes were significantly different between groups. The mean percentage brain volume change (PBVC) calculated using SIENA was -0.46 +/- 0.71 %, and did not differ between groups. VBM showed several regions with a significant increase or decrease in volume; however, SIENA showed that edge displacement values were negative in most regions. CONCLUSION: Even with scanners of the exact same model, scanner drift, and inter-scanner variability can cancel out actual longitudinal brain volume change. SIENA, which corrects for differences in imaging geometry using the outer skull surface for both time points, can reduce the effects of scanner drift and inter-scanner variability on longitudinal morphometric results. PMID- 21692136 TI - Oxytocin stimulates adult neurogenesis even under conditions of stress and elevated glucocorticoids. AB - Oxytocin has been linked to social behavior, including social recognition, pair bonding and parenting, but its potential role in promoting neuronal growth has not been investigated. We show here that oxytocin, but not vasopressin, stimulates both cell proliferation and adult neurogenesis in the hippocampus of rats. Oxytocin is also capable of stimulating adult neurogenesis in rats subjected to glucocorticoid administration or cold water swim stress. These findings suggest that oxytocin stimulates neuronal growth and may protect against the suppressive effects of stress hormones on hippocampal plasticity. PMID- 21692139 TI - Effect of isoflurane anesthesia and hypothermia on the hepatic kinetics of Gd-EOB DTPA: evaluation using MRI of conscious mice. AB - PURPOSE: To develop a method for body magnetic resonance imaging (MRI) of conscious mice and investigate the effect of isoflurane anesthesia and hypothermia on the hepatic kinetics of gadoxetate disodium (Gd-EOB-DTPA). MATERIALS AND METHODS: Conscious or anesthetized mice were restrained on a holder and the rectal temperature was measured serially. Serial MRI of the liver was performed after intravenous injection of Gd-EOB-DTPA with or without temperature control. Three mice were studied for each condition. RESULTS: The temperature dropped rapidly in anesthetized mice beside the MR unit. The decline was less prominent in conscious mice. The temperature decreased less in anesthetized mice and remained constant in conscious mice in the radiofrequency (RF) coil. The washout of Gd-EOB-DTPA was slower in anesthetized hypothermic mice than in conscious normothermic mice. Warmed anesthetized mice showed faster washout, and cooled conscious mice showed delayed washout. Severer hypothermia in anesthetized mice resulted in weaker initial enhancement and slower washout. CONCLUSION: By separately manipulating the presence or absence of anesthesia and hypothermia, we demonstrated that washout of Gd-EOB-DTPA was delayed under hypothermia, regardless of anesthesia. Serial body MRI of conscious mice was feasible and allowed the evaluation of kinetics of a contrast agent, while excluding the possible effects of anesthesia. PMID- 21692138 TI - Initial results on development and application of statistical atlas of femoral cartilage in osteoarthritis to determine sex differences in structure: data from the Osteoarthritis Initiative. AB - PURPOSE: To create an average atlas of knee femoral cartilage morphology, to apply the atlas for quantitative assessment of osteoarthritis (OA), and to study localized sex differences. MATERIALS AND METHODS: High-resolution 3D magnetic resonance imaging (MRI) data of the knee cartilage collected at 3 T as part of the Osteoarthritis Initiative (OAI) were used. An atlas was created based on images from 30 male Caucasian high-risk subjects with no symptomatic OA at baseline. A female cohort of age- and disease-matched Caucasian subjects was also selected from the OAI database. The Jacobian determinant was calculated from the deformation vector fields that nonlinearly registered each subject to the atlas. Statistical analysis based on the general linear model was used to test for regions of significant differences in the Jacobian values between the two cohorts. RESULTS: The average Jacobian was larger in women (1.2 +/- 0.078) than in men (1.08 +/- 0.097), showing that after global scaling to the male template, the female cartilage was thicker in most regions. Regions showing significant structural differences include the medial weight bearing region, the trochlear (femoral) side of the patellofemoral compartment, and the lateral posterior condyle. CONCLUSION: Sex-based differences in cartilage structure were localized using tensor based morphometry in a cohort of high-risk subjects. PMID- 21692140 TI - A descriptive study evaluating Health Canada's risk communications. AB - PURPOSE: Risk assessment for natural health products (NHPs) may not be evaluated similarly to therapeutic products by Health Canada in terms of notification of harms to consumers and health professionals. In this descriptive study, we evaluated risk communications (RCs) issued by Health Canada for NHPs and for therapeutic products, looking for differences in a number of variables. METHODS: Risk communications issued by Health Canada in 2006 were independently evaluated by two investigators for whether the harm was actual or potential, for the seriousness and nature of harm, the origin of report, publication type, and degree of association. Disagreements were brought before a third reviewer for adjudication. RESULTS: During the study period, Health Canada issued 42 RCs for each of NHPs and therapeutic products. Most (86%) NHP RCs were issued for potential harm from contamination and adulteration, whereas 69% of therapeutic product RCs were issued due to actual harms (p < 0.0001). Two deaths had been associated with NHP use, compared with 15 deaths associated with the use of therapeutic products (p = 0.0048). The degree of association between product and harm was higher among NHP RCs compared with that among therapeutic product RCs (p < 0.0001). All reports issued for NHPs originated from foreign sources or Health Canada, whereas 69% of therapeutic product RCs were issued by drug manufacturers. CONCLUSIONS: We identified important differences in the RCs issued for NHPs versus those for therapeutic products. Standardized formats for RCs are recommended. PMID- 21692141 TI - Auditory motion direction encoding in auditory cortex and high-level visual cortex. AB - The aim of this functional magnetic resonance imaging (fMRI) study was to identify human brain areas that are sensitive to the direction of auditory motion. Such directional sensitivity was assessed in a hypothesis-free manner by analyzing fMRI response patterns across the entire brain volume using a spherical searchlight approach. In addition, we assessed directional sensitivity in three predefined brain areas that have been associated with auditory motion perception in previous neuroimaging studies. These were the primary auditory cortex, the planum temporale and the visual motion complex (hMT/V5+). Our whole-brain analysis revealed that the direction of sound-source movement could be decoded from fMRI response patterns in the right auditory cortex and in a high-level visual area located in the right lateral occipital cortex. Our region-of-interest based analysis showed that the decoding of the direction of auditory motion was most reliable with activation patterns of the left and right planum temporale. Auditory motion direction could not be decoded from activation patterns in hMT/V5+. These findings provide further evidence for the planum temporale playing a central role in supporting auditory motion perception. In addition, our findings suggest a cross-modal transfer of directional information to high-level visual cortex in healthy humans. PMID- 21692143 TI - A common right fronto-parietal network for numerosity and duration processing: an fMRI study. AB - Numerosity and duration processing have been modeled by a functional mechanism taking the form of an accumulator working under two different operative modes. Separate investigations of their cerebral substrates have revealed partly similar patterns of activation, mainly in parietal and frontal areas. However, the precise cerebral implementation of the accumulator model within these areas has not yet been directly assessed. In this study, we asked participants to categorize the numerosity of flashed dot sequences or the duration of single dot displays, and we used functional magnetic resonance imaging (fMRI) to examine the common neural correlates of these processes. The results reveal a large right lateralized fronto-parietal network, including the intraparietal sulcus (IPS) and areas in the precentral, middle and superior frontal gyri, which is activated by both numerosity and duration processing. Complementary psychophysiological interaction (PPI) analyses show a functional connectivity between the right IPS and the frontal areas in both tasks, whereas the right IPS was functionally connected to the left IPS and the right precentral area in the numerosity categorization task only. We propose that the right IPS underlies a common magnitude processing system for both numerosity and duration, possibly corresponding to the encoding and accumulation stages of the accumulator model, whereas the frontal areas are involved in subsequent working-memory storage and decision-making processes. PMID- 21692142 TI - Brain structure anomalies in autism spectrum disorder--a meta-analysis of VBM studies using anatomic likelihood estimation. AB - Autism spectrum disorders (ASD) are pervasive developmental disorders with characteristic core symptoms such as impairments in social interaction, deviance in communication, repetitive and stereotyped behavior, and impaired motor skills. Anomalies of brain structure have repeatedly been hypothesized to play a major role in the etiopathogenesis of the disorder. Our objective was to perform unbiased meta-analysis on brain structure changes as reported in the current ASD literature. We thus conducted a comprehensive search for morphometric studies by Pubmed query and literature review. We used a revised version of the activation likelihood estimation (ALE) approach for coordinate-based meta-analysis of neuroimaging results. Probabilistic cytoarchitectonic maps were applied to compare the localization of the obtained significant effects to histological areas. Each of the significant ALE clusters was analyzed separately for age effects on gray and white matter density changes. We found six significant clusters of convergence indicating disturbances in the brain structure of ASD patients, including the lateral occipital lobe, the pericentral region, the medial temporal lobe, the basal ganglia, and proximate to the right parietal operculum. Our study provides the first quantitative summary of brain structure changes reported in literature on autism spectrum disorders. In contrast to the rather small sample sizes of the original studies, our meta-analysis encompasses data of 277 ASD patients and 303 healthy controls. This unbiased summary provided evidence for consistent structural abnormalities in spite of heterogeneous diagnostic criteria and voxel-based morphometry (VBM) methodology, but also hinted at a dependency of VBM findings on the age of the patients. PMID- 21692144 TI - Transcranial magnetic stimulation and motor plasticity in human lateral cerebellum: dual effect on saccadic adaptation. AB - The cerebellum is a key area for movement control and sensory-motor plasticity. Its medial part is considered as the exclusive cerebellar center controlling the accuracy and adaptive calibration of saccadic eye movements. However, the contribution of other zones situated in its lateral part is unknown. We addressed this question in healthy adult volunteers by using magnetic resonance imaging (MRI)-guided transcranial magnetic stimulation (TMS). The double-step target paradigm was used to adaptively lengthen or shorten saccades. TMS pulses over the right hemisphere of the cerebellum were delivered at 0, 30, or 60 ms after saccade detection in separate recording sessions. The effects on saccadic adaptation were assessed relative to a fourth session where TMS was applied to Vertex as a control site. First, TMS applied upon saccade detection before the adaptation phase reduced saccade accuracy. Second, TMS applied during the adaptation phase had a dual effect on saccadic plasticity: adaptation after effects revealed a potentiation of the adaptive lengthening and a depression of the adaptive shortening of saccades. For the first time, we demonstrate that TMS on lateral cerebellum can influence plasticity mechanisms underlying motor performance. These findings also provide the first evidence that the human cerebellar hemispheres are involved in the control of saccade accuracy and in saccadic adaptation, with possibly different neuronal populations concerned in adaptive lengthening and shortening. Overall, these results require a reappraisal of current models of cerebellar contribution to oculomotor plasticity. PMID- 21692146 TI - Neurophysiologic correlates of fMRI in human motor cortex. AB - The neurophysiological underpinnings of functional magnetic resonance imaging (fMRI) are not well understood. To understand the relationship between the fMRI blood oxygen level dependent (BOLD) signal and neurophysiology across large areas of cortex, we compared task related BOLD change during simple finger movement to brain surface electric potentials measured on a similar spatial scale using electrocorticography (ECoG). We found that spectral power increases in high frequencies (65-95 Hz), which have been related to local neuronal activity, colocalized with spatially focal BOLD peaks on primary sensorimotor areas. Independent of high frequencies, decreases in low frequency rhythms (<30 Hz), thought to reflect an aspect of cortical-subcortical interaction, colocalized with weaker BOLD signal increase. A spatial regression analysis showed that there was a direct correlation between the amplitude of the task induced BOLD change on different areas of primary sensorimotor cortex and the amplitude of the high frequency change. Low frequency change explained an additional, different part of the spatial BOLD variance. Together, these spectral power changes explained a significant 36% of the spatial variance in the BOLD signal change (R(2) = 0.36). These results suggest that BOLD signal change is largely induced by two separate neurophysiological mechanisms, one being spatially focal neuronal processing and the other spatially distributed low frequency rhythms. PMID- 21692145 TI - Understanding specific effects of prenatal alcohol exposure on brain structure in young adults. AB - Prenatal alcohol exposure (PAE) is associated with various adverse effects on human brain and behavior. Recently, neuroimaging studies have begun to identify PAE effects on specific brain structures. Investigation of such specific PAE effects is important for understanding the teratogenic mechanism of PAE on human brain, which is critical for differentiating PAE from other disorders. In this structural MRI study with young adults, PAE effects on the volumes of automatically segmented cortical and subcortical regions of interest (ROIs) were evaluated both through a group difference approach and a parametric approach. In the group difference approach (comparing among two PAE and a control groups), a disproportionate PAE effect was found in several occipital and temporal regions. This result is inconsistent with previous studies with child samples. Moreover, a gender difference in PAE effect was shown in some cortical ROIs. These findings suggest that sampling and gender may be important factors for interpreting specific PAE effects on human brain. With the parametric approach, it was demonstrated that the higher the PAE level, the smaller the entire brain, the lower the IQ. Several cortical and subcortical ROIs also exhibited a negative correlation between the PAE level and ROI volume. Furthermore, our data showed that the PAE effect on the brain could not be interpreted by the PAE effect on general physical growth until the young adult age. This study provides valuable insight into specific effects of PAE on human brain and suggests important implications for future studies in this field. PMID- 21692147 TI - Medial temporal contributions to successful face-name learning. AB - The brain mechanisms that enable us to form durable associations between different types of information are not completely understood. Although the hippocampus is widely thought to play a substantial role in forming associations, the role of surrounding cortical regions in the medial temporal lobe, including perirhinal and parahippocampal cortex, is controversial. Using anatomically constrained functional magnetic resonance imaging, we assessed medial temporal contributions to learning arbitrary associations between faces and names. By sorting learning trials based on subsequent performance in associative and item specific memory tests, we characterized brain activity associated with successful face-name associative learning. We found that right hippocampal activity was greater when corresponding face-name associations were subsequently remembered than when only a face or a name, but not both, were remembered, or when single item information or associative information was not remembered. Neither perirhinal nor parahippocampal cortex encoding activity differed across these same conditions. Furthermore, right hippocampal activity during successful face name association learning was strongly correlated with activity in cortical regions involved in multimodal integration, supporting the idea that interactions between the hippocampus and neocortex contribute to associative memory. These results specifically implicate the hippocampus in associative memory formation, in keeping with theoretical formulations in which contributions to across-domain binding differ among brain structures in the medial temporal region. PMID- 21692151 TI - Organocatalytic enantioselective acyl transfer onto racemic as well as meso alcohols, amines, and thiols. AB - Acyl transfer is at the heart of functional-group transfers utilized both in nature and in the chemical laboratory. Acylations are part of the natural assembly machinery for the generation of complex molecules and for energy transport in biological systems. The recognition of covalent acyl-enzyme intermediates led to both mechanistic studies as well as the development of biomimetic approaches. Consequently, chemists first used the tools of nature in the form of enzymes and naturally occurring alkaloids as catalysts, before eventually developing a large variety of synthetic small molecules for selective acyl transfer. In contrast to nature, chemists utilize acylation reactions as a practical way for stereoselection and functional-group protection. Indeed, the number of studies concerning acyl transfer has significantly increased over the last 15 years. This Review examines and highlights these recent developments with the focus as given in the title. PMID- 21692149 TI - Two new phospholipase D isoforms of Loxosceles laeta: cloning, heterologous expression, functional characterization, and potential biotechnological application. AB - Toxin phospholipases-D present in the venom of Loxosceles spiders is the principal responsible for local and systemic effects observed in the loxoscelism. In this study, we describe the cloning, expression, functional evaluation, and potential biotechnological application of cDNAs, which code for two new phospholipase D isoforms, LIPLD1 and LIPLD2, of the spider Loxosceles laeta. The recombinant protein rLIPLD1 had hydrolytic activity on sphingomyelin and in vitro hemolytic activity on human red blood cells, whereas rLIPLD2 was inactive. The purified recombinant proteins and the venom are recognized by polyclonal anti rLIPLD1 and rLIPLD2 sera produced in animals and conferred immunoprotection against the venom. These new isoforms reinforce the importance of the multigene family of phospholipases-D present in Loxosceles spiders. A highly immunogenic inactive isoform such as rLIPLD2 raises important expectation for its use as a potential immunogenic inducer of the immunoprotective response to the toxic action of the venom of Loxosceles laeta. PMID- 21692152 TI - Screening of a combinatorial homing peptide library for selective cellular delivery. PMID- 21692148 TI - Working memory load modulation of parieto-frontal connections: evidence from dynamic causal modeling. AB - Previous neuroimaging studies have shown that working memory load has marked effects on regional neural activation. However, the mechanism through which working memory load modulates brain connectivity is still unclear. In this study, this issue was addressed using dynamic causal modeling (DCM) based on functional magnetic resonance imaging (fMRI) data. Eighteen normal healthy subjects were scanned while they performed a working memory task with variable memory load, as parameterized by two levels of memory delay and three levels of digit load (number of digits presented in each visual stimulus). Eight regions of interest, i.e., bilateral middle frontal gyrus (MFG), anterior cingulate cortex (ACC), inferior frontal cortex (IFC), and posterior parietal cortex (PPC), were chosen for DCM analyses. Analysis of the behavioral data during the fMRI scan revealed that accuracy decreased as digit load increased. Bayesian inference on model structure indicated that a bilinear DCM in which memory delay was the driving input to bilateral PPC and in which digit load modulated several parieto-frontal connections was the optimal model. Analysis of model parameters showed that higher digit load enhanced connection from L PPC to L IFC, and lower digit load inhibited connection from R PPC to L ACC. These findings suggest that working memory load modulates brain connectivity in a parieto-frontal network, and may reflect altered neuronal processes, e.g., information processing or error monitoring, with the change in working memory load. Hum Brain Mapp, 2012. (c) 2011 Wiley Periodicals, Inc. PMID- 21692154 TI - Analysis of the broadening of X-ray photoelectron spectroscopy peaks for ionic crystals. PMID- 21692155 TI - One beta hairpin follows the other: exploring refolding pathways and kinetics of the transmembrane beta-barrel protein OmpG. PMID- 21692156 TI - Spontaneous generation of highly emissive RGB organic nanospheres. PMID- 21692157 TI - Pd-catalyzed synthesis of Ar-SCF3 compounds under mild conditions. PMID- 21692158 TI - Synthesis, electronic structure, and ethylene polymerization activity of bis(imino)pyridine cobalt alkyl cations. AB - A new spin on polymers: the title cations comprise low-spin Co(II) centers with neutral bis(imino)pyridine chelating ligands. These complexes serve as single component ethylene polymerization catalysts and offer insight into the mechanism of chain growth and catalyst deactivation, which occurs by forming inactive cationic bis(imino)pyridine cobalt complexes with a diethyl ether ligand. PMID- 21692160 TI - Ground- and excited-state vibrational coherence dynamics in Bacteriorhodopsin probed with degenerate four-wave-mixing experiments. AB - Vibrational coherence dynamics in the all-trans retinal chromophore in Bacteriorhodopsin (BR) are investigated by means of temporally and spectrally resolved degenerate four-wave-mixing experiments. The coherence dynamics depend on the excitation wavelength when BR samples are excited at different wavelengths in a spectral range between 520 nm to above 620 nm. The trends in the dynamics observed by tuning of the excitation wavelength allow an assignment of the wave packet dynamics to ground- and excited-state potential energy surfaces. Specifically, the intensity of so-called "out-of-plane" modes of polyene-chain substituents increases for excitation wavelengths near 500 nm. It is shown that this is consistent with the assignment of out-of-plane modes to excited-state coherence dynamics. Moreover, intense low-frequency coherence dynamics around 200 cm(-1) are observed for signal detection in two different spectral regions of excited-state absorption. These modulations are assigned to excited-state dynamics due to the observed dependence on the excitation wavelength. In addition, we show that generally high-frequency modes (>1010 cm(-1)) originate from wave packet motion in the electronic ground state of all-trans retinal. PMID- 21692159 TI - Generating DNA synbodies from previously discovered peptides. PMID- 21692161 TI - Double-oxygen-atom transfer in reactions of Ce(m)O(2m)(+) (m=2-6) with C2H2. AB - Cerium oxide cluster cations (Ce(m)O(n)(+), m=2-16; n=2m, 2m +/- 1 and 2m +/- 2) are prepared by laser ablation and reacted with acetylene (C(2)H(2)) in a fast flow reactor. A time-of-flight mass spectrometer is used to detect the cluster distribution before and after the reactions. Reactions of stoichiometric Ce(m)O(2m)(+) (m=2-6) with C(2)H(2) produce Ce(m)O(2m-2)(+) clusters, which indicates a "double-oxygen-atom transfer" reaction Ce(m)O(2m)(+) + C(2)H(2) -> Ce(m)O(2m-2)(+) + (CHO)(2) (ethanedial). A single-oxygen-atom transfer reaction channel is also identified as Ce(m)O(2m)(+) + C(2)H(2) -> Ce(m)O(2m-1)(+) + C(2)H(2)O (at least for m=2 and 3). Density functional theory calculations are performed to study reaction mechanisms of Ce(2)O(4)(+) + C(2)H(2), and the calculated results confirm that both the single- and double-oxygen-atom transfer channels are thermodynamically and kinetically favourable. PMID- 21692162 TI - The prominent enhancing effect of the cation-pi interaction on the halogen hydride halogen bond in M1???C6H5X???HM2. AB - We designed M(1)???C(6)H(5)X???HM(2) (M(1) =Li(+), Na(+); X=Cl, Br; M(2) =Li, Na, BeH, MgH) complexes to enhance halogen-hydride halogen bonding with a cation-pi interaction. The interaction strength has been estimated mainly in terms of the binding distance and the interaction energy. The results show that halogen hydride halogen bonding is strengthened greatly by a cation-pi interaction. The interaction energy in the triads is two to six times as much as that in the dyads. The largest interaction energy is -8.31 kcal mol(-1) for the halogen bond in the Li(+)???C(6)H(5)Br???HNa complex. The nature of the cation, the halogen donor, and the metal hydride influence the nature of the halogen bond. The enhancement effect of Li(+) on the halogen bond is larger than that of Na(+). The halogen bond in the Cl donor has a greater enhancement than that in the Br one. The metal hydride imposes its effect in the order HBeH 4f transition of Ce(3+) ions. The Ce(3+) emission intensity in Sr(6) AlP(5)O(20):Ce phosphor was higher than that in Ba(6) AlP(5)O(20):Ce and it may be useful for scintillation applications. PMID- 21692166 TI - Water-soluble mercaptoundecanoic acid (MUA)-coated CdTe quantum dots: one-step microwave synthesis, characterization and cancer cell imaging. AB - In this study, a one-step approach for aqueous synthesis of highly luminescent semiconductors, CdTe quantum dots (QDs), using long-chain thiols mercaptoundecanoic acid (MUA) as surface ligand, was developed in a microwave irradiation system. The synthetic conditions were systematically investigated. The as-prepared MUA-coated QDs were characterized by various spectroscopy techniques, transmission electron microscopy (TEM) and X-ray powder diffraction (XRD). The experimental results document that MUA-coated CdTe QDs have small diameter, good stability, high luminescence and long lifetime. Particularly, it was confirmed, using fluorescence correlation spectroscopy (FCS) that, compared with other ligand, MUA formed a thicker ligand layer on the QD surfaces, which will help their stability and conjugation with biomolecules. Furthermore, MUA coated QDs were successfully used for HeLa cell imaging. PMID- 21692168 TI - Successful extracorporeal membrane oxygenation support patients with malignancy and septic shock. PMID- 21692167 TI - A terbium-sensitized spectrofluorimetric method for determination of catecholamines in a serum sample with micelle medium. AB - A terbium-sensitized spectrofluorimetric method has been developed for determination of catecholamines such as norepinephrine (NE), epinephrine (EP) and dopamine (DA), using sodium dodecyl benzene sulphonate (SDBS). Fluorescence sensitization of terbium ions (Tb(3+) ) by complexation with catecholamines in the presence of SDBS was observed. The fluorescence intensities of the Tb(3+) catecholamine complexes were highly enhanced by introducing SDBS with an emission maximum at 545 nm after excitation at 290 nm. The conditions for the complex formation of Tb(3+) -catecholamine were investigated systematically and optimized to determine catecholamines in a serum sample. Under the optimum conditions, the fluorescence intensities of the Tb(3+) -catecholamine complexes were increased linearly with the concentration of NE, EP and DA over the ranges 2.5 * 10(-10) 1.0 * 10(-8) , 2.5 * 10(-10) -1.0 * 10(-8) and 2.5 * 10(-9) -1.0 * 10(-7) g/mL with correlation coefficients of 0.999, 0.999 and 0.9996, respectively. The limits of detection (3delta) of NE, EP and DA were found to be 4.6 * 10(-11) , 7.8 * 10(-11) and 8.38 * 10(-10) g/mL, respectively. Precision of the method was tested at the concentration level of 1.2 * 10(-7) g/mL for five replicate measurements of NE, EP and DA, giving relative standard deviations (RSDs) of 1.41%, 1.23% and 1.89%, respectively. The interaction mechanism of the Tb(3+) catecholamine complexes system was investigated and presented with ultraviolet absorption spectra. The proposed method has been applied for the quantitative determination of NE, EP and DA in a spiked serum sample and a pharmaceutical preparation sample. PMID- 21692169 TI - Indices: attractive delusions. PMID- 21692170 TI - Conducting site-specific assessments of selenium bioaccumulation in aquatic systems. AB - Selenium (Se) is a chemical of concern at many locations across North America and elsewhere, and site-specific conditions are important when evaluating its bioaccumulation and effects in aquatic ecosystems. Most regulatory criteria and guidelines are based on waterborne Se concentrations. In contrast, the draft water quality chronic criterion of the US Environmental Protection Agency (USEPA) is based on Se concentrations in whole-body fish, and current information suggests the agency will issue a new draft criterion based in part on fish egg and/or ovary Se concentrations. However, implementation guidance is not available from the agency for either of these tissue-based criteria. Therefore, we describe a phased approach for field and laboratory assessments of Se bioaccumulation in fish and aquatic-dependent birds that can be applied in different environmental settings with the goal of developing and interpreting a tissue-based Se value. We recommend here the use of decision trees, conceptual models, and data quality objectives toward defining what should be done during the assessment, plus sampling and monitoring procedures for the assessment. First, available tissue or waterborne Se concentrations should be compared to tissue residue guidelines or adopted water quality criteria and guidelines. When needed, reproductive toxicity testing and assessment of fish populations should also be conducted in the area of interest. In addition, extensive data on the effects of Se on fish and bird species have been developed, and describing the associations between fish or bird egg tissue, aqueous Se, and potential effects is important for sites where Se may be a concern. Selenium bioaccumulation and toxicity also are of concern for amphibians and oviparous reptiles, but interpretive information is very limited for those species. Recent science indicates that effects are more strongly related to tissue concentrations of Se (especially in the eggs or ovaries of oviparous vertebrates) than to waterborne concentrations. Overall, we conclude that the approach for site-specific assessment must be flexible enough to allow what is appropriate for the situation. Furthermore, risk management and remediation decisions should be based on combined biology and chemistry data, using multiple lines of evidence in the assessment. PMID- 21692171 TI - Predicting the threats of chemicals to wildlife: what are the challenges? PMID- 21692173 TI - Individual versus population effects in concentration-response modeling. PMID- 21692174 TI - Importance of characterizing nanoparticles before conducting toxicity tests. PMID- 21692175 TI - Integrated assessment modeling for climate change: why we need it. PMID- 21692176 TI - Altered egg size and selenium concentrations during and following exposure of fathead minnows (Pimephales promelas) to an industrial effluent. PMID- 21692177 TI - Is it safe to use the word "safe"? PMID- 21692178 TI - Lymphocyte phenotypic subsets in umbilical cord blood compared to peripheral blood from related mothers. PMID- 21692179 TI - Patterning nanostructured, synthetic, polymeric receptors by simultaneous projection photolithography, nanomolding, and molecular imprinting. AB - Microscope projection photolithography is combined with nanomolding and molecular imprinting for the fast microfabrication of molecularly imprinted polymer (MIP) arrays in the form of micrometric islands of nanofilaments. Dot diameters from 70 90 MUm are easily obtained using a 10* objective and a photomask carrying the desired pattern. The dots are composed of parallel nanofilaments of a high aspect ratio, 150 nm in diameter and several micrometers in length, which are obtained through a nanomolding procedure on porous alumina. The arrays are molecularly imprinted with the small molecule fluorescein or with the protein myoglobin. The fluorescein MIP arrays are able to specifically recognize their target, as demonstrated by fluorescence microscopy. A four-fold increase in binding capacity and imprinting factor (IF = 13) is obtained compared to non-nanostructured porous dots. Imprinting of the nanofilament arrays with the protein myoglobin as the template is also possible and allows for a high imprinting factor of 4.3. Such nanostructured microarrays of synthetic receptors obtained by projection photolithography have great potential in biosensor and biochip development. PMID- 21692180 TI - Wrapping graphene sheets around organic wires for making memory devices. AB - Hybrids of organic semiconductors and graphene can generate a whole new class of materials with enhanced properties. A simple solution-phase route to synthesize a hybrid material made of organic nanowires and graphene oxide (GO) sheets is demonstrated by sonicating tetracene molecules and GO together in diluted fuming nitric acid. The self-assembled tetracene-derived organic wires become encapsulated by GO sheets during the reaction to produce an interconnected, one dimensional/two-dimensional lamellar film. Memory devices fabricated using the hybrid film as the sandwiched layer between aluminum electrodes exhibit excellent electrical bistability. The charge retention properties are attributed to charge transfer and a charge-trapping/detrapping mechanism operational at the interfaces and isolated matrices of the GO-tetracene hybrid. PMID- 21692181 TI - Quantifying the nanomachinery of the nanoparticle-biomolecule interface. AB - A study is presented of the nanomechanical phenomena experienced by nanoparticle conjugated biomolecules. A thermodynamic framework is developed to describe the binding of thrombin-binding aptamer (TBA) to thrombin when the TBA is conjugated to nanorods. Binding results in nanorod aggregation (viz. directed self assembly), which is detectable by absorption spectroscopy. The analysis introduces the energy of aggregation, separating it into TBA-thrombin recognition and surface-work contributions. Consequently, it is demonstrated that self assembly is driven by the interplay of surface work and thrombin-TBA recognition. It is shown that the work at the surface is about -10 kJ mol(-1) and results from the accumulation of in-plane molecular forces of pN magnitude and with a lifetime of <1 s, which arises from TBA nanoscale rearrangements fuelled by thrombin directed nanorod aggregation. The obtained surface work can map aggregation regimes as a function of different nanoparticle surface conditions. Also, the thermodynamic treatment can be used to obtain quantitative information on surface effects impacting biomolecules on nanoparticle surfaces. PMID- 21692182 TI - Carbon-nanotube through-silicon via interconnects for three-dimensional integration. AB - Interconnection of carbon-nanotube (CNT)-filled through-silicon vias is demonstrated through an easy-to-implement process based on mechanical fastening. Direct CNT-to-CNT and CNT-to-Au contacts are realized at the microscale, and their specific contact resistances extracted from electrical measurements are approximately 1.2 * 10(-3) Omega cm(2) and 4.5 * 10(-4) Omega cm(2) , respectively. PMID- 21692183 TI - Design and synthesis of novel dual-action compounds targeting the adenosine A(2A) receptor and adenosine transporter for neuroprotection. AB - A novel compound, N6-(4-hydroxybenzyl)adenosine, isolated from Gastrodia elata and which has been shown to be a potential therapeutic agent for preventing and treating neurodegenerative disease, was found to target both the adenosine A(2A) receptor (A(2A) R) and the equilibrative nucleoside transporter 1 (ENT1). As A(2A) R and ENT1 are proximal in the synaptic crevice of striatum, where the mutant huntingtin aggregate is located, the dual-action compounds that concomitantly target these two membrane proteins may be beneficial for the therapy of Huntington's disease. To design the desired dual-action compounds, pharmacophore models of the A(2A) R agonists and the ENT1 inhibitors were constructed. Accordingly, potentially active compounds were designed and synthesized by chemical modification of adenosine, particularly at the N6 and C5' positions, if the predicted activity was within an acceptable range. Indeed, some of the designed compounds exhibit significant dual-action properties toward both A(2A) R and ENT1. Both pharmacophore models exhibit good statistical correlation between predicted and measured activities. In agreement with competitive ligand binding assay results, these compounds also prevent apoptosis in serum-deprived PC12 cells, rendering a crucial function in neuroprotection and potential utility in the treatment of neurodegenerative diseases. PMID- 21692185 TI - Application of the guanidine-acylguanidine bioisosteric approach to argininamide type NPY Y2 receptor antagonists. AB - Strongly basic groups such as guanidine moieties are crucial structural elements, but they compromise the drug-likeness of numerous biologically active compounds, including ligands of G-protein-coupled receptors (GPCRs). As part of a project focused on the search for guanidine bioisosteres, argininamide-type neuropeptide Y (NPY) Y2 receptor (Y2R) antagonists related to BIIE0246 were synthesized. Starting from ornithine derivatives, N(G) -acylated argininamides were obtained by guanidinylation with tailor-made mono-Boc-protected N-acyl-S methylisothioureas. The compounds were investigated for Y2R antagonism (calcium assays), Y2R affinity, and NPY receptor subtype selectivity (flow cytometric binding assays). Most of the N(G) -substituted (S)-argininamides showed Y2R antagonistic activities and binding affinities similar to those of the parent compound, whereas N(G)-acylated or -carbamoylated analogues with a terminal amine were superior (Y2R: K(i) and K(B) values in the low nanomolar range). This demonstrates that the basicity of the compounds, although 4-5 orders of magnitude lower than that of guanidines, is sufficient to form key interactions with acidic amino acids of the Y2R. The acylguanidines bind with high affinity and selectivity to Y2R over the Y1, Y4, and Y5 receptors. As derivatization of the amino group is tolerated, these compounds can be considered building blocks for the preparation of versatile fluorescent and radiolabeled pharmacological tools for in vitro studies of the Y2R. The results support the concept of bioisosteric guanidine-acylguanidine exchange as a broadly applicable approach to retain pharmacological activity despite decreased basicity. PMID- 21692184 TI - Antimalarial mannoxanes: hybrid antimalarial drugs with outstanding oral activity profiles and a potential dual mechanism of action. PMID- 21692186 TI - Direct oxidation of methane to hydrogen peroxide and organic oxygenates in a double dielectric plasma reactor. PMID- 21692187 TI - Conversion of ethanol into polyolefin building blocks: reaction pathways on nickel ion-loaded mesoporous silica. PMID- 21692188 TI - Expression and function of KCNQ channels in larval zebrafish. AB - Members of the K(v)7 family generate a subthreshold potassium current, termed M current, that regulates the excitability of principal central neurons. Mutations in two members of this family, K(v)7.2 (KCNQ2) and K(v)7.3 (KCNQ3) are associated with a neurological disorder known as benign familial neonatal convulsion (BFNC). Despite their importance in normal and pathological brain function, developmental expression and function of these channels remains relatively unexplored. Here, we examined the temporal expression of K(v)7 channel subunits in zebrafish larvae using a real-time quantitative PCR approach. Spatial expression in the larval zebrafish brain was assessed using whole-mount in situ hybridization. The mRNA for three members of the K(v)7 family (KCNQ2, 3 and 5) is reported in zebrafish between two and seven days post-fertilization (dpf). Using electrophysiological techniques, we show that inhibitors of K(v)7 channels (linopirdine and XE991) induce burst discharge activity in immature zebrafish between 3 and 7 dpf. This abnormal electrical activity is blocked by a K(v)7 channel opener (retigabine) and was also shown to evoke convulsive behaviors in freely swimming zebrafish. Using morpholino oligonucleotides directed against KCNQ3, we confirmed a role for KCNQ channels in generation of electrical burst discharges. These results indicate that functional K(v)7 channels are expressed in the larval zebrafish nervous system and could play a direct role in generation of seizure activity. PMID- 21692189 TI - Brain regionalization: of signaling centers and boundaries. AB - Our knowledge of the general mechanisms controlling the formation of the vertebrate central nervous system has advanced tremendously in the last decade. Here, we discuss the impact of the combined use of cell manipulation, in vivo imaging and genetics in the zebrafish on recent progress in understanding how signaling processes progressively control regionalization of the central nervous system. We highlight the unresolved issues and speculate upon the fundamental role the zebrafish will continue having in answering them. PMID- 21692190 TI - Expression of BDNF and NT-3 during the ontogeny and regeneration of the lacertidian (Gallotia galloti) visual system. AB - Retinal ganglion cell (RGC) axons regrow spontaneously after optic nerve (ON) transection in G. galloti. Because brain-derived neurotrophic factor (BDNF) is considered the major neurotrophin participating in vertebrate visual system development and promotes RGC survival, we investigated its distribution using dual-labeling immunohistochemistry for neuronal and glial markers. We examined the developing and regenerating lizard visual system at 1, 3, 6, 9, and 12 months postlesion to comparatively evaluate BDNF expression patterns. BDNF was detected from midembryonic stages (E35) in both retinal plexiform layers, and in radial glial processes in the tectum. Moreover, RGC axon staining was detected at late prenatal stages (E39), showing a transient punctate staining which progressed in a temporo-spatial pattern that was similar to myelination. Strong expression in RGC axons was maintained in adults. However, transient downregulation of BDNF staining occurred on the experimental side one month after ON transection followed by a gradual recovery with extensive punctate/swelling distribution and persistent upregulation at 12 months. Conversely, quantitative PCR analysis for 1 and 12 months regenerate lizards showed downregulation of the ratio of BDNF mRNA expression at 12 months and nonsignificant changes of NT-3 transcripts. In summary, we demonstrate that BDNF and NT-3 are abundantly expressed during lizard visual system ontogeny and regeneration suggesting their participation in the development, maintenance and plasticity of the system. PMID- 21692191 TI - Micropatterned ECM substrates reveal complementary contribution of low and high affinity ligands to neurite outgrowth. AB - Growth and guidance of developing or regenerating axons require sensing of environmental cues (EC) by the growth cone. To explore the role of a spatially defined distribution of ligands on guidance, extension, and branching, we used a microcontact-printing technique allowing to deposit ligands as discrete spots of a size smaller than a cell body. Micropatterned substrates (MS) were created with varying distance between spots and two different ligands (laminin (LN) and fibronectin (FN)). Dissociated dorsal root ganglion neurons were seeded on either monocomponent MS made from LN or FN alone, or multicomponent MS made from alternating lines of LN and FN spots. On monocomponent MS the high-affinity ligand LN not only stimulated neurite extension, but also provided guidance and branching control, associated with marked cytoskeleton remodeling. The latter was assessed by evaluating the increase in rigidity of the distal neurite segment by Atomic Force Microscopy. In contrast, FN alone acts as a low-affinity ligand which dramatically limits neurite outgrowth. Surprisingly, observation of growth cone dynamics on multicomponent MS revealed that FN constitute a transient support for neurite progression, facilitating exploration of other EC present within a certain distance. Such a mutual contribution of high and low affinity ligands to neurite outgrowth is consistent with a recent theory of force regulation of dynamic adhesion sites showing cell's sensitivity to EC properties would actually depend on the rate of change of the reacting force, the latter controlling the otherwise instantaneous chemical binding process. PMID- 21692192 TI - An axonemal PP2A B-subunit is required for PP2A localization and flagellar motility. AB - Analysis of Chlamydomonas axonemes revealed that the protein phosphatase, PP2A, is localized to the outer doublet microtubules and is implicated in regulation of dynein-driven motility. We tested the hypothesis that PP2A is localized to the axoneme by a specialized, highly conserved 55-kDa B-type subunit identified in the Chlamydomonas flagellar proteome. The B-subunit gene is defective in the motility mutant pf4. Consistent with our hypothesis, both the B- and C- subunits of PP2A fail to assemble in pf4 axonemes, while the dyneins and other axonemal structures are fully assembled in pf4 axonemes. Two pf4 intragenic revertants were recovered that restore PP2A to the axonemes and re-establish nearly wild type motility. The revertants confirmed that the slow-swimming Pf4 phenotype is a result of the defective PP2A B-subunit. These results demonstrate that the axonemal B-subunit is, in part, an anchor protein required for PP2A localization and that PP2A is required for normal ciliary motility. PMID- 21692193 TI - Sequential assembly of flagellar radial spokes. AB - The unicellular alga Chlamydomonas can assemble two 10 MUm flagella in 1 h from proteins synthesized in the cell body. Targeting and transporting these proteins to the flagella are simplified by preassembly of macromolecular complexes in the cell body. Radial spokes are flagellar complexes that are partially assembled in the cell body before entering the flagella. On the axoneme, radial spokes are "T" shaped structures with a head of five proteins and a stalk of 18 proteins that sediment together at 20S. In the cell body, radial spokes are partially assembled; about half of the radial spoke proteins (RSPs) form a 12S complex. In mutants lacking a single RSP, smaller spoke subassemblies were identified. When extracts from two such mutants were mixed in vitro the 12S complex was assembled from several smaller complexes demonstrating that portions of the stepwise assembly of radial spoke assembly can be carried out in vitro to elucidate the order of spoke assembly in the cell body. PMID- 21692194 TI - Chest radiographic presenting features and radiographic progression of pneumocystis pneumonia in South African children. AB - PURPOSE: To describe the radiographic features of PCP in South African children, including the progression of changes and the impact of HIV-infection and respiratory co-infections. METHODS: A paediatric radiologist blinded to clinical details retrospectively reported the chest radiographs of children diagnosed with PCP at a South Africa paediatric hospital between January 2003 and June 2006 inclusive. Radiographic features were correlated with clinical findings and compared using Fisher's exact test and Wilcoxon's ranks-sum test. Institutional ethics approval was obtained. RESULTS: Of 113 cases of PCP, 110 (97.3%) had presenting and 96 (84.9%) follow-up radiographs; 88 (82%) were HIV-infected; 65 (59%) had respiratory co-infection; 48 (43%) died in hospital. The commonest presenting radiographic findings were increased lung volumes (n = 86; 78%) and diffuse parenchymal opacification (n = 70; 64%); 89 (92.7%) ultimately progressed to diffuse alveolar opacification. Median time to maximum pulmonary opacification was 72 hours (inter-quartile range (IQR): 24-144 hrs). Pulmonary interstitial emphysema (PIE) developed in 33 patients (30%). There was no significant difference in the radiographic features of PCP when comparison was made between i) HIV-infected and -uninfected children, ii) those with and without respiratory co-infection and iii) fatal cases and survivors (P > 0.05 in all cases). CONCLUSION: Increased lung volumes and PIE should be recognised as features of PCP in South African children. HIV-infection and respiratory co-infections do not influence the radiographic features of PCP in our setting. PMID- 21692195 TI - Profiling highly conserved microrna expression in recombinant IgG-producing and parental Chinese hamster ovary cells. AB - MicroRNAs (miRNAs) play important roles in global gene regulation. Researchers in recombinant protein production have proposed miRNAs as biomarkers and cell engineering targets. However, miRNA expression remains understudied in Chinese Hamster Ovary cells, one of the most commonly used host cell systems for therapeutic protein production. To profile highly conserved miRNA expression, we used the miRCURYTM miRNA array for screening miRNAs in CHO cells. The selection criteria for further miRNA profiling included positive hybridization signals and experimentally validated predicted regulatory targets. On the basis of screening, we selected 16 miRNAs for quantitative RT-PCR profiling. We profiled miR expression in parental CHO DG44 and CHO K1 cell lines as well as four recombinant DG44-derived CHO lines producing a recombinant human IgG. We observed that miR 221 and miR-222 were significantly downregulated in all IgG-producing cell lines when compared with parental DG44, whereas miR-125b was significantly downregulated in one IgG-producing line. In another IgG-producing line, miR-19a was significantly upregulated. miRNA expression was also profiled in two of these lines that were amplified by stepwise increase of methotrexate. In both amplified cell lines, let-7b and miR-221 were significantly downregulated. In parental CHO K1, let-7b, miR-15b, and miR-17 were significantly downregulated when compared with DG44. The results reported here are the first steps toward profiling highly conserved miRNAs and studying the clonal difference in miRNA expression in CHO cells and may shed light on using miRNAs in cell engineering. PMID- 21692196 TI - Selectivity and delignification kinetics for oxidative short-term lime pretreatment of poplar wood, Part I: Constant-pressure. AB - Kinetic models applied to oxygen bleaching of paper pulp focus on the degradation of polymers, either lignin or carbohydrates. Traditionally, they separately model different moieties that degrade at three different rates: rapid, medium, and slow. These models were successfully applied to lignin and carbohydrate degradation of poplar wood submitted to oxidative pretreatment with lime at the following conditions: temperature 110-180 degrees C, total pressure 7.9-21.7 bar, and excess lime loading of 0.5 g Ca(OH)2 per gram dry biomass. These conditions were held constant for 1-6 h. The models properly fit experimental data and were used to determine pretreatment selectivity in two fashions: differential and integral. By assessing selectivity, the detrimental effect of pretreatment on carbohydrates at high temperatures and at low lignin content was determined. The models can be used to identify pretreatment conditions that selectively remove lignin while preserving carbohydrates. Lignin removal>=50% with glucan preservation>=90% was observed for differential glucan selectivities between ~10 and ~30 g lignin degraded per gram glucan degraded. Pretreatment conditions complying with these reference values were preferably observed at 140 degrees C, total pressure>=14.7 bars, and for pretreatment times between 2 and 6 h depending on the total pressure (the higher the pressure, the less time). They were also observed at 160 degrees C, total pressure of 14.7 and 21.7 bars, and pretreatment time of 2 h. Generally, at 110 degrees C lignin removal is insufficient and at 180 degrees C carbohydrates do not preserve well. PMID- 21692197 TI - Automated live cell imaging systems reveal dynamic cell behavior. AB - Automated time-lapsed microscopy provides unique research opportunities to visualize cells and subcellular components in experiments with time-dependent parameters. As accessibility to these systems is increasing, we review here their use in cell science with a focus on stem cell research. Although the use of time lapsed imaging to answer biological questions dates back nearly 150 years, only recently have the use of an environmentally controlled chamber and robotic stage controllers allowed for high-throughput continuous imaging over long periods at the cell and subcellular levels. Numerous automated imaging systems are now available from both companies that specialize in live cell imaging and from major microscope manufacturers. We discuss the key components of robots used for time lapsed live microscopic imaging, and the unique data that can be obtained from image analysis. We show how automated features enhance experimentation by providing examples of uniquely quantified proliferation and migration live cell imaging data. In addition to providing an efficient system that drastically reduces man-hours and consumes fewer laboratory resources, this technology greatly enhances cell science by providing a unique dataset of temporal changes in cell activity. PMID- 21692198 TI - Synthesis and performance of 3D-megaporous structures for enzyme immobilization and protein capture. AB - The preparation of megaporous bodies, with potential applications in biotechnology, was attempted by following several strategies. As a first step, naive and robust scaffolds were produced by polymerization of selected monomers in the presence of a highly soluble cross-linker agent. Ion-exchange function was incorporated by particle embedding, direct chemical synthesis, or radiation induced grafting. The total ionic capacity of such systems was 1.5 mmol H(+)/g, 1.4 mmol H(+)/g, and 17 mmol H(+)/g, respectively. These values were in agreement with the ability to bind model proteins: observed dynamic binding capacity at 50% breakthrough was ?7.2 mg bovine serum albumin/g, ?7.4 hen egg-white lysozyme (HEWL) mg/g, and ?108 HEWL mg/g. In the later case, total (static) binding capacity reached 220 mg/g. It was observed that the structure and size of the megapores remained unaffected by the grafting procedure which, however, allowed for the highest protein binding capacity. Lysozyme supported on grafted body showed extensive clarification activity against a Micrococcus lysodekticus suspension in the flow-through mode, i.e., 90% destruction of suspended microbial cells was obtained with a residence time ~ 18 min. Both protein capture and biocatalysis applications are conceivable with the 3D-megaporous materials described in this work. PMID- 21692199 TI - Analysis of aggregate size as a process variable affecting paclitaxel accumulation in Taxus suspension cultures. AB - Plant cell aggregates have long been implicated in affecting cellular metabolism in suspension culture, yet the rigorous characterization of aggregate size as a process variable and its effect on bioprocess performance has not been demonstrated. Aggregate fractionation and analysis of biomass-associated product is commonly used to assess the effect of aggregation, but we establish that this method is flawed under certain conditions and does not necessarily agree with comprehensive studies of total culture performance. Leveraging recent advances to routinely measure aggregate size distributions, we developed a simple method to manipulate aggregate size and evaluate its effect on the culture as a whole, and found that Taxus suspension cultures with smaller aggregates produced significantly more paclitaxel than cultures with larger aggregates in two cell lines over a range of aggregate sizes, and where biomass accumulation was equivalent before elicitation with methyl jasmonate. Taxus cuspidata (T. cuspidata) P93AF cultures with mean aggregate sizes of 690 and 1,100 MUm produced 22 and 11 mg/L paclitaxel, respectively, a twofold increase for smaller aggregates, and T. cuspidata P991 cultures with mean aggregate sizes of 400 and 840 MUm produced 6 and 0.3 mg/L paclitaxel, respectively, an increase of 20-fold for smaller aggregates. These results demonstrate the importance of validating experiments aimed at a specific phenomenon with total process studies, and provide a basis for treating aggregate size as a targeted process variable for rational control strategies. PMID- 21692200 TI - The role of adhesion molecules ICAM-1 and VCAM-1 in herpes simplex keratitis. AB - PURPOSE: To elucidate the role of adhesion molecules in the pathogenesis of herpes simplex keratitis. METHODS: Fifty female Balb/c mice (4~6 weeks old, 14~22 g weight) were divided into two groups randomly. Forty were infected by herpes simplex virus and the other 10 were used as normal controls. All mice were fed under the same conditions. Corneas of these mice were collected for immunohistochemical testing on day 14 and 21 after infection. RESULTS: ICAM-1 was mainly expressed in the basal cells of the corneal epithelia and vascular endothelia of the infected mice. A substantial amount of VCAM-1 was also expressed in the corneal vascular endothelial cells of infected mice, and was also found in inflammatory cells in the epithelial and stromal layers of the corneas. CONCLUSION: Adhesion molecules ICAM-1 and VCAM-1 were involved in the progression of herpex simplex keratitis. They may accelerate the progress of inflammation by mediating the extravsation of inflammatory cells from vessels into the infected sites. PMID- 21692201 TI - CD4+ T cells from behcet patients produce high levels of IL-17. AB - PURPOSE: To investigate the role of interleukin (IL)-17-producing CD4+ T cells in Behcet disease (BD). METHODS: Blood samples were drawn from eight BD patients with active uveitis, eight BD patients with inactive uveitis and eight normal controls, respectively. PBMCs were prepared from heparinized blood by Ficoll Hypaque density-gradient centrifugation. Peripheral CD4+ T cells were purified by Human CD4 Microbeads (MACS). The purity rate of CD4+ T cells was detected using flow cytometry. Purified CD4+ T cells were stimulated with or without anti-CD3 and anti-CD28 antibodies in the presence or absence of recombinant-IL-23 (rIL-23) or recombinant-IL-12 (rIL-12) for 72 hours. The concentrations of IL-17, IFN gamma and IL-4 in the collected supernatants from CD4+ T cells were measured using a Duoset ELISA Development kit. RESULTS: The results showed that the levels of IL-17 and IFN-gamma observed in active BD patients were significantly higher as compared with those in inactive patients and normal controls. There was no significant difference concerning IL-4 production between BD patients and normal controls. rIL-23 significantly augmented the production of IL-17 by CD4+ T cells from both BD patients and normal controls. Both rIL-23 and rIL-12 could increase IFN-gamma production by CD4+ T cells from BD patients and normal controls. Moreover, the effect of rIL-12 was more robust compared with that of rIL-23. Neither rIL-23 nor rIL-12 exerted any effect on IL-4 production. CONCLUSION: rIL 23 can promote the production of IL-17 by CD4+ T cells in BD patients. The upregulated IL-17 levels may be related with the intraocular inflammation of Behcet patients. PMID- 21692202 TI - Pattern scan laser photocoagulator on retinopathy: an annual clinical application summary. AB - PURPOSE: To evaluate the clinical efficacy of Pattern Scan Laser Photocoagulator (PASCAL) by observing the efficacy of PASCAL on retinopathy. METHODS: A total of 92 patients with retinopathy (121 eyes) who underwent PASCAL between December 2008 and February 2009 in our center were retrospectively analyzed to evaluate the visual acuity changes and recovery conditions of the patients from baseline to posterior to the treatment. The retinopathy included: diabetic retinopathy, ischemic retinal vein occlusion (IRVO), central serous chorioretinopathy (CSC), retinal periphlebitis (Eales disease) and retinal degeneration/holes. RESULTS: The patients were subject to a 12-month follow up after PASCAL. The visual acuity findings were stated as below: for diabetic retinopathy (73 eyes), 10 eyes had improved visual acuity; 55 eyes were stabilized and 8 eyes progressed; for IRVO (13 eyes), 4 eyes showed improvement, 6 eyes were stabilized and 3 eyes progressed; for CSC (9 eyes), 6 eyes were alleviated and 3 eyes progressed; for retinal periphlebitis (5 eyes), 2 eyes had enhanced visual acuity and 3 eyes showed stable visual acuity; for retinal degeneration/holes (21 eyes), 5 eyes presented improved visual acuity, 16 eyes were stabilized and no eye progressed. Indirect ophthalmoscopic reexamination confirmed secured blockage by laser spots and favorable absorption of the retinal edema and newborn capillaries. No obvious leakage was observed during fundus fluorescein angiography and no laser-related ocular adverse effect was reported. CONCLUSION: PASCAL is accurate, effective and well-tolerated. The duration of short laser pulse falls within the safety range, ensuring the stabilization and improvement in the patient's visual acuity. The parameters, long-term efficacy and complications of PASCAL should be further demonstrated by performing long-term clinical trials with larger sample size. PMID- 21692204 TI - Analysis of optic coherence tomography for congenital macular retinoschisis. AB - PURPOSE: To investigate the pathological characteristics of congenital macular retinoschisis by optic coherence tomography (OCT). METHODS: The data of 7 cases (14 eyes) with congenital macular retinoschisis were collected. Electroretinogram (ERG), fundus fluorecein angiography (FFA) and OCT examination were performed, respectively. RESULTS: The OCT images showed schisis cavity in all eyes. Schisis was confined to the fovea and parafovea in 2 eyes (1 patient). Schisis was involved in entire macular area in 12 eyes (6 patients). Inner nuclear layer (INL) schisis was seen in all eyes. Schisis was located at both INL and outer nuclear layer (ONL)/outer plexiform layer (OPL) in 2 of the 14 eyes. Besides the schisis cavity, small cysts within ganglion cell layer were found in 3 eyes. The small cysts were confined to parafoveal area. The OCT images of both eyes in one patient were similar but not exactly the same or symmetrical. CONCLUSION: Morphology, extension and schisis location in congenital macular retinoschisis have respective diversity. PMID- 21692203 TI - The effect of siRNA-VEGF on the growth of REC in retinal pigment epithelial cell and retinal endothelial cell co-culture system. AB - PURPOSE: To investigate the effect of small interfering RNA (siRNA) targeting VEGF of retinal pigment epithelium (RPE) cells on the growth activity of human retinal vascular endothelial cells (RECs) under a co-culture system. METHODS: By applying the vector (pGPU6)-based siRNA plasmid gene silence system, we specifically silenced VEGF expression of RPE cells (ARPE-19) through plasmid (pGPU6-VEGFA-siRNA) transfection. Reverse transcription polymerase chain reaction (RT-PCR) was applied for selecting the most efficient siRNA segment among three pGPU6-VEGF-siRNA groups (siRNA-1, siRNA-2 and siRNA-3). Treated RPE cells were co cultured with RECs in a co-culture system made up of a 24-well culture plate and transwell inserts assembled inside During 7-day culture period, the growth capacity of RECs were observed and tested in the form of cell counting assay. Three groups were established in this study: RPE cells transfected with pGPU6 VEGF-siRNA and co-cultured with RECs (group A), RPE cells transfected with siRNA null vector and co-cultured with RECs (group B), and RECs cultured alone (group C). RESULTS: After transfection, VEGF expression of RPE cells in three pGPU6-VEGF siRNA groups (siRNA-1, siRNA-2 and siRNA-3) evaluated by RT-PCR were 2.56 +/- 0.45, 1.17 +/- 0.38 and 4.39 +/- 0.51, respectively (n=10). siRNA-2 was selected as the foremost segment for transfection (P<0.05, SNK-q test). During the 7-day co-culture period, an influence upon the growth of RECs was observed. Growth curve of RECs under co-culture showed a lower growth rate in group A than in group B (P<0.05, dunnett's test), but no significant difference between group A and group C was noted ( P>0.05, dunnett's test). RECs in group A proliferated much faster during the first four days post-transfection. CONCLUSION: Delivery of siRNA targeting VEGF plays an efficient role in down-regulating VEGF expression in RPE cells, therefore modulating the growth activity of RECs under a co-culture system in vitro. The application of this technique may provide novel evidence for the prevention and treatment of retinal neovascularisation diseases. PMID- 21692206 TI - The influence of phacoemulsification on corneal endothelial cells at varying blood glucose levels. AB - PURPOSE: To investigate the influence of phacoemulsification on corneal endothelial cells in diabetes patients and normal controls. METHODS: Phacoemulsification and intraocular lens implantation were performed on 75 patients with diabetic cataract (126 eyes) who were divided into two groups: Experimental group 1 (Glu <= 6mmol/L); Experimental group 2 (Glu 6-10 mmol/L) and 65 non-diabetic controls (112 eyes). The density and percentage of hexagonal cells and coefficient of variation of the corneal endothelia were measured before surgery and 1 day, 1 month and 3 months postoperatively. RESULTS: There was no statistical difference in the density and percentage of hexagonal cells and coefficient of variation of the corneal endothelia prior to phacoemulsification (P>0. 05) between the three groups. The density and percentage of hexagonal cells of the corneal endothelia decreased significantly after surgery in all three group (P<0.05), while the Coefficient of variation increased in all groups (P< 0.05). The rate of loss of corneal endothelial cells in the diabetic groups was significantly higher than for the control group (P<0.05), the percentage of hexagonal cells in the diabetic groups was significantly lower than for the control group (P<0.05), and the coefficient of variation in the diabetic groups was significantly higher than for the control group (P<0.05) at 1 day, 1 month and 3 months post-operatively. There was no statistical difference between the two diabetic groups in terms of these post-operative measurements. CONCLUSION: The corneal endothelium of diabetic patients is more prone to damage from phacoemulsification. It is advisable to evaluate the corneal endothelium routinely prior to phacoemulsification, particularly in diabetic persons. PMID- 21692205 TI - Intravitreous high expression level of netrin-1 in patients with proliferative diabetic retinopathy. AB - PURPOSE: To investigate the significance of netrin-1 and vascular endothelial growth factor (VEGF) in the pathogenesis of retinal angiogenesis, the levels of netrin-1 and VEGF in the vitreous fluid and serum of the proliferative diabetic retinopathy (PDR) and non-proliferative diabetic retinopathy (non-PDR) patients were measured. We then determined the netrin-1 and VEGF expression in the oxygen induced retinopathy (OIR) mice retinas. METHODS: A total of 18 eyes from 18 patients were included in our study and 10 of them were collected from PDR patients and 8 from non-PDR patients. Undiluted vitreous fluid samples were collected during pars plana vitrectomy. Appropriate blood samples were collected if possible. Netrin-1 and VEGF levels in the vitreous fluid and plasma were determined by Enzyme-linked Immunosorbent Assays. OIR mice models were established, and netrin-1 and VEGF levels were determined by immunohistochemistry analysis. RESULTS: The levels of netrin-1 and VEGF in the vitreous of PDR patients were significantly higher than those in the controls (Mediannetrin 1=509.94 vs. 85.91 pg/ml, P<0.001 and Median VEGF=762.60 vs. 77.52 pg pg/ml, P<0.001). Netrin-1 was mainly expressed in GCL and INL of the retina in mice. Both netrin-1 and VEGF were up-regulated in OIR mice. CONCLUSION: Netrin-1 and VEGF levels were elevated in vitreous fluid of the PDR patients and the OIR mice retinas. Therefore, netrin-1 may play important roles in pathological retinal angiogenesis. PMID- 21692207 TI - Hormone administration promotes the epithelium healing in patients with recurrent corneal epithelial exfoliation. AB - PURPOSE: To investigate the effects of hormone administration upon epithelium healing in patients with recurrent corneal epithelial exfoliation. METHODS: The recurrence rate of 56 patients with recurrent corneal epithelial exfoliation was compared after 3-month follow up, 30 patients of whom received the basic treatment of bFGF and pressure bandage plus prednisone administration (combination treatment group, ie. A) and the other 26 patients received the basic treatment alone (single treatment group, ie. B). RESULTS: No patients showed recurrence in the combination treatment group. But there were 20 patients (76.92%) in the basic treatment group recurred. chi2 test showed that chi2=35.9. The two groups had significant difference regarding the recurrence of corneal epithelial exfoliation (P<0.01). CONCLUSION: For the patients with recurrent corneal epithelial exfoliation, hormone administration should be considered to reduce the recurrence and protect the function of cornea as a supplement to the basic treatment. PMID- 21692208 TI - Analysis on reasons and treatment approaches for shallow anterior chamber after glaucoma surgery. AB - PURPOSE: To analyze the causes of shallow anterior chamber after glaucoma surgery, and explore effective treatments correspondingly. METHODS: A total of 183 glaucoma patients (218 eyes) underwent trabeculectomy, and shallow anterior chambers were observed after surgery. The causes were analyzed and appropriate approaches were employed accordingly. RESULTS: Postoperatively, shallow anterior chamber occurred in 42 eyes (19.3%) .Among those, 24 eyes (57.1%) had excessive filtrations, 8 eyes (19.0%) showed delayed anterior chamber formation, 5 eyes (11.9%) presented with choroidal detachments, 4 eyes (9.5%) displayed conjunctival flap leakages, and 1 eye had (2.4%) ciliary block. Most shallow anterior chambers can be effectively improved after appropriate treatment. CONCLUSION: Shallow anterior chamber can be caused by a variety of reasons, mainly by excessive filtration. We should actively take reasonable measures to improve the symptom and try to avoid its occurrence. PMID- 21692209 TI - Sulcus Transscleral Intraocular Lens Suture Fixation through Small Scleral Tunnel Incision. AB - PURPOSE: To evaluate the clinical efficiency and safety of sulcus transscleral intraocular lens suture fixation with small incision through scleral tunnel in eyes the with posterior capsule defect or insufficient zonula support. METHODS: Thirty nine eyes with severe posterior capsule defect and zonula damages caused by small-incision cataract surgery, and those with capsule absence or intraocular lens dislocation were selected in this investigation from February 2007 to December 2009. Sulcus transscleral intraocular lens suture combined with puncture needle-guided external approachab and "one- or two-point fixation" method in the small sclera tunnel incision were employed. RESULTS: The mean follow-up was 12.1 months (range from 3 to 28 months). Six eyes were complicated by some eye diseases postoperatively. The best-corrected visual acuity was 20/40 or better in other 34 eyes (87.17%). All eyes with secondary IOL fixation presented equal or better naked visual acuity than best-corrected visual acuity best-corrected preoperatively. No intraoperative and postoperative complications such as hemorrhage, retinal detachment, intraocular lens tilt and decentration occurred. CONCLUSION: Sulcus transscleral intraocular lens suture fixation via small sclera tunnel incision was easy to operate and master, required less operative time, and made primary intraocular lens fixation more effective in eyes with posterior capsule defect or insufficient zonula support in small sclera tunnel incision surgery. In addition, the technique was safe and efficient for secondary intraocular lens fixation. PMID- 21692210 TI - Lens coloboma and associated ocular malformations. AB - PURPOSE: Lens coloboma is a rare congenital disorder of crystalline lens characterized by notching of the equator of the lens. Coloboma can occur in isolation or with other ocular malformations. The authors reported 5 cases of lens coloboma associated with some ocular malformations. METHODS: Case reports. The clinical features, imaging findings and associated ocular malformations were reported. RESULTS: One case was not associated with ocular anomalies. One patient was involved with iris and choroid coloboma; another subject suffered from total cataract; and the fourth patient was affected by lens dislocation. The remaining case included aniridia. The pathogenic mechanisms and relationship of the ocular malformations have been discussed. CONCLUSION: Lens coloboma can be associated with other ocular malformations, such as iris coloboma, choroid colobma, localized or total caratact. PMID- 21692211 TI - A case of secondary glaucoma due to bilateral anterior chamber shallowing caused by Marfan's syndrome. AB - PURPOSE: To report the clinical manifestations and treatment of a case of secondary glaucoma evolving from bilateral anterior chamber flattening caused by Marfan's syndrome. METHODS: The ophthalmic and systemic features, B-scan and UBM characteristics were recorded. Therapy and efficacy were analyzed. RESULTS: Marfan's syndrome, in this case, caused bilateral iris-lens diaphragm anterior dislocation, anterior chamber flattening, pupillary block, angle closure, and finally resulted in persistent increased intraocular pressure (IOP). After undergoing pars plana vitrectomy and lensectomy combined with anterior chamber reformation, the visual acuity of the patient's right eye increased from 6/150 to 6/7.5 (best-corrected) and that of the left eye was improved from 6/100 to 6/10 (best-corrected). The IOP of the right eye fell to 18 mmHg, and the left eye to 12 mmHg. CONCLUSION: Marfan's syndrome can cause bilateral anterior chambers flattening, and induce secondary angle closure glaucoma. Combined pars plana vitrectomy, lensectomy and anterior chamberplasty can re-form the anterior chamber, control IOP and maintain visual function. PMID- 21692212 TI - Effects of erectile dysfunction drugs on eyes. AB - With the increasingly extensive application of erectile dysfunction (ED) drugs , it is of importance for an ophthalmologist to understand the association between these drugs and human eyes. In this study, we retrospectively studied the effects of ED drugs on human eyes, including visual symptoms, ophthalmological electrophysiology, ocular blood flow, intraocular pressure, visual field, retina, cerebral hemodynamics and nervous system and retinal blood vessels, particularly focusing on the relationship between these agents and nonarteritic ischemic optic neuropathy (NAION), in order to highlight the ocular adverse effects induced by these agents thus contributing to preventive measures. PMID- 21692213 TI - [Rheumatoid arthritis: early detection - early treatment. Lasting remission: a realistic therapy goal]. PMID- 21692214 TI - [Psychosomatic medicine. Diagnosis after vague criteria]. PMID- 21692215 TI - [Vaccination for adults in daily use]. PMID- 21692216 TI - [On the article "Anesthesia for thoracic surgery: a challenge for the twenty first century"]. PMID- 21692217 TI - [Low-flow xenon anesthesia in surgical patients with hypertension]. AB - A comparative study of central hemodynamics in 60 patients with essential hypertension during low flow anesthesia with xenon and nitrous oxide is carried out. The main group consisted of 30 patients, 22 male and 8 female, in the median age of 45.9 +/- 23 years. 22 patients out of those had 2nd stage essential hypertension, while the other 8 had 3rd stage. The control group consisted of 30 patients, 20 male and 10 female, in the median age of 45.1 + 1.3 years. 4 patients had 3rd stage essential hypertension, 26 patients had 2nd stage. The both groups were clinically comparable by the character and severity of the main disease, the carried out surgery (open cholecystectomy) and the qualification of surgeons. Results of the research showed, that low flow monoanesthesia with xenon abruptly eradicated the unfavourable consequences of induction of anesthesia (3-5 mg/kg of sodium thiopental or 2-2.5 mg/kg of propofol) and had a positive effect on the parameters of central hemodynamics of patients with essential hypertension. Xenon anesthesia, compared to nitrous oxide, rapidly stabilized the parameters of blood pressure and heart rate and can be recommended as a method of choice in patients with essential hypertension and compromised myocarium. Nitrous oxide with bolus of regular fentanyl doses doesn't reliable anesthesiological protection during open cholecystectomy and shows signs of toxicity. PMID- 21692218 TI - [Comparative study of infusion therapy options in patients with hemorrhagic shock]. AB - This work presents the results of treatment of 60 patients with 2nd degree hemorrhagic shock at pre-hospital and hospital stages by different variations of infusion therapy. It is established that balanced infusion therapy in patients with 2nd degree hemorrhagic shock helps to stabilize the system hemodynamic and improve the general condition. The balanced infusion therapy does not lead to unfavorable changes in acid-alkaline and electrolyte balance. PMID- 21692219 TI - [Prophylaxis of ischemic heart lesions during chronic heart failure with complex therapy using Q10 coenzyme]. AB - Dysfunction of energy processes in the myocardium, resulting the background of ischemic syndrome, and inadequate intake of energy substrates process and/or breach of energetic cofactors of oxidation are an important pathogenetic aspects of the progression of myocardial dysfunction and congestive heart failure. Level of Q10 Coenzyme plays a key role in the functioning of the respiratory mitochondrial chains, exerting a significant influence on the synthesis of ATP. The article provides data on the use of Q10 coenzyme in the treatment of 76 patients with circulatory failure. The data obtained points on the improvement of myocardial contractility, increased exercise tolerance, reduced content of the final products of lipid peroxidation in plasma, a positive effect on blood lipid profile with the addition of Qudesan to standard therapy of heart failure. PMID- 21692220 TI - [Treatment outcome of chemotherapy with superselective cerebral artery catheterization in vegetative state patients]. AB - The purpose of the study is to assess the impact of superselective neurotransmitter metabolic therapy in patients in a vegetative state. Superselective intraarterial infusion was conducted on 26 patients with relevant international criteria for the diagnosis of vegetative state. Comprehensive assessment of neurologic symptoms and severity of low metabolism on PET scan allowed to select the vascular pool, for the catheter installation. The catheter was placed either in the carotid or the vertebrobasilar pool. Infusion of neurotransmitter agents was conducted for 7 days continuously. Control of the level of metabolism of labeled glucose in the brain (PET) was performed within 2 weeks after arterial infusion. 14 out of 26 patients showed a positive trend of changes in energy metabolism of the brain. However, only 7 out of 14 patients showed further recovery of consciousness. The data confirms that the delivery path and a combination of medications play a definite role in the effectiveness of vegetative state therapy. PMID- 21692221 TI - [Concept of mechanisms of anesthetic and therapeutic properties of xenon]. AB - The molecular theory of L. Poling is a genius example of scientific prediction, made in the middle of 20th century, when the studies about clathrates and methods of roentgen structured analysis were doing their first steps. The views expressed in this message are some additions on the structure of xenon clathrates, function free xenon water associates and the use of cameras in the liberated associates of the water molecules, for the process of supramolecular detoxification and attempts to develop this theory more widely, to better understand the mechanisms of xenon anesthesia and treatment for further justification of its therapeutic features as well as for the use of other inert gases (Ar, Kr) in modern medicine. PMID- 21692222 TI - [Thrombophilia and principle of thrombosis prevention in obstetrics]. AB - One of the major causes of maternity death are complications of venous thromboembolism (VT). Risk of their occurrence during pregnancy is 5 to 10 times higher comparing to non-pregnant women. Hereditary trombophilia and antiphospholipid syndrome increase the risk of complications of venous thromboembolism significantly. In addition to VT, trombophilia is associated with miscarriage, placental abruption and severe preeclampsia. The aggravating factor is the presence of certain limitations in administration of some medications for thrombosis prophylaxis during pregnancy. Issues of medical care in pregnant patients with thrombophilia, artificial heart valves or acute VT complications are highlighted in the article, as well as principles of thrombosis prophylaxis during cesarean section or in women with VT in anamnesis. Evidence based recommendations of the recent American College of Chest Physicians consensus conference are presented for each issue. PMID- 21692223 TI - [Current issues of adaptation to hypoxia. Signal mechanisms and their role in system regulation]. AB - A bioenergetic mechanism for development of urgent and long-term adaptation to hypoxia is considered. Hypoxia induces reprogramming of respiratory chain function and switching from oxidation of NAD-related substrates (complex I) to succinate oxidation (complex II). Transient, reversible, compensatory activation of respiratory chain complex II is a major mechanism of urgent adaptation to hypoxia necessary for 1) succinate-related energy synthesis in conditions of oxygen deficiency and formation of urgent resistance in the body; 2) succinate related stabilization of HIF-1alpha and initiation of its transcriptional activity related with formation of long-term adaptation; 3) succinate-related activation of a succinate-specific receptor CPR91. Therefore succinate is a signaling molecule, which effects are realized at three levels in hypoxia, intramitochondrial, intracellular and intercellular. Tactics and strategy for the antihypoxic defense and development of antihypoxants with energotropic action are considered. PMID- 21692224 TI - [Mesenchymal stem cells transplantation in the treatment of radiation skin lesions]. AB - Transplantation of mesenchymal stem cells, both at early and later stage after local exposure of rats source beta radiation dose, 90Sr/90Y 140 GR, stimulates recovery of damaged skin. Diminution area local radiation injuries and accelerate healing radiation ulcers. Clinically shows the high efficiency of the transplantations autologous mesenchymal stem cells in treatment of deep beam ulcers, intractable standard conservative treatment. Found promising application of mesenchymal stem cells for treatment of severe local radiation injuries and the need to develop the best possible conditions for their use. PMID- 21692225 TI - [Too complex?]. PMID- 21692226 TI - Scalpel solidarity: surgery in Palestine. PMID- 21692227 TI - Mental health care for US veterans heavily criticised. PMID- 21692228 TI - Advance decisions, chronic mental illness, and everyday care. PMID- 21692229 TI - Guy Fontaine and arrhythmogenic right ventricular dysplasia. AB - Cardiomyopathies are the Focus of this EHJ issue. Guy Fontaine, an electrical engineer, then a physician, played a pivotal role in the discovery of ARVD. PMID- 21692231 TI - Fitness to fly: experts prefer 'why not?' to 'don't'. AB - A new attempt to clarify guidelines for advising cardiovascular patients when they can fly emphasizes that the aircraft cabin poses no major health threat and that the stability of the condition is a key factor in giving advice, reports Barry Shurlock, PhD. PMID- 21692234 TI - The public world of insect vibrational communication. AB - Food webs involving plants, herbivorous insects and their predators account for 75% of terrestrial biodiversity (Price 2002). Within the abundant arthropod community on plants, myriad ecological and social interactions depend on the perception and production of plant-borne mechanical vibrations (Hill 2008). Study of ecological relationships has shown, for example, that termites monitor the vibrations produced by competing colonies in the same tree trunk (Evans et al. 2009), that stink bugs and spiders attend to the incidental vibrations produced by insects feeding or walking on plants (Pfannenstiel et al. 1995, Barth 1998) and that caterpillars can distinguish among the foraging-related vibrations produced by their invertebrate predators (Castellanos & Barbosa 2006). Study of social interactions has revealed that many insects and spiders have evolved the ability to generate intricate patterns of substrate vibration, allowing them to communicate with potential mates or members of their social group (Cokl & Virant Doberlet 2003; Hill 2008). Surprisingly, research on the role of substrate vibrations in social and ecological interactions has for the most part proceeded independently, in spite of evidence from other communication modalities - acoustic, visual, chemical and electrical - that predators attend to the signals of their prey (Zuk & Kolluru 1998; Stoddard 1999). The study by Virant-Doberlet et al. (2011) in this issue of Molecular Ecology now helps bring these two areas of vibration research together, showing that the foraging behaviour of a spider is influenced by the vibrational mating signals of its leafhopper prey. PMID- 21692233 TI - The power of paired genomes. AB - Species interactions are fundamental to ecology. Classic studies of competition, predation, parasitism and mutualism between macroscopic organisms have provided a foundation for the discipline, but many of the most important and intimate ecological interactions are microscopic in scale. These microscopic interactions include those occurring between eukaryotic hosts and their microbial symbionts. Such symbioses, ubiquitous in nature, provide experimental challenges because the partners often cannot live outside the symbiosis. With respect to the symbionts, this precludes utilizing classical microbiological and genetic techniques that require in vitro cultivation. Genomics, however, has rapidly changed the study of symbioses. In this issue of Molecular Ecology, MacDonald et al. (2011), coupling symbiont whole-genome sequencing, experimental studies and metabolic modelling, provide novel insights into one of the best-studied symbioses, that between aphids and their obligate, nutrient-provisioning, intracellular bacteria, Buchnera aphidicola (Fig. 1). MacDonald and colleagues assessed variation in the ability of aphid-Buchnera pairs to thrive on artificial diets missing different amino acids. As shown previously (e.g. Wilkinson & Douglas 2003), aphid-Buchnera pairs can differ in their requirements for external sources of essential amino acids. Such phenotypic variation could result from differences in Buchnera's amino acid biosynthetic capabilities or in the ability of aphids to interact with their symbionts. Whole-genome sequencing of the Buchnera genomes from four aphid lines with alternate nutritional phenotypes revealed that the environmental nutrients required by the aphid-Buchnera pairs could not be explained by sequence variation in the symbionts. Instead, a novel metabolic modelling approach suggested that much of the variation in nutritional phenotype could be explained by host variation in the capacity to provide necessary nutrient precursors to their symbionts. MacDonald et al.'s work complements a recent study by Vogel & Moran (2011), who through crossing experiments investigating the inheritance of a nutritional phenotype associated with a frameshift mutation in a Buchnera amino acid biosynthesis gene powerfully demonstrated that different host genotypes paired with the same symbiont genome could exhibit substantially different nutritional requirements.? Thus, while there is little doubt that Buchnera are evolutionarily central to the nutritional ecology of aphids, the current work by MacDonald et al. (2011) together with that of Vogel & Moran (2011) surprisingly demonstrates host dominance in defining and controlling the ecological niche of this particular symbiosis. PMID- 21692235 TI - The efficacy of pre-operative oral medication of lornoxicam and diclofenac potassium on the success of inferior alveolar nerve block in patients with irreversible pulpitis: a double-blind, randomised controlled clinical trial. AB - AIM: To determine the effect of administration of pre-operative lornoxicam (LNX) or diclofenac potassium (DP) on the success of inferior alveolar nerve blocks (IANB) in patients with irreversible pulpitis in a double-blind randomised controlled trial. METHODOLOGY: One hundred and fourteen patients with irreversible pulpitis of a mandibular posterior tooth participated. Patients indicated their pain scores on a Heft Parker visual analogue scale, after which they were randomly divided into three groups (n = 38). The subjects received identical capsules containing 8 mg LNX, 50 mg DP or cellulose powder (placebo, PLAC), 1 h before administration of IANB with 2% lidocaine containing 1 : 200 000 epinephrine. Lip numbness was assessed after 15 min, following which the teeth were tested with cold spray and their responses (negative or positive) were recorded. Access cavities were then prepared and success of IANB was defined as the absence of pain during access preparation and root canal instrumentation. The data were analysed using chi-squared tests. RESULTS: The percentages of teeth giving a negative response to cold test were 42.8% (PLAC), 78.5% (LNX) and 67.8% (DP), with no significant differences amongst the groups (P > 0.05). The success rates for the IANB in descending order were 71.4% (LNX), 53.5% (DP) and 28.5 (PLAC). A significant (P < 0.001) difference was found between the LNX and the PLAC groups only. CONCLUSIONS: Pre-operative administration of LNX significantly improved the efficacy of IANB in patients with irreversible pulpitis, whilst the effect of pre-medication with DP was not significantly different from the PLAC. PMID- 21692236 TI - Euthanasia. PMID- 21692237 TI - Compressive sensing for biomedical imaging. PMID- 21692238 TI - Conflicts in maintaining biodiversity at multiple scales. AB - Biodiversity consists of multiple scales, including functional diversity in ecological traits, species diversity and genetic diversity within species, and is declining across the globe, largely in response to human activities. While species extinctions are the most obvious aspect of this, there has also been a more insidious loss of genetic diversity within species. While a vast literature concerns each of these scales of biodiversity, less is known about how different scales affect one another. In particular, genetic and species diversity may influence each other in numerous ways, both positively and negatively. However, we know little about the mechanism behind these patterns. In this issue of Molecular Ecology, Nestmann et al. (2011) experimentally explore the effect of species and functional diversity and composition of grassland plant communities on the genetic structure of one of the component species. Increasing species richness led to greater changes in the genetic composition of the focal populations over 4 years, primarily because of genetic drift in smaller population sizes. However, there were also genetic changes in response to particular plant functional groups, indicating selective differences driven by plant community composition. These results suggest that different levels of biodiversity can trade-off in communities, which may prove a challenge for conservation biologists seeking to preserve all aspects of biodiversity. PMID- 21692239 TI - Electron microscopy morphology of the mitochondrial network in gliomas and their vascular microenvironment. AB - Gliomas still represent a serious and discouraging brain tumor; despite of the diversity of therapeutic modalities, the prognosis for patients is still poor. Understanding the structural and functional characteristics of the vascular microenvironment in gliomas is essential for the design of future therapeutic strategies. This review describes and analyzes the electron microscopy morphology of the mitochondrial network in human gliomas and their vascular microenvironment. Heterogenous mitochondrial network alterations in glioma cells and in microvascular environment are implicated directly and indirectly in the processes linked to hypoxia-tolerant and hypoxia-sensitive cells phenotype, effects of the hypoxia-inducible factor-1alpha, increased expression of several glycolytic protein isoforms as well as fatty acid synthase, and survivin. The prevalent existence of partial and total cristolysis observed suggests that oxidative phosphorylation is severely compromised. A mixed therapy emerged as the most appropriate. PMID- 21692240 TI - AICAR inhibits cancer cell growth and triggers cell-type distinct effects on OXPHOS biogenesis, oxidative stress and Akt activation. AB - The AMP-activated protein kinase agonist AICAR mimics a low intracellular energy state and inhibits the proliferation of cancer cells by different mechanisms, which may depend on the bioenergetic signature of these cells. AICAR can also stimulate mitochondrial biogenesis in myoblasts, neurons and HeLa cells. Yet, whether the reactivation of oxidative phosphorylation biogenesis by AICAR contributes to the growth arrest of cancer cells remains undetermined. To investigate this possibility, we looked at the impact of 24- and 48-hour treatments with 750 MUM AICAR on human cancer cell lines (HeLa, DU145, and HEPG2), non-cancer cells (EM64, FM14, and HLF), embryonic cells (MRC5) and Rho(0) cells. We determined the bioenergetic profile of these cells and assessed the effect of AICAR on oxidative phosphorylation biogeneis, cell viability and cell proliferation, ROS generation, mitochondrial membrane potential and apoptosis induction. We also followed possible changes in metabolic regulators such as Akt and Hif1-alpha stabilization which might participate to the anti-proliferative effect of AICAR. Our results demonstrated a strong and cancer-specific anti growth effect of AICAR that may be explained by three different modes according to cell type: the first mode included stimulation of the mitochondrial apoptotic pathway however with compensatory activation of Akt and upregulation of oxidative phosphorylation. In the second mode of action of AICAR Akt phosphorylation was reduced. In the third mode of action, apoptosis was activated by different pathways. The sensitivity to AICAR was higher in cells with a low steady-state ATP content and a high proliferation rate. PMID- 21692241 TI - Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. AB - Normal differentiated cells rely primarily on mitochondrial oxidative phosphorylation to produce adenosine triphosphate (ATP) to maintain their viability and functions by using three major bioenergetic fuels: glucose, glutamine and fatty acids. Many cancer cells, however, rely on aerobic glycolysis for their growth and survival, and recent studies indicate that some cancer cells depend on glutamine as well. This altered metabolism in cancers occurs through oncogene activation or loss of tumor suppressor genes in multiple signaling pathways, including the phosphoinositide 3-kinase and Myc pathways. Relatively little is known, however, about the role of fatty acids as a bioenergetic fuel in growth and survival of cancer cells. Here, we report that human glioblastoma SF188 cells oxidize fatty acids and that inhibition of fatty acid beta-oxidation by etomoxir, a carnitine palmitoyltransferase 1 inhibitor, markedly reduces cellular ATP levels and viability. We also found that inhibition of fatty acid oxidation controls the NADPH level. In the presence of reactive oxygen species scavenger tiron, however, ATP depletion is prevented without restoring fatty acid oxidation. This suggests that oxidative stress may lead to bioenergetic failure and cell death. Our work provides evidence that mitochondrial fatty acid oxidation may provide NADPH for defense against oxidative stress and prevent ATP loss and cell death. PMID- 21692242 TI - What adult worker model? A critical look at recent social policy reform in Europe from a gender and family perspective. AB - Analyses regularly feature claims that European welfare states are in the process of creating an adult worker model. The theoretical and empirical basis of this argument is examined here by looking first at the conceptual foundations of the adult worker model formulation and then at the extent to which social policy reform in western Europe fits with the argument. It is suggested that the adult worker formulation is under-specified. A framework incorporating four dimensions the treatment of individuals vis-a-vis their family role and status for the purposes of social rights, the treatment of care, the treatment of the family as a social institution, and the extent to which gender inequality is problematized is developed and then applied. The empirical analysis reveals a strong move towards individualization as social policy promotes and valorizes individual agency and self-sufficiency and shifts some childcare from the family. Yet evidence is also found of continued (albeit changed) familism. Rather than an unequivocal move to an individualized worker model then, a dual earner, gender specialized, family arrangement is being promoted. The latter is the middle way between the old dependencies and the new "independence." This makes for complexity and even ambiguity in policy, a manifestation of which is that reform within countries involves concurrent moves in several directions. PMID- 21692243 TI - Not just maternalism: marriage and fatherhood in American welfare policy. AB - The United States' 1996 welfare reforms are often interpreted as a historical break in transitioning from supporting motherhood to commodifiying women's labor. However, this cannot account for welfare reform's emphasis upon heterosexual marriage and fatherhood promotion. The paper traces continuities and shifts in over a century of familial regulation through American welfare policy, specifying the place of marriage promotion within welfare policy. Up until 1996, families were key sites of intervention through which the American welfare state was erected, especially through single women as mothers - not wives. However, as of the 1960s, concern with African American men's "failed" familial commitments turned policymakers toward concern over marriage promotion for women and men. While marriage "disincentives" for aid recipients were lifted in the 1960s, the 1996 reforms structured a new form of nuclear family governance actively promoting marriage rooted in, but distinct from, the previous. Given the historical absence of welfare policies available to poor men, Temporary Assistance for Needy Families' (TANF) marriage promotion policies have positioned poor women as nodes connecting the state to poor men, simultaneously structuring poor women as breadwinners, mothers, and wives. Recent welfare reform has also started to target poor men directly, especially in fatherhood and marriage promotion initiatives. The article highlights how, in addition to workfare policies, marriage promotion is a neoliberal policy shifting risk to the shoulders of the poor, aiming to produce "strong families" for the purposes of social security. PMID- 21692244 TI - "Let us help them to raise their children into good citizens": the Lone-Parent Families Act and the wages of care-giving in Israel. AB - Based on the assumption that the construction of meaning in the process of policy making is crucial if we wish to understand the gender outcomes of social policy, this article analyzes the parliamentary debates that preceded and accompanied the legislation of the Israeli Mono-Parental Families Act, 1992. It focuses on the enunciation of gender roles and relations in the discourses that framed and justified the Act as well as on how the capacity to establish and maintain autonomous households was constructed and legitimized. Two sets of discourses emerged during the deliberations over the Act, each of which endeavored to interpret the needs, identities, and capacities for action among lone-parent families. The article shows how a specific version of the capacity to establish and maintain autonomous households-that of caregivers who happen to be workers was privileged in the policy paradigm underlying the Act. The alternative vision that of workers with caregiving responsibilities-was marginalized and eventually disregarded in the final wording and implementation of the Act. The article concludes with an analysis of the socio-political processes that underlie the prioritization of the version, which was ultimately expressed in the implementation of the Act. It is suggested that a state-level collective identity project shaped by demographic concerns and geo-political factors and changes in the political economy combined to define the needs, identities, and capacities for action of lone-parent families in terms of a model of motherhood in which care-giving trumped paid work. PMID- 21692245 TI - Do family policy regimes matter for children's well-being? AB - Researchers have studied the impact of different welfare state regimes, and particularly family policy regimes, on gender equality. Very little research has been conducted, however, on the association between different family policy regimes and children's well-being. This article explores how the different family policy regimes of twenty OECD countries relate to children's well-being in the areas of child poverty, child mortality, and educational attainment and achievement. We focus specifically on three family policies: family cash and tax benefits, paid parenting leaves, and public child care support. Using panel data for the years 1995, 2000, and 2005, we test the association between these policies and child well-being while holding constant for a number of structural and policy variables. Our analysis shows that the dual-earner regimes, combining high levels of support for paid parenting leaves and public child care, are strongly associated with low levels of child poverty and child mortality. We find little long-term effect of family policies on educational achievement, but a significant positive correlation between high family policy support and higher educational attainment. We conclude that family policies have a significant impact on improving children's well-being, and that dual-earner regimes represent the best practice for promoting children's health and development. PMID- 21692246 TI - Choices and life chances: feminism and the politics of generational change. AB - The perception that young women are disengaged from feminist politics has provoked a great deal of tension between feminist generations. Recent feminist research into generational change has largely avoided this tension by focusing on the shifting meanings of feminism and the discrepancy between young women's reluctance to identify as "feminists" and their general acceptance of feminist attitudes toward gender issues. Nevertheless, in an era when gender equity goals seem to be if not slipping backwards then lacking urgency, young women are less likely to identify with a collective feminist politics than are older women. Underpinned by the findings of a major study of the attitudes toward work, family, and retirement of three generations of Australian women, this paper develops an approach that helps explain this reluctance. Drawing on the work of Karl Mannheim, the paper suggests that the cultural currents shaping the consciousness of different generations of women impact significantly on gender identity. The implications of this cultural shift are considered in the context of feminist politics and the contemporary "culture wars." PMID- 21692247 TI - [ERAS (enhanced recovery after surgery) Protocol and the evidence]. PMID- 21692248 TI - [Prevention of ischemia/reperfusion injury -Postconditioning-]. PMID- 21692249 TI - [Post-cardiac arrest syndrome]. PMID- 21692250 TI - [Neurovascular unit: a breakthrough in anesthetic management of cerebral circulation]. PMID- 21692251 TI - [Emerging role of hydrogen sulfide in biology]. PMID- 21692252 TI - [Where chemistry works wonders when it comes to washing clothes and more]. PMID- 21692253 TI - [Chronic postoperative pain after general anesthesia with or without a single dose preincisional paravertebral nerve block in radical breast cancer surgery]. AB - BACKGROUND AND OBJECTIVE: Over 50% of patients still experience pain a year after mastectomy with or without lymphadenectomy. We aimed to determine the association between anesthetic technique, acute postoperative pain intensity, and the development of chronic postoperative pain. PATIENTS AND METHODS: Forty patients were randomly assigned to receive general anesthesia with or without a paravertebral nerve block for modified radical mastectomy. Postoperative pain was assessed on a visual analog scale at 60 minutes and 24 hours; the patients were also asked to respond to a telephone questionnaire on chronic pain 4 to 5 months later. RESULTS: No significant differences in acute pain were observed. Twenty nine responded to the telephone questionnaire. Only 1 patient in the paravertebral block group reported chronic neuropathic pain and none had phantom breast pain. Only 1 patient (6.7%) in the paravertebral block group reported chronic neuropathic pain and none had phantom breast pain. In the group that received general anesthesia alone, 1 patient reported phantom breast pain and 6 patients had neuropathic pain, associated with phantom breast pain in 2 cases (incidence of chronic pain 50%; P = .01, Fischer exact test; relative risk, 7.5, 95% confidence interval, 1.0-53.5). The incidences of myofascial pain (neck muscle tightness) were similar in the 2 groups. CONCLUSIONS: Four to 5 months after mastectomy, fewer cases of chronic pain developed in the group operated under general anesthesia with a preincisional paravertebral block than in the group that received only general anesthesia, with postoperative morphine chloride for analgesia. PMID- 21692254 TI - [Health status and health needs assessment--state of the art of the public health practice in Croatia]. AB - Public health practice performance is measured through its three core functions, i.e. assessment, policy development and assurance. We describe the existing health status and health care needs assessment practices in the Republic of Croatia. Health care needs assessment in Croatia includes mortality and morbidity information available through vital records but does not include community input (opinion and attitude) and participation. Health needs are not analyzed in order to determine the causes of health problems. Analysis of health needs of the population groups at highest risk also does not exist. Resources assessment is not part of the process, so we do not know how adequate the existing health resources are. In the Croatian health care system practice, the assessment function is limited through the almost exclusive use of the routine health and demographic statistics. Academic public health has introduced other kinds of more participative, subgroups oriented, qualitative methodologies but in daily routine, these methods are hardly used. Since health needs assessment is one of the core public health functions, in the future its practice has to be reoriented from pure monitoring towards identifying and solving community health problems. Partnership with community has to be a cornerstone for more efficient health needs assessment practice. In the light of previous statement, we present and discuss new trends in the assessment practice in Croatia, i.e. revision of routine health data collection, ways of performing intervention aimed health surveys, naturalistic approach in health needs assessment, and health needs research of population groups at highest risk. PMID- 21692255 TI - [Evaluation of the action plan for Roma people in health area]. AB - By virtue of the national program for Romanies and participation in the Decade of Roma Inclusion 2005-2015, Croatia has chosen its strategic standpoint toward programs of social inclusion of Romanies in four priority areas: housing, education, employment and health. The objectives of the Roma Action Plan (AP) for 2005-2015 in the health area focus on: * ensuring equal availability of health services through information about personal rights and health insurance options; * child health improvement and care, as well as mortality reduction; * raising health awareness and care in terms of safe motherhood, family planning and reproductive health; * financial support to schooling of Roma people in health professions In order to monitor the implementation of AP and measure the availability of health care and condition, certain indicators of the number and coverage of Romanies are crucial for each of the above objectives: indicators for the Roma informed about personal rights resulting from the mandatory health insurance; for Romanies who have health insurance; for vaccinated Romani children, for Romani newborns born in maternity hospitals, for prenatal and pregnancy health care in Romani women, for Romanies included in family planning, for the mortality rate and causes of death in Romanies, and for the Roma receiving scholarships for education in health professions. Most of these indicators are only obtainable through special studies, while routinely monitored indicators simply do not satisfy quantitative needs. Another problem is Romanies not stating their ethnic denomination. Consequently, routine Roma mortality and cause of death statistics are unreliable. At the state level, no specific indicators of implementation could be obtained for any of the above health objectives, while some were obtainable for specific units of local and self government (Baranja, Medimurje and Primorje-Goranska County). According to the research, more than 50% of Romanies in Croatia are situated in Medimurje, where they make up 3.4% of overall population, but also 53% of recipients of unemployment compensation. In Medimurje County, local and EU funds were used to undertake certain measures of protection from infectious diseases, alongside health education in combating ignorance and mistrust of Roma towards vaccination. Baranja used state budget funds to conduct preventive examinations of Romani women who have no health insurance, and to educate them in health measures of safe motherhood, family planning and infant health care. Although the AP includes a series of measures for improving Romanies' health, it cannot be implemented or its effects measured without clearly defined organizers of activities, resources assigned for implementation, and process and outcome indicators. PMID- 21692256 TI - [Decentralization and how to conduct it as a revolution or an evolution? County public health and management capacity building as a prerequisite for successful decentralization in the Republic of Croatia]. AB - AIM: Based on the results of the first phase of the County Public Health Capacity Building Program named Health-Plan for It, implemented in the Republic of Croatia during the 2002-2008 period, this article analyzes the relationship between training of the county teams and their ability to develop health policy. Our hypothesis was that decentralized model of health planning and management would not occur just by changing legislation alone. Counties in Croatia needed educational support (learning-by-doing training) in order to improve public health practices at the county level. SAMPLE AND METHODS: During the 2002-2005 period, the first 15 county teams (so-called first cycle counties) completed their training. The teams consisted of 12 to 15 members, representatives of political and executive component, technical component (public health professionals, representatives of health and social welfare institutions) and community members (non-government sector and media). Teams were trained in cohorts. Three counties passed together through the six-month process of modular training (four education modules, with four days of intensive training and "homework" between modules) at the time. The remaining 5 counties (second-cycle counties) completed the same kind of training in 2007-2008. The Public Health Performance Matrix (the Local Public Health Practice Performance Measures instrument developed by the US CDC Public Health Practice Program Office) was used as an evaluation instrument. Each county team had to fill it out at the beginning of education. RESULTS: Comparison of the Public Health Performance Matrices of first cycle counties (training in 2002-2005) with those of the second cycle counties (trained several years later) yielded no differences. Although training materials were publicly available (accessible through the Croatian Healthy Cities web pages) for years, the second cycle counties did not spontaneously (without training) increase their county-level capacities for participative health needs assessment, health planning, and provision of health services tailored to the local needs. CONCLUSION: Results of this study showed that decentralized model of health planning and management in Croatia could not be developed without educational support given to the lower level of administration. Only through the training process (the Health-Plan for It County Public Health Capacity Building Program), county teams had managed to develop policy function and create County Health Profiles and Strategic Framework of the County Health Plan PMID- 21692257 TI - [Health system research in the Republic of Croatia 1990-2010]. AB - AIM: The aim of this study was to determine the scope and contents of peer reviewed scientific publications that bring the results of the Health System Research (HSR) in the Republic of Croatia during the 1990-2010 period. The basic guidelines are in line with the research project, Health Services Research into European Policy and Practice (HSREPP). This project is being implemented with the aim of identifying, evaluating and improving the contribution of Health System Research to the development of Health Policy in Europe. This study included scientific publications indexed in the PubMed database and master theses and doctoral dissertations published at Schools of Medicine in Zagreb, Osijek, Rijeka and Split during the 1990-2010 period. In accordance with the project methodology, scientific publications indexed in PubMed (http://www.ncbi.nlm.nih.gov/pubmed) were searched for by the key words "Croatia AND (Health Care System OR Health System OR Healthcare System)". Then, the database of scientific publications indexed in PubMed was narrowed by key words divided into 4 groups according to HSREPP instructions. The search for master theses and doctoral dissertations was carried out by direct inspection of the completed works in the library of Andrija Stampar School of Public Health, School of Medicine, University of Zagreb. Access to master theses and doctoral dissertations at the other three medical schools was done by the Internet. We analyzed the collected summaries of all publications, master theses and doctoral dissertations and excluded all those that did not correspond to our research. RESULTS: Using this method, we found a total of 536 publications indexed in PubMed-in, 70 master theses and 22 doctoral dissertations meeting the study criteria. For further analysis, we separately considered master theses and doctoral dissertations on the one side, and scientific publications indexed in PubMed on the other side. All papers were listed by the year of publication, the author and the means of publication. Upon inclusion of the key words, 277 papers met the required criteria. After abstract analysis, 158 PubMed indexed papers were found to meet all the criteria and addressed the Health System Research in Croatia. There was a significant increase in the number of published papers during the 5-year study period. Upon analysis of the summary contents of master theses and doctoral dissertations, we separated 6 doctoral dissertations and 35 master theses that met the criteria of the research. They were divided into four groups: research of macro-, mezzo- and micro-level of Health System and assessment of Health Care System results. The group investigating the organization and delivery of health services (meso-level) and the group investigating health technology assessment (micro/meso-level) predominated. There were only a small number of high quality researches dealing with HSR in Croatia. Descriptive approach to the analysis predominated. Reform interventions require research, but are not part of the designed strategy. Funding of HSR is an important issue. The research in Croatia is financed by the Croatian Ministry of Science, Education and Sports. In the UK and the USA, HSR is funded by the National Health Services. In all publications, we could not find a systematic research of the Health System; however, we recognized a growing trend in the number of articles dealing with HSR in Croatia over the past 20 years. Comparison of the number of papers on the Health Care System in Croatia indicated a significant lag in comparison to Western Europe, and similarity with the countries of Eastern Europe. PMID- 21692258 TI - [CroDiab web and improvement of diabetes care at the primary health care level]. AB - BACKGROUND AND AIM: Diabetes is a complex metabolic disorder regarded as one of the most significant public health issues of the 21S century. Keeping a diabetes registry facilitates monitoring of the epidemiological situation, while a structured approach to the registration of diabetic patients (reporting on an optimum information cluster for the follow-up and improvement of diabetes care) contributes to better regulation of patient risk factors. Active patient reporting at the primary health care level has begun in 2006 with setting up the legislative background. The aim of this study was to establish the effect of the CroDiab registry on metabolic parameters in type 2 diabetic patients treated at primary health care level by comparing diabetes indicators between the regularly annually reported type 2 diabetic patients and those that were only intermittently reported to the registry from 2006 until 2008. METHODS: Family physicians submit their reports mainly via CroDiab web, a Croatian web-based system for the collection of data on diabetic patients, which enables analysis of the basic clinical and public health indices. The levels of fasting and postprandial blood glucose, HbA1c, triglycerides, total cholesterol, HDL- and LDL cholesterol, systolic and diastolic blood pressure, and body mass index were analyzed in 2006 and 2008, and compared between the two study groups. RESULTS: At baseline, differences between the intermittently reported (I) and regularly reported (R) groups were only observed in the systolic (I 142.4+/-16.6, R 136.8+/ 16.6 mm Hg; p<0.001) and diastolic (1 83.9+/-8.2, R 82.1+/-10.0 mm Hg; P=0.002) blood pressure, while at the end of the study period differences were also recorded in postprandial blood glucose (I 10.63+3.12, R 10.02+/-3.44 mmol/L; P=0.024), HbA1c (I 7.97+/-1.52, R 7.39+/-1.17%; P<0.001), total cholesterol (I 5.60+/-1.15, R 5.25+/-1.13 mmol/L; p<0.001) and LDL-cholesterol (I 3.28+/-0.93, R 2.98+/-0.92 mmol/L; P<0.001). There were no statistically significant differences in body mass index, fasting glucose, HDL-cholesterol and triglycerides. DISCUSSION AND CONCLUSION: Electronic medical records and structured health care are associated with increased benefits and improvement in metabolic indicators at the primary health care level. Regular reporting and monitoring via CroDiab registry lead to a significant improvement in the majority of metabolic indicators, which is less marked with intermittent reporting. The more pronounced effect observed in the group of patients that were regularly covered by the registry could be attributed to a more comprehensive and regular insight and better patient care associated with continuous monitoring. Further efforts are therefore needed to achieve the widest possible implementation of the CroDiab web system to improve diabetes care at the primary health care level. PMID- 21692259 TI - [Does Croatia have hospital surplus?]. AB - BACKGROUND: In addition to human resources in health care, hospitals are unavoidable factor in international deliberations of development level of health systems. Besides education of health workers, equipped devices and efficiency of work in hospitals, it is important to compare the number of hospitals, their size, type of hospitals, their distribution and availability to users. These elements are essential to the overall quality and efficiency of health work of an area. AIM: To identify and analyze the hospital by the number, type and size, number and type of beds in them, and the disposition in relation to population and unit area (km2) in Croatia, County of Split-Dalmatia and other European countries in total and by groups of European countries by the gross national product per capita (GDP pc), in 2007. Based on the analysis, to answer the question whether Croatia has a sufficient number of hospitals, particularly in County of Split-Dalmatia and Dalmatia. METHOD: In this article are used methods of descriptive epidemiology based on available electronic data of the WHO Office for Europe. RESULTS: Of the 44 European countries, Croatia is in the 35th place with a total of 79 hospitals (1.7 hospitals/100,000 population; Europe 3.4/100,000). Without 10 hospital wards, and 6-of-hospital maternity, Croatian average is 1.4/100,000 which places Croatia in 41st place. By the number of acute hospitals with no out-patient clinic and maternity wards, Croatia is in the penultimate 43rd place with 36 hospitals (0.8/100,000; Europe 2.6/100,000). According to the average number of beds/100,000 population, Croatia is at the 23rd place (Europe: 489 beds/100,000 population; Croatia: 352 beds/100,000). By the size of the hospitals per average number of hospital beds per one acute hospital Croatia has no clinic and outpatient hospitals (446) which puts Croatia in the second place behind the Netherlands (541). According to the number of acute hospitals/1,000 km2 with no out-patient clinic and maternity wards, Croatia is at the 39th place (0.6/1,000 km2; European average without Russia: 2.3/1,000 km2). In Croatia, most hospitals/100,000 population has County of Pozega-Slavonia (3.5/100,000), while the least are in Split-Dalmatia County (0.4/100,000). The most acute hospitals are in County of Pozega-Slavonia (2.3/100,000), and the least in County of Split-Dalmatia (0.2/100,000) or 7 times less than the Croatian average, and 13 times less than the European average. By the number of acute hospitals with no out-patient clinic and maternity wards/1,000 km2 in Croatia, there are most hospitals together, in City of Zagreb and County of Zagreb (3/1000 km2), and the least in County of Lika-Senj and County of Split-Dalmatia (0.2/1,000 km2). DISCUSSION: Croatia is getting behind by the number of hospitals, compared to Europe, especially concerning acute hospitals. Given the density and area unit in the Southern Croatia there is a striking lack of acute hospitals, causing a disparity in the availability of hospital and specialist health care. To make hospital and specialist health care available to the 170,000 inhabitants of Dalmatia, who are more than an hour away from the hospital, it is necessary to replace outpatient-clinics and maternity hospitals with the general hospitals. CONCLUSION: Given the fact that Croatia is at the top of Europe by the size of the hospitals by the number of beds for acute patients, and there is the sufficient number of beds to population, but also a lack of spatial coverage of acute hospitals and therefore poor availability of hospital and specialist care for the advisory large population of south and east of the state and Istria. Croatia should achieve further necessary hospital facilities by planning and building small municipal/town/local hospitals for acute patients with the necessary agreed facilities at the headquarters of the former health centers where already exists specialist diagnostic and therapeutic activities of secondary level health care. PMID- 21692260 TI - [National colorectal cancer screening program in the Republic of Croatia- experiences, outcomes and obstacles in the program implementation in the Medimurje County]. AB - BACKGROUND: In the Medimurje County, colorectal cancer (CRC) poses a serious health problem. According to the incidence of CRC in men and women, and mortality in men, it is the second most common malignancy, and the leading one in women. Compared with the average in Croatia, the CRC mortality rate in Medimurje County is higher. CRC mortality can be reduced by repeat screening by fecal occult blood testing (FOBT). It is important to ensure successful implementation and continuous improvement of the national CRC program it Medimurje County. AIMS AND METHODS: This report describes the implementation of CRC screening in Medimurje County and performance indicators from the first 2.5 years. The main obstacles and suggestion for improvement are presented. Study results are compared with international references. The Institute of Public Health of Medimurje County has to collect data on the uptake, tests, lesions and key indicators needed for monitoring and epidemiologic evaluation of the program. RESULTS: Medimurje County is located in the northern part of the Republic of Croatia. The target group includes approximately 30,000 individuals suitable for CRC screening (aged 50-74 years). In the first screening round, between January 2008 and September 2010, 19,722 invitation letters with test kits (gFOBT) were sent to people born 1933 1945 and 1955-1957. The overall attendance to screening was 28.1%. Blood in the stool was detected in 12.6% of the individuals presenting for screening. The waiting time for follow up colonoscopy was too long (median 113 days). Colonoscopy rate reached 87.7/100 people with positive test. A total of 22 individuals were diagnosed with cancer and the percentage of cancer detected by colonoscopy was 6.4% (results were available for a total of 346 colonoscopies performed in people born between 1933 and 1942). The main limitations to program implementation are inappropriate software for data collection and the lack of a protocol for standardized data collection; the rate of positive test results is unacceptably high, local colonoscopy service is insufficient and waiting time for colonoscopy too long. Also, the inclusion of general practitioners (GPs) in the program has proved inadequate. The role of local public health institutes as coordinators is of crucial importance, but financial and human resources are inadequate. DISCUSSION: The participation rate in Medimurje County is higher than the national average, but lower in comparison with other neighboring countries that also use the same methods. Immunochemical FOBT had higher participation rate than guaiac test, so we should consider the choice of iFOBT in our program. Reminder letters had a significant impact on participation, so this strategy should be adopted. For better success of the program, the involvement of GPs should increase and it is important to make a strategic plan to improve the population and GP awareness of the screening program importance. CONCLUSION: The national program is tested in local conditions and it needs change based on the difficulties observed. The results of program implementation are quite satisfactory considering the conditions in which it is carried out, but less satisfactory than those reported from the neighboring countries. In the next period, the program should be allocated due financial and human resources, and it is important to agree upon a strategy that would yield the best results. PMID- 21692261 TI - [Monitoring of nitrate content in drinking water in Koprivnica-Krizevci County]. AB - AIMS: The aim of the study was to establish nitrate concentrations in drinking water originating from shallow wells across Koprivnica-Krizevci County, to assess the influence of agricultural point sources on nitrate water contamination, and to explore the correlations between water nitrate concentrations and agro ecologic factors. METHODS: During the 2002-2007 period, a total of 1170 potable water samples were taken from 104 shallow wells across Koprivnica-Krizevci County. Given the geographical and developmental determinants, the investigated area was divided into three sections: Koprivnica, Krizevci and Durdevac areas. Potable water was sampled throughout the 6-year, all season-period conformant to the HRN ISO 5667-3 standard. Nitrate concentrations in potable water samples were established using ion chromatography (HRN EN ISO 10304-1:1998). The total amount of downfalls subsequently correlated to nitrate concentrations was determined by summing up individual metric values provided by the State Meteorological and Hydrological Service. Data were analyzed in a descriptive manner and compared to the maximal allowable concentrations (MAC) stipulated under the Ordinance on Potable Water Safety, as well as to the limit values recommended under the Nitrates Directive. The X2-test produced statistically significant differences. RESULTS: In 25% (n=294) of water samples, nitrate concentration exceeded MAC. The majority of unsafe samples were recovered in Krizevci area (38%; n=382), followed by Koprivnica (23%; n=613) and Durdevac area (6%; n=175). The mean range spanned from 0.1 to 279.0 mg/L, while the total mean nitrate concentration was 41.7 mg/L. The highest mean nitrate concentration of 53.9 mg/L was measured in Krizevci area, followed by 38.8 mg/L in Koprivnica and the lowest 24.9 mg/L in Durdevac area. Out of 75% of safe water samples, the measured nitrate concentration was below 25 mg/L limit value recommended under the Directive in as much as 52% of samples. Given the detected nitrate concentrations in the sampled well water, the wells were classified as satisfactory, occasionally unsatisfactory and unsatisfactory. The influence of point sources was assessed based on their distance. In roughly 50% of samples taken from occasionally or definitely unsatisfactory wells, point sources were located up to 10 meters away, while in as much as 93% of samples taken from satisfactory wells the point sources were situated over 20 meters away (p<0.01). For some of the wells, statistically significant positive (r=0.45 to 0.87) or negative (r=-0.30 to -0.66) correlations between the amount of downfalls and nitrate concentrations were established, while in the third well group this correlation (r=-0.14 to -0.24) was lacking. DISCUSSION AND CONCLUSIONS: The results obtained are comparable to those of similar studies undertaken in regions having a similar agro-ecological and agricultural profile. Across the Koprivnica-Krizevci County, differences in the underground water quality may arise as a consequence of water contamination due to distinctive agricultural activities. The range of the mean nitrate concentrations established in potable water samples recovered from shallow wells was wide; the total mean nitrate concentration was relatively high (41.7 mg/L). The distribution of relative concentrations revealed 25% of samples to have nitrate concentrations higher than MAC under the Ordinance. Spatial distribution revealed the majority of unsafe water samples to stem from Krizevci area (38%), consistent with the majority of large husbandries situated therein. Contaminating point sources located not farther than 10 meters from shallow wells significantly influence the quality of drawn water. Respective of correlations between the amount of downfalls and water nitrate concentrations, both negative and positive links were established. PMID- 21692262 TI - [Pharmacoeconomic indicators of cardiovascular drug utilization in the Republic of Croatia and city of Zagreb in 2008]. AB - BACKGROUND: In comparison with original drugs, generic drugs have the same efficacy but considerably lower price and should therefore be preferred to original drugs on prescribing. The aim of the present study was to assess outpatient utilization and rationality of cardiovascular drug prescribing in the City of Zagreb and Republic of Croatia based on the generic to original drug prescribing ratio. METHODS: Data on the financial indicators and number of cardiovascular drug packages issued in 2008 were obtained from the Croatian Institute of Health Insurance. These data were used to calculate the number of defined daily doses (DDD) and number of DDD per 1000 inhabitants per day (DDD/1000/day). The index of generic/original drug utilization was determined for Zagreb and Croatia as a measure for assessment of prescribing rationality; the significance of difference was determined by X2-test. RESULTS: The rate of prescribing original cardiovascular drugs was significantly higher in Zagreb as compared with Croatia as a whole. The index of prescribing generic versus original drugs was 1.20 (249/208 DDD/1000/day) in Zagreb and 1.65 (249/151 DDD/1000/day) in Croatia. Difference in the utilization of generic drugs between Zagreb and Croatia as determined by X2-test (the level of statistical significance was set at P<0.05) was statistically significant (P=0.021). The highest differences were recorded in the most widely prescribed drug groups, i.e. ACE inhibitors with the generic/original drug index of 1.38 in Zagreb and 2.02 in Croatia; and hypolipemics with the generic/original drug index of 0.96 in Zagreb and 1.34 in Croatia. According to financial indicators, the generic/original drug index was 1.44 in Croatia and only 0.96 in Zagreb. CONCLUSION: The significantly greater influence of pharmaceutical industry marketing in Zagreb entailed the significantly higher rate of original drug prescribing, which is associated with considerably greater drug expenses. Measures to stimulate prescribing generic drugs should be launched at the national level. PMID- 21692263 TI - [Maintenance of work ability among hospital health care professionals]. AB - AIM: The aim of this study was to investigate the values of the Work Ability Index (WAI) and to analyze the factors that may be associated with work ability among hospital health care professionals. METHODS: A total of 1856 health care professionals employed at 5 Zagreb hospitals participated in this cross-sectional study. Data were collected using the Work Ability Index Questionnaire and Occupational Stress Assessment Questionnaire for hospital health care professionals. RESULTS: The average WAI of all participants was 38.68+/-6.28, indicating very good work ability. WAI was significantly higher in men than in women, 40.43+/-5.81 and 38.27+/-6.32, respectively (p<0.001). Younger participants had greater WAI compared with those of older age groups (p<0.001). There was a substantial difference in the proportions of participants in the categories of WAI (poor, good, very good and excellent) between physicians and nurses (p<0.001). Although physicians were considerably older than nurses (p<0.001), the proportion of those with excellent WAI was greater among physicians than among nurses, suggesting that the jobs of highly educated participants, which are characterized by broad decision-making latitude and promotion possibilities maintain work ability better in comparison with low decision-making latitude jobs and low control jobs. About 5 percent of all participants had poor WAI. We identified the following significant predictors of suboptimal WAI among health care professionals: female sex, age, service accrual, and stressors related to organization and financial issues (p<0.001), risks and hazards (p=0.040), and shift work (p=0.001). CONCLUSION: The average WAI of all participants indicated very good work ability, but small percent of them had poor WAI. Our results suggest the need of preventive measures that would target maintenance of work ability at an organizational and individual level. The organizational level should include the provision of a sufficient number of workers, adequate financial resources for work and adequate salaries, less paperwork, positive collaboration with the public, especially media, and education of medical staff on the risks and hazards at work. The individual level should include individual assessment of sensitivity to night work and shift work considering age and health status, and training in stress management techniques. PMID- 21692264 TI - [Community health course--student's evaluation]. AB - INTRODUCTION: Since 1952, Andrija Stampar School of Public Health, School of Medicine, University of Zagreb, has provided a community health course, based on the medical education approach that the main fields of physicians' action are human settlements and not only consulting rooms and clinics. AIM: The aim of the study was to compare community health course students' evaluations immediately after attending the course at the 4th and 6th study years. SUBJECTS AND METHODS: The survey included 224 4th year medical students attending the community course during the academic year 2007-2008 and 192 same-generation 6th year students (85.7%) during the academic year 2009-2010. Students were required to fill out an evaluation questionnaire about the activities during the community health course using grades from 1-poor to 5-excellent, and to write personal remarks and essay. RESULTS: The academic year 2007-2008 students (n=224) were very satisfied (grades 5 and 4) with preparatory seminar (98% of students), final seminar (97%), course organization (90%) and course contents (89%). The same grades were allocated by 98% of students to public health field research, 94% to work in community nurse service, 93% to work in family practice and health promotion in school and kindergarten, and 87% to water sampling. Satisfaction with the community health course was very emotionally described in final essays: "... work with community nurse service in the poorest part of Croatia has changed my life. I have learned in only few hours to wish less and to give more. Every physician should experience it, because that is real life". Results of the same-generation students (n=192) in the academic year 2009-2010, now at 6th study year, showed them to be still very satisfied (grades 5 and 4) with the activities in the community health course: 94% with health promotion, 92% with work in the community nurse service and family medicine, 86% with course contents, 82% with course organization, 78% with final seminar, 64% with preparatory seminar, 63% with field research, and 49% with water sampling. DISCUSSION: At some medical schools, there are similar attempts to bring students more closely to life conditions, especially to rural communities. Different schools of medicine in the world have attempted to improve and adapt current curricula towards community oriented education of medical students during undergraduate study and residency. In some countries, there is also the need of improvement of health care in rural areas. CONCLUSION: Results of the course evaluation showed that students had recognized the exceptional value of community health course as a whole. They perceived it as the most valuable and most useful experience in their medical study. By participating in local health care and social care activities in rural area, they got an insight into both the health care system and socio-medical determinants of health. PMID- 21692265 TI - [Quality improvement of health care services in Croatian emergency medicine]. AB - Emergency medical services (EMS) in the Republic of Croatia are currently organized as part of the existing health care system and delivered in the form of pre-hospital and hospital EMS. The pre-hospital EMS are delivered by standalone EMS Centers, EMS units set up in community health centers, and by general practitioners working in shifts and on call in remote and scarcely populated areas. In hospitals, each ward usually has its own emergency reception area, and only in a couple of cases there is an integrated emergency admission unit for the entire hospital. The current EMS structure does not meet the basic requirements that would make an EMS system optimal, i.e. equal quality, equal access, effectiveness and appropriate equipment. The EMS Restructuring Project is part of the Croatian health care system reform and is addressed by the National Health Development Strategy 2006-2011. As part of restructuring efforts, the Croatian National Institute of Emergency Medicine, 21 County Institutes of Emergency Medicine and county-level call centers are going to be set up. In addition, the project will introduce the following: integrated emergency admission areas at hospitals; telemedicine as part of emergency medicine; emergency medicine specialty for physicians and additional specialized training for nurses/technicians; separation of emergency and non-emergency transport; standards for vehicles and equipment and guidelines/protocols/algorithms for care. The Croatian National Institute of Emergency Medicine is an umbrella EMS organization. It shapes the EMS in Croatia and proposes, plans, monitors and analyzes EMS actions in Croatia. In addition, it submits a proposal of the Emergency Medicine Network to the minister, sets standards for EMS transport, and coordinates, guides and supervises the work of County Institutes of Emergency Medicine. County Institutes organize and deliver pre-hospital EMS in their counties. Integrated hospital emergency admission units represent a single point of entry for all emergencies at a particular hospital. Upon triage, depending on the level of emergency, patients are provided with appropriate care and treatment. The introduction of EMS specialty for physicians and additional specialized training for nurses/ technicians is going to increase competencies of all EMS team members. The main objectives of the EMS Restructuring Project to be achieved in the 5-year period are the following: to reduce the response time of pre-hospital EMS teams to 10 minutes in urban areas and 20 minutes in rural areas in 20% of team interventions; to bring patients to hospital within the "golden hour" in 80% of cases; to have 200 physicians specialized in emergency medicine; and to have 220 nurses/technicians that have successfully completed their specialized training in emergency medicine. The objectives are going to be monitored through indicators as part of the World Bank Project for which data have already been collected throughout Croatia: number of interventions; number of emergency interventions; time between call receipt and arrival to scene; time between call receipt and arrival to hospital emergency reception area; percentage of arrivals to hospital by EMS vehicles within 12 hours of symptom onset; polytrauma and cardiac arrest survival rate before admission to hospital; time spent in hospital emergency reception areas and integrated hospital emergency admission units; polytrauma and cardiac arrest survival rate within 24 hours of hospital admission; number of integrated hospital emergency admission units per county; and number of pre-hospital EMS teams per capita. PMID- 21692266 TI - [Efficacy of public health surveillance systems]. AB - Public health surveillance system (PHSS) serves for continuous and systematic data collection, analysis and interpretation, in order to enable planning, implementation and evaluation of public health practice. PHSS should alert to events (usually unwanted), assist to create public health policy and strategies, document effects and achieving the goals as well as setting public health priorities. Surveillance systems monitor communicable and non-communicable diseases, health resources and public health programs and interventions. The main drawback of the existing PHSS is fragmentation and delay of information, usually not up-to-date. Modern information and communication technology enables getting data from hospitals and other health information systems directly, and use them for surveillance. Our model of surveillance system appeared as not standalone but an integrated system getting data that are by-product of frontline workers. Therefore, the electronic health records should be the source of data for disease surveillance. Medical, nurse and similar schools as well as the Ministry of Health and health institutions could be data sources for health personnel surveillance. Medical devices can be monitored by data coming from institutions and bodies dealing with such devices. Public health programs defined by institutions and bodies can be monitored by them and others taking part in implementation. Therefore, they all can be the source of data for surveillance of public health programs and interventions. Without such systems, any rationalization in health care and better quality is not possible. Therefore, the present public health surveillance system should be improved, as we have suggested, by using current information and communication technology and integrating the data that are by-product of the frontline worker, and by including the end users in system development at the very beginning. PMID- 21692267 TI - [Quality of health care, accreditation, and health technology assessment in Croatia: role of agency for quality and accreditation in health]. AB - Avedis Donabedian defined the quality of care as the kind of care, which is expected to maximize an inclusive measure of patient welfare, after taking into account the balance of expected gains and losses associated with the process of care in all its segments. According to the World Medical Assembly, physicians and health care institutions have an ethical and professional obligation to strive for continuous quality improvement of services and patient safety with the ultimate goal to improve both individual patient outcomes as well as population health. Health technology assessment (HTA) is a multidisciplinary process that summarizes information about the medical, social, economic and ethical issues related to the use of a health technology in a systematic, transparent, unbiased, robust manner, with the aim to formulate safe and effective health policies that are patient focused and seek to achieve the highest value. The Agency for Quality and Accreditation in Health was established in 2007 as a legal, public, independent, nonprofit institution under the Act on Quality of Health Care. The Agency has three departments: Department of Quality and Education, Department of Accreditation, and Department of Development, Research, and Health Technology Assessment. According to the Act, the Agency should provide the procedure of granting, renewal and cancellation of accreditation of healthcare providers; proposing to the Minister, in cooperation with professional associations, the plan and program for healthcare quality assurance, improvement, promotion and monitoring; proposing the healthcare quality standards as well as the accreditation standards to the Minister; keeping a register of accreditations and providing a database related to accreditation, healthcare quality improvement, and education; providing education in the field of healthcare quality assurance, improvement and promotion; providing the HTA procedure and HTA database, supervising the healthcare insurance standards, and providing other services in the field of healthcare quality assurance, improvement, promotion and monitoring, according to the Act. Formal activities of the Agency in the field of HTA actually began in summer 2009. In the field of quality and accreditation, the plan and program of healthcare quality assurance, improvement, promotion and monitoring was finished and published in October 2010; preparation of the healthcare quality standards as well as the accreditation standards is still in process, with the aim to start accreditation process at 10 hospitals in 2011. Education in the field of healthcare quality assurance, improvement and promotion has been established as a continuous process from the beginning. The Agency is member of the International Society for Quality in Health Care (ISQua) and participates in the work of the European Accreditation Network (EAN). In the field of HTA, the Agency has established international collaboration and support, which resulted in its appointment and participation in the European network for Health Technology Assessment (EUnetHTA) Joint Action Project as a EUnetHTA Partner, as well as its membership in the international society, HTAi. TAIEX project has been approved as a two-day workshop in December 2010. The Croatian HTA Guidelines have been issued with the aim to start the HTA process and reports that should serve as recommendations, as a support to policy-makers at the national level, in particular the Croatian Ministry of Health and Social Welfare, and Croatian Institute of Health Insurance, in making evidence-informed decisions on the strategic planning, investment, management and implementation of technologies in health care, on funding (reimbursement) and coverage of health technologies, and at hospital level on the request from hospital directors and policy teams. In conclusion, establishment of all these measures in Croatia is by no means an easy and quick process, however, we do believe that it is feasible through continuous and close collaboration of all those involved. PMID- 21692268 TI - [Adverse health events and health hazards reflections of epidemiologists and environmentalists]. AB - In this article we present management of water resources in Croatia as a model of integral approach in public health interventions. The links between provision of clean water, sanitation and good health are so strong that today management and water protection are deeply integrated in primary health care. This article is a follow up on topics presented on 2nd Croatian congress on preventive medicine and health promotion which gave us "state of art" in Croatian public health. We strongly believe that every system has its own advantages and downsides, and only by knowing the system well and continuous improvement we can protect ourselves in time of health, social or economic crisis. The model of water protection showed that to prevent and overcome the variety of water-related health risks, implementation of various activities that include general environmental protection, development of water management system, permanent water quality monitoring and control, and improvement of standards and legislative is needed. On the other hand if there is no holistic approach, to the public health problems, all the efforts in just one field will not result in health indicators improvement. Constant monitoring and uniform analysis of data could help to identify possible risks of adverse effects of various environmental factors and possible burden of disease as a consequence. That information could be a point of arguing with local governments and communities for public health interventions. It is important that epidemiological and environmental data do not remain in the domain of academic discussion or statistics, and never reach primary health care which could use them in direct health care providing. Information exchange in real time is important for the real time public health intervention. Primary health care is the front line in communication with patients and diagnostics of disease as well as prevention, and they need to have access to all relevant data. PMID- 21692269 TI - [Preventive work in family medicine--proactive approach]. AB - The role of general practitioner/family physician (GP/FP) in disease prevention and health promotion is strongly supported by research and health policies. The position of GPs/FPs in the health care system and their close, sustained contact with their patients and local community makes preventive care an integral part of GP/FP routine work. The spectrum of caring for patients in general practice/family medicine is actually very large, going from intervention on health care determinants to palliative care. The prevention-related activities are more or less present at each step of this "healthcare continuum". The significant gaps between GP/FP knowledge and practices persist in the use of evidence-based recommendations for health promotion and disease prevention. We describe the role of GP/FP in preventive care and report data on preventive care activities in the Croatian Family Medicine Service. More objective evidence is needed to see what GPs/FPs actually do in practice. For this reason, it is critical that GPs/FPs systematically record the most relevant preventive and health promotion activities that they perform. Furthermore, their performance of the preventive program should be regularly monitored, evaluated and professionally and financially validated. We present the preventive program based on these principles in Family Medicine Service proposed by the Ministry of Health and Social Welfare Working Group on Reform of Primary Health Care. PMID- 21692270 TI - [Analysis of the results of mammography screening in Dubrovnik-Neretva County in the 2006-2009 period]. AB - AIM: To analyze the results of the first cycle of mammography screening during implementation of the National Program for Early Breast Cancer Detection (National Program) for women aged 50-69 in the Dubrovnik-Neretva County (DNC) in the 2006-2009 period, and to present new cases of breast cancer among women undergoing screening. METHODS: Data were collected from the DNC Institute of Public Health database. Mammography results were classified according to the Breast Imaging Reporting and Data System (BI-RADS classification). Descriptive method was used to analyze the results of mammography screening. RESULTS: A total of 19,475 women aged 50-69 were invited to the first cycle of mammography screening for early breast cancer detection, conducted from October 2006 to October 2009 in DNC. The overall turnout in mammography screening was 59.5%; according to age groups, it was 61.8%, 60.6%, 58.5% and 56.8% for 50-54, 55-59, 60-64 and 65-69 age group, respectively. According to BI-RADS classification, BI RADS 0 was recorded in 886 (10.0%), BI-RADS 1 in 2993 (33.8%), BI-RADS 2 in 4023 (45.4%), BI-RADS 3 in 864 (9.8%), BI-RADS 4 in 87 (1.0%) and BI-RADS 5 in eight (0.1%) women. Fifty-seven new cases of breast cancer were diagnosed in the first cycle of mammography screening. Among newly diagnosed cases of breast cancer, in the category of BI-RADS 0, 4 and 5 malignancy was confirmed in 55.6%, 13.9% and 30.6% within 45 days, 46-90 days and more than 3 months of mammography. DISCUSSION: Study results indicated a total turnout on mammography screening of 59.5%, which was below the goal set in the National Program of 70%, and also below the acceptable response rate of 70% or more according to the European guidelines for quality assurance in breast cancer screening. Comparison of our rate of newly diagnosed cancer cases (6.3/1000 screened women) with the rates from other countries (range, 1.8 to 10.1/1000) published in the literature, our rate of mammography screening was in the middle of other countries' range. The "recall rate" in DNC was 11.1%, which is higher than acceptable (acceptable, <7%). The National Program specifies that diagnostic evaluation of all women with suspect findings should be completed within one month, however, in DNC 48.5% of women with newly diagnosed breast cancer of the BI-RADS 4 or 5 group were processed within a month. Diagnostic evaluation of all women with suspect findings was difficult to achieve due to the lack of necessary equipment and experts. CONCLUSION: It is crucial to ensure quality and systematic promotion of the importance of mammography screening, to improve the level of cooperation between all holders of program activities, and to shorten the time interval between mammography recording and additional diagnostic and therapeutic procedures for women with lesions suspect of malignancy (to provide appropriate diagnostic and therapeutic care). PMID- 21692271 TI - [National program of early detection of cancer in Croatia]. AB - INTRODUCTION: A well organized and conducted program of cancer screening at the population level should be scientifically based, cost-effective at long term, and designed on the good practice examples. Appropriate diagnosis and treatment should be warranted by high rate of target population inclusion, while appropriate diagnosis and treatment should be warranted for those with positive findings. AIM: The aim is to present implementation of the national programs of early detection of breast and colon cancer in Croatia. RESULTS: In the first cycle screening for breast cancer (since the end of 2006), a total of 720,981 women were invited for mammography, of which 58.5% presented for screening, with more than 1500 cases of breast cancer detected. A total of 808,913 tests were distributed for colon cancer screening from the end of 2007 to the beginning of 2010, of which only 19.9% were returned, 7.7% of these positive. Colonoscopy yielded 77.5% of pathologic findings, including 388 (5.99%) carcinomas, 2492 (38.46%) polyps, 1641 hemorrhoids and 998 diverticula. CONCLUSION: In Croatia, the public health service has made maximal use of all its resources in the national programs of early cancer detection. Great efforts and time, along with continuous education of all those involved in the program, have been invested in preparatory activities, organization and coordination of the program, contacts and collaboration with family physicians, specialist units, mass media, regional and local authorities, partnership with non-governmental societies, monitoring, evaluation and quality control. PMID- 21692272 TI - [Review of the program of early detection of cervical cancer in women in Primorsko-Goranska County in 2009]. AB - INTRODUCTION: Cervical cancer is the most common cancer in women, the second most frequent malignancy in women and the second most common cause of death in women suffering from cancer worldwide. In 2009, in the Primorje-Goranska County 52 (4.1%) women were hospitalized for the treatment of cervical cancer. AIM: The aim of this paper is to show the methodology and results of the County program in 2009. METHODS: The County Institute of Public Health (IPH) has been conducting this screening program systematically since 2006. In 2009, screening was conducted at six gynecologic practices with coverage of 6000 women. Prior to Program performance, the IPH provide the gynecologists with all necessary logistics (brushes for cytobrush technique, Pap tests, addressed envelopes, invitation letters and patient questionnaires). The gynecologists include women by random choice, each gynecologist around 1000 women of the specified age group. They send invitations to women with specified date and time of testing. Swabs are referred to the Cytology Laboratory, Rijeka University Hospital Center in Rijeka. For the purpose of this Program, IPH has designed a questionnaire for women, containing 13 questions. Patients give the questionnaires back to the gynecologists, who send them to the IPH for statistical analysis. Data collected from the questionnaires and Pap test findings are entered in a specially designed computer program. During Program implementation, the IPH, gynecologists and cytologists work together to improve the quality of testing. For the purpose of education of women about sexual health and to improving the response rate, IPH has created and distributed 10,000 educational brochures entitled Sexual health of women, the knowledge is power. RESULTS: In 2009, the response rate in the Program was 41.9% (n=2514). Cytologic analysis of Pap tests yielded 94.5% of negative results and 5.1% of abnormal findings. Adequacy of 99.6% of Pap smears was satisfactory, while 0.4% of samples were of poor quality that could not be analyzed. Results showed 66.7% of women to undergo gynecologic examination once a year, whereas 17.9% of women had not been for gynecologic examination for more than 3 years. The majority (90.7%) of women that participated in the Program were visiting the chosen gynecologist at primary health care. DISCUSSION: Throughout the Program implementation, the leading problem continued to be low turnout of gynecologists for inclusion in the Program and poor turnout of invited women. The cause of this problem lies in the insufficient number of gynecologic teams and too many women in care of one gynecologist. This problem points to the need of restructuring of primary health care for women with emphasis on the number of health professionals. Results of the analysis of two questions in the questionnaire indicated inadequate knowledge of women about the importance of regular gynecologic control. When planning screening program in the coming years, attention should be focused on the motivation of women of younger age groups as well as those that are irregularly controlled. CONCLUSION: Organized screening can reduce the risk and mortality of cervical cancer. It is also known that with a relatively small investment but with better health care organization, the response of women can increase. Taking into account the threat posed by cervical cancer for women's health and social burden, the need of prevention strategies, primarily screening tests, is clear as a means for early detection of the problem and timely removal of abnormal cells. PMID- 21692273 TI - [Examples of results of pharmaceutical cerebrovascular protection, with special emphasis on the statins]. AB - Despite that hypercholesterinemia is not a risk factor of stroke, treatment with statins is able to reduce these events in a clinically relevant degree. Intervention trials suggest that while for primary prevention, statins are effective in conventional dose, after stroke or TIA this is true only if LDL cholesterol is reduced below 1,8 mmol/L. To reach this goal, usually intensive antilipid treatment is necessary. There are studies showing beneficial impacts of other lipid drugs, beyond statins, i.e. fibrates and fish oil (among the settings of primary, and secondary preventions, respectively). Against cerebro-vascular events, pleiotropic effects of some antihypertensive and antidiabetic medications can also be established. PMID- 21692274 TI - [The role of sleep dynamics and delta homeostasis in cognitive functions]. AB - The paper is aimed to introduce the neuronal network basis of dynamic sleep processes, including the micro-structure of sleep and the relationship of sleep dynamics with homeostatic regulation and plastic changes during sleep. Newer studies tend to show that beyond the wellknown long-term homeostatic and circadian regulation of NREM sleep, sleep is regulated by a stimulus and arousal dependent flexible defense system, the elements of which participate in sleep delta homeostasis. Within the EEG elements of sleep a more larger amount represents reactible type as it was thought previously. Both the events of wake state and sensory input during sleep are shaping the sleep EEG in a function- and localisation specific way and the next day cognitive functios are determined by these changes. PMID- 21692275 TI - [Neurology 2009: a survey of Hungarian neurology capacities, their utilization and of neurologists, based on 2009 institutional reports in Hungary]. AB - A detailed information on the quantitative and qualitative features and the regional distribution of the current neurological services at the national level is necessary for the planning of health care provision for the future. We present the characteristics of the current neurological services analyzing the database of the National Health Insurance Fund for 2009. This database is exceptionally large and detailed compared to similar data sources in Europe. We examine the number of patients and cases treated both in hospitals and at outpatient units, and also present the distribution of major diagnoses based on ICD-10. We discuss the major problems in three groups: the decrease of capacities; the fragmentation of capacities; and the uneven distribution of workload on neurologists. Number of neurological hospital beds, weekly hours of neurological outpatient capacity, and the number of neurologists are presented. In the analysis of the utilization of capacities we give the number of patients, the number of cases and the financing of the professional performance. We characterize the workload of neurologists by the mean daily number of patients seen by a neurologist, by the number of outpatient units served by one neurologist during the year, and by the proportion of the total workload on each neurologist. Neurological capacities significantly decreased in the period of 2004-2009: 12 hospital neurological wards were closed, and with further decreases in bed numbers the original 3733 neurological beds decreased to 2812. In four counties--Bacs, Heves, Tolna and Vas--only a single neurological ward survived. The capacity withdrawn from inpatient care was not transferred into outpatient services. In 2009 there were 179 hospitals and 419 independent outpatient centers in Hungary. Of the 179 hospitals 55 had neurological beds and a further 42 hospitals offered only outpatient neurological service. Neurological outpatient service is offered in Hungary altogether by 185 institutions: 97 hospitals and 88 independent outpatient centers. Suboptimal outpatient services (less than 30 hours per week) cover 57% of the outpatient capacities. There is an over fivefold difference among counties in capacities: the number of inhabitants per hospital bed ranges between 2167-13 017, and the number of inhabitants per one neurologist outpatient hour between 495-2663. In 2009 there were 1310 board certified neurologists in Hungary, of these only 834 participated at least once during the year in exclusively neurological service, and there was a large difference in workload among individual neurologists. The gross mean income of a 30-hour-per-week average neurological outpatient practice based on performance reports was 871 thousand HUF (about 4350 USD or 3160 EUR) per month. In recent years the neurological capacities significantly decreased and fragmented, do not correspond regionally to the number of population to be served, and their profitability does not cover the conditions of self sufficient operation. This analysis will help health care providers and decision makers to recognize and address the current problems and design the neurological health care system for the coming years. PMID- 21692276 TI - [Neuropsychiatry--in Hungary and in other countries]. PMID- 21692277 TI - [Randomized controlled study on dysphagia after stroke treated with deep insertion of Chonggu (EX-HN 27) by electroacupuncture]. AB - OBJECTIVE: To explore the therapeutic effect of dysphagia after stroke treated with different depth of Chonggu (EX-HN 27) by electroacupuncture. METHODS: Two hundreds and eighty-three cases of dysphagia after stroke were randomly divided into Chonggu (EX-HN 27) deep insertion group (99 cases), Chonggu (EX-HN 27) shallow insertion group (94 cases) and traditional acupuncture group (90 cases) based on multi-central randomized control and blinding methods. Besides routine therapy, Chonggu (EX-HN 27) and Lianquan (CV 23) were selected in the Chonggu (EX HN 27) deep insertion group and the Chonggu (EX-HN 27) shallow insertion group; the needles were inserted for 60-75 mm and 30 mm respectively and the electroacupuncture was applied in both groups; in traditional acupuncture group, Fengchi (GB 20), Yifeng (TE 17), Wangu (GB 12) and Lianquan (CV 23), etc. were selected. The needles were retained for 30 min, twice a day and 30 treatments totally in 3 groups. The clinical therapeutic effects were evaluated by Kubota's Water Drinking Test Scale, Standard Swallowing Function Scale and TCM Scale of Dysphagia After Stroke. RESULTS: The total effective rate was 97.0% (96/99) in the Chonggu (EX-HN 27) deep insertion group, superior to that of 64.9% (61/94) in Chonggu (EX-HN 27) shallow insertion group and 70.0% (63/90) in traditional acupuncture group (both P < 0.05). Compared with the scores before and after treatment, significant differences were presented statistically in score reduction of TCM Scale in Chonggu (EX-HN 27) shallow insertion group (P < 0.01); the scores of Kubota's Water Drinking Test Scale, Standard Swallowing Function Scale and TCM Scale of Dysphagia After Stroke were obviously reduced in Chonggu (EX-HN 27) deep insertion group and traditional acupuncture group (all P < 0.01); compared with the scores between groups after treatment, the reduction of scores in Chonggu (EX-HN 27) deep insertion group was superior to those in Chonggu (EX HN 27) shallow insertion group and traditional acupuncture group ( P < 0.05, P < 0.01) respectively. CONCLUSION: Puncture at Chonggu (EX-HN 27) can improve the dysfunction of swallowing after stroke; it is safe and effective, and the needle should be inserted deeply. PMID- 21692278 TI - [Case of neurosis in heat invasion of the blood type]. PMID- 21692279 TI - [Effects of eye acupuncture on SEPCT-determined cerebral blood flow in patients with cerebral infarction]. AB - OBJECTIVE To verify the correlation between the points of eye acupuncture and zang-fu function so as to provide the theoretical evidence for the principle of point selection in eye acupuncture therapy. METHODS: Sixty cases of cerebral infarction were treated with different points according to syndrome differentiation of Chinese medicine. MAIN POINTS: upper energizer area and lower energizer area. Supplementary points: liver area, kidney area and spleen area for hyperactivity of wind, phlegm and fire; liver area and spleen area for blockage of wind, phlegm and stasis; stomach area and large intestine area for excess fu syndrome due to phlegm heat; heart area and spleen area for qi deficiency and blood stasis; liver area and kidney area for yin deficiency and wind stirring. The single photon emission computed tomography (SPECT) was adopted to observe the changes in blood flow in local foci before and after treatment with eye acupuncture. RESULTS: After the treatment with eye acupuncture therapy, the intake ratio of region of interest (ROI) between the lesion area and corresponding area on the opposite side was 0.74 +/- 0.12 before eye acupuncture and was 0.91 +/- 0.08 after treatment, indicating significant statistical difference in comparison (P < 0.05). After eye acupuncture, cerebral blood flow increased apparently. CONCLUSION: The point selection according to syndrome differentiation in eye acupuncture therapy may increase local brain blood flow in the patients with cerebral infarction and improve the state of brain ischemia so that the correlation can be proved between the points of eye acupuncture and zang fu function. PMID- 21692280 TI - [Ear expansion and hearing loss treated by acupuncture]. PMID- 21692281 TI - [Intervention on network craving and encephalofluctuogram in patients with internet addiction disorder: a randomized controlled trial]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) combined with psychological interference on abstinence symptom such as network craving and anxiety in internet addiction disorder (IAD) and explore its mechanism. METHODS: One hundred and twenty cases of IAD were randomly divided into EA group, psychotherapy group and EA plus psychotherapy group (combined therapy group). In EA group, Baihui (GV 20), Sishencong (EX-HN 1), Hegu (LI 4), Neiguan (PC 6), Taichong (LR 3) and Sanyinjiao (SP 6) were selected in EA, once every 2 days, for 20 sessions totally. In psychotherapy group, the cognition and behavior therapy was applied, once every 4 days, for 10 sessions totally. In combined therapy group, EA combined with psychological interference was administered. The changes in IAD self-scale table, network craving scale, ZUNG self-rating anxiety scale (SAS) and S spectrum of encephalofluctuogram (ET) were observed before and after treatment. RESULTS: After treatment, the results of IAD self-scale table, network craving scale and ZUNG SAS in combined therapy group were reduced significantly as compared with those before treatment (all P < 0.01) and the score of IAD self scale table was lower significantly as compared with EA group and psychotherapy group (P < 0.01, P < 0.05), and the score of network craving scale was lower than that in psychotherapy group (P < 0.01). S11 spectrum in combined therapy group decreased significantly as compared with that before treatment (P < 0.05) and was lower significantly as compared with psychotherapy group and EA group (both P < 0.05). CONCLUSION: Electroacupuncture combined with psychological interference can reduce network craving and anxiety of IAD patients and its mechanism is probably related with the decrease of dopamine content in central system. PMID- 21692282 TI - [Clinical observation of integrated acupuncture and herbal medicine for constipation of excess fu syndrome due to phlegm heat in acute cerebral infarction]. AB - OBJECTIVE: To explore the optimal therapy for constipation of excess fu syndrome due to phlegm heat in acute cerebral infarction. METHODS: One hundred and sixty cases were randomized into acupuncture plus herbal medicine group, Chinese herbal medicine group, acupuncture group and Glycerine Enema group, 40 cases in each one. All the patients of 4 groups had received the conventional management in neurological internal medicine department and acupuncture according to the theory of SHI's regaining consciousness. Additionally, in acupuncture plus herbal medicine group, acupuncture and oral administration of Chinese herbal medicine were adopted. Acupuncture was applied to Shaoshang (LU 11), Shangyang (LI 1), Fenglong (ST 40), Tianshu (ST 25), Zhigou (TE 6), etc. Chinese herbal medicine was composed of Jinyinhua (Lonicera Japonica), Liangqiao (Fructus Forysthiae; Weeping Forsythia), Huangqin (Radix Scutellariae), Zhizi (Gardenia jasminoides Ellis; Cape Jasmine), Dannanxing (Rhizoma Arisaematis Cum Bile), Quangualou (Fructus Trichosanthis), etc. In acupuncture group, acupuncture was used simply. In Chinese herbal medicine group, only Chinese herbal medicine was administered orally. In Glycerine Enema group, Glycerine Enema was adopted. The interval time of defecation, stool quality, efficacy on constipation and nerve function score in 7 days and 21 days after treatment were compared among groups. RESULTS: After 7 days treatment of constipation, the total effective rate was 97.5% (39/40) in acupuncture plus herbal medicine group, which was superior apparently to 87.5% (35/40) in Chinese herbal medicine group, 82.5% (33/40) in acupuncture group and 80.0% (32/40) in Glycerine Enema group (all P < 0.05). After 21 days treatment, the total effective rate of constipation was 92.5% (37/40) in acupuncture plus herbal medicine group, which was superior apparently to 82.5% (33/40) in Chinese herbal medicine group. 80.5% (32/40) in acupuncture group and 67.5% (27/40) in Glycerine Enema group (all P < 0.01). The differences in the interval time of defection, stool quality and nerve function score after 7 days and 21 days treatment were significant statistically in comparison among 4 groups (P < 0.05, P < 0.01). The results in acupuncture plus herbal medicine group were superior apparently to the other groups. CONCLUSION: The integrated acupuncture and herbal medicine is effective definitely on constipation in acute cerebral infarction. Additionally, this therapy may improve the clinical efficacy of cerebral infarction and suggest the coordination between acupuncture-moxibustion and Chinese herbal medicine. PMID- 21692283 TI - [Observation of therapeutic effects on cervical vertigo treated with different methods]. AB - OBJECTIVE: To compare the therapeutic effects of routine acupuncture, the electroacupuncture and the combined therapy of electroacupuncture and acupoint injection. METHODS: Ninety-one cases were randomly divided into a routine acupuncture group (30 cases), an electroacupuncture group (31 cases), and a combined therapy of electroacupuncture and acupoint injection group (30 cases). Zusanli (ST 36), Fengchi (GB 20), Anmian (Extra), Taiyang (EX-HN 5), Hegu (LI 4), Yintang (EX-HN 3), Baihui (GV 20) and Sishengcong (EX-HN 1) were selected among 3 groups. Even manipulation was applied in routine acupuncture group; G 6805 electroacupuncture apparatus was added in electroacupuncture group; in combined therapy of electroacupuncture and acupoint injection group, electroacupuncture was applied, besides, Vitamin B12 0.5 mg and 0.2%/ Lidocaine 2 mL were injected at Fengchi (GB 20) and Anmian (Extra). Twenty treatments were given in 4 weeks. The changes of average blood flow of vertebral artery and basilar artery before and after treatment were observed and graded by the cervical vertigo syndrome and function score; the therapeutic effects were evaluated as well. RESULTS: The average blood flow of vertebral artery and basilar artery, and the cervical vertigo syndrome and function score were improved in 3 groups (all P < 0.01), in which, it was more obvious in combined therapy of electroacupuncture and acupoint injection group than in others (P < 0.05, P < 0.01), and it in electroacupuncture group was superior to that in routine acupuncture group (P < 0.05). The effective rate was 63.3% (19/30) in routine acupuncture group, 80.6% (25/31) in electroacupuncture group and 90.3% (28/30) in combined therapy of electroacupuncture and acupoint injection group, indicating the significant differences among them (P < 0.05, P < 0.01). CONCLUSION: The routine acupuncture, electroacupuncture, and combined therapy of electroacupuncture and acupoint injection are effective for cervical vertigo; the combined therapy is the best, and electroacupuncture comes second. It illustrates that the routine acupuncture, electroacupuncture, and combined therapy of electroacupuncture and acupoint injection have additive effects on treatment of cervical vertigo. PMID- 21692284 TI - [Observation of therapeutic effect on perineal, crissal and progenital pruritus treated with acupuncture according to differentiation]. AB - OBJECTIVE: To observe the therapeutic effect and safety of perineal, crissal and progenital pruritus treated with acupuncture according to differentiation. METHODS: Self-control method was applied in these 32 cases. Changqiang (GV 1), Huiyin (CV 1), Qugu (CV 2), Sanyinjiao (SP 6) and Ashi points etc. were punctured as main points, and adjunct points were added according to differentiation: Taichong (LR 3) and Ququan (LR 8) etc. were added for wind and heat excess of liver meridian, Xuehai (SP 10) and Quchi (LI 11) etc. were added for blood deficiency and wind dryness. Itchiness, skin lesions sign scores and therapeutic effects were observed before and after treatment. RESULTS: The total scores of itchiness before and after treatment were 6.06 +/- 1.46 and 2.19 +/- 1.71 respectively, and the total scores of skin lesions sign were 4.38 +/- 2.21 and 1.50 +/- 1.44, indicating that the scores and the total scores of itchiness and skin lesions sign reduced obviously after treatment (P < 0.05, P < 0.01); the cured and markedly effective rate was 73.4% (11/15) for wind and heat excess of liver meridian, and 70.6% (12/17) for blood deficiency and wind dryness, presenting similar therapeutic effect (P > 0.05). Hematoma or ecchymosis appeared in 2 cases, and disappeared spontaneously after 2-3 days, without obvious adverse reaction. CONCLUSION: Simple perineal, crissal and progenital pruritus treated with acupuncture according to differentiation is effective, safe and applicable. PMID- 21692285 TI - [Effect of electroacupuncture at Chengshan (BL 57) on postoperative pain of mixed hemorrhoids]. AB - OBJECTIVE: To discuss the effect of electroacupuncture at Chengshan (BL 57) on postoperative pain of mixed hemorrhoids. METHODS: One hundred and twenty cases with postoperative pain of mixed hemorrhoids were divided into an electroacupuncture group (60 cases) and a medication group (60 cases) randomly. The disperse-dense wave in frequency of 2Hz/100Hz at Chengshan (BL 57) were used in the electroacupuncture group. Its first treatment was in 30 min after the operation, and then it was given once a day after hip bath in the morning. 2 tablets of Naproxen Sunstained Release Capsule were taken in 30 min after operation in the medication group, and then it was taken 2 tablets a day before dressing change. After 4 times of treatment, evaluate the changing condition of Visual Analogue Scale (VAS) at 5 h, 24 h, 48 h and 72 h after operation. RESULTS: The VAS at 5 h, 24 h, 48 h and 72 h after operation in the electroacupuncture group (6.78 +/- 2.12, 5.56 +/- 1.87, 4.34 +/- 2.23 and 3.15 +/- 2.11) were all lower than those in the medication group (7.56 +/- 2.01, 6.23 +/- 1.15, 5.57 +/- 2.21 and 4.34 +/- 2.12), and the difference was statistically significant (all P < 0.05). CONCLUSION: Electroacupuncture at Chengshan (BL 57) can reduce the postoperative pain of mixed hemorrhoids. PMID- 21692286 TI - [Herpes zoster treated with meridian-collateral electric information therapy combined with pricking and cupping]. AB - OBJECTIVE: To explore the best acupoints for the treatment of herpes zoster. METHODS: Two hundred cases were randomized into an observation group and a control group, 100 cases in each one. In observation group, meridian-collateral electric information diagnosis and treatment instrument was used to detect meridian and collateral so as to find out the relevant "sick meridian open" for electric stimulation, bloodletting and cupping. In control group, Acyclovir was administered orally. RESULTS: In observation group, it had been dectcted that "sick meridian open" were mostly localized in Ashi point (Extra), Zhangmen (LR 13), Daimai (GB 26), Qimen (LR 14), Dabao (SP 15), etc. The totally effective rate in observation group was 100.0% (100/100) that was superior to 60.0% (60/100) in control group (P < 0.000 1). Additionally, the time for pain relief, blister relief and scarring in observation group was shorter obviously than that in control group (P < 0.000 1). There was no case of post-herpetic neuralgia in observation group, but the incidence of it in control group was 26.0% (26/100). CONCLUSION: Meridian-collateral diagnosis and treatment instrument detects "sick meridian open" for electric stimulation and bloodletting and cupping in the treatment of herpes zoster, which can effectively relieve pain and prevent from post-herpetic neuralgia promptly. PMID- 21692288 TI - [Case of radiation-induced xerostomia]. PMID- 21692287 TI - [Case of deep-rooted ulcer on the face]. PMID- 21692289 TI - [Effects of needle retaining at Zusanli (ST 36) on hemodynamic change of anterior tibial artery]. AB - OBJECTIVE: To observe the effects of needle retaining on hemodynamic change and investigate the significance of retaining needle. METHODS: Manual acupuncture was performed at the left Zusanli (ST 36) of 26 healthy adult volunteers who have not receiued acupuncture. 26 cases were randomly divided into a needle retaining group and a quick needling group, 13 cases in each group. Hemodynamic parameters of the anterior tibial artery were observed with color Doppler ultrasound before needling and 0, 1, 2, 3, 4 and 5 minutes after needle manipulation. Hemodynamic parameters were also compared between the two groups 0, 1, 2, 3, 4 and 5 minutes after needle manipulation. RESULTS: There were no significant difference in V(max) and Vm between 0, 1, 2, 3, 4 and 5 minutes after needling manipulation (all P > 0.05). CONCLUSION: Needle retaining can not change regional hemodynamic. PMID- 21692290 TI - [Medical ozone injection at cervical Jiaji (EX B2) points for treatment of 60 cases of cervical spondylopathy of cervical type]. PMID- 21692291 TI - [Randomized controlled study on proximal needling for sciatica]. AB - OBJECTIVE: To compare the effect of proximal needling and routine acupuncture for sciatica. METHODS: Sixty patients with sciatica were randomly divided into a proximal needling group and a routine acupuncture group, 30 cases in each group. The proximal needling group was treated by proximal needling at Huantiao (GB 30). The routine acupuncture group was treated by acupuncture at Huantiao (GB 30), Yinmen (BL 37), Weizhong (BL 40), Yanglingquan (GB 34) etc. with routine acupuncture method. The Numerical Pain Rating Scales (NPRS) the Japanese Orthopaedic Association Scores (JOA) were all observed before, after treatment and in following up. RESULTS: The total effective rates were 100.0% (30/30) in both groups, with no significant difference between the two groups (P > 0.05) in 3 month follow up. After 5 treatments, the total improvement rate of 100.0% (30/30) in the proximal needling group was super to that of 80.0% (24/30) in the routine acupuncture group. The NPRS and JOA scores were all improved significantly after 5 treatment and in following up compared with those before treatment in two groups (all P < 0.01). After treatments, the improvement of the NPRS and JOA scores in the proximal needling group was greater than those in the routine acupuncture group (both P < 0.05). CONCLUSION: The proximal needling treatment has rapid and obvious therapeutic effect and analgesia on sciatica. PMID- 21692292 TI - [Professor Chen Quan-xin's experiences on treatment of facial paralysis]. AB - OBJECTIVE: The clinical experiences of Professor Chen Quan-xin on treatment of facial paralysis are introduced. Based on the theory of Chinese medicine and instructed by differentiation of syndromes, Professor Chen attached great importance on analysis of etiology and pathology in modern medicine, and emphasized on treatment of facial paralysis according to different classifications and stages in combination of differentiation of syndromes and differentiation of diseases. His selection of point is refined and accurate. Conduct of qi through needling manipulations and reinforcing and reducing methods in various degrees are promoted by him as well. And it is held that obvious enhancement of the therapeutic effect can be achieved since other treatments are combined according to different types and stages of the disease. PMID- 21692293 TI - [Exploration of the application of detective pressing method in LIN's scalp acupuncture]. AB - The origin, theoretic basis and operation of detective pressing method in clinical application of LIN's scalp acupuncture are introduced in this paper and its advantages in clinical practice are explored. It is found that the therapy could reduce the sense of fear in patients, localize the points precisely, guide treatment and develop the ideas of treatment. Under the guide of modern science in the brain, the therapy could be used to treat much more cerebral diseases. PMID- 21692294 TI - [Meaning of "nose is too dry ... acupuncture on yang meridians engorgement vein"]. PMID- 21692295 TI - [Effects of penetration therapy with scalp electroacupuncture on gene expressions of nerve growth factors in substantia nigra of rats with Parkinson's disease]. AB - OBJECTIVE: To explore the protective mechanism of penetration therapy with scalp electroacupuncture on Parkinson's disease (PD). METHODS: Thirty-six Wistar rats were randomly divided into a normal group, a sham operation group, a model group and a penetration therapy group, 9 rats in each group. The sham operation group was operated by micro-injection with normal saline in the left corpus striatum. The model group and penetration therapy group were generated by micro-injection with 6-hydroxydopamine in the left corpus striatum to prepare rotation model of PD. The penetration therapy group was treated by penetration therapy with scalp electroacupuncture through "Baihui" (GV 20) to "Taiyang" (EX-HN 5), once each day, 6 days for one course, altogether 2 courses, and there was no treatment in the other two groups. (1) Immunohistochemical method was used to test the morphology and count of positive cells of tyrosine hydroxylase (TH). (2) In situ hybridization histochemistry was applied to detect the mRNA expression of brain derived neurotrophic factor (BDNF). RESULTS: (1) The areal density (AD), numerical density (ND) and integrating optic density (IOD) of the positive neurons of TH in substantia nigra in the penetration therapy group were 0.065 +/- 0.011, 0.014 +/- 0.003 and 0.470 +/- 0.099, respectively, which were higher than 0.039 +/- 0.008, 0.008 +/- 0.002 and 0.266 +/- 0.065 in the model group (all P < 0.05). (2) The AD, ND and IOD of the mRNA expression of BDNF in substantia nigra in the penetration therapy group were 0.100 +/- 0.012, 0.014 +/- 0.003 and 1.158 +/- 0.130, respectively, which were higher than 0.047 +/- 0.012, 0.007 +/- 0.001 and 0.602 +/- 0.108 in the model group (all P < 0.05). CONCLUSION: The penetration therapy with scalp electroacupuncture has a better protective effect on dopaminergic neurons in substantia nigra of rats with PD. The protective mechanism is related to the provocation of neural nourishment so as to improve the morphous of dopaminergic neurons and increase the number of dopaminergic neurons. PMID- 21692296 TI - [Pain on finger tip treated by pricking blood of Jing-well points]. PMID- 21692297 TI - [Effects of electroacupuncture preconditioning at "Neiguan" (PC 6) on gene expression of myocardial opioid receptors in rats with myocardial ischemia reperfusion injury]. AB - OBJECTIVE: To explore the protective effects of electroacupuncture preconditioning at "Neiguan" (PC 6) on myocardial ischemia reperfusion injury (MIRI) and the mechanism. METHODS: Forty-eight male Wistar rats were randomly divided into a sham operation group (group N), a MIRI group (group M) and an electroacupuncture group (group E). The MIRI model was generated by ligating the left anterior descending artery (LAD) for 30 min followed by reperfusion for 120 min. The partition sutures in group N were passed under the LAD without ligation. The rats in group E were pretreated with electroacupuncture applied at bilateral "Neiguan" (PC 6) for 20 min once a day on 3 consecutive days before ischemia. The area at risk and infarct size and the serum levels of CK-MB and LDH were measured. The morphological changes were observed by light microscopy. The mRNA expressions of delta and kappa opioid receptor (DOR and KOR) were determined by real-time RT-PCR. RESULTS: The myocardial infarct size in group E was significant smaller than that in group M (P < 0.05). The contents of CK-MB and LDH were (980 +/- 92) U/L and (2 743 +/- 124) U/L in group M which were significant higher than (312 +/- 41) U/L and (530 +/- 56) U/L in group N (both P < 0.01) and (572 +/- 70) U/L and (1 819 +/- 97) U/L in group E (both P < 0.01). The mRNA expressions of DOR and KOR had no significant difference between group M and N (both P > 0.05), while the DOR expression in group E was significant higher than that in group M and N (both P < 0.01). There was no significant difference in KOR expression among three groups (all P > 0.05). CONCLUSION: The cardiac protective effects of electroacupuncture preconditioning at "Neiguan" (PC 6) on MIRI may be mediated by increasing expression of delta opioid receptor in myocardium. PMID- 21692298 TI - [Pricking at scalp points for infantile diarrhea]. PMID- 21692299 TI - [Effects of laparoscopic cholecystectomy under different anesthetic methods on T lymphocyte immune function and postoperative analgesia]. AB - OBJECTIVE: To compare the differences in the effect of laparoscopic cholecystectomy (LC) with different anesthetic methods on T-lymphocyte immune function and postoperative analgesia as well as validate the specificity of meridian points. METHODS: Ninety cases of LC were randomized into three groups, named group A (compound general anesthesia group with meridian points involved), group B (compound general anesthesia group with placebo points involved) and group C (general anesthesia group). In group A, electroacupuncture was applied at first for 15 to 30 min to bilateral Hegu (LI 4), Neiguan (PC 6), Zusanli (ST 36), Yanglingquan (GB 34) and Quchi (LI 11). Afterwards, the general anesthesia was conducted and electric stimulation lasted till the end of operation. In group B, the points adopted were the midpoints between the meridians in which the acupoints were selected in group A and the adjacent meridians on the lateral side, at the level of selected meridian points correspondingly. The method and time of electroacupuncture were same as those in group A. In group C, the general anesthesia was adopted simply. The changes of T-lymphocyte subgroup were detected before anesthesia, in 2 h, 1 day and 3 days after operation separately; and the dose of narcotic in operation as well as the dose of analgesia pumper in 4 h, 6 h, 8 h, 24 h and 44 h after operation separately. RESULTS: (1) In comparison between the result 2 h after operation and that before operation, the levels of CD3+, CD4+ and CD8+ in all of three groups were lower than those before operation. Except that the change in CD4+ in group A did not present significant statistical difference as compared with that before operation (P > 0.05), all of the other differences in T-lymphocyte subgroup indicated statistical significance (all P < 0.05). The ratio of CD4+/CD8+ in three groups was higher than that before operation, but the difference in group A was significant statistically (P < 0.05). In 3 days after operation, the levels of CD3+, CD4+ and CD4+/CD8+ were all higher than those before operation, indicating significant statistical differences (all P < 0.05) except CD4+/CD8+ in group B (P > 0.05). (2) In group A, during operation, the dose of narcotic reduced apparently (P < 0.05). (3) Separately, in 4, 6 and 8 h after operation, the dose of analgesia pumper reduced significantly in group A (all P < 0.05). CONCLUSION: Compound general anesthesia with meridian points involved can increase pain threshold of human body, reduce the dose of narcotic during operation, alleviate the suppression in body immune regulation due to stress reaction of general anesthesia and operation, prolong the time-effect of postoperative analgesia and explain the specificity of meridian points. PMID- 21692300 TI - [Key points on clinical trial of acupuncture]. AB - Suggestions such as how to enhance the rationality of designation of clinical trails, regulate the evaluation system on therapeutic effects, control the quality strictly and unify the standard of report on key points of acupuncture clinical trials from the aspects of designation, therapeutic evaluation, quality control and report standard were expounded in this paper. Highlights such as perspective of acupuncture in qualitative investigation and practical clinical trails were explored as well in this paper. And some international and domestic disputes in the related fields such as placebo acupuncture and selection of acupoints were discussed and analyzed so as to provide methodological instruction for acupuncture clinical trails and promote its normalization process. PMID- 21692301 TI - [Eight aspects of acupuncture standardization]. AB - According to the theory and method of standardization, based on the current situation and characteristics of acupuncture standardized research, eight important aspects are introduced in our project of acupuncture standardization. The acupuncture standard is summarized from different expert's experiences, thus it will not impede the effectiveness of a treatment by an individual doctor; the classical literature is the principle of acupuncture standard, and the scientific investigation is the basis of acupuncture standard; the acupuncture standard should emphasize the combination of application and science; the standard itself and different standards should be in consistent; the state acupuncture standard should be in agreement with the international standards; the acupuncture standardization is to establish the optimum order in order to achieve the optimum effectiveness of the treatment; the law and organizations are the instructions, and the current acupuncture standard is the recommended standard; acupuncture standardization should reflect the characteristics of traditional Chinese medicine. PMID- 21692303 TI - [Chinese translation of "nerve" and its influences on research of meridians and collaterals]. AB - Authors investigated the whole introduction and translation course of the word "nerve" into China during the Ming dynasty (1368-1644), Qing dynasty(1644-1911) and the Republic of China (1912-1949), when western medicine was introduced into the East, as well as its influences on the cognition and researches of meridians and collaterals. The result shows that "nerve" was once translated into "Xijin" and "Naoqijin" in the Ming and Qing dynasties. Only until the period of the late Qing dynasty and the early stage of the Republic of China, the word "Shenjing", which is known as the unique Chinese translation of nerve nowadays, was introduced from Japan. From that time on, the Chinese physicians started to explore the relation between nerves and meridians, which led to the transform of the academic methodology on essence of meridian. Thus, profound as well as prolong influences were made on study of meridians and collaterals until nowadays. PMID- 21692302 TI - [The development of fire-needle and the improvement of its application]. AB - Based on the literature research on the development and application of fire needle, the materials, the manufacturing process and application in clinic practices were studied. The major type, application and the representative experts of fire-needle in the contemporary era were summarized in this paper. The application fire-needle is more and more expanding in clinic practices, and the modern type of fire-needle should be promoted at present. PMID- 21692304 TI - [Immediate effect on blood pressure of acupuncture at Renying (ST 9) in 53 cases of hypertension patient]. PMID- 21692305 TI - [Story life CHENG Dan-an's, works and his achievements on acupuncture and moxibustion science]. AB - Mr. CHENG Dan-an, who devoted himself to the renaissance of the course of modern Chinese acupuncture, the establishment of acupuncture education unit, correspondence education, acupuncture personnel fostering and publication of periodicals on acupuncture, has great contribution to the academic exchanges and popularization of acupuncture. Mr. CHENG has completed over 10 articles and more than 20 works and translations. According to him, mechanism on meridians, collaterals, acupoints and acupuncture techniques were explored with the promotion on application of "Shen" and "qi" in clinic. Pulse and tongue diagnosis as well as acupuncture treatment were supplemented into Shanghanlun (Treatise on Febrile Diseases). And great importance was attached on the scientific validity and practicability. His professional ethics and dedication are worth to be learned by all medical workers nowadays. His acupuncture theories and academic achievements still inspire us today, which are also taken as the origin for the innovation and development of modern acupuncture science. PMID- 21692306 TI - [Dr. YANG Lian-de: an outstanding specialist of acupuncture]. AB - Dr. YANG Lian-de is an outstanding specialist of acupuncture in China. With experiences of 60 years in clinical practice, education and scientific research, he has integrated the knowledge of both western and Chinese medicine, accumulated steadily, made innovation on acupuncture manipulations, acupuncture treatment on diseases such as diabetes, psychosis and asthma and contributed greatly to the integration of western and Chinese medicine. PMID- 21692307 TI - [Sixty cases of chronic colitis treated with fire needle]. PMID- 21692308 TI - [Effect of acupuncture on the activity of gastrointestinal electricity]. AB - Based on the summarization of literatures on regulation of gastrointestinal electricity with acupuncture, the regulation effect of acupuncture, its influencing factors and its mechanism were analyzed in this article. It is found that the regulation effect can be influenced by many factors such as different acupuncture techniques, frequency, point selection, manipulations and the physical condition of the object. The effect of acupuncture appears great variety, which manifests as reinforced, inhibited or a kind of two-way regulation. And it is also held that the effect of acupuncture relies on the integrity of the nerve system. Nuclei, neurotransmitters, body fluid and gastrointestinal hormone also take part in the acupuncture effect. Therefore, studies on mechanism of acupuncture effect on gastrointestinal electricity should be strengthened in the future. PMID- 21692309 TI - [Efficiency, adequacy, economic efficiency: the lessons of poor countries to rich ...]. PMID- 21692310 TI - [Rapid diagnostic tests (RDT): the cure-all for the practitioner?]. AB - Many rapid diagnostic tests (RDT) for the diagnosis of infectious diseases have been developed over the last 20 years. These allow (1) administering a treatment immediately in case of a potentially fatal disease, (2) prescribing a specific rather than presumptive treatment, (3) quickly introducing measures aimed at interrupting the transmission of the disease, (4) avoiding useless antibiotic treatments and (5) implementing a sequential diagnostic strategy to avoid extensive investigations. Using the example of malaria, a new strategy that includes a RDT as first-line emergency diagnostic tool and, when negative, delayed microscopy at the laboratory opening time is implemented in Lausanne since 1999. This strategy has been shown to be safe. Each TDR has its own characteristics that imperatively need to be known by the practitioner if he/she wants to use it in a rational way. PMID- 21692311 TI - [Indications for PCR in travel medicine]. AB - The use of PCR-based molecular diagnosis in travel medicine remains limited to specific indications such as clinical suspicion of some of the viral hemorrhagic fevers (e.g. Ebola, Marburg), differential diagnosis between Entamoeba histolytica (pathogen) and E. dispar (non pathogen) in the stools, and parasitological diagnosis of cutaneous leishmaniasis. The scope of indications is likely to expand in the coming years with the development of techniques (e.g. multiplex PCR) able to identify several pathogens from a single sample. Simplification and cost-reduction of molecular techniques, which would allow for more equitable access to these diagnostic tools in countries where the targeted diseases are highly prevalent, pose major technological and ethical challenges. PMID- 21692312 TI - [How can serology contribute to the diagnosis of parasitic diseases?]. AB - From a technical standpoint the most widely used tests for serology include the ELISA (enzyme linked immunosorbent assay), the IFA (indirect fluorescence assay), and the immunoblot. ELISA tests are widely used as screening assays since they harbor a high sensitivity. The main pitfall of serologies is the frequency of cross-reactions, especially between the different helminths. This is why positive results should be confirmed by a second test method with a higher specificity. Results need also to be put in the perspective of the patient history, clinical signs and laboratory findings. Serological tests are most appropriate when the parasite cannot be documented by direct examination (by eye or under the microscope) and during the pre-patent period. Serologies for parasites are also useful when an unexplained eosinophilia is present. PMID- 21692313 TI - [Melioidosis: a poorly known tropical disease]. AB - A 35 year-old man was admitted to the hospital for fever upon returning from the Caribbean area. He died 48 hours later, after developing pulmonary lesions that were complicated by multi-organ failure, despite rapid diagnosis of melioidosis by mass spectrometry on blood cultures. Melioidosis is a rare bacterial disease in the traveller that is caused by Burkholderia pseudomallei. Although the clinical presentation is variable, pneumonia is the most frequent finding. Diagnosis may be considered in travellers returning from tropical and subtropical regions, especially during rainy seasons. Accordingly, when confronted with a patient who presents with fever after travelling, it is important to carefully specify the regions visited, potential expositions, and rapidly offer adequate laboratory testing. PMID- 21692314 TI - [Quadrivalent meningococcal conjugate vaccine]. AB - Meningoccocal meningitis is still a severe disease. In Switzerland the predominant serotypes are serotype B and C, but this could change as other groups predominate elsewhere. The indications for immunizing against meningococcal infections as described in the Swiss recommendations will be reviewed. New quadrivalent vaccines conjugated with a protein and efficient against serogroup ACWY will soon be available in our country. They show a number of advantages in term of type of protection and should simplify the current vaccination schedule while giving a better coverage against various serogroups, especially for travellers, but also for children at risk for complications. PMID- 21692315 TI - [Practical ECG problems in the elderly. Case number 17]. PMID- 21692316 TI - [Interactive seminars or how to optimally integrate our postgraduate and continuing education!]. PMID- 21692317 TI - [Osteoporosis: evaluation and fracture risk]. PMID- 21692318 TI - [Atypical presentations of sleep apnea syndrome]. PMID- 21692319 TI - [Approach to and evaluation of pain in the elderly: mission impossible?]. PMID- 21692320 TI - [Chronic pain and depression]. PMID- 21692321 TI - [Thrombophilia: is there a need to investigate?]. PMID- 21692322 TI - [The obese hypertensive patient. Weight loss, exercise or medication?]. PMID- 21692324 TI - [How to set up an emergency kit]. PMID- 21692323 TI - [Critical reading of an article evaluating a diagnostic test]. PMID- 21692325 TI - [Migrant patients: cross-cultural issues, specific skills]. PMID- 21692326 TI - [Dyslipidemias: is it necessary to treat or not treat? An approach based on scientific evidence in 2011]. PMID- 21692327 TI - [From diagnosis to death, when to start palliative care?]. PMID- 21692328 TI - [Management of postthrombotic syndrome]. PMID- 21692329 TI - [Hypertension in children and adolescents]. PMID- 21692330 TI - [Management of type 2 diabetes in 2011: what benchmarks do physicians have?]. PMID- 21692331 TI - [Syncope: initial evaluation and management]. PMID- 21692332 TI - [Sarcopenia: definition, methods of measurement, therapeutic future]. PMID- 21692333 TI - [Urinary incontinence in the female elderly patient: diagnosis and management]. PMID- 21692334 TI - [What can be done to prevent the occurrence of dementia?]. PMID- 21692335 TI - [Differential diagnosis and management of hyponatremia]. PMID- 21692337 TI - [Speaking about yourself during a medical consultation]. PMID- 21692336 TI - [Detection of the risk of malnutrition in the elderly]. PMID- 21692338 TI - [Transgenic salmon are approaching our plates]. PMID- 21692339 TI - [The dangers of screen time among adolescents]. PMID- 21692340 TI - [The paradox of liberalism]. PMID- 21692341 TI - [Medical and prophylactic properties lipids and antioxidants derived from sea hydrobionts]. AB - Recent researches in the field of studying medical-preventive activity of lipids and natural antioxidants derived from sea hydrobionts at carbohydrate and lipid metabolic imbalances were analyzed. On experimental models of hyperlipidemia and a diabetes the optimum dozes and polyunsaturated fat acids omega-3/omega-6 in structure of phospho- and glycolipids derived from sea macrophytes Sargassum pallidum, Ulva fenestrata, Zostera marina, and also antioxidants-- polyhydroxynaphthoquinone a echinochrome. A derived from flat sea urchin Scaphechinus mirabilis and mixes of polyphenols from sea grass Zostera marina were determined. Prospective mechanisms of polar lipids, containing various polyunsaturated fat acids and specified above antioxidants are presented on the basis of the received results and the analysis of published data. PMID- 21692342 TI - [Effects of green tea extract and its components on antioxidant status and activities of xenobiotic metabolizing enzymes of rats]. AB - Dietary administration of green tea extract (GTE) or epigallocatechin gallate (EGCG), quercetin (Qu) or caffeine (Cf) in doses equal to their concentration in GTE led to an increase of serum and liver antioxidant capacity and strengthening stability of microsomal and lysosomal membranes in rats. The antioxidant efficiency of EGCG and Qu was considerably higher than that of GTE. There were significant differences in the effects of EGCG, Qu and GTE on the activities and expression of mRNA for CYP1A1, CYP1A2 and CYP3A1. But feeding both GTE and Cf to rats results in similar elevated activities of CYP1A1, CYP1A2, UDP-glucuronosyl transferase and glutathion transferase. Our results suggest that Cf is the main contributor to GTE effects on activities of xenobiotic metabolizing enzymes. PMID- 21692343 TI - [The study of apoptosis of hepatocytes of rats for estimation safety and efficacy of application biologically active substances]. AB - The magnitude of apoptosis of hepatocytes of rats that were within 2 weeks on a balanced complete semi-synthetic diet supplemented with extract of green tea, epigallocatechin gallate (EGCG), quercetin, coffein (1-4th experimental groups accordingly) is studied. The contents EGCG, quercetin and coffein in rats of 2 4th experimental groups correspond to their content in diet of rats 1 experimental group, and equally contents in tonic beverage. It is determined that application in diets extract of green tea and its compounds does not damage effect on hepatocytes of rats. The use of diets with the inclusion of extract of green tea, quercetin and coffein provides the clear tendency to stabilize the plasma membrane of hepatocytes comparison with rats of control group (rats fed the same diet but without the inclusion of the above-mentioned biologically active substances). PMID- 21692344 TI - [Variability of the plasma proteome in healthy people (report 1)]. AB - The last decade has seen intense development of proteomic technologies have opened new perspectives for rapid large-scale screening of biological samples in order to find biomarkers of various diseases or conditions. However, in order to adequately evaluate the possibility of using protein as a biomarker, it is necessary to know how much its concentration varies widely in healthy people. This project aims to explore the limits of the concentration of protein components of plasma in healthy people. PMID- 21692345 TI - [Study composition of lactoflora of the large intestine in patients with food allergy and irritable bowel syndrome]. AB - Patients of different ages with various forms of food allergy and also with the irritable bowel syndrome with locks are studied. The quantitative levels of bifido- and lactoflora of large intestine, the qualitative characteristics of lactoflora population, including specific gravity of individual representatives in the sum of the isolates, are investigated, species composition is identified. Shown that food allergy, irrespective of the disease manifestation form induces the balance disturbance of bifido- and lactoflora in large intestine, significantly affects the reduction in the number of species of Lactococcus and Leuconostoc spp. and on the narrowing of the enzymatically active species of Lactobacillus spp. PMID- 21692346 TI - [Influence food products enrichment pro- and prebiotics on microecology status of man]. AB - Analyzes the feasibility of complex use of preparations containing lactulose, nutritive soy fortifier, pectin, alginate natrium and their complexes in technology of products on the basis of meat raw material as the components providing selectivity bifidofadjusting of activity. PMID- 21692347 TI - [Contamination of imported and native food products by toxic elements (comparative aspect)]. AB - Analyzed data from monitoring chemical contamination by toxic elements of imported and native food products. PMID- 21692348 TI - [Effectiveness analysis established in Russia and hygienic standards for the use of food dyes]. AB - Analysis of the income of diet and frequency of use of food additives--dyes in food production showed that established in Russia hygienic standards provide compliance with acceptable doses of these substances. For the first time in Russia an assessment of dietary intake of several food dyes, possessing biological activity is conducted. The average daily intake by using such substances can reach (as % of physiological needs of the adult population): riboflavin--180%, curcumin--60%, beta-carotene--25%, anthocyanins--10%, canthaxanthin (lutein, lycopene)--5%. PMID- 21692349 TI - [The estimation of risk of deficit consumption of proteins, vitamins and substance mineral adult population of Samara]. AB - Survey of the brainwork workers with low physical activity has revealed the risks of inadequate consumption of fiber, calcium, iron, vitamins B1, B2, C, A, due to mismanagement of their consumption. PMID- 21692350 TI - [Substantiation of the program of realization of bases of the state policy of a healthy nutrition of population of the Samara Region for the period till 2020 year]. AB - Substantiate the need for long-term program of sanitation the diet of the population of the Samara Region. A systemic analysis of actual nutrition of different population groups in the region showed an excessive consumption of fats and added sugar--the main risk factors of obesity, cardiovascular diseases and diabetes mellitus. The risks of inadequate consumption of vitamins B, calcium, iron, caused by the irrational combination of the foodstuff use, are revealed. PMID- 21692351 TI - [Prophylaxis iodine deficit: information support]. AB - An insufficient intake of micronutrients has massive and permanent nature and influence negatively to health, growth and vitality of the entire nation. One third part of Russian schoolchildren suffer from deficiency of iron and iodine. Every year in Russia 215,000 children are born with brain damages associated with iodine deficiency. Raising the public awareness regarding the risks and prevention of micronutrient deficiency is the key issue of public health and nutrition. The study which included 4500 respondents in the Urals Federal District showed 2-4-fold increase awareness of the respondents in different positions after the communication campaign for prevention of micronutrient deficiency. PMID- 21692352 TI - [Effect of microwave on migration in the model environment of chemicals from materials that come into contact with foodstuffs]. AB - Under the influence of microwaves is migration of chemical and metals used in manufacture for these furnaces. This confirms the need for research to develop modes of training materials used in the manufacture of utensils used in microwave ovens. PMID- 21692353 TI - [Method of quantitative content soya protein determination in cooked meats using indirect immune-enzyme analysis]. AB - With the help of immune-enzyme analysis the amount of soy protein was determined in cooked meats. The results obtained are subjected to mathematical processing, also shows the metrological performance of the method. PMID- 21692354 TI - [Analyses of special foods for sportsmen (received for 2007-2010 years)]. AB - Review of about special foods for sportsmen (SFS) when 80% of which were imported and to be received for 2007-2010 years is presented. Discrepancy with demands of Russian legislation of some SFS (about 30%) is noted. Sufficiently wide spectrum of proposed products and tendency to progressive complication of SFS composition are observed. Data obtained let to suggest that possibility to have more expected effectiveness when such products are used can be one of explanation of that tendency. PMID- 21692357 TI - Hospital activities in organ donation program in Saudi Arabia. PMID- 21692356 TI - [Nursing home as family]. PMID- 21692358 TI - The politics of death: from abortion to health care - how the hysterical style overtook the national debate. PMID- 21692359 TI - An in vitro model to assess the performance of topical antioxidants. PMID- 21692360 TI - The relevance of fat oxidation capacity to obesity in human subjects. PMID- 21692361 TI - Forget the mental status test--and learn to listen. PMID- 21692362 TI - It's too soon to recommend probiotics for colic. PMID- 21692363 TI - Antipsychotic drugs and the risk of venous thromboembolism. PMID- 21692364 TI - The treatment: why is it so difficult to develop drugs for cancer? PMID- 21692365 TI - Bacterial infection remains a leading cause of death in both Western and developing world. Preface. PMID- 21692367 TI - Efflux pumps of gram-negative bacteria: genetic responses to stress and the modulation of their activity by pH, inhibitors, and phenothiazines. PMID- 21692366 TI - Structure and mechanism of RND-type multidrug efflux pumps. PMID- 21692369 TI - The MFS efflux proteins of gram-positive and gram-negative bacteria. PMID- 21692370 TI - Efflux pumps as an important mechanism for quinolone resistance. PMID- 21692368 TI - Efflux pumps of the resistance-nodulation-division family: a perspective of their structure, function, and regulation in gram-negative bacteria. PMID- 21692373 TI - R. Milton Johnson an expanding role for financial leaders. PMID- 21692374 TI - Decoding the alphabet soup of future audit risks. AB - 2011 will bring a rise in audit threats facing healthcare organizations. Zone program integrity contractor audits, which can look back 10 years, are potentially most onerous. Providers should take a proactive approach that works in all audit situations. Implementing a clinical documentation improvement program and focusing on physician education are key to reducing revenue losses. PMID- 21692372 TI - A survey of oxidative paracatalytic reactions catalyzed by enzymes that generate carbanionic intermediates: implications for ROS production, cancer etiology, and neurodegenerative diseases. PMID- 21692375 TI - How to fill key leadership positions strategically. AB - To fill strategic positions in their organizations with top talent, nursing and finance leaders can: Start by determining which jobs are truly "mission critical". Align the individuals in these positions on strategic teams Strengthen partnerships between key clinical leaders, such as the CMO and CNO PMID- 21692376 TI - Value-driving strategies for hospitals. PMID- 21692377 TI - HFMA Chair Greg Adams: a winning attitude. PMID- 21692378 TI - Starting a medical home: better health at lower cost. AB - At Adventist HealthCare, a patient-centered medical home pilot project: Helped improve the health of high-risk members while increasing the efficiency of healthcare delivery. Supported the primary care physicians treating the high-risk patients. Reduced the costs of treating the patients. PMID- 21692371 TI - Xenobiotic efflux in bacteria and fungi: a genomics update. PMID- 21692379 TI - Douglas Hastings: identifying legal and strategic challenges of accountable care. PMID- 21692380 TI - Benchmarking boon: tapping publicly available data to improve performance. AB - Publicly available data can help hospitals benchmark their experience against that of their peers to identify unexpected variations and potential opportunities for improvement. Medicare Provider Analysis and Review data and Medicare cost report data can be used to analyze a hospital's experience by medical service area and by Medicare-severity-adjusted DRG. Such an analysis provides an excellent first step for more in-depth analysis that can hone in on potential problem areas, such as inaccurate documentation or coding. PMID- 21692381 TI - Medicare ACOs no longer mythical creatures. AB - The proposed rule regarding accountable care organizations (ACOs), issued March 31 by the Centers for Medicare & Medicaid Services (CMS), included not only what was expected, but also a fair measure of what was not expected. Under CMS's proposal, ACOs would need to report on 65 different quality metrics to participate in the Medicare pilot program. ACOs would be eligible to share savings with CMS based on their overall quality scores and financial outcomes, and they would assume risk on one of two tracks. PMID- 21692382 TI - Responding to reform: 5 strategies for reinventing the revenue cycle. AB - Among of the biggest challenges that will affect hospital revenue cycles in an era of reform, five are related to the following concerns: Reduced payment, Compliance reforms, Quality improvement initiatives, Payment reform, Expansion of insurance coverage. PMID- 21692383 TI - Redesigning physician compensation and improving ED performance. AB - Redesigning a physician compensation system in the emergency department (ED) should include goals of improving quality, productivity, and patient satisfaction. Tips for hospital administrators: A contemporary ED information system is needed to ensure that the ED is essentially a paperless operation. Transparency, internally and externally, is essential. ED physicians should perform as individuals, yet as members of a team. Incentives, especially incentive compensation, should strike a balance between individual and team performance. PMID- 21692384 TI - Shared services centers can drive significant savings. AB - A study of more than 30 U.S. integrated delivery systems (IDSs) found that implementing effective shared services centers can drive significant cost savings in human resources, accounts payable, and procurement. Many IDSs have not adopted effective shared services strategies. Implementing administrative shared services involves low risk and a relatively low start-up investment. PMID- 21692385 TI - HIT adoption key to provider success under healthcare reform. PMID- 21692386 TI - What would you do? How do we develop the scale and scope needed for the future? PMID- 21692387 TI - Innovation--to renew or change? PMID- 21692388 TI - Occupational health. PMID- 21692389 TI - Evidence of new innovations: investing in evidence synthesis, generation and translation ensures public health innovations improve population health. PMID- 21692390 TI - In practice. PMID- 21692391 TI - Out with the old. PMID- 21692392 TI - Active ageing. PMID- 21692393 TI - Perspectives in public health. PMID- 21692394 TI - A new vision for care: looking beyond the NHS to the whole care ecosystem. PMID- 21692395 TI - Spend to save: synergy and innovation in public health. PMID- 21692396 TI - Innovation and the new landscape for public health. PMID- 21692397 TI - Lean thinking in NHS blood and transplant. PMID- 21692398 TI - Innovating to achieve sustainable wellbeing inside the built environment. PMID- 21692399 TI - Planning to innovate. Designing change or caught up in a game? AB - In this article I engage with some orthodox theories of the management of innovation and change, which take for granted the idea that they can be predicted and controlled. Organizations are thought to be systems with boundaries, which managers acting as engineers, or doctors, can 'diagnose' and restore to 'health', or order differently. As an alternative, and by drawing on an experience of working with health service managers, I argue instead that change and innovation arise as a result of the interweaving of everyone's intentions. Organizations are sites of intense political interaction and contestation, and exactly what emerges is unpredictable and unplannable, even by the most powerful individuals and groups. PMID- 21692400 TI - Report of an evaluation of a nurse-led dementia outreach service for people with the behavioural and psychological symptoms of dementia living in residential aged care facilities. AB - BACKGROUND: This paper describes the implementation and evaluation of a Dementia Outreach Service (DEMOS). The service is led by the first Nurse Practitioner in Dementia Care in the State of Queensland in Australia and is highly innovative in terms of its mode of delivery. The evaluation took place due to a perception that new models such as the DEMOS often fail to gain momentum due to a lack of data on their effectiveness and efficiency. METHOD: The parameters of the project were to evaluate the extent to which the DEMOS met its key deliverables, focusing specifically on outcomes for residential aged care facilities (RACF) residents and staff. The study involved both quantitative and qualitative data collection. Qualitative data was collected through interviews, focus groups and reflective journals. A survey which was administered at three stages of the 12 months of the study was the main source of quantitative data. Additional statistical data was collected from relevant healthcare providers. FINDINGS: Twenty RACFs within a specific health service district participated in the study. This included an intervention group of 7 facilities (which received the service) and a control group of 13. A total of 320 RACF staff participated in Stage 1 of the study, although due to staff attrition this had reduced to 153 (54.6%) at Stage 3. Attrition rates were much lower in the 7 intervention facilities, with 67.9% of the original sample remaining at Stage 3. To augment the quantitative data collected as above, drawing on a range of qualitative techniques the researchers canvassed the perceptions, thoughts and opinions of differing stakeholders. The qualitative data proved extremely valuable in confirming the success of DEMOS. KEY SUCCESS AREAS: Increased self-confidence among staff in dealing with residents with dementia; reduced stress among staff; reductions in the instances of difficult behaviours; reduced referrals to acute sector services; high levels of satisfaction among RACF management regarding DEMOS; and a process of continuous improvement of DEMOS based on stakeholder feedback. IMPLICATIONS FOR PRACTICE: Recommendations for the future directions of the service include: The continued support and expansion of DEMOS; An increase in the DEMOS service portfolio to actively assist facilities to change the culture of care amongst RACF carers; and Showcasing of DEMOS as an example of 'best practice' in dementia care to argue the need for provision of additional Nurse Practitioners specializing in dementia care. PMID- 21692401 TI - GP consortia: navigating ambiguity to produce greater public value? AB - The UK's NHS is about to be significantly remodelled according to a white paper published in July 2010 that outlines the devolution of commissioning responsibilities away from strategic health authorities and primary care trusts to consortia of GPs, which are to be established at local level. Details of how the new GP consortia will operate are as yet unclear, but in essence they will be strategic alliances and it is likely that they will develop more or less formal arrangements between consortia partners, such as those of a commercial joint venture. This article draws on primary research into strategic alliances between organizations in all sectors. It suggests that there can be significant challenges for those working within strategic alliances, given that these tend to be beset by ambiguity and political tensions. In a context of ever greater transparency and accountability, it will be crucial to attend to the human aspects of strategic alliances since these represent significant risk if neglected. Conversely, alliances also offer the opportunity to develop the synergy of people, organizations and communities to deliver greater public value. Successful collaborations need to get three things right: governance, operations and behaviours. Relationships between consortia partners have a significant bearing on their ability to deliver desired outcomes. They must be able to build and maintain trust. Consortia partners will need sophisticated negotiating and stakeholder management skills and must be able to engage the public in setting the strategic goals for which they will be accountable. They also need strategic and operational management skills and must be able to cope with ambiguity and manage complexity. This paper argues that specific forms of leadership are needed in collaborative arrangements to mobilize people for positive action. People must work together by willingly and effectively pooling their initiative and expertise, and create a product or energy that is greater than the sum of their parts. The nature of leadership required to produce such high performance outcomes is likely to supersede leadership that is the result of structural relationships or of individual action. In particular, distributed leadership is likely to be relevant. PMID- 21692402 TI - Implementing public health in secondary care: a Rotherham perspective on strategy development and implementation. AB - AIMS: This paper reports an approach to develop and implement a public health strategy in secondary care and uses smoking cessation as a means for measuring success. METHODS: Rotherham Foundation Hospital Trust recognized its unique role to promote, prevent and protect health and well-being in Rotherham. Following consultation across key departments, the trust developed a public health strategy encompassing five priorities. RESULTS: We report ongoing commitment and engagement following the launch of the public health strategy. Over a period of one year (April 2008 to March 2009) 269 front-line staff were trained on smoking cessation brief interventions. We report 890 referrals to smoking cessation, resulting in 414 setting a quit date and 143 four-week quitters (35% conversion rate). Despite progress in implementing smoking cessation, more communication is required to ensure that GPs and hospital staff continue to maximize patient outcomes through brief interventions. CONCLUSIONS: The paper provides an approach to implement public health in secondary care. The Commissioning for Quality and Innovation (CQUIN) payment framework would be a useful tool to ensure key public health areas such as smoking cessation are systemized in secondary care. PMID- 21692403 TI - The effect of neostigmine on postoperative ileus and the healing of colon anastomoses. AB - OBJECTIVES: The aim of this study was to assess the effects of neostigmine on the postoperative ileus and the healing of colon anastomoses. BACKGROUND: Anastomotic leaks and postoperative ileus are among the most important complications in colorectal surgery. Nutritional status of the patient is one of the most important factors of the anastomoses healing. METHODS: Forty Wistar-albino rats were randomly assigned to (1) colon anastomoses + protein-enriched diet + 1 microg neostigmine, (2) colon anastomoses + protein-enriched diet, (3) colon anastomoses + 30 % dextrose + 1 microg neostigmine, (4) colon anastomoses + 30% dextrose. Body weights, quantities of the consumed products and feces weight change were measured at the first and second 48 hours postoperatively. All rats were sacrificed on the 5th postoperative day. Then, the healing of anastomosis was evaluated by measuring of body weights, burst pressure and hydroxyproline level. RESULTS: There were significant differences between the groups 1 and 2 (p < 0.001), and the groups 3 and 4 regarding the preoperative and postoperative mean weight (p < 0.001). The group 2 did not show any weight loss, whereas the group 1 demonstrated a significant weight gain (p < 0.001). The group 4 showed a significant weight reduction compared to the preoperative period, while the group 3 exhibited a significantly lower weight loss compared to the group 4 (p < 0.001). There were significant differences regarding the burst pressure and hydroxyproline level values of groups with and without neostigmine administration (p < 0.001). CONCLUSION: Starting the early intake of nutrition with neostigmine in the postoperative period reduced the postoperative ileus and increased the healing of colon anastomoses (Tab. 4, Fig. 5, Ref. 27). PMID- 21692405 TI - Evaluation of TGF beta1 expression and comparison the thickness of different aorta layers in experimental diabetes. AB - BACKGROUND: It was aimed to investigate the effects of experimental diabetes on TGF beta1 expression and tunica intima and media thickness in abdominal and thoracic aorta. METHODS: Fourteen three months old female rats were divided into two groups, non-diabetic and streptozotocin (STZ) induced diabetic group. Hematoxylin-Eosin and Verhoeff's Van Gieson elastic staining and TGF beta1 immunohistochemistry staining were performed. Abdominal and thoracic intima and media thickness of aortas were measured with the oculometer. RESULTS: Evaluation of intima and media thickness measurements showed no significant statistical differences between non-diabetic and diabetic groups. TGF beta1 expression increased significantly in thoracic diabetic (TD) group. CONCLUSION: The 60 day duration of diabetes is not sufficiently enough time for the development of pathological changes that could lead to thickening in aortic intima-media layers. TGF beta1 expression was negative in the abdominal aorta that can predispose to the development of atherosclerosis, which could develop overtime. This finding may be interpreted as an appropriate basis for the development of atherosclerosis. In the thoracic aorta TGF beta1 may coordinate cellular events such as tissue repair (Fig. 5, Ref. 23). PMID- 21692404 TI - Selenium supplementation prevents lipid peroxidation caused by arduous exercise in rat brain tissue. AB - BACKGROUND: The objective of the present study is to examine how selenium supplementation affects lipid peroxidation in the brain tissue of rats subjected to acute swimming exercise. METHODS: The study was carried out on 32 Spraque Dawley adult male rats, which were allocated equally to four groups, namely general control (Group 1), selenium-supplemented control (0.6 mg/kg/day sodium selenite) (Group 2), swimming control (Group 3), and selenium-supplemented swimming group (6 mg/kg/day sodium selenite) (Group 4). Selenium supplementations were carried out by intraperitoneal (i.p.) route for four weeks. At the end of supplementation, animals in groups 3 and 4 were subjected to acute swimming. Brain tissue samples were collected from decapitated animals to determine malondialdehyde (MDA) levels using a spectrophotometer according to "Schimadzu 1601, Japan" Uchiyama and Mihara and GSH levels using a spectrophotometer according to Ellmann. RESULTS: The highest MDA values in the brain tissue were obtained in Group 3 (p < 0.001). MDA values in Group 4 were higher than those in Groups 1 and 2 (p < 0.001). Brain tissue MDA values in Groups 1 and 2 did not differ. Group 4 had the highest brain GSH levels (p < 0.001). Brain tissue glutathione (GSH) levels in Group 3 were higher than those in Groups 1 and 2 (p < 0.001). CONCLUSION: Results of the study indicate that acute swimming exercise in rats increased the lipid peroxidation in the brain tissue of rats, while selenium supplementation prevented the free-radical formation by enhancing the antioxidant activity (Tab. 1, Ref. 24). PMID- 21692406 TI - Effect of boron supplementation on plasma element distribution in ovariectomized rats subjected to acute swimming exercise. AB - BACKGROUND: This study aims to examine how boron supplementation affects distribution of elements in the plasma of rats whose ovaries were removed and who were subjected to swimming exercise. METHODS: The study included 80 Sprague Dawley type female rats, which were equally allocated to 8 groups. Group 1: General control, Group 2: Exercise control; Group 3: Ovariectomized control, Group 4: Ovariectomized exercise, Group 5: IP (intraperitoneal) boron supplemented control, Group 6: IP boron-supplemented exercise, Group 7: Ovariectomized, IP boron-supplemented exercise, group 8: Ovariectomized, IP boron supplemented. Following the exercise, blood samples were collected from all animals by decapitation, and analyzed in terms of plasma copper, iron, phosphorus, magnesium, calcium, and zinc using an atomic absorption spectrophotometer. RESULTS: Groups 1 and 5 had the lowest copper (p < 0.01) and the highest zinc and calcium (p < 0.01) levels, in comparison to other groups. Phosphorus levels in groups 3, 5 and 8 were significantly lower than those in other groups (p < 0.01). Magnesium levels in groups 3, 5 and 8 were higher, relative to the levels in other groups (p < 0.01). CONCLUSION: Results of the study indicate that acute swimming exercise in ovariectomized rats supplemented with boron leads to significant modifications in the distribution of some trace elements in the plasma. It can be emphasized as a separate result of this study that changes in copper, zinc and calcium levels were independent of boron supplementation (Tab. 2, Ref. 14). PMID- 21692407 TI - Treatment results of non-varicose bleeding from upper gastrointestinal tract. AB - Treatment results of non-varicose bleeding from upper gastrointestinal tract are changing by improved endoscopic methods and introduction of new drugs in treatment. OBJECTIVE: Objective of this work was to compare the results in treatment of patients with non-varicose bleeding from upper gastrointestinal tract in two different 5-years periods. MATERIAL: We hospitalised 229 patients with non-varicose bleeding from upper gastrointestinal tract at the Department of Surgery in Faculty Hospital of Martin in the period 1992-1996. (161 men and 68 women, average age 56.7, patients up to 60 were 42.4%). 203 patients were hospitalised in the years 2003-2008 (146 men and 57 women, average age 61.5, patients up to 60 were 54%). METHODS: We compared both groups by retrospective analysis and we evaluated differences by using statistical methods (nonparametric test of independence of the qualitative data). RESULTS: There was only minimal difference in primary conservative and endoscopic haemostasis in both groups. Relaps of bleeding was the same in both groups. Definitive conservative and endoscopic haemostasis was higher by 3.2% in the period 2003-2008 and number of urgent operations decreased by 5.1%. Differences in total mortality were minimal between both groups but postoperative mortality was higher by 5.9% in the years 2003-2008. CONCLUSION: Number of urgent operations decreased due to improved results in definitive conservative and endoscopic haemostasis in the treatment of non-varicose bleeding from upper gastroinestinal tract. There was no significant change in the relaps of bleeding. There were only minimal changes in total mortality between both groups, but postoperative mortality increased in the second period (Tab. 8, Ref. 35). PMID- 21692408 TI - Prevention of postoperative nausea and vomiting with a small dose of propofol combined with dexamethasone 4 mg or dexamethasone 8 mg in patients undergoing middle ear surgery: a prospective, randomized, double-blind study. AB - OBJECTIVE: Postoperative nausea and vomiting (PONV) is a common complication after middle ear surgery. We have aimed to compare the administration of a subhypnotic dose of propofol with dexamethasone 4 mg or 8 mg and placebo in prevention of postoperative nausea and vomiting (PONV) after middle ear surgery. METHOD: This clinical research was performed at Yuksek Ihtisas Hospital Kirikkale. The study included 105 adult patients scheduled for a middle ear operation. The patients were randomly assigned into three groups. The patients in Group I received propofol in a dose of 0.5 mg x kg(-1) plus 4 mg of dexamethasone while Group II was administered with propofol in a dose of 0.5 mg x kg(-1) plus 8 mg of dexamethasone, and Group III was given 0.9% saline solution. Within the framework of the study we evaluated the number of patients suffering from nausea and vomiting at 0-4, 4-12, and 12-24 hours postoperatively, and the necessity to use additional antiemetics. RESULTS: The comparison of data showed that at up to four hours, the incidence of vomiting was 28.6% in Group 1, 22.9% in Group II, and 65.7% in Group III. The incidence rates in Group I and Group II were significantly lower than that in Group III (p < 0.05), while the rate of antiemetic drug usage was higher in Group III than in Group I and Group II (p < 0.05). The Nausea Vomiting Scale scores were also significantly higher in Group III than in Group I and Group II (p < 0.05). There were no significant differences between the values at 4-12 and 12-24 hours. CONCLUSION: The administration of a subhypnotic dose of propofol plus 4 mg of dexamethasone at the end of surgery was found to be at least as effective as propofol plus 8 mg of dexamethasone in preventing the PONV in the early postoperative period in adult patients undergoing middle ear surgery (Tab. 4, Ref. 34). PMID- 21692409 TI - Comparison of local steroid injection into carpal tunnel via proximal and distal approach in patients with carpal tunnel syndrome. AB - OBJECTIVE: Carpal tunnel syndrome (CTS) is the most common peripheral neuropathy presented to physicians. There are several non-surgical treatments methods, such as; splinting of wrist, physical therapy modalities, non-steroidal anti inflammatory drugs ((NSAIDs), injection of corticosteroids, etc. In this study, we aimed to compare the effects of proximal and distal approach to the carpal tunnel regarding the steroid injection application in patients with idiopathic CTS for confirmed nerve conduction studies (NCS). MATERIAL AND METHODS: A total of 19 bilateral CTS patients were enrolled in this study and randomly assigned into 1 of the 2 groups according to the local steroid injection (triamsinolone asetonide 20 mg), either via proximal (10 patients, 20 wrist, 1 M, 9 F)) or distal (palmar) approach (9 patients, 18 wrist, 3M, 6 F) into the carpal tunnel. Clinical and NCS examination were done before and at 3 weeks and 3 months after the injection. Also, severity of night pain, muscle strength, disability by Boston carpal tunnel assessment score (BCTS), HAQ were assessed at baseline and at 3 weeks and 3 months after the injection. All patients were used hand-wrist splint during 3 weeks after injection. RESULTS: There were significant reductions in pain and disability scores between the baseline and follow-up periods. There was not a significant difference between the both groups. There were significant improvement in patients' global assessment in patients from the distal injection group. NCSs showed that electrophysiological improvement was slow. CONCLUSION: This study showed that steroid injection from distal approach (palmar) into the carpal tunnel on patients with CTS is very comfortable, easy, effective and alternative (Tab. 3, Fig. 5, Ref. 11). PMID- 21692410 TI - The effect of prenatal factors on the development of colon cancer. AB - BACKGROUND: There is some evidence that prenatal factors can play a role in the development of colon cancer. Children with an old parent age at the time of birth were observed to develop certain childhood cancers more frequently. OBJECTIVE: This trial was designed to investigate the effects of some prenatal factors on colon cancer risk. Particularly, investigation of the effect of advanced parent age on colon cancer development risk was targeted. MATERIALS AND METHODS: In this study 117 in or out patients diagnosed with colon cancer and 234 control subjects were included. Definitive diagnostic results and dates of diagnosis were determined from pathological reports. Groups were asked for the parent age, smoking habits, sociodemographic, environmental, familial and reproductive traits. The results were compared between the patients and the control group. RESULTS: It was determined that children may have higher risk if mother and father are more than 30 at birth (p = 0.018, p = 0.020). While the mean mother age at birth was 25.6 +/- 5.72 in patients, it was 24.7 +/- 6.90 in the controls. The difference was not statistically significant (p < 0.056). The mean father age at birth was 29.4 +/- 6.58 in patients and 27.4 +/- 7.47 in the controls. The difference was statistically significant (p < 0.001). Smoking of mother was one of the important risk factors of colon cancer (p = 0.044). CONCLUSION: Our data supports that some prenatal factors such as high parental age at birth and mother -smoker may be risk factors for some cancers in children. This is the first study to report that high parental age at birth and exposure to smoke prenatally increase the risk or colon cancer (Tab. 7, Ref. 28). PMID- 21692411 TI - The main differences in oral exposures in children and adults. AB - OBJECTIVES: This study aimed to determine the epidemiological differences between children and adult oral exposures in patients admitted to the busiest emergency department (ED) in the Eastern Anatolia region of Turkey. METHODS: The characteristics of 1950 patients were investigated retrospectively and in a cross sectional manner in a two-year period. RESULTS: The ratio of poisoning exposures among all emergency admissions was 0.6%. Of these, 44.5% were children, and 54.4% were unintentional. The mortality rate was 0.1% and the rate of hospitalization was 14.9%. Among the children and adults, 50.3% and 29.5% were male, respectively. While the first two causes of exposures in both children and adults were licit drugs and foods, there were differences in other causes. Among causes, licit drugs and corrosive materials constituted the forefront in the 0-1 and 1-5 year age groups. In parasuicidal causes, the most common exposure was found to be licit drugs, followed by organophosphates. The most common cause of hospitalization was plants (60.5%). The hospitalization rate was found to be significantly high in males and unintentional exposures. The rate of admissions to the psychiatry polyclinic following exposure was 15%. CONCLUSION: This study hereby presents the original findings as to predict the problems in exposures. The distribution of etiological agents and suicidal intent rate may differ among pediatric and adult population (Tab. 4, Fig. 1, Ref. 50). PMID- 21692412 TI - Tamoxifen/norfloxacin interaction leading to QT interval prolongation in a female patient with extracranial meningioma. AB - The authors report on a case of tamoxifen/norfloxacin interaction leading to QT interval prolongation in an 83-year-old female patient with extracranial meningioma treated with radiation and hormonal therapy (with Tamoxifen). This case report highlights the potential risk of tamoxifen causing depression of electrical impulse in sinoatrial node, leading to symptomatic sinus bradycardia with prolonged QT interval. At the same time it indicates the need to be on the look out for drug interactions (in our case between tamoxifen and norfloxacin), as well as to be aware of other drugs possibly inducing QT interval prolongation (Fig. 2, Ref. 7). PMID- 21692413 TI - Autoimmune hypothyroidism: might its presence be useful to support the diagnosis of sarcoidosis in a patient with acute symmetrical oligoarthritis? AB - Acute sarcoid arthritis may be present in isolation or as part of Lofgren's syndrome. Its true incidence is unclear since the diagnosis may be difficult when patients present with articular symptoms alone. The diagnosis of sarcoid arthritis is based upon suggestive clinical, imaging, synovial fluid findings, and in some cases upon synovial biopsy. The finding of sterile noncaseating granulomatous inflammation on biopsy is supportive, but it is not pathognomic of sarcoidosis. On the other hand, sarcoidosis has been associated with autoimmune diseases, especially with autoimmune thyroid disease. We believe that it might be of interest to evaluate thyroid function testing in patients with clinical features consistent with sarcoid arthritis, and the diagnosis of sarcoidosis should be considered in patients who present with symmetrical arthritis and thyroid autoimmune disease. We describe herein a patient with subclinical autoimmune hypothyroidism and an acute symmetrical oligoarthritis, with a clinical presentation and laboratory data consistent with acute sarcoid arthritis (Ref. 14). PMID- 21692414 TI - Probably the oldest patient with the diagnosis of medullar conus teratoma. AB - BACKGROUND: Authors present a case report of a 60 year old patient suffering from several movement and sensitivity disorders lasting for several months. On magnetic resonance scans a huge extramedular intradural structure was described. Patient underwent three operations and the same number of histological investigations. Furthermore we have performed bacteriological investigations because of the presence of suspicious pus during the surgery. RESULTS: Even after the third investigation the evidence of mature teratoma has been established. After successful passing of three surgeries, the patient has no sphincter disorders and she is able to walk with the sticks and she has only small sensitivity deterioration. CONCLUSION: All forms of teratoma are chemo- and radioresistent, so beside total extirpation we have no relevant possibilities to cure this tumour. The size of the extirpation is mostly limited by the time of appearance, the size of the tumour and by the potential damages of the normal spinal cord tissue, which could be protected by using neurophysiology (Fig. 3, Ref. 9). PMID- 21692415 TI - Celiac disease manifested during the treatment of chronic hepatitis C by pegylated alpha interferon and ribavirin. AB - Authors report a case of patient suffering from haemophilia A and hepatitis C virus infection acquired probably after blood transfusions and substitution factors application. He was treated with pegylated interferon alpha and ribavirin, with the development of malabsorption symptoms during the therapy. Celiac disease was established by histological, histochemical and serological examinations. oth, interferon alpha and ribavirin treatment as well as virus of hepatitis C may trigger coeliac disease in genetically predisposed individuals. The immunological mechanism of celiac disease include balance disruption between Th1 and Th2 immunological response with Th1 predominance. Only few similar cases have been published in the professional literature to date. Development of celiac disease during interferon alpha therapy with haemophilia A was not published until now (Fig. 3, Ref. 13). PMID- 21692416 TI - Complications of misuse of Bacillus Calmette-Guerin. AB - Intravesical BCG is a good treatment choice for vesical carcinomas. Nevertheless, it can also become a mortal toxin when applied in a wrong way. The application routes of the prescribed drug should be rigorously described to patients and detailed instructions regarding the ways of application such as intravesical application should be given to the persons taking this medicine (Ref. 9). PMID- 21692417 TI - Liquid-based cytology test use by office-based physicians: United States, 2006 2007. AB - BACKGROUND: In the United States, liquid-based cytology (LBC) has become a common screening method for cervical cancer. However, the extent of LBC use, and how it varies by patient and practice characteristics, is unknown. OBJECTIVE: This report describes the ordering and provision of Papanicolaou (Pap) tests, with a major focus on the extent to which LBC has supplanted conventional cytology. The type of Pap test is examined for visits made to primary care physicians in 2006 2007 by females aged 15-64. METHODS: Estimates of Pap test cytology use (both LBC and conventional) are based on combined data from the 2006-2007 National Ambulatory Medical Care Survey (NAMCS), an annual nationally representative survey of visits to nonfederal office-based physicians in the United States, as well as on information reported by sample physicians in Cervical Cancer Screening Supplements fielded as part of NAMCS during the same years. RESULTS: In 2006 2007, LBC was used in approximately 75% of Pap tests for which the type of cytology was known. LBC was less likely to be used for Medicare patients than for privately insured patients, although LBC use did not vary significantly according to the other patient or practice characteristics examined. CONCLUSION: The high percentage of LBC use by office-based physicians in 2006-2007 confirms the widespread use of this screening method among primary care providers, as has been reported in the literature. PMID- 21692419 TI - Orientation-specific aftereffects to mentally generated lines. AB - After staring at a pattern of tilted lines, subsequent lines appear to be tilted in the opposite direction (direct tilt aftereffect, TAE). In a previous fMRI study we have demonstrated a direct TAE solely induced by the mental imagination accompanied by adaptation of orientation-selective neurons located in the extrastriate cortex, supporting the assumption of a perception-like coding of mental images. In this study we enlarge and specify the evidence for a perception like coding of orientation-imagination. First, we replicated the previously detected direct TAE induced by line imagination with altered design-variations to control possible perceptual task confounds. Second, we tried to induce two other orientation-specific aftereffects: indirect TAE and contrast-threshold elevation aftereffect by mental imagery. The results replicate a robust direct TAE by mental imagery and by visual stimulation, with no influence of attentional resource allocation or perceptual task confounds. We could not induce an indirect TAE, but observed a perception bias in the opposite direction of the indirect TAE. The mental imagery of lines induced no orientation-selective contrast threshold elevation aftereffect. In general, mental imagery seems to influence visual perception, indicating that perceptual resources are used by mental imagery. However, the utilisation of visual resources seems to be somewhat different from utilisation by perception. PMID- 21692418 TI - How little do we need for 3-D shape perception? AB - How little do we need to perceive 3-D shape in monocular natural images? The shape-from-texture and shape-from-shading perspectives would motivate that 3-D perception vanishes once low-level cues are disrupted. Is this the case in human vision? Or can top-down influences salvage the percept? In this study we probe this question by employing a gauge-figure paradigm similar to that used by Koenderink et al (1992, Perception & Psychophysics 52 487-496). Subjects were presented degraded natural images and instructed to make local assessments of slant and tilt at various locations thereby quantifying their internal 3-D percept. Analysis of subjects' responses reveals recognition to be a significant influence thereby allowing subjects to perceive 3-D shape at high levels of degradation. Specifically, we identify the 'medium-blur' condition, images approximately 32 pixels on a side, to be the limit for accurate 3-D shape perception. In addition, we find that degradation affects the perceived slant of point-estimates making images look flatter as degradation increases. A subsequent condition that eliminates texture and shading but preserves contour and recognition reveals how bottom-up and top-down cues can combine for accurate 3-D shape perception. PMID- 21692420 TI - Aesthetic preferences in the size of images of real-world objects. AB - Konkle and Oliva (in press, Journal of Experimental Psychology: Human Perception and Performance) found that the preferred ('canonical') visual size of a picture of an object within a frame is proportional to the logarithm of its known physical size. They used within-participants designs on several tasks, including having participants adjust the object's size to 'look best'. We examined visual size preference in 2AFC tasks with explicit aesthetic instructions to choose: "which of each pair you like best". We also used both within- and between participants conditions to investigate the possible role of demand characteristics. In experiments 1 and 2, participants saw all possible image pairs depicting the same object at six different sizes for twelve real-world objects that varied in physical size. Significant effects of known physical size were present, regardless of whether participants made judgments about a single object (the between-participants design) or about all objects intermixed (the within-participants design). Experiment 3 showed a reduced effect when the amount of image detail present at different visual sizes was kept constant by posterizing the images. The results are discussed in terms of ecological biases on aesthetic preferences. PMID- 21692421 TI - Flexible resource allocation for the detection of changing visual features. AB - Failure to detect change under circumstances where visual input is interrupted or attention is distracted is indicative of the capacity limits of visual short-term memory. The current study attempts to probe the nature of these limits. In experiment 1, the appearance of single Gabor patches was altered across colour, size, or speed, and set size was manipulated by means of a visual cue. In experiment 2, performance for detecting single and multiple changes to Gabor patches was compared under the constraint that the inherent detectability of each individual change was the same. Experiment 1 yielded a particular set size (4) and a particular level of change magnitude at which performance was equivalent across change type. On the basis of these parameter values, experiment 2 revealed that the detectability of two features changing within one object was the same as the detectability of a single feature changing across two objects, and that this level of detectability could be predicted by a simple model of probability summation. Together, these results suggest that performance is determined by the magnitude of featural changes independently of the way they are distributed across objects. We suggest they are adequately explained by a flexible-resource allocation model rather than a slot-allocation model. PMID- 21692422 TI - Adaptation may cause some of the face caricature effect. AB - One of the ways to demonstrate a caricature preference is to ask participants to adjust a face image over a range from anti-caricature to caricature until it shows the best likeness to a specific individual. Since facial adaptation, whereby exposure to a face influences subsequent perception of faces, is rapid, it is possible that adaptation promotes the selection of a caricatured image. We tested whether giving participants a reference average face image, to counteract any adaptation, would reduce the degree of caricature selected for famous faces. Results confirmed a significant decrease but, even without an average, participants chose an anti-caricatured image. These data suggest a role for adaptation in generating caricature preferences while also suggesting such preferences are not inevitable. PMID- 21692423 TI - The validity of composite photographs for assessing masculinity preferences. AB - Among non-human animals, exaggerated male traits may signal immunocompetence and are often attractive to females. This finding has not been reliably replicated in human populations, however, where preferences for feminised male faces are often observed in experiments. Some authors have suggested that certain experimental approaches, and in particular the use of 'composite', or averaged, photographs, may lack ecological validity and elicit misleading responses. This may account for reports of preferences for femininity. To date, however, experiments have varied on numerous, often confounded, methodological dimensions, making the contribution of different factors difficult to assess. To address this, we conducted an experiment to examine the influence of stimulus type on participant responses. Masculinity preferences were measured using both composite photographs and the photographs from which they were composed, while all other methodological variables were held constant. In contrast to predictions by previous authors, composites elicited significantly stronger overall preferences for masculinity, especially when textural information was reduced during the averaging process. The existence of preferences for feminised male faces is unlikely to be explained by the use of composite photographs alone. PMID- 21692424 TI - The psychometrics of photographic cropping: the influence of colour, meaning, and expertise. AB - Cropping is the central act of photography, the viewfinder of a camera being used to crop a portion of the visual world which is then surrounded with a frame. Six studies are described which show that the act of cropping is carried out reliably and confidently by both expert and non-expert participants. Two studies confirm that some croppers are better croppers than others, their cropped images being preferred aesthetically over the croppings of less-good croppers. Colour had little impact on cropping decisions, whereas thresholded monochrome images ('Mooney images') dramatically altered crop positions. That suggests that cropping can be driven top-down, by the meaning of objects in photographs, but the fact that the Mooneyised images are still cropped consistently, suggests that image structure, perhaps in the form of low-level image properties, may still be important. Experts crop pictures differently from non-experts, and they take longer, viewing a wider range of possible crops, pausing longer to assess crops, and using more formal terminology when reflecting on their cropping decisions. Experts' crops are not, however, preferred more, either by non-expert viewers or by expert viewers. Cropping, it is suggested, is an ideal paradigm for experimental aesthetics, allowing precise experimental control with Fechner's Method of Production, a technique which normally is not easy to use. PMID- 21692425 TI - The paddle move commonly used in magic tricks as a means for analysing the perceptual limits of combined motion trajectories. AB - Following Gustav Kuhn's inspiring technique of using magicians' acts as a source of insight into cognitive sciences, we used the 'paddle move' for testing the psychophysics of combined movement trajectories. The paddle move is a standard technique in magic consisting of a combined rotating and tilting movement. Careful control of the mutual speed parameters of the two movements makes it possible to inhibit the perception of the rotation, letting the 'magic' effect emerge--a sudden change of the tilted object. By using 3-D animated computer graphics we analysed the interaction of different angular speeds and the object shape/size parameters in evoking this motion disappearance effect. An angular speed of 540 degrees s(-1) (1.5 rev. s(-1)) sufficed to inhibit the perception of the rotary movement with the smallest object showing the strongest effect. 90.7% of the 172 participants were not able to perceive the rotary movement at an angular speed of 1125 degrees s(-1) (3.125 rev. s(-1)). Further analysis by multiple linear regression revealed major influences on the effectiveness of the magic trick of object height and object area, demonstrating the applicability of analysing key factors of magic tricks to reveal limits of the perceptual system. PMID- 21692426 TI - The phantom head. AB - A student volunteer was asked to stand just behind a mannequin so that the student was looking at the back of the mannequin's plastic head. The experimenter stood off to one side and used her two hands to stroke and tap the back of the student's head in perfect synchrony with the back of the mannequin's head. After 1-2 min the majority of naive subjects tested began experiencing the sensations as emerging from the mannequin's head rather than from their own, demonstrating a novel 'phantom-head' illusion. The fact that sensory referral here occurs to a part of the body that is not normally visually accessible challenges the leading Hebbian explanation of the well-studied rubber-hand illusion. PMID- 21692427 TI - "It's time to take a stand": depicting crosshairs can indeed promote violence. AB - There is abundant evidence that people derive meaning from signs (Krippendorff, 1989 Design Issues 5 9-39) and that signs influence attitudes (Landau et al, 2010 Psychological Bulletin 136 1045 - 1067). We put to a test whether the use of crosshairs in a map can be viewed as representing violence. In a fictive scenario describing a plague of foxes, members of a Dutch household panel were confronted with a map that showed inflicted areas either by crosshairs or by neutral markers (plain circles). Respondents indicated the extent to which they favoured two solutions: killing-by-shooting or capturing-and-relocating. The results show that crosshairs indeed shape people's attitudes more towards the violent solution of shooting the foxes. Therefore, especially when used in heated public debates, the possibly violence-inducing effect of such visual metaphors should not be underestimated. PMID- 21692428 TI - Unconventional vertical word-order impairs reading. AB - Western written languages unfold across both the horizontal (from left to right) and the vertical (from top to bottom) dimensions. Culturally determined horizontal reading/writing habits are so pervasive that their influence can be found not only in visual scanning but also in performance across different domains and tasks. However, little is known on the effects of vertical word order. In the present study, a lexical decision task is used to show that reading performance is less efficient when verbal material is vertically arranged following a bottom-to-top order. PMID- 21692429 TI - To see or not to see: effects of visual feedback on performance and intuitions of quarterbacks in American football. AB - We investigated the ability of quarterbacks in American football to intercept a moving receiver with a football in occluded and normal viewing conditions, and whether they can accurately predict their own success. Quarterbacks were successful in almost 80% of the trials in the occlusion condition, statistically as successful as in the normal viewing condition. Quarterbacks' predictions of their own success accounted for little variance in actual success. We propose that quarterbacks may attempt to generate a constant target-heading angle between where the football is thrown and the receiver, which may explain the high success rate in the occlusion condition. PMID- 21692430 TI - An obstacle to health: when the body blocks insulin from doing its job. PMID- 21692431 TI - The balanced diet: what it means and why it's so important. PMID- 21692432 TI - Low salt, full flavor: herbs and spices take center stage in new versions of these typically high-sodium dishes. PMID- 21692433 TI - Beyond brown rice. PMID- 21692434 TI - Yummy, creamy, healthy. Dips, dressings, and spreads are great ways to bring good fats into. PMID- 21692435 TI - Home care and hospice leaders 'March on Washington'. PMID- 21692436 TI - Private duty home care: what it means to real people across the nation. AB - Private duty home care is growing rapidly to accommodate the needs of more and more seniors, disabled persons, and those with chronic conditions as these populations themselves are fast expanding and projected to continue to do so in the coming years and decades. The services that private duty/privately paid home care providers deliver each day to individuals across the United States can be absolutely essential to allowing them to remain in their own homes and communities leading as active and healthy lives as possible and continuing to contribute in the work force and to society as they are able. Requirements vary from state to state, and while most private duty agencies provide nonmedical companionship, homemaker, and personal care services--often described as assistance with activities of daily living--some incorporate licensed medical care as well. PMID- 21692437 TI - Clearing up misconceptions & imperceptions of privately paid home care. AB - In today's fast-paced and ever-changing world, clarity is at a premium. But clarity is an imperative as we private duty/private pay home care providers try to grasp the true social, political, and economic dynamics we now face. Without it, the seniors, disabled, and infirm of all ages we serve stand to suffer the most. PMID- 21692439 TI - Ditch the 'stiff upper lip'. PMID- 21692438 TI - Taking the angst out of bathing. PMID- 21692440 TI - Night of the big moon. PMID- 21692441 TI - Doing the right thing for our nation's elderly, infirm, and disabled. PMID- 21692442 TI - Chirality-preserving growth of helical filaments in the B4 phase of bent-core liquid crystals. AB - The growth of helical filaments in the B4 liquid-crystal phase was investigated in mixtures of the bent-core and calamitic mesogens NOBOW and 8CB. Freezing-point depression led to nucleation of the NOBOW B4 phase directly from the isotropic phase in the mixtures, forming large left- and right-handed chiral domains that were easily observed in the microscope. We show that these domains are composed of homochiral helical filaments formed in a nucleation and growth process that starts from a nucleus of arbitrary chirality and continues with chirality preserving growth of the filaments. A model that accounts for the observed local homochirality and phase coherence of the branched filaments is proposed. This model will help in providing a better understanding of the nature of the B4 phase and controlling its growth and morphology for applications, such as the use of the helical nanophase as a nanoheterogeneous medium. PMID- 21692443 TI - Structure and absolute configuration of helosides A and B, new saponins from Chamaelirium luteum. AB - Investigation of Chamaelirium luteum roots led to the isolation of two new steroidal saponins, helosides A and B, that contain a previously unreported aglycone, helogenin. Their structures and absolute configuration were elucidated through MS-MS, NMR, chemical degradation, and X-ray crystallography. PMID- 21692444 TI - Reactive semiconductor nanocrystals for chemoselective biolabeling and multiplexed analysis. AB - Effective biological application of nanocrystalline semiconductor quantum dots continues to be hampered by the lack of easily implemented and widely applicable labeling chemistries. Here, we introduce two new orthogonal nanocrystal bioconjugation chemistries that overcome many of the labeling issues associated with currently utilized approaches. These chemistries specifically target either (1) the ubiquitous amines found on proteins or (2) thiols present in either antibody hinge regions or recombinantly introduced into other proteins to facilitate site-specific labeling. The amine chemistry incorporates aniline catalyzed hydrazone bond formation, while the sulfhydryl chemistry utilizes nanocrystals displaying surface activated maleimide groups. Both reactive chemistries are rapidly implemented, yielding purified nanocrystal-protein bioconjugates in as little as 3 h. Following initial characterization of the nanocrystal materials, the wide applicability and strong multiplexing potential of these chemistries are demonstrated in an array of applications including immunoassays, immunolabeling in both cellular and tissue samples, in vivo cellular uptake, and flow cytometry. Side-by-side comparison of the immunolabeled cells suggested a functional equivalence between results generated with the amine and thiol-labeled antibody-nanocrystal bioconjugates in that format. Three-color labeling was achieved in the cellular uptake format, with no significant toxicity observed while simultaneous five-color labeling of different epitopes was demonstrated for the immunolabeled tissue sample. Novel labeling applications are also facilitated by these chemistries, as highlighted by the ability to directly label cellular membranes in adherent cell cultures with the thiol-reactive chemistry. PMID- 21692445 TI - Modeling contaminant concentration distributions in China's centralized source waters. AB - Characterizing contaminant occurrences in China's centralized source waters can provide an understanding of source water quality for stakeholders. The single factor (i.e., worst contaminant) water-quality assessment method, commonly used in Chinese official analysis and publications, provides a qualitative summary of the country's water-quality status but does not specify the extent and degree of specific contaminant occurrences at the national level. Such information is needed for developing scientifically sound management strategies. This article presents a Bayesian hierarchical modeling approach for estimating contaminant concentration distributions in China's centralized source waters using arsenic and fluoride as examples. The data used are from the most recent national census of centralized source waters in 2006. The article uses three commonly used source water stratification methods to establish alternative hierarchical structures reflecting alternative model assumptions as well as competing management needs in characterizing pollutant occurrences. The results indicate that the probability of arsenic exceeding the standard of 0.05 mg/L is about 0.96-1.68% and the probability of fluoride exceeding 1 mg/L is about 9.56-9.96% nationally, both with strong spatial patterns. The article also discusses the use of the Bayesian approach for establishing a source water-quality information management system as well as other applications of our methods. PMID- 21692446 TI - Hyperpolarized [1-13C]-ascorbic and dehydroascorbic acid: vitamin C as a probe for imaging redox status in vivo. AB - Dynamic nuclear polarization (DNP) of (13)C-labeled metabolic substrates in vitro and their subsequent intravenous administration allow both the location of the hyperpolarized substrate and the dynamics of its subsequent conversion into other metabolic products to be detected in vivo. We report here the hyperpolarization of [1-(13)C]-ascorbic acid (AA) and [1-(13)C]-dehydroascorbic acid (DHA), the reduced and oxidized forms of vitamin C, respectively, and evaluate their performance as probes of tumor redox state. Solution-state polarization of 10.5 +/- 1.3% was achieved for both forms at pH 3.2, whereas at pH 7.0, [1-(13)C]-AA retained polarization of 5.1 +/- 0.6% and [1-(13)C]-DHA retained 8.2 +/- 1.1%. The spin-lattice relaxation times (T(1)'s) for these labeled nuclei are long at 9.4 T: 15.9 +/- 0.7 s for AA and 20.5 +/- 0.9 s for DHA. Extracellular oxidation of [1-(13)C]-AA and intracellular reduction of [1-(13)C]-DHA were observed in suspensions of murine lymphoma cells. The spontaneous reaction of DHA with the cellular antioxidant glutathione was monitored in vitro and was approximately 100 fold lower than the rate observed in cell suspensions, indicating enzymatic involvement in the intracellular reduction. [1-(13)C]-DHA reduction was also detected in lymphoma tumors in vivo. In contrast, no detectable oxidation of [1 (13)C]-AA was measured in the same tumors, consistent with the notion that tumors maintain a reduced microenvironment. This study demonstrates that hyperpolarized (13)C-labeled vitamin C could be used as a noninvasive biomarker of redox status in vivo, which has the potential to translate to the clinic. PMID- 21692447 TI - GPU accelerated chemical similarity calculation for compound library comparison. AB - Chemical similarity calculation plays an important role in compound library design, virtual screening, and "lead" optimization. In this manuscript, we present a novel GPU-accelerated algorithm for all-vs-all Tanimoto matrix calculation and nearest neighbor search. By taking advantage of multicore GPU architecture and CUDA parallel programming technology, the algorithm is up to 39 times superior to the existing commercial software that runs on CPUs. Because of the utilization of intrinsic GPU instructions, this approach is nearly 10 times faster than existing GPU-accelerated sparse vector algorithm, when Unity fingerprints are used for Tanimoto calculation. The GPU program that implements this new method takes about 20 min to complete the calculation of Tanimoto coefficients between 32 M PubChem compounds and 10K Active Probes compounds, i.e., 324G Tanimoto coefficients, on a 128-CUDA-core GPU. PMID- 21692448 TI - Self-assembled targeted nanoparticles: evolution of technologies and bench to bedside translation. AB - Nanoparticles (NPs) have become an important tool in many industries including healthcare. The use of NPs for drug delivery and imaging has introduced exciting opportunities for the improvement of disease diagnosis and treatment. Over the past two decades, several first-generation therapeutic NP products have entered the market. Despite the lack of controlled release and molecular targeting properties in these products, they improved the therapeutic benefit of clinically validated drugs by enhancing drug tolerability and/or efficacy. NP-based imaging agents have also improved the sensitivity and specificity of different diagnostic modalities. The introduction of controlled-release properties and targeting ligands toward the development of next-generation NPs should enable the development of safer and more effective therapeutic NPs and facilitate their application in theranostic nanomedicine. Targeted and controlled-release NPs can drastically alter the pharmacological characteristics of their payload, including their pharmacokinetic and, in some cases, their pharmacodynamic properties. As a result, these NPs can improve drug properties beyond what can be achieved through classic medicinal chemistry. Despite their enormous potential, the translation of targeted NPs into clinical development has faced considerable challenges. One significant problem has been the difficulty in developing targeted NPs with optimal biophysicochemical properties while using robust processes that facilitate scale-up and manufacturing. Recently, efforts have focused on developing NPs through self-assembly or high-throughput processes to facilitate the development and screening of NPs with these distinct properties and the subsequent scale-up of their manufacture. We have also undertaken parallel efforts to integrate additional functionality within therapeutic and imaging NPs, including the ability to carry more than one payload, to respond to environmental triggers, and to provide real-time feedback. In addition, novel targeting approaches are being developed to enhance the tissue-, cell-, or subcellular specific delivery of NPs for a myriad of important diseases. These include the selection of internalizing ligands for enhanced receptor-mediated NP uptake and the development of extracellular targeting ligands for vascular tissue accumulation of NPs. In this Account, we primarily review the evolution of marketed NP technologies. We also recount our efforts in the design and optimization of NPs for medical applications, which formed the foundation for the clinical translation of the first-in-man targeted and controlled-release NPs (BIND-014) for cancer therapy. PMID- 21692449 TI - One-step photochemical synthesis of permanent, nonleaching, ultrathin antimicrobial coatings for textiles and plastics. AB - Antimicrobial copolymers of hydrophobic N-alkyl and benzophenone containing polyethylenimines were synthesized from commercially available linear poly(2 ethyl-2-oxazoline), and covalently attached to surfaces of synthetic polymers, cotton, and modified silicon oxide using mild photo-cross-linking. Specifically, these polymers were applied to polypropylene, poly(vinyl chloride), polyethylene, cotton, and alkyl-coated oxide surfaces using solution casting or spray coating and then covalently cross-linked rendering permanent, nonleaching antimicrobial surfaces. The photochemical grafting of pendant benzophenones allows immobilization to any surface that contains a C-H bond. Incubating the modified materials with either Staphylococcus aureus or Escherichia coli demonstrated that the modified surfaces had substantial antimicrobial capacity against both Gram positive and Gram-negative bacteria (>98% microbial death). PMID- 21692450 TI - Reversible fluorescent probe for highly selective and sensitive detection of mercapto biomolecules. AB - A coumarin-derived complex, Hg(2)L(2), was reported as a highly sensitive and selective probe for the detection of mercapto biomolecules in aqueous solution. The addition of Cys to a 99% aqueous solution of Hg(2)L(2) resulted in rapid and remarkable fluorescence OFF-ON (emission at 525 nm) due to the ligand-exchange reaction of Cys with L coordinated to Hg(2+). The increased fluorescence can be completely quenched by Hg(2+) and recovered again by the subsequent addition of Cys. Such a fluorescence OFF-ON circle can be repeated at least 10 times by the alterative addition of Cys and Hg(2+) to the solution of Hg(2)L(2), indicating that it can be used as a convertible and reversible probe for the detection of Cys. The interconversion of Hg(2)L(2) and L via the decomplexation/complexation by the modulation of Cys/Hg(2+) was definitely verified from their crystal structures. Other competitive amino acids without a thiol group cannot induce any fluorescence changes, implying that Hg(2)L(2) can selectively determine mercapto biomolecules. Using confocal fluorescence imaging, L/Hg(2)L(2) as a pair of reversible probes can be further applied to track and monitor the self detoxification process of Hg(2+) ions in SYS5 cells. PMID- 21692451 TI - Behavior of Ag3 clusters inside a nanometer-sized space of ZSM-5 zeolite. AB - We found from DFT calculations that Ag-Ag orbital interactions as well as Ag-O electrostatic interactions determine the structures of three silver cations inside a nanometer-sized cavity of ZSM-5 (Ag(3)-ZSM-5) in lower and higher spin states. Both interactions strongly depend on the number of Al atoms substituted for Si atoms on the ZSM-5 framework (ZSM-5(Al(n))), where n ranges from 1 to 3. In smaller n, stronger Ag-Ag orbital interactions and weaker Ag-O electrostatic interactions operate. Accordingly, there are significant dependencies of the structures of three silver cations on the number of Al atoms. In lower spin states of Ag(3)-ZSM-5(Al(1)) and Ag(3)-ZSM-5(Al(2)), D(3h)-like triangle clusters are contained inside ZSM-5 whereas their higher spin states have triangle clusters distorted significantly from the D(3h) structure. In lower spin states, the totally symmetric orbital consisting of 5s(Ag) orbitals is responsible for cluster formation, whereas in higher spin states occupation of a 5s(Ag)-based orbital with one node results in significant distortion of the triangle clusters. The distortion can be partially understood by analogies to Jahn-Teller distortion of the bare D(3h) Ag(3)(+) cluster in the triplet spin state. When n is 3, we found that three silver cations are isolated in a lower spin state and that a linear cluster consisting of two silver cations is formed in a higher spin state. Thus, we demonstrate from DFT calculations that the number of Al atoms can control the properties of three silver cations inside a ZSM-5 cavity. Since the structural and electronic features of the enclosed silver clusters can link to their catalytic properties, the DFT findings can help us to understand the catalytic activity of Ag-ZSM-5. PMID- 21692452 TI - Two new ternary complexes of copper(II) with tetracycline or doxycycline and 1,10 phenanthroline and their potential as antitumoral: cytotoxicity and DNA cleavage. AB - This paper reports on the synthesis and characterization of two new ternary copper(II) complexes: [Cu(doxycycline)(1,10 phenanthroline)(H(2)O)(ClO(4))](ClO(4)) (1) and [Cu(tetracycline)(1,10 phenanthroline)(H(2)O)(ClO(4))](ClO(4)) (2). These compounds exhibit a distorted tetragonal geometry around copper, which is coordinated to two bidentate ligands, 1,10-phenanthroline and tetracycline or doxycyline, a water molecule, and a perchlorate ion weakly bonded in the axial positions. In both compounds, copper(II) binds to tetracyclines via the oxygen of the hydroxyl group and oxygen of the amide group at ring A and to 1,10-phenanthroline via its two heterocyclic nitrogens. We have evaluated the binding of the new complexes to DNA, their capacity to cleave it, their cytotoxic activity, and uptake in tumoral cells. The complexes bind to DNA preferentially by the major groove, and then cleave its strands by an oxidative mechanism involving the generation of ROS. The cleavage of DNA was inhibited by radical inhibitors and/or trappers such as superoxide dismutase, DMSO, and the copper(I) chelator bathocuproine. The enzyme T4 DNA ligase was not able to relegate the products of DNA cleavage, which indicates that the cleavage does not occur via a hydrolytic mechanism. Both complexes present an expressive plasmid DNA cleavage activity generating single- and double strand breaks, under mild reaction conditions, and even in the absence of any additional oxidant or reducing agent. In the same experimental conditions, [Cu(phen)(2)](2+) is approximately 100-fold less active than our complexes. These complexes are among the most potent DNA cleavage agents reported so far. Both complexes inhibit the growth of K562 cells with the IC(50) values of 1.93 and 2.59 MUmol L(-1) for compounds 1 and 2, respectively. The complexes are more active than the free ligands, and their cytotoxic activity correlates with intracellular copper concentration and the number of Cu-DNA adducts formed inside cells. PMID- 21692453 TI - Damping of the acoustic vibrations of individual gold nanoparticles. AB - In this letter, the ultrafast vibrational dynamics of individual gold nanorings has been investigated by femtosecond transient absorption spectroscopy. Two acoustic vibration modes have been detected and identified. The influence of the mechanical coupling at the nanoparticle/substrate interface on the acoustic vibrations of the nano-objects is discussed. Moreover, by changing the environment of the nanoring, we provide a clear evidence of the impact of the surrounding medium on the damping of the acoustic vibrations. Such results are reported here for the first time on individual nanoparticles. This work points out a new sensing method based on the sensitivity of the acoustic vibration damping to the surrounding medium. PMID- 21692454 TI - Microstructure investigation on micropore formation in microporous silica materials prepared via a catalytic sol-gel process by small angle X-ray scattering. AB - The so-called sol-gel technique has been shown to be a template-free, efficient way to create functional porous silica materials having uniform micropores. This appears to be closely linked with a postulation that the formation of weakly branched polymer-like aggregates in a precursor solution is a key to the uniform micropore generation. However, how such a polymer-like structure can precisely be controlled, and further, how the generated low-fractal dimension solution structure is imprinted on the solid silica materials still remain elusive. Here we present fabrication of microporous silica from tetramethyl orthosilicate (TMOS) using a recently developed catalytic sol-gel process based on a nonionic hydroxyacetone (HA) catalyst. Small angle X-ray scattering (SAXS), nitrogen adsorption porosimetry, and transmission electron microscope (TEM) allowed us to observe the whole structural evolution, ranging from polymer-like aggregates in the precursor solution to agglomeration with heat treatment and microporous morphology of silica powders after drying and hydrolysis. Using the HA catalyst with short chain monohydric alcohols (methanol or ethanol) in the precursor solution, polymer-like aggregates having microscopic correlation length (or mesh size) < 2 nm and low fractal dimensions ~2, which is identical to that of an ideal coil polymer, can selectively be synthesized, yielding the uniform micropores with diameters <2 nm in the solid materials. In contrast, the absence of HA or substitution of 1-propanol led to considerably different scattering behavior reflecting the particle-like aggregate formation in the precursor solution, which resulted in the formation of mesopores (diameter >2 nm) in the solid product due to apertures between the particle-like aggregates. The data demonstrate that the extremely fine porous silica architecture comes essentially from a gaussian polymer-like nature of the silica aggregates in the precursor having the microscopic mesh-size and their successful imprint on the solid product. The result offers a general but significantly efficient route to creating precisely designed fine porous silica materials under mild condition that serve as low refractive index and efficient thermal insulation materials in their practical applications. PMID- 21692455 TI - Metabolic labeling of chondrocytes for the quantitative analysis of the interleukin-1-beta-mediated modulation of their intracellular and extracellular proteomes. AB - Chondrocytes are widely used as an in vitro model of cartilage diseases such as osteoarthritis (OA). As the unique residents of mature cartilage, they are responsible of the synthesis and release of proteins essential for a proper tissue turnover. In this work, the stable isotope labeling with amino acids in cell culture (SILAC) technique has been standardized in primary human articular chondrocytes (HACs) for quantitative proteomic analyses. Then, it has been employed to study those protein modifications caused by the proinflammatory cytokine Interleukin-1beta (IL-1beta), a well-known OA mediator, in these cells. Quantitative analysis of the IL-1beta-treated HACs proteome revealed a global increase in cellular chaperones concurrent with a down-regulation of the actin cytoskeleton. HACs secretome analysis led to the identification and quantification of 115 proteins and unveiled the effects of the cytokine on the cartilage extracellular matrix metabolism. Among those modulated proteins, three protein clusters were found to be remarkably increased by IL-1beta: proinflammatory mediators and proteases, type VI collagen and proteins known to bind this molecule, and proteins related with the TGF-beta pathway. On the other hand, secretion of aggrecan, two vitamin K-dependent proteins, and thrombospondin, among others, was strongly reduced. Altogether, these data demonstrate the usefulness of metabolic labeling for quantitative proteomics studies in HACs, show the complementarity of intracellular proteome and secretome analyses, and provide a comprehensive study of the IL-1beta-mediated effects on these cells. Proteins identified in the secretome approach have a potential use as biomarkers or therapeutic targets for OA. PMID- 21692456 TI - "Nanohybrids" based on pH-responsive hydrogels and inorganic nanoparticles for drug delivery and sensor applications. AB - Allyl-PEG capped inorganic NPs, including magnetic iron oxide (IONPs), fluorescent CdSe/ZnS quantum dots (QDs), and metallic gold (AuNPs of 5 and 10 nm) both individually and in combination, were covalently attached to pH-responsive poly(2-vinylpyridine-co-divinylbenzene) nanogels via a facile and robust one-step surfactant-free emulsion polymerization procedure. Control of the NPs associated to the nanogels was achieved by the late injection of the NPs to the polymerization solution at a stage when just polymeric radicals were present. Remarkably, by varying the total amount of NPs injected, the swelling behavior could be affected. Furthermore, the magnetic response as well as the optical features of the nanogels containing either IONPs or QDs could be modified. In addition, a radical quenching in case of gold nanoparticles was observed, thus affecting the final nanogel geometry. PMID- 21692457 TI - Proteomic signatures in thapsigargin-treated hepatoma cells. AB - Thapsigargin, an inhibitor of the endoplasmic reticulum (ER) calcium transporters, generates Ca(2+)-store depletion within the ER and simultaneously increases Ca(2+) level in the cytosol. Perturbation of Ca(2+) homeostasis leads cells to cope with stressful conditions, including ER stress, which affect the folding of newly synthesized proteins and induce the accumulation of unfolded polypeptides and eventually apoptosis, via activation of the unfolded protein response pathway. In the present work, we analyzed the proteome changes in human hepatoma cells following acute treatment with thapsigargin. We highlighted a peculiar pattern of protein expression, marked by altered expression of calcium dependent proteins, and of proteins involved in secretory pathways or in cell survival. For specific deregulated proteins, the thapsigargin-induced proteomic signature was compared by Western blotting to that resulting from the treatment of hepatoma cells with reducing agents or with proteasome inhibitors, to elicit endoplasmic reticulum stress by additional means and to reveal novel, potential targets of the unfolded protein response pathway. PMID- 21692458 TI - Fate of perfluorinated carboxylates and sulfonates during snowmelt within an urban watershed. AB - The transport dynamics of perfluorinated carboxylic acids and sulfonates during snowmelt in the highly urbanized Highland Creek watershed in Toronto, Canada was investigated by analyzing river water, bulk snow, and groundwater, sampled in February and March 2010, by means of liquid chromatography-tandem mass spectrometry. Perfluorohexanoate, perfluorooctanoate, and perfluorooctane sulfonate were dominant in river water, with concentrations of 4.0-14 ng.L(-1), 2.2-7.9 ng.L(-1), and 2.1-6.5 ng.L(-1), respectively. Relatively high levels of perfluorohexanoate may be related to the recent partial replacement in various consumer products of perfluorooctyl substances with shorter-chained perfluorinated compounds (PFCs). Highest PFC concentrations were found within the more urbanized part of the drainage area, suggestive of residential, industrial, and/or traffic-related sources. The riverine flux of PFCs increased during the snowmelt period, but only approximately one-fifth of the increased flux can be attributed to PFCs present in the snowpack, mostly because concentration in snow are generally quite low compared to those in river water. The remainder of the increased flux must be due to the mobilization of PFCs by the high flow conditions prevalent during snowmelt. Run-off behavior was clearly dependent on perfluoroalkyl chain length: Dilution with relatively clean snowmelt water caused a drop in the river water concentrations of short-chain PFCs at high flow during early melting. This prevented an early concentration peak of those water-soluble PFCs within the stream, as could have been expected in response to their early release from a melting snowpack. Instead, concentrations of particle-associated long-chain PFCs in creek water peaked early in the melt, presumably because high flow mobilized contaminated particles from impervious surfaces in the more urbanized areas of the watershed. The ability to enter the subsurface and deeper groundwater aquifers increased with the PFCs' water solubility, that is, was inversely related to perfluoroalkyl chain length. PMID- 21692459 TI - Development of a highly sensitive fluorescence probe for hydrogen peroxide. AB - Hydrogen peroxide is believed to play a role in cellular signal transduction by reversible oxidation of proteins. Here, we report the design and synthesis of a novel fluorescence probe for hydrogen peroxide, utilizing a photoinduced electron transfer strategy based on benzil chemistry to control the fluorescence. The practical value of this highly sensitive and selective fluorescence probe, NBzF, was confirmed by its application to imaging of hydrogen peroxide generation in live RAW 264.7 macrophages. NBzF was also employed for live cell imaging of hydrogen peroxide generated as a signaling molecule in A431 human epidermoid carcinoma cells. PMID- 21692460 TI - Chemical topology: complex molecular knots, links, and entanglements. PMID- 21692461 TI - Growth mechanisms involved in the synthesis of smooth and microtextured films by acetylene magnetron discharges. AB - The growth of hydrogenated amorphous carbons (a-C:H) produced by continuous or pulsed discharges of acetylene (C(2)H(2)) in an unbalanced magnetron setup was investigated. At 5 * 10(-3) Torr, only smooth films are obtained, whereas at 5 * 10(-1) Torr using a pulsed discharge some microtextured films are formed if the duty cycle is low. The morphology of these microtextured films consists of nanoparticles, filamentary particles, and particular agglomerates ("microflowers"). This paper presents a study of acetylene gas phase polymerization by mass spectrometry, and a detailed analysis of bulk structure of films by combining three techniques which include IR spectroscopy, Raman spectroscopy, and laser desorption/ionization Fourier transform mass spectrometry (LDI-FTMS). Finally, based on the study of gas phase and film structure, we propose a model for the growth of both smooth and microtextured films. PMID- 21692462 TI - Site competition during coadsorption of acetone with methanol and water on TiO2(110). AB - The competitive interaction between acetone and two solvent molecules (methanol and water) for surface sites on rutile TiO(2)(110) was studied using temperature programmed desorption (TPD). On a vacuum-annealed TiO(2)(110) surface, which possessed ~5% oxygen vacancy sites, excess methanol displaced preadsorbed acetone molecules to weakly bound and physisorbed desorption states below 200 K. In contrast, acetone molecules were stabilized on an oxidized surface against displacement by methanol through formation of acetone diolate species. The behavior of acetone with methanol differs from the interactions between acetone and water which are less competitive. Examination of acetone + methanol and acetone + water multilayer combinations shows that acetone is more compatible in water-ice films than in methanol-ice films, presumably because water has greater potential as a hydrogen-bond donor than does methanol. Acetone molecules displaced from the TiO(2)(110) surface by water are more likely to be retained in the near-surface region, in turn having a greater opportunity to revisit the surface, than when methanol is used as a coadsorbate. PMID- 21692463 TI - The use of highly ordered vesicle gels as template for the formation of silica gels. AB - A spontaneously forming gel of unilamellar vesicles based on sodium oleate (Na oleate) and 1-octanol as amphiphiles has been employed as a template in the formation of a silica gel formed by the hydrolysis of the inorganic precursor tetraethyl orthosilicate (TEOS). Up to about 10 wt % TEOS can be incorporated into this vesicle gel without phase separation and in a fully homogeneous formation process by simple mixing of the components. The process itself relies solely upon the self-organizing properties of this amphiphilic template system. The formation process was followed by means of time-resolved turbidity, rheology, and small-angle neutron scattering (SANS) experiments. It can be concluded that the presence of the precursor TEOS affects the kinetics of the process but the original vesicle gel structure is retained even up to highest TEOS content. The kinetic studies confirm that under the chosen conditions the vesicle formation proceeds much faster than the hydrolysis of TEOS and the subsequent formation of the silica gel. SANS displays in the low q-range an additional scattering due to the silica gel network, i.e., a hybrid material of an amphiphilic vesicle gel and an inorganic oxide gel is formed. Thus, this method is a very facile novel route of forming a highly ordered silica/vesicle gel by employing a self-organizing amphiphilic system as template and the formation of the silica network proceeds in a fully homogeneous fashion under kinetic control. PMID- 21692464 TI - Ab initio study of the adsorption of NO on the Rh6(+) cluster. AB - The process of NO adsorption on the cationic cluster Rh(6)(+) is investigated using the density-functional theory (DFT) with the generalized gradient approximation (GGA) to exchange and correlation. We determine the geometries, electronic structure, and relevant energies for different structural and spin isomers of Rh(6)(0,+/-), and we study the consecutive adsorption of two NO molecules on the cationic cluster Rh(6)(+). With regard to the first NO molecule, different adsorption energies are found for the ground state octahedral structure of the bare cationic cluster and for the first isomer, which, having a prism-type structure, undergoes a structural transition to an octahedral symmetry upon dissociative adsorption of NO. Several dissociative NO adsorption processes are analyzed in comparison with molecular adsorption of NO to give support to the first step of the reaction inferred from experiments. With regard to the adsorption of a second NO molecule, the intermediate with lowest energy contains a preformed N(2) molecule. The energy of that complex is about 0.7 eV smaller than the sum of the free N(2) energy plus the lowest energy of the Rh(6)(+)-O(2) complex. This complex is composed of two separated O atoms occupying adjacent 2 fold bridging positions of the nearly undistorted Rh(6)(+) octahedral cluster. These findings are in qualitative agreement with experiments. PMID- 21692465 TI - Lithium-assisted plastic deformation of silicon electrodes in lithium-ion batteries: a first-principles theoretical study. AB - Silicon can host a large amount of lithium, making it a promising electrode for high-capacity lithium-ion batteries. Recent experiments indicate that silicon experiences large plastic deformation upon Li absorption, which can significantly decrease the stresses induced by lithiation and thus mitigate fracture failure of electrodes. These issues become especially relevant in nanostructured electrodes with confined geometries. On the basis of first-principles calculations, we present a study of the microscopic deformation mechanism of lithiated silicon at relatively low Li concentration, which captures the onset of plasticity induced by lithiation. We find that lithium insertion leads to breaking of Si-Si bonds and formation of weaker bonds between neighboring Si and Li atoms, which results in a decrease in Young's modulus, a reduction in strength, and a brittle-to ductile transition with increasing Li concentration. The microscopic mechanism of large plastic deformation is attributed to continuous lithium-assisted breaking and re-forming of Si-Si bonds and the creation of nanopores. PMID- 21692466 TI - Atomic-level study of adsorption, conformational change, and dimerization of an alpha-helical peptide at graphene surface. AB - Recent circular dichroism spectroscopy and scanning tunneling microscopy study reported that a de novo designed alpha-helical peptide (with amino acid sequence DELERRIRELEARIK) would transform to beta-sheet structure as well as random coil structure upon the addition of graphite particles to the peptide solution and aggregate into ordered beta-sheet-rich assemblies at the graphite surface. However, the atomic-level information about the dynamics of early stage conformational transition at water-graphite interface and the driving force underlying the structural transition is largely unknown. In this study, we have investigated the conformational dynamics of two chains of the alpha-helical peptide in the absence and presence of a graphene sheet by performing all-atom molecular dynamic simulations in explicit solvent at 310 and 330 K. Our simulations show that consistent with the signal measured experimentally under physiological buffer conditions, two chains are mostly dimeric and keep alpha helical structure in solution, whereas they unfold and assemble into an amorphous dimer at graphene surface. The beta-sheet conformation is not observed in all MD runs within the 15-200 ns times scale, which indicates that the alpha-helix to beta-sheet transition for this short peptide at graphite surface is a slow process, similar to the slow transition dynamics of globular protein reported experimentally. By analyzing all MD trajectories, we found that (1) the formation of alpha-helical dimer in solution is mostly driven by interpeptide hydrophobic interactions; (2) the adsorption and the alpha-helix unfolding of the peptide at graphene surface is initiated from the C-terminal region due to strong interactions between residues Arg13-Ile14-Lys15 and graphene surface; (3) the extent of helix unfolding strongly depends on the interaction strength between the peptide and graphene surface; and (4) the dimerization of two unfolded peptide chains at graphene surface results from the interplay between peptide graphene and peptide-peptide interactions. This study would provide significant insight into the detailed mechanism of graphite-induced conformational transition and dimerization prior to the formation of beta-sheet assemblies of this short synthetic alpha-helical peptide. PMID- 21692467 TI - A formal synthesis of SCH 351448. AB - An efficient formal synthesis of SCH 351448 was accomplished through the tandem cross-metathesis (CM)/oxa-Michael, the 1,4-syn aldol, the tandem oxidation/oxa Michael, and the Suzuki coupling reaction. PMID- 21692468 TI - Electrocyclization of phosphahexatrienes: an approach to lambda5-phosphinines. AB - We experimentally verified an assumption that the substitution of a carbon atom with a pentavalent phosphorus atom in 1-alkoxy (dialkylamino) hexatrienes will not hamper its ability to electrocyclize. A series of 1-, 3-, and 5 phosphahexatrienes were synthesized. It was shown that parent lambda(5) phosphinines could be synthesized by electrocyclization of the 3- and 5 phosphahexatrienes. The resultant electrocyclization is a convenient method for the synthesis of parent lambda(5)-phosphinines bearing different substituents on the phosphorus atom. PMID- 21692469 TI - In vivo termini amino acid labeling for quantitative proteomics. AB - Quantitative proteomics is one of the research hotspots in the proteomics field and presently maturing rapidly into an important branch. The two most typical quantitative methods, stable isotope labeling with amino acids in cell culture (SILAC) and isobaric tags for relative and absolute quantification (iTRAQ), have been widely and effectively applied in solving various biological and medical problems. Here, we describe a novel quantitative strategy, termed "IVTAL", for in vivo termini amino acid labeling, which combines some advantages of the two methods above. The core of this strategy is a set of heavy amino acid (13)C(6) arginine and (13)C(6)-lysine and specific endoproteinase Lys-N and Arg-C that yield some labeled isobaric peptides by cell culture and enzymatic digestion, which are indistinguishable in the MS scan but exhibit multiple MS/MS reporter b, y ion pairs in a full mass range that support quantitation. Relative quantification of cell states can be achieved by calculating the intensity ratio of the corresponding reporter b, y ions in the MS/MS scan. The experimental analysis for various proportions of mixed HeLa cell samples indicated that the novel strategy showed an abundance of reliable quantitative information, a high sensitivity, and a good dynamic range of nearly 2 orders of magnitude. IVTAL, as a highly accurate and reliable quantitative proteomic approach, is expected to be compatible with any cell culture system and to be especially effective for the analysis of multiple post-translational modificational sites in one peptide. PMID- 21692470 TI - Transparent conductive films consisting of ultralarge graphene sheets produced by Langmuir-Blodgett assembly. AB - Monolayer graphene oxide (GO) sheets with sizes ranging from a few to ~200 MUm are synthesized based on a chemical method and are sorted out to obtain four different grades having uniform sizes. Transparent conductive films are produced using the ultralarge graphene oxide (UL-GO) sheets that are deposited layer-by layer on a substrate using the Langmuir-Blodgett (LB) assembly technique. The density and degree of wrinkling of the UL-GO monolayers are turned from dilute, close-packed flat UL-GO to graphene oxide wrinkles (GOWs) and concentrated graphene oxide wrinkles (CGOWs) by varying the LB processing conditions. The method demonstrated here opens up a new avenue for high-yield fabrication of GOWs or CGOWs that are considered promising materials for hydrogen storage, supercapacitors, and nanomechanical devices. The films produced from UL-GO sheets with a close-packed flat structure exhibit exceptionally high electrical conductivity and transparency after thermal reduction and chemical doping treatments. A remarkable sheet resistance of ~500 Omega/sq at 90% transparency is obtained, which outperforms the graphene films grown on a Ni substrate by chemical vapor deposition. The technique used in this work to produce transparent conductive UL-GO thin films is facile, inexpensive, and tunable for mass production. PMID- 21692471 TI - In vivo imaging of transplanted islets with 64Cu-DO3A-VS-Cys40-Exendin-4 by targeting GLP-1 receptor. AB - Glucagon-like peptide 1 receptor (GLP-1R) is highly expressed in pancreatic islets, especially on beta-cells. Therefore, a properly labeled ligand that binds to GLP-1R could be used for in vivo pancreatic islet imaging. Because native GLP 1 is degraded rapidly by dipeptidyl peptidase-IV (DPP-IV), a more stable agonist of GLP-1 such as Exendin-4 is a preferred imaging agent. In this study, DO3A-VS Cys(40)-Exendin-4 was prepared through the conjugation of DO3A-VS with Cys(40) Exendin-4. The in vitro binding affinity of DO3A-VS-Cys(40)-Exendin-4 was evaluated in INS-1 cells, which overexpress GLP-1R. After (64)Cu labeling, biodistribution studies and microPET imaging of (64)Cu-DO3A-VS-Cys(40)-Exendin-4 were performed on both subcutaneous INS-1 tumors and islet transplantation models. The subcutaneous INS-1 tumor was clearly visualized with microPET imaging after the injection of (64)Cu-DO3A-VS-Cys(40)-Exendin-4. GLP-1R positive organs, such as pancreas and lung, showed high uptake. Tumor uptake was saturable, reduced dramatically by a 20-fold excess of unlabeled Exendin-4. In the intraportal islet transplantation models, (64)Cu-DO3A-VS-Cys(40)-Exendin-4 demonstrated almost two times higher uptake compared with normal mice. (64)Cu DO3A-VS-Cys(40)-Exendin-4 demonstrated persistent and specific uptake in the mouse pancreas, the subcutaneous insulinoma mouse model, and the intraportal human islet transplantation mouse model. This novel PET probe may be suitable for in vivo pancreatic islets imaging in the human. PMID- 21692472 TI - Vicinal 1H-1H NMR coupling constants from density functional theory as reliable tools for stereochemical analysis of highly flexible multichiral center molecules. AB - A protocol for stereochemical analysis, based on the systematic comparison between theoretical and experimental vicinal (1)H-(1)H NMR coupling constants, was developed and applied to a series of flexible compounds (1-8) derived from the 6-heptenyl-5,6-dihydro-2H-pyran-2-one framework. The method included a broad conformational search, followed by geometry optimization at the DFT B3LYP/DGDZVP level, calculation of the vibrational frequencies, thermochemical parameters, magnetic shielding tensors, and the total NMR spin-spin coupling constants. Three scaling factors, depending on the carbon atom hybridizations, were found for the (1)H-C-C-(1)H vicinal coupling constants: f((sp3)-(sp3)) = 0.910, f((sp3)-(sp2)) = 0.929, and f((sp2)-(sp2))= 0.977. A remarkable correlation between the theoretical (J(pre)) and experimental (1)H-(1)H NMR (J(exp)) coupling constants for spicigerolide (1), a cytotoxic natural product, and some of its synthetic stereoisomers (2-4) demonstrated the predictive value of this approach for the stereochemical assignment of highly flexible compounds containing multiple chiral centers. The stereochemistry of two natural 6-heptenyl-5,6-dihydro-2H-pyran-2 ones (14 and 15) containing diverse functional groups in the heptenyl side chain was also analyzed by application of this combined theoretical and experimental approach, confirming its reliability. Additionally, a geometrical analysis for the conformations of 1-8 revealed that weak hydrogen bonds substantially guide the conformational behavior of the tetraacyloxy-6-heptenyl-2H-pyran-2-ones. PMID- 21692474 TI - Voltammetric determination of the antioxidant capacity in wine samples using a carbon nanotube modified electrode. AB - A direct determination of gallic acid was achieved at a carbon paste electrode modified with carbon nanotubes under differential pulse voltammetry conditions. The values obtained for gallic acid were used to estimate the antioxidant properties of the wine sample based on gallic acid oxidation. The proposed method is based on the gallic acid oxidation process at a modified carbon paste electrode (MCPE) containing 30% (m/m) of carbon nanotubes monitored at 0.35 V versus Ag/AgCl (KCl 3 mol L(-1)). Using the optimized experimental conditions, the calibration curve for gallic acid was linear in the concentration range from 5.0 * 10(-7) to 1.5 * 10(-5) mol L(-1) with a detection limit of 3.0 * 10(-7) mol L(-1). The MCPE was successfully applied for the determination of the antioxidant capacity for red and white wine samples without interference of glucose and ascorbic acid, and the obtained results were compared with the standard spectrophotometric method. PMID- 21692473 TI - Scalable manufacturing of plasmonic nanodisk dimers and cusp nanostructures using salting-out quenching method and colloidal lithography. AB - Localization of large electric fields in plasmonic nanostructures enables various processes such as single-molecule detection, higher harmonic light generation, and control of molecular fluorescence and absorption. High-throughput, simple nanofabrication techniques are essential for implementing plasmonic nanostructures with large electric fields for practical applications. In this article we demonstrate a scalable, rapid, and inexpensive fabrication method based on the salting-out quenching technique and colloidal lithography for the fabrication of two types of nanostructures with large electric field: nanodisk dimers and cusp nanostructures. Our technique relies on fabricating polystyrene doublets from single beads by controlled aggregation and later using them as soft masks to fabricate metal nanodisk dimers and nanocusp structures. Both of these structures have a well-defined geometry for the localization of large electric fields comparable to structures fabricated by conventional nanofabrication techniques. We also show that various parameters in the fabrication process can be adjusted to tune the geometry of the final structures and control their plasmonic properties. With advantages in throughput, cost, and geometric tunability, our fabrication method can be valuable in many applications that require plasmonic nanostructures with large electric fields. PMID- 21692475 TI - Rearrangements and interconversions of heteroatom-substituted isocyanates, isothiocyanates, nitrile oxides, and nitrile sulfides, RX-NCY and RY-CNX. AB - Isocyanates and isothiocyanates of the type RX-NCY (X and Y = O or S) and the isomeric nitrile oxides and nitrile sulfides RY-CNX are highly reactive compounds. A number of potential 1,4-shifts of substituent groups of the type R-Y CNX -> R-X-N?C?Y, 1,3-shifts R-C(?Y)-N?X -> R-X-N?C?Y, and 1,2-shifts R-C(?Y)-N?X -> R-Y-CNX have been evaluated computationally. The results obtained for the relatively new functional MPW1K and the well-established B3LYP, together with a triple-zeta quality basis set, are very similar. The 1,3- and 1,4-halogen shifts in the title compounds are usually highly exothermic and possess low activation barriers. 1,3-Aryl shifts are feasible for for 5e -> 6e (Ar-CO-NSO(2) -> Ar-SO(2) NCO) with activation barriers of less than 40 kcal/mol. Additionally, several 1,3 and 1,4-hydrogen shifts and the 1,4-methyl-shift in methoxynitrile sulfide MeO CNS to methylsulfenyl isocyanate MeS-NCO (4c -> 6c) are potentially feasible. The 1,2-shift reactions 4b -> 5b (HO-NCS -> H-CS-NO) and 4c -> 5c (Ar-O-CNS-> Ar-CO NS) are good candidates for experimental observation with activation energies around 30 kcal/mol. PMID- 21692476 TI - Possible origin of the inverse and direct Hofmeister series for lysozyme at low and high salt concentrations. AB - Protein solubility studies below the isoelectric point exhibit a direct Hofmeister series at high salt concentrations and an inverse Hofmeister series at low salt concentrations. The efficiencies of different anions measured by salt concentrations needed to effect precipitation at fixed cations are the usual Hofmeister series (Cl(-) > NO(3)(-) > Br(-) > ClO(4)(-) > I(-) > SCN(-)). The sequence is reversed at low concentrations. This has been known for over a century. Reversal of the Hofmeister series is not peculiar to proteins. Its origin poses a key test for any theoretical model. Such specific ion effects in the cloud points of lysozyme suspensions have recently been revisited. Here, a model for lysozymes is considered that takes into account forces acting on ions that are missing from classical theory. It is shown that both direct and reverse Hofmeister effects can be predicted quantitatively. The attractive/repulsive force between two protein molecules was calculated. To do this, a modification of Poisson-Boltzmann theory is used that accounts for the effects of ion polarizabilities and ion sizes obtained from ab initio calculations. At low salt concentrations, the adsorption of the more polarizable anions is enhanced by ion surface dispersion interactions. The increased adsorption screens the protein surface charge, thus reducing the surface forces to give an inverse Hofmeister series. At high concentrations, enhanced adsorption of the more polarizable counterions (anions) leads to an effective reversal in surface charge. Consequently, an increase in co-ion (cations) adsorption occurs, resulting in an increase in surface forces. It will be demonstrated that among the different contributions determining the predicted specific ion effect the entropic term due to anions is the main responsible for the Hofmeister sequence at low salt concentrations. Conversely, the entropic term due to cations determines the Hofmeister sequence at high salt concentrations. This behavior is a remarkable example of the charge-reversal phenomenon. PMID- 21692477 TI - Electrocatalytic oxidation of formate by [Ni(P(R)2N(R')2)2(CH3CN)]2+ complexes. AB - [Ni(P(R)(2)N(R')(2))(2)(CH(3)CN)](2+) complexes with R = Ph, R' = 4-MeOPh or R = Cy, R' = Ph , and a mixed-ligand [Ni(P(R)(2)N(R')(2))(P(R''(2))N(R'(2)))(CH(3)CN)](2+) with R = Cy, R' = Ph, R'' = Ph, have been synthesized and characterized by single-crystal X-ray crystallography. These and previously reported complexes are shown to be electrocatalysts for the oxidation of formate in solution to produce CO(2), protons, and electrons, with rates that are first-order in catalyst and formate at formate concentrations below ~0.04 M (34 equiv). At concentrations above ~0.06 M formate (52 equiv), catalytic rates become nearly independent of formate concentration. For the catalysts studied, maximum observed turnover frequencies vary from <1.1 to 15.8 s(-1) at room temperature, which are the highest rates yet reported for formate oxidation by homogeneous catalysts. These catalysts are the only base-metal electrocatalysts as well as the only homogeneous electrocatalysts reported to date for the oxidation of formate. An acetate complex demonstrating an eta(1)-OC(O)CH(3) binding mode to nickel has also been synthesized and characterized by single-crystal X-ray crystallography. Based on this structure and the electrochemical and spectroscopic data, a mechanistic scheme for electrocatalytic formate oxidation is proposed which involves formate binding followed by a rate-limiting proton and two-electron transfer step accompanied by CO(2) liberation. The pendant amines have been demonstrated to be essential for electrocatalysis, as no activity toward formate oxidation was observed for the similar [Ni(depe)(2)](2+) (depe = 1,2-bis(diethylphosphino)ethane) complex. PMID- 21692478 TI - Docking performance of fragments and druglike compounds. AB - This paper addresses two questions of key interest to researchers working with protein-ligand docking methods: (i) Why is there such a large variation in docking performance between different test sets reported in the literature? (ii) Are fragments more difficult to dock than druglike compounds? To answer these, we construct a test set of in-house X-ray structures of protein-ligand complexes from drug discovery projects, half of which contain fragment ligands, the other half druglike ligands. We find that a key factor affecting docking performance is ligand efficiency (LE). High LE compounds are significantly easier to dock than low LE compounds, which we believe could explain the differences observed between test sets reported in the literature. There is no significant difference in docking performance between fragments and druglike compounds, but the reasons why dockings fail appear to be different. PMID- 21692479 TI - Discovery and structure-activity relationships of modified salicylanilides as cell permeable inhibitors of poly(ADP-ribose) glycohydrolase (PARG). AB - The metabolism of poly(ADP-ribose) (PAR) in response to DNA strand breaks, which involves the concerted activities of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG), modulates cell recovery or cell death depending upon the level of DNA damage. While PARP inhibitors show high promise in clinical trials because of their low toxicity and selectivity for BRCA related cancers, evaluation of the therapeutic potential of PARG is limited by the lack of well-validated cell permeable inhibitors. In this study, target-related affinity profiling (TRAP), an alternative to high-throughput screening, was used to identify a number of druglike compounds from several chemical classes that demonstrated PARG inhibition in the low-micromolar range. A number of analogues of one of the most active chemotypes were synthesized to explore the structure activity relationship (SAR) for that series. This led to the discovery of a putative pharmacophore for PARG inhibition that contains a modified salicylanilide structure. Interestingly, these compounds also inhibit PARP-1, indicating strong homology in the active sites of PARG and PARP-1 and raising a new challenge for development of PARG specific inhibitors. The cellular activity of a lead inhibitor was demonstrated by the inhibition of both PARP and PARG activity in squamous cell carcinoma cells, although preferential inhibition of PARG relative to PARP was observed. The ability of inhibitors to modulate PAR metabolism via simultaneous effects on PARPs and PARG may represent a new approach for therapeutic development. PMID- 21692480 TI - Source and nature of inhaled atmospheric dust from trace element analyses of human bronchial fluids. AB - Rapid volcanic eruptions quickly ejecting large amounts of dust provoke the accumulation of heavy metals in people living in surrounding areas. Analyses of bronchoalveolar lavage samples (BAL) collected from people exposed to the paroxysmal 2001 Etna eruption revealed a strong enrichment of many toxic heavy metals. Comparing the BAL to the dust composition of southeastern Sicily, we found that only V, Cr, Mn, Fe, Co, and U enrichment could be related to the volcanic event, whereas Ni, Cu, Cd, and Pb contents come from the dissolution of particles of anthropogenic origin. Furthermore, the nature of these inhaled anthropogenic particles was revealed by anomalous La and partially Ce concentrations in BAL that were consistent with a mixture of road dust and petroleum refinery emissions. Our results indicate that trace element distribution in BAL is a suitable tracer of human exposure to different sources of inhaled atmospheric particulates, allowing investigations into the origin of source materials inhaled by people subjected to atmospheric fallout. PMID- 21692481 TI - New insights to the use of ethanol in automotive fuels: a stable isotopic tracer for fossil- and bio-fuel combustion inputs to the atmosphere. AB - Ethanol is currently receiving increased attention because of its use as a biofuel or fuel additive and because of its influence on air quality. We used stable isotopic ratio measurements of (13)C/(12)C in ethanol emitted from vehicles and a small group of tropical plants to establish ethanol's delta(13)C end-member signatures. Ethanol emitted in exhaust is distinctly different from that emitted by tropical plants and can serve as a unique stable isotopic tracer for transportation-related inputs to the atmosphere. Ethanol's unique isotopic signature in fuel is related to corn, a C4 plant and the primary source of ethanol in the U.S. We estimated a kinetic isotope effect (KIE) for ethanol's oxidative loss in the atmosphere and used previous assumptions with respect to the fractionation that may occur during wet and dry deposition. A small number of interpretive model calculations were used for source apportionment of ethanol and to understand the associated effects resulting from atmospheric removal. The models incorporated our end-member signatures and ambient measurements of ethanol, known or estimated source strengths and removal magnitudes, and estimated KIEs associated with atmospheric removal processes for ethanol. We compared transportation-related ethanol signatures to those from biogenic sources and used a set of ambient measurements to apportion each source contribution in Miami, Florida-a moderately polluted, but well ventilated urban location. PMID- 21692483 TI - Hydrophobic interactions increase attachment of gum Arabic- and PVP-coated Ag nanoparticles to hydrophobic surfaces. AB - A fundamental understanding of attachment of surface-coated nanoparticles (NPs) is essential to predict the distribution and potential risks of NPs in the environment. Column deposition studies were used to examine the effect of surface coating hydrophobicity on NP attachment to collector surfaces in mixtures with varying ratios of octadecylichlorosilane (OTS)-coated (hydrophobic) glass beads and clean silica (hydrophilic) glass beads. Silver nanoparticles (AgNPs) coated with organic coatings of varying hydrophobicity, including citrate, polyvinylpyrrolidone (PVP), and gum arabic (GA), were used. The attachment efficiencies of GA and PVP AgNPs increased by 2- and 4-fold, respectively, for OTS-coated glass beads compared to clean glass beads. Citrate AgNPs showed no substantial change in attachment efficiency for hydrophobic compared to hydrophilic surfaces. The attachment efficiency of PVP-, GA-, and citrate-coated AgNPs to hydrophobic collector surfaces correlated with the relative hydrophobicity of the coatings. The differences in the observed attachment efficiencies among AgNPs could not be explained by classical DLVO, suggesting that hydrophobic interactions between AgNPs and OTS-coated glass beads were responsible for the increase in attachment of surface-coated AgNPs with greater hydrophobicity. This study indicates that the overall attachment efficiency of AgNPs will be influenced by the hydrophobicity of the NP coating and the fraction of hydrophobic surfaces in the environment. PMID- 21692484 TI - Enantioenriched compounds via enzyme-catalyzed redox reactions. PMID- 21692482 TI - A multidisciplinary approach to probing enthalpy-entropy compensation and the interfacial mobility model. AB - In recent years, interfacial mobility has gained popularity as a model with which to rationalize both affinity in ligand binding and the often observed phenomenon of enthalpy-entropy compensation. While protein contraction and reduced mobility, as demonstrated by computational and NMR techniques respectively, have been correlated to entropies of binding for a variety of systems, to our knowledge, Raman difference spectroscopy has never been included in these analyses. Here, nonresonance Raman difference spectroscopy, isothermal titration calorimetry, and X-ray crystallography were utilized to correlate protein contraction, as demonstrated by an increase in protein interior packing and decreased residual protein movement, with trends of enthalpy-entropy compensation. These results are in accord with the interfacial mobility model and lend additional credence to this view of protein activity. PMID- 21692486 TI - Protonated N-confused porphyrin dimer: formation, structure, and guest binding. AB - The protonation of 3,3'-bis(meso-tetratolyl-2-aza-21-carbaporphyrin) with various acids was studied. The stepwise formation of mono-, di-, and tetracationic species was shown on the basis of UV-vis-near-IR and low-temperature (1)H NMR. Upon going from di- to tetraprotonated form, the bis(porphyrinoid) skeleton changes its conformation from cisoid to bent-transoid, which was found by single crystal X-ray analyses, 2D NMR, and density functional theory (DFT) calculations. The formation of cation-anion complexes was established in both the solid state and solution. The substitution of anions was studied by spectrophotometric and (1)H NMR titrations. A pronounced decrease of the HOMO-LUMO gap in the tetraprotonated species was shown by cyclovoltametry and time-dependent DFT calculations. PMID- 21692487 TI - Electronic perturbations of iron dipyrrinato complexes via ligand beta halogenation and meso-fluoroarylation. AB - Systematic electronic variations were introduced into the monoanionic dipyrrinato ligand scaffold via halogenation of the pyrrolic beta-positions and/or via the use of fluorinated aryl substituents in the ligand bridgehead position in order to synthesize proligands of the type 1,9-dimesityl-beta-R(4)-5-Ar-dipyrrin [R = H, Cl, Br, I; Ar = mesityl, 3,5-(F(3)C)(2)C(6)H(3), C(6)F(5) in ligand 5 position; beta = 2,3,7,8 ligand substitution; abbreviated ((beta,Ar)L)H]. The electronic perturbations were probed using standard electronic absorption and electrochemical techniques on the different ligand variations and their divalent iron complexes. The free-ligand variations cause modest shifts in the electronic absorption maxima (lambda(max): 464-499 nm) and more pronounced shifts in the electrochemical redox potentials for one-electron proligand reductions (E(1/2): 1.25 to -1.99 V) and oxidations (E(1/2): +0.52 to +1.14 V vs [Cp(2)Fe](+/0)). Installation of iron into the dipyrrinato scaffolds was effected via deprotonation of the proligands followed by treatment with FeCl(2) and excess pyridine in tetrahydrofuran to afford complexes of the type ((beta,Ar)L)FeCl(py) (py = pyridine). The electrochemical and spectroscopic behavior of these complexes varies significantly across the series: the redox potential of the fully reversible Fe(III/II) couple spans more than 400 mV (E(1/2): -0.34 to +0.50 V vs [Cp(2)Fe](+/0)); lambda(max) spans more than 40 nm (506-548 nm); and the (57)Fe Mossbauer quadrupole splitting (|DeltaE(Q)|) spans nearly 2.0 mm/s while the isomer shift (delta) remains essentially constant (0.86-0.89 mm/s) across the series. These effects demonstrate how peripheral variation of the dipyrrinato ligand scaffold can allow systematic variation of the chemical and physical properties of iron dipyrrinato complexes. PMID- 21692488 TI - Rh-catalyzed transannulation of N-tosyl-1,2,3-triazoles with terminal alkynes. AB - The first transannulation of 1,2,3-triazoles with terminal alkynes into pyrroles is reported. The reaction proceeds in the presence of a Rh(2)(oct)(4)/AgOCOCF(3) binary catalyst system providing a straightforward approach to 1,2,4 trisubstituted pyrroles in good to excellent yields. PMID- 21692489 TI - Effect of milk and brewing method on black tea catechin bioaccessibility. AB - The aim of this study was to investigate whether milk reduces the bioaccessibility of tea catechins, which would compromise tea beneficial effects ascribed to polyphenols. Adding milk to black tea has been shown to lead to polyphenol-protein complexes. So far, data on the intestinal stability of polyphenol-protein complexes are scarce. English black tea (0.93 +/- 0.06 mol/L total catechins) and Indian black tea (1.83 +/- 0.08 mol/L catechins) were prepared with skimmed or full-fat milk and subjected to simulated gastric, small intestinal, and brush border digestion. Adding milk (5.6-40%) to tea results in a decrease of total catechin (TCAT) recovery. However, the bioaccessibilities of TCAT of tea with milk versus tea controls were comparable (p > 0.05). The type of milk did not influence TCAT recovery during all digestive stages (p > 0.05). Polyphenol-protein complexes are degraded during digestion. It is very unlikely that consumption of tea with or without milk will result in differences in catechin plasma concentration. PMID- 21692490 TI - Discrete-state representation of ion permeation coupled to fast gating in a model of CLC-chloride channels: analytic estimation of the state-to-state rate constants. AB - Analytical estimation of state-to-state rate constants is carried out for a recently developed discrete state model of chloride ion motion in a CLC chloride channel (Coalson and Cheng, J. Phys. Chem. B 2010, 114, 1424). In the original presentation of this model, the same rate constants were evaluated via three dimensional Brownian dynamics simulations. The underlying dynamical theory is an appropriate single- or multiparticle three-dimensional Smoluchowski equation. Taking advantage of approximate geometric symmetries (based on the details of the model channel geometry), well-known formulas for state-to-state transition rates are appealed to herein and adapted as necessary to the problem at hand. Rates of ionic influx from a bulk electrolyte reservoir to the nearest binding site within the channel pore are particularly challenging to compute analytically because they reflect multi-ion interactions (as opposed to single-ion dynamics). A simple empirical correction factor is added to the single-ion rate constant formula in this case to account for the saturation of influx rate constants with increasing bulk Cl(-) concentration. Overall, the agreement between all analytically estimated rate constants is within a factor of 2 of those computed via three dimensional Brownian dynamics simulations, and often better than this. Current concentration curves obtained using rate constants derived from these two different computational approaches agree to within 25%. PMID- 21692491 TI - Tuning the interaction energy of hydrogen bonds: the effect of the substituent. AB - The effect of the substituent R in the hydrogen bonding properties of FH...FR (R = H, Al, Li, Cl and CCH) complexes has been studied by theoretical calculations. The dependency of the interaction energy with the hydrogen bond distance and R is explained in terms of the topologies of the electron density and the electrostatic potential. A simple model of the hydrogen bond interaction energy, which can be assimilated to an interaction potential, is defined in terms of a stabilizing mutual polarization of the monomers and an overall destabilizing contribution associated with the electron density reorganization when the overlap of the closed shells is large enough. This model shows an excellent agreement with the ab initio interaction energies and is common for all the analyzed complexes. The substituent effect is represented in the model by a single parameter that can be calculated from the electron distribution in the acceptor atom region. The perturbation in the hydrogen bonding interaction induced by the change of R presents a close similarity with that produced by an external electric field of the same order of magnitude than those found in crystalline solids, indicating that both perturbations should play a significant and similar role on the properties of hydrogen bonds in condensed matter. PMID- 21692492 TI - The potent antimalarial peptide cyclosporin A induces the aggregation and permeabilization of sphingomyelin-rich membranes. AB - Cyclosporin A (CsA) is a hydrophobic peptide drug produced by the fungus Tolypocladium inflatum. CsA is commonly used as an immunosuppressive drug, but it also has antimalarial activity. The immunosuppressive activity of CsA is clearly due to its association with specific proteins of immune cells such as cyclophilins. By contrast, the antimalarial properties of this peptide are completely independent of the association with a parasite's cyclophilins. Because of its hydrophobicity, CsA may interact with biological membranes, which may participate in its therapeutic effect. Recently, we have shown a marked preference of CsA for insertion into sphingomyelin (SM) monolayers. In this article, we measure for the first time the ability of CsA to induce permeabilization and aggregation and to change the lipid order, especially in the presence of SM. Calcein-release experiments permitted us to show that CsA causes the leakage of the fluorescent probe from SM-rich liposomes by 40% and PC liposomes by 11%, suggesting a lipid-selective effect. Electron microscopy and dynamic light scattering experiments confirmed the different interaction of CsA with SM and PC vesicles: it formed much larger aggregates with SM than with PC. Our results taken together suggest that CsA could specifically weaken and aggregate SM-rich membranes, which could in turn explain why CsA is efficient in the treatment of malaria. Indeed, CsA could inhibit the development of Plasmodium by permeabilizing and aggregating the SM-rich membrane network formed by the parasite during its intraerythrocytic growth cycle. PMID- 21692494 TI - Computational study of the properties and reactions of small molecules containing O, S, and Se. AB - The reactions and properties of a series of chalcogen-containing compounds (CH(3))(2)X and (CH(3))(2)C?X, where X = O, S, and Se, were studied computationally at the CBS-QB3 level to examine the differences among these molecules. The reactions and properties investigated include the double bond dissociation energy, the ionization potential, the interaction energies with a series of acids including a proton, CH(3)(+), Li(+), MeLi, and MeOH, and the enolization energies of the (CH(3))(2)C?X species. The effect of substituting the O of acetamide with S or Se also was studied. The changes that result from these reactions were examined via changes in structure and changes in charge distribution using the Hirshfeld charges. PMID- 21692493 TI - Ultrasensitive identification of localization variants of modified peptides using ion mobility spectrometry. AB - Localization of the modification sites on peptides is challenging, particularly when multiple modifications or mixtures of localization isomers (variants) are involved. Such variants commonly coelute in liquid chromatography and may be undistinguishable in tandem mass spectrometry (MS/MS) for lack of unique fragments. Here, we have resolved the variants of singly and doubly phosphorylated peptides employing drift tube ion mobility spectrometry (IMS) coupled to time-of-flight mass spectrometry. Even with a moderate IMS resolving power of ~80-100, substantial separation was achieved for both 2+ and 3+ ions normally generated by electrospray ionization, including for the variants indistinguishable by MS/MS. Variants often exhibit a distribution of 3-D conformers, which can be adjusted for optimum IMS separation by prior field heating of ions in a funnel trap. The peak assignments were confirmed using MS/MS after IMS separation, but known species could be identified using just the ion mobility "tag". Avoiding the MS/MS step lowers the detection limit of localization variants to <100 amol, an order of magnitude better than that provided by electron transfer dissociation in an Orbitrap MS. PMID- 21692495 TI - Effect of gold nanoparticle aggregation on cell uptake and toxicity. AB - Aggregation appears to be a ubiquitous phenomenon among all nanoparticles and its influence in mediating cellular uptake and interactions remain unclear. Here we developed a simple technique to produce transferrin-coated gold nanoparticle aggregates of different sizes and characterized their uptake and toxicity in three different cell lines. While the aggregation did not elicit a unique toxic response, the uptake patterns were different between single and aggregated nanoparticles. There was a 25% decrease in uptake of aggregated nanoparticles with HeLa and A549 cells in comparison to single and monodisperse nanoparticles. However, there was a 2-fold increase in MDA-MB 435 cell uptake for the largest synthesized aggregates. These contrasting results suggest that cell type and the mechanism of interactions may play a significant role. This study highlights the need to investigate the behavior of aggregates with cells on a case-by-case basis and the importance of aggregation in mediating targeting and intracellular trafficking. PMID- 21692496 TI - Synthesis with structural and electronic characterization of homoleptic Fe(II)- and Fe(III)-fluorinated phenolate complexes. AB - Four Fe(III) compounds and one Fe(II) compound containing mononuclear, homoleptic, fluorinated phenolate anions of the form [Fe(OAr)(m)](n-) have been prepared in which Ar(F) = C(6)F(5) and Ar' = 3,5-C(6)(CF(3))(2)H(3): (Ph(4)P)(2)[Fe(OAr(F))(5)], 1, (Me(4)N)(2)[Fe(OAr(F))(5)], 2, {K(18-crown 6)}(2)[Fe(OAr(F))(5)], 3a, {K(18-crown-6)}(2)[Fe(OAr')(5)], 3b, and {K(18-crown 6)}(2)[Fe(OAr(F))(4)], 6. Two dinuclear Fe(III) compounds have also been prepared: {K(18-crown-6)}(2)[(OAr(F))(3)Fe(MU(2)-O)Fe(OAr(F))(3)], 4, and {K(18 crown-6)}(2)[(OAr(F))(3)Fe(MU(2)-OAr(F))(2)Fe(OAr(F))(3)], 5. These compounds have been characterized with UV-vis spectroscopy, elemental analysis, Evans method susceptibility, and X-ray crystallography. All-electron, geometry optimized DFT calculations on four [Ti(IV)(OAr)(4)] and four [Fe(III)(OAr)(4)](-) species (Ar = 2,3,5,6-C(6)Me(4)H, C(6)H(5), 2,4,6-C(6)Cl(3)H(2), C(6)F(5)) with GGA-BP and hybrid B3LYP basis sets demonstrated that, under D(2d) symmetry, pi donation from the O 2p orbitals is primarily into the d(xy) and d(z(2)) orbitals. The degree of donation is qualitatively consistent with expectations based on ligand Bronsted basicity and supports the contention that fluorinated phenolate ligands facilitate isolation of nonbridged homoleptic complexes due to their reduced pi basicity at oxygen. PMID- 21692497 TI - Kbeta X-ray emission spectroscopy offers unique chemical bonding insights: revisiting the electronic structure of ferrocene. AB - Kbeta X-ray emission spectroscopy (XES) is emerging as a powerful tool for the study of chemical bonding. Analyses of the Kbeta XES of ferrocene (Fc) and ferrocenium (Fc(+)) are presented as further demonstrations of the capabilities of the technique. Assignments of the valence to core (V2C) region of these spectra as electric dipole-allowed cyclopentadienyl (Cp) -> Fe 1s transitions demonstrate that XES affords electronic structural insight into the energetics of ligand-based molecular orbitals (MOs). Combined with K-edge X-ray absorption spectroscopy (XAS), we show that XES can provide analogous information to photoemission spectroscopy (PES). Density functional theory (DFT) analyses reveal that the V2C transitions in Fc/Fc(+) derive their intensity from Fe 4p admixture (on the order of 5-10%) into the Cp-based MOs from which they originate. These 4p admixtures confer bonding character to the Cp-based a(2u) and e(1u) MOs to at least the extent of backbonding contributions to frontier MOs from higher-lying Cp pi* MOs. PMID- 21692498 TI - Synthesis, structure, chemical stability, and electrical properties of Nb-, Zr-, and Nb-codoped BaCeO3 perovskites. AB - We report the effect of donor-doped perovskite-type BaCeO(3) on the chemical stability in CO(2) and boiling H(2)O and electrical transport properties in various gas atmospheres that include ambient air, N(2), H(2), and wet and dry H(2). Formation of perovskite-like BaCe(1-x)Nb(x)O(3+/-delta) and BaCe(0.9 x)Zr(x)Nb(0.1)O(3+/-delta) (x = 0.1; 0.2) was confirmed using powder X-ray diffraction (XRD) and electron diffraction (ED). The lattice constant was found to decrease with increasing Nb in BaCe(1-x)Nb(x)O(3+/-delta), which is consistent with Shannon's ionic radius trend. Like BaCeO(3), BaCe(1-x)Nb(x)O(3+/-delta) was found to be chemically unstable in 50% CO(2) at 700 degrees C, while Zr doping for Ce improves the structural stability of BaCe(1-x)Nb(x)O(3+/-delta). AC impedance spectroscopy was used to estimate electrical conductivity, and it was found to vary with the atmospheric conditions and showed mixed ionic and electronic conduction in H(2)-containing atmosphere. Arrhenius-like behavior was observed for BaCe(0.9-x)Zr(x)Nb(0.1)O(3+/-delta) at 400-700 degrees C, while Zr free BaCe(1-x)Nb(x)O(3+/-delta) exhibits non-Arrhenius behavior at the same temperature range. Among the perovskite-type oxides investigated in the present work, BaCe(0.8)Zr(0.1)Nb(0.1)O(3+/-delta) showed the highest bulk electrical conductivity of 1.3 * 10(-3) S cm(-1) in wet H(2) at 500 degrees C, which is comparable to CO(2) and H(2)O unstable high-temperature Y-doped BaCeO(3) proton conductors. PMID- 21692499 TI - Oxygen centered radicals in iodine chemical oscillators. AB - The existence of free radicals in iodine-based oscillatory systems has been debated for some time. Recently, we have reported the presence of reactive oxygen species (ROS) in the iodide-peroxide system in acidic medium, which is common to all iodine--based oscillatory systems ( J. Phys. Chem. A 2011 , 115 , 2247--2249 ). In this work, the goal was to identify the ROS produced in this system using an EPR spin trap which can distinguish between hydroxyl (HO(*)) and hydroperoxyl (HOO(*)) radicals. The formation of the hydroperoxyl radical was observed and a possible explanation for the low EPR signal of hydroxyl radical was proposed. PMID- 21692500 TI - Effect of dispersion on adsorption of atrazine by aqueous suspensions of fullerenes. AB - With the widespread application of fullerenes, it is critical to assess their environmental behaviors and their impacts on the transport and bioavailability of organic contaminants. The effects of fullerene particle size, chemistry of the solution, and natural organic matter on the adsorption of atrazine by aqueous dispersions of fullerenes (C(60)) were investigated in this work. The results showed that the Polanyi-Manes model could fit the adsorption isotherms well. Smaller sizes of fullerene particles led to increased available sites and, consequently, enhanced the adsorption of atrazine on C(60). However, intensely dispersed C(60) systems might not possess suitably high adsorptive capacities due to surface chemistry change. Adsorption of atrazine by aqueous dispersions of C(60) increased with a decrease in the pH of the solution. Introduction of humic acid significantly reduced the size of the C(60) particles, and resulted in the increase of the adsorption amount. Fullerene materials, once released into the aquatic environment, are inclined to form aqueous suspensions with different degrees of dispersion, which would greatly affect the transport and fate of organic contaminants. PMID- 21692501 TI - Structure-activity relationships of GHRP-6 azapeptide ligands of the CD36 scavenger receptor by solid-phase submonomer azapeptide synthesis. AB - The cluster of differentiation 36 (CD36) class B scavenger receptor binds a variety of biologically endogenous ligands in addition to synthetic peptides (i.e., growth hormone-releasing peptides, GHRPs), which modulate biological function related to anti-angiogenic and anti-atherosclerotic activities. Affinity labeling had previously shown that GHRP-6 analogues such as hexarelin, [2-Me W(2)]GHRP-6 (1), bind to the lysine-rich domain of the CD36 receptor. Moreover, the azapeptide analogue [aza-F(4)]GHRP-6, 2, exhibited a characteristic beta-turn conformation as described by CD and NMR spectroscopy and a slightly higher CD36 binding affinity relative to hexarelin (1.34 and 2.37 MUM, respectively), suggesting receptor binding was mediated by the conformation and the aromatic residues of these peptide sequences. Ligand-receptor binding interactions were thus explored using azapeptides to examine influences of side-chain diversity and backbone conformation. In particular, considering that aromatic cation interactions may contribute to binding affinity, we have explored the potential of introducing salt bridges to furnish GHRP-6 azapeptide ligands of the CD36 receptor. Fifteen aza-glutamic acid analogues related to 2 were prepared by submonomer solid-phase synthesis. The azapeptide side chains were installed by novel approaches featuring alkylation of resin-bound semicarbazone with Michael acceptors and activated allylic acetates in the presence of phosphazene base (BTPP). Moreover, certain Michael adducts underwent intramolecular cyclization during semicarbazone deprotection, leading to novel pyrrazoline and aza pyroglutamate N-terminal residues. Structural studies indicated that contingent on sequence the [aza-Glu]GHRP-6 analogues exhibited CD spectra characteristic of random coil, polyproline type II and beta-turn secondary structures in aqueous media. In covalent competition binding studies with the GHRP-6 prototype hexarelin bearing a radiotracer, certain [aza-Glu]GHRP-6 azapeptides retained relatively high (2-27 MUM) affinity for the CD36 scavenger receptor. PMID- 21692502 TI - Efficient removal of heavy metal ions from aqueous systems with the assembly of anisotropic layered double hydroxide nanocrystals@carbon nanosphere. AB - We report on the efficient removal of heavy metal ions from simulated wastewater with a nanostructured assembly. The nanoassembly was obtained via direct assembling the performed anisotropic layered double hydroxide nanocrystals (LDH NCs) onto the surface of carbon nanospheres (labeled as LDH-NCs@CNs). It was found that the maximum adsorption capacity of the nanoassembly toward Cu(2+) was ~ 19.93 mg g(-1) when the initial Cu(2+) concentration was 10.0 mg L(-1), displaying a high efficiency for the removal of heavy metal ions. The Freundlich adsorption isotherm was applicable to describe the removal processes. Kinetics of the Cu(2+) removal was found to follow pseudo-second-order rate equation. Furthermore, the as-prepared building unit of the assembly, including LDH-NCs, CNs, and the assembly, as well as Cu(2+)-adsorbed assembly, were carefully examined by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), nitrogen sorption measurements, and X-ray photoelectron spectroscopy (XPS). Based on the characterization results, a possible mechanism of Cu(2+) removal with the assembly of LDH-NCs@CNs was proposed. Comparison experiments show that the adsorption capacity of the resulting LDH-NCs@CNs assembly was much higher than its any building unit alone (CNs or LDH-NCs), exhibiting the deliberation of the assembly on water decontamination. This work provides a very efficient, fast and convenient approach for exploring promising nanoassembly materials for water treatment. PMID- 21692503 TI - Identification of a lacosamide binding protein using an affinity bait and chemical reporter strategy: 14-3-3 zeta. AB - We have advanced a useful strategy to elucidate binding partners of ligands (drugs) with modest binding affinity. Key to this strategy is attaching to the ligand an affinity bait (AB) and a chemical reporter (CR) group, where the AB irreversibly attaches the ligand to the receptor upon binding and the CR group is employed for receptor detection and isolation. We have tested this AB&CR strategy using lacosamide ((R)-1), a low-molecular-weight antiepileptic drug. We demonstrate that using a (R)-lacosamide AB&CR agent ((R)-2) 14-3-3 zeta in rodent brain soluble lysates is preferentially adducted, adduction is stereospecific with respect to the AB&CR agent, and adduction depends upon the presence of endogenous levels of the small molecule metabolite xanthine. Substitution of lacosamide AB agent ((R)-5) for (R)-2 led to the identification of the 14-3-3 zeta adduction site (K120) by mass spectrometry. Competition experiments using increasing amounts of (R)-1 in the presence of (R)-2 demonstrated that (R)-1 binds at or near the (R)-2 modification site on 14-3-3 zeta. Structure-activity studies of xanthine derivatives provided information concerning the likely binding interaction between this metabolite and recombinant 14-3-3 zeta. Documentation of the 14-3-3 zeta-xanthine interaction was obtained with isothermal calorimetry using xanthine and the xanthine analogue 1,7 dimethylxanthine. PMID- 21692505 TI - Isotope-edited FTIR of alkaline phosphatase resolves paradoxical ligand binding properties and suggests a role for ground-state destabilization. AB - Escherichia coli alkaline phosphatase (AP) can hydrolyze a variety of chemically diverse phosphate monoesters while making contacts solely to the transferred phosphoryl group and its incoming and outgoing atoms. Strong interactions between AP and the transferred phosphoryl group are not present in the ground state despite the apparent similarity of the phosphoryl group in the ground and transition states. Such modest ground-state affinity is required to curtail substrate saturation and product inhibition and to allow efficient catalysis. To investigate how AP achieves limited affinity for its ground state, we first compared binding affinities of several related AP ligands. This comparison revealed a paradox: AP has a much stronger affinity for inorganic phosphate (P(i)) than for related compounds that are similar to P(i) geometrically and in overall charge but lack a transferable proton. We postulated that the P(i) proton could play an important role via transfer to the nearby anion, the active site serine nucleophile (Ser102), resulting in the attenuation of electrostatic repulsion between bound P(i) and the Ser102 oxyanion and the binding of P(i) in its trianionic form adjacent to a now neutral Ser residue. To test this model, isotope-edited Fourier transform infrared (FTIR) spectroscopy was used to investigate the ionic structure of AP-bound P(i). The FTIR results indicate that the P(i) trianion is bound and, in conjunction with previous studies of pH dependent P(i) binding and other results, suggest that P(i) dianion transfers its proton to the Ser102 anion of AP. This internal proton-transfer results in stronger P(i) binding presumably because the additional negative charge on the trianionic P(i) allows stronger electrostatic interactions within the AP active site and because the electrostatic repulsion between bound P(i) and anionic Ser102 is eliminated when the transferred P(i) proton neutralizes Ser102. Indeed, when Ser102 is neutralized the P(i) trianion binds AP with a calculated K(d) of <=290 fM. These results suggest that electrostatic repulsion between Ser102 and negatively charged phosphate ester substrates contributes to catalysis by the preferential destabilization of the reaction's E.S ground state. PMID- 21692506 TI - Highly sensitive detection of proteins and bacteria in aqueous solution using surface-enhanced Raman scattering and optical fibers. AB - We report the detection of the proteins lysozyme and cytochrome c as well as the live bacterial cells of Shewanella oneidensis MR-1 in aqueous solutions with sensitivities order(s) of magnitude higher than those previously reported. Two highly sensitive surface-enhanced Raman scattering (SERS)-based biosensors using optical fibers have been employed for such label-free macromolecule detections. The first sensor is based on a tip-coated multimode fiber (TCMMF) with a double substrate "sandwich" structure, and a detection limit of 0.2 MUg/mL is achieved in protein detections. The second sensor is based on a liquid core photonic crystal fiber (LCPCF) with a better confinement of light inside the fiber core, and a detection limit of 10(6) cells/mL is achieved for the bacteria detection. Both SERS biosensors show great potential for highly sensitive and molecule specific detection and identification of biomolecules. PMID- 21692504 TI - A substrate-free activity-based protein profiling screen for the discovery of selective PREPL inhibitors. AB - Peptidases play vital roles in physiology through the biosynthesis, degradation, and regulation of peptides. Prolyl endopeptidase-like (PREPL) is a newly described member of the prolyl peptidase family, with significant homology to mammalian prolyl endopeptidase and the bacterial peptidase oligopeptidase B. The biochemistry and biology of PREPL are of fundamental interest due to this enzyme's homology to the biomedically important prolyl peptidases and its localization in the central nervous system. Furthermore, genetic studies of patients suffering from hypotonia-cystinuria syndrome (HCS) have revealed a deletion of a portion of the genome that includes the PREPL gene. HCS symptoms thought to be caused by lack of PREPL include neuromuscular and mild cognitive deficits. A number of complementary approaches, ranging from biochemistry to genetics, will be required to understand the biochemical, cellular, physiological, and pathological mechanisms regulated by PREPL. We are particularly interested in investigating physiological substrates and pathways controlled by PREPL. Here, we use a fluorescence polarization activity-based protein profiling (fluopol-ABPP) assay to discover selective small-molecule inhibitors of PREPL. Fluopol-ABPP is a substrate-free approach that is ideally suited for studying serine hydrolases for which no substrates are known, such as PREPL. After screening over 300,000 compounds using fluopol-ABPP, we employed a number of secondary assays to confirm assay hits and characterize a group of 3 oxo-1-phenyl-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile and 1-alkyl-3-oxo 3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridine-4-carbonitrile PREPL inhibitors that are able to block PREPL activity in cells. Moreover, when administered to mice, 1 isobutyl-3-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridine-4-carbonitrile distributes to the brain, indicating that it may be useful for in vivo studies. The application of fluopol-ABPP has led to the first reported PREPL inhibitors, and these inhibitors will be of great value in studying the biochemistry of PREPL and in eventually understanding the link between PREPL and HCS. PMID- 21692507 TI - Triply bonded stannaacetylene (RC=SnR): theoretical designs and characterization. AB - The effect of substitution on the potential energy surfaces of RC=SnR (R = F, H, OH, CH(3), SiH(3), Tbt, Ar*, SiMe(SitBu(3))(2), and SiiPrDis(2)) was explored using density functional theories (B3LYP/LANL2DZdp and B3PW91/Def2-QZVP). Our theoretical investigations indicate that all the triply bonded RC=SnR molecules prefer to adopt a trans-bent geometry, which is in good agreement with the theoretical model (mode B). In addition, we demonstrate that the stabilities of the RC=SnR compounds bearing smaller substituents (R = F, H, OH, CH(3), and SiH(3)) decrease in the order R(2)C?Sn: > RC=SnR > :C?SnR(2). On the other hand, the triply bonded R'C=SnR' molecules with bulkier substituents (R' = Tbt, Ar*, SiMe(SitBu(3))(2), and SiiPrDis(2)) were found to possess the global minimum on the singlet potential energy surface and are both kinetically and thermodynamically stable. Further, we used the B3LYP computations to predict the stability of stannaacetylene bearing the very bulky phosphine ligand. Our theoretical observations strongly suggest that both the electronic and the steric effects of bulky substituents play an important role in making triply bonded stannaacetylene (RC=SnR) an intriguing synthetic target. PMID- 21692509 TI - Dissipation and transport of clopyralid in soil: effect of application strategies. AB - At present there are no herbicide uses registered for broadleaf weed control in buckwheat. Clopyralid, mixed with desmedipham, was anticipated to provide early season broadleaf weed suppression with minimal crop injury. However, field trials resulted in limited success, which brought into question the fate and availability of clopyralid for weed control. A 4-year field study was conducted in Lithuania to evaluate the dissipation of clopyralid in Haplic Luvisol sandy loam soil and the influence of application rate, application timing, and coapplication with desmedipham on its degradation and transport. Clopyralid dissipation was rapid; 50% dissipation times, in the surface 5 cm, averaged over the 4 years of the study, were <7 days. Application rate (90 versus 180 g ai ha( 1)), timing (pre-emergence versus postemergence), and coapplication with desmedipham (360 g ai ha(-1)) did not significantly influence clopyralid dissipation. Clopyralid dissipation by leaching was not a significant factor; at 7-21 days after application, <8 MUg kg(-1) was found at the 10-20 cm depth. Understanding the dissipation of herbicides and the influence of application strategies on herbicide fate will allow for informed decisions and improved efficacy of weed control. On the basis of the results of this research, weed scientists can now determine whether increased rates of clopyralid would provide sufficient residual chemical for adequate weed control without crop injury. PMID- 21692510 TI - Structurally designed synthesis of mechanically stable poly(benzoxazine-co-resol) based porous carbon monoliths and their application as high-performance CO2 capture sorbents. AB - Porous carbon monoliths with defined multilength scale pore structures, a nitrogen-containing framework, and high mechanical strength were synthesized through a self-assembly of poly(benzoxazine-co-resol) and a carbonization process. Importantly, this synthesis can be easily scaled up to prepare carbon monoliths with identical pore structures. By controlling the reaction conditions, porous carbon monoliths exhibit fully interconnected macroporosity and mesoporosity with cubic Im3m symmetry and can withstand a press pressure of up to 15.6 MPa. The use of amines in the synthesis results in a nitrogen-containing framework of the carbon monolith, as evidenced by the cross-polarization magic angle-spinning NMR characterization. With such designed structures, the carbon monoliths show outstanding CO(2) capture and separation capacities, high selectivity, and facile regeneration at room temperature. At ~1 bar, the equilibrium capacities of the monoliths are in the range of 3.3-4.9 mmol g(-1) at 0 degrees C and of 2.6-3.3 mmol g(-1) at 25 degrees C, while the dynamic capacities are in the range of 2.7-4.1 wt % at 25 degrees C using 14% (v/v) CO(2) in N(2). The carbon monoliths exhibit high selectivity for the capture of CO(2) over N(2) from a CO(2)/N(2) mixture, with a separation factor ranging from 13 to 28. Meanwhile, they undergo a facile CO(2) release in an argon stream at 25 degrees C, indicating a good regeneration capacity. PMID- 21692508 TI - A vaccine strategy that induces protective immunity against heroin. AB - Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. A vaccine capable of blocking heroin's effects could provide a long lasting and sustainable adjunct to heroin addiction therapy. Heroin, however, presents a particularly challenging immunotherapeutic target, as it is metabolized to multiple psychoactive molecules. To reconcile this dilemma, we examined the idea of a singular vaccine with the potential to display multiple drug-like antigens; thus two haptens were synthesized, one heroin-like and another morphine-like in chemical structure. A key feature in this approach is that immunopresentation with the heroin-like hapten is thought to be immunochemically dynamic such that multiple haptens are simultaneously presented to the immune system. We demonstrate the significance of this approach through the extremely rapid generation of robust polyclonal antibody titers with remarkable specificity. Importantly, both the antinociceptive effects of heroin and acquisition of heroin self-administration were blocked in rats vaccinated using the heroin-like hapten. PMID- 21692511 TI - A convenient strategy for quantitative determination of drug concentrations in tissue homogenates using a liquid chromatography/tandem mass spectrometry assay for plasma samples. AB - Quantitative determination of drug concentrations in tissue homogenates via liquid chromatography-tandem mass spectrometry (LC-MS/MS) is commonly conducted using the standards and analytical quality controls (QCs) prepared in the same matrix (tissue homogenates), to keep the matrix and its effects consistent on the analytes during sample extraction and analysis. In this manuscript, we proposed to analyze tissue homogenate samples using an LC-MS/MS assay with the standards and analytical QCs prepared in plasma after tissue homogenate samples were appropriately diluted with plasma. BMS-650032 was used as a model compound, and its validated dog plasma assay was used for dog liver sample analyses. The tissue matrix effect was evaluated by diluting liver homogenate QCs with drug-free plasma at different dilution factors to determine the minimum required dilution factor (MRDF) at which tissue matrix has insignificant impact to the plasma assay. The percentage deviation of the measured concentration from the nominal concentration was used as an indicator of the tissue matrix effect. The results suggested that the tissue matrix effect was decreased as the plasma dilution factor increased. Based on the results of the tissue matrix effect evaluation, liver homogenate samples were analyzed after appropriate dilutions with plasma at the MRDF or greater dilution factors. The results confirmed that this approach generates accurate data, and the process is very convenient and economic. This approach has been used on the analyses of different tissues (liver and brain) and biofluid (bile) to support several drug development programs. PMID- 21692512 TI - Zinc oxide-coated plasmonic chip modified with a bispecific antibody for sensitive detection of a fluorescent labeled-antigen. AB - A plasmonic biosensor chip of silver-coated PMMA grating with a zinc oxide (ZnO) overlayer is fabricated for surface plasmon field-enhanced fluorescence (SPF) detection of Cy5-labeled green fluorescent protein (GFP). A bispecific antibody (anti-GFP x anti-ZnO antibody) prepared in our lab is densely immobilized on the sensor chip for GFP detection. The sensitivity of the plasmonic biosensors is improved due to densely packed antibodies and ZnO-coating that suppresses nonspecific protein adsorption and fluorescent quenching. With the ZnO-coated plasmonic chip, Cy5-labeled GFP of 10 pM can be detected through SPF. This sensitivity is 100 higher compared with the normal fluorescent detection on a ZnO coated glass slide. PMID- 21692513 TI - Tillage, cover-crop residue management, and irrigation incorporation impact on fomesafen runoff. AB - Intensive glyphosate use has contributed to the evolution and occurrence of glyphosate-resistant weeds that threaten production of many crops. Sustained use of this highly valued herbicide requires rotation and/or substitution of herbicides with different modes of action. Cotton growers have shown considerable interest in the protoporphyrinogen oxidase inhibitor, fomesafen. Following registration for cotton in 2008, use has increased rapidly. Environmental fate data in major use areas are needed to appropriately evaluate risks. Field-based rainfall simulation was used to evaluate fomesafen runoff potential with and without irrigation incorporation in a conventional tillage system (CT) and when conservation tillage (CsT) was practiced with and without cover crop residue rolling. Without irrigation incorporation, relatively high runoff, about 5% of applied, was measured from the CT system, indicating that this compound may present a runoff risk. Runoff was reduced by >50% when the herbicide was irrigation incorporated after application or when used with a CsT system. Data indicate that these practices should be implemented whenever possible to reduce fomesafen runoff risk. Results also raised concerns about leaching and potential groundwater contamination and crop injury due to rapid washoff from cover crop residues in CsT systems. Further work is needed to address these concerns. PMID- 21692514 TI - Bent alkanes in a new thiourea-containing capsule. AB - The synthesis of a cavitand featuring thiourea hydrogen bonding sites and its dimerization in the presence of suitable guests are reported. Dimerization creates a capsule host wider than the corresponding urea or imide structures, and longer alkanes can be accommodated. Specifically, n-C(15)H(32) is encapsulated, but this guest appears folded inside as deduced from NMR studies. Apparently, the plasticity of hydrogen bonds between thiourea groups allows a stable encapsulation complex to persist in solution even though the guest is contorted. PMID- 21692515 TI - Accurate determination of succinimide degradation products using high fidelity trypsin digestion peptide map analysis. AB - We report an efficient, high fidelity trypsin digestion method for peptide map analysis. This method minimizes artifacts caused by the sample preparation process, and we show its utility for the accurate determination of succinimide formation in a degraded monoclonal antibody product. A basic charge variant was detected by imaged capillary isoelectric focusing and was shown with reduced antigen binding and biological activity. Samples were reduced under denaturing conditions at pH 5.0, and digestion of the reduced protein with porcine trypsin was performed at pH 7.0 for 1 h. Following reversed phase high-performance liquid chromatography and online mass spectrometric analysis, succinimide formation was identified at Asp30 in the light chain. This result contrasts with the observation of only iso-Asp and Asp residues under conventional sample preparation conditions, which are therefore concluded to be artificially generated. The Asp30 residue is seen in the cocrystal structure model to participate in favorable charge interaction with an antigen molecule. Formation of succinimide and the resulting loss of negative charge are therefore hypothesized to be the degradation mechanism. After treatment of the degraded antibody sample to mildly alkaline pH conditions, we observed only Asp residue as the succinimide hydrolysis product and concurrent recovery of biological activity. PMID- 21692517 TI - Direct generation of silica nanowire-based thin film on various substrates with tunable surface nanostructure and extreme repellency toward complex liquids. AB - We report our new achievement on the direct generation of linear polyethylenimine@silica hybrid and silica thin films on various substrates, which is composed of 10 nm nanowire silica structure with tunable micro/nano hierarchical surface morphology. We found that a process for the rapid and controlled self-assembly of crystalline template layer of linear polyethylenimine on substrate surface is critical for the formation of ultrathin silica nanowire structure and micro/nano hierarchical morphology, since the template linear polyethylenimine layer directly promotes the hydrolytic condensation of alkoxysilanes. Templated silica mineralization on the self-assembled linear polyethylenimine layer was confirmed by the studies of X-ray photoelectron spectroscopy (XPS) and thin film X-ray diffraction (XRD). The surface of silica nanostructure and hierarchy could be well controlled by simply adjusting the conditions for LPEI assembly, such as the polymer concentrations and substrate surface property. After a simple fluorocarbon modification, the hierarchical silica nanowire thin film demonstrated robust and reliable super-repelling property toward a series of aqueous liquids (such as commercial inkjet (IJ) ink, soy source, milk). Comparative studies clearly confirmed the critical importance of surface hierarchy for enhancing super-repelling property. Moreover, we found that the forcibly formed dirty sports (both wet and dry) from the complexly composed liquids on the super-antiwetting surface could be easily and completely cleaned by simple water drop flow. We expect these tailored nanosurfaces would have the potentials for practical technological applications, such as liquid transferring, self-cleaning, microfluid, and biomedical-related devices. PMID- 21692518 TI - Planar limit-assisted structural interpretation of saturates/aromatics/resins/asphaltenes fractionated crude oil compounds observed by Fourier transform ion cyclotron resonance mass spectrometry. AB - Planar limits, defined as lines generated by connecting maximum double-bond equivalence (DBE) values at given carbon numbers, are proposed as a means of predicting and understanding the molecular structure of compounds in crude oil. The slopes and y-intercepts of the lines are determined by the DBE/carbon number ratios of functional groups defining the planar limits. For example, the planar limit generated by a serial addition of saturated cyclic rings has a slope of 0.25. The planar limit formed by the linear and nonlinear addition of benzene rings yields lines with slopes of 0.75 and 1, respectively. The y-intercepts of these lines were determined by additional functional groups added within a series of molecules. Plots of DBE versus carbon number for S(1) class compounds observed by Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) showed that saturates/aromatics/resins/asphaltenes (SARA) fractions exhibited unique slopes and y-intercepts. The slope of the planar limit observed from a saturates fraction matched well with the slope of a planar limit generated by the serial addition of saturated cyclic rings. The slopes of planar limits of aromatics and resins fractions were very similar to that obtained from the linear addition of benzene rings. Finally, the slope of the asphaltenes fraction was almost identical to the slope obtained from the nonlinear addition of benzene rings. Simulated and experimental data show that SARA fractions exhibit different molecular structure characteristics. On the basis of the slope and y-intercept of the planar limit, the structures of molecules in SARA fractions were predicted and suggested. The use of planar limits for structural interpretation is not limited to crude oil compounds but can also be used to study other organic mixtures such as humic substances or metabolites. PMID- 21692516 TI - A statistical method for assessing peptide identification confidence in accurate mass and time tag proteomics. AB - Current algorithms for quantifying peptide identification confidence in the accurate mass and time (AMT) tag approach assume that the AMT tags themselves have been correctly identified. However, there is uncertainty in the identification of AMT tags, because this is based on matching LC-MS/MS fragmentation spectra to peptide sequences. In this paper, we incorporate confidence measures for the AMT tag identifications into the calculation of probabilities for correct matches to an AMT tag database, resulting in a more accurate overall measure of identification confidence for the AMT tag approach. The method is referenced as Statistical Tools for AMT Tag Confidence (STAC). STAC additionally provides a uniqueness probability (UP) to help distinguish between multiple matches to an AMT tag and a method to calculate an overall false discovery rate (FDR). STAC is freely available for download, as both a command line and a Windows graphical application. PMID- 21692519 TI - Coordination polymer chains of dimeric pyrogallol[4]arene capsules. AB - Copper seamed dimeric metal-organic pyrogallol[4]arene capsules have been synthesized and engineered into coordination polymer chains, either by direct coordination or with additional bridging ligands. The formation of this copper capsule also demonstrates selective formation of either hexameric or dimeric metal-organic capsules. PMID- 21692521 TI - Supramolecular ribbons from amphiphilic trisamides self-assembly. AB - Two amphiphilic C(3)-symmetric OPE-based trisamides have been synthesized and their self-assembling features investigated in solution and on surface. Variable temperature UV-vis experiments demonstrate the cooperative supramolecular polymerization of these trisamides that self-assemble by the operation of triple C?O...H-N H-bonding arrays between the amide functional groups and pi-pi stacking between the aromatic units. The helical organization of the aggregates has been demonstrated by circular dichroism at a concentration as low as 1 * 10(-4) M in acetonitrile. In the reported trisamides, the large hydrophobic aromatic core acts as a solvophobic module impeding the interaction between the polar TEG chains and the amide H-bonds. This strategy makes unnecessary the separation of the amide functional groups to the polar tri(ethylene glycol) chains by paraffinic fragments. Achiral trisamide 1 self-assembles into flat ribbon-like structures that experience an amplification of chirality by the addition of a small amount of chiral 2 that generates twisted stripes. PMID- 21692520 TI - Duplex and triplex formation of mixed pyrimidine oligonucleotides with stacking of phenyl-triazole moieties in the major groove. AB - 5-(1-Phenyl-1,2,3-triazol-4-yl)-2'-deoxycytidine was synthesized from a modified CuAAC protocol and incorporated into mixed pyrimidine oligonucleotide sequences together with the corresponding 5-(1-phenyl-1,2,3-triazol-4-yl)-2'-deoxyuridine. With consecutive incorporations of the two modified nucleosides, improved duplex formation with a complementary RNA and improved triplex formation with a complementary DNA duplex were observed. The improvement is due to pi-pi stacking of the phenyl-triazole moieties in the major groove. The strongest stacking and most pronounced positive influence on thermal stability was found in between the uridine analogues or with the cytidine analogue placed in the 3' direction to the uridine analogue. Modeling indicated a different orientation of the phenyl triazole moieties in the major groove to account for the difference between the two nucleotides. The modified oligonucleotides were all found to be significantly stabilized toward nucleolytic degration. PMID- 21692522 TI - Synthesis of a series of aromatic benziporphyrins and heteroanalogues via tripyrrane-like intermediates derived from resorcinol and 2-methylresorcinol. AB - Tripyrrane analogues were prepared by reacting resorcinol or 2-methylresorcinol with 2 equiv of an acetoxymethylpyrrole in the presence of p-toluenesulfonic acid and calcium chloride. Following removal of the benzyl ester protective groups, the resorcinol-derived benzitripyrrane was reacted with a pyrrole dialdehyde to give an aromatic hydroxyoxybenziporphyrin. However, furan and thiophene dialdehydes gave highly insoluble products that could not be fully characterized. The methylresorcinol-derived tripyrrane analogue reacted with pyrrole, furan, thiophene, and selenophene dialdehydes to give unstable porphyrinoids that were further oxidized with [bis(trifluoroacetoxy)iodo]benzene to give stable benziporphyrin derivatives. These oxidized benziporphyrins showed strongly diatropic properties by proton NMR spectroscopy where the differences in chemical shifts (Deltadelta) were >18 ppm in some cases. The selenophene-derived system was further characterized by X-ray crystallography, and these results showed that one of the pyrrole subunits in this crowded structure was tilted by 21 degrees relative to the mean macrocyclic plane. The tripyrrolic system reacted with silver(I) acetate to give the corresponding silver(III) organometallic complex. Regioselective alkylation with methyl or ethyl iodide and potassium carbonate gave diastereomeric mixtures of N-alkyl derivatives, and the N-ethyl substitution products showed highly diastereotopic characteristics. PMID- 21692523 TI - Modifying the body distribution of HPMA-based copolymers by molecular weight and aggregate formation. AB - There is a recognized need to create well-defined polymer probes for in vivo and clinical positron emission tomography (PET) imaging to guide the development of new generation polymer therapeutics. Using the RAFT polymerization technique in combination with the reactive ester approach, here we have synthesized well defined and narrowly distributed N-(2-hydroxypropyl)methacrylamide homopolymers (pHPMA) (P1* and P2*) and random HPMA copolymers consisting of hydrophilic HPMA and hydrophobic lauryl methacrylate comonomers (P3* and P4*). The polymers had molecular weights below (P1* and P3*) and above the renal threshold (P2* and P4*). Whereas the homopolymers dissolve in isotonic solution as individual coils, the random copolymers form larger aggregates above their critical micelle concentration (~ 40 nm), as determined by fluorescence correlation spectroscopy. Structure-property relationships of the pharmacokinetics and biodistribution of the different polymer architectures were monitored in the living organism following radiolabeling with the positron emitter (18)F via fluoroethylation within a few hours. Ex vivo organ biodistribution and in vivo MUPET imaging studies in male Copenhagen rats revealed that both size and the nature of the aggregate formation (hydrophobically modified copolymers) played a major role in blood clearance and biodistribution, especially concerning liver and kidney accumulation. The high-molecular-weight random copolymer P4* (hydrophobically modified), in particular, combines low liver uptake with enhanced blood circulation properties, showing the potential of hydrophobic interactions, as seen for the represented model system, that are valuable for future drug carrier design. PMID- 21692524 TI - Anti-Kasha's rule fluorescence emission in (2-ferrocenyl)indene generated by a twisted intramolecular charge-transfer (TICT) process. AB - A twisted intramolecular charge-transfer (TICT) process has been identified in (2 ferrocenyl)indene. This photochemical process explains the anti-Kasha's rule fluorescence emission observed for this system. Experimental and model investigations on (2-ferrocenyl)tetramethylindene and (2-ferrocenyl) hexamethylindene were also performed, in order to evaluate the effect of a steric hindrance on the TICT mechanism. The energy of the lowest main excited states was computed with a TD-DFT approach, as a function of the rotation of the dihedral angle between the indene and the cyclopentadienyl planes. To the best of our knowledge, this is the first example of TICT generated by metal-to-ligand charge transfer (MLCT) in a ferrocene-containing complex and, more generally, the first case of complexes in which a metal center is directly involved. PMID- 21692525 TI - Bond characterization on a Cr-Cr quintuple bond: a combined experimental and theoretical study. AB - A combined experimental and theoretical charge density study on a quintuply bonded dichromium complex, Cr(2)(dipp)(2) (dipp = (Ar)NC(H)N(Ar) and Ar = 2,6-i Pr(2)-C(6)H(3)), is performed. Two dipp ligands are bridged between two Cr ions; each Cr atom is coordinated to two N atoms of the ligands in a linear fashion. The Cr atom is in a low oxidation state, Cr(I), and in low coordination number condition, which stabilizes a metal-metal multiple bond, in this case, a quintuple bond. Indeed, it gives an ultrashort Cr-Cr bond distance of 1.7492(1) A in the complex. The bond characterization of such a quintuple bond is undertaken both experimentally by high-resolution single-crystal X-ray diffraction and theoretically by density functional calculation (DFT). Electron densities are depicted via deformation density and Laplacian distributions. Bond characterizations of the complex are presented in terms of topological properties, Fermi hole function, source function (SF), and natural bonding orbital (NBO) analysis. The electron density at the Cr-Cr bond critical point (BCP) is 1.70 e/A(3), quite a high value for metal-metal bonding and mainly contributed from the metal ion itself. The quintuple bond is confirmed with one sigma, two pi, and two delta interactions by NBO analysis and Fermi hole function. The molecular orbitals (MOs) illustrate that five bonding orbitals are predominantly contributed from the 3d orbitals of the Cr(I) ion. The effective bond order from NBO analysis is 4.60. The detail comparison between experiment and theory will be given. Additionally, three closely related complexes are calculated for systematic comparison. PMID- 21692526 TI - An analytical pipeline for MALDI in-source decay mass spectrometry imaging. AB - In-source decay (ISD) fragmentation as combined with matrix-assisted laser desorption/ionization (MALDI) mass spectrometry allows protein sequencing directly from mass spectra. Acquisition of MALDI-ISD mass spectra from tissue samples is achieved using an appropriate MALDI matrix, such as 1,5 diaminonaphthalene (DAN). Recent efforts have focused on combining MALDI-ISD with mass spectrometry imaging (MSI) to provide simultaneous sequencing and localization of proteins over a thin tissue surface. Successfully coupling these approaches requires the development of new data analysis tools, but first, investigating the properties of MALDI-ISD as applied to mixtures of protein standards reveals a high sensitivity to the relative protein ionization efficiency. This finding translates to the protein mixtures found in tissues and is used to inform the development of an analytical pipeline for data analysis in MALDI-ISD MS imaging, including software to identify the most pertinent spectra, to sequence protein mixtures, and to generate ion images for comparison with tissue morphology. The ability to simultaneously identify and localize proteins is demonstrated by using the analytical pipeline on three tissue sections from porcine eye lens, resulting in localizations for crystallins and cytochrome c. The variety of protein identifications provided by MALDI-ISD-MSI between tissue sections creates a discovery tool, and the analytical pipeline makes this process more efficient. PMID- 21692527 TI - Controlling bandgap energy and multivibronic modes of a poly(2,5-thiophene-1,4 dialkoxyphenylene) derivative by gamma photons. AB - In this work, the influence of gamma radiation on electronic, structural, and vibrational properties of a poly(2,5-thiophene-1,4-dialkoxyphenylene) derivative is studied by optical absorption and photoluminescence. A Gaussian fit of emission spectra within Franck-Condon vertical transitions formalism was carried out in order to understand how vibronic coupling is affected by the dose, because an unexpected luminescence behavior was observed. Aiming to understand the ionizing radiation-matter interaction processes, we employed a molecular modeling procedure, through the use of a semiempirical method (AM1) applied to conjugated oligomers' conformational structure and equilibrium geometries, to clarify the defects induction for the used doses. From AM1 optimized structures, electronic transitions were calculated by ZINDO/S-CI semiempirical method to measure the chain scission degree. Moreover, with the results presented in this work, it is possible to come up with a new physical-chemical route to treat and increase conjugated polymers' efficiency. Finally, we believe that the present paper contributes to the literature about defects on conjugated polymers. PMID- 21692528 TI - Design and synthesis of ATP-based nucleotide analogues and profiling of nucleotide-binding proteins. AB - Two nucleotide-based probes were designed and synthesized in order to enrich samples for specific classes of proteins by affinity-based protein profiling. We focused on the profiling of adenine nucleotide-binding proteins. Two properties were considered in the design of the probes: the bait needs to bind adenine nucleotide-binding proteins with high affinity and carry a second functional group suitable and easily accessible for coupling to a chromatography resin. For this purpose, we synthesized p-biotinyl amidobenzoic acid-ATP (p-BABA-ATP) and p biotinyl aminomethylbenzoic acid-ATP (p-BAMBA-ATP). p-BABA-ATP and p-BAMBA-ATP both bind to ATP-binding cassette (ABC) proteins with at least 10-fold higher affinity than ATP. Several ABC transporters could be enriched using p-BABA-ATP or p-BAMBA-ATP. PMID- 21692529 TI - Thermal rate constant calculation of the NF + F reactive system multiple arrangements. AB - In this work we analyzed the multiple channels of the reaction NF+F through the evaluation of thermal rate constants with both Wigner and Eckart tunneling corrections. Minimum energy paths and intrinsic reaction coordinates of the systems were obtained and accurately studied in order to ensure the consistency of our results. Specifically, we investigated the NF + F = N + F(2), NF + F = NF + F, and NF(2) = NF + F, reactive systems. As experimental data are available for the latter reaction, we were able to conclude that our thermal rate constants are in agreement for a wide range of temperatures. The here performed study is relevant to the understanding of the decomposition process of nitrogen trifluoride (NF(3)). PMID- 21692530 TI - On the origin of the solid-state thermochromism and thermal fatigue of polycyclic overcrowded enes. AB - Aimed at unraveling the relative contribution of the folding, twisting and bending in the mechanism of the solid-state thermochromism of overcrowded polycyclic aromatic enes (PAEs), the structures of two typical heteromeric and homomeric representatives, 2-(thioxanthen-9-ylidene)indane-1,3-dione (1) and 9,9' bi-9(10H)-anthracenylidene-10,10'-dione (bianthrone, 2), were studied by temperature-resolved single crystal X-ray diffraction (120-530 K) and solid-state UV-visible spectroscopy. Aside from negligibly small unfolding of the tricyclic moiety of 1, this first direct diffraction study of the high-temperature structures of solid PAEs did not unravel any significant and detectable changes in the time- and space-averaged intramolecular structures, thus, showing that the PAE-type thermochromism is not due to phase transitions or to major and permanent molecular distortions of a large portion of the material that would be caused by folding, twisting and/or bending. Instead, the experimental observations and theoretical modeling indicated that the color change is probably due to a dynamic process, where the absorption spectrum changes as a result of enhanced thermal oscillations of the two halves of the molecules around the central bridge. In addition to the reversible coloration, we also observed irreversible processes of thermal fatigue that afford stable chemical products that absorb in the visible region. We showed that the stable products are conductive and they act electrocatalytically toward oxidation of several biomarkers. PMID- 21692531 TI - Sequential activation and deactivation of protein function using spectrally differentiated caged phosphoamino acids. AB - Photolabile caging groups, including the 1-(2-nitrophenyl)ethyl (NPE) group, have been applied to probe many biological processes, including protein phosphorylation. Although studies with NPE-caged phosphoamino acids have provided valuable information, these investigations have been limited to the use of only one caged species in a single experiment. To expand the scope of these tools, we have developed an approach for sequentially uncaging two different phosphopeptides in one system, enabling interrogation of multiple phosphorylation events. We present the synthesis of [7-(diethylamino)coumarin-4-yl]methyl (DEACM) caged phosphorylated serine, threonine, and tyrosine building blocks for Fmoc based solid-phase peptide synthesis to allow convenient incorporation of these residues into peptides and proteins. Exposure of DEACM- and NPE-caged phosphopeptides to 420 nm light selectively releases the DEACM group without affecting the NPE-caged peptide. This then enables a subsequent irradiation event at 365 nm to remove the NPE group and liberate a second phosphopeptide. We demonstrate the versatility of this general sequential uncaging approach by applying it to control Wip1 phosphatase with two wavelengths of light. PMID- 21692532 TI - Solid-phase receptor-based assay for the detection of cyclic imines by chemiluminescence, fluorescence, or colorimetry. AB - The spirolides and gymnodimines are marine phycotoxins included in the group of cyclic imines. The toxicity of these compounds to humans is still unknown, although their toxicity by intraperitoneal injection in rodents is very high. A receptor-based method was developed using the competition of the 13-desmethyl spirolide C with biotin-labeled alpha-bungarotoxin for binding to nicotinic acetylcholine receptors and the immobilization of the alpha-bungarotoxin-receptor complex on streptavidin-coated surfaces. The quantification of the immobilized receptor can be achieved using a specific antibody. Finally, after the addition of a secondary antibody labeled with horseradish peroxidase, three alternative substrates of this enzyme generate a chemiluminescent, fluorescent, or colorimetric signal. The assay performs well in shellfish extracts and the detection range is 5-150 nM of 13-desmethyl spirolide C in shellfish extracts, which is at least 5 times more sensitive than the existing fluorescence polarization assay. This assay can also detect gymnodimine, although with 10 times lower sensitivity than the spirolide. The detection of cyclic imines with microplate assays would be useful for screening purposes in order to reduce the number of samples to be processed by bioassays or analytical methods. PMID- 21692533 TI - Role of hydration force in the self-assembly of collagens and amyloid steric zipper filaments. AB - In protein self-assembly, types of surfaces determine the force between them. Yet the extent to which the surrounding water contributes to this force remains as a fundamental question. Here we study three self-assembling filament systems that respectively have hydrated (collagen), dry nonpolar, and dry polar (amyloid) interfaces. Using molecular dynamics simulations, we calculate and compare local hydration maps and hydration forces. We find that the primary hydration shells are formed all over the surface, regardless of the types of the underlying amino acids. The weakly oscillating hydration force arises from coalescence and depletion of hydration shells as two filaments approach, whereas local water diffusion, orientation, or hydrogen-bonding events have no direct effect. Hydration forces between hydrated, polar, and nonpolar interfaces differ in the amplitude and phase of the oscillation relative to the equilibrium surface separation. Therefore, water-mediated interactions between these protein surfaces, ranging in character from "hydrophobic" to "hydrophilic", have a common molecular origin based on the robustly formed hydration shells, which is likely applicable to a broad range of biomolecular assemblies whose interfacial geometry is similar in length scale to those of the present study. PMID- 21692535 TI - New insight into the IR-spectra/structure relationship in amyloid fibrils: a theoretical study on a prion peptide. AB - Molecular-level structural information on amyloid aggregates is of great importance for the understanding of protein-misfolding-related deseases. Nevertheless, this kind of information is experimentally difficult to obtain. In this work, we used molecular dynamics (MD) simulations combined with a mixed quantum mechanics/molecular mechanics theoretical methodology, the perturbed matrix method (PMM), in order to study the amide I' IR spectrum of fibrils formed by a short peptide, the H1 peptide, derived from residues 109 through 122 of the Syrian hamster prion protein. The PMM/MD approach allows isolation of the amide I' signal arising from any desired peptide group of the polypeptide chain and quantification of the effect of the excitonic coupling on the frequency position. The calculated single-residue signals were found to be in good agreement with the experimental site-specific spectra obtained by means of isotope-labeled IR spectroscopy, providing a means for their interpretation at the molecular level. In particular, our results confirm the experimental hypothesis that residues ala117 are aligned in all strands and that the alignment gives rise to a red shift of the corresponding site-specific amide I' mode due to strong excitonic coupling among the ala117 peptide groups. In addition, our data show that a red shift of the amide I' band due to strong excitonic coupling can also occur for amino acids adjacent in sequence to the aligned ones. Thus, a red shift of the signal of a given isotope-labeled amino acid does not necessarily imply that the peptide groups under consideration are aligned in the beta-sheet. PMID- 21692534 TI - NMR analysis of a stress response metabolic signaling network. AB - We previously hypothesized that Staphylococcus epidermidis senses a diverse set of environmental and nutritional factors associated with biofilm formation through a modulation in the activity of the tricarboxylic acid (TCA) cycle. Herein, we report our further investigation of the impact of additional environmental stress factors on TCA cycle activity and provide a detailed description of our NMR methodology. S. epidermidis wild-type strain 1457 was treated with stressors that are associated with biofilm formation, a sublethal dose of tetracycline, 5% NaCl, 2% glucose, and autoinducer-2 (AI-2). As controls and to integrate our current data with our previous study, 4% ethanol stress and iron-limitation were also used. Consistent with our prior observations, the effect of many environmental stress factors on the S. epidermidis metabolome was essentially identical to the effect of TCA cycle inactivation in the aconitase mutant strain 1457-acnA::tetM. A detailed quantitative analysis of metabolite concentration changes using 2D (1)H-(13)C HSQC and (1)H-(1)H TOCSY spectra identified a network of 37 metabolites uniformly affected by the stressors and TCA cycle inactivation. We postulate that the TCA cycle acts as the central pathway in a metabolic signaling network. PMID- 21692536 TI - Ultrafast twisting dynamics in the excited state of auramine. AB - Relaxation dynamics of the excited state of bis-[4-(dimethylamino)-phenyl] methaniminium chloride (Auramine) has been investigated using subpicosecond time resolved absorption spectroscopic technique in both aprotic and alcoholic solvents. The locally excited (LE) state, formed following photoexcitation of Auramine using 400 nm light, undergoes intramolecular charge transfer (ICT) process, which is accompanied by the twisting of the dimethylanilino groups. Time evolution of the transient absorption-stimulated emission spectra as well as the wavelength dependence of the temporal dynamics investigated in each kind of solvents suggest that the relaxation process proceeds via the formation of at least two transient states (TS I and TS II), which are geometrical conformers and consecutively formed following the decay of the LE state. Twisting of the dimethylaniline groups are nearly barrierless processes, the rates of which show linear correlation both with the macroscopic or shear viscosities as well as the solvation times of the solvents. Time-dependent and fractional viscosity dependence of the relaxation rates of the LE and the TS I states in aprotic solvents suggest the multidimensionality of the reaction coordinate as well as reveal the viscoelastic property of the solvents. However, in normal alcohols, in addition to these two factors, activation energy of the solvent viscosity may be another important factor for the slower twisting dynamics of Auramine in alcohols. To explain the viscosity dependence of the decay time of the TS II state, which undergoes an efficient internal conversion process to the ground state, the possibility of occurrence of different mechanisms, such as, energy gap law, involvement of intramolecular high frequency modes, as well as the phenyl group twisting motion on a potential energy surface having a photochemical funnel, have been discussed. TDDFT method has been applied to obtain the optimized electronic structures of the transient states but it has been possible to obtain only that for the TS II state. PMID- 21692537 TI - Organic matter-solid phase interactions are critical for predicting arsenic release and plant uptake in Bangladesh paddy soils. AB - Agroecological zones within Bangladesh with low levels of arsenic in groundwater and soils produce rice that is high in arsenic with respect to other producing regions of the globe. Little is known about arsenic cycling in these soils and the labile fractions relevant for plant uptake when flooded. Soil porewater dynamics of field soils (n = 39) were recreated under standardized laboratory conditions to investigate the mobility and interplay of arsenic, Fe, Si, C, and other elements, in relation to rice grain element composition, using the dynamic sampling technique diffusive gradients in thin films (DGT). Based on a simple model using only labile DGT measured arsenic and dissolved organic carbon (DOC), concentrations of arsenic in Aman (Monsoon season) rice grain were predicted reliably. DOC was the strongest determinant of arsenic solid-solution phase partitioning, while arsenic release to the soil porewater was shown to be decoupled from that of Fe. This study demonstrates the dual importance of organic matter (OM), in terms of enhancing arsenic release from soils, while reducing bioavailability by sequestering arsenic in solution. PMID- 21692538 TI - Comment on "Modeling miscanthus in the soil and water assessment tool (SWAT) to simulate its water quality effects as a bioenergy crop". PMID- 21692540 TI - Self-assembly of alkylthiosulfates on gold: role of electrolyte and trace water in the solvent. AB - Spontaneous self-assembly of alkylthiosulfates on gold produce monolayers similar to the corresponding alkanethiols. Alkylthiosulfate self-assembly from THF solutions is inhibited in the presence of tetrabutylammonium tetrafluoroborate electrolyte. The mechanism of alkylthiosulfate self-assembly and the role of electrolyte and trace water in the solvent are investigated using open-circuit potential measurements, contact angle goniometry and redox electron transfer blocking experiments to explore the hypothesis that trace water present in the solvent facilitates monolayer formation on gold. Furthermore, the unique behavior of tetrabutylammonium tetrafluoroborate, compared to other tetrabutylammonium electrolytes, on the inhibition of alkylthiosulfate self-assembly has been explained. PMID- 21692541 TI - Structural dynamics of the S4 voltage-sensor helix in lipid bilayers lacking phosphate groups. AB - Voltage-dependent K(+) (Kv) channels require lipid phosphates for functioning. The S4 helix, which carries the gating charges in the voltage-sensing domain (VSD), inserts into membranes while being stabilized by a protein-lipid interface in which lipid phosphates play an essential role. To examine the physical basis of the protein-lipid interface in the absence of lipid phosphates, we performed molecular dynamics (MD) simulations of a KvAP S4 variant (S4mut) in bilayers with and without lipid phosphates. We find that, in dioleoyltrimethylammoniumpropane (DOTAP) bilayers lacking lipid phosphates, the gating charges are solvated by anionic counterions and, hence, lack the bilayer support provided by phosphate containing palmitoyloleoylglycerophosphocholine (POPC) bilayers. The result is a water-permeable bilayer with significantly smaller deformations around the peptide. Together, these results provide an explanation for the nonfunctionality of VSDs in terms of a destabilizing protein-lipid interface. PMID- 21692542 TI - Composition and stability of anthocyanins from purple Solanum tuberosum and their protective influence on Cr(VI) targeted to bovine serum albumin. AB - Anthocyanins from the purple Solanum tuberosum newly cultivated by the Taian Academy of Agricultural Sciences were extracted and analyzed using high performance liquid chromatography (HPLC) and UV-vis spectroscopy. Four individual anthocyanins were detected as the major components, and the total anthocyanin content was 273.5 +/- 14.3 mg of cyanidin-3-glucoside equiv/100 g of dry seeds. Results of color stability showed that the purple S. tuberosum anthocyanins (PSTAs) are more stable under low pH and temperatures. Heat and general food additives have fine compatibility with PSTAs; however, they are very sensitive with oxidant and reduction. The influence of PSTAs on Cr(VI) targeted to bovine serum albumin (BSA) was also studied. The quenching of BSA fluorescence caused by Cr(VI) could be delayed by PSTAs. UV-vis and circular dichroism (CD) data suggested that PSTAs can protect the secondary and tertiary structures of BSA by probably interacting with Cr(VI) in advance. PMID- 21692543 TI - Differences in soil mobility and degradability between water-dispersible CdSe and CdSe/ZnS quantum dots. AB - The relative leaching potential and degradation of water-dispersible CdSe and CdSe/ZnS quantum dots (QDs) were evaluated using small-scale soil columns. The potential of QDs to release toxic Cd(2+) and/or Se(2-)/SeO(3)(2-) ions upon degradation is of environmental concern and warrants investigation. Both classes of QDs exhibited limited soil mobility in CaCl(2), with more than 70% of the total Cd and Se species from QDs retained in the top soil after passing 10 column volumes of solution through the soil column. However, mobilization of Cd- and Se species was observed when EDTA was used as the leaching solution. Approximately 98% of the total Cd(2+) loaded leached out from the Cd(2+)-spiked soil, while only 30% and 60% leached out from the CdSe and CdSe/ZnS QD-spiked soils, respectively. Soil column profiles and analysis of leachates suggest that intact QDs leached through the soil. Longer incubation (15 days) in soil prior to leaching indicated some degradation and/or surface modification of both QDs. These results suggest that chelating agents in the environment can enhance the soil mobility of intact and degraded QDs. It is apparent that QDs in soil, including the polymer-coated CdSe/ZnS QDs that are generally assumed to possess a higher degree of environmental stability, can undergo chemical transformations, which subsequently dictate their overall mobility. PMID- 21692544 TI - Tetravalent metal complexes as a new family of catalysts for copolymerization of epoxides with carbon dioxide. AB - New tetravalent metal complexes with a trianionic [ONNO]-tetradentate ligand and an ancillary chloride ligand were synthesized as catalysts for the copolymerization of epoxides with carbon dioxide (CO(2)). All of the titanium, zirconium, germanium, and tin complexes were found to copolymerize epoxides with CO(2). In particular, the copolymerization of propylene oxide with CO(2) gave the almost-completely alternating copolymers by using titanium or germanium complexes. These results are the first example of the copolymerization using tetravalent metal complexes as a main component of catalysts. PMID- 21692545 TI - Genetic susceptibility in sepsis: implications for the pediatric population. PMID- 21692546 TI - Management of immune thrombocytopenic purpura in children: potential role of novel agents. AB - The treatment of immune thrombocytopenic purpura (ITP) in children is controversial, requiring individualized assessment of the patient and consideration of treatment options. If the platelet count is >10 000/MUL and the patient is asymptomatic, a 'watch and wait' strategy is appropriate since most children with ITP will recover completely without pharmacotherapy. If therapy is indicated because of bleeding or a platelet count <10 000/MUL, then treatment with glucocorticoids, intravenous immunoglobulin (IVIg), or anti-D are possible initial choices. Glucocorticoid treatment is the least expensive and is our usual first choice of therapy. Its use assumes that the blood counts and blood film have been evaluated to ensure the absence of evidence of alternative diagnoses, such as thrombotic thrombocytopenic purpura or incipient acute leukemia. IVIg is expensive and often causes severe headache, nausea and vomiting, and requires hospitalization at our institution. Anti-D therapy is also expensive and can only be used in patients who are Rhesus D positive. These therapies, even if only transiently effective, can be repeated if necessary. Children usually recover from newly diagnosed ITP, with or without multiple courses of medical therapy. If the disease becomes 'persistent' with severe thrombocytopenia and/or bleeding, and is no longer responsive to the three first-line therapies, the next approach includes the use of thrombopoietin receptor agonists or rituximab. When the disease persists for more than 1 year, it is considered chronic, and, if symptomatic, it may become necessary to consider third-line therapies, including splenectomy, alternative immunosuppressive agents, or combination or investigative chemoimmunotherapy. This review considers the indications, mechanism of action, and effectiveness of the traditional and novel treatment options for patients with ITP. PMID- 21692547 TI - Antidepressants and psychostimulants in pediatric populations: is there an association with mania? AB - This article reviews the literature that examines whether exposure to psychostimulants or antidepressants precipitates or exacerbates manic symptoms, or decreases the age at onset of mania in pediatric populations. A PubMed search using relevant key words identified studies targeting five distinct clinical groups: (i) youth without a diagnosis of bipolar disorder (BD) at the time of exposure to psychostimulants; (ii) youth with a diagnosis of BD at the time of exposure to psychostimulants; (iii) youth without a diagnosis of BD at the time of exposure to antidepressants; (iv) youth with a diagnosis of BD at the time of exposure to antidepressants; and (v) youth who develop BD after exposure to these medications. In patients with attention-deficit hyperactivity disorder (ADHD), the risk for mania was found to be relatively low with the use of psychostimulants. For patients with BD and ADHD, effective mood stabilization is important prior to adding a stimulant. For children with depression and/or anxiety, the risk of antidepressant-induced mania (AIM) was generally low (<2%), but the risk of general 'activation' secondary to a selective serotonin reuptake inhibitor (SSRI) may be greater (2-10%). However, rates of AIM in specialty clinics appear to be much higher. SSRIs may be particularly problematic in specific populations, such as those with some symptoms of mania or a family history of BD, but the precise risk is unknown. There is no clear evidence that stimulants or SSRIs accelerate the natural course of BD development in overall samples, but in individual cases prescribers should proceed cautiously when using these agents in youth already at risk for developing BD, such as those with ADHD and mood dysregulation, a history of prior AIM, a history of psychosis, or a family history of BD. PMID- 21692549 TI - Pediatric clinical trials in Latin America and Guyana: present views of local practitioners and ways to embrace the future. AB - BACKGROUND: Global pediatric research has recently received increased attention by health professionals, and research and government institutions. Since the approval of the FDA Pediatric Exclusivity Provision and the EU Paediatric Regulation, pharmaceutical companies have begun to look to developing/transitional countries for international pediatric research collaboration as a way of facilitating the recruitment of patients to clinical trials. Among countries identified as being 'developing/transitional' some were in the North, Central, and South American regions. OBJECTIVE AND METHODS: The aim of this study was to ascertain views from local practitioners on awareness and understanding of pediatric clinical research and to clarify resources and training required by pediatricians engaging in such research in the North, Central, and South American regions. A brief survey was disseminated via Sociedad Iberoamericana de Neonatologia (SIBEN) and several other randomly selected pediatric institutions. This survey provided information for a Paediatric Global Research meeting at WorldPharma 2010 (Copenhagen, Denmark). RESULTS: Pediatricians (n = 55) from seven countries in Latin America and Guyana replied to the survey. They appeared to be enthusiastic about embracing the opportunity to participate in meaningful research to improve treatment of children worldwide. However, some challenges remain to be addressed around good clinical practice in the conduct of trials, education, and training of professionals, and the availability and use of resources. CONCLUSION: The survey indicated a considerable depth of interest in the improvement of the pediatric clinical research environment in Latin America. There is some momentum toward the development of a Latin American network for the facilitation and supervision of pediatric clinical research. PMID- 21692548 TI - Pharmacologic management of high-risk neuroblastoma in children. AB - Neuroblastoma is the most common extracranial solid tumor of childhood. It accounts for 15% of pediatric cancer deaths. Children with high-risk disease have a 3-year event-free survival rate of only 20%. Chemotherapy is the mainstay of treatment in children with advanced neuroblastoma. The aim of this article was to review and critically evaluate the pharmacotherapy of neuroblastoma, using peer reviewed and review literature from 2000-11. All peer reviewed, published human subject studies of therapy for neuroblastoma in children were included. Animal model and in vitro studies were included only if they added to the understanding of the mechanism of a proposed or existing human neuroblastoma therapy. Current therapeutic options for neuroblastoma involve insufficient differentiation of normal from neoplastic tissue. Critically needed new approaches will increasingly exploit targeting of therapy for unique characteristics of the neuroblastoma cell. Pharmacotherapy for neuroblastoma still suffers from an inadequate therapeutic window. Enhancement of toxicity for tumor and safety for normal tissues will entail innovation in targeting neuroblastoma cells and rescuing or protecting normal tissue elements. PMID- 21692550 TI - Long-term follow-up of statin treatment in a cohort of children with familial hypercholesterolemia: efficacy and tolerability. AB - BACKGROUND: Early identification of children with familial hypercholesterolemia (FH) makes it possible to start lipid-lowering therapy at a young age in order to prevent cardiovascular disease. Numerous randomized, often placebo-controlled, studies have assessed the efficacy and safety of statins in children with FH. OBJECTIVE: The aim of this pragmatic observational study was to evaluate pravastatin treatment efficacy and tolerability for a long period of time, and to assess how these results translate in 'real-life' clinical practice. METHODS: We analyzed all medical files of young hypercholesterolemic patients referred to two specialized French centers. This population of 185 pravastatin-treated children with FH, with a mean baseline cholesterol level above 300 mg/dL, in most of whom genetic diagnosis was achieved, was followed-up for a mean duration of 2 years 2 months. The mean age for starting pravastatin was 11 years; in one of five children, treatment was started before the age of 8 years, mostly because of severe hypercholesterolemia or a family history of coronary heart disease. RESULTS: A 16.9-19.2% decrease in total cholesterol level (21-24% for low-density lipoprotein cholesterol) was observed. Growth and puberty were not affected by statin treatment. A review of the medical files showed that 13% of children had side effects, most of which were minor; four of these children had muscular symptoms possibly related to the treatment. This frequency is lower than that observed in adults, and comparable to other studies in children. CONCLUSIONS: In this large cohort of FH children, the efficacy and tolerability of pravastatin therapy in real-life conditions was demonstrated to be similar to that in randomized controlled studies. PMID- 21692552 TI - [A nuclear document in the central core of the moral debates of our time]. AB - We summarize the contents of the Instruction Dignitas personae and briefly attempt to explain why we find ourselves before an impossible debate when we talk about human life, its conception and reception. We will also try to provide some light as we try to escape this cul de sac so characteristic in the moral discussions of our time. To do so, we seek the help of the moral philosopher, Alasdair MacIntyre, whose life's work makes him especially suited to identifying the anthropological paradoxes that we are facing nowadays and which are very much related to the different issues mentioned in the Instruction. PMID- 21692551 TI - Cost effectiveness of denosumab compared with oral bisphosphonates in the treatment of post-menopausal osteoporotic women in Belgium. AB - BACKGROUND: Denosumab has recently been shown to be well tolerated, to increase bone mineral density (BMD) and to significantly reduce the risk of hip, vertebral and non-vertebral fractures in the FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial. It is becoming increasingly important to evaluate not only the therapeutic value of a new drug but also the cost effectiveness compared with the most relevant treatment alternatives. OBJECTIVE: The objective of this study was to estimate the cost effectiveness of denosumab compared with oral bisphosphonates (branded and generic drugs) in the treatment of post-menopausal osteoporotic women in Belgium. METHODS: Cost effectiveness of 3 years of treatment with denosumab was compared with branded risedronate and branded and generic alendronate using an updated version of a previously validated Markov microsimulation model. The model was populated with relevant cost, adherence and epidemiological data for Belgium from a payer perspective and the results were presented as costs per QALY gained (&U20AC;, year 2009 values). Analyses were performed in populations (aged >=60 years) in which osteoporosis medications are currently reimbursed in many European countries, i.e. those with BMD T-score of -2.5 or less or prevalent vertebral fracture. Patients receiving denosumab were assumed to have a 46% lower risk of discontinuation than those receiving oral bisphosphonates, and the effect of denosumab after treatment cessation was assumed to decline linearly to zero over a maximum of 1 year. RESULTS: Denosumab was cost effective compared with all other therapies, assuming a willingness to pay of &U20AC;40 000 per QALY gained. In particular, denosumab was found to be cost effective compared with branded alendronate and risedronate at a threshold value of &U20AC;30 000 per QALY and denosumab was dominant (i.e. lower cost and greater effectiveness) compared with risedronate from the age of 70 years in women with a T-score of -2.5 or less and no prior fractures. The cost effectiveness of denosumab compared with generic alendronate was estimated at &U20AC;38 514, &U20AC;22 220 and &U20AC;27 862 per QALY for women aged 60, 70 and 80 years, respectively, with T-scores of -2.5 or less. The equivalent values were &U20AC;37 167, &U20AC;19 718 and &U20AC;19 638 per QALY for women with prevalent vertebral fractures. CONCLUSION: This study suggests, on the basis of currently available data, that denosumab is a cost effective strategy compared with oral bisphosphonates (including generic alendronate) for the treatment of post-menopausal osteoporotic women, aged >=60 years in Belgium. Denosumab therefore appears to have the potential to become a first-line treatment for post-menopausal women with osteoporosis. However, further studies would be required to evaluate the long-term safety and adherence of denosumab in real-world clinical practice as well as head-to-head effectiveness compared with oral bisphosphonates. PMID- 21692553 TI - [Ethical analysis and commentary of Dignitas Personae document: from continuity toward the innovation]. AB - In 2008 [corrected] the Catholic Church published a document entitled Dignitas Personae (DP) about a range of bioethical issues related to the areas of assisted reproduction and human genetics. The objective of this paper is analyzing the issues treated in the same and comments the novelty of his arguments in the bioethical thinking of the Catholic Church. DP document has an introduction, three parts and a conclusion. The publication of document is due to recent advances that have occurred in recent years in the two areas mentioned above. This advances were not analyzed in a previously document called Donum Vitae (DV). DP analyzes these new advances from the anthropological and ethical approaches of DV. Not intending to contradict DV, the DP applies the arguments of DV to new situations. In both the title and elsewhere in the text it is affirmed that the human embryo has the dignity of human person. From this principle DP analyzes issues such as the status of the human embryo, intracytoplasmic sperm injection, (ICSI), preimplantation diagnosis, embryo cryopreservation, contragestion, embryo reduction etc. In these matters, as in the questions such as human genetics, cloning, gene therapy or the use of biological material obtained from abortions, the document reaffirms previous ideas of the Catholic Church, applies them to new problems or develops new arguments that will require further reflection. In conclusion, the document is very useful for understanding the current bioethical thinking of the Catholic Church on these issues; it clarifies certain disputes, suggesting new arguments, and leaves other issues to free discussion and subsequent interventions of the Catholic Magisterium. Finally, the document reaffirms the commitment of the Catholic Church to the poor of our techno scientific society, the proletariat of the new century: human embryos. PMID- 21692554 TI - [Noninvasive prenatal genetic diagnosis: a bioethical reflection on the use of noninvasive prenatal diagnosis from the analysis of nucleic acids present in maternal peripheral blood]. AB - The use of techniques that analyse the fetal nucleic acids present in maternal peripheral blood for the preparation of non-invasive prenatal genetic diagnosis, is a clinical reality in the case of certain diseases. In the coming years, it will become part of the routine monitoring for fetal diagnosis. This study analyzes the current status of these techniques as well as the major ethical issues arising from the relationship between - prenatal diagnosis and eugenic abortion, and the specific problems posed by - prenatal genetic diagnosis based an analysis of the nucleic acids present in maternal peripheral blood. Among the conclusions are the following: we make a positive ethical evaluation of the technique when it is aimed at pregnant women who are in a situation of high risk, defined on the basis of medical standards and ethics, without compromising the integrity of the fetus. We make a negative ethical evaluation when non-invasive prenatal genetic diagnosis has a eugenic purpose and will establish a connection between prenatal diagnosis and eugenic abortion in case of a positive result. Non invasive prenatal diagnosis increases the image of the disabled person as an individual that has to be excluded from society. The widespread use of non invasive prenatal diagnosis will decrease the autonomy of women / couples when it comes to making decisions. Health authorities may use non-invasive prenatal diagnosis as a way of "preventing" genetic diseases, since it will lower costs, increase the number of malformed fetuses detected and a decrease the number of indirect abortions involving invasive techniques. PMID- 21692555 TI - [Ethic evaluation of sexual health programs on adolescence]. AB - In public health services, the interest in sexuality seems to turning from traditional topics such as potential treatments for male erectile dysfunction, psychosomatic disorders, the control of premature ejaculation and contraception. Instead, an increasingly prominent role is being given to prevention strategies carried out by means of campaigns or through sexual health programme sin schools. The different teaching strategies that underlie these programmes, which in many cases lack social consensus but are often promoted by international organizations such as WHO or UNESCO, reveal not only divergent ethical conceptions and worldviews on the meaning of sexuality, but also conflicting starting points, means and goals, focusing either on barrier-contraceptive methods or on sexual abstinence and personal responsibility. There is therefore a pressing need to understand the scientific evidence underlying each educational approach and the ethical postulates of each pedagogical proposal. This paper presents an outline of a six-point adolescent sexuality education program, which is respectful of individuals' ethical convictions. Given that few works on preventive medicine issues include an ethical evaluation of the steps followed in their development, this article also proposes a systematic evaluation of strategies for sexual health in the community that is developed through four steps verifying the following aspects: 1) the accuracy of information, 2) the level of evidence, 3) efficiency and 4) non-maleficence about the target population of each health program. The methodology used in these sexual health programs is another aspect that will verify their ethical consistence or, conversely, their absence of ethical values. We emphasize the duty of designers of programme for children not to carry then out against the will of their parents or tutors, and not conceal sensitive and relevant information. PMID- 21692556 TI - Large-scale production of functional recombinant CAR in a baculovirus- insect cell system. AB - Coxsackievirus group B and adenovirus receptor (CAR) is a major receptor for the adenovirus groups that has drawn overall attention over the past decade. Although this protein could potentially be used as an agent for the blocking of adenovirus infection, large-scale production of highly purified human CAR in eukaryotic expression system has not been reported. In the present study, we showed the construction of recombinant baculovirus highly-expressing the extracellular domain of human coxsackievirus-adenovirus receptor (exCAR) in High Five insect cells. The recombinant exCAR was recovered from the cell culture medium as a secreted soluble protein and purified by Ni-NTA affinity chromatography. The final yield of recombinant exCAR was about 8-10 mg/l of supernatant with the purity of 96.3%. Binding activity assay showed that the recombinant exCAR exhibited an intact ability of binding to the knob domain of the adenovirus type 5 fiber protein (Ad fiber knob) displayed by T7 phage. These results showed that the recombinant human exCAR produced in insect cells and purified by Ni-NTA chromatography retained its ability to bind to the Ad fiber knob and could potentially be used in therapy of adenovirus infection. PMID- 21692557 TI - Ubiquitins of Bombyx mori nucleopolyhedrovirus and Helicoverpa armigera nucleopolyhedrovirus show distinct subcellular localization in infected cells. AB - Ubiquitin (UB) is a conserved protein that regulates a number of processes in eukaryotic cells. Nearly all lepidopteran baculoviruses encode UB homologs showing a partial sequence identity with human UB (Hu-UB). In this study, the sequence, predicted 3D-structure and subcellular localization of UB homologs encoded by two different nucleopolyhedroviruses of Bombyx mori (BmNPV) and Helicoverpa armigera (HaNPV) were compared. UBs of BmNPV and HaNPV (Bm-UB, Ha-UB, respectively) shared only 73% of sequence identity of the different aa in relation to Hu-UB being localized in non-conserved parts, namely in two heterogeneous regions of aa 15-32 and aa 53-60. Interestingly, Bm-UB and Ha-UB share the same seven lysines except for an additional Lys54 in Bm-UB. However, in spite of the sequence heterogeneity, Bm-UB and Ha-UB have a similar predicted 3D structure. A difference in their subcellular localization during virus growth in insect cell lines was found in the late stage of formation of occlusion-derived virus (ODV). In particular Bm-UB was localized mainly and evenly in the nucleus, while Ha-UB on the nuclear membrane. These data suggest that (i) UBs, besides being engaged in various cellular processes, have a role in specific processes of virus growth, and (ii) Bm-UB and Ha-UB may show certain different activities associated with the virus growth. PMID- 21692558 TI - Identification and functional studies of HLA-A0201 restricted CTL epitopes in the X protein of hepatitis B virus. AB - Cytotoxic T lymphocyte (CTL) epitopes in the X protein (HBx) of hepatitis B virus (HBV) may play a key role in the viral control and liver damage. The aim of this study was to identify and study the function of HLA-A0201 restricted CTL epitopes in HBx of HBV genotypes B and C that are epidemic in China. Four nonapeptides signed HBx1: VLCLRPVGA, HBx2: CLFKDWEEL, HBx3: VLHKRTLGL, and HBx4: HLSLRGLPV were predicated by computational analysis and manually confirmed by defining the peptide supermotif, extended motif, and quantitative motif. Synthesized peptides were examined for their affinity and binding stability with HLA-A0201. After being analyzed by enzyme-linked immunospot (ELISPOT) and cytolytic activity assays, the HBx2 epitope was selected for a construction of HLA-A0201-peptide tetramers. The tetramer staining method was used to analyze peripheral blood mononuclear cells (PBMCs) isolated from HBV-infected patients at different disease stages (chronic hepatitis, liver cirrhosis, and hepatoma). Compared with CTL epitopes in the HBV envelope or polymerase, HBx2 is also a potential HLA A0201 restricted CTL epitope, what may have a clinical implication. PMID- 21692560 TI - Molecular analysis of the coat protein gene of peanut stripe virus from China. AB - Peanut stripe virus (PStV) is one of the most common viruses infecting peanut that causes great economic losses every year. The 3'-terminal 1082 bp of 74 PStV isolates collected from 12 districts of Shandong province, China were sequenced. Their coat protein (CP) genes were 864 bp in length and shared identities of 98.0%~100% and 98.3% ~100% at nt and aa levels. The identities between the CP genes of these isolates and other 36 isolates from the GenBank were 93.5%~100% and 92.0%~100% at nt and aa levels, respectively. PStV isolates can be clustered into two phylogenetic groups. The isolates from United States, mainland China, and Indonesia formed group I and those from Viet Nam, Thailand, and Taiwan formed group II. The PStV isolates in group I can be further classified to two subgroups. The gene flow of PStV populations within a country was frequent, but that between countries was infrequent. PMID- 21692559 TI - T7 phage displaying latent membrane protein 1 of Epstein-Barr virus elicits humoral and cellular immune responses in rats. AB - The latent membrane protein 1 (LMP1) encoded by Epstein-Barr virus (EBV) has become a potential target in EBV-associated tumor prevention and treatment due to its multiple biological effects. In this study, the recombinant T7 phage displaying full-length LMP1 protein was cloned and used as an immunogen to immunize rats. Results of flow cytometry, Western blot analysis, and ELISA confirmed that both humoral and cellular immune responses were elicited in the immunized rats. Our data suggested that T7 phage was an efficient antigen carrier. The recombinant T7-LMP1 phage reconstitutes the antigenic and immunogenic properties of LMP1 and can serve as a vaccine against EBV. PMID- 21692561 TI - A gel-capture assay for characterizing the sialyl-glycan selectivity of influenza viruses. AB - Sialic acids (SA) usually linked to galactose (Gal) in an alpha2,6- or alpha2,3 configuration are considered the main cell receptors for influenza viruses, in particular for their hemagglutinins (HA). The typing of influenza virus HA receptor selectivity is relevant for understanding the transmissibility of avian and swine viruses to the human population. In this study we developed a simple and inexpensive gel-capture assay (GCA) of the influenza virus HA receptor binding selectivity. Its principle is the binding of soluble influenza virus to pentasaccharide analogs, representatives of receptors of human and avian influenza viruses, immobilized on a gel resin. The human and avian analogs consisted of a sialyllactose-N-tetraose c (LSTc) [Neu5Ac(alpha2,6)Gal(beta1 3)GlcNAc(beta1-3)Gal(beta1-4)Glc] and a sialyllactose-N-tetraose a (LSTa) [Neu5Ac(alpha2,3)Gal(beta1-3)GlcNAc(beta1-3)Gal(beta1-4)Glc], respectively. Following equilibration, the unbound virus is washed away and the bound one is assayed via HA by densitometry as a function of the analog concentration. Using GCA, the receptor selectivity of three influenza viruses of different HA subtype was investigated. The results showed that the egg-adapted A/California/07/2009 (H1N1) virus exhibited an avian alpha2,3-linked LSTa selectivity, however, it retained the ability to bind to the alpha2,6-linked LSTc human receptor analog. Influenza B virus B/Florida/4/2006 showed alpha2,6-linked LSTc selectivity and a poor alpha2,3-linked LSTa avidity. The H3N2 virus A/Wisconsin/15/2009 displayed almost comparable avidity for both receptor analogs with a marginally greater alpha2,3-linked LSTa avidity. The described assay protocol provides a simple and rapid method for the characterization of influenza virus HA receptor binding selectivity. PMID- 21692562 TI - Immunogenicity of the envelope GP3 protein of porcine reproductive and respiratory syndrome virus displayed on baculovirus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) has been recognized as one of the most important pathogens of pigs throughout the world. The minor envelope protein GP3 of PRRSV plays an important role in clearing of the virus infection and protecting the animals. In this study, a recombinant baculovirus (BacSC-GP3) expressing His6-tagged GP3 with the transmembrane (TM) and cytoplasmic (CT) domains of envelope protein gp64 was constructed and its immunogenicity was evaluated in mouse and piglet models. The His6-tagged GP3 was successfully displayed on the surface of virions as well as virus-infected Sf-9 cells. The animals immunized with BacSC-GP3 gave a slightly higher (piglets) up to a markedly higher (mice) humoral and lymphocyte proliferation responses than those that received a commercial killed vaccine. This is the first study on the immunogenicity of recombinant GP3-baculovirus, which indicates that the latter can represent an alternative strategy for developing a more effective PRRSV vaccine. PMID- 21692563 TI - Overexpression of alpha-2,6 sialyltransferase stimulates propagation of human influenza viruses in Vero cells. AB - Human influenza viruses are major concern as the leading cause of global pandemics. In infecting cells, they preferentially bind to sialyloligosaccharides containing terminal N-acetyl sialic acid linked to galactose by an alpha-2,6 linkage (NeuAcalpha2,6Gal). The amount of NeuAcalpha2,6Gal in Vero cells, which are predominantly used for production of influenza vaccines over the past 30 years, may not be as high as that in epithelial cells of human respiratory tract, what leads to the suboptimal virus growth in Vero cells. In this study, we stably transfected Vero cells with cDNA of human alpha-2,6-sialyltransferase (SIAT1), an enzyme catalyzing alpha-2,6-sialylation of galactose on glycoproteins. Overexpression of SIAT1 in the transfected Vero cells (Vero-SIAT1 cells) was confirmed by Western blot analysis and immunofluorescence microscopy. Vero-SIAT1 cells expressed 7 times higher amounts of NeuAcalpha2,6Gal, but 3 times lower amounts of NeuAcalpha2,3Gal as compared to parental Vero cells. Furthermore, the influenza viruses A (H1N1 and H3N2) and B grew in Vero-SIAT1 cells to the higher titers than in Vero cells. Taken together, these results imply that Vero-SIAT1 cells are useful not only for the propagation of human influenza viruses, but also for the preparation of influenza vaccines. PMID- 21692564 TI - Establishment of novel cell lines latently infected with human immunodeficiency virus 1. AB - Many human immunodeficiency virus 1 (HIV-1) researchers focus on the developing new anti-reservoir therapy to eradicate HIV-1 provirus from the HIV-1-infected patients. HIV-1 provirus is the major obstacle for effective HIV-1 treatment because it integrates into the host genome and can produce a virus progeny after stopping highly active antiretroviral therapy (HAART). We established two novel cell lines latently infected with HIV-1 by limiting dilution cloning of A3.01 cells infected with HIV-1. Analysis of the flanking sequence of HIV-1 proviral DNA integrated into chromosomal cellular DNA revealed that proviral DNA was inserted into different sites of different chromosomes in the two examined cell lines. In these lines, virus reactivation could be induced by a phorbol 12 myristate 13-acetate (PMA) treatment that resulted in a marked increase of the production HIV-1 p24 antigen and appearance of the infectious virus. The novel cell lines latently infected with HIV-1 represent further tool for the study of molecular mechanisms of viral latency and development of anti-reservoir therapy of HIV-1 infection. PMID- 21692565 TI - Increased prevalence of Kaposi?s sarcoma-associated herpesvirus in the Kaposi?s sarcoma-endemic area of western Kenya in 1981-2000. AB - Kaposi?s sarcoma (KS) had been endemic in Africa before the appearance of human immunodeficiency viruses (HIV) in 1985. Incidence of African KS has increased over the time and the risk of contracting KS become greater in HIV-positive as opposed to HIV-negative individuals. KS specimens were collected in 1981-2000 from 228 surgical cases originating from a KS-endemic area of Western Kenya and examined for Kaposi?s sarcoma-associated herpesvirus (KSHV) by an immunoperoxidase assay. The results showed that the specimens from 1981-1985 (before the HIV epidemic) were KSHV-positive in 10.3% in contrast to the KSHV positivity of 50.1-63.5% in 1986-2000. The linear increase of KSHV positivity in 1981-2000 was statistically significant. The most plausible explanation for the increased prevalence of KSHV in KS cases is that the endemic KS has changed to the epidemic one. PMID- 21692566 TI - Enhanced protection of mice against Japanese encephalitis virus infection by combinations of monoclonal antibodies to glycoprotein E. AB - In the present study, the protective effect of various combinations of four monoclonal antibodies (MAbs) to glycoprotein E (gpE) of Japanese encephalitis virus (JEV) on the JEV-infected mice was studied. The MAbs were characterized as hemagglutination-inhibition-positive and JEV-specific (Hs). In the protective experiment, mice were first administered single MAbs or their combinations intraperitoneally (i.p.) and 24 hrs later infected with the virus intracerebrally (i.c.). The results showed that single MAbs protected the mice to the extent of 45-65%, while combinations of two or three MAbs gave 85-90% or 100% protection, respectively. The enhanced effect of combinations of several Hs MAbs might be due to the sharing of neutralization epitopes recognized by the Hs MAbs. These results suggested that a combination of at least three epitopes represented by the Hs MAbs should be included in an effective JEV vaccine. PMID- 21692567 TI - Minimal size of prototype foamy virus integrase for nuclear localization. AB - We have reported previously that the prototype foamy virus (PFV) integrase (IN) has a strong nuclear localization signal (NLS) in its C-terminal domain, in particular in a region of aa 306-334 including highly karyophilic arginines or lysines at positions 308, 313, 318, 324, and 329. In this study, we used various mutants of the C-terminal domain to further analyze its karyophilic determinants. Plasmids expressing these mutants fused to maltose binding protein (MBP) and enhanced green fluorescent protein (EGFP) were transfected to COS-1 cells and subcellular localization of these fluorescent fusion proteins was determined by fluorescent microscopy. The results revealed that a maximum karyophilicity was exhibited by a region longer than the previously described one of 29 aa (aa 306 334), in particular by a 64 aa region (aa 289-352) with Arg341 and Lys349 as critical determinants. PMID- 21692568 TI - Comparison of ELISA and virus neutralization test in assaying serum antibodies to bovine herpesvirus 1. PMID- 21692569 TI - A silence element involved in Kaposi?s sarcoma-associated herpesvirus ORF11 gene expression. PMID- 21692570 TI - Hepatitis B virus with pre-S2 deletion is more prevalent in hepatocellular carcinoma than in chronic active hepatitis and asymptomatic carriers. PMID- 21692571 TI - HIV/AIDS: the continuing challenges of mental health nursing: introducing a special issue on HIV/AIDS. PMID- 21692573 TI - The burden of secrecy among South African adolescents orphaned By HIV and AIDS. AB - HIV thrives in an atmosphere of silence and secrecy. The stigma, real or feared, of HIV/AIDS is often a barrier to support and care that adolescent orphans need. The purpose of this article is to describe the burden of silence borne by adolescents orphaned by HIV and AIDS. A phenomenological study using photography and photo-elicitation was done among orphaned adolescents. Fifteen adolescents orphaned by HIV and AIDS, living in an urban area of South Africa, participated in the study. Participants photographed objects, such as graveyards, hearses, and a room where a parent committed suicide. These photographed objects were grouped as symbols of death. Nature and people also were photographed. Photo-elicitation revealed the psychosocial impact that results from the secrecy about parental cause of death. Implications for mental health practitioners are also discussed. PMID- 21692572 TI - Living in silence: a grounded theory study of vulnerability in the context of HIV infection. AB - Clients with HIV infection have been conceptualized as a vulnerable population. Although some researchers have examined vulnerability with clients with HIV infection, a theory of vulnerability in the context of HIV infection is non existent. The purpose of this study was to describe, using qualitative methodology, the process by which vulnerability occurs in the context of HIV infection. Grounded theory methodology was used to sample and analyze data from 15 qualitative interviews of adults with HIV infection. Data were collected until data saturation was reached. A theory that describes the process by which vulnerability occurs in the context of HIV infection, Living in Silence, emerged from the data. Living in Silence consists of four categories: Confronting Mortality and Illness, Struggling with Change, Encountering a Lack of Psychosocial Support, and Experiencing Vulnerability. Clients living with HIV experience vulnerability. Nursing interventions to decrease the risks of vulnerability should be directed toward the holistic needs of clients and toward increasing psychosocial support. PMID- 21692574 TI - Development of an instrument to measure internalized stigma in those with HIV/AIDS. AB - Stigma has grave consequences for persons living with HIV/AIDS. Stigma hampers prevention of HIV transmission to sexual partners and to unborn babies, diagnosis, and early treatment, and negatively affects mental and physical health, quality of life, and life satisfaction. Internalized stigma of HIV/AIDS may have even more severe consequences than perceived or enacted stigma. The purpose of this study was to develop an instrument to measure internalized stigma in those with HIV/AIDS. Data were drawn from the Rural Women's Health Project. Research assistants administered structured interviews at baseline, 3 months, and 6 months. Instruments used in these analyses included a demographic data form, the Centers for Epidemiological Studies Depression Scale (CES-D), the Perceived Stigma Scale (PSS), and the Internalized Stigma of AIDS Tool (ISAT). Exploratory factor analysis confirmed that the ten items of the ISAT measure a single factor that explains 88% of the variance in the construct. Internal consistency was demonstrated by a Cronbach's alpha of .91 (Time 1), .92 (Time 2), and .92 (Time 3). Convergent validity was supported with significant positive correlations with the CES-D (rho = 0.33, p < 0.0001) and the PSS (rho = 0.56, < 0.0001). The Internalized Stigma of AIDS Tool appears to be a reliable and valid instrument to measure internalization of the stigma of HIV/AIDS. It may be of value in research and clinical assessment. PMID- 21692575 TI - Reasons for HIV disclosure and non-disclosure: an exploratory study of rural African American men. AB - Disclosure of one's HIV status to others is an important decision. There are benefits and risks to be considered. Also decisions must be made about the recipients of the disclosure. This study explored reasons for disclosure and non disclosure among rural African American men in the south. Audiotaped interviews were conducted with 40 men. The most common reasons for disclosure were to relieve stress, satisfy the need to tell, help others, and to receive support. The most common reasons for non-disclosure were the fear of negative reaction or stigma, the fear of the disclosure recipient telling others, a belief that there was no need to tell, not being ready to tell, and not wanting to burden others with the disclosure. PMID- 21692576 TI - Social context of rural Women with HIV/AIDS. AB - The South has more AIDS cases than any other region of the US, with most new diagnoses among African American women (56%). In a previous study, a peer counseling intervention for rural women with HIV/AIDS was developed and tested. The purpose of this analysis was to describe, from the peer counselors' perspective, the predominant concerns of the women, contextualized by living in isolated, impoverished circumstances in the rural Deep South. Following home visits, peer counselors recorded a description of the encounter. A multidisciplinary qualitative research group extracted, coded, and thematized the chief concerns and context of the women's lives. Findings provide a vivid portrait of HIV-infected women experiencing deeply troubling psychological and physiological symptoms of HIV/AIDS against the contextual ground of poverty and isolation. Themes include: (1) struggle/effort; (2) stigma/hiding; (3) loss/depression; and (4) independence/ dependence. These women lived in extremely difficult life circumstances that reflected not only a devastating chronic illness, but a life of poverty and abuse. Appropriate care for HIV-infected women living in the rural Deep South will need to address the whole context of their lives. PMID- 21692577 TI - Role of spirituality in HIV-infected mothers. AB - The purpose of this study was to describe the processes by which HIV-infected mothers manage mothering. A semi-structured guide was used to facilitate discussion from a convenience sample of 15 mothers. The core category was "The Process of Living for My Children." "Leaning on God" was a part of "Taking Care of Myself" and reflected the ways in which the mothers used spiritual aspects to manage mothering and live with HIV infection. Leaning on God was an important tool in managing mothering and self-care. Health care providers can enhance this tool by being aware of their own values and beliefs. PMID- 21692578 TI - Correlates of depression among rural women living with AIDS in Southern India. AB - Although depression may be commonly experienced by persons living with AIDS, it may be challenging for health care providers to identify persons who are suffering from depression symptoms, particularly if they are living in the more isolated rural areas of India. The purpose of this study is to assess correlates of depression among women living with AIDS in rural Andhra Pradesh, India. A total of 68 rural women living with AIDS (WLA) completed baseline data and were assessed by means of structured instruments. Regression modeling revealed that disclosure avoidance and making at least six health care visits in the last six months were all associated with depression. Further, living with a spouse was associated with lower depressive symptom scores. Stigma was not found to be associated with depression. Understanding correlates of depression can lead the way toward designing culturally-tailored interventions that can mitigate disclosure avoidance and improve the health of women. A more comprehensive health focus may be needed to empower the women to seek quality care for both physical health, as well as mental health, symptomatology. PMID- 21692579 TI - The importance of knowing the patient. PMID- 21692580 TI - Can our words produce action? PMID- 21692583 TI - Stigma in abortion care: application to a grounded theory study. AB - A recent research study found that being more directly involved in medical abortion places greater demands on the nurses. The demands required by nurses working in abortion care may be increased by the stigma attached to such an antisocial action. This paper presents an application of stigma theory, as espoused by Goffman, based on a qualitative research study on abortion. It is argued that women attending for abortion are stigmatised and nurses, although 'wise', have an affiliate stigma through their close association with the procedure. It is proposed that the situation can be ameliorated by addressing stigma at policy, local and personal levels. Examples from other areas of practice are outlined for possible application to practice. PMID- 21692584 TI - Factors influencing young women's sexual and reproductive health. AB - This descriptive study of first year university students, utilising a survey questionnaire, explored sources of information including, but not limited to, the media, factors influencing decision making and young women's health seeking behaviours in terms of reproductive and sexual health. The overall aim was to add to the body of knowledge for health professionals developing appropriate programs targeting adolescents and young women. Understanding of sexual and reproductive health was variable with only approximately half of respondents demonstrating an adequate understanding. Contrary to an increasing picture of this generation as increasingly engaging in risky and potentially damaging behaviour as depicted in Female chauvinist pigs: The rise of raunch culture by Levy (2005), respondents in this study appeared for the most part to take considered decisions utilising the sources at hand, including popular magazines, while also grappling with expectations imposed by a culture that sexualises girls at younger and younger ages and depicts promiscuity as the norm. The importance of family values, particularly mothers as role models, emerged as important determinants of behaviour, while religious values were identified as important to only 15% of respondents. At the same time, pressure to engage in sex at younger and younger ages and continuing pressure to engage in unprotected and risky sex was a concern. Cynicism was expressed regarding the double standard perceived to be still operating in relation to young men's and women's sexual health. Young women in the study were forceful in identifying a need for a much better approach to education within schools directed at both sexes and one that is factual, relevant and all encompassing. PMID- 21692585 TI - Behind the scales: child and family health nurses taking care of women's emotional wellbeing. AB - This study, on the home visiting practice of child and family health nurses, looked at their often unacknowledged role in supporting women's emotional health and well being, and how difficult it is to articulate this work. Observations of home visits, and recorded group and individual interviews with nurses were conducted in this ethnographic study, in regional Australia. The data was analysed using thematic analysis. The tension between the nurse's role in caring for the baby and taking care of women's emotional health and wellbeing emerged as a major theme. Manifest and latent functions are used to describe the nature of community child health nurses' practice where nurses covertly address the health and wellbeing needs of the mother via the overt function of monitoring the child's health and development. Nurses often use a focus on the baby to legitimate addressing women's emotional health and wellbeing. PMID- 21692586 TI - Continuous primary nursing care increases satisfaction with nursing care and reduces postpartum problems for hospitalized pregnant women. AB - OBJECTIVE: To compare the differences in practicing continuous primary nursing care (CPNC) versus task-centered nursing care (TCNC) with regard to patient satisfaction with nursing care and early postpartum health problems for hospitalized pregnant women. DESIGN: All participants filled out the satisfaction with nursing care questionnaire, breastfeeding knowledge questionnaire, and early postpartum problem questionnaire. SETTING: Participants in the CPNC group received continuous individualized primary nursing care and participants in the TCNC group received task-centered nursing care during their perinatal period. PARTICIPANTS: Using a randomized controlled trial, 470 hospitalized pregnant women participated in the study with 230 pregnant women in the CPNC group and 240 in TCNC group. DATA ANALYSIS: Questionnaire data were collected, calculated, and statistically analyzed using independent t-tests or Chi(2) tests along with power analysis. RESULTS: Participants in the CPNC group reported significantly higher overall satisfaction with nursing care (t(468) = 5.936, p < .001), had more breastfeeding knowledge (t(468) = 5.633, p < .001), and were more likely to breast feed six weeks after delivery (Chi(2) (1) = 39.237, p < .001) than those in the TCNC group. Participants in the CPNC group also showed a significantly lower occurrence of postpartum urinary retention (Fisher exact test was used, p < .002) and breast discomfort (Chi(2) (3) = 34.482, p < .001) than those in the TCNC group. CONCLUSION: Practicing continuous primary nursing care was more effective than practicing traditional task-centered nursing care for hospitalized pregnant women in increasing satisfaction with nursing care, enhancing breastfeeding, and reducing early postpartum problems. PMID- 21692587 TI - Children's postoperative pro re nata (PRN) analgesia: nurses' administration practices. AB - AIMS AND OBJECTIVES: This paper reports a study aimed at exploring the nursing practices associated with the administration of pro re nata (PRN) postoperative analgesia to children, and at gaining a preliminary understanding of the decisions that nurses make about this important intervention. BACKGROUND: Nurses are responsible for assessing and administering the appropriate medication at the appropriate time to the child in pain. There was scant published research about the administration of postoperative PRN analgesia to children, or about the decision-making processes inherent in this aspect of clinical nursing care. DESIGN: A sequential mixed methods explanatory study with two data collection phases - quantitative followed by qualitative - was conducted. RESULTS: Nurses used multiple strategies to ascertain children's need for postoperative PRN analgesia, including reference to pain assessment tools, focussing on the behavioural cues of children, involving parents and children, and drawing upon personal and professional backgrounds and experience. Evaluation of the effectiveness of PRN postoperative analgesia was poorly communicated. CONCLUSIONS: Decision-making associated with the selection and administration of appropriate analgesia to children is complex. Inservice education should be developed and offered to nurses working with children postoperatively to ensure the appropriate use of PRN pain relief. RELEVANCE TO CLINICAL PRACTICE: Documentation surrounding this task is poor and needs to be addressed as a matter of urgency to ensure quality patient outcomes. PMID- 21692589 TI - Monitoring and evaluation of a large-scale community-based program: recommendations for overcoming barriers to structured implementation. AB - Accountability for the use of limited health resources requires quality information for ongoing monitoring of program effectiveness. We outline the challenges involved in the monitoring and evaluation of a large-scale community nurse home visiting program. Efforts to establish and maintain rigorous assessment were impaired by interrelated difficulties, impacting on the quality of information collected. The consequences and outcomes of these challenges are discussed. Recommendations to facilitate the monitoring and evaluation of community-based programs are made. Successful program monitoring and evaluation, guided by these recommendations, will support the ongoing review of program activities and evidence-based decision making to inform current operation and future planning. PMID- 21692588 TI - Comparing Jordanian nurses' job stressors in stressful and non stressful clinical areas. AB - AIMS AND OBJECTIVES: To examine if Jordanian nurses' job stressors are different in various practice areas in hospitals, particularly in stressful or non stressful clinical areas of work. BACKGROUND: Nursing is a stressful profession. Nurses' job stressors have been studied in Jordan, but none compared job stressors in different clinical areas. There is a need to identify nurses' job stressors in different clinical areas to better manage them. METHODS: A descriptive correlational design was used. Data about job stressors and demographics were collected from a convenience sample of 464 Jordanian nurses working in Jordanian hospitals. Nursing Stress Scale was used to measure nurses' job stressors. FINDINGS: Nurses' job stressors experienced by nurses working in stressful areas were significantly different from those stressors experienced by nurses working in non-stressful areas in five subscales out of seven. Nurses' job stressors in non-stressful areas were best predicted by one variable, 'model of nursing care provision', whereas nurses' job stressors in stressful areas were best predicted by two variables: 'shift worked' and 'level of education'. CONCLUSIONS: Providing access to educational programs, not only in clinical areas, but in teamwork, communication, family interactions, and stress management will reduce nurses' job stressors in different clinical areas. RELEVANCE TO CLINICAL PRACTICE: Knowing different stressors in different clinical areas among Jordanian nurses help nurse managers and hospital administrators to adopt strategies that manage job stressors effectively in different clinical areas of work. Examples of these strategies are scheduling, reduce workload, and improve work environment. PMID- 21692590 TI - Nursing home placement of older parents: an exploration of adult children's role and responsibilities. AB - Chinese societies like most others are experiencing social change that impacts on models of care for older parents. There is tension between social change and traditional values of filial piety. The eldest son and his wife are expected to care for aged parents but that can be a challenge in modern industrial societies. This paper reports on research undertaken in Taiwan to explore changing values for aged care. It aimed to investigate how the roles and responsibilities of adult children of nursing home residents are changing. It involved aged care facility residents, their families and professional carers. PMID- 21692591 TI - 'Once I became a pensioner I became a nobody - a non entity': the story of one woman's experience of the health care system. AB - This article highlights one socially isolated older person's experiences of ageing in a large metropolitan Australian location and the problems she encounters in attempting to access appropriate and timely health care. As society moves into a phase of rapid demographic ageing, this personal account provides health professionals with an in-depth insight into what it can be like to live in social isolation as one ages and needs ever increasing health care. Win is part of a larger study investigating difficulties encountered by socially isolated older people in accessing health care needs, and preferred her real name to be used for this article. All other names used are fictitious to preserve anonymity. PMID- 21692592 TI - Defining pastoral care for older people in residential care. AB - The concept and definition of pastoral care in aged care remains ambiguous. This paper reports on the defining characteristics and meaning of pastoral care from the perspective of older recipients, their family members and pastoral care workers. Using a qualitative descriptive approach semi-structured in-depth interviews were conducted with 18 pastoral care workers and 11 older people. Transcribed data were analysed using NVivo software and coded for emerging themes. The defining characteristics of pastoral care that emerged from analysis of transcribed interviews were: a trusting relationship, spiritual support, emotional support and practical support. Findings also portray the role of the pastoral care worker as spiritual guide, confidante, and emotional and practical supporter acting within a trusting relationship. Future studies should confirm these results by exploring the perceptions of experts in the field of pastoral care. PMID- 21692593 TI - Establishing the Eden AlternativeTM in Australia and New Zealand. AB - The Eden AlternativeTM is a philosophy of personal, organisational and environmental transformation founded by Dr. William Thomas, a Harvard trained geriatrician. He wanted to create a living environment in existing aged care institutions to eliminate loneliness, helplessness and boredom from the lives of residents, which he argued were the plagues of ageing that account for the bulk of their suffering. The Eden AlternativeTM is a contemporary approach to long term care, designed to combat these plagues of ageing, by incorporating companionship, a sense of purpose, variety and spontaneity into the day-to-day experience of aged care residents. Creating a warm, loving and caring 'home' that enriches the lives of all who live and work in it, is the overarching goal of The Eden AlternativeTM. The locus of decision-making is with the resident, which ensures the right of each resident to a life worth living. This exemplar outlines the inception and growth of The Eden AlternativeTM in Australia and New Zealand. PMID- 21692594 TI - The lived experience of perimenopause and menopause. AB - Menopause is a universal life experience, and yet there is a paucity of qualitative research giving voice to women who actually live this important life transition. Historically, menopause has been conceived as a pathological condition, and therefore, medicalized by healthcare providers. The purpose of the study was to give voice to the menopausal experiences of women. The research question was: What has your experience been with perimenopause and/or menopause? Thirteen women, meeting inclusion criteria and obtained through snowball effect, were interviewed. Data were collected through semi-structured interviews and drawings. The women interviewed repeatedly had questions and concerns regarding perimenopause, and often reported receiving conflicting and confusing information. The transition theory (Meleis, 2010) was used to understand the thematic results. Three major themes emerged: My Body, Sharing with Others: Not My Mother and Going on with Life. PMID- 21692595 TI - Interpersonal challenges as a constraint on care: the experience of nurses' care of patients who use illicit drugs. AB - Men and women who use illicit drugs have a heavy reliance on health care in emergency departments and acute care wards. Nurses' care however, is known to be constrained by inadequate drug education and policy and practice standards. This paper describes an additional constraint on care, namely, patients' behaviour. The findings are part of a broader mixed-methods study of nurses' therapeutic attitude to this patient group. The themes of violence, manipulation and irresponsibility emerged from the data analysis of written reports provided by a sub-sample (N = 311) of the main study sample. Recommendations are made for assisting nurses to reconceptualise their role with this patient group, and importantly, for an increase in violence management education and organisational role support, safety and security measures. Finally, further research in the field is recommended so that a comprehensive analysis of the difficulties faced by nurses and patients can be made. PMID- 21692596 TI - Evaluation of the organisation and delivery of patient-centred acute nursing care. AB - The key driver for this study arose from two serious untoward incidents that occurred in a large district general hospital in the United Kingdom. Following investigation of both these events the Director of Nursing in post at that time believed that poor organisation and delivery of care may have been a contributory factor. This paper reports the findings on one phase of a multi-phase study and focuses upon the perceptions and experiences of the hospital staff around the organisation and delivery of patient-centred acute nursing care. Although we saw little evidence of multi-disciplinary approaches to care, it was evident that the issue which had the biggest impact upon both the organisation and delivery of care was staffing levels. PMID- 21692597 TI - The god within. AB - This is a new feature of Substance Use and Misuse that the editors hope will bring a new focus on substance use and misuse throughout history and in diverse cultures. Up until modern times, cultures throughout history have associated different substances with specific deities, incorporated them into specific myths, and used substances in specific rituals. Examining these associations is likely to give insight into how these substances were viewed in various cultures and the place that they had in those cultures. Consequently, we offer this new feature exploring these associations as a way of increasing understanding of the functions of substance use in different cultures over historical time. PMID- 21692598 TI - Undifferentiated gonadal tissue, Y chromosome instability, and tumors in XY gonadal dysgenesis. AB - Patients with XY gonadal dysgenesis are at increased risk of developing gonadal tumors. The etiology of several cases of XY gonadal dysgenesis remains unknown, but X/XY gonadal mosaicism has been hypothesized to play a role. At the histologic level, the presence of persistent primitive sex cords containing immature germ cells in dysgenetic gonads (an entity called undifferentiated gonadal tissue, or UGT) was recently described, and these immature germ cells are thought to be at risk of neoplastic transformation. To further investigate both these aspects, we retrospectively studied the gonads from 30 patients with pure (22) and mixed (8) gonadal dysgenesis. Cytogenetic analyses performed on 35 gonads revealed that structurally abnormal Y chromosomes were lost in a majority of cells from the gonads, explaining the gonadal dysgenesis of patients bearing a rearranged Y chromosome. On the other hand, normal Y chromosomes were less often lost in gonads of patients with gonadal dysgenesis. At the histologic level, 43 of the 51 gonads presented areas characteristic of a streak; 13 of these streak gonads also presented areas of UGT. Structures resembling sex cords but without germ cells were found in many of the streaks not containing UGT, suggesting that UGT was initially present. Of the 13 gonads containing both UGT and a streak, 9 developed a tumor. The proximity of UGT with the tumors as well as the immunostaining patterns (PLAP+, OCT3/4+, and CD117/KIT+) suggests that germ cells found in UGT are a risk factor for gonadal tumors. PMID- 21692599 TI - Osiris of bread and beer. PMID- 21692600 TI - Drug-related deaths in France in 2007: estimates and implications. AB - Compared with other European countries, France's low number of drug use-related deaths may appear enviable. Previous studies have suggested significant underreporting. The three official records listing drug-related deaths in France in 2007 were cross-checked. Different capture-recapture techniques were applied. The estimated numbers of drug-related deaths differ from the official figures. Different explanations and proposals to improve the recordings are consequently discussed. However, there are doubts as to the reliability of at least one of the records and the consequent accuracy of the proportion of overlapping cases. Estimates should be handled with caution and interpreted as upper bounds. PMID- 21692601 TI - Effect of ticagrelor on the pharmacokinetics of ethinyl oestradiol and levonorgestrel in healthy volunteers. AB - BACKGROUND: Cytochrome P450 3 A is involved in ticagrelor and ethinyl oestradiol/levonorgestrel metabolism; so a potential drug-drug interaction may occur. OBJECTIVES: To assess: ticagrelor effects on ethinyl oestradiol/levonorgestrel pharmacokinetics, endogenous sex hormone levels; ethinyl oestradiol/levonorgestrel effects on ticagrelor pharmacokinetics; tolerability of ticagrelor + ethinyl oestradiol/levonorgestrel. METHODS: This trial was a randomized, double-blind, two-way crossover, single-center study. Twenty-two healthy female volunteers (on stable ethinyl oestradiol/levonorgestrel) received 90 mg ticagrelor or placebo twice daily with ethinyl oestradiol/levonorgestrel (0.03 mg/0.15 mg; Nordette) on cycle days 1-21. Volunteers crossed over treatment on day 1/cycle 2. Pharmacokinetic parameters were evaluated on cycle day 21, and endogenous hormones assayed on cycle days 1, 7, 14 and 21. CLINICAL TRIAL REGISTRATION NUMBER: NCT006895906. RESULTS: Ethinyl oestradiol absorption was rapid (median t(max) approximately 1 hour), and was not affected by ticagrelor. Ticagrelor co-administration (90% confidence interval [CI]) increased AUC(0-tau), C(min), and C(max) of ethinyl oestradiol by 20% (1.03 1.40), 20% (0.96-1.50) and 31% (1.18-1.44), respectively. Ticagrelor had no effect on levonorgestrel pharmacokinetic parameters versus placebo (90% CI: AUC(0 tau) 0.97-1.10; C(min) 0.94-1.10; C(max) 1.02-1.16). Steady-state ticagrelor, and AR-C124910XX (major and equally pharmacologically active metabolite), AUC(0-tau), C(max), and t(max) were comparable with published findings. Pre-dose ticagrelor and AR-C124910XX plasma concentrations were higher on cycle day 21 versus days 7 and 14. Endogenous sex hormone plasma levels were unaffected by ticagrelor. Co administration of ticagrelor with ethinyl oestradiol/levonorgestrel was well tolerated. Study limitations included: no ticagrelor-only arm; only one type of oral contraceptive; short study duration; using oestradiol/levonorgestrel pharmacokinetic parameters as surrogate marker for contraceptive efficacy. CONCLUSIONS: Ticagrelor co-administration with ethinyl oestradiol/levonorgestrel increased ethinyl oestradiol exposure by approximately 20%, with no effect on levonorgestrel pharmacokinetics. No clinically relevant effect on contraceptive efficacy is expected with ethinyl oestradiol/levonorgestrel and ticagrelor co administration. PMID- 21692602 TI - Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review. AB - OBJECTIVES: Tuberous sclerosis complex (TSC) is a progressive genetic disorder characterized by pervasive benign tumor growth. We sought to assess the current understanding of burden of TSC-related neurological manifestations. METHODS: We systematically searched MEDLINE- and EMBASE-indexed, English-language literature (5/2000-5/2010) and non-indexed materials. RESULTS: In total, 119 articles were included, 115 on epidemiology and treatment. Recent prevalence estimates from Ireland and Taiwan report TSC in 1:14,000-25,000 individuals, below older estimates of 1:10,000. While neurological manifestations are common, treatment is largely unaddressed by guidelines and focuses on symptoms, with resection standard for subependymal giant cell astrocytomas (SEGAs) and common practice for refractory epilepsy. Antiepileptic drugs and mammalian target of rapamycin inhibitors safely, effectively minimize the need for surgery for severe epilepsy and SEGAs. CONCLUSION: Morbidity and treatment burden of prevalent neurological manifestations is significant, suggesting substantial economic and humanistic burden; however, these areas are poorly studied, indicating total disease burden is unknown. Future research should assess quality of life, caregiver burden, and costs. PMID- 21692603 TI - Drug use as boundary play: a qualitative exploration of gay circuit parties. AB - Research findings have revealed that gay circuit parties may be locations that are disproportionately responsible for the increasing rates of many STIs/HIV among gay/bisexual men. Theories have been put forth that this may be the case because circuit parties are locales of prevalent drug use and unsafe sex. To explore the relationship between these two phenomena, in-depth qualitative interviews were undertaken with 17 men who (1) have sex with other men, (2) attended gay circuit parties in Montreal, Canada, in 2007. These revealed that drugs (including alcohol) were used intentionally to engage in unsafe sex, and then to justify this behavior after the fact. This process we called boundary play. PMID- 21692604 TI - Contextual determinants of alcohol consumption changes and preventive alcohol policies: a 12-country European study in progress. AB - Beginning with France in the 1950s, alcohol consumption has decreased in Southern European countries with few or no preventive alcohol policy measures being implemented, while alcohol consumption has been increasing in Northern European countries where historically more restrictive alcohol control policies were in place, even though more recently they were loosened. At the same time, Central and Eastern Europe have shown an intermediate behavior. We propose that country specific changes in alcohol consumption between 1960 and 2008 are explained by a combination of a number of factors: (1) preventive alcohol policies and (2) social, cultural, economic, and demographic determinants. This article describes the methodology of a research study designed to understand the complex interactions that have occurred throughout Europe over the past five decades. These include changes in alcohol consumption, drinking patterns and alcohol related harm, and the actual determinants of such changes. PMID- 21692605 TI - Impact of initiation timing of SSRI or SNRI on depressed adolescent healthcare utilization and costs. AB - BACKGROUND: Adolescents with newly diagnosed depression may not receive timely antidepressant therapy. Clinical and economic effects of early versus late treatment initiation are unclear. OBJECTIVE: To compare effects of early versus late initiation of second-generation (SSRI/SNRI) antidepressants on emergency room (ER) visits, hospitalizations and healthcare costs in adolescents with depression. METHODS: Patients aged 12-17 with a diagnosis of depression were identified in a claims database (1999-2007). Patients initiating antidepressants within 1 month of initial diagnosis were considered early initiators; patients initiating within 2-12 months were late initiators. Clinical resource use and healthcare costs were measured during the 6-month pre-index and 12-month post index (study) periods and compared descriptively between groups. Logistic regression compared healthcare services utilization; a generalized linear model compared costs. All models were adjusted for baseline characteristics, including demographics, comorbidities, and healthcare services utilization. RESULTS: A total of 7344 adolescents met study criteria. 4415 (60%) initiated antidepressant treatment within 1 month of diagnosis. At baseline, early initiators had more all cause inpatient visits (14 vs. 7%) and all-cause ER visits than late initiators (25 vs. 21%, both p<0.01). They had higher medical ($1434 vs. $1160) and total costs ($1565 vs. $1290) (both p<0.01). In the study period, late initiators had higher risk of ER visits (OR=1.13, p=0.03). They incurred higher medical costs ($5415 vs. $4061) and higher total healthcare costs ($6001 vs. $4907), but lower adjusted drug costs ($767 vs. $888) (all p<0.01). LIMITATIONS: Clinical data are scarce in the claims database, and the ability to observe disease severity and reasons for delayed treatment is limited. The definition of early and late initiation was based on empirical analysis, and no clear cutoff was identified beyond what was observed in the data. CONCLUSIONS: Adolescents who initiated SSRI/SNRI therapy earlier experienced lower risk of ER visits and had lower total costs compared to late initiators. PMID- 21692606 TI - Mirtazapine induced mania in a woman with major depression in the absence of features of bipolarity. PMID- 21692607 TI - Combination antidepressants in Australia: a right or wrong? PMID- 21692608 TI - Role of common genetic variants on the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis. PMID- 21692610 TI - Combined CYP2C9, VKORC1 and CYP4F2 frequencies among Amerindians, Mozambicans and Brazilians. PMID- 21692611 TI - Research highlights. SNPs affecting efficacy and safety of statin therapy. PMID- 21692612 TI - Conference scene: Progressing biomarkers from basic discovery to companion diagnostics. PMID- 21692614 TI - Pharmacogenetics and individualized therapy in children: immunosuppressants, antidepressants, anticancer and anti-inflammatory drugs. AB - Pharmacogenetic polymorphisms that change the amino acid sequences in coding regions only account for part of the interindividual differences in disease susceptibility and drug response. Additional pharmacogenomic and epigenetic factors are also involved. In children, pharmacogenetic studies are limited, although it has been clear for many years that the interactions between developmental patterns of drug-metabolizing enzymes and transporters have a major impact on dose exposure with age-specific dosage requirements. This article will analyze the factors affecting variability in drug response in children and focus on the pharmacogenetic polymorphisms of immunosuppressants, antidepressants, anticancer and anti-inflammatory drugs. Additional pharmacogenetic and epigenetic studies should be performed to allow the individualization of therapy in children. PMID- 21692615 TI - DNA amplification techniques in pharmacogenomics. AB - The variable predisposition of patients, both to disease susceptibility and drug response, is well established. It is largely attributed to genetic, as well as epigenetic variations between individuals, which may be inherited or acquired. The most common variation in the human genome is the SNP, which occurs throughout the genome, both within coding and noncoding regions. Characterization of SNPs in the context of both inherited and acquired conditions, such as cancer, are a main focus of many genotyping procedures. The demand for identifying (diagnosing) targeted SNPs or other variations, as well as the application of genome-wide screens, is continuously directing the development of new technologies. In general, most methods require a DNA amplification step to provide the amounts of DNA needed for the SNP detection step. In addition, DNA amplification is an important step when investigating other types of genomic information, for instance when addressing repeat, deletion, copy number variation or epigenetic regulation by DNA methylation. Besides the widely used PCR technique, there are several alternative approaches for genomic DNA amplification suitable for supporting the detection of genomic variation. In this article, we describe and evaluate a number of techniques, and discuss possible future prospects of DNA amplification in the fields of pharmacogenetics and pharmacogenomics. PMID- 21692613 TI - A pragmatic randomized controlled trial of thiopurine methyltransferase genotyping prior to azathioprine treatment: the TARGET study. AB - AIM: To conduct a pragmatic, randomized controlled trial to assess whether thiopurine methyltransferase (TPMT) genotyping prior to azathioprine reduces adverse drug reactions (ADRs). METHODS: A total of 333 participants were randomized 1:1 to undergo TPMT genotyping prior to azathioprine or to commence treatment without genotyping. RESULTS: There was no difference in the primary outcome of stopping azathioprine due to an adverse reaction (ADR, p = 0.59) between the two study arms. ADRs were more common in older patients (p = 0.01). There was no increase in stopping azathioprine due to ADRs in TPMT heterozygotes compared with wild-type individuals. The single individual with TPMT variant homozygosity experienced severe neutropenia. CONCLUSION: Our work supports the strong evidence that individuals with TPMT variant homozygosity are at high risk of severe neutropenia, whereas TPMT heterozygotes are not at increased risk of ADRs at standard doses of azathioprine. PMID- 21692616 TI - Pharmacogenomics of the triazole antifungal agent voriconazole. AB - Genetic polymorphisms in drug-metabolizing enzymes are frequently responsible for high variability in the pharmacokinetics of certain drugs leading to large variations in drug efficacy and adverse drug effects, or large ranges of the doses required for optimal drug efficacy. Voriconazole is a triazole antifungal agent which has been available for several years and has potent in vitro and in vivo activity against a broad spectrum of medically important pathogens, including Aspergillus, Cryptococcus and Candida. Voriconazole is extensively metabolized by the cytochrome P450 system with CYP2C19 being the major route for elimination. Thus, polymorphisms in the CYP2C19 gene have substantial impact on the pharmacokinetics of voriconazole and its interactions with other drugs. This article summarizes the current knowledge regarding CYP2C19 and discusses the influences of other drug-metabolizing enzymes and drug transporters on voriconazole disposition. PMID- 21692617 TI - Update on the pharmacogenomics of proton pump inhibitors. AB - Proton pump inhibitors (PPIs) are widely used for the treatment of gastroesophageal reflux disease as well as other acid-related disorders. PPIs are metabolized primarily via the CYP2C19 and CYP3A4 isoenzymes; their activity is influenced both by exogenous and endogenous (pharmacogenetic) factors. The CYP2C19 polymorphism affects the metabolism of PPIs, causing large individual pharmacokinetic variations. Differences in the CYP2C19-mediated metabolism can produce marked interpatient variability in acid suppression, in drug-interaction potential and in clinical efficacy. Understanding the pharmacokinetic properties of PPIs and examining the pharmacogenetic alterations may help clinicians optimize PPI therapy and administer individual treatment, especially to nonresponder patients with gastroesophageal reflux disease or ulcer or after failed eradication therapy. PMID- 21692618 TI - Ethical considerations for pharmacogenomic testing in pediatric clinical care and research. AB - The information gained from pharmacogenomic testing is becoming increasingly recognized as an opportunity to improve our current dosing strategies for children. The identification of gene polymorphisms that influence drug disposition and effect can be used to help predict a child's susceptibility to toxicity and/or response to a particular drug or therapeutic regimen. However, the potential consequences of performing genomic analysis in children raise important ethical considerations. Although the level of risk introduced remains partially hypothetical, awareness of the ethical concerns and protective legislation will be an important part of fully informing patients, families, clinicians, and researchers about the risks and benefits of pharmacogenomic testing in children. Where it can be done without loss of benefit, risk reduction is a moral imperative, and so the ethical complexities related to pharmacogenomics must be addressed in an ongoing way as we continue to learn more about the value of the technology to children. PMID- 21692619 TI - Pharmacogenetics and rational drug use around the world. AB - The WHO embraces evidence-based medicine to formulate an essential medicines list (EML) considering disease prevalence, drug efficacy, drug safety and cost effectiveness. The EML is used by developing countries to build a national formulary. As pharmacogenetics in developed countries evolves, the Pharmacogenetics for Every Nation Initiative (PGENI) convened with representatives from China, Mexico, Ghana and South Africa in August 2009 to evaluate the use of human pharmacogenetics to enhance global drug use policy. The diseases causing mortality, the lack of integration of pharmacovigilance at the national formulary level, the pharmacogenetics research agenda and pharmacogenetics clinician education did not differ greatly among the countries. While there are many unanswered questions, systematically incorporating pharmacogenetics at the national formulary level promises to improve global drug use. PMID- 21692620 TI - Human lymphoblastoid cell lines: a goldmine for the biobankomics era. AB - Biobanking became a necessity for translating genetic discoveries into clinical practice. Approaches to personalized medicine require a new model system for functional and pharmacogenomic studies of a variety of accumulating genetic variations, as well as new research environments such as biobankomics. Human lymphoblastoid cell lines (LCLs) will provide a valuable tool to meet such new demands in the biobankomics era. The National Biobank of Korea (NBK), which is leading the Korea Biobank Project, has a large collection of LCLs derived mostly from population-based cohort samples. Using a special long-term subculture collection of NBK LCLs, biological characteristics of early passage LCLs and terminally immortalized LCLs have been investigated to promote the utilization of LCLs and provide well quality-controlled LCLs for genetic and pharmacogenomic studies. As LCLs have been successfully phenotyped for cytotoxicity in response to various stimulators, including chemotherapeutic agents, environmental chemicals and irradiation, the utility of LCLs will increase in the future. Here, we discuss current and future applications of NBK LCLs for the biobankomics era. PMID- 21692622 TI - Urinary incontinence in a community sample of older adults: prevalence and impact on quality of life. AB - PURPOSE: To measure the prevalence of urinary incontinence (UI) in a community dwelling sample and the impact of self-reported UI on well-being and activity in older men and women. METHOD: Participants were older adults aged >=65 years. Measures included the frequency of urgency incontinence, depression, positive and negative affect and social activity, independence in activities of daily living (IADL) and self-rated health. The data were collected by face to face interview (1994) and computer assisted telephone interviews (1996). RESULTS: Of the 796 participants, 28% experienced urgency incontinence and 21% reported stress incontinence occasionally or often, with higher rates among women. The threshold for the impact on depression, negative affect and IADL was with occasional occurrence of urinary urgency incontinence. For positive affect and self-rated health, the threshold was experiencing urinary urgency incontinence often. The presence of urinary stress incontinence was associated with depression, IADL dependence, self-rated health and positive affect. Overall, women with incontinence had higher negative affect scores, but men with stress incontinence had higher scores than those without. CONCLUSIONS: The impact of incontinence highlights the need for more effective management of the condition. The threshold for the effects of urinary urgency incontinence on mental health and functionality is lower than for the effects on general health. There is a need to consider how older people judge the impact of UI in the design of targeted health promotion programmes. PMID- 21692625 TI - Evaluation of periodontal status and effectiveness of non-surgical treatment in patients with type 2 diabetes mellitus in Taiwan for a 1-year period. AB - BACKGROUND: The periodontal status and effects of non-surgical periodontal treatment in patients with type 2 diabetes mellitus and periodontal disease are assessed. METHODS: One-hundred patients with type 2 diabetes (mean +/- SD hemoglobin (Hb)A1c level: 7.3% +/- 0.94%) and periodontal disease were recruited for this study. The group with moderate-to-severe periodontal disease included patients with >1 tooth with a probing depth (PD) >=5 mm and >2 teeth with a clinical attachment loss (AL) >= 6mm, and the group with mild periodontal disease included patients with <1 affected tooth, and >2 affected with a clinical AL >= 6mm. Patients (28 patients in the mild group and 72 patients in the moderate-to severe group) underwent non-surgical periodontal treatments. We analyzed differences in serum concentrations of metabolic parameters (glycated hemoglobin and low-density lipoprotein), inflammatory parameters (interleukin [IL]-1beta and C-reactive protein [CRP]), and periodontal parameters between the two groups before treatment and at 3, 6, 9, and 12 months post-therapy. RESULTS: Seventy five patients with diabetes (21 patients in the mild group and 54 patients in the moderate-to-severe group) completed the study. Significant differences in the plaque index (PI), gingival index (GI), PD, and clinical AL at examination times were observed in the whole cohort (P <0.05). We observed significant differences in the PI, GI, and PD in the moderate-to-severe group (P <0.05), whereas there was only a significant difference in PD in the mild group (P <0.05) between baseline and 12 months post-treatment. Both groups experienced improved glycemic control, but the difference was insignificant. CRP and IL-1beta levels were significantly different at examination times for the whole cohort (P <0.05). No significant positive association among metabolic and inflammatory parameters at 12 months post-therapy were found. CONCLUSION: Non-surgical periodontal treatment improved and maintained the periodontal health of patients with well-controlled diabetes, but no significant reduction of metabolic parameters was observed over a 1-year period. PMID- 21692626 TI - Periodontal risk assessment model in a sample of regular and irregular compliers under maintenance therapy: a 3-year prospective study. AB - BACKGROUND: The purpose of this study is to investigate the association of the periodontal risk assessment (PRA) model with the recurrence of periodontitis and tooth loss during periodontal maintenance therapy (PMT). METHODS: In a prospective PMT program, 75 regular complier (RC) and 89 erratic complier (EC) patients were selected. A periodontal examination and PRA were performed after active periodontal therapy and after 3 years of PMT. Risk profiles (low, moderate, or high) of participants were evaluated, and the recurrence of periodontitis and tooth loss were analyzed using univariate and multivariate analyses. RESULTS: RCs showed less recurrence of periodontitis and tooth loss than ECs (P <0.05). Rates of periodontitis recurrence in RCs and ECs were 2.7% and 3.4%, respectively, for the moderate-risk profile and 6.7% and 11.2%, respectively, for the high-risk profile. During PMT, 49 teeth (0.65 +/- 1.4 teeth per participant) were lost in the RC group, and 70 teeth (0.78 +/- 2.1 teeth per participant) were lost in the EC group. High-risk profile participants showed more recurrence of periodontitis and lost significantly more teeth than did participants with moderate- or low-risk profiles in RC and EC groups (P <0.05). CONCLUSION: The risk profile influenced the recurrence of periodontitis and tooth loss. RCs had less recurrence of periodontitis and less tooth loss. The PRA model can be useful in particularizing the risk of patients and adjusting recall intervals. PMID- 21692627 TI - The thickness of facial alveolar bone overlying healthy maxillary anterior teeth. AB - BACKGROUND: A facial bone (<2 mm) overlying maxillary anterior teeth may be prone to resorptive processes after extraction and immediate implant placement. A thin bone contributes to risk of bone fenestration, dehiscence, and soft-tissue recession. This study measures the distance between the cemento-enamel junction (CEJ) and alveolar bone crest and the thickness of facial alveolar bone at points 1 to 5 mm from the bone crest for the six maxillary anterior teeth. METHODS: Sixty-six tomographic scans (31 males and 35 females; aged 17 to 69 years; mean age: 39.9 years) of intact anterior maxilla were randomly selected and evaluated by two calibrated and independent examiners (MG and TP). RESULTS: A high variation of CEJ-bone crest (0.8 to 7.2 mm) was detected. A significantly larger CEJ-bone crest was measured in smokers (P <0.05) and patients who were >=50 years old (P <0.05). The average bone thickness at 3 mm from the CEJ for the maxillary right central incisor was 1.41 mm and for the maxillary left central incisor was 1.45 mm. For the maxillary right and left lateral incisors, the crestal bone thickness averaged 1.73 and 1.59 mm, respectively. For the maxillary right and left canines, the crestal bone thickness averaged 1.47 and 1.60 mm, respectively. CONCLUSIONS: The present study supports the finding of a predominantly thin facial bone overlying the six maxillary anterior teeth. Therefore, it is essential to make informed treatment decisions based on thorough site evaluation before immediate implant placement. PMID- 21692628 TI - Microcomputed tomographic and histologic analysis of animal experimental degree II furcation defects treated with porous titanium granules or deproteinized bovine bone. AB - BACKGROUND: Titanium is an interesting material for osseous reconstruction given its thrombogenic properties. The aim of this study is to compare the potential of porous titanium granules (PTGs) with sham and deproteinized bovine bone mineral (DBBM) in the reconstructive treatment of surgically created buccal, degree II furcation defects in mini-pigs. METHODS: Buccal degree II furcation defects were surgically created in maxillary premolar teeth in adult, female, mini-pigs and filled with PTG or DBBM or were left empty (sham). After 6 weeks of healing, pigs were euthanized. Teeth with defects were excised en bloc and analyzed by microcomputed tomography (microCT) and histology. RESULTS: The histologic analysis showed significantly more vertical bone formation in both PTG and sham groups compared to DBBM-treated defects (P <0.01). The microCT analysis showed significantly more bucco-palatal bone formation in furcations treated with PTG compared to the DBBM and sham (P <0.05). Bucco-palatal cylindrical microCT cores demonstrated a median defect fill of 96.8% for PTG-implanted defects, which was significantly greater than sham (72.2%) and DBBM (62.0%) (P <0.001) treatments. Significantly more regenerated periodontal ligament was seen for sham than DBBM treated defects (P <0.05). Root resorption lacunae were small and infrequent and did not differ among groups. CONCLUSIONS: The results of this study in mini-pigs suggest that PTG may integrate well in alveolar bone and supports osseous regrowth in degree II furcation defects. Moreover, PTG seems safe to use in close proximity to root surfaces. Clinical studies will be necessary to further explore these experimental animal findings. PMID- 21692629 TI - Effect of early orthodontic force on periodontal healing after autotransplantation of permanent incisors in beagle dogs. AB - BACKGROUND: Masticatory stimulation during the healing period may promote periodontal ligament healing. The aim of the present study is to investigate the effect of orthodontic force on the periodontal healing of autotransplanted teeth. METHODS: A total of 30 teeth from four dogs were endodontically treated to prevent subsequent inflammatory root resorption. The teeth were atraumatically extracted and autotransplanted to the other side of the same jaw. A continuous 50 g orthodontic force was applied during the first, second, and fourth weeks after autotransplantation. After 8 weeks, the animals were sacrificed using vital perfusion fixation, and the teeth were histologically prepared and evaluated following the Andreasen method. RESULTS: The application of force in the first, second, and fourth weeks after autotransplantation resulted in a lower occurrence of ankylosis. The first- and second-week loading groups differed significantly from the control group (P <0.05); however, significantly more resorption and less complete healing were observed in the first-week loading group than in the other groups (P <0.05). CONCLUSION: The results of this study demonstrate that orthodontic force promotes periodontal ligament healing and that early force loading may prevent dentoalveolar ankylosis; however, a period of rest of >=2 weeks is recommended for the autotransplants before loading. PMID- 21692630 TI - Cervical enamel projections and associated pouch-like opening in mandibular furcations. AB - BACKGROUND: Cervical enamel projections (CEPs) have been listed among the tooth associated risk factors that could lead to isolated furcation defects around molar teeth. This is more likely when Grade III CEPs are present. However, the histologic aspects of the CEP interface with regard to the presence or absence of cementum over the enamel projection within the furcation have not been well described. This study was initially undertaken to evaluate this relationship. METHODS: Thirty-five mandibular molars with Grade III CEPs were selected from a collection of extracted teeth and evaluated for the presence of cementum covering these areas by stereomicroscopy, light microscopy, and scanning electron microscopy (SEM). RESULTS: Sixteen of the 35 teeth (45.7%) with Grade III CEPs appeared completely covered by cementum. SEM evaluation showed the presence of a narrow pouch-like opening between cementum and enamel in 15 of 16 teeth (93.8%). Light microscopy evaluation confirmed the presence of the pouch along with some indication of residual degenerated mesenchymal tissue within the defects. SEM evaluation showed the presence of globular bodies in this pouch. CONCLUSIONS: This study reports on the presence of a pouch-like opening between the enamel and cementum in mandibular molars with Grade III CEPs. The clinical significance of these cementum pouches has yet to be determined but bacterial contamination of these pouch-like structures in areas of furcation periodontal breakdown may serve as a nidus for recolonization and disease recurrence or for the development of furcation caries if exposed to the oral cavity after surgical procedures. PMID- 21692631 TI - A novel organotypic dento-epithelial culture model: effect of Fusobacterium nucleatum biofilm on B-defensin-2, -3, and LL-37 expression. AB - BACKGROUND: In the present study, the expression and localization of three epithelial peptides (human beta-defensin [hBD]-2 and -3, and cathelicidin [LL 37]) are studied in an organotypic dento-epithelial (OD-E) model exposed to Fusobacterium nucleatum (Fn) biofilm. METHODS: Biofilm of Fn ATCC 25586 or AHN 9508 were produced by culturing each strain on semipermeable membranes. The OD-E model was constructed by seeding keratinocytes on fibroblast-containing collagen gels and by placing dentin pieces on the top. A 3-day-old biofilm was placed on the top of the OD-E and the coculture was incubated for 5 hours or 24 hours. Production of epithelial antimicrobial peptides was determined immunohistochemically. RESULTS: After 5 hours of incubation, the biofilm of each Fn strain stimulated expression of hBD-2 and -3. hBD-2 was localized on superficial layers and hBD-3 on basal cell layers of the epithelium and dento epithelial junctions, whereas LL-37 was only weakly expressed. After 24 hours, hBD-2 expression was extended toward basal cell layers of the epithelium. In contrast, hBD-3 expression extended toward superficial layers of the epithelium. In the case of Fn AHN 9508 biofilm, LL-37 was localized in the cell layers of the dento-epithelial junction. CONCLUSION: In our OD-E model, epithelial antimicrobial peptide responses to Fn biofilms have distinct regulation and localization characteristics, resembling those known to occur in the gingival epithelium in vivo. PMID- 21692632 TI - Immunohistochemical analysis of CD45RO+ T cells and vascular endothelial growth factor expression in cyclosporin A-induced rat gingival tissue. AB - BACKGROUND: The aim of this study is to evaluate CD4(+), CD8(+), and CD45RO(+) T cells, and vascular endothelial growth factor (VEGF) expression in cyclosporin A (CsA)-induced rat overgrown gingival tissue during an 8-week period. METHODS: Sixty male Sprague-Dawley rats weighing 200 to 250 g were used in this study. Mandibular first molars were ligated with 3-0 silk suture. The rats received daily doses of 0.09% NaCl (control group) or 10 mg/kg body weight of CsA (test group) by intraperitoneal injections. Five rats from the control group and 10 rats from the test group were sacrificed at each experimental period (2, 4, 6, and 8 weeks after the beginning of CsA treatment). The specimens were examined immunohistochemically. RESULTS: CD4(+), CD8(+), and CD45RO(+) T cells, and VEGF expression were more prevalent in the CsA-treated group than in the control group (P <0.05). VEGF was significantly correlated with CD4(+) T cells, CD4(+)/CD8(+) ratio, and CD45RO(+) cells (P <0.05). CONCLUSION: Based on our findings, we conclude that VEGF, a major regulator of angiogenesis, and CD4(+), CD8(+), and CD45RO(+) memory T cells play a key role in CsA-induced gingival overgrowth. PMID- 21692633 TI - Histologic comparison of healing after ridge preservation using human demineralized bone matrix putty with one versus two different-sized bone particles. AB - BACKGROUND: Ridge preservation can minimize the loss of alveolar bone subsequent to tooth extraction in preparation for implant therapy. The purpose of this study is to histologically and clinically compare human demineralized bone matrix (DBM) putty with one size of bone particles (SPS) to human DBM putty with two different sizes of bone particles (multiple particle sizes [MPS]) in ridge preservation after molar extractions. METHODS: Molar tooth extraction and ridge preservation were performed in 20 participants for each treatment group. Approximately 20 weeks after grafting, core biopsies were obtained during implant placement and analyzed under light microscopy. Specimens were analyzed for the percentage area of vital bone, residual graft particles, and non-mineralized structures (connective tissue/other non-mineralized tissue [CT]). Changes in alveolar ridge dimensions were also determined. RESULTS: Sixteen participants in the SPS group and 14 in the MPS group completed the study. The SPS group had a mean of 49% vital bone, 8% residual graft, and 43% CT. The MPS group had 53%, 5%, and 42%, respectively. Patients in both groups lost a mean of <1 mm alveolar height on the buccal and lingual aspects and <1.5 mm of total ridge width. There were no statistically significant differences between the two groups for any clinical or histologic parameters. CONCLUSION: The results of this study suggest that addition of larger bone particles to DBM putty does not offer additional benefit in the preservation of alveolar bone after the extraction of molar teeth. PMID- 21692634 TI - Cytokine profile in the gingival crevicular fluid of periodontitis patients with and without type 2 diabetes: a literature review. AB - BACKGROUND: Periodontitis may occur in patients with and without type 2 diabetes (T2D). It may be hypothesized that the gingival crevicular fluid (GCF) cytokine profile in patients with periodontitis with poorly controlled T2D may differ from the GCF cytokine profile in medically healthy individuals with periodontitis. The aim was to review the cytokine profiles in the GCF of patients with periodontitis with and without T2D. METHODS: Databases were searched from 1988 to August 2011 using different combinations of various keywords. Titles and abstracts of articles that satisfied the eligibility criteria were screened by the authors and checked for agreement. Only articles published in English were included. RESULTS: Ten studies were included. Two studies reported GCF concentrations of interleukin (IL)-6 to be higher in patients with periodontitis with T2D compared to medically healthy patients with periodontitis. Two studies showed GCF IL-6 levels to be higher in periodontitis with T2D compared to medically healthy subjects without periodontitis. In one study GCF levels of IL-17, IL-23, and interferon-gamma were higher in patients with periodontitis with T2D compared to medically healthy patients with periodontitis. In one study, GCF concentrations of IL-8 were significantly higher in patients with periodontitis with T2D compared to medically healthy individuals with periodontitis. Three studies reported GCF levels of IL-1alpha to be significantly higher in patients with periodontitis with T2D compared to medically healthy individuals with periodontitis. CONCLUSION: The GCF cytokine profile in patients with and without T2D seems to be governed by the intensity of periodontal inflammation and the role of T2D in this regard is rather secondary. PMID- 21692635 TI - TNF receptors in Kupffer cells. AB - INTRODUCTION: Somatostatin is a mediator of immune functions and has been used as an antineoplastic agent in animal models and human neoplasias. We have demonstrated that Octreotide inhibits only LPS induced secretion of proinflammatory cytokines including TNFa by Kupffer cells (KC). We, therefore, tested the hypothesis that somatostatin modulates the expression of tumor necrosis factor alpha (TNF?) receptors and apoptosis of KC. METHODS: Rat KC were isolated by centrifugal elutriation. TNFR1 and TNFR2 expression was studied by RT PCR, quantitative PCR, Western Blot and immunofluorescence before and after Octreotide pre-incubation. Apoptosis was assessed by quantitative measurement of cytoplasmic histone-associated DNA fragments. TNFa mRNA expression was assessed by semiquantitative PCR and TNFa was measured in cell supernatants by ELISA. RESULTS: TNFR1 and TNFR2 mRNA are constitutively expressed in KC. Octreotide incubation increased both receptors expression with a peak at 6?h and return to basal levels at 24?h. TNFR1 was mostly influenced. However, only increase in TNFR2 protein was identified, whereas a band at 90 kD was present instead of a band at 55 kD as expected for TNFR1. TNF? mRNA expression was inhibited by Octreotide and a significant inhibition was observed at 48?h. TNF had no effect on KC apoptosis, whereas Octreotide significantly increased their apoptosis, and this effect was not influenced by co-incubation with TNFa. CONCLUSION: TNFR1 and TNFR2 are constitutively expressed in KC and their expression is strongly increased by somatostatin. Moreover, somatostatin increases KC apoptosis. These findings may in part explain the antineoplasmatic effect of somatostatin. PMID- 21692636 TI - Enhanced viral intergenic region-specific short interfering RNA accumulation and DNA methylation correlates with resistance against a geminivirus. AB - RNA silencing mediated by short-interfering RNA (siRNA) is used by plants as a defense against viruses. In the case of geminiviruses, viral DNA is targeted at the transcriptional level, while virus-derived transcripts are targeted by posttranscriptional silencing. Mungbean yellow mosaic India virus (MYMIV), a bipartite geminivirus, causes yellow mosaic disease in soybean (Glycine max). A soybean variety resistant to this disease has been identified (line PK416). To understand the molecular mechanism underlying this resistance, distribution of MYMIV-derived siRNAs along the viral genome was compared in resistant and susceptible plants, using samples obtained in the first few days following inoculation. We observed that, in the resistant soybean variety, most of the virus-derived siRNAs were complementary to the intergenic region (IR), while in the susceptible variety (line JS335), a majority of the siRNAs corresponded to coding regions of the viral genome. Most of the IR-specific siRNA molecules produced in the resistant plants were 24 nt in size. Bisulfite sequencing showed that, in the resistant plants, a higher level of methylation occurred in the IR of viral DNA. PMID- 21692637 TI - Identification of an operon, Pil-Chp, that controls twitching motility and virulence in Xylella fastidiosa. AB - Xylella fastidiosa is an important phytopathogenic bacterium that causes many serious plant diseases, including Pierce's disease of grapevines. Disease manifestation by X. fastidiosa is associated with the expression of several factors, including the type IV pili that are required for twitching motility. We provide evidence that an operon, named Pil-Chp, with genes homologous to those found in chemotaxis systems, regulates twitching motility. Transposon insertion into the pilL gene of the operon resulted in loss of twitching motility (pilL is homologous to cheA genes encoding kinases). The X. fastidiosa mutant maintained the type IV pili, indicating that the disrupted pilL or downstream operon genes are involved in pili function, and not biogenesis. The mutated X. fastidiosa produced less biofilm than wild-type cells, indicating that the operon contributes to biofilm formation. Finally, in planta the mutant produced delayed and less severe disease, indicating that the Pil-Chp operon contributes to the virulence of X. fastidiosa, presumably through its role in twitching motility. PMID- 21692638 TI - Medicago truncatula IPD3 is a member of the common symbiotic signaling pathway required for rhizobial and mycorrhizal symbioses. AB - Legumes form endosymbiotic associations with nitrogen-fixing bacteria and arbuscular mycorrhizal (AM) fungi which facilitate nutrient uptake. Both symbiotic interactions require a molecular signal exchange between the plant and the symbiont, and this involves a conserved symbiosis (Sym) signaling pathway. In order to identify plant genes required for intracellular accommodation of nitrogen-fixing bacteria and AM fungi, we characterized Medicago truncatula symbiotic mutants defective for rhizobial infection of nodule cells and colonization of root cells by AM hyphae. Here, we describe mutants impaired in the interacting protein of DMI3 (IPD3) gene, which has been identified earlier as an interacting partner of the calcium/calmodulin-dependent protein, a member of the Sym pathway. The ipd3 mutants are impaired in both rhizobial and mycorrhizal colonization and we show that IPD3 is necessary for appropriate Nod-factor induced gene expression. This indicates that IPD3 is a member of the common Sym pathway. We observed differences in the severity of ipd3 mutants that appear to be the result of the genetic background. This supports the hypothesis that IPD3 function is partially redundant and, thus, additional genetic components must exist that have analogous functions to IPD3. This explains why mutations in an essential component of the Sym pathway have defects at late stages of the symbiotic interactions. PMID- 21692639 TI - An inter-laboratory retrospective analysis of immunotoxicological endpoints in non-human primates: T-cell-dependent antibody responses. AB - The Immunotoxicology Technical Committee of HESI sponsored a retrospective analysis of T-cell-dependent antibody responses in non-human primates (NHP). Antibody responses to keyhole limpet hemocyanin (KLH), tetanus toxoid (TT), and/or sheep red blood cells (SRBC) in 178 NHP (from 8 sponsors, 13 testing sites, 30 studies) were statistically analyzed. Rates of positive or negative anti-KLH, -TT, and -SRBC primary and secondary IgM and IgG responses were compared. The influence of gender, country of origin, and previous immunization with a different antigen on response rate and kinetics of anti-KLH and anti-TT responses were analyzed. In addition, the magnitude of the antibody responses and the impact of the above-mentioned factors were analyzed. In addition, based upon the inter-individual variability of the peak response values, power calculations were conducted. The analysis demonstrated that the rates of positive responses were similar between the two genders, were high for KLH, SRBC, and TT challenges by 21 days following immunization (87, 100, and 84%, respectively, for IgGs) and did not include statistically significant differences based on NHP country of origin. Mean peak secondary responses were greater than peak primary responses; the magnitude of the response to KLH was increased by incomplete Freund's adjuvant (IFA). Gender had little effect on the magnitude and variability of these responses. KLH and TT were associated with similar inter-animal variability, whereas in some situations KLH responses were less variable than responses to SRBC. The data suggested that inter-animal variability with KLH was similar with or without IFA. Power analysis illustrated that animal group sizes of typical standard toxicology studies (generally <= 4/sex) are likely to detect only fairly large treatment effects. However, combining males and females, when appropriate, will improve the power: an N of 8 to 12 could detect <= 3.1-fold differences in anti-KLH IgG responses. PMID- 21692640 TI - Safety and efficacy of low-fluence, high-repetition rate versus high-fluence, low repetition rate 810-nm diode laser for permanent hair removal--a split-face comparison study. AB - BACKGROUND: This study was designed to evaluate the hypothesis that low-level fluences done repetitively on a hair follicle will produce permanent hair removal with less discomfort and fewer side effects than a single high-fluence pulse. OBJECTIVE: To compare the safety and efficacy of a low-fluence, high-repetition rate versus a high-fluence, low-repetition rate 810-nm diode laser for permanent hair reduction in patients with facial hirsutism. METHODS: Forty-two female patients with confirmed polycystic ovaries by ultrasonography with facial hirsutism were subjected to the low-fluence, high-repetition Soprano(r) XL laser in SHR mode and the LightSheerTM laser on each side of the face using preset parameters once a month for six sessions. Hair counts were done at the end of the sixth session using a 'Hi Quality Hair Analysis Program System' and the pain score was recorded by a visual analog scale. RESULTS: The overall median reduction of hair was 90.5% with the Soprano XL and 85% with the LightSheer, with a standard deviation of 7 and 8.5 respectively. DISCUSSION: This new technology, with low fluence and high repetition, showed a statistically insignificant increase in hair reduction compared to the LightSheer, but did show a significant reduction in hair thickness and a low pain score. PMID- 21692641 TI - Treatment of refractory axillary hyperhidrosis with a 1320-nm Nd:YAG laser. AB - Axillary hyperhidrosis consists of excessive underarm sweating and can be a clinical challenge for physicians and a significant social stressor for patients. A patient presented with this condition with symptoms that were resistant to traditional treatments. Subdermal 1320-nm Nd:YAG treatment resulted in a satisfactory improvement. PMID- 21692642 TI - Effective treatment of Hailey-Hailey disease with a long-pulsed (5 ms) alexandrite laser. AB - Familial benign pemphigus (Hailey-Hailey disease) is often resistant to conventional treatments. This report describes a 35-year-old Asian American male with a 12-year history of recalcitrant Hailey-Hailey disease who was treated with a long-pulsed alexandrite laser. Fluences ranged from 12 to 20 J/cm with a 5-ms pulse duration (spot sizes: 10-15 mm). Cold air cooling was used during the sessions. There was 50% improvement noted after the first treatment. Within 10 treatments, there was 95% clearance. Complete resolution was achieved by the thirteenth treatment. The lesions have been clear or nearly clear (greater than 95%) for the past 2 years. Once clearance was achieved, five maintenance laser treatments were initiated at 3-month intervals and eventually discontinued for 12 months without relapse. PMID- 21692643 TI - Distribution of Potato virus Y in potato plant organs, tissues, and cells. AB - The distribution of Potato virus Y (PVY) in the systemically infected potato (Solanum tuberosum) plants of the highly susceptible cultivar Igor was investigated. Virus presence and accumulation was analyzed in different plant organs and tissues using real-time polymerase chain reaction and transmission electron microscopy (TEM) negative staining methods. To get a complete insight into the location of viral RNA within the tissue, in situ hybridization was developed and optimized for the detection of PVY RNA at the cellular level. PVY was shown to accumulate in all studied leaf and stem tissues, in shoot tips, roots, and tubers; however, the level of virus accumulation was specific for each organ or tissue. The highest amounts of viral RNA and viral particles were found in symptomatic leaves and stem. By observing cell ultrastructure with TEM, viral cytoplasmic inclusion bodies were localized in close vicinity to the epidermis and in trichomes. Our results show that viral RNA, viral particles, and cytoplasmic inclusion bodies colocalize within the same type of cells or in close vicinity. PMID- 21692644 TI - Baseline sensitivity of natural population and resistance of mutants in Phytophthora capsici to zoxamide. AB - Laboratory experiments were conducted to determine the baseline sensitivity of Phytophthora capsici and its risk for developing resistance to zoxamide. In total, 158 P. capsici isolates were collected from China. All 158 isolates were sensitive to zoxamide, with effective concentrations for 50% inhibition of mycelial growth of 0.023 to 0.383 MUg/ml and a mean of 0.114 MUg/ml, which showed a skewed unimodal distribution. Zoxamide-resistant mutants of P. capsici were obtained by either treating mycelial culture and zoospores with ultraviolet irradiation or adapting a culture on zoxamide-amended plates. The frequency of resistance selection averaged 1.8 * 10(-7). Resistant isolates were also derived by selfing or crossing two sexually compatible isolates, resulting in a mean selection frequency of 0.47. The resistance factor (RF) for zoxamide was 25 to 100 in P. capsici mutants. Through 10 culture transfers, the mutants maintained high levels of RF (between 14 and 134) and had almost equal fitness as their wild type parents in mycelial growth, sporulation, and virulence. There was no cross resistance between zoxamide and either flumorph, metalaxyl, azoxystrobin, or etridiazole. Based on the results above, P. capsici can develop resistance to zoxamide, and the risk is predicted to be moderate in nature. PMID- 21692645 TI - Genetic differentiation at microsatellite loci among populations of Mycosphaerella graminicola from California, Indiana, Kansas, and North Dakota. AB - Mycosphaerella graminicola causes Septoria tritici blotch (STB) in wheat (Triticum aestivum) and is considered one of the most devastating pathogens of that crop in the United States. Although the genetic structures of M. graminicola populations from different countries have been analyzed using various molecular markers, relatively little is known about M. graminicola populations from geographically distinct areas of the United States and, in particular, of those from spring versus winter wheat. These are exposed to great differences in environmental conditions, length and season of host-free periods, and resistance sources used in geographically separated wheat breeding programs. Thus, there is more likely to be genetic differentiation between populations from spring versus winter wheat than there is among those within each region. To test this hypothesis, 330 single-spore isolates of M. graminicola representing 11 populations (1 from facultative winter wheat in California, 2 from spring wheat in North Dakota, and 8 from winter wheat in Indiana and Kansas) were analyzed for mating type frequency and for genetic variation at 17 microsatellite or simple sequence repeat (SSR) loci. Analysis of clone-corrected data revealed an equal distribution of both mating types in the populations from Kansas, Indiana, and North Dakota, but a deviation from a 1:1 ratio in the California population. In total, 306 haplotypes were detected, almost all of which were unique in all 11 populations. High levels of gene diversity (H = 0.31 to 0.56) were observed within the 11 populations. Significant (P <= 0.05) gametic disequilibrium, as measured by the index of association (rBarD), was observed in California, one Indiana population (IN1), and three populations (KS1, KS2, and KS3) in Kansas that could not be explained by linkage. Corrected standardized fixation index (G"(ST)) values were 0.000 to 0.621 between the 11 populations and the majority of pairwise comparisons were statistically significant (P <= 0.001), suggesting some differentiation between populations. Analysis of molecular variance showed that there was a small but statistically significant level of genetic differentiation between populations from spring versus winter wheat. However, most of the total genetic variation (>98%) occurred within spring and winter wheat regions while <2% was due to genetic differentiation between these regions. Taken together, these results provide evidence that sexual recombination occurs frequently in the M. graminicola populations sampled and that most populations are genetically differentiated over the major spring- and winter-wheat-growing regions of the United States. PMID- 21692646 TI - Stability and fitness of pyraclostrobin- and boscalid-resistant phenotypes in field isolates of Botrytis cinerea from apple. AB - Phenotype stability, fitness, and competitive ability of pyraclostrobin- and boscalid-resistant isolates of Botrytis cinerea from apple were investigated. Stability of resistance was determined after consecutive transfers on potato dextrose agar (PDA) or being cycled on apple fruit. In vitro fitness components mycelial growth, osmotic sensitivity, conidial germination, and sporulation were evaluated on agar media. Pathogenicity, virulence and sporulation on apple fruit were evaluated at both 20 and 0 degrees C. Competition between fungicide resistant and -sensitive isolates on apple fruit also was evaluated. Resistance to the two fungicides was retained at levels similar to that of the initial generation after 20 and 10 transfers on PDA and five and three disease cycles on apple fruit at 20 and 0 degrees C, respectively. Great variability in individual fitness components tested was observed among isolates within the same phenotype groups either sensitive or resistant to the fungicides but, when compared as phenotype groups, there were no significant differences in the mean values of these fitness components between resistant and sensitive phenotypes except that the phenotype resistant only to boscalid produced fewer conidia in vitro than sensitive isolates. Resistant isolates were as pathogenic and virulent on apple fruit as sensitive isolates. There was no significant correlation between the values of individual fitness components tested and the level of resistance to pyraclostrobin or boscalid, except that virulence at 20 degrees C positively correlated with the level of resistance to the two fungicides. The final frequency of pyraclostrobin-resistant individuals in the populations was significantly decreased compared with the initial generation and no boscalid resistant individuals were detected after four disease cycles on apple fruit inoculated with a pair mixture of a dual-sensitive isolate and one isolate each of the three phenotypes resistant to pyraclostrobin, boscalid, or both. The results suggest that resistance of B. cinerea to pyraclostrobin and boscalid was stable in the absence of the fungicides and that resistance to the two fungicides did not significantly impair individual fitness components tested. However, both pyraclostrobin- and boscalid-resistant isolates exhibited competitive disadvantage over the dual-sensitive isolate on apple fruit. PMID- 21692647 TI - Association mapping of quantitative resistance to Phaeosphaeria nodorum in spring wheat landraces from the USDA National Small Grains Collection. AB - Stagonospora nodorum blotch (SNB), caused by Phaeosphaeria nodorum, is a destructive disease of wheat (Triticum aestivum) found throughout the United States. Host resistance is the only economically feasible option for managing the disease; however, few SNB-resistant wheat cultivars are known to exist. In this study, we report findings from an association mapping (AM) of resistance to P. nodorum in 567 spring wheat landraces of diverse geographic origin. The accessions were evaluated for seedling resistance to P. nodorum in a greenhouse. Phenotypic data and 625 polymorphic diversity array technology (DArT) markers have been used for linkage disequilibrium (LD) and association analyses. The results showed that seven DArT markers on five chromosomes (2D, 3B, 5B, 6A, and 7A) were significantly associated with resistance to P. nodorum. Genetic regions on 2D, 3B, and 5B correspond to previously mapped quantitative trait loci (QTL) conferring resistance to P. nodorum whereas the remaining QTL appeared to be novel. These results demonstrate that the use of AM is an effective method for identifying new genomic regions associated with resistance to P. nodorum in spring wheat landraces. Additionally, the novel resistance found in this study could be useful in wheat breeding aimed at controlling SNB. PMID- 21692648 TI - Imbalanced estrogen metabolism in the brain: possible relevance to the etiology of Parkinson's disease. AB - Damage to DNA by dopamine quinone and/or catechol estrogen quinones may play a significant role in the initiation of Parkinson's disease (PD). Depurinating estrogen-DNA adducts are shed from cells and excreted in urine. The aim of this study was to discover whether higher levels of estrogen-DNA adducts are associated with PD. Forty estrogen metabolites, conjugates, and DNA adducts were analyzed in urine samples from 20 PD cases and 40 matched controls by using ultra performance liquid chromatography/tandem mass spectrometry. The levels of adducts in cases versus controls (P < 0.005) suggest that unbalanced estrogen metabolism could play a causal role in the initiation of PD. PMID- 21692649 TI - Correlation between the systemic clearance of drugs and their food effects in humans. AB - CONTEXT: Food effects were defined as positive, when coadministration of food causes an increase in the extent of absorption (AUC(0-infinity)) of a drug when compared with fasted state drug administration and no effect when coadministration of food causes no change in AUC(0-infinity). In general, low solubility drugs exhibit positive food effects due to improved solubility in fed state administration. But, certain high-solubility and high-permeability drugs that undergo extensive presystemic metabolism exhibit positive food effects because of the increased splanchnic hepatic blood flow in the fed state presumably causing a fraction of drug to bypass first-pass metabolism during absorption. OBJECTIVE: In this study, systemic clearance (Cl) of structurally diverse high-permeability and high-solubility drugs was correlated to their food effects to explore whether drugs undergoing low clearance exhibited no food effects and drugs undergoing high clearance exhibited positive food effects. METHODS: Six drugs exhibiting positive food effects and nine drugs exhibiting no food effects (for comparison) were selected for linear regression analysis. RESULTS: Regression analysis of the selected drugs indicated that percent food effects correlated linearly to Cl and fitted the equation: percent food effects = 0.9163 * Cl - 6.4789. The R(2), p-value and power of the regression model were >0.88, 0.9999, respectively indicating the direct correlation between Cl and food effects of the selected model drugs; other statistical tests validated the model. CONCLUSION: The model indicated that high-solubility and high-permeability drugs undergoing Cl of more than 27 L/h may exhibit statistically significant positive food effects. PMID- 21692651 TI - Detrimental effect of fast neutrons on cultured immature rat hippocampal cells: relative biological effectiveness of in vitro cell death indices. AB - This in vitro study compared the detrimental effect and relative biological effectiveness (RBE) of high-linear energy transfer (LET) fast neutrons on rat immature hippocampal cultured cells with those of low-LET gamma rays. Immature hippocampal cells were exposed to fast neutrons or gamma rays. Cytotoxicity and cell viability were analyzed using a lactate dehydrogenase (LDH)-release assay and a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, respectively. The cytotoxicity and cell viability with fast neutrons or gamma rays varied in a dose-dependent pattern. In the LDH release and MTT assay indices, the RBEs of fast neutrons were approximately 2.35 and 2.42, respectively. Fast neutrons markedly induced apoptotic changes in immature hippocampal cells with increased expression of active caspase-3 and cleaved poly(ADP-ribose) polymerase. Increased cytotoxicity and decreased cell viability in immature hippocampal cells were seen in a dose-dependent pattern after fast neutron and gamma irradiation. Fast neutrons have a higher RBE for cell death indices than gamma rays. PMID- 21692650 TI - Brain-targeted delivery of paclitaxel using glutathione-coated nanoparticles for brain cancers. AB - Paclitaxel is not effective for treatment of brain cancers because it cannot cross the blood-brain barrier (BBB) due to efflux by P-glycoprotein (P-gp). In this work, glutathione-coated poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) of paclitaxel were developed for brain targeting for treatment of brain cancers. P-gp ATPase assay was used to evaluate the NP as potential substrates. The NP showed a particle size suitable for BBB permeation (particle size around 200 nm) and higher cellular uptake of the NP was demonstrated in RG2 cells. The P gp ATPase assay suggested that the NP were not substrate for P-gp and would not be effluxed by P-gp present in the BBB. The in vitro release profile of the NP exhibited no initial burst release and showed sustained drug release. The proposed coated NP showed significantly higher cytotoxicity in RG2 cells compared with uncoated NP (p <= 0.05). Tubulin immunofluorescent study showed higher cell death by the NP due to increased microtubule stabilization. In vivo brain uptake study in mice showed higher brain uptake of the NP containing coumarin-6 compared with solution. The proposed brain-targeted NP delivery of paclitaxel could be an effective treatment for the brain cancers. PMID- 21692652 TI - Uncertainties on lung doses from inhaled plutonium. AB - In a recent epidemiological study, Bayesian uncertainties on lung doses have been calculated to determine lung cancer risk from occupational exposures to plutonium. These calculations used a revised version of the Human Respiratory Tract Model (HRTM) published by the ICRP. In addition to the Bayesian analyses, which give probability distributions of doses, point estimates of doses (single estimates without uncertainty) were also provided for that study using the existing HRTM as it is described in ICRP Publication 66; these are to be used in a preliminary analysis of risk. To infer the differences between the point estimates and Bayesian uncertainty analyses, this paper applies the methodology to former workers of the United Kingdom Atomic Energy Authority (UKAEA), who constituted a subset of the study cohort. The resulting probability distributions of lung doses are compared with the point estimates obtained for each worker. It is shown that mean posterior lung doses are around two- to fourfold higher than point estimates and that uncertainties on doses vary over a wide range, greater than two orders of magnitude for some lung tissues. In addition, we demonstrate that uncertainties on the parameter values, rather than the model structure, are largely responsible for these effects. Of these it appears to be the parameters describing absorption from the lungs to blood that have the greatest impact on estimates of lung doses from urine bioassay. Therefore, accurate determination of the chemical form of inhaled plutonium and the absorption parameter values for these materials is important for obtaining reliable estimates of lung doses and hence risk from occupational exposures to plutonium. PMID- 21692653 TI - Boron determination in liver tissue by combining quantitative neutron capture radiography (QNCR) and histological analysis for BNCT treatment planning at the TRIGA Mainz. AB - The typical primary malignancies of the liver are hepatocellular carcinoma and cholangiocarcinoma, whereas colorectal liver metastases are the most frequently occurring secondary tumors. In many cases, only palliative treatment is possible. Boron neutron capture therapy (BNCT) represents a technique that potentially destroys tumor tissue selectively by use of externally induced, locally confined secondary particle irradiation. In 2001 and 2003, BNCT was applied to two patients with colorectal liver metastases in Pavia, Italy. To scrutinize the rationale of BNCT, a clinical pilot study on patients with colorectal liver metastases was carried out at the University of Mainz. The distribution of the (10)B carrier (p-borono-phenylalanine) in the liver and its uptake in cancerous and tumor-free tissue were determined, focusing on a potential correlation between the uptake of p-borono-phenylalanine and the biological characteristics of cancerous tissue. Samples were analyzed using quantitative neutron capture radiography of cryosections combined with histological analysis. Methodological aspects of the combination of these techniques and results from four patients enrolled in the study are presented that indicate that the uptake of p-borono phenylalanine strongly depends on the metabolic activity of cells. PMID- 21692654 TI - UVC radiation induces downregulation of EGF receptor via phosphorylation at serine 1046/1047 in human pancreatic cancer cells. AB - Epidermal growth factor receptor (EGFR) is overexpressed in human pancreatic cancer and is one of the clinical targets in its treatment. In the present study we investigated the mechanism underlying ultraviolet C (UVC)-radiation-induced cell growth inhibition and downregulation of EGFR in human pancreatic cancer cells (Panc1 and KP3). The cell proliferation assay indicated that Panc1 and KP3 cells were more sensitive to UVC radiation, and their growth was significantly inhibited compared to cells of the normal human pancreatic epithelial cell line, PE. Although EGFR levels was extremely low in PE cells, EGFR were highly overexpressed in Panc1 and KP3 cells, and UVC radiation downregulated the expression of EGFR in a time-dependent manner and induced phosphorylation of EGFR at Ser1046/1047 (S1046/7) in Panc1 and KP3 cells. UVC radiation induced activation of p38 mitogen-activated protein kinase (MAPK), and EGFR phosphorylation at S1046/7 induced by UVC radiation was markedly attenuated by the inhibition of p38 MAPK. Moreover, fluorescence microscopy revealed that p38 MAPK activated by UVC radiation triggered EGFR internalization and that this was not correlated with c-Cbl, an ubiquitin ligase, which plays an important role in EGF-induced EGFR downregulation. Taken together, our results suggest that in pancreatic cancer cells UVC radiation induced desensitization of the cells to EGFR stimuli via phosphorylation of EGFR at S1046/7 by activation of p38 MAPK, independent of c-Cbl. PMID- 21692655 TI - Cell surface marker phenotypes and gene expression profiles of murine radiation induced acute myeloid leukemia stem cells are similar to those of common myeloid progenitors. AB - Radiation exposure induces acute myeloid leukemia (AML) in humans and mice. Recent studies postulated that AML stem cells of spontaneous human AML arise from hematopoietic stem cells. However, other studies support the possibility that short-lived committed progenitors transform into AML stem cells, accompanied by a particular gene mutation. It remains unclear whether AML stem cells are present in radiation-induced AML, and information regarding AML-initiating cells is lacking. In this study, we identified and analyzed AML stem cells of mice with radiation-induced AML. The AML stem cells were identified by transplanting 100 bone marrow cells from mice with radiation-induced AML. We injected 100 cells of each of seven cell populations corresponding to different stages of hematopoietic cell differentiation and compared the latencies of AMLs induced in recipient mice. The identified radiation-induced AML stem cells frequently displayed similarities in both CD antigen and gene expression profiles with normal common myeloid progenitors. The number of common myeloid progenitor-like AML stem cells was significantly increased in mice with radiation-induced AML, but the progeny of common myeloid progenitors was decreased. In addition, analysis of radiation effects on the hematopoietic system showed that common myeloid progenitor cells were extremely radiosensitive and that their numbers remained at low levels for more than 2 months after radiation exposure. Our results suggest that murine radiation-induced AML stem cells arise from radiosensitive cells at a common myeloid progenitor stage. PMID- 21692656 TI - Radiosensitivity of early and late M-phase HeLa cells isolated by a combination of fluorescent ubiquitination-based cell cycle indicator (Fucci) and mitotic shake-off. AB - The mitotic shake-off method revealed the remarkable variation of radiosensitivity of HeLa cells during the cell cycle: M phase shows the greatest radiosensitivity and late S phase the greatest radioresistance. This method harvests all M-phase cells with a round shape, making it impossible to further subdivide M-phase cells. Recently, the fluorescent ubiquitination-based cell cycle indicator (Fucci) was developed; this system basically causes cells in G(1) to emit red fluorescence and other cells to emit green fluorescence. Because the green fluorescence rapidly disappears at late M phase, two-dimensional flow cytometry analysis can usually detect a green(high)/red(low) fraction including S , G(2)- and early M-phase cells but not a transitional fraction between green(high)/red(low) and green(low)/red(low) including late M-phase cells. However, combining the shake-off method concentrated the transitional fraction, which enabled us to separate early and late M-phase cells without using any drugs. Here we demonstrate for the first time that cells in early M phase are more radiosensitive than those in late M phase, implying that early M phase is the most radiosensitive sub-phase during the cell cycle. PMID- 21692657 TI - Myelin regeneration: a recapitulation of development? AB - The developmental process of myelination and the adult regenerative process of remyelination share the common objective of investing nerve axons with myelin sheaths. A central question in myelin biology is the extent to which the mechanisms of these two processes are conserved, a concept encapsulated in the recapitulation hypothesis of remyelination. This question also has relevance for translating myelin biology into a better understanding of and eventual treatments for human myelin disorders. Here we review the current evidence for the recapitulation hypothesis and discuss recent findings in the development and regeneration of myelin in the context of human neurological disease. PMID- 21692658 TI - Transcriptional control of the terminal fate of monoaminergic neurons. AB - Monoaminergic neurons are critical functional components of all nervous systems across phylogeny. The terminally differentiated state of individual types of monoaminergic neurons is defined by the coordinated expression of a battery of genes that instructs the synthesis and transport of specific monoamines, such as serotonin or dopamine. Dysfunction or deregulation of several of these enzymes and transporter system has been proposed to be the underlying basis of several pathological conditions. We review here the state of knowledge of the nature of the transcriptional regulatory programs that control the expression of what we term monoaminergic gene batteries (enzymes and transporters for specific monoamines) and thereby define the terminally differentiated state of monoaminergic neurons. We review several case studies in vertebrate and invertebrate model systems and propose that the coordinated expression of the genes that define individual monoaminergic cell types may be brought about by transcriptional coregulatory strategies. PMID- 21692659 TI - Olfactory maps in the brain. AB - The responses of neural elements in many sensory areas of the brain vary systematically with their physical position, leading to a topographic representation of the outside world. Sensory representation in the olfactory system has been harder to decipher, in part because it is difficult to find appropriate metrics to characterize odor space and to sample this space densely. Recent experiments have shown that the arrangement of glomeruli, the elementary units of processing, is relatively invariant across individuals in a species, yet it is flexible enough to accommodate new sensors that might be added. Evidence supports the existence of coarse spatial domains carved out on a genetic or functional basis, but a systematic organization of odor responses or neural circuits on a local scale is not evident. Experiments and theory that relate the properties of odorant receptors to the detailed wiring diagram of the downstream olfactory circuits and to behaviors they trigger may reveal the design principles that have emerged during evolution. PMID- 21692660 TI - Deep brain stimulation for psychiatric disorders. AB - Medications, psychotherapy, and other treatments are effective for many patients with psychiatric disorders. However, with currently available interventions, a substantial number of patients experience incomplete resolution of symptoms, and relapse rates are high. In the search for better treatments, increasing interest has focused on focal neuromodulation. This focus has been driven by improved neuroanatomical models of mood, thought, and behavior regulation, as well as by more advanced strategies for directly and focally altering neural activity. Deep brain stimulation (DBS) is one of the most invasive focal neuromodulation techniques available; data have supported its safety and efficacy in a number of movement disorders. Investigators have produced preliminary data on the safety and efficacy of DBS for several psychiatric disorders, as well. In this review, we describe the development and justification for testing DBS for various psychiatric disorders, carefully consider the available clinical data, and briefly discuss potential mechanisms of action. PMID- 21692661 TI - The development and application of optogenetics. AB - Genetically encoded, single-component optogenetic tools have made a significant impact on neuroscience, enabling specific modulation of selected cells within complex neural tissues. As the optogenetic toolbox contents grow and diversify, the opportunities for neuroscience continue to grow. In this review, we outline the development of currently available single-component optogenetic tools and summarize the application of various optogenetic tools in diverse model organisms. PMID- 21692663 TI - A second ALS patient having an L67P mutation in exon 3 of the Cu/Zn superoxide dismutase gene. PMID- 21692662 TI - Spatial neglect and attention networks. AB - Unilateral spatial neglect is a common neurological syndrome following predominantly right hemisphere injuries and is characterized by both spatial and non-spatial deficits. Core spatial deficits involve mechanisms for saliency coding, spatial attention, and short-term memory and occur in conjunction with nonspatial deficits that involve reorienting, target detection, and arousal/vigilance. We argue that neglect is better explained by the dysfunction of distributed cortical networks for the control of attention than by structural damage of specific brain regions. Ventral lesions in right parietal, temporal, and frontal cortex that cause neglect directly impair nonspatial functions partly mediated by a ventral frontoparietal attention network. Structural damage in ventral cortex also induces physiological abnormalities of task-evoked activity and functional connectivity in a dorsal frontoparietal network that controls spatial attention. The anatomy and right hemisphere dominance of neglect follow from the anatomy and laterality of the ventral regions that interact with the dorsal attention network. PMID- 21692664 TI - Evaluation of the effects of 18 non-synonymous single-nucleotide polymorphisms of CYP450 2C19 on in vitro drug inhibition potential by a fluorescence-based high throughput assay. AB - To comprehensively understand the effects of CYP2C19 genetic polymorphisms on inhibition-based drug-drug interactions (DDIs), 18 human CYP2C19 non-synonymous single-nucleotide polymorphic variants and the wild-type isoform (CYP2C19.1A) were expressed in yeast cells. Using a fluorescence-based high-throughput method, the kinetic constants of these variants, as well as the inhibition constants for 10 drugs, were determined. CYP2C19.5B and CYP2C19.6 showed no activity towards CEC (3-cyano-7-ethoxycoumarin) O-deethylation. CYP2C19.8, CYP2C19.9, CYP2C19.10, CYP2C19.16, CYP2C19.19, E122A and A161P* (an allele containing both A161P and I331V) exhibited significantly reduced catalytic activities compared with CYP2C19.1A. The inhibition assay showed that the CYP2C19 genotype significantly affected the in vitro drug inhibition potential. Although the effect on drug inhibition potential is genotype- and inhibitor-dependent, there was an obvious trend: drugs tended to exhibit higher IC50 values (i.e. decreased inhibition potential) towards variants with reduced activity compared with variants with normal activity. This indicated that patients with reduced-function alleles may be less susceptible to CYP2C19-related DDIs. In this study, we provided the first in vitro evidence of CYP2C19 genotype-dependent effects on drug inhibition potential. This work greatly extends our understanding of the functional consequences of CYP2C19 genetic polymorphisms, and thus should prove valuable for CYP2C19 genotype-based therapy. PMID- 21692665 TI - Radiofrequency-induced heat therapy as first-line treatment for cutaneous leishmaniasis. PMID- 21692667 TI - Darunavir: an effective protease inhibitor for HIV-infected patients. AB - Darunavir is a new-generation nonpeptidic HIV protease inhibitor (PI), used with low doses of ritonavir for pharmacologic enhancement (boosting). It has demonstrated potent activity against multidrug-resistant HIV, with a robust resistance profile and a distinct set of mutations. In heavily treatment experienced patients with HIV infection, darunavir administered twice daily with ritonavir has shown higher rates of efficacy than the control PI. In less treatment-experienced patients, boosted darunavir was noninferior to boosted lopinavir. In treatment-naive patients, boosted darunavir administered once daily was noninferior to boosted lopinavir, and showed higher virologic and immunological response rates in patients with high baseline viral load and low baseline CD4(+) cell counts. Monotherapy with boosted darunavir is an acceptable option in some specific conditions. Boosted darunavir was generally well tolerated, with lower incidence of diarrhea and a more favorable lipid profile than boosted lopinavir in treatment-naive patients. PMID- 21692668 TI - The rise of antimicrobial resistance: a clear and present danger. AB - The Australian Society for Antimicrobials aims to facilitate the acquisition and dissemination of knowledge in the field of antimicrobials. Members and delegates come from a diverse range of professions including physicians, microbiologists, scientists, pharmacists, veterinarians and industry representatives from pharmaceutical and biomedical companies. Membership is primarily based in Australia and New Zealand, but extends to Asia, North America, Europe and the UK. A total of 330 participants attended the 2011 Annual Scientific Meeting with plenary speakers from the USA, Spain and Australia. This meeting report focuses on two key areas of antimicrobial resistance: community-associated methicillin resistant Staphylococcus aureus and resistance in Gram-negative organisms. PMID- 21692670 TI - Predicting bacteremia by procalcitonin levels in patients evaluated for sepsis in the emergency department. AB - Evaluation of: Riedel S, Melendez JH, An AT, Rosenbaum JE, Zenilman JM. Procalcitonin as a marker for the detection of bacteremia and sepsis in the emergency department. Am. J. Clin. Pathol. 135(2), 182-189 (2011). In a recent report, Riedel et al. proposed a procalcitonin cutoff of 0.1 ng/ml to rule out bacteremia in adult patients presenting to the emergency department with systemic infections. Procalcitonin levels were higher in patients with true bacteremia than in patients with negative blood cultures or bacteremia due to possible contaminants. For prediction of bacteremia, a procalcitonin level of 0.1 ng/ml had an excellent negative predictive value of 96.3%, and a good sensitivity of 75%, specificity of 70.6% and area under the curve of 0.73, but poor positive predictive value of 12.8%. Based on the results in this study, we propose that a procalcitonin value of 0.1 ng/ml or less could be used to rule out bacteremia (NPV: 96.3%). PMID- 21692669 TI - Lessons from maraviroc clinical trials. AB - Evaluation of: Gulick RM, Lalezari J, Goodrich J et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N. Engl. J. Med. 359, 1429-1441 (2008). Maraviroc is the first commercially available HIV chemokine receptor antagonist targeting HIV that utilizes the CCR5 chemokine receptor (R5 tropic). The Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment Experienced Patients (MOTIVATE) trials were two randomized, placebo-controlled studies designed to demonstrate the activity of maraviroc in triple-class experienced HIV individuals, with a primary end point of viral load suppression at 48 weeks. Maraviroc outperformed the placebo plus optimized background (OBT) arm, and exhibited a favorable safety profile with low discontinuation rates, which equaled those of the placebo plus OBT group. The results of these trials led to maraviroc receiving regulatory approval for the treatment of HIV. PMID- 21692671 TI - Vancomycin dosing and monitoring 2 years after the guidelines. AB - Administration of vancomycin continues to be common despite perceived concerns of increased MICs, treatment failures and toxicity. In 2009, a consensus guideline was published in an effort to optimize dosing and monitoring of this useful agent. It was unique in targeting a specific antibiotic rather than a disease state or organism. However, a lack of prospective randomized double-blinded trials upon which to base guidelines was noted. In addition, several questions were raised and remain unanswered. Since guideline publication, new data has added to our understanding of the implications of aggressive dosing and subsequent monitoring. The following article discusses research published within the last 2 years. PMID- 21692672 TI - Serologic assays for influenza surveillance, diagnosis and vaccine evaluation. AB - Serological techniques play a critical role in various aspects of influenza surveillance, vaccine development and evaluation, and sometimes in diagnosis, particularly for novel influenza virus infections of humans. Because individuals are repeatedly exposed to antigenically and genetically diverse influenza viruses over a lifetime, the gold standard for detection of a recent influenza virus infection or response to current vaccination is the demonstration of a seroconversion, a fourfold or greater rise in antibody titer relative to a baseline sample, to a circulating influenza strain or vaccine component. The hemagglutination-inhibition assay remains the most widely used assay to detect strain-specific serum antibodies to influenza. The hemagglutination-inhibition assay is also used to monitor antigenic changes among influenza viruses which are constantly evolving; such antigenic data is essential for consideration of changes in influenza vaccine composition. The use of the hemagglutinin-specific microneutralization assay has increased, in part, owing to its sensitivity for detection of human antibodies to novel influenza viruses of animal origin. Neutralization assays using replication-incompetent pseudotyped particles may be advantageous in some laboratory settings for detection of antibodies to influenza viruses with heightened biocontainment requirements. The use of standardized protocols and antibody standards are important steps to improve reproducibility and interlaboratory comparability of results of serologic assays for influenza viruses. PMID- 21692673 TI - Management of viral infections in solid organ transplant recipients. AB - Management of viral infections after transplantation involves antiviral drug therapy (if available) and reduction in immunosuppression, which allows for development of pathogen-specific immunity to the offending virus. Prevention of viral infections is of the utmost importance, and this may be accomplished through vaccination, antiviral strategies and infection control measures. This article discusses the current management of selected viral pathogens that cause clinical illness in solid organ transplant recipients. The benefits and toxicities of antiviral therapies are discussed in the context of prevention and treatment of various viral diseases. The emerging issue of antiviral resistance is emphasized for cytomegalovirus, recurrent hepatitis B and influenza, while the importance of immunominimization is discussed in the management of BK nephropathy and virus-associated malignancies. PMID- 21692674 TI - Leprosy and HIV coinfection: a critical approach. AB - An increase in leprosy among HIV patients, similar to that observed in patients with TB, was expected approximately 20 years ago. Studies conducted in the 1990s together with those reported recently seemed to indicate that a coinfection with HIV did not alter the incidence and the clinical spectrum of leprosy and that each disease progressed as a single infection. By contrast, in countries with a high seroprevalence of HIV, TB was noted to increase. Explanations may be provided by the differences in the incubation time, the biology and toxicity of Mycobacterium leprae and Mycobacterium tuberculosis. After the introduction of HAART the leprosy-HIV coinfection manifested itself as an immune reconstitution inflammatory syndrome (IRIS), typically as paucibacillary leprosy with type 1 leprosy reaction. The incidence of leprosy in HIV-infected patients has never been properly investigated. IRIS-leprosy is probably underestimated and recent data showed that the incidence of leprosy in HIV patients under HAART was higher than previously thought. PMID- 21692675 TI - The utility of diagnostic tests for enteric fever in endemic locations. AB - Enteric fever, an infection caused by Salmonella enterica serovar Typhi and serovar Paratyphi A, is common and endemic in many areas of the Asian and African continents. In endemic areas, diagnostic tests are needed to diagnose acute cases for clinical management, to detect convalescent and chronic fecal carriage and for contact tracing. A suitable test may also allow an assessment of disease burden in a community to determine the need for vaccination programs. Each specific role may warrant a dedicated test, utilizing different samples, targets and methods to serve their respective purpose. Current diagnostic methods are poor. Blood culture is insufficiently sensitive and technically demanding, and bone marrow culture, although more sensitive, is infrequently performed. Antibody and antigen-detection tests lend themselves to point-of-care format but remain insufficiently sensitive and specific for this role. There are concerns about the sensitivity of nucleic acid amplification tests and they have not become widely adopted. However, new approaches using genomics, proteomics, transcriptomics, in vivo-induced antigen and immunoaffinity proteomics-based technologies are being employed to identify new antigens, gene targets and metabolic products that could be used as a basis for more effective diagnostic tests. If novel tests are to be credible and widely used they require rigorous evaluation in endemic areas in studies with appropriate selection of patients, adequate sample sizes and proper attention to a gold standard reference. Here, we discuss the range of methods currently used for diagnosing enteric fever in endemic locations and we suggest new technologies which may improve enteric fever diagnostics over the coming years. PMID- 21692676 TI - Neuroimaging of pediatric brain infections. AB - Neuroimaging plays an important and growing role in the diagnosis and therapeutic management of pediatric brain infections. This article describes the spectrum of imaging findings associated with major pediatric viral and bacterial brain infections, outlining the role of current imaging technology in the differential diagnoses of brain injury, detection of complications and therapy monitoring. MRI is the tool of choice in the evaluation of brain infections and particular attention is devoted to the role of diffusion-weighted imaging and magnetic resonance spectroscopy. This article considers viral and bacterial infection in their different modalities of presentation as congenital, acute and subacute/chronic disease. With regard to congenital infections, the growing role of fetal MRI as a valuable complement to ultrasound in the prenatal assessment of brain damage is emphasized. PMID- 21692678 TI - Cardiovascular disease risk factors in homeless people. AB - BACKGROUND: Cardiovascular diseases (CVD) are associated with significant morbidity and mortality, which is highest in Eastern Europe including Estonia. Accumulating evidence suggests that life-style is associated with the development of CVD. The aim of this study was to evaluate the informative power of common CVD related markers under unhealthy conditions. SUBJECTS: Subjects (n = 51; mean age 45 years; 90% men) were recruited from a shelter for homeless people in Tallinn, Estonia, and consisted of persons who constantly used alcohol or surrogates, smoked, and were in a bad physical condition (amputated toes, necrotic ulcers, etc.). METHODS: Blood pressure, pulse rate, and waist circumference were measured, and body mass index (BMI) was calculated. The following markers were measured in blood serum: total cholesterol (TChol), high-density lipoprotein cholesterol (HDL-Chol), low-density lipoprotein cholesterol (LDL-Chol), plasma triglycerides (TG), apolipoproteins A-l (ApoA1) and B (ApoB), lipoprotein(a) (Lp(a)), glycated hemoglobin (HbA1c), glucose (Gluc), high-sensitivity C-reactive protein (hsCRP), serum carbohydrate-deficient transferrin (CDT), gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Except smoking, the anamnestic information considering eating habits, declared alcohol consumption and medication intake were not included in the analysis due to the low credibility of self-reported data. RESULTS: More than half of the investigated patients had values of measured markers (hsCRP, TChol, LDL-Chol, TG, HbA1c, ApoA1, ApoB, Lp(a), Gluc) within normal range. Surprisingly, 100% of subjects had HDL-Chol within endemic norm. CONCLUSION: This study demonstrates that traditional markers, commonly used for prediction and diagnosis and treatment of CVD, are not always applicable to homeless people, apparently due to their aberrant life-style. PMID- 21692679 TI - In vitro evaluation and biodistribution of HER2-targeted liposomes loaded with an (125)I-labelled DNA-intercalator. AB - BACKGROUND: Increasing attention is currently focussed on the issue of finding strategies for the delivery of Auger-electron-emitting radionuclides into tumor cell nuclei. PURPOSE: In this study, we investigated tumor-cell uptake and cell killing ability in vitro as well as in vivo biodistribution of an (125)I-labelled anthracycline derivative administered by means of HER2-targeted liposomes. METHODS: Anthracycline derivative Comp1 was radiolabelled with Auger-emitting (125)I and encapsulated in liposomes (DSPC:Chol:DSPE-PEG) using pH-gradient loading. Single-chain fragment F5 was anchored to the liposomes as targeting device for HER2. Uptake and specificity of (125)I-Comp1 delivered via targeting and non-targeting liposomes were analysed in cultured HER2-overexpressing cells. Cell-killing efficacy was evaluated in SKOV3 cells and biodistribution for up to 48 h was studied after intraperitoneal injection in tumor-bearing female BALB/c nu/nu mice. RESULTS: (125)I-Comp1 was specifically taken up by the cultured cells when administered by means of HER2-targeted liposomes and a clear dose-effect correlation in survival of cells was seen with increasing specific activity. The biodistribution studies revealed that (125)I-Comp1 accumulated in tumors when distributed using HER2-targeted liposomes and that this effect was absent when using non-targeting liposomes. CONCLUSION: The HER2-targeted liposomes possess the properties needed to bring about tumor-specific delivery and therapeutic effect of (125)I-Comp1. PMID- 21692680 TI - Procalcitonin-guided antibiotic therapy for chronic obstructive pulmonary disease exacerbations. AB - The aim of this article is to review the current literature examining the use of procalcitonin-guided antibiotic therapy for management of chronic obstructive pulmonary disease (COPD) exacerbations. Procalcitonin is a serum marker that rises in response to bacterial infections, but remains low in nonbacterial infections and other proinflammatory conditions. To date, there are four randomized clinical trials which compare procalcitonin-guided antibiotic therapy to standard therapy in patients with COPD exacerbations. In all four trials the use of procalcitonin was associated with a reduction in antibiotic use (prescription and/or duration) without an increase in the rates of adverse patient outcomes including death, admission to the intensive care unit, re exacerbation and readmission to the hospital. This data is clinically significant and suggests that the use of procalcitonin-guided antibiotic therapy has the potential to decrease unnecessary antibiotic use in nonbacterial COPD exacerbations, thereby curtailing the spread of antibiotic-resistant bacteria, reducing antibiotic-related adverse reactions, including Clostridium difficile infection, and potentially reducing healthcare costs. PMID- 21692681 TI - Anti-inflammatory activity of injectable dexamethasone acetate-loaded nanostructured lipid carriers. AB - This work studied the intravenous injection formulation of nanostructured lipid carriers (NLCs) loaded with dexamethasone acetate (DA), a poorly water-soluble drug. The goal of this study was to design nanoparticles which could improve therapeutic efficacy of DA on inflammations. Based on the optimized results of single-factor screening experiment, DA-loaded NLCs (DA-NLCs) prepared by an emulsification-ultrasound method were found to be relatively uniform in size (178 +/- 4 nm) with a negative zeta potential (-38 +/- 4 mV). The average drug entrapment efficiency was 91 +/- 3 %. In vitro release tests indicated DA-NLCs possessed a sustained release characteristic and the accumulative release percentage was near 80 % at 23 h. DA-NLCs exhibited an average peak concentration of DA (7.6 MUg/ml) in the pleural exudate after intravenous administration to an experimental model of gamma-carrageenan-induced pleuritis rats, which was 8.3 times higher than that of free DA (0.9 MUg/ml). The gamma-carrageenan-induced edema test showed that the anti-acute inflammatory activity of DA-NLCs was stronger than that of free drug at the same drug concentration (P<0.05). In addition, biodistribution results clearly indicated that DA-NLCs preferentially accumulated in mice livers and lungs after intravenous injection. These results revealed that injectable NLCs may serve as a promising carrier for DA, greatly enhancing the selective effect on inflammatory sites, reducing systematic side effects and may be a potential carrier to increase therapeutic efficacy on inflammatory diseases. PMID- 21692682 TI - Composition of the essential oil constituents from leaves and stems of Korean Coriandrum sativum and their immunotoxicity activity on the Aedes aegypti L. AB - The leaves and stems of Coriandrum sativum were extracted and the essential oil composition and immunotoxicity effects were studied. The analyses were conducted by gas chromatography-mass spectroscopy (GC-MS), which revealed the essential oils of C. sativum leaves and stems. Thirty-nine components representing 99.62% of the total oil were identified from the leaves. The major components are cyclododecanol (23.11%), tetradecanal (17.86%), 2-dodecenal (9.93%), 1-decanol (7.24%), 13-tetradecenal (6.85%), 1-dodecanol (6.54%), dodecanal (5.16%), 1 undecanol (2.28%), and decanal (2.33%). Thirty-eight components representing 98.46% of the total oil were identified from the stems of the coriander. The major components are phytol (61.86%), 15-methyltricyclo[6.5.2(13,14),0(7,15)] pentadeca-1,3,5,7,9,11,13-heptene (7.01%), dodecanal (3.18%), and 1-dodecanol (2.47%). The leaf oil had significant toxic effects against the larvae of Aedes aegypti with an LC50 value of 26.93 ppm and an LC90 value of 37.69 ppm and the stem oil has toxic effects against the larvae of A. aegypti with an LC50 value of 29.39 ppm and an LC90 value of 39.95 ppm. Also, the above data indicate that the major compounds may play an important role in the toxicity of essential oils. PMID- 21692683 TI - Bridging global gene expression candidates in first trimester placentas with susceptibility loci from linkage studies of preeclampsia. AB - Preeclampsia is as a leading cause of maternal and perinatal morbidity and mortality. Prevention, early identification, and individualized treatments may become feasible if reliable early biomarkers can be developed. Towards a systems biology framework, this review synthesizes prior linkage studies and genome scans of preeclampsia with candidates identified in a global gene expression microarray analysis of chorionic villus sampling (CVS) specimens from women who subsequently developed preeclampsia. Nearly 40% of these CVS candidate genes occurred in previously identified susceptibility loci for preeclampsia. Integration of genetic epidemiologic and functional gene expression data could help to elucidate preeclampsia as a complex disease resulting from multiple maternal and fetal/placental factors that each contributes a greater or lesser effect. These loci and related candidate genes are set to substantially improve insights into the first trimester pathogenesis of this pregnancy disorder. PMID- 21692684 TI - Two cases of Lowe syndrome presenting as increased fetal nuchal translucency. PMID- 21692685 TI - Clinical significance of pleural effusion mesothelin in malignant pleural mesothelioma. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM has a limited response to conventional chemotherapy and radiotherapy, so early diagnosis of MPM is very important. This study investigated the pleural effusion mesothelin levels in patients with MPM and compared them to those of a population with a non malignant pleuritis or lung cancer involving malignant pleural effusion. METHODS: The pleural effusion mesothelin concentrations were measured in 45 MPM patients and 53 non-MPM individuals (24 individuals with non-malignant pleural effusions and 29 individuals with lung cancer involving malignant pleural effusion). RESULTS: This study demonstrated that patients with MPM had significantly higher pleural effusion mesothelin levels than a population with non-malignant pleuritis or lung cancer involving malignant pleural effusion. The difference in overall survival between the groups with pleural effusion mesothelin levels lower and higher than the assumed cut-off of 10 nM was significant. CONCLUSIONS: The data suggest that the pleural effusion mesothelin concentration could be useful as an aid for the diagnosis of MPM. PMID- 21692686 TI - The value of N-terminal proB-type natriuretic peptide for early identification of myocardial infarction in patients with high-risk non-ST-elevation acute coronary syndromes. AB - BACKGROUND: N-terminal proB-type natriuretic peptide (NT-proBNP) is a marker of biomechanical strain, secreted by cardiomyocytes in response to ischemia. As necrosis occurs after prolonged ischemia, a rise in NT-proBNP concentration could precede a rise in markers of necrosis. METHODS: The aim of the study was to evaluate whether NT-proBNP is able to identify those patients with an evolving myocardial infarction (MI) with high-risk non-ST-elevation acute coronary syndromes (NSTE-ACS). Data were analyzed from a prospective cohort of 103 high risk NSTE-ACS patients admitted within 6 h after onset of pain and treated with an early invasive strategy. NT-proBNP samples, obtained immediately upon admission, were related to the presence of an in hospital MI. The optimal cut-off value for NT-proBNP was determined using receiver-operating characteristics (ROC) curve analysis. RESULTS: Analyses was performed separately for creatinine kinase MB-mass (CKMB) and troponin T (TnT) based MI definitions. In both cases, a NT proBNP concentration above 40 pmol/L (339 ng/L) at admission proved to be independently associated with the presence of MI. The diagnostic odds ratio (OR) for CKMB-MI was 4.9 (confidence interval 2.0-11.9, p<0.001). The diagnostic OR for TnT-MI was 4.9 (1.8-14.4, p=0.003). Adjusting for differences in baseline variables did not weaken the diagnostic OR. In addition, elevated NT-proBNP concentrations were related to unfavour-able demographic, physical and biochemical parameters. CONCLUSIONS: With a dichotomous cut-off value, a single elevated NT-proBNP (>40 pmol/L) at admission provides independent information about the presence of MI in high-risk NSTE-ACS patients. PMID- 21692687 TI - Role of transcription factors in neurogenesis after cerebral ischemia. AB - Studies have revealed that the adult mammalian brain has the capacity to regenerate some neurons after cerebral ischemia. And this perspective on neurogenesis adds to the conceptual framework for strategies for the repair of ischemia-induced brain injury, that is, if the effect of ischemia-induced neurogenesis is enhanced, then the recovery of brain function after stroke can be promoted. Neurogenesis is a multistep process that requires the proliferation of neural stem/progenitor cells, migration and that new cells differentiate, survive and integrate into existing neural networks. For that to occur, the same concerted action of various factors is needed, especially transcription factors which regulate the expression of many moleculars and interact with them to promote neurogenesis. This review article gives a brief overview of some transcription factors (NF-kappaB, Hes, STAT3, AP-1, CREB, HIF1, Pax6, Tcf/Lef, Gli, Sox2, Olig2, Dlx2, TLX, Bmi-1) in ischemia-induced neurogenesis. PMID- 21692688 TI - Drug delivery embolization systems: a physician's perspective. AB - INTRODUCTION: The number of patients suffering from primary and secondary liver tumoral diseases is on the increase worldwide. The development of new technologies and drugs requires an increasingly multidisciplinary approach in the management of these diseases. Therapies should be based on scientifically supported guidelines and at the same time should be designed to suit the individual patient. In this decision-making process, an understanding of the advantages and disadvantages of every treatment is very important. The efficacy of transarterial chemoembolization (TACE) in improving survival and its role in the management of hepatocellular carcinoma (HCC) have been demonstrated in several clinical trials. The introduction of drug-eluting beads seems to have overcome some of the limitations of conventional TACE. AREAS COVERED: This review provides an overview of the spread of primary and secondary liver cancers, then it explains the basis for the use of conventional TACE and its potential benefits and, finally, outlines its clinical application and possible future uses. EXPERT OPINION: The management of the treatment of focal liver lesions is a difficult process, which must involve various specialists such as the interventional radiologist. The use of drug-eluting microspheres seems to improve the results of TACE both in HCC and in colorectal liver metastases. PMID- 21692689 TI - The impact of prefertilization chronic mild stress on postnatal morphometric development. AB - OBJECTIVE: The aim of the present study was to examine the effects of chronic mild stress (CMS) induced before the fertilization on gestational maternal weight, length of gestation, and postnatal morphometric development. MATERIAL AND METHOD: Study is carried out on 18 Wistar albino rats; six females in the stress group, six females in the control group, and six males to be used for mating. CMS was induced in rats of the stress group for 4 weeks, followed by a post-CMS waiting period of 5-weeks. Rats were left for mating at the end of the post-CMS period. Weight gain in pregnant rats was monitored and length of gestation and litter size were recorded in the stress and control groups. Growth parameters of pups pertaining to the body, cranium, thorax, and limbs were measured until week 11. FINDINGS: Weight gained by pregnant rats in the stress group was less than the control group. Increases in mean morphometric parameters from day 0 to week 11 in the stress group were less than the control group (p < 0.05). Furthermore, when developmental parameters at weeks 7, 9, and 11 were compared between genders, females in the stress group were found more affected than males (p < 0.05). CONCLUSION: CMS sustained before fertilization has a negative effect on gestational maternal weight and postnatal morphometric development of pups, more prominently in females. PMID- 21692690 TI - Basic science offers a challenge for developing hemoglobin based oxygen carriers into therapeutic agents. AB - Experimental data, obtained during the course of several years, are connected into a coherent picture, which may help research for the development of HBOCs as therapeutic agents. Oxygen affinity, scavenging of nitric oxide, and yield of production of hemoglobin based oxygen carriers were the areas under consideration. PMID- 21692692 TI - Vaccines in clinical trials: cancer. PMID- 21692693 TI - Multifunctional vaccines in cancer: the 'triad' approach. PMID- 21692691 TI - Radiation metabolomics and its potential in biodosimetry. AB - PURPOSE: Radiation exposure triggers a complex network of molecular and cellular responses that impacts metabolic processes and alters the levels of metabolites. Such metabolites have potential as biomarkers for radiation dosimetry. This review provides an overview of radiation signalling and metabolism, of metabolomic approaches used in the discovery phase, and of instrumentation with the potential to assess radiation injury in the field. APPROACH: Recent developments in fast, high-resolution chromatography and mass spectrometry and new data analysis methods allow the quantitative assessment of thousands of metabolites based on biofluids obtained non-invasively. This complex analysis leads to the discovery-phase identification of groups of metabolites useful for screening and biodosimetry by targeted quantitative measurement. Instrumentation for target analysis can be simpler than that used for discovery, so we examine current technologies based on ion mobility. CONCLUSIONS: Recent published results and ongoing studies examine the complex changes in the levels of many metabolites caused by radiation exposure, and identify groups of small-molecule biomarkers for radiation biodosimetry. Based on results showing separation orthogonal to mass, chemical noise suppression, and high sensitivity, differential mobility mass spectrometry (DMS-MS) ion mobility spectrometry appears highly promising for the development of deployable instrumentation. PMID- 21692694 TI - Adaptive clinical trial designs proposed to accelerate development of HIV vaccines. PMID- 21692695 TI - Heat shock protein-peptide complex in the treatment of glioblastoma. AB - Vaccination immunotherapies offer the promise of long-term tumor control, and preclinical trials have found promising results. Active immunotherapy uses the adaptive immune response to specifically kill tumor cells. Tumor-specific antigens are processed by antigen-presenting cells and recognized by specific effector lymphocytes. However, basic vaccination strategies with tumor lysates have been unsuccessful in inducing antiglioma immunity in clinical trials. Gliomas are known to modulate the activity of antigen-presenting cells to reduce antitumor immune activity. Recently, tumor-derived heat shock proteins have been found to more effectively activate the immune response. Widely expressed, heat shock proteins are thought to present protein peptide fragments in a format conducive to processing by antigen-presenting cells. As a part of the protein synthesis machinery, peptides complexed with heat shock proteins are effectively representative of antigens expressed by the cell; these peptides convey the specificity of this vaccination strategy. The heat shock protein-peptide vaccine is one of many promising immunotherapeutic strategies being evaluated in clinical trials. These can be broadly classified as active, passive and adoptive, each with advantages and disadvantages. Here, we compare and contrast heat shock protein-peptide vaccines with other immunotherapies and describe the outcomes of clinical trials to date. PMID- 21692696 TI - CDX-1307: a novel vaccine under study as treatment for muscle-invasive bladder cancer. AB - Cancer vaccines have demonstrated clinical benefit, however greater efficacy could be achieved by enhancing their immunogenicity. Owing to cancer vaccines depending on uptake and cross-presentation of tumor antigens by antigen presenting cells (APCs), we hypothesized that greater immunogenicity would accompany strategies that direct antigen to APC-expressed mannose receptors, initiating a pathway increasing class I and II presentation to T cells. CDX-1307 consists of a human monoclonal antibody targeting the mannose receptor, fused to the human chorionic gonadotropin-beta chain (hCG-beta), a tumor antigen frequently expressed by epithelial cancers including bladder cancer. In Phase I studies of cancer patients, CDX-1307 was well tolerated and induced significant hCG-beta-specific cellular and humoral immune responses when co-administered with GM-CSF and the Toll-like receptor agonists resiquimod and poly-ICLC. An ongoing Phase II trial evaluates CDX-1307 in patients with newly diagnosed, resectable, hCG-beta-expressing bladder cancer, where low tumor burden and early intervention may provide greater potential for benefit. PMID- 21692698 TI - Breast cancer vaccines: ongoing National Cancer Institute-registered clinical trials. AB - Advances in the molecular characterization of human tumors have led to increased interest in the development of targeted therapeutics to include cancer vaccines. The recent success of sipuleucel-T, an autologous cellular vaccine administered to patients with hormone-refractory metastatic prostate cancer, suggests that this is a viable therapeutic option in the management of patients with solid tumors. This article focuses on breast cancer vaccines emphasizing delivery platforms, target antigens and novel strategies designed to enhance response to vaccination that are being evaluated in ongoing Phase II clinical trials. PMID- 21692697 TI - From clinical trials to clinical practice: therapeutic cancer vaccines for the treatment of prostate cancer. AB - Therapeutic options for patients with metastatic castration-resistant prostate cancer are increasing, spurring an urgent need to better understand which treatments are best for individual patients. The recent approval of a first-in class agent, sipuleucel-T, has intensified this need. This therapeutic cancer vaccine has demonstrated a survival advantage in two Phase III trials, but does not alter progression in the short term. Therefore, a new therapeutic approach for patients with metastatic castration-resistant prostate cancer is taking shape, based on broader understanding of available therapies. This new clinical approach seeks to maximize patient benefit from treatment, minimize associated toxicities, and may have far-reaching implications for other therapeutic cancer vaccines currently in clinical development. PMID- 21692699 TI - Vaccine-based clinical trials in ovarian cancer. AB - Ovarian cancer vaccines are one of the new treatment strategies under investigation in epithelial ovarian cancer. This article discusses the results of different immunization strategies, points out potential pitfalls in study designs and provides possible solutions for augmentation of clinical efficacy. Most ovarian cancer vaccines have not yet evolved beyond Phase I/II studies, which do not primarily evaluate clinical efficacy. Although different approaches of antigen-specific immunization generally result in antigen-specific immune responses, clinical benefit is not consistently observed. Based on the currently available results, we emphasize the necessity of multimodal treatment of ovarian cancer, combining classical cytoreductive surgery, (neo)adjuvant chemotherapy, immunotherapy and/or targeted therapy. PMID- 21692701 TI - Idiotype vaccines for lymphoma therapy. AB - Despite having been the first cancer vaccine to provide clear-cut evidence of biological and clinical efficacy as well as of clinical benefit in humans, idiotype vaccines have failed to become the first therapeutic cancer vaccine to be granted regulatory approval. Indeed, idiotypic vaccination is still an experimental therapeutic option for some types of B-cell malignancy over 20 years after its first use in patients with lymphoma. The ultimate reason for this situation lies in the recent failure of three large-scale, independent, randomized trials to achieve their respective main clinical end points. Interestingly, each trial had been designed with intrinsic pitfalls that are likely to have influenced, and perhaps even entirely compromized, all chances each study had to succeed. Therefore, it is difficult to conclude whether any of the different idiotype vaccines employed so far may still represent an ideal candidate for further trials. Meanwhile, other idiotype vaccine formulations are under active investigation. PMID- 21692700 TI - Clinical peptide vaccination trials for leukemia patients. AB - The favorable graft-versus-leukemia (GVL) effect that occurs after stem cell transplantation suggests that T cells can eradicate leukemia blasts. T cells specifically recognize peptides and exert an antileukemia effect. Several leukemia-associated antigens (LAAs) have been found to be overexpressed in malignant cells from patients with acute or chronic leukemia leading to the generation of peptide-based leukemia immunotherapy. Peptide vaccination with LAAs, whose expression is low in normal tissue, such as the receptor for hyaluronic acid-mediated motility (RHAMM), Wilms tumor 1 (WT1), proteinase-3 (PR 3) and the breakpoint cluster region-Abelson (bcr-abl) has been reported to induce leukemia-specific T-cell responses in patients with a variety of hematological malignancies. Moreover, the immune responses achieved after vaccination positively correlated with good clinical outcomes, that is complete remission. Large efforts have been made to optimize the dose and format of vaccines, as well as their adjuvants, in small pilot trials. In this article we summarize clinical Phase I and II peptide vaccination trials with RHAMM, WT1, PR 3 and bcr-abl for leukemia patients. PMID- 21692702 TI - Neuroendocrine cancer vaccines in clinical trials. AB - This article focuses on neuroendocrine cancer vaccines that have been evaluated in human clinical trials within the last 5 years. The definition of what constitutes a neuroendocrine tumor requires clarification. Strategies and barriers common to cancer vaccines are highlighted. In general, neuroendocrine cancer is rare; however, special attention will be paid to neuroblastoma and small-cell-lung cancer owing to their relatively higher prevalence. A variety of other neuroendocrine tumor vaccine trials will also be addressed. The common problem of generating only sporadic tumor-specific immune responses that are of low-magnitude will be discussed in detail, with recommendations for future directions. PMID- 21692703 TI - Clinical trials of vaccines for immunotherapy in pancreatic cancer. AB - A greater understanding of the molecular events that trigger oncogenesis and events that negatively regulate immune responses has allowed for the development of targeted therapies with specific vaccines to match tumor antigens coupled with immunotherapy specifically directed against that tumor's immunosuppressive microenvironment. In order to be effective, vaccine therapies need to both expand the immune response to tumors and overcome immunosuppressive microenvironments therein. Specifically, targeted therapy must be personalized for each cancer patient. While the idea of personalized targeted therapy may seem like a daunting task, it may not be that difficult as it could involve a relatively simple genetic test to identify gene mutations and additional immunohistochemical staining of tumors with antibodies directed against markers of negative immune regulation. The additional cost to personalize cancer therapy with these diagnostic tests is relatively small in comparison to the cost afforded to our healthcare system when inappropriate targeting therapies are administered to patients whose tumors do not express the targets of either the vaccine or the immune modulator. Despite the large cost, cancer patients whose tumors lack the targets of these therapies often receive no benefit from the therapy. The most illogical approach is to develop a study design and perform clinical trials of potential novel targeting drugs without knowledge or confirmation that the patients' tumors express the targets. Current cancer trials for pancreatic cancer patients are discussed in this article. PMID- 21692704 TI - Vaccination therapy in renal cell carcinoma: current position and future options in metastatic and localized disease. AB - As renal cell carcinoma represents one of the most immune-responsive cancers, immunotherapy exhibits a suitable treatment basis. Beside nonspecific stimulation via cytokines, passive specific and active immunotherapy are also appropriate options to recognize and destroy tumor cells. For more than 30 years, research regarding vaccination therapy has been of special interest for the treatment of renal cell carcinoma. However, apart from occasional promising results in Phase I and II trials, vaccination therapy is still considered experimental in this tumor entity, especially owing to missing results from Phase III trials demonstrating clinical efficacy. In the present article, we review data from completed clinical trials of vaccination therapy and also discuss scheduled future trials, in order to assess the current position and possible future fields of application of vaccination therapy in renal cell carcinoma in the era of recently developed targeted therapies. PMID- 21692705 TI - Melanoma vaccines: developments over the past 10 years. AB - Decades of preclinical evaluation and clinical trials into melanoma vaccines have yielded spectacular progress in our understanding of melanoma antigens and the immune mechanisms of tumor rejection. Key insights and the results of their clinical evaluation are reviewed in this article. Unfortunately, durable clinical benefit following vaccination remains uncommon. Two recent clinical advances that will impact on melanoma vaccine development are trials with inhibitors of CTLA-4 and oncogenic BRAF. Long-term therapeutic control of melanoma will require integration of specific active immunotherapy with these emerging successful therapies from the disparate fields of immune regulation and signal transduction. PMID- 21692706 TI - Vaccines for glioblastoma and high-grade glioma. AB - Vaccination by administering tumor antigen plus cell-free or cellular adjuvant has garnered hope for more effective, less toxic therapy for patients with malignant brain tumors including glioblastoma multiforme. To determine if this approach demonstrates ample clinical promise, all published reports of vaccination for glioma were evaluated. These reports suggest vaccination is associated with low toxicity and favorable clinical outcomes. The possibility of selection bias is evident in many published vaccine trials, but several of the more recent ones appropriately attempt to account for bias. Effective induction of antitumor immunity is consistently observed, and, in the latest trials, correlates with significant clinical improvement. PMID- 21692707 TI - Non-small-cell lung carcinoma vaccines in clinical trials. AB - Non-small-cell lung cancer (NSCLC) is not considered to be immunogenic, but it may provide an accessible target for the properly primed immune system. Identifying lung tumor antigens and presenting them in the optimal context may enable the immune system to generate anti-lung tumor effector cells, which are usually absent. Despite encouraging preclinical and Phase I-II data, no specific active cancer vaccine has been approved for NSCLC therapy to date. Patient selection and measurable immune response methodology assessment could explain these negative results. Vaccine therapy has recently been re-emerging as a potential approach. This article discusses the Phase I, II and III trials investigating the most promising vaccines in the treatment of patients affected by any stage of NSCLC, thus providing a perspective on the future of this approach in this setting. PMID- 21692708 TI - Colorectal cancer vaccines in clinical trials. AB - This article elucidates current strategies of active immunotherapy for colorectal cancer patients with a focus on T-cell mediated immunotherapy. Poor prognosis of especially stage III and IV colorectal cancer patients emphasizes the need for advanced therapeutic intervention. Here, we refer to clinical trials using either tumor cell-derived vaccines or tumor antigen vaccines with a special interest on safety, induced immune responses, clinical benefit and efforts to improve the clinical impact of these vaccines in the context of colorectal cancer treatment. PMID- 21692710 TI - Epidemiological trends in incidence and mortality of hepatobiliary cancers in Germany. AB - OBJECTIVE: While marked changes in the frequency of hepatobiliary malignancies, most notably hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), have been observed in different populations, no such data have been reported for Germany. We aimed to provide epidemiological data on recent trends in liver-related mortality, specifically mortality from hepatobiliary malignancies, in Germany. MATERIAL AND METHODS: We used incidence and mortality data to determine changes in the frequency of malignant and non-malignant liver disease in Germany over the past 30 years. RESULTS: While overall liver disease mortality has slightly declined in Germany, deaths from hepatobiliary malignancies have declined in women, but remained constant in men. Among hepatobiliary malignancies, ICC stands out, because mortality has more than tripled both in men and women between 1998 and 2008. This is mirrored by a marked increase in new cases reported to local cancer registries, that is, incidence. Over the same time period, HCC and extrahepatic cholangiocarcinoma (ECC) have remained largely constant while gall bladder cancers (GBC) have declined twofold. The rapid rise in ICC is in line with finding from different regions worldwide, but in contrast to recent data from Denmark and France, two of Germany's direct neighbors. CONCLUSIONS: The incidence of and mortality from ICC are rising markedly in Germany. The risk factors underlying this trend are as yet unclear. PMID- 21692711 TI - Cytomegalovirus infection of the upper gastrointestinal tract: a clinical and pathological study of 30 cases. AB - OBJECTIVE: The study reviews the endoscopic and histological features of human cytomegalovirus (HCMV) infections of the upper gastrointestinal (UGI) tract. MATERIALS AND METHODS: Clinical histories, endoscopic findings and bioptic specimens of 30 cases of HCMV infection of the UGI tract, diagnosed in a University Hospital in a 10-year period, were reviewed. In all cases, viral inclusion bodies were detected in routine histopathological sections and the diagnosis was confirmed with immunohistochemistry. RESULTS: Six patients were HIV+, whereas four had received organ transplantations, one was affected by common variable immunodeficiency and four had a recent history of malignancy. No other pathologic condition was evidenced in the remaining 15 cases. Mucosal alterations were endoscopically observed in the stomach (19 cases), esophagus (9), cardias (6) and duodenum (1), and multiple organs being synchronously affected in five patients (3 HIV+, 2 with history of malignancy). The antropyloric area was the most frequently affected site. Single ulcers were detected in 11 cases and multiple ulcers in 8, whereas mucosal thickenings (in the form of localized thickenings, polyps or rugal hypertrophy) were present in 13 patients. Thickenings of the mucosa were detected only in the stomach. At histology, necrotic material and granulation tissue were associated with moderate or marked lympho-plasmacytic infiltrate and foveolar hyperplasia in ulcerative lesions, whereas lesions labeled as mucosal thickenings showed mild or moderate chronic inflammatory infiltrate and foveolar hyperplasia. CONCLUSIONS: Endoscopic manifestations of UGI tract involvement in HCMV infection are not specific, varying from erythematous mucosa to ulcers to mucosal thickenings. PMID- 21692714 TI - Research fraud--where to from here? PMID- 21692712 TI - Contemporary use of endoscopic retrograde cholangiopancreatography (ERCP): a Norwegian prospective, multicenter study. AB - OBJECTIVE: Novel imaging modalities have supplanted endoscopic retrograde cholangiopancreatography (ERCP) for the diagnosis of hepatobiliary pancreatic diseases, but the use of ERCP as a diagnostic and therapeutic tool in current clinical practice is not well known. The main objective of this study was to describe and evaluate contemporary use of ERCP in Norway. MATERIAL AND METHODS: Prospective and consecutive data were collected between January 2007 and December 2009 from voluntary institutional reports of ERCP activity at participating hospitals in the Gastronet database. RESULTS: A total of 3840 procedures at 14 hospitals were registered during the study period. Data from 3809 procedures (53% females) were available for evaluation. Patients were >=60 years of age in 2567 (67%) procedures. High co-morbidity (ASA score >=3) was present in 32% of patients. The main indication for ERCP was evaluation and therapy of bile duct related disorders. Successful bile duct cannulation was achieved in 93%. Pre-cut sphincterotomy was performed in 5% of procedures, and a guide wire to facilitate duct access was employed in 63%. Sphincterotomy, treatment for common bile duct stones (CBDS), and an insertion or change of bile duct stents were the most commonly employed procedures. Complications occurred in 10% of the patients, with a procedure-related mortality of 1%. CONCLUSIONS: In Norway, ERCP is predominantly performed for CBDS and biliary strictures in elderly patients with associated co-morbidity. Patient selection, indications, and procedures are in concert with international guidelines and recommendations. Disease patterns in Norway differ slightly from those observed in central Europe and North America. PMID- 21692715 TI - What is happening with hip replacement? PMID- 21692716 TI - Fraud in fluid resuscitation research. PMID- 21692717 TI - Asking the hard questions about safety and quality indicators. PMID- 21692718 TI - Congenital cytomegalovirus--time to diagnosis, management and clinical sequelae in Australia: opportunities for earlier identification. AB - OBJECTIVES: To report on the burden of disease in Australian infants with congenital cytomegalovirus (cCMV) infection in the era of neonatal hearing screening and improved diagnostic techniques. DESIGN, SETTING AND PARTICIPANTS: National data were collected from across Australia via the Australian Paediatric Surveillance Unit (APSU) with monthly reporting by > 1000 clinicians between January 1999 and February 2009. For each reported case, data on investigations and epidemiological and clinical features were analysed. Detailed clinical reviews were performed on 42 infants in two Sydney tertiary paediatric infectious diseases clinics. RESULTS: There were 195 infants with cCMV identified, including 126 definite and 69 probable cases. Of these, 175 (90%) were symptomatic and only 15 were treated with antiviral agents. Identification was delayed beyond 60 days of age in 30 cases (15%). During the period of study, neonatal hearing screening was introduced for most Australian infants. Detection of hearing loss increased from 19% of cCMV cases in 1999-2003 to 31% in 2004-2009. Of 42 infants whose cases were reviewed in detail, 33 (79%) had symptomatic disease. DNA detection of CMV, using polymerase chain reaction testing of newborn screening cards, was useful in retrospective identification, and was strongly correlated with the presence of clinical sequelae (15/18; 83%). CONCLUSIONS: Congenital CMV is underdiagnosed, infrequently treated, and often manifests as isolated hearing loss. Delayed diagnoses both before and after the introduction of neonatal hearing screening represent missed treatment and management opportunities and are likely to lead to poorer, life-long outcomes for these children. Retrospective analysis of newborn screening cards for CMV should be undertaken for infants with sensorineural hearing loss, to identify unrecognised cCMV. PMID- 21692719 TI - A therapeutic equivalence program: evidence-based promotion of more efficient use of medicines. AB - OBJECTIVE: The development of an effective therapeutic equivalence program (TEP) through the collaborative support of medical staff, using the principles of disinvestment. DESIGN AND SETTING: A TEP was introduced at Southern Health, a metropolitan health service in Melbourne, in the 2006-07 financial year. Therapeutic classes were selected for the TEP by stakeholder consensus, and a preferred medication for each class was selected on the basis of cost considerations and therapeutic equivalence. New patients were commenced on preferred medicines, but patients receiving another medicine from a therapeutic class included in the program were not automatically switched to the preferred medicine. For the first 4 years of the program, prescribing patterns were monitored, and savings achieved (due to lower prices for and increased use of preferred medicines) were calculated on a monthly basis. MAIN OUTCOME MEASURES: Prescribing trends for preferred medicines, as a measure of acceptance of the TEP, and savings produced by the program. RESULTS: Over the 4-year study period, 11 therapeutic classes were targeted. The use of all preferred medicines increased once they become part of the TEP and a total of $3.16 million was saved. The annual savings increased each year, and the rate of increase was six times that of the increase in patient separations. CONCLUSIONS: The TEP at Southern Health resulted in significant savings. It showed that, by using a collaborative and evidence-based approach, the principles of disinvestment can be applied to use of medicines. PMID- 21692720 TI - Mapping the limits of safety reporting systems in health care--what lessons can we actually learn? AB - OBJECTIVES: To assess the utility of Australian health care incident reporting systems and determine the depth of information available within a typical system. DESIGN AND SETTING: Incidents relating to patient misidentification occurring between 2004 and 2008 were selected from a sample extracted from a number of Australian health services' incident reporting systems using a manual search function. MAIN OUTCOME MEASURES: Incident type, aetiology (error type) and recovery (error-detection mechanism). Analyses were performed to determine category saturation. RESULTS: All 487 selected incidents could be classified according to incident type. The most prevalent incident type was medication being administered to the wrong patient (25.7%, 125), followed by incidents where a procedure was performed on the wrong patient (15.2%, 74) and incidents where an order for pathology or medical imaging was mislabelled (7.0%, 34). Category saturation was achieved quickly, with about half the total number of incident types identified in the first 13.5% of the incidents. All 43 incident types were classified within 76.2% of the dataset. Fifty-two incident reports (10.7%) included sufficient information to classify specific incident aetiology, and 288 reports (59.1%) had sufficient detailed information to classify a specific incident recovery mechanism. CONCLUSIONS: Incident reporting systems enable the classification of the surface features of an incident and identify common incident types. However, current systems provide little useful information on the underlying aetiology or incident recovery functions. Our study highlights several limitations of incident reporting systems, and provides guidance for improving the use of such systems in quality and safety improvement. PMID- 21692721 TI - Is money spent on quality improvement better spent on clinical care? - Yes. PMID- 21692722 TI - Is money spent on quality improvement better spent on clinical care? - No. PMID- 21692723 TI - Social media and the medical profession. AB - Use of social media by doctors and medical students is common and growing. Although professional standards and codes of ethics that govern the behaviour of medical practitioners in Australia and New Zealand do not currently encompass social media, these codes need to evolve, because professional standards continue to apply in this setting. Inappropriate use of social media can result in harm to patients and the profession, including breaches of confidentiality, defamation of colleagues or employers, and violation of doctor-patient boundaries. The professional integrity of doctors and medical students can also be damaged through problematic interprofessional online relationships, and unintended exposure of personal information to the public, employers or universities. Doctors need to exercise extreme care in their use of social media to ensure they maintain professional standards. PMID- 21692724 TI - Using hospital standardised mortality ratios to assess quality of care--proceed with extreme caution. AB - Australian Health Ministers have endorsed the hospital standardised mortality ratio (HSMR) as a key indicator of quality and safety, and efforts are currently underway towards its national implementation. In the United Kingdom, Canada, the Netherlands and the United States, the HSMR has been used for several years within organisations to monitor performance and response to various quality and safety programs. In the UK and Canada, the HSMR is also publicly reported and used to compare performance between hospitals. The validity and reliability of the HSMR as a screening tool for distinguishing low-quality from high-quality hospitals remain in doubt, and it has not yet been proven that HSMR reporting necessarily leads to worthwhile improvement in quality of care and patient outcomes. Institutions may respond to an unfavourable HSMR by "gaming" administrative data and risk-adjustment models or implementing inappropriate changes to care. Despite its apparent low cost and ease of measurement, the HSMR is currently not "fit for purpose" as a screening tool for detecting low-quality hospitals and should not be used in making interhospital comparisons. It may be better suited to monitoring changes in outcomes over time within individual institutions. PMID- 21692725 TI - Cobalt toxicity--an emerging clinical problem in patients with metal-on-metal hip prostheses? AB - We report two Australian patients with possible cobalt toxicity related to metal on-metal total hip replacements. Both patients were treated for osteoarthritis with a DePuy ASR (articular surface replacement) XL Acetabular Hip System prosthesis, which contains cobalt and chromium, and which has recently been recalled from the market. PMID- 21692726 TI - Murine typhus returns to New South Wales: a case of isolated meningoencephalitis with raised intracranial pressure. AB - Murine typhus (MT) occurs worldwide, but, in Australia, is only regularly diagnosed in south-west Western Australia. Meningoencephalitis is an uncommon complication of MT, often accompanied by rash or systemic involvement. We report a case of MT presenting exclusively with meningoencephalitis, raised intracranial pressure, papilloedema and bilateral 6th cranial nerve palsies. MT should be considered in patients with "aseptic" meningitis or meningoencephalitis, even in the absence of other typical features of a typhus-like illness. PMID- 21692727 TI - Wake up with make-up: complication of cosmetic lid tattoo. PMID- 21692728 TI - Lymphatic filariasis in Australia: an update on presentation, diagnosis and treatment. PMID- 21692729 TI - Public reporting of hospital outcomes: a challenging road ahead. AB - Public reporting of patient outcomes following hospitalisation in Australia is limited compared with other countries. This will change, given recent commitments by state and federal governments to an Australian reporting program as part of health reform. There are numerous challenges in the design and implementation of such a program, including strategic decisions, statistical methods, and preventing risk aversion and perverse behaviour. Experience in other countries is likely to provide valuable lessons and tools for Australia as it seeks to build its reporting capacity. PMID- 21692730 TI - The ASR Hip Resurfacing System: my experience. PMID- 21692731 TI - Allergic contact dermatitis in health care workers to diazolidinyl urea present in antimicrobial hand gel. PMID- 21692732 TI - Consumption of alcohol-based hand sanitisers by hospital inpatients. PMID- 21692733 TI - How accurate are hospital scales? PMID- 21692734 TI - A new algorithm for the management of stable coronary artery disease incorporating CT coronary angiography and fractional flow reserve: how we can improve outcomes and reduce costs. PMID- 21692735 TI - Population and treatment-based incidence estimates of atypical fractures. PMID- 21692736 TI - Doctors breaching patient privacy: Orwell redux. PMID- 21692737 TI - The natural history of an infectious disease: MacFarlane Burnet's contribution to the epidemiology of poliomyelitis. PMID- 21692738 TI - Alerting genetic relatives to a risk of serious inherited disease without a patient's consent. PMID- 21692739 TI - The Easter bunny and the chocolate conspiracy. PMID- 21692740 TI - Therapeutic potential of high mobility group box-1 in ischemic injury and tissue regeneration. AB - High-mobility group box-1 (HMGB1) is a nuclear protein that acts as a cytokine when released into the extracellular milieu by necrotic and inflammatory cells, and is involved in inflammatory responses and tissue repair. This protein is released passively during cellular necrosis by almost all cells that have a nucleus, but is also actively secreted by immune cells such as macrophages and monocytes. This cytokine plays a key role in mediating the local and systemic responses to several stimuli and might have therapeutic relevance. Indeed, vessel associated stem cells, injected into the general circulation of dystrophic mice, migrate to sites of tissue damage in response to the HMGB1 signal, by a nuclear factor-kappaB dependent mechanism. Moreover, endogenous HMGB1 enhances angiogenesis and restores cardiac function in a murine model of myocardial infarction, and the exogenous administration of HMGB1 after myocardial infarction leads to the recovery of left ventricular function through the regeneration of cardiomyocytes. Finally, recent findings show that endogenous HMGB1 is crucial for ischemia-induced angiogenesis in diabetic mice and that HMGB1 protein administration enhances collateral blood flow in the ischemic hind limbs of diabetic mice through a VEGF-dependent manner. The mechanisms of action of this protein are complex and are not well known or defined. The objective of this review is to evaluate the data regarding the tissue regeneration effects of HMGB1, with the aim of providing practical considerations about this topic for the management of subjects affected by ischemic and degenerative diseases. PMID- 21692741 TI - Pathophysiology of thrombosis and potential targeted therapies in antiphospholipid syndrome. AB - The antiphospholipid syndrome (APS) is an autoimmune disease in which recurrent vascular thrombosis, pregnancy morbidity or a combination of these events is associated with the persistent presence of circulating antiphospholipid antibodies (aPL). Evidence shows that the dominant antigenic targets for aPL in APS are phospholipid-binding plasma proteins such as b2glycoprotein I and prothrombin. The pathogenic role of aPL in thrombosis is widely accepted but the mechanisms by which these antibodies mediate disease are only partially understood. aPL may affect the normal procoagulant and anticoagulant reactions occurring on cell surface, and also may interact with certain cells, altering the expression and secretion of procoagulant substances. The intracellular signal transduction triggered by aPL has been a focus of intensive research and the p38 mitogen activated protein kinase (MAPK) pathway has been revealed as a major player in the aPL-mediated cell activation. In addition, some candidates as cell receptor for phospholipid-binding plasma proteins have been identified. The recognition of the intracellular signaling triggered by aPL is a step forward in the design of new modalities of targeted therapies for thrombosis in APS including specific inhibitors of MAPK pathway or antagonists of the putative receptors. Furthermore, novel findings regarding the role of aPL in T-cells responses mark new advances in the understanding of the immunological reactions in APS and open new insights into possible therapeutic approaches to APS. In this article, we review the pathophysiological mechanisms of thrombosis and the specific new targeted therapies for the treatment in APS. PMID- 21692742 TI - TAP-binding peptides prediction by QSAR modeling based on amino acid structural information. AB - The transporter associated with antigen processing (TAP) is essential for peptide delivery from the cytosol into the lumen of the endoplasmic reticulum (ER), where these peptides are loaded on a major histocompatibility complex (MHC) I molecules and form peptide-MHC complex. The peptide-MHC leaves the ER and displays their antigenic cargo on the cell surface to cytotoxic T cells. In this study, 89 physicochemical properties of amino acid were collected from AAIndex database, and used to characterize the peptides which were binding to TAP. Then, the stepwise regression (STR) was used to optimize the parameters which characterized the TAP binding peptides, and the multiple linear regression (MLR) was used to construct the quantitative structural activity relationship (QSAR) model based on optimized parameters. The quantitative models had good reliability and predictive ability: the Q2 of "leave one out" validation is 0.676 and R2 of test dataset is 0.722 respectively. Additionally, the standardized coefficients of the models could demonstrate the attributions for each position of epitope and determine which special amino acid is suitable at any position of the peptide. Therefore, the QSAR model constructed by STR-MLR has many advantages, such as, easier calculation and explanation, good performance, and definite physiochemical indication, which could be used to guide the design and modification of the TAP binding peptide. PMID- 21692743 TI - Structure-retention relationship study of HPLC data of antiepileptic hydantoin analogues. AB - In the study, 18 antiepileptic hydantoin analogues were investigated by means of reversed-phase HPLC on C-18 stationary phase and eluent acetonitrile-water. Quantitative structure-retention relationship (QSRR) study has been applied in order to understand factors that affect the retention which is closely correlated to the activity (ED50 values). To overview the compounds for similarities and dissimilarities principal component analysis (PCA) has been applied. Six multiple linear regression models based on the most relevant descriptors were developed. Descriptors for MLR were selected according to variable importance calculated by partial least squares (PLS) analysis. Besides ALOGP the most important is aromatic ratio for mobile phases with more than 45% of acetonitrile, as well as electrotopological states when the % of acetonitrile is less than 40%. High agreement between experimental and predicted retention, obtained in the validation procedure, indicated the good quality of the derived QSRR models. For individual linear models, crossvalidation squared correlation coefficients (Q2) ranging from 0.697 to 0.837 were obtained. The residual values (difference between observed and calculated) agreed well within experimental error. Additionally, models were compared in terms of the smallest residual value by recently developed method of ranking based on the sum of ranking differences (SRD). PMID- 21692744 TI - Active-pocket size differentiating insectile from bacterial chitinolytic beta-N acetyl-D-hexosaminidases. AB - Chitinolytic beta-N-acetyl-D-hexosaminidase is a branch of the GH20 (glycoside hydrolase family 20) beta-N-acetyl-D-hexosaminidases that is only distributed in insects and micro-organisms, and is therefore a potential target for the action of insecticides. PUGNAc [O-(2-acetamido-2-deoxy-D-glucopyransylidene)-amino-N phenylcarbamate] was initially identified as an inhibitor against GH20 beta-N acetyl-D-hexosaminidases. So far no crystal structure of PUGNAc in complex with any GH20 beta-N-acetyl-D-hexosaminidase has been reported. We show in the present study that the sensitivities of chitinolytic beta-N-acetyl-D-hexosaminidases towards PUGNAc can vary by 100-fold, with the order being OfHex1 (Ostrinia furnacalis beta-N-acetyl-D-hexosaminidase) 0) and severe caries (pufa index > 0), respectively. In the adjusted models, having caries was significantly related to toothache and problems eating certain foods as well as to be absent from school and ashamed to smile, whereas having severe caries was significantly related to toothache and problems eating certain foods only. Neither caries nor severe caries was related to stop playing with other children. CONCLUSIONS: This study shows that caries and severe caries may have a considerable impact on some aspects of preschool children's quality of life. PMID- 21692752 TI - Investigation of Bartonella acquisition and transmission in Xenopsylla ramesis fleas (Siphonaptera: Pulicidae). AB - Bartonella are emerging and re-emerging pathogens affecting humans and a wide variety of animals including rodents. Horizontal transmission of Bartonella species by different hematophagous vectors is well acknowledged but vertical transmission (from mother to offspring) is questionable and was never explored in fleas. The aim of this study was to investigate whether the rodent flea, Xenopsylla ramesis, can acquire native Bartonella from wild rodents and transmit it transovarially. For this aim, Bartonella-free laboratory-reared X. ramesis fleas were placed on six naturally Bartonella-infected rodents and six species matched Bartonella-negative rodents (three Meriones crassus jirds, two Gerbillus nanus gerbils and one Gerbillus dasyurus gerbil) for 7 days, 12-14h per day. The fleas that were placed on the Bartonella-positive rodents acquired four different Bartonella genotypes. Eggs and larvae laid and developed, respectively, by fleas from both rodent groups were collected daily for 7 days and molecularly screened for Bartonella. All eggs and larvae from both groups were found to be negative for Bartonella DNA. Interestingly, two of five gut voids regurgitated by Bartonella-positive fleas contained Bartonella DNA. The naturally infected rodents remained persistently infected with Bartonella for at least 89 days suggesting their capability to serve as competent reservoirs for Bartonella species. The findings in this study indicate that X. ramesis fleas can acquire several Bartonella strains from wild rodents but cannot transmit Bartonella transovarially. PMID- 21692753 TI - Post-stroke fatigue and return to work: a 2-year follow-up. AB - BACKGROUND: Post-stroke fatigue may affect the ability to return to work but quantitative studies are lacking. METHOD: We included 83 first-ever stroke patients <60 years and employed either full-time (n = 77) or part-time (n = 6) at baseline. The patients were recruited from stroke units at Aarhus University Hospital between 2003 and 2005 and were followed for 2 years. Fatigue was assessed by the Multidimensional Fatigue Inventory. Pathological fatigue was defined as a score >=12 on the General Fatigue dimension. Return to paid work was defined as working at least 10 h per week. Data were analyzed using multivariable logistic regression. RESULTS: A total of 58% of patients had returned to paid work after 2 years. The adjusted Odds Ratio (OR) for returning to paid work was 0.39 (95% confidence interval (CI) 0.16-1.08) for patients with a General Fatigue score >=12 at baseline. Persisting pathological fatigue after 2 years of follow up was associated with a lower chance of returning to paid work [adjusted OR 0.29 (95% CI 0.11-0.74)]. Higher scores of General Fatigue at follow-up also correlated negatively with the chance of returning to paid work when analyzing fatigue on a continuous scale (adjusted OR 0.87, 95% CI 0.80-0.94 for each point increase in General Fatigue). CONCLUSIONS: Post-stroke fatigue appears to be an independent determinant of not being able to resume paid work following stroke. PMID- 21692754 TI - A Swedish version of the 16-item Parkinson fatigue scale (PFS-16). AB - BACKGROUND: The PFS-16 is a 16-item fatigue scale for Parkinson's disease (PD) developed in the UK. However, documented translations and psychometric evaluations are sparse. AIM: To translate the PFS-16 into Swedish and conduct initial testing of its psychometric properties. METHODS: Following translation, the PFS-16 was administered twice (2 weeks apart) to 30 people with PD (18 men; mean age/PD duration, 60/6.4 years). The PFS-16 uses five response categories (1 = strongly disagree, 5 = strongly agree), and the total score is the mean over item scores (1-5; 5 = more fatigue). An alternative, dichotomised scoring method has also been suggested (total score, 0-16; 16 = more fatigue). Scaling assumptions, floor/ceiling effects, reliability, and correlations with other variables including the generic fatigue scale Functional Assessment of Chronic Illness Therapy - Fatigue scale (FACIT-F) were tested. RESULTS: Scaling assumptions were generally supported for the original scoring [range of mean (SD) item scores, 2.1-3.3 (1-1.4); corrected item-total correlations, >=0.40], but not for dichotomised scoring [range of mean (SD) item scores, 0.1-0.6 (0.3-0.5); corrected item-total correlations, >=0.16]. Reliabilities were >=0.88. Floor effects were absent (original scoring) and >23% (dichotomised scoring); there were no ceiling effects. Correlations with other variables followed expectations (e.g. -0.88 with FACIT-F scores). CONCLUSIONS: These observations support the psychometric properties of the Swedish PFS-16, but cautions against dichotomised scoring. PMID- 21692755 TI - Glucose metabolism in small subcortical structures in Parkinson's disease. AB - OBJECTIVES: Evidence from experimental animal models of Parkinson's disease (PD) suggests a characteristic pattern of metabolic perturbation in discrete, very small basal ganglia structures. These structures are generally too small to allow valid investigation by conventional positron emission tomography (PET) cameras. However, the high-resolution research tomograph (HRRT) PET system has a resolution of 2 mm, sufficient for the investigation of important structures such as the pallidum and thalamic subnuclei. MATERIALS AND METHODS: Using the HRRT, we performed [(18)F]-fluorodeoxyglucose (FDG) scans on 21 patients with PD and 11 age-matched controls. We employed three types of normalization: white matter, global mean, and data-driven normalization. We performed volume-of-interest analyses of small subcortical gray matter structures. Voxel-based comparisons were performed to investigate the extent of cortical hypometabolism. RESULTS: The most significant level of relative subcortical hypermetabolism was detected in the external pallidum (GPe), irrespective of normalization strategy. Hypermetabolism was suggested also in the internal pallidum, thalamic subnuclei, and the putamen. Widespread cortical hypometabolism was seen in a pattern very similar to previously reported patterns in patients with PD. CONCLUSION: The presence and extent of subcortical hypermetabolism in PD is dependent on type of normalization. However, the present findings suggest that PD, in addition to widespread cortical hypometabolism, is probably characterized by true hypermetabolism in the GPe. This finding was predicted by the animal 2 deoxyglucose autoradiography literature, in which high-magnitude hypermetabolism was also most robustly detected in the GPe. PMID- 21692756 TI - Risk factors for emergency postpartum hysterectomy: the neglected role of previous surgically induced abortions. AB - The objective of this retrospective case-control study was to identify clinical factors associated with emergency peripartum hysterectomy. Deliveries from January 2003 through October 2009 in this tertiary care obstetrics hospital were reviewed. Cases were women who underwent emergency peripartum hysterectomy. Controls were those who delivered immediately after the cases but in whom hysterectomy was not needed. They were matched to cases in a 5:1 ratio. Thirty eight cases and 190 controls were selected. Variables found to be significantly associated with emergency postpartum hysterectomy were a stage III-IV placenta previa (p<0.001), previous surgical abortions (p=0.001) and number of fetuses (p=0.039). The corresponding adjusted odds ratios were 40.2 (95% confidence interval 5.6-287.0), 6.0 (95% confidence interval 2.1-17.2) and 7.8 (95% confidence interval 1.1-55.0), respectively. The study confirms the detrimental role of major placenta previa in influencing the risk of postpartum hysterectomy, but also suggests multiple pregnancy and surgical abortion as potential additional risk factors. PMID- 21692757 TI - Placental abruption and premature rupture of membranes. AB - OBJECTIVE: To assess whether premature rupture of membranes (PROM) is associated with placental abruption. DESIGN: Population-based study. SETTING: Data were extracted from the Medical Birth Registry of Norway. POPULATION: All women with PROM (18,889 cases), including 3,077 cases of preterm premature rupture of membranes (p-PROM), among a total of 355 416 singleton births in Norway during 1999-2005 with gestational age 17-44 weeks. METHODS: Logistic regression was used to assess whether placental abruption was associated with PROM in preterm and term births. MAIN OUTCOME MEASURES: Placental abruption. RESULTS: The occurrence of placental abruption in p-PROM was higher than in the total study population, 11.0 per 1,000 (34 of 3 077) vs. 4.2 per 1 000 (1 495 of 355 416; adjusted odds ratio 2.6, 95% confidence interval 1.8-3.7). Restricting the analyses to preterm births, the occurrence of placental abruption was less in p-PROM (11.0 per 1,000) than in births without p-PROM (36.1 per 1 000; adjusted odds ratio 0.3, 95% confidence interval 0.2-0.4). In term births, no statistically significant association was observed. CONCLUSIONS: The findings suggest that in p-PROM the risk of placental abruption is not higher than in other preterm births; rather the opposite. However, comparing the risks in p-PROM and the total gestational age range, the present study confirmed results reported in previous studies of a higher risk of placental abruption in p-PROM than in the total birth population. PMID- 21692758 TI - Vaginal prolapse--perceptions and healthcare-seeking behavior among women prior to gynecological surgery. AB - OBJECTIVE: To investigate perceptions of vaginal prolapse and healthcare-seeking behavior in women prior to gynecological surgery. DESIGN: Prospective, cross sectional study using a web-based questionnaire. SETTING: Clinics including patients in the Swedish National Register for Gynecological Surgery (Gynop register). POPULATION: 214 women with vaginal prolapse and 347 women without prolapse as reference patients. METHODS: A questionnaire was developed for assessment of women's perception of prolapse and their healthcare-seeking behavior. Data were collected through the Gynop-register. For comparisons between the study groups, Student's t-test and the chi-squared test were used. MAIN OUTCOME MEASURES: Perceptions of prolapse, healthcare-seeking behavior, and source of information. RESULTS: The most common definition of prolapse reported by the women was presence of a vaginal bulge. Reasons for seeking healthcare were interference with physical activity and increasing symptoms. One in five women with prolapse could not relate the symptoms to prolapse. Participants in the prolapse group gained less information on their own condition from brochures and public media compared to participants in the reference group (p<0.001). CONCLUSION: There appeared to be a lack of information on pelvic organ prolapse in the public domain. Healthcare professionals have a significant role to play in informing women about symptoms related to the condition and the available treatment options. PMID- 21692759 TI - Evaluation of a novel needle guide for ultrasound-guided phantom vessel cannulation. AB - We evaluated a novel, sled-mounted needle guide for ultrasound-guided vessel cannulation. Fifty medical students were randomly assigned to use ultrasound with the sled (sled group, n = 23) or ultrasound without the sled (control group, n = 27) for vessel cannulation in a phantom. For each of 15 attempts we recorded cannulation time and designated a successful cannulation as 1 and a failure as 0. Our primary outcome was the mean overall success rate. The median (IQR [range]) number of successes in the sled group and control group were 15.0 (13.0-15.0 [11.0-15.0]) and 11.0 (9.0-13.0 [6.0-15.0]), respectively (p < 0.001). Cannulation time decreased from the first to the last attempt in the sled group from 7.0 s (6.0-10.0 [4.0-16]) s to 4.0 s (3.0-4.0 [1.0-6.0]) s and in the control group from 35.0 s (27.0-35.0 [11.0-35.0]) s to 7.0 s (5.0-10.0 [3.0 25.0]) s. The sled group demonstrated a shorter cannulation time at each attempt (p < 0.001). The novel sled improved the success rate and efficiency of ultrasound-guided phantom vessel cannulation. PMID- 21692760 TI - Ideal versus corrected body weight for dosage of sugammadex in morbidly obese patients. AB - To date, the dosing of sugammadex is based on real body weight without taking fat content into account. We compared the reversal of profound rocuronium-induced neuromuscular blockade in morbidly obese patients using doses of sugammadex based on four different weight corrections. One hundred morbidly obese patients, scheduled for laparoscopic bariatric surgery under propofol-sufentanil anaesthesia, were randomly assigned four groups: ideal body weight; ideal body weight + 20%; ideal body weight + 40%; and real body weight. Patients received sugammadex 2 mg.kg(-1), when adductor pollicis monitoring showed two responses. The primary endpoint was full decurarisation. Secondary endpoints were the ability to get into bed independently on arrival to the post-anaesthetic care unit and clinical signs of residual paralysis. There was no residual paralysis in any patient. Morbidly obese patients can safely be decurarised from rocuronium induced neuromuscular blockade T1-T2 with sugammadex dosed at 2 mg.kg(-1) ideal body weight + 40% (p < 0.0001). PMID- 21692761 TI - Postoperative hypothermia and patient outcomes after elective cardiac surgery. AB - Hypothermia after elective cardiac surgery is an important physiological abnormality and is associated with increased morbidity and mortality. The Australian and New Zealand intensive care adult patient database was studied to obtain the lowest and highest temperature in the first 24 h after surgery. Hypothermia was defined as core temperature < 36 degrees C; transient hypothermia as temperature < 36 degrees C that was corrected within 24 h; and persistent hypothermia as hypothermia that was not corrected within 24 h. Hypothermia occurred in 28,587 out of a total of 43,158 consecutive patients (66%) and was persistent in 111 (0.3%). Transient hypothermia was not independently associated with increased hospital mortality (OR = 0.9, 95% CI 0.8 1.1), whereas persistent hypothermia was associated with markedly increased risk of death (OR = 6.3, 95% CI = 3.3-12.0). Hypothermia is common in postoperative cardiac surgery patients during the first 24 h after ICU admission but, if transient, is not independently associated with an increased risk of death. PMID- 21692762 TI - Varicella-zoster virus antigen expression of eccrine gland and duct epithelium in herpes zoster lesions. AB - BACKGROUND: It is well known that varicella-zoster virus (VZV) exhibits tropism for the epidermis and follicular epithelium, while little attention has been paid to eccrine gland and duct involvement by VZV. The presence of herpetic syringitis in immunocompromised hosts suggested the possibility of eccrine gland and duct involvement by VZV. OBJECTIVES: To determine whether VZV antigens could be detected in eccrine gland or duct epithelium of herpes zoster (HZ) lesions obtained at various intervals after the onset of a rash, and whether this expression could also be detected in eccrine units from other inflammatory disease lesions suggestive of VZV infection. METHODS: We investigated immunohistochemically in vivo localization of VZV glycoprotein E (gE) antigen in HZ lesions and control inflammatory disease lesions, using the murine monoclonal antibody directed against the VZV gE. RESULTS: VZV gE was differentially detected in the epidermis, follicular and eccrine epithelium, and dermal infiltrating cells in HZ lesions obtained at various intervals after onset. The VZV gE was most persistently detected in eccrine units, regardless of the age of individual HZ lesions, compared with keratinocytes and follicular epithelium. the ge expression was also observed in other inflammatory disease lesions suggestive of vzv infection. CONCLUSIONS: Immunohistochemical detection of VZV gE in eccrine epithelium can be a subtle clue to the diagnosis of HZ which displays most unusual manifestations, and VZV-related disorders. PMID- 21692763 TI - IgG-induced clustering of desmogleins 1 and 3 in skin of patients with pemphigus fits with the desmoglein nonassembly depletion hypothesis. AB - BACKGROUND: In pemphigus circulating IgG is present with the desmosomal cadherins desmoglein (Dsg) 1 and 3. In the epidermis of patients, this IgG deposits in a pattern that is often partly granular and does not reflect the normal Dsg distribution. OBJECTIVE: To understand why the IgG deposits in a granular pattern in the skin of patients with pemphigus. PATIENTS/METHODS: We analysed the distribution of IgG and desmosomal adhesion molecules in skin biopsies of 18 patients with pemphigus vulgaris (PV) and 10 with pemphigus foliaceus (PF) by double staining immunofluorescence. The effect of IgG on desmosomal proteins was studied in an in vitro skin model. RESULTS: In PF skin Dsg1, but not Dsg3, was aberrantly distributed in the same partly granular pattern as the IgG. Vice versa, in skin of PV patients with anti-Dsg3 antibodies, Dsg3, but not Dsg1, colocalized with the granular IgG. Plakoglobin also coclustered with IgG and Dsg, but this was far more prominent with Dsg1 than with Dsg3. In areas of heavy Dsg1 clustering, but not in areas of heavy Dsg3 clustering, intercellular widening between keratinocytes was present. Patient IgG, but not Fab fragments, induced the same Dsg clustering in vitro. CONCLUSIONS: The IgG-induced clustering of the Dsg autoantigens underlies the granular IgG deposition in patient skin. In PF and in mucocutaneous PV, Dsg1 clustering, but not Dsg3 clustering, correlates with nonacantholytic intercellular widening between desmosomes. In the patient the Dsg becomes sequestered from desmosomal components which fits in with the desmoglein nonassembly depletion hypothesis, indicating that targeted nonjunctional Dsg is no longer available to be incorporated into desmosomes and this leads to disturbed assembly, and Dsg-depleted desmosomes. PMID- 21692764 TI - Skin conditions are the commonest new reason people present to general practitioners in England and Wales. AB - BACKGROUND: Knowledge of the prevalence and incidence of skin conditions is a prerequisite for designing clinical services and providing appropriate training for primary health care professionals. In the U.K. the general practitioner and practice nurse are the first point of medical contact for persons with skin conditions. OBJECTIVES: We aimed to obtain contemporary data in age-, gender- and diagnosis-specific detail on persons presenting to primary care with skin problems. Comparisons were made with similar data for other major disease groups and with similar data from other recent years. METHODS: We used surveillance data collected in the Weekly Returns Service (WRS) of the Royal College of General Practitioners during 2006 and trend data for subsequent years. The WRS sentinel practices monitor all consultations by clinical diagnosis in a representative population of 950,000 in England and Wales. RESULTS: For conditions included in chapter XII of the International Classification of Diseases Ninth Revision (ICD9), 15% of the population consulted; a further 9% presented with skin problems classified elsewhere in the ICD9, making a total of 24%. There was no evidence of increasing or decreasing trend since 2006. Skin infections were the commonest diagnostic group, while 20% of children < 12 months were diagnosed with atopic eczema. Considered collectively, the incidence of new episodes of skin disorders (including diagnoses outside chapter XII) exceeded incidences for all other major disease groupings. CONCLUSIONS: Compared with other major disease groups, skin conditions are the most frequent reason for consultation in general practice. This result emphasizes the need for appropriate education and training for all medical students and particularly for continuing education in dermatology for all primary health care professionals. PMID- 21692765 TI - Nephrogenic systemic fibrosis is found only among gadolinium-exposed patients with renal insufficiency: a case-control study from Denmark. AB - BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a systemic fibrosing disease associated with exposure to gadolinium-based contrast agents (GBCA) in patients with renal insufficiency. OBJECTIVES: To report the prevalence of NSF in a well defined cohort of patients with renal insufficiency exposed to GBCA, to investigate if GBCA-unexposed controls showed signs of NSF and to evaluate selected risk factors among NSF cases and GBCA-exposed controls. METHODS: A study among GBCA-exposed patients with renal insufficiency (n=565) was conducted to identify cases of NSF. The NSF cases found were age and sex matched and clinically compared with GBCA-exposed and unexposed patients with renal insufficiency in a case-control study. RESULTS: We identified 17 NSF cases. No signs of NSF were observed among the controls. The prevalence of NSF was 4.7%, highest among patients with chronic kidney disease (CKD) stage 5 exposed to GBCA and undergoing haemodialysis or peritoneal dialysis. Three NSF cases were identified among patients with CKD stage 3 and 4. Three patients developed NSF after macrocyclic GBCA exposure. NSF cases had a tendency to have higher serum phosphate concentrations than GBCA-exposed controls. CONCLUSIONS: Our study supports the view that GBCA is a major risk factor for NSF. Importantly, we found that patients with CKD stage 3 and 4 can be at risk of NSF. NSF may also be triggered by macrocyclic GBCA. Further, we observed a trend for higher phosphate levels in NSF cases compared with controls. The important findings drawn from this case-control study indicate that NSF is not an overlooked condition among patients with renal insufficiency not exposed to GBCA. PMID- 21692766 TI - Genetic association of HLA-DQB1 and HLA-DRB1 polymorphisms with alopecia areata in the Italian population. AB - BACKGROUND: Alopecia areata (AA) is a multifactorial disease characterized by hair loss especially from the scalp. As for other autoimmune conditions, the major histocompatibility complex (HLA) region is associated with AA susceptibility. OBJECTIVE: To provide evidence for the association of specific HLA-DQB1 and HLA-DRB1 alleles with AA in an Italian population, using a case control approach. METHODS: We performed a case-control study to investigate whether HLA-DQB1 and -DRB1 alleles predispose to AA in the Italian population. HLA class II typing was performed in 85 patients with AA and 210 healthy controls from the same ethnic group. RESULTS: An increased frequency of DQB1*03, coding for DQ7 heterodimers, and a decreased rate of the DQB1*06 allele were observed in patients when compared with controls; the greatest and significant difference was in the group of cases with a more severe phenotype [AA>50% patients (more than 50% hair loss) vs. controls, P=4.5*10(-3) , P(c)=0.031, odds ratio (OR) 2.01, 95% confidence interval (CI) 1.22-3.31 and P=2.5*10(-3) , P(c)=0.017, OR 0.22, 95% CI 0.07-0.72, respectively]. DQB1*03, serologically related to DQ8 or coding for DQ9 molecules, was not associated with AA susceptibility. Out of all patients, 65.9% carried DQ7 heterodimers compared with 49.5% of the controls (P=7.3*10(-3) , OR 1.97, 95% CI 1.17-3.32) and DQ7 prevalence rose to 76.3% in patients with AA>50% (P=1.7*10(-3) , OR 3.28, 95% CI 1.48-7.27). No significant difference was found in the distribution of DRB1 variants or phenotypes among cases and controls. CONCLUSION: Our data show a correlation between the HLA-DQB1 locus and the occurrence of AA in Italy supporting DQB1*03(DQ7) as a predisposing allele for the disease and the relevance of the HLA genetic test in the clinical management of AA. PMID- 21692767 TI - A functional promoter polymorphism of the human IL18 gene is associated with aspirin-induced urticaria. AB - BACKGROUND: Urticaria is the commonest cutaneous reaction caused by aspirin or other nonsteroidal anti-inflammatory drugs. The pathogenesis of aspirin-induced urticaria (AIU) is not fully understood, but appears to involve mast cell activation and neutrophil infiltration. OBJECTIVES: To investigate the genetic contribution of interleukin (IL)-18, which can amplify acute inflammation by promoting mast cell activation, neutrophil migration and cytokine production, to the pathogenesis of AIU. METHODS: A case-control association study was performed using 275 patients with AIU and 196 normal healthy controls in a Korean population. Two promoter polymorphisms of the IL18 gene (-607A/C and -137G/C) were genotyped using the primer extension method. The functional effect of the IL18 gene promoter polymorphism was investigated through in vitro studies including a luciferase reporter assay and electrophoretic mobility shift assays (EMSAs) and ex vivo studies involving neutrophil chemotaxis assays. RESULTS: A significant association was detected between both AIU in general and the aspirin intolerant acute urticaria (AIAU) phenotype and the IL18 promoter polymorphism 607A/C. Patients with AIAU showed higher frequencies of the C(-607) G(-137) haplotype, ht1 [CG], compared with controls (P=0.02). Moreover, ht1 [CG] showed a high transcript haplotype by the luciferase activity assay, and EMSAs identified a -607C allele-specific DNA-binding protein as CREB2. Neutrophil chemotactic activity was highest in subjects with AIU exhibiting the high transcript haplotype, ht1 [CG] (P=0.019). CONCLUSIONS: The high transcript haplotype ht1 [CG] of the IL18 gene may contribute to the development of acute cutaneous inflammation sensitive to aspirin, leading to the clinical presentation of AIAU. PMID- 21692768 TI - Cross-reactivity among some metals in a murine metal allergy model. AB - BACKGROUND: Information concerning cross-reactivity among metal allergens is scarce. We previously devised a murine metal allergy model using lipopolysaccharide (LPS) as an adjuvant. LPS reduces the minimum allergy-inducing concentration (MAIC) of metals at both the sensitization and the elicitation steps. OBJECTIVES: Here, we examined allergic cross-reactivity among some metals in this murine model, and compared the effects of ultrapure (99.99% or more) and low purity (93-99%) metal salts. METHODS: A mixture of a metal salt and Escherichia coli LPS was injected intraperitoneally into BALB/c mice (0.25 mL per mouse). Ten days later, metal salts (with or without LPS) were challenged to ear pinnas (20 MUL per ear), and ear swelling was measured. RESULTS: Among the ultrapure metals tested (Ni, Pd, Co, Cr, Cu and Au), only Ni and Pd cross reacted. In this cross-reaction, their MAICs were at the same level. Combined challenge with Ni and Pd at sub-MAICs (but not at higher concentrations) produced an additive effect. Surprisingly, mice sensitized with low purity Ni reacted to all the tested low purity metals (Ni, Pd, Co and Cr), and the low purity metals were shown to contain contaminant metals. CONCLUSIONS: In our model: (i) Ni and Pd (members of the same group in the periodic table of elements) cross-react with each other, (ii) this cross-reaction may depend on true and false antigens forming metal-protein complexes with similar spatial geometries, (iii) Co, Cr, Cu and Au do not cross-react with each other, (iv) in low purity materials, trace contaminant metals may be sufficient to evoke allergy, and thus (v) high purity metal salts should be considered for use in clinical patch testing. PMID- 21692769 TI - Patient-reported outcomes in psoriasis research and practice. PMID- 21692770 TI - Costs and cost-effectiveness analysis of treatment in children with eczema by nurse practitioner vs. dermatologist: results of a randomized, controlled trial and a review of international costs. AB - BACKGROUND: In a randomized, controlled trial (RCT) on childhood eczema we reported that substituting nurse practitioners (NPs) for dermatologists resulted in similar outcomes of eczema severity and in the quality of life, and higher patient satisfaction. OBJECTIVES: To determine costs and cost-effectiveness of care provided by NPs vs. dermatologists and to compare our results with those in studies from other countries. METHODS: We estimated the healthcare costs, family costs and the costs in other sectors alongside the RCT. All the costs were linked to quality of life [Infants' Dermatitis Quality of Life Index (IDQOL), Children's Dermatology Life Quality Index (CDLQI)] and to patient satisfaction (Client Satisfaction Questionnaire-8) to determine the incremental cost-effectiveness ratio (ICER). We also examined all the reported studies on the costs of childhood eczema. RESULTS: The mean annual healthcare costs, family costs and costs in other sectors were ?658, ?302 and ?21, respectively, in the NP group and ?801, ?608 and ?0.93, respectively, in the dermatologist group. The ICER in the NP group compared with the dermatologist group indicated ?925 and ?751 savings per one point less improvement in IDQOL and CDLQI, respectively, and ?251 savings per one point more satisfaction in the NP group at 12 months. The mean annual healthcare costs and family costs varied considerably in the six identified studies. CONCLUSIONS: Substituting NPs for dermatologists is both cost-saving and cost-effective. The treatment of choice is that provided by the NPs as it is similarly effective to treatment provided by a dermatologist with a higher parent satisfaction. International comparisons are difficult because the types of costs determined, the units and unit prices, and eczema severity all differ between studies. PMID- 21692771 TI - A topical combination of rapamycin and tacrolimus for the treatment of angiofibroma due to tuberous sclerosis complex (TSC): a pilot study of nine Japanese patients with TSC of different disease severity. AB - BACKGROUND: Dysregulation of mTOR signalling by mutations in tuberin and/or hamartin leads to the formation of tuberous sclerosis complex (TSC). Trials to treat TSC using mTOR inhibitors, including rapamycin, have been performed. Although rapamycin improves many TSC lesions, significant side-effects appear after systemic administration. Topical administration has been recommended. OBJECTIVES: The efficacy of rapamycin-tacrolimus ointment was examined for TSC related angiofibroma. METHODS: Left-right comparisons of the tacrolimus ointments with/without 0.2% rapamycin was conducted in symmetrical facial angiofibromas in nine patients with definitive TSC. After the 3-month treatment, a cumulative score for redness, flatness and papule size was used to evaluate the efficacy of the treatment. Blood rapamycin levels were analysed by liquid chromatography electrospray mass spectrometry (LC-ESI/MS). RESULTS: At the end of the treatment, all of the scores significantly improved for rapamycin-tacrolimus treatment compared with tacrolimus alone. No adverse reactions were noted and blood levels of rapamycin were below the detection limit in all cases. CONCLUSIONS: Topical application of rapamycin-tacrolimus ointment is a safe and useful treatment for TSC-related angiofibroma. PMID- 21692772 TI - A comparative split-face study of photodynamic therapy with indocyanine green and indole-3-acetic acid for the treatment of acne vulgaris. AB - BACKGROUND: Recently, photodynamic therapy (PDT) using a variety of light sources and photosensitizers has been used for the treatment of acne vulgaris. PDT with aminolaevulinic or methylaminolaevulinic acid has also been used in clinical trials as a treatment for acne, but adverse effects such as pain, erythema and pustular eruption are common. Indocyanine green (ICG) and indole-3-acetic acid (IAA), newer photosensitizers, are known to have minimal adverse effects. OBJECTIVES: This study was designed to compare the safety and efficacy of PDT using ICG and PDT using IAA in the treatment of mild to moderate acne vulgaris. METHODS: In this prospective, single-blind, clinical trial, 34 patients with mild to moderate acne were treated with IAA with green light (520 nm) on half of the face and with ICG with near-infrared radiation (805 nm) on the other half. The procedure was carried out five times at 1-week intervals. RESULTS: With regard to acne lesions (inflammatory and noninflammatory) and sebum secretion, there were statistically significant reductions at each time point compared with the baseline values (P < 0.05). However, there were no statistically significant differences between the two treatment types (P > 0.05). Both ICG-PDT and IAA-PDT showed better responses for inflammatory lesions than for noninflammatory lesions (P < 0.05). Subjective satisfaction score were statistically significant at 4 and 5 weeks of treatment as well as at 1, 2 and 3 months follow-up (P < 0.05). CONCLUSIONS: Both PDT with ICG and PDT with IAA are safe and effective for the treatment of mild to moderate acne vulgaris. PMID- 21692773 TI - Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. AB - Rosacea is a common chronic skin disease affecting the face. There are numerous treatment options, but it is unclear which are the most effective. The aim of this review was to assess the evidence for the efficacy and safety of treatments for rosacea. Searches included the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index, and Ongoing Trials Registers (updated February 2011). Randomized controlled trials in people with moderate to severe rosacea were included. Fifty-eight trials, including 27 from the original review, comprising 6633 participants were included in this updated review. Interventions included topical metronidazole, oral antibiotics, topical azelaic cream or gel, topical benzoyl peroxide and/or combined with topical antibiotics, sulphacetamide/sulphur, and others. There was some evidence that topical metronidazole and azelaic acid were more effective than placebo. Two trials indicated that doxycycline 40mg was more effective than placebo. There was no statistically significant difference in effectiveness between doxycycline 40mg and 100mg but there were fewer adverse effects. One study reported that ciclosporin ophthalmic emulsion was significantly more effective than artificial tears for treating ocular rosacea. Although the majority of included studies were assessed as being at high or unclear risk of bias, there was some evidence to support the effectiveness of topical metronidazole, azelaic acid and doxycycline (40mg) in the treatment of moderate to severe rosacea, and ciclosporin 0.05% ophthalmic emulsion for ocular rosacea. Further well-designed, adequately powered randomized controlled trials are required. PMID- 21692774 TI - Immunofluorescence serration pattern analysis as a diagnostic criterion in antilaminin-332 mucous membrane pemphigoid: immunopathological findings and clinical experience in 10 Dutch patients. AB - BACKGROUND: Antilaminin-332 mucous membrane pemphigoid (anti-LN-332 MMP) is a chronic subepidermal blistering disease characterized by IgG anti-epidermal basement membrane zone (BMZ) autoantibodies against laminin-332 (LN-332). PATIENTS: with anti-LN-332 MMP have an increased relative risk of malignancy. Laboratory techniques that are difficult to obtain are needed for diagnosis of anti-LN-332 MMP. Objectives To incorporate direct immunofluorescence (DIF) serration pattern analysis of IgG depositions in the diagnostic criteria of anti LN-332 MMP. METHODS: Patients who met our revised inclusion criteria for anti-LN 332 MMP were selected from our biobank over the period 1997-2009. Inclusion criteria were clinical symptoms, DIF serration pattern analysis, indirect immunofluorescence (IIF) on salt-split skin, and antigen-specificity analysis of the serum including immunoblotting and/or immunoprecipitation and/or enzyme linked immunosorbent assay (ELISA) against native LN-332. RESULTS: Ten patients met the inclusion criteria. A malignancy was found in two patients (20%). In all patients in whom it was performed (n = 9), DIF showed linear IgG deposition along the BMZ in an n-serrated pattern. Nine sera reacted by salt-split skin analysis and bound to the dermal side of the split skin. ELISA against native LN-332 was positive in 78% of the tested sera. CONCLUSIONS: Anti-LN-332 MMP can clinically resemble other forms of pemphigoid. Although state-of-the-art laboratory diagnostics are necessary for definite diagnosis, the combination of simple DIF serration pattern and IIF salt-split skin analysis will exclude other forms of MMP and epidermolysis bullosa acquisita from the differential diagnosis. Because of the increased risk for malignancy patients should be thoroughly oncologically screened. PMID- 21692775 TI - Novel filaggrin mutation but no other loss-of-function variants found in Ethiopian patients with atopic dermatitis. AB - BACKGROUND: Filaggrin is a key protein involved in maintaining skin barrier function and hydration. Mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and are a major predisposing factor for atopic dermatitis (AD) in individuals of European and Asian descent. It has been proposed that FLG mutations are population specific and a difference in the spectra of mutations between different ancestral groups has been described. However, it is unknown whether FLG mutations in the African population are a causative genetic factor for IV and predispose to AD, or whether other mechanisms are more prominent. OBJECTIVES: The present aim was to investigate the role of FLG mutations as predisposing factors for IV or AD among individuals from Ethiopia. METHODS: A case series of Ethiopian patients with AD (n = 103) and IV (n = 7) together with controls (n = 103; subjects without past or present history of AD, dry skin or atopic manifestations) was collected at the outpatient dermatology clinics at ALERT Dermatology Hospital, Tikur Anbessa Hospital and Gondar University Hospital, Ethiopia. AD was diagnosed by a dermatologist using the U.K. Working Party's diagnostic criteria. The IV diagnosis was based on clinical examination and genetic testing of the steroid sulphatase gene to exclude X-linked recessive ichthyosis. Patients were studied with direct sequencing (n = 40) and/or allelic discrimination (n = 110). Immunohistochemical analysis was performed for filaggrin expression in the skin of patients (n = 7) and controls (n = 2). RESULTS: The Ethiopian patients and controls were genotyped for the four previously described common European FLG null mutations (R501X, 2282del4, S3247X, R2447X) and no carriers were found. In one patient with AD a novel heterozygous 2 bp deletion, 632del2, leading to a premature stop codon was revealed by direct sequencing. No additional carrier of this deletion or other mutations was found. In addition, no difference in filaggrin expression was detected in AD or IV skin compared with healthy control skin. CONCLUSIONS: Our results indicate that FLG loss-of-function-variants are less common in patients with IV and AD in the Ethiopian population, suggesting that other factors may be of importance in the pathogenesis in this ethnic group. PMID- 21692776 TI - Treatment of facial angiofibromas with topical application of oral rapamycin solution (1mgmL(-1) ) in two patients with tuberous sclerosis. PMID- 21692777 TI - Midline axon guidance and human genetic disorders. AB - In bilaterally symmetric animals, many axons cross the midline to interconnect the left and right sides of the central nervous system (CNS). This process is critical for the establishment of neural circuits that control the proper integration of information perceived by the organism and the resulting response. While neurons at different levels of the CNS project axons across the midline, the molecules that regulate this process are common to many if not all midline crossing regions. This article reviews the molecules that function as guidance cues at the midline in the developing vertebrate spinal cord, cortico-spinal tract and corpus callosum. As well, we describe the mutations that have been identified in humans that are linked to axon guidance and midline-crossing defects. PMID- 21692778 TI - Clinical and pharmacy utilization outcomes with brand to generic antiepileptic switches in patients with epilepsy. AB - PURPOSE: To determine if switching from select branded to generic equivalent antiepileptic drugs (AEDs) in patients with epilepsy is associated with adverse outcomes. METHODS: A retrospective cohort study using a large health insurance plan claims database comparing patients with epilepsy who switched from brand to generic equivalent phenytoin, lamotrigine, or divalproex after 6 months (switch cohorts) to matched patients who remained on the brand (nonswitch cohorts). Primary outcomes measured include the incidence rate ratio (IRR) of discontinuation of the index AED; change in dose of index AED or addition of another AED; and the event rate ratio (ERR) of the composite of all-cause emergency department (ED) visits or hospitalizations. KEY FINDINGS: Lamotrigine and divalproex showed no differences in AED utilization changes between the switchers and nonswitchers [IRR for lamotrigine 1.00, 95% confidence interval (CI) 0.84-1.19; IRR for divalproex 1.02, 95% CI, 0.88-1.42]. Compared with nonswitchers, the phenytoin switch cohort had greater incidence of AED utilization changes (IRR 1.85, 95% CI 1.50-2.29). The switch versus nonswitch cohorts did not demonstrate differences in ED visits or hospitalizations for the studied AEDs (ERR for phenytoin 0.96, 95% CI 0.80-1.16; ERR for lamotrigine 0.97, 95% CI 0.80-1.17; ERR for divalproex 0.83, 95% CI 0.66-1.06). SIGNIFICANCE: Brand to generic switching of phenytoin was not associated with more clinical events but was associated with increased index drug discontinuations, dose changes, or therapy augmentations. Lamotrigine or divalproex brand to generic switching was not associated with increased incidence of events or utilization changes compared with patients remaining on the branded product. Changes in AED utilization may be more sensitive than ED visits and hospitalizations for detecting adverse outcomes. PMID- 21692779 TI - The effect of topiramate monotherapy on bone mineral density and markers of bone and mineral metabolism in premenopausal women with epilepsy. AB - PURPOSE: To investigate the effect of topiramate on bone mass and metabolism in premenopausal women with epilepsy. METHODS: Thirty-six women on long-term (at least 1 year) topiramate monotherapy were compared with 36 women taking carbamazepine, 32 women taking valproate, and 36 age- and sex-matched controls. Subjects completed bone mineral density (BMD) studies. Serum was analyzed for indices of bone metabolism. KEY FINDINGS: BMD Z-scores, and serum 25 hydroxyvitamin D and 1alpha,25-dihydroxyvitamin D(3) concentrations did not differ among the groups. Serum calcium concentrations were significantly lower in patients receiving topiramate than in those receiving valproate, and in patients receiving carbamazepine than in those receiving valproate and controls. Patients taking topiramate had lower levels of parathyroid hormone compared with controls and those taking carbamazepine or valproate. Patients receiving topiramate had higher levels of bone-specific alkaline phosphatase and osteocalcin when compared with controls and higher levels of C-terminal telopeptide of type 1 collagen when compared with those taking carbamazepine or valproate. Patients receiving carbamazepine had higher levels of bone-specific alkaline phosphatase compared with controls and those receiving valproate. Serum bicarbonate concentrations were significantly lower in patients receiving topiramate than in the other groups. SIGNIFICANCE: Our results demonstrate that use of topiramate is associated with lower parathyroid hormone and bicarbonate concentrations along with mild hypocalcemia and increased bone turnover, which suggests that topiramate may have long-term effects on bone. PMID- 21692780 TI - Excitatory action of GABA on immature neurons is not due to absence of ketone bodies metabolites or other energy substrates. AB - Brain slices incubated with glucose have provided most of our knowledge on cellular, synaptic, and network driven mechanisms. It has been recently suggested that gamma-aminobutyric acid (GABA) excites neonatal neurons in conventional glucose-perfused slices but not when ketone bodies metabolites, pyruvate, and/or lactate are added, suggesting that the excitatory actions of GABA are due to energy deprivation when glucose is the sole energy source. In this article, we review the vast number of studies that show that slices are not energy deprived in glucose-containing medium, and that addition of other energy substrates at physiologic concentrations does not alter the excitatory actions of GABA on neonatal neurons. In contrast, lactate, like other weak acids, can produce an intracellular acidification that will cause a reduction of intracellular chloride and a shift of GABA actions. The effects of high concentrations of lactate, and particularly of pyruvate (4-5 mm), as used are relevant primarily to pathologic conditions; these concentrations not being found in the brain in normal "control" conditions. Slices in glucose-containing medium may not be ideal, but additional energy substrates neither correspond to physiologic conditions nor alter GABA actions. In keeping with extensive observations in a wide range of animal species and brain structures, GABA depolarizes immature neurons and the reduction of the intracellular concentration of chloride ([Cl(-)](i)) is a basic property of brain maturation that has been preserved throughout evolution. In addition, this developmental sequence has important clinical implications, notably concerning the higher incidence of seizures early in life and their long-lasting deleterious sequels. Immature neurons have difficulties exporting chloride that accumulates during seizures, leading to permanent increase of [Cl(-)](i) that converts the inhibitory actions of GABA to excitatory and hampers the efficacy of GABA-acting antiepileptic drugs. PMID- 21692781 TI - The Caries Assessment Spectrum and Treatment (CAST) index: rational and development. AB - Serious difficulties in reporting results were encountered when using ICDAS II and PUFA separately in an epidemiological survey in a child population in Brazil. That necessitated the development of a comprehensive but pragmatic caries assessment index. This publication describes the rationale, development and content of a novel caries assessment index. Strengths and weaknesses of ICDAS II, PUFA and other indices were analysed. The novel caries index developed for use in epidemiological surveys is termed 'Caries Assessment Spectrum and Treatment' (CAST). 'Spectrum' indicates what is considered the main strength of the new index - its usefulness in describing the complete range of stages of carious lesion progression: from no carious lesion, through caries protection (sealant) and caries cure (restoration) to lesions in enamel and dentine, and the advanced stages of carious lesion progression in pulpal and tooth-surrounding tissue. CAST combines elements of the ICDAS II and PUFA indices, and the M- and F-components of the DMF index. A DMF score can easily be calculated from the CAST score, thereby enabling retention of the use of existing DMF scores. The CAST index for use in epidemiological surveys is very promising. It should be validated and its reliability and usefulness be tested in different age groups in different countries and cultures. PMID- 21692782 TI - Political priority of global oral health: an analysis of reasons for international neglect. AB - Global Oral Health suffers from a lack of political attention, particularly in low- and middle-income countries. This paper analyses the reasons for this political neglect through the lens of four areas of political power: the power of the ideas, the power of the issue, the power of the actors, and the power of the political context (using a modified Political Power Framework by Shiffman and Smith. Lancet370 [2007] 1370). The analysis reveals that political priority for global oral health is low, resulting from a set of complex issues deeply rooted in the current global oral health sector, its stakeholders and their remit, the lack of coherence and coalescence; as well as the lack of agreement on the problem, its portrayal and possible solutions. The shortcomings and weaknesses demonstrated in the analysis range from rather basic matters, such as defining the issue in an agreed way, to complex and multi-levelled issues concerning appropriate data collection and agreement on adequate solutions. The political priority of Global Oral Health can only be improved by addressing the underlying reasons that resulted in the wide disconnection between the international health discourse and the small sector of Global Oral Health. We hope that this analysis may serve as a starting point for a long overdue, broad and candid international analysis of political, social, cultural, communication, financial and other factors related to better prioritisation of oral health. Without such an analysis and the resulting concerted action the inequities in Global Oral Health will grow and increasingly impact on health systems, development and, most importantly, human lives. PMID- 21692783 TI - Efficacy of an electric toothbrush on plaque control compared to two manual toothbrushes. AB - OBJECTIVES: This study aimed to compare an electric toothbrush with two manual toothbrushes, in their relative efficacy to control plaque. DESIGN: Randomised clinical trial. SETTING: Kerman Dental School, Iran. PARTICIPANTS: Forty-five volunteer dental students were randomly assigned to one of three groups. All subjects received a baseline plaque assessment using O'Leary plaque index, and then a prophylaxis to achieve the plaque index of zero. Subjects were trained to brush twice daily, with their assigned device and return after 1week and then after 2weeks for plaque assessment. Chi-squared and ANOVA were mainly used. MAIN OUTCOME MEASURE: Plaque assessment using O'Leary plaque index. RESULTS: Although Jordan toothbrush consistently resulted in lower plaque indices compared to both manual toothbrushes, those differences were not statistically significant, F(2, 42)=2.45, P=0.10. Plaque reduction from week 1 to week 2 was significant in Jordan Power group (60%, from 13.46 to 5.44, P=0.010) and Panbehriz Classic group (53%, from 20.92 to 9.91, P=0.007). CONCLUSION: The results of this study shows no evidence of statistically significant difference in respect to plaque control, between Jordan Power electric toothbrush and either of Oral-B Advantage or Panbehriz Classic manual brushes in a group of dental students after 2weeks. PMID- 21692784 TI - Holding up the oral health safety net: the role of National Health Service Corps alumni dentists in North Carolina. AB - BACKGROUND: Access to oral health care among low income populations is a growing problem. The National Health Service Corps (NHSC) might increase the supply of dentists motivated to provide services for this population. OBJECTIVE: To determine if North Carolina dentists who began a service obligation with the NHSC in 1990-1999 continued to provide care for underserved populations and if they differ from non-NHSC alumni primary care dentists who started practice in the state during that same period. METHODS: All 19 NHSC alumni and 50 comparison dentists were surveyed by mail. NHSC alumni also responded to selected items in a telephone follow-up interview. The two groups were compared using difference of means tests and multivariate contingency tables. RESULTS: National Health Service Corps alumni were more likely to be African-American (38%vs. 10%), work in safety net practices (84%vs. 23%), and see more publicly insured patients (60%vs. 19%) than comparison dentists. Yet their job satisfaction was comparable to non-NHSC alumni dentists. Analyses suggested that current practice in safety net settings is affected by dentists' race, altruistic motivations and previous NHSC participation. CONCLUSION AND POLICY IMPLICATION: Targeted recruitment of African-American dentists and others wanting to work in underserved communities could amplify the effectiveness of the financial incentive of NHSC loan repayment and induce dentists to remain in 'safety net' settings. PMID- 21692785 TI - Dental caries prevalence and treatment needs of 5- to 12-year-old children in relation to area-based income and immigrant background in Greece. AB - OBJECTIVES: To investigate the association between certain socio-demographic characteristics and dental health status of 5- to 12-year-old children attending public kindergarten and primary schools in Piraeus, Greece. METHODS: Gender, age, place of residence, immigrant background and area-based income were associated with dental caries prevalence, treatment needs and oral hygiene level in 5,116 children. RESULTS: The mean number of decayed, missing and filled deciduous teeth (dmft) and Unmet Restorative Treatment Needs Index (UTN) at 6 year-olds were 1.54 and 84.6% respectively, and the DMFT and UTN at 12-year-olds were 1.35 and 71.8%. Caries experience/severity significantly increased with age, whereas treatment needs and oral hygiene level decreased (P<0.001). Immigrant background and low area-based income was associated with poorer oral health outcomes. The above associations retained statistical significance after multivariate analysis. Children who live in areas with lower average income present 1.20 to 2.14 greater risk of having higher caries severity and poorer oral hygiene in comparison to those living in more affluent areas, and children with an immigrant background have 1.68 to 4.34 higher likelihood to present higher dmft and DMFT values, higher unmet treatment needs, and poorer oral hygiene levels compared to their Greek counterparts above and beyond the effect of the other risk factors assessed. CONCLUSIONS: The present study revealed a socio-demographic gradient in oral health status and treatment needs of children in Piraeus, Greece. PMID- 21692786 TI - Social nicotine dependence in Australian dental undergraduate students. AB - OBJECTIVES: This study aimed to investigate dental undergraduate students' tobacco usage and social nicotine dependence in Australia. A special interest was to identify the role of factors such as age, gender, year of dental education and cohabitants' smoking status for social nicotine dependence. MATERIALS AND METHODS: A sample of 252, first-to-fifth year undergraduate students in an Australian dental school was used. Each completed a self-administered questionnaire. RESULTS: The smoking rate was 4.8%. Current smokers displayed higher social nicotine dependence than those that had never smoked (t=3.1, df=244, P=0.002). Dental undergraduate students that showed higher social nicotine dependence (P=0.001, OR=1.3, 95% CI: 1.1-1.6), or that had smoking cohabitants (P=0.016, OR=4.8, 95% CI: 1.3-17.0), were more likely to smoke. Students' social nicotine dependence increased with year of dental study (P=0.043, beta=0.4, t=2.0). Social nicotine dependence enhanced tobacco usage among Year-1-to-4 students (P=0.005, OR=1.4, 95% CI: 1.1-1.7) but not Year-5 undergraduates (P=0.432). CONCLUSIONS: Social nicotine dependence has become a developing issue in dental education. Tobacco control should be highlighted in the dental curriculum. Future investigations into the effects of dental education on social nocotine dependence and tobacco usage are indicated. PMID- 21692787 TI - Oral health status of 5-year-old Aborigine children compared with similar aged marginalised group in south western India. AB - OBJECTIVE: To compare and assess oral health status of 5-year-old Aborigine children with similar aged, marginalised children in coastal region of south western India. MATERIALS AND METHODS: A total of 418 Aborigine children were invited to participate in the study and a total of 428, 5-year-olds were selected randomly for comparison from other government schools to form the other marginalised group. The WHO (1997) proforma was used for clinical examinations. Chi Square test was used to compare between categorical variables. Mann-Whitney U test was used for comparison between the two groups for quantitative variables. Logistic and linear regression analysis was performed to determine the importance of the factors associated with caries status. Odds ratio was calculated for all variables with 95% confidence intervals. P<=0.05 was considered as statistically significant. RESULTS: Dental fluorosis was present in 50 (11.9%) Aborigine children, whereas in the other marginalised group 7 (1.6%) children had dental fluorosis (P<=0.001). Untreated dental caries was 76.3% for the Aborigine children and 70.3% in the comparison group. Mean dmft values in the two groups were 4.13+/-3.90 and 3.58+/-3.60, respectively (P>0.01). High frequency of between-meal sugar consumption was related to dental caries (OR =1.20; P=0.001). Utilisation of dental care and dental fluorosis were inversely related to dental caries (OR=1.16; P=0.001 and OR=1.91; P=0.001). CONCLUSION: The study revealed poor oral health status among both the marginalised groups. Significant differences were noted between the two groups with respect to oral hygiene practices, dietary habits, and dental utilisation pattern. Schools for tribal children, male gender, low frequency of cleaning teeth and higher in between-meal sugar consumption were significantly related to dental caries. PMID- 21692788 TI - Assessment of errors and misused statistics in dental research. AB - OBJECTIVES: The goal of the study is to assess the level of misused statistics or statistical errors in dental research, and identify the major source of statistical errors prevalent in dental literature. METHODS: A total of 418 papers, published between 1995 and 2009, was randomly selected from 10 well established dental journals. Every paper in the sample underwent careful scrutiny for the correct use of statistics. Of these, there were 111 papers for which we were unable to judge whether or not the use of statistics was appropriate, due to insufficient information presented in the paper; leaving 307 papers for this study. A paper with at least one statistical error has been classified as 'Misuse of statistics', and a paper without any statistical errors as 'Acceptable'. Statistical errors also included misinterpretation of statistical analytical results. RESULT: Our investigation showed that 149 were acceptable and 158 contained at least one misuse of statistics or a statistical error. CONCLUSION: This gave the misuse rate of 51.5%, which is slightly lower than that reported by several studies completed for the medical literature. PMID- 21692789 TI - Oral health behaviours according to demographic characteristics in Korean adolescents: a national representative sample. AB - OBJECTIVES: To provide information on how to teach correct oral health behaviour to youths and to develop programmes to that end, this study examined the oral health behaviour and demographic characteristics of adolescents. METHODS: The raw data of 'The Third 2007 Youth Health Behavior Online Survey' carried out by the Korea Center for Disease Control and Prevention were analysed. Independent t-test, one-way ANOVA, and chi-squared analyses were used to assess the relationships between oral health behaviours and demographic characteristics. RESULTS: The oral health behaviour of the adolescents who were investigated differed significantly depending on their demographic characteristics (P<0.001). Tooth brushing frequency differed significantly depending on gender and student grade (P<0.001) and the frequency of visits to a dental clinic differed depending on the gender, student grade, type of residential area (urban/rural), and type of school (middle or high) (P<0.001). School grade, type of residential area, and type of school also affected the likelihood of receiving preventive dental treatment (P<0.001). CONCLUSIONS: Adolescents who were in lower grades, female, and lived in large urban communities visited dental clinics more frequently and received more preventive dental treatment than adolescents who were in higher grades, male and resided in small urban and rural areas. These results highlight the need for the further development and dissemination of oral health programmes. PMID- 21692790 TI - The impact of depression and anxiety disorder symptoms on the health-related quality of life of children and adolescents with epilepsy. AB - This study evaluated the effects of depression and anxiety disorder symptoms on the health-related quality of life (HRQOL) of children and adolescents with epilepsy. Sixty children and adolescents and their parents participated in the study. Symptoms of anxiety disorders were identified by the Screen for Child Anxiety Related Emotional Disorders questionnaire (SCARED) and symptoms of depression by the Mood and Feeling Questionnaire (MFQ). The Pediatric Quality of Life Inventory (PedsQL) was used for HRQOL assessments. A series of simple and partial correlations revealed that the levels of HRQOL significantly decrease as symptoms of depression or anxiety disorders increase and vice versa. Stepwise regression method of children's ratings resulted in a final model of school achievement and symptoms of generalized anxiety and separation anxiety disorder as predictors that explain 50.9% of the variation in HRQOL (F = 11.21, p < 0.000). For parents' ratings, the final model included symptoms of depression and separation anxiety disorder as predictors that explain 38.4% of the variation in HRQOL (F = 10.82, p < 0.000). In summary, symptoms of depression and generalized and separation anxiety disorders have the most significant impact on HRQOL. PMID- 21692791 TI - A retrospective population-based study on seizures related to childhood vaccination. AB - PURPOSE: Cases of severe childhood epilepsies in temporal association with vaccination have great impact on the acceptance of vaccination programs by parents and health care providers. However, little is known about the type and frequency of seizures and epilepsy syndromes following vaccination. This study aims to describe the clinical features of children presenting with seizures after vaccination using a register-based cohort. METHODS: We surveyed the national German database of adverse events following immunization (AEFI) for reported seizures and epilepsies in children aged 0-6 years. All cases reported in 2006 2008 were analyzed retrospectively; available clinical information was reevaluated and classified by seizure type and epilepsy syndrome. KEY FINDINGS: In total, 328 cases reported between 2006 and 2008 were included. Data supportive of seizures or epilepsy were present in 247 (75.3%) of 328 patients with a mean interval between the vaccination and the epileptic event of 24 h and 7.5 days for inactivated and attenuated vaccines, respectively. Fifty-one (15.5%) of 328 patients presented with syncope, hypotonic-hyporesponsive episodes, or other nonepileptic events. Information was insufficient for classification into epileptic versus nonepileptic events in 30 (11.3%) of 328 patients. For cases with confirmed seizures, febrile seizures were present in 121 (49%) of 247 cases, and 38 (15.4%) of 247 patients had single afebrile seizures. Status epilepticus was described in 21 (8.5%) of 247 patients. Thirty-one (12.6%) of 247 patients presented with various pediatric epilepsy syndromes. Severe childhood epilepsies (Dravet syndrome, West syndrome, Lennox-Gastaut syndrome, or Doose syndrome) were diagnosed in 29 (11.7%) of 247 patients, with the vaccination-associated event being the first documented seizure in 15 (51.7%) of 29 patients. SIGNIFICANCE: Vaccination-associated seizures present in the setting of various epilepsy syndromes, including severe childhood epilepsies in >10% of cases. Early diagnosis of the corresponding epilepsy syndromes and confirmation of an underlying etiology is important for treatment decisions, genetic counseling, and public health evaluation of vaccine safety. PMID- 21692792 TI - The prevalence of atypical presentations and comorbidities of benign childhood epilepsy with centrotemporal spikes. AB - PURPOSE: Benign childhood epilepsy with centrotemporal spikes (BCECTS) is the most common epileptic syndrome in childhood. The outcome is usually excellent, but there are some atypical forms of BCECTS with less favorable outcomes. The aim of this study was to delineate the frequency of these atypical features among patients with BCECTS. METHODS: We conducted a retrospective chart study by retrieving the medical records of all consecutive patients with BCECTS who were evaluated in four pediatric neurology outpatient clinics in Israel between the years 1991 and 2008. KEY FINDINGS: A total of 196 patients with BCECTS were identified (78 female and 118 male; mean age at time of diagnosis 7.64 years, range 1.5-14). The mean duration of follow-up was 4.43 years (range 2-11). Nine patients (4.6%) developed electrical status epilepticus in slow waves sleep (ESES) during follow-up, four (2%) had Landau-Kleffner syndrome, three (1.5%) had BCECTS with frequent refractory seizures, two (1%) had BCECTS with falls at presentation, one (0.5%) had a "classic" atypical variant, and one (0.5%) had oromotor dysfunction. None had rolandic status epilepticus. Sixty-one patients (31%) had attention deficit hyperactivity disorder (ADHD), 43 (21.9%) had specific cognitive deficits, and 23 (11.7%) had behavioral abnormalities, including aggressiveness, anxiety disorders, depression, and pervasive developmental disorder (PDD). SIGNIFICANCE: The prevalence of most atypical forms of BCECTS other than ESES is low. There is, however, a high prevalence of ADHD and specific cognitive deficits among patients with BCECTS. PMID- 21692793 TI - Epilepsy causing pupillary hippus: an unusual semiology. AB - Altered pupillary behavior is commonly present during and following epileptic seizures, but symptomatic pupillary hippus as the main feature of a seizure has not been reported in the modern literature. We present the case of a woman with epileptic seizures consisting of sustained fluctuation of perception of brightness. Bilateral pupillary hippus is the main semiologic feature.This autonomic phenomenon is selective for the pupils and does not involve other autonomic-mediated responses. An ictal video illustrates this phenomenon. The epileptogenic region, determined by ictal scalp and intracranial electroencephalography (EEG), is localized in the right posterior parietooccipital areas. Pupillary reflexes can be overridden by cortical input; here authors review the literature and discus the physiologic mechanisms underlying this autonomic phenomenon. Fluctuation in perceptual brightness during epileptic seizures may have a basis in ictal pupillary hippus. PMID- 21692794 TI - Seizure prediction with spectral power of EEG using cost-sensitive support vector machines. AB - PURPOSE: We propose a patient-specific algorithm for seizure prediction using multiple features of spectral power from electroencephalogram (EEG) and support vector machine (SVM) classification. METHODS: The proposed patient-specific algorithm consists of preprocessing, feature extraction, SVM classification, and postprocessing. Preprocessing removes artifacts of intracranial EEG recordings and they are further preprocessed in bipolar and/or time-differential methods. Features of spectral power of raw, or bipolar and/or time-differential intracranial EEG (iEEG) recordings in nine bands are extracted from a sliding 20 s-long and half-overlapped window. Nine bands are selected based on standard EEG frequency bands, but the wide gamma bands are split into four. Cost-sensitive SVMs are used for classification of preictal and interictal samples, and double cross-validation is used to achieve in-sample optimization and out-of-sample testing. We postprocess SVM classification outputs using the Kalman Filter and it removes sporadic and isolated false alarms. The algorithm has been tested on iEEG of 18 patients of 20 available in the Freiburg EEG database who had three or more seizure events. To investigate the discriminability of the features between preictal and interictal, we use the Kernel Fisher Discriminant analysis. KEY FINDINGS: The proposed patient-specific algorithm for seizure prediction has achieved high sensitivity of 97.5% with total 80 seizure events and a low false alarm rate of 0.27 per hour and total false prediction times of 13.0% over a total of 433.2 interictal hours by bipolar preprocessing (92.5% sensitivity, a false positive rate of 0.20 per hour, and false prediction times of 9.5% by time differential preprocessing). This high prediction rate demonstrates that seizures can be predicted by the patient-specific approach using linear features of spectral power and nonlinear classifiers. Bipolar and/or time-differential preprocessing significantly improves sensitivity and specificity. Spectral powers in high gamma bands are the most discriminating features between preictal and interictal. SIGNIFICANCE: High sensitivity and specificity are achieved by nonlinear classification of linear features of spectral power. Power changes in certain frequency bands already demonstrated their possibilities for seizure prediction indicators, but we have demonstrated that combining those spectral power features and classifying them in a multivariate approach led to much higher prediction rates. Employing only linear features is advantageous, especially when it comes to an implantable device, because they can be computed rapidly with low power consumption. PMID- 21692795 TI - Refractory neonatal epilepsy with a de novo duplication of chromosome 2q24.2q24.3. AB - There are only two reports on epileptic patients associated with microduplication of 2q. We found a de novo duplication of chromosome 2q24.2q24.3 in another infant with neonatal epilepsy. The patient had refractory focal seizures since the third day of life. Her seizures were refractory against phenobarbital and levetiracetam, but were controlled by valproate. Array comparative genomic hybridization revealed a 5.3-Mb duplication of 2q24.2q24.3, where at least 22 genes including a cluster of voltage-gated sodium channel genes (SCN1A, SCN2A, SCN3A, SCN7A, and SCN9A) and one noncoding RNA are located. PMID- 21692796 TI - In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human P-glycoprotein. AB - PURPOSE: Antiepileptic drugs (AEDs) are widely used not only in the treatment of epilepsy but also as treatments for psychiatric disorders. Pharmacoresistance of AEDs in the treatment of epilepsy and psychiatric disorders is a serious problem. Transport of antiepileptic drugs by P-glycoprotein (Pgp, ABCB1, or MDR1), which is overexpressed in the blood-brain barrier, may be a mechanism for resistance of AEDs. For most AEDs, conflicting evidence precludes consensus on whether they are substrates of Pgp. The objective of this study was to evaluate whether analogs and metabolites of the AED carbamazepine are substrates of human Pgp. METHODS: Polarized cell lines MDCKII and LLC transfected with the human MDR1 gene were used in the bidirectional transport assay and concentration equilibrium transport assay. The expression of Pgp was detected by real-time polymerase chain reaction (PCR) and immunofluorescent staining. Rhodamine-123 uptake was also determined. KEY FINDINGS: Pgp did not transport carbamazepine, but it did transport its active metabolite carbamazepine-10,11-epoxide. Pgp also pumped eslicarbazepine acetate and oxcarbazepine, as well as their active metabolite (S)-licarbazepine. Transport of the drugs was in the order of ESL>OXC>S-LC>CBZ-E in concentration equilibrium conditions. The transport of these drugs was blocked by Pgp inhibitors tariquidar and verapamil. SIGNIFICANCE: All carbamazepine analogs or metabolites tested are Pgp substrates, except for carbamazepine. These data suggest that resistance to carbamazepine, oxcarbazepine, or eslicarbazepine acetate may be attributed to increased efflux function of Pgp because they or their active metabolites are Pgp substrates. PMID- 21692798 TI - Variation in personality and behavioural plasticity across four populations of the great tit Parus major. AB - 1. Interest in the evolutionary origin and maintenance of individual behavioural variation and behavioural plasticity has increased in recent years. 2. Consistent individual behavioural differences imply limited behavioural plasticity, but the proximate causes and wider consequences of this potential constraint remain poorly understood. To date, few attempts have been made to explore whether individual variation in behavioural plasticity exists, either within or between populations. 3. We assayed 'exploration behaviour' among wild-caught individual great tits Parus major when exposed to a novel environment room in four populations across Europe. We quantified levels of individual variation within and between populations in average behaviour, and in behavioural plasticity with respect to (i) repeated exposure to the room (test sequence), (ii) the time of year in which the assays were conducted and (iii) the interval between successive tests, all of which indicate habituation to novelty and are therefore of functional significance. 4. Consistent individual differences ('I') in behaviour were present in all populations; repeatability (range: 0.34-0.42) did not vary between populations. Exploration behaviour was also plastic, increasing with test sequence - but less so when the interval between subsequent tests was relatively large - and time of year; populations differed in the magnitude of plasticity with respect to time of year and test interval. Finally, the between-individual variance in exploration behaviour increased significantly from first to repeat tests in all populations. Individuals with high initial scores showed greater increases in exploration score than individuals with low initial scores; individual by environment interaction ('I * E') with respect to test sequence did not vary between populations. 5. Our findings imply that individual variation in both average level of behaviour and behavioural plasticity may generally characterize wild great tit populations and may largely be shaped by mechanisms acting within populations. Experimental approaches are now needed to confirm that individual differences in behavioural plasticity (habituation) - not other hidden biological factors - caused the observed patterns of I * E. Establishing the evolutionary causes and consequences of this variation in habituation to novelty constitutes an exciting future challenge. PMID- 21692797 TI - Metastatic pheochromocytoma: does the size and age matter? AB - BACKGROUND: Pheochromocytomas are tumours arising from chromaffin tissue located in the adrenal medulla associated with typical symptoms and signs which may occasionally develop metastases, which are defined as the presence of tumour cells at sites where these cells are not found. This retrospective analysis was focused on clinical, genetic and histopathologic characteristics of primary metastatic versus primary benign pheochromocytomas. MATERIALS AND METHODS: We identified 41 subjects with metastatic pheochromocytoma and 108 subjects with apparently benign pheochromocytoma. We assessed dimension and biochemical profile of the primary tumour, age at presentation and time to develop metastases. RESULTS: Subjects with metastatic pheochromocytoma presented at a significantly younger age (41.4 +/- 14.7 vs. 50.2 +/- 13.7 years; P < 0.001) with larger primary tumours (8.38 +/- 3.27 vs. 6.18 +/- 2.75 cm; P < 0.001) and secreted more frequently norepinephrine (95.1% vs. 83.3%; P = 0.046) compared to subjects with apparently benign pheochromocytomas. No significant differences were found in the incidence of genetic mutations in both groups of subjects (25.7% in the metastatic group and 14.7% in the benign group; P = 0.13). From available histopathologic markers of potential malignancy, only necrosis occurred more frequently in subjects with metastatic pheochromocytoma (27.6% vs. 0%; P < 0.001). The median time to develop metastases was 3.6 years with the longest interval 24 years. CONCLUSIONS: In conclusion, regardless of a genetic background, the size of a primary pheochromocytoma and age of its first presentation are two independent risk factors associated with the development of metastatic disease. PMID- 21692799 TI - FIB-SEM cathodoluminescence tomography: practical and theoretical considerations. AB - Focused ion beam-scanning electron microscope (FIB-SEM) tomography is a powerful application in obtaining three-dimensional (3D) information. The FIB creates a cross section and subsequently removes thin slices. The SEM takes images using secondary or backscattered electrons, or maps every slice using X-rays and/or electron backscatter diffraction patterns. The objective of this study is to assess the possibilities of combining FIB-SEM tomography with cathodoluminescence (CL) imaging. The intensity of CL emission is related to variations in defect or impurity concentrations. A potential problem with FIB-SEM CL tomography is that ion milling may change the defect state of the material and the CL emission. In addition the conventional tilted sample geometry used in FIB-SEM tomography is not compatible with conventional CL detectors. Here we examine the influence of the FIB on CL emission in natural diamond and the feasibility of FIB-SEM CL tomography. A systematic investigation establishes that the ion beam influences CL emission of diamond, with a dependency on both the ion beam and electron beam acceleration voltage. CL emission in natural diamond is enhanced particularly at low ion beam and electron beam voltages. This enhancement of the CL emission can be partly explained by an increase in surface defects induced by ion milling. CL emission enhancement could be used to improve the CL image quality. To conduct FIB-SEM CL tomography, a recently developed novel specimen geometry is adopted to enable sequential ion milling and CL imaging on an untilted sample. We show that CL imaging can be manually combined with FIB-SEM tomography with a modified protocol for 3D microstructure reconstruction. In principle, automated FIB-SEM CL tomography should be feasible, provided that dedicated CL detectors are developed that allow subsequent milling and CL imaging without manual intervention, as the current CL detector needs to be manually retracted before a slice can be milled. Due to the required high electron beam acceleration voltage for CL emission, the resolution for FIB-SEM CL tomography is currently limited to several hundreds of nm in XY and up to 650 nm in Z for diamonds. Opaque materials are likely to have an improved Z resolution, as CL emission generated deeper in the material is not able to escape from it. PMID- 21692800 TI - Biochemical properties and in vivo effects of the SOD1 zinc-binding site mutant (H80G). AB - This study presents the initial characterization of transgenic mice with mutations in a primary zinc-binding residue (H80), either alone or with a G93A mutation. H80G;G93A superoxide dismutase 1 (SOD1) transgenic mice developed paralysis with motor neuron loss, and ubiquitin inclusion-type rather than mitochondrial vacuolar pathology. Unlike G93A SOD1-related disease, the course was not accelerated by over-expression of copper chaperone for SOD1. H80G SOD1 transgenic mice did not manifest disease at levels of SOD1 transgene expressed. The H80G mutation altered certain biochemical parameters of both human wild-type SOD1 and G93A SOD1. The H80G mutation does not substantially change the age dependent accumulation of G93A SOD1 aggregates and hydrophobic species in spinal cord. However, both H80G;G93A SOD1 and H80G SOD1 lack dismutase activity, the ability to form homodimers, and co-operativity with copper chaperone for SOD1, indicating that their dimerization interface is abnormal. The H80G mutation also made SOD1 susceptible to protease digestion. The H80G mutation alters the redox properties of SOD1. G93A SOD1 exists in either reduced or oxidized form, whereas H80G;G93A SOD1 and H80G SOD1 exist only in a reduced state. The inability of SOD1 with an H80G mutation to take part in normal oxidation-reduction reactions has important ramifications for disease mechanisms and pathology in vivo. PMID- 21692801 TI - Potentiation of MU-opioid receptor-mediated signaling by ketamine. AB - Ketamine, a clinically relevant drug, has been shown to enhance opioid-induced analgesia and prevent hyperalgesia. However, the molecular mechanisms involved are not clearly understood. As previous studies found that activation of opioid receptors leads to the phosphorylation of mitogen-activated protein kinases, we investigated whether ketamine could modulate MU-opioid receptor (MUOR)-mediated ERK1/2 phosphorylation. We find that acute treatment with ketamine enhances (~2- to 3-fold) the levels of opioid-induced ERK1/2 phosphorylation in recombinant as well as cells endogenously expressing MUOR. Interestingly, we find that in the absence of ketamine ERK1/2 signaling is desensitized 10 min after opioid exposure whereas in its presence significant levels (~3-fold over basal) are detected. In addition, ketamine increases the rate of resensitization of opioid-mediated ERK1/2 signaling (15 min in its presence vs. 30 min in its absence). These results suggest that ketamine increases the effectiveness of opiate-induced signaling by affecting multiple mechanisms. In addition, these effects are observed in heterologous cells expressing MUOR suggesting a non-NMDA receptor mediated action of ketamine. Together this could, in part, account for the observed effects of ketamine on the enhancement of the analgesic effects of opiates as well as in the duration of opiate-induced analgesia. PMID- 21692802 TI - Repeated exposure to cocaine alters medial prefrontal cortex dopamine D2-like receptor modulation of glutamate and dopamine neurotransmission within the mesocorticolimbic system. AB - Repeated exposure to cocaine progressively increases drug-induced locomotor activity, which is termed behavioral sensitization. Previous studies have demonstrated that sensitization to cocaine is associated with a decrease in dopamine D2 receptor function in the medial prefrontal cortex. The present report tested the hypothesis that reduced medial prefrontal cortex D2 receptor function as a result of repeated cocaine exposure results in augmented excitatory transmission to the nucleus accumbens and ventral tegmental area, possibly as a partial result of enhanced inhibition of local dopamine release. Dual probe microdialysis experiments were conducted in male Sprague-Dawley rats 1, 7 or 30 days following the last of four daily injections of saline (1.0 mL/kg) or cocaine (15 mg/kg). Infusion of quinpirole (0.01, 1.0 and 100 MUM), a D2-like receptor agonist, into the medial prefrontal cortex produced a dose-dependent decrease in cortical, nucleus accumbens and ventral tegmental area extracellular glutamate levels in control but not sensitized animals. Quinpirole also reduced basal dopamine levels in the medial prefrontal cortex in sensitized animals following 1 day of withdrawal from cocaine. Following 30 days of withdrawal, quinpirole also reduced dopamine levels in sensitized animals relative to saline controls, but not relative to baseline levels. These findings indicate that the expression of sensitization to cocaine is associated with altered modulation of mesocorticolimbic glutamatergic transmission at the level of the medial prefrontal cortex. PMID- 21692803 TI - Identification of pectin methylesterase 3 as a basic pectin methylesterase isoform involved in adventitious rooting in Arabidopsis thaliana. AB - * Here, we focused on the biochemical characterization of the Arabidopsis thaliana pectin methylesterase 3 gene (AtPME3; At3g14310) and its role in plant development. * A combination of biochemical, gene expression, Fourier transform infrared (FT-IR) microspectroscopy and reverse genetics approaches were used. * We showed that AtPME3 is ubiquitously expressed in A. thaliana, particularly in vascular tissues. In cell wall-enriched fractions, only the mature part of the protein was identified, suggesting that it is processed before targeting the cell wall. In all the organs tested, PME activity was reduced in the atpme3-1 mutant compared with the wild type. This was related to the disappearance of an activity band corresponding to a pI of 9.6 revealed by a zymogram. Analysis of the cell wall composition showed that the degree of methylesterification (DM) of galacturonic acids was affected in the atpme3-1 mutant. A change in the number of adventitious roots was found in the mutant, which correlated with the expression of the gene in adventitious root primordia. * Our results enable the characterization of AtPME3 as a major basic PME isoform in A. thaliana and highlight its role in adventitious rooting. PMID- 21692804 TI - The Arabidopsis Ca(2+) -dependent protein kinase CPK12 negatively regulates abscisic acid signaling in seed germination and post-germination growth. AB - * Ca(2+) -dependent protein kinase (CDPK) is believed to be involved in abscisic acid (ABA) signaling, and several members of the Arabidopsis CDPK superfamily have been identified as positive ABA signaling regulators, but it remains unknown if CDPK negatively regulates ABA signaling. * Here, we investigated the function of an Arabidopsis (Arabidopsis thaliana) CDPK, CPK12, in ABA signaling pathway. * We generated Arabidopsis CPK12-RNAi lines, and observed that downregulation of CPK12 resulted in ABA hypersensitivity in seed germination and post-germination growth, and altered expression of a set of ABA-responsive genes. Expression assay showed that CPK12 was ubiquitously expressed and localized to both cytosol and nucleus. Biochemical assays showed that CPK12 interacted with, phosphorylated and stimulated a type 2C protein phosphatase ABI2, and phosphorylated two ABA responsive transcription factors (ABF1 and ABF4) in vitro. * Our findings show that the Arabidopsis CPK12 is a negative ABA-signaling regulator in seed germination and post-germination growth, suggesting that different members of the CDPK family may constitute a regulation loop by functioning positively and negatively in ABA signal transduction. PMID- 21692805 TI - The tonoplast copper transporter COPT5 acts as an exporter and is required for interorgan allocation of copper in Arabidopsis thaliana. AB - Copper is an essential micronutrient for all organisms because it serves as a cofactor of several proteins involved in electron transfer. Elevated copper concentrations can cause toxic effects and organisms have established suitable mechanisms to regulate the uptake and internal distribution of copper to balance the content at an optimal concentration. In recent studies, a family of copper transporters (COPT) with high homology to other eukaryotic copper transporters (Ctr) has been identified in Arabidopsis thaliana. In this study we clarified the physiological function of COPT5. This carrier is located in the tonoplast and functions as a vacuolar copper exporter. Mutants lacking this transporter have altered copper contents in different organs when compared with wild-type plants. We were able to detect copper accumulation in the root and a decreased copper content in siliques and seeds when the COPT5 gene is mutated by T-DNA insertion. Vacuoles purified from copt5 T-DNA-insertion mutants show remarkably increased copper concentrations compared with wild-type organelles. We assume that on the cellular level COPT5 is important for copper export from the vacuole and on the level of the whole plant it is involved in the interorgan reallocation of copper ions from the root to reproductive organs. PMID- 21692806 TI - Deferral from donating blood of men who have sex with men: impact on the risk of HIV transmission by transfusion in France. AB - BACKGROUND: In France, men who have sex with men (MSM) are permanently excluded from blood donation. This policy is felt to be discriminatory by MSM activists. Furthermore, the policy is not fully respected because some MSM do not report their sexual behaviour before donating. METHODS: We estimated the fraction of the current risk of HIV attributed to MSM. We then constructed a model based on data obtained from behavioural and epidemiological surveys to assess the impact of a new strategy in which MSM would only be deferred if they report more than one sexual partner in the last 12 months. RESULTS: Thirty-one HIV seroconversions occurred among repeat donors between 2006 and 2008, giving a risk of one in 2 440 000 donations. Fifteen of these seroconversions (48%) were MSM. If all MSM had abstained from donating blood, the risk would have been 1 in 4 700 000 donations, half the current risk. The new strategy would result in an overall HIV risk of between 1 in 3 000 000 (close to the current risk) to 1 in 650 000 donations (3.7 times higher than the current risk). CONCLUSIONS: Changing the current MSM deferral policy may increase the risk of transfusion-transmission of HIV. However, this does not take into account a possible better compliance with MSM with a less stringent policy that would be perceived as more equitable. Conversely, relaxing the policy could encourage some MSM to seek an HIV test in blood centres. Thus, further qualitative study is needed to assess possible changes in compliance linked to a new policy. PMID- 21692807 TI - Flood-resilient waterfront development in New York City: bridging flood insurance, building codes, and flood zoning. AB - Waterfronts are attractive areas for many-often competing-uses in New York City (NYC) and are seen as multifunctional locations for economic, environmental, and social activities on the interface between land and water. The NYC waterfront plays a crucial role as a first line of flood defense and in managing flood risk and protecting the city from future climate change and sea-level rise. The city of New York has embarked on a climate adaptation program (PlaNYC) outlining the policies needed to anticipate the impacts of climate change. As part of this policy, the Department of City Planning has recently prepared Vision 2020: New York City Comprehensive Waterfront Plan for the over 500 miles of NYC waterfront (NYC-DCP, 2011). An integral part of the vision is to improve resilience to climate change and sea-level rise. This study seeks to provide guidance for advancing the goals of NYC Vision 2020 by assessing how flood insurance, flood zoning, and building code policies can contribute to waterfront development that is more resilient to climate change. PMID- 21692808 TI - Contact allergy and human biomonitoring--an overview with a focus on metals. AB - Humans are widely exposed to chemicals. Today, there is an increased acknowledgement of the importance of measuring human and environmental exposures to man-made or refined chemicals. Different approaches have been applied over time, but during the past 25 years, there has been a general trend towards the use of human biomonitoring. A few studies have used human biomonitoring methodology to track contact allergens together with information on patch test reactivity. Hypothetically, the internal load of reactive chemicals might modify the immune response to haptens and the propensity to sensitize and elicit allergic contact dermatitis or develop tolerance. This review offers a general overview of human biomonitoring, including information about its typical application and methodology. Furthermore, studies that have attempted to perform simultaneous biomonitoring and patch testing are reviewed. It is concluded that all studies conducted until the present have focused on one or two routes of exposure (typically skin and oral exposure, but also skin and airway exposure), whereas no studies have investigated all routes at the same time. Also, there is a need for prospective studies, as all epidemiological studies so far have been cross-sectional. PMID- 21692809 TI - Hand eczema in hairdressers: a Danish register-based study of the prevalence of hand eczema and its career consequences. AB - BACKGROUND: Occupational hand eczema is common in hairdressers, owing to wet work and hairdressing chemicals. OBJECTIVES: To estimate the prevalence of hand eczema and its career consequences among hairdressers in Denmark. METHODS: A register based study was conducted, comprising all graduates from hairdressing vocational schools from 1985 to 2007 (n = 7840). The participants received a self administered postal questionnaire including questions on hand eczema, atopic dermatitis, and career change. A response rate of 67.9% (n = 5324) was obtained. RESULTS: Of the respondents, 44.3% no longer worked as hairdressers and had worked for an average of 8.4 years in the profession before leaving it. Hand eczema was more common among ex-hairdressers (48.4%) than among current hairdressers (37.6%) (p < 0.0001), and significantly more ex-hairdressers (26.8%) than current hairdressers (15.7%) had chronic hand eczema (p < 0.0001). Of the respondents with hand eczema, 75% were aged 15-24 years at onset, and 45.5% gave hand eczema as a reason for career change. In this group, logistic regression analysis showed that chronic hand eczema contributed the most to the decision to change career (odds ratio 50.12; 95% confidence interval 18.3-137). CONCLUSIONS: Hairdressers work an average of 8.4 years in the profession before leaving it, and hand eczema contributes significantly to this career change. PMID- 21692810 TI - Sensory irritation caused by two organic solvents-short-time single application and repeated occlusive test in stingers and non-stingers. AB - BACKGROUND: Neurosensory irritation is a subjective phenomenon induced by a number of chemicals. Objectives. To investigate the sensory irritation induced by two organic solvents - n-octane and cumene - between two groups of volunteers, stingers and non-stingers, identified as such according to the results of a lactic acid stinging test (LAST). METHODS: The immediate effects of the solvents were directly compared in a single simultaneous application test. The reaction intensities over time were studied in a repetitive irritation test over 4 days. The volunteers graded the reaction intensities by the use of a labelled magnitude scale. RESULTS: Cumene induced significantly stronger sensory irritation than octane in both the single and the repeated applications. Both substances induced less subjective irritation the more times the volunteers were exposed. The decline with time for cumene was statistically significant for the non-stingers but not for the stingers. However, no significant differences regarding the reaction intensities were detected in the direct comparisons of stingers and non stingers. CONCLUSIONS. Further studies with larger sample sizes are needed to investigate a potential connection between the responsiveness to the sensory irritation caused by lipophilic irritants and lactic acid. PMID- 21692811 TI - Risk of sensitization to preservatives estimated on the basis of patch test data and exposure, according to a sample of 3541 leave-on products. AB - BACKGROUND: The risk of sensitization cannot be derived from the frequency of sensitization to allergens alone, but exposure should be considered. OBJECTIVE: To estimate the risk of sensitization to selected preservatives. METHODS: The occurrence of preservatives in 3541 leave-on products based on the labelling of the ingredients was documented. Frequency of sensitization to preservatives was analysed on the basis of Information Network of Departments of Dermatology data for 2006-2009. As an estimate of sensitization risk, the sensitization exposure quotient (SEQ) was calculated as the quotient of the relative frequency of sensitization and the relative frequency of use. RESULTS: The SEQs varied greatly, offering a ranking regarding risk of sensitization: phenoxyethanol (SEQ: 0.06), benzyl alcohol (0.30), parabens (0.35), sorbates (0.92), benzoates (1.35), formaldehyde-releasers (1.6), methylisothiazolinone (MI) (1.7), iodopropynyl butylcarbamate (3.4), methylchloroisothiazolinone/MI (9.0), and 2-bromo-2 nitropropane-1,3-diol (13). There was a good correlation between the ranking of substances according to potency (hazard) and the ranking of the SEQ (risk). CONCLUSION: High frequencies of sensitization may be put into perspective by the frequent use of certain preservatives. Despite infrequent use, others (with higher potencies or too high use concentrations) may turn out to be associated with an increased risk. Hazard assessment should be supplemented by risk assessment. PMID- 21692812 TI - Pharmacokinetics of the cytochrome P-450 substrates phenytoin, theophylline, and diazepam in healthy Greyhound dogs. AB - The purpose of this study was to determine the pharmacokinetics of phenytoin, theophylline, and diazepam in six healthy Greyhound dogs. Additionally, the pharmacokinetics of the diazepam metabolites, oxazepam and nordiazepam, after diazepam administration was determined. Phenytoin sodium (12 mg/kg), aminophylline (10 mg/kg), and diazepam (0.5 mg/kg) were administered IV on separate occasions, and blood was collected at predetermined time points for the quantification of plasma drug concentrations by fluorescence polarization immunoassay (phenytoin, theophylline) or mass spectrometry (diazepam, oxazepam, and nordiazepam). The terminal half-life was 4.9, 9.2, and 1.0 h, respectively, for phenytoin, theophylline, and diazepam, and 6.2 and 2.4 h for oxazepam and nordiazepam after IV diazepam. The clearance was of 2.37, 0.935, and 27.9 mL . min/kg, respectively, for phenytoin, theophylline, and diazepam. The C(MAX) was 44.7 and 305.2 ng/mL for oxazepam and nordiazepam, respectively, after diazepam administration. Temazepam was not detected above 5 ng/mL in any sample after IV diazepam. PMID- 21692813 TI - Responses to water stress of gas exchange and metabolites in Eucalyptus and Acacia spp. AB - Studies of water stress commonly examine either gas exchange or leaf metabolites, and many fail to quantify the concentration of CO2 in the chloroplasts (C(c)). We redress these limitations by quantifying C(c) from discrimination against 13CO2 and using gas chromatography-mass spectrometry (GC-MS) for leaf metabolite profiling. Five Eucalyptus and two Acacia species from semi-arid to mesic habitats were subjected to a 2 month water stress treatment (Psi(pre-dawn) = -1.7 to -2.3 MPa). Carbohydrates dominated the leaf metabolite profiles of species from dry areas, whereas organic acids dominated the metabolite profiles of species from wet areas. Water stress caused large decreases in photosynthesis and C(c), increases in 17-33 metabolites and decreases in 0-9 metabolites. In most species, fructose, glucose and sucrose made major contributions to osmotic adjustment. In Acacia, significant osmotic adjustment was also caused by increases in pinitol, pipecolic acid and trans-4-hydroxypipecolic acid. There were also increases in low-abundance metabolites (e.g. proline and erythritol), and metabolites that are indicative of stress-induced changes in metabolism [e.g. gamma-aminobutyric acid (GABA) shunt, photorespiration, phenylpropanoid pathway]. The response of gas exchange to water stress and rewatering is rather consistent among species originating from mesic to semi-arid habitats, and the general response of metabolites to water stress is rather similar, although the specific metabolites involved may vary. PMID- 21692814 TI - Compound-specific differences in (13)C of soluble carbohydrates in leaves and phloem of 6-month-old Eucalyptus globulus (Labill). AB - Movement of photoassimilates from leaves to phloem is an important step for the flux of carbon through plants. Fractionation of carbon isotopes during this process may influence their abundance in heterotrophic tissues. We subjected Eucalyptus globulus to 20, 25 and 28 degrees C ambient growth temperatures and measured compound-specific delta(13)C of carbohydrates obtained from leaves and bled phloem sap. We compared delta(13)C of sucrose and raffinose obtained from leaf or phloem and of total leaf soluble carbon, with modelled values predicted by leaf gas exchange. Changes in delta(13)C of sucrose and raffinose obtained from either leaves or phloem sap were more tightly coupled to changes in c(i)/c(a) than was delta(13)C of leaf soluble carbon. At 25 and 28 degrees C, sucrose and raffinose were enriched in (13)C compared to leaf soluble carbon and predicted values - irrespective of tissue type. Phloem sucrose was depleted and raffinose enriched in (13)C compared to leaf extracts. Intermolecular and tissue specific delta(13)C reveal that multiple systematic factors influence (13)C composition during export to phloem. Predicting sensitivity of these factors to changes in plant physiological status will improve our ability to infer plant function at a range of temporal and spatial scales. PMID- 21692815 TI - Surface distribution and depths profiling of particulate organic UV absorbers by Raman imaging and tape stripping. AB - Tape stripping in conjunction with scanning Raman microscopy was used for assessing the lateral and vertical distribution of an organic particulate UV filter, methylene bis-benzotriazolyl tetramethylbutylphenol (MBBT), in a sunscreen formulation. On the volar forearms of three volunteers, 1 mg cm(-2) formulation containing 10% MBBT was applied, and the average amount of MBBT was measured by Raman scanning microscopy in 15 consecutive tape strippings. The recovery of MBBT was 91.1% with 30.2% localizing on the skin surface (first strip), 42.5% in the upper stratum corneum (strips 2-5) and from 3.6 down to 0.8% in each of the 10 consecutive layers. The concentration of surface deposits of MBBT differed by a factor of 300 between folds, furrows and pores on the one hand and the interjacent ridges on the other hand. Seventy-five per cent of the applied particles occupied a fifth of the evaluated area - where concentrating in folds and furrows - as was confirmed by 3-D reconstruction. On interjacent ridges, 8.6% of MBBT distributed as very thin films preferentially. MBBT localized at sites not connected with the surface, such as in truncated pores or as potentially penetrated material amounted to 0.06% or to a twentieth of the 1.4% found in the lowest skin strippings. Scanning Raman microscopy in combination with tape stripping documented the lateral and vertical distribution quantitatively and at cellular (12.5 MUm) lateral resolution. Our results confirmed an earlier report on the vertical distribution of organic particles applied to skin and was in line with similar reports on TiO(2) distribution. PMID- 21692816 TI - Impact of subacute ruminal acidosis (SARA) adaptation and recovery on the density and diversity of bacteria in the rumen of dairy cows. AB - Subacute ruminal acidosis (SARA) is characterized by ruminal pH depression and microbial perturbation. The impact of SARA adaptation and recovery on rumen bacterial density and diversity was investigated following high-grain feeding. Four ruminally cannulated dairy cows were fed a hay diet, transitioned to a 65% grain diet for 3 weeks, and returned to the hay diet for 3 weeks. Rumen fluid, rumen solids, and feces were sampled during weeks 0 (hay), 1 and 3 (high grain), and 4 and 6 (hay). SARA was diagnosed during week 1, with a pH below 5.6 for 4.6+/-1.4 h. Bacterial density was significantly lower in the rumen solids with high grain (P=0.047). Rumen fluid clone libraries from weeks 0, 3, and 6 were assessed at the 98% level and 154 operational taxonomic units were resolved. Week 3 diversity significantly differed from week 0, and community structure differed from weeks 0 and 6 (P<0.0001). Clones belonging to the phylum Firmicutes predominated. Compared with the hay diet, the high-grain diet contained clones from Selenomonas ruminantium and Succiniclasticum ruminis, but lacked Eubacterium spp. SARA adaptation was found to significantly alter bacterial density, diversity, and community structure, warranting further investigation into the role bacteria play in SARA adaptation. PMID- 21692817 TI - Influence of the diet on the microbial diversity of faecal and gastrointestinal contents in gilthead sea bream (Sparus aurata) and intestinal contents in goldfish (Carassius auratus). AB - Fish intestinal microbiota changes with the diet and this effect is of particular interest considering the increasing substitution of fish meal by plant protein sources. The objective of this work was to study the effects of partial substitution of fish meal with lupin and rapeseed meals on gut microbiota of the gilthead sea bream (Sparus aurata) and in goldfish (Carassius auratus). Faecal, gastrointestinal and intestinal contents were characterized using culture-based and molecular methods. Vibrionaceae was high in faeces and in the intestine of sea bream, while a more diverse microbiota was retrieved from the stomach, where Bacillales and Flavobacteriaceae appeared to be influenced by the diet. PCR denaturing gradient gel electrophoresis profiles revealed a high diversity of the microbiota transiting in the sea bream digestive tract, with a shift between gastric and intestinal communities, especially in the group fed with lupin meal. The goldfish was different, with a predominance of Aeromonas spp., Shewanella putrefaciens and Staphylococcus spp. among the aerotolerant-cultivable bacteria. The culture-independent methods revealed the presence of anaerobes like Cetobacterium somerae, and that of Vibrio spp., likely in a viable, but noncultivable state. There was a trend towards decreasing diversity in goldfish microbiota with the partial substitution by lupin, which seemed to inhibit some taxa. PMID- 21692818 TI - Verrucomicrobia subdivision 1 strains display a difference in the colonization of the leek (Allium porrum) rhizosphere. AB - Strains CHC12 and CHC8, belonging to, respectively, Luteolibacter and Candidatus genus Rhizospheria (Verrucomicrobia subdivision 1), were recently isolated from the leek rhizosphere. The key question addressed in this study was: does attraction to and colonization of the rhizosphere occur in the same way for both strains? Therefore, the fate of the two strains was studied near in vitro-grown leek roots and in soil zones proximate to and at a further distance from roots in a model plant-soil microcosm set-up. Quantitative PCR detection with specific primers was used, as the cultivation of these bacteria from soil is extremely fastidious. The data indicated that natural populations of Luteolibacter (akin to strain CHC12) had lower numbers in the rhizosphere than in the corresponding bulk soil. On the other hand, the populations of Candidatus genus Rhizospheria, i.e. strain CHC8, showed higher numbers in the rhizosphere than in the bulk soil. Increased strain CHC8 cell-equivalent numbers in the rhizosphere were not only the result of in situ cell multiplication, but also of the migration of cells towards the roots. Luteolibacter and Candidatus genus Rhizospheria cells displayed differences in attraction to the rhizosphere and colonization thereof, irrespective of the fact that both belonged to Verrucomicrobia subdivision 1. PMID- 21692819 TI - Occurrence and potential pathogenesis of Vibrio cholerae, Vibrio parahaemolyticus and Vibrio vulnificus on the South Coast of Sweden. AB - During the summer of 2006, several wound infections - of which three were fatal - caused by Vibrio cholerae were reported from patients who had been exposed to water from the Baltic Sea. Before these reports, we initiated a sampling project investigating the occurrence of potential human pathogenic V. cholerae, Vibrio vulnificus and Vibrio parahaemolyticus in The Sound between Sweden and Denmark. The Blue mussel (Mytilus edulis) was used as an indicator to follow the occurrence of vibrios over time. Molecular analyses showed high frequencies of the most potent human pathogenic Vibrio spp.; 53% of mussel samples were positive for V. cholerae (although none were positive for the cholera toxin gene), 63% for V. vulnificus and 79% for V. parahaemolyticus (of which 47% were tdh(+) and/or trh(+)). Viable vibrios were also isolated from the mussel meat and screened for virulence by PCR. The mortality of eukaryotic cells when exposed to bacteria was tested in vivo, with results showing that the Vibrio strains, independent of species and origin, were harmful to the cells. Despite severe infections and several deaths, no report on potential human pathogenic vibrios in this area had been published before this study. PMID- 21692820 TI - Review article: the diagnosis and investigation of obscure gastrointestinal bleeding. AB - BACKGROUND: Obscure gastrointestinal bleeding (OGIB) is a commonly encountered clinical problem in gastroenterology and is associated with significant morbidity and mortality. The investigation and management of OGIB has changed dramatically over the past decade with the advent of newer gastroenterological and radiological technologies. AIM: To review the current evidence on the diagnosis and investigation of OGIB. METHODS: We searched the PubMed database (1985-2010) for full original articles in English-language journals relevant to the investigation of OGIB. The search terms we used were 'gastrointestinal bleeding' or 'gastrointestinal hemorrhage' or 'small bowel bleeding' each in combination with 'obscure', or 'capsule endoscopy', or 'enteroscopy' or 'enterography' or 'enteroclysis'. RESULTS: Capsule endoscopy (CE) or double balloon enteroscopy (DBE) should be first line investigations. They are complimentary procedures with comparable high diagnostic yields. DBE is also able to provide therapeutic intervention. Newer technologies such as single balloon and spiral enteroscopy are currently being evaluated. Radiological and nuclear medicine investigations, such as CT enterography and CT enteroclysis, are alternative diagnostic tools when CE or DBE are contraindicated. Repeating the gastroscopy and/or colonoscopy may be considered in selective situations. An algorithm for investigation of obscure bleeding is proposed. CONCLUSIONS: The development of capsule endoscopy and double balloon enteroscopy has transformed the approach to the evaluation and management of obscure gastrointestinal bleeding over the past decade. Older diagnostic modalities still play a complementary, but increasingly selective role. PMID- 21692821 TI - Review article: colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease strongly associated with inflammatory bowel disease (IBD). IBD patients diagnosed with PSC have an increased risk of colorectal dysplasia and cancer. AIMS: To review the available evidence regarding colorectal neoplasia epidemiology, preventive strategies and outcomes in patients with PSC and IBD, and to advance some hypotheses regarding possible mechanisms involved in cancer pathogenesis in these patients. METHODS: A PubMed search was conducted for the English language publications with predetermined search criteria. Reference lists from studies selected were manually searched to identify further relevant reports. Relevant manuscripts considering colorectal neoplasia in patients with PSC-IBD were selected. RESULTS: Primary sclerosing cholangitis increases the risk of colorectal neoplasia in patients with ulcerative colitis; fewer data are available for Crohn's disease. PSC-IBD patients tend to be younger at diagnosis of IBD and at diagnosis of colorectal cancer. Colorectal cancer in PSC-IBD patients predominates in the right colon. The increased risk of neoplasia is maintained after liver transplant and proctocolectomy. The role of ursodeoxycholic acid as a chemopreventive agent is controversial. The mechanisms underlying increased risk of colorectal neoplasia in these patients remain unknown. CONCLUSIONS: A more comprehensive understanding of the mechanisms involved in colorectal neoplasia development in PSC-IBD patients is needed. Until then, early cancer detection through enrolment in surveillance programmes is the only available strategy to decrease cancer risk. PMID- 21692822 TI - Randomised clinical trial: efficacy of peginterferon alfa-2a in HBeAg positive chronic hepatitis B patients with lamivudine resistance. AB - BACKGROUND: Previous studies suggested that a finite course of peginterferon alfa 2a may offer an alternative rescue therapy for patients with lamivudine resistance. However, because of the limitation of study design and small sample size, it is difficult to make definitive conclusion. AIM: To explore the role of peginterferon alfa-2a, in the rescue treatment of HBeAg-positive chronic hepatitis B patients with lamivudine resistance. METHODS: In this randomised study, chronic hepatitis B patients with lamivudine resistance were treated with peginterferon alfa-2a for 48 weeks (n=155) or adefovir for 72 weeks (n=80). All enrolled patients were treated with lamivudine for the first 12weeks. RESULTS: At 6 months posttreatment, 14.6% (18/123) of peginterferon alfa-2a-treated patients achieved HBeAg seroconversion, in contrast to 3.8% (3/80) of adefovir-treated patients after 72 weeks continuous therapy (P=0.01). For peginterferon alfa-2a treated patients, the rate of HBeAg seroconversion at week 72 was significantly higher in patients who had HBsAg decline >0.5 Log(10) IU/mL from baseline at week 24, compared with patients with HBsAg decline <=0.5 Log(10) IU/mL from baseline at week 24 (25.5% vs. 7.7%, P=0.01). After 72 weeks continuous adefovir treatment, 22.5% of patients achieved HBV DNA <80 IU/mL, compared with 10.6% in peginterferon alfa-2a-treated patients at 6months off-treatment (P=0.02). CONCLUSIONS: Overall, the response to peginterferon alfa-2a among patients with lamivudine resistance was suboptimal. HBeAg seroconversion rate at week 72 by 48 weeks peginterferon alfa-2a treatment was higher than continuous adefovir therapy. Monitoring HBsAg levels can help to predict response to peginterferon alfa-2a. PMID- 21692823 TI - Information provision and problem-solving processes in Japanese breast cancer survivors with lymphoedema symptoms. AB - BACKGROUND: In Japan, a high proportion of breast cancer (BC) survivors develop lymphoedema as a consequence of the treatment received. Japanese BC survivors are generally not provided with standardised information about risks, early signs and symptom management. The effects of (in)adequate information on the problem solving processes among Japanese BC survivors with lymphoedema symptoms have not been investigated. PURPOSE: The aim of this study was to explore how the provision of medical information by doctors affected the problem-solving processes of Japanese BC survivors with lymphoedema symptoms. METHOD: Ten Japanese BC survivors participated in audio-taped focus group discussions. Transcripts were analysed using an inductive thematic analysis. RESULTS: Analysis identified two phases during which participants attempted to address problems with managing their lymphoedema symptoms - a help-seeking phase and an evaluation phase. Perceptions of information provision affected emotional responses to the onset and cognitive appraisals of lymphoedema symptoms (seen as accepted or burden). However, perceptions of information provision did not affect help seeking behaviours from surgeons or adherence behaviours. Participants often perceived compression sleeves as inefficient and not worth continuing. CONCLUSION: This study suggests that information provision is a key process in helping BC patients to adjust to symptoms of lymphoedema. In order to promote effective symptom management, doctors and nurses should provide support not only during the help-seeking phase but also the evaluation phase. Further research on the most effective ways to change negative treatment beliefs should be conducted. PMID- 21692825 TI - Arterial remodelling following pressure overload by aortic constriction: an overlooked and potentially fertile research area. PMID- 21692824 TI - Online self-help tools for the relatives of persons with depression -- a feasibility study. AB - BACKGROUND: The Internet's potential as health care tool should be explored. AIM: One objective was to determine the feasibility of constructing a digitally based tool through an iterative design process in cooperation with potential users. The tool's purpose is to alleviate hardships in daily life of relatives of persons with depression. An additional aim was to explore motivation and hindrances to using the tool as a basis for design decisions. METHOD: An iterative design approach, including data collection through focus groups and with paper and web-based prototypes, was used. RESULTS: Cooperation with potential users, using an iterative design process, was valuable in developing the digitally based tool. Motivations (i.e. to create understanding and rehabilitate oneself) and hindrances (i.e. lack of time or energy) to using the tool were illuminated. Design decisions were based on consideration towards participants' privacy concerns, needs of support and the depression's influence on the relatives' daily life. CONCLUSION: Prototypes and cooperation with potential users were essential and valuable for the iterative development of the website. PMID- 21692826 TI - Calcium-sensing receptors induce apoptosis during simulated ischaemia-reperfusion in Buffalo rat liver cells. AB - 1. Calcium-sensing receptors (CaSR) exist in a variety of tissues. In 2010, we first identified its functional expression in Buffalo rat liver (BRL) cells and demonstrated that the activation of CaSR was involved in an increased intracellular calcium through the Gq subunit-phospholipase C-inositol triphosphate pathway. However, its role and related mechanism in hepatic ischaemia/reperfusion (I/R) injury is still unclear. 2. Therefore, in the present study, BRL cells were incubated in ischaemia-mimetic solution for 4 h, then reincubated in the normal culture medium for 10 h to establish a simulated I/R model. We assayed the apoptotic ratio of BRL cells by flow cytometry and Hoechst 33342 staining; analyzed the expression of CaSR, cytochrome c (Cyt-c), caspase-3, Bcl-2, Bax, extracellular signal-regulated protein kinase (ERK), and p38 by Western blotting; and measured the concentration of intracellular calcium by laser-scanning confocal microscopy. 3. The results showed that simulated I/R increased the expression of CaSR and induced apoptosis in BRL cells. GdCl(3), a specific activator of CaSR, further increased CaSR expression, intracellular calcium, and apoptosis in BRL cells during I/R. The activation of CaSR downregulated Bcl-2 expression, upregulated Cyt-c, caspase-3, and Bax expressions, and promoted p38 and ERK-1/2 phosphorylation. 4. In conclusion, increased CaSR expression plays a vital role in apoptosis induced by I/R injury, in which its mechanism is related with calcium overload and the activation of the mitochondrial and mitogen-activated protein kinase apoptotic pathways. The regulation of CaSR activity might serve as a novel pharmacological target to prevent and treat liver disease. PMID- 21692827 TI - Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitis. AB - AIMS: Infliximab, an anti-tumour necrosis factor alpha monoclonal antibody, has profoundly modified the treatment of several inflammatory diseases. The objective was to assess the influence of methotrexate on the variability of infliximab pharmacokinetics and concentration-effect relationship in axial ankylosing spondylitis (AAS) patients. METHODS: Twenty-six patients with AAS were included in a prospective study. They were treated by infliximab 5 mg kg-1 infusions at weeks 0, 2, 6, 12 and 18. Infliximab concentrations were measured before, and 2 and 4 h after each infusion, and at each intermediate visit (weeks 1, 3, 4, 5, 8, 10 and 14). Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was measured at each visit. Infliximab pharmacokinetics was described using a two compartment model with first-order distribution and elimination constants. A population approach was used. Infliximab pharmacodynamics was described using the area under the BASDAI curve. RESULTS: A total of 507 blood samples and 329 BASDAI measurements were collected. The following pharmacokinetic parameters were obtained (interindividual coefficient of variation): volumes of distribution for the central compartment = 2.4 l (9.6%) and peripheral compartment = 1.8 l (26%), systemic clearance = 0.23 l day-1 (22%) and intercompartment clearance = 2.3 l day-1. Methotrexate influenced neither pharmacokinetic nor BASDAI variability. CONCLUSIONS: Using the present dosage, the clinical efficacy of infliximab is only weakly influenced by its serum concentrations. The results do not support the combination of methotrexate with infliximab in ankylosing spondylitis. PMID- 21692828 TI - The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors. AB - BACKGROUND: Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet. AIMS: To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy. METHODS: Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability. RESULTS: Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S warfarin clearance was estimated to be 0.144 l h-1 (95% confidence interval 0.131, 0.157) in a 70 kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6 l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R warfarin clearance was estimated to be 0.125 l h-1 (95% confidence interval 0.115, 0.135) in a 70 kg individual aged 69.8 years with the wild-type CYP2C19 and CYP3A4 genotypes, and the volume of distribution was 10.9 l (95% confidence interval 8.63, 13.2). CONCLUSIONS: Our analysis, based on exposure rather than dose, provides quantitative estimates of the clinical and genetic factors impacting on the clearance of both the S- and R-enantiomers of warfarin, which can be used in developing improved dosing algorithms. PMID- 21692829 TI - Effect of grapefruit juice on the pharmacokinetics of docetaxel in cancer patients: a case report. PMID- 21692830 TI - Non-technical skills in histopathology: definition and discussion. AB - Health care is a high-risk industry, with most documented adverse incidents being associated with 'human factors' including cognitive and social skills termed 'non technical skills'. Non-technical skills complement the diagnostic and specialist skills and professional attributes required by medical practitioners, including histopathologists, and can enhance the quality of practice and delivery of health care services and thus contribute to patient safety. This review aims to introduce histopathologists to non-technical skills and how these pertain to everyday histopathological practice. Drawing from other domains in medicine, specifically anaesthesia and surgery, a variety of non-technical skills are identified and described in the context of histopathology to illustrate the role each plays, often collectively, in daily practice. The generic non-technical skills are defined as situation awareness, decision-making, communication, teamwork, leadership, managing stress and coping with fatigue. Example scenarios from histopathology are presented and the contributions to outcomes made by non technical skills are explained. Consideration of these specific non-technical skills as a component in histopathology training may benefit practitioners as well as assuring patient safety. PMID- 21692831 TI - Phenotyping in the archaea: optimization of growth parameters and analysis of mutants of Haloferax volcanii. AB - A method to grow the halophilic archaeon Haloferax volcanii in microtiter plates has been optimized and now allows the parallel generation of very reproducible growth curves. The doubling time in a synthetic medium with glucose is around 6 h. The method was used to optimize glucose and casamino acid concentrations, to clarify carbon source usage and to analyze vitamin dependence. The characterization of osmotolerance revealed that after a lag phase of 24 h, H. volcanii is able to grow at salt concentrations as low as 0.7 M NaCl, much lower than the 1.4 M NaCl described as the lowest concentration until now. The application of oxidative stresses showed that H. volcanii exhibits a reaction to paraquat that is delayed by about 10 h. Surprisingly, only one of two amino acid auxotrophic mutants could be fully supplemented by the addition of the respective amino acid. Analysis of eight sRNA gene deletion mutants exemplified that the method can be applied for bona fide phenotyping of mutant collections. This method for the parallel analysis of many cultures contributes towards making H. volcanii an archaeal model species for functional genomic approaches. PMID- 21692832 TI - Typing of bacteriophages by randomly amplified polymorphic DNA (RAPD)-PCR to assess genetic diversity. AB - The recent boom in phage therapy and phage biocontrol requires the design of suitable cocktails of genetically different bacteriophages. The current methods for typing phages need significant quantities of purified DNA, may require a priori genetic information and are cost and time consuming. We have evaluated the randomly amplified polymorphic DNA (RAPD)-PCR technique to produce unique and reproducible band patterns from 26 different bacteriophages infecting Staphylococcus epidermidis, Staphylococcus aureus, Lactococcus lactis, Escherichia coli, Streptococcus thermophilus, Bacillus subtilis and Lactobacillus casei bacterial strains. Initially, purified DNA and phage suspensions of seven selected phages were used as a template. The conditions that were found to be optimal 8 MUM of 10-mer primers, 3 MUM magnesium oxalacetate and 5% dimethyl sulfoxide. The RAPD genomic fingerprints using a phage titer suspension higher than 10(9) PFU mL(-1) were highly reproducible. Clustering by the Pearson correlation coefficient and the unweighted pair group method with arithmetic averages clustering algorithm correlated largely with genetically different phages infecting the same bacterial species, although closely related phages with a similar DNA restriction pattern were indistinguishable. The results support the use of RAPD-PCR for quick typing of phage isolates and preliminary assessment of their genetic diversity bypassing tedious DNA purification protocols and previous knowledge of their sequence. PMID- 21692833 TI - Factors associated with the oral health-related quality of life in elderly persons in dental clinic: validation of a Mandarin Chinese version of GOHAI. AB - OBJECTIVES: To translate the original English version of Geriatric Oral Health Assessment Index (GOHAI) into Mandarin Chinese and assess its reliability and validity for use among the elderly in inland China and to explore the factors associated with oral health-related quality of life (OHRQoL). METHODS: The original English version of GOHAI was translated, back-translated and cross culturally adapted. The psychometric properties of GOHAI-M were assessed in a sample of 263 people aged 60 years and over and OHRQoL was examined in 221 subjects using GOHAI-M. Multiple regression analysis was conducted. RESULTS: Internal consistency of the GOHAI-M was excellent (Cronbach's alpha:0.81). Split half reliability coefficient was 0.80, and item-scale correlation coefficient ranged from 0.25 to 0.71. Self-rated oral health was significantly associated with OHRQoL (r(s)=0.505, p<0.01). The relation coefficient between GOHAI-M and self-perceived need for dental treatment and number of missing teeth were 0.231 and -0.653, respectively (p<0.05). Multiple regression analysis found that better OHRQoL was significantly associated with better self-ratings of oral health (beta=0.497, p=0.01), number of missing teeth (beta=0.187, p<0.01) and life satisfaction (beta=0.132, p<0.05). CONCLUSION: The Mandarin Chinese version of GOHAI demonstrates acceptable reliability and validity. OHRQoL is associated with self-rated oral health, number of missing teeth and satisfaction with life. PMID- 21692834 TI - The evaluation of oral health in stroke patients. AB - OBJECTIVE: As tooth loss has been suggested as a potential risk factor for stroke, oral examinations were carried out on stroke patients to review the oral condition of those patients. METHOD: The subjects were patients consecutively discharged from the recovery rehabilitation unit of Hiroshima City General Rehabilitation Center between April 2008 and December 2009. All patients were offered oral examination and 358 of 443 patients accepted. Patients receiving dental examination were divided into two groups: one group comprising stroke patients and the second, patients with other disorders. These two groups were then compared for the number of remaining teeth by age group. RESULTS: Among the examined patients, the number of remaining teeth in stroke patients in their 50s and 60s was significantly lower than for patients in corresponding age groups (18.4 +/- 9.4 vs. 24.5 +/- 5.4 and 18.3 +/- 9.2 vs. 22.2 +/- 7.2, respectively, with p < 0.05 for both age groups) who were hospitalised for other conditions. In addition, the number of remaining teeth in stroke patients in their 50s was also significantly lower than the number reported in the Survey of Dental Diseases (24.1 +/- 6.1; p < 0.05). CONCLUSION: The results of this study suggest an association between tooth loss and early occurrence of stroke. PMID- 21692835 TI - The burden of childhood psoriasis. AB - A pilot study of the effect on quality of life of childhood psoriasis is presented. Of the children interviewed, 65% experienced stigmatization to a certain extent, 71% reported itching, and 43% complained about fatigue. Clinicians should pay attention to these items to initiate patient-tailored treatment. PMID- 21692836 TI - A congenital case of circumscribed acral hypokeratosis. AB - Circumscribed acral hypokeratosis is a disorder characterized by areas of erythematous depressed skin with distinct histopathological findings typically found on the palmar and plantar surfaces. Most patients are middle-aged women who report a multiyear history. We present an 10-year-old African American boy who had an asymptomatic, irregularly shaped erythematous lesion on his left medial foot that had been present since birth. A biopsy showed an abrupt, well demarcated decrease in the thickness of the stratum corneum layer, with no parakeratosis, that was consistent with a diagnosis of circumscribed hypokeratosis. This represents the first pediatric and congenital case of circumscribed hypokeratosis reported. We review the literature and discuss the ramifications of a congenital case on understanding the etiology of circumscribed hypokeratosis. PMID- 21692838 TI - Ectodermal abnormalities in patients with Kabuki syndrome. AB - Kabuki syndrome (KS) is extensively described in the literature and characterized by a typical facial gestalt in combination with postnatal short stature, hypotonia, joint laxity, developmental delay, persistent fetal fingertip pads, and an ever-growing group of congenital abnormalities. In this study, we focus on some ectodermal manifestations that we have observed. We studied seven patients who fulfilled the clinical criteria for KS and undertook a detailed clinical, dental, cytogenetic, and immunoglobulin assessments. In addition, microscopic hair examinations were performed on all patients and compared with matched control patients. All patients had receding of the anterior hair line, but five had evident sparse frontal scalp hair. They all showed peculiar similar microscopic hair abnormalities in the form of twisting of the hair shafts, irregularity of the diameter of the hair, and trichorrhexis nodosa. In addition, hypoplastic nails, cafe-au-lait patches, and missing upper lateral incisors were observed in 57.1%, 28.6%, and 14.3% of the patients, respectively. Variable orodental anomalies were seen in all the patients with an everted lower lip found in four patients (57.1%). This report provides further evidence that some cases of KS have ectodermal involvement. PMID- 21692837 TI - Efficacy of oral prednisolone use in the treatment of infantile hemangiomas in Indian children. AB - Approximately 10% to 15% of patients with infantile hemangioma (IH) require treatment that needs to be individualized according to the size, location, and type of IH. Oral corticosteroids [CS] have been the mainstay of therapy, but dose and duration of therapy have been variably reported in literature. The possible side effects with high dose CS is a constant deterrant. Twenty infants with IH requiring therapy were treated with prednisolone at a dose of 3 to 4 mg/kg/day. Response to therapy, adverse effects, and risk of rebound growth were monitored. All of the treated lesions responded to prednisolone at 3.1 mg/kg/day given for a mean duration of 9.16 weeks by showing a cessation of active growth; 90% of patients showed partial to excellent response (Grade 2 to Grade 4 improvement). In the remaining 10% of patients there was <25% regression in the lesion. The total duration of therapy with tapering doses was 29.9 weeks. No cases of rebound growth were seen. The incidence of adverse effects was low, with one patient developing CS-induced hypertension (5%). Oral CS, given at appropriate doses, are a reasonably safe and highly efficacious treatment modality for IH. To prevent the risk of rebound growth, adequate prolongation of therapy is required. PMID- 21692839 TI - Onychophagia-induced longitudinal melanonychia. AB - An otherwise-healthy 13-year-old girl with previously normal nails developed longitudinal pigmented bands on multiple fingernails. Physical examination revealed faintly pigmented bands on multiple fingernails and on the left fifth toenail. We believed that the cause of the pigmented bands was onychophagia induced longitudinal melanonychia, a rare phenomenon, which emphasizes the need for dermatologists to question patients with melanonychia about their nail biting habits because they may not be forthcoming with this information. PMID- 21692840 TI - Childhood erythema nodosum associated with kerion celsi: a case report and review of literature. AB - Erythema nodosum (EN) in association with kerion celsi is a rare condition in children, with only 11 cases having been reported in the English literature. We describe a new case in a 7-year-old boy in whom the disorder had begun 2 months before. He had many inflamed, boggy, suppurative nodules over the left occipitoparietal area of the scalp and, 2 weeks later, developed multiple painful, erythematous subcutaneous nodules of the shins, thighs, and upper limbs. EN was confirmed by histologic examination. Our review of the literature of all cases of EN during kerion showed that it usually occurs at or slightly after the height of infection or after drug introduction. Trichophyton mentagrophytes was involved in the majority of cases, and improvement of EN usually occurs with griseofulvin. PMID- 21692841 TI - Accessory scrotum attached to a peduncular perineal lipoma. AB - In this study, we report on the case of a newborn boy diagnosed after birth with an accessory scrotum attached to a peduncular type of perineal lipoma without any other associated congenital anomalies. The neonate underwent a simple surgical excision of the lipoma and accessory scrotum in the first month of life, and his postoperative course was uneventful. Histologic examination revealed normal scrotal skin and adipose tissue. Accessory scrotum has a high incidence of association with perineal lipoma (83% of reported cases) and other urogenital and anorectal anomalies, but urogenital or anorectal anomalies were not seen in our patient. PMID- 21692842 TI - A new SPINK5 mutation in a patient with Netherton syndrome: a case report. AB - We report on a case of Netherton syndrome showing a new SPINK5 mutation (c.957_960dupTGGT duplication in exon 11), associated with partial defect of biotinidase. PMID- 21692843 TI - The role of a specialized approach for patients with diabetes, critical ischaemia and foot ulcers not previously considered for proactive management. AB - AIMS: To analyse the outcome of the proactive management of patients with diabetes, critical limb ischaemia and foot ulcers using percutaneous transluminal angioplasty as the only vascular procedure and adjuvant conservative surgery when indicated. METHODS: A retrospective study of patients with diabetes included in our database who sought a second opinion in our unit and met the following criteria: foot ulcer and critical limb ischaemia in patients for whom any proactive vascular treatment had not previously been considered by other teams. RESULTS: Twenty patients underwent endovascular procedures. Success was achieved in 19 cases (95%). No post-operative mortality (within 30 days after the procedure) was found. Additional surgery was required in eight cases (40%): one calcaneal ostectomy and seven minor amputations. The need for surgery was associated with infection (P < 0.01). Limb salvage was sustained during a mean period of follow-up of 642 days (SD 488) in 19 cases (95%). Healing was achieved in 14 cases (70%), four are still healing (20%), one underwent major amputation (5%) and the last one died before being healed (5%). Three patients died during follow-up (15%). CONCLUSIONS: Management of patients with diabetes, foot ulcers and critical limb ischaemia by means of a proactive approach including endovascular procedures in specialized settings provides a high rate of limb salvage. This may result in lowering the number of lower limb amputations in our community. PMID- 21692844 TI - Satisfaction with continuous glucose monitoring in adults and youths with Type 1 diabetes. AB - AIMS: To describe satisfaction with continuous glucose monitoring in Type 1 diabetes; to correlate continuous glucose monitoring satisfaction scores with usage; and to identify common themes in perceived benefits and barriers of monitoring reported by adults, youths and the parents of youths in the Juvenile Diabetes Research Foundation continuous glucose monitoring trials. METHODS: The Continuous Glucose Monitoring Satisfaction Scale questionnaire was completed after 6 months of monitoring. Participants also answered open-ended queries of positive and negative attributes of continuous glucose monitoring. RESULTS: More frequent monitoring was associated with higher satisfaction for adults (n = 224), youths (n = 208) and parents of youths (n = 192) (all P < 0.001) in both the 'benefits' and 'hassles' sub-scales of the Continuous Glucose Monitoring Satisfaction Scale, but the greatest differences between the two groups involved scores on hassle items. Common barriers to monitoring use included insertion pain, system alarms and body issues; while common benefits included glucose trend data, opportunities to self-correct out-of-range glucose levels and to detect hypoglycaemia. CONCLUSIONS: As frequent use of continuous glucose monitoring is associated with improved glycaemic control without increased hypoglycaemia it is important to overcome barriers, reinforce benefits and set realistic expectations for this technology in order to promote its more consistent and frequent use in individuals with Type 1 diabetes. PMID- 21692845 TI - Leukocyte telomere length is associated with complications of type 2 diabetes mellitus. AB - OBJECTIVE: The key goal of diabetes management is to prevent complications. While the patho-physiological mechanisms responsible for diabetes complications have been extensively studied, at present it is impossible to predict which patient with diabetes could develop complications. In recent years, the role of leukocyte telomere length in the pathogenesis of cardiovascular disease and Type 2 diabetes has been investigated. However, studies aiming to investigate the role of telomeres in the development and progression of Type 2 diabetes, as well as diabetic complications, are still lacking. As a consequence, this study aimed to verify whether leukocyte telomere length is associated with the presence and the number of diabetic complications in a sample of patients with Type 2 diabetes. METHODS: This is a cross-sectional study. Nine hundred and one subjects were enrolled, including 501 patients with Type 2 diabetes, of whom 284 had at least one complication and 217 were without complications, and 400 control subjects. Leukocyte telomere length was measured by quantitative real-time PCR. RESULTS: Patients with diabetes complications had significantly shorter leukocyte telomere length than both patients without diabetes complications and healthy control subjects. Moreover, among patients with diabetes complications, leukocyte telomere length became significantly and gradually shorter with the increasing number of diabetes complications. The magnitude of the effect of the decrease of the abundance of telomeric template vs. a single-copy gene length (T/S ratio) on complications is described by the estimated odds ratio OR=5.44 (95%CI 3.52-8.42). CONCLUSIONS: The results of the study support the hypothesis that telomere attrition may be a marker associated with the presence and the number of diabetic complications. PMID- 21692846 TI - Effect of an anesthesia with propofol compared with desflurane on free radical production and liver function after partial hepatectomy. AB - Propofol has shown antioxidant properties, but no study has focused on liver resection surgery. The aim of this study was to investigate the effect of an anesthesia with propofol compared with desflurane on oxidative stress and hepatic function during and after partial hepatectomy. This was a prospective randomized study performed on two parallel groups. The primary endpoint was malondialdehyde (MDA) plasma concentration 30 min after hepatic vascular unclamping. Hepatic damages were evaluated by plasma levels of alpha-glutathione S-transferase (alpha GST) 120 min after hepatic vascular unclamping and of aminotransferases at 120 min and on days 1, 2, 5, and 10. Liver function recovery was assessed by monoethylglycinexylidide (MEGX) formation 15 min after lidocaine injection on day 2 and by prothrombin time and plasma factor V at 120 min and on days 1, 2, 5, and 10. Thirty patients were analyzed (propofol group: 17; desflurane group: 13). There was no significant difference between groups for MDA plasma concentration 30 min after hepatic vascular unclamping (mean +/- standard-deviation: 1.28 +/- 0.40 and 1.21 +/- 0.29 in propofol and desflurane groups, respectively, P = 0.608). Plasma levels of alpha-GST at 120 min were lower in propofol than in desflurane group (142.2 +/- 75.4 vs. 205.7 +/- 66.5, P = 0.023), and MEGX on day 2 was higher (0.092 +/- 0.096 vs. 0.036 +/- 0.020, P = 0.007). No differences between groups were observed with regard to plasma levels of aminotransferases, prothrombin time, and plasma factor V. Our study showed that in patients undergoing partial hepatectomy, propofol did not reduce MDA formation but seemed to display a protective effect on hepatic damages and liver function when compared to desflurane. PMID- 21692847 TI - The effects of triple vs. dual and monotherapy with rosiglitazone, glimepiride, and atorvastatin on lipid profile and glycemic control in type 2 diabetes mellitus rats. AB - The present study was undertaken to investigate the effects of triple oral therapy and different combination of rosiglitazone, atorvastatin, and glimepiride on streptozotocin (STZ)-induced diabetic rats. The various biochemical parameters studied included glycosylated hemoglobin (A1c), fasting plasma sugar levels, triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and very low-density lipoprotein (VLDL) cholesterol in diabetic and normal rats. The present study demonstrates that atorvastatin could increase the effect of rosiglitazone and glimepiride and lipid lowering effect of combination of rosiglitazone and glimepiride (GLIM). According to our finding, similar results for rosiglitazone plus atorvastatin were obtained in terms of correcting lipid parameters, whereas the suppressive action of triple oral therapy of rosiglitazone and glimepiride, and atorvastatin on blood glucose, total cholesterol, LDL, VLDL, HDL cholesterol, and triglyceride was more beneficial than that of dual therapy of different combinations and monotherapy. PMID- 21692848 TI - Feasibility of cerebral MRI in non-sedated preterm-born infants at term equivalent age: report of a single centre. AB - AIM: MRI is gaining in importance as an imaging tool for brain development and injury in preterm infants. The aim of this study was to evaluate the feasibility of performing MRI in non-sedated preterm-born infants at term-equivalent age (TEA). METHODS: A total of 89 infants born before 32 gestational weeks were recruited. Infants were scanned without sedation. Duration of the entire examination including scan repetition and interruptions was registered. RESULTS: Of the 89 infants, 56 (63%) underwent MRI at TEA. Out-patients required a significantly shorter total MR examination time than did in-patients (32 +/- 12 vs. 54 +/- 10 min, p < 0.01). Of the 56 infants, 39 (69.6%) were examined without interruption. Only four (7.2%) of the 56 scans were unusable because of motion artefacts. Mean duration of all scans was 36 +/- 14 min. In cases with no interruptions, sessions were completed within 32 +/- 12 min; MR sessions with interruption lasted 45 +/- 13 min. CONCLUSION: A well-trained team is indispensable in obtaining best-quality images as a prerequisite for good counselling. From our experience, we worked out a guideline to ensure that scans in stable non-sedated preterm-born infants at TEA run smoothly and provide high quality images. PMID- 21692850 TI - Chromosome abnormalities defined by conventional cytogenetics in plasma cell leukemia: what have we learned about its biology? AB - Cancer cells are characterized by having chromosomal abnormalities. The number of aberrations and the specific chromosomes affected are likely correlated with tumor progression. In this study, we analyzed the karyotype of 126 plasma cell leukemia (PCL) patients to identify the most frequently occurring imbalances and to design a model of karyotypic evolution. The Mitelman database of chromosome was searched and abnormal karyotypes were assessed. The main clones were analyzed and chromosomal gains and losses were used to design a model of genetic acquisition based on the calculation of a variable called time to occurrence. Our comprehensive study of genetic abnormalities of a large number of PCL karyotypes suggests that PCL is mainly characterized by the presence of whole chromosome losses as well as IgH rearrangements which is similar to that observed in non hyperdiploid multiple myeloma (MM). Temporal analysis suggests that most PCL have around 10 abnormalities at diagnosis. It is possible that accumulation of abnormalities such as 17p13 (TP53) and 1p losses may trigger the extramedullary features of PCL. Our study demonstrates that cytogenetics is a valuable tool to evaluate the role of genetic imbalances on karyotypic evolution by using a mathematical model. PMID- 21692849 TI - Investigating the role of CD38 and functionally related molecular risk factors in the CLL NOD/SCID xenograft model. AB - We explored the role of CD38 and functionally associated molecular risk factors in a recently described chronic lymphocytic leukemia (CLL) nonobese diabetic/ severe combined immunodeficient xenograft model. Intravenous injection of peripheral blood mononuclear cells from 73 patients with CLL into 244 mice resulted in robust engraftment of leukemic cells into the murine spleens detected 4 wks after transplantation. Leukemic cell engraftment correlated significantly (P < 0.05) with markers reflecting disease activity, e.g., Binet stage and lymphocyte doubling time, and the expression of molecular risk factors including CD38, CD49d, ZAP-70, and IgVH mutational status. Increased engraftment levels of CD38+ as compared to CD38- CLL cells could be attributed, in part, to leukemic cell proliferation as evidenced by combined immunostaining of murine spleen sections for Ki-67 and CD20. In short-term (24 h) homing assays, CD38+ CLL cells migrated more efficiently to the bone marrow of the recipient animals than their CD38- counterparts. Finally, CD38 expression by the leukemic cells was found to be dynamic in that it was regulated not only by elements of the murine microenvironment but also by co-engrafting non-malignant human T cells. This model could be useful for evaluating the biological basis of CLL growth in the context of the hematopoietic microenvironment as well as preclinical testing of novel compounds. PMID- 21692851 TI - Allogeneic hematopoietic transplantation using haploidentical donor vs. unrelated cord blood donor in pediatric patients: a single-center retrospective study. AB - We retrospectively analyzed outcomes in 67 children with acute leukemia who received hematopoietic stem cell transplantation from alternative allogeneic donors: 29 received a haploidentical family donor and 38, an unrelated cord blood donor. All transplantations were performed from 1996 through 2010 in our center. Neutrophil and platelet engraftment were significantly delayed after cord blood transplantation. The median times to neutrophil and platelet recovery were 13 d (7-34) and 11 d (5-70) after haploidentical transplant and 20 d (9-125) and 56 d (12-200) after cord blood (P < 0.001). All supportive care measures included red blood cell, and platelet transfusions were significantly increased in cord blood transplantation group.Transplant-related mortality rates was lower with haplo donors (25 +/- 9%) than with cord blood donors (47 +/- 9%) (P < 0.05). Acute graft-versus-host disease (GVHD) more than grade II was also lower in haploidentical transplants (19 +/- 7%) than in cord blood transplants (44 +/- 10%) (P < 0.03). Relapse and chronic GVHD incidence were not significantly different in the two groups. Leukemia-free survival was higher after haploidentical transplants (44 +/- 10%) than after cord blood transplants (33 +/- 7%) (P < 0.03). Main differences were observed in patients diagnosed with acute lymphoblastic leukemia: haplo, 41 +/- 13%; cord blood, 26 +/- 9% (P < 0.03) and in advanced phase of disease: haplo, 37 +/- 14%; cord blood, 21 +/- 8% (P < 0.05). In conclusion, haploidentical transplants are a good and promising alternative option for patients with childhood leukemia who lack an human leukocyte antigen-matched donor (sibling or unrelated donor). PMID- 21692854 TI - A severe neonatal presentation of factor II deficiency. AB - Prothrombin deficiency is an autosomal recessive disorder associated with moderate or severe bleeding tendency. In this study, a three-month-old boy with non-consanguineous parents was referred for convulsions because of intracerebral hemorrhage. Standard coagulation tests revealed that the patient's plasma prothrombin activity was 12%, while his father's and mother's levels were 55% and 70%, respectively. Analysis of the prothrombin gene revealed that this patient is a compound heterozygote for two missense mutations: one maternally inherited point mutation in the propeptide (p.Arg4Gln) and one paternally inherited mutation in the kringle-2 (p.Arg220Pro) domain. Structural analysis was performed and confirmed that the resulting mutations were inferred to respectively affect the cleavage of the propeptide from the Gla domain, and the stability of the kringle-2 domain, both resulting in a severe hypoprothrombinemia. In unusually bleeding newborn of non-consanguineous parents, rare severe homozygous bleeding disorders need to be considered to facilitate early diagnosis and treatment. PMID- 21692852 TI - Cost effectiveness of treatments for relapsed/refractory multiple myeloma: response to a methodology. RE: Hornberger J, Rickert J, Dhawan R, Liwing J, Aschan J, Lothgren M. The cost effectiveness of bortezomib in relapsed/refractory multiple myeloma: Swedish perspective. European Journal of Haematology 2010; 85 (6):484-491. PMID- 21692855 TI - Patterns and predictors of personal exposure to indoor air pollution from biomass combustion among women and children in rural China. AB - Indoor air pollution (IAP) from domestic biomass combustion is an important health risk factor, yet direct measurements of personal IAP exposure are scarce. We measured 24-h integrated gravimetric exposure to particles < 2.5 MUm in aerodynamic diameter (particulate matter, PM2.5) in 280 adult women and 240 children in rural Yunnan, China. We also measured indoor PM2.5 concentrations in a random sample of 44 kitchens. The geometric mean winter PM2.5 exposure among adult women was twice that of summer exposure [117 MUg/m3 (95% CI: 107, 128) vs. 55 MUg/m3 (95% CI: 49, 62)]. Children's geometric mean exposure in summer was 53 MUg/m3 (95% CI: 46, 61). Indoor PM2.5 concentrations were moderately correlated with women's personal exposure (r=0.58), but not for children. Ventilation during cooking, cookstove maintenance, and kitchen structure were significant predictors of personal PM2.5 exposure among women primarily cooking with biomass. These findings can be used to develop exposure assessment models for future epidemiologic research and inform interventions and policies aimed at reducing IAP exposure. PRACTICAL IMPLICATIONS: Our results suggest that reducing overall PM pollution exposure in this population may be best achieved by reducing winter exposure. Behavioral interventions such as increasing ventilation during cooking or encouraging stove cleaning and maintenance may help achieve these reductions. PMID- 21692856 TI - Dental implant suprastructures using cobalt-chromium alloy compared with gold alloy framework veneered with ceramic or acrylic resin: a retrospective cohort study up to 18 years. AB - BACKGROUND: An association between the long-term success and survival of implant supported prostheses as a function of biomaterial combinations has not been established. The use of cast cobalt-chromium for the suprastructure framework may be an alternative to the conventional approach of using type 3 gold alloys. MATERIALS AND METHODS: A retrospective chart audit of all patients who had received implant-supported fixed dental prostheses (FDP) before 1996 was identified in a private practice clinic. Data were recorded for FDPs made from four combinations of alloy frameworks and veneering material, i.e. type 3 gold and cobalt-chromium with ceramic or prefabricated acrylic teeth. The extracted data from the charts were subjected to explorative statistical tests including Kaplan-Meier survival analyses. RESULTS: Patients (n=198) with 270 short and extensive FDPs supported entirely by 1117 implants were identified. The average follow-up observation periods varied between 4 and 220 months, with an average of 120 months. The success and survival, as well as event rates and types of biological and technical complications, were similar for implant-supported FDPs using cobalt-chromium and type 3 gold alloy frameworks veneered with ceramics or prefabricated acrylic teeth. An influence of the suprastructure biomaterial combination on the clinical performance of the individual supporting implants could not be established. CONCLUSIONS: Implant-supported FDPs made from type 3 gold or cobalt-chromium frameworks and veneered with ceramic or prefabricated acrylic teeth demonstrate comparable clinical performance. The biomaterial combinations do not appear to influence the success or survival of the individual implants. PMID- 21692857 TI - Evaluation of a biodegradable synthetic hydrogel used as a guided bone regeneration membrane: an experimental study in dogs. AB - OBJECTIVES: To test whether or not an experimental polyethylene glycol (PEG) membrane maintains the bone graft volume and contributes to the preservation of the ridge contour in comparison with a commercially available synthetic membrane. MATERIALS AND METHODS: In 18 dogs, all mandibular premolars and the first molars were extracted. Ten weeks later, acute standardized defects were prepared. The defects of four dogs were randomly assigned to three modalities: (1) PEG plus deproteinized bovine bone mineral (DBBM) (PEG), (2) a resorbable glycolide trimethylene carbonate membrane plus DBBM (PGA-TMC), and (3) DBBM alone (DBBM). These dogs were then sacrificed for the baseline measurements. The remaining defects of 14 dogs were randomly assigned to (1) PEG plus DBBM, (2) PGA-TMC plus DBBM, (3) DBBM, and (4) empty defect. The dogs were sacrificed at baseline (n=4), 4 weeks (n=7), or at 16 weeks (n=7). Mixed model regressions and the non parametric Brunner-Langer method were applied for statistical analysis. RESULTS: At baseline, equal tissue augmentation was observed in all groups. At 4 and 16 weeks, the greatest augmented area fractions were calculated for PEG (103%; 107%, respectively), followed by PGA-TMC (98%; 91%), DBBM (85%; 78%), and empty (46%; 54%), being statistically significant different (P<0.001) between PEG and empty at 4 and 16 weeks, and PEG and DBBM at 16 weeks. The overall decrease (P<=0.01) in the amount of bone graft between baseline and 16 weeks was -14% (PEG), -22% (PGA-TMC), and -23% (DBBM). CONCLUSIONS: The study demonstrates that the combination of the PEG membrane with DBBM maintains the bone graft volume over time better than controls. The PEG membrane with DBBM was also the most effective method to preserve the ridge contour. PMID- 21692858 TI - A tale of two plaques: convergent mechanisms of T-cell-mediated inflammation in psoriasis and atherosclerosis. AB - Psoriasis and atherosclerosis are diseases in which effector T lymphocytes such as Helper T cells type 1 (Th1) and 17 (Th17) play integral roles in disease pathogenesis and progression. Regulatory T cells (Treg) also exert clinically important anti-inflammatory effects that are pathologically altered in psoriasis and atherosclerosis. We review the immunological pathways involving Th1, Th17 and Treg cells that are common to psoriasis and atherosclerosis. These shared pathways provide the basis for mechanisms that may explain the epidemiologic observation that patients with psoriasis have an increased risk of heart disease. Improved understanding of these pathways will guide future experiments and may lead to the development of therapeutics that prevent or treat cardiovascular complications in patients with psoriasis. PMID- 21692859 TI - Tissue microarray analysis of RANKL in cutaneous lupus erythematosus and psoriasis. AB - Recently, it was discovered that the receptor activator of nuclear factor kappaB (RANK)/RANK ligand (RANKL) is part of an important signal transduction pathway for tissue homoeostasis. Therefore, we were interested in investigating RANKL expression in the epidermis of skin lesions from patients with different subtypes of cutaneous lupus erythematosus (CLE) and psoriasis as well as normal healthy donors. Using the tissue microarray technique, skin biopsy specimens were evaluated by immunohistochemistry. RANKL showed a significantly increased expression in the epidermis of skin biopsy specimens from patients with psoriasis (median: 4, range: 0-5) compared to patients with CLE (median: 0, range: 0-4) (P<0.001). No significant differences in epidermal RANKL expression between the CLE subtypes were detected. These data show a different expression of RANKL in the epidermis of skin lesions from patients with CLE compared to those with psoriasis suggesting that RANKL might play an important role in the pathogenesis of the disease. PMID- 21692860 TI - Bioactive tetrapeptide GEKG boosts extracellular matrix formation: in vitro and in vivo molecular and clinical proof. AB - The 'matrikine' concept claims that processing of the precursors for collagen results in the formation of peptides such as KTTKS which in turn augments extracellular matrix (ECM) production. In the present study, we show the development of an anti-ageing active from an in silico approach by molecular design resulting in the tetrapeptide GEKG derived from ECM proteins. The efficacy of the peptide to significantly induce collagen production of the protein level and mRNA level has been demonstrated in vitro in human dermal fibroblasts and in vivo in a double-blind, randomized, placebo-controlled study enroling 10 volunteers with an average age of 48.2 years. The effect of GEKG on facial wrinkles was studied in 30 volunteers using state of the art fringe projection, which allows determination of surface roughness in three-dimensions. Here, only GEKG but not the placebo was able to significantly decrease skin roughness as a measure for wrinkles. PMID- 21692861 TI - Extracellular matrix in angiogenesis: dynamic structures with translational potential. AB - The vascular network is an integral component of most organs. Beyond assuring an adequate supply of oxygen and nutrients for normal tissue function, vascular structures provide also a critical interface in the balance of tissue homoeostasis and immune functions. Therefore, understanding the biology of the vascular system is a challenging and important objective because it is vital to many physiological and pathological processes. Unravelling mechanisms of blood vessel expansion and remodelling would offer therapeutic options to ameliorate disorders that are currently leading causes of mortality and morbidity, including cardiovascular diseases, cancer, chronic inflammatory disorders, diabetic retinopathy, tissue defects caused by trauma or chronic skin ulcers. This article will review cellular and molecular mechanisms controlling angiogenesis in the light of recent reports and data from our own laboratories. We will focus on the interaction of growth factors with extracellular matrix (ECM) components during the formation of vascular structures in health and disease. Finally, this article will provide a rationale for targeting the ECM-morphogen interplay for therapeutic angiogenesis. PMID- 21692862 TI - "Preclinical" MSA in definite Creutzfeldt-Jakob disease. AB - Multiple system atrophy (MSA) is a sporadic alpha-synucleinopathy clinically characterized by variable degrees of parkinsonism, cerebellar ataxia and autonomic dysfunction. The histopathological hallmark of MSA is glial cytoplasmic inclusion (GCI). It is considered to represent the earliest stage of the degenerative process in MSA and to precede neuronal degeneration. Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal, rapidly progressive dementia generally associated with ataxia, pyramidal and extrapyramidal symptoms and myoclonus. Definite diagnosis needs neuropathological demonstration of variable degrees of spongiform degeneration of neuropil, neuronal loss, astro- and microgliosis, and the presence of abnormal deposits of the misfolded prion protein PrP(res) . Both diseases, CJD and MSA are infrequent among neurodegenerative diseases. In the present report we describe clinical and neuropathological findings of a previously healthy 64-year-old woman who developed symptoms of classical CJD. At post mortem examination, the brain showed in addition to classical methionine/methionine PrP(res) type 1 (MM1) sCJD changes and moderate Alzheimer-type pathology, features of "preclinical" MSA with minimal histopathological changes. These were characterized by discrete amounts of alpha-synuclein immunoreacive glial cytoplasmic inclusions in the striato nigral system, isolated intraneuronal inclusions in pigmented neurons of the substantia nigra, as well as some vermiform intranuclear inclusions. To our knowledge, this is the first report on the coexistence of definite sCJD and "minimal changes" MSA in the same patient. PMID- 21692863 TI - Cerebellopontine angle subependymoma without fourth ventricle extension: an uncommon tumor in a rare location. AB - Subependymomas are benign tumors that occur predominantly in the ventricular system. We describe a case of a 57-year-old man with a large cerebellopontine angle (CPA) tumor which expanded into the jugular foramen. Complete surgical excision of the tumor was achieved through a retrosigmoid approach and the histopathological diagnosis was subependymoma. Subependymomas located exclusively in the CPA without extension into the fourth ventricle are extremely rare. The mainly pathological features and the difficulty in correctly diagnosing these cases preoperatively, even with MRI, are discussed. PMID- 21692864 TI - Diagnostic implications of histological analysis of neurosurgical aspirate in addition to routine resections. AB - Many neurosurgical centers use surgical aspirators to remove brain tumor tissue. The resulting aspirate consists of fragmented viable tumor, normal or tumor infiltrated brain tissue as well as necrotic tissue, depending on the type of tumor. Typically, such fragmented aspirate material is collected but discarded and not included when making the histopathological diagnosis. Whereas the general suitability of surgical aspirate for histological diagnosis and immunohistochemical staining has been reported previously, we have systematically investigated whether the collection and histological examination of surgical aspirate has an impact on diagnosis, in particular on the tumor grading, by providing additional features. Surgical and aspirate specimens from 85 consecutive neurosurgical procedures were collected and routinely processed. Sixty-five of the 85 specimens were intrinsic brain tumors and the remainder consisted of metastatic tumors, meningiomas, schwannomas and lymphomas. Important diagnostic features seen in surgical aspirate were microvascular proliferation (n = 3), more representative necrosis (n = 2), and gemistocytic component (n = 2). In one case, microvasular proliferations were seen in the aspirate only, leading to a change of diagnosis. Collection of surgical aspirate also generates additional archival material which can be microdissected and used for tissue microarrays or for molecular studies. PMID- 21692865 TI - Coexistence of adamantinomatous and squamous-papillary type craniopharyngioma: case report and discussion of etiology and pathology. AB - Craniopharyngiomas are histopathologically classified as adamantinomatous type (AD) and squamous-papillary type (SP). However coexistence of a mixed type seen on histopathologic specimens has not been reported. In this report, a patient diagnosed with mixed type craniopharyngioma is presented and the etiology and pathologic features are discussed. PMID- 21692866 TI - Prostate cancer detection after a negative prostate biopsy: lessons learnt in the Cleveland Clinic experience. AB - Urologists are often faced with the dilemma of managing patients with a negative initial prostate biopsy in whom clinical or pathological risk for prostate cancer still exists. Such real-life challenging scenarios might raise questions such as: Who should undergo further biopsies? What are the optimal predictors for prostate cancer on subsequent biopsies? What is the optimal biopsy protocol that should be used? When to stop the biopsy cascade? The last decade has witnessed numerous studies that have analyzed factors conferring a significant risk for cancer discovered on repeat biopsies. We and others have developed predictive models to aid decision-making regarding pursuing further biopsies. For decades, high-grade prostatic intraepithelial neoplasia has been considered a strong risk indicator for subsequent cancer. However, it has been recently shown that only through segmentation of this heterogeneous population does the real risk profile emerge. Biopsy templates underwent modification regarding the number and location of cores with emergence of the transrectal or brachytherapy grid transperineal saturation biopsy. However, the best biopsy protocol remains controversial. We have refined the initial biopsy template to a 14 core initial biopsy template that optimizes cancer detection, and have shown that transrectal saturation biopsy significantly improves cancer detection for repeat biopsy. Another concern is the overdiagnosis of clinically insignificant cancer on repeat biopsies, so we explored ways to limit this, and to deal with its ramifications. Through carrying out a Medline literature search, we critically evaluated pertinent articles together with emphasis of our own journey in this arena to assist in the decision making process for repeat biopsy population. PMID- 21692867 TI - Editorial comment to prostate cancer detection after a negative prostate biopsy: lessons learnt in the Cleveland Clinic experience. PMID- 21692868 TI - Airborne contact dermatitis to tetrazepam in geriatric nurses--a report of 10 cases. AB - BACKGROUND: Tetrazepam, a benzodiazepine, is a frequently used muscle relaxant. The most common adverse reactions are neurological and gastrointestinal. Cutaneous reactions to tetrazepam are rare and occur predominantly after systemic administration. OBJECTIVE: To present 10 health care professionals who developed airborne contact dermatitis to tetrazepam due to occupational exposure to tetrazepam dusts. MATERIALS AND METHODS: We report a series of 10 cases observed in our department between January 2006 and March 2011 where tetrazepam was identified to cause allergic airborne contact dermatitis. Affected individuals were employed as (geriatric) nursing staff, exposed to tetrazepam on a regular occupational basis when crushing tablets for their patients. Upon investigation, patients were patch tested with commercial and customized allergens. This included tetrazepam and in five cases diazepam. Tetrazepam revealed strong positive reactions in all patients. Additional diazepam sensitization was observed in three subjects. Following local treatment and occupational preventive action, patients recovered from their skin symptoms. CONCLUSIONS: Allergic contact sensitization to tetrazepam and cross sensitization to diazepam seems to be underestimated and not appropriately diagnosed in patch test clinics, as it is so far insufficiently patch tested. They should be considered when allergic contact dermatitis is suspected, particularly in professionally exposed staff, and tested as supplemental allergens. PMID- 21692869 TI - The effectiveness of anticellulite treatment using tripolar radiofrequency monitored by classic and high-frequency ultrasound. AB - BACKGROUND: Cellulite affects nearly 85% of the female population. Given the size of the phenomenon, we are continuously looking for effective ways to reduce cellulite. Reliable monitoring of anticellulite treatment remains a problem. OBJECTIVE: The main aim of the study was to evaluate the effectiveness of anticellulite treatment carried out using radiofrequency (RF), which was monitored by classical and high-frequency ultrasound. METHODS: Twenty-eight women underwent anticellulite treatment using RF, 17 women were in the placebo group. The therapy was monitored by classical and high-frequency ultrasound. The examinations evaluated the thickness of the epidermal echo, dermis thickness, dermis echogenicity, the length of the subcutaneous tissue bands growing into the dermis, the presence or absence of oedema, the thickness of subcutaneous tissue as well as thigh circumference and the stage of cellulite (according to the Nurnberger-Muller scale). RESULTS: Cellulite was reduced in 89.286% of the women who underwent RF treatment. After the therapy, the following observations were made: a decrease in the thickness of the dermis and subcutaneous tissue, an increase in echogenicity reflecting on the increase in the number of collagen fibres, decreased subcutaneous tissue growing into bands in the dermis, and the reduction of oedema. In the placebo group, no statistically significant changes of the above parameters were observed. CONCLUSION: Radiofrequency enables cellulite reduction. A crucial aspect is proper monitoring of the progress of such therapy, which ultrasound allows. PMID- 21692870 TI - Is atopy and autoimmunity more prevalent in patients with alopecia areata? A comparative study. AB - OBJECTIVE: We aimed to determine whether there was a difference between adult and paediatric alopecia areata patients with respect to the severity and pattern of the disease, nail changes and personal and family history of autoimmune diseases and also in comparison with controls. METHODS: Two groups were included: patients with onset of alopecia before the age of <=18 years and >18 years. The total number of the patients were 124. The control group was comprised of 114 age- and gender-matched patients. RESULTS: There were 81 adults and 43 children. No statistically significant difference was present between disease severity and gender, age, personal and family history of autoimmune disease in the adult and paediatric group (P > 0.5). Thirteen adults with scalp involvement had nail changes. 61.5% had mild and 38.46% had severe disease (P > 0.5). Of the 43 paediatric patients, 10 patients had nail changes. Severe alopecia was present in 40% of patients with nail changes; however, 9.1% had severe alopecia in patients without nail changes (P = 0.04). There was no statistical significance in patients with and without familial autoimmune diseases when compared with pattern and severity of the diseases between the two groups. CONCLUSION: The frequencies of autoimmune and atopic diseases were not different between adult and paediatric patients and the control group. We did not find a statistically significance between disease severity and personal and family history of autoimmune disease in the two groups. Disease severity was not related to nail changes in the adult group. However, severe alopecia areata was more prevalent in children with nail changes. Furthermore, ophiasis pattern was more prevalent in the paediatric group with nail changes compared with the adult group. PMID- 21692871 TI - Phytate and phytase in fish nutrition. AB - Phytate formed during maturation of plant seeds and grains is a common constituent of plant-derived fish feed. Phytate-bound phosphorus (P) is not available to gastric or agastric fish. A major concern about the presence of phytate in the aquafeed is its negative effect on growth performance, nutrient and energy utilization, and mineral uptake. Bound phytate-P, can be effectively converted to available-P by phytase. During the last decade, phytase has been used by aqua feed industries to enhance the growth performance, nutrient utilization and bioavailability of macro and micro minerals in fish and also to reduce the P pollution into the aquatic environment. Phytase activity is highly dependent on the pH of the fish gut. Unlike mammals, fish are either gastric or agastric, and hence, the action of dietary phytase varies from species to species. In comparison to poultry and swine production, the use of phytase in fish feed is still in an unproven stage. This review discusses effects of phytate on fish, dephytinisation processes, phytase and pathway for phytate degradation, phytase production systems, mode of phytase application, bioefficacy of phytase, effects of phytase on growth performance, nutrient utilization and aquatic environment pollution, and optimum dosage of phytase in fish diets. PMID- 21692872 TI - Physiological and blood biochemical variables in horses exercising on a treadmill submerged in water. AB - The blood lactate concentration (LA) and heart rate (HR) of 10 horses exercising in water on a treadmill were examined. With the water at 10 and 50% of the withers height (WH), the blood LA increased up to mean values around 1.9 mm during the standardized exercise test (SET) until after step 3 of 5 (each step lasted 5 min, speed increasing step by step). Thereafter, blood LA of horses remained constant, while with the water at 80% of WH, the blood LA decreased from the mean peak of 2.16 +/- 0.62 mm after the 4th step. The HR of the horses increased to 132 +/- 14 beats/min until the 3rd step of SET with the water at 10% of WH, up to the 2nd step with the water at 50% (134 +/- 10 beats/min) and up to the 1st step only with the water at 80% of WH (134 +/- 10 beats/min). In another SET, horses were exercised five times for 5 min at the maximal attainable speed of 5.5 m/s in water at 20% of the withers height in step 1, 35% in step 2, 49% in step 3, 63% in step 4 and 77% in step 5. On using this SET, blood LA increased to 1.91 +/- 0.25 mm until after the 2nd step and decreased after the 3rd step. The HR increased between before commencing SET and the 1st step (143 +/- 13 beats/min) and remained constant thereafter. In conclusion, increasing water height and speed of exercise does not augment continuously blood LA and HR of horses exercising in water treadmills. PMID- 21692873 TI - Effects of dietary pyridoxine on haemato-immunological responses of Labeo rohita fingerlings reared at higher water temperature. AB - A sixty-day feeding trial was carried out to elucidate the effect of dietary pyridoxine (PN) on hemato-immunological parameters in Labeo rohita fingerlings exposed to an elevated temperature (ET) of 33 degrees C. Two hundred and seventy fingerlings (6.71 +/- 0.32 g) were randomly distributed into six treatments in triplicates (15 fish/tank). Five iso-nitrogenous (356.3 +/- 2.7 g/kg crude protein) purified diets were prepared with graded levels (0, 10, 50, 100 and 200 mg/kg diet) of PN. Six treatment groups were P10T26 (10 mg PN + ambient temperature (26 degrees C), P0T33 (0 mg PN + ET), P10T33 (10 mg PN + ET), P50T33 (50 mg PN + ET), P100T33 (100 mg PN + ET) and P200T33 (200 mg PN + ET). The responses of L. rohita fingerlings to dietary PN were assessed in terms of growth and by analysing some hemato-immunological parameters. When PN supplementation increased from 10 to 200 mg/kg diet, a significant improvement in weight gain percentage was observed. Erythrocyte (RBC) count, leucocyte (WBC) count, haemoglobin content and respiratory burst activity were significantly (p < 0.05) higher in 100 mg PN/kg diet-fed group than their non-PN-fed counterpart. Also, serum albumin, globulin and lysozyme activity were found significantly (p < 0.05) higher in PN-fed groups. The overall results indicated that dietary PN supplementation at 100 mg/kg diet may reverse the negative effects caused by ET and may protect the haemato-immunological status of L. rohita fingerlings reared at higher water temperature. PMID- 21692874 TI - Crystal structures of DntR inducer binding domains in complex with salicylate offer insights into the activation of LysR-type transcriptional regulators. AB - Activation of LysR-type transcription factors (LTTRs) is thought to result from conformational changes that occur when inducer molecules bind to their Inducer Binding Domains (IBDs). However, the exact nature of these changes remains to be fully elucidated. We present the crystal structures of two truncated constructs of the LTTR DntR in their apo- forms and in complex with its natural inducer molecule, salicylate. These provide a fuller picture of the conformational changes that can occur in LTTR IBDs and offer insights that may be relevant when considering the mechanism of activation of LTTRs. Two of the crystal structures show that DntR IBDs can bind up to two inducer molecules. The full extent of conformational changes observed is achieved only when inducer molecules are bound in both binding sites identified. Point mutations disrupting the putative secondary binding site produce DntR variants with a reduced response to salicylate in a whole cell system, suggesting that this site is functionally relevant. PMID- 21692875 TI - Transcriptional regulation of MG_149, an osmoinducible lipoprotein gene from Mycoplasma genitalium. AB - Transcriptional regulation remains poorly understood in Mycoplasma genitalium, the smallest self-replicating cell and the causative agent of a spectrum of urogenital diseases. Previously, we reported that MG_149, a lipoprotein-encoding gene, was highly induced under physiological hyperosmolarity conditions. In this study we further analysed MG_149 transcription with a focus on the identification of promoter elements and regulatory mechanisms. We established MG_149 as a genuine osmoinducible gene that exhibited the highest transcript abundance compared with other lipoprotein genes. Using genetic approaches, we demonstrated that the -10 region of the MG_149 promoter was essential for osmoinduction. Moreover, we showed that MG_149 osmoinduction was regulated by DNA supercoiling, as the presence of novobiocin decreased MG_149 expression in a dose-dependent manner. Taken together, these results indicate that DNA supercoiling participates in controlling MG_149 expression during in vivo-like conditions. PMID- 21692876 TI - Regulation of fructooligosaccharide metabolism in an extra-intestinal pathogenic Escherichia coli strain. AB - A gene cluster involved in the metabolism of prebiotic short-chain fructooligosaccharides (scFOS) has recently been identified in the extra intestinal avian pathogenic Escherichia coli strain BEN2908. This gene cluster, called the fos locus, plays a major role in the initiation stage of chicken intestinal colonization. This locus is composed of six genes organized as an operon encoding a sugar transporter and enzymes involved in scFOS metabolism, and of a divergently transcribed gene encoding a transcriptional regulator, FosR, belonging to the LacI/GalR family. To decipher the regulation of scFOS metabolism, we monitored the fos operon promoter activity using a luciferase reporter gene assay. We demonstrated that the expression of fos genes is repressed by FosR, controlled by catabolite repression and induced in the presence of scFOS. Using electrophoretic mobility shift assays and surface plasmon resonance experiments, we showed that FosR binds to two operator sequences of the fos operon promoter region. This binding to DNA was inhibited in the presence of scFOS, especially by GF2. We then propose a model of scFOS metabolism regulation in a pathogenic bacterium, which will help to identify the environmental conditions required for fos gene expression and to understand the role of this locus in intestinal colonization. PMID- 21692877 TI - Two linked genes encoding a secreted effector and a membrane protein are essential for Ustilago maydis-induced tumour formation. AB - Ustilago maydis is a biotrophic fungal pathogen that colonizes living tissue of its host plant maize. Based on transcriptional upregulation during biotrophic development we identified the pit (proteins important for tumours) cluster, a novel gene cluster comprising four genes of which two are predicted to encode secreted effectors. Disruption of the gene cluster abolishes U. maydis-induced tumour formation and this phenotype can be caused by deleting either pit1 encoding a transmembrane protein or pit2 encoding a secreted protein. Pit1 localizes to the fungal plasma membrane at hyphal tips, endosomes and vacuoles while Pit2 is secreted to the biotrophic interface. Both Deltapit1 and Deltapit2 mutants are able to penetrate maize epidermis and grow intracellularly at sites of infection but fail to spread in the infected leaf. Microarray analysis shows an indistinguishable response of the plant to infection by Deltapit1 and Deltapit2 mutant strains. Transcriptional activation of maize defence genes in infections with Deltapit1/2 mutant strains indicates that the mutants have a defect in suppressing plant immune responses. Our results suggest that the activity of Pit1 and Pit2 during tumour formation might be functionally linked and we discuss possibilities for a putative functional connection of the two proteins. PMID- 21692878 TI - Activity and expression of steroidogenic enzymes in the brain of adult zebrafish. AB - The brain of adult teleost fish exhibits several unique and interesting features, notably an intense neurogenic activity linked to persistence of radial glial cells acting as neural progenitors, and a high aromatase activity supported by strong expression of the cyp19a1b gene. Strikingly, cyp19a1b expression is restricted to radial glial cells, suggesting that estrogens are able to modulate their activity. This raises the question of the origin, central or peripheral, of C19 androgens available for aromatization. This study aimed to investigate the activity and expression of other main steroidogenic enzymes in the brain of adult zebrafish. We demonstrate by high-performance liquid chromatography that the zebrafish brain has the ability to convert [3H]-pregnenolone into a variety of radiolabeled steroids such as 17OH-pregnenolone, dehydroepiandrosterone, androstenedione, testosterone, dihydro-testosterone, estrone, estradiol, progesterone, and dihydro- and tetrahydro-progesterone. Next, we show by in situ hybridization that messengers for key steroidogenic enzymes, such as Cyp11a1 (P450(SCC)), 3beta-Hsd, Cyp17 and Cyp19a1b, are widely expressed in the forebrain where they exhibit an overall similar pattern. By combining aromatase B immunohistochemistry with in situ hybridization, we show that cyp11a1, 3beta-hsd and cyp17 messengers are found in part in aromatase B-positive radial processes, suggesting mRNA export. This set of results provides the first demonstration that the brain of fish can produce true neurosteroids, possibly in radial glial cells. Given that radial glial cells are brain stem cells during the entire lifespan of fish, it is suggested that at least some of these neurosteroids are implicated in the persisting neurogenic process. PMID- 21692879 TI - Transplantation of Flk-1+ human bone marrow-derived mesenchymal stem cells promotes angiogenesis and neurogenesis after cerebral ischemia in rats. AB - Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) is a potential therapy for cerebral ischemia. Although BMSCs-induced angiogenesis is considered important for neurological functional recovery, the neurorestorative mechanisms are not fully understood. We examined whether BMSCs-induced angiogenesis enhances cerebral tissue perfusion and creates a suitable microenvironment within the ischemic brain, which in turn accelerates endogenous neurogenesis and leads to improved functional recovery. Adult female rats subjected to 2 h middle cerebral artery occlusion (MCAO) were transplanted with a subpopulation of human BMSCs from male donors (Flk-1+ hBMSCs) or saline into the ipsilateral brain parenchymal at 3 days after MCAO. Flk-1+ hBMSCs-treated rats exhibited significant behavioral recovery, beginning at 2 weeks after cerebral ischemia compared with controls. Moreover, rats treated with Flk-1+ hBMSCs showed increased glucose metabolic activity and reduced infarct volume. Flk-1+ hBMSCs treatment significantly increased the expression of vascular endothelial growth factor and brain-derived neurotrophic factor, promoted angiogenesis, and facilitated cerebral blood flow in the ischemic boundary zone. Further, Flk-1+ hBMSCs treatment enhanced proliferation of neural stem/progenitor cells (NSPCs) in the subventricular zone and subgranular zone of the hippocampus. Finally, more NSPCs migrated toward the ischemic lesion and differentiated to mature neurons or glial cells with less apoptosis in Flk-1+ hBMSCs-treated rats. These data indicate that angiogenesis induced by Flk-1+ hBMSCs promotes endogenous neurogenesis, which may cause functional recovery after cerebral ischemia. PMID- 21692881 TI - Glucosensing in parvocellular neurons of the rat hypothalamic paraventricular nucleus. AB - Specialized hypothalamic neurons responding to rising extracellular glucose via increases or decreases in their electrical activity [glucose-excited (GE) and glucose-inhibited (GI) cells, respectively] have been reported in the hypothalamic arcuate, ventromedial and lateral nuclei. The hypothalamic paraventricular nucleus (PVN) is an important neurosecretory and preautonomic output nucleus. We tested whether parvocellular PVN neurons also possess glucosensing properties, using patch-clamp recording and immunocytochemistry. Putative neurosecretory (p-NS) and preautonomic (p-PA) cells were identified electrophysiologically. Although parvocellular neurons were insensitive to transitions from 10 to 2.5 mm glucose, approximately 68% of p-PA cells responded directly to glucopenia (mimicked by a step to 0.2 mm glucose) with an increased membrane conductance. Of these, approximately 24% hyperpolarized (accompanied by an outward current) and thus were GE, approximately 26% depolarized (with an inward current, thus GI) and approximately 18% did not change membrane potential. The concentration dependence of the glucose response was similar for both GE and GI cells (EC(50) of 0.67-0.7 mm), but was steep, with Hill slopes of 3-4. The K(ATP) channel blockers glibenclamide and tolbutamide did not prevent, while the K(ATP) channel opener diazoxide did not mimic, the effects of low glucose on GE neurons. Moreover, the K(ATP) sulfonylurea receptor SUR1 was not detected in glucosensitive neurons. We conclude that the PVN contains previously unknown GE and GI cells that could participate in regulation of autonomic functions. GE neurons in the PVN sense ambient glucose via a unique mechanism, probably independent of K(ATP) channels, in contrast to neurons in other hypothalamic nuclei. PMID- 21692880 TI - Localization of GABA-A receptor alpha subunits on neurochemically distinct cell types in the rat locus coeruleus. AB - The locus coeruleus (LC) provides the major source of noradrenaline to the central nervous system and is modulated by neurochemically diverse afferents. LC function is central to arousal, memory, cognition and the stress response, with dysfunction of the LC-noradrenergic axis implicated in debilitating psychiatric disorders. The precise targeting of neurotransmitter receptors within the LC is essential for processing the information contained in diverse afferents and thus LC output. The inhibitory modulation of LC neurons is thought to be effected mainly through GABA-A receptors (GABA(A)Rs). Diverse GABA(A)Rs are pentameric complexes assembled from a repertoire of subunits resulting in substantial diversity in their molecular, functional and pharmacological properties throughout the brain. The precise location of distinct GABA(A) R subunits in subregions of the LC, and the neurochemical identity of the cells that express them, remains to be determined. Here, we show that the GABA(A)R alpha1 subunit is expressed exclusively in neurochemically and morphologically diverse non noradrenergic cell types within the LC, which may innervate the principal noradrenergic cells. Thus, the GABA(A)R alpha1 subunit could provide a neurochemical signature for a pool of local circuit interneurons in the LC. In contrast, non-overlapping GABA(A)R alpha2 and alpha3 subunit-immunoreactive puncta were enriched on noradrenergic dendrites and, to a lesser extent, on somata. The study reveals a cell-type- and domain-specific expression pattern of distinct GABA(A)R subunits in the LC. These data will serve as a template for understanding inhibitory modulation of this region and facilitate more directed pharmacological strategies for disorders arising from the impairment of LC function. PMID- 21692882 TI - Structure and function of medial temporal and posteromedial cortices in early Alzheimer's disease. AB - Medial temporal lobe (MTL) atrophy and posteromedial cortical hypometabolism are consistent imaging findings in Alzheimer's disease (AD). As the MTL memory structures are affected early in the course of AD by neurofibrillary tangle pathology, the posteromedial metabolic abnormalities have been postulated to represent remote effects of MTL alterations. In this study, we investigated with functional MRI (fMRI) the structure-function relationship between the MTL and posteromedial regions, including the retrosplenial, posterior cingulate and precuneal cortices, in 21 older controls (OCs), 18 subjects with amnestic mild cognitive impairment (MCI) and 16 AD patients during a word list learning task. In the voxel-based morphometric and volumetric analyses, the MCI subjects showed smaller entorhinal volume than OCs (P = 0.0001), whereas there was no difference in the hippocampal or posteromedial volume. AD patients, as compared with MCI patients, showed pronounced loss of volume in the entorhinal (P = 0.0001), hippocampal (P = 0.01) and posteromedial (P = 0.001) regions. The normal pattern of posteromedial fMRI task-induced deactivation during active encoding of words was observed bilaterally in the OCs, but only in restricted unilateral left posteromedial areas in the MCI and AD patients. Across all subjects, more extensive impairment of the retrosplenial and posterior cingulate function was significantly related to smaller entorhinal (P = 0.001) and hippocampal (P = 0.0002) volume. These findings demonstrate that entorhinal atrophy and posteromedial cortical dysfunction are early characteristics of prodromal AD, and precede and/or overwhelm atrophy of the hippocampus and posteromedial cortices. Disturbances in posteromedial cortical function are associated with morphological changes in the MTL across the continuum from normal aging to clinical AD. PMID- 21692883 TI - Fast network oscillations in vitro exhibit a slow decay of temporal auto correlations. AB - Ongoing neuronal oscillations in vivo exhibit non-random amplitude fluctuations as reflected in a slow decay of temporal auto-correlations that persist for tens of seconds. Interestingly, the decay of auto-correlations is altered in several brain-related disorders, including epilepsy, depression and Alzheimer's disease, suggesting that the temporal structure of oscillations depends on intact neuronal networks in the brain. Whether structured amplitude modulation occurs only in the intact brain or whether isolated neuronal networks can also give rise to amplitude modulation with a slow decay is not known. Here, we examined the temporal structure of cholinergic fast network oscillations in acute hippocampal slices. For the first time, we show that a slow decay of temporal correlations can emerge from synchronized activity in isolated hippocampal networks from mice, and is maximal at intermediate concentrations of the cholinergic agonist carbachol. Using zolpidem, a positive allosteric modulator of GABA(A) receptor function, we found that increased inhibition leads to longer oscillation bursts and more persistent temporal correlations. In addition, we asked if these findings were unique for mouse hippocampus, and we therefore analysed cholinergic fast network oscillations in rat prefrontal cortex slices. We observed significant temporal correlations, which were similar in strength to those found in mouse hippocampus and human cortex. Taken together, our data indicate that fast network oscillations with temporal correlations can be induced in isolated networks in vitro in different species and brain areas, and therefore may serve as model systems to investigate how altered temporal correlations in disease may be rescued with pharmacology. PMID- 21692884 TI - Cholinergic control of cortical network interactions enables feedback-mediated attentional modulation. AB - Attention increases our ability to detect behaviorally relevant stimuli. At the neuronal level this is supported by increased firing rates of neurons representing the attended object. In primary visual cortex an attention-mediated activity increase depends on the presence of the neuromodulator acetylcholine. Using a spiking network model of visual cortex we have investigated how acetylcholine interacts with biased feedback to enable attentional processing. Although acetylcholine affects cortical processing in a multitude of manners, we restricted our analysis to four of its main established actions. These were (i) a reduction in firing rate adaptation by reduction in M-currents (muscarinic), (ii) an increase in thalamocortical synaptic efficacy by nicotinic presynaptic receptors, (iii) a reduction in lateral interactions by muscarinic presynaptic receptors, and (iv) an increase in inhibitory drive by muscarinic receptors located on inhibitory interneurons. We found that acetylcholine contributes to feedback-mediated attentional modulation, mostly by reducing intracortical interactions and also to some extent by increasing the inhibitory drive. These findings help explain why acetylcholine is necessary for top-down-driven attentional modulation, and suggest a close interdependence of cholinergic and feedback drive in mediating cognitive function. PMID- 21692885 TI - Chronic stress modulation of prefrontal cortical NMDA receptor expression disrupts limbic structure-prefrontal cortex interaction. AB - Chronic stress causes various detrimental effects including cognitive and affective dysfunctions. Given the recent findings emphasizing the importance of information processing between the prefrontal cortex (PFC) and limbic structures on cognitive and affective functions, impairments of these functions caused by chronic stress may be associated with stress-induced adaptive and maladaptive responses in limbic structure-PFC interaction. In this study we have shown that chronic stress disrupts limbic structure-PFC interaction by modulating N-methyl-D aspartate (NMDA) receptor expression in the PFC. We found that chronic stress decreased expression of NR1, NR2A and NR2B subunits of NMDA receptors in the PFC but not in the motor cortex. However, the reduction in NR2B subunits of NMDA receptors was larger in the dorsal part than the ventral part of PFC. In agreement with this observation, administration of the NMDA antagonist that was more selective for NMDA receptors containing NR2B subunits induced alterations of synchronous local field potentials between the PFC and limbic structures, synaptic plasticity induction in the limbic structure-PFC pathway, and spike firing of PFC neurons that were similar to those observed in the dorsal PFC of rats exposed to chronic stress. In contrast, administration of the NMDA antagonist that was not subunit-selective resulted in electrophysiological alterations resembling to those observed in the ventral PFC of rats exposed to chronic stress. These results suggest that chronic stress disrupts NMDA receptor dependent limbic structure-PFC information processing. PMID- 21692886 TI - Multiple memory traces after associative learning in the honey bee antennal lobe. AB - We investigated the effect of associative learning on early sensory processing, by combining classical conditioning with in vivo calcium-imaging of secondary olfactory neurons, the projection neurons (PNs) in the honey bee antennal lobe (AL). We trained bees in a differential conditioning paradigm in which one odour (A+) was paired with a reward, while another odour (B-) was presented without a reward. Two to five hours after differential conditioning, the two odour-response patterns became more different in bees that learned to discriminate between A and B, but not in bees that did not discriminate. This learning-related change in neural odour representations can be traced back to glomerulus-specific neural plasticity, which depended on the response profile of the glomerulus before training. (i) Glomeruli responding to A but not to B generally increased in response strength. (ii) Glomeruli responding to B but not to A did not change in response strength. (iii) Glomeruli responding to A and B decreased in response strength. (iv) Glomeruli not responding to A or B increased in response strength. The data are consistent with a neural network model of the AL, which we based on two plastic synapse types and two well-known learning rules: associative, reinforcer-dependent Hebbian plasticity at synapses between olfactory receptor neurons (ORNs) and PNs; and reinforcer-independent Hebbian plasticity at synapses between local interneurons and ORNs. The observed changes strengthen the idea that odour learning optimizes odour representations, and facilitates the detection and discrimination of learned odours. PMID- 21692887 TI - Brain-derived neurotrophic factor rapidly increases AMPA receptor surface expression in rat nucleus accumbens. AB - In the rodent nucleus accumbens (NAc), cocaine elevates levels of brain-derived neurotrophic factor (BDNF). Conversely, BDNF can augment cocaine-related behavioral responses. The latter could reflect enhancement of alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) transmission, because AMPARs in the NAc mediate some cocaine-induced behaviors. Furthermore, in vitro studies in other cell types show that BDNF can promote AMPAR synaptic delivery. In this study, we investigated whether BDNF similarly promotes AMPAR trafficking in the adult rat NAc. After unilateral intracranial injection of BDNF into NAc core or shell, rats were killed at post-injection times ranging from 30 min to 3 days. NAc core or shell tissue from both injected and non-injected hemispheres was analysed by Western blotting. A protein cross-linking assay was used to measure AMPAR surface expression. Assessment of tropomyosin receptor kinase B signaling demonstrated that injected BDNF was biologically active. BDNF injection into NAc core, but not NAc shell, led to a protein synthesis- and extracellular signal-regulated kinase-dependent increase in cell surface GluA1 and a trend towards increased total GluA1. This was detected 30 min post-injection but not at longer time-points. GluA2 and GluA3 were unaffected, suggesting an effect of BDNF on homomeric GluA1 Ca(2+) -permeable AMPARs. These results demonstrate that exogenous BDNF rapidly increases AMPAR surface expression in the rat NAc core, raising the possibility of a relationship between increases in endogenous BDNF levels and alterations in AMPAR transmission observed in the NAc of cocaine experienced rats. PMID- 21692888 TI - Genetic effect of single-nucleotide polymorphisms in the PPARGC1B gene on airway hyperreactivity in asthmatic patients. AB - BACKGROUND: Peroxisome proliferator-activated receptor gamma coactivator 1 beta (PPARGC1B) is a co-activator for intracellular receptors such as the estrogen receptor, PPAR, and glucocorticoid receptor, which are involved in asthma development. OBJECTIVES: Genetic association of single-nucleotide polymorphisms (SNPs) in the PPARGC1B gene with the risk of asthma and airway hyperreactivity (AHR) was investigated, as well as the functional effects of these SNPs on PPARGC1B gene and protein expression. METHODS: Direct sequencing of DNA from 24 Korean was performed to identify PPARGC1B SNPs. Genotyping was done in 264 controls and 949 asthmatics using single-base extension methods. PPARGC1B mRNA levels were measured using real-time PCR methodology. Luciferase and electrophoretic mobility shift assays (EMSA) were performed to functionally analyse PPARGC1B SNPs on promoter. RESULTS: Eighteen SNPs and one insertion/deletion polymorphism were identified, and seven SNPs were genotyped. No significant difference existed in the distribution of SNPs and haplotypes between the asthmatics and controls. However, the allele frequency of -427C>T and +102525G>A;R265Q showed a significant association with log-transformed PC(20) methacholine values in the asthmatics (P=0.005-0.0004). Real-time PCR demonstrated higher PPARGC1B mRNA levels in asthmatics having -427CC allele than in those having -427TT or CT alleles (P=0.048). The ratio of the mRNA expression for each PPARGC1B exon4-mRNA compared with the wild type was similar in peripheral blood mononuclear cells carrying the +102525G>A allele. Luciferase reporter assays revealed that -427C allele caused higher promoter activity than 427T allele. EMSA demonstrated that -427C allele exhibited stronger binding activity to a nuclear protein in 293T cells than did the -427T allele. CONCLUSIONS AND CLINICAL RELEVANCE: Polymorphisms of -427C>T on the promoter and those of +102525G>A on exon 5 of the PPARGC1B gene may affect the development of AHR through the modulation of PPARGC1B gene products. The PPARGC1B genotypes may serve as genetic markers for AHR. PMID- 21692889 TI - Working hours and alcohol problems in early adulthood. AB - AIMS: To examine the associations between working hours and alcohol-related problems during early adulthood. DESIGN AND SETTING: Longitudinal study of a birth cohort born in Christchurch, New Zealand in 1977 and studied to age 30. PARTICIPANTS: A total of 1019 participants with data available for working hours and alcohol-related problems at either age 25 or 30. MEASUREMENTS: Weekly working hours in paid employment; frequent alcohol use; diagnosis of alcohol abuse/dependence; number of symptoms of alcohol abuse/dependence. Associations between working hours and alcohol-related problems were adjusted for covariates including measures of: parental and family background; personality and behaviour; IQ and educational achievement; recent negative life events; recent mental health problems; and current partner and family circumstances. FINDINGS: Longer work hours were associated significantly with more frequent alcohol use (P < 0.0001), higher rates of alcohol abuse/dependence (P = 0.0001) and a greater number of alcohol abuse/dependence symptoms (P = 0.01). These associations were adjusted for a wide range of confounding factors. After adjustment there remained significant (P < 0.05) associations between working hours and alcohol-related problems, with those working 50 or more hours per week having rates of alcohol related problems 1.8-3.3 times higher than those who were not working. The associations between work hours and alcohol use were similar for males and females. CONCLUSIONS: Longer work hours appear to be associated with higher rates of alcohol-related problems, including more frequent alcohol use, higher rates of alcohol abuse/dependence and a greater number of alcohol abuse/dependence symptoms. These associations remain even after extensive adjustment for confounding. PMID- 21692891 TI - The "invulnerability" of the adult conduction system to anti-Ro/SSA antibodies? A matter of calcium channel expression on the cardiomyocyte. PMID- 21692890 TI - Intelligence quotient (IQ) in adolescence and later risk of alcohol-related hospital admissions and deaths--37-year follow-up of Swedish conscripts. AB - AIMS: To investigate the relationship between intelligence measured at ages 18-19 and later alcohol-related hospital admission and mortality among men, while controlling for possible confounders. DESIGN: Cohort study. SETTING AND PARTICIPANTS: A total of 49,321 Swedish men who were conscripted for military training in 1969-70 and followed until 2007. MEASUREMENTS: Intelligence quotient (IQ) measured at conscription is the exposure, while alcohol-related hospital admission and death are the two outcomes. Adjustments for following variables were made: early life circumstances [childhood socio-economic position (SEP), father's drinking], mental health, social adjustment and behavioural factors measured at age 18 (psychiatric diagnosis, contact with police and child care, low emotional control, daily smoking, risky use of alcohol) and adult social position (attained education, SEP and income at age 40). FINDINGS: IQ had an inverse and graded association with later alcohol-related problems. For alcohol related hospital admissions the crude hazard ratio (HR) was 1.29 (95% CI = 1.26 1.31) and for alcohol-related mortality it was 1.21 (95% CI = 1.17-1.24) for every one point decrease on the nine-point IQ scale. Adjustment for risk factors measured at age 18 attenuated the association somewhat for both outcomes. After adjustment for social position as adult, the HR was considerably lower resulting in a HR of 1.06 (95% CI = 1.02-1.10) for alcohol-related hospital admissions and 1.01 (95% CI = 0.95-1.08) for alcohol-related mortality. CONCLUSIONS: In Swedish men there is an association between IQ in early adulthood and later alcohol related hospital admission and death. Social position as adult could be an important contributory factor. PMID- 21692892 TI - Achieving favorable very long-term outcomes after catheter ablation for atrial fibrillation: an exciting adventure or delusional quest? PMID- 21692893 TI - The "shock factor": ICD configuration and programming to optimize shock treatment. PMID- 21692894 TI - Confined driver of atrial fibrillation in the superior vena cava. PMID- 21692895 TI - Deep sedation for catheter ablation of atrial fibrillation: a prospective study in 650 consecutive patients. AB - INTRODUCTION: Catheter ablation of atrial fibrillation (AF) is a highly invasive and relatively long-lasting procedure with specific requirements for patient sedation. The feasibility and safety of deep sedation is described in a prospective study of 650 consecutive patients. METHODS: Sedation was initiated with an intravenous (iv) bolus of midazolam, and analgesia with an iv fentanyl bolus. After an iv propofol bolus, maintenance of sedation was achieved with continuous iv administration of propofol with a guide dose of 5 mg per kg per hour. Heart rate, invasive arterial blood pressure, and oxygenation were continuously monitored. The administration of sedation and analgesia medication were performed by a nurse under the supervision and instructions of the electrophysiologist. RESULTS: The mean dose of the initial midazolam bolus was 2.4 +/- 0.7 mg and of the initial propofol bolus 32 +/- 11 mg. The beginning dose of continuous propofol infusion was 352 +/- 66 mg/h; titration to the desired effect of deep sedation required adjustment on an average of 3.8 +/- 2.6 times leading to a maintenance dose of continuous propofol infusion of 399 +/- 99 mg/h. No major sedation-related complications were observed. Endotracheal intubation was necessary in none of the patients. Heart rate, invasive arterial blood pressure, and oxygenation remained stable during sedation. CONCLUSION: Deep sedation for catheter ablation of AF is feasible and safe. Especially, the goal of keeping the patient in deep sedation while maintaining spontaneous ventilation and cardiovascular hemodynamic stability was accomplished. Endotracheal intubation or consultation of an anesthesiologist was not necessary in any patient. PMID- 21692896 TI - An unusual level of block in a patient with an unusual accessory pathway. PMID- 21692897 TI - Identifying the relationship between the non-PV triggers and the critical CFAE sites post-PVAI to curtail the extent of atrial ablation in longstanding persistent AF. AB - BACKGROUND: Complex fractionated atrial electrograms (CFAE) ablation has been performed in addition to pulmonary veins (PV) isolation to increase the success rate of atrial fibrillation (AF) ablation in patients with longstanding (LS) persistent AF. The mechanism underlying the clinical benefit of CFAE ablation remains, however, poorly understood. OBJECTIVE: We compared the impact of CFAE ablation on the prevalence of non-PV atrial triggers inducing AF in 2 groups of patients with LS persistent AF. One group underwent PVAI alone, and the other group underwent PVAI plus CFAE ablation. In addition, we correlated the site of non-PV triggers with the presence of CFAE. METHODS: A total of 98 consecutive patients with symptomatic drug refractory LS persistent AF presenting for ablation had a preablation electroanatomic CFAE map. Patients randomized to either isolation of the PVs and posterior wall (PVAI) (group I, n = 48 pts) or PVAI and biatrial ablation of CFAEs (group II, 50 pts). After ablation, infusion of isoproterenol up to 30 mcg/min was given to reveal non PV foci inducing AF. Those foci were mapped and correlated with CFAE regions and ablated. RESULTS: A total of 19 patients (76%) with PV foci inducing AF were associated with either stable or transient CFAE after PVAI, respectively, in 12 patients (48%) and 7 patients (28%). A total of 20 (42%) non-PV triggers were observed in group I versus 5 (10%) in group II (P < 0.001) in 18 and 5 patients, respectively. After a mean f/u of 17.2 +/- 5.2 months, 33 (69%) patients in group I and 36 (72%) patients in group II were in SR (P = NS). CONCLUSION: Non-PV triggers inducing AF post-PVAI were associated with the presence of stable or transient CFAE in 48% and 28% of cases, respectively, in LS persistent AF. CFAE ablation after PVAI was associated with a significantly higher elimination of those non-PV triggers. This suggests that at least part of the beneficial effect achieved by CFAE ablation reflects elimination of non-PV AF triggers. PMID- 21692898 TI - High washout rate of iodine-123-metaiodobenzylguanidine imaging predicts the outcome of catheter ablation of atrial fibrillation. AB - INTRODUCTION: Excessive sympathetic nervous activity may contribute to atrial fibrillation (AF) recurrences after ablation, but its precise role remains controversial. The goals of this study were to assess the effects of AF on the iodine-123-metaiodobenzylguanidine ((123) I-MIBG) findings and to elucidate its impact on the procedural outcome in patients undergoing a first-time catheter ablation to treat AF. METHODS AND RESULTS: This study included 88 consecutive patients with paroxysmal (n = 48) or persistent (n = 40) AF who underwent radiofrequency catheter ablation and (123) I-MIBG scintigraphy. Five days after the ablation of AF, (123) I-MIBG scintigraphy was performed during sinus rhythm. Anterior planar imaging was obtained at 15 minutes and 180 minutes and the washout rate of the (123) I-MIBG was calculated. The (123) I-MIBG scintigraphy demonstrated an enhanced adrenergic nervous function (high washout rate) and decreased adrenergic nervous distribution (low heart to mediastinum ratios) in patients with both paroxysmal and persistent AF. During a mean follow-up period of 13.5 +/- 2.2 months after the ablation, 25 (28%) patients had AF recurrences. The univariate predictors of an AF recurrence were the duration of the AF history, left atrial dimension, and washout rate of the (123) I-MIBG. Only the (123) I-MIBG washout rate was a multivariate predictor of an AF recurrence (hazard ratio: 1.6, 95% confidence interval: 1.004-1.125, P = 0.037). CONCLUSIONS: Excessive sympathetic nervous activation may be one of the mechanisms of AF recurrences. The evaluation of the cardiac nerve activity using (123) I-MIBG scintigraphy shortly after the AF ablation may be a promising tool to predict the patient's outcome. PMID- 21692899 TI - Evaluation of contraceptive potential of a novel epididymal sperm protein SFP2 in a mouse model. AB - PROBLEM: Sperm flagellar protein 2 (SFP2), which was earlier identified using a novel combinatorial approach, was evaluated for its contraceptive potential in mice. METHOD OF STUDY: Male mice were actively immunized with two synthetic peptides of SFP2. Antipeptide antibody was characterized by Western blot and indirect immunofluorescence. Immune response was monitored, and mating studies were performed 6 and 22 weeks post-immunization. RESULT: Antibodies to the SFP2 peptide 1 recognized a doublet at 220- to 230-kDa region only in the epididymal protein extract. Peptide 1 antibody recognized the cognate protein on spermatozoa from mouse, rat, and human. Histological analysis of testis and epididymis of the immunized mice indicated no deleterious effect. Incubation of sperm with the immune sera of peptide 1 caused significant reduction in motility and viability but did not agglutinate sperm. Only synthetic peptide 1 gave rise to high-level antibodies in all the immunized mice, which on mating resulted in reduced fertility rate (20%) when compared with PBS control animals (100%). The antibody levels in the immunized males declined by 22 weeks post-immunization, resulting in 100% reinstatement of fertility. CONCLUSION: These data provide an experimental basis for the development of effective contraceptive vaccine based on new epididymal target. PMID- 21692900 TI - Acute pain management curriculum for emergency medicine residency programs. AB - Pain is the most common reason people visit emergency departments (EDs); this implies that emergency physicians (EPs) should be experts in managing acute painful conditions. The current trend in the literature, however, demonstrates that EPs possess inadequate knowledge and lack formal training in acute pain management. The purpose of this article is to create a formal educational curriculum that would assist emergency medicine (EM) residents in proper assessment and treatment of acute pain, as well as in providing a solid theoretical and practical knowledge base for managing acute pain in the ED. The authors propose a series of lectures, case-oriented study groups, practical small group sessions, and class-specific didactics with the goal of enhancing the theoretical and practical knowledge of acute pain management in the ED. PMID- 21692901 TI - The role of triage nurse ordering on mitigating overcrowding in emergency departments: a systematic review. AB - OBJECTIVES: The objective was to examine the effectiveness of triage nurse ordering (TNO) on mitigating the effect of emergency department (ED) overcrowding. METHODS: Electronic databases (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, SCOPUS, Web of Science, HealthSTAR, Dissertation Abstracts, ABI/INFORM Global), controlled trial registry websites, conference proceedings, study references, experts in the field, and correspondence with authors were used to identify potentially relevant studies. Interventional studies in which TNO was used to influence ED overcrowding metrics (length of stay [LOS] and physician initial assessment [PIA]) were included in the review. Two reviewers independently assessed study eligibility and methodologic quality. Mean differences were calculated and reported with corresponding 95% confidence intervals (CIs). RESULTS: From more than 14,000 potentially relevant studies, 14 were included in the systematic review. Most were single-center ED studies; the overall quality was rated as weak, due to methodologic deficiencies and variable outcome reporting. TNO was associated with a 37-minute mean reduction (95% CI = -44.10 to -30.30 minutes) in the overall ED LOS in one randomized clinical trial (RCT); a 51-minute mean reduction (95% CI = 56.3 to -45.5 minutes) was observed in non-RCTs. When applied to injured subjects with suspected fractures, TNO interventions reduced ED LOS by 20 minutes (95% CI = -37.5 to -1.9 minutes) in three RCTs and by 18 minutes (95% CI = -23.2 to 13.2) in two non-RCTs. No significant reduction in PIA was observed in two RCTs. CONCLUSIONS: Overall, TNO appears to be an effective intervention to reduce ED LOS, especially in injury and/or suspected fracture cases. The available evidence is limited by small numbers of studies, weak methodologic quality, and incomplete reporting. Future studies should focus on a better description of the contextual factors surrounding these interventions and exploring the impact of TNO on other indicators of productivity and satisfaction with health care delivery. PMID- 21692904 TI - Novel treatment for immune neuropathies on the horizon. AB - Immune neuropathies represent a heterogeneous spectrum of acute and chronic peripheral nerve disorders of autoimmune origin. Despite the current available treatment options, immune neuropathies are still associated with severe neurological deficits and poor clinical prognosis. However, during the last years, significant advances have been made in unraveling some of the underlying pathomechanisms. The exploration of novel therapeutic approaches including monoclonal antibodies and oral immunosuppressants, known from other autoimmune disorders such as multiple sclerosis, suggests new approaches to treatment. Here, we review the available clinical data as well as the scientific rationale and expected benefits and risks for these strategies. PMID- 21692902 TI - An empirical assessment of boarding and quality of care: delays in care among chest pain, pneumonia, and cellulitis patients. AB - BACKGROUND: As hospital crowding has increased, more patients have ended up boarding in the emergency department (ED) awaiting their inpatient beds. To the best of our knowledge, no study has compared the quality of care of boarded and nonboarded patients. OBJECTIVES: This study sought to examine whether being a boarded patient and boarding longer were associated with more delays, medication errors, and adverse events among ED patients admitted with chest pain, pneumonia, or cellulitis. METHODS: This study was a retrospective cohort design in which data collection was accomplished via medical record review from two urban teaching hospitals. Patients admitted with chest pain, pneumonia, or cellulitis between August 2004 and January 2005 were eligible for inclusion. Our outcomes measures were: 1) delays in administration of home medications, cardiac enzyme tests, partial thromboplastin time (PTT), and antibiotics; 2) medication errors; and 3) adverse events or near misses. Primary independent variables were boarded status, boarding time, and boarded time interval. Multiple logistic regression models controlling for patient, ED, and hospital characteristics were used. RESULTS: A total of 1,431 patient charts were included: 811 with chest pain, 387 with pneumonia, and 233 with cellulitis. Boarding time was associated with an increased odds of home medication delays (adjusted odds ratio [AOR] = 1.07, 95% confidence interval [CI] = 1.05 to 1.10), as were boarded time intervals of 12, 18, and 24 hours. Boarding time also was associated with lower odds of having a late cardiac enzyme test (AOR = 0.93, 95% CI = 0.88 to 0.97). CONCLUSIONS: Boarding was associated with home medication delays, but fewer cardiac enzyme test delays. Boarding was not associated with delayed PTT checks, antibiotic administration, medication errors, or adverse events/near misses. These findings likely reflect the inherent resources of the ED and the inpatient units. PMID- 21692905 TI - An open label clinical trial of complement inhibition in multifocal motor neuropathy. AB - Human and animal studies on antibody-mediated neuropathy implicate complement in pathogenesis. In animal models complement inhibition is therapeutically beneficial. The monoclonal antibody, eculizumab (SolirisTM, Alexion Pharmaceuticals, Cheshire, CT), prevents cleavage of C5 and thus inhibits terminal complement activation. In an open label study, 13 multifocal motor neuropathy patients received eculizumab for 14 weeks, 10 of whom were concomitantly receiving intravenous immunoglobulin. The primary outcome was safety of eculizumab, and the secondary outcomes included change in intravenous immunoglobulin (IVIg) dosing frequency, performance, and electrophysiological parameters. Adverse events were minor during the study. Nine of 10 patients on IVIg maintenance continued to require IVIg. IVIg dosing interval was not different between the run-in and the treatment period. There were improvements in patient-rated subjective scores and selected clinical and electrophysiological measurements. Overall, a small treatment effect occurred in some patients that appeared supplementary to and independent of the IVIg treatment effect, and occurred more frequently in patients with higher baseline motor function. PMID- 21692906 TI - A smooth transition protocol for patients with multifocal motor neuropathy going from intravenous to subcutaneous immunoglobulin therapy: an open-label proof-of concept study. AB - Intravenous immunoglobulin (IVIG) is the first-line therapy for multifocal motor neuropathy (MMN). This open-label multi-centre study (NCT00701662) assessed the efficacy, safety, and convenience of subcutaneous immunoglobulin (SCIG) in patients with MMN over 6 months, as an alternative to IVIG. Eight MMN patients (42-66 years), on stable IVIG dosing, received weekly SCIG at doses equivalent to previous IVIG using a "smooth transition protocol". Primary efficacy endpoint was the change from baseline to week 24 in muscle strength. Disability, motor function, and health-related quality of life (HRQL) endpoints were also assessed. One patient deteriorated despite dose increase and was withdrawn. Muscle strength, disability, motor function, and health status were unchanged in all seven study completers who rated home treatment as extremely good. Four experienced 18 adverse events, of which only two were moderate. This study suggests that MMN patients with stable clinical course on regular IVIG can be switched to SCIG at the same monthly dose without deterioration and with a sustained overall improvement in HRQL. PMID- 21692907 TI - Dorsal cutaneous branch of the ulnar nerve: a light and electron microscopy histometric study. AB - This study describes the normal morphology and morphometry of the dorsal cutaneous branch of the ulnar nerve (DCBU) in humans. Fourteen nerves of eight donors were prepared by conventional techniques for paraffin and epoxy resin embedding. Semiautomatic morphometric analysis was performed by means of specific computer software. Histograms of the myelinated and unmyelinated fiber population and the G-ratio distribution of fibers were plotted. Myelinated fiber density per nerve varied from 5,910 to 10,166 fibers/mm(2) , with an average of 8,170 +/- 393 fibers/mm(2) . The distribution was bimodal with peaks at 4.0 and 9.5 um. Unmyelinated fiber density per nerve varied from 50,985 to 127,108, with an average of 78,474 +/- 6,610 fibers/mm(2) , with a unimodal distribution displaying a peak at 0.8 um. This study thus adds information about the fascicles and myelinated and unmyelinated fibers of DCBU nerves in normal people, which may be useful in further studies concerning ulnar nerve neuropathies, mainly leprosy neuropathy. PMID- 21692908 TI - Phenotype expression in women with CMT1X. AB - Charcot-Marie-Tooth disease type 1X (CMT1X) is the second most common inherited peripheral neuropathy. Women with CMT1X typically have a less severe phenotype than men, perhaps because of X-inactivation patterns. Our objective was to determine the phenotype of women with CMT1X and whether X-inactivation patterns in white blood cells (WBCs) differ between females with CMT1X and controls. Thirty-one women with CMT1X were evaluated using the CMT neuropathy score (CMTNS) and the CMT symptom score in cross-sectional and longitudinal analyses. Lower scores correspond to less disability. WBCs were analyzed for X-inactivation pattern by androgen receptor X-inactivation assay in 14 patients and 23 controls. The 31 women's mean CMTNS was 8.35. Two-thirds of the cohort had a mild CMTNS (mean 4.85) and one-third had a moderate CMTNS (mean 14.73). Three patients had a CMTNS of 0. The pattern of X-inactivation did not differ between the affected and control groups. Women with CMT1X presented with variable impairment independent of age, type of mutation, or location of mutation. No evidence supported the presence of a gap junction beta-1 (GJB1) mutation affecting the pattern of X inactivation in blood. Further studies are planned to determine whether X inactivation is the mechanism for CMT1X females' variable phenotypes. PMID- 21692909 TI - Symptoms of activity-induced weakness in peripheral nervous system disorders. AB - Activity-induced weakness was reported in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). This was attributed to activity-dependent conduction block (CB) arising in demyelinated axons. It is not known if activity-induced weakness is common, nor if it is specific for MMN and CIDP. We, therefore, carried out an investigation by questionnaire in 64 MMN patients, 52 CIDP patients, 48 progressive spinal muscular atrophy (PSMA) patients, and 30 normal subjects. Subjects were asked if they experienced an increase in weakness when performing 10 common tasks. The percentage of tasks causing activity-induced weakness was higher in the patient groups than in the normal subjects (p < 0.001). The risk of activity-induced weakness exceeding that in normal subjects was sixfold higher for each patient group when adjusted for sex, age, and a fatigue score. With further adjustment for scores of weakness and axon loss, no significant differences were found between the patient groups. In conclusion, activity-induced weakness is frequently reported in MMN and CIDP. It is, however, not specific for these neuropathies as PSMA patients reported it to the same extent. PMID- 21692910 TI - The phenotype of the Gly94fsX222 PMP22 insertion. AB - Point mutations in PMP22 are relatively rare and the phenotype may vary from mild hereditary neuropathy with liability to pressure palsies (HNPP) to severe Charcot Marie-Tooth type 1 (CMT1). We describe the phenotype of the Gly94fsX222 mutation in the PMP22 gene. Medical records of all patients were reviewed and 11 patients were re-examined. EMG was carried out in nine patients and nerve biopsy in one. Thirteen patients originating from seven families with a Gly94fsX222 mutation were included and consisted of 10 women and 3 men with a median age of 41 years (range 7-67). Five index patients were originally suspected of CMT1. Ten patients had abnormal motor skills during childhood. Nine patients had a history of pressure palsies. Involvement of the olfactory, trigeminal, facial, and pudendal nerves occurred in three patients. Twelve patients had pes cavus and one scoliosis. Distal anterior leg and distal arm weakness were found in 12 and 4 patients, respectively. Twelve patients had distal leg sensory abnormalities. Electrophysiological examination revealed a demyelinating sensorimotor neuropathy, both resembling CMT1 and HNPP. Sural nerve biopsy showed demyelinating neuropathy with presence of tomacula. More than three-fourths of the patients with Gly94fsX222 mutation demonstrated a CMT1 phenotype combined with transient deficits. Clinicians should test for this mutation in those patients exhibiting a generalised neuropathy combined with compressive like episodes. PMID- 21692911 TI - Variable presentations of TTR-related familial amyloid polyneuropathy in seventeen patients. AB - Autosomal-dominant transthyretin (TTR)-related amyloidosis usually manifests in the second to fourth decade with a length-dependent axonal neuropathy with prominent involvement of the small fibers and multi-organ systemic failure. We retrospectively analyzed seventeen probands, including thirteen apparently isolated cases, carrying eight mutations of TTR gene (age of onset = 60.4 +/- 13.5 years). Thirteen patients were initially un/misdiagnosed; interval from onset to definite diagnosis was 3.3 +/- 2.3 years. Inaugural syndromes were a length-dependent motor-sensory neuropathy in seven cases, a sensory neuropathy in four, an isolated carpal tunnel syndrome in three, a pure dysautonomia in two, and a painful neuropathy in one. Atypical presentations included demyelinating nerve conduction changes with increased cerebrospinal fluid proteins resembling chronic inflammatory demyelinating polyradiculoneuropathy and a predominantly motor involvement resembling a motor neuron disorder. Misleading findings also included amyloid-negative abdominal fat aspirate/biopsy, biclonal gammopathy, and hepatitis C virus (HCV) seropositivity. Sural nerve biopsy detected amyloid deposits in thirteen of fifteen patients, including one case with a previous negative biopsy. TTR-immunohistochemistry was necessary to complete the diagnosis of primary amyloidosis light chain in a patient with biclonal gammopathy. A recurrent p.Phe64Leu mutation manifested in the seventh decade with painful motor sensory polyneuropathy, dysautonomia, bulbar palsies, and fasciculations. TTR should be tested in a wide clinical spectrum of cryptogenetic, progressive, and motor-sensory neuropathies even manifesting with a very late onset. PMID- 21692912 TI - Inhibitory effects of visible 650-nm and infrared 808-nm laser irradiation on somatosensory and compound muscle action potentials in rat sciatic nerve: implications for laser-induced analgesia. AB - Low-level laser therapy (LLLT) has been shown in clinical trials to relieve chronic pain and the World Health Organization has added LLLT to their guidelines for treatment of chronic neck pain. The mechanisms for the pain-relieving effects of LLLT are however poorly understood. We therefore assessed the effects of laser irradiation (LI) on somatosensory-evoked potentials (SSEPs) and compound muscle action potentials (CMAPs) in a series of experiments using visible (lambda = 650 nm) or infrared (lambda = 808 nm) LI applied transcutaneously to points on the hind limbs of rats overlying the course of the sciatic nerve. This approximates the clinical application of LLLT. The 650-nm LI decreased SSEP amplitudes and increased latency after 20 min. CMAP proximal amplitudes and hip/ankle (H/A) ratios decreased at 10 and 20 min with increases in proximal latencies approaching significance. The 808-nm LI decreased SSEP amplitudes and increased latencies at 10 and 20 min. CMAP proximal amplitudes and H/A ratios decreased at 10 and 20 min. Latencies were not significantly increased. All LI changes for both wavelengths returned to baseline by 48 h. These results strengthen the hypothesis that a neural mechanism underlies the clinical effectiveness of LLLT for painful conditions. PMID- 21692913 TI - Very early electrodiagnostic findings in Guillain-Barre syndrome. AB - Electrodiagnostic studies play a key role in the evaluation of patients with Guillain-Barre syndrome (GBS). However, at early stages patients may not meet current neurophysiologic criteria. We report electrodiagnostic findings for 18 patients with suspected GBS within 4 days of clinical onset. Fifteen patients (83%) showed abnormality in the motor nerve conduction study. Prolonged distal motor latency (DML) was the most frequent demyelinating parameter (seen in 55% of patients). Abnormal late responses were noted in 14 patients (77%). Electrodiagnostic study of cranial nerves was abnormal in eight (44%), and motor nerve conduction velocity was abnormal in only six patients (23%). The study shows a predominant motor neuropathy pattern followed by a sural-sparing pattern; no patients showed a strictly normal electrodiagnostic study. Reduced distal compound muscle action potential and prolonged DML in the demyelinating range were associated with severity of GBS on admission. After the electrodiagnostic study, 5 patients (27%) already fulfilled electrodiagnostic criteria for acute inflammatory demyelinating polyneuropathy (AIDP), 1 (5%) for the axonal variant of GBS, and 13 (72%) were classified as equivocal. We conclude that exhaustive electrodiagnostic studies of patients with suspected GBS in very early stages are useful in the diagnosis and management of the condition. PMID- 21692915 TI - Home-based IVIg treatment is convenient and time-saving in patients with multifocal motor neuropathy. PMID- 21692914 TI - Two recessive intermediate Charcot-Marie-Tooth patients with GDAP1 mutations. AB - Various phenotypes have been reported in Charcot-Marie-Tooth (CMT) disease carrying mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene. Here, we report two recessive intermediate Charcot-Marie-Tooth (RI-CMT) patients with GDAP1 missense mutations: a His256Arg homozygous mutation (c.767A>G + c.767A>G) and compound mutations of heterozygous Pro111His (c.332C>A) and Val219Gly (c.656T>G). The Pro111His and Val219Gly are unreported mutations, but the His256Arg was previously reported. In both patients, histopathological findings showed well-documented features of mixed demyelinating and axonal neuropathies, and nerve conduction velocities fall in the intermediate range. In addition, the patterns of fatty substitutions in leg magnetic resonance imaging (MRI) were different by the mutation sites within the same GDAP1 gene. PMID- 21692916 TI - The efficacy of subcutaneous immunoglobulin administration in chronic inflammatory demyelinating polyneuropathy responders to intravenous immunoglobulin. PMID- 21692917 TI - Screening for antecedent Campylobacter jejuni infections and anti-ganglioside antibodies in idiopathic neuralgic amyotrophy. PMID- 21692918 TI - How to set up a severe asthma service. AB - Severe asthma affects 5-20% of the asthma population but is discordantly responsible for the major burden of illness and impairment to quality of life. Patients with severe asthma continue to experience ongoing symptoms despite maximal therapy. A severe asthma service provides a systematic approach to the management of the disease and aids in confirming the correct diagnosis, managing comorbid conditions that may mimic or aggravate asthma, and provides the environment to optimize treatment and asthma self-management skills and education. A severe asthma service is also the ideal environment for trialling add-on therapies and hence can improve patient outcomes and clinical practice. Within such a service there are many opportunities for training and research. In this article we describe the purpose of a severe asthma clinic, the necessary components of a service including staffing and facilities and the processes for trialling additional therapies used in the management of severe asthma. PMID- 21692919 TI - Interface between normal and transformed epithelial cells: a road to a novel type of cancer prevention and treatment. AB - Cell transformation arises from activation of oncoproteins and / or inactivation of tumor suppressor proteins. During the initial stage of carcinogenesis, transformation occurs in a single cell within an epithelial monolayer. However, it is not known what happens at the interface between normal and transformed cells once the initial transformation has occurred. Using elaborate cell culture systems, recent reports have shown that interactions between normal and transformed epithelial cells can induce various phenomena. For example, when Ras- or Src-transformed cells are surrounded by normal epithelial cells, multiple signaling pathways are activated and the transformed cells are apically extruded from the epithelium. In addition, normal and certain types of transformed cells compete with each other for cell survival, and the transformed cells undergo apoptosis. Importantly, when transformed cells alone are present, neither apoptosis nor elimination from epithelia occurs, indicating that the presence of surrounding normal cells influences the signaling pathways and fate of transformed cells. Comparable phenomena are also observed in zebrafish and mice in vivo model systems. In this review, I will introduce this newly emerging research field and discuss how these studies can potentially lead to establishment of novel types of cancer prevention and treatment. PMID- 21692920 TI - Women and inherited bleeding disorders. PMID- 21692921 TI - Diagnosis and management of women with bleeding disorders--international guidelines and consensus from an international expert panel. PMID- 21692923 TI - Prenatal diagnosis and preimplantation genetic diagnosis: novel technologies and state of the art of PGD in different regions of the world. AB - Prenatal diagnosis (PND) aims to provide accurate, rapid results as early in pregnancy as possible. Conventional PND involves sampling cells of foetal origin by chorionic villus sampling at 11-14th weeks of pregnancy or amniocentesis after 15th week. These are invasive procedures and have a small but significant rate of 0.5% to 1% for loss of pregnancy. An alternative to existing methods for conventional PND for couples at risk of transmitting a genetic disease to their child is preimplantation genetic diagnosis (PGD). PGD is a newly emerging form of a very early prenatal diagnosis. The technique combines assisted reproductive technology with molecular genetics and cytogenetics to allow the identification of abnormality in embryos prior to implantation. The diagnosis of genetic disease in human preimplantation embryos was pioneered in the late 1980s for testing of aneuploidy, single gene and X-linked disease, such as cystic fibrosis, haemophilia and chromosomal abnormalities. The PGD-related legal and ethical issues have been debated at many levels both nationally and internationally. The attitude towards PGD varies substantially not only in different parts of the world but also within the Europe, owing to scientific, cultural and religious differences. PGD has become widely practised throughout the world for various indications and can substantially decrease the eventual risks of passing a genetic undesired condition of the offspring. Nevertheless, its extension to some new and non-medical indications has raised ethical concerns, in particular its potential eugenic dimension. PMID- 21692922 TI - Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres. AB - Inherited bleeding disorders are especially problematic for affected girls and women due to the monthly occurrence of menstrual periods and the effects on reproductive health. Although heavy menstrual bleeding (HMB) is the most common manifestation, females with inherited bleeding disorders (FBD) experience other bleeding symptoms throughout the lifespan that can lead to increased morbidity and impairment of daily activities. The purpose of this article is to describe the utility of a female-focused surveillance effort [female Universal Data Collection (UDC) project] in the United States Haemophilia Treatment Centres (HTCs) and to describe the baseline frequency and spectrum of diagnoses and outcomes. All FBD aged 2 years and older receiving care at selected HTCs were eligible for enrollment. Demographic data, diagnoses and historical data regarding bleeding symptoms, treatments, gynaecological abnormalities and obstetrical outcomes were analysed. Analyses represent data collected from 2009 to 2010. The most frequent diagnoses were type 1 von Willebrand's disease (VWD) (195/319; 61.1%), VWD type unknown (49/319; 15.4%) and factor VIII deficiency (40/319; 12.5%). HMB was the most common bleeding symptom (198/253; 78.3%); however, 157 (49.2%) participants reported greater than four symptoms. Oral contraceptives were used most frequently to treat HMB (90/165; 54.5%), followed by desmopressin [1-8 deamino-D-arginine vasopressin (DDAVP)] (56/165; 33.9%). Various pregnancy and childbirth complications were reported, including bleeding during miscarriage (33/43; 76.7%) and postpartum haemorrhage (PPH) (41/109; 37.6%). FBD experience multiple bleeding symptoms and obstetrical-gynaecological morbidity. The female UDC is the first prospective, longitudinal surveillance in the US focusing on FBD and has the potential to further identify complications and reduce adverse outcomes in this population. PMID- 21692924 TI - Preimplantation genetic diagnosis--a historical annotation: first PGD baby turns fifteen. PMID- 21692925 TI - Management of pregnancy, labour and delivery in women with inherited bleeding disorders. AB - Pregnancy, labour and delivery present intrinsic haemostatic challenges to women with and carriers of bleeding disorders and their offspring. Deficiency of fibrinogen and factor XIII are associated with miscarriage, placental abruption and foetal loss. The risk of antenatal complications including antepartum haemorrhage is unknown in women with other bleeding disorders. There is a significant risk of postpartum haemorrhage (primary and secondary) in women with all types of bleeding disorders. This can be serious and life threatening in those with severe defects such as Bernard Soulier syndrome and Glanzmann's thrombasthenia. Three to four percent of infants with haemophilia experience cranial bleeding that occurs during labour and delivery. The safest method of delivery for affected babies remains controversial. However, the rate of planned Caesarean section is increasing among known carriers of haemophilia. If vaginal delivery is planned, prolonged labour and difficult delivery especially vacuum extraction are associated with the highest risk of cranial bleeding and should be avoided. The optimal management of pregnancy in women with inherited bleeding disorders requires a multidisciplinary approach and advanced individualized management plan taking into consideration obstetric and bleeding risk factors. Women with mild or moderate bleeding disorders can be managed at their local maternity unit in close collaboration with a tertiary centre. However, those with severe or rare disorders or carrying an affected infant should be managed in a tertiary centre with an onsite Haemophilia centre. PMID- 21692926 TI - Women with inherited bleeding disorders--experience as an affected woman and as a treating doctor. PMID- 21692927 TI - Quality of life in women with bleeding disorders. AB - The assessment of health-related quality of life (HRQOL) has been increasingly used over the last years, is regarded one of the most relevant health outcome measures and is included as secondary and primary endpoint in clinical and observational trials. Bleeding disorders and their treatment impact on patients' HRQOL, especially in women with bleeding disorders and can affect the everyday life of patients and their families. In women with inherited bleeding disorders, menorrhagia is the most common symptom, manifest by significant bleeding and pain leading to limitation in conducting daily activities and changes in social functioning with an adverse effect on women's HRQOL. Only few studies used validated questionnaires for the assessment of HRQOL in women with bleeding disorders, mainly generic instruments. Few disease-specific instruments are available for the adequate assessment of the impact of menorrhagia on HRQOL, namely the Ruta Menorrhagia Severity Scale, the menorrhagia multi-attribute utility scale and the Menorrhagia Impact Questionnaire. The von Willebrand disease (VWD)-QOL questionnaire, a disease-specific questionnaire for patients with VWD contains a specific dimension 'menstruation' for women. These studies revealed that menorrhagia has a larger impact on HRQOL in women with inherited bleeding disorders compared with women with normal haemostasis. Moreover, age, type of VWD and gender have an influence on the HRQOL of patients with VWD. The need of disease-specific instruments for an adequate assessment of HRQOL in women with bleeding disorders could be demonstrated in these studies. PMID- 21692928 TI - The long-term psychological management of women and girls with inherited bleeding disorders. AB - A woman with an inherited bleeding disorder faces two main challenges: managing her symptoms medically and integrating her condition into her daily life. Health professionals have an obligation to support young girls and women affected with these disorders as they negotiate the life-cycle transition of their condition. This support should include helping women to integrate their diagnosis into a new sense of self. The psychological effects of menorrhagia can also be addressed by working with key family members such as a young patient's mother or a woman's partner to prevent the experience of body shame. Couples require support to sustain their sexual relationship and to develop communal coping strategies as they face the challenges that menorrhagia brings to their relationship. These may include both fertility and pregnancy issues. Maintaining contact with the medical team can benefit women approaching the menopause by preparing them psychologically for the change and its associated symptoms. PMID- 21692929 TI - How to deal with medical and social aspects of bleeding disorders--preparing women and the family in developing countries. AB - There is a considerable number of women with inherited bleeding disorders in Iran. von Willebrand disease, Glanzman thrombasthenia and factor XIII deficiency are the most common coagulation disorders. The main cause of this high rate of coagulation disorders is attributed to a high rate of consanguineous marriages in Iran. Medical care continues to improve for individuals affected with coagulation disorders in Iran. However, these disorders continue to have a significant impact on the affected Iranian women. As a result of the hereditary nature of these disorders, the impact extends to the psychosocial dimension of the lives of the women. Therefore it is recommended that women with coagulation disorders are provided with psychological and social support along with coagulation therapy. PMID- 21692930 TI - Adefovir serum levels do not differ between responders and nonresponders. AB - Primary or secondary failure of adefovir dipivoxil (ADV) therapy of chronic hepatitis B is not infrequent. The reasons for suboptimal responses are not well defined. In HIV and hepatitis C virus infection, failure of antiviral drug therapy has been linked with low blood drug levels. We have studied 20 well defined patients with chronic hepatitis B who were treated with ADV for drug and virus kinetics. Importantly, neither Cmax levels (mean 26 ng/mL, range 14-59 ng/mL) nor the time to maximal drug levels (mean 4 h, range 2-8 h) differed between patients showing a complete virological response to adefovir (n = 10), patients with secondary treatment failure (n = 7) and patients with suboptimal primary response (hepatitis B virus-DNA >10,000 IU/mL after 6 months of treatment; n = 3). Thus, adefovir treatment failure is unlikely to be due to an inability to mount sufficient drug levels in the blood. PMID- 21692931 TI - An early decrease in serum HBeAg titre is a strong predictor of virological response to entecavir in HBeAg-positive patients. AB - Quantification of HBeAg levels has been found to be useful in monitoring and predicting the outcomes of interferon and lamivudine treatment in HBeAg-positive patients. The aim of this study was to determine whether quantification of HBeAg at baseline and on treatment could predict which patients would achieve HBeAg seroconversion after 96 weeks of entecavir therapy. Sixty-five HBeAg-positive naive chronic hepatitis B patients who were treated with entecavir at a dose of 0.5 mg once daily for 96 weeks were evaluated. Serum HBV DNA levels were assessed at baseline, week 24, 48 and 96; serum HBeAg levels were assessed at baseline, week 12, 24, 48, 72 and 96. Serum HBeAg levels were associated with a higher likelihood of HBeAg seroconversion to entecavir at weeks 96 than serum HBV DNA levels both at baseline and on treatment (at baseline: OR = 9.932, P = 0.003 vs. OR = 5.045, P = 0.036; on treatment: OR = 112.5, P < 0.0001 vs. OR = 47.782, P < 0.0001). A maintained reduction in HBeAg > 65% of pretreatment HBeAg values after 24 weeks of entecavir therapy is the strongest predictor for HBeAg seroconversion at week 96 (OR = 70.578, P < 0.0001). Quantification of HBeAg at the start and early during therapy showed a higher predictive value than that of HBV DNA for HBeAg seroconversion by entecavir. A significant decrease in serum HBeAg levels at week 24 may be a useful on-treatment measurement in the early phase for predicting HBeAg seroconversion and identifying patients who will most likely benefit from finite entecavir treatment. PMID- 21692932 TI - Viral level is an indicator of long-term outcome of hepatitis B virus e antigen negative carriers with persistently normal serum alanine aminotransferase levels. AB - The association between viral level and the long-term outcomes of hepatitis B virus (HBV) carriers who test negative for hepatitis B virus e antigen (HBeAg) but have persistently normal serum alanine aminotransferase levels (PNALT) remains unclear. We examined hepatocarcinogenesis, hepatitis reactivation, predictive factors and the time course of HBV DNA levels during follow-up in 104 HBeAg-negative Japanese carriers with PNALT. During a mean follow-up period of 6.4 +/- 3.4 years, 5 patients (4.8%) had hepatocarcinogenesis and 14 (13.5%) had hepatitis reactivation. At 5 and 10 years, the cumulative rates of hepatocarcinogenesis were 2.4% and 9.9%, while those of hepatitis activation were 13.7% and 15.5%, respectively. An HBV DNA level of >=5 log10 copies/mL was the sole predictor of hepatocarcinogenesis with a univariate analysis. An HBV DNA level of >=5 log10 copies/mL and an alanine aminotransferase (ALT) level of >20 to <=40 IU/L were independent predictors of hepatitis reactivation in a Cox model. Because there was no association between hepatocarcinogenesis and ALT activity, the HBV DNA level was considered an essential predictor. In addition, the baseline HBV DNA level was related to the future level and was not subject to wide fluctuations. Our results showed that an HBV DNA level of >=5 log10 copies/mL predicts subsequent hepatocarcinogenesis and hepatitis reactivation in HBeAg-negative carriers with PNALT. As the baseline HBV DNA level reflects the future level, appropriate clinical management according to the viral level is expected to decrease future risk. PMID- 21692933 TI - Significant changes in liver stiffness measurements in patients with chronic hepatitis B: 3-year follow-up study. AB - For patients with chronic hepatitis B (CHB) infection, changes in liver stiffness measurement (LSM) over time are not known. We examined changes longitudinally in a cohort of patients. Four hundred and twenty-six patients with CHB underwent transient elastography. Patients were followed regularly, and repeat elastography was performed at 3 years. Hepatitis serology, viral load and routine liver biochemistry were monitored. Of the 426 patients, 38 (9%) were hepatitis B e antigen (HBeAg)-positive, 293 (69%) were HBeAg-negative and 95 (22%) were patients with prior hepatitis B surface antigen (HBsAg) seroclearance. A total of 110 patients received oral antiviral therapy. There was a significant decline of LSMs at the follow-up measurement compared to baseline (6.1 vs 7.8 kPa respectively, P = 0.002) in treated patients who had elevated alanine aminotransferase (ALT) at baseline and subsequent normalization after 3 years (normal ALT limit being 30 U/L for males and 19 U/L for females). In nontreated patients, only the patients with persistently normal ALT at both time points had significantly lower LSMs at the follow-up measurement compared to baseline: 4.9 vs 5.3 kPa, respectively, in patients who remained positive for HBsAg (P = 0.005) and 5.1 vs. 5.4 kPa, respectively, in patients who had HBsAg seroclearance (P = 0.026). In patients who remained positive for HBsAg, independent factors associated with a significant decline in LSM of >=1 kPa included antiviral therapy (P = 0.011) and the ALT levels at the follow-up time point (P = 0.024). Thus, in patients with CHB, a significant decline in LSM after 3 years was observed in treated patients with ALT normalization and in untreated patients who had persistently normal ALT. Antiviral therapy and follow-up ALT levels were independent significant factors associated with a decline in LSM. PMID- 21692934 TI - Unawareness of HBV infection among inpatients in a Southern Italian hospital. AB - Hepatitis B virus (HBV) infection may run undetected. Unawareness of an ongoing infection delays the diagnosis of HBV-related liver disease and favours the spread of the virus. We have evaluated among hepatitis B surface antigen-positive (HBsAg) inpatients admitted to a Southern Italian hospital the proportion of those aware of their carrier status and correlated the status to signs of liver disease. All patients admitted to the San Giovanni Rotondo Hospital from March 2008 to July 2009 were tested for HBV and hepatitis C virus (HCV) markers, and those positive for HBsAg were interviewed and underwent examinations for liver function and abdominal ultrasound. Overall, of 25,000 patients admitted during the observation period 311 (1.2%) were positive for HBsAg, most of them (98%) being anti-HBe positive. HCV and HDV co-infections were ascertained in 2.9% and 0.6% of cases, respectively. Two hundred and fifty-three subjects (81%) agreed to undergo further investigation, 132 of them (52%) were HBV-DNA positive. One hundred and two patients (40.3%) were unaware of their infection; this was encountered among 29% of HBV-DNA-positive and 52% of HBV-DNA-negative subjects (P < 0.01). Subjects already aware of their infection were more likely to present with abnormal alanine aminotransferase (ALT) levels (27%vs 15%), serological presence of HBV-DNA (63.6% vs. 36%) and liver cirrhosis (30%vs. 13%). A high proportion of HBsAg-positive patients (40.3%) were unaware of their infection, which had evolved to the stage of liver cirrhosis in a consistent percentage of them. PMID- 21692935 TI - Large-scale survey of naturally occurring HBV polymerase mutations associated with anti-HBV drug resistance in untreated patients with chronic hepatitis B. AB - Drug resistance is a major limitation for the long-term efficacy of antiviral therapy with nucleos(t)ide analogues (NAs) in chronic hepatitis B (CHB). Antiviral resistance mutations may pre-exist in the overall viral population of untreated patients. We aimed to assess the prevalence of such hepatitis B virus (HBV) variants in a large cohort of NAs-naive patients with CHB and to explore possible association with viral and host variables. Serum samples from 286 NAs naive consecutive patients with CHB were tested for serum HBV-DNA, and 255 of them having HBV-DNA > 1000 IU/mL were further analysed for drug resistance mutations by INNO-LiPA HBV DRv2/v3. NAs-naive patients analysed were mainly men (73%), Caucasians (85%), hepatitis B e Antigen (HBeAg) negative (79%) and genotype D (69%), with a mean age of 43.2 +/- 13.4 years. HBV mutations associated with antiviral drug resistance were detected in 13 (5%) patients: three patients infected with HBV genotype C had the rtM204V + rtL180M mutations associated with lamivudine (LMV) resistance. Four patients had the rtI233V mutation that may reduce sensitivity to adefovir, and three patients had the rtM250L/V mutation typical of entecavir resistance. LMV compensatory mutations rtL80V and rtV173L were seen in two and one patients, respectively. No relationship was seen between presence of resistant or compensatory mutations and HBV-DNA levels, HBeAg/anti-HBe status or previous IFN therapy. These results confirm that HBV mutations, which confer resistance against currently available anti-HBV NAs, may already exist in patients who have never received the drug. PMID- 21692936 TI - Discriminant value of serum HBV DNA levels as predictors of liver fibrosis in chronic hepatitis B. AB - Current guidelines recommend antiviral therapy in chronic hepatitis B (HBV) patients with significant histological disease. We aimed to compare histological fibrosis (METAVIR, >=F2) in patients with HBV DNA >=20,000 IU/mL vs. >=2000 IU/mL and identify predictors of fibrosis. We performed prospective liver biopsies on 203 HBeAg-negative patients in four groups: Group I (n = 55): HBV DNA >=20,000 IU/mL and persistently elevated alanine aminotransferase (ALT) levels (PEALT; >40 U/L); Group II (n = 34): HBV DNA >=20,000 IU/mL and persistently normal ALT (PNALT); Group III (n = 40): HBV DNA <20,000 IU/mL and PEALT; and Group IV (n = 74): HBV DNA <20,000 IU/mL, and PNALT. We reanalysed all groups in relation to updated cut-off for treatable viremia (2000 IU/mL). Genotype D was detected in 86% of patients. Hepatic fibrosis >=F2 was detected in 72.7%, 52.9%, 57.5% and 18.9% in Groups I-IV, respectively (P < 0.0001). Except in Group II with a trend for lower >=F2 fibrosis (P = 0.067), there was no significant difference by using HBV DNA cut-off 20,000 vs. 2000 IU/mL. Multivariate logistic regression analysis identified study Group IV (OR, 0.0276; CI: 0.088-0.868; P = 0.0276) and milder (A0-1) necroinflammatory grade (OR, 0.135; CI: 0.063-0.287; P < 0.0001) as independent predictors of >=F2 fibrosis. The specificity, positive and negative predictive values for PEALT in detection of >=F2 fibrosis for viremia >=2000 IU/mL (80%, 69% and 65%, respectively) or >=20,000 IU/mL (86%, 73% and 63%, respectively) were similar, with a marginal gain in sensitivity (51% vs. 42%, respectively). Significant fibrosis is prevalent in a large proportion of HBeAg negative patients with high viremia and persistently normal ALT. Lower HBV DNA cut-offs could be adopted with marginal gains in fibrosis detection and without loss of diagnostic accuracy. PMID- 21692937 TI - Correlation between promoter methylation of glutathione-S-tranferase P1 and oxidative stress in acute-on-chronic hepatitis B liver failure. AB - Promoter methylation of glutathione-S-transferase P1 (GSTP1) may be involved in liver damage caused by oxidative stress in acute-on-chronic hepatitis B-induced liver failure (ACHBLF). This study aimed to explore GSTP1 promoter methylation status and oxidative stress in such patients. DNA was extracted from peripheral blood mononuclear cells (PBMCs) of patients with acute-on-chronic liver hepatitis B-induced liver failure, chronic hepatitis B (CHB) and normal controls, followed by sodium-bisulfite treatment and methylation-specific PCR (MSP) analysis. Plasma malondialdehyde (MDA) adducts levels were detected by enzyme-linked immunosorbent assay as oxidative stress marker. Model for end-stage liver disease (MELD) score was employed to estimate the severity of the liver failure. Eleven of 35 patients with acute-on-chronic liver failure and 3 of 35 patients with stab le hepatitis B displayed GSTP1 promoter methylation, and the difference was significant (chi2) = 5.71, P = 0.02). No differences in standard liver function tests were found in patients with acute-on-chronic liver failure with and without GSTP1 promoter methylation although the levels of total bilirubin were greater in those with methylation. The levels of MDA adducts were significantly higher in patients with liver failure when compared to those with CHB (12.44 +/- 5.38 pmol/mg vs 8.42 +/- 5.49 pmol/mg, P < 0.01), and in the patients with liver failure who had promoter methylation the levels were higher than in those who did not (15.2 +/- 4.68 pmol/mg vs 11.17 +/- 5.29 pmol/mg, P < 0.01). The MELD score was not significantly different between methylated and unmethylated patients with liver failure (P > 0.05), although MDA adducts were correlated with MELD scores in patients with acute-on-chronic liver failure (r = 0.579, P < 0.01). GSTP1 promoter methylation may facilitate oxidative stress-associated liver damage in ACHBLF, and oxidative stress is correlated with ACHBLF severity. PMID- 21692938 TI - Trends in incidence of hepatocellular carcinoma after diagnosis of hepatitis B or C infection: a population-based cohort study, 1992-2007. AB - Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the major risk factors for hepatocellular carcinoma (HCC). We examined trends in the incidence of HCC among a population-based cohort of people infected with HBV or HCV. HBV and HCV cases notified to the New South Wales Health Department between 1992 and 2007 were linked to the Central Cancer Registry, Registry of Births, Deaths and Marriages, and National HIV/AIDS Registries. Crude HCC incidence rates were estimated using person-time methodology. Age-standardized incidence rates were calculated using the 2001 Australian population. Trends in incidence were examined using join point regression models. Between 1992 and 2007, 1201 people had a linked HCC record: 556 of those with HBV; 592 with HCV; 45 with HBV/HCV co infection; and 8 with HIV co-infection. The overall age-standardized HCC incidence rates declined non-significantly from 148.0 (95% confidence intervals (CI) 63.7, 287.4) per 100,000 population in 1995 to 101.2 (95% CI 67.3, 144.6) in 2007 among the HBV monoinfected group and significantly from 151.8 (95% CI 62.4, 299.8) per 100,000 population to 75.3 (95% CI 50.8, 105.5) among the HCV monoinfected group. However, incidence rates in the HCV monoinfected group progressively increased from the period 1992-1997 to 2004-2007 when adjusted for age, sex, and birth cohort, and the total number of cases per annum continued to increase. Despite declines in the age-adjusted incidence rates of HCC over time, the absolute number of cases increased likely due to the ageing cohort and an increasing prevalence of both hepatitis B and C in Australia. PMID- 21692939 TI - Circulating microRNAs in hepatitis B virus-infected patients. AB - MicroRNAs (miRNAs) are stably present in human serum. The relationship between circulating miRNAs and hepatitis B virus (HBV) infected liver disease has not been previously reported. Applied Biosystems array-based miRNA expression profiling was performed on pooled sera obtained from identified groups of chronic asymptomatic carriers (ASC), patients with chronic hepatitis B (CHB) and HBV associated acute-on-chronic liver failure (ACLF), as well as healthy controls (HC). Nine miRNAs were verified in more clinical samples by RT-PCR. The correlation between miRNAs expression and the relationship between miRNA levels and clinical characteristics was analysed. Results showed that circulating miRNAs were detected in all disease and control samples, and their numbers increased with symptom severity, from 37 in HC, 77 in ASC, 101 in CHB, to 135 in ACLF. The expression levels of most miRNAs were also up-regulated in HBV-infected patients when compared to HC. Expression of the liver-specific miR-122 was significantly up-regulated in HBV-infected patients. Concomitant regulation of miRNAs not in clusters was disrupted by HBV infection. However, such disruption was not observed for miRNAs in paralogous clusters. Furthermore, the level of miRNAs in the CHB serum was up-regulated most in hepatitis B e antigen-positive patients. The expression levels of miR-122 and miR-194 correlated negatively with the age of patients with CHB or ACLF. Functional analysis showed that miR-122 could inhibit HBV replication in Huh7 and HepG2 cells. In all, our study revealed that a number of miRNAs were differentially expressed during HBV infection and underscored the potential importance of miR-122 in the infection process. PMID- 21692940 TI - Frequency and clinical outcomes of flares related to nucleos(t)ide analogue therapy in patients with chronic hepatitis B. AB - Flares in chronic hepatitis B are often detrimental but sometimes lead to sustained immune control and disease remission. The aim of this study was to estimate the frequency of hepatitis flares which occur during and/or after cessation of nucleos(t)ide analogue (NA) therapy, and to assess their outcomes. In a single centre cohort study we investigated 227 patients who received a total of 351 NA treatment courses. NA therapy was discontinued after 149 treatment courses. In total, 27 flares were observed during 9779 on-treatment patient months. The frequency was estimated as 3.2 per 100 person-years (95% CI 2.2-4.7). Lamivudine (LAM)-treated patients demonstrated the highest frequency (4.9/100 person-years, 95% CI 3.2-7.4). Twenty (74%) of 27 on-therapy flares were associated with development of genotypic resistance, which all occurred during LAM therapy. NA withdrawal flares occurred after a median post-treatment follow up of 3.5 months in 17 (11%) of 149 treatment discontinuations. No flares were observed in patients who switched to another antiviral agent (n = 51). None of the on-therapy and withdrawal flares related to NA therapy were associated with sustained disease remission, and seven flares resulted in decompensated liver disease. In this study, flares related to NA therapy never led to immune control and sustained disease remission, and sometimes resulted in decompensated liver disease. PMID- 21692941 TI - Interference of hepatitis C virus replication in cell culture by antisense peptide nucleic acids targeting the X-RNA. AB - The RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV) is the essential catalytic enzyme for viral genome replication. It initiates minus strand RNA synthesis from a highly conserved 98-nt sequence, called the X-RNA, at the 3'-end of the plus-strand viral genome. In this study, we evaluated the antiviral effects of peptide nucleic acids (PNAs) targeting the X-RNA. Our in vitro RdRp assay results showed that PNAs targeting the three major stem-loop (SL) domains of X-RNA can inhibit RNA synthesis initiation. Delivery of X-RNA targeted PNAs by fusing the PNAs to cell-penetrating peptides (CPPs) into HCV replicating cells effectively suppressed HCV replication. Electrophoretic mobility shift assays revealed that the PNA targeting the SL3 region at the 5' end of X-RNA dissociated the viral RdRp from the X-RNA. Furthermore, delivery of the SL3-targeted PNA into HCV-infected cells resulted in the suppression of HCV RNA replication without activation of interferon beta expression. Collectively, our results indicate that the HCV X-RNA can be effectively targeted by CPP-fused PNAs to block RNA-protein and/or RNA-RNA interactions essential for viral RNA replication and identify X-RNA SL3 as an RdRp binding site crucial for HCV replication. In addition, the ability to inhibit RNA synthesis initiation by targeting HCV X-RNA using antisense PNAs suggests their promising therapeutic potential against HCV infection. PMID- 21692942 TI - Impact of HAART exposure and associated lipodystrophy on advanced liver fibrosis in HIV/HCV-coinfected patients. AB - The impact of antiretroviral drug exposure and associated lipodystrophy and/or insulin resistance (IR) on advanced liver fibrosis in HIV/HCV-coinfected patients is not fully documented. We determined the prevalence of advanced liver fibrosis (defined by hepatic stiffness >=9.5 kPa) and associated factors, focusing on the impact of highly active antiretroviral therapy and its major adverse effects (lipodystrophy and IR), in 671 HIV/HCV-coinfected patients included in the ANRS CO13 HEPAVIH cohort. One hundred ninety patients (28.3%) had advanced liver fibrosis. In univariate analysis, advanced liver fibrosis was significantly associated with male sex, higher body mass index, HCV infection through intravenous drug use, a lower absolute CD4 cell count, a longer history of antiretroviral treatment, longer durations of protease inhibitors, non-nucleoside reverse transcriptase inhibitors and NRTI exposure, lipodystrophy, diabetes, and a high homeostasis model assessment method (HOMA) value. The only antiretroviral drugs associated with advanced liver fibrosis were efavirenz, stavudine and didanosine. In multivariate analysis, male sex (OR 2.0, 95% CI 1.1-3.5; P = 0.018), HCV infection through intravenous drug use (OR 2.0, 95% CI 1.1-3.6; P = 0.018), lipodystrophy (OR 2.0, 95% CI 1.2-3.3; P = 0.01), median didanosine exposure longer than 5 months (OR 1.7, 95% CI 1.0-2.8; P = 0.04) and a high HOMA value (OR 1.1, 95% CI 1.0-1.2; P = 0.005) remained significantly associated with advanced liver fibrosis. Mitochondrial toxicity and IR thus appear to play a key role in liver damage associated with HIV/HCV-coinfection, and this should be taken into account when selecting and optimizing antiretroviral therapy. Antiretroviral drugs with strong mitochondrial toxicity (e.g. didanosine) or a major effect on glucose metabolism should be avoided. PMID- 21692943 TI - San-Huang-Xie-Xin-Tang extract suppresses hepatitis C virus replication and virus induced cyclooxygenase-2 expression. AB - Chronic hepatitis C virus (HCV) infection is associated with chronic inflammation of liver, which leads to the development of cirrhosis and hepatocellular carcinoma (HCC). Because of severe side effects and only a 50-70% cure rate in genotype 1 HCV-infected patients upon current standard treatment with pegylated interferon-alpha plus ribavirin, new therapeutic regimens are still needed. San Huang-Xie-Xin-Tang (SHXT) is a transitional Chinese herbal formula, composed of Rhei rhizoma, Scutellaria radix and Coptidis rhizome, and possesses anti inflammatory effect. Here, we describe a (+)-catechin-containing fraction extracted from SHXT, referred as SHXT-frC, exhibited effective inhibition of HCV replication, with selectivity index value (SI; CC50 /EC50) of 84, and displayed synergistic anti-HCV effects when combined with interferon-alpha, HCV protease inhibitor telaprevir or polymerase inhibitor 2'-C-methylcytidine. The activation of factor-kappaB (NF-kappaB) and cyclooxygenase-2 (COX-2) signalling pathway has particular relevance to HCV-associated HCC. SHXT-frC treatment also caused a concentration-dependent decrease in the induction of COX-2 and NF-kappaB expression caused by either HCV replication or HCV NS5A protein. Collectively, SHXT-frC could be an adjuvant treatment for patients with HCV-induced liver diseases. PMID- 21692945 TI - Knowledge, attitudes and behaviours associated with the provision of hepatitis C care by Canadian family physicians. AB - The role of primary care physicians in providing care for hepatitis C virus (HCV) infection is increasingly emphasized, but many gaps and challenges remain. This study explores family physicians' knowledge, attitudes and practices associated with providing care for HCV infection. Seven hundred and forty-nine members of the College of Family Physicians of Canada (CFPC) completed a self-administered survey examining knowledge, attitudes and behaviours regarding HCV infection screening and care. Multivariate analyses were performed using the outcome, HCV care provision, and variables based on a conceptual model of practice guideline adherence. Family physicians providing basic-advanced HCV care were more likely to be older, practice in a rural setting, have injection drug users (IDU) in their practice and have higher levels of knowledge about the initial assessment (OR = 1.77; 95% CI = 1.23-2.54) and treatment of HCV (OR = 1.74; 95% CI = 1.24 2.43). They were also less likely to believe that family physicians do not have a role in HCV care (OR = 0.41; 95% CI = 0.30-0.58). Educational programmes should target physicians less likely to provide HCV care, namely family physicians practicing in urban areas and those who do not care for any IDU patients. Training and continuing medical education programmes that aim to shift family physicians' attitudes about the provision of HCV care by promoting their roles as integral to HCV care could contribute to easing the burden on consultant physicians and lead to improved access to treatment for HCV infection. PMID- 21692944 TI - IL28B polymorphisms determine early viral kinetics and treatment outcome in patients receiving peginterferon/ribavirin for chronic hepatitis C genotype 1. AB - Single nucleotide polymorphisms (SNPs) upstream of IL28B predict the outcome of treatment in chronic hepatitis C virus (HCV) infection, but their impact on viral kinetics and relation to other predictors are not well known. Here, two SNPs, rs12979860 and rs8099917, were analysed and related to early viral kinetics during treatment in 110 patients with HCV genotype 1 infection. The reduction of HCV RNA after 7 days of therapy was more pronounced (P < 0.0001) in patients with CC(rs12979860) or TT(rs8099917) than in patients carrying TT(rs12979860) or GG(rs8099917), respectively. The two SNPs were in linkage disequilibrium (d' = 1, r2 = 0.44), but CC(rs12979860) was less common (43% vs. 71%) than TT(rs8099917). Patients carrying both CC(rs12979860) and TT(rs8099917) genotypes achieved lower levels of HCV RNA at week 4 than those with CT or TT at rs12979860 and TT(rs8099917) (P = 0.0004). The viral elimination was significantly influenced by rs12979860 independently of baseline viral load, age or fibrosis. This translated into high rates of sustained viral response (SVR) among patients carrying CC(rs12979860) despite the presence of high viral load at baseline (SVR 74%), high age (SVR 79%) or severe liver fibrosis (SVR 83%). We conclude that the IL28B variability influences the antiviral efficiency of interferon/ribavirin therapy and has a strong impact on SVR, independently of traditional response predictors. A combined assessment of these SNPs in conjunction with other response predictors may better predict outcome in difficult-to-treat patients. PMID- 21692946 TI - CD154, a marker of antigen-specific stimulation of CD4 T cells, is associated with response to treatment in patients with chronic HCV infection. AB - CD4 T-cell function is crucial for the eradication of HCV, and insufficient function is observed in chronic carriers. The monitoring of T-cell responses is complicated by the scarcity of antigen-specific T cells and the relative inefficiency of virus-specific T cells to produce effector cytokines. CD154 is a marker of activation expressed on T cells induced through their T-cell receptor. We analysed CD4 T-cell responses in 72 patients with chronic or resolved HCV infection (23 treatment naive, 49 treatment experienced, including 16 who had achieved a sustained response). In an additional prospective protocol, 20 of the chronically infected patients were analysed before and after 8-12 weeks of combination therapy with peg-interferon-alpha and ribavirin. T-cell responses were measured by detecting the expression of CD154 and Th1 cytokines after stimulation with recombinant HCV proteins and were correlated with pretreatment status and outcome of therapy. Broader T-cell responses were observed in treatment naive than in experienced patients, while the outcome of a preceding therapy regimen did not influence T-cell responses. In the prospective cohort, an on-treatment increase in CD154+ cytokine- T-cell activity was associated with response to treatment, while a decrease was observed in nonresponders. Stronger antigen-independent activity of CD154+ cytokine+ T cells was observed in responders than in nonresponders. Our data indicate that CD154 as a marker of activation of CD4 T cells is a suitable tool for the analysis of T-cell responses in patients with HCV infection. PMID- 21692947 TI - Hepatitis C virus replication in Caucasian HIV controllers. AB - Whether HIV controllers, patients who spontaneously control HIV viraemia, are able to control hepatitis C virus (HCV) infection, in terms of spontaneous clearance or lower HCV replication, is not well understood. To assess to what extent Caucasian HIV controllers are able to control HCV replication and potential associated factors, plasma HIV-1 and HCV RNA levels, anti-HCV antibodies, HCV genotype and human leucocyte antigens (HLA) typing were determined in samples from 75 HIV controllers (33 viraemic controllers, <1000 HIV 1 RNA copies/mL, and 42 elite controllers, <40 HIV-1 RNA copies/mL) and compared with 261 HIV-infected noncontrollers. We did not find differences in the HCV spontaneous clearance rates between groups. However, we interestingly found a lower HCV viral load in HIV controllers, alongside a different distribution of HCV genotypes in relation to the comparison group. In addition, HLA-B57 was associated with a lower HCV viral load in the control group and HIV controllers, and conversely, HLA-B35 with higher HCV viral load in HIV controllers. The subrepresentation of HCV genotype 1 and the overrepresentation of HLA-B57 only partly explained the lower HCV viral load found in HIV controllers. In fact, HIV controller status was independently associated with lower HCV viral load, together with HCV genotype non-1, the presence of HLA-B57 and absence of HLA-B35. Caucasian HIV controllers are able to better control HCV replication, in terms of lower HCV viral load levels. These findings support the idea that some common host mechanisms are involved in the defence against these two persistent infections. PMID- 21692948 TI - Reproducibility of liver stiffness measurements in hepatitis C virus (HCV) infected patients in Egypt. AB - Elastometry has demonstrated good accuracy, but little is known about its reproducibility. The aim of this study was to assess the intra- and inter operator reproducibility of liver stiffness measurement among hepatitis C virus (HCV)-infected patients in Egypt. The study was conducted among HCV-infected patients referred for treatment evaluation in two hepatitis treatment centres of Cairo. Two operators took liver stiffness measurement two times per patient the same day. Intra- and inter-reproducibility were estimated by different methods: Bland and Altman graphics, variation coefficient, intraclass correlation coefficient and Kappa coefficient; 7.1 kPa was used as the threshold of significant (>=F2) fibrosis whenever needed. Fifty-eight patients were included in the study, and 216 measurements were taken. Failure rate was 7% and associated with overweight. For a value of 7.1 kPa, the inter-operator 95% limits of agreement were estimated at +/-2.88 kPa. Intra- and inter-operator coefficients of variation ranged between 11% and 15%, intraclass correlation coefficients [95% confidence interval] between 0.94 [0.86-0.97] and 0.97 [0.95-0.99], and Kappa coefficients between 0.65 [0.44-0.88] and 0.92 [0.81-1.00]. The reliability of liver stiffness measurement is questionable when considering the decision to initiate antiviral therapy because of the percentage of discordance between measurements is notable, especially in the intermediate fibrosis stages. PMID- 21692949 TI - Acute hepatitis C infection lowers serum lipid levels. AB - Chronic hepatitis C infection is associated with hypolipidaemia that resolves with viral clearance. Lipid levels in a subgroup of patients rebound to levels that may increase the risk of coronary heart disease. The impact of acute hepatitis C infection and its clearance on lipid levels is unknown. We undertook a retrospective evaluation of subjects with acute hepatitis C infection evaluating lipid levels before, during and following acute infection. Thirty eight subjects with acute hepatitis C infection had lipid levels available. Twelve patients had pre-infection and intra-infection lipid levels available. Cholesterol (197.8-152.4 mg/dL, P = 0.025), low-density lipoprotein (LDL) (116.1 76.3 mg/dL, P = 0.001) and non-high-density lipoprotein (non-HDL) cholesterol (164.0-122.7 mg/dL, P = 0.007) decreased dramatically during acute hepatitis C virus infection. Nineteen patients who achieved viral clearance had lipid levels available during infection and following resolution of infection. In these patients, cholesterol (145.0-176.0 mg/dL, P = 0.01), LDL (87.0-110.1 P = 0.0046) and non-HDL cholesterol (108.6-133.6 mg/dL, P = 0.008) increased significantly. No change was seen in patients who developed chronic infection. Four patients had lipid levels before, during and following resolution of infections and had increased postinfection LDL, cholesterol and non-HDL cholesterol from pre infection levels, indicating acute infection may be associated with an increase in postinfection lipid levels and may confer an increased risk of coronary heart disease. Acute hepatitis C infection results in hypolipidaemia with decreased LDL, cholesterol and non-HDL cholesterol levels that increase following infection resolution. Levels may increase above pre-infection baseline lipid levels and should be monitored. PMID- 21692950 TI - TyG index, HOMA score and viral load in patients with chronic hepatitis C due to genotype 1. AB - The triglycerides * glucose (TyG) index is a recently proposed surrogate marker of insulin resistance (IR), calculated from fasting plasma triglyceride and glucose concentrations. We tested the host and viral factors associated with Tyg and homeostasis model assessment (HOMA) scores, comparing their associations with histological features and with sustained virological response (SVR) in patients with genotype 1 chronic hepatitis C(G1CHC). Three hundred and forty consecutive patients with G1CHC were considered. All had a liver biopsy scored by one pathologist for staging and grading (Scheuer), and graded for steatosis, which was considered moderate-severe if >=30%. Anthropometric and metabolic measurements, including IR measured by both HOMA and TyG, were registered. By linear regression analysis, TyG was independently associated with waist circumference (WC), total cholesterol, presence of arterial hypertension, Log10 HCV-RNA and steatosis. Similarly, WC and steatosis were significantly associated with HOMA. Older age (OR, 1.036; 95%CI, 1.004-1.070, P = 0.02), higher WC (1.031; 1.004-1.060; P = 0.02) and higher TyG (11.496; 3.163-41.784; P < 0.001) were linked to moderate-to-severe steatosis (>=30%) by multiple logistic regression analysis. When TyG was replaced by HOMA-IR in the model, the latter remained significantly associated with steatosis >=30% (1.237; 1.058-1.448; P = 0.008). Receiver operating characteristic curves showed a similar performance of TyG (AUC 0.682) and HOMA-IR (AUC 0.699) in predicting moderate-severe steatosis. No independent associations were found between both TyG and HOMA and fibrosis or SVR. In patients with G1CHC , TyG, an easy-to-calculate and low-cost surrogate marker of IR, is linked to liver steatosis and shows an independent association with viral load. PMID- 21692951 TI - Granulocyte colony-stimulating factor for hepatitis C therapy-associated neutropenia: systematic review and economic evaluation. AB - Hepatitis C virus (HCV) treatment requires maximal adherence to pegylated interferon (Peg-IFN) and ribavirin to achieve a sustained virologic response (SVR). Neutropenia is the most common cause for Peg-IFN dose reduction. Our objectives were to evaluate the effectiveness, safety and cost-effectiveness of granulocyte colony-stimulating factor (G-CSF) versus Peg-IFN dose reduction for HCV therapy-associated neutropenia in treatment naive adults. We conducted a systematic review to identify controlled trials and observational studies. Study selection, quality assessment and data extraction were completed independently by two investigators. Cost-effectiveness and cost-utility analyses compared G-CSF with dose reduction. Nineteen studies were included. In one trial, the SVR for those receiving G-CSF was 54.5% (95% CI: 34.7-73.1) compared with 26.3% (95% CI: 11.8-48.8) for dose reduction. The remaining studies were case series or retrospective cohorts and provided weak evidence for the relationship between SVR and G-CSF. The risk of adverse events, including infection, associated with G-CSF was low (13.1%; 95% CI: 8.0-20.8) and clinically insignificant. G-CSF had an incremental cost-effectiveness ratio of $41,701 per SVR achieved in genotype 1, and $16,115 per SVR achieved in genotype 2 or 3. Estimates were robust under a variety of resource and intervention scenarios. While administration of G-CSF may enable patients to remain on or resume optimal HCV therapy, there was weak evidence that this improves the likelihood of SVR compared with dose reduction. Adverse effects of G-CSF are mild. The economic evaluation was inconclusive. PMID- 21692952 TI - Pregnancy outcomes associated with viral hepatitis. AB - The aim of this study was to examine the contribution of hepatitis B virus (HBV) and hepatitis C virus (HCV) to pregnancy-related complications including gestational diabetes mellitus (GDM), preterm birth (PTB), intrauterine growth restriction (IUGR), pre-eclampsia, antepartum haemorrhage and cholestasis. The Nationwide Inpatient Sample was queried for all pregnancy-related discharges, pregnancy complications and viral hepatitis from 1995 to 2005. Logistic regression was used to examine the association between HBV, HCV, HBV + HCV and pregnancy-related complications including GDM, PTB, IUGR, pre-eclampsia, antepartum haemorrhage, cholestasis and caesarean delivery. Model covariates included maternal age, race, insurance status, substance use and medical complications including liver complication, hypertension, HIV, anaemia, thrombocytopenia and sexually transmitted infections. Of 297 664 pregnant women data available for analysis, 1446 had a coded diagnosis of HBV, HCV or both. High risk behaviours, such as smoking, alcohol and substance use were higher in women with either HBV or HCV. Women with HBV had an increased risk for PTB (aOR 1.65, CI [1.3, 2.0]) but a decreased risk for caesarean delivery (aOR 0.686, CI [0.53, 0.88]). Individuals with HCV had an increased risk for GDM (aOR 1.6, CI [1.0, 2.6]). Individuals with both HBV and HCV co-infection had an increased risk for antepartum haemorrhage (aOR 2.82, CI [1.1, 7.2]). There was no association of viral hepatitis with IUGR or pre-eclampsia. Women with hepatitis have an increased risk for complications during pregnancy. Research to determine the efficacy and cost-effectiveness of counselling patients about potential risks for adverse outcomes is warranted. PMID- 21692953 TI - A functional polymorphism in pre-microRNA-196a-2 contributes to the susceptibility of hepatocellular carcinoma in a Turkish population: a case control study. AB - MicroRNAs (miRNAs) are an abundant class of small nonprotein-coding RNAs with posttranscriptional regulatory functions as tumour suppressors and oncogenes. Aberrant expression and structural alteration of miRNAs are thought to participate in tumourigenesis and cancer development. It has been suggested that the presence of single-nucleotide polymorphisms in precursor miRNAs (pre-miRNAs) can alter miRNA processing, expression, and/or binding to target mRNA and represent another type of genetic variability that can contribute to the development of human cancers. Recent studies have indicated that the miR-196a-2 rs11614913 (C->T) polymorphism could alter mature miR-196a-2 expression and target mRNA binding. To determine the association of the miR-196a-2 rs11614913 polymorphism with the risk of hepatocellular carcinoma (HCC) development in a Turkish population, a hospital-based case-control study was designed consisting of 185 subjects with HCC and 185 cancer-free control subjects matched for age, gender, smoking and alcohol status. The genotype frequency of the miR-196a-2 rs11614913 polymorphism was determined by using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. Our data shows that the CC genotype of the miR-196a-2 rs11614913 polymorphism is associated with increased risk of HCC development in this Turkish population (OR = 2.41, 95% CI: 1.30-4.50, P = 0.005). Furthermore, according to stratified analysis, a significant association was observed between the homozygote CC genotype and HCC risk in the subgroups of male gender (OR = 3.12, 95% CI: 1.53-6.34, P = 0.002) and patients with hepatitis B virus (HBV)-related HCC (OR = 2.88, 95% CI: 1.33 6.22, P = 0.007). Because our results suggest for the first time that the miR 196a-2 rs11614913 polymorphism may be a genetic susceptibility factor for HCC (especially in the male gender and HBV-infected patients) in the Turkish population, further independent studies are required to validate our findings in a larger series, as well as in patients of different ethnic origins. PMID- 21692954 TI - Hepatitis B surface antigen monitoring and management of chronic hepatitis B. AB - Serum hepatitis B surface antigen (HBsAg) levels reflect intrahepatic hepatitis B virus (HBV) covalently closed circular DNA and may be a valuable addition to HBV DNA in the management of patients with chronic hepatitis B (CHB). Among HBeAg negative CHB patients with low HBV DNA levels, HBsAg quantification may help distinguish those with active CHB from true inactive carriers with a very favourable prognosis, thus limiting the need for long-term intensive monitoring of ALT and HBV DNA levels. In patients treated with peginterferon (PEG-IFN), achievement of a decline in HBsAg during therapy appears to be an important marker for treatment outcome, and several groups have proposed stopping rules based on HBsAg thresholds. A recently described stopping rule incorporating a combination of HBsAg and HBV DNA levels can accurately identify HBeAg-negative patients, especially those with HBV genotype D, not responding to PEG-IFN. Current applications of HBsAg levels in the monitoring of patients treated with nucleo(s)tide analogues are still being evaluated. First data from these studies show that HBsAg decline, and thus subsequent clearance, is confined to those with an active immune response to HBV, such as HBeAg-positive patients with elevated ALT, or those who achieve HBeAg clearance. PMID- 21692955 TI - Interleukin-21 is upregulated in hepatitis B-related acute-on-chronic liver failure and associated with severity of liver disease. AB - The immune mechanism(s) that lead to hepatitis B-related acute-on-chronic liver failure (HB-ACLF) are poorly understood. Interleukin-21 is a newly discovered cytokine that is involved in autoimmune and inflammatory diseases. Its potential role in HB-ACLF remains unknown. The serum levels of 12 immune cytokines measured by cytometric bead arrays and the frequency of IL-21-secreting CD4+ T cells in peripheral blood mononuclear cells (PBMC) measured by intracellular cytokine staining were compared in moderate chronic hepatitis B (M-CHB, n = 20), severe chronic hepatitis B (S-CHB, n = 20), HB-ACLF (n = 39) and healthy controls (n = 10). PBMC from M-CHB patients or healthy subjects were stimulated with rhIL-21 in vitro, and cytokines in supernatants were measured by FlowCytomix. The frequencies of IL-21-secreting CD4+ T cells were higher in HB-ACLF (both P < 0.001) and S-CHB (P = 0.002 and 0.001) as compared to M-CHB patients and controls. Serum IL-21 levels were highest (P < 0.001) in HB-ACLF and positively associated with high MELD score (P = 0.001) and mortality (P = 0.038). Recovery from HB-ACLF was associated with reduced serum IL-21 levels (P = 0.003) and lower CD4+ IL-21(+) T-cell frequency (P = 0.006). The secretions of IL-1beta (P < 0.001), IL-6 (P < 0.001), IL-10 (P < 0.001), IFN-gamma (P = 0.001) and TNF-alpha (P = 0.042) from PBMC were significantly increased with rhIL-21 stimulation. In summary, IL-21 has a causal role in the development of severe liver inflammation, which is upregulated in HB-ACLF and associated with severity of liver disease. PMID- 21692956 TI - Long-term outcome of chronic hepatitis C in a population-based cohort and impact of antiviral therapy: a propensity-adjusted analysis. AB - This population-based study aimed to assess the determinants of the outcome of chronic hepatitis C with analysis of the impact of antiviral therapy with or without sustained virological response (SVR) on cirrhosis decompensation, hepatocellular carcinoma, liver-related and non-liver-related mortality. A total of 1159 HCV-positive patients newly detected between 1994 and 2001 were included. For each outcome, the prognostic effect of patients' baseline characteristics was estimated by time-dependent Cox models using age as the time-scale and adjusting for treatment received during follow-up. The impact of antiviral therapy was assessed by using a propensity score in a sample including 184 patients treated in the first 24 months following diagnosis who were matched to 184 untreated patients. At the end of a 59-month median follow-up, 100 cases of compensated disease, 58 liver cancer and 163 deaths (55 liver related) were recorded. The 5 year rates of decompensated cirrhosis, hepatocellular carcinoma, liver-related and non-liver-related death were 4.4%, 2.7%, 5.0% and 8.9%, respectively. Multivariate analyses identified two variables with pejorative influence: alcohol consumption (RR = 4.29 for CD; RR = 5.76 for HCC; RR = 6.69 for liver-related death; P < 0.0001); HCV diagnosis unrelated to systematic screening (RR = 2.25 for CD; RR = 3.05 for HCC; RR = 4.31 for liver-related death, P < 0.03). In the matched subset, no significant benefit of antiviral therapy was observed. Nevertheless, among the 144 patients who achieved SVR, no death was observed. This population-based study showed substantial rates of decompensated cirrhosis, hepatocellular carcinoma and non-liver-related mortality. Alcohol consumption and absence of systematic screening were significant determinants of poor outcome, whereas treatment did not have significant influence. PMID- 21692957 TI - Accuracy of circulating cathodic antigen tests for rapid mapping of Schistosoma mansoni and S. haematobium infections in Southern Sudan. AB - OBJECTIVE: To evaluate the diagnostic accuracy of a circulating cathodic antigen (CCA) urine dipstick test for detecting Schistosoma mansoni and S. haematobium alongside an integrated rapid mapping survey in Southern Sudan. METHODS AND RESULTS: A total of 373 children aged 5-16 years were included in the study. Of these 26.0% were infected with S. haematobium and 24.5% were infected with S. mansoni, as identified by urine filtration or single Kato-Katz thick smear, respectively. The CCA performed moderately in detecting S. mansoni, with sensitivity of 89.1% and specificity of 74.2%, and poorly in detecting S. haematobium infections, with a sensitivity of 36.8% and specificity of 78.9%. This may be a slight underestimate of true CCA accuracy, since only single stool and urine samples were examined by microscopy. The true 'gold standard' for comparison would have been the collection of multiple stool samples over consecutive days. CONCLUSION: The poor CCA accuracy for diagnosis of urinary schistosomiasis means that this test is currently not suitable for rapid mapping of schistosomiasis in areas where both S. mansoni and S. haematobium may be endemic. PMID- 21692958 TI - Endemic and opportunistic infections in Brazilian solid organ transplant recipients. AB - OBJECTIVE: To evaluate the frequency and clinical features of endemic and other opportunistic infections in liver or kidney transplant recipients in four transplant centres in different geographical areas of Brazil. METHODS: Retrospective analysis of medical and laboratory records of four transplant centres on endemic and other opportunistic infections in liver or kidney transplant recipients. Analyses were performed with spss statistical software. RESULTS: From 2001 to 2006, 1046 kidney and 708 liver transplants were registered in all centres. The average age was 42 years. Among 82 (4.7%) cases with infections, the most frequent was tuberculosis (2.0%), followed by systemic protozoal infections (0.7%), toxoplasmosis (0.4%) and visceral leishmaniasis (0.3%). Systemic fungal infections occurred in 0.6%, of which 0.4% were cryptococcosis and 0.2% were histoplasmosis. Dengue was the only systemic viral infection and was registered in two cases (0.1%), of which one was classified as the classic form and the other as dengue haemorrhagic fever. Nocardiosis was described in one case (0.05%). The infectious agents most frequently associated with diarrhoea were Blastocystis sp., Schistosoma mansoni and Strongyloides stercoralis. CONCLUSIONS: Opportunistic Infections in transplant patients have a wide spectrum and may vary from asymptomatic to severe infections with high mortality. A better understanding of the epidemiology of endemic pathogens and clinical manifestations can contribute to the establishment of an early diagnosis as well as correct treatment aimed at decreasing morbidity and mortality. PMID- 21692959 TI - Ambulance service within a comprehensive intervention for reproductive health in remote settings: a cost-effective intervention. AB - OBJECTIVE: To assess the cost-effectiveness of an ambulance service within a comprehensive hospital/community-based program aimed at improving access and quality of reproductive health in poor-resources settings. METHODS: Obstetrical cases referred to the hospital with the ambulance during a 3-month period were prospectively recorded. Clinical indications were used to determine the effectiveness of the referral; the direct costs of the service were calculated. Overall effectiveness was then measured against WHO thresholds. RESULTS: Ninety two obstetrical referrals were recorded. Eleven (12%) were considered effective, corresponding to 611.7 years saved. Cost per year saved was 15.82 US dollars which about half of WHO's 30 US dollar benchmark defining very attractive interventions. Sensitivity analyses on the costs of the ambulance and the rate of effective referrals emphasized the robustness of the result. CONCLUSIONS: The cost-effectiveness profile of an ambulance service within a series of interventions aimed at improving reproductive health in remote settings is very attractive. PMID- 21692960 TI - Health-seeking behaviour among adults with prolonged cough in Vietnam. AB - OBJECTIVE: To assess health-seeking behaviour among adults with prolonged cough in a population-based, nationally representative sample in Vietnam. METHODS: Cross-sectional survey conducted from September 2006 to July 2007. All inhabitants aged >=15 years were invited for screening for cough, history of tuberculosis (TB) treatment and chest X-ray (CXR) examination. TB suspects, defined as any survey participant with CXR abnormalities consistent with TB, or productive cough for more than 2 weeks or TB treatment either currently or in the preceding 2 years submitted sputum specimens for smear examination and culture and provided information on health-seeking behaviour in an in-depth interview. RESULTS: Of 94 179 persons participating in the survey, 4.6% had prolonged productive cough. Forty-four percentage of those had sought health care and reported pharmacies (35%), commune health posts (29%), public hospitals (24%) and private physicians (10%) as first point of contact. Only 7% had undergone sputum smear examination. Of TB suspects with prolonged productive cough, 2.9% were diagnosed with TB; 10.2% of these reported smear and 21.9% reported X-ray examination when visiting a health care facility. The average patient delay was 4.1 weeks (95% CI: 3.9-4.4) among cough suspects and 4.0 weeks (95% CI: 3.1-4.9) among TB cases. CONCLUSIONS: In this Vietnamese survey, nearly half of persons with cough for more than 2 weeks had visited a health care provider. The commonest first health facility contacted was the pharmacy. Sputum smears were rarely examined, except in the provincial TB hospital. Our findings highlight the need to improve diagnostic practices by retraining health staff on the performance of sputum examination for TB suspects. PMID- 21692961 TI - Developing resilient children and families when parents have mental illness: a family-focused approach. AB - There is substantial evidence supporting the need for effective intervention for children and families living with parental mental illness. However, translation of this knowledge into mental health workforce practice remains variable, with a range of clinical practices and models of care evident. Nurses, who constitute the majority of the mental health workforce, are in prime positions to support children and families and provide preventative measures, identify those at risk, and intervene early. In this paper, we provide a framework for practice for nurses working with consumer parents. We contend that traditional models of nursing practice concentrating on the consumer are insufficient in meeting the needs of children and families living with parental mental illness. A focus on families needs to be core business for mental health nurses. A family-focused approach can be used to prevent problems for children and their families, and identify their strengths as well as vulnerabilities. Family-focused care is a useful framework from which to support families and address the challenges that might arise from parental mental illness, and to build individual and family resilience. PMID- 21692962 TI - Biogeography and variability of eleven mineral elements in plant leaves across gradients of climate, soil and plant functional type in China. AB - Understanding variation of plant nutrients is largely limited to nitrogen and to a lesser extent phosphorus. Here we analyse patterns of variation in 11 elements (nitrogen/phosphorus/potassium/calcium/magnesium/sulphur/silicon/iron/sodium/mang nese/aluminium) in leaves of 1900 plant species across China. The concentrations of these elements show significant latitudinal and longitudinal trends, driven by significant influences of climate, soil and plant functional type. Precipitation explains more variation than temperature for all elements except phosphorus and aluminium, and the 11 elements differentiate in relation to climate, soil and functional type. Variability (assessed as the coefficient of variation) and environmental sensitivity (slope of responses to environmental gradients) are lowest for elements that are required in the highest concentrations, most abundant and most often limiting in nature (the Stability of Limiting Elements Hypothesis). Our findings can help initiate a more holistic approach to ecological plant nutrition and lay the groundwork for the eventual development of multiple element biogeochemical models. PMID- 21692963 TI - Recurrence of colonic diverticular bleeding and associated risk factors. AB - AIM: Colonic diverticular bleeding often recurs, but the risk factors remain unclear. Our aim was to identify risk factors for recurrence in patients with diverticular bleeding. METHOD: Seventy-two hospitalized patients who were diagnosed with diverticular bleeding between 2004 and 2008 were analyzed. Rebleeding was considered as the main outcome measure, with the duration until recurrence identified from medical records. Potential risk factors for rebleeding, such as underlying pathologies, medication and smoking and drinking habits, were investigated from the medical records on initial admission. RESULTS: Of the 72 patients, 19 had a diverticular disease on the right, 16 on the left side and 37 on both sides of the colon. Recurrence was identified in 27 (38%) patients at a median interval of 1535 days. The cumulative incidence of rebleeding at 6, 12 and 24 months was 15%, 20% and 33%. Multivariate analysis revealed nonsteroid anti-inflammatory drugs (NSAIDs) (hazard ratio (HR), 2.57; 95% confidence interval (CI), 0.89-7.46; P=0.08), antiplatelet drugs (HR, 2.39; 95% CI, 1.01-5.67; P=0.05) and hypertension (HR, 4.16; 95% CI, 1.22-14.2; P=0.02) to be risk factors for rebleeding. CONCLUSION: Patients with colonic diverticular bleeding show high recurrence rates within a short period. Risk factors for recurrence have been identified as the use of NSAIDs or antiplatelet drugs and hypertension. PMID- 21692964 TI - It's the procedure not the patient: the operative approach is independently associated with an increased risk of complications after rectal prolapse repair. AB - AIM: This study compares 30-day outcomes following rectal prolapse repair, examining potential surgical and patient factors associated with perioperative complications. METHOD: Using the NSQIP database, patients with rectal prolapse were categorized by surgical approach to repair (perineal or abdominal) and abdominal cases were further subdivided by procedure (resection compared with rectopexy alone). Univariate and multivariate analyses compared major and minor complication rates between the groups. RESULTS: Of 1275 patients, the perineal group (n=706, 55%) was older, with more comorbidity, than those undergoing an abdominal procedure. There were fewer minor (odd ratio (OR)=0.35; 95% confidence interval (CI), 0.20-0.60; P=0.0038) and major complications (OR=0.46; 95% CI, 0.31-0.80; P=0.0038) in the perineal compared with the abdominal cohort. There was a significant increase in major complications amongst patients undergoing a resection compared with rectopexy only (OR=2.15; 95% CI, 1.10-4.41; P=0.0299). There was no difference in major complications between abdominal rectopexy and a perineal approach, but the latter had a lower chance of minor complications (OR=0.47; 95% CI, 0.24-0.94; P=0.0287). CONCLUSION: A perineal approach is safer than an abdominal approach to the treatment of rectal prolapse. Regarding an abdominal operation, rectopexy has fewer major complications than resection. PMID- 21692965 TI - Ecological assembly rules in plant communities--approaches, patterns and prospects. AB - Understanding how communities of living organisms assemble has been a central question in ecology since the early days of the discipline. Disentangling the different processes involved in community assembly is not only interesting in itself but also crucial for an understanding of how communities will behave under future environmental scenarios. The traditional concept of assembly rules reflects the notion that species do not co-occur randomly but are restricted in their co-occurrence by interspecific competition. This concept can be redefined in a more general framework where the co-occurrence of species is a product of chance, historical patterns of speciation and migration, dispersal, abiotic environmental factors, and biotic interactions, with none of these processes being mutually exclusive. Here we present a survey and meta-analyses of 59 papers that compare observed patterns in plant communities with null models simulating random patterns of species assembly. According to the type of data under study and the different methods that are applied to detect community assembly, we distinguish four main types of approach in the published literature: species co occurrence, niche limitation, guild proportionality and limiting similarity. Results from our meta-analyses suggest that non-random co-occurrence of plant species is not a widespread phenomenon. However, whether this finding reflects the individualistic nature of plant communities or is caused by methodological shortcomings associated with the studies considered cannot be discerned from the available metadata. We advocate that more thorough surveys be conducted using a set of standardized methods to test for the existence of assembly rules in data sets spanning larger biological and geographical scales than have been considered until now. We underpin this general advice with guidelines that should be considered in future assembly rules research. This will enable us to draw more accurate and general conclusions about the non-random aspect of assembly in plant communities. PMID- 21692966 TI - Motivational interviewing to improve weight loss in overweight and/or obese patients: a systematic review and meta-analysis of randomized controlled trials. AB - Motivational interviewing, a directive, patient-centred counselling approach focused on exploring and resolving ambivalence, has emerged as an effective therapeutic approach within the addictions field. However, the effectiveness of motivational interviewing in weight-loss interventions is unclear. Electronic databases were systematically searched for randomized controlled trials evaluating behaviour change interventions using motivational interviewing in overweight or obese adults. Standardized mean difference (SMD) for change in body mass, reported as either body mass index (BMI; kg m(-2) ) or body weight (kg), was the primary outcome, with weighted mean difference (WMD) for change in body weight and BMI as secondary outcomes. The search strategy yielded 3540 citations and of the 101 potentially relevant studies, 12 met the inclusion criteria and 11 were included for meta-analysis. Motivational interviewing was associated with a greater reduction in body mass compared to controls (SMD = -0.51 [95% CI -1.04, 0.01]). There was a significant reduction in body weight (kg) for those in the intervention group compared with those in the control group (WMD = -1.47 kg [95% CI -2.05, -0.88]). For the BMI outcome, the WMD was -0.25 kg m(-2) (95% CI -0.50, 0.01). Motivational interviewing appears to enhance weight loss in overweight and obese patients. PMID- 21692967 TI - The relevance of increased fat oxidation for body-weight management: metabolic inflexibility in the predisposition to weight gain. AB - Cells, tissues and organisms have the ability to rapidly switch substrate oxidation from carbohydrate to fat in response to changes in nutrient intake, and to changes in energy demands, environmental cues and internal signals. In healthy, metabolically normal individuals, substrate switching occurs rapidly and completely; in other words, substrate switching is 'flexible'. A growing body of evidence demonstrates that a blunted substrate switching from low- to high-fat oxidation exists in obese individuals, as well as in pre-obese and post-obese, and that this 'metabolic inflexibility' may be a genetically determined trait. A decreased fat oxidation can lead to a positive energy balance under conditions of high-fat feeding, due to depletion of glycogen stores that stimulates appetite and energy intake through glucostatic and glucogenostatic mechanisms, e.g. hepatic sensing of glycogen stores. Several genetic polymorphisms and single nucleotide polymorphisms have been identified that are associated with low-fat oxidation rates and metabolic inflexibility, and genetic identification of susceptible individuals may lead to personalized prevention of weight gain using fat oxidation stimulants ('fat burners') in the future. PMID- 21692968 TI - Antenatal domestic violence, maternal mental health and subsequent child behaviour: a cohort study. AB - OBJECTIVE: To investigate the long-term impact of antenatal domestic violence on maternal psychiatric morbidity and child behaviour. DESIGN: Cohort study. SETTING: Avon, UK. POPULATION OR SAMPLE: A birth cohort of 13,617 children and mother dyads were followed to 42 months of age. METHODS: Experiences of domestic violence and depressive symptoms were gathered at 18 weeks of gestation and up to 33 months after birth, together with maternal, paternal and child characteristics. MAIN OUTCOME MEASURES: Child behavioural problems were assessed at 42 months using the Revised Rutter Questionnaire. ANALYSIS: Logistic regression with the use of multiple imputation employing chained equations for missing data. RESULTS: Antenatal domestic violence was associated with high levels of maternal antenatal (odds ratio [OR], 4.02; 95% confidence interval [CI], 3.4-4.8) and postnatal (OR, 1.29; 95% CI, 1.02-1.63) depressive symptoms after adjustment for potential confounders. Antenatal domestic violence predicted future behavioural problems at 42 months in the child before adjustment for possible confounding and mediating factors (OR, 1.87; 95% CI, 1.45-2.40); this association was not significant after adjustment for high levels of maternal antenatal depressive symptoms, postnatal depressive symptoms or domestic violence since birth. CONCLUSIONS: Antenatal domestic violence is associated with high levels of both maternal antenatal and postnatal depressive symptoms. It is also associated with postnatal violence, and both are associated with future behavioural problems in the child at 42 months. This is partly mediated by maternal depressive symptoms in the ante- or postnatal period. PMID- 21692969 TI - Replacement of gabapentin with pregabalin in postherpetic neuralgia therapy. AB - PURPOSE: Although both gabapentin and pregabalin are first-line drugs for neuropathic pain including postherpetic neuralgia (PHN), no report has directly compared the magnitude of pain relief and the incidence of side effects of both drugs. By substituting gabapentin with pregabalin in postherpetic neuralgia therapy, we can compare the two drugs. METHODS: In 32 PHN patients being administered gabapentin, without changing the frequency of dosing, the drug was substituted with pregabalin at one-sixth dosage of gabapentin. After 2 weeks, an interview was conducted about the visual analog scale (VAS) pain score, changes in the time of onset of action and duration of action after the substitution of drug and side effects (such as somnolence, dizziness, and peripheral edema). In addition, the dosage was increased while paying careful attention to the side effects (titration) in 22 patients who requested a dosage increase among those whom VAS pain score of >=25 mm remained even after the substitution. RESULTS: No significant changes were observed in VAS pain scores after the substitution of gabapentin with pregabalin. Regarding the time of onset of action and the duration of action after the substitution, the highest number of patients answered that no change occurred compared with the previous drug, followed by the patients who answered that the time of onset of action became quicker, and the duration of action became longer. The incidence of somnolence and dizziness showed no significant difference before and after the substitution, but peripheral edema showed a significant increase after the substitution. The level of side effects of both drugs was mild, and continued medication was possible. In the patient group where pregabalin dosage was increased, the VAS pain score decreased significantly compared with that before and after increase the dosage (P < 0.05). On the other hand, in nine out of 22 patients in the group where the dosage was increased, side effects appeared or were exacerbated. In two out of nine patients, it was necessary to reduce the dosage to the initial volume. CONCLUSION: It was suggested that the analgesic action of pregabalin in PHN was six times that of gabapentin in terms of effectiveness in dosage conversion. Regarding the side effects, although the incidence of the peripheral edema was higher with pregabalin compared with gabapentin, this finding is not conclusive because the present study was conducted in a small number of subjects. Although pain reduction can be expected to increase with pregabalin dosage, it is necessary to increase the dosage gradually and carefully because of exacerbation of side effects. PMID- 21692970 TI - Botulinum type A toxin complex for the relief of upper back myofascial pain syndrome: how do fixed-location injections compare with trigger point-focused injections? AB - OBJECTIVE: This was a prospective, randomized, double-blind, placebo-controlled, 12-week, multicenter study to evaluate the efficacy and tolerability of fixed location injections of botulinum type A toxin (BoNT-A, Dysport) in predetermined injection sites in patients with myofascial pain syndrome of the upper back. DESIGN: Patients with moderate-to-severe myofascial pain syndrome affecting cervical and/or shoulder muscles (10 trigger points, disease duration 6-24 months) and moderate-to-severe pain intensity were randomized to BoNT-A (N = 81) or saline (N = 72). INTERVENTION: Patients received treatment into 10 predetermined fixed injection sites in the head, neck, and shoulder (40 units of BoNT-A per site or saline, a total of 400 units of BoNT-A). OUTCOME MEASURES: The primary efficacy outcome was the proportion of patients with mild or no pain at week 5 (responders). Secondary outcomes included changes in pain intensity and the number of pain-free days per week. RESULTS: At week 5, 49% (37/76) of BoNT-A patients and 38% (27/72) of placebo patients had responded to treatment (P = 0.1873). Duration of daily pain was reduced in the BoNT-A group compared with the placebo group from week 5, with statistically significant differences at weeks 9 and 10 (P = 0.04 for both). Treatment was well tolerated. CONCLUSION: Fixed location treatment with BoNT-A of patients with upper back myofascial pain syndrome did not lead to a significant improvement of the main target parameter in week 5 after treatment. Only in week 8 were significant differences found. Several secondary parameters, such as physicians' global assessment and patients' global assessment, significantly favored BoNT-A over placebo at weeks 8 and 12. PMID- 21692971 TI - Pregabalin assay in a patient with widespread neuropathic pain and late onset gluten intolerance. AB - OBJECTIVE: The aim of this study was to determine the pharmacokinetics of pregabalin in a patient with malabsorption secondary to celiac disease and compare the findings with the data available from pre-existing studies in healthy volunteer controls. METHODS: A 39-year-old man consented to a 24-hour pregabalin assay with sequential pre and post-dose blood sampling. RESULTS: The blood levels measured in this subject were no different to healthy male volunteers enrolled in previous studies. CONCLUSION: Although the results obtained are encouraging, the wide spectrum of effects and interactions of various drugs in malabsorption would suggest that therapy of any kind should be considered at individual level and monitored with blood assays. PMID- 21692973 TI - Left stellate ganglion blockade for the management of drug-resistant electrical storm. AB - BACKGROUND: Electrical storm (ES) is a syndrome characterized by rapidly recurrent ventricular fibrillation or tachycardia. The most common precipitants include ongoing or recent myocardial ischemia, exacerbating congestive heart failure, arrhythmogenic medications, and electrolyte disturbances. OBJECTIVE: We describe the case of a patient who developed ES seventy-two hours status post triple vessel coronary artery bypass grafting that did not respond to conservative treatment and required approximately 70 electrical shocks. CONCLUSION: The patient was rapidly stabilized following left stellate ganglion blockade. PMID- 21692972 TI - Rectus sheath catheters for continuous analgesia after laparotomy--without postoperative opioid use. AB - OBJECTIVE: Opioid and epidural analgesia have been the mainstay for postoperative pain control following laparotomies, yet have many potential side effects, risks, and limitations. This case report offers an alternative to opioid as well as epidural analgesia, which may be beneficial in some patients. DESIGN: We report a case of a patient who underwent a laparotomy with extensive lysis of adhesions who was treated postoperatively with continuous bilateral rectus sheath catheters and multimodal adjuncts including gabapentin, clonidine, and nonsteroidal anti inflammatories. RESULTS: We successfully used a novel, multimodal approach that avoided the use of epidural analgesia and postoperative opioids. The patient was extremely satisfied, reported minimal discomfort, ambulated early, advanced her diet quickly, and was discharged home after a short hospital stay. CONCLUSIONS: This report may be the first description of a successful multimodal postoperative analgesic regimen including continuous bilateral rectus sheath blocks without inpatient postoperative opioid use or epidural analgesia following a midline laparotomy. PMID- 21692974 TI - An evolutionary stress-response hypothesis for chronic widespread pain (fibromyalgia syndrome). AB - OBJECTIVE: The study aimed to seek a unifying biological basis for the phenomena encompassed in fibromyalgia syndrome (chronic widespread pain and associated morbidities). SETTING: While much progress has been made in the last decade in understanding chronic widespread pain, its pathogenesis remains stubbornly obscure and its treatment difficult. Two themes are gaining currency in the field: that chronic widespread pain is the result of central sensitization of nociception, and that chronic pain is somehow related to activation of a global stress response. DESIGN: In this article we merge these two ideas within the perspective of evolutionary biology to generate a hypothesis about the critical molecular pathway involved in chronic stress response activation, namely substance P and its preferred receptor, neurokinin-1 (NK-1R), which has many empirically testable implications. CONCLUSION: Drawing on diverse findings in neurobiology, immunology, physiology, and comparative biology, we suggest that the form of central sensitization that leads to the profound phenomenological features of chronic widespread pain is part of a whole-organism stress response, which is evolutionarily conserved, following a general pattern found in the simplest living systems. PMID- 21692975 TI - Factorial validity and reliability of the Chinese version of the Pain Vigilance and Awareness Questionnaire (ChPVAQ) in a sample of Chinese patients with chronic pain. AB - PURPOSE: The Pain Vigilance and Awareness Questionnaire (PVAQ) has been shown to be a reliable measure for assessing attention to pain. Different factor structures have been reported in Western populations; yet, whether the known factor models could be replicated in non-Western populations and the psychometric properties of the scale remain unclear. This study aimed to examine the factorial validity and psychometric properties of the Chinese version of the PVAQ (ChPVAQ). METHODS: A total of 242 Chinese patients with chronic pain completed the ChPVAQ, the Chronic Pain Grade questionnaire, the Chinese version of the 11-item version of the Tampa Scale for Kinesiophobia (ChTSK-11), the Hospital Anxiety and Depression Scale (HADS), and questions assessing socio-demographic characteristics. RESULTS: Results of confirmatory factor analyses showed that of the nine competing models tested, McCracken's two-factor correlated model for the 13-item version of PVAQ (PVAQ-13) demonstrated the best data-model fit (CFI = 0.93). The two subscales and the entire scale of ChPVAQ-13 obtained moderately high internal consistency (Cronbach's alphas: 0.75-0.77). The ChPVAQ-13 scales showed significant positive correlations with HADS, ChTSK11, pain intensity, and disability scores. Results of hierarchical multiple regression analyses showed the ChPVAQ-13 scales predicted concurrent depression (F[4,187] = 6.01, P < 0.001) and pain disability (F[4,190] = 3.54, P < 0.05) scores. Passive Awareness emerged as significant independent predictor of concurrent depression (standardized beta coefficient [std beta] = 0.17, P < 0.05) and pain disability (std beta = 0.24, P < 0.01), while Active Vigilance (std beta = 0.19, P < 0.05) predicted concurrent pain disability. CONCLUSIONS: Our results offer preliminary evidence for the factorial validity and reliability the ChPVAQ-13. PMID- 21692976 TI - Ultrasound-guided cervical nerve root block: spread of solution and clinical effect. AB - OBJECTIVES: We investigated the clinical effects and accuracy of ultrasound guided cervical nerve root block. Additionally, spinal level and spread of injected solution were confirmed by anatomic dissection of fresh cadavers. DESIGN SETTING, PATIENTS, AND INTERVENTIONS: Twelve patients diagnosed with mono radiculopathy between C5-7 underwent ultrasound-guided nerve root block. An insulated needle was advanced with an in-plane approach using nerve stimulation and 2 mL of 0.375% ropivacaine with 4 mg of dexamethasone was injected using nerve stimulation. Ultrasound-guided C5-7 nerve root block was also performed in ten fresh cadavers. Blue dye (2 mL) was injected onto each nerve root and anatomic dissection was performed to confirm the exact spinal level and spread pattern of the dye. RESULTS: Pain score before the procedure (65 [46-80], median [interquartile range]) was decreased to 25 [3-31] at 24 hours (P = 0.003) and 40 [28-66] at 30 days (P = 0.02) after the root block. Obvious side effects were not seen. All target nerve roots in patients and cadavers were correctly identified by ultrasound imaging. The needle tip did not reach the pedicle of the vertebral arch in the anteroposterior view of fluoroscopy, and spread pattern of contrast medium was extraforaminal and extraneural. CONCLUSIONS: This study suggests that injected solution by ultrasound-guided cervical nerve root block mainly spreads to the extraforaminal direction compared with conventional fluoroscopic technique. Therefore, present clinical study involves possibility of safer selective nerve root block with sufficient analgesic effects by ultrasound guidance, despite the absence of intraforaminal epidural spread of solution. PMID- 21692977 TI - Relationship between paraoxonase-1 activity, its Q192R genetic variant and clopidogrel responsiveness in the ADRIE study. PMID- 21692978 TI - Novel insights into the development of atherosclerosis in hemophilia A mouse models. AB - BACKGROUND: Cardiovascular diseases in aging people with hemophilia (PWH) represent a growing concern. The underlying hypocoagulability probably provides a protective effect against acute thrombus formation, but the limited data available show no preventive effect against the development of atherogenesis in PWH. Atherosclerosis-prone mice are attractive tools for the study of atherosclerosis development, and may provide insights into disease progression in PWH. METHODS: Severe hemophilia A (factor VIII-deficient [FVIII(o)]) mice were crossed with mice lacking apolipoprotein E (ApoE(-/-)) or mice lacking the LDL receptor (LDLR(-/-)), and then compared to hemostatically normal littermate controls. After mice had received atherogenic diets for 8, 22 or 37 weeks, atherosclerotic lesion size and phenotypic characterization were analyzed in the aortic sinus and whole aortas. RESULTS: ApoE(-/-)/FVIII(o) mice showed a time dependent protective effect against the development of atherosclerosis, beginning after 22 diet-weeks and persisting to 37 diet-weeks in both the aorta sinus and whole aorta as compared with ApoE(-/-) mice. Notably, the FVIII deficiency did not influence the progression of atherosclerosis in the FVIII(o)/LDLR(-/-) model as compared with controls at early or late time points. CONCLUSIONS: Hypocoagulability ameliorates vascular disease in the ApoE-deficient model in a lipid-independent manner. Interestingly, FVIII deficiency did not affect the development of atherosclerosis in LDLR(-/-) mice. In contrast to the ApoE model, the LDLR model resembles the lipid profile that is commonly observed in humans with atherosclerosis. These findings, to a certain extent, support the notion of atherosclerosis development in the complete absence of FVIII. PMID- 21692979 TI - Monocyte count and procoagulant functions are associated with risk of venous thromboembolism: the Tromso study. PMID- 21692980 TI - Genetic polymorphisms and microRNAs: new direction in molecular epidemiology of solid cancer. AB - MicroRNAs (miRNAs) are small non-coding RNAs, which regulate gene expression. Single nucleotide polymorphisms (SNPs) may occur in miRNA biogenesis pathway genes, primary miRNA, pre-miRNA or a mature miRNA sequence. Such polymorphisms may be functional with respect to biogenesis and actions of mature miRNA. Specific SNPs were identified in predicted miRNA target sites within 3' untranslated regions of mRNAs. These SNPs have a potential to affect the efficiency of miRNA binding to the target sites or can create or disrupt binding sites. Resulting gene dysregulation may involve changes in phenotype and may eventually prove critical for the susceptibility to cancer and its onset as well as for estimates of prognosis and therapy response. In this review, we provide a comprehensive list of potentially functional miRNA-related SNPs and summarize their importance as candidate cancer biomarkers. PMID- 21692982 TI - Water channels in platelet volume regulation. AB - The regulation of platelet volume significantly affects its function. Because water is the major molecule in cells and its active transport via water channels called aquaporins (AQPs) have been implicated in cellular and organelle volume regulation, the presence of water channels in platelets and their potential role in platelet volume regulation was investigated. G-protein-mediated AQP regulation in secretory vesicle swelling has previously been reported in neurons and in pancreatic acinar cells. Mercuric chloride has been demonstrated to inhibit most AQPs except AQP6, which is stimulated by the compound. Exposure of platelets to HgCl(2)-induced swelling in a dose-dependent manner, suggesting the presence of AQP6 in platelets. Immunoblot analysis of platelet protein confirmed the presence of AQP6, and also of G(alphao), G(alphai-1) and G(alphai-3) proteins. Results from this study demonstrate for the first time that in platelets AQP6 is involved in cell volume regulation via a G-protein-mediated pathway. PMID- 21692981 TI - How do tenascins influence the birth and life of a malignant cell? AB - Tenascins are large glycoproteins found in embryonic and adult extracellular matrices. Of the four family members, two have been shown to be overexpressed in the microenvironment of solid tumours: tenascin-C and tenascin-W. The regular presence of these proteins in tumours suggests a role in tumourigenesis, which has been investigated intensively for tenascin-C and recently for tenascin-W as well. In this review, we follow a malignant cell starting from its birth through its potential metastatic journey and describe how tenascin-C and tenascin-W contribute to these successive steps of tumourigenesis. We consider the importance of the mechanical aspect in tenascin signalling. Furthermore, we discuss studies describing tenascin-C as an important component of stem cell niches and present examples reporting its role in cancer therapy resistance. PMID- 21692984 TI - K ATP channel agonists preserve connexin43 protein in infarcted rats by a protein kinase C-dependent pathway. AB - Downward remodelling of gap junctional proteins between myocytes may trigger ventricular arrhythmia after myocardial infarction. We have demonstrated that ATP sensitive potassium (K(ATP)) channel agonists attenuated post-infarction arrhythmias. However, the involved mechanisms remain unclear. The purpose of this study was to determine whether K(ATP) channel agonists can attenuate arrhythmias through preserving protein kinase C (PKC)-(epsilon)dependent connexin43 level after myocardial infarction. Male Wistar rats after ligating coronary artery were randomized to either vehicle, nicorandil, pinacidil, glibenclamide or a combination of nicorandil and glibenclamide or pinacidil and glibenclamide for 4 weeks. To elucidate the role of PKC(epsilon) in the modulation of connexin43 level, carbachol and myristoylated PKC(epsilon) V1-2 peptide were also assessed. Myocardial connexin43 level was significantly decreased in vehicle-treated infarcted rats compared with sham. Attenuated connexin43 level was blunted after administering K(ATP) channel agonists, assessed by immunofluorescent analysis, Western blotting, and real-time quantitative reverse transcription-PCR of connexin43. Arrhythmic scores during programmed stimulation in the K(ATP) channel agonists-treated rats were significantly lower than those treated with vehicle. The beneficial effects of K(ATP) channel agonists were blocked by either glibenclamide or 5-hydroxydecanoate. Addition of the PKC activator, phorbol 12 myristate 13-acetate and the specific PKC(epsilon) agonist, carbachol, blocked the effects of nicorandil on connexin43 phosphorylation and dye permeability. The specific PKC(epsilon) antagonist, myristoylated PKC(epsilon) V1-2 peptide, did not have additional beneficial effects on connexin43 phosphorylation compared with rats treated with nicorandil alone. Chronic use of K(ATP) channel agonists after infarction, resulting in enhanced connexin43 level through a PKC(epsilon) dependent pathway, may attenuate the arrhythmogenic response to programmed electrical stimulation. PMID- 21692985 TI - Anti-inflammatory potential of allyl-isothiocyanate--role of Nrf2, NF-(kappa) B and microRNA-155. AB - In this study, the underlying mechanisms of the potential anti-inflammatory properties of allyl-isothiocyanate (AITC) were analysed in vitro and in vivo. Murine RAW264.7 macrophages stimulated with lipopolysaccharide (LPS) were supplemented with increasing concentrations of AITC. In addition, C57BL/6 mice (n= 10 per group) were fed a pro-inflammatory high-fat diet and AITC was administered orally via gavage for 7 days. Biomarkers of inflammation were determined both in cultured cells and in mice. AITC significantly decreased tumour necrosis factor alpha mRNA levels and its secretion in LPS stimulated RAW264.7 macrophages. Furthermore, gene expression of other pro-inflammatory markers including interleukin-1beta and inducible nitric oxide synthase were down regulated following AITC treatment. AITC decreased nuclear p65 protein levels, a subunit of the transcription factor NF-kappaB. Importantly, our data indicate that AITC significantly attenuated microRNA-155 levels in LPS-stimulated RAW264.7 macrophages in a dose-dependent manner. The anti-inflammatory effects of AITC were accompanied by an increase in Nrf2 nuclear translocation and consequently by an increase of mRNA and protein levels of the Nrf2 target gene heme-oxygenase 1. AITC was slightly less potent than sulforaphane (used as a positive control) in down-regulating inflammation in LPS-stimulated macrophages. A significant increase in nuclear Nrf2 and heme-oxygenase 1 gene expression and only a moderate down-regulation of interleukin-1beta and microRNA-155 levels due to AITC was found in mouse liver. Present data suggest that AITC exhibits potent anti inflammatory activity in cultured macrophages in vitro but has only little anti inflammatory activity in mice in vivo. PMID- 21692987 TI - MiR-210: an important player in the pathogenesis of preeclampsia? PMID- 21692986 TI - Profilin1 facilitates staurosporine-triggered apoptosis by stabilizing the integrin beta1-actin complex in breast cancer cells. AB - Profilin1 (Pfn1) functions as a tumour suppressor against malignant phenotypes of cancer cells. A minimum level of Pfn1 is critical for the differentiation of human epithelial cells, and its lower expression correlates with the tumourigenesis of breast cancer cells and tissues. However, the molecular mechanisms underlying its anti-tumour action remain largely unknown. In this study, we found that stable expression of ectopic Pfn1 sensitized the breast cancer cell line MDA-MB-468 to apoptosis induced by staurosporine, a widely used natural apoptosis-inducing agent. Pfn1 overexpression could also up-regulate the expression of integrin alpha5beta1, which has been shown to inhibit the transformed phenotype of cancer cells. Furthermore, the Pfn1-facilitated apoptosis induced by staurosporine was blocked in cells attached to a supplementary fibronectin substrate, which serves as a ligand of integrin alpha5beta1. These results suggest that the insufficient fibronectin caused by the integrin alpha5beta1 up-regulation might activate a signalling pathway leading to an increase of cellular apoptosis. Moreover, Pfn1 that primarily functions to promote local superstructure formation involving actin filaments and integrin beta1 may contribute to its promotion on apoptosis. Our study indicated a previously uncharacterized role of Pfn1 in mediating staurosporine-inducing apoptosis in breast cancer cells via up-regulating integrin alpha5beta1, and suggested a new target for breast cancer therapy. PMID- 21692989 TI - Tyrosine phosphorylation of tau regulates its interactions with Fyn SH2 domains, but not SH3 domains, altering the cellular localization of tau. AB - Recent reports have demonstrated that interactions between the microtubule associated protein tau and the nonreceptor tyrosine kinase Fyn play a critical role in mediating synaptic toxicity and neuronal loss in response to beta-amyloid (Abeta) in models of Alzheimer's disease. Disruption of interactions between Fyn and tau may thus have the potential to protect neurons from Abeta-induced neurotoxicity. Here, we investigated tau and Fyn interactions and the potential implications for positioning of these proteins in membrane microdomains. Tau is known to bind to Fyn via its Src-homology (SH)3 domain, an association regulated by phosphorylation of PXXP motifs in tau. Here, we show that Pro216 within the PXXP(213-216) motif in tau plays an important role in mediating the interaction of tau with Fyn-SH3. We also show that tau interacts with the SH2 domain of Fyn, and that this association, unlike that of Fyn-SH3, is influenced by Fyn-mediated tyrosine phosphorylation of tau. In particular, phosphorylation of tau at Tyr18, a reported target of Fyn, is important for mediating Fyn-SH2-tau interactions. Finally, we show that tyrosine phosphorylation influences the localization of tau to detergent-resistant membrane microdomains in primary cortical neurons, and that this trafficking is Fyn-dependent. These findings may have implications for the development of novel therapeutic strategies aimed at disrupting the tau/Fyn mediated synaptic dysfunction that occurs in response to elevated Abeta levels in neurodegenerative disease. PMID- 21692988 TI - No effect of 5HTTLPR or BDNF Val66Met polymorphism on hippocampal morphology in major depression. AB - Neuroimaging research implicates the hippocampus in the aetiology of major depressive disorder (MDD). Imaging genetics studies have investigated the influence of the serotonin transporter-linked polymorphic region (5HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on the hippocampus in healthy individuals and patients with depression (MDD). However, conflicting results have led to inconclusive evidence about the effect of 5HTTLPR or BDNF on hippocampal volume (HCV). We hypothesized that analysis methods based on three dimensional (3D) hippocampal shape mapping could offer improved sensitivity to clarify these effects. Magnetic resonance imaging data were collected in parallel samples of 111 healthy individuals and 84 MDD patients. Manual hippocampal segmentation was conducted and the resulting data used to investigate the influence of 5HTTLPR and BDNF Val66Met genotypes on HCV and 3D shape within each sample. Hippocampal volume normalized by intracranial volume (ICV) showed no significant difference between 5HTTLPR S allele carriers and L/L homozygotes or between BDNF Met allele carriers and Val/Val homozygotes in the group of healthy individuals. Moreover, there was no significant difference in normalized HCV between 5HTTLPR diallelic and triallelic classifications or between the BDNF Val66Met genotypes in MDD patients, although there was a relationship between BDNF Val66Met and ICV. Shape analysis detected dispersed between-group differences, but these effects did not survive multiple testing correction. In this study, there was no evidence of a genetic effect for 5HTTLPR or BDNF Val66Met on hippocampal morphology in either healthy individuals or MDD patients despite the relatively large sample sizes and sensitive methodology. PMID- 21692990 TI - Affinity and kinetics of proprotein convertase subtilisin/kexin type 9 binding to low-density lipoprotein receptors on HepG2 cells. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates the number of cell surface low-density lipoprotein receptors (LDLRs) and the levels of low-density lipoprotein cholesterol in plasma. Intact cells have not previously been used to determine the characteristics of binding of PCSK9 to LDLR. Using PCSK9 iodinated by the tyramine cellobiose (TC) method ([(125)I]TC-PCSK9), we measured the affinity and kinetics of binding of PCSK9 to LDLR on HepG2 cells at 4 degrees C. The extent of [(125)I]TC-PCSK9 binding increased as cell surface LDLR density increased. Unlabeled wild-type and two gain-of-function mutants of PCSK9 reduced binding of [(125)I]TC-PCSK9. The Scatchard plot of the binding-inhibition curve was curvilinear, indicative of high-affinity and low-affinity sites for PCSK9 binding on HepG2 cells. Nonlinear regression analysis of the binding data also indicated that a two-site model better fitted the data. The time course of [(125)I]TC-PCSK9 binding showed two phases in the association kinetics. Dissociation of [(125)I]TC-PCSK9 also occurred in two phases. Unlabeled PCSK9 accelerated the dissociation of [(125)I]TC-PCSK9. At low pH, only one phase of dissociation was apparent. Furthermore, the dissociation of [(125)I]TC-PCSK9 under pre-equilibrium conditions was faster than under equilibrium conditions. Overall, the data suggest that PCSK9 binding to cell surface LDLR cannot be described by a simple bimolecular reaction. Possible interpretations that can account for these observations are discussed. PMID- 21692991 TI - Effects on drainage of the mediastinum and pleura during negative pressure wound therapy when using a rigid barrier to prevent heart rupture. AB - Right ventricular heart rupture is a devastating complication associated with negative pressure wound therapy (NPWT) following cardiac surgery. The use of a rigid disc has been suggested to offer protection against this lethal complication by preventing the heart from being drawn up towards, and damaged by, the sharp sternum edges. The aim of the present study was to compare the wound fluid evacuation from the pericardium and the left pleura when using NPWT with such a disc between the sternal edges and the heart, and when using conventional NPWT. Six pigs underwent median sternotomy followed by NPWT at -120 mmHg, using foam, with or without a rigid plastic disc between the heart and the sternal edges. A 250 ml saline was infused into the pericardium, and the time required for fluid evacuation was measured. A 500 ml saline was infused into the left pleura and the time for fluid evacuation measured. The pericardium was effectively drained of 250 ml fluid in both cases [conventional NPWT: 24 +/- 0.7 seconds, NPWT with the disc: 25 +/- 1.1 seconds (n.s.)]. The left pleura was effectively drained when using NPWT with the disc, but was not drained at all when using conventional NPWT. The left pleura could be effectively drained of 500 ml fluid when a rigid perforated plastic disc was inserted between the sternal edges and the heart during NPWT. Significantly less drainage of the left pleura was possible when using conventional NPWT without the disc. The pericardium was equally good drained using NPWT with or without the disc. PMID- 21692992 TI - Detection of two HLA-A alleles, A*31:30 and A*26:20, in two Taiwanese volunteer bone marrow donors by sequence-based typing. AB - We here report detection of a novel sequence of HLA-A*31:30 and a confirmatory sequence of HLA*26:20 from two Taiwanese individuals. The sequence of A*31:30 is identical to that of A*31:01:02 in exons 2 and 3, except one nucleotide (n.t.) substitution c.539T > G resulting in p.Leu180Trp. The sequence of A*26:20 is identical to A*26:01:01 in exons 2 and 3, except a segment of the sequence from n.t. 78 to n.t.102. The mismatched sequence segment is identical to a sequence segment of A*02:03:01, suggesting that the formation of A*26:20 was resulted from a DNA recombination event between A*26:01:01 and A*02:03:01 sequences. A*26:20 differs from A*26:01:01 with c.98A > T resulting in p.Tyr33Phe. PMID- 21692993 TI - Estradiol and thermoregulation in adult endotoxemic rats exposed to lipopolysaccharide in neonatal life. AB - AIMS: Early life immune challenge has been considered an adaptive defense strategy against potential pathogens when the innate immune system is not completely developed. This study assesses whether neonatal endotoxin challenge alters body temperature response in adult female rats during endotoxemic shock and also, whether ovarian hormones may participate in this response. METHODS: Rats were intraperitoneally injected with lipopolysacharide (LPS) or saline at post-natal day 14, then as adults they were submitted to endotoxemic shock. RESULTS: The LPS injection in adult neonatal Saline rats caused an initial hypothermia, followed by a febrile response. However, neonatal LPS showed an increased hypothermic response and an attenuation of fever. The bilateral ovariectomy abolished the difference in body temperature between the neonatal LPS and saline rats. To determine the dependence of ovarian hormones, ovariectomized rats treated with estradiol cypionate (ECP) restored hypothermia and the suppressed febrile response. However, the same results were not obtained when the animals were supplemented with ECP and medroxyprogesterone acetate (MPA). The neonatal LPS rats displayed a significant reduction in TNF-alpha levels and an increase in IL-10 levels when compared with saline animals. The ECP injection significantly enhanced IL-10 and suppressed TNF-alpha in neonatal LPS, but it did not change the inflammatory response in the saline rats. The ECP + MPA regiment in the neonatal LPS rats reduced TNF-alpha, but eliminated IL-10 stimulation in comparison with the saline group. CONCLUSION: The present investigation shows that neonatal LPS challenge alters the thermoregulatory response during endotoxemic shock in adulthood and the mechanism for this difference could be mediated by sex hormones, especially estradiol. PMID- 21692994 TI - Using the laboratory to predict recurrent venous thrombosis. AB - Characterisation of heritable thrombophilic defects has facilitated an understanding of the complex mechanisms influencing risk of venous thromboembolism. In parallel with this, the importance of gene-environment interaction in the development of this disease has become apparent. However, testing for a limited number of heritable thrombophilic defects (first generation thrombophilia testing) has not been shown to predict likelihood of recurrent venous thrombosis to any useful degree. This paradox whereby thrombophilia testing identifies defects associated with an increased risk of a first venous thrombosis but not of a particularly high risk of recurrence is likely the result of limitations imposed by a limited dichotomous testing strategy compounded by test inaccuracy and imprecision. Consequently, the observed intermediate phenotype (defined by limited dichotomous testing) is not concordant with the risk of recurrent venous thrombosis. Whilst a simple dichotomous testing strategy for a limited number of heritable thrombophilic defects has not been shown to have useful clinical predictive value, proof-of-principle is emerging for testing of multiple genetic factors in predicting the likelihood of recurrent thrombosis. In addition, recent studies indicate that measurement of the global activity of the coagulation system using either biomarkers or measuring the thrombin generating potential (second generation thrombophilia testing) may have useful clinical predictive value for recurrent thrombosis. The assessment of the intermediate phenotype by global coagulation tests and genome-wide mutation and SNP (single nucleotide polymorphisms) detection may provide complimentary approaches to the quantification of risk of recurrence and enable a move towards more patient-focussed rather than disease-focussed care. PMID- 21692995 TI - Distinctive hematological abnormalities in East Asian neonates and children with Down syndrome. AB - INTRODUCTION: Neonates with Down syndrome (DS) are predisposed to developing transient abnormal myelopoiesis (TAM) and acute myeloid leukemia (AML) associated with DS. However, there is a paucity of data on hematological aberrations and GATA1 mutations in neonates with DS in East Asian populations. METHODS: Total 109 patients with DS who had one or more CBCs obtained were enrolled. The molecular analysis of the GATA1 gene performed in 10 patients (three TAM, three AML associated with DS at diagnosis, one remission case of AML associated with DS and three DS without TAM or AML). RESULTS: East Asian DS neonates showed low frequency of thrombocytopenia, uncommon neutrophilia and higher prevalence rate of TAM compared to previous reports from western countries. GATA1 mutations were identified in almost all TAM and AML associated with DS samples, but were not detected in the samples from DS without TAM or AML associated with DS. CONCLUSION: East Asian DS neonates and children showed distinctive spectrum of hematological abnormalities. PMID- 21692996 TI - Kinetics of pDCs, mDCs, gammadeltaT cells and regulatory T cells in association with graft versus host disease after hematopoietic stem cell transplantation. AB - INTRODUCTION: Although the roles of each low-frequency immunocompetent cells such as dendritic cells (DCs), gammadeltaT cells, and Treg cells in induction of acute or chronic graft versus host disease (GVHD) have been discussed in several reports, there are few papers dealing with an evaluation of these immunocompetent cells together and simultaneously in patients with hematopoietic stem cell transplantation (HSCT) and explored the kinetics of these cells in association with GVHD. METHODS: In the present study, we assessed the number of plasmacytoid DCs (pDCs), myeloid DCs (mDCs), gammadeltaT cells and Treg cells serially in patients who received allogeneic HSCT and analyzed the relationship of these cells with acute or chronic GVHD (cGVHD) by using flow cytometry. RESULTS: The percentages and numbers of pDCs, mDC1s and gammadeltaT cells were significantly lowered in the patients with acute GVHD (aGVHD) compared with those with no GVHD. On the contrary, the percentages and numbers of Treg cells were significantly elevated in the patients with aGVHD compared with those with no GVHD. As to the association with cGVHD, Treg cells were elevated in the patients with cGVHD, compared with those with no GVHD. CONCLUSION: The present study revealed an association of pDCs, mDCs, gammadeltaT cells and Treg cells with induction or treatment of GVHD. PMID- 21692997 TI - A novel, variant BCR-ABL1 transcript not detected by standard real-time quantitative PCR in a patient with chronic myeloid leukaemia. PMID- 21692998 TI - Repeat haematinic requests in patients with previous normal results: the scale of the problem in elderly patients at a district general hospital. AB - Repeating normal laboratory tests can waste resources. This study aimed to quantify unnecessary repeat haematinic tests taken from the elderly in a district general hospital. Haematinic tests (ferritin, B12, serum folate) from patients age >= 70 years were reviewed for repeat tests during an 8-week period. Questionnaires were given to doctors to establish when the considered repeating a 'borderline low normal' result to be clinically justifiable. 7.7% of all haematinic tests were repeat tests and of these, the majority (83%) was performed following a previously normal result. Thirteen of 24 doctors believed repeating a normal result at the bottom of the normal range ('borderline low normal') was justifiable. After excluding 'borderline low normal' results, 6.0% (at minimum) of repeat tests were done following a previous normal result and were unnecessary. This audit showed that there are a significant number of unnecessary repeat haematinic tests being performed. PMID- 21692999 TI - Genotyping HapSTR loci: phase determination from direct sequencing of PCR products. AB - HapSTRs combine information from a microsatellite (or simple tandem repeat, STR) with one or more single nucleotide polymorphisms in the DNA sequence immediately flanking the STR. These loci may offer increased power for the estimation of demographic parameters, but also present some challenges for data collection and analysis. We describe a process for inferring HapSTR alleles, including the flanking haplotypes, STR alleles and their phase relative to each other, directly from DNA sequence electropherograms of PCR products from heterozygous individuals. Our approach eliminates the need for more costly and time-consuming processes, such as cloning or acrylamide gel electrophoresis to separate alleles prior to sequencing. PMID- 21693000 TI - Recent discoveries of armyworms in Japan and their species identification using DNA barcoding. AB - Long columns of migrating larval sciarid armyworms were discovered in central and northern Japan, specifically Kanagawa, Gunma, Miyagi and Akita prefectures, as well as Hokkaido. This is the first examination of armyworms in East Asia. In Europe, armyworms have been identified as Sciara militaris, belonging to the family Sciaridae (sciarid flies or black fungus gnats), by rearing them to adulthood. In Japan, we were unable to obtain live samples for rearing; therefore, DNA barcodes were obtained from the samples of armyworms collected in the Gunma and Miyagi prefectures. The DNA barcodes were compared with those obtained from the following samples: pupae of S. militaris from UK, adults of Sciara kitakamiensis, Sciara humeralis, Sciara hemerobioides, Sciara thoracica, Sciara helvola and Sciara melanostyla from Japan, and adults of one undescribed Sciara species from Malaysia. Neighbour-joining, maximum parsimony, and maximum likelihood analyses revealed that the armyworms discovered in Japan are S. kitakamiensis. Although adults of this species have been recorded in several locations in Japan, this is the first report of migrating larval armyworms. DNA barcodes were effectively used to link different life stages of this species. The average intraspecific and interspecific pairwise genetic distances of the genus Sciara were 0.3% and 12.6%, respectively. The present study illustrates that DNA barcodes are an effective means of identifying sciarid flies in Japan. PMID- 21693001 TI - The first workshop towards the control of cestode zoonoses in Asia and Africa. AB - The first workshop towards the control of cestode zoonoses in Asia and Africa was held in Asahikawa Medical University, Japan on 15 and 16 Feb 2011. This meeting was fully supported by the Asian Science and Technology Strategic Cooperation Promotion Programs sponsored by the Special Coordination Funds for Promoting Science and Technology, the Ministry of Education Japan (MEXT) for 3 years from 2010 to Akira Ito. A total of 24 researchers from 9 countries joined together and discussed the present situation and problems towards the control of cestode zoonoses. As the meeting was simultaneously for the establishment of joint international, either bilateral or multilateral collaboration projects, the main purposes were directed to 1) how to detect taeniasis/cysticercosis infected patients, 2) how to differentiate Taenia solium from two other human Taenia species, T. saginata and T. asiatica, 3) how to evaluate T. asiatica based on the evidence of hybrid and hybrid-derived adult tapeworms from Thailand and China, 4) how to evaluate T. solium and T. hyaenae and other Taenia species from the wild animals in Ethiopia, and 5) how to detect echinococcosis patients and 6) how to differentiate Echinococcus species worldwide. Such important topics are summarized in this meeting report. PMID- 21693002 TI - Suicide death and hospital-treated suicidal behaviour in asylum seekers in the Netherlands: a national registry-based study. AB - BACKGROUND: Several suicide and suicidal behaviour risk factors are highly prevalent in asylum seekers, but there is little insight into the suicide death rate and the suicidal behaviour incidence in this population. The main objective of this study is to assess the burden of suicide and hospital-treated non-fatal suicidal behaviour in asylum seekers in the Netherlands and to identify factors that could guide prevention. METHODS: We obtained data on cases of suicide and suicidal behaviour from all asylum seeker reception centres in the Netherlands (period 2002-2007, age 15+). The suicide death rates in this population and in subgroups by sex, age and region of origin were compared with the rate in the Dutch population; the rates of hospital-treated suicidal behaviour were compared with that in the population of The Hague using indirect age group standardization. RESULTS: The study included 35 suicide deaths and 290 cases of hospital-treated suicidal behaviour. The suicide death rate and the incidence of hospital-treated suicidal behaviour differed between subgroups by sex and region of origin. For male asylum seekers, the suicide death rate was higher than that of the Dutch population (N = 32; RR = 2.0, 95%CI 1.37-2.83). No difference was found between suicide mortality in female asylum seekers and in the female general population of the Netherlands (N = 3; RR = 0.73; 95%CI 0.15-2.07). The incidence of hospital-treated suicidal behaviour was high in comparison with the population of The Hague for males and females from Europe and the Middle East/South West Asia, and low for males and females from Africa. Health professionals knew about mental health problems prior to the suicidal behaviour for 80% of the hospital-treated suicidal behaviour cases in asylum seekers. CONCLUSIONS: In this study the suicide death rate was higher in male asylum seekers than in males in the reference population. The incidence of hospital treated suicidal behaviour was higher in several subgroups of asylum seekers than that in the reference population. We conclude that measures to prevent suicide and suicidal behaviour among asylum seekers in the Netherlands are indicated. PMID- 21693003 TI - Volumetric intensity-modulated Arc (RapidArc) therapy for primary hepatocellular carcinoma: comparison with intensity-modulated radiotherapy and 3-D conformal radiotherapy. AB - BACKGROUND: To compare the RapidArc plan for primary hepatocellular carcinoma (HCC) with 3-D conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) plans using dosimetric analysis. METHODS: Nine patients with unresectable HCC were enrolled in this study. Dosimetric values for RapidArc, IMRT, and 3DCRT were calculated for total doses of 45~50.4 Gy using 1.8 Gy/day. The parameters included the conformal index (CI), homogeneity index (HI), and hot spot (V107%) for the planned target volume (PTV) as well as the monitor units (MUs) for plan efficiency, the mean dose (Dmean) for the organs at risk (OAR) and the maximal dose at 1% volume (D1%) for the spinal cord. The percentage of the normal liver volume receiving >= 40, > 30, > 20, and > 10 Gy (V40 Gy, V30 Gy, V20 Gy, and V10 Gy) and the normal tissue complication probability (NTCP) were also evaluated to determine liver toxicity. RESULTS: All three methods achieved comparable homogeneity for the PTV. RapidArc achieved significantly better CI and V107% values than IMRT or 3DCRT (p < 0.05). The MUs were significantly lower for RapidArc (323.8 +/- 60.7) and 3DCRT (322.3 +/- 28.6) than for IMRT (1165.4 +/- 170.7) (p < 0.001). IMRT achieved a significantly lower Dmean of the normal liver than did 3DCRT or RapidArc (p = 0.001). 3DCRT had higher V40Gy and V30 Gy values for the normal liver than did RapidArc or IMRT. Although the V10 Gy to the normal liver was higher with RapidArc (75.8 +/- 13.1%) than with 3DCRT or IMRT (60.5 +/- 10.2% and 57.2 +/- 10.0%, respectively; p < 0.01), the NTCP did not differ significantly between RapidArc (4.38 +/- 2.69) and IMRT (3.98 +/- 3.00) and both were better than 3DCRT (7.57 +/- 4.36) (p = 0.02). CONCLUSIONS: RapidArc provided favorable tumor coverage compared with IMRT or 3DCRT, but RapidArc is not superior to IMRT in terms of liver protection. Further studies are needed to establish treatment outcome differences between the three approaches. PMID- 21693004 TI - CONTIGuator: a bacterial genomes finishing tool for structural insights on draft genomes. AB - Recent developments in sequencing technologies have given the opportunity to sequence many bacterial genomes with limited cost and labor, compared to previous techniques. However, a limiting step of genome sequencing is the finishing process, needed to infer the relative position of each contig and close sequencing gaps. An additional degree of complexity is given by bacterial species harboring more than one replicon, which are not contemplated by the currently available programs. The availability of a large number of bacterial genomes allows geneticists to use complete genomes (possibly from the same species) as templates for contigs mapping.Here we present CONTIGuator, a software tool for contigs mapping over a reference genome which allows the visualization of a map of contigs, underlining loss and/or gain of genetic elements and permitting to finish multipartite genomes. The functionality of CONTIGuator was tested using four genomes, demonstrating its improved performances compared to currently available programs.Our approach appears efficient, with a clear visualization, allowing the user to perform comparative structural genomics analysis on draft genomes. CONTIGuator is a Python script for Linux environments and can be used on normal desktop machines and can be downloaded from http://contiguator.sourceforge.net. PMID- 21693005 TI - "Case files from the University of Florida: When an Earache is more than an Earache": A case report. AB - Brain abscess is not a common diagnosis as there are only approximately 2000 cases reported each year in the United States. There are three main routes of access to the brain including contiguous infection from the oropharynx, direct implantation and hematogenously. We present a case of brain abscess in a child who had multiple visits for ear pain to various physicians including pediatricians and to emergency departments. Additionally, the microbiology of brain abscesses is briefly discussed, as is treatment. PMID- 21693006 TI - Increased incidence of myelodysplastic syndrome and acute myeloid leukemia following breast cancer treatment with radiation alone or combined with chemotherapy: a registry cohort analysis 1990-2005. AB - BACKGROUND: Our objective was to measure myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) risk associated with radiation and/or chemotherapy breast cancer (BC) treatment. METHODS: Our study cohort was composed of BC patients diagnosed from 1990 to 2005 and followed up for blood disorders, mean length of follow up = 7.17 years, range 2-18 years. 5790 TNM stage 0-III patients treated with surgery alone, radiation and/or chemotherapy were included. Patients without surgery (n = 111), with stem cell transplantation (n = 98), unknown or non-standard chemotherapy regimens (n = 94), lost to follow up (n = 66) or 'cancer status unknown' (n = 67) were excluded. Rates observed at our community based cancer care institution were compared to SEER incidence data for rate ratio (RR) calculations. RESULTS: 17 cases of MDS/AML (10 MDS/7 AML) occurred during the follow up period, crude rate .29% (95% CI = .17, .47), SEER comparison RR = 3.94 (95% CI = 2.34, 6.15). The RR of MDS in patients age < 65 comparing our cohort incidence to SEER incidence data was 10.88 (95% CI = 3.84, 24.03) and the RR of AML in patients age < 65 was 5.32 (95% CI = 1.31, 14.04). No significant increased risk of MDS or AML was observed in women >= 65 or the surgery/chemotherapy-only group. A RR of 3.32 (95% CI = 1.42, 6.45) was observed in the surgery/radiation-only group and a RR of 6.32 (95% CI = 3.03, 11.45) in the surgery/radiation/chemotherapy group. 3 out of 10 MDS cases died of disease at an average 3.8 months post diagnosis and five of seven AML cases died at an average 9 months post diagnosis. CONCLUSIONS: An elevated rate of MDS and AML was observed among breast cancer patients < 65, those treated with radiation and those treated with radiation and chemotherapy compared to available population incidence data. Although a small number of patients are affected, leukemia risk associated with treatment and younger age is significant. PMID- 21693007 TI - Prednisolone and acupuncture in Bell's palsy: study protocol for a randomized, controlled trial. AB - BACKGROUND: There are a variety of treatment options for Bell's palsy. Evidence from randomized controlled trials indicates corticosteroids can be used as a proven therapy for Bell's palsy. Acupuncture is one of the most commonly used methods to treat Bell's palsy in China. Recent studies suggest that staging treatment is more suitable for Bell's palsy, according to different path-stages of this disease. The aim of this study is to compare the effects of prednisolone and staging acupuncture in the recovery of the affected facial nerve, and to verify whether prednisolone in combination with staging acupuncture is more effective than prednisolone alone for Bell's palsy in a large number of patients. METHODS/DESIGN: In this article, we report the design and protocol of a large sample multi-center randomized controlled trial to treat Bell's palsy with prednisolone and/or acupuncture. In total, 1200 patients aged 18 to 75 years within 72 h of onset of acute, unilateral, peripheral facial palsy will be assessed. There are six treatment groups, with four treated according to different path-stages and two not. These patients are randomly assigned to be in one of the following six treatment groups, i.e. 1) placebo prednisolone group, 2) prednisolone group, 3) placebo prednisolone plus acute stage acupuncture group, 4) prednisolone plus acute stage acupuncture group, 5) placebo prednisolone plus resting stage acupuncture group, 6) prednisolone plus resting stage acupuncture group. The primary outcome is the time to complete recovery of facial function, assessed by Sunnybrook system and House-Brackmann scale. The secondary outcomes include the incidence of ipsilateral pain in the early stage of palsy (and the duration of this pain), the proportion of patients with severe pain, the occurrence of synkinesis, facial spasm or contracture, and the severity of residual facial symptoms during the study period. DISCUSSION: The result of this trial will assess the efficacy of using prednisolone and staging acupuncture to treat Bell's palsy, and to determine a best combination therapy with prednisolone and acupuncture for treating Bell's palsy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01201642. PMID- 21693009 TI - Reversible dilated cardiomyopathy caused by hypothyroidism. AB - The association between lack of thyroid hormones and cardiac dysfunction has been well described. We report two new cases of patients with dilated cardiomyopathy (DCM), revealing a periphery hypothyroidism and for whom cardiac function significantly improved after L thyroxin substitutive treatment. Our cases highlight the necessity to perform thyroid function testing to investigate the etiology of non ischemic DCM. PMID- 21693008 TI - International children's accelerometry database (ICAD): design and methods. AB - BACKGROUND: Over the past decade, accelerometers have increased in popularity as an objective measure of physical activity in free-living individuals. Evidence suggests that objective measures, rather than subjective tools such as questionnaires, are more likely to detect associations between physical activity and health in children. To date, a number of studies of children and adolescents across diverse cultures around the globe have collected accelerometer measures of physical activity accompanied by a broad range of predictor variables and associated health outcomes. The International Children's Accelerometry Database (ICAD) project pooled and reduced raw accelerometer data using standardized methods to create comparable outcome variables across studies. Such data pooling has the potential to improve our knowledge regarding the strength of relationships between physical activity and health. This manuscript describes the contributing studies, outlines the standardized methods used to process the accelerometer data and provides the initial questions which will be addressed using this novel data repository. METHODS: Between September 2008 and May 2010 46,131 raw Actigraph data files and accompanying anthropometric, demographic and health data collected on children (aged 3-18 years) were obtained from 20 studies worldwide and data was reduced using standardized analytical methods. RESULTS: When using >= 8, >= 10 and >= 12 hrs of wear per day as a criterion, 96%, 93.5% and 86.2% of the males, respectively, and 96.3%, 93.7% and 86% of the females, respectively, had at least one valid day of data. CONCLUSIONS: Pooling raw accelerometer data and accompanying phenotypic data from a number of studies has the potential to: a) increase statistical power due to a large sample size, b) create a more heterogeneous and potentially more representative sample, c) standardize and optimize the analytical methods used in the generation of outcome variables, and d) provide a means to study the causes of inter-study variability in physical activity. Methodological challenges include inflated variability in accelerometry measurements and the wide variation in tools and methods used to collect non-accelerometer data. PMID- 21693010 TI - Sunitinib inhibits lymphatic endothelial cell functions and lymph node metastasis in a breast cancer model through inhibition of vascular endothelial growth factor receptor 3. AB - INTRODUCTION: Metastasis is a common event and the main cause of death in cancer patients. Lymphangiogenesis refers to the formation of new lymphatic vessels and is thought to be involved in the development of metastasis. Sunitinib is a multi kinase inhibitor that blocks receptor tyrosine kinase activity, including that of vascular endothelial growth factor receptors (VEGFRs). Although sunitinib is a clinically available angiogenesis inhibitor, its effects on lymphangiogenesis and lymph node metastasis remain unclear. The purpose of this study was to investigate the effects of sunitinib on vascular endothelial growth factor receptor 3 (VEGFR-3) and a related event, lymphangiogenesis. METHODS: The effects of sunitinib on the degree of phosphorylation of VEGFR-2/3 and other signaling molecules was examined in lymphatic endothelial cells (LECs) treated with the drug; VEGF-induced LEC growth, migration, and tube formation were also examined. For the in vivo study, luciferase-expressing breast cancer cells were transplanted into mammary fat pads of mice; the microvessel and lymphatic vessel density was then measured after treatment with sunitinib and anti-VEGFR-2 antibody. RESULTS: First, in human LECs, sunitinib blocked both VEGFR-2 and VEGFR 3 phosphorylation induced by VEGF-C or VEGF-D, and abrogated the activation of the downstream molecules extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt. Furthermore, sunitinib attenuated the cell-proliferation activity induced by VEGF-C/D and prevented VEGF-C-induced migration and tube formation of the LECs; however, anti-VEGFR2 treatment shows only a partial effect on the growth and functions of the LECs. We used a breast cancer cell line expressing luciferase as a metastatic cancer model. Sunitinib treatment (40 mg/kg/day) inhibited the growth of the primary tumor transplanted in the mammary fat pad of the mice and significantly reduced the number of blood and lymphatic vessels in the tumor. Furthermore, the development of axillary lymph node metastasis, detected by bioluminescent imaging, was markedly suppressed. This effect of sunitinib was more potent than that of DC101, an anti-mouse VEGFR-2 antibody. CONCLUSIONS: The results suggest that sunitinib might be beneficial for the treatment of breast cancer by suppressing lymphangiogenesis and lymph node metastasis, through inhibition, particularly important, of VEGFR-3. PMID- 21693011 TI - Effect of the vitamin B12-binding protein haptocorrin present in human milk on a panel of commensal and pathogenic bacteria. AB - BACKGROUND: Haptocorrin is a vitamin B12-binding protein present in high amounts in different body fluids including human milk. Haptocorrin has previously been shown to inhibit the growth of specific E. coli strains, and the aim of the present study was to elucidate whether the antibacterial properties of this protein may exert a general defense against pathogens and/or affect the composition of the developing microbiota in the gastrointestinal tracts of breastfed infants. FINDINGS: The present work was the first systematic study of the effect of haptocorrin on bacterial growth, and included 34 commensal and pathogenic bacteria to which infants are likely to be exposed. Well-diffusion assays addressing antibacterial effects were performed with human milk, haptocorrin-free human milk, porcine holo-haptocorrin (saturated with B-12) and human apo-haptocorrin (unsaturated). Human milk inhibited the growth of S. thermophilus and the pathogenic strains L. monocytogenes LO28, L. monocytogenes 4446 and L. monocytogenes 7291, but the inhibition could not be ascribed to haptocorrin. Human apo-haptocorrin inhibited the growth of only a single bacterial strain (Bifidobacterium breve), while porcine holo-haptocorrin did not show any inhibitory effect. CONCLUSIONS: Our results suggest that haptocorrin does not have a general antibacterial activity, and thereby contradict the existing hypothesis implicating such an effect. The study contributes to the knowledge on the potential impact of breastfeeding on the establishment of a healthy microbiota in infants. PMID- 21693012 TI - Gender-related outcome difference is related to course of sepsis on mixed ICUs: a prospective, observational clinical study. AB - INTRODUCTION: Impact of gender on severe infections is in highly controversial discussion with natural survival advantage of females described in animal studies but contradictory to those described human data. This study aims to describe the impact of gender on outcome in mixed intensive care units (ICUs) with a special focus on sepsis. METHODS: We performed a prospective, observational, clinical trial at Charite University Hospital in Berlin, Germany. Over a period of 180 days, patients were screened, undergoing care in three mainly surgical ICUs. In total, 709 adults were included in the analysis, comprising the main population ([female] n = 309, [male] n = 400) including 327 as the sepsis subgroup ([female] n = 130, [male] n = 197). RESULTS: Basic characteristics differed between genders in terms of age, lifestyle factors, comorbidities, and SOFA-score (Sequential Organ Failure Assessment). Quality and quantity of antibiotic therapy in means of antibiotic-free days, daily antibiotic use, daily costs of antibiotics, time to antibiotics, and guideline adherence did not differ between genders. ICU mortality was comparable in the main population ([female] 10.7% versus [male] 9.0%; P = 0.523), but differed significantly in sepsis patients with [female] 23.1% versus [male] 13.7% (P = 0.037). This was confirmed in multivariate regression analysis with OR = 1.966 (95% CI, 1.045 to 3.701; P = 0.036) for females compared with males. CONCLUSIONS: No differences in patients' outcome were noted related to gender aspects in mainly surgical ICUs. However, for patients with sepsis, an increase of mortality is related to the female sex. PMID- 21693013 TI - Deregulation upon DNA damage revealed by joint analysis of context-specific perturbation data. AB - BACKGROUND: Deregulation between two different cell populations manifests itself in changing gene expression patterns and changing regulatory interactions. Accumulating knowledge about biological networks creates an opportunity to study these changes in their cellular context. RESULTS: We analyze re-wiring of regulatory networks based on cell population-specific perturbation data and knowledge about signaling pathways and their target genes. We quantify deregulation by merging regulatory signal from the two cell populations into one score. This joint approach, called JODA, proves advantageous over separate analysis of the cell populations and analysis without incorporation of knowledge. JODA is implemented and freely available in a Bioconductor package 'joda'. CONCLUSIONS: Using JODA, we show wide-spread re-wiring of gene regulatory networks upon neocarzinostatin-induced DNA damage in Human cells. We recover 645 deregulated genes in thirteen functional clusters performing the rich program of response to damage. We find that the clusters contain many previously characterized neocarzinostatin target genes. We investigate connectivity between those genes, explaining their cooperation in performing the common functions. We review genes with the most extreme deregulation scores, reporting their involvement in response to DNA damage. Finally, we investigate the indirect impact of the ATM pathway on the deregulated genes, and build a hypothetical hierarchy of direct regulation. These results prove that JODA is a step forward to a systems level, mechanistic understanding of changes in gene regulation between different cell populations. PMID- 21693015 TI - Tattoo removal in the typical adolescent. AB - BACKGROUND: Although popular tattoos are often regretted later on for different reasons. Nevertheless, tattoo removal is a complicated and costly procedure seldom providing satisfactory results. The aim of this study was to investigate the awareness of the implications of tattoo removal among a substantial sample of Italian secondary school adolescents. FINDINGS: Students were recruited by a stratified convenience sample and surveyed by a self administered questionnaire. Logistic regression analysis was performed, reporting adjusted Odds Ratios (OR), with 95% Confidence Interval (CI).4,277 pupils returned a usable questionnaire. Piercings were more frequently undertaken than tattoos. Only 40% of the respondents were aware of the issues related to tattoo removal. Males and pupils with younger fathers were less likely to be aware, whereas students satisfied with their physical appearance and those with a positive attitude towards body art were more likely to be aware. CONCLUSIONS: Male adolescents with younger fathers can be regarded as the ideal target of corporate health education programs driven by school counsellors and primary care physicians. PMID- 21693014 TI - "Nested" cryptic diversity in a widespread marine ecosystem engineer: a challenge for detecting biological invasions. AB - BACKGROUND: Ecosystem engineers facilitate habitat formation and enhance biodiversity, but when they become invasive, they present a critical threat to native communities because they can drastically alter the receiving habitat. Management of such species thus needs to be a priority, but the poorly resolved taxonomy of many ecosystem engineers represents a major obstacle to correctly identifying them as being either native or introduced. We address this dilemma by studying the sea squirt Pyura stolonifera, an important ecosystem engineer that dominates coastal communities particularly in the southern hemisphere. Using DNA sequence data from four independently evolving loci, we aimed to determine levels of cryptic diversity, the invasive or native status of each regional population, and the most appropriate sampling design for identifying the geographic ranges of each evolutionary unit. RESULTS: Extensive sampling in Africa, Australasia and South America revealed the existence of "nested" levels of cryptic diversity, in which at least five distinct species can be further subdivided into smaller-scale genetic lineages. The ranges of several evolutionary units are limited by well documented biogeographic disjunctions. Evidence for both cryptic native diversity and the existence of invasive populations allows us to considerably refine our view of the native versus introduced status of the evolutionary units within Pyura stolonifera in the different coastal communities they dominate. CONCLUSIONS: This study illustrates the degree of taxonomic complexity that can exist within widespread species for which there is little taxonomic expertise, and it highlights the challenges involved in distinguishing between indigenous and introduced populations. The fact that multiple genetic lineages can be native to a single geographic region indicates that it is imperative to obtain samples from as many different habitat types and biotic zones as possible when attempting to identify the source region of a putative invader. "Nested" cryptic diversity, and the difficulties in correctly identifying invasive species that arise from it, represent a major challenge for managing biodiversity. PMID- 21693016 TI - Comparative genome analysis and genome-guided physiological analysis of Roseobacter litoralis. AB - BACKGROUND: Roseobacter litoralis OCh149, the type species of the genus, and Roseobacter denitrificans OCh114 were the first described organisms of the Roseobacter clade, an ecologically important group of marine bacteria. Both species were isolated from seaweed and are able to perform aerobic anoxygenic photosynthesis. RESULTS: The genome of R. litoralis OCh149 contains one circular chromosome of 4,505,211 bp and three plasmids of 93,578 bp (pRLO149_94), 83,129 bp (pRLO149_83) and 63,532 bp (pRLO149_63). Of the 4537 genes predicted for R. litoralis, 1122 (24.7%) are not present in the genome of R. denitrificans. Many of the unique genes of R. litoralis are located in genomic islands and on plasmids. On pRLO149_83 several potential heavy metal resistance genes are encoded which are not present in the genome of R. denitrificans. The comparison of the heavy metal tolerance of the two organisms showed an increased zinc tolerance of R. litoralis. In contrast to R. denitrificans, the photosynthesis genes of R. litoralis are plasmid encoded. The activity of the photosynthetic apparatus was confirmed by respiration rate measurements, indicating a growth phase dependent response to light. Comparative genomics with other members of the Roseobacter clade revealed several genomic regions that were only conserved in the two Roseobacter species. One of those regions encodes a variety of genes that might play a role in host association of the organisms. The catabolism of different carbon and nitrogen sources was predicted from the genome and combined with experimental data. In several cases, e.g. the degradation of some algal osmolytes and sugars, the genome-derived predictions of the metabolic pathways in R. litoralis differed from the phenotype. CONCLUSIONS: The genomic differences between the two Roseobacter species are mainly due to lateral gene transfer and genomic rearrangements. Plasmid pRLO149_83 contains predominantly recently acquired genetic material whereas pRLO149_94 was probably translocated from the chromosome. Plasmid pRLO149_63 and one plasmid of R. denitrifcans (pTB2) seem to have a common ancestor and are important for cell envelope biosynthesis. Several new mechanisms of substrate degradation were indicated from the combination of experimental and genomic data. The photosynthetic activity of R. litoralis is probably regulated by nutrient availability. PMID- 21693017 TI - NORMA-Gene: a simple and robust method for qPCR normalization based on target gene data. AB - BACKGROUND: Normalization of target gene expression, measured by real-time quantitative PCR (qPCR), is a requirement for reducing experimental bias and thereby improving data quality. The currently used normalization approach is based on using one or more reference genes. Yet, this approach extends the experimental work load and suffers from assumptions that may be difficult to meet and to validate. RESULTS: We developed a data driven normalization algorithm (NORMA-Gene). An analysis of the performance of NORMA-Gene compared to reference gene normalization on artificially generated data-sets showed that the NORMA-Gene normalization yielded more precise results under a large range of parameters tested. Furthermore, when tested on three very different real qPCR data-sets NORMA-Gene was shown to be best at reducing variance due to experimental bias in all three data-sets compared to normalization based on the use of reference gene(s). CONCLUSIONS: Here we present the NORMA-Gene algorithm that is applicable to all biological and biomedical qPCR studies, especially those that are based on a limited number of assayed genes. The method is based on a data-driven normalization and is useful for as little as five target genes comprising the data-set. NORMA-Gene does not require the identification and validation of reference genes allowing researchers to focus their efforts on studying target genes of biological relevance. PMID- 21693018 TI - Tiludronate treatment improves structural changes and symptoms of osteoarthritis in the canine anterior cruciate ligament model. AB - INTRODUCTION: The aim of this prospective, randomized, controlled, double-blind study was to evaluate the effects of tiludronate (TLN), a bisphosphonate, on structural, biochemical and molecular changes and function in an experimental dog model of osteoarthritis (OA). METHODS: Baseline values were established the week preceding surgical transection of the right cranial/anterior cruciate ligament, with eight dogs serving as OA placebo controls and eight others receiving four TLN injections (2 mg/kg subcutaneously) at two-week intervals starting the day of surgery for eight weeks. At baseline, Week 4 and Week 8, the functional outcome was evaluated using kinetic gait analysis, telemetered locomotor actimetry and video-automated behaviour capture. Pain impairment was assessed using a composite numerical rating scale (NRS), a visual analog scale, and electrodermal activity (EDA). At necropsy (Week 8), macroscopic and histomorphological analyses of synovium, cartilage and subchondral bone of the femoral condyles and tibial plateaus were assessed. Immunohistochemistry of cartilage (matrix metalloproteinase (MMP)-1, MMP-13, and a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS5)) and subchondral bone (cathepsin K) was performed. Synovial fluid was analyzed for inflammatory (PGE(2) and nitrite/nitrate levels) biomarkers. Statistical analyses (mixed and generalized linear models) were performed with an alpha-threshold of 0.05. RESULTS: A better functional outcome was observed in TLN dogs than OA placebo controls. Hence, TLN dogs had lower gait disability (P = 0.04 at Week 8) and NRS score (P = 0.03, group effect), and demonstrated behaviours of painless condition with the video capture (P < 0.04). Dogs treated with TLN demonstrated a trend toward improved actimetry and less pain according to EDA. Macroscopically, both groups had similar level of morphometric lesions, TLN-treated dogs having less joint effusion (P = 0.01), reduced synovial fluid levels of PGE(2) (P = 0.02), nitrites/nitrates (P = 0.01), lower synovitis score (P < 0.01) and a greater subchondral bone surface (P < 0.01). Immunohistochemical staining revealed lower levels in TLN-treated dogs of MMP-13 (P = 0.02), ADAMTS5 (P = 0.02) in cartilage and cathepsin K (P = 0.02) in subchondral bone. CONCLUSION: Tiludronate treatment demonstrated a positive effect on gait disability and joint symptoms. This is likely related to the positive influence of the treatment at improving some OA structural changes and reducing the synthesis of catabolic and inflammatory mediators. PMID- 21693019 TI - Effectiveness of treatment with pegylated interferon and ribavirin in an unselected population of patients with chronic hepatitis C: a Danish nationwide cohort study. AB - BACKGROUND: The effect of peginterferon and ribavirin treatment on chronic hepatitis C virus (HCV) infection has been established in several controlled clinical studies. However, the effectiveness of treatment and predictors of treatment success in routine clinical practice remains to be established. Our aim was to estimate the effectiveness of peginterferon and ribavirin treatment in unselected HCV patients handled in routine clinical practice. The endpoint was sustained virological response (SVR), determined by the absence of HCV RNA 24 weeks after the end of treatment. METHODS: We determined the proportion of SVR in a nationwide, population-based cohort of 432 patients with chronic HCV infection who were starting treatment, and analyzed the impact of known covariates on SVR by using a logistic regression analysis. RESULTS: The majority of treated patients had genotype 1 (133 patients) and genotype 2/3 (285 patients) infections, with 44% and 72%, respectively, obtaining SVR. Other than genotype, the predictors of SVR were age<=45 years at the start of treatment, completion of unmodified treatment, the absence of cirrhosis and non-European origin. CONCLUSIONS: The effectiveness of peginterferon and ribavirin treatment for chronic hepatitis C in a routine clinical practice is comparable to that observed in controlled clinical trials, with a higher SVR rate in genotype 2 and 3 patients compared to genotype 1 patients. Our data further indicate that age at start of treatment is a strong predictor of SVR irrespective of HCV genotype, with patients 45 years or younger having a higher SVR rate. PMID- 21693020 TI - A simple clinical model for planning transfusion quantities in heart surgery. AB - BACKGROUND: Patients undergoing heart surgery continue to be the largest demand on blood transfusions. The need for transfusion is based on the risk of complications due to poor cell oxygenation, however large transfusions are associated with increased morbidity and risk of mortality in heart surgery patients. The aim of this study was to identify preoperative and intraoperative risk factors for transfusion and create a reliable model for planning transfusion quantities in heart surgery procedures. METHODS: We performed an observational study on 3315 consecutive patients who underwent cardiac surgery between January 2000 and December 2007. To estimate the number of packs of red blood cells (PRBC) transfused during heart surgery, we developed a multivariate regression model with discrete coefficients by selecting dummy variables as regressors in a stepwise manner. Model performance was assessed statistically by splitting cases into training and testing sets of the same size, and clinically by investigating the clinical course details of about one quarter of the patients in whom the difference between model estimates and actual number of PRBC transfused was higher than the root mean squared error. RESULTS: Ten preoperative and intraoperative dichotomous variables were entered in the model. Approximating the regression coefficients to the nearest half unit, each dummy regressor equal to one gave a number of half PRBC. The model assigned 4 units for kidney failure requiring preoperative dialysis, 2.5 units for cardiogenic shock, 2 units for minimum hematocrit at cardiopulmonary bypass less than or equal to 20%, 1.5 units for emergency operation, 1 unit for preoperative hematocrit less than or equal to 40%, cardiopulmonary bypass time greater than 130 minutes and type of surgery different from isolated artery bypass grafting, and 0.5 units for urgent operation, age over 70 years and systemic arterial hypertension. CONCLUSIONS: The regression model proved reliable for quantitative planning of number of PRBC in patients undergoing heart surgery. Besides enabling more rational resource allocation of costly blood-conservation strategies and blood bank resources, the results indicated a strong association between some essential postoperative variables and differences between the model estimate and the actual number of packs transfused. PMID- 21693021 TI - Determinants of antigenicity and specificity in immune response for protein sequences. AB - BACKGROUND: Target specific antibodies are pivotal for the design of vaccines, immunodiagnostic tests, studies on proteomics for cancer biomarker discovery, identification of protein-DNA and other interactions, and small and large biochemical assays. Therefore, it is important to understand the properties of protein sequences that are important for antigenicity and to identify small peptide epitopes and large regions in the linear sequence of the proteins whose utilization result in specific antibodies. RESULTS: Our analysis using protein properties suggested that sequence composition combined with evolutionary information and predicted secondary structure, as well as solvent accessibility is sufficient to predict successful peptide epitopes. The antigenicity and the specificity in immune response were also found to depend on the epitope length. We trained the B-Cell Epitope Oracle (BEOracle), a support vector machine (SVM) classifier, for the identification of continuous B-Cell epitopes with these protein properties as learning features. The BEOracle achieved an F1-measure of 81.37% on a large validation set. The BEOracle classifier outperformed the classical methods based on propensity and sophisticated methods like BCPred and Bepipred for B-Cell epitope prediction. The BEOracle classifier also identified peptides for the ChIP-grade antibodies from the modENCODE/ENCODE projects with 96.88% accuracy. High BEOracle score for peptides showed some correlation with the antibody intensity on Immunofluorescence studies done on fly embryos. Finally, a second SVM classifier, the B-Cell Region Oracle (BROracle) was trained with the BEOracle scores as features to predict the performance of antibodies generated with large protein regions with high accuracy. The BROracle classifier achieved accuracies of 75.26-63.88% on a validation set with immunofluorescence, immunohistochemistry, protein arrays and western blot results from Protein Atlas database. CONCLUSIONS: Together our results suggest that antigenicity is a local property of the protein sequences and that protein sequence properties of composition, secondary structure, solvent accessibility and evolutionary conservation are the determinants of antigenicity and specificity in immune response. Moreover, specificity in immune response could also be accurately predicted for large protein regions without the knowledge of the protein tertiary structure or the presence of discontinuous epitopes. The dataset prepared in this work and the classifier models are available for download at https://sites.google.com/site/oracleclassifiers/. PMID- 21693022 TI - A local glucose-and oxygen concentration-based insulin secretion model for pancreatic islets. AB - BACKGROUND: Because insulin is the main regulator of glucose homeostasis, quantitative models describing the dynamics of glucose-induced insulin secretion are of obvious interest. Here, a computational model is introduced that focuses not on organism-level concentrations, but on the quantitative modeling of local, cellular-level glucose-insulin dynamics by incorporating the detailed spatial distribution of the concentrations of interest within isolated avascular pancreatic islets. METHODS: All nutrient consumption and hormone release rates were assumed to follow Hill-type sigmoid dependences on local concentrations. Insulin secretion rates depend on both the glucose concentration and its time gradient, resulting in second-and first-phase responses, respectively. Since hypoxia may also be an important limiting factor in avascular islets, oxygen and cell viability considerations were also built in by incorporating and extending our previous islet cell oxygen consumption model. A finite element method (FEM) framework is used to combine reactive rates with mass transport by convection and diffusion as well as fluid-mechanics. RESULTS: The model was calibrated using experimental results from dynamic glucose-stimulated insulin release (GSIR) perifusion studies with isolated islets. Further optimization is still needed, but calculated insulin responses to stepwise increments in the incoming glucose concentration are in good agreement with existing experimental insulin release data characterizing glucose and oxygen dependence. The model makes possible the detailed description of the intraislet spatial distributions of insulin, glucose, and oxygen levels. In agreement with recent observations, modeling also suggests that smaller islets perform better when transplanted and/or encapsulated. CONCLUSIONS: An insulin secretion model was implemented by coupling local consumption and release rates to calculations of the spatial distributions of all species of interest. The resulting glucose-insulin control system fits in the general framework of a sigmoid proportional-integral-derivative controller, a generalized PID controller, more suitable for biological systems, which are always nonlinear due to the maximum response being limited. Because of the general framework of the implementation, simulations can be carried out for arbitrary geometries including cultured, perifused, transplanted, and encapsulated islets. PMID- 21693023 TI - The association between microvascular and macrovascular endothelial function in patients with rheumatoid arthritis: a cross-sectional study. AB - INTRODUCTION: Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). One of the earliest manifestations of CVD is endothelial dysfunction (ED). ED can occur in both the microcirculation and the macrocirculation, and these manifestations might be relatively independent of each other. Little is known about the association between endothelial function in the microcirculation and the macrocirculation in RA. The objectives of the present study were to examine the relationship between microvascular and macrovascular endothelial function in patients with RA. METHODS: Ninety-nine RA patients (72 females, mean age (+/- SD) 56 +/- 12 years), underwent assessments of endothelial-dependent (acetylcholine) and endothelial-independent (sodium nitroprusside) microvascular vasodilatory function (laser Doppler imaging with iontophoresis), as well as endothelial-dependent (flow-mediated dilation) and endothelial-independent (glyceryl trinitrate-mediated dilation) macrovascular vasodilatory function. Vasodilatory function was calculated as the percentage increase after each stimulus was applied relative to baseline values. RESULTS: Pearson correlations showed that microvascular endothelial-dependent function was not associated with macrovascular endothelial-dependent function (r (90 patients) = 0.10, P = 0.34). Similarly, microvascular endothelial-independent function was not related to macrovascular endothelial-independent function (r (89 patients) = 0.00, P = 0.99). CONCLUSIONS: Microvascular and macrovascular endothelial function were independent of each other in patients with RA, suggesting differential regulation of endothelial function in these two vascular beds. Assessments of both vascular beds may provide more meaningful clinical information on vascular risk in RA, but this hypothesis needs to be confirmed in long-term prospective studies. PMID- 21693024 TI - Mapping quantitative trait loci (QTL) in sheep. IV. Analysis of lactation persistency and extended lactation traits in sheep. AB - BACKGROUND: In sheep dairy production, total lactation performance, and length of lactation of lactation are of economic significance. A more persistent lactation has been associated with improved udder health. An extended lactation is defined by a longer period of milkability. This study is the first investigation to examine the presence of quantitative trait loci (QTL) for extended lactation and lactation persistency in sheep. METHODS: An (Awassi * Merino) * Merino single sire backcross family with 172 ewes was used to map QTL for lactation persistency and extended lactation traits on a framework map of 189 loci across all autosomes. The Wood model was fitted to data from multiple lactations to estimate parameters of ovine lactation curves, and these estimates were used to derive measures of lactation persistency and extended lactation traits of milk, protein, fat, lactose, useful yield, and somatic cell score. These derived traits were subjected to QTL analyses using maximum likelihood estimation and regression analysis. RESULTS: Overall, one highly significant (LOD > 3.0), four significant (2.0 < LOD < 3.0) and five suggestive (1.7 < LOD < 2.0) QTL were detected across all traits in common by both mapping methods. One additional suggestive QTL was identified using maximum likelihood estimation, and four suggestive (0.01 < P < 0.05) and two significant (P < 0.01) QTL using the regression approach only. All detected QTL had effect sizes in the range of 0.48 to 0.64 SD, corresponding to QTL heritabilities of 3.1 to 8.9%. The comparison of the detected QTL with results in cattle showed conserved linkage regions. Most of the QTL identified for lactation persistency and extended lactation did not coincide. This suggests that persistency and extended lactation for the same as well as different milk yield and component traits are not controlled by the same genes. CONCLUSION: This study identified ten novel QTL for lactation persistency and extended lactation in sheep, but results suggest that lactation persistency and extended lactation do not have a major gene in common. These results provide a basis for further validation in extended families and other breeds as well as targeting regions for genome-wide association mapping using high-density SNP arrays. PMID- 21693025 TI - Individualised controlled ovarian stimulation (iCOS): maximising success rates for assisted reproductive technology patients. AB - BACKGROUND: In the last two decades, pregnancy rates for patients undergoing in vitro fertilisation (IVF) have significantly increased. Some of the major advances responsible for this improvement were the introduction of controlled ovarian stimulation (COS) for the induction of multiple follicle development, and the utilisation of mid-luteal gonadotropin-releasing hormone agonists to achieve pituitary down-regulation and full control of the cycle. As a result, a combination of a gonadotropin-releasing hormone agonist with high doses (150-450 IU/day) of recombinant follicle-stimulating hormone has become the current standard approach for ovarian stimulation. However, given the heterogeneity of patients embarking on IVF, and the fact that many different drugs can be used alone or in different combinations (generating multiple potential protocols of controlled ovarian stimulation), we consider the need to identify special populations of patients and adapt treatment protocols accordingly, and to implement a more individualised approach to COS. DISCUSSION: Studies on mild, minimal and natural IVF cycles have yielded promising results, but have focused on fresh embryo transfers and included relatively young patient populations who generally have the potential for more favourable outcomes. The efficacy of these protocols in patients with a poorer prognosis remains to be tested. When comparing protocols for COS, it is important to think beyond current primary endpoints, and to consider the ideal quality and quantity of oocytes and embryos being produced per stimulated patient, in order to achieve a pregnancy. We should also focus on the cumulative pregnancy rate, which is based on outcomes from fresh and frozen embryos from the same cycle of stimulation. Individualised COS (iCOS) determined by the use of biomarkers to test ovarian reserve has the potential to optimise outcomes and reduce safety issues by adapting treatment protocols according to each patient's specific characteristics. As new objective endocrine, paracrine, functional and/or genetic biomarkers of response are developed, iCOS can be refined further still, and this will be a significant step towards a personalised approach for IVF. CONCLUSIONS: A variety of COS protocols have been adopted, with mixed success, but no single approach is appropriate for all patients within a given population. We suggest that treatment protocols should be adapted for individual patients through iCOS; this approach promises to be one of the first steps towards implementing personalised medicine in reproductive science. PMID- 21693026 TI - Platelet factor-4 and its p17-70 peptide inhibit myeloma proliferation and angiogenesis in vivo. AB - BACKGROUND: Angiogenesis plays an important role in the development of multiple myeloma (MM). The interaction between MM cells and the bone marrow microenvironment stimulates the proliferation and migration of endothelial progenitor cells (EPCs). Vascular endothelial growth factor (VEGF) contributes to the formation of new blood vessels by actively recruiting circulating EPCs. The production of proangiogenic and antiangiogenic factors is also dysregulated in MM. Platelet factor 4 (PF4) is a potent angiostatic cytokine that inhibits angiogenesis and tumor growth in several animal models. METHODS: In this study, we stably transfected human myeloma cell lines with the PF4 gene or the sequence encoding its more potent p17-70 peptide and investigated the effects of PF4 and p17-70 on angiogenesis and tumor growth in vitro and in a SCID-rab myeloma model. RESULTS: PF4 and p17-70 significantly attenuated VEGF production, both in vitro and in vivo. In a migration study using a Transwell system, PF4 or p17-70 markedly suppressed the migration of co-cultured human endothelial progenitor cells. PF4 or p17-70 also caused a significant reduction in microvessel densities in myeloma xenografts and markedly reduced the tumor volume in the SCID mice. Kaplan-Meier analysis demonstrated that PF4 and p17-70 significantly extended the overall survival of SCID mice bearing human myeloma xenografts. CONCLUSIONS: Our findings indicate that PF4 or p17-70 could be valuable in combating multiple myeloma by disrupting tumor angiogenesis. PMID- 21693027 TI - Prevention of: self harm in British South Asian women: study protocol of an exploratory RCT of culturally adapted manual assisted Problem Solving Training (C MAP). AB - BACKGROUND: Suicide is a major public health problem worldwide. In the UK suicide is the second most common cause of death in people aged 15-24 years. Self harm is one of the commonest reasons for medical admission in the UK. In the year following a suicide attempt the risk of a repeat attempt or death by suicide may be up to 100 times greater than in people who have never attempted suicide. Research evidence shows increased risk of suicide and attempted suicide among British South Asian women. There are concerns about the current service provision and its appropriateness for this community due to the low numbers that get involved with the services. Both problem solving and interpersonal forms of psychotherapy are beneficial in the treatment of patients who self harm and could potentially be helpful in this ethnic group.The paper describes the trial protocol of adapting and evaluating a culturally appropriate psychological treatment for the adult British South Asian women who self harm. METHODS: We plan to test a culturally adapted Problem Solving Therapy (C- MAP) in British South Asian women who self harm. Eight sessions of problem solving each lasting approximately 50 minutes will be delivered over 3 months. The intervention will be assessed using a prospective rater blind randomized controlled design comparing with treatment as usual (TAU). Outcome assessments will be carried out at 3 and 6 months. A sub group of the participants will be invited for qualitative interviews. DISCUSSION: This study will test the feasibility and acceptability of the C- MAP in British South Asian women. We will be informed on whether a culturally adapted brief psychological intervention compared with treatment as usual for self-harm results in decreased hopelessness and suicidal ideation. This will also enable us to collect necessary information on recruitment, effect size, the optimal delivery method and acceptability of the intervention in preparation for a definitive RCT using repetition of self harm and cost effectiveness as primary outcome measures. TRIAL REGISTRATION: Current Controlled Trials 08/H1013/6. PMID- 21693028 TI - Hormonal, follicular and endometrial dynamics in letrozole-treated versus natural cycles in patients undergoing controlled ovarian stimulation. AB - The objective of this study was to compare letrozole-stimulated cycles to natural cycles in 208 patients undergoing intrauterine insemination (IUI) between July of 2004 and January of 2007. Group I (n = 47) received cycle monitoring only (natural group), Group II (n = 125) received letrozole 2.5 mg/day on cycle days three to seven, and Group III (n = 36) received letrozole 5 mg/day on cycle days three to seven. There were no differences between the groups in endometrial thickness or P4 on the day of hCG. Estradiol levels had higher variation in the second half of the follicular phase in both letrozole-treated groups compared to the control group. Estradiol per preovulatory follicle was similar in both letrozole cycles to that observed in the natural cycles. LH was lower on the day of hCG administration in the letrozole 2.5 mg/day group vs. the natural group. In summary, letrozole results in some minor changes in follicular, hormonal and endometrial dynamics compared to natural cycles. Increased folliculogenesis and pregnancy rates were observed in the letrozole-treated groups compared to the natural group. These findings need to be confirmed in larger, prospective studies. PMID- 21693029 TI - One stop crisis centres: A policy analysis of the Malaysian response to intimate partner violence. AB - BACKGROUND: This article aims to investigate the processes, actors and other influencing factors behind the development and the national scale-up of the One Stop Crisis Centre (OSCC) policy and the subsequent health model for violence response. METHODS: Methods used included policy analysis of legal, policy and regulatory framework documents, and in-depth interviews with key informants from governmental and non-governmental organisations in two States of Malaysia. RESULTS: The findings show that women's NGOs and health professionals were instrumental in the formulation and scaling-up of the OSCC policy. However, the subsequent breakdown of the NGO-health coalition negatively impacted on the long term implementation of the policy, which lacked financial resources and clear policy guidance from the Ministry of Health. CONCLUSION: The findings confirm that a clearly-defined partnership between NGOs and health staff can be very powerful for influencing the legal and policy environment in which health care services for intimate partner violence are developed. It is critical to gain high level support from the Ministry of Health in order to institutionalise the violence-response across the entire health care system. Without clear operational details and resources policy implementation cannot be fully ensured and taken to scale. PMID- 21693030 TI - Extended letrozole regimen versus clomiphene citrate for superovulation in patients with unexplained infertility undergoing intrauterine insemination: a randomized controlled trial. AB - BACKGROUND: The aim of this randomized controlled trial was to compare the efficacy of extended letrozole regimen with clomiphene citrate in women with unexplained infertility undergoing superovulation and intrauterine insemination (IUI). METHODS: Two hundred and fourteen patients with unexplained infertility were randomized into two equal groups using computer generated list and were treated by either letrozole 2.5 mg/day from cycle day 1 to 9 (extended letrozole group, 211 cycles) or clomiphene citrate 100 mg/day from cycle day 3 to 7 (clomiphene citrate group,210 cycles). Intrauterine insemination was performed 36 to 40 hours after HCG administration. RESULTS: Both groups were comparable with regard to number of mature follicles (2.24 +/- 0.80 Vs 2.13 +/- 0.76) and the day of HCG administration. Serum estradiol was significantly greater in clomiphene citrate group (356 +/- 151 Vs 822 +/- 302 pg/ml, P = < 0.001) and the endometrial thickness was significantly greater in extended letrozole group (9.10 +/- 1.84 Vs 8.18 +/- 1.93 mm, P = < 0.001).The pregnancy rate per cycle and cumulative pregnancy rate were significantly greater in extended letrozole group (18.96% Vs 11.43% and 37.73% Vs 22.86%, respectively). CONCLUSION: The extended letrozole regimen had a superior efficacy as compared with clomiphene citrate in patients of unexplained infertility undergoing superovulation and IUI. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01232075. PMID- 21693032 TI - Changes in multi-segment foot biomechanics with a heat-mouldable semi-custom foot orthotic device. AB - BACKGROUND: Semi-custom foot orthoses (SCO) are thought to be a cost-effective alternative to custom-made devices. However, previous biomechanical research involving either custom or SCO has only focused on rearfoot biomechanics. The purpose of this study was therefore to determine changes in multi-segment foot biomechanics during shod walking with and without an SCO. We chose to investigate an SCO device that incorporates a heat-moulding process, to further understand if the moulding process would significantly alter rearfoot, midfoot, or shank kinematics as compared to a no-orthotic condition. We hypothesized the SCO, whether moulded or non-moulded, would reduce peak rearfoot eversion, tibial internal rotation, arch deformation, and plantar fascia strain as compared to the no-orthoses condition. METHODS: Twenty participants had retroreflective markers placed on the right limb to represent forefoot, midfoot, rearfoot and shank segments. 3D kinematics were recorded using an 8-camera motion capture system while participants walked on a treadmill. RESULTS: Plantar fascia strain was reduced by 34% when participants walked in either the moulded or non-moulded SCO condition compared to no-orthoses. However, there were no significant differences in peak rearfoot eversion, tibial internal rotation, or medial longitudinal arch angles between any conditions. CONCLUSIONS: A semi-custom moulded orthotic does not control rearfoot, shank, or arch deformation but does, however, reduce plantar fascia strain compared to walking without an orthoses. Heat-moulding the orthotic device does not have a measurable effect on any biomechanical variables compared to the non-moulded condition. These data may, in part, help explain the clinical efficacy of orthotic devices. PMID- 21693031 TI - Adaptation of a visualized loop-mediated isothermal amplification technique for field detection of Plasmodium vivax infection. AB - BACKGROUND: Loop-mediated isothermal amplification (LAMP) is a high performance method for detecting DNA and holds promise for use in the molecular detection of infectious pathogens, including Plasmodium spp. However, in most malaria-endemic areas, which are often resource-limited, current LAMP methods are not feasible for diagnosis due to difficulties in accurately interpreting results with problems of sensitive visualization of amplified products, and the risk of contamination resulting from the high quantity of amplified DNA produced. In this study, we establish a novel visualized LAMP method in a closed-tube system, and validate it for the diagnosis of malaria under simulated field conditions. METHODS: A visualized LAMP method was established by the addition of a microcrystalline wax-dye capsule containing the highly sensitive DNA fluorescence dye SYBR Green I to a normal LAMP reaction prior to the initiation of the reaction. A total of 89 blood samples were collected on filter paper and processed using a simple boiling method for DNA extraction, and then tested by the visualized LAMP method for Plasmodium vivax infection. RESULTS: The wax capsule remained intact during isothermal amplification, and released the DNA dye to the reaction mixture only when the temperature was raised to the melting point following amplification. Soon after cooling down, the solidified wax sealed the reaction mix at the bottom of the tube, thus minimizing the risk of aerosol contamination. Compared to microscopy, the sensitivity and specificity of LAMP were 98.3% (95% confidence interval (CI): 91.1-99.7%) and 100% (95% CI: 88.3 100%), and were in close agreement with a nested polymerase chain reaction method. CONCLUSIONS: This novel, cheap and quick visualized LAMP method is feasible for malaria diagnosis in resource-limited field settings. PMID- 21693033 TI - Aromatase inhibitors in stimulated IVF cycles. AB - Aromatase inhibitors have been introduced as a new treatment modality that could challenge clomiphene citrate as an ovulation induction regiment in patients with PCOS. Although several randomized trials have been conducted regarding their use as ovulation induction agents, only few trials are available regarding their efficacy in IVF stimulated cycles. Current available evidence support that letrozole may have a promising role in stimulated IVF cycles, either when administered during the follicular phase for ovarian stimulation. Especially for women with poor ovarian response, letrozole appears to have the potential to increase clinical pregnancy rates when combined with gonadotropins, whereas at the same time reduces the total gonadotropin dose required for ovarian stimulation. However, given that in all of the trials letrozole has been administered in GnRH antagonist cycles, it is intriguing to test in the future how it may perform when used in GnRH agonist cycles. Finally administration of letrozole during luteal phase in IVF cycles offers another treatment modality for patients at high risk for OHSS taking into account that it drastically reduces estradiol levels. PMID- 21693034 TI - Letrozole or clomiphene citrate as first line for anovulatory infertility: a debate. AB - Clomiphene citrate has been traditionally used as the drug of choice in treating women with anovulatory infertility. In the last decade letrozole, an aromatase inhibitor has emerged as alternative ovulation induction agent. Literature confirms that letrozole has a definitive role in anovulatory women who have not responded to the clomiphene therapy. However its role as an alternative to clomiphene as first line therapy continues to be debated. Although it is probable that the overall benefits of letrozole surpass clomiphene citrate, currently available data does not confirm this view. There is need for large well-designed trials. PMID- 21693035 TI - Persistence of accuracy of genomic estimated breeding values over generations in layer chickens. AB - BACKGROUND: The predictive ability of genomic estimated breeding values (GEBV) originates both from associations between high-density markers and QTL (Quantitative Trait Loci) and from pedigree information. Thus, GEBV are expected to provide more persistent accuracy over successive generations than breeding values estimated using pedigree-based methods. The objective of this study was to evaluate the accuracy of GEBV in a closed population of layer chickens and to quantify their persistence over five successive generations using marker or pedigree information. METHODS: The training data consisted of 16 traits and 777 genotyped animals from two generations of a brown-egg layer breeding line, 295 of which had individual phenotype records, while others had phenotypes on 2,738 non genotyped relatives, or similar data accumulated over up to five generations. Validation data included phenotyped and genotyped birds from five subsequent generations (on average 306 birds/generation). Birds were genotyped for 23,356 segregating SNP. Animal models using genomic or pedigree relationship matrices and Bayesian model averaging methods were used for training analyses. Accuracy was evaluated as the correlation between EBV and phenotype in validation divided by the square root of trait heritability. RESULTS: Pedigree relationships in outbred populations are reduced by 50% at each meiosis, therefore accuracy is expected to decrease by the square root of 0.5 every generation, as observed for pedigree-based EBV (Estimated Breeding Values). In contrast the GEBV accuracy was more persistent, although the drop in accuracy was substantial in the first generation. Traits that were considered to be influenced by fewer QTL and to have a higher heritability maintained a higher GEBV accuracy over generations. In conclusion, GEBV capture information beyond pedigree relationships, but retraining every generation is recommended for genomic selection in closed breeding populations. PMID- 21693036 TI - The emerging use of aromatase inhibitors for endometriosis treatment. AB - Endometriosis is defined as the growth of endometrial tissue outside of the uterine cavity. The disease occurs primarily in women of reproductive age but recurrent endometriosis is also detected in post-menopausal women. Regardless of age, endometriosis is associated with pain and reduces the quality of life for millions of women world-wide. Conventional therapies focus on reducing systemic levels of estrogen which results in cessation of endometriotic implant growth and pain symptoms associated with the disease. However, these treatments are not effective in all women and are not without side effects. Based upon the discovery that endometriotic tissue over-expresses aromatase, an enzyme critical for estrogen production, emphasis has been placed upon the use of aromatase inhibitors for the treatment of endometriosis and its associated symptoms. This article will review the rationale behind the use of aromatase inhibitors in treating endometriosis and summarize those studies which have evaluated the use of aromatase inhibitors in the treatment of endometriosis and its associated symptoms. PMID- 21693037 TI - Letrozole and norethisterone acetate versus letrozole and triptorelin in the treatment of endometriosis related pain symptoms: a randomized controlled trial. AB - BACKGROUND: When aromatase inhibitors are used to treat premenopausal women with endometriosis, additional drugs should be used to effectively down-regulate gonadal estrogen biosynthesis. This randomized prospective open-label study compared the efficacy in treating pain symptoms and the tolerability of letrozole combined with either norethisterone acetate or triptorelin. METHODS: Women with pain symptoms caused by rectovaginal endometriosis were treated with letrozole (2.5 mg/day) and were randomized to also receive either oral norethisterone acetate (2.5 mg/day; group N) or intramuscular injection of triptorelin (11.25 mg every 3 months; group T). The scheduled length of treatment was 6 months. A visual analogue scale and a multidimensional categorical rating scale were used to assess the severity of pain symptoms. The volume of the endometriotic nodules was estimated by ultrasonography using virtual organ computer-aided analysis. Adverse effects of treatment were recorded. RESULTS: A total of 35 women were randomized between the two treatment protocols. Significantly more patients in group N rated their treatment as satisfactory or very satisfactory (64.7%) as compared to group T (22.2%; p=0.028). The intensity of both non-menstrual pelvic pain and deep dyspareunia significantly decreased during treatment in both study groups, though no statistically meaningful difference between the two groups was apparent. Reduction in the volume of endometriotic nodules was significantly greater in group T than in group N. Interruption of treatment due to adverse effects significantly differed between the groups, with 8 women in group T (44.4%) and 1 woman in group N (5.9%) interrupting treatment (p=0.018). Similarly, 14 women included in group T (77.8%) and 6 women included in group N (35.3%) experienced adverse effects of treatment (p=0.018). During treatment, mineral bone density significantly decreased in group T but not in group N. CONCLUSIONS: Aromatase inhibitors reduce the intensity of endometriosis-related pain symptoms. Combining letrozole with oral norethisterone acetate was associated with a lower incidence of adverse effects and a lower discontinuation rate than combining letrozole with triptorelin. PMID- 21693038 TI - Use of aromatase inhibitors to treat endometriosis-related pain symptoms: a systematic review. AB - This systematic review aims to assess the efficacy of aromatase inhibitors (AIs) in treating pain symptoms caused by endometriosis. A comprehensive literature search was conducted to identify all the published studies evaluating the efficacy of type II nonsteroidal aromatase inhibitors (anastrozole and letrozole) in treating endometriosis-related pain symptoms. The MEDLINE, EMBASE, PubMed, and SCOPUS databases and the Cochrane System Reviews were searched up to October 2010. This review comprises of the results of 10 publications fitting the inclusion criteria; these studies included a total of 251 women. Five studies were prospective non-comparative, four were randomized controlled trials (RCTs) and one was a prospective patient preference trial. Seven studies examined the efficacy of AIs in improving endometriosis-related pain symptoms, whilst three RCTs investigated the use of AIs as post-operative therapy in preventing the recurrence of pain symptoms after surgery for endometriosis. All the observational studies demonstrated that AIs combined with either progestogens or oral contraceptive pill reduce the severity of pain symptoms and improve quality of life. One patient preference study demonstrated that letrozole combined with norethisterone acetate is more effective in reducing pain and deep dyspareunia than norethisterone acetate alone. However, letrozole causes a higher incidence of adverse effects and does not improve patients' satisfaction or influence recurrence of symptoms after discontinuation of treatment. A RCT showed that combining letrozole with norethisterone acetate causes a lower incidence of adverse effects and lower discontinuation rate than combining letrozole with triptorelin. Two RCTs demonstrated that, after surgical treatment of endometriosis, the administration of AIs combined with gonadotropin releasing hormone analogue for 6 months reduces the risk of endometriosis recurrence when compared with gonadotropin releasing hormone analogue alone. In conclusion, AIs effectively reduce the severity of endometriosis-related pain symptoms. Since endometriosis is a chronic disease, future investigations should clarify whether the long-term administration of AIs is superior to currently available endocrine therapies in terms of improvement of pain, adverse effects and patient satisfaction. PMID- 21693039 TI - Aromatase inhibitors in post-menopausal endometriosis. AB - Postmenopausal endometriosis is a rare clinical condition. The diagnosis and treatment of an endometriotic lesion in postmenopausal women is complicated. First line treatment choice should be surgical, given that there is a potential risk of malignancy. Medical treatment may be considered as second line or as an alternate first line treatment whenever surgery is contradicted and aims to alter the hormonal pathway leading to endometriosis progress. Different hormonal regimens have been administered to these patients, with conflicting however results. Aromatase inhibitors (AIs) represent one of the most recently used drugs for postmenopausal endometriosis. Clinical data for the use of (AIs) in postmenopausal patients is scarce. Up to date only 5 case reports are available regarding the use of these agents in postmenopausal women. Although definite conclusions may be premature, AIs appear to considerably improve patients' symptoms and reduce endometriotic lesions size. Nonetheless the subsequent induced reduction in estrogen production, leads to certain short-term and long term adverse effects. Despite the limited available data, AIs appear to represent a new promising method which may improve symptoms and treat these patients, either as first line treatment, when surgery is contraindicated or as a second line for recurrences following surgical treatment. However, careful monitoring of patients' risk profile and further research regarding long-term effects and side effects of these agents is essential prior implementing them in everyday clinical practice. PMID- 21693040 TI - Staphylococcus aureus Biofilm and Planktonic cultures differentially impact gene expression, mapk phosphorylation, and cytokine production in human keratinocytes. AB - BACKGROUND: Many chronic diseases, such as non-healing wounds are characterized by prolonged inflammation and respond poorly to conventional treatment. Bacterial biofilms are a major impediment to wound healing. Persistent infection of the skin allows the formation of complex bacterial communities termed biofilm. Bacteria living in biofilms are phenotypically distinct from their planktonic counterparts and are orders of magnitude more resistant to antibiotics, host immune response, and environmental stress. Staphylococcus aureus is prevalent in cutaneous infections such as chronic wounds and is an important human pathogen. RESULTS: The impact of S. aureus soluble products in biofilm-conditioned medium (BCM) or in planktonic-conditioned medium (PCM) on human keratinocytes was investigated. Proteomic analysis of BCM and PCM revealed differential protein compositions with PCM containing several enzymes involved in glycolysis. Global gene expression of keratinocytes exposed to biofilm and planktonic S. aureus was analyzed after four hours of exposure. Gene ontology terms associated with responses to bacteria, inflammation, apoptosis, chemotaxis, and signal transduction were enriched in BCM treated keratinocytes. Several transcripts encoding cytokines were also upregulated by BCM after four hours. ELISA analysis of cytokines confirmed microarray results at four hours and revealed that after 24 hours of exposure, S. aureus biofilm induced sustained low level cytokine production compared to near exponential increases of cytokines in planktonic treated keratinocytes. The reduction in cytokines produced by keratinocytes exposed to biofilm was accompanied by suppressed phosphorylation of MAPKs. Chemical inhibition of MAPKs did not drastically reduce cytokine production in BCM-treated keratinocytes suggesting that the majority of cytokine production is mediated through MAPK-independent mechanisms. CONCLUSIONS: Collectively the results indicate that S. aureus biofilms induce a distinct inflammatory response compared to their planktonic counterparts. The differential gene expression and production of inflammatory cytokines by biofilm and planktonic cultures in keratinocytes could have implications for the formation and persistence of chronic wounds. The formation of a biofilm should be considered in any study investigating host response to bacteria. PMID- 21693041 TI - Potential utility of natural products as regulators of breast cancer-associated aromatase promoters. AB - Aromatase, the key enzyme in estrogen biosynthesis, converts androstenedione to estrone and testosterone to estradiol. The enzyme is expressed in various tissues such as ovary, placenta, bone, brain, skin, and adipose tissue. Aromatase enzyme is encoded by a single gene CYP 19A1 and its expression is controlled by tissue specific promoters. Aromatase mRNA is primarily transcribed from promoter I.4 in normal breast tissue and physiological levels of aromatase are found in breast adipose stromal fibroblasts. Under the conditions of breast cancer, as a result of the activation of a distinct set of aromatase promoters (I.3, II, and I.7) aromatase expression is enhanced leading to local overproduction of estrogen that promotes breast cancer. Aromatase is considered as a potential target for endocrine treatment of breast cancer but due to nonspecific reduction of aromatase activity in other tissues, aromatase inhibitors (AIs) are associated with undesirable side effects such as bone loss, and abnormal lipid metabolism. Inhibition of aromatase expression by inactivating breast tumor-specific aromatase promoters can selectively block estrogen production at the tumor site. Although several synthetic chemical compounds and nuclear receptor ligands are known to inhibit the activity of the tumor-specific aromatase promoters, further development of more specific and efficacious drugs without adverse effects is still warranted. Plants are rich in chemopreventive agents that have a great potential to be used in chemotherapy for hormone dependent breast cancer which could serve as a source for natural AIs. In this brief review, we summarize the studies on phytochemicals such as biochanin A, genistein, quercetin, isoliquiritigenin, resveratrol, and grape seed extracts related to their effect on the activation of breast cancer-associated aromatase promoters and discuss their aromatase inhibitory potential to be used as safer chemotherapeutic agents for specific hormone-dependent breast cancer. PMID- 21693042 TI - Prevalence of non-communicable diseases in Brazilian children: follow-up at school age of two Brazilian birth cohorts of the 1990's. AB - BACKGROUND: Few cohort studies have been conducted in low and middle-income countries to investigate non-communicable diseases among school-aged children. This article aims to describe the methodology of two birth cohorts, started in 1994 in Ribeirao Preto (RP), a more developed city, and in 1997/98 in Sao Luis (SL), a less developed town. METHODS: Prevalences of some non-communicable diseases during the first follow-up of these cohorts were estimated and compared. Data on singleton live births were obtained at birth (2858 in RP and 2443 in SL). The follow-up at school age was conducted in RP in 2004/05, when the children were 9-11 years old and in SL in 2005/06, when the children were 7-9 years old. Follow-up rates were 68.7% in RP (790 included) and 72.7% in SL (673 participants). The groups of low (<2500 g) and high (>= 4250 g) birthweight were oversampled and estimates were corrected by weighting. RESULTS: In the more developed city there was a higher percentage of non-nutritive sucking habits (69.1% vs 47.9%), lifetime bottle use (89.6% vs 68.3%), higher prevalence of primary headache in the last 15 days (27.9% vs 13.0%), higher positive skin tests for allergens (44.3% vs 25.3%) and higher prevalence of overweight (18.2% vs 3.6%), obesity (9.5% vs 1.8%) and hypertension (10.9% vs 4.6%). In the less developed city there was a larger percentage of children with below average cognitive function (28.9% vs 12.2%), mental health problems (47.4% vs 38.4%), depression (21.6% vs 6.0%) and underweight (5.8% vs 3.6%). There was no difference in the prevalence of bruxism, recurrent abdominal pain, asthma and bronchial hyperresponsiveness between cities. CONCLUSIONS: Some non-communicable diseases were highly prevalent, especially in the more developed city. Some high rates suggest that the burden of non-communicable diseases will be high in the future, especially mental health problems. PMID- 21693043 TI - Aromatase inhibitors and antiepileptic drugs: a computational systems biology analysis. AB - BACKGROUND: The present study compares antiepileptic drugs and aromatase (CYP19) inhibitors for chemical and structural similarity. Human aromatase is well known as an important pharmacological target in anti-breast cancer therapy, but recent research demonstrates its role in epileptic seizures, as well. The current antiepileptic treatment methods cause severe side effects that endanger patient health and often preclude continued use. As a result, less toxic and more tolerable antiepileptic drugs (AEDs) are needed, especially since every individual responds differently to given treatment options. METHODS: Through a pharmacophore search, this study shows that a model previously designed to search for new classes of aromatase inhibitors is able to identify antiepileptic drugs from the set of drugs approved by the Food and Drug Administration. Chemical and structural similarity analyses were performed using five potent AIs, and these studies returned a set of AEDs that the model identifies as hits. RESULTS: The pharmacophore model returned 73% (19 out of 26) of the drugs used specifically to treat epilepsy and approximately 82% (51 out of 62) of the compounds with anticonvulsant properties. Therefore, this study supports the possibility of identifying AEDs with a pharmacophore model that had originally been designed to identify new classes of aromatase inhibitors. Potential candidates for anticonvulsant therapy identified in this manner are also reported. Additionally, the chemical and structural similarity between antiepileptic compounds and aromatase inhibitors is proved using similarity analyses. CONCLUSIONS: This study demonstrates that a pharmacophore search using a model based on aromatase inhibition and the enzyme's structural features can be used to screen for new candidates for antiepileptic therapy. In fact, potent aromatase inhibitors and current antiepileptic compounds display significant - over 70% - chemical and structural similarity, and the similarity analyses performed propose a number of antiepileptic compounds with high potential for aromatase inhibition. PMID- 21693044 TI - Night-time splinting after fasciectomy or dermo-fasciectomy for Dupuytren's contracture: a pragmatic, multi-centre, randomised controlled trial. AB - BACKGROUND: Dupuytren's disease is a progressive fibroproliferative disorder which can result in fixed flexion contractures of digits and impaired hand function. Standard treatment involves surgical release or excision followed by post-operative hand therapy and splinting, however the evidence supporting night splinting is of low quality and equivocal. METHODS: A multi-centre, pragmatic, open, randomised controlled trial was conducted to evaluate the effect of night splinting on self-reported function, finger extension and satisfaction in patients undergoing fasciectomy or dermofasciectomy. 154 patients from 5 regional hospitals were randomised after surgery to receive hand therapy only (n = 77) or hand therapy with night-splinting (n = 77). Primary outcome was self-reported function using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. Secondary outcomes were finger range of motion and patient satisfaction. Primary analysis was by intention to treat. RESULTS: 148 (96%) patients completed follow-up at 12 months. No statistically significant differences were observed on the DASH questionnaire (0-100 scale: adjusted mean diff. 0.66, 95%CI - 2.79 to 4.11, p = 0.703), total extension deficit of operated digits (degrees: adjusted mean diff 5.11, 95%CI -2.33 to 12.55, p = 0.172) or patient satisfaction (0-10 numerical rating scale: adjusted mean diff -0.35, 95%CI -1.04 to 0.34, p = 0.315) at 1 year post surgery. Similarly, in a secondary per protocol analysis no statistically significant differences were observed between the groups in any of the outcomes. CONCLUSIONS: No differences were observed in self-reported upper limb disability or active range of motion between a group of patients who were all routinely splinted after surgery and a group of patients receiving hand therapy and only splinted if and when contractures occurred. Given the added expense of therapists' time, thermoplastic materials and the potential inconvenience to patients having to wear a device, the routine addition of night-time splinting for all patients after fasciectomy or dermofasciectomy is not recommended except where extension deficits reoccur. TRIAL REGISTRATION: The trial was registered as an International Standard Randomised Controlled Trial ISRCTN57079614. PMID- 21693045 TI - Effectiveness of anti-inflammatory treatment versus antibiotic therapy and placebo for patients with non-complicated acute bronchitis with purulent sputum. The BAAP Study protocol. AB - BACKGROUND: Acute bronchitis is one of the most prevalent respiratory infections in primary care, and in more than 90% of the cases antibiotics are prescribed, mainly when purulent expectoration is present. However, this process is usually viral in origin and the benefits of antibiotic treatment are marginal. On the other hand, in recent years bronchitis has been considered more as an inflammatory than an infectious process. Thus, the aim of this study is to evaluate the clinical effectiveness of a schedule of an oral anti-inflammatory compared with an antibiotic regimen and another group assigned to receive a placebo. METHODS AND DESIGN: A total of 420 patients from 15 to 70 years of age with no associated comorbidity, presenting respiratory tract infection of at least one week of evolution, with cough as the predominant symptom, the presence of purulent expectoration and at least one other symptom of the respiratory tract (dyspnoea, wheezing, chest discomfort or pain), with no alternative explanation such as pneumonia, will be included in a prospective, randomised and controlled, clinical trial with placebo. The patients will be randomised to receive one of three treatments: ibuprofen, amoxycillin and clavulanic acid or placebo for 10 days. The main outcome measure is the number of days with frequent cough defined by the symptom diary with a score of 1 or more. DISCUSSION: This trial is designed to evaluate the number of days with frequent cough with anti inflammatory treatment compared with antimicrobial treatment and placebo in previously healthy patients with a clinical picture of acute bronchitis and purulent expectoration. It is hypothesized that anti-inflammatory treatment is more effective than antibiotic treatment to reduce cough, which is the most disturbing symptom for patients with this infection. TRIAL REGISTRATION: ISRCTN07852892. PMID- 21693047 TI - Oxidative stress and counteracting mechanisms in hormone receptor positive, triple-negative and basal-like breast carcinomas. AB - BACKGROUND: Triple-negative breast cancer (TNBC) and basal-like breast cancer (BLBC) are breast cancer subtypes with an especially poor prognosis. 8 Hydroxydeoxyguanosine (8-OHdG) is a widely used marker of oxidative stress and the redox-state-regulating enzymes peroxiredoxins (PRDXs) are efficient at depressing excessive reactive oxygen species. NF-E2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) are redox-sensitive transcription factors that regulate PRDX expression. This is the first study to assess oxidative stress and or cell redox state-regulating enzymes in TNBC and BLBC. METHODS: We assessed immunohistochemical expression of 8-OHdG, Nrf2, Keap1, PRDX III and PRDX IV in 79 women with invasive ductal breast carcinomas. Of these tumors, 37 represented TNBC (grade II-III tumors with total lack of ER, PR and human epidermal growth factor receptor 2 [HER2] expression). Control cases (n = 42) were ER-positive, PR-positive and HER2-negative. Of the 37 TNBCs, 31 had BLBC phenotype (TNBC with expression of cytokeratin 5/6 or epidermal growth factor receptor 1). RESULTS: Patients with TNBC had worse breast cancer-specific survival (BCSS) than the control group (p = 0.015). Expression of 8-OHdG was significantly lower in TNBC than in the non-TNBC group (p < 0.005). 8-OHdG immunostaining was associated with better BCSS (p = 0.01), small tumor size (p < 0.0001) and low grade (p < 0.0005). Keap1 overexpression was observed in the TNBC cohort (p = 0.001) and Keap1-positive patients had worse BCSS than Keap1-negative women (p = 0.014). PRDX IV was overexpressed in the TNBC vs. the non-TNBC group (p = 0.022). CONCLUSIONS: Cellular redox state markers may be promising targets when elucidating the pathogenesis of TNBC. PMID- 21693048 TI - Antibody recognition of the glycoprotein g of viral haemorrhagic septicemia virus (VHSV) purified in large amounts from insect larvae. AB - BACKGROUND: There are currently no purification methods capable of producing the large amounts of fish rhabdoviral glycoprotein G (gpG) required for diagnosis and immunisation purposes or for studying structure and molecular mechanisms of action of this molecule (ie. pH-dependent membrane fusion). As a result of the unavailability of large amounts of the gpG from viral haemorrhagic septicaemia rhabdovirus (VHSV), one of the most dangerous viruses affecting cultured salmonid species, research interests in this field are severely hampered. Previous purification methods to obtain recombinant gpG from VHSV in E. coli, yeast and baculovirus grown in insect cells have not produced soluble conformations or acceptable yields. The development of large-scale purification methods for gpGs will also further research into other fish rhabdoviruses, such as infectious haematopoietic necrosis virus (IHNV), spring carp viremia virus (SVCV), hirame rhabdovirus (HIRRV) and snakehead rhabdovirus (SHRV). FINDINGS: Here we designed a method to produce milligram amounts of soluble VHSV gpG. Only the transmembrane and carboxy terminal-deleted (amino acid 21 to 465) gpG was efficiently expressed in insect larvae. Recognition of G21-465 by beta-mercaptoethanol-dependent neutralizing monoclonal antibodies (N-MAbs) and pH-dependent recognition by sera from VHSV-hyperimmunized or VHSV-infected rainbow trout (Oncorhynchus mykiss) was demonstrated. CONCLUSIONS: Given that the purified G21-465 conserved some of its most important properties, this method might be suitable for the large-scale production of fish rhabdoviral gpGs for use in diagnosis, fusion and antigenicity studies. PMID- 21693046 TI - Aromatase inhibitors in men: effects and therapeutic options. AB - Aromatase inhibitors effectively delay epiphysial maturation in boys and improve testosterone levels in adult men Therefore, aromatase inhibitors may be used to increase adult height in boys with gonadotropin-independent precocious puberty, idiopathic short stature and constitutional delay of puberty. Long-term efficacy and safety of the use of aromatase inhibitors has not yet been established in males, however, and their routine use is therefore not yet recommended. PMID- 21693049 TI - Computational study of noise in a large signal transduction network. AB - BACKGROUND: Biochemical systems are inherently noisy due to the discrete reaction events that occur in a random manner. Although noise is often perceived as a disturbing factor, the system might actually benefit from it. In order to understand the role of noise better, its quality must be studied in a quantitative manner. Computational analysis and modeling play an essential role in this demanding endeavor. RESULTS: We implemented a large nonlinear signal transduction network combining protein kinase C, mitogen-activated protein kinase, phospholipase A2, and beta isoform of phospholipase C networks. We simulated the network in 300 different cellular volumes using the exact Gillespie stochastic simulation algorithm and analyzed the results in both the time and frequency domain. In order to perform simulations in a reasonable time, we used modern parallel computing techniques. The analysis revealed that time and frequency domain characteristics depend on the system volume. The simulation results also indicated that there are several kinds of noise processes in the network, all of them representing different kinds of low-frequency fluctuations. In the simulations, the power of noise decreased on all frequencies when the system volume was increased. CONCLUSIONS: We concluded that basic frequency domain techniques can be applied to the analysis of simulation results produced by the Gillespie stochastic simulation algorithm. This approach is suited not only to the study of fluctuations but also to the study of pure noise processes. Noise seems to have an important role in biochemical systems and its properties can be numerically studied by simulating the reacting system in different cellular volumes. Parallel computing techniques make it possible to run massive simulations in hundreds of volumes and, as a result, accurate statistics can be obtained from computational studies. PMID- 21693050 TI - Perceived protein needs and measured protein intake in collegiate male athletes: an observational study. AB - BACKGROUND: Protein needs for athletes are likely higher than those for the general population. However, athletes may perceive their protein needs to be excessively high. The purpose of this research was to compare collegiate athletes' perceived protein needs and measured protein intake to the recommended protein intake (RDI) for healthy adults (i.e. 0.8 g/kg/d) and to the maximum beneficial level for strength-trained athletes (i.e. 2.0 g/kg/day). METHODS: Perceived protein needs were quantified in 42 strength-trained collegiate male athletes by using a survey that asked the athletes to provide their perception about protein needs in specific quantitative terms (i.e. g/kg/d). Perceived protein needs were also determined by having the athletes select a daylong menu that they perceived to have adequate protein content from a collection of 5 isoenergetic menus, which differed in terms of protein content. Actual protein intake was quantified using 3-day food records and nutrient analysis. Single sample t-tests were used to compare protein intake and perceived protein needs to 0.8 g/kg/day and 2.0 g/kg/day. RESULTS: When asked to provide, in quantitative terms, protein needs for athletes, 67% of the athletes indicated "do not know." Of the remaining 33% of athletes, all gave values greater than 2.0 g/kg/d (mean 21.5 +/- 11.2 g/kg/d, p = 0.14 vs. 2.0 g/kg/d). Based on the menu selection method for determining perceived protein needs, the athletes indicated that their protein needs were 2.4 +/- 0.2 g/kg/d, which was greater than the RDI for protein (p < 0.0001) and tended to be greater than the maximally beneficial protein intake of 2.0 g/kg/d (p = 0.13). Measured protein intake was 2.0 +/- 0.1 g/kg/d, which was greater than the RDI (p < 0.0001) but not different from the maximally beneficial protein intake of 2.0 g/kg/d (p = 0.84). CONCLUSIONS: Male collegiate athletes recognize that their protein needs are higher than that of the general population and consume significantly more protein than recommended in the RDI. However, it also appears that athletes are not aware of objective recommendations for protein intake and may perceive their needs to be excessively high. This study highlights the need for nutrition education in collegiate athletes, in particular nutrition education on macronutrient distribution and protein needs. PMID- 21693051 TI - A comparison of a new multinomial stopping rule with stopping rules of fleming and gehan in single arm phase II cancer clinical trials. AB - BACKGROUND: Response rate (RR) alone may be insensitive to drug activity in phase II trials. Early progressive disease (EPD) could improve sensitivity as well as increase stage I stopping rates. This study compares the previously developed dual endpoint stopping rule (DESR), which incorporates both RR and EPD into a two stage, phase II trial, with rules using only RR. METHODS: Stopping rules according to the DESR were compared with studies conducted under the Fleming (16 trials) or Gehan (23 trials) designs. The RR hypothesis for the DESR was consistent with the comparison studies (ralt = 0.2, rnul = 0.05). Two parameter sets were used for EPD rates of interest and disinterest respectively (epdalt, epdnul): (0.4, 0.6) and (0.3, 0.5). RESULTS: Compared with Fleming, the DESR was more likely to allow stage two of accrual and to reject the null hypothesis (Hnul) after stage two, with rejection being more common with EPD parameters (0.4, 0.6) than (0.3, 0.5). Compared with Gehan, both DESR parameter sets accepted Hnul in 15 trials after stage I compared with 8 trials by Gehan, with consistent conclusions in all 23 trials after stage II. CONCLUSIONS: The DESR may reject Hnul when EPD rates alone are low, and thereby may improve phase II trial sensitivity to active, cytostatic drugs having limited response rates. Conversely, the DESR may invoke early stopping when response rates are low and EPD rates are high, thus shortening trials when drug activity is unlikely. EPD parameters should be chosen specific to each trial. PMID- 21693052 TI - Comparative BAC-based mapping in the white-throated sparrow, a novel behavioral genomics model, using interspecies overgo hybridization. AB - BACKGROUND: The genomics era has produced an arsenal of resources from sequenced organisms allowing researchers to target species that do not have comparable mapping and sequence information. These new "non-model" organisms offer unique opportunities to examine environmental effects on genomic patterns and processes. Here we use comparative mapping as a first step in characterizing the genome organization of a novel animal model, the white-throated sparrow (Zonotrichia albicollis), which occurs as white or tan morphs that exhibit alternative behaviors and physiology. Morph is determined by the presence or absence of a complex chromosomal rearrangement. This species is an ideal model for behavioral genomics because the association between genotype and phenotype is absolute, making it possible to identify the genomic bases of phenotypic variation. FINDINGS: We initiated a genomic study in this species by characterizing the white-throated sparrow BAC library via filter hybridization with overgo probes designed for the chicken, turkey, and zebra finch. Cross-species hybridization resulted in 640 positive sparrow BACs assigned to 77 chicken loci across almost all macro-and microchromosomes, with a focus on the chromosomes associated with morph. Out of 216 overgos, 36% of the probes hybridized successfully, with an average number of 3.0 positive sparrow BACs per overgo. CONCLUSIONS: These data will be utilized for determining chromosomal architecture and for fine-scale mapping of candidate genes associated with phenotypic differences. Our research confirms the utility of interspecies hybridization for developing comparative maps in other non-model organisms. PMID- 21693053 TI - The microbiological profile and presence of bloodstream infection influence mortality rates in necrotizing fasciitis. AB - INTRODUCTION: Necrotizing fasciitis (NF) is a life threatening infectious disease with a high mortality rate. We carried out a microbiological characterization of the causative pathogens. We investigated the correlation of mortality in NF with bloodstream infection and with the presence of co-morbidities. METHODS: In this retrospective study, we analyzed 323 patients who presented with necrotizing fasciitis at two different institutions. Bloodstream infection (BSI) was defined as a positive blood culture result. The patients were categorized as survivors and non-survivors. Eleven clinically important variables which were statistically significant by univariate analysis were selected for multivariate regression analysis and a stepwise logistic regression model was developed to determine the association between BSI and mortality. RESULTS: Univariate logistic regression analysis showed that patients with hypotension, heart disease, liver disease, presence of Vibrio spp. in wound cultures, presence of fungus in wound cultures, and presence of Streptococcus group A, Aeromonas spp. or Vibrio spp. in blood cultures, had a significantly higher risk of in-hospital mortality. Our multivariate logistic regression analysis showed a higher risk of mortality in patients with pre-existing conditions like hypotension, heart disease, and liver disease. Multivariate logistic regression analysis also showed that presence of Vibrio spp in wound cultures, and presence of Streptococcus Group A in blood cultures were associated with a high risk of mortality while debridement > = 3 was associated with improved survival. CONCLUSIONS: Mortality in patients with necrotizing fasciitis was significantly associated with the presence of Vibrio in wound cultures and Streptococcus group A in blood cultures. PMID- 21693054 TI - Audio-biofeedback training for posture and balance in patients with Parkinson's disease. AB - BACKGROUND: Patients with Parkinson's disease (PD) suffer from dysrhythmic and disturbed gait, impaired balance, and decreased postural responses. These alterations lead to falls, especially as the disease progresses. Based on the observation that postural control improved in patients with vestibular dysfunction after audio-biofeedback training, we tested the feasibility and effects of this training modality in patients with PD. METHODS: Seven patients with PD were included in a pilot study comprised of a six weeks intervention program. The training was individualized to each patient's needs and was delivered using an audio-biofeedback (ABF) system with headphones. The training was focused on improving posture, sit-to-stand abilities, and dynamic balance in various positions. Non-parametric statistics were used to evaluate training effects. RESULTS: The ABF system was well accepted by all participants with no adverse events reported. Patients declared high satisfaction with the training. A significant improvement of balance, as assessed by the Berg Balance Scale, was observed (improvement of 3% p = 0.032), and a trend in the Timed up and go test (improvement of 11%; p = 0.07) was also seen. In addition, the training appeared to have a positive influence on psychosocial aspects of the disease as assessed by the Parkinson's disease quality of life questionnaire (PDQ-39) and the level of depression as assessed by the Geriatric Depression Scale. CONCLUSIONS: This is, to our knowledge, the first report demonstrating that audio-biofeedback training for patients with PD is feasible and is associated with improvements of balance and several psychosocial aspects. PMID- 21693055 TI - Warwick-Edinburgh Mental Well-being Scale (WEMWBS): validated for teenage school students in England and Scotland. A mixed methods assessment. AB - BACKGROUND: Understanding and measuring mental health and wellbeing amongst teenagers has recently become a priority. The Warwick-Edinburgh Mental Well-being Scale (WEMWBS) is validated for measuring mental wellbeing in populations aged 16 years and over in the UK. We report here a study designed to establish the validity and reliability of WEMWBS in teenagers in the UK. METHODS: WEMWBS and comparator scales, together with socio-demographic information and self-reported health, were incorporated into a self-administered questionnaire given to pupils aged 13 to 16 years in six schools in Scotland and England. Psychometric properties including internal consistency, correlations with comparator scales, test-retest stability and unidimensionality were investigated for WEMWBS. Twelve focus groups were undertaken to assess acceptability and comprehensibility of WEMWBS and were taped, transcribed and analysed thematically. RESULTS: A total of 1,650 teenagers completed the questionnaire (response rate 80.8%). Mean WEMWBS score was 48.8 (SD 6.8; median 49). Response scores covered the full range (from 14 to 70). WEMWBS demonstrated strong internal consistency and a high Cronbach's alpha of 0.87 (95% CI (0.85-0.88), n = 1517). Measures of construct validity gave values as predicted. The correlation coefficient for WEMWBS total score and psychological wellbeing domain of the Kidscreen-27 was 0.59 (95% CI [0.55; 0.62]); for the Mental Health Continuum Short Form (MHC-SF) was 0.65, 95% CI [0.62; 0.69]; and for the WHO (WHO-5) Well-being Index 0.57 (95% CI [0.53; 0.61]). The correlation coefficient for the Strengths and Difficulties Questionnaire (SDQ) was -0.44 (95% CI [-0.49; -0.40]) and for the 12-item General Health Questionnaire (GHQ12) -0.45 (95% CI [-0.49; -0.40]). Test-retest reliability was acceptable (Intraclass correlation coefficient (ICC) 0.66 (95% CI [0.59; 0.72] n = 212)). Confirmatory factor analysis demonstrated one underlying factor. WEMWBS was significantly associated with the Family Affluence Score (WEMWBS increased with increasing household socio-economic status) and had a positive association with the physical health dimension of the Kidscreen-27, but was unrelated to age, gender or location/school. Eighty students took part in focus groups. In general, although some students considered some items open to misunderstanding or misinterpretation, WEMWBS was received positively and was considered comprehensible, and acceptable. CONCLUSIONS: WEMWBS is a psychometrically strong population measure of mental wellbeing, and can be used for this purpose in teenagers aged 13 and over. PMID- 21693056 TI - Epidemiology of traffic injuries and motor vehicles utilization in the capital of Iran: a population based study. AB - BACKGROUND: Road traffic injuries are a serious public health problem worldwide. The incidence rate of fatal road traffic injuries is 26.4 per 100000 in the Eastern Mediterranean Region. Road traffic injuries are a major public health problem in Iran. Different routine sources are available for road traffic injuries in Iran, but they present several limitations.This study aimed to determine the epidemiology of road traffic injuries in greater Tehran, using a population-based approach which is less prone to under-estimation compared to service-based data. METHODS: In the year 2008, 2488 households were randomly selected for a face to face interview. Trained interviewers referred to the selected households to collect the subjects' demographic information, as well as their motor vehicle utilization and traffic injuries during the year prior to data collection. All interviews were recorded using a digital voice recorder and reviewed by a quality control team the day after the interview. The Student's t test and ANOVA were used to analyze continuous variables. Chi-square test including a test for trend for ordinal data- was used to analyze categorical variables. Ninety-five percent confidence interval was calculated for point estimates of incidences using Poisson or binomial distribution assumptions accordingly. RESULTS: There were 119 traffic injury cases including 3 deaths (33 per 100 000) in the survey sample (n = 9100). The annual incidence of all traffic injuries for 1000 population was 13.1 (95% CI: 10.8 - 15.6), and that of fatal traffic injuries was 33.0 per 100 000 population (95% CI: 6.80 - 96.32). The annual incidence of collision traffic injury for 1000 motorcycles was 95. CONCLUSION: This population-based study demonstrates that the morbidity rate of RTIs is about ten times higher than the national figures reported by other available sources; and this can serve as an important warning to countries like Iran to prioritize this issue in their public health activities. To ensure more safety on our roads, we need to establish an injury surveillance system, and a more accurate national data capture system on RTIs. PMID- 21693057 TI - Blood pressure long term regulation: a neural network model of the set point development. AB - BACKGROUND: The notion of the nucleus tractus solitarius (NTS) as a comparator evaluating the error signal between its rostral neural structures (RNS) and the cardiovascular receptor afferents into it has been recently presented. From this perspective, stress can cause hypertension via set point changes, so offering an answer to an old question. Even though the local blood flow to tissues is influenced by circulating vasoactive hormones and also by local factors, there is yet significant sympathetic control. It is well established that the state of maturation of sympathetic innervation of blood vessels at birth varies across animal species and it takes place mostly during the postnatal period. During ontogeny, chemoreceptors are functional; they discharge when the partial pressures of oxygen and carbon dioxide in the arterial blood are not normal. METHODS: The model is a simple biological plausible adaptative neural network to simulate the development of the sympathetic nervous control. It is hypothesized that during ontogeny, from the RNS afferents to the NTS, the optimal level of each sympathetic efferent discharge is learned through the chemoreceptors' feedback. Its mean discharge leads to normal oxygen and carbon dioxide levels in each tissue. Thus, the sympathetic efferent discharge sets at the optimal level if, despite maximal drift, the local blood flow is compensated for by autoregulation. Such optimal level produces minimum chemoreceptor output, which must be maintained by the nervous system. Since blood flow is controlled by arterial blood pressure, the long-term mean level is stabilized to regulate oxygen and carbon dioxide levels. After development, the cardiopulmonary reflexes play an important role in controlling efferent sympathetic nerve activity to the kidneys and modulating sodium and water excretion. RESULTS: Starting from fixed RNS afferents to the NTS and random synaptic weight values, the sympathetic efferents converged to the optimal values. When learning was completed, the output from the chemoreceptors became zero because the sympathetic efferents led to normal partial pressures of oxygen and carbon dioxide. CONCLUSIONS: We introduce here a simple simulating computational theory to study, from a neurophysiologic point of view, the sympathetic development of cardiovascular regulation due to feedback signals sent off by cardiovascular receptors. The model simulates, too, how the NTS, as emergent property, acts as a comparator and how its rostral afferents behave as set point. PMID- 21693058 TI - Instructional multimedia: an investigation of student and instructor attitudes and student study behavior. AB - BACKGROUND: Educators in allied health and medical education programs utilize instructional multimedia to facilitate psychomotor skill acquisition in students. This study examines the effects of instructional multimedia on student and instructor attitudes and student study behavior. METHODS: Subjects consisted of 45 student physical therapists from two universities. Two skill sets were taught during the course of the study. Skill set one consisted of knee examination techniques and skill set two consisted of ankle/foot examination techniques. For each skill set, subjects were randomly assigned to either a control group or an experimental group. The control group was taught with live demonstration of the examination skills, while the experimental group was taught using multimedia. A cross-over design was utilized so that subjects in the control group for skill set one served as the experimental group for skill set two, and vice versa. During the last week of the study, students and instructors completed written questionnaires to assess attitude toward teaching methods, and students answered questions regarding study behavior. RESULTS: There were no differences between the two instructional groups in attitudes, but students in the experimental group for skill set two reported greater study time alone compared to other groups. CONCLUSIONS: Multimedia provides an efficient method to teach psychomotor skills to students entering the health professions. Both students and instructors identified advantages and disadvantages for both instructional techniques. Reponses relative to instructional multimedia emphasized efficiency, processing level, autonomy, and detail of instruction compared to live presentation. Students and instructors identified conflicting views of instructional detail and control of the content. PMID- 21693059 TI - The transitioning experiences of internationally-educated nurses into a Canadian health care system: A focused ethnography. AB - BACKGROUND: Beyond well-documented credentialing issues, internationally-educated nurses (IENs) may need considerable support in transitioning into new social and health care environments. This study was undertaken to gain an understanding of transitioning experiences of IENs upon relocation to Canada, while creating policy and practice recommendations applicable globally for improving the quality of transitioning and the retention of IENs. METHODS: A focused ethnography of newly-recruited IENs was conducted, using individual semi-structured interviews at both one-to-three months (Phase 1) and nine-to-twelve months post-relocation (Phase 2). A purposive sample of IENs was recruited during their orientation at a local college, to a health authority within western Canada which had recruited them for employment throughout the region. The interviews were recorded and transcribed, and data was managed using qualitative analytical software. Data analysis was informed by Roper and Shapira's framework for focused ethnography. RESULTS: Twenty three IENs consented to participate in 31 interviews. All IENs which indicated interest during their orientation sessions consented to the interviews, yet 14 did not complete the Phase 2 interview due to reorganization of health services and relocation. The ethno-culturally diverse group had an average age of 36.4 years, were primarily educated to first degree level or higher, and were largely (under) employed as "Graduate Nurses". Many IENs reported negative experiences related to their work contract and overall support upon arrival. There were striking differences in nursing practice and some experiences of perceived discrimination. The primary area of discontentment was the apparent communication breakdown at the recruitment stage with subsequent discrepancy in expected professional role and financial reimbursement. CONCLUSIONS: Explicit and clear communication is needed between employers and recruitment agencies to avoid employment contract misunderstandings and to enable clear interpretation of the credentialing processes. Pre-arrival orientation of IENs including health care communications should be encouraged and supported by the recruiting institution. Moreover, employers should provide more structured and comprehensive workplace orientation to IENs with consistent preceptorship. Similar to findings of many other studies, diversity should be valued and incorporated into the professional culture by nurse managers. PMID- 21693060 TI - Insomnia - treatment pathways, costs and quality of life. AB - BACKGROUND: Insomnia is perhaps the most common sleep disorder in the general population, and is characterised by a range of complaints around difficulties in initiating and maintaining sleep, together with impaired waking function. There is little quantitative information on treatment pathways, costs and outcomes. The aims of this New Zealand study were to determine from which healthcare practitioners patients with insomnia sought treatment, treatment pathways followed, the net costs of treatment and the quality of life improvements obtained. METHODS: The study was retrospective and prevalence based, and was both cost effectiveness (CEA) and a cost utility (CUA) analysis. Micro costing techniques were used and a societal analytic perspective was adopted. A deterministic decision tree model was used to estimate base case values, and a stochastic version, with Monte Carlo simulation, was used to perform sensitivity analysis. A probability and cost were attached to each event which enabled the costs for the treatment pathways and average treatment cost to be calculated. The inputs to the model were prevalence, event probabilities, resource utilisations, and unit costs. Direct costs and QALYs gained were evaluated. RESULTS: The total net benefit of treating a person with insomnia was $482 (the total base case cost of $145 less health costs avoided of $628). When these results were applied to the total at-risk population in New Zealand additional treatment costs incurred were $6.6 million, costs avoided $28.4 million and net benefits were $21.8 million. The incremental net benefit when insomnia was "successfully" treated was $3,072 per QALY gained. CONCLUSIONS: The study has brought to light a number of problems relating to the treatment of insomnia in New Zealand. There is both inadequate access to publicly funded treatment and insufficient publicly available information from which a consumer is able to make an informed decision on the treatment and provider options. This study suggests that successful treatment of insomnia leads to direct cost savings and improved quality of life. PMID- 21693061 TI - Expression of tissue factor in adenocarcinoma and squamous cell carcinoma of the uterine cervix: implications for immunotherapy with hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor. AB - BACKGROUND: Cervical cancer continues to be an important worldwide health problem for women. Up to 35% of patients who are diagnosed with and appropriately treated for cervical cancer will recur and treatment results are poor for recurrent disease. Given these sobering statistics, development of novel therapies for cervical cancer remains a high priority. We evaluated the expression of Tissue Factor (TF) in cervical cancer and the potential of hI-con1, an antibody-like molecule targeted against TF, as a novel form of immunotherapy against multiple primary cervical carcinoma cell lines with squamous- and adenocarcinoma histology. METHODS: Because TF is a transmembrane receptor for coagulation factor VII/VIIa (fVII), in this study we evaluated the in vitro expression of TF in cervical carcinoma cell lines by immunohistochemistry (IHC), real time-PCR (qRT PCR) and flow cytometry. Sensitivity to hI-con1-dependent cell-mediated cytotoxicity (IDCC) was evaluated in 5-hrs-51chromium-release-assays against cervical cancer cell lines in vitro. RESULTS: Cytoplasmic and/or membrane TF expression was observed in 8 out of 8 (100%) of the tumor tissues tested by IHC and in 100% (11 out of 11) of the cervical carcinoma cell lines tested by real time-PCR and flow cytometry but not in normal cervical keratinocytes (p=0.0023 qRT-PCR; p=0.0042 flow cytometry). All primary cervical cancer cell lines tested overexpressing TF, regardless of their histology, were highly sensitive to IDCC (mean killing+/-SD, 56.2%+/-15.9%, range, 32.4%-76.9%, p<0.001), while negligible cytotoxicity was seen in the absence of hI-con1 or in the presence of rituximab control-antibody. Low doses of interleukin-2 further increased the cytotoxic effect induced by hI-con1 (p=0.025) while human serum did not significantly decrease IDCC against cervical cancer cell lines (p=0.597). CONCLUSIONS: TF is highly expressed in squamous and adenocarcinoma of the uterine cervix. hI-con1 induces strong cytotoxicity against primary cervical cancer cell lines overexpressing TF and may represent a novel therapeutic agent for the treatment of cervical cancer refractory to standard treatment modalities. PMID- 21693062 TI - Binary classification of protein molecules into intrinsically disordered and ordered segments. AB - BACKGROUND: Although structural domains in proteins (SDs) are important, half of the regions in the human proteome are currently left with no SD assignments. These unassigned regions consist not only of novel SDs, but also of intrinsically disordered (ID) regions since proteins, especially those in eukaryotes, generally contain a significant fraction of ID regions. As ID regions can be inferred from amino acid sequences, a method that combines SD and ID region assignments can determine the fractions of SDs and ID regions in any proteome. RESULTS: In contrast to other available ID prediction programs that merely identify likely ID regions, the DICHOT system we previously developed classifies the entire protein sequence into SDs and ID regions. Application of DICHOT to the human proteome revealed that residue-wise ID regions constitute 35%, SDs with similarity to PDB structures comprise 52%, while SDs with no similarity to PDB structures account for the remaining 13%. The last group consists of novel structural domains, termed cryptic domains, which serve as good targets of structural genomics. The DICHOT method applied to the proteomes of other model organisms indicated that eukaryotes generally have high ID contents, while prokaryotes do not. In human proteins, ID contents differ among subcellular localizations: nuclear proteins had the highest residue-wise ID fraction (47%), while mitochondrial proteins exhibited the lowest (13%). Phosphorylation and O-linked glycosylation sites were found to be located preferentially in ID regions. As O-linked glycans are attached to residues in the extracellular regions of proteins, the modification is likely to protect the ID regions from proteolytic cleavage in the extracellular environment. Alternative splicing events tend to occur more frequently in ID regions. We interpret this as evidence that natural selection is operating at the protein level in alternative splicing. CONCLUSIONS: We classified entire regions of proteins into the two categories, SDs and ID regions and thereby obtained various kinds of complete genome-wide statistics. The results of the present study are important basic information for understanding protein structural architectures and have been made publicly available at http://spock.genes.nig.ac.jp/~genome/DICHOT. PMID- 21693063 TI - Alcohol use behaviors and risk of metabolic syndrome in South Korean middle-aged men. AB - BACKGROUND: It is thought that small volumes of alcohol may have positive effects on health. However, excessive drinking results in serious health problems. An accurate method to determine individual alcohol use behaviors are needed to assess objectively the extent to which drinking affects health. This study investigated the association between risk of metabolic syndrome (MetS) and alcohol use behaviors in middle-aged South Korean men using the Alcohol Use Disorders Identification Test. METHODS: This study used data from the South Korea National Health and Nutrition Examination (KNHANES) IV (2008), which extracted the standard survey household by using the proportional systematic sampling method. Data of 714 participants from KNHANES IV, 2008 were analyzed using Surveyfreq and Surveylogistic regression to investigate the association between MetS and alcohol use behaviors in middle-aged South Korean men. RESULTS: After adjustment for education, smoking, and physical activity, alcohol use behaviors were significantly associated with an increased risk of hypertension [odds ratio (OR) = 2.54, 95% confidence interval (CI) = 1.5-4.06 in the hazardous group; OR = 2.99, 95% CI = 1.84-4.92 in the problem group]; impaired fasting glucose (OR = 2.15, 95% CI = 1.16-3.99 in the hazardous group; OR = 2.48, 95% CI = 1.42-4.33 in the problem group); dyslipidemia (OR = 2.19, 95% CI = 1.38-3.47 in the problem group); abdominal obesity (OR = 1.93, 95% CI = 1.17-3.19 in the hazardous group; OR = 1.85, 95% CI = 1.17-2.92 in the problem group); and MetS (OR = 2.16, 95% CI = 1.24-3.77 in the hazardous group; OR = 2.54, 95% CI = 1.41-4.58 in problem group). CONCLUSIONS: This study found that excessive alcohol use behaviors increased the risk of hypertension, diabetes, dyslipidemia, abdominal obesity, and MetS. Considering the rising rate of alcohol consumption and heavy drinking at single sittings, a culture of less risky alcohol consumption must be established to promote health among middle-aged men. PMID- 21693064 TI - Structure of catalytic domain of Matriptase in complex with Sunflower trypsin inhibitor-1. AB - BACKGROUND: Matriptase is a type II transmembrane serine protease that is found on the surfaces of epithelial cells and certain cancer cells. Matriptase has been implicated in the degradation of certain extracellular matrix components as well as the activation of various cellular proteins and proteases, including hepatocyte growth factor and urokinase. Sunflower trypsin inhibitor-1 (SFTI-1), a cyclic peptide inhibitor originally isolated from sunflower seeds, exhibits potent inhibitory activity toward matriptase. RESULTS: We have engineered and produced recombinant proteins of the matriptase protease domain, and have determined the crystal structures of the protease:SFTI-1 complex at 2.0 A as well as the protease:benzamidine complex at 1.2 A. These structures elaborate the structural basis of substrate selectivity of matriptase, and show that the matriptase S1 substrate specificity pocket is larger enough to allow movement of benzamidine inside the S1 pocket. Our study also reveals that SFTI-1 binds to matriptase in a way similar to its binding to trypsin despite the significantly different isoelectric points of the two proteins (5.6 vs. 8.2). CONCLUSIONS: This work helps to define the structural basis of substrate specificity of matriptase and the interactions between the inhibitor and protease. The complex structure also provides a structural template for designing new SFTI-1 derivatives with better potency and selectivity against matriptase and other proteases. PMID- 21693065 TI - Sparse PLS discriminant analysis: biologically relevant feature selection and graphical displays for multiclass problems. AB - BACKGROUND: Variable selection on high throughput biological data, such as gene expression or single nucleotide polymorphisms (SNPs), becomes inevitable to select relevant information and, therefore, to better characterize diseases or assess genetic structure. There are different ways to perform variable selection in large data sets. Statistical tests are commonly used to identify differentially expressed features for explanatory purposes, whereas Machine Learning wrapper approaches can be used for predictive purposes. In the case of multiple highly correlated variables, another option is to use multivariate exploratory approaches to give more insight into cell biology, biological pathways or complex traits. RESULTS: A simple extension of a sparse PLS exploratory approach is proposed to perform variable selection in a multiclass classification framework. CONCLUSIONS: sPLS-DA has a classification performance similar to other wrapper or sparse discriminant analysis approaches on public microarray and SNP data sets. More importantly, sPLS-DA is clearly competitive in terms of computational efficiency and superior in terms of interpretability of the results via valuable graphical outputs. sPLS-DA is available in the R package mixOmics, which is dedicated to the analysis of large biological data sets. PMID- 21693066 TI - Evolutionary history of Otophysi (Teleostei), a major clade of the modern freshwater fishes: Pangaean origin and Mesozoic radiation. AB - BACKGROUND: Freshwater harbors approximately 12,000 fish species accounting for 43% of the diversity of all modern fish. A single ancestral lineage evolved into about two-thirds of this enormous biodiversity (~ 7900 spp.) and is currently distributed throughout the world's continents except Antarctica. Despite such remarkable species diversity and ubiquity, the evolutionary history of this major freshwater fish clade, Otophysi, remains largely unexplored. To gain insight into the history of otophysan diversification, we constructed a timetree based on whole mitogenome sequences across 110 species representing 55 of the 64 families. RESULTS: Partitioned maximum likelihood analysis based on unambiguously aligned sequences (9923 bp) confidently recovered the monophyly of Otophysi and the two constituent subgroups (Cypriniformes and Characiphysi). The latter clade comprised three orders (Gymnotiformes, Characiformes, Siluriformes), and Gymnotiformes was sister to the latter two groups. One of the two suborders in Characiformes (Characoidei) was more closely related to Siluriformes than to its own suborder (Citharinoidei), rendering the characiforms paraphyletic. Although this novel relationship did not receive strong statistical support, it was supported by analyzing independent nuclear markers. A relaxed molecular clock Bayesian analysis of the divergence times and reconstruction of ancestral habitats on the timetree suggest a Pangaean origin and Mesozoic radiation of otophysans. CONCLUSIONS: The present timetree demonstrates that survival of the ancestral lineages through the two consecutive mass extinctions on Pangaea, and subsequent radiations during the Jurassic through early Cretaceous shaped the modern familial diversity of otophysans. This evolutionary scenario is consistent with recent arguments based on biogeographic inferences and molecular divergence time estimates. No fossil otophysan, however, has been recorded before the Albian, the early Cretaceous 100-112 Ma, creating an over 100 million year time span without fossil evidence. This formidable ghost range partially reflects a genuine difference between the estimated ages of stem group origin (molecular divergence time) and crown group morphological diversification (fossil divergence time); the ghost range, however, would be filled with discoveries of older fossils that can be used as more reasonable time constraints as well as with developments of more realistic models that capture the rates of molecular sequences accurately. PMID- 21693067 TI - 9q22 Deletion--first familial case. AB - BACKGROUND: Only 29 cases of constitutional 9q22 deletions have been published and all have been sporadic. Most associate with Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS, MIM #109400) due to haploinsufficiency of the PTCH1 gene (MIM *601309). METHODS AND RESULTS: We report two mentally retarded female siblings and their cognitively normal father, all carrying a similar 5.3 Mb microdeletion at 9q22.2q22.32, detected by array CGH (244 K). The deletion does not involve the PTCH1 gene, but instead 30 other gene,s including the ROR2 gene (MIM *602337) which causing both brachydactyly type 1 (MIM #113000) and Robinow syndrome (MIM #268310), and the immunologically active SYK gene (MIM *600085). The deletion in the father was de novo and FISH analysis of blood lymphocytes did not suggest mosaicism. All three patients share similar mild dysmorphic features with downslanting palpebral fissures, narrow, high bridged nose with small nares, long, deeply grooved philtrum, ears with broad helix and uplifted lobuli, and small toenails. All have significant dysarthria and suffer from continuous middle ear and upper respiratory infections. The father also has a funnel chest and unilateral hypoplastic kidney but the daughters have no malformations. CONCLUSIONS: This is the first report of a familial constitutional 9q22 deletion and the first deletion studied by array-CGH which does not involve the PTCH1 gene. The phenotype and penetrance are variable and the deletion found in the cognitively normal normal father poses a challenge in genetic counseling. PMID- 21693068 TI - Bacterial membrane activity of alpha-peptide/beta-peptoid chimeras: influence of amino acid composition and chain length on the activity against different bacterial strains. AB - BACKGROUND: Characterization and use of antimicrobial peptides (AMPs) requires that their mode of action is determined. The interaction of membrane-active peptides with their target is often established using model membranes, however, the actual permeabilization of live bacterial cells and subsequent killing is usually not tested. In this report, six alpha-peptide/beta-peptoid chimeras were examined for the effect of amino acid/peptoid substitutions and chain length on the membrane perturbation and subsequent killing of food-borne and clinical bacterial isolates. RESULTS: All six AMP analogues inhibited growth of twelve food-borne and clinical bacterial strains including Extended Spectrum Beta Lactamase-producing Escherichia coli. In general, the Minimum Inhibitory Concentrations (MIC) against Gram-positive and -negative bacteria were similar, ranging from 1 to 5 MUM. The type of cationic amino acid only had a minor effect on MIC values, whereas chain length had a profound influence on activity. All chimeras were less active against Serratia marcescens (MICs above 46 MUM). The chimeras were bactericidal and induced leakage of ATP from Staphylococcus aureus and S. marcescens with similar time of onset and reduction in the number of viable cells. EDTA pre-treatment of S. marcescens and E. coli followed by treatment with chimeras resulted in pronounced killing indicating that disintegration of the Gram-negative outer membrane eliminated innate differences in susceptibility. Chimera chain length did not influence the degree of ATP leakage, but the amount of intracellular ATP remaining in the cell after treatment was influenced by chimera length with the longest analogue causing complete depletion of intracellular ATP. Hence some chimeras caused a complete disruption of the membrane, and this was parallel by the largest reduction in number of viable bacteria. CONCLUSION: We found that chain length but not type of cationic amino acid influenced the antibacterial activity of a series of synthetic alpha-peptide/beta-peptoid chimeras. The synthetic chimeras exert their killing effect by permeabilization of the bacterial cell envelope, and the outer membrane may act as a barrier in Gram-negative bacteria. The tolerance of S. marcescens to chimeras may be due to differences in the composition of the lipopolysaccharide layer also responsible for its resistance to polymyxin B. PMID- 21693069 TI - Genotyping the hepatitis B virus with a fragment of the HBV DNA polymerase gene in Shenyang, China. AB - The hepatitis B virus (HBV) has been classified into eight genotypes (A-H) based on intergenotypic divergence of at least 8% in the complete nucleotide sequence or more than 4% in the S gene. To facilitate the investigation of the relationship between the efficacy of drug treatment and the mutation with specific genotype of HBV, we have established a new genotyping strategy based on a fragment of the HBV DNA polymerase gene. Pairwise sequence and phylogenetic analyses were performed using CLUSTAL V (DNASTAR) on the eight (A-H) standard full-length nucleotide sequences of HBV DNA from GenBank (NCBI) and the corresponding semi-nested PCR products from the HBV DNA polymerase gene. The differences in the semi-nested PCR fragments of the polymerase genes among genotypes A through F were greater than 4%, which is consistent with the intergenotypic divergence of at least 4% in HBV DNA S gene sequences. Genotyping using the semi-nested PCR products of the DNA polymerase genes revealed that only genotypes B, C, and D were present in the 50 cases, from Shenyang, China, with a distribution of 11 cases (22%), 25 cases (50%), and 14 cases (28%) respectively. These results demonstrate that our new genotyping method utilizing a fragment of the HBV DNA polymerase gene is valid and can be employed as a general genotyping strategy in areas with prevalent HBV genotypes A through F. In Shenyang, China, genotypes C, B, and D were identified with this new genotyping method, and genotype C was demonstrated to be the dominant genotype. PMID- 21693070 TI - Unusual manifestation of Erdheim-Chester disease. AB - BACKGROUND: Erdheim-Chester disease (ECD) is a rare multisystem non-Langerhans cell histiocytosis that is characterized histologically by xanthogranulomatous infiltrates and radiologically by symmetrical sclerosis of long bones. The xanthomatous process is characterized by prominent foamy histiocytes staining positive for CD68, occasionally for PS100 and negative for S100 and CD1a. Gastroenterological involvement is exceedingly rare. CASE PRESENTATION: This case report describes the case of a 69-year-old man who presented otherwise well to the gastroenterology department with unspecific abdominal symptoms, nausea, vomiting and weight loss. ECD involving the gastrointestinal tract was confirmed clinically, radiologically and histologically. CONCLUSION: Gastroenterological manifestation of ECD is rare but should be considered in the differential diagnosis in patients presenting with evidence of multi-organ disease and typical radiological features of Erdheim-Chester disease elsewhere. PMID- 21693071 TI - High level soluble expression, one-step purification and characterization of HIV 1 p24 protein. AB - BACKGROUND: P24 protein is the major core protein of HIV virus particle and has been suggested as a specific target for antiviral strategies. Recombinant p24 protein with natural antigenic activity would be useful for various studies, such as diagnostic reagents and multi-component HIV vaccine development. The aim of this study was to express and purify the p24 protein in soluble form in E.coli. RESULTS: According to the sequence of the p24 gene, a pair of primers was designed, and the target sequence of 700 bp was amplified using PCR. The PCR product was cloned into pQE30 vector, generating the recombinant plasmid pQE30 p24. SDS-PAGE analysis showed that the His-tagged recombinant p24 protein was highly expressed in soluble form after induction in E. coli strain BL21. The recombinant protein was purified by nickel affinity chromatography and used to react with HIV infected sera. The results showed that the recombinant p24 protein could specifically react with the HIV infected sera. To study the immunogenicity of this soluble recombinant p24 protein, it was used to immunize mice for the preparation of polyclonal antibody. Subsequent ELISA and Western-Blot analysis demonstrated that the p24 protein had proper immunogenicity in inducing mice to produce HIV p24 specific antibodies. CONCLUSION: In this work, we report the high level soluble expression of HIV-1 p24 protein in E. coli. This soluble recombinant p24 protein specifically react with HIV infected sera and elicit HIV p24 specific antibodies in mice, indicating this soluble recombinant p24 protein could be a promising reagent for HIV diagnosis. PMID- 21693072 TI - Therapeutic efficacy of topical application of dexamethasone to the round window niche after acoustic trauma caused by intensive impulse noise in guinea pigs. AB - OBJECTIVE: To assess the therapeutic efficacy of dexamethasone administered topically to the round window niche, following acoustic trauma induced by intensive impulse noise, in guinea pigs. METHODS: Adult, male, albino guinea pigs with a normal Preyer's reflex were exposed to 80 impulse noises (peak value 167 dB, duration 0.5 ms, interval 2 s). Dexamethasone (40 mg/ml) or saline was then topically applied to the round window niche. Each animal's auditory brainstem response was measured before and one day after exposure, and three weeks after topical treatment. Cochlear morphology was examined to assess hair cell loss and spiral ganglion cell damage. To assess oxidative activity, cochlear malondialdehyde and superoxide dismutase concentrations were determined three weeks post-treatment. Following topical application, the pharmacokinetic characteristics of dexamethasone in cochlear perilymph were analysed using high performance liquid chromatography. RESULTS: Animals receiving dexamethasone showed reduced noise-induced outer hair cell loss (three weeks post-treatment), and significant attenuation of noise-induced auditory brainstem response threshold shifts (one day post-exposure and three weeks post-treatment), compared with controls. There was no difference in spiral ganglion morphology. Animals receiving dexamethasone also showed a significantly lower malondialdehyde concentration and a higher superoxide dismutase concentration, post-exposure. Following topical application, the perilymph dexamethasone level peaked at 5330.522 ug/ml (15 minutes post-treatment), and was 299.797 ug/ml 360 minutes later. CONCLUSION: Topical application of dexamethasone to the round window niche has protective effects against intensive impulse noise induced trauma in the guinea pig cochlea. This drug can diffuse into the inner ear through the round window membrane and persist in the perilymph for a relatively long period. The mechanism of protection may involve an anti-oxidant effect. PMID- 21693073 TI - An animal model for endoscopic endonasal surgery and dacryocystorhinostomy training: uses and limitations of the lamb's head. AB - OBJECTIVES: Structured training in endoscopic sinus surgery is essential, considering the serious potential complications. We have developed a detailed endoscopic endonasal surgery training programme, using a lamb's head model. This study aimed to assess the possibilities of using such a model for endoscopic dacryocystorhinostomy training. MATERIALS AND METHODS: Dacryocystography was performed on lamb's head models, which were then meticulously dissected, both macroscopically and endoscopically, to assess the nasolacrimal system. RESULTS: Dacryocystography showed the absence of a lacrimal sac in all the lamb's heads dissected. This result was confirmed by dissection. CONCLUSION: Lamb's heads are excellent models with which to teach endoscopic sinus surgery techniques. However, this study clearly demonstrated the absence of a lacrimal sac in all such models dissected. Thus, this animal model is inappropriate for endoscopic dacryocystorhinostomy training. PMID- 21693074 TI - Transnasal endoscopic management of angiofibroma extending to pterygopalatine and infratemporal fossae. AB - INTRODUCTION: Surgical approaches to the pterygopalatine and infratemporal fossae are complex and cause significant morbidity. The commonest benign tumour to extend to the pterygopalatine and infratemporal fossae is angiofibroma. PATIENTS AND METHODS: This prospective study included 15 male patients aged 12-27 years with recurrent, severe epistaxis. After computed tomography and magnetic resonance imaging, a modified Wormald and Robinson's two-surgeon approach was used. Follow up, with endoscopy and magnetic resonance imaging, ranged from two to five years. RESULTS: Twelve patients were cured (endoscopically and radiologically). Three patients suffered recurrence, one each in the lateral sphenoid wall, pterygoid canal and infratemporal fossa. Revision surgery was performed, but one patient suffered another recurrence (lateral sphenoid wall with cavernous sinus infiltration) and was referred for gamma knife surgery. CONCLUSION: This endoscopic two-surgeon technique is an excellent approach for managing angiofibroma extending to the pterygopalatine and infratemporal fossae. Our modification markedly decreased morbidity by avoiding septum opening and sublabial incision, and by enabling better haemostasis (via maxillary artery control). Recurrence may be minimised by careful examination of the lateral sphenoid wall, pterygoid canal and infratemporal fossa pterygoid muscles. PMID- 21693076 TI - Challenges encountered in the diagnosis of tuberculous otitis media: case report and literature review. AB - OBJECTIVE: To report a rare case of tuberculous otitis media, and to highlight barriers to clinical and microbiological diagnosis. METHOD: Case report and literature review. RESULTS: Tuberculous otitis media is a rare cause of chronic ear infection in the UK. Its symptoms may mimic a range of other otological conditions, including otitis media, chronic suppurative otitis media, cholesteatoma and necrotising otitis media. CONCLUSION: This case report highlights the challenges of obtaining a clinical diagnosis of tuberculous otitis media, and emphasises the fact that screening for acid-fast bacilli is not sufficient, in isolation, to rule out mycobacterial infection. PMID- 21693075 TI - Facial muscle contraction in response to mechanical stretch after severe facial nerve injury: Clapham's sign. AB - INTRODUCTION: Following the onset of facial palsy, physiotherapists routinely inspect the inside of the patient's mouth and cheek for complications such as ulceration or trauma. In several patients with complete facial nerve palsy, it was noticed that when the cheek was stretched there was subsequent spasm of the muscles of facial expression. This also occurred in patients whose facial nerve had been transected. CASE REPORTS: We present four patients in whom this response was demonstrated. We consider the mechanism of this response and its relevance in the management of patients with facial paralysis. CONCLUSION: Following severe or complete denervation, contraction of the facial muscles following mechanical stretch provides evidence of preservation of activity in the facial muscle's excitation-contraction apparatus. Further research will investigate the clinical significance of this sign and whether it can be used as an early predicator of the development of synkinesis, as well as its relevance to facial nerve grafting and repair. PMID- 21693077 TI - Pitfalls in the management of monaural deafness. AB - OBJECTIVE: We report a patient who underwent cochlear implantation in an ear with long-term deafness, after an acoustic neuroma had been removed surgically from the other, hitherto good ear and the cochlear nerve had subsequently been resected to relieve severe tinnitus. METHOD: Case report. RESULTS: The patient could not tolerate the cochlear implant, because of a moderate headache due to the stimulation level necessary for environmental sound discrimination. CONCLUSION: Cochlear implantation in patients with long-term deafness should be considered carefully, even if deafness is monaural. PMID- 21693078 TI - Nasal myiasis by Oestrus ovis second stage larva in an immunocompetent man: case report and literature review. AB - OBJECTIVE: We report a case of an Oestrus ovis larva which developed into the second larval stage within a healthy, immunocompetent human, and we review the relevant literature. METHODS: Clinical case report and Pubmed search of reports of human nasal myiasis due to Oestrus ovis, especially those describing the larval stage. RESULTS: Humans are not normally hosts of the sheep nasal bot fly, but infestations by its larvae have been described. The eye is the most common site, but larvae have occasionally been found in the human nose. Transformation of larvae into the second and third stages, within the human nose, is even more uncommon. CONCLUSION: To the best of our knowledge, we report the first Swedish case, and the third case world-wide, of Oestrus ovis larval development beyond the first larval stage, within an immunocompetent, healthy human. PMID- 21693079 TI - Successful repair of tubercular tracheal stenosis: a rare case report. AB - OBJECTIVE: We report a rare case of successful surgical management of tubercular tracheal stenosis. There was no history of tracheostomy except for trauma management. CASE REPORT: A 24-year-old man presented with breathing difficulty. He had previously sustained blunt chest injury, a fractured mandible and minor head injury in a traffic accident. Despite successful mandibular fracture fixation, he subsequently developed progressive breathing difficulty with stridor. The patient was treated successfully with surgical resection and bronchoplastic reconstruction. Post-operatively, endotracheal tuberculosis was diagnosed. CONCLUSION: Endotracheal tuberculosis is rare despite the high incidence of pulmonary tuberculosis in India. Early diagnosis and prompt treatment are necessary to prevent tuberculous tracheobronchial stenosis, an extremely rare but serious clinical problem which can cause obstructive pneumonia and exertional dyspnoea. Surgical resection and bronchoplastic reconstruction is the established treatment for such stenosis. Patients with active tuberculosis usually respond to conventional antitubercular treatment. PMID- 21693080 TI - Anterograde-retrograde rendezvous approach for radiation-induced complete upper oesophageal sphincter stenosis: case report and literature review. AB - BACKGROUND: Strictures of the hypopharynx and oesophagus are frequently observed following (chemo)radiation. Anterograde dilatation of a complete stenosis carries a high risk of perforation. An alternative is described: a combined anterograde retrograde approach. CASE REPORT: A 75-year-old man developed complete stenosis of the oesophageal inlet after primary radiotherapy for laryngeal carcinoma and full percutaneous endoscopic gastrostomy feeding. To prevent creation of a false route into the mediastinum, a dilatation wire was introduced in a retrograde fashion into the oesophagus, through the gastrostomy opening. The wire was endoscopically identified from the proximal side and then passed through a perforation created by CO2 laser. Anterograde dilatation was safely performed, and the patient returned to a normal diet. There is consensus in the literature that blind anterograde dilatation carries a high risk of perforation; therefore, an anterograde-retrograde rendezvous technique is advisable. CONCLUSION: In cases of complete obstruction of the oesophageal inlet, anterograde-retrograde dilatation represents a safe technique with which to restore enteric continuity. PMID- 21693081 TI - Microvascular decompression may be an effective treatment for nervus intermedius neuralgia. PMID- 21693082 TI - What a human being is. PMID- 21693083 TI - The role of early electroclinical assessment in improving the evaluation of patients with disorders of consciousness. AB - We all share the need to optimise the evaluation of patients with disorders of consciousness (DOC), given the high rate of misdiagnosis of vegetative state based on clinical examination. We believe that one way to do this is to optimise assessment from the early stages, in order to reduce discontinuity between the hospital and rehabilitation phases. While clinical observation remains the "gold standard" for the diagnostic assessment of patients with DOC, neurophysiological investigations (electroencephalography, short latency evoked potentials and event related potentials) could help to further understanding of the pathophysiology underlying the state of unresponsiveness, differentiate coma from other apparently similar conditions (i.e., locked-in and locked-in-like syndromes), and potentially integrate prognostic evaluation with monitoring of the evolution of the clinical state. Moreover, these techniques have the considerable advantage of being available at the bedside. Discontinuity between the hospital and rehabilitation phases is rightly considered to be one of the critical points in the assessment of patients with DOC. In our view, a continuum of expert neurological assessment that begins with monitoring of the acute phase (focusing on evolution of primary brain damage and secondary complications) and follows through to the patient's discharge from the intensive care unit (focusing on the pathophysiology of brain damage and prognostication based on clinical, neuroimaging and neurophysiological tests) could help to: i) optimise the rehabilitation programme according to the expectations of recovery; ii) provide a basis for comparison with subsequent periodic re-evaluations; iii) ensure uniformity of assessment regardless of the heterogeneity of care facilities; and iv) characterise a subset of patients who, showing discrepancies between neurophysiological tests and clinical status, are more likely to undergo unexpected recovery. PMID- 21693084 TI - Vegetative state, minimally conscious state, akinetic mutism and Parkinsonism as a continuum of recovery from disorders of consciousness: an exploratory and preliminary study. AB - The aim of this study was to review the usefulness of clinical and instrumental evaluation in individuals with disorders of consciousness (DOC). Thirteen subjects with severe acquired brain injury (ABI) and a diagnosis of DOC were evaluated using the Coma Recovery Scale in its revised version (CRS-R) and a new global disability index, the Post-Coma Scale (PCS). These instruments were administered both by a neutral examiner (professional) and by a professional in the presence of a caregiver. All patients were also scored using the International Classification of Functioning, Disability and Health (ICF). A statistically significant correlation between CRS-R and PCS was demonstrated. However, there also emerged significant differences in responsiveness between professional versus caregiver+professional assessment using the two scales. The emotional stimulation provided by significant others (caregivers) during administration of DOC evaluation scales may improve the assessment of responsiveness. PMID- 21693085 TI - Automated EEG entropy measurements in coma, vegetative state/unresponsive wakefulness syndrome and minimally conscious state. AB - Monitoring the level of consciousness in brain-injured patients with disorders of consciousness is crucial as it provides diagnostic and prognostic information. Behavioral assessment remains the gold standard for assessing consciousness but previous studies have shown a high rate of misdiagnosis. This study aimed to investigate the usefulness of electroencephalography (EEG) entropy measurements in differentiating unconscious (coma or vegetative) from minimally conscious patients. Left fronto-temporal EEG recordings (10-minute resting state epochs) were prospectively obtained in 56 patients and 16 age-matched healthy volunteers. Patients were assessed in the acute (<=1 month post-injury; n=29) or chronic (>1 month post-injury; n=27) stage. The etiology was traumatic in 23 patients. Automated online EEG entropy calculations (providing an arbitrary value ranging from 0 to 91) were compared with behavioral assessments (Coma Recovery Scale Revised) and outcome. EEG entropy correlated with Coma Recovery Scale total scores (r=0.49). Mean EEG entropy values were higher in minimally conscious (73+/ 19; mean and standard deviation) than in vegetative/unresponsive wakefulness syndrome patients (45+/-28). Receiver operating characteristic analysis revealed an entropy cut-off value of 52 differentiating acute unconscious from minimally conscious patients (sensitivity 89% and specificity 90%). In chronic patients, entropy measurements offered no reliable diagnostic information. EEG entropy measurements did not allow prediction of outcome. User-independent time-frequency balanced spectral EEG entropy measurements seem to constitute an interesting diagnostic - albeit not prognostic - tool for assessing neural network complexity in disorders of consciousness in the acute setting. Future studies are needed before using this tool in routine clinical practice, and these should seek to improve automated EEG quantification paradigms in order to reduce the remaining false negative and false positive findings. PMID- 21693086 TI - Oscillatory brain activity in vegetative and minimally conscious state during a sentence comprehension task. AB - Patients with altered states of consciousness continue to constitute a major challenge in terms of clinical assessment, treatment and daily management. Furthermore, the exploration of brain function in severely brain-damaged patients represents a unique lesional approach to the scientific study of consciousness. Electroencephalography is one means of identifying covert behaviour in the absence of motor activity in these critically ill patients. Here we focus on a language processing task which assesses whether vegetative (n=10) and minimally conscious state patients (n=4) (vs control subjects, n=14) understand semantic information on a sentence level ("The opposite of black is... white/yellow/nice"). Results indicate that only MCS but not VS patients show differential processing of unrelated ("nice") and antonym ("white") words in the form of parietal alpha (10-12Hz) event-related synchronization and desynchronization (ERS/ERD), respectively. Controls show a more typical pattern, characterized by alpha ERD in response to unrelated words and alpha ERS in response to antonyms. PMID- 21693087 TI - Resting state activity in patients with disorders of consciousness. AB - Recent advances in the study of spontaneous brain activity have demonstrated activity patterns that emerge with no task performance or sensory stimulation; these discoveries hold promise for the study of higher-order associative network functionality. Additionally, such advances are argued to be relevant in pathological states, such as disorders of consciousness (DOC), i.e., coma, vegetative and minimally conscious states. Recent studies on resting state activity in DOC, measured with functional magnetic resonance imaging (fMRI) techniques, show that functional connectivity is disrupted in the task-negative or the default mode network. However, the two main approaches employed in the analysis of resting state functional connectivity data (i.e., hypothesis-driven seed-voxel and data-driven independent component analysis) present multiple methodological difficulties, especially in non-collaborative DOC patients. Improvements in motion artifact removal and spatial normalization are needed before fMRI resting state data can be used as proper biomarkers in severe brain injury. However, we anticipate that such developments will boost clinical resting state fMRI studies, allowing for easy and fast acquisitions and ultimately improve the diagnosis and prognosis in the absence of DOC patients' active collaboration in data acquisition. PMID- 21693089 TI - Disorders of consciousness and communication. Ethical motivations and communication-enabling attributes of consciousness. AB - Envisaged extensions of a functional magnetic resonance imaging (fMRI) technique allowing communication with patients affected by disorders of consciousness are here examined in connection with subjective symptom reporting, informed consent, and continued medical care decision-making. The principles of medical beneficence, personal autonomy protection, and the right to participate in social life are isolated as appropriate sources of ethical motivations for the use of fMRI-enabled communication. Consciousness requirements for each communication context are identified on the basis of qualitative distinctions between the access, phenomenal, and narrative varieties of consciousness. Ethically motivated uses of fMRI-enabled communication are hierarchically organized in terms of progressively more demanding consciousness requirements for successful communication. The outcomes of this analysis can be used to curb unrealistic expectations of these new scientific developments, and to promote mutual trust between medical doctors, patient surrogates and families. PMID- 21693088 TI - Post-anoxic vegetative state: imaging and prognostic perspectives. AB - Prognostic determination of patients in coma after resuscitation from cardiac arrest is a common and difficult requirement with significant ethical, social and legal implications. We set out to seek markers that can be used for the early detection of patients with a poor prognosis, so as to reduce uncertainty over treatment and non-treatment decisions, and to improve relationships with families. We reviewed the medical literature from 1991 to 2010, using key words such as post-anoxic coma, post-anoxic vegetative state, vegetative state prognosis, recovery after cardiac arrest. Neurological examination, electrophysiology, imaging, and biochemical markers are all useful tools for estimating patients' chances of recovery from cardiac arrest. It seems unlikely that any single test will prove to have 100% predictive value for outcome; but the combination of various prognostic markers, as shown in some articles, could increase the reliability of outcome prediction. However, further research is needed. PMID- 21693090 TI - Cognitive rehabilitation in non-communicative brain-damaged patients. AB - Conscious patients with severe motor and speech disorders have great difficulty interacting with the environment and communicating with other people. Several augmentative communication devices are now available to exploit these patients' expressive potential, but their use often demands considerable cognitive effort. Non-communicative patients with severe brain lesions may have, in addition, specific cognitive deficits that hinder the efficient use of augmentative communication methods. Some neuropsychological batteries are now available for testing these patients. On the basis of such cognitive assessments, cognitive rehabilitation training can now be applied, but we underline that this training must be tailored to single patients in order to allow them to communicate autonomously and efficiently. PMID- 21693091 TI - My 21 years with the Journal of Psychiatry and Neuroscience, with observations on editors, editorial boards, authors and reviewers. PMID- 21693092 TI - Managing anxiety and depressive symptoms in adults with autism-spectrum disorders. PMID- 21693093 TI - Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls. AB - BACKGROUND: Patients with schizophrenia show increased brain and cerebrospinal fluid (CSF) concentrations of the endogenous N-methyl-D-aspartate receptor antagonist kynurenic acid (KYNA). This compound is an end-metabolite of the kynurenine pathway, and its formation indirectly depends on the activity of kynurenine 3-monooxygenase (KMO), the enzyme converting kynurenine to 3 hydroxykynurenine. METHODS: We analyzed the association between KMO gene polymorphisms and CSF concentrations of KYNA in patients with schizophrenia and healthy controls. Fifteen single nucleotide polymorphisms (SNPs) were selected covering KMO and were analyzed in UNPHASED. RESULTS: We included 17 patients with schizophrenia and 33 controls in our study. We found an association between a KMO SNP (rs1053230), encoding an amino acid change of potential importance for substrate interaction, and CSF concentrations of KYNA. LIMITATIONS: Given the limited sample size, the results are tentative until replication. CONCLUSION: Our results suggest that the nonsynonymous KMO SNP rs1053230 influences CSF concentrations of KYNA. PMID- 21693096 TI - Tumor necrosis factor alpha promoter polymorphisms in Mexican patients with dengue fever. AB - Increased levels of tumor necrosis factor alpha (TNF-alpha) in patients with dengue have been reported. Various polymorphisms have been identified in the promoter region of the TNF-alpha gene that may affect its transcription. The purpose of the present study was to evaluate the relationship between polymorphisms of TNF-alpha gene and the genetic susceptibility to dengue fever in a group of patients from Morelos State, Mexico. The TNF-alpha polymorphisms (positions -238 and -308) were determined by PCR-RFLP technique in 130 patients with dengue (85 with dengue fever and 45 with dengue hemorrhagic fever) and 169 healthy controls. The patients were selected from cases reported in Morelos State from 1997 to 2003. The whole group of dengue patients showed a decreased frequency of TNF-alpha -238 A allele when compared to healthy controls (p = 0.01, OR = 0.19, 95%CI = 0.02-0.78). When the analysis was made separately in dengue fever and dengue hemorrhagic fever patients, the decreased frequency of TNF-alpha -238 A allele only remained significant in patients with DHF when compared to healthy controls (p = 0.034). This work suggests a possible association of TNF alpha -238 A allele with protection to develop symptomatic disease. PMID- 21693094 TI - Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction. AB - The insular cortex is one of the brain regions that show consistent abnormalities in both structural and functional neuroimaging studies of schizophrenia. In healthy individuals, the insula has been implicated in a myriad of physiologic functions. The anterior cingulate cortex (ACC) and insula together constitute the salience network, an intrinsic large-scale network showing strong functional connectivity. Considering the insula as a functional unit along with the ACC provides an integrated understanding of the role of the insula in information processing. In this review, we bring together evidence from imaging studies to understand the role of the salience network in schizophrenia and propose a model of insular dysfunction in psychosis. PMID- 21693097 TI - Quantification of oxidized levels of specific RNA species using an aldehyde reactive probe. AB - Emerging evidence has shown that oxidation of RNA, including messenger RNA (mRNA), is elevated in several age-related diseases, although investigation of oxidized levels of individual RNA species has been limited. Recently we reported that an aldehyde reactive probe (ARP) quantitatively reacts with oxidatively modified depurinated/depyrimidinated (abasic) RNA. Here we report a novel method to isolate oxidized RNA using ARP and streptavidin beads. An oligo RNA containing abasic sites that were derivatized with ARP was pulled down by streptavidin beads, whereas a control oligo RNA was not. In vitro oxidized RNA, as well as total cellular RNA, isolated from oxidatively stressed cells was also pulled down, dependent on oxidation level, and concentrated in the pull-down fraction. Quantitative reverse transcription polymerase chain reaction (RT-PCR) using RNA in the pull-down fraction demonstrated that several gene transcripts were uniquely increased in the fraction by oxidative stress. Thus, our method selectively concentrates oxidized RNA by pull-down and enables the assessment of oxidation levels of individual RNA species. PMID- 21693098 TI - Molecular imaging of epidermal growth factor receptor kinase activity. AB - Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is commonly altered in different tumor types, leading to abnormally regulated kinase activity and excessive activation of downstream signaling cascades, including cell proliferation, differentiation, and migration. To investigate the EGFR signaling events in real time and in living cells and animals, here we describe a multidomain chimeric reporter whose bioluminescence can be used as a surrogate for EGFR kinase activity. This luciferase-based reporter was developed in squamous cell carcinoma cells (UMSCC1) to generate a cancer therapy model for imaging EGFR. The reporter is designed to act as a phosphorylated substrate of EGFR and reconstitutes luciferase activity when it is not phosphorylated, thereby providing a robust indication of EGFR inhibition. We validated the reporter in vitro and demonstrated that its activity could be differentially modulated by EGFR tyrosine kinase inhibition with erlotonib or receptor activation with epidermal growth factor. Further experiments in vivo demonstrated quantitative and dynamic monitoring of EGFR tyrosine kinase activity in xenograft. Results obtained from these studies provide unique insight into pharmacokinetics and pharmacodynamics of agents that modulate EGFR activity, revealing the usefulness of this reporter in evaluating drug availability and cell targeting in both living cells and mouse models. PMID- 21693099 TI - Specific detection of Mycobacterium sp. genomic DNA using dual labeled gold nanoparticle based electrochemical biosensor. AB - The present study was aimed at the development and evaluation of a DNA electrochemical biosensor for Mycobacterium sp. genomic DNA detection in a clinical specimen using a signal amplifier as dual-labeled AuNPs. The DNA electrochemical biosensors were fabricated using a sandwich detection strategy involving two kinds of DNA probes specific to Mycobacterium sp. genomic DNA. The probes of enzyme ALP and the detector probe both conjugated on the AuNPs and subsequently hybridized with target DNA immobilized in a SAM/ITO electrode followed by characterization with CV, EIS, and DPV analysis using the electroactive species para-nitrophenol generated by ALP through hydrolysis of para-nitrophenol phosphate. The effect of enhanced sensitivity was obtained due to the AuNPs carrying numerous ALPs per hybridization and a detection limit of 1.25 ng/ml genomic DNA was determined under optimized conditions. The dual labeled AuNP-facilitated electrochemical sensor was also evaluated by clinical sputum samples, showing a higher sensitivity and specificity and the outcome was in agreement with the PCR analysis. In conclusion, the developed electrochemical sensor demonstrated unique sensitivity and specificity for both genomic DNA and sputum samples and can be employed as a regular diagnostics tool for Mycobacterium sp. monitoring in clinical samples. PMID- 21693100 TI - Importance of RNA analysis in interpretation of reporter gene expression data. AB - Reporter gene assays have proven to be an important tool in analyzing cis and trans factors that influence gene expression. However, they have sometimes been adapted for studies in which they are not totally reliable. Modifications that change the RNA expressed from the reporter gene may result in regulation of reporter gene expression at multiple levels simultaneously. The data provided here illustrate the difficulties that may arise from posttranscription regulation in various reporter gene formats. This serves as a warning that further RNA studies may be necessary, if comparisons are to be made between reporter constructs whose RNA is not identical. PMID- 21693101 TI - A bioluminescence method for direct measurement of phosphodiesterase activity. AB - We have adapted bioluminescence methods to be able to measure phosphodiesterase (PDE) activity in a one-step technique. The method employs a four-enzyme system (PDE, adenylate kinase (AK) using excess CTP instead of ATP as substrate, pyruvate kinase (PK), and firefly luciferase) to generate ATP, with measurement of the concomitant luciferase-light emission. Since AK, PK, and luciferase reactions are coupled to recur in a cyclic manner, AMP recycling maintains a constant rate of ATP formation, proportional to the steady-state AMP concentration. The cycle can be initiated by the PDE reaction that yields AMP. As long as the PDE reaction is rate limiting, the system is effectively at steady state and the bioluminescence kinetics progresses at a constant rate proportional to the PDE activity. In the absence of cAMP and PDE, low concentrations of AMP trigger the AMP cycling, which allows standardizing the system. The sensitivity of the method enables detection of <1 MUU (pmol/min) of PDE activity in cell extracts containing 0.25-10 MUg protein. Assays utilizing pure enzyme showed that 0.2 mM IBMX completely inhibited PDE activity. This single-step enzyme- and substrate-coupled cyclic-reaction system yields a simplified, sensitive, reproducible, and accurate method for quantifying PDE activities in small biological samples. PMID- 21693102 TI - Anti-obesity and anti-hyperglycemic effects of the dietary citrus limonoid nomilin in mice fed a high-fat diet. AB - TGR5 is a member of the G protein-coupled receptor family and is activated by bile acids (BAs). TGR5 is thought to be a promising drug target for metabolic diseases because the activation of TGR5 prevents obesity and hyperglycemia in mice fed a high-fat diet (HFD). In the present study, we identified a naturally occurring limonoid, nomilin, as an activator of TGR5. Unlike BAs, nomilin did not exhibit the farnesoid X receptor ligand activity. Although the nomilin derivative obacunone was capable of activating TGR5, limonin (the most abundant limonoid in citrus seeds) was not a TGR5 activator. When male C57BL/6J mice fed a HFD for 9 weeks were further fed a HFD either alone or supplemented with 0.2%w/w nomilin for 77 days, nomilin-treated mice had lower body weight, serum glucose, serum insulin, and enhanced glucose tolerance. Our results suggest a novel biological function of nomilin as an agent having anti-obesity and anti-hyperglycemic effects that are likely to be mediated through the activation of TGR5. PMID- 21693103 TI - Acidosis leads to brain dysfunctions through impairing cortical GABAergic neurons. AB - Acidosis, associated with metabolic disorders, leads to the pathological changes of cognition and behavior in the clinical practices of neurology and psychology. The cellular mechanisms underlying these cerebral dysfunctions remain unclear. By using electrophysiological approach and changing extracellular pH, we have investigated the effects of acidic environment on cortical GABAergic neurons in terms of their abilities of firing spikes and responses to synaptic inputs. Artificial cerebral spinal fluid in low pH impairs the responses to excitatory synaptic inputs and the abilities of encoding sequential spikes at these GABAergic neurons. The impairments of neuronal spiking are associated with the increases of refractory periods and threshold potentials. Our studies reveal that acidosis may impair cortical GABAergic neurons and in turn deteriorate brain functions, in which their final targets are voltage-gated sodium channels and glutamate receptor-channels. PMID- 21693104 TI - Fibrotic response induced by angiotensin-II requires NAD(P)H oxidase-induced reactive oxygen species (ROS) in skeletal muscle cells. AB - Fibrotic disorders are typified by excessive connective tissue and extracellular matrix (ECM) deposition that precludes normal healing processes in different tissues. Angiotensin-II (Ang-II) is involved in the fibrotic response. Several muscular dystrophies are characterized by extensive fibrosis. However, the exact role of Ang-II in skeletal muscle fibrosis is unknown. Here we show that myoblasts responded to Ang-II by increasing protein levels of connective tissue growth factor (CTGF/CCN2), collagen-III and fibronectin. These Ang-II-induced pro fibrotic effects were mediated by AT-1 receptors. Remarkably, Ang-II induced reactive oxygen species (ROS) via a NAD(P)H oxidase-dependent mechanism, as shown by inhibition of ROS production via the NAD(P)H oxidase inhibitors diphenylene iodonium (DPI) and apocynin. This increase in ROS is critical for Ang-II-induced fibrotic effects, as indicated by the decrease in Ang-II-induced CTGF and fibronectin levels by DPI and apocynin. We also show that Ang-II-induced ROS production and fibrosis require PKC activity as indicated by the generic PKC inhibitor chelerythrine. These results strongly suggest that the fibrotic response induced by Ang-II is mediated by AT-1 receptor and requires NAD(P)H induced ROS in skeletal muscle cells. PMID- 21693105 TI - Neuraminidase inhibitor R-125489--a promising drug for treating influenza virus: steered molecular dynamics approach. AB - Two neuraminidase inhibitors, oseltamivir and zanamivir, are important drug treatments for influenza. Oseltamivir-resistant mutants of the influenza virus A/H1N1 and A/H5N1 have emerged, necessitating the development of new long-acting antiviral agents. One such agent is a new neuraminidase inhibitor R-125489 and its prodrug CS-8958. An atomic level understanding of the nature of this antiviral agents binding is still missing. We address this gap in our knowledge by applying steered molecular dynamics (SMD) simulations to different subtypes of seasonal and highly pathogenic influenza viruses. We show that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. Based on results obtained by SMD and the molecular mechanics-Poisson-Boltzmann surface area method, we predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus as its binding affinity does not vary much across these systems. The high correlation level between theoretically determined rupture forces and experimental data on binding energies for the large number of systems studied here implies that SMD is a promising tool for drug design. PMID- 21693106 TI - Overexpression of Nrdp1/FLRF sensitizes cells to oxidative stress. AB - Nrdp1 is a RING finger containing ubiquitin E3 ligase that interacts with and modulates activity of multiple proteins, including ErbB3 and Parkin, a causative protein for early onset recessive juvenile parkinsonism (AR-JP). To investigate the functions of Nrdp1, we have generated stable Tet-On inducible HEK293 cells that overexpress Flag-tagged full length Nrdp1, N-terminal Nrdp1 and C-terminal Nrdp1. We demonstrate that overexpression of full-length Nrdp1, not Nrdp1 N terminus or Nrdp1 C-terminus in cultured HEK293 cells, inhibits cell growth. In addition, we have treated cells with hydroxynonenal (HNE), 6-hydroxydopamine (6 OHDA), and hydrogen peroxide (H(2)O(2)) at different concentrations. We have found that Nrdp1 overexpression sensitizes HEK293 cells to oxidative stressors in a dosage-dependent manner. Our data provide insights into understanding the potential role of Nrdp1 in cell growth, apoptosis and oxidative stress, and in the pathogenesis of Parkinson's disease. PMID- 21693107 TI - Focal adhesion kinase signaling pathway is involved in mechanotransduction in MG 63 cells. AB - Interstitial fluid flow, generated upon induced movement of extracellular fluid after mechanical loading, activates many signal transduction pathways in bone cells. The mechanisms of mechanobiology in bone tissue are still not clearly understood. Recently focal adhesion kinase (FAK) was shown to be involved in mechanotransduction in a number of cells. This study was designed to characterize the functional roles of FAK in mediating osteoblast response to mechanical steady state fluid shear stress (FSS). We reported here that FSS (15 dynes/cm(2)) induced activation of FAK and formation of FAK.Grb2.Sos ternary complex in MG-63 cells, which was necessary for activation of the downstream mitogen-activated protein kinase pathway signaling molecules extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). Our results also showed that transfection of FAK (F397Y) plasmid, a negative mutant of FAK, blocked the increased expression of binding factor alpha 1, osterix, osteocalcin and alkaline phosphatase induced by FSS in MG-63 cells. These results demonstrate that FAK signaling is critical for FSS-induced activation of ERK and JNK, and for promotion of osteoblast differentiation and osteogenesis via its association with Grb2/Sos complex. PMID- 21693108 TI - Estrogen inhibits the early development of mouse follicles through regulating the expression of Kit ligand. AB - Estrogen inhibits cyst breakdown and primordial follicle assembling of germ cells, but little is known about the underlying mechanisms. We aimed to analyze the effects of estrogen on the early development of mouse follicles using an in vitro ovary culture system and in vivo injection. Newborn mouse ovarian tissues were cultured in vitro for 2 or 4 days with estrogen of 0 M, 10(-8) M and 10(-4) M, respectively, and neonatal mice were injected with 5mg/kg/day estrogen. We found that the percentages of different-stage follicles significantly varied between the control and estrogen-treated groups. In vitro experiments showed that the unassembled follicles accounted for 70.5+/-2.7% and the primordial follicles accounted for 29.5+/-2.7% in the treatment group, but in the control group, ovaries had 61.7+/-8.4% unassembled follicles. In vivo experiments showed that the percentages of unassembled follicles and primordial follicles were 37.1+/ 5.2% and 51.6+/-2.4% in the control group, while they were 72.6+/-5.2% and 25.1+/ 5.5% in the treatment group. Moreover, we analyzed the expression of Kit ligand in mouse ovaries treated by estrogen with real-time PCR and western blot technology, and found that compared with the control group, both mRNA and protein expression levels were decreased in the treatment group (P<0.05). These results indicate that estrogen inhibits the development of mouse ovarian follicles by regulating the expression of Kit ligand. PMID- 21693109 TI - Liver X Receptor: an oxysterol sensor and a major player in the control of lipogenesis. AB - De novo fatty acid biosynthesis is also called lipogenesis. It is a metabolic pathway that provides the cells with fatty acids required for major cellular processes such as energy storage, membrane structures and lipid signaling. In this article we will review the role of the Liver X Receptors (LXRs), nuclear receptors that sense oxysterols, in the transcriptional regulation of genes involved in lipogenesis. PMID- 21693110 TI - Elevated plasma myeloperoxidase concentration in adults with obesity. PMID- 21693111 TI - A comparison of two FDA approved lamotrigine immunoassays with ultra-high performance liquid chromatography tandem mass spectrometry. AB - BACKGROUND: Lamotrigine is an anti-epileptic drug used as adjunct therapy for seizures. Lamotrigine is commonly used in pregnant women with epilepsy, a population in which therapeutic drug monitoring (TDM) is useful to optimize dose. Drug-drug interactions that can induce or inhibit metabolism or elimination and impaired hepatic function are also possible indications for lamotrigine TDM. Chromatographic techniques are currently used for performing most TDM of lamotrigine, but this may change, as automated immunoassays were recently introduced. METHODS: Immunoassays available through Seradyn and ARK Diagnostics were validated using a Beckman AU400e automated chemistry analyzer. The intra-day precision was accessed with 5 replicates of three quality control materials, and inter-assay precision was estimated by assaying the same material over 4 days. Linearity was evaluated by serially diluting a spiked sample and measuring it in duplicate. The 2 methods were compared with ultra high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) using 44 authentic patient specimens. RESULTS: The intra-day (n=5) and inter-assay (n=20) coefficients of variation were <=7.5% for the 3 levels tested. The analytical measurement ranges were confirmed as stated by the manufacturers (0 or 1-40 MUg/ml). The percent recovery of the quality control materials and Deming regression for the 44 patient results showed good agreement of both immunoassays when compared to the UPLC-MS/MS assay. CONCLUSION: The lamotrigine assays studied here produced a slightly lower result than UPLC-MS/MS but were precise and easy to perform. PMID- 21693112 TI - Gastric cancer - The role of matrix metalloproteinases in tumor progression. AB - Gastric cancer (GC) is a very aggressive malignant tumor of gastrointestinal tract due to its invasive nature and early metastatic ability. Degradation of the extracellular matrix (ECM) and basement membrane (BM) barriers are essential steps in the pathology of GC. Matrix metalloproteinases (MMPs) play a crucial role in the process due to their ability to degrade and rearrange these barriers to support and facilitate tumor cell migration. Therefore, these enzymes affect early carcinogenesis, tumor development and growth as well as the invasion of cancer cells at primary and metastatic sites. The endogenous inhibitors of matrix metalloproteinases (TIMPs) inhibit the active forms of MMPs and regulate the processes of their activation. The imbalance between MMPs and TIMPs may facilitate the progression of neoplastic cells. The enhanced levels of various MMPs and TIMPs have been observed in the tissue, plasma and serum of patients with many types of tumor, including gastric cancer. Moreover, levels of MMPs and TIMPs in the tissues as well as in the blood of GC patients correlated with tumor stage, depth of tumor invasion, presence of nodal and distant metastases. Selected MMPs and their tissue inhibitors were proved to be independent prognostic factors for GC patients' survival. However, further studies concerning the role of MMPs and their inhibitors in tumor biology are necessary. PMID- 21693113 TI - Evolution of a system sensitive to stochastic noise: P3.p cell fate in Caenorhabditis. AB - The C. elegans cell lineage is overall invariant. One rare instance of variability concerns P3.p, the most anterior vulva precursor cell, which may either fuse with the epidermis without dividing, or remain competent to form vulval tissue and divide. Here we examine the evolutionary properties of this stochastic variation in P3.p fate. In the Caenorhabditis genus, high P3.p competence is ancestral and reduction in P3.p competence and division frequency occurred in C. sp. 14 and in a clade of nine species. Within this clade, the frequency of P3.p division further varies within and among species, being intermediate in C. elegans and low in C. briggsae. P3.p fate frequency is sensitive to random mutation accumulation, suggesting that this trait may evolve rapidly because of its sensitivity to mutational impact. P3.p fate depends on LIN 39/Hox5 expression and we find that the peak of LIN-39/Hox5 protein level is displaced posteriorly in C. briggsae compared to C. elegans. However, P3.p fate specification is most sensitive to the dose of EGL-20 and CWN-1, two Wnts that are secreted in a long-range gradient from the posterior end of C. elegans larvae (accompanying article). A half-dose of either of these Wnts is sufficient to affect division frequency in C. elegans N2 to levels similar to those in C. briggsae. Symmetrically, we show that an increase in Wnt dose rescues anterior competence in C. briggsae. We propose that evolutionary variation in the concentration or interpretation of the long-range Wnt gradient may be involved in the rapid evolution of P3.p fate in Caenorhabditis. PMID- 21693114 TI - Dual origins of the prechordal cranium in the chicken embryo. AB - The prechordal cranium, or the anterior half of the neurocranial base, is a key structure for understanding the development and evolution of the vertebrate cranium, but its embryonic configuration is not well understood. It arises initially as a pair of cartilaginous rods, the trabeculae, which have been thought to fuse later into a single central stem called the trabecula communis (TC). Involvement of another element, the intertrabecula, has also been suggested to occur rostral to the trabecular rods and form the medial region of the prechordal cranium. Here, we examined the origin of the avian prechordal cranium, especially the TC, by observing the craniogenic and precraniogenic stages of chicken embryos using molecular markers, and by focal labeling of the ectomesenchyme forming the prechordal cranium. Subsequent to formation of the paired trabeculae, a cartilaginous mass appeared at the midline to connect their anterior ends. During this midline cartilage formation, we did not observe any progressive medial expansion of the trabeculae. The cartilages consisted of premandibular ectomesenchyme derived from the cranial neural crest. This was further divided anteroposteriorly into two portions, derived from two neural crest cell streams rostral and caudal to the optic vesicle, called preoptic and postoptic neural crest cells, respectively. Fate-mapping analysis elucidated that the postoptic neural crest cells were distributed exclusively in the lateroposterior part of the prechordal cranium corresponding to the trabeculae, whereas the preoptic stream of cells occupied the middle anterior part, differentiating into a cartilage mass corresponding to the intertrabecula. These results suggest that the central stem of the prechordal cranium of gnathostomes is composed of two kinds of distinct cartilaginous modules: a pair of trabeculae and a median intertrabecula, each derived from neural crest cells populating distinct places of the craniofacial primordia through specific migratory pathways. PMID- 21693115 TI - Melatonin protects against clomiphene citrate-induced generation of hydrogen peroxide and morphological apoptotic changes in rat eggs. AB - The present study was aimed to determine whether clomiphene citrate-induces generation of hydrogen peroxide in ovary, if so, whether melatonin could scavenge hydrogen peroxide and protect against clomiphene citrate-induced morphological apoptotic changes in rat eggs. For this purpose, forty five sexually immature female rats were given single intramuscular injection of 10 IU pregnant mare's serum gonadotropin for 48 h followed by single injections of 10 IU human chorionic gonadotropin and clomiphene citrate (10 mg/kg bw) with or without melatonin (20 mg/kg bw) for 16 h. The histology of ovary, ovulation rate, hydrogen peroxide concentration and catalase activity in ovary and morphological changes in ovulated eggs were analyzed. Co-administration of clomiphene citrate along with human chorionic gonadotropin significantly increased hydrogen peroxide concentration and inhibited catalase activity in ovary, inhibited ovulation rate and induced egg apoptosis. Supplementation of melatonin reduced hydrogen peroxide concentration and increased catalase activity in the ovary, delayed meiotic cell cycle progression in follicular oocytes as well as in ovulated eggs since extrusion of first polar body was still in progress even after ovulation and protected against clomiphene citrate-induced egg apoptosis. These results clearly suggest that the melatonin reduces oxidative stress by scavenging hydrogen peroxide produced in the ovary after clomiphene citrate treatment, slows down meiotic cell cycle progression in eggs and protects against clomiphene citrate induced apoptosis in rat eggs. PMID- 21693117 TI - Vasoactive support in the optimization of post-cardiac arrest hemodynamic status: from pharmacology to clinical practice. AB - As a critical component of post-resuscitation care, prompt optimization of hemodynamic status by means of targeted interventions is vital in order to maximize the likelihood of good outcome. Vasoactive agents play an essential role in the supportive care of post cardiac arrest patients. The administration of these agents is associated with serious side-effects and therefore they should be used in the minimal dose necessary to achieve low-normal mean arterial pressure and adequate systematic perfusion. Careful and frequent serial evaluation of the patient is important primarily to assess volume status and adequacy of circulatory support. Continuous monitoring of blood pressure and laboratory parameters is essential both to accurately titrate therapy and because inotropes and vasopressors have the potential to induce life-threatening side-effects. The clinical efficacy of inotropes and vasopressors has been largely investigated through examination of their impact on hemodynamic end points, and clinical practice has been driven in part by expert opinion, extrapolation from animal studies, and physician preference. Clearly these agents should all be considered as supportive measures to stabilize the patient prior to some form of definitive therapy. PMID- 21693116 TI - Carnosine pretreatment protects against hypoxia-ischemia brain damage in the neonatal rat model. AB - Perinatal hypoxia-ischemia brain injury is a major cause of mortality and morbidity in neonates and lacks an effective treatment thus far. Carnosine has been demonstrated to play a neuroprotective role in the adult brain injuries. However, there is no information available concerning its neuroprotective role in the immature brains after hypoxia-ischemia insults. Therefore, we investigated whether carnosine could also confer neuroprotective effects in a neonatal rat hypoxia-ischemia model. Hypoxia-ischemia was induced in rats on postnatal day 7 (P7). Carnosine (250 mg/kg) was administered intraperitoneally, 30 min prior to hypoxia-ischemia induction. Morphological brain injury and biochemical markers of apoptosis and oxidative stress were evaluated 24 h after hypoxia-ischemia induction. Cognitive performance was evaluated by the Morris Water Maze test on P28-P33. We found that pretreatment with carnosine significantly reduced the infarct volume and the number of terminal-deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells in the hypoxia-ischemia brain. Carnosine also inhibited mRNA expression of apoptosis-inducing factor(AIF) and caspase-3, which was accompanied by an increase in superoxide dismutase(SOD)activity and a decrease in the malondialdehyde(MDA)level in carnosine-treated rats. Furthermore, carnosine also improved the spatial learning and memory abilities of rats declined due to hypoxia-ischemia. These results demonstrate that carnosine can protect rats against hypoxia-ischemia-induced brain damage by antioxidation. PMID- 21693118 TI - Synergistic activity of curcumin with methotrexate in ameliorating Freund's Complete Adjuvant induced arthritis with reduced hepatotoxicity in experimental animals. AB - Methotrexate is employed in low doses for the treatment of rheumatoid arthritis. One of the major drawbacks with methotrexate is hepatotoxicity resulting in poor compliance of therapy. Curcumin is an extensively used spice possessing both anti arthritic and hepatoprotective potential. The present study was aimed at investigating the effect of curcumin (30 and 100 mg/kg) in combination with subtherapeutic dose of methotrexate (1 mg/kg) is salvaging hepatotoxicity, oxidative stress and producing synergistic anti-arthritic action with methotrexate. Wistar albino rats were induced with arthritis by subplantar injection of Freund's Complete Adjuvant and pronounced arthritis was seen after 9 days of injection. Groups of animals were treated with subtherapeutic dose of methotrexate followed half an hour later with 30 and 100mg/kg of curcumin from day 9 up to days 45 by intraperitoneal route. Methotrexate treatment in Freund's Complete Adjuvant induced arthritic animals produced elevation in the levels of aminotransferases, alkaline phosphatase, total and direct bilirubin. Enhanced oxidative stress in terms of measured lipid peroxides was observed in the methotrexate treated group. Curcumin significantly circumvented hepatotoxicity induced by methotrexate as evidenced by a change in biochemical markers possibly due to its strong anti-oxidant action. Hepatoprotective potential of curcumin was also confirmed from histological evaluation. Sub-therapeutic dose of methotrexate elicited substantial anti-arthritic action when used in combination with curcumin implying that the latter potentiated its action. Concomitant administration of curcumin with methotrexate was also found to minimize liver damage. PMID- 21693119 TI - Molecular mechanisms underlying the corneal endothelial pump. AB - The corneal endothelium is responsible for maintaining the hydration of the cornea. This is through a "Pump-Leak" mechanism where the active transport properties of the endothelium represent the "Pump" and the stromal swelling pressure represents the "Leak". For the "Pump", Na(+), K(+) ATPase activity and the presence of HCO(3)(-), Cl(-), and carbonic anhydrase activity are required. Several basolateral (stromal side) anion transporters, apical (facing the aqueous humor) ion channels and water channels have been identified that could support a model for ion secretion as the basis for the endothelial pump, however evidence of sustained anion fluxes, osmotic gradients or the need for water channels is lacking. This has prompted consideration of other models, such as Electro osmosis, and consideration of metabolite flux as components of the endothelial pump. Although the conditions under which the "Pump" is supported are known, a complete model of the endothelial "Pump" has yet to emerge. PMID- 21693120 TI - The protective effects of beta-lactam antibiotics in motor neuron disorders. AB - In the June issue of Experimental Neurology, Nizzardo and colleagues demonstrate that the beta-lactam antibiotic ceftriaxone is neuroprotective in a mouse model of spinal muscular atrophy. Here I review their main findings and the relevance to previous and future work on motor neuron disorders and for developing therapeutic strategies. PMID- 21693121 TI - Central PGE2 exhibits anxiolytic-like activity via EP1 and EP4 receptors in a manner dependent on serotonin 5-HT1A, dopamine D1 and GABAA receptors. AB - We found that centrally administered prostaglandin (PG) E(2) exhibited anxiolytic like activity in the elevated plus-maze and open field test in mice. Agonists selective for EP(1) and EP(4) receptors, among four receptor subtypes for PGE(2), mimicked the anxiolytic-like activity of PGE(2). The anxiolytic-like activity of PGE(2) was blocked by an EP(1) or EP(4) antagonist, as well as in EP(4) but not EP(1) knockout mice. Central activation of either EP(1) or EP(4) receptors resulted in anxiolytic-like activity. The PGE(2)-induced anxiolytic-like activity was inhibited by antagonists for serotonin 5-HT(1A), dopamine D(1) and GABA(A) receptors. Taken together, PGE(2) exhibits anxiolytic-like activity via EP(1) and EP(4) receptors, with downstream involvement of 5-HT(1A), D(1) and GABA(A) receptor systems. PMID- 21693122 TI - Epigenetics. PMID- 21693123 TI - In vitro and in vivo transfection of primary phagocytes via microbubble-mediated intraphagosomal sonoporation. AB - The professional phagocytes, such as macrophages and dendritic cells, are the subject of numerous research efforts in immunology and cell biology. The use of primary phagocytes in these investigations however, are limited by their inherent resistance to transfection with DNA constructs. As a result, the use of phagocyte like immortalized cell lines is widespread. While these cell lines are transfection permissive, they are generally regarded as poor biological substitutes for primary phagocytes. By exploiting the phagocytic machinery of primary phagocytes, we developed a non-viral method of DNA transfection of macrophages that employs intraphagosomal sonoporation mediated by internalized lipid-based microbubbles. This approach enables the transfection of primary phagocytes in vitro, with a modest, but reliable efficiency. Furthermore, this methodology was readily adapted to transfect murine peritoneal macrophages in vivo. This technology has immediate application to current research efforts and has potential for use in gene therapy and vaccination strategies. PMID- 21693124 TI - Presence of bioactive lysophosphatidic acid in renal effluent of rats with unilateral ureteral obstruction. AB - AIMS: Abnormal production of lysophosphatidic acid (LPA), an important lysophospholipid mediator, in the kidney was examined to participate in the pathogenesis of renal fibrosis in rats. The secretory lysophospholipase D activity of autotoxin was considered as a possible pathway for extracellular production of LPA in the pathological renal fluids. MAIN METHODS: In this study of rats with unilateral ureteral obstruction for two weeks, we measured concentrations of LPA and its precursor, lysophosphatidylcholine stored in the urinary bladder and present in the swollen pelvis of the ligated kidney as well as the corresponding blood plasma by liquid chromatography-tandem mass spectrometry. KEY FINDINGS: We found that concentrations of LPA and lysophosphatidylcholine accumulated in the effluent in the swollen pelvis of the ligated kidney of unilateral ureteral obstruction rats were much higher than those in the urinary bladder. The molecular species composition of LPA in the former was considerably different from that in the blood plasma, indicating the involvement of an additional source other than the blood circulation supplying LPA to the effluent in the swollen kidney. A potential mechanism is increased release of LPA from activated renal cells in the ureter-ligated kidney. SIGNIFICANCE: Both pathways for supply of extracellular LPA may participate in the induction and progression of renal tubulofibrosis. PMID- 21693125 TI - A population of immature cerebellar parallel fibre synapses are insensitive to adenosine but are inhibited by hypoxia. AB - The purine adenosine plays an important role in a number of physiological and pathological processes and is neuroprotective during hypoxia and ischemia. The major effect of adenosine is to suppress network activity via the activation of A(1) receptors. Here we report that in immature cerebellar slices, the activation of A(1) receptors has variable effects on parallel fibre synaptic transmission, ranging from zero depression to an almost complete abolition of transmission. Concentration-response curves suggest that the heterogeneity of inhibition stems from differences in A(1) receptor properties which could include coupling to downstream effectors. There is less variation in the effects of adenosine at parallel fibre synapses in slices from older rats and thus adenosine signalling appears developmentally regulated. In the cerebellum, hypoxia increases the concentration of extracellular adenosine leading to the activation of A(1) receptors (at adenosine-sensitive parallel fibre synapses) and the suppression of glutamate release. It would be predicted that the synapses that were insensitive to adenosine would be less depressed by hypoxia and thus maintain function during metabolic stress. However those synapses which were insensitive to adenosine were rapidly inhibited by hypoxia via a mechanism which was not reversed by blocking A(1) receptors. Thus another mechanism must be responsible for the hypoxia mediated depression at these synapses. These different mechanisms of depression may be important for cell survival and for maintenance of cerebellar function following oxygen starvation. PMID- 21693126 TI - Do GluA1 knockout mice exhibit behavioral abnormalities relevant to the negative or cognitive symptoms of schizophrenia and schizoaffective disorder? AB - The glutamate system has been strongly implicated in the pathophysiology of psychotic illnesses, including schizophrenia and schizoaffective disorder. We recently found that knockout (KO) mice lacking the AMPA GluA1 subunit displayed behavioral abnormalities relevant to some of the positive symptoms of these disorders. Here we phenotyped GluA1 KO mice for behavioral phenotypes pertinent to negative and cognitive/executive symptoms. GluA1 KO mice were tested for conspecific social interactions, the acquisition and extinction of an operant response for food-reward, operant-based pairwise visual discrimination and reversal learning, and impulsive choice in a delay-based cost/benefit decision making T-maze task. Results showed that GluA1 KO mice engaged in less social interaction than wildtype (WT) controls when tested in a non-habituated, novel environment, but, conversely, displayed more social interaction in a well habituated, familiar environment. GluA1 KO mice were faster to acquire an operant stimulus-response for food reward than WT and were subsequently slower to extinguish the response. Genotypes showed similar pairwise discrimination learning and reversal, although GluA1 KO mice made fewer errors during early reversal. GluA1 KO mice also displayed increased impulsive choice, being less inclined to choose a delayed, larger reward when given a choice between this and a smaller, immediate reward, compared to WT mice. Finally, sucrose preference did not differ between genotypes. Collectively, these data add to the growing evidence that GluA1 KO mice display at least some phenotypic abnormalities mimicking those found in schizophrenia/schizoaffective disorder. Although these mice, like any other single mutant line, are unlikely to model the entire disease, they may nevertheless provide a useful tool for studying the role of GluA1 in certain aspects of the pathophysiology of major psychotic illness. PMID- 21693127 TI - Effects of olanzapine, sertindole and clozapine on MK-801 induced visual memory deficits in mice. AB - We investigated the effects of the second generation antipsychotics olanzapine, sertindole and clozapine on visual recognition memory using the novel object recognition (NOR) test in naive and MK-801-treated animals. The effects of drug treatment on locomotion and anxiety were also determined using the open field test. Male Balb-c mice were treated with olanzapine (0.2, 0.4 and 0.6 mg/kg; i.p.), sertindole (0.63, 1.3 and 2.5mg/kg; s.c.) or clozapine (0.5 and 1mg/kg; i.p.), and cognitive deficits were induced by MK-801 (0.2mg/kg; i.p.) administration. Olanzapine treatment decreased the ratio index in the NOR test, whereas sertindole and clozapine had no effect in naive mice. MK-801-induced cognitive impairment was reversed by treatment with olanzapine, sertindole or clozapine. While olanzapine, sertindole and clozapine had no effect on the anxiety of naive mice as determined by the open field test, MK-801 significantly increased the total distance traveled, time spent in the center zone and the velocity of the animals. MK-801-induced effects on locomotion and anxiety in the open field test were reversed by olanzapine, sertindole or clozapine treatment. The results of the present study demonstrated that olanzapine, sertindole and clozapine improved cognition in MK-801 treated mice, and indicate that these drugs have a potential to improve cognition in schizophrenia. PMID- 21693128 TI - Infusions of neuropeptide Y into the lateral septum reduce anxiety-related behaviors in the rat. AB - Neuropeptide Y (NPY) is one of the most abundant peptides in mammalian brain and NPY-like-immunoreactivity is highly expressed in the lateral septum, an area extensively involved in anxiety regulation. NPY counteracts the neurochemical and behavioral responses to acute threat in animal models, and intracerebroventricular (i.c.v.) administration of NPY at low doses is anxiolytic. Less is known about the specific contributions of the lateral septum to NPY-mediated anxiety regulation. In Experiment 1, the effects of infusions of NPY (1.5 MUg) into the lateral septum were investigated in three animal models of anxiety: the elevated plus-maze, novelty-induced suppression of feeding, and shock-probe burying tests. Experiment 2 examined the role of the NPY Y1 receptor in these models by co-infusing the Y1 antagonist BIBO 3304 (0.15 MUg, 0.30 MUg) with NPY into the lateral septum. In the elevated plus-maze, there were no changes in rats' open arm exploration, the index of anxiety reduction in this test. In the novelty-induced suppression of feeding test, rats infused with NPY showed decreases in the latency to consume a palatable snack in a novel (but not familiar) environment, suggesting a reduction in anxiety independent of increases in appetite. This anxiolysis was attenuated by co-infusion with BIBO 3304 (0.30 MUg) in Experiment 2. Lastly, rats infused with NPY showed decreases in the duration of burying behavior in the shock-probe burying test, also indicative of anxiety reduction. However, unlike in the feeding test, BIBO 3304 did not attenuate the NPY-induced anxiolysis in the shock-probe test. It is concluded that NPY produces anxiolytic-like actions in the lateral septum in two animal models of anxiety: the novelty-induced suppression of feeding, and shock-probe burying tests, and that this anxiolysis is dependent on Y1 receptor activation in the feeding test. PMID- 21693129 TI - Chronic coffee and caffeine ingestion effects on the cognitive function and antioxidant system of rat brains. AB - Coffee is a popular beverage consumed worldwide and its effect on health protection has been well studied throughout literature. This study investigates the effect of chronic coffee and caffeine ingestion on cognitive behavior and the antioxidant system of rat brains. The paradigms of open field and object recognition were used to assess locomotor and exploratory activities, as well as learning and memory. The antioxidant system was evaluated by determining the activities of glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD), as well as the lipid peroxidation and reduced glutathione content. Five groups of male rats were fed for approximately 80 days with different diets: control diet (CD), fed a control diet; 3% coffee diet (3%Co) and 6% coffee diet (6%Co), both fed a diet containing brewed coffee; 0.04% caffeine diet (0.04%Ca) and 0.08% caffeine diet (0.08%Ca), both fed a control diet supplemented with caffeine. The estimated caffeine intake was approximately 20 and 40 mg/kg per day, for the 3%Co-0.04%Ca and 6%Co-0.08%Ca treatments, respectively. At 90 days of life, the animals were subjected to the behavioral tasks and then sacrificed. The results indicated that the intake of coffee, similar to caffeine, improved long-term memory when tested with object recognition; however, this was not accompanied by an increase in locomotor and exploratory activities. In addition, chronic coffee and caffeine ingestion reduced the lipid peroxidation of brain membranes and increased the concentration of reduced-glutathione. The activities of the GR and SOD were similarly increased, but no change in GPx activity could be observed. Thus, besides improving cognitive function, our data show that chronic coffee consumption modulates the endogenous antioxidant system in the brain. Therefore, chronic coffee ingestion, through the protection of the antioxidant system, may play an important role in preventing age-associated decline in the cognitive function. PMID- 21693130 TI - Blockade of 5-HT7 receptors reduces tactile allodynia in the rat. AB - This study assessed the role of systemic and spinal 5-HT(7) receptors on rats submitted to spinal nerve injury. In addition, the 5-HT(7) receptors level in dorsal root ganglion and spinal cord was also determined. Tactile allodynia was induced by L5/L6 spinal nerve ligation. Systemic (0.01-10mg/kg) or spinal (0.3-30 MUg) administration of the selective 5-HT(7) receptor antagonist SB-269970 but not vehicle reduced in a dose-dependent manner established tactile allodynia. This effect was maintained for about 6h. SB-269970 was more potent and effective by the spinal administration route than through systemic injection. Spinal nerve ligation reduced expression of 5-HT(7) receptors in the ipsilateral but not contralateral dorsal root ganglia. Moreover, 5-HT(7) receptor levels were lower in the ipsilateral dorsal spinal cord of neuropathic rats compared to naive and sham rats. No changes in the receptor levels were observed in the contralateral dorsal spinal cord and in both regions of the ventral spinal cord. Data suggest that spinal 5-HT(7) receptors play a pronociceptive role in neuropathic rats. Results also indicate that spinal nerve injury leads to a reduced 5-HT(7) receptors level in pain processing-related areas which may result from its nociceptive role in this model. Data suggest that selective 5-HT(7) receptor antagonists may function as analgesics in nerve injury pain states. PMID- 21693131 TI - Graft copolymerization of ethylacrylate onto xanthan gum, using potassium peroxydisulfate as an initiator. AB - Graft copolymer of xanthan gum (XG) and ethylacrylate (EA) has been synthesized by free radical polymerization using potassium peroxydisulfate (KPS) as an initiator in an air atmosphere. The grafting parameters, i.e. grafting ratio and efficiency decrease with increase in concentration of xanthan gum from 0.050 mg/25 mL to 0.350 mg/25 mL, but these grafting parameters increase with increase in concentration of ethylacrylate from 9*10(-2) to 17*10(-2) ML(-1), and KPS from 15*10(-3) to 35*10(-3) ML(-1). The graft copolymer has been characterized by FTIR, XRD, TGA and SEM analysis. The grafted copolymer was also evaluated as efficient Zn(2+) metal binder. The grafted copolymer shows improvement in the stability, solubility as well as their sorbing capacity. Thus graft copolymer formed could find applications in metal ion removal and in drug delivery. PMID- 21693132 TI - Serotonin and decision making processes. AB - Serotonin (5-HT) is an important player in decision making. Serotonergic antidepressant, anxiolytic and antipsychotic drugs are extensively used in the treatment of neuropsychiatric disorders characterized by impaired decision making, and exert both beneficial and harmful effects in patients. Detailed insight into the serotonergic mechanisms underlying decision making is needed to strengthen the first and weaken the latter. Although much remains to be done to achieve this, accumulating studies begin to deliver a coherent view. Thus, high central 5-HT levels are generally associated with improved reversal learning, improved attentional set shifting, decreased delay discounting, and increased response inhibition, but a failure to use outcome representations. Based on 5 HT's evolutionary role, I hypothesize that 5-HT integrates expected, or changes in, relevant sensory and emotional internal/external information, leading to vigilance behaviour affecting various decision making processes. 5-HT receptor subtypes play distinctive roles in decision making. 5-HT(2A) agonists and 5-HT2c antagonists decrease compulsivity, whereas 5-HT(2A) antagonists and 5-HT(2C) agonists decrease impulsivity. 5-HT(6) antagonists univocally affect decision making processes. PMID- 21693133 TI - Competing clocks: metabolic status moderates signals from the master circadian pacemaker. AB - Food anticipation and its behavioural manifestation, food anticipatory activity (FAA), require entrainment of a suprachiasmatic nucleus (SCN) independent circadian mechanism, a food entrainable oscillator (FEO), with an unknown neural substrate. While the FEO entrains to fasting/feeding related cues and drives FAA independently of the pacemaker in the SCN, it must disengage the suppressing signals of the SCN for the behavioural and physiological manifestations of meal anticipation to occur outside of the typical period of arousal. This review provides a brief overview of mammalian circadian biology before summarizing experimental data demonstrating several mechanisms by which this may occur, including: reducing activation of SCN cells receiving retinal input, transient disorganization of SCN outputs, and reduced sensitivity to SCN signals in hypothalamic sites responsible for integrating homeostatic and circadian information. Further investigation of these mechanisms will be key to elucidating pharmacological or behavioural interventions that suppress the negative psychological and health effects of light-driven circadian rhythms in humans, specifically those with work schedules that do not conform to the solar day. PMID- 21693134 TI - Comparative activity of biodegradable nanoparticles with aluminum adjuvants: antigen uptake by dendritic cells and induction of immune response in mice. AB - Biodegradable poly(gamma-glutamic acid) (gamma-PGA) nanoparticles (NPs) are considered to be an excellent antigen carrier. Antigen-carrying gamma-PGA NPs were examined for their uptake by murine dendritic cells (DCs) and subsequent induction of antigen-specific immune responses in mice and compared with aluminum (AL) adjuvants. Ovalbumin (OVA)-carrying NPs (FITC-OVA-NPs) were taken up much more efficiently by DCs than OVA alone or its AL-associated form. Both OVA-NPs and OVA+AL were detected in an intracellular lysosome compartment of DCs. Furthermore, the uptake of gamma-PGA NPs was inhibited in the presence of pinocytosis and phagocytosis inhibitors. Significantly higher induction of antigen-specific CD8(+) T cells was observed in mice immunized with OVA-carrying gamma-PGA NPs than in those immunized with OVA alone, OVA+AL, OVA+3-O-desacyl-4' monophosphoryl lipid A (MPL), and OVA+AL+MPL. Thus, gamma-PGA NPs may have great potential as an effective vaccine carrier and adjuvant for clinical use. PMID- 21693135 TI - G glycoprotein amino acid residues required for human monoclonal antibody RAB1 neutralization are conserved in rabies virus street isolates. AB - Replacement of polyclonal anti-rabies immunoglobulin (RIG) used in rabies post exposure prophylaxis (PEP) with a monoclonal antibody will eliminate cost and availability constraints that currently exist using RIG in the developing world. The human monoclonal antibody RAB1 has been shown to neutralize all rabies street isolates tested; however for the laboratory-adapted fixed strain, CVS-11, mutation in the G glycoprotein of amino acid 336 from asparagine (N) to aspartic acid (D) resulted in resistance to neutralization. Interestingly, this same mutation in the G glycoprotein of a second laboratory-adapted fixed strain (ERA) did not confer resistance to RAB1 neutralization. Using cell surface staining and lentivirus pseudotyped with rabies virus G glycoprotein (RABVpp), we identified an amino acid alteration in CVS-11 (K346), not present in ERA (R346), which was required in combination with D336 to confer resistance to RAB1. A complete analysis of G glycoprotein sequences from GenBank demonstrated that no identified rabies isolates contain the necessary combination of G glycoprotein mutations for resistance to RAB1 neutralization, consistent with the broad neutralization of RAB1 observed in direct viral neutralization experiments with street isolates. All combinations of amino acids 336 and 346 reported in the sequence database were engineered into the ERA G glycoprotein and RAB1 was able to neutralize RABVpp bearing ERA G glycoprotein containing all known combinations at these critical residues. These data demonstrate that RAB1 has the capacity to neutralize all identified rabies isolates and a minimum of two distinct mutations in the G glycoprotein are required for abrogation of RAB1 neutralization. PMID- 21693136 TI - Cholecystokinin-producing (I) cells of intestinal mucosa in dexamethasone-treated rats. AB - The aim of this study was to investigate the morphological, immunohistochemical and ultrastructural changes of cholecystokinin-producing (I) cells of gastrointestinal mucosa in dexamethasone-treated rats (D). After 12-daily intraperitoneal administration of 2mg/kg dexamethasone, rats developed diabetes similar to human diabetes mellitus type 2. The mean diameter of the duodenum was significantly decreased due to significant reduction of volume fraction and profile area of lamina propria. There was a decrease in volume fraction and number of cholecystokinin (CCK)-producing cells per mm(2) of mucosa, as well as their numerical density, but without statistical significance. Also, dexamethasone induced appearance of hyperactive duodenal I-cells with small number of granules and dilated endoplasmic reticulum. In conclusion, the present study showed that morphological changes in duodenum cholecystokinin-producing (I) cells occurred in diabetic rats, in a manner which, suggests compensatory effort of CCK cells in diabetic condition. PMID- 21693137 TI - Targeted disruption of Mcm10 causes defective embryonic cell proliferation and early embryo lethality. AB - Minichromosome maintenance 10 (MCM10) is a conserved, abundant nuclear protein, which plays a key role in the initiation of eukaryotic chromosomal DNA replication and elongation. To elucidate the physiological importance of MCM10 in vivo, we generated conventional knockout mice. No MCM10-null embryos were recovered after E8.5, and the mutation was found to be lethal before the implantation stage. Mutant embryos showed apparently normal growth until the morula stage, but growth defects after this stage. The dramatic reduction of 5 bromo-2-deoxyuridine (BrdU) incorporation in the mutant embryo, followed by cell death, suggests that defective cell proliferation may underlie this developmental failure. Taken together, these findings provide the first unequivocal genetic evidence for an essential and non-redundant physiological role of MCM10 during murine peri-implantation development. PMID- 21693138 TI - Application of leftover sample material from waterborne protozoa monitoring for the molecular detection of Bacteroidales and fecal source tracking markers. AB - In this study, we examined the potential for detecting fecal bacteria and microbial source tracking markers in samples discarded during the concentration of Cryptosporidium and Giardia using USEPA Method 1623. Recovery rates for different fecal bacteria were determined in sewage spiked samples and environmental waters using different group-specific and host-specific PCR assays. Bacteroidales DNA recovery ranged from 59 to 71% for aliquots of supernatant collected after the elution step. The recovery of human-specific Bacteroidales DNA from sewage spiked samples was 54% in the elution step. An additional 1-7% Bacteroidales DNA was recovered after the immunomagnetic separation step, while recovery from the pellet left after the immunomagnetic separation of protozoa parasites was substantially lower. Comparison of Bacteroidales 16S rRNA gene sequences from elution and immunomagnetic separation discarded samples indicated that the distribution of clones was not statistically different, suggesting that there were no recovery biases introduced by these steps. Human- and cow-specific Bacteroidales and fecal indicator bacteria (i.e., enterococci,) were also detected in the discarded fractions of environmental samples collected from different geographic locations. Overall, the results of this study demonstrated the potential application of leftover sample fractions that are currently discarded for the PCR detection of fecal bacterial indicators and molecular source tracking. PMID- 21693139 TI - Identification of Mycoplasmas using a fluorophore-free microarray and infrared chemical imaging (IRCI). AB - A novel application of mid-infrared chemical imaging (IRCI) for the fluorophore free detection and identification of mycoplasma species is reported for the first time. The PCR-amplified biotinylated targets hybridized to microarray probes were treated with streptavidin-gold nanoparticles followed by silver enhancement. This modification has the potential to expand the implementation of DNA microarray techniques in laboratories involved in the detection of cell substrates, other biological products, and clinical materials for the presence of mycoplasmas. PMID- 21693140 TI - Astrocytic-neuronal crosstalk: implications for neuroprotection from brain injury. AB - The older neurocentric view of the central nervous system (CNS) has changed radically with the growing understanding of the many essential functions of astrocytes. Advances in our understanding of astrocytes include new observations about their structure, organization, function and supportive actions to other cells. Although the contribution of astrocytes to the process of brain injury has not been clearly defined, it is thought that their ability to provide support to neurons after cerebral damage is critical. Astrocytes play a fundamental role in the pathogenesis of brain injury-associated neuronal death, and this secondary injury is primarily a consequence of the failure of astrocytes to support the essential metabolic needs of neurons. These needs include K+ buffering, glutamate clearance, brain antioxidant defense, close metabolic coupling with neurons, and the modulation of neuronal excitability. In this review, we will focus on astrocytic activities that can both protect and endanger neurons, and discuss how manipulating these functions provides a novel and important strategy to enhance neuronal survival and improve the outcome following brain injury. PMID- 21693141 TI - Wound healing activity of the human antimicrobial peptide LL37. AB - Antimicrobial peptides (AMPs) are part of the innate immune system and are generally defined as cationic, amphipathic peptides, with less than 50 amino acids, including multiple arginine and lysine residues. The human cathelicidin antimicrobial peptide LL37 can be found at different concentrations in many different cells, tissues and body fluids and has a broad spectrum of antimicrobial and immunomodulatory activities. The healing of wound is a complex process that involves different steps: hemostasis, inflammation, remodeling/granulation tissue formation and re-epithelialization. Inflammation and angiogenesis are two fundamental physiological conditions implicated in this process. We have recently developed a new method for the expression and purification of recombinant LL37. In this work, we show that the recombinant peptide P-LL37 with a N-terminus proline preserves its immunophysiological properties in vitro and in vivo. P-LL37 neutralized the activation of macrophages by lipopolysaccharide (LPS). Besides, the peptide induced proliferation, migration and tubule-like structures formation by endothelial cells. Wound healing experiments were performed in dexamethasone-treated mice to study the effect of LL37 on angiogenesis and wound regeneration. The topical application of synthetic and recombinant LL37 increased vascularization and re epithelialization. Taken together, these results clearly demonstrate that LL37 may have a key role in wound regeneration through vascularization. PMID- 21693142 TI - PAC1hop, null and hip receptors mediate differential signaling through cyclic AMP and calcium leading to splice variant-specific gene induction in neural cells. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP)-mediated activation of its G protein-coupled receptor PAC1 results in activation of the two G proteins Gs and Gq to alter second messenger generation and gene transcription in the nervous system, important for homeostatic responses to stress and injury. Heterologous expression of the three major splice variants of the rat PAC1 receptor, PAC1hop, null and hip, in neural NG108-15 cells conferred PACAP mediated intracellular cAMP generation, while elevation of [Ca(2+)](i) occurred only in PAC1hop-, and to a lesser extent in PAC1null-expressing cells. Induction of vasoactive intestinal polypeptide (VIP) and stanniocalcin 1 (STC1), two genes potentially involved in PACAP's homeostatic responses, was examined as a function of the expressed PAC1 variant. VIP induction was greatest in PAC1hop-expressing cells, suggesting that a maximal transcriptional response requires combinatorial signaling through both cAMP and Ca(2+). STC1 induction was similar for all three receptor splice variants and was mimicked by the adenylate cyclase activator forskolin, indicating that cAMP elevation is sufficient to induce STC1. The degree of activation of two different second messenger pathways appears to determine the transcriptional response, suggesting that cellular responses to stressors are fine-tuned through differential receptor isoform expression. Signaling to the VIP gene proceeded through cAMP and protein kinase A (PKA) in these cells, independently of the MAP kinase ERK1/2. STC1 gene induction by PACAP was dependent on cAMP and ERK1/2, independently of PKA. Differential gene induction via different cAMP dependent signaling pathways potentially provides further targets for the design of treatments for stress-associated disorders. PMID- 21693143 TI - Antifungal activity of novel synthetic peptides by accumulation of reactive oxygen species (ROS) and disruption of cell wall against Candida albicans. AB - In the present work, we investigated the antifungal activity of two de novo designed, antimicrobial peptides VS2 and VS3, incorporating unnatural amino acid alpha,beta-dehydrophenylalanine (DeltaPhe). We observed that the low-hemolytic peptides could irreversibly inhibit the growth of various Candida species and multidrug resistance strains at MIC(80) values ranging from 15.62 MUM to 250 MUM. Synergy experiments showed that MIC(80) of the peptides was drastically reduced in combination with an antifungal drug fluconazole. The dye PI uptake assay was used to demonstrate peptide induced cell membrane permeabilization. Intracellular localization of the FITC-labeled peptides in Candida albicans was studied by confocal microscopy and FACS. Killing kinetics, PI uptake assay, and the intracellular presence of FITC-peptides suggested that growth inhibition is not solely a consequence of increased membrane permeabilization. We showed that entry of the peptide in Candida cells resulted in accumulation of reactive oxygen species (ROS) leading to cell necrosis. Morphological alteration in Candida cells caused by the peptides was visualized by electron microscopy. We propose that de novo designed VS2 and VS3 peptides have multiple detrimental effects on target fungi, which ultimately result in cell wall disruption and killing. Therefore, these peptides represent a good template for further design and development as antifungal agents. PMID- 21693144 TI - Short-term alterations in hippocampal glutamate transport system caused by one single neonatal seizure episode: implications on behavioral performance in adulthood. AB - Impairment in the activity and expression of glutamate transporters has been found in experimental models of epilepsy in adult animals. However, there are few studies investigating alterations on glutamate transporters caused by epilepsy in newborn animals, especially in the early periods after seizures. In this study, alterations in the hippocampal glutamate transporters activity and immunocontent were investigated in neonatal rats (7 days old) submitted to kainate-induced seizures model. Glutamate uptake, glutamate transporters (GLT-1, GLAST, EAAC1) and glutamine synthetase (GS) were assessed in hippocampal slices obtained 12 h, 24 h, 48 h, 72 h and 60 days after seizures. Immunoreactivity for hippocampal GFAP, NeuN and DAPI were assessed 24 h after seizure. Behavioral analysis (elevated-plus maze and inhibitory avoidance task) was also investigated in the adult animals (60 days old). The decrease on glutamate uptake was observed in hippocampal slices obtained 24 h after seizures. The immunocontent of GLT-1 increased at 12 h and decreased at 24 h (+62% and -20%, respectively), while GLAST increased up to 48 h after seizures. No alterations were observed for EAAC1 and GS. It should be mentioned that there were no long-term changes in tested glutamate transporters at 60 days after kainate treatment. GFAP immunoreactivity increased in all hippocampal subfields (CA1, CA3 and dentate gyrus) with no alterations in NeuN and DAPI staining. In the adulthood, kainate-treated rats showed anxiety-related behavior and lower performance in the inhibitory avoidance task. Our findings indicate that acute modifications on hippocampal glutamate transporters triggered by a single convulsive event in early life may play a role in the behavioral alterations observed in adulthood. PMID- 21693145 TI - Parity decreases methamphetamine-induced striatal dopaminergic perturbation. AB - The role of parity upon methamphetamine-induced neurotoxicity of the striatal dopaminergic system was assessed. Female CD-1 mice either remained nulliparous or underwent one or three complete pregnancies and were designated as the 0, 1 or 3 pregnancy groups. The mice were then treated with a neurotoxic regimen of methamphetamine (MA--40 mg/kg) or its saline vehicle (control) and striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were measured at 7-days post-MA. Basal levels of striatal DA, DOPAC and the DOPAC/DA ratio were similar among the saline (control) 0, 1 and 3 pregnancy groups. In response to MA, striatal DA and DOPAC were significantly decreased in the 0 and 1 pregnancy as compared with the control group. Mice with 3 pregnancies showed DA and DOPAC levels that did not differ from controls and were significantly greater than the 0 pregnancy group. The DOPAC/DA ratios of the 0 pregnancy group were significantly greater than all other groups (control, 1 and 3 pregnancy) which failed to differ among each other. These results demonstrate that parity decreases MA-induced striatal dopaminergic neurotoxicity, and the degree of this neuroprotection is related to the number of pregnancies experienced. PMID- 21693146 TI - Caveolin-1 inhibits oligodendroglial differentiation of neural stem/progenitor cells through modulating beta-catenin expression. AB - In the present study, we aim to elucidate the role of caveolin-1 (Cav-1) in modulating oligodendroglial differentiation of neural progenitor cells (NPCs) in vivo and in vitro. For in vivo experiments, we investigated oligodendroglial differentiation by detecting the expressions of 2',3'-cyclic nucleotide 3' phosphodiesterase (CNPase) and beta-catenin in the brains of wild type mice and Cav-1 knockout mice. Cav-1 knockout mice revealed more oligodendroglial differentiation, but lower levels of beta-catenin expression than wild type mice. For in vitro experiments, we observed the potential roles of Cav-1 in modulating beta-catenin expression and oligodendroglial differentiation in isolated cultured NPCs by manipulating Cav-1 expression with Cav-1 scaffolding domain peptide and Cav-1 RNA silencing approach. In the differentiating NPCs, Cav-1 scaffolding domain peptide markedly inhibited oligodendroglial formation, but up-regulated the expression of beta-catenin. In contrast, the knockdown of Cav-1 promoted oligodendroglial differentiation of NPCs, but down-regulated the expression of beta-catenin. Taken together, these results directly prove that caveolin-1 can inhibit oligodendroglial differentiation of NPCs through modulating beta-catenin expression. PMID- 21693147 TI - Unilateral lesion of the nigrostriatal pathway decreases the response of fast spiking interneurons in the medial prefrontal cortex to 5-HT1A receptor agonist and expression of the receptor in parvalbumin-positive neurons in the rat. AB - 5-Hydroxytryptamine(1A) (5-HT(1A)) receptors are expressed in the prefrontal cortical interneurons. Among these interneurons, calcium-binding protein parvalbumin (PV)-positive fast spiking (FS) interneurons play an important role in regulatory function of the prefrontal cortex. In the present study, the response of medial prefrontal cortex (mPFC) FS interneurons to the selective 5 HT(1A) receptor agonist 8-OH-DPAT and change in expression of 5-HT(1A) receptor on PV-positive neurons were examined in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) by using extracellular recording and double-labeling immunofluorescence histochemistry. Systemic administration of 8-OH-DPAT (1-243 MUg/kg, i.v.) dose-dependently inhibited the mean firing rate of the FS interneurons in sham-operated and the lesioned rats, respectively. The cumulative doses producing inhibition in the lesioned rats (243 MUg/kg) was significantly higher than that of sham-operated rats (27 MUg/kg). Furthermore, the local application of 8-OH-DPAT (0.01 MUg) in the mPFC inhibited the FS interneurons in sham-operated rats, while having no effect on firing rate of the FS interneurons in the lesioned rats. In contrast to sham-operated rats, the lesion of the SNc in rats did not cause the change of PV-positive neurons in the prelimbic prefrontal cortex, a subregion of the mPFC, whereas the lesion of the SNc markedly reduced in percentage of PV-positive neurons expressing 5-HT(1A) receptors. Our results indicate that degeneration of the nigrostriatal pathway results in the decreased response of FS interneurons in the mPFC to 5-HT(1A) receptor stimulation, which attributes to down-regulation of 5-HT(1A) receptor expression in these interneurons. PMID- 21693148 TI - Parkinson's disease-associated mutations in alpha-synuclein and UCH-L1 inhibit the unconventional secretion of UCH-L1. AB - Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is an intracellular protein abundantly expressed in neurons, and a mutation in UCH-L1 has been identified in familial Parkinson's disease. UCH-L1 has been detected in human cerebrospinal fluid, raising the possibility that UCH-L1 is secreted from neurons. In the present study, we showed that a portion of UCH-L1 is secreted from cultured cells. The secretion of D30K UCH-L1, which lacks ubiquitin binding activity, was decreased compared with that of wild-type UCH-L1, while the secretion of C90S UCH L1, which lacks hydrolase activity, was not. Treatment with Brefeldin A, an inhibitor of vesicle transport from the endoplasmic reticulum to the Golgi, did not block the secretion of UCH-L1, indicating that UCH-L1 is secreted by an unconventional pathway. The UCH-L1 sequence from Leu-32 to Leu-39 is similar to the unconventional secretory signal sequence of engrailed 2, and substitution of the leucines within this region (L32S/L32A/L34S/L34A/L39S/L39A) reduced the secretion of UCH-L1. We found that the Parkinson's disease-associated mutation I93M in UCH-L1 decreased the secretion of I93M UCH-L1. In addition, Parkinson's disease-linked alpha-synuclein mutants reduced the secretion of endogenous UCH L1. Our results indicate that the hydrolase activity is not necessary for the unconventional secretion of UCH-L1, and suggest that the ubiquitin binding activity and the sequence between Leu-32 and Leu-39 are involved in the secretion. Moreover, the secretion of UCH-L1 could be involved in the pathology of Parkinson's disease. PMID- 21693149 TI - Protective effect of melatonin on 3-NP induced striatal interneuron injury in rats. AB - To confirm the effect of melatonin on 3-nitropropionic acid (3-NP)-induced striatal interneuron injury in rats, behavioral test, histology, immunohistochemistry and Western blotting were respectively used to characterize the behavioral changes of experimental animals in motor and cognition, the morphological changes of striatal interneurons and the expression level of protein markers induced by 3-NP. The results showed that (1) 3-NP induced dysfunction of experimental animals in movement, motor coordination and cognition could be relieved by melatonin treatment; (2) The 3-NP-induced lesion area was unvaryingly in dorsolateral striatum, with almost all neuronal loss in the lesion core, however, lots of neurons survived after melatonin treatment; (3) Immunohistochemical staining of the four interneuron types (parvalbuminergic, cholinergic, calretinergic, and neuropeptide Y-neuronal nitric oxide synthase co containing) showed that, in the lesion core of 3-NP group, loss of the four interneuron types was obvious, but in transition zone, the processes and varicosities of calretinergic, and neuropeptide Y-neuronal nitric oxide synthase co-containing interneurons increased significantly. Melatonin treatment reduced the loss of the four interneuron types in the lesion core, and inhibited the increase of processes and varicosities in the transition zone; (4) Consistent with above results, the expression level of five interneuron protein markers were significantly increased in the striatum after melatonin treatment. Notably, in both the transition zone and the lesion core induced by 3-NP, TUNEL-positive cells were detected, but decreased significantly after melatonin treatment. The present results indicate that melatonin effectively protects the striatal neurons against the injury induced by 3-NP in rats. PMID- 21693150 TI - Induction of conditioned place preference and dopamine release by salsolinol in posterior VTA of rats: involvement of MU-opioid receptors. AB - Salsolinol (Sal), locally administered into the posterior VTA (pVTA) of rats, produces psychomotor responses and reinforcing effects, probably, through the activation of MU-opioid receptors (MORs). The neurochemical correlates of these phenomena are, however, practically unknown. In this paper, we explore the neurochemical events and the mechanisms involved in these behaviors. To do that, we test the ability of Sal, directly microinjected into the pVTA, to induce conditioned place preference (CPP) and to increase dopamine levels in the nucleus accumbens shell. Bilateral injections of 30 pmol of Sal induced a strong CPP (rats spent around 70% of the total test time), a result that could be explained by the fact that Sal microinjected into the pVTA increased DA levels in the ipsilateral accumbens up to 141% of baseline. The local pretreatment with beta FNA, an antagonist of MORs, prevented this increase, supporting our hypothesis on the involvement of MORs in the Sal-derived effects. PMID- 21693151 TI - Aroclor1254 interferes with estrogen receptor-mediated neuroprotection against beta-amyloid toxicity in cholinergic SN56 cells. AB - Because estrogen plays important neurotrophic and neuroprotective roles in the brain by activating estrogen receptors (ERs), disruption of normal estrogen signaling can leave neurons vulnerable to a variety of insults, including beta amyloid peptide (Abeta). Aroclor1254 (A1254) belongs to the endocrine-disrupting chemical (EDC) polychlorinated biphenyls and has anti-estrogenic properties. In the present study, we evaluated the effect of A1254 on the protective activity of estrogen against Abeta toxicity in differentiated cholinergic SN56 cells. Aged Abeta25-35 causes apoptotic cell death in differentiated SN56 cells, and the cytotoxic evidences are effectively rescued by estrogen. We found that A1254 abolishes the neuroprotective activity of estrogen against Abeta toxicity, and attenuates the suppressive effect of estrogen on Abeta-induced tau phosphorylation and JNK activation. The effects of A1254 on the neuroprotective effects of estrogen in Abeta toxicity are very similar to the effects of the estrogen receptor antagonist ICI182,780. Thus, exposure to EDCs that have anti estrogenic activity might interfere with normal estrogen-activated neuroprotective signaling events and leave neurons more vulnerable to dangerous stimuli. Our present results provide new understanding of the mechanisms contributing to the harmful effects of EDCs on the function and viability of neurons, and the possible relevance of EDCs in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. PMID- 21693152 TI - Caveolin-1 interacts with alpha-synuclein and mediates toxic actions of cellular alpha-synuclein overexpression. AB - Caveolin-1 (Cav-1) is a transmembrane protein which clusters proteins and lipids at the cell membrane into a subclass of lipid rafts named caveolae. To increase our understanding about putative functions of Cav-1 in neuronal cells, we used mouse brain extracts and a novel technology coupling surface plasmon resonance to mass spectrometry to find binding partners to Cav-1. An interaction between Cav-1 and alpha-synclein was found and confirmed in reciprocal pulldown experiments. Genetic overexpression of alpha-synclein in mouse neuroblastoma Neuro2A cells (N2A) expectedly decreased cell survival, but also significantly increased the levels of Cav-1. Furthermore, si-RNA-mediated knockdown of Cav-1 counteracted cell death induced by overexpression of alpha-synuclein. We also used an inhibitor of proteasome (MG132) to induce cell death in a Parkinson's disease context. Cav-1 knockdown had no effect on cell death induced by MG132. Conversely, treating the cells with mevastatin, an inhibitor of cholesterol synthesis, inhibits cell death induced by MG132, but not by alpha synuclein overexpression. It can be concluded that Cav-1 may play a functional role in neuronal cells by virtue of its physical interaction with alpha-synuclein and regulate alpha synuclein-mediated actions on cell death, processes known to be involved in synucleinopathies including Parkinson's disease. PMID- 21693153 TI - Coordinated interactions between actin and microtubules through crosslinkers in neurite retraction induced by lysophosphatidic acid. AB - Neurite development requires rearrangement of cytoskeletal elements, which are mechanically and functionally integrated with each other. Although the process of how an extracellular signal induces rearrangement of a single element has been closely examined, the mechanisms by which the signal regulates cytoskeletal integration during cell shape changes are poorly understood. We previously reported that lysophosphatidic acid (LPA) induces actin polymerization-dependent microtubule (MT) rearrangement, leading to neurite retraction in cultured neurons. Here we examined whether the crosslinker proteins were involved in LPA induced neurite retraction using immortalized mouse neuroblast TR cells. When the MT-binding domains of MACF (MT actin-crosslinking factor) were exogenously expressed in TR cells, MTs were found to be stabilized and become resistant to exposure to LPA. On the other hand, expression of MT-associated protein 2c showed no effect on LPA-induced neurite retraction. These findings suggest that MACF is involved in actin-dependent MT rearrangement during LPA-induced neurite retraction. PMID- 21693154 TI - Norepinephrine transporter (NET) knock-out upregulates dopamine and serotonin transporters in the mouse brain. AB - The noradrenaline, serotonin and dopamine transporters are three main transporters, which are the target of the antidepressant drugs. In the present study we demonstrate that the life-long deletion of the noradrenaline transporter (NET) induced up-regulation of two other monoamine transporters, dopamine and serotonin (DAT and SERT, respectively). An increase in the binding of [(3)H]paroxetine to the SERT and [(3)H]GBR12935 to the DAT was observed in various brain regions of NET-KO mice, without alterations of mRNA encoding these transporters, as measured by in situ hybridization. This important finding impacts the interpretation of previous data indicating the supersensitizity of NET-KO mice for psychostimulants or stronger effect of citalopram in behavioral tests. While using the NET-KO mice in various psychopharmacological studies is very important, one has to be aware that these mice lack NET from the earliest period of their existence, thus compensatory alterations do take place and have to be considered when it comes to interpretation of the obtained results. PMID- 21693156 TI - Recurrent apnoea post immunisation: Informing re-immunisation policy. AB - BACKGROUND: Preterm infants should receive immunisations according to their chronological, rather than gestational, age however concern about possible adverse events following immunisation (AEFI) in this group often means routine immunisations are delayed. A small number of infants may have apnoea with or without bradycardia temporally associated with immunisation. The risk factors for, and recurrence rate of apnoea with subsequent immunisations are unknown, which makes planning for subsequent immunisations for these highly vulnerable infants difficult. AIM: To determine recurrence rates for apnoea temporally associated with immunisation in preterm and term infants and to explore potential risk factors associated with recurrent apnoea in preterm infants. METHOD: A retrospective analysis of all apnoea +/-bradycardia AEFIs in preterm and term infants, reported to the Surveillance of Adverse Events Following Vaccination In the Community (SAEFVIC), Victoria, Australia over a 3-year period from May 2007 to April 2010. Apnoea +/-bradycardia was defined as temporally associated with immunisation if it occurred up to 48h after immunisation. RESULTS: 7 out of 38 [18%, 95% confidence interval 6-31%] preterm infants with apnoea +/-bradycardia post initial immunisation had recurrent apnoea with subsequent immunisations. Possible risk factors for recurrence included: lower birth weight (p=0.04) and ongoing hospitalisation for complications relating to prematurity (p=0.01). No preterm infant with recurrent apnoea had a third episode of apnoea with subsequent immunisation. None of the 8 term infants with a reported apnoea AEFI had recurrence of apnoea with subsequent immunisation. CONCLUSION: There is a risk of recurrence of apnoea associated with immunisation in preterm infants. We recommend that preterm infants with apnoea post immunisation should receive reliable cardio-respiratory monitoring for a minimum of 24h following the next scheduled immunisation. PMID- 21693155 TI - Prime-boost vaccination with heterologous live vectors encoding SIV gag and multimeric HIV-1 gp160 protein: efficacy against repeated mucosal R5 clade C SHIV challenges. AB - We sought to induce primate immunodeficiency virus-specific cellular and neutralizing antibody (nAb) responses in rhesus macaques (RM) through a bimodal vaccine approach. RM were immunized intragastrically (i.g.) with the live attenuated Listeria monocytogenes (Lm) vector Lmdd-BdopSIVgag encoding SIVmac239 gag. SIV Gag-specific cellular responses were boosted by intranasal and intratracheal administration of replication-competent adenovirus (Ad5hr-SIVgag) encoding the same gag. To broaden antiviral immunity, the RM were immunized with multimeric HIV clade C (HIV-C) gp160 and HIV Tat. SIV Gag-specific cellular immune responses and HIV-1 nAb developed in some RM. The animals were challenged intrarectally with five low doses of R5 SHIV-1157ipEL-p, encoding a heterologous HIV-C Env (22.1% divergent to the Env immunogen). All five controls became viremic. One out of ten vaccinees was completely protected and another had low peak viremia. Sera from the completely and partially protected RM neutralized the challenge virus > 90%; these RM also had strong SIV Gag-specific proliferation of CD8+ T cells. Peak and area under the curve of plasma viremia (during acute phase) among vaccinees was lower than for controls, but did not attain significance. The completely protected RM showed persistently low numbers of the alpha4beta7-expressing CD4+ T cells; the latter have been implicated as preferential virus targets in vivo. Thus, vaccine-induced immune responses and relatively lower numbers of potential target cells were associated with protection. PMID- 21693157 TI - Predictors of acceptance of H1N1 influenza vaccination by FDNY firefighters and EMS workers. AB - BACKGROUND: There is a widely recognized need for vaccination of health care workers (HCWs). We undertook this study to assess the 2009-2010 H1N1 vaccination rates in ~14,000 firefighters and emergency medical service (EMS) workers at the Fire Department of New York (FDNY) and to determine predictors of H1N1 vaccine acceptance. METHODS: After 9/11/01, FDNY developed a bio-preparedness drill where units are dispatched to FDNY-BIOPOD (biologic points of distributions) for rapid distribution of medications/vaccines in the event of a biological disaster. Since 2005, FDNY offers free, voluntary seasonal influenza vaccination during routine medical monitoring/treatment examinations and at FDNY-BIOPOD. In 2009, FDNY BIOPOD instead offered the H1N1 vaccine. We report on FDNY H1N1 vaccination rates and on predictors of acceptance using bivariate and multivariable techniques. RESULTS: Overall, 10,612 (77%) FDNY workers were offered H1N1 vaccination, of whom 5831 (55%) accepted. Acceptance was 57.2% during FDNY-BIOPOD compared with 34.4% during medical monitoring/treatment exams (p=0.0001). Workers who accepted prior seasonal influenza vaccinations were 4 times more likely to accept H1N1 vaccination (AOR=4.4, CI(95)=4.0-4.8). CONCLUSION: FDNY offered H1N1 vaccination to 77% of its workforce during the 2009-2010 season. Prior seasonal vaccine acceptance and vaccination in a group setting such as FDNY-BIOPOD dramatically increased acceptance of the H1N1 vaccine. However, within a voluntary program, additional strategies are needed to further increase vaccine acceptance in first responders and other HCWs. PMID- 21693158 TI - Humoral immunogenicity of an HIV-1 envelope residue 649-684 membrane-proximal region peptide fused to the plague antigen F1-V. AB - The membrane-proximal region spanning residues 649-684 of the HIV-1 envelope protein gp41 (MPR649-684) is an attractive vaccine target for humoral immunity that blocks viral transcytosis across the mucosal epithelia. However, induction of high-titer MPR649-684-specific antibodies remains a challenging task. To explore potential solutions for this challenge, we tested a new translational fusion protein comprising the plague F1-V antigen and MPR649-684 (F1-V-MPR649 684). We employed systemic immunization for initial feasibility analyses. Despite strong immunogenicity demonstrated for the immunogen, repeated systemic immunizations of mice with F1-V-MPR649-684 hardly induced MPR649-684-specific IgG. In contrast, a single immunization with F1-V-MPR649-684 mounted a significant anti-MPR649-684 IgG response in animals that were primed with another MPR649-684 fusion protein based on the cholera toxin B subunit. Additional boost immunizations with F1-V-MPR649-684 recalled and maintained the antibody response and expanded the number of specific antibody-secreting B cells. Thus, while F1-V MPR649-684 alone was not sufficiently immunogenic to induce detectable levels of MPR649-684-specific antibodies, these results suggest that prime-boost immunization using heterologous antigen-display platforms may overcome the poor humoral immunogenicity of MPR649-684 for the induction of durable humoral immunity. Further studies are warranted to evaluate the feasibility of this strategy in mucosal immunization. Lastly, our findings add to a growing body of evidence in support of this strategy for immunogen design for poorly immunogenic epitopes besides the MPR of HIV-1's transmembrane envelope protein. PMID- 21693159 TI - Spontaneously Hypertensive Rats (SHR) present deficits in prepulse inhibition of startle specifically reverted by clozapine. AB - Deficits in an operational measure of sensorimotor gating - the prepulse inhibition of startle (PPI) - are presented in psychiatric disorders such as schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD). Some previous studies showed that the spontaneously hypertensive rats (SHR) present PPI deficit. Although SHR is suggested as an animal model to study ADHD, we have suggested that the behavioral phenotype of this strain mimics some aspects of schizophrenia. The aim of this study was to characterize the PPI response in SHR. Pharmacological characterization consisted in the evaluation of the effects of the following drugs administered to adult Wistar rats (WR) and SHR previously to the PPI test: amphetamine (used for ADHD and also a psychotomimetic drug), haloperidol and clozapine (antipsychotic drugs), metoclopramide (dopamine antagonist without antipsychotic properties) and carbamazepine (mood stabilizer). Our results showed that SHR presented reduced PPI. This deficit was similar to that induced by amphetamine in WR. Only the atypical antipsychotic clozapine improved the PPI deficit observed in SHR. These findings reinforce the SHR strain as an animal model to study several aspects of schizophrenia, including the abnormalities in sensorimotor gating associated with this disease. PMID- 21693160 TI - Phloroglucinol (PG) purified from Ecklonia cava attenuates radiation-induced apoptosis in blood lymphocytes and splenocytes. AB - Phloroglucinol (PG), a polyphenol compound of Eckloniacava known as brown algae abundant in Jeju island, has been proposed to exert the antioxidative and cytoprotective effects against oxidative stress. In this study, we confirmed that PG protected mice from damages caused by ionizing radiation and investigated its protection mechanism in detail. The result showed that PG increased the viability of splenocytes without cytotoxicity. Also, PG significantly enhanced the proliferation of splenocytes by limiting the increment of sub-G(1) DNA contents via the inhibition of reactive oxygen species production in 2 Gy-irradiated splenocytes. In addition, PG significantly decreased DNA damage and the number of apoptotic fragments in lymphocytes against oxidative stress. Also, PG increased the counts of endogenous spleen CFUs, compared with only ionizing radiation irradiated mice. These results demonstrate the multi-faceted protection mechanisms of PG in mice against oxidative stress caused by ionizing radiation, providing the benefit of inhibiting apoptosis and strengthening hematopoiesis. PMID- 21693161 TI - Effects of phosphorus supplied in soil on subcellular distribution and chemical forms of cadmium in two Chinese flowering cabbage (Brassica parachinensis L.) cultivars differing in cadmium accumulation. AB - Differences in the subcellular distribution and chemical speciation of Cd between two Chinese flowering cabbage (Brassica parachinensis L.) cultivars, Lubao70 (LB70, low-Cd cultivar) and ChixinNO.4 (CX4, high-Cd cultivar) were investigated under various soil Cd and P treatments. Subcellular fractionation of Cd containing tissues showed that a higher proportion of Cd was bound to the cell wall fraction of LB70 than that of CX4, indicating that Cd compartment functioned better in LB70. Compared to CX4, LB70 had lower proportions of Cd in inorganic form and water-soluble form, but higher proportions of Cd in proteins/pectates integrated form, implying that the low Cd accumulation in LB70 is associated with the low in vivo mobility of Cd. In both cultivars, shoot and root Cd concentration and translocation of Cd from the roots to the shoots obviously decreased with increasing soil P level. It was found that phosphorus (P) played important roles in Cd uptake and translocation via the processes involved in bonding Cd to the cell wall fraction and forming Cd-phosphate complexes. It is suggested that use of low-Cd cultivars in conjunction with P supply is a much useful way to reduce the pollution risk of Cd in the food chain. PMID- 21693162 TI - Butanol extract of Ecklonia cava prevents production and aggregation of beta amyloid, and reduces beta-amyloid mediated neuronal death. AB - Beta-amyloid (Abeta) is a major pathogenic peptide for Alzheimer's disease (AD) and is generated by the processing of amyloid precursor protein (APP). The Abeta monomers aggregate into oligomeric and fibrillar forms which have been implicated as the toxic species inducing the neuronal dysfunction. Brown algae Ecklonia cava is known for its anti-oxidant and anti-inflammatory functions. Therefore, we tested the effect of E. cava extract on the production and aggregation of Abeta peptides. The butanol extract of E. cava reduced Abeta secretion from HEK293 cells expressing APP with Swedish mutation and increased soluble APPalpha and C terminal fragment-alpha (CTFalpha), of which activity was similar to BACE (beta site of APP cleaving enzyme) inhibitors. Furthermore, the extract inhibited Abeta oligomerization, particularly mid-size oligomer formation, confirmed by the ultrastructural morphology. Congo red, thioflavin T assays, and electron microscopy showed that the extract inhibited Abeta fibril formation effectively. Finally, the extract protected primary cortical neurons from various Abeta induced cell deaths, especially oligomer-induced death. Although further study is needed to test the effectiveness of the extract in vivo, our results demonstrate, for the first time, that the butanol extract of E. cava could be used as an anti Abeta agent for AD therapeutics. PMID- 21693163 TI - Safety evaluation of steroidal saponin DT-13 isolated from the tuber of Liriope muscari (Decne.) Baily. AB - Steroidal saponin DT-13 (25 (R, S)-ruscogenin-1-O-[beta-D-glucopyranosyl - (1 >2)] [beta-D-xylopyranosyl-(1->3)]-beta-D-fucopyranoside) is the main active component of the tube of Liriope muscari (Decne.) Baily and has been studied as a candidate drug for cancer metastasis. The objective of this study was to evaluate the safety of DT-13 systematically by genotoxicity and acute oral toxicity and subchronic 90-day oral gavage toxicity. Results of Ames test confirmed that DT-13 did not induce mutations in histidine auxotrophs Salmonella typhimurium (TA 97, TA 98, TA 100 and TA 102) both in the presence and absence of metabolic activation system at the doses of 0.05-500 MUg/plate. Meanwhile, DT-13 did not induce clastogenicity at doses of 1250, 2500 and 5000 mg/kg in mouse micronucleus test. And the single oral dose of DT-13 at 5000 mg/kg did not produce mortality or significant changes in the general behavior and gross appearance of the internal organs of mice. In subchronic toxicity study, DT-13 was administrated to Sprague-Dawley rats via oral gavage at doses of 10, 60 and 360 mg/kg for 90 days. Necropsy, hematological and biochemical analysis, and histopathological examination did not reveal any remarkable and treatment related changes. In conclusion, DT-13 is of low toxicity at the tested doses. PMID- 21693164 TI - Cholesterol reduction and lack of genotoxic or toxic effects in mice after repeated 21-day oral intake of lemongrass (Cymbopogon citratus) essential oil. AB - Cymbopogon citratus (lemongrass) is currently used in traditional folk medicine. Although this species presents widespread use, there are no scientific data on its efficacy or safety after repeated treatments. Therefore, this work investigated the toxicity and genotoxicity of this lemongrass's essential oil (EO) in male Swiss mice. The single LD(50) based on a 24h acute oral toxicity study was found to be around 3500 mg/kg. In a repeated-dose 21-day oral toxicity study, mice were randomly assigned to two control groups, saline- or Tween 80 0.01%-treated groups, or one of the three experimental groups receiving lemongrass EO (1, 10 or 100mg/kg). No significant changes in gross pathology, body weight, absolute or relative organ weights, histology (brain, heart, kidneys, liver, lungs, stomach, spleen and urinary bladder), urinalysis or clinical biochemistry were observed in EO-treated mice relative to the control groups. Additionally, blood cholesterol was reduced after EO-treatment at the highest dose tested. Similarly, data from the comet assay in peripheral blood cells showed no genotoxic effect from the EO. In conclusion, our findings verified the safety of lemongrass intake at the doses used in folk medicine and indicated the beneficial effect of reducing the blood cholesterol level. PMID- 21693165 TI - Decursin from Angelicagigas Nakai induces apoptosis in RC-58T/h/SA#4 primary human prostate cancer cells via a mitochondria-related caspase pathway. AB - Decursin is a major biological active component of Angelicagigas Nakai and is known to induce apoptosis of metastatic prostatic cancer cells. However, the apoptotic mechanism of decursin using primary malignant tumor (RC-58T/h/SA#4) derived human prostate cells is not known. In the present study, we show that treatment of prostate cancer cells with decursin inhibited cell proliferation in a dose-dependent manner. Decursin also induced apoptosis in RC-58T/h/SA#4 cells, as determined by flow cytometry, Hoechst 33258 staining, and DNA fragmentation. Decursin caused activation of caspases-8, -9, and -3 and promoted the apoptotic action of caspase-8-mediated Bid cleavage. Decursin increased the protein levels of Bax and cytosolic cytochrome c as well as cleavage of PARP while decreasing the protein levels of Bcl-2. Furthermore, the caspase-independent mitochondrial apoptosis factor, apoptosis-inducing factor (AIF), was upregulated by treatment with decursin. Taken together, these findings indicate that decursin inhibited the proliferation of RC-58T/h/SA#4 cells through induction of apoptosis, which is mediated by both caspase-dependent and -independent apoptotic pathways. PMID- 21693166 TI - A stabilizing and denaturing dual-effect for natural polyamines interacting with G-quadruplexes depending on concentration. AB - Both G-quadruplexes and natural polyamines are intimately associated with tumor growth and proliferation. The effect of the natural polyamines on telomeric and some oncogenic G-quadruplexes including bcl-2, c-kit, and c-myc G-quadruplexes has been studied by using absorption, fluorescence, CD, and NMR methods. The results exhibited an interesting dual-effect depending on polyamines concentration. Polyamines promote and stabilize G-quadruplexes under a lower concentration (less than 1mM) but denature G-quadruplexes under a higher concentration (more than 1mM). Probably the electrostatic and hydrophobic effect of polyamines and the hydrogen-bonding interaction between guanines and polyamines were respectively responsible for the stabilizing and denaturing effect. PMID- 21693167 TI - Is there tonic immobility in humans? Biological evidence from victims of traumatic stress. AB - Tonic immobility, characterized by profound motor inhibition, is elicited under inescapable threat in many species. To fully support the existence of tonic immobility in humans, our aim was to elicit this reaction in a laboratory setting and measure it objectively. To mimic exposure to life-threatening events in the lab, trauma-exposed participants with PTSD (n=18) and without PTSD (n=15) listened to the script of their autobiographical trauma. Posturography and electrocardiography were employed. Reports of script-induced immobility were associated with restricted area of body sway and were correlated with accelerated heart rate and diminished heart rate variability, implying that tonic immobility is preserved in humans as an involuntary defensive strategy. Immobility reports seemed more evident in PTSD, suggesting that, in some patients, tonic immobility may be elicited during re-experiencing episodes in daily life. This study provided a measure of tonic immobility, a peritraumatic reaction for which cumulative clinical evidence had linked to the severity of PTSD. PMID- 21693168 TI - Inhibition of estrogen actions in human cancer? Current status and the future: a tribute to the late Professor Michael Reed. PMID- 21693170 TI - Steroid sulfatase: a pivotal player in estrogen synthesis and metabolism. AB - Steroid sulfatase plays a pivotal role in regulating the formation of biologically active steroids from inactive steroid sulfates. It is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be subsequently reduced to steroids with estrogenic properties (i.e. estradiol and androstenediol) that can stimulate the growth of tumors in hormone-responsive tissues of the breast, endometrium and prostate. Hence, the action of steroid sulfatase is implicated in physiological processes and pathological conditions. It has been five years since our group last reviewed the important role of this enzyme in steroid synthesis and the progress made in the development of potent inhibitors of this important enzyme target. This timely review therefore concentrates on recent advances in steroid sulfatase research, and summarises the findings of clinical trials with Irosustat (BN83495), the only steroid sulfatase inhibitor that is being trialed in postmenopausal women with breast or endometrial cancer. PMID- 21693169 TI - The role of vitamin D receptor mutations in the development of alopecia. AB - Hereditary Vitamin D Resistant Rickets (HVDRR) is a rare disease caused by mutations in the vitamin D receptor (VDR). The consequence of defective VDR is the inability to absorb calcium normally in the intestine. This leads to a constellation of metabolic abnormalities including hypocalcemia, secondary hyperparathyroidism and hypophosphatemia that cause the development of rickets at an early age in affected children. An interesting additional abnormality is the presence of alopecia in some children depending on the nature of the VDR mutation. The data indicate that VDR mutations that cause defects in DNA binding, RXR heterodimerization or absence of the VDR cause alopecia while mutations that alter VDR affinity for 1,25(OH)(2)D(3) or disrupt coactivator interactions do not cause alopecia. The cumulative findings indicate that hair follicle cycling is dependent on unliganded actions of the VDR. Further research is ongoing to elucidate the role of the VDR in hair growth and differentiation. PMID- 21693171 TI - Direct intra-accumbal infusion of a beta-adrenergic receptor antagonist abolishes WIN 55,212-2-induced aversion. AB - The cannabinoid system is known to interact with a variety of neuromodulators in the central nervous system and impacts diverse behaviors. Previous studies have demonstrated that limbic norepinephrine is a critical determinant in the behavioral expression of cannabinoid-induced aversion. The present study was carried out to define the adrenergic receptor subtype involved in mediating cannabinoid-induced behavioral responses. An acute microinjection of the beta1 adrenergic receptor blocker, betaxolol, directly into the nucleus accumbens (Acb), was able to prevent WIN 55,212-2-induced aversion, but not lithium-induced aversion, as measured in a place conditioning paradigm. These results suggest that noradrenergic transmission in the Acb is important for cannabinoid-induced aversion and that beta-adrenergic antagonists may be effective in counteracting negative side effects of cannabinoid-based agents. PMID- 21693172 TI - The relationship between the neuromodulator adenosine and behavioral symptoms of autism. AB - The neuromodulator adenosine is an endogenous sleep promoter, neuroprotector and anticonvulsant, and people with autism often suffer from sleep disruption and/or seizures. We hypothesized that increasing adenosine can decrease behavioral symptoms of autism spectrum disorders, and, based on published research, specific physiological stimuli are expected to increase brain adenosine. To test the relationship between adenosine and autism, we developed a customized parent-based questionnaire to assess child participation in activities expected to influence adenosine and quantify behavioral changes following these experiences. Parents were naive to study hypotheses and all conditions were pre-assigned. Results demonstrate significantly better behavior associated with events pre-established as predicted to increase rather than decrease or have no influence on adenosine. Understanding the physiological relationship between adenosine and autism could open new therapeutic strategies--potentially preventing seizures, improving sleep, and reducing social and behavioral dysfunction. PMID- 21693173 TI - Molecular evolution of the transferrin family and associated receptors. AB - BACKGROUND: In vertebrates, serum transferrins are essential iron transporters that have bind and release Fe(III) in response to receptor binding and changes in pH. Some family members such as lactoferrin and melanotransferrin can also bind iron while others have lost this ability and have gained other functions, e.g., inhibitor of carbonic anhydrase (mammals), saxiphilin (frogs) and otolith matrix protein 1 (fish). SCOPE OF REVIEW: This article provides an overview of the known transferrin family members and their associated receptors and interacting partners. MAJOR CONCLUSIONS: The number of transferrin genes has proliferated as a result of multiple duplication events, and the resulting paralogs have developed a wide array of new functions. Some homologs in the most primitive metazoan groups resemble both serum and melanotransferrins, but the major yolk proteins show considerable divergence from the rest of the family. Among the transferrin receptors, the lack of TFR2 in birds and reptiles, and the lack of any TFR homologs among the insects draw attention to the differences in iron transport and regulation in those groups. GENERAL SIGNIFICANCE: The transferrin family members are important because of their clinical significance, interesting biochemical properties, and evolutionary history. More work is needed to better understand the functions and evolution of the non-vertebrate family members. This article is part of a Special Issue entitled Molecular Mechanisms of Iron Transport and Disorders. PMID- 21693174 TI - Current applications of molecular imaging and luminescence-based techniques in traditional Chinese medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM), which is fundamentally different from Western medicine, has been widely investigated using various approaches. Cellular- or molecular-based imaging has been used to investigate and illuminate the various challenges identified and progress made using therapeutic methods in TCM. Insight into the processes of TCM at the cellular and molecular changes and the ability to image these processes will enhance our understanding of various diseases of TCM and will provide new tools to diagnose and treat patients. MATERIALS AND METHODS: Various TCM therapies including herbs and formulations, acupuncture and moxibustion, massage, Gua Sha, and diet therapy have been analyzed using positron emission tomography, single photon emission computed tomography, functional magnetic resonance imaging and ultrasound and optical imaging. These imaging tools have kept pace with developments in molecular biology, nuclear medicine, and computer technology. RESULTS: We provide an overview of recent developments in demystifying ancient knowledge - like the power of energy flow and blood flow meridians, and serial naturopathies - which are essential to visually and vividly recognize the body using modern technology. CONCLUSIONS: In TCM, treatment can be individualized in a holistic or systematic view that is consistent with molecular imaging technologies. Future studies might include using molecular imaging in conjunction with TCM to easily diagnose or monitor patients naturally and noninvasively. PMID- 21693175 TI - Comparative study of antioxidant and anti-inflammatory activities and genotoxicity of alcoholic and aqueous extracts of four Fabiana species that grow in mountainous area of Argentina. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fabiana species (Solanaceae family) extracts have long been used in Argentinean traditional medicine as anti-inflammatories, antiseptic, bone fractures and others diseases, but there is no scientific evidence which supports their use. AIM OF THE STUDY: The present study was conducted to evaluate the ability of aqueous and ethanolic extracts of four Fabiana species (Fabiana bryoides Phil., Fabiana punensis A.C. Arroyo, Fabiana densa J. Remy and Fabiana patagonica Speg.) to inhibit key enzymes in inflammatory processes, free radical scavenging properties and genotoxic effects. MATERIALS AND METHODS: HPLC-DAD of aqueous and ethanolic extracts from four Fabiana species was established. All Fabiana extracts were evaluated on their ability to inhibit hyaluronidase and lipoxygenase enzymes to assess their activity against inflammatory mediators. Antioxidant capacity was determined using the 2,2'-azino-bis 3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and the 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging assays and beta-carotene linolenic acid assay. Genotoxicity was evaluated by the Ames assay. RESULTS: The results indicated that the chromatographic patterns of four Fabiana species were different in quantity and absorption intensity of peaks. The alcoholic extract of Fabiana punensis was the most active scavenger of DPPH and ABTS(+) radicals (SC(50) values of 3.85 +/- 0.24 and 2.56 +/- 0.10 MUgGAE/mL, respectively). Fabiana patagonica extracts exhibited the highest peroxyl radical scavenging activity compared with the other three taxa (IC(50) values between 1.00 +/- 0.04 and 4.46 +/- 0.40 MUg GAE/mL for all extracts) and anti-lipoxygenase activity with IC(50) values between 12.5 and 15.5 MUg GAE/mL. The absence of mutagenicity indicates that the DNA does not seem to be a relevant target for these extracts. Fabiana bryoides ethanolic extract showed an interesting effect: it inhibited spontaneous mutagenesis, which could be considered as an antimutagenic effect in the TA98 (+S9) and TA100 (+S9/-S9) strains. The potency differences found between the species could be consequence of the different phytochemical pattern observed by HPLC. CONCLUSIONS: The inhibitory effects on lipoxygenase and hyaluronidase, free radical scavenging activities and lack of genotoxicity of Fabiana extracts may support the folk use of Fabiana punensis, Fabiana patagonica, Fabiana bryoides and Fabiana densa as inhibitor of inflammatory mediators. PMID- 21693176 TI - Antiproliferative effect of a traditional remedy, Himatanthus articulatus bark, on human cancer cell lines. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Himatanthus articulatus (Vahl) Woodson (Apocynaceae) is a tree occurring in the Amazon region. The local population uses its bark against to external tumors and cancer. AIM OF THE STUDY: Evaluated the antiproliferative activity of the crude extract and their fractions against human tumors cells. MATERIALS AND METHODS: The antiproliferative responses of the crude extract and their fractions were colorimetrically evaluated by sulforhodamine B (SRB) assay against HT-29 (colon adenocarcinoma); NCI-H460 (non-small cell lung carcinoma); MCF-7 (breast cancer); OVCAR-3 (ovarian adenocarcinoma) and RXF-393 (renal cell carcinoma) as well as against NIH-3T3 (mouse embryo fibroblast cell). RESULTS: The cytotoxicity data from the crude extract allowed considering active only in the NCI-H460 cell line. However, the antiproliferative activity was much more pronounced at the chloroformic fraction in all cell lines tested. The butanolic fraction demonstrated activity against to HT-29, MCF-7, RXF-393 and OVCAR-3 cells. The ethyl acetate fraction demonstrated activity only in RXF-393 and the aqueous residue did not present antiproliferative effect. CONCLUSIONS: Through the popular use we find that the crude extracts of Himatanthus articulatus bark displayed weak cytotoxic. However, the butanolic fraction showed to be active only against to tumor cell lines while chloroformic fraction possesses high activity being similar to the positive control. Both fractions have been selected for future bio-guided fractionation and isolation of active compounds. PMID- 21693177 TI - Proceedings of the sixteenth international workshop on in vitro toxicology. PMID- 21693178 TI - Determination of dynamic doxorubicin-EC50 value in an automated high-content workstation for cellular assays. AB - To overcome the problems of endpoint tests routinely required for EC50 determination, we utilized a novel automated high-content workstation and calculated a time-resolved EC50 value of MCF-7 mamma carcinoma cells treated with a pharmacologic agent. Measuring parameters were the cellular oxygen consumption and the extracellular acidification. These parameters were detected in real-time and label free with optochemical sensor spots in a modified 24-well sensor plate. In particular, the objective was to compare the measuring data of the workstation with a classical standard resazurin cell assay and to transfer the benefit of continuously recorded metabolic data of the workstation to practical time resolved information about the effect of the applied active reagent (doxorubicin). MCF-7 cells were treated with a broad range of doxorubicin concentrations (100 MUM to 1 nM) over 24 h and cellular activities were investigated with both, the resazurin assay and the automated workstation. Twenty four hours after treatment, the resazurin assay showed an EC50 value (6.3 MUM) which was about one decade above the value obtained from oxygen consumption rate (0.37 MUM) and extracellular acidification rate (0.72 MUM), measured with the workstation. Presumably, the differences are due to the different metabolic nature and regulation behind these measuring parameters. By polynomial fitting of continuously recorded metabolic data, we were able to point out a dynamic, time resolved EC50 characteristic for different time points. The workstation is a powerful tool to record in vitro kinetic data of pharmacologic effects in vital cells in an automated experimental run. PMID- 21693179 TI - Protective effect of diazoxide against antimycin A-induced mitochondrial dysfunction in osteoblastic MC3T3-E1 cells. AB - Treatment of various types of cells with diazoxide has been shown to precondition cells to subsequent injuries and inhibit cell death. In this study, the protective effects of diazoxide against pharmacological inhibition of the respiratory chain were studied using osteoblastic MC3T3-E1 cells treated with antimycin A (AMA), which inhibits complex III of the electron transport system. Diazoxide restored mitochondrial membrane potential dissipation, inactivation of complex IV, ATP loss, and intracellular calcium elevation that was induced by AMA treatment, and prevented cell death. The results imply that diazoxide protects osteoblasts from AMA-induced cell death via improved mitochondrial function. Moreover, diazoxide scavenged mitochondrial superoxide anions generated by AMA, and prevented nitrotyrosine increase and thioredoxin reductase inactivation induced by AMA, suggesting that diazoxide may be useful to protect mitochondria from a burst of oxidative stress. Our results demonstrate that diazoxide may reduce or prevent osteoblasts degeneration in osteoporosis. PMID- 21693180 TI - Atrazine induces transcriptional changes in marker genes associated with steroidogenesis in primary cultures of rat Leydig cells. AB - Reproductive toxicity of atrazine (ATZ) is well reported in mammals. However, the underlying mechanisms are poorly understood and need to be explored. Thus, we investigate ATZ induced transcriptional changes in selected markers of steroidogenesis in primary cultures of rat interstitial Leydig cells (ILCs). Cytotoxic studies were carried out by exposing the cells to ATZ (0.5-50 MUg/mL or 2.32-232 MUM) for 24-72 h, whereas; the exposure period of expression studies was for 2 h. ATZ exposure of (25 and 50 MUg/ml) for 48 h onwards was found to be cytotoxic in MTT (dimethylthiazol-diphenyl tetrazolium bromide salt) assay, while in NRU (neutral red uptake) assay, cytotoxicity could be recorded at 50 MUg/ml exposure of 72 h only. A significant dose dependent induction in the levels of mRNA expression of genes of steroidogenic acute regulatory protein (STAR), cytochrome P45011A1, 3beta-hydroxysteroid dehydrogenase (3beta-HSD), and other steroidogenic proteins were observed in cells exposed to ATZ. Our data suggest the applicability of these selected marker genes of steroidogenesis as an indicator of short term exposure of ATZ induced testicular toxicity in rats interstitial Leydig cells (ILCs). PMID- 21693181 TI - Directed sequencing and annotation of three Dicentrarchus labrax L. chromosomes by applying Sanger- and pyrosequencing technologies on pooled DNA of comparatively mapped BAC clones. AB - Dicentrarchus labrax is one of the major marine aquaculture species in the European Union. In this study, we have developed a directed-sequencing strategy to sequence three sea bass chromosomes and compared results with other teleosts. Three BAC DNA pools were created from sea bass BAC clones that mapped to stickleback chromosomes/groups V, XVII and XXI. The pools were sequenced to 17 39x coverage by pyrosequencing. Data assembly was supported by Sanger reads and mate pair data and resulted in superscaffolds of 13.2 Mb, 17.5 Mb and 13.7 Mb respectively. Annotation features of the superscaffolds include 1477 genes. We analyzed size change of exon, intron and intergenic sequence between teleost species and deduced a simple model for the evolution of genome composition in teleost lineage. Combination of second generation sequencing technologies, Sanger sequencing and genome partitioning strategies allows "high-quality draft assemblies" of chromosome-sized superscaffolds, which are crucial for the prediction and annotation of complete genes. PMID- 21693182 TI - The effects of daily distress and personality on genital HSV shedding and lesions in a randomized, double-blind, placebo-controlled, crossover trial of acyclovir in HSV-2 seropositive women. AB - Herpes simplex virus (HSV) infections are ubiquitous in humans, but the determinants of clinical and virologic severity are not completely understood. Prior research has suggested that psychological distress can be a co-factor in reactivation of latent HSV infection. Personality traits such as extraversion and neuroticism influence stress attributions and may inform the relationship between psychological distress and health outcomes. Earlier studies in this area have primarily focused on subjective reports of HSV lesion recurrence, but such reports may be influenced by both personality traits and distress. We report results from a randomized, double-blind, placebo-controlled, crossover trial of acyclovir in 19 women for whom personality was assessed at baseline and daily assessments of genital lesions, stress, anxiety, and depression levels were collected for 22 weeks. In addition, daily swabs of the genital mucosa were collected to assess HSV-2 viral reactivation. We found that daily stress predicted genital lesion frequency, and that daily stress, anxiety, and depression predicted genital lesion onset approximately 5 days before onset. Anxiety was also associated with genital lesions 3 days after onset. Distress and viral reactivation were not associated; and no personality traits were associated with any of the outcomes. These results support the hypothesis that psychological distress is both a cause and a consequence of genital lesion episodes. PMID- 21693183 TI - Lack of association of indoleamine 2,3-dioxygenase polymorphisms with interferon alpha-related depression in hepatitis C. AB - BACKGROUND: Major depression is a frequent adverse effect of interferon-alpha (IFN-alpha) therapy. Although the indoleamine 2,3-dioxygenase (IDO) enzyme seems to be involved in the pathophysiology of IFN-alpha-induced depression, no pharmacogenetic study has investigated whether variation in the IDO gene modifies vulnerability to this adverse effect. METHODS: A cross-sectional study assessing 277 hepatitis C patients recruited in two specialized outpatient clinics of Brazil. They were interviewed with the Mini International Neuropsychiatric Interview (MINI) approximately 1 month after the end of IFN-alpha plus ribavirin therapy. Genomic DNA of individuals was extracted from venous blood. Three IDO single-nucleotide polymorphisms (SNPs) were genotyped (rs3824259; rs10089084 and rs35099072). RESULTS: MINI indicated that 21.3% of the sample met criteria for a major depressive episode during the course of IFN-alpha therapy. No association with the diagnosis of a major depressive episode during the course of IFN-alpha therapy was observed genotype or allele-wise (p>0.05). Current major depression and/or current anxiety disorder was significantly associated with IFN-alpha related depression (p<0.005). However, gender, age, route of infection, result of the antiviral treatment, past history of substance use disorders, depression or any other psychiatric disorder showed no association with IFN-alpha-related depression (p>0.05). CONCLUSIONS: Our results suggest no influence of the variants in the IDO gene and the diagnosis of interferon-alpha-related depression in the Brazilian population. Interferon-alpha-related depression may impose persistent psychopathology on at least 15% of the depressed patients even 2 years after antiviral therapy termination. The cross-sectional design is a limitation of our study, predisposing memory bias. Prospective pharmacogenetic studies are warranted to continue investigation of the impact of IDO polymorphisms on the development of IFN-alpha-induced depression. PMID- 21693184 TI - Reduced Th2 cytokine production by sarcoidosis patients in clinical remission with chronic fatigue. AB - When the inflammatory phase of sarcoidosis has resolved, complaints of chronic fatigue frequently persist. Low-grade residual inflammatory activity may play a role in maintaining chronic fatigue. The aim of this study was to compare in vitro cytokine/chemokine production and plasma cytokine/chemokine levels between chronically fatigued and non-fatigued patients with sarcoidosis in clinical remission. Patients with sarcoidosis in clinical remission were assigned to a non fatigued group (n=38) or a fatigued group (n=34) based on the standardized cut off of the fatigue questionnaire Checklist Individual Strength. Cytokines/chemokines in plasma and in supernatants of whole blood cultures stimulated with either a T cell mitogen or lipopolysaccharide were quantified by multiplex analysis. Associations of cytokine/chemokine profiles with chronic fatigue were analyzed by multivariate analysis of variance and principal component analysis followed by logistic regression. Principal component analysis of T cell mitogen-induced cytokine/chemokine production identified three components that explained 76% of the variance in the cytokine/chemokine data. Logistic regression revealed that the 'Th2 cytokine'-component which mainly consists of interleukin (IL)-4, IL-5 and IL-10 was significantly and negatively associated with chronic fatigue. In addition, multivariate analysis revealed higher levels of LPS-induced IL-8 and lower levels of plasma monocyte chemoattractant protein (MCP)-1 in the fatigued group compared to the non fatigued group. In chronically fatigued sarcoidosis patients in clinical remission, we found a cytokine/chemokine profile which is suggestive for a less competent Th2 counterbalancing capacity, that may contribute to the persistence of chronic fatigue. PMID- 21693185 TI - The associations of adiposity, physical activity and inflammation with fatigue in older adults. AB - Persistent feelings of fatigue are a widespread complaint reported by older adults, and are associated with detriments in health and quality of life. The aim of this study was to determine the influence of weight status, habitual physical activity and inflammation, after controlling for common psychosocial variables such as depression, on perceptions of fatigue in relatively healthy older adults. Older men and women (N=182, age=69.2+/-6.7 years, 98 men) were assessed for adiposity via dual-energy X-ray absorptiometry, physical activity (PA) using accelerometers, systemic inflammation [serum C-reactive protein (CRP), interleukin-6 (IL-6), sIL-6R and WBC count], fatigue according to the Multidimensional Fatigue Inventory (MFI), sleep using the Pittsburgh Sleep Quality Index (PSQI) and depression via the Geriatric Depression Scale (GDS). Men and women reported similar levels of fatigue in all dimensions (p>0.05) except women reported higher levels of mental fatigue than men (p=0.049). With the exception of mental fatigue, adiposity was positively, and physical activity was inversely associated with all other dimension of fatigue (r range=0.20-0.42, and 0.18 to -0.37, respectively). CRP, IL-6 and WBC were also related to several dimensions of fatigue (r range=0.15-0.26). Regression analyses revealed that after controlling for other factors, including depression and sleep quality, adiposity independently explained a significant amount of the variance in general and physical fatigue. In addition to depression and sleep quality, adiposity may represent a potential target for reducing fatigue in older adults. PMID- 21693186 TI - Relaxin-3 systems in the brain--the first 10 years. AB - The relaxin-3 gene was identified in 2001 by searching the human genome database for homologues of the relaxin hormone, and was subsequently discovered to encode a highly conserved neuropeptide in mammals and lower species. In the decade since its discovery there have been significant advances in our knowledge of the peptide, including the identification of its cognate receptor (a type 1 G-protein coupled receptor, GPCR135 or RXFP3), an understanding of its structure-activity and associated cellular signalling, and the elucidation of key neuroanatomical aspects of relaxin-3/RXFP3 networks in mammalian brain. The latter studies revealed that relaxin-3 is expressed within GABA neurons of the brainstem including an area known as the nucleus incertus, and that ascending relaxin-3 projections innervate a broad range of RXFP3-rich forebrain areas. These maps provided a foundation for pharmacological and physiological studies to elucidate the neurobiological nature of relaxin-3/RXFP3 signalling in vivo. Recent findings from our laboratory and others suggest the relaxin-3 neural network represents a newly identified ascending arousal system, able to modulate a range of interrelated functions including responses to stress, spatial and emotional memory, feeding and metabolism, motivation and reward, and circadian rhythm and sleep/wake states. More research is now required to discover further important facts about relaxin-3 neurons, such as their various regulatory inputs, and to characterise populations of RXFP3-positive neurons and determine their influence on particular neural circuits, physiology and complex behaviour. PMID- 21693187 TI - iNOS/NO signaling regulates apoptosis induced by glycochenodeoxycholate in hepatocytes. AB - Inducible nitric oxide synthase (iNOS) and nitric oxide (NO) can ameliorate apoptosis induced by toxic glycochenodeoxycholate (GCDC) in hepatocytes. However, the underlying molecular mechanisms are not yet understood in detail. This study is to clarify the function of iNOS/NO and its mechanisms during the apoptotic process. The apoptosis was brought about by GCDC in rat primary hepatocytes. iNOS/NO signaling was then investigated. iNOS inhibitor 1400W enhanced the GCDC induced apoptosis as reflected by caspase-3 activity and TUNEL assay. Exogenous NO regulated the apoptosis subsequent to NO donor S-nitroso-N-acetyl penicillamine (SNAP) or sodium nitroprusside (SNP). The GCDC-induced apoptosis was decreased with 0.1mM SNAP or 0.15mM SNP, while it was increased with 0.8mM SNAP or 1.2mM SNP. The endogenous iNOS inhibited apoptosis, but the exogenous NO played a dual role during the GCDC-induced apoptosis. There was a potential iNOS/Akt/survivin axis that inhibited the hepatocyte apoptosis in low doses of NO donors. In contrast, high doses of NO donors activated CHOP through p38MAP-kinase (p38MAPK), upregulated TRAIL receptor DR5, and suppressed survivin. Consequently the high doses of NO donors promoted the apoptosis in hepatocytes. Our data suggest that the iNOS/NO signaling can modulate Akt/survivin and p38MAPK/CHOP pathways to mediate the GCDC-induced the apoptosis in hepatocytes. These signaling pathways may serve as targets for therapeutic intervention in cholestatic liver disease. PMID- 21693188 TI - Essence of affinity and specificity of peanut agglutinin-immobilized fluorescent nanospheres with surface poly(N-vinylacetamide) chains for colorectal cancer. AB - We have designed a novel colonoscopic imaging agent that is composed of submicron sized fluorescent polystyrene nanospheres with two functional groups - peanut agglutinin (PNA) and poly(N-vinylaceamide) (PNVA) - on their surfaces. PNA is a targeting moiety that binds to beta-d-galactosyl-(1-3)-N-acetyl-d-galactosamine (Gal-beta(1-3)GalNAc), which is the terminal sugar of the Thomsen-Friedenreich antigen that is specifically expressed on the mucosal side of colorectal cancer cells; it is anchored on the nanosphere surface via a poly(methacrylic) acid (PMAA) linker. PNVA is immobilized to enhance the specificity of PNA by reducing nonspecific interactions between the imaging agent and normal tissues. The essential nature of both functional groups was evaluated through in vivo experiments using PNA-free and PNVA-free nanospheres. The imaging agent recognized specifically tumors on the cecal mucosa of immune-deficient mice in which human colorectal cancer cells had been implanted; however, the recognition capability disappeared when PNA was replaced with wheat germ agglutinin, which has no affinity for Gal-beta(1-3)GalNAc. PNA-free nanospheres with exclusively surface PNVA chains rarely adhered to the cecal mucosa of normal mice that did not undergo the cancer cell implantation. In contrast, there were strong nonspecific interactions between normal tissues and PNA-free nanospheres with exclusively surface PMAA chains. In vivo data proved that PNA and PNVA were essential for biorecognition for tumor tissues and a reduction of nonspecific interactions with normal tissues, respectively. PMID- 21693189 TI - Formulation of multiparticulate systems as lyophilised orally disintegrating tablets. AB - The current study aimed to exploit the electrostatic associative interaction between carrageenan and gelatin to optimise a formulation of lyophilised orally disintegrating tablets (ODTs) suitable for multiparticulate delivery. A central composite face centred (CCF) design was applied to study the influence of formulation variables (gelatin, carrageenan and alanine concentrations) on the crucial responses of the formulation (disintegration time, hardness, viscosity and pH). The disintegration time and viscosity were controlled by the associative interaction between gelatin and carrageenan upon hydration which forms a strong complex that increases the viscosity of the stock solution and forms tablet with higher resistant to disintegration in aqueous medium. Therefore, the levels of carrageenan, gelatin and their interaction in the formulation were the significant factors. In terms of hardness, increasing gelatin and alanine concentration was the most effective way to improve tablet hardness. Accordingly, optimum concentrations of these excipients were needed to find the best balance that fulfilled all formulation requirements. The revised model showed high degree of predictability and optimisation reliability and therefore was successful in developing an ODT formulation with optimised properties that were able deliver enteric coated multiparticulates of omeprazole without compromising their functionality. PMID- 21693191 TI - Effects of dietary chitosan and Bacillus subtilis on the growth performance, non specific immunity and disease resistance of cobia, Rachycentron canadum. AB - The present study was performed to investigate the effects of various levels of dietary Bacillus subtilis and chitosan on the growth performance, non-specific immunity and protection against Vibrio harveyi infection in cobia, Rachycentron canadum. Fish were fed with the control diet and six different experimental diets containing three graded levels of B. subtilis at 2 * 10(10) CFU g(-1) (0.0, 1.0, 2.0 g kg(-1) diet) for each of two levels of chitosan (3.0 and 6.0 g kg(-1) diet). The results of 8 weeks feeding trial showed that the survival rate ranged from 81.3% to 84.0% with no significant difference (P > 0.05). The SGR (%) in the fish fed with dietary treatments was significantly higher than that of the control fish except diet 6 group with 2.0 g kg(-1)B. subtilis and 3.0 g kg(-1) chitosan. The serum lysozyme activities were significantly higher in 6.0 g kg(-1) chitosan groups and no significant differences were observed among B. subtilis levels. The serum ACP activities were significantly higher in 3.0 g kg(-1) chitosan groups at 0.0 and 1.0 g kg(-1)B. subtilis levels; at low chitosan level, the cobia fed diets with 1.0 g kg(-1)B. subtilis had significantly higher serum ACP activity, but at high chitosan level, the cobia fed diets with 2.0 g kg(-1)B. subtilis had significantly higher serum ACP activity. The phagocytosis and respiratory burst activity in the fish fed with dietary treatments was significantly higher than that of the control fish except diet 3 group with 6.0 g kg(-1) chitosan. Moreover, fish fed the diet containing 2.0 g kg(-1)B. subtilis and 6.0 g kg(-1) chitosan had significantly higher post-challenge survival on the 7th day following V. harveyi infection and post-challenge survival showed clearly the synergistic effect of chitosan and B. subtilis. Based on these results, the combination of 1.0 g kg(-1)B. subtilis and 6.0 g kg(-1) chitosan is optimal for the growth, innate immunity and disease resistance of cobia with an 8-week oral administration. PMID- 21693190 TI - Heterologous production, purification and characterization of enzymatically active Sindbis virus nonstructural protein nsP1. AB - Alphavirus nonstructural protein nsP1 possesses distinct methyltransferase (MTase) and guanylyltransferase (GTase) activities involved in the capping of viral RNAs. In alphaviruses, the methylation of GTP occurs before RNA transguanylation and nsP1 forms a covalent complex with m(7)GMP unlike the host mRNA guanylyltransferase which forms GMP-enzyme complex. In this study, full length SINV nsP1 was expressed in a soluble form with an N-terminal histidine tag in Escherichia coli and purified to homogeneity. The purified protein is enzymatically active and contains both MTase and GTase activity indicating that SINV nsP1 does not require membrane association for its enzymatic function. Biochemical analysis shows that detergents abolish nsP1 GTase activity, whereas nonionic detergents do not affect MTase activity. Furthermore, SINV nsP1 contains the metal-ion dependent GTase, whereas MTase does not require a metal ion. Circular dichroism spectroscopic analysis of purified protein indicate that nsP1 has a mixed alpha/beta structure and is in the folded native conformation. PMID- 21693192 TI - Molecular phylogenetic relationships and phenotypic diversity in miniaturized toadlets, genus Brachycephalus (Amphibia: Anura: Brachycephalidae). AB - Toadlets of the genus Brachycephalus are endemic to the Atlantic rainforests of southeastern and southern Brazil. The 14 species currently described have snout vent lengths less than 18 mm and are thought to have evolved through miniaturization: an evolutionary process leading to an extremely small adult body size. Here, we present the first comprehensive phylogenetic analysis for Brachycephalus, using a multilocus approach based on two nuclear (Rag-1 and Tyr) and three mitochondrial (Cyt b, 12S, and 16S rRNA) gene regions. Phylogenetic relationships were inferred using a partitioned Bayesian analysis of concatenated sequences and the hierarchical Bayesian method (BEST) that estimates species trees based on the multispecies coalescent model. Individual gene trees showed conflict and also varied in resolution. With the exception of the mitochondrial gene tree, no gene tree was completely resolved. The concatenated gene tree was completely resolved and is identical in topology and degree of statistical support to the individual mtDNA gene tree. On the other hand, the BEST species tree showed reduced significant node support relative to the concatenate tree and recovered a basal trichotomy, although some bipartitions were significantly supported at the tips of the species tree. Comparison of the log likelihoods for the concatenated and BEST trees suggests that the method implemented in BEST explains the multilocus data for Brachycephalus better than the Bayesian analysis of concatenated data. Landmark-based geometric morphometrics revealed marked variation in cranial shape between the species of Brachycephalus. In addition, a statistically significant association was demonstrated between variation in cranial shape and genetic distances estimated from the mtDNA and nuclear loci. Notably, B. ephippium and B. garbeana that are predicted to be sister-species in the individual and concatenated gene trees and the BEST species tree share an evolutionary novelty, the hyperossified dorsal plate. PMID- 21693193 TI - Multilocus phylogenetic analysis of the genus Atherina (Pisces: Atherinidae). AB - Sand-smelts are small fishes inhabiting inshore, brackish and freshwater environments and with a distribution in the eastern Atlantic and Mediterranean Sea, extending south into the Indian Ocean. Here, we present a broad phylogenetic analysis of the genus Atherina using three mitochondrial (control region, 12S and 16S) and two nuclear markers (rhodopsin and 2nd intron of S7). Phylogenetic analyses fully support the monophyly of the genus. Two anti-tropical clades were identified, separating the South African Atherina breviceps from the north eastern Atlantic and Mediterranean Atherina' species. In European waters, two groups were found. The first clade formed by a well supported species-pair: Atherina presbyter (eastern Atlantic) and Atherina hepsetus (Mediterranean), both living in marine waters; a second clade included Atherina boyeri (brackish and freshwater environments) and two independent lineages of marine punctated and non punctated fishes, recently proposed as separate species. Sequence divergence values strongly suggest multiple species within the A. boyeri complex. PMID- 21693195 TI - Vitamin A: a multifunctional tool for development. AB - Extensive research carried out over the last 100 years has established that the fat-soluble organic compound vitamin A plays crucial roles in early development, organogenesis, cell proliferation, differentiation and apoptosis as well as in tissue homeostasis. Given its importance during development, the delivery of vitamin A to the embryo is very tightly regulated with perturbations leading to severe malformations. This review discusses the roles of vitamin A during human development and the molecular mechanisms controlling its biological effects, hence bridging the gap between human development and molecular genetic work carried out in animal models. Vitamin A delivery during pregnancy and its developmental teratology in humans are thus discussed alongside work on model organisms, such as chicken or mice, revealing the molecular layout and functions of vitamin A metabolism and signaling. We conclude that, during development, vitamin A-derived signals are very tightly controlled in time and space and that this complex regulation is achieved by elaborate autoregulatory loops and by sophisticated interactions with other signaling cascades. PMID- 21693197 TI - Isolation, characterization, and distribution of somatostatin receptor subtype 2 (SSTR 2) mRNA in rainbow trout (Oncorhynchus mykiss), and regulation of its expression by glucose. AB - In this study, cDNA for a somatostatin receptor variant (somatostatin receptor subtype 2, SSTR 2) was isolated, cloned, and sequenced from rainbow trout. A 1821 nt cDNA was isolated and found to contain a single initiation site 387-nt from the most 5' end, an open reading frame of 1116-nt, and a single putative polyadenylation site 189-nt from the most 3' end. The encoded protein contains 372 amino acids and contains seven membrane-spanning domains. Based on structural analysis, the protein was identified as a subtype 2 SSTR. These data support the emergence of a multigenic SSTR family early in the course of vertebrate evolution, concomitant with or perhaps prior to the divergence of boney fish. The distribution of SSTR 2 mRNA in tissues was determined by quantitative real time PCR (QRT-PCR). SSTR 2 was most abundant in the brain (where it was detected in the telencephalon, optic tectum, and hypothalamus), skeletal muscle, and liver, but it also was present in the endocrine pancreas (Brockmann body) and various regions of the gastrointestinal tract (esophagus, stomach, intestine). SSTR 2 mRNA was most abundant in the brain, muscle, and liver. In vitro the Brockmann body and liver with increasing concentrations of glucose (1, 4, 10mM) resulted in increased expression of SSTR 2 mRNA. These findings contribute to the understanding of the evolution of the SSTR family and provide insight into the roles of SSTR 2 in fish. PMID- 21693196 TI - Roles of the Aspergillus nidulans UDP-galactofuranose transporter, UgtA in hyphal morphogenesis, cell wall architecture, conidiation, and drug sensitivity. AB - Galactofuranose (Galf) is the 5-member-ring form of galactose found in the walls of fungi including Aspergillus, but not in mammals. UDP-galactofuranose mutase (UgmA, ANID_3112.1) generates UDP-Galf from UDP-galactopyranose (6-member ring form). UgmA-GFP is cytoplasmic, so the UDP-Galf residues it produces must be transported into an endomembrane compartment prior to incorporation into cell wall components. ANID_3113.1 (which we call UgtA) was identified as being likely to encode the A. nidulans UDP-Galf transporter, based on its high amino acid sequence identity with A. fumigatus GlfB. The ugtADelta phenotype resembled that of ugmADelta, which had compact colonies, wide, highly branched hyphae, and reduced sporulation. Like ugmADelta, the ugtADelta hyphal walls were threefold thicker than wild type strains (but different in appearance in TEM), and accumulated exogenous material in liquid culture. AfglfB restored wild type growth in the ugtADelta strain, showing that these genes have homologous function. Immunostaining with EBA2 showed that ugtADelta hyphae and conidiophores lacked Galf, which was restored in the AfglfB-complemented strain. Unlike wild type and ugmADelta strains, some ugtADelta metulae produced triplets of phialides, rather than pairs. Compared to wild type strains, spore production for ugtADelta was reduced to 1%, and spore germination was reduced to half. UgtA-GFP had a punctate distribution in hyphae, phialides, and young spores. Notably, the ugtADelta strain was significantly more sensitive than wild type to Caspofungin, which inhibits beta-glucan synthesis, suggesting that drugs that could be developed to target UgtA function would be useful in combination antifungal therapy. PMID- 21693194 TI - The supply of choline is important for fetal progenitor cells. AB - Fetal progenitor cells proliferate, migrate, differentiate and undergo apoptosis at specific times during fetal development. Choline is needed by these cells for membrane synthesis and for methylation. There is growing evidence that this nutrient also modulates epigenetic regulation of gene expression in both neuronal and endothelial progenitor cells, thereby modifying brain development. It is likely that these mechanisms explain why, in rodent models, maternal dietary intake of choline influences both angiogenesis and neurogenesis in fetal hippocampus, and results in life-long changes in memory function. This also may explain why women eating diets low in choline have a greater risk of having a baby with a birth defect. Choline is mainly found in foods that contain fat and cholesterol, and intake of such foods has diminished in response dietary advice from nutritionists and physicians. Forty years ago, diets commonly contained choline-rich foods but now women in the USA tend to eat diets low in choline content. Premenopausal women normally may require less choline in their diet than do men and postmenopausal women, because estrogen induces the gene for the enzyme catalyzing endogenous biosynthesis of the choline-containing phospholipid phosphatidylcholine. However, many women have a single nucleotide polymorphism (SNP) that blocks the induction of endogenous biosynthesis, thereby making them require more dietary choline. When these women eat diets low in choline, the supply of this nutrient to the fetus is likely to be inadequate, and may perturb progenitor cell proliferation, migration, differentiation and apoptosis. PMID- 21693198 TI - Drosophila arf72A acts as an essential regulator of endoplasmic reticulum quality control and suppresses autosomal-dominant retinopathy. AB - The eukaryotic endoplasmic reticulum operates multiple quality control mechanisms to ensure that only properly folded proteins are exported to their final destinations via the secretory pathway and those that are not are destroyed via the degradation pathway. However, molecular mechanisms underlying such regulated exportation to these distinct routes are unknown. In this article, we report the role of Drosophila arf72A--the fly homologue of the mammalian Arl1 - in the quality checks of proteins and in the autosomal-dominant retinopathy. ARF72A localizes to the Golgi membranes of Drosophila photoreceptor cells, consistent with mammalian Arl1 localization in cell culture systems. A loss of arf72A function changes the membrane character of the endoplasmic reticulum and shifts the membrane balance between the endoplasmic reticulum and the Golgi complex toward the Golgi complex, resulting in over-proliferated Golgi complexes and accelerated protein secretion. Interestingly, our study indicated that more ARF72A localized on the endoplasmic reticulum in the ninaE(D1) photoreceptor cell, a Drosophila model of autosomal-dominant retinitis pigmentosa, compared to that in the wild-type. In addition, arf72A loss was shown to rescue the ninaE(D1) related membrane accumulation and the rhodopsin maturation defect, and suppress ninaE(D1)-triggered retinal degeneration, indicating that rhodopsin accumulated in the endoplasmic reticulum bypasses the quality checks. While previous studies of ARF small GTPases have focused on their roles in vesicular budding and transport between the specific organelles, our findings establish an additional function of arf72A in the quality check machinery of the endoplasmic reticulum distinguishing the cargoes for secretion from those for degradation. PMID- 21693200 TI - Embryonic development of endothermy. AB - During embryonic development of homeothermic animals like birds and mammals transition from ectothermy to endothermy occurs especially in precocial species of both taxa. Based on some evolutionary aspects of the development of endothermy the review focuses on the prenatal development of endothermy and of the thermoregulatory system using the precocial bird as a model. During final incubation precocial bird embryos have all the prerequisites to respond to environmental (temperature) influences in a nearly appropriate way. Autonomic, neuronal and molecular mechanisms underlying the development of endothermy are established and the transition of the thermoregulatory system from a control system without feedback into a system with feedback mechanisms occurs. Precocial bird embryos are endothermic, but not homeothermic if incubation temperature decreases below the normal level, which seems to be associated with summit metabolism. At increased incubation temperatures the embryos are able to stabilize their body temperature. Therefore, above normal temperatures, homoeothermy can occur over a limited temperature range. PMID- 21693201 TI - Comparison of the osteoblastic activity conferred on Si-doped hydroxyapatite scaffolds by different osteostatin coatings. AB - Parathyroid hormone-related protein (107-111) (osteostatin) induces osteogenic effects in osteoblasts in vitro and in regenerating bone in mice and rabbits. In this study we used osteoblastic MC3T3-E1 cell cultures to evaluate and compare the bioactivity of this peptide either adsorbed or covalently bound (by its C terminus) to Si-doped hydroxyapatite (Si-HA) scaffolds after organic (-NH(2)) functionalization. By these means osteostatin can be locally released or kept anchored to the scaffold surface. This was confirmed by chemical analysis and by testing the efficiency of osteostatin-loaded Si-HA scaffolds (placed in Transwell chambers) in healing a scratch wound in mouse pluripotent mesenchymal C3H10T1/2 cells. Our results show that exposure of MC3T3-E1 cell monolayers to Si-HA scaffolds with both types of osteostatin coating (deliverable or immobilized), in contrast to those without peptide, similarly stimulated cell growth and matrix mineralization. These findings demonstrate that osteostatin release from Si-HA scaffolds is not essential to promote osteoblastic growth and function in vitro, and lend credence to considering osteostatin a bone regenerating factor. PMID- 21693202 TI - Methacrylate polymer layers bearing poly(ethylene oxide) and phosphorylcholine side chains as non-fouling surfaces: in vitro interactions with plasma proteins and platelets. AB - Two methacrylate monomers, oligo(ethylene glycol) methyl ether methacrylate (OEGMA; MW=300 g mol(-1), poly(ethylene glycol) (PEG) side chains of average length n=4.5) and 2-methacryloyloxyethyl phosphorylcholine (MPC; MW=295 g mol( 1)), were grafted from silicon wafer surfaces via surface-initiated atom transfer radical polymerization. The grafted surfaces were used as model PEG and phosphorylcholine surface systems to allow comparison of the effectiveness of these two motifs in the prevention of plasma protein adsorption and platelet adhesion. It was found that at high graft density fibrinogen adsorption from plasma on the poly(MPC) and poly(OEGMA) surfaces for a given graft chain length was comparable and extremely low. At low graft density, poly(OEGMA) was slightly more effective than poly(MPC) in resisting fibrinogen adsorption from plasma. Flowing whole blood experiments showed that at low graft density the poly(OEGMA) surfaces were more resistant to fibrinogen adsorption and platelet adhesion than the poly(MPC) surfaces. At high graft density, both the poly(MPC) and poly(OEGMA) surfaces were highly resistant to fibrinogen and platelets. Immunoblots of proteins eluted from the surfaces after contact with human plasma were probed with antibodies against a range of proteins, including the contact phase clotting factors, fibrinogen, albumin, complement C3, IgG, vitronectin and apolipoprotein A-I. The blot responses were weak on the poly(MPC) and poly(OEGMA) surfaces at low graft density and zero at high graft density, again indicating strongly protein resistant properties for these surfaces. Since the side chains of the poly(OEGMA) are about 50% greater in size than those of poly(MPC), the difference in protein resistance between the poly(MPC) and poly(OEGMA) surfaces at low graft density may be due to the difference in surface coverage of the two graft types. PMID- 21693203 TI - Profiling the peptidome of the venom from the social wasp Agelaia pallipes pallipes. AB - The wasp Agelaia pallipes pallipes is one of the most aggressive species from the neotropical region, causing many stinging accidents every year, characterized by severe envenoming reactions. The identification of peptides is important for understanding the envenoming process; however, the tiny amount of venom produced by these insects makes this task a challenge, using classical analytical approaches. Thus, the venom was previously fractionated, and the sequences were obtained through the use of electrospray ionization with a tridimensional ion trap and time-of-flight mass analysis under CID conditions. This approach permitted the sequence assignment of nine peptides. The presence of type -d and w ions generated from the fragmentation of the side chains was used to resolve I/L ambiguity. The distinction between K and Q residues was achieved through esterification of the alpha- and epsilon-amino groups in the peptides, followed by mass spectrometry analysis. Six of these peptides were short, linear and polycationic, while the three other peptides presented a single disulfide bridge. The use of reduction and alkylation protocols, followed by ESI-IT-TOF/MS analysis under CID conditions, permitted easy sequencing of the three peptides presenting this post-translational modification. These peptides presented activity related to mast cell degranulation, hemolysis, or even the chemotaxis of leukocytes. PMID- 21693204 TI - New-onset diabetes after renal transplantation: diagnosis, incidence, risk factors, impact on outcomes, and novel implications. AB - OBJECTIVE: New-onset diabetes after transplantation (NODAT) is a multifactorial, complex metabolic disorder associated with impaired long-term graft function, reduced recipient survival, and increased risks of cardiovascular disease and infectious complications. The impact of NODAT is generally underestimated partly due to the inconsistent criteria that have been previously used for its diagnosis and to the generally short observation periods. The aim of this article was to review the recent literature on NODAT and to highlight the novel implications. FINDINGS: The 2010 American Diabetes Association guidelines provide useful, simplified criteria to unify the diagnosis including application of hemoglobin A1C levels. We sought to establish the impact of various modifiable and nonmodifiable risk factors. A vast number of papers have examined the effects of immunosuppressive medications on the development of NODAT: Neither calcineurin inhibitor nor sirolimus (SRL) or steroids seems to be innocent of contributing to it. Immunosuppressants account for 74% of the occurrence of NODAT. Among modifiable risk factors, obesity is independent and significant, with great prevalence in the population. In additional to lifestyle modifications, the role of bariatric surgery (BS) either before or after transplantation is highlighted herein as a strategy to reduce disease in the view of the results among overweight, nontransplanted patients. SUMMARY: Because of the strong association between high glucose values in the early posttransplant period and the development of NODAT, the condition must be recognized early after (or even before) transplantation by intensive screening. Patients at risk for NODAT must modify appropriate risk factors and particularly undergo pretransplant planning and/or posttransplant adjustment individualizing immunosuppressive therapy to mitigate the risk of this serious complication. PMID- 21693205 TI - Posttransplantation lymphoproliferative disorder in kidney and heart transplant recipients receiving thymoglobulin: a systematic review. AB - Posttransplantation lymphoproliferative disorder (PTLD) is an important complication of transplantation. Risk factors include increased overall immunosuppression exposure and inadequate antiviral prophylaxis; however, the effects of T-cell-depleting agents on PTLD are unclear. A systematic literature review was conducted to assess PTLD in clinical studies published 1999-2009 in transplant patients with >= 3 years follow-up who received Thymoglobulin for induction. Twenty studies were identified (12 kidney, 7 heart, and 1 liver), of which 3 were excluded for insufficient PTLD reporting. The final study group comprised 2,246 kidney and heart transplant recipients (liver study excluded) who received Thymoglobulin. At a median follow-up of 5 years, the incidence of PTLD was 0.98% (kidney, 0.93%; heart, 1.05%) among Thymoglobulin-treated patients. The cumulative Thymoglobulin dose reported in these studies was not associated with the development of PTLD (P = NS). However, incidence of PTLD was significantly lower with antiviral prophylaxis (0.63%) than without (1.87%; P = .013). Heart transplant recipients not receiving antiviral prophylaxis had the highest PTLD incidence, possibly attributable to a greater overall immunosuppressive burden. This analysis revealed that PTLD incidences in kidney and heart transplant recipients receiving Thymoglobulin were low overall and perhaps related more to concomitant anti-viral prophylaxis use. PMID- 21693206 TI - Does stroke volume variation predict intraoperative blood loss in living right donor hepatectomy? AB - BACKGROUND: Although stroke volume variation (SVV) is a valuable index of preload responsiveness, there is limited information about the association between low SVV and increased hepatectomy-related bleeding. We therefore evaluated whether SVV predicts blood loss during living donor hepatectomy. METHODS: We evaluated 93 adult liver donors undergoing right hepatectomy for transplantation. Arterial blood pressure, heart rate, body temperature, central venous pressure, SVV, cardiac output, and systemic vascular resistance were measured. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed to determine independent factors and optimal cutoff values of hemodynamic parameters for predicting intraoperative blood loss >= 700 mL. RESULTS: Of these 93 donors, 36 (38.7%) had blood loss >= 700 mL. Univariate logistic regression analysis showed that factors associated with blood loss >= 700 mL included heart rate, SVV, cardiac output, and systemic vascular resistance. Multivariate logistic regression analysis revealed that only SVV was an independent predictor of blood loss >= 700 mL. ROC curve analysis showed that the optimal cutoff value for SVV predicting blood loss >= 700 mL was 6% (area under the curve = 0.64). CONCLUSIONS: SVV is a significant independent predictor of blood loss >= 700 mL during donor hepatectomy, suggesting that low SVV may provide useful information on intraoperative bleeding in donors undergoing right hepatectomy. PMID- 21693207 TI - Transplantation with kidney paired donation to increase the donor pool: a single center experience. AB - BACKGROUND: A living either related or unrelated donor transplant leads to a better outcome in terms of patient and graft survivals compared with one from a deceased donor. Desensitization protocols are expensive and labor intensive. The use of unrelated living donors has the greatest potential to increase the number of donors in the future, when no willing living donor is available due to blood group and/or human leukocyte antigen incompatibility. Herein, we have reported our results with a living donor exchange program. AIMS: To determine the feasibility and effectiveness of kidney paired donation (KPD) to manage patients with incompatible donors as well as present patient and graft survivals, serum creatinine (S.Cr) levels, and rejection episodes. RESULTS: Between June 2000 and December 2009, we performed KPD transplants in 36 recipients to avoid blood group incompatibility (n = 28) or to avoid a positive crossmatch (n = 8). At a median follow-up of 27.7 months (range, 5.83-119.8). The patient survival rate was 88.9% and the graft survival rate was 94.4%. Four patients developed acute cellular rejection episodes (11.1%) and 3 (8.3%) acute antibody-mediated rejection. At 1, 3, and 5 years, the mean S.Cr values were 1.42 +/- 0.28 mg% (n = 28) 1.61 +/- 0.51 (n = 22) and 1.24 +/- 0.15 (n = 8), respectively. CONCLUSIONS: The incidence of acute rejection episodes and patient/graft survivals were acceptable in our KPD program. The use of unrelated living donors has great potential to increase the number of donors in the future; a national KPD program should be encouraged in India. PMID- 21693208 TI - Retroperitoneal laparoscopic live-donor nephrectomy: introduction of simple hand assisted technique (without hand port). AB - OBJECTIVE: Compared with the transperitoneal approach, retroperitoneal laparoscopic live-donor nephrectomy offers a substantial advantage. However, retroperitoneal access is more difficult because of the limited working space. The objective of this study was to report our experience with hand-assisted retroperitoneal laparoscopic live-donor nephrectomy without a hand port. MATERIALS AND METHODS: Intraoperative and immediate postoperative surgical outcomes were reviewed for 23 modified retroperitoneal laparoscopic live-donor nephrectomies performed from May 2009 to January 2010. All kidneys were from living related donors. No prisoners or organs from prisoners were used in this study. RESULTS: Retroperitoneal laparoscopic live-donor nephrectomy was successfully completed in all patients, without conversion to open surgery. Mean (range) operative was 114 (98-130) minutes; warm ischemia time was 1.6 (1.3-2.1) minutes; estimated blood loss was 20 (10-50) mL; and postoperative hospital stay was 6.9 (5-10) days. No serious complications such as massive bleeding or bowel injury occurred. In 1 patient, a hematoma of renal fossa developed, which was successfully treated at repeat operation. All kidneys demonstrated good primary function except 1 that exhibited delayed graft function. CONCLUSIONS: Retroperitoneal laparoscopic live-donor nephrectomy combines the benefits of both hand assistance and the retroperitoneal approach, to minimize the risk of short- and long-term complications associated with the transabdominal approach. The technique could be a cost-effective procedure suitable for use in developing countries. PMID- 21693209 TI - Impact of the educational resource one life ... many gifts on attitudes of secondary school students towards organ and tissue donation and transplantation. AB - BACKGROUND: Increased awareness of organ donation/transplantation has been found to have a positive influence on organ donation rates. One Life ... Many Gifts is a curriculum resource in Ontario, Canada, to educate and raise awareness for senior secondary school students about the importance of organ and tissue donation and transplantation. Teachers administered pre- and post- attitudinal surveys to senior secondary school students to evaluate changes in their attitudes toward organ and tissue donation and transplantation. In this study, the effect of the One Life ... Many Gifts educational intervention on changing the attitudes and awareness of organ donation and transplantation of senior secondary students was assessed. METHODS: Mann-Whitney U tests were used to compare the pre- and post-surveys as a whole and then again for the data from individual schools. Kruskal-Wallis H-tests were used to compare data between schools. RESULTS: A total of 1832 pre- and 1440 post-educational surveys returned to Trillium Gift of Life Network were assessed in the 2008-2009 academic year. Overall, comparison of all pre- and post-educational program survey data showed significant improvement in the students' attitudes toward organs and tissue donation and transplantation (P = .00625). CONCLUSION: The One Life ... Many Gifts program made an impact on changing the attitudes toward and awareness of organ donation among high school students in Ontario. Evaluation of its impact on donor registration and organ donation among the students and their parents is complex and remains to be seen. PMID- 21693210 TI - Preliminary analysis of factors influencing organ donation rates in China. AB - In recent years, the People's Republic of China has experienced advancements in organ transplant surgical techniques, growing transplant waiting lists, and stagnant organ donation rates. All of these factors have pressured China to find ways to increase brain-dead cadaveric donation rates to narrow the gap between organ supply and demand. The objective of this work was to review the factors influencing brain-dead cadaveric donation rates in China including legislation, brain-death criteria, and clinical practice as well as cultural and public attitudes toward brain death and organ donation, for comparisons with other countries. PMID- 21693211 TI - Knowledge and attitudes toward organ/tissue donation and transplantation among health care professionals working in organ transplantation or dialysis units. AB - OBJECTIVE: To evaluate the awareness and attitudes of health care professionals toward organ/tissue donation and transplantation. METHODS: We included 309 health care professionals from 27 dialysis centers and eight organ transplantation centers in Istanbul in the present study conducted from April 2008 to August 2008. The 24-item questionnaire, including items concerning sociodemographic features and knowledge about and attitudes toward organ/tissue donation and transplantation, was applied by face-to-face interviews. RESULTS: An organ/tissue donation card was completed among 77% of subjects, while 90% were identified as supporting transplantation. The main reasons identified for lack of donation were lack of confidence (59.7%), fear of procurement (31.5%), and inappropriate use of harvested organs (18.1%). CONCLUSION: In conclusion, targeting health care professionals in the first place and development of nationwide media and educational campaigns on the ethical, moral, as well as religious dimensions of transplantation and donation seem crucial to increase the number of individuals who can act as role models via their positive impact on the general public's attitudes toward organ donation. PMID- 21693212 TI - Knowledge and behavior among health professionals in relation to cadaveric organ donation and transplantation: a questionnaire-based analysis in Portuguese hospitals. AB - OBJECTIVE: To assess knowledge and behavior relative to cadaveric organ donation and transplantation among physicians and nurses working at nine Portuguese hospitals. METHODS: This prospective study between May and October 2009 included 495 questionnaires that were returned among 840 that were delivered, a 59% response rate. The transplant questionnaire comprised three main sections: section 1, sociodemographic-professional variables of the participants with nine questions; section 2, generic questions on organ donation and transplantation with 12 questions; and section 3 evaluated knowledge with 20 specific questions on organ donation and transplantation. RESULTS: Sixty-one percent of the participants were females, with 40% of the overall cohort between 31 and 40 years old; 62% married; 63% working in the emergency department; and 78% nurses. Although 78% of the participants stated that they had undergone specific training on organ donation and transplantation, 62% felt that they needed more training. The reasons evoked for the low rate of donation included difficulties in initiating the process of organ donation, in diagnosing cerebral death and in obtaining necessary human resources. There were no significant differences in knowledge between physicians and nurses concerning specific organ donation and transplantation issues. Having had specific training on organ donation and transplantation was significantly associated with correct answers to several questions, including those pertaining to knowledge of the national legislation on organ donation and transplantation. CONCLUSIONS: The present study showed a lack of specific knowledge and training on organ donation and transplantation issue. It also suggested that for hospital staff to successfully act as initiators of the organ procurement process, more information and education are necessary. This effort could significantly increase the rate of organ donation and transplantation in Portugal. PMID- 21693213 TI - Kidney donation after cardiac death in Korea. AB - Organ donation after cardiac death (DCD) has been suggested due to the shortage of allografts in Korea. We investigated the outcomes of 446 deceased donor kidney transplant recipients in our center between September 1, 1995, and December 31, 2009. Twenty-four (5.4%) of those patients received DCD kidney grafts. The DCD group had a long intensive care unit stay, frequent inotropics use (such as norepinephrine and dopamine), low mean blood pressure and estimated glomerular filtration rate, and high serum creatinine and deceased donor scores compared to the standard criteria donor (SCD) group and the expanded criteria donor (ECD) group. Mean true warm ischemic time of the DCD group was 59.7 minutes based on asystole time. The DCD group had a long hospital stay after transplantation, but there was no statistically significant difference in delayed graft function and primary nonfunction. Serum creatinine levels at 3 months after transplantation in the ECD and DCD group were significantly higher than the SCD group (P < .001) but lower in the DCD group than in the ECD group at 6 months and 9 months (P < .001 and P = .004) posttransplantation. There were no statistically significant differences in serum creatinine levels or in the graft survival rates between groups at 12 months (P = .160 and P = .737). The use of DCD attracted Korean surgeons because DCD allografts are equivalent to a heart-beating donor. Donors who die during the evaluation of brain death should not be abandoned for procurement, and we need to try to harvest allografts after cardiac death (type 4 DCD) to expand donor pools. PMID- 21693214 TI - Organ donor found to have von Hippel-Lindau disease: case report. AB - Multiple pancreatic cyst in combination with central nervous system hemangioma may be associated with Von Hippel-Lindau disease. The disease manifests with other systemic benign and malignant lesions. The risk of associated malignancy makes it imperative to review target organs before proceeding to transplantation, but does not preclude it completely if proper evaluation is performed. We present a case of an organ donor found to have multiple pancreatic cysts. Evaluation and transplantation decisions are discussed. PMID- 21693215 TI - Protective effect of N-acetylcysteine on early outcomes of deceased renal transplantation. AB - We investigated the effects of the antioxidant N-acetylcysteine (NAC) on early outcomes of deceased donor renal transplantation. Between April 2005 and June 2008, adult primary graft recipients of deceased renal donors were assigned to treatment (n = 38) or control (n = 36) groups and evaluated for 90 days and one year after renal transplantation. The treatment group received NAC orally (600 mg twice daily) from day 0 to 7 postoperatively. Renal function was determined by serum creatinine, MDRD and Cockcroft-Gault estimated GFR (eGFR), delayed graft function (DGF) and dialysis free Kaplan-Meier estimate curve. Serum levels of thiobarbituric acid reactive substances (TBARS), were employed as markers of oxidative stress. The NAC group displayed a lower mean serum creatinine during the first 90 days (P = .026) and at 1 year after transplantation (P = .005). Furthermore, the NAC group showed a higher mean eGFR throughout the first 90 days and at 1 year. DGF was lower among the NAC group (P = .017) and these recipients required fewer days of dialysis (P = .012). Oxidative stress was significantly attenuated with NAC (P < .001). Our results suggested that NAC enhanced early outcomes of deceased donor renal transplantation by attenuating oxidative stress. PMID- 21693216 TI - Protective effects of deferoxamine mesylate preconditioning on pancreatic tissue in orthotopic liver autotransplantation in rats. AB - BACKGROUND: Deferoxamine mesylate is known to ameliorate tissue ischemia reperfusion injury. This study was designed to explore the impact of deferoxamine mesylate preconditioning (DMP) on pancreatic tissue and its possible effects during orthotopic liver autotransplantation. METHODS: A modified orthotopic liver autotransplantation model was used to simulate pancreatic ischemia-reperfusion injury. Sprague-Dawley rats (0.25-0.30 kg) were randomly divided into normal control, autotransplantation (AT), systemic deferoxamine mesylate preconditioning (SDMP), and partial deferoxamine mesylate conditioning (PDMC) groups. The SDMP group was injected with deferoxamine mesylate (75-90 mg; 300 mg/kg), via the celiac artery at 24 and 48 hours before surgery. During surgery, the PDMC group underwent liver perfusion by means of deferoxamine mesylate solution (20 ml; 0.6 mmol/L) rather than Ringer's lactate solution, with no prior preconditioning. At 6, 24, and 48 hours after surgery, the rats were sacrificed to sample their pancreatic tissues for the expression of hypoxia-inducible factor-1alpha (HIF 1alpha) and malondialdehyde (MDA) content. The samples were subjected to blood chemistry analyses, light and transmission electron microscopic morphological studies, and quantitative measurement of HIF-1alpha expression. RESULTS: The serum levels of amylase, lipase, and MDA in SDMP and PDMC groups were significantly lower than those in the AT group at 6, 24, and 48 hours after orthotopic liver autotransplantation (P < .05). Light and electron microscopic analyses showed much more severe pancreatic injury in the autotransplantation than in the SDMP and PDMC groups. The HIF-1alpha expression was increased in the SDMP and PDMC groups more than in the autotransplantation group (P < .05). CONCLUSIONS: Deferoxamine mesylate preconditioning protected pancreatic tissue in orthotopic liver autotransplantation in rats. Inhibition of oxidative toxic reactions and up-regulated expression of HIF-1alpha protein are possible mechanisms. PMID- 21693217 TI - Astragaloside IV protects against ischemia reperfusion in a murine model of orthotopic liver transplantation. AB - AIM: The aim of this study was to determine whether Astragaloside IV (AST-IV) inhibited the transcriptional activity of nuclear factor-kappaB (NF-kappaB), attenuating liver transplant ischemia-reperfusion injury (IRI). METHODS: Sprague Dawley (SD) rats were randomly divided into 2 groups: donors given AST-IV (1.5 mL; 100 MUg/mL, intravenous [IV]) 1 hour before surgery (n = 32), versus controls treated with 1.5 mL physiological saline (n = 32). Orthotropic liver transplantation was performed according to the Kamada technique. Eight animals in each group were followed for seven days after surgery to assess survival. The remaining hosts in each group were divided into 3 subgroups (n = 8) to be examined at 3, 6, and 24 hours after portal vein reperfusion. We analyzed levels of alanine aminotransferase (ALT), tumor necrosis factor (TNF)-alpha, and NF kappaB transcriptional activity and performed a morphological study of liver tissues, NF-kappaB, and glucocorticoid receptor (GR) expression in Kupffer cells (KCs). RESULTS: Pretreatment with AST-IV significantly improved survival rates and liver function, attenuating liver parenchymal cell damage by down-regulating TNF-alpha levels and NF-kappaB expressions, inhibiting NF-kappaB transcriptional activity, up-regulating GR expression. CONCLUSION: AST-IV attenuated hepatic IRI by inhibiting NF-kappaB transcriptional activity. The mechanism may relate to up regulation of GR expression. PMID- 21693218 TI - Inhibition of Toll-like receptor 4 with vasoactive intestinal peptide attenuates liver ischemia-reperfusion injury. AB - BACKGROUND: Toll-like receptor 4 (TLR4) has attracted a great deal of attention in ischemia-reperfusion (IR) injury in recent years. Vasoactive intestinal peptide (VIP) plays an important role in anti-inflammatory and immunomodulatory activity in several animal models. There are no data available regarding the effect of VIP on TLR4 expression in IR injury in vivo. In the present study, we study the effect of VIP on TLR4 expression in mouse macrophage cell line RAW 264.7 and a mouse partial IR model. METHODS: The potential inhibitory effect of VIP on TLR4 mRNA and protein in a mouse macrophage cell line and in a mouse model of partial warm hepatic IR injury was assessed. We also assessed the expression tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in this model. RESULTS: Expression of TLR4 mRNA levels was significantly decreased at 6, 12, and 24 hours after treat with VIP in mouse macrophage cell line RAW 264.7. Expression of TLR4 mRNA, TLR4 protein, alanine aminotransferase, TNF-alpha, and IL-6 levels were significantly increased in the IR group but significantly decreased in groups pretreated with VIP at a concentration of 5 and 10 nmol. Hematoxylin and eosin staining show apparent edema and necrosis were observed in the IR group, but in the VIP pretreatment group, edema and necrosis in IR modes were reduced. CONCLUSION: This study showed that VIP might inhibit TLR4 in vitro and in vivo, and pretreatment with VIP might inhibited TLR4 activation and reduced warm IR injury. PMID- 21693219 TI - Fructose 1-6 bisphosphate versus University of Wisconsin solution for rat liver preservation: does FBP prevent early mitochondrial injury? AB - BACKGROUND: Fructose 1,6-biphosphate (FBP) has been shown to exert therapeutic effects in models of ischemia-reperfusion in organs other than the liver. This study compared FBP and University of Wisconsin (UW) solution during cold storage and reperfusion, among mitochondria of adult male Wistar rat livers. METHODS: Adult male Wistar rats were assigned to two groups according to the preservation solution used; UW or FBP Aspartate transaminase (AST), alanine transferase (ALT); and lactic dehydrogenase (LDH) were measured in samples of the storage solution obtained at 2, 4 and 6 hours of preservation. After 6 hours of cold storage, we reperfused the liver, taking blood samples to measure AST, ALT, LDH, and throbarbituric acid reactive substances (TBARS). Hepatic fragments were processed for histologic analysis; for determinations of TBARS, catalase, and nitric oxide as well as for mitochondrial evaluation by infrared spectroscopy. RESULTS: During cold preservation, levels of AST and LDH in the storage solution were lower among the FBP group, but after reperfusion, serum levels of AST, ALT, and LDH were higher in this group, as was catalase activity. TBARS and nitric oxide were comparable between the groups. In the UW group there was a higher amide I/amide II ratio than in the FBP group, suggesting an abnormal protein structure of the mitochondrial membrane. No signs of preservation injury were observed in any liver biopsy, but sinusoidal congestion was present in livers preserved with FBP. CONCLUSION: FBP showed a protective effect for preservation during cold storage seeming to protect the mitochondrial membrane although it did not prevent reperfusion injury. PMID- 21693220 TI - Determination of apparent diffusion coefficient to quantitatively study partial hepatic ischemia reperfusion injury in a rabbit model. AB - BACKGROUND: Animal models of partial hepatic ischemia-reperfusion injury (IRI) have potential benefits for decision making and clinical management after liver transplantation or massive hepatic resection. We evaluated changes in apparent diffusion coefficient (ADC) in rabbits with partial hepatic IRI using 3.0 T magnetic resonance diffusion-weighted imaging (DWI). METHODS: Rabbits underwent 60 minutes of left lobar ischemia followed by 0.5, 2, 6, 12, 24, or 48 hours of reperfusion (n = 6 each). DWI spin echo-echo planar imaging (SE-EPI) was performed with b values of 50, 100, 200, 300, 500, and 600 s/mm(2). RESULTS: There was a significant difference between the ADCs at 0.5 hour and sham groups when b values were <300 s/mm(2) and between the six hour and sham groups with b = 50 and 100 s/mm(2). The ADC values were lower in the 24-hour group with b values of 50, 100, 200, and 300 s/mm(2) (all P < .01) but significantly increased in the 48-hour group when b = 500 and 600 s/mm(2) compared with the sham group (all P < .01). ADC did not change significantly in the 2-hour and 12-hour groups compared with the control group. CONCLUSIONS: In this study 3.0 T DWI dynamically monitored the pathological processes of liver IRI, revealing the microvascular disorder with a perfusion-sensitive ADC at the lower b values (<300 s/mm(2)), particularly in the early stages. PMID- 21693221 TI - Effects of n-3 polyunsaturated fatty acids on hepatic tight junction after partial hepatectomy in rats. AB - OBJECTIVE: To explore the effects of n-3 polyunsaturated fatty acid (PUFA) on the hepatic tight junction in rat liver after partial hepatectomy. MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into 4 groups: sham operation, 70% hepatectomy, 70% hepatectomy with administration of 1 mL/kg n-3 PUFA, and 70% hepatectomy with administration of 2 mL/kg n-3 PUFA. Morphologic features of the hepatic tight junction were observed at transmission electron microscopy, and expression of the tight junction proteins occludin, claudin-3, and ZO-1 was studied using Western blot analysis. RESULTS: The hepatic tight junction structure became loosened 3 days after 70% hepatectomy. The levels of tight junction occludin decreased markedly, whereas claudin-3 and ZO-1 levels increased 2- or 3-fold over control levels. Supplementation of n-3 PUFA alleviated the changes in tight junction structure and occludin expression. CONCLUSION: n-3 PUFA has protective effects on hepatic tight junction structure after 70% hepatectomy, which were attributed in part to modulation of occludin expression. PMID- 21693223 TI - Effect of milrinone on ischemia-reperfusion injury in the rat kidney. AB - BACKGROUND: Milrinone (MIL), a phosphodiesterase (PDE) 3 inhibitor, exhibits cardiotonic and angioectatic effects. Various PDE inhibitors have been shown to suppress inflammatory cytokines. In this study, we evaluated the angioectatic and anti-inflammatory cytokine effects of MIL on renal function after warm ischemia in a rat ischemia-reperfusion (I-R) injury model. MATERIALS AND METHODS: MIL or control solution was perfused from the left renal artery to the right kidney, and the left kidney was excised. The right renal artery, vein, and ureter were clamped and then released after 50 minutes to produce warm ischemia. We evaluated control (n = 7), MIL (n = 7), and sham operation (n = 7) groups for serum creatinine, blood urea nitrogen (BUN), blood flow, expression of tumor necrosis factor (TNF)-alpha mRNA, apoptosis index, and histological evidence of acute tubular necrosis. RESULTS: Serum creatinine and BUN concentrations peaked at 24 hours after reperfusion. MIL treatment significantly reduced serum creatinine (control group 1.27 +/- 0.45 mg/dL vs MIL group 0.77 +/- 0.19 mg/dL, P < .05; sham 0.35 +/- 0.2 mg/dL) and BUN (control 67.6 +/- 13.6 mg/dL vs MIL 51.0 +/- 8.8 mg/dL, P < .05; sham 23.0 +/- 4.2 mg/dL) levels at 24 hours. Thereafter, serum creatinine and BUN concentrations in the MIL group remained significantly lower compared with the control group for 120 hours (P < .05). MIL group exhibited significantly higher tissue blood flow, less acute tubular necrosis, lower expression of TNF-alpha mRNA in renal tissue, and lower apoptotic index (P < .05). CONCLUSIONS: MIL maintained renal tissue blood flow by its vasodilatory effect, suppressed expression of TNF-alpha mRNA by increasing intracellular cyclic adenosine monophosphate, and ultimately decreased tubular cell apoptosis, thus protecting renal function after warm I-R injury. PMID- 21693222 TI - Hepatocyte viability and adenosine triphosphate content decrease linearly over time during conventional cold storage of rat liver grafts. AB - INTRODUCTION: The gold standard in organ preservation is static cold storage (SCS) using University of Wisconsin solution (UW). Although it is well-known that there is a finite limit to SCS preservation, and that there is a correlation between the adenosine triphosphate (ATP) levels and organ function post preservation, a quantitative relationship has not been established, which is important in understanding the fundamental limitations to preservation, minimizing cold ischemic injury, and hence maximizing use of the donor organ pool. AIM: This study determines the time limits of cellular viability and metabolic function during SCS, and characterizes the relationship between cellular viability and energetic state using clinically relevant techniques in organ preservation. METHODS: Rat livers were procured and stored using conventional storage in UW solution at 4 degrees C. Viability was assessed by determining the amount of viable hepatocytes and intracellular ATP content after 0, 24, 48, 72, and 120 hours of storage. RESULTS: Numbers of viable hepatocytes that were isolated from these livers decreased steadily during SCS. After 5 days, viable hepatocytes decreased from 25.95 * 10(6) to 0.87 * 10(6) cells/gram tissue. Intracellular ATP content decreased from 9.63 to 0.93 moles/g tissue. Statistical analysis of variance established a linear relation for both parameters as a function of time (P < .05). CONCLUSION: The linear correlation between hepatocyte viability, ATP content, and storage time suggests a shared physiological foundation. These findings confirm ATP as direct predictor for organ quality in the context of liver preservation, which will aid quantitative assessment of donor organs for various applications. PMID- 21693224 TI - Progressive development of renal vascular dysfunction in brain death implicates reversible alterations of nitric oxide metabolism. AB - BACKGROUND: Vascular endothelial dysfunction occurs in the kidney graft from marginal brain death (BD) donors and may be responsible for a low success rate after transplantation. METHODS: BD was induced in 16 dogs for 6 hours. Immediately after the inflation of the intracranial balloon, the treated group (n = 8) received 40 mg/kg bolus followed by 3 mg/kg/min infusion of L-arginine for 30 minutes. Renal vascular function and hemodynamic and biochemical parameters were determined. RESULTS: BD caused vasoconstriction, increase in renal venous nitrite (4.9 +/- 0.8 versus 2.6 +/- 0.1, P < .05) and myeloperoxidase levels (1.43 +/- 0.04 versus 2.43 +/- 0.23, P < .001), and reduced vasodilatation of renal artery to acetylcholine. Larginine diminished the renal vasoconstriction induced by 6 hour BD (RVR = 0.92 +/- 0.06 versus 1.38 +/- 0.003 in controls, P < .05), maintained renal oxygen extraction in physiological range (17.5 +/- 4.6% versus 25.4 +/- 2.9% in controls, P < .05) and prevented the rise of myeloperoxidase (1.69 +/- 0.19, P < .05 versus controls) and nitrite levels (3.3 +/- 0.5, P < .05), followed by preservation of endothelium dependent vasodilatation (P < .05 versus controls). CONCLUSIONS: The findings suggest that exogenous L-arginine supplementation may preserve endothelial vascular function in the kidney before prelevation from marginal BD donors. PMID- 21693225 TI - Inhibition of IkappaB Kinase beta attenuates hypoxia-induced inflammatory mediators in rat renal tubular cells. AB - OBJECTIVE: Inflammation is now believed to play a major role in the pathophysiology of ischemic acute kidney injury (AKI), which is thought to be directly regulated by nuclear factor-kappaB (NF-kappaB). Our previous study indicated that ischemic preconditioning (IPC) alleviated renal ischemic reperfusion injury due to inhibition of IkappaB kinase beta (IKK beta) activity. Using small interfering RNA (siRNA) to silence the expression of IKKbeta, which consists of the IKK complex residing at a key convergence site that leads to NF kappaB activation in multiple signaling pathways, we protected organs from ischemic AKI. Herein, we have report a siRNA-based treatment to prevent ischemic AKI. METHODS: Ischemic AKI was induced by a hypoxia-mimicking agent cobalt chloride (CoCl(2)). The therapeutic effects of IKKbeta-specific siRNA were evaluated on the expression of interleukin (IL)-18, neutrophil gelatinase associated lipocalin (NGAL), and cell apoptosis. RESULTS: Compared with CoCl(2) induced NRK52E cells, pretransfected IKKbeta-specific siRNA reduced the expression of IL-18 and NGAL to 62.5% and 50.4% in messenger RNA (mRNA) and to 57.2% and 62.7% in protein levels, respectively. The necrosis index in the IKKbeta-specific siRNA transfected group was decreased compared with a nonspecific siRNA transfected group. CONCLUSIONS: These data revealed that hypoxia-induced inflammatory responses were IKKbeta/NF-kappaB-dependent. Knockdown of IKKbeta by siRNA suppressed the transcription IKKbeta/NF-kappaB mediated inflammatory mediators in tumor necrosis factor-alpha or CoCl(2)-treated tubular epithelial cells, and decreased CoCl(2)-induced cell death, which may be a useful, preventive and therapeutic strategy for ischemic AKI. PMID- 21693226 TI - Factors influencing rat survival in a warm renal ischemia model: time to adapt the protocols. AB - INTRODUCTION: Survival in warm renal ischemia models is not only dependent on the treatment or surgical technique being evaluated, but also on factors inherent to the model itself. Use of rats of various strains in previous studies makes interstudy comparison difficult when trying to design an appropriate model control that would yield intermediate survival. In this study, impact of rat strain on survival after prolonged warm renal ischemia in the setting of delivery controlled inhalational anesthesia was evaluated. MATERIALS AND METHODS: Under general delivery-controlled inhalation anesthesia with isoflurane, Dahl salt sensitive, Wistar-Furth, Sprague-Dawley, and spontaneously hypertensive rats (n = 66 rats) were subjected to 150 minutes of unilateral renal warm ischemia time, subsequent reperfusion, and contralateral nephrectomy. Animals were followed up for 1 month, after which survivors were euthanized and morphologic changes in kidneys were scored. RESULTS: Thirty-day survival was: Dahl salt sensitive, 78%; Wistar-Furth, 67%; Sprague-Dawley, 55%; and spontaneously hypertensive rats, 0% (P < .0001). Histologic acute injury scores were higher for non-survivors versus 30-day survivors (P < .0001). CONCLUSION: Our data strongly suggest that rat strain is a major factor influencing survival and that strain and warm ischemia time selections must be considered together when designing a model control yielding intermediate survival. Further study is warranted in order to compare the effect of delivery-controlled inhalational versus historical anesthesia methods on animal survival. PMID- 21693227 TI - Cardioprotection of 17,18-epoxyeicostetraenoic acid in ischemia/reperfusion is mediated by cyclooxygenase-2: a study in a rat model. AB - BACKGROUND/PURPOSE: Arachidonic acid and related cardioprotective eicosanoids are released in myocardial ischemia/reperfusion injury. The present study analyzes the effects of the eicosapentaenoic acid derived 17,18-epoxyeicostetraenoic acid on isolated cardiomyocytes and investigates whether 17,18-epoxyeicostetraenoic acid serves as a potential factor in the cardio-depressant postischemic effluent. BASIC PROCEDURES: After 10 minutes of global ex vivo stop-flow ischemia, adult rat hearts were reperfused and coronary postischemic effluent was collected over a period of 30 seconds. Nonischemic effluent was collected prior to ischemia. The effects of 17,18-epoxyeicostetraenoic acid on calcium (Ca(2+)) metabolism and contraction frequency of isolated neonatal rat cardiomyocytes were tested and compared with the effects of prior collected postischemic and nonischemic effluents. Isolated neonatal cardiomyocytes were preincubated with selective (NS 398, SC-560) and nonselective cyclooxygenase inhibitors (indomethacin) to determine whether cardio-depressive effects are mediated by cyclooxygenase. FINDINGS: In contrast to the nonischemic effluent, both 17,18 epoxyeicostetraenoic acid and the postischemic effluent induced a comparable decrease of the Ca(2+) transient and the contraction frequency (P < .05 vs control). The cardio-depressive effects of 17,18-epoxyeicostetraenoic acid and the postischemic effluent were significantly attenuated after preincubation with the unselective cyclooxygenase inhibitor indomethacin and the selective cyclooxygenase-2 inhibitor NS-398 (P < .05 vs control). Selective cyclooxygenase 1 inhibition with SC-560 did not influence the effect of 17,18 epoxyeicostetraenoic acid and the postischemic effluent. CONCLUSIONS: Our data show that the cardio-depressive effects of 17,18-epoxyeicostetraenoic acid are comparable with the postischemic effluent and are mediated by cyclooxygenase-2. Our results suggest a potential cardioprotective role of the eicosanoid 17,18 epoxyeicostetraenoic acid in heart ischemia/reperfusion injury. PMID- 21693228 TI - Comparing the performance of rat lungs preserved for 6 or 12 hours after perfusion with low-potassium dextran or histidine-tryptophan-ketoglutarate. AB - INTRODUCTION: In lung transplantation, graft dysfunction is a frequent cause of mortality; the etiopathogenesis is related to ischemia-reperfusion injury. We sought to compare the lung performance of rats after reperfusion after presentation with 3 solutions at 2 ischemia times. METHODS: We randomized 60 male Wistar rats to undergo anterograde perfusion via the pulmonary artery with low potassium dextran (LPD), histidine-tryptophan ketoglutarate (HTK), or saline. After extraction, the heart-lung blocks were preserved in a solution at hypothermia for 6 or 12 hours before perfusion with homologous blood for 60 minutes using ex vivo system Isolated Perfused Rat or Guinea Pig Lung System (Harvard Apparatus). Respiratory mechanics, pulmonary weight, pulmonary artery pressure (PAP), and relative lung oxygenation capacity (ROC) measurements were obtained every 10 minutes. RESULTS: Comparing tidal volume (TV), compliance, resistance, ROC, PAP, and pulmonary weight the LPD, HTK, and saline group did not differ at 6 and 12 hours. The TV was higher in the lungs with 6-hour ischemia in the LPD, HTK, and saline groups. Compliance was higher in the lungs with 6-hour ischemia in the LPD and saline groups. There were no differences in ROC values comparing lungs with 6- versus 12-hour ischemia in the LPD group. A significant difference was observed between lungs in the HTK and saline groups. Resistance was higher in the lungs with 12-hour ischemia among the LPD, HTK, and saline groups. There was a gradual weight increase in the lungs, particularly those undergoing 12-hour ischemia, despite the absence of a significant difference between groups. CONCLUSION: Rat lungs perfused with LPD and HTK preservation solutions showed similar reperfusion performances in this ex-vivo perfusion model. PMID- 21693229 TI - Comparison of extracellular-type-Kyoto solution and Perfadex as a preservation solution in a pig ex vivo lung perfusion model: impact of potassium level. AB - BACKGROUND: The ex vivo lung perfusion (EVLP) system has been used successfully to assess donor lungs. Perfadex (PX) is usually the flush and preservation solution in EVLP systems. We have used the extracellular-type-Kyoto (ET-K) solution containing 44 mEq/L potassium for clinical lung transplantation, investigating whether it rather than PX affects the EVLP system. METHODS: We used domestic slaughterhouse pigs to analyze the EVLP system. After 20-minute warm ischemia and 6-hour cold ischemia, EVLP was performed for 2 hours. Pig heart-lung blocks were divided into the PX (n = 5) and ET-K (n = 5) groups depending on the flush/cold preservation solution. At the beginning, we discarded the first 100 mL of effluent in the PX group and the first 200 mL in the ET-K group. We measured pulmonary physiological data and potassium levels. RESULTS: In both groups, perfusion for 2 hours showed no differences between the 2 groups with respect to the final flow, pulmonary arterial pressure, pulmonary vascular resistance, PaO(2)/FiO(2), and shunt fraction. The potassium level in the perfusate was 4.4 mEq/L for the PX and 5.4 mEq/L for the ET-K group. CONCLUSION: The pig EVLP system was not affected when ET-K was used instead of PX as the flush/preservation solution. The initial 200 mL of effluent should be discarded when using the ET-K to ensure that the potassium level does not increase. PMID- 21693230 TI - Cardiovascular risk assessment among potential kidney transplant candidates and perioperative outcome: analysis of 75 consecutive Middle Eastern patients. AB - BACKGROUND: Evaluation of coronary artery disease (CAD) is a nonstandardized practice before kidney transplantation. The aim of this study was to assess the adequacy of cardiovascular investigations in relation to cardiovascular outcomes of Middle Eastern patients undergoing renal transplantation. METHODS: Seventy five consecutive patients with end-stage renal disease in Qatar were prospectively evaluated between April 2005 and March 2008. They subsequently underwent kidney transplantation. Our prespecified protocol utilized noninvasive and/or invasive tests for the evaluation. RESULTS: The median age was 51 years including 68% men, and 87% of patients maintained on dialysis. Overall, 21 (28%) patients showed evidence of CAD, an incidence that was much higher among patients with diabetes (81%). There were 13 (17%) subjects shown to have CAD by coronary angiography in the absence of a background CAD history. The perioperative cardiovascular course was uneventful in the majority of patients except for five who developed acute coronary syndrome without mortality. CONCLUSION: This study confirmed the high incidence of CAD among kidney transplant candidates. Myocardial perfusion testing was not predictive of perioperative cardiac events. The incidence of perioperative cardiac complications was low; five patients (6.6%) developed acute coronary syndrome. This study suggested that kidney transplantation can be performed safely in the majority of patients regardless of age and even among those with prior evidence of CAD. PMID- 21693231 TI - Advanced donor age alone is not a risk factor for graft survival in kidney transplantation. AB - BACKGROUND: The use of kidneys from elderly deceased donors has substantially increased organ supply, although it is associated with worse graft function and survival rates. The risk of kidneys from elderly donors as well as expanded criteria donors (ECDs) on kidney transplant outcome was investigated. PATIENTS AND METHODS: Seventy-five kidney transplants from ECDs over a 5-year period were reviewed retrospectively. Old age and increased donor risk variables were analyzed separately in relation to graft function and survival. RESULTS: Sixty four of 75 (85.3%) recipients had functioning grafts 5 years posttransplant. The overall actuarial graft survivals from 1 to 5 years were 87.5%, 68.1%, 57.3%, 55.4%, and 47.3%, respectively. Early graft function gave 47 (62.7%) kidneys remarkable actuarial survivals of 100.0%, 88.3%, 75.8%, 75.8%, and 68.4% at 1 to 5 years posttransplant, and 28 (37.3%) kidneys had delayed graft function with substantially decreased actuarial survival rates, ranging from 66.7% to 23.2%. Kidneys from elderly donors had considerable actuarial graft survival rates of 100.0%, 83.3%, 76.9%, 76.9%, and 67.0% from 1 to 5 years, respectively; these were the best graft survival rates compared with kidneys from the other donor categories. The other donor risk variables when associated with advanced age of any had an adverse effect on recipient graft function and survival, but no single risk variable alone, or a combination of any two, showed any statistically significant variability. CONCLUSION: Elderly kidney donors provided a substantial organ pool expansion without affecting patient and graft survival in many patients. ECDs can be utilized safely if adequate measures are taken. PMID- 21693232 TI - Impact of human leukocyte antigen-DR mismatch status on kidney graft survival in a predominantly African-American population under the newer immunosuppressive era. AB - BACKGROUND: Human leukocyte antigen (HLA)-DR has been shown to be immunogenic and associated with poor long-term graft function. However, under potent induction immunosuppression with antithymocyte globulin, the impact of the HLA-DR remains unclear. METHOD: We reviewed 672 renal transplant recipients who received their transplants between 1998 and 2007. All patients received antithymocyte globulin as induction therapy followed by tacrolimus + prednisone + mycophenolate mofetil for maintenance immunosuppression. We divided the patients into three groups according to HLA-DR mismatch status (zero, one, or two mismatches). RESULTS: The three groups were different in total number of mismatches, deceased donor transplant, and delayed graft function, respectively. By Kaplan-Meier survival analysis, actuarial graft survival was significantly lower in the HLA-DR two mismatches group (72%) compared to HLA-DR zero mismatches group (78.5%) or HLA-DR one mismatch group (78.5%; P = .05, by log-rank test). Using Cox regression analysis, the risk of graft failure with two HLA-DR mismatches as compared with zero HLA-DR mismatches was 1.6 (95% confidence interval = 1.0-2.44, P = .049). When adjusted for age, wait time, race, type of transplant, retransplant status, T-cell flow crossmatch, delayed graft function, acute rejection, HLA-A and HLA-B, the effect of HLA-DR on survival was not significant (P = .55). CONCLUSION: The independent effect of HLA-DR mismatches on adverse graft survival is diminished under potent antibody induction and maintenance immunosuppression in our predominantly African-American population. PMID- 21693233 TI - Operational tolerance in living-related renal transplantation: a single-center experience. AB - INTRODUCTION: Various methods have been tried to induce operational tolerance in organ transplantation. We present a single-center experience using 6 tolerance induction protocols (TIP) in living-related renal transplantation. METHODS: We evaluated 6 TIP protocols: (1) peripheral blood stem cells employed (n = 38); (2) midified the protocol by portal infusion (n = 292); (3) the second protocol plus TIP+DST+BM+intrathymic and intramarrow infusion plus low-dose, nonmyeloablative conditioning employed (n = 174), (4) the third protocol of TIP plus cultured hematopoietic stem cells (HSC) with target-specific irradiation (n = 290); (5) TIP 4 plus thymus, intramarrow infusion, and target-specific irradiation converted to total lymphoid irradiation (TLI) (n = 366); and (6) TIP 5 plus bortzomib-TLI (n = 165). Patient/donor demographics were comparable. RESULTS: We evaluated patient and graft survival, rejection episodes, recurrence, drug toxicity, and chimerism revealed; groups 4 and 5 showed better survival, graft function, chimerism, and decreased rejection episodes compared with previous protocols. Serum creatinine (mg/dL) at 1 year was 1.5, 1.39, 1.5, 1.51, 1.46, and 1.41, and at 5 years, 1.69, 1.72, 1.82 and 1.59, in groups 1-6, respectively. Chronic rejection episodes were 10.5%, 14.1%, 10.4%, 9.3%, 3.5%, 1.7%, and 1.8% respectively. Patient survival of groups 1, 2, and 3 at 1, 5, and 10 years was 86.5%, 56.8%, and 40.1%; 89.4%, 69.1%, and 56.4%; and 89.6%, 67.7%, and 64.6%, respectively; of group 4 for 1 and 5 years was 92.4% and 81.8%; for groups 5 and 6 for 1 year was 94% and 96.3%, respectively. The death-censored graft survival of groups 1, 2, and 3 at 1, 5, and 10 years was 91.9%, 70.3%, and 64.7%; 89%, 66%, and 57.6%; and 86.7%, 67%, and 42.5%, respectively. In group 4 for 1 and 5 years was 87.9% and 74.7%; and for groups 5 and 6 for 1 year was 94% and 96.5%, respectively. CONCLUSION: TIP results showed improved graft/patient survivals, minimum immunosuppression, and fewer rejection episodes and recurrence. PMID- 21693234 TI - Analysis of 80 dual-kidney transplantations: a multicenter experience. AB - INTRODUCTION: The use of kidneys from expanded criteria donors (ECD) is an attractive strategy to enlarge the pool of organs available for transplantation. Considering the fact that ECD organs have a reduced nephron mass, they are preferentially allocated for dual-kidney transplantation (DKT). Authors have reported excellent results of DKT when pretransplant ECD organs are evaluated for histological scores. The aim of this study was to evaluate DKT donor and recipient characteristics for comparison with DKT posttransplant outcomes versus those of recipients of single-kidney transplantations from expanded criteria (edSKT) and ideal donors (idSKT). We analyzed the potential prognostic factors involved in DKT among a population derived from three transplant centers. MATERIALS AND METHODS: Between 2001 and 2007, DKT (n = 80) were performed based upon the ECD kidney allocation assessed by biopsy. RESULTS: The average donor ages for the DKT, edSKT, and idSKT groups were 68.8 +/- 7.8, 65.3 +/- 7.2, and 40.1 +/- 13.8 years, respectively (P < .001). The number of human leukocyte antigen mismatches was greater in the DKT group (3.1 +/- 1.2, P < .05). Patient and graft 5-year survival rates were similar among DKT, edSKT, and idSKT recipients, namely, 97.5% versus 95.8% versus 96.9% and 93.7% versus 87.4% versus 86.9%, respectively. Mean serum creatinine values at discharge were lower in the DKT and idSKT recipients (1.5 +/- 0.9 and 1.6 +/- 0.7 mg/dL; P < .05) compared with the edSKT group (1.9 +/- 0.7 mg/dL). Correlations between supposed prognostic factors and survival among the DKT group noted worse outcomes in reoperation cases (P < .05). CONCLUSION: We confirmed that DKT produced successful outcomes. An accurate surgical procedure is particularly important to try to avoid reoperations. In our experience, the use of a biopsy as an absolute criterion to allocate ECD kidneys may be too protective. PMID- 21693235 TI - Outcome of kidney transplantation following end-stage renal disease due to reflux nephropathy. AB - BACKGROUND: Reflux nephropathy (RN) has an important place among the etiologies of end-stage renal disease (ESRD). In this retrospective study we sought to analyze posttransplantation complications among renal transplant recipients whose primary disease was RN. METHODS: Seven hundred forty-five patients who underwent transplantation in our institution between 1983 and 2006 were included in the study. The outcomes of patients with RN (Group 1) were compared with a control group (Group 2) that consisted of age-matched, nondiabetic patients whose primary disease was chronic glomerulonephritis or unknown etiologies. RESULTS: Group 1 consisted of 52 patients, including 20 males with a mean overall age of 25 years. Group 2 included 47 patients, including 21 males with a mean age of 27 years. There was no significant difference with regard to age, gender, donor type, donor age, modality of hemodialysis, or HLA match between the 2 groups. Group 1 graft survival rates in the first and fifth years were 95% and 90%, respectively, and in Group 2 they were 86% and 70%, respectively (P = .302 and P = .072, respectively). There was no significant difference with respect to follow-up duration, hospital stay, or incidence of biopsy-proven or clinically suspected acute rejection episodes between the groups. During the 6-year follow-up, the incidence of biopsy-proven chronic allograft nephropathy was the same in both groups. One patient in Group 1 and 2 in Group 2 died of cardiovascular issues; 1 Group 2 patient died of infection. The frequency of urinary tract infection in Group 1 was greater than that of Group 2 (40% vs, 23%; P = NS). CONCLUSION: Despite the higher incidence of urinary tract infections, there was no significant difference in posttransplantation complications or patient and graft survival rates between RN patients compared with the control group. PMID- 21693236 TI - In vivo 31P MR spectroscopy of human kidney grafts using the 2D-chemical shift imaging method. AB - The aim of this work was to evaluate the possibility to use in vivo (31)P magnetic resonance spectroscopy (MRS) for the diagnosis of kidney graft dysfunction after transplantation. We examined 68 kidney grafted patients using a 1.5 T MR scanner. (31)P MRS was performed using the 2D-chemical shift imaging method. The patients were divided into 4 groups: acute rejection episode; acute tubular necrosis; late graft dysfunction; or good renal function. We measured the signal intensities of phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), and alpha-, beta-, gamma-adenosine triphosphate (ATP; with contributions of alpha- and beta-adenosine diphosphate) and their ratios. Patients with an acute rejection episodes showed a significantly elevated PME/beta-ATP and PDE/beta-ATP, PME/Pi, and PDE/Pi signal ratios compared with the control group. The group with acute tubular necrosis had decreased ratios. Patients with late graft dysfunction revealed only an insignificant decrease in PME/Pi and PDE/Pi ratios. We concluded that (31)P MRS was capable of distinguishing the two main causes of graft dysfunction early after transplantation. PMID- 21693237 TI - Protocol biopsy of a transplanted kidney as a tool for monitoring adequacy of immunosuppressive therapy: 10 years of experience from a single transplant center. AB - BACKGROUND: The aims of this prospective study were to determine the prevalence of clinically silent rejection changes and of nephrotoxicity of calcineurin inhibitors among repeated protocol biopsies of transplanted kidneys and to assess their impacts on chronic graft function and damage at the end of 1 year. METHODS: We performed 424 protocol biopsies among 158 patients over the first year after transplantation. We monitored parameters of graft function and progression of chronic changes among subjects with clinically silent rejection or toxicity for comparison with a control cohort showing normal histological findings. The results of statistical tests were considered to be significant at a level of P < .05. RESULTS: At 3 weeks, 3 months, and 12 months, there were normal histological findings among 30 (19%), 21 (14.8%), and 14 (11.3%) patients, respectively; subclinical rejection changes occurred in 49 (31%), 36 (25.4%), and 20 (16.2%) grafts, respectively. At the third week, histological signs of toxicity occurred in 33 (20.9%) patients with significant persistence despite reductions in calcineurin inhibitor doses. At the end of 1 year of follow-up, both subclinical and toxic changes produced similar increases in chronic changes as quantified by the Banff score and were significantly different from the control group (P < .05). Serum creatinine concentrations and glomerular filtration rates did not accurately reflect the degree of graft damage in the early posttransplantation period. CONCLUSIONS: Subclinical rejection and toxic changes among a significant proportion of grafts are associated with progression of chronic changes already over the first year following transplantation. Hence they represent independent risk factors for the development of irreversible graft damage. Protocol biopsy seems to be an important method to monitor immunosuppressive therapy. PMID- 21693238 TI - Sirolimus therapy predisposes to new-onset diabetes mellitus after renal transplantation: a long-term analysis of various treatment regimens. AB - PURPOSE: This retrospective analysis evaluated the impacts of sirolimus (SRL), cyclosporine (CsA), and steroids (S) on the occurrence, treatment, and complications of new-onset diabetes after transplantation (NODAT). METHODS: We compared 4 groups: group 1, SRL plus full-exposure CsA/S (n = 118); group 2, full exposure CsA/S/no SRL +/- antiproliferative drug (n = 141); group 3, SRL plus reduced CsA exposure/S (n = 212); and group 4, no SRL/full-exposure CsA/S +/- antiproliferative drug (n = 43). RESULTS: NODAT rates reflected the level of CsA exposure; at 10 years 54% versus 30% for groups 1 versus 2 (P = .0001); at 5 years 30% versus 21% for Groups 3 versus 4 (P = .3); 81% of cases were detected within 1 year. The lower NODAT rate in group 3 reflected a benefit of reduced CsA exposure (P = .02; hazard ratio (HR), 1.006). Group 1 showed higher CsA (P = .0001) and lower SRL concentrations (P = .016) versus group 3. CsA exposure closely correlating with NODAT among group 1 (P = .0001) was the major difference between groups 1 and 3 (P = .04; HR, 0.97). Differences in steroid treatment did not play a significant role in NODAT. Comparing groups 1 and 2, SRL was an independent risk factor for NODAT (P = .004; HR, 3.5). CONCLUSIONS: Our 10-year experience revealed SRL to be an etiologic agent for NODAT, displaying interactive, possibly pharmacokinetic, and pharmacodynamic effects with concomitant CsA in combination treatment. PMID- 21693239 TI - Impact on health-related quality of life in kidney transplant recipients with late posttransplant anemia administered darbepoetin alfa: results from the STRATA study. AB - Posttransplant anemia (PTA) is a common, multifactorial condition that has a substantial negative impact on patients' health-related quality of life (HRQOL). Erythropoietin-stimulating agents are an effective treatment for PTA, but there is little research on HRQOL in posttransplant patients. This multicenter, prospective study enrolled adults with PTA (hemoglobin [Hb] < 11.0 g/dL). Subjects (n = 66) received subcutaneous darbepoetin alfa every 2 weeks for 24 weeks. Hb and patient-reported outcomes using the Short Form (SF)-36 questionnaire were assessed. Mean (standard deviation) Hb concentration increased from 9.9 (1.2) g/dL at baseline to 11.7 (1.3) g/dL during the evaluation period (14 to 24 weeks). At baseline, SF-36 scores in all the eight domains were lower (worse) compared with the general population and patients with other chronic conditions. In subjects with baseline Hb < 10 g/dL, SF-36 subscales and component summary scores were lower than in subjects with Hb >= 10 g/dL. Following treatment with darbepoetin alfa, statistically significant improvements were observed for all subjects in physical component summary (0.5 points, P < .001), physical functioning (11.8 points, P = .001), limitations due to physical health (26.5 points, P < .001), bodily pain (7.7 points, P = .01), limitations due to emotional health (15.7 points, P = .01), and vitality (12.8 points, P < .001) from baseline to week 24. Clinically significant improvements (>5 points) were observed in six subscales: physical functioning, limitations due to physical health, limitations due to emotional health, bodily pain, social functioning, and vitality. Darbepoetin alfa in kidney transplant recipients with PTA significantly increased Hb concentrations and improved HRQOL scores. PMID- 21693240 TI - Association of the metabolic syndrome and long-term renal function in kidney donors. AB - BACKGROUND: Metabolic syndrome (MetS) may represent risk factor for long-term renal function of kidneys from living donors. The aim of this study was to evaluate the impact of MetS on renal function in donors. METHODS: Data regarding the presence or absence of MetS and renal function, as assessed by estimated glomerular filtration rate (eGFR) were obtained from 140 kidney donors before nephrectomy (BN) and at follow-up (AF). Donors were divided into those with (group 1; n =28) versus without MetS (group 2; n = 112). RESULTS: Comparing the groups, we observed a significantly greater reduction in eGFR among the group with MetS BN versus AF 27.5% (19.3-33.0) versus 21.4% (9.6-34.1 P = .02) respectively using a Cox regression model, including age, gender, serum uric acid, body mass index (BMI), and basal eGFR, MetS BN (hazard ratio = 2.2; 95% confidence interval [CI], 1.21-4.01; p = .01) was an independent factor associated with a greater risk of a-eGFR <70 mL/min/1.73 m(2) at follow-up (P < .001). Additionally, age (hazard ratio = 1.03%; 95% CI, 1.01-1.06; P < .001), and female gender (hazard ratio = 1.86; 95% CI, 1.03-3.36; P = .03) were associated with a greater decrease in eGFR. Individuals with MetS BN showed a GFR <70 mL/min/1.73 m(2) at significantly shorter follow-up time (5.6 +/- 0.8 years) versus persons without MetS (12.8 +/- 1.0 years; P = .001) CONCLUSION: Kidney donors with MetS BN experiment a significantly greater decrease in eGFR at follow up. PMID- 21693241 TI - Adiponectin gene polymorphisms are associated with posttransplantation diabetes mellitus in Chinese renal allograft recipients. AB - BACKGROUND: Posttransplantation diabetes mellitus (PTDM) is a well-recognized renal transplantation complication that is associated with increased graft loss, morbidity, and mortality. Adiponectin gene polymorphisms are associated with type 2 diabetes. However, it remains unknown whether these polymorphisms increase the risk for development of PTDM. Therefore, the aim of this study was to investigate the association between the adiponectin gene polymorphism and the risk of PTDM among Chinese renal allograft recipients. METHODS: We genotyped 398 unrelated renal allograft recipients without a prior diagnosis of diabetes, including 97 PTDM and 301 without PTDM, for adiponectin gene variants: single nucleotide polymorphisms at position 45 and 276, that is, SNP-45: T/G, SNP-276: G/T, using the polymerase chain reaction-restriction fragment length polymorphism assay. No prisoners or organs from prisoners were used in the study. RESULTS: The G allele of SNP-276 was significantly more frequent in PTDM than non-PTDM subjects (P = .041). For SNP-45 and SNP-276, the incidence of PTDM was significantly higher in patients with the GG genotype than those with the TG and TT genotypes (48.1% vs 21.5% and 23.6% and 30.7% vs 18.5% and 22.8%; (P = .011 and .024, respectively). Even after adjusting for age and sex, the effects of the SNP-45 genotypes for GG compared to TT (odds ratio [OR] = 3.108, P = .009) and GG compared to TG (OR = 3.620, P = .004) as well as for SNP-276 genotypes GG compared to TG (OR = 2.203, P = .002) and body mass index at transplantation (OR = 1.099, P = .024) remained significant. CONCLUSIONS: These data suggested that SNP-45 and SNP-276 of the adiponectin gene were significantly associated with an increased risk for PTDM among Chinese renal allograft recipients. PMID- 21693242 TI - Dyslipidemia in human kidney transplant recipients receiving cyclosporine and tacrolimus is associated with different expression of CD36 on peripheral blood monocytes. AB - PURPOSE: We studied the mechanisms by which immunosuppressants result, in dyslipidemia among human kidney transplant recipients. METHODS: Seventy-five living donor kidney transplant recipients were enrolled in our study with informed consent and the approval of out Institutional Ethics Committee. Each donor-recipient pair were relatives, there were no prisoners. The serum lipid profile, the expression of CD36 on peripheral blood monocytes, and the whole blood concentrations of cyclosporine (CsA) or tacrolimus (FK506) were determined at various times after transplantation. RESULTS: CsA significantly increased serum lipid concentrations. The CsA concentration correlated positively with low density lipoprotein cholesterol (LDL) levels, whereas FK506 showed no significant effect on serum lipid level. There was a positive correlation between the CsA concentrations and the expression of CD36; FK507 showed no significant effect on CD36 expression. CONCLUSIONS: Hyperlipidemia in kidney transplant recipients treated with CsA was associated with overexpression of CD36 on peripheral blood monocytes. PMID- 21693243 TI - Vascular endothelial function of sirolimus maintenance regimen in renal transplant recipients. AB - Endothelial dysfunction is of vital importance as it may cause ischemia and dysfunction in various organs, especially the heart and kidneys. Despite this problem being well documented in patients with end-stage renal disease, there are insufficient data considering this issue to demand sirolimus use in renal transplantation. One potential cause of endothelial dysfunction in renal transplantation patients may be the use of the conventional protocols with cyclosporine [CsA]- versus sirolimus-based therapy. We studied 22 renal transplant recipients including on CsA (n = 14; group I, and sirolimus (n = 8; group II). Endothelial functions of the brachial artery were evaluated using high resolution vascular ultrasound. Endothelium-dependent and-independent vasodilatations were assessed by sublingual nitroglycerine (NTG). Results are presented as percentage from baseline values. Significant endothelial dysfunction was noted among renal transplant patients treated with CsA. Endothelium-dependent vasodilatation was 3.6% +/- 2.8% in group I and 14.5% +/- 3.2% in group II (P < 0.002). The increase in brachial artery diameter after sublingual NTG measured 9.9% +/- 4.7% versus 22.1% +/- 5.9% in groups I and group II, respectively. This observation indicated that endothelial vasodilatation was preserved among patients on sirolimus but not CsA therapy. We concluded that endothelial vasodilatation is impaired in renal transplant recipients. Moreover, sirolimus seems to be more useful than CsA to overcome the compromised vasculature as observed in diabetic and elderly patients. PMID- 21693244 TI - Urologic complications in more than 2500 kidney transplantations performed at the Saint Barnabas healthcare system. AB - We report our urologic complications based on one urologist's experience during a 17-year period on more than 2500 ureteral reimplantation operations performed at the time of kidney transplant. Among 2548 ureteroneocystostomies performed by the transplant urologist, a 5.5% urologic complication rate was observed. This included vesicoureteral reflux (3%), ureteral strictures (1.3%), urine leak (0.9%), and uteropelvic junction obstruction (0.3%). The factors for low urologic complication rates include the use of a shorter segment of ureter using the Lich Gregoir technique (compared to the Politano-Leadbetter technique) and the routine use of indwelling stents. In addition, having one transplant urologist performing all ureteral reimplantations and managing all urologic complications provided consistency in results. PMID- 21693245 TI - Use of stenting in living donor kidney transplantation: does it reduce vesicoureteral complications? AB - The risk of urologic complications after kidney transplantation is 0% to 30%. We studied the impact of prophylactic stent placement during transplantation by assessing the necessity for a percutaneous nephrostomy (PCN) after living kidney transplantation. From January 2003 to December 2007, 342 living donor kidney transplantations were performed. Intra- and postoperative data were collected retrospectively from 285 patients with stent and 57 without. Baseline characteristics were not significantly different between groups, except for the number of previous transplantations: 31 (11%) patients with versus 16 (28%) without stent had a history of >1 transplantation (P < .001). From patients with PCN, 55 (87%) patients in the stented group received a PCN <3 months versus 11 (100%) in the nonstented group (P = .71). The reoperation rate for urologic complications was similar in both groups (3% (stented) versus 5% (nonstented; P = .43). In multivariate analysis, risk for PCN was similar in both groups (odds ratio 1.21, 95% confidence interval 0.5-2.5). Recipient survival was not significantly different. One- and 3-year death-censored graft survival was not significantly different between stented (89% and 84%) and nonstented group (90% and 85%, P = .71 and P = .96). Ureteral stent insertion is not associated with a reduced rate of PCN placement in living donor kidney transplantation. PMID- 21693246 TI - A technique for kidney retransplantation after simultaneous kidney pancreas transplantation. AB - Isolated failure of the renal graft after simultaneous kidney-pancreas transplantation (SPK) is a rare but potential outcome. Many of these patients are candidates for kidney retransplantation. This paper describes a series of 3 patients who underwent successful kidney retransplantation after SPK. The operation was completed through an extraperitoneal incision without disruption of the pancreas graft or need for a transplant nephrectomy. PMID- 21693247 TI - Glomerulitis during acute cellular rejection may be a surrogate marker of vasculitis in renal allografts--better index for diagnosis of vasculitis. AB - BACKGROUND: The Banff criteria (from 2005 to 2009) use "T cell-mediated rejection" to indicate acute cellular rejection. Vasculitis in smaller arteries is an important diagnostic criterion for moderate and severe T cell-mediated rejection. The renal allograft endothelium is a significant target of inflammatory response-mediated tissue damage. Medium-size arteries (arcuate arteries) are mostly absent in routine allograft biopsies, so identification of vasculitis relies on its identification in small arteries (arterioles to interlobar arteries). Although inflammation in terminal vessels such as the glomerular capillaries has been previously recognized, their role in grading the rejection process is not well characterized. We therefore evaluated the expression of CD3-positive T lymphocytes and CD68-positive macrophages in glomeruli, small arteries, and arcuate arteries of nephrectomy specimens obtained from transplant and renal tumor patients. METHODS: The study group included 21 renal explant subjects with nonreversible moderate to severe T cell-mediated rejection (IIa to III) and/or severe chronic changes. The control group comprised 17 individuals with nephrectomy for renal tumors. In each case, a large renal section from cortex to medulla was stained for CD3 and CD68 by immunohistochemical method. CD3-positive T lymphocytes and CD68-positive macrophages per balanced high-power field were counted in glomeruli, interlobar arteries, and arcuate arteries. RESULTS: In control kidney sections, neither CD3 positive T lymphocytes nor CD68-positive macrophages were noted in glomeruli, interlobar arteries, or arcuate arteries. In the study group, 15/21 showed diffuse C4d positivity. Also in the study group, positive CD3 and CD68 counts in glomeruli were significantly correlated to both interlobar and arcuate artery counts by linear regression analysis. CONCLUSION: We conclude that in renal allograft biopsies, T lymphocytes and macrophages in the glomeruli not only represent a separate entity, "transplant glomerulitis," but also may be a surrogate marker of vasculitis present in larger vascular beds. Comparable amounts of T cells and macrophages imply that "acute cellular rejection" may be a better terminology to reflect the true inflammatory status. PMID- 21693248 TI - Cytomegalovirus genotypes gB1 and gH1 are the most predominant genotypes among renal transplant recipients in Kuwait. AB - BACKGROUND: The human cytomegalovirus (HCMV) is a common pathogen responsible for asymptomatic and persistent infections in healthy individuals. However, cytomegalovirus infections are a major cause of morbidity and mortality in immunocompromised patients, especially in recipients of solid-organ transplants and AIDS patients. METHODS: HCMV DNA from 42 patients who received kidney transplants between 2004 and 2008 were subjected to polymerase chain reaction and restriction fragment length polymorphism to identify HCMV gB and gH genotypes. RESULTS: HCMV gB1 and gH1 genotypes were the most the predominant HCMV genotypes (P < .05, P < .05, respectively). In addition, both HCMV gB1 and gH1 genotype were significantly more often associated with the development of fever with leukopenia and severe HCMV disease than other gB or gH2 genotypes. No significant differences were observed among viral loads between the HCMV genotypes among infected individuals. CONCLUSION: This study demonstrated the prevalence and role of HCMV genotypes in infection and disease in renal transplant patients in Kuwait. PMID- 21693249 TI - Association between urothelial carcinoma after renal transplantation and infection by human papillomavirus types 16 and 18. AB - OBJECTIVE: To explore the association between urothelial carcinoma following renal transplantation and infection by human papillomavirus (HPV) types 16 and 18. MATERIALS AND METHODS: Of 3780 patients who underwent renal transplantation, we identified 90 cases of urothelial carcinoma. Tumor tissues collected from the 90 renal transplant recipients were compared with those from 30 nontransplanted patients with bladder cancer (control group) for HPV types 16 and 18 using polymerase chain reactions. RESULTS: Seven transplanted patients were HPV positive: HPV-16 was detected in 3 patients with bladder cancer (3/90; 3.3%), and HPV-18 in 2 patients with bilateral pelvic ureteral carcinoma (2/90; 2.2%), and 2 patients with bladder cancer (2/90; 2.2%). Only 2 cases from the control group were HPV positive (both HPV-18; 2/30; 5%). The difference between the RTR and control groups was not significant (P > .05). CONCLUSION: Malignant tumors in the urinary system following renal transplantation did not seems to be associated with infection by HPV-16 or -18. PMID- 21693250 TI - Reduction of gastrointestinal complications in renal graft recipients after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium. AB - Gastrointestinal (GI) complications such as diarrhea or indigestion frequently occur in renal graft recipients treated with mycophenolate mofetil (MMF), requiring dose reductions to reduce side effects, thereby increasing the risk of rejection episodes and graft loss. In a prospective clinical trial, the immunosuppressive therapy of renal graft recipients was converted from MMF to enteric-coated mycophenolate sodium (EC-MPS) to identify a strategy to reduce GI symptoms without dose reduction. At baseline and 6-8 weeks later patients filled in 4 questionnaires related to GI symptoms and general and health-related quality of life. In 15 German study centers, 196 renal graft recipients (mean age 49.5 +/ 13.5 years; male/female, 120/76) were included; 51.0% of patients suffered from GI complications at baseline. The Gastrointestinal Symptom Rating Scale score decreased significantly (P < .001) in patients with GI complications from 2.61 +/ 0.86 at baseline to 2.14 +/- 0.86 at visit 2. Health-related and general quality of life improved significantly. Fifty percent of patients with GI symptoms and 34% of the total per protocol population reported an improvement of their physical condition after converting the medication. In conclusion, conversion from MMF to EC-MPS reduces GI complications in renal graft recipients, reduces the patients' physical discomfort, and maintains their quality of life. (ClinicalTrials.gov number NCT00149968.). PMID- 21693251 TI - A perspective on cirrhotic cardiomyopathy. AB - Cardiac dysfunction in patients with cirrhosis and potential clinical implications have long been known, but the pathophysiology and potential targets for therapeutic intervention are still under investigation and are only now becoming understood. The pathophysiological changes result in systolic dysfunction, diastolic dysfunction, and electrophysiological changes. Here, we aim to review cirrhotic cardiomyopathy from a cellular and physiological model and how these patients develop overt heart failure in the setting of stress, such as infection, ascites, and procedures including transjugular intrahepatic portosystemic shunt, portocaval shunts, and orthotopic liver transplantation. We will also review the most current, although limited, available therapeutic modalities. PMID- 21693252 TI - Effect of propranolol on the relationship between QT interval and vagal modulation of heart rate variability in cirrhotic patients awaiting liver transplantation. AB - BACKGROUND: Prolonged corrected QT (QT(c)) interval and vagal dysfunction are common occurrences in liver cirrhosis and are determinants of mortality in patients with chronic liver disease. We evaluated whether propranolol can affect the relationship between QT(c) interval and cardiac vagal control of heart rate variability (HRV) in cirrhotic patients awaiting liver transplantation. METHODS: We compared 50 cirrhotic patients (M/F = 43/7, 52.6 +/- 8.4 years, Child-Pugh class A/B/C: 9/24/17) receiving propranolol with a sex-, age-, and liver disease severity-matched control group of 50 patients (M/F = 43/7, 52.0 +/- 8.3 year, Child-Pugh class A/B/C: 9/24/17) not receiving propranolol. Among the parameters evaluated were QT(c) interval and cardiac vagal indices of HRV, including the root mean square of successive differences in R-R intervals (RMSSD); spectral power in the high-frequency range (HF); standard deviation (SD)1 in Poincare plot; and sample entropy. Correlations between QT(c) interval and vagal indices of HRV were analyzed. RESULTS: The mean duration of preoperative propranolol treatment in the propranolol group was 19.4 +/- 24.7 months. QT(c) interval was significantly lower, whereas RMSSD, HF, SD1, and sample entropy were significantly higher in the propranolol group than in the control group. Correlation coefficients between QT(c) interval and RMSSD, HF, SD1, and sample entropy were higher in the propranolol group than in the control group. CONCLUSIONS: The prolonged QT(c) interval observed in cirrhotic patients may be reduced by propranolol administration, an effect attributable to improved vagal cardiac modulation. These findings suggest that propranolol may have a beneficial effect on perioperative mortality in cirrhotic patients awaiting liver transplantation. PMID- 21693253 TI - Comparison of acute physiology and chronic health evaluation II death risk, Child Pugh, Charlson, and model for end-stage liver disease indexes to predict early mortality after liver transplantation. AB - OBJECTIVE: This study sought to determine which prognostic index was the most efficient to predict early (1-month) mortality of patients undergoing orthotopic liver transplantation (OLT). MATERIALS AND METHODS: This retrospective study included 63 patients including 49 males and 14 females of overall median age 51.6 +/- 9.7 years who were admitted to the intensive care unit (ICU) of a tertiary hospital. The Acute Physiology and Chronic Health Evaluation II (APACHE II) death risk, Child-Pugh, Charlson, and Model for End-stage Liver Disease (MELD) indices pre-OLT and post-OLT were analyzed by generation of receiver operating characteristic (ROC) curves to determine the area under the ROC curve (AUC), as a predictive factor for each index. The level of significance was set at P < .05. RESULTS: The general 1-month posttransplantation mortality rate of OLT patients was 19% (n = 12 p). The AUC was 0.81 (confidence interval [CI] = 0.66-0.96; sensitivity = 72.5; specificity = 83.3) for APACHE II death risk; 0.74 (CI = 0.57 0.92; sensitivity = 76.5; specificity = 66.7) for MELD post-OLT; 0.70 (CI = 0.54 0.85; sensitivity = 64.7; specificity = 66.7) for Child-Pugh; 0.57 (CI = 0.36 0.78; sensitivity = 74.5; specificity = 50.0) for Charlson; and 0.50 (CI = 0.32 0.69; sensitivity = 98.0; specificity = 16.7) for MELD Pre-OLT. CONCLUSION: Among the studied indices, the APACHE II death risk scoring system was the most effective to predict early mortality after OLT. PMID- 21693254 TI - Does general anesthesia with inhalation anesthetics worsen hypoxemia in patients with end-stage liver disease and an intrapulmonary shunt? AB - Hepatopulmonary syndrome (HPS) is common among patients with end-stage liver disease (ESLD); however, the effects of general anesthesia on oxygenation capacity have not been studied in these patients. The aim of this study was to evaluate the effects of general anesthesia with inhalation anesthetics on oxygenation parameters according to intrapulmonary shunt grade in patients undergoing liver transplantation. Fifty-eight liver transplant recipients were divided into 2 groups according to the intrapulmonary shunt grade as determined using preoperative echocardiography using the microbubble-syringe technique. Patients in the 'no shunt' group (n = 44) had either no detectable or a mild shunt, whereas those in the "shunt" group (n = 14) displayed moderate to severe changes. Arterial blood gas analysis was performed twice for each patient: preoperatively and 30 minutes after induction of general anesthesia. We calculated arterial oxygen partial pressure-to-FiO(2) ratio (PaO(2)/FiO(2)), alveolar-arterial oxygen difference (A-aDO(2)), age-corrected A-aDO(2), A-aDO(2) to-inspiratory oxygen fraction ratio (AaDO(2)/FiO(2)), and alveolar oxygen partial pressure-to-PaO(2) ratio (PAO(2)/PaO(2)). In the preoperative period, the PaO(2) was lower in the shunt compared with the no shunt group (77.8 +/- 24.3 vs 92.9 +/- 14.5, respectively; P = .016), as was the PaO(2)/FiO(2). A-aDO(2), age corrected A-aDO(2), A-aDO(2)/FiO(2), and PAO(2)/PaO(2) were all greater in the shunt group preoperatively. After induction of general anesthesia, all parameters increased in both groups, but the differences between the 2 groups were no longer significant. Patients with ESLD who underwent liver transplantation with a moderate to severe intrapulmonary shunt showed lower preoperative oxygenation capacities than those without a shunt or with a mild shunt. General anesthesia decreased oxygenation capacity in all patients, but the differences between the 2 groups were no longer significant after induction. PMID- 21693255 TI - Starting hemoglobin value predicts early phase prognosis after liver transplantation. AB - Few studies have addressed the relationship between starting hemoglobin (Hb) value and early phase prognosis after liver transplantation (OLT). The aim of our study was to determine the relationship between the starting Hb value and the early phase prognosis after OLT by retrospectively reviewing the medical records of 102 consecutive recipients. Within this cohort, 47 patients had pulmonary complications after OLT, including eight cases of pulmonary edema, 12 cases of acute lung injury, six cases of acute respiratory distress syndrome, and 21 cases of pneumonia. According to whether the patients had pulmonary complications or not, they were categorized into the "no" versus the pulmonary complication groups. Twenty-two perioperative variables were analyzed in both groups to screen for variables that affected early pulmonary complications. A starting Hb <= 100 g/L was an independent risk factor for postoperative pulmonary complications. The duration to initial passage of flatus and the intensive care unit length of stay were significantly prolonged in patients with starting Hb values <= 100 g/L; these patients had poorer arterial blood gas analyses. The starting Hb value predicted the early phase prognosis after OLT for cirrhosis-associated hepatocellular carcinoma. PMID- 21693256 TI - Superparamagnectic iron oxide-enhanced magnetic resonance for tumor surveillance in cirrhotic liver before liver transplantation with explanted liver correlation. AB - OBJECTIVE: The aim of this study was to determine the accuracy of superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI) in the detection of liver tumors in patients with liver cirrhosis before liver transplantation (LT). PATIENTS AND METHODS: Twenty-one patients with moderate to severe liver cirrhoses (Child-Pugh score B or C) underwent SPIO-enhanced MRI before LT. SPIO-enhanced MRI was composed of SPIO-enhanced T1-weighted images, T2 weighted turbo spin-echo, and T2*-weighted sequences. The detection of malignant liver tumor was based on hepatic lesions that remain with hyper-signal intensity on SPIO-enhanced delayed T2 and T2*-weighted images. The imaging was compared with findings during histopathologic evaluation of the explanted liver. RESULTS: Forty-two liver nodules were found in 16 of the 21 patients. Thirty-six malignant hepatic neoplasms were detected at histopathologic evaluation. SPIO-enhanced MRI depicted 30 of 36 malignant hepatic neoplasms. Patient-based analysis showed that the sensitivity, specificity, and accuracy of MRI were 93.75%, 100%, and 95.2%, respectively. For lesion-based analysis, the sensitivity, specificity, and the area under the receiver operating characteristic (ROC) curve were 90%, 100%, and 0.95, respectively, for lesions >2 cm. CONCLUSIONS: SPIO-enhanced MRI can be used as an additional diagnostic tool for the detection and characterization of malignant tumors in cirrhotic livers. This diagnostic evaluation is accurate to triage patients for LT. PMID- 21693257 TI - A retrospective case-control study of intraoperative cardiac dysfunction in elderly patients (>=60 years) undergoing live donor liver transplantation. AB - BACKGROUND: The age range of patients accepted for the orthotopic liver transplantation (OLT) has widened. Concerns have arisen, therefore, about the ability of the hearts of elderly patients to manage these stressful conditions. The aim of this study was to investigate the preoperative echocardiographic findings and the intraoperative cardiac dysfunction among elderly cirrhotic recipients undergoing live donor OLT. METHODS: In this retrospective case-control study we evaluated clinical data, echocardiography, and intraoperative right sided heart hemodynamic measurements from 2007 and 2009 among 56 recipients aged at least 60 years who were matched for gender and the severity of cirrhosis. Intraoperative cardiac dysfunction was defined as a decreased left ventricular stroke work index despite an increase in right ventricular end diastolic volume index (RVEDVI) or pulmonary artery occlusion pressure (PAOP). We compared measurements at predetermined times during the anhepatic and neohepatic periods with those at baseline. RESULTS: Older recipients (mean, 63 years; range, 60-69) showed significantly reduced early diastolic annular velocity (E'), early maximal ventricular filling velocity (E)/late filling velocity (A) ratio, and increased A on echocardiography versus younger recipients (mean 48 years; range, 31-56). We observed negative correlation between age and E' (r = -0.44; P < .001) and a positive correlation between age and E/E' (r = 0.31; P < .01). The incidence of intraoperative cardiac dysfunction did not differ between case and control groups with an increase of RVEDVI (11.4% vs 10.6%) or PAOP (27.2% vs 25.0%) during the anhepatic and neohepatic periods. A higher proportion of older recipients needed inotropic agents during OLT (60.7% vs 39.3%; P = .04). CONCLUSIONS: OLT patients of ar least 60 years of age may not show a greater incidence of cardiac dysfunction during OLT versus younger ones, although older recipients showed reduced diastolic function and more frequently required inotropic support. PMID- 21693258 TI - Evaluation of intraoperative brain natriuretic peptide as a predictor of 1-year mortality after liver transplantation. AB - BACKGROUND: Although brain natriuretic peptide (BNP), a marker of cardiac dysfunction, has been known to predict postoperative mortality, little is known about the postoperative prognostic ability of BNP in liver transplantation (OLT) recipients. We aimed to determine whether intraoperative BNP level can predict 1 year all-cause mortality after OLT. METHODS: We retrospectively investigated 525 OLT recipients. BNP and hemodynamic parameters were simultaneously measured 1 hour after induction of anesthesia. Cox regression analysis and receiver operating characteristic curve analysis were performed to determine clinical predictors and optimal cutoff values of post-OLT mortality. RESULTS: The 1-year all-cause mortality rate was 9.7% (51/525). Median BNP concentration was significantly higher in nonsurvivors than in survivors (114 vs 56 pg/mL, P < .001). Significant factors in univariate Cox regression analysis were Child-Pugh score, model for end-stage liver disease (MELD) score, logBNP, hemoglobin, creatinine, heart rate, systolic pulmonary arterial pressure, and central venous pressure. In multivariate Cox regression analysis, independent predictors of posttransplant mortality were MELD score and logBNP. However, simultaneously measured hemodynamic parameters did not remain predictors. BNP levels greater than a cutoff of 136 pg/mL (specificity = 83.5%, negative predictive value = 93.6%) were associated with increased post-OLT mortality (log-rank test P < .001). CONCLUSIONS: Intraoperative BNP level is an independent predictor of 1 year all-cause mortality after OLT with a high negative predictive value, suggesting that its measurement appears useful in identifying patients at low risk of post-OLT mortality. PMID- 21693259 TI - Preoperative echocardiographic indices associated with elevated brain natriuretic peptide in liver transplant recipients. AB - BACKGROUND: Cardiac dysfunction may be present in patients with liver cirrhosis. Brain natriuretic peptide (BNP) concentration is a widely used biomarker for heart failure. We evaluated whether elevated BNP reflects cardiac dysfunction, as assessed by preoperative echocardiography, in liver transplant recipients. METHODS: We assessed 122 liver transplant recipients (94 males, 28 females; age, 50 +/- 8 years). All underwent preoperative echocardiography, including measurements of heart chamber size, mass, ejection fraction, systolic pressure gradient between right ventricle and right atrium (PGsys [RV - RA]), mitral inflow velocities including early (E) and late (A) transmitral flow velocities, E/A, and deceleration time of E. Tissue Doppler imaging (TDI) was also performed to evaluate systolic (S'), early diastolic (E'), and late diastolic (A') myocardial velocities, E'/A', EAS index: E'/(A' * S'), and E/E'. Univariate and multivariate logistic regression analyses were performed to determine echocardiographic indices for predicting BNP >= 100 pg/mL. RESULTS: Of 122 recipients, 87 (71%) had BNP < 100 pg/mL (median, 32.0 pg/mL; interquartile range [IQR], 18.0-50.0), and 35 (29%) had BNP >= 100 pg/mL (median, 163.0 pg/mL; IQR, 136.0-479.0). Univariate analysis showed that E (P < .001), PGsys (RV-RA) (P < .001), and E/E' (P = .038) were significantly associated with BNP >= 100 pg/mL. Multivariate analysis showed that PGsys (RV - RA) was the only independent predictor of BNP >= 100 pg/mL (odds ratio, 1.171; 95% confidence interval, 1.091 1.258; P < .001). CONCLUSION: PGsys (RV - RA) is an echocardiographic index independently associated with BNP >= 100 pg/mL, suggesting that elevated BNP in patients with end-stage liver disease may reflect increased pulmonary arterial pressure, rather than systolic and diastolic dysfunction assessed by TDI. PMID- 21693260 TI - Decreased circulating CD4+CD25highFoxp3+ T cells during acute rejection in liver transplant patients. AB - BACKGROUND: CD4(+)CD25(high)FoxP3(+) regulatory T (Treg) cells have been implicated to maintain immunologic tolerance. They have been investigated in acute renal allografts rejection episodes (ARE). This study was performed to examine the frequency of peripheral blood (PB) CD4(+)CD25(high)FoxP3(+) Treg cells among liver transplantation patients with prior benign end-stage liver diseases in relation to ARE. METHODS: This prospective analysis of 55 patients who underwent liver transplantation from 2004 to 2009 did not include prisoners either as donors or recipients. PB was obtained from liver transplant patients longitudinally: pretransplantation, posttransplantation within 1 year, and at the time of an episode of ARE to measure by flow cytometry circulating CD4(+)CD25(high)FoxP3(+) T cells. Blood samples were drawn during ARE with concomitant liver biopsies. The rejector group was defined in the 14/55 cases who suffered an ARE; in the other patients with stable liver function were classified as the nonrejector group. We compared the number of circulating CD4(+)CD25(high)FoxP3(+) T cells between the 2 groups. RESULTS: There was no difference in the levels of circulating CD4(+)CD25(high)FoxP3(+) T cells pretransplantation. Interestingly, circulating CD4(+)CD25(high)FoxP3(+) T cells were significantly lower among the rejector compared with the nonrejector (2.23 +/- 0.54% vs 2.99 +/- 0.86%; P < .01). Longitudinal analysis revealed circulating CD4(+)CD25(high)FoxP3(+) T cells of patients in the rejector group to be significantly lower during rejection than during quiescence (2.23 +/- 0.54% vs 3.68 +/- 0.70%; P < .0001). The frequency of circulating CD4(+)CD25(high)FoxP3(+) T cells negatively correlated with a Rejection Activity Index (r = -0.80; P < .01). CONCLUSION: Monitoring peripheral CD4(+)CD25(high)FoxP3(+) T cell levels may be useful to evaluate the immune state, potentially acting as a sensitive marker for ARE diagnosis among liver transplantation patients. Moreover, they may contribute to the mechanisms of Treg-mediated acceptance of liver transplantations. PMID- 21693261 TI - The extended abdominal wall flap for transplantation. AB - INTRODUCTION AND AIMS: Patients with extensive loss of the abdominal wall tissue have few options for restoring the abdominal cavity. Composite tissue allotransplantation has been used for limited abdominal wall reconstruction in the setting of visceral transplantation, yet replacement of the entire abdominal wall has not been described. The purpose of this study was to determine the maximal abdominal skin surface available through an external iliac/femoral cuff based pedicle. MATERIALS AND METHODS: Five human cadaveric abdominal walls were injected with methylene blue to analyze skin perfusion based on either the deep inferior epigastric artery (DIEA; n = 5) or a cuff of external iliac/femoral artery (n = 5) containing the deep circumflex iliac, deep inferior epigastric, and superficial inferior epigastric, and superficial circumflex iliac arteries. RESULTS: Abdominal wall flaps were taken full thickness from the costal margin to the midaxillary line and down to the pubic tubercle and proximal thigh. In all specimens, the deep inferior epigastric, deep circumflex iliac, superficial inferior epigastric, and superficial circumflex iliac arteries were found to originate within a 4-cm cuff of the external iliac/femoral artery. Abdominal wall flaps injected through a unilateral external iliac/femoral segment had a significantly greater degree of total flap perfusion than those injected through the DIEA alone (76.5% +/- 4% vs 57.2% +/- 5%; Student t test, P < .05). CONCLUSIONS: Perfusion of a large portion of the abdominal wall is possible using a single-vessel anastomosis through a short segment of the external iliac/femoral system. Perfusion is significantly greater than that based on the DIEA vessel alone. PMID- 21693262 TI - Intraoperative calcium-related risk factors for biochemical acute pancreatitis after living-donor liver transplantation. AB - Laboratory-based biochemical acute pancreatitis (BAP) is considered to be a benign but common complication after liver transplantation (LT), which to compensate for transfusion-related hypocalcemia, usually demands a large quantity of exogenous calcium which may be associated with pancreatic injury. We sought to investigate the relationship between intraoperative calcium-related factors and BAP occurrence after living-donor LT. Perioperative data, including intraoperative calcium chloride administration and serum calcium levels, were reviewed from 217 patients who underwent living-donor LT. Hyperamylasemia (>= 458 U/L) was used to define posttransplantation BAP according to previous reports. Posttransplantation BAP was identified among 37 patients (17.3%), who showed a greater death rate than those in the non-BAP group (21.6% vs 8.6%; P = .013). Compared to with calcium-related parameters, the 2 groups showed differences in the amount of calcium chloride administered during the preanhepatic phase, the serum calcium surge during the initial 2 h after the liver graft reperfusion, the last serum calcium level, and the amount of transfused pack red blood cells (P < .05). However, after multivariate adjustment, only the amount of administered calcium chloride during the preanhepatic phase (odds ratios, 2.11-5.87, depending an amount) and the serum calcium surge during the initial 2 hours after liver graft reperfusion (odds ratio, 2.34) were selected as risk factors for posttransplantation BAP. The risk ratio of posttransplantation BAP increased in proportion to the administered amount of calcium chloride. In conclusion, limiting excessive calcium administration during the preanhepatic phase and close monitoring of the serum calcium surge after reperfusion may be required to prevent posttransplantation BAP in living-donor LT. PMID- 21693263 TI - Statistical modeling of hemodynamic changes during orthotopic liver transplantation: predictive value for outcome and effect of marginal donors. AB - AIM: This study analyzed hemodynamic recordings collected on a beat-to-beat basis during orthotopic liver transplantation (OLT). The first aim was to construct a graphic that will represent hemodynamic profile during OLT. The second aim was to compare the intraoperative hemodynamic pattern of survivors versus nonsurvivors and those who received a liver from normal versus marginal donors. METHODS: Hemodynamic data (including cardiac output, cardiac index, stroke volume [SV] and SV index, systemic vascular resistance [SVR] and SVR index, mean arterial pressure, and heart rate) were collected from 100 consecutive adult OLT patients with the use of a lithium dilution cardiac output (LiDCO plus) monitor. A LOESS (Robust Locally Weighted Regression and Smoothing Scatterplots) smoother was used to give a more easily interpreted graph. Patients were grouped with respect to survival at 30 days (survivors vs nonsurvivors) and quality of graft (marginal vs normal). RESULTS: We constructed graphics that represented all intraopetative hemodynamic data during OLT for 100 consecutive procedures. It confirmed hyperdynamic circulation during OLT. Statistical analysis did not reveal significant differences regarding intraoperative hemodynamic data between survivors and nonsurvivors, or between patients receiving normal versus marginal grafts. CONCLUSION: This study shows changes in the hemodynamic profile during OLT, measured on a beat-to-beat basis. Intraoperative hemodynamic changes did not predict patients who did not survive OLT. Beat-to-beat monitoring did not reveal significant hemodynamic instability following transplantation of marginal grafts. PMID- 21693264 TI - Versatility of right gastroepiploic and gastroduodenal arteries for arterial reconstruction in adult living donor liver transplantation. AB - BACKGROUND: In cases where there is severe intimal dissection in the recipient hepatic artery (HA), or if the HA has been used already and additional operations are needed due to graft rejection or arterial occlusion, an alternative is necessary. In the present study, we have reported the feasibility of using the right gastroepiploic artery (RGEA) and gastroduodenal artery (GDA) in various situations where the HA is not a feasible option. METHODS: Among 463 patients who underwent primary adult-to-adult living donor liver transplantation from January 2002 to July 2010, eight subjects required alternative vessels. Four recipients displayed severe intimal injury associated with previous transarterial chemoembolization (TACE); two, required a salvage operation due to hepatic artery thrombosis (HAT); and two, retransplantations due to chronic rejection. The RGEA was used in five and the GDA in three patients. RESULTS: Postoperative Doppler ultrasonography and three-dimensional computed tomography showed patent arterial flow in all patients. However, HAT recurred in one patient who underwent a salvage operation with the RGEA; she died 2 months later. Two other patients died due to wound infection and respiratory failure within 3 months despite intact hepatic arterial flow. Four patients had no further complications during follow up (mean = 33 months). CONCLUSION: Although there was a discrepancy in the diameter of the HA and the RGEA (or GDA), there was no problem with mobilization and microanastomosis. We therefore believe that these vessels can be good alternatives when the hepatic artery is unavailable. PMID- 21693265 TI - Long-term outcome of hepatic artery reconstruction during living-donor liver transplantation. AB - BACKGROUND: Hepatic artery thrombosis (HAT) after living-donor liver transplantation (LDLT) is a potentially life-threatening complication. Although the introduction of microsurgical techniques has significantly decreased the incidence of HAT after LDLT, it remains a challenge for microsurgeons. We previously reported the use of the microsurgical hepatic arterial reconstruction technique during LDLT using the head-mounted surgical binocular system. METHODS: In this study, we describe the long-term outcome of microsurgical hepatic artery reconstruction using the head-mounted surgical binocular system and our hepatic arterial reconstruction techniques on LDLT patients, including intimal dissection cases and clinical courses. Between August 2001 and February 2010, 146 patients underwent LDLT at our institution. Using a surgical loupe, the Varioscope AF3, which is a head-mounted surgical binocular system with automatic focusing and continuous zoom magnification from 3.6* to 7.2*, 150 arteries of 146 liver grafts were reconstructed. When the tunica intima was separated from the tunica media, suturing was performed from the inside of the vessels to the outside using an 8-0 monofilament Prolene with double needles, which facilitates secure sutures with good intima adaptation. RESULTS: The 1- and 3-year survival rates of the 146 patients were 80.3% and 74.9%, respectively, with a mean follow-up of 40.2 months. The mean diameter of the graft hepatic artery was 2.79 mm. HAT was not encountered in this series of patients. CONCLUSION: The use of the Varioscope and the application of our suturing techniques have provided entirely satisfactory long-term results of hepatic artery reconstruction during LDLT, even in intimal dissection cases. PMID- 21693266 TI - Detrimental effect of aprotinin ban on amount of blood loss during liver transplantation: single-center experience. AB - BACKGROUND: Aprotinin, a plasmin inhibitor, had been used for reduction of intraoperative bleeding caused by hyperfibrinolysis during extensive surgery. Prophylaxis with aprotinin to limit blood loss during orthotopic liver transplantation (OLT) had been widely applied until the drug was weaned off the therapeutic list for severe complications. We compared the need for blood and blood products transfusion in patients undergoing OLT with and without the use of aprotinin. MATERIALS AND METHODS: A retrospective analysis was performed on 150 patients, who underwent OLT between March 2004 and August 2008 and were divided into 2 groups: the APRO group (n = 111) after induction of anesthesia was given a bolus of 500 kIU of aprotinin in a 30-minutes infusion followed by 140 kIU/h till the end of the OLT in which aprotinin was not administered, and the NON-APRO group (n = 39). RESULTS: Patients from the NON-APRO group needed significantly more units of packed red blood cells (PRBC) than the APRO group (5.53 +/- 4.89 vs 3.99 +/- 3.58 units; P = .037). Avoidance of aprotinin administration (beta = 1.408), Child-Pugh score (beta = 0.519), and duration of anhepatic phase (beta = 0.03) affected the volume of transfused blood according to multiple regression analysis (P < .05). CONCLUSIONS: Our study confirmed the important prophylactic role aprotinin used to have during OLT in limiting the need for blood transfusions. Further research and progress in methods of blood loss minimization and monitoring of hemostasis are needed to warrant safe liver transplantation. PMID- 21693267 TI - New prognostic model for adult-to-adult living donor liver transplant recipients. AB - Adult-to-adult living donor liver transplantation (A-A LDLT) is an effective therapeutic modality to treat patients with end-stage liver disease. The aims of this study were to identify recipient characteristics of A-A LDLT seeking to determine variables that affected patient survival. We retrospectively examined a cohort of 154 consecutive A-A LDLT recipients with end-stage liver disease in our center over 4 years. All donors volunteered to give their partial livers with written consent. There were no organs from prisoners and no prisoner subjects. The overall survivals at 1, 2, 3, 6, 12, 24, 36, and 48 months were 93.5%, 90.9%, 88.9%, 86.3%, 80%, 65.6%, 63.8%, and 63.8%, respectively. About 31 pre- and intraoperative factors were analyzed to identify correlations with posttransplant survival using the Cox proportional-hazards regression model. Recipient age, serum creatinine concentration, intraoperative blood loss, and graft-to-recipient weight ratio were significant predictors of survival after transplantation. The prognostic index model, which was calculated by combining these four prognostic values with their regression coefficients, showed a c-statistic of 0.706 (95% confidence interval [CI] = 0.621-0.792) compared with the Model for End-stage Liver Disease value of 0.546 (95% CI = 0.350-0.558). There was a significant difference between the predictions achieved with the two models (P = .012). In conclusion, selecting younger recipients, better pretransplant renal condition, reduced intraoperative blood loss, and graft-to-recipient size match appeared to be advantageous to achieve better survivals among patients undergoing A-A LDLT. PMID- 21693268 TI - Split liver transplantation. AB - We analyzed the results of 55 patients who underwent split liver transplantation at our center between September 1996 and December 2008, 30 adults (54.5%) and 25 children (45.5%). Median follow-up was 12 years. Overall patient survival was 71%, adult 70% and pediatric 72%. Mean patient survival was 61.58 months, and mean graft survival was 44.35 months. Pediatric survival and pediatric graft survival after 1 and 5 years were 84% and 72% and 72% and 52.4%, respectively. Adult survival and adult graft survival after 1 and 5 years were 75% and 66.2% and 60.7% and 51.5%, respectively. Twelve patients required retransplantation, 6 for primary nonfunction, 3 for chronic rejection, and 3 for vascular complications. Blood groups of the recipient patients were: 34 O, 14 A, 7 B, and 0 AB. The use of split liver for adult and pediatric populations allows us to expand the cadaveric donor pool and has the potential to significantly reduce waiting list mortality, especially for certain blood groups. PMID- 21693269 TI - Rehospitalization after kidney transplantation during the first year: length, causes and relationship with long-term patient and graft survival. AB - INTRODUCTION: There is a wide interest in epidemiologic studies assessing different causes of post-kidney transplantation rehospitalization. However, there is a paucity of knowledge on the long-term survival and graft function of rehospitalized kidney transplant recipients during the first year. Knowledge of posttransplant rehospitalization causes may help guide the preventive program at the first year. In our study, we assess causes for hospitalization and investigate the long-term patient and graft survival after non-fatal rehospitalization in kidney recipients during the first year. MATERIALS AND METHODS: We retrospectively studied the medical histories of 419 kidney transplant recipients whose operations were performed between 1986 and 2009 at Charles Nicolle Hospital, in Tunis, Tunisia. Among these patients, a total of 296 posttransplant rehospitalizations of kidney transplant recipients during the first year occurring in 191 (45.5%) patients were assessed. Clinical characteristics of the patients, including gender, age, reason for kidney failure, weight, height, blood group, length of pretransplant dialysis, immunosuppressive regimen, postoperative complications, the length of hospital stay, transplantation-admission interval, causes of rehospitalizations, graft loss, and mortality rate were reviewed. For donors, these demographics included age, gender, blood group, type of donor (deceased or living), and relationship to the recipient. Because rehospitalizations are possible for more than one cause, the sum of frequencies of rehospitalization causes is more than 100%. RESULTS: There was 1 rehospitalization in 121 patients, 2 rehospitalizations in 47 patients, 3 rehospitalizations in 15 patients, 4 rehospitalizations in 5 patients, 5 rehospitalizations in 2 patients and 6 rehospitalizations in 1 patient. Rehospitalization was more frequent for diabetic patients without significant association. The causes of rehospitalization were infection in 221 cases (55.5%), renal dysfunction in 106 cases (26%), cardiovascular event in 10 cases (2.4%), and diabetic ketoacidosis in 11 cases (2.7%). The length of hospital stay was 22.5 +/- 29.6 days, 20.15 +/- 22.16 days, 25 +/- 30 days and 23.4 +/- 27.5 days, respectively, in the first, second, third, and fifth rehospitalizations. Median hospital stay for all rehospitalizations was between 14 and 16 days. The risk factors of rehospitalization were: use of mycophenolate mofetile (P = .0072), use of cyclosporine (P = .0073), and cytomegalovirus infection (P < .001). There was no significant correlation between rehospitalization and either lost of graft and death. CONCLUSIONS: During the first year after kidney transplantation, rehospitalization was especially required because of infections and renal dysfunction. The risk factors of rehospitalization were cadaveric graft, use of mycophenolate mofetil, use of cyclosporine, and cytomegalovirus infection. To prevent and minimize rehospitalizations during the first year, a specific preventive program based on infection prevention and graft function monitoring should be established. PMID- 21693270 TI - Prospective validation of a simple laboratory score to predict outcome after orthotopic liver transplantation. AB - OBJECTIVE: To establish a score to predict 30-day mortality and graft loss retrospectively and to validate the score prospectively. PATIENTS AND METHODS: Retrospectively in 296 liver transplant recipients, a score was developed that included the peak aspartate aminotransferase concentration within the first week and gamma-glutamyltransferase and bilirubin concentrations at day 7 to predict graft loss or patient death within 30 days. The score was then prospectively validated in 86 patients undergoing liver transplantation. RESULTS: From the retrospective training cohort, cut-off values for prediction of adverse outcomes were determined using receiver operating characteristic curve analysis for peak aspartate aminotransferase (>1870 IU/mL), gamma-glutamyltransferase (<214 IU/mL), and bilirubin (>5.75 mg/dL). Sensitivity and specificity of the score to predict an end point from the retrospective cohort were excellently reproduced in the prospective cohort. Overall, fulfillment of at least 2 criteria predicted graft loss or death within 30 days with sensitivity of 0.70 and specificity of 0.78. No patients with values that remained below all 3 thresholds experienced graft loss or death within 30 days. CONCLUSIONS: This simple score calculated from standard laboratory values within the first week after liver transplantation enables prediction of graft loss and patient death within 30 days after transplantation. Early identification of patients at risk may help to improve outcomes by observing these patients more closely and allocating resources for them. PMID- 21693271 TI - Suitable calcineurin inhibitor concentrations for liver transplant recipients in the Chinese population. AB - AIM: The aim was to deduce suitable calcineurin inhibitor concentrations for the Chinese liver transplantation population. METHODS: We retrospectively studied 97 liver transplant recipients who displayed stable liver and renal function. No grafts were obtained from prisoners, procurements were performed with donor consent conforming to international ethics regulations. At 3, 6, and 12 months, we increased the concentrations and doses of calcineurin inhibitors as well as the values of alanine transaminase and serum creatinine. RESULTS: Twenty-eight recipients received cyclosporine and 69 tacrolimus. The mean cyclosporine daily dosages were 203 +/- 62 mg at 3, 188 +/- 55 mg at 6, and 173 +/- 52 mg at 12 months, the tacrolimus daily dosages were 3.08 +/- 0.98, 2.82 +/- 0.98, and 2.58 +/- 0.93 mg, respectively. The corresponding mean cyclosporine peak concentrations (C(2)) were 806 +/- 322 ng/mL, 681 +/- 206 ng/mL, and 644 +/- 190 ng/mL and the mean tacrolimus trought concentrations (C(0)) 6.61 +/- 3.02 ng/mL, 5.85 +/- 2.44 ng/mL, and 5.22 +/- 2.33 ng/mL, respectively. In both groups, transaminases and serum creatinine were stable over time. CONCLUSIONS: An individualized immunosuppressive regimen for the local population is necessary. We delayed calcineurin inhibitors with subsequent low-dose mycophenolate mofetil plus minimized calcineurin inhibitors, which seemed to be nephroprotective and safe for Chinese liver transplantation patients. PMID- 21693272 TI - Motivations and decision-making dilemmas of overseas liver transplantation: Taiwan recipients' perspectives. AB - PURPOSE: This study sought to explore the motivation and dilemmas in the decision making process encountered by Taiwan overseas orthotopic liver transplant (OLT) recipients. PATIENTS AND METHODS: We used an exploratory qualitative research method on a sample of transplant recipients. Face-to-face in-depth interviews were performed with a semistructured interview guide. Data were evaluated by qualitative content analysis. RESULTS: We interviewed 15 patients including 11 males and 4 females aged between 41 and 68 years (mean = 57.3) including 14 who received OLT in China and one in the United States. The most important motivations were saving lives from end-stage liver disease and avoiding a hopeless sense of their residual lives with the psychological torture of a waiting death. Their decision-making process leading to overseas OLT could be divided into several phases among which the phase of transplant data evaluation and decision was the most critical one. Nevertheless, every stage and phase had its unique contents, factors, and dilemmas. CONCLUSION: This study demonstrated that patients encountered various dilemmas at different phases in the decision making process of considering overseas OLT. This information is important for care providers and policy makers in dealing with patients who consider overseas OLT. PMID- 21693273 TI - Liver retransplantation in superobese patients: a single center experience. AB - A retrospective review of patients who had body mass indeces greater than 40 kg/m(2) who underwent liver retransplantation (LR) from February 1998 to December 2008 at our institution. There were 73 patients who had body mass indeces greater than 40 kg/m(2) and had orthotopic liver transplantation. Six of 73 patients required retransplantation. Median time between orthotopic liver transplantation and LR was 131 days (range, 2 to 2812 days). Indications for LR were ischemic cholangiopathy, hepatic necrosis, recurrent hepatitis C, and primary non function. Four patients are still alive with median survival of 37 months after LR. Two patients had perioperative death. PMID- 21693274 TI - Update on biliary strictures in liver transplants. AB - Biliary complications continue to be the Achilles heel of orthotopic liver transplantation. These include ischemic-type biliary lesions that mostly affect liver allografts donated after cardiac and lead to increased morbidity and retransplantation in patients undergoing liver transplantation. Although this entity has been recognized for >20 years, the true mechanism of injury remains unknown. Identification of the pathogenesis will likely lead to the increased use of grafts donated after cardiac death and thus increase the organ pool. This update reviews the risk factors that have been implicated in ischemic-type biliary lesion formation, potential therapies, and mechanisms that might lead to their formation. PMID- 21693275 TI - Simultaneous surgical repair for combined biliary and arterial stenoses after liver transplantation. AB - After orthotopic liver transplantation (OLT), hepatic artery stenoses (HAS) and biliary strictures (BS) are frequent. These complications remain a significant cause of graft loss and patient death. The present study reported a group of 7 patients in whom both HAS and BS were identified and treated surgically in the same surgical session. The median times to diagnosis were 42 (range, 5-120) and 84 (range, 15-280) days after OLT for biliary and arterial stenosis, respectively. The mortality was nil. Two patients (28%) developed postoperative complications. The median hospital stay was 16 days (range, 10-42). All patients are alive; there was no graft loss. With a median of 76 months' follow-up (range, 38-132), only 1 patient (14%) developed recurrence of both BS and HAS. In patients with coincident biliary and artery stenosis, concomitant surgical repair is feasible, offering good long-term results. PMID- 21693276 TI - Chronic hepatic artery occlusion with collateral formation: imaging findings and outcomes. AB - OBJECTIVE: The imaging findings, clinical presentation, and outcome in post liver transplantation patients with hepatic arterial collaterals are reviewed. MATERIALS AND METHODS: Adult post orthotopic liver transplantation patients who underwent an angiography at our institution for suspected hepatic arterial abnormality during an approximately 10-year period were included in our study. A retrospective review of all cases that had hepatic arterial collaterals detected on angiography was then performed. Angiographic findings were correlated with the findings on ultrasound and other imaging studies. Liver function at the time of angiography was recorded. Clinical outcomes were reviewed. RESULTS: Of the 129 angiographies performed in the approximately 10-year period, 24 (19.4%) were found to have collaterals on angiography. Maximum size of the collaterals seen on angiography was 3 mm. Twenty patients (83%) with collaterals are currently alive. Twelve patients (50%) had a normal outcome and did not develop any complications on follow-up; however, the rest developed complications. Eleven patients (41.7%) had complication related to the liver ischemia and 2 patients (8.3%) developed malignancy (posttransplant lymphoproliferative disease). CONCLUSION: Collaterals seen in patients with chronic hepatic artery occlusion are usually small in caliber and their significance is unclear. Recognition and understanding of this phenomenon is important as this subset of patients may not need urgent surgical re-exploration/vascular intervention. PMID- 21693277 TI - Early diagnostic value of plasma PCT and BG assay for CRBSI after OLT. AB - AIM: The aim was to evaluate the role of procalcitonin (PCT) and (1-3)-beta-D glucan (BG) tests for early detection or exclusion of central venous catheter related bloodstream infections (CRBSI) in patients after orthotopic liver transplantation (OLT). METHODS: Fifty-five patients with clinically suspected CRBSI were assessed after OLT in this prospective study. On the day of clinical suspicion of CRBSI, blood samples were obtained from central venous catheters and a peripheral vein for blood cultures and from a peripheral vein for PCT and BG tests. Plasma PCT and BG values were measured by using an immunoluminometric assay and Fungitell BG assay, respectively. No prisoners or organs from prisoners were used in this study. RESULTS: Twenty-five patients (45%) were diagnosed with CRBIS. Among them, 13 (52%) displayed gram-positive bacteriemia, 11 (44%) gram negative bacteriemia, and 1 (4%) fungemia. The PCT values were higher in CRBSI than in non-CRBSI patients (P = .003). CRBSI patients did not show significant increases in plasma BG values compared with non-CRBSI subjects (P = .051). PCT and BG area under receiver operating characteristic curves were 0.840 and 0.486, respectively. Sensitivity, specificity, and positive and negative predictive values of a PCT of >= 3.1 ng/mL for the diagnosis of CRBSI were 0.72, 0.87, 0.82, and 0.79, respectively. The figures for a BG of >= 83 pg/mL were 0.32, 0.90, 0.73, and 0.61, respectively. Among the 24 patients with bacteria infections, PCT was higher in patients with gram-negative than those with gram-positive bacterial infections (P = .022). CONCLUSION: We concluded that the PCT assay may be a useful rapid diagnostic adjunct for the diagnosis of suspected CRBSI in OLT patients. PMID- 21693278 TI - Safety of ultra-rapid intravenous infusion of hepatitis B immunoglobulin in liver transplant recipients. AB - PURPOSE: To evaluate the safety of institutional protocol for ultra-rapid hepatitis B immunoglobulin (HBIG) infusion (10,000 IU in 30 minutes) for hepatitis B virus prophylaxis in adult liver transplant recipients. METHODS: In this case-controlled study, prospectively recruited liver transplant recipients received ultra-rapid infusions of HBIG (10,000 units in 30 minutes) for 6 months. The historical control group consisted of patients who had received 1-hour HBIG infusions (conventional rapid infusion) for the precedent 6 months. RESULTS: We found that 1472 patients had received 5744 ultra-rapid HBIG infusions, whereas 1343 patients had received 5200 conventional rapid HBIG infusions. Adverse side effects were observed after 7 (0.13%) and 9 (0.16%) infusions, respectively (P = .763). The number of infusions per month increased significantly, from 878 +/- 34 before the introduction of ultra-rapid infusion to 957 +/- 29 afterwards (P < .001), an increase of 10.5%. The maximal capacity of HBIG infusions per day in the outpatient clinic increased from 53 for conventional rapid infusion to 65 for ultra-rapid infusion, without expansion of the outpatient facility or equipment. CONCLUSIONS: Nearly all adult liver recipients able to tolerate 1-hour infusions of HBIG can also tolerate ultra-rapid infusions well. Thus, it seems to be reasonable to perform ultra-rapid infusion protocol widely for patient convenience. PMID- 21693279 TI - Laparoscopic incisional hernia repair after solid-organ transplantation. AB - BACKGROUND: Incisional hernias are a frequent problem after liver transplantation. Mesh repair techniques including laparoscopic repair have been employed in order to address this problem. We have introduced intraperitoneal onlay mesh repair (IPOM) in 2008 because of advantages that had been reported in the literature. To perform a structured comparison of methods and outcomes, we compared patients who have been treated with IPOM and those who have been treated conventionally. METHODS: We included 29 consecutive patients (15 IPOM, 14 conventional hernia repair [CHR] who have been analyzed and have been examined clinically and sonographically during their follow-up. RESULTS: Recurrence rate was 6% (IPOM) and 50% (CHR), complication rate was 33% (IPOM) and 21% (CHR), mean hospital stay was 7.2 (IPOM) and 9.7 (CHR) days. None of the 29 patients had an impaired wound healing or infectious complications. Of the 29 patients, 10 received sirolimus for immunosuppression, which was switched preoperatively to a calcineurin inhibitor. CONCLUSION: IPOM results in a shorter hospital stay. The complication rate with IPOM was higher compared with CHR, recurrence rate was considerably lower. The role of perioperative sirolimus switch needs to be interpreted with caution, but should be further investigated because of potential advantages with respect to fewer wound healing complications. PMID- 21693280 TI - Effect of splenic artery embolization for splenic artery steal syndrome in liver transplant recipients: estimation at computed tomography based on changes in caliber of related arteries. AB - PURPOSE: To estimate the effect of splenic artery embolization (SAE) on blood flow in orthotopic liver transplantation (OLT) recipients with splenic artery steal syndrome (SASS) based on changes in caliber of related arteries upon serial computed tomography (CT) scans. METHODS: Between 2004 and 2007, nine OLT recipients with SASS underwent SAE. They had CT scans before and after SAE: short , mid-, and long-term, ie, approximately 1 week, 1 month, and 1 year, respectively. The diameters of the celiac axis (CA), common hepatic artery (CHA), and splenic artery (SA) were measured with arterial phase of each CT scan and the ratios of SA to CHA diameter (SA/CHA) calculated to analyze their changes during the follow-up period. RESULTS: The diameters of celiac axis, CHA, and SA and SA/CHA changed most rapidly during the short-term period. The CHA diameter significantly increased short-term post-SAE by CT and slightly decreased thereafter. However, the mid-term and long-term post-SAE CT values were still significantly greater than those on the pre-SAE CT. The SA diameter steadily decreased throughout the follow-up. The SA/CHA decreased until the mid-term. The SA diameter and SA/CHA were significantly smaller upon mid-term and long-term post-SAE CT compared with those at pre-SAE CT. CONCLUSIONS: The effect of SAE to improve hepatic arterial flow in OLT recipients with SASS might be expected for at least approximately one year. The effect maximally occurred during the short term after SAE on the basis of changes in the caliber of related arteries upon CT. PMID- 21693281 TI - Myocardial perfusion is a useful screening test for the evaluation of cardiovascular risk in patients undergoing simultaneous pancreas kidney transplantation. AB - Cardiovascular disease is the leading cause of death in simultaneous pancreas kidney transplantation (SPKT) patients. SPKT is increasingly being undertaken to manage patients with advanced diabetic nephropathy and type 1 diabetes mellitus. Traditionally, invasive angiography has been used as a tool to diagnose significant coronary disease and inform decision making with regard to coronary revascularization prior to transplantation. In our retrospective analysis of 167 consecutive patients who underwent SPKT in our center, we show that using myocardial perfusion scintigraphy (MPS) as the first-line screening tool is highly sensitive without exposing the patient to undue investigative procedural risks (or an unacceptably high false-negative rate) and it provides 1-year cardiovascular outcomes that are comparable with those of patients managed via the more traditional but riskier invasive route. PMID- 21693282 TI - 31-Phosphorus magnetic resonance spectroscopy for dynamic assessment of adenosine triphosphate levels in pancreas preserved by the two-layer method. AB - Cold preservation injury influences islet graft function. Reliable tools for real time assessment of pancreas viability before islet isolation are lacking. Phosphorus magnetic resonance spectroscopy ((31)P-MRS) was used immediately after organ harvest to study rat pancreases at 4 degrees C to 6 degrees C in five randomized preservation groups: Marshall's solution, static two-layer method (TLM), continuous TLM with oxygen perfused at 0.5 L/min, and static TLM or continuous TLM both the latter following 30 minutes of warm ischemia (WI). (31)P spectra were analyzed for phosphomonoesters, inorganic phosphate (Pi) and alpha-, beta-and gamma-nucleotide triphosphate. Intergroup rates of change of [gamma adenosine triphosphate (ATP)]/[Pi] and [beta-ATP]/[Pi] throughout preservation period were significantly different. For continuous TLM there was an increase relative to baseline (0.043 (SD0.033) h(-1) and 0.029 (0.029) h(-1), respectively) but a decrease for both static TLM (-0.023 (0.016) h(-1) and 0.015 (0.026), P < .001 and < .05, respectively) and Marshall's (-0.049 (0.025) h(-1) and -0.036 (0.019) h(-1), respectively, both P < .001) with respect to continuous TLM. Rate of decrease was similar for the Marshall's and static TLM groups. [gamma-ATP]/[Pi] and [beta-ATP]/[Pi] increased with WI continuous TLM (0.008 [0.009] h(-1) and 0.007 [0.008] hr(-1), respectively) but decreased for WI static TLM (-0.018 (0.008) h(-1) and -0.014 (0.004) hr(-1), respectively, P < .001). (31)P-MRS is an effective tool for noninvasive assessment of pancreas bioenergetics. Continuous TLM preserves cellular bioenergetics and is superior to current non-perfluorocar bone based solutions for pancreas preservation. PMID- 21693283 TI - Pretreatment with bilirubin protects islet against oxidative injury during isolation and purification. AB - BACKGROUND: A high yield of pure, viable islets is one of the most important prerequisites for successful islet transplantation. However, during isolation and purification, many factors may cause oxidative stress, impacting islet viability. Accumulating evidence indicates that bilirubin (BR) not only has antioxidative but also has cytoprotective activities. In this study, we investigated whether pretreatment with bilirubin would protect islets against oxidative damage during isolation and purification. METHODS: Wistar rats were randomly divided into control and BR groups. The latter rats received an injection of BR 2 hours before islet isolation, whereas the controls received vehicle. Islet purity was determined using a dithizone stain. Survival rate and viability were determined using acridine orange and propidium iodide staining and the Cell Counting Kit-8 Kit. Islet function was quantified by testing glucose-stimulated insulin secretion. Islet damage caused by oxidative stress was quantified by measuring the malondialdehyde (MDA) in freshly isolated islets. RESULTS: Pretreatment with bilirubin did not enhance the purity, but significantly enhanced the survival rate and viability of the islets. Islet function in the BR group was significantly better than that in the control cohort. The MDA level was 0.62 +/- 0.23 nmol/L/MUg protein in the BR group, which was significantly lower (P < .05) than that in controls (1.31 +/- 0.34 nmol/L/MUg protein). CONCLUSIONS: We concluded that oxidative stress during islet isolation and purification can be mitigated by BR pretreatment. BR exerts antioxidant and cytoprotective properties by reducing lipid peroxidation (MDA) and enhancing islet viability and function. Pretreatment with BR may become a simple, clinical applicable means to improve human islet isolation and transplantation outcomes. PMID- 21693284 TI - Endothelin-1 markedly decreases the blood perfusion of transplanted pancreatic islets in rats. AB - BACKGROUND: Transplantation of insulin-producing beta-cells is the only available curative treatment for type 1 diabetes. However, graft function declines within the first years after transplantation, which may reflect inadequate vascular engraftment. Endothelin-1 (ET-1) is a potent vasoconstrictor whose production is regulated by both hypoxia and inflammation. Moreover, the plasma concentration of ET-1 is elevated in patients with type 1 diabetes. The aim of this study was to investigate the gene expression and effects of ET-1 and its 2 receptor antagonists, BQ123 and BQ788, on blood flow in syngeneic rat islet transplants. METHODS: Pancreatic islets from Wistar Furth rats were isolated and transplanted syngeneically under the kidney capsule. Transplant and kidney cortex blood flow was measured using laser Doppler flowmetry after administration of ET-1 via topical application, or after administration of BQ123 and BQ788 intravenously. The grafts and isolated islets were analyzed for mRNA expression of ET-1, ET(A) receptor, ET(B) receptor, and endothelin-converting enzyme 1 using by reverse transcription polymerase chain reaction. RESULTS: ET-1 markedly decreased transplant blood flow (77.5 +/- 4.4% 1 minute after administration; n = 6), whereas neither BQ123 nor BQ788 had vascular effects. No differences in relative gene expression between the grafts and freshly isolated control islets were seen for ET-1 (0.65 +/- 0.14 [n = 8] vs 0.79 +/- 0.24 [n = 5]), ET(A) receptor (0.37 +/- 0.14 [n = 8] vs 0.25 +/- 0.04 [n =5]), ET(B) receptor (4.78 +/- 1.43 [n = 8] vs 1.94 +/- 0.32 [n = 5]), or endothelin converting enzyme 1 (7.25 +/- 1.88 [n = 8] vs 11.83 +/- 0.95 [n = 5]) when expressed as 2(-DeltaCt). CONCLUSION: Exogenous ET-1 strongly affects the blood perfusion of transplanted islets, and endogenous levels can, if up-regulated, contribute to graft failure. PMID- 21693285 TI - Application of the paraboloidal model to assess mucosal changes following segmental intestinal transplantation in children. AB - Segmental living related small intestinal transplantation (LRSITx) is a therapeutic option for conditions that present with short gut syndromes. Recovery of small intestinal mucosa after transplantation is critical to function. We examined the posttransplant mucosal changes to understand the absorptive capabilities of transplanted small intestine. The study of human subjects is constrained by limited biopsy material; therefore, we developed a technique of villus area measurement by extrapolation from two-dimensional surgical biopsy images. Using a detailed model of the villus as the gold standard, two simpler models (cylindrical and paraboloid) were tested. Comparisons with the accurate measurement revealed that the cylinder model does not compare well in early posttransplant biopsies. The paraboloid function developed in this article worked very well under all conditions. The simplicity of the paraboloid model and its robustness made high-quality estimates of the absorptive surface area from abundant data relatively easy. The remodeling expected in the initial stages of growth was also captured by this model. Time-dependent villus growth curves were obtained for transplanted bowel. Serial biopsies showed an initial "reconstruction" dip around 2 weeks after transplant, followed by continuous growth of villus surface area. An eventual plateau resulted at an average of 6 months after transplant. This growth of villi was shown to parallel the improved absorption of electrolytes, amino acids, and water. PMID- 21693286 TI - Quantification of intraepithelial lymphocytes in normal pediatric small intestinal allograft and native ilea. AB - BACKGROUND: The small bowel acts as one of the first lines of defense against intraluminal infections and antigenic stimuli. Pediatric small bowel transplant patients are at particular risk from such agents, especially viral enteridities. Quantification of intraepithelial lymphocytes (IEL) in architecturally normal small intestinal mucosal biopsies plays an important role in the diagnosis of conditions such as celiac disease and some viral infections. No studies to date have been done to quantify IEL numbers in pediatric small bowel allografts and in native pediatric ilea. Our study investigated the IEL:enterocyte (EC) ratio in pediatric allograft and native ilea. METHODS: Hematoxylin and eosin slides from 50 surveillance endoscopic biopsies of small bowel allografts taken from patients <8 years of age and 50 terminal ileal biopsies from aged-matched control populations were reviewed. IEL:EC ratios were averaged from five well-oriented villi in each case. IEC numbers were compared between biopsies from proximal (afferent) and distal (efferent) limbs of double-barrel allograft stomas, as well as native terminal ilea. RESULTS: Within small bowel allografts, the average number of villus tip IELs was 1.3/20 ECs (standard deviation [SD] 0.6) in the proximal limb and 1.0/20 ECs in the distal (SD 0.6 P < .01). This value was significantly lower than in the control ilea (2.1/20 EC [SD 0.6]; P < .01, each). The overall distribution of lymphocytes was in a similar pattern throughout the villus with IEL:EC ratios on villus sides from proximal allografts, distal allografts, and native ilea being 1:20, 0.8:20, and 2:20, respectively. CONCLUSIONS: The results suggest that approximately one to two IEL per 20 ECs at villus tips may represent a "normal" intraepithelial inflammatory cell population in small bowel allografts. The value is lower than that seen in age-matched native ileal biopsies. IEL numbers are significantly higher in the proximal limb compared to the distal limb of double-barrel stomas. PMID- 21693287 TI - Everolimus plus dosage reduction of cyclosporine in cardiac transplant recipients with chronic kidney disease: a two-year follow-up study. AB - The calcineurin inhibitor cyclosporine (CSA) displays nephrotoxic side effects. We switched 95 maintenance heart transplant recipients with chronic kidney disease (CKD) stages 3-4 from CSA to everolimus (EVL). The CSA dosage was reduced by 50%. Kidney function, lipid metabolism, and cardiac function investigated during a 2-year follow-up were compared with heart transplant recipients with CKD stages 2-3 who continued to receive CSA (CSA group; n = 84). Whereas 64/95 patients received reduced CSA plus EVL during the entire follow-up period (EVL continued subgroup, ECN), 31 discontinued EVL (EVL discontinued subgroup, EDS) after 4.3 months (median) because of various clinically relevant adverse events. Glomerular filtration rates (estimated using the modification of diet in renal disease formula) increased by 4.0 mL/min/1.73 m(2) in the ECN subgroup but decreased by 2.4 mL/min/1.73 m(2) and 9.0 mL/min/1.73 m(2) in the EDS subgroup and the CSA group, respectively (P < .001). Triglyceride and total cholesterol concentrations increased significantly among the ECN group, but remained constant in the EDS subgroup and the CSA group. Statin use was increased by 15% in the ECN group (P < .01). Mortality and cardiac rejection rates did not differ significantly among the 3 groups. In summary, EVL combined with low-dose CSA had modest beneficial effects on kidney function in heart transplant recipients with CKD stages 3-4. A significant percentage of patients had to stop EVL because of various adverse events. PMID- 21693288 TI - Calcineurin inhibitor-free immunosuppression using everolimus (Certican) after heart transplantation: 2 years' follow-up from the University Hospital Munster. AB - BACKGROUND: Everolimus is a proliferation-signal inhibitor which was introduced for heart transplant recipients in 2004. To date, there are only sparse data about long-term calcineurin inhibitor (CNI)-free immunosuppression using everolimus. METHODS: After heart transplantation, patients receiving everolimus were consecutively enrolled. Reasons for switching to everolimus were side effects of CNI immunosuppression, such as deterioration of kidney function and recurrent rejection episodes. All 60 patients underwent standardized switching protocols, 42 patients completed 24-month follow-up. Blood was sampled for lipid status, renal function, routine controls, and levels of immunosuppressive agents. On days 0, 14, and 28, and then every 3 months, echocardiography and physical examination were performed. RESULTS: After switching to everolimus, most patients recovered from the side effects. Renal function improved significantly after 24 months (creatinine, 2.1 +/- 0.6 vs 1.8 +/- 1 mg/dL; P < .001; creatinine clearance, 41.8 +/- 22 vs 48.6 +/- 21.8 mL/min; P < .001). Median blood pressure increased from 120.0/75.0 mm Hg at baseline to 123.8/80.0 mm Hg at month 24 (P values .008 and .003 for systolic and diastolic pressures, respectively). Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Levels of interleukin-6 were stable between baseline and 24-month levels. Temporary adverse events occurred in 8 patients [13.3%: interstitial pneumonia (n = 2), skin disorders (n = 2); reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3)]. CONCLUSION: CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance of heart transplant recipients. Arterial hypertension and renal function significantly improved. CNI-induced side effects, such as tremor, peripheral edema, hirsutism, and gingival hyperplasia, markedly improved in most patients. PMID- 21693289 TI - Efficacy and safety of sirolimus and everolimus in heart transplant patients: a retrospective analysis. AB - BACKGROUND: Since its introduction as an immunosuppressant in the late 1990s, sirolimus (SRL) has been used to prevent rejections after heart transplantation (HTx) in the United States. An analogue, everolimus (ERL) has been mainly used in Europe. We performed a retrospective longitudinal single-center study to evaluate efficacy and side effects of SRL and ERL. PATIENTS AND METHODS: We analyzed 71 patients, 39 in the SRL and 32 in the ERL group. The following data were collected: Trough levels of SRL and ERL, biopsy-proven rejections, renal function, blood lipids, hematology, blood pressure, pulse rate, and side effects (via an anonymous questionnaire). Follow-up time was 6 months. No prisoners or organs from prisoners were used in the study. RESULTS: Introduction of SRL or ERL into therapy took place 44 or 42 months (average) after HTx. SRL and ERL were equally effective in preventing rejection (8/39 versus 6/32). Hemoglobin levels decreased slightly in the SRL group (nonsignificant). Leucocytes and thrombocyte levels decreased in both groups (P < .05 only in the ERL group). Creatinine levels remained unchanged. Cholesterol and triglyceride levels increased significantly in the SRL group. High-density lipoprotein levels increased significantly in the ERL group. Vital signs remained stable in both groups. Side effects (mainly edema, gastrointestinal symptoms and infections) were considerable and prompted discontinuation in 39% of all patients in both groups. Infections were more frequent in SRL (18/39 versus 12/32, nonsignificant). Calcineurin therapy could be reduced by 25% in SRL and 45% in ERL. CONCLUSION: The impact of SRL and ERL on laboratory values and rejection rates, as well as on clinical parameters, is similar with a slight advantage to ERL regarding lipids and rate of infections (not significant). Both SRL and ERL allow an important reduction of calcineurin-therapy; however, both drugs have considerable side effects, which often require discontinuation of therapy. PMID- 21693290 TI - Increased incidence of acute graft rejection on calcineurin inhibitor-free immunosuppression after heart transplantation. AB - BACKGROUND: Calcineurin inhibitor (CNI)-free immunosuppression is used increasingly after heart transplantation to avoid CNI toxicity, but in the absence of a randomized trial, concerns remain over an increased rejection risk. METHODS: We studied the incidence of graft rejection episodes among all cardiac graft recipients, beginning with the first introduction of CNI-free protocols. We compared events during CNI-free and CNI-containing immunosuppression among 231 transplant recipients of overall mean age 55.2 +/- 11.8 years, from a mean 5.2 +/ 5.4 years after transplantation through a mean follow-up of 3.1 +/- 1.4 years. We considered as acute rejection episodes requiring treatment those of International Society for Heart and Lung Transplantation. RESULTS: During the total follow-up of 685 patient years (CNI-containing, 563; CNI-free, 122), we performed 1,374 biopsies which diagnosed 78 rejection episodes. More biopsies were performed in CNI-free patients: biopsies/patient-month of CNI-containing, 0.13 versus CNI-free, 0.22 (P < .05). The incidence of rejection episodes per patient-month was significantly higher on CNI-free compared with CNI therapy, among patients switched both early and later after heart transplantation, namely, within 1 year, 0.119 versus 0.035 (P = .02); beyond 1 year, 0.011 versus 0.004 (P = .007); beyond 2 years, 0.007 versus 0.003 (P = .04); and beyond 5 years: 0.00578 versus 0.00173 (P = .04). CONCLUSIONS: Rejection incidence during CNI free immunosuppression protocols after heart transplantation was significantly increased in both early and later postoperative periods. Given the potentially long delay to rejection occurrence, patients should be monitored closely for several months after a switch to CNI-free immunosuppressive protocols. PMID- 21693291 TI - Treatment of intractable interstitial lung injury with alemtuzumab after lung transplantation. AB - A 44-year-old woman underwent left single-lung transplantation for end-stage emphysema due to alpha1-antitrypsin deficiency in January 2010. Cyclosporine, azathioprine, and prednisolone were administered for immunosuppression and antithymocyte globulin for induction therapy at the time of transplantation. Routine examination of a lung biopsy, 4 months after transplantation, showed nonspecific, diffuse interstitial inflammation with alveolar septal fibrosis. The patient's clinical status and imaging studies, consistent with nonspecific interstitial pneumonitis, which was considered as signs of acute rejection, worsened within 2 weeks, despite high-dose steroids, change of calcineurin inhibitor, and plasmapheresis. Within a few days after a single, 10-mg, intravenous dose of alemtuzumab, the patient's health improved markedly. She has remained stable for 4 months on a standard, ambulatory, posttransplant antirejection drug regimen. We have since successfully treated with alemtuzumab three additional patients who developed interstitial lung injury after lung transplantation, who are also summarized in this report. PMID- 21693292 TI - Combined heart and kidney transplantation provides an excellent survival and decreases risk of cardiac cellular rejection and coronary allograft vasculopathy. AB - BACKGROUND: We analyzed the results of combined heart-kidney transplantation (CHKTx) over a 10-year period. METHODS: Between September 1996 and May 2007 at Mayo Clinic, 12 patients (age 52 +/- 12.2 years) underwent CHKTx as a simultaneous procedure in 10 recipients and as a staged procedure in two recipients with unstable hemodynamics after heart transplantation. RESULTS: There was no operative mortality. Patient survival rates for the CHKTx recipients at 1 and 3 months and 6 years were 91%, 83%, and 83% and did not differ from isolated heart transplantation (IHTx) recipients (97%, 95%, and 79%, P = 0.61). The freedom from cardiac allograft rejection (>= grade 2) at 3 months was 73% for CHKTx and had not changed during further follow-up; for IHTx, freedom from rejection at 3 months and 1 and 6 years was 61%, 56%, and 42% (P = .08). Heart and renal allograft survival was 100% with and left ventricular ejection fraction 66% +/- 8.4% and glomerular filtration rate 61 +/- 25 at last follow-up. There were no signs of cardiac allograft vasculopathy in the CHKTx recipients. CONCLUSION: CHKTx yields favorable long-term outcome, with a low incidence of cardiac rejection and vasculopathy. Simultaneous CHKTx appears feasible, if hemodynamics is satisfactory. This approach expands the selection criteria for transplantation in patients with coexisting end-stage cardiac and renal disease. PMID- 21693293 TI - Tumor necrosis factor-related apoptosis-inducing ligand is a marker of kidney function and inflammation in heart and kidney transplant recipients. AB - BACKGROUND: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was originally identified as the third member of the TNF superfamily to induce apoptosis. TRAIL is normally expressed in many human tissues including kidney. Circulating soluble TRAIL is a negative marker for inflammation and is inversely associated with the mortality risk in chronic kidney disease patients. One increasingly prevalent complication in heart transplant recipients appears to be chronic kidney disease. MATERIALS AND METHODS: The aim of the study was to assess TRAIL concentration in 136 heart transplant recipients and 80 prevalent kidney allograft recipients in relation to kidney function. Complete blood count, urea, serum lipids, fasting glucose, creatinine, NT-proBNP were studied. Soluble TRAIL, hsCR P, interleukin-6 (IL-6), von willebrand factor (vWF) were assayed using commercially available kits. RESULTS: Heart transplant recipients had significantly higher serum creatinine, urea, cholesterol, triglycerides, fasting glucose, white blood cell count, serum TRAIL and lower estimated glomerular filtration rate than the control group. Similar results were obtained for kidney allograft recipients. Serum TRAIL levels fell, together with decline in glomerular filtration rate in heart transplant patients. Serum TRAIL was related to age, kidney function, erythrocyte count, hemoglobin, NT-proBNP, New York Heart Association class, presence of diabetes, high-density lipoprotein (HDL), IL-6, and ejection fraction. Age and HDL turn out to be predictors of TRAIL in heart transplant recipients. In kidney transplant recipients, TRAIL was related, in univariate analysis, to age, NT-proBNP, time after transplantation, kidney function, and vWF. In multiple regression analysis, predictors of TRAIL were vWF and time after transplantation. CONCLUSION: TRAIL may represent a surrogate marker of endothelial dysfunction and atherosclerosis as these processes are accelerated in heart and kidney dysfunction. PMID- 21693294 TI - Effect of pulmonary hypertension in patients with end-stage lung disease on posttransplantation outcomes. AB - A subgroup of patients with end-stage lung disease develop secondary pulmonary hypertension (PH). PH results in worse prognosis in these patients. However, it is unclear if this effect prevails in the immediate- and long-term outcomes of these patients after lung transplantation (LT). The objective of this study was to evaluate the effect of pretransplantation PH on immediate- or long-term posttransplantation outcomes. A retrospective chart review of post-LT patients at Henry Ford Hospital from January 1995 through January 2008 was done. Patients were grouped by presence or absence of PH and were compared using chi-square or Fisher exact tests for categorical variables and t tests or Wilcoxon rank sum tests for continuous variables. Kaplan-Meier estimation was used to evaluate primary and secondary outcomes. Among the patients included in the study, 25 had PH. This group consisted mostly of females (68%). There was no difference in the indication or type of LT in the 2 groups. There was no statistically significant difference in freedom from bronchiolitis obliterans syndrome (BOS; P = .42), time to onset of BOS (P = .82), grade of BOS (P = .21), or cummulative acute rejection (CAR) score (P = .66). There was no difference in overall mortality at 3 and 5 years (P = .57) or time to death (P = .25). Number of A1 rejection episodes was the only significant predictor for BOS (P = .001). In conclusion, PH due to end stage lung disease does not have any effect on early or late posttransplantation outcomes. There is predisposition for females with end-stage lung disease to develop secondary PH more so than males. The number of A1 rejections increases the likelihood of development of BOS. A larger multicenter study is needed to confirm the results of this pilot study. PMID- 21693295 TI - Prophylaxis of cytomegalovirus disease in mismatched patients after heart transplantation using combined antiviral and immunoglobulin therapy. AB - BACKGROUND: Cytomegalovirus (CMV) is a common cause of infection and morbidity after heart transplantation. Seronegative recipients (R-) of seropositive donor hearts (D+) are at high risk for CMV disease. We compared three different CMV prophylaxis regimens using combined antiviral and immunoglobulin therapy. METHODS: In 99 patients who survived more than 30 days after heart transplant, all received induction with antilymphocytic therapy and triple-drug therapy. In group A, D+R- patients received one dose of intravenous immunoglobulin (IVIG) followed by one dose of CMV-specific immunoglobulin (CMV-IVIG), and intravenous ganciclovir (GCV) for 4 weeks followed by 11 months of oral acyclovir (ACV). In group B, D+R- patients received one dose IVIG followed by five doses of CMV-IVIG and intravenous GCV for 14 weeks followed by 9 months of oral ACV. In group C, D+R- patients were treated with the same regimen as for group B, except oral ACV was replaced with oral GCV. RESULTS: The actuarial freedom from CMV disease for D+R- patients at 1 month, 1 year, and 2 years after transplantation in group A was 100%, 25% +/- 15%, and 25% +/- 15%, respectively; group B was 100%, 67% +/- 27%, and 67% +/- 27%; group C was 100%, 83% +/- 15%, and 83% +/- 15% (P < .01, groups B and C vs group A). By comparison, the actuarial freedom from CMV disease for seropositive recipients (D-R+ or D+R+) at 1 month, 1 year, and 2 years in group A was 100%, 87% +/- 7%, and 82% +/- 8%, respectively; group B was 100%, 88% +/- 8%, and 75% +/- 11%; group C was 100%, 72% +/- 9%, and 72% +/- 9% (P = NS among groups). Rejection rates did not differ among the three groups. CONCLUSIONS: A longer course of intravenous GCV with multiple doses of CMV-IVIG was a more effective prophylaxis regimen against CMV disease for the high-risk group of seronegative recipients of seropositive donor hearts. PMID- 21693296 TI - Long-term maintenance therapy for post-cardiac transplant monoclonal lymphoproliferative disorder: caveat mammalian target of rapamycin. AB - A 53-year-old Caucasian male suffering from idiopathic dilated cardiomyopathy underwent cardiac transplantation. Fifty-seven days following transplant, he developed posttransplant lymphoproliferative disorder (PTLD), which was Epstein Barr virus positive. The initial episode of PTLD was treated with a dose reduction in cyclosporine (CsA) and a 4-week course of rituximab. Subsequent biopsies showed resolution of PTLD. One year posttreatment, his evaluation revealed severe cardiac allograft vasculopathy (CAV). The patient was switched to sirolimus-based immunosuppression regimen with gradual up-titration of sirolimus in combination with complete withdrawal of previously administered Calcineurin based immunosuppression approach. The switchover was carried out over a 6-week period. In the following 3 years, there was CAV regression as well as PTLD remission, without any significant episode of rejection. Despite frequent relapses with this form of PTLD, the patient remains in remission, 8 years posttransplantation. In summary, sirolimus has been demonstrated to attenuate the progression of CAV, and this case report illustrates that regression of CAV is possible. In addition to preventing rejection, mammalian target of rapamycin inhibitors directly suppress signaling pathways leading to PTLD and may be effective monotherapy for preventing rejection and suppressing PTLD. PMID- 21693297 TI - Soluble tumor necrosis factor-like weak inducer of apoptosis plasma levels as a novel biomarker of endothelial function in prevalent orthotopic heart transplant recipients. AB - BACKGROUND: Nonrenal solid organ transplantation is now an established method of therapy with significantly improved outcome over the last years; however, an increasingly prevalent complication in this population is chronic kidney disease. Endothelial dysfunction is highly prevalent in both cardiovascular disease and chronic kidney disease. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily of cytokines. MATERIALS AND METHODS: The aim of the study was to assess TWEAK concentration in 134 prevalent heart transplant recipients in relation to kidney function. Complete blood count, urea, serum lipids, fasting glucose, creatinine, NT-proBNP were studied. Soluble TWEAK was assayed using commercially available kits from Bender MedSystems (VIenna, Austria). High-sensitivity C-reactive protein was assayed using commercially available kits from American Diagnostica (Greenwich, Conn, USA). RESULTS: Heart transplant recipients had significantly higher serum creatinine, urea, cholesterol, triglycerides, fasting glucose, white blood cell count, lower TWEAK levels and lower estimated glomerular filtration rate (eGFR) than the control group. Serum TWEAK levels fell together with New York Heart Association (NYHA) class and rise in GFR. Serum TWEAK was related to kidney function, NYHA class, NT-proBNP, and triglycerides. Kidney function and NYHA class turn out to be predictors of TWEAK in heart transplant recipients. CONCLUSION: TWEAK level is dependent on kidney and heart function. It might also represent a surrogate marker of endothelial dysfunction and atherosclerosis. PMID- 21693298 TI - Rapid decline in glomerular filtration rate during the first weeks following heart transplantation. AB - We hypothesized that a decrease in renal function is seen immediately after heart transplantation (HTX) with little recovery over time. Twelve consecutive patients had their glomerular filtration rate (GFR) measured using (51)Cr ethylenediaminetetraacetic acid (EDTA) measured GFR (mGFR) before transplantation and at 1, 2, 3, and 26 weeks after transplantation. The mGFR decreased by 28% and 24% during the first 3 and 26 weeks, respectively, with mean blood cyclosporine concentration as an independent risk factor for the decrease in mGFR. The identification of cyclosporine A (CsA) as the most important risk factor for the rapid and sustained decrease in renal function supports the need for more studies on renoprotective strategies immediately after HTX. PMID- 21693299 TI - Complications of endomyocardial biopsy in heart transplant patients: a retrospective study of 2117 consecutive procedures. AB - BACKGROUND: Endomyocardial biopsy (EMB) remains the gold standard for the diagnosis of graft rejection after heart transplantation (HT). Our purpose was to evaluate the rate of complications of this invasive procedure. METHODS: This was a retrospective study of 175 patients, who were transplanted between November 2003 and October 2010 and survived more than 1 month after surgery. We evaluated the number of inconclusive EMB and described the incidence, nature, and subsequent management of several complications associated with this procedure. RESULTS: Over a period of approximately 7 years, we performed 2217 EMB yielding 4972 specimens, namely, an average of 2.3 fragments per procedure. The majority of EMBs (95.3%) were performed by the femoral approach. Only 12 EMB (0.57%) were inconclusive. The overall complication rate was 0.71%. During puncture, one patient experienced a vasovagal reaction and another one, a femoral artery false aneurysm. During the biopsy, there was one case of cardiac perforation with tamponade, two cases of supraventricular tachycardia, and three atrioventricular conduction abnormalities. In 19 patients, histological analysis revealed chordal tissue, but only two patients developed mild tricuspid regurgitation. We observed five cases of coronary artery fistulae. The clinical outcomes were favorable in all cases. CONCLUSION: EMB proved to be a suitable, safe method to monitor rejection after HT. PMID- 21693300 TI - Correlation between the kinetics of CD3+ chimerism and the incidence of graft versus-host disease in patients undergoing allogeneic hematopoietic stem cell transplantation. AB - INTRODUCTION: Graft-versus-host disease (GvHD) remains a significant complication after allogeneic hematopoietic stem cell transplantation (HSCT). Early diagnosis and treatment may improve patient outcomes. A prospective study to investigate the relationship between chimerism kinetics and the development of acute or chronic GvHD was carried out. Split chimerism in association with the onset of GvHD was also analyzed. METHODS: Thirty-three patients with hematologic diseases treated with allogeneic HSCT were analyzed. They were conditioned with myeloablative or reduced intensity regimens and grafted with peripheral blood (PB) or bone marrow stem cells. GvHD prophylaxis consisted of cyclosporine and methotrexate. Chimerism evaluation was performed on PB mononuclear cells and purified cell subsets consisting of separated CD3(+) T cells, monocytes (CD14(+)), and granulocytes (CD15(+)). Chimerism analysis was performed at 30, 60, 120, and a median of 200 days after HSCT. RESULTS: Acute GvHD was diagnosed in 19 patients and chronic GvHD in 16. On day 30, no relation was found between the level of donor chimerism and aGvHD. Upon univariate analysis, decreasing mixed chimerism among CD3(+) and infused CD34(+) cell numbers was significantly correlated with acute GvHD development, while the PB stem cell source, reduced intensity conditioning regimen, and female donor sex were associated with an increased risk of chronic GvHD. In multivariate analysis, the risk of acute GvHD correlated only with the CD34(+) cell dose, while the risk of extensive chronic GvHD was associated with high CD3(+) donor chimerism on day 30. Patients with versus without split chimerism (T cell vs myeloid lines) did not differ statistically in their incidence of acute GvHD or chronic GvHD. CONCLUSION: Our results supported the belief that chimerism kinetics or longitudinal chimerism evaluation is of greater significance than isolated absolute values of the percentage of chimerism at a single point after HSCT. The observations suggest that longitudinal monitoring of chimerism in CD3(+) T-cell subsets is an acceptable method to predict the development of GvHD among patients undergoing HSCT. PMID- 21693301 TI - Autologous stem cell transplantation for systemic lupus erythematosus: report of efficacy and safety at 7 years of follow-up in 17 patients. AB - INTRODUCTION: We observed the efficacy and toxicity of autologous stem cell transplantation (auto-SCT) for patients with systemic lupus erythematosus (SLE). METHODS: Seventeen patients with SLE were treated with auto-SCT. No prisoners were used in the study. Peripheral blood stem cells were mobilized with cyclophosphamide (Cy) and granulocyte colony-stimulating factor. After a conditioning regimen of Cy and antithymocyte globulin, we reinfused stem cells. The probabilities of overall survival (OS) and progression-free survival (PFS) were used to assess the efficacy and adverse experiences, to detect the toxicities of the treatment. RESULTS: The median follow-up time was 89 months (range 33-110). Probabilities of 7-year OS and PFS were 82.4% +/- 9.2% and 64.7% +/- 11.6%, respectively. The principal adverse events included allergy, infection, elevation of liver enzymes, bone pain, and heart failure. Two patients died due to severe pneumonia and heart failure at 33 and 64 months after transplantation, respectively. CONCLUSIONS: Our 7-year follow-up results suggested that auto-SCT seemed beneficial for SLE patients. PMID- 21693303 TI - Dry eye disease in chronic graft-versus-host disease: results from a Spanish retrospective cohort study. AB - We describe the incidence, clinical features, and final outcome of dry eye disease (DED) associated with chronic graft-versus-host disease (GVHD) over a 5 year period. We reviewed 109 clinical charts from patients undergoing hematopoietic stem cell transplantation (HSCT) between January 2000 and December 2005, abstracting data from the 57 patients who developed chronic GVHD and survived at least 180 days after allogenic HSCT. DED occurred in 22 (40%) patients at an average of 16.5 months after HSCT. Photophobia, irritation, and foreign body sensation were the most frequent symptoms, while punctate keratitis was the most common sign. DED tended to improve over time, with fewer than 5% of patients requiring more than two topical medications at the end of follow-up. Our study represented a formal evaluation of DED incidence among Spanish chronic GVHD patients. It is of utmost importance to assure patients will undergo a comprehensive ophthalmologic evaluation throughout their follow-up. PMID- 21693302 TI - Basiliximab for the treatment of steroid-refractory acute graft-versus-host disease after unmanipulated HLA-mismatched/haploidentical hematopoietic stem cell transplantation. AB - BACKGROUND: Anti-CD(25) monoclonal antibodies (Mabs) have been evaluated for the treatment of steroid-refractory acute graft-versus-host disease (GVHD) in patients undergoing hematopoietic stem cell transplantation (HSCT) mainly with matched donors for years, but there is little attention concerning patients with unmanipulated human leukocyte antigen (HLA)-mismatched/haploidentical transplantations. We investigated the efficacy and safety of the chimeric Mab, basiliximab, to treat steroid-refractory acute GVHD after unmanipulated mismatched/haploidentical HSCT. METHODS: Fifty-three patients who developed steroid-refractory acute GVHD between July 2005 and July 2009 were treated at our institute with basiliximab. No prisoners were used in this study. RESULTS: Forty six among 53 patients responded, including 37 complete remissions at a median response of 6 days from Mab initiation. There were 29 episodes of viral reactivations, 25 bacterial infections, and 11 probable fungal infections. Thirty four out of 49 patients who could be evaluated developed chronic GVHD. Twenty eight of 53 subjects (52.8%) were alive at a median follow-up of 16 months (range, 2-57) posttransplantation. The Kaplan-Meier probability of a 3-year event free survival was 47.7%. The causes of death were infection alone (n = 15), progressive GVHD with infection (n = 3), relapse (n = 3), and other etiologies (n = 4). CONCLUSION: These data suggested that basiliximab was effective to treat steroid-refractory acute GVHD after unmanipulated HLA-mismatched/haploidentical stem cell transplantation. PMID- 21693304 TI - Early posttransplantation hemoglobin level corresponds with chronic renal dysfunction in heart transplant recipients. AB - BACKGROUND: The risk factors for moderate or severe chronic renal dysfunction (MSCRD) among heart transplant recipients may be distinct from those previously recognized owing to recently improved clinical care. METHODS: We examined the clinical records of 88 adult patients who underwent first heart transplantations from 2000 to 2005 and survived 2 years. MSCRD was defined as a glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) at 2 years after transplantation. Fifty patients were included in the MSCRD group and 38 in the non-MSCRD group. RESULTS: Loss of renal function was observed largely during the first 9 months after transplantation in the MSCRD group. The pretransplantation GFR was lower in the MSCRD group. Besides older age in the MSCRD group, there were no differences in baseline characteristics, immunosuppressive regimens, incidences of acute rejection episodes, cardiac allograft vasculopathy, or severe infections. The MSCRD group showed permanent lower posttransplantation hemoglobin levels. In multivariate logistic regression analysis, recipient age, pretransplantation GFR, postoperative intensive care unit stay and hemoglobin level at 9 month were unfavorable factors for posttransplantation MSCRD. CONCLUSIONS: In addition to recipient age and pretransplantation GFR as well established risk factors, our results suggest a prognostic value of a low early hemoglobin level for the development of chronic renal dysfunction after heart transplantation. PMID- 21693305 TI - Cytomegalovirus infection in mesenchymal stem cells and their activation could be enhanced by nuclear factor-kappaB inhibitor pyrrolidinedithiocarbamate in vitro. AB - Because of the central role of the transcription factor nuclear factor (NF) kappaB in cell survival and proliferation in many kinds of cancer cells, NF kappaB inhibitors may have a potential role in cancer therapy. Currently, many NF kappaB inhibitors are used for immunosuppression to treat hematologic malignancy patients after stem cell transplantation (SCT). Human cytomegalovirus (HCMV) infection is one of the most common complications following SCT. Some workers have reported that HCMV infection has a close relationship to NF-kappaB activation; however, the specific effects of NF-kappaB inhibitors, such as pyrrolidinedithiocarbamate (PDTC), on infection with and activation of CMV in mesenchymal stem cells (MSCs) remain unknown. In our study, we isolated MSCs from the bone marrows of healthy human donors for infection with 1 tcid(50) of HCMV with or without 1 MUmol/L PDTC. After 48 hours of culture in dmem supplemented with 10% (volume per volume) fetal calf serum, we tested MSCs using reverse transcription-polymerase chain reaction (RT-PCR) assays to detect messenger RNA (mRNA) expression of HCMV immediate early (IE) gene and the GAPDH gene. Flow cytometry was used to detect HCMV pp65 antigen-positive cells and transmission electron microscopy (TEM) for intra cellular HCMV particles. We observed that the shape of the MSCs changed in response to infection by 1 TCID(50) of HCMV. MSCs infected by 1 TCID(50) of HCMV in combination with 1 MUmol/L of PDTC changed their shapes more profoundly; almost all cells went from a thin elongated profile to a round, thick ball. In contrast, the shape of cells treated with PDTC alone or the HCMV mock-infected elements did not change. The RT-PCR assay showed that there was a bright band corresponding to HCMV IE mRNA in MSCs infected with 1 TCID(50) of HCMV in combination with 1 MUmol/L of PDTC, as compared with cells infected by only 1 TCID(50) of HCMV. The HCMV mock-infected MSCs did not express HCMV IE mRNA. Using flow cytometry, we detected more HCMV pp65 antigen-positive cells among MSCs infected with 1 TCID(50) of HCMV in combination with 1 MUmol/L of PDTC. HCMV particles were observed by TEM in the nucleus and cytoplasm of MSCs infected with HCMV. There were more HCMV particles in cells infected by HCMV in combination with PDTC. In conclusion, NF-kappaB activation may affect HCMV infection efficiency of MSCs. An NF-kappaB inhibitor increased the infection by activation of HCMV in MSCs, thus we should pay close attention to HCMV infection when we prescribe an NF-kappaB inhibitor in clinical settings. PMID- 21693306 TI - Porcine partial liver transplantation without veno-venous bypass: an effective model for small-for-size liver graft injury. AB - OBJECTIVE: Partial liver transplantation is currently gaining wider acceptance, which alleviates donor organ shortage, but also reveals the problem of small-for size (SFS) syndrome. The precise mechanism behind it remains unknown. Large animal models for SFS syndrome are being developed using veno-venous bypass (VVB), however, splenectomies have often become necessary making the models useless for clinical situations. This study establishes a clinically well simulated and effective model of SFS graft injury without VVB. METHODS: In this study, 30% and 100% of liver grafts were orthotopically transplanted to pigs in groups A (n = 12) and B (n = 5), respectively, both without VVB. Intraoperative hemodynamics and metabolic parameters were assessed consecutively. The operative survival rates were evaluated during 7 days of follow-up as well as the serum biochemical profiles, the kinesis of portal pressure gradient, and the pathological findings. RESULTS: All the recipients survived the anhepatic period except one in group A who died of irretrievable acidosis. The tolerance rate for non-VVB were 91.7% (11/12) in group A and 100% (5/5) in group B with no significant differences. The 7-day survival rate in group A was significantly less than that for group B (50% versus 100%, P < .05) with more prolonged prothrombin times, increased bilirubin and alanine aminotransferase levels, and persistantly higher values of portal pressure gradient during almost the entire follow-up period. Accordingly, the pathological findings clarified more severe microvascular impairments in group A than group B. CONCLUSION: These data suggest that the model of pigs transplanting with 30% liver grafts without VVB is safe and reproducible. The good clinical simulation on operative procedures and clinicopathological performance indicates it is a more rational model for further research on SFS syndrome. PMID- 21693307 TI - Interleukin-23 promotes natural killer T-cell production of IL-17 during rat liver transplantation. AB - INTRODUCTION: Cytokine interleukin-17 (IL-17) is a key proinflammatory mediator promoting allograft cytokine and chemokine production. In addition to Th17 cells, natural killer T (NKT) cells have also been shown to be capable of rapidly producing IL-17 after activation. METHODS: The levels of IL-17 and IL-23 of liver allografts were determined using enzyme-linked immunosorbent assay (ELISA). IL-17 positive cells in CD1d CD4+ cells of grafts were detected using flow cytometry. RESULTS: High expression of IL-17 and IL-23 was observed in liver allografts. The ratios of NKT cells were dramatically increased in the allograft group compared with that in the control group (P < .01). In vitro, blockage of IL-23 using anti IL-23 antibody can inhibit increasing expression of IL-17 (P < .01). CONCLUSION: NKT cells contribute to production of IL-17 mediated by IL-23 on a rat acute allograft rejection model of orthotopic liver transplantation (OLT). PMID- 21693308 TI - CXCR1 deficiency does not alter liver regeneration after partial hepatectomy in mice. AB - Previous studies have shown that CXC chemokines containing Glu-Leu-Arg (ELR) in their amino-terminus stimulate hepatocyte proliferation and liver regeneration after partial hepatectomy. These ELR+CXC chemokines bind to two receptors, CXCR1 and CXCR2. Previous work has shown that CXCR2 is involved in the proliferative effects of CXC chemokines. However, the function of CXCR1 during the regenerative response has not been studied. The aim of the current study was to investigate the role of CXCR1 in liver regeneration after partial hepatectomy. C57BL/6 (wild type) or CXCR1-/- mice were subjected to 70% partial hepatectomy or sham surgery and sacrificed on day 2 and 4 after operation. There were no significant differences in liver-to-body weight ratio or hepatocyte proliferation. The data suggest that CXCR1 does not mediate the proliferative effects of ELR+ CXC chemokines during liver regeneration after partial hepatectomy. PMID- 21693309 TI - Expression of glucocorticoid-induced tumor necrosis factor receptor ligand in rat graft after liver transplantation. AB - BACKGROUND: Costimulation between the glucocorticoid-induced tumor necrosis factor receptor and its ligand (GITRL) breaks immunologic tolerance induced by regulatory T cells. The purpose of this research was to examine the involvement of GITRL during rat liver transplantation, the survival of which depends on interactions between regulatory T cells and Kupffer cells (KCs). METHODS: Recipients were divided into 2 groups: The allograft group underwent orthotopic liver transplantation from male Lewis to Brown Norway (BN) rats and the isograft group, BN-to-BN liver transplantation. We evaluated 2-week survival rates, histologic changes, as well as serum and supernatant levels of tumor necrosis factor-alpha (TNF-alpha); GITRL, and TNF-alpha expressions in the graft, and GITRL expression by graft-derived KCs. RESULTS: TNF-alpha levels were increased in plasma and in the supernates of KCs during allograft transplantation compared with isograft liver transplantation (P <.05). The expressions of TNF-alpha and GITRL in liver grafts were increased during acute rejection. Furthermore, the expression of GITRL on KCs derived from allografts was increased compared with isografts (P < .05). CONCLUSION: GITRL expression on KCs may mediate acute rejection in liver transplantation. PMID- 21693310 TI - Antibody-mediated response in rat liver chronic rejection. AB - PURPOSE: The aim was to study the effect of an antibody-mediated response on rat chronic liver rejection. METHODS: Liver transplantation was performed in rats assigned to one of the 3 treatment groups: group A, Brown Norway (BN) to BN + CsA; group B, dark Agouti (DA) to BN; and group C, DA to BN + CsA. In addition to survival and histopathologic assessment, we examined donor-specific antibodies in sera and C4d staining in the transplanted liver. RESULTS: In rats with chronic rejection, high levels of IgG1 were detected from day 7, reaching peak levels at postoperative days 60-90, showing significance compared with the acute rejection (P < .05) and the syngeneic groups (P < .01). There was more C4d deposition in vessels and portal stroma of the livers from recipients displaying chronic rejection compared with recipients showing acute rejection or of syngeneic origin (P < .05). CONCLUSION: Antibody-mediated responses might play important roles in the development of chronic liver allograft rejection. PMID- 21693311 TI - Heme oxygenase-1 expression and its significance for acute rejection following kidney transplantation in rats. AB - OBJECTIVE: To analyze rejection and antiapoptotic effects of heme oxygenase-1 (HO 1) in kidney transplantations, to investigate the protective effects of endogenous HO-1 induced by hemin on acute rat kidney allograft rejection. METHODS: We selected 27 Brown-Norway rats and 27 male Lewis rats as donors and recipients, respectively, randomly dividing them into three groups: kidney transplantation alone, hemin treatment group, and cyclosporine (CsA) group (n = 18). Six recipient rats were harvested on the first, fifth, or seventh days after operation among each group to examine histopathologic changes in renal tissue, HO 1 protein expression, and acute rejection as well as to measure serum creatinine values. RESULTS: HO-1 expression in both the kidney transplantation model group and the hemin-induced groups were higher compared with the CsA group (P < .05 .01). The expression increased with the aggravation of rejection; the expression in the CsA group also increased after transplantation but was obviously lower than that of the hemin-induced group (P < .01). The rejection process was relatively mild as indenset by histopathologic examination. The serum creatinine levels among the hemin-induced group were lower compared to the kidney transplantation control group (P < .05), but higher compared to the CsA group (P < .05). CONCLUSION: HO-1 provided protection of allografts against rejection in rats, but such effects were poorer than those achieved using potent immunosuppressive agents like CsA. PMID- 21693312 TI - Tranilast prevents the progression of chronic cyclosporine nephrotoxicity through regulation of transforming growth factor beta/Smad pathways. AB - PURPOSE: Our aim was to investigate the role of tranilast in transforming growth factor (TGF) beta/Smad pathways using a rat model of chronic cyclosporine (CsA) nephrotoxicity. METHODS: Thirty Sprague-Dawley (SD) rats were equally randomized in to 5 groups for gavage treatments daily for 4 weeks: normal control (N), olive oil; CsA (25 mg/kg), (M) CsA plus low-dose tranilast group (T1; CsA 25 mg/kg and tranilast 100 mg/kg); CsA plus medium-dose tranilast group (T2; CsA 25 mg/kg and tranilast 200 mg/kg); and CsA plus high-dose tranilast group (T4; CsA 25 mg/kg and tranilast 400 mg/kg). Kidneys were harvested at the end of the fourth week. TGF-beta1 as well as Smad3 and Smad7 were detected by reverse-transcription polymerase chain reaction and immunohistochemistry. RESULTS: The administration of tranilast decreased the expression of TGF-beta1 and Smad3 by CsA-treated rats, whereas it increased both mRNA and protein levels of Smad7. Semiquantitative analysis of mRNA production revealed these treatments to markedly reduce the amount of TGF-beta1: T1: 0.8452 +/- 0.0825 vs 0.8529 +/- 0.0606 (P < .05); T2: 0.8414 +/- 0.0696 vs 0.8529 +/- 0.0606 (P < .05); T4: 0.8336 +/- 0.0592 vs 0.8529 +/- 0.0606 (P < .05). For Smad3: T1: 0.8581 +/- 0.0328 vs 0.8613 +/- 0.0542 (P < .05); T2: 0.8528 +/- 0.0599 vs 0.8613 +/- 0.0542 (P < .05); T4: 0.8436 +/- 0.0185 vs 0.8613 +/- 0.0542 (P < .05). The significantly elevated dose-dependent amounts of Smad7 were: T1: 0.9026 +/- 0.0522 vs 0.8678 +/- 0.0246, (P < .05); T2: 0.9087 +/- 0.0506 vs 0.8678 +/- 0.0246 (P < .05); T4: 0.9151 +/- 0.0793 vs 0.8678 +/- 0.0246 (P < .05). CONCLUSION: Regulation of TGF-beta/Smad pathways is one of the mechanisims by which tranilast mitigates the progression of chronic CsA nephrotoxicity in rats. PMID- 21693313 TI - Effect of CD4+ memory T cells on rejection response of ectopic heart transplantation in mice. AB - BACKGROUND: CD4(+) memory T cells mediate resistance of the body to infection by exotic pathogens. This study investigated the effects of alloreactive CD4(+) memory T cells on acute graft rejection responses toward ectopic hearts in the abdominal cavities of mice. METHODS: BALB/C mice were used as recipients and C57BL/6 mice as donors. The animals in the CD4(+) memory T-cell group were infused with CD4(+) memory T cells, those in the other group were infused with nonsensitized CD4(+) T cells, and those in the control group received no CD4(+) T cells. Heart transplantation was performed at 3 weeks after the cell infusion with cyclosporine administered beginning 1 day before transplantation via intraperitoneal injection. RESULTS: The survival among the CD4(+) memory T-cell group was significantly shorter than that of the nonsensitized CD4(+) T-cell group or the control group (P < .01; n = 10). There was no significant difference between the survival times of the nonsensitized CD4(+) T-cell group and the control group (P > .05; n = 10). On the 5th day after the transplantation of heart, the histologic grades of the nonsensitized CD4(+) T-cell and the blank control group were lower than those of the CD4(+) memory T-cell group. There was no significant difference in the histologic grades between the nonsensitized CD4(+) T-cell and control groups. CONCLUSION: The CD4(+) memory T cells that mediate acute rejection of allografted hearts are insensitive to cyclosporine. PMID- 21693314 TI - Immunoregulation effect by overexpression of heme oxygenase-1 on cardiac xenotransplantation. AB - OBJECTIVE: This study was designed to investigate the effect of the overexpression of heme oxygenase-1 (HO-1) on the immunoregulation in the model of abdominal cardiac xenotransplantation from the guinea pig to the rat. MATERIALS AND METHODS: To increase the expression of HO-1, both donors and recipients were injected with heme through the abdomen before the operation. The donors (guniea pigs) and the recipients (Sprague-Dawley [SD] rats) were divided randomly into three groups: group A, the heart from a guinea pig transplanted into the abdomen of an SD rat; group B, the recipients were injected with Chinese cobra venom factor (CVF) into the abdomen (40 MUg/kg and 60 MUg/kg 24 hours later) prior to transplantation; group C, CVF + HO-1 high-expression group: donors and recipients were abdominally injected with heme (75 MUmol/kg for 2 days before transplantation). The mean survival time (MST), pathological changes, the positive area of HO-1 in the grafted hearts, as well as the expressions of C-C chemokine receptor 5 (CCR5), intercellular adhesion molecule-1 (ICAM-1), and natural killer (NK) cell activity in recipients. RESULTS: 1. The MST was longest in group C treated with heme. 2. The pathologic changes of hyperacute rejection were showed on the donor heart in group A, while delayed xenograft rejection changes took place on donor heart in other groups. 3. Compared with group B, The HO-1 positive area in the donor hearts of group C was significantly higher. (P < .05). 4. The lever of ICAM-1 and CCR5 in the peripheral blood of recipients (pg/mL) was attenuated in group C injected with heme. 5. Compared with group B, the activity of NK cell in the peripheral blood of recipients was much lower in group C (P < .05). CONCLUSION: The MST was prolonged by increasing expressions of HO-1, but acute vascular rejection was not completely overcome. Activation of vascular endothelial cells could be decreased by strengthening the expression of HO-1. NK cell activity was weakened by reinforced expression of HO-1. PMID- 21693315 TI - The use of a prostacyclin analog, iloprost, as an adjunct to uterus preservation with histidine-tryptophan-ketoglutarate solution. AB - INTRODUCTION: Although assisted reproductive techniques have made most causes of both male and female infertility treatable, uterine factor infertility is not able to therapy. Therefore, transplantation of the uterus has been suggested as a future possible cure. Organ preservation solutions seek to reduce reperfusion injury. Since iloprost is an antioxidant with cytoprotective properties, we investigated its potential positive effects in histidine-tryptophan-ketoglutarate (HTK) solution after 4 or 24 h cold storage period of the rat uterus. METHODS: We divided 24 female Wistar-albino rats into four groups: Group 1 had the uterus tissue stored in HTK solution at 4 degrees C for 4h. Group 2, the tissue was stored in HTK solution combined with iloprost (10(-8) M) for 4h at 4 degrees C. The same procedures were repeated for 24 h for Groups 3 and 4 respectively. Tissue levels of malondialdehyde (MDA) and nitric oxide (NO), as indicators of oxidative stress were determined with histopathological evaluations. RESULTS: MDA and NO levels were compared between the group 1 vs 3; and 2 vs 4. No significant difference was observed between the groups. Cold storage for 24 h produced alterations in histological appearances that were mitigated by the addition of iloprost to HTK solution. CONCLUSION: In conclusion, addition of iloprost to HTK solution reversed the histological alterations after 24h-cold storage of the rat uterus. PMID- 21693316 TI - The effect of human fetal liver-derived mesenchymal stem cells on CD34+ hematopoietic stem cell repopulation in NOD/Shi-scid/IL-2Ra(null) mice. AB - Mesenchymal stem cells (MSCs) are progenitors that are capable of differentiating into mesenchymal tissues. They are known to support allogeneic hematopoietic stem cell transplantation by facilitating engraftment without increasing the risk of graft-versus-host disease. We optimized culture conditions for human fetal liver derived MSCs (hFL-MSCs) to investigate the role of hFL-MSCs on repopulation of hematopoietic stem cells in NOD/Shi-scid/IL-2Rgamma(null) (NOG) mice using CD34(+) hematopoietic stem cells (HSCs) derived from umbilical cord blood (UCB). FL-MSCs and CD34(+) HSCs were prepared from fetal liver and UCB, respectively. Twenty-four hours after irradiation, CD34(+) HSCs and hFL-MSCs were injected intravenously and intratibially into NOG mice. During 24 weeks posttransplantation, engraftment levels of human cells were analyzed in bone marrow, peripheral blood, and spleen of transplanted mice by flow cytometry. hFL MSCs showed a fibroblast-like morphology and immunophenotypic characteristics appropriate for MSCs. hFL-MSCs prolonged the survival of NOG mice that had been cotransplanted with UCB CD34(+) cells. Fluorescence-activated cell-sorting analysis showed that engraftment of human cells was increased by cotransplantation of hFL-MSCs. However, significant enhancement of human cell engraftment was not detected in NOG mice regardless of the number of cotransplanted MSCs. Although survival of repopulating NOG mice and engraftment of human cells were prolonged by cotransplantation of hFL-MSCs, 8.0 * 10(6) MSCs were not sufficient to increase HSC engraftment in irradiated NOG mice in vivo. PMID- 21693318 TI - Local application of rapamycin inhibits vein graft restenosis in rabbits. AB - OBJECTIVE: The aim of this study was to investigate whether local application of rapamycin reduced neointimal formation in a rabbit model of venous disease. METHODS: Each rabbit (n = 30; 2.5-3.5 kg) received a treated and a control graft. For the treated graft, 0.3 rapamycin mg was applied locally in Pluronic gel. The control graft received only the Pluronic gel. Grafts were harvested at 28 days for morphometric, immunohistochemical, and flow cytometry analysis. RESULTS: In the control group, the intimal thickness was 63.72 +/- 14.0 MUm; in treated group, it was 77.76 +/- 14.9 MUm (P < .05). Immunohistochemically, proliferation cell nuclear antigen-positive cells were present in the control group and in the treatment group but not in normal external jugular veins. The control group showed much stronger expression than the treatment group (P < .05). Flow cytometry showed, among the control group, decreased G(0)G(1)-stage cells and increased S/G(2)M-stage cells. Among the treatment group, S/G(2)M stage cells were decreased compared with the control. The progression indexes of the control and treatment groups were 29.3 +/- 7.15 and 20.1 +/- 9.48, respectively, a remarkable decrease (P < .05). Proliferating cells in the control group were apparently inhibited by rapamycin. The treatment group showed positive staining for P27(kip1), but neither the control group nor the normal external jugular veins showed positive results (P < .05). The degree of reduction in intimal thickness and inhibition of proliferating cells in the treatment group correlated with the expression of P27(kip1). CONCLUSIONS: We observed that perivascular application of rapamycin inhibited neointimal hyperplasia of vein grafts in a rabbit model, an effect that appeared to result from increased P27(kip1) expression. PMID- 21693317 TI - Nonsurgical periodontal therapy combined with laser and photodynamic therapies for periodontal disease in immunosuppressed rats. AB - BACKGROUND: Periodontal disease is often associated with systemic diseases and is characterized by destruction of the tissues supporting the teeth. Patients using immunosuppressive drugs such as tacrolimus are among those who suffer from tissue destruction. OBJECTIVE: We sought to evaluate the effects of laser and photodynamic therapies (PDT; nonsurgical) as an adjunct to scaling and rootplaning (SRP) in the treatment of corona-induced periodontitis in rats immunosuppressed with tacrolimus (Prograf). MATERIALS AND METHODS: The animals were divided into 5 groups. Each groups had 6 rats. Group I, the control group, received only saline solution throughout the study period of 42 days and did not receive periodontal treatment; group II received saline solution and SRP; group III received tacrolimus (1 mg/kg per day) and was treated with SRP; group IV animals were treated identically to group III and then administered laser treatment; and in group V, the animals were treated identically to group III and then administered PDT. RESULTS: Statistical analysis indicated decreased bone loss with the progression of time (P = .035). There was no difference between the bone loss associated with the types of treatment administered to groups I, II, and III (P > .9) or groups IV and V (P > .6). The analysis also indicated that immunosuppression was not a bone loss-determining factor. CONCLUSION: Laser and PDT therapies were effective as an adjunctive treatment to SRP in reducing bone loss caused by experimental periodontitis induced in animals being treated systemically with tacrolimus. PMID- 21693319 TI - Thalidomide attenuates graft arteriosclerosis of aortic transplant in a rat model. AB - OBJECTIVE: The purpose of the current study was to evaluate the effects of thalidomide on graft arteriosclerosis. MATERIALS AND METHODS: Male Lewis rats received abdominal aorta grafts from male Brown-Norway rats. The animals were divided into 4 groups: no treatment controls, a low-dose group that received thalidomide (50 mg/kg per day), a middle dose group that received thalidomide (100 mg/kg per day), and a high-dose group that received thalidomide (200 mg/kg per day) by daily intragastric administration. Rats were humanely killed at 60 days after surgery. The grafted aortas were analyzed by histology, immunohistochemistry, and Western blot analysis. The serum was analyzed by an enzyme-linked immunosorbent assay (ELISA). RESULTS: The neointimal thickness of the thalidomide treated aortas was significantly thinner compared with that of no treatment aortas (P < .05). Vascular endothelial growth factor (VEGF), platelet derived growth factor, and intracellular adhesian molecule (ICAM-1) protein expression in the treatment group were significantly lower than those in the control group (P < .05). Moreover, thalidomide significantly inhibited the production of VEGF and ICAM-1 in serum (P < .05). CONCLUSION: Our data suggested that thalidomide can attenuate graft arteriosclerosis so as to protect aortic grafts. PMID- 21693320 TI - Treatment of early avascular necrosis of femoral head by small intestinal submucosal matrix with peripheral blood stem cells. AB - BACKGROUND: Avascular necrosis of the femoral head (ANFH) is a highly mutilating disease. There are no effective ways to treat early femoral head ischemia. Peripheral blood stem cell (PBSC) transplantation may be superior to conventional bone marrow transplantation. Small intestinal submucosae matrix (SIS) is composed of highly conserved collagens, glycoproteins, proteoglycans, and glycoaminoglycans in their natural configuration and concentrations. When implanted in a number of microenvironments in vivo, SIS has been used to induce proliferation, remodeling, and regeneration of host tissues. This study was designed to verify the curative effects of PBSC and SIS transplantation-induced vascular regeneration to improve ischemic femoral head necrosis in rabbits. METHODS: 32 New Zealand white rabbits underwent ischemic femoral head necrosis modeling in both hindlimbs by liquid-nitrogen refrigeration. All rabbits were intraperitoneally injected with grannlocytectomy-stimulating factor (250 MUg/kg/d), except for normal control subjects injected with equivalent saline solution. After separation of peripheral blood stem cells (PBSCs), 64 femoral heads in 32 rabbits were randomly divided into 4 groups: group A, cancellous bone and peripheral blood stem cells cultured with small intestinal submucosa; group B, cancellous bone and PBSCs; group C, cancellous bone autografts; and group D, no treatment. The specimens were harvested at 4 and 8 weeks after surgery. All specimens were examined to observe angiogenesis and osteogenesis repairing the avascular necrosis of the femoral head by using gross observation, x-ray, histology, and immunohistochemical staining. RESULTS: In 4 weeks after peripheral stem cell transplantation, the standing ability and activity of the transplanted hindlimbs were improved remarkably, but there were no obvious changes in the control limbs. X-rays showed a greater density of grafts than the host bone in groups A,B, and group C was unchanged at 4 weeks. Histology revealed many osteoprogenitor cells and osteoblasts and no inflammatory cell infiltration at 4 weeks with much new bone formed at 8 weeks in group A and at 4 weeks in group B. The cancellous bone autograft was absorbed completely at 8 weeks in group C. There was little osteoid tissue formed in group D at 8 weeks. The zone of new bone formation in group A was greater than that in group B (P < .05), but there was no significant difference between groups A and C (P > .05). Immunohistochemical staining with CD31 mouse antibody showed greater amounts and zones of new blood vessels in groups A and B at 4 and 8 weeks and little evidence in group D. There was no significant difference between groups A and B (P > .05) and significant differences between groups A and B versus C and D (P < .05). CONCLUSION: Transplantation of PBSCs cultured with SIS effectively improved ischemic femoral head necrosis. PMID- 21693321 TI - Antigen-specific T-regulatory cells can extend skin graft survival time in mice. AB - This study investigated the effects of donor antigen-specific CD4(+)CD25(+) T regulatory cells (Tregs) on skin allografts in mice. An allogeneic skin transplant model was established using donor C57BL/6 or DBA and recipient BALB/c mice. Recipients were divided into 4 groups: control group without intervention (CON; C57BL/6 to BALB/c), rapamycin gavage group (RAP; C57BL/6 to BALB/c), CD4(+)CD25(+) Tregs-treated group (TRE; C57BL/6 to BALB/c), in which recipients received transfusions of CD4(+)CD25(+) Tregs stimulated with C57BL/6-derived immature dendritic cells, and the third-party donor group (DBA; DBA to BALB/c) in which recipients received transfusions of BALB/c CD4(+)CD25(+) Tregs stimulated with C57BL/6-derived immature dendritic cells. Mean (SD) survival time of the skin allografts in the TRE group was 17.0 (3.4) days, significantly longer than in the other groups: CON, 6.9 (1.9) days; RAP, 10.3 (3.0) days; and DBA, 10.8 (3.6) days. The TRE group demonstrated a significantly greater expression of transforming growth factor-beta and interleukin (IL)-10. Donor antigen-specific CD4(+)CD25(+) Tregs effectively extend skin allograft survival in mice. PMID- 21693322 TI - Recipient type-specific engineered regulatory T cells prevent graft-vs-host disease after allogeneic bone marrow transplantation in mice. AB - Adoptive transfer of regulatory T cells (Tregs), in particular, recipient-type specific Tregs (sTregs), represents a promising approach to prevent graft-vs-host disease (GvHD) after allogeneic bone marrow transplantation. The objective of this study was to investigate whether engineered sTregs could prevent GvHD after bone marrow transplantation. Lentiviral vector forkhead box P3 (Foxp3)/pXZ9 containing Foxp3-IRES-GFP fragment and its mock control pXZ9 was constructed. Lentiviruses were produced via transient 3-plasmid transfection. BALB/c CD4+CD25 T cells were infected with lentiviruses and further stimulated using anti CD3epsilon and anti-CD28 antibody (engineered irrelevant-Tregs [irTregs]) or C57BL/6 splenocytes (engineered sTregs). The expression of Tregs marks, production of cytokines, cell proliferation rate, and suppression function of Foxp3/pXZ9 infected cells were similar to natural Tregs. Irradiation BABL/c recipient were injected with C57BL/6 donor T cell-depleted bone marrow (TCD-BM) cells (1 * 10(7)) and C57BL/6 splenocytes (1 * 10(7)) together with engineered sTregs, irTregs, or natural Tregs (5 * 10(6)). Irradiated BABL/c mice received TCD-BM cells only, TCD-BM cells plus splenocytes, or splenocytes and pXZ9 transduced cells (control). Recipient survival, short-term GvHD scores, and the Th1 subpopulation were monitored. Recipients of a combination of TCD-BM cells and splenocytes developed lethal GVHD. When engineered sTregs were added, 80% of recipients survived at least 60 days after transplantation; this survival rate was much higher than in any other group. The GvHD scores between the 3 Tregs groups did not demonstrate significance. Compared with other sources of Tregs in vivo, engineered sTregs strongly suppressed Th1 cell expansion. Therefore, a an in vitro strategy was developed to generate engineered sTregs. These cells demonstrated similar phenotypes and stable suppressive capacity as natural Tregs. Like natural Tregs, co-injection of engineered Tregs protected recipients from lethal GvHD in a murine model of GvHD. The engineered sTregs were superior to irTregs in minimizing murine GvHD. PMID- 21693323 TI - Transforming growth factor-beta1 modulates lipopolysaccharide-induced cytokine/chemokine production and inhibits nuclear factor-kappaB, extracellular signal-regulated kinases and p38 activation in dendritic cells in mice. AB - Tolerogenic dendritic cells (DCs) are crucial for peripheral tolerance mediated by a variety of cytokines, including transforming growth factor-beta1 (TGF beta1). We have observed that TGF-beta1-treated DCs (TGFbeta-DCs) were resistant to the maturation stimulus of lipopolysaccharide (LPS) and that TGF-beta1 down regulated Toll-like receptor 4 (TLR4) expression on DCs. The purpose of this study was to analyze whether TGF-beta1 affected the production of cytokines/chemokines and proteins in the TLR4 signal transduction pathway following LPS stimulation. We observed that TGF-beta1 induced a significant increase in interleukin (IL)-10, impaired IL-12 secretion, and attenuated messenger RNA (mRNA) expression of chemokines CCL2, CCL3, and CXCL10 in DCs following LPS administration. We also noted that TGF-beta1 suppressed LPS-induced activation of nuclear factor (NF)-kappaB, extracellular signal-related kinases (ERK)-1/2, and p38 in DCs. Taken together, our results identified the suppressive effects of TGF-beta1 on TLR4 signal transduction, strengthening the notion that TGFbeta-DCs are a unique type of tolerogenic DC exhibiting distinct characteristics. PMID- 21693324 TI - Mycotic pseudoaneurysm of the ascending aorta after heart transplantation: case report. AB - Mycotic pseudoaneurysm of the ascending aorta is a rare but potentially life threatening complication after orthotopic heart transplantation. We present a case of a 53-year-old man who developed a mycotic pseudoaneurysm of the ascending aorta after orthotopic heart transplantation. The pseudoaneurysm was surgically resected and the ascending aorta was replaced with allograft. The Gram stain and multiple cultures of the pseudoaneurysm wall revealed that the causative microorganism was coagulase-negative Staphylococcus. To the best of our knowledge, this is the first case report that describes mycotic pseudoaneurysm owing to coagulase-negative Staphylococcus infection after heart transplantation. Although S aureus and Pseudomonas aeruginosa are common pathogens in previously published literatures describing mycotic pseudoaneurysms in heart transplant recipients, coagulase-negative Staphylococcus is aslo an important and virulent pathogen that can cause mycotic aortic pseudoaneurysm in immunosuppressed patients. Once diagnosed, aggressive surgical treatment with prudent operative strategy, appropriate postoperative antibiotic therapy and close follow-up by radiographic study are mandatory in managing patients with this potentially fatal condition. PMID- 21693325 TI - Minimally invasive resection of a right atrial mass in a cardiac transplant recipient: a case report. AB - Intracardiac thrombus formation usually occurs in the left-sided cavities of the heart, most frequently in the presence of atrial fibrillation or cardiomyopathy. We report the case of an initially unclear mass developing in the right atrium (RA) of a heart transplant recipient, which was subsequently resected via a minimally invasive surgical approach. Access via right anterior minithoracotomy using videoscopic assistance allowed for uncomplicated RA thrombectomy in the presented case, avoiding reentry sternotomy with the potential risk of cardiac injury and without aortic cross-clamping or cardioplegic arrest. The patient is doing fine with excellent graft function at the latest follow-up 4 months after minimally invasive thrombectomy and 30 months after cardiac transplantation. To the best of our knowledge, this is the first report describing minimally invasive resection of a right atrial thrombus in a heart transplant recipient. PMID- 21693326 TI - Successful lung retransplantation after extended use of extracorporeal membrane oxygenation as a bridge. AB - Redo lung transplantation remains a major clinical challenge and its indication for patients with early allograft dysfunction is difficult to determine. We report a case of potentially fatal early allograft dysfunction owing to possible acute cellular rejection after single lung transplantation in a patient who underwent redo double lung transplantation after successful use of extracorporeal membrane oxygenation as a bridge, which resulted in a successful outcome. PMID- 21693327 TI - Liver transplantation to treat suspected hepatocellular carcinoma in iron-free foci in congenital hemochromatosis: case report. AB - Hepatocellular carcinoma (HCC) commonly develops in cirrhotic or noncirrhotic livers affected by congenital hemochromatosis. In patients with congenital hemochromatosis and HCC, liver transplantation is a therapeutic option with a 5 year posttransplantation survival rate as high as 80%. Herein is reported congenital hemochromatosis in a 37-year-old man. During a routine checkup, 2 liver nodules were detected. Signal characteristics at magnetic resonance imaging indicated the presence of iron-free foci (IFF). The serum alpha-fetoprotein concentration was within the range of normal, and repeated liver biopsy did not show histomorphologic signs of malignancy but confirmed the presence of IFF in surrounding siderosis. The patient was listed for liver transplantation with match MELD (Model of End-Stage Liver Disease including exceptions) because of suspected HCC. After 173 days on the waiting list, liver transplantation was performed successfully. Histologic examination of the explanted liver confirmed 2 HCC lesions with a diameter of 0.9 cm in the exact projection as the IFF detected at magnetic resonance imaging. At 20 months of rapamycin-based immunosuppression therapy, there were no signs of HCC recurrence. This is, to our knowledge, the first report of liver transplantation performed to treat suspected HCC based on the finding of IFF in congenital hemochromatosis, with histopathologic confirmation of the diagnosis of HCC after transplantation. According to this case and the current literature, IFF in patients with congenital hemochromatosis should be considered preneoplastic lesions vulnerable to possible development of HCC. PMID- 21693328 TI - Liver transplantation is possible in some patients with liver metastasis of colon cancer. AB - Liver metastases from colorectal cancer are an absolute contraindication for liver transplantation. Aggressive therapy with liver resection and local chemotherapy in selected patients may be able to provide long-term cure. Given the risks of tumor recurrence, whether patients with post chemotherapy complications leading to liver failure should be offered transplantation is a challenging question in an era of limited organ availability. Herein we have presented 2 cases of liver transplantation performed in patients with colorectal cancer metastases treated with liver resection followed by hepatic artery infusion chemotherapy leading to development of sclerosing cholangitis and eventual liver failure. This report demonstrates that liver transplantation may be an option in selected patients with colorectal cancer liver metastases that have been well treated. PMID- 21693329 TI - The use of terlipressin for management of dynamic left ventricular outflow tract obstruction complicating orthotropic liver transplantation: a case report. AB - We describe a patient with structurally normal heart who developed hemodynamic instability during orthotropic liver transplantation caused by severe dynamic left ventricular outflow tract obstruction. Successful management of this adverse event was facilitated by the use of intravenous terlipressin. The case highlights a role for terlipressin as a selective vasopressin receptor agonist with subsequent effects on systemic vascular resistance. PMID- 21693330 TI - Neutrophilic reversible airways dysfunction after liver transplantation: a case report. AB - In the present case report we have described a 46-year-old female patient who underwent a liver transplantation in 1998 for polycystic disease and developed a syndrome of increasing dyspnea, with sputum production and a progressive decline in pulmonary function [forced expiratory volume in one second (FEV(1)) (decreased from 153% predicted to 87% predicted). Further examination revealed an impressive tree in a bud pattern with diffuse peribronchiolar infiltrates on computed axial tomographic scan of the thorax. Sputum cultures remained negative. Bronchoscopic central airway biopsy specimens showed lymphocytic bronchitis; sputum induction showed 92% neutrophils. This condition was similar to the bronchiolitis obliterans syndrome after lung transplantation, although the specific neutrophilic phenotype of bronchiolitis obliterans syndrome has recently been renamed as neutrophilic reversible allograft/airway dysfunction, based on a progressive decline in FEV(1), neutrophilic airway inflammation and its response to neomacrolides. Additional azithromycin treatment resulted in complete recovery in our patient, with normalization of FEV(1) and computed axial tomographic scan of the thorax at 3 months after initiation. This case report suggests that neutrophilic reversible allograft airway dysfunction can no longer be diagnosed only after lung transplantation. Moreover, it demonstrates that this condition is not always related to allograft rejection, but rather may be induced by non immunologic factors, which remain to be further investigated. PMID- 21693331 TI - Hepatic artery thrombosis after liver transplantation: three case reports. AB - OBJECTIVE: To explore the surgical techniques of hepatic artery reconstruction in liver transplantation (OLT) and the choice of treatment for hepatic artery thrombosis (HAT). METHODS: We analyzed hepatic artery reconstructions based on 234 cadaveric donor liver transplantations and seven living related liver transplantations from April 2003 to February 2009. Anastomosis time was compared between the groups with respect to vascular caliber. Interventional thrombolysis or early thrombectomy and hepatic artery reconstruction was implemented in three HAT cases. RESULTS: The hepatic artery anastomoses for vessels less than 3 mm in diameter (n = 78) required 33.6 +/- 21.3 minutes which were significantly greater compared with those for vessels more than 3 mm in diameter (n = 163; 19.4 +/- 7.4 minutes). Among two patients (0.83%) who developed early HAT within the first week after the operation, one was successfully treated by interventional thrombolysis, but the other required an urgent conduit between the aorta and the graft after attempted thrombolysis. Only one patient (0.41%) displayed a delayed HAT without special management, but recovered liver function upon follow-up. DISCUSSION: Early detection and proper revascularization measures can yield satisfactory results after HAT. PMID- 21693332 TI - End-stage liver cirrhosis with severe autoimmune hemolytic anemia, treated by blood type-incompatible living donor liver transplantation: a case report. AB - We present a case of successful living donor liver transplantation (LDLT) for liver cirrhosis caused by hepatitis B virus with severe autoimmune hemolytic anemia (AIHA) using an ABO-incompatible (ABOi) graft. The patient was a 47-year old woman who had a history of ruptured esophageal varices, accumulation of intractable ascites, frequent hepatic encephalopathy and severe anemia, with a hemoglobin value of approximately 3 g/dL due to AIHA. We treated the patient by LDLT using an ABOi liver graft. The treatment strategy included anti-CD20 antibody, plasma exchange and transfusion before LDLT. The patient's anemia improved after surgery; she required only 2 units of irradiated red blood cell concentrates-leukocytes reduced. The patient was discharged from the hospital on postoperative day 35. Two years after surgery, the patient still shows normal hepatic and hematological findings. The immunomodulation protocol for ABOi LDLT was effective not only to avoid humoral reactions associated with ABOi LDLT, but also those associated with AIHA. PMID- 21693333 TI - Neo-suprahepatic cava: a case report of a modified technique for domino liver transplantation. AB - Domino liver transplantation, introduced in 1997, originally consisted of a graft from a patient with familial amyloidotic polyneuropathy used as a donor for a compatible recipient, thus increasing the pool of hepatic grafts for liver transplantation. The aim of this report was to present a modification on the technique for outflow reconstruction in domino liver transplantation first proposed by Liu et al and Cescon et al. In this description we proposed a new technique that differs from the one mentioned above by performing a neo suprahepatic cava, constructed using only an iliac vein graft, facilitating the anastomosis as if it was a regular cadaveric liver transplant. PMID- 21693334 TI - Supradiaphragmatic approach for Budd-Chiari syndrome with transjugular intrahepatic portosystemic shunt stent in combination with inferior vena cava reconstruction during living donor liver transplantation: a case report. AB - Treatment of Budd-Chiari syndrome consists of medical management, surgical shunt, transjugular intrahepatic portosystemic shunt (TIPS), and liver transplantation. Liver transplantation is indicated only when other treatments have failed. A 36 year-old Japanese man underwent living-donor liver transplantation after radiologic intervention procedures. Because of the position of the TIPS stent and the damaged vascular lesion of Budd-Chiari syndrome, a supradiaphragmatic approach was employed to achieve a safe total hepatectomy. Moreover, after resection of damaged portion of the inferior vena cava (IVC), an artificial vascular graft was utilized to fill the IVC gap. The postoperative course was uneventful; no serious complications were experienced within 2 years after liver transplantation. This supradiaphragmatic IVC approach and IVC reconstruction technique emphasized the option of surgical techniques to decrease the operative risk during liver transplantation for Budd-Chiari syndrome. PMID- 21693335 TI - Eculizumab for the treatment of de novo thrombotic microangiopathy post simultaneous pancreas-kidney transplantation--a case report. AB - A 34-year-old female recipient of a simultaneous pancreas-kidney transplant presented 7 days posttransplant with acute renal allograft dysfunction, thrombocytopenia, and microangiopathic hemolytic anemia. Renal biopsy revealed acute antibody-mediated rejection (AMR) and acute thrombotic microangiopathy (TMA). Clinical and laboratory manifestations, which had only partly responded to treatment with daily plasma exchange and intravenous immunoglobulin, resolved rapidly and completely to eculizumab (Soliris, Alexion Pharmaceuticals, Inc., Cheshire, Conn), a complement factor C5 antibody. De novo posttransplant TMA is a rare and serious complication that can lead to graft loss in up to one third of cases. This is the first report of successful treatment of de novo TMA with eculizumab, which has previously shown benefit in recurrent atypical hemolytic uremic syndrome as well as in refractory acute AMR. Targeted complement inhibition offers the promise of a safe and effective therapeutic strategy in de novo TMA, especially in light of recent evidence suggesting that genetic mutations in complement regulatory proteins may predispose transplant recipients to this serious disease. PMID- 21693336 TI - A case report: hepatic posttransplant lymphoproliferative disorder in a non-liver transplant patient. AB - Posttransplant lymphoproliferative disorder (PTLD) is the most common malignancy in children after solid organ transplantation. We present a patient, who developed Epstein-Barr virus (EBV)-related PTLD in the liver after renal transplantation. A 10-year-old EBV-seronegative boy with cystinosis underwent a living related preemptive renal transplantation. He received antiviral prophylaxis with valacyclovir. At 5.5 months posttransplantation he displayed a primary EBV infection with an high fever, hepatosplenomegaly, monocytosis, and positive EBV DNA levels. Two months there after, a hypoechoic nodular 20-mm lesion in the left lobe of liver was detected on abdominal ultrasonography, performed because of anorexia and weight loss. EBV-DNA copy number was 7820 copies per milliliter. Liver biopsy showed a diffuse large B-cell lymphoma that was compatible with PTLD. We stopped all immunosupressive agents other than prednisolone. Chemotherapy consisting of two courses of cyclophosphamide, vincristine, prednisolone, and adriamycin was followed by rituximab. Within 2 months, the lesion resolved and within 18 months, he was free of disease. PMID- 21693337 TI - Single transplanted kidneys from a 90-year-old deceased donor perform acceptably at 1 year. AB - Most centers are reluctant to accept expanded criteria donors above 70 to 75 years of age. We accepted kidneys from a 90-year-old male and report the 1-year outcome. The kidneys were used as single transplants and both had immediate graft function. Recipient A was a 71-year-old male, with cold ischemia time of 4 hours 49 minutes. One rejection was successfully treated with intravenous methylprednisolone. At 1 year, serum creatinine was 146 MUmol/L with estimated glomerular filtration rate (eGFR) 41 mL/min. Recipient B was a 79-year-old male with known panel-reactive antibody positivity prior to transplantation. Cold ischemia time was 10 hours 4 minutes. He experienced no rejections. At 1 year serum-creatinine was 99 MUmol/L with eGFR 63 mL/min. Both recipients performed a surveillance biopsy at 1 year with identical findings: interstitial fibrosis and tubular atrophy grade 1 with moderate to severe arteriolosclerosis. We conclude that both kidneys performed acceptably 1 year after engraftment. The use of old kidneys in old recipients gives them a properly functioning kidney and improves quality of life. Longer observation is needed. PMID- 21693338 TI - Extracorporeal shockwave lithotripsy of ureteral stone in a patient with en bloc kidney transplantation: a case report. AB - We report a case of ureterolithiasis in a patient with an en bloc kidney transplantation, using extracorporeal shockwave lithotripsy (ESWL). The patient presented with asymptomatic macrohematuria. Computed tomography revealed a ureteral calculus just below the pyeloureteral junction with hydronephrosis of the medially positioned kidney. Took two sessions of ESWL were required for complete disintegration of the stone. At 3 years after successful treatment, the patient has an excellent functioning and stone-free graft. PMID- 21693339 TI - Successful long-term use of sitagliptin for the treatment of new-onset diabetes mellitus after solid organ transplantation: a case report. AB - AIMS: To describe 2.5 years of exposure to sitagliptin on glycemic control, immunosuppressive therapy, and adverse events following solid organ transplantation. CASE REPORT: A 63-year-old Caucasian male received an orthotopic heart transplantation in June of 2006 secondary to idiopathic nonischemic cardiomyopathy. He was diagnosed with new-onset diabetes mellitus after transplantation (NODAT). Sitagliptin monotherapy was initiated in August 2007 and continued for 2.5 years. RESULTS: Hemoglobin A(1c) increased from 5.8% to 6.1%, but the recommended glycemic target of <7% was maintained over time and improvements in fasting home blood glucose monitoring values were achieved. Tacrolimus concentrations were not altered. Only minor dose adjustments to tacrolimus and mycophenolate mofetil were required. Maintenance corticosteroid dose remained unchanged and there was no evidence of biopsy-proven acute rejection. No adverse events were reported. DISCUSSION: This case report demonstrates that long-term sitagliptin treatment for NODAT may be effective, safe, and well tolerated in solid organ transplant recipients. PMID- 21693342 TI - Single-row versus double-row rotator cuff repair: the controversy continues. PMID- 21693343 TI - Single- versus double-row rotator cuff repair: the jury is still out. PMID- 21693345 TI - Biomechanical analysis of pullout strengths of rotator cuff and glenoid anchors: 2011 update. AB - PURPOSE: To evaluate the biomechanical and design characteristics of newer suture anchors. METHODS: Suture anchors were tested in fresh porcine metaphyseal cortex and cancellous troughs by use of an established protocol. A mechanical testing machine applied tensile loads parallel to the axis of insertion at 12.5 mm/s until failure, and mean anchor failure strengths were calculated. The mode of failure was recorded. Rotator cuff anchors tested included the Doubleplay and Opus SpeedScrew (ArthroCare Sports Medicine, Sunnyvale, CA); PEEK Intraline and PEEK Zip (Stryker, San Jose, CA); Paladin, SuperRevo FT, and CrossFT (ConMed Linvatec, Largo, FL); Piton (Tornier, Warsaw, IN); Ti Screw, ALLthread PEEK, LactoScrew, ALLthread Ti, and ALLthread PEEK knotless (Biomet Sports Medicine, Warsaw, IN). Glenoid anchors included the Gryphon BR P (DePuy-Mitek, Raynham, MA) and JuggerKnot 1.4 (Biomet Sports Medicine). RESULTS: Mean cortical failure loads for cuff anchors were as follows: Doubleplay 5.0, 279 N; Doubleplay 6.5, 338 N; Opus SpeedScrew 5.5, 356 N; Opus SpeedScrew 6.5, 336 N; PEEK Intraline 5.5, 263 N; PEEK Intraline 6.5, 344 N; PEEK Zip 5.5, 435 N; PEEK Zip 6.5, 502 N; Paladin 5.0, 500 N; Paladin 6.5, 521 N; SuperRevo FT, 496 N; CrossFT, 569 N; Piton, 379 N; Ti Screw 5.0, 457 N; Ti Screw 6.5, 443 N; ALLthread PEEK 5.5, 476 N; LactoScrew 5.5, 403 N; ALLthread Ti 5.0, 526 N; ALLthread Ti 6.5, 653 N; and ALLthread PEEK knotless, 441 N). Mean cortical failure loads for glenoid anchors were 161 N for Gryphon BR P and 239 N for JuggerKnot 1.4. Mean cancellous bone failure loads for cuff anchors were Doubleplay 5.0, 263 N; Doubleplay 6.5, 340 N; Opus SpeedScrew 5.5, 356 N; Opus SpeedScrew 6.5, 344 N; PEEK Intraline 5.5, 274 N; PEEK Intraline 6.5, 327 N; PEEK Zip 5.5, 401 N; PEEK Zip 6.5, 396 N; Paladin 5.0, 427 N; Paladin 6.5, 491 N; SuperRevo FT, 483 N; CrossFT, 547 N; Piton, 365 N; Ti Screw 5.0, 420 N; Ti Screw 6.5, 448 N; ALLthread PEEK 5.5, 475 N; LactoScrew 5.5, 435 N; ALLthread Ti 5.0, 512 N; ALLthread Ti 6.5, 612 N; and ALLthread PEEK knotless, 466 N). Mean cancellous failure loads for glenoid anchors were 117 N for Gryphon BR P and 194 N for JuggerKnot 1.4. None of the anchors had pullout as the predominant failure mode. Eyelet failure was the predominant failure mode for Doubleplay, Opus SpeedScrew, PEEK Intraline, Gryphon BR P, ALLthread Ti 6.5, ALLthread PEEK 5.5, and LactoScrew. CONCLUSIONS: Failure load was not dependent on anchor location (cancellous or cortical bone) (P = .58) but was dependent on anchor type (cuff anchor or glenoid anchor) (P < .001). CLINICAL RELEVANCE: Whereas larger fully threaded screw anchors designed for rotator cuff repair showed higher failure strengths than smaller non-screw anchors designed for glenoid repairs (P < .05), the larger version of a screw anchor for a cuff repair did not provide a statistically greater failure load than the smaller screw anchor. PMID- 21693346 TI - Reducing the size of the meniscal allograft decreases the percentage of extrusion after meniscal allograft transplantation. AB - PURPOSE: The purpose was to evaluate the amount of extrusion and clinical and radiographic outcomes of meniscal allograft transplantation (MAT) after use of a modified Pollard method to measure the size of the meniscus. METHODS: We analyzed 36 patients who underwent MAT between September 2002 and June 2008. Eighteen patients had preoperative allograft sizing by the conventional Pollard sizing method, and the other 18 had the size measured by our modified method, reducing the total size of the graft by 5% from the Pollard method. The mean follow-up period was 31.4 months (range, 24 to 36 months). We compared the absolute amount of extrusion and the relative percentage of extrusion between the 2 groups. We also compared the Lysholm knee score, amount of joint space narrowing on radiographs, and Kellgren-Lawrence grade. RESULTS: The absolute amount of extrusion did not differ significantly between the 2 groups. However, the mean relative percentage of extrusion was lower in the modified Pollard group (P = .037). The mean Lysholm knee score increased in all patients, but there was no significant difference between the 2 groups. There was no significant difference in terms of radiographic outcomes. CONCLUSIONS: Reducing the graft size by 5% from the Pollard method decreases the percentage of meniscal extrusion after MAT without any adverse outcome clinically or radiographically. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 21693347 TI - Medial meniscus allograft transplantation using a modified bone plug technique: clinical, radiologic, and arthroscopic results. AB - PURPOSE: To determine clinical, radiologic, and arthroscopic results of our meniscus allograft transplantation (MAT) by use of modified bone plug technique, which permits easy passage of the allograft by reducing the size of the posterior bone plug. METHODS: From December 2004 to December 2008, 22 consecutive patients (20 men and 2 women) with a mean age of 35.9 years underwent medial MAT with the modified bone plug method. The Lysholm score and International Knee Documentation Committee subjective knee score were documented. Joint space narrowing and Kellgren-Lawrence grade changes were evaluated on radiographs, and graft healing status, arthrosis changes in cartilage, and meniscal extrusion were investigated by magnetic resonance imaging (MRI). RESULTS: The mean follow-up was 24.9 months. The mean Lysholm score improved significantly, from 68.2 to 89.7 (P = .002). The International Knee Documentation Committee subjective knee score improved significantly, from 60.3 to 85.4 (P = .003). Joint space narrowing was insignificant, and arthrosis progression was observed in 3 of 22 cases (13.6%) on radiographs. On MRI, complete healing of the grafts was observed in 18 cases (100%), 15 cases (83.3%), and 17 cases (94.4%) at the anterior root, posterior root, and meniscal rim, respectively. Mean meniscal extrusion was 4.35 +/- 1.76 mm, and arthrosis progression was observed in 4 of 18 cases (22.2%). During second-look arthroscopy, complete healing of the grafts was observed in 11 cases (100%), 9 cases (81.8%), and 10 cases (90.9%) at the anterior root, posterior root, and meniscal rim, respectively. Cartilage degeneration was advanced in 4 cases (36.4%). No significant correlations were found between meniscal extrusion and other outcomes. CONCLUSIONS: Our modified bone plug method was an effective surgical method. MRI and second-look arthroscopic examinations showed sound evidence of graft healing. Meniscal extrusion was observed in most cases but was not correlated with other clinical and radiologic outcomes. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 21693348 TI - The position of the posterolateral bundle femoral tunnel during arthroscopic double-bundle anterior cruciate ligament reconstruction: a cadaveric study. AB - PURPOSE: The purpose was to find a simple guideline to help establish accurate positioning of the posterolateral bundle (PLB) femoral bone tunnel during double bundle anterior cruciate ligament reconstruction by measuring the distance between the center of the PLB femoral footprint to the shallow and the deep articular cartilage borders of the lateral wall of the intercondylar notch. METHODS: The femoral insertions of the anteromedial bundle and PLB of the anterior cruciate ligament were dissected in 22 male cadaveric knees, aged 25 to 45 years. By use of the intercondylar notch as the landmark, the distances between the center of the PLB femoral footprint and the shallow and the deep articular cartilage borders of the lateral wall of the intercondylar notch were measured with the knees flexed at 90 degrees . The measured data (mean +/- standard deviation) were evaluated and compared. RESULTS: The center of the PLB was positioned 8.60 +/- 1.52 mm and 8.65 +/- 1.54 mm from the shallow and the deep cartilage borders of the lateral wall of the intercondylar notch, respectively (P = .95). The distance between the center of the PLB footprint to the low cartilage border of the lateral intercondylar wall was 5.05 +/- 0.76 mm. CONCLUSIONS: The findings suggest that the position of the center of the PLB femoral footprint is at the middle of the line joining the shallow and the deep borders of the femoral cartilage. CLINICAL RELEVANCE: Surgeons can use our results as a guideline and use the PLB footprint remnant as a reference at the same time to locate the femoral PLB tunnel in a simple, easy, and repeatable way. PMID- 21693349 TI - Single-row repair versus double-row repair of full-thickness rotator cuff tears. AB - PURPOSE: The purpose of this meta-analysis was to assess whether there are differences in the outcomes between single-row and double-row rotator cuff repair. METHODS: Using MEDLINE, SCOPUS, SCIRUS, CINAHL, and the Cochrane Library, as well as a hand search, we searched for articles comparing single-row and double-row rotator cuff repair that were published before September 2009. The controlled clinical studies that met the inclusion and exclusion criteria were assessed for quality of methodology. Two of the authors performed this review and assessment. Any disagreements were resolved by the third author. RESULTS: Three randomized controlled studies and two controlled clinical cohort studies were included in this meta-analysis. These studies were assessed as having a moderate to high level of evidence. The results showed that double-row repair improved tendon healing and provided greater external rotation but with significantly increased operative time. Furthermore, this study found that double-row repair decreased the recurrence rate. However, there were no statistically significant differences found in shoulder function as assessed by Constant score; American Shoulder and Elbow Surgeons (ASES) score; University of California, Los Angeles (UCLA) score; Western Ontario Rotator Cuff (WORC) index; Disabilities of the Arm, Shoulder and Hand (DASH) score; muscle strength; forward flexion; internal rotation; patient satisfaction; return to work; and adverse events. CONCLUSIONS: Despite the fact that double-row repair shows a significantly higher rate of tendon healing and greater external rotation than does single-row repair, there is no significant improvement in shoulder function, muscle strength, forward flexion, internal rotation, patient satisfaction, or return to work. LEVEL OF EVIDENCE: Level II, meta-analysis of Level I and Level II studies. PMID- 21693350 TI - Arthroscopic surgery in athletes with osteochondritis dissecans of the elbow. AB - PURPOSE: Osteochondritis dissecans (OCD) of the elbow is an avascular necrosis of the articular cartilage and underlying subchondral bone that occurs in the capitellum. The purpose of this review is to evaluate the results of arthroscopic surgery, including debridement, fragment fixation, micro-fracturing, and osteochondral autografting, in athletes with OCD of the elbow. METHODS: We searched PubMed, EMBASE, and the Cochrane library using the following main terms: osteochondritis dissecans, elbow, and surgical intervention. The 9 selected articles were criticized by use of a quality assessment tool derived from the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. RESULTS: The included studies had low methodologic quality and showed satisfactory results regarding pain, return to sports, and elbow function. CONCLUSIONS: This review suggests that surgical treatment must be contemplated after a period of unsuccessful conservative therapy for athletes with OCD. Nevertheless, larger studies with enhanced methodologic quality and longer follow up should be performed to support this conclusion. LEVEL OF EVIDENCE: Level III, systematic review of Level IV studies. PMID- 21693351 TI - Fluoroscopic demonstration of femoroacetabular impingement during hip arthroscopy. AB - Femoroacetabular impingement is a cause of hip pain that in selected cases can be treated by removal of impinging bone (osteoplasty). No absolute parameters for osteoplasty exist. We present a technique for dynamic evaluation of bony impingement and control of arthroscopic osteoplasty using intraoperative fluoroscopy. With the patient supine on a fracture table, the C-arm is positioned between the legs. Femoral anteversion is measured with the C-arm vertical and the hip flexed 90 degrees (Dunn view). The C-arm is then tilted back 25 degrees from vertical to create a profile view of the anterior rim, and the hip is flexed under fluoroscopy to find the location of maximum head/neck deformity. Because the distance between rim and neck is apparent, a spot view in that position is used to plan the osteoplasties. Impingement is demonstrated by forced internal rotation and is obvious as bony contact, movement of the pelvis, or joint subluxation. Osteoplasty of the neck is performed with the hip extended and the C arm tilted to reproduce the view of the maximum neck deformity. The dynamic examination is repeated to confirm adequacy of the osteoplasty and improvement in internal rotation. Hip deformities could be efficiently identified and individually corrected. PMID- 21693352 TI - The rarely encountered rim fracture that contributes to both femoroacetabular impingement and hip stability: a report of 2 cases of arthroscopic partial excision and internal fixation. AB - Femoroacetabular impingement (FAI) can be associated with labral ossification, acetabular rim fractures, and os acetabuli. Typically, these fragments can be completely excised as part of a femoroacetabular impingement correction procedure. In rare instances, however, larger, weight-bearing fragments contribute to pincer-type impingement, but complete removal might create structural instability or dysplasia. We report the results of 2 such cases where partial resection of a rim fracture and internal fixation of the remaining fragment were performed to correct the impingement while preserving adequate acetabular coverage. Predictable pain relief, healing of the stabilized rim fragment, and improved outcome scoring were achieved in both cases at 2-year follow-up evaluation. PMID- 21693353 TI - [Natural history and management of retroperitoneal sarcoma: Review of the literature by the Oncology committee of the French association of urology]. AB - INTRODUCTION: The objective of this article of review is to precise the natural history and rules of treatment of retroperitoneal sarcoma. These elements are sometimes ignored of the urologists. MATERIAL AND METHOD: A systematic review of the literature over the 15 last years was carried out on Medline database. RESULTS: The sarcomas of the retroperitoine are found with diagnosis delay because they don't have specific symptoms. The imagery is sometimes characteristic but only percutaneous biopsy is able to confirm the diagnosis. Retroperitoneal sarcomas are characterized by the high rate of local recurrence, which is related to the survival rate. The main prognostic factors are negative margins and grade of the tumor. The role of adjuvant radiotherapy is limited by the radio sensitivity of the abdominal viscera and the postoperative rehandlings. Today, the role of the neoadjuvant radiotherapy is in evaluation in prospective study. The effectiveness of chemotherapy is limited. CONCLUSION: Complete compartmental surgery without tumor rupture is the cornerstone of treatment. This complex surgery should be performed in a high-volume center. PMID- 21693354 TI - [Active surveillance for localized prostate cancer]. AB - Active surveillance as an alternative approach to immediate curative treatment is demonstrated for an increasing number of patients with low risk prostate cancer. Optimization of selection and surveillance criteria to guarantee a low risk issue to patients are discussed in this review. They lead to consider active surveillance as an option rather than a standard of care for patients ideally included in clinical research protocols. PMID- 21693355 TI - [Ischemic lesions in kidneys after extracorporeal shock wave lithotripsy demonstrated by Proton NMR spectroscopy of urine samples]. AB - PURPOSE: The aim of this prospective study was to investigate the effect of extracorporeal shock wave lithotripsy (SWL) on kidneys of patients with pyelic stone disease. The effects of SWL were assessed by high-resolution proton nuclear magnetic resonance (HNMR) spectroscopy of urine samples. METHODS: Twenty-three patients, aged 31-80years (mean: 55years), with pyelic stone disease were investigated before and after SWL. Multiparameter analysis was performed by HNMR spectroscopy of urine samples collected before and 5h after SWL (second miction post-SWL). RESULTS: The most relevant resonances determined by HNMR spectroscopy were acetate, lactate, trimethylamine N-oxide and amino acids. Excretion of these markers increased significantly in comparison with pre-SWL urinary samples. CONCLUSION: These results show that early ischemic damage occurs after SWL. Post SWL. HNMR spectroscopy is an effective tool for noninvasive follow-up of renal damage. PMID- 21693356 TI - [In-hospital stays for urolithiasis: analysis of French national data]. AB - INTRODUCTION: Urolithiasis is of health economics concern since it is very frequent. However, there is few data upon its issue in France. METHODS: We have analyzed the data issued from the national coding system for in-hospital stays and interventions, using urolithiasis codes and compared between public and private sectors. We have observed evolution of procedures and stays until 2009. RESULTS: Public and private sectors were quite similar in terms of stays numbers (144,324 in 2009, and an evaluated total cost of more than 168 millions of euros). Since 2000, there has been an increase of more than 20% in the number of stays in the public sector and a stagnation in the private one. Public and private sectors appeared different in terms of: (1) stays without intervention (53 vs 26%; p<0.0001); (2) stays without associated diagnosis (5.78 vs 8.41%; p<0.0001). Since 2006, there has been a stagnation for percutaneous and surgical interventions (less than 5% of the number of interventions) whereas there has been a clear increase in endoscopic (+29% in private sector and +16% in public one) and lithotriptic (+19 and +5%) interventions. CONCLUSION: There were strong disparities between public and private sectors. Endoscopic interventions and lithotrity sessions have shown a sustained increase. Surgical and percutaneous interventions have shown a stagnation. PMID- 21693357 TI - [Pelvic lymphadenectomy in prostate cancer: Should it be realized by laparoscopy?]. AB - AIM: Laparoscopic pelvic lymphadenectomy in localized prostatic cancer is performed since the 1990s, lessens the postoperative complications and respects carcinologic's principles (No. lymph nodes removed and lymph nodes metastasis). In order to verify that these objectives are achieved, we compared our results of pelvic lymphadenectomy by laparotomy and by laparoscopy for the past 12 years. PATIENTS AND METHODS: Between January 1997 and June 2008, 36 (23.8%) patients underwent open pelvic lymphadenectomy and 76.16% (115 cases) laparoscopic pelvic lymphadenectomy. We did a retrospective and comparative analysis of data including the preoperative characteristics, per- and postoperative complication as well pathologic results. RESULTS: Preoperative data were comparable between both groups. The comparison of the peroperative data showed an increased bleeding volume in the open group (105.6+/-420.9mL; 12.1+/-96.1mL: P=0.001) and longer operative time in the laparoscopic group (103.7+/-83.9min; 132.8+/-40.9min: P=0.006). Postoperative complications were similar. Pathologic results showed a significantly more important number of lymph nodes removed in the open group (7.2+/-3.5; 5.7+/-3.2: P=0.022), but the positive rate similar in both groups (13.9%; 22.6%: P=0.258). In order to remove "the learning curve effect", we compared 36 open pelvic lymphadenectomy to the last 36 laparoscopic pelvic lymphadenectomy. In the laparoscopic group the patients showed an upper Gleason score (6.3+/-1.1; 7+/-1: P=0.005); but there was no difference for the operative time, number of lymph nodes removed and the complications rates. CONCLUSIONS: After training, laparoscopic pelvic lymphadenectomy was similar to open pelvic lymphadenectomy. PMID- 21693358 TI - [Radical retropubic prostatectomy (RRP) without postoperative bladder catheter: study about 14 cases]. AB - OBJECTIVES: To report the feasibility of radical retropubic prostatectomy (RRP) without postoperative bladder catheter. MATERIAL & METHODS: We report our experience in 14 patients (mean age 62 [48-75]) who underwent radical retropubic prostatectomy for localised prostatic adenocarcinoma from May 2006 to January 2010. The surgical technique was performed as classically described, without bladder neck preservation (tennis-racket closure), with or without nerve sparing (JP). The criteria that led us not to drain were the satisfactory urethral length, a tension-free anastomosis performed on a bladder catheter with separate sutures, and a lack of anastomotic leack after bladder filling with 200cc. RESULTS: The mean hospital stay was 4 days (3-8). Ten patients (71.4%) needed intermittent bladder catherism four times (1-11) before starting micturitions, without any technical difficulties. No anastomic leack was reported. Nine patients (64.3%) were continent leaving the hospital. With a mean follow-up of 30 months (5-48), all of 14 patients (100%) were perfectly continent. No anastomotic stricture was reported. CONCLUSION: RRP without postoperative bladder catheter was feasible, with no other early or late complication associated. Early and late continence were perfect (100% at 2 years). PMID- 21693359 TI - [Double spinofixation laparoscopic versus laparoscopic robot-assisted: Morbidity, anatomical and functional short-term results]. AB - OBJECTIVE: The purpose of our study was to compare the morbidity and the short term anatomical and functional outcome of the double promontofixation according to the surgical access laparoscopic versus laparoscopic robot-assisted. METHODS: Forty-six patients were operated for anterior and posterior promontofixation with two mesh between March 2008 and February 2010, 19 were robot-assisted (PR) and 27 laparoscopic (PL). All the patients were contacted again by telephone to answer a questionnaire estimating the functional results. RESULTS: Both groups (PR vs PL) were comparable in terms of age, score ASA and of surgical histories. There was no difference in terms of hospital stay nor per- and postoperative complications. The mean operating time was significantly more important in the group PR (P=0.049). With a mean follow-up of 10,7+/-7,8 months (PL) versus 8,8+/-5,9 months (PR), the anatomical result was good without recurrence in 93,5% of the cases. The rate of recurrence was similar in both groups with three patients who had a cystocele grade 2, two in the group PR and one in the group PL (P=0.411). The urinary and sexual functional results were comparable between both groups with an improvement of the rate of dyspareunia and dysuria. However we observed more postoperative constipation in the group PR (10/19 vs 6/27, P=0.033). CONCLUSION: The robot-assisted laparoscopic promontofixation is a reproducible technique with a morbidity and anatomical and functional results comparable to the laparoscopic way. PMID- 21693360 TI - [A survey from the French Urology Association about sick leave prescriptions by 145 surgeons]. AB - OBJECTIVES: To describe and evaluate prescriptions of sick leave by urology surgeons for different kinds of interventions. METHODS: Between January and April 2006, a web-based survey was completed by urology surgeons on a voluntary basis. The analyzed data pertained to personal characteristics of the surgeons, mean duration of sick leave for 15 interventions and the type of job of the patient (strenuous or not). Analyses were performed with software SASTM version 9.2. Descriptive analyses were performed and Kruskal-Wallis test was used to search for statistically significant differences between variables (p<0,05). RESULTS: One hundred and forty-eight surgeons were involved and 145 answers could be analyzed. Mean age of the surgeons was 46,3+/-9,4years. Urology surgeons were in the public sector (n=73/140; 52%), in private practice (n=43/140; 31%) or both (n=24/140; 17%). Kruskal-Wallis test showed that all patients who had a job considered as strenuous had significantly longer sick leave prescriptions. Younger surgeons (under 40) used to prescribe shorter sick leaves than their older counterparts. CONCLUSION: Sick leave prescriptions of the urology surgeons were globally homogeneous in this survey. Only a few interventions were the occasion of discordant prescriptions depending upon the age or practice (public/private) of the surgeons. Several hypotheses could be further explored as regard the source of variation in sick leave prescriptions. These results are usable for those stakeholders who are interested in continuous medical education and evaluation. PMID- 21693361 TI - [Management and follow-up of antenatally diagnosed primary megaureters]. AB - INTRODUCTION AND OBJECTIVES: To study the diagnostic and outcome aspects of antenatally diagnosed primary megaureters and analyse the results of the postnatal medicochirurgical management. PATIENTS AND METHODS: The authors report a retrospective analysis of 12 patients been born between 1998 and 2009 with primary megaureter antenatally diagnosed between 20 and 32weeks of gestation. A postnatal radiological assessment comprising urinary tract ultrasound, DTPA or MAG3 renal scintigraphy, retrograde cystography, DMSA renal scintigraphy and intravenous urography was performed. All the patients were put under urinary antiseptic treatment and followed since the birth. RESULTS: This study comprised nine boys and three girls, all been born at term with normal trophicity. Mean age of antenatal diagnosis of hydronephrosis was 26weeks of gestation. Mean age of definitive postnatal diagnosis was ten months. Left megaureter was seen in five children, right in two cases and five patients had bilateral megaureter comprising a total of 17 renal units of which eight units were non-obstructed/non refluxing, three units were refluxing, five units were obstructed and one unit was obstructed and refluxing. Megaureter was associated to controlateral ureteropelvic junction obstruction syndrome in one patient and to ipsilateral ureteral duplicity with a superior polar kidney in another case. Renal function was less than 20% in four renal units. The mean follow-up was four years (range : 10months to 11years). Outcome was marked by urinary infections in seven cases of which four patients had non-obstructed/non-refluxing megaureter. Six patients required surgical correction, two for non-obstructed/non-refluxing megaureter complicated with urinary recurring infections, three for obstructed megaureter with severe renal functional deterioration and one patient for bilateral refluxing megaureter grade V. Two other patients required surgical treatment, one for controlateral ureteropelvic junction obstruction syndrome and the other for ipsilateral ureteral duplicity with destroyed superior polar kidney. Mean age at surgery was 22,6months (range : 6 months to 7 years). CONCLUSION: Half of our patients with antenatal diagnosis of primary megaureter required surgical correction. Urinary recurring infections, renal functional deterioration less than 20% and importance of ureteral dilatation with vesico-ureteric reflux grade V were predictive factors for surgery. PMID- 21693362 TI - [Cardiac metastasis of renal cell carcinoma, a rare location]. AB - The renal carcinoma is situated in the third rank of the urologic cancers. It is metastatic in a third of the cases, when we made the diagnosis of the cancer. Lungs, bone, the liver, the suprarenal gland and the brain stay metastatic sites of preference. Some metastatic locations are anecdotal and made the object of some publications. We report the case of a cardiac metastasis of renal carcinoma at an old patient 81 years old operated for cardiac tumor. PMID- 21693363 TI - [Diffuse xanthogranulomatous pyelonephritis in infant]. AB - We report a case of a renal mass in a 4-month boy, which occured during the assessment of a pelvi-calyceal dilatation diagnosed at 23 weeks of gestational age. There was no history of urinary infection, fever or weight loss. Physical examination revealed a mass of the left flank with significant flank tenderness. Laboratory test showed a biological inflammatory syndrome and urine culture was negative. Investigations including ultrasound and computed tomography scan were suggestive of diffuse xanthogranulomatous pyelonephritis with a non-functioning left kidney. Left total nephrectomy was performed through a lumbar incision with an extraperitoneal approach. The kidney was enlarged with a dilated pelvis containing pus upstream of a proximal ureteral atretic segment. Pathological examination of the kidney confirmed the diagnosis of diffuse xanthogranulomatous pyelonephritis. The boy remains well at 1 year follow-up. Xanthogranulomatous pyelonephritis is very rare in infants. It is an uncommon severe progressive renal infection resulting in destruction of renal parenchyma, histologically replaced by xanthomatous cells and granulomatous reaction. Pathogenesis of xanthogranulomatous pyelonephritis remains unclear. But it is well known that urinary tract obstruction and renal lithiasis are determining factors. It can occur in variant clinical forms but its symptoms remain non-specific. Curative treatment consists in nephrectomy and definitive diagnosis is made on histological examination of the kidney. This diagnosis should be discussed when a renal mass occurs in a context of malformative uropathy and xanthogranulomatous pyelonephritis have to be included in the differential diagnosis of renal mass in infants and children. PMID- 21693364 TI - [Rectal bladder: answer to the comment of Alain Ruffion]. PMID- 21693365 TI - [Obesity in childhood and adolescence: a heterogeneous disease with new pathophysiological bases]. PMID- 21693366 TI - Mechanical circulatory assistance in children. PMID- 21693367 TI - Non-adherence to aspirin in patients undergoing coronary stenting: negative impact of comorbid conditions and implications for clinical management. AB - BACKGROUND: Premature discontinuation of and reduced adherence to antiplatelet therapy have been identified as major risk factors for stent thrombosis and poor prognosis after acute coronary syndrome. AIM: We aimed to identify correlates of non-adherence to aspirin among patients who had undergone coronary stenting. METHODS: We prospectively included all patients who had undergone coronary stenting in our institution. Response to aspirin was assessed during the hospital phase with arachidonic acid-induced platelet aggregation (AA-Ag) and only good responders to aspirin (AA-Ag<30%) were included in the study for longitudinal assessment (n=308). Response to aspirin was reassessed 1 month after hospital discharge and non-responders received a directly observed intake of aspirin to exclude any biological non-response due to bioavailability problems. After excluding patients with such problems, response to aspirin based on platelet function testing was used to estimate non-adherence to aspirin after coronary stenting. A logistic regression model was used to identify predictors of non adherence. RESULTS: Non-adherence to aspirin concerned 14% of the study sample (n=43). After adjustment for age, those who reported the highest risk of non adherence to aspirin were migrants (odds ratio [95% confidence interval], 8.3 [3.5-19.8], followed by patients receiving treatment for diabetes (4.5 [1.9 10.9]). Smokers had a threefold risk of non-adherence (3.1 [1.4-6.9]). CONCLUSIONS: Non-adherence to aspirin is relatively frequent in populations at high risk of cardiovascular events. Appropriate case management and special interventions targeting these groups need to be implemented to avoid fatal events and assure long-term adherence to treatment. PMID- 21693368 TI - Protective effects of salvianolate on microvascular flow in a porcine model of myocardial ischaemia and reperfusion. AB - BACKGROUND: Microvascular reflow is crucial for myocyte survival during ischaemia/reperfusion injury. AIMS: We aimed to assess if salvianolate, a highly purified aqueous extract from Radix salviae miltiorrhizae, could improve impaired microvascular reflow induced by ischaemia/reperfusion injury, using a porcine closed-chest model. METHODS: Left anterior descending coronary artery ligation was created by balloon occlusion for 2 h followed by reperfusion for 14 days. Salvianolate was administrated intravenously for 7 days at low dose (5 mg/kg/day), high dose (10 mg/kg/day) or high dose combined with one 20 mg intracoronary bolus injection just at the beginning of reperfusion. Control-group animals were only given the same volume of saline. RESULTS: After 14 days of reperfusion, animals treated with high-dose salvianolate showed improved myocardial perfusion assessed by real-time myocardial contrast echocardiography and coloured microspheres. The beneficial effect was further supported by increased capillary density and decreased infarct size. All these effects eventually resulted in well-preserved cardiac function detected by echocardiography. Moreover, we also demonstrated that salvianolate administration was associated with elevated superoxide dismutase activity, thioredoxin activity and glutathione concentration, and reduced malondialdehyde concentration, which, in turn, resulted in a significant decrease in terminal deoxynucleotide transferase-mediated dUTP nick end labelling-positive cells and an increased ratio of Bcl-2 to Bax expression. CONCLUSION: Intravenous salvianolate at a dose of 10 mg/kg/day for 7 days had significant beneficial effects on myocardial microvascular reflow, which were associated with decreased oxidative stress and apoptosis. PMID- 21693369 TI - Cardiac implantable devices: surveillance of surgical site infections and assessment of professional practices. AB - BACKGROUND: A programme for quality assurance and prevention of infection risk during implantation of cardiac medical devices (pacemakers and defibrillators) was set up in our hospital. AIM: We sought to assess surgical site infection rate and compliance with infection-control practices (principally antibiotic prophylaxis). METHODS: Surgical site infections associated with implanted medical devices were monitored in patients during a 6-month period and a 1-year follow up. Professional practices concerning the use of prophylactic antibiotics in surgery were assessed. RESULTS: The surgical site infection rate was 2.3%. Overall compliance was 45% for the use of antibiotic prophylaxis. CONCLUSIONS: Optimal compliance with antibiotic prophylaxis was not reached in the present series, which demonstrated a surgical site infection rate of 2.3%. More effort must be made to achieve full compliance with preventive measures in the implantation of medical devices. PMID- 21693370 TI - Implantation and patient profiles for pacemakers and cardioverter-defibrillators in France (2008-2009). AB - BACKGROUND: An ageing population and the extension of indications will in all probability result in an increasing number of cardiac device implantations. METHODS: Patients implanted in 2008 and 2009 were identified by means of the French National Hospital Discharge database to establish the implantation rate and the National Health Insurance (NHI) Information System database for patient profiles (76% of the population). RESULTS: Of the 64,306 pacemaker implantations (1003.7 per million inhabitants [pmi]) in 2009, 21.4% were single chamber, 75.4% double chamber and 3.2% triple chamber (CRT-P). Of the 9028 cardioverter defibrillator implantations (140.8 pmi) in 2009, 30.1% were single chamber, 27.5% double chamber and 42.5% triple chamber (CRT-D), accounting for 65% of cardiac resynchronization therapy (CRT) implants. Among NHI beneficiaries, 58.6% of cardioverter-defibrillators were implanted for primary prevention. Between 2008 and 2009, CRT-P implantations increased by 8.8% and CRT-D implantations by 29.3%. Regional variations in implantation rates were observed regarding single-chamber pacemakers (15-33%) and CRT-D among CRT (46.2-73.8%). Pacemaker implantations cost ?158.4 million overall, 4.5% of which was for CRT-P; cardioverter defibrillator implantations cost ?96 million, 49% of which was for CRT-D. For NHI beneficiaries, 11.9% of CRT-P patients and 6.5% of CRT-D patients already had a device of the same type implanted in the 3 preceding years. CONCLUSION: The results confirm the increase in cardioverter-defibrillator implantations in France. The implantation rate remains lower than that in the USA but falls within the European average. Reasons behind significant regional variations in implantation rates need further study. PMID- 21693371 TI - How to calculate left ventricular mass in routine practice? An echocardiographic versus cardiac magnetic resonance study. AB - BACKGROUND: An accurate assessment of left ventricular (LV) mass is important for the detection of LV hypertrophy. AIMS: To assess the accuracy of four echocardiographic imaging modalities for assessing LV mass compared with cardiac magnetic resonance (CMR). METHODS: We prospectively studied 40 consecutive patients, who underwent an echocardiographic examination using four imaging modalities (M-mode fundamental imaging [FI], M-mode harmonic imaging [HI], two dimensional [2D] FI and 2D HI) and CMR (our gold standard for LV mass measurement). All echocardiographic measurements were performed by two independent observers. RESULTS: All echocardiographic modes significantly overestimated LV mass compared with CMR (P<=0.04), except 2D FI (P=0.25). This overestimation was significantly higher with HI (up to 15.5%) compared with FI (up to 5.7%; P<=0.04). Significant correlations were observed between the different echocardiographic methods and the two observers. The interobserver agreement over LV mass measurement was lower with FI (intraclass coefficient [ICC] range, 0.66-0.73) than with HI (ICC range, 0.72-0.82), and the best agreement was obtained with 2D HI (ICC, 0.82). Good agreement between CMR and all echocardiographic methods was observed among the smallest LV diameters (ICC range, 0.62-0.85), but not among the largest LV diameters (ICC range, 0-0.22). CONCLUSIONS: HI overestimates LV mass compared with FI and CMR; this leads to overestimation of prevalence of LV hypertrophy in a population of hypertensive patients. HI improves interobserver reproducibility of LV mass measurement compared with FI, leading to a significant decrease in the number of patients required for clinical trials evaluating LV mass regression. Accuracy of LV mass measurement by echocardiography is affected by LV geometry. PMID- 21693372 TI - Evaluating periodontal risk for patients at risk of or suffering from atherosclerosis: recent biological hypotheses and therapeutic consequences. AB - Cardiovascular disease, such as atherosclerosis, is the main cause of mortality in developed countries. Most atherosclerosis risk factors have been identified and are treated, improving patient cardiovascular status and reducing mortality, but some remain unknown. Periodontal disease is generally defined as inflammatory disease initiated by accumulation of dental bacterial plaque, leading to the destruction of tissues that support the teeth. Severe forms have a high prevalence (15% of the population) and are associated with the presence of virulent pathogens such as Porphyromonas gingivalis. Epidemiological studies have shown that severe periodontal disease negatively influences cardiovascular status. The aim of this paper was to present a synthesis of the most recent biological data related to the link between periodontal and cardiovascular disease. The potential biological mechanisms involved in these two inflammatory diseases (bacteriological theory, inflammatory theory, immune theory) were developed. According to the observed positive effects of periodontal treatment on systemic conditions, the benefit of a reinforced collaboration between dentists and cardiologists was discussed, especially for patients at risk for cardiovascular disease. PMID- 21693373 TI - Left ventricular outflow tract parasystole. PMID- 21693374 TI - Double-orifice mitral valve assessed by two- and three-dimensional echocardiography in a newborn. PMID- 21693375 TI - Coexisting renal artery aneurysm and adrenal adenoma in resistant hypertension. PMID- 21693376 TI - Isolated cleft of the posterior mitral valve leaflet assessed by real-time 3D echocardiography. PMID- 21693377 TI - Interaction of right- and left-edge prosodic boundaries in syntactic parsing. AB - This electrophysiological study investigated how right- and left-edge prosodic boundary tones interact in the processing of syntactic structure. Swedish sentences of the type 'Peter hit Larry(NP2) and Jason(NP3) fell/hard...' were used. A verb ('fell') requires a clause boundary between NP2 and NP3, whereas an adverb ('hard') implies continuation of the first clause, which incorporates NP3 as a coordinated object. The effects of right-edge prosody associated with NP2 and left-edge prosody associated with NP3 were tested. Results suggest interaction between prosodic right- and left-edge boundary cues both at the earliest stages of processing the left-edge boundary tone on NP3 and at the immediately following word category distinction. Right-edge boundary tones on NP2 yielded an early positive deflection (P200) and a later positivity (CPS). Left edge tones on NP3 showed a P200 effect only if preceded by a right-edge boundary on NP2. In the absence of a prosodic right-edge boundary, left-edge tones instead yielded an early negativity (N100), suggesting that they were unexpected. At the following word category distinction point, adverbs, showing continuation of the first clause, produced an anterior negativity when preceded by both right- and left-edge prosodic boundaries. The negativity is thought to reflect detection of a syntactically incorrect word category. Syntactically un-preferred constructions with an adverb following NP3 received generally lower acceptability ratings and gave rise to a P600 effect in all conditions. Syntactically preferred constructions with verbs following NP3 showed a similar P600 only when not preceded by either right- or left-edge boundary tones. PMID- 21693379 TI - The battle of the sexes: women win out in gastrointestinal surgery. AB - BACKGROUND: Women have been shown to have worse outcomes compared with men after cardiac surgery, but fare better after traumatic injury. No study considers the impact of gender on outcomes after major gastrointestinal surgery. We hypothesize that the physiologic insults of a major abdominal operation are similar to an injury model; therefore, women will have improved outcomes. MATERIAL AND METHODS: We performed a retrospective review of the NIS database from 1998 to 2007. Patients undergoing major gastrointestinal surgery were identified by ICD-9 procedure codes: esophageal (42.4), gastric (43.5-43.9), small intestine (45.6), large intestine (45.7-45.8 and 17.3), rectal (48.4-48.6), hepatic (50.2-50.3), biliary (51.3 and 51.6), and pancreatic (52.5-52.7). Exclusion criteria included age over 60 y and under 18 y, multiple operations, and a sexual developmental disorder (25.52, 75.27, and 25.9). The primary outcome measure was in-hospital death. RESULTS: A total of 307,124 patients were identified, of whom 50.3% were women. Overall, there were 6574 (2.14%) deaths; 2.45% of men and 1.84% of women died (P < 0.001). In multivariate analysis, women were 21.1% less likely to die than men (OR = 0.789, 95% CI = 0.74-0.84). When subset analysis was performed, women had improved mortality in the following types of surgery: gastric (OR = 0.751, 95% CI = 0.60-0.94), small intestine (OR = 0.704, 95% CI = 0.63-0.79), large intestine (OR = 0.845, 95% CI = 0.77--0.93), hepatic (OR = 0.562, 95% CI = 0.41-0.77), and pancreatic (OR = 0.658, 95% CI = 0.49-0.89, see Fig. 1). CONCLUSIONS: Our study demonstrates that women may have improved outcomes after some types of major gastrointestinal surgery; however, the mechanism by which this occurs is unclear. Future studies are needed to further evaluate this interesting phenomenon. PMID- 21693378 TI - Using Uniject to increase the use of prophylactic oxytocin for management of the third stage of labor in Latin America. AB - OBJECTIVE: To evaluate a multifaceted intervention for effectiveness in increasing the use of prophylactic oxytocin by birth attendants (obstetricians, midwives, and nurses) working in small maternity hospitals in Argentina. METHODS: A before-and-after quasi-experimental study was conducted in 5 small maternity hospitals. The study intervention consisted of training birth attendants in the active management of the third stage of labor, distributing oxytocin in Uniject (Hipofisina BIOL Uniject; Laboratorios BIOL, Buenos Aires, Argentina), and using posters as reminders. The primary outcome was the rate of prophylactic oxytocin use in the 6 months before and the 6 months of the intervention period. Secondary outcomes included use of controlled cord traction and uterine massage, and birth attendants' acceptance of the use of oxytocin in Uniject. RESULTS: The use of prophylactic oxytocin showed a median rate of 14.6% at baseline and 85.6% during the intervention period. 96% of birth attendants reported that the Uniject device facilitated oxytocin 1 administration. DISCUSSION: Prophylactic oxytocin in the third stage of labor is a beneficial intervention with current low use, particularly in low- and middle-income countries. If the results shown in the present study were further replicated, this strategy could be an effective method for improving prophylactic oxytocin use in other similar Latin American hospitals. PMID- 21693380 TI - Degradation of pharmaceutical beta-blockers by electrochemical advanced oxidation processes using a flow plant with a solar compound parabolic collector. AB - The degradation of the beta-blockers atenolol, metoprolol tartrate and propranolol hydrochloride was studied by electro-Fenton (EF) and solar photoelectro-Fenton (SPEF). Solutions of 10 L of 100 mg L-1 of total organic carbon of each drug in 0.1 M Na2SO4 with 0.5 mM Fe2+ of pH 3.0 were treated in a recirculation flow plant with an electrochemical reactor coupled with a solar compound parabolic collector. Single Pt/carbon felt (CF) and boron-doped diamond (BDD)/air-diffusion electrode (ADE) cells and combined Pt/ADE-Pt/CF and BDD/ADE Pt/CF cells were used. SPEF treatments were more potent with the latter cell, yielding 95-97% mineralization with 100% of maximum current efficiency and energy consumptions of about 0.250 kWh g TOC-1. However, the Pt/ADE-Pt/CF cell gave much lower energy consumptions of about 0.080 kWh g TOC-1 with slightly lower mineralization of 88-93%, then being more useful for its possible application at industrial level. The EF method led to a poorer mineralization and was more potent using the combined cells by the additional production of hydroxyl radicals (*OH) from Fenton's reaction from the fast Fe2+ regeneration at the CF cathode. Organics were also more rapidly destroyed at BDD than at Pt anode. The decay kinetics of beta-blockers always followed a pseudo first-order reaction, although in SPEF, it was accelerated by the additional production of *OH from the action of UV light of solar irradiation. Aromatic intermediates were also destroyed by hydroxyl radicals. Ultimate carboxylic acids like oxalic and oxamic remained in the treated solutions by EF, but their Fe(III) complexes were photolyzed by solar irradiation in SPEF, thus explaining its higher oxidation power. NO3- was the predominant inorganic ion lost in EF, whereas the SPEF process favored the production of NH4+ ion and volatile N-derivatives. PMID- 21693381 TI - Increased circulating levels of basement-membrane components in patients with abdominal aortic aneurysms--a pilot study. AB - AIM: The decision for abdominal aortic aneurysm (AAA) repair is based on aneurysm size. However, smaller aneurysms can rupture, while larger ones can remain stable. New variables and markers are needed to better select patients at high rupture risk. The study was done to analyse if AAA patients have increased levels of circulating basement-membrane (BM) fragments. DESIGN: Circulating levels of BM components type IV and XVIII collagen were measured by enzyme-linked immunosorbent assay (ELISA) in 10 patients with AAA, nine patients with peripheral artery disease (PAD) and 10 healthy controls (CON). RESULTS: AAA patients had significantly increased levels of type IV and XVIII collagen compared with CON (134.0 +/- 24.8 ng ml(-1) vs. 104.5 +/- 16.4 ng ml(-1); p = 0.005 and 149.0 +/- 56.9 ng ml(-1) vs. 59.6 +/- 8.7 ng ml(-1); p < 0.001, respectively). The PAD patients did not have significantly increased levels of these fragments when compared with CON. In addition, the AAA patients had significantly increased level of type XVIII collagen (149.0 +/- 56.9 ng ml(-1) vs. 58.3 +/- 25.4 ng/ml(-1); p < 0.01) when compared with the PAD group. CONCLUSION: Based on this preliminary analysis of a small number of subjects, patients with AAA had significantly increased levels of circulating BM components. BM fragments should be studied further to establish their potential role as biomarkers for AAA. PMID- 21693382 TI - Local anaesthesia for endovascular repair of infrarenal aortic aneurysms. AB - OBJECTIVE: The study aimed to analyse and report the results of a 'local anaesthesia first' approach in elective endovascular aneurysm repair (EVAR) patients. MATERIAL AND METHODS: Between January 2007 and August 2010, a total of 217 continuous patients (187 men, median age 76 years, range 52-94 years) underwent elective EVAR using this approach, with predefined exclusion criteria for local anaesthesia (LA). A retrospective analysis regarding technical feasibility, mortality, complication and endoleak rate was performed. The results are reported as an observational study. RESULTS: LA was applied in 183 patients (84%), regional anaesthesia (RA) in nine patients (4%) and general anaesthesia (GA) in 25 patients (12%). Anaesthetic conversion from LA to GA was necessary in 14 patients (7.6%). Airway obstruction (n = 4) and persistent coughing (n = 3) were the most common causes for conversion to GA. Thirty-day mortality in the LA group was 2.7%, with 16/183 patients (8.7%) experiencing postoperative complications. All type I endoleaks (n = 5, 2.7%) occurred in patients with LA and challenging aneurysm morphologies. CONCLUSIONS: A 'local anaesthesia first' strategy can successfully be applied in 75% of patients undergoing EVAR. The use of LA can impact imaging quality and thus precise endograft placement, which should be considered in patients with challenging aneurysm morphologies. PMID- 21693383 TI - Comments regarding 'Limb salvage using bypass to perigeniculate arteries'. PMID- 21693384 TI - Simvastatin exerts favourable effects on neointimal formation in a mouse model of vein graft. AB - BACKGROUND: Simvastatin inhibits human saphenous vein neointima formation in human saphenous vein organ cultures. However, it is not known if simvastatin actually inhibits vein graft intima hyperplasia in vivo, and the underlying mechanisms behind that. In this study, we used a murine vein graft model to address these issues. METHODS AND RESULTS: Vein grafting was performed among C57BL/6 J mice treated with low-dose (2 mg kg(-1)) or high-dose (20 mg kg(-1)) simvastatin or vehicle subcutaneously 72 h before and then daily after surgery. As compared to the vehicle, simvastatin dose-dependently significantly inhibited vein graft intima hyperplasia 4 weeks after surgeries. Immunohistochemistry studies suggested that vein graft neointima was mainly composed of vascular smooth muscle cells (VSMCs), and the rate of proliferating cell nuclear antigen (PCNA)-positive cells in the intima of vein grafts was significantly lower in simvastatin-treated groups than in control group. We isolated VSMC from mouse vena cava, simvastatin significantly reduced VSMC proliferation, and platelet derived growth factor (PDGF)-induced VSMC migration in a dose-dependent manner. CONCLUSION: Simvastatin inhibits neointima formation of mouse vein graft under normocholesterolaemic condition in vivo, the mechanisms might be associated with inhibitory effects of simvastatin on VSMC proliferation and migration. PMID- 21693385 TI - Repair of ruptured abdominal aortic aneurysm in octogenarians. AB - OBJECTIVE: To determine whether advanced age was independently associated with prohibitive surgical risks or impaired long-term prognosis after ruptured aortic aneurysm repair. DESIGN: Post-hoc analysis of prospective cohort. MATERIALS: Consecutive patients undergoing ruptured aneurysm repair between January 2001 and December 2010 at a tertiary referral centre. METHODS: Surgical mortality (i.e., <30 days) was compared between octogenarians and younger patients using logistic regression modelling to adjust for suspected confounders and to identify prognostic factors. Long-term survival was compared with matched national populations. RESULTS: Sixty of 248 involved patients were octogenarians (24%) and almost all were offered open repair (n = 237). Surgical mortality of octogenarians was 26.7% (adjusted odds ratio (OR) 2.1; 95% confidence interval (CI), 0.9-5.2) and confounded by cardiac disease. Hypovolaemic shock predicted perioperative death of octogenarians best (OR 5.1; 95%CI, 1.1-23.4; P = 0.037). After successful repair, annual mortality of octogenarians averaged 13.7% vs. 5.2% for younger patients. At 2 years, octogenarian survival was at 94% of the expected 'normal' survival in the general population (vs. 96% for younger patients). CONCLUSIONS: Surgical mortality of ruptured aneurysm repair was not independently related to advanced age but mainly driven by cardiac disease and manifest hypovolaemic shock. An almost normal long-term prognosis of aged patients after successful repair justifies even attempts of open repair, particularly in carefully selected patients. PMID- 21693386 TI - Special section on Grand Challenges in Neuroengineering. PMID- 21693387 TI - Ramp-preserving denoising for conductivity image reconstruction in magnetic resonance electrical impedance tomography. AB - In magnetic resonance electrical impedance tomography, among several conductivity image reconstruction algorithms, the harmonic B(z) algorithm has been successfully applied to B(z) data from phantoms and animals. The algorithm is, however, sensitive to measurement noise in B(z) data. Especially, in in vivo animal and human experiments where injection current amplitudes are limited within a few milliampere at most, measured B(z) data tend to have a low SNR. In addition, magnetic resonance (MR) signal void in outer layers of bones and gas filled organs, for example, produces salt-pepper noise in the MR phase and, consequently, B(z) images. The B(z) images typically present areas of sloped transitions, which can be assimilated to ramps. Conductivity contrasts change ramp slopes in B(z) images and it is critical to preserve positions of those ramps to correctly recover edges in conductivity images. In this paper, we propose a ramp-preserving denoising method utilizing a structure tensor. Using an eigenvalue analysis, we identified local regions of salt-pepper noise. Outside the identified local regions, we applied an anisotropic smoothing to reduce noise while preserving their ramp structures. Inside the local regions of salt-pepper noise, we used an isotropic smoothing. After validating the proposed denoising method through numerical simulations, we applied it to in vivo animal imaging experiments. Both numerical simulation and experimental results show significant improvements in the quality of reconstructed conductivity images. PMID- 21693388 TI - Automated segmentation of the lumbar pedicle in CT images for spinal fusion surgery. AB - Exact information about the shape of a lumbar pedicle can increase operation accuracy and safety during computer-aided spinal fusion surgery, which requires extreme caution on the part of the surgeon, due to the complexity and delicacy of the procedure. In this paper, a robust framework for segmenting the lumbar pedicle in computed tomography (CT) images is presented. The framework that has been designed takes a CT image, which includes the lumbar pedicle as input, and provides the segmented lumbar pedicle in the form of 3-D voxel sets. This multistep approach begins with 2-D dynamic thresholding using local optimal thresholds, followed by procedures to recover the spine geometry in a high curvature environment. A subsequent canal reference determination using proposed thinning-based integrated cost is then performed. Based on the obtained segmented vertebra and canal reference, the edge of the spinal pedicle is segmented. This framework has been tested on 84 lumbar vertebrae of 19 patients requiring spinal fusion. It was successfully applied, resulting in an average success rate of 93.22 % and a final mean error of 0.14 +/- 0.05 mm. Precision errors were smaller than 1 % for spine pedicle volumes. Intra- and interoperator precision errors were not significantly different. PMID- 21693389 TI - About the stability of phase shifts between slow oscillations around 0.1 Hz in cardiovascular and cerebral systems. AB - One important feature of the baroreflex loop is its strong preference for oscillations around 0.1 Hz. In this study, we investigated heart rate intervals, arterial blood pressure (BP), and prefrontal oxyhemoglobin changes during 5 min rest and during brisk finger movements in 19 healthy subjects. We analyzed the phase coupling around 0.1 Hz between cardiovascular and (de)oxyhemoglobin oscillations, using the cross-spectral method. The analyses revealed phase shifts for slow oscillations in BP and heart rate intervals between -10 degrees and 118 degrees (BP always leading). These phase shifts increased significantly (p<0.01) in the movement session. The coupling between cardiovascular and oxyhemoglobin oscillations was less clear. Only 12 subjects demonstrated a phase coupling (COH(2) >= 0.5) between oxyhemoglobin and BP oscillations. This may be explained by an overwhelming proportion of nonlinearity in cardiovascular and hemodynamic systems. The phase shifts between slow cardiovascular and hemodynamic oscillations are relatively stable subject-specific biometric features and could be of interest for person identification in addition to other biometric data. Slow BP-coupled oscillations in prefrontal oxyhemoglobin changes can seriously impair the detection of mentally induced hemodynamic changes in an optical brain computer interface, a novel nonmuscular communication system. PMID- 21693390 TI - Directional acoustic underwater thruster. AB - This study describes a tested prototype for a controllable directional underwater thruster with no moving parts. During operation, a high-intensity acoustic wave creates directional water jets and the device moves itself in the opposite direction. When the underwater thruster moves along a non-vertical angle, it can produce straight backward thrust of 2.3 mN and lateral thrust of 0.6 mN in parallel with the device surface, with a total thrust-to-weight ratio of 2:1. To enhance the acoustic streaming effect, a self-focusing acoustic transducer (SFAT) with air reflectors is used to focus the acoustic wave. PMID- 21693391 TI - Linear electro-optic properties of orthorhombic PZN-8%PT single crystal. AB - The optical transmittance spectra of relaxor ferroelectric 0.92Pb(Zn(1/3)Nb(2/3))O(3)-0.08PbTiO(3) (PZN-8%PT) single crystals poled along different directions have been systematically studied at room temperature. After being poled along the [011] direction, the transmittance of induced orthorhombic PZN-8%PT single crystal is more than 50% from 0.5 to 5.7 MUm, which is much higher than that poled along the [001] and [111] directions. The refractive indices and linear electro-optic properties of the orthorhombic PZN-8%PT single crystal were characterized at a wavelength of 632.8 nm. Large electro-optic responses were observed, (gamma33) = 220 pm/V, (gamma13) = 62 pm/V, and (gamma23) = 23 pm/V. Thus, orthorhombic PZN-8%PT single crystal is a promising material for high-performance electro-optic devices. PMID- 21693392 TI - Passive elastography: shear-wave tomography from physiological-noise correlation in soft tissues. AB - Inspired by seismic-noise correlation and time reversal, a shear-wave tomography of soft tissues using an ultrafast ultrasonic scanner is presented here. Free from the need for controlled shear-wave sources, this passive elastography is based on Green's function retrieval and takes advantage of the permanent physiological noise of the human body. PMID- 21693393 TI - Full tensorial elastic, piezoelectric, and dielectric properties characterization of [011]-poled PZN-9%PT single crystal. AB - Transverse piezoelectric property of 0.91Pb(Zn(1/3)Nb(2/3))O(3)-0.09PbTiO(3) (PZN 9%PT) single crystal poled along [011] direction under different fields have been investigated, the poling field giving the best property was between 350 and 650 V/mm at room temperature. Full tensorial elastic, dielectric, and piezoelectric properties of PZN-9%PT single crystal poled along the [011] direction under 500 V/mm have been determined by resonance and ultrasonic methods. It was found that the electromechanical coupling coefficients k(32) and k(33) can reach 0.90 and 0.89 and the piezoelectric coefficients d(32) and d(15) are -1705 and 2012 pC/N, respectively. This complete set of physical properties can provide convenience for piezoelectric device fabrication and domain engineering studies. PMID- 21693394 TI - Precipitation phenomena in and electrical resistivity of high-temperature treated langatate (La3Ta0.5Ga5.5O14). AB - La(3)Ta(0.5)Ga(5.5)O(14) (LTG) single crystals, which have no phase transition up to the melting point, were heat-treated in air at temperatures from 1000 degrees C to 1450 degrees C for 10 h. LaTaO(4) (LT) and LaGaO(3) (LG), which coexist with LTG in the three-phase region on the Ga-poor side, precipitated on the surface of the crystal for heat treatments above 1300 degrees C because of Ga evaporation during the heat treatment. The Ga-poor state near the surface of the 1450 degrees C heat-treated specimen was confirmed by electron probe micro-analysis measurements. The electrical resistivity of LTG single crystals decreased by heat treatment in the range of 1000 degrees C to 1200 degrees C for 10 h in air, where no precipitation was observed, whereas the resistivity increased with heat treatment over 1400 degrees C for 10 h in air. The electrical resistivity of the Ga-poor surface region was higher than that of the interior. PMID- 21693395 TI - Tunable capacitors employing BZN/BST thin films for RF applications. AB - Tunable parallel-plate capacitors employing Bi(1.5)Zn(1.0)Nb(1.5)O(7)/Ba(0.5)Sr(0.5)TiO(3) (BZN/BST) thin films for RF applications are reported. The intermediate frequency measurements indicate that the BZN/BST-based varactors demonstrate large tunability of 39% at 40 V and high device quality factor of 300 at 1 MHz. The devices maintain quite low leakage current density even under a high applied bias. The quality factor analysis shows that the device quality factor is highly dependent on conductor loss of electrodes at frequencies above 1 MHz. The phase shifter employing BZN/BST-based varactors exhibits lower insertion loss than does employing semiconductor diodes at a designed frequency of 445 MHz, demonstrating the potential of tunable capacitors employing BZN/BST thin films for RF applications. PMID- 21693396 TI - Design analysis of miniature quartz resonator using two-dimensional finite element model. AB - This study focused on 2-D miniature quartz plates. By assigning appropriate boundary condition using finite element modeling (FEM), the vibration of a quartz plate was analyzed for converse piezoelectric effect. The quality and stability of the resonance of a quartz plate was determined by examining changes on the response curve of resonant frequency when the length of plate was decreased or increased. A graphical user interface (GUI) was adopted to assist the finite element software to calculate the frequency responses with different length of a large number of quartz plates, and to conclude a detailed curve of resonant frequency versus size. With this diagram, changes of the resonant mode for quartz plates caused by length variation can be easily observed. An optimum size of the quartz plate is obtained from the curve. Moreover, analyses were also conducted on the electrode coverage of a quartz plate and the mass-loading effect of metallic electrodes for this study, to discuss the influence on the resonant frequencies of quartz plates. PMID- 21693397 TI - A low noise and ultra-narrow bandwidth frequency-locked loop based on the beat method. AB - A novel frequency-locked loop (FLL) based on the beat method is proposed in this paper. Compared with other frequency feedback loops, this FLL is a digital loop with simple structure and very low noise. As shown in the experimental results, this FLL can be used to reduce close-in phase noise on atomic frequency standards, through which a composite frequency standard with ultra-low phase noise and low cost can be easily realized. PMID- 21693398 TI - A new transducer receive transfer function calibration method: application to microbubble backscattering cross-section measurements at high frequency. AB - When comparing acoustic scattering experiments with theory, the relationship between the pressure generated by a scatterer at the surface of a transducer and the induced voltage must be known. Methods have been previously proposed to measure the receive transfer function that rely on several assumptions. A new, experimental method for measuring the acoustic response of a spherically-focused transducer, using a hydrophone at twice the focal distance, is proposed that requires a minimum number of assumptions and calculations. The receive transfer function of a spherically-focused, high-frequency transducer was calculated, and found to be within 10% of the receive transfer function calculated assuming reciprocity. Further, using the receive transfer function, the effective backscattering cross-section of bound microbubbles interrogated at 30 MHz was measured to be, on average, 65% of the geometric backscattering cross-section, with significant size-independent variability. These results give insight into selecting the optimal microbubble size distribution for linear microbubble imaging at high frequencies. PMID- 21693399 TI - Implementation of vibro-acoustography on a clinical ultrasound system. AB - Vibro-acoustography is an ultrasound-based imaging modality that uses two ultrasound beams of slightly different frequencies to produce images based on the acoustic response caused by harmonic ultrasound radiation force excitation at the difference frequency between the two ultrasound frequencies. Vibro-acoustography has demonstrated feasibility and usefulness in imaging of breast and prostate tissue. However, previous studies have been performed either in controlled water tank settings or a prototype breast scanner equipped with a water tank. To make vibro-acoustography more accessible and relevant to clinical use, we report here on the implementation of vibro-acoustography on a General Electric Vivid 7 ultrasound scanner. In this paper, we will describe software and hardware modifications that were performed to make vibro- acoustography functional on this system. We will discuss aperture definition for the two ultrasound beams and beamforming using a linear-array transducer. Experimental results from beam measurements and phantom imaging studies will be shown. The implementation of vibro-acoustography provides a step toward clinical translation of this imaging modality for applications in various organs including breast, prostate, thyroid, kidney, and liver. PMID- 21693400 TI - Effects of non-optimal focusing on dual-frequency ultrasound measurements of bone. AB - In pulse-echo (PE) ultrasound measurements, the use of focused transducers is desirable for quantitative assessment of bone characteristics because of the attenuation in the overlying soft tissues. However, the variable thickness and composition of the soft tissue overlying bone affect the focal depth of the ultrasound beam and induce errors into the measurements. To compensate for the attenuation-related effects caused by the interfering soft tissue (i.e., fat and lean tissue), a dual-frequency ultrasound (DFUS) technique was recently introduced. The aim of this study was to investigate the effect of non-optimal focal depth of the ultrasound beam on the determination of the integrated reflection coefficient (IRC) of bone when overlaid by an interfering layer composed of oil and water. The feasibility of the DFUS-based correction of the IRC was evaluated through numerical simulations and experimental measurements. Even when the interfering layer-bone interface was out of focus, the total thickness of the interfering layer could be accurately determined with the technique. However, based on the simulations, the errors in the determination of the composition of the interfering layer increased (0.004 to 113.8%) with the increase in distance between the interfering layer-bone interface and the focus of the ultrasound beam. Attenuation compensation, based on the true composition of the interfering layer, resulted in an average relative error of 22.3% in the IRC values calculated from the simulations. Interestingly, the attenuation compensation with the interfering layer composition estimated using the DFUS technique resulted in a smaller average relative error of 14.9% in the IRC values. The simulations suggest that DFUS can reduce the errors induced by soft tissue in bone PE ultrasound measurements. The experimental measurements indicate that the accuracy of the IRC measurements is rather similar when using DFUS correction or correction based on the true composition of the interfering layer. However, the results suggest that accurate determination of soft tissue composition may be difficult without optimal focusing of the ultrasound beam on the soft tissue-bone interface. PMID- 21693402 TI - Effects of gas pockets on high-intensity focused ultrasound field. AB - The paper describes experimental and numerical studies of the effects of gas pockets on a high-intensity focused ultrasound (HIFU) field. Air bubbles ranging from 0.8 to 2.4 mm in radius were produced in transparent polyacrylamide tissue mimicking gels. A single-element 3.5-MHz HIFU transducer was used to sonicate the gel phantoms. The changes in the HIFU beam pattern for air bubbles at different positions were visualized by the Schlieren method. Quantitative measurements of pressure at the HIFU focus by a calibrated needle hydrophone showed considerable reduction in the focal pressure with the presence of an air pocket. The presence of a single 1.2-mm-radius air bubble, at a 5 mm axial pre-focal position, reduced the focal intensity by 50% and increased the lateral focal dimension by 50%. For air bubbles at pre-focal position close to the focus, lesion formation was observed not at the theoretical focus, but in front of the air bubble and the air bubble became a barrier for the post-focal ultrasound propagation. The effects of reflection were simulated numerically and were compared with the experiments. The results can be used as guidelines for evaluation of potential safety concerns produced by trapped gas-pockets in various HIFU therapies. PMID- 21693401 TI - The ultrasound brain helmet: new transducers and volume registration for in vivo simultaneous multi-transducer 3-D transcranial imaging. AB - Because stroke remains an important and time-sensitive health concern in developed nations, we present a system capable of fusing 3-D transcranial ultrasound volumes acquired from two sides of the head. This system uses custom sparse array transducers built on flexible multilayer circuits that can be positioned for simultaneous imaging through both temporal acoustic windows, allowing for potential registration of multiple real-time 3-D scans of cerebral vasculature. We examine hardware considerations for new matrix arrays-transducer design and interconnects-in this application. Specifically, it is proposed that SNR may be increased by reducing the length of probe cables. This claim is evaluated as part of the presented system through simulation, experimental data, and in vivo imaging. Ultimately, gains in SNR of 7 dB are realized by replacing a standard probe cable with a much shorter flex interconnect; higher gains may be possible using ribbon-based probe cables. In vivo images are presented, showing cerebral arteries with and without the use of microbubble contrast agent; they have been registered and fused using a simple algorithm which maximizes normalized cross-correlation. PMID- 21693404 TI - Fast characterization of aluminum plates with TV-holography measurements of the frequency spectrum of multimode, quasi- monochromatic Lamb waves. AB - We introduce a novel approach for measuring the frequency spectrum of Lamb waves and, subsequently, for obtaining the thickness and the bulk wave velocities of isotropic, homogeneous plates. It is based on Fourier transforming a set of spatial and temporal samples of the acoustic displacement but, in contrast to the traditional approach that employs dense temporal sampling and a reduced set of spatial sampling locations, our data set is a sequence of 2-D high-resolution maps of the instantaneous out-of-plane displacement obtained with TV holography. We have devised three variants to obtain a set of points of the wavenumber frequency space, based, respectively, on the spatial (1-D or 2-D) and on the spatio-temporal (3-D) Fourier transforms. The whole process to obtain these points can be easily automated and substantial time savings can be achieved, compared with other full-field techniques that require human intervention or with pointwise scanned probes. Experimental demonstration of the three variants with quasimonochromatic multimode Lamb waves in aluminum plates is presented. The characteristic parameters of the plates are calculated by fitting the theoretical model to the experimental points of the frequency spectrum. The analysis of the uncertainties shows that the accuracy of the method is only slightly lower than the accuracy of a previously reported method based on measuring the wavelength of single-modes, for which the data acquisition procedure is much slower. PMID- 21693403 TI - A wireless batteryless deep-seated implantable ultrasonic pulser-receiver powered by magnetic coupling. AB - This study tests a deep-seated implantable ultrasonic pulser-receiver, powered wirelessly by magnetic coupling. A 30-cm energy-transmitting coil was designed to wrap around the body, and was driven by a current of 1.2 A rms at a frequency of 5.7 MHz to generate a magnetic field. A 2-cm receiving coil was positioned at the center of the primary coil for receiving the magnetic energy and powering the implantable device. A capacitor-diode voltage multiplier in the implantable circuit was used to step-up the receiving coil voltage from 12.5 to 50 V to operate an ultrasonic pulser. FEA magnetic field simulations, bench-top, and ex vivo rabbit measurements showed that the magnetic energy absorption in body tissue is negligible and that the magnetic coupling is not sensitive to receiving coil placement. The receiving coil and the power conditioning circuits in the implantable device do not contain ferromagnetic material, so a magnetic-resonance compatible device can be achieved. A 5-MHz ultrasound transducer was used to test the implantable circuit, operating in pulse-echo mode. The received echo was amplified, envelope-detected, frequency-modulated, and transmitted out of the rabbit body by a radio wave. The modulated echo envelope signal was received by an external receiver located about 10 cm away from the primary coil. The study concludes that operation of a batteryless and wireless deep-seated implantable ultrasonic pulser-receiver powered by coplanar magnetic coupling is feasible. PMID- 21693405 TI - Extensions of nonlinear B/A parameter imaging methods for echo mode. AB - This paper investigates nonlinear B/A parameter imaging in ultrasound echo mode. First, the B/A estimation methods which can be extended to echo mode are identified. The finite amplitude approaches are found to be excellent candidates to assess the nonlinear parameter because of their experimental simplicity, supported by a strong mathematical background. Second, three nonlinear coefficient measurement methods, thus far proposed for applications in homogeneous media, are extended to heterogeneous media. In particular, the simulations show that the extended comparative method (ECM) offers the best results when the probe diffraction effects are taken into consideration. The first experimental images obtained by applying the ECM for two different phantoms are also presented, showing the feasibility of B/A imaging. PMID- 21693406 TI - Optimal cuts to extract the third-order elastic constants of langasite single crystals. AB - Optimal cuts to determine the third-order elastic constants of langasite single crystals by the resonator method are proposed. By designing a small number of langasite resonators with optimal cut angles and measuring their force-frequency effects, the third-order elastic constants of langasite single crystals may be extracted separately. The numerical method to search for these optimal cut angles is presented. All 14 third-order elastic constants may be determined through a series of experimental measurements. This method will simplify traditional methods used to determine the third-order elastic constants and could potentially produce more accurate results. PMID- 21693407 TI - Observation of induced longitudinal and shear acoustic phonons by Brillouin scattering. AB - To improve the accuracy of velocity measurements in the Brillouin scattering technique using weak thermal phonons, we have used induced coherent phonons, which intensify the scattering. To induce phonons in the gigahertz range, we used a c-axis tilted ZnO film transducer that was developed in our laboratory. This allowed us to induce longitudinal and shear acoustic phonons effectively at hypersonic frequencies. As a result, we obtained scattered light in the silica glass sample that was much more intense than that obtained from the thermal phonons. Because the Brillouin scattering from induced phonons was measured, the shift frequency was that of the electric signal applied to the ZnO transducer. Strong peaks lead to a reduction of the measurement time. This is useful for two dimensional mapping of thin film elasticity using Brillouin scattering. Additionally, Brillouin scattering enables the simultaneous measurement of longitudinal and shear phonon velocities in the sample plane. This opens up a potential new technique for non-destructive elasticity measurements of various materials. PMID- 21693408 TI - Interfacial waves in dissimilar piezoelectric cubic crystals with an imperfect bonding. AB - This paper studies propagation of shear waves along a weak interface of two dissimilar piezoelectric cubic crystals. Two piezoelectric cubic crystals are bonded along a specified cut direction. For an imperfect electrode interface, a dispersion relation of interfacial waves is derived explicitly. Numerical solutions are evaluated for several commonly-used piezoelectric cubic crystals. Our results show that interfacial imperfection alters the velocity of the interfacial shear waves. In particular, sometimes the interfacial shear waves may not exist for a perfect grounded interface and exist only for an imperfect electrode interface. PMID- 21693409 TI - A 32 x 32 element row-column addressed capacitive micromachined ultrasonic transducer. AB - This paper presents characterization and initial imaging results of a 32 x 32 element two-dimensional capacitive micromachined ultrasonic transducer array. The devices are fabricated using a wafer bonding process in which both the insulation layer and the membrane are user-deposited silicon nitride. The transducers use a row-column addressing scheme to simplify the fabrication process and beamformer. By adjusting the number of rows and columns that are biased, the effective aperture of the transducer can be adjusted. This is significant because it permits imaging in the near-field of the transducer without the use of a lens. The effect on the transmit beam profile is demonstrated. The transducer has a center frequency of 5.9 MHz and a relative bandwidth of 110%. Images of horizontal and vertical wires are taken to demonstrate image resolution. A three dimensional image of four pin heads is also demonstrated. PMID- 21693410 TI - Sources of image degradation in fundamental and harmonic ultrasound imaging: a nonlinear, full-wave, simulation study. AB - A full-wave equation that describes nonlinear propagation in a heterogeneous attenuating medium is solved numerically with finite differences in the time domain. This numerical method is used to simulate propagation of a diagnostic ultrasound pulse through a measured representation of the human abdomen with heterogeneities in speed of sound, attenuation, density, and nonlinearity. Conventional delay-and-sum beamforming is used to generate point spread functions (PSFs) that display the effects of these heterogeneities. For the particular imaging configuration that is modeled, these PSFs reveal that the primary source of degradation in fundamental imaging is due to reverberation from near-field structures. Compared with fundamental imaging, reverberation clutter in harmonic imaging is 27.1 dB lower. Simulated tissue with uniform velocity but unchanged impedance characteristics indicates that for harmonic imaging, the primary source of degradation is phase aberration. PMID- 21693411 TI - Standing stability enhancement with an intelligent powered transfemoral prosthesis. AB - The authors have developed a ground-adaptive standing controller for a powered knee and ankle prosthesis which is intended to enhance the standing stability of transfemoral amputees. The finite-state-based controller includes a ground searching phase, a slope estimation phase, and a joint impedance modulation phase, which together enable the prosthesis to quickly conform to the ground and provide stabilizing assistance to the user. In order to assess the efficacy of the ground-adaptive standing controller, the control approach was implemented on a powered knee and ankle prosthesis, and experimental data were collected on an amputee subject for a variety of standing conditions. Results indicate that the controller can estimate the ground slope within +/-1 degrees over a range of +/ 15 degrees , and that it can provide appropriate joint impedances for standing on slopes within this range. PMID- 21693412 TI - Finite element modeling and modal analysis of the human spine vibration configuration. AB - This study was designed to investigate the modal characteristics of the human spine. A 3-D finite element model of the spine T12-Pelvis segment was used to extract resonant frequencies and modal modes of the human spine. By finite element modal analysis and harmonic response analysis, several lower vibration modes in the flexion-extension, lateral bending, and vertical directions were obtained and its vibration configurations were shown in this paper. The results indicate that the lowest resonant frequency of the model is in the flexion extension direction. The second-order resonant frequency is in the lateral bending direction and the third-order resonant frequency of the T12-Pelvis model is in the vertical direction. The results also show that lumbar spinal vertebrae conduct the rotation action during whole body vibration (WBV). The vibration configurations of the lumbar spine can explore the motion mechanism of different lumbar components under WBV and make us to understand the vibration-induced spine diseases. The findings in this study will be helpful to understand WBV-related injury of the spine in clinics and the ergonomics design and development of mechanical production to protect human spine safety. PMID- 21693413 TI - Multiscale entropy analysis of pulse wave velocity for assessing atherosclerosis in the aged and diabetic. AB - This study proposed a dynamic pulse wave velocity (PWV)-based biomedical parameter in assessing the degree of atherosclerosis for the aged and diabetic populations. Totally, 91 subjects were recruited from a single medical institution between July 2009 and October 2010. The subjects were divided into four groups: young healthy adults (Group 1, n = 22), healthy upper middle-aged adults (Group 2, n = 28), type 2 diabetics with satisfactory blood sugar control (Group 3, n = 21), and unsatisfactory blood sugar control (Group 4, n = 20). A self-developed six-channel electrocardiography (ECG)-PWV-based equipment was used to acquire 1000 successive recordings of PWV(foot) values within 30 min. The data, thus, obtained were analyzed with multiscale entropy (MSE). Large-scale MSE index (MEI(LS)) was chosen as the assessment parameter. Not only did MEI(LS) successfully differentiate between subjects in Groups 1 and 2, but it also showed a significant difference between Groups 3 and 4. Compared with the conventional parameter of PWV(foot) and MEI on R-R interval [i.e., MEI(RRI)] in evaluating the degree of atherosclerotic change, the dynamic parameter, MEI(LS) (PWV), could better reflect the impact of age and blood sugar control on the progression of atherosclerosis. PMID- 21693414 TI - Common-mode differential-mode (CMDM) method for double-nuclear MR signal excitation and reception at ultrahigh fields. AB - Double-tuned radio-frequency (RF) coils for heteronuclear mangentic resonance (MR) require sufficient electromagnetic isolation between the two resonators operating at two Larmor frequencies and independent tuning in order to attain highly efficient signal acquisition at each frequency. In this work, a novel method for double-tuned coil design at 7T based on the concept of common-mode differential-mode (CMDM) was developed and tested. Common mode (CM) and differential mode (DM) currents exist within two coupled parallel transmission lines, e.g., microstrip lines, yielding two different current distributions. The electromagnetic (EM) fields of the CM and DM are orthogonal to each other, and thus, the two modes are intrinsically EM decoupled. The modes can be tuned independently to desired frequencies, thus satisfying the requirement of dual frequency MR applications. To demonstrate the feasibility and efficiency of the proposed CMDM technique, CMDM surface coils and volume coils using microstrip transmission line for (1)H and (13)C MRI/MRSI were designed, constructed, and tested at 7T. Bench test results showed that the isolations between the two frequency channels of the CMDM surface coil and volume coil were better than -30 and -25 dB, respectively. High quality MR phantom images were also obtained using the CMDM coils. The performance of the CMDM technique was validated through a comparison with the conventional two-pole design method at 7T. The proposed CMDM technique can be also implemented by using other coil techniques such as lumped element method, and can be applied to designing double-tuned parallel imaging coil arrays. Furthermore, if the two resonant modes of a CMDM coil were tuned to the same frequency, the CMDM coil becomes a quadrature coil due to the intrinsic orthogonal field distribution of CM and DM. PMID- 21693415 TI - Cerebral artery-vein separation using 0.1-Hz oscillation in dual-wavelength optical imaging. AB - We present a novel artery-vein separation method using 0.1-Hz oscillation at two wavelengths with optical imaging of intrinsic signals (OIS). The 0.1-Hz oscillation at a green light wavelength of 546 nm exhibits greater amplitude in arteries than in veins and is primarily caused by vasomotion, whereas the 0.1-Hz oscillation at a red light wavelength of 630 nm exhibits greater amplitude in veins than in arteries and is primarily caused by changes of deoxyhemoglobin concentration. This spectral feature enables cortical arteries and veins to be segmented independently. The arteries can be segmented on the 0.1-Hz amplitude image at 546 nm using matched filters of a modified dual Gaussian model combining with a single Gaussian model. The veins are a combination of vessels segmented on both amplitude images at the two wavelengths using multiscale matched filters of single Gaussian model. Our method can separate most of the thin arteries and veins from each other, especially the thin arteries with low contrast in raw gray images. In vivo OIS experiments demonstrate the separation ability of the 0.1-Hz based segmentation method in cerebral cortex of eight rats. Two validation studies were undertaken to evaluate the performance of the method by quantifying the arterial and venous length based on a reference standard. The results indicate that our 0.1-Hz method is very effective in separating both large and thin arteries and veins regardless of vessel crossover or overlapping to great extent in comparison with previous methods. PMID- 21693416 TI - The singular value filter: a general filter design strategy for PCA-based signal separation in medical ultrasound imaging. AB - A general filtering method, called the singular value filter (SVF), is presented as a framework for principal component analysis (PCA) based filter design in medical ultrasound imaging. The SVF approach operates by projecting the original data onto a new set of bases determined from PCA using singular value decomposition (SVD). The shape of the SVF weighting function, which relates the singular value spectrum of the input data to the filtering coefficients assigned to each basis function, is designed in accordance with a signal model and statistical assumptions regarding the underlying source signals. In this paper, we applied SVF for the specific application of clutter artifact rejection in diagnostic ultrasound imaging. SVF was compared to a conventional PCA-based filtering technique, which we refer to as the blind source separation (BSS) method, as well as a simple frequency-based finite impulse response (FIR) filter used as a baseline for comparison. The performance of each filter was quantified in simulated lesion images as well as experimental cardiac ultrasound data. SVF was demonstrated in both simulation and experimental results, over a wide range of imaging conditions, to outperform the BSS and FIR filtering methods in terms of contrast-to-noise ratio (CNR) and motion tracking performance. In experimental mouse heart data, SVF provided excellent artifact suppression with an average CNR improvement of 1.8 dB with over 40% reduction in displacement tracking error. It was further demonstrated from simulation and experimental results that SVF provided superior clutter rejection, as reflected in larger CNR values, when filtering was achieved using complex pulse-echo received data and non-binary filter coefficients. PMID- 21693417 TI - Local linear discriminant analysis framework using sample neighbors. AB - The linear discriminant analysis (LDA) is a very popular linear feature extraction approach. The algorithms of LDA usually perform well under the following two assumptions. The first assumption is that the global data structure is consistent with the local data structure. The second assumption is that the input data classes are Gaussian distributions. However, in real-world applications, these assumptions are not always satisfied. In this paper, we propose an improved LDA framework, the local LDA (LLDA), which can perform well without needing to satisfy the above two assumptions. Our LLDA framework can effectively capture the local structure of samples. According to different types of local data structure, our LLDA framework incorporates several different forms of linear feature extraction approaches, such as the classical LDA and principal component analysis. The proposed framework includes two LLDA algorithms: a vector based LLDA algorithm and a matrix-based LLDA (MLLDA) algorithm. MLLDA is directly applicable to image recognition, such as face recognition. Our algorithms need to train only a small portion of the whole training set before testing a sample. They are suitable for learning large-scale databases especially when the input data dimensions are very high and can achieve high classification accuracy. Extensive experiments show that the proposed algorithms can obtain good classification results. PMID- 21693418 TI - Sparse demixing of hyperspectral images. AB - In the LMM for hyperspectral images, all the image spectra lie on a high dimensional simplex with corners called endmembers. Given a set of endmembers, the standard calculation of fractional abundances with constrained least squares typically identifies the spectra as combinations of most, if not all, endmembers. We assume instead that pixels are combinations of only a few endmembers, yielding abundance vectors that are sparse. We introduce sparse demixing (SD), which is a method that is similar to orthogonal matching pursuit, for calculating these sparse abundances. We demonstrate that SD outperforms an existing L(1) demixing algorithm, which we prove to depend adversely on the angles between endmembers. We combine SD with dictionary learning methods to calculate automatically endmembers for a provided set of spectra. Applying it to an airborne visible/infrared imaging spectrometer image of Cuprite, NV, yields endmembers that compare favorably with signatures from the USGS spectral library. PMID- 21693419 TI - Preconditioning for edge-preserving image super resolution. AB - We propose a simple preconditioning method for accelerating the solution of edge preserving image super-resolution (SR) problems in which a linear shift-invariant point spread function is employed. Our technique involves reordering the high resolution (HR) pixels in a similar manner to what is done in preconditioning methods for quadratic SR formulations. However, due to the edge preserving requirements, the Hessian matrix of the cost function varies during the minimization process. We develop an efficient update scheme for the preconditioner in order to cope with this situation. Unlike some other acceleration strategies that round the displacement values between the low resolution (LR) images on the HR grid, the proposed method does not sacrifice the optimality of the observation model. In addition, we describe a technique for preconditioning SR problems involving rational magnification factors. The use of such factors is motivated in part by the fact that, under certain circumstances, optimal SR zooms are nonintegers. We show that, by reordering the pixels of the LR images, the structure of the problem to solve is modified in such a way that preconditioners based on circulant operators can be used. PMID- 21693420 TI - PSF estimation via gradient domain correlation. AB - This paper proposes an efficient method to estimate the point spread function (PSF) of a blurred image using image gradients spatial correlation. A patch-based image degradation model is proposed for estimating the sample covariance matrix of the gradient domain natural image. Based on the fact that the gradients of clean natural images are approximately uncorrelated to each other, we estimated the autocorrelation function of the PSF from the covariance matrix of gradient domain blurred image using the proposed patch-based image degradation model. The PSF is computed using a phase retrieval technique to remove the ambiguity introduced by the absence of the phase. Experimental results show that the proposed method significantly reduces the computational burden in PSF estimation, compared with existing methods, while giving comparable blurring kernel. PMID- 21693421 TI - Nonparametric Bayesian dictionary learning for analysis of noisy and incomplete images. AB - Nonparametric Bayesian methods are considered for recovery of imagery based upon compressive, incomplete, and/or noisy measurements. A truncated beta-Bernoulli process is employed to infer an appropriate dictionary for the data under test and also for image recovery. In the context of compressive sensing, significant improvements in image recovery are manifested using learned dictionaries, relative to using standard orthonormal image expansions. The compressive measurement projections are also optimized for the learned dictionary. Additionally, we consider simpler (incomplete) measurements, defined by measuring a subset of image pixels, uniformly selected at random. Spatial interrelationships within imagery are exploited through use of the Dirichlet and probit stick-breaking processes. Several example results are presented, with comparisons to other methods in the literature. PMID- 21693422 TI - Highly parallel line-based image coding for many cores. AB - Computers are developing along with a new trend from the dual-core and quad-core processors to ones with tens or even hundreds of cores. Multimedia, as one of the most important applications in computers, has an urgent need to design parallel coding algorithms for compression. Taking intraframe/image coding as a start point, this paper proposes a pure line-by-line coding scheme (LBLC) to meet the need. In LBLC, an input image is processed line by line sequentially, and each line is divided into small fixed-length segments. The compression of all segments from prediction to entropy coding is completely independent and concurrent at many cores. Results on a general-purpose computer show that our scheme can get a 13.9 times speedup with 15 cores at the encoder and a 10.3 times speedup at the decoder. Ideally, such near-linear speeding relation with the number of cores can be kept for more than 100 cores. In addition to the high parallelism, the proposed scheme can perform comparatively or even better than the H.264 high profile above middle bit rates. At near-lossless coding, it outperforms H.264 more than 10 dB. At lossless coding, up to 14% bit-rate reduction is observed compared with H.264 lossless coding at the high 4:4:4 profile. PMID- 21693423 TI - Analyzing image deblurring through three paradigms. AB - To recover a sharp version from a blurred image is a long-standing inverse problem. In this paper, we analyze the research on this topic both theoretically and experimentally through three paradigms: 1) the deterministic filter; 2) Bayesian estimation; and 3) the conjunctive deblurring algorithm (CODA), which performs the deterministic filter and Bayesian estimation in a conjunctive manner. We point out the weaknesses of the deterministic filter and unify the limitation latent in two kinds of Bayesian estimators. We further explain why the CODA is able to handle quite large blurs beyond Bayesian estimation. Finally, we propose a novel method to overcome several unreported limitations of the CODA. Although extensive experiments demonstrate that our method outperforms state-of the-art methods with a large margin, some common problems of image deblurring still remain unsolved and should attract further research efforts. PMID- 21693424 TI - A secret-sharing-based method for authentication of grayscale document images via the use of the PNG image with a data repair capability. AB - A new blind authentication method based on the secret sharing technique with a data repair capability for grayscale document images via the use of the Portable Network Graphics (PNG) image is proposed. An authentication signal is generated for each block of a grayscale document image, which, together with the binarized block content, is transformed into several shares using the Shamir secret sharing scheme. The involved parameters are carefully chosen so that as many shares as possible are generated and embedded into an alpha channel plane. The alpha channel plane is then combined with the original grayscale image to form a PNG image. During the embedding process, the computed share values are mapped into a range of alpha channel values near their maximum value of 255 to yield a transparent stego-image with a disguise effect. In the process of image authentication, an image block is marked as tampered if the authentication signal computed from the current block content does not match that extracted from the shares embedded in the alpha channel plane. Data repairing is then applied to each tampered block by a reverse Shamir scheme after collecting two shares from unmarked blocks. Measures for protecting the security of the data hidden in the alpha channel are also proposed. Good experimental results prove the effectiveness of the proposed method for real applications. PMID- 21693425 TI - A primal-dual method for total-variation-based wavelet domain inpainting. AB - Loss of information in a wavelet domain can occur during storage or transmission when the images are formatted and stored in terms of wavelet coefficients. This calls for image inpainting in wavelet domains. In this paper, a variational approach is used to formulate the reconstruction problem. We propose a simple but very efficient iterative scheme to calculate an optimal solution and prove its convergence. Numerical results are presented to show the performance of the proposed algorithm. PMID- 21693426 TI - An energy-based model for the image edge-histogram specification problem. AB - In this correspondence, we present an original energy-based model that achieves the edge-histogram specification of a real input image and thus extends the exact specification method of the image luminance (or gray level) distribution recently proposed by Coltuc et al. Our edge-histogram specification approach is stated as an optimization problem in which each edge of a real input image will tend iteratively toward some specified gradient magnitude values given by a target edge distribution (or a normalized edge histogram possibly estimated from a target image). To this end, a hybrid optimization scheme combining a global and deterministic conjugate-gradient-based procedure and a local stochastic search using the Metropolis criterion is proposed herein to find a reliable solution to our energy-based model. Experimental results are presented, and several applications follow from this procedure. PMID- 21693427 TI - A computational model for the stimulation of rat sciatic nerve using a transverse intrafascicular multichannel electrode. AB - Neuroprostheses based on electrical stimulation could potentially help disabled persons. They are based on neural interface that aim at creating an intimate contact with neural cells. The efficacy of neuroprostheses can be improved by increasing the selectivity of the neural interfaces used to stimulate specific subsets of cells. Selectivity is strongly influenced by interface design. Computer models can be useful for exploring the high dimensional space of design parameters with the aim to provide guidelines for the development of more efficient electrodes, with minimal animal use and optimization of manufacturing processes. The purpose of this study was to implement a realistic model of the performance of a transverse intrafascicular multichannel electrode (TIME) implanted into the rat sciatic nerve. A realistic finite element method (FEM) model was developed taking into account the anatomical and physiological features of the rat sciatic nerve. Electric potentials were calculated and interpolated voltages were applied to the model of a rat sciatic nerve axon, based on experimental biophysical data. Results indicate that high intra-fascicular and inter-fascicular selectivity values with low current levels can be achieved with TIMEs. The selectivity of TIMEs was also compared to an extraneural electrode, showing that higher selectivity with less current can be obtained. Using this model, the robustness of electrode performances for translational and rotational displacements were evaluated. PMID- 21693429 TI - Highlights from the new drug session at the Biennial International Congress On Schizophrenia Research, April 2-6, 2011. AB - The 2011 International Congress on Schizophrenia Research, held in Colorado Springs, Colorado, attracted nearly 1,200 attendees to the Broadmoor Hotel from 2 6 April 2011, not to mention the satellite meetings on cognition and the schizophrenia prodrome. With the gracious assistance of Congress directors Carol Tamminga and Chuck Schulz, as well as meeting staff Dorothy Denton and Cristan Tamminga, we bring you the following report on the Congress' "New Drug Session: Advances in Medication Development and Assessment." PMID- 21693430 TI - Changes in weight and other metabolic indicators in persons with schizophrenia following a switch to aripiprazole. AB - For patients who gain a troublesome amount of weight on antipsychotics, switching to a less obesogenic agent is an option. Aripiprazole appears to cause less weight gain than many other antipsychotics. We report on changes in weight, and other risk factors for heart disease, in thirty-three schizophrenia patients who agreed to switch from other antipsychotics to aripiprazole in an open, flexible dose, eight-week trial. All patients were successfully switched. There were no significant changes in PANSS symptom scores or in CGI. Weight (Wt), waist circumference (WC), and low-density lipoprotein (LDL) decreased significantly in the group as a whole. In patients switched from olanzapine to aripiprazole, Wt, WC, LDL, fasting glucose, and triglycerides were significantly decreased as compared to baseline. Substantial decreases in several risk factors were also seen in patients switched from quetiapine, but these changes did not reach statistical significance. PMID- 21693431 TI - Knowledge about HIV in people with schizophrenia: a general population comparison. AB - BACKGROUND: Patients with schizophrenia are at higher risk for human immunodeficiency virus infection (HIV) positivity compared to the general population. Only a limited number of studies have evaluated the knowledge about HIV in people with schizophrenia. OBJECTIVES: To compare the knowledge about HIV between people with schizophrenia and the general population. METHODS: The knowledge about HIV was assessed with a questionnaire used in the general health survey of the Belgian population in 2004. RESULTS: Patients with schizophrenia had a significantly better knowledge about nontransmissible contacts compared to the general population (43.2% vs. 32.6%, df=1, chi-square=11.0; p=0.0009). There was no difference regarding the knowledge about protective methods (50.7% vs. 55.9%, df=1, chi-square=2.45; p=0.12). Patients had a better appreciation about the severity and treatment options for acquired immunodeficiency syndrome (AIDS) (54.6% vs. 37.9%, df=1, chi-square=25.91; p<0.0001). CONCLUSIONS: Although the overall knowledge about HIV in patients with schizophrenia is better than that of the general population, it is far from optimal. There is a need for systematic educational programs to improve knowledge. PMID- 21693432 TI - Training for assessment of negative symptoms of schizophrenia across languages and cultures: comparison of the NSA-16 with the PANSS Negative Subscale and Negative Symptom factor. AB - BACKGROUND: The 16-item Negative Symptom Assessment scale (NSA-16) has been validated in English-speaking raters. We analyzed the level of agreement achieved among raters of different nationalities using the NSA-16 and the Positive and Negative Syndrome Scale (PANSS) negative subscale and Marder negative factor. METHODS: Raters participating in two international trials were trained in the use of each instrument through lectures and feedback on their ratings of at least one videotaped interview of a schizophrenic patient. Overall and regional (North America, Western Europe, Eastern Europe, South/Central America, and Australia and South Africa combined) kappa values were calculated and mean total scores were compared (1-way analysis of variance) by region for each instrument. In addition, within-scales variance was calculated by item to help identify negative symptoms that were particularly challenging to obtain agreement on across cultures. RESULTS: In the combined group of international raters, the kappa values for ratings of the NSA-16, PANSS negative subscale, and Marder negative factors were 0.89, 0.84, and 0.82, respectively. Kappa values calculated by geographic region ranged from 0.87 to 0.94 for the NSA-16 compared with 0.82 to 0.86 for the PANSS negative subscale and 0.79 to 0.87 for the PANSS Marder negative factor. CONCLUSIONS: Despite cultural and linguistic differences among raters, standardizing measurement of negative symptoms in international clinical trials is possible using available rating scales: NSA-16, PANSS negative subscale, and Marder negative subscale. Agreement among raters was at least as high using the NSA-16 as using the PANSS instruments. PMID- 21693433 TI - Social outcome in clinically recovered first-episode schizophrenia in a naturalistic, ten-year, follow-up study in India. AB - BACKGROUND: Remission of symptoms and clinical outcome seldom capture real-life outcome in schizophrenia. Measurement of social outcome provides a culturally meaningful indicator of how a patient is performing his or her role after recovery. The present study examined the status of social outcome on multidimensional parameters in a cohort of clinically recovered patients in a ten year, long-term study of first-episode schizophrenia. METHODS: First-episode hospitalized patients were recruited for a long-term outcome study. At the ten year end point, those patients who showed good clinical outcome were assessed on culture-specific parameters of social outcome to find out the true nature of recovery in schizophrenia. RESULTS: Sixty-one recovered patients showed differential outcome on various social parameters after ten years. Overall, 52.5% of patients showed good social recovery on all four social parameters. We found that 19 subjects (31.1%) were functioning socially satisfactorily, 10 subjects (16.4%) were productive in day-to-day life, 29 (48.3%) were economically independent, and 11 (18.3%) were satisfied with their education and new skills. CONCLUSIONS: This study shows that not all patients who show clinical recovery have also improved in social functions on socially relevant parameters. Half of the patients continued to have limitations in the areas of social function (the ability to earn a sufficient income and conform to the expected social role). Social parameters need to be considered in everyday practice when defining outcome status. PMID- 21693434 TI - Hypomania secondary to a change in altitude in an adolescent male. PMID- 21693436 TI - Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes. AB - Improved in vitro systems for predicting drug-induced toxicity are needed in the pharmaceutical and biotechnology industries to decrease late-stage drug attrition. One unmet need is an early screen for cardiotoxicity, which accounts for about one third of safety-based withdrawn pharmaceuticals. Herein, the first published report of a high-throughput functional assay employing a monolayer of beating human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is described, detailing a model that accurately detects drug-induced cardiac abnormalities. Using 96-well plates with interdigitated electrode arrays that assess impedance, the rhythmic, synchronous contractions of the iPSC-CMs were detected. Treatment of the iPSC-CMs with 28 different compounds with known cardiac effects resulted in compound-specific changes in the beat rate and/or the amplitude of the impedance measurement. Changes in impedance for the compounds tested were comparable with the results from a related technology, electric field potential assessment obtained from microelectrode arrays. Using the results from the set of compounds, an index of drug-induced arrhythmias was calculated, enabling the determination of a drug's proarrhythmic potential. This system of interrogating human cardiac function in vitro opens new opportunities for predicting cardiac toxicity and studying cardiac biology. PMID- 21693435 TI - cAMP-dependent cytosolic mislocalization of p27(kip)-cyclin D1 during quinol thioether-induced tuberous sclerosis renal cell carcinoma. AB - The loss of tuberin, the tuberous sclerosis-2 (Tsc-2) gene product, is associated with cytoplasmic mislocalization of p27 in uterine leiomyomas derived from Eker rats (Tsc-2(EK/+)) and in human metastatic renal cell carcinoma tissue. Signaling associated with cytoplasmic mislocalization of p27 in renal cancer is relatively unknown. Renal tumors derived from 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ)-treated Tsc-2(EK/+) rats, and null for tuberin, display elevated nuclear and cytosolic p27, with parallel increases in cytosolic cyclin D1 levels. Similar changes are observed in TGHQ-transformed renal epithelial cells derived from Tsc 2(EK/+) rats (QTRRE cells), which, in addition to the cytoplasmic mislocalization of p27 and cyclin D1, exhibit high ERK, B-Raf, and Raf-1 kinase activity. Renal tumor xenografts, derived from subcutaneous injection of QTRRE cells into nude mice, also display increases in cytosolic mislocalization of p27 and cyclin D1. Dibutyryl cAMP and/or phosphodiesterase inhibitors (PIs; pentoxifylline or theophylline) increase Rap1B activation, B-Raf kinase activity, and cytosolic p27/cyclin D1 protein levels in QTRRE cells. Inhibition of Raf kinases with either sorafenib or B-Raf small interfering RNA (siRNA) caused a mitogen activated protein kinase-mediated downregulation of p27. Moreover, decreases in cyclin D1 were also associated with p27 siRNA knockdown in QTRRE cells. Finally, theophylline-mediated increases in p27 and cyclin D1 were attenuated by sorafenib, which modulated Raf/MEK/ERK signaling. Collectively, these data suggest that the cAMP/Rap1B/B-Raf pathway modulates the expression of p27 and the cytoplasmic mislocalization of p27-cyclin D1 in tuberous sclerosis gene-regulated renal cancer. Therefore, the loss of tuberin and engagement of the cAMP pathway may independently direct p27-cyclin D1 cytosolic stabilization during renal tumor formation. PMID- 21693437 TI - Diversification at transcription factor binding sites within a species and the implications for environmental adaptation. AB - Evolution of new cellular functions can be achieved both by changes in protein coding sequences and by alteration of expression patterns. Variation of expression may lead to changes in cellular function with relatively little change in genomic sequence. We therefore hypothesize that one of the first signals of functional divergence should be evolution of transcription factor-binding sites (TFBSs). This adaptation should be detectable as substantial variation in the TFBSs of alleles. New data sets allow the first analyses of intraspecies variation from large number of whole-genome sequences. Using data from the Saccharomyces Genome Resequencing Project, we have analyzed variation in TFBSs. We find a large degree of variation both between these closely related strains and between pairs of duplicated genes. There is a correlation between changes in promoter regions and changes in coding sequences, indicating a coupling of changes in expression and function. We show that 1) the types genes with diverged promoters vary between strains from different environments and 2) that patterns of divergence in promoters consistent with positive selection are detectable in alleles between strains and on duplicate promoters. This variation is likely to reflect adaptation to each strain's natural environment. We conclude that, even within a species, we detect signs of selection acting on promoter regions that may act to alter expression patterns. These changes may indicate functional innovation in multiple genes and across the whole genome. Change in function could represent adaptation to the environment and be a precursor to speciation. PMID- 21693438 TI - Comparative analyses of DNA methylation and sequence evolution using Nasonia genomes. AB - The functional and evolutionary significance of DNA methylation in insect genomes remains to be resolved. Nasonia is well situated for comparative analyses of DNA methylation and genome evolution, since the genomes of a moderately distant outgroup species as well as closely related sibling species are available. Using direct sequencing of bisulfite-converted DNA, we uncovered a substantial level of DNA methylation in 17 of 18 Nasonia vitripennis genes and a strong correlation between methylation level and CpG depletion. Notably, in the sex-determining locus transformer, the exon that is alternatively spliced between the sexes is heavily methylated in both males and females, whereas other exons are only sparsely methylated. Orthologous genes of the honeybee and Nasonia show highly similar relative levels of CpG depletion, despite ~190 My divergence. Densely and sparsely methylated genes in these species also exhibit similar functional enrichments. We found that the degree of CpG depletion is negatively correlated with substitution rates between closely related Nasonia species for synonymous, nonsynonymous, and intron sites. This suggests that mutation rates increase with decreasing levels of germ line methylation. Thus, DNA methylation is prevalent in the Nasonia genome, may participate in regulatory processes such as sex determination and alternative splicing, and is correlated with several aspects of genome and sequence evolution. PMID- 21693439 TI - Molecular evolution across the Asteraceae: micro- and macroevolutionary processes. AB - The Asteraceae (Compositae) is a large family of over 20,000 wild, weedy, and domesticated species that comprise approximately 10% of all angiosperms, including annual and perennial herbs, shrubs and trees, and species on every continent except Antarctica. As a result, the Asteraceae provide a unique opportunity to understand the evolutionary genomics of lineage radiation and diversification at numerous phylogenetic scales. Using publicly available expressed sequence tags from 22 species representing four of the major Asteraceae lineages, we assessed neutral and nonneutral evolutionary processes across this diverse plant family. We used bioinformatic tools to identify candidate genes under selection in each species. Evolution at silent and coding sites were assessed for different Gene Ontology functional categories to compare rates of evolution over both short and long evolutionary timescales. Our results indicate that patterns of molecular change across the family are surprisingly consistent on a macroevolutionary timescale and much more so more than would be predicted from the analysis of one (or many) examples of microevolution. These analyses also point to particular classes of genes that may be crucial in shaping the radiation of this diverse plant family. Similar analyses of nuclear and chloroplast genes in six other plant families confirm that many of these patterns are common features of the plant kingdom. PMID- 21693441 TI - Advances in the treatment of peripheral vascular disease in diabetes and reduction of major amputations. PMID- 21693442 TI - Prevalence of deep venous incompetence and microvascular abnormalities in patients with diabetes mellitus. AB - The involvement of venous disease in the diabetic neuropathic foot is widely accepted. This article reports the result of prevalence of venous incompetence, impaired calf vein hemodynamics, and loss of microvascular control in the skin over the dorsum of the foot in an effort to document whether increased retrograde pressure caused by venous incompetence or loss of sympathetic regulation of the microcirculation is present in the diabetic patient who is at risk of foot disease. It was found that 64% and 70.7% of diabetic patients had deep venous incompetence in their right and left legs, respectively, which was statistically significantly greater than what was found in a previous report on the general population (P < .05); 42.7% and 49.3% of patients had a reduced venous refilling time in the right and left legs, respectively, and 30.7% and 33.3% of patients had loss of the arteriovenous response in the right and left legs. Some previous reports have suggested evidence of hemodynamic and morphological changes in patients with diabetic foot disease. The outstanding contribution of this report is the finding of venous incompetence in patients with diabetes but not foot disease. Because some 15% of the population with diabetes develop foot complications, the reported observations offer hope of alleviating symptoms if not preventing ulcers. PMID- 21693443 TI - Two-step autologous grafting using HYAFF scaffolds in treating difficult diabetic foot ulcers: results of a multicenter, randomized controlled clinical trial with long-term follow-up. AB - This study evaluated the efficacy and tolerability of an autologous tissue engineered graft--a 2-step HYAFF autograft--in the treatment of diabetic foot ulcers compared with standard care. In all, 180 patients with dorsal or plantar diabetic foot ulcers (unhealed for >=1 month) were randomized to receive Hyalograft-3D autograft first and then Laserskin autograft after 2 weeks (n = 90; treatment group) or nonadherent paraffin gauze (n = 90; control group). Efficacy and adverse events were assessed weekly for 12 weeks, at 20 weeks, and at 18 months. The primary efficacy outcome was complete ulcer healing at 12 weeks. Wound debridement, adequate pressure relief, and infection control were provided to both groups. At 12 weeks, complete ulcer healing was similar in both groups (24% of treated vs 21% controls). A 50% reduction in ulcer area was achieved significantly faster in the treatment group (mean 40 vs 50 days; P = .018). Weekly percentage ulcer reduction was consistently higher in the treatment group. At 20 weeks, ulcer healing was achieved in 50% of the treated group as compared with 43% of controls. Dorsal ulcers had a 2.17-fold better chance of wound healing per unit time following autograft treatment (P = .047). In a subgroup with hard-to-heal ulcers, there was a 3.65-fold better chance of wound healing following autograft treatment of dorsal ulcers (P = .035). Adverse events were similar in both groups. The study results demonstrated the potential of this bioengineered substitutes to manage hard-to-heal dorsal foot ulcers. PMID- 21693444 TI - Muscle transposition and circumferential vacuum-assisted closure to salvage the knee joint in transtibial amputation of the leg: case report. AB - Degloving injury is the avulsion of the skin off the underlying muscle and bone, which may also involve the latter structures in high-energy trauma. This study reports the case of a 33-year-old male patient who sustained a motorcycle accident and presented with hypovolemic shock, multiple fractures, and multiplanar degloving injury of the leg. The foot and distal leg was not salvageable, and a transtibial amputation with anterior transposition of the posterior compartment muscles was performed; however, a circumferential skin necrosis involving the stump and the knee joint occurred. The wound granulated rapidly using circumferential vacuum-assisted closure therapy and subsequently repaired with split thickness skin grafts. The authors found the topical negative pressure using the Vacuum Assisted Closure (VAC) technique Trademark KCI, Texas, USA, method to be helpful in the care of lower extremity degloving injury, enabling less frequent dressing changes and facilitating formation of granulation tissue with rapid preparation of the wound bed for salvage of the knee joint. PMID- 21693445 TI - Pseudoainhum of the toe with underlying chronic lower-limb ischemia. AB - BACKGROUND: Ainhum and pseudoainhum are the conditions identified by the presence of a constriction band, usually over the extremities. CASE DETAILS: We report a case of pseudoainhum in a Caucasian female with underlying chronic lower limb peripheral arterial disease (PAD). The management of pseudoainhum in patients with PAD is discussed. CONCLUSION: Revascularization of the limb should be considered in the management of patients with pseudoainhum when it is associated with severe PAD. Improved tissue perfusion prevents further ischemia and reduces the risk of developing nonhealing ulcers. PMID- 21693446 TI - Puncture wounds in the diabetic foot: importance of X-ray in diagnosis. AB - It is well recognised that septic sequelae of puncture wounds are worse in diabetics. Since much of the spreading foot sepsis from puncture wounds is deep to the deep fascia, and because the sole of the foot has thick skin and subcutaneous fibrous septae, crepitus is not as easily appreciated as it is at other sites. Also the rubor of the inflammatory response is minimal in subfascial sepsis and it is therefore easy to underestimate the extent of deep gangrene. The absence of pain due to neuropathy also masks the inflammatory reaction and makes a foreign body or severe osteomyelitis less obvious clinically. These cases demonstrate the value of routine and early radiographs in the assessment of puncture wounds in diabetic feet. PMID- 21693447 TI - Squamous cell carcinoma developing in a diabetic foot ulcer. AB - Documented cases of malignant transformation of foot ulcer in a diabetic patient in medical literature are very few. This study presents 2 interesting cases of long-standing diabetic foot ulcer, which were subsequently diagnosed to have squamous cell carcinoma on histopathological examination. PMID- 21693448 TI - News from Shanghai: the emergence of a new union. PMID- 21693453 TI - Giant ganglioneuroma of the posterior mediastinum. AB - We report the case of a 45-year-old female referred to us with progressive shortness of breath and a huge left mediastinal mass. Computed tomography of the chest revealed a mass occupying the posterior mediastinum and extending from the apex caudally to the left hemidiaphragm. Further magnetic resonance imaging demonstrated tumor extension to the left interverteberal foramina of T5-T6 and T6 T7. Excision of the mass was performed through a left posterolateral thoracotomy. Histology confirmed a mediastinal ganglioneuroma. This is an unusual tumor with more than one extension in the spine. Ganglioneuromas are rare tumors of the peripheral nervous system. Most of these tumors are, however, retroperitoneal and are more common in children and young adults. Ganglioneuromas arise from neural crest cells. These tumors are mostly asymptomatic, but some may present with hypertension and flushing. Massive tumors can present with pressure symptoms. PMID- 21693454 TI - Using the level of Service Inventory-Revised to improve assessment and treatment in drug court. AB - More than 2,000 drug courts in the United States provide supervision and substance-abuse treatment to thousands of offenders. Yet the treatment continuum from assessment to aftercare is underexplored. The effectiveness of the Level of Service Inventory-Revised (LSI-R) as a risk assessment tool is well established. However, fewer studies have considered its use in guiding treatment strategies. In using the LSI-R, the drug court program relied on the structured interview protocol (not the risk classification scores) to identify criminogenic needs that then helped determine placement in a high- or low-needs treatment track. To evaluate the effectiveness of these treatment placement decisions, this research used the LSI-R scores to examine individual and group differences (N = 182). Significant and substantive differences at the individual and group levels were found thus providing empirical support for using the LSI-R as a link between assessment and treatment. Implications for developing standards and practice protocols for drug courts are discussed. PMID- 21693455 TI - What does randomisation achieve? PMID- 21693456 TI - Evidence-based policymaking in global health - the payoffs and pitfalls. PMID- 21693457 TI - For sick-listed people with chronic low back pain, an integrated care programme costs society less and returns participants to work faster than usual management. PMID- 21693458 TI - Impact of a clonal outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae in the development and evolution of bloodstream infections by K. pneumoniae and Escherichia coli: an 11 year experience in Oxfordshire, UK. AB - OBJECTIVES: The objectives of this study were: (i) to describe an outbreak of multidrug-resistant Klebsiella pneumoniae in our population; (ii) to identify the potential source of this outbreak by examining antibiotic resistance trends in urocultures; (iii) to evaluate the contribution of this outbreak to resistance patterns over time in the two commonest Gram-negative blood culture isolates, namely K. pneumoniae and Escherichia coli; and (iv) to assess risk factors for multidrug resistance and the impact of this resistance on mortality and length of stay. METHODS: We searched Microbiology and Patient Administration Service databases retrospectively and describe resistance trends in E. coli and K. pneumoniae bloodstream infections (BSIs) in Oxfordshire, UK, over an 11 year period. RESULTS: An outbreak of a multidrug-resistant, CTX-M-15 extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae clone was identified and shown by multilocus sequence typing to belong to a novel sequence type designated ST490. This was associated with a sporadic change in resistance rates in K. pneumoniae BSIs with rates of multidrug resistance (defined as resistance to three or more antibiotic classes) reaching 40%. A case-control study showed prior antibiotic exposure as a risk factor for infection with this organism. During the same time period, rates of ESBL-producing Klebsiella spp. isolated from urocultures increased from 0.5% to almost 6%. By contrast, the rate of multidrug resistance in E. coli rose more steadily from 0% in 2000 to 10% in 2010. CONCLUSIONS: Changes in resistance rates may be associated with outbreaks of resistant clones in K. pneumoniae. Changing resistance patterns may affect important health economic issues such as length of stay. PMID- 21693459 TI - Nationwide hospital antibiotic consumption in Slovenia. PMID- 21693460 TI - Molecular characterization of blaNDM-1 in an Acinetobacter baumannii strain isolated in Germany in 2007. AB - OBJECTIVES: To investigate the genetic environment of the metallo-beta-lactamase gene bla(NDM-1) in an Acinetobacter baumannii isolated in 2007 in a German hospital. METHODS: Antimicrobial susceptibility testing was performed and resistance genes were characterized by PCR amplification and sequencing. Transferability of beta-lactam resistance was tested by broth mating assays and transformation of plasmids. The genetic background of bla(NDM-1) was analysed by primer walking. Typing of the A. baumannii strain was performed by repetitive extragenic palindromic sequence-based PCR (rep-PCR) using the DiversiLab system. RESULTS: The multidrug-resistant A. baumannii isolate harboured beta-lactamase genes bla(NDM-1) and intrinsic bla(OXA-64), but without the insertion sequence ISAba1 often located upstream. Transfer of carbapenem resistance by conjugation and transformation failed. Hybridization of isolated plasmid DNA with bla(NDM) probes was not successful. Shotgun cloning of whole genomic DNA and sequence analyses revealed that bla(NDM-1) was located between two insertion elements of ISAba125. Furthermore, this bla(NDM-1)-containing transposon structure was integrated into a chromosomal gene encoding a putative A. baumannii major facilitator superfamily (MFS) metabolite/H+ symporter. CONCLUSIONS: The metallo beta-lactamase gene bla(NDM-1) in this A. baumannii strain was integrated in the chromosome on a new transposon structure composed of two copies of insertion sequence ISAba125. The variability of the genetic environment of bla(NDM-1) likely facilitates the rapid dissemination of this gene within many Gram-negative bacterial species. PMID- 21693461 TI - Inhibition of DNA gyrase and DNA topoisomerase IV of Staphylococcus aureus and Escherichia coli by aminocoumarin antibiotics. AB - OBJECTIVES: Aminocoumarin antibiotics are potent inhibitors of bacterial DNA gyrase. We investigated the inhibitory and antibacterial activity of naturally occurring aminocoumarin antibiotics and six structural analogues (novclobiocins) against DNA gyrase and DNA topoisomerase IV from Escherichia coli and Staphylococcus aureus as well as the effect of potassium and sodium glutamate on the activity of these enzymes. METHODS: The inhibitory concentrations of the aminocoumarins were determined in gyrase supercoiling assays and topoisomerase IV decatenation assays. Both subunits of S. aureus topoisomerase IV were purified as His-Tag proteins in E. coli. The MIC was tested in vivo for the control organisms E. coli ATCC 25922 and S. aureus ATCC 29213. RESULTS: DNA gyrase is the primary target in vitro of all investigated aminocoumarins. With the exception of simocyclinone D8, all other aminocoumarins inhibited S. aureus gyrase on average 6-fold more effectively than E. coli gyrase. Potassium glutamate is essential for the activity of S. aureus gyrase and increases the sensitivity of E. coli gyrase to aminocoumarins >= 10-fold. The antibacterial activity of the tested compounds mirrored their relative activities against topoisomerases. CONCLUSIONS: The study provides insights about the substituents that are important for the inhibitory activity of aminocoumarins against the target enzymes, which will facilitate the rational design of improved antibiotics. PMID- 21693462 TI - Fluoroquinolone resistance in Escherichia coli and Klebsiella pneumoniae over 18 years: effect of different systems for eliminating duplicates. PMID- 21693463 TI - Silent spread of IMP-13-producing Pseudomonas aeruginosa belonging to sequence type 621 in Belgium. PMID- 21693464 TI - Identifying unintended consequences of quality indicators: a qualitative study. AB - BACKGROUND: For the first 5 years of the UK primary care pay for performance scheme, the Quality and Outcomes Framework (QOF), quality indicators were introduced without piloting. However, in 2009, potential new indicators were piloted in a nationally representative sample of practices. This paper describes an in-depth exploration of family physician, nurse and other primary-care practice staff views of the value of piloting with a particular focus on unintended consequences of 13 potential new QOF indicators. METHOD: Fifty-seven family-practice professionals were interviewed in 24 representative practices across England. RESULTS: Almost all interviewees emphasised the value of piloting in terms of an opportunity to identify unintended consequences of potential QOF indicators in 'real world' settings with staff who deliver day-to-day care to patients. Four particular types of unintended consequences were identified: measure fixation, tunnel vision, misinterpretation and potential gaming. 'Measure fixation,' an inappropriate attention on isolated aspects of care, appeared to be the key unintended consequence. In particular, if the palliative care indicator had been introduced without piloting, this might have incentivised poorer care in a minority of practices with potential harm to vulnerable patients. CONCLUSIONS: It is important to identify concerns and experiences about unintended consequences of indicators at an early stage when there is time to remove or adapt problem indicators. Since the UK government currently spends over L1 billion each year on QOF, the L150,000 spent on each piloting cohort (0.0005% of the total QOF budget) appears to be good value for money. PMID- 21693465 TI - Quality improvement project to reduce perioperative opioid oversedation events in a paediatric hospital. AB - BACKGROUND: Narcotics are responsible for many adverse drug events in children and there has been an increase in opioid oversedation events in hospitalised patients. OBJECTIVES: To use improvement methods to prevent perioperative opioid oversedation adverse events while continuing to provide appropriate pain control. METHODS: Interventions included revising the post-anaesthesia order form so that prescribers could choose only one narcotic and one dose for moderate pain and one narcotic and one dose for severe pain, modifying a nursing tool to provide more objective criteria for assessing patient sedation level, and restructuring the pain service. Clinicians on the Acute Pain Service saw all postoperative patients receiving intravenous patient-controlled analgesia or neuraxial narcotics in the mornings and afternoons and a nurse saw them on weekday evenings. RESULTS: The rate of opioid-related oversedation events decreased from 0.15 per 1000 patient days at baseline to 0.111 during the intervention period to 0.074 in the post intervention period. The days between events increased from 21.0 to 27.5 to 48.8 during the same periods. The number of opioid-related oversedation events decreased from 22 to 17 to 5 during these periods, respectively. CONCLUSIONS: Opioid-related oversedation events decreased over the course of the study. Because the perioperative period is an especially likely time for opioid oversedation events, strict opioid prescribing practices, while maintaining adequate pain control and improved sedation assessment during the perioperative period, were emphasised. The restructured pain service and increased visits by pain team experts were also associated with the reduction in oversedation events. PMID- 21693466 TI - The introduction of a surgical safety checklist in a tertiary referral obstetric centre. AB - BACKGROUND Surgery-related adverse events remain a significant and often under reported problem. In a recent study, the introduction of a perioperative checklist by the WHO reduced deaths and complications by 46% and 36% respectively. The authors wished to evaluate the introduction of a surgical safety checklist in a busy obstetric tertiary referral centre by assessing staff attitudes, checklist compliance and effects upon patients. METHODS A questionnaire-based assessment was performed on staff working in obstetric theatres before and after the introduction of the surgical safety checklist. Checklist compliance was assessed at 3 months and 1 year. Patients were asked questions relating to the performance of the surgical safety checklist in order to evaluate any anxiety caused. RESULTS Non-medical staff were significantly more likely than medical staff to feel familiar with other team members both before (p<0.001) and after (p=0.03) the introduction of the checklist. 69.6% of all staff felt that interprofessional communication had improved following the introduction of the checklist. Compliance with pre- and postoperative checks was 61.2% and 67.6%, respectively, improving to 79.7% and 84.7% after 1 year. Although the majority of patients were aware of the checks being performed, this did not provoke anxiety. CONCLUSION Following consultation with staff and patients, the authors managed to institute and sustain the performance of a surgical safety checklist for elective cases in obstetric theatres. While significant progress has been made, the authors recognise that further work is required in order to further evaluate and optimise this process. PMID- 21693467 TI - Disaggregating measurement uncertainty from population variability and Bayesian treatment of uncensored results. AB - In making low-level radioactivity measurements of populations, it is commonly observed that a substantial portion of net results is negative. Furthermore, the observed variance of the measurement results arises from a combination of measurement uncertainty and population variability. This paper presents a method for disaggregating measurement uncertainty from population variability to produce a probability density function (PDF) of possibly true results. To do this, simple, justifiable and reasonable assumptions are made about the relationship of the measurements to the measurands (the 'true values'). The measurements are assumed to be unbiased, that is, that their average value is the average of the measurands. Using traditional estimates of each measurement's uncertainty, a likelihood PDF for each individual's measurand is produced. Then using the same assumptions and all the data from the population of individuals, a prior PDF of measurands for the population is produced. The prior PDF is non-negative, and the average is equal to the average of the measurement results for the population. Using Bayes's theorem, posterior PDFs of each individual measurand are calculated. The uncertainty in these bayesian posterior PDFs appears to be all Berkson with no remaining classical component. The method is applied to baseline bioassay data from the Hanford site. The data include (90)Sr urinalysis measurements of 128 people, (137)Cs in vivo measurements of 5337 people and (239)Pu urinalysis measurements of 3270 people. The method produces excellent results for the (90)Sr and (137)Cs measurements, since there are non-zero concentrations of these global fallout radionuclides in people who have not been occupationally exposed. The method does not work for the (239)Pu measurements in non-occupationally exposed people because the population average is essentially zero relative to the sensitivity of the measurement technique. The method is shown to give results similar to classical statistical inference when the measurements have relatively small uncertainty. PMID- 21693468 TI - Increase in optic nerve sheath diameter induced by epidural blood patch: a preliminary report. AB - BACKGROUND: Post-dural puncture headache (PDPH) might be related to cerebrospinal fluid hypotension. Studies in brain-injured patients have shown a good relationship between optic nerve sheath diameter (ONSD) measured by ocular sonography and invasively measured intracranial pressure (ICP). The aim of this study was to evaluate changes in ONSD after lumbar epidural blood patch (EBP). METHODS: Consecutive subjects receiving an EBP for PDPH were included. ONSD and pain measurements were performed before (T(0)), 10 min (M(10)), 2 h (H(2)), and 20 h (H(20)) after the EBP. RESULTS: Ten subjects were included. ONSD [median (inter-quartile range)] increased with time after EBP, from 4.8 mm (4.5-5.1) at T(0) to 5.2 mm (4.9-5.7) at M(10) (P=0.005 vs T(0)), 5.5 mm (5.1-6.0) at H(2) (P=0.007 vs T(0)), and 5.8 mm (5.2-6.3) at H(20) (P=0.02 vs T(0)). EBP was clinically successful in nine of 10 subjects. In subjects in whom EBP was successful, ONSD significantly increased at M(10) and T(2) compared with T(0) (P=0.004 and 0.008, respectively) but did not reach statistical significance at H(20) (P=0.06). In the subject in whom EBP failed, a small increase in ONSD was observed over time. CONCLUSIONS: In this preliminary report, EBP was followed by ONSD enlargement in subjects with successful EBP, but not in the subject with EBP failure. Since ONSD is a surrogate marker of ICP, this suggests that a sustained increase in ICP is associated with successful EBP. PMID- 21693469 TI - Population pharmacokinetic analysis of ropivacaine and its metabolite 2',6' pipecoloxylidide from pooled data in neonates, infants, and children. AB - BACKGROUND: The aim was to characterize ropivacaine and 2',6'-pipecoloxylidide (PPX) pharmacokinetics and factors affecting them in paediatric anaesthesia. METHODS: Population pharmacokinetics of ropivacaine and its active metabolite PPX were estimated after single and continuous ropivacaine blocks in 192 patients aged 0-12 yr from six pooled published studies. Unbound and total ropivacaine and PPX plasma concentration and PPX urinary excretion data were used for non-linear mixed-effects modelling by NONMEM. Covariates included age, body weight, gender, ethnic origin, ASA, site and method of administration, and total dose. RESULTS: One-compartment first-order pharmacokinetic models incorporating linear binding of ropivacaine and PPX to alpha(1)-acid glycoprotein were used. After accounting for the effect of body weight, clearance of unbound ropivacaine and PPX reached 41% and 89% of their mature values, respectively, at the age of 6 months. Ropivacaine half-life decreased with age from 13 h in the newborn to 3 h beyond 1 yr. PPX half-life differed from 19 h in the newborn to 8-11 h between 1 and 12 months to 17 h after 1 yr. Simulations indicate that for a single caudal block, the recommended dose could be increased by a factor of 2.9 (0-1 month group) and 6.3 (1-12 yr group) before the unbound plasma concentrations would cross the threshold for systemic toxicity. Corresponding factors for continuous epidural infusion are 1.8 and 4.9. CONCLUSIONS: Ropivacaine and PPX unbound clearance depends on body weight and age. The results support approved dose recommendations of ropivacaine for the paediatric population. PMID- 21693470 TI - Uncalibrated arterial pressure waveform analysis for cardiac output monitoring is biased by low peripheral resistance in patients with intracranial haemorrhage. AB - BACKGROUND: Cardiac output (CO) monitoring by uncalibrated arterial pressure waveform analysis (APCO) using the FloTrac/VigileoTM is feasible in patients with intracranial haemorrhage, but the results of validation studies are contradictory. The aim of the present study was to analyse the clinical agreement between the intermittent bolus thermodilution technique (TDCO) and APCO in patients with non-traumatic intracranial haemorrhage. METHODS: This was a prospective observational clinical study in a university level intensive care unit. We studied patients who underwent CO monitoring according to clinical indications using TDCO. Simultaneously, APCO was applied using the radial arterial pressure curve. The difference in CO values measured by APCO with a mid chest calibration level was compared with a calibration level at the angle of the eye. RESULTS: A total of 407 data pairs from 16 patients were obtained. The mean CO(TDCO) was 7.6 litre min(-1) and CO(APCO) was 6.0 litre min(-1), with a bias corrected for repeated measures of 1.5 litre min(-1) and 95% limits of agreement of -2.4 to 5.4 litre min(-1). The percentage error was 58%. The increasing bias correlated with low peripheral resistance (rho=-0.53, P=0.036). The calibration level at the patient's eye angle did not affect CO values (median bias 0 litre min(-1) with 25th-75th percentile -0.1 to 0.2 litre min(-1)). CONCLUSIONS: The second generation of FloTrac((r))/Vigileo((r)) monitoring system underestimates the TDCO in patients with non-traumatic intracranial haemorrhage. The bias correlates with measured systemic vascular resistance. The upper calibration level does not affect the results. PMID- 21693471 TI - Depression, anxiety and physical function: exploring the strength of causality. AB - BACKGROUND: Depression, anxiety and physical function may be bi-directionally related. We aim to estimate the strength of the longitudinal associations between depression, anxiety and physical function. METHODS: Prospective cohort study of general practice attendees across Europe (N=4757) assessed at baseline, 6, 12 and 24 months. Main outcome measures were Diagnostic and Statistical Manual of Mental Disorders-IV major depression, Patient Health Questionnaire anxiety and Short Form 12 physical function. Complete-case analyses using random coefficient models and logistic regression models were performed. RESULTS: Those with depression (beta=-1.90, 95% CI -3.42 to -0.39), anxiety (beta=-4.12, 95% CI -5.39 to -2.86) or depression and anxiety (beta=-5.74, 95% CI -7.38 to -4.10) had lower levels of physical function at baseline and over time compared with no diagnosis after adjustment for potential confounders. Physical function increased over time, but the rate of increase was not different between the groups. When compared with depression, those with anxiety (beta=-2.22, 95% CI -4.08 to -0.36) or depression and anxiety (beta=-3.83, 95% CI -5.95 to -1.71) had significantly lower levels of physical function at baseline. Lower levels of physical function at baseline were associated with onset of depression (OR 1.83, 95% CI 1.08 to 3.10) but even stronger with anxiety (OR 2.79, 95% CI 1.52 to 5.12) or depression and anxiety (OR 5.05, 95% CI 2.55 to 9.99) during 24 months compared with no dysfunction, after adjustment for potential confounders. CONCLUSION: It is essential to prevent lower levels of physical function as this is likely to lead to onset of depression and anxiety over time. PMID- 21693473 TI - A nutrition labeling intervention in worksite cafeterias: an implementation evaluation across two large catering companies in the Netherlands. AB - By both increasing the availability of healthy foods and labeling these products with the Choices logo, caterers may facilitate employees to make a healthier choice in their worksite cafeterias. The aim of this study was to explore which attributes influence the implementation of the Choices logo in worksite cafeterias in the Netherlands. Questionnaires were completed by catering managers of 316 cafeterias of two large caterers in the Netherlands (response rate 49.8%). Attributes from the Diffusion of Innovations Theory were used to investigate whether they could predict implementation. Compatibility (consistency with the beliefs of the catering manager; OR = 1.52), voluntariness (perception of the implementation as voluntary; OR = 0.50), result demonstrability (ability to communicate the implementation; OR = 1.52) and complexity in the sense of time (time needed for implementation; OR = 0.70) were the best predictors for the frequency of offering fresh Choices products (all significant). For the frequency of using Choices promotion material, voluntariness (OR = 0.54), result demonstrability (OR = 1.51) and relative advantage (perceived advantage of the implementation; OR = 1.44) were the best predictors (all significant). In conclusion, this study provides unique insights into which perceived attributes influence the implementation of a nutrition logo in worksite cafeterias. To increase the implementation, the Choices logo should be consistent with catering managers' ideas about healthy food, the workload of implementing the logo should be limited and it could be recommended to incorporate the logo in the health policy of the caterer. PMID- 21693472 TI - The impact of housing improvement and socio-environmental factors on common childhood illnesses: a cohort study in Indigenous Australian communities. AB - BACKGROUND: Improvements in health are an important expected outcome of many housing infrastructure programs. The authors aimed to determine if improvement in the notoriously poor housing infrastructure in Australian Indigenous communities results in reduction in common childhood illness and to identify important mediating factors in this relationship. METHODS: The authors conducted a prospective cohort study of 418 children aged 7 years or younger in 10 Australian Indigenous communities, which benefited most substantially from government-funded housing programs over 2004-2005. Data on functional and hygienic state of houses, reports of common childhood illness and on socio-economic conditions were collected through inspection of household infrastructure and interviews with children's carers and householders. RESULTS: After adjustment for a range of potential confounding variables, the analysis showed no consistent reduction in carers' reporting of common childhood illnesses in association with improvements in household infrastructure, either for specific illnesses or for these illnesses in general. While there was strong association between improvement in household infrastructure and improvement of hygienic condition of the house, there were only marginal improvements in crowding. CONCLUSIONS: High levels of household crowding and poor social, economic and environmental conditions in many Australian Indigenous communities appear to place major constraints on the potential for building programs to impact on the occurrence of common childhood illness. These findings reinforce the need for building programs to be supported by a range of social, behavioural and community-wide environmental interventions in order for the potential health gains of improved housing to be more fully realised. PMID- 21693474 TI - 'Trying to make it all come together': structuration and employed mothers' experience of family food provisioning in Canada. AB - This research examined the aetiology of employed mothers' food choice and food provisioning decisions using a qualitative, grounded theory methodology. Semi structured interviews using the Food Choice Map were conducted with eleven middle income employed mothers of elementary school-age children. Results demonstrated that the women exhibited conflicting identities with respect to food choice and provisioning. As 'good mothers' they were the primary food and nutrition caregivers for the family, desiring to provide healthy, homemade foods their families preferred at shared family meals. They also sought to be independent selves, working outside the home, within the context of a busy modern family. Increased food autonomy of children, and lack of time due to working outside the home and children's involvement in extracurricular activities, were significant influences on their food choice and provisioning. This resulted in frequently being unable to live up to their expectations of consistently providing healthy homemade foods and having shared family meals. To cope, the women frequently relied on processed convenience and fast foods despite their acknowledged inferior nutritional status. Using Giddens' structuration theory, the dynamic relationships between the women's food choice and provisioning actions, their identities and larger structures including socio-cultural norms, conditions of work and the industrial food system were explored. The ensuing dietary pattern of the women and their families increases the risk of poor health outcomes, including obesity. These results have implications for public health responses to improve population health by shifting the focus from individual-level maternal influences to structural influences on diet. PMID- 21693475 TI - Maternal cigarette smoking is associated with reduced high-density lipoprotein cholesterol in healthy 8-year-old children. AB - AIMS: Smoking in pregnancy is common. Its effects on lipoprotein levels and arterial structure in childhood are not well characterized. We aimed to determine the effects of maternal smoking in pregnancy on lipoprotein levels and arterial wall thickness in healthy pre-pubertal children. METHODS AND RESULTS: A community based longitudinal study with prospective ascertainment of exposure to smoking in pregnancy and environmental tobacco smoke (ETS) since birth and then lipoprotein and arterial measurements at age 8 years. In 616 newborn infants (gestation >36 weeks and birth weight >2.5 kg) data were collected prospectively by questionnaire on smoking in pregnancy and ETS exposure in childhood. At age 8 years, 405 of the children had measurements of lipoproteins, blood pressure (BP) and carotid intima-media thickness. Children born to mothers who smoked in pregnancy had lower HDL cholesterol [1.32 vs. 1.50 mmol/L, 95% confidence interval (CI) for difference -0.28 to -0.08, P = 0.0005], higher triglycerides (1.36 vs. 1.20 mmol/L, 95% CI for ratio 1.01-1.30, P = 0.04) and higher systolic BP (102.1 vs. 99.9 mmHg, 95% CI for difference 0.6-3.8, P = 0.006). After adjustment for maternal passive smoking, post-natal ETS exposure, gender, breast feeding duration, physical inactivity, and adiposity, smoking in pregnancy remained significantly associated with lower HDL cholesterol (difference = -0.22 mmol/L, 95% CI -0.36 to -0.08, P = 0.003) but not with higher systolic BP. Neither smoking in pregnancy nor post-natal ETS exposure was associated with alterations of carotid artery wall thickness. CONCLUSION: Smoking in pregnancy is independently associated with significantly lower HDL cholesterol in healthy 8 year-old children. PMID- 21693476 TI - Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel. AB - AIMS: To perform a meta-analysis of the association between CYP2C19 loss- and gain-of-function variants and cardiovascular outcomes and bleeding in patients with coronary artery disease treated with clopidogrel, and to explore the causes of heterogeneity between studies. METHODS: A comprehensive literature search was conducted. A random-effects model was used to summarise the results. In the presence of between-study heterogeneity, a meta-regression analysis was performed to identify study characteristics explaining this heterogeneity. RESULTS: Patients who carried a loss-of-function allele, mainly CYP2C19*2, did not present an increased risk of a cardiovascular event, HR =1.23 (95% CI 0.97 to 1.55). Substantial heterogeneity was observed between studies (I(2) =35.6), which was partially explained by the study sample size: the pooled HR was higher among studies with a sample size <500 patients (HR =3.55; 95% CI 1.66 to 7.56) and lower among studies with a sample size >=500 (HR =1.06; 95% CI 0.89 to 1.26). CYP2C19*2 was associated with an increased risk of a stent thrombosis (HR =2.24; 95% CI 1.52 to 3.30). The gain-of-function allele, mainly CYP2C19*17, was associated with a lower risk of cardiovascular events (HR =0.75; 95% CI 0.66 to 0.87) and a higher risk of major bleeding (HR =1.26; 95% CI 1.05 to 1.50). CONCLUSIONS: Not only CYP2C19 loss-of-function but also gain-of-function alleles should be considered to define the pharmacogenetic response to clopidogrel. The results question the relevance of the CYP2C19 loss-of-function alleles in the prediction of major cardiovascular events beyond stent thrombosis in coronary patients treated with clopidogrel. The gain-of-function variant is associated with a lower risk of cardiovascular events but a higher risk of bleeding. PMID- 21693477 TI - Hospital characteristics are associated with patient outcomes following out-of hospital cardiac arrest. AB - OBJECTIVE: Post-resuscitation care may influence outcome following transport to hospital after resuscitation from out-of-hospital cardiac arrest (OHCA). This study aimed to determine whether receiving hospital characteristics such as 24-h cardiac catheterisation services, total bed number or OHCA patient volume influence the rate of survival. SETTING: Data were analysed from the Victorian Ambulance Cardiac Arrest Registry of patients from January 2003 to March 2010 who were transported to hospital with return of spontaneous circulation (ROSC) after OHCA. RESULTS: Ambulance paramedics attended 9971 patients with OHCA of suspected cardiac cause during the study period. Of these, 2902 (29%) achieved ROSC and were transported to one of 70 hospitals. 1816 (63%) were treated at hospitals with 24-h cardiac interventional services. After adjusting for differences in baseline characteristics, hospital factors significantly associated with survival were treatment at hospitals with 24-h cardiac interventional services (OR 1.40; 95% CI 1.12 to 1.74, p=0.003) and patient reception between 08:00 and 17:00 hours (OR 1.34; 95% CI 1.10 to 1.64, p=0.004). OHCA patient volume and total hospital bed number were not independently associated with outcome. CONCLUSION: Hospital characteristics are associated with improved survival in patients with OHCA. This finding has implications for the establishment of regionalised systems of care for patients who have been resuscitated from OHCA. PMID- 21693478 TI - A proposed theoretical definition to address the undercounting of injury deaths. PMID- 21693479 TI - A coughing spine. PMID- 21693480 TI - Efficiency of translation termination in humans is highly dependent upon nucleotides in the neighbourhood of a (premature) termination codon. AB - BACKGROUND: Spontaneous read-through of a premature termination codon (PTC) has so far not been observed in patients carrying nonsense mutations. This report describes a patient with junctional epidermolysis bullosa who was expected to die because of compound heterozygous nonsense mutations in the gene LAMA3 (R943X/R1159X), but was rescued by spontaneous read-through of the R943X allele. RESULTS AND CONCLUSION: FACS analysis of cells carrying various PTCs surrounded by their natural neighbouring codons revealed significant reporter gene expression despite the PTC only for this patient's genetic context. Gene expression could be abolished by replacing the first or third nucleotide before, or one of the two nucleotides following the PTC. Site-directed mutagenesis was used to identify genotypes allowing PTC read-through. The genetic context of the LAMA3 mutation R943X is close to a hypothetical consensus sequence for maximum PTC read-through. Bioinformatic analysis showed that this consensus sequence is present in four sequences from the NCBI reference database, each of which contains another in-frame termination codon three or four codons apart. This indicates strong selective pressure against leaky termination codons in the human genome. This patient's mutated full length mRNA escaped nonsense-mediated decay, leading to LAMA3 mRNA levels similar to those of a healthy control, and full length laminin alpha3 could be detected in culture supernatant of the patient's keratinocytes. Immunofluorescence analyses of skin biopsies and continuous clinical improvement of the patient's condition suggested accumulation of intact laminin-332 in the epidermal basement membrane. These findings provide important clues for the prediction of PTC read-through in human genetic disease. PMID- 21693481 TI - Expert nurses and the division of labour in hospitals. AB - This article analyses nursing expertise with a particular focus at the level of clinical and organizational practice. Through an examination of a specialist team of hospital nurses, and drawing on the concept of a community of practice, the article provides a critique of discussions of nursing expertise which can be overly normative, individualistic or divorced from practice. The theoretical background to our analysis is the division of labour in health care; the case study on which this analysis is based is a particular health policy: the introduction of critical care outreach services. The empirical portions of the article are based on a qualitative study of eight such services in England. In the first part of the analysis we elaborate on three ways in which 'expertise' can be deployed in practice: teaching and training; consultancy and advice; and practical clinical action. Each of these is shown to be related to the development of a community of practice. In the second part of the analysis we examine in more detail the impact of outreach nurses on the division of labour in health care and on traditional occupational hierarchies. A general implication of our findings is that expertise has fundamentally social characteristics which need to be acknowledged in academic and policy discourse. PMID- 21693482 TI - Preoperative diagnosis of ductal carcinoma in situ arising within a mammary fibroadenoma: a case report. AB - Fibroadenoma is the most common form of benign breast tumor and the most common breast tumor in women under 30 years of age. However, carcinoma arising within a fibroadenoma is unusual, with over 100 cases reported in the literature. Histological diagnosis is typically unexpected. A 46-year-old female with no family history of breast malignancies was admitted for an elastic hard lump in the upper-outer quadrant of her right breast. At a clinic that she visited previously, her condition was diagnosed by core needle biopsy with four specimens showing fibroadenoma with borderline atypical ductal hyperplasia at pathology. Excisional biopsy was recommended for pathological diagnosis. The patient requested a definitive diagnosis and alternative treatment to tumorectomy. More biopsy specimens were needed for pathological diagnosis; therefore, ultrasonography-guided vacuum-assisted core needle biopsies were obtained, confirming ductal carcinoma in situ with questionable microinvasion of intracanalicular- and pericanalicular-type fibroadenoma. Right breast-conserving surgery and sentinel lymph node biopsy were immediately performed for radical therapy. We present this case to increase awareness of this entity and stress the need for histological evaluation of some breast masses. PMID- 21693483 TI - Relationship between hematotoxicity and serum albumin level in the treatment of head and neck cancers with concurrent chemoradiotherapy using cisplatin. AB - OBJECTIVE: Patients with locally advanced head and neck cancer were treated with concurrent chemoradiotherapy using three courses of cisplatin. However, many patients were unable to complete the scheduled cisplatin treatment due to adverse effects. The objective of this study was to retrospectively elucidate the source of the low completion rate of cisplatin courses. METHODS: Between November 2007 and 28 May 2010, patients with head and neck cancer were treated with curative intent according to the concurrent chemoradiotherapy protocol (66-70 Gy at 2 Gy/day with cisplatin 80 mg/m(2) on Days 1, 22 and 43). Treatment courses, hematological data and other parameters were investigated, and the treatment completion rates and reasons for treatment failure were analyzed. RESULTS: Among the 28 patients, cisplatin was administered during the period of radiotherapy a total of 3 times in 9 (32%) patients, 2 times in 15 (54%) patients and only 1 time in 4 (14%) patients. Multiple regression analysis of the development of neutropenia at 3 weeks after the first cisplatin administration revealed that the serum albumin level was a significant explanatory variable (R(2)= 0.664, beta = 0.517, P< 0.01). Pearson's product-moment correlation coefficient showed a strong correlation between the serum albumin level and the neutrophil count after 3 weeks (r = 0.605, P< 0.01). CONCLUSIONS: The treatment completion rate by this protocol was low in head and neck cancer patients even when the cisplatin dose was reduced to 80 mg/m(2). This tendency was seen in patients with a low serum albumin level. PMID- 21693484 TI - Salvage radiotherapy for prostate-specific antigen relapse after radical prostatectomy for prostate cancer: a single-center experience. AB - OBJECTIVE: The aim of this study was to investigate the efficacy and prognostic factors of salvage radiotherapy for prostate-specific antigen relapse after radical prostatectomy for prostate cancer at a single center in Japan. METHODS: A retrospective review of the medical records of 51 patients who underwent salvage radiotherapy for prostate-specific antigen relapse after radical prostatectomy was carried out. Salvage radiotherapy was undergone for the single indication of at least two consecutive prostate-specific antigen elevations >0.1 ng/ml. Salvage radiotherapy was delivered to the prostatic bed at a total dose of 60 or 64 Gy. Late toxicity was scored according to the Common Terminology Criteria for Adverse Events 3.0. RESULTS: A total dose of 60 and 64 Gy were administered to 26 and 25 patients, respectively. The median prostate-specific antigen level at the initiation of radiotherapy was 0.29 ng/ml (range, 0.11-1.10 ng/ml). With a median follow-up of 57.3 months (range, 9.9-134.0 months), the prostate-specific antigen relapse-free rate at 5 years was 50.7%. Multivariate analysis using Cox's proportional hazards regression model revealed that the Gleason score at radical prostatectomy >=8 significantly predicted prostate-specific antigen relapse after salvage radiotherapy (hazard ratio 4.531; 95% confidence interval 1.413-14.535; P=0.011). The prostate-specific antigen relapse-free rate at 5 years in the Gleason score at radical prostatectomy <=7 and at radical prostatectomy >=8 was 62.7 and 15.4%, respectively. CONCLUSIONS: Salvage radiotherapy was effective for prostate-specific antigen relapse after radical prostatectomy with tolerable toxicities in Japanese patients. A high Gleason score seemed to be a poor prognostic factor. PMID- 21693485 TI - Service users' personal experience and interpretation of mental illness: oriental narratives. AB - BACKGROUND: Service users' perception of mental illness is vital because it points out a viable direction that practitioners can follow to fully understand service users in their own sociocultural context. MATERIAL: Qualitative research findings include mental health service users' roles and identities, their perceptions of mental illness and their personal experiences of psychiatric stigma. DISCUSSION: While there are similar phenomena regarding mental illness stigma between East and West, there are culturally distinctive characteristics found in Taiwan. CONCLUSIONS: Based on personal perceptions and experiences, mental health service users have interpreted illness and performed the patient role in their own way. PMID- 21693486 TI - The influence of gender role on the prediction of antisocial behaviour and somatization. AB - BACKGROUND: Previous research has demonstrated a sex-differentiated relationship between antisocial behaviour and somatization. One explanation posited is that societal expectations about male and female behaviour may influence a sex differentiated expression of a common diathesis, but this idea has not been directly tested. AIMS: The current study examined the potential contribution of gender role in the prediction of antisocial and somatic symptomatology, controlling for biological sex, impulsivity and negative affect. METHODS: Linear regression was used to examine the influence of gender role on somatic and antisocial symptomatology. Path analysis was used to examine whether relationships among these variables differed significantly for men and women. Participants were 349 undergraduate students in southeastern USA. RESULTS: Masculine gender role was positively related to antisocial behaviour, while feminine gender role was negatively related to antisocial behaviour. Gender role did not predict somatization. CONCLUSIONS: Gender role may be important to the expression of antisocial behaviour, but does not influence somatic symptoms. Current findings underscore the need to consider that observed sex differences in antisocial behaviour might actually be affected by gender role, and highlight the importance of considering societal expectations of male and female behaviour when examining apparent sex differences in behaviour. PMID- 21693487 TI - Self-harm and attempted suicide among UK armed forces personnel: results of a cross-sectional survey. AB - AIMS: Little has been reported on self-harm among the UK Armed Forces, partly due to the difficulties in recording self-harm, within an often-difficult-to-reach population. This study assesses the lifetime prevalence of attempted suicide and self-harm within currently serving and ex-service personnel of the UK Armed Forces. METHODS: Telephone interviews were conducted with 821 personnel who had previously participated in the King's Centre for Military Health Research military health study. Within the telephone interview, participants were asked about attempted suicide and episodes of self-harm. RESULTS: A lifetime prevalence of 5.6% for intentional self-harm (self-harm or attempted suicide) was reported. Intentional self-harm was associated with psychological morbidity (in particular, post-traumatic stress disorder) and adverse experiences in childhood. Ex-service personnel reported lifetime prevalence more than double that of serving personnel (10.5% vs 4.2%, respectively). Participants reporting intentional self-harm were younger (34.4 years vs 39.8 years). CONCLUSION: A lifetime prevalence of 5.6% for attempted suicide and self-harm is higher than previous research has suggested. Younger service personnel, those who have experienced adversity in childhood, those with other psychological morbidity, and ex-service personnel are more likely to report self-harm behaviours. PMID- 21693488 TI - First spinosaurid dinosaur from Australia and the cosmopolitanism of Cretaceous dinosaur faunas. AB - A cervical vertebra from the Early Cretaceous of Victoria represents the first Australian spinosaurid theropod dinosaur. This discovery significantly extends the geographical range of spinosaurids, suggesting that the clade obtained a near global distribution before the onset of Pangaean fragmentation. The combined presence of spinosaurid, neovenatorid, tyrannosauroid and dromaeosaurid theropods in the Australian Cretaceous undermines previous suggestions that the dinosaur fauna of this region was either largely endemic or predominantly 'Gondwanan' in composition. Many lineages are well-represented in both Laurasia and Gondwana, and these observations suggest that Early-'middle' Cretaceous theropod clades possessed more cosmopolitan distributions than assumed previously, and that caution is necessary when attempting to establish palaeobiogeographic patterns on the basis of a patchily distributed fossil record. PMID- 21693489 TI - Epidemiological consequences of a newly discovered cryptic subgroup of Anopheles gambiae. AB - A cryptic subgroup of Anopheles gambiae sensu stricto mosquitoes was recently discovered in West Africa. This 'GOUNDRY' subgroup has increased susceptibility to Plasmodium falciparum, the most deadly form of malaria. Unusual for this major malaria vector, GOUNDRY mosquitoes also seem to bite exclusively outdoors. A mathematical model is developed to assess the epidemiological implications of current vector control tools, bednets and indoor residual spray, preferentially suppressing the more typical indoor biting mosquitoes. It is demonstrated that even if the GOUNDRY mosquitoes have a decreased preference for human blood, vector controls which select for increased GOUNDRY abundance relative to their indoor biting counterparts risks intensifying malaria transmission. Given the widely observed phenomenon of outdoor biting by major malaria vectors, this behaviour should not be ignored in future modelling efforts and warrants serious consideration in control programme strategy. PMID- 21693492 TI - Systemic lupus erythematosus flare up manifestation as cerebral and spinal subarachnoid hemorrhage. AB - Subarachnoid hemorrhage (SAH) is an uncommon complication of systemic lupus erythematosus (SLE). Here we report a 52-year-old woman with flare up of lupus activity, manifesting as spontaneous cerebral and spinal SAH due to central nervous system vasculitis. The patient received external ventricular drainage for hydrocephalus and pulse steroid and intravenous cyclophosphamide therapies. Her neurological deficits gradually improved with only minimal gait unsteadiness at discharge. Although very rare, cerebral and spinal SAH related to vasculitis could be one of the presentations of SLE flare up. PMID- 21693490 TI - Mechanisms of hierarchical reinforcement learning in corticostriatal circuits 1: computational analysis. AB - Growing evidence suggests that the prefrontal cortex (PFC) is organized hierarchically, with more anterior regions having increasingly abstract representations. How does this organization support hierarchical cognitive control and the rapid discovery of abstract action rules? We present computational models at different levels of description. A neural circuit model simulates interacting corticostriatal circuits organized hierarchically. In each circuit, the basal ganglia gate frontal actions, with some striatal units gating the inputs to PFC and others gating the outputs to influence response selection. Learning at all of these levels is accomplished via dopaminergic reward prediction error signals in each corticostriatal circuit. This functionality allows the system to exhibit conditional if-then hypothesis testing and to learn rapidly in environments with hierarchical structure. We also develop a hybrid Bayesian-reinforcement learning mixture of experts (MoE) model, which can estimate the most likely hypothesis state of individual participants based on their observed sequence of choices and rewards. This model yields accurate probabilistic estimates about which hypotheses are attended by manipulating attentional states in the generative neural model and recovering them with the MoE model. This 2-pronged modeling approach leads to multiple quantitative predictions that are tested with functional magnetic resonance imaging in the companion paper. PMID- 21693491 TI - Mechanisms of hierarchical reinforcement learning in cortico-striatal circuits 2: evidence from fMRI. AB - The frontal lobes may be organized hierarchically such that more rostral frontal regions modulate cognitive control operations in caudal regions. In our companion paper (Frank MJ, Badre D. 2011. Mechanisms of hierarchical reinforcement learning in corticostriatal circuits I: computational analysis. 22:509-526), we provide novel neural circuit and algorithmic models of hierarchical cognitive control in cortico-striatal circuits. Here, we test key model predictions using functional magnetic resonance imaging (fMRI). Our neural circuit model proposes that contextual representations in rostral frontal cortex influence the striatal gating of contextual representations in caudal frontal cortex. Reinforcement learning operates at each level, such that the system adaptively learns to gate higher order contextual information into rostral regions. Our algorithmic Bayesian "mixture of experts" model captures the key computations of this neural model and provides trial-by-trial estimates of the learner's latent hypothesis states. In the present paper, we used these quantitative estimates to reanalyze fMRI data from a hierarchical reinforcement learning task reported in Badre D, Kayser AS, D'Esposito M. 2010. Frontal cortex and the discovery of abstract action rules. Neuron. 66:315--326. Results validate key predictions of the models and provide evidence for an individual cortico-striatal circuit for reinforcement learning of hierarchical structure at a specific level of policy abstraction. These findings are initially consistent with the proposal that hierarchical control in frontal cortex may emerge from interactions among nested cortico striatal circuits at different levels of abstraction. PMID- 21693493 TI - Changes in the expression of telomere maintenance genes might play a role in the pathogenesis of systemic lupus erythematosus. AB - Previous studies demonstrated that telomerase activity increased while telomere length shortened in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE). This study aimed to examine the changes of telomere maintenance genes and their clinical significance in SLE. The mRNA level of telomeric proteins in PBMCs, including shelterin complex (TRF1, TRF2, POT1, TPP1, TIN2 and hRAP1), a set of multifunctional proteins involved in telomere maintenance (MRE11, KU80 and RPA1), and Ki67, was measured using real-time quantitative PCR in 56 SLE patients (36 treated and 20 untreated; 32 with renal involvement and 24 without renal involvement) and 46 healthy subjects (controls). The expression of TPP1, TIN2, POT1 and KU80 was significantly reduced while that of TRF2 and MRE11 increased in SLE patients (p < 0.05, respectively); significant difference was not found in the expression of TRF1, hRAP1, RPA1 and Ki67 (p > 0.05, respectively). The expression of TRF2, MRE11 and Ki67 was much higher in untreated SLE patients than in controls or treated SLE patients (p < 0.05, respectively); the expression of hRAP1 was much higher in SLE patients with renal involvement than in controls or SLE patients without renal involvement (p < 0.05, respectively). Significant positive correlation was found between level of KU80 and C3, TPP1 and TIN2, TPP1 and POT1, while significant negative correlation was found between KU80 and serum total globulins, TIN2 and RF, TPP1 and SLEDAI score (p < 0.05, respectively). In conclusion, altered expression of telomere maintenance genes might be involved in the pathogenesis of SLE. Further study in expression and functions of telomeric proteins would be needed. PMID- 21693494 TI - A retrospective study of pulmonary infarction in patients with systemic lupus erythematosus from southern Taiwan. AB - Since large-scale reports of pulmonary infarction in systemic lupus erythematosus (SLE) are limited, a retrospective study was performed for this manifestation in 773 hospitalized patients in southern Taiwan from 1999 to 2009. Pulmonary infarction was defined as the presence of pulmonary embolism, persistent pulmonary infiltrates, and characteristic clinical symptoms. Demographic, clinical, laboratory, and radiological images data were analyzed. There were 12 patients with pulmonary embolism and 9 of them had antiphospholipid syndrome (APS). Six patients (19 to 53 years, average 38.2 +/- 12.6) with 9 episodes of lung infarction were identified. All cases were APS and four episodes had coincidental venous thromboembolism. There were four episodes of bilateral infarction and seven episodes of larger central pulmonary artery embolism. Heparin therapy was routinely prescribed and thrombolytic agents were added in two episodes. Successful recovery was noted in all patients. In conclusion, there was a 0.8% incidence of pulmonary infarction in patients with SLE, all with the risk factor of APS. Differentiation between pulmonary infarction and pneumonia in lupus patients should be made; they have similar chest radiography with lung consolidation but require a different clinical approach in management. Although this report is a retrospective study with relatively small numbers of lupus patients with lung infarcts, our observation might provide beneficial information on the clinical features and radiological presentations during the disease evolution of pulmonary infarction in SLE with APS. PMID- 21693495 TI - The British Menopause Society: next steps 2011. PMID- 21693497 TI - Modernizing the NHS: observations and recommendations from the British Menopause Society. AB - Women's health often declines in middle and old age for reasons that are avoidable. Simple measures including lifestyle change could make a significant difference. Education of women is all important. The BMS feels that the provision of a simple health check of all women at the age of 50 years would provide an excellent opportunity that would serve as a screening as well as an educational visit at which balanced information about appropriate treatments and lifestyle changes in natural and premature menopause should be given to empower women to make an informed choice. PMID- 21693498 TI - Bazedoxifene: a new selective estrogen receptor modulator for postmenopausal osteoporosis. AB - An ongoing need for safe and effective pharmacological therapies exists for postmenopausal osteoporosis, which imposes a significant burden on both women and the health-care system. Bazedoxifene is a novel selective estrogen receptor modulator with a unique tissue-selectivity profile. In phase 3 clinical trials of nearly 10,000 postmenopausal women, bazedoxifene was shown to significantly reduce the risk of new vertebral fracture versus placebo, with favourable effects on bone mineral density, bone turnover markers and the lipid profile. Moreover, in a subgroup of women at increased risk of fracture, bazedoxifene significantly decreased non-vertebral fracture risk versus both placebo and raloxifene. Bazedoxifene has been shown to be safe and well tolerated, with no evidence of endometrial or breast stimulation. These data suggest that bazedoxifene may offer significant clinical benefit for postmenopausal women with or at risk of developing osteoporosis, which may subsequently lessen the medical and economic burden of this disease. PMID- 21693499 TI - Management of the menopause: integrated health-care pathway for the menopausal woman. AB - Management of the menopausal woman has become controversial since publication of the results of the Women's Health Initiative and the Million Women Study from 2002 onwards. This health-care pathway summarizes the role of hormone replacement therapy and non-estrogen-based treatments as well as alternative and complementary therapies. It is based on the fifth edition of Management of the Menopause and was updated on 5 April 2011. PMID- 21693500 TI - Setting and maintaining standards in menopause care: audit of current practice in a specialist clinic. AB - Standards are an important way of demonstrating quality of care in any given setting. The British Menopause Society (BMS) has produced guidelines as to what should be recorded at the initial menopause consultation. A retrospective audit of case-notes of women attending Poole Menopause Centre was undertaken using these criteria as audit standards. Although areas of good practice were highlighted, the published criteria were met for only five of the 23 standards. An action plan to improve the documentation to achieve these standards has been formulated. PMID- 21693501 TI - Advice given to women undergoing gynaecological surgery in relation to menopause, symptoms and hormone replacement therapy: could and should we improve the service we provide? AB - A retrospective case-note study was undertaken to look at recorded details relating to information/advice given to women prior to or at the time of their gynaecological surgery with regard to possible effects of menopause/menopausal symptoms or advice given about hormone replacement therapy. PMID- 21693502 TI - National Osteoporosis Society's Position statement on hormone replacement therapy in the prevention and treatment of osteoporosis. AB - Hormone replacement therapy (HRT) has been shown to increase bone density, reduce the risk of fracture and can successfully relieve menopausal symptoms. From a time when HRT was the major therapeutic option for the management of osteoporosis, women and their clinicians now have a range of treatments available. Following the publication of the Women's Health Initiative (WHI) and the Million Women Study highlighting potential side-effects, such as breast cancer, heart disease and stroke, many doctors and women are now reluctant to use HRT. The National Osteoporosis Society felt that the role of HRT in the management of osteoporosis needed to be clarified. Using the Charity's expert clinical and scientific advisers, and through public consultation with members and key stakeholders, a Position Statement has been published. We conclude that HRT has a role to play in the management of osteoporosis in postmenopausal women below the age of 60 years. The key recommendations of the Position Statement are presented in this paper. PMID- 21693503 TI - Role of bisphosphonates in the management of postmenopausal osteoporosis: an update on recent safety anxieties. AB - Following their introduction in the 1990s, bisphosphonates have become the mainstay of treatment in the management of postmenopausal osteoporosis, and their use continues to rise. Commonly noted adverse effects in clinical practice include gastrointestinal side-effects, acute phase reactions (predominately seen with intravenous preparations) cutaneous reactions and more rarely, ocular side effects. However, recent reports of potentially serious adverse effects of bisphosphonate therapy, including atypical subtrochanteric and femoral shaft fractures, atrial fibrillation, oesophageal carcinoma and osteonecrosis of the jaw, have prompted concerns regarding the long-term safety of this class of drugs. This review summarizes the benefits and potential adverse effects of bisphosphonates used in the treatment of postmenopausal osteoporosis. Although evidence of a definitive casual relationship between bisphosphonate therapy and serious adverse effects is lacking, concern remains particularly in relation to atypical subtrochanteric and femoral shaft fractures. This has important consequences in terms of determining optimum duration of therapy and how best to target therapy at those most at risk. Recently, attention has focused on individual fracture risk assessment in order to optimize the risk-benefit ratio of treatment for individual patients. A review of the role of hormone replacement therapy in younger women with significant risk of osteoporotic fractures may be timely in these circumstances. PMID- 21693504 TI - Impact of changes in blood pressure during the treatment of acute decompensated heart failure on renal and clinical outcomes. AB - AIMS: One of the primary determinants of blood flow in regional vascular beds is perfusion pressure. Our aim was to investigate if reduction in blood pressure during the treatment of decompensated heart failure would be associated with worsening renal function (WRF). Our secondary aim was to evaluate the prognostic significance of this potentially treatment-induced form of WRF. METHODS AND RESULTS: Subjects included in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial limited data were studied (386 patients). Reduction in systolic blood pressure (SBP) was greater in patients experiencing WRF (-10.3 +/- 18.5 vs. -2.8 +/- 16.0 mmHg, P < 0.001) with larger reductions associated with greater odds for WRF (odds ratio = 1.3 per 10 mmHg reduction, P < 0.001). Systolic blood pressure reduction (relative change > median) was associated with greater doses of in-hospital oral vasodilators (P <= 0.017), thiazide diuretic use (P = 0.035), and greater weight reduction (P = 0.023). In patients with SBP-reduction, WRF was not associated with worsened survival [adjusted hazard ratio (HR) = 0.76, P = 0.58]. However, in patients without SBP-reduction, WRF was strongly associated with increased mortality (adjusted HR = 5.3, P < 0.001, P interaction = 0.001). CONCLUSION: During the treatment of decompensated heart failure, significant blood pressure reduction is strongly associated with WRF. However, WRF that occurs in the setting of SBP-reduction is not associated with an adverse prognosis, whereas WRF in the absence of this provocation is strongly associated with increased mortality. These data suggest that WRF may represent the final common pathway of several mechanistically distinct processes, each with potentially different prognostic implications. PMID- 21693505 TI - A novel function of TDIF-related peptides: promotion of axillary bud formation. AB - Small peptides derived from the CLAVATA3/EMBRYO SURROUNDING REGION-related (CLE) gene family play a key role in various cell-cell communications in land plants. Among them, tracheary element differentiation inhibition factor (TDIF; CLE41/CLE44 peptide) and CLE42 peptide of Arabidopsis have almost identical amino acid sequences and act as inhibitors of tracheary element differentiation. In this study, we report a novel function of TDIF and CLE42. We found by the GUS (beta-glucuronidase) reporter gene assay that while CLE41 and CLE44 are expressed preferentially in vascular bundles, CLE42 is expressed strongly in the shoot apical meristem (SAM) and axillary meristems. Overexpression of CLE42 and CLE41 enhanced axillary bud formation in the leaf and cotyledon axils. Before floral transition, the emergence of axillary buds in these plants occurred in an acropetal order. Exogenous supply of either TDIF or CLE42 peptide to the wild type induced similar excess bud emergence. In vascular bundles, the TDIF RECEPTOR (TDR) acts as the main receptor for TDIF. The axillary bud emergence of tdr mutants was little affected by either of the peptides. It was confirmed by scanning electron microscopy that peptide-treated wild-type plants form an axillary meristem-like structure earlier than non-treated plants. SHOOT MERISTEMLESS (STM), a marker gene for meristems, was up-regulated in peptide treated plants before the axillary meristem becomes morphologically distinguishable. These results indicate that CLE42 peptide and TDIF have an activity to enhance axillary bud formation via the TDR. Judging from its expression pattern, CLE42 may play an important role in the regulation of secondary shoot development. PMID- 21693506 TI - Late presentation of a diaphragmatic hernia. PMID- 21693507 TI - Increased heart rate variability during nondirective meditation. AB - PURPOSE: Meditation practices are in use for relaxation and stress reduction. Some studies indicate beneficial cardiovascular health effects of meditation. The effects on the autonomous nervous system seem to vary among techniques. The purpose of the present study was to identify autonomic nerve activity changes during nondirective meditation. MATERIALS AND METHODS: Heart rate variability (HRV), blood pressure variability (BPV), and baroreflex sensitivity (BRS) were monitored in 27 middle-aged healthy participants of both genders, first during 20 min regular rest with eyes closed, thereafter practising Acem meditation for 20 min. Haemodynamic and autonomic data were collected continuously (beat-to-beat) and non-invasively. HRV and BPV parameters were estimated by power spectral analyses, computed by an autoregressive model. Spontaneous activity of baroreceptors were determined by the sequence method. Primary outcomes were changes in HRV, BPV, and BRS between rest and meditation. RESULTS: HRV increased in the low-frequency (LF) and high-frequency (HF) bands during meditation, compared with rest (p = 0.014, 0.013, respectively). Power spectral density of the RR-intervals increased as well (p = 0.012). LF/HF ratio decreased non significantly, and a reduction of LF-BPV power was observed during meditation (p < 0.001). There was no significant difference in BRS. Respiration and heart rates remained unchanged. Blood pressure increased slightly during meditation. CONCLUSION: There is an increased parasympathetic and reduced sympathetic nerve activity and increased overall HRV, while practising the technique. Hence, nondirective meditation by the middle aged may contribute towards a reduction of cardiovascular risk. PMID- 21693508 TI - Development of the musculoskeletal system: meeting the neighbors. AB - In March 2011, researchers met for the second Batsheva Seminar on Integrative Perspectives on the Development of the Musculoskeletal System. This meeting was a unique opportunity for researchers working on muscle, connective tissue, tendons, ligaments and bone to discuss the development of the musculoskeleton, recognizing that it is an integrated, functional system. The talks and discussions at this meeting highlighted that interactions between the different tissue components are crucial for musculoskeletal morphogenesis. PMID- 21693510 TI - Ci-Pem-1 localizes to the nucleus and represses somatic gene transcription in the germline of Ciona intestinalis embryos. AB - In many animal embryos, germ-cell formation depends on maternal factors located in the germ plasm. To ensure the development of germ cells, germline progenitors must be prevented from differentiating inappropriately into somatic cells. A common mechanism for this appears to be the active repression of somatic gene transcription. Species-specific germ-plasm components, such as Pgc in Drosophila and PIE-1 in C. elegans, establish germline transcriptional quiescence by inhibiting general transcriptional machineries. In the ascidian Ciona intestinalis, although transcriptional repression in the germline has been proposed, the factors and mechanisms involved have been unknown. We found that the protein products of Ci-pem-1 RNA, which is an ascidian-specific component of the postplasm (the germ plasm equivalent in ascidians), localized to the nucleus of germline blastomeres, as well as to the postplasm. Morpholino oligonucleotide mediated Ci-pem-1 knockdown resulted in the ectopic expression of several somatic genes that are usually silent in the germline. In the Ci-pem-1 knockdown embryos, the expression of both beta-catenin- and GATAa-dependent genes was derepressed in the germline blastomeres, suggesting that Ci-Pem-1 broadly represses germline mRNA transcription. Immunoprecipitation assays showed that Ci-Pem-1 could interact with two C. intestinalis homologs of Groucho, which is a general co repressor of mRNA transcription. These results suggest that Ci-pem-1 is the C. intestinalis version of a germ-plasm RNA whose protein product represses the transcription of somatic genes during specification of the germ-cell fate, and that this repression may be operated through interactions between Ci-Pem-1 and Groucho co-repressors. PMID- 21693509 TI - The stem cell niche: lessons from the Drosophila testis. AB - In metazoans, tissue maintenance and regeneration depend on adult stem cells, which are characterized by their ability to self-renew and generate differentiating progeny in response to the needs of the tissues in which they reside. In the Drosophila testis, germline and somatic stem cells are housed together in a common niche, where they are regulated by local signals, epigenetic mechanisms and systemic factors. These stem cell populations in the Drosophila testis have the unique advantage of being easy to identify and manipulate, and hence much progress has been made in understanding how this niche operates. Here, we summarize recent work on stem cells in the adult Drosophila testis and discuss the remarkable ability of these stem cells to respond to change within the niche. PMID- 21693511 TI - Cxcl12 evolution--subfunctionalization of a ligand through altered interaction with the chemokine receptor. AB - The active migration of primordial germ cells (PGCs) from their site of specification towards their target is a valuable model for investigating directed cell migration within the complex environment of the developing embryo. In several vertebrates, PGC migration is guided by Cxcl12, a member of the chemokine superfamily. Interestingly, two distinct Cxcl12 paralogs are expressed in zebrafish embryos and contribute to the chemotattractive landscape. Although this offers versatility in the use of chemokine signals, it also requires a mechanism through which migrating cells prioritize the relevant cues that they encounter. Here, we show that PGCs respond preferentially to one of the paralogs and define the molecular basis for this biased behavior. We find that a single amino acid exchange switches the relative affinity of the Cxcl12 ligands for one of the duplicated Cxcr4 receptors, thereby determining the functional specialization of each chemokine that elicits a distinct function in a distinct process. This scenario represents an example of protein subfunctionalization--the specialization of two gene copies to perform complementary functions following gene duplication--which in this case is based on receptor-ligand interaction. Such specialization increases the complexity and flexibility of chemokine signaling in controlling concurrent developmental processes. PMID- 21693512 TI - Sprouty genes prevent excessive FGF signalling in multiple cell types throughout development of the cerebellum. AB - Fibroblast growth factors (FGFs) and regulators of the FGF signalling pathway are expressed in several cell types within the cerebellum throughout its development. Although much is known about the function of this pathway during the establishment of the cerebellar territory during early embryogenesis, the role of this pathway during later developmental stages is still poorly understood. Here, we investigated the function of sprouty genes (Spry1, Spry2 and Spry4), which encode feedback antagonists of FGF signalling, during cerebellar development in the mouse. Simultaneous deletion of more than one of these genes resulted in a number of defects, including mediolateral expansion of the cerebellar vermis, reduced thickness of the granule cell layer and abnormal foliation. Analysis of cerebellar development revealed that the anterior cerebellar neuroepithelium in the early embryonic cerebellum was expanded and that granule cell proliferation during late embryogenesis and early postnatal development was reduced. We show that the granule cell proliferation deficit correlated with reduced sonic hedgehog (SHH) expression and signalling. A reduction in Fgfr1 dosage during development rescued these defects, confirming that the abnormalities are due to excess FGF signalling. Our data indicate that sprouty acts both cell autonomously in granule cell precursors and non-cell autonomously to regulate granule cell number. Taken together, our data demonstrate that FGF signalling levels have to be tightly controlled throughout cerebellar development in order to maintain the normal development of multiple cell types. PMID- 21693513 TI - Neuropilin-2 promotes branching morphogenesis in the mouse mammary gland. AB - Although the neuropilins were characterized as semaphorin receptors that regulate axon guidance, they also function as vascular endothelial growth factor (VEGF) receptors and contribute to the development of other tissues. Here, we assessed the role of NRP2 in mouse mammary gland development based on our observation that NRP2 is expressed preferentially in the terminal end buds of developing glands. A floxed NRP2 mouse was bred with an MMTV-Cre strain to generate a mammary gland specific knockout of NRP2. MMTV-Cre;NRP2(loxP/loxP) mice exhibited significant defects in branching morphogenesis and ductal outgrowth compared with either littermate MMTV-Cre;NRP2(+/loxP) or MMTV-Cre mice. Mechanistic insight into this morphological defect was obtained from a mouse mammary cell line in which we observed that VEGF(165), an NRP2 ligand, induces branching morphogenesis in 3D cultures and that branching is dependent upon NRP2 as shown using shRNAs and a function-blocking antibody. Epithelial cells in the mouse mammary gland express VEGF, supporting the hypothesis that this NRP2 ligand contributes to mammary gland morphogenesis. Importantly, we demonstrate that VEGF and NRP2 activate focal adhesion kinase (FAK) and promote FAK-dependent branching morphogenesis in vitro. The significance of this mechanism is substantiated by our finding that FAK activation is diminished significantly in developing MMTV-Cre;NRP2(loxP/loxP) mammary glands compared with control glands. Together, our data reveal a VEGF/NRP2/FAK signaling axis that is important for branching morphogenesis and mammary gland development. In a broader context, our data support an emerging hypothesis that directional outgrowth and branching morphogenesis in a variety of tissues are influenced by signals that were identified initially for their role in axon guidance. PMID- 21693514 TI - RETINOBLASTOMA-RELATED PROTEIN controls the transition to autotrophic plant development. AB - Seedling establishment is a crucial phase during plant development when the germinating heterotrophic embryo switches to autotrophic growth and development. Positive regulators of embryonic development need to be turned off, while the cell cycle machinery is activated to allow cell cycle entry and organ primordia initiation. However, it is not yet understood how the molecular mechanisms responsible for the onset of cell division, metabolism changes and cell differentiation are coordinated during this transition. Here, we demonstrate that the Arabidopsis thaliana RETINOBLASTOMA-RELATED protein (RBR) ortholog of the animal tumor suppressor retinoblastoma (pRB) not only controls the expression of cell cycle-related genes, but is also required for persistent shut-down of late embryonic genes by increasing their histone H3K27 trimethylation. Seedlings with reduced RBR function arrest development after germination, and stimulation with low amounts of sucrose induces transcription of late embryonic genes and causes ectopic cell division. Our results suggest a model in which RBR acts antagonistically to sucrose by negatively regulating the cell cycle and repressing embryonic genes. Thus, RBR is a positive regulator of the developmental switch from embryonic heterotrophic growth to autotrophic growth. This establishes RBR as a new integrator of metabolic and developmental decisions. PMID- 21693516 TI - HALF FILLED promotes reproductive tract development and fertilization efficiency in Arabidopsis thaliana. AB - Successful fertilization in angiosperms requires the growth of pollen tubes through the female reproductive tract as they seek out unfertilized ovules. In Arabidopsis, the reproductive tract begins with the stigma, where pollen grains initially adhere, and extends through the transmitting tract of the style and ovary. In wild-type plants, cells within the transmitting tract produce a rich extracellular matrix and undergo programmed cell death to facilitate pollen movement. Here, we show that the HAF, BEE1 and BEE3 genes encode closely related bHLH transcription factors that act redundantly to specify reproductive tract tissues. These three genes are expressed in distinct but overlapping patterns within the reproductive tract, and in haf bee1 bee3 triple mutants extracellular matrix formation and cell death fail to occur within the transmitting tract. We used a minimal pollination assay to show that HAF is necessary and sufficient to promote fertilization efficiency. Our studies further show that HAF expression depends on the NTT gene and on an auxin signaling pathway mediated by the ARF6, ARF8 and HEC genes. PMID- 21693515 TI - A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia. AB - Placental trophoblasts (TBs) invade and remodel uterine vessels with an arterial bias. This process, which involves vascular mimicry, re-routes maternal blood to the placenta, but fails in pre-eclampsia. We investigated Notch family members in both contexts, as they play important roles in arterial differentiation/function. Immunoanalyses of tissue sections showed step-wise modulation of Notch receptors/ligands during human TB invasion. Inhibition of Notch signaling reduced invasion of cultured human TBs and expression of the arterial marker EFNB2. In mouse placentas, Notch activity was highest in endovascular TBs. Conditional deletion of Notch2, the only receptor upregulated during mouse TB invasion, reduced arterial invasion, the size of maternal blood canals by 30-40% and placental perfusion by 23%. By E11.5, there was litter-wide lethality in proportion to the number of mutant offspring. In pre-eclampsia, expression of the Notch ligand JAG1 was absent in perivascular and endovascular TBs. We conclude that Notch signaling is crucial for TB vascular invasion. PMID- 21693517 TI - Rac1 mediates morphogenetic responses to intercellular signals in the gastrulating mouse embryo. AB - The establishment of the mammalian body plan depends on signal-regulated cell migration and adhesion, processes that are controlled by the Rho family of GTPases. Here we use a conditional allele of Rac1, the only Rac gene expressed early in development, to define its roles in the gastrulating mouse embryo. Embryos that lack Rac1 in the epiblast (Rac1Deltaepi) initiate development normally: the signaling pathways required for gastrulation are active, definitive endoderm and all classes of mesoderm are specified, and the neural plate is formed. After the initiation of gastrulation, Rac1Deltaepi embryos have an enlarged primitive streak, make only a small amount of paraxial mesoderm, and the lateral anlage of the heart do not fuse at the midline. Because these phenotypes are also seen in Nap1 mutants, we conclude that Rac1 acts upstream of the Nap1/WAVE complex to promote migration of the nascent mesoderm. In addition to migration phenotypes, Rac1Deltaepi cells fail to adhere to matrix, which leads to extensive cell death. Cell death is largely rescued in Rac1Deltaepi mutants that are heterozygous for a null mutation in Pten, providing evidence that Rac1 is required to link signals from the basement membrane to activation of the PI3K-Akt pathway in vivo. Surprisingly, the frequency of apoptosis is greater in the anterior half of the embryo, suggesting that cell survival can be promoted either by matrix adhesion or by signals from the posterior primitive streak. Rac1 also has essential roles in morphogenesis of the posterior notochordal plate (the node) and the midline. PMID- 21693518 TI - Apical deficiency triggers JNK-dependent apoptosis in the embryonic epidermis of Drosophila. AB - Epithelial homeostasis and the avoidance of diseases such as cancer require the elimination of defective cells by apoptosis. Here, we investigate how loss of apical determinants triggers apoptosis in the embryonic epidermis of Drosophila. Transcriptional profiling and in situ hybridisation show that JNK signalling is upregulated in mutants lacking Crumbs or other apical determinants. This leads to transcriptional activation of the pro-apoptotic gene reaper and to apoptosis. Suppression of JNK signalling by overexpression of Puckered, a feedback inhibitor of the pathway, prevents reaper upregulation and apoptosis. Moreover, removal of endogenous Puckered leads to ectopic reaper expression. Importantly, disruption of the basolateral domain in the embryonic epidermis does not trigger JNK signalling or apoptosis. We suggest that apical, not basolateral, integrity could be intrinsically required for the survival of epithelial cells. In apically deficient embryos, JNK signalling is activated throughout the epidermis. Yet, in the dorsal region, reaper expression is not activated and cells survive. One characteristic of these surviving cells is that they retain discernible adherens junctions despite the apical deficit. We suggest that junctional integrity could restrain the pro-apoptotic influence of JNK signalling. PMID- 21693520 TI - Spatial, temporal and molecular hierarchies in the link between death, delamination and dorsal closure. AB - Dead cells in most epithelia are eliminated by cell extrusion. Here, we explore whether cell delamination in the amnioserosa, a seemingly stochastic event that results in the extrusion of a small fraction of cells and known to provide a force for dorsal closure, is contingent upon the receipt of an apoptotic signal. Through the analysis of mutant combinations and the profiling of apoptotic signals in situ, we establish spatial, temporal and molecular hierarchies in the link between death and delamination. We show that although an apoptotic signal is necessary and sufficient to provide cell-autonomous instructions for delamination, its induction during natural delamination occurs downstream of mitochondrial fragmentation. We further show that apoptotic regulators can influence both delamination and dorsal closure cell non-autonomously, presumably by influencing tissue mechanics. The spatial heterogeneities in delamination frequency and mitochondrial morphology suggest that mechanical stresses may underlie the activation of the apoptotic cascade through their influence on mitochondrial dynamics. Our results document for the first time the temporal propagation of an apoptotic signal in the context of cell behaviours that accomplish morphogenesis during development. They highlight the importance of mitochondrial dynamics and tissue mechanics in its regulation. Together, they provide novel insights into how apoptotic signals can be deployed to pattern tissues. PMID- 21693519 TI - Planar polarity pathway and Nance-Horan syndrome-like 1b have essential cell autonomous functions in neuronal migration. AB - Components of the planar cell polarity (PCP) pathway are required for the caudal tangential migration of facial branchiomotor (FBM) neurons, but how PCP signaling regulates this migration is not understood. In a forward genetic screen, we identified a new gene, nhsl1b, required for FBM neuron migration. nhsl1b encodes a WAVE-homology domain-containing protein related to human Nance-Horan syndrome (NHS) protein and Drosophila GUK-holder (Gukh), which have been shown to interact with components of the WAVE regulatory complex that controls cytoskeletal dynamics and with the polarity protein Scribble, respectively. Nhsl1b localizes to FBM neuron membrane protrusions and interacts physically and genetically with Scrib to control FBM neuron migration. Using chimeric analysis, we show that FBM neurons have two modes of migration: one involving interactions between the neurons and their planar-polarized environment, and an alternative, collective mode involving interactions between the neurons themselves. We demonstrate that the first mode of migration requires the cell-autonomous functions of Nhsl1b and the PCP components Scrib and Vangl2 in addition to the non-autonomous functions of Scrib and Vangl2, which serve to polarize the epithelial cells in the environment of the migrating neurons. These results define a role for Nhsl1b as a neuronal effector of PCP signaling and indicate that proper FBM neuron migration is directly controlled by PCP signaling between the epithelium and the migrating neurons. PMID- 21693521 TI - Msx genes define a population of mural cell precursors required for head blood vessel maturation. AB - Vessels are primarily formed from an inner endothelial layer that is secondarily covered by mural cells, namely vascular smooth muscle cells (VSMCs) in arteries and veins and pericytes in capillaries and veinules. We previously showed that, in the mouse embryo, Msx1(lacZ) and Msx2(lacZ) are expressed in mural cells and in a few endothelial cells. To unravel the role of Msx genes in vascular development, we have inactivated the two Msx genes specifically in mural cells by combining the Msx1(lacZ), Msx2(lox) and Sm22alpha-Cre alleles. Optical projection tomography demonstrated abnormal branching of the cephalic vessels in E11.5 mutant embryos. The carotid and vertebral arteries showed an increase in caliber that was related to reduced vascular smooth muscle coverage. Taking advantage of a newly constructed Msx1(CreERT2) allele, we demonstrated by lineage tracing that the primary defect lies in a population of VSMC precursors. The abnormal phenotype that ensues is a consequence of impaired BMP signaling in the VSMC precursors that leads to downregulation of the metalloprotease 2 (Mmp2) and Mmp9 genes, which are essential for cell migration and integration into the mural layer. Improper coverage by VSMCs secondarily leads to incomplete maturation of the endothelial layer. Our results demonstrate that both Msx1 and Msx2 are required for the recruitment of a population of neural crest-derived VSMCs. PMID- 21693523 TI - hnRNP K post-transcriptionally co-regulates multiple cytoskeletal genes needed for axonogenesis. AB - The RNA-binding protein, hnRNP K, is essential for axonogenesis. Suppressing its expression in Xenopus embryos yields terminally specified neurons with severely disorganized microtubules, microfilaments and neurofilaments, raising the hypothesis that hnRNP K post-transcriptionally regulates multiple transcripts of proteins that organize the axonal cytoskeleton. To identify downstream candidates for this regulation, RNAs that co-immunoprecipitated from juvenile brain with hnRNP K were identified on microarrays. A substantial number of these transcripts were linked to the cytoskeleton and to intracellular localization, trafficking and transport. Injection into embryos of a non-coding RNA bearing multiple copies of an hnRNP K RNA-binding consensus sequence found within these transcripts largely phenocopied hnRNP K knockdown, further supporting the idea that it regulates axonogenesis through its binding to downstream target RNAs. For further study of regulation by hnRNP K of the cytoskeleton during axon outgrowth, we focused on three validated RNAs representing elements associated with all three polymers - Arp2, tau and an alpha-internexin-like neurofilament. All three were co-regulated post-transcriptionally by hnRNP K, as hnRNP K knockdown yielded comparable defects in their nuclear export and translation but not transcription. Directly knocking down expression of all three together, but not each one individually, substantially reproduced the axonless phenotype, providing further evidence that regulation of axonogenesis by hnRNP K occurs largely through pleiotropic effects on cytoskeletal-associated targets. These experiments provide evidence that hnRNP K is the nexus of a novel post-transcriptional regulatory module controlling the synthesis of proteins that integrate all three cytoskeletal polymers to form the axon. PMID- 21693524 TI - Alcohol consumption limits should be lowered for over 65s, say psychiatrists. PMID- 21693522 TI - How to make stripes: deciphering the transition from non-periodic to periodic patterns in Drosophila segmentation. AB - The generation of metameric body plans is a key process in development. In Drosophila segmentation, periodicity is established rapidly through the complex transcriptional regulation of the pair-rule genes. The 'primary' pair-rule genes generate their 7-stripe expression through stripe-specific cis-regulatory elements controlled by the preceding non-periodic maternal and gap gene patterns, whereas 'secondary' pair-rule genes are thought to rely on 7-stripe elements that read off the already periodic primary pair-rule patterns. Using a combination of computational and experimental approaches, we have conducted a comprehensive systems-level examination of the regulatory architecture underlying pair-rule stripe formation. We find that runt (run), fushi tarazu (ftz) and odd skipped (odd) establish most of their pattern through stripe-specific elements, arguing for a reclassification of ftz and odd as primary pair-rule genes. In the case of run, we observe long-range cis-regulation across multiple intervening genes. The 7-stripe elements of run, ftz and odd are active concurrently with the stripe specific elements, indicating that maternal/gap-mediated control and pair-rule gene cross-regulation are closely integrated. Stripe-specific elements fall into three distinct classes based on their principal repressive gap factor input; stripe positions along the gap gradients correlate with the strength of predicted input. The prevalence of cis-elements that generate two stripes and their genomic organization suggest that single-stripe elements arose by splitting and subfunctionalization of ancestral dual-stripe elements. Overall, our study provides a greatly improved understanding of how periodic patterns are established in the Drosophila embryo. PMID- 21693525 TI - High risk prescribing in primary care patients particularly vulnerable to adverse drug events: cross sectional population database analysis in Scottish general practice. AB - OBJECTIVE: To examine the prevalence and patterns of high risk prescribing, defined as potentially inappropriate prescribing of drugs to primary care patients particularly vulnerable to adverse drug events. DESIGN: Cross sectional population database analysis. SETTING: General practices in Scotland. PARTICIPANTS: 315 Scottish general practices with 1.76 million registered patients, 139 404 (7.9%) of whom were defined as particularly vulnerable to adverse drug events because of age, comorbidity, or co-prescription. MAIN OUTCOME MEASURES: How reliably each of 15 indicators-four each for non-steroidal anti inflammatory drugs, co-prescription with warfarin, and prescribing in heart failure, two for dose instructions for methotrexate, and one for antipsychotic prescribing in dementia-and a composite of all 15 could distinguish practices in terms of their rates of high risk prescribing; and characteristics of patients and practices associated with high risk prescribing in a multilevel model. RESULTS: 19 308 of 139 404 (13.9%, 95% confidence interval 13.7% to 14.0%) patients had received at least one high risk prescription in the past year. This composite indicator was a reasonably reliable measure of practice rates of high risk prescribing (reliability >0.7 for 95.6% of practices, >0.8 for 88.2%). The patient characteristic most strongly associated with high risk prescribing was the number of drugs prescribed (>11 long term prescribed drugs v 0; odds ratio 7.90, 95% confidence interval 7.19 to 8.68). After adjustment for patient characteristics, rates of high risk prescribing varied by fourfold between practices, which was not explained by structural characteristics of the practices. CONCLUSIONS: Almost 14% of patients defined as particularly vulnerable to adverse drug events were prescribed one or more high risk drugs. The composite indicator of high risk prescribing used could identify practices as having above average or below average high risk prescribing rates with reasonable confidence. After adjustment, only the number of drugs prescribed long term to patients was strongly associated with high risk prescribing, and considerable unexplained variation existed between practices. High risk prescribing will often be appropriate, but the large variation between practices suggests opportunities for improvement. PMID- 21693526 TI - Management of hip fracture in adults: summary of NICE guidance. PMID- 21693527 TI - NICE recommends same day surgery for hip fracture patients. PMID- 21693528 TI - Access to stroke prevention surgery varies widely in UK. PMID- 21693529 TI - Magnetic resonance imaging is to be exempt from European rules restricting use of electromagnetic fields. PMID- 21693530 TI - New Zealand agency comes under pressure to pay more for drugs. PMID- 21693531 TI - Hospital prepares to test use of "cloud" technology for sharing patient records. PMID- 21693532 TI - Priorities for women with lymphoedema after treatment for breast cancer: population based cohort study. AB - OBJECTIVE: To explore the perceived unmet needs among women treated for breast cancer and in whom symptoms and signs indicate the presence of lymphoedema. DESIGN: Population based cross sectional survey with a purpose designed questionnaire (60 items). SETTING: Cancer registries of New South Wales, Victoria, and South Australia. PARTICIPANTS: 237 women with symptoms and signs indicative of lymphoedema from an initial 1930 eligible women. MAIN OUTCOME MEASURE: Unmet needs in the previous month across psychological, health system and information, physical and daily living, patient care and support, sexuality needs, body image, and financial domains. RESULTS: The 10 items most commonly identified as a "moderate to high current need" included having their doctor and allied health workers being fully informed about lymphoedema, acknowledge the seriousness of the condition, and be willing to treat it. Women also wanted access to up to date treatments, both mainstream and alternative, and financial assistance for their garments. The three factors that explained most of the variance were: information and support (11 items), which accounted for 49% of the variance; body image and self esteem (seven items; 7% variance); and health system (seven items; 5% variance). Examination of these three factors showed that while the levels of need were generally low, they were common. CONCLUSION: To address the needs of women with lymphoedema and perhaps to prevent progression of lymphoedema, it is important that practitioners do not dismiss mild symptoms and that women are referred to an appropriate specialist. PMID- 21693533 TI - Why patient safety is such a tough nut to crack. PMID- 21693534 TI - Sex selection in Asia has debilitating effects on women's health, says UN. PMID- 21693535 TI - Most of world's refugees are hosted by poor countries, shows report. PMID- 21693536 TI - Investigation into home care of elderly people shows cases of "serious neglect". PMID- 21693537 TI - Pressure grows for government to "grasp the nettle" and close hospitals. PMID- 21693538 TI - Apoptosis-related protein-2 triggers melanoma cell death by a mechanism including both endoplasmic reticulum stress and mitochondrial dysregulation. AB - Metastatic cancers including melanoma are frequently associated with increased resistance to apoptosis induced by various therapeutic modalities, and the success of systemic therapy for the treatment of metastatic melanoma is minimal. In the present study, we demonstrated the ability of apoptosis-related protein (APR)-2 to trigger cell death via mechanism mediated by both endoplasmic reticulum (ER) stress [as evidenced by the increase of intracellular Ca(2+) release, the activation of both, inositol-requiring enzyme 1alpha (IRE1alpha) and calpain and cleavage of caspase-4] and mitochondrial dysregulation as evidenced by the loss of mitochondrial membrane potential, Cytochrome c release and cleavage of caspases-9 and -3, and poly adenosine diphosphate ribose polymerase (PARP). Also, the activation of apoptosis signal-regulating kinase (ASK) 1, c-jun N-terminal kinase (JNK) and the transcription factors AP-1 and p53, and the induction of Bax expression were noted in APR-2-expressing cells. Both immune fluorescence staining and western blotting revealed the localization of APR-2 at ER and Bax protein at both mitochondria and ER. However, data of inhibitory experiments demonstrated that APR-2-induced apoptosis of melanoma cells is mediated by three parallel pathways: one of them IRE1/tumour necrosis factor receptor-associated factor 2/ASK1/JNK/Cyt.c/caspase-9/caspase-3/PARP) seems to be mitochondrial dependent, whereas, the other two pathways namely calpain/caspase 4/caspase-9/caspase-3/PARP and protein kinase RNA-like ER kinase/ATF4/C/EBP homologous protein (CHOP)/Bim seem to be mitochondrial independent. In conclusion, our data provide insight into the molecular mechanism of APR-2 induced apoptosis and suggest APR-2 gene transfer as an alternative approach for the treatment of chemoresistance melanoma metastasis. PMID- 21693540 TI - Heterothermy, and the energetic consequences of huddling in small migrating passerine birds. AB - The success of migration of small passerine birds depends largely on effective refueling at stopover sites. In our previous studies, we found that hypothermia facilitates accumulation of fuel at the beginning of a stopover. Later we found that blackcaps, Sylvia atricapilla, might further reduce their energy expenditure by huddling while at rest. Here, we report experimental results supporting our hypothesis that huddling is beneficial to small migrating passerines both from energetic and thermoregulatory points of view. To test this hypothesis we measured metabolic rates and body temperatures of seven blackcaps placed in respirometry chambers overnight, either solitarily or in groups of three or four at ambient temperatures of 5, 10, and 15 degrees C. Concurring with our predictions, huddling blackcaps maintained higher body temperatures than did solitary birds, but had mass-specific metabolic rates lower by ~30% than those of solitary individuals. Based on our previous studies, we estimated energy savings through huddling to be comparable to energy savings through hypothermia in solitary blackcaps and suggest that huddling may be an important way of saving energy for small passerine birds resting at migratory stopovers. At the same time it might offer the additional benefit of lower risk of predation. In this light, we predict that huddling occurs frequently in nature, leading to significant savings of energy, faster accumulation of fuel, presumably lower risk of becoming a prey, more successful migration, and eventually increased fitness. PMID- 21693539 TI - Indole-3-carbinol downregulation of telomerase gene expression requires the inhibition of estrogen receptor-alpha and Sp1 transcription factor interactions within the hTERT promoter and mediates the G1 cell cycle arrest of human breast cancer cells. AB - Indole-3-carbinol (I3C), a naturally occurring hydrolysis product of glucobrassicin from cruciferous vegetables such as broccoli, cabbage and Brussels sprouts, is an anticancer phytochemical that triggers complementary sets of antiproliferative pathways to induce a cell cycle arrest of estrogen-responsive MCF7 breast cancer cells. I3C strongly downregulated transcript expression of the catalytic subunit of the human telomerase (hTERT) gene, which correlated with the dose-dependent indole-mediated G(1) cell cycle arrest without altering the transcript levels of the RNA template (hTR) for telomerase elongation. Exogenous expression of hTERT driven by a constitutive promoter prevented the I3C-induced cell cycle arrest and rescued the I3C inhibition of telomerase enzymatic activity and activation of cellular senescence. Time course studies showed that I3C downregulated expression of estrogen receptor-alpha (ERalpha) and cyclin dependent kinase-6 transcripts levels (which is regulated through the Sp1 transcription factor) prior to the downregulation of hTERT suggesting a mechanistic link. Chromatin immunoprecipitation assays demonstrated that I3C disrupted endogenous interactions of both ERalpha and Sp1 with an estrogen response element-Sp1 composite element within the hTERT promoter. I3C inhibited 17beta-estradiol stimulated hTERT expression and stimulated the production of threonine-phosphorylated Sp1, which inhibits Sp1-DNA interactions. Exogenous expression of both ERalpha and Sp1, but not either alone, in MCF7 cells blocked the I3C-mediated downregulation of hTERT expression. These results demonstrate that I3C disrupts the combined ERalpha- and Sp1-driven transcription of hTERT gene expression, which plays a significant role in the I3C-induced cell cycle arrest of human breast cancer cells. PMID- 21693541 TI - Relationship of external influence to parental distress in decision making regarding children with a life-threatening illness. AB - OBJECTIVE: To examine the relationship of external influence to parental distress when making a decision about research or treatment for a child with a life threatening illness and to test potential moderators of this relationship. METHODS: Parents (n = 219) who made a decision about research or treatment for a child completed measures of external influence, distress, decision-making preference, and coping. RESULTS: More external influence was associated with more hostility, uncertainty, and confusion. Decision-making preference and coping style moderated the relationship between external influence and distress: More external influence was associated with more distress when decision-making preference was low and task-focused coping was high. CONCLUSIONS: External influence appears to be related to distress in parents making research and treatment decisions for children with life-threatening illnesses. However, it is important to consider parent characteristics, such as decision-making preference and coping style, when examining the effects of contextual factors on distress during decision making. PMID- 21693542 TI - Mothers' acceptance-rejection of their children infected with HIV: the role of the mothers' social axioms, psychological distress, and relationships with the partner. AB - OBJECTIVE: The present study examines the effect of having a child infected with HIV on the mother-child relationship. The study also examines how the mother's social axioms, psychological distress, and relationships with her partner affect her parenting of the child infected with HIV. METHOD: The study was conducted in Kazakhstan in the wake of a children's HIV epidemic. Mothers of children infected with HIV (n = 53) were compared to mothers of healthy children (n = 97). RESULTS: Compared to mothers of healthy children, mothers of children infected with HIV reported a higher level of acceptance of their children as well as a stronger belief in the "reward for application" axiom, a higher level of religiosity, and better relationships with their partner. Among mothers of both healthy children and children infected with HIV, the belief in the "reward for application" axiom, a low level of social cynicism, and good relationships with their partner was associated with a higher level of acceptance of their children. Among mothers of healthy children but not among mothers of children infected with HIV, psychological distress was associated with a lower level of acceptance of their children. CONCLUSIONS: Mothers of children infected with HIV demonstrated a mobilization pattern of adjustment to their child's illness. PMID- 21693543 TI - Lung Aspergillosis in renal cell carcinoma patient treated with sunitinib. PMID- 21693544 TI - Cellular responses induced by cerium oxide nanoparticles: induction of intracellular calcium level and oxidative stress on culture cells. AB - Cerium oxide (CeO(2)) is an important metal oxide used for industrial products. Many investigations about the cellular influence of CeO(2) nanoparticles have been done, but results are contradictory. It has been reported that CeO(2) nanoparticles have an anti-oxidative effect in cells, but it has also been reported that CeO(2) nanoparticles induce oxidative stress. We investigated the potential influence on cells and the mechanisms induced by CeO(2) nanoparticles in vitro. We prepared a stable CeO(2) culture medium dispersion. Cellular responses in CeO(2) medium-exposed cells were examined. Cellular uptake of CeO(2) nanoparticles was observed. After 24-h exposure, a high concentration of CeO(2) nanoparticles (~200 mg/ml) induced an increase in the intracellular level of reactive oxygen species (ROS); a low concentration of CeO(2) nanoparticles induced a decrease in the intracellular ROS level. On the other hand, exposure of CeO(2) nanoparticle for 24 h had little influence on the cell viability. Exposure of CeO(2) nanoparticles increased the intracellular Ca(2+) concentration and also Calpain was activated. These results suggest that CeO(2) nanoparticles have a potential to induce intracellular oxidative stress and increase the intracellular Ca(2+) level, but these influences are small. PMID- 21693545 TI - Characterization of three different single chain antibodies recognizing non reducing terminal mannose residues expressed in Escherichia coli by an inducible T7 expression system. AB - We previously isolated phage antibodies from a phage library displaying human single chain antibodies (scFvs) by screening with a mannotriose (Man3)-bearing lipid. Of four independent scFv genes originally characterized, 5A3 gene products were purified as fusion proteins such as a scFv-human IgG1 Fc form, but stable clones secreting 1A4 and 1G4 scFv-Fc proteins had never been established. Thus, bacterial expression systems were used to purify 1A4 and 1G4 scFv gene products as soluble forms. Purification of 1A4 and 1G4 scFv proteins from inclusion bodies was also carried out together with purification of 5A3 scFv protein in order to compare their Man3-binding abilities. The present studies demonstrated that 1A4 and 1G4 scFv proteins have a higher affinity for Man3 than 5A3 scFv protein, which may determine whether scFv-Fc proteins expressed in mammalian cells are retained in the ER or secreted. Furthermore, the inhibitory effects of anti-Man3 1G4 scFv and anti-Tn antigen scFv proteins on MCF-7 cell growth were evaluated. Despite the fact that no obvious difference was detected in cell growth, microscopic observations revealed inhibition of foci formation in cells grown in the presence of the anti-carbohydrate scFv proteins. This finding provides a basis for the development of cancer therapeutics. PMID- 21693546 TI - Essential in vivo roles of the platelet activation receptor CLEC-2 in tumour metastasis, lymphangiogenesis and thrombus formation. AB - We have recently identified C-type lectin-like receptor 2 (CLEC-2) as a receptor for the platelet activating snake venom rhodocytin. CLEC-2 elicits powerful platelet activation signals in conjunction with single YxxL motif in its cytoplasmic tail, Src, Syk kinases, and phospholipase Cgamma2. An endogenous ligand of CLEC-2 has been identified as podoplanin, which is a membrane protein of tumour cells and facilitates tumour metastasis by inducing platelet activation. Studies of CLEC-2-deficient mice have revealed several physiological roles of CLEC-2. Podoplanin is also expressed in lymphatic endothelial cells. In the developmental stages, when the primary lymph sac is derived from the cardinal vein, podoplanin activates platelets in lymphatic endothelial cells, which facilitates blood/lymphatic vessel separation. Moreover, CLEC-2 is involved in thrombus stabilization under flow conditions in part through homophilic interactions. The absence of CLEC-2 does not significantly increase bleeding tendency, implying that CLEC-2 may be a good target protein for anti-platelet drugs in addition to anti-metastatic drugs. PMID- 21693547 TI - High-resolution magnetic resonance angiography of digital arteries in SSc patients on 3 Tesla: preliminary study. AB - OBJECTIVE: We sought to evaluate the use of high-resolution three-dimensional time of flight (3D TOF) magnetic resonance angiography (MRA) at 3 Tesla in the visualization of digital arteries in SSc patients. METHODS: A total of 33 patients with SSc [32 females and 1 male; mean (s.d.) age 37.0 (10.2) years; median number of years since onset of RP 3.4 (2.8) years] and 7 healthy controls [6 females and 1 male; mean (s.d.) age 30.7 (3.5) years] were examined on a 3T MR system. A modified high spatial resolution (voxel size = 0.35 * 0.35 * 0.5 mm(3)) 3D TOF MRA (repetition time/echo time = 19/4.4 ms, flip angle = 15 degrees , slice thickness = 1 mm) was performed during a total scan time of 8 min 22 s. The source images and maximum intensity projection reconstruction were studied; the digital arteries count and lumen area of the selective section of the vessel were measured independently by two experienced radiologists and compared with that of the control ones; and a four-level grading system was made according to the severity. Statistical analysis was performed with t-test and P < 0.05 was used as the criterion. RESULTS: We detected the eight digital arteries in the four fingers (without the thumb) of each case and got a 47.58% presentation in general in the SSc group, and artery No. 5 had the highest presentation rate (70.97%). Statistics showed that the digital arteries No. 1 (P = 0.058) and No. 3 (P = 0.093) had no difference in the lumen area (P > 0.05). We finally got 3 cases in Grade 1, 14 cases in Grade 2, 9 cases in Grade 3 and 5 cases in Grade 4. CONCLUSION: MRA of the digital arteries in the described technique is a promising method for us to judge the severity of microvascular involvement in finger vessels of SSc patients. PMID- 21693548 TI - The role of hepatitis B virus X protein is related to its differential intracellular localization. AB - Chronic hepatitis B virus (HBV) infection has been strongly associated with hepatocellular carcinoma. HBV encodes an oncogenic hepatitis B virus X protein (HBx), which is a multifunctional regulator that modulates signal transduction, transcription, cell cycle progress, protein degradation, apoptosis, and genetic stability through direct and indirect interaction with host factors. The subcellular localization of HBx is primarily cytoplasmic, with a small fraction in the nucleus. In addition, high levels of HBx expression lead to an abnormal mitochondrial distribution. The dynamic distribution of HBx could be important to the multiple functions of HBx at different stages of the HBV life cycle. This short review presents an overview of the differential roles of HBx as a function of its intracellular localization. PMID- 21693549 TI - Switching from long-term benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a double-blind, placebo-controlled trial. AB - To evaluate the efficacy of pregabalin in facilitating taper off chronic benzodiazepines, outpatients (N = 106) with a lifetime diagnosis of generalized anxiety disorder (current diagnosis could be subthreshold) who had been treated with a benzodiazepine for 8-52 weeks were stabilized for 2-4 weeks on alprazolam in the range of 1-4 mg/day. Patients were then randomized to 12 weeks of double blind treatment with either pregabalin 300-600 mg/day or placebo while undergoing a gradual benzodiazepine taper at a rate of 25% per week, followed by a 6-week benzodiazepine-free phase during which they continued double-blind study treatment. Outcome measures included ability to remain benzodiazepine-free (primary) as well as changes in Hamilton Anxiety Rating Scale (HAM)-A and Physician Withdrawal Checklist (PWC). At endpoint, a non-significant higher proportion of patients remained benzodiazepine-free receiving pregabalin compared with placebo (51.4% vs 37.0%). Treatment with pregabalin was associated with significantly greater endpoint reduction in the HAM-A total score versus placebo (-2.5 vs +1.3; p < 0.001), and lower endpoint mean PWC scores (6.5 vs 10.3; p = 0.012). Thirty patients (53%) in the pregabalin group and 19 patients (37%) in the placebo group completed the study, reducing the power to detect a significant difference on the primary outcome. The results on the anxiety and withdrawal severity measures suggest that switching to pregabalin may be a safe and effective method for discontinuing long-term benzodiazepine therapy. PMID- 21693550 TI - Clinically unintended medication switches and inability to prescribe preferred medications under Medicare Part D. AB - Medicare Part D has expanded medication access; however, there is some evidence that dually eligible psychiatric patients have experienced medication access problems. The aim of this study was to characterize medication switches and access problems for dually eligible psychiatric patients and associations with adverse events, including emergency department visits, hospitalizations, homelessness, and incarceration. Reports on 986 systematically sampled, dually eligible patients were obtained from a random sample of practicing psychiatrists. A total of 27.6% of previously stable patients had to switch medications because clinically indicated and preferred refills were not covered or approved. An additional 14.0% were unable to have clinically indicated/preferred medications prescribed because of drug coverage/approval. Adjusting for case-mix, switched patients (p = 0.0009) and patients with problems obtaining clinically indicated medications (p = 0.0004) had significantly higher adverse event rates. Patients at greatest risk were prescribed a medication in a different class or could not be prescribed clinically-indicated atypical antipsychotics, other antidepressants, mood stabilizers, or stimulants. Patients with problems obtaining clinically preferred/indicated antipsychotics had a 17.6 times increased odds (p = 0.0039) of adverse events. These findings call for caution in medication switches for stable patients and support prescription drug policies promoting access to clinically indicated medications and continuity for clinically stable patients. PMID- 21693551 TI - The endocannabinoid system in the regulation of emotions throughout lifespan: a discussion on therapeutic perspectives. AB - Alterations in emotion regulation processes may form the basis of psychopathologies. The endocannabinoid (eCB) system, composed of endogenous ligands, the enzymatic machinery in charge of their metabolism and the specific metabotropic receptors, has emerged as a major neuromodulatory system critically involved in the control of emotional homeostasis and stress responsiveness. Data from animal models indicate that the eCB system plays a key role in brain development, and is probably involved in the control of emotional states from early developmental stages. The present review summarizes the latest information on the role of the eCB system in emotionality and anxiety-related disorders throughout the lifespan. Putative therapeutic strategies based on the pharmacological modulation of this system will be discussed. Given the fact that the pharmacological modulation of the eCB system has recently arisen as a promising strategy in the management of anxiety and mood disorders, the potential efficacy of this pharmacological approach (i.e. blockers of the catabolic pathway) will be discussed, as well as pharmacological alternatives such as modulators of cannabinoid receptors other than the classical CB1 receptor, or administration of other plant-derived compounds (e.g. cannabidiol). PMID- 21693552 TI - A meta-analysis of selective serotonin reuptake inhibitors in acute coronary syndrome: cause for concern. PMID- 21693553 TI - Relaxin polymorphisms associated with metabolic disturbance in patients treated with antipsychotics. AB - People with schizophrenia have an increased risk of metabolic syndrome, with consequent elevated morbidity and mortality, largely due to cardiovascular disease. Metabolic disorders comprise obesity, dyslipidemia and elevated levels of triglycerides, hypertension, and disturbed insulin and glucose metabolism. The elevated risk of metabolic syndrome in individuals suffering from schizophrenia is believed to be multifactorial, related to a genetic predisposition, lifestyle characteristics and treatment with antipsychotic medications. Relaxin 3 (RLN3, also known as INSL7) is a recently identified member of the insulin/relaxin superfamily that plays a role in the regulation of appetite and body weight control. RLN3 stimulates relaxin-3 receptor 1 (relaxin/insulin-like family peptide receptor 3, RXFP3) and relaxin receptor 2 (relaxin/insulin-like family peptide receptor 4, RXFP4). We have investigated the role of ten polymorphisms in these genes (RLN3 rs12327666, rs1982632, and rs7249702, RLN3R1 rs42868, rs6861957, rs7702361, and rs35399, and RLN3R2 rs11264422, rs1018730 and rs12124383) in the occurrence of metabolic syndrome phenotypes (obesity, diabetes, hypercholesterolemia, hypertrigyceridemia, and hypertension) in a cross sectional cohort of 419 US Caucasian patients treated with antipsychotic drugs. We found several associations between relaxin polymorphisms and hypecholesterolemia, obesity and diabetes, suggesting a role for the relaxin/insulin pathway in the development of metabolic disturbance observed in patients treated with antipsychotics. PMID- 21693554 TI - Specific targeting of the GABA-A receptor alpha5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice. AB - An imbalance between inhibitory and excitatory neurotransmission has been proposed to contribute to altered brain function in individuals with Down syndrome (DS). Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system and accordingly treatment with GABA-A antagonists can efficiently restore cognitive functions of Ts65Dn mice, a genetic model for DS. However, GABA-A antagonists are also convulsant which preclude their use for therapeutic intervention in DS individuals. Here, we have evaluated safer strategies to release GABAergic inhibition using a GABA-A benzodiazepine receptor inverse agonist selective for the alpha5-subtype (alpha5IA). We demonstrate that alpha5IA restores learning and memory functions of Ts65Dn mice in the novel-object recognition and in the Morris water maze tasks. Furthermore, we show that following behavioural stimulation, alpha5IA enhances learning-evoked immediate early gene products in specific brain regions involved in cognition. Importantly, acute and chronic treatments with alpha5IA do not induce any convulsant or anxiogenic effects that are associated with GABA-A antagonists or non-selective inverse agonists of the GABA-A-benzodiazepine receptors. Finally, chronic treatment with alpha5IA did not induce histological alterations in the brain, liver and kidney of mice. Our results suggest that non convulsant alpha5-selective GABA-A inverse agonists could improve learning and memory deficits in DS individuals. PMID- 21693555 TI - Rational, modular adaptation of enzyme-free DNA circuits to multiple detection methods. AB - Signal amplification is a key component of molecular detection. Enzyme-free signal amplification is especially appealing for the development of low-cost, point-of-care diagnostics. It has been previously shown that enzyme-free DNA circuits with signal-amplification capacity can be designed using a mechanism called 'catalyzed hairpin assembly'. However, it is unclear whether the efficiency and modularity of such circuits is suitable for multiple analytical applications. We have therefore designed and characterized a simplified DNA circuit based on catalyzed hairpin assembly, and applied it to multiple different analytical formats, including fluorescent, colorimetric, and electrochemical and signaling. By optimizing the design of previous hairpin-based catalytic assemblies we found that our circuit has almost zero background and a high catalytic efficiency, with a k(cat) value above 1 min(-1). The inherent modularity of the circuit allowed us to readily adapt our circuit to detect both RNA and small molecule analytes. Overall, these data demonstrate that catalyzed hairpin assembly is suitable for analyte detection and signal amplification in a 'plug-and-play' fashion. PMID- 21693556 TI - Inferring causative variants in microRNA target sites. AB - MicroRNAs (miRNAs) regulate genes post transcription by pairing with messenger RNA (mRNA). Variants such as single nucleotide polymorphisms (SNPs) in miRNA regulatory regions might result in altered protein levels and disease. Genome wide association studies (GWAS) aim at identifying genomic regions that contain variants associated with disease, but lack tools for finding causative variants. We present a computational tool that can help identifying SNPs associated with diseases, by focusing on SNPs affecting miRNA-regulation of genes. The tool predicts the effects of SNPs in miRNA target sites and uses linkage disequilibrium to map these miRNA-related variants to SNPs of interest in GWAS. We compared our predicted SNP effects in miRNA target sites with measured SNP effects from allelic imbalance sequencing. Our predictions fit measured effects better than effects based on differences in free energy or differences of TargetScan context scores. We also used our tool to analyse data from published breast cancer and Parkinson's disease GWAS and significant trait-associated SNPs from the NHGRI GWAS Catalog. A database of predicted SNP effects is available at http://www.bigr.medisin.ntnu.no/mirsnpscore/. The database is based on haplotype data from the CEU HapMap population and miRNAs from miRBase 16.0. PMID- 21693557 TI - From face to interface recognition: a differential geometric approach to distinguish DNA from RNA binding surfaces. AB - Protein nucleic acid interactions play a critical role in all steps of the gene expression pathway. Nucleic acid (NA) binding proteins interact with their partners, DNA or RNA, via distinct regions on their surface that are characterized by an ensemble of chemical, physical and geometrical properties. In this study, we introduce a novel methodology based on differential geometry, commonly used in face recognition, to characterize and predict NA binding surfaces on proteins. Applying the method on experimentally solved three dimensional structures of proteins we successfully classify double-stranded DNA (dsDNA) from single-stranded RNA (ssRNA) binding proteins, with 83% accuracy. We show that the method is insensitive to conformational changes that occur upon binding and can be applicable for de novo protein-function prediction. Remarkably, when concentrating on the zinc finger motif, we distinguish successfully between RNA and DNA binding interfaces possessing the same binding motif even within the same protein, as demonstrated for the RNA polymerase transcription-factor, TFIIIA. In conclusion, we present a novel methodology to characterize protein surfaces, which can accurately tell apart dsDNA from an ssRNA binding interfaces. The strength of our method in recognizing fine-tuned differences on NA binding interfaces make it applicable for many other molecular recognition problems, with potential implications for drug design. PMID- 21693558 TI - Formation of m2G6 in Methanocaldococcus jannaschii tRNA catalyzed by the novel methyltransferase Trm14. AB - The modified nucleosides N(2)-methylguanosine and N(2)(2)-dimethylguanosine in transfer RNA occur at five positions in the D and anticodon arms, and at positions G6 and G7 in the acceptor stem. Trm1 and Trm11 enzymes are known to be responsible for several of the D/anticodon arm modifications, but methylases catalyzing post-transcriptional m(2)G synthesis in the acceptor stem are uncharacterized. Here, we report that the MJ0438 gene from Methanocaldococcus jannaschii encodes a novel S-adenosylmethionine-dependent methyltransferase, now identified as Trm14, which generates m(2)G at position 6 in tRNA(Cys). The 381 amino acid Trm14 protein possesses a canonical RNA recognition THUMP domain at the amino terminus, followed by a gamma-class Rossmann fold amino methyltransferase catalytic domain featuring the signature NPPY active site motif. Trm14 is associated with cluster of orthologous groups (COG) 0116, and most closely resembles the m(2)G10 tRNA methylase Trm11. Phylogenetic analysis reveals a canonical archaeal/bacterial evolutionary separation with 20-30% sequence identities between the two branches, but it is likely that the detailed functions of COG 0116 enzymes differ between the archaeal and bacterial domains. In the archaeal branch, the protein is found exclusively in thermophiles. More distantly related Trm14 homologs were also identified in eukaryotes known to possess the m(2)G6 tRNA modification. PMID- 21693559 TI - KINARI-Web: a server for protein rigidity analysis. AB - KINARI-Web is an interactive web server for performing rigidity analysis and visually exploring rigidity properties of proteins. It also provides tools for pre-processing the input data, such as selecting relevant chains from PDB files, adding hydrogen atoms and identifying stabilizing interactions. KINARI-Web offers a quick-start option for beginners, and highly customizable features for the experienced user. Chains, residues or atoms, as well as stabilizing constraints can be selected, removed or added, and the user can designate how different chemical interactions should be modeled during rigidity analysis. The enhanced Jmol-based visualizer allows for zooming in, highlighting or investigating different calculated rigidity properties of a molecular structure. KINARI-Web is freely available at http://kinari.cs.umass.edu. PMID- 21693560 TI - Overlapping signals for translational regulation and packaging of influenza A virus segment 2. AB - Influenza A virus segment 2 mRNA expresses three polypeptides: PB1, PB1-F2 and PB1-N40, from AUGs 1, 4 and 5 respectively. Two short open reading frames (sORFs) initiated by AUGs 2 and 3 are also present. To understand translational regulation in this system, we systematically mutated AUGs 1-4 and monitored polypeptide synthesis from plasmids and recombinant viruses. This identified sORF2 as a key regulatory element with opposing effects on PB1-F2 and PB1-N40 expression. We propose a model in which AUGs 1-4 are accessed by leaky ribosomal scanning, with sORF2 repressing synthesis of downstream PB1-F2. However, sORF2 also up-regulates PB1-N40 expression, most likely by a reinitiation mechanism that permits skipping of AUG4. Surprisingly, we also found that in contrast to plasmid-driven expression, viruses with improved AUG1 initiation contexts produced less PB1 in infected cells and replicated poorly, producing virions with elevated particle:PFU ratios. Analysis of the genome content of virus particles showed reduced packaging of the mutant segment 2 vRNAs. Overall, we conclude that segment 2 mRNA translation is regulated by a combination of leaky ribosomal scanning and reinitiation, and that the sequences surrounding the PB1 AUG codon are multifunctional, containing overlapping signals for translation initiation and for segment-specific packaging. PMID- 21693561 TI - Intrachromosomal tandem duplication and repeat expansion during attempts to inactivate the subtelomeric essential gene GSH1 in Leishmania. AB - Gamma-glutamylcysteine synthetase encoded by GSH1 is the rate-limiting enzyme in the biosynthesis of glutathione and trypanothione in Leishmania. Attempts to generate GSH1 null mutants by gene disruption failed in Leishmania infantum. Removal of even a single allele invariably led to the generation of an extra copy of GSH1, maintaining two intact wild-type alleles. In the second and even third round of inactivation, the markers integrated at the homologous locus but always preserved two intact copies of GSH1. We probed into the mechanism of GSH1 duplication. GSH1 is subtelomeric on chromosome 18 and Southern blot analysis indicated that a 10-kb fragment flanked by 466-bp direct repeated sequences was duplicated in tandem on the same chromosomal allele each time GSH1 was targeted. Polymerase chain reaction analysis and sequencing confirmed the generation of novel junctions created at the level of the 466-bp repeats consequent to locus duplication. In loss of heterozygosity attempts, the same repeated sequences were utilized for generating extrachromosomal circular amplicons. Our results are consistent with break-induced replication as a mechanism for the generation of this regional polyploidy to compensate for the inactivation of an essential gene. This chromosomal repeat expansion through repeated sequences could be implicated in locus duplication in Leishmania. PMID- 21693562 TI - Folic acid supplementation can adversely affect murine neural tube closure and embryonic survival. AB - Neural tube defects (NTDs), a common birth defect in humans, result from the failure of the embryonic neural tube (NT) to close properly. NT closure is a complex, poorly understood morphogenetic process influenced by genes and environment. The most effective environmental influence in decreasing the risk for NTDs is folic acid (FA) fortification and supplementation, and these findings led to the recommendation of periconceptual FA intake and mandatory fortification of the US grain supply in 1998. To explore the relationship between genetics and responsiveness to FA supplementation, we used five mouse NTDs models-Zic2, Shroom3, Frem2, Grhl2 (Grainyhead-like 2) and L3P (Line3P)-and a long-term generational FA supplementation scheme. Contrary to expectations, we find that three genetic mutants respond adversely to FA supplementation with increased incidence of NTDs in homozygous mutants, occurrence of NTDs in heterozygous embryos and embryonic lethality prior to NT closure. Because of these unexpected responses, we examined NTD risk after short-term FA supplementation. Our results indicate that, for the same genetic allele, NTD risk can depend on the length of FA exposure. Our data indicate that, depending on the gene mutation, FA supplementation may adversely influence embryonic development and NT closure. PMID- 21693563 TI - Increasing expression and decreasing degradation of SMN ameliorate the spinal muscular atrophy phenotype in mice. AB - Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by reduced levels of the survival motor neuron (SMN) protein. Here we show that the proteasome inhibitor, bortezomib, increases SMN in cultured cells and in peripheral tissues of SMA model mice. Bortezomib-treated animals had improved motor function, which was associated with reduced spinal cord and muscle pathology and improved neuromuscular junction size, but no change in survival. Combining bortezomib with the histone deacetylase inhibitor trichostatin A (TSA) resulted in a synergistic increase in SMN protein levels in mouse tissue and extended survival of SMA mice more than TSA alone. Our results demonstrate that a combined regimen of drugs that decrease SMN protein degradation and increase SMN gene transcription synergistically increases SMN levels and improves the lifespan of SMA model mice. Moreover, this study indicates that while increasing SMN levels in the central nervous system may help extend survival, peripheral tissues can also be targeted to improve the SMA disease phenotype. PMID- 21693564 TI - A targeted metabolic protocol with D-ribose for off-pump coronary artery bypass procedures: a retrospective analysis. AB - OBJECTIVES: Coronary revascularization using cardiopulmonary bypass is an effective surgical procedure for ischemic coronary artery disease. Complications associated with cardiopulmonary bypass have included cerebral vascular accidents, neurocognitive disorders, renal dysfunction, and acute systemic inflammatory responses. Within the last two decades off-pump coronary artery bypass has emerged as an approach to reduce the incidence of these complications, as well as shorten hospital stays and recovery times. Many patients with coronary artery disease have insulin resistance and altered energy metabolism, which can exacerbate around the time of coronary revascularization. D-ribose has been shown to enhance the recovery of high-energy phosphates following myocardial ischemia. We hypothesized that patient outcomes could improve using a perioperative metabolic protocol with D-ribose. METHODS: A perioperative metabolic protocol was used in 366 patients undergoing off-pump coronary artery bypass during 2004-2008. D-ribose was added in 308 of these 366 patients. Data were collected prospectively as part of the Society of Thoracic Surgeons database and retrospectively analyzed. RESULTS: D-ribose patients were generally similar to those who did not receive D-ribose. There was one death, two patients suffered strokes and renal failure requiring dialysis occurred in two patients postoperatively among the entire group of patients. D-ribose patients enjoyed a greater improvement in cardiac index postrevascularization compared with non-D ribose patients (37% vs. 17%, respectively, p < 0.001). CONCLUSIONS: This metabolic protocol was associated with very low mortality and morbidity with a significant early postoperative improvement in cardiac index using D-ribose supplementation. These preliminary results support a prospective randomized trial using this protocol and D-ribose. PMID- 21693565 TI - MMP-2 and MMP-9 in lymph-node-positive bladder cancer. AB - BACKGROUND: Matrix metalloproteinases (MMP), particularly MMP-2 and MMP-9, participate in tumour progression and metastasis in various cancers. Their significance in urothelial cancer of the bladder (UCB) is unclear. Expression analysis of MMP-2 and MMP-9 in tissue microarrays (TMA) constructed of corresponding samples from histopathological normal urothelium, tumour centre and invasion front of primary tumours and lymph-node (LN) metastases might help to elucidate their relevance in UCB. METHOD: MMP-2 and MMP-9 expression was evaluated in TMA of 150 surgically treated LN-positive UCB patients. Biomarker expression was correlated with tumour characteristics (primary tumour and LN stage, number, total diameter and extracapsular extension of LN metastases) and overall survival. RESULTS: While there was a significant increase in MMP-9 expression from normal urothelium over primary tumours to metastases (median scores: 20, 50, 65; p<0.005), no such trend was observed in MMP-2 (median scores: 5, 22, 10; p<0.005). A comparison of expression in the tumour centre and the invasion front showed no difference in both MMP. No association between expression and histopathological tumour characteristics was identified. There was a non-significant trend for a more favourable outcome for patients with high MMP 2 expression in primary tumours. CONCLUSION: In LN-positive UCB, MMP-2 and MMP-9 expression was not increased at the invasion front, suggesting an infiltration strategy independent of MMP-2 and MMP-9 activity. Larger series are needed to detect a potential significant trend for favourable outcome in cancers with high MMP-2 expression. PMID- 21693566 TI - The Israeli abortion committees' process of decision making: an ethical analysis. AB - The Israeli law of abortions (1977) legally authorises hospital committees to decide upon women's requests for selective abortion. One of the law's clauses determines that abortions can be approved in cases of an embryopathy. However, the law does not provide any clear definitions of those fetal 'physical or mental defects' in terms of severity and/or likelihood, which remain open to interpretation by the committee members. This paper aimed to determine which ethical methodologies are used by committee members and advisors as they face the dilemma of abortion approval due to mild to moderate possible embryopathy. Twenty interviews demonstrated that they use mainly a combination of deontology and a contextual-relational model. Their ethical considerations are both contextual such as the family's/woman's relational network and are influenced by the ethical principles of autonomy and in cases of late abortions the value of life. The findings reveal a paradoxical picture: on the one hand, committee members hold liberal perceptions and in practice abortion requests are very seldom rejected. On the other hand, the Israeli abortion law and practice of abortion committees is still problematical from liberal and feminist rights perspectives. This paradox is discussed further by reflecting upon the relevant theory as well as the Israeli context. The paper concludes by suggesting that within the specific Israeli sociopolitical climate the requirement for committee approval of what should be a private decision might be necessary in order to placate religious or other opposition to abortion. PMID- 21693567 TI - Research and complicity: the case of Julius Hallervorden. AB - The charge of complicity has been raised in debates over the ethics of fetal tissue transplantation and embryonic stem cell research. However, the applicability of the concept of complicity to these types of research is neither clear nor uncontroversial. This article discusses the historical case of Julius Hallervorden, a distinguished German neuropathologist who conducted research on brains of mentally handicapped patients killed in the context of the Nazi 'euthanasia' programme. It is argued that this case constitutes a paradigm of complicity in research that is useful in assessing complicity in contemporary research ethics. PMID- 21693568 TI - Potential risk factors for recurrence of pulmonary tuberculosis. PMID- 21693569 TI - Home tracheotomy mechanical ventilation in patients with amyotrophic lateral sclerosis: causes, complications and 1-year survival. AB - BACKGROUND: Home tracheotomy mechanical ventilation (HTMV) can prolong survival in patients with amyotrophic lateral sclerosis (ALS) when non-invasive ventilation (NIV) fails, but knowledge about HTMV is scarce. The aim of this study was to determine the causes of tracheotomy and the main issues of 1-year HTMV in a cohort of patients with ALS. METHODS: A prospective study of all patients needing HTMV was performed in a referral respiratory care unit (RCU) from April 2001 to January 2010. Patients' informed decisions about HTMV were fully respected. Caregivers were trained and could telephone the RCU. Hospital staff made home visits. RESULTS: All patients (n=116) agreed to participate and a tracheotomy was needed for 76, mainly due to bulbar dysfunction. Of the 38 who had a tracheotomy, in 21 it was performed in an acute setting and in 17 as a non emergency procedure. In 19 patients the tracheotomy was related to the inadequacy of mechanically assisted coughing (MAC) to maintain normal oxygen saturation. During HTMV, 19 patients required hospitalisation, 12 with respiratory problems. The 1-year survival rate was 78.9%, with a mean survival of 10.39 months (95% CI 9.36 to 11.43). Sudden death was the main cause of death (n=9) and only one patient died from respiratory causes. No predictive factors for survival were found. CONCLUSIONS: Besides NIV inadequacy, the ineffectiveness of mechanically assisted coughing appears to be a relevant cause of tracheotomy for patients with ALS with severe bulbar dysfunction. Patients choosing HTMV provided by a referral RCU could have a good 1-year survival rate, respiratory problems being the main cause of hospitalisation but not of death. PMID- 21693570 TI - General practice and social service partnership for better clinical outcomes, patient self efficacy and lifestyle behaviours of diabetic care: randomised control trial of a chronic care model. AB - BACKGROUND: The International Diabetes Attitudes, Wishes, and Needs (DAWN) programmes have shown the existence of a critical gap in self management support and access to the support system. This study aims to evaluate the effectiveness of the diabetes mellitus (DM) self management programme, with partnership between general practice and social work, on clinical outcomes, patient self efficacy and lifestyle behaviours. METHODS: In this is single blind randomised controlled trial, subjects were recruited from patients attending general outpatient clinics in the Hospital Authority New Territory East Cluster of Hong Kong. 157 subjects meeting the inclusion criteria completed the study and were randomly assigned to the experimental or control group. The experimental group underwent the six sessions of weekly DM self management course with emphasis on self efficacy and participatory approach. The outcome measurements included HbA1c concentration, DM self efficacy scale, dietary behaviours, body mass index (BMI), and waist: hip ratio. RESULTS: Baseline assessment observed no significant differences between experimental and control groups for the variables related to outcomes. For the experimental group, the proportion of subjects with normal HbA1c increased from 4.5% (3/66) at baseline to 28.6% (19/66) at week 28 (p<0.001), but there was insignificant improvement in the control group (3.9% to 11.8%, p=0.13). Repeated measure of analysis of variance showed pronounced improvement in DM self efficacy scale and BMI among the experimental group with significant interaction. Dietary behaviours also improved significantly in the experimental group. CONCLUSION: The DM care model with partnership between general practice and social work demonstrated better diabetic control with improvement of self efficacy and minimisation of risk behaviours. TRIAL REGISTRATION: Current Controlled Trials ISRCTN78882965. PMID- 21693571 TI - Relationship between clock and star drawing and the degree of hepatic encephalopathy. AB - PURPOSE OF THE STUDY Current hepatic encephalopathy grading tools are limited because of complexity or subjectivity. The degree of constructional apraxia could serve as a simple, objective and reproducible tool to grade encephalopathy. STUDY DESIGN In this cross-sectional study of patients with chronic liver disease, the degree of constructional apraxia was judged by their ability to copy a star and clock face and compared with conventional encephalopathy grading by the West Haven Criteria (WHC) and the Porto Systemic Encephalopathy Index (PSEI). Three blinded observers independently graded the figures. Sensitivity, specificity and positive predictive value (PPV) of clock and star scores (score 0 implying no encephalopathy and >0 hepatic encephalopathy) were assessed against conventional scoring systems (WHC grade >0 or PSEI >=0.33 indicating encephalopathy). Mosaic and box plots were generated to assess if the degree of constructional apraxia correlated with the severity of encephalopathy. RESULTS 71 patients were studied between October 2008 and July 2009; 11 (15.4%) had WHC grade 0, 32 (45%) grade 1, and 28 (39.4%) grades 2 and 3 encephalopathy. The sensitivity, specificity and PPV of the clock drawing for the diagnosis of encephalopathy was 85%, 80%, and 96%, respectively, and 77%, 70%, and 94%, respectively, for the star drawing. Box plots and intervals on mean PSEI showed an increasing relationship between clock/star scores and PSEI. There was substantial agreement between WHC and clock (weighted kappa 0.61) and star scores (weighted kappa 0.71). Inter-observer reliability was at least 0.70 for star and at least 0.79 for the clock score. CONCLUSION Clock and star drawing may serve as reproducible, inexpensive bedside tools for diagnosing and grading the severity of hepatic encephalopathy. PMID- 21693572 TI - How Dutch medical residents perceive their competency as manager in the revised postgraduate medical curriculum. AB - INTRODUCTION: In 2005, competency based training was introduced into the curriculum of the postgraduate training of Dutch medical residents. The role as manager is one of the seven competencies and, compared to the other roles, it is presently thought to receive little attention during training. The goal of this study was to investigate medical residents' understanding of this competency and how they perceive their role as manager. METHODS: In October 2009, 506 residents from different specialties in four teaching hospitals were invited via email to participate in the study. A 29-item Likert scale questionnaire was designed to investigate residents perceived healthcare management skills and knowledge in four management areas. RESULTS: 177 of 506 residents (35%) responded to the survey. More than half of the residents (106/177, 60%) did not feel confident in their (contract) negotiating skills and 56% (98/175) stated that they lacked sufficient knowledge of how the Dutch healthcare system is financed and organised. The residents were most confident in their ability to handle feedback (151/177, 85%), medical information data registration (168/173, 97%), and how to allocate healthcare resources based on evidence based principles (143/173, 83%). CONCLUSION: These results demonstrate that residents in the Netherlands perceive their knowledge and skills in certain essential medical management concepts to be inadequate. The results suggest that a course in medical management should be considered as a mandatory part of the curricula of residency training programmes. PMID- 21693573 TI - Cardiopulmonary exercise testing for the evaluation of perioperative risk in non cardiopulmonary surgery. AB - The use of cardiopulmonary exercise testing (CPET) as a preoperative risk stratification tool for a range of non-cardiopulmonary surgery is increasing. The utility of CPET in this role is dependent on the technology being able to identify accurately and reliably those patients at increased risk of perioperative events when compared with existing risk stratification tools. This article identifies and reviews systematically the current literature regarding the use of CPET as a preoperative tool for stratifying risk in major non cardiopulmonary surgery. Specifically, it focuses on evaluating the capacity of CPET variables to predict the risk of postoperative complications and mortality in comparison to other methods of risk assessment. Furthermore, the potential for combining results from CPET and non-CPET methods of risk prediction to enhance the capacity to identify high risk patients is considered. The review indicates that CPET can identify patients at increased risk of adverse perioperative outcomes. However, the selection of variables and threshold values to indicate high risk differ for different surgical procedures and underlying conditions. Furthermore, the available data suggest that CPET variables outperform alternative methods of preoperative risk stratification. Several studies also identify that CPET variables may be used in combination with non-CPET variables to increase perioperative risk prediction accuracy. These findings illustrate that CPET has the capacity to identify patients at increased risk of adverse outcome before a range of non-cardiopulmonary surgical procedures. Further research is required to optimise its use, potentially by combining CPET results with alternative methods of risk stratification. PMID- 21693574 TI - KLP6: a newly identified kinesin that regulates the morphology and transport of mitochondria in neuronal cells. AB - Mitochondria utilize diverse cytoskeleton-based mechanisms to control their functions and morphology. Here, we report a role for kinesin-like protein KLP6, a newly identified member of the kinesin family, in mitochondrial morphology and dynamics. An RNA interference screen using Caenorhabditis elegans led us to identify a C. elegans KLP-6 involved in maintaining mitochondrial morphology. We cloned a cDNA coding for a rat homolog of C. elegans KLP-6, which is an uncharacterized kinesin in vertebrates. A rat KLP6 mutant protein lacking the motor domain induced changes in mitochondrial morphology and significantly decreased mitochondrial motility in HeLa cells, but did not affect the morphology of other organelles. In addition, the KLP6 mutant inhibited transport of mitochondria during anterograde movement in differentiated neuro 2a cells. To date, two kinesins, KIF1Balpha and kinesin heavy chain (KHC; also known as KIF5) have been shown to be involved in the distribution of mitochondria in neurons. Expression of the kinesin heavy chain/KIF5 mutant prevented mitochondria from entering into neurites, whereas both the KLP6 and KIF1Balpha mutants decreased mitochondrial transport in axonal neurites. Furthermore, both KLP6 and KIF1Balpha bind to KBP, a KIF1-binding protein required for axonal outgrowth and mitochondrial distribution. Thus, KLP6 is a newly identified kinesin family member that regulates mitochondrial morphology and transport. PMID- 21693575 TI - S100B protein regulates myoblast proliferation and differentiation by activating FGFR1 in a bFGF-dependent manner. AB - S100B protein has been shown to exert anti-myogenic and mitogenic effects in myoblast cultures through inhibition of the myogenic p38 MAPK and activation of the mitogenic ERK1/2. However, the receptor mediating these effects had not been identified. Here, we show that S100B increases and/or stabilizes the binding of basic fibroblast growth factor (bFGF) to bFGF receptor 1 (FGFR1) by interacting with bFGF, thereby enhancing FGFR1 activation and the mitogenic and anti-myogenic effects of FGFR1. S100B also binds to its canonical receptor RAGE (receptor for advanced glycation end-products), a multi-ligand receptor previously shown to transduce a pro-myogenic signal when activated by HMGB1, and recruits RAGE into a RAGE-S100B-bFGF-FGFR1 complex. However, when bound to S100B-bFGF-FGFR1, RAGE can no longer stimulate myogenic differentiation, whereas in the absence of either bFGF or FGFR1, binding of S100B to RAGE results in stimulation of RAGE anti mitogenic and promyogenic signaling. An S100B-bFGF-FGFR1 complex also forms in Rage(-/-) myoblasts, leading to enhanced proliferation and reduced differentiation, which points to a dispensability of RAGE for the inhibitory effects of S100B on myoblasts under the present experimental conditions. These results reveal a new S100B-interacting protein - bFGF - in the extracellular milieu and suggest that S100B stimulates myoblast proliferation and inhibits myogenic differentiation by activating FGFR1 in a bFGF-dependent manner. PMID- 21693576 TI - The Ddc2/ATRIP checkpoint protein monitors meiotic recombination intermediates. AB - During meiosis, accurate segregation of intact chromosomes is essential for generating healthy gametes. Defects in recombination and/or chromosome synapsis activate the pachytene checkpoint, which delays meiotic cell cycle progression to avoid aberrant chromosome segregation and formation of defective gametes. Here, we characterize the role of the conserved DNA damage checkpoint protein Ddc2/ATRIP in this meiotic surveillance mechanism. We show that deletion of DDC2 relieves the checkpoint-dependent meiotic block that occurs in Saccharomyces cerevisiae mutants defective in various aspects of meiotic chromosome dynamics and results in the generation of faulty meiotic products. Moreover, production of the Ddc2 protein is induced during meiotic prophase, accumulates in checkpoint arrested mutants and localizes to distinctive chromosomal foci. Formation of meiotic Ddc2 foci requires the generation of Spo11-dependent DNA double-strand breaks (DSBs), and is impaired in an RPA mutant. Chromatin immunoprecipitation analysis reveals that Ddc2 accumulates at meiotic DSB sites, indicating that Ddc2 senses the presence of meiotic recombination intermediates. Furthermore, pachytene checkpoint signaling is defective in the ddc2 mutant. In addition, we show that mammalian ATRIP colocalizes with ATR, TopBP1 and RPA at unsynapsed regions of mouse meiotic chromosomes. Thus, our results point to an evolutionary conserved role for Ddc2/ATRIP in monitoring meiotic chromosome metabolism. PMID- 21693577 TI - TGFB1 disrupts the angiogenic potential of microvascular endothelial cells of the corpus luteum. AB - Cyclical formation and regression of the ovarian corpus luteum is required for reproduction. During luteal regression, the microvasculature of the corpus luteum is extensively disrupted. Prostaglandin F2alpha, a primary signal for luteal regression, induces the expression of transforming growth factor beta1 (TGFB1) in the corpus luteum. This study determined the actions of TGFB1 on microvascular endothelial cells isolated from the bovine corpus luteum (CLENDO cells). We hypothesized that TGFB1 participates in the disruption of the microvasculature during luteal regression. TGFB1 activated the canonical SMAD signaling pathway in CLENDO cells. TGFB1 (1 ng/ml) significantly reduced both basal and fetal-calf serum-stimulated DNA synthesis, without reducing cell viability. TGFB1 also significantly reduced CLENDO cell transwell migration and disrupted the formation of capillary-like structures when CLENDO cells were plated on Matrigel. By contrast, CLENDO cells plated on fibrillar collagen I gels did not form capillary like structures and TGFB1 induced cell death. Additionally, TGFB1 caused loss of VE-cadherin from cellular junctions and loss of cell-cell contacts, and increased the permeability of confluent CLENDO cell monolayers. These studies demonstrate that TGFB1 acts directly on CLENDO cells to limit endothelial cell function and suggest that TGFB1 might act in the disassembly of capillaries observed during luteal regression. PMID- 21693578 TI - Streptolysin O clearance through sequestration into blebs that bud passively from the plasma membrane. AB - Cells survive exposure to bacterial pore-forming toxins, such as streptolysin O (SLO), through mechanisms that remain unclear. Previous studies have suggested that these toxins are cleared by endocytosis. However, the experiments reported here failed to reveal any evidence for endocytosis of SLO, nor did they reveal any signs of damage to endosomal membranes predicted from such endocytosis. Instead, we illustrate that SLO induces a characteristic form of plasma membrane blebbing that allows cells to shed SLO by the process known as ectocytosis. Specifically, 'deep-etch' electron microscopy of cells exposed to SLO illustrates that the toxin is rapidly sequestered into domains in the plasmalemma greatly enriched in SLO pores, and these domains bleb outwards and bud from the cell surface into the medium. Such ectocytosis is even observed in cells that have been chemically fixed before exposure to SLO, suggesting that it is caused by a direct physical action of the toxin on the cell membrane, rather than by an active cellular reaction. We conclude, therefore, that ectocytosis is an important means for SLO clearance and hypothesize that this is a primary method by which cells defend themselves generally against pore-forming toxins. PMID- 21693579 TI - Sequoia establishes tip-cell number in Drosophila trachea by regulating FGF levels. AB - Competition and determination of leading and trailing cells during collective cell migration is a widespread phenomenon in development, wound healing and tumour invasion. Here, we analyse this issue during in vivo ganglionic branch cell migration in the Drosophila tracheal system. We identify Sequoia (Seq) as a negative transcriptional regulator of Branchless (Bnl), a Drosophila FGF homologue, and observe that modulation of Bnl levels determines how many cells will lead this migrating cluster, regardless of Notch lateral inhibition. Our results show that becoming a tip cell does not prevent others in the branch taking the same position, suggesting that leader choice does not depend only on sensing relative amounts of FGF receptor activity. PMID- 21693580 TI - Overexpression of HSP70 inhibits cofilin phosphorylation and promotes lymphocyte migration in heat-stressed cells. AB - Hyperthermia adversely affects cell structure and function, but also induces adaptive responses that allow cells to tolerate these stressful conditions. For example, heat-induced expression of the molecular chaperone protein HSP70 can prevent stress-induced cell death by inhibiting signaling pathways that lead to apoptosis. In this study, we used high-resolution two-dimensional gel electrophoresis and phosphoprotein staining to identify signaling pathways that are altered by hyperthermia and modulated by HSP70 expression. We found that in heat-shocked cells, the actin-severing protein cofilin acquires inhibitory Ser3 phosphorylation, which is associated with an inhibition of chemokine-stimulated cell migration. Cofilin phosphorylation appeared to occur as a result of the heat induced insolubilization of the cofilin phosphatase slingshot (SSH1-L). Overexpression of HSP70 reduced the extent of SSH1-L insolubilization and accelerated its resolubilization when cells were returned to 37 degrees C after exposure to hyperthermia, resulting in a more rapid dephosphorylation of cofilin. Cells overexpressing HSP70 also had an increased ability to undergo chemotaxis following exposure to hyperthermia. These results identify a critical heat sensitive target controlling cell migration that is regulated by HSP70 and point to a role for HSP70 in immune cell functions that depend upon the proper control of actin dynamics. PMID- 21693581 TI - Protein 4.1R regulates cell adhesion, spreading, migration and motility of mouse keratinocytes by modulating surface expression of beta1 integrin. AB - Protein 4.1R is a membrane-cytoskeleton adaptor protein that has diverse roles in controlling the cell surface expression and/or function of transmembrane proteins, and in organizing F-actin. 4.1R is expressed in keratinocytes, but its role in these cells has not been explored. Here, we have investigated the role of 4.1R in skin using 4.1R(-/-) mice. Cell adhesion, spreading, migration and motility were significantly impaired in 4.1R(-/-) keratinocytes, and 4.1R(-/-) mice exhibited defective epidermal wound healing. Cultured 4.1R(-/-) keratinocytes on fibronectin failed to form actin stress fibres and focal adhesions. Furthermore, in the absence of 4.1R, the surface expression, and consequently the activity of beta1 integrin were reduced. These data enabled the identification of a functional role for protein 4.1R in keratinocytes by modulating the surface expression of beta1 integrin, possibly through a direct association between 4.1R and beta1 integrin. PMID- 21693582 TI - Wnt5a is a cell-extrinsic factor that supports self-renewal of mouse spermatogonial stem cells. AB - The maintenance of spermatogonial stem cells (SSCs) provides the foundation for life-long spermatogenesis. Although glial-cell-line-derived neurotrophic factor and fibroblast growth factor 2 are crucial for self-renewal of SSCs, recent studies have suggested that other growth factors have important roles in controlling SSC fate. Because beta-catenin-dependent Wnt signaling promotes self renewal of various stem cell types, we hypothesized that this pathway contributes to SSC maintenance. Using transgenic reporter mice for beta-catenin-dependent signaling, we found that this signaling was not active in SSCs in vitro and in most spermatogonia in vivo. Nonetheless, a pan-Wnt antagonist significantly reduced SSC activity in vitro, suggesting that some Wnt molecules exist in our serum-free culture system and contribute to SSC maintenance. Here, we report that Wnt5a promotes SSC activity. We found that Wnt5a-expressing fibroblasts supported SSC activity better than those not expressing Wnt5a in culture, and that recombinant Wnt5a stimulated SSC maintenance. Furthermore, Wnt5a promoted SSC survival in the absence of feeder cells, and this effect was abolished by inhibiting the Jun N-terminal kinase cascade. In addition, Wnt5a blocked beta catenin-dependent signaling. We detected the expression of Wnt5a and potential Wnt5a receptors in Sertoli cells and stem/progenitor spermatogonia, respectively. These results indicate that Wnt5a is a cell-extrinsic factor that supports SSC self-renewal through beta-catenin-independent mechanisms. PMID- 21693583 TI - A calmodulin-related light chain from fission yeast that functions with myosin-I and PI 4-kinase. AB - Fission yeast myosin-I (Myo1p) not only associates with calmodulin, but also employs a second light chain called Cam2p. cam2Delta cells exhibit defects in cell polarity and growth consistent with a loss of Myo1p function. Loss of Cam2p leads to a reduction in Myo1p levels at endocytic patches and a 50% drop in the rates of Myo1p-driven actin filament motility. Thus, Cam2p plays a significant role in Myo1p function. However, further studies indicated the existence of an additional Cam2p-binding partner. Cam2p was still present at cortical patches in myo1Delta cells (or in myo1-IQ2 mutants, which lack an intact Cam2p-binding motif), whereas a cam2 null (cam2Delta) suppressed cytokinesis defects of an essential light chain (ELC) mutant known to be impaired in binding to PI 4-kinase (Pik1p). Binding studies revealed that Cam2p and the ELC compete for Pik1p. Cortical localization of Cam2p in the myo1Delta background relied on its association with Pik1p, whereas overexpression studies indicated that Cam2p, in turn, contributes to Pik1p function. The fact that the Myo1p-associated defects of a cam2Delta mutant are more potent than those of a myo1-IQ2 mutant suggests that myosin light chains can contribute to actomyosin function both directly and indirectly (via phospholipid synthesis at sites of polarized growth). PMID- 21693584 TI - The F-BAR domain protein PACSIN2 associates with Rac1 and regulates cell spreading and migration. AB - The Rac1 GTPase controls cytoskeletal dynamics and is a key regulator of cell spreading and migration mediated by signaling through effector proteins, such as the PAK kinases and the Scar and WAVE proteins. We previously identified a series of regulatory proteins that associate with Rac1 through its hypervariable C terminal domain, including the Rac1 activator beta-Pix (also known as Rho guanine nucleotide-exchange factor 7) and the membrane adapter caveolin-1. Here, we show that Rac1 associates, through its C-terminus, with the F-BAR domain protein PACSIN2, an inducer of membrane tubulation and a regulator of endocytosis. We show that Rac1 localizes with PACSIN2 at intracellular tubular structures and on early endosomes. Active Rac1 induces a loss of PACSIN2-positive tubular structures. By contrast, Rac1 inhibition results in an accumulation of PACSIN2 positive tubules. In addition, PACSIN2 appears to regulate Rac1 signaling; siRNA mediated loss of PACSIN2 increases the levels of Rac1-GTP and promotes cell spreading and migration in a wound healing assay. Moreover, ectopic expression of PACSIN2 reduces Rac1-GTP levels in a fashion that is dependent on the PACSIN2 Rac1 interaction, on the membrane-tubulating capacity of PACSIN2 and on dynamin. These data identify the BAR-domain protein PACSIN2 as a Rac1 interactor that regulates Rac1-mediated cell spreading and migration. PMID- 21693585 TI - Galectin-3 maintains cell motility from the subventricular zone to the olfactory bulb. AB - The adult brain subventricular zone (SVZ) produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB) in a specialized niche. Galectin-3 (Gal-3) regulates proliferation and migration in cancer and is expressed by activated macrophages after brain injury. The function of Gal-3 in the normal brain is unknown, but we serendipitously found that it was expressed by ependymal cells and SVZ astrocytes in uninjured mice. Ependymal cilia establish chemotactic gradients and astrocytes form glial tubes, which combine to aid neuroblast migration. Whole-mount preparations and electron microscopy revealed that both ependymal cilia and SVZ astrocytes were disrupted in Gal3(-/-) mice. Interestingly, far fewer new BrdU(+) neurons were found in the OB of Gal3(-/-) mice, than in wild-type mice 2 weeks after labeling. However, SVZ proliferation and cell death, as well as OB differentiation rates were unaltered. This suggested that decreased migration in vivo was sufficient to decrease the number of new OB neurons. Two-photon time-lapse microscopy in forebrain slices confirmed decreased migration; cells were slower and more exploratory in Gal3(-/ ) mice. Gal-3 blocking antibodies decreased migration and dissociated neuroblast cell-cell contacts, whereas recombinant Gal-3 increased migration from explants. Finally, we showed that expression of phosphorylated epidermal growth factor receptor (EGFR) was increased in Gal3(-/-) mice. These results suggest that Gal-3 is important in SVZ neuroblast migration, possibly through an EGFR-based mechanism, and reveals a role for this lectin in the uninjured brain. PMID- 21693586 TI - Rab9-dependent retrograde transport and endosomal sorting of the endopeptidase furin. AB - The endopeptidase furin and the trans-Golgi network protein TGN38 are membrane proteins that recycle between the TGN and plasma membrane. TGN38 is transported by a retromer-dependent pathway from early endosomes to the TGN, whereas the intracellular transport of furin is poorly defined. Here we have identified the itinerary and transport requirements of furin. Using internalisation assays, we show that furin transits the early and late endosomes en route to the TGN. The GTPase Rab9 and the TGN golgin GCC185, components of the late endosome-to-TGN pathway, were required for efficient TGN retrieval of furin. By contrast, TGN38 trafficking was independent of Rab9 and GCC185. To identify the sorting signals for the early endosome-to-TGN pathway, the trafficking of furin-TGN38 chimeras was investigated. The diversion of furin from the Rab9-dependent late-endosome-to TGN pathway to the retromer-dependent early-endosome-to-TGN pathway required both the transmembrane domain and cytoplasmic tail of TGN38. We present evidence to suggest that the length of the transmembrane domain is a contributing factor in endosomal sorting. Overall, these data show that furin uses the Rab9-dependent pathway from late endosomes and that retrograde transport directly from early endosomes is dependent on both the transmembrane domain and the cytoplasmic tail. PMID- 21693587 TI - Real-time monitoring of redox changes in the mammalian endoplasmic reticulum. AB - Redox-sensitive GFPs with engineered disulphide bonds have been used previously to monitor redox status in the cytosol and mitochondria of living cells. The usefulness of these redox probes depends on the reduction potential of the disulphide, with low values suiting the cytosol and mitochondrion, and higher values suiting the more oxidising environment of the endoplasmic reticulum (ER). Here, we targeted a modified redox-sensitive GFP (roGFP1-iL), with a relatively high reduction potential, to the ER of mammalian cells. We showed that the disulphide is partially oxidised, allowing roGFP1-iL to monitor changes in ER redox status. When cells were treated with puromycin, the redox balance became more reducing, suggesting that the release of nascent chains from ribosomes alters the ER redox balance. In addition, downregulating Ero1alpha prevented normal rapid recovery from dithiothreitol (DTT), whereas downregulating peroxiredoxin IV had no such effect. This result illustrates the contribution of the Ero1alpha oxidative pathway to ER redox balance. This first report of the use of roGFP to study the ER of mammalian cells demonstrates that roGFP1-iL can be used to monitor real-time changes to the redox status in individual living cells. PMID- 21693588 TI - Lipid droplets are functionally connected to the endoplasmic reticulum in Saccharomyces cerevisiae. AB - Cells store metabolic energy in the form of neutral lipids that are deposited within lipid droplets (LDs). In this study, we examine the biogenesis of LDs and the transport of integral membrane proteins from the endoplasmic reticulum (ER) to newly formed LDs. In cells that lack LDs, otherwise LD-localized membrane proteins are homogenously distributed in the ER membrane. Under these conditions, transcriptional induction of a diacylglycerol acyltransferase that catalyzes the formation of the storage lipid triacylglycerol (TAG), Lro1, is sufficient to drive LD formation. Newly formed LDs originate from the ER membrane where they become decorated by marker proteins. Induction of LDs by expression of the second TAG-synthesizing integral membrane protein, Dga1, reveals that Dga1 itself moves from the ER membrane to concentrate on LDs. Photobleaching experiments (FRAP) indicate that relocation of membrane proteins from the ER to LDs is independent of temperature and energy, and thus not mediated by classical vesicular transport routes. LD-localized membrane proteins are homogenously distributed at the perimeter of LDs, they are free to move over the LD surface and can even relocate back into the ER, indicating that they are not restricted to specialized sites on LDs. These observations indicate that LDs are functionally connected to the ER membrane and that this connection allows the efficient partitioning of membrane proteins between the two compartments. PMID- 21693589 TI - A functional channel is necessary for growth suppression by Cx37. AB - Connexin 37 (Cx37) profoundly suppresses the proliferation of rat insulinoma (Rin) cells by unknown mechanisms. To determine whether a functional pore domain is necessary for Cx37-mediated growth suppression, we introduced a mutation that converted threonine 154 into alanine (T154A). Like other connexins mutated at the homologous site, Cx37-T154A localized to appositional membrane but failed to form functional channels and exerted a dominant-negative effect on coexpressed wild type Cx37 or Cx43. Unlike the wild-type protein, Cx37-T154A did not suppress the proliferation of Rin cells and did not, with serum deprivation, result in cell cycle arrest. Furthermore, progression through the cell cycle was unaffected by expression of Cx37-T154A. These results indicate that a pore-forming domain that is able to form functional channels is essential for the anti-proliferative, cell cycle arrest and serum-sensitivity effects of Cx37, and furthermore that the normally localized C-terminal domain is not sufficient for these effects of Cx37. PMID- 21693590 TI - Localization of phosphorylated CK2alpha to the mitotic spindle requires the peptidyl-prolyl isomerase Pin1. AB - CK2 is a serine/threonine kinase with many substrates, largely unknown modes of regulation and essential roles in mitotic progression. CK2alpha, a catalytic subunit of CK2, is phosphorylated in mitosis, and here we examine the effect of phosphorylation on CK2alpha localization. Using phosphospecific antibodies, we show that CK2alpha localizes to the mitotic spindle in a phosphorylation dependent manner. Mitotic spindle localization requires the unique C-terminus of CK2alpha, and involves a novel regulatory mechanism in which phosphorylation of CK2alpha facilitates binding to the peptidyl-prolyl isomerase Pin1, which is required for CK2alpha mitotic spindle localization. This could explain how the constitutive activity of CK2alpha might be targeted towards mitotic substrates. Furthermore, because Pin1 has many important spindle substrates, this might represent a general mechanism for localization of mitotic signalling proteins. PMID- 21693592 TI - Screening under scrutiny. PMID- 21693591 TI - Apple polyphenols require T cells to ameliorate dextran sulfate sodium-induced colitis and dampen proinflammatory cytokine expression. AB - Human IBD, including UC and Crohn's disease, is characterized by a chronic, relapsing, and remitting condition that exhibits various features of immunological inflammation and affects at least one/1000 people in Western countries. Polyphenol extracts from a variety of plants have been shown to have immunomodulatory and anti-inflammatory effects. In this study, treatment with APP was investigated to ameliorate chemically induced colitis. Oral but not peritoneal administration of APP during colitis induction significantly protected C57BL/6 mice against disease, as evidenced by the lack of weight loss, colonic inflammation, and shortening of the colon. APP administration dampened the mRNA expression of IL-1beta, TNF-alpha, IL-6, IL-17, IL-22, CXCL9, CXCL10, CXCL11, and IFN-gamma in the colons of mice with colitis. APP-mediated protection requires T cells, as protection was abated in Rag-1(-/-) or TCRalpha(-/-) mice but not in IL 10(-/-), IRF-1(-/-), MUMT, or TCRdelta(-/-) mice. Administration of APP during colitis to TCRalpha(-/-) mice actually enhanced proinflammatory cytokine expression, further demonstrating a requirement for TCRalphabeta cells in APP mediated protection. APP treatment also inhibited CXCR3 expression by TCRalphabeta cells, but not B or NK cells, in the colons of mice with colitis; however, depletion of CD4(+) or CD8(+) T cells alone did not abolish APP-mediated protection. Collectively, these results show that oral administration of APP protects against experimental colitis and diminishes proinflammatory cytokine expression via T cells. PMID- 21693594 TI - Downregulation of Filamin A interacting protein 1-like is associated with promoter methylation and induces an invasive phenotype in ovarian cancer. AB - Ovarian cancer is the most lethal gynecologic malignancy with a five-year survival rate below 25% for patients with stages III and IV disease. Identifying key mediators of ovarian cancer invasion and metastasis is critical to the development of more effective therapeutic interventions. We previously identified Filamin A interacting protein 1-like (FILIP1L) as an important mediator of cell proliferation and migration. In addition, targeted expression of FILIP1L in tumors inhibited tumor growth in vivo. In our present study, we confirmed that both mRNA and protein expression of FILIP1L were downregulated in ovarian cancer cells compared with normal ovarian epithelial cells. FILIP1L expression was inversely correlated with the invasive potential of ovarian cancer cell lines and clinical ovarian cancer specimens. We also provide evidence that DNA methylation is a mechanism by which FILIP1L is downregulated in ovarian cancer. The CpG island in the FILIP1L promoter was heavily methylated in ovarian cancer cells. Methylation status of the FILIP1L promoter was inversely correlated with FILIP1L expression in ovarian cell lines and clinical ovarian specimens. Reduced methylation in the FILIP1L promoter following treatment with a DNA demethylating agent was associated with restoration of FILIP1L expression in ovarian cancer cells. A transcription activator, cAMP-responsive element binding protein (CREB) was shown to bind to the CREB/ATF site in the CpG island of the FILIP1L promoter. Overall, these findings suggest that downregulation of FILIP1L associated with DNA methylation is related with the invasive phenotype in ovarian cancer and that modulation of FILIP1L expression has the potential to be a target for ovarian cancer therapy. PMID- 21693595 TI - MicroRNA-138 modulates DNA damage response by repressing histone H2AX expression. AB - Precise regulation of DNA damage response is crucial for cellular survival after DNA damage, and its abrogation often results in genomic instability in cancer. Phosphorylated histone H2AX (gammaH2AX) forms nuclear foci at sites of DNA damage and facilitates DNA damage response and repair. MicroRNAs (miRNA) are short, nonprotein-encoding RNA molecules, which posttranscriptionally regulate gene expression by repressing translation of and/or degrading mRNA. How miRNAs modulate DNA damage response is largely unknown. In this study, we developed a cell-based screening assay using ionizing radiation (IR)-induced gammaH2AX foci formation in a human osteosarcoma cell line, U2OS, as the readout. By screening a library of human miRNA mimics, we identified several miRNAs that inhibited gammaH2AX foci formation. Among them, miR-138 directly targeted the histone H2AX 3'-untranslated region, reduced histone H2AX expression, and induced chromosomal instability after DNA damage. Overexpression of miR-138 inhibited homologous recombination and enhanced cellular sensitivity to multiple DNA-damaging agents (cisplatin, camptothecin, and IR). Reintroduction of histone H2AX in miR-138 overexpressing cells attenuated miR-138-mediated sensitization to cisplatin and camptothecin. Our study suggests that miR-138 is an important regulator of genomic stability and a potential therapeutic agent to improve the efficacy of radiotherapy and chemotherapy with DNA-damaging agents. PMID- 21693596 TI - c-MYC oncoprotein dictates transcriptional profiles of ATP-binding cassette transporter genes in chronic myelogenous leukemia CD34+ hematopoietic progenitor cells. AB - Resistance to chemotherapeutic agents remains one of the major impediments to a successful treatment of chronic myeloid leukemia (CML). Misregulation of the activity of a specific group of ATP-binding cassette transporters (ABC) is responsible for reducing the intracellular concentration of drugs in leukemic cells. Moreover, a consistent body of evidence also suggests that ABC transporters play a role in cancer progression beyond the efflux of cytotoxic drugs. Despite a large number of studies that investigated the function of the ABC transporters, little is known about the transcriptional regulation of the ABC genes. Here, we present data showing that the oncoprotein c-MYC is a direct transcriptional regulator of a large set of ABC transporters in CML. Furthermore, molecular analysis carried out in CD34+ hematopoietic cell precursors of 21 CML patients reveals that the overexpression of ABC transporters driven by c-MYC is a peculiar characteristic of the CD34+ population in CML and was not found either in the population of mononuclear cells from which they had been purified nor in CD34+ cells isolated from healthy donors. Finally, we describe how the methylation state of CpG islands may regulate the access of c-MYC to ABCG2 gene promoter, a well-studied gene associated with multidrug resistance in CML, hence, affecting its expression. Taken together, our findings support a model in which c MYC-driven transcriptional events, combined with epigenetic mechanisms, direct and regulate the expression of ABC genes with possible implications in tumor malignancy and drug efflux in CML. PMID- 21693597 TI - Methyl-binding domain protein 2-dependent proliferation and survival of breast cancer cells. AB - Methyl cytosine binding domain protein 2 (MBD2) has been shown to bind to and mediate repression of methylated tumor suppressor genes in cancer cells, where repatterning of CpG methylation and associated gene silencing is common. We have investigated the role of MBD2 in breast cancer cell growth and tumor suppressor gene expression. We show that stable short hairpin RNA (shRNA)-mediated knockdown of MBD2 leads to growth suppression of cultured human mammary epithelial cancer lines, SK-BR-3, MDA-MB-231, and MDA-MB-435. The peak antiproliferative occurs only after sustained, stable MBD2 knockdown. Once established, the growth inhibition persists over time and leads to a markedly decreased propensity for aggressive breast cancer cell lines to form in vivo xenograft tumors in Bagg Albino (BALB)/C nu/nu mice. The growth effects of MBD2 knockdown are accompanied by derepression of tumor suppressor genes, including DAPK1 and KLK10. Chromatin immunoprecipitation assays and bisulfite sequencing show MBD2 binding directly to the hyper methylated and CpG-rich promoters of both DAPK1 and KLK10. Remarkably, the promoter CpG island-associated methylation of these genes remained stable despite robust transcriptional activation in MBD2 knockdown cells. Expression of a shRNA-resistant MBD2 protein resulted in restoration of growth and resilencing of the MBD2-dependent tumor suppressor genes. Our data suggest that uncoupling CpG methylation from repressive chromatin remodeling and histone modifications by removing MBD2 is sufficient to initiate and maintain tumor suppressor gene transcription and suppress neoplastic cell growth. These results show a role for MBD2 in cancer progression and provide support for the prospect of targeting MBD2 therapeutically in aggressive breast cancers. PMID- 21693598 TI - Effects of foveal ablation on the pattern of peripheral refractive errors in normal and form-deprived infant rhesus monkeys (Macaca mulatta). AB - PURPOSE. The purpose of this study was to determine whether visual signals from the fovea contribute to the changes in the pattern of peripheral refractions associated with form deprivation myopia in monkeys. METHODS. Monocular form deprivation was produced in 18 rhesus monkeys by securing diffusers in front of their treated eyes between 22 +/- 2 and 155 +/- 17 days of age. In eight of these form-deprived monkeys, the fovea and most of the perifovea of the treated eye were ablated by laser photocoagulation at the start of the diffuser-rearing period. Each eye's refractive status was measured by retinoscopy along the pupillary axis and at 15 degrees intervals along the horizontal meridian to eccentricities of 45 degrees . Control data were obtained from 12 normal monkeys and five monkeys that had monocular foveal ablations and were subsequently reared with unrestricted vision. RESULTS. Foveal ablation, by itself, did not produce systematic alterations in either the central or peripheral refractive errors of the treated eyes. In addition, foveal ablation did not alter the patterns of peripheral refractions in monkeys with form-deprivation myopia. The patterns of peripheral refractive errors in the two groups of form-deprived monkeys, either with or without foveal ablation, were qualitatively similar (treated eyes: F = 0.31, P = 0.74; anisometropia: F = 0.61, P = 0.59), but significantly different from those found in the normal monkeys (F = 8.46 and 9.38 respectively, P < 0.05). CONCLUSIONS. Central retinal signals do not contribute in an essential way to the alterations in eye shape that occur during the development of vision induced axial myopia. PMID- 21693599 TI - Spatial resolution and perception of patterns mediated by a subretinal 16 electrode array in patients blinded by hereditary retinal dystrophies. AB - PURPOSE: The perception of 11 persons blinded by hereditary retinal degeneration elicited by a subretinally implanted 16-electrode array used for light independent direct stimulation of the retina is described. This device is part of the Tubingen retina implant, which also employs a light-sensitive, multiphotodiode array (MPDA). The ability to reliably recognize complex spatial percepts was investigated. METHODS: Eleven blind volunteers received implants and participated in standardized psychophysical tests investigating the size and shape of perceptions elicited by single-electrode activation, multiple-electrode activation, and activation of compound patterns such as simplified letters. RESULTS: Visual percepts were elicited reliably in 8 of 11 patients. On single electrode activation, percepts were generally described as round spots of light of distinguishable localization in the visual field. On activation of a pattern of electrodes, percepts matched that pattern when electrodes were activated sequentially. Patterns such as horizontal or vertical bars were identified reliably; the most recent participant was able to recognize simplified letters presented on the 16-electrode array. The smallest distance between sites of concurrent retinal stimulation still yielding discernible spots of light was assessed to be 280 MUm, corresponding to a logMAR of 1.78. CONCLUSIONS: Subretinal electric stimulation can yield reliable, predictable percepts. Patterned perception is feasible, enabling blind persons to recognize shapes and discriminate different letters. Stimulation paradigms must be optimized, to further increase spatial resolution, demanding a better understanding of physical and biological effects of single versus repetitive stimulation (ClinicalTrials.gov number, NCT00515814). PMID- 21693600 TI - Image registration and multimodal imaging of reticular pseudodrusen. AB - PURPOSE: To characterize reticular pseudodrusen (RPD) by using a point-to-point comparison of the reticular pattern on infrared reflectance (IR), autofluorescence (AF), and red-free (RF) images registered with en face sections of the choroid from spectral domain optical coherence tomography (SD-OCT) scans. METHODS: A cross-sectional, retrospective study of all patients with the diagnosis of AMD who presented to the Doheny Retina Institute between December 2007 and November 2009 was conducted to identify patients with RPD. IR, AF, and RF images were obtained using confocal scanning laser ophthalmoscopy and were manually registered to OCT choroidal sections to study the location of RPD. The main outcome measured was point-to-point localization of RPD across multiple imaging modalities. RESULTS: Of the 153 patients with AMD, 51 had RPD. In all 51 patients (97 eyes), RPD appeared as areas of hypoautofluorescence and hyporeflectance on AF and IR imaging, respectively, and as hyporeflective interlacing networks on RF. Reticular lesions on AF, IR, and RF images consistently colocalized with stromal regions between large choroidal vessels on registered en face choroidal sections. In contrast, outer retinal changes and subretinal deposits tended to localize immediately adjacent to the RPD. CONCLUSIONS: Point-to-point correlation of registered IR, AF, and RF images consistently localizes the reticular pattern to the intervascular choroidal stroma on en face OCT sections. In contrast, subretinal deposits and disturbances of the inner outer segment on OCT did not colocalize with the RPD, and may represent secondary mechanical or biologic disturbances in the overlying RPE and outer retina. PMID- 21693601 TI - What is causing active trachoma? The role of nonchlamydial bacterial pathogens in a low prevalence setting. AB - PURPOSE: In low prevalence settings, clinically active follicular trachoma (TF) is often found in the absence of detectable Chlamydia trachomatis. The reasons for this persistent follicular phenotype are not well understood; one possible explanation is that other bacterial species are provoking the inflammatory response. This study investigated the relationship between TF, C. trachomatis, and nonchlamydial bacterial infection. METHODS: A cross-sectional survey was conducted in a trachoma endemic village in Tanzania. All available children were examined for trachoma and swabs were collected for microbiologic culture (blood and chocolate agar) and C. trachomatis PCR (Amplicor). RESULTS: Four hundred seventy-three children under 10 years of age were recruited for this study. The prevalences of TF and C. trachomatis were 13.7% and 5.3%, respectively, and were not associated. Bacteria were cultured from 305 (64.5%) swab samples; 162 (34.3%) grew a pathogen (with or without a commensal organism) and 143 (30.2%) grew commensal bacteria only. The most common pathogens were Streptococcus pneumoniae and Haemophilus influenzae (type B and non-type B). The presence of bacterial pathogens was associated with TF (odds ratio, 4.68; 95% confidence interval, 2.31 9.50; P < 0.001). CONCLUSIONS: In regions with low levels of endemic trachoma, it is possible that much of the TF that is observed is attributable to nonchlamydial bacterial pathogens. It is plausible that individuals who have previously developed a follicular conjunctivitis in response to C. trachomatis may more readily reform conjunctival follicles when challenged with certain other bacterial species. PMID- 21693602 TI - Spectral-domain optical coherence tomography as an indicator of fluorescein angiography leakage from choroidal neovascularization. AB - PURPOSE: To evaluate spectral-domain optical coherence tomography (SD-OCT) findings that predict angiographic leakage in choroidal neovascularization (CNV). METHODS: SD-OCT and fluorescein angiography (FA) images of 93 eyes of 93 patients were retrospectively analyzed. All patients were previously treated with anti vascular endothelial growth factor agents for CNV from age-related macular degeneration. FA images were analyzed to assess the presence of leakage. SD-OCT images were analyzed to identify the overall presence of fluid, as well as specific patterns of fluid presentation, including intraretinal cystic spaces (ICS), retinal pigment epithelium detachment (PED), and neurosensory detachment (NSD). The presence of ultrastructural features such as intraretinal hyperreflective flecks and the inherent reflectivity and boundary definition of the subretinal material were evaluated. Both the association and the sensitivity, specificity, and both positive and negative predictive values of SD-OCT findings compared with FA leakage were calculated. RESULTS: A statistically significant association between SD-OCT findings and FA leakage was found for eyes that displayed fluid, NSD, intraretinal flecks, and low reflectivity or undefined boundaries from subretinal material, and not for PED or ICS. Sensitivity and specificity for SD-OCT findings were, respectively: 94% and 27% for fluid; 68% and 88% for NSD; 81% and 83% for intraretinal flecks; 63% and 92% for undefined boundaries of subretinal material; and 94% and 87% for low reflectivity from subretinal material. CONCLUSIONS: The evidence of fluid on SD-OCT is sensitive but nonspecific in identifying FA leaky CNV. The assessment of neurosensory detachment as well as other ultrastructural elements may increase the specificity of analysis. PMID- 21693603 TI - Nine-year incidence and risk factors for retinal vein occlusion in a general Japanese population: the Hisayama Study. AB - PURPOSE: To estimate the long-term cumulative incidence and risk factors for retinal vein occlusion (RVO) in a population-based cohort study of Japanese. METHODS: In 1998, a total of 1775 individuals aged 40 years or older underwent a baseline eye examination. Of those, 1369 subjects (77.1%) took part in the follow up eye examination in 2007 and were enrolled in the present study. Each participant underwent a comprehensive examination. The diagnosis of RVO, including branch (BRVO) and central RVO (CRVO), was determined by grading color fundus photographs. Logistic regression analysis was performed to determine risk factors for RVO. RESULTS: The 9-year cumulative incidence of RVO was 3.0% (2.7% for BRVO and 0.3% for CRVO). The age-specific cumulative incidence of RVO significantly increased with age (P for trend = 0.03). After adjusting for age and sex, higher diastolic blood pressure and chronic kidney disease (CKD) were significantly associated with RVO. In multivariate analysis, higher diastolic blood pressure (per 10 mm Hg) (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.14 to 2.01) and CKD (OR, 2.23; 95% CI, 1.02 to 4.89) remained independently significant risk factors for RVO. In stratified analysis, the risk of RVO was higher in subjects with CKD than that in subjects without CKD in both the nonhypertension and the hypertension groups. CONCLUSIONS: These findings suggest that the incidence of RVO is higher in Japanese than that in other Asians and Caucasians, and that higher blood pressure and CKD are independent risk factors for RVO in the Japanese. PMID- 21693604 TI - Reading pixelized paragraphs of Chinese characters using simulated prosthetic vision. AB - PURPOSE: Visual prostheses offer a possibility of restoring useful reading ability to the blind. The psychophysics of simulating reading with a prosthesis using pixelized text has attracted attention recently. This study was an examination of the reading accuracy and efficiency of pixelized Chinese paragraphs after different parameters were altered. METHODS: Forty native Chinese speakers with normal or corrected visual acuity (20/20) participated in four experiments. Reading accuracy and efficiency were measured after changing the character resolution, character size, pixel dropout percentage, number of gray levels, and luminance. RESULTS: A 5 degrees * 5 degrees character appeared to be the optimal size necessary for accurate pixelized reading. Reading accuracy close to 100% could be achieved with 10 * 10 pixels/character and ~60% with a 6 * 6 pixel resolution. Pixel dropout adversely affected accuracy, and paragraphs with a 50% dropout were unreadable. Luminance had little effect; however, the number of gray levels significantly affected reading performance. Paragraph reading was at least 5% more accurate at each resolution than was the accuracy of Chinese character recognition. CONCLUSIONS: Character size and resolution, pixel dropout, and the number of gray levels clearly affected the reading performance of pixelized Chinese paragraphs. Compared with pixelized character recognition, pixelized Chinese paragraph reading achieved higher accuracy; thus, optimal Chinese reading performance may require prostheses with more electrodes (1000) than are required to read paragraphs in the Latin alphabet (500). PMID- 21693605 TI - Characteristics and possible visual consequences of photopsias as vision measures are reduced in retinitis pigmentosa. AB - PURPOSE: This study explored whether the location of photopsias (spontaneous phosphenes) in retinitis pigmentosa (RP) is related to the severity of vision loss, as has been suggested. METHODS: Thirty-two RP subjects self-completed an online survey about photopsias, approximately 1 to 2 months after ETDRS visual acuity (VA), Pelli-Robson contrast sensitivity (CS), and Goldmann visual field (VF) measures were obtained. RESULTS: The odds of noting photopsias only or mostly in areas of vision increased as vision was reduced across subjects, by 56% for every 0.1 logMAR VA (95% CI, 1.04-2.33; P = 0.03), 22% for every 0.1 logCS (95% CI, 1.02-1.46; P = 0.03), and 40% for every 1 unit logVF diameter (95% CI, 0.99-1.98; P = 0.06). The odds of noting photopias only in the periphery were reduced by 20% for every 0.1 logCS reduction (95% CI, 0.64-1.02; P = 0.066), and 18% for every 1 unit logVF diameter reduction (95% CI, 0.67-1.001; P = 0.051). For every 0.1 logMAR VA reduction, the odds of indicating that photopsias were located across a larger area over time were 30% greater (95% CI, 1.002-1.70; P = 0.048). The odds of being more aware of photopsias over time were increased as vision was reduced by 48% for every 0.1 logMAR VA (95% CI, 1.04-2.11; P = 0.03) and 18% for every 0.1 logCS (95% CI, 1.01-1.38; P = 0.04). The odds of reporting that photopsias interfere with vision were significantly greater when the photopsias occurred daily, more frequently, or across larger areas over time. CONCLUSIONS: These cross-sectional data indicate that in later RP stages, photopsias located more centrally, over larger regions, in areas with vision, and/or observed more frequently may obstruct vision at times and are a potential hindrance for patients' functioning or when obtaining vision measures. PMID- 21693606 TI - In vitro models for glaucoma research: effects of hydrostatic pressure. AB - PURPOSE: The response of cells (e.g., optic nerve head [ONH] cells) to mechanical stress is important in glaucoma. Studies have reported the biological effects of hydrostatic pressure on ONH cells cultured on a rigid substrate. An apparatus, designed to independently vary hydrostatic pressure and gas tension (including oxygen tension) in culture medium, was used to evaluate the effects of pressure and tension on cell migration, shape, and alpha-tubulin architecture in a transformed cell line (DITNC1 rat cortical astrocytes). METHODS: During the assay period, cells were exposed to one of four experimental configurations: (1) control pressure and control gas tension; (2) high-pressure (7.4 mm Hg) and reduced gas tension; (3) control pressure and reduced gas tension; and (4) high pressure and control gas tension. RESULTS: Calculations suggested that the cells in configurations 2 and 3 were hypoxic, as confirmed by direct measurements in configuration 2. No effects of hydrostatic pressure were observed on cell migration or alpha-tubulin architecture. However, cells cultured under low gas tension (configurations 2 and 3) showed increased migration at 48 and 72 hours (P < 0.05). CONCLUSIONS: A hydrostatic pressure of 7.4 mm Hg has no effect on DITNC1 astrocytes cultured on rigid coverslips, whereas hypoxia associated with a fluid column creating this pressure does. These results differ from those in a previous report, the results of which may be explained by altered gas tensions in the culture medium. Steps are recommended for control of secondary effects when testing the effect of pressure on cultured cells. PMID- 21693607 TI - The impact of the severity of vision loss on vision-related quality of life in India: an evaluation of the IND-VFQ-33. AB - PURPOSE: To validate the 33-item Indian Vision Functioning Questionnaire (IND-VFQ 33), a vision-specific scale, and determine the relationship between the severity of vision impairment (VI) and vision-related quality of life (VRQoL). METHODS: In this cross-sectional, observational study 273 participants with VI from cataract were recruited from a South Indian eye hospital. Participants underwent a clinical examination and completed the IND-VFQ-33 scale. The psychometric properties of the IND-VFQ-33 and its subscales were assessed using Rasch analysis, exploring key indices such as instrument unidimensionality, discriminant ability, and targeting of item difficulty to patient ability. RESULTS: Rasch analysis demonstrated the validity of the IND-VFQ-33 to assess VRQoL through four subscales (i.e., vision-specific mobility, activity limitation, psychosocial impact, and visual symptoms), but not as an overall measure. In adjusted multivariate analysis models, those with severe VI and blindness reported significantly poorer vision-specific mobility and activity limitation (mean change, -18.82, P = 0.007 and -29.48, P < 0.001, respectively) compared with those with no VI. These decrements in vision-specific functioning were both clinically significant. Lack of schooling and schooling up to completion of primary school were associated with poorer vision-specific mobility and visual symptoms, respectively. CONCLUSIONS: Using a psychometrically valid IND-VFQ, only severe VI and blindness led to a clinically meaningful decline in vision-specific mobility and activity limitation. This finding reflects the current protocol for cataract surgery referral in developing or transitional countries, where priority is given to patients with at least moderate to severe VI. PMID- 21693608 TI - The effect of intravitreal injection of bevacizumab on retinal circulation in patients with neovascular macular degeneration. AB - PURPOSE: Intravitreal (ITV) injection of anti-VEGFs like bevacizumab are widely used to treat neovascular AMD. However, VEGF is essential for biologic functions such as blood pressure regulation. Indeed, anti-VEGF intravenous administration is associated with hypertension. Therefore, the effect of ITV bevacizumab on retinal circulation was examined. METHODS: Twenty-three patients with neovascular AMD treated with three repeat ITV injections of bevacizumab were recruited. Blood arteriolar diameter and flow measurements were performed with a bidirectional laser Doppler flowmeter at baseline, 1 week after the first injection, just before the second injection, and 5 weeks after the third injection. Scanning laser Doppler flowmetry was used to assess the effect of bevacizumab on tissue perfusion at the first and fourth visits. RESULTS: Arteriolar diameter significantly decreased from 122.5 +/- 14.5 MUm to 118.9 +/- 14.0 MUm (P = 0.03) during the first week to reach a mean value of 117.2 +/- 13.7 MUm at the end of the study (P < 0.01). Arterial blood flow did not change significantly. Neuroretinal rim perfusion decreased from 181.1 +/- 84.1 arbitrary flow units to 167.7 +/- 76.5 arbitrary flow units, which was borderline significant (P = 0.06). No significant change was observed in the peripapillary retina. CONCLUSIONS: Arteriolar diameter decreased significantly after the first injection and persisted until the end of the study suggesting a long-term effect of bevacizumab on vascular tone. However, the blood flow change is not significant. A borderline significant decrease in neuroretinal rim perfusion was observed and suggests that the neuroretinal rim may be more sensitive than the peripapillary retina to the effects of bevacizumab. PMID- 21693609 TI - Effect of miR-23 on oxidant-induced injury in human retinal pigment epithelial cells. AB - PURPOSE: Micro(mi)RNAs negatively regulate a wide variety of genes through degradation or posttranslational inhibition of their target genes. The purpose of this study was to investigate the role of miR-23a in modulating RPE cell survival and gene expression in response to oxidative damage. METHODS: The expression level of miR-23a was measured in macular retinal pigment epithelial (RPE) cells of donor eyes with aged-related macular degeneration (AMD) and age-matched normal eyes by using qRT-PCR. Cultured human ARPE-19 cells were transfected with miR-23a mimic or inhibitor. Cell viability was assessed by the MTT assay. Apoptosis was determined by incubating cells with hydrogen peroxide (H(2)O(2)) or t butylhydroperoxide (tBH). Caspase-3 activity and DNA fragmentation were measured by enzyme-linked immunosorbent assays. The protein relevant to apoptosis, such as Fas expression level, was analyzed by Western blot analysis. RESULTS: miR-23a expression was significantly downregulated in macular RPE cells from AMD eyes. H(2)O(2)-induced ARPE-19 cell death and apoptosis were increased by an miR-23a inhibitor and decreased by an miR-23a mimic. Computational analysis found a putative target site of miR-23a in the 3'UTR of Fas mRNA, which was verified by a luciferase reporter assay. Forced overexpression of miR-23a decreased H(2)O(2) or tBH-induced Fas upregulation, and this effect was blocked by downregulation of miR-23a. CONCLUSIONS: The protection of RPE cells against oxidative damage is afforded by miR-23a through regulation of Fas, which may be a novel therapeutic target in retinal degenerative diseases. PMID- 21693610 TI - Swelling-activated potassium channel in porcine pigmented ciliary epithelial cells. AB - PURPOSE: Ion channels in the ciliary epithelium play critical roles in the formation of aqueous humor in the eye. The present study identified a novel, swelling-activated K(+) current in freshly dissociated porcine pigmented ciliary epithelial cells. METHODS: Ciliary epithelial cells were freshly dissociated from porcine eyes. Whole-cell currents were recorded by the patch-clamp technique in pigmented and nonpigmented ciliary epithelial cell (PCE-NPCE) pairs or single PCE cells. RESULTS: The 0-current potential was -49 +/- 13 mV in PCE-NPCE cell pairs (n = 97) and -52 +/- 12 mV in single PCE cells (n = 30). Whole-cell currents in these cells were dominated by an outwardly rectifying K(+) current activated by potentials more positive than -90 mV, which never inactivated during prolonged depolarization. The K(+) current was significantly augmented by hypotonic cell perfusion. External Ba(2+) was a blocker of this K(+) conductance (IC(50) of 0.38 mM), but the conductance was insensitive to external TEA(+). Linopirdine, a specific inhibitor of KCNQ channels, effectively blocked the K(+) current in these PCE cells. CONCLUSIONS: Porcine PCE cells express a swelling-activated K(+) channel, which may be a member of the KCNQ/Kv7 channel family. This K(+) channel is active near resting potentials and could contribute to the regulation of cell volume and water transport via the ciliary epithelia. PMID- 21693611 TI - Role of the intravitreal growth factors in the pathogenesis of idiopathic epiretinal membrane. AB - PURPOSE: The aim of the present study is to evaluate the roles of TGFs beta1 and beta2, glial cell line-derived neurotrophic factor (GDNF), and nerve growth factor (NGF) in the pathogenesis of idiopathic epiretinal membrane (ERM). METHODS: Eight patients, six males and two females, with an average age of 60.25 +/- 17.16 years (range, 33-75 years) who were affected by idiopathic ERM were enrolled in the study. All patients underwent standard pars plana vitrectomy surgery with membrane removal and specific ELISA was performed to evaluate TGFbeta1, TGFbeta2, GDNF, and NGF in the vitreous samples. This was repeated after acidification of the samples with hydrochloric acid. RESULTS: Before acidification, ELISA analysis revealed a significant increase of TGFbeta2 in the samples with idiopathic ERM (327.98 +/- 99.58 pg/mL; range, 206.864-466.235 pg/mL) compared to the control group (187.17 +/- 58.20 pg/mL; range, 132.758 271.707 pg/mL; t = 3.4; P < 0.05). A statistically significant difference was also obtained after acidification of the samples (618.15 +/- 201.43 pg/mL; range, 409.795-866.215 pg/mL compared to 265.04 +/- 98.15 pg/mL; range, 152.478-352.101 pg/mL; t = 4.5; P < 0.05). Notably, before acidification the differences in NGF between the two groups were not statistically significant (t = 0.79; P = 0.46), while after acidification a significant increase of the NGF levels in ERM samples was found in comparison with the control group (723.41 +/- 235.4 vs. 242.84 +/- 104.61; t = 3; P < 0.05). CONCLUSIONS: The present study reveals that TGFbeta2 and NGF are associated with idiopathic ERMs, suggesting a novel compensatory mechanism so far never proposed. PMID- 21693612 TI - The OV-TL 12/30 clone of anti-cytokeratin 7 antibody as a new marker of corneal conjunctivalization in patients with limbal stem cell deficiency. AB - PURPOSE: To present cytokeratin (CK)7 (OV-TL 12/30 clone) as a newly identified, reliable marker for distinguishing between the conjunctival and corneal surface epithelia, which will contribute to the precise diagnosis of limbal stem cell deficiency (LSCD). METHODS: Corneal and conjunctival epithelial imprints from 12 cadaveric bulbi and from 9 patients with clinically diagnosed LSCD were used for CK7 and CK19 immunocytochemistry. Specimens on nitroacetate cellulose filter papers obtained from the patients were stained with a combination of periodic acid-Schiff (PAS) and Gill's modified Papanicolaou stains, to assess the presence of goblet cells (GCs). RESULTS: CK7 was present in almost all superficial conjunctival epithelial cells from the cadaveric specimens. No immunostaining was observed on the corneal surface. A prominent sharp border of stain was found between the positive conjunctiva and the completely negative epithelium of the central cornea. A more gradual centrifugal decrease in the number of positive cells between the conjunctiva and cornea was observed for CK19. Several CK19 positive cells were detected in the central corneal epithelium. All corneal specimens from affected eyes (unilateral as well as bilateral LSCD patients) revealed strong positivity for CK7, and GCs were present in only 78% of patients. CONCLUSIONS: In cases in which GCs are severely decreased or are absent from the conjunctival surface, the detection of CK7 (OV-TL 12/30 clone) clearly confirms the overgrowth of the conjunctival epithelium over the cornea. Moreover, CK7 is a more reliable marker for distinguishing between the corneal and conjunctival epithelia compared with CK19. PMID- 21693613 TI - Early perfusion of a free RPE-choroid graft in patients with exudative macular degeneration can be imaged with spectral domain-OCT. AB - PURPOSE: To study early flow and revascularization in a free, autologous, retinal pigment epithelium (RPE)-choroid graft. METHODS: This prospective cohort study used spectral domain-optical coherence tomography (SD-OCT) after RPE-choroid graft surgery in 12 patients. This SD-OCT was combined with fluorescein angiography (FA) and indocyanine green angiography (ICGA) in 5 patients. RESULTS: SD-OCT revealed that vessel diameter, number of vessels, and graft thickness increased in 10 of 12 patients, starting between 3 and 10 days after surgery. A subsequent decrease in thickness was found in all 10 patients, beginning as early as 8 days after surgery. Initially, the graft vessels were optically clearer than the underlying choroidal recipient vessels. Between 8 and 30 days after surgery, the optically clear vessels became gray, similar to the recipient choroid. FA and ICGA revealed perfusion in 4 of 5 patients between postoperative days 6 and 15. Between postoperative days 12 and 60, the entire choroidal structure of the graft was visible on ICGA. CONCLUSIONS; These data suggest that enlargement of vessel diameter, increase in the number of choroidal vessels, and graft thickening visualized by SD-OCT correspond with the ingrowth of afferent vessels, as demonstrated by ICGA. The subsequent establishment of efferent vessels results in flow, imaged as a change in color of the graft's vessels from optically clear to gray, graft thinning on SD-OCT, and complete revascularization on ICGA. SD-OCT, a noninvasive examination, can be used to demonstrate early graft perfusion in patients (trialregister.nl/trialreg/admin/rctview.asp number, NTR1768). PMID- 21693614 TI - Combining structural and functional measurements to improve detection of glaucoma progression using Bayesian hierarchical models. AB - PURPOSE: To present and evaluate a new methodology for combining longitudinal information from structural and functional tests to improve detection of glaucoma progression and estimation of rates of change. METHODS: This observational cohort study included 434 eyes of 257 participants observed for an average of 4.2 +/- 1.1 years and recruited from the Diagnostic Innovations in Glaucoma Study (DIGS). The subjects were examined annually with standard automated perimetry, optic disc stereophotographs, and scanning laser polarimetry with enhanced corneal compensation. Rates of change over time were measured using the visual field index (VFI) and average retinal nerve fiber layer thickness (TSNIT average). A bayesian hierarchical model was built to integrate information from the longitudinal measures and classify individual eyes as progressing or not. Estimates of sensitivity and specificity of the bayesian method were compared with those obtained by the conventional approach of ordinary least-squares (OLS) regression. RESULTS: The bayesian method identified a significantly higher proportion of the 405 glaucomatous and suspect eyes as having progressed when compared with the OLS method (22.7% vs. 12.8%; P < 0.001), while having the same specificity of 100% in 29 healthy eyes. In addition, the bayesian method identified a significantly higher proportion of eyes with progression by optic disc stereophotographs compared with the OLS method (74% vs. 37%; P = 0.001). CONCLUSIONS: A bayesian hierarchical modeling approach for combining functional and structural tests performed significantly better than the OLS method for detection of glaucoma progression. (ClinicalTrials.gov number, NCT00221897.). PMID- 21693615 TI - Training in contrast detection improves motion perception of sinewave gratings in amblyopia. AB - PURPOSE. One critical concern about using perceptual learning to treat amblyopia is whether training with one particular stimulus and task generalizes to other stimuli and tasks. In the spatial domain, it has been found that the bandwidth of contrast sensitivity improvement is much broader in amblyopes than in normals. Because previous studies suggested the local motion deficits in amblyopia are explained by the spatial vision deficits, the hypothesis for this study was that training in the spatial domain could benefit motion perception of sinewave gratings. METHODS. Nine adult amblyopes (mean age, 22.1 +/- 5.6 years) were trained in a contrast detection task in the amblyopic eye for 10 days. Visual acuity, spatial contrast sensitivity functions, and temporal modulation transfer functions (MTF) for sinewave motion detection and discrimination were measured for each eye before and after training. Eight adult amblyopes (mean age, 22.6 +/- 6.7 years) served as control subjects. RESULTS. In the amblyopic eye, training improved (1) contrast sensitivity by 6.6 dB (or 113.8%) across spatial frequencies, with a bandwidth of 4.4 octaves; (2) sensitivity of motion detection and discrimination by 3.2 dB (or 44.5%) and 3.7 dB (or 53.1%) across temporal frequencies, with bandwidths of 3.9 and 3.1 octaves, respectively; (3) visual acuity by 3.2 dB (or 44.5%). The fellow eye also showed a small amount of improvement in contrast sensitivities and no significant change in motion perception. Control subjects who received no training demonstrated no obvious improvement in any measure. CONCLUSIONS. The results demonstrate substantial plasticity in the amblyopic visual system, and provide additional empirical support for perceptual learning as a potential treatment for amblyopia. PMID- 21693616 TI - Multiplex ligation-dependent probe amplification of conjunctival melanoma reveals common BRAF V600E gene mutation and gene copy number changes. AB - PURPOSE: To determine the occurrence of BRAF V600E gene mutations and copy number changes of all autosome arms and genes known to be frequently altered in tumorigenesis in primary and metastatic conjunctival melanomas (CoMs). METHODS: DNA (200 ng) was analyzed by three multiplex ligation-dependent probe amplification assays (P027 uveal melanoma, P036 human telomere, and P206 spitzoid melanoma). RESULTS: Eight of 16 primary tumor samples and 4 of 6 metastatic samples showed BRAF V600E gene mutations. CDKN1A and RUNX2 (both 6p21.2) were amplified in 11 and 16 of 21 primary CoMs, respectively. In metastatic CoMs, MLH1 (3p22.1) and TIMP2 (17q25.3) were frequently amplified, and MGMT (20q26.3) and ECHS1 (10q26.3) were frequently deleted. The BDH (3q), FLJ20265 (4p), OPRL1 (20q), and PAO (10q) genes, representing the telomeres of their respective chromosome arms in the P036 assay, were frequently amplified in metastatic CoMs. No statistically significant associations were identified between BRAF mutation or CDKN1A or RUNX2 amplification and sex, age, histologic cell type, or patient survival. CONCLUSIONS: No copy number changes were associated exclusively with metastatic CoMs. However, further investigation of the role of CDKN1A and RUNX2 in CoMs development and that of MLH1, TIMP2, MGMT, and ECHS1 in metastatic CoMs is warranted. Validation of the observed gene and chromosome arm copy number changes in a larger cohort of primary and metastatic CoMs is necessary to identify the patients at highest risk for CoMs metastasis. PMID- 21693617 TI - Incorrect citation. PMID- 21693618 TI - Gene expression analysis characterizes antemortem stress and has implications for establishing cause of death. AB - Within the field of forensic pathology, determination of the cause of death depends upon identifying physical changes in the corpse or finding diagnostic laboratory abnormalities. When such perturbations are absent, definitive assignment of a cause of death may be difficult or impossible. An example of such a problem is sudden infant death syndrome (SIDS), a common cause of neonatal mortality that does not produce physical findings or laboratory abnormalities. Although respiratory failure as a cause of SIDS represents the most widely held hypothesis, sudden cardiac death and hyperthermia have also been advanced as possible causes. We hypothesize that each of these physiological stresses would produce a different pattern of premortem gene expression and that these patterns of gene expression would remain evident in tissues collected postmortem. If these patterns were sufficiently distinctive, they could be used to identify the cause of death. Using an infant mouse model, we compared gene expression patterns in liver tissue after sudden death, lethal hyperthermia, and lethal hypoxia. Each of these conditions produced readily distinguishable differences in gene expression patterns. With the K-nearest neighbor classification algorithm, only 10 genes are necessary to correctly classify samples. If the liver tissue was not harvested immediately after death, additional alteration in gene expression patterns resulted; however, these alterations did not affect the group of genes used to classify the samples. Our findings suggest that gene expression analysis from tissues collected postmortem may provide useful clues about certain physiologic stresses that may precede death. PMID- 21693619 TI - Shelf life prediction of fresh Italian pork sausage modified atmosphere packed. AB - The shelf life of fresh Italian pork sausages packed in modified atmosphere was studied. Samples were packed using different levels of oxygen (high and low) with different levels of carbon dioxide (high-low) in the atmospheres headspace and were stored at 4 degrees C for 9 days. Microbial, physiochemical and sensory parameters were analyzed during storage. A consumer test was performed to determine the critical acceptability levels. Sensory data were mathematically modelled to estimate product shelf life. A first-order kinetic model and a Weibull-type model aptly described, respectively, the changes in fresh pork sausage odor and color over storage time. These models may be used to predict the sensory shelf life of fresh pork sausage. Results showed that 20% O(2) and 70% CO(2) extend fresh pork sausage shelf life to 9 days at 4 degrees C. The microbial quality of the samples at the critical sensory level of acceptability was within the range of microbial acceptability. PMID- 21693620 TI - Inhibition of eukaryotic translation elongation by the antitumor natural product Mycalamide B. AB - Mycalamide B (MycB) is a marine sponge-derived natural product with potent antitumor activity. Although it has been shown to inhibit protein synthesis, the molecular mechanism of action by MycB remains incompletely understood. We verified the inhibition of translation elongation by in vitro HCV IRES dual luciferase assays, ribosome assembly, and in vivo [(35)S]methinione labeling experiments. Similar to cycloheximide (CHX), MycB inhibits translation elongation through blockade of eEF2-mediated translocation without affecting the eEF1A mediated loading of tRNA onto the ribosome, AUG recognition, or dipeptide synthesis. Using chemical footprinting, we identified the MycB binding site proximal to the C3993 28S rRNA residue on the large ribosomal subunit. However, there are also subtle, but significant differences in the detailed mechanisms of action of MycB and CHX. First, MycB arrests the ribosome on the mRNA one codon ahead of CHX. Second, MycB specifically blocked tRNA binding to the E-site of the large ribosomal subunit. Moreover, they display different polysome profiles in vivo. Together, these observations shed new light on the mechanism of inhibition of translation elongation by MycB. PMID- 21693621 TI - microRNAs modulate iPS cell generation. AB - Although induced pluripotent stem cells (iPSCs) hold great promise for customized regenerative medicine, the molecular basis of reprogramming is largely unknown. Overcoming barriers that maintain cell identities is a critical step in the reprogramming of differentiated cells. Since microRNAs (miRNAs) modulate target genes tissue-specifically, we reasoned that distinct mouse embryonic fibroblast (MEF)-enriched miRNAs post-transcriptionally modulate proteins that function as reprogramming barriers. Inhibiting these miRNAs should influence cell signaling to lower those barriers. Here we show that depleting miR-21 and miR-29a enhances reprogramming efficiency in MEFs. We also show that the p53 and ERK1/2 pathways are regulated by miR-21 and miR-29a and function in reprogramming. In addition, we provide the first evidence that c-Myc enhances reprogramming partly by repressing MEF-enriched miRNAs, such as miR-21 and miR-29a. Our results demonstrate the significance of miRNA function in regulating multiple signaling networks involved in iPSC generation. These studies should facilitate development of clinically applicable reprogramming strategies. PMID- 21693622 TI - Testosterone suppresses phospholipase D, causing sex differences in leukotriene biosynthesis in human monocytes. AB - Sex disparities in inflammation have been reported, but the cellular and molecular basis for these discrepancies is unknown. Monocytes are central effector cells in immunity and possess high capacities to produce proinflammatory leukotrienes (LTs). Here, we investigated sex differences in the activation of 5 lipoxygenase (5-LO), the key enzyme in LT biosynthesis, in human peripheral monocytes. In cells from females, 5-LO product formation was 1.8-fold higher than in cells from males, as evaluated by HPLC. When female monocytes were resuspended in plasma from males, 5-LO products were significantly lower than in female plasma. Interestingly, 5alpha-dihydrotestosterone (5alpha-DHT, 10 nM) repressed LT synthesis in female cells down to the levels observed in males, while estradiol (100 nM) was without effect, and progesterone (100 nM) caused only a slight inhibition. 5alpha-DHT (10 nM) caused ERK phosphorylation and inhibition of phospholipase D (PLD), as evaluated by Western blot and measurement of PLD activity via radioenzymatic diacylglyceride (DAG) and nonradioactive choline assays. Accordingly, PLD activity and DAG formation were 1.4- to 1.8-fold lower in male vs. female monocytes connected to increased ERK phosphorylation. Our data indicate that ERK activation by androgens in monocytes represses PLD activity, resulting in impaired 5-LO product formation due to lack of activating DAGs. PMID- 21693623 TI - A dynamic model of membrane-bound phospholipase Cbeta2 activation by Gbetagamma subunits. AB - Phospholipase C (PLC) beta2, a well studied member of the family of enzymes that catalyze the hydrolysis of the membrane lipid phosphatidylinositol 4,5 bisphosphate (PIP2) into secondary messengers, can be activated by the Gbetagamma subunits of heterotrimeric G-proteins in a manner that depends on the presence and composition of the associated phospholipid membrane surface. The N-terminal pleckstrin homology (PH) domain of PLCbeta2 mediates both the response to Gbetagamma and membrane binding, but how these interactions are coupled to yield an activated catalytic core remains unknown. Here we propose a mechanism based on molecular models of truncated PLCbeta2 in its activated form complexed with Gbetagamma and in the catalytically inactive/membrane-bound form, obtained with the application of protein-protein docking algorithms and coarse-grained molecular dynamics simulations. These models were probed experimentally, and the inferences were confirmed by results from a combination of molecular biology and fluorescence assays. Results from the dynamic simulations of the molecular models and their interactions with various lipid bilayers identify the determinants of PLCbeta2-PH domain specificity for Gbetagamma and lipid membranes and suggest a mechanism for the previously reported dependence of Gbetagamma activation on the associated membrane composition. Together, these findings explain the roles of the different activators in terms of their effect on the orientations of the PH and catalytic core domains relative to the lipid membranes. PMID- 21693624 TI - Mechanism of the anti-proliferative action of 25-hydroxy-19-nor-vitamin D(3) in human prostate cells. AB - According to the prevailing paradigm, 1alpha-hydroxylation of 25-hydroxyvitamin D(3) (25(OH)D(3)) and its analogs is a pre-requisite step for their biological effects. We previously reported that 25-hydroxy-19-nor-vitamin D(3) (25(OH)-19 nor-D(3)) had anti-proliferative activity in a cell line, PZ-HPV-7, which was derived from human non-cancerous prostate tissue, and suggested that 25(OH)-19 nor-D(3) acted after 1alpha-hydroxylation by vitamin D 1alpha-hydroxylase (CYP27B1). However, metabolic studies of 25(OH)-19-nor-D(3) using recombinant CYP27B1 revealed that 25(OH)-19-nor-D(3) was rarely subjected to 1alpha hydroxylation. Therefore, in this report, we attempted to clarify the mechanism of 25(OH)-19-nor-D(3) action in intact cells using PZ-HPV-7 prostate cells. After incubating the cells with 25(OH)-19-nor-D(3), eight metabolites of 24-hydroxylase (CYP24A1) were detected, whereas no products of CYP27B1 including 1alpha,25 dihydroxy-19-nor-vitamin D(3) (1alpha,25(OH)(2)-19-nor-D(3)) were found. Furthermore, the time-dependent nuclear translocation of vitamin D receptor (VDR) and the subsequent transactivation of cyp24A1 gene in the presence of 25(OH)-19 nor-D(3) were almost identical as those induced by 1alpha,25(OH)(2)-19-nor-D(3). These results strongly suggest that 25(OH)-19-nor-D(3) directly binds to VDR as a ligand and transports VDR into the nucleus to induce transcription of cyp24A1 gene. In addition, knock down of cyp27B1 gene did not affect the anti proliferative activity of 25(OH)-19-nor-D(3), whereas knock down of VDR attenuated the inhibitory effect. Thus, our results clearly demonstrate that the anti-proliferative activity of 25(OH)-19-nor-D(3) is VDR dependent but 1alpha hydroxylation independent, suggesting that 25(OH)D(3) analogs such as 25(OH)-19 nor-D(3) could be attractive candidates for anticancer therapy. PMID- 21693625 TI - Alterations in adhesion junction precede gap junction remodelling during the development of heart failure in cardiomyopathic hamsters. AB - AIMS: The intercalated disc (ID) contains two complexes, the adhesion junction (AJ) and the gap junction (GJ). We studied ID remodelling and its potential role in arrhythmogenesis and investigated the effects of olmesartan on ID remodelling during development of heart failure (HF) in UM-X7.1 cardiomyopathic hamsters. METHODS AND RESULTS: The UM-X7.1 hamsters showed left ventricular (LV) hypertrophy by the age of 10-15 weeks and a moderate impairment in LV contractility at 20 weeks. At age 10-15 weeks, 10-20% of the hamsters died suddenly without HF, and ventricular tachycardia (VT)/ventricular fibrillation (VF) was induced in ~30% of hamsters. Electron microscopy showed that density linking cell-to-cell adhesion was irregular and unclearly defined, and filamentous structures attached to electron-dense components were arranged in disorder. Western blotting showed that the total cellular expression level of beta-catenin was decreased, and expression of nuclear beta-catenin, which functions as a T-cell factor/lymphocyte enhancer binding factor transcriptional activator, was also remarkably decreased. At age 20 weeks, LV connexin43 expression showed a remarkable decrease, and the VT/VF induction rate was ~90%. In UM-X7.1 hamsters, olmesartan improved abnormal ID ultrastructural changes, attenuated the decrease of total cellular and nuclear beta-catenin expression, decreased VT/VF induction, and improved survival rate. CONCLUSION: These results suggest that changes in AJ protein precede connexin43 GJ alterations, and ID remodelling might contribute to arrhythmogenesis during the development of HF. Angiotensin receptor blockade might be a new therapy for lethal ventricular arrhythmia by modulating both AJ and GJ remodelling. PMID- 21693626 TI - Vitamin D-related genetic variants, interactions with vitamin D exposure, and breast cancer risk among Caucasian women in Ontario. AB - BACKGROUND: Vitamin D, from diet and sunlight exposure, may be associated with reduced breast-cancer risk. This study investigated if candidate gene variants in vitamin D pathways are associated with breast cancer risk, or modify the associations between breast cancer and vitamin D exposure. METHODS: Breast cancer cases aged 25 to 74 years were identified from the Ontario Cancer Registry (histopathologically confirmed and diagnosed 2002-2003) and population-based controls were identified through random digit dialing of Ontario households. Saliva (DNA) was available for 1,777 cases and 1,839 controls. Multivariate logistic regression was used to evaluate associations between 19 single nucleotide polymorphisms (SNP) in vitamin D related genes, including vitamin D binding protein (GC), vitamin D receptor (VDR), and cytochrome P450 type 24A1 (CYP24A1). Statistical interactions were assessed using the likelihood ratio test. RESULTS: Some SNPs were found to be significantly associated with breast cancer risk. For example, breast cancer risk was associated with the GC rs7041 TT genotype (age-adjusted odds ratio (OR) = 1.23; 95% CI: 1.01, 1.51) and inversely with the VDR Fok1 (rs2228570) ff genotype (OR = 0.71; 95% CI: 0.57, 0.88). Few significant gene-environment interactions were observed between dietary vitamin D and genetic variants. CONCLUSION: Our study suggests certain vitamin D related genetic variants may influence breast-cancer risk and we found limited evidence that genetic variants modify the associations between vitamin D exposure and breast cancer risk. IMPACT: Variation in vitamin D-related genotypes may help to explain inconsistent results from previous epidemiologic studies and may lead to targeted prevention strategies. PMID- 21693627 TI - Localized fibroglandular tissue as a predictor of future tumor location within the breast. AB - BACKGROUND: Mammographic density (MD) is a strong marker of breast cancer risk, but it is unclear whether tumors arise specifically within dense tissue. METHODS: In 231 British women diagnosed with breast cancer after at least one negative annual screening during a mammographic screening trial, we assessed whether tumor location was related to localized MD 5 years prior to diagnosis. Radiologists identified tumor locations on digitised films. We used a validated algorithm to align serial images from the same woman to locate the corresponding point on the prediagnostic film. A virtual 1 cm square grid was overlaid on prediagnostic films and MD calculated for each square within a woman's breast (mean = 271 squares/film). Conditional logistic regression, matching on a woman's breast, was used to estimate the odds of a tumor arising in a square in relation to its prediagnostic square-specific MD. RESULTS: Median (interquartile range) prediagnostic MD was 98.2% (46.8%-100%) in 1 cm-squares that subsequently contained the tumor and 41.0% (31.5%-53.9%) for the whole breast. The odds of a tumor arising in a 1 cm-square were, respectively, 6.1 (95% CI: 1.9-20.1), 16.6 (5.2-53.2), and 25.5-fold (8.1-80.3) higher for squares in the second, third, and fourth quartiles of prediagnostic MD relative to those in the lowest quartile within that breast (P(trend) < 0.001). The corresponding odds ratios were 2.3 (1.3-4.0), 3.9 (2.3-6.4), and 4.6 (2.8-7.6) if a 3 cm-square grid was used. CONCLUSION: Tumors arise predominantly within the radiodense breast tissue. IMPACT: Localized MD may be used as a predictor of subsequent tumor location within the breast. PMID- 21693628 TI - Biomarkers related to one-carbon metabolism as potential risk factors for distal colorectal adenomas. AB - BACKGROUND: Efficient one-carbon metabolism, which requires adequate supply of methyl group donors and B-vitamins, may protect against colorectal carcinogenesis. However, plasma folate and vitamins B2 and B12 have inconsistently been associated with colorectal cancer risk, and there have been no previous studies relating plasma concentrations of methionine, choline, and betaine to this outcome. METHODS: This study comprised 10,601 individuals, 50 to 64 years of age, participating in the Norwegian Colorectal Cancer Prevention (NORCCAP) screening study. Using logistic regression analyses, we crosssectionally investigated associations between distal colorectal adenoma occurrence-potential precursor lesions of colorectal carcinomas-and plasma concentrations of methyl group donors and B-vitamins, and polymorphisms of genes related to one-carbon metabolism. RESULTS: Screening revealed 1,809 subjects (17.1%) with at least one adenoma. The occurrence of high-risk adenomas (observed in 421 subjects) was inversely associated with plasma concentrations of methionine (highest versus lowest quartile: odds ratio (OR) = 0.61; 95% confidence interval (CI) = 0.45-0.83), betaine: OR = 0.74; 95% CI = 0.54-1.02, the vitamin B2 form flavin-mononucleotide (FMN): OR = 0.65; 95% CI = 0.49-0.88, and the vitamin B6 form pyridoxal 5'-phosphate (PLP): OR = 0.69; 95% CI = 0.51 0.95, but not with folate, choline, vitamin B12 concentrations, or with the studied polymorphisms. High methionine concentration in combination with high vitamin B2 or B6 concentrations was associated with lower occurrence of high-risk adenomas compared with these factors individually. CONCLUSIONS: High plasma concentrations of methionine and betaine, and vitamins B2 and B6 may reduce risk of developing colorectal adenomas. IMPACT: In addition to B-vitamins, methyl group donors such as methionine and betaine may play a role in colorectal carcinogenesis. PMID- 21693629 TI - A role for the low-affinity A2B adenosine receptor in regulating superoxide generation by murine neutrophils. AB - The formation of adenosine dampens inflammation by inhibiting most cells of the immune system. Among its actions on neutrophils, adenosine suppresses superoxide generation and regulates chemotactic activity. To date, most evidence implicates the G(s) protein-coupled A(2A) adenosine receptor (AR) as the primary AR subtype responsible for mediating the actions of adenosine on neutrophils by stimulating cAMP production. Given that the A(2B)AR is now known to be expressed in neutrophils and that it is a G(s) protein-coupled receptor, we examined in this study whether it signals to suppress neutrophil activities by using 2-[6-amino 3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY 60-6583), a new agonist for the human A(2B)AR that was confirmed in preliminary studies to be a potent and highly selective agonist for the murine A(2B)AR. We found that treating mouse neutrophils with low concentrations (10(-9) and 10(-8) M) of BAY 60-6583 inhibited formylated-methionine-leucine-phenylalanine (fMLP) stimulated superoxide production by either naive neutrophils, tumor necrosis factor-alpha-primed neutrophils, or neutrophils isolated from mice treated systemically with lipopolysaccharide. This inhibitory action of BAY 60-6583 was confirmed to involve the A(2B)AR in experiments using neutrophils obtained from A(2B)AR gene knockout mice. It is noteworthy that BAY 60-6583 increased fMLP stimulated superoxide production at higher concentrations (>1 MUM), which was attributed to an AR-independent effect. In a standard Boyden chamber migration assay, BAY 60-6583 alone did not stimulate neutrophil chemotaxis or influence chemotaxis in response to fMLP. These results indicate that the A(2B)AR signals to suppress oxidase activity by murine neutrophils, supporting the idea that this low-affinity receptor for adenosine participates along with the A(2A)AR in regulating the proinflammatory actions of neutrophils. PMID- 21693630 TI - The repressor element 1-silencing transcription factor is a novel molecular target for the neurotoxic effect of the polychlorinated biphenyl mixture aroclor 1254 in neuroblastoma SH-SY5Y cells. AB - Chronic exposure to polychlorinated biphenyls (PCBs), a class of ubiquitous environmental toxicants, causes neurocognitive anomalies. The transcription factor repressor element 1-silencing transcription factor (REST) plays a critical role in neuronal phenotype elaboration in both neural progenitor cells and non neuronal cells. Here, we investigated the possible relationship between PCBs and REST in neuroblastoma SH-SY5Y cells. In these cells, chronic exposure to the PCB mixture Aroclor 1254 (A-1254; 5-30 MUg/ml) caused dose-dependent cell death via the induction of calpain but not caspase-3. Intriguingly, this effect was prevented by the calpain inhibitor calpeptin. Furthermore, A-1254 enhanced REST mRNA and protein expression levels after both 24 and 48 h. REST down-regulation by small interfering RNA prevented A-1254-induced cell death. In addition, A-1254 enhanced the binding of REST to the synapsin 1 gene promoter, and synapsin 1 knockdown potentiated A-1254-induced cell death. A-1254 (10 MUg/ml) also increased the expression of the two REST cofactors, the REST corepressor and the mammalian SIN3 homolog A transcription regulator. Moreover, the PCB mixture decreased acetylation of the histone proteins H3 and H4. It is noteworthy that the histone deacetylase inhibitor trichostatin A prevented such decreases and reduced the A-1254-induced neurotoxic effect. Collectively, these results suggest that A-1254 exerts its toxic effect via REST by down-regulating synapsin 1 and decreasing H3 and H4 acetylation. PMID- 21693631 TI - Grey matter abnormality in autism spectrum disorder: an activation likelihood estimation meta-analysis study. AB - BACKGROUND: Autism spectrum disorder (ASD) is defined on a clinical basis by impairments in social interaction, verbal and non-verbal communication, and repetitive or stereotyped behaviours. Voxel based morphometry (VBM), a technique that gives a probabilistic measure of local grey matter (GM) and white matter concentration, has been used to study ASD patients: modifications in GM volume have been found in various brain regions, such as the corpus callosum, brainstem, amygdala, hippocampus and cerebellum. However, the findings are inconsistent with respect to the specific localisation and direction of GM modifications, and no paper has attempted to statistically summarise the results available in the literature. METHODS: The present study is a quantitative meta-analysis of the current VBM findings aimed at delineating the cortical regions with consistently increased or reduced GM concentrations. The activation likelihood estimation (ALE) was used, which is a quantitative voxel based meta-analysis method which can be used to estimate consistent activations across different imaging studies. Co-occurrence statistics of a PubMed query were generated, employing 'autism spectrum disorder' as the neuroanatomical lexicon. RESULTS: Significant ALE values related to GM increases were observed bilaterally in the cerebellum, in the middle temporal gyrus, in the right anterior cingulate cortex, caudate head, insula, fusiform gyrus, precuneus and posterior cingulate cortex, and in the left lingual gyrus. GM decreases were observed bilaterally in the cerebellar tonsil and inferior parietal lobule, in the right amygdala, insula, middle temporal gyrus, caudate tail and precuneus and in the left precentral gyrus. PMID- 21693632 TI - Xenomelia: a new right parietal lobe syndrome. AB - BACKGROUND: Damage to the right parietal lobe has long been associated with various disorders of body image. The authors have recently suggested that an unusual behavioural condition in which otherwise rational individuals desire the amputation of a healthy limb might also arise from right parietal dysfunction. METHODS: Four subjects who desired the amputation of healthy legs (two right, one left and one, at first, bilateral and then left only) were recruited and underwent magnetoencephalography (MEG) scans during tactile stimulation of sites above and below the desired amputation line. Regions of interest (ROIs) in each hemisphere (superior parietal lobule (SPL), inferior parietal lobule, S1, M1, insula, premotor cortex and precuneus) were defined using FreeSurfer software. RESULTS: Analysis of average MEG activity across the 40-140 ms post-stimulation timeframe was carried out using an unpaired t test. This revealed significantly reduced activation only in the right SPL ROI for the subjects' affected legs when compared with both subjects' unaffected legs and that of controls. CONCLUSIONS: The right SPL is a cortical area that appears ideally placed to unify disparate sensory inputs to create a coherent sense of having a body. The authors propose that inadequate activation of the right SPL leads to the unnatural situation in which the sufferers can feel the limb in question being touched without it actually incorporating into their body image, with a resulting desire for amputation. The authors introduce the term 'xenomelia' as a more appropriate name than apotemnophilia or body integrity identity disorder, for what appears to be an unrecognised right parietal lobe syndrome. PMID- 21693633 TI - Nicotine trained as a negative feature passes the retardation-of-acquisition and summation tests of a conditioned inhibitor. AB - Nicotine functions as a negative feature in a Pavlovian discriminated goal tracking task. Whether withholding of responding to the conditional stimulus (CS) reflects nicotine functioning as a conditioned inhibitor is unknown. Accordingly, the present research sought to determine whether nicotine trained as a negative feature passed the retardation-of-acquisition and summation tests, thus characterizing it as a pharmacological (interoceptive) conditioned inhibitor. In the retardation test, rats received either nicotine (0.4 mg/kg) or chlordiazepoxide (5 mg/kg) negative feature training in which the drug state signaled when a 15-sec light CS would not be paired with sucrose; light was paired with sucrose on intermixed saline sessions. Following acquisition of the discrimination, both groups received nicotine CS training in which sucrose was intermittently available on nicotine but not intermixed saline sessions. Acquisition of conditioned responding to the nicotine CS was slower in the nicotine negative feature group than in the chlordiazepoxide negative feature group. In the summation test, rats were assigned to either the nicotine negative feature group or a pseudoconditioning control. In this control, the light CS was paired with sucrose on half the nicotine and half the saline sessions. Both groups also received excitatory training in which a white noise CS was paired with sucrose. The summation test consisted of presenting the white noise in conjunction with nicotine. Conditioned responding evoked by the white noise was decreased in the negative feature but not the pseudoconditioning group. Combined, the results provide the first evidence that an interoceptive stimulus (nicotine) can become a conditioned inhibitor. PMID- 21693634 TI - Selective inactivation of adenosine A(2A) receptors in striatal neurons enhances working memory and reversal learning. AB - The adenosine A(2A) receptor (A(2A)R) is highly enriched in the striatum where it is uniquely positioned to integrate dopaminergic, glutamatergic, and other signals to modulate cognition. Although previous studies support the hypothesis that A(2A)R inactivation can be pro-cognitive, analyses of A(2A)R's effects on cognitive functions have been restricted to a small subset of cognitive domains. Furthermore, the relative contribution of A(2A)Rs in distinct brain regions remains largely unknown. Here, we studied the regulation of multiple memory processes by brain region-specific populations of A(2A)Rs. Specifically, we evaluated the cognitive impacts of conditional A(2A)R deletion restricted to either the entire forebrain (i.e., cerebral cortex, hippocampus, and striatum, fb A(2A)R KO) or to striatum alone (st-A(2A)R KO) in recognition memory, working memory, reference memory, and reversal learning. This comprehensive, comparative analysis showed for the first time that depletion of A(2A)R-dependent signaling in either the entire forebrain or striatum alone is associated with two specific phenotypes indicative of cognitive flexibility-enhanced working memory and enhanced reversal learning. These selective pro-cognitive phenotypes seemed largely attributed to inactivation of striatal A(2A)Rs as they were captured by A(2A)R deletion restricted to striatal neurons. Neither spatial reference memory acquisition nor spatial recognition memory were grossly affected, and no evidence for compensatory changes in striatal or cortical D(1), D(2), or A(1) receptor expression was found. This study provides the first direct demonstration that targeting striatal A(2A)Rs may be an effective, novel strategy to facilitate cognitive flexibility under normal and pathologic conditions. PMID- 21693635 TI - Differential dependence of Pavlovian incentive motivation and instrumental incentive learning processes on dopamine signaling. AB - Here we attempted to clarify the role of dopamine signaling in reward seeking. In Experiment 1, we assessed the effects of the dopamine D(1)/D(2) receptor antagonist flupenthixol (0.5 mg/kg i.p.) on Pavlovian incentive motivation and found that flupenthixol blocked the ability of a conditioned stimulus to enhance both goal approach and instrumental performance (Pavlovian-to-instrumental transfer). In Experiment 2 we assessed the effects of flupenthixol on reward palatability during post-training noncontingent re-exposure to the sucrose reward in either a control 3-h or novel 23-h food-deprived state. Flupenthixol, although effective in blocking the Pavlovian goal approach, was without effect on palatability or the increase in reward palatability induced by the upshift in motivational state. This noncontingent re-exposure provided an opportunity for instrumental incentive learning, the process by which rats encode the value of a reward for use in updating reward-seeking actions. Flupenthixol administered prior to the instrumental incentive learning opportunity did not affect the increase in subsequent off-drug reward-seeking actions induced by that experience. These data suggest that although dopamine signaling is necessary for Pavlovian incentive motivation, it is not necessary for changes in reward experience, or for the instrumental incentive learning process that translates this experience into the incentive value used to drive reward-seeking actions, and provide further evidence that Pavlovian and instrumental incentive learning processes are dissociable. PMID- 21693637 TI - New channelrhodopsin with a red-shifted spectrum and rapid kinetics from Mesostigma viride. AB - Light control of motility behavior (phototaxis and photophobic responses) in green flagellate algae is mediated by sensory rhodopsins homologous to phototaxis receptors and light-driven ion transporters in prokaryotic organisms. In the phototaxis process, excitation of the algal sensory rhodopsins leads to generation of transmembrane photoreceptor currents. When expressed in animal cells, the algal phototaxis receptors function as light-gated cation channels, which has earned them the name "channelrhodopsins." Channelrhodopsins have become useful molecular tools for light control of cellular activity. Only four channelrhodopsins, identified in Chlamydomonas reinhardtii and Volvox carteri, have been reported so far. By screening light-induced currents among algal species, we identified that the phylogenetically distant flagellate Mesostigma viride showed photoelectrical responses in vivo with properties suggesting a channelrhodopsin especially promising for optogenetic use. We cloned an M. viride channelrhodopsin, MChR1, and studied its channel activity upon heterologous expression. Action spectra in HEK293 cells match those of the photocurrents observed in M. viride cells. Comparison of the more divergent MChR1 sequence to the previously studied phylogenetically clustered homologs and study of several MChR1 mutants refine our understanding of the sequence determinants of channelrhodopsin function. We found that MChR1 has the most red-shifted and pH independent spectral sensitivity so far reported, matches or surpasses known channelrhodopsins' channel kinetics features, and undergoes minimal inactivation upon sustained illumination. This combination of properties makes MChR1 a promising candidate for optogenetic applications. PMID- 21693636 TI - Differing time dependencies of object recognition memory impairments produced by nicotinic and muscarinic cholinergic antagonism in perirhinal cortex. AB - The roles of muscarinic and nicotinic cholinergic receptors in perirhinal cortex in object recognition memory were compared. Rats' discrimination of a novel object preference test (NOP) test was measured after either systemic or local infusion into the perirhinal cortex of the nicotinic receptor antagonist methyllycaconitine (MLA), which targets alpha-7 (alpha7) amongst other nicotinic receptors or the muscarinic receptor antagonists scopolamine, AFDX-384, and pirenzepine. Methyllycaconitine administered systemically or intraperirhinally before acquisition impaired recognition memory tested after a 24-h, but not a 20 min delay. In contrast, all three muscarinic antagonists produced a similar, unusual pattern of impairment with amnesia after a 20-min delay, but remembrance after a 24-h delay. Thus, the amnesic effects of nicotinic and muscarinic antagonism were doubly dissociated across the 20-min and 24-h delays. The same pattern of shorter-term but not longer-term memory impairment was found for scopolamine whether the object preference test was carried out in a square arena or a Y-maze and whether rats of the Dark Agouti or Lister-hooded strains were used. Coinfusion of MLA and either scopolamine or AFDX-384 produced an impairment profile matching that for MLA. Hence, the antagonists did not act additively when coadministered. These findings establish an important role in recognition memory for both nicotinic and muscarinic cholinergic receptors in perirhinal cortex, and provide a challenge to simple ideas about the role of cholinergic processes in recognition memory: The effects of muscarinic and nicotinic antagonism are neither independent nor additive. PMID- 21693638 TI - High levels of recombination among Streptococcus pneumoniae isolates from the Gambia. AB - We carried out multilocus sequence typing (MLST) on 148 pneumococcal carriage isolates collected from children <24 months old in the Upper River Division, the Gambia. MLST revealed a diverse population. Seventy-six different sequence types (STs) were found, the most common of which were 802 and 919, associated with 23F and 6A serotypes, respectively. Comparison with the MLST database showed that only 11 of the STs found in the present sample had been reported outside Africa. Six STs showed evidence of capsular switching (172, 802, 847, 1730, 1736, and 1737). Serotype switches were confirmed by microarrays that detected capsule genes. Of isolates analyzed by using microarrays, 40/69 (58%) harbored the tetM resistance determinant. A statistical genetic analysis to detect recombination found that 49/144 (34%) isolates showed significant (P<0.05) evidence of admixture, which is greater than that observed in similar samples from the United Kingdom (5%) and Finland (2%). We hypothesize that large amounts of admixture could reflect the high prevalence of multiple carriage in this region, leading to more opportunities for homologous recombination between strains. This could have consequences for the population response to conjugate vaccination. PMID- 21693639 TI - Alcohol marketing and youth drinking: a rejoinder to the alcohol industry. PMID- 21693640 TI - Baclofen: what's in a word? A world of difference. PMID- 21693642 TI - Impact of alcohol marketing on youth drinking. PMID- 21693643 TI - Paleo-Green Revolution for rice. PMID- 21693644 TI - Range contraction in large pelagic predators. AB - Large reductions in the abundance of exploited land predators have led to significant range contractions for those species. This pattern can be formalized as the range-abundance relationship, a general macroecological pattern that has important implications for the conservation of threatened species. Here we ask whether similar responses may have occurred in highly mobile pelagic predators, specifically 13 species of tuna and billfish. We analyzed two multidecadal global data sets on the spatial distribution of catches and fishing effort targeting these species and compared these with available abundance time series from stock assessments. We calculated the effort needed to reliably detect the presence of a species and then computed observed range sizes in each decade from 1960 to 2000. Results suggest significant range contractions in 9 of the 13 species considered here (between 2% and 46% loss of observed range) and significant range expansions in two species (11-29% increase). Species that have undergone the largest declines in abundance and are of particular conservation concern tended to show the largest range contractions. These include all three species of bluefin tuna and several marlin species. In contrast, skipjack tuna, which may have increased its abundance in the Pacific, has also expanded its range size. These results mirror patterns described for many land predators, despite considerable differences in habitat, mobility, and dispersal, and imply ecological extirpation of heavily exploited species across parts of their range. PMID- 21693645 TI - How hydrophobic molecules traverse the outer membranes of gram-negative bacteria. PMID- 21693647 TI - Measurement of c-axis angular orientation in calcite (CaCO3) nanocrystals using X ray absorption spectroscopy. AB - We demonstrate that the ability to manipulate the polarization of synchrotron radiation can be exploited to enhance the capabilities of X-ray absorption near edge structure (XANES) spectroscopy, to include linear dichroism effects. By acquiring spectra at the same photon energies but different polarizations, and using a photoelectron emission spectromicroscope (PEEM), one can quantitatively determine the angular orientation of micro- and nanocrystals with a spatial resolution down to 10 nm. XANES-PEEM instruments are already present at most synchrotrons, hence these methods are readily available. The methods are demonstrated here on geologic calcite (CaCO(3)) and used to investigate the prismatic layer of a mollusk shell, Pinctada fucata. These XANES-PEEM data reveal multiply oriented nanocrystals within calcite prisms, previously thought to be monocrystalline. The subdivision into multiply oriented nanocrystals, spread by more than 50 degrees , may explain the excellent mechanical properties of the prismatic layer, known for decades but never explained. PMID- 21693646 TI - R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. AB - The Wnt/beta-catenin signaling system plays essential roles in embryonic development and in the self-renewal and maintenance of adult stem cells. R spondins (RSPOs) are a group of secreted proteins that enhance Wnt/beta-catenin signaling and have pleiotropic functions in development and stem cell growth. LGR5, an orphan receptor of the G protein-coupled receptor (GPCR) superfamily, is specifically expressed in stem cells of the intestinal crypt and hair follicle. Knockout of LGR5 in the mouse results in neonatal lethality. LGR4, a receptor closely related to LGR5, also has essential roles in development, as its knockout leads to reduced viability and retarded growth. Overexpression of both receptors has been reported in several types of cancer. Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/beta-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. Interestingly, neither receptor is coupled to heterotrimeric G proteins or to beta-arrestin when stimulated by the R-spondins, indicating a unique mechanism of action. The findings provide a basis for stem cell-specific effects of Wnt/beta catenin signaling and for the broad range of functions LGR4, LGR5, and the R spondins have in normal and malignant growth. PMID- 21693648 TI - Adapting the information-motivation-behavioral skills model: predicting HIV related sexual risk among sexual minority youth. AB - Young sexual minority males are among those at highest risk for HIV infection, yet we know relatively little about the impact of sexual identity development on HIV risk. This study used cross-sectional data to investigate factors associated with HIV-related sexual risk among a sample of sexual minority males (n = 156), ages 14 to 21 years, using an extended version of the information-motivation behavioral skills (IMB) model tailored for this population. Path analysis results indicated that the extended model predicted a sizable amount of primary and secondary sexual risk (r (2) = .35 and .42). In addition to increasing HIV prevention information and motivation and decreasing substance use, study findings suggest that interventions with young sexual minority males should focus on sexual identity development factors including youths' attitudes toward LBGT people, sex-centered versus identity-centered development, and with specific emphasis on youth with non-male exclusive sexual orientations. PMID- 21693649 TI - Isolated musculocutaneous neuropathy in an adolescent baseball pitcher. AB - Injury of the musculocutaneous nerve very rarely occurs in the absence of concomitant injury to other components of the brachial plexus. Until now, the few cases of isolated musculocutaneous nerve palsies have been reported only in adults. We report a case of isolated musculocutaneous neuropathy in a uniquely talented adolescent baseball pitcher. The biomechanics underlying this adolescent's ability to throw with high velocity likely contributed to the musculocutaneous nerve injury in this case. PMID- 21693650 TI - Neurodevelopmental outcomes in very low-birth-weight infants in Korea: 1998-2007 vs 1989-1997. AB - The authors reviewed the medical records of very low-birth-weight infants admitted from 1998 to 2007 and compared neurodevelopmental outcomes with their previously reported data from 1989 to 1997. The recent group included 824 infants, and the previous group included 471 infants. Neurodevelopmental outcomes were classified into cerebral palsy and non-cerebral palsy neurodevelopmental impairment. In the recent group, the survival rate was significantly higher (79.4% vs 66.2%), the rate of cerebral palsy was lower (7.9% vs 10.5%), and the rate of non-cerebral palsy neurodevelopmental impairment was higher (6.0% vs 4.5%) but not significant. The survival rate increased significantly over time, but there was no significant change in neurodevelopmental outcomes over time. Multivariate analysis indicated that abnormal neurosonographic findings, using assisted ventilation, vaginal delivery, and abnormal brainstem auditory evoked potential, were associated with increased risk for cerebral palsy. PMID- 21693651 TI - Clinical characterization of gastroenteritis-related seizures in children: impact of fever and serum sodium levels. AB - Gastroenteritis-related seizures have increasingly gained attention in recent years. Most cases follow a brief, benign course with very few episodes of seizure recurrence and without development of epilepsy. Published reports usually do not make a distinction between febrile and afebrile patients, and most authors include only nonfebrile convulsions in their reported series. This study evaluated the impact of fever in children presenting with seizures during a mild gastroenteritis episode and found that the presence or absence of fever did not affect seizure characteristics or duration. However, mild hyponatremia affected some seizure features, particularly seizure duration, as hyponatremic children sustained more prolonged seizures than patients with normal serum sodium levels, irrespective of body temperature. PMID- 21693652 TI - Neonatal cerebral sinovenous thrombosis: neuroimaging and long-term follow-up. AB - Neonates are known to have a higher risk of cerebral sinovenous thrombosis than children of other age groups. The exact incidence in neonates remains unknown and is likely to be underestimated, as clinical presentation is nonspecific and diagnosis can only be made when dedicated neuroimaging techniques, including computed tomographic venography or magnetic resonance venography, are performed. Associated intracranial lesions are common and some, such as a unilateral thalamic hemorrhage, should suggest cerebral sinovenous thrombosis as the underlying etiology. Neurodevelopmental outcome is poor in approximately 50% of these infants and is adversely affected by associated parenchymal lesions. Anticoagulation therapy will limit propagation of the clot and possibly the development or enhancement of parenchymal lesions. Multicenter randomized clinical trials are urgently needed to address many of these important issues. PMID- 21693653 TI - An innovative faith-based healthy eating program: from class assignment to real world application of PRECEDE/PROCEED. AB - The Fostering African American Improvement in Total Health! (FAITH!) Nutrition Education Program is a theory-based, multicomponent health intervention developed and operated in partnership with an East Baltimore church. The program aims to improve eating habits, as well as knowledge and beliefs about healthy eating, among African American adults in order to prevent diseases related to dietary choices. This article addresses the development, design, and formative research that informed the FAITH! program. The main program components are also discussed. Program design used a framework for strategic intervention planning (PRECEDE PROCEED), and health education theories informed the evaluation process. Formative research was conducted to incorporate the needs and assets of the priority population. The main program components are culturally tailored educational materials, lectures and discussions on diet and related diseases, video presentations on healthy eating, healthy cooking demonstrations/food samples, evaluation, and a church-run healthy food pantry. PMID- 21693654 TI - Effects of vibration on the proteome expression of anterior cruciate ligament cells. AB - Recent reports have suggested that vibration has beneficial effects on knee healing response; however, the biomechanism of these beneficial effects still need to be determined on the anterior cruciate ligament (ACL) cell level. In this study, we applied a 20 Hz vibration to ACL cells, which produced a 20% increase (P < 0.001) in cell activity and 17% increase (P < 0.001) in intracellular sulfated glycosaminoglycan levels. In the 20 Hz vibration-stimulated ACL cell group, eight up-regulated (100 ~ 300%) protein spots were identified compared with the control group by proteomics analysis. Among these proteins, Annexin A2 and Prolyl 4 hydroxylase (PH4B) were shown to have a 71% and 16% higher expression, respectively, in the 20 Hz vibration-stimulated ACL cell group by Western blotting (P < 0.001). These results indicate that vibration produces a positive cellular environment, and Annexin A2 and prolyl 4 hydroxylase are expected to help ligament repair and ACL cell proliferation by controlling cell membrane and extracellular matrix formation. PMID- 21693655 TI - p53 Expression in node-positive breast cancer patients: results from the Cancer and Leukemia Group B 9344 Trial (159905). AB - PURPOSE: p53 as a prognostic and predictive factor in early-stage breast cancer has had mixed results. We studied p53 protein expression, by immunohistochemistry, in a randomized clinical trial of stage II patients treated with adjuvant doxorubicin and cyclophosphamide with or without paclitaxel [Cancer and Leukemia Group B (CALGB) 9344, INT0148]. PATIENTS AND METHODS: Epithelial p53 expression was evaluated using two immunohistochemical antibodies (DO7 and 1801) in formalin-fixed, paraffin-embedded tissue from patients with node-positive breast cancer who were randomized to four cycles of cyclophosphamide and one of three doses of doxorubicin (60, 75, or 90 mg/m(2); AC) and to receive four subsequent cycles of paclitaxel (T) or not. Prognostic and predictive value of p53 protein expression was assessed, independent of treatment assignment, for escalating doses of doxorubicin or addition of T with endpoints of relapse-free (RFS) and overall survival (OS). RESULTS: Of 3,121 patients, 1,887 patient specimens treated on C9344 were obtained, passed quality control, and evaluated for p53 expression. Expression was 23% and 27% for mAbs 1801 and D07, respectively, with 92% concordance. In univariate analysis, p53 positivity was associated with worse OS with either antibody, but only p53 staining with monoclonal antibody 1801 had significantly worse RFS. In multivariate analysis, p53 was not predictive of RFS or OS from either doxorubicin dose escalation or addition of paclitaxel regardless of the antibody. CONCLUSION: Nuclear staining of p53 by immunohistochemistry is associated with worse prognosis in node positive patients treated with adjuvant doxorubicin-based chemotherapy but is not a useful predictor of benefit from doxorubicin dose escalation or the addition of paclitaxel. PMID- 21693656 TI - BARD1 expression predicts outcome in colon cancer. AB - PURPOSE: BARD1 is a BRCA1-binding partner with tumor suppressive properties. Aberrant splice variants of BARD1 have been detected in various cancers, and it has been postulated that the presence of some splice variants is cancer specific. This is the first study assessing BARD1 expression patterns and correlation with clinical outcome in colon cancer. EXPERIMENTAL DESIGN: We analyzed colon cancer samples for the occurrence of BARD1 splice variants, characterized novel BARD1 splice variants, and quantified the mRNA expression levels of these isoforms in primary colon cancers and their corresponding normal tissue. We tested the correlation of full-length BARD1 protein expression and clinical outcome in primary colon cancer samples. RESULTS: In addition to the full-length BARD1 mRNA, we now find 19 distinct BARD1 splice variants in colon cancer. Contrary to previous assumptions, these splice variants also occur in the adjacent normal colon tissue. Although BARD1 splice variants account for a considerable amount of BARD1 mRNA in both cancer and normal colon samples, distinct variants show a cancer-specific regulation pattern. Consistent with its role as tumor suppressor, we further find that the expression of the full-length BARD1 protein predicts outcome in colon cancer and that loss of full-length BARD1 protein is associated with a poor prognosis (P = 0.0002). CONCLUSION: Taken together, this is the first report to suggest that BARD1 regulation is an important pathway in colon cancer and that the BARD1 full-length protein may be a useful marker to improve risk stratification in colon cancer patients. PMID- 21693657 TI - Imatinib sensitivity in BCR-ABL1-positive chronic myeloid leukemia cells is regulated by the remaining normal ABL1 allele. AB - Chronic myeloid leukemia in chronic phase (CML-CP) cells that harbor oncogenic BCR-ABL1 and normal ABL1 allele often become resistant to the ABL1 kinase inhibitor imatinib. Here, we report that loss of the remaining normal ABL1 allele in these tumors, which results from cryptic interstitial deletion in 9q34 in patients who did not achieve a complete cytogenetic remission (CCyR) during treatment, engenders a novel unexpected mechanism of imatinib resistance. BCR ABL1-positive Abl1(-/-) leukemia cells were refractory to imatinib as indicated by persistent BCR-ABL1-mediated tyrosine phosphorylation, lack of BCR-ABL1 protein degradation, increased cell survival, and clonogenic activity. Expression of ABL1 kinase, but not a kinase-dead mutant, restored the antileukemic effects of imatinib in ABL1-negative chronic myelogenous leukemia (CML) cells and in BCR ABL1-positive Abl1(-/-) murine leukemia cells. The intracellular concentration of imatinib and expression of its transporters were not affected, although proteins involved in BCR-ABL1 degradation were downregulated in Abl1(-/-) cells. Furthermore, 12 genes associated with imatinib resistance were favorably deregulated in Abl1(-/-) leukemia. Taken together, our results indicate that loss of the normal ABL1 kinase may serve as a key prognostic factor that exerts major impact on CML treatment outcomes. PMID- 21693658 TI - Small RNA sequencing and functional characterization reveals MicroRNA-143 tumor suppressor activity in liposarcoma. AB - Liposarcoma remains the most common mesenchymal cancer, with a mortality rate of 60% among patients with this disease. To address the present lack of therapeutic options, we embarked upon a study of microRNA (miRNA) expression alterations associated with liposarcomagenesis with the goal of exploiting differentially expressed miRNAs and the gene products they regulate as potential therapeutic targets. MicroRNA expression was profiled in samples of normal adipose tissue, well-differentiated liposarcoma, and dedifferentiated liposarcoma by both deep sequencing of small RNA libraries and hybridization-based Agilent microarrays. The expression profiles discriminated liposarcoma from normal adipose tissue and well differentiated from dedifferentiated disease. We defined over 40 miRNAs that were dysregulated in dedifferentiated liposarcomas in both the sequencing and the microarray analysis. The upregulated miRNAs included two cancer-associated species (miR-21 and miR-26a), and the downregulated miRNAs included two species that were highly abundant in adipose tissue (miR-143 and miR-145). Restoring miR 143 expression in dedifferentiated liposarcoma cells inhibited proliferation, induced apoptosis, and decreased expression of BCL2, topoisomerase 2A, protein regulator of cytokinesis 1 (PRC1), and polo-like kinase 1 (PLK1). The downregulation of PRC1 and its docking partner PLK1 suggests that miR-143 inhibits cytokinesis in these cells. In support of this idea, treatment with a PLK1 inhibitor potently induced G(2)-M growth arrest and apoptosis in liposarcoma cells. Taken together, our findings suggest that miR-143 re-expression vectors or selective agents directed at miR-143 or its targets may have therapeutic value in dedifferentiated liposarcoma. PMID- 21693659 TI - Percutaneous image-guided biopsy of the spleen: systematic review and meta analysis of the complication rate and diagnostic accuracy. AB - PURPOSE: To use meta-analysis to determine the complication rate and diagnostic accuracy of image-guided percutaneous needle biopsy of the spleen. MATERIALS AND METHODS: Several electronic databases were searched through July 2010 without language restrictions. Two reviewers independently selected studies that met the inclusion criteria for the diagnostic accuracy and complication rate arms of the study. Study data were independently extracted by the two reviewers. The primary 2 * 2 data were investigated with a random-effects meta-analysis of sensitivity and specificity. The complication rate data were investigated with a random effects meta-analysis; sensitivity analysis of complication rate, excluding needles larger than 18 gauge, was performed. RESULTS: Four studies met the inclusion criteria for the diagnostic accuracy arm (639 patients), and nine met the inclusion criteria for the complication rate arm (741 patients). The meta analysis showed a pooled sensitivity of 87.0% (95% confidence interval [CI]: 80.7%, 91.4%) and specificity of 96.4% (95% CI: 81.4%, 99.4%). The pooled major complication rate was 2.2% (95% CI: 0.8%, 5.6%). Sensitivity analysis with the removal of biopsies performed with needles larger than 18 gauge showed a major complication rate of 1.3% (95% CI: 0.6%, 2.5%). The most commonly encountered complications were hemorrhage followed by pain. CONCLUSION: Image-guided percutaneous biopsy of the spleen demonstrates high diagnostic accuracy and a major complication rate, for needles 18 gauge or smaller, that is similar to that reported for the liver and kidney. This technique should be considered a favorable alternative to splenectomy. PMID- 21693660 TI - Evaluation of heavily calcified vessels with coronary CT angiography: comparison of iterative and filtered back projection image reconstruction. AB - PURPOSE: To prospectively compare traditional filtered back projection (FBP) and iterative image reconstruction for the evaluation of heavily calcified arteries with coronary computed tomography (CT) angiography. MATERIALS AND METHODS: The study had institutional review board approval and was HIPAA compliant. Written informed consent was obtained from all patients. Fifty-five consecutive patients (35 men, 20 women; mean age, 58 years +/- 12 [standard deviation]) with Agatston scores of at least 400 underwent coronary CT angiography and cardiac catheterization. Image data were reconstructed with both FBP and iterative reconstruction techniques with corresponding cardiac algorithms. Image noise and subjective image quality were compared. To objectively assess the effect of FBP and iterative reconstruction on blooming artifacts, volumes of circumscribed calcifications were measured with dedicated volume analysis software. FBP and iterative reconstruction series were independently evaluated for coronary artery stenosis greater than 50%, and their diagnostic accuracy was compared, with cardiac catheterization as the reference standard. Statistical analyses included paired t tests, Kruskal-Wallis analysis of variance, and a modified McNemar test. RESULTS: Image noise measured significantly lower (P = .011-.035) with iterative reconstruction instead of FBP. Image quality was rated significantly higher (P = .031 and .042) with iterative reconstruction series than with FBP. Calcification volumes measured significantly lower (P = .019 and .026) with iterative reconstruction (44.3 mm(3) +/- 64.7 and 46.2 mm(3) +/- 68.8) than with FBP (54.5 mm(3) +/- 69.5 and 56.3 mm(3) +/- 72.5). Iterative reconstruction significantly improved some measures of per-segment diagnostic accuracy of coronary CT angiography for the detection of significant stenosis compared with FBP (accuracy: 95.9% vs 91.8%, P = .0001; specificity: 95.8% vs 91.2%, P = .0001; positive predictive value: 76.9% vs 61.1%, P = .0001). CONCLUSION: Iterative reconstruction reduces image noise and blooming artifacts from calcifications, leading to improved diagnostic accuracy of coronary CT angiography in patients with heavily calcified coronary arteries. PMID- 21693661 TI - Localized scleroderma: MR findings and clinical features. AB - PURPOSE: To describe musculoskeletal manifestations seen at magnetic resonance (MR) imaging in patients with localized scleroderma (LS) and to examine the relationship of MR findings to clinical subtypes and clinically suspected musculoskeletal features. MATERIALS AND METHODS: Institutional review board approval was obtained. Forty-three patients (30 female, 13 male; mean age, 42 years) with LS underwent MR imaging with a 1.5-T MR imager between November 2005 and June 2010. Findings were classified into clinical subtypes according to recently published consensus criteria. Images were evaluated for morphologic changes and signal abnormalities of subcutaneous fat septa, muscle fasciae, intramuscular septa, joint and/or tendon sheath synovia, entheses, and bone marrow. Clinically suspicious features of musculoskeletal manifestations-such as articular or periarticular pain, joint contractures, swelling, and increased warmth of the joints or extremities-were recorded. RESULTS: Musculoskeletal involvement was detected with MR imaging in 32 (74%) of 43 patients. It was detected with MR imaging in 26 (96%) of 27 patients in whom it was clinically suspected and in six (38%) of 16 patients in whom it was not clinically suspected. We found fascial thickening (26 [60%] of 43 patients), increased fascial enhancement (23 [53%] of 43 patients), articular synovitis (17 [40%] of 43 patients), tenosynovitis (nine [21%] of 43 patients), perifascial enhancement (seven [16%] of 43 patients), myositis (six [14%] of 43 patients), enthesitis (three [7%] of 43 patients), bone marrow involvement (two [5%] of 43 patients), and subcutaneous septal thickening (28 [65%] of 43 patients). The highest prevalence of musculoskeletal involvement was seen in patients with pansclerotic morphea. CONCLUSION: MR imaging reveals musculoskeletal involvement in patients with localized scleroderma. PMID- 21693662 TI - Detection of pancreatic carcinoma and liver metastases with gadoxetic acid enhanced MR imaging: comparison with contrast-enhanced multi-detector row CT. AB - PURPOSE: To intraindividually compare gadoxetic acid-enhanced magnetic resonance (MR) imaging with contrast material-enhanced multi-detector row computed tomography (CT) in detection of pancreatic carcinoma and liver metastases. MATERIALS AND METHODS: The ethics committee approved this retrospective study with waiver of informed consent. This study included 100 patients (53 men, 47 women; mean age, 67.8 years) consisting of 54 patients with pathologically confirmed pancreatic carcinoma (mean size, 33 mm) and 46 without a pancreatic lesion. Sixty-two liver metastases (mean size, 10 mm) in 15 patients with pancreatic carcinoma were diagnosed at pathologic examination or multimodality assessment. Three readers blinded to the final diagnosis interpreted all MR (precontrast T1- and T2-weighted and gadoxetic acid-enhanced dynamic and hepatocyte phase MR images) and tetraphasic dynamic contrast-enhanced CT images and graded the presence (or absence) of pancreatic carcinoma and liver metastasis on patient-by-patient and lesion-by-lesion bases. Receiver operating characteristic analysis, McNemar test, and Fisher test were performed to compare the diagnostic performance of CT and MR imaging. RESULTS: No significant differences were observed between CT and MR images in depiction of pancreatic carcinoma. However, MR imaging had greater sensitivity in depicting liver metastasis than did CT for two of the three readers in the MR imaging-versus-CT analysis (85% vs 69%, P = .046) and for all three readers in the lesion-by-lesion analysis (92%-94% vs 74%-76%, P = .030-.044). CONCLUSION: Gadoxetic acid-enhanced MR imaging was equivalent to dynamic contrast-enhanced CT in depicting pancreatic carcinoma and had better sensitivity for depicting liver metastases, suggesting the usefulness of gadoxetic acid-enhanced MR imaging for evaluation of patients with pancreatic carcinoma. PMID- 21693664 TI - Distribution of gluten proteins in bread wheat (Triticum aestivum) grain. AB - BACKGROUND AND AIMS: Gluten proteins are the major storage protein fraction in the mature wheat grain. They are restricted to the starchy endosperm, which forms white flour on milling, and interact during grain development to form large polymers which form a continuous proteinaceous network when flour is mixed with water to give dough. This network confers viscosity and elasticity to the dough, enabling the production of leavened products. The starchy endosperm is not a homogeneous tissue and quantitative and qualitative gradients exist for the major components: protein, starch and cell wall polysaccharides. Gradients in protein content and composition are the most evident and are of particular interest because of the major role played by the gluten proteins in determining grain processing quality. METHODS: Protein gradients in the starchy endosperm were investigated using antibodies for specific gluten protein types for immunolocalization in developing grains and for western blot analysis of protein extracts from flour fractions obtained by sequential abrasion (pearling) to prepare tissue layers. KEY RESULTS: Differential patterns of distribution were found for the high-molecular-weight subunits of glutenin (HMW-GS) and gamma gliadins when compared with the low-molecular-weight subunits of glutenin (LMW GS), omega- and alpha-gliadins. The first two types of gluten protein are more abundant in the inner endosperm layers and the latter more abundant in the subaleurone. Immunolocalization also showed that segregation of gluten proteins occurs both between and within protein bodies during protein deposition and may still be retained in the mature grain. CONCLUSIONS: Quantitative and qualitative gradients in gluten protein composition are established during grain development. These gradients may be due to the origin of subaleurone cells, which unlike other starchy endosperm cells derive from the re-differentiation of aleurone cells, but could also result from the action of specific regulatory signals produced by the maternal tissue on specific domains of the gluten protein gene promoters. PMID- 21693665 TI - Five vicariant genera from Gondwana: the Velloziaceae as shown by molecules and morphology [corrected]. AB - BACKGROUND AND AIMS: The amount of data collected previously for Velloziaceae neither clarified relationships within the family nor helped determine an appropriate classification, which has led to huge discordance among treatment by different authors. To achieve an acceptable phylogenetic result and understand the evolution and roles of characters in supporting groups, a total evidence analysis was developed which included approx. 20 % of the species and all recognized genera and sections of Velloziaceae, plus outgroups representatives of related families within Pandanales. METHODS: Analyses were undertaken with 48 species of Velloziaceae, representing all ten genera, with DNA sequences from the atpB-rbcL spacer, trnL-trnF spacer, trnL intron, trnH-psbA spacer, ITS ribosomal DNA spacers and morphology. KEY RESULTS: Four groups consistently emerge from the analyses. Persistent leaves, two phloem strands, stem cortex divided in three regions and violet tepals support Acanthochlamys as sister to Velloziaceae s.s., which are supported mainly by leaves with marginal bundles, transfusion tracheids and inflorescence without axis. Within Velloziaceae s.s., an African Xerophyta + Talbotia clade is uniquely supported by basal loculicidal capsules; an American clade, Barbacenia s.l. + Barbaceniopsis + Nanuza + Vellozia, is supported by only homoplastic characters. Barbacenia s.l. (= Aylthonia + Barbacenia + Burlemarxia + Pleurostima) is supported by a double sheath in leaf vascular bundles and a corona; Barbaceniopsis + Nanuza + Vellozia is not supported by an unambiguous character, but Barbaceniopsis is supported by five characters, including diclinous flowers, Nanuza + Vellozia is supported mainly by horizontal stigma lobes and stem inner cortex cells with secondary walls, and Vellozia alone is supported mainly by pollen in tetrads. CONCLUSIONS: The results imply recognition of five genera (Acanthochlamys (Xerophyta (Barbacenia (Barbaceniopsis, Vellozia)))), solving the long-standing controversies among recent classifications of the family. They also suggest a Gondwanan origin for Velloziaceae, with a vicariant pattern of distribution. PMID- 21693666 TI - Origin of triploid Arachis pintoi (Leguminosae) by autopolyploidy evidenced by FISH and meiotic behaviour. AB - BACKGROUND AND AIMS: Polyploidy is a dominant feature of flowering-plant genomes, including those of many important crop species. Arachis is a largely diploid genus with just four polyploid species. Two of them are economically important: the cultivated peanut and A. glabrata, a tropical forage crop. Even though it is usually accepted that polyploids within papilionoid legumes have arisen via hybridization and further chromosome doubling, it has been recently suggested that peanut arose through bilateral sexual polyploidization. In this paper, the polyploid nature of the recent, spontaneously originated triploid cytotype of the tropical lucerne, A. pintoi, was analysed, and thereby the mechanism by which polyploids may arise in the genus. METHODS: Chromosome morphology of 2x and 3x A. pintoi was determined by the Feulgens technique and the rDNA sites were mapped by FISH. To investigate whether polyploidization occurred by means of unreduced gametes, a detailed analysis of the microsporogenesis and pollen grains was made. KEY RESULTS: The 2x and 3x plants presented 9m + 1sm and a satellited chromosome type 2 in each haploid genome. Physical mapping revealed a cluster of 18S-26S rDNA, proximally located on chromosome 6, and two 5S rDNA loci on chromosomes 3 and 5. Diploid plants presented 10II in meiosis while trivalents were observed in all triploids, with a maximum of 10III by cell. Diploid A. pintoi produced normal tetrads, but also triads, dyads and monads. Two types of pollen grains were detected: (1) normal-sized with a prolate shape and (2) large ones with a tetrahedral morphology. CONCLUSIONS: Karyotype and meiotic analysis demonstrate that the 3x clone of A. pintoi arose by autopolyploidy. The occurrence of unreduced gametes strongly supports unilateral sexual polyploidization as the most probable mechanism that could have led to the origin of the triploid cytotype. This mechanism of polyploidization would probably be one of the most important mechanisms involved in the origin of economically important species of Arachis, either by triploid bridge or bilateral sexual polyploidization. PMID- 21693667 TI - Correlation between number and position of floral organs in Arabidopsis. AB - BACKGROUND AND AIMS: The study of variation in number, position and type of floral organs may serve as a key to understanding the mechanisms underlying their variation, and will make it possible to improve the analysis of gene function in model plant species by means of a more accurate characterization of mutant phenotypes. The present analysis was carried out in order to understand the correlation between number and position of floral organs in Arabidopsis thaliana. METHODS: An analysis of number and position of organs in flowers of wild type as well as in a series of mutations with floral organ position alterations was carried out, using light and electron microscopy. Variation common to different genotypes was analysed by means of individual diagrams, upon which generalized diagrams depicting variation in number and position of organs, were built by superimposition. KEY RESULTS AND CONCLUSIONS: It is shown that in the Arabidopsis flower a correlation exists between positions of petals and sepals, as well as between positions of stamens and carpels, whereas the position of carpels does not seem to depend on number and position of petals and stamens. This suggests that the position of organs in the basal (sepals) and apical (carpels) parts of the flower are determined before that in the intermediate zone. This assumption is consistent with the results of mathematical modelling and is supposed to be the consequence of stem-cell activity in the flower. PMID- 21693668 TI - QTL analysis of heterostyly in Primula sieboldii and its application for morph identification in wild populations. AB - BACKGROUND AND AIMS: Primula sieboldii is a perennial clonal herb that is distributed around the Sea of Japan and is endangered in Japan. Its breeding system is characterized by heteromorphic self-incompatibility, and the morph ratio within a population is very important for reproductive success. The aims of this study were to construct a linkage map, map the S locus as a qualitative trait and quantitative trait loci (QTLs) for floral morphological traits related to heterostyly, and predict the morph type in wild populations by using molecular markers for devising a conservation strategy. METHODS: A linkage map was constructed with 126 markers. The QTLs for four floral traits and the S locus were mapped. Using the genotypes of loci that were located near both the S locus and the QTLs with large effects, morphs of 59 wild genets were predicted. KEY RESULTS: The linkage map consisted of 14 linkage groups (LGs). The S locus was mapped to LG 7. Major QTLs for stigma and anther heights were detected in the same region as the S locus. These QTLs exhibited high logarithm of the odds scores and explained a high percentage of the phenotypic variance (>85 %). By analysing these two traits within each morph, additional QTLs for each trait were detected. Using the four loci linked to the S locus, the morphs of 43 genets in three wild populations could be predicted. CONCLUSIONS: This is the first report of a linkage map and QTL analysis for floral morphology related to heterostyly in P. sieboldii. Floral morphologies related to heterostyly are controlled by the S locus in LG 7 and by several QTLs in other LGs. Additionally, this study showed that molecular markers are effective tools for investigating morph ratios in a population containing the non-flowering individuals or during the non-flowering seasons. PMID- 21693669 TI - Pain, disability, and depression in osteoarthritis: effects of race and sex. AB - OBJECTIVES: A cross-sectional study examined how race and sex affect associations among osteoarthritis (OA) pain, disability, and depression in 363 older adults with diagnosed knee OA. METHOD: African American (Black; N = 94) and non-Hispanic White (White; N = 269) men and women self-reported pain, disability, depressive symptoms, arthritis history, general health, and demographic information. RESULTS: Women experienced greater pain and marginally greater disability than men; African Americans reported greater disability and marginally greater pain than non-Hispanic Whites. These effects varied with education, health, and arthritis history. In ordinary least squares regression analyses, race and pain independently predicted depression. Significant interactions of race, sex, and disability were driven by a lack of relationship between depression and disability among African American men. DISCUSSION: Race and sex influence affective response to OA pain and disability in complex ways, with African American men showing paradoxical effects. Further research is needed to elucidate mechanisms of this moderation effect. PMID- 21693670 TI - Temporal interpersonal emotion systems: the "TIES" that form relationships. AB - Emotion is often framed as an intrapersonal system comprised of subcomponents such as experience, behavior, and physiology that interact over time to give rise to emotional states. What is missing is that many emotions occur in the context of social interaction or ongoing relationships. When this happens, the result can be conceptualized as a temporal interpersonal emotion system (TIES) in which the subcomponents of emotion interact not only within the individual but across the partners as well. The present review (a) suggests that TIES can be understood in terms of the characteristics of dynamic systems, (b) reviews examples from diverse research that has investigated characteristics of TIES, (c) attempts to clarify the overlapping terms that have been used to refer to those characteristics by mapping them to the statistical, mathematical, and graphical models that have been used to represent TIES, and (d) offers pragmatic advice for analyzing TIES data. PMID- 21693671 TI - Heterosis in rice seedlings: its relationship to gibberellin content and expression of gibberellin metabolism and signaling genes. AB - Despite the accumulation of data on the genetic and molecular understanding of heterosis, there is little information on the regulation of heterosis at the physiological level. In this study, we performed a quantitative analysis of endogenous gibberellin (GA) content and expression profiling of the GA metabolism and signaling genes to investigate the possible relationship between GA signaling and heterosis for seedling development in rice (Oryza sativa). The materials used were an incomplete diallele set of 3 * 3 crosses and the six parents. In the growing shoots of the seedlings at 20 d after sowing, significant positive correlations between the contents of some GA species and performance and heterosis based on shoot dry mass were detected. Expression analyses of GA related genes by real-time reverse transcription-polymerase chain reaction revealed that 13 out of the 16 GA-related genes examined exhibited significant differential expression among the F1 hybrid and its parents, acting predominantly in the modes of overdominance and positive dominance. Expression levels of nine genes in the hybrids displayed significant positive correlations with the heterosis of shoot dry mass. These results imply that GAs play a positive role in the regulation of heterosis for rice seedling development. In shoots plus root axes of 4-d-old germinating seeds that had undergone the deetiolation, mimicking normal germination in soil, the axis dry mass was positively correlated with the content of GA29 but negatively correlated with that of GA19. Our findings provide supporting evidence for GAs playing an important regulatory role in heterosis for rice seedling development. PMID- 21693672 TI - Jasmonate controls polypeptide patterning in undamaged tissue in wounded Arabidopsis leaves. AB - Wounding initiates a strong and largely jasmonate-dependent remodelling of the transcriptome in the leaf blades of Arabidopsis (Arabidopsis thaliana). How much control do jasmonates exert on wound-induced protein repatterning in leaves? Replicated shotgun proteomic analyses of 2.5-mm-wide leaf strips adjacent to wounds revealed 106 differentially regulated proteins. Many of these gene products have not emerged as being wound regulated in transcriptomic studies. From experiments using the jasmonic acid (JA)-deficient allene oxide synthase mutant we estimated that approximately 95% of wound-stimulated changes in protein levels were deregulated in the absence of JA. The levels of two tonoplast proteins already implicated in defense response regulation, TWO-PORE CHANNEL1 and the calcium-V-ATPase ACA4 increased on wounding, but their transcripts were not wound inducible. The data suggest new roles for jasmonate in controlling the levels of calcium-regulated pumps and transporters, proteins involved in targeted proteolysis, a putative bacterial virulence factor target, a light-dependent catalyst, and a key redox-controlled enzyme in glutathione synthesis. Extending the latter observation we found that wounding increased the proportion of oxidized glutathione in leaves, but only in plants able to synthesize JA. The oxidizing conditions generated through JA signaling near wounds help to define the cellular environment in which proteome remodelling occurs. PMID- 21693673 TI - Model-based analysis of Arabidopsis leaf epidermal cells reveals distinct division and expansion patterns for pavement and guard cells. AB - To efficiently capture sunlight for photosynthesis, leaves typically develop into a flat and thin structure. This development is driven by cell division and expansion, but the individual contribution of these processes is currently unknown, mainly because of the experimental difficulties to disentangle them in a developing organ, due to their tight interconnection. To circumvent this problem, we built a mathematic model that describes the possible division patterns and expansion rates for individual epidermal cells. This model was used to fit experimental data on cell numbers and sizes obtained over time intervals of 1 d throughout the development of the first leaf pair of Arabidopsis (Arabidopsis thaliana). The parameters were obtained by a derivative-free optimization method that minimizes the differences between the predicted and experimentally observed cell size distributions. The model allowed us to calculate probabilities for a cell to divide into guard or pavement cells, the maximum size at which it can divide, and its average cell division and expansion rates at each point during the leaf developmental process. Surprisingly, average cell cycle duration remained constant throughout leaf development, whereas no evidence for a maximum cell size threshold for cell division of pavement cells was found. Furthermore, the model predicted that neighboring cells of different sizes within the epidermis expand at distinctly different relative rates, which could be verified by direct observations. We conclude that cell division seems to occur independently from the status of cell expansion, whereas the cell cycle might act as a timer rather than as a size-regulated machinery. PMID- 21693674 TI - Mouse primary uterine cell coculture system revisited: ovarian hormones mimic the aspects of in vivo uterine cell proliferation. AB - Previously, the uterine epithelial-stromal coculture system had limited success mimicking in vivo ovarian hormone-dependent cell-specific proliferation. Here, we established a mouse primary uterine coculture system, in which cells collected in pseudopregnancy specifically on d 4 are conducive to supporting hormone-induced cell-specific proliferation. When two cell types are placed in coculture without direct contact via cell culture inserts (nonadjacent), as opposed to with contact (adjacent), epithelial cells exhibit significant proliferation by estradiol 17beta (E2), whereas progesterone in combination with E2 caused inhibition of epithelial cell proliferation and a major shift in proliferation from epithelial to stromal cells. Epithelial cell integrity, with respect to E-cadherin expression, persisted in nonadjacent, but not adjacent, conditions. In subsequent studies of nonadjacent cocultures, localization of estrogen receptor (ER)alpha and progesterone receptor (PR), but not ERbeta, appeared to be abundant, presumably indicating that specific ER or PR coregulator expression might be responsible for this difference. Consistently, an agonist of ERalpha, but not ERbeta, was supportive of proliferation, and antagonists of ER or PR totally eliminated cell-specific proliferation by hormones. RT-PCR analyses also revealed that hormone-responsive genes primarily exhibit appropriate regulation. Finally, suppression of immunoglobulin heavy chain binding protein, a critical regulator of ERalpha signaling, in epithelial and/or stromal cells caused dramatic inhibition of E2-dependent epithelial cell proliferation, suggesting that a molecular perturbation approach is applicable to mimic in vivo uterine control. In conclusion, our established coculture system may serve as a useful alternative model to explore in vivo aspects of cell proliferation via communication between the epithelial and stromal compartments under the direction of ovarian hormones. PMID- 21693675 TI - Minireview: Intrinsic and extrinsic factors in thyroid gland development: an update. AB - In vertebrates the portion of the thyroid gland synthesizing the thyroid hormones develops from a small group of endodermal cells in the foregut. The nature of the signals that lead to the biochemical and morphogenetic events responsible for the organization of these cells into the adult thyroid gland has only recently become evident. In this review we summarize recent developments in the understanding of these processes, derived from evidence collected in several organisms. PMID- 21693676 TI - Minireview: Hormones and human sexual orientation. AB - Many people believe that sexual orientation (homosexuality vs. heterosexuality) is determined by education and social constraints. There are, however, a large number of studies indicating that prenatal factors have an important influence on this critical feature of human sexuality. Sexual orientation is a sexually differentiated trait (over 90% of men are attracted to women and vice versa). In animals and men, many sexually differentiated characteristics are organized during early life by sex steroids, and one can wonder whether the same mechanism also affects human sexual orientation. Two types of evidence support this notion. First, multiple sexually differentiated behavioral, physiological, or even morphological traits are significantly different in homosexual and heterosexual populations. Because some of these traits are known to be organized by prenatal steroids, including testosterone, these differences suggest that homosexual subjects were, on average, exposed to atypical endocrine conditions during development. Second, clinical conditions associated with significant endocrine changes during embryonic life often result in an increased incidence of homosexuality. It seems therefore that the prenatal endocrine environment has a significant influence on human sexual orientation but a large fraction of the variance in this behavioral characteristic remains unexplained to date. Genetic differences affecting behavior either in a direct manner or by changing embryonic hormone secretion or action may also be involved. How these biological prenatal factors interact with postnatal social factors to determine life-long sexual orientation remains to be determined. PMID- 21693677 TI - Evidence that the arcuate nucleus is an important site of progesterone negative feedback in the ewe. AB - There is now considerable evidence that dynorphin neurons mediate the negative feedback actions of progesterone to inhibit GnRH and LH pulse frequency, but the specific neurons have yet to be identified. In ewes, dynorphin neurons in the arcuate nucleus (ARC) and preoptic area (POA) are likely candidates based on colocalization with progesterone receptors. These studies tested the hypothesis that progesterone negative feedback occurs in either the ARC or POA by determining whether microimplants of progesterone into either site would inhibit LH pulse frequency (study 1) and whether microimplants of the progesterone receptor antagonist, RU486, would disrupt the inhibitory effects of peripheral progesterone (study 2). Both studies were done in ovariectomized (OVX) and estradiol-treated OVX ewes. In study 1, no inhibitory effects of progesterone were observed during treatment in either area. In study 2, microimplants of RU486 into the ARC disrupted the negative-feedback actions of peripheral progesterone treatments on LH pulse frequency in both OVX and OVX+estradiol ewes. In contrast, microimplants of RU486 into the POA had no effect on the ability of systemic progesterone to inhibit LH pulse frequency. We thus conclude that the ARC is one important site of progesterone-negative feedback in the ewe. These data, which are the first evidence on the neural sites in which progesterone inhibits GnRH pulse frequency in any species, are consistent with the hypothesis that ARC dynorphin neurons mediate this action of progesterone. PMID- 21693678 TI - Targeted deletion of adipocytes by apoptosis leads to adipose tissue recruitment of alternatively activated M2 macrophages. AB - Obesity is frequently associated with an infiltration of macrophages into adipose tissue. Adipocyte dysfunction causes a phenotypic switch of macrophages from an alternatively activated M2-like phenotype towards a proinflammatory M1 phenotype. The cross talk between adipocytes and infiltrating immune cells, in particular macrophages, is thought to contribute to local and eventually systemic inflammation. Here, we tested the phenotypic impact of a lack of adipocytes on the inflammatory status of macrophages. We took advantage of the fat apoptosis through targeted activation of caspase-8 (FAT-ATTAC) mouse model that allows for the inducible system-wide elimination of adipocytes through a proapoptotic mechanism and followed the degree and type of inflammatory response upon ablation of live adipocytes. Analysis of depots 2 wk after elimination of adipocytes resulted in markedly reduced levels of adipose tissue and a robust down regulation of circulating adipokines. Quantitative PCR and immunohistochemistry on epididymal and inguinal fat depots revealed an increase of the macrophage markers F4/80 and CD11c. Using polychromatic flow cytometry, we observed an up regulation of alternatively activated M2 macrophage markers (CD206 and CD301) on the majority of F4/80 positive cells. Apoptosis of adipocytes is sufficient to initiate a large influx of macrophages into the remnant fat pads. However, these macrophages are alternatively activated, antiinflammatory M2 macrophages and not M1 cells. We conclude that adipocyte death is sufficient to initiate macrophage infiltration, and live adipocytes are required to initiate and/or sustain a proinflammatory response within the infiltrating macrophages in adipose tissue. PMID- 21693679 TI - Apolipoprotein CIII reduces proinflammatory cytokine-induced apoptosis in rat pancreatic islets via the Akt prosurvival pathway. AB - Apolipoprotein CIII (ApoCIII) is mainly synthesized in the liver and is important for triglyceride metabolism. The plasma concentration of ApoCIII is elevated in patients with type 1 diabetes (T1D), and in vitro ApoCIII causes apoptosis in pancreatic beta-cells in the absence of inflammatory stress. Here, we investigated the effects of ApoCIII on function, signaling, and viability in intact rat pancreatic islets exposed to proinflammatory cytokines to model the intraislet inflammatory milieu in T1D. In contrast to earlier observations in mouse beta-cells, exposure of rat islets to ApoCIII alone (50 MUg/ml) did not cause apoptosis. In the presence of the islet-cytotoxic cytokines IL-1beta + interferon-gamma, ApoCIII reduced cytokine-mediated islet cell death and impairment of beta-cell function. ApoCIII had no effects on mitogen-activated protein kinases (c-Jun N-terminal kinase, p38, and ERK) and had no impact on IL 1beta-induced c-Jun N-terminal kinase activation. However, ApoCIII augmented cytokine-mediated nitric oxide (NO) production and inducible NO synthase expression. Further, ApoCIII caused degradation of the nuclear factor kappaB inhibitor inhibitor of kappaB and stimulated Ser473-phosphorylation of the survival serine-threonine kinase Akt. Inhibition of the Akt signaling pathway by the phosphatidylinositol 3 kinase inhibitor LY294002 counteracted the antiapoptotic effect of ApoCIII on cytokine-induced apoptosis. We conclude that ApoCIII in the presence of T1D-relevant proinflammatory cytokines reduces rat pancreatic islet cell apoptosis via Akt. PMID- 21693681 TI - The impact of hypodontia: a qualitative study on the experiences of patients. AB - Congenital absence of teeth affects 2-6 per cent of the population, but its impact on quality of life (QoL) is not fully understood. The symptoms of hypodontia can vary and therefore also the treatment and management of this condition. Determining and understanding the possible impact of hypodontia on patients could inform and improve the management of such patients. A purposive sample of 10 participants aged 16-25 years (five males and five females) with mild, moderate, or severe hypodontia at various stages of treatment was recruited. The participants had previously completed a 49-item Oral Health Impact Profile (OHIP) questionnaire with summary scores ranging from 24 to 143. All subjects participated in semi-structured interviews, and these were transcribed and analysed using NVivo software. The results show that the role of hypodontia patients in the treatment decision-making process changes significantly as they move from childhood to adulthood. Participants indicated dissatisfaction with the lack of communication with dental services throughout early adolescence as they became more cognizant of their condition which in turn led to concerns with regard to appearance which impacted on their psychosocial well-being. Hypodontia patients expect improved communication with dental practitioners and services as they become more cognizant of their condition and wish to become more actively involved in the decision-making process regarding their current and future treatment. PMID- 21693680 TI - Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4. AB - The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists, exendin-4 and liraglutide, suppress food intake and body weight. The mediating site(s) of action for the anorectic effects produced by peripheral administration of these GLP-1R agonists are not known. Experiments addressed whether food intake suppression after i.p. delivery of exendin-4 and liraglutide is mediated exclusively by peripheral GLP-1R or also involves direct central nervous system (CNS) GLP-1R activation. Results showed that CNS delivery [third intracerebroventricular (3(rd) ICV)] of the GLP-1R antagonist exendin-(9-39) (100 MUg), attenuated the intake suppression by i.p. liraglutide (10 MUg) and exendin 4 (3 MUg), particularly at 6 h and 24 h. Control experiments show that these findings appear to be based neither on the GLP-1R antagonist acting as a nonspecific competing orexigenic signal nor on blockade of peripheral GLP-1R via efflux of exendin-(9-39) to the periphery. To assess the contribution of GLP-1R expressed on subdiaphragmatic vagal afferents to the anorectic effects of liraglutide and exendin-4, food intake was compared in rats with complete subdiaphragmatic vagal deafferentation and surgical controls after i.p. delivery of the agonists. Both liraglutide and exendin-4 suppressed food intake at 3 h, 6 h, and 24 h for controls; for subdiaphragmatic vagal deafferentation rats higher doses of the GLP-1R agonists were needed for significant food intake suppression, which was observed at 6 h and 24 h after liraglutide and at 24 h after exendin-4. CONCLUSION: Food intake suppression after peripheral administration of exendin-4 and liraglutide is mediated by activation of GLP-1R expressed on vagal afferents as well as direct CNS GLP-1R activation. PMID- 21693682 TI - Choosing peritoneal dialysis reduces the risk of invasive access interventions. AB - BACKGROUND: Patients choosing between hemodialysis (HD) and peritoneal dialysis (PD) should be well informed of the risks and benefits of each modality. Invasive access interventions are important outcomes because frequent interventions lower patient's quality of life and consume limited resources. The objective of this study was to compare the risk of access interventions between the two modalities. METHODS: Three hundred and sixty-nine incident chronic dialysis patients were prospectively enrolled at four Canadian centers that were eligible for both modalities, received at least 4 months of pre-dialysis care and started dialysis electively as an outpatient. Two hundred and twenty-four (61%) chose PD and 145 (39%) chose HD. Patients were followed for an average of 1.3 years (range 0.07 3.6 years). RESULTS: In the PD group, there were fewer access interventions (2.5 versus 3.1 interventions per patient, adjusted odds ratio of 0.79 for PD versus HD, P = 0.005) and a lower intervention rate (2.3 versus 1.9 per patient-year, adjusted rate ratio of 0.81 for PD versus HD, P = 0.04). PD catheters were less likely to experience primary failure (4.6 versus 32%, P < 0.0001), showed a trend toward lower intervention rates during use (0.8 versus 1.2 per patient-year, P = 0.06), and had equal patency compared to fistulae (1-year patency of 84 versus 88%, P = 0.48). Patients managed exclusively with HD catheters (28% of the HD group) required 1.7 interventions per patient and an intervention rate of 1.9 per patient-year. CONCLUSION: Patients who choose PD require fewer access interventions to maintain dialysis access than patients choosing HD. PMID- 21693683 TI - Views of health professionals on the role of primary care in the follow-up of men with prostate cancer. AB - BACKGROUND: Follow-up care for prostate cancer has traditionally been led by secondary care in hospital out-patient clinics. As the number of men with prostate cancer increases and secondary care resources face pressure, alternative follow-up models are being sought. Current National Institute for Health and Clinical Excellence guidance recommends follow-up outside the hospital setting for patients who are stable 2 years following radical treatment and for those undergoing 'watchful waiting'. OBJECTIVE: To describe current practice in a sample of relevant health care professionals and to seek their views on the role of primary care in prostate cancer follow-up. METHODS: Semi-structured telephone interviews with 38 UK health care professionals, from both secondary and primary care. Transcripts were analysed using the constant comparative method. RESULTS: There are marked variations in current follow-up practice around the country, with hospital-based follow-up ranging from 6 months to lifetime. The predominant, although not universal, view expressed was that there is both scope and support for primary care to play a greater role, particularly for men with stable disease. This was qualified by the need for supporting education, including guidance on interpretation of prostate-specific antigen values, introduction of robust follow-up systems in primary care, easy access back into secondary (hospital) care, a mechanism for ensuring follow-up data can still be collected for audit purposes and appropriate resourcing. CONCLUSIONS: If primary care is to play a significant role in providing high-quality follow-up care for men with prostate cancer, then steps need to be taken to address the barriers to increased primary care involvement identified by this study. PMID- 21693684 TI - Everywhere you go, everyone is saying condom, condom. But are they being used consistently? Reflections of South African male students about male and female condom use. AB - Young men in South Africa can play a critical role in preventing new human immunodeficiency virus (HIV) infections, yet are seldom targeted for HIV prevention. While reported condom use at last sex has increased considerably among young people, consistent condom use remains a challenge. In this study, 74 male higher education students gave their perspectives on male and female condoms in 10 focus group discussions. All believed that condoms should be used when wanting to prevent conception and protect against HIV, although many indicated that consistent condom use was seldom attained, if at all. Three possible situations for not using condoms were noted: (i) when sex happens in the heat of the moment and condoms are unavailable, (ii) when sexual partnerships have matured and (iii) when female partners implicitly accept unprotected sex. Men viewed it as their responsibility to have male condoms available, but attitudes about whose decision it was to initiate condom use were mixed. Almost all sexually active men had male condom experience; however, very few had used female condoms. Prevention initiatives should challenge traditional gendered norms that underpin poor condom uptake and continued use and build on the apparent shifts in these norms that are allowing women greater sexual agency. PMID- 21693685 TI - UKEMS/Dutch EMS-sponsored workshop on biomarkers of exposure and oxidative DNA damage & 7th GUM-32P-postlabelling workshop, University of Munster, Munster, Germany, 28-29 March 2011. AB - Environmental exposures are a major concern for human cancer. However, the precise contribution of specific risk factors and their interactions, both with each other and with genotype, continue to be difficult to elucidate. The exposome is the comprehensive characterisation of an individual's lifetime exposure history (Wild, C. P. (2009) Environmental exposure measurement in cancer epidemiology. Mutagenesis, 24, 117-125). Unravelling complex environmental and genetic aetiologies in order to plan effective public health interventions demands that both environmental exposures and genetic variations are reliably measured. The development, validation and application of biomarkers of exposure are manifestly critical to the future of cancer epidemiology. The aim of this workshop at the University of Munster was to discuss the current status of exposure biomarkers in cancer molecular epidemiology as well as new findings achieved by applying the methods to studies of mechanisms of human cancer. Day 1 focused on biomarkers of exposure (i.e. carcinogen DNA adducts), effect and susceptibility to gain greater understanding of environmental cancer risks and their modulation. Day 2 focused on the role of oxidative stress and DNA damage in human carcinogenesis including methodologies used for the measurement of oxidatively induced DNA lesions in human cells or tissues and the possible use of these lesions as cancer biomarkers. PMID- 21693687 TI - Aging biology and novel targets for drug discovery. AB - Despite remarkable technological advances in genetics and drug screening, the discovery of new pharmacotherapies has slowed and new approaches to drug development are needed. Research into the biology of aging is generating many novel targets for drug development that may delay all age-related diseases and be used long term by the entire population. Drugs that successfully delay the aging process will clearly become "blockbusters." To date, the most promising leads have come from studies of the cellular pathways mediating the longevity effects of caloric restriction (CR), particularly target of rapamycin and the sirtuins. Similar research into pathways governing other hormetic responses that influence aging is likely to yield even more targets. As aging becomes a more attractive target for drug development, there will be increasing demand to develop biomarkers of aging as surrogate outcomes for the testing of the effects of new agents on the aging process. PMID- 21693688 TI - The nurse's medication day. AB - The medication administration stage of the medication-use process is especially vulnerable to error because errors are least likely to be caught before reaching the patient. Medication administration, however, remains poorly understood. In this article we describe medication administration as observed in an ethnographic study conducted on one medical unit and one surgical unit. A central finding was that medication administration entailed a complex mixture of varied and often competing demands that temporally structured the nurses' entire workday. Articulation work was evident in time management strategies nurses used to handle demands from institutional policies, technical devices, patients, the physical environment, and the medications themselves. The average number of doses of medication per patient was more than double the number policy groups have indicated. Medication administration is not simply the giving of drugs, nor does it have clearly defined temporal boundaries. Because of its inseparability from other nurses' work, medication administration inherently entails interruption, thereby calling into question the current emphasis on reducing interruptions as a tactic to decrease medication errors. PMID- 21693689 TI - Gut-liver interaction in triglyceride-rich lipoprotein metabolism. AB - The liver and intestine have complementary and coordinated roles in lipoprotein metabolism. Despite their highly specialized functions, assembly and secretion of triglyceride-rich lipoproteins (TRL; apoB-100-containing VLDL in the liver and apoB-48-containing chylomicrons in the intestine) are regulated by many of the same hormonal, inflammatory, nutritional, and metabolic factors. Furthermore, lipoprotein metabolism in these two organs may be affected in a similar fashion by certain disorders. In insulin resistance, for example, overproduction of TRL by both liver and intestine is a prominent component of and underlies other features of a complex dyslipidemia and increased risk of atherosclerosis. The intestine is gaining increasing recognition for its importance in affecting whole body lipid homeostasis, in part through its interaction with the liver. This review aims to integrate recent advances in our understanding of these processes and attempts to provide insight into the factors that coordinate lipid homeostasis in these two organs in health and disease. PMID- 21693690 TI - NOD1 activation induces proinflammatory gene expression and insulin resistance in 3T3-L1 adipocytes. AB - Chronic inflammation is associated with obesity and insulin resistance; however, the underlying mechanisms are not fully understood. Pattern recognition receptors Toll-like receptors and nucleotide-oligomerization domain-containing proteins play critical roles in innate immune response. Here, we report that activation of nucleotide binding oligomerization domain-containing protein-1 (NOD1) in adipocytes induces proinflammatory response and impairs insulin signaling and insulin-induced glucose uptake. NOD1 and NOD2 mRNA are markedly increased in differentiated murine 3T3-L1 adipocytes and human primary adipocyte culture upon adipocyte conversion. Moreover, NOD1 mRNA is markedly increased only in the fat tissues in diet-induced obese mice, but not in genetically obese ob/ob mice. Stimulation of NOD1 with a synthetic ligand Tri-DAP induces proinflammatory chemokine MCP-1, RANTES, and cytokine TNF-alpha and MIP-2 (human IL-8 homolog) and IL-6 mRNA expression in 3T3-L1 adipocytes in a time- and dose-dependent manner. Similar proinflammatory profiles are observed in human primary adipocyte culture stimulated with Tri-DAP. Furthermore, NOD1 activation suppresses insulin signaling, as revealed by attenuated tyrosine phosphorylation and increased inhibitory serine phosphorylation, of IRS-1 and attenuated phosphorylation of Akt and downstream target GSK3alpha/3beta, resulting in decreased insulin-induced glucose uptake in 3T3-L1 adipocytes. Together, our results suggest that NOD1 may play an important role in adipose inflammation and insulin resistance in diet induced obesity. PMID- 21693691 TI - SOX9 and SF1 are involved in cyclic AMP-mediated upregulation of anti-Mullerian gene expression in the testicular prepubertal Sertoli cell line SMAT1. AB - In Sertoli cells, anti-Mullerian hormone (AMH) expression is upregulated by FSH via cyclic AMP (cAMP), although no classical cAMP response elements exist in the AMH promoter. The response to cAMP involves NF-kappaB and AP2; however, targeted mutagenesis of their binding sites in the AMH promoter do not completely abolish the response. In this work we assessed whether SOX9, SF1, GATA4, and AP1 might represent alternative pathways involved in cAMP-mediated AMH upregulation, using real-time RT-PCR (qPCR), targeted mutagenesis, luciferase assays, and immunocytochemistry in the Sertoli cell line SMAT1. We also explored the signaling cascades potentially involved. In qPCR experiments, Amh, Sox9, Sf1, and Gata4 mRNA levels increased after SMAT1 cells were incubated with cAMP. Blocking PKA abolished the effect of cAMP on Sox9, Sf1, and Gata4 expression, inhibiting PI3K/PKB impaired the effect on Sf1 and Gata4, and reducing MEK1/2 and p38 MAPK activities curtailed Gata4 increase. SOX9 and SF1 translocated to the nucleus after incubation with cAMP. Mutations of the SOX9 or SF1 sites, but not of GAT4 or AP1 sites, precluded the response of a 3,063-bp AMH promoter to cAMP. In conclusion, in the Sertoli cell line SMAT1 cAMP upregulates SOX9, SF1, and GATA4 expression and induces SOX9 and SF1 nuclear translocation mainly through PKA, although other kinases may also participate. SOX9 and SF1 binding to the AMH promoter is essential to increase the activity of the AMH promoter in response to cAMP. PMID- 21693693 TI - Insulin regulates menin expression, cytoplasmic localization, and interaction with FOXO1. AB - Menin is the ubiquitously expressed nuclear protein product of the MEN1 gene, which interacts with PKB/Akt in the cytoplasm to inhibit its activity. This study describes a novel insulin-dependent mechanism of menin regulation and interaction with other metabolic proteins. We show that insulin downregulated menin in a time dependent manner via the human insulin receptor. Inhibition analysis indicated a critical role for the protein kinase Akt in regulation of menin expression and localization. Insulin-mediated decrease in menin expression was abrogated by the PI3K/Akt inhibitor LY-294002 at early time points, from 2 to 7 h. Furthermore, exposure to insulin resulted in the cytoplasmic localization of menin and increased interaction with FOXO1. Fasting followed by refeeding modulates serum insulin levels, which corresponded to an increase in menin interaction with FOXO1 in the liver. Liver-specific hemizygous deletion of menin resulted in increased expression of FOXO1 target genes, namely IGFBP-1, PGC-1alpha, insulin receptor, Akt, and G-6-Pase. This study provides evidence that menin expression and localization are regulated by insulin signaling and that this regulation triggers an increase in its interaction with FOXO1 via Akt with metabolic consequences. PMID- 21693692 TI - Knockout of the murine cysteine dioxygenase gene results in severe impairment in ability to synthesize taurine and an increased catabolism of cysteine to hydrogen sulfide. AB - Cysteine homeostasis is dependent on the regulation of cysteine dioxygenase (CDO) in response to changes in sulfur amino acid intake. CDO oxidizes cysteine to cysteinesulfinate, which is further metabolized to either taurine or to pyruvate plus sulfate. To gain insight into the physiological function of CDO and the consequence of a loss of CDO activity, mice carrying a null CDO allele (CDO(+/-) mice) were crossed to generate CDO(-/-), CDO(+/-), and CDO(+/+) mice. CDO(-/-) mice exhibited postnatal mortality, growth deficit, and connective tissue pathology. CDO(-/-) mice had extremely low taurine levels and somewhat elevated cysteine levels, consistent with the lack of flux through CDO-dependent catabolic pathways. However, plasma sulfate levels were slightly higher in CDO(-/-) mice than in CDO(+/-) or CDO(+/+) mice, and tissue levels of acid-labile sulfide were elevated, indicating an increase in cysteine catabolism by cysteine desulfhydration pathways. Null mice had lower hepatic cytochrome c oxidase levels, suggesting impaired electron transport capacity. Supplementation of mice with taurine improved survival of male pups but otherwise had little effect on the phenotype of the CDO(-/-) mice. H(2)S has been identified as an important gaseous signaling molecule as well as a toxicant, and pathology may be due to dysregulation of H(2)S production. Control of cysteine levels by regulation of CDO may be necessary to maintain low H(2)S/sulfane sulfur levels and facilitate the use of H(2)S as a signaling molecule. PMID- 21693694 TI - Developmental analysis of a Medicago truncatula smooth leaf margin1 mutant reveals context-dependent effects on compound leaf development. AB - Compound leaf development requires highly regulated cell proliferation, differentiation, and expansion patterns. We identified loss-of-function alleles at the SMOOTH LEAF MARGIN1 (SLM1) locus in Medicago truncatula, a model legume species with trifoliate adult leaves. SLM1 encodes an auxin efflux carrier protein and is the ortholog of Arabidopsis thaliana PIN-FORMED1 (PIN1). Auxin distribution is impaired in the slm1 mutant, resulting in pleiotropic phenotypes in different organs. The most striking change in slm1 is the increase in the number of terminal leaflets and a simultaneous reduction in the number of lateral leaflets, accompanied by reduced expression of SINGLE LEAFLET1 (SGL1), an ortholog of LEAFY. Characterization of the mutant indicates that distinct developmental domains exist in the formation of terminal and lateral leaflets. In contrast with the pinnate compound leaves in the wild type, the slm1 sgl1 double mutant shows nonpeltately palmate leaves, suggesting that the terminal leaflet primordium in M. truncatula has a unique developmental mechanism. Further investigations on the development of leaf serrations reveal different ontogenies between distal serration and marginal serration formation as well as between serration and leaflet formation. These data suggest that regulation of the elaboration of compound leaves and serrations is context dependent and tightly correlated with the auxin/SLM1 module in M. truncatula. PMID- 21693695 TI - Live cell imaging reveals structural associations between the actin and microtubule cytoskeleton in Arabidopsis. AB - In eukaryotic cells, the actin and microtubule (MT) cytoskeletal networks are dynamic structures that organize intracellular processes and facilitate their rapid reorganization. In plant cells, actin filaments (AFs) and MTs are essential for cell growth and morphogenesis. However, dynamic interactions between these two essential components in live cells have not been explored. Here, we use spinning-disc confocal microscopy to dissect interaction and cooperation between cortical AFs and MTs in Arabidopsis thaliana, utilizing fluorescent reporter constructs for both components. Quantitative analyses revealed altered AF dynamics associated with the positions and orientations of cortical MTs. Reorganization and reassembly of the AF array was dependent on the MTs following drug-induced depolymerization, whereby short AFs initially appeared colocalized with MTs, and displayed motility along MTs. We also observed that light-induced reorganization of MTs occurred in concert with changes in AF behavior. Our results indicate dynamic interaction between the cortical actin and MT cytoskeletons in interphase plant cells. PMID- 21693697 TI - Prevalence of adverse drug events in ambulatory care: a systematic review. AB - OBJECTIVE: Most medications are prescribed, dispensed, and administered in ambulatory care settings, yet little information exists on the adverse effects of drugs in this setting. This review was conducted to estimate the prevalence of adverse drug events (ADEs) and the proportion of preventable ADEs in ambulatory care settings; compare data for different age groups including children, adults, and elderly patients; and review drug classes most commonly associated with ADEs. DATA SOURCES: Four electronic databases-PubMed (1966-March 2011), International Pharmaceutical Abstracts (1970-March 2011), EMBASE (1980-March 2011), and the Cochrane Database of Systematic Reviews (1993-March 2011)-were systematically searched for published data. Bibliographies of retrieved articles were searched individually for additional relevant studies. STUDY SELECTION: A standardized definition of an ADE was used to select studies in populations living in the community, with medical visits to primary care facilities, nonspecialty ambulatory care facilities, and/or admissions to a hospital for medication related adverse events. DATA EXTRACTION: Data were extracted using a standardized table. Forty-three studies met our inclusion criteria. DATA SYNTHESIS: The median ADE prevalence rate for retrospective studies was 3.3% (interquartile range [IQR] 2.3-7.1%) vs 9.65% (IQR 3.3-17.35%) for prospective studies. Median preventable ADE rates in ambulatory care-based studies were 16.5%, and 52.9% for hospital based studies. Median prevalence rates by age group ranged from 2.45% for children to 5.27% for adults, 16.1% for elderly patients, and 3.45% for studies including all ages. CONCLUSIONS: Despite a recent increase in publications on ADEs in the ambulatory care setting, most studies remain hospital based. Notable differences in prevalence rates by age groups and by responsible drug categories provide guidance on how to direct attention toward effective targets for improvement of medication safety in ambulatory care settings. PMID- 21693696 TI - The Arabidopsis leucine-rich repeat receptor-like kinases BAK1/SERK3 and BKK1/SERK4 are required for innate immunity to hemibiotrophic and biotrophic pathogens. AB - Recognition of pathogen-associated molecular patterns (PAMPs) by surface localized pattern recognition receptors (PRRs) constitutes an important layer of innate immunity in plants. The leucine-rich repeat (LRR) receptor kinases EF-TU RECEPTOR (EFR) and FLAGELLIN SENSING2 (FLS2) are the PRRs for the peptide PAMPs elf18 and flg22, which are derived from bacterial EF-Tu and flagellin, respectively. Using coimmunoprecipitation and mass spectrometry analyses, we demonstrated that EFR and FLS2 undergo ligand-induced heteromerization in planta with several LRR receptor-like kinases that belong to the SOMATIC-EMBRYOGENESIS RECEPTOR-LIKE KINASE (SERK) family, including BRASSINOSTEROID INSENSITIVE1 ASSOCIATED KINASE1/SERK3 (BAK1/SERK3) and BAK1-LIKE1/SERK4 (BKK1/SERK4). Using a novel bak1 allele that does not exhibit pleiotropic defects in brassinosteroid and cell death responses, we determined that BAK1 and BKK1 cooperate genetically to achieve full signaling capability in response to elf18 and flg22 and to the damage-associated molecular pattern AtPep1. Furthermore, we demonstrated that BAK1 and BKK1 contribute to disease resistance against the hemibiotrophic bacterium Pseudomonas syringae and the obligate biotrophic oomycete Hyaloperonospora arabidopsidis. Our work reveals that the establishment of PAMP triggered immunity (PTI) relies on the rapid ligand-induced recruitment of multiple SERKs within PRR complexes and provides insight into the early PTI signaling events underlying this important layer of plant innate immunity. PMID- 21693698 TI - Treating bugs with bugs: the role of probiotics as adjunctive therapy for Helicobacter pylori. AB - OBJECTIVE: To review the literature on the role of probiotics as adjunctive therapy in the treatment of Helicobacter pylori infections. DATA SOURCES: Literature was accessed through MEDLINE (1966-March 2011) using the terms H. pylori, probiotic, Lactobacillus, Bifidobacterium, Saccharomyces, Bacillus clausii, and Propionibacterium. Article references were hand-searched for additional relevant articles and abstracts. STUDY SELECTION AND DATA EXTRACTION: All English-language articles published in full were evaluated. Randomized, double-blind, placebo-controlled trials assessing the use of probiotics combined with standard eradication therapy of H. pylori infection in adults were included in the review. DATA SYNTHESIS: Various probiotics, including Lactobacillus spp., Saccharomyces spp., Bifidobacterium spp., and B. clausii, reduce adverse effects such as nausea, taste disturbance, diarrhea, and epigastric pain, and increase tolerability of H. pylori eradication therapy. Based on the studies reviewed, probiotics do not affect H. pylori eradication rates. CONCLUSIONS: Probiotics may be beneficial in reducing adverse effects and increasing tolerability of H. pylori eradication regimens. They may especially be helpful in patients with recurrent H. pylori infection and a history of gastrointestinal adverse effects with antibiotics. Pharmacists can play an important role in educating patients regarding probiotic use during H. pylori eradication therapy. PMID- 21693699 TI - Comparison of effects of morning versus evening administration of ezetimibe/simvastatin on serum cholesterol in patients with primary hypercholesterolemia. AB - BACKGROUND: Ezetimibe, a first-in-its-class inhibitor of cholesterol absorption, is an effective agent for combined use with statins to achieve low-density lipoprotein cholesterol (LDL-C) goals. Ezetimibe in combination with simvastatin as a single-tablet formulation has proven to be highly effective in reducing serum LDL-C through the dual inhibition of cholesterol absorption and biosynthesis. The effect of time of administration on efficacy of this combination therapy has not been evaluated. OBJECTIVE: To compare the effects of morning versus evening administration of ezetimibe/simvastatin on serum cholesterol levels of patients with primary hypercholesterolemia. METHODS: In this multicenter, open-label, randomized, 2-sequence, 2-period crossover study, patients with primary hypercholesterolemia randomly received ezetimibe/simvastatin 10 mg/20 mg once daily, either in the morning (within 1 hour of breakfast) or in the evening (within 1 hour of dinner) for 6 weeks. RESULTS: Data on 171 patients (87 in the morning administration group and 84 in the evening administration group) were analyzed. A significant reduction (p <= 0.001) in the total cholesterol, triglyceride, high-density lipoprotein cholesterol, LDL-C, apo-lipoprotein B, and high-sensitivity C-reactive protein (hs-CRP) from baseline was achieved after each treatment. Noninferiority of morning administration versus evening administration was shown in the percentage reduction of the LDL-C level from baseline (difference, -1.62%; 90% CI -4.94 to 1.70). No significant difference was found between groups with respect to the percentage of changes in other lipid parameters from baseline. Furthermore, there was no significant difference in the percentage of change in hs-CRP as an antiinflammatory marker between the morning and evening administration groups. The frequency of adverse events was similar between groups. CONCLUSIONS: Morning administration of ezetimibe/simvastatin 10 mg/20 mg is noninferior to evening administration with respect to LDL-C-lowering ability. PMID- 21693700 TI - Dihydroergotamine-induced vasospastic angina in a patient taking a calcium channel blocker. AB - OBJECTIVE: To report a probable case of vasospastic angina after administration of dihydroergotamine mesylate in a patient without coronary artery disease. CASE SUMMARY: A 49-year-old woman with relapsing/remitting multiple sclerosis was admitted for severe headache and pain crisis. She received a single dose of intravenous dihydroergotamine and, within 30 minutes, experienced chest pain, nausea, and vomiting. No changes on electrocardiogram were noted, but cardiac enzyme levels were elevated. Brief episodes of chest pain persisted for several days and resolved spontaneously before the woman's discharge. She had several cardiac risk factors, including cigarette smoking, hypertension, and a family history of coronary artery disease, but cardiac catheterization on hospital day 5 revealed no underlying coronary artery disease. DISCUSSION: Although cardiovascular adverse reactions have been reported with ergotamine tartrate, dihydroergotamine has rarely been linked with such reactions, including coronary vasospasm and myocardial infarction. Prescribing information for dihydroergotamine cautions against its use in patients with coronary artery disease or risk factors for underlying coronary artery disease without a cardiac workup before initiation of therapy. This patient had several cardiac risk factors, but cardiac catheterization revealed no underlying coronary artery disease. Concomitant verapamil therapy for hypertension did not prevent the vasospastic effects of dihydroergotamine. The Naranjo probability scale revealed a probable adverse reaction of vasospastic angina associated with dihydroergotamine. CONCLUSIONS: Health-care professionals should be aware of the possibility for vasospastic angina in patients receiving dihydroergotamine who have no underlying coronary artery disease. Prescribing information should be closely followed. PMID- 21693701 TI - A small molecule that mimics the BB-loop in the Toll interleukin-1 (IL-1) receptor domain of MyD88 attenuates staphylococcal enterotoxin B-induced pro inflammatory cytokine production and toxicity in mice. AB - Toxic shock syndrome (TSS) is a clinical consequence of the profound amplification of host pro-inflammatory cytokine signaling that results from staphylococcal enterotoxin (SE) exposure. We recently reported that MyD88(-/-) mice were resistant to SEA or SEB toxic shock and displayed reduced levels of pro inflammatory cytokines in their serum. Here we report that SEB stimulation of total mononuclear cells up-regulated MyD88 in monocytes and T cells. Further, MyD88 gene silencing in primary human cells using siRNA prevented SEB or SEB plus lipopolysaccharide (LPS) induction of interleukin-1beta (IL-1beta) transcriptional activation, suggesting that MyD88-mediated signaling is an essential component of SEB toxicity. We synthesized small molecules that mimic the conserved BB-loop in the Toll/IL-1 receptor (TIR) domain of MyD88. In primary human cells, these mimetics attenuated SEB-induced pro-inflammatory cytokine production. SEB stimulation of primary cells with mimetic affected newly synthesized MyD88 and downstream signaling components. Furthermore, LPS-induced MyD88 signaling was likewise inhibited in a cell-based reporter assay. More importantly, administration of mimetic reduced cytokine responses and increased survivability in a murine SEB challenge model. Collectively, these results suggest that MyD88 BB-loop mimetics interfere with SEB-induced pro-inflammatory signaling and toxicity, thus offering a potential approach in the therapy of toxic shock. PMID- 21693703 TI - Cannabinoid receptor type 1 (CB1R) signaling regulates hepatic gluconeogenesis via induction of endoplasmic reticulum-bound transcription factor cAMP-responsive element-binding protein H (CREBH) in primary hepatocytes. AB - Activated cannabinoid 1 receptor (CB1R) signaling has been implicated in the development of phenotypes associated with fatty liver, insulin resistance, and impaired suppression of hepatic glucose output. Endoplasmic reticulum stress associated liver-specific transcription factor CREBH is emerging as a critical player in various hepatic metabolic pathways and regulates hepatic gluconeogenesis in diet-induced obese settings. In this study, we elucidated the critical role of CREBH in mediating CB1R signaling to regulate glucose homeostasis in primary rat and human hepatocytes. mRNA and protein levels and glucose production were analyzed in primary rat and human hepatocytes. ChIP assays were performed together with various transcriptional analyses using standard techniques. CB1R activation by 2-arachidonoylglycerol (2-AG) specifically induced CREBH gene expression via phosphorylation of the JNK signaling pathway and c-Jun binding to the AP-1 binding site in the CREBH gene promoter. 2-AG treatment significantly induced hepatic gluconeogenic gene expression and glucose production in primary hepatocytes, and we demonstrated that the CREBH binding site mutant significantly attenuated 2-AG-mediated activation of the gluconeogenic gene promoter. Endogenous knockdown of CREBH led to ablation of 2-AG-induced gluconeogenic gene expression and glucose production, and the CB1R antagonist AM251 or insulin exhibited repression of CREBH gene induction and subsequently inhibited gluconeogenesis in both rat and human primary hepatocytes. These results demonstrate a novel mechanism of action of activated CB1R signaling to induce hepatic gluconeogenesis via direct activation of CREBH, thereby contributing to a better understanding of the endocannabinoid signaling mechanism involved in regulating the hepatic glucose metabolism. PMID- 21693702 TI - Many ceramides. AB - Intensive research over the past 2 decades has implicated ceramide in the regulation of several cell responses. However, emerging evidence points to dramatic complexities in ceramide metabolism and structure that defy the prevailing unifying hypothesis on ceramide function that is based on the understanding of ceramide as a single entity. Here, we develop the concept that "ceramide" constitutes a family of closely related molecules, subject to metabolism by >28 enzymes and with >200 structurally distinct mammalian ceramides distinguished by specific structural modifications. These ceramides are synthesized in a combinatorial fashion with distinct enzymes responsible for the specific modifications. These multiple pathways of ceramide generation led to the hypothesis that individual ceramide molecular species are regulated by specific biochemical pathways in distinct subcellular compartments and execute distinct functions. In this minireview, we describe the "many ceramides" paradigm, along with the rationale, supporting evidence, and implications for our understanding of bioactive sphingolipids and approaches for unraveling these pathways. PMID- 21693704 TI - Invasion of Cryptococcus neoformans into human brain microvascular endothelial cells is mediated through the lipid rafts-endocytic pathway via the dual specificity tyrosine phosphorylation-regulated kinase 3 (DYRK3). AB - Cryptococcus neoformans is a neurotropic fungal pathogen, which provokes the onset of devastating meningoencephalitis. We used human brain microvascular endothelial cells (HBMEC) as the in vitro model to investigate how C. neoformans traverses across the blood-brain barrier. In this study, we present several lines of evidence indicating that C. neoformans invasion is mediated through the endocytic pathway via lipid rafts. Human CD44 molecules from lipid rafts can directly interact with hyaluronic acid, the C. neoformans ligand. Bikunin, which perturbs CD44 function in the lipid raft, can block C. neoformans adhesion and invasion of HBMEC. The lipid raft marker, ganglioside GM1, co-localizes with CD44 on the plasma membrane, and C. neoformans cells can adhere to the host cell in areas where GM1 is enriched. These findings suggest that C. neoformans entry takes place on the lipid rafts. Upon C. neoformans engagement, GM1 is internalized through vesicular structures to the nuclear membrane. This endocytic redistribution process is abolished by cytochalasin D, nocodazole, or anti-DYRK3 (dual specificity tyrosine-phosphorylation-regulated kinase 3) siRNA. Concomitantly, the knockdown of DYRK3 significantly reduces C. neoformans invasion across the HBMEC monolayer in vitro. Our data demonstrate that the lipid raft-dependent endocytosis process mediates C. neoformans internalization into HBMEC and that the CD44 protein of the hosts, cytoskeleton, and intracellular kinase-DYRK3 are involved in this process. PMID- 21693705 TI - Lipid droplet formation is dispensable for endoplasmic reticulum-associated degradation. AB - Proteins that fail to fold or assemble in the endoplasmic reticulum (ER) are destroyed by cytoplasmic proteasomes through a process known as ER-associated degradation. Substrates of this pathway are initially sequestered within the ER lumen and must therefore be dislocated across the ER membrane to be degraded. It has been proposed that generation of bicellar structures during lipid droplet formation may provide an "escape hatch" through which misfolded proteins, toxins, and viruses can exit the ER. We have directly tested this hypothesis by exploiting yeast strains defective in lipid droplet formation. Our data demonstrate that lipid droplet formation is dispensable for the dislocation of a plant toxin and the degradation of both soluble and integral membrane glycoproteins. PMID- 21693706 TI - Characterization of a novel sesquiterpene cyclase involved in (+)-caryolan-1-ol biosynthesis in Streptomyces griseus. AB - Most terpenoids have been isolated from plants and fungi and only a few from bacteria. However, an increasing number of genome sequences indicate that bacteria possess a variety of terpenoid cyclase genes. We characterized a sesquiterpene cyclase gene (SGR2079, named gcoA) found in Streptomyces griseus. When expressed in Streptomyces lividans, gcoA directed production of a sesquiterpene, isolated and determined to be (+)-caryolan-1-ol using spectroscopic analyses. (+)-Caryolan-1-ol was also detected in the crude cell lysate of wild-type S. griseus but not in a gcoA knockout mutant, indicating that GcoA is a genuine (+)-caryolan-1-ol synthase. Enzymatic properties were characterized using N-terminally histidine-tagged GcoA, produced in Escherichia coli. As expected, incubation of the recombinant GcoA protein with farnesyl diphosphate yielded (+)-caryolan-1-ol. However, a small amount of another sesquiterpene was also detected. This was identified as the bicyclic sesquiterpene hydrocarbon (+)-beta-caryophyllene by comparison with an authentic sample using GC-MS. Incorporation of a deuterium atom into the C-9 methylene of (+)-caryolan-1-ol in an in vitro GcoA reaction in deuterium oxide indicated that (+)-caryolan-1-ol was synthesized by a proton attack on the C-8/C-9 double bond of (+)-beta-caryophyllene. Several beta-caryophyllene synthases have been identified from plants, but these cannot synthesize caryolan-1-ol. Although caryolan-1-ol has been isolated previously from several plants, the enzyme responsible for its biosynthesis has not been identified previously. GcoA is thus the first known caryolan-1-ol synthase. Isolation of caryolan-1-ol from microorganisms is unprecedented. PMID- 21693708 TI - Involvement of the Fc gamma receptor in a chronic N-methyl-4-phenyl-1,2,3,6 tetrahydropyridine mouse model of dopaminergic loss. AB - Although there is growing evidence for a role of the innate immune response in Parkinson's disease, the nature of any humoral response in dopaminergic degeneration is uncertain. Here we report on a protracted N-methyl-4-phenyl 1,2,3,6-tetrahydropyridine model of dopaminergic death that potentially allows a more full adaptive humoral response to develop. Rag2 mutant mice that lack the full adaptive response (deficient in both T and B cells) are resistant to dopaminergic death and behavioral deficiencies in this model. These mice are resensitized after reconstitution with WT splenocytes. To more directly provide evidence for humoral/IgG involvement, we show that deficiency of Fcgamma receptors, which are critical for activation of macrophages/microglia by binding to IgGs, is also protective in this protracted model. FcgammaR-deficient mice display improved behavior and impaired microglial activation. Interestingly, however, Rag2 mutant but not FcgammaR-deficient mice are resistant to a more standard N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine paradigm where death is more rapid. Taken together, these data indicate that, provided sufficient time, the humoral arm of the adaptive immune system can play a critical functional role in modulating the microglial response to dopaminergic degeneration and suggest that this humoral component may participate in degeneration in Parkinson's disease. PMID- 21693709 TI - Exciting new clinical trials in cystic fibrosis: infants need not apply. PMID- 21693707 TI - Pivotal role for alpha1-antichymotrypsin in skin repair. AB - alpha1-Antichymotrypsin (alpha1-ACT) is a specific inhibitor of leukocyte-derived chymotrypsin-like proteases with largely unknown functions in tissue repair. By examining human and murine skin wounds, we showed that following mechanical injury the physiological repair response is associated with an acute phase response of alpha1-ACT and the mouse homologue Spi-2, respectively. In both species, attenuated alpha1-ACT/Spi-2 activity and gene expression at the local wound site was associated with severe wound healing defects. Topical application of recombinant alpha1-ACT to wounds of diabetic mice rescued the impaired healing phenotype. LC-MS analysis of alpha1-ACT cleavage fragments identified a novel cleavage site within the reactive center loop and showed that neutrophil elastase was the predominant protease involved in unusual alpha1-ACT cleavage and inactivation in nonhealing human wounds. These results reveal critical functions for locally acting alpha1-ACT in the acute phase response following skin injury, provide mechanistic insight into its function during the repair response, and raise novel perspectives for its potential therapeutic value in inflammation mediated tissue damage. PMID- 21693710 TI - Lung densitometry to assess progression of emphysema in chronic obstructive pulmonary disease: time to apply in the clinic? PMID- 21693711 TI - Susceptibility to acute lung injury after severe blunt trauma and its dependence on previous tobacco smoke exposure: does dose really matter? PMID- 21693712 TI - Complex Pseudomonas population structure in cystic fibrosis airway infections. PMID- 21693713 TI - Viruses and acute exacerbations of idiopathic pulmonary fibrosis: rest in peace? PMID- 21693714 TI - Individualized prediction of bronchopulmonary dysplasia risk: one step closer. PMID- 21693715 TI - The hand. PMID- 21693716 TI - Update in environmental and occupational medicine 2010. PMID- 21693717 TI - Update in cystic fibrosis 2010. PMID- 21693718 TI - What is the cause of the loud snoring--and what should be done? PMID- 21693719 TI - Impact of sleep-disordered breathing on coagulation: the role of COPD should be clarified. PMID- 21693720 TI - A decade of interferon-gamma release assays: quest for the holy grail to diagnose latent infection with mycobacterium tuberculosis? PMID- 21693721 TI - Biomarkers in community-acquired pneumonia: does chronic kidney disease matter? PMID- 21693722 TI - Risk factors for death after adult congenital heart surgery in pediatric hospitals. AB - BACKGROUND: Despite the central role that pediatric hospitals play in the surgical treatment of congenital heart disease, little is known about outcomes of adult congenital cardiac surgical care in pediatric hospitals. Risk factors for inpatient death, including adult congenital heart (ACH) surgery volume, are poorly described. METHODS AND RESULTS: We obtained inpatient data from 42 free standing pediatric hospitals using the Pediatric Health Information System data base 2000 to 2008 and selected ACH surgery admissions (ages 18 to 49 years). We examined admission characteristics and hospital surgery volume. Of 97 563 total (pediatric and adult) congenital heart surgery admissions, 3061 (3.1%) were ACH surgery admissions. Median adult age was 22 years and 39% were between ages 25 to 49 years. Most frequent surgical procedures were pulmonary valve replacement, secundum atrial septal defect repair, and aortic valve replacement. Adult mortality rate was 2.2% at discharge. Multivariable analyses identified the following risk factors for death: age 25 to 34 years (adjusted odds ratio [AOR], 2.1; P=0.009), age 35 to 49 years (AOR, 3.2; P=0.001), male sex (AOR, 1.8; P=0.04), government-sponsored insurance (AOR, 1.8; P=0.03), and higher surgical risk categories 4+ (AOR, 21.5; P=0.001). After adjusting for case mix, pediatric hospitals with high ACH surgery volume had reduced odds for death (AOR, 0.4; P=0.003). There was no relationship between total congenital heart surgery volume and ACH inpatient mortality. CONCLUSIONS: Older adults, male sex, government sponsored insurance, and greater surgical case complexity have the highest likelihood of in-hospital death when adult congenital surgery is performed in free-standing pediatric hospitals. After risk-adjustment, pediatric hospitals with high ACH surgery volume have the lowest inpatient mortality. PMID- 21693723 TI - Identifying patients hospitalized with heart failure at risk for unfavorable future quality of life. AB - BACKGROUND: Communicating prognosis to enable shared decision-making is strongly endorsed by heart failure (HF) guidelines. Patients are concerned with both their quantity and quality of life (QoL). To facilitate the recognition of patients at high risk for unfavorable future QoL or death, we created a simple prognostic tool to estimate this combined outcome. METHODS AND RESULTS: We identified factors associated with 6-month mortality or persistently unfavorable QoL, defined by Kansas City Cardiomyopathy Questionnaire (KCCQ) scores <45 at 1 and 24 weeks after hospital discharge, among 1458 patients from the Efficacy of Vasopressin Antagonism in HF Outcome Study with Tolvaptan (EVEREST). Within 24 weeks of discharge, 478 (32.8%) patients had died and 192 (13.2%) patients had serial KCCQ scores <45. After adjusting for 23 predischarge covariates, independent predictors of the combined end point included low admission KCCQ score, high B-type natriuretic peptide, hyponatremia, tachycardia, hypotension, absence of beta-blocker therapy, and history of diabetes mellitus and arrhythmia. A simplified predischarge HF score for subsequent death or unfavorable QoL had moderate discrimination (c-statistic 0.72). Predischarge clinical covariates were substantially different in predicting the QoL end point as compared with traditional death or rehospitalization end points. CONCLUSIONS: At the time of hospital discharge, readily available clinical characteristics are associated with HF patients at high risk for persistently unfavorable QoL or death over the next 6 months. Such information can target patients for whom aggressive treatment options (eg, devices or transplantation) and/or end-of-life discussions should be strongly considered before hospital discharge. PMID- 21693724 TI - Cost-effectiveness of drug-eluting stents versus bare metal stents in clinical practice. AB - BACKGROUND: Drug-eluting stents (DES) reduce the need for repeat target revascularization (TVR) compared with bare metal stents (BMS) but are more costly. The objective was to evaluate the cost-effectiveness of DES versus BMS. METHODS AND RESULTS: We evaluated clinical outcomes and costs of care over 3 years in 1147 undergoing BMS before the availability of DES and 1247 DES patients at Wake Forest University Baptist Medical Center from 2002 to 2005. Costs for index stenting, TVR, and clopidogrel use were assessed. The 2 groups were well matched for baseline characteristics. Index stenting costs were $1846 higher per patient for DES versus BMS ($1737 more to $1950 more). At 3 years, absolute TVR rates were 15.2 per 100 DES patients and 24.1 per 100 BMS patients, and as a result, cumulative TVR-related costs were $2065 less per patient for DES versus BMS ($3001 less to $1134 less). Including the cost of clopidogrel, the incremental cost-effectiveness ratio per TVR avoided with DES was $4731 through 1 year, $4703 through 2 years, and $6379 through 3 years. CONCLUSIONS: At 3 years, the higher index cost of DES versus BMS was completely offset by lower TVR related costs. However, because of extended clopidogrel use for DES, the incremental cost-effectiveness ratio per TVR avoided ranged from $4703 to $6379 over 3 years. These unadjusted observational findings provide support for the continued use of DES in routine practice but highlight the important impact of prolonged dual antiplatelet use on the cost-effectiveness of this technology. PMID- 21693725 TI - Prevalence of inadequate blood pressure control among veterans after acute ischemic stroke hospitalization: a retrospective cohort. AB - BACKGROUND: Reducing blood pressure (BP) after stroke reduces risk for recurrent events. Our aim was to describe hypertension care among veterans with ischemic stroke including BP control by discharge and over the 6 months after the stroke event. METHODS AND RESULTS: The Office of Quality and Performance Stroke Special Study included a systematic sample of veterans hospitalized for ischemic stroke in 2007. We examined BP control (<140/90 mm Hg) at discharge excluding those who died, enrolled in hospice, or had unknown discharge disposition (n=3640, n=3382 adjusted analysis). The second outcome was BP control (<140/90 mm Hg) within 6 months after stroke, excluding patients who died/readmitted within 30 days, were lost to follow-up, or did not have a BP recorded (n=2054, n=1915 adjusted analysis). The population was 62.7% white and 97.7% men; 46.9% were <65 years of age; and 29% and 37% had a history of cerebrovascular or cardiovascular disease, respectively. Among the 3640 stroke patients, 1573 (43%) had their last documented BP before discharge as >140/90 mm Hg. Black race (adjusted odds ratio, 0.77; 95% confidence interval, 0.65 to 0.91), diabetes (odds ratio, 0.73; 95% confidence interval, 0.62 to 0.86), and hypertension history (odds ratio, 0.51; 95% confidence interval, 0.42 to 0.63) were associated with lower odds for controlled BP at discharge. Of the 2054 stroke patients seen within 6 months from their index event, 673 (32.8%) remained uncontrolled. By 6 months after the event, neither race nor diabetes was associated with BP control, whereas history of hypertension continued to have lower odds of BP control. For each 10-point increase in systolic BP >140 mm Hg at discharge, odds of BP control within 6 months after discharge decreased by 12% (95% confidence interval [8%, 18%]). CONCLUSIONS: BP values in excess of national guidelines are common after stroke. Forty-three percent of patients were discharged with an elevated BP, and 33% remained uncontrolled by 6 months. PMID- 21693727 TI - Strides in melanoma announced: maximizing value comes next. PMID- 21693726 TI - The relationship between serum ghrelin and the risk of gastric and esophagogastric junctional adenocarcinomas. AB - BACKGROUND: Cancers of the upper gastrointestinal tract remain a substantial cause of morbidity and mortality worldwide. Ghrelin is a hormone produced in the oxyntic glands of the stomach, and under conditions of chronic inflammation and atrophy, serum ghrelin concentrations decrease. However, the relationship between ghrelin and the risk of gastric and esophagogastric junctional cancers has not been investigated. METHODS: We conducted a nested case-control study within the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study to examine the relationship between serum ghrelin concentration and the risk of gastric noncardia adenocarcinoma (GNCA) and esophagogastric junctional adenocarcinoma (EGJA). Data from 261 GNCA patients, 98 EGJA patients, and 441 control subjects were analyzed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression with adjustment for potential confounders. Lag analysis was also performed to investigate the temporal nature of the associations between baseline serum pepsinogen I and ghrelin in GNCA and EGJA patients. All statistical tests were two-sided. RESULTS: Lower concentrations of serum ghrelin were statistically significantly associated with an increased risk of both GNCA (adjusted OR = 1.75, 95% CI = 1.49 to 2.04; P < .001) and EGJA (adjusted OR = 1.56, 95% CI = 1.28 to 1.89, P < .001). A multivariable model found that the risk of both GNCA and EGJA were statistically significantly increased for those individuals in the lowest quartile of serum ghrelin levels compared with those in the highest quartile (OR of GNCA = 5.63, 95% CI = 3.16 to 10.03; OR of EGJA = 4.90, 95% CI = 2.11 to 11.35). The statistical significance of these associations remained even after restricting the analysis to those patients who developed cancer more than 10 years after baseline serum ghrelin measurements. CONCLUSION: Low baseline concentrations of serum ghrelin were associated with a statistically significant increase in the risk of GNCA and EGJA, suggesting a potential role for gastric hormones in carcinogenesis. PMID- 21693728 TI - From genome to drugs: where do we stand? PMID- 21693729 TI - ASCO 2011: broadening the horizons of cancer research. PMID- 21693731 TI - The cover. Red rose with ruby throat. PMID- 21693732 TI - A piece of my mind. Sleepless. PMID- 21693730 TI - Comprehensive field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma. AB - BACKGROUND: Although genetic studies have reported a number of loci associated with cutaneous melanoma (CM) risk, a comprehensive synopsis of genetic association studies published in the field and systematic meta-analysis for all eligible polymorphisms have not been reported. METHODS: We systematically annotated data from all genetic association studies published in the CM field (n = 145), including data from genome-wide association studies (GWAS), and performed random-effects meta-analyses across all eligible polymorphisms on the basis of four or more independent case-control datasets in the main analyses. Supplementary analyses of three available datasets derived from GWAS and GWAS replication studies were also done. Nominally statistically significant associations between polymorphisms and CM were graded for the strength of epidemiological evidence on the basis of the Human Genome Epidemiology Network Venice criteria. All statistical tests were two-sided. RESULTS: Forty-two polymorphisms across 18 independent loci evaluated in four or more datasets including candidate gene studies and available GWAS data were subjected to meta analysis. Eight loci were identified in the main meta-analyses as being associated with a risk of CM (P < .05) of which four loci showed a genome-wide statistically significant association (P < 1 * 10(-7)), including 16q24.3 (MC1R), 20q11.22 (MYH7B/PIGU/ASIP), 11q14.3 (TYR), and 5p13.2 (SLC45A2). Grading of the cumulative evidence by the Venice criteria suggested strong epidemiological credibility for all four loci with genome-wide statistical significance and one additional gene at 9p23 (TYRP1). In the supplementary meta-analyses, a locus at 9p21.3 (CDKN2A/MTAP) reached genome-wide statistical significance with CM and had strong epidemiological credibility. CONCLUSIONS: To the best of our knowledge, this is the first comprehensive field synopsis and systematic meta-analysis to identify genes associated with an increased susceptibility to CM. PMID- 21693733 TI - Group releases new guideline on options for treating painful diabetic neuropathy. PMID- 21693734 TI - Ambulatory centers match hospital safety for outpatient colonoscopy, study says. PMID- 21693735 TI - Social distancing helpful in Mexico during flu pandemic. PMID- 21693736 TI - Standard- vs high-dose clopidogrel after percutaneous coronary intervention. PMID- 21693737 TI - Standard- vs high-dose clopidogrel after percutaneous coronary intervention. PMID- 21693738 TI - Metrics for monitoring glycemic control. PMID- 21693739 TI - Pregnancy, addiction, and incarceration. PMID- 21693740 TI - Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. AB - CONTEXT: Rheumatoid arthritis (RA) and psoriasis have been linked with insulin resistance and diabetes mellitus (DM). Prior investigations suggest that systemic immunosuppressive drugs may improve insulin resistance and reduce the risk of DM. OBJECTIVE: To compare the risk of newly recorded DM among participants diagnosed with RA or psoriasis based on use of a variety of disease-modifying antirheumatic drugs (DMARDs). DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study among 121,280 patients with a diagnosis of either RA or psoriasis on at least 2 visits. The analyses were conducted in the context of 2 large health insurance programs, 1 in Canada and 1 in the United States, using administrative data. The mean follow-up was 5.8 months and began with the first prescription for a DMARD after study eligibility was met. Drug regimens were categorized into 4 mutually exclusive groups: (1) tumor necrosis factor (TNF) inhibitors with or without other DMARDs; (2) methotrexate without TNF inhibitors or hydroxychloroquine; (3) hydroxychloroquine without TNF inhibitors or methotrexate; or (4) other nonbiologic DMARDs without TNF inhibitors, methotrexate, or hydroxychloroquine (reference exposure). MAIN OUTCOME MEASURE: Newly recorded DM as evidenced by a new diagnosis of DM with use of a DM-specific medication. RESULTS: The study cohort consisted of 13,905 participants with 22,493 treatment episodes starting 1 of the categories of DMARD regimens between January 1996 and June 2008. New diabetes cases and respective incidence rates per 1000 person-years were: other nonbiologic DMARDs (55 cases among 3993 treatment episodes; rate, 50.2; 95% confidence interval [CI], 47.3-53.2); TNF inhibitors (80 cases among 4623 treatment episodes; rate, 19.7; 95% CI, 19.1-20.3); methotrexate (82 cases among 8195 treatment episodes; rate, 23.8; 95% CI, 23.0-24.6); and hydroxychloroquine (50 cases among 5682 treatment episodes; rate, 22.2; 95% CI, 21.3-23.1). The multivariate adjusted hazard ratios for DM were 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, 0.77 (95% CI, 0.53-1.13) for methotrexate, and 0.54 (95% CI, 0.36 0.80) for hydroxychloroquine compared with other nonbiologic DMARDS. CONCLUSION: Among patients with RA or psoriasis, the adjusted risk of DM was lower for individuals starting a TNF inhibitor or hydroxychloroquine compared with initiation of other nonbiologic DMARDs. PMID- 21693741 TI - Temporal trends in the prevalence of diabetic kidney disease in the United States. AB - CONTEXT: Diabetes is the leading cause of kidney disease in the developed world. Over time, the prevalence of diabetic kidney disease (DKD) may increase due to the expanding size of the diabetes population or decrease due to the implementation of diabetes therapies. OBJECTIVE: To define temporal changes in DKD prevalence in the United States. DESIGN, SETTING, AND PARTICIPANTS: Cross sectional analyses of the Third National Health and Nutrition Examination Survey (NHANES III) from 1988-1994 (N = 15,073), NHANES 1999-2004 (N = 13,045), and NHANES 2005-2008 (N = 9588). Participants with diabetes were defined by levels of hemoglobin A(1c) of 6.5% or greater, use of glucose-lowering medications, or both (n = 1431 in NHANES III; n = 1443 in NHANES 1999-2004; n = 1280 in NHANES 2005 2008). MAIN OUTCOME MEASURES: Diabetic kidney disease was defined as diabetes with albuminuria (ratio of urine albumin to creatinine >=30 mg/g), impaired glomerular filtration rate (<60 mL/min/1.73 m(2) estimated using the Chronic Kidney Disease Epidemiology Collaboration formula), or both. Prevalence of albuminuria was adjusted to estimate persistent albuminuria. RESULTS: The prevalence of DKD in the US population was 2.2% (95% confidence interval [CI], 1.8%-2.6%) in NHANES III, 2.8% (95% CI, 2.4%-3.1%) in NHANES 1999-2004, and 3.3% (95% CI, 2.8%-3.7%) in NHANES 2005-2008 (P <.001 for trend). The prevalence of DKD increased in direct proportion to the prevalence of diabetes, without a change in the prevalence of DKD among those with diabetes. Among persons with diabetes, use of glucose-lowering medications increased from 56.2% (95% CI, 52.1% 60.4%) in NHANES III to 74.2% (95% CI, 70.4%-78.0%) in NHANES 2005-2008 (P <.001); use of renin-angiotensin-aldosterone system inhibitors increased from 11.2% (95% CI, 9.0%-13.4%) to 40.6% (95% CI, 37.2%-43.9%), respectively (P <.001); the prevalence of impaired glomerular filtration rate increased from 14.9% (95% CI, 12.1%-17.8%) to 17.7% (95% CI, 15.2%-20.2%), respectively (P = .03); and the prevalence of albuminuria decreased from 27.3% (95% CI, 22.0% 32.7%) to 23.7% (95% CI, 19.3%-28.0%), respectively, but this was not statistically significant (P = .07). CONCLUSIONS: Prevalence of DKD in the United States increased from 1988 to 2008 in proportion to the prevalence of diabetes. Among persons with diabetes, prevalence of DKD was stable despite increased use of glucose-lowering medications and renin-angiotensin-aldosterone system inhibitors. PMID- 21693742 TI - Association of door-in to door-out time with reperfusion delays and outcomes among patients transferred for primary percutaneous coronary intervention. AB - CONTEXT: Patients with ST-elevation myocardial infarction (STEMI) requiring interhospital transfer for primary percutaneous coronary intervention (PCI) often have prolonged overall door-to-balloon (DTB) times from first hospital presentation to second hospital PCI. Door-in to door-out (DIDO) time, defined as the duration of time from arrival to discharge at the first or STEMI referral hospital, is a new clinical performance measure, and a DIDO time of 30 minutes or less is recommended to expedite reperfusion care. OBJECTIVE: To characterize time to reperfusion and patient outcomes associated with a DIDO time of 30 minutes or less. DESIGN, SETTING, AND PATIENTS: Retrospective cohort of 14,821 patients with STEMI transferred to 298 STEMI receiving centers for primary PCI in the ACTION Registry-Get With the Guidelines between January 2007 and March 2010. MAIN OUTCOME MEASURES: Factors associated with a DIDO time greater than 30 minutes, overall DTB times, and risk-adjusted in-hospital mortality. RESULTS: Median DIDO time was 68 minutes (interquartile range, 43-120 minutes), and only 1627 patients (11%) had DIDO times of 30 minutes or less. Significant factors associated with a DIDO time greater than 30 minutes included older age, female sex, off-hours presentation, and non-emergency medical services transport to the first hospital. Patients with a DIDO time of 30 minutes or less were significantly more likely to have an overall DTB time of 90 minutes or less compared with patients with DIDO times greater than 30 minutes (60% [95% confidence interval {CI}, 57%-62%] vs 13% [95% CI, 12%-13%]; P < .001). Among patients with DIDO times greater than 30 minutes, only 0.6% (95% CI, 0.5%-0.8%) had an absolute contraindication to fibrinolysis. Observed in-hospital mortality was significantly higher among patients with DIDO times greater than 30 minutes vs patients with DIDO times of 30 minutes or less (5.9% [95% CI, 5.5%-6.3%] vs 2.7% [95% CI, 1.9%-3.5%]; P < .001; adjusted odds ratio for in-hospital mortality, 1.56 [95% CI, 1.15-2.12]). CONCLUSION: A DIDO time of 30 minutes or less was observed in only a small proportion of patients transferred for primary PCI but was associated with shorter reperfusion delays and lower in-hospital mortality. PMID- 21693743 TI - Smoking and prostate cancer survival and recurrence. AB - CONTEXT: Studies of smoking in relation to prostate cancer mortality or recurrence in prostate cancer patients are limited, with few prostate cancer specific outcomes. OBJECTIVE: To assess the relation of cigarette smoking and smoking cessation with overall, prostate cancer-specific, and cardiovascular disease (CVD) mortality and biochemical recurrence among men with prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study of 5366 men diagnosed with prostate cancer between 1986 and 2006 in the Health Professionals Follow-Up Study. MAIN OUTCOME MEASURES: Hazard ratios (HRs) for overall, prostate cancer-specific, and CVD mortality, and biochemical recurrence, defined by an increase in prostate-specific antigen (PSA) levels. RESULTS: There were 1630 deaths, 524 (32%) due to prostate cancer and 416 (26%) to CVD, and 878 biochemical recurrences. Absolute crude rates for prostate cancer-specific death for never vs current smokers were 9.6 vs 15.3 per 1000 person-years; for all cause mortality, the corresponding rates were 27.3 and 53.0 per 1000 person years. In multivariable analysis, current vs never smokers had an increased risk of prostate cancer mortality (HR, 1.61; 95% confidence interval [CI], 1.11-2.32), as did current smokers with clinical stage T1 through T3 (HR, 1.80; 95% CI, 1.04 3.12). Current smokers also had increased risk of biochemical recurrence (HR, 1.61; 95% CI, 1.16-2.22), total mortality (HR, 2.28; 95% CI, 1.87-2.80), and CVD mortality (HR, 2.13; 95% CI, 1.39-3.26). After adjusting for clinical stage and grade (likely intermediates of the relation of smoking with prostate cancer recurrence and survival), current smokers had increased risk of prostate cancer mortality (HR, 1.38; 95% CI, 0.94-2.03), as did current smokers with clinical stage T1 through T3 (HR, 1.41; 95% CI, 0.80-2.49); they also had an increased risk of biochemical recurrence (HR, 1.47; 95% CI, 1.06-2.04). Greater number of pack-years was associated with significantly increased risk of prostate cancer mortality but not biochemical recurrence. Current smokers of 40 or more pack years vs never smokers had increased prostate cancer mortality (HR, 1.82; 95% CI, 1.03-3.20) and biochemical recurrence (HR, 1.48; 95% CI, 0.88-2.48). Compared with current smokers, those who had quit smoking for 10 or more years (HR, 0.60; 95% CI, 0.42-0.87) or who have quit for less than 10 years but smoked less than 20 pack-years (HR, 0.64; 95% CI, 0.28-1.45) had prostate cancer mortality risks similar to never smokers (HR, 0.61; 95% CI, 0.42-0.88). CONCLUSIONS: Smoking at the time of prostate cancer diagnosis is associated with increased overall and CVD mortality and prostate cancer-specific mortality and recurrence. Men who have quit for at least 10 years have prostate cancer-specific mortality risks similar to those who have never smoked. PMID- 21693744 TI - Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. AB - CONTEXT: A recent meta-analysis demonstrated that statin therapy is associated with excess risk of developing diabetes mellitus. OBJECTIVE: To investigate whether intensive-dose statin therapy is associated with increased risk of new onset diabetes compared with moderate-dose statin therapy. DATA SOURCES: We identified relevant trials in a literature search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (January 1, 1996, through March 31, 2011). Unpublished data were obtained from investigators. STUDY SELECTION: We included randomized controlled end-point trials that compared intensive-dose statin therapy with moderate-dose statin therapy and included more than 1000 participants who were followed up for more than 1 year. DATA EXTRACTION: Tabular data provided for each trial described baseline characteristics and numbers of participants developing diabetes and experiencing major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization). We calculated trial-specific odds ratios (ORs) for new-onset diabetes and major cardiovascular events and combined these using random-effects model meta-analysis. Between-study heterogeneity was assessed using the I(2) statistic. RESULTS: In 5 statin trials with 32,752 participants without diabetes at baseline, 2749 developed diabetes (1449 assigned intensive-dose therapy, 1300 assigned moderate-dose therapy, representing 2.0 additional cases in the intensive-dose group per 1000 patient-years) and 6684 experienced cardiovascular events (3134 and 3550, respectively, representing 6.5 fewer cases in the intensive-dose group per 1000 patient-years) over a weighted mean (SD) follow-up of 4.9 (1.9) years. Odds ratios were 1.12 (95% confidence interval [CI], 1.04 1.22; I(2) = 0%) for new-onset diabetes and 0.84 (95% CI, 0.75-0.94; I(2) = 74%) for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy. As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events. CONCLUSION: In a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate dose statin therapy. PMID- 21693745 TI - Vitamin D and prevention of cardiovascular disease and diabetes: why the evidence falls short. PMID- 21693746 TI - Direct-to-consumer cardiac screening and suspect risk evaluation. PMID- 21693748 TI - Physician assistants--one less doctor(ate) in the house. PMID- 21693747 TI - Health advocacy organizations and evidence-based medicine. PMID- 21693749 TI - Can treatment of chronic inflammatory diseases reduce the risk of diabetes mellitus? PMID- 21693750 TI - Onward. PMID- 21693751 TI - JAMA patient page. Diabetes. PMID- 21693752 TI - Efforts underway to curb drug shortages. PMID- 21693753 TI - Editor's Choice: StatBite drug shortages, 2001-2010. PMID- 21693754 TI - Duke scandal highlights need for genomics research criteria. PMID- 21693755 TI - AIDS-related cancers increase in Africa. PMID- 21693756 TI - Estrogen's dual nature? Studies highlight effects on breast cancer. PMID- 21693757 TI - Kill one bird with two stones: potential efficacy of BCR-ABL and autophagy inhibition in CML. AB - The introduction of imatinib in the treatment of chronic myeloid leukemia (CML) represents the most successful example of targeted therapy in human cancer. However, leukemic stem cells are insensitive to tyrosine kinase inhibitors (TKIs) and contribute to the persistence of disease by representing a reservoir of selfrenewing cells that replenish the disease after drug discontinuation. This finding has refocused the interest of scientists toward drug combinations, ie, treating with TKIs and simultaneously targeting alternative survival mechanisms. One candidate target mechanism is autophagy, a cellular recycling process that acts as a cytoprotective shield in CML cells in response to TKI-induced stress and in other cancer cells surviving in an inhospitable microenvironment. On that basis, inhibition of autophagy has now become an exciting option for combination treatment in cancer, and clinical trials have been initiated in solid and hemopoietic tumors such as CML, chronic lymphocytic leukemia, and multiple myeloma. This review describes the biology of CML and elucidates how the molecular driver BCR-ABL led to the development of TKIs. We then discuss the molecular regulation of autophagy and the potential for autophagy inhibition as the next step in our attempt to tackle the problem of CML persistence to offer a curative option. PMID- 21693758 TI - alpha4 integrin levels on mobilized peripheral blood stem cells predict rapidity of engraftment in patients receiving autologous stem cell transplantation. AB - Rapidness of leukocyte engraftment in patients receiving peripheral blood stem cell transplantation is clinically important because the risk of fatal opportunistic infections increases with time to engraftment. Adhesion receptor molecules on hematopoietic stem cells (HSCs) have been shown to modulate homing and engraftment of HSCs. Therefore, we correlated expression levels of alpha4 (CD49d) and alpha6 (CD49f) integrins in the CD34(+) HSC compartment with time to engraftment. Leukapheresis products from 103 patients were retrospectively analyzed for CD34, CD38, CD3, CD49f, and CD49d surface molecules by multiparameter flow cytometry. High expression levels of alpha4 integrin, but not alpha6 integrin on CD34(+) cells, were associated with regular engraftment of leukocytes (days 8-19), whereas low surface expression correlated with delayed recovery (> 19 days; P < .0005). We show that alpha4 integrin expression levels on HSCs in leukapheresis products predict the engraftment capacity of mobilized peripheral blood stem cells in peripheral blood stem cell transplantation patients. PMID- 21693759 TI - Plasmacytoid dendritic cells are recruited to the colorectum and contribute to immune activation during pathogenic SIV infection in rhesus macaques. AB - In SIV/HIV infection, the gastrointestinal tissue dominates as an important site because of the impact of massive mucosal CD4 depletion and immune activation induced tissue pathology. Unlike AIDS-susceptible rhesus macaques, natural hosts do not progress to AIDS and resolve immune activation earlier. Here, we examine the role of dendritic cells (DCs) in mediating immune activation and disease progression. We demonstrate that plasmacytoid DCs (pDCs) in the blood up-regulate beta7-integrin and are rapidly recruited to the colorectum after a pathogenic SIV infection in rhesus macaques. These pDCs were capable of producing proinflammatory cytokines and primed a T cytotoxic 1 response in vitro. Consistent with the up-regulation of beta7-integrin on pDCs, in vivo blockade of alpha4beta7-integrin dampened pDC recruitment to the colorectum and resulted in reduced immune activation. The up-regulation of beta7-integrin expression on pDCs in the blood also was observed in HIV-infected humans but not in chronically SIV infected sooty mangabeys that show low levels of immune activation. Our results uncover a new mechanism by which pDCs influence immune activation in colorectal tissue after pathogenic immunodeficiency virus infections. PMID- 21693760 TI - The munc13-4-rab27 complex is specifically required for tethering secretory lysosomes at the plasma membrane. AB - Cytotoxic T lymphocytes (CTLs) kill target cells through the polarized release of lytic molecules from secretory lysosomes. Loss of munc13-4 function inhibits this process and causes familial hemophagocytic lymphohistiocytosis type 3 (FHL3). munc13-4 binds rab27a, but the necessity of the complex remains enigmatic, because studies in knockout models suggest separate functions. In the present study, we describe a noncanonical rab27a-binding motif in the N-terminus of munc13-4. Point mutants in this sequence have severely impaired rab27a binding, allowing dissection of rab27a requirements in munc13-4 function. The munc13-4 rab27a complex is not needed for secretory lysosome maturation, as shown by complementation in CTLs from FHL3 patients and in a mast cell line silenced for munc13-4. In contrast, fusion of secretory lysosomes with, and content release at the plasma membrane during degranulation, strictly required the munc13-4-rab27a complex. Total internal reflection fluorescence microscopy imaging revealed that the complex corrals motile secretory lysosomes beneath the plasma membrane during degranulation and controls their docking. The propensity to stall motility of secretory lysosomes is lost in cells expressing munc13-4 point mutants that do not bind rab27. In summary, these results uncovered a mechanism for tethering secretory lysosomes to the plasma membrane that is essential for degranulation in immune cells. PMID- 21693761 TI - Agammaglobulinemia associated with BCR- B cells and enhanced expression of CD19. AB - Expression of a BCR is critical for B-cell development and survival. We have identified 4 patients with agammaglobulinemia and markedly reduced but detectable B cells in the peripheral circulation. These B cells have an unusual phenotype characterized by increased expression of CD19 but no BCR. The cells are positive for CD20, CD22, and CD38, but not for Annexin 5 or activation markers, including CD69, CD83, or CD86. EBV lines derived from these B cells lack functionally rearranged immunoglobulin heavy-chain transcripts, as shown by PCR-rapid amplification of cDNA ends (PCR-RACE). Analysis of BM from 2 of the patients showed a severe reduction in the number of pro-B cells as well as pre-B cells. Functionally rearranged heavy-chain transcripts were identified, indicating that machinery to rearrange immunoglobulin genes was intact. Flow cytometry of B lineage cells suggested accelerated acquisition of maturation markers in early B cell precursors and increased phosphorylation of signal transduction molecules. Further, expression of TdT, a molecule that is normally down-regulated by a functional pre-BCR complex, was decreased. We hypothesize that the accelerated maturation, increased expression of CD19, and lack of a BCR were due to the constitutive activation of the BCR signal transduction pathway in these patients. PMID- 21693762 TI - Partners in crime: ubiquitin-mediated degradation and autophagy. AB - Recent focus on autophagy research has led to new insights on the involvement of ubiquitin (Ub)-mediated signaling as a selectivity factor in autophagy, which is generally considered a nonselective global degradation system. Emerging reports have demonstrated active crosstalk between the Ub-dependent proteolytic system and autophagy. This article highlights recent reports describing Ub-mediated selective autophagy regulated by the Toll-like receptor 4-induced immune response. PMID- 21693763 TI - HIF-1alpha mediates tumor hypoxia to confer a perpetual mesenchymal phenotype for malignant progression. AB - Although tumor progression involves genetic and epigenetic alterations to normal cellular biology, the underlying mechanisms of these changes remain obscure. Numerous studies have shown that hypoxia-inducible factor 1alpha (HIF-1alpha) is overexpressed in many human cancers and up-regulates a host of hypoxia-responsive genes for cancer growth and survival. We recently identified an alternative mechanism of HIF-1alpha function that induces genetic alterations by suppressing DNA repair. Here, we show that long-term hypoxia, which mimics the tumor microenvironment, drives a perpetual epithelial-mesenchymal transition (EMT) through up-regulation of the zinc finger E-box binding homeobox protein ZEB2, whereas short-term hypoxia induces a reversible EMT that requires the transcription factor Twist1. Moreover, we show that the perpetual EMT driven by chronic hypoxia depends on HIF-1alpha induction of genetic alterations rather than its canonical transcriptional activator function. These mesenchymal tumor cells not only acquire tumorigenicity but also display characteristics of advanced cancers, including necrosis, aggressive invasion, and metastasis. Hence, these results reveal a mechanism by which HIF-1alpha promotes a perpetual mesenchymal phenotype, thereby advancing tumor progression. PMID- 21693764 TI - Comparative proteomic analysis identifies a role for SUMO in protein quality control. AB - The small ubiquitin-like modifiers (SUMOs) alter the functions of diverse cellular proteins by covalent posttranslational modification and thus influence many cellular functions, including gene transcription, cell cycle, and DNA repair. Although conjugation by ubiquitin and SUMO-2/3 are largely functionally and mechanistically independent from one another, both appear to increase under conditions of proteasome inhibition. To better understand the relationship between SUMO and protein degradation by the proteasome, we performed a quantitative proteomic analysis of SUMO-2 substrates after short- and long-term inhibition of the proteasome with MG132. Comparisons with changes to the SUMO-2 conjugate subproteome in response to heat stress revealed qualitative and quantitative parallels between both conditions; however, in contrast to heat stress, the MG132-triggered increase in SUMO-2 conjugation depended strictly on protein synthesis, implying that the accumulation of newly synthesized, misfolded proteins destined for degradation by the proteasome triggered the SUMO conjugation response. Furthermore, proteasomal inhibition resulted in the accumulation of conjugated forms of all SUMO paralogs in insoluble protein inclusions and in the accumulation on SUMO-2 substrates of lysine-63-linked polyubiquitin chains, which are not thought to serve as signals for proteasome mediated degradation. Together, these findings suggest multiple, proteasome independent roles for SUMOs in the cellular response to the accumulation of misfolded proteins. PMID- 21693765 TI - A novel high-throughput screening assay for discovery of molecules that increase cellular tetrahydrobiopterin. AB - Tetrahydrobiopterin (BH(4)) is an essential cofactor for the nitric oxide (NO) synthases and the aromatic amino acid hydroxylases. Insufficient BH(4) has been implicated in various cardiovascular and neurological disorders. GTP cyclohydrolase 1 (GTPCH-1) is the rate-limiting enzyme for de novo biosynthesis of BH(4). The authors have recently shown that the interaction of GTPCH-1 with GTP cyclohydrolase feedback regulatory protein (GFRP) inhibits endothelial GTPCH 1 enzyme activity, BH(4) levels, and NO production. They propose that agents that disrupt the GTPCH-1/GFRP interaction can increase cellular GTPCH-1 activity, BH(4) levels, and NO production. They developed and optimized a novel time resolved fluorescence resonance energy transfer (TR-FRET) assay to monitor the interaction of GTPCH-1 and GFRP. This assay is highly sensitive and stable and has a signal-to-background ratio (S/B) greater than 12 and a Z' factor greater than 0.8. This assay was used in an ultra-high-throughput screening (uHTS) format to screen the Library of Pharmacologically Active Compounds. Using independent protein-protein interaction and cellular activity assays, the authors identified compounds that disrupt GTPCH-1/GFRP binding and increase endothelial cell biopterin levels. Thus, this TR-FRET assay could be applied in future uHTS of additional libraries to search for molecules that increase GTPCH-1 activity and BH(4) levels. PMID- 21693766 TI - Multiplexed reporter gene assays: monitoring the cell viability and the compound kinetics on luciferase activity. AB - High-throughput screening assays with multiple readouts enable one to monitor multiple assay parameters. By capturing as much information about the underlying biology as possible, the detection of true actives can be improved. This report describes an extension to standard luciferase reporter gene assays that enables multiple parameters to be monitored from each sample. The report describes multiplexing luciferase assays with an orthogonal readout monitoring cell viability using reduction of resazurin. In addition, this technical note shows that by using the luciferin substrate in live cells, an assay time course can be recorded. This enables the identification of nonactive or unspecific compounds that act by inhibiting luciferase, as well as compounds altering gene expression or cell growth. PMID- 21693767 TI - Automated triplexed hepatocyte-based viability and CYP1A and -3A induction assays. AB - Cytochrome P450 (CYP) enzymes are key players in drug metabolism. Therefore, it is essential to understand how these enzymes can be affected by xenobiotics with regards to induction and toxicity to avoid potential drug-drug interactions. Typically, information has been gathered by combining data from multiple experiments, which is time-consuming and labor intensive, and interassay variability may lead to misinterpretation. Monitoring CYP induction and cytotoxicity by xenobiotics using an automated, multiplexed format can decrease workload and increase data confidence. Here the authors demonstrate the ability to monitor CYP1A and CYP3A4 induction, combined with a cytotoxicity measurement, from a single microplate well using cryopreserved human hepatocytes. The assay procedure was automated in a 384-well format, including cell manipulations, compound titration and transfer, and reagent dispensing, using simple robotic instrumentation. EC(50) and E(max) values were derived for multiple known CYP1A and -3A4 inducers. Induction and toxicological responses in the triplex system were validated based on literature values from conventional single-parameter assays. Validation and pharmacology data confirm that multiplexed cell-based CYP assays can simplify workload, save time and effort, and generate biologically relevant data. PMID- 21693768 TI - Clinical and molecular characterization of diffuse large B-cell lymphomas with 13q14.3 deletion. AB - BACKGROUND: Deletions at 13q14.3 are common in chronic lymphocytic leukemia and are also present in diffuse large B-cell lymphomas (DLBCL) but never in immunodeficiency-related DLBCL. To characterize DLBCL with 13q14.3 deletions, we combined genome-wide DNA profiling, gene expression and clinical data in a large DLBCL series treated with rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 days (R-CHOP21). PATIENTS AND METHODS: Affymetrix GeneChip Human Mapping 250K NspI and U133 plus 2.0 gene were used. MicroRNA (miRNA) expression was studied were by real-time PCR. Median follow-up of patients was 4.9 years. RESULTS: Deletions at 13q14.3, comprising DLEU2/MIR15A/MIR16, occurred in 22/166 (13%) cases. The deletion was wider, including also RB1, in 19/22 cases. Samples with del(13q14.3) had concomitant specific aberrations. No reduced MIR15A/MIR16 expression was observed, but 172 transcripts were significantly differential expressed. Among the deregulated genes, there were RB1 and FAS, both commonly deleted at genomic level. No differences in outcome were observed in patients treated with R-CHOP21. CONCLUSIONS: Cases with 13q14.3 deletions appear as group of DLBCL characterized by common genetic and biologic features. Deletions at 13q14.3 might contribute to DLBCL pathogenesis by two mechanisms: deregulating the cell cycle control mainly due RB1 loss and contributing to immune escape, due to FAS down-regulation. PMID- 21693769 TI - Vascular and pharmacokinetic effects of EndoTAG-1 in patients with advanced cancer and liver metastasis. AB - BACKGROUND: EndoTAG-1 (ET), a novel formulation of cationic liposomes carrying embedded paclitaxel (Taxol), shows antitumoral activity, targeting tumor endothelial cells in solid tumors. Patients with advanced metastatic cancer were evaluated investigating effects on pharmacokinetics and tumor vasculature using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and contrast enhanced ultrasound (CEUS). PATIENTS AND METHODS: The pharmacokinetic (PK) profile of ET (22 mg/m(2) i.v.) was evaluated after single and repeated doses. DCE-MRI and CEUS explored hepatic metastases before, during and after the 4-week treatment cycle. Angiogenic biomarkers were assessed. Tumor response was evaluated by modified RECIST. RESULTS: The PK profile demonstrated slight accumulation of paclitaxel after repeated doses. DCE-MRI parameters K(trans) and/or iAUC(60) showed a trend to decrease. Changes of blood flow-dependent parameters of DCE-MRI and CEUS were well correlated. Angiogenic biomarkers revealed no clear trend. ET was generally well tolerated; common toxic effects were fatigue and hypersensitivity reactions. Nine (9 of 18) patients had stable disease after the first treatment cycle. Four patients without disease progression continued treatment. CONCLUSIONS: This study including multiple pretreated patients with different metastatic cancer revealed individually distinctive hemodynamic alterations by DCE-MRI. The PK profiles of ET were similar as observed previously. PMID- 21693770 TI - Paclitaxel efficacy and toxicity in older women with metastatic breast cancer: combined analysis of CALGB 9342 and 9840. AB - BACKGROUND: Two Cancer and Leukemia Group B (CALGB) studies were utilized to determine the efficacy and tolerability of paclitaxel (Taxol) in older patients with metastatic breast cancer. PATIENTS AND METHODS: CALGB 9840 evaluated weekly paclitaxel (80 mg/m(2)) versus paclitaxel every 3 weeks (175 mg/m(2)); CALGB 9342 evaluated three doses of paclitaxel as follows: 175, 210 and 250 mg/m(2) each over 3 h every 3 weeks. Of the 1048 patients, paclitaxel was used first line in 57%. The groups: (i) <55 years (45%), (ii) 55-64 years (29%), and (iii) >=65 years (26%). RESULTS: Tumor response was also similar among age groups. First line therapy (P = 0.0001) and better performance status (PS) (P = 0.018) were significantly related to higher response. Age did not significantly relate to overall survival (OS) or progression-free survival (PFS). First-line therapy, better PS, estrogen receptor positive status and a fewer number of metastatic sites were significantly related to improved OS and PFS. The grade >=3 toxic effects that increased linearly with age were leucopenia (P = 0.0099), granulocytopenia (P = 0.022), anorexia (P = 0.028), bilirubin elevation (P = 0.0035) and neurotoxicity (P < 0.0001). Patients over 65 years receiving second line therapy had the shortest time to neurotoxicity. CONCLUSIONS: Older women with breast cancer derive similar efficacy from treatment with paclitaxel as younger women. Older women are at increased risk for specific toxic effects. PMID- 21693771 TI - Disparity between functional recovery and daily use of the upper and lower extremities during subacute stroke rehabilitation. AB - BACKGROUND: Although inpatient rehabilitation may enhance an individual's functional ability after stroke, it is not known whether these improvements are accompanied by an increase in daily use of the arms and legs. OBJECTIVES: To determine the change in daily use of the upper and lower extremities of stroke patients during rehabilitation and to compare these values with that of community dwelling older adults. METHODS: A total of 60 stroke patients underwent functional assessments and also wore 3 accelerometers for 3 consecutive weekdays on admission to rehabilitation and 3 weeks later prior to hospital discharge. The number of steps and upper-extremity activity counts were measured over the waking hours and during daily use for occupational therapy (OT) and physical therapy (PT) sessions. Healthy older adults (n = 40) also wore 3 accelerometers for 5 consecutive days. RESULTS: Stroke patients demonstrated a significant increase in mobility function, and this was accompanied by an increase in daily walking over the entire day as well as in PT. However, increases in daily walking were found predominantly in patients who were wheelchair users (and not walkers) at the time of admission. Control walking values (5202 steps) were more than 17 times that of stroke patients. Despite significant improvements in paretic hand function, no increase in daily use of the paretic or nonparetic hand was found over the entire day or in PT. CONCLUSIONS: A disparity between functional recovery and increases in daily use of the upper and lower extremities was found during inpatient stroke rehabilitation. PMID- 21693772 TI - A novel command signal for motor neuroprosthetic control. AB - BACKGROUND: Neuroprostheses can restore functions such as hand grasp or standing to individuals with spinal cord injury (SCI) using electrical stimulation to elicit movements in paralyzed muscles. Implanted neuroprostheses currently use electromyographic (EMG) activity from muscles above the lesion that remain under volitional control as a command input. Systems in development use a networked approach and will allow for restoration of multiple functions but will require additional command signals to control the system, especially in individuals with high-level tetraplegia. OBJECTIVE: The objective of this study was to investigate the feasibility of using muscles innervated below the injury level as command sources for a neuroprosthesis. Recent anatomical and physiological studies have demonstrated the presence of intact axons across the lesion, even in those diagnosed with a clinically complete SCI; hence, EMG activity may be present in muscles with no sign of movement. METHODS: Twelve participants with motor complete SCI were enrolled and EMG was recorded with surface electrodes from 8 muscles below the knee in each leg. RESULTS: Significant activity was evident in 89% of the 192 muscles studied during attempted movements of the foot and lower limb. At least 2 muscles from each participant were identified as potential command signals for a neuroprosthesis based on 2-state, threshold classification. CONCLUSIONS: Results suggest that voluntary activity is present and recordable in below lesion muscles even after clinically complete SCI. PMID- 21693773 TI - DYNLT3 is required for chromosome alignment during mouse oocyte meiotic maturation. AB - Dynein light chain, Tctex-type 3 (DYNLT3), is a member of the cytoplasmic dynein DYNLT light chain family and has been reported to have a potential role in chromosome congression in human mitosis. However, its role in mammalian meiosis is unclear. In this study, we examined its localization, expression, and functions in mouse oocyte meiosis. Immunofluorescent staining showed that DYNLT3 was restricted to the germinal vesicle and associated with kinetochores at the germinal vesicle breakdown stage, metaphase I and metaphase II. The expression level of DYNLT3 was similar at all meiotic stages. Depletion of DYNLT3 by antibody injection resulted in chromosome misalignment and decrease of the polar body extrusion rate. We further found that DYNLT3-depleted oocytes displayed kinetochore-microtubule detachments. Chromosome-spread experiments showed that depletion of DYNLT3 inhibited the metaphase-anaphase transition by preventing homologous chromosome segregation in meiosis I. Our data suggest that DYNLT3 is required for chromosome alignment and homologous chromosome segregation during mouse oocyte meiosis. PMID- 21693774 TI - Cofilin and slingshot localization in the epithelium of uterine endometrium changes during the menstrual cycle and in endometriosis. AB - Regulation of the actin cytoskeleton is essential for epithelial cell polarity and protein trafficking within human uterine epithelium. The actin-binding protein cofilin is involved in regulation of actin dynamics by promoting actin branching and cytoskeleton reorganization. Dual immunohistochemical staining of cofilin and G-actin (represented by DNAse I staining) revealed cofilin-G-actin colocalization in the apical side of luminal epithelial cells of human uterine endometrium during the proliferative phase of the menstrual cycle. Interestingly, during the secretory phase of the menstrual cycle, cofilin was only present on the basolateral side. To determine whether the disease endometriosis causes a different pattern of actin remodeling, we investigated an established baboon model of induced endometriosis. The cofilin pattern in the secretory phase of baboons with endometriosis was similar to the proliferative phase in normal animals; cofilin was observed in the apical parts of luminal and glandular epithelium. A phosphatase regulating the activity of cofilin, slingshot (SSH1), revealed a similar staining pattern within these tissues. These patterns were confirmed through quantitative image analysis. Quantification of messenger RNA (mRNA) detected upregulated SSH1 and suggested a progesterone resistance-related pattern of nuclear steroid hormone receptors, but no change in membrane progesterone receptors (mPR alpha or mPR beta) was observed in endometriosis. Our data indicate that the severe dyssynchrony during menstrual cycle phases in endometriosis is connected with improper cytoskeleton rearrangements. We suggest that cofilin-mediated actin reorganization in uterine epithelial cells might be important in preparation for blastocyst implantation; dysregulation of this reorganization may lead to decreased fertility in endometriosis. PMID- 21693775 TI - Novel therapies targeting endometriosis. AB - Endometriosis is an often painful disorder in which the endometrial glands and stroma grow outside the uterus. The disease affects women's quality of life and is a common cause of infertility. In this review, we describe promising new developments in the field based on in vitro assays and rodent models, each of which has the potential to be beneficial in the treatment of this disease. We will specifically describe the role of anti-inflammatory drugs, selective estrogen, or progesterone modulators, statins, antiangiogenic agents, and the potential for targeting stem cells as likely methods to hone in and eliminate endometriosis. The most promising of these potential therapies are currently slated for further testing in both rodent and nonhuman primate trials. PMID- 21693777 TI - Ceftriaxone preconditioning confers neuroprotection in neonatal rats through glutamate transporter 1 upregulation. AB - OBJECTIVE: This study investigated the hypothesis that ceftriaxone preconditioning ameliorates brain damage in neonatal animals through glutamate transporter 1 (GLT-1) upregulation. STUDY DESIGN: Sprague Dawley rats were pretreated with ceftriaxone, erythromycin, minocycline, or saline for 5 consecutive days starting from postnatal day 2 (P2), and GLT-1/glutamate aspartate transporter (GLAST) messenger RNA (mRNA) and protein levels were examined in the P7 brains. After ceftriaxone or saline preconditioning, the P7 rats underwent hypoxic-ischemic (H-I) procedure or sham operation. One week after the procedure (P14), hematoxylin-eosin staining, microtubule-associated protein 2 (MAP-2) immunostaining, and transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay were used to examine neuronal damage and possible neurotoxicity. RESULTS: Repeated ceftriaxone injections significantly increased GLT-1 mRNA and protein levels but not GLAST. Following such treatment and H-I procedure, the MAP-2-positive area increased and TUNEL-positive cells decreased. CONCLUSION: Antenatal ceftriaxone may help to provide neuroprotection in the immature brain and become a new prophylactic strategy to reduce neonatal encephalopathy in clinical perinatal medicine. PMID- 21693776 TI - Differential effects of low-dose endotoxin on the cerebral circulation during pregnancy. AB - It is well-known that the pregnant state is associated with increased sensitivity to endotoxin in renal and uterine circulations; however, the effects on the cerebral circulation are not known. Intravenous infusion of low-dose lipopolysaccharide ([LPS]; 1.5 MUg/kg) to pregnant Wistar rats on day 15 of pregnancy caused significantly decreased myogenic tone of posterior cerebral arteries on day 20, which was not seen in similarly treated nonpregnant rats. Pregnancy alone was associated with a 2-to 4-fold increase in inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha), and interferon gamma (IFN-gamma) messenger RNA (mRNA) in cerebral arteries compared to nonpregnant, suggesting that the cerebral circulation is in a state of inflammation during pregnancy. After LPS treatment, cerebral arteries from pregnant animals had increased iNOS and TNF-alpha compared to LPS-treated nonpregnant animals, but decreased interleukin 10 (IL-10) and IFN-gamma. These results demonstrate that pregnancy enhances sensitivity to the effects of LPS in the cerebral circulation, which may be due to an enhanced inflammatory state during pregnancy. PMID- 21693779 TI - Differential methylation of imprinted genes in growth-restricted placentas. AB - A complex network of epigenetic factors participates in regulating the monoallelic expression of a small subset of genes (~1%) in the human genome. This phenomenon goes under the definition of genomic imprinting, a parent-of-origin effect that, when altered during early embryogenesis, may influence fetal development into adulthood. Pertubations in genomic imprinting have been associated with placental and fetal growth restrictions. We analyzed the differential DNA methylation of all known imprinted genes on 10 appropriate-for gestational-age, clinically normal, placentas and 7 severe intrauterine growth restricted placentas. Samples were pooled according to the diagnosis and analyzed by methylated DNA immunoprecipitation (MeDIP) on a tiling microarray platform. The distribution of the differentially methylated regions (DMRs) identified in growth-restricted placentas showed a slight tendency toward hypermethylation. Imprinted genes not expressed in placenta showed a unique DMR profile with the fewest hyper- and hypomethylated DMRs. Promoter and CpG island DMRs were sporadic and randomly distributed. The vast majority of DMR identified (~99%) were mapped in introns, showing no common sequence features. Also, by using the more advanced array data mining softwares, no significant patterns emerged. In contrast, differential methylation showed a highly significant correlation with gene length. Overall these data suggest that differential methylation changes in growth-restricted placentas occur throughout the genomic regions, encompassing genes actively expressed in the placenta. These findings warrant caution in interpreting the significance of genes carrying clustered DMRs because the distribution of DMRs in a gene may be attributed as a function of its length rather than as a specific biological role. PMID- 21693778 TI - Expression of coagulation-related protein genes during LPS-induced preterm delivery in the pregnant mouse. AB - Preterm delivery (PTD) has been associated with inflammation along with activation of the coagulation pathway. These studies sought to characterize the expression of several coagulation pathway genes including plasminogen activator inhibitor 1 (PAI-1), tissue factor (TF), protease-activated receptor 1 (Par1), protease-activated receptor 2 (Par2), fibrinogen-like protein 2 (Fgl2), and thrombomodulin (TM) during lipopolysaccharide (LPS)-induced PTD in day 15 pregnant CD-1 mice. Western blot studies confirmed protein expression for PAI-1, Par1, Par2, Fgl2, and TM in the mouse uterus. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) confirmed increased PAI-1 messenger RNA (mRNA) in the uteri, lung, kidney, and liver tissues at 2 to 6 hours after LPS injection. In contrast, TF expression significantly decreased by 12 hours in uterine tissue; whereas, its expression was unchanged in the other maternal tissues. The uterine mRNA for Par1, Par2, Fgl2, and TM remained stable. In summary, these studies have confirmed expression of coagulation pathway genes within the pregnant uterus; some of which are modulated during LPS-induced PTD. PMID- 21693780 TI - Expression of keratinocyte growth factor in goat ovaries and its effects on preantral follicles within cultured ovarian cortex. AB - The aims of this study were to evaluate the expression of keratinocyte growth factor (KGF) in goat ovaries and to study its effects on preantral follicle survival and development. The ovaries were used for immunohistochemistry or for in vitro culture for 1 or 7 days with KGF (0, 1, 10, 50, 100, 150, or 200 ng/mL). Noncultured (fresh control) and cultured ovarian slices were processed for histological analysis and transmission electron microscopy (TEM). The results showed that after 7 days of in vitro culture, all treatments had a significant reduction in the percentage of normal follicles compared with the fresh control. After 7 days of culture, the highest KGF concentrations (150 and 200 ng/mL) induced a significant reduction in the percentage of normal follicles compared with the tissues cultured in the absence (alpha-MEM(+) alone) or presence of 1, 10, and 50 ng/mL KGF. Transmission electron microscopy confirmed follicular integrity after 7 days of culture in 1 ng/mL KGF. In addition, compared with the fresh control, the percentage of growing follicles was significantly increased in all treatments after 1 or 7 days of culture. Immunohistochemical analyses showed the expression of KGF in oocytes and granulosa cells in all follicle developmental stages as well as in thecal and stromal cells. In conclusion, this study demonstrated that, at the lowest concentration (1 ng/mL), KGF maintained the ultrastructure of goat preantral follicles cultured in vitro for up to 7 days. Furthermore, the KGF protein was widely distributed in goat ovaries, especially in ovarian follicles. PMID- 21693782 TI - Representation of surface luminance and contrast in primary visual cortex. AB - In visual perception, object identification requires both the ability to define regions of uniform luminance and zones of luminance contrast. Neural processes underlying contrast detection have been well studied, while those defining luminance remain poorly understood and controversial. Partially because stimuli comprised of uniform luminance are relatively ineffective in driving responses of cortical neurons, little effort has been made to systematically compare responses of individual neurons to both uniform luminance and contrast. Using large static uniform luminance and contrast stimuli, modulated temporally in luminance or contrast, we found a continuum of responses ranging from a few cells modulated only by luminance (luminance-only), to many cells modulated by both luminance and contrast (luminance-contrast), and to many others modulated only by contrast (contrast-only) in primary visual cortex. Moreover, luminance-contrast cells had broader orientation tuning, larger receptive field (RF) and lower spatial frequency Preference, on average, than contrast-only cells. Contrast-only cells had contrast responses more linearly correlated to the spatial structure of their RFs than luminance-contrast cells. Taken together these results suggest that luminance and contrast are represented, to some degree, by independent mechanisms that may be shaped by different classes of subcortical and/or cortical inputs. PMID- 21693781 TI - Proteomic analyses reveal an acidic prime side specificity for the astacin metalloprotease family reflected by physiological substrates. AB - Astacins are secreted and membrane-bound metalloproteases with clear associations to many important pathological and physiological processes. Yet with only a few substrates described their biological roles are enigmatic. Moreover, the lack of knowledge of astacin cleavage site specificities hampers assay and drug development. Using PICS (proteomic identification of protease cleavage site specificity) and TAILS (terminal amine isotopic labeling of substrates) degradomics approaches >3000 cleavage sites were proteomically identified for five different astacins. Such broad coverage enables family-wide determination of specificities N- and C-terminal to the scissile peptide bond. Remarkably, meprin alpha, meprin beta, and LAST_MAM proteases exhibit a strong preference for aspartate in the peptide (P)1' position because of a conserved positively charged residue in the active cleft subsite (S)1'. This unparalleled specificity has not been found for other families of extracellular proteases. Interestingly, cleavage specificity is also strongly influenced by proline in P2' or P3' leading to a rare example of subsite cooperativity. This specificity characterizes the astacins as unique contributors to extracellular proteolysis that is corroborated by known cleavage sites in procollagen I+III, VEGF (vascular endothelial growth factor)-A, IL (interleukin)-1beta, and pro-kallikrein 7. Indeed, cleavage sites in VEGF-A and pro-kallikrein 7 identified by terminal amine isotopic labeling of substrates matched those reported by Edman degradation. Moreover, the novel substrate FGF-19 was validated biochemically and shown to exhibit altered biological activity after meprin processing. PMID- 21693783 TI - Brain basis of phonological awareness for spoken language in children and its disruption in dyslexia. AB - Phonological awareness, knowledge that speech is composed of syllables and phonemes, is critical for learning to read. Phonological awareness precedes and predicts successful transition from language to literacy, and weakness in phonological awareness is a leading cause of dyslexia, but the brain basis of phonological awareness for spoken language in children is unknown. We used functional magnetic resonance imaging to identify the neural correlates of phonological awareness using an auditory word-rhyming task in children who were typical readers or who had dyslexia (ages 7-13) and a younger group of kindergarteners (ages 5-6). Typically developing children, but not children with dyslexia, recruited left dorsolateral prefrontal cortex (DLPFC) when making explicit phonological judgments. Kindergarteners, who were matched to the older children with dyslexia on standardized tests of phonological awareness, also recruited left DLPFC. Left DLPFC may play a critical role in the development of phonological awareness for spoken language critical for reading and in the etiology of dyslexia. PMID- 21693784 TI - Cortical network for gaze control in humans revealed using multimodal MRI. AB - Functional magnetic resonance imaging (fMRI) techniques allow definition of cortical nodes that are presumed to be components of large-scale distributed brain networks involved in cognitive processes. However, very few investigations examine whether such functionally defined areas are in fact structurally connected. Here, we used combined fMRI and diffusion MRI-based tractography to define the cortical network involved in saccadic eye movement control in humans. The results of this multimodal imaging approach demonstrate white matter pathways connecting the frontal eye fields and supplementary eye fields, consistent with the known connectivity of these regions in macaque monkeys. Importantly, however, these connections appeared to be more prominent in the right hemisphere of humans. In addition, there was evidence of a dorsal frontoparietal pathway connecting the frontal eye field and the inferior parietal lobe, also right hemisphere dominant, consistent with specialization of the right hemisphere for directed attention in humans. These findings demonstrate the utility and potential of using multimodal imaging techniques to define large-scale distributed brain networks, including those that demonstrate known hemispheric asymmetries in humans. PMID- 21693785 TI - Spatial and temporal bias in the mitotic origins of somatostatin- and parvalbumin expressing interneuron subgroups and the chandelier subtype in the medial ganglionic eminence. AB - GABAergic interneurons modulate cortical activity through the actions of distinct subgroups. Recent studies using interneuron transplants have shown tremendous promise as cell-based therapies for seizure disorders, Parkinson's disease, and in the study of neocortical plasticity. Previous reports identified a spatial bias for the origins of parvalbumin (PV)- and somatostatin (SST)-expressing interneuron subgroups within the medial ganglionic eminence (MGE). In the current study, the mitotic origins of these interneurons are examined by harvesting MGE cells at 2 time points and evaluating their neurochemical profiles after transplantation into neonatal mouse cortex. Although the dorsal MGE (dMGE)-SST and ventral MGE (vMGE)-PV bias were confirmed, both subgroups originate from progenitors located throughout the MGE. The dMGE bias was also found for SST subgroups that coexpress calretinin or reelin. In contrast, another major subgroup of SST interneuron, neuropeptide Y-expressing, does not appear to originate within the MGE. Finally, novel evidence is provided that a clinically important subtype of PV-expressing interneuron, the chandelier (axo-axonic) cell, is greatly enriched in transplants from the vMGE at embryonic day 15. These findings have important implications both for the study of interneuron fate determination and for studies that use interneuron precursor transplantation to alter cortical activity. PMID- 21693786 TI - Localization of endocardial ectopic activity by means of noninvasive endocardial surface current density reconstruction. AB - Localization of the source of cardiac ectopic activity has direct clinical benefits for determining the location of the corresponding ectopic focus. In this study, a recently developed current-density (CD)-based localization approach was experimentally evaluated in noninvasively localizing the origin of the cardiac ectopic activity from body-surface potential maps (BSPMs) in a well-controlled experimental setting. The cardiac ectopic activities were induced in four well controlled intact pigs by single-site pacing at various sites within the left ventricle (LV). In each pacing study, the origin of the induced ectopic activity was localized by reconstructing the CD distribution on the endocardial surface of the LV from the measured BSPMs and compared with the estimated single moving dipole (SMD) solution and precise pacing site (PS). Over the 60 analyzed beats corresponding to ten pacing sites (six for each), the mean and standard deviation of the distance between the locations of maximum CD value and the corresponding PSs were 16.9 mm and 4.6 mm, respectively. In comparison, the averaged distance between the SMD locations and the corresponding PSs was slightly larger (18.4 +/- 3.4 mm). The obtained CD distribution of activated sources extending from the stimulus site also showed high consistency with the endocardial potential maps estimated by a minimally invasive endocardial mapping system. The present experimental results suggest that the CD method is able to locate the approximate site of the origin of a cardiac ectopic activity, and that the distribution of the CD can portray the propagation of early activation of an ectopic beat. PMID- 21693787 TI - An electric field induced in the retina and brain at threshold magnetic flux density causing magnetophosphenes. AB - For magnetic field exposures at extremely low frequencies, the electrostimulatory response with the lowest threshold is the magnetophosphene, a response that corresponds to an adult exposed to a 20 Hz magnetic field of nominally 8.14 mT. In the IEEE standard C95.6 (2002), the corresponding in situ field in the retinal locus of an adult-sized ellipsoidal was calculated to be 53 mV m(-1). However, the associated dose in the retina and brain at a high level of resolution in anatomically correct human models is incompletely characterized. Furthermore, the dose maxima in tissue computed with voxel human models are prone to staircasing errors, particularly for the low-frequency dosimetry. In the analyses presented in this paper, analytical and quasi-static finite-difference time-domain (FDTD) solutions were first compared for a three-layer sphere exposed to a uniform 50 Hz magnetic field. Staircasing errors in the FDTD results were observed at the tissue interface, and were greatest at the skin-air boundary. The 99th percentile value was within 3% of the analytic maximum, depending on model resolution, and thus may be considered a close approximation of the analytic maximum. For the adult anatomical model, TARO, exposed to a uniform magnetic field, the differences in the 99th percentile value of in situ electric fields for 2 mm and 1 mm voxel models were at most several per cent. For various human models exposed at the magnetophosphene threshold at three orthogonal field orientations, the in situ electric field in the brain was between 10% and 70% greater than the analytical IEEE threshold of 53 mV m(-1), and in the retina was lower by roughly 50% for two horizontal orientations (anterior-posterior and lateral), and greater by about 15% for a vertically oriented field. Considering a reduction factor or safety factors of several folds applied to electrostimulatory thresholds, the 99th percentile dose to a tissue calculated with voxel human models may be used as an estimate of the tissue's maximum dose. PMID- 21693788 TI - Automated carotid artery intima layer regional segmentation. AB - Evaluation of the carotid artery wall is essential for the assessment of a patient's cardiovascular risk or for the diagnosis of cardiovascular pathologies. This paper presents a new, completely user-independent algorithm called carotid artery intima layer regional segmentation (CAILRS, a class of AtheroEdgeTM systems), which automatically segments the intima layer of the far wall of the carotid ultrasound artery based on mean shift classification applied to the far wall. Further, the system extracts the lumen-intima and media-adventitia borders in the far wall of the carotid artery. Our new system is characterized and validated by comparing CAILRS borders with the manual tracings carried out by experts. The new technique is also benchmarked with a semi-automatic technique based on a first-order absolute moment edge operator (FOAM) and compared to our previous edge-based automated methods such as CALEX (Molinari et al 2010 J. Ultrasound Med. 29 399-418, 2010 IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57 1112-24), CULEX (Delsanto et al 2007 IEEE Trans. Instrum. Meas. 56 1265-74, Molinari et al 2010 IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57 1112-24), CALSFOAM (Molinari et al Int. Angiol. (at press)), and CAUDLES-EF (Molinari et al J. Digit. Imaging (at press)). Our multi-institutional database consisted of 300 longitudinal B-mode carotid images. In comparison to semi-automated FOAM, CAILRS showed the IMT bias of -0.035 +/- 0.186 mm while FOAM showed -0.016 +/- 0.258 mm. Our IMT was slightly underestimated with respect to the ground truth IMT, but showed uniform behavior over the entire database. CAILRS outperformed all the four previous automated methods. The system's figure of merit was 95.6%, which was lower than that of the semi-automated method (98%), but higher than that of the other automated techniques. PMID- 21693789 TI - A practical method for depth of interaction determination in monolithic scintillator PET detectors. AB - Several new methods for determining the depth of interaction (DOI) of annihilation photons in monolithic scintillator detectors with single-sided, multi-pixel readout are investigated. The aim is to develop a DOI decoding method that allows for practical implementation in a positron emission tomography system. Specifically, calibration data, obtained with perpendicularly incident gamma photons only, are being used. Furthermore, neither detector modifications nor a priori knowledge of the light transport and/or signal variances is required. For this purpose, a clustering approach is utilized in combination with different parameters correlated with the DOI, such as the degree of similarity to a set of reference light distributions, the measured intensity on the sensor pixel(s) closest to the interaction position and the peak intensity of the measured light distribution. The proposed methods were tested experimentally on a detector comprised of a 20 mm * 20 mm * 12 mm polished LYSO:Ce crystal coupled to a 4 * 4 multi-anode photomultiplier. The method based on the linearly interpolated measured intensities on the sensor pixels closest to the estimated (x, y)-coordinate outperformed the other methods, yielding DOI resolutions between ~1 and ~4.5 mm FWHM depending on the DOI, the (x, y) resolution and the amount of reference data used. PMID- 21693790 TI - The use of a realistic VMAT delivery emulator to optimize dynamic machine parameters for improved treatment efficiency. AB - The delivery of volumetric modulated arc therapy (VMAT) requires the simultaneous movement of the linear accelerator gantry, multi-leaf collimators and jaws while the dose rate is varied. In this study, a VMAT delivery emulator was developed to accurately predict the characteristics of a given treatment plan, incorporating realistic parameters for gantry inertia and the variation in leaf speed with respect to gravity. The emulator was used to assess the impact of dynamic machine parameters on the delivery efficiency, using a set of prostate and head and neck VMAT plans. Initially, assuming a VMAT system with fixed dose rate bins, the allowable leaf and jaw speeds were increased and a significant improvement in treatment time and average dose rate was observed. The software was then adapted to simulate a VMAT system with continuously varying dose rate, and the increase in delivery efficiency was quantified, along with the impact of an increased leaf and jaw speed. Finally, a set of optimal dynamic machine parameters was derived assuming an idealized scenario in which the treatment is delivered in a single arc at constant maximum gantry speed. PMID- 21693791 TI - Interference between PET and MRI sub-systems in a silicon-photomultiplier-based PET/MRI system. AB - The silicon-photomultiplier (Si-PM) is a promising photodetector, especially for integrated PET/MRI systems, due to its small size, high gain, and low sensitivity to static magnetic fields. The major problem using a Si-PM-based PET system within the MRI system is the interference between the PET and MRI units. We measured the interference by combining a Si-PM-based PET system with a permanent magnet MRI system. When the RF signal-induced pulse height exceeded the lower energy threshold level of the PET system, interference between the Si-PM-based PET system and MRI system was detected. The prompt as well as the delayed coincidence count rates of the Si-PM-based PET system increased significantly. These noise counts produced severe artifacts on the reconstructed images of the Si-PM-based PET system. In terms of the effect of the Si-PM-based PET system on the MRI system, although no susceptibility artifact was observed on the MR images, electronic noise from the PET detector ring was detected by the RF coil and reduced the signal-to-noise ratio (S/N) of the MR images. The S/N degradation of the MR images was reduced when the distance between the RF coil and the Si-PM based PET system was increased. We conclude that reducing the interference between the PET and MRI systems is essential for achieving the optimum performance of integrated Si-PM PET/MRI systems. PMID- 21693792 TI - SPECT using asymmetric pinholes with truncated projections. AB - Tomographic systems employing truncated projections have been developed for parallel and fan beam collimation and for cone beam CT but the idea has not been extensively explored in pinhole single photon emission computed tomography (SPECT). In this paper, we explore the sampling requirements and system performance of SPECT systems with asymmetric pinhole collimators and truncated projections. We demonstrate that complete 3D sampling can be achieved by using multiple detectors with truncated asymmetric pinholes, offset axially from each other, and a spiral orbit. The use of truncated projections can be exploited in the design of pinhole SPECT systems by moving the pinholes closer to the subject, resulting in increased sensitivity and improved spatial resolution. Truncated and untruncated pinhole systems were evaluated using the contrast-to-noise ratio (CNR) calculated from the linearized local impulse response as a figure of merit. The CNR for the truncated pinhole system was up to 60% greater than that for the untruncated system at matched resolution for a source voxel near the centre of a uniform phantom and 30% greater at the edge. We conclude that an object can be reconstructed from asymmetric pinholes with truncated projections, which leads to potentially important design considerations and applications in single- and multi pinhole SPECT. PMID- 21693793 TI - Monte Carlo modeling and optimization of contrast-enhanced radiotherapy of brain tumors. AB - Contrast-enhanced radiotherapy involves the use of a kilovoltage x-ray beam to impart a tumoricidal dose to a target into which a radiological contrast agent has previously been loaded in order to increase the x-ray absorption efficiency. In this treatment modality the selection of the proper x-ray spectrum is important since at the energy range of interest the penetration ability of the x ray beam is limited. For the treatment of brain tumors, the situation is further complicated by the presence of the skull, which also absorbs kilovoltage x-ray in a very efficient manner. In this work, using Monte Carlo simulation, a realistic patient model and the Cimmino algorithm, several irradiation techniques and x-ray spectra are evaluated for two possible clinical scenarios with respect to the location of the target, these being a tumor located at the center of the head and at a position close to the surface of the head. It will be shown that x-ray spectra, such as those produced by a conventional x-ray generator, are capable of producing absorbed dose distributions with excellent uniformity in the target as well as dose differential of at least 20% of the prescribed tumor dose between this and the surrounding brain tissue, when the tumor is located at the center of the head. However, for tumors with a lateral displacement from the center and close to the skull, while the absorbed dose distribution in the target is also quite uniform and the dose to the surrounding brain tissue is within an acceptable range, hot spots in the skull arise which are above what is considered a safe limit. A comparison with previously reported results using mono-energetic x-ray beams such as those produced by a radiation synchrotron is also presented and it is shown that the absorbed dose distributions rendered by this type of beam are very similar to those obtained with a conventional x-ray beam. PMID- 21693794 TI - Design, implementation and testing of an implantable impedance-based feedback controlled neural gastric stimulator. AB - Functional neural gastrointestinal electrical stimulation (NGES) is a methodology of gastric electrical stimulation that can be applied as a possible treatment for disorders such as obesity and gastroparesis. NGES is capable of generating strong lumen-occluding local contractions that can produce retrograde or antegrade movement of gastric content. A feedback-controlled implantable NGES system has been designed, implemented and tested both in laboratory conditions and in an acute animal setting. The feedback system, based on gastric tissue impedance change, is aimed at reducing battery energy requirements and managing the phenomenon of gastric tissue accommodation. Acute animal testing was undertaken in four mongrel dogs (2 M, 2 F, weight 25.53 +/- 7.3 kg) that underwent subserosal two-channel electrode implantation. Three force transducers sutured serosally along the gastric axis and a wireless signal acquisition system were utilized to record stimulation-generated contractions and tissue impedance variations respectively. Mechanically induced contractions in the stomach were utilized to indirectly generate a tissue impedance change that was detected by the feedback system. Results showed that increasing or decreasing impedance changes were detected by the implantable stimulator and that therapy can be triggered as a result. The implantable feedback system brings NGES one step closer to long term treatment of burdening gastric motility disorders in humans. PMID- 21693795 TI - Multivariate classification of systemic vascular resistance using photoplethysmography. AB - Systemic vascular resistance (SVR) classification is useful for the diagnosis and prognosis of critical pathophysiological conditions, with the ability to identify patients with abnormally high or low SVR of immense clinical value. In this study, a supervised classifier, based on Bayes' rule, is employed to classify a heterogeneous group of intensive care unit patients (N = 48) as being below (SVR < 900 dyn s cm(-5)), within (900 ? SVR ? 1200 dyn s cm(-5)) or above (SVR > 1200 dyn s cm(-5)) the clinically accepted range for normal SVR. Features derived from the finger photoplethysmogram (PPG) waveform and other routine cardiovascular measurements (heart rate and mean arterial pressure) were used as inputs to the classifier. In the construction of the classifier model, two techniques were used to approximate the class conditional probability densities--a single Gaussian distribution model (also known as discriminant analysis) and a non-parametric model using the Parzen window kernel density estimation method. An exhaustive feature search was performed to select a feature subset that maximized the performance indicator, Cohen's kappa coefficient (kappa). The Gaussian model with multiple features achieved the best overall kappa coefficient (kappa = 0.57), although the results from the non-parametric model were comparable (kappa = 0.51). The optimum subset in the Gaussian model consisted of PPG waveform variability features, including the low-frequency to high-frequency ratio (LF/HF) and the normalized mid-frequency power (MF(NU)), in addition to the PPG pulse wave features, such as pulse width, peak-to-notch time, reflection index, and notch time ratio. The classifier performed particularly well in discriminating low SVR, with a sensitivity of 85%, specificity of 86%, positive predictive value of 88% and a negative predictive value of 82%. The results highlight the feasibility of deploying a multivariate statistical approach of SVR classification in the clinical setting, simply using a non-invasive and easy-to measure PPG waveform signal. PMID- 21693796 TI - Cycling cadence affects heart rate variability. AB - The purpose of this study was to examine the effect different cycling cadences have on heart rate variability (HRV) when exercising at constant power outputs. Sixteen males had ECG and respiratory measurements recorded at rest and during 8, 10 min periods of cycling at four different cadences (40, 60, 80 and 100 revs min(-1)) and two power outputs (0 W (unloaded) and 100 W (loaded)). The cycling periods were performed following a Latin square design. Spectral analyses of R-R intervals by fast Fourier transforms were used to quantify absolute frequency domain HRV indices (ms(2)) during the final 5 min of each bout, which were then log transformed using the natural logarithm (Ln). HRV indices of high frequency (HF) power were reduced when cadence was increased (during unloaded cycling (0 W) log transformed HF power decreased from a mean [SD] of 6.3 [1.4] Ln ms(2) at 40 revs min(-1) to 3.9 [1.3] Ln ms(2) at 100 revs min(-1)). During loaded cycling (at 100 W), the low to high frequency (LF:HF) ratio formed a 'J' shaped curve as cadence increased from 40 revs min(-1) (1.4 [0.4]) to 100 revs min(-1) (1.9 [0.7]), but dipped below the 40 revs min(-1) values during the 60 revs min(-1) 1.1 (0.3) and 80 revs min(-1) 1.2 (0.6) cadence conditions. Cardiac frequency (f(C)) and ventilatory variables were strongly correlated with frequency domain HRV indices (r = -0.80 to -0.95). It is concluded that HRV indices are influenced by both cycling cadence and power output; this is mediated by the f(C) and ventilatory changes that occur as cadence or exercise intensity is increased. Consequently, if HRV is assessed during exercise, both power output/exercise intensity and cadence should be standardized. PMID- 21693797 TI - Visualization of spin dynamics in single nanosized magnetic elements. AB - The design of future spintronic devices requires a quantitative understanding of the microscopic linear and nonlinear spin relaxation processes governing the magnetization reversal in nanometer-scale ferromagnetic systems. Ferromagnetic resonance is the method of choice for a quantitative analysis of relaxation rates, magnetic anisotropy and susceptibility in a single experiment. The approach offers the possibility of coherent control and manipulation of nanoscaled structures by microwave irradiation. Here, we analyze the different excitation modes in a single nanometer-sized ferromagnetic stripe. Measurements are performed using a microresonator set-up which offers a sensitivity to quantitatively analyze the dynamic and static magnetic properties of single nanomagnets with volumes of (100 nm)(3). Uniform as well as non-uniform volume modes of the spin wave excitation spectrum are identified and found to be in excellent agreement with the results of micromagnetic simulations which allow the visualization of the spatial distribution of these modes in the nanostructures. PMID- 21693798 TI - PTCDA on Cu(111) partially covered with NaCl. AB - The organic molecule 3,4,9,10-perylene-tetracarboxylic dianhydride (PTCDA) was studied by means of scanning tunneling microscopy (STM) on thin insulating NaCl films grown on a Cu(111) single crystal. The deposition of approximately two monolayers (ML) of sodium chloride onto a Cu(111) substrate at a sample temperature of about 350 K causes a rather rough growth of (100)-oriented NaCl islands up to a local height of 4 ML. For submonolayer coverages (0.1 and 0.4 ML) of PTCDA on a Cu(111) surface partly covered with NaCl, two different rod structures of PTCDA were found on the copper surface, which are in contrast to previously published data for PTCDA on Cu(111) showing a herringbone-like arrangement. These findings can be explained by the formation of a Na(x)-PTCDA complex. On NaCl covered areas, single PTCDA molecules adsorb at vacancies of [010] and [001] oriented steps of the NaCl(100) islands. In this case, the electrostatic forces between the polar step edges and the PTCDA molecules are dominant. The terraces of the alkali halide surface are free of PTCDA molecules. PMID- 21693799 TI - Macro- and micro-strain in GaN nanowires on Si(111). AB - We analyze the strain state of GaN nanowire ensembles by x-ray diffraction. The nanowires are grown by molecular beam epitaxy on a Si(111) substrate in a self organized manner. On a macroscopic scale, the nanowires are found to be free of strain. However, coalescence of the nanowires results in micro-strain with a magnitude from +/- (0.015)% to +/- (0.03)%. This micro-strain contributes to the linewidth observed in low-temperature photoluminescence spectra. PMID- 21693800 TI - Effect of hydrophilicity of carbon nanotube arrays on the release rate and activity of recombinant human bone morphogenetic protein-2. AB - Novel nanostructures such as vertically aligned carbon nanotube (CNT) arrays have received increasing interest as drug delivery carriers. In the present study, two CNT arrays with extreme surface wettabilities are fabricated and their effects on the release of recombinant human bone morphogenetic protein-2 (rhBMP-2) are investigated. It is found that the superhydrophilic arrays retained a larger amount of rhBMP-2 than the superhydrophobic ones. Further use of a poloxamer diffusion layer delayed the initial burst and resulted in a greater total amount of rhBMP-2 released from both surfaces. In addition, rhBMP-2 bound to the superhydrophilic CNT arrays remained bioactive while they denatured on the superhydrophobic surfaces. These results are related to the combined effects of rhBMP-2 molecules interacting with poloxamer and the surface, which could be essential in the development of advanced carriers with tailored surface functionalities. PMID- 21693801 TI - A sustained release formulation of chitosan modified PLCL:poloxamer blend nanoparticles loaded with optical agent for animal imaging. AB - The objective of this study was to develop optical imaging agent loaded biodegradable nanoparticles with indocynanine green (ICG) using chitosan modified poly(L-lactide-co-epsilon-caprolactone) (PLCL):poloxamer (Pluronic F68) blended polymer. Nanoparticles were formulated with an emulsification solvent diffusion technique using PLCL and poloxamer as blend-polymers. Polyvinyl alcohol (PVA) and chitosan were used as stabilizers. The particle size, shape and zeta potential of the formulated nanoparticles and the release kinetics of ICG from these nanoparticles were determined. Further, biodistribution of these nanoparticles was studied in mice at various time points until 24 h following intravenous administration, using a non-invasive imaging system. The average particle size of the nanoparticles was found to be 146 +/- 3.7 to 260 +/- 4.5 nm. The zeta potential progressively increased from - 41.6 to + 25.3 mV with increasing amounts of chitosan. Particle size and shape of the nanoparticles were studied using transmission electron microscopy (TEM) which revealed the particles to be smooth and spherical in shape. These nanoparticles were efficiently delivered to the cytoplasm of the cells, as observed in prostate and breast cancer cells using confocal laser scanning microscopy. In vitro release studies indicated sustained release of ICG from the nanoparticles over a period of seven days. Nanoparticle distribution results in mice showing improved uptake and accumulation with chitosan modified nanoparticles in various organs and slower clearance at different time points over a 24 h period as compared to unmodified nanoparticles. The successful formulation of such cationically modified nanoparticles for encapsulating optical agents may lead to a potential deep tissue imaging technique for tumor detection, diagnosis and therapy. PMID- 21693802 TI - A new REBO potential based atomistic structural model for graphene sheets. AB - A new atomistic structural model is developed here for graphene sheets based on the stiffnesses from the REBO potential. Using this model, the flexural vibration natural frequencies and buckling loads of rectangular single-layer graphene sheets of different sizes, chiralities and boundary conditions are calculated. The newly developed atomistic structural model is verified by comparing the calculated fundamental natural frequencies for small-sized graphene sheets with those obtained from ab initio density functional theory (DFT) frequency analysis. The vibration and buckling analysis results are also compared with those of an earlier atomistic structural model based on the AMBER potential as well as the equivalent continuum model for graphene sheets. Through this study, it is observed that graphene sheets display very slight anisotropic characteristics in flexural vibration and buckling. Also, it is shown that the atomistic structural model cannot be replaced by a classical equivalent continuum model such as a plate model. Most significantly, we verify that the new atomistic structural model based on the REBO potential predicts more accurate natural frequencies and buckling loads for graphene sheets, which are considerably lower than those predicted by the earlier atomistic structural model based on the AMBER potential. PMID- 21693803 TI - Mapping leakage currents in a nanostructure fabricated via local anodic oxidation. AB - The functionality of nanostructures fabricated via local anodic oxidation is limited by undesired leakage currents. We use low-temperature scanning gate microscopy to pin down the spatial position where leakage currents are most likely to occur. We show that leakage currents do not flow homogeneously along the complete barrier but at distinct weak points such as crossings of two oxide lines. These findings can be used to improve the design of such nanostructures. PMID- 21693804 TI - Impact of agglomeration on the relaxometric properties of paramagnetic ultra small gadolinium oxide nanoparticles. AB - Ultra-small gadolinium oxide nanoparticles (US-Gd(2)O(3)) are used to provide 'positive' contrast effects in magnetic resonance imaging (MRI), and are being considered for molecular and cellular imaging applications. However, these nanoparticles can aggregate over time in aqueous medium, as well as when internalized into cells. This study is aimed at measuring in vitro, in aqueous medium, the impact of aggregation on the relaxometric properties of paramagnetic US-Gd(2)O(3) particles. First, the nanoparticle core size as well as aggregation behaviour was assessed by HRTEM. DLS (hydrodynamic diameter) was used to measure the hydrodynamic diameter of nanoparticles and nanoaggregates. The relaxometric properties were measured by NMRD profiling, as well as with (1)H NMR relaxometers. Then, the positive contrast enhancement effect was assessed by using magnetic resonance scanners (at 1.5 and 7 T). At every magnetic field, the longitudinal relaxivity (r(1)) decreased upon agglomeration, while remaining high enough to provide positive contrast. On the other hand, the transverse relaxivity (r(2)) slightly decreased at 0.47 and 1.41 T, but it was enhanced at higher fields (7 and 11.7 T) upon agglomeration. All NMRD profiles revealed a characteristic relaxivity peak in the range 60-100 MHz, suggesting the possibility to use US-Gd(2)O(3) as an efficient 'positive-T(1)' contrast agent at clinical magnetic fields (1-3 T), in spite of aggregation. PMID- 21693805 TI - Heterostructure terahertz devices. AB - The terahertz (THz) range of frequencies is borderline between microwave electronics and photonics. It corresponds to the frequency bands of molecular and lattice vibrations in gases, fluids, and solids. The importance of the THz range is in part due to numerous potential and emerging applications which include imaging and characterization, detection of hazardous substances, environmental monitoring, radio astronomy, covert inter-satellite communications, as well as biological and medical applications. During the last decades marked progress has been achieved in the development, fabrication, and practical implementation of THz devices and systems. This is primarily owing to the utilization of gaseous and free electron lasers and frequency converters using nonlinear optical phenomena as sources of THz radiation. However, such devices and hence the systems based on them are fairly cumbersome. This continuously stimulates an extensive search for new compact and efficient THz sources based on semiconductor heterostructures. Despite tremendous efforts lasting several decades, the so called THz gap unbridged by semiconductor heterostructure electron and optoelectron devices still exists providing appropriate levels of power of the generated THz radiation. The invention and realization of quantum cascade lasers made of multiple quantum-well heterostructures already resulted in the partial solution of the problem in question, namely, in the successful coverage of the high-frequency portion of the THz gap (2-3 THz and higher). Further advancement to lower frequencies meets, perhaps, fundamental difficulties. All this necessitates further extensive theoretical and experimental studies of more or less traditional and novel semiconductor heterostructures as a basis for sources of THz radiation. This special issue includes 11 excellent original papers submitted by several research teams representing 14 institutions in Europe, America, and Asia. Several device concepts which appear to be feasible for the realization of novel THz devices are put forward and discussed in this collection of experimental and theoretical papers. The issue starts with a paper by Akis et al which deals with a theoretical study of the operation of high electron mobility transistors at THz frequencies. For this, the authors use the numerical simulations using a full-band, cellular Monte Carlo transport model coupled to a full Poisson equation solver. The next three papers by Reklaitis, Balocco et al , and Mikhailov and Zieglel are devoted to considering new ideas related to frequency multiplication which can lead to the up-conversion of ac signals to THz frequencies. For this purpose, different concepts of the devices based on nontrivial heterostructures and materials are proposed and studied. The paper by Knap et al provides an overview of the authors experimental results on the plasma effects infield effect transistors. These effects can be used for the resonant detection of THz radiation and its emission. The observed THz emission from more complex device structures, namely, dual grating gate heterostrucures, which is attributed to the self-excitation of plasma waves, is discussed by Otsuji and his co-workers. The following two papers (by Ryzhii et al and Popov et al) deal with the development of device models and using the one which could explain the results of experimental observations described in the paper by Otsuji et al . In both these papers, the mechanisms of plasma wave instability in spatially periodic heterostructures are analyzed. In the paper by Starikov and his colleagues, an idea to utilize the transit-time resonance assisted by optical phonon emissionis revived and revisited. As demonstrated, this mechanism in the electron system in nitride-made heterostructures can lead to negative dynamic conductivity in the THz range of frequencies and, hence, be used for the generation of THz radiation. In the paper by Millithaler et al, Monte Carlo simulations are used to study the voltage fluctuationsaffected by the plasma oscillations in two-terminal heterostructures with an n-type InGaAs channel.Finally, the paper by Liu {?it et al} is devoted to the concept of quantum cascade THz lasers using resonant tunneling in quantum dot systems instead of the standard multiple quantum well heterostructures.I would like to express my deep gratitude to all of the authors for having submitted high-quality papers. I am confident that this special issue will substantially promote further progress in THz technology. PMID- 21693806 TI - Interaction between the chain and ladder subsystems in (Ca,Sr,La)(14)Cu(24)O(41) compounds. AB - We investigate the influence of structural modulations on the electronic properties of incommensurate (Ca,Sr,La)(14)Cu(24)O(41) compounds by band structure calculations based on density functional theory and the local density approximation (LDA). Using a supercell approach with ten CuO(2) chain and seven Cu(2)O(3) ladder segments, we take into account the major effects of the structural incommensurability. We find that the LDA electronic states show very little response to these modulations. The coupling between the electronic and structural degrees of freedom, hence, can be well described in terms of two independent subsystems. The incommensurate charge density waves (CDWs) in the chains and the ladders are formed independently of each other. PMID- 21693807 TI - Doping poly[2-methoxy-5-(2'-ethylhexyloxy)-1,4-phenylenevinylene] with PbSe nanoparticles or fullerenes. AB - The positions of the molecular orbitals of the conjugated semiconducting polymer, poly[2-methoxy-5-(2'-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV), relative to the Fermi level, shift when lead selenide (PbSe) quantum dots or the fullerene based molecule [(6)]-1-(3-(methoxycarbonyl)propyl)-[(5)]-1-phenyl-[5,6]-C61, known as PCBM, are dispersed in the polymer host. This is evident from the consistent shifts of occupied molecular orbitals and the valence band edge to greater binding energies and a decrease in density of states near the Fermi level, as probed by photoemission. In the case of PbSe nanocrystal quantum dots, far smaller binding energy shifts were observed. This behavior seems more characteristic of a charge donor, though PbSe and PCBM should act as charge acceptors. In the case of both dopants, what doping does exist occurs only with small concentrations (<10%). MEH-PPV doped with a large-Z semiconducting material, such as PbSe nanocrystal quantum dots, is a candidate for use as a good gamma radiation detector. PMID- 21693808 TI - Magnetoresistance of nanoscale molecular devices based on Aharonov-Bohm interferometry. AB - Control of conductance in molecular junctions is of key importance in the growing field of molecular electronics. The current in these junctions is often controlled by an electric gate designed to shift conductance peaks into the low bias regime. Magnetic fields, on the other hand, have rarely been used due to the small magnetic flux captured by molecular conductors (an exception is the Kondo effect in single-molecule transistors). This is in contrast to a related field, electronic transport through mesoscopic devices, where considerable activity with magnetic fields has led to a rich description of transport. The scarcity of experimental activity is due to the belief that significant magnetic response is obtained only when the magnetic flux is of the order of the quantum flux, while attaining such a flux for molecular and nanoscale devices requires unrealistic magnetic fields. Here we review recent theoretical work regarding the essential physical requirements necessary for the construction of nanometer-scale magnetoresistance devices based on an Aharonov-Bohm molecular interferometer. We show that control of the conductance properties using small fractions of a magnetic flux can be achieved by carefully adjusting the lifetime of the conducting electrons through a pre-selected single state that is well separated from other states due to quantum confinement effects. Using a simple analytical model and more elaborate atomistic calculations we demonstrate that magnetic fields which give rise to a magnetic flux comparable to 10(-3) of the quantum flux can be used to switch a class of different molecular and nanometer rings, ranging from quantum corrals, carbon nanotubes and even a molecular ring composed of polyconjugated aromatic materials. The unique characteristics of the magnetic field as a gate is further discussed and demonstrated in two different directions. First, a three-terminal molecular router devices that can function as a parallel logic gate, processing two logic operations simultaneously, is presented. Second, the role of inelastic effects arising from electron-phonon couplings on the magnetoresistance properties is analyzed. We show that a remarkable difference between electric and magnetic gating is also revealed when inelastic effects become significant. The inelastic broadening of response curves to electric gates is replaced by a narrowing of magnetoconductance peaks, thereby enhancing the sensitivity of the device. PMID- 21693809 TI - Full-band cellular Monte Carlo simulations of terahertz high electron mobility transistors. AB - High electron mobility transistors (HEMTs) have become important for high frequency and low noise applications. There are devices now operating with a cutoff frequency, f(T), of several 100 GHz. Through simulation, we have been investigating how these frequencies may be pushed even higher, and have found that it may be possible to achieve an f(T) of over 3 THz. For this, we have used a full-band, cellular Monte Carlo transport program, coupled to a full Poisson solver, to study a variety of InAs-rich, InGaAs pseudomorphic HEMTs and their response at high frequency, concentrating on devices with a structure (from the substrate) InP/InAlAs/InGaAs/InAlAs/InGaAs, with the quantum well composed of In(0.75)Ga(0.25)As. We have studied gate lengths over the range 10-70 nm and various source-drain spacings. The performance of scaled devices has been evaluated to determine the ultimate frequency limit. Here, the importance of the effective gate length has been evaluated from the properties internal to the device. PMID- 21693810 TI - Terahertz-frequency InN/GaN heterostructure-barrier varactor diodes. AB - Frequency multipliers based on the single-barrier and double-barrier InN/GaN heterostructure varactor diodes are suggested. The DC and large-signal AC vertical electron transport in the InN/GaN diodes are investigated by ensemble Monte Carlo simulations. It is found that InN/GaN heterostructure-barrier varactor diodes are able to operate as efficient frequency multipliers in the frequency range up to 1 THz. PMID- 21693811 TI - THz operation of asymmetric-nanochannel devices. AB - The THz spectrum lies between microwaves and the mid-infrared, a region that remains largely unexplored mainly due to the bottleneck issue of lacking compact, solid state, emitters and detectors. Here, we report on a novel asymmetric nanochannel device, known as the self-switching device, which can operate at frequencies up to 2.5 THz for temperature up to 150 K. This is, to our knowledge, not only the simplest diode but also the quickest acting electronic nanodevice reported to date. The radiation was generated by the free electron laser FELIX (Netherlands). The dependences of the device efficiency as a function of the electric bias, radiation intensity, radiation frequency and temperature are reported. PMID- 21693812 TI - Nonlinear electromagnetic response of graphene: frequency multiplication and the self-consistent-field effects. AB - Graphene is a recently discovered carbon-based material with unique physical properties. This is a monolayer of graphite, and the two-dimensional electrons and holes in it are described by the effective Dirac equation with a vanishing effective mass. As a consequence, the electromagnetic response of graphene is predicted to be strongly nonlinear. We develop a quasi-classical kinetic theory of the nonlinear electromagnetic response of graphene, taking into account the self-consistent-field effects. The response of the system to both harmonic and pulse excitation is considered. The frequency multiplication effect, resulting from the nonlinearity of the electromagnetic response, is studied under realistic experimental conditions. The frequency upconversion efficiency is analyzed as a function of the applied electric field and parameters of the samples. Possible applications of graphene in terahertz electronics are discussed. PMID- 21693813 TI - Plasma wave oscillations in nanometer field effect transistors for terahertz detection and emission. AB - The channel of a field effect transistor can act as a resonator for plasma waves propagating in a two-dimensional electron gas. The plasma frequency increases with reduction of the channel length and can reach the terahertz (THz) range for nanometer size transistors. Recent experimental results show these transistors can be potential candidates for a new class of THz detectors and emitters. This work gives an overview of our recent relevant experimental results. We also outline unresolved problems and questions concerning THz detection and emission by nanometer transistors. PMID- 21693814 TI - Emission of terahertz radiation from dual grating gate plasmon-resonant emitters fabricated with InGaP/InGaAs/GaAs material systems. AB - This paper reviews recent advances in our original 2D-plasmon-resonant terahertz emitters. The structure is based on a high-electron-mobility transistor and featured with doubly interdigitated grating gates. The dual grating gates can alternately modulate the 2D electron densities to periodically distribute the plasmonic cavities along the channel, acting as an antenna. The device can emit broadband terahertz radiation even at room temperature from self-oscillating 2D plasmons under the DC-biased conditions. When the device is subjected to laser illumination, photo-generated carriers stimulate the plasma oscillation, resulting in enhancement of the emission. The first sample was fabricated with standard GaAs-based heterostructure material systems, achieving room temperature terahertz emission. The second sample was fabricated in a double-decked HEMT structure in which the grating gate metal layer was replaced with the semiconducting upper-deck 2D electron layer, resulting in enhancement of emission by one order of magnitude. PMID- 21693815 TI - Mechanism of self-excitation of terahertz plasma oscillations in periodically double-gated electron channels. AB - We develop a device model for a heterostructure device with an electron channel and with a periodic system of interdigitated gates. Using this model, we find the conditions of the self-excitation of plasma oscillations in portions of the channel. It is shown that the self-excitation of plasma oscillations in these devices and the terahertz emission observed in the experiments (Otsuji et al 2006 Appl. Phys. Lett. 89 263502; Meziani et al 2007 Appl. Phys. Lett. 90 061105; Otsuji et al 2007 Solid-State Electron. 51 1319) might be attributed to the electron-transit-time effect in the barrier regions. PMID- 21693816 TI - Plasma wave instability and amplification of terahertz radiation in field-effect transistor arrays. AB - We show that the strong amplification of terahertz radiation takes place in an array of field-effect transistors at small DC drain currents due to hydrodynamic plasmon instability of the collective plasmon mode. Planar designs compatible with standard integrated circuit fabrication processes and strong coupling of terahertz radiation to plasmon modes in FET arrays make such arrays very attractive for potential applications in solid-state terahertz amplifiers and emitters. PMID- 21693817 TI - Terahertz generation in nitrides due to transit-time resonance assisted by optical phonon emission. AB - The conditions for THz radiation generation caused by electron transit-time resonance in momentum and real spaces under optical phonon emission are analyzed for nitride-based materials and their structures. It is shown that such a mechanism provides a unique possibility to realize sub-THz and THz radiation generation at the border between the electro-optical and electronic techniques by using two alternative approaches: (i) amplification of transverse electromagnetic waves in 3D bulk materials and 2D quantum wells, and (ii) longitudinal current field instabilities in sub-micron and micron n(+)nn(+) diodes. Estimations of frequency regions, output power and efficiency of the generation demonstrate that nitrides are promising materials for THz radiation generation. PMID- 21693818 TI - Terahertz oscillations in ultra-thin n-In(0.53)Ga(0.47)As ungated channels. AB - Using a self-consistent Monte Carlo simulator we investigate the spectrum of voltage fluctuations of an n-type InGaAs two-terminal layer of variable thickness W in the range 1-100 nm and variable length L in the range 0.01-10 um embedded in an external dielectric medium. Calculations are performed at T = 300 K for different dopings and in the presence of an external bias of increasing strength. When the bias is well below the threshold for the Gunn effect the spectrum peaks at the plasma oscillations of the electron gas. For W>=100 nm and carrier concentrations of 10(17)-10(18) cm(-3) the peaks are in good agreement with the standard three-dimensional (3D) expression of the plasma frequency. For W<=10 nm the results exhibit a plasma frequency that depends on the length of the layer, thus implying that the oscillation mode is dispersive. The corresponding frequency covers a wide range of values 0.1-10 THz and is in agreement with the two-dimensional (2D) expression of the plasma frequency obtained for a collisionless regime within the in-plane approximation for the electric field. A region of cross-over between the 2D and 3D behaviours of the plasma frequency is shown for W>10 nm. When the bias is above the threshold for the Gunn effect, we observe the washing out of the plasma peak and the onset of a frequency peak associated with the transit time of the Gunn domain located in the sub-terahertz frequency region. PMID- 21693819 TI - Quantum dots for terahertz generation. AB - Nanostructures made of semiconductors, such as quantum wells and quantum dots (QD), are well known, and some have been incorporated in practical devices. Here we focus on novel structures made of QDs and related devices for terahertz (THz) generation. Their potential advantages, such as low threshold current density, high characteristic temperature, increased differential gain, etc, make QDs promising candidates for light emitting applications in the THz region. Our idea of using resonant tunneling through QDs is presented, and initial results on devices consisting of self-assembled InAs QDs in an undoped GaAs matrix, with a design incorporating a GaInNAs/GaAs short period superlattice, are discussed. Moreover, shallow impurities are also being explored for possible THz emission: the idea is based on the tunneling through bound states of individual donor or acceptor impurities in the quantum well. Initial results on devices having an AlGaAs/GaAs double-barrier resonant tunneling structure are discussed. PMID- 21693820 TI - Size dependence of the Mossbauer recoilless fraction in beta-Sn nanocrystals. AB - We study the size dependence of the Mossbauer recoilless fraction in beta-Sn nanocrystals by performing conversion electron Mossbauer spectroscopy at different temperatures. The Mossbauer recoilless fraction is intimately related to dynamical processes involving the nuclei during the gamma-ray emission. The beta-Sn nanocrystals are embedded in a SiO(2) matrix, and they have a mean diameter ranging from 7 to 17 nm. A lowering of the recoilless fraction with decreasing cluster size is observed. The smallest nanocrystals reveal a 60% reduction of the recoilless fraction compared to the bulk value, while for the largest clusters we observe the same Mossbauer recoilless fraction as in the bulk. This suggests that the dynamical properties of the beta-Sn nanocrystals in SiO(2) approach those of the bulk for a critical mean diameter above 16 nm. The experimental results are compared with theoretical values obtained by a continuum model in which the relevant parameters are determined ab initio. PMID- 21693821 TI - Rigorous description of exchange-correlation energy of many-electron systems. AB - With the eigenfunctional theory, we study a general interacting electron system, and give a rigorous expression of its ground state energy, which is composed of two parts: one part is contributed by the non-interacting electrons, and the other one is represented by the correlation functions that are controlled by the electron correlation. Moreover, according to the rigorous expression of the ground state energy, an effective scheme beyond the local density approximation of the density functional theory is proposed. As a simple example for a spin-1/2 XXZ chain, under the linear approximation in solving the equation of the phase field, the ground state energy obtained by the present scheme is quite close to that of the Bethe ansatz. PMID- 21693822 TI - Effect of nanometric grain size on electronic-transport, magneto-transport and magnetic properties of La(0.7)Ba(0.3)MnO(3) nanoparticles. AB - We have investigated the effect of nanometric grain size on electronic-transport, magneto-transport and magnetic properties of single-phase La(0.7)Ba(0.3)MnO(3) (LBMO) nanoparticles having an average grain size in the nanometric regime (21-35 nm). We have observed that both the metal-insulator transition temperature (T(P)) and para-ferromagnetic transition temperature (T(C)) shift to lower temperature with a decrease in average grain size. For the entire series of samples, a distinct minima in resistivity at a temperature (T(min)) followed by an upturn at a very low temperature (<=47 K) is observed. We have attributed the steeper low temperature (~47 K) resistivity upturn in the smaller grain size sample than that in the larger grain size sample below T(min) to the increased value of charging energy (E(C)). E(C) has been estimated to be 1.3, 0.56 and 0.04 K for an average grain size of 21, 25 and 30 nm, respectively. Magneto-transport measurements show that the magnitude of low field MR (LFMR) varies with average grain size. In order to investigate the MR behavior of LBMO nanoparticles, we have analyzed our data in the light of a phenomenological model, based on spin-polarized transport of conduction electrons at the grain boundaries. Magneto-transport measurements show that the magnitude of low field MR (LFMR), as well as of high field MR (HFMR), remains constant up to sufficiently high temperature (~50 K) and then drops sharply with temperature. We found that this strange temperature dependence of MR is decided predominantly by the nature of the temperature response of the surface magnetization (M(S)) of nanosized magnetic particles. PMID- 21693823 TI - Low temperature specific heat of superconducting ternary intermetallics La(3)Pd(4)Ge(4), La(3)Ni(4)Si(4), and La(3)Ni(4)Ge(4) with U(3)Ni(4)Si(4)-type structure. AB - A systematic investigation on the thermodynamic properties of La-based ternary intermetallic superconductors crystallizing in a U(3)Ni(4)Si(4)-type structure is presented. The U(3)Ni(4)Si(4)-type structure consists of a characteristic intergrowth of periodic BaAl(4) (ThCr(2)Si(2))- and AlB(2)-type segments. Pristine low temperature specific heat data for recently discovered members La(3)Ni(4)Si(4) and La(3)Ni(4)Ge(4) with T(c)s of 1.0 and 0.7 K, respectively, are presented as well as La(3)Pd(4)Ge(4) with the highest T(c) of 2.5 K in the U(3)Ni(4)Si(4)-type group. Owing to the higher T(c)s of U(3)Ni(4)Si(4)-type superconductors than the related ThCr(2)Si(2)-type compounds, comparisons are drawn in our investigations of the ternary intermetallics of LaPd(2)Ge(2), LaNi(2)Si(2), and LaNi(2)Ge(2) having a ThCr(2)Si(2)-type structure. Our investigations of the thermodynamic properties show that La(3)Ni(4)Si(4) and La(3)Ni(4)Ge(4) have higher values of gamma(n), N(E(F)), and Theta(D) than La(3)Pd(4)Ge(4). The same trend was found in ThCr(2)Si(2)-type compounds of LaPd(2)Ge(2), LaNi(2)Si(2), and LaNi(2)Ge(2). It turns out that the difference in T(c) between La(3)Pd(4)Ge(4), La(3)Ni(4)Si(4), and La(3)Ni(4)Ge(4), as well as the relatively higher T(c) of the U(3)Ni(4)Si(4)-type superconductors than of the related ThCr(2)Si(2)-type compounds, are largely due to the strength of electron phonon coupling. PMID- 21693824 TI - Crystal-field energy level analysis for Nd(3+) ions at the low symmetry C(1) site in [Nd(hfa)(4)(H(2)O)](N(C(2)H(5))(4)) single crystals. AB - Optical absorption measurements of Nd(3+) ions in single crystals of [Nd(hfa)(4)(H(2)O)](N(C(2)H(5))(4)) (hfa = hexafluoroacetyloacetonate), denoted Nd(hfa) for short, have been carried out at 4.2 and 298 K. This compound crystallizes in the monoclinic system (space group P 2(1)/n). Each Nd ion is coordinated to eight oxygen atoms that originate from the hexafluoroacetylacetonate ligands and one oxygen atom from the water molecule. A total of 85 experimental crystal-field (CF) energy levels arising from the Nd(3+) (4f(3)) electronic configuration were identified in the optical spectra and assigned. A three-step CF analysis was carried out in terms of a parametric Hamiltonian for the actual C(1) symmetry at the Nd(3+) ion sites. In the first step, a total of 27 CF parameters (CFPs) in the Wybourne notation B(kq), admissible by group theory, were determined in a preliminary fitting constrained by the angular overlap model predictions. The resulting CFP set was reduced to 24 specific independent CFPs using appropriate standardization transformations. Optimizations of the second-rank CFPs and extended scanning of the parameter space were employed in the second step to improve reliability of the CFP sets, which is rather a difficult task in the case of no site symmetry. Finally, seven free-ion parameters and 24 CFPs were freely varied, yielding an rms deviation between the calculated energy levels and the 85 observed ones of 11.1 cm(-1). Our approach also allows prediction of the energy levels of Nd(3+) ions that are hidden in the spectral range overlapping with strong ligand absorption, which is essential for understanding the inter-ionic energy transfer. The orientation of the axis system associated with the fitted CF parameters w.r.t. the crystallographic axes is established. The procedure adopted in our calculations may be considered as a general framework for analysis of CF levels of lanthanide ions at low (triclinic) symmetry sites. PMID- 21693825 TI - Experimental observation of glassy dynamics driven by gas adsorption on porous silicon. AB - We report on electrical resistance measurements of mesoporous silicon samples at room temperature, in the presence of various dosages of ammonia, showing very slow non-exponential responses of the system to any variation of ammonia pressure. Resistance always relaxes according to a stretched exponential law, independently of the sign of the variation. Moreover, the system remembers its own history, and memory effects can be accounted for in a very simple way in the framework of the same relaxation law. A possible extrinsic scenario based on rearrangement of trapped charges is proposed and discussed. These findings suggest that mesoporous silicon in the presence of polar molecules may be regarded as a suitable system for the study of glassy dynamics by means of electrical measurements at RT. PMID- 21693826 TI - Dynamical properties and instability of local fluorite BaF(2) structure around doped Mn(2+) ions-EPR and electron spin echo studies. AB - The electron paramagnetic resonance (EPR) and electron spin echo (ESE) were measured at the X-band for Mn(2+) in a BaF(2) crystal in the temperature range 4.2-300 K. In addition to the cubic symmetry centre, two other lower concentration tetragonal centres were identified. Temperature variations and computer simulation of the EPR spectrum confirm that the cubic symmetry of the MnF(8) centre is deformed to two T(d) tetrahedra of different dimensions at around 45 K. Electron spin relaxation was measured in the temperature range 4.2 35 K, where the ESE signal was detectable. For higher temperature the Mn(2+) dynamics produces homogeneously broadened EPR lines. At the lowest temperatures the spin-lattice relaxation is governed by ordinary phonon processes with 1/T(1)~T(5). The efficiency of these processes rapidly decreases and at about 11 K a local mode of energy 17 cm(-1) becomes the relaxation mechanism. Phase relaxation observed as ESE signal dephasing indicates that after the local deformation jumps (tunnelling with frequency 4 * 10(8) s(-1)) between the two tetrahedral configurations appear, with the energy barrier being the local mode energy. This motion is directly visible as a resonance-type enhancement of the ESE dephasing rate 1/T(M) around 11 K. Only the cubic centre displays the above dynamics. PMID- 21693827 TI - Binding between endohedral Na atoms in Si clathrate I; a first principles study. AB - We investigate the binding nature of the endohedral sodium atoms with the density functional theory methods, presuming that the clathrate I consists of a sheaf of one-dimensional connections of Na@Si(24) cages interleaved in three perpendicular directions. Each sodium atom loses 30% of the 3s(1) charge to the frame, forming an ionic bond with the cage atoms; the rest of the electron contributes to the covalent bond between the nearest Na atoms. The presumption is proved to be valid; the configuration of the two Na atoms in the nearest Si(24) cages is more stable by 0.189 eV than that in the Si(20) and Si(24) cages. The energy of the beads of the two distorted Na atoms is more stable by 0.104 eV than that of the two infinitely separated Na atoms. The covalent bond explains both the preferential occupancies in the Si(24) cages and the low anisotropic displacement parameters of the endohedral atoms in the Si(24) cages in the [100] directions of the clathrate I. PMID- 21693828 TI - Evolution with hole doping of the electronic excitation spectrum in the cuprate superconductors. AB - The recent scanning tunnelling results of Alldredge and co-workers on Bi-2212 and of Hanaguri and co-workers on Na-CCOC (Ca(2-x)Na(x)CuO(2)Cl(2)) are examined from the perspective of the Bardeen-Cooper-Schrieffer (BCS)/Bose-Einstein condensation boson-fermion resonant crossover model for the mixed-valence high temperature superconductor (HTSC) cuprates. The model specifies the two energy scales controlling the development of HTSC behaviour and the dichotomy often now alluded to between nodal and antinodal phenomena in the HTSC cuprates. An indication is extracted from the data as to how the choice of the particular HTSC system sees these two basic energy scales ([Formula: see text], the local pair binding energy, and Delta(sc), the nodal BCS-like gap parameter) evolve with doping and change in the degree of metallization of the structurally and electronically perturbed mixed-valent environment. PMID- 21693829 TI - A new method to detect the vortex glass phase and its evidence in YBCO. AB - The evidence of the vortex glass phase has been obtained by analysing the nonlinear magnetic response of type-II superconductors. The method introduced here is based on a combined frequency dependence analysis of the real and imaginary part of the 1st and 3rd harmonics of the AC magnetic susceptibility. The analysis has been performed by taking into account both the components and the Cole-Cole plots (i.e. the imaginary part as a function of the real part). Numerical simulations have been used to identify the fingerprints of the magnetic behaviour in the vortex glass phase. These characteristics allowed the vortex glass phase to be distinguished from the other disordered phases, even those showing similar electrical properties. Finally, this method has been successfully applied to detecting the vortex glass phase in an YBCO bulk melt-textured sample. PMID- 21693830 TI - Testing isotherm models and recovering empirical relationships for adsorption in microporous carbons using virtual carbon models and grand canonical Monte Carlo simulations. AB - Using the plausible model of activated carbon proposed by Harris and co-workers and grand canonical Monte Carlo simulations, we study the applicability of standard methods for describing adsorption data on microporous carbons widely used in adsorption science. Two carbon structures are studied, one with a small distribution of micropores in the range up to 1 nm, and the other with micropores covering a wide range of porosity. For both structures, adsorption isotherms of noble gases (from Ne to Xe), carbon tetrachloride and benzene are simulated. The data obtained are considered in terms of Dubinin-Radushkevich plots. Moreover, for benzene and carbon tetrachloride the temperature invariance of the characteristic curve is also studied. We show that using simulated data some empirical relationships obtained from experiment can be successfully recovered. Next we test the applicability of Dubinin's related models including the Dubinin Izotova, Dubinin-Radushkevich-Stoeckli, and Jaroniec-Choma equations. The results obtained demonstrate the limits and applications of the models studied in the field of carbon porosity characterization. PMID- 21693831 TI - Dipolar interactions and their influence on the critical single domain grain size of Ni in layered Ni/Al(2)O(3) composites. AB - Pulsed laser deposition has been used to fabricate Ni/Al(2)O(3) multilayer composites in which Ni nanoparticles with diameters in the range of 3-60 nm are embedded as layers in an insulating Al(2)O(3) host. At fixed temperatures, the coercive fields plotted as a function of particle size show well-defined peaks, which define a critical size that delineates a crossover from coherently rotating single domain to multiple domain behavior. We observe a shift in peak position to higher grain size as temperature increases and describe this shift with theory that takes into account the decreasing influence of dipolar magnetic interactions from thermally induced random orientations of neighboring grains. PMID- 21693832 TI - Effects of size distribution on hysteresis losses of magnetic nanoparticles for hyperthermia. AB - For understanding hysteresis losses of magnetic nanoparticles to be used for magnetic particle hyperthermia the effect of size distribution on the dependence of hysteresis losses on magnetic field amplitude is studied on the basis of a phenomenological model in the size range from superparamagnetism to magnetic multi-domains-roughly 10 up to 100 nm. Relying on experimental data for the size dependence of coercivity, an empirical expression for the dependence of hysteresis loss on field amplitude and particle size is derived for hypothetical monodisperse particle ensembles. Considering experimentally observable size distributions, the dependence of loss on distribution parameters-mean particle size and variance-is studied. There, field amplitude is taken into account as an important parameter, which for technical and biomedical reasons in hyperthermia equipment is restricted. Experimental results for different particle types with mean diameter of 30 nm may be well reproduced theoretically if a small loss contribution of Rayleigh type is taken into account. Results show that the Stoner Wohlfarth model for single domain magnetization reversal via homogeneous rotation cannot explain experimental observations. In particular, in magnetosomes which are distinguished by nearly ideal crystallographic shapes and narrow size distribution large friction-like losses occur even for small field amplitude. Parameters of the high frequency field for hyperthermia (amplitude and frequency) as well as of the size distribution of applied particles are discussed with respect to attaining maximum specific heating power. PMID- 21693833 TI - Annealing of radiation induced oxygen deficient point defects in amorphous silicon dioxide: evidence for a distribution of the reaction activation energies. AB - The selective annealing of point defects with different activation energies is studied, by performing sequences of thermal treatments on gamma irradiated silica samples in the temperature range 300-450 degrees C. Our experiments show that the dependence on time of the concentration of two irradiation induced point defects in silica, named ODC(II) (standing for oxygen deficient centre II) and the E(gamma)(') centre, at a given temperature depends on the thermal history of the sample for both of the centres studied; moreover in the long time limit this concentration reaches an asymptotic value that depends on the treatment temperature alone. These results suggest the existence of a distribution of the activation energies of the reaction process responsible for the annealing of the defects investigated, intimately related to the intrinsic disorder of the amorphous lattice. Furthermore, our data show that the thermal treatment can modify this distribution of activation energies and as a consequence the thermal properties of the centre itself. PMID- 21693834 TI - Computer simulations of biaxial nematics. AB - Biaxial nematic (N(b)) liquid crystals are a fascinating condensed matter phase that has baffled, for more than thirty years, scientists engaged in the challenge of demonstrating its actual existence, and which has only recently been experimentally found. During this period computer simulations of model N(b) have played an important role, both in providing the basic physical properties to be expected from these systems, and in giving clues about the molecular features essential for the thermodynamic stability of N(b) phases. However, simulation studies are expected to be even more crucial in the future for unravelling the structural features of biaxial mesogens at the molecular level, and for helping in the design and optimization of devices towards the technological deployment of N(b) materials. This review article gives an overview of the simulation work performed so far, and relying on the recent experimental findings, focuses on the still unanswered questions which will determine the future challenges in the field. PMID- 21693835 TI - Molecular theory of layer contraction in smectic liquid crystals. AB - The period of the layered structure in smectic A and smectic C liquid crystal phases has been calculated numerically by direct minimization of the mean-field free energy which takes into account the interaction between molecules in adjacent smectic layers. The smectic layer spacing is calculated for two systems characterized by conventional and anomalously weak layer contraction in the smectic C phase. It is then compared with the simple estimate based on the average projection of the molecular long axis on the smectic layer normal. For both systems, temperature variation of the average molecular projection is qualitatively similar to that of the calculated layer spacing although certain quantitative deviations exist. PMID- 21693836 TI - Entropy production and stability during radial displacement of fluid in Hele-Shaw cell. AB - The entropy production in the problem of the radial displacement of a fluid in the Hele-Shaw cell is determined. The morphological stability of the interface between the displaced and displacing fluids is studied using the linear analysis for stability and the maximum entropy production principle. Regions, in which different forms of the interface can coexist, are predicted. These regions are analyzed depending on the cell size, the injected flow rate, and the ratio of the fluid viscosities. PMID- 21693837 TI - Density functional study of amorphous, liquid and crystalline Ge(2)Sb(2)Te(5): homopolar bonds and/or AB alternation? AB - The amorphous, liquid and crystalline phases of the phase change material Ge(2)Sb(2)Te(5) (GST) have been studied by means of density functional/molecular dynamics simulations. The large sample (460 atoms and 52 vacancies in the unit cell) and long simulations (hundreds of picoseconds) provide much new information. Here we extend our original analysis (2007 Phys. Rev. B 76 235201) in important ways: partial coordination numbers and radial distribution functions, bond angle distributions, new local order parameters, vibration frequencies, and the charges on atoms and vacancies. The valence band densities of states in amorphous and crystalline GST are compared with ones from x-ray photoemission spectroscopy. The results for the liquid phase are new and those for the crystalline phase much expanded. GST shows pronounced AB alternation (A: Ge, Sb; B: Te), especially in its amorphous phase, and ABAB squares play a central role in the amorphous to crystalline transition. We comment on earlier speculations concerning the nature of the amorphous to crystalline transition. PMID- 21693838 TI - Stability of the fcc structure in block copolymer systems. AB - The stability of the face-centered cubic (fcc) structure in microphase separated copolymers is investigated by a coarse-grained approach. Direct simulations of the equation for the microphase separation in three dimensions indicate that there is a narrow area above a certain degree of segregation in the phase diagram, where the fcc structure is the most stable structure. By employing the mode expansion, we have confirmed that the fcc structure can form as a metastable structure even in the weak segregation regime. PMID- 21693839 TI - Correlation between magnetic properties and the electronic structures of soft magnetic ternary Fe(78-x)Y(x)B(22) (x = 4-9) bulk metallic glasses. AB - Fe and Y K-edge extended x-ray absorption fine structure, Fe(Y) L(3,2)-edge (L(3) edge) x-ray absorption near-edge structure (XANES) and valence-band photoemission spectroscopy (VB-PES) measurements have been carried out to study soft magnetic ternary Fe(78-x)Y(x)B(22) bulk metallic glasses (BMGs). The combined XANES and VB PES results do not show broadening of the Fe 3d band to support the previous interpretation of the reduction of the magnetic moment in BMGs by Y-induced decrease of exchange splitting of Fe 3d orbitals. Instead, the density of delocalized/itinerant Fe 3d states in the vicinity of the Fermi level is found to be reduced by Y substitution, which reduces the strength of itinerant-states mediated ferromagnetic coupling between local spins on the Fe ions and the total magnetic moment of the Fe-based BMGs. PMID- 21693840 TI - Pretransitional behaviour in the vicinity of the isotropic-nematic transition of strongly polar compounds. AB - The isotropic-nematic transition, being weakly first order, exhibits pretransitional effects signifying the appearance of the nematic-like regions in the isotropic phase. In the isotropic phase, strongly polar liquid crystals, such as the popular alkyl and alkoxy cyano biphenyl behave in a non-standard fashion: whereas far away from the transition the dielectric constant epsilon(iso) has a 1/T dependence (a feature also commonly seen in polar liquids), on approaching the nematic phase the trend reverses resulting in a maximum in epsilon(iso), at a temperature slightly above the transition, an effect explained on the basis of short-range correlations with an antiparallel association of the neighbouring molecules. Recently, there has been a revival in studies on this behaviour to possibly associate it with the order of transition. Here we report dielectric measurements carried in the vicinity of this transition for a number of compounds having different molecular structures including a bent core system, but with a common feature that the molecules possess a strong terminal polar group, nitro in one case and cyano in the rest. Surprisingly, the convex shape of the thermal variation of epsilon(iso) was more an exception than the rule. In materials that exhibit such an anomaly we find a linear correlation between deltaepsilon = (epsilon(peak)-epsilon(IN))/epsilon(IN) and deltaT = T(peak)-T(IN), where epsilon(peak) is the maximum value of the dielectric constant in the isotropic phase, epsilon(IN) the value at the transition, and T(peak) and T(IN) the corresponding temperatures. PMID- 21693841 TI - Anharmonic processes of scattering and absorption of slow quasi-transverse modes in cubic crystals with positive and negative anisotropies of second-order elastic moduli. AB - The quasi-transverse ultrasound absorption during anharmonic processes of the scattering in cubic crystals with positive (Ge, Si, diamond and InSb) and negative (KCl and NaCl) anisotropies of the second-order elastic moduli is studied. Mechanisms underlying the relaxation of the slow quasi-transverse mode by two slow (the SSS mechanism) or two fast (the SFF) modes are discussed in the long-wavelength approximation. Angular dependences of the ultrasound absorption for the SSS, SFF and Landau-Rumer relaxation mechanisms are analyzed in terms of the anisotropic continuum model. The full absorption of the slow quasi-transverse mode is determined. It is shown that the SSS and SFF relaxation mechanisms are due to the cubic anisotropy of the crystals, leading to the interaction between noncollinear phonons. Two most important cases-the wavevectors of phonons are in the cube face plane or the diagonal planes-are considered. In crystals with a considerable anisotropy of the elastic energy (Ge, Si, InSb, KCl and NaCl) the total contribution of the SSS and SFF relaxation mechanisms to the full absorption is either several times or one to two orders of magnitude larger than the contribution from the Landau-Rumer mechanism depending on the direction. Much of the dominance of the former relaxation mechanisms over the Landau-Rumer mechanism is explained by second-order elastic moduli. PMID- 21693842 TI - Andreev reflection and Aharonov-Bohm oscillations through a parallel-coupled double quantum dot with spin-flip scattering. AB - Using nonequilibrium Green's function techniques, we investigate Andreev reflection and Aharonov-Bohm oscillations through a parallel-coupled double quantum dot connected with a ferromagnetic lead and a superconductor lead. The possibility of controlling Andreev reflection and Aharonov-Bohm oscillations of the system is explored by tuning the interdot coupling, the gate voltage, the magnetic flux, and the intradot spin-flip scattering. When the spin-flip scattering increases, Fano resonant peaks resulting from the asymmetrical levels of the two quantum dots begin to split, and Aharonov-Bohm oscillations are suppressed. Due to the interdot coupling, one strongly and one weakly coupled state of the system can be formed. The magnetic flux can exchange the function of the two states, which leads to a swap effect. PMID- 21693843 TI - Muon spin relaxation study of LaTiO(3) and YTiO(3). AB - We report muon spin relaxation (MUSR) measurements on two Ti(3+) containing perovskites, LaTiO(3) and YTiO(3), which display long-range magnetic order at low temperature. For both materials, oscillations in the time dependence of the muon polarization are observed which are consistent with three-dimensional magnetic order. From our data we identify two magnetically inequivalent muon stopping sites. The MUSR results are compared with the magnetic structures of these compounds previously derived from neutron diffraction and MUSR studies on structurally similar compounds. PMID- 21693844 TI - Infrared reflectance and photoemission spectroscopy studies across the phase transition boundary in thin film vanadium dioxide. AB - Optical properties and valence band density of states near the Fermi level of high-quality VO(2) thin films have been investigated by mid-infrared reflectometry and hard-UV (hnu = 150 eV) photoemission spectroscopy. An exceptionally large change in reflectance from 2 to 94% is found upon the thermally driven metal-insulator transition (MIT). The infrared dispersion spectra of the reflectance across the MIT are presented and evidence for the percolative nature of the MIT is pointed out. The discrepancy between the MIT temperatures defined from the electrical and optical properties is found and its origin is discussed. The manifestation of the MIT is observed in the photoemission spectra of the V 3d levels. The analysis of the changes of the V 3d density of states is done and the top valence band shift upon the MIT is measured to be 0.6 eV. PMID- 21693845 TI - Effects of photoacoustic measurements on a nanostructured ZnSe mechanically alloyed. AB - Zinc-blende ZnSe powder, with particles containing nanometric grains, was prepared using the mechanical alloying technique, from an equiatomic mixture of elemental Zn and Se powders. An important interfacial component was observed in the as-milled powder, which affects its thermal and optical properties. In order to obtain a high-quality zinc-blende ZnSe powder an annealing process was applied. The structural properties of both as-milled and annealed powders were characterized by an x-ray diffraction technique. The effects of defect centers on the optical band gap of both as-milled and annealed zinc-blende ZnSe powders were studied through optical absorbance measurements. The results showed a substantial broadening and a shift of the band gap energy to lower values in the as-milled powder, while for the annealed sample no effects were observed. For the annealed sample, the measured band gap energy value is in good agreement with those reported in the literature. A sequence of photoacoustic absorption measurements of the as-milled ZnSe sample showed that the absorbed energy promotes a structural relaxation. This relaxation causes a change in the heat transfer mechanism from thermal diffusion to thermoelastic bending and a reduction in the thermal diffusivity values. Similar measurements of the annealed nanostructured ZnSe sample showed the thermal diffusivity value to have a high degree of stability, and to be in good agreement with values reported in the literature. PMID- 21693846 TI - Calculations for displacive omega-phase transformations in Ti-Al alloys with Nb additions at finite temperature. AB - We examine by means of first-principles calculations the bcc-like (bcc: body centered cubic) to omega-like phase transformations in Ti-Al alloys with Nb additions at finite temperature. To simulate the alloy we use different discrete atomic configurations in a six atom unit cell of the stoichiometry Ti(3)Al(2)Nb. Calculated ground state energies show an instability in the ternary Ti(3)Al(2)Nb alloy against the omega structure type atomic displacement. To better understand the role of entropy in the stability/instability of these systems, the first principles calculations are extended to finite temperature by including various contributions to the free energy. In particular, the vibrational free energy is calculated within a quasiharmonic approximation. It is shown that the bcc structure is stabilized by the contribution of the low energy modes to the lattice entropy against omega type atomic displacements. We find that configurational entropy plays a major role in the omega to B8(2) transformation. Calculated lattice parameters and transition temperatures are found to be in excellent agreement with experiment. PMID- 21693847 TI - Phonon-induced decoherence of spin-orbit-driven coherent oscillations in a single InGaAs quantum dot. AB - The effect of direct spin-phonon interactions on spin-orbit-driven coherent oscillations in a single quantum dot proposed by Debald and Emary (2005 Phys. Rev. Lett. 94 226803) is investigated theoretically in terms of the perturbation treatment based on a unitary transformation. It is shown that the decoherence rate induced by acoustic phonons strongly depends on the spin-orbit coupling strength, the magnetic field strength and the dot size. PMID- 21693848 TI - (1)H-NMR and charge transport in metallic polypyrrole at ultra-low temperatures and high magnetic fields. AB - The temperature dependence of conductivity, proton spin relaxation time (T(1)) and magnetoconductance (MC) in metallic polypyrrole (PPy) doped with PF(6)(-) have been carried out at mK temperatures and high magnetic fields. At T<1 K both electron-electron interaction (EEI) and hopping contributes to conductivity. The temperature dependence of a proton T(1) is classified in three regimes: (a) for T<6 K-relaxation mechanism follows a modified Korringa relation due to EEI and disorder, (b) for 6 K50 K-relaxation is due to the dipolar interaction modulated by the reorientation of the symmetric PF(6) groups following the Bloembergen, Purcell and Pound (BPP) model. The data analysis shows that the Korringa ratio is enhanced by an order of magnitude. The positive and negative MC at T<250 mK is due to the contributions from weak localization and Coulomb-correlated hopping transport, respectively. The role of EEI is observed to be consistent in conductivity, T(1) and MC data, especially at T<1 K. PMID- 21693849 TI - Effect of isoelectronic substitution on magnetic properties of Ni(2)Mn(GaB) Heusler alloys. AB - We have studied the structural and magnetic properties of Ni(2)MnGa(1-x)B(x) Heusler alloys with 0<=x<=0.25 using x-ray diffraction, thermal expansion, electrical resistivity, and magnetization measurements. The magnetization measurements were made within the temperature interval of 5-400 K and at applied magnetic field of 0-5 T. The samples with low B concentrations (x<0.05) were found to be of the cubic L2(1) phase at 300 K. A martensitic phase along with the cubic L2(1) phase appears for x>=0.05, and the amount of the martensitic phase was found to increase with increasing x. The critical concentration of the boron substitution (within which Heusler phases exist) was found to be around x = 0.1. The cubic cell parameter was observed to decrease with increasing x in the interval 0<=x<=0.1. The alloys were ferromagnetically ordered at 5 K and the saturation magnetization (M(S)) was found to decrease with increasing boron concentration. The Curie temperatures (T(C)) and martensitic transition temperatures (T(M)) for the alloys with 0<=x<=0.25 have been determined and a phase (T-x) diagram has been constructed. T(M) increases rapidly and T(C) decreases slowly with increasing B concentration in the interval 0<=x<=0.1. The dependence of the phase transition temperatures and magnetization on B concentration is discussed. PMID- 21693850 TI - Titanium and native defects in LiBH(4) and NaAlH(4). AB - We report combined density functional studies and thermodynamic considerations on Ti-related and native defects in lithium borohydride and sodium alanate. Ti atoms introduced into the bulk of LiBH(4) are thermodynamically unfavorable for all their oxidation states, while high oxidation states of Ti(n+) cations may become thermodynamically stable in the bulk of NaAlH(4) at certain thermodynamic conditions. Neutral hydrogen vacancies and interstitials or cation vacancies are less stable than their charged counterparts in both compounds. In sodium alanate, the formation of native defects leads to changes of the coordination number of aluminum, while in lithium borohydride BH(4) groups change their mutual orientation but B-H bonds remain intact. The electronic band alignment in LiBH(4) and NaAlH(4) is different. PMID- 21693851 TI - Critical behavior of double perovskite La(2)NiMnO(6). AB - The critical behavior of the double perovskite La(2)NiMnO(6) was investigated by measurement of the magnetization around the Curie temperature T(C). The magnetic data were analyzed in the critical region using the Kouvel-Fisher method to yield the critical exponents of beta = 0.408 +/- 0.011 with T(C) = 270.50 (from the temperature dependence of the spontaneous magnetization below T(C)) and gamma = 1.295 +/- 0.015 with T(C) = 271.10 (from the temperature dependence of the inverse initial susceptibility above T(C)). The critical magnetization isotherm M(T(C),H) gives delta = 4.139 +/- 0.090. The critical exponents obtained by this method obey the Widom scaling relation delta = 1+gamma/beta, implying the critical exponents are reliable. The values of critical exponents are close to those predicted by the three-dimensional (3D) Heisenberg model with short-range interactions. PMID- 21693852 TI - Radiation defects in CaF(2) and SrF(2) crystals doped with cadmium or zinc. AB - The formation of radiation defects in calcium and strontium fluoride single crystals doped with cadmium or zinc has been investigated by luminescence and absorption spectroscopy, as well as by electron spin resonance spectroscopy. It was found that x-irradiation could convert divalent impurity ions located at essentially cubic sites into the univalent state. Three types of Cd(+) or Zn(+) centers differing by local environment with point symmetries O(h), C(3v) and C(2v) are identified in the crystals. The formation of the last two results from the interaction between reduced impurities in the cubic environment and anion vacancies. The latter are intrinsic radiation defects and are not created by x irradiation in undoped crystals. We also discuss the possible implications of the electric field of the charge impurity defects on separation of the intrinsic radiation defects in these crystals. PMID- 21693853 TI - Ab initio density functional theory investigation of crystalline bundles of polygonized single-walled silicon carbide nanotubes. AB - By using ab initio density functional theory, the structural characterizations and electronic properties of two large-diameter (13, 13) and (14, 14) armchair silicon carbide nanotube (SiCNT) bundles are investigated. Full structural optimizations show that the cross sections of these large-diameter SiCNTs in the bundles have a nearly hexagonal shape. The effects of inter-tube coupling on the electronic dispersions of large-diameter SiCNT bundles are demonstrated. By comparing the band structures of the triangular lattices of (14, 14) SiCNTs with nearly hexagonal and circular cross sections we found that the polygonization of the tubes in the bundle leads to a further dispersion of the occupied bands and an increase in the bandgap by 0.18 eV. PMID- 21693854 TI - Spatially resolved characterization of Xe ion irradiated LiF crystals using static field gradient NMR. AB - Spatially resolved (19)F and (7)Li nuclear magnetic resonance (NMR) spin-lattice relaxation rates have been measured in LiF crystals irradiated with 1.44 GeV Xe ions at fluences from 10(10) to 10(12) ions cm(-2). In addition, the F-centre concentration has been measured by optical absorption spectroscopy and the concentration of paramagnetic centres by electron paramagnetic resonance (EPR). Within the ion range, the relaxation rate turns out to increase linearly with the concentration of paramagnetic centres but super-linearly with the F-centre concentration. Beyond the ion range, the relaxation rate is still significantly enhanced compared to non-irradiated LiF. PMID- 21693855 TI - High-spin magnetic states in the two-orbital Hubbard model on a tetrahedron. AB - We present a study of the two-orbital degenerate Hubbard model in which the exact numerical solution on a regular tetrahedron is obtained via suitable implementation of the symmetries generated by the spin, the pairing and the orbital pseudospin operators. In particular, we show that a large variety of high spin magnetic ground states can develop away from half filling, depending on the values of the electron density and the parameters of the model. As the tetrahedron is the simplest finite-size cluster where hopping processes connect all pairs of sites with constant probability, the study is extended by providing the exact analytical solution of the model on an infinite lattice in the unconstrained hopping limit. PMID- 21693856 TI - Bulk phonon scattering in perturbed quasi-3D multichannel crystallographic waveguide. AB - In the present paper, we concentrate on the influence of local defects on scattering properties of elastic waves in perturbed crystalline quasi-three dimensional nanostructures in the harmonic approximation. Our model consists of three infinite atomic planes, assimilated into a perfect waveguide in which different distributions of scatterers (or defects) are inserted in the bulk. We have investigated phonon transmission and conductance for three bulk defect configurations. The numerical treatment of the problem, based on the Landauer approach, resorts to the matching method initially employed for the study of surface localized phonons and resonances. We present a detailed study of the defect-induced fluctuations in the transmission spectra. These fluctuations can be related to Fano resonances and Fabry-Perot oscillations. The first is due to the coupling between localized defect states and the perfect waveguide propagating modes whereas the latter results from the interference between incidental and reflected waves. Numerical results reveal the intimate relation between transmission spectra and localized impurity states and provide a basis for the understanding of conductance spectroscopy experiments in disordered mesoscopic systems. PMID- 21693857 TI - Transport and magnetic properties of Fe(x)VSe(2) (x = 0-0.33). AB - We present the results of the effect of Fe intercalation on the structural, transport and magnetic properties of 1T-VSe(2). Intercalation of iron suppresses the charge density wave transition at 110 K in 1T-VSe(2). And for more than 10% Fe concentration a new kind of first-order transition appears below 160 K in our resistivity results. The transition becomes stronger with a broad hysteresis (80 160 K) for 33% Fe intercalation. The anomalies are absent in the thermopower measurements of polycrystalline Fe(x)VSe(2) compounds (x = 0-0.33). The susceptibility measurements between 2 and 300 K and the magnetization in a high magnetic field up to 14 T at 2 K are reported. The Fe atoms are in the low-spin ( S = 1/2) state of Fe(3+) and the compounds show the absence of any magnetic order at low temperatures. PMID- 21693858 TI - Effects of hydrostatic pressure on the electron [Formula: see text] factor and g factor anisotropy in GaAs-(Ga, Al)As quantum wells under magnetic fields. AB - The hydrostatic-pressure effects on the electron-effective Lande [Formula: see text] factor and g-factor anisotropy in semiconductor GaAs-Ga(1-x)Al(x)As quantum wells under magnetic fields are studied. The [Formula: see text] factor is computed by considering the non-parabolicity and anisotropy of the conduction band through the Ogg-McCombe effective Hamiltonian, and numerical results are displayed as functions of the applied hydrostatic pressure, magnetic fields, and quantum-well widths. Good agreement between theoretical results and experimental measurements in GaAs-(Ga, Al)As quantum wells for the electron g factor and g factor anisotropy at low values of the applied magnetic field and in the absence of hydrostatic pressure is obtained. Present results open up new possibilities for manipulating the electron-effective g factor in semiconductor heterostructures. PMID- 21693859 TI - Spin fluctuations probed by NMR in paramagnetic spinel LiV(2)O(4): a self consistent renormalization theory. AB - Low-frequency spin fluctuation dynamics in paramagnetic spinel LiV(2)O(4), a rare 3d-electron heavy-fermion system, is investigated. A parametrized self-consistent renormalization (SCR) theory of the dominant AFM spin fluctuations is developed and applied to describe temperature and pressure dependences of the low-T nuclear spin-lattice relaxation rate 1/T(1) in this material. The experimental data for 1/T(1) available down to ~1 K are well reproduced by the SCR theory, showing the development of AFM spin fluctuations as the paramagnetic metal approaches a magnetic instability under the applied pressure. The low-T upturn of 1/T(1)T detected below 0.6 K under the highest applied pressure of 4.74 GPa is explained as the nuclear spin relaxation effect due to the spin freezing of magnetic defects unavoidably present in the measured sample of LiV(2)O(4). PMID- 21693860 TI - Superconducting current path and flux line shape in NbTiTa obtained by inter diffusion process. AB - This investigation presents a comprehensive characterization of magnetic and transport properties of an interesting superconducting wire, Nb-Ti-Ta, obtained through the solid-state diffusion between Nb-12 at.%Ta alloy and pure Ti. The physical properties obtained from magnetic and transport measurements related to the microstructure unambiguously confirmed a previous proposition that the superconducting currents flow in the center of the diffusion layer, which has a steep composition variation. The determination of the critical field also confirmed that the flux line core size is not constant, and in addition it was possible to determine that, in the center of the layer, the flux line core is smaller than at the borders. A possible core shape design is proposed. Among the wires studied, the one that presented the best critical current density was achieved for a diffusion layer with a composition of about Nb-32%Ti-10%Ta, obtained with a heat treatment at 700 degrees C during 120 h, in agreement with previous studies. It was determined that this wire has the higher upper critical field, indicating that the optimization of the superconducting behavior is related to an intrinsic property of the ternary alloy. PMID- 21693861 TI - Low-temperature magnetic and transport properties of single-crystal CeCoGe. AB - The low-temperature properties of single-crystal CeCoGe were investigated by specific heat C(T,H), magnetoresistivity rho(T,H), and differential susceptibility measurements chi(T,H). The zero-field low-temperature specific heat evolves as C = gammaT+betaT(3) = 42T+23.5T(3) mJ mol(-1) K(-1). On comparing its gamma = 42 mJ mol(-1) K(-1) with that of LaCoGe (12 mJ mol(-1) K(-2)) it is inferred that both 3d (Co) and 4f (Ce) orbitals contribute to the density of states at the Fermi level. Assuming that its phonic contribution to the specific heat is similar to LaCoGe (beta = 0.5 mJ mol(-1) K(-4)), then the extra cubic term in the specific heat (23T(3) mJ mol(-1) K(-1)) must be due to magnon excitation within the antiferromagnetically ordered state, T100 K, the higher energy emission component appears, arising from the thermally populated emitting (3)P(1) level. The visible emission spectrum consists of two dominant strongly overlapped broad bands with large Stokes shifts. At 4.2 K, their decay times are ~10(-5) s and decrease with increasing temperature. Both of the visible emission bands are assumed to have an exciton origin. The lower-energy band is ascribed to an exciton, localized near a single Bi(3+) ion. The higher-energy band shows a stronger intensity dependence on the Bi(3+) content and is assumed to arise from an exciton localized near a dimer Bi(3+) center. The origin and structure of the corresponding excited states is considered and the processes, taking place in the excited states, are discussed. PMID- 21693990 TI - Substitution behavior of Si in Al(3)Ti (D0(22)): a first-principles study. AB - A first-principles total-energy plane-wave pseudopotential method based on density functional theory has been used to investigate the site preference of Si in Al(3)Ti. The site preference parameter S has been calculated and the value of S decreases on increasing Si concentration, but is always greater than 1 while the Si concentration is lower than 25 at.%, indicating Si has a strong site preference for the Al sublattice. The physical origin of the site preference of Si in Al(3)Ti was studied by calculating the densities of states (DOSs) of the Al(3)Ti-Si systems. The heat of formation and the DOS of the position of the Fermi energy level were also studied to analyze the site preference of Si in Al(3)Ti. PMID- 21693991 TI - Ground-state properties of the two-site Hubbard-Holstein model: an exact solution. AB - We study the two-site Hubbard-Holstein model by using an extended phonon coherent state. For the nontrivial singlet bipolarons, the double occupancy probability, the fidelity and the entanglement entropy are calculated to characterize the ground-state properties in both two-site and single-site bipolaron-dominated regimes. We use the localized minimum of the fidelity to define a crossover and plot the bipolaron phase diagram, which separates the large and small entanglement region. Furthermore, the relation between the bipolaron entanglement and the correlation functions demonstrates that the large entanglement corresponds to the large magnitude of lattice deformations induced by electrons. PMID- 21693992 TI - (11)B and (195)Pt NMR study of heavy-fermion compound CePt(2)B(2)C. AB - We report (11)B and (195)Pt NMR Knight shift K and spin-lattice relaxation rate 1/T(1) in CePt(2)B(2)C in the range 4-315 K. The quadrupolar coupling constant, nu(Q) for boron nuclei is 790 +/- 10 kHz. The change of hyperfine field, H(hf), is observed below 30 K in the K versus susceptibility, chi, plot. The calculated value of H(hf) at the (11)B ((195)Pt) is 0.156 (6.86) kOe/MU(B) in the range 30 300 K and ~0 (0.22) kOe/MU(B) below 30 K. The 1/T(1) versus T curve shows some exotic behavior. The Ce 4f spin contribution to the nuclear relaxation rate (1/T(1f)) in each case is obtained by subtracting the T(1K)(-1) estimated from its La analog, i.e. LaPt(2)B(2)C. In the case of (11)B resonance, in the temperature range of 300-100 K, (1/T(1f)) is independent of T, suggesting a Curie Weiss behavior of the imaginary part of the dynamic susceptibility. It then shows a slow but continuous increment in the range 100-70 K, indicating a signature of the development of short-range magnetic correlation among the Ce 4f spins. Below 70 K, this enhancement of 1/T(1f) is completely suppressed and it decreases sharply, indicating a suppression of the effect of magnetic correlation, due to the dominance of the Kondo effect over the RKKY interaction. 1/T(1f), follows ~T(alpha), with an exponent alpha~0.7 in the range 4-30 K for (195)Pt and in the range 8-30 K for (11)B resonance. This is a characteristics of a non-Fermi-liquid like behavior. However, in the case of (11)B, there is again a clear change in the slope of the 1/T(1f) versus T curve below 8 K, with the value of alpha = 1.0, as if the behavior of the conduction electrons approaches towards a Fermi liquid, when probed near the (11)B site. PMID- 21693993 TI - The evolution of Griffiths-phase-like features and colossal magnetoresistance in La(1-x)Ca(x)MnO(3) (0.18 <= x <= 0.27) across the compositional metal-insulator boundary. AB - Detailed measurements of the magnetic and transport properties of single crystals of La(1-x)Ca(x)MnO(3) (0.18 <= x <= 0.27) are summarized, and lead to the following conclusions. While temperature-dependent (magneto-) resistance measurements narrow the compositionally modulated metal-insulator (M-I) transition to lie between 0.19 <= x(c) <= 0.20 in the series studied, comparisons between the latter magnetic data provide the first unequivocal demonstration that (i) the presence of Griffiths-phase-like (GP) features do not guarantee colossal magnetoresistance (CMR), while confirming (ii) that neither are the appearance of such features a prerequisite for CMR. These data also reveal that (iii) whereas continuous magnetic transitions occur for 0.18 <= x <= 0.25, the universality class of these transitions belongs to that of a nearest-neighbour 3D Heisenberg model only for x<=0.20, beyond which complications due to GP-like behaviour occur. The implications of the variation (or lack thereof) in critical exponents and particularly critical amplitudes and temperatures across the compositionally mediated M-I transition support the assertion that the dominant mechanism underlying ferromagnetism across the M-I transition changes from ferromagnetic super-exchange (SE) stabilized by orbital ordering in the insulating phase to double-exchange (DE) in the orbitally disordered metallic regime. The variations in the acoustic spin-wave stiffness, D, and the coercive field, H(C), support this conclusion. These SE and DE interaction mechanisms are demonstrated to not only belong to the same universality class but are also characterized by comparable coupling strengths. Nevertheless, their percolation thresholds are manifestly different in this system. PMID- 21693994 TI - Interplay between magnetism and superconductivity and the appearance of a second superconducting transition in alpha-FeSe at high pressure. AB - We synthesized tetragonal alpha-FeSe by melting a powder mixture of iron and selenium at high pressure. Subsequent annealing at normal pressure results in removing traces of hexagonal beta-FeSe, formation of a rather sharp transition to a superconducting state at T(c)~7 K, and the appearance of a magnetic transition near T(M) = 120 K. Resistivity and ac-susceptibility were measured on the annealed sample at hydrostatic pressure up to 4.5 GPa. A magnetic transition visible in ac-susceptibility shifts down under pressure and a resistive anomaly typical for a spin density wave (SDW) antiferromagnetic transition develops near the susceptibility anomaly. T(c), determined by the appearance of a diamagnetic response in susceptibility, increases linearly under pressure at a rate dT(c)/dP = 3.5 K GPa(-1). Below 1.5 GPa, the resistive superconducting transition is sharp, the width of transition does not change with pressure and, T(c), determined by a peak in drho/dT, increases at a rate ~3.5 K GPa(-1). At higher pressure, a giant broadening of the resistive transition develops. This effect cannot be explained by possible pressure gradients in the sample and is inherent to alpha-FeSe. The dependences drho(T)/dT show a signature for a second peak above 3 GPa which is indicative of the appearance of another superconducting state in alpha-FeSe at high pressure. We argue that this second superconducting phase coexists with SDW antiferromagnetism in a partial volume fraction and originates from pairing of charge carriers from other sheets of the Fermi surface. PMID- 21693995 TI - The band structure and Fermi surface of (Sr(3)Sc(2)O(5))Fe(2)As(2). AB - Inspired by the experience in CuO-based superconductor that a larger spacing distance between CuO planes induced a higher T(C), some researchers synthesized (Sr(3)Sc(2)O(5))Fe(2)As(2) and related compounds with spacing distances between FeAs planes as large as 15 A and expected a higher T(C). Our density functional calculations indicate that the Fermi surface of (Sr(3)Sc(2)O(5))Fe(2)As(2) is very similar to that of LaOFeAs, while the projected band structure shows some differences. From Fermi surface nesting and the calculated Lindhard response function chi(q), we predict that a spin density wave (SDW) and stripe antiferromagnetism (AF) may exist in the undoped compound and that electron or hole doping will suppress this SDW state. Similar to LaFeAsO, both the stabilization energy and the moment are very sensitive to the As atom positions. Because of the considerable similarity to LaFeAsO, (Sr(3)Sc(2)O(5))Fe(2)As(2) is expected to become a superconductor with electron or hole doping. PMID- 21693996 TI - Quantum oscillations in the high frequency magnetoacoustic response of a quasi two-dimensional metal. AB - In this work we present the results of theoretical analysis of magnetic quantum oscillations of the velocity and attenuation of high frequency ultrasound waves traveling in quasi-two-dimensional (Q2D) conductors. We chose a geometry where both the wavevector of the longitudinal sound wave and the external magnetic field are directed along the axis of symmetry of the Fermi surface. Assuming a moderately weak Fermi surface corrugation, we showed that the oscillating correction to the sound velocity may include a special term besides an ordinary contribution originating from quantum oscillations of the charge carrier density of states at the Fermi surface. This additional term is generated by a 'phase stability' resonance occurring when the charge carrier velocity in the direction of the wave propagation equals the sound velocity. The two oscillating contributions to the sound velocity are shown to differ in phase and shape, and they may have the same order of magnitude. The appearance of the extra term may bring about significant changes in magnetic quantum oscillations of the velocity of sound in Q2D conductors, especially at low temperatures. PMID- 21693997 TI - Unconventional superconductivity in YNi(2)B(2)C. AB - We use the semiclassical (Doppler shift) approximation to calculate magnetic field angle-dependent density of states and thermal conductivity kappa(zz) for a superconductor with a quasi-two-dimensional Fermi surface and line nodes along k(x) = 0 and k(y) = 0. The results are shown to be in good quantitative agreement with experimental results obtained for YNi(2)B(2)C (Izawa K et al 2002 Phys. Rev. Lett. 89 137006). PMID- 21693998 TI - Raman scattering study of background electron density in InN: a hydrodynamical approach to the LO-phonon-plasmon coupled modes. AB - We use a hydrodynamical approach to analyse the long-wavelength LO-phonon-plasmon coupled modes observed in a set of high-quality MBE-grown InN epilayers with electron densities varying over one order of magnitude, from ~2 * 10(18) to ~2 * 10(19) cm(-3). The samples were characterized by scanning electron microscopy, x ray diffraction and Hall measurements. The correlation observed between the E(2)(high) mode frequency, and hence residual strain, and the electron density measured in the layers indicates that the differences in background electron density may be associated with threading dislocations. Owing to the low Raman signal, only the L(-) branch of the coupled modes can be unambiguously observed. The frequency of the L(-) Raman peak is, however, sensitive enough to the free electron density to allow its determination from lineshape fits to the spectra. These were carried out using an extended hydrodynamical model. Given the small bandgap energy and large conduction band nonparabolicity of InN, suitable expressions for the optical effective mass and mean square velocity that enter the hydrodynamical model were derived. Electron density values extracted from L( ) lineshape fits agree reasonably well with Hall determinations. PMID- 21693999 TI - Microscopic theory of longitudinal sound velocity in charge ordered manganites. AB - A microscopic theory of longitudinal sound velocity in a manganite system is reported here. The manganite system is described by a model Hamiltonian consisting of charge density wave (CDW) interaction in the e(g) band, an exchange interaction between spins of the itinerant e(g) band electrons and the core t(2g) electrons, and the Heisenberg interaction of the core level spins. The magnetization and the CDW order parameters are considered within mean-field approximations. The phonon Green's function was calculated by Zubarev's technique and hence the longitudinal velocity of sound was finally calculated for the manganite system. The results show that the elastic spring involved in the velocity of sound exhibits strong stiffening in the CDW phase with a decrease in temperature as observed in experiments. PMID- 21694000 TI - First-principles calculation on the Curie temperature of Gd(3)NiSi(2). AB - The electronic structure and magnetic properties for Gd(3)NiSi(2) have been studied theoretically from a first-principles density functional calculation. The energy band structure is calculated in a local spin density approximation (LSDA), and in a LSDA+Hubbard U approach (LSDA+U), respectively. For Gd atoms, in the LSDA+U approximation, seven spin-up 4f bands are fully occupied and situated at the bottom of Si s states, while the spin-down 4f hole levels are completely unoccupied and well above the Fermi level. The calculated magnetic moments for the three Gd sites vary from 7.13 to 7.16 u(B), leading to a total magnetization of 21.5 u(B) per formula unit including the small induced moments at Ni and Si atoms. The exchange coupling parameters for the nearest Gd-Gd pairs (J(Gd-Gd)) are 0.16 mRyd, 0.14 mRyd and 0.19 mRyd in the three Gd sub-lattices, respectively. The inter-site distance dependence of J(Gd-Gd) shows a RKKY-like oscillation. The estimated Curie temperature is about 251 K from the calculated exchange coupling parameters based on the mean-field approximation, in good agreement with the experimental value (T(C)(exp.) = 215 K). PMID- 21694001 TI - Flexible relaxor materials: Ba(2)Pr(x)Nd(1-x)FeNb(4)O(15) tetragonal tungsten bronze solid solution. AB - Relaxors are very interesting materials but most of the time they are restricted to perovskite materials and thus their flexibility is limited. We have previously shown that tetragonal tungsten bronze (TTB) niobate Ba(2)PrFeNb(4)O(15) was a relaxor below 170 K and that Ba(2)NdFeNb(4)O(15) displays a ferroelectric behavior with a T(C) = 323 K. On scanning the whole solid solution Ba(2)Pr(x)Nd(1 x)FeNb(4)O(15) (x = 0, 0.2, 0.4, 0.5, 0.6, 0.8 and 1), we demonstrate here a continuous crossover between these end member behaviors with a coexistence of ferroelectricity and relaxor in the intermediate range. This tunability is ascribed to the peculiar structure of the TTB networks which is more open than the classical perovskites. This allows for the coexistence of long range and short range orders and thus opens up the range of relaxor materials. PMID- 21694002 TI - Non-collinearity and spin frustration in the itinerant kagome ferromagnet Fe(3)Sn(2). AB - Frustrated itinerant ferromagnets, with non-collinear static spin structures, are an exciting class of material as their spin chirality can introduce a Berry phase in the electronic scattering and lead to exotic electronic phenomena such as the anomalous Hall effect (AHE). This study presents a reexamination of the magnetic properties of Fe(3)Sn(2), a metallic ferromagnet, based on the two-dimensional kagome bilayer structure. Previously thought of as a conventional ferromagnet, we show using a combination of SQUID (superconducting quantum interference device) measurements, symmetry analysis and powder neutron diffraction that Fe(3)Sn(2) is a frustrated ferromagnet with a temperature-dependent non-collinear spin structure. The complexity of the magnetic interactions is further evidenced by a re-entrant spin glass transition ([Formula: see text] K) at temperatures far below the main ferromagnetic transition (T(C) = 640 K). Fe(3)Sn(2) therefore provides a rare example of a frustrated itinerant ferromagnet. Further, as well as being of great fundamental interest our studies highlight the potential of Fe(3)Sn(2) for practical application in spintronics technology, as the AHE arising from the ferromagnetism in this material is expected to be enhanced by the coupling between the conduction electrons and the non-trivial magnetic structure over an exceptionally wide temperature range. PMID- 21694003 TI - Magnetic field induced ferroelectric to relaxor crossover in Tb(1-x)Ca(x)MnO(3). AB - The influence of magnetic field on the electrical properties of Tb(1 x)Ca(x)MnO(3) has been investigated by means of dielectric, polarization and neutron diffraction measurements. A field of 6 T applied along the b-axis induces a crossover from ferroelectric to relaxor behavior for the x = 0.02 compound at temperatures close to the ferroelectric transition. The mechanism of this field induced crossover involves a decrease in the coherence length of the Mn-spin spiral structure due to increasing electron hopping rates associated with double exchange. Moreover, a large negative magnetocapacitance is observed at the freezing temperature for x = 0.05, which originates from suppression of the relaxor state and thus represents a new mechanism of magnetocapacitance. PMID- 21694004 TI - New transformation mechanism for a zinc-blende to rocksalt phase transformation in MgS. AB - The stability of the zinc-blende structured MgS is studied using a constant pressure ab initio molecular dynamics technique. A phase transition into a rocksalt structure is observed through the simulation. The zinc-blende to rocksalt phase transformation proceeds via two rhombohedral intermediate phases within R3m (No:160) and [Formula: see text] (No:166) symmetries and does not involve any bond breaking. This mechanism is different from the previously observed mechanism in molecular dynamics simulations. PMID- 21694005 TI - Stable phases of iron at terapascal pressures. AB - We have used density-functional-theory methods to study phases of iron at terapascal (TPa) pressures. Hexagonal-close-packed (hcp) iron is stable from below 0.1 TPa to multi-TPa pressures, where we find a window of 7-21 TPa in which the face-centred-cubic (fcc) phase is slightly more stable. At 34 TPa we find a transition to a body-centred-tetragonal (bct) phase, which is a small distortion of the body-centred-cubic (bcc) structure. The bcc phase also becomes more stable than the hcp above 35 TPa. The bct and bcc phases become considerably more stable than hcp and fcc at even higher pressures, and we expect this result to hold at high temperatures. PMID- 21694006 TI - A nonlocal shell model for mode transformation in single-walled carbon nanotubes. AB - A second-order strain gradient nonlocal shell model is established to study the mode transformation in single-walled carbon nanotubes (SWCNTs). Nonlocal length is calibrated carefully for SWCNTs in reference to molecular dynamics (MD) simulations through analysis of nonlocal length effects on the frequencies of the radial breathing mode (RBM) and circumferential flexural modes (CFMs) and its effects on mode transformation. All analyses show that only a negative second order nonlocal shell model is appropriate to SWCNTs. Nonlocal length is evidently related to vibration modes and the radius-to-thickness ratio. It is found that a nonlocal length is approximately 0.1 nm in an average sense when RBM frequency is concerned. A nonlocal length of 0.122-0.259 nm is indicated for the mode transformation in a selected group of armchair SWCNTs. 2:1 and 1:1 internal resonances are found for the same SWCNT based on different models, which implies that the internal resonance mechanism depends on the model employed. Furthermore, it is shown that an effective thickness of approximately 0.1 nm is more appropriate to SWCNTs than 0.066 nm. PMID- 21694007 TI - Quantum confinement and magnetic-field effects on the electron g factor in GaAs (Ga, Al)As cylindrical quantum dots. AB - We have performed a theoretical study of the quantum confinement (geometrical and barrier potential confinements) and axis-parallel applied magnetic-field effects on the conduction-electron effective Lande g factor in GaAs-(Ga, Al)As cylindrical quantum dots. Numerical calculations of the g factor are performed by using the Ogg-McCombe effective Hamiltonian-which includes non-parabolicity and anisotropy effects-for the conduction-band electrons. The quantum dot is assumed to consist of a finite-length cylinder of GaAs surrounded by a Ga(1-x)Al(x)As barrier. Theoretical results are given as functions of the Al concentration in the Ga(1-x)Al(x)As barrier, radius, lengths and applied magnetic fields. We have studied the competition between the quantum confinement and applied magnetic field, finding that in this type of heterostructure the geometrical confinement and Al concentration determine the behavior of the electron effective Lande [Formula: see text] factor, as compared to the effect of the applied magnetic field. Present theoretical results are in good agreement with experimental reports in the limiting geometry of a quantum well, and with previous theoretical findings in the limiting case of a quantum well wire. PMID- 21694008 TI - Quantum phase transition and underscreened Kondo effect in electron transport through parallel double quantum dots. AB - We investigate electronic transport through a parallel double quantum dot (DQD) system with strong on-site Coulomb interaction and capacitive interdot coupling. By applying the numerical renormalization group (NRG) method, the ground state of the system and the transmission probability at zero temperature have been obtained. For a system of quantum dots with degenerate energy levels and small interdot tunnel coupling, the spin correlations between the DQDs is ferromagnetic and the ground state of the system is a spin-1 triplet state. The linear conductance will reach the unitary limit (2e(2)/h) due to the underscreened Kondo effect at low temperature. As the interdot tunnel coupling increases, there is a quantum phase transition from ferromagnetic to antiferromagnetic spin correlation in DQDs and the linear conductance is strongly suppressed. PMID- 21694009 TI - Superconductivity and structure of gallium under nanoconfinement. AB - Superconductivity and crystalline structure were studied for two nanocomposites consisting of gallium loaded porous glasses with different pore sizes. The superconducting transition temperatures were found to differ from those in known bulk gallium modifications. The transition temperatures 7.1 and 6.7 K were ascribed to two new confined gallium structures, iota- and kappa-Ga, observed by synchrotron radiation x-ray powder diffraction. The evolution of superconductivity on decreasing the pore filling with gallium was also studied. PMID- 21694010 TI - Exact analytic solutions for a Dirac electron moving in graphene under magnetic fields. AB - Exact analytical solutions for the bound states of a graphene Dirac electron in various magnetic fields with translational symmetry are obtained. In order to solve the time-independent Dirac-Weyl equation the factorization method used in supersymmetric quantum mechanics is adapted to this problem. The behavior of the discrete spectrum, probability and current densities are discussed. PMID- 21694011 TI - The elastic stability, bifurcation and ideal strength of gold under hydrostatic stress: an ab initio calculation. AB - In this paper, we employ an ab initio density functional theory calculation to investigate the elastic stability of face-centered cubic Au under hydrostatic deformation. We identify the elastic stiffness constant B(ijkl) as the coefficient in the stress-strain relation for an arbitrary deformed state, and use it to test the stability condition. We show that this criterion bears the same physics as that proposed earlier by Frenkel and Orowan and agrees with the Born-Hill criterion. The results from those two approaches agree well with each other. We show that the stability limit, or instability, of the perfect Au crystal under hydrostatic expansion is not associated with the bulk stiffness modulus as predicted in the previous work; rather it is caused by a shear instability associated with the vanishing rhombohedral shear stiffness modulus. The deviation of the deformation mode from the primary hydrostatic loading path signals a bifurcation or symmetry breaking in the ideal crystal. The corresponding ideal hydrostatic strength for Au is 19.2 GPa at the Lagrangian expansion strain of ~0.06. In the case of compression, Au remains stable over the entire pressure range in our calculation. PMID- 21694012 TI - Modeling local structure using crystal field and spin Hamiltonian parameters: the tetragonal Fe(K)(3+)-O(I)(2-) defect center in KTaO(3) crystal. AB - The local structure and the spin Hamiltonian (SH) parameters, including the zero field-splitting (ZFS) parameters D and (a+2F/3), and the Zeeman g factors [Formula: see text] and [Formula: see text], are theoretically investigated for the Fe(K)(3+)-O(I)(2-) center in KTaO(3) crystal. The microscopic SH (MSH) parameters are modeled within the framework of the crystal field (CF) theory employing the CF analysis (CFA) package, which also incorporates the MSH modules. Our approach takes into account the spin-orbit interaction as well as the spin spin and spin-other-orbit interactions omitted in previous studies. The superposition model (SPM) calculations are carried out to provide input CF parameters for the CFA/MSH package. The combined SPM-CFA/MSH approach is used to consider various structural models for the Fe(K)(3+)-O(I)(2-) defect center in KTaO(3). This modeling reveals that the off-center displacement of the Fe(3+) ions, Delta(1)(Fe(3+)), combined with an inward relaxation of the nearest oxygen ligands, Delta(2)(O(2-)), and the existence of the interstitial oxygen O(I)(2-) give rise to a strong tetragonal crystal field. This finding may explain the large ZFS experimentally observed for the Fe(K)(3+)-O(I)(2-) center in KTaO(3). Matching the theoretical MSH predictions with the available structural data as well as electron magnetic resonance (EMR) and optical spectroscopy data enables predicting reasonable ranges of values of Delta(1)(Fe(3+)) and Delta(2)(O(2-)) as well as the possible location of O(I)(2-) ligands around Fe(3+) ions in KTaO(3). The defect structure model obtained using the SPM-CFA/MSH approach reproduces very well the ranges of the experimental SH parameters D, [Formula: see text] and [Formula: see text] and importantly yields not only the correct magnitude of D but also the sign, unlike previous studies. More reliable predictions may be achieved when experimental data on (a+2F/3) and/or crystal field energy levels become available. Comparison of our results with those arising from alternative models existing in the literature indicates considerable advantages of our method and presumably higher reliability of our predictions. PMID- 21694013 TI - Stabilities and fragmentation energies of Si(n) clusters (n = 2-33). AB - The structures of Si(n) (n = 2-33) were confirmed by genetic algorithm (GA)/tight binding (TB) search and ab initio calculations at the B3LYP/6- 311++G(2d) and PW91/6-311++G(2d) level, respectively. The fragmentation energies, binding energies, second differences in energy, and highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) gaps in the size range 2<=n<=33 were calculated and analyzed systematically. We extended the cluster size involved in the fragmentation analyses up to Si(33), and studied the multi-step fragmentations of Si(n). The calculated result is similar to the fragmentation behavior of small silicon clusters studied previously, showing that Si(6), Si(7), and Si(10) have relatively larger stabilities and appear more frequently in the fragmentation products of large silicon clusters, which is in good agreement with the experimental observations. PMID- 21694014 TI - Optical properties of LiGaS(2): an ab initio study and spectroscopic ellipsometry measurement. AB - Electronic and optical properties of lithium thiogallate crystal, LiGaS(2), have been investigated by both experimental and theoretical methods. The plane-wave pseudopotential method based on DFT theory has been used for band structure calculations. The electronic parameters of Ga 3d orbitals have been corrected by the DFT+U methods to be consistent with those measured with x-ray photoemission spectroscopy. Evolution of optical constants of LiGaS(2) over a wide spectral range was determined by developed first-principles theory and dispersion curves were compared with optical parameters defined by spectroscopic ellipsometry in the photon energy range 1.2-5.0 eV. Good agreement has been achieved between theoretical and experimental results. PMID- 21694015 TI - Structural and electronic properties of lutecia from first principles. AB - The structural and electronic properties of lutecia (C-type Lu(2)O(3)) have been investigated using the projected augmented wave (PAW) method based on the periodic density functional theory (DFT). Two models for the localized Lu 4f electrons have been employed, in which the f electrons are treated as a part of the inner core and as valence electrons, respectively. With the former model, the Perdew-Burke-Ernzerhof (PBE) calculations yield a crystal structure in good agreement with experiments, while with the latter model, the PBE+U results show that the optimum U(eff) parameter value is dependent on the property investigated. The variation of structural properties with respect to the model used and the U(eff) value chosen has been rationalized in terms of the repulsive interaction between Lu 4f and O 2p electrons owing to the insufficient self interaction cancelation associated with the localized f electrons in the DFT functional. Based on the calculated results, a practical scheme is proposed for the calculation of Lu(2)O(3) and the related materials in cases where the f electronic properties are relevant. PMID- 21694016 TI - Characteristic crossing point (T(*)~2.7 K) in specific heat curves of samples RuSr(2)Gd(1.5)Ce(0.5)Cu(2)O(10-delta) taken for different values of magnetic field. AB - Magnetic properties of polycrystalline samples of RuSr(2)(Gd(1.5)Ce(0.5))Cu(2)O(10-delta), as-prepared (by solid-state reaction) and annealed (12 h at 845 degrees C) in pure oxygen at different pressure (30, 62 and 78 atm) are presented. The specific heat and magnetization were investigated in the temperature range 1.8-300 K with a magnetic field up to 8 T. The specific heat, C(T), shows a jump at the superconducting transition (with an onset at T~37.5 K). Below 20 K, a Schottky-type anomaly becomes apparent in C(T). This low-temperature anomaly can be attributed to splitting of the ground term (8)S(7/2) of paramagnetic Gd(3+) ions by internal and external magnetic fields. It is found that curves C(T) taken for different values of magnetic field have the same crossing point (at T(*)~2.7 K) for all the samples studied. At the same time, C(H) curves taken for different temperatures have a crossing point at a characteristic field H(*)~3.7 T. These effects can be considered as a manifestation of the crossing point phenomenon which is supposed to be inherent for strongly correlated electron systems. PMID- 21694017 TI - Mossbauer study of superconducting NdFeAsO(0.88)F(0.12) and its parent compound NdFeAsO. AB - (57)Fe Mossbauer spectroscopy has been used to investigate the magnetic order of non-superconducting NdFeAsO (T(N) = 140 K) and superconducting NdFeAsO(0.88)F(0.12) (T(c) = 45 K). A magnetic hyperfine field B(hf) was observed at the (57)Fe nucleus below T(N)~140 K for NdFeAsO. Below ~2 K an increase of B(hf) relative to the saturation value was attributed to the transferred B(hf) at the Fe site resulting from the collinear antiferromagnetic (AF) spin structure of the Nd moments. The analysis of the spectra is consistent with a commensurate AF order of Fe spins. No B(hf) is observed in superconducting NdFeAsO(0.88)F(0.12) down to 1.5 K. PMID- 21694018 TI - Evidence for two electronic components in high-temperature superconductivity from NMR. AB - A new analysis of (63)Cu and (17)O NMR shift data on La(1.85)Sr(0.15)CuO(4) is reported that supports earlier work arguing for a two-component description of La(1.85)Sr(0.15)CuO(4), but conflicts with the widely held view that the cuprates are a one-component system. The data are analyzed in terms of two components A and B with susceptibilities chi(AA), chi(AB)(= chi(BA)) and chi(BB). We find that above T(c), chi(AB) and chi(BB) are independent of temperature and obtain for the first time the temperature dependence of all three susceptibilities above T(c) as well as the complete temperature dependence of chi(AA)+chi(AB) and chi(AB)+chi(BB) below T(c). The form of the results agrees with that recently proposed by Barzykin and Pines. PMID- 21694019 TI - Geometry, electronic structure and thermodynamic stability of intrinsic point defects in indium oxide. AB - Intrinsic point defects in indium oxide, including vacancies, interstitials as well as antisites, are studied by means of first-principles calculations within density functional theory using the generalized gradient approximation together with on-site corrections. Finite-size effects are corrected by an extrapolation procedure in order to obtain defect formation energies at infinite dilution. The results show that all intrinsic donor defects have shallow states and are capable of producing free electrons in the conduction band. This applies in particular to the oxygen vacancy. Since it has also a low formation energy, we find that the oxygen vacancy should be the major donor in this material explaining the n-type conductivity as well as the non-stoichiometry of indium oxide. In addition, we show that there are a wealth of oxygen dumbbell-like defects which are thermodynamically relevant under oxidizing conditions. Finally, we discuss defect induced changes of the electronic structure. PMID- 21694020 TI - Phase diagram of a quantum Hall pseudospin ferromagnet in a two-subband electron system. AB - We employ the self-consistent local density approximation and the microscopic Hartree-Fock theory to investigate the quantum Hall pseudospin ferromagnets at the Landau levels degenerate regime of a single quantum well with two-subbands filled. We carry out a detailed calculation of the pseudospin anisotropy energy using real experimental parameters and obtain the phase diagrams that would be accessed experimentally by changing the electron density and the bias voltage. We find that an easy-plane and easy-axis quantum Hall pseudospin ferromagnet can form at total filling factors nu = 3 and nu = 4, respectively, which are consistent with experimental observation. Our study provides some insight into the symmetry of the ground state and may help in understanding the underlying mechanism. PMID- 21694021 TI - Landau model for the elastic properties of the ferroelastic crystal Rb(4)LiH(3)(SO(4))(4). AB - Using sound velocity measurements, we report a detailed investigation of the elastic properties of Rb(4)LiH(3)(SO(4))(4) realized as a function of temperature and pressure. Results are compared to predictions of a phenomenological Landau model. Supported by recent Raman scattering measurements, we assume that the [Formula: see text] structural transformation observed at T(c) = 134 K corresponds to a pseudo-proper ferroelastic transition. For the numerical analysis, all coupling parameters are determined using the temperature dependence of the frequency of the soft optical B mode, the temperature dependence of spontaneous strains, and the pressure dependence dT(c)/dP = 191 +/- 2 K GPa(-1) also determined in this work. Our comparison indicates that the [Formula: see text] structural transition in Rb(4)LiH(3)(SO(4))(4) is fully consistent with predictions derived using our pseudo-proper ferroelastic model. Thus, all data presented in this paper corroborate that the mechanism leading to the structural transition at T(c) = 134 K results from the softening of the B optical mode observed at 31 cm(-1). This detailed analysis also refutes the idea that Rb(4)LiH(3)(SO(4))(4) shows incomplete softening of the soft acoustic mode also associated with that structural transition. PMID- 21694022 TI - Temperature and size dependence of electron magnetic resonance spectra of Ni nanoparticles embedded in an amorphous SiO(2) matrix. AB - Investigations of spin dynamics in Ni nanoparticles (NPs) with diameters D = 3.8, 11.7, 15 and 21 nm embedded in an amorphous SiO(2) matrix of composition 15/85 (Ni/SiO(2)) are reported using EMR (electron magnetic resonance) spectroscopy at 9.28 GHz. Three resonance lines are observed whose EMR parameters, namely linewidth DeltaH, resonance field H(r) and intensity I(o), are measured from 5 to 300 K. Line 1 with temperature-independent DeltaH = 50 Oe and g~2, and intensity varying as 1/T, is shown to result from paramagnetic defects in the SiO(2) matrix. Lines 2 and 3, with g~2.2 and 8, respectively, and temperature-dependent EMR parameters are assigned to Ni NPs. While line 2 with g~2.2 is due to the majority of Ni NPs, the source of line 3 is discussed in terms of two possibilities: (i) large clusters of blocked Ni NPs and (ii) the inherent part of the composite asymmetric line made up of lines 2 and 3 predicted by the Raikher Stepanov (RS) model for dispersed ferromagnets. The temperature dependence of DeltaH (full width at half-maximum) of the composite line obtained by integration of the EMR spectra decreases with the increase in temperature, reaching a minimum near 300 K in agreement with the RS model. The observed decreasing asymmetry of the composite absorption spectra with increasing temperature is also in agreement with the predictions of the RS model, thus providing a satisfactory explanation for the observed temperature dependence of the EMR spectra of Ni NPs. Large clusters of blocked Ni NPs as the source of line 3 are ruled out and additional tests for the RS model are proposed. The decreasing magnetization with decreasing particle size of Ni NPs observed here is discussed in terms of the possible roles of the surface disordered spins and Ni-SiO(2) interaction. PMID- 21694023 TI - Low-temperature magnetic and transport anisotropy in manganite thin films. AB - The stability of striped magnetic phases in films of La(1-x)A(x)MnO(3) perovskites is investigated. A variational analysis is developed for different film thicknesses at fixed hole density (x = 0.3) and the competition among magnetic phases as a function of the transfer integral and the temperature is analyzed. The stabilization of an in-plane striped magnetic phase is observed with reducing the film thickness at low temperatures below the metal-insulator transition temperature. Within the adopted variational scheme, treating perturbatively the residual electron-phonon interaction, the dependence of the in plane resistivity on temperature for different thicknesses is calculated. At low temperatures, due to the striped magnetic phase, the resistivity shows an important in-plane anisotropy. The obtained results are found to be consistent with experiments. PMID- 21694024 TI - Development of electrical polarization at an antiferromagnetic transition in FeVO(4). AB - We have probed changes in the magnetic, electrical, dielectric, optical, and thermodynamic properties of iron vanadate (FeVO(4)) at two magnetic phase transitions. FeVO(4) exhibits two antiferromagnetic transitions at T(N1) = 22 K and T(N2) = 15 K. Below 15 K FeVO(4) develops an electric polarization, concomitant with the second antiferromagnetic transition and indicating strong magnetoelectric coupling. The powder averaged zero field electric polarization for the polycrystalline FeVO(4) sample is 6 uC m(-2) and can be switched by reversing the poling voltage. The peaks for certain Raman modes at larger wavenumbers shift to slightly higher energies in the temperature range between T(N1) and T(N2), but there is practically no change in the Raman spectra between the paramagnetic and ground states. These Raman features help to clarify the microscopic mechanisms for magnetoelectric coupling in FeVO(4). PMID- 21694025 TI - Interplay of dopant, defects and electronic structure in driving ferromagnetism in Co-doped oxides: TiO(2), CeO(2) and ZnO. AB - A comprehensive study of the defects and impurity (Co)-driven ferromagnetism is undertaken in the oxide semiconductors: TiO(2), ZnO and CeO(2). The effect of magnetic (Co(2+)) and non-magnetic (Cu(2+)) impurities in conjunction with defects, such as oxygen vacancies (V(o)), have been thoroughly investigated. Analyses of the x-ray diffraction (XRD) and x-ray photoelectron spectroscopy (XPS) data reveal the incorporation of cobalt in the lattice, with no signature of cobalt segregation. It is shown that oxygen vacancies are necessary for the ferromagnetic coupling in the Co-doped oxides mentioned above. The possible exchange mechanisms responsible for the ferromagnetism are discussed in light of the energy levels of dopants in the host oxides. In addition, Co and Cu co-doped TiO(2) samples are studied in order to understand the role of point defects in establishing room temperature ferromagnetism. The parameters calculated from the bound magnetic polaron (BMP) and Jorgensen's optical electronegativity models offer a satisfactory explanation of the defect-driven ferromagnetism in the doped/co-doped samples. PMID- 21694026 TI - Equilibrium susceptibilities of superparamagnets: longitudinal and transverse, quantum and classical. AB - The equilibrium susceptibility of uniaxial paramagnets is studied in a unified framework which permits us to connect traditional results of the theory of quantum paramagnets, S = 1/2,1,3/2,..., with molecular magnetic clusters, S~5,10,20 all the way up (S = 30,50,100,...,) to the theory of classical superparamagnets. This is done using standard tools of quantum statistical mechanics and linear-response theory (the Kubo correlator formalism). Several features of the temperature dependence of the susceptibility curves (crossovers, peaks, deviations from Curie law) are studied and their scalings with S identified and characterized. Both the longitudinal and transverse susceptibilities are discussed, as well as the response of the ensemble with anisotropy axes oriented at random. For the latter case a simple approximate formula is derived too, and its range of validity assessed, which could be used in the modelization of experiments. PMID- 21694027 TI - Evidence for a subtle structural symmetry breaking in EuB(6). AB - This work presents a systematic Raman scattering study and first-principles calculations for the EuB(6) system. Evidence for the presence of an incipient (~1 * 10(-4) A) tetragonal symmetry break of its crystalline structure was found. Forbidden Raman modes at omega(fRm(1))~1170 cm(-1), omega(fRm(2))~1400 cm(-1), and omega(fRm(3))~1500 cm(-1) were observed. The tetragonal symmetry of omega(fRm(2)) and omega(fRm(3)) together with spin-polarized first-principles simulations of the structural and magnetic properties fully support such a break of symmetry. Our data and calculations explain the occurrence of ferromagnetism in Eu hexaborides, previously reported. PMID- 21694028 TI - Crossover from incommensurate to commensurate magnetic orderings in CoCr(2)O(4). AB - The conical spin order of multiferroic CoCr(2)O(4) has been studied by a neutron diffraction to investigate its magnetic phase transitions at temperatures below 40 K. Magnetic order of a spiral spin component with an incommensurate propagation vector of (0.63, 0.63, 0) was observed at 26 K, while at 14.5 K, the incommensurate conical spin order showed a transition into the fixed commensurate propagation vector of (2/3,2/3,0). In addition, two satellite peaks with propagation vectors of (0.035, 0, 0) and (0, 0.035, 0) from the commensurate vector were observed. The widths of these peaks indicate a long-range magnetic order. This new magnetic configuration below 14.5 K may lead to a new model of multiferroic behavior differing from the well-known spin-current model for magnetic ferroelectricity. PMID- 21694029 TI - Spontaneous trimerization in two-dimensional antiferromagnets. AB - In this paper, we propose an exotic quantum paramagnetic state in two-dimensional antiferromagnets-the spontaneous trimer state-which is the direct product state of the trimers of spins. Each trimer is a singlet state formed by three neighboring spins with SU(3) symmetry. A frustrated spin-1 Heisenberg model in the kagome lattice is investigated. By analogy to the pseudo-potential approach in the fractional quantum Hall effect (FQHE), we find that the trimer state provides a good description for the exact ground state of this model. Other interesting properties, such as the local excitations as well as magnetization plateaus have also been investigated. PMID- 21694031 TI - Analysis of H(c2)(theta,T) for Mg(B(1-x)C(x))(2) single crystals by using the dirty two-gap model. AB - To understand the effect of carbon doping on the superconductivity in MgB(2), we obtained the angle- and temperature-dependent upper critical fields [H(c2)(theta) and H(c2)(T)] for Mg(B(1-x)C(x))(2) single crystals (x = 0.06 and 0.1) from resistivity measurements while varying the temperature, the field, and the direction of the field. The detailed values of the diffusivity for two different directions for each sigma-band and pi-band were obtained to explain both the temperature- and the angle-dependent H(c2) by using the dirty-limit two-gap model. The induced impurity scattering of the sigma-band and the pi-band for both the ab-plane and the c-direction is studied. PMID- 21694030 TI - The interplay between surface-water and hydrogen bonding in a water adlayer on Pt(111) and Ag(111). AB - The structure of a water adlayer on a Pt(111) surface is investigated by means of extensive first-principles calculations. Allowing for proton disorder, the ground state energy for the [Formula: see text] structure can be found. This results from an interplay between water/metal chemical bonding and the hydrogen bonding of the water network. This picture is supported by substituting Pt(111) with Ag(111): the almost inert surface allows for the reconstruction of the hydrogen network. PMID- 21694032 TI - Study of dielectric, magnetic, ferroelectric and magnetoelectric properties in the PbMn(x)Ti(1-x)O(3) system at room temperature. AB - We report magnetoelectric coupling at room temperature between ferroelectric and magnetic order parameters in Mn-doped PbTiO(3) compounds prepared by a solid state reaction method. X-ray diffraction showed that PbMn(x)Ti(1-x)O(3) (x = 0.1, 0.3 and 0.5) compounds were single phase. The Mn substitution reduced the lattice distortion, i.e., the c/a ratio, and hence the ferroelectric Curie temperature (T(C)) decreased with increasing Mn content. High-temperature magnetization measurements showed that the ferromagnetic Curie temperature (T(M)) decreases with increasing Mn in PbMn(x)Ti(1-x)O(3). An anomaly in the dielectric constant (epsilon) was observed in the vicinity of the ferromagnetic transition temperature. These samples exhibited magnetism and ferroelectricity simultaneously at room temperature, which was evidenced from the coexistence of saturated magnetization and polarization hysteresis loops. An enhancement in saturation polarization after poling the samples in the magnetic field was evidence of magnetoelectric coupling at room temperature. An enhancement of 11 13% in polarization was observed after poling the samples in a magnetic field at 1.2 T. PMID- 21694033 TI - Design rules to achieve high-T(C) ferromagnetism in (Ga, Mn)As alloys. AB - The Curie temperature T(C) of ferromagnetic semiconductor alloys depends not only on the alloy composition, but also on the spatial configuration of the magnetic impurities. Here we use a set of first-principle-calculated Curie temperatures to uncover-via a statistical, 'data mining' approach-the rules that govern the dependence of T(C) on the configuration of Mn substitutional impurities in GaAs. We find that T(C) is lowered (raised) when the average number of first (third and fourth) nearest-neighbour Mn pairs increases, suggesting simple atom-by-atom strategies to achieve high T(C) in (Ga, Mn)As alloys. PMID- 21694034 TI - Magnetic structure of CeRhIn(5) under magnetic field. AB - The magnetically ordered ground state of CeRhIn(5) at ambient pressure and zero magnetic field is an incommensurate helicoidal phase with the propagation vector k = (1/2,1/2,0.298) and the magnetic moment in the basal plane of the tetragonal structure. We determined by neutron diffraction the two different magnetically ordered phases of CeRhIn(5) evidenced by bulk measurements under applied magnetic field in the basal plane. The low temperature high magnetic phase corresponds to a commensurate sine-wave structure of the magnetization with k = (1/2,1/2,1/4). At high temperature, the phase is incommensurate with k = (1/2,1/2,0.298) and a possible small ellipticity. The propagation vector of this phase is the same as that of the zero-field structure. PMID- 21694035 TI - Structural transitions of non-helical Au nanotubes induced by axial compression. AB - Based on density functional calculations, we have found that axial compression can induce structural transitions between Au(n,n) and Au(2n,n) nanotubes. The corresponding energy barriers increase with n. Although Au(2n,n) nanotubes are energitically more stable, the energy difference between Au(n,n) and Au(2n,n) decreases with n. The structural transitions are believed to be unique in those nanotubes with metallic bonds, while nanotubes with covalent bonds, such as carbon nanotubes, will not have these features. PMID- 21694036 TI - Signatures of the Dirac electron in the flux dependence of total persistent currents in isolated Aharonov-Bohm rings. AB - This paper deals with the total persistent current at T = 0 produced by the exact energy solution of the Dirac electron moving on isolated 1D Aharonov-Bohm rings. Leading contributions concerning the non-relativistic limit are written down for large values of the electron number. Usual non-relativistic currents get reproduced, but now in terms of a reversed parity of the electron number. Such an 'anomaly' is able to serve as a signature of the Dirac electron referred to above. PMID- 21694037 TI - Foaming behaviour of polymer-surfactant solutions. AB - We study the effect of a non-ionic amphiphilic polymer (PEG-100 stearate also called Myrj 59) on the foaming behaviour of aqueous solutions of an anionic surfactant (sodium dodecyl sulfate or SDS). The SDS concentration was kept fixed while the Myrj 59 concentration was varied. Measurements of foamability, surface tension and electrical conductivity were carried out. The results show two opposite effects depending on the polymer concentration: foamability is higher when the Myrj 59 concentration is low; however, it decreases considerably when the polymer concentration is increased. This behaviour is due to the polymer adsorption at the air/liquid interface at lower polymer concentrations, and to the formation of a polymer-surfactant complex in the bulk at higher concentrations. The results are confirmed by surface tension and electrical conductivity measurements, which are interpreted in terms of the microstructure of the polymer-surfactant solutions. The observed behaviour is due to the amphiphilic nature of the studied polymer. The increased hydrophobicity of Myrj 59, compared to that of water-soluble polymers like PEG or PEO, increases its 'reactivity' towards SDS, i.e. the strength of its interaction with this anionic surfactant. Our results show that hydrophobically modified polymers have potential applications as additives in order to control the foaming properties of surfactant solutions. PMID- 21694038 TI - Singularities in polarization resolved angular patterns: transmittance of nematic liquid crystal cells. AB - We study the angular structure of polarization of light transmitted through a nematic liquid crystal (NLC) cell by theoretically analysing the polarization state as a function of the incidence angles. For a uniformly aligned NLC cell, the 4 * 4 matrix formalism and the orthogonality relations are used to derive the exact expressions for the transmission and reflection matrices. The polarization resolved angular patterns in the two-dimensional projection plane are characterized in terms of the polarization singularities such as C-points (points of circular polarization) and L-lines (lines of linear polarization). For linearly polarized plane waves incident on the homeotropically aligned cell, we present the results of detailed theoretical analysis describing the structure of the polarization singularities. We apply the theory to compute the polarization patterns for various orientational structures in the NLC cell and discuss the effects induced by director orientation and biaxiality. PMID- 21694039 TI - First-principles study of the elastic and thermodynamic properties of CaSiO(3) perovskite. AB - The thermodynamic and elastic properties of CaSiO(3) perovskite are investigated at high pressures and temperatures using the plane wave pseudopotential method within the local density approximation. The athermal elastic moduli of CaSiO(3) perovskite are calculated as a function of pressure up to 200 GPa. The calculated results are in excellent agreement with available experimental data at high pressure, and compare favourably with other pseudopotential predictions over the pressure regime studied. It is also found that the elastic anisotropy drops rapidly with the increase of pressure initially, and then decreases more slowly at higher pressures. The thermodynamic properties of CaSiO(3) perovskite are predicted using the quasi-harmonic Debye model for the first time; the heat capacity and the thermal expansion coefficient agree with the observed values at ambient conditions and the other calculations at high pressures and temperatures. PMID- 21694040 TI - Molecular-network-ionic structure transitions in liquid AlCl(3) and ZnCl(2) halogenides under pressure. AB - We present the in situ high-pressure-high-temperature x-ray diffraction study of the liquid AlCl(3) and ZnCl(2) halogenides having a quasi-molecular network structure in liquid state at normal pressure. These liquids are intermediate between pure covalent and ionic melts. Structural study of these liquid halogenides is indicative of a rapid and strong breakdown of an intermediate range order in a tetrahedral network of melts for the initial pressure range, 0 2.5 GPa for AlCl(3) and 0-1.8 GPa for ZnCl(2), and points to rather sharp transitions in liquids with the formation of a short-range order structure similar to ionic melt structures around 4 GPa for AlCl(3) and 3 GPa for ZnCl(2). Thus, pseudo-covalent liquid halogenides like AlCl(3) and ZnCl(2) provide testimony to two phenomena under high pressures, namely, a gradual decay of structural correlations in the tetrahedral network of the melt and a sharp transition from molecular-network to ionic structure in liquid on further compression. Such a two-stage structural transformation under pressure is the general feature for a wide class of simple melts, including most of the pseudo covalent halogenides. PMID- 21694041 TI - A note on the effects of liquid viscoelasticity and wall slip on foam drainage. AB - A foam drainage model is modified to attempt the description of foams made of viscoelastic liquids (such as polymer solutions). In particular, the standard approach to foam drainage dominated by viscous dissipation in Plateau borders is modified to take into account the elastic forces acting on the fluid within Plateau borders, and slipping of the polymer solution at the walls of Plateau borders. It is shown that, in the case of forced drainage, the resulting differential equations reduce to the same one obtained in the case of Newtonian liquids, which is satisfied by the well-known solitary wave solution. According to these results, the fluid elasticity has no effect on the drainage velocity, while the wall slip assumption is compatible with recent observations showing a faster drainage velocity in the forced drainage experiment. PMID- 21694042 TI - The shape of soap films and Plateau borders. AB - We have calculated the shapes of flat liquid films, and of the transition region to the associated Plateau borders (PBs), by integrating the Laplace equation with a position-dependent surface tension gamma(x), where 2x is the local film thickness. We discuss films in either zero or non-zero gravity, using standard gamma(x) potentials for the interaction between the two bounding surfaces. We have investigated the effects of the film flatness, liquid underpressure, and gravity on the shape of films and their PBs. Films may exhibit 'humps' and/or 'dips' associated with inflection points and minima of the film thickness. Finally, we propose an asymptotic analytical solution for the film width profile. PMID- 21694043 TI - Characteristic temperatures of glassy behaviour in a simple liquid. AB - A model for the metastable liquid in terms of holes present in the amorphous structure is considered using the classical density functional theory (DFT). For a one component Lennard-Jones liquid we obtain the temperature dependence of the free volume v(f) in the metastable state. A temperature T(0), similar to that of the characteristic transition of the free volume theory, is identified by extrapolating v(f)(T) to zero. The Kauzmann temperature T(K) is also obtained here by extrapolating the entropy difference between the supercooled state and that of the crystal to zero. We compare the temperatures T(0) and T(K) obtained in our model with other two characteristic temperatures for glassy behaviour, namely (a) the dynamic transition temperature T(c) of the mode coupling theory (MCT) and (b) the glass transition temperature T(g) which was obtained by Leonardo et al (2000 Phys. Rev. Lett. 84 6054) from studying the violation of the fluctuation-dissipation theorem. All the four temperatures, obtained from independent routes, are located with respect to the melting temperature T(m) in a manner which is in agreement with experiments. PMID- 21694044 TI - Ab initio study of the uranyl oxide hydrates: a proton transfer mediated by water. AB - We present a first-principles study of the UO(3).n(H(2)O) uranyl oxide hydrates, namely, schoepite (n = 2.25), metaschoepite (n = 2) and dehydrated metaschoepite (n = 1.75), which appear as the alteration U(VI) products of aqueous corrosion of nuclear fuel. For these compounds, the calculated enthalpy of formation is in good agreement with calorimetry and solubility measurements. We discuss the key electronic state factors behind the phase stability of uranyl oxide hydrates. An unexplored proton-transfer mechanism, which produces the H(3)O hydronium ions in UO(3).nH(2)O, has been studied using ab initio molecular dynamics simulations at room temperature. For the hydronium ion, a very short lifetime of around 20 fs has been suggested. PMID- 21694045 TI - Transport properties of an Aharonov-Bohm ring with strong interdot Coulomb interaction. AB - Based on the Keldysh Green's function technique and the equation-of-motion method, we investigate theoretically the electronic transport properties of an Aharonov-Bohm ring with embedded coupled double quantum dots connected to two electrodes in a symmetrical parallel configuration in the presence of strong interdot Coulomb interaction. Special attention is paid to the effects of the interdot Coulomb interaction on the transport properties. It has been shown numerically that the interdot Coulomb interaction gives rise to four electronic states in the ring. The quantum interferences between two strongly coupled electronic states and two weakly coupled ones lead to two Breit-Wigner and two Fano resonances in the linear conductance spectrum with the magnetic flux switched on or the imbalance between the energy levels of two quantum dots. The positions and shapes of the four resonances can be controlled by adjusting the magnetic flux through the device or energy levels of the two quantum dots. When the Fermi energy levels in the leads sweep across the weakly coupled electronic states, the negative differential conductance (NDC) is developed in the current voltage characteristics for the non-equilibrium case. PMID- 21694046 TI - Magnetic properties of NpNiGa(5). AB - We have investigated a polycrystalline sample of NpNiGa(5) by magnetization, specific heat and (237)Np Mossbauer spectroscopy. We confirm that a ferromagnetic order sets in at T(C)~30 K and that NpNiGa(5) undergoes a second transition at T(N)~18 K. Mossbauer data indicate that the transition at T(N) is accompanied by a steep increase of the Np magnetic moment, which saturates to a value of 0.94 u(B), in good agreement with the recently published neutron diffraction results. The Sommerfeld specific heat coefficient gamma = 114 mJ mol(-1) K(-2) is the highest among the NpTGa(5) compounds. It compares to the ones observed in the PuTGa(5) superconductors. The trend of the isomer shift along the NpTGa(5) (T = Fe, Co, Ni, Rh) series points to a tendency towards localization of the 5f electrons when increasing the number of d electrons of the transition metal T. Neither fully localized nor fully itinerant models are able to reproduce the whole experimental data. Realistic models should include the dual nature of the 5f electrons, i.e. consider the difference in the degree of itinerancy among 5f electrons in the NpTGa(5) compounds. PMID- 21694047 TI - A methodology for coupling an atomic model with a continuum model using an extended Lagrange function. AB - We propose a hybrid method combining an atomic model and a continuum model, in which the displacement field of the continuum is introduced as a new degree of freedom by extending Andersen's Lagrange function for constant-pressure molecular dynamics. We applied our method to a one-dimensional hybrid model which is composed of an atomic chain and springs. Large-scale fluctuation of the atomic system is found in the hybrid model. The density of states of the phonon is derived, and the large-scale fluctuation induces the generation of a variety of states of phonons. It is shown that the hybrid model proposed by our methodology enables us to perform large-scale simulations without intensive computations. PMID- 21694048 TI - Effects of neodymium incorporation on the structural and luminescence properties of the YAl(3)(BO(3))(4)-NdAl(3)(BO(3))(4) system. AB - The luminescence of Nd(3+) ions in Nd(x)Y(1-x)Al(3)(BO(3))(4) (Nd:YAB) single crystals has been investigated as a function of the neodymium concentration in order to evidence the relation between the structural and spectroscopic properties in this nonlinear laser system. The analysis of the experimental data allowed us to individuate four different composition ranges. For moderate concentrations (x<0.2) the lattice parameters are nearly constant, and the emission spectra arise from Nd(3+) ions in unperturbed crystal sites. For concentrations in the 0.20.9 the final formation of the NdAl(3)(BO(3))(4) (NAB) monoclinic phase is complete, and a new local ordering around Nd(3+) is very evident in the spectral features. PMID- 21694049 TI - Room-temperature ferromagnetism in pure and Co doped CeO(2) powders. AB - We report the room-temperature (RT) ferromagnetism (FM) observed in pure and Co doped CeO(2) powder. An insulating nonmagnetic CeO(2) single crystal, after grinding into fine powder, shows an RT-FM with a small magnetization of 0.0045 emu g(-1). However, the CeO(2) powder became paramagnetic after oxygen annealing, which strongly suggests an oxygen vacancy meditated FM ordering. Furthermore, by doping Co into CeO(2) powder the FM can significantly enhance through a F-centre exchange (FCE) coupling mechanism, in which both oxygen vacancies and magnetic ions are involved. As the Co content increases, the FM of Co doped CeO(2) initially increases to a maximum 0.47 emu g(-1), and then degrades very quickly. The complex correlation between the Co content and saturation magnetization was well interpreted by supposing the coexistence of three subsets of Co ions in CeO(2). Our results reveal that the large RT-FM observed in Co doped CeO(2) powder originates from a combination effect of oxygen vacancies and transition metal doping. PMID- 21694050 TI - Second amorphous-to-crystalline phase transformation in Cu(60)Ti(20)Zr(20) bulk metallic glass. AB - The second amorphous-to-crystalline phase transformation in Cu(60)Ti(20)Zr(20) bulk metallic glass was investigated by differential scanning calorimetry and x ray diffractometry. The difference of the Gibbs free energies between the amorphous phase and the crystalline products during the transformation is estimated to be about 2.46 kJ mol(-1) at 753 K, much smaller than the 61 kJ mol( 1) obtained assuming that it is a polymorphic transformation. It was revealed that the phase transformation occurs through a eutectic crystallization of Cu(51)Zr(14) and Cu(2)TiZr, having an effective activation energy of the order of 400 kJ mol(-1). The average Avrami exponent n is about 2.0, indicating that the crystallization is diffusion controlled. PMID- 21694051 TI - Spin-dependent transport caused by the local magnetic moments inserted in the Aharonov-Bohm rings. AB - We analyse the conductance of an Aharonov-Bohm (AB) ring with a quantum point contact (QPC) that is inserted in one of its arms and which contains a single electron. The conductance of the device is calculated as a function of the one dimensional (1D) carrier concentration and the value of the magnetic field perpendicular to the plane of the AB ring. The exchange interaction between the electron localized inside QPC and freely propagating electrons is shown to modify the conductance pattern at small carrier concentration significantly, giving rise to the effects related to the formation of the '0.7 feature' in the quantum conductance staircase. PMID- 21694052 TI - Magnetic resonance in nanoparticles: between ferro- and paramagnetism. AB - Magnetic nanoparticles of gamma-Fe(2)O(3) coated with organic molecules and suspended in liquid and solid matrices, as well as non-diluted magnetic fluid, have been studied by electron magnetic resonance (EMR) at 77-380 K. Slightly asymmetric spectra observed at room temperature become much broader and symmetric, and shift to lower fields upon cooling. An additional narrow spectral component (with a line-width of 30 G) is found in diluted samples; its magnitude obeys the Arrhenius law with an activation temperature of about 850 K. The longitudinal spin-relaxation time, T(1)~10 ns, is determined by a specially developed modulation method. The angular dependence of the EMR signal position in field-freezing samples points to substantial alignment, suggesting the formation of dipolar-coupled aggregates. The shift and broadening of the spectrum upon cooling are assigned to the effect of the surface-related anisotropy. To describe the overall spectral shape, the 'quantization' model is used which includes summation of resonance transitions over the whole energy spectrum of a nanoparticle considered as a giant exchange cluster. This approach, supplemented with some phenomenological assumptions, provides satisfactory agreement with the experimental data. PMID- 21694053 TI - Characterization of the size and orientation of Na and Cl(2) nanocrystals in electron irradiated NaCl crystals by means of synchrotron radiation. AB - Samples of synthetic NaCl crystals have been exposed to doses of electron irradiation up to 10(-2) TGy (1 Trad) at about 100 degrees C, and studied subsequently at T = 95 K by means of synchrotron radiation (SR). In addition to the earlier established Kurdjumov-Sachs orientation relationship (K-S OR) for Na precipitates, the following OR is revealed between solid chlorine and the host NaCl crystal system: [Formula: see text], [Formula: see text]. The size and shape of the Cl(2) precipitates has been studied as a function of the amount of radiation damage (i.e. the concentrations of Na and Cl(2)). PMID- 21694054 TI - Effect of electron/hole doping on the transport properties of lanthanum manganites LaMnO(3). AB - We report the results of electrical resistivity, magnetic susceptibility and thermoelectric power measurements on the stoichiometric hole-doped La(0.8)Ca(0.2)MnO(3) and electron-doped La(0.8)Ce(0.2)MnO(3) manganites. The resistivity and thermopower data show a metal-insulator phase transition for both samples. Magnetic susceptibility measurement confirms that both the samples undergo a transition from paramagnetic to ferromagnetic phase at defined Curie temperatures T(c) = 240 K (La(0.8)Ca(0.2)MnO(3)) and 263 K (La(0.8)Ce(0.2)MnO(3)). The electrical resistivity data are then theoretically analysed within the framework of the classical electron-phonon model of resistivity, i.e. the Bloch-Gruneisen model. Detailed analysis of the electrical resistivity of electron- and hole-doped manganites suggests that besides the electron-phonon effect another possibility for the change in carrier density arises due to the presence of electron correlation in the metallic system. From the thermopower S(T) results, we suggest that its behaviour is determined by competition among the several operating scattering mechanisms for the heat carriers and a balance between carrier diffusion and phonon drag contributions in the polycrystalline samples of hole-doped La(0.8)Ca(0.2)MnO(3) and electron-doped La(0.8)Ce(0.2)MnO(3) manganites. PMID- 21694055 TI - A remarkable transformation of magnetic resonance spectra as a result of a mutual influence of coexisting para- and ferromagnetic phases. AB - In this work, we carry out the analysis of the resonance absorption of electromagnetic radiation for the system in which para- and ferromagnetic phases coexist over a wide temperature region. It is found that taking account of the mutual influence of coexisting phases gives rise to the appearance of substantial changes in the curves of resonance absorption and values of resonance fields, as well as to making the geometry of a phase distribution dependent on an external magnetic field. Near the temperature boundaries of the phase coexistence region, the expressions for description of the curves of the dispersive absorption of electromagnetic radiation are obtained and the rules of the behaviour of the resonance fields for each of the phases are specified. As follows from the calculations, the resonance field for the paramagnetic phase becomes dependent on the shape of the sample, the saturation magnetization and the fraction of ferromagnetic phase. It is shown that the character of magnetic resonance spectra and the features of their temperature change agree well with the experimental data, obtained by various groups of researchers on the single crystalline and polycrystalline samples of doped perovskite manganites. PMID- 21694056 TI - Dimensionality crossover in the induced magnetization of Pd layers. AB - The magnetic ordering of a series of samples consisting of ultrathin Fe layers embedded in Pd was investigated using the magneto-optical Kerr effect. The samples consisted of a single Fe layer with nominal thickness 0.2<=d(Fe)<=1.6 monolayers sandwiched between two 20 monolayer Pd layers. A dimensionality crossover from two dimensions to three dimensions occurs as d(Fe) is increased from 0.4 to 1.0 monolayers. First-principles calculations were performed in order to determine the magnetic profile, and we used a spin-wave quantum well model for obtaining a qualitative description of the dimensionality crossover. The results clearly prove the existence of a dimensionality crossover in the induced magnetization, opening new routes for addressing the influence of extension on order. PMID- 21694057 TI - Dopant rearrangement and superconductivity in Bi(2)Sr(2-x)La(x)CuO(6) thin films under annealing. AB - By combining x-ray diffraction (XRD), x-ray photoemission spectroscopy (XPS) and AC susceptibility measurements we investigate the evolution of structural and superconducting properties of La-doped Bi-2201 thin films grown by pulsed laser deposition (PLD) under different annealing conditions. We find that the main effect of oxygen annealing is to improve the crystal coherence by enabling La cation migration to the Sr sites. This activates the desired hole doping. Short time Ar annealing removes the interstitial oxygen between the BiO layers, fine adjusting the effective hole doping. The superconducting critical temperature is consequently enhanced. However, longer annealings result in phase separation and segregation of the homologous compound Bi-1201. We attribute this effect to the loss of Bi during the annealing. PMID- 21694058 TI - On the compression behaviour of (Ti(0.5),V(0.5))(2)AlC and (Ti(0.5),Nb(0.5))(2)AlC to quasi-hydrostatic pressures above 50 GPa. AB - Using a synchrotron x-ray radiation source and a diamond anvil cell we measured the functional dependences of the lattice parameters of (Ti(0.5),V(0.5))(2)AlC and (Ti(0.5),Nb(0.5))(2)AlC to quasi-hydrostatic pressure of the order of 50 GPa. Like for other solids in this family of layered ternary carbides and nitrides, the bulk moduli (~183 GPa) are high and no phase transformations were observed. The bulk moduli of the solid solution compositions were lower than those of the end members. The effect was much more dramatic when Ti replaced Nb in Nb(2)AlC than when it replaced V in V(2)AlC. In the former case the modulus drops by 13% from 209 GPa, with the softening coming almost exclusively from the c-axis. This somewhat surprising result is ascribed to the corrugation of the Ti-Nb planes in (Ti(0.5),Nb(0.5))(2)AlC. When Ti replaced V in V(2)AlC the drop in modulus was 8%. PMID- 21694059 TI - A quantitative study of valence electron transfer in the skutterudite compound CoP(3) by combining x-ray induced Auger and photoelectron spectroscopy. AB - We use the sum of the ionization and Auger energy, the so-called Auger parameter, measured from the x-ray photoelectron spectrum, to study the valence electron distribution in the skutterudite CoP(3). The electron transfer between Co and P was estimated using models relating changes in Auger parameter values to charge transfer. It was found that each P atom gains 0.24 e(-), and considering the unit formula CoP(3) this is equivalent to a donation of 0.72 e(-) per Co atom. This is in agreement with a recent electron energy-loss spectroscopy study, which indicates a charge transfer of 0.77 e(-)/atom from Co to P. PMID- 21694060 TI - Electromagnetic wave propagation in quasi-periodic photonic circuits. AB - We study theoretically and experimentally the properties of quasiperiodic one dimensional serial loop structures made of segments and loops arranged according to a Fibonacci sequence (FS). Two systems are considered. (i) By inserting the FS horizontally between two waveguides, we give experimental evidence of the scaling behaviour of the amplitude and the phase of the transmission coefficient. (ii) By grafting the FS vertically along a guide, we obtain from the maxima of the transmission coefficient the eigenmodes of the finite structure (assuming the vanishing of the magnetic field at the boundaries of the FS). We show that these two systems (i) and (ii) exhibit the property of self-similarity of order three at certain frequencies where the quasiperiodicity is most effective. In addition, because of the different boundary conditions imposed on the ends of the FS, we show that horizontal and vertical structures give different information on the localization of the different modes inside the FS. Finally, we show that the eigenmodes of the finite FS coincide exactly with the surface modes of two semi infinite superlattices obtained by the cleavage of an infinite superlattice formed by a periodic repetition of a given FS. PMID- 21694061 TI - Grain boundary properties of ice doped with small concentrations of potassium chloride (KCl). AB - The grain boundary (GB) migration rate was studied in ice bicrystals obtained from 1 to 10 umol l(-1) (0.02 to 0.2 ppm) potassium chloride (KCl) water solutions and annealed at temperatures above -20 degrees C for 170 days. GB mobility was determined as a function of annealing temperature and solute concentration. The GB mobility values obtained show a systematic dependence on the solute concentration. For the first time, it was observed in ice that small concentrations of impurity decrease the GB mobility, as occurs in other materials. The results also indicate possible changes of the GB structure in the annealing temperature range studied. PMID- 21694062 TI - CO adsorption on a Au/Ni(111) surface alloy-a DFT study. AB - The adsorption of CO on a Au/Ni(111) surface alloy has been investigated using ab initio density-functional calculations. We show that, in contrast to a Au adatom on a Ni(111) surface, a Au impurity binds CO only very weakly. In addition, the impurity induces a reduction of the adsorption energies which is strictly localized to its immediate neighbourhood. The consequences for possible reaction scenarios are discussed. PMID- 21694063 TI - Ferroic nanoclusters in relaxors: the effect of oxygen vacancies. AB - Single crystals of PbSc(0.5)Ta(0.5)O(3) with suppressed and enhanced oxygen deficiencies and different degrees of long-range B-site ordering were studied by Raman spectroscopy in order to clarify the significance of the different factors for the formation and growth of ferroic clusters in relaxors. It is shown that the presence of oxygen vacancies impacts more strongly on the incipient ferroic clustering than the degree of long-range B-site ordering. The oxygen deficiency hinders the formation of ferroelectric crystalline-type nanoregions, regardless of the presence/absence of long-range B(')/B('')-ordered regions. The low degree of defects in the O system enhances the long-range ferroelectric ordering, even in entirely B-site-disordered materials. PMID- 21694064 TI - Discrete modes of a ferromagnetic stripe dipolarly coupled to a ferromagnetic film: a Brillouin light scattering study. AB - Spin wave excitations in a magnetic structure consisting of a series of long permalloy stripes of a rectangular cross section magnetized along the stripe length and situated above a continuous permalloy film are studied both experimentally and theoretically. Stripes and continuous film are coupled by dipole-dipole interaction across 10 nm thick Cu spacers. Experimental measurements made using the Brillouin light scattering technique (with the light wavevector oriented along the stripe width) provide evidence for one dispersive spin wave mode associated with the continuous film and several discrete non dispersive modes resonating within the finite width of the stripes.To interpret the experimental spectra, an analytic theory based on the spin wave formalism for finite-width magnetic stripes has been developed, achieving a good qualitative and partly quantitative description of the experimentally observed spin wave spectrum of the system. In particular, it is explained why the presence of a continuous magnetic film near the magnetic stripe leads to a substantial decrease of the frequencies of the discrete dipolar spin wave modes localized within the stripes. A more quantitative description of the measured frequencies and of the spatial profiles of the spin wave eigenmodes has been obtained by numerical calculations performed using a finite element method. PMID- 21694065 TI - Theory of enhanced Raman scattering for circular stratified semiconductor cylinder. AB - Based on the electrodynamic theory, we have calculated the scattering fields of infinitely long dielectric nanocylinders with silver coating, and compared them with those of a pure silicon cylinder. The calculation result indicates that there exists an enhanced electric field in the silver-coated silicon nanocylinder and shows a great Raman enhancement factor (~10(12)) as compared with bulk silicon. For a special area in the silver-coated silicon nanocylinder, the enhancement comes up to 4 * 10(13). PMID- 21694066 TI - Structure and photoluminescence of (Ca,Eu)(2)SiS(4) powders. AB - The photoluminescence of Ca(2)SiS(4):Eu powders was investigated in detail as a function of europium concentration (from 0.1% Ca substitution to the fully substituted Eu(2)SiS(4)). At low europium dopant concentration (<10%) the powders crystallize in an orthorhombic structure and the emission spectrum is dominated by two broad emission bands, at 564 and 660 nm. The emission can be tuned from yellow (CIE x = 0.46,y = 0.53) to red (CIE x = 0.65,y = 0.35) by variation of the Eu concentration. An energetic coupling exists between both bands, leading to a broad excitation wavelength range. Powders with high europium concentration (>40%) crystallize in a monoclinic structure, details of which were determined by Rietveld refinement of x-ray diffraction data. For the composition CaEuSiS(4) (i.e. 50% substitution), the luminescence peaks at 614 nm, shifting to shorter wavelengths upon further substitution of Ca by Eu. Although considerable thermal quenching is present at room temperature in the fully Eu-substituted compound, Eu(2)SiS(4) is still photoluminescent, with a peak emission wavelength of 577 nm. A strong correlation is found between the crystallographic and luminescent properties of the (Ca,Eu)(2)SiS(4) powders. The broad emission and excitation bands make this phosphor a good candidate for use in phosphor-converted light emitting diodes (pcLEDs). PMID- 21694067 TI - Phase coexistence in [111] electric-field-cooled 0.7Pb (Mg(1/3)Nb(2/3))O(3) 0.3PbTiO(3) crystals. AB - Features of phase coexistence in polydomain 0.7Pb(Mg(1/3)Nb(2/3))O(3)-0.3PbTiO(3) crystals cooled under an applied [111] electric field E have been investigated. A sequence of ferroelectric phases as well as the elastic matching between coexisting phases in heterophase states has been analysed for cases where the angle between the spontaneous polarization vector of each domain type and the applied E vector remains equal in each ferroelectric phase. This analysis is based on a method that involves distortion matrices of the polydomain phases and invariants of interfaces regarded as quadric surfaces separating the phases. Results are represented in a system of diagrams linking domain states and interfaces at first-order phase transitions observed in [111] field-cooled 0.7Pb(Mg(1/3)Nb(2/3))O(3)-0.3PbTiO(3) crystals. A 'fine' structure of the domain state-interface diagrams related to tetragonal-orthorhombic phase coexistence has been revealed. It has been shown that conditions for complete stress relaxation in different heterophase states are achieved for a phase sequence of [Formula: see text] tetragonal [Formula: see text] near single-domain orthorhombic [Formula: see text] single-domain monoclinic of the B type. PMID- 21694068 TI - Multiple magnetic phase transitions in Tb(3)Cu(4)Si(4). AB - A polycrystalline sample of Tb(3)Cu(4)Si(4) was investigated by means of magnetometric, electrical resistivity, thermopower and heat capacity measurements. This paper also includes reanalyses of former neutron diffraction data. The compound crystallizes in a Gd(3)Cu(4)Ge(4)-type orthorhombic structure (Immm space group), in which the Tb ions occupy two inequivalent sites (2d and 4e). The bulk results indicate that these two magnetic sublattices order antiferromagnetically at different temperatures, in agreement with the neutron diffraction data. PMID- 21694069 TI - Comment on 'Absorption in one-dimensional metallic-dielectric photonic crystals'. AB - Using the transfer matrix method for calculating the transmittance, absorptance and photon density of states of one-dimensional metallic-dielectric photonic crystals, we investigate the origin of the absorption enhancement in these photonic systems. The effect of the metallic layer thickness on the electric field distribution is discussed. PMID- 21694070 TI - Surface passivation for tight-binding calculations of covalent solids. AB - Simulation of a cluster representing a finite portion of a larger covalently bonded system requires the passivation of the cluster surface. We compute the effects of an explicit hybrid orbital passivation (EHOP) on the atomic structure in a model bulk, three-dimensional, narrow gap semiconductor, which is very different from the wide gap, quasi-one-dimensional organic molecules where most passivation schemes have been studied in detail. The EHOP approach is directly applicable to minimal atomic orbital basis methods such as tight-binding. Each broken bond is passivated by a hybrid created from an explicitly expressed linear combination of basis orbitals, chosen to represent the contribution of the missing neighbour, e.g. a sp(3) hybrid for a single bond. The method is tested by computing the forces on atoms near a point defect as a function of cluster geometry. We show that, compared to alternatives such as pseudo-hydrogen passivation, the force on an atom converges to the correct bulk limit more quickly as a function of cluster radius, and that the force is more stable with respect to perturbations in the position of the cluster centre. The EHOP method also obviates the need for parameterizing the interactions between the system atoms and the passivating atoms. The method is useful for cluster calculations of non-periodic defects in large systems and for hybrid schemes that simulate large systems by treating finite regions with a quantum-mechanical model, coupled to an interatomic potential description of the rest of the system. PMID- 21694071 TI - Optical characterization of a Cd(0.85)Mg(0.15)Se mixed crystal. AB - We present an optical characterization of a Bridgman-grown wurtzite-type Cd(0.85)Mg(0.15)Se mixed crystal in the near-band-edge interband transitions using temperature-dependent contactless electroreflectance (CER) and photoreflectance (PR) in the temperature range 15-400 K. The interband excitonic transitions A and C originating from the band edge and spin-orbital splitting critical points of the sample, respectively, have been observed in the CER/PR spectra. The transition energies and broadening function of the excitonic features are determined via a lineshape fit to the CER/PR spectra. The parameters that describe the temperature dependence of the transition energies of excitons A and C, and the broadening function of exciton A, are evaluated and discussed. PMID- 21694072 TI - Optical reflectance anisotropy of buried Fe nanostructures on vicinal W(110). AB - The optical anisotropy of Au protected Fe layers grown on a vicinal W(110) surface has been investigated using reflectance anisotropy spectroscopy (RAS). Iron nanostripes formed at submonolayer coverage, as well as Fe layers up to 3 ML coverage, were protected by 12 and 16 nm gold caps and measured ex situ under ambient conditions. The RAS is dominated by structures originating in the interfacial W(110) region, modified by the absorption in the Au cap and possibly by uniaxial strain in the Au cap itself. The Fe nanostructures themselves do not produce a significant RAS signature but, nevertheless, differences with Fe coverage were identified and explained in terms of a simple isotropic Fe absorbing layer, together with strain relief in the W/Fe/Au interfacial region. PMID- 21694073 TI - Room-temperature growth of Mg on Si(111): stepwise versus continuous deposition. AB - Using low-energy electron diffraction and scanning tunnelling microscopy, we studied the formation of Mg silicide and metallic Mg islands on a Si(111)-7 * 7 surface at room temperature as a function of Mg coverage. We found that the mechanism by which Mg islands grew on the Si(111)-7 * 7 surface, and the morphology of the islands that formed, depended on whether the Mg deposition was performed in a stepwise or continuous manner. When Mg was deposited in a stepwise manner, with 1 h between deposition events, an amorphous Mg silicide overlayer formed on the Si(111)-7 * 7 surface during the initial stage of deposition (up to 2.0 ML Mg coverage), as shown by the observation of delta7 * 7 and 1 * 1 low energy electron diffraction patterns. Upon further stepwise Mg deposition, round shaped Mg islands grew on the amorphous Mg silicide layer, as shown by scanning tunnelling microscopy and the emergence of a 1 * 1 low-energy electron diffraction pattern. If, on the other hand, the Mg was deposited continuously in a single step, hexagonal Mg islands formed on the flat Mg silicide layers, and a [Formula: see text] and 1 * 1 mixed phase was observed. Moreover, using scanning tunnelling spectroscopy, we confirmed the semiconducting and metallic nature of the Mg silicide layer and hexagonal Mg islands on the Si(111)-7 * 7 surface depending on their Mg coverage, respectively. PMID- 21694074 TI - Phonons in the ordered c(2 * 2) phases of Na and Li on Al(001). AB - The vibrational properties of the Al(001)-c(2 * 2)-Na (Li) ordered phases formed by alkali atoms (Na and Li) on the Al(001) surface at low and room temperatures are presented. The equilibrium structural characteristics, phonon dispersions and polarization of vibrational modes as well as the local density of phonon states are calculated using the embedded-atom method. The obtained structural parameters are in close agreement with experimental data. PMID- 21694075 TI - A high-resolution core-level photoemission study of the Au/4H-SiC(0001) ([Formula: see text]) interface. AB - We present a systematic study of different reconstructions obtained after deposition of Au on the [Formula: see text]-4H-SiC(0001) surface. For 1-2 monolayers (ML) Au and annealing temperature T(anneal)~675 degrees C, a 3 * 3 reconstruction was observed. For 4 ML Au and T(anneal)~650 degrees C, a [Formula: see text] reconstruction appeared, while 5 ML Au annealed at 700 degrees C reconstructed to give a [Formula: see text] pattern. From the Si 2p and Au 4f core-level components, we propose interface models, depending on the amount of Au on the surface and the annealing temperature. For 1-4 ML Au annealed at 650 675 degrees C, gold diffuses under the topmost Si into the SiC and forms a silicide. An additional Si component in our Si 2p spectra is related to the interface between the silicide and SiC. For 5 ML Au annealed at 700 degrees C, silicide is also formed at the surface, covering unreacted Au on top of the SiC substrate. The interface Si component is also observed in the Si 2p spectra of this surface. The key role in [Formula: see text]-4H-SiC(0001) interface formation is played by diffusion and the silicon-richness of the surface. PMID- 21694076 TI - Electronic minibands in complex basis superlattices: a numerically stable calculation. AB - A numerically stable method for accurately determining the energy minibands of superlattices with arbitrary numbers of layers per cell is presented. Using a graph model with tangent and secant functions, we derive a set of concise and closed-form miniband edge equations for determining the miniband structure using topology theory. With the present method, it is not necessary to calculate the cosine of the Bloch phase, which may show a numerical overflow in calculation. Numerical results show that use of the miniband edge equations has better numerical stability than traditional methods in calculating the minibands of complex basis superlattices. PMID- 21694077 TI - Self-consistent density functional calculation of the image potential at a metal surface. AB - It is well known that the exchange-correlation (XC) potential at a metal surface has an image-like asymptotic behaviour given by -1/4(z-z(0)), where z is the coordinate perpendicular to the surface. Using a suitable fully non-local functional prescription, we evaluate self-consistently the XC potential with the correct image behaviour for simple jellium surfaces in the range of metallic densities. This allows a proper comparison between the corresponding image-plane position, z(0), and other related quantities such as the centroid of an induced charge by an external perturbation. As a by-product, we assess the routinely used local density approximation when evaluating electron density profiles, work functions, and surface energies by focusing on the XC effects included in the fully non-local description. PMID- 21694078 TI - Effects of external stress on defect complexes in semiconductors. AB - Crystal field gradients that exist at lattice sites in solids depend on the symmetry of charge distribution around atomic sites. The charge symmetry could be broken either by the presence of impurity complexes in the host matrix or by external stress on the samples, which leads to an observable magnitude of electric field gradients (EFGs). The perturbed gamma-gamma angular correlation (PAC) method is employed here to investigate the effect of uniaxial stress on (111)Cd sites in crystalline doped semiconductors. PMID- 21694079 TI - Electric field induced collapse of the charge-ordered phase in manganites. AB - The colossal electroresistance in manganites accompanies the insulator-to-metal phase transition induced by the electric field. A phenomenological phase transition model is proposed to study this electric field induced collapse of the charge-ordered phase. The hysteresis of the phase transition is well explained using the effective medium approximation. The volume fraction of the metallic region at the metal-to-insulator transition point is estimated as 30%. PMID- 21694080 TI - Effect of Co doping on the structural, optical and magnetic properties of ZnO nanoparticles. AB - We report the results of a detailed investigation of sol-gel-synthesized nanoscale Zn(1-x)Co(x)O powders processed at 350 degrees C with 0<=x<=0.12 to understand how the structural, morphological, optical and magnetic properties of ZnO are modified by Co doping, in addition to searching for the theoretically predicted ferromagnetism. With x increasing to 0.03, both lattice parameters a and c of the hexagonal ZnO decreased, suggesting substitutional doping of Co at the tetrahedral Zn(2+) sites. For x>0.03, these trends reversed and the lattice showed a gradual expansion as x approached 0.12, probably due to additional interstitial incorporation of Co. Raman spectroscopy measurements showed a rapid change in the ZnO peak positions for x>0.03, suggesting significant disorder and changes in the ZnO structure, in support of additional interstitial Co doping possibility. Combined x-ray photoelectron spectroscopy (XPS), electron paramagnetic resonance spectroscopy, photoluminescence spectroscopy and diffuse reflectance spectroscopy showed clear evidence for tetrahedrally coordinated high spin Co(2+) ions occupying the lattice sites of ZnO host system, which became saturated for x>0.03. Magnetic measurements showed a paramagnetic behaviour in Zn(1-x)Co(x)O with increasing antiferromagnetic interactions as x increased to 0.10. Surprisingly, a weak ferromagnetic behaviour was observed for the sample with x = 0.12 with a characteristic hysteresis loop showing a coercivity H(c)~350 Oe, 25% remanence M(r), a low saturation magnetization M(s)~0.04 emu g(-1) and with a Curie temperature T(c)~540 K. The XPS data collected from Zn(1-x)Co(x)O samples showed a gradual increase in the oxygen concentration, changing the oxygen-deficient undoped ZnO to an excess oxygen state for x = 0.12. This indicates that such high Co concentrations and appropriate oxygen stoichiometry may be needed to achieve adequate ferromagnetic exchange coupling between the incorporated Co(2+) ions. PMID- 21694081 TI - Magnetic order in FeCr(2)S(4)-type chalcogenide spinels. AB - The thiospinels of composition FeCr(2)S(4) and Fe(1+x)Cr(2-2x)Sn(x)S(4) with 0=2-3). PMID- 21694088 TI - Competition between ferromagnetism and antiferromagnetism: origin of large magnetoresistance in polycrystalline SrRu(1-x)Mn(x)O(3) (0<=x<=1). AB - Polycrystalline SrRu(1-x)Mn(x)O(3) (0<=x<=1) perovskite oxides have been prepared by a conventional solid-state reaction technique. Magnetic and magnetotransport properties are measured using a superconducting quantum interference device (SQUID, Quantum Design MPMS) over a temperature range of 4-300 K. The substitution of Mn ions for Ru drives the system from a ferromagnetic state, SrRuO(3), to an antiferromagnetic state, SrMnO(3), which is basically similar to observations in single-crystal SrRu(1-x)Mn(x)O(3) (Cao et al 2005 Phys. Rev. B 71 035104). However, the measurement of dc magnetization and ac susceptibility indicates that magnetic phase transition with x is more complicated and pronounced than those in single crystals. The phase transition process as temperature is reduced covers paramagnetism-antiferromagnetism (PM-AFM), paramagnetism-ferromagnetism (PM-FM) and ferromagnetism-cluster glass-spin glass (FM/CG/SG) etc. In particular, we observe a large low-temperature magnetoresistance (MR) of -41% for the sample x = 0.55, which is the largest MR measured in Mn-doped SrRuO(3). The experiment has verified that the large MR stems predominantly from a unique spin glass state in the polycrystalline alloy. These results substantiate that Ru-based oxides doped with 3d/4d transition metals have the potential for use in spintronics devices due to their adjustable phase transition, depending upon the level and nature of 3d/4d ion doping. PMID- 21694089 TI - First-principles investigation of strain effects on the energy gaps in silicon nanoclusters. AB - First-principles density functional calculations were performed to study strain effects on the energy gaps in silicon nanoclusters with diameter ranging from 0.6 to 2 nm. Hydrostatic and non-hydrostatic strains have been found to affect the energy gaps differently. For the same strain energy density, non-hydrostatic strain leads to a significantly larger change in the energy gap of silicon clusters compared to that of the hydrostatic strain case. In contrast, hydrostatic and non-hydrostatic strain effects on the energy gaps of bulk Si or larger size Si quantum dots are comparable. Non-hydrostatic strains break the tetrahedral bonding symmetry in silicon, resulting in significant variation in the energy gaps due to the splitting of the degenerate orbitals in the clusters. Our results suggest that the combination of energy gaps and strains permits the engineering of photoluminescence in silicon nanoclusters and offers the possibility of designing novel optical devices and chemical sensors. PMID- 21694090 TI - First-principles study of the stability of atomic Ag lines epitaxial to self assembled Bi nanolines. AB - The stability of single-atom-wide Ag lines epitaxial to a Bi nanoline (a double line of Bi dimers self-assembled on the Si(001) surface) is examined from first principles. The lattice-matched Ag line, which has a coincident-site lattice (CSL) relationship with the Bi nanoline, is found more stable than pseudomorphic ones such as monomer and dimer lines. The greater stability of the single-row CSL line against the double-row one indicates the feasibility of single-row lines. The greater stability of the triple-row line however suggests that the single-row lines should be grown under kinetically controlled conditions. PMID- 21694091 TI - Phase separation and size effects in Pr(0.70)Ba(0.30)MnO(3+delta) perovskite manganites. AB - The crystal structure and magnetotransport properties of the A-site ionic ordered state in Pr(0.70)Ba(0.30)MnO(3+delta) (delta = 0, 0.025) have been investigated. It is shown that such a state can be formed in complex manganites with cation ratios [Formula: see text] by using a 'two-step' reduction-reoxidization method. The parent A-site ionic disordered Pr(0.70)Ba(0.30)MnO(3+delta) (delta = 0) compound is an orthorhombic (SG = Imma, Z = 4) ferromagnet with Curie temperature T(C)~173 K and ground-state spontaneous magnetic moment sigma(S)~3.70 u(B)/f.u. It exhibits two metal-insulator transitions, at T(I)~128 K and T(II)~173 K, as well as two peaks of magnetoresistance ~74% and ~79% in a field of 50 kOe. The parent A-site ionic disordered Pr(0.70)Ba(0.30)MnO(3+delta) (delta = 0) sample used in our studies has an average grain size [Formula: see text]. Successive annealing of this sample in vacuum P[O(2)]~10(-4) Pa and then in air at T = 800 degrees C leads to the destruction of its initial grain structure and to its chemical separation into two phases: (i) oxygen stoichiometric A-site ordered PrBaMn(2)O(6) with a tetragonal (SG = P4/mmm, Z = 2) perovskite-like unit cell and Curie temperature T(C)~313 K and (ii) oxygen superstoichiometric A-site disordered Pr(0.90)Ba(0.10)MnO(3.05) with an orthorhombic (SG = Pnma, Z = 4) perovskite-like unit cell and Curie temperature T(C)~133 K. This processed sample has a spontaneous magnetic moment sigma(S)~2.82 u(B)/f.u. in its ground state, and sigma(S)~0.59 MU(B)/f.u. at T~300 K. It also exhibits a magnetoresistance of ~14% at ~313 K in a field of 50 kOe. This processed sample has a reduced average grain size [Formula: see text] nm. The two magnetic phases, Pr(0.90)Ba(0.10)MnO(3.05) and PrBaMn(2)O(6), are exchange-coupled. For Pr(0.90)Ba(0.10)MnO(3.05) the temperature hysteresis is ~22 K in a field of 10 Oe and ~5 K in a field of 1 kOe. The observed magnetic properties are interpreted in terms of chemical phase separation, grain size, and A-site ionic ordering effects. PMID- 21694092 TI - Transport driven by spatially modulated noise in a periodic tube. AB - This paper investigates a three-dimensional periodic tube driven by spatially modulated Gaussian white noise. We derive an analytical expression for the net current by introducing entropic barriers. It is found that the phase shift between the entirely symmetric tube and noise modulation can break the symmetry of the generalized potential and induce directed transport. The sign of the current is determined by the phase shift. The current is a peaked function of the bottleneck radius. The interplay between the asymmetric tube and noise modulation can also induce a net current. PMID- 21694093 TI - Effect of pressure on the magnetic properties of TM(3)[Cr(CN)(6)](2).12H(2)O. AB - We present the results of magnetization and AC susceptibility measurements performed on ferrimagnetic Mn(3)(2+)[Cr(III)(CN)(6)](2).12H(2)O and ferromagnetic Ni(3)(2+)[Cr(III)(CN)(6)](2).12H(2)O systems under pressures up to 0.9 GPa in a commercial SQUID magnetometer. The magnetization process is affected by pressure: magnetization saturates at higher magnetic field, saturated magnetization MU(s) of Ni(3)[Cr(CN)(6)](2) is reduced and almost unaffected for Mn(3)[Cr(CN)(6)](2) at low temperatures. The Curie temperature T(C) of Mn(3)[Cr(CN)(6)](2) increases with the applied pressure, DeltaT(C)/Deltap = 25.5 K GPa(-1), due to a strengthened super-exchange antiferromagnetic interaction J(AF), but it is not affected significantly in the case of Ni(3)[Cr(CN)(6)](2) with a dominant ferromagnetic J(F) super-exchange interaction. The increase in the J(AF) interaction is attributed to the enhanced value of the single electron overlapping integral S and the energy gap Delta of the mixed molecular orbitals t(2g) (Mn(2+)) and t(2g) (Cr(III)) induced by pressure. PMID- 21694094 TI - Correlation of structural, magnetic and transport properties with the tolerance factor in a low-doped La(0.875)Sr(0.125-x)Ca(x)MnO(3), (0 <=x<=0.125) system: cross-over from Mott to Shklovskii-Efros variable range hopping conduction. AB - Samples of the low-doped manganite La(0.875)Sr(0.125-x)Ca(x)MnO(3) (0<=x<=0.125) have been synthesized and the effect on the structural, magnetic and transport properties of decreasing the tolerance factor by replacing larger Sr(2+) ions with smaller Ca(2+) ions are reported. For samples with x>=0.0625, a concentration (x) dependent structural transition (rhombohedral ([Formula: see text]) to orthorhombic (Pnma)) has been detected at room temperature and the Curie temperature T(C) is found to decrease with increased Ca doping level. For samples with x<=0.0625, a narrow metallic region exists and the corresponding insulator to metal transition temperature T(MI) decreases with increasing Ca content, i.e. decreasing tolerance factor. In the paramagnetic region, x dependent crossover from Mott variable range hopping (Mott-VRH) to Shklovskii Efros variable range hopping (SE-VRH) occurs as the Ca content increases. The thermoelectric power (TEP) of the samples increases substantially, varying inversely with the tolerance factor. These results are analysed from the consideration of increased bending of the Mn-O-Mn bond with the decrease of the average ionic radius of the A-site element [Formula: see text] and the tolerance factor t, which causes narrowing of the bandwidth, decrease of mobility of e(g) electrons and weakening of the double exchange (DE) interaction associated with the substitution of Ca. PMID- 21694095 TI - Crystal structure and stability of beta-Na(2)ThF(6) at non-ambient conditions. AB - The crystal structure and stability of beta-Na(2)ThF(6) at non-ambient conditions have been studied with calorimetric analysis, second harmonic generation measurements, and (19)F and (23)Na magic-angle spinning nuclear magnetic resonance (MAS NMR) spectroscopy, as well as synchrotron x-ray single-crystal and powder diffraction. The twinned structure (P321, Z = 1) is built of chains of capped trigonal prisms around the Th atoms formed along the c-axis through sharing of the basal faces. More distorted capped trigonal prisms around the Na atoms share their basal and equatorial faces with each other. The twin operation is a two-fold rotation around the c-axis. beta-Na(2)ThF(6) is stable in the temperature and pressure ranges of 100-954 K and 0.0001-6.4 GPa, respectively. The Na-F distances are more compressible than the Th-F distances. A hypothetical ferroelastoelectric and ferrobielastic [Formula: see text] phase transition is discussed. PMID- 21694096 TI - In situ Raman spectroscopy of pressure-induced changes in LaBGeO(5) glass: hysteresis and plastic deformation. AB - In situ micro-Raman spectroscopy was performed on lanthanum borogermanate (LBG) glasses, compressed in a diamond anvil cell at ambient temperature. Up to 5.6 GPa the structural changes are reversible, whereas experiments performed at 10 GPa and higher are characterized by hysteresis loops. A noticeable change of evolution of the main Raman band at 800 cm(-1) has been evidenced around 8 GPa. Indeed, at such a pressure, this Raman band is shifted in the opposite direction while the pressure is still increasing. This change of slopes may be the sign of a pressure-induced coordination number change. Upon decompression the Raman shift of this band follows a different path from the one during compression. When the sample is returned to ambient pressure, it shows a shifted and lightly modified Raman spectrum, suggesting that a new amorphous phase for LBG glass is reached under high pressure and still exists at atmospheric pressure. However, a comparison with LaBGeO(5) crystals with the same composition shows that this material has a full elastic behaviour in the same pressure range. PMID- 21694097 TI - Maximum entropy method and multipole analysis of the bonding in sodium and vanadium metals. AB - The nature of bonding and the charge distribution in sodium and vanadium metals have been analysed using the reported x-ray data of these metals. The maximum entropy method (MEM) and multipole analysis have been used. The bonding in these metals has been elucidated and analysed. The mid-bond densities in sodium and vanadium are found to be 0.014 and 0.723 electron A(-3) respectively, giving an indication of the strength of the bonds in these materials. From the multipole analysis, the sodium atom is found to contract more than the vanadium atom. PMID- 21694098 TI - Exciton effect in deformed carbon nanotubes. AB - The exciton states in deformed single-walled carbon nanotubes (SWNTs), under two kinds of strain, i.e., uniaxial and torsional, are theoretically studied in the Su-Schrieffer-Heeger (SSH) model, supplemented by long-range Coulomb interactions. It is found that for semiconducting zigzag tubes, the exciton binding energy E(b) and the (quasi-)continuum edge E(c) are very sensitive to the uniaxial strain, but not to the torsional one, showing two different kinds of variation behaviour of E(b) with increasing uniaxial strain, of which one decreases monotonically, and the other first increases and then decreases. Additionally, the excitons in torsionally distorted armchair tubes and uniaxially strained metallic zigzag tubes have also been studied, showing increased E(b) and E(c) with increasing strain. PMID- 21694099 TI - Bismuth charge disproportionation in semiconducting BaPb(x)Bi(1-x)O(3) studied by infrared reflection spectroscopy. AB - The infrared reflectivity spectra of semiconducting BaPb(x)Bi(1-x)O(3) single crystals are measured. From the oscillator strength of the bismuth charge disproportionation mode we compute the compositional dependence of the Born and Szigeti effective-charge difference between two inequivalent bismuth sites. The Szigeti effective-charge decreases and is found to become zero as the Pb doping approaches the critical value of the semiconductor-metal transition. This behaviour is associated with the Pb composition induced closing of the indirect energy gap, which takes place prior to the direct gap. It further demonstrates that the long-range order of the bismuth charge disproportionation completely vanishes in the metallic phase. It is found that a strong dynamical charge transfer takes place along the bismuth-oxygen-bismuth bond enhanced by the lattice vibration. The results are compared with those of Ba(1-x)K(x)BiO(3) system. PMID- 21694100 TI - Crystal growth and magnetic properties of Ln(4)MGa(12) (Ln = Dy-Er; M = Pd, Pt). AB - Single crystals of Ln(4)MGa(12) (Ln = Dy, Ho, Er; M = Pd,Pt) were synthesized by a flux technique using excess Ga and characterized by single crystal x-ray diffraction. Ln(4)MGa(12) (Ln = Dy, Ho, Er; M = Pd,Pt) crystallize in the cubic space group [Formula: see text] (no. 229) with lattice parameter a~8.5 A, Z = 2. Magnetic measurements show that Dy(4)PdGa(12) and Er(4)PdGa(12) are antiferromagnetic with transitions at T(N) = 10 and 5.2 K, respectively, while Ho(4)PdGa(12) does not show any magnetic ordering down to 2 K. Ln(4)PtGa(12) (Ln = Dy, Ho, Er) order antiferromagnetically at T(N) = 9.8, 3.6 and 5.1 K for Dy(4)PtGa(12), Ho(4)PtGa(12) and Er(4)PtGa(12), respectively. The electrical resistivity data show metallic behaviour. Large positive magnetoresistance is shown for each compound, up to 900% at 3 K and 9 T for the Ho(4)PtGa(12) analogue. PMID- 21694101 TI - Half metallic ferromagnets. AB - Since its introduction by de Groot and colleagues in the early 1980s [1], the concept of half metallic ferromagnetism has attracted great interest. Idealized, half-metals have only one spin channel for conduction: the spin-polarized band structure exhibits metallic behavior for one spin channel, while the other spin band structure exhibits a gap at the Fermi level. Due to the gap for one spin direction, the density of states at the Fermi level has, theoretically, 100 & spin polarization. This gap in the density of states in one spin at the Fermi level, for example ? so N(?) (E(F)) = 0, also causes the resistance of that channel to go to infinity. At zero or low temperatures, the nonquasiparticle density of states (electron correlation effects), magnons and spin disorder reduce the polarization from the idealized 100 & polarization. At higher temperatures magnon-phonon coupling and irreversible compositional changes affect polarization further. Strategies for assessing and reducing the effects of finite temperatures on the polarization are now gaining attention. The controversies surrounding the polarization stability of half metallic ferromagnets are not, however, limited to the consideration of finite temperature effects alone. While many novel half metallic materials have been predicted, materials fabrication can be challenging. Defects, surface and interface segregation, and structural stability can lead to profound decreases in polarization, but can also suppress long period magnons. There is a 'delicate balance of energies required to obtain half metallic behaviour: to avoid spin flip scattering, tiny adjustments in atomic positions might occur so that a gap opens up in the other spin channel' [2]. When considering 'spintronics' devices, a common alibi for the study of half metallic systems, surfaces and interfaces become important. Free enthalpy differences between the surface and the bulk will lead to spin minority surface and interface states, as well as surface and interface reconstructions. Thus spin injection, i.e. the spin polarization of the current through the interface, may be effectively reduced to very low values, although the non-equilibrium spin polarization of the electron density can have very high values in select devices. Underlying these issues is the need to consider the definition of polarization: not all polarizations are equal. Polarization depends on the measurement. We do not always measure a polarization that follows the usual definition of spin polarization, and in many cases, it is not exactly clear what polarization has been measured. For example, there are corrections for the Fermi velocity nu(?,?) and spin relaxation tau(?,?): [Formula: see text] where n = 1 applies to the ballistic regime and n = 2 applies to the diffuse regime [3]. Neglecting interfaces and other complications, the diffuse regime (n = 2) should be the spin polarization of the bulk conductivity while ballistic regime (n = 1) is the polarization of the tunnel current and, in principle, Andreev reflection. As a result, suitable spin dependent Fermi velocity corrections might overcome an otherwise lackluster polarization for some device structures. Even measurements of polarization that are Fermi velocity independent (n = 0) may still depend on the wave vector and details of the interface band structure: as in the case of spin polarized photoemission and inverse photoemission. This special issue cannot possibly give due justice to all the various aspects of the physics of half metallic systems. By including both advocates and critics of half metallic ferromagnetism, the special issue should provide at least a taste of the controversies and challenges that exist in the study of half metallic ferromagnets. It may be that 'nature abhors half-metallicity' [2], and that relatively minor structural and thermal perturbations have a disproportionally strong effect on the density of states at the Fermi level, but in spite of much study half metallicity remains fascinating and much insight is still needed including both experiment and improvements to band structure calculations. References [1] de Groot R A, Mueller F M, Van Engen P G and Buschow K H J 1984 Phys. Rev. Lett.50 2024 [2] paraphrase of remarks by Hathaway K, private communication, U.S. Office of Naval Research [3] Mazin I I 1999 Phys. Rev. Lett. 83 1427. PMID- 21694102 TI - Non-quasiparticle effects in half-metallic ferromagnets. AB - The unusual electronic structure of the half-metallic ferromagnets (HMF) is analysed taking account of correlation effects (electron-magnon interaction, in particular spin-polaron effects). Special attention is paid to the so-called non quasiparticle (NQP) (incoherent) states which arise in the minority- (majority-) spin gap above (below) the Fermi level and which may make considerable contributions to the electronic properties. First-principles calculations of the NQP states in HMF within the local-density approximation plus dynamical mean field theory (LDA+DMFT) are reviewed. These states can be probed, in particular, by spin-polarized scanning tunnelling microscopy. They also lead to observable effects in core-hole spectroscopy, nuclear magnetic relaxation and contribute to the temperature dependence of impurity resistivity, etc. The peculiarities of the transport properties of three- and two-dimensional HMF are discussed, which are connected with the absence of one-magnon spin-flip scattering processes. PMID- 21694103 TI - Finite-temperature depolarization in half metals. AB - The temperature dependence of the spin polarization of type-I half-metallic ferromagnets is investigated and compared with that of other magnetic materials, such as semimetals, strong and weak ferromagnets, and exchange-enhanced Pauli paramagnets. Stable atomic moments, as realized by strong intra-atomic exchange, exhibit a nonzero spin-down density of states (DOS) at finite temperatures. This thermal spin mixing means that the conductivity of the 'insulating' spin channel is always nonzero and that half-metallic ferromagnetism is an idealized limit. At zero temperature, similar effects are caused by intersublattice interactions, spin-orbit coupling and crystal imperfections. With increasing interatomic hopping, the moment becomes unstable, and Stoner-type thermal excitations yield an additional reduction of the spin polarization. In the Stoner limit, the hybridization gap closes far below the Curie temperature, and the corresponding transition temperature T(*) increases with increasing hybridization gap and decreasing band width. Correlations are analysed by a version of the Kondo model and by an unrestricted Hartree-Fock approximation, and it is argued that correlations are less important than the leading one-electron contributions. PMID- 21694104 TI - Half metals: from formal theory to real material issues. AB - At the basic level of collinear spin density functional theory, half metallic ferromagnets represent a fundamentally different state of matter: for low-energy physics the spin degree of freedom is absent, although the system is spin polarized. This makes such systems highly attractive for spintronics applications, but also introduces fundamental new phenomena such as a superconducting state in which the concept of 'spin-pairing' never appears. A fully relativistic theory introduces spin-orbit coupling and destroys the precise aspect of half metallicity; does this make 'half metals' a half truth? Obviously not in any real sense: spin-orbit coupling arises as a perturbative effect, and although necessitating reconsideration from the formal viewpoint, leaves half metallicity as a qualitatively distinct state. We provide a simple model that suggests that in appropriate circumstances this qualitative distinction may even survive strong spin-orbit coupling. PMID- 21694105 TI - Magnons in ferromagnetic metallic manganites. AB - Ferromagnetic (FM) manganites, a group of likely half-metallic oxides, are of special interest not only because they are a testing ground for the classical double-exchange interaction mechanism for the 'colossal' magnetoresistance, but also because they exhibit an extraordinary arena of emergent phenomena. These emergent phenomena are related to the complexity associated with strong interplay between charge, spin, orbital, and lattice. In this review, we focus on the use of inelastic neutron scattering to study the spin dynamics, mainly the magnon excitations in this class of FM metallic materials. In particular, we discuss the unusual magnon softening and damping near the Brillouin zone boundary in relatively narrow-band compounds with strong Jahn-Teller lattice distortion and charge-orbital correlations. The anomalous behaviours of magnons in these compounds indicate the likelihood of cooperative excitations involving spin and lattice as well as orbital degrees of freedom. PMID- 21694106 TI - 100% spin accumulation in non-half-metallic ferromagnet-semiconductor junctions. AB - We show that the spin polarization of electron density in non-magnetic degenerate semiconductors can achieve 100%. The effect of 100% spin accumulation does not require a half-metallic ferromagnetic contact and can be realized in ferromagnet semiconductor FM-n(+)-n junctions even at moderate spin selectivity of the FM n(+) contact when the electrons with spin 'up' are extracted from n semiconductor through the heavily doped n(+) layer into the ferromagnet and the electrons with spin 'down' are accumulated near the n(+)-n interface. We derived a general equation relating spin polarization of the current to that of the electron density in non-magnetic semiconductors. We found that the effect of complete spin polarization is achieved near the n(+)-n interface when the concentration of the spin 'up' electrons tends to zero in this region while the diffusion current of these electrons remains finite. PMID- 21694107 TI - The role of topological spin defects in magnetotransport of CrO(2). AB - We investigated the temperature dependence of the resistivity for a wide temperature range for CrO(2)(100) epitaxial films. The temperature derivative drho/dT definitely shows the same character as the magnetic heat capacity anomaly in the critical regime even in a finite magnetic field and the critical exponents (alpha) deduced are consistent with those of 3D Heisenberg ferromagnets. In addition, we found that the spin dependent resistivity over a wide temperature range can be simply proportional to the density of diluted topological spin defects (Skyrmion strings) suggesting that those nontrivial topological defects scatter conduction electrons just like impurities. The excitation energy of such topological defects is quite comparable to that obtained by anomalous Hall effect analysis of the Ye et al model based on the Berry phase. The overall results give a simple picture wherein the density of the topological defects can be a dominant mechanism of resistivity, like the anomalous Hall effect. The results concerning the critical exponent analysis and intuition concerning scattering centres of magnetic disorder suggest a specific picture of the Fisher-Langer model. PMID- 21694108 TI - Using half-metallic manganite interfaces to reveal insights into spintronics. AB - A half-metal has been defined as a material with propagating electron states at the Fermi energy only for one of the two possible spin projections, and as such has been promoted as an interesting research direction for spin electronics. This review details recent advances on manganite thin film research within the field of spintronics, before presenting the structural, electronic and spin-polarized solid-state tunnelling transport studies that we have performed on heterostructures involving La(2/3)Sr(1/3)MnO(3) thin films separated by SrTiO(3) barriers. These experiments demonstrate that, with a polarization of spin [Formula: see text] electrons at the Fermi level that can reach 99%, the La(2/3)Sr(1/3)MnO(3)/SrTiO(3) interface for all practical purposes exhibits half metallic behaviour. We offer insight into the electronic structure of the interface, including the electronic symmetry of any remaining spin [Formula: see text] states at the Fermi level. Finally, we present experiments that use the experimental half-metallic property of manganites as tools to reveal novel features of spintronics. PMID- 21694109 TI - The case against half-metallicity in La(0.7)Sr(0.3)MnO(3). AB - Half-metallic ferromagnets are universally believed to be of great importance for a multitude of spintronic applications, including non-volatile logic and memory, spin transistors and many other recently proposed devices. While many materials have been predicted to be half-metallic, experimental confirmation of this exciting effect is still very controversial, particularly for optimally doped La(0.7)Sr(0.3)MnO(3) (LSMO). In this paper we will review some of the techniques used for spin polarization measurements and, in particular, the results obtained for LSMO. It was argued in Nadgorny et al (2001 Phys. Rev. B 63 184433) that LSMO is a transport half-metal, rather than a conventional half-metal with no minority electrons at the Fermi level at T = 0 K. We will discuss some of the more recent measurements in LSMO and see how well this conclusion stacks up against these new results. PMID- 21694110 TI - Suppressed magnetization at the surfaces and interfaces of ferromagnetic metallic manganites. AB - What happens to ferromagnetism at the surfaces and interfaces of manganites? With the competition between charge, spin, and orbital degrees of freedom, it is not surprising that the surface behaviour may be profoundly different to that of the bulk. Using a powerful combination of two surface probes, tunnelling and polarized x-ray interactions, this paper reviews our work on the nature of the electronic and magnetic states at manganite surfaces and interfaces. The general observation is that ferromagnetism is not the lowest energy state at the surface or interface, which results in a suppression or even loss of ferromagnetic order at the surface. Two cases will be discussed ranging from the surface of the quasi 2D bilayer manganite (La(2-2x)Sr(1+2x)Mn(2)O(7)) to the 3D perovskite (La(2/3)Sr(1/3)MnO(3))/SrTiO(3) interface. For the bilayer manganite, which is ferromagnetic and conducting in the bulk, these probes present clear evidence for an intrinsic insulating non-ferromagnetic surface layer atop adjacent subsurface layers that display the full bulk magnetization. This abrupt intrinsic magnetic interface is attributed to the weak inter-bilayer coupling native to these quasi two-dimensional materials. This is in marked contrast to the situation for the non-layered manganite system (La(2/3)Sr(1/3)MnO(3)/SrTiO(3)), whose magnetization near the interface is less than half the bulk value at low temperatures and decreases with increasing temperature at a faster rate than that for the bulk. PMID- 21694111 TI - Epitaxial growth and surface properties of half-metal NiMnSb films. AB - We present, herein, an extended study of the half-Heusler alloy NiMnSb, starting with the deposition technique, continuing with the basic structural and magnetic properties of the thin films, and finishing with the electronic and compositional properties of their surfaces. The experimental methods we apply combine magnetization and magnetoresistivity measurements, atomic force microscopy, ferromagnetic resonance, x-ray and neutron diffraction, low energy electron diffraction, angle resolved x-ray photoemission, extended x-ray absorption fine structure spectroscopy, soft x-ray magnetic circular dichroism and spin polarized inverse photoemission spectroscopy. We find that stoichiometric surfaces exhibit close to 100% spin polarization at the centre of the surface Brillouin zone at the Fermi edge at ambient temperatures. There is strong evidence for a moment reordering transition at around 80 K which marks the crossover from a high polarization state (T<80 K) to a more representative metallic ferromagnetic state (T>80 K). The results from the different experimental techniques are successively reviewed, with special emphasis on the interplay between composition and electronic structure of the NiMnSb film surfaces. Surface segregation, consistent with a difference in free enthalpy between the surface and the bulk, is induced by annealing treatments. This surface segregation greatly reduces the surface polarization. PMID- 21694112 TI - Optimizing performance of half-metals at finite temperature. AB - Several aspects of half-metallic magnetism at finite temperature are discussed. Since NiMnSb is the simplest half-metal and the longest known it will be used as an example. Also it is a half-metal with remarkable little on-site Coulomb repulsion. Consequently it is a half-metal that is not notably corrupted by non quasiparticle states. There exists an anomaly at 90 K, described before, that will be shown to be unrelated to the position of the Fermi level in the bandgap. Several substitutions are investigated that could shed some light on the origin of the transition. The calculated phonon spectrum is compared with experimental neutron scattering data. Finally, the spin-polarization of interfaces of NiMnSb with the transition metal based non-magnetic semiconductors NiTiSn and CoTiSb is investigated and the electronic structure of an infinite two-dimensional array of NiMnSb quantum dots embedded in NiScSb is reported. PMID- 21694113 TI - Spin-polarization and electronic properties of half-metallic Heusler alloys calculated from first principles. AB - Half-metallic Heusler alloys are amongst the most promising materials for future magneto-electronic applications. We review some recent results on the electronic properties of these compounds. The origin of the gap in these half-metallic alloys and its connection to the magnetic properties are well understood. Changing the lattice parameter slightly shifts the Fermi level. Spin-orbit coupling induces states within the gap but the alloys keep a very high degree of spin polarization at the Fermi level. Small degrees of doping and disorder as well as defects with low formation energy have little effect on the properties of the gap, while temperature effects can lead to a quick loss of half-metallicity. Finally, we discuss two special issues: the case of quaternary Heusler alloys and the half-metallic ferrimagnets. PMID- 21694114 TI - Surface states and surface stability in half-metallic systems: the cases of zinc blende-structure MnSb {111}A, {111}B and {001}. AB - The surface properties of half-metallic materials can have a profound impact upon their possible utility for spintronic devices, and are therefore of significant interest. Here, we present the results of comprehensive density functional calculations for the {111}A, {111}B and {001} surfaces of the half-metallic zinc blende phase of MnSb. We predict trimerized and dimerized reconstructions to be favourable whenever geometrically feasible, and our thermodynamic analysis strongly suggests termination with an Sb layer in all the cases studied. The electronic band-structure of the reconstructed Sb-terminated {001} surface is found to retain its half-metallicity, whereas the unfavourable Mn-terminated surface does not. The reconstructed Sb-terminated {111}A and {111}B surfaces are likewise half-metallic, and again the unfavourable Mn-terminated surfaces are not. PMID- 21694115 TI - Polarization reduction in half-metallic Heusler alloys: the effect of point defects and interfaces with semiconductors. AB - Half-metallic full-Heusler alloys represent a promising class of materials for spintronic applications. However, (i) intrinsic point defects in Heusler compounds can be detrimental with respect to their predicted 100% spin polarization at the Fermi level and (ii) when joined to mainstream semiconductors the presence of interface states-which destroys half-metallicity-can degrade their performance. Here, we present an overview of recent first-principles calculations performed to explore both these issues. In particular, we focus on ab initio FLAPW calculations performed for Co(2)MnGe and Co(2)MnSi in the presence of intrinsic defects (such as stoichiometric atomic swaps as well as non stoichiometric antisites) and when interfaced with GaAs and Ge. Our findings show that Mn antisites, due to their low formation energies, can easily occur, in excellent consistency with experimental observations, and that they do not destroy half-metallicity. On the other hand, Co antisites, which also show a modest formation energy, give rise to defect states at the Fermi level. As for the [001]-ordered interfaces, we show that the strong hybridization in proximity to the junction gives rise to rather broad interface states that locally destroy half-metallicity. However, the bulk gaps (both in the minority spin channel for the Heusler alloy and for both spin channels in the semiconducting side) are fully recovered within a few layers away from the junction. PMID- 21694116 TI - Calculated magneto-optical Kerr spectra of the half-Heusler compounds AuMnX (X = In, Sn, Sb). AB - The ferromagnetic ground states of the half-Heusler compounds AuMnX (X = In, Sn, Sb) have been calculated in the framework of the local spin-density approximation (LSDA) to density functional theory (DFT). AuMnSn is computed to be a half metallic ferromagnet, whereas AuMnIn and AuMnSb are not half-metallic, due to their different band filling. The computed relativistic electronic structures served as inputs to calculate the magneto-optical Kerr rotations and ellipticities for all three materials. In the case of AuMnSn the largest, zero temperature, polar Kerr rotation has been found to be -0.45 degrees at about 1 eV photon energy. The computed MOKE spectra of AuMnSn are in qualitative agreement with recent experiments. The largest Kerr rotations of AuMnIn and AuMnSb have been calculated to be +0.64 degrees at 4.3 eV and -0.85 degrees at 0.9 eV, respectively. PMID- 21694117 TI - Magnetite: a search for the half-metallic state. AB - We present a detailed study of the spin-dependent electronic structure of thin epitaxial magnetite films of different crystallographic orientations. Using spin- and angle-resolved photoelectron spectroscopy at room temperature, we determine for epitaxial Fe(3)O(4)(111) films a maximum spin polarization value of -(80 +/- 5)% near E(F). The spin-resolved photoelectron spectra for binding energies between 1.5 eV and E(F) show good agreement with the spin-split band structure from density functional theory (DFT) calculations which predict an overall energy gap in the spin-up electron bands in high symmetry directions, thus providing evidence for the half-metallic ferromagnetic state of Fe(3)O(4) in the [111] direction. In the case of the Fe(3)O(4)(100) surface, both the spin-resolved photoelectron spectroscopy experiments and the DFT density of states give evidence for a half-metal to metal transition: the measured spin polarization of about -(55 +/- 10)% at E(F) and the theoretical value of -40% are significantly lower than the -100% predicted by local spin density approximation (LSDA) calculations for the bulk magnetite crystal as well as the -(80 +/- 5)% obtained for the Fe(3)O(4)(111) films. The experimental findings were corroborated by DFT calculations as due to a surface reconstruction leading to the electronic states in the majority-spin band gap and thus to the reduced spin polarization. PMID- 21694118 TI - Spin resolved photoelectron spectroscopy of Fe(3)O(4): the case against half metallicity. AB - Many materials have been theoretically predicted to be half-metallic, and hence suitable for use as pure spin sources in spintronic devices. Yet to date, remarkably few of these predictions have been experimentally verified. We have used spin polarized photoelectron spectroscopy to study one candidate half metallic system, Fe(3)O(4). Such experiments are normally hampered by difficulties in producing clean stoichiometric surfaces with a polarization that is truly representative of that of the bulk. However, by utilizing higher photon energies than have traditionally been used for such experiments, we can study polarization in 'as received' samples, essentially 'looking through' the disrupted surface. High quality, strain relieved, ex situ prepared Fe(3)O(4) films have been thoroughly characterized by diffraction, transport and magnetometry studies of their crystallographic, electronic and magnetic properties. The spectroscopic results are found to agree fairly closely with previously published experimental data on in situ grown thin films and cleaved single crystals. However, despite the higher photoelectron kinetic energies of the experiment, it has not been possible to observe 100% polarization at the Fermi level. Hence, our data do not support the claim of true half-metallicity for Fe(3)O(4). PMID- 21694119 TI - Composition controlled spin polarization in Co(1-x)Fe(x)S(2) alloys. AB - The transition metal (TM) chalcogenides of the form TMX(2) (X = S or Se) have been studied for decades due to their interesting electronic and magnetic properties such as metamagnetism and metal-insulator transitions. In particular, the Co(1-x)Fe(x)S(2) alloys were the subject of investigation in the 1970s due to general interest in itinerant ferromagnetism. In recent years (2000-present) it has been shown, both by electronic structure calculations and detailed experimental investigations, that Co(1-x)Fe(x)S(2) is a model system for the investigation of highly spin polarized ferromagnetism. The radically different electronic properties of the two endpoint compounds (CoS(2) is a narrow bandwidth ferromagnetic metal, while FeS(2) is a diamagnetic semiconductor), in a system forming a substitutional solid solution allows for composition control of the Fermi level relative to the spin split bands, and therefore composition controlled conduction electron spin polarization. In essence, the recent work has shown that the concept of 'band engineering' can be applied to half-metallic ferromagnets and that high spin polarization can be deliberately engineered. Experiments reveal tunability in both sign and magnitude of the spin polarization at the Fermi level, with maximum values obtained to date of 85% at low temperatures. In this paper we review the properties of Co(1-x)Fe(x)S(2) alloys, with an emphasis on properties of relevance to half-metallicity. Crystal structure, electronic structure, synthesis, magnetic properties, transport properties, direct probes of the spin polarization, and measurements of the total density of states at the Fermi level are all discussed. We conclude with a discussion of the factors that influence, or even limit, the spin polarization, along with a discussion of opportunities and problems for future investigation, particularly with regard to fundamental studies of spintronic devices. PMID- 21694120 TI - Electronic, magnetic and transport properties of rare-earth monopnictides. AB - The electronic structures and magnetic properties of many rare-earth monopnictides are reviewed in this article. Possible candidate materials for spintronics devices from the rare-earth monopnictide family, i.e. high polarization (nominally half-metallic) ferromagnets and antiferromagnets, are identified. We attempt to provide a unified picture of the electronic properties of these strongly correlated systems. The relative merits of several ab initio theoretical methods, useful in the study of the rare-earth monopnictides, are discussed. We present our current understanding of the possible half-metallicity, semiconductor-metal transitions, and magnetic orderings in the rare-earth monopnictides. Finally, we propose some potential strategies to improve the magnetic and electronic properties of these candidate materials for spintronics devices. PMID- 21694121 TI - A review of the electronic and magnetic properties of tetrahedrally bonded half metallic ferromagnets. AB - The emergence of the field of spintronics has brought half-metallic ferromagnets to the centre of scientific research. A lot of interest was focused on newly created transition-metal pnictides (such as CrAs) and chalcogenides (such as CrTe) in the metastable zinc-blende lattice structure. These compounds were found to have the advantage of high Curie temperatures in addition to their structural similarity to semiconductors. Significant theoretical activity has been devoted to the study of the electronic and magnetic properties of these compounds in an effort to achieve a better control of their experimental behaviour in realistic applications. This paper is devoted to an overview of the studies of these compounds, with emphasis on theoretical results, covering their bulk properties (electronic structure, magnetism, stability of the zinc-blende phase, stability of ferromagnetism) as well as low-dimensional structures (surfaces, interfaces, nanodots and transition-metal delta-doped semiconductors) and phenomena that can possibly destroy the half-metallic property, like structural distortions or defects. PMID- 21694122 TI - Search for new half-metallic ferromagnets in zinc blende CaSi and CaGe by first principles calculations. AB - We present an investigation on the electronic structure and ferromagnetism for the hypothetical zinc blende (ZB) CaSi and CaGe by using first-principles full potential linearized augmented plane-wave (FP-LAPW) calculations. It is found that ZB CaSi and CaGe are half-metallic (HM) ferromagnets without any transition metal component; they have a magnetic moment of 2.000 u(B) per formula unit. Analysis of the density of states and magnetic moment indicates that their magnetism mainly originates from the spin polarization of anion p states and the hybridization between the anion p states and the Ca d states. We also find that the half-metallicity can be maintained even when the lattice constant of ZB CaSi and CaGe is compressed up to 8% and 5%, respectively. The absence of the transition-metal atoms makes ZB CaSi and CaGe attractive not only as materials for possible spintronics devices but also as model objects for the study of new mechanisms of the formation of half-metallic ferromagnetism in s-p electron systems. PMID- 21694123 TI - The First Eighteen Years of Reverse Monte Carlo Modelling, a workshop held in Budapest, Hungary (28-30th September 2006). AB - This Special Issue contains a collection of papers reflecting the content of the third workshop on reverse Monte Carlo (RMC) methods, held in a hotel on hills overlooking Budapest at the end of September 2006. Over forty participants gathered to hear talks and discuss a broad range of science based on the RMC technique in very convivial surroundings. Reverse Monte Carlo modelling is a method for producing three-dimensional disordered structural models in quantitative agreement with experimental data. The method was developed in the late 1980s and has since achieved wide acceptance within the scientific community [1]. It is particularly suitable for studies of the structures of liquid and amorphous materials, although it may also be applied effectively to the structural analysis of disordered crystalline systems. Since the previous RMC workshop in 2003 [2] there have been several developments in the technique, particularly as applied to crystals, and in the range of its application, most noticeable being the routine modelling of multiple data sets for a given problem; the latter growing through the increasing quality and availability of x-ray total scattering data from synchrotron x-ray sources. The RMC workshop was particularly beneficial, providing a forum for those workers in the field to take stock of past achievements and to look forward to future developments. It is our hope that the collection of papers within this Special Issue will also communicate this to the wider scientific community, providing a balance between papers that have more of an introductory review flavour and those that concentrate on current state of the art research opportunities using the RMC method. Furthermore, by including a small number of papers from colleagues working on similar disordered problems with complementary analysis techniques, we hope that the RMC method may be placed in a broader scientific context. The papers within this special issue have been arranged into four groups: those concerning liquids (1-8), amorphous (9-13) and crystalline materials (14-17) and those of a more general nature (18-23). Within these groupings, there are descriptions of RMCProfile (18) and RMCt (23), programs which use RMC methods to analyse total scattering from crystalline materials and to model inelastic neutron scattering data, respectively. There is also work using the related EPSR (6) and PDFfit (19) techniques, developments of the RMC method for analysis of single crystal electron diffraction (16) or polarised neutron diffraction (7), and examples of simultaneous RMC modelling of neutron and x-ray total scattering and XAS data (13, 10) . We are very grateful to IoP Publishing for their willingness to publish the proceedings of this meeting in a Special Issue of Journal of Physics: Condensed Matter. References [1] McGreevy R L 2001 J. Phys.: Cond. Matter 13 R877 [2] RMC-2 Workshop Proceedings 2005 J. Phys.: Cond. Matter 17 S1-S174. PMID- 21694124 TI - Comparison of partial structures of melts of superionic AgI and CuI and non superionic AgCl. AB - Neutron and high-energy x-ray diffraction analyses of molten AgI have been performed and the partial structures are discussed in detail with the aid of the structural modelling procedure of the reverse Monte Carlo (RMC) technique by comparison with those of molten CuI and AgCl. It is well known that AgI and CuI have a superionic solid phase below the melting point, in which the cations favour a tetrahedral configuration, while solid AgCl has a rock-salt structure with an octahedral environment around both Ag and Cl atoms. Even in the molten states, there is a significant difference between superionic and non-superionic melts. The cation is located on the triangular plain formed by three iodine ions in molten AgCl and CuI, while molten AgCl favours a 90 degrees Cl-Ag-Cl bond angle, which is understood to maintain a similar local environment to that in the solid state. The atomic configurations of the RMC model suggest that the cation distributions in superionic melts of CuI and AgI exhibit large fluctuations, while Ag ions in the non-superionic melts of AgCl are distributed much more uniformly. PMID- 21694125 TI - Polyanions in molten KPb-a paradox explained? AB - We have created new models of the structure of liquid KPb at 873, 1473 and 1873 K. These are used to illustrate specific points concerning the 'existence' of Pb(4)(4-) polyanions or 'Zintl' ions. We conclude that such groupings exist but are only transient, probably with a timescale of the order of 1 ps. All of the existing experimental data are consistent with such a model. PMID- 21694126 TI - Orientational correlations in liquid, supercritical and gaseous carbon dioxide. AB - Neutron and x-ray diffraction results obtained for liquid CO(2) have been modelled by means of the reverse Monte Carlo method. Partial pair correlation functions, centre-centre pair correlation functions and relative orientations of molecular axes as a function of distances between molecular centres have been calculated from the models. It was found that well defined orientational correlations exist in the liquid state. Close to the critical point, these correlations seem to disappear, but further away from the critical point, in the high density supercritical state, they reappear. Using large particle configurations, the density fluctuations close to the critical point could be visualized. PMID- 21694127 TI - The structure of liquid iodomethane, CH(3)I/CD(3)I. AB - An x-ray diffraction measurement has been performed on liquid iodomethane using the BL04B2 beamline at the SPring-8 synchrotron radiation facility (Japan). The corrected structure factor, together with the results of an earlier neutron diffraction study, has been interpreted by means of reverse Monte Carlo modelling. This approach provides large structural models, containing thousands of atoms that are consistent with the experimental data within their uncertainties. From these models, partial structure factors and radial distribution functions were calculated. It is demonstrated that, for a satisfactory description of the intermolecular correlations, the presence of x ray data is vital. Orientational correlations between neighbouring molecules have been found to be much better defined than if they were due to excluded volume effects only. PMID- 21694128 TI - On the structure of liquid phosphorous tribromide (PBr(3)). AB - We have interpreted the structure factor of liquid PBr(3), as measured by Misawa et al (1990 J. Chem. Phys. 92 5486) on a pulsed neutron source, by means of reverse Monte Carlo (RMC) modelling. We have used the method of fixed neighbour constraints, which accounts for the flexibility of the molecules. From the RMC models, partial pair correlation functions and cosine distributions of intra- and inter-molecular angles were calculated. Comparisons with reference systems, which were generated by hard sphere Monte Carlo simulation, were also carried out. We were able to find unique orientational correlations in liquid PBr(3) in terms of the cosine distribution of [Formula: see text] angles (the Br atom being in the centre), involving one intra-molecular P-Br and one inter-molecular [Formula: see text] nearest-neighbour distance. PMID- 21694129 TI - Joint structure refinement of x-ray and neutron diffraction data on disordered materials: application to liquid water. AB - X-ray diffraction data on liquids and disordered solids often provide useful complementary structural information to neutron diffraction data. Interpretation of the x-ray diffraction pattern, which is produced by scattering from the atomic electrons rather than from the atomic nuclei as in the case of neutron diffraction, is, however, complicated by the Q-dependent electronic form factors, which cause the x-ray diffraction signal to decline rapidly with increasing Q, where Q is the wave vector change in the diffraction experiment. The problem is particularly important in cases such as water where there is a significant molecular polarization caused by charge transfer within the molecule. This means that the electron form factors applicable to the molecule in the condensed environment often deviate from their free atom values. The technique of empirical potential structure refinement (EPSR) is used here to focus on the problem of forming a single atomistic structural model which is simultaneously consistent with both x-ray and neutron diffraction data. The case of liquid water is treated explicitly. It is found that x-ray data for water do indeed provide a powerful constraint on possible structural models, but that the Q-range of the different x ray data sets (maximum Q ranges from 10.8 to ~17.0 A(-1) for different x-ray experiments), combined with variations between different data sets, means that it is not possible to rigorously define the precise position and height of the first peak in the OO radial distribution function. Equally, it is found that two different neutron datasets on water, although measured to a maximum Q of at least 30 A(-1), give rise to further small uncertainties in the position of the hydrogen bond peaks. One general conclusion from the combined use of neutron and x-ray data is that many of the classical water potentials may have a core which is too repulsive at short distances. This produces too sharp a peak in r-space at too short a distance. A softer core potential is proposed here. PMID- 21694130 TI - The structure of liquid water by polarized neutron diffraction and reverse Monte Carlo modelling. AB - The coherent static structure factor of water has been investigated by polarized neutron diffraction. Polarization analysis allows us to separate the huge incoherent scattering background from hydrogen and to obtain high quality data of the coherent scattering from four different mixtures of liquid H(2)O and D(2)O. The information obtained by the variation of the scattering contrast confines the configurational space of water and is used by the reverse Monte Carlo technique to model the total structure factors. Structural characteristics have been calculated directly from the resulting sets of particle coordinates. Consistency with existing partial pair correlation functions, derived without the application of polarized neutrons, was checked by incorporating them into our reverse Monte Carlo calculations. We also performed Monte Carlo simulations of a hard sphere system, which provides an accurate estimate of the information content of the measured data. It is shown that the present combination of polarized neutron scattering and reverse Monte Carlo structural modelling is a promising approach towards a detailed understanding of the microscopic structure of water. PMID- 21694131 TI - Hydration of ions in aqueous RbCl solutions. AB - Structural studies have been carried out on aqueous rubidium chloride solutions at three concentrations. Particle configurations consistent with neutron and x ray diffraction data were obtained by reverse Monte Carlo modelling. By applying several coordination constraints, the generally accepted concept concerning the hydration of chloride ions could be tested in detail. The structural models generated may be made consistent with Cl(-) ions surrounded by six neighbouring water molecules, of which only three can connect to the ion via straight Cl...H-O (hydrogen bond) angles. PMID- 21694132 TI - Network structure of 0.7SiO(2)-0.3Na(2)O glass from neutron and x-ray diffraction and RMC modelling. AB - The structure of 0.7SiO(2)-0.3Na(2)O glass was investigated by means of neutron and high-energy x-ray diffraction. The maximum momentum transfer was 35 and 23.5 A(-1) for the two experiments. The two datasets were modelled simultaneously by the reverse Monte Carlo simulation technique. By using reasonable constraints it was possible to separate the six partial pair correlation functions. Nearest neighbour distances, coordination numbers and bond angle distributions have been revealed. It was found that 63% of the O atoms are in the bridging position. The Na-O distance is 2.29 A and the coordination number is 2.5. The Na-Na nearest neighbour distance is 2.6 A, a value significantly smaller than previously reported. Neighbouring sodium ions tend to be located at the same oxygen atom. The average Si-O ring size is 7.6. PMID- 21694133 TI - Atomic structure of As(25)Si(40)Te(35) glass. AB - Glassy As(25)Si(40)Te(35) has been studied by x-ray and neutron diffraction as well as x-ray absorption spectroscopy (EXAFS) at As and Te K-edges. Simultaneous modelling of the four independent measurements by means of the reverse Monte Carlo (RMC) simulation technique allowed the separation of partial pair distribution functions and estimation of the corresponding coordination numbers. It is shown that the atomic structure of As(25)Si(40)Te(35) glass can be presented as a three-dimensional network of twofold coordinated Te, threefold coordinated As and fourfold coordinated Si atoms. PMID- 21694135 TI - 'Wrong bonds' in sputtered amorphous Ge(2)Sb(2)Te(5). AB - The structure of sputtered amorphous Ge(2)Sb(2)Te(5) was investigated by high energy x-ray diffraction, neutron diffraction and Ge-, Sb- and Te K-edge EXAFS measurements. The five datasets were modelled simultaneously in the framework of the reverse Monte Carlo simulation technique. It was found that apart from Te-Sb and Te-Ge bonds existing in the crystalline phases, Ge-Ge and Sb-Ge bonding is also significant in sputtered amorphous Ge(2)Sb(2)Te(5). According to our results, all components obey the '8-N' rule. PMID- 21694134 TI - Possibility of reverse Monte Carlo modelling for hydrogenated amorphous Si deposited on reactive ion etched Si substrate. AB - We examined the x-ray diffraction (XRD) patterns of hydrogenated amorphous Si (a Si:H) and of crystalline Si (c-Si) substrate for high-Q measurements. A structural analysis of thin films on substrates is important for the development of real devices. A transmission geometry with high-energy x-rays was used for this investigation, together with very thin substrates, in an effort to reduce substrate signals. A small area of the substrate was etched using the reactive ion etching (RIE) plasma process to maintain free-standing structures, and a-Si was deposited using catalytic chemical vapour deposition techniques. The x-ray beam was focused on the processed area and a-Si diffraction using a thin Si layer was measured. Unlike a-Si:H films on substrates without etching, we succeeded in detecting amorphous signals from samples deposited on the processed substrate. Application of reverse Monte Carlo (RMC) modelling using these data and subtracting Si substrate peaks was investigated. Direct subtraction and MCGR program (Pusztai and McGreevy 1997 Physica B 234-236 357-8) normalization for the ratio estimation between c-Si and a-Si:H structure factors was employed. MCGR normalization was found to improve subtraction of the c-Si peaks and the first peak at r = 2.3 in the pair distribution function g(r) could be calculated. PMID- 21694136 TI - Structural change of crystalline and amorphous-Ge(2)Sb(2)Te(5) by reverse Monte Carlo analysis of x-ray diffraction data and extended x-ray absorption fine structure data. AB - Reverse Monte Carlo analyses of crystalline and amorphous Ge(2)Sb(2)Te(5) thin films were carried out using x-ray diffraction data and three spectra from extended x-ray absorption fine structure measurements. To produce a crystal model, we employed a large system with 12 800 Ge, 12 800 Sb and 32 000 Te atoms. The obtained model for the crystal structure was used for the initial configuration of the amorphous model. As a result of a series of reverse Monte Carlo analyses with various constraints, we found that the partial pair distribution function in the amorphous state with the largest deviation from the crystal state is a Ge-Sb pair and the distance is less than 2.7 A. This suggests that Sb atoms in amorphous Ge(2)Sb(2)Te(5) thin film have a four-coordinate within 3.2 A. PMID- 21694137 TI - Neutron total scattering and reverse Monte Carlo study of cation ordering in Ca(x)Sr(1-x)TiO(3). AB - We use neutron total scattering measurements with reverse Monte Carlo analysis methods incorporating an atom-swapping algorithm to identify the short-range Ca/Sr cation ordering within the Ca(x)Sr(1-x)TiO(3) solid solution (compositions x = 0.2,0.5,0.8). Our results show that nearest-neighbour pairs have a strong tendency for unlike Ca/Sr first-neighbour coordination in the x = 0.2 and 0.5 cases. In the x = 0.5 case the Ca/Sr ordering results in a structure with space group P 2(1)nm. In contrast, there is much less short-range cation ordering in the x = 0.8 case. PMID- 21694138 TI - Local structure in ZrW(2)O(8) from neutron total scattering. AB - The local structure of the low-temperature ordered phase of the negative thermal expansion (NTE) material ZrW(2)O(8) has been investigated by reverse Monte Carlo (RMC) modelling of neutron total scattering data. The local structure is described using the instantaneous distributions of bond lengths and angles obtained from the RMC-derived models which are simultaneously consistent with the average crystal structure. These results, together with their variation with temperature, show that the majority of the mean squared displacements of the atoms are accounted for by rigid unit mode (RUM) motions of the ZrO(6) octahedra and WO(4) tetrahedra. The detailed structural description presented in this paper further supports the dominance of the basic RUM interpretation of NTE in ZrW(2)O(8) where rigid ZrO(6) and WO(4) polyhedra are joined by flexible Zr-O-W linkages. PMID- 21694139 TI - Real-space refinement of single-crystal electron diffuse scattering and its application to Bi(2)Ru(2)O(7-delta). AB - A real-space atomistic refinement approach to the analysis of experimental electron diffraction patterns is described. The method employs the reverse Monte Carlo algorithm to produce atomistic configurations capable of qualitatively reproducing diffuse electron scattering patterns. Its implementation in the program EDRMC is described in detail, together with a number of additional constraints/restraints that can be used to guide the refinement process. In particular, appropriate restraints ensure the individual atomic displacements introduced to model the diffuse scattering patterns are simultaneously consistent with the known average structure. The approach is then used to interpret electron diffraction patterns measured for Bi(2)Ru(2)O(7-delta). The diffuse scattering patterns observed are shown to arise primarily from concerted translations of Bi atoms. These translations can be interpreted in terms of rotations of [O(')Bi(4) ] tetrahedra correlated along the [Formula: see text] crystal axes and uncorrelated along orthogonal directions. PMID- 21694140 TI - Two-dimensional pattern reverse Monte Carlo method for modelling the structures of nano-particles in uniaxial elongated rubbers. AB - Two-dimensional pattern reverse Monte Carlo (2D pattern RMC) analysis is performed to model the structures of nano-particles in uniaxially elongated rubbers using two-dimensional patterns of structure factor of the nano-particles obtained by time-resolved two-dimensional ultra-small angle x-ray scattering. Four spot patterns are observed for a large elongation ratio and the shapes change with increasing elongation ratio. We performed the 2D pattern RMC method for the uniaxial system in order to make a model of the structures from the two dimensional structure factors. The preliminary results of the 2D pattern RMC analysis of the two-dimensional structure factors of silica particles in a uniaxially elongated styrene-butadiene rubber are presented. PMID- 21694141 TI - RMCProfile: reverse Monte Carlo for polycrystalline materials. AB - A new approach to the reverse Monte Carlo analysis of total scattering data from polycrystalline materials is presented. The essential new feature is the incorporation of an explicit analysis of the Bragg peaks using a profile refinement, taking account of the instrument resolution function. Other new features including fitting data from magnetic materials, modelling lattice site disorder and new restraint and constraint options. The new method is demonstrated by a brief review of studies carried out during its development. The new program RMCProfile represents a significant advance in the analysis of polycrystalline total scattering data, especially where the local structure is to be explored within the true constraints of the long-range average structure. PMID- 21694143 TI - Interactions from diffraction data: historical and comprehensive overview of simulation assisted methods. AB - A large part of statistical mechanics is concerned with the determination of condensed matter structure on the basis of known microscopic interactions. An increasing emphasis has been put on the opposite situation in the last decades as well, where structural data, e.g. pair-distance statistics, are known from diffraction experiments, and one looks for the corresponding interaction functions. The solution of this inverse problem was searched for within the integral equation theories of condensed matter in the early investigations, but before long computer simulation assisted methods were suggested. The interest in this field showed an increasing trend after some attempts appeared in the late 1980s. Several methods were published in the 1990s, and one-two methods appear annually nowadays. In this paper a comprehensive and historical overview is given on the solution of the inverse problem with simulation assisted methods. Emphasis is put on the theoretical grounds of the methods, on the choice of possible input structural functions, on the numerically local or global schemes of the potential modifications, on some advantages and limits of the different methods and on the scientific impact of the methods. PMID- 21694142 TI - PDFfit2 and PDFgui: computer programs for studying nanostructure in crystals. AB - PDFfit2 is a program as well as a library for real-space refinement of crystal structures. It is capable of fitting a theoretical three-dimensional (3D) structure to atomic pair distribution function data and is ideal for nanoscale investigations. The fit system accounts for lattice constants, atomic positions and anisotropic atomic displacement parameters, correlated atomic motion, and experimental factors that may affect the data. The atomic positions and thermal coefficients can be constrained to follow the symmetry requirements of an arbitrary space group. The PDFfit2 engine is written in C++ and is accessible via Python, allowing it to inter-operate with other Python programs. PDFgui is a graphical interface built on the PDFfit2 engine. PDFgui organizes fits and simplifies many data analysis tasks, such as configuring and plotting multiple fits. PDFfit2 and PDFgui are freely available via the Internet. PMID- 21694144 TI - Effective potentials from complex simulations: a potential-matching algorithm and remarks on coarse-grained potentials. AB - The projection of complex interactions onto simple distance-dependent or angle dependent classical mechanical functions is a long-standing theoretical challenge in the field of computational sciences concerning biomolecules, colloids, aggregates and simple systems as well. The construction of an effective potential may be based on theoretical assumptions, on the application of fitting procedures on experimental data and on the simplification of complex molecular simulations. Recently, a force-matching method was elaborated to project the data of Car Parrinello ab initio molecular dynamics simulations onto two-particle classical interactions (Izvekov et al 2004 J. Chem. Phys. 120 10896). We have developed a potential-matching algorithm as a practical analogue of this force-matching method. The algorithm requires a large number of configurations (particle positions) and a single value of the potential energy for each configuration. We show the details of the algorithm and the test calculations on simple systems. The test calculation on water showed an example in which a similar structure was obtained for qualitatively different pair interactions. The application of the algorithm on reverse Monte Carlo configurations was tried as well. We detected inconsistencies in a part of our calculations. We found that the coarse graining of potentials cannot be performed perfectly both for the structural and the thermodynamic data. For example, if one applies an inverse method with an input of the pair-correlation function, it provides energetics data for the configurations uniquely. These energetics data can be different from the desired ones obtained by all atom simulations, as occurred in the testing of our potential-matching method. PMID- 21694145 TI - Development of the time-dependent reverse Monte Carlo simulation, RMCt. AB - The aim of the present work is to develop a method of time-dependent reverse Monte Carlo modelling (RMCt), to model the atomic dynamics of materials based on data from inelastic neutron scattering experiments, such as the dynamic pair correlation function, g(r,t) or the dynamic structure factor, S(Q,omega). PMID- 21694146 TI - International conference on quantum simulators and design, hiroshima, Japan, 3-6 december 2006. AB - This special issue of Journal of Physics: Condensed Matter comprises selected papers from the 1st International Conference on Quantum Simulators and Design (QSD2006) held in Hiroshima, Japan, 3-6 December 2006. This conference was organized under the auspices of the Development of New Quantum Simulators and Quantum Design Grant-in-Aid for Scientific Research on Priority Areas, Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and Hiroshima University Quantum design is a computational approach to the development of new materials with specified properties and functionalities. The basic ingredient is the use of quantum simulations to design a material that meets a given specification of properties and functionalities. For this to be successful, the quantum simulation should be highly reliable and be applicable to systems of realistic size. A central interest is, therefore, the development of new methods of quantum simulation and quantum design. This includes methods beyond the local density approximation of density functional theory (LDA), order N methods, methods dealing with excitations and reactions, and so on, as well as the application of these methods to the design of new materials and devices. The field of quantum design has developed rapidly in the past few years and this conference provides an international forum for experimental and theoretical researchers to exchange ideas. A total of 183 delegates from 8 countries participated in the conference. There were 18 invited talks, 16 oral presentations and 100 posters. There were many new ideas and we foresee dramatic progress in the coming years. The 2nd International Conference on Quantum Simulators and Design will be held in Tokyo, Japan, 31 May-3 June 2008. PMID- 21694147 TI - Relationship between the geometric structure and conductance oscillation in nanowires. AB - A theoretical analysis of the electron transport properties of plain and bumpy jellium nanowires suspended between semi-infinite jellium electrodes is carried out, and the possibility of the experimental observation of the conductance oscillation with a period longer than the two-atom length is discussed. In both the nanowires, the transmission trace as a function of the nanowire length exhibits oscillatory behaviour. The period of the oscillation of the plain nanowire corresponds to pi divided by the Bloch wavenumber of the electrons in the nanowire region. However, the period of the oscillation of the bumpy nanowire results in the least common multiple of pi divided by the Bloch wavenumber and the geometric period of the nanowire. Our result indicates that the conductance oscillation with a period longer than the two-atom length can be experimentally observed if nanowires without any defects are formed in experiments. PMID- 21694148 TI - First-principles study of the electronic structures and dielectric properties of the Si/SiO(2) interface. AB - A first-principles study of the electronic structures and dielectric properties of Si/SiO(2) interfaces is implemented. Comparing the interfaces with and without defects, we explore the relationship between the defects and the dielectric properties, and also discuss the effect of the defects on the leakage current between the gate electrode and silicon substrate. We found that the electrons around the Fermi level percolate into the SiO(2) layers, which reduces the effective oxide thickness and is expected to enhance the leakage current. The dangling bonds largely affect the dielectric properties of the interface and the termination of dangling bonds by hydrogen atoms is successful in suppressing the increase of the dielectric constant. PMID- 21694149 TI - Spin-mixing conductances of metallic and half-metallic magnetic layers. AB - The spin-mixing conductance of a thin ferromagnetic layer attached epitaxially to two semi-infinite non-magnetic metallic leads is formulated in terms of non equilibrium Green's functions. The spin-mixing conductance is obtained as a response of the spin torque acting on the ferromagnet with respect to the spin accumulation in one of the leads, while the spin torque is defined as a time derivative of the spin magnetic moment. The equivalence of the derived formula with a previous expression of the Landauer-Buttiker scattering theory is sketched and an implementation within the ab initio tight-binding linear muffin-tin orbital method is briefly described. Applications are made for metallic Co- and Ni-based slabs embedded between Cu(111) leads and for half-metallic Co(2)MnSi films sandwiched by Cr(001) leads. The calculated results throw serious doubts on the general validity of two features: fast convergence of the spin-mixing conductance with increasing thickness of the magnetic layer and negligible values of the imaginary part of the spin-mixing conductance as compared to the real part. PMID- 21694150 TI - Design of a d(1)-analogue of cuprates: Sr(2)VO(4) and Ba(2)VO(4) under pressure. AB - By means of a combination of the local density approximation and dynamical mean field theory (LDA + DMFT), we study the possibility of making a d(1) analogue of d(9) cuprates on the basis of Sr(2)VO(4). We calculate the electronic structure of Sr(2)VO(4) under pressure, and show that while the material is a 1/6-filled three-band system at ambient pressure with a small level splitting between the d(xy)- and d(yz/zx)-bands, an orbital polarization occurs under sufficiently high uniaxial pressure in the c-direction. While all energy scales are relatively small, the electronic structure of Sr(2)VO(4) under pressure is similar to that of La(2)CuO(4); it is a two-dimensional half-filled single-band system which has, relative to the nearest neighbour hopping, a similar Coulomb repulsion and next nearest neighbour hopping. We also study the effect of substituting Sr by Ba, i.e., chemical pressure, and show that the pressure needed for the orbital polarization is considerably reduced. PMID- 21694151 TI - A path-integration calculation method based on the real-space finite-difference scheme. AB - We propose a new path-integration calculation method to treat the time evolution of a wavefunction within the framework of the real-space finite-difference formalism, and also develop an effective scheme to compute the scattering wavefunction for an incident electron with arbitrary energy, in which an impulse wavefunction is adopted as an initial state of the time evolution. In this method, once the time evolution of the initial impulse wavefunction is calculated, all of the solutions in the scattering problem can be derived by means of Fourier analysis of the time-evolved wavefunction, which leads to a reduction of the calculation time. In order to test the applicability of our newly developed simulation procedures, we implemented simulations for the one dimensional scattering problem. Each simulation showed the usefulness of the present scheme by yielding the steady scattering states in agreement with exact ones. PMID- 21694152 TI - Effective band structure of correlated materials: the case of VO(2). AB - Vanadium dioxide VO(2) and its metal-insulator transition at T = 340 K continue to receive considerable interest. The question whether the physics of the insulating low-temperature phase is dominated by the Mott or the Peierls scenario, i.e. by correlation or band effects, is still under debate. A recent cluster dynamical mean field theory calculation (Biermann et al 2005 Phys. Rev. Lett. 94 026404) suggests a combination of both effects, characterizing the transition as of a correlation-assisted Peierls type. In this paper we present a detailed analysis of the excitation spectrum of the insulating M1 phase of VO(2), based on this calculation. We implement a scheme to analytically continue self energies from Matsubara to real frequencies, and study the physics of the strong interactions, as well as the corresponding changes with respect to the density functional theory band structure within the local density approximation (LDA). We find that in the M1 phase lifetime effects are rather negligible, indeed allowing for an effective band structure description. A frequency-independent but orbital dependent potential, constructed as an approximation to the full cluster dynamical mean field self-energy, turns out to satisfactorily reproduce the fully interacting one-particle spectrum, acting as a scissors operator which pushes the a(1g) bonding and e(g)(pi) bands apart and, thus, opens the gap. PMID- 21694153 TI - Control of impurity diffusion in silicon by IR laser excitation. AB - Control of the diffusion of a specific impurity species is desirable in Si device processes. IR laser excitation matching the impurity vibration mode is a promising method for this purpose. To illustrate the effectiveness of this method, first-principles molecular dynamics simulation has been applied. Technical issues of the simulation are described in detail. It is seen that resonant effects can be reproduced in adiabatic molecular dynamics simulations by applying an external force on the impurity only. The present study forms the basis for further developments of this approach. PMID- 21694154 TI - Magnetic anisotropies of iron on the Pt(111) surface. AB - We have studied magnetic anisotropies of Fe atoms on the platinum (111) surface, employing a fully relativistic pseudopotential and plane wave method with the local spin density approximation. We investigated three surface structures with different Fe monolayer coverages: full coverage, half-coverage and quarter coverage. The effect of surface relaxation has been included. It was found that the magnetic easy axis of the system is within the surface plane for all systems investigated. In the system of an Fe chain on Pt(111), having an anisotropic local structure, the magnetic anisotropy energy is much enhanced after surface relaxation. This absolute value is larger compared with the value for bulk alloy and the magnetic easy axis is directed parallel to the alignment of Fe atoms. PMID- 21694155 TI - Hydrogen desorption from nanostructured graphite: ab initio molecular-dynamics studies. AB - We have carried out hybrid ab initio/classical molecular-dynamics simulations for the model system of hydrogen-adsorbed nanostructured graphite. We have investigated the effect of the recrystallization of the nanostructured graphite to the bonding states of hydrogen atoms at 1000 K and the desorption mechanism of the hydrogen dimer from the graphite at 2000 K. We have shown that the recrystallization weakens the bond between the hydrogen and the carbon atoms and the desorption of hydrogen atoms, as the hydrogen dimer occurs at 2000 K. PMID- 21694156 TI - Applying computational nanomaterials design to the reactive ion etching of NiO thin films-a preliminary investigation. AB - We have developed and proposed a model for reactive ion etching (RIE) process design of nickel oxide thin films using a computational materials design based on ab initio calculations. On etching NiO, we found that it was necessary to have hydrogen-based reactive gases in the initial state in order to enhance RIE (e.g. NH(3), CH(4)). We strongly suggest the use of CH(4) or any H-based gas source other than CHF(3) to enhance RIE process. PMID- 21694157 TI - Oxygen at high pressures: a theoretical approach to monoatomic phases. AB - We have studied the zeta-phase of solid oxygen using the generalized gradient approximation in the density functional approach. Calculations of total energies and pressures have been carried out for the prototype of diatomic zeta-phase and other hypothetical monoatomic crystal structures. The diatomic phase was found to be stable over a wide range of pressure (100-2000 GPa). The stacking of molecular layers is discussed in comparison with the available experimental data. PMID- 21694158 TI - Ferromagnetism and spinodal decomposition in dilute magnetic nitride semiconductors. AB - We propose a materials design for dilute magnetic semiconductors (DMS) based on first-principles calculations by using the Korringa-Kohn-Rostoker coherent potential approximation method. We develop an accurate method for calculations of the Curie temperature (T(C)) of DMS and show that the mean field approximation completely fails to predict T(C) for DMS, in particular for wide gap nitride DMS where the exchange interaction is short ranged. The T(C) calculated for homogeneous DMS by using the present method agrees very well with available experimental values. For more realistic material design, we simulate spinodal nanodecomposition by applying the Monte Carlo method to the Ising model with ab initio chemical pair interactions between magnetic impurities in DMS. It is found that by controlling the dimensionality of the decomposition, various characteristic phases occur in DMS. It is suggested that superparamagnetic blocking phenomena should be important for understanding the magnetism of wide gap DMS. PMID- 21694159 TI - Band calculations for 4f systems based on the dynamical mean field theory. AB - Recent band calculations for Ce compounds based on the dynamical mean field theory (DMFT) are reported. The auxiliary impurity problem has been solved by a method named NCAf(2)vc, which includes the correct exchange process of the [Formula: see text] virtual excitation, the crystalline field splitting (CFS), and the spin-orbit interaction (SOI) of the self-energy. These are necessary features in the quantitative band theory for Ce compounds. The results of applications on Ce metal and Ce-monopnictides are presented. PMID- 21694160 TI - Magnetic properties of 3d pyrite-type mixed crystals calculated by the full potential KKR-CPA method. AB - The electronic and magnetic properties of pyrite-type mixed crystals M(1 x)M(x)(')S(2) (M, M(') = Fe,Co,Ni) were investigated by use of the full-potential Korringa-Kohn-Rostoker (KKR) method combined with the coherent potential approximation (CPA). The results well explain the systematic behaviour of these systems as long as they are in a metallic phase. It is also concluded that the full-potential treatment is necessary to describe these anisotropic systems. PMID- 21694161 TI - Comparison between the vorticity expansion approximation and the local density approximation of the current-density functional theory from the viewpoint of sum rules. AB - We compare the vorticity expansion approximation (VEA) with the local density approximation (LDA) of the current-density functional theory from the viewpoint of sum rules. The VEA formulae satisfy all sum rules which are derived from uniform and nonuniform coordinate scaling properties, while the LDA formulae do not satisfy at least about a third of the sum rules. The validity of the VEA formula is thus confirmed successfully. PMID- 21694162 TI - First principles molecular dynamics study of catalytic reactions of biological macromolecular systems: toward analyses with QM/MM hybrid molecular simulations. AB - First principles molecular dynamics simulations performed on a fully solvated RNA model structure allowed us to investigate the mechanism for enzymatic cleavage reactions, in vitro, of RNA enzymes (ribozymes). The concerted action of two metal catalysts turns out to be the most efficient way to promote, on the one hand, the proton abstraction from 2(')-OH that triggers the nucleophilic attack and, on the other hand, the cleavage of the P-O(5(')) bond. In fact, the elimination of one of the two metal cations leads to an increase in the activation energy of the reaction. The simulated pathway shows that an OH(-) in the coordination shell of the Mg(2+) close to O(2(')) promotes the initial proton abstraction and prevents its transfer to the ribozyme. This suggests that, in a real ribozyme, the double-metal-ion reaction mechanism is preferred with respect to single-metal-ion mechanisms either in the presence or in absence of the OH(-) anion. Finally, an insight into the importance of hybrid quantum mechanics/molecular mechanics (QM/MM) schemes is discussed in view of the modelling of a realistic system carrying all the features of a true ribozyme. PMID- 21694163 TI - Quantum effects in a cylindrical carbon-nanotube capacitor. AB - We have theoretically investigated the electric polarization and capacitance in a nano-scale coaxial-cylindrical capacitor made of a double-walled carbon nanotube, (6,0)@(36,0), using a first-principles density-functional method with the enforced Fermi-energy difference scheme. We show that the distribution of the accumulated charge in the inner tube is quantum-mechanically spilled outward, while that in the outer tube is penetrating inward. Reflecting these charge spills, the electrostatic capacitance of the system is larger than what would be expected from classical theory. Furthermore, the total capacitance of the system is smaller than the electrostatic capacitance, which is another quantum effect showing large contributions from the DOS of the electrodes to the capacitance. We believe that these two quantum effects in the capacitance are important for the successful design of carbon-nanotube devices. PMID- 21694164 TI - Simultaneous equations for calculating the pair density. AB - We propose a practical scheme for calculating the pair density (PD) on the basis of the density functional theory. In order to avoid the N-representability problem of the PD, we implement the variational principle within the set of PDs that are constructed from the single Slater determinants (SSDs). For the kinetic energy functional, we utilize the approximate form that is developed by means of the electron-coordinate scaling laws. The variational principle results in the simultaneous equations for constituent orbitals of the SSD. It yields the best one within the SSD-representable PDs. PMID- 21694165 TI - First-principles molecular dynamics study of proton transfer mechanism in bovine cytochrome c oxidase. AB - Density functional based first-principles molecular dynamics calculations, performed on a model system extracted from the bovine cytochrome c oxidase, have been performed in an attempt to inspect the proton transfer mechanism across a peptide group. Our model system includes the specific Tyr440-Ser441 peptide group involved in a novel proton transfer path and shows that the Y440-S441 enol peptide group [-C(OH) = N-], which is a structural isomer of a keto form [-CO-NH ], is the product of the deprotonation of an imidic acid [-C(OH)-NH-] occurring in the vicinity of the deprotonated aspartic acid residue. For the subsequent enol-to-keto tautomerization, a direct H(+) transfer path in the Y440-S441 peptide group has been identified, in which the transition state takes a distorted four-membered ring structure. PMID- 21694166 TI - Thermoelectric power calculation by the Boltzmann equation: Na(x)CoO(2). AB - A full-potential augmented-plane-wave (FLAPW) band-structure calculation in the local density approximation (LDA) was carried out for hexagonal Na(x)CoO(2) (x = 0.45, 0.55, 0.66 and 0.75). The Seebeck tensor was estimated by the Boltzmann theory, assuming that the relaxation time is constant on the Fermi surface. The Seebeck tensor is extremely anisotropic; the c-axis Seebeck coefficient varies dramatically with the Na content. The calculation reproduces the experiment semiquantitatively. PMID- 21694167 TI - Noncollinear magnetism and exchange interaction in spin-spiral structures of thin film Fe(110). AB - Spin-spiral structures in a free-standing Fe(110) monolayer are determined by the first-principles film full-potential linearized augmented plane wave method with intra-atomic noncollinear magnetism. The results obtained predict that the spin spiral structures are energetically favourable over the collinear ferromagnetic state. The interatomic exchange parameters, which are evaluated from the formation energy of the spin-spiral structures, indicate that a competition between the nearest-neighbour ferromagnetic interaction and the long-distant antiferromagnetic interactions leads to the stabilization of the spin-spiral structures. In addition, the spin-orbit coupling is found to play an important role in determining the magnetic ground state. PMID- 21694168 TI - Structural properties of nanometre-sized ZnO crystals doped with Co. AB - Nanometre-sized ZnO crystals doped with Co were synthesized by a co-precipitation method combined with a thermal treatment. By changing the reaction temperature, we can control the crystallite size from roughly 10 nm particles to 20 nm * 200 nm nm rods grown along the hexagonal c-direction. X-ray diffraction and Raman scattering showed growth of high-quality wurtzite ZnO crystals incorporating Co systematically in the ZnO host lattice in the tested range of [Co]<3.0 mol%. Electronic transitions of Co in the oxygen tetrahedron were also observed in optical absorption, giving supporting evidence for systematic substitution of Co into the Zn site. PMID- 21694169 TI - Observation of phonons in multiferroic BiFeO(3) single crystals by Raman scattering. AB - We have grown BiFeO(3) bulk single crystals by a flux method and characterized the phonon spectra in detail by Raman scattering in the temperature range 4-1100 K. All the 13 Raman-active phonon modes predicted by group theory, 4A(1)+9E, were observed at low temperature and successfully assigned by a polarized Raman measurement. Moreover, drastic spectral changes in the Raman spectra were observed at temperatures 600-700 K and 1000-1100 K. These features are discussed from the viewpoint of phonon coupling with the magnetic ordering and the structural phase transition, respectively. PMID- 21694170 TI - First-principles study of the geometry of Ag nanowires growing on a self assembled Bi nanoline. AB - Epitaxial Ag nanowires on a self-assembled Bi nanoline on the Si(001) surface are examined for their geometry and energetic stability at the level of the generalized-gradient approximation. The orientations examined are Ag(001)[100], Ag(110)[100], Ag(111)[110], and Ag(001)[110], where the indices refer to the plane and the direction parallel to the Si(001) surface and the Bi nanoline, respectively. The wires are found to have mostly bulklike structure, except that Ag(001) monolayers undergo extensive reconstruction. The calculated electronic band structure indicates that the Ag wires are metallic wires. Particularly stable among the wires are the Ag(111) wires, having a coincident site lattice interface with the Bi nanoline. The energetic stability generally improves with thickness, indicating that Ag grows through three-dimensional nucleation on the Bi nanoline. PMID- 21694171 TI - Calculated electronic structures and Neel temperatures of half-metallic diluted antiferromagnetic semiconductors. AB - The possibility of half-metallic diluted antiferromagnetic semiconductors of II VI compounds is investigated on the basis of first-principles electronic structure calculation. The electronic structures of ZnS, ZnSe, ZnO, CdS and CdSe doped with two kinds of 3d transition metal ions are calculated using the Korringa-Kohn-Rostoker (KKR) method and their magnetic transition temperatures are determined using a cluster-type approximation. It is predicted that II-VI compound semiconductors doped with two kinds of magnetic ions might be good candidates for half-metallic antiferromagnets. PMID- 21694172 TI - Measurement and calculation of the differential reflectance spectrum of hydrogen terminated silicon surfaces having different crystal orientations. AB - The differential reflectance spectrum between the (001) and the (111) hydrogen terminated Si surfaces without native oxidation is investigated. Careful measurements using developed apparatus and an ultra-clean process are performed. The measured spectrum is compared with the reported one (Chongsawangvirod and Irene 1991 J. Electrochem. Soc. 138 1748-52), and is shown to be roughly identical even though a native oxidation effect exists. The theoretical calculation based on density-functional theory (DFT) and local density approximation (LDA) is also performed. The peak positions in the calculated and the measured spectra are in good accordance with each other, while the magnitudes of the peaks are in relatively worse agreement. Although the inclusion of advanced approximations would provide more accurate results, a qualitative reproduction is achieved in this study as well. It is concluded that the origin of the spectrum is mainly in the deformation of the bulk states induced by surface perturbation. PMID- 21694173 TI - Coherent tunnelling conductance in magnetic tunnel junctions of half-metallic full Heusler alloys with MgO barriers. AB - We have carried out electronic structure and transport calculations for magnetic tunnel junctions (MTJ) composed of MgO and a half-metallic full Heusler alloy Co(2)MnSi on the basis of the density functional theory and the Landauer formula. We find that the density of states of Co atoms at the Co(2)MnSi/MgO(001) interface shifts toward the higher energy side due to the reduced symmetry, leading to a reduction of the spin polarization at the interface. Furthermore, we show that the majority-spin transmittance as a function of the in-plane wavevector [Formula: see text] has a broad peak centred at [Formula: see text] due to the tunnelling from the Delta(1) channel of Co(2)MnSi, while the transmittance from the Delta(5) channel is three orders of magnitude smaller than that of the Delta(1) channel. These results indicate that coherent tunnelling through the Delta(1) band is dominant also in an MTJ with Co(2)MnSi and an MgO barrier, like in Fe/MgO/Fe(001) MTJ and related systems. PMID- 21694174 TI - Determination of the Mott insulating transition by the multi-reference density functional theory. AB - It is shown that a momentum boost technique applied to the extended Kohn-Sham scheme enables the computational determination of the Mott insulating transition. Self-consistent solutions are given for correlated electron systems by first principles calculations defined by the multi-reference density functional theory, in which the effective short-range interaction can be determined by the fluctuation reference method. An extension of the Harriman construction is made for the twisted boundary condition in order to define the momentum-boost technique in the first-principles manner. For an effectively half-filled-band system, the momentum-boost method tells that the period of a metallic ground state by the local density approximation (LDA) calculation is shortened to the least period of the insulating phase, indicating the occurrence of the Mott insulating transition. PMID- 21694175 TI - Applications of path-integral renormalization group method combined with density functional theory. AB - The path-integral renormalization group method is an efficient tool for computing electronic structure of strongly correlated electron systems. Combined with the conventional density functional approaches as a hybrid scheme, it offers a first principles method for complex materials with involved electron correlation effects. We assess the efficiency and applicability of the hybrid scheme by examining applications to Sr(2)VO(4) and YVO(3). PMID- 21694176 TI - Energetics and electronic structure of armchair nanotubes with topological line defects. AB - We study the electronic structure and energetics of carbon nanotubes with topological line defects consisting of fused pentagons and octagon rings by means of first-principles calculation in density functional theory and tight-binding molecular dynamics simulations. The tubes with the topological line defects are found to exhibit magnetic ordering where polarized electron spins are localized around the topological defect and ferromagnetically aligned along the defect. Our analyses of the electronic energy band and spin density distributions reveal that this ferromagnetic spin ordering is associated with the edge states that are inherent in the graphite ribbon with zigzag edges. The tight-binding molecular dynamics simulations show that the nanotubes with the topological line defects are thermally stable up to temperature of 3000 K and disrupted over 4000 K. PMID- 21694177 TI - First-principles KKR-CPA calculation of interactions between concentration fluctuations. AB - The aim of this work is to develop the method of calculating atomic interactions in metals and semiconductors on the basis of first-principles electronic structure calculation. A new method to calculate the atomic interactions in the framework of KKR-CPA is proposed. In this approach two specific atoms embedded in a CPA medium are considered and the effects of both electron-electron interactions and multiple scattering, which are neglected in the generalized perturbation method (GPM), are fully taken into account. The calculated atomic interactions show that these effects are important for alloys containing transition-metal alloys such as FeAl. On the other hand, in the case of AuCu, where the d states lie considerably below the Fermi level, the effects are less important. PMID- 21694178 TI - First-principles calculation of the Curie temperature Slater-Pauling curve. AB - It is well known that the magnetizations as a function of the valence electron number per atom of 3d transition metal substitutional alloys form the so-called Slater-Pauling curve. Similarly, the Curie temperatures of these alloys also show systematic behaviour against the valence electron number. Though this fact has long been known, no attempt has been made so far to explain this behaviour from first principles. In this paper we calculate T(C) of 3d transition metal alloys in the framework of first-principles electronic structure calculation based on the local density approximation. PMID- 21694179 TI - CO adsorption effects on the electronic properties of Fe tape-porphyrin. AB - We investigated the electronic properties of Fe tape-porphyrin and the effect of CO adsorption on it within the framework of density functional theory. As for the numerical results, we found that the Fe tape-porphyrin is metallic, and that the CO-adsorbed Fe tape-porphyrin is an insulator. Comparing the electronic structures of the Fe porphyrin molecule and the CO-adsorbed one, we found that the metal-insulator transition is caused by the hybridization of the d(xz) and d(yz) orbitals of Fe with the pi(g)(*) orbital of CO. PMID- 21694180 TI - The first-principles multi-component molecular orbital approach to bound states of positron with the 2-deoxyglucose molecule as a reagent of positron emission tomography. AB - Characteristic features of the positron binding properties of 2-deoxyglucose molecules of C(6)H(11)O(5)F and C(6)H(11)O(6)(-), which are used as reagents of positron emission tomography (PET), are discussed based on the results obtained by a first-principles multi-component molecular orbital calculation. This method can take the positron-electron coupling into account under the mean-field approximation. Due to the large electronic polarization, the positron affinity of anionic C(6)H(11)O(6)(-) is much greater than that of neutral C(6)H(11)O(5)F. PMID- 21694181 TI - Quasiparticle self-consistent GW method: a short summary. AB - We have developed a quasiparticle self-consistent GW method (QSGW), which is a new self-consistent method to calculate the electronic structure within the GW approximation. The method is formulated based on the idea of a self-consistent perturbation; the non-interacting Green function G(0), which is the starting point for GWA to obtain G, is determined self-consistently so as to minimize the perturbative correction generated by GWA. After self-consistency is attained, we have G(0), W (the screened Coulomb interaction) and G self-consistently. This G(0) can be interpreted as the optimum non-interacting propagator for the quasiparticles. We will summarize some theoretical discussions to justify QSGW. Then we will survey results which have been obtained up to now: e.g., band gaps for normal semiconductors are predicted to a precision of 0.1-0.3 eV; the self consistency including the off-diagonal part is required for NiO and MnO; and so on. There are still some remaining disagreements with experiments; however, they are very systematic, and can be explained from the neglect of excitonic effects. PMID- 21694182 TI - Ab initio calculations for high-pressure phases of Ar(H(2))(2). AB - High-pressure structures of Ar(H(2))(2) are studied with possible molecular dissociation and metallization using density functional theory in the local density approximation (LDA) and generalized gradient approximation (GGA) for the exchange-correlation energy. We have estimated the transition pressure from the low-pressure MgZn(2)-type structure to the high-pressure AlB(2)-type structure to be around 240 GPa. The band gap of the MgZn(2)-type structure does not close, while the band gap of the AlB(2) closes at 420 GPa, which is much higher than the pressure of the band gap closure in pure hydrogen obtained by the same GGA. The lattice vibrations in those structures are also studied. The frequencies of the vibronic motions show good agreement with experiments. The molecular dissociation of the hydrogen in Ar(H(2))(2) occurs at higher pressures than in pure hydrogen. PMID- 21694183 TI - The computational materials design of (Ga, Cr)N: effects of co-doping on exchange interactions. AB - We investigate the effect of O or Be co-doping on the exchange interaction between Cr spins in (Ga, Cr)N by means of first-principles calculations based on the density-functional theory. The ferromagnetic exchange interactions are reduced by doping Be around Cr. On the other hand, O doping reduces the ferromagnetic interaction remarkably only for the case of Cr-O-Cr complex formation. The enhancement of the ferromagnetic exchange interaction cannot be achieved by doping O or Be impurities. However, the O and Be impurities can help the clustering of Cr atoms due to the enhancement of the attractive interaction between Cr atoms. PMID- 21694184 TI - Raman scattering studies on multiferroic YMnO(3). AB - YMnO(3) is a multiferroic material in which ferroelectric and antiferromagnetic ordering can coexist. We have studied a YMnO(3) bulk crystal in detail by Raman scattering in a wide temperature range of 15-1200 K, with comparison to a previous experiment at room temperature and a theoretical prediction for Raman active phonon modes. In the low-temperature ferroelectric phase, the observed phonon spectra showed anomalous temperature variation at the Neel temperature, T(N)~80 K, suggesting a coupling between the spin and phonon systems below T(N). Furthermore, spectra for the high-temperature paraelectric phase, reported here for the first time, showed a sudden change at the Curie temperature T(C)>900 K, suggesting an abrupt structural phase change from the ferroelectric to the paraelectric phase. PMID- 21694185 TI - A comparative study of the interaction of platinum with group 4A (germanium, tin and lead) porphyrins. AB - Because of its vast number of applications and high price many studies have been made on how to reduce the amount of platinum in catalysts. One method includes dispersing platinum nanoparticles in porous support materials. But electrically conductive carbon-based support materials-needed for fuel cell electrodes-permit nanoparticles to migrate and form larger clusters, leading to reduced catalytic activity over time. To find a solution to this problem, we modelled the interaction of group 4A metal porphyrins (germanium (II) porphyrin (GePor), tin (II) porphyrin (SnPor) and lead (II) porphyrin (PbPor)) with platinum (Pt) using density functional theory. We showed that platinum can bond strongly on both germanium porphyrin and tin porphyrin. More importantly, valence Pt d-orbital characteristics dominate their HOMO and HOMO-1. Our study indicates that dispersing Pt as individual atoms on a SnPor and GePor surface is a good way to minimize platinum load in carbon-based reduction catalysts for reactions involving mainly the HOMO and HOMO-1 of Pt, of which the oxygen reduction reaction in fuel cells is an example. PMID- 21694186 TI - Valence control of alpha-rhombohedral boron by electronic doping. AB - It was previously predicted that doping Li into semiconducting boron (alpha rhombohedral) brought metallic character to the matrix and possibility a high T(c) superconductor. However, experiments show that Li doping of alpha rhombohedral boron is difficult. In this paper, the potential for Li doping of boron is re-examined using the ab initio pseudopotential method. Based on the calculated formation enthalpy, an efficient method for doping is proposed. The method utilizes high pressure, such as 10 GPa. Slight changes in the structural parameters for Li insertion are also resolved, which may be useful for the experimental detection of Li in boron. The stability of alpha-rhombohedral boron at high pressures is also compared to that of Ga-type structure, which has been put forth as a candidate for the high-pressure phase. The present study gives further confirmation of the stability of alpha-rhombohedral boron at least up to 70 GPa. PMID- 21694187 TI - Dynamics simulation of a pi-conjugated light-harvesting dendrimer. AB - Carrying out a semi-classical Ehrenfest dynamics simulation based on the time dependent density functional theory, we investigate the light-harvesting property of a pi-conjugated dendrimer, star-shaped stilbenoid phthalocyanine (SSS1Pc) with oligo (p-phenylenevinylene) peripheries and show that an electron and a hole transfer from the periphery to the core through a pi-conjugated network when an electron is selectively excited in the periphery. The one-way electron and hole transfer occurs more easily in dendrimers with a planar structure than in those with steric hindrance because pi-conjugation is well maintained in the planar structure. The present results explain recent experiments. PMID- 21694188 TI - Accuracy control in ultra-large-scale electronic structure calculations. AB - Numerical aspects are investigated in ultra-large-scale electronic structure calculations. Accuracy control methods in process (molecular-dynamics) calculations are focused upon. Flexible control methods are proposed so as to control variational freedoms, automatically at each time step, within the framework of generalized Wannier state theory. The method is demonstrated in a silicon cleavage simulation with 10(2)-10(5) atoms. The idea is of general importance among process calculations and is also used in Krylov subspace theory, which is another large-scale calculation theory. PMID- 21694189 TI - Pathways for SO(2) dissociation on Cu(100): density functional theory. AB - The dissociation of SO(2) on Cu(100) and the diffusion of the co-adsorbed decomposition products S and O were investigated using density functional theory based calculations. Two dissociation pathways were considered: (P1) [Formula: see text] and (P2) [Formula: see text], the difference being in the formation of the intermediate product SO. It is found that P1 is favored kinetically with a total effective dissociation barrier of 0.78 eV compared to P2 which has 1.58 eV. The transition state leading to the formation of O+SO is found to be a result of the weakened interaction between the O of SO and the surface while the transition state for breaking SO is seen to be that of the repulsive nature of co-adsorbed S and O. The co-adsorbed S has a lower diffusion barrier of 0.41 eV compared to O which has a barrier ranging from 0.49 to 0.95 eV. PMID- 21694190 TI - Adsorption states of methylthiolate on the Au(111) surface. AB - We have studied the adsorption structures of methylthiolate (MeS) on the Au(111) surface using density functional theory. The most stable adsorption structure of MeS is the MeS-Au-MeS configuration, which has been proposed by Maksymovych and co-workers (2006 Phys. Rev. Lett. 97 146103), followed by the bridge configuration. The calculated work function change and vibrational mode analysis for the two configurations agree quite well with the experimental results. These results strongly support the conclusion that the MeS-Au-MeS and the bridge configurations coexist on the MeS adsorbed Au(111) surface. PMID- 21694191 TI - Proceedings of the 13th Conference on Liquid and Amorphous Metals (LAM13) (Ekaterinburg, Russia, 8-14 July 2007). PMID- 21694192 TI - Co-publication with Journal of Physics: Conference Series. AB - The 13th Conference on Liquid and Amorphous Metals (LAM13) was held from 8-13 July 2007 in Ekaterinburg, Russia. Papers from invited lectures and full-scale oral reports are published in Journal of Physics: Condensed Matter. Papers from brief oral reports and posters will be published in an upcoming issue of Journal of Physics: Conference Series. PMID- 21694193 TI - Fluid-bicontinuous gels stabilized by interfacial colloids: low and high molecular weight fluids. AB - Carefully tuned composite materials can have properties wholly unlike those of their separate constituents. We review the development of one example: colloid stabilized emulsions with bicontinuous liquid domains. These non-equilibrium structures resemble the sponge mesophase of surfactants; however, in the colloid stabilized case the interface separating the liquid domains is itself semi-solid. The arrangement of domains is created by arresting liquid-liquid phase separation via spinodal decomposition. Dispersed colloids exhibiting partial wettability become trapped on the newly created interface and jam together as the domains coarsen. Similar structures have been created in polymer blends stabilized using either interfacial nanoparticles or clay platelets. Here it has been possible to create the domain arrangement either by phase separation or by direct mixing of the melt. The low molecular weight liquid and polymer based structures have been developed independently and much can be learnt by comparing the two. PMID- 21694194 TI - Study of liquid metals as a basis for nanoscience. AB - There are two ways to proceed with nanoscience: so-called top-down and bottom-up methods. Usually, the former methods are thought of as in the province of physicists and the latter in that of chemists. However, this is not entirely true because the physics of disordered matter, especially liquid metals, is well developed bottom-up science and it has indeed provided nanoscience with basic ideas and theoretical tools such as ab initio molecular dynamics (MD) simulations. Here we wish to present experimental studies on such phenomena that originate from quantum mechanical properties and subsequently lead to classical non-equilibrium processes: among these are slow dynamics due to metal-nonmetal transitions in liquids, and wetting and dewetting transitions of liquid semiconductors. Since all these phenomena are related to a spatiotemporal range far wider than that treated by the present ab initio MD simulations, it is desirable that new progress in theoretical physics be stimulated, resulting in further developments in nanoscience. PMID- 21694195 TI - Structural and electronic properties of expanding fluid metals. AB - It has been theoretically predicted that interacting electron gas suffers a negative compressibility when the electron density is sufficiently reduced. Dielectric anomaly is another expression of compressional instability in which the static dielectric function of electron gas changes sign from positive to negative. In a medium with a negative dielectric function, like charges can attract. Expanding fluid alkali metals are the ideal system in which such instability of electron gas can be probed via the structural response of ions. We have performed x-ray diffraction and small angle x-ray scattering measurements using synchrotron radiation for expanding fluid rubidium and cesium. On the basis of the experimental results we discuss the existence of compressional instability and dielectric anomaly in three-dimensional electron gas. PMID- 21694196 TI - Understanding the resistivity and absolute thermoelectric power of disordered metals and alloys. AB - We recall definitions of the electronic transport properties, direct coefficients like electrical and thermal transport conductivities and crossed thermoelectric coefficients like the Seebeck, Peltier and Thomson coefficients. We discuss the links between the different electronic transport coefficients and the experimental problems in measuring these properties in liquid metals. The electronic transport properties are interpreted in terms of the scattering of electrons by 'pseudo-atoms'. The absolute thermoelectric power (ATP), thermopower or Seebeck coefficient is known as the derivative of the electrical resistivity versus energy. The key is to understand the concept of resistivity versus energy. We show that the resistivity follows approximately a 1/E curve. The structure factor modulates this curve and, for a Fermi energy corresponding to noble and divalent metals, induces a positive thermopower when the free electron theory predicts a negative one. A second modulation is introduced by the pseudopotential squared form factor or equivalently by the squared t matrix of the scattering potential. This term sometimes introduces an anti-resonance (divalent metals) which lowers the resistivity, and sometimes a resonance having an important effect on the transition metals. Following the position of the Fermi energy, the thermopower can be positive or negative. For heavy semi-metals, the density of states splits into an s and a p band, themselves different from a free electron E(0.5) curve. The electrons available to be scattered enter the Ziman formula. Thus if the density of states is not a free electron one, a third modulation of the [Formula: see text] curve is needed, which also can change the sign of the thermopower. For alloys, different contributions weighted by the concentrations are needed to explain the concentration dependent resistivity or thermopower. The formalism is the same for amorphous metals. It is possible that this mechanism can be extended to high-temperature crystalline alloys or even disordered semiconductors since we can separate the transport coefficients between the effect of the number of charge carriers and a scattering term linked to carrier mobility. PMID- 21694197 TI - Analysis of the electronic structure of liquid rubidium by the methods of ab initio molecular dynamics, linear muffin-tin orbitals and recursion. AB - It is well known that liquid rubidium shows some unusual properties at low densities. The ab initio SIESTA package and the supercell technique within the linear muffin-tin orbital method were used to investigate this phenomenon. Electronic structures of liquid rubidium at different temperatures from the melting point up to the critical point were obtained. The atomic structure for the supercell technique was simulated for a cluster of 4000 atoms by the Schommers method on the basis of experimental structure factors of Rb obtained by Tamura and co-workers at different temperatures (from 373 up to 1973 K). The Kubo Greenwood formula was applied for the calculations of the melt conductivity. The results obtained indicate that the metal-nonmetal transition in liquid rubidium is not connected to the gap at the Fermi energy in the density of electronic states, but, more likely, with electron localization on some kind of atomic cluster. PMID- 21694198 TI - Unidirectional solidification of binary melts from a cooled boundary: analytical solutions of a nonlinear diffusion-limited problem. AB - A model is presented that describes nonstationary solidification of binary melts or solutions from a cooled boundary maintained at a time-dependent temperature. Heat and mass transfer processes are described on the basis of the principles of a mushy layer, which divides pure solid material and a liquid phase. Nonlinear equations characterizing the dynamics of the phase transition boundaries are deduced. Approximate analytical solutions of the model under consideration are constructed. A method for controlling the external temperature at a cooled wall in order to obtain a required solidification velocity is discussed. PMID- 21694199 TI - Pressure dependence of the structure of liquid copper halides. AB - X-ray diffraction of liquid CuI, CuBr and CuCl has been measured up to 19 GPa using synchrotron radiations. Static structure factor S(Q) and pair distribution function g(r) were obtained. For liquid CuI, CuBr and CuCl, S(Q) and g(r) change their shapes continuously with increasing pressure, indicating anisotropic compression of the local structures. The pressure dependence of the peak position ratio r(2)/r(1) of g(r) shows that Cu atoms are located in a tetrahedral site at low pressures and then in an octahedral site at high pressures in these liquid copper halides. At higher pressures, the local structure of liquid CuCl is similar to the intermediate structure between NaCl and CsCl structures. These results are compared with the pressure-induced structural transformation in the crystalline phase. PMID- 21694200 TI - The possibility of transverse excitation modes in liquid Ga. AB - The dynamic structure factor S(Q,omega) of liquid Ga was measured at 100 degrees C using a high resolution inelastic x-ray scattering (IXS) spectrometer at 3-ID C/APS. The spectra obtained clearly demonstrate the existence of longitudinal propagating modes at small Q values, like a previous IXS result at 42 degrees C obtained by Scopigno et al and an inelastic neutron scattering (INS) one at 47 degrees C obtained by Bove et al, but unlike an INS study at 57 degrees C by Bermejo et al. The dispersion relation of the excitations deviates positively from the hydrodynamic prediction by about 13%. There are two new findings from this experiment. Firstly, an additional lower energy excitation is necessary to reproduce S(Q,omega) spectra in the Q range beyond 10 nm(-1), in agreement with the result of a first-principles molecular dynamic simulation, which may indicate a transverse acoustic mode in this peculiar liquid metal. Secondly, the quasielastic line comprises a Gaussian contribution at Q values near the first maximum in S(Q), which may indicate the existence of short-lived covalent correlation in liquid Ga with a lifetime of 0.39 ps. PMID- 21694201 TI - Liquid-liquid phase transitions: analytical approaches. AB - We consider liquid-liquid phase transitions as an indication of the local structure of condensed substances and investigate their statistics and thermodynamics. In this area there are two analytical approaches which describe the transitions: the first is purely phenomenological, while the second deals with intermolecular couplings. In the present work, we discuss the features of the above approaches and their applicability to metallic liquids. PMID- 21694202 TI - Thermodynamic investigations of ternary liquid alloys. AB - A review of different methods for determining thermodynamic quantities is given. The electromotive force (EMF) method with a liquid and solid electrolyte, the calorimetric and differential scanning calorimetry (DSC) methods, and vapour pressure experiments like the isopiestic and Knudsen effusion methods are discussed. PMID- 21694203 TI - Composition design for Laves phase-related body-centered cubic-V solid solution alloys with large hydrogen storage capacities. AB - This paper analyzes the characteristics of alloy compositions with large hydrogen storage capacities in Laves phase-related body-centered cubic (bcc) solid solution alloy systems using the cluster line approach. Since a dense-packed icosahedral cluster A(6)B(7) characterizes the local structure of AB(2) Laves phases, in an A-B-C ternary system, such as Ti-Cr (Mn, Fe)-V, where A-B forms AB(2) Laves phases while A-C and B-C tend to form solid solutions, a cluster line A(6)B(7)-C is constructed by linking A(6)B(7) to C. The alloy compositions with large hydrogen storage capacities are generally located near this line and are approximately expressed with the cluster-plus-glue-atom model. The cluster line alloys (Ti(6)Cr(7))(100-x)V(x) (x = 2.5-70 at.%) exhibit different structures and hence different hydrogen storage capacities with increasing V content. The alloys (Ti(6)Cr(7))(95)V(5) and Ti(30)Cr(40)V(30) with bcc solid solution structure satisfy the cluster-plus-glue-atom model. PMID- 21694204 TI - The Wills-Harrison approach to the thermodynamics of binary liquid transition metal alloys. AB - In the present study, the Wills-Harrison approach in conjunction with the Bretonnet-Silbert local model pseudopotential is applied to the thermodynamics of binary transition-metal liquid alloys. The calculation is performed in the framework of the variational method of thermodynamic perturbation theory with a hard-sphere reference system. The Vashishta-Singwi exchange-correlation function and the Nozieres-Pines exchange-correlation energy are used. The free energy of mixing for liquid Fe-Co alloy is calculated at different compositions near the melting temperature. The agreement with the experimental data is quite satisfactory. PMID- 21694205 TI - Liquid carbon density and resistivity. AB - As was shown in Gathers et al (1974 Report UCRL-51644 (Lawrence Livermore Laboratory, September 14)), graphite specimens of low initial densities (heated at gas pressure 2-4 kbar) contract to higher density still in the solid state and then continue further expanding up to the melting line. This effect was included in the analysis of our experimental results on the fast heating of graphite specimens in thick-walled capillary tubes. At low pressures (up to 4 kbar) the liquid carbon density gamma~1.2 g cm(-3). In that case the resistivity of liquid carbon rho~2200 uOmega cm. Liquid carbon under high pressures (P>=50 kbar) has a high density (gamma>=1.8 g cm(-3)), and the resistivity equals ~600-730 uOmega cm. PMID- 21694206 TI - Cavitation in liquid metals under negative pressures. Molecular dynamics modeling and simulation. AB - An approach to study cavitation in stretched liquids via molecular dynamics (MD) simulation is presented. It is based on the stochastic properties of MD and allows one to study cavitation as a stochastic phenomenon. The approach is used to study equation of state and stability limits of the metastable liquid phase, cavitation kinetics and dynamics properties for different temperatures. Particular examples of metals under consideration include Pb, Li and Pb(83)Li(17). Quantitative and qualitative disagreements between the classic nucleation theory estimates and the MD results are found. The Kolmogorov-Johnson Mehl-Avrami equation is used as an alternative way to estimate cavitation rate. The two methods show good mutual agreement. Decay at a constant stretching rate is also considered. PMID- 21694207 TI - First-principles simulation of supercooled liquid alloys. AB - Accurate simulation of multicomponent alloys demands a first-principles approach because empirical potentials become increasingly inaccurate and difficult to develop with each additional constituent element. In contrast, the computational difficulty of simulating an alloy from first principles remains essentially independent of the number of elements. However, equilibration times increase with the number of elements, regardless of the choice of interaction, owing to the need for longer-range diffusion to adequately sample configuration space. The difficulty is exacerbated at low temperatures because of the rapid decline of diffusion constants. Here we discuss the application of replica exchange molecular dynamics to aid equilibration of supercooled alloys, and we also mention the possibility of Hamiltonian exchange molecular dynamics to accelerate equilibration at high temperatures. PMID- 21694208 TI - The structure model of a cubic aperiodic phase ('quasicrystal without forbidden symmetry axes'). AB - A model structure of the aperiodic cubic phase (a cubic quasicrystal) has been constructed as a periodical packing of hierarchical octahedral clusters which were composed of truncated tetrahedra (Friauf-Laves polyhedra) and chains of Frank-Kasper polyhedra with 14 vertices. The construction of the hierarchical model for the cubic aperiodic phase became possible due to the discovery of a new space subdivision with equal edges and with vertices belonging to two orbits of the space group Fm3m. The subdivision is characterized by unique values and unique relations between the coordinates of the starting points of two orbits. Calculated x-ray diffraction patterns for the proposed hierarchical model are in qualitative agreement with published experimental x-ray patterns for aperiodical phases observed in melt-quenched Mg-Al and Fe-Nb-B-Si alloys. PMID- 21694209 TI - Premelting phenomena in ionic crystals. AB - The theory of the premelting phenomena in ionic crystals has been developed on the basis of the concept of heterophase fluctuation in the vicinity of their melting points. The size of the liquid-like clusters is estimated by the theory using the experimental specific heat value. Molecular dynamics simulations are also performed in NaCl and AgBr crystals to examine the ionic configuration in the premelting region. The structural features are discussed using the Lindemann instability criterion. PMID- 21694210 TI - The fractal skeleton of the atomic structure of amorphous metals. AB - The atomic structure of pure amorphous Re and Re-Tb amorphous alloys was studied by the molecular dynamics method. Analysis of the atomic structure of amorphous metals was performed within the framework of percolation theory and fractal geometry. The structure of amorphous metals consists of dense and sparse areas. We established that the dense areas form the fractal skeleton of an amorphous material. The distribution of clusters by size, the probability of an atom belonging to the largest cluster, the fractal dimensionality of the percolation cluster and the concentration dependence of the percolation radius were calculated. Correlation between some physical properties of amorphous metals and their cluster structure was established. PMID- 21694211 TI - Structure of the liquid-vapor interfaces of Ga, In and the eutectic Ga-In alloy an ab initio study. AB - We report the results of ab initio molecular dynamics simulations for the liquid vapor interface of the liquid metals Ga, In and the eutectic binary alloy Ga-In (16.5% In) for which experimental data are available. The study was performed by using samples of 3000 particles in a slab geometry with periodic boundary conditions. In those systems, the total ionic density distributions along the normal to the interface display some layering and in the case of the Ga-In alloy there appears a highly enriched layer of the lower surface tension component located outermost at the interface. The results are compared with the available experimental data. PMID- 21694212 TI - Indentation as a probe for pressure sensitivity of metallic glasses. AB - The question of hydrostatic pressure or normal stress dependence of the flow and fracture behaviour of bulk metallic glasses is addressed. Data from several types of mechanical tests indicate that flow is hardly sensitive to pressures or normal stresses, while fracture is normal stress sensitive and not pressure dependent. Besides, instrumented indentation adequately probes a low pressure dependence of flow, while a normal stress dependence is hardly noticeable. PMID- 21694213 TI - Electronic and atomic disorder in icosahedral AlPdRe. AB - Relations between electronic and atomic disorder of i-AlPdRe have been investigated by studies of neutron irradiated and annealed samples. The advantage with this technique is that a single sample can be monitored over a significant range of varying electronic properties, without concern for any influence of varying impurities. X-ray diffraction, the electrical resistivity and its temperature dependence, and the magnetoresistance are studied. The results show that annealings of an irradiated sample lead to improvement of the atomic order, as reflected in increased intensities of the x-ray diffraction peaks, while electronic properties change in the direction of increasing electronic disorder towards a metal-insulator transition. The observed relation in quasicrystals that improved atomic structure is associated with stronger anomalies in transport properties is thus also seen in i-AlPdRe. In particular, the variation of the diffusion constant in the region of small values of the resistivity is found to be similar for annealed polygrain samples and for single grain samples with varying Pd concentration, as evaluated from literature data, indicating a similar development of electronic disorder in both sets of samples. However, the problem remains as to why the resistivity is small in single grain samples which are atomically well-ordered. The possibility of a strong sensitivity to concentration differences is pointed out. PMID- 21694214 TI - Thermodynamic properties of Al-Mn, Al-Cu, and Al-Fe-Cu melts and their relations to liquid and quasicrystal structure. AB - Thermodynamic properties of molten Al-Mn, Al-Cu and Al-Fe-Cu alloys in a wide temperature range of 1123-1878 K and the whole range of concentrations have been studied using the integral effusion method and Knudsen mass spectrometry. Thermodynamic functions of melts were described by the associated solution model. The possibility of icosahedral quasicrystal (i-QC) precipitation from liquid Al Mn and Al-Cu-Fe alloys was found to be a consequence of the existence in liquid associates (clusters). A geometric model is suggested for the structure of associates in liquid. PMID- 21694215 TI - Colloid-polymer mixtures in the presence of quenched disorder: a theoretical and computer simulation study. AB - We use theory and computer simulation to study the structure and phase behavior of colloid-polymer mixtures in the presence of quenched disorder. The Asakura Oosawa model (AO) (Asakura and Oosawa 1954 J. Chem. Phys. 22 1255) is used to describe the colloid-colloid, colloid-polymer, and polymer-polymer pair interactions. We then investigate the behavior of this model in the presence of frozen-in (quenched) obstacles. The obstacles will be placed according to two different scenarios, both of which are experimentally feasible. In the first scenario, polymers are distributed at positions drawn from an ideal gas configuration. In the second scenario, colloidal particles are distributed at positions drawn from an equilibrium hard sphere configuration. We investigate how the unmixing transition of the AO model is affected by the type of quenched disorder. The theoretical formalism is based on the replica method of Given and Stell (1994 Physica A 209 495). Our foremost aim is to test the accuracy of three common closures to the replica Ornstein-Zernike equations, namely the hypernetted chain, the Percus-Yevick, and the Martinov-Sarkisov equations. The accuracy is determined by comparison with grand canonical Monte Carlo simulations. We find that, for quenched polymer disorder, all three closures perform remarkably well. However, when quenched colloid disorder is considered, i.e. the second mentioned scenario, the predictions of all three closures worsen dramatically. PMID- 21694216 TI - Transport coefficients of soft repulsive particle fluids. AB - Molecular dynamics computer simulation has been used to compute the self diffusion coefficient, D, and shear viscosity, eta(s), of soft-sphere fluids, in which the particles interact through the soft-sphere pair potential, phi(r) = epsilon(sigma/r)(n), where n measures the steepness or stiffness of the potential, epsilon and sigma are a characteristic energy and distance, respectively. The simulations were carried out on monodisperse systems for a range of n values from the hard-sphere ([Formula: see text]) limit down to n = 4 over a range of densities. An ideal glass transition value was estimated from the limit where D and [Formula: see text] for each value of n. Nucleation of the crystalline phase was found to intervene prior to the formation of the glass itself, as has been found previously for hard spheres (i.e. [Formula: see text]). With increasing softness the glass transition moves further within the solid part of the phase diagram, as predicted by Cardenas and Tosi (2005 Phys. Lett. A 336 423), although the volume fractions at the glass transition estimated by the current procedure here are systematically lower than the predictions of that study. PMID- 21694217 TI - Modeling the atomic structure of an amorphous NiZr(3) alloy by anomalous wide angle x-ray scattering and reverse Monte Carlo simulation. AB - The amorphous atomic structure of a melt-spun NiZr(3) alloy was investigated using the anomalous wide angle x-ray scattering (AWAXS) and reverse Monte Carlo (RMC) simulation techniques. The AWAXS data were collected at four incident photon energies, including ones close to the Ni and Zr K-edges, and four total structure factors S(K) were derived. Differential structure factors DAS(K) around the Ni and Zr atoms were calculated through the difference between the scattered intensities on a per-atom scale obtained at incident photon energy pairs (8330, 9455 eV) and (15622, 17993 eV). The contribution of the partial S(Ni-Ni)(K) for the Ni-DAS(K) factor is six times bigger than the one for the S(K) factors. Then, the use of the Ni-DAS(K) factor with four S(K) factors as input data for the RMC simulations has permitted us to obtain more stable partial S(Ni-Ni)(K), S(Ni Zr)(K) and S(Zr-Zr)(K) factors. The partial S(ij)(K) factors are very close to those reported earlier for the amorphous NiZr(2) alloy. The structural data (coordination numbers and interatomic distances) for the first neighbors for both amorphous NiZr(2) and NiZr(3) alloys are also very similar. PMID- 21694218 TI - The critical state in a random 3D Josephson net created by transport current. AB - The set of weak links connecting superconducting grains of ceramics forms a random three-dimensional Josephson net. The temperature and size dependences of the critical currents in bismuth-based and yttrium-based high-temperature superconducting ceramic samples consisting of randomly oriented grains have been studied in zero magnetic field. It is shown that the critical current in samples having various cross-sectional shapes can be presented as the product of temperature and size dependent factors. The transport critical current is a homogeneous function of the cross-sectional shape dimensions. The size dependent factor is a universal function describing properties of the weak link Josephson net. The exponent of this function is independent of the temperature, the type of superconducting material, the existence (or lack) of a Josephson net in the sample, and the method used for varying the sample cross-section. The transport critical current density and induced magnetic field are homogeneous functions of coordinates. It is shown that the critical current density has a power law dependence on the magnetic field. PMID- 21694219 TI - Electronic structure of Ce(n)M(m)In(2m+3n), where n = 1, 2; m = 0, 1;M = Co, Rh or Ir: experiment and calculations. AB - We present a detailed study of the electronic structure of the Ce(n)M(m)In(2m+3n) (M = Co, Rh, Ir; n = 1, 2 and m = 0, 1) series of Ce intermetallic compounds and of the reference LaIn(3) compound. The ground state of these heavy-fermion (HF) materials can be tuned between antiferromagnetic (AF) and superconducting (SC), with pressure or doping as the tuning parameter. Performing the x-ray photoelectron spectroscopy (XPS) measurements on the Ce 3d core levels as well as on the valence band states we analyse the dependence of both the Ce 4f band character and physical properties on the kind of transition metal atom M and on the number of CeIn(3) layers intervened by the MIn(2) layers in the investigated family of compounds. We draw a parallel between the XPS valence band spectra and ab initio band structure calculations based on the full-potential linearized augmented plane-wave (FP-LAPW) method. We analyse changes in valence band states within the whole family of materials. We compare the experimental magnetic moments on Ce atoms with the theoretical ones calculated within different approximations for exchange-correlation potential. Finally, we have shown that the Ce 4f electrons participate in bonding formation for all investigated compounds. Our study indicates that the observed changes in the 4f band on-site hybridization energy result from the reconstruction of the charge density distribution driven by transition metal atoms inserted into the CeIn(3) structure. PMID- 21694220 TI - The phase transition, and elastic and thermodynamic properties of CaS derived from first-principles calculations. AB - First-principles calculations of the crystal structures, phase transition, and elastic properties of B1-B2 phase calcium sulfide (CaS) have been carried out with the plane-wave pseudopotential density functional theory method. The calculated values (for crystal structures and the phase transition) are in very good agreement with experimental data as well as with some of the existing model calculations. The dependence of the elastic constants c(ij), the aggregate elastic modulus, the deviation from the Cauchy relation, and the elastic anisotropy on pressure have been investigated. The normalized elastic constants c(ij)' have been introduced to investigate the elasticity of CaS in detail. Moreover, the variation of the Poisson ratio, Debye temperature, and longitudinal and transverse elastic wave velocity with pressure P up to 70 GPa at 0 K have been investigated for the first time. PMID- 21694221 TI - Structure and thermal properties of yttrium alumino-phosphate glasses. AB - The structure and thermal properties of yttrium alumino-phosphate glasses, of nominal composition (Y(2)O(3))(0.31-z)(Al(2)O(3))(z)(P(2)O(5))(0.69) with [Formula: see text], were studied by using a combination of neutron diffraction, (27)Al and (31)P magic angle spinning nuclear magnetic resonance, differential scanning calorimetry and thermal gravimetric analysis methods. The Vickers hardness of the glasses was also measured. The data are compared to those obtained for pseudo-binary Al(2)O(3)-P(2)O(5) glasses and the structure of all these materials is rationalized in terms of a generic model for vitreous phosphate materials in which Y(3+) and Al(3+) act as modifying cations that bind only to the terminal (non-bridging) oxygen atoms of PO(4) tetrahedra. The results are used to help elucidate the phenomenon of rare-earth clustering in phosphate glasses which can be reduced by substituting Al(3+) ions for rare-earth R(3+) ions at fixed modifier content. PMID- 21694222 TI - Structural study on Ni nanowires in an anodic alumina membrane by using in situ heating extended x-ray absorption fine structure and x-ray diffraction techniques. AB - Polycrystalline Ni nanowires have been prepared by electrochemical deposition in an anodic alumina membrane template with a nanopore size of about 60 nm. In situ heating extended x-ray absorption fine structure and x-ray diffraction techniques are used to probe the atomic structures. The nanowires are identified as being mixtures of nanocrystallites and amorphous phase. The nanocrystallites have the same thermal expansion coefficient, of 1.7 * 10(-5) K(-1), as Ni bulk; however, the amorphous phase has a much larger thermal expansion coefficient of 3.5 * 10( 5) K(-1). Details of the Ni nanowire structures are discussed in this paper. PMID- 21694223 TI - Spin polarization of tunneling current in barriers with spin-orbit coupling. AB - We present a general method for evaluating the maximum transmitted spin polarization and optimal spin axis for an arbitrary spin-orbit coupling (SOC) barrier system, in which the spins lie in the azimuthal plane and finite spin polarization is achieved by wavevector filtering of electrons. Besides momentum filtering, another prerequisite for finite spin polarization is asymmetric occupation or transmission probabilities of the eigenstates of the SOC Hamiltonian. This is achieved most efficiently by resonant tunneling through multiple SOC barriers. We apply our analysis to common SOC mechanisms in semiconductors: pure bulk Dresselhaus SOC, heterostructures with mixed Dresselhaus and Rashba SOC and strain-induced SOC. In particular, we find that the interplay between Dresselhaus and Rashba SOC effects can yield several advantageous features for spin filter and spin injector functions, such as increased robustness to wavevector spread of electrons. PMID- 21694224 TI - Characteristics of the collective dielectric relaxation mode of the incommensurate SmC(alpha)(*) phase. AB - Employing the dielectric relaxation spectroscopy technique, we have observed two different characteristics of the collective relaxation mode of an incommensurate SmC(alpha)(*) phase. Recent theoretical advances predict two different natures for the dielectric relaxation mode in the SmC(alpha)(*) phase. Our experimental results confirm two different behaviours of the relaxation mode in different temperature ranges for this phase for one unique compound having an exceptionally wide temperature range (~9 degrees C) for the SmC(alpha)(*) phase. PMID- 21694225 TI - The signature of subsurface Kondo impurities in the local tunnel current. AB - The conductance of a tunnel point contact in a scanning tunneling microscope-like geometry having a single defect placed below the surface is investigated theoretically. The effect of multiple electron scattering by the defect after reflections by the metal surface is taken into account. In the approximation of s wave scattering the dependence of the conductance on the applied voltage and the position of the defect is obtained. The results are illustrated for a model s wave phase shift describing Kondo resonance scattering. We demonstrate that multiple electron scattering by the magnetic impurity plays a decisive role in the point contact conductance at voltages near the Kondo resonance. We find that the sign and shape of the Kondo anomaly depends on the position of the defect. PMID- 21694226 TI - Density functional calculation of transition metal adatom adsorption on graphene. AB - The functionalization of graphene (a single graphite layer) by the addition of transition metal atoms of Mn, Fe and Co to its surface has been investigated computationally using density functional theory. In the calculation, the graphene surface supercell was constructed from a single layer of graphite (0001) surface separated by vertical vacuum layers 2 nm thick. We found that the center of the hexagonal ring formed by carbon from graphene is the most stable site for Mn, Fe, Co to stay after optimization. The calculated spin-polarized band structures of the graphene encapsulating the Mn adatom indicate that the conduction bands are modified and move down due to the coupling between the Mn atom and graphene. For Fe adsorbed on the graphene surface, it is semi-half-metallic, and the spin polarization P is found to be 100%. The system of Co adatom on graphene exhibits metallic electronic structure due to the density of states (DOS) peak at the band center with both majority and minority spins. Local density of states analyses indicate a larger promotion of 4s electrons into the 3d state in Fe and Co, resulting in lower local moments compared to an Mn adatom on the graphite surface. PMID- 21694227 TI - Thermal expansion and magnetostriction of pure and doped RAgSb(2) (R = Y, Sm, La) single crystals. AB - Data on temperature-dependent, anisotropic thermal expansion in pure and doped RAgSb(2) (R = Y, Sm, La) single crystals are presented. Using the Ehrenfest relation and heat capacity measurements, uniaxial pressure derivatives for long range magnetic ordering and charge density wave transition temperatures are evaluated and compared with the results of the direct measurements under hydrostatic pressure. In-plane and c-axis pressure have opposite effects on the phase transitions in these materials, with in-plane effects being significantly weaker. Quantum oscillations in magnetostriction were observed for the three pure compounds, with the possible detection of new frequencies in SmAgSb(2) and LaAgSb(2). The uniaxial (along the c-axis) pressure derivatives of the dominant extreme orbits (beta) were evaluated for YAgSb(2) and LaAgSb(2). PMID- 21694228 TI - An ultrasonic study on complex charge ordering phenomena for La(1-x)Sr(x)FeO(3). AB - The complex charge ordering phenomena for polycrystalline La(1-x)Sr(x)FeO(3) (1/3<=x<=2/3) have been studied by measuring the low temperature magnetization, resistivity and the longitudinal ultrasonic velocity (V(l)). At low doping levels (1/3<=x<=0.5), a dramatic velocity increase is observed below 210 K, and the relative stiffening of V(l) is proportional to the Sr concentration. The analysis suggests that this feature may correspond to the short-range charge ordering state of Fe(3+) and Fe(4+). At high doping levels (0.510(6)) agree well with the dependences found in the framework of a boundary layer approximation. If a nonuniform magnetic field is applied, the theoretically predicted additive action of gravitation and magnetic convection on the heat transfer intensity is confirmed. In the presence of a uniform field, the changes of heat transfer intensity are insignificant despite the action of strong internal field gradients induced by the nonmagnetic cylinders themselves. PMID- 21694258 TI - Transverse gradient diffusion in a polydisperse dilute suspension of magnetic spheres during sedimentation. AB - In this work we investigate the pair interaction of magnetic particles in a dilute polydisperse sedimenting suspension. The suspension is composed of magnetic spherical forms of different radii and densities immersed in a Newtonian fluid, settling due to the gravity. When in close contact, the particles may exert on each other a magnetic force due to a permanent magnetization. We restrict our attention to dispersions of micromagnetic composite with negligible Brownian motion. The calculations of the relative particle trajectories are based on direct computations of the hydrodynamic interactions among rigid spheres in the regime of low particle Reynolds number. Depending on the relative importance of the interparticle forces and gravity, the collisions may result in aggregation or simply in a breaking of the particle relative trajectory time reversibility. After summing over all possible encounters, the transverse self-diffusion and down-gradient diffusion coefficients that describe the cross-flow migration of the particles are calculated. Our calculation shows first evidence and the significance of the diffusion process arising from magnetic interactions in dilute non-Brownian suspensions. PMID- 21694259 TI - Drift of ferrocolloids through a cylindrical grid by magnetic force. AB - The subject of the paper is to investigate the coupling phenomena of magnetic and non-uniform temperature fields in ferrofluids. The coupling creates a special kind of mass transfer and an inhomogeneous concentration of ferrofluid arises especially near bodies, where higher field gradients are present. Particular attention is paid to the oriented mass transfer, i.e. the magnitude and direction of ferrofluid flux with respect to the temperature gradient and magnetic field. Quantitatively, oriented phoretic transport can be characterized by the magnetic Soret coefficient and osmotic pressure difference. The problem is solved using two-dimensional (2D) numerical simulations for the periodic structure of the bodies. Special attention is paid to the magnetic bulk force as the driving force. PMID- 21694260 TI - Specific heating power of fatty acid and phospholipid stabilized magnetic fluids in an alternating magnetic field. AB - Magnetic fluids (MFs) with a similar narrow size distribution of the iron oxide core were stabilized with lauric acid (MF 1), oleate (MF 2) or, after dialysis in the presence of liposomes, with phospholipid molecules (MF 3 and MF 4, respectively). The hydrodynamic sizes of the MF 1 and MF 3 were half those found for MF 2 and MF 4. The MFs were exposed to inductive heating in an alternating magnetic field at a frequency of 200 kHz and a maximum magnetic field strength of 3.8 kA m(-1). Specific absorption rates (SAR) of 294 +/- 42 (MF 1), 214 +/- 16 (MF 2), 297 +/- 13 (MF 3) and 213 +/- 6 W g(-1) Fe (MF 4) were obtained. The data for MF 2 and MF 4 were identical to those found for the commercially available ferucarbotran. The biomedical relevance of the phospholipid-coated MFs is briefly discussed. PMID- 21694261 TI - Oscillatory squeeze flow of suspensions of magnetic polymerized chains. AB - We report a rheological study of suspensions of non-Brownian chain-like magnetic particles in the presence of magnetic fields. These particles have been synthesized using spherical iron particles by linking them with a polymer and are called polymerized chains. We have shown that, in oscillatory squeeze mode, the suspensions of such chain-like particles develop yield stress several times higher than that of conventional magnetorheological fluids based on spherical iron particles. This is explained in terms of solid friction between polymerized chains, which form entangled aggregates in the presence of a magnetic field. For the suspension of spherical particles, the squeezing force increases with the magnetic field intensity at low magnetic fields, but decreases dramatically at higher fields because of cavitation or air entrainment. Such a decrease in transmitted force does not take place in suspensions of polymerized chains, at least for fields smaller than 30 kA m(-1), which could make these suspensions preferable for application in squeeze-film dampers. PMID- 21694262 TI - Magnetically induced hyperthermia: size-dependent heating power of gamma Fe(2)O(3) nanoparticles. AB - By combining magnetic properties with nanosized biocompatible materials, superparamagnetic nanoparticles may serve as colloidal heating mediators for cancer therapy. This unique potential has attracted attention for designing new magnetic nanoparticles with high efficiency heating properties. Their heating power under high frequency magnetic field is governed by the mechanisms of magnetic energy dissipation for single-domain particles due both to internal Neel fluctuations of the particle magnetic moment and to the external Brownian fluctuations. These mechanisms are highly sensitive to the crystal size, the particle material, and the solvent properties. Here we explore the heating properties of maghemite particles with large particle sizes, in the range 15-50 nm, synthesized through a new procedure which includes a hydrothermal process. Particle shape and size distribution, hydrodynamic volume, and magnetic anisotropy are characterized, respectively, by transmission electron microscopy, dynamic magnetically induced birefringence, and ferromagnetic resonance. Together with our previous data on low diameter particles (Fortin J P et al 2007 J. Am. Chem. Soc 129 2628-35), this study provides the whole size dependence of heating efficiency in the range 5-50 nm and assesses the balance between Neel and Brownian contributions to thermal losses. In agreement with theoretical predictions, the heating efficiency shows a maximum for an optimal size of about 15 nm. PMID- 21694263 TI - Numerical investigation of thermomagnetic convection in a heated cylinder under the magnetic field of a solenoid. AB - The main objective of this paper is the numerical investigation of the process of thermomagnetic convection of a special temperature sensitive ferrofluid. The fluid is studied in a cylindrical domain, with constant temperatures on the top and bottom ends and adiabatic boundary conditions on the sidewalls. The thermomagnetic convection is generated by a non-uniform constant magnetic field of a solenoid, which is placed in a hollow area inside the domain. It has been found that the efficiency of convective heat transfer in such a set-up can be increased up to sevenfold by magnetic field within the studied range of parameters. PMID- 21694264 TI - Parametric modulation of thermomagnetic convection in magnetic fluids. AB - Previous theoretical investigations on thermal flow in a horizontal fluid layer have shown that the critical temperature difference, where heat transfer changes from diffusion to convective flow, depends on the frequency of a time-modulated driving force. The driving force of thermal convection is the buoyancy force resulting from the interaction of gravity and the density gradient provided by a temperature difference in the vertical direction of a horizontal fluid layer. An experimental investigation of such phenomena fails because of technical problems arising if buoyancy is to be changed by altering the temperature difference or gravitational acceleration. The possibility of influencing convective flow in a horizontal magnetic fluid layer by magnetic forces might provide us with a means to solve the problem of a time-modulated magnetic driving force. An experimental setup to investigate the dependence of the critical temperature difference on the frequency of the driving force has been designed and implemented. First results show that the time modulation of the driving force has significant influence on the strength of the convective flow. In particular a pronounced minimum in the strength of convection has been found for a particular frequency. PMID- 21694265 TI - Piezoresistivity of magnetorheological elastomers. AB - Magnetorheological elastomers are smart materials made by aligning magnetic microparticles inside a liquid polymer before the curing process has started. Once cured, the composite presents new properties such as a large change of elasticity when applying a magnetic field. We analyze here another specific property of these materials which is the piezoresistivity. Two cases are studied: one where the particles inside the matrix are not in contact and the other where they are in contact. We show that in the first case we observe an exponential dependence of the resistivity versus pressure and in the second case a power law dependence. These behaviors are explained with the help of a conductivity model based on the dependence of the tunnel effect on the area of contact. PMID- 21694266 TI - Rheological investigations of ferrofluids with a shear stress controlled rheometer. AB - The appearance of field- and shear-dependent changes of viscosity-the magnetoviscous effect-is correlated to the formation of chains and structures of magnetic nanoparticles. Moreover, the formation of these structures leads to the appearance of viscoelastic effects or other non-Newtonian features in ferrofluids in the presence of a magnetic field. In order to describe these phenomena, different theoretical approaches have been developed which explain the mechanism of these effects with different assumptions. One point in which these models differ, and which has to be clarified, is the appearance of yield stress and its dependence on magnetic field strength. With this aim, a stress controlled rheometer has been designed to prove the existence of this very small field dependent yield stress for ferrofluids. The results presented here show a dependence of the yield stress on the magnetic field strength as well as on the interparticle interaction and particle size distribution. Finally, yield stress experiments have been performed for different geometries of the shear cell in order to get more information about the microstructure formed by the magnetic particles. PMID- 21694267 TI - Rheological properties of magnetic suspensions. AB - We present results of a theoretical study of the magnetorheological viscosity eta of a suspension versus the applied magnetic field H and shear rate [Formula: see text]. It is supposed that the macroscopic rheological effects are provided by linear chain-like aggregates. Unlike in traditional models, the natural statistical distribution of the chains over the number of particles in them is taken into account. The results obtained explain important features of the rheological eta versus [Formula: see text] law, which has been detected in experiments but qualitatively contradicts known theories of rheological properties of magnetic suspensions. PMID- 21694268 TI - Capillary viscosimetry on ferrofluids. AB - Experiments performed for different ferrofluids under shear flow have shown that an increase of the magnetic field strength applied to the sample yields an increase of the fluid's viscosity, the so called magnetoviscous effect. It has been shown that the magnitude of the effect is strongly related to the modification of the microstructure of ferrofluids and can be influenced by varying both the dipole-dipole interaction between the particles and the concentration of large particles within the fluid. This result has been further used to synthesize new ferrofluids which, on one hand, are more compatible for technical applications but, on the other hand, led to difficulties for the experimenters in measuring the viscous behavior in the presence of a magnetic field. To overcome this problem, a specially designed ferrofluid-compatible capillary viscometer has been developed. Within this paper, the experimental setup as well as experimental results concerning the investigation of the magnetoviscous effect in both diluted and concentrated cobalt-based ferrofluids are presented. PMID- 21694269 TI - Hysteresis and multiple stable configurations in a magnetic fluid system. AB - A magnetic liquid in a horizontal Hele-Shaw cell is subjected to a vertical magnetic field. The width of the magnetic fluid finger is measured as a function of applied field and compared to a theoretical model. The theoretical model uses an energy minimization procedure and predicts a double energy minimum, hysteresis, and discontinuous transitions between a circle and a finger. The experimental data set agrees very well with the theory for a well-defined magnetic fluid finger. Near the transitions, the experiments show hysteresis and support for a double energy minimum; however, the agreement is not quite so good. The discrepancy between theory and experiment near the transition region is likely due to the simplified finger model used in the theory. PMID- 21694270 TI - Flow regime classification in air-magnetic fluid two-phase flow. AB - A new experimental/numerical technique of classification of flow regimes (flow patterns) in air-magnetic fluid two-phase flow is proposed in the present paper. The proposed technique utilizes the electromagnetic induction to obtain time series signals of the electromotive force, allowing us to make a non-contact measurement. Firstly, an experiment is carried out to obtain the time-series signals in a vertical upward air-magnetic fluid two-phase flow. The signals obtained are first treated using two kinds of wavelet transforms. The data sets treated are then used as input vectors for an artificial neural network (ANN) with supervised training. In the present study, flow regimes are classified into bubbly, slug, churn and annular flows, which are generally the main flow regimes. To validate the flow regimes, a visualization experiment is also performed with a glycerin solution that has roughly the same physical properties, i.e., kinetic viscosity and surface tension, as a magnetic fluid used in the present study. The flow regimes from the visualization are used as targets in an ANN and also used in the estimation of the accuracy of the present method. As a result, ANNs using radial basis functions are shown to be the most appropriate for the present classification of flow regimes, leading to small classification errors. PMID- 21694271 TI - A magnetic fluid microdevice using insect wings. AB - A magnetic fluid microdevice using Diptera insect wings is proposed and constructed. The magnetic fluid device is composed of insect wings, a small permanent magnet, coil, and kerosene-based magnetic fluid. First, the structural properties of insect wings are studied through measurements of certain morphological parameters. Secondly, the novel type of microwind energy converter is constructed. Thirdly, the power generation characteristics of the magnetic fluid microdevice using insect wings are examined. It is found that the output power is roughly proportional to the cube of the airflow velocity. PMID- 21694272 TI - Modeling bubbles and droplets in magnetic fluids. AB - We develop, test and apply a volume of fluid (VOF) type code for the direct numerical simulation of two-fluid configurations of magnetic fluids with dynamic interfaces. Equilibrium magnetization and linear magnetic material are assumed and uniform imposed magnetic fields are considered, although extensions to nonlinear materials and to fields with spatio-temporal variability are possible. Models are computed for configurations of bubbles of non-magnetic fluid rising in ferrofluid and droplets of ferrofluid falling through non-magnetic fluid. Bubbles and droplets exhibit similar changes of shape in the presence of vertical fields, due to a combination of elongation along the field lines and the fluid dynamics of ordinary rising or falling at small Bond number. Bubbles become more prolate than droplets under the same parameters and are accordingly found to break up more readily than droplets in stronger fields. Indirect effects are observed, such as the change in rise time and the consequent changes in the flow due to increased Reynolds number. PMID- 21694273 TI - Multiple-length-scale patterning of magnetic nanoparticles by stamp assisted deposition. AB - Control of the size and spatial distribution of materials at multiple length scales is one of the most compelling issues in nanotechnology research. We report a multiple-length-scale patterning of pure magnetic particles as well as biocompatible magnetic particles based on a printing technique named micro injection molding in capillaries. The magnetic particles were prepared by a technique of co-precipitation of ferric and ferrous salts in an alkali medium. We demonstrate that the morphology and the size of the patterning nanoparticles can be controlled by simply controlling the concentration of the solution. Our method exploits the self-organization of the nanoparticles in a solution confined between a stamp and the surfaces of a substrate, exploiting confinement and competing interactions between the adsorbate and the substrate. Our approach represents a remarkable example of an integrated top-down/bottom-up process. PMID- 21694274 TI - Application of a magnetic fluid seal to rotary blood pumps. AB - A magnetic fluid seal enables mechanical contact-free rotation of a shaft without frictional heat and material wear and hence has excellent durability. However, the durability of a magnetic fluid seal decreases in liquid. The life of a seal applied to a rotary blood pump is not known. We have developed a magnetic fluid seal that has a shield mechanism minimizing the influence of the rotary pump on the magnetic fluid. The developed magnetic fluid seal worked for over 286 days in a continuous flow condition, for 24 days (on-going) in a pulsatile flow condition and for 24 h (electively terminated) in blood flow. The magnetic fluid seal is promising as a shaft seal for rotary blood pumps. PMID- 21694275 TI - Optimal design of a tuned liquid damper using a magnetic fluid with one electromagnet. AB - Characteristics of a tuned magnetic fluid damper are examined. The optimal depth of a magnetic fluid in a cylindrical container is calculated using a linear analysis of a magnetic fluid sloshing. In order to avoid swirling in lower depth fluids, several experiments using greater fluid depths are carried out and a good damping range is obtained. PMID- 21694276 TI - Study of audio speakers containing ferrofluid. AB - This work validates a method for increasing the radial restoring force on the voice coil in audio speakers containing ferrofluid. In addition, a study is made of factors influencing splash loss of the ferrofluid due to shock. Ferrohydrodynamic analysis is employed throughout to model behavior, and predictions are compared to experimental data. PMID- 21694277 TI - Research on a haptic sensor made using MCF conductive rubber. AB - To provide a new composite material having a high electrical sensitivity in the fields of robotics and sensing, a magnetic rubber having network-like magnetic clusters was developed by utilizing a magnetic compound fluid (MCF). MCF rubber with small deformations can provide an effective sensor. In this paper, we report many experiments in which changes of the MCF rubber's resistance were observed when the rubber was compressed and a deformation was generated; we then made a trial haptic sensor using the MCF conductive rubber and performed many experiments to observe changes of the electrical resistance of the sensor. The results of experiments showed that the proposed sensor made with MCF conductive rubber is useful for sensing small amounts of pressure or small deformations. PMID- 21694278 TI - Linear patterning of magnetically labeled Dictyostelium cells to display confined development. AB - In severe nutriment conditions, the social amoeba Dictyostelium discoideum enters a particular life cycle where it forms multicellular patterns to achieve aggregation. Extensively observed from an initial dispersed state, its developmental program can usefully be studied from a confined population to implement theoretical developments regarding biological self-organization. The challenge is then to form a cell assembly of well-defined geometrical dimensions without hindering cell behavior. To achieve this goal, we imposed transient constraints by applying temporary external magnetic gradients to trap magnetically labeled cells. Deposits of various numbers of cells were geometrically characterized for different magnetic exposure conditions. We demonstrated that the cell deposit was organized as a three-dimensional (3D) structure by both stacking layers of cells and extending these layers in the substrate plane. This structure evolves during the aggregation phase, forming periodic aggregative centers along the linear initial pattern. PMID- 21694279 TI - Encapsulation of anticancer drug and magnetic particles in biodegradable polymer nanospheres. AB - In this study, we have prepared PLGA (poly-D,L-lactide-co-glycolide) nanospheres loaded with biocompatible magnetic fluid and anticancer drug taxol by a modified nanoprecipitation technique and investigated their magnetic properties. A magnetic fluid, MF-PEG, with a biocompatible layer of polyethylene glycol (PEG), was chosen as a magnetic carrier. The PLGA, whose copolymer ratio of D,L-lactide to glycolide is 85:15, was utilized as a capsulation material. Taxol, as an important anticancer drug, was chosen for its significant role against a wide range of tumours. The morphology and particle size distributions of the prepared nanospheres were investigated by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and showed a spherical shape of prepared nanospheres with size 250 nm. Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermogravimetry (TGA) analysis confirmed incorporation of magnetic particles and taxol into the PLGA polymer. The results showed good encapsulation with magnetite content 21.5 wt% and taxol 0.5 wt%. Magnetic properties of magnetic fluids and taxol within the PLGA polymer matrix were investigated by SQUID magnetometry from 4.2 to 300 K. The SQUID measurements showed superparamagnetism of prepared nanospheres with a blocking temperature of 160 K and saturation magnetization 1.4 mT. PMID- 21694280 TI - Microcomputed tomography analysis of ferrofluids used for cancer treatment. AB - In order to reduce the side effects generated by the most common cancer treatment therapies, chemo- and radiotherapy, two new approaches are being investigated. These new approaches are magnetic drug targeting (MDT) and magnetic hyperthermia, and are based on the use of magnetic nanoparticles. In the first one, these magnetic nanoparticles are used as drug carriers and the success of the treatment depends on the correct distribution of the drug within the tumour tissue. Computed tomography analysis has been performed on tumour tissue after MDT in order to find out the distribution of the nanoparticles. The measurements have been carried out in two different laboratories, one based on a synchrotron beamline and another one with a cone x-ray source. First results show that the drug carriers form clusters within the tumour tissue. PMID- 21694281 TI - Isolation of genomic DNA using magnetic nanoparticles as a solid-phase support. AB - In recent years, techniques employing magnetizable solid-phase supports (MSPS) have found application in numerous biological fields. This magnetic separation procedure offers several advantages in terms of subjecting the analyte to very little mechanical stress compared to other methods. Secondly, these methods are non-laborious, cheap, and often highly scalable. The current paper details a genomic DNA isolation method optimized in our laboratory using magnetic nanoparticles as a solid-phase support. The quality and yields of the isolated DNA from all the samples using magnetic nanoparticles were higher or equivalent to the traditional DNA extraction procedures. Additionally, the magnetic method takes less than 15 min to extract polymerase chain reaction (PCR) ready genomic DNA as against several hours taken by traditional phenol-chloroform extraction protocols. Moreover, the isolated DNA was found to be compatible in PCR amplification and restriction endonuclease digestion. The developed procedure is quick, inexpensive, robust, and it does not require the use of organic solvents or sophisticated instruments, which makes it more amenable to automation and miniaturization. PMID- 21694283 TI - Local structure of liquid Ge(1)Sb(2)Te(4) for rewritable data storage use. AB - Phase-change materials based on chalcogenide alloys have been widely used for optical data storage and are promising materials for nonvolatile electrical memory use. However, the mechanism behind the utilization is unclear as yet. Since the rewritable data storage involved an extremely fast laser melt-quenched process for chalcogenide alloys, the liquid structure of which is one key to investigating the mechanism of the fast reversible phase transition and hence rewritable data storage, here by means of ab initio molecular dynamics we have studied the local structure of liquid Ge(1)Sb(2)Te(4). The results show that the liquid structure gives a picture of most Sb atoms being octahedrally coordinated, and the coexistence of tetrahedral and fivefold coordination at octahedral sites for Ge atoms, while Te atoms are essentially fourfold and threefold coordinated at octahedral sites, as characterized by partial pair correlation functions and bond angle distributions. The local structure of liquid Ge(1)Sb(2)Te(4) generally resembles that of the crystalline form, except for the much lower coordination number. It may be this unique liquid structure that results in the fast and reversible phase transition between crystalline and amorphous states. PMID- 21694282 TI - Chemically induced transition phenomena in polyurethanes as seen from generalized mode Gruneisen parameters. AB - Many phenomenological properties of reactive polymers like polyurethanes increase or decrease continuously in the course of the curing process before saturating at the end of the chemical reaction. This holds true for instance for the mass density, the refractive index, the chemical turnover and the hypersonic properties. The reason for this monotone behaviour is that the chemical reaction behaves like a continuous succession of irreversible phase transitions. These transitions are superposed by the sol-gel transition and possibly by the chemically induced glass transition, with the drawback that the latter two highlighted transitions are often hidden by the underlying curing process. In this work we propose generalized mode Gruneisen parameters as an alternative probe for elucidating the polymerization process itself and the closely related transition phenomena. As a model system we use polyurethane composed of a diisocyanate and varying ratios of difunctional and trifunctional alcohols. PMID- 21694284 TI - Phase separation, crystallization and polyamorphism in the Y(2)O(3)-Al(2)O(3) system. AB - A detailed study of glass formation from aerodynamically levitated liquids in the (Y(2)O(3))(x)(Al(2)O(3))(1-x) system for the composition range 0.21<=x<=0.41 was undertaken by using pyrometric, optical imaging and x-ray diffraction methods. Homogeneous and clear single-phase glasses were produced over the composition range [Formula: see text]. For Y(2)O(3)-rich compositions ([Formula: see text]), cloudy materials were produced which contain inclusions of crystalline yttrium aluminium garnet (YAG) of diameter up to 40 um in a glassy matrix. For Y(2)O(3) poor compositions around x = 0.24, cloudy materials were also produced, but it was not possible to deduce whether this resulted from (i) sub-micron inclusions of a nano-crystalline or glassy material in a glassy matrix or (ii) a glass formed by spinodal decomposition. For x = 0.21, however, the sample cloudiness results from crystallization into at least two phases comprising yttrium aluminium perovskite and alumina. The associated pyrometric cooling curve shows slow recalescence events with a continuous and slow evolution of excess heat which contrasts with the sharp recalescence events observed for the crystallization of YAG at compositions near x = 0.375. The materials that are the most likely candidates for demonstrating homogeneous nucleation of a second liquid phase occur around x = 0.25, which corresponds to the limit for formation of a continuous random network of corner-shared AlO(4) tetrahedra. PMID- 21694285 TI - Glass-liquid-glass reentrance in mono-component colloidal dispersions. AB - The self-consistent generalized Langevin equation (SCGLE) theory of colloid dynamics is employed to describe the ergodic-non-ergodic transition in model mono disperse colloidal dispersions whose particles interact through hard-sphere plus short-ranged attractive forces. The ergodic-non-ergodic phase diagram in the temperature-concentration state space is determined for the hard-sphere plus attractive Yukawa model within the mean spherical approximation for the static structure factor by solving a remarkably simple equation for the localization length of the colloidal particles. Finite real values of this property signals non-ergodicity and determines the non-ergodic parameters f(k) and f(s)(k). The resulting phase diagram for this system, which involves the existence of reentrant (repulsive and attractive) glass states, is compared with the corresponding prediction of mode coupling theory. Although both theories coincide in the general features of this phase diagram, there are also clear qualitative differences. One of the most relevant is the SCGLE prediction that the ergodic attractive glass transition does not preempt the gas-liquid phase transition, but always intersects the corresponding spinodal curve on its high-concentration side. We also calculate the ergodic-non-ergodic phase diagram for the sticky hard sphere model to illustrate the dependence of the predicted SCGLE dynamic phase diagram on the choice of one important constituent element of the SCGLE theory. PMID- 21694286 TI - Revisiting the total ion yield x-ray absorption spectra of liquid water microjets. AB - Measurements of the total ion yield (TIY) x-ray absorption spectrum (XAS) of liquid water by Wilson et al (2002 J. Phys.: Condens. Matter 14 L221 and 2001 J. Phys. Chem. B 105 3346) have been revisited in light of new experimental and theoretical efforts by our group. Previously, the TIY spectrum was interpreted as a distinct measure of the electronic structure of the liquid water surface. However, our new results indicate that the previously obtained spectrum may have suffered from as yet unidentified experimental artifacts. Although computational results indicate that the liquid water surface should exhibit a TIY-XAS that is fundamentally distinguishable from the bulk liquid XAS, the new experimental results suggest that the observable TIY-XAS is actually nearly identical in appearance to the total electron yield (TEY-)XAS, which is a bulk probe. This surprising similarity between the observed TIY-XAS and TEY-XAS likely results from large contributions from x-ray induced electron stimulated desorption of ions, and does not necessarily indicate that the electronic structure of the bulk liquid and liquid surface are identical. PMID- 21694287 TI - Temperature dependent next-neighbour dynamics of liquid lead. AB - The temperature dependence of the density correlation function at next-neighbour distances has been investigated for the liquid metal lead. This correlation function is a sensitive parameter for changes in the local environment and its Fourier transform was measured in a coherent inelastic neutron scattering experiment. The zero-frequency amplitude related to the long time decay of density fluctuations decreases in a nonlinear way and indicates a change in dynamics above the melting point. The derived generalized longitudinal viscosity shows a decrease near this temperature range. From these observations we suppose that solidification sets in on a microscopic level distinct above the melting point. PMID- 21694288 TI - Structural characterization of water and ice in mesoporous SBA-15 silicas: II. The 'almost-filled' case for 86 A pore diameter. AB - Neutron diffraction measurements for D(2)O in SBA-15 silica of pore diameter 86 A have been made in a temperature range from 300 to 100 K. The pore-filling factor for the liquid phase is 0.95, resulting in an 'almost-filled' sample. The nucleation and transformation of the ice phase were determined for cooling and warming cycles at two different rates. The primary nucleation event at 258 K leads to a defective form of ice-I with predominantly cubic ice features. For temperatures below the main nucleation event, the data indicate the formation of an interfacial layer of disordered water/ice that varies with temperature and is reversible. The main diffraction peak for the water phase shows similar features to those observed in earlier studies, indicating enhanced hydrogen bonding and network correlations for the confined phase as the temperature is decreased. A detailed profile analysis of the triplet peak is presented in the accompanying paper (Seyed-Yazdi et al 2008 J. Phys.: Condens. Matter 20 205108). PMID- 21694289 TI - Structural characterization of water/ice formation in SBA-15 silicas: III. The triplet profile for 86 A pore diameter. AB - The diffraction results for the formation of ice in 86 A diameter pores of a SBA 15 silica sample are analysed to provide information on the characteristics of the ice created in the pores. The asymmetric triplet at ~1.7 A(-1), which involves several overlapping peaks, is particularly relevant to the different ice phases and contains a number of components that can be individually identified. The use of a set of three peaks with an asymmetric profile to represent the possibility of facetted growth in the pores was found to give an unsatisfactory fit to the data. The alternative method involving the introduction of additional peaks with a normal symmetric profile was found to give excellent fits with five components and was the preferred analytic procedure. Three peaks could be directly linked to the positions for the triplet of hexagonal ice, I(h), and one of the other two broad peaks could be associated with a form of amorphous ice. The variation of the peak intensity (and position) was systematic with temperature for both cooling and heating runs. The results indicate that a disordered state of ice is formed as a component with the defective crystalline ices. The position of a broad diffraction peak is intermediate between that of high-density and low-density amorphous ice. The remaining component peak is less broad but does not relate directly to any of the known ice phases and cannot be assigned to any specific structural feature at the present time. PMID- 21694290 TI - Re-entrant-like relaxor behaviour in the new 0.99BaTiO(3)-0.01AgNbO(3) solid solution. AB - A new solid solution of 0.99BaTiO(3)-0.01AgNbO(3) was prepared by a solid state reaction. Its structural, dielectric and ferroelectric properties were investigated. Besides the three phase transitions associated with pure BaTiO(3), the dielectric permittivity shows an additional peak around 100 degrees C. This peak exhibits a dielectric relaxation satisfying the Vogel-Fulcher law, indicating typical relaxor behaviour. The relaxor state occurs after the paraelectric to ferroelectric phase transition upon cooling, i.e., inside the ferroelectric phase, indicating a re-entrant-like phenomenon. This unusual phase transition sequence has never been reported in canonical lead-based ferroelectrics. Moreover, the relaxor state arises from a tetragonal phase rather than from a cubic phase as observed in conventional complex perovskite relaxors. PMID- 21694291 TI - Quantum paraelectricity coexisting with a ferroelectric metastable state in single crystals of NaNbO(3): a new quantum effect. AB - We experimentally show that, in contrast to the data having been collected so far, some single crystals of NaNbO(3) exhibit a dielectric permittivity of several thousand, at low T, and this value is saturated when approaching 0 K on cooling. Other sodium niobate crystals (having larger dielectric losses) present a first-order phase transition to a ferroelectric phase on cooling (at 80-200 K). The width of the thermal hysteresis in these crystals increases when the temperature of the phase transition obtained on heating decreases. The dielectric permittivity at the phase transition obtained on cooling shows a tendency to increase and saturate, when the thermal hysteresis increases. We identify the ground state of the sodium niobate crystal exhibiting the smallest dielectric losses (in the studied set of crystals) as a novel quantum paraelectric state coexisting with a metastable ferroelectric state. In principle, the crystal presenting the state of quantum paraelectricity can be considered as having the largest (among the crystals studied) thermal hysteresis, for which the low boundary is below 0 K. PMID- 21694292 TI - Ferromagnetic insulating and spin glass behavior in Cr substituted La(0.85)Ag(0.15)MnO(3) compounds. AB - Single phase samples of polycrystalline La(0.85)Ag(0.15)Mn(1-y)Cr(y)O(3) (y = 0, 0.05, 0.10, 0.15, 0.20) were prepared by the solid-state route. These samples were studied by recording x-ray diffraction patterns to investigate their crystal structure, by measuring temperature and frequency variations of ac susceptibility and high temperature magnetization to investigate their magnetic properties and by measuring magneto-resistivity. X-ray diffraction patterns could be refined by using the [Formula: see text] space group. The lattice parameters and Mn-O bond lengths were found to decrease with Cr doping. Paramagnetic to ferromagnetic transitions followed by low temperature spin glass like behavior have been observed from ac susceptibility results. The above transitions could be understood on the basis of double exchange ferromagnetic interaction in Mn(3+) O(2-)-Mn(4+), super-exchange ferromagnetic interaction in Cr(3+)-O(2-)-Mn(3+) and super-exchange antiferromagnetic interaction in Mn(4+)-O(2-)-Mn(4+) networks. Even though a strong ferromagnetic signal was observed in all the Cr doped samples, no metal-insulator transition has been observed. Thus Cr doping gives rise to a ferromagnetic insulating state and the Cr might take part in super exchange ferromagnetic interactions. Colossal magneto-resistivity has been observed up to 20% of Cr doping in a wide temperature range down to low temperatures. PMID- 21694293 TI - Cross-sectional transmission electron microscopic study of irradiation induced nano-crystallization of nickel in a W/Ni multilayer. AB - The present study reports the cross-sectional transmission electron microscopic investigations of swift heavy ion-irradiation induced nano-size recrystallization of Ni in a nearly immiscible W/Ni multilayer structure. Multilayer structures (MLS) of [W(25 A)/Ni(25 A)](10BL) were grown on Si-(100) substrate by the ion beam sputtering technique. The as-synthesized MLS were subjected to 120 MeV Au(9+) ion-irradiation to a fluence of ~5 * 10(13) ions cm(-2). Wide-angle x-ray diffraction studies of pristine as well as irradiated W/Ni multilayers show deterioration of the superlattice structure, whereas x-ray reflectivity (XRR) measurement reveals a nearly unaffected microstructure after irradiation. Analysis of the XRR data using 'Parratt's formalism' does show a significant increase of W/Ni interface roughness. Cross-sectional transmission electron microscopy (TEM) studies carried out in diffraction and imaging modes (including bright-field and dark-field imaging), show that at high irradiation dose the intralayer microstructure of Ni becomes nano-crystalline (1-2 nm). During these irradiation induced changes of the intralayer microstructure, the interlayer definition of the W and Ni layers still remains intact. The observed nano recrystallization of Ni has been attributed to competition between low miscibility of the W/Ni interface and the ion-beam induced mixing kinetics. PMID- 21694294 TI - Charge transfer and coherence dynamics of a tunnelling system coupled to an harmonic oscillator. AB - We study the transition probability and coherence of a two-site system, interacting with an oscillator. Both properties depend on the initial preparation. The oscillator is prepared in a thermal state and, even though it cannot be considered as an extended bath, it produces decoherence because of the large number of states involved in the dynamics. In the case in which the oscillator is initially displaced, a coherent dynamics of charge entangled with oscillator modes takes place. Coherency is, however, degraded as far as the oscillator mass increases, producing an increasingly large recoherence time. Calculations are carried on by exact diagonalization and compared with two semiclassical approximations. The role of the quantum effects are highlighted in the long time dynamics, where semiclassical approaches give rise to a dissipative behaviour. Moreover, we find that the oscillator dynamics has to be taken into account, even in a semiclassical approximation, in order to reproduce a thermally activated enhancement of the transition probability. PMID- 21694295 TI - Magnetostructural phase transitions in Ni(50)Mn(25+x)Sb(25-x) Heusler alloys. AB - The structural and magnetic properties of Ni(50)Mn(25+x)Sb(25-x) (0<=x<=18) Heusler alloys have been investigated by x-ray diffraction, magnetization, thermal expansion, and electrical resistivity measurements. Austenitic phases with the L2(1) cubic crystal cell and martensitic phases with Pmm2 orthorhombic structures have been observed at room temperature in alloys with 0<=x<=12.5 and 13<=x<=14, respectively. The Curie temperatures of the austenitic phases decrease linearly with increasing x and change from 370 (x = 0) to 340 K (x = 12.5). In the concentration 7=13.5 the temperature exceeds the Curie temperature of the austenitic phase (340 K). The alloys in their martensitic phases exhibit complex magnetic behavior. The phase diagram with respect to temperature and composition of the Ni(50)Mn(25+x)Sb(25-x) system has been determined, where the following magnetic phases have been observed in the martensitic state: antiferromagnetic phase (14=2 kbar. The temperature pressure phase diagram showing the non-monotonic dependence of the superconducting transition temperature T(c) on pressure P is presented. PMID- 21694334 TI - Oxide surfaces. AB - Although the history of metal oxides and their surfaces goes back several decades to landmark studies, such as Mott and Peierls' explanation of electrical insulation in materials that are predicted in band theory to be conducting, or the observation by Morin of the superfast metal-to-insulator transition in vanadium dioxide, it is only in the last two decades that the world of condensed matter physics has become increasingly dominated by research into complex metal oxides. This has been driven most notably by an attempt to better understand and describe the fundamental physical processes behind their seemingly endless spectrum of properties, which in turn has also led to the discovery of novel phenomena, most prominently demonstrated by the discovery of high-temperature superconductivity in 1986, colossal magnetoresistance in 1994, and most recently, the formation of a two-dimensional conducting layer at the interface between two band insulators in 2004. One important reason why metal oxides, particularly in the form of thin films, have become such a popular subject for basic condensed matter research is that they offer a uniquely versatile materials base for the development of novel technologies. They owe this versatility both to the many different elemental combinations that lead to structurally similar forms, and also to the fact that in many cases, the strong interaction between the valence electrons means that there is a subtle interplay between structure and magnetic and electronic properties. This aspect has led in recent years to the birth or renaissance of research fields such as spintronics, orbital ordering, and multiferroics. Surfaces and interfaces are especially interesting in these strongly-correlated electron systems, where the rearrangement of electrical charge resulting from a minimization of surface or interfacial energy can have unexpected and often exciting consequences. Indeed, as the drive to miniaturize devices well below the micron size continues, the fraction of material constituting 'non-bulklike' properties is becoming increasingly significant. On the other hand, the degree of sophistication needed to understand and predict these complex systems has driven a complementary thrust in theoretical modelling, beginning as long ago as 1963, with Hubbard's addition to the tight-binding model of the formulation of conduction in terms of a hopping integral. The present level of understanding is now so advanced that theory and experiment are no longer so distinct, both gaining further insights from one another. The aim of this special issue in the Journal of Physics: Condensed Matter is to convey to the reader the most up-to-date understanding of the physics of the surfaces, interfaces, and thin films of complex metal oxides, in a clear and accessible manner. The order of the 16 contributions reflects the broad range of disciplines within this field, beginning with general considerations and theoretical models, continuing with film growth techniques and characterization, and concluding with material types and devices. It is fairly safe to assume that research in this area will enjoy as illustrious and long-lived a future as it has had a past. As such, it is hoped that this contribution will accurately reflect this status in the first decade of the 21st Century and long provide a reference for physicists continuing on this exciting Odyssey. PMID- 21694335 TI - Perovskites and thin films-crystallography and chemistry. AB - We discuss the crystallographic and chemical basis of the perovskite family (ABX(3)) of oxides that are used in different thin film applications. Starting with the original structure we extend our scope to several modifications. Basic parameters like the ionic radii, the tolerance factor, the occupation of the oxygen sublattice and their effect on the structural parameters will be mentioned together with examples of relationships between structural and physical properties in the bulk and at interfaces. PMID- 21694336 TI - Charge transfer in heterostructures of strongly correlated materials. AB - In this work, recent theoretical investigations by the authors in the area of oxide multilayers are briefly reviewed. The calculations were carried out using model Hamiltonians and a variety of non-perturbative techniques. Moreover, new results are also included here. They correspond to the generation of a metallic state by mixing insulators in a multilayer geometry, using the Hubbard and double exchange models. For the latter, the resulting metallic state is also ferromagnetic. This illustrates how electron or hole doping via transfer of charge in multilayers can lead to the study of phase diagrams of transition metal oxides in the clean limit. Currently, these phase diagrams are much affected by the disordering standard chemical doping procedure, which introduces quenched disorder in the material. PMID- 21694337 TI - Polarity in oxide ultrathin films. AB - Relying on first-principles calculations within density functional theory and on an analytical model for the electronic structure, we present an overview of specific electronic and structural features of polar ultrathin films. MgO(111) unsupported films of finite thickness are chosen as a generic system, in order to extract general concepts associated with polarity at the nanoscale, relate them to the well-known semi-infinite case, and unravel specific scenarios of polarity compensation which are not present for the latter. Size dependent behavior of the compensating charge and formation energy, changes in crystallographic structure, and the possibility of substantial lattice distortions throughout entire films are analyzed and discussed. PMID- 21694338 TI - Molecular beam epitaxial growth of doped oxide semiconductors. AB - Molecular beam epitaxy coupled with the use of activated oxygen is shown to be a powerful tool for the growth of well-defined, structurally excellent oxide semiconductor films. The basics of the methodology are discussed. Several case studies are presented to illustrate some of the physical phenomena that can be investigated; these include Cr- and Co-doped TiO(2) anatase, Ti-doped alpha Fe(2)O(3) hematite, and N-doped TiO(2) rutile. PMID- 21694339 TI - Recent advances in pulsed-laser deposition of complex oxides. AB - Pulsed-laser deposition (PLD) is one of the most promising techniques for the formation of complex-oxide heterostructures, superlattices, and well controlled interfaces. The first part of this paper presents a review of several useful modifications of the process, including methods inspired by combinatorial approaches. We then discuss detailed growth kinetics results, which illustrate that 'true' layer-by-layer (LBL) growth can only be approached, not fully met, even though many characterization techniques reveal interfaces with unexpected sharpness. Time-resolved surface x-ray diffraction measurements show that crystallization and the majority of interlayer mass transport occur on timescales that are comparable to those of the plume/substrate interaction, providing direct experimental evidence that a growth regime exists in which non-thermal processes dominate PLD. This understanding shows how kinetic growth manipulation can bring PLD closer to ideal LBL than any other growth method available today. PMID- 21694340 TI - Reactive sputter deposition of metal oxide nanolaminates. AB - We discuss the reactive sputter deposition of metal oxide nanolaminates on unheated substrates using four archetypical examples: ZrO(2)-Al(2)O(3), HfO(2) Al(2)O(3), ZrO(2)-Y(2)O(3,) and ZrO(2)-TiO(2). The pseudobinary bulk phase diagrams corresponding to these nanolaminates represent three types of interfaces. I. Complete immiscibility (ZrO(2)-Al(2)O(3) and HfO(2)-Al(2)O(3)). II. Complete miscibility (ZrO(2)-Y(2)O(3)). III. Limited miscibility without a common end-member lattice (ZrO(2)-TiO(2)). We found that, although reactive sputter deposition is a far-from-equilibrium process, thermodynamic considerations strongly influence both phase formation within layers and at interfaces. We show that pseudobinary phase diagrams can be used to predict interfacial cation mixing in the nanolaminates. However, size effects must be considered to predict specific structures. In the absence of pseudoepitaxy, size effects play a significant role in determining the nanocrystalline phases that form within a layer (e.g. tetragonal ZrO(2), tetragonal HfO(2), and orthorhombic HfO(2)) and at interfaces (e.g. monoclinic (Zr,Ti)O(2)). These phases are not bulk standard temperature and pressure phases. Their formation is understood in terms of self-assembly into the lowest energy structure in individual critical nuclei. PMID- 21694341 TI - High-T(c) superconducting thin films with composition control on a sub-unit cell level; the effect of the polar nature of the cuprates. AB - Inspired by the work of Ohtomo and Hwang in 2004, we shed new light on thin films of layered cuprate high-T(c) superconductors (HTS). In principle all HTS materials consist of charged perovskite-like layers which in thin films can lead to polar discontinuities at the interfaces of different materials. The resulting charge redistribution has to occur but we expect it to be far more complex than in the LaAlO(3)/SrTiO(3) system since copper can be multivalent. This makes it hard to predict what will happen in terms of transport or even magnetic properties compared to the 'simple' insulator LaAlO(3). Nevertheless, we point out that the picture of systems of charged layers is important and necessary to fully understand heterostructures of these complex materials. PMID- 21694342 TI - In situ x-ray reflectivity studies of dynamics and morphology during heteroepitaxial complex oxide thin film growth. AB - We present a method, based on refraction effects in continuous, stratified media, for quantitative analysis of specular x-ray reflectivity from interfaces with atomic-scale roughness. Roughness at interfaces has previously been incorporated into this framework via Fourier transform of a continuous height distribution, but this approach breaks down when roughness approaches the atomic scale and manifests discrete character. By modeling the overall roughness at interfaces as a convolution of discrete and continuous height distributions, we have extended the applicability of this reflectivity model to atomic-scale roughness. The parameterization of thickness and roughness enables quantitative analysis of time resolved in situ reflectivity studies of thin film growth, modeling step-flow, layer-by-layer and three-dimensional growth within a single framework. We present the application of this model to the analysis of anti-Bragg growth oscillations measured in situ during heteroepitaxial growth of La(0.7)Sr(0.3)MnO(3) on [Formula: see text] SrTiO(3) at different temperatures and pressures, and discuss the evolution of surface morphology. PMID- 21694343 TI - Neutron studies of magnetic oxide thin films. AB - We describe the use of neutron scattering techniques such as reflectivity and diffraction for the study of oxide thin films. We first describe how neutron reflectivity can complement x-ray reflectivity for the study of some oxide materials. We then emphasize magnetic thin films which have become an important field of study in the 1990s, following the discovery of new phenomena in heterostructures: magnetic exchange coupling, exchange bias coupling at antiferro/ferromagnetic interfaces, enhanced magnetism in ultrathin films or tunnel magnetoresistance for example. We show how neutron scattering can provide detailed quantitative information about the magnetization depth profiles of thin films and about the magnetic order in epitaxial films. PMID- 21694344 TI - Characterization of oxide films by MeV ion beam techniques. AB - MeV ion beam techniques can provide highly quantitative compositional analysis of surfaces and thin layers. This quantitativeness is due to the very well known elastic nuclear scattering cross-sections of MeV particles. The most commonly used techniques are Rutherford backscattering spectrometry and elastic recoil detection analysis. Owing to the energy loss of ions in the material, whole compositional depth profiles can be obtained in a single short measurement almost nondestructively. The sensitivity to oxygen can be enhanced by the use of nuclear resonances or forward scattering techniques. State-of-the-art ion beam analysis can determine thin film stoichiometries with an accuracy of 1% and a depth resolution in the low nm range. An overview of the available techniques is given and illustrated with examples. PMID- 21694345 TI - Dielectric binary oxide films as waveguide laser media: a review. AB - Sapphire (alpha-Al(2)O(3)), amorphous and polycrystalline Al(2)O(3), tantalum pentoxide Ta(2)O(5) and the sesquioxides Y(2)O(3), Sc(2)O(3), and Lu(2)O(3) are excellent laser hosts due to their very good thermomechanical properties, broad transparency range and ease of doping with active ions. This article reviews recent research towards the realization of active optical films and the demonstration of gain and laser operation in the waveguides produced from these materials. Compound structures in which laser operation has been demonstrated are highlighted together with the applied fabrication techniques, and details of the laser performance are presented. PMID- 21694346 TI - Conducting interfaces between polar and non-polar insulating perovskites. AB - Two-dimensional electron gases in semiconductors have found use in applications such as optoelectronics, high-power radio-frequency and magnetoelectronic devices. The ability to grow heterostructures of oxides exhibiting similar effects is a significant step towards the fabrication of all-oxide devices. Here, we give an overview of recent studies of two-dimensional electron gases formed at the interface between polar and non-polar perovskites. We discuss the proposed explanations of the origin of the conductivity and properties of the ground state. PMID- 21694347 TI - Ultrathin, ordered oxide films on metal surfaces. AB - Metal oxides and oxide thin films are extensively used as active catalysts and catalytic supports, as well as in many other important technical applications. Unlike TiO(2), which is a semiconductor and can be investigated using a variety of surface science techniques, most metal oxides are insulators, which seriously restricts their use as model surfaces with modern surface science techniques. This difficulty can be circumvented by synthesizing ultrathin oxide films a few nanometers in thickness with well-defined structures, that mimic the corresponding bulk oxides yet are thin enough to be sufficiently conducting. In this review, preparations, structures, electronic and chemical properties of four representative oxides, alumina, magnesium oxide, silica, and titania, are addressed. Of these MgO is found to grow in a layer-by-layer fashion, allowing preparation of crystalline thin film structures with varying thicknesses. Crystalline TiO(2) and Ti(2)O(3) can also be synthesized, whereas SiO(2) and Al(2)O(3), although amenable to synthesis as well-defined monolayer structures, have only been grown to date as amorphous multilayers. PMID- 21694348 TI - Antiferromagnetic LaFeO(3) thin films and their effect on exchange bias. AB - Antiferromagnetic (AFM) orthoferrites are interesting model systems for exploring the correlation between their crystalline and AFM domains and the resulting exchange bias when coupled to a ferromagnetic layer. In particular, LaFeO(3) (LFO) has a Neel temperature, T(N) = 740 K, which is the highest in the orthoferrite family. The recent developments of synchrotron radiation-based photoelectron emission microscopy (PEEM) have provided the possibility of studying AFM domain structures as well as the magnetic coupling between the AFM and the adjacent ferromagnetic (FM) layer, domain by domain. Thin films of LFO have proved excellent candidates for such studies because their AFM domains are well defined and large enough to be readily imaged by PEEM. This paper reviews the growth, structural and magnetic properties of LFO thin films as well as exchange coupling to a FM layer. The strong correlation between structural and AFM domains in this material allows us to investigate the exchange coupling as a function of the domain configuration, which can be changed by using different substrate material and substrate orientation. A significant increase of the exchange bias field by a factor of about 10 was obtained when LFO was diluted with Ni atoms in the volume part. In this sample, the structural domain boundary became corrugated due to substitutional defects. Our results indicate that the details of the precise domain boundary configuration strongly affect the exchange coupling. PMID- 21694349 TI - New phenomena at the interfaces of very thin ferroelectric oxides. AB - We present a brief review of the role of interfacial physics in ferroelectric oxides, with an emphasis on the importance of boundary conditions that determine the properties of very thin ferroelectric films and superlattices. As well as discussing the screening problem, and the role of strain and electrostatics in ferroelectrics, we highlight some of the possibilities in fine period superlattices where the high density of interfaces can lead to new and potentially useful phenomena. PMID- 21694350 TI - Long range spin ferromagnetic order with zero magnetization in (111)Sm(1 x)Gd(x)Al(2) films. AB - Bulk Sm(1-x)Gd(x)Al(2) (0.01 A and 14484 T > C from six confirmed LHON patients were interrogated to validate this biochip format. Further, fourteen Chinese LHON pedigrees and twenty-five unrelated healthy individuals were investigated by the LHON biochip, direct sequencing and pyrosequencing, respectively. The biochip was found to be able efficiently to discriminate homoplasmic and heteroplasmic mtDNA mutations in LHON. Biochip analysis revealed that twelve of eighteen LHON symptomatic cases from the 14 Chinese pedigree harbored the mutations either 11778G > A, 14484T > C or 3460G > A, respectively, accounting for 66.7%. The mutation 11778G > A in these patients was homoplasmic and prevalent (55.5%, 10 of 18 cases). The mutations 3460G > A and 3394T > C were found to co-exist in one LHON case. The mutation 13708G > A appeared in one LHON pedigree. Smaller amount of sampling and reaction volume, easier target preparation, fast and high-throughput were the main advantages of the biochip over direct DNA sequencing and pyrosequencing. Our findings suggested that primary mutations of 11778G > A, 14484T > C or 3460G > A are main variants of mtDNA gene leading to LHON in China. The biochip would easily be implemented in clinical diagnosis. PMID- 21694445 TI - Fibronectin, plasminogen activator inhibitor type 1 (PAI-1) and uterine artery Doppler velocimetry as markers of preeclampsia. AB - OBJECTIVE: The purpose of this study was to examine plasma levels of fibronectin and plasminogen inhibitor type 1 (PAI-1), and alterations in uterine artery (UtA) waveforms throughout normotensive and preeclamptic pregnancies and to analyze its predictive value for the detection of preeclampsia within the second trimester of pregnancy. MATERIAL AND METHODS: Blood samples were collected from 102 healthy, nulliparous women between the 24th and 26th gestational week. Preeclampsia developed in 13 patients; 89 normotensive control subjects were matched from the same cohort. Plasma samples were assayed for fibronectin and PAI-1 by enzyme linked immunosorbent assay. Color pulsed Doppler examinations of UtA were performed after blood sampling. Trends were compared between two groups. RESULTS: Maternal plasma fibronectin and PAI-1 levels and average PI, RI and S/D ratios of patients with preeclampsia were significantly higher (p< 0.05). The best cut-off values for predicting preeclampsia of fibronectin, PAI-1, PI, RI, S/D ratio based on ROC curve analysis were 290 mg/ml, 77.3 ng/ml, 1,0615, 0.605 and 2,59 respectively. The areas under the curve equal to 0.705, 0.753, 0.689, 0.695 and 0.699 for fibronectin, PAI-1 and uterine artery Doppler PI, RI, S/D ratio were determined for the prediction of preeclampsia. CONCLUSIONS: Fibronectin, PAI-1 and UtA Doppler are potentially useful predictors of preeclampsia. Maternal plasma PAI-1 combinated with fibronectin had the highest predictive values in our study. PMID- 21694446 TI - Associations of single nucleotide polymorphisms in the adiponectin gene with adiponectin levels and cardio-metabolic risk factors in patients with cancer. AB - OBJECTIVES: The aims of this study are to (1) study the influence of polymorphisms in adiponectin gene on adiponectin levels and potential associations with breast, prostate and colon cancer; (2) investigate the associations of adiponectin levels with other adipokines and breast, prostate and colon cancers. SUBJECTS: We measured fasting adiponectin, leptin, insulin, Sex steroids in 132 (66 females, 66 males) cancer patients and 68 age and sex matched apparently healthy subjects. Body Mass Index (BMI) and waist circumference were used as indices of obesity. Insulin Resistance was assessed using Homeostasis Model Assessment (HOMA). Three single nucleotide polymorphisms (SNP rs182052 (G 10066-A), SNP rs1501299 (276G > T), SNP rs224176 (45T > G) in adiponectin gene were studied using Real Time Polymerase Chain Reaction. RESULTS: GG genotype of SNP rs1501299 was significantly associated with higher levels of adiponectin (OR=1.2, 95%CI(1.03-1.3), p = 0.02); breast (OR=8.6, 95%CI(1.03-71), p = 0.04), colon cancers (OR= 12, 95%CI(1.2-115), p =0.03). GT genotype was also associated significantly with colon cancer (OR=2.6, 95%CI (1.1-6), p =0.03). However SNP rs224176 was associated with only breast cancer. CONCLUSION: Our results demonstrate that adiponectin gene SNP rs1501299 and SNP rs224176 may be the predisposing factors in some cancers but our results differ from what has been reported in other populations suggesting a complex relationship between genetic variations and phenotypic adiponectin levels. PMID- 21694447 TI - The dynamics of CD147 in Alzheimer's disease development and pathology. AB - CD147, also known as basigin, EMMPRIN, neurothelin, TCSF, M6, HT7, OX47, or gp42, is a transmembrane glycoprotein of the immunoglobulin super-family. It is expressed in many neuronal and non-neuronal tissues including the hippocampus, pre-frontal cortex thyroid, heart, early erythroid, amygdala, and placenta. This protein is involved in various cellular and biological functions, such as lymphocyte migration and maturation, tissue repair cancer progression, T and B lymphocyte activation, and induction of extracellular matrix metalloproteinase. The CD147 protein interacts with other proteins such as cyclophilin A (CyPA), Cyclophilin B (CyPB), sterol carrier protein (SCP), caveolin-1 and integrins, and can influence amyloid-beta (Abeta) peptide levels, a protein that is central to Alzheimer's disease (AD) pathogenesis. Mechanisms by which CD147 regulate Abeta levels remain unclear, thus in this review we discuss its involvement in Abeta production and clearance and potential mechanisms by which controlling CD147 levels could impact on Abeta accumulation and AD pathogenesis. PMID- 21694448 TI - Review and meta-analysis of biomarkers and diagnostic imaging in Alzheimer's disease. AB - Mild Alzheimer's disease (AD) is often difficult to differentiate from mild cognitive impairment (MCI) or non-AD dementias. A multitude of diagnostic biomarkers and advanced imaging strategies have been developed to aid in the diagnosis and management of AD. We sought to review and analyze the published evidence on key test characteristics of major diagnostic strategies to formulate best estimates of sensitivity (SN) and specificity (SP). A systematic review was undertaken to locate and abstract all studies of biomarkers or diagnostic imaging for AD published in English from January 1990 to March 2010 that provided estimates of SN and SP. Meta-analysis was performed using a bivariate mixed effects binary regression model. We calculated -SN, SP, and area under the receiver operating curves (AUROC), with confidence and prediction contours. Of 1,840 unique studies identified, 119 presented primary data sufficient for analysis. SN and SP were calculated against non-demented controls, non-AD dementias with and without MCI, if available. Compared to non-demented controls, FDG-PET demonstrated the highest AUROC (0.96), with 90% SN (95%CI 84% to 94%), and 89% SP (95% CI 81% to 94%). FDG-PET also was most accurate in discriminating AD from demented controls (including MCI) with AUROC 0.91, and 92% SN (95%CI 84% to 96%) and 78% SP (95% CI 69% to 85%). For discrimination of AD from non-AD dementias (excluding MCI), CSF Ptau, and SPECT produced identical AUROC (0.86). Diagnostic strategies for AD show wide variation in test characteristics and some show promise for use in clinical practice. PMID- 21694449 TI - Quantifying the pathophysiological timeline of Alzheimer's disease. AB - Hypothetical models of AD progression typically relate clinical stages of AD to sequential changes in CSF biomarkers, imaging, and cognition. However, quantifying the continuous trajectories proposed by these models over time is difficult because of the difficulty in relating the dynamics of different biomarkers during a clinical trial that is significantly shorter than the duration of the disease. We seek to show that through proper synchronization, it is possible to de-convolve these trends and quantify the periods of time associated with different pathophysiological changes associated with Alzheimer's disease (AD). We developed a model that replicated the observed progression of ADAS-Cog 13 scores and used this as a more precise estimate of disease-duration and thus pathologic stage. We then synchronized cerebrospinal fluid (CSF) and imaging biomarkers according to our new disease timeline. By de-convolving disease progression via ADAS-Cog 13, we were able to confirm the predictions of previous hypothetical models of disease progression as well as establish concrete timelines for different pathobiological events. Specifically, our work supports a sequential pattern of biomarker changes in AD in which reduction in CSF Abeta(42) and brain atrophy precede the increases in CSF tau and phospho-tau. PMID- 21694450 TI - Physical fitness as a protective factor for cognitive impairment in a prospective population-based study in Germany. AB - To evaluate the predictive effects of subjective measures of physical activity (PA) and objective measures of physical fitness (PF) on dementia risk, Participants of the prospective population-based ILSE-study (*1930-1932; 12-year follow-up) were examined at three examination waves (t1 : 1993/94; t2 : 1997/98; t3 : 2005/07). 381 subjects of the original cohort (n = 500) were re-examined at t3. 29% of the subjects who were cognitively healthy at baseline received the diagnosis of mild cognitive impairment (MCI) and 7% of Alzheimer's disease (AD). Subjects were screened for physical and mental health using medical interviews, physical, and neuropsychological examinations. Participants completed a questionnaire on their current and past PA at t1. Subjects were classified as physically active if they reported a regular sport activity for at least 2 hours per week in the past year. Muscular strength (handgrip) and motor coordination (balance) served as objective indicators of PF. Subjects who passed the balance test at t1 had a reduced risk of developing MCI/AD at t3 (OR = 0.35, 95%CI 0.19 0.66, p < 0.01) and performed significantly better on various neuropsychological measures. Muscular strength or subjective reports of PA did not predict MCI/AD development. Our results confirm the hypothesis that PF acts as a protective factor for the development of cognitive disorders. In our study, context, motor coordination served as a better predictor than muscular strength or self-rated PA. Since subjects with cognitive disorders due to cerebral and/or systemic disorders were excluded from the analyses, our findings suggest that the effect of skill-related PF extends beyond the reduction of cardiovascular risk factors. PMID- 21694451 TI - Amyloid-beta-induced mitochondrial dysfunction impairs the autophagic lysosomal pathway in a tubulin dependent pathway. AB - Mitochondrial dysfunction is observed in Alzheimer's disease (AD) brain and peripheral tissues. Amyloid-beta (Abeta) peptides are known to interact with several proteins inside the mitochondria, leading to mitochondrial dysfunction. Recent studies have provided substantial evidence that mitochondria serve as direct targets for Abeta-mediated neuronal toxicity. The observations that Abeta progressively accumulates in cortical mitochondria from AD patients and transgenic AD type mouse models suggest the role of mitochondrial Abeta in the pathogenesis or development of AD. Herein, we studied the downstream signaling pathways induced by Abeta-mediated mitochondrial metabolism alterations and its consequences on cellular fate. We found that Abeta peptides induced an increase in NAD+levels and a decrease in ATP levels, which was related with decreases in acetylated tubulin levels and tau hyperphosphorylation. As a result of microtubule disruption, alterations in macroautophagy, like a decrease in autophagossome degradation and altered cellular distribution of LC3B, were found. Taxol, a microtubule stabilizer drug, was able to restore microtubule network and to prevent cell death induced by Abeta peptides. Our data shows for the first time that mitochondrial and cytosolic Abeta oligomers were significantly reduced upon microtubule dynamics re-establishment. These observations point out that an intervention at a microtubule level may be effective as a disease modifying therapy. PMID- 21694452 TI - Amyloid-beta protein precursor family members: a review from homology to biological function. AB - Alzheimer's disease (AD) is one of the most common forms of neurodegenerative disease. Amyloid-beta peptide (Abeta) is the most crucial molecule related to the pathological development of AD. Amyloid-beta protein precursor (AbetaPP) is one of AbetaPP family members with conserved type I transmembrane. The genetic mutations of AbetaPP and the abnormity of its post-transcription and proteolytic processing contribute to the elevation of Abeta. The accumulation of Abeta in senile plaques is believed to be the most important event in AD pathology. Therefore, as a key upstream molecule of Abeta, AbetaPP is related to the AD pathology, but the biological function of AbetaPP is still not fully clear. AbetaPP-like proteins are widely expressed in multicellular eukaryotes. AbetaPP like homologous genes and proteins are highly conserved in various organisms from invertebrates to mammals. AbetaPP-like genes undergo similarly pathways of transcription and post-transcription processing, and AbetaPP-like proteins is proteolyzed by the similar alpha-cleavage and the beta-cleavage pathways. Based on the homology and the resemble domains, AbetaPP may play similar roles in organisms. In this article, we reviewed homology and structures of AbetaPP family members in organisms and further discussed potential biological function in normal and AD brains. PMID- 21694453 TI - Tauons and prions: infamous cousins? AB - The paradigm of Alzheimer's disease (AD) is one subject to frequent change: what was thought to be a rare form of pre-senile dementia was revealed as a wide spread malady; where amyloid-beta was deemed the sole causative agent for the better part of 20 years, tau protein was shown to play a crucial role in AD genesis. With the discovery of possible prion-like phenomena in this disease supposedly driven by cell-autonomous processes, an evaluation of the similarities and differences between tau-driven neurodegeneration and prion disease becomes necessary. In this article, we provide a comparison of the template agent genesis, filament assembly, as well as intra- and inter-individual spread of prions and tauons. PMID- 21694455 TI - Dementia-associated mortality at thirteen years in the NEDICES Cohort Study. AB - To evaluate the mortality, thirteen years after the baseline wave (1994), of participants suffering dementia in the Neurological Disorders in Central Spain (NEDICES) Cohort Study, we conducted a population-based cohort study in the elderly (65 years and more) with 5,278 screened participants at baseline. Mortality has been evaluated by means of the National Death Registry of Spain at 1-5-2007, 13 years after enrolment. Cox's proportional hazards regression models were used to evaluate the hazard of death according to dementia severity and type, adjusting for potential covariates (gender, age, level of education, and co morbidity). Survival was estimated using Kaplan-Meier method. Of the 5,278 participants screened at baseline, 306 had dementia. Mortality at 13 years was: 275 deaths (89.9%) in dementia subjects; and 2,426 (49.0%) in subjects without dementia. Mortality was higher and statistically significant in dementia subjects. The degree of dementia (DSM-III-R) correlated with the risk of mortality, from mild (HR = 2.23; CI: 1.77-2.82) to moderate (HR =3.10; CI: 2.47 3.89) and severe dementia (HR = 4.98; CI: 3.85-6.44). Survival was similar in Alzheimer's disease and vascular dementia. Factors associated with higher mortality in Cox proportional hazard models were older age, male gender, and comorbidity. Using Population Attributable risk (PAR%), dementia was related to 11.3% of all deaths. Dementia intensity increases the mortality risk at ten years in the NEDICES Study as in other cohort studies. Age, gender, and co-morbidity are associated with higher mortality in dementia patients. Almost one third of deaths in persons over 85 years-old could be attributable to dementia. PMID- 21694454 TI - Short-term hormone therapy with transdermal estradiol improves cognition for postmenopausal women with Alzheimer's disease: results of a randomized controlled trial. AB - We aimed to conduct a placebo-controlled, double-blind, parallel-group design intervention study to evaluate the therapeutic efficacy of hormone therapy (HT) in postmenopausal women with mild to moderate Alzheimer's disease (AD). The trial was designed to evaluate the dose-dependent effects of transdermal 17-beta estradiol, unopposed and opposed with medroxyprogesterone (MPA, Provera(c)), for 12 months in 43 postmenopausal women with AD. Participants were assessed using cognitive measures at baseline, months 1, 3, 6, and 12 of treatment and eight weeks post treatment (month 15). The dropout rate was 49% across 12 months. As a result of the Women's Health Initiative (WHI) and anticipated increased attrition, the protocol was modified to examine data only at time points where attrition was less than 30%. The results of sensitivity analyses indicated robust and reliable data collected in the first three months of the trial. Data collected in the first three months of the trial for forty-three participants were analyzed. HT had favorable cognitive effects across multiple cognitive domains, including visual memory (p-values < 0.030) and semantic memory (p-values < 0.037) in postmenopausal women with AD. Moreover, treatment-related changes in plasma estradiol were positively correlated with improvements in visual memory. Short-term HT that includes the use of estradiol has favorable effects on cognition in women with AD. PMID- 21694456 TI - Using diffusion tensor imaging and mixed-effects models to investigate primary and secondary white matter degeneration in Alzheimer's disease and mild cognitive impairment. AB - White matter (WM) degeneration in Alzheimer's disease (AD) and mild cognitive impairment (MCI) may be a key indicator of early damage in AD. Here, we analyzed WM diffusion tensor data using Tract-Based Spatial Statistics in conjunction with mixed-effects models. Four indices of diffusion were assessed in 61 healthy control, 19 non-amnestic MCIs, 14 amnestic MCIs, and 9 AD patients. The aim of the study was to use advanced mixed-effects models to investigate the retrogenesis hypothesis of AD, which suggests that tracts that are late to myelinate in ontogenetic development are the earliest to be affected in AD. Our results show that a number of late-myelinating pathways, including the parahippocampal region and the inferior longitudinal fasciculus, were predominantly affected by changes in WM volume. Conversely, early-myelinating pathways were found to be affected by a combination of both WM and gray matter (GM) atrophy. A model of the entire WM structure of the brain returned GM models for two indices of diffusion, suggesting that more complex regional landscapes of diffusion lie hidden beneath a global analysis of the entire brain. Our results warn against an explanation of white matter damage that points simply to one of two mechanisms: secondary degeneration or direct damage of myelin. We suggest that tracts may be affected by both mechanisms, with the balance depending on whether tracts are early or late-myelinating. A greater understanding of the pattern of WM changes in AD may prove useful for the early detection of AD. PMID- 21694457 TI - Caspase-12 activation is involved in amyloid-beta protein-induced synaptic toxicity. AB - Synapse loss is considered to be the best correlate of cognitive impairments in Alzheimer's disease (AD), and growing evidence supports the notion that certain events that trigger neuronal death in AD can be initiated by the local activation of caspases within the synaptic compartment. We have demonstrated previously that presynaptic terminals are particularly vulnerable to endoplasmic-reticulum (ER) stress depending of amyloid-beta protein (Abeta). This toxicity included a notable reduction of actin and synaptophysin protein and mitochondrial dysfunction. This synaptic damage was prevented by incubation with a wide range of caspase inhibitor, suggesting the activation of local synaptic apoptotic mechanisms. The ER-resident caspase-12 was initially identified as a mediator of Abeta neurotoxicity. Thus, the current study was conducted to explore the presence and local activation of the caspase-12 in cortical and hippocampal synaptosomes isolated from rat and from the triple transgenic mouse model of AD (3xTg-AD) in the presence of Abeta and ryanodine. Under these conditions, we found mitochondrial failure accompanied by a reduction in actin levels which was dependent on caspase-12 activation suggesting its participation in Abeta-induced synaptic toxicity. PMID- 21694458 TI - Validation of ELISA methods for quantification of total tau and phosporylated tau181 in human cerebrospinal fluid with measurement in specimens from two Alzheimer's disease studies. AB - Tau measurements in cerebrospinal fluid (CSF) are gaining acceptance as aids to diagnosis of Alzheimer's disease (AD) and differentiation from other dementias. Two ELISA assays, the INNOTEST(r) hTAU Ag and the INNOTEST(r) PHOSPHO-TAU(181P) for quantification of t-tau and p-tau181 respectively, have been validated to regulatory standards. Validation parameters were determined by repeated testing of human CSF pools. Specimens from Phase 2 studies of the gamma-secretase inhibitor semagacestat and the therapeutic antibody solanezumab at baseline and following 12-14 weeks of treatment were also tested. Estimated intra-assay CV for repeated testing of 3 CSF pools were <=11.5% and RE varied between -14.1% and +6.4%. Inter-assay CV for t-tau was <5% and RE was within +/-8%. For p-tau181, inter-assay CV was <9% and RE was within +/-2.5%. Total CV (intra-assay plus inter-assay) were below 10% for both analytes. Up to 20-fold dilutional linearity was demonstrated for both analytes. Stability of t-tau and p-tau181 was demonstrated in CSF during five freeze-thaw cycles at <=-20 degrees C and <=-70 degrees C and at 18-22 degrees C for up to 24 h. Neither semagacestat nor solanezumab interfered with either assay. Inter-individual t-tau and p-tau181 concentrations were highly variable but intra-individual variations were small. These assays are suitable for analysis of CSF t-tau and p-tau181 in a single laboratory supporting multi-center AD clinical trials. No effect of treatment with semagacestat or solanezumab was observed in response to three months of drug administration. PMID- 21694459 TI - Amyloid-beta aggregation on model lipid membranes: an atomic force microscopy study. AB - Amyloid fibril formation is generally associated with many neurodegenerative disorders, including Alzheimer's disease (AD). Although fibril plaque formation is associated with biological membranes in vivo, the role of the cell surfaces in amyloid fibril formation and the molecular mechanism of amyloid toxicity are not well understood. Understanding the details of amyloid interaction with lipid membrane may shed light on the mechanism of amyloid toxicity. Using atomic force microscopy, we investigated aggregation of amyloid-beta1-42 (Abeta1-42) on model phospholipid membranes as a function of time and membrane composition. Neutral, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dioleoyl-sn-glycero-3 phosphocholine (DOPC), anionic - 1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac glycerol) (sodium salt) (DOPG), and cationic - 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), were used to study the effect of lipid type on amyloid binding. We showed that both the charge on the lipid head group and lipid phase affect the interaction of amyloid oligomers with the membrane surface changing the rate of adsorption and causing changes in membrane structure and structure of amyloid deposits. We observed that amyloid aggregates progressively accumulate in a similar manner on the surface of neutral DPPC gel phase membrane and on the surface of fluid phase negatively charged DOPG membrane. In contrast to DPPC and DOPG, positively charged fluid DOTAP membrane and neutral fluid phase DOPC membrane contain amyloid deposits with reduced height, which suggests fusing of Abeta1-42 into the lipid membrane surface. PMID- 21694460 TI - Detection of amyloid-beta protein precursor homo-interactions using beta galactosidase enzyme fragment complementation. AB - Amyloidogenic processing of the amyloid-beta protein precursor (AbetaPP) produces amyloid-beta peptides (Abeta), the major constituent of amyloid plaques in the brains of Alzheimer's disease (AD) patients. Experimental evidence suggests that increased dimerization of AbetaPP increases Abeta while decreased dimerization of AbetaPP decreases Abeta production. If true, developing tools for detecting AbetaPP-AbetaPP interactions to understand AbetaPP processing leading to Abeta production would be important. Here, we developed the method of beta galactosidase (beta-gal) enzyme fragment complementation as a means to detect AbetaPP-AbetaPP interactions. Inactive beta-gal fragments are independently tagged to the C-terminal ends of monomeric AbetaPPs, and will come together to form a functional enzyme upon AbetaPP-AbetaPP interactions. Successful detection of beta-gal activity has been used to qualitatively visualize and quantify the amount of AbetaPP dimers or higher oligomers. This method can be used to enhance our understanding of the biological processes dependent upon AbetaPP-AbetaPP interactions. PMID- 21694461 TI - A randomized controlled trial of high-dose vitamin D2 followed by intranasal insulin in Alzheimer's disease. AB - Poor vitamin D nutrition is linked with dementia, but vitamin D has not been tested in a randomized controlled trial (RCT) in Alzheimer's disease (AD). Nasal insulin acutely improves cognition and vitamin D upregulates insulin receptor expression and enhances insulin action. In an RCT we examined the effect of high dose vitamin D followed by nasal insulin on memory and disability in mild moderate AD. 63 community-dwelling individuals aged > 60 were recruited; 32 with mild-moderate disease (Folstein Mini-Mental State Examination [MMSE] score 12-24) met entry criteria and were randomized. All took low-dose vitamin D (1000 IU/day) throughout. After run-in (8 weeks), they were randomized to additional high-dose D/placebo for 8 weeks, followed immediately by randomization to nasal insulin (60 IU qid)/placebo for 48 h. Primary outcome measures were Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) and Disability Assessment in Dementia (after high-dose D) and ADAS-cog and Wechsler Memory Scale-Revised Logical memory (WMS-R LM) for immediate and delayed recall (after nasal insulin). Baseline median (interquartile range, IR) age, MMSE, and ADAS-cog were 77.5 (69 80), 19.5 (17-22), and 25.5 (20-31), respectively. Median 25OHD increased from 49 to 60 nM (p < 0.01) after run-in and was 187 nM after high-dose vitamin D and 72 nM after placebo (p < 0.001). Neither cognition nor disability changed significantly after high-dose D. ADAS-cog improved by a median (IR) of 9 (1-11) with nasal insulin after placebo high-dose vitamin D (p = 0.02), but may represent regression to the mean as WLS-R LM did not change. We conclude that high-dose vitamin D provides no benefit for cognition or disability over low-dose vitamin D in mild-moderate AD. PMID- 21694462 TI - Green tea epigallocatechin-3-gallate (EGCG) and other flavonoids reduce Alzheimer's amyloid-induced mitochondrial dysfunction. AB - Amyloid-beta (Abeta)-induced mitochondrial dysfunction may play a role in the onset and progression of Alzheimer's disease (AD). Therefore, therapeutics targeted to improve mitochondrial function could be beneficial. Plant-derived flavonoids have shown promise in improving certain AD phenotypes, but the overall mechanism of action(s) through which flavonoids protect from AD is still unknown. To identify flavonoids and other natural products that may correct amyloid induced mitochondrial dysfunction, 25 natural products were screened for their ability to restore altered mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, or ATP levels in neuroblastoma cells expressing mutant amyloid-beta protein precursor (AbetaPP). Epigallocatechin-3-gallate (EGCG) and luteolin were identified as the top two mitochondrial restorative compounds from the in vitro screen. EGCG was further tested in vivo to determine its effects on brain mitochondrial function in an AbetaPP/PS-1 (presenilin 1) double mutant transgenic mouse model of AD. EGCG treatment restored mitochondrial respiratory rates, MMP, ROS production, and ATP levels by 50 to 85% in mitochondria isolated from the hippocampus, cortex, and striatum. The results of this study lend further credence to the notion that EGCG and other flavonoids, such as luteolin, are 'multipotent therapeutic agents' that not only reduce toxic levels of brain Abeta, but also hold the potential to protect neuronal mitochondrial function in AD. PMID- 21694463 TI - Investigation of matrix metalloproteinases, MMP-2 and MMP-9, in plasma reveals a decrease of MMP-2 in Alzheimer's disease. AB - Pathological changes in the Alzheimer's disease (AD) brain include amyoid-beta (Abeta) plaques, and neurofibrillary tangles, as well as neuronal death and synaptic loss. Matrix metalloproteinases MMP-2 and MMP-9 are known to degrade Abeta, and their expressions are increased in the AD brain, in particular in the astrocytes surrounding amyloid plaque. To investigate a possible association between plasma metalloproteinases and AD, we quantified MMP-2 and MMP-9 activities in the plasma of healthy controls (HC, n = 56), cases with mild cognitive impairment (MCI, n = 45), and AD (n = 50). All cases had previously been imaged with Pittsburgh compound B (PiB) and had a Mini-Mental Status Examination (MMSE) assessment. MMP-2 and MMP-9 activity was determined using gelatine-zymography. There was a significant 1.5-fold decrease in MMP-2 activity in the AD group compared to HC (p < 0.001) and a 1.4-fold decrease compared to MCI (p < 0.01). There was no difference in MMP-9 levels between the three groups. A positive correlation was identified between MMP-2 plasma activity and MMSE score (r = 0.16, p < 0.05), but there was no association with PiB. This is the first report of a change in MMP-2 activity in AD plasma and these findings may provide some insight into AD pathogenesis. PMID- 21694464 TI - Diagnostic and prognostic tissuemarkers in clear cell and papillary renal cell carcinoma. AB - PURPOSE: Approximately one-third of all Renal Cell Carcinoma (RCC) patients undergoing a nephrectomy face metastatic disease. The availability of novel therapeutics for metastatic patients underscores the importance of identifying patients at risk of recurrence or patients responding well to specific therapies. Unlike clear cell RCC (ccRCC), information on biomarkers for the papillary subtype (pRCC) remains limited. In this review, we identified tissue markers that are differentially expressed between subtypes and may be of diagnostic use. In addition, markers with promising prognostic power for ccRCC and/or pRCC are described and their clinical value is discussed. MATERIALS AND METHODS: To identify diagnostic markers that differentiate between pRCC and ccRCC a Pubmed search was performed, limited to original articles published in the English language between 1990 and 2009, using the terms pRCC/papillary RCC/papillary renal cell carcinoma/papillary kidney cancer, biomarker/biomarkers, protein expression, mass spectrometry and immunohistochemistry. Prognostic markers for ccRCC and pRCC were identified using the search terms kidney cancer, renal cell carcinoma, prognostic marker, biomarker and prognosis. Only markers with independent prognostic value in multivariable analysis were included. RESULTS: 25 proteins are differentially expressed between ccRCC and pRCC, reflecting the molecularly distinct nature of these subtypes. 5 of these proteins were externally validated, which shows their diagnostic potential. Whereas 48 biomarkers with independent prognostic power have been identified for ccRCC patients, only CD44, CA9, p53, Ki67 and PCNA have shown prognostic value in multiple studies. Expression of IMP-3 and VEGF-R2 are independent predictors of survival of pRCC patients, although this is shown in single studies. CONCLUSIONS: So far 5 validated diagnostic markers are able to differentiate between ccRCC and pRCC. Few independent prognostic markers have been identified for pRCC in single studies, compared to numerous biomarkers identified for the more common ccRCC. Despite the abundance of promising markers for ccRCC, their exact role in clinical decision making still needs to be established through validation studies. PMID- 21694465 TI - Analysis of GP73 in patients with HCC as a function of anti-cancer treatment. AB - In this study, we examined the level of Golgi protein 73 (GP73) in the serum of 9 patients as a function of anti-liver cancer treatment. Although the numbers are small, a clear trend was observed. Patients who remained tumor free (up to 6 years post-treatment) showed reductions in GP73 at the first time point available post-treatment. In contrast, patients who had high levels GP73 post treatment all had re-occurrence within a 5 year period. These data are preliminary but dramatically imply that this marker may have value in the monitoring of HCC patients and may be elevated even when small, undetectable tumors are present. PMID- 21694466 TI - Expression of MMP-1 in histopathological different grades of oral squamous cell carcinoma and in normal buccal mucosa - an immunohistochemical study. AB - INTRODUCTION: Oral Cancer (OC) is the sixth most common cancer worldwide, while being the most common cancer among Indian males and the third most common cause of their deaths. 70-94% of all the malignancies arising within the oral cavity are oral squamous cell carcinomas (OSCC). Researches show that altered expression of matrix metalloproteinases (MMPs) may have a vital role in regulating the tumor microenvironment of head and neck carcinomas. AIM: To evaluate the expression of MMP-1 in histopathologically different grades of OSCC, to evaluate its expression in normal buccal mucosa (NBM), and to compare the expressions between these two groups, using the streptavidin horseradish peroxidase biotin labeled immuno histochemistry (IHC) technique. RESULT: 100% of OSCC showed cytoplasmic immune reactivity for MMP-1 in the epithelial and connective tissue cells. Their expression was elevated as the histopathological grade differed from well to poorly differentiated. 100% of epithelial cells and 80% of connective tissue of NBM expressed MMP-1.The immune reactivity was significantly over-expressed in OSCC in comparison to NBM. CONCLUSION: Evidence indicates that the elevated MMP-1 protein expression is associated with higher histopathological grade of OSCC. NBM express MMP-1 diffusely and weakly. MMP-1 immune reactivity increases as OC progresses from NBM to well to poorly differentiated OSCC. PMID- 21694467 TI - Glucocorticoid-induced TNFR family-related receptor (GITR)-expression in tumor infiltrating leucocytes (TILs) is associated with the pathogenesis of esophageal adenocarcinomas with and without Barrett's mucosa. AB - BACKGROUND: Esophageal adenocarcinomas (EACs) arise due to gastroesophageal reflux, with Barrett's esophagus (BE) regarded as precancerous lesion. Glucocorticoid-induced TNFR family-related Receptor (GITR)-mediated inflammation of tumor infiltrating leucocytes (TILs) in the tumor microenvironment might play a role during the multistep carcinogenetic process as either tumor promoting factor according to an inflammatory microenvironment or as a feature of anti tumor activity. METHODS: Immunohistochemical analysis of GITR expression was analyzed in esophageal cancer (n=70: 41 EAC with BE, 19 EAC without BE, and n=10 esophageal squamous-cell carcinomas, ESCC), the adenocarcinoma cell line OE-33, and peripheral blood leucocytes (PBLs) of EAC patients, furthermore in biopsies of BE without intraepithelial neoplasia (IN) (n=18). Results were correlated with clinicopathological parameters and five-year survival rates. Immunohistochemical GITR expression results were confirmed on mRNA level (RT-PCR). RESULTS: Quantification showed a significant increase of 25% GITR positive TILs in EAC with BE (p< 0.05) compared to 13% in adjacent BE, 24% in EAC without BE, 14% in ESCC, and 1% in BE without IN. High GITR levels were not significantly associated with clinicopathologic features which may predict worse clinical outcome and had no impact on survival (p= 0.7878). Increased GITR expression of peripheral blood leucocytes (PBLs) in EAC patients was shown on protein level (32%) and confirmed by RT-PCR (3.7-fold difference compared to normal tissue). CONCLUSIONS: This study provides for the first time evidence that GITR expression of TILs is associated in the pathogenesis of Barrett's esophagus. Our findings suggest that GITR-expression of TILs is associated with cancer progression. Its role as either tumor promoting factor %according to an in the inflammatory microenvironment or as a feature of anti-tumor activity and promising target for molecular therapies needs to be substantiated in further investigations. PMID- 21694468 TI - Plasma tyrosine kinase activity as a potential biomarker in BCR-ABL1-targeted therapy. AB - In targeted therapy using tyrosine kinase inhibitors (TKIs), measurement of TK activities could be beneficial for diagnosis, identification of potential responders, and monitoring treatment efficacy. Here we evaluated the utility of measuring circulating TK (cTK) activity directly from plasma in leukemia patients positive for the BCR-ABL1. Plasma cTK activity was measured from 46 patients with newly diagnosed chronic myelogenous leukemia (CML), 24 with multidrug-resistant CML, 24 with BCR-ABL1-positive acute lymphocytic leukemia (ALL), and 38 healthy donors. Circulating TK activity was significantly higher in CML (median 801.93 U/mL, range 18.10-3932.30 U/mL) and BCR-ABL1-positive ALL patients (median 659.55 U/mL, range 0-1626.90 U/mL) than in healthy donors (median 82.85 U/mL, range 0.63 852.80 U/mL) (P < 0.001). Plasma cTK activity was closely correlated with cellular BCR-ABL1 kinase activation as indicated by phosphorylation of the downstream signaling proteins CRKL (P < 0.001) and STAT-5 (P= 0.003). However, cTK activity was not associated with BCR-ABL1 transcript level and was independent of BCR-ABL1 mutation type. Ex vivo inhibition of imatinib and dasatinib on plasma cTK activity was severely diminished in patients harboring T315I mutation. Ex vivo testing measuring the effect of TKIs on plasma cTK activity thus hold promise as drug sensitivity tests for predicting and monitoring response to specific TKIs. PMID- 21694469 TI - Correlation of D dimer and factor VIII levels with histopathology in patients with breast carcinoma. AB - INTRODUCTION: There is evidence that the components of the coagulation/fibrinolytic system play a role in cancer biology and angiogenesis. Studies reveal that at the time of diagnosis, majority of the cancer patients have laboratory evidence of systemic coagulation activation. Our purpose was to investigate the significance of D-Dimer (product of fibrin degradation) and factor VIII levels in breast cancer and to evaluate its relationship with other variables such as histological characteristics, lymph node status and immunohistochemistry markers (ER, PR and Her-2neu). MATERIALS AND METHODS: A prospective study was conducted in the Department of Surgery in collaboration with Departments of Medicine, Pathology and Radiodiagnosis & Imaging, Maulana Azad Medical College & Lok Nayak Hospital, New Delhi. Fifty patients with diagnosed cancer breast who were treated in surgery department were evaluated for D Dimer and factor VIII levels. D-dimer and Factor VIII levels were measured three times i.e. at the time of commencement of treatment then after three cycles of Chemotherapy (CAF Regimen) and finally after six weeks of surgery. RESULTS: Significantly higher levels of D Dimer and factor VIII were observed in tumors with significant lymphovascular and adipose tissue invasion in comparison to localized tumors. The reduction in D-dimer and Factor VIII values after Surgery was significant for both D-dimer (p value 0.000) and Factor VIII (p value 0.000). The reduction in D-dimer after 3 cycles of chemotherapy was significant for D dimer (575.51 +/- 572.47 ng/ml vs. 422.45 +/- 363.58 ng/ml; p value 0.046) but not significant for Factor VIII (307.83 +/- 184.47 ng/ml vs. 288.78 +/- 163.02 ng/ml; p value 0.151). CONCLUSION: D-dimer and factor VIII may be used as yardstick for systemic adjuvant therapy in node negative < 1 cm breast cancer. D dimer may prove to be a safe, convenient and easily available biomarker which can be combined with conventional sentinel node biopsy in clinically node negative breast cancer to assess metastatic disease in axilla and reduce false negative results. PMID- 21694470 TI - The development of Laue techniques for single-pulse diffraction of chemical complexes: time-resolved Laue diffraction on a binuclear rhodium metal-organic complex. AB - A modified Laue method is shown to produce excited-state structures at atomic resolution of a quality competitive with those from monochromatic experiments. The much faster data collection allows the use of only one or a few X-ray pulses per data frame, which minimizes crystal damage caused by laser exposure of the samples and optimizes the attainable time resolution. The method has been applied to crystals of the alpha-modification of Rh(2)(MU-PNP)(2)(PNP)(2) (BPh(4))(2) [PNP = CH(3)N(P(OCH(3))(2))(2), Ph = phenyl]. The experimental results show a shortening of the Rh-Rh distance in the organometallic complex of 0.136 (8) A on excitation and are quantitatively supported by quantum-mechanical (QM)/molecular mechanics (MM) theoretical calculations which take into account the confining effect of the crystal environment, but not by theoretical results on the isolated complex, demonstrating the defining effect of the crystal matrix. PMID- 21694471 TI - Kinematic diffraction on a structure with periodically varying scattering function. AB - A theory is developed to describe the kinematic diffraction response of a crystal when it is subjected to a periodically varying external perturbation. It is shown that if a part of the local electron density varies linearly with an external stimulus, the diffracted signal is not only a function of the stimulation frequency Omega, but also of its double 2Omega. These frequency components can provide, under certain conditions, selective access to partial diffraction contributions that are normally summed up in the interference pattern. A phasing process applied to partial diffraction terms would allow recovery of the substructure actively responding to the stimulus. Two ways of frequency filtering are discussed (demodulation and correlation) with respect to extracting information from such an experiment. Also considered is the effect of the variation of different structural parameters on the diffraction intensity that have to be accounted for while planning modulation-enhanced experiments. Finally, the advantages and limitations of the proposed concept are discussed, together with possible experiments. PMID- 21694472 TI - Using molecular-dynamics simulations to understand and improve the treatment of anharmonic vibrations. I. Study of positional parameters. AB - Molecular-dynamics-derived numerical probability density functions (PDFs) have been used to illustrate the effect of different models for thermal motion on the parameters refined in a crystal structure determination. Specifically, anharmonic curved or asymmetric PDFs have been modelled using the traditional harmonic approximation and the anharmonic Gram-Charlier series treatment. The results show that in cases of extreme anharmonicity the mean and covariance matrix of the harmonic treatment can deviate significantly from physically meaningful values. The use of a Gram-Charlier anharmonic PDF gives means and covariance matrices closer to the true (numerically determined) anharmonic values. The physical significance of the maxima of the anharmonic distributions (the most probable or mode positions) is also discussed. As the data sets used for the modelling process are theoretical in origin, these most probable positions can be compared to equilibrium positions that represent the system at the bottom of its potential energy surface. The two types of position differ significantly in some cases but the most probable position is still worthy of report in crystal structure determinations. PMID- 21694473 TI - Using molecular-dynamics simulations to understand and improve the treatment of anharmonic vibrations. II. Developing and assessing new Debye-Waller factors. AB - Two new anharmonic forms for the Debye-Waller factor, aimed at modelling curvilinear and asymmetric motion, have been introduced. These forms permit the refinement of structures with these types of anharmonic motion using a small number of additional parameters. Molecular-dynamics-derived numerical probability density functions (PDFs) have been used to assess the merit of these new functions in real space. The comparison is favourable particularly for the curvilinear PDF based on a parabolic coordinate system change of a trivariate Gaussian distribution. The initial results also suggest that high-order even terms from the Gram-Charlier series may be important for modelling methyl-group libration. The molecular-dynamics data sets provide useful insights into the nature of anharmonic thermal motion. Addressing the problem in real space allows intuitive PDFs to be developed but numerical methods may be necessary for these methods to be implemented in refinement programs as an analytical Debye-Waller factor cannot always be obtained. PMID- 21694474 TI - Addressing the amorphous content issue in quantitative phase analysis: the certification of NIST standard reference material 676a. AB - A non-diffracting surface layer exists at any boundary of a crystal and can comprise a mass fraction of several percent in a finely divided solid. This has led to the long-standing issue of amorphous content in standards for quantitative phase analysis (QPA). NIST standard reference material (SRM) 676a is a corundum (alpha-Al(2)O(3)) powder, certified with respect to phase purity for use as an internal standard in powder diffraction QPA. The amorphous content of SRM 676a is determined by comparing diffraction data from mixtures with samples of silicon powders that were engineered to vary their specific surface area. Under the (supported) assumption that the thickness of an amorphous surface layer on Si was invariant, this provided a method to control the crystalline/amorphous ratio of the silicon components of 50/50 weight mixtures of SRM 676a with silicon. Powder diffraction experiments utilizing neutron time-of-flight and 25 keV and 67 keV X ray energies quantified the crystalline phase fractions from a series of specimens. Results from Rietveld analyses, which included a model for extinction effects in the silicon, of these data were extrapolated to the limit of zero amorphous content of the Si powder. The certified phase purity of SRM 676a is 99.02% +/- 1.11% (95% confidence interval). This novel certification method permits quantification of amorphous content for any sample of interest, by spiking with SRM 676a. PMID- 21694475 TI - Estimation of the variance in any point of an electron-density map for any space group. AB - In a recent paper [Giacovazzo & Mazzone (2011). Acta Cryst. A67, 210-218] a mathematical expression of the variance at any point of the unit cell has been described. The formulas were derived in P1 for any type of Fourier synthesis (observed, difference and hybrid) under the following hypothesis: the current phases are distributed on the trigonometric circle about the correct values according to von Mises distributions. This general hypothesis allows the variance expressions to be valid at any stage of the phasing process. In this paper the method has been extended to any space group, no matter whether centric or acentric. The properties of the variance generated by space-group symmetry are described; in particular it is shown that the variance is strictly connected with the implication transformations, which are basic for Patterson deconvolution. General formulas simultaneously taking into account phase uncertainty and measurement errors have been obtained, valid no matter what the quality of the model. PMID- 21694476 TI - Linear transformations of variance/covariance matrices. AB - Many applications in crystallography require the use of linear transformations on parameters and their standard uncertainties. While the transformation of the parameters is textbook knowledge, the transformation of the standard uncertainties is more complicated and needs the full variance/covariance matrix. For the transformation of second-rank tensors it is suggested that the 3 * 3 matrix is re-written into a 9 * 1 vector. The transformation of the corresponding variance/covariance matrix is then straightforward and easily implemented into computer software. This method is applied in the transformation of anisotropic displacement parameters, the calculation of equivalent isotropic displacement parameters, the comparison of refinements in different space-group settings and the calculation of standard uncertainties of eigenvalues. PMID- 21694477 TI - Anomalous extinction of X-rays diffracted in strongly deformed crystals. AB - The extinction concept is extended for very thin non-ideal crystals. It is shown that for a large gradient, the integrated reflected intensity exhibits a prominent extinction minimum. This anomaly is an interbranch effect, occurring for crystals with thicknesses of the order of the interbranch extinction length. Different possibilities for applying this newly developed extinction theory to X ray integrated wave topography are discussed. PMID- 21694478 TI - Relaxation of the resolution requirements for direct-methods phasing. AB - Shake-and-bake phasing methods have permitted the ab initio solution of crystal structures containing more than 1000 independent non-H light atoms (C, N, O). The success of these procedures is critically dependent upon having diffraction data measured to at least 1.2 A resolution. A new target function R(2)(phi(h)) is introduced into the shake-and-bake procedure along with a real difference map strategy whereby this resolution limit can be appreciably lowered toward 1.5 A. These improvements, when applied to moderately high resolution data, may now allow one the possibility to solve structures that are twice as large as could have been solved previously. PMID- 21694479 TI - The similarity types of primitive parallelohedra in E(d), 2 <= d <= 5. AB - The similarity types of parallelohedra are defined and a complete classification of the primitive parallelohedra in E(d), 2 <= d <= 5, is given. PMID- 21694480 TI - High-resolution study of (222, 113) three-beam diffraction in Ge. AB - The results of high-resolution analysis of the (222, >113) three-beam diffraction in Ge are presented. For monochromatization and angular collimation of the incident synchrotron beam a multi-crystal arrangement in a dispersive setup in both vertical and horizontal planes was used in an attempt to experimentally approach plane-wave incident conditions. Using this setup, for various azimuthal angles the polar angular curves which are very close to theoretical computer simulations for the plane monochromatic wave were measured. The effect of the strong two-beam 222 diffraction was observed for the first time with the maximum reflectivity close to 60% even though the total reflection of the incident beam into a forbidden reflection was not achieved owing to absorption. The structure factor of the 222 reflection in Ge was experimentally determined. PMID- 21694481 TI - Seitz notation for symmetry operations of space groups. AB - Space-group symmetry operations are given a geometric description and a short hand matrix notation in International Tables for Crystallography, Volume A, Space Group Symmetry. We give here the space-group symmetry operations subtables with the corresponding Seitz (R?t) notation for each included symmetry operation. PMID- 21694483 TI - [Prediction of post-operative mortality in patients with cirrhosis: growth of child to MELD]. PMID- 21694484 TI - [Individualized surgery for gastric cancer]. AB - Recently, tailored and multidisciplinary treatment of gastric cancer was emerging in the field of clinical oncology. Gastric cancer is the most frequently diagnosed cancer in Korea. Surgery is the only possible curative procedure, and extensive gastrectomy and D2 lymph node dissection has been accepted as standard treatment in all gastric cancer patients until recently. In early gastric cancer, many researchers established the indications of limited surgery including endoscopic mucosal resection based on various well-collected retrospective data. Limited surgery and minimally invasive surgery contribute to quality of life in gastric cancer patients. In advanced gastric cancer, eastern surgeons believe that D2 lymph node dissection is standard treatment if done by credential surgeons in specialized centers despite of different opinion of western surgeon. In addition, adjuvant chemotherapy after good local control by D2 dissection has gained survival benefit rather than D2 dissection alone in randomized trials. In conclusion, present confronted issue is to establish tailored treatments of individualized patients through extent of disease in gastric cancer patients. PMID- 21694485 TI - [Usefulness of model for end-stage liver disease score for predicting mortality after intra-abdominal surgery in patients with liver cirrhosis in a single hospital]. AB - BACKGROUND/AIMS: Recent studies have suggested that the model for end-stage liver disease (MELD) score is superior to the Child-Turcotte-Pugh (CTP) score as a predictor of postoperative mortality, especially up to 90 days. This study aimed to determine whether MELD score can predict the postoperative outcome of patients with liver cirrhosis in Korea. METHODS: We reviewed the medical records of 98 patients with liver cirrhosis who underwent intra-abdominal surgery under generalized anesthesia between March 2003 and December 2008 at Kangbuk Samsung Hospital. Univariate and multivariate cox proportional hazards analyses were performed to determine the correlation between risk factors and mortality. RESULTS: Eighty-two percent of patients (n=80) were male. Mean MELD score was 10.82 +/- 3.84. Common causes of liver cirrhosis were hepatitis B (57.2%) and alcohol (22.4%). Ninety-day mortality ranged from 2.1% (MELD score, <= 9) to 25% (MELD score, >= 17). By multivariate analysis, MELD score > 9 (HR 2.490; [95% CI 1.116-5.554; p=.026]) and American Society of Anesthesiologists Class >= IV (HR 2.433; [95% CI 1.039-5.695; p=.041]) predicted mortality at 30 days after surgery. Only MELD score was a predictor of prognosis at 90 days (HR 2.446; [95% CI 1.118-5.352; p=.025]). Etiology of cirrhosis and CTP score were not predictors of mortality. CONCLUSIONS: MELD score was a useful predictive parameter of postoperative mortality at 30 days and 90 days, independent of the etiology of cirrhosis. PMID- 21694486 TI - [Molecular and clinical characterization of hepatitis a virus in Gwangju and Jeonnam province]. AB - BACKGROUND/AIMS: Dominant genotype of hepatitis A virus (HAV) in Korea had been known to be genotype 1A in 1990s. Recently, the epidemiologic change of HAV genotype was reported with an upsurge of acute hepatitis A in Korea. The aim of this study was to investigate the change of HAV genotypes and clinical characteristics in Gwangju and Jeonnam province. METHODS: From November 2008 to October 2009, a total of 82 patients with acute hepatitis A were enrolled prospectively. HAV genotype was determined using reverse transcriptase polymerase chain reaction and sequencing of the PCR products of VP1/2A region of HAV. RESULTS: HAV RNA was detected in 82% (67/82). The genotype IIIA (88%, 59 cases) was significantly more frequent than genotype IA (12%, 8 cases) (p <= 0.01). The subtypes of genotype IIIA were AJ299467 Norway (49%), HA-JNG04-09 Japan (27%), HS 14-12-00 Spain (22%) and H-122 Sweden (2%). The subtypes of IA were FH1 Japan (50%) and HA J04-3 Japan (50%). The substitutions of amino acid were more frequent in genotype IIIA than IA (p<= 0.01). There was no difference in the clinical characteristics between the patients with genotype IIIA and IA. CONCLUSIONS: Genotype IIIA was a dominant genotype of recent HAV infection in Gwangju and Jeonnam province. This study provides valuable epidemiologic information of genetic distributions of HAV in Korea. PMID- 21694487 TI - [Recurrent common bile duct stone and endoscopic treatment after endoscopic papillary large balloon dilatation with minor endoscopic sphincterotomy]. AB - BACKGROUND/AIMS: Recent studies have reported the potentials of endoscopic papillary large balloon dilatation (EPLBD) with minor endoscopic sphincterotomy (EST) for the complete removal of common bile duct (CBD) stone in the high risk groups. However, there have been no reports about the recurrence of the CBD stone after EPLBD with minor EST. The aim of this study was to evlauate the recurrence of CBD stone after EPLBD with minor EST. METHODS: A total of 1,036 patients who underwent endoscopic treatment due to CBD stones at Pusan University Hospital were enrolled. The patients were classified into two groups: those who underwent EPLBD with minor EST (group 1) and those who underwent EST treatment (group 2). We investigated clinical factors and recurrence rate between two groups. RESULTS: The recurrence of CBD stone occurred in total of 74 patients (7%), and the recurrence rates of CBD stone were 21/321 (6.5%) in Group 1 and 53/715 (7.4%) in Group 2. There were no difference in the presence of diverticulum and the number and size of recurrent CBD stone between the two groups. In case of diverticulum existence, recurrence rates were 12/158 (7.6%) in Group 1 and 21/101 (20.8%) in Group 2. When compared to the case of no diverticulum existence (Group 1: 9/163 [5.5%], Group 2: 32/614 [5.2%]), the recurrence rate of CBD stone was significantly lower if treated after EPLBD with minor EST (p < 0.01). CONCLUSIONS: CBD stone that recurs after going through EPLBD with minor EST can be successfully removed with an endoscopic treatment. The recurrence of CBD stone was especially lower in cases with periampullary diverticulum and treated with EPLBD with minor EST. Our results will be helpful in endoscopic retreatment and preventing the recurrence of CBD stone. PMID- 21694488 TI - [Clinical characteristics of pancreatic metastases]. AB - BACKGROUND/AIMS: Histologically confirmed metastatic pancreatic cancers are infrequent. The aim of this study was to analyze clinical, therapeutic and prognostic features of pancreatic metastases. METHODS: We retrospectively evaluated stage of primary malignancies, interval between diagnosis of primary tumors and detection of pancreatic metastases, treatment for metastases to the pancreas, survival rate, and prognostic factors in 31 patients with pancreatic metastases. RESULTS: The mean age at the time of primary cancer diagnosis was 52.4 +/- 13.2 years. Primary cancers were renal cell carcinoma (n=16), non-small cell lung cancer (n=6), small cell lung cancer (n=3), colorectal carcinoma (n=2), osteosarcoma (n=1), gastric carcinoma (n=1), malignant melanoma (n=1), and thymic carcinoma (n=1). Pancreatic metastases were synchronous in six cases and metachronous in twenty five cases, with median interval time of 40.8 months (range 3-186) between the diagnosis of primary tumor and detection of pancreatic metastases. The median survival after the detection of the metastases was 16 months. In multivariate analysis, non-renal cell carcinoma as primary malignancy and positive symptom related to pancreatic metastases were associated with poor prognosis (hazard ratio [HR], 8.33; 95% CI, 2.1-33; p=0.003, and HR, 4.02; 95% CI, 1.27-12.7; p=0.018). CONCLUSIONS: Metastatic tumors to the pancreas have to be kept in mind when a patient with pancreatic mass has a history of other malignancy, even if treated several years before. In the absence of widely metastatic disease, aggressive diagnostic and therapeutic approach may offer the chance of long-term survival in selected patients. PMID- 21694489 TI - [A case of natural killer like T cell lymphoma misdiagnosed as Behcet's Enteritis of the terminal ileum]. AB - Primary natural killer (NK) cell like T cell lymphoma of the terminal ileum is extremely rare. It most frequently occurs in the nasal or paranasal areas and less frequently in the skin, the soft tissue, and the gastrointestinal tract. NK/T cell lymphoma involving gastrointestinal tract has characteristic endoscopic features of Inflammatory bowel disease. We herein describe a first case of primary NK/T cell lymphoma misdiagnosed as Behcet's enteritis of the terminal ileum colonoscopically and complicated by cecal bleeding and perforation. PMID- 21694490 TI - Ileal stenosis occurred 3 months after blunt abdominal trauma. AB - We present a case of ileal stenosis with delayed presentation 3 months after car accident. Ileal stenosis after blunt abdominal trauma is a rare clinical entity. We present CT and small bowel series 3 months after trauma. Image showed segmental thickening of intestinal wall and proximal bowel dilation. At surgery, a stenotic bowel loop was adjacent to a fibrotic mesentery. Histological examination showed ulcers, inflammatory cells and fibroblasts infiltrated to the muscularis mucosae, submucosa, and mesentery. The most likely cause, supported by most authors, implicates an injury to the mesentery. Post-traumatic ischemic bowel stenosis may result from even small tears and contusions of mesentery. Posttraumatic intestinal stenosis should be included in the differential diagnosis in a patient with a history of blunt abdominal trauma and signs of intestinal obstruction. PMID- 21694491 TI - [Left-sided ulcerative colitis reactivated and aggravated during clostridium difficile infection]. AB - Clostridium difficile (C. difficile) infection appears to be closely related to reactivation, diagnostic delay, and disease progression in patients with inflammatory bowel disease. However, whether C. difficile infection triggers the reactivation of inflammatory bowel disease or vice versa is not certain. We report a case of reactivated and progressed left ulcerative colitis following C. difficile infection in a 56-year-old woman. A series of endoscopic findings in this case report strongly supports a causative role of C. difficile infection on the reactivation and progression of ulcerative colitis. PMID- 21694492 TI - [A case of tuberculous peritonitis developed during chemotherapy for tuberculous pleurisy as paradoxical response]. AB - After the start of anti-tuberculous treatment, paradoxical worsening of tuberculous lesions has been described. However, abdominal tuberculosis as paradoxical response is relatively rare. This report describes the 26-year-old female who suffered from peritoneal tuberculosis while treating tuberculous pleurisy with anti-tuberculous medications. It was considered as paradoxical response, rather than treatment failure or else. She was successfully managed with continuing initial anti-tuberculous medications. When a patient on anti tuberculous medications is presented with abdominal symptoms, the possibility of paradoxical response should be considered to avoid unnecessary tests and treatments, which may result in more suffering of the patient. Herein, we report a case of peritoneal tuberculosis as paradoxical response while treating tuberculous pleurisy. PMID- 21694493 TI - [Hepatocellular adenoma treated with radiofrequency ablation in young male]. PMID- 21694495 TI - Endothelial progenitor cell transplantation decreases lymphangiogenesis and adverse myocardial remodeling in a mouse model of acute myocardial infarction. AB - Cardiac lymphatic system in the remodeling after acute myocardial infarction (AMI) has been overlooked. We wanted to investigate the role of bone marrow derived endothelial progenitor cells (EPCs) and their contribution to lymphatic distribution in myocardial remodeling after AMI. Mouse (C57bl/6J) MI models were created by ligation of the left anterior descending coronary artery and were treated with phosphate buffered saline (PBS) or EPCs. Real-time RT-PCR with 2- to 4-week myocardial tissue samples revealed that lymphangiogenetic factors such as vascular endothelial growth factor (VEGF)-C (8.5 fold, P < 0.05), VEGF-D (6.1 fold, P < 0.05), Lyve-1 (15 fold, P < 0.05), and Prox-1 (11 fold, P < 0.05) were expressed at significantly higher levels in the PBS group than the EPC group. The PBS group also showed a significantly higher density of lymphatic vessels in the peri-infarction area. Echocardiography showed that from 2 weeks after the treatment, left ventricle (LV) dimensions at both systole and diastole were significantly smaller in the EPC group than in the PBS group (P < 0.01) and LV fractional shortening was higher in the EPC group accordingly (P < 0.01). Lymphangiogenic markers increased in a mouse MI model. EPC transplantation decreased lymphangiogenesis and adverse ventricular remodeling after AMI. These novel findings suggest that new lymphatic vessels may be formed in severely damaged myocardium, and may be involved in adverse myocardial remodeling after AMI. PMID- 21694496 TI - How prenylation and S-acylation regulate subcellular targeting and function of ROP GTPases. AB - Rho of Plants (ROP) small G proteins function at discrete domains of the plasma and possibly endo membranes. ROPs are synthesized as soluble proteins and their attachment to membranes and partitioning in membrane microdomains are facilitated by the posttranslational lipid modifications prenylation and/or S-acylation. Based on their amino acid sequences, ROPs can be classified into two major subgroups: type-I ROPs terminate with a canonical CaaX box motif and are prenylated primarily by geranylgeranyltransferase-I (GGT-I) and to a lesser extent by farnesyltransferase (FT). Type-II ROPs terminate with a plant specific GC-CG box domain and are attached to the plasma membrane by stable S-acylation. In addition, type-I and possibly also type-II ROPs undergo activation dependent transient S-acylation in the G-domain and consequent partitioning into lipid rafts. Surprisingly, although geranylgeranylation is required for the membrane attachment of type-I ROPs and the gamma subunits of heterotrimeric G proteins, Arabidopsis mutants lacking GGT-I function have a mild phenotype compared to wild type plants. The mild phenotype of the ggt-I mutants suggested that farnesylation by FT may compensate for the loss of GGT-I function and that possibly the prenylated type-I and S-acylated type-II ROPS have some overlapping functions. In a paper recently published in Plant Physiology we examined the role of the prenyl group type in type-I ROP function and membrane interaction dynamics and the functional redundancy between type-I and type-II ROPs. This study complements a second paper in which we examined the role of G-domain transient S-acylation in the membrane interaction dynamics and signaling by type-I ROPs. Together these two studies provide a framework for realizing the role of prenylation and S acylation in subcellular targeting, membrane interaction dynamics and signaling by ROP GTPases. PMID- 21694497 TI - Strigolactones' ability to regulate root development may be executed by induction of the ethylene pathway. AB - The newly defined phytohormones strigolactones (SLs) were recently shown to act as regulators of root development. Their positive effect on root-hair (RH) elongation enabled examination of their cross talk with auxin and ethylene. Analysis of wild-type plants and hormone-signaling mutants combined with hormonal treatments suggested that SLs and ethylene regulate RH elongation via a common regulatory pathway, in which ethylene is epistatic to SLs. The SL and auxin hormonal pathways were suggested to converge for regulation of RH elongation; this convergence was suggested to be mediated via the ethylene pathway, and to include regulation of auxin transport. PMID- 21694498 TI - Cyclooxygenase-1 is involved in the inhibition of hippocampal neurogenesis after lipopolysaccharide-induced neuroinflammation. AB - Growing evidence indicates that neuroinflammation can alter adult neurogenesis by mechanisms as yet unclear. We have previously demonstrated that the neuroinflammatory response and neuronal damage after lipopolysaccharide (LPS) injection is reduced in cyclooxygenase-1 deficient (COX-1(-/-)) mice. In this study, we investigated the role of COX-1 on hippocampal neurogenesis during LPS induced neuroinflammation, using COX-1(-/-) and wild type (WT) mice. We found that LPS-induced neuroinflammation resulted in the decrease of proliferation, survival and differentiation of hippocampal progenitor cells in WT but not in COX 1(-/-) mice. Thus, we demonstrate for the first time that COX-1 is involved in the inhibition of BrdU progenitor cells in proliferation and hippocampal neurogenesis after LPS. These results suggest that COX-1 may represent a viable therapeutic target to reduce neuroinflammation and promote neurogenesis in neurodegenerative diseases with a strong inflammatory component. PMID- 21694499 TI - Diversity of the autochthonous colonic microbiota. AB - A longstanding hypothesis in intestinal microbial ecology is that autochthonous microbes (resident) play a role that is distinct from allochthonous microbes (transient microbes in the fecal stream). A challenge has been to identify this pool of microbes. We used laser capture microdissection to collect microbes from the mouse ascending colon. This area contains transverse folds that mimic human intestinal folds and contains a distinct population of intestinal microbes that is associated with the mucosa. Our analysis of bacterial 16S rRNA genes showed that this area was enriched for Lachnospiraceae and Ruminococcaceae. In this addendum, we further compare this community to studies of mucosa-associated microbes in humans. This analysis reveals common phylogenetic groups of bacteria that are present in both mouse and human. However, we found microorganisms at the genus and species levels including Faecalibacterium prausnitzii which appears to be specific for humans. We propose that that examination of the mucosa-associated microbes in wild type and genetically modified mice will be a valuable component to define host microbial interactions that are essential for homeostasis. PMID- 21694501 TI - Densitometric threshold and vertebral fractures in heart transplant patients. AB - BACKGROUND: Bone disease is one of the major complications of solid organ transplantation, causes considerable morbidity, and most patients are treated with immunosuppressant drugs after graft. The majority of studies reported rapid bone loss and an increased incidence of fractures after transplantation. The aim of our study was to evaluate osteoporosis and fracture prevalence, bone metabolism, and the effect of immunosuppressant agents on bone after heart transplantation. METHODS: We planned a cross-sectional study in 180 heart transplant patients recruited from 3 different centers with a less than 10 years from graft. Each patient underwent a densitometric scan, and in 157 of them, an x ray of the spine was performed to evaluate fractures. Biochemical assessment of bone metabolism was made at the time of the visit. Physical activity, diet, and calcium intake were evaluated using a specific questionnaire. RESULTS: Vertebral fractures were diagnosed in 40% of subjects, but densitometric osteoporosis was observed only in 13% of spine and in 25% of hip scans. Interestingly, increasing T-score threshold up to -1.5 standard deviation, the prevalence of fractured patient improved significantly, reaching 60% in both genders. Bone content was inversely correlated with glucocorticoids, while a positive correlation was found with cyclosporine A. Almost all subjects had vitamin D deficiency. CONCLUSIONS: Standard densitometric criteria are unreliable to identify bone fragility after transplantation, and a different threshold (-1.5 standard deviation) should be considered. Transplanted patients should be adequately supplemented with vitamin D, and the effects of immunosuppressant agents on bone need further investigation. PMID- 21694504 TI - Surgery and smoking at first and second hand: time to act. PMID- 21694505 TI - The Cooper-Dennis "process for administering anaesthetics". PMID- 21694507 TI - Lung injury prediction models to improve perioperative management: let's hit the bull's-eye! PMID- 21694508 TI - Pediatric surgery and parental smoking behavior. AB - BACKGROUND: Secondhand smoke exposure poses health risks to children, including increased risks for anesthesia. In adult smokers, surgery serves as a teachable moment to motivate quitting. For parents who smoke, having a child undergo surgery may also serve as a teachable moment for smoking behavioral change. This study determined if there is an association between children undergoing a surgical procedure and changes in their parents' smoking behavior. METHODS: Secondary analyses were performed using logistic regression analysis of 2005 survey data from the National Health Interview Survey. Analyses included 9,289 parent respondents who provided information on both themselves and their children. RESULTS: Of the sampled children, 1,112 (12.6%, 95% CI:11.7, 13.4) lived in a home with at least one person who smoked inside in a usual week. In multivariate analysis of the relationship between parent and child surgical history in the past 12 months and smoking behavior, surgery in either the parent (odds ratio 2.19, 95% CI: 1.55, 3.08) or child (odds ratio 2.61, 95% CI: 1.56, 4.35) was associated with an increased likelihood of a quit attempt by the parent. However, these attempts were more likely to be successful if the parents (odds ratio 2.35, 95% CI: 1.35, 4.07), not their child (odds ratio 0.51, 95% CI: 0.20, 1.28), had surgery within the past 12 months. CONCLUSIONS: Parents who smoke were more likely to make a quit attempt within the past 12 months if their children had surgery within this time, but they were not more likely to succeed in maintaining abstinence and thus could benefit from assistance. PMID- 21694502 TI - The immunopathobiology of syphilis: the manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity. AB - Syphilis has plagued mankind for centuries and is currently resurgent in the Western hemisphere. Although there has been a significant reduction of tertiary disease and recognition of facilitative interactions with human immunodeficiency virus infection, the natural history of syphilis has remained largely unchanged; thus, new strategies are required to more effectively combat this pathogen. The immunopathologic features of experimental syphilis in the rabbit; the course, stages, and pathology of human syphilis; and a comparison of human syphilis with leprosy suggest that the clinical course of syphilis and its tissue manifestations are determined by the balance between delayed-type hypersensitivity (DTH) and humoral immunity to the causative agent, Treponema pallidum. A strong DTH response is associated with clearance of the infecting organisms in a well-developed chancre, whereas a cytotoxic T-cell response or strong humoral antibody response is associated with prolonged infection and progression to tertiary disease. Many of the protean symptoms/appearances of secondary and tertiary human syphilis are manifestations of immune reactions that fail to clear the organism, due to a lack of recruitment and, more importantly, activation of macrophages by sensitized CD4 T cells. The Bacillus Calmette-Guerin vaccination can enhance DTH and has been shown to produce a low, but measurable, beneficial effect in the prevention of leprosy, a disease that shows a disease spectrum with characteristics in common with syphilis. In the prevention of syphilis, a potential vaccine protective against syphilis should be designed to augment the DTH response. PMID- 21694509 TI - Genome-wide Association study using pooled DNA to identify candidate markers mediating susceptibility to postoperative nausea and vomiting. AB - BACKGROUND: A family history has been established as a risk factor for postoperative nausea and vomiting (PONV), but the identities of susceptibility genes remain unknown. The goal of this study was to identify the genetic loci that may contribute to PONV susceptibility in an adult population. METHODS: The authors performed a genome-wide association study involving pooling of DNA obtained from 122 patients with severe PONV and 129 matched controls. Each pool was hybridized to a single nucleotide polymorphism (SNP) microarray, and probe intensity was used to predict allele frequency. Differences in allele frequency between SNP in the PONV and control groups were ranked after accounting for the pooling error. The highest ranking SNPs were selected for individual genotyping in the subjects from whom the DNA pool was comprised and in the new verification cohort consisting of 208 subjects (104 PONV patients and 104 controls). RESULTS: The authors identified 41 SNP targets showing substantial difference in allelic frequency between pools. These markers were first genotyped in the individual DNA samples from which the pools were comprised. The authors observed evidence for an association between PONV and 19 different loci in the genome. In the separate verification cohort, the association with PONV was observed for four SNPs. This association remained significant after correcting for multiple testing (P < 0.0023) for one SNP (rs2165870), which is located upstream of the promoter for the muscarinic acetylcholine receptor 3 subtype (CHRM3) gene. CONCLUSIONS: The authors performed the genome-wide association study for PONV using pooled DNA samples. Through individual genotyping, they confirmed association of at least one SNP that is predictive of PONV susceptibility. PMID- 21694511 TI - Belskie's 1971 Medallion of John Snow. PMID- 21694512 TI - Alvatunder bottle by the hisey dental manufacturing company. PMID- 21694510 TI - Derivation and diagnostic accuracy of the surgical lung injury prediction model. AB - BACKGROUND: Acute lung injury (ALI) is a serious postoperative complication with limited treatment options. A preoperative risk-prediction model would assist clinicians and scientists interested in ALI. The objective of this investigation was to develop a surgical lung injury prediction (SLIP) model to predict risk of postoperative ALI based on readily available preoperative risk factors. METHODS: Secondary analysis of a prospective cohort investigation including adult patients undergoing high-risk surgery. Preoperative risk factors for postoperative ALI were identified and evaluated for inclusion in the SLIP model. Multivariate logistic regression was used to develop the model. Model performance was assessed with the area under the receiver operating characteristic curve and the Hosmer Lemeshow goodness-of-fit test. RESULTS: Out of 4,366 patients, 113 (2.6%) developed early postoperative ALI. Predictors of postoperative ALI in multivariate analysis that were maintained in the final SLIP model included high risk cardiac, vascular, or thoracic surgery, diabetes mellitus, chronic obstructive pulmonary disease, gastroesophageal reflux disease, and alcohol abuse. The SLIP score distinguished patients who developed early postoperative ALI from those who did not with an area under the receiver operating characteristic curve (95% CI) of 0.82 (0.78-0.86). The model was well calibrated (Hosmer-Lemeshow, P = 0.55). Internal validation using 10-fold cross-validation noted minimal loss of diagnostic accuracy with a mean +/- SD area under the receiver operating characteristic curve of 0.79 +/- 0.08. CONCLUSIONS: Using readily available preoperative risk factors, we developed the SLIP scoring system to predict risk of early postoperative ALI. PMID- 21694513 TI - Ether and me by Will Rogers. PMID- 21694514 TI - Images in anesthesiology: a large gastric Bezoar: preanesthetic considerations. PMID- 21694516 TI - Seeing eye to eye on ophthalmic regional anesthesia. PMID- 21694517 TI - Don't forget the heart when looking at the risk of postoperative pulmonary complications. PMID- 21694519 TI - Pulmonary postoperative complications: is there a place for anesthesia? PMID- 21694520 TI - Halogenated anesthetics and intensive care unit sedation: a note of caution. PMID- 21694522 TI - Incomplete validation of risk stratification indices. PMID- 21694525 TI - Certification in sleep medicine. PMID- 21694526 TI - A training model for orienting newly hired nurses to an organization's electronic health record. PMID- 21694530 TI - Epiploic appendagitis. PMID- 21694531 TI - Supplementation of N-3 LCPUFA to the diet of children older than 2 years: a commentary by the ESPGHAN Committee on Nutrition. AB - The aim of this commentary is to review data on the effect of supplementation of paediatric patients ages 2 years or older with n-3 long-chain polyunsaturated fatty acids (LCPUFA). Some evidence for a positive effect on functional outcome in children with attention-deficit/hyperactivity disorder (ADHD) was found; however, benefit was seen in only about half of the randomised controlled trials (RCT), and studies varied widely not only in dose and form of supplementation but also in the functional outcome parameter tested. The committee concludes that there are insufficient data to recommend n-3 LCPUFA supplementation in the treatment of children with ADHD, but further research on n-3 LCPUFA supplementation in ADHD may be worthwhile. The committee was unable to find evidence of a favourable effect of n-3 LCPUFA supplementation on cognitive function in children. Although no benefit of n-3 LCPUFA supplementation was seen for major clinical outcome parameters in children with cystic fibrosis, a potentially beneficial shift towards less-inflammatory eicosanoid profiles seen in 2 studies provides grounds for further investigation; it is possible that earlier and longer supplementation periods may be needed to demonstrate clinical effect. For children with phenylketonuria, the limited data available suggest that supplementation of n-3 LCPUFA to the diet is both feasible and safe, but offers only transient benefit in visual function. For children with bronchial asthma there are insufficient data to suggest that LCPUFA supplementation has a beneficial effect. The committee advises paediatricians that most health claims about supplementation of n-3 LCPUFA in various diseases in children and adolescents are not supported by convincing scientific data. PMID- 21694533 TI - Leukocytapheresis in pediatric patients with ulcerative colitis. AB - OBJECTIVE: Leukocytapheresis (LCAP) is a nonpharmacologic therapy that has recently been used to treat ulcerative colitis (UC). This multicenter open-label study prospectively assessed the efficacy and safety of LCAP in pediatric patients with UC. PATIENTS AND METHODS: Twenty-three patients ages 8 to 16 years with moderate (n = 19) to severe (n = 4) steroid-resistant UC were enrolled. One of 2 LCAP columns with different volumes (model EX and the half-volume model EI) was selected, according to body weight. LCAP was performed once per week for 5 consecutive weeks. Clinical and laboratory data were collected at predetermined time points. The primary endpoint was decreased stool frequency/hematochezia score, and secondary endpoints were clinical, laboratory, and endoscopic improvements. RESULTS: The stool frequency/hematochezia score decreased significantly from 4.5 +/- 1.2 before treatment to 1.6 +/- 1.9 after the fifth treatment. Clinical parameters, including stool frequency, presence of visible blood, abdominal pain, and body temperature, were significantly improved. Fecal calprotectin decreased significantly. Endoscopic findings evaluated using Matts score also improved (P < 0.01). The steroid dose decreased from 1.1 +/- 0.4 mg/kg before treatment to 0.8 +/- 0.5 mg/kg after treatment. There were no significant differences in changes between the EX and EI columns. The incidence of adverse effects was 61%, although none was serious. The most common adverse effects were decreased hematocrit and hemoglobin concentration. CONCLUSIONS: The present study showed that LCAP was well tolerated in children with UC, mostly moderate, and was as effective as in adults. The types of pediatric patients best suited to LCAP remain to be determined. PMID- 21694534 TI - Immunophenotyping of peripheral eosinophils demonstrates activation in eosinophilic esophagitis. AB - BACKGROUND AND AIM: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by upper gastrointestinal symptoms and the presence of high numbers of eosinophils in the esophagus. Although eosinophils in the esophagus have been found to be activated in subjects with EoE, detailed studies of intracellular signaling pathways involved in the mechanism of activation of eosinophils in EoE have heretofore been limited. The aim of the study was to assess whether any surface molecules or transcription factors are activated in peripheral eosinophils in subjects with EoE. METHODS: Eosinophils and CD3+ lymphocytes were identified directly from 50 MUL of whole blood of EoE and control subjects. Using Hi-FACS, levels of surface activation markers, including CD66b, and intracellular phosphoepitopes, including phosphorylated forms of signal transducer and activator of transcription (phospho-STAT) 1 and 6, were measured within each cell subset. RESULTS: Levels of surface CD66b as well as levels of intracellular phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were significantly higher for untreated subjects with EoE vs healthy controls (P < 0.05). Levels of phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were lower in subjects with EoE on therapy versus untreated subjects with EoE (P < 0.05). CONCLUSIONS: Levels of phospho-STAT1 and phospho STAT6, transcription factors involved in inflammatory processes, were both significantly higher in peripheral eosinophils from untreated (ie, newly diagnosed) subjects with EoE versus subjects with EoE on therapy, healthy controls. Blood-based measurements of CD66b and phospho-STAT levels in peripheral eosinophils may be beneficial for identifying EoE. PMID- 21694535 TI - Significance of molecular testing for congenital chloride diarrhea. AB - OBJECTIVES: Autosomal recessive, congenital chloride diarrhea (CLD) is a form of persistent secretory diarrhea, presenting with polyhydramnios and intractable diarrhea from birth. CLD is caused by mutations in the SLC26A3 gene, encoding a Na+-independent Cl/HCO3- exchanger. The diagnosis is generally made on the basis of high fecal chloride concentration in patients with serum electrolyte homoeostasis corrected by salt substitution. We aimed to evaluate the role of diagnostic genetic testing in CLD. PATIENTS AND METHODS: Clinical and laboratory data were collected from 8 unrelated children diagnosed as having or suspected to have CLD. The evaluation included physical examination, routine clinical chemistry, and SLC26A3 mutation analysis by direct sequencing of DNA extracted from buccal swabs or peripheral leukocytes. RESULTS: CLD was initially diagnosed on high fecal chloride concentrations in 7 patients, and by mutation analysis in 1 patient. In 3 of these patients the correct diagnosis was made more than 6 months after birth. We identified SLC26A3 mutations on both alleles in all 8 patients with CLD, including 3 novel missense and 4 novel truncating mutations. We present a compilation of reported SLC26A3 mutations and polymorphisms. CONCLUSIONS: The diagnosis and therapy of CLD were considerably delayed in 3 of 8 patients from this series, highlighting the potential of misdiagnosing CLD. We add 7 novel mutations, including 3 missense changes of highly conserved residues to a total of 41 mutations in this gene. Molecular analysis is efficient and should be considered as a means of early diagnosis of CLD, especially if the clinical diagnosis remains uncertain. PMID- 21694532 TI - Skeletal health of children and adolescents with inflammatory bowel disease. AB - Current evidence points to suboptimal bone health in children and adolescents with inflammatory bowel disease (IBD) when compared with their healthy peers. This compromise is evident from diagnosis. The clinical consequences and long term outcome of this finding are still unknown. The mechanism of suboptimal bone health in children and adolescents with IBD lays mainly in reduced bone formation, but also reduced bone resorption, processes necessary for bone growth. Factors contributing to this derangement are inflammation, delayed growth and puberty, lean mass deficits, and use of glucocorticoids. We recognize that evidence is sparse on the topic of bone health in children and adolescents with IBD. In this clinical guideline, based on current evidence, we provide recommendations on screening and monitoring bone health in children and adolescents with IBD, including modalities to achieve this and their limitations; monitoring of parameters of growth, pubertal development, and reasons for concern; evaluation of vitamin D status and vitamin D and calcium intake; exercise; and nutritional support. We also report on the current evidence of the effect of biologics on bone health in children and adolescents with IBD, as well as the role of bone active medications such as bisphosphonates. Finally, we summarize the existing numerous gaps in knowledge and potential subjects for future research endeavors. PMID- 21694536 TI - Use of deamidated gliadin peptide antibodies to monitor diet compliance in childhood celiac disease. AB - OBJECTIVE: The aim of this study was to evaluate performance of serum antibodies against deamidated gliadin peptides (a-DGPs) in detecting compliance with gluten free diet (GFD) in children with celiac disease (CD). PATIENTS AND METHODS: Serum samples were collected the same day of endoscopy in 95 children with CD and 106 controls. We preliminarily calculated the cutoff of a-DGP immunoglobulin A (IgA) and a-DGP IgA+G in our population by receiver operating characteristic (ROC) curves. Of 95 children with CD, 28 were studied during the first year after GFD introduction, with interview and serum collection every 3 months. In addition, serum samples were collected in 106 children with CD on GFD for more than 1 year (range 1-14). In both groups of children with CD on GFD, we compared a-DGP IgA and IgA+G performance in monitoring compliance with GFD with anti-tissue transglutaminase antibodies (anti-tTG) IgA and anti-gliadin antibody (AGA) IgA. RESULTS: The cutoff resulted in 13.1 arbitrary units (AU) for a-DGP IgA (sensitivity 87.4, 95% confidence interval [CI] 79%-92%, specificity 97.2, 95% CI 92%-99%) and 16.5 for a-DGP IgA+G (sensitivity 94.7, 95% CI 88%-98%, specificity 89.6, 95% CI 84%-95%). In the first year of GFD, at 6 to 8 months prevalence of positive a-DGPs was significantly higher in partially versus strictly compliant children, and at 9 to 12 months only prevalence of positive a-DGP IgA+G remained significantly higher. Moreover, at 9 to 12 months sensitivity to detect transgressions to GFD was 44% for a-DGP IgA and 100% for a-DGP IgA+G (P = 0.03). In the 106 children on GFD for more than 1 year, sensitivity to detect transgressions to GFD was 60% for a-DGP IgA and 76% for a-DGP IgA+G. Anti-tTG IgA and AGA IgA sensitivity was much lower (24% and 4%, respectively). The 4 tests showed comparable high specificity. CONCLUSIONS: Both a-DGPs showed higher sensitivity than anti-tTG IgA and AGA IgA in monitoring compliance with GFD, but a-DGP IgA+G seemed to perform better. a-DGPs did not outperform anti-tTG IgA for CD screening. PMID- 21694537 TI - Treatment of infants and toddlers with cystic fibrosis-related pancreatic insufficiency and fat malabsorption with pancrelipase MT. AB - BACKGROUND: Pancreatic enzyme replacement therapy (PERT) improves nutritional status and growth in patients with cystic fibrosis (CF) with pancreatic insufficiency (PI). The current recommendation for infants and young children, who are not able to swallow the whole capsule, is to open the capsule and mix the beads in a spoon with some applesauce; however, the efficacy and safety data of this approach are currently lacking. The aim of this study was to assess the efficacy, palatability (ease of swallowing), and safety of 4 dose levels of pancrelipase microtablets (Pancrease MT) in infants and young children with CF related PI. PATIENTS AND METHODS: This study was a phase II randomized, investigator-blinded, parallel-group pilot study in DNA-proven infants with CF and PI. The study design included a run-in period (days 1-5) and an experimental period (days 6-11). Pancrelipase microtablets (2-mm, enteric coated) were provided orally. Sixteen subjects, 6 to 30 months of age, were provided 500 U lipase/kg/meal for 5 days (baseline period). Subsequently, subjects were randomly assigned to 1 of 4 treatment groups (each n = 4), receiving 500, 1000, 1500, or 2000 U (Ph. EUR) of lipase/kg/meal, respectively, for 5 days (experimental period). The primary endpoint was medication efficacy assessed by the 72-hour fecal fat excretion, expressed as coefficient of fecal fat absorption (CFA), and 13C mixed triglyceride breath test. Secondary endpoints were safety and palatability. RESULTS: Overall compliance, defined as used study medication, was 89% to 99% for the entire study. None of the 4 dose regimens significantly influenced the CFA, relative to the baseline period (median range 83%-93%). During the run-in period the median cumulative % 13C was 11 (range -8 to 59). After randomization the median cumulative % 13C was 18 (range 14-23) in the 500 U, 14 (range -1 to 17) in the 1000-U, 10 (range 10-27) in the 1500-U, and 3 (range 1-49) in the 2000-U groups. Palatability was scored fair to good by the parents in each of the treatment groups. Gastrointestinal symptoms were reported in some patients, including common adverse events reported in clinical trials involving pancreatic enzyme therapy. No serious or other adverse events were reported. CONCLUSION: Treatment with Pancrease MT at a dosage of 500 U lipase/kg/meal resulted in a CFA of approximately 89% in pediatric subjects ages 6 to 30 months with PI resulting from CF. Pancrease MT doses were well tolerated and mean palatability was scored as fair to good. Present results do not indicate that a dosage higher than 500 U (Ph. EUR) lipase/kg/meal increases the coefficient of fat absorption in a cohort of infants 6 to 30 months of age. PMID- 21694538 TI - Helicobacter pylori eradication rates in children upon susceptibility testing based on noninvasive stool polymerase chain reaction versus gastric tissue culture. AB - BACKGROUND AND OBJECTIVES: In children with clarithromycin-resistant Helicobacter pylori, clarithromycin-containing therapies often fail. The present study aimed to assess the outcome of tailored therapy upon noninvasive versus invasive H pylori susceptibility testing. PATIENTS AND METHODS: A retrospective cohort study was conducted in a pediatric outpatient clinic located in a region where H pylori clarithromycin resistance is highly prevalent. Between June 2007 and September 2009, 96 infected children (mean age 10.8 years), naive to H pylori eradication treatment, were prescribed triple eradication therapies. These therapies were individually tailored upon susceptibility testing performed either noninvasively using stool polymerase chain reaction (stool PCR group) or invasively using endoscopy, biopsy, and culturing of gastric biopsies (gastric biopsy group). Eradication was defined by negative results upon noninvasive testing including stool PCR at least 5 weeks after the end of treatment. RESULTS: H pylori was eradicated in 43 of 55 stool PCR group versus 30 of 41 gastric biopsy group children (78.2% vs 73.2%, P = 0.63). Of those H pylori strains with pretherapeutic clarithromycin susceptibility, 78.8% were eradicated in the stool PCR group and 69.2% in the gastric biopsy group (P = 0.41) following clarithromycin-containing therapy; clarithromycin resistance was acquired by 4.1% of strains in the former group versus 12% in the latter (P = 0.33). CONCLUSIONS: Stool PCR is as effective as the invasive approach of H pylori susceptibility testing for targeting resistance-guided eradication treatments in children. Furthermore, stool PCR is a useful tool for tracking the emergence of clarithromycin resistance following eradication treatment. PMID- 21694539 TI - Two-day bowel preparation with polyethylene glycol 3350 and bisacodyl: a new, safe, and effective regimen for colonoscopy in children. AB - OBJECTIVES: To assess the safety, efficacy, and acceptance of a 2-day bowel preparation with polyethylene glycol (PEG) 3350 without electrolytes and bisacodyl for colonoscopy in children. PATIENTS AND METHODS: In a prospective study, 111 children of mean age 11.9 years were given 2 g/kg of PEG and a 5-mg tablet of bisacodyl daily for 2 days before colonoscopy. Stool frequency, consistency, and adverse effects were monitored for the duration of the bowel preparation. Compliance and quality of colonic preparation were assessed on the day of the colonoscopy. RESULTS: The average daily stool frequency increased from a baseline of 2, to 4* on day 1, and 6.5* on day 2 of the bowel preparation (*P < 0.001 for difference vs baseline). The colonic preparations were rated as excellent or good in 92% and 93% of the patients in the right and left colon, respectively. Adverse effects were mild nausea (19%), abdominal pain (11%), and vomiting (4%). The compliance was rated as excellent in 95% of the patients. CONCLUSIONS: A 2-day bowel preparation with PEG and bisacodyl is safe, effective, and well accepted for colonoscopy in children without any major adverse effects. PMID- 21694540 TI - Defecation disorders in children after surgery for Hirschsprung disease. AB - BACKGROUND AND OBJECTIVE: The majority of children with Hirschsprung disease (HD) after corrective surgery (CS) develop protracted defecation disorders (DDs) such as constipation, fecal incontinence, and/or enterocolitis. The aim of this investigation was to determine the diagnoses, therapies, and long-term clinical outcomes using a systematic algorithm to address protracted DD in children with HD after CS. METHODS: Retrospective review of children with HD after CS cared for using a systematic algorithm at a tertiary care center. Potential anatomic etiologies were evaluated for first. Clinical outcome was categorized into 4 groups based on symptom severity, time interval from last enterocolitis episode, laxative usage, and/or rectal therapies at the time of last follow-up. RESULTS: Fifty-seven children were identified, of whom 51 (89.5%) had obstructive symptoms and/or enterocolitis and 6 (10.5%) had nonretentive fecal incontinence. Nonintractable constipation responsive to laxatives was identified in 10 (17.5%), colonic dysmotility in 4 (7.0%), nonrelaxing anal sphincter as a primary etiology in 22 (38.6%), bacterial overgrowth in 2 (3.5%), food intolerance in 2 (3.5%), and rapid transit in 2 (3.5%). Further surgical intervention was undertaken in 22 (38.6%), including 9 (15.8%) for residual aganglionosis. Mean follow-up was 41.4 +/- 4.5 months. Clinical outcomes were excellent in 16 (28.1%), good in 22 (38.6%), fair in 1 (1.8%), and poor in 18 (31.6%). Children with enterocolitis were more likely to have an excellent or good clinical outcome. CONCLUSIONS: The majority of children with HD and protracted DD after CS have a favorable long term clinical outcome when following a systematic algorithm. PMID- 21694541 TI - Urotensin II levels are an important marker for the severity of portal hypertension in children. AB - BACKGROUND AND AIM: Urotensin II (U-II), a somatostatin-like cyclic peptide, was recently identified as the most potent human vasoconstrictor peptide; however, the contribution of U-II-mediated alterations in peripheral vascular tone in disease states such as chronic liver disease and portal hypertension is poorly characterised. There are no data examining U-II in chronic liver disease in children. In this study, we aimed to determine whether U-II levels in healthy children are ontogenically regulated and we explored the effect of chronic liver disease on peripheral circulating U-II levels. MATERIALS AND METHODS: U-II levels from healthy controls (n = 129) were compared with a healthy adult population (n = 80) in addition to a well-characterised cohort of children with chronic liver disease (n = 20). U-II was measured by radioimmunoassay. RESULTS: There was no correlation between U-II and age in healthy children (r2 = 0, P = 0.8). U-II levels were similar between the paediatric and the adult control populations (1.35 +/- 0.96 vs 1.25 +/- 0.78, P = 0.8). U-II was significantly elevated in children with liver disease compared with controls (1.35 +/- 0.96 pmol/L vs 3.56 +/- 2.21 pmol/L; P < 0.001). In addition, U-II levels positively correlated with severity of liver disease as determined by Child-Pugh score (P < 0.05) and paediatric end-stage liver disease score (P < 0.001). Levels of U-II also correlated with long-term clinical outcome. CONCLUSIONS: These data suggest that U-II is an important marker of severity of portal hypertension in children. It is independent of age and may be a potential therapeutic target in the chronic liver disease population. PMID- 21694542 TI - Vitamin D supplementation and status in infants: a prospective cohort observational study. AB - OBJECTIVE: Vitamin D status in infants depends on supplementation. We examined the vitamin D status in relation to supplementation dose and scheme in infants. PATIENTS AND METHODS: One hundred thirty-four infants age 6 months and 98 infants age 12 months (drop out 27%) were investigated. Vitamin D intake (diet, supplements), anthropometry, and 25-hydroxyvitamin D (25-OHD) serum concentration at the 6th and 12th months were assessed. RESULTS: Vitamin D intake of 1062 +/- 694 IU at the 6th month was not different from that at the 12th month (937 +/- 618 IU). Vitamin D intake expressed in international units per kilogram of body weight decreased from 141 +/- 80 IU/kg at the 6th month to 93 +/- 62 IU/kg at the 12th month (P < 0.0001), which was associated with a reduction in 25-OHD from 43 +/- 20 ng/mL to 29 +/- 12 ng/mL, respectively (P < 0.0001). In the subgroup of everyday supplemented infants (n = 43), vitamin D intake decreased from 143 +/- 88 IU/kg at the 6th month to 118 +/- 60 IU/kg at the 12th month (P < 0.05), which coincided with a reduction of 25-OHD from 40 +/- 19 ng/mL to 32 +/- 13 ng/mL (P < 0.01). In the subgroup with variable supplementation habits (n = 32), vitamin D intake decreased from 146 +/- 79 IU/kg to 77 +/- 56 IU/kg (P < 0.001), which was associated with a reduction of 25-OHD from 42 +/- 21 ng/mL to 25 +/- 8 ng/mL (P < 0.0001). 25-OHD concentration change between the 6th and the 12th months negatively correlated with the 25-OHD level assessed at the 6th month (r = -0.82; P < 0.0001). CONCLUSIONS: Vitamin D supplementation of infants should consider their rapid body weight increment. We postulate vitamin D daily dose close to 100 IU/kg body weight as favorable for infants up to age 12 months. PMID- 21694543 TI - Asymptomatic granulomatous vulvitis and granulomatous cheilitis in childhood: the need for Crohn disease workup. PMID- 21694544 TI - Infantile colitis as a novel presentation of familial Mediterranean fever responding to colchicine therapy. PMID- 21694545 TI - Successful treatment of eosinophilia-associated Budd-Chiari syndrome in a child. PMID- 21694546 TI - A 3-year-old with immunoglobulin G4-associated cholangitis. PMID- 21694548 TI - Re: What have we learned about acute pancreatitis in children? PMID- 21694549 TI - Safety and efficacy of high-dose acarbose treatment for dumping syndrome. AB - Dumping syndrome (DS) is a complication of Nissen fundoplication. Dietary strategies can ameliorate symptoms, but this approach is not always foolproof. Limited evidence reports the efficacy of acarbose for children who are unresponsive to feeding manipulations. We report 8 patients with DS aged between 7 and 24 months. In 4 of 8 nutritional strategies failed, and acarbose treatment was started. The initial dose was 25 mg for meals, and increased until postprandial glucose was stable. In 3 of 4 children the final dose was higher than previously reported, without adverse effects. Acarbose is useful to treat DS in cases of failure of dietary strategies. PMID- 21694550 TI - Oral choline supplementation in children with intestinal failure. AB - Choline deficiency leads to steatohepatitis, elevated transaminases, susceptibility to septic shock, and an increased risk of central catheter thrombosis. Children with intestinal failure (IF) are at risk for choline deficiency. In an unblinded, open-label study, we studied 7 children with IF on parenteral nutrition, measured their plasma free choline level, and, if low, supplemented enterally with adequate intake (AI) doses of choline. Four to 6 weeks later we remeasured their plasma free choline. Unlike adults, infants did not respond to oral choline supplementation at AI doses. Additionally, we have calculated plasma free choline percentiles versus age for normal children. PMID- 21694551 TI - Measurement of mucosal conductivity by MII is a potential marker of mucosal integrity restored in infants on acid-suppression therapy. AB - Esophageal multichannel intraluminal impedance (MII) allows measurement of the conductivity of adjacent contents. During esophageal rest, raw impedance levels may represent mucosal integrity. We assessed the influence of proton pump inhibitors (PPIs) on presumed mucosal integrity by reanalyzing raw MII levels of 21 pH-MII tracings from infants with gastroesophageal reflux (GER) disease before and after esomeprazole treatment. Median (interquartile range) esophageal MII increased during treatment, 938 (652-1304) versus 1885 (1360-2183) Ohm, P < 0.0001. Patients with lower MII levels demonstrated a larger increase on therapy: Spearman r2 = 0.28, P = 0.014. No correlation with standard GER parameters was observed. In conclusion, PPI therapy increases MII levels in infants with symptomatic GER disease. PMID- 21694552 TI - ESPGHAN presents first Distinguished Service Award at AGM 2010. PMID- 21694553 TI - Successful pregnancy after busulfan/cytoxan conditioning regimen for AML. AB - The number of patients who have had successful pregnancies following hematopoietic stem cell transplant during childhood remains under investigation. As the number of survivors increase and enter adulthood, we continue to learn more about fertility in these patients. In this case report we report the case of a 27 year-old female who had a normal full term delivery 19 years following a myeloablative autologous transplant for relapsed acute myelogenous leukemia. PMID- 21694554 TI - A retrospective study of malaria in pediatric oncology patients in Senegal. AB - We retrospectively studied the outcome of malaria infection in pediatric oncology patients presenting to a single institution in Senegal, West Africa over a 10 year period (2000 to 2009). We investigated whether myelosuppression (secondary to chemotherapy) was associated with increased case fatality from malaria. Anonymized clinical and laboratory data were recorded. Severe anemia was defined as hemoglobin less than 6 g/dL, leucopenia as total white blood cell count less than 4*109/L, neutropenia as less than 1*109/L, and "lymphopenia" as non neutrophil component less than 2.5*109/L. Primary outcome was death within 1 month of malaria diagnosis, from coma or multiple organ failure, in the absence of another infectious cause. Data analysis was carried out with SPSS (v16.0) using Fisher exact test (P<0.05, significant). Fifty-five malarial cases were confirmed in 54 patients (total 400 patients; overall incidence 14%). Four cases were excluded because of lack of outcome data. Of the remaining 51 episodes, at 1 month after malaria diagnosis, 46 recovered (90.2%) and 5 died (9.8%). There was no association with severe anemia, leucopenia, neutropenia, or lymphopenia (P=1.00, P=0.28, P=0.53, and P=0.22, respectively). Despite the high incidence of myelosuppression in pediatric oncology patients, we found no evidence that this was associated with increased fatality of malaria episodes. PMID- 21694555 TI - Should protein be included in CHO-based sports supplements? PMID- 21694556 TI - American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. AB - The purpose of this Position Stand is to provide guidance to professionals who counsel and prescribe individualized exercise to apparently healthy adults of all ages. These recommendations also may apply to adults with certain chronic diseases or disabilities, when appropriately evaluated and advised by a health professional. This document supersedes the 1998 American College of Sports Medicine (ACSM) Position Stand, "The Recommended Quantity and Quality of Exercise for Developing and Maintaining Cardiorespiratory and Muscular Fitness, and Flexibility in Healthy Adults." The scientific evidence demonstrating the beneficial effects of exercise is indisputable, and the benefits of exercise far outweigh the risks in most adults. A program of regular exercise that includes cardiorespiratory, resistance, flexibility, and neuromotor exercise training beyond activities of daily living to improve and maintain physical fitness and health is essential for most adults. The ACSM recommends that most adults engage in moderate-intensity cardiorespiratory exercise training for >=30 min.d on >=5 d.wk for a total of >=150 min.wk, vigorous-intensity cardiorespiratory exercise training for >=20 min.d on >=3 d.wk (>=75 min.wk), or a combination of moderate- and vigorous-intensity exercise to achieve a total energy expenditure of >=500 1000 MET.min.wk. On 2-3 d.wk, adults should also perform resistance exercises for each of the major muscle groups, and neuromotor exercise involving balance, agility, and coordination. Crucial to maintaining joint range of movement, completing a series of flexibility exercises for each the major muscle-tendon groups (a total of 60 s per exercise) on >=2 d.wk is recommended. The exercise program should be modified according to an individual's habitual physical activity, physical function, health status, exercise responses, and stated goals. Adults who are unable or unwilling to meet the exercise targets outlined here still can benefit from engaging in amounts of exercise less than recommended. In addition to exercising regularly, there are health benefits in concurrently reducing total time engaged in sedentary pursuits and also by interspersing frequent, short bouts of standing and physical activity between periods of sedentary activity, even in physically active adults. Behaviorally based exercise interventions, the use of behavior change strategies, supervision by an experienced fitness instructor, and exercise that is pleasant and enjoyable can improve adoption and adherence to prescribed exercise programs. Educating adults about and screening for signs and symptoms of CHD and gradual progression of exercise intensity and volume may reduce the risks of exercise. Consultations with a medical professional and diagnostic exercise testing for CHD are useful when clinically indicated but are not recommended for universal screening to enhance the safety of exercise. PMID- 21694557 TI - Comparison of Canadian medical graduates and international medical graduates in Canada: 1989-2007. AB - PURPOSE: To compare Canadian medical graduates (CMGs) and international medical graduates (IMGs) who completed postgraduate medical education in Canada from 1989 to 2007 by age, gender, specialty, and practice characteristics. METHOD: Data on all CMGs and IMGs who completed residencies or fellowships in Canada from 1989 to 2007 were extracted from the Canadian Post-M.D. Education Registry. Data from 1989-1993 and 2003-2007 were pooled for analysis. RESULTS: A total of 8,501 CMGs and 1,828 IMGs completed post-MD training at Canadian institutions between 1989 and 1993 inclusive; 7,734 CMGs and 1,879 IMGs completed such training between 2003 and 2007. From 1989-1993 to 2003-2007, the average age of CMGs increased from 29.8 to 31.1 years, and average age of IMGs increased from 36.1 to 37.0 years. From 1989-1993 to 2003-2007, the percentage of women increased from 41% (3,471/8,501) to 52% (4,016/7,734) and from 28% (509/1,828) to 42% (791/1,879) for CMGs and IMGs, respectively. The proportion of CMGs who trained in family medicine declined from 54% (4,568/8,501) to 38% (2,921/7,734) from 1989-1993 to 2003-2007. The percentage of IMGs who trained in family medicine increased from 19% (344/1,828) to 37% (699/1,879) during the same period. CONCLUSIONS: IMGs tended to be older, more likely to be men, and more likely to pursue family medicine than their CMG counterparts. These differences have implications in designing future health care policy and recruiting physicians from abroad. Other countries could look at their own physician demographics using this study's methods. PMID- 21694558 TI - Medical students' self-reported empathy and simulated patients' assessments of student empathy: an analysis by gender and ethnicity. AB - PURPOSE: To examine the contribution of students' gender and ethnicity to assessments by simulated patients (SPs) of medical students' empathy, and to compare the results with students' self-assessments of their own empathy. METHOD: In 2008, the authors used three different tools to assess the empathy of 248 third-year medical students. Students completed the Jefferson Scale of Physician Empathy (JSPE), and SPs completed the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE) and a global rating of empathy (GRE) in 10 objective structured clinical examination (OSCE) encounters. RESULTS: Of the 248 students who completed an end-of-third-year OSCE, 176 (71%) also completed the JSPE. Results showed that women scored higher than men on all three measures of empathy. The authors detected no significant difference between white and Asian American students on their self-report JSPE scores. However, the SPs' assessments on the JSPPPE and on the GRE were significantly lower, indicating less empathy, for Asian American students. CONCLUSIONS: A tool for SPs to assess students' empathy during an OSCE could be helpful for unmasking some deficits in empathy in students during the third year of medical school. Because the authors found no significant differences on self-reported empathy, the differences they observed in the SPs' assessments of white and Asian American students were unexpected and need further exploration. These findings call for investigation into the reasons for such differences so that OSCEs and other examinations comply with the guidelines for fairness in educational and psychological testing as recommended by professional testing organizations. PMID- 21694559 TI - Job characteristics and job satisfaction among physicians involved with research in the veterans health administration. AB - PURPOSE: Research conducted by physicians generates knowledge and has led to important advances and changes in the health care system. Physician retention is a concern facing many health care systems, and job satisfaction and attitudes play a role in retention. This study examined whether physicians who are involved with research have greater job satisfaction and more positive job characteristics perceptions. METHOD: Cross-sectional analysis examined this research question using a sample of 7,734 physicians across 135 medical centers in the Department of Veterans Affairs (VA) in 2008. Using existing survey results, ratings on job characteristics (job autonomy, skill development opportunities, work and family balance, and performance feedback) and job satisfaction were regressed on research involvement in a multilevel hierarchical generalized linear model. The model controlled for physician-level characteristics and organization-level characteristics related to research activities. RESULTS: Analyses revealed that physicians who spent part of their time involved with research activities were more likely to report favorable job characteristics ratings. Physicians involved with research were also more likely to be satisfied with their job. Physicians who worked in medical centers with greater levels of research funding were more likely to report favorable ratings for job characteristics and job satisfaction. CONCLUSIONS: Involvement with research was associated with more favorable job characteristics and job satisfaction perceptions among physicians in VA. Although there is a time and opportunity cost involved with research, medical centers that provide physicians with the opportunity to conduct research may have a more satisfied workforce. PMID- 21694560 TI - Enhancing the reliability of the multiple mini-interview for selecting prospective health care leaders. AB - PURPOSE: The David Geffen School of Medicine at UCLA Program in Medical Education (UCLA-PRIME) used a 12-station multiple mini-interview (MMI) circuit to assess applicants. The authors sought to determine the reliability of the MMI, potential bias in scores, and the degree of acceptance by interviewers and applicants. METHOD: In 2009, 28 interviewers interviewed a cohort of 76 applicants. An anonymous survey assessed interviewers' and applicants' satisfaction with the MMI process and perceived bias. Psychometric properties were determined with generalizability and decision theory. The process was repeated the following year with a new cohort of 78 applicants and minor modifications aimed at improving reliability. RESULTS: The MMI format was well received by both applicants and interviewers. No bias based on gender or disadvantaged status was found. The preliminary reliability of the MMI in 2009 was 0.58-lower than reported in previous studies-but improved in 2010 to 0.71 after an easy station was replaced with a more challenging one and a new scoring rubric was introduced. CONCLUSIONS: This interview technique proved to be reliable and was seen as transparent, uniform, and fair. The predictive validity of this process remains to be determined. PMID- 21694561 TI - Dropout rates in medical students at one school before and after the installation of admission tests in Austria. AB - PURPOSE: Admission to medical studies in Austria since academic year 2005-2006 has been regulated by admission tests. At the Medical University of Graz, an admission test focusing on secondary-school-level knowledge in natural sciences has been used for this purpose. The impact of this important change on dropout rates of female versus male students and older versus younger students is reported. METHOD: All 2,860 students admitted to the human medicine diploma program at the Medical University of Graz from academic years 2002-2003 to 2008 2009 were included. Nonparametric and semiparametric survival analysis techniques were employed to compare cumulative probability of dropout between demographic groups. RESULTS: Cumulative probability of dropout was significantly reduced in students selected by active admission procedure versus those admitted openly (P < .0001). Relative hazard ratio of selected versus openly admitted students was only 0.145 (95% CI, 0.106-0.198). Among openly admitted students, but not for selected ones, the cumulative probabilities for dropout were higher for females (P < .0001) and for older students (P < .0001). Generally, dropout hazard is highest during the second year of study. CONCLUSIONS: The introduction of admission testing significantly decreased the cumulative probability for dropout. In openly admitted students a significantly higher risk for dropout was found in female students and in older students, whereas no such effects can be detected after admission testing. Future research should focus on the sex dependence, with the aim of improving success rates among female applicants on the admission tests. PMID- 21694562 TI - Part-time physician faculty in a pediatrics department: a study of equity in compensation and academic advancement. AB - PURPOSE: To assess equity in compensation and academic advancement in an academic pediatrics department in which a large proportion of the physician faculty hold part-time appointments. METHOD: The authors analyzed anonymized data from Vanderbilt University School of Medicine Department of Pediatrics databases for physician faculty (faculty with MD or MD/PhD degrees) employed during July 1, 2007 to June 30, 2008. The primary outcomes were total compensation and years at assistant professor rank. They compared compensation and years at junior rank by part-time versus full-time status, controlling for gender, rank, track, years since first appointment as an assistant professor, and clinical productivity. RESULTS: Of the 119 physician faculty in the department, 112 met inclusion criteria. Among those 112 faculty, 23 (21%) were part-time and 89 (79%) were full time faculty. Part-time faculty were more likely than full-time faculty to be women (74% versus 28%, P < .001) and married (100% versus 84%, P = .042). Analyses accounting for gender, years since first appointment, rank, clinical productivity, and track did not demonstrate significant differences in compensation by part-time versus full-time status. In other adjusted analyses, faculty with part-time appointments spent an average of 2.48 more years as an assistant professor than did faculty with full-time appointments. CONCLUSIONS: Overall group differences in total compensation were not apparent in this department, but physician faculty with part-time appointments spent more time at the rank of assistant professor. This study provides a model for determining and analyzing compensation and effort to ensure equity and transparency across faculty. PMID- 21694563 TI - Introducing the Professionalism Mini-Evaluation Exercise (P-MEX) in Japan: results from a multicenter, cross-sectional study. AB - PURPOSE: Despite the growing importance of and interest in medical professionalism, there is no standardized tool for its measurement. The authors sought to verify the validity, reliability, and generalizability of the Professionalism Mini-Evaluation Exercise (P-MEX), a previously developed and tested tool, in the context of Japanese hospitals. METHOD: A multicenter, cross sectional evaluation study was performed to investigate the validity, reliability, and generalizability of the P-MEX in seven Japanese hospitals. In 2009-2010, 378 evaluators (attending physicians, nurses, peers, and junior residents) completed 360-degree assessments of 165 residents and fellows using the P-MEX. The content validity and criterion-related validity were examined, and the construct validity of the P-MEX was investigated by performing confirmatory factor analysis through a structural equation model. The reliability was tested using generalizability analysis. RESULTS: The contents of the P-MEX achieved good acceptance in a preliminary working group, and the poststudy survey revealed that 302 (79.9%) evaluators rated the P-MEX items as appropriate, indicating good content validity. The correlation coefficient between P-MEX scores and external criteria was 0.78 (P < .001), demonstrating good criterion-related validity. Confirmatory factor analysis verified high path coefficient (0.60-0.99) and adequate goodness of fit of the model. The generalizability analysis yielded a high dependability coefficient, suggesting good reliability, except when evaluators were peers or junior residents. CONCLUSIONS: Findings show evidence of adequate validity, reliability, and generalizability of the P-MEX in Japanese hospital settings. The P-MEX is the only evaluation tool for medical professionalism verified in both a Western and East Asian cultural context. PMID- 21694564 TI - The gender gap in high-impact psychiatry journals. AB - PURPOSE: The number of women in medicine generally and in psychiatry specifically has increased considerably during the past 40 years, but the lack of advancement of women in academic medicine is still concerning. This study explores the changes in female authorship patterns in three high-impact general psychiatric journals. METHOD: The authors categorized articles published in 1994 and 2007 by the Archives of General Psychiatry, The American Journal of Psychiatry, and The British Journal of Psychiatry according to the characteristics of the psychiatric research and the gender of each author for all articles. RESULTS: Overall, the percentage of female authors increased from 24.6% in 1994 to 33.6% in 2007. The authors found the greatest increases in the percentages of female authors in the areas most relevant to an academic career-first authorship (from 17.1% in 1994 to 35.3% in 2007) and original research articles (from 18.4% in 1994 to 42.7% in 2007)-and in articles on the topic with the most growth over the same time frame neuroimaging (from 14.7% in 1994 to 43.2% in 2007). The percentages of female authors of editorials rose from only 13.5% in 1994 to 26.2% in 2007. In 2007, women made up only 25% of the editorial boards of the journals under study (up from 16% in 1994). CONCLUSIONS: Despite considerable gains, women still are underrepresented in academic psychiatry, including in leadership positions. Ongoing efforts and interventions are required to promote further advances and gender equity. PMID- 21694565 TI - Faculty career tracks at U.S. medical schools. AB - PURPOSE: To describe faculty career tracks at U.S. MD-granting schools and explore which institutional characteristics are associated with the career tracks. METHOD: Between 2008 and 2009, the authors sought the faculty policies of 129 accredited MD-granting U.S. medical schools, through online searching and requests to faculty affairs representatives. An inventory of tenured and nontenured career tracks was conducted in the areas of teaching, research, and clinical care. Career track data were analyzed according to institutional characteristics. RESULTS: Complete data were collected from 98 schools (76%). On average, schools offered 3.6 career tracks to all faculty (range 1-8). Of the 353 career tracks identified, 210 were nontenured. Overall, schools offered more research tracks than education or clinical tracks. Of the 79 schools with clearly defined career tracks, 78 offered at least one clinical track; 34 offered at least one education track. Approximately 25% of the clinical tracks were tenured; 41% of the education tracks were tenured. Of the 98 schools, 61% used modified titles for faculty pursuing nontenure tracks. Schools that offered more career tracks were more likely to use modified titles for their nontenured clinical and research faculty. Schools with a smaller faculty size offered a greater number of clinical tracks, whereas community-based schools offered fewer clinical tracks. Research-intensive schools provided significantly more tenured clinical tracks. CONCLUSIONS: There is great variation in faculty tracks and policies across institutions. This research may help institutions craft their own faculty policies and help students, residents, and faculty in making career decisions. PMID- 21694566 TI - A national cohort study of MD-PhD graduates of medical schools with and without funding from the National Institute of General Medical Sciences' Medical Scientist Training Program. AB - PURPOSE: To determine whether prematriculation characteristics and career-setting preferences of MD-PhD graduates differ according to their schools' funding from the National Institute of General Medical Sciences' Medical Scientist Training Program (MSTP). METHOD: The Association of American Medical Colleges provided deidentified records for the national cohort of all 1993-2000 U.S. medical school matriculants, 3,180 of whom graduated with dual MD-PhD degrees by March 2, 2009. The authors examined prematriculation characteristics, educational outcomes, and career-setting preferences at graduation in association with MD-PhD program graduation from schools with long-standing MSTP-funded, recent MSTP-funded, and non-MSTP-funded programs. RESULTS: Of 3,142 MD-PhD graduates with prematriculation data, 30% were women and 36% were nonwhite. Graduates from long standing MSTP-funded schools (63% of 3,142 graduates) composed a more highly selective group academically (based on Medical College Admission Test scores) than did graduates from recent MSTP-funded (6%) and non-MSTP-funded schools (31%). Women and nonwhite graduates were more likely to have graduated from long standing MSTP-funded schools. Controlling for MSTP funding and other variables, graduates with total debt of $100,000 or more were more likely to indicate non research-related career-setting preferences (nonuniversity clinical practice: odds ratio [OR] 3.58, 95% confidence interval [CI] 1.86-6.87; undecided/other: OR 2.15, 95% CI 1.29-3.60). Neither gender nor race/ethnicity was independently associated with graduates' career-setting preferences. CONCLUSIONS: Women and nonwhite MD-PhD graduates more likely graduated from long-standing MSTP than non MSTP-funded schools. Controlling for institutional MSTP funding, MD-PhD graduates with high debt were more likely to indicate non-research-related career-setting preferences. PMID- 21694567 TI - Do deans and teaching hospital CEOs agree on what it takes to be a successful clinical department chair? AB - PURPOSE: To compare perceptions and perspectives of medical school deans and hospital chief executive officers (CEOs) regarding roles, responsibilities, and attributes of effective clinical department chairs. METHOD: In 2009, the authors surveyed the deans of 126 U.S. medical schools and the CEOs of the primary teaching hospitals in the schools' academic health centers. All were queried on 34 items about clinical department chair performance in six categories (mission prioritization, leadership responsibilities, leadership values, skill sets, barriers to success, and competitive differentiators). RESULTS: Eighty-four deans (67%) and 57 CEOs (45%) responded. Both groups ranked ensuring good patient care as the chair's primary responsibility; agreement between CEOs on that responsibility was much stronger than among deans (P < .01). CEOs placed greater emphasis on getting results (P < .01), whereas mentoring was a higher priority for deans (P < .01). CEOs identified the inability to work within budgeted resources as a barrier to chair success more than did deans (P < .01). CEOs reported that high-quality care and cutting-edge hospital technologies were keys to competitive distinction, whereas deans put more weight on clinical and translational research and educating future physicians. The majority of deans and CEOs rated the alignment and relationship between themselves and their counterpart as "excellent" or "good." CONCLUSIONS: Deans and their "partner" hospital CEOs agreed on most of the attributes, skills, and responsibilities characterizing the successful clinical department chair. CEOs were biased toward patient care, clinical quality, and results, whereas deans placed more emphasis on research, education, and mentoring. PMID- 21694568 TI - Reproducibility of literature search reporting in medical education reviews. AB - PURPOSE: Medical education literature has been found to lack key components of scientific reporting, including adequate descriptions of literature searches, thus preventing medical educators from replicating and building on previous scholarship. The purpose of this study was to examine the reproducibility of search strategies as reported in medical education literature reviews. METHOD: The authors searched for and identified literature reviews published in 2009 in Academic Medicine, Teaching and Learning in Medicine, and Medical Education. They searched for citations whose titles included the words "meta-analysis," "systematic literature review," "systematic review," or "literature review," or whose publication type MEDLINE listed as "meta-analysis" or "review." The authors created a checklist to identify key characteristics of literature searches and of literature search reporting within the full text of the reviews. The authors deemed searches reproducible only if the review reported both a search date and Boolean operators. RESULTS: Of the 34 reviews meeting the inclusion criteria, 19 (56%) explicitly described a literature search and mentioned MEDLINE; however, only 14 (41%) also mentioned searches of nonmedical databases. Eighteen reviews (53%) listed search terms, but only 6 (18%) listed Medical Subject Headings, and only 2 (6%) mentioned Boolean operators. Fifteen (44%) noted the use of limits. None of the reviews included reproducible searches. CONCLUSIONS: According to this analysis, literature search strategies in medical education reviews are highly variable and generally not reproducible. The authors provide recommendations to facilitate future high-quality, transparent, and reproducible literature searches. PMID- 21694569 TI - Toward shared decision making: using the OPTION scale to analyze resident-patient consultations in family medicine. AB - PURPOSE: Do residents in family medicine practice share decision making with patients during consultations? This study used a validated scale to score family medicine residents' shared decision-making (SDM) skills in primary care consultations and to determine whether residents' demographic characteristics were correlated with their scores. METHOD: Between January 2009 and April 2010 at two Canadian academic health centers, the authors recruited unique dyads of patients consulting in primary care and family medicine residents. They recorded, transcribed, and assessed consultations using the Observing Patient Involvement in Decision Making (OPTION) scale, which measures 12 SDM-specific behaviors on a scale of 0% to 100% (high score = better SDM). They calculated descriptive and inferential statistics for the scores. RESULTS: From 212 eligible residents, the authors recruited 152 unique patient-resident dyads (participation rate = 75%): 68 dyads from 13 clinics in London, Ontario, and 84 from six family medicine units in Quebec City, Quebec. The mean global OPTION score was 24% +/- 8%; the mean score for each of the 12 items ranged from 4% to 37%. Five of the 12 behaviors obtained a mean score below "a minimal attempt is made to exhibit the behavior" (i.e., <25%). There was a positive correlation between the score and the duration of the consultation (r = 0.24, P = .003), with longer consultations producing higher scores. CONCLUSIONS: Participating family medicine residents have not integrated SDM behaviors, which may also pertain to residencies elsewhere. Interventions are required to foster family medicine residents' practice of SDM. PMID- 21694570 TI - Empathic and sympathetic orientations toward patient care: conceptualization, measurement, and psychometrics. AB - PURPOSE: To develop instruments for measuring empathic and sympathetic orientations in patient care and to provide evidence in support of their psychometrics. METHOD: Third-year medical students at Jefferson Medical College responded to four clinical vignettes in 2010. For each vignette, students indicated the extent of their agreement with an empathic response (conveying their understanding of patients' concerns) and with a sympathetic response (sharing patients' feelings). The authors calculated, based on students' responses to the clinical vignettes, two measures of empathic and sympathetic orientation. Students also completed the Jefferson Scale of Empathy (JSE) and the Interpersonal Reactivity Index (IRI). RESULTS: Of the 258 students in the class, 201 (78%) responded to all four vignettes and completed the JSE and IRI. The authors confirmed construct validity of the measures of empathic and sympathetic orientation through factor analysis. The empathic orientation was significantly associated with the measure of empathy (as measured by the JSE) but not with measures of sympathy (as measured by specific scales of the IRI). Conversely, sympathetic orientation was significantly associated with measures of sympathy. Thus, these results support the validity of the empathic and sympathetic orientation measures as assessed by four clinical vignettes. Coefficient alphas for the two measures were, respectively, 0.79 and 0.84. CONCLUSIONS: The validated measures of empathic and sympathetic orientation provide research opportunities to enhance the understanding of the contributions of empathy and sympathy to physicians' competence and patient outcomes. PMID- 21694571 TI - Exploring the psychometric properties of the humanistic teaching practices effectiveness questionnaire, an instrument to measure the humanistic qualities of medical teachers. AB - PURPOSE: To describe the development and psychometric properties of the Humanistic Teaching Practices Effectiveness Questionnaire (HTPE), an instrument that measures the humanistic skills of attending physicians within an academic health center (AHC) department of medicine. METHOD: From August 2005 through March 2007, the authors distributed the HTPE, along with other standard faculty evaluations, to internal medicine and medicine/pediatrics residents at a single midwestern AHC (the Indiana University School of Medicine), in an effort to assess the instrument's validity and reliability. RESULTS: The data set included 886 completed HTPE questionnaires, representing 73% of the 1,212 administered. Exploratory factor analysis demonstrated a single major factor with high internal consistency reliability. The correlation between the HTPE and routine teaching evaluation tools was low. Interrater reliability was only fair (0.17). Total HTPE scores were not significantly different between female and male attending physicians. CONCLUSIONS: The 10-item HTPE provides reliable and valid information on the humanistic teaching practices of internal medicine faculty at a single AHC. The ability to reliably measure these practices provides a framework for understanding and promoting the skills to effectively demonstrate humanism at the bedside and in the clinic. The low correlation between the HTPE and other faculty evaluations suggests that the former measures a unique domain in attending physicians' performance. The HTPE items cluster together as a single construct allowing educators to choose fewer items without compromising reliability; however, moderate interrater reliability indicates that multiple raters are required to produce reliable scores. PMID- 21694572 TI - Differences in disease presentation, treatment outcomes, and toxicities in African American patients treated with radiation therapy for prostate cancer. AB - OBJECTIVES: We analyzed differences in disease presentation, outcomes, and toxicities between African American (AA) and White (W) men treated with definitive radiation therapy for their prostate cancer. METHODS: Three thousand one hundred eighty cases of prostate cancer treated with various radiation modalities at a single institution were reviewed. The cohort consisted of 92% W patients and 8% AA patients. Clinical and pathologic characteristics at presentation, treatment outcomes, and related toxicities were analyzed between the 2 groups. The median follow-up was 6.6 years (0.6 to 22.4 y). RESULTS: At presentation, AA men were younger (P<0.001) and more likely to have a Gleason score of >=7 (47.9% vs. 39.2%, P=0.006). No difference in the 5 or 10-year rates of biochemical failure, disease-free survival, or distant metastases were noted. Although there was a trend for improved 10-year overall survival for AA men (65.3% vs. 57.4%, P=0.06), cause-specific survival was significantly improved at 10 years (98.6% vs. 90.6%, P=0.002). Similar findings were seen when controlling for radiation therapy dose, the use of hormonal therapy, and modality of radiation therapy used. Overall, genitourinary/gastrointestinal toxicities were similar regardless of the modality used. CONCLUSIONS: Despite differences in presenting characteristics, AA men did not have inferior clinical outcomes but rather improved cause-specific survival when treated with standard of care radiation therapy. Regardless of the treatment modality used, toxicities between AA and W men were comparable. PMID- 21694573 TI - Bortezomib-cyclophosphamide-dexamethasone for relapsing multiple myeloma. AB - OBJECTIVES: In vitro studies have shown synergistic antimyeloma effects with the combination of bortezomib and alkylating agents. Combinations of bortezomib, cyclophosphamide, and dexamethasone are rational with the prospect of superior antitumor activity with independent toxicity. METHODS: Between December 2004 and April 2007, we treated 44 patients with relapsing multiple myeloma with the combination of bortezomib 1.3 mg/m intravenously on days 1, 4, 8, 11; dexamethasone 20 mg/m orally daily for 4 days beginning on days 1, 9 and 17; and cyclophosphamide 70 mg/m orally twice daily for 4 days. A second course was given 1 month later. RESULTS: Clinical response was observed in 32 patients (73%) including 26 with disease in partial remission (59%), and 6 with disease in complete remission (14%). Side effects were uncommon and mild, except for grade 3 thrombocytopenia in 15%, infection in 5% and constipation in 2% of patients. The median remission time of responding patients was 10 months that contributed to significantly longer median survival for patients with responsive disease (33 mo) than for those with unresponsive disease (12 mo) (P < 0.01). CONCLUSION: Bortezomib-cyclophosphamide-dexamethasone was an effective, well-tolerated combination for the treatment of relapsing multiple myeloma. PMID- 21694574 TI - Androgen deprivation therapy and definitive radiotherapy for prostate cancer. AB - Adjuvant androgen deprivation therapy (ADT) improves outcomes of patients receiving definitive radiotherapy (RT) for local-regionally advanced prostate cancer. However, patients in most randomized trials had more advanced disease than observed in many practices and were treated with suboptimal RT doses. Although data are conflicting, long-term ADT likely has adverse side-effects in patients with comorbidities. We recommend 6 months of ADT monotherapy with gonadotropin-releasing hormone agonist and RT for patients with high-risk prostate cancer (>=T2c, Gleason Score 8 to 10, and/or prostate-specific antigen >=20 ng/mL) with minimal or no comorbidities. Adjuvant ADT for unfavorable intermediate-risk patients with a Gleason Score of 4+3=7 is also reasonable. PMID- 21694575 TI - Does adrenal size matter? PMID- 21694576 TI - Randomized controlled trial of dual antiplatelet therapy in patients undergoing surgery for critical limb ischemia. PMID- 21694577 TI - Do preoperative inflammatory markers impact on outcome after liver transplantation for hepatocellular carcinoma? PMID- 21694579 TI - Limitations regarding double-blinding, adherence to the intention to treat principle, and postoperative dosage of paracetamol. PMID- 21694580 TI - A novel and potentially unifying mechanism for shock induced early coagulopathy. PMID- 21694581 TI - Preoperative glucocorticoid use in major abdominal surgery: systematic review and meta-analysis of randomized trials. AB - OBJECTIVE: To determine the clinical safety and efficacy of preoperative glucocorticoid (GC) administration in major abdominal surgery with regards to short term outcomes. BACKGROUND: Previous randomized controlled trials (RCTs) in major abdominal surgery have displayed conflicting results regarding the short term benefits of preoperative GC administration. Importantly, the safety of this intervention has not been conclusively determined. METHODS: A systematic review and quantitative meta-analysis was conducted of all RCTs exploring preoperative GC administration in major abdominal surgery for the endpoints of complications, hospital length of stay (LOS) and serum IL-6 on postoperative day one. Subset analyses by procedure were planned "a priori." RESULTS: Eleven RCTs of moderate quality, comprising 439 patients in total, were included in the final analysis. Preoperative GC use decreased complications (OR = 0.37; 95% CI, 0.21-0.64; P < 0.01), LOS (mean = 1.97 days; 95% CI, -3.33 to -0.61; P = 0.01), and serum IL-6 (mean: -55 pg/mL; 95% CI, -82.30 to -27.91; P < 0.01). Preoperative GCs decreased complications in hepatic resection (OR = 0.28; 95% CI, 0.14-0.55; P < 0.01) and mean LOS (mean LOS: -2.66; 95% CI, -5.01 to -0.32; P = 0.03). GCs reduced mean LOS in patients undergoing colorectal surgery (mean LOS: -0.98; 95% CI, -1.67 to 0.27; P = 0.01). There was no difference in complication rates (OR: 0.45; 95% CI, 0.16-1.32; P = 0.15) or anastomotic leaks specifically. CONCLUSIONS: Preoperative administration of GCs decreases complications and LOS after major abdominal surgery as a likely consequence of attenuating the postsurgical inflammatory response. There is no evidence of increased complications in colorectal surgery. PMID- 21694582 TI - Usefulness of contrast-enhanced intraoperative ultrasound using Sonazoid in patients with hepatocellular carcinoma. AB - OBJECTIVE: To assess the usefulness of contrast-enhanced intraoperative ultrasound (CE-IOUS) using Sonazoid (gaseous perflubutane) in patients with hepatocellular carcinoma (HCC). BACKGROUND: Contrast-enhanced intraoperative ultrasound using Sonazoid, a novel ultrasonic contrast agent enabling Kupffer imaging, may enable differentiation of HCC among new focal liver lesions found during fundamental intraoperative ultrasound (fundamental-NFLLs). METHODS: Between February 2007 and February 2009, a total of 192 consecutive patients were enrolled. Fundamental intraoperative ultrasound and CE-IOUS were performed successively after laparotomy. The vascularity of 1 representative lesion was examined in harmonic mode for approximately 1 minute after the intravenous injection of Sonazoid (vascular phase). Approximately 15 minutes after the vascular phase, total liver scanning in the harmonic mode was commenced (Kupffer phase). One additional injection of Sonazoid was allowed to examine the vascularity of another lesion, if necessary. A tentative diagnosis of HCC was made when a lesion was either hypervascular during the vascular phase or hypoechoic during the Kupffer phase. A final diagnosis of HCC was made on the basis of the results of a histological examination or dynamic computed tomography findings obtained during the 12-month postoperative period. RESULTS: Seventy-nine fundamental-NFLLs were found in 50 patients (26%), 17 (22%) of which were finally diagnosed as HCC. The sensitivity, specificity, and accuracy of CE-IOUS for differentiating HCC among fundamental-NFLLs were 65%, 94%, and 87%, respectively. Contrast-enhanced intraoperative ultrasound identified 21 additional new hypoechoic lesions in 16 patients, of which 14 lesions (67%) in 11 patients were finally diagnosed as HCC. This prospective study protocol was approved by the institutional review board of the Tokyo University Hospital. An English-language summary of the protocol was submitted (registration ID: UMIN000003046) to the Clinical Trials Registry managed by the University Hospital Medical Information Network in Japan (http://www.umin.ac.jp/ctr/index.htm). CONCLUSIONS: With help of CE-IOUS using Sonazoid, more accurate intraoperative staging for HCC can be performed. PMID- 21694583 TI - Influence of margins on overall survival after hepatic resection for colorectal metastasis: a meta-analysis. AB - OBJECTIVE: The aim of our study was to conduct a meta-analysis of reports published on hepatic resection for colorectal liver metastasis (CRLM) and determine whether a negative margin of 1 cm or more confers a survival advantage over subcentimeter negative margins. BACKGROUND: Surgical margin is an important prognostic factor in patients undergoing hepatic resection for CRLM. Although there is a consensus that positive margins portend a worse outcome than negative margins, the extent of negative margins remains controversial. METHODS: A PubMed search was conducted to identify articles on hepatic resection for CRLM. The 357 initially located articles were screened to identify 90 articles of interest. The texts of these 90 articles were completely reviewed to finalize 18 articles for inclusion in the study on the basis of absolute and relative inclusion criteria. Patients with positive margins were excluded from the meta-analysis. Meta analysis was performed using STATA 9.2 statistical software. RESULTS: A total of 4821 patients with negative margins from the 18 studies were included in the meta analysis. The overall 5-year survival for all patients was 41% [95% confidence interval (CI), 40%-43%]. The overall 5-year survival for the >=1 cm negative margin subgroup was 46% (95% CI, 44%-48%) when compared with 38% (95% CI, 36% 40%) for less than 1 cm negative margin subgroup. The odds ratio for 1-cm or more negative margins was found to be 0.773 (95% CI, 0.638-0.938; P = 0.009) when compared with less than 1 cm negative margins. CONCLUSIONS: The results of this meta-analysis demonstrate that in patients undergoing hepatic resection for CRLM, a negative margin of 1 cm or more confers a survival advantage when compared with subcentimeter negative margins. PMID- 21694585 TI - Method for technology-delivered healthcare measures. AB - Current healthcare literature lacks development and evaluation methods for research and practice measures administered by technology. Researchers with varying levels of informatics experience are developing technology-delivered measures because of the numerous advantages they offer. Hasty development of technology-delivered measures can present issues that negatively influence administration and psychometric properties. The Method for Technology-delivered Healthcare Measures is designed to systematically guide the development and evaluation of technology-delivered measures. The five-step Method for Technology delivered Healthcare Measures includes establishment of content, e-Health literacy, technology delivery, expert usability, and participant usability. Background information and Method for Technology-delivered Healthcare Measures steps are detailed. PMID- 21694584 TI - Effects of selective dopaminergic compounds on a delay-discounting task. AB - Impulsivity is widely regarded as a multidimensional trait that encompasses two or more distinct patterns of behavior, and dopaminergic systems are implicated in the expression of impulsive behavior in both humans and animal subjects. Impulsive choice, or the tendency to choose rewards associated with relatively little or no delay, has been extensively studied in humans and animal subjects using delay-discounting tasks. Here, delay-discounting procedures were used to assess the effects of receptor-selective dopaminergic agonists, antagonists, and dopamine transporter ligands on choices of immediate versus delayed sucrose pellets. The effects of d-amphetamine, GBR 12909, apomorphine, SKF 81297, sumanirole, pramipexole, ABT-724, SCH 23390, L-741,626, PG01037, and L-745,870 were assessed in 24 Sprague-Dawley rats. The only drugs to affect impulsive choice selectively without altering undelayed choice were the D1-like antagonist, SCH 23390 (0.01 mg/kg), and the D4 partial agonist, ABT-724 (3.2 mg/kg), which both increased impulsive choice. The shared effects of these compounds may be explained by their localization within the prefrontal cortex on different groups of neurons. None of the selective agonists and antagonists tested reduced impulsive choice, so further research is needed to determine if direct dopaminergic agonists or antagonists may be therapeutically useful in the treatment of impulse-control disorders. PMID- 21694586 TI - Sports-related injuries in youth athletes: is overscheduling a risk factor? AB - OBJECTIVE: To examine the association between "overscheduling" and sports-related overuse and acute injuries in young athletes and to identify other potential contributing factors to create a working definition for "overscheduling injury." DESIGN: Survey. SETTING: Six university-based sports medicine clinics in North America. PARTICIPANTS: Athletes aged 6 to 18 years (13.8 +/- 2.6) and their parents and pediatric sports medicine-trained physicians. INTERVENTIONS: Questionnaires developed from literature review and expert consensus to investigate overscheduling and sports-related injuries were completed over a 3 month period. MAIN OUTCOME MEASURES: Physician's clinical diagnosis and injury categorization: acute not fatigue related (AI), overuse not fatigue related (OI), acute fatigue related (AFI), or overuse fatigue related (OFI). RESULTS: Overall, 360 questionnaires were completed (84% response rate). Overuse not fatigue related injuries were encountered most often (44.7%), compared with AI (41.9%) and OFI (9.7%). Number of practices within 48 hours before injury was higher (1.7 +/- 1.5) for athletes with OI versus those with AI (1.3 +/- 1.4; P = 0.025). Athlete or parent perception of excessive play/training without adequate rest in the days before the injury was related to overuse (P = 0.016) and fatigue-related injuries (P = 0.010). Fatigue-related injuries were related to sleeping <=6 hours the night before the injury (P = 0.028). CONCLUSIONS: When scheduling youth sporting events, potential activity volume and intensity over any 48-hour period, recovery time between all training and competition bouts, and potential between day sleep time (>= 7 hours) should be considered to optimize safety. An overscheduling injury can be defined as an injury related to excessive planned physical activity without adequate time for rest and recovery, including between training sessions/competitions and consecutive days. PMID- 21694587 TI - Equestrian injuries caused by horse kicks: first results of a prospective multicenter study. AB - OBJECTIVE: To analyze horse-related accidents caused by hoof kicks. DESIGN: Prospective study to evaluate hoof kick-related accidents. SETTING: Multicenter study, including 9 trauma centers in Hamburg, Germany. PATIENTS: Patients who were treated as the result of a hoof kick between January 1, 2010, and May 1, 2010, were included in the study. MAIN OUTCOME MEASURES: Horse and rider qualifications, riders' use of protective equipment, location and activity at time of accident, mechanism of injury, injuries sustained, and treatment required for these injuries. RESULTS: Twenty-four equestrians received hoof kicks. The average age was 22.6 years (range, 7-34 years). All accidents (100%) occurred while the equestrians were handing or grooming the horse. Two riders (8.3%) wore a helmet at time of accident. Sixteen riders (66.7%) suffered orbital, midface, or mandible fractures; 8 riders (33.3%) had injuries on other parts of the body. CONCLUSIONS: Hoof kick injuries account for a significant proportion of equine injuries and occur when riders are dismounted, most frequently when grooming without wearing protective equipment. Head and facial injuries occur most frequently and suggest that mandatory helmet and facial grill use should be considered during all horse-related activities. PMID- 21694588 TI - Anterior cruciate ligament reconstruction: a multicenter prospective cohort study evaluating 3 different grafts using same bone drilling method. AB - OBJECTIVE: To compare the clinical outcomes after anterior cruciate ligament (ACL) reconstruction with bone-patellar tendon-bone autograft (BPTBAu), BPTB allograft (BPTBAll), or hamstring (semitendinosus-gracilis) tendon autograft (HTAu), performing bone drilling with same methods in terms of transtibial drilling, orientation, positioning, and width of femoral and tibial tunnels. DESIGN: Multicenter prospective cohort study (level of evidence II). SETTING: Departments of Orthopedic Surgery of Centro Medico Teknon (Barcelona, Spain) Clinica Universitaria de Navarra (Navarra, Spain), and Clinica FREMAP (Gijon, Spain). PATIENTS: All patients with ACL tears attending 3 different institutions between January 2004 and June 2006 were approached for eligibility and those meeting inclusion criteria finally participated in this study. INTERVENTION: Each institution was assigned to perform a specific surgical technique. Patients were prospectively followed after undergoing ACL reconstruction with BPTBAu, BPTBAll, or HTAu, with a minimum follow-up of 24 months. MAIN OUTCOME MEASURES: Included knee laxity and International Knee Documentation Committee (IKDC) score. Knee laxity was assessed with the KT-1000 arthrometer (evaluated with neutral and external rotation positions) and both Lachman and pivot shift tests. Additional outcomes included main symptoms (anterior knee pain, swelling, crepitation, and instability), disturbance in knee sensation, visual analogue scale (VAS) for satisfaction with surgery, range of motion (ROM), and isokinetic knee strength. RESULTS: There were no significant differences among the 3 groups for any of the clinical outcomes, except for a slightly greater KT-1000-measured knee laxity in external rotation in the BPTBAu compared with the other groups. All patients demonstrated grade A or B of the IKDC. The mean VAS for satisfaction with surgery in all patients was 8.5. CONCLUSIONS: The selection of the surgical technique for ACL reconstruction may be based on the surgeon's preferences. PMID- 21694589 TI - Are splanchnic hemodynamics related to the development of gastrointestinal symptoms in Ironman triathletes? A prospective cohort study. AB - OBJECTIVE: To determine if prerace to postrace changes in superior mesenteric artery (SMA) and coeliac artery hemodynamics were related to the development of gastrointestinal (GI) symptoms during a triathlon. DESIGN: Prospective cohort study. SETTING: Field study at an international Ironman Triathlon. PARTICIPANTS: Fifty-nine Ironman triathletes of whom 59% (n = 35) reported GI symptoms (GI group) during the race and 41% (n = 24) remained asymptomatic (CON group). ASSESSMENT OF RISK FACTORS: Prerace questionnaire (personal details, racing and training history, personal general medical history, and medication) and splanchnic hemodynamics. MAIN OUTCOME MEASURES: Prerace and postrace measurements of splanchnic hemodynamics [artery diameter, systolic velocity, diastolic velocity, and resistive index (RI) of the SMA and coeliac artery] using duplex Doppler ultrasound. RESULTS: There was a significant decrease in the diameter of the SMA after the race (P = 0.003) and a significant decrease in the RI of the SMA and coeliac artery (P < 0.001) in both the GI and CON groups, but there were no significant differences between the groups. The only significant risk factor for the development of GI symptoms was younger age (P = 0.041). Other risk factors, including high-intensity exercise, poorly trained athlete, and medication use, were not associated with the development of GI symptoms. CONCLUSIONS: The hypothesis that altered blood flow is related to the development of GI symptoms in endurance athletes is not supported by the results of this study. Other mechanisms for GI symptoms associated with endurance exercise should be investigated. PMID- 21694590 TI - Premature osteoarthritis of the hip in unicyclists: two case reports. PMID- 21694591 TI - Time to stability differences between male and female dancers after landing from a jump on flat and inclined floors. AB - OBJECTIVE: To determine the effect of gender and inclined floor on time to stability (TTS) after landing from a vertical jump. DESIGN: This study used a repeated measures design with male and female professional dancers landing on a flat and 4 inclined floors. A repeated measures univariate analysis of variance (gender * floor) was performed on TTS in the anterior-posterior and medial lateral directions. SETTING: Biomechanics laboratory. PARTICIPANTS: Twenty-three female and 13 male professional dancers. INDEPENDENT VARIABLES: Gender and floor inclination (flat, posterior, anterior, lateral, and medial). MAIN OUTCOME MEASURES: Time to stability in the anterior-posterior and medial-lateral directions after landing from a vertical jump. RESULTS: Female dancers exhibited longer TTS in both directions (P <= 0.05). Floor inclination or the interaction of gender * floor did not have an effect on TTS (P > 0.3). CONCLUSIONS: Female dancers exhibited longer TTS after landing from a vertical jump compared with their male counterparts. This balance difference may be a factor related to the higher rate of ankle sprain among female dancers. Additionally, professional dancers exhibited similar TTS when landing on flat and inclined floors. PMID- 21694592 TI - Patterns of mouthguard utilization among atom and pee wee minor ice hockey players: a pilot study. AB - OBJECTIVE: To determine if youth hockey players wear their mouthguards properly, and if not, why? DESIGN: Descriptive cross-sectional study. SETTING: Tecumseh Shoreline Minor Hockey Association, Tecumseh, Ontario, Canada, during the 2007 2008 season. PARTICIPANTS: Subjects were 180 travel hockey players of the Tecumseh Shoreline Minor Hockey Association at the Atom or Pee Wee level (aged 9 12 y) or their competitors. ASSESSMENT OF RISK FACTORS: Players were asked to complete a survey addressing mouthguard wear under their coach's supervision. MAIN OUTCOME MEASURES: The type of mouthguard, whether mouthguards were worn at all and worn properly, and the reasons for noncompliance. The incidence of concussion and association to mouthguard-wearing tendencies were also assessed. RESULTS: Sixty-eight percent [95% confidence interval (CI), 60.4%-74.5%] of subjects always wore their mouthguards, but only 31.7% (95% CI, 25.0%-39.0%) wore them properly during games and 51.1% (95% CI, 43.6%-58.6%) during practice. Custom-made mouthguards were most likely to be worn properly, followed by boil and-bite and stock-type guards. Younger players wore mouthguards more consistently than older players (P < 0.01). Reasons for not wearing the guard included the following: 43.0% (95% CI, 35.4%-50.4%) of subjects felt it made talking difficult, 27.4% (95% CI, 20.9%-34.3%) felt it uncomfortable, 23.9% (95% CI, 17.9%-30.8%) felt it made breathing difficult, and 12.4% (95% CI, 8.3%-17.9%) thought it did not fit correctly. The incidence of concussion was 17.8%, but the study was underpowered for any association with mouthguard type. CONCLUSIONS: Even when mouthguards are mandated to be worn in a children's travel hockey league, young players self-report that they routinely fail to wear them properly. PMID- 21694593 TI - Knee flexor muscle responses under fatigue after harvesting the hamstrings for anterior cruciate ligament reconstruction. [corrected]. AB - OBJECTIVE: To investigate if harvesting of semitendinosus (ST) and gracilis for anterior cruciate ligament (ACL) reconstruction will have an effect in coordinative firing pattern of the hamstrings under fatigue. We hypothesized that fatigue will increase the electromechanical delay (EMD) of the hamstrings on the harvested site and impair the synchronization between the medial and lateral hamstrings, in terms of muscle activity onsets. DESIGN: Prospective nonrandomized study. SETTING: Institutional. PATIENTS: Twelve ACL reconstructed patients with hamstrings, 2 years postoperatively. INTERVENTIONS: The patients performed a fatigue protocol with 25 continuous maximal isometric voluntary contractions of 8 second duration with 2-second intervals. MAIN OUTCOME MEASURES: The electromyography activity of biceps femoris (BF) and ST was recorded bilaterally and simultaneously with the torque measurements. The dependent variable examined was the EMD difference between BF and ST (muscle activation pattern). RESULTS: The fatigue protocol caused significant differences for the EMD values for both the intact and the reconstructed leg, demonstrating the influence of fatigue in EMD. However, the synchronization pattern between the medial and lateral hamstrings did not change significantly throughout the fatiguing protocol, revealing a balanced effect of fatigue. CONCLUSIONS: Although the EMD of ST and BF was significantly increased due to fatigue, as expected, their synchronization pattern as identified by the difference in their EMDs remained the same. Thus, the reconstructed knee responded in a balanced manner and the hamstrings firing pattern remained the same, despite the intervention to the ST tendon. PMID- 21694594 TI - Sport-related concussions: knowledge translation among minor hockey coaches. AB - OBJECTIVE: The objective of this study was to investigate minor hockey coaches' knowledge base of sport-related concussions. DESIGN: Cross-sectional survey. SETTING: Subjects independently completed the written survey at preseason organizational meetings. PARTICIPANTS: One hundred seventy-eight active coaches spanning 5 age levels (ages 5-15 years). Coaches reported 2.62 +/- 3.73 years of coaching experience. MAIN OUTCOME MEASURES: Resources where coaches obtained information about concussions, perceptions of variables associated with concussions, knowledge level of issues associated with concussions, and decision making practices. RESULTS: Newspapers and magazines were the most frequent source of information regarding concussions, yet were rated as not very helpful. Family physicians were less frequently sought but were rated as most helpful. A majority of coaches reported limited knowledge about concussions but rated this knowledge as being important. There was a significant relationship between head coaching experience and concussion knowledge [R = 0.09, F3,156 = 4.41, P = 0.005]. Most coaches demonstrated a good knowledge base of common issues associated with concussions, and a majority of individuals correctly identified return-to-play practices. CONCLUSIONS: A majority of minor hockey coaches correctly recognized and understood issues related to sport-related concussions. Results suggested that knowledge translation through various formal and informal sources has had a positive effect. However, a majority of coaches reported having limited knowledge about concussions yet consider it an important topic. PMID- 21694595 TI - Management and outcome of microbial anterior scleritis. AB - PURPOSE: To evaluate the prevalence, predisposing factors, and outcomes of bacterial and fungal scleritis. METHODS: We reviewed the clinical findings, therapeutic interventions, and visual outcomes of patients with suppurative scleral inflammation without preceding microbial keratitis who had microorganisms isolated from scleral scrapings. DESIGN: Retrospective interventional case series. RESULTS: Of 349 patients with scleritis diagnosed from 1999 to 2009, 6 adults (1.7%) presented with suppurative inflammation of the anterior sclera due to Pseudomonas aeruginosa (2), Streptococcus pneumoniae (2), Staphylococcus aureus (1), and Scedosporium apiospermum/Pseudallescheria boydii (1). Each had ocular surgery of the affected eye before presentation. Intraocular extension occurred in 2 eyes. After local and systemic antimicrobial therapy, all improved without evisceration or enucleation, and 4 attained vision of 20/60 or better. CONCLUSIONS: Bacterial or fungal scleritis is an uncommon ocular infection that can belatedly follow anterior segment procedures. Antimicrobial therapy and surgical intervention can successfully control progressive suppuration and reduce vision-limiting complications. PMID- 21694596 TI - Three-month clinical outcomes with static and dynamic cyclotorsion correction using the SCHWIND AMARIS. AB - PURPOSE: To evaluate intraoperative static and dynamic cyclotorsions and postoperative outcomes on astigmatism and high-order aberration in astigmatic or aberrated eyes that underwent laser in situ keratomileusis treatments with advanced cyclotorsion control using the SCHWIND AMARIS. METHODS: Fifty eyes (30 for aberration neutral and 20 for corneal wavefront) were treated. Treatments were planned with Custom Ablation Manager and ablations were performed using the SCHWIND AMARIS. Laser in situ keratomileusis flaps were cut with an LDV femtosecond laser. Cyclotorsional movements were evaluated for static cyclotorsion component (SCC) for mean and repeatability, and for dynamic cyclotorsion component (DCC) for mean and amplitude. Clinical outcomes were evaluated for predictability, refractive outcome, safety, and wavefront aberration. RESULTS: Registration rates were 90% for SCC and 98% for DCC. SCC was within +/- 5 degrees in 64% of cases. Repeatability of SCC was +/- 1 degree in 88% of cases. Mean DCC was within +/- 1 degree in 98% of cases, partly compensating for SCC. DCC amplitude was within +/- 2 degrees in 84% of cases. At 3-month follow-up, 88% of eyes were within +/- 0.50 diopter (D) of astigmatism. Mean defocus was -0.06 +/- 0.24 D and astigmatism was 0.27 +/- 0.20 D. Best spectacle-corrected visual acuity improved in 42% of eyes versus 2% losing 1 line. In corneal wavefront-customized treatments, coma, trefoil, spherical aberration, and root mean square high-order magnitudes at 6-mm analysis diameter were reduced by -0.04, -0.13, -0.04, and -0.10 MUm, respectively. CONCLUSIONS: Laser in situ keratomileusis with advanced cyclotorsion compensation using the SCHWIND AMARIS is safe and predictable and yields superior visual outcomes. Refractions and high-order aberrations were reduced to subclinical values without applying additional nomograms, showing the excellent performance of the system. PMID- 21694597 TI - Retrephination of eccentric donor graft for descemet stripping automated endothelial keratoplasty. AB - We describe a technique of intraoperative eccentric retrephination of Descemet stripping automated endothelial keratoplasty (DSAEK) donor graft to avoid the presence of epithelium on the graft lenticule. Trephination of the DSAEK graft may prove to be very challenging for surgeons, especially when flap diameter is small; this can result in an eccentric trephination and the presence of epithelium on the graft. Insertion of epithelium with DSAEK donor graft into the anterior chamber could result in epithelial ingrowth and downgrowth, complications that may lead to poor visual outcomes, graft detachment, and anterior chamber angle closure. A second eccentric retrephination is a simple and easy-to-perform intraoperative surgical step that could avoid the presence of corneal epithelium on the DSAEK donor graft. PMID- 21694598 TI - The AMA method of estimation of hearing disability: a validation study. AB - OBJECTIVE: To test the assumptions of the 1979 American Medical Association (AMA) method for estimation of hearing disability. DESIGN: One thousand and one patients attending five regional audiology centers competed conventional audiometric testing and the Communication Profile for the Hearing Impaired. A Communication Performance (CP) score calculated from scales of the Communication Profile for the Hearing Impaired served as the gold standard for self-assessed hearing disability. Pure-tone thresholds and word recognition scores (WRSs), and combinations thereof, were compared with the CP scores using correlation and multiple regression analysis. RESULTS: Several different better-ear pure-tone averages (PTAs) correlated reasonably well with self-assessed CP; none were significantly better than the 0.5, 1, 2, and 3 kHz PTA used in the current AMA method. Better-ear to worse-ear weights ranging from 3:1 to 9:1 performed similarly, but none were better than the AMA better-ear weight of 5:1. The AMA method assumes no disability below 25 dB HL and linear growth of disability above this "low fence"; this study showed a similar relationship between PTA and self assessed hearing disability. There were too few subjects with severe and profound speech-frequency losses to permit validation of the AMA "high fence" of 92 dB HL. Combining pure-tone thresholds and WRSs improved prediction of hearing disability only very slightly. CONCLUSIONS: This study supports the continued use of the 1979 AMA method. Incorporation of WRSs, as typically measured clinically, into methods of estimating hearing disability is not supported because of negligible improvement in accuracy and inability to control exaggeration for speech tests in medical-legal settings. PMID- 21694599 TI - Morphometrical and immunohistochemical study of intrahepatic bile ducts in biliary atresia. AB - BACKGROUND: Extrahepatic biliary atresia results from a progressive destruction of the bile ducts by an inflammatory fibrosing process which leads ultimately to cirrhosis of biliary type. The etiology of the disorder remains unknown. The histological features include cholestasis, ductular proliferation, eventual loss of intrahepatic bile ducts, and ducts with primitive embryonic shape (ductal plate malformation). PURPOSE: To examine the morphological changes of the biliary intrahepatic ducts, we aimed at investigating the cell proliferation and the diameter of the interlobular bile ducts in extrahepatic biliary atresia, and in normal liver children. METHODS: Liver samples from 35 patients with biliary atresia and 10 from control normal children were used. Immunoexpression of cytokeratin 19 was evaluated and a double-staining procedure was performed with cytokeratin 8/proliferating cell nuclear antigen. The stereological measurements of the intrahepatic bile ducts diameter were evaluated by a computerized system of image analysis. RESULTS: The patterns of intrahepatic cholangiopathy in biliary atresia were obstructive features (42.86%), paucity of intrahepatic bile ducts (20%), ductal plate malformation (28.57%), and ductal plate malformation associated with paucity of intrahepatic bile ducts (8.57%). The average external diameter of interlobular bile ducts in biliary atresia was smaller than that of the control infant livers. Among the four patterns of biliary atresia cholangiopathies, those associated with ductopenia showed the smallest bile duct diameter. There was a negative correlation between the bile duct to portal space ratio and the age of the child at the time of Kasai portoenterostomy. Only in biliary atresia are the bile duct cells stained with proliferating cell nuclear antigen. CONCLUSION: (i) In biliary atresia, both ductular metaplasia and ductular proliferation were observed; (ii) biliary atresia associated with ductopenia showed narrowing of interlobular ducts, probably as a consequence of degeneration with atrophy and fibrosis. PMID- 21694600 TI - Use of movement imagery in neurorehabilitation: researching effects of a complex intervention. AB - Since the beginning of the new millennium, the use of mental practice and movement imagery within several medical professions in rehabilitation and therapy has received an increased attention. Before this introduction in healthcare, the use of movement imagery was mainly researched in sports science. Mental practice is a complex intervention. When a complex intervention is applied in a new target group or population, the intervention is most likely needed to be adjusted, developed, and evaluated. Recently, a dissertation has been published in which the researchers describe their efforts to transfer the use of movement imagery in sports to rehabilitation. This study reports two aspects from this research project: (a) What did the researcher do? (b) What do the results mean for future research? First, however, some background information is given, in which the use of movement imagery in athletes is discussed. PMID- 21694601 TI - Effects of awareness interventions on children's attitudes toward peers with a visual impairment. AB - The purpose of this study was to explore the effect of two awareness programs (6 day vs. 1-day programs) on children's attitudes toward peers with a visual impairment. Three hundred and forty-four Spanish physical education students (164 girls and 180 boys) aged 10-15 years, took part in the study. A modified version of the Attitudes Toward Disability Questionnaire (ATDQ) was used, which includes three sub-scales: (i) cognitive perceptions, (ii) emotional perception, and (iii) behavioral readiness to interact with children with disabilities. The questionnaire was filled out during the regular physical education class before and immediately after the awareness activity. The 6-day didactical unit included a lecture on visual impairments and a video describing visual impairments and the game of 5-a-side soccer (first lesson), sensibilization activities toward visual impairment (second and third lessons), training and competitive 5-a-side soccer tasks using blindfolded goggles (fourth and fifth lessons), and a sport show and chat with soccer players with a visual impairment (sixth lesson). The 1-day awareness unit only included the final session of the didactical activity. Repeated measures analysis of variance revealed significant time effects in the cognitive, emotional, and behavioral subscales. Sex also was found to demonstrate significant effects, in which women showed more favorable results than men. A time-by-group intervention effect was only demonstrated in the cognitive sub scale, and the 6-day didactic intervention was more effective than the 1-day awareness unit. PMID- 21694602 TI - Review of self-awareness and its clinical application in stroke rehabilitation. AB - The objectives of this study were (i) to explore, following a literature review, the concepts of self-awareness, its assessment, and intervention for self awareness deficits, as well as its clinical significance in stroke rehabilitation; and (ii) to apply the concepts of self-awareness in the context of a rehabilitation program. The search was conducted by the electronic databases Web of Science, Science Direct, MEDLINE, and PsychcInfo. A systematic literature search of publications written in English between 1980 and 2010 was conducted using the keywords, self-awareness or self-regulation. The search was limited to the following keywords: stroke, deficits, assessment, intervention, and rehabilitation. Two important conceptual models, namely, the Pyramid Model of Self-Awareness and the Dynamic Comprehensive Model of Awareness, were reviewed. Suggestions were made to the constraint-induced movement therapy for enhancement of both assessment and treatment of self-awareness deficits. In conclusion, self awareness is essential for the success of rehabilitation. It is hoped that more studies can be conducted on the effectiveness of awareness enhancement programs incorporated in on-going therapies can be conducted, so that the evidence base can be further built up in this evolving area of practice. PMID- 21694603 TI - Unnecessary antiretroviral treatment switches and accumulation of HIV resistance mutations; two arguments for viral load monitoring in Africa. AB - OBJECTIVES: This study aimed to investigate the consequences of using clinicoimmunological criteria to detect antiretroviral treatment (ART) failure and guide regimen switches in HIV-infected adults in sub-Saharan Africa. Frequencies of unnecessary switches, patterns of HIV drug resistance, and risk factors for the accumulation of nucleoside reverse transcriptase inhibitor (NRTI) associated mutations were evaluated. METHODS: Cross-sectional analysis of adults switching ART regimens at 13 clinical sites in 6 African countries was performed. Two types of failure identification were compared: diagnosis of clinicoimmunological failure without viral load testing (CIF only) or CIF with local targeted viral load testing (targeted VL). After study enrollment, reference HIV RNA and genotype were determined retrospectively. Logistic regression assessed factors associated with multiple thymidine analogue mutations (TAMs) and NRTI cross-resistance (>=2 TAMs or Q151M or K65R/K70E). RESULTS: Of 250 patients with CIF switching to second-line ART, targeted VL was performed in 186. Unnecessary switch at reference HIV RNA <1000 copies per milliliter occurred in 46.9% of CIF only patients versus 12.4% of patients with targeted VL (P < 0.001). NRTI cross-resistance was observed in 48.0% of 183 specimens available for genotypic analysis, comprising >=2 TAMs (37.7%), K65R (7.1%), K70E (3.3%), or Q151M (3.3%). The presence of NRTI cross-resistance was associated with the duration of ART exposure and zidovudine use. CONCLUSIONS: Clinicoimmunological monitoring without viral load testing resulted in frequent unnecessary regimen switches. Prolonged treatment failure was indicated by extensive NRTI cross resistance. Access to virological monitoring should be expanded to prevent inappropriate switches, enable early failure detection and preserve second-line treatment options in Africa. PMID- 21694604 TI - Repeated assessments of food security predict CD4 change in the setting of antiretroviral therapy. AB - Food insecurity is highly prevalent in HIV-infected populations, and analyses utilizing multiple assessments of food security to predict CD4 change are lacking. Five hundred Ninety-two patients with >= 4 food security assessments were followed prospectively. In the final model, for patients using antiretroviral therapy, increases in CD4 counts were on average 99.5 cells less for individuals with at least 1 episode of food insecurity compared with those consistently food secure (P < 0.001). Other sociodemographic factors were not predictive. Repeated assessments of food security are potent predictors of treatment response notwithstanding antiretroviral therapy use. Potential mechanisms for this association are proposed. PMID- 21694605 TI - Cardiovascular disease risk in pediatric HIV: the need for population-specific guidelines. PMID- 21694607 TI - Evaluation of large-scale combination HIV prevention programs: essential issues. AB - HIV prevention research has shifted to the evaluation of combination prevention programs whereby biomedical, behavioral, and structural interventions are implemented concurrently to maximize synergies among interventions. However, these kinds of combination prevention packages, particularly when implemented at scale, pose significant evaluation challenges, including how best to determine impact and how and whether to measure the effectiveness of component strategies. In addition, methodological challenges unique to HIV infection such as the absence of a reliable incidence assay, the lack of naive control groups, and no suitable surrogates further complicate rigorous evaluation. In this commentary, we discuss the key considerations for planning impact evaluations of combination HIV prevention programs in light of these challenges, including defining the evaluable package, determining which component programs require independent assessment of impact, choosing study designs with valid counterfactuals, selecting appropriate outcomes of interest, and the importance of mid-course program corrections. PMID- 21694606 TI - Extraspousal partnerships in a community in rural Uganda with high HIV prevalence: a cross-sectional population-based study using linked spousal data. AB - BACKGROUND: The role of concurrent sexual partnerships in the HIV epidemic in sub Saharan Africa is not well understood. Although most infections in Africa occur among married individuals, transmission may occur from both spousal and extraspousal partnerships. This article explores extraspousal partnerships as a form of concurrency, examining the association with HIV status, demographic characteristics, and sexual behaviors in a population-based cohort in rural Uganda. METHODS: Prevalence of extraspousal partnerships was estimated using cross-sectional data from 2008, and adjusted odds ratios (aOR) were estimated for factors associated with the prevalence of extraspousal partnerships using logistic regression. Among men who were not in polygynous marriages, we used linked spousal data to investigate the association between extraspousal partnerships and wives' serostatus. RESULTS: Extraspousal partnerships in the past year were reported by 17% of married men and 2% of married women. Among both men and women, extraspousal partnerships were associated with not knowing their partners' HIV status (men: aOR = 1.74; 95% CI: 1.13 to 2.67; women: aOR = 1.76; 95% CI: 1.13 to 2.75), and extraspousal partnerships were also associated with increased condom use for men. There was no evidence that men reporting extraspousal partnerships were at increased risk of HIV (aOR = 0.98; 95% CI: 0.48 to 2.01), or that a woman's risk of HIV was associated with her husband reporting extraspousal partnerships (aOR = 0.68; 95% CI: 0.29 to 1.57). CONCLUSIONS: For both men and women, extraspousal partnerships were associated with not knowing their partners' HIV status. There was no evidence of an association of extraspousal partnerships with HIV serostatus in this cross-sectional analysis. PMID- 21694608 TI - Genotypic resistance at viral rebound among patients who received lopinavir/ritonavir-based or efavirenz-based first antiretroviral therapy in South Africa. AB - Nonnucleoside reverse transcriptase inhibitor-drug resistance mutations (DRM) are increasingly reported in Africans failing their first antiretroviral regimen. The Phidisa II trial randomized treatment-naive participants to lopinavir/ritonavir or efavirenz with stavudine + lamivudine or zidovudine + didanosine. We report the prevalence of DRM in subjects who achieved HIV RNA <400 copies per milliliter at 6 months, but subsequently had 2 consecutive HIV RNA >1000 copies per milliliter. Sixty-eight participants fulfilled the inclusion criteria. nonnucleoside reverse transcriptase inhibitor-DRM were found in 17 of 36 (47.2%) efavirenz recipients, and M184V/I mutation in 14 of 40 (35.0%) lamivudine recipients. No protease inhibitor mutation was identified in 38 lopinavir/ritonavir recipients. This is one of the first studies in Africa confirming the paucity of protease inhibitor-associated DRM despite virologic failure. PMID- 21694609 TI - Control of intragastric pH and its relationship to gastroesophageal reflux disease outcomes. AB - Pharmacologic treatment of gastroesophageal reflux disease (GERD) is accomplished almost exclusively with medications whose primary mechanism of action is to inhibit or neutralize gastric acidity, thus treating the disease by reducing exposure to the primary injurious agent and not by decreasing actual reflux. Although clinical trials assess healing of erosive esophagitis, improvement of GERD symptoms, and quality of life (the ultimate measures of therapeutic success), pharmacodynamic studies that measure gastric acid control have been used as 1 method of assessment of the potential clinical efficacy of acid suppressant medications. Continuous intragastric pH monitoring has been used extensively to evaluate therapeutic dosing for proton pump inhibitors and comparatively characterize their antisecretory efficacy. However, the link between observed changes in gastric pH and GERD outcomes is not well established. This review summarizes and critically evaluates available evidence linking intragastric pH and GERD outcomes. A search of the published literature for relevant studies, combined with the authors' knowledge of the field, revealed few studies that directly evaluated the correlation between intragastric pH and clinical outcomes. Despite the clinical relevance of heartburn and related symptoms as an outcome for GERD patients, most intragastric pH studies that did assess outcomes were limited in their evaluation of these symptoms because healing of erosions rather than symptom relief was specified as the primary endpoint. Well-designed, long-term outcome studies are still needed to elucidate the link among GERD symptoms, acid suppressive therapy, and 24-hour gastric pH profiles. PMID- 21694610 TI - Alcohol consumption is inversely correlated with insulin resistance, independent of metabolic syndrome factors and fatty liver diseases. AB - BACKGROUND AND AIM: The role of alcohol consumption in insulin resistance remains unclear. The aim of this study was to examine the association between alcohol consumption and insulin resistance in a large asymptomatic population. METHODS: A total of 2463 asymptomatic Japanese men aged 28 years or above undergoing a comprehensive health checkup including an oral glucose tolerance test between May 2007 and April 2010 were recruited. Participants positive for hepatitis B or C virus, abstinent alcoholics, those taking hepatotoxic drugs, those with chronic renal or hepatic failure, and those under treatment for metabolic disorders were excluded. Fatty liver was defined ultrasonographically. Visceral and subcutaneous adipose tissues were measured with computed tomography. The homeostasis model assessment of insulin resistance (HOMA-IR) score was determined to estimate insulin resistance. The association between alcohol consumption and HOMA-IR score was investigated with multivariate regression analysis. RESULTS: A total of 1902 participants were eligible for this cross-sectional survey. A significant difference in distribution of each drinking category was noted between 249 participants with insulin resistance (HOMA-IR >=2.5) and 1653 participants without insulin resistance (HOMA-IR <2.5; P=0.001). Light (40 to 140 g/wk), moderate (140 to 280 g/wk), and heavy alcohol consumption was inversely associated with HOMA-IR scores (coefficients=-0.125, -0.127, and -0.162; P=0.007, 0.011, and 0.006, respectively) with multivariate analysis after adjusting for potential confounding variables, including visceral and subcutaneous adipose tissues, metabolic profiles, fatty liver, and liver enzyme activities. CONCLUSIONS: Alcohol consumption was inversely associated with insulin resistance, independent of central obesity, metabolic profiles, and fatty liver diseases. PMID- 21694611 TI - Influence of HLA-DQ2 and DQ8 on severity in celiac Disease. AB - BACKGROUND: HLA-DQB1*02 homozygosity was shown to be more common in patients with complicated rather than uncomplicated celiac disease (CD). GOALS: To study HLA DQA1 and DQB1 profile in adult patients with different forms of CD, including patients with complicated and potential CD, the most affected and the most preserved histologic end of the pathologic celiac spectrum. STUDY: HLA-DQA1 and DQB1 molecular typing was performed in 218 adult CD patients (169 with uncomplicated CD, 27 with complicated CD, and 22 with potential CD) and 224 healthy stem cell donors. HLA-DQA1 and DQB1 gene polymorphism was analyzed using polymerase chain reaction sequence-specific primers and/or reverse polymerase chain reaction sequence-specific oligonucleotides techniques. RESULTS: As expected, the frequency of HLA-DQB1*02 allele, DQB1*02 homozygosity, and DQB1*0302 gene were statistically different in the 4 groups. However, multivariate analysis demonstrated that patients with potential CD have a higher frequency of both HLA-DQB1*0302 and HLA-DQB1*0603 alleles and a reduced frequency of DQB1*02 homozygosity compared with patients with uncomplicated and complicated CD. CONCLUSIONS: The increased frequency of DQB1*0302 and the reduced frequency of DQB1*02 homozygosity in potential CD is consistent with the idea that different clinical/pathologic evolutions might be related to different immunogeneses. This could be clinically relevant in the future. PMID- 21694612 TI - Serotonin-selective reuptake inhibitors and nonsteroidal anti-inflammatory drugs- important considerations of adverse interactions especially for the treatment of myalgic encephalomyelitis/chronic fatigue syndrome. PMID- 21694614 TI - Efficacy and safety of mifepristone for the treatment of psychotic depression. AB - Open-label studies and randomized clinical trials have suggested that mifepristone may be effective for the treatment of major depression with psychotic features (psychotic depression). A recent study reported a correlation between mifepristone plasma concentration and clinical response. The current study aimed to evaluate the safety and efficacy of mifepristone and, secondarily, to test whether response was significantly greater among patients with mifepristone plasma concentrations above an a priori hypothesized threshold. A total of 433 patients who met criteria for psychotic depression were randomly assigned to receive 7 days of either mifepristone (300, 600, or 1200 mg) or placebo. Response was defined as a 50% reduction in psychotic symptoms on both days 7 and 56. Cochran-Mantel-Haenszel tests compared (1) the proportion of responders among patients assigned mifepristone versus placebo and (2) the proportion of responders among the subset of patients with plasma concentrations greater than 1660 ng/mL versus placebo. Mifepristone was well tolerated at all 3 doses. The proportion of responders randomized to mifepristone did not statistically differ from placebo. Patients with trough mifepristone plasma concentrations greater than 1660 ng/mL were significantly more likely to have a rapid and sustained reduction in psychotic symptoms than those who received placebo. The study failed to demonstrate efficacy on its primary end point. However, the replication of a statistically significant linear association between mifepristone plasma concentration and clinical response indicates that mifepristone at sufficient plasma levels may potentially be effective in rapidly and durably reducing the psychotic symptoms of patients with psychotic depression. PMID- 21694613 TI - A randomized, double-blind study of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with generalized anxiety disorder. AB - This study evaluated once-daily, extended-release quetiapine fumarate (quetiapine XR) monotherapy in generalized anxiety disorder (GAD). This was a 10-week (8-week active treatment/2-week posttreatment drug-discontinuation/tapering phase), double-blind, randomized, placebo-controlled study (D1448C00009). Primary end point was change from randomization at week 8 in Hamilton Anxiety Rating Scale (HAM-A) total score. Overall, 951 patients with GAD were randomized (quetiapine XR: 50 mg/d, n = 234; 150 mg/d, n = 241; 300 mg/d, n = 241; placebo, n = 235). At week 8, HAM-A total scores significantly (P < 0.001) improved versus placebo ( 11.10) with quetiapine XR 50 mg/d (-13.31) and 150 mg/d (-13.54), but not 300 mg/d (-11.87; P = 0.240). At week 1, HAM-A total scores significantly improved versus placebo (-5.94) with quetiapine XR 50 mg/d (-7.47; P < 0.01), 150 mg/d ( 8.19; P < 0.001), and 300 mg/d (-7.23; P < 0.01). Versus placebo at week 8, quetiapine XR 50 and 150 mg/d significantly improved HAM-A psychic (P < 0.01 and P < 0.001, respectively) and somatic (P < 0.001; P < 0.01, respectively) cluster scores, HAM-A response (>= 50% total score reduction; P < 0.05), and Clinical Global Impression-Improvement categorical changes (P < 0.05). For quetiapine XR 150 mg/d, significant (P < 0.05) improvements were seen for HAM-A remission (total score, <= 7) and Clinical Global Impression-Severity of Illness scores. For quetiapine XR 300 mg/d, improvements in these secondary variables were not significantly different versus placebo. Pittsburgh Sleep Quality Index global scores improved with all 3 doses (quetiapine: XR 50 mg/d, -4.07 [P < 0.05]; 150 mg/d, -4.38 [P < 0.05]; 300 mg/d, -3.97 [P < 0.05], versus -3.31 with placebo). Adverse events (>10% with quetiapine XR) were dry mouth, somnolence, sedation, dizziness, headache, and fatigue. Quetiapine XR (50/150 mg/d) monotherapy was effective at week 8 in patients with GAD; symptom improvement was seen at week 1 for all doses (50/150/300 mg/d). Safety and tolerability were consistent with the known profile of quetiapine. PMID- 21694615 TI - Duloxetine for depression and the incidence of hepatic events in adults. AB - Elevated hepatic enzyme levels and hepatic injuries have been associated with duloxetine use in clinical trials and spontaneous reports, but the association of duloxetine with a broad spectrum of hepatic outcomes has not been assessed observationally. This cohort study of adult duloxetine initiators between 2004 and 2006 based on the Ingenix Research Data Mart involved 6 matched comparator cohorts, including 4 antidepressant initiator groups (venlafaxine, nefazodone, selective serotonin reuptake inhibitors, and tricyclic antidepressants), depressed but untreated patients, and individuals without depression. The cohorts were followed up for hepatic events, and proportional hazards regression compared duloxetine initiators with comparator cohorts, whereas Poisson regression compared duloxetine usage categories to account for changed therapy during follow up. Approximately 64,000 person-years among 21,457 duloxetine initiators and comparator cohorts yielded 51 hepatic outcome events. Venlafaxine initiators (incidence rate ratio [IRR] = 0.34; 95% confidence interval [CI], 0.12-0.95) and the cohort without depression (IRR = 0.30; 95% CI, 0.10-0.93) had lower incidences of combined hepatic events than duloxetine initiators, whereas no other differences in hepatic events were observed for duloxetine initiators relative to selective serotonin reuptake inhibitors, tricyclic antidepressants, and untreated depressed patients. In as-treated analyses, relative to nonuse, current (IRR = 4.30; 95% CI, 1.45-12.81) and recent (IRR = 5.93; 95% CI, 1.63 21.55) duloxetine use was associated with greater incidence of less severe hepatic outcomes but not hepatic-related death and potential acute hepatic failure. Although duloxetine does not seem to increase the risk of hepatic related death or acute hepatic failure, it may be associated with an increased risk of certain less severe hepatic events. PMID- 21694616 TI - CYP2B6 polymorphisms influence the plasma concentration and clearance of the methadone S-enantiomer. AB - Methadone is a racemic compound composed of the R-form and S-form enantiomers. The drug is usually used in maintenance therapy for the heroin-addicted patients. In our previous study, we found that the cytochrome P-450 (CYP) isozyme 2B6 preferentially metabolizes the S-methadone enantiomer. We thus tested whether CYP2B6 gene polymorphisms had any influence on the concentration or clearance of methadone. Ten single nucleotide polymorphisms within this gene region were evaluated in 366 patients undergoing methadone maintenance for at least 3 months. The plasma steady-state levels of racemic methadone and its metabolite 2 ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine were then measured in these individuals. The rs10403955 (T allele in intron 1), rs3745274 (G allele in exon 4), rs2279345 (T allele in intron 5), and rs707265 (A allele in exon 9) CYP2B6 allele types were found to be significantly associated with a higher clearance, a lower plasma concentration, and a lower concentration-to-dosage (C/D) ratio of (S)-methadone (P < 0.0017). Two haplotype blocks of a trinucleotide haplotype (rs8100458-rs10500282-rs10403955 in intron 1) and a hexanucleotide haplotype (rs2279342-rs3745274-rs2279343-rs2279345-rs1038376-rs707265 from intron 2 to exon 9) were constructed within CYP2B6. The major combinations of T-T-T and A-G-A-T-A A of these particular haplotypes showed significant associations with the plasma concentrations of S-methadone and its C/D ratio (P < 0.0001, respectively). We conclude that genetic polymorphisms in the CYP2B6 gene may therefore be indicators of the clearance, plasma concentration and C/D ratio of S-methadone. PMID- 21694617 TI - Switching antidepressant class does not improve response or remission in treatment-resistant depression. AB - OBJECTIVE: The management of treatment-resistant depression is a much debated issue. In particular, the evidence supporting the commonly suggested sequential use of antidepressants from 2 different pharmacological classes is weak. This retrospective study was undertaken to investigate whether there is a better response in nonresponders switched to a different class of antidepressants (across-class) compared with nonresponders switched to an antidepressant from the same class (within-class). METHODS: Three hundred forty patients with primary major depressive disorder were recruited in the context of a European multicenter project. Subjects whose current depressive episode had failed to respond to a first antidepressant trial of adequate dose and duration were included. RESULTS: There was no significant difference in response or remission rates between the across-class and within-class groups after controlling for possible confounders. CONCLUSIONS: In depressed nonresponders to a previous antidepressant treatment, switching to a different class of antidepressants was not associated with a better response or remission rate. PMID- 21694618 TI - Prevalence and psychological impact of antidepressant-associated sexual dysfunction: a study from North India. AB - This study attempted to estimate the prevalence and impact of sexual dysfunction on quality of life, treatment compliance, and dyadic adjustment with spouse. For this, 100 consenting subjects who had history of unipolar depression (as per Mini International Neuropsychiatric Interview) and were in remission (Hamilton Depression Rating Scale, <7) at time of intake and met the selection criteria were recruited. Then, they were assessed on Hamilton Anxiety Scale, Global Assessment of Functioning Scale, Compliance Rating Scale, Arizona Sexual Experience Questionnaire, World Health Organization Quality Of Life scale-BREF Version, and Dyadic Adjustment Scale. Twenty-three subjects were found to have sexual dysfunction. Nine subjects had dysfunction in the domain of desire, 5 had arousal difficulty, 6 subjects had problem with erection, and 8 subjects had problem with orgasm. Some of the subjects (n = 5) had sexual dysfunction in more than 1 domain. Significant difference was found between those with and without sexual dysfunction on dyadic adjustment scale and quality of life scale. However, no significant difference was seen on compliance rating scale and global assessment of functioning scale. From this study, it can be concluded that approximately one fourth of married male subjects experience antidepressant associated sexual dysfunction. Antidepressant-associated sexual dysfunction contributes to poor quality of life and possibly contributes to poor marital adjustment. Hence, proper identification and management of sexual dysfunction is important to improve overall outcome of depression. PMID- 21694619 TI - Antipsychotic-associated mental side effects and their relationship to dopamine D2 receptor occupancy in striatal subdivisions: a high-resolution PET study with [11C]raclopride. AB - We examined the relationship between antipsychotic-associated mental side effects and dopamine D2 receptor occupancy in striatal subdivisions using high-resolution positron emission tomography with [11C]raclopride to better characterize the neurochemical mechanism underlying these adverse effects. Twenty-one patients with schizophrenia receiving stable doses of antipsychotics and 24 age- and sex matched healthy controls completed 3-Tesla magnetic resonance imaging and high resolution positron emission tomography scans with [11C]raclopride to measure D2 receptor binding potential (BP ND) in the striatum. The D2 receptor BP ND was obtained using a Logan plot, and receptor occupancy was calculated as the percentage reduction of receptor BP ND with drug treatment relative to baseline. The data obtained from age- and sex-matched healthy controls were used as an estimate of the patients' baseline, as previously proposed. Antipsychotic associated mental side effects were measured with the Liverpool University Neuroleptic Side Effect Rating Scale. The whole striatal D2 receptor occupancy ranged from 54% to 95%. The analysis revealed that the Liverpool University Neuroleptic Side Effect Rating Scale score had significant positive associations with D2 occupancy in the precommissural dorsal caudate, postcommissural caudate, and ventral striatum. The results suggest that mental side effects of antipsychotics are associated with D2 receptor blockade in the associative and limbic subdivisions of the striatum, which are considered to play a crucial role in cognition and reward motivation. PMID- 21694620 TI - Plasma olanzapine in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1999-2009. AB - Olanzapine therapeutic drug monitoring (TDM) is the measurement of plasma olanzapine to assess adherence and guide dosage. We have audited data from an olanzapine TDM service, 1999-2009. Multiple linear regression analysis was conducted to investigate the contribution of dose, age, sex, body weight, and smoking status to the plasma olanzapine concentration. There were 5856 samples from 3207 patients. The prescribed olanzapine dosage was 2.5 to 95 mg/d. No olanzapine was detected in 6% of samples. For olanzapine dosages of 2.5 to 20 mg/d, only 35% of results were within a suggested target range of 20 to 39 ng/mL. At doses above 20 mg/d, 30% to 59% of results were 60 ng/mL or greater depending on dose band. In patients aged 17 years or younger (92 samples), median plasma olanzapine was higher than that in adult patients at almost all olanzapine doses. Multiple linear regression analysis of results from 627 adults from whom complete data were available showed that dose, smoking status, sex, age, and body weight together explained 24% the variance in plasma olanzapine. Degree of adherence, timing of sample postdose, drug-drug interactions, and pharmacogenetic factors also may have contributed to the observed variance. However, it is clear that female nonsmokers had higher plasma olanzapine concentrations for a given dose than male smokers. Olanzapine TDM is useful in assessing adherence and may have a role in limiting olanzapine dosage to minimize the risk of long-term toxicity. PMID- 21694621 TI - Antidepressant use and cognitive functioning in older medical patients with major or minor depression: a prospective cohort study with database linkage. AB - OBJECTIVE: The long-term cognitive effect of antidepressant medications in older persons is not well understood, especially in those with minor depression and complex medical conditions. The objective of this study is to examine this relationship in older medical patients with different depression diagnoses. METHODS: 281 medical inpatients aged 65 years and older from 2 acute care hospitals in Montreal, Canada, were diagnosed as with major or minor depression or without depression according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. They were followed up with the Mini-Mental State Examination for cognitive function and the Hamilton Depression Rating Scale for depressive symptoms at baseline and 3, 6, and 12 months after discharge. Antidepressant medication was ascertained from a provincial prescription database and quantified as cumulative exposures over each follow-up interval. RESULTS: During the 12-month follow-up period, 1027 antidepressant prescriptions were filled. The most frequently prescribed antidepressant agents were citalopram (0.81 prescriptions per person), sertraline (0.76), and paroxetine (0.66). Antidepressant use was not associated with cognitive changes among patients with major depression or without depression but was associated with an increased Mini Mental State Examination score in patients with minor depression (1.4 points; 95% confidence interval, 0.1-2.6), independent of change in the severity of depression symptoms, concomitant benzodiazepine or psychotropic drug use, and other potentially important confounders. CONCLUSIONS: In this cohort of older medical patients, antidepressant use for 12 months did not lead to significant cognitive impairment. The small cognitive improvement among minor depression associated with antidepressant use deserves further investigation. PMID- 21694622 TI - Discriminative-stimulus, subject-rated, and physiological effects of methamphetamine in humans pretreated with aripiprazole. AB - Methamphetamine is thought to produce its behavioral effects by facilitating release of dopamine, serotonin (5-HT) and norepinephrine. Results from animal studies support this notion, whereas results from human laboratory studies have not consistently demonstrated the importance of monoamine systems in the behavioral effects of methamphetamine. Human drug-discrimination procedures are well suited to assess neuropharmacological mechanisms of the training drug by studying pharmacological manipulation. In this human laboratory study, 6 participants with a history of recreational stimulant use learned to discriminate 10 mg oral methamphetamine. After acquiring the discrimination (ie, >= 80% correct responding on 4 consecutive sessions), the effects of a range of doses of methamphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with 0 and 20 mg aripiprazole (a partial agonist at D2 and 5-HT1A receptors), were assessed. Methamphetamine alone functioned as a discriminative stimulus, produced prototypical stimulant-like subject-rated drug effects (eg, increased ratings of Good Effects, Talkative-Friendly, and Willing to Pay For) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion methamphetamine-appropriate responding or produce subject-rated effects but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of methamphetamine, as well as some of the subject-rated drug effects. These results indicate that monoamine systems likely play a role in the behavioral effects of methamphetamine in humans. Moreover, given the concordance between past results with d-amphetamine and the present findings, d amphetamine can likely serve as a model for the pharmacological effects of methamphetamine. PMID- 21694623 TI - Open-label trial of aripiprazole in the treatment of trichotillomania. AB - BACKGROUND: Serotonin reuptake inhibitors have been disappointing in the treatment of trichotillomania (TTM). Recent evidence suggests that medications that modulate dopamine may be helpful in this disorder. OBJECTIVE: To determine if the D2 partial agonist aripiprazole would be effective in the treatment of TTM. METHODS: Twelve subjects participated in an 8-week, open-label, flexible dose study of aripiprazole treatment of TTM. Primary end points were reduction in the Massachusetts General Hospital Hair Pulling Scale (MGHHPS) and MGHHPS Actual Pulling Subscale (MGHHPS-APS). Secondary end points were the Clinical Global Impressions-Improvement Scale, Hamilton Anxiety Scale, Hamilton Depression Scale, Beck Depression Inventory, and Beck Anxiety Inventory. RESULTS: Eleven of 12 subjects had 2 or more assessments; one subject dropped out during the first week. For subjects with 2 or more assessments, there was a significant mean reduction in both primary end points, the MGHHPS score (mean change, 7.8; SD, +/- 7.8; P <= 0.01) and the MGHHPS-APS score (mean change, 3.9; SD, +/- 4.1; P <= 0.02). Seven subjects had a greater than 50% reduction in MGHHPS; 7 subjects had an exit Clinical Global Impressions-Improvement Scale of 2 or lower, and 5 participants had absolute exit scores of 3 or lower on the MGHHPS and 1 or lower on the MGHHPS-APS. There were no significant changes in mood-related secondary end points. The mean aripiprazole dose for all completers (N = 11) was 7.5 mg/d (+/- 3.4 mg/d). CONCLUSIONS: This small open-label study suggests that aripiprazole is a promising treatment for the treatment of trichotillomania. Larger double-blind, placebo-controlled studies are needed to follow up on these findings. PMID- 21694624 TI - Bone mineral density and osteoporosis risk in older patients with schizophrenia. AB - OBJECTIVE: People with schizophrenia are at a higher risk for osteoporosis. The authors investigated the prevalence of low bone density and its risk factors in older Korean patients with schizophrenia. METHOD: In cross-sectional study, 327 inpatients with schizophrenia were screened. Among them, 229 patients older than 50 years participated in this study. The control group consisted of healthy volunteers who were of similar ages (n = 125). Bone density was measured in the lumbar spine and the neck, trochanter, and ward regions of the right proximal femur by dual-energy x-ray absorptiometry. Clinical variables such as alcohol use, cigarette smoking, and fracture history were obtained. The Student t test, Pearson chi2 test, Wilcoxon rank sum test, and logistic regression analysis were used. RESULTS: The prevalence of osteoporosis was significantly higher in patients with schizophrenia compared with healthy controls (34.9% vs 18.4%, P = 0.0043). Within the schizophrenia group, female subjects had a significantly higher prevalence of osteoporosis than male subjects (48.4% vs 25.7%, P = 0.0014); however, no sex differences were identified in the healthy control group. The actual bone density and t scores in patients with schizophrenia were significantly lower in all sites than in healthy controls. Among patients with schizophrenia, smokers and alcohol abuser showed lower bone density compared with those who did not smoke or drink. The lifetime prevalence of fracture was significantly higher in patients with schizophrenia (24.0%) compared with healthy controls (5.6%; P = 0.001). CONCLUSIONS: Our results emphasize that older patients with schizophrenia are at risk for low bone density. Cigarette smoking and alcohol abuse are associated with low bone density in patients with schizophrenia. PMID- 21694625 TI - Relationship between a history of a suicide attempt and treatment outcomes in patients with depression. AB - This study aimed to investigate the sociodemographic and clinical correlates of a history of a suicide attempt in people with depression and their relationship with treatment outcomes and subsequent suicidal ideation and deliberate self harm. Patients with depressive disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were recruited from 18 hospitals across South Korea. Data on sociodemographic and clinical characteristics were obtained, and scales assessing depression, anxiety, and general functioning were administered during the first 12 weeks of antidepressant treatment. Baseline characteristics, responses to treatment, and suicidal ideation/deliberate self-harm during the follow-up period were compared according to a reported history or not of a suicide attempt. In a total of 723 participants, 143 (19.8%) with a history of a suicide attempt had an earlier age of onset, longer duration of illness, and a greater number of depressive episodes. Levels of depression and anxiety were significantly higher at baseline in this group who also experienced significantly lower remission and response rates, as well as longer time to remission. The case group was more likely to experience new suicidal ideation and carry out a deliberate self-harm act during the 12-week treatment period. In conclusion, a history of a suicide attempt in a Korean population with depression was characterized by more severe psychopathology, poorer treatment outcomes, and higher subsequent suicidal ideation and self-harm. Therefore, more intensive and longer-term treatment with particular ongoing clinical attention to risk is indicated in patients with these distinct, chronic, and severe forms of depression and ongoing high suicide risk. PMID- 21694626 TI - Differential effectiveness of antipsychotics in borderline personality disorder: meta-analyses of placebo-controlled, randomized clinical trials on symptomatic outcome domains. AB - OBJECTIVE: In clinical practice, antipsychotic drugs are widely used in borderline personality disorder (BPD). To evaluate current pharmacological treatment algorithms and guidelines for BPD, the authors reviewed and meta analyzed studies on the effectiveness of antipsychotics on specific symptom domains in BPD. METHODS: The literature was searched for placebo-controlled, randomized clinical trials (PC-RCTs) on the effectiveness of antipsychotics regarding cognitive perceptual symptoms, impulsive behavioral dyscontrol, and affective dysregulation (with subdomains depressed mood, anxiety, anger, and mood lability) in BPD. Studies whose primary emphasis was on the treatment of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition schizotypal personality disorder or Axis I disorders were excluded. RESULTS: Meta-analyses were conducted using 11 retrieved studies including 1152 borderline patients. Antipsychotics have a significant effect on cognitive perceptual symptoms (9 PC RCTs; standardized mean difference [SMD], 0.23) and mood lability (5 PC-RCTs; SMD, 0.20) as well as on global functioning (8 PC-RCTs; SMD, 0.25), but these effects have to be qualified as small. Antipsychotics have a more pronounced effect on anger (9 PC-RCTs; SMD, 0.39). Antipsychotics did not have a significant effect on impulsive behavioral dyscontrol, depressed mood, and anxiety in BPD. CONCLUSION: Drug therapy tailored to well-defined symptom domains can have beneficial effects in BPD. At short term, antipsychotics can have significant effects on cognitive-perceptual symptoms, anger, and mood lability, but the wide and long-term use of antipsychotics in these patients remains controversial. The findings from this study raise questions on current pharmacological algorithms and clinical guidelines. PMID- 21694627 TI - Absence of psychostimulant effects of a supratherapeutic dose of tianeptine: a placebo-controlled study versus methylphenidate in young healthy volunteers. AB - OBJECTIVE: The primary objective of the present study was to assess the potential psychostimulant effect of a single oral supratherapeutic dose of tianeptine (75 mg in 1 shot) in young healthy volunteers compared with methylphenidate (40 mg) and placebo. METHOD: Eighteen healthy young male and female volunteers with no history of psychostimulant abuse completed this balanced, crossover, placebo controlled study. Subjective and behavioral effects were assessed before treatment and 1, 2, 3, 4, and 8 hours after drug intake. Subjective effects of the drugs were recorded using self-questionnaire Addiction Research Center Inventory (ARCI 49). In addition, the Profile of Mood Scale, Visual Analog Scale, and attention/vigilance tests (choice reaction time and critical flicker fusion test) were used to evaluate mood state, subjective feeling, and sustained attention, respectively. RESULTS: Analysis on changes from baseline, from 1 to 8 hours, showed statistically significant differences between treatment groups for 2 of the 5 ARCI subscales: amphetamine and morphine benzedrine scales. A trend to significance was observed for Lysergic Acid Diethylamide scale. Indeed, although tianeptine did not significantly change any ARCI scores, methylphenidate significantly increased amphetamine and morphine benzedrine scores of the ARCI compared with placebo. No significant treatment effect was observed on the Profile of Mood Scale and the visual analog scale. Analyses of attention and vigilance tests showed a psychostimulant effect for methylphenidate on choice reaction time (decrease of recognition time) and critical flicker fusion test (higher frequency). CONCLUSIONS: A single administration of a supratherapeutic dose of tianeptine does not induce psychostimulant effect in young healthy volunteers in contrast to methylphenidate at a therapeutic dose. These findings suggest an absence of psychostimulant liability of tianeptine in a therapeutic situation. PMID- 21694628 TI - Psychomotor performance after intake of zopiclone compared with intake of ethanol: a randomized, controlled, double-blinded trial. AB - The sleep medicine zopiclone (eszopiclone) is commonly used in most Western countries. The focus on legislation for possible traffic-impairing nonalcohol drugs have caused a need for comparing traffic relevant behavior after intake of commonly used psychoactive drugs to blood alcohol concentrations (BACs). We aimed to compare psychomotor effects at 3 levels of behavior at different blood zopiclone concentrations to effects seen at different BACs. We performed a randomized double-blinded trial on 16 healthy volunteers who received either 10 or 5 mg zopiclone, 50 g ethanol or placebo in a crossover design. The volunteers performed computerized tests at baseline, 1, 3.5, and 6.5 hours after intake, accompanied by blood sampling. Impairment was found at all 3 behavior levels. For zopiclone, impairment was most pronounced at behavior level 1 (automotive behavior); a mean blood zopiclone concentration at 39 MUg/L achieved 1 hour after intake of 10 mg zopiclone was accompanied by more impairment than BAC 0.074 %. At behavior levels 2 (control behavior) and 3 (executive planning), the psychomotor impairment accompanying approximately 39 MUg/L zopiclone seemed comparable to a BAC of approximately 0.074%. No test components were impaired at 6.5 hours after intake. PMID- 21694629 TI - Dopamine D2 receptor occupancy and clinical effects: a systematic review and pooled analysis. AB - Positron emission tomography (PET) studies proposed a therapeutic window of D2 receptor occupancy (65%-80%) of antipsychotics for the treatment of schizophrenia in young adults. However, this conclusion has been drawn from clinical PET studies using small sample sizes (<20). Prospective PET studies that measured D2 occupancy levels and assessed extrapyramidal side effects (EPS) and/or treatment response induced by antipsychotics (excluding partial agonists) were identified, using MEDLINE and EMBASE (last search: March 2010). Individual subjects were divided into 2 groups based on EPS status (ie, presence or lack of newly emergent EPS) and treatment response (ie, a >= 25% or >= 50% reduction in the Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale). To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cutoff points in the D2 occupancy were calculated: Accuracy = (True Positive + True Negative) / Total N. Twelve studies, including a total of 82 subjects, were included in our analyses. The cutoff points associated with 0.5 or greater in both sensitivity and specificity with the greatest accuracy were 77% to 78% for EPS, 60% for a 25% or greater symptom reduction, and 72% for a 50% or greater symptom reduction. These findings support the presence of a therapeutic window of 60% to 78% D2 occupancy of antipsychotics in young adults with schizophrenia and may suggest the presence of a continuum of effectiveness with increasing occupancy within this therapeutic window. PMID- 21694630 TI - A pilot study to improve venipuncture compliance in children and adolescents with autism spectrum disorders. AB - OBJECTIVE: Medical procedures, particularly venipuncture (the puncture of a vein especially for the withdrawal of blood), can cause serious distress and behavior disturbance for many children. Noncompliance to blood draws can have significant ramifications in both research and clinical settings. The negative reactions may be exacerbated in individuals with autism spectrum disorders. Even so, there has been little research into the prevalence of the problem or effective intervention procedures. In response to these concerns, we developed and evaluated the Blood Draw Intervention Program. The program was designed to be easy to use, require little provider or family time, effectively reduce negative behaviors, and increase blood draw compliance. METHOD: In a quasi-randomized trial over the course of ~ 18 months, 58 of 210 families with children with autism spectrum disorders participating in a larger study of phenotypic and genotypic factors reported significant concerns about blood draws and elected to use the Blood Draw Intervention Program. RESULTS: Completion of the program increased blood draw compliance rates from 85.4% to 96.6% (odds ratio = 4.80; 95% confidence interval = 1.12, 20.59; p = .03). CONCLUSION: Results indicate the efficacy of the program in a research setting and suggest a potential clinical application. The current intervention, unlike many others for the same or similar difficulties proposed in the past, was successful without requiring extensive time, training, or effort on the part of providers and parents or their children, nor did it require large scale institutional changes. PMID- 21694631 TI - Occurrence and predictors of developmental impairments in 3-year-old children with congenital heart defects. AB - OBJECTIVE: To examine the occurrence of developmental impairments in 3-year-old children with varying severity of congenital heart defects (CHD) and to identify predictors associated with developmental impairment in children with severe CHD. METHODS: Prospective data collected at birth, 6, 18, and 36 months from the Norwegian Mother and Child Cohort Study (MoBa), conducted by the Norwegian Institute of Public Health, were linked with a nationwide medical CHD registry, and 175 three year olds with CHD in a cohort of 44,044 children were identified. Children with mild/moderate (n = 115) and severe (n = 60) CHD were compared with children without CHD (43,929) on motor, communication, and social impairments as reported by mothers in Norwegian Mother and Child Cohort Study questionnaires. Predictors of developmental impairment were analyzed for the group with severe CHD. RESULTS: Children with severe CHD had >3 times higher odds of communication and gross motor impairments compared with controls, and had 2 times higher odds of any developmental impairment compared with controls. Children with mild and moderate CHD had >2 times higher odds of gross motor impairment but did not otherwise differ from controls. Predictors of impairment identified were previous developmental impairments and smaller head circumference at birth. CONCLUSION: Children with severe CHD have increased odds of developmental impairments at age 3 years. Early developmental impairments are associated with later developmental impairments, suggesting lasting impairments and not merely temporary delay. Patient-specific conditions at birth should be considered and motor and communication support provided to potentially improve outcomes in children with CHD. PMID- 21694632 TI - Heterogeneity of lower esophageal sphincter function in children with achalasia. AB - BACKGROUND AND AIM: Achalasia is a rare esophageal motor disorder in children. The manometric hallmarks are esophageal body aperistalsis, lack of lower esophageal sphincter (LES) relaxation, and high LES pressure. However, LES relaxation and function may be heterogeneous, making the diagnosis difficult at times. The aim of the study was to describe LES function in children with achalasia. PATIENTS AND METHODS: The present study is a retrospective review of manometric tracings of pediatric patients with achalasia and controls. LES response after each swallow was evaluated. LES parameters were defined as homogeneous (normal or abnormal) if the same response was observed in >75% of swallows. Otherwise, the LES parameters were considered heterogeneous. RESULTS: Twenty-nine patients with achalasia and 16 control patients were included. All of the controls had normal LES pressure and relaxation in all of the wet swallows. In the achalasia group, some LES relaxation was present in 74% of swallows and 25% of swallows had normal relaxation. Depending on the parameter, a heterogeneous LES (resting pressure, relaxation, residual pressure, and duration of relaxation) was observed in 27.6% to 34.5% of patients with achalasia versus 0% of the controls (P < 0.001). The rest of the patients with achalasia had homogeneous abnormal responses versus homogeneous normal responses in 100% of control patients (P < 0.001). CONCLUSIONS: The LES function in pediatric patients with achalasia is heterogeneous. The classic description of a nonrelaxing high pressure LES in patients with achalasia is rarely found in children. Partial relaxations are common, and normal relaxations may be present. PMID- 21694633 TI - Infliximab as salvage therapy in paediatric intestinal transplant with steroid- and thymoglobulin-resistant late acute rejection. PMID- 21694634 TI - Cost-effectiveness analysis of adjunct VSL#3 therapy versus standard medical therapy in pediatric ulcerative colitis. AB - BACKGROUND: Inflammatory bowel diseases (IBDs) are costly chronic gastrointestinal diseases, with pediatric IBD representing increased costs per patient compared to adult disease. Health care expenditures for ulcerative colitis (UC) are >$2 billion annually. It is not clear whether the addition of VSL#3 to standard medical therapy in UC induction and maintenance of remission is a cost-effective strategy. PATIENTS AND METHODS: We performed a systematic review of the literature and created a Markov model simulating a cohort of 10-year-old patients with severe UC, studying them until 100 years of age or death. We compared 2 strategies: standard medical therapy versus medical therapy + VSL#3. For both strategies, we assumed that patients progressed through escalating therapies--mesalamine, azathioprine, and infliximab--before receiving a colectomy + ileal pouch anal anastamosis (IPAA) if the 3 medical therapy options were exhausted. The primary outcome measure was the incremental cost-effectiveness ratio (ICER), defined as the difference of costs between strategies for each quality-adjusted life-year (QALY) gained. One-way sensitivity analyses were performed on variables to determine the key variables affecting cost effectiveness. RESULTS: Standard medical care accrued a lifetime cost of $203,317 per patient, compared to $212,582 per patient for medical therapy + VSL#3. Lifetime QALYs gained was comparable for standard medical therapy and medical therapy + VSL#3 at 24.93 versus 25.05, respectively. Using the definition of ICER <50,000/QALY as a cost-effective intervention, medical therapy + VSL#3 produced an ICER of $79,910 per QALY gained, making this strategy cost-ineffective. Sensitivity analyses showed that 4 key parameters could affect the cost effectiveness of the 2 strategies: cost of colectomy + IPAA, maintenance cost after surgery, probability of developing pouchitis after surgery, and the quality of life after a colectomy + IPAA. High surgical and postsurgical costs, a high probability of developing pouchitis, and a low quality of life after a colectomy + IPAA could make adjunct VSL#3 use a cost-effective strategy. CONCLUSIONS: Given present data, adjunct VSL#3 use for pediatric UC induction and maintenance of remission is not cost-effective, although several key parameters could make this strategy cost-effective. The quality of life after an IPAA is the single most important variable predicting whether this procedure benefits patients over escalating standard medical therapy. PMID- 21694635 TI - Systemic Mycobacterium avium complex infection during antitumor necrosis factor alpha therapy in pediatric Crohn disease. PMID- 21694636 TI - Decrease of total subcutaneous adipose tissue from infancy to childhood. AB - OBJECTIVES: The observation and research of body composition is a topic of present interest. For the assessment of health and variables influencing growth and nutrition, it is of utmost interest to focus on the population of young children. SUBJECTS AND METHODS: The measurements of subcutaneous body fat distribution in a sample of clinically healthy children ages 0 to 7 years were examined. The optical device LIPOMETER was applied to measure the thickness of subcutaneous adipose tissue layers (in millimeters) at 15 well-defined body sites. This set of measurement points defines the subcutaneous adipose tissue topography. In the present study, subcutaneous adipose tissue topography was determined in 275 healthy children (128 girls and 147 boys) divided into 3 age groups. RESULTS: The results of the measurements are presented in 3 levels: total subcutaneous adipose tissue, 4 body regions, and 15 body sites. Our results show a clear physiological decrease in subcutaneous body fat in boys (-43.8%) and girls (-39.8%). One interesting finding was that the decrease occurs mainly in the trunk, abdomen, and lower extremities, whereas the body fat distribution of the upper extremities did not differ. Furthermore, slight subcutaneous adipose tissue topography differences between both sexes were found. CONCLUSIONS: The present study provides basic documentation of subcutaneous adipose tissue topography in healthy children ages 0 to 7 years. An accurate description of subcutaneous adipose tissue topography in healthy subjects could help to characterize various diseases in relation to overnutrition and malnutrition throughout childhood. PMID- 21694637 TI - Exploring potential noninvasive biomarkers in eosinophilic esophagitis in children. AB - BACKGROUND AND AIMS: Eosinophilic esophagitis (EE) continues to present clinical challenges, including a need for noninvasive tools to manage the disease. To identify a marker able to assess disease status in lieu of repeated endoscopies, we examined 3 noninvasive biomarkers, serum interleukin (IL)-5, serum eosinophil derived neurotoxin (EDN), and stool EDN, and examined possible correlations of these with disease phenotype and activity (symptoms and histology) in a longitudinal study of children with EE. SUBJECTS AND METHODS: Children with EE were studied for up to 24 weeks (12 weeks on 1 of 2 corticosteroid therapies and 12 weeks off therapy). Twenty children with normal esophagogastroduodenoscopies with biopsies were enrolled as controls. Serum IL-5, serum EDN, and stool EDN were measured at weeks 0, 4, 12, 18, and 24 in children with EE, and at baseline alone for controls. Primary and secondary statistical analyses (excluding and including outlier values of the biomarkers, respectively) were performed. RESULTS: Sixty subjects with EE (46 [75%] boys, mean age 7.5 +/- 4.4 years) and 20 normal controls (10 [50%] boys, mean age 6.7 +/- 4.1 years) were included. Significant changes in serum EDN (significant decrease from baseline to week 4, and then rebound from week 4 to week 12) occurred. Serum EDN levels were stable after week 12. Serum IL-5 and stool EDN levels in subjects with EE were not statistically different from those of the control subjects when each time point for the cases was compared with the controls' 1-time measurement. CONCLUSIONS: Serum EDN levels were significantly higher in subjects with EE than in controls, and the results suggest a possible role, after additional future studies, for serum EDN in establishing EE diagnosis, assessing response to therapy, and/or monitoring for relapse or quiescence. PMID- 21694638 TI - Impact of personalized feeding program in 100 NICU infants: pathophysiology-based approach for better outcomes. AB - OBJECTIVES: In neonatal intensive care unit infants referred for home-tube feeding methods, we evaluated the effect of an innovative diagnostic and management approach on feeding outcomes at discharge and 1 year, by comparing data from historical controls; we hypothesized that clinical and aerodigestive motility characteristics at evaluation were predictive of feeding outcomes at discharge; we assessed the economic impact of feeding outcomes. PATIENTS AND METHODS: Patients (N = 100) who were referred for development of long-term feeding management strategy at 46.4 +/- 13.1 weeks' postmenstrual age were compared with 50 historical controls that received routine care. The focused approach included swallow-integrated pharyngoesophageal manometry, individualized feeding strategy, and prospective follow-up. Feeding success was defined as ability to achieve oral feedings at discharge and 1 year. Motility characteristics were evaluated in relation to feeding success or failure at discharge. RESULTS: Higher feeding success was achieved in the innovative feeding program (vs historical controls) at discharge (51% vs 10%, P < 0.0001) and at 1 year (84.3% vs 42.9%, P < 0.0001), at a reduced economic burden (P < 0.05). Contributing factors to the innovative program's feeding success (vs feeding failure) were earlier evaluation and discharge (both P < 0.05), greater peristaltic reflex-frequency to provocation (P < 0.05), normal pharyngeal manometry (P < 0.05), oral feeding challenge success (P < 0.05), and suck-swallow breath-esophageal swallow sequence (P < 0.05). Probability of feeding success demonstrated a prediction rate of 79.6%. CONCLUSIONS: Short-term and long-term feeding outcomes in complex neonates can be significantly improved with innovative feeding strategies at a reduced cost. Clinical and aerodigestive motility characteristics were predictive of outcomes. PMID- 21694640 TI - Hematogenous osteomyelitis of the patella. AB - Osteomyelitis is an uncommon infection that is considered to be a childhood disease. Diagnosis is frequently delayed, as it is a very rare condition and also because of its variable presentation. After an accurate diagnosis and treatment, the outcome is favorable in children. We present one case without recent previous infection, antecedent trauma, or penetrating injury, illustrating the difficulties in diagnosis. Nontraumatic osteomyelitis of the patella should be regarded as a rare hematogenous infection. A high index of suspicion should be addressed for early recognition. Study design is level of evidence: level IV. PMID- 21694639 TI - Congenital hepatic fibrosis and portal hypertension in autosomal dominant polycystic kidney disease. AB - OBJECTIVES: Autosomal dominant (ADPKD) and recessive (ARPKD) polycystic kidney diseases are the most common hepatorenal fibrocystic diseases (ciliopathies). Characteristics of liver disease of these disorders are quite different. All of the patients with ARPKD have congenital hepatic fibrosis (CHF) often complicated by portal hypertension. In contrast, typical liver involvement in ADPKD is polycystic liver disease, although rare atypical cases with CHF are reported. Our goal was to describe the characteristics of CHF in ADPKD. PATIENTS AND METHODS: As a part of an intramural study of the National Institutes of Health on ciliopathies (www.clinicaltrials.gov, trial NCT00068224), we evaluated 8 patients from 3 ADPKD families with CHF. We present their clinical, biochemical, imaging, and PKD1 and PKHD1 sequencing results. In addition, we tabulate the characteristics of 15 previously reported patients with ADPKD-CHF from 11 families. RESULTS: In all of the 19 patients with ADPKD-CHF (9 boys, 10 girls), portal hypertension was the main manifestation of CHF; hepatocelllular function was preserved and liver enzymes were largely normal. In all of the 14 families, CHF was not inherited vertically, that is the parents of the index cases had PKD but did not have CHF-suggesting modifier gene(s). Our 3 families had pathogenic mutations in PKD1; sequencing of the PKHD1 gene as a potential modifier did not reveal any mutations. CONCLUSIONS: Characteristics of CHF in ADPKD are similar to CHF in ARPKD. ADPKD-CHF is caused by PKD1 mutations, with probable contribution from modifying gene(s). Given that both boys and girls are affected, these modifier(s) are likely located on autosomal chromosome(s) and less likely X linked. PMID- 21694641 TI - SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer in plasma. AB - INTRODUCTION: Recently, analysis of DNA methylation of the SHOX2 locus was shown to reliably identify lung cancer in bronchial aspirates of patients with disease. As a plasma-based assay would expand the possible applications of the SHOX2 biomarker, this study aimed to develop a modified SHOX2 assay for use in a blood based test and to analyze the performance of this optimized SHOX2 methylation assay in plasma. METHODS: Quantitative real-time polymerase chain reaction was used to analyze DNA methylation of SHOX2 in plasma samples from 411 individuals. A training study (20 stage IV patients with lung cancer and 20 controls) was performed to show the feasibility of detecting the SHOX2 biomarker in blood and to determine a methylation cutoff for patient classification. The resulting cutoff was verified in a testing study composed of 371 plasma samples from patients with lung cancer and controls. RESULTS: DNA methylation of SHOX2 could be used as a biomarker to distinguish between malignant lung disease and controls at a sensitivity of 60% (95% confidence interval: 53-67%) and a specificity of 90% (95% confidence interval: 84-94%). Cancer in patients with stages II (72%), III (55%), and IV (83%) was detected at a higher sensitivity when compared with stage I patients. Small cell lung cancer (80%) and squamous cell carcinoma (63%) were detected at the highest sensitivity when compared with adenocarcinomas. CONCLUSIONS: SHOX2 DNA methylation is a biomarker for detecting the presence of malignant lung disease in blood plasma from patients with lung cancer. PMID- 21694642 TI - Association of sarcoidosis and immune thrombocytopenia: presentation and outcome in a series of 20 patients. AB - The association of sarcoidosis and immune thrombocytopenia (ITP) has rarely been investigated. The aim of the current retrospective study was to investigate the clinical and biological phenotypes and outcome of this association in a large series of recent patients. Twenty patients (50% men) were included. Median age at sarcoidosis and ITP diagnosis was 36 (range, 10-83 yr) and 38 (range, 21-83 yr) years, respectively. In 11 of 20 (55%) patients, sarcoidosis onset preceded ITP (median interval, 48 mo; range, 6-216 mo). In 5 of 20 (25%) patients, the 2 conditions occurred concomitantly. In 4 of 20 (20%) patients, ITP onset preceded sarcoidosis (median interval, 68 mo; range, 15-153 mo). In 4 cases, sarcoidosis and ITP were not concomitant, since 1 condition was cured before the other was declared. In 12 of 20 (60%) patients there was a simultaneous onset or relapse of both ITP and sarcoidosis. Sarcoidosis phenotype was characterized by an acute onset in 40% of patients. The visceral involvement included thoracic sites in 19 of 20 (95%) patients and extrathoracic sites in 16 of 20 (80%) patients. At ITP onset, median platelet count was 11 * 10/L (range, 3-90); 17 (85%) patients had a platelet count <30 * 10/L. Seven (35%) patients had a bleeding score >8 without visceral bleeding.Nineteen of the 20 (95%) patients were treated specifically for ITP. After the first-line therapy (prednisone at 1 mg/kg per day for at least 3 consecutive weeks in all patients; with IVIg in addition for 10 patients with severe bleeding score), 12 of 19 (63%) patients achieved a complete response, 6 (31.5%) had a partial response, and only 1 patient failed to respond. At the end of ITP follow-up (median, 70 mo; range, 12-142 mo), 18 (90%) patients achieved a complete response, 1 achieved a partial response, and 1 had no response. After a median follow-up of 105 months, 13 of 20 (65%) patients had persistent sarcoidosis requiring prolonged therapy, and thus sarcoidosis represented the main long-term concern. Main conclusions were 1) ITP presentation was usually severe, but response to treatment was favorable in almost all cases, with no death and no severe bleeding, in contrast with older reports, 2) sarcoidosis was remarkable for the high proportion of cases with an acute onset, a chronic course, and the need for prolonged prednisone therapy, 3) sarcoidosis and ITP onset and evolution were not always synchronous. PMID- 21694643 TI - Organ dysfunction and muscular disability in myotonic dystrophy type 1. AB - Myotonic dystrophy type 1 (DM1) is a multisystemic disorder characterized by muscle weakness and multiple organ impairment, especially the eyes, lung, and heart. We conducted the current study to analyze the prevalence and intercorrelation among these disorders and their respective relationships with muscular disability. We assessed medical history, anthropometric data, lung volumes, arterial and venous blood samples, surface 12-lead electrocardiogram, echocardiography, ophthalmologic examination, and muscular impairment rating scale (MIRS) in 106 patients (48 male and 58 female) with DM1, aged 43.7 +/- 12.8 years. Obesity, hypertriglyceridemia, and diabetes were found in respectively 25.6%, 47.6%, and 17.1% of patients. Disabling cataract was found in 43.4%, and was independently predicted by age and MIRS. Restrictive lung disease was noted in 34%, and was predicted by MIRS, CTG repeat expansion, and body mass index. Conduction disorders were found in 30.2% of patients and were predicted by left ventricular ejection fraction, MIRS, and CTG repeat expansion.We found significant relationships between cataract, restrictive lung disease, and conduction disorders: patients with cataract and those with conduction disorders exhibited more severe restrictive lung disease than the other patients. Conversely, the relative risk of restrictive lung disease was 2.42 (1% confidence interval [CI], 1.06-5.51) in patients with cataract and 2.54 (1% CI, 1.26-5.07) in patients with conduction disorders. Multivariate analysis revealed that MIRS was the only independent predictor for conduction disorders and restrictive lung disease. MIRS >=3 and MIRS >=4 were the best simple cutoff values to predict, respectively, lung and cardiac involvements.To conclude, muscular disability, ophthalmologic, and cardiac and pulmonary involvement are strongly correlated. Particular attention should be given to these entities in patients with distal or proximal muscular weakness. PMID- 21694644 TI - Multiple-valve infective endocarditis: clinical, microbiologic, echocardiographic, and prognostic profile. AB - Whether infection in more than 1 valve worsens the prognosis for endocarditis remains untested. We conducted the current study to determine the profile of multiple-valve endocarditis, compare multiple-valve endocarditis with single valve endocarditis, and determine predictors of outcome. We conducted a prospective and observational study including 680 episodes of infective endocarditis consecutively diagnosed at 3 tertiary centers. Multiple valve involvement was present in 115 episodes (17%), and single valve involvement in 530 (78%). In the remaining 35 cases, valvular involvement could not be documented. Mean age of patients with multiple valve endocarditis was 58 years. Clinical complications were frequent (heart failure 65%, renal failure 44%, systemic embolisms 24%). The microorganism most frequently isolated was Staphylococcus aureus (22%).Factors predictive of in-hospital mortality in the univariate analysis were septic shock, prosthetic endocarditis, heart failure, and persistent infection. In the multivariate analysis, we detected heart failure (odds ratios [OR], 4.7; 95% confidence interval [CI], 1.6-13.8) and persistent infection (OR, 4.3; 95% CI, 1.7-10.8) as predictors of in-hospital mortality. Compared to single-valve endocarditis, multiple-valve disease was associated more frequently with heart failure (65% vs. 50%, p = 0.03), perivalvular complications (41% vs. 21%, p < 0.001), and heart surgery (70% vs. 54%, p = 0.002). Despite these differences, in-hospital mortality was similar (28% vs. 30%, p = 0.647). In conclusion, multiple-valve endocarditis has a poor clinical course. Mortality is similar to that of single-valve endocarditis, probably in relation with aggressive therapy including surgery in many patients. Heart failure and persistent infection are independent predictors of death. PMID- 21694646 TI - The role of fluconazole in the treatment of Candida endocarditis: a meta analysis. AB - The treatment of Candida infective endocarditis generally involves infected valve removal accompanied by antifungal therapy with amphotericin B or a lipid-based derivative, with or without flucytosine. While often used as chronic suppressive therapy in these patients, the precise role for fluconazole has not been established. We conducted a meta-analysis of 64 literature cases of Candida endocarditis whose management did not include valve replacement but who received fluconazole, alone or concurrently or in sequence with 1 or more other antifungal drugs.Forty-nine (77%) patients were cured (n = 44) or improved (n = 5), 4 relapsed (6%), and 11 failed (10 of whom died) (17%). Among 19 patients for whom fluconazole was administered as the sole antifungal therapy, 11 (58%) were cured or improved. In contrast, among 45 patients who received 1 or more other antifungal agents in addition to fluconazole, 38 (84%) were cured or improved (p = 0.02). Eighteen of 21 (86%) patients with native valve infection were cured or improved compared with 13 of 19 (68%) patients with prosthetic valve endocarditis (p = 0.13). The mean duration of successful fluconazole regimens was 134 days. Twenty of 21 (95%) patients who received fluconazole as chronic suppressive therapy for >=6 months were cured. Prognosis was independent of Candida species or patient age. Among 23 historical controls managed with fluconazole-containing antifungal therapy plus valvular surgery, survival was 91%.In conclusion, fluconazole-containing, combination antifungal therapy, with or without concomitant valve replacement, and followed by prolonged, perhaps indefinite fluconazole suppression, is effective in patients with Candida endocarditis. PMID- 21694645 TI - Mycobacterium genavense infections: a retrospective multicenter study in France, 1996-2007. AB - Mycobacterium genavense, a nontuberculous mycobacterium, led to devastating infections in patients with acquired immunodeficiency syndrome (AIDS) before highly active antiretroviral therapy (HAART) was available, as well as in other immunocompromised patients. We conducted the current study to describe the features of this infection in patients infected with human immunodeficiency virus (HIV) in the HAART era and in non HIV-infected patients.We conducted a retrospective cohort survey in France. All patients with M. genavense infection diagnosed from 1996 to 2007 at the National Reference Center, Institut Pasteur, Paris, were identified and their clinical, laboratory, and microbiologic data were centralized in a single database. Twenty-five cases of M. genavense infection originating from 19 centers were identified. Twenty patients had AIDS, 3 had solid organ transplantation, and 2 had sarcoidosis. Sixty-four percent (n = 16) were male, mean age was 42 years, and median CD4 count was 13/mm (range, 0 148/mm) in patients with AIDS. Twenty-four patients had disseminated infection with fever (75%, n = 18), weight loss (79%, n = 19), abdominal pain (71%, n = 17), diarrhea (62.5%, n = 15), splenomegaly (71%, n = 17), hepatomegaly (62.5%, n = 15), or abdominal adenopathy (62.5%, n = 15). M. genavense was isolated from the lymph node (n = 13), intestinal biopsy (n = 9), blood (n = 6), sputum (n = 3), stool (n = 3), and bone marrow (n = 5). Eleven patients (44%) died, 8 (32%) were considered cured with no residual symptoms, and 6 (24%) had chronic symptoms. The 1-year survival rate was 72%.The prognosis of M. genavense infection in HIV-infected patients has dramatically improved with HAART. Clinical presentations in HIV and non-HIV immunocompromised patients were similar. PMID- 21694647 TI - Left-sided Pseudomonas aeruginosa endocarditis in patients without injection drug use. AB - We aimed to determine the clinical features, predisposing factors, and outcome of left-sided Pseudomonas aeruginosa endocarditis in persons with no history of injection drug use. We performed a retrospective review of patient medical records from Mayo Clinic (Rochester, MN; Scottsdale, AZ; and Jacksonville, FL) for all cases of left-sided P. aeruginosa endocarditis. We identified 4 cases. We present these cases, as well as a review of the English-language medical literature. Data gathered included the year the case was reported; the valve involved; treatment, including valve replacement surgery; and outcome, if known. Left-sided P. aeruginosa endocarditis in persons without injection drug use is a rare but serious infection, with a history of instrumentation as a common predisposing condition. Valvular surgery is indicated, when possible, for the best chance of survival, along with extended therapy with combination antibiotics for complete recovery. PMID- 21694648 TI - Rhombencephalitis: a series of 97 patients. AB - The term rhombencephalitis refers to inflammatory diseases affecting the hindbrain (brainstem and cerebellum). Rhombencephalitis has a wide variety of etiologies, some of them potentially severe and life threatening without proper early treatment. In this retrospective observational study, we reviewed the records of consecutively hospitalized patients at University Hospital of Bellvitge (Barcelona, Spain) from January 1990 to December 2008. Rhombencephalitis was defined as a brainstem and/or cerebellar condition demonstrated clinically or by neuroimaging, with pleocytosis (>4 cells/mm) in cerebrospinal fluid. Ninety-seven patients (48 female; mean age, 37 yr; range, 14 79 yr) fulfilled these criteria. We reviewed their clinical, cerebrospinal fluid, and radiologic characteristics. The mean follow-up was 5 years (range, 0-20 yr). The etiologies of rhombencephalitis were as follows: unknown cause (n = 31), multiple sclerosis (n = 28), Behcet disease (n = 10), Listeria monocytogenes infection (n = 9), paraneoplastic syndrome (n = 6) (3 cases associated with anti Yo antibodies and 3 with anti-Tr antibodies), Epstein-Barr virus (n = 4), tuberculosis (n = 2), pneumococcal infection (n = 2), systemic lupus erythematosus (n = 1), lymphoma (n = 1), Brucella species infection (n = 1), JC virus (n = 1), and relapsing polychondritis (n = 1). Certain clinical, cerebrospinal fluid, and radiologic characteristics that are commonly seen in some of these etiologies can guide us in the first approach to the etiologic diagnosis of rhombencephalitis. PMID- 21694649 TI - Nicergoline improves dysphagia by upregulating substance P in the elderly. AB - Dysphagia induces silent aspiration, which is a known risk factor for aspiration pneumonia in the elderly. Dysphagia is associated with impaired substance P secretion. Because nicergoline was recently reported to enhance substance P secretion, it may improve dysphagia by upregulating substance P; however, roles for nicergoline in this process have not been demonstrated. We therefore compared the effects of nicergoline on serum substance P and dysphagia with the effects of imidapril, an angiotensin-converting enzyme (ACE) inhibitor whose efficacy in improving dysphagia and preventing pneumonia has been previously demonstrated.We randomly assigned 60 elderly patients with both dysphagia and a previous history of pneumonia to receive either imidapril (5 mg/d; n = 30) or nicergoline (15 mg/d; n = 30) for 6 months. Primary outcomes were the effects of these drugs on the substance P level and dysphagia 4 weeks after the start of treatment. Secondary outcome was the effect of these drugs on pneumonia recurrence during the 6 months of treatment.Significant elevations of serum substance P were obtained by both medications after 4 weeks of treatment. Patients whose dysphagia was improved showed significantly increased serum levels of substance P. There was no statistically significant difference in the overall proportion of patients who showed improvements in dysphagia and pneumonia recurrence with imidapril or nicergoline treatment. Nicergoline, but not imidapril, seemed to be more effective at improving dysphagia and elevating serum substance P in patients with dementia.In conclusion, nicergoline has a comparable effect to ACE inhibitors for improving dysphagia. Nicergoline might be a novel regimen for the treatment of dysphagia in the elderly who are not treatable with ACE inhibitors. PMID- 21694650 TI - Preventing Staphylococcus aureus bacteremia and sepsis in patients with Staphylococcus aureus colonization of intravascular catheters: a retrospective multicenter study and meta-analysis. AB - Two previous studies in tertiary care hospitals identified Staphylococcus aureus colonization of intravascular (IV) catheters as a strong predictor of subsequent S. aureus bacteremia (SAB), even in the absence of clinical signs of systemic infection. Bacteremia was effectively prevented by timely antibiotic therapy. We conducted this study to corroborate the validity of these findings in non university hospitals.Using the laboratory information management systems of the clinical microbiology departments in 6 Dutch hospitals, we identified patients who had IV catheters from which S. aureus was cultured between January 1, 2003, and December 31, 2008. Patients with demonstrated SAB between 7 days before catheter removal and 24 hours after catheter removal were excluded. We extracted clinical and demographic patient data from the patients' medical records. The primary risk factor was initiation of anti-staphylococcal antibiotic therapy within 24 hours, and the primary endpoint was SAB >24 hours after IV catheter removal. Subsequently, we performed a systematic review and meta-analysis of all observational studies evaluating the effect of antibiotic therapy for S. aureus IV catheter tip colonization.In the current study, 18 of the 192 included patients developed subsequent SAB, which was associated with not receiving antibiotic therapy within 24 hours (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.1-15.6) and with documented exit-site infection (OR, 3.3; 95% CI, 1.2 9.3). When we combined these results with results of a previous study in a university hospital, a third risk factor was also associated with subsequent SAB, namely corticosteroid therapy (OR, 2.9; 95% CI, 1.3-6.3). We identified 3 other studies, in addition to the present study, in a systematic review. In the meta analysis of these studies, antibiotic therapy yielded an absolute risk reduction of 13.6% for subsequent SAB. The number needed to treat to prevent 1 episode of SAB was 7.4.We conclude that early initiation of antibiotic therapy for IV catheters colonized with S. aureus prevents subsequent SAB. PMID- 21694651 TI - Serum ferritin levels are associated with metabolic syndrome in postmenopausal women but not in premenopausal women. AB - OBJECTIVE: Ferritin, a marker of total body iron stores, is known to be associated with the risk of having metabolic syndrome and has been demonstrated to increase after the onset of menopause. Postmenopause status is an important determinant of metabolic syndrome. The aim of this study was to perform a menopause status-specific analysis of the association between ferritin levels and metabolic syndrome. METHODS: We conducted a cross-sectional study of 3,082 participants (1,691 premenopausal women and 1,391 postmenopausal women), all of whom were enrolled in the Korean National Health and Nutrition Examination Survey 2007. RESULTS: Premenopausal and postmenopausal women with metabolic syndrome had higher ferritin levels than did those without metabolic syndrome. After adjustments for age; body mass index; alcohol intake; smoking history; exercise; hormone therapy use; hemoglobin, aspartate aminotransferase, and alanine aminotransferase levels; and intake of energy and iron, multivariate logistic regression analysis revealed that postmenopausal women with ferritin levels in the third tertile had an increased risk of having metabolic syndrome (odds ratio, 1.62; 95% CI, 1.04-2.81) compared with postmenopausal women with levels in the first quartile. No such association was detected in premenopausal women. CONCLUSIONS: Increased ferritin levels may be a determinant for metabolic syndrome in postmenopausal women but not in premenopausal women. PMID- 21694654 TI - Intracranial pressure and pulsatility index. PMID- 21694655 TI - Risk prediction with carotid MRI. PMID- 21694656 TI - Landmarks for the Sigmoid Sinus. PMID- 21694657 TI - Sex and the cytokines: are there fundamental differences in response to brain injury? PMID- 21694658 TI - Use of the microangiographic fluoroscope for coiling of intracranial aneurysms. AB - BACKGROUND: Neurointervention is an ever-evolving specialty with tools including microcatheters, microwires, and coils that allow treatment of pathological conditions in increasingly smaller intracranial arteries, requiring increasing accuracy. As endovascular tools evolve, so too should the imaging. OBJECTIVE: To detail the use of microangiography performed with a novel fluoroscope during coiling of intracranial aneurysms in 2 separate patients and discuss the benefits and potential limitations of the technology. METHODS: The microangiographic fluoroscope (MAF) is an ultra high-resolution x-ray detector with superior resolution over a small field of view. The MAF can be incorporated into a standard angiographic C-arm system for use during endovascular procedures. RESULTS: The MAF was useful for improved visualization during endovascular coiling of 2 unruptured intracranial aneurysms, without adding significant time to the procedure. No significant residual aneurysm filling was identified post coiling, and no complications occurred. CONCLUSION: The MAF is a high-resolution detector developed for use in neurointerventional cases in which superior image quality over a small field of view is required. It has been used with success for coiling of 2 unruptured aneurysms at our institution. It shows promise as an important tool in improving the accuracy with which neurointerventionists can perform certain intracranial procedures. PMID- 21694659 TI - Interferon-gamma release assay performance for diagnosing tuberculosis disease in 0- to 5-year-old children. AB - QuantiFERON-TB Gold In-Tube performance was evaluated in 19 French immunocompetent children (0.29-5.36 years; median: 1.52) with active tuberculosis. The rate of indeterminates results was 0/19 and the rates of positivity were 6/10 and 9/9 in <2 and 2- to 5-year-old children, respectively. QuantiFERON-TB Gold In-Tube in association with tuberculin skin test could improve diagnosis of tuberculosis even in young children. PMID- 21694660 TI - Children with retinopathy-negative cerebral malaria: a pathophysiologic puzzle. AB - BACKGROUND: Cerebral malaria, defined as otherwise unexplained coma in a patient with circulating parasitemia, is a common disease in the developing world. The clinical diagnosis lacks specificity and children with other underlying causes of coma might be misdiagnosed as having cerebral malaria. The presence of malarial retinopathy can be used to differentiate children whose comas are caused by Plasmodium falciparum and its attendant pathophysiologies from those with other reasons for their abnormal mental status. Children with cerebral malaria who lack malarial retinopathy have not previously been described. METHODS: All patients admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi, during a 12 month period with a clinical diagnosis of cerebral malaria were evaluated for the presence of malarial retinopathy. Thirty-two patients lacked retinopathy findings. Clinical, laboratory, and radiologic information data were collected. RESULTS: Thirty-two cases of retinopathy-negative cerebral malaria are presented. CONCLUSIONS: Children with retinopathy-negative cerebral malaria share a common clinical phenotype with lower rates of mortality compared with those who have malarial retinopathy. There are at least 4 possible pathophysiologic explanations for this common condition. PMID- 21694661 TI - An outbreak of adenovirus type 7 in a residential facility for severely disabled children. AB - BACKGROUND: Adenoviruses cause a variety of clinical symptoms, involving the respiratory, gastrointestinal, urogenital, and neurologic systems. Only a few of the 55 known serotypes of adenovirus that affect humans can cause outbreaks of respiratory tract infection. AIM: To describe the characteristics and clinical manifestations of severe respiratory disease contracted by 8 physically and cognitively disabled children during a very short outbreak of adenovirus serotype 7 infection in a residential facility. METHODS: The clinical, imaging, and laboratory findings of the patients who were hospitalized with severe respiratory symptoms were retrospectively reviewed. Molecular typing of the adenovirus was performed. RESULTS: During 10 days in February 2010, 8 severely disabled children, 9 months to 5 years of age (median 22.5 months), from the same residential facility, were hospitalized due to severe acute respiratory disease with hypoxemia. Four of them (50%) needed mechanical ventilation for 2 to 8 days and one developed multisystem failure, including acute renal failure. Adenovirus serotype 7 was detected in the respiratory specimens of all 8 children. Two patients were treated with intravenous cidofovir. All 8 patients survived and were discharged after hospitalization of 6 to 15 (median: 11.5) days. The epidemiologic investigation revealed that all the 8 affected children shared a playroom and a caregiver worked with them while suffering fever, sore throat, and conjunctivitis before the onset of the outbreak. CONCLUSIONS: Adenovirus type 7 may cause short outbreaks of infection in institutions, causing children to develop life-threatening disease. Early detection of pathogens causing respiratory infections in institutions, isolation, and other preventive precautions are advocated. Moreover, vaccination of health care providers in institutions with the currently available live, oral adenovirus vaccine for types 4 and 7 should be considered. PMID- 21694662 TI - Liver transplantation for hepatocellular carcinoma: defining the impact of using extended criteria liver allografts. AB - BACKGROUND: This series compares outcomes of patients with hepatocellular carcinoma (HCC) listed for orthotopic liver transplantation (OLT) within and outside Milan criteria, and determines the impact of extended criteria liver allografts (ECD). METHODS: Records of patients listed for liver transplantation at a single center from 1998 to 2007 were reviewed retrospectively. RESULTS: Ninety-seven HCC patients were listed for OLT, 77 underwent transplantation; 47 received ECDs and 30 standard organs. ECDs were more frequently allocated to outside Milan recipients. Wait time for OLT was shorter for outside Milan patients (4 vs. 7 months P=0.04) but hazard rate of dropout was higher (26%, 46%, and 73% at 6,12, and 24 months compared with 2%, 14%, and 60% P<0.01). Tumor size more than 3 cm (P=0.02) and model for end-stage liver disease score at listing more than 11 (P=0.04) were independent predictors of dropout. Hazard rate of OLT was similar within and outside Milan (61%, 80%, and 90% at 6, 12, and 24 months vs. 60%, 70%, and 86% P=0.38). Post-OLT survival at 1 year and 4 years were 88% and 63% within Milan compared with 79% and 62% among Milan out recipients (P=0.95). No significant post-OLT survival predictor was found. CONCLUSION: The use of ECD organs provided patients with HCCs outside Milan criteria access to liver transplant at a rate comparable to patients within Milan and model for end stage liver disease HCC priority. Similar patient survival post-OLT can be achieved using standard or ECD organs. The higher risk of drop out in patients outside Milan, and even within Milan, with tumors more than 3 cm justifies the use of ECD organs for timely transplantation. PMID- 21694663 TI - Teriparatide efficacy in the treatment of severe hypocalcemia after kidney transplantation in parathyroidectomized patients: a series of five case reports. AB - BACKGROUND: Teriparatide is a recombinant human parathormone (PTH 1-34) currently approved for the treatment of osteoporosis with high risk of fracture. In this study, we analyze the efficacy and safety profile of teriparatide therapy in severe and prolonged hypocalcemia after kidney transplantation in patients previously submitted to parathyroidectomy. METHODS: The authors report results from a series of five hemodialyzed patients (mean age: 50+/-15 years; three female) previously submitted to parathyroidectomy to control secondary hyperparathyroidism. All patients had developed severe refractory hypocalcemia (calcium minimum levels: 5+/-1.4 mg/dL) early after kidney transplantation. The effect of teriparatide in calcemia and phosphatemia levels was analyzed, and variations in calcium and vitamin D analog requirements were analyzed. Secondary effects and serum creatinine changes were also ascertained. RESULTS: Teriparatide therapy was initiated 32+/-14 days after the development of hypocalcemia. As a result, calcemia levels increased (median+/-standard deviation [SD]: 6.7+/-0.8 vs. 8.5+/-0.8 mg/dL, P=0.024) allowing suspension of intravenous calcium in two patients and reduction of calcitriol doses (mean+/-SD: 1.1+/-0.38 vs. 0.55+/-0.27 MUg/day, P=0.004). In addition, phosphatemia levels (median+/-SD: 5.1+/-1.5 vs. 3.9+/-0.5 mg/dL, P=0.09) and calcium carbonate requirements (mean+/-SD: 13.8+/ 9.4 vs. 7.2 +/-3.7 g/day, P=0.9) exhibited declining trends. No secondary effects were observed and creatinemia remained stable. CONCLUSIONS: Our data strongly suggest that refractory hypocalcemia after kidney transplantation in patients with low PTH levels can be successfully treated with teriparatide. PTH analog therapy leads to faster normalization of calcemia, permits earlier suspension of intravenous calcium supplementation, and reduces calcitriol requirements. PMID- 21694664 TI - Improved rejection prophylaxis with an initially intensified dosing regimen of enteric-coated mycophenolate sodium in de novo renal transplant recipients. AB - BACKGROUND: Approximately half of cyclosporine A-treated renal transplant recipients do not reach sufficient mycophenolic acid (MPA) exposure in the first weeks posttransplantation with standard MPA dosing regimens. METHODS: Here, we present a prospectively planned meta-analysis of data from two 6-month parallel run studies that evaluated the effect of an initially intensified versus standard dosing regimen of enteric-coated mycophenolate sodium (EC-MPS). Four hundred forty-one de novo renal transplant recipients were randomized (1:1) to intensified (2 weeks 2880 mg/d; subsequently 4 weeks 2160 mg/d; followed by 1440 mg/d) or standard (1440 mg/d) EC-MPS, with concomitant cyclosporine A treatment and steroids with or without anti-IL-2R induction. Primary endpoint was treatment failure (biopsy-proven acute rejection [BPAR], graft loss, or death) at month 6 posttransplantation. RESULTS: Treatment failure rates were 17.4% in intensified and 22.4% in standard groups (P=0.110). The incidence of BPAR was 13.8% (intensified) vs. 19.3% (standard; P=0.034). A total of 80.5% (intensified) versus 39.0% (standard) of patients achieved 12 hr MPA-area under the curve more than 30 MUg.hr/mL as early as day 3 posttransplant. Renal function, gastrointestinal symptom rating scores, and safety profiles were comparable between treatment groups. CONCLUSION: The initially intensified EC-MPS dosing regimen was associated with higher MPA exposure, significantly lower rate of BPAR, and comparable safety. However, the intensified regimen did not affect graft function or survival. PMID- 21694665 TI - Generation of soluble human tumor necrosis factor-alpha receptor 1-Fc transgenic pig. AB - BACKGROUND: Acute humoral xenograft rejection (AHXR) is an important barrier to xenograft survival. Human tumor necrosis factor-alpha (hTNF-alpha) is one of the essential mediators of AHXR and induces activation of porcine endothelial cells (PECs), resulting in upregulation of major histocompatibility complex molecules, adhesion molecules, and proinflammatory chemokines. We investigated whether introduction of a soluble human tumor necrosis factor receptor I-Fc (shTNFRI-Fc) fusion gene can suppress activation of PECs and, more importantly, produced shTNFRI-Fc transgenic pigs. METHODS: The shTNFRI-Fc gene expression vector was constructed and inserted into PECs. The inhibitory effects of shTNFRI-Fc were tested by luciferase assay, reverse-transcriptase polymerase chain reaction, and flow cytometry. A shTNFRI-Fc transgenic pig was generated by somatic cell nuclear transfer. The expression of shTNFRI-Fc in the transgenic pig was evaluated by PCR, western blot, enzyme-linked immunosorbent assay, and immunohistochemistry. The inhibitory effects of shTNFRI-Fc in the serum obtained from the transgenic pig were also tested. RESULTS: In comparison with control green fluorescent protein, shTNFRI-Fc protein showed much stronger inhibitory effects on NF-kappaB activation in the HEK293-NF-kappaB-luciferase reporting cell line, expression of chemokines and adhesion molecules in PECs, and TNF-alpha-mediated cytotoxicity. We successfully generated shTNFRI-Fc transgenic pig. Sera obtained from the transgenic pig inhibited induction of chemokines, and E-selectin in PECs stimulated with Human TNF-alpha. CONCLUSIONS: We have generated transgenic pigs producing shTNFRI-Fc protein that can inhibit TNF-alpha-mediated activation of PECs. Because TNF-alpha is an important mediator of xenograft rejection, the use of xenografts that can produce shTNFRI-Fc proteins de novo could be an effective approach in overcoming a considerable component of the xenograft rejection process, especially AHXR. PMID- 21694666 TI - Effects of acute gamma irradiation on physiological traits and flavonoid accumulation of Centella asiatica. AB - In the present study, two accessions of Centella asiatica (CA03 and CA23) were subjected to gamma radiation to examine the response of these accessions in terms of survival rate, flavonoid contents, leaf gas exchange and leaf mass. Radiation Sensitivity Tests revealed that based on the survival rate, the LD(50) (gamma doses that killed 50% of the plantlets) of the plantlets were achieved at 60 Gy for CA03 and 40 Gy for CA23. The nodal segments were irradiated with gamma rays at does of 30 and 40 Gy for Centella asiatica accession 'CA03' and 20 and 30 Gy for accession 'CA23. The nodal segment response to the radiation was evaluated by recording the flavonoid content, leaf gas exchange and leaf biomass. The experiment was designed as RCBD with five replications. Results demonstrated that the irradiated plantlets exhibited greater total flavonoid contents (in eight weeks) significantly than the control where the control also exhibited the highest total flavonoid contents in the sixth week of growth; 2.64 +/- 0.02 mg/g DW in CA03 and 8.94 +/- 0.04 mg/g DW in CA23. The total flavonoid content was found to be highest after eight weeks of growth, and this, accordingly, stands as the best time for leaf harvest. Biochemical differentiation based on total flavonoid content revealed that irradiated plantlets in CA23 at 20 and 30 Gy after eight weeks contained the highest total flavonoid concentrations (16.827 +/ 0.02; 16.837 +/- 0.008 mg/g DW, respectively) whereas in CA03 exposed to 30 and 40 Gy was found to have the lowest total flavonid content (5.83 +/- 0.11; 5.75 +/ 0.03 mg/g DW). Based on the results gathered in this study, significant differences were found between irradiated accessions and control ones in relation to the leaf gas. The highest PN and gs were detected in CA23 as control followed by CA23 irradiated to 20Gy (CA23G20) and CA23G30 and the lowest PN and gs were observed in CA03 irradiated to 40Gy (CA03G40). Moreover, there were no significant differences in terms of PN and gs among the irradiated plants in each accession. The WUE of both irradiated accessions of Centella asiatica were reduced as compared with the control plants (p < 0.01) while Ci and E were enhanced. There were no significant differences in the gas exchange parameters among radiated plants in each accession. Moreover, malondialdehyde (MDA) of accessions after gamma treatments were significantly higher than the control, however, flavonoids which were higher concentration in irradiated plants can scavenge surplus free radicals. Therefore, the findings of this study have proven an efficient method of in vitro mutagenesis through gamma radiation based on the pharmaceutical demand to create economically superior mutants of C. asiatica. In other words, the results of this study suggest that gamma irradiation on C. asiatica can produce mutants of agricultural and economical importance. PMID- 21694667 TI - Enantioselective Evans-Tishchenko reduction of beta-hydroxyketone catalyzed by lithium binaphtholate. AB - Lithium diphenylbinaphtholate catalyzed the enantioselective Evans-Tishchenko reduction of achiral beta-hydroxyketones to afford monoacyl-protected 1,3-diols with high stereoselectivities. In the reaction of racemic beta-hydroxyketones, kinetic optical resolution occurred in a highly stereoselective manner. PMID- 21694668 TI - Ru/Me-BIPAM-catalyzed asymmetric addition of arylboronic acids to aliphatic aldehydes and alpha-ketoesters. AB - A ruthenium-catalyzed asymmetric arylation of aliphatic aldehydes and alpha ketoesters with arylboronic acids has been developed, giving chiral alkyl(aryl)methanols and alpha-hydroxy esters in good yields. The use of a chiral bidentate phosphoramidite ligand (Me-BIPAM) achieved excellent enantioselectivities. PMID- 21694669 TI - Synthetic dye--inorganic salt hybrid colorants for application in thermoplastics. AB - Common synthetic dyes, e.g., Weak Acid Pink Red B (APRB, C.I. 18073), Mordant Blue 9 (MB, C.I.14855) and Acid Brilliant Blue 6B (ABB6B, C.I. 42660), can be removed from water by in situ hybridization with CaCO(3), BaSO(4) and Ca(3)(PO(4))(2) and the resulting hybrids thus prepared used as plastic colorants. All the hybrids can be processed into polypropylene (PP) at 200 degrees C with good color intensity, color brightness and homogeneous dispersion. The BaSO(4)-MB hybrid exhibits better migration resistance to acid and alkali, and stronger covering power than the BaSO(4)-MB mixture. The thermal stability and UV resistance of the Ca(3)(PO(4))(2)-ABB6B hybrid are better than those of the Ca(3)(PO(4))(2)-ABB6B mixture. The crystallinity of PP is enhanced by incorporation of these hybrids and the use of these hybrids as colorants in PP instead of the dyes alone is determined to be feasible. PMID- 21694670 TI - Cholesterol-lowering activity of the major polyphenols in grape seed. AB - The major polyphenols in grape seed have been shown to have beneficial health effects in the prevention of dyslipidemia and cardiovascular diseases. In this present study, we investigated the cholesterol-lowering activity of three major polyphenolic compounds found in grape seed. The results showed that gallic acid, catechin, and epicatechin significantly inhibited pancreatic cholesterol esterase in a concentration-dependent manner. Moreover, they bound to taurocholic acid, taurodeoxycholic acid, and glycodeoxycholic acid at levels ranging from 38.6% to 28.2%. At the concentration of 0.2 mg/mL, gallic acid, catechin, and epicatechin reduced the formation of cholesterol micelles 27.26 +/- 2.17%, 11.88 +/- 0.75%, and 19.49 +/- 3.71%, respectively. These findings clearly demonstrate that three major polyphenolic compounds present in a particular grape seed have cholesterol lowering activity by inhibiting pancreatic cholesterol esterase, binding of bile acids, and reducing solubility of cholesterol in micelles which may result in delayed cholesterol absorption. PMID- 21694671 TI - Two-carbon homologation of aldehydes and ketones to alpha,beta-unsaturated aldehydes. AB - Phosphonate reagents were developed for the two-carbon homologation of aldehydes or ketones to unbranched- or methyl-branched alpha,beta-unsaturated aldehydes. The phosphonate reagents, diethyl methylformyl-2-phosphonate dimethylhydrazone and diethyl ethylformyl-2-phosphonate dimethylhydrazone, contained a protected aldehyde group instead of the usual ester group. A homologation cycle entailed condensation of the reagent with the starting aldehyde, followed by removal of the dimethylhydrazone protective group with a biphasic mixture of 1 M HCl and petroleum ether. This robust two-step process worked with a variety of aldehydes and ketones. Overall isolated yields of unsaturated aldehyde products ranged from 71% to 86% after the condensation and deprotection steps. PMID- 21694672 TI - Nematocidal flavone-C-glycosides against the root-knot nematode (Meloidogyne incognita) from Arisaema erubescens tubers. AB - A screening of several Chinese medicinal herbs for nematicidal properties showed that Arisaema erubescens (Wall.) Schott tubers possessed significant nematicidal activity against the root-knot nematode (Meloidogyne incognita). From the ethanol extract, two nematicidal flavone-C-glycosides were isolated by bioassay-guided fractionation. The compounds were identified as schaftoside and isoschaftoside on the basis of their phytochemical and spectral data. Schaftoside and isoschaftoside possessed strong nematicidal activity against M. incognita (LC(50) = 114.66 MUg/mL and 323.09 MUg/mL, respectively) while the crude extract of A. erubescens exhibited nematicidal activity against the root-knot nematode with a LC(50) value of 258.11 MUg/mL. PMID- 21694673 TI - Crystallization and characterization of an inflammatory lectin purified from the seeds of Dioclea wilsonii. AB - DwL, a lectin extracted from the seeds of Dioclea wilsonii, is a metalloprotein with strong agglutinating activity against rabbit and ABO erythrocytes, inhibited by glucose and mannose. DwL was purified by affinity chromatography on a Sephadex G-50 column and ion exchange chromatography on a HiTrap SP XL column. SDS-PAGE revealed three electrophoretic bands corresponding to the alpha (25,634 +/- 2 Da), beta (12,873 +/- 2 Da) and gamma (12,779 +/- 2 Da) chains. Protein sequencing was done by Tandem Mass Spectrometry. The primary sequence featured 237 amino acids and was highly homologous to other reported Diocleinae lectins. A complete X-ray dataset was collected at 2.0 A for X-Man-complexed DWL crystals produced by the vapor diffusion method. The crystals were orthorhombic and belonged to the space group I222, with the unit-cell parameters a = 59.6, b = 67.9 and c = 109.0 A. DWL differed in potency from other ConA-like lectins and was found to induce neutrophil migration in rats, making it particularly useful in structural/functional studies of this class of proteins. PMID- 21694674 TI - Characteristic aroma compounds from different pineapple parts. AB - Characteristic aroma volatile compounds from different parts of cayenne pineapple were analyzed by headspace-solid phase microextraction (HS-SPME) and gas chromatography-mass spectrometry (GC/MS). The main volatile compounds were esters, terpenes, ketones and aldehydes. The number and content of aroma compounds detected in pulp were higher than those found in core. In pulp, the characteristic aroma compounds were ethyl 2-methylbutanoate, ethyl hexanoate, 2,5 dimethyl-4-hydroxy-3(2H)-furanone (DMHF), decanal, ethyl 3 (methylthio)propionate, ethyl butanoate, and ethyl (E)-3-hexenoate; while in core the main compounds were ethyl 2-methylbutanoate, ethyl hexanoate and DMHF. The highest odor units were found to correspond to ethyl 2-methylbutanoate, followed by ethyl hexanoate and DMHF. The odor units found for pulp were higher than those for core. PMID- 21694675 TI - Methoxymethyl (MOM) group nitrogen protection of pyrimidines bearing C-6 acyclic side-chains. AB - Novel N-methoxymethylated (MOM) pyrimidine (4-13) and pyrimidine-2,4-diones (15 17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position of the pyrimidine moiety were synthesized. Synthetic methods via O persilylated or N-anionic uracil derivatives have been evaluated for the synthesis of N-1- and/or N-3-MOM pyrimidine derivatives with C-6 acyclic side chains. A synthetic approach using an activated N-anionic pyrimidine derivative afforded the desired N,N-1,3-diMOM and N-1-MOM pyrimidines 4 and 5 in good yield. Introduction of fluorine into the side-chain was performed with DAST as the fluorinating reagent to give a N,N-1,3-diMOM pyrimidine 13 with a 1-fluoro-3 hydroxyisobutyl moiety at C-6. Conformational study of the monotritylated N-1-MOM pyrimidine 12 by the use of the NOE experiments revealed the predominant conformation of the compound to be one where the hydroxymethyl group in the C-6 side-chain is close to the N-1-MOM moiety, while the OMTr is in proximity to the CH(3)-5 group. Contrary to this no NOE enhancements between the N-1-MOM group and hydroxymethyl or fluoromethyl protons in 13 were observed, which suggested a nonrestricted rotation along the C-6 side-chain. Fluorinated N,N-1,3-diMOM pyrimidine 13 emerged as a model compound for development of tracer molecules for non-invasive imaging of gene expression using positron emission tomography (PET). PMID- 21694676 TI - Synthesis and cytotoxic evaluation of novel N-methyl-4-phenoxypicolinamide derivatives. AB - A series of N-methyl-4-phenoxypicolinamide derivatives were synthesized and evaluated in vitro for their cytotoxic activity against A549, H460 and HT29 cell lines. Pharmacological data indicated that some of the target compounds possessed marked antiproliferative activity, superior to that of the reference drug sorafenib. As the most promising compound, 8e exhibited potent cytotoxicity with the IC(50) value of 3.6, 1.7 and 3.0 MUM against A549, H460 and HT-29 cell lines, respectively. PMID- 21694677 TI - Reactions of some new thienothiophene derivatives. AB - Facile and convenient syntheses of bisdimethylthieno[2,3-b]thiophen-2,5-diyl bis(oxazole-2-amine), bis(1H-imidazol-2-amine), bis((3a)-H-indole),[1,2 a]pyrimidine), bis(1H-imidazo[1,2-b][1,2,4]triazole) and bis(9H benzo[d]imidazo[1,2-a]imidazole) derivatives incorporating a thieno[2,3 b]thiophene moiety from the versatile and readily accessible 1,1'(3,4 dimethylthieno[2,3-b]thiophene-2,5-diyl)-bis(2-bromo-ethanone) (1) are described. PMID- 21694678 TI - Phytochemical analysis and in vitro antimicrobial and free-radical-scavenging activities of the essential oils from Euryops arabicus and Laggera decurrens. AB - The essential oils of the aerial part of two Asteraceae species, namely Euryops arabicus Steud. and Laggera decurrens (Vahl.) Hepper and Wood, were studied by GC and GC/MS. In parallel the antimicrobial and antioxidant activities were evaluated. The investigation led to the identification of 48 and 44 compounds for both plants, respectively. The essential oil of E. arabicus was rich in oxygenated sesquiterpenes (39.9%). The oil also contained a high content of sesquiterpene hydrocarbons (24.1%). Compounds such as caryophyllene oxide (8.6%), T-cadinol (7.0%), spathulenol (5.2%), (E)-beta-caryophyllene (6.0%) and 2-epi-(E) beta-caryophyllene (6.0%) were the main constituents of the oil. Oxygenated monoterpenes also predominated in L. decurrens (46.3%). The thymoquinone derivative, 3-methoxy-2-methyl-5-(1-methylethyl)-2,5-cyclohexadiene-1,4-dione (28.1%), thymol (5.7%) and eudesma-11-en-4a-ol (7.0%) were the most abundant constituents. Both essential oils showed antimicrobial activity with MIC-values between 0.13-5.25 mg/mL. Furthermore, only the essential oil of L. decurrens exhibited a strong antioxidant activity (91%) at 500 ug/mL. PMID- 21694679 TI - Inhibitory activity of flavonoids against class I phosphatidylinositol 3-kinase isoforms. AB - Class I PI3 Kinase (PI3K) phosphorylates phosphatidylinositol 4,5-bisphophate (PIP2) to generate the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) and therefore plays an important role in fundamental cellular responses such as proliferation. There are four isoforms of class I PI3K which are known to have different functions and relate to various diseases such as cancer and inflammation. Flavonoids are abundant in fruits, vegetables and plant-derived beverages such as tea. So far, various pharmacological effects of flavonoids have been reported. We previously reported that the flavonoid baicalein exhibits potent PI3K-inhibitory activity. Recently we examined the inhibitory activity of eighteen flavonoids against PI3Ka by using an in vitro homogenous time resolved fluorescence (HTRF) kinase assay, and deduced their structure-activity relationships by comparing the activities of the analogues. Our result suggests that the number of hydroxyl groups in the A and B rings might promote the activity, while loss of C2-C3 double bond might reduce the activity. Furthermore, the activity against 4 class I PI3K isoforms of some selected flavonoids was investigated, and the results indicate that the flavonoids seem to exhibit more potent activity on PI3Ka and d isoforms compared with that on PI3Kb and g isoforms. PMID- 21694680 TI - Identification of N6,N6-dimethyladenosine in transfer RNA from Mycobacterium bovis Bacille Calmette-Guerin. AB - There are more than 100 different ribonucleoside structures incorporated as post transcriptional modifications, mainly in tRNA and rRNA of both prokaryotes and eukaryotes, and emerging evidence suggests that these modifications function as a system in the translational control of cellular responses. However, our understanding of this system is hampered by the paucity of information about the complete set of RNA modifications present in individual organisms. To this end, we have employed a chromatography-coupled mass spectrometric approach to define the spectrum of modified ribonucleosides in microbial species, starting with Mycobacterium bovis BCG. This approach revealed a variety of ribonucleoside candidates in tRNA from BCG, of which 12 were definitively identified based on comparisons to synthetic standards and 5 were tentatively identified by exact mass comparisons to RNA modification databases. Among the ribonucleosides observed in BCG tRNA was one not previously described in tRNA, which we have now characterized as N6,N6-dimethyladenosine. PMID- 21694681 TI - Serum paraoxonase enzyme activity and oxidative stress in obese subjects. AB - INTRODUCTION: Obesity is an important risk factor for atherosclerotic cardiovascular disease. Paraoxonase-1 (PON1) may play a significant role in the prevention of obesity-related accelerated atherosclerosis by hydrolyzing lipid peroxides in oxidized low-density lipoproteins. OBJECTIVES: The aim of this study was to evaluate PON1 and arylesterase enzyme activities and lipid hydroperoxide (LOOH) levels, and to investigate whether there is increased susceptibility to atherogenesis in obese subjects, which might be reflected by increased oxidative stress and decreased PON1 activity. We also aimed to investigate the association between PON1 activity and body mass index (BMI) in this patient group. PATIENTS AND METHODS: The study involved 25 obese subjects and 23 controls. Serum PON1 and arylesterase activity was measured spectrophotometrically. LOOH levels were measured by the FOX-2 assay. RESULTS: Serum basal/salt-stimulated PON1 and arylesterase activities were significantly lower in obese subjects than in controls (P <0.001 for both enzymes), while LOOH levels were significantly higher (P <0.001). BMI was significantly correlated with PON1, arylesterase and LOOH levels (P <0.001, r = -0.720; P <0.001, r = -0.634; P <0.001, r = 0.491; respectively). Serum high-density lipoprotein (HDL) levels were positively correlated with PON1 activity (r = 0.347, P <0.05). CONCLUSIONS: Our results indicate that obese subjects have increased oxidative stress and decreased PON1 activity, which might contribute to accelerated atherosclerosis. A decrease in PON1 activity seems positively correlated with BMI and inversely correlated with HDL levels. PMID- 21694682 TI - Locus of control and selected mental health variables in asthmatics: what are the associations with dyspnea? AB - INTRODUCTION: The literature provides ambiguous information concerning the associations between asthma and psychopathology. The concept of the locus of control (LOC) can shed some light on the psychosomatic aspects of asthma. OBJECTIVES: The aim of the study was to analyze the relationship between dyspnea perception and psychopathological symptoms in asthma. We also tested how a tendency to attribute the LOC affects the relations between psychopathology and dyspnea. PATIENTS AND METHODS: We examined 111 consecutive, unselected asthma patients, including 74 women and 37 men. The mean age was 49.79 +/- 14.19 years, with no significant differences between sexes. There were mainly patients with level 2 (38.7%) and level 4 (35.1%) of asthma severity according to the Global Initiative for Asthma classification. Sociodemographic data were collected and the General Health Questionnaire (GHQ) by Goldberg and the Locus of Control questionnaire by Rotter were applied. The level of dyspnea was assessed by patients on the 10-point Borg scale. Spirometry tests were performed. RESULTS: Gender, education, and LOC differentiated patients according to psychopathological symptoms. There were no differences in psychopathology between the groups with different levels of asthma severity. In women, there was a significant correlation between intensity of dyspnea and higher scores on all GHQ scales; in men, the correlation was observed only for the depression subscale and the general scale. CONCLUSIONS: Psychopathological disorders are more significantly associated with subjective asthma symptoms than with asthma severity. Gender, education, and a tendency to attribute the LOC internally may be significant for this association. PMID- 21694683 TI - What's new in stroke? The top 10 studies of 2009-2011: part I. AB - Five important studies from 2009-2011 that influence the clinical management of stroke and threatened stroke are summarized. Pooled analysis of individual patient data from 8 randomized trials testing intravenous tissue plasminogen activator confirmed important benefits for patients treated 3 to 4.5 hours after stroke onset, but treatment after 4.5 hours was associated with a higher mortality. Blood pressure lowering with candesartan in the first few days after stroke was of no benefit and was possibly harmful (SCAST trial). Thigh-length graduated compression stockings did not reduce venous thromboembolism after acute stroke and were associated with skin complications (CLOTS Trial 1). Long-term follow-up showed that endovascular coiling was as good as neurosurgical clipping for patients with small, ruptured intracranial aneurysms (ISAT trial). Percutaneous closure of a patent foramen ovale offered no apparent benefit to young patients with cryptogenic ischemic stroke based on the first randomized trial testing this intervention, but the number of stroke events was insufficient to draw definitive conclusions (CLOSURE I trial). PMID- 21694684 TI - What's new in stroke? The top 10 studies of 2009-2011: part II. AB - Five studies published between 2009 and 2011 are reviewed that importantly inform stroke prevention for patients with atrial fibrillation (AF) or with cervical carotid artery stenosis. Two large, phase III randomized trials tested novel oral anticoagulants for stroke prevention in patients with AF: the direct thrombin inhibitor dabigatran 150 mg twice daily was superior to adjusted-dose warfarin (RE-LY trial) and the direct factor Xa inhibitor apixaban was far superior to aspirin in patients deemed unsuitable for warfarin (AVERROES trial). For both novel anticoagulants, major bleeding rates were similar to the comparator treatment. Clopidogrel plus aspirin was more efficacious than aspirin alone for prevention of stroke in patients with AF deemed unsuitable for warfarin, but major bleeding was significantly increased with dual antiplatelet therapy (ACTIVE A trial). Two large randomized trials (CREST, ICSS) provide the best available data on the short-term risks of carotid artery stenting vs. endarterectomy. In both trials, periprocedural stroke was more frequent with stenting than with endarterectomy, but the increased risk was largely confined to patients >70 years old. For younger patients, periprocedural risks were comparable with stenting or endarterectomy, but long-term outcomes are required to assess the relative merits of the two procedures. PMID- 21694685 TI - How should clinicians and patients choose antihyperglycemic agents?: an evidence based approach. AB - The choice of antihyperglycemic agents has become more complex as new drug classes have appeared and evidence about their efficacy and safety accumulates. Unfortunately, direct and fair comparisons are lacking and the clinician and patient are left to decide among agents with different safety and burden profiles. Furthermore, the relative efficacy of these agents beyond their ability to lower hemoglobin A1c - that is, in their ability to reduce the risk of diabetes complications - remains uncertain. In this sea of uncertainty, interests other than those of the patient actively shape choices. It is our expectation that better evidence, better policy and better decisions will eventually become routine in the care of patients with diabetes. PMID- 21694686 TI - High-throughput measurement and classification of organic P in environmental samples. AB - Many types of organic phosphorus (P) molecules exist in environmental samples. Traditional P measurements do not detect these organic P compounds since they do not react with colorimetric reagents. Enzymatic hydrolysis (EH) is an emerging method for accurately characterizing organic P forms in environmental samples. This method is only trumped in accuracy by Phosphorus-31 Nuclear Magnetic Resonance Spectroscopy ((31)P-NMR)--a method that is expensive and requires specialized technical training. We have adapted an enzymatic hydrolysis method capable of measuring three classes of phosphorus (monoester P, diester P and inorganic P) to a microplate reader system. This method provides researchers with a fast, accurate, affordable and user-friendly means to measure P species in soils, sediments, manures and, if concentrated, aquatic samples. This is the only high-throughput method for measuring the forms and enzyme-lability of organic P that can be performed in a standard laboratory. The resulting data provides insight to scientists studying system nutrient content and eutrophication potential. PMID- 21694687 TI - Characterizing bacterial volatiles using secondary electrospray ionization mass spectrometry (SESI-MS). AB - Secondary electrospray ionization mass spectrometry (SESI-MS) is a method developed for the rapid detection of volatile compounds, without the need for sample pretreatment. The method was first described by Fenn and colleagues and has been applied to the detection of illicit drugs and explosives, the characterization of skin volatiles, and the analysis of breath. SESI ionization occurs by proton transfer reactions between the electrospray solution and the volatile analyte, and is therefore suitable for the analysis of hetero-organic molecules, just as in traditional electrospray ionization (ESI). However, unlike standard ESI, the proton transfer process of SESI occurs in the vapor phase rather than in solution (Fig. 1), and therefore SESI is best suited for detecting organic volatiles and aerosols. We are expanding the use of SESI-MS to the detection of bacterial volatiles as a method for bacterial identification and characterization. We have demonstrated that SESI-MS volatile fingerprinting, combined with a statistical analysis method, can be used to differentiate bacterial genera, species, and mixed cultures in a variety of growth media. Here we provide the steps for obtaining bacterial volatile fingerprints using SESI-MS, including the instrumental parameters that should be optimized to ensure robust bacterial identification and characterization. PMID- 21694688 TI - ampliPHOX colorimetric detection on a DNA microarray for influenza. AB - DNA microarrays have emerged as a powerful tool for pathogen detection. For instance, many examples of the ability to type and subtype influenza virus have been demonstrated. The identification and subtyping of influenza on DNA microarrays has applications in both public health and the clinic for early detection, rapid intervention, and minimizing the impact of an influenza pandemic. Traditional fluorescence is currently the most commonly used microarray detection method. However, as microarray technology progresses towards clinical use, replacing expensive instrumentation with low cost detection technology exhibiting similar performance characteristics to fluorescence will make microarray assays more attractive and cost-effective. The ampliPHOX colorimetric detection technology is intended for research applications, and has a limit of detection within one order of magnitude of traditional fluorescence, with a main advantage being an approximate ten-fold lower instrument cost compared to the confocal microarray scanners required for fluorescence microarray detection. Another advantage is the compact size of the instrument which allows for portability and flexibility, unlike traditional fluorescence instruments. Because the polymerization technology is not as inherently linear as fluorescence detection, however, it is best suited for lower density microarray applications in which a yes/no answer for the presence of a certain sequence is desired, such as for pathogen detection arrays. Currently the maximum spot density compatible with ampliPHOX detection is ~1800 spots/array. Because of the spot density limitations, higher density microarrays are not suitable for ampliPHOX detection. Here, we present ampliPHOX colorimetric detection technology as a method of signal amplification on a low density microarray developed for the detection and characterization of influenza viruses (FluChip). Although this protocol uses the FluChip (a DNA microarray) as one specific application of ampliPHOX detection, any microarray incorporating biotinylated target can be labeled and detected in a similar manner. The microarray design and biotinylation of the target to be captured are the responsibility of the user. Once the biotinylated target has been captured on the array, ampliPHOX detection can be performed by first tagging the array with a streptavidin-label conjugate (ampliTAG). Upon light exposure using the ampliPHOX Reader instrument, polymerization of a monomer solution (ampliPHY) occurs only in regions containing ampliTAG-labeled targets. The polymer formed can be subsequently stained with a non-toxic solution to improve visual contrast, followed by imaging and analysis using a simple software package (ampliVIEW). The entire FluChip assay from un-extracted sample to result can be performed in about 6 hours, and the ampliPHOX detection steps described above can be completed in about 30 min. PMID- 21694689 TI - Detection of infectious virus from field-collected mosquitoes by vero cell culture assay. AB - Mosquitoes transmit a number of distinct viruses including important human pathogens such as West Nile virus, dengue virus, and chickungunya virus. Many of these viruses have intensified in their endemic ranges and expanded to new territories, necessitating effective surveillance and control programs to respond to these threats. One strategy to monitor virus activity involves collecting large numbers of mosquitoes from endemic sites and testing them for viral infection. In this article, we describe how to handle, process, and screen field collected mosquitoes for infectious virus by Vero cell culture assay. Mosquitoes are sorted by trap location and species, and grouped into pools containing <=50 individuals. Pooled specimens are homogenized in buffered saline using a mixer mill and the aqueous phase is inoculated onto confluent Vero cell cultures (Clone E6). Cell cultures are monitored for cytopathic effect from days 3-7 post inoculation and any viruses grown in cell culture are identified by the appropriate diagnostic assays. By utilizing this approach, we have isolated 9 different viruses from mosquitoes collected in Connecticut, USA, and among these, 5 are known to cause human disease. Three of these viruses (West Nile virus, Potosi virus, and La Crosse virus) represent new records for North America or the New England region since 1999. The ability to detect a wide diversity of viruses is critical to monitoring both established and newly emerging viruses in the mosquito population. PMID- 21694690 TI - The mouse cremaster muscle preparation for intravital imaging of the microcirculation. AB - Throughout the body, the maintenance of homeostasis requires the constant supply of oxygen and nutrients concomitant with removal of metabolic by-products. This balance is achieved by the movement of blood through the microcirculation, which encompasses the smallest branches of the vascular supply throughout all tissues and organs. Arterioles branch from arteries to form networks that control the distribution and magnitude of oxygenated blood flowing into the multitude of capillaries intimately associated with parenchymal cells. Capillaries provide a large surface area for diffusional exchange between tissue cells and the blood supply. Venules collect capillary effluent and converge as they return deoxygenated blood towards the heart. To observe these processes in real time requires an experimental approach for visualizing and manipulating the living microcirculation. The cremaster muscle of rats was first used as a model for studying inflammation using histology and electron microscopy post mortem. The first in vivo report of the exposed intact rat cremaster muscle investigated microvascular responses to vasoactive drugs using reflected light. However curvature of the muscle and lack of focused illumination limited the usefulness of this preparation. The major breakthrough entailed opening the muscle, detaching it from the testicle and spreading it radially as a flat sheet for transillumination under a compound microscope. While shown to be a valuable preparation to study the physiology of the microcirculation in rats and hamsters, the cremaster muscle in mice has proven particularly useful in dissecting cellular pathways involved in regulating microvascular function and real-time imaging of intercellular signaling. The cremaster muscle is derived from the internal oblique and transverse abdominus muscles as the testes descend through the inguinal canal. It serves to support (Greek: cremaster = suspender) and maintain temperature of the testes. As described here, the cremaster muscle is prepared as a thin flat sheet for outstanding optical resolution. With the mouse maintained at a stable body temperature and plane of anesthesia, surgical preparation involves freeing the muscle from surrounding tissue and the testes, spreading it onto transparent pedestal of silastic rubber and securing the edges with insect pins while irrigating it continuously with physiological salt solution. The present protocol utilizes transgenic mice expressing GCaMP2 in arteriolar endothelial cells. GCaMP2 is a genetically encoded fluorescent calcium indicator molecule. Widefield imaging and an intensified charge-coupled device camera enable in vivo study of calcium signaling in the arteriolar endothelium. PMID- 21694691 TI - Microiontophoresis and micromanipulation for intravital fluorescence imaging of the microcirculation. AB - Microiontophoresis entails passage of current through a micropipette tip to deliver a solute at a designated site within an experimental preparation. Microiontophoresis can simulate synaptic transmission by delivering neurotransmitters and neuropeptides onto neurons reproducibly. Negligible volume (fluid) displacement avoids mechanical disturbance to the experimental preparation. Adapting these techniques to the microcirculation has enabled mechanisms of vasodilation and vasoconstriction to be studied at the microscopic level in vivo. A key advantage of such localized delivery is enabling vasomotor responses to be studied at defined sites within a microvascular network without evoking systemic or reflexive changes in blood pressure and tissue blood flow, thereby revealing intrinsic properties of microvessels. A limitation of microiontophoresis is that the precise concentration of agent delivered to the site of interest is difficult to ascertain. Nevertheless, its release from the micropipette tip is proportional to the intensity and duration of the ejection current, such that reproducible stimulus-response relationships can be readily determined under defined experimental conditions (described below). Additional factors affecting microiontophoretic delivery include solute concentration and its ionization in solution. The internal diameter of the micropipette tip should be ~ 1 MUm or less to minimize diffusional 'leak', which can be counteracted with a retaining current. Thus an outward (positive) current is used to eject a cation and a negative current used to retain it within the micropipette. Fabrication of micropipettes is facilitated with sophisticated electronic pullers. Micropipettes are pulled from glass capillary tubes containing a filament that 'wicks' solution into the tip of the micropipette when filled from the back end ("backfilled"). This is done by inserting a microcapillary tube connected to a syringe containing the solution of interest and ejecting the solution into the lumen of the micropipette. Micromanipulators enable desired placement of micropipettes within the experimental preparation. Micromanipulators mounted on a movable base can be positioned around the preparation according to the topography of microvascular networks (developed below). The present protocol demonstrates microiontophoresis of acetylcholine (ACh(+) Cl(-)) onto an arteriole of the mouse cremaster muscle preparation (See associated protocol: JoVE ID#2874) to produce endothelium dependent vasodilation. Stimulus delivery is synchronized with digitized image acquisition using an electronic trigger. The use of Cx40(BAC)-GCaMP2 transgenic mice enables visualization of intracellular calcium responses underlying vasodilation in arteriolar endothelial cells in the living microcirculation. PMID- 21694692 TI - Sequencing of bacterial microflora in peripheral blood: our experience with HIV infected patients. AB - The healthy gastrointestinal tract is physiologically colonized by a large variety of commensal microbes that influence the development of the humoral and cellular mucosal immune system. Microbiota is shielded from the immune system via a strong mucosal barrier. Infections and antibiotics are known to alter both the normal gastrointestinal tract barrier and the composition of resident bacteria, which may result in possible immune abnormalities. HIV causes a breach in the gastrointestinal barrier with progressive failure of mucosal immunity and leakage into the systemic circulation of bacterial bioproducts, such as lipopolysaccharide and bacterial DNA fragments, which contribute to systemic immune activation. Microbial translocation is implicated in HIV/AIDS immunopathogenesis and response to therapy. We aimed to characterise the composition of bacteria translocating in peripheral blood of HIV-infected patients. To pursue our aim we set up a PCR reaction for the panbacteric 16S ribosomial gene followed by a sequencing analysis. Briefly, whole blood from both HIV-infected and healthy subjects is used. Given that healthy individuals present normal intestinal homeostasis no translocation of microflora is expected in these patients. Following whole blood collection by venipuncture and plasma separation, DNA is extracted from plasma and used to perform a broad range PCR reaction for the panbacteric 16S ribosomial gene. Following PCR product purification, cloning and sequencing analyses are performed. PMID- 21694693 TI - Introduction to the ultrasound targeted microbubble destruction technique. AB - In UTMD, bioactive molecules, such as negatively charged plasmid DNA vectors encoding a gene of interest, are added to the cationic shells of lipid microbubble contrast agents. In mice these vector-carrying microbubbles can be administered intravenously or directly to the left ventricle of the heart. In larger animals they can also be infused through an intracoronary catheter. The subsequent delivery from the circulation to a target organ occurs by acoustic cavitation at a resonant frequency of the microbubbles. It seems likely that the mechanical energy generated by the microbubble destruction results in transient pore formation in or between the endothelial cells of the microvasculature of the targeted region. As a result of this sonoporation effect, the transfection efficiency into and across the endothelial cells is enhanced, and transgene encoding vectors are deposited into the surrounding tissue. Plasmid DNA remaining in the circulation is rapidly degraded by nucleases in the blood, which further reduces the likelihood of delivery to non-sonicated tissues and leads to highly specific target-organ transfection. PMID- 21694694 TI - Isolation of brain-infiltrating leukocytes. AB - We describe a method for preparing brain infiltrating leukocytes (BILs) from mice. We demonstrate how to infect mice with Theiler's murine encephalomyelitis virus (TMEV) via a rapid intracranial injection technique and how to purify a leukocyte-enriched population of infiltrating cells from whole brain. Briefly, mice are anesthetized with isoflurane in a closed chamber and are free-hand injected with a Hamilton syringe into the frontal cortex. Mice are then killed at various times after infection by isoflurane overdose and whole brains are extracted and homogenized in RPMI with a Tenbroeck tissue grinder. Brain homogenates are centrifuged through a continuous 30% Percoll gradient to remove the myelin and other cell debris. The cell suspension is then strained at 40 MUm, washed and centrifuged on a discontinuous Ficoll-Paque Plus gradient to select and purify the leukocytes. The leukocytes are then washed and resuspended in appropriate buffers for immunophenotyping by flow cytometry. Flow cytometry reveals a population of innate immune cells at the early stages of infection in C57BL/6 mice. At 24 hours post infection, multiple subsets of immune cells are present in the BILs, with an enriched population of Gr1(+), CD11b(+) and F4/80(+)cells. Therefore, this method is useful in characterizing the immune response to acute infection in the brain. PMID- 21694695 TI - Modeling neural immune signaling of episodic and chronic migraine using spreading depression in vitro. AB - Migraine and its transformation to chronic migraine are healthcare burdens in need of improved treatment options. We seek to define how neural immune signaling modulates the susceptibility to migraine, modeled in vitro using spreading depression (SD), as a means to develop novel therapeutic targets for episodic and chronic migraine. SD is the likely cause of migraine aura and migraine pain. It is a paroxysmal loss of neuronal function triggered by initially increased neuronal activity, which slowly propagates within susceptible brain regions. Normal brain function is exquisitely sensitive to, and relies on, coincident low level immune signaling. Thus, neural immune signaling likely affects electrical activity of SD, and therefore migraine. Pain perception studies of SD in whole animals are fraught with difficulties, but whole animals are well suited to examine systems biology aspects of migraine since SD activates trigeminal nociceptive pathways. However, whole animal studies alone cannot be used to decipher the cellular and neural circuit mechanisms of SD. Instead, in vitro preparations where environmental conditions can be controlled are necessary. Here, it is important to recognize limitations of acute slices and distinct advantages of hippocampal slice cultures. Acute brain slices cannot reveal subtle changes in immune signaling since preparing the slices alone triggers: pro inflammatory changes that last days, epileptiform behavior due to high levels of oxygen tension needed to vitalize the slices, and irreversible cell injury at anoxic slice centers. In contrast, we examine immune signaling in mature hippocampal slice cultures since the cultures closely parallel their in vivo counterpart with mature trisynaptic function; show quiescent astrocytes, microglia, and cytokine levels; and SD is easily induced in an unanesthetized preparation. Furthermore, the slices are long-lived and SD can be induced on consecutive days without injury, making this preparation the sole means to-date capable of modeling the neuroimmune consequences of chronic SD, and thus perhaps chronic migraine. We use electrophysiological techniques and non-invasive imaging to measure neuronal cell and circuit functions coincident with SD. Neural immune gene expression variables are measured with qPCR screening, qPCR arrays, and, importantly, use of cDNA preamplification for detection of ultra-low level targets such as interferon-gamma using whole, regional, or specific cell enhanced (via laser dissection microscopy) sampling. Cytokine cascade signaling is further assessed with multiplexed phosphoprotein related targets with gene expression and phosphoprotein changes confirmed via cell-specific immunostaining. Pharmacological and siRNA strategies are used to mimic and modulate SD immune signaling. PMID- 21694696 TI - Engineering biological-based vascular grafts using a pulsatile bioreactor. AB - Much effort has been devoted to develop and advance the methodology to regenerate functional small-diameter arterial bypasses. In the physiological environment, both mechanical and chemical stimulation are required to maintain the proper development and functionality of arterial vessels. Bioreactor culture systems developed by our group are designed to support vessel regeneration within a precisely controlled chemo-mechanical environment mimicking that of native vessels. Our bioreactor assembly and maintenance procedures are fairly simple and highly repeatable. Smooth muscle cells (SMCs) are seeded onto a tubular polyglycolic acid (PGA) mesh that is threaded over compliant silicone tubing and cultured in the bioreactor with or without pulsatile stimulation for up to 12 weeks. There are four main attributes that distinguish our bioreactor from some predecessors. 1) Unlike other culture systems that simulate only the biochemical surrounding of native blood vessels, our bioreactor also creates a physiological pulsatile environment by applying cyclic radial strain to the vessels in culture. 2) Multiple engineered vessels can be cultured simultaneously under different mechanical conditions within a controlled chemical environment. 3) The bioreactor allows a mono layer of endothelial cells (EC) to be easily coated onto the luminal side of engineered vessels for animal implantation models. 4) Our bioreactor can also culture engineered vessels with different diameter size ranged from 1 mm to 3 mm, saving the effort to tailor each individual bioreactor to fit a specific diameter size. The engineered vessels cultured in our bioreactor resemble native blood vessels histologically to some degree. Cells in the vessel walls express mature SMC contractile markers such as smooth muscle myosin heavy chain (SMMHC). A substantial amount of collagen is deposited within the extracellular matrix, which is responsible for ultimate mechanical strength of the engineered vessels. Biochemical analysis also indicates that collagen content of engineered vessels is comparable to that of native arteries. Importantly, the pulsatile bioreactor has consistently regenerated vessels that exhibit mechanical properties that permit successful implantation experiments in animal models. Additionally, this bioreactor can be further modified to allow real-time assessment and tracking of collagen remodeling over time, non invasively, using a non-linear optical microscopy (NLOM). To conclude, this bioreactor should serve as an excellent platform to study the fundamental mechanisms that regulate the regeneration of functional small-diameter vascular grafts. PMID- 21694697 TI - Plasma lithography surface patterning for creation of cell networks. AB - Systematic manipulation of a cell microenvironment with micro- and nanoscale resolution is often required for deciphering various cellular and molecular phenomena. To address this requirement, we have developed a plasma lithography technique to manipulate the cellular microenvironment by creating a patterned surface with feature sizes ranging from 100 nm to millimeters. The goal of this technique is to be able to study, in a controlled way, the behaviors of individual cells as well as groups of cells and their interactions. This plasma lithography method is based on selective modification of the surface chemistry on a substrate by means of shielding the contact of low-temperature plasma with a physical mold. This selective shielding leaves a chemical pattern which can guide cell attachment and movement. This pattern, or surface template, can then be used to create networks of cells whose structure can mimic that found in nature and produces a controllable environment for experimental investigations. The technique is well suited to studying biological phenomenon as it produces stable surface patterns on transparent polymeric substrates in a biocompatible manner. The surface patterns last for weeks to months and can thus guide interaction with cells for long time periods which facilitates the study of long-term cellular processes, such as differentiation and adaption. The modification to the surface is primarily chemical in nature and thus does not introduce topographical or physical interference for interpretation of results. It also does not involve any harsh or toxic substances to achieve patterning and is compatible for tissue culture. Furthermore, it can be applied to modify various types of polymeric substrates, which due to the ability to tune their properties are ideal for and are widely used in biological applications. The resolution achievable is also beneficial, as isolation of specific processes such as migration, adhesion, or binding allows for discrete, clear observations at the single to multicell level. This method has been employed to form diverse networks of different cell types for investigations involving migration, signaling, tissue formation, and the behavior and interactions of neurons arraigned in a network. PMID- 21694698 TI - Effect of Web-based lifestyle modification on weight control: a meta-analysis. AB - OBJECTIVE: Web-based treatment programs are attractive in primary care because of their ability to reach numerous individuals at low cost. Our aim of this meta analysis is to systematically review the weight loss or maintenance effect of the Internet component in obesity treatment programs. METHODS: MEDLINE and EMBASE literature searches were conducted to identify studies investigating the effect of Web-based individualized advice on lifestyle modification on weight loss. Randomized controlled trials that consisted of a Web-user experimental and non Web user control group were included. Weight changes in the experimental group in comparison with the control group were pooled with a random-effects model. RESULTS: A total of 23 studies comprising 8697 participants were included. Overall, using the Internet had a modest but significant additional weight-loss effect compared with non-Web user control groups (-0.68 kg, P=0.03). In comparison with the control group, stratified analysis indicated that using the Internet as an adjunct to obesity care was effective (-1.00 kg, P<0.001), but that using it as a substitute for face-to-face support was unfavorable (+1.27 kg, P=0.01). An additional effect on weight control was observed when the aim of using the Internet was initial weight loss (-1.01 kg; P=0.03), but was not observed when the aim was weight maintenance (+0.68 kg; P=0.26). The relative effect was diminished with longer educational periods (P-trend=0.04) and was insignificant (-0.20 kg; P=0.75) in studies with educational periods of 12 months or more. CONCLUSION: The current meta-analysis indicates that the Internet component in obesity treatment programs has a modest effect on weight control. However, the effect was inconsistent, largely depending on the type of usage of the Internet or the period of its use. PMID- 21694699 TI - Association between impulsivity, reward responsiveness and body mass index in children. AB - BACKGROUND: Childhood obesity is a major health problem. An association between children's body mass index (BMI) and overeating has been established, but mechanisms leading to overeating are poorly understood. The personality characteristics impulsivity and reward responsiveness may be involved in the tendency to overeat. Impulsivity might relate to overeating through poor inhibition of food intake; reward responsiveness through the rewarding value of food. OBJECTIVE: This study aimed to reveal the relationships between impulsivity, reward responsiveness, overeating and BMI in a sample of 346 Dutch children aged 6-13 years. The BMI distribution in the sample was representative of the BMI distribution in the Dutch pediatric population. METHODS: Impulsivity and reward responsiveness were measured with the Dutch version of the parent report Sensitivity to Punishment and Sensitivity to Reward Questionnaire for children. Overeating was assessed with the Dutch translation of the parent-report Children's Eating Behaviour Questionnaire. RESULTS: Overeating, impulsivity and reward responsiveness were significantly associated with childhood BMI. Mediation analysis revealed that impulsivity and reward responsiveness equally and significantly predicted BMI indirectly through overeating. CONCLUSIONS: The personality characteristics impulsivity and reward responsiveness predict childhood BMI indirectly through overeating. This suggests that these personality characteristics are risk factors for obesity. PMID- 21694700 TI - Exogenous peptide YY3-36 and Exendin-4 further decrease food intake, whereas octreotide increases food intake in rats after Roux-en-Y gastric bypass. AB - BACKGROUND: Patients show an elevated postprandial satiety gut hormone release after Roux-en-Y Gastric bypass (gastric bypass). The altered gut hormone response appears to have a prominent role in the reduction of appetite and body weight (BW) after gastric bypass. Patients with insufficient BW loss after gastric bypass have an attenuated postprandial gut hormone response in comparison with patients who lost an adequate amount of BW. The effects of additional gut hormone administration after gastric bypass are unknown. METHODS: The effects of peripheral administration of peptide YY3-36 (PYY3-36; 300 nmol kg(-1)), glucagon like peptide-1 (GLP-1) analogue Exendin-4 (20 nmol kg(-1)) and somatostatin analogue octreotide (10 MUg kg(-1)) on feeding and BW were evaluated in rats after gastric bypass. RESULTS: Gastric bypass rats weighed (P<0.01) and ate less on postoperative day 5 (P<0.001) and thereafter, whereas postprandial plasma PYY and GLP-1 levels were higher compared with sham-operated controls (P<0.001). Administration of both PYY3-36 and Exendin-4 led to a further decrease in food intake in bypass rats compared with saline treatment (P=0.02 and P<0.0001, respectively). Similar reduction in food intake was observed in sham rats (P=0.02 and P<0.001, respectively). Exendin-4 treatment resulted in a significant BW loss in bypass (P=0.03) and sham rats (P=0.04). Subsequent treatment with octreotide led to an increase in food intake in bypass (P=0.007), but not in sham rats (P=0.87). CONCLUSION: Peripheral administration of PYY3-36 and Exendin-4 reduces short-term food intake, whereas octreotide increases short-term food intake in rats after gastric bypass. The endogenous gut hormone response after gastric bypass can thus potentially be further enhanced by additional exogenous therapy with pharmacological doses of gut hormones in patients with insufficient weight loss or weight regain after surgery. PMID- 21694701 TI - The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications. AB - Obesity and vitamin D deficiency have both been recognized as major public health issues worldwide, and there is growing evidence that they are related, although the cause-effect relationship remains unclear. Could obesity be contributing to low circulating 25-hydroxyvitamin D concentrations? Alternatively, could low vitamin D status predispose to obesity? In this review, the relationship between low circulating 25-hydroxyvitamin D and obesity, and possible underlying reasons from both perspectives, is presented. One potential mechanism by which obesity could contribute to low serum 25-hydroxyvitamin D is adipose sequestration of vitamin D. On the other hand, adipose tissue has both the vitamin D receptor and the ability to synthesize 1,25-dihydroxyvitamin D, and there is evidence that vitamin D may regulate adipose tissue mass, differentiation and metabolism in ways that might contribute to obesity. Of particular interest, vitamin D deficiency is common both before and after bariatric surgery, and is often difficult to treat, particularly with the more malabsorptive procedures. Additional research is needed to elucidate the complex and multifaceted factors underlying the association between low circulating 25-hydroxyvitamin D and obesity, and to identify optimal treatment approaches in obese individuals and in bariatric surgical patients both before and after surgery. PMID- 21694702 TI - Dual function MITO-Porter, a nano carrier integrating both efficient cytoplasmic delivery and mitochondrial macromolecule delivery. AB - Mitochondrial dysfunction is associated with a variety of human diseases including inherited mitochondrial diseases, neurodegenerative disorders, diabetes mellitus, and cancer. Effective medical therapies for mitochondrial diseases will ultimately require an optimal drug delivery system, which will likely be achieved through innovations in the nanotechnology of intracellular trafficking. To achieve efficient mitochondrial drug delivery, two independent processes, i.e., "cytoplasmic delivery through the cell membrane" and "mitochondrial delivery through the mitochondrial membrane" are required. In previous studies, we developed an octaarginine (R8) modified nano carrier for efficient cytoplasmic delivery, showing that R8-modified liposomes were internalized into cells efficiently. On the other hand, we also constructed MITO-Porter for the mitochondrial delivery of macromolecules, a liposome-based carrier that delivers cargos to mitochondria via membrane fusion. Here, we report the development of a dual function MITO-Porter (DF-MITO-Porter), based on the concept of integrating both R8-modified liposomes and MITO-Porter. We show that the DF-MITO-Porter effectively delivers exogenous macro-biomolecules into the mitochondrial matrix, and provide a demonstration of its potential use in therapies aimed at mitochondrial DNA. PMID- 21694703 TI - Directed differentiation of human embryonic stem cells to interrogate the cardiac gene regulatory network. AB - The limited ability of the heart to regenerate has prompted development of new systems to produce cardiomyocytes for therapeutics. While differentiation of human embryonic stem cells (hESCs) into cardiomyocytes has been well documented, the process remains inefficient and/or expensive, and progress would be facilitated by better understanding the early genetic events that cause cardiac specification. By maintaining a transgenic cardiac-specific MYH6-monomeric red fluorescent protein (mRFP) reporter hESC line in conditions that promote pluripotency, we tested the ability of combinations of 15 genes to induce cardiac specification. Screening identified GATA4 plus TBX5 as the minimum requirement to activate the cardiac gene regulatory network and produce mRFP(+) cells, while a combination of GATA4, TBX5, NKX2.5, and BAF60c (GTNB) was necessary to generate beating cardiomyocytes positive for cTnI and alpha-actinin. Including the chemotherapeutic agent, Ara-C, from day 10 of induced differentiation enriched for cTnI/alpha-actinin double positive cells to 45%. Transient expression of GTNB for 5-7 days was necessary to activate the cardiogenesis through progenitor intermediates in a manner consistent with normal heart development. This system provides a route to test the effect of different factors on human cardiac differentiation and will be useful in understanding the network failures that underlie disease phenotypes. PMID- 21694704 TI - Human cryptochrome exhibits light-dependent magnetosensitivity. AB - Humans are not believed to have a magnetic sense, even though many animals use the Earth's magnetic field for orientation and navigation. One model of magnetosensing in animals proposes that geomagnetic fields are perceived by light sensitive chemical reactions involving the flavoprotein cryptochrome (CRY). Here we show using a transgenic approach that human CRY2, which is heavily expressed in the retina, can function as a magnetosensor in the magnetoreception system of Drosophila and that it does so in a light-dependent manner. The results show that human CRY2 has the molecular capability to function as a light-sensitive magnetosensor and reopen an area of sensory biology that is ready for further exploration in humans. PMID- 21694705 TI - Promotion of water-mediated carbon removal by nanostructured barium oxide/nickel interfaces in solid oxide fuel cells. AB - The existing Ni-yttria-stabilized zirconia anodes in solid oxide fuel cells (SOFCs) perform poorly in carbon-containing fuels because of coking and deactivation at desired operating temperatures. Here we report a new anode with nanostructured barium oxide/nickel (BaO/Ni) interfaces for low-cost SOFCs, demonstrating high power density and stability in C(3)H(8), CO and gasified carbon fuels at 750 degrees C. Synchrotron-based X-ray analyses and microscopy reveal that nanosized BaO islands grow on the Ni surface, creating numerous nanostructured BaO/Ni interfaces that readily adsorb water and facilitate water mediated carbon removal reactions. Density functional theory calculations predict that the dissociated OH from H(2)O on BaO reacts with C on Ni near the BaO/Ni interface to produce CO and H species, which are then electrochemically oxidized at the triple-phase boundaries of the anode. This anode offers potential for ushering in a new generation of SOFCs for efficient, low-emission conversion of readily available fuels to electricity. PMID- 21694706 TI - Long-term projections and acclimatization scenarios of temperature-related mortality in Europe. AB - The steady increase in greenhouse gas concentrations is inducing a detectable rise in global temperatures. The sensitivity of human societies to warming temperatures is, however, a transcendental question not comprehensively addressed to date. Here we show the link between temperature, humidity and daily numbers of deaths in nearly 200 European regions, which are subsequently used to infer transient projections of mortality under state-of-the-art high-resolution greenhouse gas scenario simulations. Our analyses point to a change in the seasonality of mortality, with maximum monthly incidence progressively shifting from winter to summer. The results also show that the rise in heat-related mortality will start to completely compensate the reduction of deaths from cold during the second half of the century, amounting to an average drop in human lifespan of up 3-4 months in 2070-2100. Nevertheless, projections suggest that human lifespan might indeed increase if a substantial degree of adaptation to warm temperatures takes place. PMID- 21694707 TI - Sas-4 provides a scaffold for cytoplasmic complexes and tethers them in a centrosome. AB - Centrosomes are conserved organelles that are essential for accurate cell division and cilium formation. A centrosome consists of a pair of centrioles surrounded by a protein network of pericentriolar material (PCM) that is essential for the centrosome's function. In this study, we show that Sas-4 provides a scaffold for cytoplasmic complexes (named S-CAP), which include CNN, Asl and D-PLP, proteins that are all found in the centrosomes at the vicinity of the centriole. When Sas-4 is absent, nascent procentrioles are unstable and lack PCM, and functional centrosomes are not generated. When Sas-4 is mutated, so that it cannot form S-CAP complexes, centrosomes are present but with dramatically reduced levels of PCM. Finally, purified S-CAP complexes or recombinant Sas-4 can bind centrosomes stripped of PCM, whereas recombinant CNN or Asl cannot. In summary, PCM assembly begins in the cytosol where Sas-4 provides a scaffold for pre-assembled cytoplasmic complexes before tethering of the complexes in a centrosome. PMID- 21694708 TI - Burning vegetation produces cyanohydrins that liberate cyanide and stimulate seed germination. AB - Cyanide is well known for its toxicity towards living organisms. Many plants use cyanide as a defensive agent against herbivores, releasing it through the enzymatic hydrolysis of endogenous cyanogenic compounds. At low concentrations, cyanide has been proposed to have a regulatory role in many plant processes including stimulation of seed germination. However, no ecological role for cyanide in seed germination has been established. In the present study, we show that burning plant material produces the cyanohydrin, glyceronitrile. We also show that, in the presence of water, glyceronitrile is slowly hydrolysed to release cyanide that stimulates seed germination of a diverse range of fire responsive species from different continents. We propose that glyceronitrile serves as an ecological store for cyanide and is an important cue for stimulating seed germination and landscape regeneration after fires. PMID- 21694709 TI - Statistically induced phase transitions and anyons in 1D optical lattices. AB - Anyons--particles carrying fractional statistics that interpolate between bosons and fermions--have been conjectured to exist in low-dimensional systems. In the context of the fractional quantum Hall effect, quasi-particles made of electrons take the role of anyons whose statistical exchange phase is fixed by the filling factor. Here we propose an experimental setup to create anyons in one-dimensional lattices with fully tuneable exchange statistics. In our setup, anyons are created by bosons with occupation-dependent hopping amplitudes, which can be realized by assisted Raman tunnelling. The statistical angle can thus be controlled in situ by modifying the relative phase of external driving fields. This opens the fascinating possibility of smoothly transmuting bosons via anyons into fermions and of inducing a phase transition by the mere control of the particle statistics as a free parameter. In particular, we demonstrate how to induce a quantum phase transition from a superfluid into an exotic Mott-like state where the particle distribution exhibits plateaus at fractional densities. PMID- 21694710 TI - The vectorial control of magnetization by light. AB - Application of coherent light-matter interactions has recently been extended to the ultrafast control of magnetization. An important but unrealized technique is the manipulation of magnetization vector motion to make it follow an arbitrarily designed multidimensional trajectory. Here we demonstrate a full manipulation of two-dimensional magnetic oscillations in antiferromagnetic NiO with a pair of polarization-twisted femtosecond laser pulses. We employ Raman-type nonlinear optical processes, wherein magnetic oscillations are impulsively induced with a controlled initial phase. Their azimuthal angle follows well-defined selection rules that have been determined by the symmetries of the materials. We emphasize that the temporal variation of the laser-pulse polarization angle enables us to control the phase and amplitude of the two degenerate modes, independently. These results lead to a new concept of the vectorial control of magnetization by light. PMID- 21694711 TI - Biologically inspired achromatic waveplates for visible light. AB - Waveplates are planar devices used in optics and optoelectronics to change the polarization state of light. Made of anisotropic dielectric materials such as crystals and thin films, waveplates are not known to exhibit achromatic performance over the visible regime. Inspired by the microvillar structure of R8 cells functioning as polarization converters in the eyes of stomatopod crustaceans, we conceived, designed, fabricated and tested periodically multilayered structures comprising two different types of arrays of nanorods. Morphologically analogous to the ocular cells, here we show that the periodically multilayered structures can function as achromatic waveplates over the visible regime. PMID- 21694712 TI - Collective fluorescence enhancement in nanoparticle clusters. AB - Many nanoscale systems are known to emit light intermittently under continuous illumination. In the fluorescence of single semiconductor nanoparticles, the distributions of bright and dark periods ('on' and 'off' times) follow Levy statistics. Although fluorescence from single-quantum dots and from macroscopic quantum dot ensembles has been studied, there has been little study of fluorescence from small ensembles. Here we show that blinking nanorods (NRs) interact with each other in a cluster, and the interactions affect the blinking statistics. The on-times in the fluorescence of a NR cluster increase dramatically; in a cluster with N NRs, the maximum on-time increases by a factor of N or more compared with the combined signal from N well-separated NRs. Our study emphasizes the use of statistical properties in identifying the collective dynamics. The scaling of this interaction-induced increase of on-times with number of NRs reveals a novel collective effect at the nanoscale. PMID- 21694714 TI - Observing chaos for quantum-dot microlasers with external feedback. AB - Chaos presents a striking and fascinating phenomenon of nonlinear systems. A common aspect of such systems is the presence of feedback that couples the output signal partially back to the input. Feedback coupling can be well controlled in optoelectronic devices such as conventional semiconductor lasers that provide bench-top platforms for the study of chaotic behaviour and high bit rate random number generation. Here we experimentally demonstrate that chaos can be observed for quantum-dot microlasers operating close to the quantum limit at nW output powers. Applying self-feedback to a quantum-dot microlaser results in a dramatic change in the photon statistics wherein strong, super-thermal photon bunching is indicative of random-intensity fluctuations associated with the spiked emission of light. Our experiments reveal that gain competition of few quantum dots in the active layer enhances the influence of self-feedback and will open up new avenues for the study of chaos in quantum systems. PMID- 21694713 TI - Requirement of calcium-activated chloride channels in the activation of mouse vomeronasal neurons. AB - In terrestrial vertebrates, the vomeronasal organ (VNO) detects and transduces pheromone signals. VNO activation is thought to be mediated by the transient receptor potential C2 (TRPC2) channel. The aberrant behavioural phenotypes observed in TRPC2-/- mice are generally attributed to the lost VNO function. Recently, calcium-activated chloride channels have been shown to contribute to VNO activation. Here we show that CACCs can be activated in VNO slice preparations from the TRPC2-/- mice and this activation is blocked by pharmacological agents that inhibit intracellular Ca(2+) release. Urine-evoked Cl(-) current is sufficient to drive spiking changes in VNO neurons from both wild-type (WT) and TRPC2-/- mice. Moreover, blocking Cl(-) conductance essentially abolishes VNO activation in WT neurons. These results suggest a TRPC2 independent signalling pathway in the VNO and the requirement of calcium activated chloride channels currents to mediate pheromone activation. Our data further suggest that TRPC2-/- mice retain partial VNO function. PMID- 21694715 TI - Size limits the formation of liquid jets during bubble bursting. AB - A bubble reaching an air-liquid interface usually bursts and forms a liquid jet. Jetting is relevant to climate and health as it is a source of aerosol droplets from breaking waves. Jetting has been observed for large bubbles with radii of R?100 MUm. However, few studies have been devoted to small bubbles (R<100 MUm) despite the entrainment of a large number of such bubbles in sea water. Here we show that jet formation is inhibited by bubble size; a jet is not formed during bursting for bubbles smaller than a critical size. Using ultrafast X-ray and optical imaging methods, we build a phase diagram for jetting and the absence of jetting. Our results demonstrate that jetting in bubble bursting is analogous to pinching-off in liquid coalescence. The coalescence mechanism for bubble bursting may be useful in preventing jet formation in industry and improving climate models concerning aerosol production. PMID- 21694716 TI - Cross-species discovery of syncretic drug combinations that potentiate the antifungal fluconazole. AB - Resistance to widely used fungistatic drugs, particularly to the ergosterol biosynthesis inhibitor fluconazole, threatens millions of immunocompromised patients susceptible to invasive fungal infections. The dense network structure of synthetic lethal genetic interactions in yeast suggests that combinatorial network inhibition may afford increased drug efficacy and specificity. We carried out systematic screens with a bioactive library enriched for off-patent drugs to identify compounds that potentiate fluconazole action in pathogenic Candida and Cryptococcus strains and the model yeast Saccharomyces. Many compounds exhibited species- or genus-specific synergism, and often improved fluconazole from fungistatic to fungicidal activity. Mode of action studies revealed two classes of synergistic compound, which either perturbed membrane permeability or inhibited sphingolipid biosynthesis. Synergistic drug interactions were rationalized by global genetic interaction networks and, notably, higher order drug combinations further potentiated the activity of fluconazole. Synergistic combinations were active against fluconazole-resistant clinical isolates and an in vivo model of Cryptococcus infection. The systematic repurposing of approved drugs against a spectrum of pathogens thus identifies network vulnerabilities that may be exploited to increase the activity and repertoire of antifungal agents. PMID- 21694717 TI - Economics of membrane occupancy and respiro-fermentation. AB - The simultaneous utilization of efficient respiration and inefficient fermentation even in the presence of abundant oxygen is a puzzling phenomenon commonly observed in bacteria, yeasts, and cancer cells. Despite extensive research, the biochemical basis for this phenomenon remains obscure. We hypothesize that the outcome of a competition for membrane space between glucose transporters and respiratory chain (which we refer to as economics of membrane occupancy) proteins influences respiration and fermentation. By incorporating a sole constraint based on this concept in the genome-scale metabolic model of Escherichia coli, we were able to simulate respiro-fermentation. Further analysis of the impact of this constraint revealed differential utilization of the cytochromes and faster glucose uptake under anaerobic conditions than under aerobic conditions. Based on these simulations, we propose that bacterial cells manage the composition of their cytoplasmic membrane to maintain optimal ATP production by switching between oxidative and substrate-level phosphorylation. These results suggest that the membrane occupancy constraint may be a fundamental governing constraint of cellular metabolism and physiology, and establishes a direct link between cell morphology and physiology. PMID- 21694718 TI - Predicting selective drug targets in cancer through metabolic networks. AB - The interest in studying metabolic alterations in cancer and their potential role as novel targets for therapy has been rejuvenated in recent years. Here, we report the development of the first genome-scale network model of cancer metabolism, validated by correctly identifying genes essential for cellular proliferation in cancer cell lines. The model predicts 52 cytostatic drug targets, of which 40% are targeted by known, approved or experimental anticancer drugs, and the rest are new. It further predicts combinations of synthetic lethal drug targets, whose synergy is validated using available drug efficacy and gene expression measurements across the NCI-60 cancer cell line collection. Finally, potential selective treatments for specific cancers that depend on cancer type specific downregulation of gene expression and somatic mutations are compiled. PMID- 21694719 TI - Genome-wide dFOXO targets and topology of the transcriptomic response to stress and insulin signalling. AB - FoxO transcription factors, inhibited by insulin/insulin-like growth factor signalling (IIS), are crucial players in numerous organismal processes including lifespan. Using genomic tools, we uncover over 700 direct dFOXO targets in adult female Drosophila. dFOXO is directly required for transcription of several IIS components and interacting pathways, such as TOR, in the wild-type fly. The genomic locations occupied by dFOXO in adults are different from those observed in larvae or cultured cells. These locations remain unchanged upon activation by stresses or reduced IIS, but the binding is increased and additional targets activated upon genetic reduction in IIS. We identify the part of the IIS transcriptional response directly controlled by dFOXO and the indirect effects and show that parts of the transcriptional response to IIS reduction do not require dfoxo. Promoter analyses revealed GATA and other forkhead factors as candidate mediators of the indirect and dfoxo-independent effects. We demonstrate genome-wide evolutionary conservation of dFOXO targets between the fly and the worm Caenorhabditis elegans, enriched for a second tier of regulators including the dHR96/daf-12 nuclear hormone receptor. PMID- 21694720 TI - Autoregulation of Parkin activity through its ubiquitin-like domain. AB - Parkin is an E3-ubiquitin ligase belonging to the RBR (RING-InBetweenRING-RING family), and is involved in the neurodegenerative disorder Parkinson's disease. Autosomal recessive juvenile Parkinsonism, which is one of the most common familial forms of the disease, is directly linked to mutations in the parkin gene. However, the molecular mechanisms of Parkin dysfunction in the disease state remain to be established. We now demonstrate that the ubiquitin-like domain of Parkin functions to inhibit its autoubiquitination. Moreover pathogenic Parkin mutations disrupt this autoinhibition, resulting in a constitutively active molecule. In addition, we show that the mechanism of autoregulation involves ubiquitin binding by a C-terminal region of Parkin. Our observations provide important molecular insights into the underlying basis of Parkinson's disease, and in the regulation of RBR E3-ligase activity. PMID- 21694721 TI - TCF/Lef1 activity controls establishment of diverse stem and progenitor cell compartments in mouse epidermis. AB - Mammalian epidermis consists of the interfollicular epidermis, hair follicles (HFs) and associated sebaceous glands (SGs). It is constantly renewed by stem and progenitor cell populations that have been identified and each compartment features a distinct mechanism of cellular turnover during renewal. The functional relationship between the diverse stem cell (SC) pools is not known and molecular signals regulating the establishment and maintenance of SC compartments are not well understood. Here, we performed lineage tracing experiments to demonstrate that progeny of HF bulge SCs transit through other SC compartments, suggesting a hierarchy of competent multipotent keratinocytes contributing to tissue renewal. The bulge was identified as a bipotent SC compartment that drives both cyclic regeneration of HFs and continuous renewal of SGs. Our data demonstrate that aberrant signalling by TCF/Lef1, transcription factors crucial for bulge SC activation and hair differentiation, results in development of ectopic SGs originating from bulge cells. This process of de novo SG formation is accompanied by the establishment of new progenitor niches. Detailed molecular analysis suggests the recapitulation of steps of tissue morphogenesis. PMID- 21694722 TI - Drosophila Set1 is the major histone H3 lysine 4 trimethyltransferase with role in transcription. AB - Histone H3 lysine 4 trimethylation (H3K4me3) is a major hallmark of promoter proximal histones at transcribed genes. Here, we report that a previously uncharacterized Drosophila H3K4 methyltransferase, dSet1, and not the other putative histone H3K4 methyltransferases (Trithorax; Trithorax-related protein), is predominantly responsible for histone H3K4 trimethylation. Functional and proteomics studies reveal that dSet1 is a component of a conserved H3K4 trimethyltransferase complex and polytene staining and live cell imaging assays show widespread association of dSet1 with transcriptionally active genes. dSet1 is present at the promoter region of all tested genes, including activated Hsp70 and Hsp26 heat shock genes and is required for optimal mRNA accumulation from the tested genes. In the case of Hsp70, the mRNA production defect in dSet1 RNAi treated cells is accompanied by retention of Pol II at promoters. Our data suggest that dSet1-dependent H3K4me3 is responsible for the generation of a chromatin structure at active promoters that ensures optimal Pol II release into productive elongation. PMID- 21694723 TI - Targeting colon cancer stem cells using a new curcumin analogue, GO-Y030. AB - BACKGROUND: Persistent activation of signal transducers and activators of transcription 3 (STAT3) is commonly detected in many types of cancer, including colon cancer. To date, whether STAT3 is activated and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, in colon cancer stem cells are still unknown. METHODS: Flow cytometry was used to isolate colon cancer stem cells, which are characterised by both aldehyde dehydrogenase (ALDH) positive and CD133-positive subpopulations (ALDH(+)/CD133(+)). The levels of STAT3 phosphorylation and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, that targets STAT3 in colon cancer stem cells were examined. RESULTS: Our results observed that ALDH(+)/CD133(+) colon cancer cells expressed higher levels of phosphorylated STAT3 than ALDH-negative/CD133-negative colon cancer cells, suggesting that STAT3 is activated in colon cancer stem cells. GO-Y030 and curcumin inhibited STAT3 phosphorylation, cell viability, tumoursphere formation in colon cancer stem cells. GO-Y030 also reduced STAT3 downstream target gene expression and induced apoptosis in colon cancer stem cells. Furthermore, GO-Y030 suppressed tumour growth of cancer stem cells from both SW480 and HCT-116 colon cancer cell lines in the mouse model. CONCLUSION: Our results indicate that STAT3 is a novel therapeutic target in colon cancer stem cells, and inhibition of activated STAT3 in cancer stem cells by GO-Y030 may offer an effective treatment for colorectal cancer. PMID- 21694724 TI - Stability of BRAF V600E mutation in metastatic melanoma: new insights for therapeutic success? PMID- 21694725 TI - EGFR gene copy number assessment from areas with highest EGFR expression predicts response to anti-EGFR therapy in colorectal cancer. AB - BACKGROUND: Only 40-70% of metastatic colorectal cancers (mCRCs) with wild-type (WT) KRAS oncogene respond to anti-epidermal growth factor receptor (anti-EGFR) antibody treatment. EGFR amplification has been suggested as an additional marker to predict the response. However, improved methods for bringing the EGFR analysis into routine laboratory are needed. METHODS: The material consisted of 80 patients with mCRC, 54 of them receiving anti-EGFR therapy. EGFR gene copy number (GCN) was analysed by automated silver in situ hybridisation (SISH). Immunohistochemical EGFR protein analysis was used to guide SISH assessment. RESULTS: Clinical benefit was seen in 73% of high (>= 4.0) EGFR GCN patients, in comparison with 59% of KRAS WT patients. Only 20% of low EGFR GCN patients responded to therapy. A high EGFR GCN number associated with longer progression free survival (P<0.0001) and overall survival (P=0.004). Together with KRAS analysis, EGFR GCN identified the responsive patients to anti-EGFR therapy more accurately than either test alone. The clinical benefit rate of KRAS WT/high EGFR GCN tumours was 82%. CONCLUSION: Our results show that automated EGFR SISH, in combination with KRAS mutation analysis, can be a useful and easily applicable technique in routine diagnostic practise for selecting patients for anti-EGFR therapy. PMID- 21694726 TI - The treatment of early breast cancer in women over the age of 70. AB - One third of all breast cancers are diagnosed in women aged 70 or over. Older women are a heterogeneous population who are under-represented in clinical trials, and as a result uncertainty can exist as to what represents optimal treatment. This minireview, from an international authorship, summarises the existing evidence surrounding the management of early breast cancer in women aged 70 and over. The use of primary surgery and endocrine therapy, and adjuvant chemotherapy, radiotherapy, endocrine therapy and trastuzumab are discussed. Reference is made to ongoing clinical trials in this area and areas of controversy are highlighted. PMID- 21694727 TI - Transcription factors and molecular epigenetic marks underlying EpCAM overexpression in ovarian cancer. AB - BACKGROUND: The epithelial cell adhesion molecule (EpCAM) is overexpressed on carcinomas, and its downregulation inhibits the oncogenic potential of multiple tumour types. Here, we investigated underlying mechanisms of epcam overexpression in ovarian carcinoma. METHODS: Expression of EpCAM and DNA methylation (bisulphite sequencing) was determined for ovarian cancer cell lines. The association of histone modifications and 16 transcription factors with the epcam promoter was analysed by chromatin immunoprecipitation. Treatment with 5-Aza-2' deoxycytidine (5-AZAC) was used to induce EpCAM expression. RESULTS: Expression of EpCAM was correlated with DNA methylation and histone modifications. Treatment with 5-AZAC induced EpCAM expression in negative cells. Ten transcription factors were associated with the epcam gene in EpCAM expressing cells, but not in EpCAM negative cells. Methylation of an Sp1 probe inhibited the binding of nuclear extract proteins in electromobility shift assays; such DNA methylation sensitivity was not observed for an NF-kappaB probe. CONCLUSION: This study provides insights in transcriptional regulation of epcam in ovarian cancer. Epigenetic parameters associated with EpCAM overexpression are potentially reversible, allowing novel strategies for sustained silencing of EpCAM expression. PMID- 21694728 TI - Dietary cadmium exposure and risk of epithelial ovarian cancer in a prospective cohort of Swedish women. AB - BACKGROUND: The proposed cadmium-induced oestrogen mimicking effects in reproductive tissues, suggest a role of this widespread food contaminant in the development of hormone-dependent malignancies. METHODS: We prospectively evaluated the association between tertiles of dietary cadmium exposure and epithelial ovarian cancer in 60,889 women from the population-based Swedish Mammography Cohort. Dietary cadmium was estimated using a food-frequency questionnaire at baseline (1987-1990) and in 1997. Multivariable-adjusted rate ratios (RR) were evaluated using Cox proportional hazards models. RESULTS: During a mean follow-up of 18.9 years (1,149,470 person-years), we identified 409 incident cases of epithelial ovarian cancer, including 215 serous, 27 mucinous, 62 endometrioid and 12 clear cell tumours. We found no association between dietary cadmium exposure and the risk of ovarian cancer. Compared with the lowest tertile of cadmium exposure, the multivariable-adjusted RR for the highest tertile was 0.90 (95% confidence interval (CI): 0.71-1.15) for total epithelial ovarian cancer. Likewise, no association was observed in subtypes modelled with continuous dietary cadmium exposure; multivariable RR for each 1 MUg per day increment of cadmium: 0.97 (95% CI: 0.93-1.02) for serous tumours, 0.94 (95% CI: 0.82-1.07) for mucinous tumours and 1.00 (95% CI: 0.92-1.08) for endometrioid and clear cell tumours. CONCLUSION: Our study suggests that dietary cadmium exposure is not likely to have a substantial role in ovarian cancer development. PMID- 21694729 TI - Health-related quality of life anticipated with different management strategies for paediatric febrile neutropaenia. AB - BACKGROUND: To describe (1) anticipated health-related quality of life during different strategies for febrile neutropaenia (FN) management and (2) attributes of those preferring inpatient management. METHODS: Respondents were parents of children 0-18 years and children 12-18 years receiving cancer treatment. Anticipated health-related quality of life was elicited for four different FN management strategies: entire inpatient, early discharge, outpatient oral and outpatient intravenous (i.v.) therapy. Tools used to measure health-related quality of life were visual analogue scale (VAS), willingness to pay and time trade off. RESULTS: A total of 155 parents and 43 children participated. For parents, median VAS scores were highest for early discharge (5.9, interquartile range 4.4-7.2) and outpatient i.v. (5.9, interquartile range 4.4-7.3). For children, median scores were highest for early discharge (6.1, interquartile range 4.6-7.2). In contrast, the most commonly preferred strategy for parents and children was inpatient in 55.0% and 37.2%, respectively. Higher current child health-related quality of life was associated with a stronger preference for outpatient management. CONCLUSION: Early discharge and outpatient i.v. management are associated with higher anticipated health-related quality of life, although the most commonly preferred strategy was inpatient care. This data may help with determining more cost-effective strategies for paediatric FN. PMID- 21694730 TI - The high mannose-type glycan binding lectin actinohivin: dimerization greatly improves anti-HIV activity. AB - The actinomycete-derived lectin actinohivin (AH) inhibits entry of HIV-1 to susceptible cells at low nM concentrations. The cooperative binding of three segments of AH to three high mannose-type glycans (HMTGs) of HIV-1 gp120 generates specific and strong anti-HIV activity. Dimerization of AH effectively improves anti-HIV activity by increasing the number of HMTG-binding pockets. AH dimers were prepared using an Escherichia coli expression system and their anti syncytium formation and anti-HIV activities were evaluated. Each dimer was constructed by a head-to-tail fusion of two AH molecules, with or without a spacer. As a result, His-TEV-AH/RTB(132-143)/AH, which has the residues 132-143 of ricin toxin B-chain (RTB) as a spacer, had 20-fold higher anti-syncytium formation activity and also exhibited 2-30-fold higher anti-HIV activity than AH against various clinically isolated HIV-1 strains, including drug-resistant ones. Mutation analysis implies that all six HMTG-binding pockets of the dimer participated in HMTG binding. Several AH dimers with different spacer sequences showed diverse activities, suggesting that the spacer sequence is an important factor to create higher anti-HIV activity. A dimer with improved anti-HIV activity would be a good candidate for investigation as a potential microbicide to prevent HIV transmission. PMID- 21694731 TI - Pain: Blocking painful interactions. PMID- 21694732 TI - Sensory systems: A promising line of defence. PMID- 21694733 TI - Mapping genetic loci that interact with myostatin to affect growth traits. AB - Myostatin, or GDF8, is an inhibitor of skeletal muscle growth. A non-functional myostatin mutation leads to a double muscling phenotype in some species, for example, mice, cattle and humans. Previous studies have indicated that there are loci in the genome that interact with myostatin to control backfat depth and other complex traits. We now report a quantitative trait loci (QTL) mapping study designed to identify loci that interact with myostatin to impact growth traits in mice. Body weight and average daily gain traits were collected on F2 progeny derived from a myostatin-null C57BL/6 strain by M16i cross. In all, 44 main effect QTL were detected above a 5% genome-wide significance threshold when an interval mapping method was used. An additional 37 QTL were identified to significantly interact with myostatin, sex or reciprocal cross. A total of 12 of these QTL interacted with myostatin genotype. These results provide a foundation for the further fine mapping of genome regions that harbor loci that interact with myostatin. PMID- 21694734 TI - Copy number variants and infantile spasms: evidence for abnormalities in ventral forebrain development and pathways of synaptic function. AB - Infantile spasms (ISS) are an epilepsy disorder frequently associated with severe developmental outcome and have diverse genetic etiologies. We ascertained 11 subjects with ISS and novel copy number variants (CNVs) and combined these with a new cohort with deletion 1p36 and ISS, and additional published patients with ISS and other chromosomal abnormalities. Using bioinformatics tools, we analyzed the gene content of these CNVs for enrichment in pathways of pathogenesis. Several important findings emerged. First, the gene content was enriched for the gene regulatory network involved in ventral forebrain development. Second, genes in pathways of synaptic function were overrepresented, significantly those involved in synaptic vesicle transport. Evidence also suggested roles for GABAergic synapses and the postsynaptic density. Third, we confirm the association of ISS with duplication of 14q12 and maternally inherited duplication of 15q11q13, and report the association with duplication of 21q21. We also present a patient with ISS and deletion 7q11.3 not involving MAGI2. Finally, we provide evidence that ISS in deletion 1p36 may be associated with deletion of KLHL17 and expand the epilepsy phenotype in that syndrome to include early infantile epileptic encephalopathy. Several of the identified pathways share functional links, and abnormalities of forebrain synaptic growth and function may form a common biologic mechanism underlying both ISS and autism. This study demonstrates a novel approach to the study of gene content in subjects with ISS and copy number variation, and contributes further evidence to support specific pathways of pathogenesis. PMID- 21694736 TI - Application of SNP array for rapid prenatal diagnosis: implementation, genetic counselling and diagnostic flow. AB - We report on the validation and implementation of the HumanCytoSNP-12 array (Illumina) (HCS) in prenatal diagnosis. In total, 64 samples were used to validate the Illumina platform (20 with a known (sub) microscopic chromosome abnormality, 5 with known maternal cell contamination (MCC) and 39 normal control samples). There were no false-positive or false-negative results. In addition to the diagnostic possibilities of arrayCGH, the HCS allows detection of regions of homozygosity (ROH), triploidy and helps recognising MCC. Moreover, in two cases of MCC, a deletion was correctly detected. Furthermore we found out that only about 50 ng of DNA is required, which allows a reporting time of only 3 days. We also present a prospective pilot study of 61 fetuses with ultrasound abnormalities and a normal karyotype tested with HCS. In 4 out of 61 (6.5%) fetuses, a clinically relevant abnormality was detected. We designed and present pre-test genetic counselling information on categories of possible test outcomes. On the basis of this information, about 90% of the parents chose to be informed about adverse health outcomes of their future child at infancy and childhood, and 55% also about outcomes at an adult stage. The latter issue regarding the right of the future child itself to decide whether or not to know this information needs to be addressed. PMID- 21694735 TI - The tRNAMet 4435A>G mutation in the mitochondrial haplogroup G2a1 is responsible for maternally inherited hypertension in a Chinese pedigree. AB - Mutations in mitochondrial DNA (mtDNA) have been associated with hypertension in several pedigrees with maternal inheritance. However, the pathophysiology of maternally inherited hypertension remains poorly understood. We reported here clinical, genetic evaluations and molecular analysis of mtDNA in a three generation Han Chinese family with essential hypertension. Eight of 17 matrilineal relatives exhibited a wide range of severity in essential hypertension, whereas none of the offsprings of the affected father had hypertension. The age-at-onset of hypertension in the maternal kindred varied from 31 to 65 years, with an average of 52 years. Sequence analysis of mtDNA in this pedigree identified the known homoplasmic 4435A>G mutation, which is located at immediately 3' end to the anticodon, corresponding to the conventional position 37 of tRNA(Met), and 41 variants belonging to the Asian haplogroup G2a1. In contrast, the 4435A>G mutation occurred among mtDNA haplogroups B5a, D, M7a2 and J. The adenine (A37) at this position of tRNA(Met) is extraordinarily conserved from bacteria to human mitochondria. This modified A37 was shown to contribute to the high fidelity of codon recognition, structural formation and stabilization of functional tRNAs. However, 41 other mtDNA variants in this pedigree were the known polymorphisms. The occurrence of the 4435A>G mutation in two genetically unrelated families affected by hypertension indicates that this mutation is involved in hypertension. Our present investigations further supported our previous findings that the 4435A>G mutation acted as an inherited risk factor for the development of hypertension. Our findings will be helpful for counseling families of maternally inherited hypertension. PMID- 21694737 TI - Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989. AB - Neurofibromatosis 1 (NF1) is a comparatively common autosomal dominant disorder. However, relatively few studies have assessed lifetime risk; and information about the effect of NF1 on mortality remains uncertain. NF1 patients were identified using The North West regional family Genetic Register, which covers the 4.1 million people living in North West England, including the regions of Greater Manchester, Cheshire and Cumbria. Data relating to tumours and malignancies were obtained from The North West Cancer Intelligence Service. Death data for the general North West population were obtained from the Office of National Statistics. We identified 1186 individuals with NF1, of whom 1023 lived within the strict regional boundaries (constituting a region of North West England bound by The Pennines to the east and Irish Sea to the west, but excluding the conurbation of Liverpool (Merseyside) and the Wirral peninsula) and 131 had died. MPNST and glioma were found to be the two most common causes of reduced life expectancy among NF1 patients. In Kaplan-Meier analyses the median survival for NF1 patients was shown to be 71.5 years, with women living ~7.4 years longer than men. On average both men and women lived ~8 years less than their counterparts in the general population. Reduction in life expectancy for NF1 patients was found to be much lower (8 years) than the previously estimated 15-year decrease. Limitations relating to the underreporting of NF1 on death certificates were once again highlighted and should be considered in future investigations. PMID- 21694738 TI - Genetic determination of human facial morphology: links between cleft-lips and normal variation. AB - Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and other previous studies showed distinctly differing facial distance measurements when comparing unaffected relatives of NSCL/P patients with normal controls. Here, we test the hypothesis that genetic loci involved in NSCL/P also influence normal variation in facial morphology. We tested 11 SNPs from 10 genomic regions previously showing replicated evidence of association with NSCL/P for association with normal variation of nose width and bizygomatic distance in two cohorts from Germany (N=529) and the Netherlands (N=2497). The two most significant associations found were between nose width and SNP rs1258763 near the GREM1 gene in the German cohort (P=6 * 10(-4)), and between bizygomatic distance and SNP rs987525 at 8q24.21 near the CCDC26 gene (P=0.017) in the Dutch sample. A genetic prediction model explained 2% of phenotype variation in nose width in the German and 0.5% of bizygomatic distance variation in the Dutch cohort. Although preliminary, our data provide a first link between genetic loci involved in a pathological facial trait such as NSCL/P and variation of normal facial morphology. Moreover, we present a first approach for understanding the genetic basis of human facial appearance, a highly intriguing trait with implications on clinical practice, clinical genetics, forensic intelligence, social interactions and personal identity. PMID- 21694739 TI - [About review articles]. PMID- 21694740 TI - [The pandemic in Austevoll]. PMID- 21694741 TI - [Evidence-based medicine or vulgar cochranism?]. PMID- 21694742 TI - [Increased control or academic creativeness]. PMID- 21694743 TI - [Psychologists should get the right of referral]. PMID- 21694744 TI - [The blood pressure level in a Norwegian population--the significance of inheritance and lifestyle]. AB - BACKGROUND: The aim of this study was to find the prevalence of inherited and lifestyle-related risk factors for hypertension and their association with hypertension specified for age and sex. MATERIAL AND METHOD: The study was based on data from 62,296 people aged 20-79 who participated in the second health study for Nord-Trondelag county (HUNT2). The prevalence of hypertension was examined in people with measured blood pressure and body mass index (BMI) in addition to information on use of medication for hypertension, and hypertension in first degree relatives. In a subgroup not using medication for hypertension we used multiple linear regression to model the blood pressure as a function of lifestyle related factors and information on cardiovascular disease and diabetes in first degree relatives. RESULTS: The prevalence of hypertension was examined in 42,117 subjects and varied from 7 % to 85 % for the different gender and age groups. Around 15 % were obese and approximately 50 % reported hypertension in relatives. Obesity as a single risk factor was associated with an up to four times higher risk of hypertension. In women aged 20-29 there was a synergistic interaction of hypertension in relatives and obesity, whereas the relationship was additive in the other sex and age categories. For 30,577 persons with complete data, blood pressure was modelled mathematically. In subjects with hypertension in relatives the systolic blood pressure was 3 mmHg higher for both genders. In obese subjects the systolic blood pressure was 10 and 7 mmHg higher than in corresponding reference groups of women and men respectively. INTERPRETATION: Hypertension in relatives and obesity are frequently occurring and strongly associated with hypertension. The relative risk of hypertension was particularly high in young obese women. In this group there was a statistically significant synergistic interaction between these risk factors for hypertension. PMID- 21694745 TI - Sacral nerve stimulation. AB - BACKGROUND: Sacral nerve stimulation implies electrical stimulation of a sacral nerve root by an electrode and a pacemaker. Within the past few years, sacral nerve stimulation has become a possible treatment option for selected patients with urinary retention, urinary incontinence, anal incontinence and constipation. The method is furthermore being tested for several other conditions. MATERIAL AND METHODS: The article presents the method and treatment results following various indications based on the authors' own experience and non-systematic PubMed search. RESULTS: During a test period an external pacemaker is used for 3-30 days, with length of test differing according to the indication. A positive test (improvement of symptoms by 50 % or more) is achieved by 70-90 % of patients with anal incontinence, 70 % with urinary non-obstructive retention, 52-77 % with urinary urge incontinence and 43-72 % with constipation. Sacral nerve stimulation may also be effective in patients with chronic pelvic pain. Following implantation of a pacemaker a sustainable effect is seen in 50-90 % of patients with a positive test. Up to 75 % of patients will need repeated follow-up including pacemaker reprogramming or reoperations due to diminished effect. The longevity of the pacemaker is 3-10 years, and it must be replaced operatively when the battery has depleted. INTERPRETATION: Treatment with sacral nerve stimulation may be efficient over time in patients with various pelvic floor dysfunctions, especially anal incontinence and non-obstructive urinary retention. Most of the patients will need close follow-up in order to maintain an optimal result. PMID- 21694747 TI - [Headache and drooping eyelid]. PMID- 21694746 TI - [Early onset dementia]. AB - BACKGROUND: It is estimated that 1,200 people under the age of 65 have been diagnosed with dementia in Norway. This article provides an overview of the types of dementia frequently seen in younger patients. MATERIAL AND METHODS: The article is based on a non-systematic search in PubMed, as well as the authors' own clinical and research experience. RESULTS: Alzheimer's disease, frontotemporal dementia, vascular dementia and dementia with Lewy bodies, are the most common types of dementia occurring more often in younger than in older patients. The cognitive symptoms are more variable in younger patients than in older. Only a small percentage of early onset dementia is caused by genetic factors. There are few diagnostic tools available for this age group and it takes considerable time to reach a correct diagnosis. Early diagnosis allows the patient and carer to plan for the future. INTERPRETATION: Physicians should be aware that dementia can occur in younger people, and more diagnostic assessments should be developed for this patient group. Better coordination from the public health authority and municipalities is needed to provide respite care for early onset dementia patients and their carers. PMID- 21694748 TI - [A young girl with abdominal pain]. AB - Abdominal pain combined with fever is common during childhood. We present a 12 year-old girl who was admitted to hospital with abdominal pain, fever and nausea, but she also complained of cough, weight loss and night sweat. Investigations revealed multiple and randomly distributed lung nodules, impaired lung function, meningitis and multiple small brain lesions, consistent with tuberculomas. The polymerase chain reaction was positive for Mycobacterium tuberculosis in sputum. Cultures of sputum and cerebrospinal fluid were also positive and confirmed miliary tuberculosis with concomitant meningitis. The result of the Mantoux test was 13 mm and that of the Quantiferon-TB Gold was 5.17 IU/ml. She was given four antituberculous drugs (isoniazide, rifampicin, pyrazinamide and ethambutol) for two months and two drugs (isoniazide and rifampicin) for an additional ten months. The intracranial tuberculomas increased in size during the first two months of treatment, but demonstrated regression after seven months. The girl was HIV-negative and had no sign of immunodeficiency, but had recently been ill with mononucleosis and varicella infections. She recovered completely. The combination of miliary tuberculosis and meningitis is uncommon, particularly among previously healthy children of this age. Temporary immune suppression, caused by viral infections, could possibly explain the unusual clinical course. Pediatricians should be aware of miliary tuberculosis as a possible diagnosis in children presenting with common symptoms. PMID- 21694749 TI - [Delayed diagnosis of formerly common disease]. PMID- 21694750 TI - [Self-help groups for substance addicts]. PMID- 21694751 TI - [Strict information requirements in optic and cosmetic surgery]. PMID- 21694753 TI - People or systems? To blame is human. The fix is to engineer. AB - Person-centered safety theories that place the burden of causality on human traits and actions have been largely dismissed in favor of systems-centered theories. Students and practitioners are now taught that accidents are caused by multiple factors and occur due to the complex interactions of numerous work system elements, human and non-human. Nevertheless, person-centered approaches to safety management still prevail. This paper explores the notion that attributing causality and blame to people persists because it is both a fundamental psychological tendency as well as an industry norm that remains strong in aviation, health care, and other industries. Consequences of that possibility are discussed and a case is made for continuing to invest in whole-system design and engineering solutions. PMID- 21694755 TI - Imaging in acute stroke. AB - Imaging in the acute setting of suspected stroke is an important topic to all emergency physicians, neurologists, neurosurgeons and neuroradiologist. When it comes to imaging, the American College of Radiology (ACR) continually updates its guidelines for imaging pathways through the ACR Appropriateness Criteria.1,2 This article is a general review of the imaging modalities currently used to assess and help guide the treatment of strokes. PMID- 21694754 TI - PDK1-Foxo1 in agouti-related peptide neurons regulates energy homeostasis by modulating food intake and energy expenditure. AB - Insulin and leptin intracellular signaling pathways converge and act synergistically on the hypothalamic phosphatidylinositol-3-OH kinase/3 phosphoinositide-dependent protein kinase 1 (PDK1). However, little is known about whether PDK1 in agouti-related peptide (AGRP) neurons contributes to energy homeostasis. We generated AGRP neuron-specific PDK1 knockout (AGRPPdk1(-/-)) mice and mice with selective expression of transactivation-defective Foxo1 (Delta256Foxo1(AGRP)Pdk1(-/-)). The AGRPPdk1(-/-) mice showed reductions in food intake, body length, and body weight. The Delta256Foxo1(AGRP)Pdk1(-/-) mice showed increased body weight, food intake, and reduced locomotor activity. After four weeks of calorie-restricted feeding, oxygen consumption and locomotor activity were elevated in AGRPPdk1(-/-) mice and reduced in Delta256Foxo1(AGRP)Pdk1(-/-) mice. In vitro, ghrelin-induced changes in [Ca(2+)](i) and inhibition of ghrelin by leptin were significantly attenuated in AGRPPdk1(-/-) neurons compared to control neurons. However, ghrelin-induced [Ca(2+)](i) changes and leptin inhibition were restored in Delta256Foxo1(AGRP)Pdk1(-/-) mice. These results suggested that PDK1 and Foxo1 signaling pathways play important roles in the control of energy homeostasis through AGRP-independent mechanisms. PMID- 21694756 TI - A new isoform of the histone demethylase JMJD2A/KDM4A is required for skeletal muscle differentiation. AB - In proliferating myoblasts, muscle specific genes are silenced by epigenetic modifications at their promoters, including histone H3K9 methylation. Derepression of the promoter of the gene encoding the myogenic factor myogenin (Myog) is key for initiation of muscle differentiation. The mechanism of H3K9 demethylation at the Myog promoter is unclear, however. Here, we identify an isoform of the histone demethylase JMJD2A/KDM4A that lacks the N-terminal demethylase domain (DeltaN-JMJD2A). The amount of DeltaN-JMJD2A increases during differentiation of C2C12 myoblasts into myotubes. Genome-wide expression profiling and exon-specific siRNA knockdown indicate that, in contrast to the full-length protein, DeltaN-JMJD2A is necessary for myotube formation and muscle specific gene expression. Moreover, DeltaN-JMJD2A promotes MyoD-induced conversion of NIH3T3 cells into muscle cells. ChIP-on-chip analysis indicates that DeltaN-JMJD2A binds to genes mainly involved in transcriptional control and that this binding is linked to gene activation. DeltaN-JMJD2A is recruited to the Myog promoter at the onset of differentiation. This binding is essential to promote the demethylation of H3K9me2 and H3K9me3. We conclude that induction of the DeltaN-JMJD2A isoform is crucial for muscle differentiation: by directing the removal of repressive chromatin marks at the Myog promoter, it promotes transcriptional activation of the Myog gene and thus contributes to initiation of muscle-specific gene expression. PMID- 21694757 TI - Genetic diversity and population history of a critically endangered primate, the northern muriqui (Brachyteles hypoxanthus). AB - Social, ecological, and historical processes affect the genetic structure of primate populations, and therefore have key implications for the conservation of endangered species. The northern muriqui (Brachyteles hypoxanthus) is a critically endangered New World monkey and a flagship species for the conservation of the Atlantic Forest hotspot. Yet, like other neotropical primates, little is known about its population history and the genetic structure of remnant populations. We analyzed the mitochondrial DNA control region of 152 northern muriquis, or 17.6% of the 864 northern muriquis from 8 of the 12 known extant populations and found no evidence of phylogeographic partitions or past population shrinkage/expansion. Bayesian and classic analyses show that this finding may be attributed to the joint contribution of female-biased dispersal, demographic stability, and a relatively large historic population size. Past population stability is consistent with a central Atlantic Forest Pleistocene refuge. In addition, the best scenario supported by an Approximate Bayesian Computation analysis, significant fixation indices (Phi(ST) = 0.49, Phi(CT) = 0.24), and population-specific haplotypes, coupled with the extirpation of intermediate populations, are indicative of a recent geographic structuring of genetic diversity during the Holocene. Genetic diversity is higher in populations living in larger areas (>2,000 hectares), but it is remarkably low in the species overall (theta = 0.018). Three populations occurring in protected reserves and one fragmented population inhabiting private lands harbor 22 out of 23 haplotypes, most of which are population-exclusive, and therefore represent patchy repositories of the species' genetic diversity. We suggest that these populations be treated as discrete units for conservation management purposes. PMID- 21694758 TI - Mammal-like organization of the avian midbrain central gray and a reappraisal of the intercollicular nucleus. AB - In mammals, rostrocaudal columns of the midbrain periaqueductal gray (PAG) regulate diverse behavioral and physiological functions, including sexual and fight-or-flight behavior, but homologous columns have not been identified in non mammalian species. In contrast to mammals, in which the PAG lies ventral to the superior colliculus and surrounds the cerebral aqueduct, birds exhibit a hypertrophied tectum that is displaced laterally, and thus the midbrain central gray (CG) extends mediolaterally rather than dorsoventrally as in mammals. We therefore hypothesized that the avian CG is organized much like a folded open PAG. To address this hypothesis, we conducted immunohistochemical comparisons of the midbrains of mice and finches, as well as Fos studies of aggressive dominance, subordinance, non-social defense and sexual behavior in territorial and gregarious finch species. We obtained excellent support for our predictions based on the folded open model of the PAG and further showed that birds possess functional and anatomical zones that form longitudinal columns similar to those in mammals. However, distinguishing characteristics of the dorsal/dorsolateral PAG, such as a dense peptidergic innervation, a longitudinal column of neuronal nitric oxide synthase neurons, and aggression-induced Fos responses, do not lie within the classical avian CG, but in the laterally adjacent intercollicular nucleus (ICo), suggesting that much of the ICo is homologous to the dorsal PAG. PMID- 21694759 TI - Using and reporting the Delphi method for selecting healthcare quality indicators: a systematic review. AB - OBJECTIVE: Delphi technique is a structured process commonly used to developed healthcare quality indicators, but there is a little recommendation for researchers who wish to use it. This study aimed 1) to describe reporting of the Delphi method to develop quality indicators, 2) to discuss specific methodological skills for quality indicators selection 3) to give guidance about this practice. METHODOLOGY AND MAIN FINDING: Three electronic data bases were searched over a 30 years period (1978-2009). All articles that used the Delphi method to select quality indicators were identified. A standardized data extraction form was developed. Four domains (questionnaire preparation, expert panel, progress of the survey and Delphi results) were assessed. Of 80 included studies, quality of reporting varied significantly between items (9% for year's number of experience of the experts to 98% for the type of Delphi used). Reporting of methodological aspects needed to evaluate the reliability of the survey was insufficient: only 39% (31/80) of studies reported response rates for all rounds, 60% (48/80) that feedback was given between rounds, 77% (62/80) the method used to achieve consensus and 57% (48/80) listed quality indicators selected at the end of the survey. A modified Delphi procedure was used in 49/78 (63%) with a physical meeting of the panel members, usually between Delphi rounds. Median number of panel members was 17(Q1:11; Q3:31). In 40/70 (57%) studies, the panel included multiple stakeholders, who were healthcare professionals in 95% (38/40) of cases. Among 75 studies describing criteria to select quality indicators, 28 (37%) used validity and 17(23%) feasibility. CONCLUSION: The use and reporting of the Delphi method for quality indicators selection need to be improved. We provide some guidance to the investigators to improve the using and reporting of the method in future surveys. PMID- 21694760 TI - Seroconverting blood donors as a resource for characterising and optimising recent infection testing algorithms for incidence estimation. AB - INTRODUCTION: Biomarker-based cross-sectional incidence estimation requires a Recent Infection Testing Algorithm (RITA) with an adequately large mean recency duration, to achieve reasonable survey counts, and a low false-recent rate, to minimise exposure to further bias and imprecision. Estimating these characteristics requires specimens from individuals with well-known seroconversion dates or confirmed long-standing infection. Specimens with well known seroconversion dates are typically rare and precious, presenting a bottleneck in the development of RITAs. METHODS: The mean recency duration and a 'false-recent rate' are estimated from data on seroconverting blood donors. Within an idealised model for the dynamics of false-recent results, blood donor specimens were used to characterise RITAs by a new method that maximises the likelihood of cohort-level recency classifications, rather than modelling individual sojourn times in recency. RESULTS: For a range of assumptions about the false-recent results (0% to 20% of biomarker response curves failing to reach the threshold distinguishing test-recent and test-non-recent infection), the mean recency duration of the Vironostika-LS ranged from 154 (95% CI: 96-231) to 274 (95% CI: 234-313) days in the South African donor population (n = 282), and from 145 (95% CI: 67-226) to 252 (95% CI: 194-308) days in the American donor population (n = 106). The significance of gender and clade on performance was rejected (p-value = 10%), and utility in incidence estimation appeared comparable to that of a BED-like RITA. Assessment of the Vitros-LS (n = 108) suggested potentially high false-recent rates. DISCUSSION: The new method facilitates RITA characterisation using widely available specimens that were previously overlooked, at the cost of possible artefacts. While accuracy and precision are insufficient to provide estimates suitable for incidence surveillance, a low-cost approach for preliminary assessments of new RITAs has been demonstrated. The Vironostika-LS and Vitros-LS warrant further analysis to provide greater precision of estimates. PMID- 21694761 TI - Genomic imbalances are confined to non-proliferating cells in paediatric patients with acute myeloid leukaemia and a normal or incomplete karyotype. AB - Leukaemia is often associated with genetic alterations such as translocations, amplifications and deletions, and recurrent chromosome abnormalities are used as markers of diagnostic and prognostic relevance. However, a proportion of acute myeloid leukaemia (AML) cases have an apparently normal karyotype despite comprehensive cytogenetic analysis. Based on conventional cytogenetic analysis of banded chromosomes, we selected a series of 23 paediatric patients with acute myeloid leukaemia and performed whole genome array comparative genome hybridization (aCGH) using DNA samples derived from the same patients. Imbalances involving large chromosomal regions or entire chromosomes were detected by aCGH in seven of the patients studied. Results were validated by fluorescence in situ hybridization (FISH) to both interphase nuclei and metaphase chromosomes using appropriate bacterial artificial chromosome (BAC) probes. The majority of these copy number alterations (CNAs) were confirmed by FISH and found to localize to the interphase rather than metaphase nuclei. Furthermore, the proliferative states of the cells analyzed by FISH were tested by immunofluorescence using an antibody against the proliferation marker pKi67. Interestingly, these experiments showed that, in the vast majority of cases, the changes appeared to be confined to interphase nuclei in a non-proliferative status. PMID- 21694762 TI - Susceptibility of Anopheles stephensi to Plasmodium gallinaceum: a trait of the mosquito, the parasite, and the environment. AB - BACKGROUND: Vector susceptibility to Plasmodium infection is treated primarily as a vector trait, although it is a composite trait expressing the joint occurrence of the parasite and the vector with genetic contributions of both. A comprehensive approach to assess the specific contribution of genetic and environmental variation on "vector susceptibility" is lacking. Here we developed and implemented a simple scheme to assess the specific contributions of the vector, the parasite, and the environment to "vector susceptibility." To the best of our knowledge this is the first study that employs such an approach. METHODOLOGY/PRINCIPAL FINDINGS: We conducted selection experiments on the vector (while holding the parasite "constant") and on the parasite (while holding the vector "constant") to estimate the genetic contributions of the mosquito and the parasite to the susceptibility of Anopheles stephensi to Plasmodium gallinaceum. We separately estimated the realized heritability of (i) susceptibility to parasite infection by the mosquito vector and (ii) parasite compatibility (transmissibility) with the vector while controlling the other. The heritabilities of vector and the parasite were higher for the prevalence, i.e., fraction of infected mosquitoes, than the corresponding heritabilities of parasite load, i.e., the number of oocysts per mosquito. CONCLUSIONS: The vector's genetics (heritability) comprised 67% of "vector susceptibility" measured by the prevalence of mosquitoes infected with P. gallinaceum oocysts, whereas the specific contribution of parasite genetics (heritability) to this trait was only 5%. Our parasite source might possess minimal genetic diversity, which could explain its low heritability (and the high value of the vector). Notably, the environment contributed 28%. These estimates are relevant only to the particular system under study, but this experimental design could be useful for other parasite-host systems. The prospects and limitations of the genetic manipulation of vector populations to render the vector resistant to the parasite are better considered on the basis of this framework. PMID- 21694763 TI - Statistical coding and decoding of heartbeat intervals. AB - The heart integrates neuroregulatory messages into specific bands of frequency, such that the overall amplitude spectrum of the cardiac output reflects the variations of the autonomic nervous system. This modulatory mechanism seems to be well adjusted to the unpredictability of the cardiac demand, maintaining a proper cardiac regulation. A longstanding theory holds that biological organisms facing an ever-changing environment are likely to evolve adaptive mechanisms to extract essential features in order to adjust their behavior. The key question, however, has been to understand how the neural circuitry self-organizes these feature detectors to select behaviorally relevant information. Previous studies in computational perception suggest that a neural population enhances information that is important for survival by minimizing the statistical redundancy of the stimuli. Herein we investigate whether the cardiac system makes use of a redundancy reduction strategy to regulate the cardiac rhythm. Based on a network of neural filters optimized to code heartbeat intervals, we learn a population code that maximizes the information across the neural ensemble. The emerging population code displays filter tuning proprieties whose characteristics explain diverse aspects of the autonomic cardiac regulation, such as the compromise between fast and slow cardiac responses. We show that the filters yield responses that are quantitatively similar to observed heart rate responses during direct sympathetic or parasympathetic nerve stimulation. Our findings suggest that the heart decodes autonomic stimuli according to information theory principles analogous to how perceptual cues are encoded by sensory systems. PMID- 21694764 TI - Educational attainment: a genome wide association study in 9538 Australians. AB - BACKGROUND: Correlations between Educational Attainment (EA) and measures of cognitive performance are as high as 0.8. This makes EA an attractive alternative phenotype for studies wishing to map genes affecting cognition due to the ease of collecting EA data compared to other cognitive phenotypes such as IQ. METHODOLOGY: In an Australian family sample of 9538 individuals we performed a genome-wide association scan (GWAS) using the imputed genotypes of ~2.4 million single nucleotide polymorphisms (SNP) for a 6-point scale measure of EA. Top hits were checked for replication in an independent sample of 968 individuals. A gene based test of association was then applied to the GWAS results. Additionally we performed prediction analyses using the GWAS results from our discovery sample to assess the percentage of EA and full scale IQ variance explained by the predicted scores. RESULTS: The best SNP fell short of having a genome-wide significant p value (p = 9.77*10(-7)). In our independent replication sample six SNPs among the top 50 hits pruned for linkage disequilibrium (r(2)<0.8) had a p-value<0.05 but only one of these SNPs survived correction for multiple testing--rs7106258 (p = 9.7*10(-4)) located in an intergenic region of chromosome 11q14.1. The gene based test results were non-significant and our prediction analyses show that the predicted scores explained little variance in EA in our replication sample. CONCLUSION: While we have identified a polymorphism chromosome 11q14.1 associated with EA, further replication is warranted. Overall, the absence of genome-wide significant p-values in our large discovery sample confirmed the high polygenic architecture of EA. Only the assembly of large samples or meta-analytic efforts will be able to assess the implication of common DNA polymorphisms in the etiology of EA. PMID- 21694765 TI - Ancient microbes from halite fluid inclusions: optimized surface sterilization and DNA extraction. AB - Fluid inclusions in evaporite minerals (halite, gypsum, etc.) potentially preserve genetic records of microbial diversity and changing environmental conditions of Earth's hydrosphere for nearly one billion years. Here we describe a robust protocol for surface sterilization and retrieval of DNA from fluid inclusions in halite that, unlike previously published methods, guarantees removal of potentially contaminating surface-bound DNA. The protocol involves microscopic visualization of cell structures, deliberate surface contamination followed by surface sterilization with acid and bleach washes, and DNA extraction using Amicon centrifugal filters. Methods were verified on halite crystals of four different ages from Saline Valley, California (modern, 36 ka, 64 ka, and 150 ka), with retrieval of algal and archaeal DNA, and characterization of the algal community using ITS1 sequences. The protocol we developed opens up new avenues for study of ancient microbial ecosystems in fluid inclusions, understanding microbial evolution across geological time, and investigating the antiquity of life on earth and other parts of the solar system. PMID- 21694766 TI - Role of calcitonin gene-related peptide in bone repair after cyclic fatigue loading. AB - BACKGROUND: Calcitonin gene related peptide (CGRP) is a neuropeptide that is abundant in the sensory neurons which innervate bone. The effects of CGRP on isolated bone cells have been widely studied, and CGRP is currently considered to be an osteoanabolic peptide that has effects on both osteoclasts and osteoblasts. However, relatively little is known about the physiological role of CGRP in-vivo in the skeletal responses to bone loading, particularly fatigue loading. METHODOLOGY/PRINCIPAL FINDINGS: We used the rat ulna end-loading model to induce fatigue damage in the ulna unilaterally during cyclic loading. We postulated that CGRP would influence skeletal responses to cyclic fatigue loading. Rats were fatigue loaded and groups of rats were infused systemically with 0.9% saline, CGRP, or the receptor antagonist, CGRP(8-37), for a 10 day study period. Ten days after fatigue loading, bone and serum CGRP concentrations, serum tartrate resistant acid phosphatase 5b (TRAP5b) concentrations, and fatigue-induced skeletal responses were quantified. We found that cyclic fatigue loading led to increased CGRP concentrations in both loaded and contralateral ulnae. Administration of CGRP(8-37) was associated with increased targeted remodeling in the fatigue-loaded ulna. Administration of CGRP or CGRP(8-37) both increased reparative bone formation over the study period. Plasma concentration of TRAP5b was not significantly influenced by either CGRP or CGRP(8-37) administration. CONCLUSIONS: CGRP signaling modulates targeted remodeling of microdamage and reparative new bone formation after bone fatigue, and may be part of a neuronal signaling pathway which has regulatory effects on load-induced repair responses within the skeleton. PMID- 21694767 TI - Global profiling of rice and poplar transcriptomes highlights key conserved circadian-controlled pathways and cis-regulatory modules. AB - BACKGROUND: Circadian clocks provide an adaptive advantage through anticipation of daily and seasonal environmental changes. In plants, the central clock oscillator is regulated by several interlocking feedback loops. It was shown that a substantial proportion of the Arabidopsis genome cycles with phases of peak expression covering the entire day. Synchronized transcriptome cycling is driven through an extensive network of diurnal and clock-regulated transcription factors and their target cis-regulatory elements. Study of the cycling transcriptome in other plant species could thus help elucidate the similarities and differences and identify hubs of regulation common to monocot and dicot plants. METHODOLOGY/PRINCIPAL FINDINGS: Using a combination of oligonucleotide microarrays and data mining pipelines, we examined daily rhythms in gene expression in one monocotyledonous and one dicotyledonous plant, rice and poplar, respectively. Cycling transcriptomes were interrogated under different diurnal (driven) and circadian (free running) light and temperature conditions. Collectively, photocycles and thermocycles regulated about 60% of the expressed nuclear genes in rice and poplar. Depending on the condition tested, up to one third of oscillating Arabidopsis-poplar-rice orthologs were phased within three hours of each other suggesting a high degree of conservation in terms of rhythmic gene expression. We identified clusters of rhythmically co-expressed genes and searched their promoter sequences to identify phase-specific cis-elements, including elements that were conserved in the promoters of Arabidopsis, poplar, and rice. CONCLUSIONS/SIGNIFICANCE: Our results show that the cycling patterns of many circadian clock genes are highly conserved across poplar, rice, and Arabidopsis. The expression of many orthologous genes in key metabolic and regulatory pathways is diurnal and/or circadian regulated and phased to similar times of day. Our results confirm previous findings in Arabidopsis of three major classes of cis-regulatory modules within the plant circadian network: the morning (ME, GBOX), evening (EE, GATA), and midnight (PBX/TBX/SBX) modules. Identification of identical overrepresented motifs in the promoters of cycling genes from different species suggests that the core diurnal/circadian cis regulatory network is deeply conserved between mono- and dicotyledonous species. PMID- 21694768 TI - Small molecule amiloride modulates oncogenic RNA alternative splicing to devitalize human cancer cells. AB - Alternative splicing involves differential exon selection of a gene transcript to generate mRNA and protein isoforms with structural and functional diversity. Abnormal alternative splicing has been shown to be associated with malignant phenotypes of cancer cells, such as chemo-resistance and invasive activity. Screening small molecules and drugs for modulating RNA splicing in human hepatocellular carcinoma cell line Huh-7, we discovered that amiloride, distinct from four pH-affecting amiloride analogues, could "normalize" the splicing of BCL X, HIPK3 and RON/MISTR1 transcripts. Our proteomic analyses of amiloride-treated cells detected hypo-phosphorylation of splicing factor SF2/ASF, and decreased levels of SRp20 and two un-identified SR proteins. We further observed decreased phosphorylation of AKT, ERK1/2 and PP1, and increased phosphorylation of p38 and JNK, suggesting that amiloride treatment down-regulates kinases and up-regulates phosphatases in the signal pathways known to affect splicing factor protein phosphorylation. These amiloride effects of "normalized" oncogenic RNA splicing and splicing factor hypo-phosphorylation were both abrogated by pre-treatment with a PP1 inhibitor. Global exon array of amiloride-treated Huh-7 cells detected splicing pattern changes involving 584 exons in 551 gene transcripts, many of which encode proteins playing key roles in ion transport, cellular matrix formation, cytoskeleton remodeling, and genome maintenance. Cellular functional analyses revealed subsequent invasion and migration defects, cell cycle disruption, cytokinesis impairment, and lethal DNA degradation in amiloride treated Huh-7 cells. Other human solid tumor and leukemic cells, but not a few normal cells, showed similar amiloride-altered RNA splicing with devitalized consequence. This study thus provides mechanistic underpinnings for exploiting small molecule modulation of RNA splicing for cancer therapeutics. PMID- 21694769 TI - Estimating the disease burden of 2009 pandemic influenza A(H1N1) from surveillance and household surveys in Greece. AB - BACKGROUND: The aim of this study was to assess the disease burden of the 2009 pandemic influenza A(H1N1) in Greece. METHODOLOGY/PRINCIPAL FINDINGS: Data on influenza-like illness (ILI), collected through cross-sectional nationwide telephone surveys of 1,000 households in Greece repeated for 25 consecutive weeks, were combined with data from H1N1 virologic surveillance to estimate the incidence and the clinical attack rate (CAR) of influenza A(H1N1). Alternative definitions of ILI (cough or sore throat and fever>38 degrees C [ILI-38] or fever 37.1-38 degrees C [ILI-37]) were used to estimate the number of symptomatic infections. The infection attack rate (IAR) was approximated using estimates from published studies on the frequency of fever in infected individuals. Data on H1N1 morbidity and mortality were used to estimate ICU admission and case fatality (CFR) rates. The epidemic peaked on week 48/2009 with approximately 750-1,500 new cases/100,000 population per week, depending on ILI-38 or ILI-37 case definition, respectively. By week 6/2010, 7.1%-15.6% of the population in Greece was estimated to be symptomatically infected with H1N1. Children 5-19 years represented the most affected population group (CAR:27%-54%), whereas individuals older than 64 years were the least affected (CAR:0.6%-2.2%). The IAR (95% CI) of influenza A(H1N1) was estimated to be 19.7% (13.3%, 26.1%). Per 1,000 symptomatic cases, based on ILI-38 case definition, 416 attended health services, 108 visited hospital emergency departments and 15 were admitted to hospitals. ICU admission rate and CFR were 37 and 17.5 per 100,000 symptomatic cases or 13.4 and 6.3 per 100,000 infections, respectively. CONCLUSIONS/SIGNIFICANCE: Influenza A(H1N1) infected one fifth and caused symptomatic infection in up to 15% of the Greek population. Although individuals older than 65 years were the least affected age group in terms of attack rate, they had 55 and 185 times higher risk of ICU admission and CFR, respectively. PMID- 21694770 TI - Computational prediction of intronic microRNA targets using host gene expression reveals novel regulatory mechanisms. AB - Approximately half of known human miRNAs are located in the introns of protein coding genes. Some of these intronic miRNAs are only expressed when their host gene is and, as such, their steady state expression levels are highly correlated with those of the host gene's mRNA. Recently host gene expression levels have been used to predict the targets of intronic miRNAs by identifying other mRNAs that they have consistent negative correlation with. This is a potentially powerful approach because it allows a large number of expression profiling studies to be used but needs refinement because mRNAs can be targeted by multiple miRNAs and not all intronic miRNAs are co-expressed with their host genes.Here we introduce InMiR, a new computational method that uses a linear-Gaussian model to predict the targets of intronic miRNAs based on the expression profiles of their host genes across a large number of datasets. Our method recovers nearly twice as many true positives at the same fixed false positive rate as a comparable method that only considers correlations. Through an analysis of 140 Affymetrix datasets from Gene Expression Omnibus, we build a network of 19,926 interactions among 57 intronic miRNAs and 3,864 targets. InMiR can also predict which host genes have expression profiles that are good surrogates for those of their intronic miRNAs. Host genes that InMiR predicts are bad surrogates contain significantly more miRNA target sites in their 3' UTRs and are significantly more likely to have predicted Pol II and Pol III promoters in their introns.We provide a dataset of 1,935 predicted mRNA targets for 22 intronic miRNAs. These prediction are supported both by sequence features and expression. By combining our results with previous reports, we distinguish three classes of intronic miRNAs: Those that are tightly regulated with their host gene; those that are likely to be expressed from the same promoter but whose host gene is highly regulated by miRNAs; and those likely to have independent promoters. PMID- 21694771 TI - Cadmium induces transcription independently of intracellular calcium mobilization. AB - BACKGROUND: Exposure to cadmium is associated with human pathologies and altered gene expression. The molecular mechanisms by which cadmium affects transcription remain unclear. It has been proposed that cadmium activates transcription by altering intracellular calcium concentration ([Ca(2+)](i)) and disrupting calcium mediated intracellular signaling processes. This hypothesis is based on several studies that may be technically problematic; including the use of BAPTA chelators, BAPTA-based fluorescent sensors, and cytotoxic concentrations of metal. METHODOLOGY/PRINCIPAL FINDING: In the present report, the effects of cadmium on [Ca(2+)](i) under non-cytotoxic and cytotoxic conditions was monitored using the protein-based calcium sensor yellow cameleon (YC3.60), which was stably expressed in HEK293 cells. In HEK293 constitutively expressing YC3.60, this calcium sensor was found to be insensitive to cadmium. Exposing HEK293::YC3.60 cells to non-cytotoxic cadmium concentrations was sufficient to induce transcription of cadmium-responsive genes but did not affect [Ca(2+)](i) mobilization or increase steady-state mRNA levels of calcium-responsive genes. In contrast, exposure to cytotoxic concentrations of cadmium significantly reduced intracellular calcium stores and altered calcium-responsive gene expression. CONCLUSIONS/SIGNIFICANCE: These data indicate that at low levels, cadmium induces transcription independently of intracellular calcium mobilization. The results also support a model whereby cytotoxic levels of cadmium activate calcium responsive transcription as a general response to metal-induced intracellular damage and not via a specific mechanism. Thus, the modulation of intracellular calcium may not be a primary mechanism by which cadmium regulates transcription. PMID- 21694772 TI - miRNA expression in colon polyps provides evidence for a multihit model of colon cancer. AB - Changes in miRNA expression are a common feature in colon cancer. Those changes occurring in the transition from normal to adenoma and from adenoma to carcinoma, however, have not been well defined. Additionally, miRNA changes among tumor subgroups of colon cancer have also not been adequately evaluated. In this study, we examined the global miRNA expression in 315 samples that included 52 normal colonic mucosa, 41 tubulovillous adenomas, 158 adenocarcinomas with proficient DNA mismatch repair (pMMR) selected for stage and age of onset, and 64 adenocarcinomas with defective DNA mismatch repair (dMMR) selected for sporadic (n = 53) and inherited colon cancer (n = 11). Sporadic dMMR tumors all had MLH1 inactivation due to promoter hypermethylation. Unsupervised PCA and cluster analysis demonstrated that normal colon tissue, adenomas, pMMR carcinomas and dMMR carcinomas were all clearly discernable. The majority of miRNAs that were differentially expressed between normal and polyp were also differentially expressed with a similar magnitude in the comparison of normal to both the pMMR and dMMR tumor groups, suggesting a stepwise progression for transformation from normal colon to carcinoma. Among the miRNAs demonstrating the largest fold up- or down-regulated changes (>=4), four novel (miR-31, miR-1, miR-9 and miR-99a) and two previously reported (miR-137 and miR-135b) miRNAs were identified in the normal/adenoma comparison. All but one of these (miR-99a) demonstrated similar expression differences in the two normal/carcinoma comparisons, suggesting that these early tumor changes are important in both the pMMR- and dMMR-derived cancers. The comparison between pMMR and dMMR tumors identified four miRNAs (miR 31, miR-552, miR-592 and miR-224) with statistically significant expression differences (>=2-fold change). PMID- 21694773 TI - HLA class I and class II associations in dengue viral infections in a Sri Lankan population. AB - BACKGROUND: HLA class I and class II alleles have been shown to be associated with the development of dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) in different populations. However, the majority of studies have been based on limited numbers of patients. In this study we aimed to investigate the HLA class I and class II alleles that are positively and negatively associated with the development of DSS in a cohort of patients with DHF and also the alleles associated with development of DHF during primary dengue infections in a Sri Lankan population. METHODOLOGY/PRINCIPAL FINDINGS: The allele frequencies of HLA class I and class II alleles were compared in 110 patients with DHF and 119 individuals from the population who had never reported a symptomatic dengue infection at the time of recruitment. We found that HLA-A*31 (corrected P = 0.01) and DRB1*08 (corrected P = 0.009) were associated with susceptibility to DSS when infected with the dengue virus, during secondary dengue infection. The frequency of DRB1*08 allele was 28.7 times higher than in the normal population in patients with DSS. HLA-A*31 allele was increased 16.6 fold in DHF who developed shock when compared to those who did not develop shock. A*24 (corrected P = 0.03) and DRB1*12 (corrected P = 0.041) were strongly associated with the development of DHF during primary dengue infection. CONCLUSIONS/SIGNIFICANCE: These data suggest that certain HLA alleles confer susceptibility/protection to severe dengue infections. As T cell epitope recognition depend on the HLA type of an individual, it would be now important to investigate how epitope specific T cells associate with primary and secondary dengue infections and in severe dengue infections. PMID- 21694774 TI - A second endolysin gene is fully embedded in-frame with the lysA gene of mycobacteriophage Ms6. AB - Mycobacteriophages are dsDNA viruses that infect mycobacterial hosts. The mycobacteriophage Ms6 accomplishes lysis by producing two cell wall hydrolytic enzymes, Lysin A (LysA) that possesses a central peptidoglycan recognition protein (PGRP) super-family conserved domain with the amidase catalytic site, that cleaves the amide bond between the N-acetylmuramic acid and L-alanine residues in the oligopeptide crosslinking chains of the peptidoglycan and Lysin B (LysB) a mycolylarabinogalactan esterase that hydrolyzes the mycolic acids from the mycolyl-arabinogalactan-peptidoglycan complex. Examination of the endolysin (lysA) DNA sequence revealed the existence of an embedded gene (lysA(241)) encoded in the same reading frame and preceded by a consensus ribosome-binding site. In the present work we show that, even though lysA is essential for Ms6 viability, phage mutants that express only the longer (Lysin(384)) or the shorter (Lysin(241)) endolysin are viable, but defective in the normal timing, progression and completion of host cell lysis. In addition, both endolysins have peptidoglycan hydrolase activity and demonstrated broad growth inhibition activity against various gram-positive bacteria and mycobacteria. PMID- 21694775 TI - Visfatin is regulated by rosiglitazone in type 2 diabetes mellitus and influenced by NFkappaB and JNK in human abdominal subcutaneous adipocytes. AB - Visfatin has been proposed as an insulin-mimicking adipocytokine, predominantly secreted from adipose tissue and correlated with obesity. However, recent studies suggest visfatin may act as a proinflammatory cytokine. Our studies sought to determine the significance of this adipocytokine and its potential role in the pathogenesis of T2DM. Firstly, we examined the effects of diabetic status on circulating visfatin levels, and several other adipocytokines, demonstrating that diabetic status increased visfatin*, TNF-alpha*** and IL-6*** compared with non diabetic subjects (*p<0.05, **p<0.01, ***p<0.001, respectively). We then assessed the effects of an insulin sensitizer, rosiglitazone (RSG), in treatment naive T2DM subjects, on circulating visfatin levels. Our findings showed that visfatin was reduced post-RSG treatment [vs. pre-treatment (*p<0.05)] accompanied by a reduction in HOMA-IR**, thus implicating a role for insulin in visfatin regulation. Further studies addressed the intracellular mechanisms by which visfatin may be regulated, and may exert pro-inflammatory effects, in human abdominal subcutaneous (Abd Sc) adipocytes. Following insulin (Ins) and RSG treatment, our in vitro findings highlighted that insulin (100 nM), alone, upregulated visfatin protein expression whereas, in combination with RSG (10 nM), it reduced visfatin*, IKKbeta** and p-JNK1/2*. Furthermore, inhibition of JNK protein exacted a significant reduction in visfatin expression (**p<0.01), whilst NF-kappaB blockade increased visfatin (*p<0.05), thus identifying JNK as the more influential factor in visfatin regulation. Additional in vitro analysis on adipokines regulating visfatin showed that only Abd Sc adipocytes treated with recombinant human (rh)IL-6 increased visfatin protein (*p<0.05), whilst rh visfatin treatment, itself, had no influence on TNF-alpha, IL-6 or resistin secretion from Sc adipocytes. These data highlight visfatin's regulation by insulin and RSG, potentially acting through NF-kappaB and JNK mechanisms, with only rh IL-6 modestly affecting visfatin regulation. Taken together, these findings suggest that visfatin may represent a pro-inflammatory cytokine that is influenced by insulin/insulin sensitivity via the NF-kappaB and JNK pathways. PMID- 21694776 TI - Functional refinement in the projection from ventral cochlear nucleus to lateral superior olive precedes hearing onset in rat. AB - Principal neurons of the lateral superior olive (LSO) compute the interaural intensity differences necessary for localizing high-frequency sounds. To perform this computation, the LSO requires precisely tuned, converging excitatory and inhibitory inputs that are driven by the two ears and that are matched for stimulus frequency. In rodents, the inhibitory inputs, which arise from the medial nucleus of the trapezoid body (MNTB), undergo extensive functional refinement during the first postnatal week. Similar functional refinement of the ascending excitatory pathway, which arises in the anteroventral cochlear nucleus (AVCN), has been assumed but has not been well studied. Using whole-cell voltage clamp in acute brainstem slices of neonatal rats, we examined developmental changes in input strength and pre- and post-synaptic properties of the VCN-LSO pathway. A key question was whether functional refinement in one of the two major input pathways might precede and then guide refinement in the opposite pathway. We find that elimination and strengthening of VCN inputs to the LSO occurs over a similar period to that seen for the ascending inhibitory (MNTB-LSO) pathway. During this period, the fractional contribution provided by NMDA receptors (NMDARs) declines while the contribution from AMPA receptors (AMPARs) increases. In the NMDAR-mediated response, GluN2B-containing NMDARs predominate in the first postnatal week and decline sharply thereafter. Finally, the progressive decrease in paired-pulse depression between birth and hearing onset allows these synapses to follow progressively higher frequencies. Our data are consistent with a model in which the excitatory and inhibitory projections to LSO are functionally refined in parallel during the first postnatal week, and they further suggest that GluN2B-containing NMDARs may mediate early refinement in the VCN-LSO pathway. PMID- 21694777 TI - Rapid analysis of vessel elements (RAVE): a tool for studying physiologic, pathologic and tumor angiogenesis. AB - Quantification of microvascular network structure is important in a myriad of emerging research fields including microvessel remodeling in response to ischemia and drug therapy, tumor angiogenesis, and retinopathy. To mitigate analyst specific variation in measurements and to ensure that measurements represent actual changes in vessel network structure and morphology, a reliable and automatic tool for quantifying microvascular network architecture is needed. Moreover, an analysis tool capable of acquiring and processing large data sets will facilitate advanced computational analysis and simulation of microvascular growth and remodeling processes and enable more high throughput discovery. To this end, we have produced an automatic and rapid vessel detection and quantification system using a MATLAB graphical user interface (GUI) that vastly reduces time spent on analysis and greatly increases repeatability. Analysis yields numerical measures of vessel volume fraction, vessel length density, fractal dimension (a measure of tortuosity), and radii of murine vascular networks. Because our GUI is open sourced to all, it can be easily modified to measure parameters such as percent coverage of non-endothelial cells, number of loops in a vascular bed, amount of perfusion and two-dimensional branch angle. Importantly, the GUI is compatible with standard fluorescent staining and imaging protocols, but also has utility analyzing brightfield vascular images, obtained, for example, in dorsal skinfold chambers. A manually measured image can be typically completed in 20 minutes to 1 hour. In stark comparison, using our GUI, image analysis time is reduced to around 1 minute. This drastic reduction in analysis time coupled with increased repeatability makes this tool valuable for all vessel research especially those requiring rapid and reproducible results, such as anti-angiogenic drug screening. PMID- 21694778 TI - Salmonella-induced mucosal lectin RegIIIbeta kills competing gut microbiota. AB - Intestinal inflammation induces alterations of the gut microbiota and promotes overgrowth of the enteric pathogen Salmonella enterica by largely unknown mechanisms. Here, we identified a host factor involved in this process. Specifically, the C-type lectin RegIIIbeta is strongly upregulated during mucosal infection and released into the gut lumen. In vitro, RegIIIbeta kills diverse commensal gut bacteria but not Salmonella enterica subspecies I serovar Typhimurium (S. Typhimurium). Protection of the pathogen was attributable to its specific cell envelope structure. Co-infection experiments with an avirulent S. Typhimurium mutant and a RegIIIbeta-sensitive commensal E. coli strain demonstrated that feeding of RegIIIbeta was sufficient for suppressing commensals in the absence of all other changes inflicted by mucosal disease. These data suggest that RegIIIbeta production by the host can promote S. Typhimurium infection by eliminating inhibitory gut microbiota. PMID- 21694779 TI - Accurate determination of the oxidative phosphorylation affinity for ADP in isolated mitochondria. AB - BACKGROUND: Mitochondrial dysfunctions appear strongly implicated in a wide range of pathologies. Therefore, there is a growing need in the determination of the normal and pathological integrated response of oxidative phosphorylation to cellular ATP demand. The present study intends to address this issue by providing a method to investigate mitochondrial oxidative phosphorylation affinity for ADP in isolated mitochondria. METHODOLOGY/PRINCIPAL FINDINGS: The proposed method is based on the simultaneous monitoring of substrate oxidation (determined polarographically) and phosphorylation (determined using the glucose-hexokinase glucose-6-phosphate dehydrogenase-NADP(+) enzymatic system) rates, coupled to the determination of actual ADP and ATP concentrations by bioluminescent assay. This enzymatic system allows the study of oxidative phosphorylation during true steady states in a wide range of ADP concentrations. We demonstrate how the application of this method allows an accurate determination of mitochondrial affinity for ADP from both oxidation (K(mVox)) and phosphorylation (K(mVp)) rates. We also demonstrate that determination of K(mVox) leads to an important overestimation of the mitochondrial affinity for ADP, indicating that mitochondrial affinity for ADP should be determined using phosphorylation rate. Finally, we show how this method allows the direct and precise determination of the mitochondrial coupling efficiency. Data obtained from rat skeletal muscle and liver mitochondria illustrate the discriminating capabilities of this method. CONCLUSIONS/SIGNIFICANCE: Because the proposed method allows the accurate determination of mitochondrial oxidative phosphorylation affinity for ADP in isolated mitochondria, it also opens the route to a better understanding of functional consequences of mitochondrial adaptations/dysfunctions arising in various physiological/pathophysiological conditions. PMID- 21694780 TI - Epigenetic dysregulation in mesenchymal stem cell aging and spontaneous differentiation. AB - BACKGROUND: Mesenchymal stem cells (MSCs) hold great promise for the treatment of difficult diseases. As MSCs represent a rare cell population, ex vivo expansion of MSCs is indispensable to obtain sufficient amounts of cells for therapies and tissue engineering. However, spontaneous differentiation and aging of MSCs occur during expansion and the molecular mechanisms involved have been poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Human MSCs in early and late passages were examined for their expression of genes involved in osteogenesis to determine their spontaneous differentiation towards osteoblasts in vitro, and of genes involved in self-renewal and proliferation for multipotent differentiation potential. In parallel, promoter DNA methylation and hostone H3 acetylation levels were determined. We found that MSCs underwent aging and spontaneous osteogenic differentiation upon regular culture expansion, with progressive downregulation of TERT and upregulation of osteogenic genes such as Runx2 and ALP. Meanwhile, the expression of genes associated with stem cell self-renewal such as Oct4 and Sox2 declined markedly. Notably, the altered expression of these genes were closely associated with epigenetic dysregulation of histone H3 acetylation in K9 and K14, but not with methylation of CpG islands in the promoter regions of most of these genes. bFGF promoted MSC proliferation and suppressed its spontaneous osteogenic differentiation, with corresponding changes in histone H3 acetylation in TERT, Oct4, Sox2, Runx2 and ALP genes. CONCLUSIONS/SIGNIFICANCE: Our results indicate that histone H3 acetylation, which can be modulated by extrinsic signals, plays a key role in regulating MSC aging and differentiation. PMID- 21694781 TI - Francisella tularensis 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase: kinetic characterization and phosphoregulation. AB - Deliberate and natural outbreaks of infectious disease, the prevalence of antibiotic resistant strains, and the ease by which antibiotic resistant bacteria can be intentionally engineered all underscore the necessity of effective vaccines and continued development of novel antimicrobial/antiviral therapeutics. Isoprenes, a group of molecules fundamentally involved in a variety of crucial biological functions, are derived from either the mevalonic acid (MVA) or methylerythritol phosphate (MEP) pathway. While mammals utilize the MVA pathway, many bacteria utilize the MEP pathway, highlighting the latter as an attractive target for antibiotic development. In this report we describe the cloning and characterization of Francisella tularensis MEP cytidylyltransferase, a MEP pathway enzyme and potential target for antibiotic development. Size exclusion chromatography indicates the protein exists as a dimer in solution. Enzyme assays produced an apparentK(MEP)(M) = 178 MUM, K(CTP)(M) = 73 MUM , k(MEP)(cat) = 1(s 1), k(CTP)(cat) = 0.8( s-1), and a k(MEP)(cat)/ K(MEP)(M) = 3.4 x 10(5) M(-1) min(-1). The enzyme exhibits a strict preference for Mg(+2) as a divalent cation and CTP as the nucleotide. Titanium dioxide chromatography-tandem mass spectrometry identified Thr141 as a site of phosphorylation. T141D and T141E site directed mutants are catalytically inactive, suggesting a mechanism for post translational control of metabolic flux through the F. tularensis MEP pathway. Overall, our study suggests that MEP cytidylyltransferase is an excellent target for the development of novel antibiotics against F. tularensis. PMID- 21694782 TI - Health related quality of life and psychological variables among a sample of asthmatics in Ile-Ife South-Western Nigeria. AB - BACKGROUND: Assessment of health related quality of life (HRQL) has become central to assessing the self-perceived impact of physical and mental impairment on patient's health. Studies have reported a high rate of psychological disturbances among asthmatics; however, the impact of these psychological factors on HRQL remains unexplored. OBJECTIVES: To assess the health related quality of life among a sample of asthmatics and to identify the psychological and clinical variables that affect quality of life among asthmatics. METHOD: A total of 81 patients attending the clinic were assessed using the Mini-Asthma Quality of Life questionnaire (Mini-AQLQ), and the Hospital Anxiety and Depression Scale (HADS). Sociodemographic and clinical variables were also obtained from the patients, the lung function was assessed using Peak Expiratory Flow Rate (PEFR). RESULTS: Mean age of all the patients was 35.22 (SD+/-14.36) with a mean duration of asthma symptoms of 17.5 (SD+/-14.4) years. Mean peak expiratory flow was 336 l/min (SD+/ 74.12). Anxiety was present in 44.4% of respondents, while 40% of respondents reported the presence of depressive symptoms, 48.1% of the respondents reported low scores on the asthma quality of life questionnaire. Poor quality of life was associated with the presence of psychological symptoms, female sex, and lower educational level. CONCLUSION: Psychosocial variables are just as important as clinical variables as determinants of health related quality of life among asthmatics. PMID- 21694783 TI - Libyan cochlear implant programme: achievements, difficulties, and future goals. AB - Cochlear implantation has become established worldwide as a safe and effective method of auditory rehabilitation of selected severely and profound deaf children and adults. Over 100,000 patients have received cochlear implants worldwide with the paediatric population proving to be the main beneficiaries. The Libyan cochlear implant programme was set up in 2004. Data relating to the patients who received cochlear implantation at Tripoli Medical Centre between October 2007 and February 2010 were analysed. Implant operations were performed on 37 patients. All patients received Med-El SONATA(TI) (100) devices. Thirty-four (91.9%) of these patients were children, whilst three (8.1%) were adults. Combined, congenital hearing loss (56.8%) and perinatal/neonatal (29.7%) were the two main aetiological factors in children. Seventeen patients (45.9%) had a positive family history of deafness. Sixteen patients (43.2%) were born to blood-related parents. The overall rate of minor and major complications was 16.2%, which is comparable to previous studies. PMID- 21694784 TI - Disaster: Challenges and perspectives. PMID- 21694785 TI - Hallucinations: Clinical aspects and management. AB - The literature on hallucinations is reviewed, including its occurrence in different psychiatric disorders, neurological disorders and normal persons. The diagnostic significance of hallucinations is also discussed. Reports of hallucinations in normal people are reviewed. The different modes of the management of hallucinations are briefly discussed. PMID- 21694786 TI - Occupational stress among tunnel workers in Sikkim. AB - BACKGROUND: Job stress has been linked to a wide range of adverse effects on mental, physical and organizational health. OBJECTIVE: The objective of this study was to determine the impact of job stress on mental, physical and social health of the underground construction workers in Sikkim. MATERIALS AND METHODS: The study population comprised of tunnel workers and a comparable group of controls. Using the interview technique, data was collected using the SF-36 General Health Survey Questionnaire. RESULTS: The study population comprised of individuals of whom more than half were below 40 years of age and was comparable to the group of controls. Majority reported good health, while poor health was reported by 22 % of the subjects under study Compared to their health status last year, 52% rated their health as somewhat worse. Majority reported that their physical health problems limited them in activities of daily life, viz., running, lifting heavy objects, participation in strenuous sports, climbing several flights of stairs, bending, stooping or kneeling and walking more than a mile, during the past four weeks. More than half of them had severe body ache in the past four weeks that interfered with both work outside home and housework. This was true for emotional problems also, which interfered with their normal social activities involving family, friends, neighbors or groups. The associations of occupational stress with physical, emotional and social life and with limitation of day-to-day activities among tunnel workers were found to be statistically significant. CONCLUSION: The results emphasize the importance of assessment of the effects of job stress and of fulfilling the need of underground workers for optimum preventive measures. PMID- 21694787 TI - In depth analysis of motivational factors at work in the health industry. AB - BACKGROUND: Motivation of health workers is necessary to generate the organizational commitment towards the patients and the hospital and therefore the knowledge about what motivates and satisfies them is very essential.The aim of the project was to investigate and analyze the various factors that help in motivation of the health workers while performing their clinical duties in the hospital. MATERIALS AND METHODS: A simple random study was conducted among 100 employees of our institute, which included doctors, staff nurses and paramedical staff. One hundred employees from Gian Sagar Institute were chosen randomly for the purpose of our study. All the employees were enquired by the questionnaire method as well as by individual interviews regarding the various motivating and demotivating factors at the work place. Detailed enquiries were performed regarding the various aspects concerning the job factors and work satisfaction. All the answers and findings were observed and recorded. RESULTS: STATISTICAL ANALYSIS USED: Simple non-parametric tests like mean, percentages and chi square tests were employed to analyze the data.The demographic profile of all the employees showed only minor differences which were statistically non-significant. Skills, task identity, task significance, autonomy, feedback, environment, job security and compensation were observed to be the important factors for the motivation of employees. The depth and the extent to which these factors were studied at work in the hospital showed remarkable differences. CONCLUSION: All the factors studied in this project are essential basis for organizational commitment, but feedback represents the factor with the highest motivation potential especially among the younger population. PMID- 21694788 TI - Assessment of hemispheric asymmetry: Development and psychometric evaluation of a chimeric face test. AB - BACKGROUND: Anomaly in hemispheric functioning has been linked with various psychiatric conditions. However, most of the procedures used to assess hemispheric asymmetry in clinical population require special training and/or complex procedures and some of the measures suffer from such methodological problems that undermine their utility for clinical use. Further, the available economical procedures such as chimeric face test (CFT) utilize facial expression of emotions posed by western expressers and are therefore less valid measures in Indian context. AIM: Taking these limitations into account, the present study makes an attempt to develop a CFT (using facial affect photographs of Indian expressers) as an alternative and economical procedure for the assessment of hemispheric asymmetry. MATERIALS AND METHODS: Using the happy and neutral expressions of eight Indian expressers, 32 chimeric faces were developed by combining the half happy and half neutral expressions. These 32 chimeric faces were presented in pairs (arranged in top-bottom fashion) in booklet form to 225 right-handed participants. Using the contemporary item analytic procedure, finally 22 pairs of chimeric faces that showed satisfactory psychometric properties were retained. These 22 pairs of chimeric faces formed the final CFT. The psychometric properties of the various items as well as that of the whole CFT were found satisfactory. RESULTS: All the items were found reliable and valid as indicated by item-total correlation and alpha-if-item deleted. The internal consistency of the CFT was also found to be highly satisfactory (Cronbach's alpha =.80). Further, the participants on the average showed a right hemispheric advantage on the CFT that provide support to its validity. The findings of intermediate analysis of the data of an ongoing project also provide preliminary evidence for the validity of the CFT. CONCLUSION: The CFT is a reliable and valid measure to assess hemispheric asymmetry in the processing of facial emotions and may prove to be an economical and useful tool in clinical setting. PMID- 21694789 TI - Development of emotional stability scale. AB - BACKGROUND: Emotional stability remains the central theme in personality studies. The concept of stable emotional behavior at any level is that which reflects the fruits of normal emotional development. The study aims at development of an emotional stability scale. MATERIALS AND METHODS: Based on available literature the components of emotional stability were identified and 250 items were developed, covering each component. Two-stage elimination of items was carried out, i.e. through judges' opinions and item analysis. RESULTS: Fifty items with highest 't' values covering 5 dimensions of emotional stability viz pessimism vs. optimism, anxiety vs. calm, aggression vs. tolerance., dependence vs. autonomy., apathy vs. empathy were retained in the final scale. Reliability as checked by Cronbach's alpha was .81 and by split half method it was .79. Content validity and construct validity were checked. Norms are given in the form of cumulative percentages. CONCLUSION: Based on the psychometric principles a 50 item, self administered 5 point Lickert type rating scale was developed for measurement of emotional stability. PMID- 21694790 TI - Efficacy of behavioral intervention in reducing anxiety and depression among medical students. AB - BACKGROUND: Now a days, college students frequently have more complex problems than they used to have over a decade ago - greater difficulties in relationships; and more severe problems, such as depression, anxiety and thoughts of suicide. Counseling helps students to understand themselves and the world around them, and to adjust themselves more efficiently and appropriately to other fellow beings. AIM: To determine as to what extent the medical students were able to cope up with their anxiety and depression with the help of counseling. MATERIALS AND METHODS: In the experimental design 'Before-and -after with control design', Beck Anxiety Inventory and Beck Depression Inventory were administered to 120 medical students who were randomly selected from a private medical college, comprising of 30 males and 30 females in each of the two groups, viz., the experimental group and the control group. STATISTICAL ANALYSIS: Means, standard deviations, t test and one-way ANOVA were used to analyze the data. RESULTS: Anxiety and depression among the students were found to be reduced after counseling. Male and female students in the experimental group showed decrease in the levels of anxiety and depression; whereas the control group, which did not get the benefit of counseling, continued to have the same levels of anxiety and depression. CONCLUSION: Counseling is helpful in building self-confidence and the capacity to adjust, by reducing anxiety and depression among medical college students. PMID- 21694791 TI - Psychiatric morbidity among diabetic patients: A hospital-based study. AB - BACKGROUND: The relationship between glucose metabolism and psychiatric illness is under the focus of clinicians for centuries. Depending on the definition used, the prevalence of depression among diabetics ranges from 8.5% to 32.5%, while that for anxiety disorders it is up to 30%. AIMS AND OBJECTIVES: To assess the prevalence of psychiatric morbidity among diabetic patients using standardized rating scales for depression and anxiety. MATERIALS AND METHODS: One hundred diagnosed patients of diabetes were assessed on the Hamilton rating scale for depression and the Hamilton rating scale for anxiety, who were attending the diabetic clinic. They were assessed on sociodemographic profile, duration of illness, type of treatment, and oral vs insulin, and then the data were analyzed on different domains. RESULTS: About 84% of the patients had comorbid depression. Females showed a high percentage of depression and anxiety, and the severity level was also higher in the females. Genital symptoms were usually reported by the males, while somatic symptoms were more prevalent in the females. PMID- 21694792 TI - Differences in levels of disability and quality of life between genders in schizophrenia remission. AB - BACKGROUND: QOL (Quality of life) and Disability have been considered inevitable components of schizophrenia from the Biopsychosocial point of view. Studies from over the world have reported significantly lower levels of QOL and higher levels of disability in schizophrenia; but there are equivocal results revealing differences in levels of disability and QOL between genders in schizophrenia. AIM: To find out the difference in the levels of QOL and disability in both the genders in schizophrenia remission. MATERIALS AND METHODS: This is cross sectional study. Sixty patients who gave consent for their participation in the study and satisfying the criterion of remission of schizophrenia, in the age group of 18-60 years, were selected. A purposive sampling technique was used. There were 34 males and 26 females in the study sample. WHO-QOL-BREF ( World Health Organization, Quality of life BREF) and WHO-DAS (World Health Organization Disability Assessment Schedule) were administered. RESULTS: There was a statistically significant difference in the levels of QOL and disability between the genders. Higher scores of WHO-QOL-BREF were seen in the male group, and higher scores of WHO-DAS were seen in the female group. CONCLUSION: Male group had better QOL, and the female group had higher disability. PMID- 21694793 TI - A case of intermittent explosive disorder. AB - A case of impulse control disorder was observed and managed. In this case, the serving soldier of the Indian army presented with explosive outbursts of extreme violence and anger, which was not clearly directed. Following this act of aggression, he would experience a sense of gratification and relief. The episodes were recurrent and resulted in assaults or destruction of property. The aggression displayed was out of proportion to any perceived provocation and the individual felt increasing tension or arousal before committing the act. He did not have any feelings of regret, remorse or guilt about the behavior. PMID- 21694794 TI - Use of propofol as adjuvant therapy in refractory delirium tremens. AB - Delirium tremens is recognized as a potentially fatal and debilitating complication of alcohol withdrawal. Use of sedatives, particularly benzodiazepines, is the cornerstone of therapy for delirium tremens. But sometimes, very heavy doses of benzodiazepines are required to control delirious symptoms. We are reporting one such case of delirium tremens, which required very heavy doses of benzodiazepines and was ultimately controlled by using infusion of propofol. Thus propofol should always be considered as an option to treat patients with resistant delirium tremens. PMID- 21694795 TI - Statistics without tears: Populations and samples. AB - Research studies are usually carried out on sample of subjects rather than whole populations. The most challenging aspect of fieldwork is drawing a random sample from the target population to which the results of the study would be generalized. In actual practice, the task is so difficult that some sampling bias occurs in almost all studies to a lesser or greater degree. In order to assess the degree of this bias, the informed reader of medical literature should have some understanding of the population from which the sample was drawn. The ultimate decision on whether the results of a particular study can be generalized to a larger population depends on this understanding. The subsequent deliberations dwell on sampling strategies for different types of research and also a brief description of different sampling methods. PMID- 21694796 TI - Periodontitis and psychological stress: A dental view. PMID- 21694797 TI - Cognitive behavioral therapy in social phobia: Indian context. PMID- 21694798 TI - Impact of age and level of experience on occupational stress experienced by non gazetted officers: A comment. PMID- 21694799 TI - Inclusion criteria for pharmacodynamic and clinical trials in chronic idiopathic constipation: pitfalls in using Rome III for functional constipation. PMID- 21694800 TI - Adopting new enrollment criteria for pharmaceutical trials in constipation: look before leaping. PMID- 21694801 TI - Prevalence of colonic adenomas in patients with nonalcoholic fatty liver disease. AB - BACKGROUND: Epidemiologic data suggest that colonic adenomas have an increased tendency to occur in patients who are obese, African American, or have a positive family history of colon cancer, or diabetes mellitus. Recent data suggest that impaired glucose tolerance, dyslipidemia, and metabolic syndrome are associated with a higher risk for colonic adenomas. Patients with nonalcoholic fatty liver disease (NAFLD) often share several of the aforementioned risk factors for colonic adenomas. However, data are lacking about the relationship between NAFLD and colonic adenomas. The aim of this study was to systematically evaluate whether NAFLD is an independent risk factor for colonic adenomas. METHODS: We performed a retrospective cohort observational study on 233 patients who underwent screening colonoscopies at Brooke Army Medical Center from November 2007 to March 2010 to assess for the association between NAFLD and colonic adenomas. Patients who had previously been found to have biopsy-proven simple steatosis (n = 65) or nonalcoholic steatohepatitis (NASH) (n = 29) were compared with a control group without fatty liver disease on sonographic imaging (n = 139). Patients were stratified based on gender, race, body mass index (BMI), and family history and adjusted for variables previously known to be associated with increased adenoma risk. RESULTS: The mean age was 54.7 +/- 6.0 years (48.5% women). Racial demographics were: 62.7% White, 18.5% Hispanic, 13.7%, African American, and 5.2% other. The mean BMI was 29.7 +/- 5.8. The prevalence of colonic adenomas was 25.1% in the control group and 24.4% in the NAFLD group to include simple steatosis and NASH (p = 1.00). Furthermore, when adjusting for known confounders to include race, BMI, and family history no significant differences were found (p = 0.33). However, the ultrasound-negative patients ranked lower in the number of adenomas per person (p = 0.016). CONCLUSIONS: There was no difference in the prevalence of colonic adenomas when comparing the NAFLD group who had undergone colonoscopy with a group of control patients without NAFLD who had undergone colonoscopy. However, patients with negative ultrasounds appeared to have a lower polyp burden. PMID- 21694802 TI - Diagnosis and management of iron deficiency anemia in the 21st century. AB - Iron deficiency is the single most prevalent nutritional deficiency worldwide. It accounts for anemia in 5% of American women and 2% of American men. The goal of this review article is to assist practitioners in understanding the physiology of iron metabolism and to aid in accurately diagnosing iron deficiency anemia. The current first line of therapy for patients with iron deficiency anemia is oral iron supplementation. Oral supplementation is cheap, safe, and effective at correcting iron deficiency anemia; however, it is not tolerated by some patients and in a subset of patients it is insufficient. Patients in whom the gastrointestinal blood loss exceeds the intestinal ability to absorb iron (e.g. intestinal angiodysplasia) may develop iron deficiency anemia refractory to oral iron supplementation. This population of patients proves to be the most challenging to manage. Historically, these patients have required numerous and frequent blood transfusions and suffer end-organ damage resultant from their refractory anemia. Intravenous iron supplementation fell out of favor secondary to the presence of infrequent but serious side effects. Newer and safer intravenous iron preparations are now available and are likely currently underutilized. This article discusses the possible use of intravenous iron supplementation in the management of patients with severe iron deficiency anemia and those who have failed oral iron supplementation. PMID- 21694803 TI - Probiotics in the prevention of antibiotic-associated diarrhoea and Clostridium difficile infection. AB - Diarrhoea, as a common side effect of antibiotics, increases treatment costs and length of stay in acute healthcare facilities. One potential strategy to prevent this side effect is the concurrent use of probiotic bacteria or yeast. This review discusses the evidence for the efficacy of probiotics in the prevention of antibiotic-associated diarrhoea and Clostridium difficile infection; the potential mechanisms by which probiotics may work; their safety; what future research is required; and recommendations for use in clinical practice. PMID- 21694804 TI - Rifaximin treatment for reduction of risk of overt hepatic encephalopathy recurrence. AB - Hepatic encephalopathy (HE) is a common problem in patients with chronic liver disease and is characterized by diminished mentation and neuromuscular abnormalities. Symptoms range from subtle cognitive changes to coma and death. Gut-derived toxins such as ammonia are thought to play a central role in the pathogenesis of HE. Treatment strategies are directed at increased elimination or reduction of gut-derived ammonia in addition to correction of dynamic conditions that provoke bouts of HE. The standard of care for treatment of acute HE is lactulose, a nonabsorbable disaccharide that is thought to increase elimination and reduce absorption of ammonia. Although lactulose seems to work in the acute setting, the rate of recurrent HE on maintenance lactulose is high. Medications have been sought that reduce the rate of recurrent HE in patients at high risk for HE but none have been identified. Rifaximin is a poorly absorbed antibiotic that is thought to reduce ammonia production by eliminating ammonia-producing colonic bacteria. Many small studies have suggested that rifaximin is effective in treating acute HE and is extremely well tolerated. This led to a randomized, placebo-controlled, multicenter, multinational trial investigating the efficacy of rifaximin over a 6-month period in reducing the risk of recurrent HE in patients at baseline, but with a history of at least two bouts of acute HE in the previous 6 months prior to enrollment. Lactulose could be administered at the discretion of the investigator. A total of 299 patients were randomized to receive rifaximin or placebo; 91% of patients in each group received lactulose. Compared with placebo, patients at high risk for recurrent HE in the rifaximin group had highly statistically significant reductions in bouts of acute HE (58%) and reductions in hospitalizations related to HE (50%) over a 6-month period. The medication was well tolerated with a side-effect profile comparable to placebo. This led to the approval of rifaximin for reduction of risk of recurrent HE by the US Food and Drug Administration in March 2010. It is recommended that patients with a history of recurrent acute HE should be maintained on rifaximin with or without lactulose to reduce the risk of recurrent HE and related hospitalization. PMID- 21694805 TI - Neurocysticercosis. AB - Neurocysticercosis (NCC) is the most common cause of acquired epilepsy in developing countries. It can present variably depending on the location and stage of cysts in the nervous system, and the host immune response. The most common presentation of parenchymal NCC is with seizures that are usually focal and brief; status epilepticus occurs in some cases. About a third of cases have headache and vomiting. Diagnosis is made by either CT or MRI. Single, small, contrast enhancing lesions are the most common; visualization of a scolex is diagnostic. Some cases have multiple cysts with a characteristic starry-sky appearance. Although treatment with cysticidal therapy continues to be debated, there is increasing evidence that it helps through increased and faster resolution of CT lesions; whether there is any improvement in long-term seizure control needs further study. It should not be used in cysticercus encephalitis or in ophthalmic NCC and used with caution in extraparenchymal NCC. It is of no use in calcified lesions. Corticosteroids are used simultaneously to reduce cerebral oedema. Seizures respond well to a single antiepileptic, and the seizure recurrence rate is low in cases with single lesions; those with multiple, persistent or calcified lesions usually have recurrent seizures. Extraparenchymal NCC is often associated with intracranial hypertension, hydrocephalous and chronic meningitis; it has a guarded prognosis; surgical intervention is required in many cases. Management of NCC needs to be individualized. NCC is potentially eradicable; proper sanitation, hygiene and animal husbandry are warranted. PMID- 21694806 TI - Symptomatic therapy in multiple sclerosis. AB - Multiple sclerosis is the most common disabling neurological disease of young adults. The ability to impact the quality of life of patients with multiple sclerosis should not only incorporate therapies that are disease modifying, but should also include a course of action for the global multidisciplinary management focused on quality of life and functional capabilities. PMID- 21694807 TI - Treatment of walking impairment in multiple sclerosis with dalfampridine. AB - Potassium channel blockade has long been considered a potential therapeutic strategy for treatment of multiple sclerosis (MS) based on the pathophysiology of demyelinated axons. Dalfampridine, which is also known as fampridine or 4 aminopyridine (4-AP), is the potassium channel blocker that has been studied most extensively in MS and other demyelinating neurologic disorders. An extended release formulation of dalfampridine was recently approved by the US Food and Drug Administration to improve walking in patients with MS. In randomized, double blind, placebo-controlled trials, with dalfampridine extended release tablets 10 mg taken twice daily, about 12 h apart, walking speed was improved in approximately one-third of treated patients; in these patients, average walking speed on therapy was about 25% above baseline. This improvement was clinically meaningful as assessed by concurrent measurement of patient-reported severity of walking-related disability. Dalfampridine extended release tablets were generally well tolerated, with a range of adverse effects that appear to be related to increases in central nervous system excitation. There is a dose-dependent increase in the occurrence of seizures at doses higher than the recommended 10 mg twice daily. PMID- 21694808 TI - Current and future treatment approaches for neuromyelitis optica. AB - Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system (CNS) characterized by severe attacks of optic neuritis and myelitis, and which, unlike multiple sclerosis (MS), commonly spares the brain in the early stages. NMO used to be considered as a special form of MS. During the past 10 years, however, the two diseases have been shown to be clearly different. NMO is a B-cell-mediated disease associated with anti-aquaporin-4 antibodies in many cases and its pathophysiology seems to be near the acute lesion of necrotizing vasculitis. Assessment of prevalence shows that NMO is far less frequent than MS, which explains the absence of randomized clinical trials and NMO treatment strategies validated by evidence-based medicine. Recently, many data have been published that suggest that the therapeutic option in NMO should be immunosuppressive rather than immunomodulatory drugs. In the present study, after a brief overview of NMO, we review therapeutic studies and propose new therapeutic strategies in the relapse and disease-modifying fields. PMID- 21694809 TI - Clinical approach to optic neuritis: pitfalls, red flags and differential diagnosis. AB - Demyelinating optic neuritis (ON) is the most common cause of optic neuropathy typically presenting with a subacute painful visual loss. In 20% of patients with multiple sclerosis (MS), ON is the presenting symptom and half of the patients with isolated ON develop MS within 15 years. The diagnosis of ON plays an important role in neurological practice. A correct and early diagnosis is necessary to ensure optimal further investigations and treatment. Other causes of optic neuropathies such as connective tissue disorders, infectious diseases, tumours or ischaemic neuropathies are less frequent but clinical and therapeutic management can differ dramatically. We present five patients admitted to our hospital with suspected demyelinating ON, but the clinical work up revealed different causes of optic neuropathy. We discuss the differential diagnosis of ON and clinical red flags that require careful diagnostic assessment of other diseases. A workflow for the diagnosis of optic neuropathies is presented. PMID- 21694810 TI - Correlation between serum gastrin and cellular proliferation in Barrett's esophagus. AB - BACKGROUND: Patients with Barrett's esophagus (BE) are commonly treated with proton-pump inhibitors (PPIs) to minimize the exposure of esophageal mucosa to stomach acid. However, the use of these medications can lead to significant hypergastrinemia in a subset of patients, which is concerning due to the known tumorigenic and proliferative effects of gastrin. The present pilot study aims to investigate a potential correlation between serum gastrin and cellular proliferation in BE. METHODS: We performed a cross-sectional analysis of patients with nondysplastic BE on PPI therapy. Fasting serum gastrin was measured on the same day as esophageal biopsies were obtained. These biopsies were then stained with Ki-67 nuclear antibody. Pearson's correlation coefficient was calculated to assess the relationship between Ki-67 index and ln(gastrin). RESULTS: A total of 10 patients were included in the study. The mean age was 62.6 (+/-8.4) years and 5 patients were male. The median serum gastrin level was 45.2 pM (interquartile range [IQR] 33-113) and the median Ki-67 index was 49.6% (IQR 23-64). We found a statistically significant positive correlation between Ki-67 index and ln(gastrin) (r = 0.64; p = 0.05). CONCLUSIONS: In nondysplastic BE patients on PPI therapy, serum gastrin levels were significantly correlated with cellular proliferation. These pilot data lend support to a potential causal effect of gastrin on neoplastic progression in BE. Longitudinal studies of patients with BE are needed to determine whether hypergastrinemia is a risk factor for the development of dysplasia and adenocarcinoma or could be used as a biomarker for disease progression. PMID- 21694811 TI - The association of bile acid excretion and atherosclerotic coronary artery disease. AB - BACKGROUND: Excess cholesterol is usually eliminated from the body by conversion to bile acids excreted in feces as bile salts. The excretion of large amounts of bile protects against atherosclerosis, while diminished excretion may lead to coronary artery disease (CAD). OBJECTIVE: To investigate a relationship between CAD and bile acid excretion. METHODS: Bile acid excretion was compared between 36 patients with proven CAD and 37 CAD-free individuals (controls). The groups were comparable for demographics and selected risk factors. All subjects received a 4 day standard diet that included ~500 mg of cholesterol. Fecal bile acids from 24 hour stool collections were measured by gas liquid chromatography. RESULTS: CAD patients excreted lower amounts of total bile acids (358 +/- 156 mg) than controls (617 +/- 293 mg; p < 0.01) and less deoxycholic acid (188.29 +/- 98.12 mg versus 325.96 +/- 198.57 mg; p < 0.0001) and less lithocholic acid (115.43 +/- 71.89 mg versus 197.27 +/- 126.87 mg; p < 0.01). Advanced age, male gender, left ventricular ejection fraction and total bile acid levels were significant independent factors that predicted CAD (p < 0.05). Mortality, CAD and cerebrovascular accident development rates were significantly lower for the controls at the 13-year follow up. CONCLUSION: CAD patients have significantly decreased bile acid excretion levels than non-CAD patients. An impaired ability to excrete cholesterol may be an additional risk factor for CAD development. PMID- 21694812 TI - Should quinolones come first in Helicobacter pylori therapy? AB - New generations of fluoroquinolones, like levofloxacin and moxifloxacin, exhibit a broad-spectrum activity against Gram-positive and Gram-negative bacteria, and have been successfully introduced into the treatment of Helicobacter pylori infection. Based on a large body of evidence, current guidelines recommend the use of levofloxacin- or moxifloxacin-containing proton-pump inhibitor (PPI) triple therapies in second-line or rescue treatment of H. pylori infection. The efficacy of standard PPI triple therapies has substantially declined during the last decade, mainly due to increasing resistance against the key antibiotics clarithromycin and metronidazole. Therefore, alternative strategies for first line therapy of H. pylori infection have been evaluated in a considerable number of clinical trials including sequential regimens, nonbismuth quadruple regimens, and quinolone-containing PPI triple therapy regimens. The aim of this paper is to summarize the current body of evidence of levofloxacin- and moxifloxacin containing regimens in first-line treatment of H. pylori infection, and to discuss the risks and benefits of these strategies in the light of increasing resistance of H. pylori to quinolones. PMID- 21694814 TI - Looking beyond symptom relief: evolution of mucosal healing in inflammatory bowel disease. AB - The focus of effective management of inflammatory bowel disease, especially Crohn's disease, has shifted from short-term symptom control to long-term modification of disease course and complications. Intestinal healing has achieved prominence as a goal of therapy that influences long-term disease course. We review the natural history of inflammatory bowel disease, the markers of disease control that may reflect outcomes and the specific role of mucosal healing. We may aim at better mucosal healing by appropriate choice of therapy, appropriate combinations of therapy and intervening early in the disease course. PMID- 21694813 TI - Treatment of irritable bowel syndrome: beyond fiber and antispasmodic agents. AB - Irritable bowel syndrome (IBS) is a chronic functional disorder of the gastrointestinal tract of unknown etiology. The diagnosis of IBS is made clinically, using symptom-based criteria such as the Manning or Rome criteria. Medical therapy for this condition has traditionally been directed towards symptom relief, using fiber or antispasmodic agents. In recent years, emerging data have confirmed the efficacy of antidepressants, psychological therapies, 5 HT(3) antagonists, 5-HT(4) agonists, and probiotics in the short-term treatment of IBS, although whether these therapies influence the long-term course of the disease is unknown. Increasing knowledge regarding the pathophysiological mechanisms underlying IBS has resulted in a number of novel molecular treatments, which show promise. These include therapies targeting gastrointestinal mucosal chloride channels and guanylate cyclase-C receptors, as well as highly selective agents influencing serotonergic transmission that, at the time of writing, do not appear to have any severe deleterious effects. In this article we provide a summary of current and emerging therapies in this field. PMID- 21694815 TI - Exploring the role of monitoring anti-TNFalpha drug and antibody levels in the management of inflammatory bowel disease. AB - Crohn's disease and ulcerative colitis are chronic inflammatory gastrointestinal disorders which often result in significant morbidity or surgery. Current treatment options are not curative and may cause significant adverse effects. The introduction of anti-tumour necrosis factor alpha (anti-TNFalpha) therapy over a decade ago was a welcome addition to the therapeutic armamentarium and revolutionized the treatment of inflammatory bowel disease (IBD). Despite their relative success, a significant proportion of patients with IBD fail to respond or subsequently lose response anti-TNFalpha therapy. This review identifies and explores the role of drug levels and immunogenicity (antibody formation) on the efficacy of anti-TNFalpha therapy and details how monitoring these parameters may help to optimize the management of patients with IBD. PMID- 21694817 TI - Nonconvulsive status epilepticus: a diagnostic and therapeutic challenge in the intensive care setting. AB - Nonconvulsive status epilepticus (NCSE) comprises a group of syndromes that display a great diversity regarding response to anticonvulsants ranging from virtually self-limiting variants to entirely refractory forms. Therefore, treatment on intensive care units (ICUs) is required only for a selection of cases. The aetiology and clinical form of NCSE are strong predictors for the overall prognosis. Absence status epilepticus is commonly seen in patients with idiopathic generalized epilepsy and is rapidly terminated by low-dose of benzodiazepines. The management of complex partial status epilepticus is straightforward in patients with pre-existing epilepsy, but poses major problems if occurring in the context of acute brain lesions. Subtle status epilepticus represents the late stage of undertreated previous overt generalized convulsive status epilepticus and always requires aggressive ICU treatment. Within the intensive care setting, the diagnostic challenge may be seen in the difficulty in delineating nonepileptic conditions such as posthypoxic, metabolic or septic encephalopathies from NCSE. Although all important forms are considered, the focus of this review lies on clinical presentations and electroencephalogram features of comatose patients treated on ICUs and possible diagnostic pitfalls. PMID- 21694818 TI - Management of vestibular migraine. AB - Vestibular migraine is considered to be the second most common cause of vertigo and the most common cause of spontaneous episodic vertigo. The duration of attacks varies from seconds to days, usually lasting minutes to hours, and they mostly occur independently of headaches. Long-lasting individual attacks are treated with generic antivertiginous and antiemetic drugs. Specific antimigraine drugs are unlikely to be very effective for rescue. The mainstay of the management of vestibular migraine is prophylactic medication. To date, there are no controlled trials available; the body of knowledge builds on case series and retrospective or observational studies. Most drugs are also used for the prevention of migraine headaches. The choice of medication should be guided by its side effect profile and the comorbidities of patients. Betablockers such as propanolol or metoprolol are preferred in patients with hypertension but in the absence of asthma. Anticonvulsants include topiramate when patients are obese, valproic acid and lamotrigine. Lamotrigine is preferred if vertigo is more frequent than headaches. Calcium antagonists include verapamil and flunarizine. If patients have anxiety, tricyclic antidepressants such as amitryptiline or nortryptiline or SSRIs and benzodiazepines such as clonazepam are recommended. Acetazolamide is effective in rare genetic disorders related to migraine-like episodic ataxia; however, its place in vestibular migraine is still to be established. Nonpharmacological measures such as diet, sleep, hygiene and avoidance of triggers are recommended as they are for migraine. Vestibular rehabilitation might be useful when there are complications such as loss of confidence in balance or visual dependence. PMID- 21694819 TI - Standard and escalating treatment of chronic inflammatory demyelinating polyradiculoneuropathy. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, immune mediated polyradiculoneuritis that is progressive or relapsing over a period of at least 8 weeks. Although the exact pathogenesis is unclear, it is thought to be mediated by both cellular and humoral immune reactions directed against the peripheral nerve myelin or axon. CIDP also involves spinal nerve roots. Early medical treatment of CIDP is important to prevent axonal loss. Only three treatment regimens for CIDP have demonstrated benefit in randomized, controlled studies: corticosteroids, plasma exchange, and intravenous immunoglobulins (IVIg). Approximately 25% of patients respond inadequately to corticosteroids, plasma exchange or IVIg. Large placebo-controlled trials with alternative immunosuppressive compounds, e.g. mycophenolate mofetil, cyclosporine, cyclophosphamide, or monoclonal antibodies, are lacking. PMID- 21694820 TI - Accuracy of identification of tissue types in endoscopic esophageal mucosal biopsies used for molecular biology studies. AB - OBJECTIVES: To determine if histopathologic assessment of esophageal biopsies harvested for research study is justified due to the heterogeneity of tissues in the esophagus, and the consequent histopathologic mis-matches with the clinical histopathology of biopsies taken at the same level. METHODS: Since 2004, patients undergoing upper endoscopy for a variety of clinical conditions were invited to provide additional esophageal biopsies; those were collected for research purpose at the same level as biopsies collected for clinical histopathology. Research biopsies were cut in two parts: one part was submitted to research histopathology and the other stored for molecular analysis. Results of clinical histopathology for each patient were summarized per biopsy level and compared to results obtained from research biopsies at the corresponding level. RESULTS: A total of 377 level summaries were obtained from 137 patients. Clinical histopathology summaries classified 123 levels (32.6%) as squamous epithelium, 84 levels (22.3%) as metaplastic columnar-lined epithelium, 135 levels (35.8%) as columnar-lined epithelium with intestinal metaplasia, 30 levels (8%) as dysplasia, and 5 levels (1.3%) as adenocarcinoma. Research histopathology matched to clinical summaries on 120 of 123 (97.5%) levels for squamous epithelium, 52 of 84 (61.9%) for metaplastic columnar-lined epithelium, and 94 of 135 (69.5%) for columnar-lined epithelium with intestinal metaplasia. There were no matches for dysplasia between the groups; however, they agreed on all five cases of AC. On 59 (70.2%) metaplastic columnar-lined epithelium levels and on 62 (46%) columnar-lined epithelium with intestinal metaplasia levels, tissue heterogeneity was observed in clinical histopathology, with portions of squamous epithelium within the samples. Matches with pure tissue samples in both clinical and research histopathology levels were observed on 22 (26.2%) levels of metaplastic columnar lined epithelium and in 55 (40.7%) levels of columnar-lined epithelium with intestinal metaplasia. CONCLUSIONS: The high proportion of mismatches and tissue heterogeneity observed, especially among columnar-lined epithelium with intestinal metaplasia and dysplasia, points to the necessity of determining the histopathology of the research samples to avoid sampling errors during molecular studies. PMID- 21694816 TI - Symptomatic therapy in multiple sclerosis: a review for a multimodal approach in clinical practice. AB - As more investigations into factors affecting the quality of life of patients with multiple sclerosis (MS) are undertaken, it is becoming increasingly apparent that certain comorbidities and associated symptoms commonly found in these patients differ in incidence, pathophysiology and other factors compared with the general population. Many of these MS-related symptoms are frequently ignored in assessments of disease status and are often not considered to be associated with the disease. Research into how such comorbidities and symptoms can be diagnosed and treated within the MS population is lacking. This information gap adds further complexity to disease management and represents an unmet need in MS, particularly as early recognition and treatment of these conditions can improve patient outcomes. In this manuscript, we sought to review the literature on the comorbidities and symptoms of MS and to summarize the evidence for treatments that have been or may be used to alleviate them. PMID- 21694821 TI - Selected luminal mucosal complications of adult celiac disease. AB - Celiac disease is a gluten-dependent intestinal disorder that appears to be associated with several clinical conditions. Some involve the luminal mucosa of the stomach and intestinal tract and may, occasionally, complicate the course of celiac disease. Collagenous colitis has been associated with celiac disease and may lead to chronic diarrhea. Conversely, some of these clinical disorders that involve the luminal mucosa of the stomach and intestine may represent the initial clinical presentation of celiac disease. These disorders should be considered in patients with celiac disease who develop recurrent or refractory symptoms despite adherence to a strict gluten-free diet. Detection of collagenous disorders that affect the luminal mucosa of the stomach or intestinal tract may result in recognition of underlying celiac disease. PMID- 21694822 TI - Developments in treating metastatic colorectal cancer: Recent international reports from ASCO 2007 and 2008. AB - INTRODUCTION: Treatment for metastatic colorectal cancer (mCRC), employing various schedules, combinations, and regimens utilizing 5-fluorouracil (5-FU), irinotecan, oxaliplatin, capecitabine, bevacizumab, and cetuximab, currently achieves an overall survival that extends to approximately two years. Major questions regarding optimal management of mCRC await resolution. METHODS: A thorough review was conducted of all mCRC abstracts, posters, and other presentations at the 2007 meeting of the American Society of Clinical Oncology (ASCO). Information was analyzed in relationship to previously published research to determine the potential impact of new data on current and future mCRC management strategies and patient outcomes. Updated data presented at ASCO 2008 relevant to these findings was also analyzed. DISCUSSION: Ongoing challenges in mCRC treatment include defining the optimal role of targeted agents such as cetuximab and bevacizumab, elaborating the mechanisms underlying their toxicities, resolving the benefits of adjuvant and neoadjuvant chemotherapy in patients who are candidates for surgical resection, establishing whether there are substantive differences between sequential and combination chemotherapy regimens, and determining the safety and tolerability of chemotherapy in elderly subjects. CONCLUSION: Recent reports presented at ASCO 2007 and 2008 indicate incremental improvements in care of patients with mCRC. Nevertheless, irinotecan, oxaliplatin, 5-FU, and to an increasing extent the targeted biologic agents bevacizumab and cetuximab continue unchallenged as first-line and later selections. PMID- 21694823 TI - Mortality associated with gastrointestinal bleeding events: Comparing short-term clinical outcomes of patients hospitalized for upper GI bleeding and acute myocardial infarction in a US managed care setting. AB - OBJECTIVES: To compare the short-term mortality rates of gastrointestinal (GI) bleeding to those of acute myocardial infarction (AMI) by estimating the 30-, 60 , and 90-day mortality among hospitalized patients. METHODS: United States national health plan claims data (1999-2003) were used to identify patients hospitalized with a GI bleeding event. Patients were propensity-matched to AMI patients with no evidence of GI bleed from the same US health plan. RESULTS: 12,437 upper GI-bleed patients and 22,847 AMI patients were identified. Propensity score matching yielded 6,923 matched pairs. Matched cohorts were found to have a similar Charlson Comorbidity Index score and to be similar on nearly all utilization and cost measures (excepting emergency room costs). A comparison of outcomes among the matched cohorts found that AMI patients had higher rates of 30-day mortality (4.35% vs 2.54%; p < 0.0001) and rehospitalization (2.56% vs 1.79%; p = 0.002), while GI bleed patients were more likely to have a repeat procedure (72.38% vs 44.95%; p < 0.001) following their initial hospitalization. The majority of the difference in overall 30-day mortality between GI bleed and AMI patients was accounted for by mortality during the initial hospitalization (1.91% vs 3.58%). CONCLUSIONS: GI bleeding events result in significant mortality similar to that of an AMI after adjusting for the initial hospitalization. PMID- 21694824 TI - Obesity and gastroesophageal reflux disease and gastroesophageal reflux symptoms in children. AB - BACKGROUND: The association between body mass index (BMI) and gastroesophageal reflux disease (GERD) has been extensively studied among adults but few studies have examined such association in children. AIMS: 1) to determine the relationship between BMI in children and GERD, and 2) to use the National Center for Health Statistics (NCHS) values for BMI as a valid source for comparison. METHODS: We identified two cohorts of children aged between two and 17 years who were seen at Texas Children's Hospital (TCH). The first cohort consisted of children diagnosed with GERD based on upper gastrointestinal endoscopic and histologic evaluation, which was recorded in the Pediatric Endoscopic Database System-Clinical Outcomes Research Initiative (PEDS-CORI) at TCH. A diagnosis of GERD was based on the presence of erosive esophagitis or esophageal ulcers. Endoscopic reports that were incomplete or did not include demographic features, indications for endoscopy, or endoscopic findings were excluded. The second cohort consisted of all children with symptoms due to gastroesophageal reflux (GER) who received outpatient gastrointestinal (GI) consultation at TCH for any 9th revision of the International Statistical Classification of Diseases (ICD-9) code suggestive of GER. There was no overlap between the two cohorts as each child was indexed only once. Children with any comorbid illnesses were excluded. MEASUREMENTS: The records for each child namely, age, gender, height, and weight were obtained on the same date as that of the diagnosis. Using the growth curves published by the NCHS, the gender/age specific weight-for-age Z-score (WAZ), and height-for-age Z-score (HAZ) were calculated. BMI was calculated as the weight in kilograms divided by height in meters squared. Children having values greater than the 95th percentile for their age/gender-specific BMI were defined as obese. RESULTS: In a one-year period (January 2006 to December 2006), a total of 627 children who attended the GI clinic at TCH were identified with GERD symptoms of whom 131 underwent endoscopic examination. The mean age was 9.7 years; 42% were females; 57% were Caucasians; 15% were African Americans, and 28% were Hispanics. Using National Health and Nutrition Examination Survey (NHANES) data obtained from the same period as the the current data as a baseline for comparison, the BMI of children diagnosed with GERD was higher than the BMI reported by NHANES data. The final analysis of test proportion showed an overall proportion of 0.207 for the current study versus NHANES data (0.174). The current study also showed that more boys than girls have BMI greater than 95th percentile (24.7% vs 16.5%, respectively, OR = 1.7, 95% CI = 1.2-2.6, p = 0.04). CONCLUSIONS: Children diagnosed with GERD or those who presented with symptoms of GERD are more likely to be obese. The findings of this study show a possible association between obesity and GERD in children. Further understanding about the co-morbidity between GERD and obesity in children may have important implications on GERD management and treatment in children. PMID- 21694825 TI - Bleeding Meckel's diverticulum in a 4-month-old infant: Treatment with laparoscopic diverticulectomy. A case report and review of the literature. AB - A bleeding Meckel's diverticulum is presented in a 4-month-old African American infant. This event is rare at this age, and our patient is only the second 4 month-old infant reported in the English literature. The infant presented with painless frank rectal bleeding, the blood being maroon-colored, and clots were found in the diaper. There was also anemia, with an hemoglobin of less than 8 gm/dl. The color of the blood suggested a bleeding site in the ileo-cecal region, a Meckel's diverticulum was suspected, which was then confirmed by an isotope scan. A typical Meckel's diverticulum was found on laparoscopic surgery, was excised, and the infant made an uneventful recovery. PMID- 21694826 TI - Response to chemoradiatiotherapy in squamous cell carcinoma of the esophagus: evaluation of some prognostic factors. AB - OBJECTIVE: To evaluate the predictive values of the expression of factor VIII, CD 34, p53, bcl-2, and DNA ploidy regarding the response to chemoradiation of squamous cell carcinoma of the esophagus. DESIGN: Retrospective analysis of pretreatment biopsies with immunohistochemistry and flow cytometry. The results were correlated to tumor response (complete vs. noncomplete) following chemoradiation with three cycles of 5-FU and cisplatin combined with 40-64 Gy of radiation. SUBJECTS: 44 consecutive patients with squamous cell carcinoma of the esophagus treated with chemoradiation with a curative intent from 1992-2000. MAIN OUTCOME MEASURES: Treatment response. RESULTS: No correlations were found between the expressions of p53, bcl-2, or DNA ploidy and tumor response to chemoradiation. A positive correlation was found between factor VIII expression and a complete tumor response (p = 0.0357). However the other marker for angiogenesis, CD-34, showed a negative correlation (p = 0.0493). Both markers indicate blood vessel density meaning that, in this study, many vessels indicated a favorable response if measured with factor VIII, but a poor response if measured with CD-34. CONCLUSION: It is not possible to predict tumor response to our chemoradiation protocol through the analysis of pretreatment expression of p53, bcl-2 or DNA ploidy in biopsy specimens. In spite of significant correlations between complete tumor responses and the expressions of the markers for angiogenesis this significance may be questionable since one of the two markers, factor VIII had a positive and the other,CD-34, a negative correlation to tumor response. PMID- 21694827 TI - Recent advances in the management of carcinoma of the rectum. AB - In the last two decades rectal cancer has changed from a surgically managed disease into a multidisciplinary treatment model resulting in considerable improvements in the survival and outcome. This has been made possible by better understanding of the tumor biology and oncogenesis, advances in diagnostic and staging investigations, and the changing concepts in surgical excision; from the days of abdominoperineal resection to the concept of "zone of upward spread" and low anterior resection to the era of total mesorectal excision and transanal excision. Efforts are on the way to risk stratification and identification of predictors of nonoperative management. Impressive advances in the adjuvant therapies have seen a sea change in the form of postoperative radiotherapy to preoperative radiotherapy to preoperative chemoradiotherapy and postoperative adjuvant chemotherapy. This multidisciplinary approach is the key to impressive local control rates, decreased metastatic rates, overall survival, and enhancement in quality of life. Newer ideas in the understanding of genetic differences in rectal cancers have stemmed from the observation that these cancers differ in their response to the adjuvant treatment. The present day research has focused these areas of biologic differences in cancers and aims to target the specific loci in malignant cells with monoclonal antibodies directed against various growth factors, key enzyme inhibition, and genetic manipulation. The future research lies in the study of gene expression, micro-array techniques, molecular markers, and better understanding of the predictors of tumor response to therapy. PMID- 21694829 TI - Do we at all need surgery to treat thrombosed external hemorrhoids? Results of a prospective cohort study. AB - BACKGROUND: It is unknown whether surgery is the gold standard for therapy of thrombosed external hemorrhoids (TEH). METHODS: A prospective cohort study of 72 adults with TEH was conducted: no surgery, no sitz baths but gentle dry cleaning with smooth toilet paper after defecation. Follow-up information was collected six months after admission by questionnaire. RESULTS: Despite our strict conservative management policy 62.5% (45/72) of patients (95% confidence interval [CI]: 51.0-74.0) described themselves as "healed" or "ameliorated", and 61.1% (44/72, 95% CI: 49.6-72.6) found our management policy as "valuable to test" or "impracticable". 13.9% (10/72, 95% CI: 5.7-22.1) of patients suspected to have recurrences. 4.2% did not know. Twenty-two of the 48 responding patients reported symptoms such as itching (18.8%), soiling (12.5%), pricking (10.4%), or a sore bottom (8.3%) once a month (59.1%, 13/22), once a week (27.3%, 6/22), or every day (13.6%, 3/22). CONCLUSIONS: The dictum that surgery is the gold standard for therapy for TEH should be checked by randomized controlled trials. PMID- 21694828 TI - New biologics in the management of Crohn's disease: focus on certolizumab pegol. AB - Crohn's disease (CD) is a chronic inflammatory condition involving the gastrointestinal tract characterized by recurrent exacerbations and remission. The disease frequently occurs in the lower part of the small bowel, but can affect any part of the digestive tract, from the mouth to the anus. The traditional goals of treatment of Crohn's disease were to induce and maintain clinical remission. More recently targets such as mucosal healing, reduced hospitalization and surgery, and improved quality of life are becoming increasingly achievable. The general principles for treatment should consider clinical activity, site and behavior of disease; however, the appropriate choice of medication depends on many factors that are the best tailored to the individual patient. This review focuses on certolizumab pegol, the first Fc-free PEGylated Fab' fragment of humanized monoclonal antibody that binds and neutralizes human tumor necrosis factor alpha. Data on indication, pharmacokinetics, efficacy, safety, and influence on quality of life are reviewed. PMID- 21694830 TI - Outcome for esophageal cancer following treatment with chemotherapy and radiotherapy but not esophagectomy: Nonsurgical treatment of esophageal cancer. AB - BACKGROUND: More than 50% of patients with esophageal cancer are not suitable for surgery. The aim of this study was to analyze the outcome of patients undergoing standard nonsurgical treatment. METHODS: Data of all patients undergoing nonsurgical treatment for esophageal cancer were identified from a prospective database. RESULTS: Seventy-five patients were treated for localized disease, and 52 for metastatic disease at diagnosis. Except for age, which was higher in patients without metastases, there were no significant differences between the patients with vs. without metastatic disease. Kaplan-Meier analysis showed a median survival of 10.8 months for all patients. There was a significant difference in survival (p < 0.001) between the groups with versus without metastases, with median survival in the patients without metastases 13.6 months versus 6.5 months in patients with metastases. Patients undergoing nonsurgical treatment for localized disease had a five-year survival of 12%. No significant difference between adenocarcinoma and squamous cell carcinoma was identified. Subanalysis of patients who received chemoradiotherapy revealed similar results to the overall group of patients. CONCLUSION: In patients with localized disease at diagnosis, long-term survival can be achieved in some patients, whereas five year survival is rare in patients who present with metastatic disease. PMID- 21694831 TI - Low serum myeloperoxidase in autistic children with gastrointestinal disease. AB - AIM: To assess serum myeloperoxidase (MPO) levels in autistic children with severe gastrointestinal (GI) disease and to test the hypothesis that there is an association between serum MPO concentration and inflammatory GI disease, including antineutrophil cytoplasmic antibodies (ANCA), previously seen in a subgroup of autistic children. SUBJECTS AND METHODS: Serum from 40 autistic children with chronic digestive disease (most with ileo-colonic lymphoid nodular hyperplasia (LNH) and inflammation of the colorectum, small bowel and/or stomach), and 48 controls (12 age-matched autistic children with no GI disease, 20 age-matched children without autism or GI disease, and 16 nonautistic individuals with no family history of autism) were tested using enzyme-linked immunosorbent assays designed to quantitate serum MPO levels. MPO serum concentration of autistic children with GI disease was compared to GI disease severity (including LNH and erythema) and presence of ANCA. RESULTS: We found that a significant number of autistic children with chronic digestive disease had low serum levels of MPO. However, there was no significant relationship between these levels and severity of GI disease, including the presence of ANCA. DISCUSSION: These results suggest a relationship between low MPO levels and GI disease seen in a subpopulation of autism spectrum disorders individuals. MPO concentration may therefore be a useful biomarker for GI disease in this group of autistic children. PMID- 21694832 TI - Efficacy and tolerability of Laxatan Granulat in patients with chronic constipation. AB - BACKGROUND: On average 12% of the population worldwide suffer from acute or chronic constipation. Pathological intestine alterations, an unhealthy diet with reduced liquid intake, and little exercise are potential reasons. Often the motility of the intestine is disturbed. Changing nutrition habits or lifestyle is not always successful. In such cases, laxatives containing macrogol and inulin are highly effective. METHODOLOGY: The efficacy and tolerability of Laxatan((r)) Granulat, a laxative containing macrogol, inulin, and mineral salts, was assessed in a drug-monitoring study of 105 patients for four weeks. RESULTS: At the end of this study, a highly significant reduction of the constipation symptoms in 98.1% of the patients was observed. No adverse events were reported during this drug monitoring study. The overall efficacy was rated as being "very good" or "good" for 96% and the overall tolerability was rated as being "very good" or "good" for 99% of patients. CONCLUSION: The combination of macrogol, inulin, and mineral salts is highly effective in the treatment of chronic constipation. Due to its prebiotic activity, inulin probably leads to proliferation of lactic acid producing bacteria. The lowered pH and increased water content probably increases the peristaltic action and therefore reduces constipation. PMID- 21694833 TI - The impact of biologics on health-related quality of life in patients with inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) is characterized by a chronic relapsing inflammation of the gastrointestinal tract. Adult IBD patients suffer from a disabling disease which greatly affects health-related quality of life (HRQoL). A worse HRQoL in these patients may result in a defensive and ineffective use of medical attention and thus higher medical costs. Because of its chronic nature, IBD may also cause psychological problems in many patients which may also influence HRQoL and care-seeking behavior. An important factor reducing HRQoL is disease activity. Induction of remission and long-term remission are important goals for improving HRQoL. Furthermore, remission is associated with a decreased need for hospitalization and surgery and increased employment, which in turn improve HRQoL. Treatment strategies available for many years are corticosteroids, 5-aminosalicylates and immunnosuppressants, but these treatments did not show significant long-term improvement on HRQoL. The biologics, which induce rapid and sustained remission, may improve HRQoL. OBJECTIVE: To review and evaluate the current literature on the effect of biologics on HRQoL of IBD patients. METHODS: We performed a MEDLINE search and reviewed the effect of different biologics on HRQoL. The following subjects and synonyms of these terms were used: inflammatory bowel disease, Crohn's disease, ulcerative colitis, quality of life, health-related quality of life, fatigue, different anti-TNF medication, and biologicals/biologics (MESH). Studies included were limited to English-language, adult population, full-text, randomized, double blind, placebo-controlled in which HRQoL was measured. RESULTS: Out of 202 identified articles, 8 randomized controlled trials (RCT) met the inclusion criteria. Two RCTs on infliximab showed significant improvement of HRQoL compared to placebo which was sustained over the long term. One RCT on adalimumab showed a significant and sustained improvement of HRQoL compared to placebo. This study showed also significant decrease of fatigue in the adalimumab-treated patients. Three RCTs on certolizumab showed a significant improvement of HRQoL in the intervention group compared to placebo. Two RCTs of natalizumab treatment were found. One study showed significant and sustained improvement compared to placebo, and also scores of HRQoL comparable to that in the general population, but in the other no significant results were found. CONCLUSION: The biologics infliximab, adalimumab, certolizumab, and natalizumab demonstrated significant improvement of HRQoL of IBD patients compared with placebo. However, we found differences in improvement of HRQoL between the different biologics. PMID- 21694834 TI - Capsule endoscopy in clinical practice: concise up-to-date overview. AB - Until recently, the small bowel was considered a 'no man's land' as the imaging modalities available for its investigation were laborious, invasive, costly, or involve significant radiation exposure. Wireless capsule endoscopy (WCE) has changed the field dramatically, over the last eight years. The established indications for small bowel WCE are obscure gastrointestinal bleed/anemia, Crohn's disease, hereditary polyposis syndromes, and to a lesser extent, evaluation of side effects of nonsteroidal anti-inflammatory medications and coeliac disease. We herein present an overview of the capsule examination, which seems to be a quickly improving area. PMID- 21694835 TI - Delayed release dexlansoprazole in the treatment of GERD and erosive esophagitis. AB - Although proton pump inhibitors (PPI) have a record of remarkable effectiveness and safety in the management of gastroesophageal reflux disease (GERD), several treatment challenges with PPI have emerged. Dexlansoprazole MR is the (R) enantiomer of lansoprazole contained in a formulation that produces two distinct releases of drug and significantly extends the duration of active plasma concentrations and % time pH > 4 beyond that of conventional single-release PPI. Dexlansoprazole MR can be administered without regard to meals or the timing of meals in most patients. Dexlansoprazole MR 60 mg demonstrated similar efficacy for healing of erosive esophagitis at 8 weeks compared with lansoprazole 30 mg, and dexlansoprazole MR 30 mg was superior to placebo for maintenance of healed erosive esophagitis at 6 months with 99% of nights and 96% of days heartburn-free over 6 months in patients taking dexlansoprazole MR 30 mg. Superior relief of heartburn occurred in patients taking dexlansoprazole MR 30 mg (55% heartburn free 24-hour periods) vs placebo (14%) for symptomatic nonerosive GERD. The safety profile of dexlansoprazole MR is similar to that of lansoprazole. The extended pharmacodynamic effects, added convenience, and efficacy and safety of dexlansoprazole MR offer a novel approach to gastric pH control in patients with acid-related disorders. PMID- 21694836 TI - Ileal tuberculosis presenting as a case of massive rectal bleeding. AB - Massive rectal bleeding is an uncommon presentation of ileal tuberculosis. Fewer than 12 cases are reported in the literature. We report a case of ileal tuberculosis presenting at the emergency department with subacute intestinal obstruction and severe rectal bleeding. The case of the massive bleeding could be identified only after an exploratory laparotomy. PMID- 21694837 TI - Patients' views of medical positioning for proctologic examination. AB - BACKGROUND: It is unknown which proctological position is most embarrassing to patients. METHODS: Individuals consecutively referred to our outpatient clinic in order to determine the causes of anal and/or abdominal complaints were randomized to complete an unvalidated six-item questionnaire which asked for their preferred proctologic positioning either before or after a proctological examination in knee-chest position followed by inspection of the anal verge, digital examination of the anal canal, and anoscopy. A third group of patients referred for gastroscopy was asked to complete the questionnaire before being gastroscoped. RESULTS: One hundred seventy-eight individuals of both genders aged 16-80 years who consecutively entered our outpatient clinic were enrolled. One third in each group had never experienced any of the offered medical positionings. Most patients favored the Sims' position if they had the choice. Randomized patients favored the knee-chest position more after experiencing it compared to those without experience (P < 0.03). Patients favored the positions they had recently experienced irrespective of the other positions offered in the questionnaire (P < 0.05). Individual answers to the question 'which position do you find most embarrassing?' did not depend on sex or age at first examination or when their last examination was performed. The majority of patients (55.2%-71.4%) held that no type of proctological positioning was most embarrassing to them. CONCLUSIONS: The medical profession is authorized to use the proctological positioning that allows the most reliable anal diagnoses. PMID- 21694838 TI - Update on the role of modified release mesalamine in the management of ulcerative colitis and Crohn's disease. AB - 5-aminosalicyclates (5-ASA) remain a key first-line therapy for patients with ulcerative colitis (UC). A range of 5-ASA preparations is available and Eudragit S((r)) coated modified release formulations of mesalamine, such as Asacol((r)), remain among the most popular choices. We here review the current understanding of the mechanism of action of 5-ASA in inflammatory bowel disease. We evaluate evidence supporting the efficacy and safety of modified release mesalamine for both induction and remission maintenance in UC, including a review of the data from the recent ASCEND studies. We also examine the controversial issue of the role of mesalamine in treatment of Crohn's disease (CD) and highlight data supporting its use following surgically induced remission of CD. Evidence supporting the use of mesalamine as prophylaxis for colorectal cancer and dysplasia will be considered. Finally, recent developments in our understanding of how to use modified release mesalamine in a safe and cost-effective manner are evaluated, including discussion of the importance of studying patient non adherence as a key component of future studies in this area. PMID- 21694839 TI - Cause for controversy? Infliximab in the treatment of ulcerative colitis: an update. AB - Infliximab is a monoclonal antibody against tumor necrosis factor (TNF) which has become an established therapy for Crohn's disease over the last 10 years. Given the similarities between Crohn's disease and ulcerative colitis (UC), it is no surprise that gastroenterologists have used infliximab in patients with UC who have failed other therapies. Although the initial controlled trials with infliximab in steroid-refractory disease were unimpressive, subsequent controlled trials have demonstrated the efficacy of infliximab in both moderate to severe disease, and as rescue-therapy to avoid colectomy. The long-term remission rates, colectomy-sparing effects, and the impact of concomitant immunomodulator therapy, remain to be determined in these patients. Whether infliximab is a superior strategy to cyclosporine in patients with steroid-refractory disease is controversial. This review examines the data on the efficacy and safety of infliximab as an induction and maintenance agent for UC. PMID- 21694840 TI - Stem cell therapeutics: potential in the treatment of inflammatory bowel disease. AB - Stem cell therapies may be valuable in treatment of inflammatory bowel disease (IBD). Here we focus on two very different types of stem cells - hematopoietic stem cells and mesenchymal stem cells. Myeloablation and hematopoietic stem cell transplantation alter host immune response by reconstituting the recipient's blood cell lines with donor cells. Autologous hematopoietic reconstitution may "reboot" mucosal immunity to a normal baseline state, but does not alter any underlying genetic predisposition to IBD. In contrast, allogeneic hematopoietic transplantation reconstitutes all blood lineages from a tissue-matched donor who presumably does not have a genetic predisposition to IBD. Compared with autologous hematopoietic transplantation, allogeneic hematopoietic transplantation carries a much greater risk of complications, including graft versus-host disease. Mesenchymal stem cells can give rise to cartilage, bone and fat in vitro, but do not reconstitute hematopoiesis after transplantation. Systemically infused mesenchymal stem cells appear to favorably downregulate host immune responses through poorly understood mechanisms. In addition, mesenchymal stem cells may be applied topically to help close fistulas associated with Crohn's disease. For all of these stem cell therapy applications for IBD, only cases and small series have been reported. Larger clinical trials are planned or ongoing. PMID- 21694841 TI - An update on the use of pantoprazole as a treatment for gastroesophageal reflux disease. AB - Gastroesophageal reflux disease (GERD) is a chronic, recurrent disease that affects nearly 19 million people in the US. The mainstay of therapy for GERD is acid suppression. Proton pump inhibitors (PPIs) are the most effective medication for both initial treatment and maintenance therapy of GERD. Pantoprazole, a first generation PPI, was approved by the FDA in 2000 for the treatment of erosive esophagitis associated with GERD. It has been used in more than 100 different countries worldwide. It is one of the few PPIs available in multiple forms: a delayed-release oral capsule, oral suspension, and intravenous. Pantoprazole been shown to improve acid reflux-related symptoms, heal esophagitis, and improve health-related quality of life more effectively than histamine-2 receptor antagonists. Evaluated in over 100 clinical trials, pantoprazole has an excellent safety profile, is as efficacious as other PPIs, and has a low incidence of drug interactions. It has also been shown to be safe and effective in special patient populations, such as the elderly and those with renal or moderate liver disease. PMID- 21694842 TI - Delayed-release oral suspension of omeprazole for the treatment of erosive esophagitis and gastroesophageal reflux disease in pediatric patients: a review. AB - Omeprazole is a proton-pump inhibitor indicated for gastroesophageal reflux disease and erosive esophagitis treatment in children. The aim of this review was to evaluate the efficacy of delayed-release oral suspension of omeprazole in childhood esophagitis, in terms of symptom relief, reduction in reflux index and/or intragastric acidity, and endoscopic and/or histological healing. We systematically searched PubMed, Cochrane and EMBASE (1990 to 2009) and identified 59 potentially relevant articles, but only 12 articles were suitable to be included in our analysis. All the studies evaluated symptom relief and reported a median relief rate of 80.4% (range 35%-100%). Five studies reported a significant reduction of the esophageal reflux index within normal limits (<7%) in all children, and 4 studies a significant reduction of intra-gastric acidity. The endoscopic healing rate, reported by 9 studies, was 84% after 8-week treatment and 95% after 12-week treatment, the latter being significantly higher than the histological healing rate (49%). In conclusion, omeprazole given at a dose ranging from 0.3 to 3.5 mg/kg once daily (median 1 mg/kg once daily) for at least 12 weeks is highly effective in childhood esophagitis. PMID- 21694843 TI - Inflammatory bowel diseases and the general practitioner's role in a region of Central Italy. AB - BACKGROUND: Inflammatory bowel diseases (IBD) are a serious burden for both patients and health care providers because of the young age at which they occur and their chronic course. AIM: The purpose of this study was to assess how general practitioners (GPs) in the area of Camerino-Matelica, Marche (Central Italy) manage their patients with IBD. MATERIALS AND METHODS: Before providing an educational course about IBD to GPs, we administered a simple questionnaire containing 10 multiple-choice questions, allowing for only one possible answer, to GPs in the target area. After the educational course we administered a satisfaction questionnaire and evaluated the hospitalization rates for IBD in the catchment area in the year following the course. RESULTS: In our GP sample, 71.8% indicated that they needed better instruction regarding IBD to enable them to diagnose the conditions given the difficulties posed by nonspecific symptoms and the need to use invasive diagnostic methods such as colonoscopy. Early results after the educational course for GPs indicate a reduced rate of hospitalization for IBD but these data must be confirmed by future research. CONCLUSIONS: If specialists and GPs managed IBD patients more carefully, their patients would probably suffer from fewer relapses and would have a better quality of life, which would be likely to mean considerable cost savings for the public health care system and society in general. PMID- 21694844 TI - Hepatic manifestations of celiac disease. AB - Different hepatic and biliary tract disorders may occur with celiac disease. Some have been hypothesized to share genetic or immunopathogenetic factors, such as primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. Other hepatic changes in celiac disease may occur with malnutrition resulting from impaired nutrient absorption, including hepatic steatosis. In addition, celiac disease may be associated with rare hepatic complications, such as hepatic T-cell lymphoma. PMID- 21694845 TI - Imatinib as the first and only treatment in Europe for adult patients at significant risk of relapse following gastrointestinal stromal tumor removal. AB - Mutations of the KIT gene are the molecular hallmark of most gastrointestinal stromal tumors (GISTs). GIST has become a model for targeted treatment of solid tumors, imatinib becoming the standard first-line treatment of these tumors in the advanced/metastatic phase. Because of the efficacy of imatinib treatment in the advanced setting, its role following resection of a primary non-metastatic GIST was investigated. The recently published phase III, double-blind, placebo controlled, multicenter ACOSOG Z9001 study showed that adjuvant therapy is safe, and significantly improves recurrence-free survival compared to placebo when given after resection. To what extent imatinib will improve overall survival has yet to be answered. What is clear is that high-risk GIST patients definitely need adjuvant therapy, and that 1 year of imatinib is not enough for the patients who do need it. The questions of optimal duration of imatinib treatment in the adjuvant setting, adequate selection of risk patients and effect of imatinib on overall survival are currently being studied. PMID- 21694846 TI - Role of prucalopride, a serotonin (5-HT(4)) receptor agonist, for the treatment of chronic constipation. AB - Constipation affects up to a quarter of the population in developed countries and is associated with poor quality of life and significant economic burden. Many patients with chronic constipation are dissatisfied with current therapy due to lack of long-term efficacy or side effects. Previous nonselective 5 hydroxytryptamine receptor 4 (5-HT(4)) agonists have been associated with significant interactions with other receptors (5-HT(1B), 5-HT(1D), and 5-HT(2B) for tegaserod; hERG for cisapride), leading to adverse cardiovascular events resulting in withdrawal of these drugs from the market. Prucalopride is a novel gastrointestinal prokinetic agent. It acts as a high affinity, highly-selective 5 HT(4) agonist. Its efficacy in patients with chronic constipation has been demonstrated in several phase II and phase III clinical trials showing significant improvements in bowel transit, bowel function, gastrointestinal symptoms, and quality of life, with benefit maintained for up to 24 months in open label, multicenter, follow-up studies. Prucalopride's high selectivity for the 5-HT(4) receptor may explain its favorable safety and tolerability profiles, even in elderly subjects with stable cardiovascular disease. Prucalopride is a well tolerated and efficacious prokinetic medication that should enhance the treatment of chronic constipation unresponsive to first-line treatments. PMID- 21694847 TI - Infliximab therapy in pediatric Crohn's disease: a review. AB - Anti-tumor necrosis factor alpha (TNF-alpha) therapy has re-defined our treatment paradigms in managing patients with Crohn's disease (CD) and ulcerative colitis. Although the ACCENT studies showed proven efficacy in the induction and maintenance of disease remission in adult patients with moderate to severe CD, the pediatric experience was instrumental in bringing forth the notion of "top down" therapy to improve overall clinical response while reducing the risk of complications resulting from long-standing active disease. Infliximab has proven efficacy in the induction and maintenance of disease remission in children and adolescents with CD. In an open-labeled study of 112 pediatric patients with moderate to severe CD, 58% achieved clinical remission on induction of infliximab (5 mg/kg) therapy. Among those patients who achieved disease remission, 56% maintained disease remission on maintenance (5 mg/kg every 8 weeks) therapy. Longitudinal follow-up studies have also shown that responsiveness to infliximab therapy also correlates well with reduced rates of hospitalization, and surgery for complication of long-standing active disease, including stricture and fistulae formation. Moreover, these children have also been shown to improve overall growth while maintaining an effective disease remission. The pediatric experience has been instructive in suggesting that the early introduction of anti TNF-alpha therapy may perhaps alter the natural history of CD in children, an observation that has stimulated a great deal of interest among gastroenterologists who care for adult patients with CD. PMID- 21694848 TI - Intestinal fermentation in patients with self-reported food hypersensitivity: painful, but protective? AB - PURPOSE: Enterometabolic disturbances may cause meal-related symptoms. We performed a functional evaluation of the intestinal microflora in patients with unexplained, self-reported food hypersensitivity by measuring fecal short-chain fatty acids (SCFAs). PATIENTS AND METHODS: Thirty-five consecutive patients with self-reported food hypersensitivity and 15 healthy volunteers of similar age, gender, and body mass index collected all feces for 72 hours. Fecal concentrations of acetic, propionic, n-butyric, i-butyric, n-valeric, i-valeric, n-caproic, and i-caproic acids were analyzed by gas-liquid chromatography. Concentrations and excretions (output) of SCFAs in patients and controls were compared and related to gastrointestinal symptoms. RESULTS: Despite nonsignificant differences between patients and controls for both total and individual SCFA concentrations and excretions, n-butyric acid comprised a higher (P = 0.035) and acetic acid a lower (P = 0.012) proportion of total SCFA in patients compared to controls. There were no significant correlations between symptom scores and concentrations or excretions of individual or total SCFAs, but the proportion of n-butyric acid was significantly higher in patients with severe symptoms compared to patients with moderate symptoms (P = 0.016). CONCLUSION: The results indicate an enterometabolic disturbance in patients with self-reported food hypersensitivity. Higher proportions of n-butyric acid may be related to abdominal symptom generation, but may also protect against organic bowel disease. Further studies are needed to clarify these aspects. PMID- 21694849 TI - Time trends in incidence of peptic ulcer bleeding and associated risk factors in Norway 1985-2008. AB - OBJECTIVE: The aim of this study was to examine time trends in the incidence of peptic ulcer bleeding and risk factors in a defined geographical area in Norway. MATERIAL AND METHODS: Retrospective data were collected for 306 patients with bleeding peptic ulcers admitted to one hospital during the 1985-1986, 1995-1996, and 2007-2008 periods. RESULTS: The incidence in 1985-1986 was 52/100,000 and in 2007-2008 was 45/100,000. In the group aged 20-75 years, the incidence decreased by 54% from 54/100000 in 1985-1986 to 25/100000 in 2007-2008 (P = 0.001) and increased by 49% in the group aged >75 years from 272/100000 to 406/100000 (P = 0.0001). The use of aspirin or nonsteroidal anti-inflammatory steroid drugs (NSAIDs) was 31% in 1985-1986 and increased to 67% in 2007-2008 (P = 0.004). In patients using aspirin or NSAIDs, Helicobacter pylori was present in 73% in 1995 1996 and in 51% in 2007-2008. H. pylori infection declined from 84% to 52% between 1995-1996 and 2007-2008. CONCLUSIONS: The incidence rate of peptic ulcer bleeding did not change between 1985-1986 and 2007-2008, but decreased in the age group <=75 years and increased in the age group >75 years. The use of low-dose aspirin and NSAIDs increased substantially over time, and H. pylori infection was still present in 51% of these patients in 2007-2008. PMID- 21694850 TI - Advances in the treatment of gastroenteropancreatic neuroendocrine tumors. AB - Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a rare and heterogeneous class of neoplasms. While surgical resection is the mainstay of treatment, non-surgical therapies play a role in the setting of unresectable and metastatic disease. The goals of medical therapy are directed both at alleviating symptoms of peptide release and shrinking tumor mass. Biotherapies such as somatostatin analogs and interferon can decrease the secretion of peptides and inhibit their end-organ effects. A second objective for treatment of unresectable GEP-NETs is limiting tumor growth. Options for limiting tumor growth include somatostatin analogs, systemic chemotherapy, locoregional therapies, ionizing radiation, external beam radiation, and newer targeted agents. In particular, angiogenesis inhibitors, tyrosine kinase inhibitors, and mTOR inhibitors have shown early promising results. The rarity of these tumors, their resistance to standard chemotherapy, and the excellent performance status of most of these patients, make a strong argument for consideration of novel therapeutic trials. PMID- 21694851 TI - Pathogenesis and clinical and economic consequences of postoperative ileus. AB - Postoperative ileus (POI) occurs frequently in patients undergoing major abdominal surgery; and only recently has there been renewed interest in understanding the pathogenesis, etiology, clinical manifestations, and clinical and economic consequences related to POI. This interest has been spurred by the potential access to novel pharmaceutical options for the management of POI. POI has a complex and multimodal pathophysiology including neurogenic, inflammatory, hormonal, and pharmacologic components. The clinical manifestations are clinically obvious and include abdominal distention, pain, nausea, vomiting, and inability to pass stools or tolerate a solid diet. Prolonged ileus has been defined as persistence of these symptoms for more than 4 days after major abdominal surgery; however the goal should be to reduce the incidence of these symptoms immediately after surgery. Clearly, the magnitude of the surgical stress and usage of opioid analgesia are the predominant causes of POI. The unappreciated sequelae of POI include increased rates in adverse surgical wound healing, reduced ambulation, atelectasis, pneumonia, urinary infections, and deep vein thrombosis. The secondary impact of these complications includes increased hospital length of stay, resource use, and healthcare costs. POI is common and the impact is underestimated. The addition of alvimopan as the first in class MU opioid inhibitor has demonstrated consistent benefit in reducing the incidence and impact of POI with reductions in length of hospital stay. POI is a common, and underappreciated complication of major abdominal surgery, and clinicians should be aware of the clinical care options, including novel pharmaceutical agents, that can successfully reduce the incidence of this postoperative complication. PMID- 21694852 TI - Evaluation of therapeutic effects and serious complications following endoscopic obliterative therapy with Histoacryl. AB - BACKGROUND AND AIMS: Our aim was to evaluate the utility of endoscopic obliterative therapy with Histoacryl for gastric varices and to investigate the incidence of serious complications. METHODS: Endoscopic obliterative therapy with Histoacryl was performed on 129 gastric variceal patients. Sixty-five patients had cardiofornical varices, and 64 had fundal varices. Forty-five of 129 patients were emergency cases and the other 84 patients were prophylactic cases. Endoscopic therapy was performed under fluoroscopy using 70% Histoacryl (Histoacryl diluted with 5% Lipiodol). RESULTS: Endoscopic hemostasis of gastric varices was successful in 45/45 (100%) emergency cases. The recurrence rate of gastric varices was 17/120 (14.2%) among patients whose variceal eradication was achieved. Additional treatment was successfully performed in all recurrent cases. The incidence of serious complications was 4/129 (3.1%), including two cases of splenic infarction, one case of pulmonary embolism, and one case of an inflammatory tumor of pancreatic tail. The two patients with splenic infarction improved with conservative medical treatment. The patient with pulmonary embolism showed no respiratory symptoms, and died of liver failure. The patient with the pancreatic tumor, which was diagnosed as an inflammatory tumor, was treated surgically. CONCLUSIONS: Endoscopic obliterative therapy with Histoacryl is a useful and relatively safe method for treatment of bleeding gastric varices. Nonetheless, careful attention must be paid to avoid potentially serious complications. PMID- 21694854 TI - Gastric cancer and the search for a good prognostic classification: a challenge. AB - INTRODUCTION: Gastric cancer is the second most common cancer worldwide. The standard treatment is radical surgical resection, but 60% of patients will present recurrence. TNM classification (6th edition, American Joint Committee on Cancer) recommends the removal of at least 15 regional lymph nodes to carry out an adequate pathological staging. But in our environment, only 20% of cases have the minimum recommended, so it would be very important to have an alternative prognostic. We designed a retrospective study to evaluate different prognostic factors in patients inadequately staged. MATERIAL AND METHODS: We focused on patients with serosal involvement (pT3). The evaluation included general parameters such as age, sex, tumor site, histological type, type of gastrectomy, histological grade, number of nodes analyzed = 10, lymph node ratio (LNR) with a 20% cutoff value, and adjuvant treatment. The association between clinicopathological variables and recurrence was investigated by univariate and multivariate logistic regression. It was considered statistically significant with P < 0.05. RESULTS: A total of 92 patients who met the criteria were studied. Median age 65 years; 68% men, 32% women; median follow-up time for the overall population, 44 months (range 15-119 months); number of nodes analyzed, median 7 (range 0-14 nodes); recurrence in 59%; median time to recurrence, 15 months (range 3-48 months); the cumulative risk of relapse at five years, 64%. Multivariate statistical analysis showed that the LNR (P = 0.03) and total number of nodes analyzed = 10 (P = 0.04) were independent predictors for the risk of recurrence. CONCLUSION: LNR and total number of nodes analyzed with a threshold of 10 (= 10 nodes analyzed) were independent predictors of recurrence in patients with gastric carcinoma pT3 and an insufficient number of nodes examined. PMID- 21694853 TI - Acute gastroenteritis: from guidelines to real life. AB - Acute gastroenteritis is a very common disease. It causes significant mortality in developing countries and significant economic burden to developed countries. Viruses are responsible for approximately 70% of episodes of acute gastroenteritis in children and rotavirus is one of the best studied of these viruses. Oral rehydration therapy is as effective as intravenous therapy in treating mild to moderate dehydration in acute gastroenteritis and is strongly recommended as the first line therapy. However, the oral rehydration solution is described as an underused simple solution. Vomiting is one of the main reasons to explain the underuse of oral rehydration therapy. Antiemetics are not routinely recommended in treating acute gastroenteritis, though they are still commonly prescribed. Ondansetron is one of the best studied antiemetics and its role in enhancing the compliance of oral rehydration therapy and decreasing the rate of hospitalization has been proved recently. The guidelines regarding the recommendation on antiemetics have been changed according to the evidence of these recent studies. PMID- 21694855 TI - Relationship between esomeprazole dose and timing to heartburn resolution in selected patients with gastroesophageal reflux disease. AB - OBJECTIVE: To increase response rates to therapy by increasing the dosage of proton pump inhibitor (PPI) therapy in patients with gastroesophageal reflux disease (GERD) whose symptoms are predominantly associated with acid reflux. METHODS: In this double-blind, randomized, proof-of-concept study, 369 patients with GERD and moderate heartburn lasting >=three days/week, a history of response to antacids/acid suppression therapy, and a positive esophageal acid perfusion test result were randomized to esomeprazole 20 or 40 mg once daily, or to 40 mg twice daily for four weeks. Heartburn symptom relief/resolution was subsequently evaluated. RESULTS: In this study population, no relationship was apparent between esomeprazole dosage and efficacy variables for sustained heartburn resolution (seven days without symptoms) at week 4 (48.0%, 44.0%, and 41.4% for esomeprazole 20 mg once daily, 40 mg once daily, and 40 mg twice daily, respectively). Nocturnal heartburn resolution with esomeprazole 40 mg twice daily showed a numeric improvement trend versus esomeprazole 20 and 40 mg once daily, but this was not statistically significant. CONCLUSIONS: Heartburn resolution rates at four weeks were similar for all esomeprazole dosages and comparable with rates reported previously, suggesting a plateau effect in terms of clinical response to acid suppression with PPI therapy in this population of selected GERD patients. PMID- 21694856 TI - Irritable bowel syndrome: diagnostic approaches in clinical practice. AB - BACKGROUND: Irritable bowel syndrome (IBS), a functional gastrointestinal disorder long considered a diagnosis of exclusion, has chronic symptoms that vary over time and overlap with those of non-IBS disorders. Traditional symptom-based criteria effectively identify IBS patients but are not easily applied in clinical practice, leaving >40% of patients to experience symptoms up to 5 years before diagnosis. OBJECTIVE: To review the diagnostic evaluation of patients with suspected IBS, strengths and weaknesses of current methodologies, and newer diagnostic tools that can augment current symptom-based criteria. METHODS: The peer-reviewed literature (PubMed) was searched for primary reports and reviews using the limiters of date (1999-2009) and English language and the search terms irritable bowel syndrome, diagnosis, gastrointestinal disease, symptom-based criteria, outcome, serology, and fecal markers. Abstracts from Digestive Disease Week 2008-2009 and reference lists of identified articles were reviewed. RESULTS: A disconnect is apparent between practice guidelines and clinical practice. The American Gastroenterological Association and American College of Gastroenterology recommend diagnosing IBS in patients without alarm features of organic disease using symptom-based criteria (eg, Rome). However, physicians report confidence in a symptom-based diagnosis without further testing only up to 42% of the time; many order laboratory tests and perform sigmoidoscopies or colonoscopies despite good evidence showing no utility for this work-up in uncomplicated cases. In the absence of diagnostic criteria easily usable in a busy practice, newer diagnostic methods, such as stool-form examination, fecal inflammatory markers, and serum biomarkers, have been proposed as adjunctive tools to aid in an IBS diagnosis by increasing physicians' confidence and changing the diagnostic paradigm to one of inclusion rather than exclusion. CONCLUSION: New adjunctive testing for IBS can augment traditional symptom-based criteria, improving the speed and safety with which a patient is diagnosed and avoiding unnecessary, sometimes invasive, testing that adds little to the diagnostic process in suspected IBS. PMID- 21694857 TI - Positive predictive values of the International Classification of Disease, 10th edition diagnoses codes for diverticular disease in the Danish National Registry of Patients. AB - OBJECTIVE: To investigate the accuracy of diagnostic coding for diverticular disease in the Danish National Registry of Patients (NRP). STUDY DESIGN AND SETTING: At Aalborg Hospital, Denmark, with a catchment area of 640,000 inhabitants, we identified 100 patients recorded in the NRP with a diagnosis of diverticular disease (International Classification of Disease codes, 10th revision [ICD-10] K572-K579) during the 1999-2008 period. We assessed the positive predictive value (PPV) as a measure of the accuracy of discharge codes for diverticular disease using information from discharge abstracts and outpatient notes as the reference standard. RESULTS: Of the 100 patients coded with diverticular disease, 49 had complicated diverticular disease, whereas 51 had uncomplicated diverticulosis. For the overall diagnosis of diverticular disease (K57), the PPV was 0.98 (95% confidence intervals [CIs]: 0.93, 0.99). For the more detailed subgroups of diagnosis indicating the presence or absence of complications (K573-K579) the PPVs ranged from 0.67 (95% CI: 0.09, 0.99) to 0.92 (95% CI: 0.52, 1.00). The diagnosis codes did not allow accurate identification of uncomplicated disease or any specific complication. However, the combined ICD 10 codes K572, K574, and K578 had a PPV of 0.91 (95% CI: 0.71, 0.99) for any complication. CONCLUSION: The diagnosis codes in the NRP can be used to identify patients with diverticular disease in general; however, they do not accurately discern patients with uncomplicated diverticulosis or with specific diverticular complications. PMID- 21694858 TI - Poor comprehension of colon preparation process in an Appalachian population. AB - Clear liquids are often part of colonoscopy preparation instructions, regardless of the active cleansing agent. Poor understanding of this facet may yield poor preparation with delays in management. We studied comprehension of this facet of colon preparation in an Appalachian population. Our survey contained demographic items and a list of food items from which subjects could select clear liquids. In Phase I, no prompting was given. In Phase II, subjects reviewed the definition of clear liquids and examples a few minutes before the survey. For Phase III, the survey contained the definition of a clear liquid and examples. Persons about to undergo colonoscopy and companions who escorted them were surveyed, since many persons have help during the preparation process. With the Fisher exact probability test, we compared the association of accurately selecting clear liquids >= or <80% of the time with education > or <=12th grade, age, gender, and subject's stated understanding of preparation. Mean age for all subjects was 52 years and 59% of subjects were female. The majority had <=12 years of education. Most subjects reported understanding their preparation instructions and yet the minority had >=80% accuracy on clear liquid selection (range 6%-16%). Phases I III represent a continuum of progressively more accessible information about clear liquids. Comparison across the 3 phases, for both patients and companions, did not reveal significantly improved clear liquid selection. Multivariate analyses of the above variables, with % correct answer as the dependent variable for all the subgroups, did not reveal any significant associations. Persons from Appalachia do not seem to understand a key portion of the colon preparation process. We demonstrate no significant predictors of understanding the clear liquid aspect of colon preparation. Simple measures to augment comprehension have no clinically significant effect. PMID- 21694859 TI - Comparison of esophageal placement of Bravo capsule system under direct endoscopic guidance with conventional placement method. AB - BACKGROUND: Conventional placement of a wireless esophageal pH monitoring device in the esophagus requires initial endoscopy to determine the distance to the gastroesophageal junction. Blind placement of the capsule by the Bravo delivery system is followed by repeat endoscopy to confirm placement. Alternatively, the capsule can be placed under direct vision during endoscopy. Currently there are no published data comparing the efficiency of one method over the other. The objective of this study was to compare the method of Bravo wireless pH device placement under direct visualization with the conventional method. METHODS: A retrospective study involving 58 patients (29 patients with indirect and 29 patients with direct visualization) who had Bravo capsule placement. The physician endoscopy procedure notes, nurse's notes, postprocedure notes, recovery notes, and pH monitoring results were reviewed. The safety of the procedures, length of the procedures, and patient tolerability were evaluated. RESULTS: None of the 58 patients had early detachment of the device and had no immediate procedure-related complications. The overall incidence of complications in both the groups was similar. No failures due to the technique were noted in either group. Average amount of time taken for the procedure was similar in both groups. CONCLUSION: The technique of placing a Bravo pH device under direct visualization is as safe and effective as the conventional method. In addition, there is an added advantage of avoiding a second endoscopic intubation in the direct visualization technique. PMID- 21694860 TI - Comparison of preference and safety of powder and liquid lactulose in adult patients with chronic constipation. AB - BACKGROUND: Chronic constipation is an important clinical condition which can result in serious discomfort and even require hospitalization. Powder and liquid lactulose are designated as clinically equivalent for the treatment of constipation, but there are significant differences in the taste, consistency, and portability of the products, which may affect patient compliance and therefore clinical outcome. AIM: To evaluate patient preference between powder and liquid lactulose in terms of overall preference, taste, consistency, and portability, and safety in terms of adverse events. METHODS: Three sites randomized patients (total n = 50) to powder or liquid lactulose for seven days with crossover. Patient preference was assessed by a questionnaire, and the occurrence of adverse events was monitored. RESULTS: Of those expressing a preference, 44% and 57% more patients preferred the taste and consistency, respectively, of powder over liquid lactulose. More than six times as many patients preferred the portability of powder compared with liquid lactulose and, overall, 77% more patients preferred powder over liquid lactulose. There was no difference between treatment groups in terms of adverse events (P = 0.635). CONCLUSIONS: More patients preferred powder compared with liquid lactulose and the products were equally safe. These findings may impact patient compliance, and therefore may affect clinical outcome. PMID- 21694861 TI - Retrospective analysis of endoscopic injection sclerotherapy for rectal varices compared with band ligation. AB - BACKGROUND AND AIMS: The study's aim was to evaluate the efficacy of endoscopic injection sclerotherapy (EIS) compared with endoscopic band ligation (EBL) in treating rectal varices. METHODS: Data from 34 consecutive patients who underwent endoscopic treatments for rectal varices were analyzed. The clinical outcomes, including complications, related to EIS or EBL retrospectively. RESULTS: In 25 of the 34 patients, EIS was performed weekly 2-5 times (mean, 2.7), and the total amount of sclerosant ranged from 3.2 to 12.0 mL (mean, 5.2 mL). After EIS, colonoscopy revealed shrinkage of the rectal varices in all 25 patients, with no complications reported. In 9 of the 34 patients, EBL was performed weekly 1-3 times (mean, 2.2), and bands were placed on the varices at 2-12 sites (mean, 8.0). After EBL, colonoscopy revealed ulcers and shrinkage of the rectal varices in all nine patients, eight of whom experienced no operative complications. The overall recurrence rate for rectal varices was 10 of 24 (41.7%), including 5 of 9 (55.6%) receiving EBL and 5 of 15 (33.3%) receiving EIS, over a 1-year follow-up period (n = 24). All four patients with recurrence of bleeding were EBL cases, versus no EIS cases (P < 0.05). CONCLUSION: EIS appears superior to EBL with regard to effectiveness and complications after endoscopic treatment of rectal varices. PMID- 21694862 TI - Epidemiology of inflammatory bowel disease among an indigent multi-ethnic population in the United States. AB - BACKGROUND: Environmental factors, including socioeconomic status, may affect inflammatory bowel disease (IBD). There is a paucity of data on the epidemiology of IBD among patients of low socioeconomic status. AIM: To examine the epidemiologic features of IBD among African-American, Hispanic, and Caucasian patients from a county hospital, where the majority of the patients are socioeconomically disadvantaged. METHODS: A retrospective study was conducted on a cohort of patients diagnosed with IBD based on clinical, radiologic, endoscopic, and histological data. We reviewed charts of adults aged 20-70 years diagnosed with IBD between 2000 and 2006. Demographic data, disease subtype, and phenotypic features of IBD were recorded based on the Montreal Classification. The data were analyzed using the chi-square, Fisher exact, Wilcoxon rank-sum, and Student's t-tests. RESULTS: The study cohort included 273 patients, with 54% female, 30% Caucasian, 44% African-American, and 26% Hispanic. Over half (54%) of the patients had Crohn's disease (CD), and 46% had ulcerative colitis (UC). The mean age at diagnosis was 40 +/- 14 years with no significant difference between CD and UC (age 43 +/- 13 versus 44.5 +/- 14, respectively; P = 0.5). Females were diagnosed at a significantly later age than males (46 +/- 13 years versus 40 +/- 13, respectively; P = 0.001). This trend remained significant for females with CD and UC, and across each racial/ethnic group. Hispanic patients were diagnosed with UC more often than Caucasian patients (64% versus 34%; odds ratio [OR] 3.5; 95% confidence interval [CI]: 1.8-6.5, P = 0.0003) or African-Americans (64% versus 43%; OR 2.3; 95% CI: 1.3-4.3, P = 0.005). Among the 147 patients with CD, 54% had fistulizing and/or stricturing disease. The prevalence of fistulizing, stricturing, and inflammatory CD was similar across all age, gender, and racial/ethnic groups. CONCLUSIONS: Within an indigent population, UC was diagnosed more often in Hispanics than CD. Females were diagnosed at a significantly older age than males across all racial/ethnic groups. There was no difference in the CD phenotypes between the three ethnic groups. Understanding the epidemiology of IBD will require examination of the interactions between gender, race/ethnicity, and environmental factors. PMID- 21694863 TI - Amino acid-responsive Crohn's disease: a case study. AB - PURPOSE: This paper reviews the clinical course of a case of severe Crohn's disease and discusses the scientific ramifications of a novel treatment approach. PATIENTS AND METHODS: A case study of a 37-year-old male with a 22-year history of Crohn's disease whose clinical course had experienced no sustained remissions. The patient was treated with a protocol that utilized serotonin and dopamine amino acid precursors administered under the guidance of organic cation transporter assay interpretation. RESULTS: Within 5 days of achieving the necessary balance of serotonin and dopamine, the patient experienced remission of symptoms. This remission has been sustained without the use of any Crohn's disease medications. CONCLUSION: In Crohn's disease, it is known that there is an increase of both synthesis and tissue levels of serotonin in specific locations. It is asserted that this is prima facie evidence of a significant imbalance in the serotonin-dopamine system, leading to serotonin toxicity. The hypothesis formulated is that improperly balanced serotonin and dopamine transport, synthesis, and metabolism is a primary defect contributing to the pathogenesis of Crohn's disease. PMID- 21694864 TI - The role of somatostatin in 67 consecutive pancreatectomies: a randomized clinical trial. AB - BACKGROUND: Somatostatin has been found to be effective in the prevention of postoperative complications in pancreatic surgery. It can inhibit the pancreatic secretions that, quite often, are responsible for complications during the postoperative period. METHODS: We randomized 67 patients in 2 groups. In the study group (n = 35), somatostatin was administered 30 minutes prior to surgery as well as intraoperatively and postoperatively. No medication was given to the control group (n = 32). Biopsies were taken and processed for electron microscopy and ultrastructural morphometric analysis. RESULTS: Administration of somatostatin reduced the exocrine granule number, and the patients suffered from fewer postoperative complications. CONCLUSIONS: Somatostatin reduces granule number and size of pancreatic cells, which can partially explain the prophylactic effect of the drug on early complications of pancreatic surgery, and which is confirmed by the clinical findings. PMID- 21694865 TI - Immunohistochemical localization of transforming growth factor beta-1 and its relationship with collagen expression in advanced liver fibrosis due to biliary atresia. AB - PURPOSE: Biliary atresia (BA) is the most common indication of liver transplantation in children. Pathogenesis of hepatic fibrosis, which is a prominent feature of BA, remains obscure. The purpose of this work was to determine the cellular sources of transforming growth factor beta-1 (TGFbeta1) and establish the relationship between TGFbeta1-producing cells and extracellular matrix producing myofibroblasts (MFBs) in advanced BA. METHODS: Trichrome staining and immunohistochemistry were carried out to determine the expression pattern of collagen and TGFbeta1 protein in explant liver specimens from patients with BA. The intensities of portal and lobular TGFbeta1 expressions were compared. Immunofluorescence technique was carried out to determine the relationship between alpha-smooth muscle actin (alpha-SMA)-positive-MFB and TGFbeta1-positve cells. RESULTS: Lobular TGFbeta1 protein expression was significantly higher than portal (89 +/- 6 versus 10 +/- 1 arbitrary units, P <= 0.05), whereas no difference was noted in livers used as control (10 +/- 1.6 versus 19 +/- 5 arbitrary units, P = 0.11). TGFbeta1 expression was more in the center of nodules versus MFB in surrounding fibrous septa. Contrary to TGFbeta1 expression, alpha1-SMA was mostly expressed in the portal structures and the adjacent fibrous septa enacting lobulation of the parenchyma. The results obtained by coimmunofluorescence staining showed no colocalization of alpha-SMA and TGFbeta1. CONCLUSIONS: TGFbeta1 protein expression is mostly localized to hepatocytes in advanced BA. These findings suggest a paracrine mechanisms of TGFbeta1-driven fibrogenesis in advanced BA. PMID- 21694866 TI - Thromboembolism in inflammatory bowel diseases: a report from Saudi Arabia. AB - Thromboembolism (TE) is a serious but under-recognized complication of inflammatory bowel disease (IBD). This is specially so in developing countries where the incidence of IBD is low. In Saudi Arabia, IBD is considered to be rare, but the incidence is increasing. Where the clinical manifestations resemble those of developed countries, TE as a complication of IBD is considered to be very rare. This report describes six IBD patients with TE. This importance of the complication of TE is stressed, and physicians caring for these patients should be aware of it in order to obviate potential morbidity and mortality. PMID- 21694867 TI - Infliximab therapy for moderately severe Crohn's disease and ulcerative colitis: a retrospective comparison over 6 years. AB - BACKGROUND: Infliximab has shown benefit in Crohn's disease (CD) and ulcerative colitis (UC). OBJECTIVE: Evaluation of long-term outcome of therapy for both diseases. METHODS: We analyzed retrospectively patients treated at infusion centers from one institution. Demographic, laboratory parameters leading up to biologic therapy and the subsequent pattern of outcomes in either disease were established as a database. Initial failure, subsequent need to change therapy, or need to adjust therapy were evaluated. Kruskal-Wallis (nonparametric) tests to compare two groups and Kaplan-Meier survival curve analysis were used to compare outcomes. RESULTS: Over approximately 6 years, 71 CD and 26 UC patients received 999 and 215 infusions, respectively, for a median of 62 months. Of these, 17% for CD and 19% for UC patients were primary failures. Following the start of infliximab, 18% of CD and 11% of UC patients required stoppage and switching to another type of therapy. In either CD or UC patients, 54% or 62%, respectively, continued therapy without the need to change to other treatments. Few serious side effects were noted. No important statistically significant differences in treatment patterns or outcome were observed between the groups. DISCUSSION: Long term treatment of both inflammatory bowel diseases reflects outcomes of clinical trials. CONCLUSIONS: This study emphasizes similarities between CD and UC and reports therapeutic success for an extended time. PMID- 21694868 TI - Treating acid reflux disease in patients with Down syndrome: pharmacological and physiological approaches. AB - Down syndrome (DS) is often accompanied by gastrointestinal disease, occurring mainly in early infancy and frequently requiring therapy. Among motility disorders, the most frequent is gastroesophageal reflux disease (GERD), which may often be misdiagnosed because of its atypical manifestations. Early diagnosis of esophageal functional disorders is essential to prevent respiratory problems, growth retardation in children, weight loss in adults, and to establish the correct type of surgery if needed. Furthermore, the involvement of the enteric nervous system in the pathophysiology of GERD in DS is not yet completely understood but seems supported by much evidence. In fact DS is often associated with motor disorders and this evidence must be considered in the choice of therapy: in particular all options available to improve motility seem to be effective in these patients. The effectiveness of therapy is strictly related to the rate of mental impairment, so that modulating therapy is essential, especially in view of the severity of the neurological status. PMID- 21694869 TI - Effects of casoxin 4 on morphine inhibition of small animal intestinal contractility and gut transit in the mouse. AB - BACKGROUND AND AIMS: Chronic opioid analgesia has the debilitating side-effect of constipation in human patients. The major aims of this study were to: 1) characterize the opioid-specific antagonism of morphine-induced inhibition of electrically driven contraction of the small intestine of mice, rats, and guinea pigs; and 2) test if the oral delivery of small milk-derived opioid antagonist peptides could block morphine-induced inhibition of intestinal transit in mice. METHODS: Mouse, rat, and guinea pig intact ileal sections were electrically stimulated to contract and inhibited with morphine in vitro. Morphine inhibition was then blocked by opioid subtype antagonists in the mouse and guinea pig. Using a polymeric dye, Poly R-478, the opioid antagonists casoxin 4 and lactoferroxin A were tested orally for blocking activity of morphine inhibition of gut transit in vivo by single or double gavage techniques. RESULTS: The guinea pig tissue was more sensitive to morphine inhibition compared with the mouse or the rat (IC(50) [half maximal inhibitory concentration] values as nmol/L +/- SEM were 34 +/- 3, 230 +/- 13, and 310 +/- 14 respectively) (P < 0.01). The inhibitory influence of opioid agonists (IC(50)) in electrically driven ileal mouse preparations were DADLE ([D-Ala(2), D-Leu(5)]-enkephalin) >= met-enkephalin >= dynorphin A >= DAMGO ([D-Ala(2), N-Me-Phe(4), Glyol(5)]-enkephalin) > morphine > morphiceptin as nmol/L 13.9, 17.3, 19.5, 23.3, 230, and 403 respectively. The mouse demonstrated predominantly kappa- and delta-opioid receptor activity with a smaller MU-opioid receptor component. Both mouse and guinea pig tissue were sensitive to casoxin 4 antagonism of morphine inhibition of contraction. In contrast to naloxone, relatively high oral doses of the MU-opioid receptor antagonists, casoxin 4 and lactoferroxin A, applied before and after morphine injection were unable to antagonize morphine inhibition of gut transit. CONCLUSIONS: Casoxin 4 reverses morphine-induced inhibition of contraction in mice and guinea pigs in vitro but fails to influence morphine inhibition of mouse small intestinal transit by the oral route. PMID- 21694870 TI - Management of achalasia. AB - Several theories on the etiology and pathophysiology of achalasia have been reported but, to date, it is widely accepted that loss of peristalsis and absence of swallow-induced relaxation of the lower esophageal sphincter are the main functional abnormalities. Treatment of achalasia often aims to alleviate the symptoms of achalasia and not to correct the underlying disorder. Medical therapy has poor efficacy, so patients who are good surgical candidates should be offered either laparoscopic myotomy or pneumatic balloon dilatation. Their own preference should be included in the decision-making process, and treatment should meet the local expertise with these procedures. Laparoscopic surgical esophagomyotomy is a safe and effective modality. It can be considered as initial management or as secondary treatment if the patient does not respond to less invasive modalities. Pneumatic dilatation has proven to be a safe, effective, and durable modality of treatment when performed by experienced individuals, and appears to be the most cost-effective alternative. For patients with multiple comorbidities and for elderly patients, who are not good surgical candidates, endoscopic injection of botulinum toxin should be considered a safe and effective procedure. However, its positive effect diminishes over time, and the need for multiple repeated sessions must be taken into consideration. In the management of patients with achalasia, nutritional aspects play an important role. When lifestyle changes are insufficient, it is necessary to proceed to percutaneous gastrostomy under radiological guidance. In the future, intraluminal myotomy or endoscopic mucosectomy will possibly be an option. Further studies are needed to investigate the role of immunosuppressive therapies in those cases in which an autoimmune etiology is suspected. PMID- 21694871 TI - High-dose rifaximin treatment alleviates global symptoms of irritable bowel syndrome. AB - BACKGROUND: To evaluate the efficacy of rifaximin for reduction of gastrointestinal symptoms in patients with irritable bowel syndrome (IBS). METHODS: Medical records were identified for consecutive patients diagnosed with IBS according to Rome III criteria, who had abnormal lactulose breath test results and had received rifaximin 1200 mg/day for 10 days. The efficacy of rifaximin for reducing gastrointestinal symptoms and for eradicating small intestinal bacterial overgrowth was ascertained in these patients. In addition, these endpoints were examined in patients who were initially unresponsive to rifaximin 1200 mg/day and received subsequent rifaximin 2400 mg/day. RESULTS: Patients who received rifaximin 1200 mg/day (n = 162) experienced a mean improvement of 52% in global IBS symptoms at the end of rifaximin treatment. Similarly, initially unresponsive patients who received additional rifaximin 2400 mg/day (n = 81) experienced a 53% mean improvement in global IBS symptoms. Forty nine percent of patients who received initial rifaximin and 47% of patients who received high-dose rifaximin achieved >=50% global symptom improvement during at least one follow-up visit. Normalization of lactulose breath test results was only apparent in some patients who received high-dose rifaximin. Rifaximin was well tolerated. CONCLUSION: Rifaximin 1200 mg/day for 10 days reduced gastrointestinal symptoms in patients with IBS. Patients with incomplete symptom resolution may respond to increased doses of rifaximin. PMID- 21694872 TI - Relationship between hepatic CTGF expression and routine blood tests at the time of liver transplantation for biliary atresia: hope or hype for a biomarker of hepatic fibrosis. AB - BACKGROUND: Progressive hepatic fibrosis (HF) is a prominent feature of biliary atresia (BA), the most common indication for liver transplantation (LT) in children. Despite its importance in BA, HF is not evaluated in routine patient care because the invasiveness of liver biopsy makes histologic monitoring of fibrosis unfeasible. Therefore, the identification of noninvasive markers to assess HF is desirable especially in children. PURPOSE: The main goal of this pilot project was to establish an investigational framework correlating hepatic expression of fibrogenic markers with routine blood tests in BA. METHODS: Using liver explants from patients with BA (n = 26), immune-expression of connective tissue growth factor (CTGF), a key fibrogenic cytokine was determined using horseradish-labeled antibodies. Expression intensities of lobular (L-CTGF) and portal (P-CTGF) CTGF were determined by using ImageJ software. These CTGF intensities were correlated with blood tests performed at the time of LT. Correlation coefficients were determined for each blood test variable versus mean L-CTGF and P-CTGF expression intensities. A P-value of less than 0.05 was considered statistically significant. RESULTS: All patients had end-stage liver disease and persistent cholestasis at the time of LT. Kendall tau (tau) rank correlation coefficient for L-CTGF and white blood cell (WBC) was inversed ( 0.52; P <= 0.02). Similar but statistically nonsignificant inverse relationships were noted between L-CTGF and prothrombin time (PT) (-0.15; P <= 0.4), international normalized ratio (INR) (-0.14; P <= 0.5), and platelet count ( 0.36; P <= 0.09). Inversed (tau) rank correlation coefficients were also evident between P-CTGF expression and gamma-glutamyl transpeptidase (GGT), PT, INR, and platelet count. Pearson correlation coefficients for combinational analysis of standardized total bilirubin (TB), alkaline phosphatase, GGT, and platelet count with L-CTGF (0.33; P = 0.3) and P-CTGF (0.06; P = 0.8), were not significant. Similar analysis for alanine aminotransferase, TB, and GGT combination (L-CTGF, 0.16; P = 0.5; P-CTGF -0.3; P = 0.2) as well as WBC, platelet count, and TB (L CTGF: -0.36; P = 0.09; P-CTGF -0.33; P = 0.13) also revealed nonsignificant results. CONCLUSION: Hepatic expression of fibrogenic markers can be correlated with routinely performed blood tests in patients with BA. We document that although a trend of inverse relationship is noted, hepatic CTGF expression does not correlate well with routinely performed blood tests in advanced BA. Further work is required to determine more reliable ways of noninvasive diagnosis of HF. PMID- 21694873 TI - Deep neck abscess: an analysis of microbial etiology and the effectiveness of antibiotics. AB - The objective was to demonstrate the aerobic and anaerobic microbiology of deep neck space abscess and to analyze the coverage rate of different empiric antimicrobial agents. A retrospective review of hospitalized patients with deep neck abscess diagnosed at a tertiary-care, general hospital between April 2001 and October 2006. The study enrolled 100 patients. The bacterial cultures of 89 patients yielded positive results (89%). The predominant aerobes were viridans streptococci, Klebsiella pneumoniae, and Staphylococcus aureus. The predominant anaerobes included species of Prevotella, Peptostreptococcus, and Bacteroides. Five different combinations of empiric antibiotics, namely regimen 1: penicillin G and clindamycin and gentamicin, regimen 2: ceftriaxone and clindamycin, regimen 3: ceftriaxone and metronidazole, regimen 4: cefuroxime and clindamycin, and regimen 5: penicillin and metronidazole, were compared using the antimicrobial susceptibility of 89 cases. The coverage rates of regimens 1, 2, 3, 4, and 5 were 67.4%, 76.4%, 70.8%, 61.8%, and 16.9%, respectively. The coverage of regimen 5 was considerably worse than that of the other four regimens (p < 0.001). Regimen 2 was significantly better than regimen 4 (p < 0.001). Regimen 2 had better coverage than regimens 1 (p = 0.096) and 3 (p = 0.302), but the difference was not statistically significant. This study demonstrates the bacteriology of deep neck abscess and analyzes the coverage rate of different empiric antimicrobial agents. Regimens 1, 2, and 3 could be good candidates for empiric antibiotics. Pathogen-directed antimicrobial therapy should be adjusted after the culture results are obtained. PMID- 21694874 TI - Successful treatment of a neonate with persistent vancomycin-resistant enterococcal bacteremia with a daptomycin-containing regimen. AB - Infections caused by vancomycin-resistant enterococci (VRE) may be difficult to treat because of the limited armamentarium of antimicrobial agents. The difficulty is compounded in pediatric patients in general and neonates in particular because many of the newer antimicrobials have not been studied or approved for children. We report a 3-week-old infant who developed enterococcal bacteremia on post-operative day 10 after a surgical palliation for complex congenital heart disease that was complicated by acute renal failure. Despite removal of vascular catheters and antimicrobial regimens that included linezolid, quinupristin/dalfopristin, ampicillin/sulbactam, rifampin, and gentamicin, bacteremia persisted. It was not cleared until daptomycin (in combination with doxycycline) was started. This is the first case of successful treatment of probable endocarditis due to VRE in a neonate using a daptomycin-containing regimen. PMID- 21694875 TI - Pilonidal sinus of the penis. AB - Pilonidal sinus is a well recognised chronic inflammatory condition which commonly affects the natal cleft and finger web space. Pilonidal sinus of the penis is a rare clinical entity; few cases have been reported previously. The treatment strategy is almost the same as treating any pilonidal sinus and involves total excision of the sinus. Our diagnosis was established on the histopathological findings rather than a clinical-based diagnosis, Follow-up is advisable since the recurrence rate is high. Our case report is one of few cases reported on pilonidal sinus all over the world. Our patient had total excision of the sinus with complete recovery. PMID- 21694876 TI - Procalcitonin implication in renal cell apoptosis induced by acute pyelonephritis in children. AB - The aim of this biomedical trial was to clarify the physiological role of procalcitonin (PCT) in renal parenchyma apoptosis and fibrosis caused by acute childhood pyelonephritis. This prospective study enrolled 183 children. All children were treated with bi-therapy according to the French consensus on acute pyelonephritis treatment dated November 16, 1990: intra-vascular administration of ceftriaxone 50 mg/kg/day and netromicine 7 mg/kg/day during the first 48 hours, followed by specific antibiotherapy suited to antibiogram. On admission, PCT, C-reactive protein, and phospholipase A2 were quantified in serum. Scintigraphy monitoring with (99m)Tc-DMSA was performed on day 4 and 9 months later, in the presence of persistent abnormalities. On day 4, 78% presented renal parenchyma alterations and 30% renal fibrosis 9 months after admission. Paradoxically, PCT level was significantly lower in the presence of renal fibrosis due to cell apoptosis (4.19 vs 7.59 MUgL(-1)). A significant increase in PCT indicated favorable progress (recovery 7.55 vs aggravation 3.34) and no difference between recovery and improvement. This result suggests the protective effect of PCT against apoptosis by nitric oxide down-regulation. PMID- 21694877 TI - New simple decontamination method improves microscopic detection and culture of mycobacteria in clinical practice. AB - This study was carried out at Dr. Cetrangolo Hospital, Buenos Aires, Argentina. The objective was to compare two digestion-decontamination procedures: the N acetyl-L-cysteine-sodium citrate-NaOH (NALC-NaOH) and a combination of 7% NaCl plus NaOH, the hypertonic saline-sodium hydroxide (HS-SH) method, in detection and recovery of mycobacteria. Microscopy detection rates before and after concentration of specimens by both methods, were also compared. The study had two phases. Phase I: comparison of the gold standard NALC-NaOH and HS-SH on paired samples involving respiratory clinical specimens by means of receiver operating characteristic curve analysis. Phase II: blinded, randomized trial to assess the performance of HS-SH versus NALC-NaOH in clinical practice. Phase I: Positive microscopy rate was significantly increased in around 2.2% after concentration in comparison to that of specimens without concentration. The calculated sensitivity values for microscopy detection increased between 15.2% (HS-SH: 73.5%) to 16.7% (NALC-NaOH: 75.0%) over those without concentration (58.3%). Phase II: similar diagnostic rates by microscopy and cultures were obtained by either HS-SH or NALC NaOH. The clinical performances were also very similar. These results and the low cost of the HS-SH procedure indicate the possibility of its implementation in clinical laboratories with high burden of tuberculosis cases and low resources. PMID- 21694879 TI - Characterization and antibiotic susceptibility of Listeria monocytogenes isolated from poultry and red meat in Morocco. AB - This study was carried out on 426 samples of raw meats collected from butcheries and supermarkets in Casablanca, Morocco. The samples were examined for the occurrence of Listeria species. Strains of Listeria monocytogenes were characterized by several biochemical tests and confirmed by polymerase chain reaction (PCR). beta-hemolytic cultures and nonhemolytic isolates were tested for biochemical properties with the Listeria API test. Among the 43 Listeria species isolates; we identified 10 strains for L. monocytogenes (23.3%), 31 strains for L. innocua (72.1%) and 2 strains for L. welshimeri (4.6%). Strains of L. monocytogenes were separated by multiplex PCR; two serogroups IIb and IVb were thus differentiated. Antibiotic susceptibility of L. monocytogenes to 21 antibiotics was determined by the disk diffusion method. All isolates were susceptible to a wide range of the tested antibiotics with the exception of nalidixic acid, colistine and cephalosporins second and third generation for which they were all resistant. PMID- 21694878 TI - Current and novel antibiotics against resistant Gram-positive bacteria. AB - The challenge posed by resistance among Gram-positive bacteria, epitomized by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and vancomycin-intermediate and -resistant S. aureus (VISA and VRSA) is being met by a new generation of antimicrobials. This review focuses on the new beta-lactams with activity against MRSA (ceftobiprole and ceftaroline) and on the new glycopeptides (oritavancin, dalbavancin, and telavancin). It will also consider the role of vancomycin in an era of existing alternatives such as linezolid, daptomycin and tigecycline. Finally, compounds in early development are described, such as iclaprim, friulimicin, and retapamulin, among others. PMID- 21694880 TI - Expression of the MexXY-OprM efflux system in Pseudomonas aeruginosa with discordant cefepime/ceftazidime susceptibility profiles. AB - While MIC distributions and percent susceptibility for cefepime and ceftazidime are generally similar among Pseudomonas aeruginosa, we noted an increasing discordance in susceptibility favoring ceftazidime at our hospital. Quantitative reverse transcriptase-polymerase chain reaction was utilized to explore overexpression of the MexXY-OprM efflux as the mechanism for this phenotype profile. Thirteen of 15 (87%) randomly selected isolates had mexY gene expression levels of 5.8-40.8-fold relative to the wild-type reference strain. While mexY overexpression was noted in the majority of isolates, other resistance mechanisms appear to contribute to the observed phenotypic profile of the Pseudomonas aeruginosa studied. Clinicians must understand not only the magnitude of difference in the MIC profiles between agents, but also the mechanism(s) responsible for these observations if strategies (ie, pharmacodynamic dosing) are to be designed to optimize patient care outcomes in the face of increasing resistance. PMID- 21694881 TI - High prevalence of multidrug-resistant MRSA in a tertiary care hospital of northern India. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an important nosocomial and community pathogen. The objectives of this study were to estimate the prevalence of multidrug-resistant MRSA strains in clinical specimens and to investigate the sensitivity pattern of these strains against various antibiotics used for treating hospitalized and out patients. Strains were identified using standard procedures, and their sensitivity pattern was investigated using such techniques as disc diffusion, minimum inhibitory concentration (MIC), and the mecA gene PCR. Among 783 isolates of S. aureus, 301 (38.44%) were methicillin-resistant, of which 217 (72.1%) were found to be multidrug-resistant. Almost all MRSA strains were resistant to penicillin, 95.68% were resistant to cotrimoxazole, 92.36% were resistant to chloramphenicol, 90.7% were resistant to norfloxacin, 76.1% were resistant to tetracycline, and 75.75% were resistant to ciprofloxacin. Vancomycin was the most effective drug, with only 0.33% of MRSA strains being resistant to it. It is concluded that antibiotics other than vancomycin can be used as anti MRSA agents after a sensitivity test so as to preclude the emergence of resistance to it and that prevailing problems in chemotherapy will escalate unless indiscriminate and irrational usage of antibiotics is checked. PMID- 21694882 TI - Micafungin in the treatment of invasive candidiasis and invasive aspergillosis. AB - Micafungin is an echinocandin antifungal agent available for clinical use in Japan, Europe, and the United States. Through inhibition of beta-1,3-glucan production, an essential component of the fungal cell wall, micafungin exhibits potent antifungal activity against key pathogenic fungi, including Candida and Aspergillus species, while contributing minimal toxicity to mammalian cells. This activity is maintained against polyene and azole-resistant isolates. Pharmacokinetic and pharmacodynamic studies have demonstrated linear kinetics both in adults and children with concentration-dependent activity observed both in vitro and in vivo. Dosage escalation studies have also demonstrated that doses much higher than those currently recommended may be administered without serious adverse effects. Clinically, micafungin has been shown to be efficacious for the treatment of invasive candidiasis and invasive aspergillosis. Furthermore, the clinical effectiveness of micafungin against these infections occurs without the drug interactions that occur with the azoles and the nephrotoxicity observed with amphotericin B formulations. This review will focus on the pharmacology, clinical microbiology, mechanisms of resistance, safety, and clinical efficacy of micafungin in the treatment of invasive candidiasis and invasive aspergillosis. PMID- 21694883 TI - The determinants of the antibiotic resistance process. AB - BACKGROUND: The use of antibiotic drugs triggers a complex interaction involving many biological, sociological, and psychological determinants. Resistance to antibiotics is a serious worldwide problem which is increasing and has implications for morbidity, mortality, and health care both in hospitals and in the community. OBJECTIVES: To analyze current research on the determinants of antibiotic resistance and comprehensively review the main factors in the process of resistance in order to aid our understanding and assessment of this problem. METHODS: We conducted a MedLine search using the key words "determinants", "antibiotic", and "antibiotic resistance" to identify publications between 1995 and 2007 on the determinants of antibiotic resistance. Publications that did not address the determinants of antibiotic resistance were excluded. RESULTS: The process and determinants of antibiotic resistance are described, beginning with the development of antibiotics, resistance and the mechanisms of resistance, sociocultural determinants of resistance, the consequences of antibiotic resistance, and alternative measures proposed to combat antibiotic resistance. CONCLUSIONS: Analysis of the published literature identified the main determinants of antibiotic resistance as irrational use of antibiotics in humans and animal species, insufficient patient education when antibiotics are prescribed, lack of guidelines for treatment and control of infections, lack of scientific information for physicians on the rational use of antibiotics, and lack of official government policy on the rational use of antibiotics in public and private hospitals. PMID- 21694884 TI - New approaches in the management of chronic hepatitis B: role of tenofovir. AB - In the field of HIV management, tenofovir disoproxil fumarate (TDF) plays a pivotal role and has been demonstrated to be a safe and well-tolerated antiviral agent. Recent data showed the efficacy of TDF in the treatment of chronically hepatitis B virus (HBV)-infected patients. TDF was superior to adefovir dipivoxil (ADV) in both nucleos(t)ide-naive HBeAg-positive and HBeAg-negative HBV patients, and appeared to be one of the most potent antiviral agents so far. In addition, several reports showed that TDF was also effective in the nucleos(t)ide experienced population, although conflicting results have been presented concerning patients with genotypic resistance to ADV. TDF seems to have a good resistance profile as well. The rtA194T mutation in association with lamivudine resistance may confer resistance to TDF, although both in vivo and in vitro studies regarding this mutation demonstrate conflicting results. As treatment with TDF may be associated with nephrotoxicity, all TDF-treated patients should be monitored for renal function at baseline and periodically thereafter. While the relative roles of interferon vs nucleos(t)ide analogues (NA) as initial anti HBV therapy remains unclear, TDF will probably become one of the key factors in HBV management both as first-choice NA for nucleos(t)ide-naive patients and as rescue therapy for nucleos(t)ide-experienced patients. PMID- 21694885 TI - Evidence based approach to the treatment of community-associated methicillin resistant Staphylococcus aureus. AB - Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have increased dramatically over the last two decades. The types of infections can range from complicated skin and skin structure infections (cSSSI) to pneumonia and endocarditis. Oral antimicrobial therapy, such as trimethoprim sulfamethoxazole, clindamycin, long-acting tetracyclines, or linezolid may provide enhanced benefit to those with uncomplicated cutaneous lesions when used in conjunction with incision and drainage in an outpatient setting. However, resistance, susceptibilities, patient-specific circumstances, and adverse effects can impact a healthcare professional's choice of antibiotics. In patients with complicated infections requiring hospitalization or parenteral treatment, vancomycin remains the drug of choice, even though increased resistance and decreased efficacy have crept into clinical practice. Linezolid, quinupristin/dalfopristin, daptomycin, and tigecycline are alternative intravenous agents for the treatment of CA-MRSA. Investigational agents such as dalbavancin, telavancin, oritivancin, iclaprim, ceftobiprole, ceftaroline, and others may expand our therapeutic armamentarium for the treatment of infections caused by CA-MRSA in the future. PMID- 21694886 TI - Doripenem in hospital infections: a focus on nosocomial pneumonia, complicated intra-abdominal infections, and complicated urinary tract infections. AB - Doripenem is the latest carbapenem on the market to date. Although not an antibiotic in a new class, it offers a glimmer of hope in combating serious infections secondary to multidrug-resistant Gram-negative bacteria when we have not seen a new class of antibacterial, particularly for Gram-negative bacteria, for more than 10 years. In vitro, doripenem exhibits a broad spectrum of activity against Gram-positive and Gram-negative bacteria, including extended-spectrum beta-lactamase (ESBL) and Amp-C beta-lactamase producing Enterobacteriaceae and anaerobes. Doripenem also exhibits better in vitro activity against Pseudomonas aeruginosa compared to other anti-pseudomonal carbapenems. It combines the desirable activities of both imipenem and meropenem. It has similar activity to imipenem against Gram-positive pathogens and has the antimicrobial spectrum of meropenem against Gram-negative organisms. Several randomized clinical trials have demonstrated that doripenem is non-inferior to meropenem, imipenem, piperacillin/tazobactam, or levofloxacin in its efficacy and safety profile in treating a wide range of serious bacterial infections including intra-abdominal infection, complicated urinary tract infection, and nosocomial pneumonia. Due to its wide spectrum of activity and good safety profile it is susceptible to misuse leading to increasing rates of resistance. Judicious use should be considered when using doripenem as a first-line agent or drug of choice for serious infections. Doripenem is a well-tolerated drug with common adverse effects including headache, nausea and diarrhea. Caution should be used in patients with hypersensitivity to carbapenems and adverse reactions to beta-lactam agents. Dosage adjustment is needed for patients with renal impairment. Doripenem has demonstrated economic and clinical benefits. It has been shown to reduce hospital length of stay and duration of mechanical ventilation for intensive care unit (ICU) patients. Therefore, doripenem is a welcome addition to our limited armamentarium of antibiotics available to treat serious bacterial infections in hospitalized patients. PMID- 21694887 TI - Anidulafungin and its role in candida infections. AB - Candida infections continue to play a significant role not only in critically ill and immunocompromised patients but also in non-compromised patients. The incidence of systemic fungal infections in the United States has been on the rise for the past 30 years. Anidulafungin and all echinocandins inhibit glucan synthase thus inhibiting the formation of 1,3-beta-D-glucan which is an essential component of the fungal cell wall. The decrease in 1,3-beta-D-glucan results in the osmotic lysis of the cell, resulting in fungicidal activity against candida. Anidulafungin is active against most species of candida and resistance to it is very rare. Two potential mechanisms conferring reduced susceptibility to the echinocandins are efflux and target alteration. The efflux pump associated with fluconazole resistance in Candida albicans can confer higher minimum inhibitory concentrations to caspofungin. The second mechanism of resistance is via mutations in the genes which code for 1,3 beta-D-glucan synthase, specifically FKS1. Because of its spectrum of activity, fungicidal nature, and tolerability it is an attractive first-line therapeutic choice for treating candidemia in both non-neutropenic and neutropenic patients. Because it is available only parenterally its role in treating mucocutaneous candidiasis is primarily in patients unable to take oral therapy. PMID- 21694888 TI - Respiratory failure caused by intrathoracic amoebiasis. AB - A 41-year-old male was admitted to the hospital with symptoms of diarrhea, fever and rapidly progressive respiratory distress. A chest radiograph and computed tomography (CT) of the chest and the abdomen showed a large amount of right pleural effusion and a large liver abscess. The patient was thus diagnosed to have amoebic colitis, amoebic liver abscess and amoebic empyema complicated with an HIV infection. The patient demonstrated agranulocytosis caused by the administration of trimethoprim-sulfamethoxazole. However, the administration of granulocyte colony-stimulating factor made it possible for the patient to successfully recover from agranulocytosis, and he thereafter demonstrated a good clinical course. PMID- 21694889 TI - Emerging agents to combat complicated and resistant infections: focus on ceftobiprole. AB - Antimicrobial resistance is a global concern. Over the past few years, considerable efforts and resources have been expended to detect, monitor, and understand at the basic level the many different facets of emerging and increasing resistance. Development of new antimicrobial agents has been matched by the development of new mechanisms of resistance by bacteria. Current antibiotics act at a variety of sites within the target bacteria, including the cross-linking enzymes in the cell wall, various ribosomal enzymes, nucleic acid polymerases, and folate synthesis. Ceftobiprole is a novel parenteral cephalosporin with high affinity for most penicillin-binding proteins, including the mecA product penicillin-binding protein 2a, rendering it active against methicillin-resistant staphylococci. Its in vitro activity against staphylococci and multiresistant pneumococci, combined with its Gram-negative spectrum comparable to that of other extended-spectrum cephalosporins, its stability against a wide range of beta-lactamases, and its pharmacokinetic and safety profiles make ceftobiprole an attractive and well tolerated new antimicrobial agent. The US Food and Drug Administration granted ceftobiprole medocaril fast track status in 2003 for the treatment of complicated skin infections and skin structure infections due to methicillin-resistant staphylococci, and subsequently extended this to treatment of hospital-acquired pneumonia, including ventilator associated pneumonia due to suspected or proven methicillin-resistant Staphylococcus aureus. PMID- 21694890 TI - Raltegravir in combination with other antiretroviral agents for the treatment of HIV infection. AB - Raltegravir, an inhibitor of the HIV-1 integrase enzyme, is the first available agent in a new class of antiretroviral drugs. Raltegravir has been studied extensively in clinical trials, and has been well tolerated and highly effective in both treatment-naive and -experienced patients. Resistance to raltegravir is unusual given its recent availability, but resistance with identified viral mutation pathways in the integrase gene in patients receiving the drug does occur. PMID- 21694891 TI - Prevention strategies for antimicrobial resistance: a systematic review of the literature. AB - Antibiotics offer great benefits by reducing the duration and severity of illnesses and aiding in infection transmission control. With this being said, the inexorable process of antimicrobial drug resistance is to some degree unavoidable. Although drug resistance will likely persist and is to be expected, the overall level can be dramatically decreased with increased attention to antibiotic overuse and the pharmacokinetic and pharmacodynamic properties of different drug formulations, and the use of proper hygiene and protective barriers. Implementation of such practices as microbial surveillance and prophylaxis has been shown to result in decreased hospital length of stay, health care costs and mortality due to drug-resistant infections. This review will summarize current progress in preventative techniques aimed at reducing the incidence of infection by antimicrobial-resistant bacteria and the emergence and spread of antimicrobial-resistant strains. By employing a variety of prevention strategies, including proper personal hygiene, prescreening for carrier status before hospital admission, disinfection of hospital rooms, and careful monitoring of antimicrobial prescribing, marked progress can be achieved in the control of drug-resistant pathogens, which can translate into more effective antimicrobial therapy. PMID- 21694892 TI - Drug resistance in community-acquired respiratory tract infections: role for an emerging antibacterial. AB - The nasopharynx is the ecological niche where evolution towards resistance occurs in respiratory tract isolates. Dynamics of different bacterial populations in antibiotic-free multibacterial niches are the baseline that antibiotic treatments can alter by shifting the competitive balance in favor of resistant populations. For this reason, antibiotic resistance is increasingly being considered to be an ecological problem. Traditionally, resistance has implied the need for development of new antibiotics for which basic efficacy and safety data are required prior to licensing. Antibiotic development is mainly focused on demonstrating clinical efficacy and setting susceptibility breakpoints for efficacy prediction. However, additional information on pharmacodynamic data predicting absence of selection of resistance and of resistant subpopulations, and specific surveillance on resistance to core antibiotics (to detect emerging resistances and its link with antibiotic consumption in the community) are valuable data in defining the role of a new antibiotic, not only from the perspective of its therapeutic potential but also from the ecologic perspective (countering resistances to core antibiotics in the community). The documented information on cefditoren gleaned from published studies in recent years is an example of the role for an emerging oral antibacterial facing current antibiotic resistance in community-acquired respiratory tract infections. PMID- 21694893 TI - Role of posaconazole in the treatment of oropharyngeal candidiasis. AB - Posaconazole is the newest azole antifungal approved by the US Food and Drug Administration, and possesses a broad spectrum of activity against numerous yeasts and filamentous fungi. It is available as an oral suspension and is generally well tolerated by patients, but gastrointestinal absorption is sometimes inadequate and remains a clinical concern in treating deep-seated infections. It is used routinely and effectively for the prophylaxis of invasive fungal infections in immunosuppressed hosts and is an effective treatment of oropharyngeal candidiasis, including azole-resistant disease. PMID- 21694894 TI - Long-term epidemiology of bacterial susceptibility profiles in adults suffering from febrile neutropenia with hematologic malignancy after antibiotic change. AB - OBJECTIVE: The aim of this study was to investigate the epidemiology and antibiotic susceptibility profiles of isolated bacterial organisms in relation to empiric treatment of neutropenic fever over a 15-year period. METHODS: All patients with or at risk for febrile neutropenia and treated in the hematology ward of the Antwerp University Hospital during 1994-2008 were prospectively included. Skin, blood, and urine cultures were taken. Oral quinolone prophylaxis was started in patients with neutropenia without fever. Empiric starting therapy consisted of amikacin in combination with cefepime. RESULTS: A total of 3624 bacteria were isolated. The most common pathogens were coagulase-negative Staphylococci (46%), followed by Escherichia coli (25%), Enterobacteriaceae (15.6%), Staphylococcus aureus (7.2%), and Pseudomonas aeruginosa (3.8%). The balance between Gram-positive and Gram-negative bacteria remained stable, with a majority of Gram-positive bacteria. A shift from oxacillin-sensitive to oxacillin resistant coagulase-negative Staphylococci was observed. Regarding susceptibility patterns, no vancomycin resistance was detected in coagulase-negative Staphylococci or in S. aureus. The E. coli susceptibility rates remained stable. However, 66% of bloodstream infections were ciprofloxacin-resistant. A reduced susceptibility of P. aeruginosa strains to meropenem was noticed. CONCLUSIONS: Improvement in antibiotic susceptibility of inducible Enterobacteriaceae following a switch of empiric antibiotic therapy was maintained 15 years after starting the latter treatment. Further improvement in antibiotic susceptibility of these bacteria to ceftazidime was observed, but continuous vigilance is warranted. PMID- 21694895 TI - The use of anti-tuberculosis therapy for latent TB infection. AB - Tuberculosis infection is of global public health significance, with millions of incident cases each year. Many cases, particularly in low-prevalence settings, result from the reactivation of latent tuberculosis infection (LTBI); potentially acquired years prior to active disease. Up to one-third of the world's population has been infected with LTBI, and so may be at risk for future active TB disease. A variety of antituberculosis medications and treatment regimens have now been evaluated in the management of LTBI, with the aim of eradicating tuberculosis bacilli and reducing the likelihood of subsequent reactivation disease. This article reviews LTBI therapies and their use in clinical contexts, and considers future directions for individual and population-based strategies in LTBI management. PMID- 21694897 TI - Acquired resistance of malarial parasites against artemisinin-based drugs: social and economic impacts. AB - Malaria, a disease of poverty and high morbidity and mortality in the tropical world, has led to a worldwide search for control measures. To that end, good antimalarial chemotherapies have been difficult to find in the global market and those that seem to be most effective are rapidly becoming ineffective due to the emergence and spread of drug resistance. Artemisinin, a very effective yet expensive antimalarial, has quickly become the recommended drug of choice when all other possibilities fail. However, for all its promise as the next great antimalarial, the outlook is bleak. Resistance is developing to artemisinin while another effective antimalarial is not in sight. Malaria endemic areas which are mostly in developing countries must deal with the multifaceted process of changing and implementing new national malaria treatment guidelines. This requires complex interactions between several sectors of the affected society which in some cases take place within the context of political instability. Moreover, the cost associated with preventing and containing the spread of antimalarial resistance is detrimental to economic progress. This review addresses the impact of artemisinin resistance on the socioeconomic structure of malaria endemic countries. PMID- 21694896 TI - Methicillin-resistant Staphylococcus aureus in HIV-infected patients. AB - Concordant with the emergence of methicillin-resistant Staphylococcus aureus (MRSA) in the community setting, colonization and infections with this pathogen have become a prevalent problem among the human immunodeficiency virus (HIV) positive population. A variety of different host- and, possibly, pathogen-related factors may play a role in explaining the increased prevalence and incidence observed. In this article, we review pathophysiology, epidemiology, clinical manifestations, and treatment of MRSA in the HIV-infected population. PMID- 21694898 TI - Daptomycin: a novel lipopeptide antibiotic against Gram-positive pathogens. AB - The aim of this review is to summarize the historical background of drug resistance of Gram-positive pathogens as well as to describe in detail the novel lipopeptide antibiotic daptomycin. Pharmacological and pharmacokinetic aspects are reviewed and the current clinical use of daptomycin is presented. Daptomycin seems to be a reliable drug in the treatment of complicated skin and skin structure infections, infective right-sided endocarditis, and bacteremia caused by Gram-positive agents. Its unique mechanism of action and its low resistance profile, together with its rapid bactericidal action make it a favorable alternative to vancomycin in multi-drug resistant cocci. The role of daptomycin in the treatment of prosthetic material infections, osteomyelitis, and urogenital infections needs to be evaluated in randomized clinical trials. PMID- 21694899 TI - Extended use of raltegravir in the treatment of HIV-1 infection: optimizing therapy. AB - Raltegravir is the first licensed compound in 2007 of the new integrase inhibitor drug class. At the dose of 400 mg twice daily, raltegravir showed a potent antiviral action in antiretroviral-naive patients when associated with tenofovir and emtricitabine. Raltegravir was also found to be highly active in antiretroviral-experienced patients with virological failure and displaying multiresistant virus, as shown with the BENCHMRK and ANRS 139 TRIO trials. Finally, the use of raltegravir was assessed in the context of a switch strategy in antiretroviral-experienced patients with virological success [human immunodeficiency virus type 1 (HIV-1) RNA below detection limit], highlighting the following mandatory criteria in this strategy: the nucleoside reverse transcriptase inhibitors associated with raltegravir have to be fully active. In the different studies, raltegravir had a favorable safety and tolerability profile. In the clinical situation a switch in virologically suppressed patients receiving a protease inhibitor, an improvement of the lipid profile was observed. Overall, when analyzing the Phase II and III trials together, only a few patients on raltegravir discontinued for adverse events. The development of resistance to raltegravir mainly involved three resistance mutations in integrase gene: Q148H/K/R, N155H, and Y143C/H/R. In conclusion, raltegravir improved the clinical management of HIV-1 infection both in antiretroviral-naive and in antiretroviral experienced patients. PMID- 21694900 TI - Multidrug and extensively drug-resistant tuberculosis from a general practice perspective. AB - Despite intensive efforts to eradicate the disease, tuberculosis continues to be a major threat to Indian society, with an estimated prevalence of 3.45 million cases in 2006. Emergence of multidrug-resistant tuberculosis has complicated eradication attempts in recent years. Incomplete and/inadequate treatment are the main causes for development of drug resistance. Directly observed therapy, short course (DOTS) is the World Health Organization (WHO) strategy for worldwide eradication of tuberculosis, and our country achieved 100% coverage for DOTS through the Revised National Tuberculosis Control Program in 2006. For patients with multidrug-resistant tuberculosis, the WHO recommends a DOTS-Plus treatment strategy. Early detection and prompt treatment of multidrug-resistant tuberculosis is crucial to avoid spread of the disease and also because of the chances of development of potentially incurable extensively drug-resistant tuberculosis in these cases. This review discusses the epidemiologic, diagnostic, and therapeutic aspects of multidrug-resistant tuberculosis, and also outlines the role of primary care doctors in the management of this dangerous disease. PMID- 21694901 TI - Clinical perspective on aztreonam lysine for inhalation in patients with cystic fibrosis. AB - Progressive obstructive lung disease is a characteristic component of cystic fibrosis (CF). It is the pulmonary manifestations, including obstruction and endobronchial infection, which directly contribute to the premature mortality of patients affected with CF. Due to the devastating effects on the pulmonary system, interest abounds in ways to improve antimicrobial delivery to the lungs and to impact clinical patient outcomes positively, whilst minimizing systemic toxicities. Recently, aztreonam lysine for inhalation solution, a new monobactam formulation, was approved by the US Food and Drug Administration for use in a subgroup of CF patients with Pseudomonas aeruginosa to improve respiratory symptoms. The purpose of this review is to present a summary of relevant pharmacologic, microbiologic, and clinical data related to the use of aztreonam lysine for inhalation in patients with CF. PMID- 21694902 TI - New strategies for the treatment of hepatitis C virus infection and implications of resistance to new direct-acting antiviral agents. AB - Persistent hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma and the major indication for liver transplantation in adults. Current standard of care treatment (SOC) with pegylated-interferon-alpha 2 and ribavirin (RBV) has a limited efficacy and is associated with significant side effects frequently associated with poor compliance or treatment discontinuation, requiring specialized and frequent monitoring. To overcome the limited efficacy of SOC, more than 50 direct-acting antiviral agents (DAA) designed to target viral-encoded proteins essential in the HCV life cycle are currently under development. The rapid selection of resistant mutants associated with the quasispecies nature of HCV with high mutation and replication rates is one of the main challenges for the new HCV therapies. Predictive host and viral factors together with combination of DAAs with or without IFN and/or RBV need to be accurately evaluated to design the most effective individualized treatment strategy within the shortest time interval and with minimum side effects. PMID- 21694903 TI - Current strategies for the prevention and management of central line-associated bloodstream infections. AB - Central venous catheters are an invaluable tool for diagnostic and therapeutic purposes in today's medicine, but their use can be complicated by bloodstream infections (BSIs). While evidence-based preventive measures are disseminated by infection control associations, the optimal management of established central line-associated BSIs has been summarized in infectious diseases guidelines. We prepared an overview of the state-of-the-art of prevention and management of central line-associated BSIs and included topics such as the role of antibiotic coated catheters, the role of catheter removal in the management, and a review of currently used antibiotic compounds and the duration of treatment. PMID- 21694904 TI - Lyme disease: the next decade. AB - Although Lyme disease remains a controversial illness, recent events have created an unprecedented opportunity to make progress against this serious tick-borne infection. Evidence presented during the legally mandated review of the restrictive Lyme guidelines of the Infectious Diseases Society of America (IDSA) has confirmed the potential for persistent infection with the Lyme spirochete, Borrelia burgdorferi, as well as the complicating role of tick-borne coinfections such as Babesia, Anaplasma, Ehrlichia, and Bartonella species associated with failure of short-course antibiotic therapy. Furthermore, renewed interest in the role of cell wall-deficient (CWD) forms in chronic bacterial infection and progress in understanding the molecular mechanisms of biofilms has focused attention on these processes in chronic Lyme disease. Recognition of the importance of CWD forms and biofilms in persistent B. burgdorferi infection should stimulate pharmaceutical research into new antimicrobial agents that target these mechanisms of chronic infection with the Lyme spirochete. Concurrent clinical implementation of proteomic screening offers a chance to correct significant deficiencies in Lyme testing. Advances in these areas have the potential to revolutionize the diagnosis and treatment of Lyme disease in the coming decade. PMID- 21694905 TI - Current treatment of choice for chronic hepatitis C infection. AB - More than three million Americans have chronic hepatitis C infection, and the disease remains one of the most common blood-borne infections in the US. Treatment is focused on the chronic form of the disease, because the acute one tends to be self-limiting. In this article, we review the recent literature regarding the most effective therapy against hepatitis C infection, to confirm the current treatment of choice for the disease. We conclude that combination therapy with pegylated interferon and ribavirin remains the initial treatment of choice. New research focusing on adjuvant therapies, such as protease and polymerase inhibitors, has yielded early data that appear to be promising. PMID- 21694906 TI - Management of Chlamydia trachomatis genital tract infection: screening and treatment challenges. AB - Chlamydia trachomatis is a prevalent sexually transmitted infection that can lead to serious reproductive morbidity. Management and control of C. trachomatis is a challenge, largely due to its asymptomatic nature and our incomplete understanding of its natural history. Although chlamydia screening programs have been implemented worldwide, several countries have observed increasing rates of reported chlamydia cases. We reviewed the literature relating to the long-term complications of C. trachomatis, as well as screening strategies, treatment, and prevention strategies for reducing chlamydia in the population. Articles from 1950-2010 were identified through a Medline search using the keyword "Chlamydia trachomatis" combined with "screening", "pelvic inflammatory disease", "endometritis", "salpingitis", "infertility", "ectopic pregnancy", "urethritis", "epididymitis", "proctitis", "prostatitis", "reinfection", "cost-effectiveness", "treatment", "vaccines", or "prevention". Progression of C. trachomatis varies, and recurrent infections are common. Currently, there is limited evidence on the effectiveness of chlamydia screening. Higher quality studies are needed to determine the efficacy of more frequent screening, on a broader range of sequelae, including infertility and ectopic pregnancy, in addition to pelvic inflammatory disease. Studies should focus on delineating the natural history of recurrent infections, paying particular attention to treatment failures. Furthermore, alternatives to screening, such as vaccines, should continue to be explored. PMID- 21694907 TI - Management of refractory Pseudomonas aeruginosa infection in cystic fibrosis. AB - Cystic fibrosis (CF) is the most common life-limiting inherited disease in Caucasian populations. The main cause of death in CF patients is respiratory failure resulting from chronic pulmonary infection. Pseudomonas aeruginosa is the most prevalent organism in the airway colonization of CF patients, and its persistence in the airways has been related to greater morbidity with a more rapid deterioration in lung function. P. aeruginosa has enormous genetic and metabolic flexibility that allows it to adapt and persist within the airways of CF patients, and it has the ability to easily acquire antimicrobial resistance. For these reasons, the management of infections and chronic colonization by P. aeruginosa remains a challenge for physicians. This article reviews the current and future antibacterial chemotherapy options for respiratory pseudomonal infection in CF patients. PMID- 21694908 TI - Update on the optimal use of voriconazole for invasive fungal infections. AB - Voriconazole is an extended-spectrum triazole with excellent bioavailability that has now become the treatment of choice for aspergillosis. It has a unique side effect profile compared with other azoles, as well as a number of clinically important drug-drug interactions. These factors, along with a correlation between increased serum levels and improved outcomes, have prompted an interest in therapeutic drug monitoring of this agent. The pharmacology and clinical outcomes data of voriconazole are presented in this review. PMID- 21694909 TI - Safety and efficacy of entecavir for the treatment of chronic hepatitis B. AB - Entecavir is a cyclopentyl deoxyguanosine analog that was approved for the treatment of the hepatitis B virus (HBV) in 2005. In Phase III trials, it showed potent HBV suppression with drops of 6- to 7-log copies/mL in HBV DNA at 1 year. In addition, rates of genotypic resistance in nucleos(t)ide-naive patients are low, reaching only 1.2% after 6 years. Safety and efficacy have been established in compensated cirrhosis and HIV-coinfected patients. Studies in decompensated cirrhosis also show efficacy. Because of potent viral suppression and a large genetic barrier to resistance, entecavir is now a first-line choice in most HBV treatment guidelines and has become an integral part of the HBV treatment armamentarium. PMID- 21694910 TI - Patterns of resistance development with integrase inhibitors in HIV. AB - Raltegravir, the only integrase (IN) inhibitor approved for use in HIV therapy, has recently been licensed. Raltegravir inhibits HIV-1 replication by blocking the IN strand transfer reaction. More than 30 mutations have been associated with resistance to raltegravir and other IN strand transfer inhibitors (INSTIs). The majority of the mutations are located in the vicinity of the IN active site within the catalytic core domain which is also the binding pocket for INSTIs. High-level resistance to INSTIs primarily involves three independent mutations at residues Q148, N155, and Y143. The mutations significantly affect replication capacity of the virus and are often accompanied by other mutations that either improve replication fitness and/or increase resistance to the inhibitors. The pattern of development of INSTI resistance mutations has been extensively studied in vitro and in vivo. This has been augmented by cell-based phenotypic studies and investigation of the mechanisms of resistance using biochemical assays. The recent elucidation of the structure of the prototype foamy virus IN, which is closely related to HIV-1, in complex with INSTIs has greatly enhanced our understanding of the evolution and mechanisms of IN drug resistance. PMID- 21694911 TI - Potential role of tigecycline in the treatment of community-acquired bacterial pneumonia. AB - Tigecycline is a member of the glycylcycline class of antimicrobials, which is structurally similar to the tetracycline class. It demonstrates potent in vitro activity against causative pathogens that are most frequently isolated in patients with community-acquired bacterial pneumonia (CABP), including (but not limited to) Streptococcus pneumoniae (both penicillin-sensitive and -resistant strains), Haemophilus influenzae and Moraxella catarrhalis (including beta lactamase-producing strains), Klebsiella pneumoniae, and 'atypical organisms' (namely Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila). Comparative randomized clinical trials to date performed in hospitalized patients receiving tigecycline 100 mg intravenous (IV) * 1 and then 50 mg IV twice daily thereafter have demonstrated efficacy and safety comparable to the comparator agent. Major adverse effects were primarily gastrointestinal in nature. Tigecycline represents a parenteral monotherapy option in hospitalized patients with CABP (especially in patients unable to receive respiratory fluoroquinolones). However, alternate and/or additional therapies should be considered in patients with more severe forms of CABP in light of recent data of increased mortality in patients receiving tigecycline for other types of severe infection. PMID- 21694913 TI - Hemipelvic osteomyelitis in a hemodialysis patient associated with methicillin resistant Staphylococcus aureus bacteremia. AB - Proper management of infected tunneled-cuffed catheters (TCC) is essential in order to avoid catastrophic consequences for the patient. Hematogenous dissemination of infection can result in serious secondary infections, including infective endocarditis, osteomyelitis, and epidural abscess. Pelvic osteomyelitis is an extremely rare condition in adults with no reported cases of infection localized to more than one pelvic bone at a time. We present a case of a hemodialysis patient who developed osteomyelitis of the entire right hemipelvis due to MRSA bacteremia after repeated attempts at TCC salvage. PMID- 21694912 TI - Telavancin, a new lipoglycopeptide antimicrobial, in complicated skin and soft tissue infections. AB - Telavancin, a novel lipoglycopeptide with rapid concentration-dependent bactericidal effects, is a semisynthetic derivative of the glycopeptide, vancomycin. Telavancin has a dual mechanism of action, ie, inhibition of peptidoglycan polymerization and disruption of the bacterial membrane. It has linear pharmacokinetics, rapid bactericidal killing, and broad spectrum activity against Gram positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus. Phase II and III clinical trials for complicated skin and skin structure infections have shown telavancin to have similar efficacy and tolerability to that of vancomycin and standard anti staphylococcal beta-lactams plus vancomycin. In Phase II trials, there was a significant difference in eradication of MRSA between groups, ie, telavancin therapy 92% and standard therapy (vancomycin, nafcillin, oxacillin, or cloxacillin) 68% (P < 0.05). In Phase III trials, among clinically evaluable patients who had MRSA isolated at baseline, the overall therapeutic response was higher in patients treated with telavancin than in patients treated with vancomycin (89.9% versus 84.7%; 95% CI -0.3, 10.5). Also, the efficacy of telavancin was not inferior to that of vancomycin for the treatment of complicated skin and skin structure infections in the clinical trials. PMID- 21694914 TI - Treatment of secondary hyperparathyroidism in kidney disease: what we know and do not know about use of calcimimetics and vitamin D analogs. AB - There is a growing understanding of the pathophysiology of secondary hyperparathyroidism (SHPT) and a recent emergence of new agents for SHPT treatment in patients with advanced kidney disease. At the same time, appreciation that mineral metabolic derangements promote vascular calcification and contribute to excess mortality, along with recognition of potentially important "non-classical" actions of vitamin D, have prompted the nephrology community to reexamine the use of various SHPT treatments, such as activated vitamin D sterols, phosphate binders, and calcimimetics. In this review, the evidence for treatment of SHPT with calcimimetics and vitamin D analogs is evaluated, with particular consideration given to recent clinical trials that have reported encouraging findings with cinacalcet use. Additionally, several controversies in the pathogenesis and treatment of SHPT are explored. The proposition that calcitriol deficiency is a true pathological state is challenged, the relative importance of the vitamin D receptor and the calcium sensing receptor in parathyroid gland function is summarized, and the potential relevance of non-classical actions of vitamin D for patients with advanced renal disease is examined. Taken collectively, the balance of evidence now supports a treatment paradigm in which calcimimetics are the most appropriate primary treatment for SHPT in the majority of end stage renal disease patients, but which nevertheless acknowledges an important role for modest doses of activated vitamin D sterols. PMID- 21694915 TI - Management of hyperphosphatemia in patients with end-stage renal disease: focus on lanthanum carbonate. AB - Elevated serum phosphate levels as a consequence of chronic kidney disease (CKD) contribute to the increased cardiovascular risk observed in dialysis patients. Protein restriction and dialysis fail to adequately prevent hyperphosphatemia, and in general treatment with oral phosphate binding agents is necessary in patients with advanced CKD. Phosphate plays a pivotal role in the development of vascular calcification, one of the factors contributing to increased cardiovascular risk in CKD patients. Treatment of hyperphosphatemia with standard calcium-based phosphate binders and vitamin D compounds can induce hypercalcemic episodes, increase the Ca * PO(4) product and thus add to the risk of ectopic mineralization. In this review, recent clinical as well as experimental data on lanthanum carbonate, a novel, non-calcium, non-resin phosphate binding agent are summarized. Although lanthanum is a metal cation no aluminium-like toxicity is observed since the bioavailability of lanthanum is extremely low and its metabolism differs from that of aluminium. Clinical studies now document the absence of toxic effects of lanthanum for up to 6 years of follow-up. The effects of lanthanum on bone, vasculature and brain are discussed and put in perspective with lanthanum pharmacokinetics. PMID- 21694916 TI - The use of everolimus in renal-transplant patients. AB - Despite advances in immunosuppressive therapy, long-term renal-transplantation outcomes have not significantly improved over the last decade. The nephrotoxicity of calcineurin inhibitors (CNIs) is an important cause of chronic allograft nephropathy (CAN), the major driver of long-term graft loss. Everolimus is a proliferation signal inhibitor with a mechanism of action that is distinct from CNIs. The efficacy and tolerability of everolimus in renal-transplant recipients have been established in a wide range of clinical trials. Importantly, synergism between everolimus and the CNI cyclosporine (CsA) permits CsA dose reduction, enabling nephrotoxicity to be minimized without compromising efficacy. Currently, everolimus is being investigated in regimens where reduced exposure CNIs are used from the initial post-transplant period to improve renal function and prevent CAN. By inhibiting the proliferation of smooth muscle cells, everolimus may itself delay the progression or development of CAN. Although everolimus is associated with specific side effects, these can generally be managed. By targeting the main causes of short- and long-term graft loss, everolimus has a key role to play in renal transplantation, which is being explored further in a number of ongoing Phase III-IV trials. PMID- 21694917 TI - Nephrotic presentation in hydatid cyst disease with predominant tubulointerstital disease. AB - Renal involvement, which can rarely occur in echinococcosis, more commonly manifests as hydatid cyst of the kidney. Scattered case reports of nephrotic syndrome secondary to hydatid cyst in the liver or lung have been reported for over two decades. The glomerular picture varied from minimal change lesion to mesangiocapillary glomerulonephritis. We report a case of predominantly tubulointerstitial nephritis with mesangioproliferative glomerulonephritis in a patient with hepatic hydatid cyst which responded to cyst resection alone. PMID- 21694918 TI - Online conductivity monitoring of dialysis adequacy versus Kt/V derived from urea reduction ratio: A prospective study from a Saudi center. AB - INTRODUCTION: Ad equate delivered dose of solute removal (as assessed by urea reduction and calculation of Kt/V) is an important determinant of clinical outcome in chronic hemodialysis (HD) patients. This requires both prescription of an adequate dose of HD and regular assessment that the delivered treatments are also adequate. Online conductivity monitoring using sodium flux as a surrogate for urea allows the repeated noninvasive measurement of Kt/V on each HD treatment. METHODS: We prospectively studied 17 (9 males, 8 females) established chronic HD patients over an eight-week period (408 treatments). A pre- and post dialyzer measurement of the conductivity is performed by two mutually independent temperature-compensated conductivity cells equipped with Fresenius 4008 S((r)) dialysis machines. Urea reduction was measured (once a week) by a single pool calculation using immediate post-treatment sampling. No changes were made to any of the dialysis prescriptions over the study period. Values of calculated Kt/V and simultaneously obtained online Kt/V were compared. RESULTS: There was a statistically significant difference between calculated Kt/V and online Kt/V over the study period. The mean calculated Kt/V was 1.37 +/- 0.09, and mean online Kt/V 1.02 +/- 0.15 (P = 0.000), calculated Kt/V >= 1.2 was achieved in all our patients while online Kt/V >= 1.2 was achieved in only 17.64 %. Yet there was moderate correlation between calculated Kt/V and online Kt/V (r(2) = 0.48). CONCLUSIONS: Online conductivity monitoring results underestimates dialysis efficiency compared to calculated Kt/V readings. This difference has to be considered when applying Kt/V to clinical practice. PMID- 21694919 TI - Incidence of thromboembolic stroke and of major bleeding in patients with atrial fibrillation and chronic kidney disease treated with and without warfarin. AB - The objective was to investigate the incidence of thromboembolic stroke in patients with chronic kidney disease (CKD) and atrial fibrillation (AF) treated with and without warfarin. We investigated the incidence of thromboembolic stroke and of major bleeding in 399 unselected patients with CKD and AF treated with warfarin to maintain an international normalized ratio (INR) between 2.0 and 3.0 (N = 232) and without warfarin (N = 167). Of the 399 patients, 93 (23%) were receiving hemodialysis, and 132 (33%) had an estimated glomerular filtration rate (GFR) of <15 mL/min/1.73 m(2) At the 31-month follow-up of patients treated with warfarin and 23-month follow-up of patients not treated with warfarin, thromboembolic stroke developed in 21 of 232 patients (9%) treated with warfarin and in 43 of 167 patients (26%) not treated with warfarin (P < 0.001). Major bleeding occurred in 32 of 232 patients (14%) treated with warfarin and in 15 of 167 patients (9%) not treated with warfarin (P not significant). Stepwise Cox regression analysis showed that significant independent predictors of thromboembolic stroke were use of warfarin (odds ratio, 0.28; P < 0.0001) and prior stroke or transient ischemic attack (odds ratio, 2.9; P < 0.05). In conclusion, this observational study showed that CKD patients with AF treated with warfarin to maintain an INR between 2.0 and 3.0 had a significant reduction in thromboembolic stroke and an insignificant increase in major bleeding. PMID- 21694920 TI - Manifestation of renal disease in obesity: pathophysiology of obesity-related dysfunction of the kidney. AB - Albuminuria in individuals whose body mass index exceeds 40 kg/m(2) is associated with the presence of large glomeruli, thickened basement membrane and epithelial cellular (podocyte) distortion. Obstructive sleep apnea magnifies glomerular injury as well, probably through a vasoconstrictive mechanism. Insulin resistance from excess fatty acids is exacerbated by decreased secretion of high molecular weight adiponectin from adipose cells in the obese state. Adiponectin potentiates insulin in its post-receptor signaling resulting in glucose oxidation in mitochondria. Recent studies of podocyte physiology have concentrated on the structural and functional requirements that prevent glomerular albumin leakage. The architecture of the podocyte involves nephrin and podocin, proteins that cooperate to keep slit pores between foot processes competent to retain albumin. Insulin and adiponectin are necessary for high-energy phosphate generation. When fatty acids bind to albumin, the toxicity to proximal renal tubules is magnified. Albumin and fatty acids are elevated in urine of individuals with obesity related nephrotic syndrome. Fatty acid accumulation and resistin inhibit insulin and adiponectin. Study of cytokines produced by adipose tissue (adiponectin and leptin) and macrophages (resistin) has led to a better understanding of the relationship between weight and hypertension. Leptin, is presumably secreted after food intake to inhibit the midbrain/hypothalamic appetite centers. Resistance to leptin results in excess signaling to hypothalamic sympathetics leading to hypertension. Demonstration of the existence of a cerebral receptor mutation provide evidence for a role in hypertension of a central nervous reflex arc in humans. Further understanding of obesity-related renal dysfunction has been accomplished recently using experimental models. Rapid weight loss following bariatric surgery may reverse renal pathology of obesity with restoration of normal blood pressure. PMID- 21694921 TI - Potential renovascular hypertension, space missions, and the role of magnesium. AB - Space flight (SF) and dust inhalation in habitats cause hypertension whereas in SF (alone) there is no consistent hypertension but reduced diurnal blood pressure (BP) variation instead. Current pharmaceutical subcutaneous delivery systems are inadequate and there is impairment in the absorption, metabolism, excretion, and deterioration of some pharmaceuticals. Data obtained from the National Aeronautics and Space Administration through the Freedom of Information Act shows that Irwin returned from his 12-day Apollo 15 mission in 1971 and was administered a bicycle stress test. With just three minutes of exercise, his BP was >275/125 mm Hg (heart rate of only 130 beats per minute). There was no acute renal insult. Irwin's apparent spontaneous remission is suggested to be related to the increase of a protective vasodilator, and his atrial natriuretic peptide (ANP) reduced with SF because of reduced plasma volume. With invariable malabsorption and loss of bone/muscle storage sites, there are significant (P < 0.0001) reductions of magnesium (Mg) required for ANP synthesis and release. Reductions of Mg and ANP can trigger pronounced angiotensin (200%), endothelin, and catecholamine elevations (clearly shown in recent years) and vicious cycles between the latter and Mg deficits. There is proteinuria, elevated creatinine, and reduced renal concentrating ability with the potential for progressive inflammatory and oxidative stress-induced renal disease and hypertension with vicious cycles. After SF, animals show myocardial endothelial injuries and increased vascular resistance of extremities in humans. Even without dust, hypertension might eventually develop from renovascular hypertension during very long missions. Without sufficient endothelial protection from pharmaceuticals, a comprehensive gene research program should begin now. PMID- 21694922 TI - Advances in the management of gout: critical appraisal of febuxostat in the control of hyperuricemia. AB - Gout recently passed rheumatoid arthritis to become the most common inflammatory arthritis in the United States (US). However, epidemiologic studies indicate that the quality of gout management is suboptimal owing to both patient and physician issues. Only three options for urate-lowering therapy are currently available in the US: allopurinol, probenecid, and recently, febuxostat. Probenecid is generally safe except for the occurrence of urolithiasis, but is only effective for the subset of patients with better kidney function. Allopurinol use is limited due to its side effects, potential toxicity of uncertain magnitude in patients with renal disease, and failure to achieve targeted serum urate levels. In part this failure may be due to the necessity for it to be titrated for optimal therapeutic effect. Febuxostat is a new medication that may offer several advantages and can be given as an alternative to allopurinol. We review the basic biology and clinical performance of febuxostat, and consider the potential utility of this agent in comparison to the older, better-established gout therapeutics. PMID- 21694923 TI - Expression of eNOS in kidneys from hypertensive patients. AB - Endothelium-derived nitric oxide (NO) is essential for maintenance and regulation of blood pressure. In animal models, altered endothelium-derived nitric oxide synthase (eNOS) expression and impaired NO generation are important factors for renal injury. However, the pattern of eNOS expression in the kidneys from hypertensive patients has not been well established. We have studied the eNOS immuno-expression in kidney biopsies from hypertensive patients. Compared to kidneys from normotensive individuals, there were no significant alterations of eNOS immuno-expression in the vasculature of patients with chronic essential hypertension. In contrast, the expression of eNOS was significantly decreased in the glomeruli and arterioles/small arteries of patients with malignant hypertension, particularly in those with significant intimal edema and myxoid degeneration or thrombi. Endothelial dysfunction is an important pathogenetic factor for chronic primary hypertension and eNOS plays a major role in the regulation of vascular tone and function. Unchanged eNOS in the kidney vasculature in chronic primary hypertension indicates that these patients have an ability to compensate. In patients with malignant hypertension, the expression of eNOS protein was diminished in the injured vasculature. Loss of the compensatory mechanism via continued release of NO to prevent vascular injury may be responsible for morphological changes typically seen in the renal vasculature in patients with accelerated hypertension. PMID- 21694924 TI - Nephrolithiasis-induced end stage renal disease. AB - INTRODUCTION: Nephrolithiasis still remains a too frequent and underappreciated cause of end stage renal disease (ESRD). METHODS AND PATIENTS: Of the entire cohort of 7128 consecutive patients who started maintenance dialysis in our nephrology department between January 1992 and December 2006, a total of 45 patients (26 women, 19 men) had renal stone disease as the cause of ESRD. The type of nephrolithiasis was determined in 45 cases and etiology in 42. The treatment and evolution of stone disease and patient's survival were studied. RESULTS: The overall proportion of nephrolithiasis related ESRD was 0.63%. The mean age was 48.4 years. Infection stones (struvite) accounted for 40%, calcium stones, 26.67% (primary hyperparathyroidism:15.56%; familial hypercalciuria: 4.44%, unknown etiology: 6.66%), primary hyperoxaluria type 1, 17.78% and uric acid lithiasis in 15.56% of cases. The mean delay of the evolution of the stone renal disease to chronic renal failure was 85.8 months. The feminine gender, obesity and elevated alkaline phosphatases >128 IU/L were significantly correlated with fast evolution of ESRD. The median evolution to ESRD was 12 months. The normal body mass index (BMI), medical treatment of stone and primary hyperoxaluria type 1 were correlated with fast evolution to ESRD. All patients were treated by hemodialysis during a mean evolution of 60 months. Sixteen patients died. The patient's survival rate at 1, 3 and 5 years was 97.6, 92.8 and 69% respectively. Hypocalcemia, cardiopathy and normal calcium-phosphate product were significantly correlated with lower survival rate. CONCLUSION: Severe forms of nephrolithiasis remain an underestimated cause of ESRD. These findings highlight the crucial importance of accurate stone analysis and metabolic evaluation to provide early diagnosis and efficient treatment for conditions leading to ESRD. PMID- 21694925 TI - Role of genetic polymorphisms in factor H and MBL genes in Tunisian patients with immunoglobulin A nephropathy. AB - The molecular mechanisms of IgA nephropathy (IgAN) remain poorly understood. Several different polymorphic genes have been investigated in order to demonstrate their possible association with this disease. It is evident that mainly alternative and lectin pathways complement activation and play an important role in renal injury of IgAN. This study was conducted to determine eventual deficiencies of factor H in the SCR20 gene region and to look for a possible association between the polymorphism (+54) exon 1 of the MBL gene and the predisposition in Tunisian patients with IgAN. We then evaluated the effects of these FH mutations and/or this MBL polymorphism on nephropathy susceptibility and progression. Polymorphism A/B (+54) in the exon1 of the MBL gene and analysis within the C-terminal domain of the protein SCR20 in the exon 22 of the factor H (FH) gene were conducted in 36 sporadic IgAN Tunisian patients and 117 age and gender matched healthy subjects recruited from blood donors, by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing respectively. The analysis of the Gly54Asp (+54) mutation of the MBL gene according to the criteria of gravity of the IgAN reveals that the patients with genotype AB present more frequently with end-stage renal disease (ESRD) compared with those of genotype AA [OR: 8, CI (1.74-54.49), P = 0.019]. Moreover, the variant allele B was statistically more frequent than the allele A in patients with an association with initial arterial high blood pressure, ESRD and class V of the Haas classification compared to those without this association (P = 0.009). The direct sequencing of exon 22 (SCR 20) of FH gene did not reveal any abnormal mutational deficiency for this factor in all patients and controls. The data did not support the hypothesis that FH is a susceptibility factor for the IgAN. However the data did show there was an association between AB (+54) exon1 MBL genotype and severe sporadic forms of this disease in Tunisian patients. Because of the small number of subjects studied, a much larger cohort of IgAN patients with varying severity of the disease and its progression would seem necessary to confirm these findings. PMID- 21694926 TI - Renovascular and renoprotective properties of telmisartan: clinical utility. AB - Chronic kidney disease (CKD) affects approximately 26 million adults in the United States and millions of others are at increased risk. Type 2 diabetes and hypertension are the two main causes of CKD. Blood pressure control is critical to slow the progression of CKD. Despite adequate control, however, patients continue to progress to end-stage renal disease. Angiotensin receptor blockers (ARBs) are commonly used in the management of hypertension and CKD and have been shown to exert renoprotective effects that are in addition to, but independent of, blood pressure lowering. Telmisartan is a long-acting ARB with pharmacological properties beyond blockade of the angiotensin II type 1 receptor, including activation of the peroxisome proliferator activated receptor-gamma (PPAR-gamma). This article reviews the beneficial renal and vascular protective effects of telmisartan. PMID- 21694927 TI - Acute effects of hemodialysis on oxidative stress parameters in chronic uremic patients: comparison of two dialysis membranes. AB - Uremic state and hemobioincompatibility are implicated in subclinical inflammation and oxidative stress and progression of atherosclerosis in the hemodialysis (HD) population. To what extent different dialysis membranes contribute to oxidative stress induced by a dialysis procedure per se is still a subject of debate. Fifteen HD patients and 15 healthy controls were enrolled in this study. Patients received two index HD sessions with a cuprophane and polysulfone membrane two weeks apart. Blood samples were collected at baseline and then before and after HD sessions. We determined serum thiobarbituric acid, protein carbonyl, and serum nitrite/nitrate levels as markers of oxidative damage. We also measured erythrocyte glutathione level, catalase, superoxide dismutase and glutathione peroxidase activity, and serum vitamin C and E levels as antioxidant markers. At baseline, HD patients, in comparison with normal controls, had a trend towards increased oxidant state and depletion of antioxidants. Cuprophane dialysis induced a higher increase in production of oxidants, along with a lower compensatory increase of antioxidants when compared with polysulfone dialysis. In conclusion, a single HD session, even when conducted with a biocompatible membrane, appears to play an important role in the imbalance between ROS production and antioxidant defense, but to a milder extent than cuprophane dialysis. PMID- 21694928 TI - Tuberculosis in children undergoing hemodialysis. AB - Tuberculosis (TB) remains a public health problem in Tunisia. Its incidence is higher in immunocompromised hosts than in the general population. In children and during hemodialysis, TB is characterized by the frequency of extrapulmonary localizations and diagnostic difficulties. The aim of this retrospective study is to evaluate the incidence of TB in Tunisian children undergoing hemodialysis and to determine its clinical features as well as the results of chemotherapy. METHOD: This retrospective study includes seven TB children among 112 children on hemodialysis at the pediatric nephrology department in Charles Nicolle Hospital from 2002 to 2008. The diagnosis of TB was established by a combination of clinical, radiological, biochemical, microbiological, and histological examinations. Treatment with anti-TB drugs, the results of therapy, and the outcome of patients were noted. RESULTS: There were four girls and three boys aged 10 to 16 years (mean, 13 years). They had been on hemodialysis for 2 to 5 years (mean, 3 years). Noted clinical features were weight loss and fever in five cases, chest pain in one case, cervical lymph node in one case, and spinal pain in one case. The organ systems involved were pleural in two cases, pulmonary in one case, peritoneal in one case, cervical lymphatic in one case, and spinal in one case. One patient was treated empirically with a good response. Diagnosis was made by isolation of mycobacterium TB in three cases, by specific histological signs observed in a lymph node biopsy in one case, in peritoneal biopsy in one case, and in discovertebral biopsy in one case. In the remaining patient, the clinical and radiological presentations were compatible with pulmonary TB. All patients received four anti-TB drugs: isoniazid, rifampicin, pyrazinamide, and ethambutol. One patient died with miliary TB. The other patients had favorable outcomes. CONCLUSIONS: TB in hemodialysis children has a nonspecific clinical presentation. Extrapulmonary locations are most common. Diagnosis is often difficult, but successful outcomes are possible when made at an early stage. PMID- 21694929 TI - Clinical utility of tolvaptan in the management of hyponatremia in heart failure patients. AB - Hyponatremia is an electrolyte disorder frequently observed in several clinical settings and common in hospitalized patients with decompensated heart failure (HF). It is caused by deregulation of arginine vasopressin (AVP) homeostasis associated with water retention in hypervolemic or in euvolemic states. While hypervolemic hypotonic hyponatremia is also seen in advanced liver cirrhosis, renal failure, and nephrotic syndrome, the bulk of evidence associating this electrolyte disorder to increasing morbidity and mortality can be found in the HF literature. Hospitalized HF patients with low serum sodium concentration have lower short-term and long-term survival, longer hospital stay and increased readmission rates. Conventional therapeutic approaches, ie, restriction of fluid intake, saline and diuretics, can be effective, but often the results are unpredictable. Recent clinical trials have demonstrated the effectiveness of nonpeptide AVP receptor antagonists (vaptans) in the treatment of hyponatremia. The vaptans induce aquaresis, an electrolyte-sparing excretion of free water resulting in the correction of serum sodium concentrations and plasma osmolality, without activation of the renin-angiotensin-aldosterone system (RAAS) or changes in renal function and blood pressure. Further prospective studies in a selected congestive HF population with hyponatremia, using clinical-status titrated dose of tolvaptan, are needed to determine whether serum sodium normalization will be translated into a better long-term prognosis. This review will focus on recent clinical trials with tolvaptan, an oral V(2) receptor antagonist, in HF patients. The ability of tolvaptan to safely increase serum sodium concentration without activating the RAAS or compromising renal function and electrolyte balance makes it an attractive agent for treating hyponatremic HF patients. PMID- 21694930 TI - Complete response of a metastatic gastroesophageal adenocarcinoma on irinotecan based chemotherapy in a dialysis patient. AB - We present the first case report of a complete response of metastatic gastroesophageal cancer in a chronic hemodialysis patient with irinotecan-based chemotherapy. An elderly dialysis patient presented with diffuse liver metastases by a gastroesophageal adenocarcinoma. He received combination chemotherapy with 5 fluorouracil and irinotecan. After six months of chemotherapy, liver scans show complete remission. The principles, practice, and experience of chemotherapy with irinotecan during dialysis are discussed. PMID- 21694931 TI - Uncontrolled hypertension secondary to leukemic cell infiltration of kidneys in a hemodialysis patient. AB - Leukemic infiltration of the kidney is usually silent, and the admission of the patients with renal dysfunction or acute kidney injury is uncommon. We present a 34-year old hemodialysis patient with new onset of uncontrolled hypertension, erythropoietin-resistant anemia, thrombocytopenia, and Bell's palsy. On admission, his blood pressure (BP) was 210/110 mmHg and he had petechiae and purpura at upper and lower extremities. Renal ultrasonography (USG) showed bilaterally enlarged kidneys without hydronephrosis, unlike his previous USG, which determined bilaterally atrophic kidneys. Acute lymphoblastic leukemia, hypertensive crisis due to bilateral leukemic cell infiltration of kidneys, tumor lysis syndrome, and leukemic involvement of the facial nerve were diagnosed. Despite intense antihypertensive management, his BP was not controlled. After prednisolone, daunorubicine, and vincristine therapy, the size of kidneys diminished and his BP dropped under normal range. In conclusion, pathological findings such as uncontrolled hypertension, flank pain, skin rashes, and abnormal blood count should be considered carefully, even in patients with end-stage renal disease receiving renal replacement therapy. PMID- 21694933 TI - Atypical hemolytic uremic syndrome and mutation analysis of factor H gene in two Tunisian families. AB - We carried out a protein and genetic investigation of the factor H gene mutations within two families presenting with a diagnostic suspicion of atypical hemolytic uremic syndrome (aHUS). The results within the patients of the first family revealed a factor H-deficiency. Direct sequencing allowed the detection of a 4 nucleotide deletion in the factor H gene. This deletion was found as the homozygote form in the proband and as the heterozygote form in the parents. Protein and functional analyses of the complement system were normal in all members of the second family. However, the molecular investigation for the father showed the presence of an amino acid substitution in the FH gene. Unfortunately, his two affected children died without being investigated for mutations. The functional consequences of these abnormal proteins are still to be demonstrated. PMID- 21694932 TI - Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment. AB - Both autosomal dominant and recessive polycystic kidney disease are conditions with severe associated morbidity and mortality. Recent advances in the understanding of the genetic and molecular pathogenesis of both ADPKD and ARPKD have resulted in new, targeted therapies designed to disrupt cell signaling pathways responsible for the abnormal cell proliferation, dedifferentiation, apoptosis, and fluid secretion characteristic of the disease. Herein we review the current understanding of the pathophysiology of these conditions, as well as the current treatments derived from our understanding of the mechanisms of these diseases. PMID- 21694934 TI - Fifteen years of losartan: what have we learned about losartan that can benefit chronic kidney disease patients? AB - Losartan, the first AT1 receptor blocker (ARB), was FDA approved 15 years ago. During those years, researchers and clinicians have developed a growing base of knowledge on the benefits of losartan, particularly for hypertension and renal disease. These benefits include decreasing proteinuria, slowing the progression of diabetic nephropathy, controlling hypertension, and decreasing stroke risk in patients with left ventricular hypertrophy. Although many of the benefits of losartan represent a class effect for ARBs, losartan has pharmacokinetic and pharmacodynamic characteristics and effects that are unique and are not a class effect. For example, a shorter duration of action is seen with this first ARB compared with other more recently approved ARBs. Losartan also has a uricosuric effect not seen in other ARBs and attenuates platelet aggregation, which is not seen or is seen to a lesser extent with the other ARBs. This review presents the physiological effects of losartan on the kidney and discusses relevant clinical outcomes. PMID- 21694935 TI - Nephroprotective action of glycosaminoglycans: why the pharmacological properties of sulodexide might be reconsidered. AB - A relatively large body of evidence supports the notion that glomerular capillary wall and mesangial alterations in diabetic nephropathy involve biochemical alterations of glycoproteins in these structures. Evidence in experimental animals rendered diabetic reveals that the administration of heparin and other anionic glycoproteins can effectively prevent the biochemical alterations that promote albuminuria. Moreover, angiotensin II inhibits heparan sulfate synthesis, while heparins modulate angiotensin II signaling in glomerular cells, inhibiting aldosterone synthesis and lowering proteinuria in diabetes patients. Sulodexide, a mixture of heparin and dermatan sulfate, appears to be a promising treatment for diabetic proteinuria partially resistant to renin-angiotensin system blocking agents. Sulodexide prevents heparan sulfate degradation, thus allowing reconstruction of heparan sulfate content and restoration of glomerular basement membrane ionic permselectivity. The antiproteinuric effect appears to be mainly related to the basal proteinuria and consequently to the duration of treatment in a relatively large number of small clinical trials. On the other hand, several sulodexide pharmacodynamic properties could improve the prognosis of chronic kidney disease patients, also independently from its antiproteinuric effect. However, sulodexide development as an antiproteinuric drug needs to be continued, in order to define which kind of patients could better respond to this treatment. PMID- 21694936 TI - Role of tacrolimus combination therapy with mycophenolate mofetil in the prevention of organ rejection in kidney transplant patients. AB - Several new medications are now available for immunosuppression in the kidney transplant field. Tacrolimus and mycophenolate mofetil were first introduced for immunosuppression in renal transplantation in the mid 1990s. Since then, the combination of tacrolimus and mycophenolate mofetil has been evaluated in numerous clinical trials. The outcomes of these trials have varied due to differences in induction and/or maintenance therapy, drug dosing and monitoring protocols, and study design. The aim of this review is to analyze the literature critically and to provide an overview of tacrolimus and mycophenolate mofetil combination therapy in renal transplantation. PMID- 21694937 TI - Cyclosporine A and steroid therapy in childhood steroid-resistant nephrotic syndrome. AB - BACKGROUND: In children, idiopathic nephrotic syndrome (INS) is primarily treated using corticosteroids. When remission is not achieved, the coadministration of potent immunosuppressant therapy becomes imperative. Cyclosporine A (CsA) is reportedly associated with a higher incidence of remission in comparison with other immunosuppressive agents. METHODS: The present study investigated the response of combination therapy using CsA and prednisolone in 30 Tunisian children with idiopathic steroid-resistant nephrotic syndrome (ISRNS). Renal histopathology was compatible with focal segmental glomerular sclerosis (FSGS) in 15 children, minimal change disease (MCD) in nine children, and diffuses mesangiale proliferation (DMP) in six children. RESULTS: The therapy protocol produced a complete remission of proteinuria in 15 patients (50%) and a partial remission in nine patients (30%). Six patients (20%) showed no response to therapy. Progression to end stage renal disease occurred in five CsA-resistant children and in four CsA-responsive patients. CsA-related nephrotoxicity was detected by renal biopsy in one patient. CONCLUSIONS: CsA remains the primary cytotoxic treatment for childhood steroid-resistant nephrotic syndrome. Its use in combination with corticosteroids provides optimum efficiency without high risk of nephrotoxicity. PMID- 21694938 TI - Long space missions, gene therapy, and the vital role of magnesium: a three pronged plan for the next 50 years. AB - Since pharmaceuticals cannot be used in space until liver and kidney dysfunctions are corrected, and with invariable malabsorption, it appears there is no alternative other than to use subcutaneous magnesium (Mg) replacements in the presence of deficiencies and use of gene therapy. I suggest beginning with the correction of as many as four gene deficiencies: atrial natriuretic peptide (ANP), nitric oxide (NO), vascular endothelial growth factor (VEGF), and erythropoietin (EPO), all as well as Mg related to perfusion and angiogenesis. There is no evidence of significant lunar radiation levels in the absence of a solar storm. It could then be determined whether this has resulted in correction of liver and kidney dysfunction. If this persists, serial additions of gene therapy will be required determining the effect of each individual gene trial on organ function. Microgravity and endothelial gaps with leaks trigger reduced plasma volume. Partial correction by use of a plasma volume substitute and development of a delivery device may reduce complexity of gene therapy. Research would be conducted both on Earth and in microgravity, with the development of subcutaneous pharmaceuticals and Mg, and a space walk-reliable subcutaneous silicon device, given that no replenishable subcutaneous device is presently available. A three-pronged approach provides a plan for the next 50 years: A. complete correction of a Mg deficit; B. partial replacement with plasma volume substitutes, and C. multiple gene factor strategy. PMID- 21694939 TI - Update on the diagnosis and management of acute kidney injury. AB - Acute kidney injury (AKI) is an independent risk factor for morbidity and mortality. This review provides essential information for the diagnosis and management of AKI. Blood urea nitrogen and serum creatinine are used for the diagnosis of AKI. The review also focuses on recent studies on the diagnosis of AKI using the RIFLE (R-renal risk, I-injury, F-failure, L-loss of kidney function, E-end stage kidney disease) and Acute Kidney Injury Network criteria, and serum and urine AKI biomarkers. Dialysis is the only Food and Drug Administration-approved therapy for AKI. Recent studies on the dose of dialysis in AKI are reviewed. PMID- 21694940 TI - Hypernatremia in a patient treated with sodium polystyrene sulfonate. AB - Severe hyperkalemia requires urgent medical attention and correction in order to prevent arrhythmic complications. Sodium polystyrene sulfonate (SPS) is a cation exchange resin commonly used in the management of hyperkalemia. A recent review raised concerns regarding its effectiveness and potential adverse effects. Hypernatremia in adults in the setting of sodium polystyrene sulfonate therapy has not been described in the literature. We report the case of a woman who developed hypernatremia in the setting of excessive SPS administration and hope to increase awareness among clinicians regarding this potential side effect of SPS therapy. PMID- 21694942 TI - Effect of angiotensin II blockade on central blood pressure and arterial stiffness in subjects with hypertension. AB - In hypertension, the blood pressure curve may be divided into two sets of components. The first set is mean arterial pressure, steady flow, and vascular resistance, thus acting on small arteries; the second set refers to large arteries, hence to pulse pressure, arterial stiffness, and wave reflections. The angiotensin-converting enzyme (ACE) inhibitor perindopril not only reduces mean arterial pressure but also acts specifically on pulse pressure. The effect on pulse pressure predominates on central rather than peripheral (brachial) large arteries, reducing aortic stiffness and most wave reflections. Such hemodynamic changes are not observed with standard beta-blockade, which reduces aortic stiffness and brachial systolic and pulse pressure but not central pulse pressure and wave reflections. In hypertensive subjects, perindopril and other ACE inhibitors seem to predict more consistently the reduction of cardiovascular events, mainly of cardiac origin, than standard beta-blockers alone. This effect is associated with the important biochemical finding that mechanotransductions of angiotensin and beta-blockade are markedly different, acting in the former specifically on the alpha5beta1 integrin complex and on the fibronectin ligand of arterial vessels. PMID- 21694943 TI - Prevalence of modifiable cardiovascular risk factors in long-term renal transplant patients. AB - BACKGROUND: Cardiovascular disease accounts for the majority of morbidity and mortality in renal transplant patients. This relates to a number of modifiable and nonmodifiable risk factors, including new onset diabetes after transplantation (NODAT). We examined the prevalence of these risk factors in a cohort of 126 renal transplant patients. METHODS: A retrospective cross-sectional study of 94 nondiabetic post-transplant (ND) patients (mean age 45.7 +/- 13.5 years) and 32 NODAT patients (55.2 +/- 9.6 years) was performed. Univariate linear regression analysis was used to identify potential factors that affected cardiovascular events. Multivariable analysis was performed on those factors found to achieve a P value of less than 0.20 after univariate analysis to test for significance in relation to cardiovascular risk as the primary factor. RESULTS: Mean serum creatinine levels were 131.1 +/- 4.3 MUmol/L and 135.2 +/- 4.9 MUmol/L at 96.9 +/- 8.7 and 79.4 +/- 14.1 months post-transplantation, respectively. Systolic pressure and pulse pressure were significantly higher in NODAT patients (P = 0.016 and P < 0.005). Adequate target blood pressures were obtained in 80% of patients. Low-density lipoprotein and high-density lipoprotein cholesterol were reduced in NODAT (P = 0.04 and P = 0.005). Homocysteine was similarly elevated in both groups (17.5 and 15.6 MUmol/L, respectively). Coronary events and/or coronary disease were present in 19.1% of ND and 37.5% of NODAT patients (P < 0.05). Cardiac deaths were three-fold more common (25% versus 7.4%) in patients with NODAT. Univariate analysis revealed diabetes and age, and subsequent multivariable analysis revealed age only, as being significantly associated with cardiovascular outcomes. CONCLUSIONS: Cardiac events are more common in patients with NODAT. Age is an important determinant of cardiovascular risk. PMID- 21694941 TI - New and improved strategies for the treatment of gout. AB - The Western world appears to be in the midst of the third great gout epidemic of all time. In this century, gout is increasing in prevalence despite an increased understanding of its risk factors and pathophysiology, and the availability of reasonably effective treatment. The main cultural factors responsible for this appear to be diet, obesity, ethanol use and medications. Excess fructose consumption is a newly recognized modifiable risk factor. The debate has been renewed concerning hyperuricemia as an independent risk factor for renal insufficiency and cardiovascular disease. Prevention is still rooted in lifestyle choices. Existing treatments have proven to be unsatisfactory in many patients with comorbidities. New treatments are available today and on the horizon for tomorrow, which offer a better quality of life for gout sufferers. These include febuxostat, a nonpurine inhibitor of xanthine oxidase with a potentially better combination of efficacy and safety than allopurinol, and investigational inhibitors of URAT-1, an anion exchanger in the proximal tubule that is critical for uric acid homeostasis. New abortive treatments include interleukin-1 antagonists that can cut short the acute attack in 1 to 2 days in persons who cannot take nonsteroidal anti-inflammatory drugs, colchicine or corticosteroids. Lastly, newer formulations of uricase have the ability to dissolve destructive tophi over weeks or months in patients who cannot use currently available hypouricemic agents. Diagnostically, ultrasound and magnetic resonance imaging offer advanced ways to diagnose gout noninvasively, and just as importantly, a way to follow the progress of tophus dissolution. The close association of hyperuricemia with metabolic syndrome, hypertension and renal insufficiency ensures that nephrologists will see increasing numbers of gout-afflicted patients. PMID- 21694944 TI - Diabetic microvascular complications: possible targets for improved macrovascular outcomes. AB - The results of recent outcome trials challenge hypotheses that tight control of both glycohemoglobin and blood pressure diminishes macrovascular events and survival among type 2 diabetic patients. Relevant questions exist regarding the adequacy of glycohemoglobin alone as a measure of diabetes control. Are we ignoring mechanisms of vasculotoxicity (profibrosis, altered angiogenesis, hypertrophy, hyperplasia, and endothelial injury) inherent in current antihyperglycemic medications? Is the polypharmacy for lowering cholesterol, triglyceride, glucose, and systolic blood pressure producing drug interactions that are too complex to be clinically identified? We review angiotensin aldosterone mechanisms of tissue injury that magnify microvascular damage caused by hyperglycemia and hypertension. Many studies describe interruption of these mechanisms, without hemodynamic consequence, in the preservation of function in type 1 diabetes. Possible interactions between the renin-angiotensin-aldosterone system and physiologic glycemic control (through pulsatile insulin release) suggest opportunities for further clinical investigation. PMID- 21694946 TI - Reinfusion of ascites during hemodialysis as a treatment of massive refractory ascites and acute renal failure. AB - Refractory ascites can occur in patients with various conditions. Although several procedures based on the reinfusion of ascitic fluid have been reported after the failure of bed rest, salt and water restriction, diuretics, intravenous administration of albumin, and repeated paracentesis, these procedures are performed for ascitic fluid removal without dialytic effect. In this study, a flow control reinfusion of ascites during hemodialysis (HD) was performed to demonstrate the efficacy of this method in a lupus patient with massive refractory ascites and respiratory and acute renal failure (ARF). The alleviation of ascites and ARF attests to the success of the flow control reinfusion of ascites during HD. This procedure can control the rate of ascites and body fluid removal simultaneously during HD using the roller pump. In conclusion, with a normal coagulation profile, the procedure of flow control reinfusion of ascites during HD is an effective alternative treatment for the alleviation of refractory ascites with renal failure. PMID- 21694945 TI - Clearing the complexity: immune complexes and their treatment in lupus nephritis. AB - Systemic lupus erythematosus (SLE) is a classic antibody-mediated systemic autoimmune disease characterised by the development of autoantibodies to ubiquitous self-antigens (such as antinuclear antibodies and antidouble-stranded DNA antibodies) and widespread deposition of immune complexes in affected tissues. Deposition of immune complexes in the kidney results in glomerular damage and occurs in all forms of lupus nephritis. The development of nephritis carries a poor prognosis and high risk of developing end-stage renal failure despite recent therapeutic advances. Here we review the role of DNA-anti-DNA immune complexes in the pathogenesis of lupus nephritis and possible new treatment strategies aimed at their control. PMID- 21694947 TI - Hypertension, poor glycemic control, and microalbuminuria in Cuban Americans with type 2 diabetes. AB - PURPOSE: To investigate to what degree the presence of hypertension (HTN) and poor glycemic control (GC) influences the likelihood of having microalbuminuria (MAU) among Cuban Americans with type 2 diabetes (T2D). METHODS: A cross sectional study conducted in Cuban Americans (n = 179) with T2D. Participants were recruited from a randomly generated mailing list purchased from Knowledge Base Marketing, Inc. Blood pressure (BP) was measured twice and averaged using an adult size cuff. Glycosylated hemoglobin (A1c) levels were measured from whole blood samples with the Roche Tina-quant method. First morning urine samples were collected from each participant to determine MAU by a semiquantitative assay (ImmunoDip). RESULTS: MAU was present in 26% of Cuban Americans with T2D. A significantly higher percentage of subjects with MA had HTN (P = 0.038) and elevated A1C (P = 0.002) than those with normoalbuminuria. Logistic regression analysis showed that after controlling for covariates, subjects with poor GC were 6.76 times more likely to have MAU if they had hypertension compared with those without hypertension (P = 0.004; 95% confidence interval [CI]: 1.83, 23.05). CONCLUSION: The clinical significance of these findings emphasizes the early detection of MAU in this Hispanic subgroup combined with BP and good GC, which are fundamentals in preventing and treating diabetes complications and improving individuals' renal and cardiovascular outcomes. PMID- 21694948 TI - Role of aliskiren in blood pressure control and renoprotection. AB - Patients with chronic renal disease are at increased risk for the development of cardiovascular disease, which is the main cause of death in this growing population. Among the risk factors involved, hypertension and proteinuria are major contributors to kidney damage and, if not controlled, may eventually lead to the progression of renal failure and end-stage renal disease. Both proteinuria and hypertension can be primary pathologic events or can appear as complications of other disease processes. Initially, these two factors may operate separately but, as progression ensues, both processes generally combine, potentiating their effects and hastening renal damage. Therefore, strategies to reduce blood pressure and proteinuria are essential in order to slow the worsening of many nephropathies. Therapies that target the renin-angiotensin system offer particular benefit, as hypertension and proteinuria can be precisely reduced with angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers. However, with this intervention, plasma renin activity remains high, and although primary endpoints may be controlled, elevated renin concentration can contribute to cardiovascular damage. Aliskiren, a direct renin inhibitor, is the first example of a novel class of antihypertensive drugs with potent antiproteinuric effects, which, alone or combined, can contribute to delaying the progression of kidney disease. PMID- 21694949 TI - Doppler angle correction in the measurement of intrarenal parameters. AB - BACKGROUND: The aim of this study was to assess differences in intrarenal artery Doppler parameters measured without and with Doppler angle correction. METHODS: We retrospectively reviewed color duplex sonography in 30 normally functioning kidneys (20 native kidneys in 10 subjects and 10 transplanted kidneys in 10 subjects) performed between January 26, 2010 and July 26, 2010. There were 10 age matched men and 10 age-matched women (mean 39.8 +/- 12.2, range 21-60 years) in this study. Depending on whether the Doppler angle was corrected in the spectral Doppler measurement, Doppler parameters including peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) measured at the interlobar artery of the kidney were divided into two groups, ie, initial Doppler parameters measured without Doppler angle correction (Group 1) and remeasured Doppler parameters with Doppler angle correction (Group 2). Values for PSV, EDV, and RI measured without Doppler angle correction were compared with those measured with Doppler angle correction, and were analyzed statistically with a paired-samples t test. RESULTS: There were statistical differences in PSV and EDV at the interlobar artery in the upper, mid, and lower poles of the kidney between Group 1 and Group 2 (all P < 0.001). PSV and EDV in Group 1 were significantly lower than in Group 2. RI in Group 1 was the same as that in Group 2 in the upper, mid, and lower poles of the kidneys. CONCLUSION: Doppler angle correction plays an important role in the accurate measurement of intrarenal blood flow velocity. The true flow velocity converted from the maximum Doppler velocity shift is produced only when the Doppler angle is 0 degrees , so that the emission sound beam is parallel to the direction of blood flow at the sampled artery. Therefore, the Doppler angle correction should be routinely applied and displayed on renal color duplex sonography. PMID- 21694950 TI - Tolvaptan, hyponatremia, and heart failure. AB - Tolvaptan is the first FDA-approved oral V(2) receptor antagonist for the treatment of euvolemic and hypervolemic hyponatremia, in patients with conditions associated with free water excess such as heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone secretion. Tolvaptan inhibits the binding of arginine vasopressin to the V(2) receptors on the collecting ducts of the kidneys resulting in aquaresis, the electrolytes sparing excretion of water. This article reviews the accumulated experience with tolvaptan and all the major clinical trials that were conducted to study its safety and efficacy and concludes by summarizing clinicians' views of its current application in clinical practice. PMID- 21694951 TI - Functionally induced changes in water transport in the proximal tubule segment of rat kidneys. AB - To eliminate freezing artifacts in the proximal tubule cells, two cryotechniques were applied to normal rat kidneys, ie, freeze substitution and special freeze drying. In addition, salt depletion and salt loading were applied to groups of rats to evaluate whether the segmental structure of the proximal tubule could be altered. In the superficial part of the renal cortex of normal kidneys, the typical first segment structure in the proximal tubule was generally present in the early postglomerular fraction of the tubule. However, in the second segment, a special cellular phenomenon was constantly present, comprising a significant intercellular space that was easily identified using a light microscope. In the third segment, in which the presence of basolateral interdigitations is minimal, the small lateral space, which was found to be present in cryopreparations between neighboring cells from the normal kidney, was found to be enlarged by heavy salt loading of short duration. It is concluded that these cryotechniques demonstrate quantitative structural variations between superficial and deep nephrons, as well as the presence of extracellular areas between the cells of the second and the third segment, representing a structural background for the essential transport of water from the proximal tubules to the peritubular capillaries. PMID- 21694952 TI - Academic job satisfaction questionnaire: Construction and validation in Saudi Arabia. AB - BACKGROUND: Colleges and universities are becoming increasingly accountable for teaching outcomes in order to meet rigorous accreditation standards. Job satisfaction (JS) seems more difficult to measure in the academic field in view of the complexity of roles, duties and responsibilities. OBJECTIVES: To compile and determine the psychometric properties of a proposed Academic Job Satisfaction Questionnaire (AJSQ) suitable for university faculty, and amenable to future upgrading. MATERIALS AND METHODS: A 46-item five-option Likert-type draft questionnaire on JS was distributed for anonymous self-reporting by all the academic staff of five colleges in University of Dammam (n=340). The outcome measures were (1) factor analysis of the questionnaire items, (2) intra-factor alpha-Coefficient of Internal Consistency Reliability, (3) inter-factor correlations, (4) comparison of psychometric properties in separately analyzed main faculty subgroups. RESULTS: The response rate was 72.9 percent. Factor analysis extracted eight factors which conjointly explained 60.3 percent of the variance in JS. These factors, in descending order of eigenvalue, were labeled "Authority", "Supervision", "Policies and Facilities", "My Work Itself", "Interpersonal Relationships", "Commitment", "Salary" and "Workload". Cronbach's alpha ranged from 0.90 in Supervision to 0.63 in Salary and Workload. All inter factor correlations were positive and significant, ranging from 0.65 to 0.23. The psychometric properties of the instrument in separately analyzed subgroups divided by sex, nationality, college and clinical duties produced fairly comparable findings. CONCLUSION: The AJSQ demonstrated good overall psychometric properties in terms of construct validity and internal consistency reliability in both the overall sample and its separately analyzed subgroups. RECOMMENDATION: To replicate these findings in larger multicenter samples of academic staff. PMID- 21694953 TI - Prevalence and associated factors of cigarette smoking among medical students at King Fahad Medical City in Riyadh of Saudi Arabia. AB - OBJECTIVE: To determine the prevalence of smoking among medical students at the medical college at King Fahad Medical City in Riyadh, and assess the association between smoking and socio-demographical factors, smoking contacts, reasons for smoking and attempts to quit. MATERIALS AND METHODS: Cross-sectional survey in which anonymous, self-administered questionnaire was used to survey the cigarette smoking habits of the first- and second-year medical students in the Faculty of Medicine, King Fahad Medical City in June 2009. RESULTS: Overall 39.8 % of the investigated students (153) had smoked before, and 17.6% were current smokers. The mean age of initiating smoking was 15.8 (+/-3.3). There were significantly more males than females. The most important reasons for smoking were leisure, imitation of other people and a means of relieving psychological pressure. Reasons for not smoking were mostly health and religion-based. Smokers tended to have friends who smoked. CONCLUSION: Cigarettes smoking is highly prevalent among medical students in the Faculty of Medicine, King Fahad Medical City. Contact with smokers particularly friends are the major risk factors for the initiation of the habit. Health and religious considerations are important motives for not smoking, quitting or attempting to quit. These findings can be of help in designing future intervention strategies. PMID- 21694954 TI - Drowning in children: Aseer Central Hospital experience, Southwestern Saudi Arabia. AB - AIM: To study the reasons, magnitude and outcome of drowning following submersion in water of children admitted to the Pediatric Intensive Care Unit in Aseer Province, Saudi Arabia. MATERIALS AND METHODS: A retrospective cohort study of all pediatric patients (0-13) years old who drowned and were admitted to the Pediatric Intensive Care Unit, Aseer Central Hospital, Southwestern Saudi Arabia, between January 1st 1999 and December 31st 2009. RESULTS: A total of 19 cases were admitted following submersion in water. The mean age was 5.2 years +/-3.8. Majority of victims (94.1%) were from the highland areas. Events most frequently occurred in the summer (46.7%), followed by spring and winter, 33.3% and 20%, respectively. Home events constituted 44.4% of submersion cases. Of these, 55.6% drowned in a washing container, While 53.4% submersed in swimming pools. Twenty two percent of these accidents occurred in the sea and in wells while 11.1% occurred in a lake. The mean duration of submersion was 4.04 minutes +/- 5.35. Cardiac arrest was reported upon arrival at hospital in 42.1% of the victims. There were seven deaths (36.8 %) and in one patient (5.2 %) there was severe brain injury. In all deceased cases, no adults were watching the children when the accidents occurred. CONCLUSION: Drowning is a significant risk factor facing our children and can claim lives. The media as well as the authority should play a major role in increasing the public awareness to minimize or prevent such a problem. PMID- 21694955 TI - Knowledge, practice and attitude toward epilepsy among primary and secondary school teachers in South Gezira locality, Gezira State, Sudan. AB - OBJECTIVE: The attitudes toward school pupils with epilepsy are influenced by the degree of school teachers' knowledge of the disorder. Teachers usually do not receive any formal instructions on epilepsy during their training. This study aims to assess school teachers' knowledge, attitude and practice when dealing with epilepsy in school children. MATERIALS AND METHODS: This study was part of a series mandated by the Gezira Epilepsy Care Programme (GECP), to obtain baseline data for a community-adapted epilepsy education program. A pretested, semi structured, 35-items questionnaire was the investigational tool. It was used to evaluate the knowledge of the basic facts about epilepsy among school teachers in this cross-sectional study. The questionnaire allowed teachers to express their opinions by means of free answers. The schools were chosen at random but not in a systematic equiprobability design. Two hundred teachers from public primary (100) and secondary (100) schools in the rural area of south Gezira Locality, Gezira State, Central Sudan, were recruited. RESULTS: In this study, the majority of respondents had never been informed about epilepsy and therefore gave evasive answers to many questions. Few of the respondents considered epilepsy as contagious. None of participants objected to having epileptic children in their classes. Only 47 teachers (47%) in the primary schools had any knowledge of the initial procedures to help a child in seizure, presenting reasonable answers, compared to 64 (64%) teachers in the secondary schools. RECOMMENDATIONS: All school teachers should be given some kind of training in health services. The GECP should involve teachers in its current training programs for caregivers and lay association to help epileptic patients. PMID- 21694956 TI - Characterization of human rotavirus subgroups and serotypes in children under five with acute gastroenteritis in a Saudi Hospital. AB - OBJECTIVES: Rotavirus is the most common cause of severe diarrhea in children. Currently, there is no published data on the prevalence of subgroups and serotypes of rotavirus in the Eastern province of Saudi Arabia. The objectives of the present study were to assess the rotavirus infection in children with acute gastroenteritis and to assess the subgroups and serotypes of rotavirus in the Children and Maternity Hospital in Dammam, Eastern Saudi Arabia. MATERIALS AND METHODS: Children under 5 years of age with gastroenteritis attending the emergency rooms, or hospitalized in the pediatric wards of in the Children and Maternity Hospital in Dammam were included in the study (N=156). Laboratory diagnosis of rotavirus shedding was established using the novel rotavirus STAT PAK immunochromatographical test. Subgroup and G-serotype of the positive stool specimens were analyzed by the ELISA method. RESULTS AND CONCLUSIONS: Using the novel immmunochromatographic assay, 37 samples were shown to be positive for rotavirus (23.7%). Subgroup I (serotype 2) was found to constitute 5.4% of the isolates and subgroup II (serotypes 1, 3 and 4) was found to constitute 56.7% of the isolates, whereas 37.8% were non-typeable. A survey of serotypes of rotavirus in the whole region as well as in the whole of Saudi Arabia will provide important information about the subgroups and groups of rotavirus in the community and may help in assessing the success of the rotavirus vaccine in the future. PMID- 21694957 TI - Role of government in public health: Current scenario in India and future scope. AB - The new agenda for Public Health in India includes the epidemiological transition, demographical transition, environmental changes and social determinants of health. Based on the principles outlined at Alma-Ata in 1978, there is an urgent call for revitalizing primary health care in order to meet these challenges. The role of the government in influencing population health is not limited within the health sector but also by various sectors outside the health systems. This article is a literature review of the existing government machinery for public health needs in India, its success, limitations and future scope. Health system strengthening, human resource development and capacity building and regulation in public health are important areas within the health sector. Contribution to health of a population also derives from social determinants of health like living conditions, nutrition, safe drinking water, sanitation, education, early child development and social security measures. Population stabilization, gender mainstreaming and empowerment, reducing the impact of climate change and disasters on health, improving community participation and governance issues are other important areas for action. Making public health a shared value across the various sectors is a politically challenging strategy, but such collective action is crucial. PMID- 21694958 TI - Periodontal disease: The sixth complication of diabetes. PMID- 21694959 TI - Preface, MSM 2011. PMID- 21694960 TI - Brain-mind dyad, human experience, the consciousness tetrad and lattice of mental operations: and further, the need to integrate knowledge from diverse disciplines. AB - Brain, Mind and Consciousness are the research concerns of psychiatrists, psychologists, neurologists, cognitive neuroscientists and philosophers. All of them are working in different and important ways to understand the workings of the brain, the mysteries of the mind and to grasp that elusive concept called consciousness. Although they are all justified in forwarding their respective researches, it is also necessary to integrate these diverse appearing understandings and try and get a comprehensive perspective that is, hopefully, more than the sum of their parts. There is also the need to understand what each one is doing, and by the other, to understand each other's basic and fundamental ideological and foundational underpinnings. This must be followed by a comprehensive and critical dialogue between the respective disciplines. Moreover, the concept of mind and consciousness in Indian thought needs careful delineation and critical/evidential enquiry to make it internationally relevant. The brain mind dyad must be understood, with brain as the structural correlate of the mind, and mind as the functional correlate of the brain. To understand human experience, we need a triad of external environment, internal environment and a consciousness that makes sense of both. We need to evolve a consensus on the definition of consciousness, for which a working definition in the form of a Consciousness Tetrad of Default, Aware, Operational and Evolved Consciousness is presented. It is equally necessary to understand the connection between physical changes in the brain and mental operations, and thereby untangle and comprehend the lattice of mental operations. Interdisciplinary work and knowledge sharing, in an atmosphere of healthy give and take of ideas, and with a view to understand the significance of each other's work, and also to critically evaluate the present corpus of knowledge from these diverse appearing fields, and then carry forward from there in a spirit of cooperative but evidential and critical enquiry - this is the goal for this monograph, and the work to follow. PMID- 21694961 TI - A journey into chaos: creativity and the unconscious. AB - The capacity to be creative, to produce new concepts, ideas, inventions, objects or art, is perhaps the most important attribute of the human brain. We know very little, however, about the nature of creativity or its neural basis. Some important questions include how should we define creativity? How is it related (or unrelated) to high intelligence? What psychological processes or environmental circumstance cause creative insights to occur? How is it related to conscious and unconscious processes? What is happening at the neural level during moments of creativity? How is it related to health or illness, and especially mental illness? This paper will review introspective accounts from highly creative individuals. These accounts suggest that unconscious processes play an important role in achieving creative insights. Neuroimaging studies of the brain during "REST" (random episodic silent thought, also referred to as the default state) suggest that the association cortices are the primary areas that are active during this state and that the brain is spontaneously reorganising and acting as a self-organising system. Neuroimaging studies also suggest that highly creative individuals have more intense activity in association cortices when performing tasks that challenge them to "make associations." Studies of creative individuals also indicate that they have a higher rate of mental illness than a noncreative comparison group, as well as a higher rate of both creativity and mental illness in their first-degree relatives. This raises interesting questions about the relationship between the nature of the unconscious, the unconscious and the predisposition to both creativity and mental illness. PMID- 21694962 TI - Consciousness, cognition and the cognitive apparatus in the vedanta tradition. AB - A human being is a complex entity consisting of the Self (also known as Consciousness), mind, senses and the body. The Vedanta tradition holds that the mind, the senses and the body are essentially different from the Self or Consciousness. It is through consciousness that we are able to know the things of the world, making use of the medium of the mind and the senses. Furthermore, the mind, though material, is able to reveal things, borrowing the light from consciousness. From the phenomenological point of view, we have to answer the following questions: how does one know the mind/the mental operations/the cogitations of the mind? Does the mind know itself? Is it possible? There is, again, the problem of the intentionality of consciousness. Is consciousness intentional? According to Vedanta, consciousness by its very nature is not intentional, but it becomes intentional through the mind. The mind or the ego is not part of the consciousness; on the contrary, it is transcendent to consciousness. It is difficult to spell out the relation between consciousness and the mind. How does consciousness, which is totally different from the mind, get related to the mind in such a way that it makes the latter capable of comprehending the things of the world? The Vedanta tradition provides the answer to this question in terms of the knower-known relation. Consciousness is pure light, self-luminous by its very nature, that is, although it reveals other objects, it is not revealed by anything else. When Sartre describes it as nothingness, bereft of even ego, it is to show that it is pure light revealing objects outside it. PMID- 21694963 TI - Neuroscience and Values: A Case Study Illustrating Developments in Policy, Training and Research in the UK and Internationally. AB - In the current climate of dramatic advances in the neurosciences, it has been widely assumed that the diagnosis of mental disorder is a matter exclusively for value-free science. Starting from a detailed case history, this paper describes how, to the contrary, values come into the diagnosis of mental disorders, directly through the criteria at the heart of psychiatry's most scientifically grounded classification, the American Psychiatric Association's DSM (Diagnostic and Statistical Manual). Various possible interpretations of the prominence of values in psychiatric diagnosis are outlined. Drawing on work in the Oxford analytic tradition of philosophy, it is shown that, properly understood, the prominence of psychiatric diagnostic values reflects the necessary engagement of psychiatry with the diversity of individual human values. This interpretation opens up psychiatric diagnostic assessment to the resources of a new skills-based approach to working with complex and conflicting values (also derived from analytic philosophy) called 'values-based practice.' Developments in values-based practice in training, policy and research in mental health are briefly outlined. The paper concludes with an indication of how the integration of values-based with evidence-based approaches provides the basis for psychiatric practice in the twenty-first century that is both science-based and person-centred. PMID- 21694964 TI - What should be the roles of conscious States and brain States in theories of mental activity? AB - Answers to the title's question have been influenced by a history in which an early science of consciousness was rejected by behaviourists on the argument that this entails commitment to ontological dualism and "free will" in the sense of indeterminism. This is, however, a confusion of theoretical assertions with metaphysical assertions. Nevertheless, a legacy within computational and information-processing views of mind rejects or de-emphasises a role for consciousness. This paper sketches a mentalistic metatheory in which conscious states are the sole carriers of symbolic representations, and thus have a central role in the explanation of mental activity and action-while specifying determinism and materialism as useful working assumptions. A mentalistic theory of causal learning, experimentally examined with phenomenal reports, is followed by examination of these questions: Are there common roles for phenomenal reports and brain imaging? Is there defensible evidence for unconscious brain states carrying symbolic representations? Are there interesting dissociations within consciousness? PMID- 21694965 TI - The neuroendocrine system and stress, emotions, thoughts and feelings. AB - The philosophy of mind is intimately connected with the philosophy of action. Therefore, concepts like free will, motivation, emotions (especially positive emotions), and also the ethical issues related to these concepts are of abiding interest. However, the concepts of consciousness and free will are usually discussed solely in linguistic, ideational and cognitive (i.e. "left brain") terms. Admittedly, consciousness requires language and the left-brain, but the aphasic right brain is equally conscious; however, what it "hears" are more likely to be music and emotions. Joy can be as conscious as the conscious motivation produced by the left-brain reading a sign that says, "Danger mines!!" However, look in the index of a Western textbook of psychology, psychiatry or philosophy for positive emotions located in the limbic system. Notice how discussion of positive spiritual/emotional issues in consciousness and motivation are scrupulously ignored. For example, the popular notions of "love" being either Eros (raw, amoral instinct) or agape (noble, non-specific valuing of all other people) miss the motivational forest for the trees. Neither Eros (hypothalamic) nor agape (cortical) has a fraction of the power to relieve stress as attachment (limbic love), yet until the 1950s attachment was neither appreciated nor discussed by academic minds. This paper will point out that the prosocial, "spiritual" positive emotions like hope, faith, forgiveness, joy, compassion and gratitude are extremely important in the relief of stress and in regulation of the neuroendocrine system, protecting us against stress. The experimental work reviewed by Antonio Damasio and Barbara Fredrickson, and the clinical example of Alcoholics Anonymous, will be used to illustrate these points. PMID- 21694966 TI - Understanding brain, mind and soul: contributions from neurology and neurosurgery. AB - Treatment of diseases of the brain by drugs or surgery necessitates an understanding of its structure and functions. The philosophical neurosurgeon soon encounters difficulties when localising the abstract concepts of mind and soul within the tangible 1300-gram organ containing 100 billion neurones. Hippocrates had focused attention on the brain as the seat of the mind. The tabula rasa postulated by Aristotle cannot be localised to a particular part of the brain with the confidence that we can localise spoken speech to Broca's area or the movement of limbs to the contralateral motor cortex. Galen's localisation of imagination, reasoning, judgement and memory in the cerebral ventricles collapsed once it was evident that the functional units-neurones-lay in the parenchyma of the brain. Experiences gained from accidental injuries (Phineas Gage) or temporal lobe resection (William Beecher Scoville); studies on how we see and hear and more recent data from functional magnetic resonance studies have made us aware of the extensive network of neurones in the cerebral hemispheres that subserve the functions of the mind. The soul or atman, credited with the ability to enliven the body, was located by ancient anatomists and philosophers in the lungs or heart, in the pineal gland (Descartes), and generally in the brain. When the deeper parts of the brain came within the reach of neurosurgeons, the brainstem proved exceptionally delicate and vulnerable. The concept of brain death after irreversible damage to it has made all of us aware of 'the cocktail of brain soup and spark' in the brainstem so necessary for life. If there be a soul in each of us, surely, it is enshrined here. PMID- 21694967 TI - The contribution of prefrontal executive processes to creating a sense of self. AB - According to several current theories, executive processes help achieve various mental actions such as remembering, planning and decision-making, by executing cognitive operations on representations held in consciousness. I plan to argue that these executive processes are partly responsible for our sense of self, because of the way they produce the impression of an active, controlling presence in consciousness. If we examine what philosophers have said about the "ego" (Descartes), "the Self" (Locke and Hume), the "self of all selves" (William James), we will find that it fits what is now known about executive processes. Hume, for instance, famously argued that he could not detect the self in consciousness, and this would correspond to the claim (made by Crick and Koch, for instance) that we are not conscious of the executive processes themselves, but rather of their results. PMID- 21694968 TI - Sickness and healing and the evolutionary foundations of mind and minding. AB - Disease represents a principal tentacle of natural selection and a staple theme of evolutionary medicine. However, it is through a small portal of entry and a very long lineage that disease as sickness entered behavioural spaces and human consciousness. This has a long evolutionary history. Anyone interested in the origins of medicine and psychiatry as social institution has to start with analysis of how mind and body were conceptualised and played out behaviourally following the pongid/hominin split and thereafter. The early evolution of medicine provides a template for clarifying elemental characteristics of mind and minding. Sickness and healing in chimpanzees represents an early manifestation of (ethno) medicine, termed a behavioural tradition, which is found played out in routines of helping, caring, and healing as well as other social behaviours. Chimpanzees seem to know they are sick since they resort to self-medication when exhibiting signs and symptoms of disease. Also, they help those exhibiting physical and cognitive disability. Among hominins, awareness of consequences and implications of sickness and coping with them represented an important feature of human consciousness and a major factor in the origins of vaunted human abilities involving language, cognition, and culture as we know them. A philosophical examination of the early evolution of sickness and healing provides a window into an understanding of evolving human capacities such as self-awareness, awareness and implications of suffering, theory of mind, altruism, conceptual grasp of sickness and healing and morality. PMID- 21694969 TI - Recent advances in brain physiology and cognitive processing. AB - The discovery of participation of astrocytes as active elements in glutamatergic tripartite synapses (composed by functional units of two neurons and one astrocyte) has led to the construction of models of cognitive functioning in the human brain, focusing on associative learning, sensory integration, conscious processing and memory formation/retrieval. We have modelled human cognitive functions by means of an ensemble of functional units (tripartite synapses) connected by gap junctions that link distributed astrocytes, allowing the formation of intra- and intercellular calcium waves that putatively mediate large scale cognitive information processing. The model contains a diagram of molecular mechanisms present in tripartite synapses and contributes to explain the physiological bases of cognitive functions. It can be potentially expanded to explain emotional functions and psychiatric phenomena. PMID- 21694970 TI - Bridging the Gap between Philosophers of Mind and Brain Researchers: The Example of Addiction. AB - Philosophers and psychologists have long tried to understand people's irrational behaviour through concepts such as weakness of will, compulsion and addiction. The scientific basis of the project has been greatly enhanced by advances in cognitive psychology and neuroscience. However, some philosophers have also been critical of the more general conclusions drawn by the scientists. This is especially true when scientific researchers start making claims that go to philosophical issues, such as free will and responsibility. Conversely, some scientists have been critical of philosophical approaches for not understanding the results of recent research. I examined some of the recent history of scientific claims about addiction, and the rise of the claims from scientists to have shown that addiction is a brain disease and that addictive behaviour is compulsive. Given the well-confirmed evidence that addicts can modulate their behaviour in response to rewards, punishments and context, it is clear that according to normal definitions of compulsivity the behaviour of addicts is not typically compulsive, suggesting that neuroscientists are making an error in their interpretation of data. Since philosophers have expertise in making distinctions between different kinds of action and categorising them as free, weak-willed and compulsive, we will achieve a better interpretation of the neuroscience of addiction when taking this philosophical work into account. Conversely, given the status of science in the modern world, philosophers have to grapple with the latest neuroscientific discoveries and show the compatibility of their philosophical theories with the data for their approaches to maintain credibility. PMID- 21694971 TI - Mind-body Dualism: A critique from a Health Perspective. AB - Philosophical theory about the nature of human beings has far reaching consequences on our understanding of various issues faced by them. Once taken as self-evident, it becomes the foundation on which knowledge gets built. The cause of concern is that this theoretical framework rarely gets questioned despite its inherent limitations and self-defeating consequences, leading to crisis in the concerned field. The field, which is facing crisis today, is that of medicine, and the paradigmatic stance that is responsible for the crisis is Cartesian dualism-a view that mind and body are essentially separate entities. This paper discusses Cartesian dualism in the context of the practice of medicine. Focusing more closely on how disease, health and treatment are defined through this position, the paper builds up its critique by throwing light on its accomplishments, limitations and self-defeating consequences. The paper also seeks to understand why this dualism is still alive despite its disavowal from philosophers, health practitioners and lay people. PMID- 21694972 TI - Freudian theory and consciousness: a conceptual analysis**. AB - This paper aims at taking a fresh look at Freudian psychoanalytical theory from a modern perspective. Freudian psychology is a science based on the unconscious (id) and the conscious (ego). Various aspects of Freudian thinking are examined from a modern perspective and the relevance of the psychoanalytical theory of consciousness is projected. Do psychoanalysis and the unconsciousness have something to teach us about consciousness? Approaching Freud from a historical, psychoanalytical, anthropological and sociological perspective, we need to look at how Freudian theory may contribute to a better understanding of consciousness. We also need to look at psychoanalytical psychotherapy and its contribution to a better understanding of body-mind dualism and consciousness as a whole. Ego psychology is considered in the present day context and it is synthesized with various psychological studies to give us a better understanding of consciousness. PMID- 21694973 TI - From data processing to mental organs: an interdisciplinary path to cognitive neuroscience. AB - Human brain is a highly evolved coordinating mechanism in the species Homo sapiens. It is only in the last 100 years that extensive knowledge of the intricate structure and complex functioning of the human brain has been acquired, though a lot is yet to be known. However, from the beginning of civilisation, people have been conscious of a 'mind' which has been considered the origin of all scientific and cultural development. Philosophers have discussed at length the various attributes of consciousness. At the same time, most of the philosophical or scientific frameworks have directly or indirectly implied mind body duality. It is now imperative that we develop an integrated approach to understand the interconnection between mind and consciousness on one hand and brain on the other. This paper begins with the proposition that the structure of the brain is analogous, at least to certain extent, to that of the computer system. Of course, it is much more sophisticated and complex. The second proposition is that the Chomskyean concept of 'mental organs' is a good working hypothesis that tries to characterise this complexity in terms of an innate cognitive framework. By following this dual approach, brain as a data processing system and brain as a superstructure of intricately linked mental organs, we can move toward a better understanding of 'mind' within the framework of empirical science. The one 'mental organ' studied extensively in Chomskyean terms is 'language faculty' which is unique in its relation to brain, mind and consciousness. PMID- 21694974 TI - The Relationship between Creativity and Mental Disorder in an African Setting. AB - BACKGROUND: There has for some time now been recognition that there was a relationship between exceptional creative talent and mental disorder. The works of Andreasen (2008) and others in this area have been very significant. However, most of the research has been carried out in USA and Europe. Very little has come out of Africa on the subject. AIM: To survey the beliefs of different groups within an African society, concerning the possibility of a relationship between creative talent and mental disorder. To assess creativity within a community of people with a formal diagnosis of mental disorder. MATERIALS AND METHODS: Some of the mythology of the Yoruba was examined for content, concerning the behaviour of certain notable individuals and the existence of psychopathology based on modern day criteria. The beliefs of members of the general public and mental health professionals concerning the existence of a relationship between creative talent and psychopathology were surveyed using a questionnaire designed for the project. A sample of patients with formal diagnoses of affective disorder or schizophrenia drawn from two units, the Lagos State University Teaching Hospital and the Federal Neuropsychiatric Hospital Yaba, were assessed for 'Creativity.' RESULTS: Although there are notable 'eccentric' figures in local mythology, the overwhelming majority of the people surveyed do not believe there is any relationship between creativity and mental illness. They however believe that engaging in creative activities helps the mentally ill to recover from illness. The mental health professionals, who were clinical psychologists and psychiatrists, had a significant minority who believed that a relationship does exist, and they also strongly assert that creative activity has a therapeutic effect for the mentally ill. A survey of in-patients diagnosed with schizophrenia and affective disorder failed to show a significant difference in the creativity of the two populations, as measured by the originality score of the Rorschach scale. The survey of patients is inconclusive, based on small sample size (ten patients with a diagnosis of schizophrenia, ten with bipolar affective disorder.). The linkage between formal mental disorder is only recognised by a significant minority of mental health professionals. A significant proportion of the population believe that creative activity aids recovery from mental illness. More research is required into this important subject in Africa. PMID- 21694975 TI - Free will, freedom of choice and frontotemporal lobar degeneration. AB - The question whether human beings have free will has been debated by philosophers and theologians for thousands of years. More recently, neuroscientists have applied novel concepts and tools in neuroscience to address this question. We submit that human beings do have free will and the physiological substrate for its exercise is contained within neural networks. We discuss the potential neurobiology of free will by exploring volitionally initiated motor activity and the behavioural-response to a stimulus-response paradigm. We also submit that the exercise of free will can be affected in patients with the certain neurological disorders such as the behavioural variant of frontotemporal dementia. Clinicopathological correlation in patients with this disorder provides an opportunity to further elucidate the neural substrate for this fundamental human attribute. We also discuss the clinical correlates of the loss of free will in this population, which is a source of significant distress to patients, significant others and care givers. PMID- 21694976 TI - Neural basis of decision-making and assessment: issues on testability and philosophical relevance. AB - Decision-making is an intricate subject in neuroscience. It is often argued that laboratorial research is not capable of dealing with the necessary complexity to study the issue. Whereas philosophers in general neglect the physiological features that constitute the main aspects of thought and behaviour, I advocate that cutting-edge neuroscientific experiments can offer us a framework to explain human behaviour in its relationship with will, self-control, inhibition, emotion and reasoning. It is my contention that self-control mechanisms can modulate more basic stimuli. Assuming the aforementioned standpoints, I show the physiological mechanisms underlying social assessment and decision-making. I also establish a difference between veridical and adaptive decision-making, useful to create experimental designs that can better mimic the complexity of our day-by-day decisions in more ecologically relevant laboratorial research. Moreover, I analyse some experiments in order to develop an epistemological reflection about the necessary neural mechanisms to social assessment and decision-making. PMID- 21694977 TI - The Concept of Thinking: A Reappraisal of Ryle's Work. AB - In The Concept of Mind, Ryle's official position seems to be that mental acts cannot be intrinsically private. In The Concept of Mind as well as his later work on thinking, Ryle views thinking as an activity that terminates in a thought, which is a state of being prepared for a performance. Thinking is characterised by what Ryle calls intention-parasitism; for it is, insofar as its underlying motive is concerned, parasitic on the final performance which will take place later. Ryle shows that acts of thinking, owing to their intention-parasitism, can be described in a tactical idiom, with reference to the final performance for which it was intended. However, this framework of intention-parasitism is not adequate to describe all instances of thinking in all their aspects, which therefore remain inextricably private. The task of this paper is to accommodate such privacy within the theoretical framework suggested in The Concept of Mind. PMID- 21694978 TI - John locke on personal identity. AB - John Locke speaks of personal identity and survival of consciousness after death. A criterion of personal identity through time is given. Such a criterion specifies, insofar as that is possible, the necessary and sufficient conditions for the survival of persons. John Locke holds that personal identity is a matter of psychological continuity. He considered personal identity (or the self) to be founded on consciousness (viz. memory), and not on the substance of either the soul or the body. PMID- 21694979 TI - Meditation and the brain: attention, control and emotion. AB - Meditation has been for long time avoided as a scientific theme because of its complexity and its religious connotations. Fortunately, in the last years, it has increasingly been studied within different neuroscientific experimental protocols. Attention and concentration are surely among the most important topics in these experiments. Notwithstanding this, inhibition of emotions and discursive thoughts are equally important to understand what is at stake during those types of mental processes. I philosophically and technically analyse and compare results from neuroimaging studies, produced by leading authorities on the theme, dealing with two types of meditation: "one-pointed concentration" and "compassion meditation". Analysing "one-pointed concentration", I show the differences between novice and expert meditation practitioners in terms of brain activity and connectivity, considering the relationship among increased attention and concentration and decreased activity in areas related to discursive thought and emotion. Analysing "compassion meditation", I show the importance of the limbic circuitry in emotion sharing. I follow the same strategy of comparing novice and expert meditation practitioners. The conclusion establishes a common structure to those different ways of dealing with emotion during meditation. PMID- 21694980 TI - A Discussion in the Mind Brain Consciousness Group 2010-2011: Let's Study the Structure that is the Very Raison de etre of Our Existence. PMID- 21694982 TI - Template for MSM Submissions. PMID- 21694981 TI - Science, Names Giving and Names Calling: Change NDM-1 to PCM. AB - A journal editor recently apologised for publishing a 2010 paper in which authors designated an enzyme as New Delhi metallo-beta-lactamase-1 (NDM-1) and its related gene bla(NDM-1) after a city, New Delhi. This name had raised an outcry in India, with health authorities, media and medical practitioners demanding New Delhi be dropped from the name. The name was actually first given in another 2009 paper, whose corresponding author remains the same as the 2010 paper. There is a tradition of eponymous names in science. But those found derogatory to races, groups, cities, and countries have been changed. For example, "Mongolism" was changed to Down's syndrome; "Australia" antigen to HBsAg; "Mexican" Swine flu to H1N1; "GRID" (Gay Related Immune Deficiency) and 4H-Disease (Haitians, Homosexuals, Haemophiliacs and Heroin Users Disease) to AIDS. It is necessary that NDM-1 also be changed to a name based on scientific characteristics. NDM-1 must be changed to PCM (plasmid-encoding carbapenem-resistant metallo-beta lactamase). It is also necessary to review the tradition of naming organisms, diseases, genes, etc. after cities, countries and races. Often, such names giving amounts to names calling. It needs to be discarded by scientists in all new names giving from now on. "Geographical" and "racial" names giving must be replaced by "scientific" names giving. Journal editors must ensure that such scientific names giving is laid down as standard guideline in paper submissions. All such names still in currency need to be phased out by replacing them with names based on scientific characteristics, or in honour of their pioneering scientist/s or institutions. The lead author of the above 2010 paper has said he was not consulted about the final draft and did not agree with the conclusions of the paper. To ensure that corresponding authors do not ride roughshod over co authors, and lead and other authors do not backtrack on papers, editors must ensure written concurrence of all authors, especially the lead author, to the final draft of a paper and include this in their guidelines for paper submissions. PMID- 21694983 TI - Medication Error Management around the Globe: An Overview. AB - Medical mistakes that include medication errors have raised concerns about medication safety. Due to high consumption of medicines and self-treatment by all, especially the aging population, the issue of proper medication use and safety is at the forefront of public health concerns globally. Each country has a different approach towards medication event monitoring that is compliant with its own health care system. This paper focuses on the efforts and endeavors of some of the countries around the world to create an efficient error reporting systems to ensure public safety. Our analysis indicates that there are established and effective medication vigilance systems in many developed countries. The different countries undertake activities which range from collecting information about prescriptions, surveying physicians about adverse drug events, and conducting sophisticated post-marketing surveillance studies. There is still need for such sophisticated system in India; however recent promising developments are occurring towards building a medication vigilance system. Development of these systems may eventually contribute to a global medication vigilance system, which could reduce concern with medication errors and safety. PMID- 21694984 TI - Pharmacological Review on Centella asiatica: A Potential Herbal Cure-all. AB - In recent times, focus on plant research has increased all over the world. Centella asiatica is an important medicinal herb that is widely used in the orient and is becoming popular in the West. Triterpenoid, saponins, the primary constituents of Centella asiatica are manly believed to be responsible for its wide therapeutic actions. Apart from wound healing, the herb is recommended for the treatment of various skin conditions such as leprosy, lupus, varicose ulcers, eczema, psoriasis, diarrhoea, fever, amenorrhea, diseases of the female genitourinary tract and also for relieving anxiety and improving cognition. The present review attempts to provide comprehensive information on pharmacology, mechanisms of action, various preclinical and clinical studies, safety precautions and current research prospects of the herb. At the same time, studies to evaluate the likelihood of interactions with drugs and herbs on simultaneous use, which is imperative for optimal and safe utilization of the herb, are discussed. PMID- 21694985 TI - Development, validation and implementation of continuous professional development programmes for community pharmacists. AB - In India, structured continuous professional development modules are not available to update the knowledge and skills of the practicing community pharmacists. A prospective study was designed to develop, validate and implement continuous professional development modules and to assess the impact of training programme on knowledge and skills of community pharmacists. Modules were developed by referring to standard texts and data bases and were validated for the content. The impact of training programme on pharmacists' knowledge and skills was assessed using suitably designed pre and post training knowledge attitude and practice questionnaires, pre and post training questionnaires for individual continuous professional development training sessions, pre and post training patient counseling skill assessment, blood pressure measurement skill assessment and capillary blood glucose check-up skill assessment check-lists. Data was analyzed by applying suitable statistical methods using InStat version 3.01 statistical software. Fourty eight community pharmacists were enrolled in to the study. A statistically significant (P<0.05) improvement was observed in post training knowledge attitude and practice scores and in post training scores of individual training sessions. A statistically significant (P<0.05) improvement was also observed in post training scores of professional skills such as Patient counseling, capillary blood glucose recording and blood pressure measurement skills. The study findings conclude that continuous training updates the knowledge and skills in practicing the pharmaceutical care in their pharmacies. PMID- 21694987 TI - Formulation and evaluation of mucoadhesive buccal films of enalapril maleate. AB - Enalapril maleate is used in the treatment of hypertension and angina pectoris. It shows low bioavailability due to high hepatic first pass metabolism. Hence the present work was undertaken to formulate mucoadhesive buccal films of enalapril maleate with an objective to improve therapeutic efficacy, patient compliance and the bioavailability. In the present study ten formulations of mucoadhesive drug delivery system of enalapril maleate were prepared as buccal films, by solvent casting technique. Sodium carboxymethylcellulose, hydroxylpropylmethylcellulose, hydroxyethylcellulose and polyvinyl pyrrolidone K-90 were used as mucoadhesive polymers. Prepared films were evaluated for their weight, thickness, surface pH, swelling index, drug content uniformity, in vitro residence time, folding endurance in vitro release and permeation studies. Films exhibited controlled release over more than 10 h in permeation studies. It was concluded that the films containing 20 mg of enalapril maleate in sodium carboxymethylcellulose 2% w/v and hydroxyethyl cellulose 2% w/v (formulation F5), showed good swelling, a convenient residence time and promising controlled drug release, thus can be selected for the development of buccal film for effective therapeutic uses. PMID- 21694986 TI - Hepatoprotective Effect of Methanol Extracts of Zingiber officinale and Cichorium intybus. AB - The present work was carried out to investigate the hepatoprotective effect of ginger, chicory and their mixture against carbon tetrachloride intoxication in rats. Carbon tetrachloride treatment significantly elevated the alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma glutamyltransferase activities and the serum triglycerides and cholesterol concentration as compared to control group. It also increased RBCs counts and Hb concentration, total or differential leucocytes counts. However it decreased platelet counts, platelet distribution width, mean platelet volume, platelet larger cell ratio. Methanol extract of ginger (250 and 500 mg/kg) and chicory (250 and 500 mg/kg) given alone or mixed (1:1 wt/wt) significantly restored the carbon tetrachloride-induced alterations in the biochemical and cellular constituents of blood. No toxic symptoms were reported in doses up to 5 g/kg. Alkaloids and/or nitrogenous bases, carbohydrates and/or glycosides, tannins, flavonoids, saponins and unsaturated sterols and/or triterpenes are the main active constituents of their methanol extract. The hepatoprotective effect of ginger and chicory was also confirmed by the histopathological examination of liver tissue. PMID- 21694988 TI - Development and evaluation of pharmacosomes of aceclofenac. AB - Pharmacosomes are amphiphilic lipid vesicular systems containing phospholipid complexes with a potential to improve bioavailability of poorly water soluble as well as poorly lipophilic drugs. To improve the water solubility, bioavailability and minimize the gastrointestinal toxicity of aceclofenac, its pharmacosomes were prepared. Aceclofenac was complexed with phosphatidylcholine (80%) in two different ratios (1:1 and 2:1) using conventional solvent evaporation technique. Pharmacosomes thus prepared were subjected to solubility and drug content evaluation, scanning electron microscopy, differential scanning calorimetry, X ray powder diffraction and in vitro dissolution study. Pharmacosomes of aceclofenac were found to be disc shaped with rough surface in scanning electron microscopy. Drug content was found to be 91.88% (w/w) for aceclofenac phospholipid complex (1:1) and 89.03% (w/w) aceclofenac-phospholipid complex (2:1). Differential scanning calorimetric thermograms and X ray powder diffraction datas confirmed the formation of phospholipid complex. Solubility and dissolution profile of the prepared complex was found to be much better than aceclofenac. PMID- 21694989 TI - Preparation and Characterization of Ethosomes for Topical delivery of Aceclofenac. AB - The aim of present study was to prepare and characterized ethosomes of aceclofenac which may deliver the drug to targeted site more efficiently than marketed gel preparation and also overcome the problems related with oral administration of drug. The formulations were prepared with varying the quantity of ethanol 10-50% (v/v), lecithin 1-4% (w/v), propylene glycol 5-20% (v/v) and evaluated for their vesicle size, shape and surface morphology, entrapment efficiency and in vitro drug permeation study. Ethosomes of average size of 1.112 MUm with a spherical shape bearing smooth surface were observed by transmission electron microscopy and surface electron microscopy. The maximum entrapment of ethosomes was 91.06+/-0.79%. Cumulative amount of drug permeated through the biological membrane was found to be in the range of 0.26+/-0.014 to 0.49+/-0.032 mg/cm(2). Stability profile of prepared system was assessed for 45 days and the results revealed that very less degradation of drug was observed during storage condition. PMID- 21694990 TI - Assessment of prevalence and mortality incidences due to poisoning in a South Indian tertiary care teaching hospital. AB - WHO reports estimate poisoning as one of the most common causes of increased morbidity and mortality rate world-wide. Various agents such as pesticides, drugs have been used for intentional and accidental poisoning in different countries. In the Indian scenario, pesticides are the most commonly used poisoning agents. To assess the prevalence and mortality incidence rate due to various poisoning agents a retrospective and prospective study conducted over a period of nine months in a tertiary care teaching hospital. Retrospective data of poisoning cases was collected from the medical records section and the prospective data of poisoning cases was collected from the emergency and causality departments. A total of 1045 poisoning related admissions were identified during the period January 2005 to September 2008. Among them, 68.40% of cases were due to intentional poisoning and 31.60% were due to accidental poisoning. Of the poisoning related admissions, 84.4% of patients recovered, whereas in 7.6% of cases condition did not improve. Mortality rate was observed 4%. Intentional poisoning was observed more in male population (60.2%) in the age group of 18-29 years. Accidental poisoning was seen more in children in the age group of 1-3 years. Incidence of overall poisoning cases were high due to pesticides (39.5%) followed by medicines (26.1%), household products (22.1%), environmental poisoning (12.1%) and heavy metals (0.2%). It was observed that availability of centralised poison information centre and treatment protocols will improvise poison management practices in tertiary care hospitals by the clinicians. PMID- 21694991 TI - A New Improved RP-HPLC Method for Assay of Rosuvastatin Calcium in Tablets. AB - A reliable and sensitive isocratic stability indicating RP-HPLC method has been developed and validated for assay of rosuvastatin calcium in tablets and for determination of content uniformity. An isocratic separation of rosuvastatin calcium was achieved on YMC C8, 150*4.6 mm i.d., 5 MUm particle size columns with a flow rate of 1.5 ml/min and using a photodiode array detector to monitor the eluate at 242 nm. The mobile phase consisted of acetonitrile: water (40:60, v/v) pH 3.5 adjusted with phosphoric acid. The drug was subjected to oxidation, hydrolysis, photolysis and thermal degradation. All degradation products in an overall analytical run time of approximately 10 min with the parent compound rosuvastatin eluting at approximately 5.2 min. Response was a linear function of drug concentration in the range of 0.5-80 MUg/ml (r(2)= 0.9993) with a limit of detection and quantification of 0.1 and 0.5 MUg/ml respectively. Accuracy (recovery) was between 99.6 and 101.7%. Degradation products resulting from the stress studies did not interfere with the detection of rosuvastatin and the assay is thus stability-indicating. PMID- 21694992 TI - Design and optimization of floating drug delivery system of acyclovir. AB - The purpose of the present work was to design and optimize floating drug delivery systems of acyclovir using psyllium husk and hydroxypropylmethylcellulose K4M as the polymers and sodium bicarbonate as a gas generating agent. The tablets were prepared by wet granulation method. A 3(2) full factorial design was used for optimization of drug release profile. The amount of psyllium husk (X1) and hydroxypropylmethylcellulose K4M (X2) were selected as independent variables. The times required for 50% (t(50%)) and 70% (t(70%)) drug dissolution were selected as dependent variables. All the designed nine batches of formulations were evaluated for hardness, friability, weight variation, drug content uniformity, swelling index, in vitro buoyancy, and in vitro drug release profile. All formulations had floating lag time below 3 min and constantly floated on dissolution medium for more than 24 h. Validity of the developed polynomial equation was verified by designing two check point formulations (C1 and C2). The closeness of predicted and observed values for t(50%) and t(70%) indicates validity of derived equations for the dependent variables. These studies indicated that the proper balance between psyllium husk and hydroxypropylmethylcellulose K4M can produce a drug dissolution profile similar to the predicted dissolution profile. The optimized formulations followed Higuchi's kinetics while the drug release mechanism was found to be anomalous type, controlled by diffusion through the swollen matrix. PMID- 21694993 TI - Studies of Antimicrobial Activities of some 4-Thiazolidinone Fused Pyrimidines, [1,5]-Benzodiazepines and their Oxygen Substituted Hydroxylamine Derivatives. AB - Thiazolidin-4-one fused pyrimidines, [1,5]-benzodiazepines and their oxygen substituted hydroxylamine derivatives have been screened for antibacterial, antifungal and antimalarial activity. Bacillus subtilis, Escherichia coli, Proteus mirabilis and Salmonella typhi were used for antibacterial screening. Aspergillus fumigatus and Candida albicans were used for antifungal screening and Plasmodium species were used for antimalarial screening. The antibacterial and antifungal activities are expressed in terms of zone of inhibition and antimalarial activity is expressed in IC(50) value. Fifteen compounds 2Xa, 2Xb, 2Xc, 2Xs, 3IV, 3Va, 3Vc, 3VIIIa, 3VIIIh, 3IXa, 3IXb, 3IXc, 3Xa, 4IXa and 4Xa were tested for antibacterial as well as antifungal activity and seven compounds 2IXb, 2Xb, 3VIIIc, 3Xc, 4IXa, 4Xa and 4IXw were tested for antimalarial activity. Streptomycin, griseofulvin and chloroquine were taken as standard drugs in antibacterial, antifungal and antimalarial activity, respectively. The compound 2Xs was found significant antimicrobial against Bacillus subtilis, E. coli, Aspergillus fumigatus and Candida albicans as well as compound 3Xa was significant antimicrobial against Bacillus subtilis, E. coli, Salmonella typhi, Aspergillus fumigatus and Candida albicans. The compound 2Xb showed significant antimalarial activity. PMID- 21694994 TI - Synthesis and Antibacterial and Antifungal Studies of Novel Nitrogen Containing Heterocycles from 5-Ethylpyridin-2-ethanol. AB - A novel series of chalcones, pyrimidines and imidazolinone is described; chalcones (4a-o) were prepared from the lead molecule 4-[2-(5-ethylpyridin-2 yl)ethoxy]benzaldehyde. Pyrimidine (5a-o) derivatives were prepared from the reaction of chalcones and guanidine nitrate in alkali media. Imidazolinones (6a o) were synthesized from reaction of pyrimidine and oxazolone derivatives (prepared by Erlenmeyer azlactone synthesis). The structures of the synthesized compounds were assigned on the basis of elemental analysis, IR, (1)H and (13)C NMR spectral data. All the products were screened against different strains of bacteria and fungi. Most of these compounds showed better inhibitory activity in comparison to the standard drugs. PMID- 21694995 TI - Assessment of Immunomodulatory Activity of Euphorbia hirta L. AB - Immune system is the major target for development of treatment strategies to improve the management of infections. Many species of Indian medicinal plants have been reported to possess active principles with immunomodulating properties. Euphorbia hirta, a pantropic herb has been reported to be pharmacologically active. This study reports one another not widely reported property of the plant, immunomodulatory activity, which has been proved using simple techniques like the macrophage activity testing, carbon clearance test and mast cell de-granulation assay. PMID- 21694996 TI - Determination of site of absorption of propranolol in rat gut using in situ single-pass intestinal perfusion. AB - Previously, permeability and site of intestinal absorption of propranolol have been reported using the Ussing chamber. In the present study, the utility of Single-Pass Intestinal Perfusion to study permeability and site of intestinal absorption of propranolol was evaluated in rats. Drug permeability in different regions of rat intestine viz. duodenum, jejunum, ileum and colon was measured. Propranolol (30 MUg/ml) solution was perfused in situ in each intestinal segment of rats. Effective permeability (Peff) of propranolol in each segment was calculated and site of absorption was determined. The Peff of propranolol in rat duodenum, jejunum, ileum and colon was calculated to be 0.3316*10(-4) cm/s, 0.4035*10(-4)cm/s, 0.5092*10(-4) cm/s and 0.7167*10(-4) cm/s, respectively. The above results suggest that permeability of propranolol was highest through colon compared to other intestinal sites, which is in close agreement to that reported previously. In conclusion, in situ single pass intestinal perfusion can be used effectively to study intestinal permeability as well as site of intestinal absorption of compounds in rats. PMID- 21694997 TI - Development and Validation of HPTLC Method for the Estimation of Almotriptan Malate in Tablet Dosage Form. AB - A new, simple, precise and accurate high performance thin layer chromatographic method has been proposed for the determination of almotriptan malate in a tablet dosage form. The drug was separated on aluminum plates precoated with silica gel 60 GF(254) with butanol:acetic acid:water (3:1:1) was used as mobilephase. Quantitative analysis was performed by densitometric scanning at 300 nm. The method was validated for linearity, accuracy, precision and robustness. The calibration plot was linear over the range of 100-700 ng/band for almotriptan malate. The method was successfully applied to the analysis of drug in a pharmaceutical dosage form. PMID- 21694998 TI - Spacer/Linker based synthesis and biological evaluation of mutual prodrugs as antiinflammatory agents. AB - Mutual prodrugs of some antiinflammatory agents were synthesized with the aim of improving the therapeutic index through prevention of gastrointestinal complications and to check the efficiency of release of the parent drug in presence of spacer. These mutual prodrugs were synthesized by direct condensation method using dicyclohexyl carbodiimide as a coupling agent and glycine as a spacer. The title compounds were characterized by spectral techniques and the release of the parent drug from mutual prodrug was studied in two different non enzymatic buffer solutions at pH 1.2, pH 7.4 and in 80% human plasma. All mutual prodrugs exhibited encouraging hydrolysis profile in 80% human plasma. Biological activity of title compounds was studied by carrageenan-induced paw edema method. From the results obtained, it was concluded that these compounds retain the antiinflammatory action. PMID- 21694999 TI - Development and evaluation of artemether parenteral microemulsion. AB - The objective of the present investigation was to develop a parenteral microemulsion delivering artemether, a hydrophobic antimalarial drug and to evaluate antimalarial activity of the microemulsion in comparison to the marketed oily injection of artemether (Larither((r))). The microemulsion was evaluated for various parameters such as globule size, ability to withstand centrifugation and freeze-thaw cycling and effect of sterilization method on the drug content and globule size. The in vivo antimalarial activity of the microemulsion was evaluated in P. berghei infected mice in comparison to the Larither(;). The stability of the microemulsion was evaluated at 5o for 1 month. The microemulsion exhibited globule size of 113 nm and it could successfully withstand centrifugation and freeze-thaw cycling. The method of sterilization did not have any significant effect on the artemether content and globule size of the microemulsion. The microemulsion showed around 1.5-fold higher antimalarial activity and higher survival as compared to that of marketed artemether injection Larither((r)) and it showed a good stability at the end of 1 month. PMID- 21695000 TI - Evaluation of Composition and Antimicrobial Activity of Supercritical Fluid Extract of Leaves of Vitex negundo. AB - Supercritical fluid extract of leaves of Vitex negundo was tested for its antimicrobial potential and was compared with that of ethanol extract, ether extract and hydrodistilled oil of leaves. The chemical constituents of extracts were studied by chromatographic techniques. Extracts were evaluated for antimicrobial potential against bacterial strains like Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and yeast Candida albicans. Extracts showed prominent antibacterial activity against Bacillus subtilis and Staphylococcus aureus. Supercritical fluid extract exhibited good antibacterial potential. PMID- 21695001 TI - In vitro Antioxidant Studies of Fruits of Artemisia nilagirica (Clarke) Pamp. AB - Antioxidant potential of fruits of Artemisia nilagirica was studied using different in vitro models like 1,1-diphenyl-2-picryl hydrazyl, 2,2-azinobis-(3 ethylbenzothizoline-6-sulphonate), nitric oxide, superoxide, hydroxyl radical and lipid peroxidation. Both the ethanol and aqueous extracts of A. nilagirica fruits at 500 MUg/ml showed maximum scavenging activity (89.33% and 89.14%) in quenching 1,1-diphenyl-2-picryl hydrazyl radical. The ethanol extract showed better scavenging activity (69.78%) of 1,1-diphenyl-2-picryl hydrazyl radical followed by the scavenging of nitric oxide radical (73.25%) compared to aqueous extract. In contrast, hydroxyl and superoxide radicals were effectively scavenged by aqueous extract. Total antioxidant capacity of ethanol and aqueous extracts at 500 MUg/ml concentration was found to be 56.21 and 62.78 mg ascorbic acid equivalents, respectively. However, both the extracts showed only moderate lipid peroxidation inhibition activity. They were also found to contain considerable total phenols and flavonoids suggesting their role as an effective free radical scavenger. These findings suggest that phenolics and flavonoids in the fruits provide substantial antioxidant activity. PMID- 21695002 TI - Novel application of hydrotropic solubilizing additives in the estimation of aspirin in tablets. AB - Highly concentrated aqueous solutions of various hydrotropic agents like sodium benzoate, sodium salicylate, sodium acetate, sodium citrate, nicotinamide and sodium ascorbate have been observed to enhance aqueous solubilities of a large number of poorly water-soluble drugs. In the present investigation hydrotropic solubilization technique has been employed to solubilize poorly water-soluble aspirin (analgesic and antipyretic drug) by 0.5 M ibuprofen sodium solution to carry out titrimetric analysis of aspirin in tablet dosage form. Results of analysis by proposed method and Phamacopoeial method are very comparable. Proposed method is new, rapid, simple, accurate, and reproducible. Statistical data proved the accuracy, reproducibility and the precision of proposed method. PMID- 21695003 TI - Designing of the mucoadhesive intravaginal spermicidal films. AB - A mucoadhesive drug delivery system for local delivery of metronidazole through vaginal route was formulated. Films were prepared by solvent evaporation method using various compositions of Carbopol, hydroxypropylmethylcellulose, chitosan, Polyox and propylene glycol. The films were evaluated for their weight, thickness, surface pH, folding endurance, mechanical, drug content uniformity, in vitro drug release, swelling, gelling and mucoadhesion property. All the films possess satisfactory film characteristics. Films made of Polyox found to possess acceptable, physicochemical, mechanical, gelling and mucoadhesion property for delivery of metronidazole. PMID- 21695004 TI - Induced Dwarf Mutant in Catharanthus roseus with Enhanced Antibacterial Activity. AB - Evaluation of an ethyl methane sulphonate-induced dwarf mutant of Catharanthus roseus (L.) G. Don revealed that the mutant exhibited marked variation in morphometric parameters. The in vitro antibacterial activity of the aqueous and alcoholic leaf extracts of the mutant and control plants was investigated against medically important bacteria. The mutant leaf extracts showed enhanced antibacterial activity against all the tested bacteria except Bacillus subtilis. PMID- 21695005 TI - Antimicrobial activity of essential oil and various extracts of fruits of greater cardamom. AB - Greater cardamom (Amomum subulatum Roxb. Zingiberaceae) commonly known as "Bari ilaichi" is a well known plant used in Ayurvedic and Unani medicine. It has been used for the treatment of various diseases and disorders like gastric ulcer. Therefore antimicrobial activity of petroleum ether, methanol and aqueous extracts from leaves and roots, essential oil and isolated vasicine from A. vasica were tested against various microorganisms. Antimicrobial activity was done by disc diffusion method. The zone of inhibition observed was compared with that of standard drugs, ciprofloxacin and fluconazole. Minimum inhibitory concentration was determined against microorganisms used in the study. The results of this study reveal that methanol extract of fruits of A. subulatum shows remarkable antimicrobial activity against Escherichia coli whereas in case of other microorganisms used it was found inferior to the standard drug used. Methanol extract of rind showed good antimicrobial activity against Staphylococcus aureus. It was found that the essential oil isolated was effective against majority of microorganisms used viz. Bacillus pumilus, Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Saccharomyces cerevisiae. PMID- 21695006 TI - In Vitro Anticancer Activity of the Root, Stem and Leaves of Withania Somnifera against Various Human Cancer Cell Lines. AB - Withania Somnifera Dunal know as Ashwagandha belong Solanaceae family. It is extensively used in most of the Indian herbal pharmaceuticals and nutraceuticals. The current study, evaluate in vitro cytotoxicity in 50% ethanol extract of root, stem and leaves of Withania Somnifera against five human cancer cell lines of four different tissues i.e. PC-3, DU-145 (prostrate), HCT-15 (colon), A-549 (lung) and IMR-32 (neuroblastoma). Root, stem and leaves extracts showed cytotoxicity activity ranging 0-98% depending on the cell lines but maximum activity was found in 50% ethanol extract of leaves of Withania Somnifera. Ethanol extract of leaves obtained from treatments T2, T3, T4 and T5 showed strong activity against PC-3 and HCT-15 with 80-98% growth inhibition, while the 50% ethanol extract of leaves from T1 treatment showed a minimum of 39% and T3 treatment showed a maximum of 98% growth inhibition against HCT-15. This investigation is the first report of the anticancer activity in various parts of Withania Somnifera cultivated in fly ash amended soil. PMID- 21695007 TI - Design, Synthesis and Evaluation of Novel 1-(Substituted Acetyl)-4-(10-Bromo-8 Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-B]Pyridine-11-Ylidene)piperidines as Antitumor Agents and Farnesyl Protein Transferase Inhibitors. AB - Eight novel 1-(substituted acetyl)-4-(10-bromo-8-chloro-5,6-dihydro-11H benzo[5,6] cyclohepta [1,2-b] pyridine-11-ylidene)piperidines were designed by incorporating zinc binding groups to enhance activity. The designed molecules were synthesized and were evaluated for antitumor activity in vitro in five cell lines and for farnesyl protein transferase inhibition. Test compounds (6a-h) exhibited antitumor activity in most of the cell lines but were less potent than adriamycin. Compound 6e was most active with IC(50) values of <15 MUM in two cell lines tested. Test compounds also exhibited potent FPT inhibitory activity and 6c was most potent with IC(50) value of <30 MUM. PMID- 21695008 TI - Development and Validation of RP-HPLC Method for the Estimation of Ivabradine Hydrochloride in Tablets. AB - A simple, sensitive, precise and robust reverse-phase high-performance liquid chromatographic method for analysis of ivabradine hydrochloride in pharmaceutical formulations was developed and validated as per ICH guidelines. The separation was performed on SS Wakosil C18AR, 250*4.6 mm, 5 MUm column with methanol:25 mM phosphate buffer (60:40 v/v), adjusted to pH 6.5 with orthophosphoric acid, added drop wise, as mobile phase. A well defined chromatographic peak of Ivabradine hydrochloride was exhibited with a retention time of 6.55+/-0.05 min and tailing factor of 1.14 at the flow rate of 0.8 ml/min and at ambient temperature, when monitored at 285 nm. The linear regression analysis data for calibration plots showed good linear relationship with R=0.9998 in the concentration range of 30 210 MUg/ml. The method was validated for precision, recovery and robustness. Intra and Inter-day precision (% relative standard deviation) were always less than 2%. The method showed the mean % recovery of 99.00 and 98.55 % for Ivabrad and Inapure tablets, respectively. The proposed method has been successfully applied to the commercial tablets without any interference of excipients. PMID- 21695009 TI - Determination and evaluation of solubility parameter of satranidazole using dioxane-water system. AB - Satranidazole, a potent broad spectrum antiprotozoal, is a poorly water-soluble drug and has low bioavailability on oral administration. One of the important methods to improve the solubility and bioavailability of a less water-soluble drug is by the use of cosolvents. The solubility enhancement produced by binary blends with a cosolvent (dioxane) was studied against the solubility parameter of solvent blends (delta(1)) to evaluate the solubility parameter of drug (delta(2)). Solubility parameter of drug (delta(2)) was evaluated in blends of dioxane-water system. The results obtained were compared with the delta(2) values obtained using Molar Volume Method and Fedor's Group Substitution Method. The binary blend water-dioxane (10:90) gave maximum solubility with an experimental delta(2) value of 11.34 (Cal/cm(3))(0.5) that was comparable to the theoretical values of 11.34 (Cal/cm(3))(0.5) determined by Molar Volume Method and 11.3928 (Cal/cm(3))(0.5) when determined by Fedor's Group Substitution Method, which is in good agreement with solubility measurement method. PMID- 21695010 TI - Dr. Kenneth R. Feingold joins our Board of Associate Editors! PMID- 21695011 TI - Lipid metabolism in the epidermis. PMID- 21695013 TI - The role of fatty acid desaturases in epidermal metabolism. AB - The lipid composition of skin is important to a variety of functions served by this organ. Therefore, skin expresses multiple enzymes that synthesize and metabolize lipids. An important class of lipid metabolism enzymes expressed in skin is the lipid desaturases. Various isoforms of stearoyl-CoA desaturase, a delta-9 desaturase, as well as a delta-6 desaturase alter the lipid composition of the skin, thereby affecting skin barrier homeostasis and consequently, whole body energy balance. This review will focus on the role of fatty acid desaturases in maintaining epidermal metabolism. PMID- 21695012 TI - Role of fatty acid transporters in epidermis: Implications for health and disease. AB - Skin epidermis is an active site of lipid synthesis. The intercellular lipids of human stratum corneum (SC) are unique in composition and quite different from the lipids found in most biological membranes. The three major lipids in the SC are free fatty acids, cholesterol and ceramides. Fatty acids can be synthesized by keratinocytes de novo and, in addition, need to be taken up from the circulation. The latter process has been shown to be protein mediated, and several fatty acid transporters are expressed in skin. Recent studies of transgenic and knockout animal models for fatty acid transporters and the identification of fatty acid transport protein 4 (FATP4 or SLC27A4) mutations as causative for Ichthyosis Prematurity Syndrome highlight the vital roles of fatty acid transport and metabolism in skin homeostasis. This review provides an overview of our current understanding of the role of fatty acids and their transporters in cutaneous biology, including their involvement in epidermal barrier generation and skin inflammation. PMID- 21695014 TI - The role of fatty acid elongation in epidermal structure and function. AB - Heterogeneous molecular species of epidermal ceramide (Cer) play critical roles in forming a competent permeability barrier of lamellar membrane structures in the stratum corneum, which is a prerequisite to preventing excess water loss for terrestrial mammals. Lipids containing very long chain lengths of fatty acids (VLCFA) (hydrocarbon chain lengths over 28) have been found in selected tissues, including epidermis. In particular, omega-hydroxy (omega-OH) VLCFA as well as Cer containing omega-OH VLCFA and omega-O-acylCer (acylCer) are unique to epidermis. The fatty acid elongation system that generates VLCFA, which requires four enzymatic steps, has been characterized, while recent studies using transgenic animals have further revealed the importance of omega-OH Cer species for barrier formation and have also elucidated the synthetic pathway of these essential Cer species in conjunction with VLCFA metabolism. This review article discusses the generation of VLCFA and unique epidermal Cer species containing VLFCA in the relation to their roles in epidermis. PMID- 21695015 TI - The expression and regulation of enzymes mediating the biosynthesis of triglycerides and phospholipids in keratinocytes/epidermis. AB - Triglycerides and phospholipids play an important role in epidermal permability barrier formation and function. They are synthesized de novo in the epidermis via the glycerol-3-phosphate pathway, catalyzed sequentially by a group of enzymes that have multiple isoforms including glycerol-3-phosphate acyltransferase (GPAT), 1-acylglycerol-3-phosphate acyltransferase (AGPAT), Lipin and diacylglycerol acyltransferase (DGAT). Here we review the current knowledge of GPAT, AGPAT, Lipin and DGAT enzymes in keratinocytes/epidermis focusing on the expression levels of the various isoforms and their localization in mouse epidermis. Additionally, the factors regulating their gene expression, including calcium induced differentiation, PPAR and LXR activators, and the effect of acute permeability barrier disruption will be discussed. PMID- 21695016 TI - Fat in the skin: Triacylglycerol metabolism in keratinocytes and its role in the development of neutral lipid storage disease. AB - Keratinocyte differentiation is essential for skin development and the formation of the skin permeability barrier. This process involves an orchestrated remodeling of lipids. The cleavage of precursor lipids from lamellar bodies by beta-glucocerebrosidase, sphingomyelinase, phospholipases and sterol sulfatase generates ceramides, non-esterified fatty acids and cholesterol for the lipid containing extracellular matrix, the lamellar membranes in the stratum corneum. The importance of triacylglycerol (TAG) hydrolysis for the formation of a functional permeability barrier was only recently appreciated. Mice with defects in TAG synthesis (acyl-CoA:diacylglycerol acyltransferase-2-knock-out) or TAG catabolism (comparative gene identification-58, -CGI-58-knock-out) develop severe permeability barrier defects and die soon after birth because of desiccation. In humans, mutations in the CGI-58 gene also cause (non-lethal) neutral lipid storage disease with ichthyosis. As a result of defective TAG synthesis or catabolism, humans and mice lack omega-(O)-acylceramides, which are essential lipid precursors for the formation of the corneocyte lipid envelope. This structure plays an important role in linking the lipid-enriched lamellar membranes to highly cross-linked corneocyte proteins. This review focuses on the current knowledge of biochemical mechanisms that are essential for epidermal neutral lipid metabolism and the formation of a functional skin permeability barrier. PMID- 21695017 TI - Acidification in the epidermis and the role of secretory phospholipases. AB - The function of the epidermis is to form an effective barrier between the dry, external environment and the interior of the body. The barrier specifically resides in the extracellular lipid membranes of the stratum corneum (SC) and an acidic pH is necessary to maintain its competency against various insults. The purpose of this review is to explore the mechanisms which are postulated to contribute to the acidification of the stratum corneum, including both exogenous and endogenous sources. However, recent research as pointed to several endogenous mechanisms as the major source of acidification, including a sodium/proton pump (NHE1) and free fatty acid conversion from phospholipids by secretory phospholipase A(2) (sPLA(2)). sPLA(2) has been shown to play a central role in the formation of the SC "acid mantle" in the early maturation of the epidermis postnatally. Many aspects of this enzyme family are complex and still being elucidated in research and the most recent findings on the localization and functions of sPL A(2)-IB, -IIA, -IIC, -IID, -IIE, -IIF, -III, -V, -X and -XII in the epidermis are presented here. Given their role in inflammatory dermatoses, such as psoriasis and atopic dermatitis, understanding this complex enzyme family can lead to novel, life-changing therapies. PMID- 21695018 TI - The role of fatty aldehyde dehydrogenase in epidermal structure and function. AB - The epidermal water barrier resides in the stratum corneum (SC) and is dependent on a highly organized network of multi-lamellar membranes comprised of a critical lipid composition. The SC membranes are formed from precursor membranes packaged in cytoplasmic lamellar bodies in the stratum granulosum and delivered to the SC by exocytosis. An abnormal lipid composition of the SC membranes often results in a disrupted water barrier and the clinical appearance of ichthyosis. This cutaneous feature is characteristic of Sjogren-Larsson syndrome (SLS), an inborn error of lipid metabolism caused by deficiency of fatty aldehyde dehydrogenase (FALDH). The contribution of FALDH to normal epidermal function has become increasingly evident with the recognition that this enzyme has an essential role in metabolism of several lipids, including fatty aldehydes and alcohols, ether glycerolipids, isoprenoid alcohols and certain lipids that undergo omega oxidation, such as leukotriene B4 and very long-chain fatty acids. In the absence of FALDH, the skin produces lamellar bodies that are empty, lack their surrounding vesicle membranes or contain granular contents rather then the usual cargo membranes. These defective organelles also have impaired exocytosis, which results in structurally abnormal, deficient multi-lamellar membranes in the SC and a leaky water barrier. Although the exact biochemical mechanism for the cutaneous pathology is still unclear, studies in SLS demonstrate the critical importance of FALDH for normal epidermal structure and function. PMID- 21695020 TI - The roles of ABCA12 in keratinocyte differentiation and lipid barrier formation in the epidermis. AB - ABCA12 is a member of the large superfamily of ATP-binding cassette (ABC) transporters, which bind and hydrolyze ATP to transport various molecules across limiting membranes or into vesicles. The ABCA subfamily members are thought to be lipid transporters. ABCA12 is a keratinocyte transmembrane lipid transporter protein associated with the transport of lipids in lamellar granules to the apical surface of granular layer keratinocytes. Extracellular lipids, including ceramide, are thought to be essential for skin barrier function. ABCA12 mutations are known to underlie the three main types of autosomal recessive congenital ichthyoses: harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma. ABCA12 mutations lead to defective lipid transport via lamellar granules in the keratinocytes, resulting in malformation of the epidermal lipid barrier and ichthyosis phenotypes. Studies of ABCA12-deficient model mice indicate that lipid transport by ABCA12 is also indispensable for intact differentiation of keratinocytes. PMID- 21695019 TI - Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism: Therapeutic implications for topical treatment of these disorders. AB - Molecular geneticists tend to conceptualize disease pathogenesis from the mutated gene outward, an approach that does not take into account the impact of barrier requirements in determining disease phenotype. An 'outside-to-inside' perspective has provided quite different explanations for the ichthyoses, including several of the disorders of distal cholesterol metabolism. Elucidation of responsible pathogenic mechanisms also is pointing to appropriate, pathogenesis (pathway) based therapeutic strategies. In the case of the lipid metabolic disorders, it takes full advantage of new molecular, genetic and cellular pathogenesis information to correct or bypass the metabolic abnormality. This approach fully exploits the unique accessibility of the skin to a topical approach. Moreover, since it will utilize topical lipids and lipid-soluble, and often generic, lipid soluble drugs, these treatments should be readily transported across the stratum corneum. If successful, this approach could initiate an entirely new departure for the therapy of the ichthyoses. Finally, because these agents are relatively safe and inexpensive, this form of treatment has the potential to be widely deployed, even in the developing world. PMID- 21695021 TI - The mechanisms by which lipids coordinately regulate the formation of the protein and lipid domains of the stratum corneum: Role of fatty acids, oxysterols, cholesterol sulfate and ceramides as signaling molecules. AB - The formation of a permeability barrier between the external environment and the host is essential for survival. To provide this barrier keratinocytes undergo a complex pathway of differentiation, which culminates in keratinocyte cornification and the formation of extracellular lipid enriched lamellar membranes in the stratum corneum. The mechanisms that coordinately regulate the parallel formation of the corneocytes and lamellar membranes are unknown. The extracellular lamellar membranes are derived from the exocytosis of lamellar bodies and to synthesize lamellar bodies the keratinocyte must have abundant quantities of cholesterol, fatty acids and ceramides. These lipids could serve as signaling molecules and thereby coordinately regulate the formation of the stratum corneum. Fatty acids activate PPARs and studies have shown that PPAR activation stimulates keratinocyte differentiation. Cholesterol is converted to oxysterols that activate LXR and studies have shown that LXR activation also stimulates keratinocyte differentation. Additionally, PPAR and LXR activation also facilitates the formation of the lipid enriched lamellar membranes. Ceramides, via a number of mechanisms also stimulate keratinocyte differentiation. Recently, studies have shown that ceramides by increasing PPAR delta also increase the expression of ABCA12, which would facilitate the formation of lamellar bodies. Finally, keratinocytes accumulate a large quantity of cholesterol sulfate, which plays a key role in regulating desquamation. Cholesterol sulfate has also been shown to stimulate keratinocyte differentiation. Thus, cholesterol, cholesterol sulfate, fatty acids and ceramides all stimulate keratinocyte differentiation and thereby could coordinately regulate the formation of the stratum corneum. PMID- 21695022 TI - Perceived environmental factors associated with physical activity among normal weight and overweight Japanese men. AB - Although it is crucial to examine the environmental correlates of physical activity (PA) for developing more effective interventions for overweight populations, limited studies have investigated differences in the environmental correlates on body mass index (BMI). The purpose of the present study was to examine the perceived environmental correlates of PA among normal-weight and overweight Japanese men. Data were analyzed for 1,420 men (aged 44.4 +/- 8.3 years), who responded to an internet-based cross-sectional survey of answering the short version of the International Physical Activity Questionnaire and its Environment Module. Binary logistic regression analyses were utilized to examine the environmental factors associated with meeting the PA recommendation (150 minutes/week) between the normal-weight and overweight men. After adjusting for socio-demographic variables, common and different environmental correlates of PA were observed among normal-weight and overweight men. Furthermore, significant interactions regarding PA were observed between BMI status and two environmental correlates: access to public transportation (P = 0.03) and crime safety during the day (P = 0.01). The results indicated that BMI status is a potential moderator between perceived environmental factors and PA and suggested that different environmental intervention approaches should be developed for overweight populations. PMID- 21695023 TI - Factors associated with American Indian cigarette smoking in rural settings. AB - INTRODUCTION: This paper reports on the prevalence, factors and patterns of cigarette smoking among rural California American Indian (AI) adults. METHODS: Thirteen Indian health clinic registries formed the random household survey sampling frame (N = 457). Measures included socio-demographics, age at smoking initiation, intention to quit, smoking usage, smoking during pregnancy, health effects of smoking, suicide attempts or ideation, history of physical abuse, neglect and the role of the environment (smoking at home and at work). Statistical tests included Chi Square and Fisher's Exact test, as well as multiple logistic regression analysis among never, former, and current smokers. RESULTS: Findings confirm high smoking prevalence among male and female participants (44% and 37% respectively). American Indians begin smoking in early adolescence (age 14.7). Also, 65% of current smokers are less than 50% Indian blood and 76% of current smokers have no intention to quit smoking. Current and former smokers are statistically more likely to report having suicidal ideation than those who never smoked. Current smokers also report being neglected and physically abused in childhood and adolescence, are statistically more likely to smoke 1/2 pack or less (39% vs. 10% who smoke 1+ pack), smoke during pregnancy, and have others who smoke in the house compared with former and never smokers. CONCLUSION: Understanding the factors associated with smoking will help to bring about policy changes and more effective programs to address the problem of high smoking rates among American Indians. PMID- 21695024 TI - An optimal centralized carbon dioxide repository for Florida, USA. AB - For over a decade, the United States Department of Energy, and engineers, geologists, and scientists from all over the world have investigated the potential for reducing atmospheric carbon emissions through carbon sequestration. Numerous reports exist analyzing the potential for sequestering carbon dioxide at various sites around the globe, but none have identified the potential for a statewide system in Florida, USA. In 2005, 83% of Florida's electrical energy was produced by natural gas, coal, or oil (e.g., fossil fuels), from power plants spread across the state. In addition, only limited research has been completed on evaluating optimal pipeline transportation networks to centralized carbon dioxide repositories. This paper describes the feasibility and preliminary locations for an optimal centralized Florida-wide carbon sequestration repository. Linear programming optimization modeling is used to plan and route an idealized pipeline network to existing Florida power plants. Further analysis of the subsurface geology in these general locations will provide insight into the suitability of the subsurface conditions and the available capacity for carbon sequestration at selected possible repository sites. The identification of the most favorable site(s) is also presented. PMID- 21695025 TI - Intensity and inhalation of smoking in the aetiology of laryngeal cancer. AB - The carcinogenic effect of smoking on laryngeal cancer is well established; however, the risk pattern for detailed smoking characteristics is less clear. Thus, the aim of this analysis was to quantify the impact of different inhalation behaviours on the risk of laryngeal cancer. We conducted a population-based case control study in Germany, frequency-matched for sex and age, using a standardized questionnaire covering lifelong smoking details, including age at start, time since quitting, types of smoking products, duration, intensity and inhalation behaviour. We found higher risks for increasing duration and intensity of smoking. A clear dose-response relationship was found in all inhalation subgroups, i.e., not only for deep inhalers, but also for those puffing on a cigarette. Clearly reduced risks could be observed for quitting smoking. Changing inhalation habits might be considered as a first step to reducing the risk of developing laryngeal cancer. However, the best way to effectively reduce laryngeal cancer risk is to quit smoking. PMID- 21695026 TI - A multidisciplinary, science-based approach to the economics of climate change. AB - Economic analyses of environmental mitigation and other interdisciplinary public policy issues can be much more useful if they critically examine what other disciplines have to say, insist on using the most relevant observational data and the scientific method, and examine lower cost alternatives to the change proposed. These general principles are illustrated by applying them to the case of climate change mitigation, one of the most interdisciplinary of public policy issues. The analysis shows how use of these principles leads to quite different conclusions than those of most previous such economic analyses, as follows: The economic benefits of reducing CO(2) emissions may be about two orders of magnitude less than those estimated by most economists because the climate sensitivity factor (CSF) is much lower than assumed by the United Nations because feedback is negative rather than positive and the effects of CO(2) emissions reductions on atmospheric CO(2) appear to be short rather than long lasting. The costs of CO(2) emissions reductions are very much higher than usually estimated because of technological and implementation problems recently identified. Geoengineering such as solar radiation management is a controversial alternative to CO(2) emissions reductions that offers opportunities to greatly decrease these large costs, change global temperatures with far greater assurance of success, and eliminate the possibility of low probability, high consequence risks of rising temperatures, but has been largely ignored by economists. CO(2) emissions reductions are economically unattractive since the very modest benefits remaining after the corrections for the above effects are quite unlikely to economically justify the much higher costs unless much lower cost geoengineering is used.The risk of catastrophic anthropogenic global warming appears to be so low that it is not currently worth doing anything to try to control it, including geoengineering. PMID- 21695027 TI - An assessment of psychological noise reduction by landscape plants. AB - The emphasis in the term 'Green Transportation' is on the word 'green'. Green transportation focuses on the construction of a slow transport system with a visually pleasing, easy and secure trip environment composed of urban parks, green roadside spaces and some other space that is full of landscape plants. This trip environment encourages residents to make trip choices that reduce fuel consumption and pollution and is one of the most important ways of popularizing green transportation. To study the psychological benefits provided by urban parks and other landscape environments, we combined a subjective approach (a questionnaire) with an objective quantitative approach (emotional tests using an electroencephalogram; EEG). Using a questionnaire survey, we found that 90% of the subjects believed that landscape plants contribute to noise reduction and that 55% overrated the plants' actual ability to attenuate noise. Two videos (showing a traffic scene and a plant scene) were shown to 40 participants on video glasses. We detected and recorded EEG values with a portable electroencephalograph, and a comparison between the results of the two groups revealed that there was a highly significant asymmetry between the EEG activity of the vegetation scene and traffic scene groups. The results suggest that the emotions aroused by noise and visual stimuli are manifested in the synchronization of beta frequency band and the desynchronization of alpha frequency band, indicating that landscape plants can moderate or buffer the effects of noise. These findings indicate that landscape plants provide excess noise attenuating effects through subjects' emotional processing, which we term 'psychological noise reduction'. PMID- 21695028 TI - A four-step method for optimising the normal water level of reservoirs based on a mathematical programming model--a case study for the Songyuan backwater dam in Jilin Province, China. AB - Determination of the optimal normal water level of reservoirs (RNWL) was investigated, incorporating environmental ecology as a primary consideration. RNWL constitutes a relatively significant eigenvalue of any water conservancy project. In the present study, a four-step method based on a mathematical programming model and suitable for RNWL decision making was developed and applied to the water conservancy project of the Songyuan backwater dam in China. System analysis, correlation analysis, significance testing, principal component analysis, sensitivity analysis, and system optimisation theory are used in the solution process. In this study, various factors that impact the economic viability, engineering characteristics, environmental and urban ecology are considered for holistic optimisation. The study shows that the proposed four-step method may provide a feasible quantitative form of support for RNWL decision making. PMID- 21695029 TI - Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community. AB - Organophosphorus (OP) pesticides are used in agriculture and several are registered for home use. As young children age they may experience different pesticide exposures due to varying diet, behavior, and other factors. We measured six OP dialkylphosphate (DAP) metabolites (three dimethyl alkylphosphates (DMAP) and three diethyl alkylphosphates (DEAP)) in urine samples collected from ~400 children living in an agricultural community when they were 6, 12, and 24 months old. We examined bivariate associations between DAP metabolite levels and determinants such as age, diet, season, and parent occupation. To evaluate independent impacts, we then used generalized linear mixed multivariable models including interaction terms with age. The final models indicated that DMAP metabolite levels increased with age. DMAP levels were also positively associated with daily servings of produce at 6- and 24-months. Among the 6-month olds, DMAP metabolite levels were higher when samples were collected during the summer/spring versus the winter/fall months. Among the 12-month olds, DMAP and DEAP metabolites were higher when children lived <= 60 meters from an agricultural field. Among the 24-month-olds, DEAP metabolite levels were higher during the summer/spring months. Our findings suggest that there are multiple determinants of OP pesticide exposures, notably dietary intake and temporal and spatial proximity to agricultural use. The impact of these determinants varied by age and class of DAP metabolite. PMID- 21695030 TI - Applying factor analysis combined with kriging and information entropy theory for mapping and evaluating the stability of groundwater quality variation in Taiwan. AB - In Taiwan many factors, whether geological parent materials, human activities, and climate change, can affect the groundwater quality and its stability. This work combines factor analysis and kriging with information entropy theory to interpret the stability of groundwater quality variation in Taiwan between 2005 and 2007. Groundwater quality demonstrated apparent differences between the northern and southern areas of Taiwan when divided by the Wu River. Approximately 52% of the monitoring wells in southern Taiwan suffered from progressing seawater intrusion, causing unstable groundwater quality. Industrial and livestock wastewaters also polluted 59.6% of the monitoring wells, resulting in elevated EC and TOC concentrations in the groundwater. In northern Taiwan, domestic wastewaters polluted city groundwater, resulting in higher NH(3)-N concentration and groundwater quality instability was apparent among 10.3% of the monitoring wells. The method proposed in this study for analyzing groundwater quality inspects common stability factors, identifies potential areas influenced by common factors, and assists in elevating and reinforcing information in support of an overall groundwater management strategy. PMID- 21695031 TI - Respiratory health symptoms among students exposed to different levels of air pollution in a Turkish city. AB - In this study, we aimed to investigate the frequency of respiratory health symptoms among high school students attending schools at industrial, urban and rural areas in a Turkish city. Three schools located in different zones of the city having different pollution characteristics were chosen based on the pollutant distribution maps using Geographical Information Systems (GIS) software. A cross-sectional survey was performed among 667 high school students in the schools. Outdoor and indoor nitrogen dioxide (NO(2)) and ozone (O(3)) concentrations were also measured by passive samplers in the same schools to investigate possible routes of exposure. Chronic pulmonary disease (OR = 1.49; 95%CI: 1.11-1.99; p = 0.008), tightness in the chest (OR = 1.57; 95%CI: 1.22 2.02; p = 0.001), morning cough (OR = 1.81 95%CI: 1.19-2.75; p = 0.006) were higher among students in the industrial zone where nitrogen dioxide and ozone levels were also highest. There were no indoor sources of nitrogen dioxide and ozone exists in the schools except for the dining hall. As a conclusion, this study has noticed that air pollution and respiratory health problems among high school students are high in industrial zones and the use of passive samplers combined with GIS is an effective tool that may be used by public health researchers to identify pollutant zones and persons at risk. PMID- 21695032 TI - Assessment of water quality in a subtropical alpine lake using multivariate statistical techniques and geostatistical mapping: a case study. AB - Concerns about the water quality in Yuan-Yang Lake (YYL), a shallow, subtropical alpine lake located in north-central Taiwan, has been rapidly increasing recently due to the natural and anthropogenic pollution. In order to understand the underlying physical and chemical processes as well as their associated spatial distribution in YYL, this study analyzes fourteen physico-chemical water quality parameters recorded at the eight sampling stations during 2008-2010 by using multivariate statistical techniques and a geostatistical method. Hierarchical clustering analysis (CA) is first applied to distinguish the three general water quality patterns among the stations, followed by the use of principle component analysis (PCA) and factor analysis (FA) to extract and recognize the major underlying factors contributing to the variations among the water quality measures. The spatial distribution of the identified major contributing factors is obtained by using a kriging method. Results show that four principal components i.e., nitrogen nutrients, meteorological factor, turbidity and nitrate factors, account for 65.52% of the total variance among the water quality parameters. The spatial distribution of principal components further confirms that nitrogen sources constitute an important pollutant contribution in the YYL. PMID- 21695033 TI - The dynamics of norovirus outbreak epidemics: recent insights. AB - Noroviruses are a major cause of gastroenteritis outbreaks worldwide. Norovirus outbreaks frequently occur as epidemics which appear to be related to both genetic and environmental factors. This review considers recent progress in understanding these factors. The norovirus genome undergoes continuous change and this appears to be important in the persistence of the virus in the community. Studies on the common GII.4 genotype have shown that some norovirus outbreak epidemics involving this genotype are correlated with specific changes in the genome. In contrast to the growing understanding of the role of genetic factors in norovirus outbreak epidemics, the role of environmental factors is less well understood. Topics reviewed here include long term excretion of norovirus in some individuals, long term survivability of norovirus in the environment, the role of meteorological factors in the control of norovirus outbreaks and the possible zoonotic transmission of the virus. PMID- 21695034 TI - The public health impact of coccidioidomycosis in Arizona and California. AB - The numbers of reported cases of coccidioidomycosis in Arizona and California have risen dramatically over the past decade, with a 97.8% and 91.1% increase in incidence rates from 2001 to 2006 in the two states, respectively. Of those cases with reported race/ethnicity information, Black/African Americans in Arizona and Hispanics and African/Americans in California experienced a disproportionately higher frequency of disease compared to other racial/ethnic groups. Lack of early diagnosis continues to be a problem, particularly in suspect community-acquired pneumonia, underscoring the need for more rapid and sensitive tests. Similarly, the inability of currently available therapeutics to reduce the duration and morbidity of this disease underscores the need for improved therapeutics and a preventive vaccine. PMID- 21695036 TI - Combining a fuzzy matter-element model with a geographic information system in eco-environmental sensitivity and distribution of land use planning. AB - Sustainable ecological and environmental development is the basis of regional development. The sensitivity classification of the ecological environment is the premise of its spatial distribution for land use planning. In this paper, a fuzzy matter-element model and factor-overlay method were employed to analyze the ecological sensitivity in Yicheng City. Four ecological indicators, including soil condition,, water condition,, atmospheric conditions and biodiversity were used to classify the ecological sensitivity. The results were categorized into five ranks: insensitive, slightly sensitive, moderately sensitive, highly sensitive and extremely sensitive zones. The spatial distribution map of environmental sensitivity for land use planning was obtained using GIS (Geographical Information System) techniques. The results illustrated that the extremely sensitive and highly sensitive areas accounted for 14.40% and 30.12% of the total area, respectively, while the moderately sensitive and slightly sensitive areas are 25.99% and 29.49%, respectively. The results provide the theoretical foundation for land use planning by categorizing all kinds of land types in Yicheng City. PMID- 21695035 TI - Malnutrition and gastrointestinal and respiratory infections in children: a public health problem. AB - Infectious disease is the major cause of morbidity and mortality in developing countries, particularly in children. Increasing evidence suggests that protein calorie malnutrition is the underlying reason for the increased susceptibility to infections observed in these areas. Moreover, certain infectious diseases also cause malnutrition, which can result in a vicious cycle. Malnutrition and bacterial gastrointestinal and respiratory infections represent a serious public health problem. The increased incidence and severity of infections in malnourished children is largely due to the deterioration of immune function; limited production and/or diminished functional capacity of all cellular components of the immune system have been reported in malnutrition. In this review, we analyze the cyclical relationship between malnutrition, immune response dysfunction, increased susceptibility to infectious disease, and metabolic responses that further alter nutritional status. The consequences of malnutrition are diverse and included: increased susceptibility to infection, impaired child development, increased mortality rate and individuals who come to function in suboptimal ways. PMID- 21695037 TI - Survey mode effects on valuation of environmental goods. AB - This article evaluates the effect of the choice of survey recruitment mode on the value of water quality in lakes, rivers, and streams. Four different modes are compared: bringing respondents to one central location after phone recruitment, mall intercepts in two states, national phone-mail survey, and an Internet survey with a national, probability-based panel. The modes differ in terms of the representativeness of the samples, non-response rates, sample selection effects, and consistency of responses. The article also shows that the estimated value of water quality can differ substantially depending on the survey mode. The national Internet panel has the most desirable properties with respect to performance on the four important survey dimensions of interest. PMID- 21695038 TI - Population surveillance of dementia mortality. AB - Geographic and temporal variation in occurrence of dementia within the US has received little attention despite its importance for generation of new etiologic hypotheses and health services research. We examine methodological problems in the use of vital statistics data for assessing variation over time, among states and within states in the US. We analyzed the US multiple cause of death files for 2005-2006 and 1999-2000 US deaths with Alzheimer's Disease (International Classification of Disease 10th revision code G30) and other dementias (codes F01, F02, R54) coded as underlying or contributing cause of death based on the death certificate. Age-adjusted death rates were computed by year, state or county for persons aged 65 years and over. In 2005-2006 combined, 555,904 total deaths occurred with any dementia type (212,386 for Alzheimer's disease) coded as underlying or contributing cause. Among the states, age-adjusted rates per 100,000 per year varied by two fold ranging from 458 in New York to 921 in Oregon. Similar geographic patterns were seen for Alzheimer's disease. However, between 1999-2000 and 2005-2006 the US death rate for all dementia increased only from 559 to 695 (24%) while that for Alzheimer's disease doubled from 135 to 266. Use of specific (G30, F01) versus non-specific diagnoses (F02, R54) varied among states and over time, explaining most of the temporal increase in rate of Alzheimer's disease. Further research is needed to assess artifacts of diagnosis, certification or coding, utilization of health services, versus biological variation as possible causes of temporal and geographic variation to enhance utility of mortality data for dementia monitoring and research. PMID- 21695039 TI - Degradation of glyphosate in soil photocatalyzed by Fe3O4/SiO2/TiO2 under solar light. AB - In this study, Fe(3)O(4)/SiO(2)/TiO(2) photocatalyst was prepared via a sol-gel method, and Fe(3)O(4) particles were used as the core of the colloid. Diffraction peaks of Fe(3)O(4) crystals are not found by XRD characterization, indicating that Fe(3)O(4) particles are well encapsulated by SiO(2). FTIR characterization shows that diffraction peaks of Ti-O-Si chemical bonds become obvious when the Fe(3)O(4) loading is more than 0.5%. SEM characterization indicates that agglomeration occurs in the Fe(3)O(4)/SiO(2)/TiO(2) photocatalyst, whereas photocatalysts modified by Fe(3)O(4)/SiO(2) present excellent visible light absorption performance and photocatalytic activity, especially when the Fe(3)O(4) loading is 0.5%. Photocatalytic degradation of glyphosate in soil by these photocatalysts under solar irradiation was investigated. Results show that 0.5% Fe(3)O(4)/SiO(2)/TiO(2) has the best photocatalytic activity. The best moisture content of soil is 30%~50%. Degradation efficiency of glyphosate reaches 89% in 2 h when the dosage of photocatalyst is 0.4 g/100 g (soil), and it increased slowly when more photocatalyst was used. Soil thickness is a very important factor for the photocatalytic rate. The thinner the soil is, the better the glyphosate degradation is. Degradation of glyphosate is not obviously affected by sunlight intensity when the intensity is below 6 mW/cm(2) or above 10 mW/cm(2), but it is accelerated significantly when the sunlight intensity increases from 6 mW/cm(2) to 10 mW/cm(2). PMID- 21695040 TI - RapiData: a practical course in macromolecular X-ray diffraction data measurement and structure solving at the NSLS. AB - RapiData provides two days of high-level lectures, then two more of experimental work on several beamlines of the National Synchrotron Light Source, for about 50 students. Students are invited to bring their own research projects for measurement, and about half of them do. The students frequently solve half a dozen structures during the course. Tutorials by the lecturers run throughout the data-collection period. The crystal-preparation laboratory is popular for tutorials and practice, and often there is a beamline available for practice. This article provides details about the organization of the course and tells some of the reasons for its success. PMID- 21695041 TI - The n-of-1 clinical trial: the ultimate strategy for individualizing medicine? AB - N-of-1 or single subject clinical trials consider an individual patient as the sole unit of observation in a study investigating the efficacy or side-effect profiles of different interventions. The ultimate goal of an n-of-1 trial is to determine the optimal or best intervention for an individual patient using objective data-driven criteria. Such trials can leverage study design and statistical techniques associated with standard population-based clinical trials, including randomization, washout and crossover periods, as well as placebo controls. Despite their obvious appeal and wide use in educational settings, n-of 1 trials have been used sparingly in medical and general clinical settings. We briefly review the history, motivation and design of n-of-1 trials and emphasize the great utility of modern wireless medical monitoring devices in their execution. We ultimately argue that n-of-1 trials demand serious attention among the health research and clinical care communities given the contemporary focus on individualized medicine. PMID- 21695043 TI - Gemcitabine: efficacy in the treatment of advanced stage nonsquamous non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer-related death in many countries. Approximately half of the patients with non-small cell lung cancer have advanced disease and systemic chemotherapy, especially platinum-based doublets, is currently the standard treatment. Several trials have recently indicated the importance of histological subtype for treatment with molecular target chemotherapy and pemetrexed. Over the last decade, gemcitabine, a pyrimidine nucleoside antimetabolite, has been one of the most effective agents for patients with advanced non-small cell lung cancer. It is unknown whether histological type is a predictor of the outcome of treatment with this agent. This is a review of the past trials and reviews of first-line treatment for advanced NSCLC, focusing on efficacy and safety of treatment with gemcitabine according to histological subtype. PMID- 21695042 TI - Varicella zoster virus latency. AB - Primary infection by varicella zoster virus (VZV) typically results in childhood chickenpox, at which time latency is established in the neurons of the cranial nerve, dorsal root and autonomic ganglia along the entire neuraxis. During latency, the histone-associated virus genome assumes a circular episomal configuration from which transcription is epigenetically regulated. The lack of an animal model in which VZV latency and reactivation can be studied, along with the difficulty in obtaining high-titer cell-free virus, has limited much of our understanding of VZV latency to descriptive studies of ganglia removed at autopsy and analogy to HSV-1, the prototype alphaherpesvirus. However, the lack of miRNA, detectable latency-associated transcript and T-cell surveillance during VZV latency highlight basic differences between the two neurotropic herpesviruses. This article focuses on VZV latency: establishment, maintenance and reactivation. Comparisons are made with HSV-1, with specific attention to differences that make these viruses unique human pathogens. PMID- 21695044 TI - Interactions of the algicidal bacterium Kordia algicida with diatoms: regulated protease excretion for specific algal lysis. AB - Interactions of planktonic bacteria with primary producers such as diatoms have great impact on plankton population dynamics. Several studies described the detrimental effect of certain bacteria on diatoms but the biochemical nature and the regulation mechanism involved in the production of the active compounds remained often elusive. Here, we investigated the interactions of the algicidal bacterium Kordia algicida with the marine diatoms Skeletonema costatum, Thalassiosira weissflogii, Phaeodactylum tricornutum, and Chaetoceros didymus. Algicidal activity was only observed towards the first three of the tested diatom species while C. didymus proved to be not susceptible. The cell free filtrate and the >30 kDa fraction of stationary K. algicida cultures is fully active, suggesting a secreted algicidal principle. The active supernatant from bacterial cultures exhibited high protease activity and inhibition experiments proved that these enzymes are involved in the observed algicidal action of the bacteria. Protease mediated interactions are not controlled by the presence of the alga but dependent on the cell density of the K. algicida culture. We show that protease release is triggered by cell free bacterial filtrates suggesting a quorum sensing dependent excretion mechanism of the algicidal protein. The K. algicida / algae interactions in the plankton are thus host specific and under the control of previously unidentified factors. PMID- 21695045 TI - Novel nanohybrids of silver particles on clay platelets for inhibiting silver resistant bacteria. AB - We develop a novel nanohybrid showing a strong antibacterial activity on all of the tested pathogens, including methicillin-resistant Staphylococcus auerus and silver-resistant E. coli. The nanohybrid consists of silver nanoparticles (AgNPs) supported on 1 nm-thick silicate platelets (NSPs). The AgNP/NSP nanohybrid enables to encapsulate bacteria and triggers death signals from the cell membrane. The geographic shape of the NSPs concentrates AgNPs but impedes their penetration into attached cells, mitigating the detrimental effect of silver ion deposition in applied tissues. Moreover, the tightly tethered AgNPs on NSP surface achieve a stronger biocidal effect than silver nitrate, but bypassing Ag(+) mechanism, on silver-resistant bacteria. This nanohybrid presents an effective and safe antimicrobial agent in a new perspective. PMID- 21695047 TI - Comparison of the efficacies of loop-mediated isothermal amplification, fluorescence smear microscopy and culture for the diagnosis of tuberculosis. AB - BACKGROUND: Despite the advent of novel diagnostic techniques, smear microscopy remains as the most practical test available in resource-limited settings for tuberculosis (TB) diagnosis. Due to the low sensitivity of microscopy and the long time required for culture, feasible and accessible rapid diagnostic methods are urgently needed. Loop-mediated Isothermal Amplification (LAMP) is a promising nucleic-acid amplification assay, which could be accessible, cost-effective and more suited for use with unpurified samples. METHODOLOGY/PRINCIPAL FINDINGS: In the current study, the objective was to assess the efficacy of a LAMP assay for tuberculosis compared with fluorescence smear microscopy as well as Lowenstein Jensen (LJ) and Mycobacteria Growth Indicator Tube (MGIT) cultures for the diagnosis of pulmonary tuberculosis using sputum samples. Smear microscopy and culture were performed for decontaminated and concentrated sputum from TB suspects and the LAMP was also performed on these specimens. The LAMP and smear microscopy were compared, in series and in parallel, to culture. LAMP and smear microscopy showed sensitivities of 79.5% and 82.1% respectively and specificities of 93.8% and 96.9% respectively, compared to culture. LAMP and smear in series had sensitivity and specificity of 79.5% and 100.0% respectively. LAMP and smear in parallel had sensitivity and specificity of 82.1% and 90.6% respectively. CONCLUSIONS/SIGNIFICANCE: The overall efficacies of LAMP and fluorescence smear microscopy in the current study were high and broadly similar. LAMP and smear in series had high specificity (100.0%) and can be used as a rule-in test combination. However, the performance of LAMP in smear negative samples was found to be insufficient. PMID- 21695046 TI - Substrate specifity profiling of the Aspergillus fumigatus proteolytic secretome reveals consensus motifs with predominance of Ile/Leu and Phe/Tyr. AB - BACKGROUND: The filamentous fungus Aspergillus fumigatus (AF) can cause devastating infections in immunocompromised individuals. Early diagnosis improves patient outcomes but remains challenging because of the limitations of current methods. To augment the clinician's toolkit for rapid diagnosis of AF infections, we are investigating AF secreted proteases as novel diagnostic targets. The AF genome encodes up to 100 secreted proteases, but fewer than 15 of these enzymes have been characterized thus far. Given the large number of proteases in the genome, studies focused on individual enzymes may overlook potential diagnostic biomarkers. METHODOLOGY AND PRINCIPAL FINDINGS: As an alternative, we employed a combinatorial library of internally quenched fluorogenic probes (IQFPs) to profile the global proteolytic secretome of an AF clinical isolate in vitro. Comparative protease activity profiling revealed 212 substrate sequences that were cleaved by AF secreted proteases but not by normal human serum. A central finding was that isoleucine, leucine, phenylalanine, and tyrosine predominated at each of the three variable positions of the library (44.1%, 59.1%, and 57.0%, respectively) among substrate sequences cleaved by AF secreted proteases. In contrast, fewer than 10% of the residues at each position of cleaved sequences were cationic or anionic. Consensus substrate motifs were cleaved by thermostable serine proteases that retained activity up to 50 degrees C. Precise proteolytic cleavage sites were reliably determined by a simple, rapid mass spectrometry based method, revealing predominantly non-prime side specificity. A comparison of the secreted protease activities of three AF clinical isolates revealed consistent protease substrate specificity fingerprints. However, secreted proteases of A. flavus, A. nidulans, and A. terreus strains exhibited striking differences in their proteolytic signatures. CONCLUSIONS: This report provides proof-of-principle for the use of protease substrate specificity profiling to define the proteolytic secretome of Aspergillus fumigatus. Expansion of this technique to protease secretion during infection could lead to development of novel approaches to fungal diagnosis. PMID- 21695048 TI - PEDF regulates vascular permeability by a gamma-secretase-mediated pathway. AB - Increased vascular permeability is an inciting event in many vascular complications including diabetic retinopathy. We have previously reported that pigment epithelium-derived factor (PEDF) is able to inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis through a novel gamma-secretase dependent pathway. In this study, we asked whether inhibition of VEGF-induced permeability by PEDF is also gamma-secretase-mediated and to dissect the potential mechanisms involved. Vascular permeability was assessed in vitro by measuring transendothelial resistance and paracellular permeability to dextran and in vivo by following leakage of intravenous FITC-labelled albumin into the retina in the presence or absence of VEGF and PEDF in varying combinations. Experiments were undertaken in the presence or absence of a gamma-secretase inhibitor. To assess junctional integrity immunohistochemistry for the adherens junction (AJ) proteins, VE-cadherin and beta-catenin, and the tight junction (TJ) protein, claudin-5 was undertaken using cultured cells and flat mount retinas. Protein expression and the association between AJ proteins, VEGF receptors (VEGFRs) and gamma-secretase constituents were determined by immunoprecipitation and Western Blot analysis. In selected experiments the effect of hypoxia on junctional integrity was also assessed. PEDF inhibition of VEGF-induced permeability, both in cultured microvascular endothelial cell monolayers and in vivo in the mouse retinal vasculature, is mediated by gamma-secretase. PEDF acted by a) preventing dissociation of AJ and TJ proteins and b) regulating both the association of VEGF receptors with AJ proteins and the subsequent phosphorylation of the AJ proteins, VE-cadherin and beta-catenin. Association of gamma-secretase with AJ proteins appears to be critical in the regulation of vascular permeability. Although hypoxia increased VEGFR expression there was a significant dissociation of VEGFR from AJ proteins. In conclusion, PEDF regulates VEGF induced vascular permeability via a novel gamma-secretase dependent pathway and targeting downstream effectors of PEDF action may represent a promising therapeutic strategy for preventing or ameliorating increased vascular permeability. PMID- 21695049 TI - Diploid-specific [corrected] genome stability genes of S. cerevisiae: genomic screen reveals haploidization as an escape from persisting DNA rearrangement stress. AB - Maintaining a stable genome is one of the most important tasks of every living cell and the mechanisms ensuring it are similar in all of them. The events leading to changes in DNA sequence (mutations) in diploid cells occur one to two orders of magnitude more frequently than in haploid cells. The majority of those events lead to loss of heterozygosity at the mutagenesis marker, thus diploid specific genome stability mechanisms can be anticipated. In a new global screen for spontaneous loss of function at heterozygous forward mutagenesis marker locus, employing three different mutagenesis markers, we selected genes whose deletion causes genetic instability in diploid Saccharomyces cerevisiae cells. We have found numerous genes connected with DNA replication and repair, remodeling of chromatin, cell cycle control, stress response, and in particular the structural maintenance of chromosome complexes. We have also identified 59 uncharacterized or dubious ORFs, which show the genome instability phenotype when deleted. For one of the strongest mutators revealed in our screen, ctf18Delta/ctf18Delta the genome instability manifests as a tendency to lose the whole set of chromosomes. We postulate that this phenomenon might diminish the devastating effects of DNA rearrangements, thereby increasing the cell's chances of surviving stressful conditions. We believe that numerous new genes implicated in genome maintenance, together with newly discovered phenomenon of ploidy reduction, will help revealing novel molecular processes involved in the genome stability of diploid cells. They also provide the clues in the quest for new therapeutic targets to cure human genome instability-related diseases. PMID- 21695050 TI - The role of neutrophils in corneal wound healing in HO-2 null mice. AB - Our studies demonstrated that Heme oxygenase (HO), in particular, the constitutive HO-2, is critical for a self-resolving inflammatory and repair response in the cornea. Epithelial injury in HO-2 null mice leads to impaired wound closure and chronic inflammation in the cornea. This study was undertaken to examine the possible relationship between HO-2 and the recruitment of neutrophils following a corneal surface injury in wild type (WT) and HO-2 knockout (HO-2(-/-)) mice treated with Gr-1 monoclonal antibody to deplete peripheral neutrophils. Epithelial injury was performed by removing the entire corneal epithelium. Infiltration of inflammatory cell into the cornea in response to injury was higher in HO-2(-/-) than in WT. However, the rate of corneal wound closure following neutrophil depletion was markedly inhibited in both WT and HO 2(-/-) mice by 60% and 85%, respectively. Neutropenia induced HO-1 expression in WT but not in HO-2(-/-) mice. Moreover, endothelial cells lacking HO-2 expressed higher levels of the Midkine and VE-cadherin and displayed strong adhesion to neutrophils suggesting that perturbation in endothelial cell function caused by HO-2 depletion underlies the increased infiltration of neutrophils into the HO-2( /-) cornea. Moreover, the fact that neutropenia worsened epithelial healing of the injured cornea in both WT and HO-2(-/-) mice suggest that cells other than neutrophils contribute to the exaggerated inflammation and impaired wound healing seen in the HO-2 null cornea. PMID- 21695051 TI - Characterization of HCV interactions with Toll-like receptors and RIG-I in liver cells. AB - BACKGROUND AND AIM: The aim of this study was to examine the mechanisms of IFN induction and viral escape. In order to accomplish the goal we compared our new hepatoma cell line LH86, which has intact TLR3 and RIG-I expression and responds to HCV by inducing IFN, with Huh7.5 cells which lack those features. METHODS: The initial interaction of LH86 cells, Huh7.5 cells or their transfected counter parts (LH86 siRIG-I, siTLR3 or siTLR7 and Huh7.5 RIG-I, TLR3 or TLR7) after infection with HCV (strain JFH-1) was studied by measuring the expression levels of IFNbeta, TRAIL, DR4, DR5 and their correlation to viral replication. RESULTS: HCV replicating RNA induces IFN in LH86 cells. The IFN induction system is functional in LH86, and the expression of the RIG-I and TLR3 in LH86 is comparable to the primary hepatocytes. Both proteins appear to play important roles in suppression of viral replication. We found that innate immunity against HCV is associated with the induction of apoptosis by RIG-I through the TRAIL pathway and the establishment of an antiviral state by TLR3. HCV envelope proteins interfere with the expression of TLR3 and RIG-I. CONCLUSION: These findings correlate with the lower expression level of PRRs in HCV chronic patients and highlight the importance of the PRRs in the initial interaction of the virus and its host cells. This work represents a novel mechanism of viral pathogenesis for HCV and demonstrates the role of PRRs in viral infection. PMID- 21695053 TI - MRI pattern recognition in multiple sclerosis normal-appearing brain areas. AB - OBJECTIVE: Here, we use pattern-classification to investigate diagnostic information for multiple sclerosis (MS; relapsing-remitting type) in lesioned areas, areas of normal-appearing grey matter (NAGM), and normal-appearing white matter (NAWM) as measured by standard MR techniques. METHODS: A lesion mapping was carried out by an experienced neurologist for Turbo Inversion Recovery Magnitude (TIRM) images of individual subjects. Combining this mapping with templates from a neuroanatomic atlas, the TIRM images were segmented into three areas of homogenous tissue types (Lesions, NAGM, and NAWM) after spatial standardization. For each area, a linear Support Vector Machine algorithm was used in multiple local classification analyses to determine the diagnostic accuracy in separating MS patients from healthy controls based on voxel tissue intensity patterns extracted from small spherical subregions of these larger areas. To control for covariates, we also excluded group-specific biases in deformation fields as a potential source of information. RESULTS: Among regions containing lesions a posterior parietal WM area was maximally informative about the clinical status (96% accuracy, p<10(-13)). Cerebellar regions were maximally informative among NAGM areas (84% accuracy, p<10(-7)). A posterior brain region was maximally informative among NAWM areas (91% accuracy, p<10(-10)). INTERPRETATION: We identified regions indicating MS in lesioned, but also NAGM, and NAWM areas. This complements the current perception that standard MR techniques mainly capture macroscopic tissue variations due to focal lesion processes. Compared to current diagnostic guidelines for MS that define areas of diagnostic information with moderate spatial specificity, we identified hotspots of MS associated tissue alterations with high specificity defined on a millimeter scale. PMID- 21695052 TI - Coe genes are expressed in differentiating neurons in the central nervous system of protostomes. AB - Genes of the coe (collier/olfactory/early B-cell factor) family encode Helix-Loop Helix transcription factors that are widely conserved in metazoans and involved in many developmental processes, neurogenesis in particular. Whereas their functions during vertebrate neural tube formation have been well documented, very little is known about their expression and role during central nervous system (CNS) development in protostomes. Here we characterized the CNS expression of coe genes in the insect Drosophila melanogaster and the polychaete annelid Platynereis dumerilii, which belong to different subgroups of protostomes and show strikingly different modes of development. In the Drosophila ventral nerve cord, we found that the Collier-expressing cells form a subpopulation of interneurons with diverse molecular identities and neurotransmitter phenotypes. We also demonstrate that collier is required for the proper differentiation of some interneurons belonging to the Eve-Lateral cluster. In Platynereis dumerilii, we cloned a single coe gene, Pdu-coe, and found that it is exclusively expressed in post mitotic neural cells. Using an original technique of in silico 3D registration, we show that Pdu-coe is co-expressed with many different neuronal markers and therefore that, like in Drosophila, its expression defines a heterogeneous population of neurons with diverse molecular identities. Our detailed characterization and comparison of coe gene expression in the CNS of two distantly-related protostomes suggest conserved roles of coe genes in neuronal differentiation in this clade. As similar roles have also been observed in vertebrates, this function was probably already established in the last common ancestor of all bilaterians. PMID- 21695054 TI - The implications of relationships between human diseases and metabolic subpathways. AB - One of the challenging problems in the etiology of diseases is to explore the relationships between initiation and progression of diseases and abnormalities in local regions of metabolic pathways. To gain insight into such relationships, we applied the "k-clique" subpathway identification method to all disease-related gene sets. For each disease, the disease risk regions of metabolic pathways were then identified and considered as subpathways associated with the disease. We finally built a disease-metabolic subpathway network (DMSPN). Through analyses based on network biology, we found that a few subpathways, such as that of cytochrome P450, were highly connected with many diseases, and most belonged to fundamental metabolisms, suggesting that abnormalities of fundamental metabolic processes tend to cause more types of diseases. According to the categories of diseases and subpathways, we tested the clustering phenomenon of diseases and metabolic subpathways in the DMSPN. The results showed that both disease nodes and subpathway nodes displayed slight clustering phenomenon. We also tested correlations between network topology and genes within disease-related metabolic subpathways, and found that within a disease-related subpathway in the DMSPN, the ratio of disease genes and the ratio of tissue-specific genes significantly increased as the number of diseases caused by the subpathway increased. Surprisingly, the ratio of essential genes significantly decreased and the ratio of housekeeping genes remained relatively unchanged. Furthermore, the coexpression levels between disease genes and other types of genes were calculated for each subpathway in the DMSPN. The results indicated that those genes intensely influenced by disease genes, including essential genes and tissue specific genes, might be significantly associated with the disease diversity of subpathways, suggesting that different kinds of genes within a disease-related subpathway may play significantly differential roles on the diversity of diseases caused by the corresponding subpathway. PMID- 21695055 TI - Expression of Fbxo7 in haematopoietic progenitor cells cooperates with p53 loss to promote lymphomagenesis. AB - Fbxo7 is an unusual F box protein that augments D-type cyclin complex formation with Cdk6, but not Cdk4 or Cdk2, and its over-expression has been demonstrated to transform immortalised fibroblasts in a Cdk6-dependent manner. Here we present new evidence in vitro and in vivo on the oncogenic potential of this regulatory protein in primary haematopoietic stem and progenitor cells (HSPCs). Increasing Fbxo7 expression in HSPCs suppressed their colony forming ability in vitro, specifically decreasing CD11b (Mac1) expression, and these effects were dependent on an intact p53 pathway. Furthermore, increased Fbxo7 levels enhanced the proliferative capacity of p53 null HSPCs when they were grown in reduced concentrations of stem cell factor. Finally, irradiated mice reconstituted with p53 null, but not wild-type, HSPCs expressing Fbxo7 showed a statistically significant increase in the incidence of T cell lymphoma in vivo. These data argue that Fbxo7 negatively regulates the proliferation and differentiation of HSPCs in a p53-dependent manner, and that in the absence of p53, Fbxo7 expression can promote T cell lymphomagenesis. PMID- 21695056 TI - The ubiquitin-like protein PLIC-1 or ubiquilin 1 inhibits TLR3-Trif signaling. AB - BACKGROUND: The innate immune responses to virus infection are initiated by either Toll-like receptors (TLR3/7/8/9) or cytoplasmic double-stranded RNA (dsRNA)-recognizing RNA helicases RIG-I and MDA5. To avoid causing injury to the host, these signaling pathways must be switched off in time by negative regulators. METHODOLOGY/PRINCIPAL FINDINGS: Through yeast-two hybrid screening, we found that an ubiquitin-like protein named protein linking integrin-associated protein to cytoskeleton 1(PLIC-1 or Ubiquilin 1) interacted with the Toll/interleukin-1 receptor (TIR) domain of TLR4. Interestingly, PLIC-1 had modest effect on TLR4-mediated signaling, but strongly suppressed the transcriptional activation of IFN-beta promoter through the TLR3-Trif-dependent pathway. Concomitantly, reduction of endogenous PLIC-1 by short-hairpin interfering RNA (shRNA) enhanced TLR3 activation both in luciferase reporter assays as well as in new castle disease virus (NDV) infected cells. An interaction between PLIC-1 and Trif was confirmed in co-immunoprecipitation (Co IP) and GST-pull-down assays. Subsequent confocal microscopic analysis revealed that PLIC-1 and Trif colocalized with the autophagosome marker LC3 in punctate subcellular structures. Finally, overexpression of PLIC-1 decreased Trif protein abundance in a Nocodazole-sensitive manner. CONCLUSIONS: Our results suggest that PLIC-1 is a novel inhibitor of the TLR3-Trif antiviral pathway by reducing the abundance of Trif. PMID- 21695057 TI - Characterization of the diversity and temporal stability of bacterial communities in human milk. AB - Recent investigations have demonstrated that human milk contains a variety of bacterial genera; however, as of yet very little work has been done to characterize the full diversity of these milk bacterial communities and their relative stability over time. To more thoroughly investigate the human milk microbiome, we utilized microbial identification techniques based on pyrosequencing of the 16S ribosomal RNA gene. Specifically, we characterized the bacterial communities present in milk samples collected from 16 women at three time-points over four weeks. Results indicated that milk bacterial communities were generally complex; several genera represented greater than 5% of the relative community abundance, and the community was often, yet not always, stable over time within an individual. These results support the conclusion that human milk, which is recommended as the optimal nutrition source for almost all healthy infants, contains a collection of bacteria more diverse than previously reported. This finding begs the question as to what role this community plays in colonization of the infant gastrointestinal tract and maintaining mammary health. PMID- 21695058 TI - Abrogation of junctional adhesion molecule-A expression induces cell apoptosis and reduces breast cancer progression. AB - Intercellular junctions promote homotypic cell to cell adhesion and transfer intracellular signals which control cell growth and apoptosis. Junctional adhesion molecule-A (JAM-A) is a transmembrane immunoglobulin located at tight junctions of normal epithelial cells of mammary ducts and glands. In the present paper we show that JAM-A acts as a survival factor for mammary carcinoma cells. JAM-A null mice expressing Polyoma Middle T under MMTV promoter develop significantly smaller mammary tumors than JAM-A positive mice. Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased. Tumor cells isolated from JAM-A null mice or 4T1 cells incubated with JAM-A blocking antibodies showed reduced growth and increased apoptosis which paralleled altered junctional architecture and adhesive function. In a breast cancer clinical data set, tissue microarray data show that JAM-A expression correlates with poor prognosis. Gene expression analysis of mouse tumor samples showed a correlation between genes enriched in human G3 tumors and genes over expressed in JAM-A +/+ mammary tumors. Conversely, genes enriched in G1 human tumors correlate with genes overexpressed in JAM-A-/- tumors. We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis. JAM-A may be considered a negative prognostic factor and a potential therapeutic target. PMID- 21695059 TI - Pink-colored grape berry is the result of short insertion in intron of color regulatory gene. AB - We report here that pink grape berries were obtained by a short insertion in the intron of the MybA1 gene, a gene that regulates grape berry color. Genetic variation was detected among the MybA1 genes from grapes cultivated worldwide. PCR analysis of the MybA1 gene demonstrated that the size of the MybA1 gene in the red allele differs among grapes. Oriental V. vinifera bearing pink berries has the longest MybA1 gene among grapes, whereas the shortest MybA1 gene was detected in occidental V. vinifera grapes. The nucleotide sequences of the MybA1 genes demonstrated that oriental V. vinifera has two additional gene fragments (44 bp and 111 bp) in the promoter region of the MybA1 gene in the red allele and another 33 bp fragment in the second intron of the MybA1 gene in the red allele. The short insertion in the intron decreased the transcription activity in the model system and retained MybA1 transcripts with unspliced intron in the total RNA. From the experiments using deletion mutants of the 33 bp short insertion, 16 bp of the 3' end in the insertion is a key structure for a defect in splicing of MybA1 transcripts. Thus, a weakly colored grape berry might be a result of the short insertion in the intron of a color regulatory gene. This is new evidence concerning the molecular mechanism of the fate of grape berry color. These findings are expected to contribute to the further understanding of the color variation in grape berries, which is correlated with the evolutional events occurring in the MybA1 gene of grapes. PMID- 21695060 TI - Determination of the proteolytic cleavage sites of the amyloid precursor-like protein 2 by the proteases ADAM10, BACE1 and gamma-secretase. AB - Regulated intramembrane proteolysis of the amyloid precursor protein (APP) by the protease activities alpha-, beta- and gamma-secretase controls the generation of the neurotoxic amyloid beta peptide. APLP2, the amyloid precursor-like protein 2, is a homolog of APP, which shows functional overlap with APP, but lacks an amyloid beta domain. Compared to APP, less is known about the proteolytic processing of APLP2, in particular in neurons, and the cleavage sites have not yet been determined. APLP2 is cleaved by the beta-secretase BACE1 and additionally by an alpha-secretase activity. The two metalloproteases ADAM10 and ADAM17 have been suggested as candidate APLP2 alpha-secretases in cell lines. Here, we used RNA interference and found that ADAM10, but not ADAM17, is required for the constitutive alpha-secretase cleavage of APLP2 in HEK293 and SH-SY5Y cells. Likewise, in primary murine neurons knock-down of ADAM10 suppressed APLP2 alpha-secretase cleavage. Using mass spectrometry we determined the proteolytic cleavage sites in the APLP2 sequence. ADAM10 was found to cleave APLP2 after arginine 670, whereas BACE1 cleaves after leucine 659. Both cleavage sites are located in close proximity to the membrane. gamma-secretase cleavage was found to occur at different peptide bonds between alanine 694 and valine 700, which is close to the N-terminus of the predicted APLP2 transmembrane domain. Determination of the APLP2 cleavage sites enables functional studies of the different APLP2 ectodomain fragments and the production of cleavage-site specific antibodies for APLP2, which may be used for biomarker development. PMID- 21695061 TI - No elevated plasma catecholamine levels during sleep in newly diagnosed, untreated hypertensives. AB - The sympatho-adrenergic system is highly involved in regulating sleep, wake and arousal states, and abnormalities in this system are regarded as a key factor in the development and progression of arterial hypertension. While hypertension is associated with a hyperadrenergic state during wakefulness, the effect of hypertension on plasma-catecholamine levels during sleep is not yet known. Twelve young participants with newly diagnosed, untreated hypertension and twelve healthy controls slept for 7 hours in the sleep laboratory. Before and after sleep, subjects rested in a supine position for 3-h periods of wakefulness. We sampled blood at a fast rate (1/10 min) and monitored blood pressure and heart rate continuously. We show that plasma NE and E levels did not differ between hypertensives and normotensive during sleep as well as before and after sleep. Blood pressure was higher in hypertensives, reaching the largest group difference in the morning after sleep. Unlike in the normotensives, in the hypertensive participants the morning rise in blood pressure did not correlate with the rise in catecholamine levels at awakening. Our results suggest that hypertension in its early stages is not associated with a strong hyperadrenergic state during sleep. In showing a diminished control of blood pressure through sympatho adrenergic signals in hypertensive participants, our data point towards a possible involvement of dysfunctional sleep-related blood pressure regulation in the development of hypertension. PMID- 21695062 TI - Role of kinesin heavy chain in Crumbs localization along the rhabdomere elongation in Drosophila photoreceptor. AB - BACKGROUND: Crumbs (Crb), a cell polarity gene, has been shown to provide a positional cue for the extension of the apical membrane domain, adherens junction (AJ), and rhabdomere along the growing proximal-distal axis during Drosophila photoreceptor morphogenesis. In developing Drosophila photoreceptors, a stabilized microtubule structure was discovered and its presence was linked to polarity protein localization. It was therefore hypothesized that the microtubules may provide trafficking routes for the polarity proteins during photoreceptor morphogenesis. This study has examined whether Kinesin heavy chain (Khc), a subunit of the microtubule-based motor Kinesin-1, is essential in polarity protein localization in developing photoreceptors. METHODOLOGY/PRINCIPAL FINDINGS: Because a genetic interaction was found between crb and khc, Crb localization was examined in the developing photoreceptors of khc mutants. khc was dispensable during early eye differentiation and development. However, khc mutant photoreceptors showed a range of abnormalities in the apical membrane domain depending on the position along the proximal-distal axis in pupal photoreceptors. The khc mutant showed a progressive mislocalization in the apical domain along the distal-proximal axis during rhabdomere elongation. The khc mutation also led to a similar progressive defect in the stabilized microtubule structures, strongly suggesting that Khc is essential for microtubule structure and Crb localization during distal to proximal rhabdomere elongation in pupal morphogenesis. This role of Khc in apical domain control was further supported by khc's gain-of-function phenotype. Khc overexpression in photoreceptors caused disruption of the apical membrane domain and the stabilized microtubules in the developing photoreceptors. CONCLUSIONS/SIGNIFICANCE: In summary, we examined the role of khc in the regulation of the apical Crb domain in developing photoreceptors. Since the rhabdomeres in developing pupal eyes grow along the distal-proximal axis, these phenotypes suggest that Khc is essential for the microtubule structures and apical membrane domains during the distal-proximal elongation of photoreceptors, but is dispensable for early eye development. PMID- 21695063 TI - Proteasome particle-rich structures are widely present in human epithelial neoplasms: correlative light, confocal and electron microscopy study. AB - A novel cytoplasmic structure has been recently characterized by confocal and electron microscopy in H. pylori-infected human gastric epithelium, as an accumulation of barrel-like proteasome reactive particles colocalized with polyubiquitinated proteins, H. pylori toxins and the NOD1 receptor. This proteasome particle-rich cytoplasmic structure (PaCS), a sort of focal proteasome hyperplasia, was also detected in dysplastic cells and was found to be enriched in SHP2 and ERK proteins, known to play a role in H. pylori-mediated gastric carcinogenesis. However, no information is available on its occurrence in neoplastic growths. In this study, surgical specimens of gastric cancer and various other human epithelial neoplasms have been investigated for PaCSs by light, confocal and electron microscopy including correlative confocal and electron microscopy (CCEM). PaCSs were detected in gastric cohesive, pulmonary large cell and bronchioloalveolar, thyroid papillary, parotid gland, hepatocellular, ovarian serous papillary, uterine cervix and colon adenocarcinomas, as well as in pancreatic serous microcystic adenoma. H. pylori bodies, their virulence factors (VacA, CagA, urease, and outer membrane proteins) and the NOD1 bacterial proteoglycan receptor were selectively concentrated inside gastric cancer PaCSs, but not in PaCSs from other neoplasms which did, however, retain proteasome and polyubiquitinated proteins reactivity. No evidence of actual microbial infection was obtained in most PaCS-positive neoplasms, except for H. pylori in gastric cancer and capsulated bacteria in a colon cancer case. Particle lysis and loss of proteasome distinctive immunoreactivities were seen in some tumour cell PaCSs, possibly ending in sequestosomes or autophagic bodies. It is concluded that PaCSs are widely represented in human neoplasms and that both non-infectious and infectious factors activating the ubiquitin-proteasome system are likely to be involved in their origin. PaCS detection might help clarify the role of the ubiquitin-proteasome system in carcinogenesis. PMID- 21695064 TI - THE RISKS OF CONCURRENT TREATMENT WITH TENOFOVIR AND AMINOGLYCOSIDES IN PATIENTS WITH HIV-ASSOCIATED TUBERCULOSIS. PMID- 21695065 TI - The Influence of Maternal History of Abuse on Parenting Knowledge and Behavior. AB - This study examined the intergenerational transmission of abuse among a sample of 681 teen, adult low, and adult high resource first-time mothers. Participants ranged in age from 14 to 36 years, with a mean of 20 years. Exposure to childhood emotional and physical abuse was associated with 6-month parenting behavior; but not parenting knowledge. Teen mothers, as opposed to adult mothers, had higher mean scores for exposure to childhood emotional and physical abuse. Adult high resource mothers reported lower mean scores on each abuse outcome than both teen and adult low resource mothers. For the total sample of mothers, as past exposure to emotional and physical abuse increased, maternal responsivity decreased, and opinions towards, and propensities for, abusive behavior increased. PMID- 21695066 TI - GENT: gene expression database of normal and tumor tissues. AB - BACKGROUND: Some oncogenes such as ERBB2 and EGFR are over-expressed in only a subset of patients. Cancer outlier profile analysis is one of computational approaches to identify outliers in gene expression data. A database with a large sample size would be a great advantage when searching for genes over-expressed in only a subset of patients. DESCRIPTION: GENT (Gene Expression database of Normal and Tumor tissues) is a web-accessible database that provides gene expression patterns across diverse human cancer and normal tissues. More than 40000 samples, profiled by Affymetrix U133A or U133plus2 platforms in many different laboratories across the world, were collected from public resources and combined into two large data sets, helping the identification of cancer outliers that are over-expressed in only a subset of patients. Gene expression patterns in nearly 1000 human cancer cell lines are also provided. In each tissue, users can retrieve gene expression patterns classified by more detailed clinical information. CONCLUSIONS: The large samples size (>24300 for U133plus2 and >16400 for U133A) of GENT provides an advantage in identifying cancer outliers. A cancer cell line gene expression database is useful for target validation by in vitro experiment. We hope GENT will be a useful resource for cancer researchers in many stages from target discovery to target validation. GENT is available at http://medicalgenome.kribb.re.kr/GENT/ or http://genome.kobic.re.kr/GENT/. PMID- 21695067 TI - Model-integrated estimation of normal tissue contamination for cancer SNP allelic copy number data. AB - SNP allelic copy number data provides intensity measurements for the two different alleles separately. We present a method that estimates the number of copies of each allele at each SNP position, using a continuous-index hidden Markov model. The method is especially suited for cancer data, since it includes the fraction of normal tissue contamination, often present when studying data from cancer tumors, into the model. The continuous-index structure takes into account the distances between the SNPs, and is thereby appropriate also when SNPs are unequally spaced. In a simulation study we show that the method performs favorably compared to previous methods even with as much as 70% normal contamination. We also provide results from applications to clinical data produced using the Affymetrix genome-wide SNP 6.0 platform. PMID- 21695068 TI - Metagenes associated with survival in non-small cell lung cancer. AB - NSCLC (non-small cell lung cancer) comprises about 80% of all lung cancer cases worldwide. Surgery is most effective treatment for patients with early-stage disease. However, 30%-55% of these patients develop recurrence within 5 years. Therefore, markers that can be used to accurately classify early-stage NSCLC patients into different prognostic groups may be helpful in selecting patients who should receive specific therapies.A previously published dataset was used to evaluate gene expression profiles of different NSCLC subtypes. A moderated two sample t-test was used to identify differentially expressed genes between all tumor samples and cancer-free control tissue, between SCC samples and AC/BC samples and between stage I tumor samples and all other tumor samples. Gene expression microarray measurements were validated using qRT-PCR.Bayesian regression analysis and Kaplan-Meier survival analysis were performed to determine metagenes associated with survival. We identified 599 genes which were down-regulated and 402 genes which were up-regulated in NSCLC compared to the normal lung tissue and 112 genes which were up-regulated and 101 genes which were down-regulated in AC/BC compared to the SCC. Further, for stage Ib patients the metagenes potentially associated with survival were identified.Genes that expressed differently between normal lung tissue and cancer showed enrichment in gene ontology terms which were associated with mitosis and proliferation. Bayesian regression and Kaplan-Meier analysis showed that gene-expression patterns and metagene profiles can be applied to predict the probability of different survival outcomes in NSCLC patients. PMID- 21695069 TI - Recurrent floods and prevalence of diarrhea among under five children: observations from Bahraich district, Uttar Pradesh, India. AB - BACKGROUND: Diarrhea is an important problem among the under-five children in India. OBJECTIVE: The paper examines long-term impacts of recurrent floods on diarrhea among under-five children in Uttar Pradesh, India. DESIGN: A two stage stratified cluster survey was conducted in flood affected (exposed) and non-flood affected areas (unexposed). RESULTS: The long-term impact of the floods was not clearly marked in the overall prevalence of diarrhea with the exposed group having prevalence of 55.1% as against 56.2% in the unexposed group of children under five. Economic condition of the household is associated with the prevalence of diarrhea in both exposed and unexposed strata. Anemia was found to be a significant risk factor for diarrhea among children in both the flood exposed and non-flood exposed populations. The recurrent floods did not have any significant effect on the prevalence of diarrhea in relation to gender, religion, caste, and household size. CONCLUSIONS: The study indicates that the long-term impacts of floods are very differently manifested than the immediate impacts. PMID- 21695070 TI - The implications of autonomy: Viewed in the light of efforts to uphold patients dignity and integrity. AB - This article focuses on Danish patients' experience of autonomy and its interplay with dignity and integrity in their meeting with health professionals. The aim is to chart the meanings and implications of autonomy for persons whose illness places them in a vulnerable life situation. The interplay between autonomy and personal dignity in the meeting with health care staff are central concepts in the framework. Data collection and findings are based on eight qualitative semi structured interviews with patients. Patients with acute, chronic, and life threatening diseases were represented including surgical as well as medical patients. The values associated with autonomy are in many ways vitalising, but may become so dominant, autonomy seeking, and pervasive that the patient's dignity is affected. Three types of patient behaviour were identified. (1) The proactive patient: Patients feel that they assume responsibility for their own situation, but it may be a responsibility that they find hard to bear. (2) The rejected patient: proactive patients take responsibility on many occasions but very active patients are at risk of being rejected with consequences for their dignity. (3) The knowledgeable patient: when patients are health care professionals, the patient's right of self-determination was managed in a variety of ways, sometimes the patient's right of autonomy was treated in a dignified way but the opposite was also evident. In one way, patients are active and willing to take responsibility for themselves, and at the same time they are "forced" to do so by health care staff. Patients would like health professionals to be more attentive and proactive. PMID- 21695071 TI - Changing patterns of tobacco use in a middle-aged population: the role of snus, gender, age, and education. AB - BACKGROUND: In Sweden, the smoking prevalence has declined. In 2007, it was among the lowest in the industrialized world. A steady increase in the use of Swedish oral moist snuff, snus, has occurred in parallel. This development is neither solicited by authorities nor the medical establishment, but rather has occurred along with increased awareness of the dangers of smoking, and has been promoted by product development and marketing of snus. OBJECTIVE: To evaluate time trends in patterns of tobacco use in northern Sweden during 1990-2007. DESIGN: Cross sectional (99,381 subjects) and longitudinal (26,867 subjects) data from the Vasterbotten Intervention Programme (VIP) 1990-2007 were analyzed. All adults in Vasterbotten County are invited to a VIP health examination at ages 40, 50, and 60 years, and until 1995 also 30 years. Smoking and use of snus were evaluated by gender, age and educational groups. Intermittent smoking was categorized as smoking. RESULTS: From the period 1990-1995 to the period 2002-2007, smoking prevalence decreased from 26 to 16% among men and from 27 to 18% among women. The differences in prevalence increased between educational groups. The decline in smoking was less and the increase of snus use was greater among those with basic education. The use of snus among basic-educated 40-year-olds reached 35% among men and 14% among women during 2002-2007. Dual smoking and snus use increased among men and women with basic education. Smoking without snus use was more prevalent among women. Gender differences in total smoking prevalence (smoking only plus dual use) were small in all age groups, but increased among those with basic education reaching 7.3% during 2002-2007, with women being more frequent smokers. Smoking prevalences were similar among never, former and current snus users. Among the 30,000 former smokers, 38% of men and 64% of women had never used snus. Longitudinal data showed a decline in total tobacco use from baseline until follow-up and this was mainly due to a smoking cessation rate of<1% a year. Snus use was started by 6.2% of the 30-year-old women (age at baseline), and this contributed to a stable prevalence of total tobacco use in this group. Seventy percent of baseline snus users still used snus at follow-up. Among smokers, 55% continued smoking, 12% of men and 7% of women switched to snus. Among those with dual tobacco use at baseline, a third of men and a fourth of women remained dual users 10 years later. CONCLUSION: There are increasing differences in tobacco use between educational groups. Higher smoking and snus use prevalence are found among those with basic education, and this is most pronounced in the younger group of this middle-aged population. In spite of a higher prevalence of smoking without snus use among women, total smoking prevalence is similar in men and women due to a higher prevalence of dual tobacco use, i.e. snus and cigarettes, among men. The increase in snus use is being paralleled by a slight increase in dual use and the smoking prevalence does not seem to be influenced by snus. This should be the subject of further studies and also have implications for tobacco control policies. PMID- 21695072 TI - Social capital and post-disaster mental health. AB - BACKGROUND: Despite national and international policies to develop social capital in disaster-affected communities, empiric evidence on the association between social capital and disaster mental health is limited and ambiguous. OBJECTIVE: The study explores the relationship between social capital and disaster mental health outcomes (PTSD, anxiety, and depression) in combination with individual factors (appraisal, coping behavior, and social support). DESIGN: This is a community-based cross-sectional study in a flood-affected town in northern England. The study is part of the MICRODIS multi-country research project that examines the impact of natural disasters. It included 232 flood-affected respondents. RESULTS: The findings showed that a considerable part of the association between cognitive and structural social capital and mental health is exerted through individual appraisal processes (i.e. property loss, primary and secondary appraisal), social support, and coping behavior. These individual factors were contingent on social capital. After the inclusion of individual characteristics, cognitive social capital was negatively related to lower mental health problems and structural social capital was positively associated to experiencing anxiety but not to PTSD or depression. Depression and anxiety showed a different pattern of association with both components of social capital. CONCLUSIONS: Individual oriented stress reducing interventions that use appraisal processes, social support, and coping as starting points could be more effective by taking into account the subjective experience of the social context in terms of trust and feelings of mutual support and reciprocity in a community. Findings indicate that affected people may especially benefit from a combination of individual stress reducing interventions and psychosocial interventions that foster cognitive social capital. PMID- 21695073 TI - A unique resource mutualism between the giant Bornean pitcher plant, Nepenthes rajah, and members of a small mammal community. AB - The carnivorous pitcher plant genus Nepenthes grows in nutrient-deficient substrates and produce jug-shaped leaf organs (pitchers) that trap arthropods as a source of N and P. A number of Bornean Nepenthes demonstrate novel nutrient acquisition strategies. Notably, three giant montane species are engaged in a mutualistic association with the mountain treeshrew, Tupaia montana, in which the treeshrew defecates into the pitchers while visiting them to feed on nectar secretions on the pitchers' lids.Although the basis of this resource mutualism has been elucidated, many aspects are yet to be investigated. We sought to provide insights into the value of the mutualism to each participant. During initial observations we discovered that the summit rat, R. baluensis, also feeds on sugary exudates of N. rajah pitchers and defecates into them, and that this behavior appears to be habitual. The scope of the study was therefore expanded to assess to what degree N. rajah interacts with the small mammal community.We found that both T. montana and R. baluensis are engaged in a mutualistic interaction with N. rajah. T .montana visit pitchers more frequently than R. baluensis, but daily scat deposition rates within pitchers do not differ, suggesting that the mutualistic relationships are of a similar strength. This study is the first to demonstrate that a mutualism exists between a carnivorous plant species and multiple members of a small mammal community. Further, the newly discovered mutualism between R. baluensis and N. rajah represents only the second ever example of a multidirectional resource-based mutualism between a mammal and a carnivorous plant. PMID- 21695074 TI - Determinants of non-vaccination against pandemic 2009 H1N1 influenza in pregnant women: a prospective cohort study. AB - BACKGROUND: In October 2009, the French government organized a national-wide, free of charge vaccination campaign against pandemic H1N1 influenza virus, especially targeting pregnant women, a high risk group for severe illness. The study objective was to evaluate pandemic flu vaccine uptake and factors associated with non-vaccination in a population of pregnant women. METHODOLOGY/PRINCIPAL FINDINGS: In a prospective cohort conducted in 3 maternity hospitals in Paris, 882 pregnant women were randomly included between October 12, 2009 and February 3, 2010, with the aim to study characteristics of pandemic influenza during pregnancy. At inclusion, socio-demographic, medical, obstetrical factors and those associated with a higher risk of flu exposition and disease spreading were systematically collected. Pandemic flu vaccine uptake was checked until delivery. 555 (62.9%) women did not get vaccinated. Determinants associated with non-vaccination in a multivariate logistic regression were: geographic origin (Sub-Saharan African origin, adjusted Odd Ratio aOR = 5.4[2.3-12.7], North African origin, aOR = 2.5[1.3-4.7] and Asian origin, aOR = 2.1[1.7-2.6] compared to French and European origin) and socio-professional categories (farmers, craftsmen and tradesmen, aOR = 2.3[2.0-2.6], intermediate professionals, aOR = 1.3[1.0-1.6], employees and manual workers, aOR = 2.5[1.4-4.4] compared to managers and intellectual professionals). The probability of not receiving pandemic flu vaccine was lower among women vaccinated against seasonal flu in the previous 5 years (aOR = 0.6[0.4-0.8]) and among those who stopped smoking before or early during pregnancy (aOR = 0.6[0.4-0.8]). Number of children less than 18 years old living at home, work in contact with children or in healthcare area, or professional contact with the public, were not associated with a higher vaccine uptake. CONCLUSIONS/SIGNIFICANCE: In this cohort of pregnant women, vaccine coverage against pandemic 2009 A/H1N1 flu was low, particularly in immigrant women and those having a low socio-economic status. To improve its effectiveness, future vaccination campaign for pregnant women should be more specifically tailored for these populations. PMID- 21695076 TI - Molecular cloning and gene expression analysis of Ercc6l in Sika deer (Cervus nippon hortulorum). AB - BACKGROUND: One important protein family that functions in nucleotide excision repair (NER) factors is the SNF2 family. A newly identified mouse ERCC6-like gene, Ercc6l (excision repair cross-complementing rodent repair deficiency, complementation group 6-like), has been shown to be another developmentally related member of the SNF2 family. METHODOLOGY/PRINCIPAL FINDINGS: In this study, Sika deer Ercc6l cDNA was first cloned and then sequenced. The full-length cDNA of the Sika deer Ercc6l gene is 4197 bp and contains a 3732 bp open reading frame that encodes a putative protein of 1243 amino acids. The similarity of Sika deer Ercc6l to Bos taurus Ercc6l is 94.05% at the amino acid sequence level. The similarity, however, is reduced to 68.42-82.21% when compared to Ercc6l orthologs in other mammals and to less than 50% compared to orthologs in Gallus gallus and Xenopus. Additionally, the expression of Ercc6l mRNA was investigated in the organs of fetal and adult Sika deer (FSD and ASD, respectively) by quantitative RT-PCR. The common expression level of Ercc6l mRNA in the heart, liver, spleen, lung, kidney, and stomach from six different developmental stages of 18 Sika deer were examined, though the expression levels in each organ varied among individual Sika deer. During development, there was a slight trend toward decreased Ercc61 mRNA expression. The highest Ercc6l expression levels were seen at 3 months old in every organ and showed the highest level of detection in the spleen of FSD. The lowest Ercc6l expression levels were seen at 3 years old. CONCLUSIONS/SIGNIFICANCE: We are the first to successfully clone Sika deer Ercc6l mRNA. Ercc6l transcript is present in almost every organ. During Sika deer development, there is a slight trend toward decreased Ercc61 mRNA expression. It is possible that Ercc6l has other roles in embryonic development and in maintaining the growth of animals. PMID- 21695075 TI - Life course trajectories of systolic blood pressure using longitudinal data from eight UK cohorts. AB - BACKGROUND: Much of our understanding of the age-related progression of systolic blood pressure (SBP) comes from cross-sectional data, which do not directly capture within-individual change. We estimated life course trajectories of SBP using longitudinal data from seven population-based cohorts and one predominantly white collar occupational cohort, each from the United Kingdom and with data covering different but overlapping age periods. METHODS AND FINDINGS: Data are from 30,372 individuals and comprise 102,583 SBP observations spanning from age 7 to 80+y. Multilevel models were fitted to each cohort. Four life course phases were evident in both sexes: a rapid increase in SBP coinciding with peak adolescent growth, a more gentle increase in early adulthood, a midlife acceleration beginning in the fourth decade, and a period of deceleration in late adulthood where increases in SBP slowed and SBP eventually declined. These phases were still present, although at lower levels, after adjusting for increases in body mass index though adulthood. The deceleration and decline in old age was less evident after excluding individuals who had taken antihypertensive medication. Compared to the population-based cohorts, the occupational cohort had a lower mean SBP, a shallower annual increase in midlife, and a later midlife acceleration. The maximum sex difference was found at age 26 (+8.2 mm Hg higher in men, 95% CI: 6.7, 9.8); women then experienced steeper rises and caught up by the seventh decade. CONCLUSIONS: Our investigation shows a general pattern of SBP progression from childhood in the UK, and suggests possible differences in this pattern during adulthood between a general population and an occupational population. Please see later in the article for the Editors' Summary. PMID- 21695077 TI - Ploidy of cell-sorted trophic and cystic forms of Pneumocystis carinii. AB - Once regarded as an AIDS-defining illness, Pneumocystis pneumonia (PcP) is nowadays prevailing in immunocompromised HIV-negative individuals such as patients receiving immunosuppressive therapies or affected by primary immunodeficiency. Moreover, Pneumocystis clinical spectrum is broadening to non severely-immunocompromised subjects who could be colonized by the fungus while remaining asymptomatic for PcP, thus being able to transmit the infection by airborne route to susceptible hosts. Although the taxonomical position of the Pneumocystis genus has been clarified, several aspects of its life cycle remain elusive such as its mode of proliferation within the alveolus or its ploidy level. As no long-term culture model exists to grow Pneumocystis organisms in vitro, an option was to use a model of immunosuppressed rat infected with Pneumocystis carinii and sort life cycle stage fractions using a high-through-put cytometer. Subsequently, ploidy levels of the P. carinii trophic and cystic form fractions were measured by flow cytometry. In the cystic form, eight contents of DNA were measured thus strengthening the fact that each mature cyst contains eight haploid spores. Following release, each spore evolves into a trophic form. The majority of the trophic form fraction was haploid in our study. Some less abundant trophic forms displayed two contents of DNA indicating that they could undergo (i) mating/fusion leading to a diploid status or (ii) asexual mitotic division or (iii) both. Even less abundant trophic forms with four contents of DNA were suggestive of mitotic divisions occurring following mating in diploid trophic forms. Of interest, was the presence of trophic forms with three contents of DNA, an unusual finding that could be related to asymmetrical mitotic divisions occurring in other fungal species to create genetic diversity at lower energetic expenses than mating. Overall, ploidy data of P. carinii life cycle stages shed new light on the complexity of its modes of proliferation. PMID- 21695078 TI - Enhanced virulence of Chlamydia muridarum respiratory infections in the absence of TLR2 activation. AB - Chlamydia trachomatis is a common sexually transmitted pathogen and is associated with infant pneumonia. Data from the female mouse model of genital tract chlamydia infection suggests a requirement for TLR2-dependent signaling in the induction of inflammation and oviduct pathology. We hypothesized that the role of TLR2 in moderating mucosal inflammation is site specific. In order to investigate this, we infected mice via the intranasal route with C. muridarum and observed that in the absence of TLR2 activation, mice had more severe disease, higher lung cytokine levels, and an exaggerated influx of neutrophils and T-cells into the lungs. This could not be explained by impaired bacterial clearance as TLR2 deficient mice cleared the infection similar to controls. These data suggest that TLR2 has an anti-inflammatory function in the lung during Chlamydia infection, and that the role of TLR2 in mucosal inflammation varies at different mucosal surfaces. PMID- 21695079 TI - Factors underlying the early limb muscle weakness in acute quadriplegic myopathy using an experimental ICU porcine model. AB - The basic mechanisms underlying acquired generalized muscle weakness and paralysis in critically ill patients remain poorly understood and may be related to prolonged mechanical ventilation/immobilization (MV) or to other triggering factors such as sepsis, systemic corticosteroid (CS) treatment and administration of neuromuscular blocking agents (NMBA). The present study aims at exploring the relative importance of these factors by using a unique porcine model. Piglets were all exposed to MV together with different combinations of endotoxin-induced sepsis, CS and NMBA for five days. Peroneal motor nerve conduction velocity and amplitude of the compound muscle action potential (CMAP) as well as biceps femoris muscle biopsy specimens were obtained immediately after anesthesia on the first day and at the end of the 5-day experimental period. Results showed that peroneal nerve motor conduction velocity is unaffected whereas the size of the CMAP decreases independently of the type of intervention, in all groups after 5 days. Otherwise, despite a preserved size, muscle fibre specific force (maximum force normalized to cross-sectional area) decreased dramatically for animals exposed to MV in combination with CS or/and sepsis. These results suggest that the rapid declines in CMAP amplitude and in force generation capacity are triggered by independent mechanisms with significant clinical and therapeutic implications. PMID- 21695080 TI - Reduced expression of fumarate hydratase in clear cell renal cancer mediates HIF 2alpha accumulation and promotes migration and invasion. AB - Germline mutations of FH, the gene that encodes for the tricarboxylic acid TCA (TCA) cycle enzyme fumarate hydratase, are associated with an inherited form of cancer referred to as Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). Individuals with HLRCC are predisposed to the development of highly malignant and lethal renal cell carcinoma (RCC). The mechanisms of tumorigenesis proposed have largely focused on the biochemical consequences of loss of FH enzymatic activity. While loss of the tumor suppressor gene von Hippel Lindau (VHL) is thought to be an initiating event for the majority of RCCs, a role for FH in sporadic renal cancer has not been explored. Here we report that FH mRNA and protein expression are reduced in clear cell renal cancer, the most common histologic variant of kidney cancer. Moreover, we demonstrate that reduced FH leads to the accumulation of hypoxia inducible factor- 2alpha (HIF-2alpha), a transcription factor known to promote renal carcinogenesis. Finally, we demonstrate that overexpression of FH in renal cancer cells inhibits cellular migration and invasion. These data provide novel insights into the tumor suppressor functions of FH in sporadic kidney cancer. PMID- 21695081 TI - Dynamic construction of stimulus values in the ventromedial prefrontal cortex. AB - Signals representing the value assigned to stimuli at the time of choice have been repeatedly observed in ventromedial prefrontal cortex (vmPFC). Yet it remains unknown how these value representations are computed from sensory and memory representations in more posterior brain regions. We used electroencephalography (EEG) while subjects evaluated appetitive and aversive food items to study how event-related responses modulated by stimulus value evolve over time. We found that value-related activity shifted from posterior to anterior, and from parietal to central to frontal sensors, across three major time windows after stimulus onset: 150-250 ms, 400-550 ms, and 700-800 ms. Exploratory localization of the EEG signal revealed a shifting network of activity moving from sensory and memory structures to areas associated with value coding, with stimulus value activity localized to vmPFC only from 400 ms onwards. Consistent with these results, functional connectivity analyses also showed a causal flow of information from temporal cortex to vmPFC. Thus, although value signals are present as early as 150 ms after stimulus onset, the value signals in vmPFC appear relatively late in the choice process, and seem to reflect the integration of incoming information from sensory and memory related regions. PMID- 21695082 TI - The definition of insulin resistance using HOMA-IR for Americans of Mexican descent using machine learning. AB - OBJECTIVE: The lack of standardized reference range for the homeostasis model assessment-estimated insulin resistance (HOMA-IR) index has limited its clinical application. This study defines the reference range of HOMA-IR index in an adult Hispanic population based with machine learning methods. METHODS: This study investigated a Hispanic population of 1854 adults, randomly selected on the basis of 2000 Census tract data in the city of Brownsville, Cameron County. Machine learning methods, support vector machine (SVM) and Bayesian Logistic Regression (BLR), were used to automatically identify measureable variables using standardized values that correlate with HOMA-IR; K-means clustering was then used to classify the individuals by insulin resistance. RESULTS: Our study showed that the best cutoff of HOMA-IR for identifying those with insulin resistance is 3.80. There are 39.1% individuals in this Hispanic population with HOMA-IR>3.80. CONCLUSIONS: Our results are dramatically different using the popular clinical cutoff of 2.60. The high sensitivity and specificity of HOMA-IR>3.80 for insulin resistance provide a critical fundamental for our further efforts to improve the public health of this Hispanic population. PMID- 21695083 TI - Shared skeletal support in a coral-hydroid symbiosis. AB - Hydroids form symbiotic relationships with a range of invertebrate hosts. Where they live with colonial invertebrates such as corals or bryozoans the hydroids may benefit from the physical support and protection of their host's hard exoskeleton, but how they interact with them is unknown. Electron microscopy was used to investigate the physical interactions between the colonial hydroid Zanclea margaritae and its reef-building coral host Acropora muricata. The hydroid tissues extend below the coral tissue surface sitting in direct contact with the host's skeleton. Although this arrangement provides the hydroid with protective support, it also presents problems of potential interference with the coral's growth processes and exposes the hydroid to overgrowth and smothering. Desmocytes located within the epidermal layer of the hydroid's perisarc-free hydrorhizae fasten it to the coral skeleton. The large apical surface area of the desmocyte and high bifurcation of the distal end within the mesoglea, as well as the clustering of desmocytes suggests that a very strong attachment between the hydroid and the coral skeleton. This is the first study to provide a detailed description of how symbiotic hydroids attach to their host's skeleton, utilising it for physical support. Results suggest that the loss of perisarc, a characteristic commonly associated with symbiosis, allows the hydroid to utilise desmocytes for attachment. The use of these anchoring structures provides a dynamic method of attachment, facilitating detachment from the coral skeleton during extension, thereby avoiding overgrowth and smothering enabling the hydroid to remain within the host colony for prolonged periods of time. PMID- 21695084 TI - Global protection and the health impact of migration interception. PMID- 21695085 TI - LyGDI, a novel SHIP-interacting protein, is a negative regulator of FcgammaR mediated phagocytosis. AB - SHIP and SHIP-2 are inositol phosphatases that regulate FcgammaR-mediated phagocytosis through catalytic as well as non-catalytic mechanisms. In this study we have used two-dimensional fluorescence difference gel electrophoresis (DIGE) analysis to identify downstream signaling proteins that uniquely associate with SHIP or SHIP-2 upon FcgammaR clustering in human monocytes. We identified LyGDI as a binding partner of SHIP, associating inducibly with the SHIP/Grb2/Shc complex. Immunodepletion and competition experiments with recombinant SHIP domains revealed that Grb2 and the proline-rich domain of SHIP were necessary for SHIP-LyGDI association. Functional studies in primary human monocytes showed that LyGDI sequesters Rac in the cytosol, preventing it from localizing to the membrane. Consistent with this, suppression of LyGDI expression resulted in significantly enhanced FcgammaR-mediated phagocytosis. PMID- 21695086 TI - Embryonic death is linked to maternal identity in the leatherback turtle (Dermochelys coriacea). AB - Leatherback turtles have an average global hatching success rate of ~50%, lower than other marine turtle species. Embryonic death has been linked to environmental factors such as precipitation and temperature, although, there is still a lot of variability that remains to be explained. We examined how nesting season, the time of nesting each season, the relative position of each clutch laid by each female each season, maternal identity and associated factors such as reproductive experience of the female (new nester versus remigrant) and period of egg retention between clutches (interclutch interval) affected hatching success and stage of embryonic death in failed eggs of leatherback turtles nesting at Playa Grande, Costa Rica. Data were collected during five nesting seasons from 2004/05 to 2008/09. Mean hatching success was 50.4%. Nesting season significantly influenced hatching success in addition to early and late stage embryonic death. Neither clutch position nor nesting time during the season had a significant affect on hatching success or the stage of embryonic death. Some leatherback females consistently produced nests with higher hatching success rates than others. Remigrant females arrived earlier to nest, produced more clutches and had higher rates of hatching success than new nesters. Reproductive experience did not affect stage of death or the duration of the interclutch interval. The length of interclutch interval had a significant affect on the proportion of eggs that failed in each clutch and the developmental stage they died at. Intrinsic factors such as maternal identity are playing a role in affecting embryonic death in the leatherback turtle. PMID- 21695087 TI - The effect of highly active antiretroviral therapy on the survival of HIV infected children in a resource-deprived setting: a cohort study. AB - BACKGROUND: The effect of highly active antiretroviral therapy (HAART) on the survival of HIV-infected children has not been well quantified. Because most pediatric HIV occurs in low- and middle-income countries, our objective was to provide a first estimate of this effect among children living in a resource deprived setting. METHODS AND FINDINGS: Observational data from HAART-naive children enrolled into an HIV care and treatment program in Kinshasa, Democratic Republic of the Congo, between December 2004 and May 2010 were analyzed. We used marginal structural models to estimate the effect of HAART on survival while accounting for time-dependent confounders affected by exposure. At the start of follow-up, the median age of the 790 children was 5.9 y, 528 (66.8%) had advanced or severe immunodeficiency, and 405 (51.3%) were in HIV clinical stage 3 or 4. The children were observed for a median of 31.2 mo and contributed a total of 2,089.8 person-years. Eighty children (10.1%) died, 619 (78.4%) initiated HAART, six (0.8%) transferred to a different care provider, and 76 (9.6%) were lost to follow-up. The mortality rate was 3.2 deaths per 100 person-years (95% confidence interval [CI] 2.4-4.2) during receipt of HAART and 6.0 deaths per 100 person years (95% CI 4.1-8.6) during receipt of primary HIV care only. The mortality hazard ratio comparing HAART with no HAART from a marginal structural model was 0.25 (95% CI 0.06-0.95). CONCLUSIONS: HAART reduced the hazard of mortality in HIV-infected children in Kinshasa by 75%, an estimate that is similar in magnitude but with lower precision than the reported effect of HAART on survival among children in the United States. Please see later in the article for the Editors' Summary. PMID- 21695088 TI - The relationship between population structure and aluminum tolerance in cultivated sorghum. AB - BACKGROUND: Acid soils comprise up to 50% of the world's arable lands and in these areas aluminum (Al) toxicity impairs root growth, strongly limiting crop yield. Food security is thereby compromised in many developing countries located in tropical and subtropical regions worldwide. In sorghum, SbMATE, an Al activated citrate transporter, underlies the Alt(SB) locus on chromosome 3 and confers Al tolerance via Al-activated root citrate release. METHODOLOGY: Population structure was studied in 254 sorghum accessions representative of the diversity present in cultivated sorghums. Al tolerance was assessed as the degree of root growth inhibition in nutrient solution containing Al. A genetic analysis based on markers flanking Alt(SB) and SbMATE expression was undertaken to assess a possible role for Alt(SB) in Al tolerant accessions. In addition, the mode of gene action was estimated concerning the Al tolerance trait. Comparisons between models that include population structure were applied to assess the importance of each subpopulation to Al tolerance. CONCLUSION/SIGNIFICANCE: Six subpopulations were revealed featuring specific racial and geographic origins. Al tolerance was found to be rather rare and present primarily in guinea and to lesser extent in caudatum subpopulations. Alt(SB) was found to play a role in Al tolerance in most of the Al tolerant accessions. A striking variation was observed in the mode of gene action for the Al tolerance trait, which ranged from almost complete recessivity to near complete dominance, with a higher frequency of partially recessive sources of Al tolerance. A possible interpretation of our results concerning the origin and evolution of Al tolerance in cultivated sorghum is discussed. This study demonstrates the importance of deeply exploring the crop diversity reservoir both for a comprehensive view of the dynamics underlying the distribution and function of Al tolerance genes and to design efficient molecular breeding strategies aimed at enhancing Al tolerance. PMID- 21695089 TI - Changes in plasma fibronectin isoform levels predict distinct clinical outcomes in critically ill patients. AB - INTRODUCTION: Concentrations of the total pool of fibronectin in plasma (TFN), and the subset of this pool that contains the alternatively spliced EDA segment (A(+)FN), are both affected by disease processes, and the latter pool has gained a reputation as a biomarker for vascular injury. We therefore wished to determine if changes in either FN pool correlate with clinical outcomes in critically ill individuals. METHODS: We analyzed a database for 57 patients with major trauma (n = 33) or sepsis syndrome (n = 24) in which plasma levels of TFN and A(+)FN had been measured at intervals, along with clinical parameters. Logistic regression analysis was performed to detect associations between predictive variables and three clinical outcomes: 1) the acute respiratory distress syndrome (ARDS), 2) milder acute lung injury designated acute hypoxemic respiratory failure (AHRF), and 3) survival to hospital discharge. RESULTS: An increase in plasma TFN during the first 24 hours of intensive care unit (ICU) observation was negatively associated with progression to ARDS (odds ratio 0.98 per 1 microgram (MUg)/ml increase, 95% CI (0.97, 1.00)) and AHRF (OR 0.97 per 1 MUg/ml increase, (0.95, 0.99)), whereas an increase in A(+)FN over the first 24 hours was positively associated with progression to AHRF (OR 1.65 per 1 MUg/ml increase, (1.04, 2.62)). Additionally, the ratio of the partial pressure of oxygen in arterial blood (PaO(2)) to the percentage of oxygen in inspired air (FIO(2)) after 24 hours was positively associated with survival (OR 1.01 per 1 unit increase in ratio, (1.00, 1.03)), along with change in A(+)FN (OR 1.30 per 1 MUg/ml increase, (0.90, 1.88)). CONCLUSIONS: Different FN isoforms may constitute predictive covariate markers for distinct clinical outcomes in critically ill patients. The data also suggest that early TFN accumulation in the circulation may confer a clinical benefit to patients at risk for acute lung injury. PMID- 21695090 TI - Ecallantide for the treatment of hereditary angiodema in adults. AB - Hereditary angioedema (HAE) is a clinical disorder characterized by a deficiency of C1 esterase inhibitor (C1-INH). HAE has traditionally been divided into two subtypes. Unique among the inherited deficiencies of the complement system, HAE Types I and II are inherited as an autosomal dominant disorder. The generation of an HAE attack is caused by the depletion and/or consumption of C1-inhibitor manifested as subcutaneous or submucosal edema of the upper airway, face, extremities, or gastrointestinal tract mediated by bradykinin. Attacks can be severe and potentially life-threatening, particularly with laryngeal involvement and treatment of acute attacks in the United States has been severely limited. In December 2009 the FDA approved ecallantide for the treatment of acute HAE attacks. Ecallantide is a small recombinant protein acting as a potent, specific and reversible inhibitor of plasma kallikrein which binds to plasma kallikrein blocking its binding site, directly inhibiting the conversion of high molecular weight kininogen to bradykinin. Administered subcutaneously, ecallantide was demonstrated in two clinical trials, EDEMA3 and EDEMA4, to decrease the length and severity of acute HAE attacks. Although there is a small risk for anaphylaxis, which limits home administration, ecallantide is a novel, safe, effective and alternative treatment for acute HAE attacks. PMID- 21695091 TI - The decade of bedbugs and fear. PMID- 21695092 TI - The impact of densification by means of informal shacks in the backyards of low cost houses on the environment and service delivery in cape town, South Africa. AB - This paper investigates the state-sponsored low cost housing provided to previously disadvantaged communities in the City of Cape Town. The strain imposed on municipal services by informal densification of unofficial backyard shacks was found to create unintended public health risks. Four subsidized low-cost housing communities were selected within the City of Cape Town in this cross-sectional survey. Data was obtained from 1080 persons with a response rate of 100%. Illegal electrical connections to backyard shacks that are made of flimsy materials posed increased fire risks. A high proportion of main house owners did not pay for water but sold water to backyard dwellers. The design of state-subsidised houses and the unplanned housing in the backyard added enormous pressure on the existing municipal infrastructure and the environment. Municipal water and sewerage systems and solid waste disposal cannot cope with the increased population density and poor sanitation behaviour of the inhabitants of these settlements. The low-cost housing program in South Africa requires improved management and prudent policies to cope with the densification of state-funded low-cost housing settlements. PMID- 21695093 TI - Environmental Health Insights into the 2011 Tohoku Japan Earth quake Disaster. PMID- 21695094 TI - Social support and hope among egyptian women with breast cancer after mastectomy. AB - INTRODUCTION: Breast cancer is the most common cancer among Egyptian women. We report the unique assessment of hope and social support outcomes of women with breast cancer after mastectomy in Egyptian community. PATIENTS AND METHODS: Between July 2009 and June 2010, three hundred and one women with newly diagnosed breast cancer joined this study. Socio-demographic data including patient's age, level of education, occupation, social status, and residence were collected by means of structured interviews based on special questionnaires. These questionnaires were designed to measure hope and social support. RESULTS: Age ranged from 21 to 88 years (median = 45.8 years and SD +/- 13.3). A low degree of hope was reported in 103 patients (34.2%), a moderate degree in 109 patients (36.2%), and a high degree in 89 patients (29.6%). A low degree of social support was reported in 119 patients (39.5%), a moderate degree in 101 patients (33.6%), and a high degree in 81 patients (26.9%). CONCLUSIONS: Social support is related to many psychological factors, which can be quantitatively analyzed and it can predict hope. However, there were no significant differences between the socio demographic variables (age, educational levels, residence and martial status) and social support, hope, and their sub-components among Egyptian women with breast cancer. PMID- 21695095 TI - Hormone receptor status in breast cancer and its relation to age and other prognostic factors. AB - BACKGROUND: Increasing evidence shows the importance of young age, estrogen receptor (ER), progesterone receptor (PR) status, and HER-2 expression in patients with breast cancers. PATIENTS AND METHODS: We organized an analytic cross-sectional study of 105 women diagnosed with breast cancer who have been operated on between 2008 to 2010. We evaluated age, size, hormone receptor status, HER-2 and P53 expression as possible indicator of lymph node involvement. RESULTS: There is a direct correlation between positive progesterone receptor status and being younger than 40 (P < 0.05). Also, compared with older women, young women had tumors that were more likely to be large in size and have higher stages (P < 0.05). Furthermore patients with negative progesterone receptor status were more likely to have HER-2 overexpression (P < 0.05). The differences in propensity to lymph node metastasis between hormone receptor statuses were not statically significant. CONCLUSIONS: Although negative progesterone receptor tumors were more likely to have HER-2 overexpression, it is possible that higher stage and larger size breast cancer in younger women is related to positive progesterone receptor status. PMID- 21695096 TI - The Relationship between Visuospatial Memory and Coping Strategies in Breast Cancer Survivors. AB - BACKGROUND: In the US there are over 2.5 million breast cancer survivors (BCSs), most of whom have required some type of intensive treatment. How individuals cope with the treatment process may relate to why neurocognitive problems arise. METHOD: We explored the impact of treatment for breast cancer (BC) on performance of the Memory Island task, both on working memory and on the general index of cognitive performance in relation to coping strategies of BCSs compared to age matched controls. RESULTS: The evidence obtained suggests a reduced performance in visuospatial memory in BCSs. Those who used emotional coping strategies displayed reduced performance in visuospatial learning and immediate memory. Those women who used problem-focused coping strategies performed better in those tasks measuring psychomotor speed, general intelligence, and delayed visuospatial memory. CONCLUSIONS: It is concluded that further investigation of the relationship between coping strategies and performance on visuospatial tasks may provide useful information on residual levels of neurocognitive deficits and psychosocial adaptation in BCSs. PMID- 21695097 TI - Intratumoral Immune Responses Can Distinguish New Primary and True Recurrence Types of Ipsilateral Breast Tumor Recurrences (IBTR). AB - Ipsilateral breast tumor recurrence (IBTR) is an increasingly common clinical challenge. IBTRs include True Recurrences (TR; persistent disease) and New Primaries (NP; de novo tumors), but discrimination between these is difficult. We assessed tumor infiltrating leukocytes (TIL) as biomarkers for distinguishing these types of IBTR using primary tumors and matched IBTRs from 24 breast cancer patients, half of which were identified as putative TRs and half as NPs using a previously reported clinical algorithm. Intratumoral lymphocyte populations (CD3, CD8, CD4, CD25, FOXP3, TIA1, CD20) and macrophages (CD68) were quantified by immunohistochemistry in each tumor. Compared to matched primaries, TRs showed significant trends towards increased CD3(+) and CD8(+) TIL, while these populations were often diminished in NPs. Comparison of IBTRs showed that TRs had significantly higher levels of CD3(+) (P = 0.0136), CD8(+) (P = 0.0092), and CD25(+) (P = 0.0159) TIL than NPs. We conclude that TIL may be a novel diagnostic biomarker to distinguish NP from TR IBTRs. PMID- 21695098 TI - Clinical development of cabazitaxel for the treatment of castration-resistant prostate cancer. AB - Castration resistant prostate cancer has historically been considered chemotherapy insensitive. However, the approval of estramustine phosphate, mitoxantrone, and docetaxel, over the past few decades, has challenged this notion. Despite these advances, until recently, only docetaxel had been shown to improve survival in patients with castration-resistant disease, and there has been no standard treatment options available for men with disease progression on docetaxel. In the last year, cabazitaxel, a novel taxane with decreased affinity for ATP-dependent drug efflux pump P-glycoprotein, became the first cytotoxic agent to demonstrate an improvement in survival in men with docetaxel-refractory disease, and has received regulatory approval for treatment in this setting. In this review, we examine the clinical development of cabazitaxel for the treatment of castration-resistant prostate cancer, as well as rationale and direction of future therapeutic investigation. PMID- 21695099 TI - Bendamustine: safety and efficacy in the management of indolent non-hodgkins lymphoma. AB - Bendamustine (Treanda, Ribomustin) was recently approved by the US Food and Drug Administration (FDA) for treatment of patients with rituximab refractory indolent lymphoma and is expected to turn into a frontline therapy option for indolent lymphoma. This compound with amphoteric properties was designed in the former Germany Democratic Republic in 1960s and re-discovered in 1990s with multiple successive well-designed studies. Bendamustine possesses a unique mechanism of action with potential antimetabolite properties, and only partial cross resistance with other alkylators. Used in combination with rituximab in vitro, bendamustine shows synergistic effects against various leukemia and lymphoma cell lines. In clinical studies, bendamustine plus rituximab is highly effective in patients with relapsed-refractory indolent lymphoma, inducing remissions in 90% or more and a median progression-free survival of 23-24 months. The optimal dosing and schedule of bendamustine administration is largely undecided and varies among studies. Results of ongoing trials and dose-finding studies will help to further help ascertain the optimal place of bendamustine in the management of indolent NHL. PMID- 21695100 TI - Safety and efficacy of vinorelbine in the treatment of non-small cell lung cancer. AB - Lung cancer remains the most frequently diagnosed cancer in the United States, excluding non-melanoma skin cancer. Non-small cell lung cancer (NSCLC) constitutes the majority (more than 80%) of lung cancer diagnoses. Systemic therapy, with either cytotoxic chemotherapy and/or targeted therapies, has been established to provide benefit to patients with NSCLC in both the adjuvant and advanced disease settings. Vinorelbine, a semi-synthetic vinca-alkaloid has been extensively tested alone and in combination with other cytotoxic or targeted agents in the treatment of NSCLC. Its safety has been well established with neutropenia, anemia, nausea, and vomiting being the most frequently encountered toxicities. The data defining the risks and benefits of vinorelbine in the treatment of NSCLC will be summarized. PMID- 21695101 TI - A case of late-onset gemcitabine lung toxicity. AB - Gemcitabine is a chemotherapeutic agent used for the treatment of a number of malignancies. Although its major dose-limiting side effect is myelosuppression, many pulmonary toxicities have been described with its use. Severe pulmonary toxicity is rare, but symptoms tend to be rapid in onset and potentially deadly. The average time from initiation of chemotherapy to onset of symptoms is less than two months. The most effective therapy is steroid administration, the efficacy of which has been variable. In this report, we describe a unique case of gemcitabine pulmonary toxicity in a patient who did not experience symptoms of pulmonary dysfunction until after 1 year of treatment. Her symptoms did not improve rapidly with steroids, nor did she rapidly decompensate as has been frequently described. To our knowledge, this is one of the first reported descriptions of late-onset gemcitabine lung toxicity. PMID- 21695102 TI - Neonatal systemic juvenile xanthogranuloma with an ominous presentation and successful treatment. AB - This case report originated from a case of neonatal multisystemic juvenile xanthogranuloma (JXG). The patient presented with blue muffin rush, cervical mass, bone destruction, lung nodule, hepatosplenomegaly, and coagulopathy and was successfully treated with Langerhans cell histiocytosis (LCH) based chemotherapy treatment. Similar cases in literature were reviewed and it seems that JXG, a relatively benign entity, when presented in its systemic form with liver involvement, could have an aggressive course and portend quite poor prognosis. Challenges and special consideration of the diagnosis, treatment, and future case observation are discussed. PMID- 21695104 TI - A comparison of the sensitivity and fecal egg counts of the McMaster egg counting and Kato-Katz thick smear methods for soil-transmitted helminths. AB - BACKGROUND: The Kato-Katz thick smear (Kato-Katz) is the diagnostic method recommended for monitoring large-scale treatment programs implemented for the control of soil-transmitted helminths (STH) in public health, yet it is difficult to standardize. A promising alternative is the McMaster egg counting method (McMaster), commonly used in veterinary parasitology, but rarely so for the detection of STH in human stool. METHODOLOGY/PRINCIPAL FINDINGS: The Kato-Katz and McMaster methods were compared for the detection of STH in 1,543 subjects resident in five countries across Africa, Asia and South America. The consistency of the performance of both methods in different trials, the validity of the fixed multiplication factor employed in the Kato-Katz method and the accuracy of these methods for estimating 'true' drug efficacies were assessed. The Kato-Katz method detected significantly more Ascaris lumbricoides infections (88.1% vs. 75.6%, p<0.001), whereas the difference in sensitivity between the two methods was non significant for hookworm (78.3% vs. 72.4%) and Trichuris trichiura (82.6% vs. 80.3%). The sensitivity of the methods varied significantly across trials and magnitude of fecal egg counts (FEC). Quantitative comparison revealed a significant correlation (Rs >0.32) in FEC between both methods, and indicated no significant difference in FEC, except for A. lumbricoides, where the Kato-Katz resulted in significantly higher FEC (14,197 eggs per gram of stool (EPG) vs. 5,982 EPG). For the Kato-Katz, the fixed multiplication factor resulted in significantly higher FEC than the multiplication factor adjusted for mass of feces examined for A. lumbricoides (16,538 EPG vs. 15,396 EPG) and T. trichiura (1,490 EPG vs. 1,363 EPG), but not for hookworm. The McMaster provided more accurate efficacy results (absolute difference to 'true' drug efficacy: 1.7% vs. 4.5%). CONCLUSIONS/SIGNIFICANCE: The McMaster is an alternative method for monitoring large-scale treatment programs. It is a robust (accurate multiplication factor) and accurate (reliable efficacy results) method, which can be easily standardized. PMID- 21695103 TI - TLR1/2 activation during heterologous prime-boost vaccination (DNA-MVA) enhances CD8+ T Cell responses providing protection against Leishmania (Viannia). AB - BACKGROUND: Leishmania (Viannia) parasites present particular challenges, as human and murine immune responses to infection are distinct from other Leishmania species, indicating a unique interaction with the host. Further, vaccination studies utilizing small animal models indicate that modalities and antigens that prevent infection by other Leishmania species are generally not protective. METHODOLOGY: Using a newly developed mouse model of chronic L. (Viannia) panamensis infection and the heterologous DNA prime - modified vaccinia virus Ankara (MVA) boost vaccination modality, we examined whether the conserved vaccine candidate antigen tryparedoxin peroxidase (TRYP) could provide protection against infection/disease. RESULTS: Heterologous prime - boost (DNA/MVA) vaccination utilizing TRYP antigen can provide protection against disease caused by L. (V.) panamensis. However, protection is dependent on modulating the innate immune response using the TLR1/2 agonist Pam3CSK4 during DNA priming. Prime-boost vaccination using DNA alone fails to protect. Prior to infection protectively vaccinated mice exhibit augmented CD4 and CD8 IFNgamma and memory responses as well as decreased IL-10 and IL-13 responses. IL-13 and IL-10 have been shown to be independently critical for disease in this model. CD8 T cells have an essential role in mediating host defense, as CD8 depletion reversed protection in the vaccinated mice; vaccinated mice depleted of CD4 T cells remained protected. Hence, vaccine-induced protection is dependent upon TLR1/2 activation instructing the generation of antigen specific CD8 cells and restricting IL-13 and IL-10 responses. CONCLUSIONS: Given the general effectiveness of prime-boost vaccination, the recalcitrance of Leishmania (Viannia) to vaccine approaches effective against other species of Leishmania is again evident. However, prime boost vaccination modality can with modulation induce protective responses, indicating that the delivery system is critical. Moreover, these results suggest that CD8 T cells should be targeted for the development of a vaccine against infection caused by Leishmania (Viannia) parasites. Further, TLR1/2 modulation may be useful in vaccines where CD8 T cell responses are critical. PMID- 21695105 TI - Identification of peptide mimotopes of Trypanosoma brucei gambiense variant surface glycoproteins. AB - BACKGROUND: The current antibody detection tests for the diagnosis of gambiense human African trypanosomiasis (HAT) are based on native variant surface glycoproteins (VSGs) of Trypanosoma brucei (T.b.) gambiense. These native VSGs are difficult to produce, and contain non-specific epitopes that may cause cross reactions. We aimed to identify mimotopic peptides for epitopes of T.b. gambiense VSGs that, when produced synthetically, can replace the native proteins in antibody detection tests. METHODOLOGY/PRINCIPAL FINDINGS: PhD.-12 and PhD.-C7C phage display peptide libraries were screened with mouse monoclonal antibodies against the predominant VSGs LiTat 1.3 and LiTat 1.5 of T.b. gambiense. Thirty seven different peptide sequences corresponding to a linear LiTat 1.5 VSG epitope and 17 sequences corresponding to a discontinuous LiTat 1.3 VSG epitope were identified. Seventeen of 22 synthetic peptides inhibited the binding of their homologous monoclonal to VSG LiTat 1.5 or LiTat 1.3. Binding of these monoclonal antibodies to respectively six and three synthetic mimotopic peptides of LiTat 1.5 and LiTat 1.3 was significantly inhibited by HAT sera (p<0.05). CONCLUSIONS/SIGNIFICANCE: We successfully identified peptides that mimic epitopes on the native trypanosomal VSGs LiTat 1.5 and LiTat 1.3. These mimotopes might have potential for the diagnosis of human African trypanosomiasis but require further evaluation and testing with a large panel of HAT positive and negative sera. PMID- 21695106 TI - Justified concern or exaggerated fear: the risk of anaphylaxis in percutaneous treatment of cystic echinococcosis-a systematic literature review. AB - Percutaneous treatment (PT) emerged in the mid-1980s as an alternative to surgery for selected cases of abdominal cystic echinococcosis (CE). Despite its efficacy and widespread use, the puncture of echinococcal cysts is still far from being universally accepted. One of the main reasons for this reluctance is the perceived risk of anaphylaxis linked to PTs. To quantify the risk of anaphylactic reactions and lethal anaphylaxis with PT, we systematically searched MEDLINE for publications on PT of CE and reviewed the PT-related complications. After including 124 publications published between 1980 and 2010, we collected a total number of 5943 PT procedures on 5517 hepatic and non-hepatic echinococcal cysts. Overall, two cases of lethal anaphylaxis and 99 reversible anaphylactic reactions were reported. Lethal anaphylaxis occurred in 0.03% of PT procedures, corresponding to 0.04% of treated cysts, while reversible allergic reactions complicated 1.7% of PTs, corresponding to 1.8% of treated echinococcal cysts. Analysis of the literature shows that lethal anaphylaxis related to percutaneous treatment of CE is an extremely rare event and is observed no more frequently than drug-related anaphylactic side effects. PMID- 21695107 TI - Geostatistical model-based estimates of Schistosomiasis prevalence among individuals aged <= 20 years in West Africa. AB - BACKGROUND: Schistosomiasis is a water-based disease that is believed to affect over 200 million people with an estimated 97% of the infections concentrated in Africa. However, these statistics are largely based on population re-adjusted data originally published by Utroska and colleagues more than 20 years ago. Hence, these estimates are outdated due to large-scale preventive chemotherapy programs, improved sanitation, water resources development and management, among other reasons. For planning, coordination, and evaluation of control activities, it is essential to possess reliable schistosomiasis prevalence maps. METHODOLOGY: We analyzed survey data compiled on a newly established open-access global neglected tropical diseases database (i) to create smooth empirical prevalence maps for Schistosoma mansoni and S. haematobium for individuals aged <= 20 years in West Africa, including Cameroon, and (ii) to derive country-specific prevalence estimates. We used Bayesian geostatistical models based on environmental predictors to take into account potential clustering due to common spatially structured exposures. Prediction at unobserved locations was facilitated by joint kriging. PRINCIPAL FINDINGS: Our models revealed that 50.8 million individuals aged <= 20 years in West Africa are infected with either S. mansoni, or S. haematobium, or both species concurrently. The country prevalence estimates ranged between 0.5% (The Gambia) and 37.1% (Liberia) for S. mansoni, and between 17.6% (The Gambia) and 51.6% (Sierra Leone) for S. haematobium. We observed that the combined prevalence for both schistosome species is two-fold lower in Gambia than previously reported, while we found an almost two-fold higher estimate for Liberia (58.3%) than reported before (30.0%). Our predictions are likely to overestimate overall country prevalence, since modeling was based on children and adolescents up to the age of 20 years who are at highest risk of infection. CONCLUSION/SIGNIFICANCE: We present the first empirical estimates for S. mansoni and S. haematobium prevalence at high spatial resolution throughout West Africa. Our prediction maps allow prioritizing of interventions in a spatially explicit manner, and will be useful for monitoring and evaluation of schistosomiasis control programs. PMID- 21695108 TI - Experimental transmission of Leishmania infantum by two major vectors: a comparison between a viscerotropic and a dermotropic strain. AB - We quantified Leishmania infantum parasites transmitted by natural vectors for the first time. Both L. infantum strains studied, dermotropic CUK3 and viscerotropic IMT373, developed well in Phlebotomus perniciosus and Lutzomyia longipalpis. They produced heavy late-stage infection and colonized the stomodeal valve, which is a prerequisite for successful transmission. Infected sand fly females, and especially those that transmit parasites, feed significantly longer on the host (1.5-1.8 times) than non-transmitting females. Quantitative PCR revealed that P. perniciosus harboured more CUK3 strain parasites, while in L. longipalpis the intensity of infection was higher for the IMT373 strain. However, in both sand fly species the parasite load transmitted was higher for the strain with dermal tropism (CUK3). All but one sand fly female infected by the IMT373 strain transmitted less than 600 promastigotes; in contrast, 29% of L. longipalpis and 14% of P. perniciosus infected with the CUK3 strain transmitted more than 1000 parasites. The parasite number transmitted by individual sand flies ranged from 4 up to 4.19*10(4) promastigotes; thus, the maximal natural dose found was still about 250 times lower than the experimental challenge dose used in previous studies. This finding emphasizes the importance of determining the natural infective dose for the development of an accurate experimental model useful for the evaluation of new drugs and vaccines. PMID- 21695110 TI - Premitotic assembly of human CENPs -T and -W switches centromeric chromatin to a mitotic state. AB - Centromeres are differentiated chromatin domains, present once per chromosome, that direct segregation of the genome in mitosis and meiosis by specifying assembly of the kinetochore. They are distinct genetic loci in that their identity in most organisms is determined not by the DNA sequences they are associated with, but through specific chromatin composition and context. The core nucleosomal protein CENP-A/cenH3 plays a primary role in centromere determination in all species and directs assembly of a large complex of associated proteins in vertebrates. While CENP-A itself is stably transmitted from one generation to the next, the nature of the template for centromere replication and its relationship to kinetochore function are as yet poorly understood. Here, we investigate the assembly and inheritance of a histone fold complex of the centromere, the CENP T/W complex, which is integrated with centromeric chromatin in association with canonical histone H3 nucleosomes. We have investigated the cell cycle regulation, timing of assembly, generational persistence, and requirement for function of CENPs -T and -W in the cell cycle in human cells. The CENP-T/W complex assembles through a dynamic exchange mechanism in late S-phase and G2, is required for mitosis in each cell cycle and does not persist across cell generations, properties reciprocal to those measured for CENP-A. We propose that the CENP-A and H3-CENP-T/W nucleosome components of the centromere are specialized for centromeric and kinetochore activities, respectively. Segregation of the assembly mechanisms for the two allows the cell to switch between chromatin configurations that reciprocally support the replication of the centromere and its conversion to a mitotic state on postreplicative chromatin. PMID- 21695111 TI - For genomes, repetition breeds diversity. PMID- 21695109 TI - Why are autism spectrum conditions more prevalent in males? AB - Autism Spectrum Conditions (ASC) are much more common in males, a bias that may offer clues to the etiology of this condition. Although the cause of this bias remains a mystery, we argue that it occurs because ASC is an extreme manifestation of the male brain. The extreme male brain (EMB) theory, first proposed in 1997, is an extension of the Empathizing-Systemizing (E-S) theory of typical sex differences that proposes that females on average have a stronger drive to empathize while males on average have a stronger drive to systemize. In this first major update since 2005, we describe some of the evidence relating to the EMB theory of ASC and consider how typical sex differences in brain structure may be relevant to ASC. One possible biological mechanism to account for the male bias is the effect of fetal testosterone (fT). We also consider alternative biological theories, the X and Y chromosome theories, and the reduced autosomal penetrance theory. None of these theories has yet been fully confirmed or refuted, though the weight of evidence in favor of the fT theory is growing from converging sources (longitudinal amniocentesis studies from pregnancy to age 10 years old, current hormone studies, and genetic association studies of SNPs in the sex steroid pathways). Ultimately, as these theories are not mutually exclusive and ASC is multi-factorial, they may help explain the male prevalence of ASC. PMID- 21695112 TI - Towards a pharmacophore for amyloid. AB - Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of beta-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. PMID- 21695115 TI - Constraints to implementing the Essential Health Package in Malawi. AB - Increasingly seen as a useful tool of health policy, Essential or Minimal Health Packages direct resources to interventions that aim to address the local burden of disease and be cost-effective. Less attention has been paid to the delivery mechanisms for such interventions. This study aimed to assess the degree to which the Essential Health Package (EHP) in Malawi was available to its population and what health system constraints impeded its full implementation. The first phase of this study comprised a survey of all facilities in three districts including interviews with all managers and clinical staff. In the second and third phase, results were discussed with District Health Management Teams and national level stakeholders, respectively, including representatives of the Ministry of Health, Central Medical Stores, donors and NGOs. The EHP in Malawi is focussing on the local burden of disease; however, key constraints to its successful implementation included a widespread shortage of staff due to vacancies but also caused by frequent trainings and meetings (only 48% of expected man days of clinical staff were available; training and meetings represented 57% of all absences in health centres). Despite the training, the percentage of health workers aware of vital diagnostic and therapeutic approaches to EHP conditions was weak. Another major constraint was shortages of vital drugs at all levels of facilities (e.g. Cotrimoxazole was sufficiently available to treat the average number of patients in only 27% of health centres). Although a few health workers noted some improvement in infrastructure and working conditions, they still considered them to be widely inadequate. In Malawi, as in similar resource poor countries, greater attention needs to be given to the health system constraints to delivering health care. Removal of these constraints should receive priority over the considerable focus on the development and implementation of essential packages of interventions. PMID- 21695113 TI - A systems level, functional genomics analysis of chronic epilepsy. AB - Neither the molecular basis of the pathologic tendency of neuronal circuits to generate spontaneous seizures (epileptogenicity) nor anti-epileptogenic mechanisms that maintain a seizure-free state are well understood. Here, we performed transcriptomic analysis in the intrahippocampal kainate model of temporal lobe epilepsy in rats using both Agilent and Codelink microarray platforms to characterize the epileptic processes. The experimental design allowed subtraction of the confounding effects of the lesion, identification of expression changes associated with epileptogenicity, and genes upregulated by seizures with potential homeostatic anti-epileptogenic effects. Using differential expression analysis, we identified several hundred expression changes in chronic epilepsy, including candidate genes associated with epileptogenicity such as Bdnf and Kcnj13. To analyze these data from a systems perspective, we applied weighted gene co-expression network analysis (WGCNA) to identify groups of co-expressed genes (modules) and their central (hub) genes. One such module contained genes upregulated in the epileptogenic region, including multiple epileptogenicity candidate genes, and was found to be involved the protection of glial cells against oxidative stress, implicating glial oxidative stress in epileptogenicity. Another distinct module corresponded to the effects of chronic seizures and represented changes in neuronal synaptic vesicle trafficking. We found that the network structure and connectivity of one hub gene, Sv2a, showed significant changes between normal and epileptogenic tissue, becoming more highly connected in epileptic brain. Since Sv2a is a target of the antiepileptic levetiracetam, this module may be important in controlling seizure activity. Bioinformatic analysis of this module also revealed a potential mechanism for the observed transcriptional changes via generation of longer alternatively polyadenlyated transcripts through the upregulation of the RNA binding protein HuD. In summary, combining conventional statistical methods and network analysis allowed us to interpret the differentially regulated genes from a systems perspective, yielding new insight into several biological pathways underlying homeostatic anti-epileptogenic effects and epileptogenicity. PMID- 21695114 TI - Sonic Hedgehog dependent phosphorylation by CK1alpha and GRK2 is required for ciliary accumulation and activation of smoothened. AB - Hedgehog (Hh) signaling regulates embryonic development and adult tissue homeostasis through the GPCR-like protein Smoothened (Smo), but how vertebrate Smo is activated remains poorly understood. In Drosophila, Hh dependent phosphorylation activates Smo. Whether this is also the case in vertebrates is unclear, owing to the marked sequence divergence between vertebrate and Drosophila Smo (dSmo) and the involvement of primary cilia in vertebrate Hh signaling. Here we demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1alpha and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation. We demonstrate that graded Hh signals induce increasing levels of mSmo phosphorylation that fine-tune its ciliary localization, conformation, and activity. We show that mSmo phosphorylation is induced by its agonists and oncogenic mutations but is blocked by its antagonist cyclopamine, and efficient mSmo phosphorylation depends on the kinesin-II ciliary motor. Furthermore, we provide evidence that Hh signaling recruits CK1alpha to initiate mSmo phosphorylation, and phosphorylation further increases the binding of CK1alpha and GRK2 to mSmo, forming a positive feedback loop that amplifies and/or sustains mSmo phosphorylation. Hence, despite divergence in their primary sequences and their subcellular trafficking, mSmo and dSmo employ analogous mechanisms for their activation. PMID- 21695116 TI - Humanized Rag1-/- gammac-/- mice support multilineage hematopoiesis and are susceptible to HIV-1 infection via systemic and vaginal routes. AB - Several new immunodeficient mouse models for human cell engraftment have recently been introduced that include the Rag2(-/-)gammac(-/-), NOD/SCID, NOD/SCIDgammac( /-) and NOD/SCIDbeta2m(-/-) strains. Transplantation of these mice with CD34(+) human hematopoietic stem cells leads to prolonged engraftment, multilineage hematopoiesis and the capacity to generate human immune responses against a variety of antigens. However, the various mouse strains used and different methods of engrafting human cells are beginning to illustrate strain specific variations in engraftment levels, duration and longevity of mouse life span. In these proof-of-concept studies we evaluated the Balb/c-Rag1(-/-)gamma(-/-) strain for engraftment by human fetal liver derived CD34(+) hematopoietic cells using the same protocol found to be effective for Balb/c-Rag2(-/-)gammac(-/-) mice. We demonstrate that these mice can be efficiently engrafted and show multilineage human hematopoiesis with human cells populating different lymphoid organs. Generation of human cells continues beyond a year and production of human immunoglobulins is noted. Infection with HIV-1 leads to chronic viremia with a resultant CD4 T cell loss. To mimic the predominant sexual viral transmission, we challenged humanized Rag1(-/-)gammac(-/-) mice with HIV-1 via vaginal route which also resulted in chronic viremia and helper T cell loss. Thus these mice can be further exploited for studying human pathogens that infect the human hematopoietic system in an in vivo setting. PMID- 21695117 TI - Adaptive traits are maintained on steep selective gradients despite gene flow and hybridization in the intertidal zone. AB - Gene flow among hybridizing species with incomplete reproductive barriers blurs species boundaries, while selection under heterogeneous local ecological conditions or along strong gradients may counteract this tendency. Congeneric, externally-fertilizing fucoid brown algae occur as distinct morphotypes along intertidal exposure gradients despite gene flow. Combining analyses of genetic and phenotypic traits, we investigate the potential for physiological resilience to emersion stressors to act as an isolating mechanism in the face of gene flow. Along vertical exposure gradients in the intertidal zone of Northern Portugal and Northwest France, the mid-low shore species Fucus vesiculosus, the upper shore species Fucus spiralis, and an intermediate distinctive morphotype of F. spiralis var. platycarpus were morphologically characterized. Two diagnostic microsatellite loci recovered 3 genetic clusters consistent with prior morphological assignment. Phylogenetic analysis based on single nucleotide polymorphisms in 14 protein coding regions unambiguously resolved 3 clades; sympatric F. vesiculosus, F. spiralis, and the allopatric (in southern Iberia) population of F. spiralis var. platycarpus. In contrast, the sympatric F. spiralis var. platycarpus (from Northern Portugal) was distributed across the 3 clades, strongly suggesting hybridization/introgression with both other entities. Common garden experiments showed that physiological resilience following exposure to desiccation/heat stress differed significantly between the 3 sympatric genetic taxa; consistent with their respective vertical distribution on steep environmental clines in exposure time. Phylogenetic analyses indicate that F. spiralis var. platycarpus is a distinct entity in allopatry, but that extensive gene flow occurs with both higher and lower shore species in sympatry. Experimental results suggest that strong selection on physiological traits across steep intertidal exposure gradients acts to maintain the 3 distinct genetic and morphological taxa within their preferred vertical distribution ranges. On the strength of distributional, genetic, physiological and morphological differences, we propose elevation of F. spiralis var. platycarpus from variety to species level, as F. guiryi. PMID- 21695118 TI - The effects of natural iron fertilisation on deep-sea ecology: the Crozet Plateau, Southern Indian Ocean. AB - The addition of iron to high-nutrient low-chlorophyll (HNLC) oceanic waters stimulates phytoplankton, leading to greater primary production. Large-scale artificial ocean iron fertilization (OIF) has been proposed as a means of mitigating anthropogenic atmospheric CO(2), but its impacts on ocean ecosystems below the photic zone are unknown. Natural OIF, through the addition of iron leached from volcanic islands, has been shown to enhance primary productivity and carbon export and so can be used to study the effects of OIF on life in the ocean. We compared two closely-located deep-sea sites (~400 km apart and both at ~4200 m water depth) to the East (naturally iron fertilized; +Fe) and South (HNLC) of the Crozet Islands in the southern Indian Ocean. Our results suggest that long-term geo-engineering of surface oceanic waters via artificial OIF would lead to significant changes in deep-sea ecosystems. We found that the +Fe area had greater supplies of organic matter inputs to the seafloor, including polyunsaturated fatty acid and carotenoid nutrients. The +Fe site also had greater densities and biomasses of large deep-sea animals with lower levels of evenness in community structuring. The species composition was also very different, with the +Fe site showing similarities to eutrophic sites in other ocean basins. Moreover, major differences occurred in the taxa at the +Fe and HNLC sites revealing the crucial role that surface oceanic conditions play in changing and structuring deep-sea benthic communities. PMID- 21695119 TI - Effectiveness of biological surrogates for predicting patterns of marine biodiversity: a global meta-analysis. AB - The use of biological surrogates as proxies for biodiversity patterns is gaining popularity, particularly in marine systems where field surveys can be expensive and species richness high. Yet, uncertainty regarding their applicability remains because of inconsistency of definitions, a lack of standard methods for estimating effectiveness, and variable spatial scales considered. We present a Bayesian meta-analysis of the effectiveness of biological surrogates in marine ecosystems. Surrogate effectiveness was defined both as the proportion of surrogacy tests where predictions based on surrogates were better than random (i.e., low probability of making a Type I error; P) and as the predictability of targets using surrogates (R(2)). A total of 264 published surrogacy tests combined with prior probabilities elicited from eight international experts demonstrated that the habitat, spatial scale, type of surrogate and statistical method used all influenced surrogate effectiveness, at least according to either P or R(2). The type of surrogate used (higher-taxa, cross-taxa or subset taxa) was the best predictor of P, with the higher-taxa surrogates outperforming all others. The marine habitat was the best predictor of R(2), with particularly low predictability in tropical reefs. Surrogate effectiveness was greatest for higher taxa surrogates at a <10-km spatial scale, in low-complexity marine habitats such as soft bottoms, and using multivariate-based methods. Comparisons with terrestrial studies in terms of the methods used to study surrogates revealed that marine applications still ignore some problems with several widely used statistical approaches to surrogacy. Our study provides a benchmark for the reliable use of biological surrogates in marine ecosystems, and highlights directions for future development of biological surrogates in predicting biodiversity. PMID- 21695120 TI - Drosophila melanogaster as a model system for studies of islet amyloid polypeptide aggregation. AB - BACKGROUND: Recent research supports that aggregation of islet amyloid polypeptide (IAPP) leads to cell death and this makes islet amyloid a plausible cause for the reduction of beta cell mass, demonstrated in patients with type 2 diabetes. IAPP is produced by the beta cells as a prohormone, and proIAPP is processed into IAPP by the prohormone convertases PC1/3 and PC2 in the secretory granules. Little is known about the pathogenesis for islet amyloid and which intracellular mechanisms are involved in amyloidogenesis and induction of cell death. METHODOLOGY/PRINCIPAL FINDINGS: We have established expression of human proIAPP (hproIAPP), human IAPP (hIAPP) and the non-amyloidogenic mouse IAPP (mIAPP) in Drosophila melanogaster, and compared survival of flies with the expression driven to different cell populations. Only flies expressing hproIAPP in neurons driven by the Gal4 driver elav(C155,Gal4) showed a reduction in lifespan whereas neither expression of hIAPP or mIAPP influenced survival. Both hIAPP and hproIAPP expression caused formation of aggregates in CNS and fat body region, and these aggregates were both stained by the dyes Congo red and pFTAA, both known to detect amyloid. Also, the morphology of the highly organized protein granules that developed in the fat body of the head in hIAPP and hproIAPP expressing flies was characterized, and determined to consist of 15.8 nm thick pentagonal rod-like structures. CONCLUSIONS/SIGNIFICANCE: These findings point to a potential for Drosophila melanogaster to serve as a model system for studies of hproIAPP and hIAPP expression with subsequent aggregation and developed pathology. PMID- 21695121 TI - Systems biology of the qa gene cluster in Neurospora crassa. AB - An ensemble of genetic networks that describe how the model fungal system, Neurospora crassa, utilizes quinic acid (QA) as a sole carbon source has been identified previously. A genetic network for QA metabolism involves the genes, qa 1F and qa-1S, that encode a transcriptional activator and repressor, respectively and structural genes, qa-2, qa-3, qa-4, qa-x, and qa-y. By a series of 4 separate and independent, model-guided, microarray experiments a total of 50 genes are identified as QA-responsive and hypothesized to be under QA-1F control and/or the control of a second QA-responsive transcription factor (NCU03643) both in the fungal binuclear Zn(II)2Cys6 cluster family. QA-1F regulation is not sufficient to explain the quantitative variation in expression profiles of the 50 QA responsive genes. QA-responsive genes include genes with products in 8 mutually connected metabolic pathways with 7 of them one step removed from the tricarboxylic (TCA) Cycle and with 7 of them one step removed from glycolysis: (1) starch and sucrose metabolism; (2) glycolysis/glucanogenesis; (3) TCA Cycle; (4) butanoate metabolism; (5) pyruvate metabolism; (6) aromatic amino acid and QA metabolism; (7) valine, leucine, and isoleucine degradation; and (8) transport of sugars and amino acids. Gene products both in aromatic amino acid and QA metabolism and transport show an immediate response to shift to QA, while genes with products in the remaining 7 metabolic modules generally show a delayed response to shift to QA. The additional QA-responsive cutinase transcription factor-1beta (NCU03643) is found to have a delayed response to shift to QA. The series of microarray experiments are used to expand the previously identified genetic network describing the qa gene cluster to include all 50 QA-responsive genes including the second transcription factor (NCU03643). These studies illustrate new methodologies from systems biology to guide model-driven discoveries about a core metabolic network involving carbon and amino acid metabolism in N. crassa. PMID- 21695122 TI - Allelic variants of melanocortin 3 receptor gene (MC3R) and weight loss in obesity: a randomised trial of hypo-energetic high- versus low-fat diets. AB - INTRODUCTION: The melanocortin system plays an important role in energy homeostasis. Mice genetically deficient in the melanocortin-3 receptor gene have a normal body weight with increased body fat, mild hypophagia compared to wild type mice. In humans, Thr6Lys and Val81Ile variants of the melanocortin-3 receptor gene (MC3R) have been associated with childhood obesity, higher BMI Z score and elevated body fat percentage compared to non-carriers. The aim of this study is to assess the association in adults between allelic variants of MC3R with weight loss induced by energy-restricted diets. SUBJECTS AND METHODS: This research is based on the NUGENOB study, a trial conducted to assess weight loss during a 10-week dietary intervention involving two different hypo-energetic (high-fat and low-fat) diets. A total of 760 obese patients were genotyped for 10 single nucleotide polymorphisms covering the single exon of MC3R gene and its flanking regions, including the missense variants Thr6Lys and Val81Ile. Linear mixed models and haplotype-based analysis were carried out to assess the potential association between genetic polymorphisms and differential weight loss, fat mass loss, waist change and resting energy expenditure changes. RESULTS: No differences in drop-out rate were found by MC3R genotypes. The rs6014646 polymorphism was significantly associated with weight loss using co-dominant (p = 0.04) and dominant models (p = 0.03). These p-values were not statistically significant after strict control for multiple testing. Haplotype-based multivariate analysis using permutations showed that rs3827103-rs1543873 (p = 0.06), rs6014646-rs6024730 (p = 0.05) and rs3746619-rs3827103 (p = 0.10) displayed near-statistical significant results in relation to weight loss. No other significant associations or gene*diet interactions were detected for weight loss, fat mass loss, waist change and resting energy expenditure changes. CONCLUSION: The study provided overall sufficient evidence to support that there is no major effect of genetic variants of MC3R and differential weight loss after a 10-week dietary intervention with hypo-energetic diets in obese Europeans. PMID- 21695123 TI - Bordetella pertussis autotransporter Vag8 binds human C1 esterase inhibitor and confers serum resistance. AB - Bordetella pertussis employs numerous strategies to evade the immune system, including the ability to resist killing via complement. Previously we have shown that B. pertussis binds a complement regulatory protein, C1 esterase inhibitor (C1inh) to its surface in a Bvg-regulated manner (i.e. during its virulence phase), but the B. pertussis factor was not identified. Here we set out to identify the B. pertussis C1inh-binding factor. Using a serum overlay assay, we found that this factor migrates at approximately 100 kDa on an SDS-PAGE gel. To identify this factor, we isolated proteins of approximately 100 kDa from wild type strain BP338 and from BP347, an isogenic Bvg mutant that does not bind C1inh. Using mass spectrometry and bioinformatics, we identified the autotransporter protein Vag8 as the putative C1inh binding protein. To prove that Vag8 binds C1inh, vag8 was disrupted in two different B. pertussis strains, namely BP338 and 18-323, and the mutants were tested for their ability to bind C1inh in a surface-binding assay. Neither mutant strain was capable of binding C1inh, whereas a complemented strain successfully bound C1inh. In addition, the passenger domain of Vag8 was expressed and purified as a histidine-tagged fusion protein and tested for C1inh-binding in an ELISA assay. Whereas the purified Vag8 passenger bound C1inh, the passenger domain of BrkA (a related autotransporter protein) failed to do so. Finally, serum assays were conducted to compare wild type and vag8 mutants. We determined that vag8 mutants from both strains were more susceptible to killing compared to their isogenic wild type counterparts. In conclusion, we have discovered a novel role for the previously uncharacterized protein Vag8 in the immune evasion of B. pertussis. Vag8 binds C1inh to the surface of the bacterium and confers serum resistance. PMID- 21695124 TI - Gene-disease network analysis reveals functional modules in mendelian, complex and environmental diseases. AB - BACKGROUND: Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. PRINCIPAL FINDINGS: We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell. CONCLUSIONS: For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors, such as drugs, contribute to diseases. AVAILABILITY: The gene-disease networks used in this study and part of the analysis are available at http://ibi.imim.es/DisGeNET/DisGeNETweb.html#Download. PMID- 21695125 TI - Positive selection shaped the convergent evolution of independently expanded kallikrein subfamilies expressed in mouse and rat saliva proteomes. AB - We performed proteomics studies of salivas from the genome mouse (C57BL/6 strain) and the genome rat (BN/SsNHsd/Mcwi strain). Our goal was to identify salivary proteins with one or more of three characteristics that may indicate that they have been involved in adaptation: 1) rapid expansion of their gene families; 2) footprints of positive selection; and/or 3) sex-limited expression. The results of our proteomics studies allow direct comparison of the proteins expressed and their levels between the sexes of the two rodent species. Twelve members of the Mus musculus species-specific kallikrein subfamily Klk1b showed sex-limited expression in the mouse saliva proteomes. By contrast, we did not find any of the Rattus norvegicus species-specific kallikrein subfamily Klk1c proteins in male or female genome rat, nor transcripts in their submandibular glands. On the other hand, we detected expression of this family as transcripts in the submandibular glands of both sexes of Sprague-Dawley rats. Using the CODEML program in the PAML package, we demonstrate that the two rodent kallikrein subfamilies have apparently evolved rapidly under the influence of positive selection that continually remodeled the amino acid sites on the same face in the members of the subfamilies. Thus, although their kallikrein subfamily expansions were independent, this evolutionary pattern has occurred in parallel in the two rodent species, suggesting a form of convergent evolution at the molecular level. On the basis of this new data, we suggest that the previous speculative function of the species-specific rodent kallikreins as important solely in wound healing in males be investigated further. In addition to or instead of that function, we propose that their sex-limited expression, coupled with their rapid evolution may be clues to an as-yet-undetermined interaction between the sexes. PMID- 21695126 TI - The combination of RAD001 and NVP-BEZ235 exerts synergistic anticancer activity against non-small cell lung cancer in vitro and in vivo. AB - The phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling axis has emerged as a novel target for cancer therapy. Agents that inhibit PI3K, mTOR or both are currently under development. The mTOR allosteric inhibitor, RAD001, and the PI3K/mTOR dual kinase inhibitor, BEZ235, are examples of these agents. We were interested in developing strategies to enhance mTOR targeted caner therapy. In this study, we found that BEZ235 alone effectively inhibited the growth of rapamycin-resistant cancer cells. Interestingly, the combination of sub-optimal concentrations of RAD001 and BEZ235 exerted synergistic inhibition of the growth of human lung cancer cells along with induction of apoptosis and G1 arrest. Furthermore, the combination was also more effective than either agent alone in inhibiting the growth of lung cancer xenografts in mice. The combination showed enhanced effects on inhibiting mTOR signaling and reducing the expression of c-Myc and cyclin D1. Taken together, our results suggest that the combination of RAD001 and BEZ235 is a novel strategy for cancer therapy. PMID- 21695127 TI - A cross-sectional study of the microeconomic impact of cardiovascular disease hospitalization in four low- and middle-income countries. AB - OBJECTIVE: To estimate individual and household economic impact of cardiovascular disease (CVD) in selected low- and middle-income countries (LMIC). BACKGROUND: Empirical evidence on the microeconomic consequences of CVD in LMIC is scarce. METHODS AND FINDINGS: We surveyed 1,657 recently hospitalized CVD patients (66% male; mean age 55.8 years) from Argentina, China, India, and Tanzania to evaluate the microeconomic and functional/productivity impact of CVD hospitalization. Respondents were stratified into three income groups. Median out-of-pocket expenditures for CVD treatment over 15 month follow-up ranged from 354 international dollars (2007 INT$, Tanzania, low-income) to INT$2,917 (India, high income). Catastrophic health spending (CHS) was present in >50% of respondents in China, India, and Tanzania. Distress financing (DF) and lost income were more common in low-income respondents. After adjustment, lack of health insurance was associated with CHS in Argentina (OR 4.73 [2.56, 8.76], India (OR 3.93 [2.23, 6.90], and Tanzania (OR 3.68 [1.86, 7.26] with a marginal association in China (OR 2.05 [0.82, 5.11]). These economic effects were accompanied by substantial decreases in individual functional health and productivity. CONCLUSIONS: Individuals in selected LMIC bear significant financial burdens following CVD hospitalization, yet with substantial variation across and within countries. Lack of insurance may drive much of the financial stress of CVD in LMIC patients and their families. PMID- 21695129 TI - A sub-microscopic gametocyte reservoir can sustain malaria transmission. AB - BACKGROUND: Novel diagnostic tools, including PCR and high field gradient magnetic fractionation (HFGMF), have improved detection of asexual Plasmodium falciparum parasites and especially infectious gametocytes in human blood. These techniques indicate a significant number of people carry gametocyte densities that fall below the conventional threshold of detection achieved by standard light microscopy (LM). METHODOLOGY/PRINCIPAL FINDINGS: To determine how low-level gametocytemia may affect transmission in present large-scale efforts for P. falciparum control in endemic areas, we developed a refinement of the classical Ross-Macdonald model of malaria transmission by introducing multiple infective compartments to model the potential impact of highly prevalent, low gametocytaemic reservoirs in the population. Models were calibrated using field based data and several numerical experiments were conducted to assess the effect of high and low gametocytemia on P. falciparum transmission and control. Special consideration was given to the impact of long-lasting insecticide-treated bed nets (LLIN), presently considered the most efficient way to prevent transmission, and particularly LLIN coverage similar to goals targeted by the Roll Back Malaria and Global Fund malaria control campaigns. Our analyses indicate that models which include only moderate-to-high gametocytemia (detectable by LM) predict finite eradication times after LLIN introduction. Models that include a low gametocytemia reservoir (requiring PCR or HFGMF detection) predict much more stable, persistent transmission. Our modeled outcomes result in significantly different estimates for the level and duration of control needed to achieve malaria elimination if submicroscopic gametocytes are included. CONCLUSIONS/SIGNIFICANCE: It will be very important to complement current methods of surveillance with enhanced diagnostic techniques to detect asexual parasites and gametocytes to more accurately plan, monitor and guide malaria control programs aimed at eliminating malaria. PMID- 21695128 TI - PCR improves diagnostic yield from lung aspiration in Malawian children with radiologically confirmed pneumonia. AB - BACKGROUND: Accurate data on childhood pneumonia aetiology are essential especially from regions where mortality is high, in order to inform case management guidelines and the potential of prevention strategies such as bacterial conjugate vaccines. Yield from blood culture is low, but lung aspirate culture provides a higher diagnostic yield. We aimed to determine if diagnostic yield could be increased further by polymerase chain reaction (PCR) detection of bacteria (Streptococcus pneumoniae and Haemophilus influenzae b) and viruses in lung aspirate fluid. METHODS: A total of 95 children with radiological focal, lobar or segmental consolidation had lung aspirate performed and sent for bacterial culture and for PCR for detection of bacteria, viruses and Pneumocystis jirovecii. In children with a pneumococcal aetiology, pneumococcal bacterial loads were calculated in blood and lung aspirate fluid. RESULTS: Blood culture identified a bacterial pathogen in only 8 patients (8%). With the addition of PCR on lung aspirate samples, causative pathogens (bacterial, viral, pneumocystis) were identified singly or as co-infections in 59 children (62%). The commonest bacterial organism was S.pneumoniae (41%), followed by H. influenzae b (6%), and the commonest virus identified was adenovirus (16%), followed by human bocavirus (HBoV) (4%), either as single or co-infection. CONCLUSIONS: In a select group of African children, lung aspirate PCR significantly improves diagnostic yield. Our study confirms a major role of S.pneumoniae and viruses in the aetiology of childhood pneumonia in Africa. PMID- 21695130 TI - The effect of using an inappropriate protein database for proteomic data analysis. AB - A recent study by Bromenshenk et al., published in PLoS One (2010), used proteomic analysis to identify peptides purportedly of Iridovirus and Nosema origin; however the validity of this finding is controversial. We show here through re-analysis of a subset of this data that many of the spectra identified by Bromenshenk et al. as deriving from Iridovirus and Nosema proteins are actually products from Apis mellifera honey bee proteins. We find no reliable evidence that proteins from Iridovirus and Nosema are present in the samples that were re-analyzed. This article is also intended as a learning exercise for illustrating some of the potential pitfalls of analysis of mass spectrometry proteomic data and to encourage authors to observe MS/MS data reporting guidelines that would facilitate recognition of analysis problems during the review process. PMID- 21695131 TI - Osteopenia due to enhanced cathepsin K release by BK channel ablation in osteoclasts. AB - BACKGROUND: The process of bone resorption by osteoclasts is regulated by Cathepsin K, the lysosomal collagenase responsible for the degradation of the organic bone matrix during bone remodeling. Recently, Cathepsin K was regarded as a potential target for therapeutic intervention of osteoporosis. However, mechanisms leading to osteopenia, which is much more common in young female population and often appears to be the clinical pre-stage of idiopathic osteoporosis, still remain to be elucidated, and molecular targets need to be identified. METHODOLOGY/PRINCIPAL FINDINGS: We found, that in juvenile bone the large conductance, voltage and Ca(2+)-activated (BK) K(+) channel, which links membrane depolarization and local increases in cytosolic calcium to hyperpolarizing K(+) outward currents, is exclusively expressed in osteoclasts. In juvenile BK-deficient (BK(-/-)) female mice, plasma Cathepsin K levels were elevated two-fold when compared to wild-type littermates. This increase was linked to an osteopenic phenotype with reduced bone mineral density in long bones and enhanced porosity of trabecular meshwork in BK(-/-) vertebrae as demonstrated by high-resolution flat-panel volume computed tomography and micro-CT. However, plasma levels of sRANKL, osteoprotegerin, estrogene, Ca(2+) and triiodthyronine as well as osteoclastogenesis were not altered in BK(-/-) females. CONCLUSION/SIGNIFICANCE: Our findings suggest that the BK channel controls resorptive osteoclast activity by regulating Cathepsin K release. Targeted deletion of BK channel in mice resulted in an osteoclast-autonomous osteopenia, becoming apparent in juvenile females. Thus, the BK(-/-) mouse-line represents a new model for juvenile osteopenia, and revealed the BK channel as putative new target for therapeutic controlling of osteoclast activity. PMID- 21695132 TI - Investigating behaviour and population dynamics of striped marlin (Kajikia audax) from the southwest Pacific Ocean with satellite tags. AB - Behaviour and distribution of striped marlin within the southwest Pacific Ocean were investigated using electronic tagging data collected from 2005-2008. A continuous-time correlated random-walk Kalman filter was used to integrate double tagging data exhibiting variable error structures into movement trajectories composed of regular time-steps. This state-space trajectory integration approach improved longitude and latitude error distributions by 38.5 km and 22.2 km respectively. Using these trajectories as inputs, a behavioural classification model was developed to infer when, and where, 'transiting' and 'area-restricted' (ARB) pseudo-behavioural states occurred. ARB tended to occur at shallower depths (108 +/- 49 m) than did transiting behaviours (127 +/- 57 m). A 16 day post release period of diminished ARB activity suggests that patterns of behaviour were affected by the capture and/or tagging events, implying that tagged animals may exhibit atypical behaviour upon release. The striped marlin in this study dove deeper and spent greater time at >= 200 m depth than those in the central and eastern Pacific Ocean. As marlin reached tropical latitudes (20-21 degrees S) they consistently reversed directions, increased swimming speed and shifted to transiting behaviour. Reversals in the tropics also coincided with increases in swimming depth, including increased time >= 250 m. Our research provides enhanced understanding of the behavioural ecology of striped marlin. This has implications for the effectiveness of spatially explicit population models and we demonstrate the need to consider geographic variation when standardizing CPUE by depth, and provide data to inform natural and recreational fishing mortality parameters. PMID- 21695133 TI - Cortical dynamics of acoustic and phonological processing in speech perception. AB - In speech perception, a functional hierarchy has been proposed by recent functional neuroimaging studies: core auditory areas on the dorsal plane of superior temporal gyrus (STG) are sensitive to basic acoustic characteristics, whereas downstream regions, specifically the left superior temporal sulcus (STS) and middle temporal gyrus (MTG) ventral to Heschl's gyrus (HG) are responsive to abstract phonological features. What is unclear so far is the relationship between the dorsal and ventral processes, especially with regard to whether low level acoustic processing is modulated by high-level phonological processing. To address the issue, we assessed sensitivity of core auditory and downstream regions to acoustic and phonological variations by using within- and across category lexical tonal continua with equal physical intervals. We found that relative to within-category variation, across-category variation elicited stronger activation in the left middle MTG (mMTG), apparently reflecting the abstract phonological representations. At the same time, activation in the core auditory region decreased, resulting from the top-down influences of phonological processing. These results support a hierarchical organization of the ventral acoustic-phonological processing stream, which originates in the right HG/STG and projects to the left mMTG. Furthermore, our study provides direct evidence that low-level acoustic analysis is modulated by high-level phonological representations, revealing the cortical dynamics of acoustic and phonological processing in speech perception. Our findings confirm the existence of reciprocal progression projections in the auditory pathways and the roles of both feed forward and feedback mechanisms in speech perception. PMID- 21695134 TI - Membrane binding of plasmid DNA and endocytic pathways are involved in electrotransfection of mammalian cells. AB - Electric field mediated gene delivery or electrotransfection is a widely used method in various studies ranging from basic cell biology research to clinical gene therapy. Yet, mechanisms of electrotransfection are still controversial. To this end, we investigated the dependence of electrotransfection efficiency (eTE) on binding of plasmid DNA (pDNA) to plasma membrane and how treatment of cells with three endocytic inhibitors (chlorpromazine, genistein, dynasore) or silencing of dynamin expression with specific, small interfering RNA (siRNA) would affect the eTE. Our data demonstrated that the presence of divalent cations (Ca(2+) and Mg(2+)) in electrotransfection buffer enhanced pDNA adsorption to cell membrane and consequently, this enhanced adsorption led to an increase in eTE, up to a certain threshold concentration for each cation. Trypsin treatment of cells at 10 min post electrotransfection stripped off membrane-bound pDNA and resulted in a significant reduction in eTE, indicating that the time period for complete cellular uptake of pDNA (between 10 and 40 min) far exceeded the lifetime of electric field-induced transient pores (~10 msec) in the cell membrane. Furthermore, treatment of cells with the siRNA and all three pharmacological inhibitors yielded substantial and statistically significant reductions in the eTE. These findings suggest that electrotransfection depends on two mechanisms: (i) binding of pDNA to cell membrane and (ii) endocytosis of membrane-bound pDNA. PMID- 21695135 TI - Nuclear outsourcing of RNA interference components to human mitochondria. AB - MicroRNAs (miRNAs) are small non-coding RNAs that associate with Argonaute proteins to regulate gene expression at the post-transcriptional level in the cytoplasm. However, recent studies have reported that some miRNAs localize to and function in other cellular compartments. Mitochondria harbour their own genetic system that may be a potential site for miRNA mediated post-transcriptional regulation. We aimed at investigating whether nuclear-encoded miRNAs can localize to and function in human mitochondria. To enable identification of mitochondrial enriched miRNAs, we profiled the mitochondrial and cytosolic RNA fractions from the same HeLa cells by miRNA microarray analysis. Mitochondria were purified using a combination of cell fractionation and immunoisolation, and assessed for the lack of protein and RNA contaminants. We found 57 miRNAs differentially expressed in HeLa mitochondria and cytosol. Of these 57, a signature of 13 nuclear-encoded miRNAs was reproducibly enriched in mitochondrial RNA and validated by RT-PCR for hsa-miR-494, hsa-miR-1275 and hsa-miR-1974. The significance of their mitochondrial localization was investigated by characterizing their genomic context, cross-species conservation and instrinsic features such as their size and thermodynamic parameters. Interestingly, the specificities of mitochondrial versus cytosolic miRNAs were underlined by significantly different structural and thermodynamic parameters. Computational targeting analysis of most mitochondrial miRNAs revealed not only nuclear but also mitochondrial-encoded targets. The functional relevance of miRNAs in mitochondria was supported by the finding of Argonaute 2 localization to mitochondria revealed by immunoblotting and confocal microscopy, and further validated by the co-immunoprecipitation of the mitochondrial transcript COX3. This study provides the first comprehensive view of the localization of RNA interference components to the mitochondria. Our data outline the molecular bases for a novel layer of crosstalk between nucleus and mitochondria through a specific subset of human miRNAs that we termed 'mitomiRs'. PMID- 21695136 TI - Control region variability of haplogroup C1d and the tempo of the peopling of the Americas. AB - BACKGROUND: Among the founding mitochondrial haplogroups involved in the peopling of the Americas, haplogroup C1d has been viewed as problematic because of its phylogeny and because of the estimates of its antiquity, apparently being much younger than other founding haplogroups. Several recent analyses, based on data from the entire mitochondrial genome, have contributed to an advance in the resolution of these problems. The aim of our analysis is to compare the conclusions drawn from the available HVR-I and HVR-II data for haplogroup C1d with the ones based on whole mitochondrial genomes. METHODOLOGY/PRINCIPAL FINDINGS: HVR-I and HVR-II sequences defined as belonging to haplogroup C1d by standard criteria were gathered from the literature as well as from population studies carried out in Uruguay. Sequence phylogeny was reconstructed using median joining networks, geographic distribution of lineages was analyzed and the age of the most recent common ancestor estimated using the rho-statistic and two different mutation rates. The putative ancestral forms of the haplogroup were found to be more widespread than the derived lineages, and the lineages defined by np 194 were found to be widely distributed and of equivalent age. CONCLUSIONS/SIGNIFICANCE: The analysis of control region sequences is found to still harbor great potential in tracing microevolutionary phenomena, especially those found to have occurred in more recent times. Based on the geographic distributions of the alleles of np 7697 and np 194, both discussed as possible basal mutations of the C1d phylogeny, we suggest that both alleles were part of the variability of the haplogroup at the time of its entrance. Moreover, based on the mutation rates of the different sites stated to be diagnostic, it is possible that the anomalies found when analyzing the haplogroup are due to paraphyly. PMID- 21695137 TI - The RNA editing pattern of cox2 mRNA is affected by point mutations in plant mitochondria. AB - The mitochondrial transcriptome from land plants undergoes hundreds of specific C to-U changes by RNA editing. These events are important since most of them occur in the coding region of mRNAs. One challenging question is to understand the mechanism of recognition of a selected C residue (editing sites) on the transcript. It has been reported that a short region surrounding the target C forms the cis-recognition elements, but individual residues on it do not play similar roles for the different editing sites. Here, we studied the role of the 1 and +1 nucleotide in wheat cox2 editing site recognition using an in organello approach. We found that four different recognition patterns can be distinguished: (a) +1 dependency, (b) -1 dependency, (c) +1/-1 dependency, and (d) no dependency on nearest neighbor residues. A striking observation was that whereas a 23 nt cis region is necessary for editing, some mutants affect the editing efficiency of unmodified distant sites. As a rule, mutations or pre-edited variants of the transcript have an impact on the complete set of editing targets. When some Cs were changed into Us, the remaining editing sites presented a higher efficiency of C-to-U conversion than in wild type mRNA. Our data suggest that the complex response observed for cox2 mRNA may be a consequence of the fate of the transcript during mitochondrial gene expression. PMID- 21695138 TI - Ex vivo treatment with a novel synthetic aminoglycoside NB54 in primary fibroblasts from Rett syndrome patients suppresses MECP2 nonsense mutations. AB - BACKGROUND: Nonsense mutations in the X-linked methyl CpG-binding protein 2 (MECP2) comprise a significant proportion of causative MECP2 mutations in Rett syndrome (RTT). Naturally occurring aminoglycosides, such as gentamicin, have been shown to enable partial suppression of nonsense mutations related to several human genetic disorders, however, their clinical applicability has been compromised by parallel findings of severe toxic effects. Recently developed synthetic NB aminoglycosides have demonstrated significantly improved effects compared to gentamicin evident in substantially higher suppression and reduced acute toxicity in vitro. RESULTS: We performed comparative study of suppression effects of the novel NB54 and gentamicin on three MECP2 nonsense mutations (R294X, R270X and R168X) common in RTT, using ex vivo treatment of primary fibroblasts from RTT patients harboring these mutations and testing for the C terminal containing full-length MeCP2. We observed that NB54 induces dose dependent suppression of MECP2 nonsense mutations more efficiently than gentamicin, which was evident at concentrations as low as 50 ug/ml. NB54 read through activity was mutation specific, with maximal full-length MeCP2 recovery in R168X (38%), R270X (27%) and R294X (18%). In addition, the recovered MeCP2 was translocated to the cell nucleus and moreover led to parallel increase in one of the most important MeCP2 downstream effectors, the brain derived neurotrophic factor (BDNF). CONCLUSION: Our findings suggest that NB54 may induce restoration of the potentially functional MeCP2 in primary RTT fibroblasts and encourage further studies of NB54 and other rationally designed aminoglycoside derivatives as potential therapeutic agents for nonsense MECP2 mutations in RTT. PMID- 21695139 TI - The development of open access journal publishing from 1993 to 2009. AB - Open Access (OA) is a model for publishing scholarly peer reviewed journals, made possible by the Internet. The full text of OA journals and articles can be freely read, as the publishing is funded through means other than subscriptions. Empirical research concerning the quantitative development of OA publishing has so far consisted of scattered individual studies providing brief snapshots, using varying methods and data sources. This study adopts a systematic method for studying the development of OA journals from their beginnings in the early 1990s until 2009. Because no comprehensive index of OA articles exists, systematic manual data collection from journal web sites was conducted based on journal level data extracted from the Directory of Open Access Journals (DOAJ). Due to the high number of journals registered in the DOAJ, almost 5000 at the time of the study, stratified random sampling was used. A separate sample of verified early pioneer OA journals was also studied. The results show a very rapid growth of OA publishing during the period 1993-2009. During the last year an estimated 191 000 articles were published in 4769 journals. Since the year 2000, the average annual growth rate has been 18% for the number of journals and 30% for the number of articles. This can be contrasted to the reported 3,5% yearly volume increase in journal publishing in general. In 2009 the share of articles in OA journals, of all peer reviewed journal articles, reached 7,7%. Overall, the results document a rapid growth in OA journal publishing over the last fifteen years. Based on the sampling results and qualitative data a division into three distinct periods is suggested: The Pioneering years (1993-1999), the Innovation years (2000-2004), and the Consolidation years (2005-2009). PMID- 21695140 TI - Non-apical membrane antigen 1 (AMA1) IgGs from Malian children interfere with functional activity of AMA1 IgGs as judged by growth inhibition assay. AB - BACKGROUND: Apical membrane antigen 1 (AMA1) is one of the best-studied blood stage malaria vaccine candidates. When an AMA1 vaccine was tested in a malaria naive population, it induced functionally active antibodies judged by Growth Inhibition Assay (GIA). However, the same vaccine failed to induce higher growth inhibitory activity in adults living in a malaria endemic area. Vaccination did induce functionally active antibodies in malaria-exposed children with less than 20% inhibition in GIA at baseline, but not in children with more than that level of baseline inhibition. METHODS: Total IgGs were purified from plasmas collected from the pediatric trial before and after immunization and pools of total IgGs were made. Another set of total IgGs was purified from U.S. adults immunized with AMA1 (US-total IgG). From these total IgGs, AMA1-specific and non-AMA1 IgGs were affinity purified and the functional activity of these IgGs was evaluated by GIA. Competition ELISA was performed with the U.S.-total IgG and non-AMA1 IgGs from malaria-exposed children. RESULTS: AMA1-specific IgGs from malaria-exposed children and U.S. vaccinees showed similar growth-inhibitory activity at the same concentrations. When mixed with U.S.-total IgG, non-AMA1 IgGs from children showed an interference effect in GIA. Interestingly, the interference effect was higher with non-AMA1 IgGs from higher titer pools. The non-AMA1 IgGs did not compete with anti-AMA1 antibody in U.S.-total IgG in the competition ELISA. CONCLUSION: Children living in a malaria endemic area have a fraction of IgGs that interferes with the biological activity of anti-AMA1 antibody as judged by GIA. While the mechanism of interference is not resolved in this study, these results suggest it is not caused by direct competition between non-AMA1 IgG and AMA1 protein. This study indicates that anti-malaria IgGs induced by natural exposure may interfere with the biological effect of antibody induced by an AMA1 based vaccine in the target population. PMID- 21695141 TI - Biochemical and functional characterization of the interaction between liprin alpha1 and GIT1: implications for the regulation of cell motility. AB - We have previously identified the scaffold protein liprin-alpha1 as an important regulator of integrin-mediated cell motility and tumor cell invasion. Liprin alpha1 may interact with different proteins, and the functional significance of these interactions in the regulation of cell motility is poorly known. Here we have addressed the involvement of the liprin-alpha1 partner GIT1 in liprin-alpha1 mediated effects on cell spreading and migration. GIT1 depletion inhibited spreading by affecting the lamellipodia, and prevented liprin-alpha1-enhanced spreading. Conversely inhibition of the formation of the liprin-alpha1-GIT complex by expression of liprin-DeltaCC3 could still enhance spreading, although to a lesser extent compared to full length liprin-alpha1. No cumulative effects were observed after depletion of both liprin-alpha1 and GIT1, suggesting that the two proteins belong to the same signaling network in the regulation of cell spreading. Our data suggest that liprin-alpha1 may compete with paxillin for binding to GIT1, while binding of betaPIX to GIT1 was unaffected by the presence of liprin-alpha1. Interestingly, GIT and liprin-alpha1 reciprocally regulated their subcellular localization, since liprin-alpha1 overexpression, but not the GIT binding-defective liprin-DeltaCC3 mutant, affected the localization of endogenous GIT at peripheral and mature central focal adhesions, while the expression of a truncated, active form of GIT1 enhanced the localization of endogenous liprin-alpha1 at the edge of spreading cells. Moreover, GIT1 was required for liprin-alpha1-enhanced haptotatic migration, although the direct interaction between liprin-alpha1 and GIT1 was not needed. Our findings show that the functional interaction between liprin-alpha1 and GIT1 cooperate in the regulation of integrin-dependent cell spreading and motility on extracellular matrix. These findings and the possible competition of liprin-alpha1 with paxillin for binding to GIT1 suggest that alternative binding of GIT1 to either liprin-alpha1 or paxillin plays distinct roles in different phases of the protrusive activity in the cell. PMID- 21695142 TI - Altered intracellular localization and mobility of SBDS protein upon mutation in Shwachman-Diamond syndrome. AB - Shwachman-Diamond Syndrome (SDS) is a rare inherited disease caused by mutations in the SBDS gene. Hematopoietic defects, exocrine pancreas dysfunction and short stature are the most prominent clinical features. To gain understanding of the molecular properties of the ubiquitously expressed SBDS protein, we examined its intracellular localization and mobility by live cell imaging techniques. We observed that SBDS full-length protein was localized in both the nucleus and cytoplasm, whereas patient-related truncated SBDS protein isoforms localize predominantly to the nucleus. Also the nucleo-cytoplasmic trafficking of these patient-related SBDS proteins was disturbed. Further studies with a series of SBDS mutant proteins revealed that three distinct motifs determine the intracellular mobility of SBDS protein. A sumoylation motif in the C-terminal domain, that is lacking in patient SBDS proteins, was found to play a pivotal role in intracellular motility. Our structure-function analyses provide new insight into localization and motility of the SBDS protein, and show that patient related mutant proteins are altered in their molecular properties, which may contribute to the clinical features observed in SDS patients. PMID- 21695144 TI - Temperature modulation of electric fields in biological matter. AB - Pulsed electric fields (PEF) have become an important minimally invasive surgical technology for various applications including genetic engineering, electrochemotherapy and tissue ablation. This study explores the hypothesis that temperature dependent electrical parameters of tissue can be used to modulate the outcome of PEF protocols, providing a new means for controlling and optimizing this minimally invasive surgical procedure. This study investigates two different applications of cooling temperatures applied during PEF. The first case utilizes an electrode which simultaneously delivers pulsed electric fields and cooling temperatures. The subsequent results demonstrate that changes in electrical properties due to temperature produced by this configuration can substantially magnify and confine the electric fields in the cooled regions while almost eliminating electric fields in surrounding regions. This method can be used to increase precision in the PEF procedure, and eliminate muscle contractions and damage to adjacent tissues. The second configuration considered introduces a third probe that is not electrically active and only applies cooling boundary conditions. This second study demonstrates that in this probe configuration the temperature induced changes in electrical properties of tissue substantially reduce the electric fields in the cooled regions. This novel treatment can potentially be used to protect sensitive tissues from the effect of the PEF. Perhaps the most important conclusion of this investigation is that temperature is a powerful and accessible mechanism to modulate and control electric fields in biological tissues and can therefore be used to optimize and control PEF treatments. PMID- 21695143 TI - Expression profiling of FSHD-1 and FSHD-2 cells during myogenic differentiation evidences common and distinctive gene dysregulation patterns. AB - BACKGROUND: Determine global gene dysregulation affecting 4q-linked (FSHD-1) and non 4q-linked (FSHD-2) cells during early stages of myogenic differentiation. This approach has been never applied to FSHD pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: By in vitro differentiation of FSHD-1 and FSHD-2 myoblasts and gene chip analysis we derived that gene expression profile is altered only in FSHD-1 myoblasts and FSHD-2 myotubes. The changes seen in FSHD-1 regarded a general defect in cell cycle progression, probably due to the upregulation of myogenic markers PAX3 and MYOD1, and a deficit of factors (SUV39H1 and HMGB2) involved in D4Z4 chromatin conformation. On the other hand, FSHD-2 mytubes were characterized by a general defect in RNA metabolism, protein synthesis and degradation and, to a lesser extent, in cell cycle. Common dysregulations regarded genes involved in response to oxidative stress and in sterol biosynthetic process. Interestingly, our results also suggest that miRNAs might be implied in both FSHD-1 and FSHD-2 gene dysregulation. Finally, in both cell differentiation systems, we did not observe a gradient of altered gene expression throughout the 4q35 chromosome. CONCLUSIONS/SIGNIFICANCE: FSHD-1 and FSHD-2 cells showed, in different steps of myogenic differentiation, a global deregulation of gene expression rather than an alteration of expression of 4q35 specific genes. In general, FSHD-1 and FSHD-2 global gene deregulation interested common and distinctive biological processes. In this regard, defects of cell cycle progression (FSHD-1 and to a lesser extent FSHD-2), protein synthesis and degradation (FSHD-2), response to oxidative stress (FSHD-1 and FSHD-2), and cholesterol homeostasis (FSHD-1 and FSHD-2) may in general impair a correct myogenesis. Taken together our results recapitulate previously reported defects of FSHD-1, and add new insights into the gene deregulation characterizing both FSHD-1 and FSHD-2, in which miRNAs may play a role. PMID- 21695145 TI - Gene constellation of influenza A virus reassortants with high growth phenotype prepared as seed candidates for vaccine production. AB - BACKGROUND: Influenza A virus vaccines undergo yearly reformulations due to the antigenic variability of the virus caused by antigenic drift and shift. It is critical to the vaccine manufacturing process to obtain influenza A seed virus that is antigenically identical to circulating wild type (wt) virus and grows to high titers in embryonated chicken eggs. Inactivated influenza A seasonal vaccines are generated by classical reassortment. The classical method takes advantage of the ability of the influenza virus to reassort based on the segmented nature of its genome. In ovo co-inoculation of a high growth or yield (hy) donor virus and a low yield wt virus with antibody selection against the donor surface antigens results in progeny viruses that grow to high titers in ovo with wt origin hemagglutinin (HA) and neuraminidase (NA) glycoproteins. In this report we determined the parental origin of the remaining six genes encoding the internal proteins that contribute to the hy phenotype in ovo. METHODOLOGY: The genetic analysis was conducted using reverse transcription-polymerase chain reaction (RT-PCR) and restriction fragment length polymorphism (RFLP). The characterization was conducted to determine the parental origin of the gene segments (hy donor virus or wt virus), gene segment ratios and constellations. Fold increase in growth of reassortant viruses compared to respective parent wt viruses was determined by hemagglutination assay titers. SIGNIFICANCE: In this study fifty-seven influenza A vaccine candidate reassortants were analyzed for the presence or absence of correlations between specific gene segment ratios, gene constellations and hy reassortant phenotype. We found two gene ratios, 6:2 and 5:3, to be the most prevalent among the hy reassortants analyzed, although other gene ratios also conferred hy in certain reassortants. PMID- 21695146 TI - The unmet need for interpreting provision in UK primary care. AB - BACKGROUND: With increasing globalisation, the challenges of providing accessible and safe healthcare to all are great. Studies show that there are substantial numbers of people who are not fluent in English to a level where they can make best use of health services. We examined how health professionals manage language barriers in a consultation. METHODS AND FINDINGS: This was a cross-sectional study in 41 UK general practices . Health professionals completed a proforma for a randomly allocated consultation session. Seventy-seven (63%) practitioners responded, from 41(59%) practices. From 1008 consultations, 555 involved patients who did not have English as a first language; 710 took place in English; 222 were in other languages, the practitioner either communicating with the patient in their own language/using an alternative language. Seven consultations were in a mixture of English/patient's own language. Patients' first languages numbered 37 (apart from English), in contrast to health practitioners, who declared at least a basic level of proficiency in 22 languages other than English. The practitioner's reported proficiency in the language used was at a basic level in 24 consultations, whereas in 21, they reported having no proficiency at all. In 57 consultations, a relative/friend interpreted and in 6, a bilingual member of staff/community worker was used. Only in 6 cases was a professional interpreter booked. The main limitation was that only one random session was selected and assessment of patient/professional fluency in English was subjective. CONCLUSIONS: It would appear that professional interpreters are under-used in relation to the need for them, with bilingual staff/family and friends being used commonly. In many cases where the patient spoke little/no English, the practitioner consulted in the patient's language but this approach was also used where reported practitioner proficiency was low. Further research in different setting is needed to substantiate these findings. PMID- 21695147 TI - A behavioral comparison of male and female adults with high functioning autism spectrum conditions. AB - Autism spectrum conditions (ASC) affect more males than females in the general population. However, within ASC it is unclear if there are phenotypic sex differences. Testing for similarities and differences between the sexes is important not only for clinical assessment but also has implications for theories of typical sex differences and of autism. Using cognitive and behavioral measures, we investigated similarities and differences between the sexes in age- and IQ-matched adults with ASC (high-functioning autism or Asperger syndrome). Of the 83 (45 males and 38 females) participants, 62 (33 males and 29 females) met Autism Diagnostic Interview-Revised (ADI-R) cut-off criteria for autism in childhood and were included in all subsequent analyses. The severity of childhood core autism symptoms did not differ between the sexes. Males and females also did not differ in self-reported empathy, systemizing, anxiety, depression, and obsessive-compulsive traits/symptoms or mentalizing performance. However, adult females with ASC showed more lifetime sensory symptoms (p = 0.036), fewer current socio-communication difficulties (p = 0.001), and more self-reported autistic traits (p = 0.012) than males. In addition, females with ASC who also had developmental language delay had lower current performance IQ than those without developmental language delay (p<0.001), a pattern not seen in males. The absence of typical sex differences in empathizing-systemizing profiles within the autism spectrum confirms a prediction from the extreme male brain theory. Behavioral sex differences within ASC may also reflect different developmental mechanisms between males and females with ASC. We discuss the importance of the superficially better socio-communication ability in adult females with ASC in terms of why females with ASC may more often go under-recognized, and receive their diagnosis later, than males. PMID- 21695148 TI - Regulation of Pax6 by CTCF during induction of mouse ES cell differentiation. AB - Pax6 plays an important role in embryonic cell (ES) differentiation during embryonic development. Expression of Pax6 undergoes from a low level to high levels following ES cell differentiation to neural stem cells, and then fades away in most of the differentiated cell types. There is a limited knowledge concerning how Pax6 is regulated in ES cell differentiation. We report that Pax6 expression in mouse ES cells was controlled by CCCTC binding factor (CTCF) through a promoter repression mechanism. Pax6 expression was significantly enhanced while CTCF activity was kept in the constant during ES cell differentiation to radial glial cells. Instead, the interaction of CTCF with Pax6 gene was regulated by decreased CTCF occupancy in its binding motifs upstream from Pax6 P0 promoter following the course of ES cell differentiation. Reduced occupancy of CTCF in the binding motif region upstream from the P0 promoter was due to increased DNA methylations in the CpG sites identified in the region. Furthermore, changes in DNA methylation levels in vitro and in vivo effectively altered methylation status of these identified CpG sites, which affected ability of CTCF to interact with the P0 promoter, resulting in increases in Pax6 expression. We conclude that there is an epigenetic mechanism involving regulations of Pax6 gene during ES cell differentiation to neural stem cells, which is through increases or decreases in methylation levels of Pax6 gene to effectively alter the ability of CTCF in control of Pax6 expression, respectively. PMID- 21695149 TI - The role of the interferon gamma release assay in assessing recent tuberculosis transmission in a hospital incident. AB - In 2007, an extensive contact screening investigation into onward transmission of tuberculosis was instigated at a hospital in Northern Ireland following diagnosis of pulmonary multi-drug resistant TB in a healthcare worker. Interferon gamma release assays (IGRAs) were used to test 333 patients and 98 staff. We investigated for evidence of onward transmission and recent infection based on analysis of clinical, demographic and IGRA data. We also described within-patient variability of IGRA results. Among patients and staff, increasing age of patients was the only factor associated with IGRA positivity. Greatest within-subject variability of IU/mL in serially-tested patients/staff was seen in those with a positive IGRA test and this did not correlate with increased exposure to the index case. IGRA positivity being largely explained by increasing age in patients and previous TB contact in staff lends weight to the conclusion that IGRA positivity reflected previous infection rather than recent transmission. PMID- 21695150 TI - Autophagy interplay with apoptosis and cell cycle regulation in the growth inhibiting effect of resveratrol in glioma cells. AB - Prognosis of patients with glioblastoma (GBM) remains very poor, thus making the development of new drugs urgent. Resveratrol (Rsv) is a natural compound that has several beneficial effects such as neuroprotection and cytotoxicity for several GBM cell lines. Here we evaluated the mechanism of action of Rsv on human GBM cell lines, focusing on the role of autophagy and its crosstalk with apoptosis and cell cycle control. We further evaluated the role of autophagy and the effect of Rsv on GBM Cancer Stem Cells (gCSCs), involved in GBM resistance and recurrence. Glioma cells treated with Rsv was tested for autophagy, apoptosis, necrosis, cell cycle and phosphorylation or expression levels of key players of these processes. Rsv induced the formation of autophagosomes in three human GBM cell lines, accompanied by an upregulation of autophagy proteins Atg5, beclin-1 and LC3-II. Inhibition of Rsv-induced autophagy triggered apoptosis, with an increase in Bax and cleavage of caspase-3. While inhibition of apoptosis or autophagy alone did not revert Rsv-induced toxicity, inhibition of both processes blocked this toxicity. Rsv also induced a S-G2/M phase arrest, accompanied by an increase on levels of pCdc2(Y15), cyclin A, E and B, and pRb (S807/811) and a decrease of cyclin D1. Interestingly, this arrest was dependent on the induction of autophagy, since inhibition of Rsv-induced autophagy abolishes cell cycle arrest and returns the phosphorylation of Cdc2(Y15) and Rb(S807/811), and levels of cyclin A, and B to control levels. Finally, inhibition of autophagy or treatment with Rsv decreased the sphere formation and the percentage of CD133 and OCT4-positive cells, markers of gCSCs. In conclusion, the crosstalk among autophagy, cell cycle and apoptosis, together with the biology of gCSCs, has to be considered in tailoring pharmacological interventions aimed to reduce glioma growth using compounds with multiple targets such as Rsv. PMID- 21695151 TI - HuB (elavl2) mRNA is restricted to the germ cells by post-transcriptional mechanisms including stabilisation of the message by DAZL. AB - The ability of germ cells to carry out a gene regulatory program distinct from the surrounding somatic tissue, and their capacity to specify an entire new organism has made them a focus of many studies that seek to understand how specific regulatory mechanisms, particularly post-transcriptional mechanisms, contribute to cell fate. In zebrafish, germ cells are specified through the inheritance of cytoplasmic determinants, termed the germ plasm, which contains a number of maternal mRNAs and proteins. Investigation of several of these messages has revealed that the restricted localisation of these mRNAs to the germ plasm and subsequent germ cells is due to cis-acting sequence elements present in their 3'UTRs. Here we show that a member of the Hu family of RNA-binding proteins, HuB, is maternally provided in the zebrafish embryo and exhibits germ cell specific expression during embryogenesis. Restriction of HuB mRNA to the germ cells is dependent on a number of sequence elements in its 3'UTR, which act to degrade the mRNA in the soma and stabilise it in the germ cells. In addition, we show that the germ cell specific RNA-binding protein DAZL is able to promote HuB mRNA stability and translation in germ cells, and further demonstrate that these activities require a 30 nucleotide element in the 3'UTR. Our study suggests that DAZL specifically binds the HuB 3'UTR and protects the message from degradation and/or enhances HuB translation, leading to the germ cell specific expression of HuB protein. PMID- 21695152 TI - Long-term effect of interferon plus ribavirin on hepatitis B surface antigen seroclearance in patients dually infected with hepatitis B and C viruses. AB - BACKGROUND: Interferon-alpha/ribavirin combination therapy might promote hepatitis B surface antigen (HBsAg) seroclearance in patients dually infected with hepatitis B and C viruses (HBV/HCV), but the long-term effect remains unclear. We aimed to investigate the rate of and the factors associated with HBsAg seroclearance during long-term follow-up after interferon-alpha/ribavirin combination therapy in HBV/HCV dually-infected patients. METHODOLOGY/PRINCIPAL FINDINGS: Eighty-one patients who received interferon-alpha/ribavirin combination therapy for 24 weeks with a follow-up period of >24 weeks were enrolled. HBV serological markers and HBV DNA were determined every 6 months. Early and late HBsAg seroclearance were defined as HBsAg loss in less or more than 6 months after end-of-treatment, respectively. Fifteen (18.5%) patients had HBsAg seroclearance during a mean follow-up period of 3.4 (0.5-5.1) years. The 5-year cumulative incidence was 25.6%. Baseline cirrhosis and HBV DNA negativity 1 year after end-of-treatment were independently predictive of HBsAg seroclearance with an odds ratio (OR), 95% confidence intervals (CI) of 16.6, 1.8-153 and 9.2, 1.4 62.1, respectively, by Cox regression hazard analysis. Four patients developed early and 11 developed late HBsAg seroclearance, respectively. Cox regression hazard analysis showed no factor was associated with early HBsAg seroclearance, whilst HBV DNA negativity 1 year after end-of-treatment was the only significant factor predicting late HBsAg loss (OR, 43.0; CI, 2.5-745). Five patients had HBsAg seroconversion with a 5-year cumulative incidence of 8.3%. HBV DNA negativity at baseline and one year after EOT had a trend for HBsAg seroconversion. HCV response did not correlate to HBsAg loss. CONCLUSIONS: We demonstrated that interferon-alpha/ribavirin had long-term effect on HBsAg seroclearance in dually HBV/HCV-infected patients. Baseline cirrhosis and seroclearance of HBV DNA 1 year after end-of-treatment were significant factors associated with HBsAg seroclearance. PMID- 21695153 TI - Efficient immunoglobulin gene disruption and targeted replacement in rabbit using zinc finger nucleases. AB - Rabbits are widely used in biomedical research, yet techniques for their precise genetic modification are lacking. We demonstrate that zinc finger nucleases (ZFNs) introduced into fertilized oocytes can inactivate a chosen gene by mutagenesis and also mediate precise homologous recombination with a DNA gene targeting vector to achieve the first gene knockout and targeted sequence replacement in rabbits. Two ZFN pairs were designed that target the rabbit immunoglobulin M (IgM) locus within exons 1 and 2. ZFN mRNAs were microinjected into pronuclear stage fertilized oocytes. Founder animals carrying distinct mutated IgM alleles were identified and bred to produce offspring. Functional knockout of the immunoglobulin heavy chain locus was confirmed by serum IgM and IgG deficiency and lack of IgM(+) and IgG(+) B lymphocytes. We then tested whether ZFN expression would enable efficient targeted sequence replacement in rabbit oocytes. ZFN mRNA was co-injected with a linear DNA vector designed to replace exon 1 of the IgM locus with ~1.9 kb of novel sequence. Double strand break induced targeted replacement occurred in up to 17% of embryos and in 18% of fetuses analyzed. Two major goals have been achieved. First, inactivation of the endogenous IgM locus, which is an essential step for the production of therapeutic human polyclonal antibodies in the rabbit. Second, establishing efficient targeted gene manipulation and homologous recombination in a refractory animal species. ZFN mediated genetic engineering in the rabbit and other mammals opens new avenues of experimentation in immunology and many other research fields. PMID- 21695154 TI - BMP9 protects septal neurons from axotomy-evoked loss of cholinergic phenotype. AB - BACKGROUND: Cholinergic projection from the septum to the hippocampus is crucial for normal cognitive function and degeneration of cells and nerve fibers within the septohippocampal pathway contributes to the pathophysiology of Alzheimer's disease. Bone morphogenetic protein (BMP) 9 is a cholinergic differentiating factor during development both in vivo and in vitro. METHODOLOGY/PRINCIPAL FINDINGS: To determine whether BMP9 could protect the adult cholinergic septohippocampal pathway from axotomy-evoked loss of the cholinergic phenotype, we performed unilateral fimbria-fornix transection in mice and treated them with a continuous intracerebroventricular infusion of BMP9 for six days. The number of choline acetyltransferase (CHAT)-positive cells was reduced by 50% in the medial septal nucleus ipsilateral to the lesion as compared to the intact, contralateral side, and BMP9 infusion prevented this loss in a dose-dependent manner. Moreover, BMP9 prevented most of the decline of hippocampal acetylcholine levels ipsilateral to the lesion, and markedly increased CHAT, choline transporter CHT, NGF receptors p75 (NGFR-p75) and TrkA (NTRK1), and NGF protein content in both the lesioned and unlesioned hippocampi. In addition, BMP9 infusion reduced bilaterally hippocampal levels of basic FGF (FGF2) protein. CONCLUSIONS/SIGNIFICANCE: These data indicate that BMP9 administration can prevent lesion-evoked impairment of the cholinergic septohippocampal neurons in adult mice and, by inducing NGF, establishes a trophic environment for these cells. PMID- 21695155 TI - Interactions between a Trawl fishery and spatial closures for biodiversity conservation in the Great Barrier Reef World Heritage Area, Australia. AB - BACKGROUND: The Queensland East Coast Otter Trawl Fishery (ECOTF) for penaeid shrimp fishes within Australia's Great Barrier Reef World Heritage Area (GBRWHA). The past decade has seen the implementation of conservation and fisheries management strategies to reduce the impact of the ECOTF on the seabed and improve biodiversity conservation. New information from electronic vessel location monitoring systems (VMS) provides an opportunity to review the interactions between the ECOTF and spatial closures for biodiversity conservation. METHODOLOGY AND RESULTS: We used fishing metrics and spatial information on the distribution of closures and modelled VMS data in a geographical information system (GIS) to assess change in effort of the trawl fishery from 2001-2009 and to quantify the exposure of 70 reef, non-reef and deep water bioregions to trawl fishing. The number of trawlers and the number of days fished almost halved between 2001 and 2009 and new spatial closures introduced in 2004 reduced the area zoned available for trawl fishing by 33%. However, we found that there was only a relatively minor change in the spatial footprint of the fishery as a result of new spatial closures. Non-reef bioregions benefited the most from new spatial closures followed by deep and reef bioregions. CONCLUSIONS/SIGNIFICANCE: Although the catch of non target species remains an issue of concern for fisheries management, the small spatial footprint of the ECOTF relative to the size of the GBRWHA means that the impact on benthic habitats is likely to be negligible. The decline in effort as a result of fishing industry structural adjustment, increasing variable costs and business decisions of fishers is likely to continue a trend to fish only in the most productive areas. This will provide protection for most benthic habitats without any further legislative or management intervention. PMID- 21695156 TI - Cancer stem cell-like cells derived from malignant peripheral nerve sheath tumors. AB - This study aims to examine whether or not cancer stem cells exist in malignant peripheral nerve sheath tumors (MPNST). Cells of established lines, primary cultures and freshly dissected tumors were cultured in serum free conditions supplemented with epidermal and fibroblast growth factors. From one established human MPNST cell line, S462, cells meeting the criteria for cancer stem cells were isolated. Clonal spheres were obtained, which could be passaged multiple times. Enrichment of stem cell-like cells in these spheres was also supported by increased expression of stem cell markers such as CD133, Oct4, Nestin and NGFR, and decreased expression of mature cell markers such as CD90 and NCAM. Furthermore, cells of these clonal S462 spheres differentiated into Schwann cells, smooth muscle/fibroblast and neurons-like cells under specific differentiation-inducing cultural conditions. Finally, subcutaneous injection of the spheres into immunodeficient nude mice led to tumor formation at a higher rate compared to the parental adherent cells (66% versus 10% at 2.5 * 10(5)). These results provide evidence for the existence of cancer stem cell-like cells in malignant peripheral nerve sheath tumors. PMID- 21695157 TI - The antiquity and evolutionary history of social behavior in bees. AB - A long-standing controversy in bee social evolution concerns whether highly eusocial behavior has evolved once or twice within the corbiculate Apidae. Corbiculate bees include the highly eusocial honey bees and stingless bees, the primitively eusocial bumble bees, and the predominantly solitary or communal orchid bees. Here we use a model-based approach to reconstruct the evolutionary history of eusociality and date the antiquity of eusocial behavior in apid bees, using a recent molecular phylogeny of the Apidae. We conclude that eusociality evolved once in the common ancestor of the corbiculate Apidae, advanced eusociality evolved independently in the honey and stingless bees, and that eusociality was lost in the orchid bees. Fossil-calibrated divergence time estimates reveal that eusociality first evolved at least 87 Mya (78 to 95 Mya) in the corbiculates, much earlier than in other groups of bees with less complex social behavior. These results provide a robust new evolutionary framework for studies of the organization and genetic basis of social behavior in honey bees and their relatives. PMID- 21695158 TI - Regulation of rDNA transcription by proto-oncogene PELP1. AB - BACKGROUND: Proline-, glutamic acid-, and leucine-rich protein (PELP1) is a novel nuclear receptor coregulator with a multitude of functions. PELP1 serves as a scaffolding protein that couples various signaling complexes with nuclear receptors and participates as a transcriptional coregulator. Recent data suggest that PELP1 expression is deregulated in hormonal cancers, and that PELP1 functions as a proto-oncogene; however, the mechanism by which PELP1 promotes oncogenesis remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: Using pharmacological inhibitors, confocal microscopy and biochemical assays, we demonstrated that PELP1 is localized in the nucleolus and that PELP1 is associated with the active ribosomal RNA transcription. Cell synchronization studies showed that PELP1 nucleolar localization varies and the greatest amount of nucleolar localization was observed during S and G2 phases. Using pharmacological compounds and CDK site mutants of PELP1, we found that CDK's activity plays an important role on PELP1 nucleolar localization. Depletion of PELP1 by siRNA decreased the expression of pre-rRNA. Reporter gene assays using ribosomal DNA (pHrD) luc-reporter revealed that PELP1WT but not PELP1MT enhanced the expression of reporter. Deletion of nucleolar domains abolished PELP1 mediated activation of the pHrD reporter. ChIP analysis revealed that PELP1 is recruited to the promoter regions of rDNA and is needed for optimal transcription of ribosomal RNA. CONCLUSIONS/SIGNIFICANCE: Collectively, our results suggest that proto-oncogene PELP1 plays a vital role in rDNA transcription. PELP1 modulation of rRNA transcription, a key step in ribosomal biogenesis may have implications in PELP1-mediated oncogenic functions. PMID- 21695159 TI - Context-related acoustic variation in male fallow deer (Dama dama) groans. AB - While social and behavioural contexts are known to affect the acoustic structure of vocal signals in several mammal species, few studies have investigated context related acoustic variation during inter-sexual advertisement and/or intra-sexual competition. Here we recorded male fallow deer groans during the breeding season and investigated how key acoustic parameters (fundamental frequency and formant frequencies) vary as a function of the social context in which they are produced. We found that in the presence of females, male fallow deer produced groans with higher mean fundamental frequency when vocal males were also present than they did when no vocal males were in close vicinity. We attribute this to the increased arousal state typically associated with this context. In addition, groan minimum formant frequency spacing was slightly, but significantly lower (indicating marginally more extended vocal tracts) when males were alone than when potential mates and/or competitors were nearby. This indicates that, contrary to our predictions, male fallow deer do not exaggerate the acoustic impression of their body size by further lowering their formant frequencies in the presence of potential mating partners and competitors. Furthermore, since the magnitude of the variation in groan minimum formant frequency spacing remains small compared to documented inter-individual differences, our findings are consistent with the hypothesis that formants are reliable static cues to body size during intra- and inter-sexual advertisement that do not concurrently encode dynamic motivation-related information. PMID- 21695160 TI - Incidence and Symptoms of High Altitude Illness in South Pole Workers: Antarctic Study of Altitude Physiology (ASAP). AB - INTRODUCTION: Each year, the US Antarctic Program rapidly transports scientists and support personnel from sea level (SL) to the South Pole (SP, 2835 m) providing a unique natural laboratory to quantify the incidence of acute mountain sickness (AMS), patterns of altitude related symptoms and the field effectiveness of acetazolamide in a highly controlled setting. We hypothesized that the combination of rapid ascent (3 hr), accentuated hypobarism (relative to altitude), cold, and immediate exertion would increase altitude illness risk. METHODS: Medically screened adults (N = 246, age = 37 +/- 11 yr, 30% female, BMI = 26 +/- 4 kg/m(2)) were recruited. All underwent SL and SP physiological evaluation, completed Lake Louise symptom questionnaires (LLSQ, to define AMS), and answered additional symptom related questions (eg, exertional dyspnea, mental status, cough, edema and general health), during the 1st week at altitude. Acetazolamide, while not mandatory, was used by 40% of participants. RESULTS: At SP, the barometric pressure resulted in physiological altitudes that approached 3400 m, while T degrees C averaged -42, humidity 0.03%. Arterial oxygen saturation averaged 89% +/- 3%. Overall, 52% developed LLSQ defined AMS. The most common symptoms reported were exertional dyspnea-(87%), sleeping difficulty (74%), headache-(66%), fatigue-(65%), and dizziness/lightheadedness-(46%). Symptom severity peaked on days 1-2, yet in >20% exertional dyspnea, fatigue and sleep problems persisted through day 7. AMS incidence was similar between those using acetazolamide and those abstaining (51 vs. 52%, P = 0.87). Those who used acetazolamide tended to be older, have less altitude experience, worse symptoms on previous exposures, and less SP experience. CONCLUSION: The incidence of AMS at SP tended to be higher than previously reports in other geographic locations at similar altitudes. Thus, the SP constitutes a more intense altitude exposure than might be expected considering physical altitude alone. Many symptoms persist, possibly due to extremely cold, arid conditions and the benefits of acetazolamide appeared negligible, though it may have prevented more severe symptoms in higher risk subjects. PMID- 21695161 TI - A multicentre randomized controlled trial of the efficacy and safety of single dose praziquantel at 40 mg/kg vs. 60 mg/kg for treating intestinal schistosomiasis in the Philippines, Mauritania, Tanzania and Brazil. AB - BACKGROUND: Praziquantel at 40 mg/kg in a single dose is the WHO recommended treatment for all forms of schistosomiasis, but 60 mg/kg is also deployed nationally. METHODOLOGY/PRINCIPAL FINDINGS: Four trial sites in the Philippines, Mauritania, Tanzania and Brazil enrolled 856 patients using a common protocol, who were randomised to receive praziquantel 40 mg/kg (n = 428) or 60 mg/kg (n = 428). While the sites differed for transmission and infection intensities (highest in Tanzania and lowest in Mauritania), no bias or heterogeneity across sites was detected for the main efficacy outcomes. The primary efficacy analysis was the comparison of cure rates on Day 21 in the intent-to-treat population for the pooled data using a logistic model to calculate Odd Ratios allowing for baseline characteristics and study site. Both doses were highly effective: the Day 21 cure rates were 91.7% (86.6%-98% at individual sites) with 40 mg/kg and 92.8% (88%-97%) with 60 mg/kg. Secondary parameters were eggs reduction rates (ERR), change in intensity of infection and reinfection rates at 6 and 12 months. On Day 21 the pooled estimate of the ERR was 91% in both arms. The Hazard Ratio for reinfections was only significant in Brazil, and in favour of 60 mg/kg on the pooled estimate (40 mg/kg: 34.3%, 60 mg/kg: 23.9%, HR = 0.78, 95% CI = [0.63;0.96]). Analysis of safety could not distinguish between disease- and drug related events. 666 patients (78%) reported 1327 adverse events (AE) 4 h post dosing. The risk of having at least one AE was higher in the 60 than in the 40 mg/kg group (83% vs. 73%, p<0.001). At 24 h post-dosing, 456 patients (54%) had 918 AEs with no difference between arms. The most frequent AE was abdominal pain at both 4 h and 24 h (40% and 24%). CONCLUSION: A higher dose of 60 mg/kg of praziquantel offers no significant efficacy advantage over standard 40 mg/kg for treating intestinal schistosomiasis caused by either S. mansoni or S. japonicum. The results of this study support WHO recommendation and should be used to inform policy decisions in the countries. PMID- 21695162 TI - The Chikungunya epidemic on La Reunion Island in 2005-2006: a cost-of-illness study. AB - BACKGROUND: This study was conducted to assess the impact of chikungunya on health costs during the epidemic that occurred on La Reunion in 2005-2006. METHODOLOGY/PRINCIPAL FINDINGS: From data collected from health agencies, the additional costs incurred by chikungunya in terms of consultations, drug consumption and absence from work were determined by a comparison with the expected costs outside the epidemic period. The cost of hospitalization was estimated from data provided by the national hospitalization database for short term care by considering all hospital stays in which the ICD-10 code A92.0 appeared. A cost-of-illness study was conducted from the perspective of the third party payer. Direct medical costs per outpatient and inpatient case were evaluated. The costs were estimated in Euros at 2006 values. Additional reimbursements for consultations with general practitioners and drugs were estimated as ? 12.4 million (range: ? 7.7 million-? 17.1 million) and ? 5 million (? 1.9 million-? 8.1 million), respectively, while the cost of hospitalization for chikungunya was estimated to be ? 8.5 million (? 5.8 million-? 8.7 million). Productivity costs were estimated as ? 17.4 million (? 6 million-? 28.9 million). The medical cost of the chikungunya epidemic was estimated as ? 43.9 million, 60% due to direct medical costs and 40% to indirect costs (? 26.5 million and ? 17.4 million, respectively). The direct medical cost was assessed as ? 90 for each outpatient and ? 2,000 for each inpatient. CONCLUSIONS/SIGNIFICANCE: The medical management of chikungunya during the epidemic on La Reunion Island was associated with an important economic burden. The estimated cost of the reported disease can be used to evaluate the cost/efficacy and cost/benefit ratios for prevention and control programmes of emerging arboviruses. PMID- 21695163 TI - Vorinostat induces reactive oxygen species and DNA damage in acute myeloid leukemia cells. AB - Histone deacetylase inhibitors (HDACi) are promising anti-cancer agents, however, their mechanisms of action remain unclear. In acute myeloid leukemia (AML) cells, HDACi have been reported to arrest growth and induce apoptosis. In this study, we elucidate details of the DNA damage induced by the HDACi vorinostat in AML cells. At clinically relevant concentrations, vorinostat induces double-strand breaks and oxidative DNA damage in AML cell lines. Additionally, AML patient blasts treated with vorinostat display increased DNA damage, followed by an increase in caspase-3/7 activity and a reduction in cell viability. Vorinostat-induced DNA damage is followed by a G2-M arrest and eventually apoptosis. We found that pre treatment with the antioxidant N-acetyl cysteine (NAC) reduces vorinostat-induced DNA double strand breaks, G2-M arrest and apoptosis. These data implicate DNA damage as an important mechanism in vorinostat-induced growth arrest and apoptosis in both AML cell lines and patient-derived blasts. This supports the continued study and development of vorinostat in AMLs that may be sensitive to DNA-damaging agents and as a combination therapy with ionizing radiation and/or other DNA damaging agents. PMID- 21695164 TI - A network of genes, genetic disorders, and brain areas. AB - The network-based approach has been used to describe the relationship among genes and various phenotypes, producing a network describing complex biological relationships. Such networks can be constructed by aggregating previously reported associations in the literature from various databases. In this work, we applied the network-based approach to investigate how different brain areas are associated to genetic disorders and genes. In particular, a tripartite network with genes, genetic diseases, and brain areas was constructed based on the associations among them reported in the literature through text mining. In the resulting network, a disproportionately large number of gene-disease and disease brain associations were attributed to a small subset of genes, diseases, and brain areas. Furthermore, a small number of brain areas were found to be associated with a large number of the same genes and diseases. These core brain regions encompassed the areas identified by the previous genome-wide association studies, and suggest potential areas of focus in the future imaging genetics research. The approach outlined in this work demonstrates the utility of the network-based approach in studying genetic effects on the brain. PMID- 21695165 TI - Serum 25-hydroxyvitamin D and risk of lung cancer in male smokers: a nested case control study. AB - BACKGROUND: A role for vitamin D in cancer risk reduction has been hypothesized, but few data exist for lung cancer. We investigated the relationship between vitamin D status, using circulating 25-hydroxyvitamin D [25(OH)D], and lung cancer risk in a nested case-control study within the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study of Finnish male smokers. METHODS: Lung cancer cases (n = 500) were randomly selected based on month of blood collection, and 500 controls were matched to them based on age and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariate-adjusted conditional logistic regression. To account for seasonal variation in 25(OH)D concentrations, season-specific and season-standardized quintiles of 25(OH)D were examined, and models were also stratified on season of blood collection (darker season = November-April and sunnier season = May October). Pre-determined, clinically-defined cutpoints for 25(OH)D and 25(OH)D as a continuous measure were also examined. RESULTS: Overall, 25(OH)D was not associated with lung cancer. Risks were 1.08 (95% CI 0.67-1.75) and 0.83 (95% CI 0.53-1.31) in the highest vs. lowest season-specific and season-standardized quintiles of 25(OH)D, respectively, and 0.91 (95% CI 0.48-1.72) for the >=75 vs. <25 nmol/L clinical categories. Inverse associations were, however, suggested for subjects with blood collections from November-April, with ORs of 0.77 (95% CI 0.41-1.45, p-trend = 0.05) and 0.65 (95% CI 0.37-1.14, p-trend = 0.07) in the highest vs. lowest season-specific and season-standardized quintiles of 25(OH)D, respectively, and 0.61 (95% CI 0.24-1.52, p-trend = 0.01) for >=75 vs. <25 nmol/L. We also found 11% lower risk for a 10 nmol/L increase in 25(OH)D in the darker season based on the continuous measure (OR = 0.89, 95% CI 0.81-0.98, p = 0.02). CONCLUSION: In this prospective study of male smokers, circulating 25(OH)D was not associated with lung cancer risk overall, although inverse associations were suggested among those whose blood was drawn during darker months. PMID- 21695166 TI - Antioxidant properties of the mung bean flavonoids on alleviating heat stress. AB - BACKGROUND: It is a widespread belief in Asian countries that mung bean soup (MBS) may afford a protective effect against heat stress. Lack of evidence supports MBS conferring a benefit in addition to water. RESULTS: Here we show that vitexin and isovitexin are the major antioxidant components in mungbean (more than 96% of them existing in the bean seed coat), and both of them could be absorbed via gavage into rat plasma. In the plasma of rats fed with mungbean coat extract before or after exposure to heat stress, the levels of malonaldehyde and activities of lactate dehydrogenase and nitric oxide synthase were remarkably reduced; the levels of total antioxidant capacity and glutathione (a quantitative assessment of oxidative stress) were significantly enhanced. CONCLUSIONS: Our results demonstrate that MBS can play additional roles to prevent heat stress injury. Characterization of the mechanisms underlying mungbean beneficial effects should help in the design of diet therapy strategies to alleviate heat stress, as well as provide reference for searching natural medicines against oxidative stress induced diseases. PMID- 21695167 TI - Multimodal stimulation of Colorado potato beetle reveals modulation of pheromone response by yellow light. AB - Orientation of insects to host plants and conspecifics is the result of detection and integration of chemical and physical cues present in the environment. Sensory organs have evolved to be sensitive to important signals, providing neural input for higher order multimodal processing and behavioral output. Here we report experiments to determine decisions made by Colorado potato beetle (CPB), Leptinotarsa decemlineata, in response to isolated stimuli and multimodal combinations of signals on a locomotion compensator. Our results show that in complete darkness and in the absence of other stimuli, pheromonal stimulation increases attraction behavior of CPB as measured in oriented displacement and walking speed. However, orientation to the pheromone is abolished when presented with the alternative stimulation of a low intensity yellow light in a dark environment. The ability of the pheromone to stimulate these diurnal beetles in the dark in the absence of other stimuli is an unexpected but interesting observation. The predominance of the phototactic response over that to pheromone when low intensity lights were offered as choices seems to confirm the diurnal nature of the insect. The biological significance of the response to pheromone in the dark is unclear. The phototactic response will play a key role in elucidating multimodal stimulation in the host-finding process of CPB, and perhaps other insects. Such information might be exploited in the design of applications to attract and trap CPB for survey or control purposes and other insect pests using similar orientation mechanisms. PMID- 21695168 TI - Impaired sprouting and axonal atrophy in cerebellar climbing fibres following in vivo silencing of the growth-associated protein GAP-43. AB - The adult mammalian central nervous system has a limited ability to establish new connections and to recover from traumatic or degenerative events. The olivo cerebellar network represents an excellent model to investigate neuroprotection and repair in the brain during adulthood, due to its high plasticity and ordered synaptic organization. To shed light on the molecular mechanisms involved in these events, we focused on the growth-associated protein GAP-43 (also known as B 50 or neuromodulin). During development, this protein plays a crucial role in growth and in branch formation of neurites, while in the adult it is only expressed in a few brain regions, including the inferior olive (IO) where climbing fibres (CFs) originate. Following axotomy GAP-43 is usually up-regulated in association with regeneration. Here we describe an in vivo lentiviral-mediated gene silencing approach, used for the first time in the olivo-cerebellar system, to efficiently and specifically downregulate GAP-43 in rodents CFs. We show that lack of GAP-43 causes an atrophy of the CF in non-traumatic conditions, consisting in a decrease of its length, branching and number of synaptic boutons. We also investigated CF regenerative ability by inducing a subtotal lesion of the IO. Noteworthy, surviving CFs lacking GAP-43 were largely unable to sprout on surrounding Purkinje cells. Collectively, our results demonstrate that GAP-43 is essential both to maintain CFs structure in non-traumatic condition and to promote sprouting after partial lesion of the IO. PMID- 21695169 TI - Plasmacytoid DC from aged mice down-regulate CD8 T cell responses by inhibiting cDC maturation after Encephalitozoon cuniculi infection. AB - Age associated impairment of immune function results in inefficient vaccination, tumor surveillance and increased severity of infections. Several alterations in adaptive immunity have been observed and recent studies report age related declines in innate immune responses to opportunistic pathogens including Encephalitozoon cuniculi. We previously demonstrated that conventional dendritic cells (cDC) from 9-month-old animals exhibit sub-optimal response to E. cuniculi infection, suggesting that age associated immune senescence begins earlier than expected. We focused this study on how age affects plasmacytoid DC (pDC) function. More specifically how aged pDC affect cDC function as we observed that the latter are the predominant activators of CD8 T cells during this infection. Our present study demonstrates that pDC from middle-aged mice (12 months) suppress young (8 week old) cDC driven CD8 T cell priming against E. cuniculi infection. The suppressive effect of pDC from older mice decreased maturation of young cDC via cell contact. Aged mouse pDC exhibited higher expression of PD-L1 and blockade of their interaction with cDC via this molecule restored cDC maturation and T cell priming. Furthermore, the PD-L1 dependent suppression of cDC T cell priming was restricted to effector function of antigen-specific CD8 T cells not their expansion. To the best of our knowledge, the data presented here is the first report highlighting a cell contact dependent, PD-L1 regulated, age associated defect in a DC subpopulation that results in a sub-optimal immune response against E. cuniculi infection. These results have broad implications for design of immunotherapeutic approaches to enhance immunity for aging populations. PMID- 21695170 TI - The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA. AB - EVI1 has pleiotropic functions during murine embryogenesis and its targeted disruption leads to prenatal death by severely affecting the development of virtually all embryonic organs. However, its functions in adult tissues are still unclear. When inappropriately expressed, EVI1 becomes one of the most aggressive oncogenes associated with human hematopoietic and solid cancers. The mechanisms by which EVI1 transforms normal cells are unknown, but we showed recently that EVI1 indirectly upregulates self-renewal and cell-cycling genes by inappropriate methylation of CpG dinucleotides in the regulatory regions of microRNA-124-3 (miR 124-3), leading to the repression of this small gene that controls normal differentiation and cell cycling of somatic cells. We used the regulatory regions of miR-124-3 as a read-out system to investigate how EVI1 induces de novo methylation of DNA. Here we show that EVI1 physically interacts with DNA methyltransferases 3a and 3b (Dnmt3a/b), which are the only de novo DNA methyltransferases identified to date in mouse and man, and that it forms an enzymatically active protein complex that induces de novo DNA methylation in vitro. This protein complex targets and binds to a precise region of miR-124-3 that is necessary for repression of a reporter gene by EVI1. Based on our findings, we propose that in cooperation with Dnmt3a/b EVI1 regulates the methylation of DNA as a sequence-specific mediator of de novo DNA methylation and that inappropriate EVI1 expression contributes to carcinogenesis through improper DNA methylation. PMID- 21695171 TI - Differential estrogen-regulation of CXCL12 chemokine receptors, CXCR4 and CXCR7, contributes to the growth effect of estrogens in breast cancer cells. AB - CXCR4 and CXCR7 are the two receptors for the chemokine CXCL12, a key mediator of the growth effect of estrogens (E2) in estrogen receptor (ER)-positive breast cancers. In this study we examined E2-regulation of the CXCL12 axis components and their involvement in the growth of breast cancer cells. CXCR4 and CXCR7 were differentially regulated by E2 which enhanced the expression of both CXCL12 and CXCR4 but repressed the expression of CXCR7. Formaldehyde-associated isolation of regulatory elements (FAIRE) revealed that E2-mediated transcriptional regulation of these genes is linked to the control of the compaction state of chromatin at their promoters. This effect could be accomplished via several distal ER-binding sites in the regions surrounding these genes, all of which are located 20-250 kb from the transcription start site. Furthermore, individual down-regulation of CXCL12, CXCR4 or CXCR7 expression as well as the inhibition of their activity significantly decreases the rate of basal cell growth. In contrast, E2-induced cell growth was differentially affected. Unlike CXCR7, the inhibition of the expression or activity of either CXCL12 or CXCR4 significantly blunted the E2 mediated stimulation of cellular growth. Besides, CXCR7 over-expression increased the basal MCF-7 cell growth rate and decreased the growth effect of E2. These findings indicate that E2 regulation of the CXCL12 signaling axis is important for the E2-mediated growth effect of breast cancer cells. These data also provide support for distinct biological functions of CXCR4 and CXCR7 and suggest that targeting CXCR4 and/or CXCR7 would have distinct molecular effects on ER-positive breast tumors. PMID- 21695172 TI - Enhanced growth and osteogenic differentiation of human osteoblast-like cells on boron-doped nanocrystalline diamond thin films. AB - Intrinsic nanocrystalline diamond (NCD) films have been proven to be promising substrates for the adhesion, growth and osteogenic differentiation of bone derived cells. To understand the role of various degrees of doping (semiconducting to metallic-like), the NCD films were deposited on silicon substrates by a microwave plasma-enhanced CVD process and their boron doping was achieved by adding trimethylboron to the CH(4):H(2) gas mixture, the B?C ratio was 133, 1000 and 6700 ppm. The room temperature electrical resistivity of the films decreased from >10 MOmega (undoped films) to 55 kOmega, 0.6 kOmega, and 0.3 kOmega (doped films with 133, 1000 and 6700 ppm of B, respectively). The increase in the number of human osteoblast-like MG 63 cells in 7-day-old cultures on NCD films was most apparent on the NCD films doped with 133 and 1000 ppm of B (153,000 +/- 14,000 and 152,000 +/- 10,000 cells/cm(2), respectively, compared to 113,000 +/- 10,000 cells/cm(2) on undoped NCD films). As measured by ELISA per mg of total protein, the cells on NCD with 133 and 1000 ppm of B also contained the highest concentrations of collagen I and alkaline phosphatase, respectively. On the NCD films with 6700 ppm of B, the cells contained the highest concentration of focal adhesion protein vinculin, and the highest amount of collagen I was adsorbed. The concentration of osteocalcin also increased with increasing level of B doping. The cell viability on all tested NCD films was almost 100%. Measurements of the concentration of ICAM-1, i.e. an immunoglobuline adhesion molecule binding inflammatory cells, suggested that the cells on the NCD films did not undergo significant immune activation. Thus, the potential of NCD films for bone tissue regeneration can be further enhanced and tailored by B doping and that B doping up to metallic-like levels is not detrimental for cells. PMID- 21695173 TI - ACE2 improves right ventricular function in a pressure overload model. AB - BACKGROUND: Right ventricular (RV) dysfunction is a complication of pulmonary hypertension and portends a poor prognosis. Pharmacological therapies targeting RV function in pulmonary hypertension may reduce symptoms, improve hemodynamics, and potentially increase survival. We hypothesize that recombinant human angiotensin-converting enzyme 2 (rhACE2) will improve RV function in a pressure overload model. RESULTS: rhACE2 administered at 1.8 mg/kg/day improved RV systolic and diastolic function in pulmonary artery banded mice as measured by in vivo hemodynamics. Specifically, rhACE2 increased RV ejection fraction and decreased RV end diastolic pressure and diastolic time constant (p<0.05). In addition, rhACE2 decreased RV hypertrophy as measured by RV/LV+S ratio (p<0.05). There were no significant negative effects of rhACE2 administration on LV function. rhACE2 had no significant effect on fibrosis as measured by trichrome staining and collagen1alpha1 expression. In pulmonary artery banded mice, rhACE2 increased Mas receptor expression and normalized connexin 37 expression. CONCLUSION: In a mouse RV load-stress model of early heart failure, rhACE2 diminished RV hypertrophy and improved RV systolic and diastolic function in association with a marker of intercellular communication. rhACE2 may be a novel treatment for RV failure. PMID- 21695174 TI - A mathematical model for the determination of steady-state cardiolipin remodeling mechanisms using lipidomic data. AB - Technical advances in lipidomic analysis have generated tremendous amounts of quantitative lipid molecular species data, whose value has not been fully explored. We describe a novel computational method to infer mechanisms of de novo lipid synthesis and remodeling from lipidomic data. We focus on the mitochondrial specific lipid cardiolipin (CL), a polyglycerol phospholipid with four acyl chains. The lengths and degree of unsaturation of these acyl chains vary across CL molecules, and regulation of these differences is important for mitochondrial energy metabolism. We developed a novel mathematical approach to determine mechanisms controlling the steady-state distribution of acyl chain combinations in CL . We analyzed mitochondrial lipids from 18 types of steady-state samples, each with at least 3 replicates, from mouse brain, heart, lung, liver, tumor cells, and tumors grown in vitro. Using a mathematical model for the CL remodeling mechanisms and a maximum likelihood approach to infer parameters, we found that for most samples the four chain positions have an independent and identical distribution, indicating they are remodeled by the same processes. Furthermore, for most brain samples and liver, the distribution of acyl chains is well-fit by a simple linear combination of the pools of acyl chains in phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylglycerol (PG). This suggests that headgroup chemistry is the key determinant of acyl donation into CL, with chain length/saturation less important. This canonical remodeling behavior appears damaged in some tumor samples, which display a consistent excess of CL molecules having particular masses. For heart and lung, the "proportional incorporation" assumption is not adequate to explain the CL distribution, suggesting additional acyl CoA-dependent remodeling that is chain type specific. Our findings indicate that CL remodeling processes can be described by a small set of quantitative relationships, and that bioinformatic approaches can help determine these processes from high-throughput lipidomic data. PMID- 21695175 TI - Epidemiology of classical Hodgkin lymphoma and its association with Epstein Barr virus in Northern China. AB - BACKGROUND: The incidence of classical Hodgkin lymphoma (cHL) and its association with Epstein-Barr virus (EBV) varies significantly with age, sex, ethnicity and geographic location. This is the first report on epidemiological features of cHL patients from Northern regions of China. These features are compared to data from a previously published Dutch cHL population. METHODOLOGY/PRINCIPAL FINDINGS: 157 cHL patients diagnosed between 1997 and 2008 in the North of China were included after histopathological re-evaluation. The Dutch population-based cohort consisted of 515 cHL patients diagnosed between 1987 and 2000. EBV status was determined by in situ hybridization of EBV- encoded small RNAs. In the Chinese population, tumor cells of 39% of the cHL patients were EBV+ and this was significantly associated with male sex, mixed cellularity subtype and young age (<20 y). The median age of the Chinese patients was 9 years younger than that of the Dutch patients (28 y vs. 37 y). In addition, the age distribution between the two populations was strikingly different in both the EBV+ subgroups (p<0.001) and the EBV- subgroups (p = 0.01). The mixed cellularity subtype was almost 3x more frequent amongst the Chinese (p<0.001). CONCLUSION/SIGNIFICANCE: CHL patients from Northern regions of China show a distinctive age distribution pattern with a striking incidence peak of EBV+ mixed cellularity cases among children and adolescents and another high incidence peak of EBV- nodular sclerosis cases in young adults. In comparison to Dutch cHL patients there are pronounced differences in age distribution, subtype and EBV status, presumably caused by complex gene-environmental interactions. PMID- 21695177 TI - Anticancer activity of 2alpha, 3alpha, 19beta, 23beta-Tetrahydroxyurs-12-en-28 oic acid (THA), a novel triterpenoid isolated from Sinojackia sarcocarpa. AB - BACKGROUND: Natural products represent an important source for agents of cancer prevention and cancer treatment. More than 60% of conventional anticancer drugs are derived from natural sources, particularly from plant-derived materials. In this study, 2alpha, 3alpha, 19beta, 23beta-tetrahydroxyurs-12-en-28-oic acid (THA), a novel triterpenoid from the leaves of Sinojackia sarcocarpa, was isolated, and its anticancer activity was investigated both in vitro and in vivo. PRINCIPAL FINDINGS: THA possessed potent tumor selected toxicity in vitro. It exhibited significantly higher cytotoxicity to the cancer cell lines A2780 and HepG2 than to IOSE144 and QSG7701, two noncancerous cell lines derived from ovary epithelium and liver, respectively. Moreover, THA showed a dose-dependent inhibitory effect on A2780 ovary tumor growth in vivo in nude mice. THA induced a dose-dependent apoptosis and G2/M cell cycle arrest in A2780 and HepG2 cells. The THA-induced cell cycle arrest was accompanied by a downregulation of Cdc2. The apoptosis induced by THA was evident by induction of DNA fragmentation, release of cytoplasmic Cytochrome c from mitochondria, activation of caspases, downregulation of Bcl-2 and upregulation of Bax. CONCLUSION: The primary data indicated that THA exhibit a high toxicity toward two cancer cells than their respective non-cancerous counterparts and has a significant anticancer activity both in vitro and in vivo. Thus, THA and/or its derivatives may have great potential in the prevention and treatment of human ovary tumors and other malignancies. PMID- 21695176 TI - Food for song: expression of c-Fos and ZENK in the zebra finch song nuclei during food aversion learning. AB - BACKGROUND: Specialized neural pathways, the song system, are required for acquiring, producing, and perceiving learned avian vocalizations. Birds that do not learn to produce their vocalizations lack telencephalic song system components. It is not known whether the song system forebrain regions are exclusively evolved for song or whether they also process information not related to song that might reflect their 'evolutionary history'. METHODOLOGY/PRINCIPAL FINDINGS: To address this question we monitored the induction of two immediate early genes (IEGs) c-Fos and ZENK in various regions of the song system in zebra finches (Taeniopygia guttata) in response to an aversive food learning paradigm; this involves the association of a food item with a noxious stimulus that affects the oropharyngeal-esophageal cavity and tongue, causing subsequent avoidance of that food item. The motor response results in beak and head movements but not vocalizations. IEGs have been extensively used to map neuro-molecular correlates of song motor production and auditory processing. As previously reported, neurons in two pallial vocal motor regions, HVC and RA, expressed IEGs after singing. Surprisingly, c-Fos was induced equivalently also after food aversion learning in the absence of singing. The density of c-Fos positive neurons was significantly higher than that of birds in control conditions. This was not the case in two other pallial song nuclei important for vocal plasticity, LMAN and Area X, although singing did induce IEGs in these structures, as reported previously. CONCLUSIONS/SIGNIFICANCE: Our results are consistent with the possibility that some of the song nuclei may participate in non-vocal learning and the populations of neurons involved in the two tasks show partial overlap. These findings underscore the previously advanced notion that the specialized forebrain pre motor nuclei controlling song evolved from circuits involved in behaviors related to feeding. PMID- 21695178 TI - Methicillin-resistant Staphylococcus aureus nasal colonization among adult patients visiting emergency department in a medical center in Taiwan. AB - BACKGROUND: Within the past 10 years, methicillin-resistant Staphylococcus aureus (MRSA) has not only been a hospital pathogen but also a community pathogen. To understand the carriage rate of methicillin-resistant Staphylococcus aureus (MRSA) among the adult patients visiting emergency department (ED), we conducted this study. METHODOLOGY/PRINCIPAL FINDINGS: From May 21 to August 12, 2009, a total of 502 adult patients visiting emergency department (ED) of a tertiary care hospital in northern Taiwan were recruited in this study and surveyed for nasal carriage of MRSA. A questionnaire regarding the risk factors for MRSA acquisition was also obtained. The overall prevalence of MRSA nasal carriage among the patients was 3.8%. The carriage rate was significantly higher in patients with risk factors for MRSA acquisition (5.94%) than those without risk factors (2.12%). Patients with urinary complaints, diabetes mellitus, chronic kidney disease and current percutaneous tube usage were significantly associated with MRSA colonization. By multiple logistic regression analysis, only current usage of catheters or tubes was the independent predictor for MRSA nasal colonization. Of the 19 MRSA, most isolates belonged to one of two linages, characterized as sequence type (ST) 239 (32%) and ST 59 (58%). The latter linage, accounting for 83% of 6 isolates from patients without risk factors, is a community-associated (CA) clone in Taiwan, while the former linage is among healthcare-associated clones. CONCLUSION/SIGNIFICANCE: A substantial proportion of patients visiting ED, particularly with current usage of percutaneous catheter or tubes, in northern Taiwan carried MRSA, mostly community strains, in nares. PMID- 21695179 TI - Sedentary behavior is not associated with cardiometabolic risk in adults with abdominal obesity. AB - OBJECTIVE: The primary aim of this study was to determine whether time spent in sedentary behaviors (SED) was associated with 2-hour glucose and insulin resistance in adults with abdominal obesity. We also examined the association between light physical activity (LPA) and sporadic (accumulated in bouts <10 minutes in duration) moderate-to-vigorous physical activity (MVPA) with glucose metabolism. METHODS: Participants were 135 inactive, abdominally obese adults recruited from Kingston, Canada. SED and physical activity were determined by accelerometry over 7 days and summarized as SED (accelerometer counts/min <100), LPA (counts/min 100-1951), and MVPA (counts/min >=1952). A 75 g oral glucose tolerance test was used to ascertain 2-hour glucose; the homeostasis model of assessment was used to determine insulin resistance (HOMA-IR); lipid, lipoproteins and blood pressure were determined using standard protocols. Secondary analyses considered the association between SED and physical activity with other cardiometabolic risk factors. RESULTS: Participants spent 627.2+/-82.9 min/d in SED, 289.0+/-91.7 min/d in LPA and 19.2+/-13.5 min/d in MVPA. Neither SED nor the physical activity variables were associated with 2-hour glucose or HOMA-IR (p>0.05). In secondary analyses, SED was not associated with any cardiometabolic risk factor (p>0.1); with the exception of blood pressure (p<0.05), LPA was not associated with any cardiometabolic risk factor (p>0.1); and MVPA was independently associated with total cholesterol and triglycerides (p<0.05). CONCLUSIONS: Objectively measured SED was not associated with 2-hr glucose or HOMA-IR. Our findings also suggest that the accumulation of LPA and sporadic MVPA is not associated with glucose metabolism in adults with abdominal obesity. PMID- 21695180 TI - Lack of association of SULT1A1 R213H polymorphism with colorectal cancer: a meta analysis. AB - BACKGROUND: A number of case-control studies were conducted to investigate the association of SULT1A1 R213H polymorphisms with colorectal cancer (CRC) in humans. But the results were not always consistent. We performed a meta-analysis to examine the association between the SULT1A1 R213H polymorphism and CRC. METHODS AND FINDINGS: Data were collected from the following electronic databases: PubMed, Elsevier Science Direct, Excerpta Medica Database, and Chinese Biomedical Literature Database, with the last report up to September 2010. A total of 12 studies including 3,549 cases and 5,610 controls based on the search criteria were involved in this meta-analysis. Overall, no significant association of this polymorphism with CRC was found (H versus R: OR = 1.04, 95%CI = 0.94 1.16, P = 0.46; HR+HH versus RR: OR = 1.01, 95%CI = 0.92-1.11, P = 0.81; HH versus RR+HR: OR = 1.01, 95%CI = 0.74-1.38, P = 0.95; HH versus RR: OR = 1.00, 95%CI = 0.77-1.31, P = 0.98; HR versus RR: OR = 1.01, 95%CI = 0.92-1.11, P = 0.86). In subgroup analysis, we also did not find any significant association in Cauasians (H versus R: OR = 1.02, 95%CI = 0.92-1.15, P = 0.68; HR+HH versus RR: OR = 0.99, 95%CI = 0.91-1.09, P = 0.90; HH versus RR+HR: OR = 1.01, 95%CI = 0.73 1.39, P = 0.97; HH versus RR: OR = 0.99, 95%CI = 0.75-1.31, P = 0.94; HR versus RR: OR = 0.99, 95%CI = 0.90-1.09, P = 0.85). The results were not materially altered after the studies which did not fulfill Hardy-Weinberg equilibrium were excluded (H versus R: OR = 1.06, 95%CI = 0.95-1.19, P = 0.31; HR+HH versus RR: OR = 1.03, 95%CI = 0.93-1.13, P = 0.56; HH versus RR+HR: OR = 1.10, 95%CI = 0.78 1.56, P = 0.57; HH versus RR: OR = 1.09, 95%CI = 0.83-1.44, P = 0.53; HR versus RR: OR = 1.02, 95%CI = 0.92-1.13, P = 0.75). CONCLUSION: This meta-analysis demonstrates that there is no association between the SULT1A1 R213H polymorphism and CRC. PMID- 21695181 TI - Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation. AB - The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance. PMID- 21695182 TI - Mitochondrial ceramide-rich macrodomains functionalize Bax upon irradiation. AB - BACKGROUND: Evidence indicates that Bax functions as a "lipidic" pore to regulate mitochondrial outer membrane permeabilization (MOMP), the apoptosis commitment step, through unknown membrane elements. Here we show mitochondrial ceramide elevation facilitates MOMP-mediated cytochrome c release in HeLa cells by generating a previously-unrecognized mitochondrial ceramide-rich macrodomain (MCRM), which we visualize and isolate, into which Bax integrates. METHODOLOGY/PRINCIPAL FINDINGS: MCRMs, virtually non-existent in resting cells, form upon irradiation coupled to ceramide synthase-mediated ceramide elevation, optimizing Bax insertion/oligomerization and MOMP. MCRMs are detected by confocal microscopy in intact HeLa cells and isolated biophysically as a light membrane fraction from HeLa cell lysates. Inhibiting ceramide generation using a well defined natural ceramide synthase inhibitor, Fumonisin B1, prevented radiation induced Bax insertion, oligomerization and MOMP. MCRM deconstruction using purified mouse hepatic mitochondria revealed ceramide alone is non-apoptogenic. Rather Bax integrates into MCRMs, oligomerizing therein, conferring 1-2 log enhanced cytochrome c release. Consistent with this mechanism, MCRM Bax isolates as high molecular weight "pore-forming" oligomers, while non-MCRM membrane contains exclusively MOMP-incompatible monomeric Bax. CONCLUSIONS/SIGNIFICANCE: Our recent studies in the C. elegans germline indicate that mitochondrial ceramide generation is obligate for radiation-induced apoptosis, although a mechanism for ceramide action was not delineated. Here we demonstrate that ceramide, generated in the mitochondrial outer membrane of mammalian cells upon irradiation, forms a platform into which Bax inserts, oligomerizes and functionalizes as a pore. We posit conceptualization of ceramide as a membrane based stress calibrator, driving membrane macrodomain organization, which in mitochondria regulates intensity of Bax-induced MOMP, and is pharmacologically tractable in vitro and in vivo. PMID- 21695183 TI - Maturation of the language network: from inter- to intrahemispheric connectivities. AB - Language development must go hand-in-hand with brain maturation. Little is known about how the brain develops to serve language processing, in particular, the processing of complex syntax, a capacity unique to humans. Behavioral reports indicate that the ability to process complex syntax is not yet adult-like by the age of seven years. Here, we apply a novel method to demonstrate that the basic neural basis of language, as revealed by low frequency fluctuation stemming from functional MRI data, differs between six-year-old children and adults in crucial aspects. Although the classical language regions are actively in place by the age of six, the functional connectivity between these regions clearly is not. In contrast to adults who show strong connectivities between frontal and temporal language regions within the left hemisphere, children's default language network is characterized by a strong functional interhemispheric connectivity, mainly between the superior temporal regions. These data indicate a functional reorganization of the neural network underlying language development towards a system that allows a close interplay between frontal and temporal regions within the left hemisphere. PMID- 21695185 TI - GPUs, a new tool of acceleration in CFD: efficiency and reliability on smoothed particle hydrodynamics methods. AB - Smoothed Particle Hydrodynamics (SPH) is a numerical method commonly used in Computational Fluid Dynamics (CFD) to simulate complex free-surface flows. Simulations with this mesh-free particle method far exceed the capacity of a single processor. In this paper, as part of a dual-functioning code for either central processing units (CPUs) or Graphics Processor Units (GPUs), a parallelisation using GPUs is presented. The GPU parallelisation technique uses the Compute Unified Device Architecture (CUDA) of nVidia devices. Simulations with more than one million particles on a single GPU card exhibit speedups of up to two orders of magnitude over using a single-core CPU. It is demonstrated that the code achieves different speedups with different CUDA-enabled GPUs. The numerical behaviour of the SPH code is validated with a standard benchmark test case of dam break flow impacting on an obstacle where good agreement with the experimental results is observed. Both the achieved speed-ups and the quantitative agreement with experiments suggest that CUDA-based GPU programming can be used in SPH methods with efficiency and reliability. PMID- 21695184 TI - Inhibition of the nicotinic acetylcholine receptors by cobra venom alpha neurotoxins: is there a perspective in lung cancer treatment? AB - Nicotine exerts its oncogenic effects through the binding to nicotinic acetylcholine receptors (nAChRs) and the activation of downstream pathways that block apoptosis and promote neo-angiogenesis. The nAChRs of the alpha7 subtype are present on a wide variety of cancer cells and their inhibition by cobra venom neurotoxins has been proposed in several articles and reviews as a potential innovative lung cancer therapy. However, since part of the published results was recently retracted, we believe that the antitumoral activity of cobra venom neurotoxins needs to be independently re-evaluated.We determined the activity of alpha-neurotoxins from Naja atra (short-chain neurotoxin, alpha-cobrotoxin) and Naja kaouthia (long-chain neurotoxin, alpha-cobratoxin) in vitro by cytotoxicity measurements in 5 lung cancer cell lines, by colony formation assay with alpha7nAChRs expressing and non-expressing cell lines and in vivo by assessing tumor growth in an orthotopic Non-Obese Diabetic/Severe Combined Immunodeficient (NOD/SCID) mouse model system utilizing different treatment schedules and dosages.No statistically significant reduction in tumor growth was observed in the treatment arms in comparison to the control for both toxins. Paradoxically alpha-cobrotoxin from Naja atra showed the tendency to enhance tumor growth although, even in this case, the statistical significance was not reached.In conclusion our results show that, in contrast with other reports, the nAChR inhibitors alpha-cobratoxin from N. kaouthia and alpha-cobrotoxin from N. atra neither suppressed tumor growth nor prolonged the survival of the treated animals. PMID- 21695186 TI - Incorporation of extranodal metastasis of gastric carcinoma into the 7th edition UICC TNM staging system. AB - BACKGROUND: To assess the clinical significance and prognostic impact of extranodal metastasis (EM) in gastric carcinoma and establish an optimal classification in the staging system. METHODOLOGY/PRINCIPAL FINDINGS: A total of 1343 patients with gastric carcinoma who underwent surgical resection were recruited to determine the frequency and prognostic significance of EMs. EMs were divided into two groups (EM1 and EM2) and then incorporated into the 7(th) edition UICC TNM staging system. EMs was detected in 179 (13.3%) of 1343 patients who underwent radical resection. Multivariate analysis identified EMs as an independent prognostic factor (HR = 1.412, 95%CI = 1.151-1.731, P<0.001). After curative operation, the overall survival rate were worse in patients with >=3 cases of EM (EM2) than those with the number of 1 and 2 cases (EM1) (P<0.001). Survival of patients with EM1 was found almost comparable to that of N3 stage (P = 0.437). Survival of patients with EM2 showed similar to that of stage IV patients (P = 0.896). By using the linear trend X(2), likelihood ratio X(2), and Akaike information criterion (AIC) test, EM1 treated as N3 stage and EM2 treated as M1 stage performed higher linear trend X(2) scores, likelihood ratio X(2) scores, and lower AIC value than the 7(th) edition UICC TNM staging system, which represented the optimum prognostic stratification, together with better homogeneity, discriminatory ability, and monotonicity of gradients. CONCLUSIONS/SIGNIFICANCE: EMs might be classified based on their number and prognostic information and should incorporate into the TNM staging system. PMID- 21695187 TI - A meta-analysis of predation risk effects on pollinator behaviour. AB - Flower-visiting animals are constantly under predation risk when foraging and hence might be expected to evolve behavioural adaptations to avoid predators. We reviewed the available published and unpublished data to assess the overall effects of predators on pollinator behaviour and to examine sources of variation in these effects. The results of our meta-analysis showed that predation risk significantly decreased flower visitation rates (by 36%) and time spent on flowers (by 51%) by pollinators. The strength of the predator effects depended neither on predator taxa and foraging mode (sit-and-wait or active hunters) nor on pollinator lifestyle (social vs. solitary). However, predator effects differed among pollinator taxa: predator presence reduced flower visitation rates and time spent on flowers by Squamata, Lepidoptera and Hymenoptera, but not by Diptera. Furthermore, larger pollinators showed weaker responses to predation risk, probably because they are more difficult to capture. Presence of live crab spiders on flowers had weaker effects on pollinator behaviour than presence of dead or artificial crab spiders or other objects (e.g. dead bees, spheres), suggesting that predator crypsis may be effective to some extent. These results add to a growing consensus on the importance of considering both predator and pollinator characteristics from a community perspective. PMID- 21695188 TI - ALDH activity selectively defines an enhanced tumor-initiating cell population relative to CD133 expression in human pancreatic adenocarcinoma. AB - BACKGROUND: Multiple studies in recent years have identified highly tumorigenic populations of cells that drive tumor formation. These cancer stem cells (CSCs), or tumor-initiating cells (TICs), exhibit properties of normal stem cells and are associated with resistance to current therapies. As pancreatic adenocarcinoma is among the most resistant human cancers to chemo-radiation therapy, we sought to evaluate the presence of cell populations with tumor-initiating capacities in human pancreatic tumors. Understanding which pancreatic cancer cell populations possess tumor-initiating capabilities is critical to characterizing and understanding the biology of pancreatic CSCs towards therapeutic ends. METHODOLOGY/PRINCIPAL FINDINGS: We have isolated populations of cells with high ALDH activity (ALDH(high)) and/or CD133 cell surface expression from human xenograft tumors established from multiple patient tumors with pancreatic adenocarcinoma (direct xenograft tumors) and from the pancreatic cancer cell line L3.6pl. Through fluorescent activated cell sorting (FACs)-mediated enrichment and depletion of selected pancreatic cancer cell populations, we sought to discriminate the relative tumorigenicity of cell populations that express the pancreatic CSC markers CD133 and aldehyde dehydrogenase (ALDH). ALDH(high) and ALDH(low) cell populations were further examined for co-expression of CD44 and/or CD24. We demonstrate that unlike cell populations demonstrating low ALDH activity, as few as 100 cells enriched for high ALDH activity were capable of tumor formation, irrespective of CD133 expression. In direct xenograft tumors, the proportions of total tumor cells expressing ALDH and/or CD133 in xenograft tumors were unchanged through a minimum of two passages. We further demonstrate that ALDH expression among patients with pancreatic adenocarcinoma is heterogeneous, but the expression is constant in serial generations of individual direct xenograft tumors established from bulk human pancreatic tumors in NOD/SCID mice. CONCLUSIONS/SIGNIFICANCE: We conclude that, in contrast to some previous studies, cell populations enriched for high ALDH activity alone are sufficient for efficient tumor-initiation with enhanced tumorigenic potential relative to CD133(+) and ALDH(low) cell populations in some direct xenograft tumors. Although cell populations enriched for CD133 expression may alone possess tumorigenic potential, they are significantly less tumorigenic than ALDH(high) cell populations. ALDH(high)/CD44(+)/CD24(+) or ALDH(low)/CD44(+)/CD24(+) phenotypes do not appear to significantly contribute to tumor formation at low numbers of inoculated tumor cells. ALDH expression broadly varies among patients with pancreatic adenocarcinoma and the apparent expression is recapitulated in serial generations of direct xenograft tumors in NOD/SCID. We have thus identified a distinct population of TICs that should lead to identification of novel targets for pancreatic cancer therapy. PMID- 21695189 TI - Predicting maximum tree heights and other traits from allometric scaling and resource limitations. AB - Terrestrial vegetation plays a central role in regulating the carbon and water cycles, and adjusting planetary albedo. As such, a clear understanding and accurate characterization of vegetation dynamics is critical to understanding and modeling the broader climate system. Maximum tree height is an important feature of forest vegetation because it is directly related to the overall scale of many ecological and environmental quantities and is an important indicator for understanding several properties of plant communities, including total standing biomass and resource use. We present a model that predicts local maximal tree height across the entire continental United States, in good agreement with data. The model combines scaling laws, which encode the average, base-line behavior of many tree characteristics, with energy budgets constrained by local resource limitations, such as precipitation, temperature and solar radiation. In addition to predicting maximum tree height in an environment, our framework can be extended to predict how other tree traits, such as stomatal density, depend on these resource constraints. Furthermore, it offers predictions for the relationship between height and whole canopy albedo, which is important for understanding the Earth's radiative budget, a critical component of the climate system. Because our model focuses on dominant features, which are represented by a small set of mechanisms, it can be easily integrated into more complicated ecological or climate models. PMID- 21695190 TI - CD1d-expressing breast cancer cells modulate NKT cell-mediated antitumor immunity in a murine model of breast cancer metastasis. AB - BACKGROUND: Tumor tolerance and immune suppression remain formidable obstacles to the efficacy of immunotherapies that harness the immune system to eradicate breast cancer. A novel syngeneic mouse model of breast cancer metastasis was developed in our lab to investigate mechanisms of immune regulation of breast cancer. Comparative analysis of low-metastatic vs. highly metastatic tumor cells isolated from these mice revealed several important genetic alterations related to immune control of cancer, including a significant downregulation of cd1d1 in the highly metastatic tumor cells. The cd1d1 gene in mice encodes the MHC class I like molecule CD1d, which presents glycolipid antigens to a specialized subset of T cells known as natural killer T (NKT) cells. We hypothesize that breast cancer cells, through downregulation of CD1d and subsequent evasion of NKT-mediated antitumor immunity, gain increased potential for metastatic tumor progression. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we demonstrate in a mouse model of breast cancer metastasis that tumor downregulation of CD1d inhibits iNKT-mediated antitumor immunity and promotes metastatic breast cancer progression in a CD1d dependent manner in vitro and in vivo. Using NKT-deficient transgenic mouse models, we demonstrate important differences between type I and type II NKT cells in their ability to regulate antitumor immunity of CD1d-expressing breast tumors. CONCLUSIONS/SIGNIFICANCE: The results of this study emphasize the importance of determining the CD1d expression status of the tumor when tailoring NKT-based immunotherapies for the prevention and treatment of metastatic breast cancer. PMID- 21695191 TI - The interplay between protein L-isoaspartyl methyltransferase activity and insulin-like signaling to extend lifespan in Caenorhabditis elegans. AB - The protein L-isoaspartyl-O-methyltransferase functions to initiate the repair of isomerized aspartyl and asparaginyl residues that spontaneously accumulate with age in a variety of organisms. Caenorhabditis elegans nematodes lacking the pcm-1 gene encoding this enzyme display a normal lifespan and phenotype under standard laboratory growth conditions. However, significant defects in development, egg laying, dauer survival, and autophagy have been observed in pcm-1 mutant nematodes when deprived of food and when exposed to oxidative stress. Interestingly, overexpression of this repair enzyme in both Drosophila and C. elegans extends adult lifespan under thermal stress. In this work, we show the involvement of the insulin/insulin-like growth factor-1 signaling (IIS) pathway in PCM-1-dependent lifespan extension in C. elegans. We demonstrate that reducing the levels of the DAF-16 downstream transcriptional effector of the IIS pathway by RNA interference reduces the lifespan extension resulting from PCM-1 overexpression. Using quantitative real-time PCR analysis, we show the up regulation of DAF-16-dependent stress response genes in the PCM-1 overexpressor animals compared to wild-type and pcm-1 mutant nematodes under mild thermal stress conditions. Additionally, similar to other long-lived C. elegans mutants in the IIS pathway, including daf-2 and age-1 mutants, PCM-1 overexpressor adult animals display increased resistance to severe thermal stress, whereas pcm-1 mutant animals survive less long under these conditions. Although we observe a higher accumulation of damaged proteins in pcm-1 mutant nematodes, the basal level of isoaspartyl residues detected in wild-type animals was not reduced by PCM-1 overexpression. Our results support a signaling role for the protein L isoaspartyl methyltransferase in lifespan extension that involves the IIS pathway, but that may be independent of its function in overall protein repair. PMID- 21695192 TI - 1,25(OH)2D3 alters growth plate maturation and bone architecture in young rats with normal renal function. AB - Whereas detrimental effects of vitamin D deficiency are known over century, the effects of vitamin D receptor activation by 1,25(OH)(2)D(3), the principal hormonal form of vitamin D, on the growing bone and its growth plate are less clear. Currently, 1,25(OH)(2)D(3) is used in pediatric patients with chronic kidney disease and mineral and bone disorder (CKD-MBD) and is strongly associated with growth retardation. Here, we investigate the effect of 1,25(OH)(2)D(3) treatment on bone development in normal young rats, unrelated to renal insufficiency. Young rats received daily i.p. injections of 1 ug/kg 1,25(OH)(2)D(3) for one week, or intermittent 3 ug/kg 1,25(OH)(2)D(3) for one month. Histological analysis revealed narrower tibial growth plates, predominantly in the hypertrophic zone of 1,25(OH)(2)D(3)-treated animals in both experimental protocols. This phenotype was supported by narrower distribution of aggrecan, collagens II and X mRNA, shown by in situ hybridization. Concomitant with altered chondrocyte maturation, 1,25(OH)(2)D(3) increased chondrocyte proliferation and apoptosis in terminal hypertrophic cells. In vitro treatment of the chondrocytic cell line ATDC5 with 1,25(OH)(2)D(3) lowered differentiation and increased proliferation dose and time-dependently. Micro-CT analysis of femurs from 1-week 1,25(OH)(2)D(3)-treated group revealed reduced cortical thickness, elevated cortical porosity, and higher trabecular number and thickness. 1-month administration resulted in a similar cortical phenotype but without effect on trabecular bone. Evaluation of fluorochrome binding with confocal microscopy revealed inhibiting effects of 1,25(OH)(2)D(3) on intracortical bone formation. This study shows negative effects of 1,25(OH)(2)D(3) on growth plate and bone which may contribute to the exacerbation of MBD in the CKD pediatric patients. PMID- 21695193 TI - Dengue virus tropism in humanized mice recapitulates human dengue fever. AB - Animal models of dengue virus disease have been very difficult to develop because of the virus' specificity for infection and replication in certain human cells. We developed a model of dengue fever in immunodeficient mice transplanted with human stem cells from umbilical cord blood. These mice show measurable signs of dengue disease as in humans (fever, viremia, erythema and thrombocytopenia), and after infection with the most virulent strain of dengue serotype 2, humanized mice showed infection in human cells in bone marrow, spleen and blood. Cytokines and chemokines were secreted by these human cells into the mouse bloodstream. We demonstrated that the pathology of dengue virus infection in these mice follows that reported in human patients, making this the first valid and relevant model for studying dengue fever pathogenesis in humans. PMID- 21695194 TI - Epidemiology, molecular characterization and antibiotic resistance of Neisseria meningitidis from patients <=15 years in Manhica, rural Mozambique. AB - BACKGROUND: The epidemiology of meningococcal disease in Mozambique and other African countries located outside the "meningitis belt" remains widely unknown. With the event of upcoming vaccines microbiological and epidemiological information is urgently needed. METHODS: Prospective surveillance for invasive bacterial infections was conducted at the Manhica District hospital (rural Mozambique) among hospitalized children below 15 years of age. Available Neisseria meningitidis isolates were serogrouped and characterized by Multilocus Sequence Typing (MLST). Antibiotic resistance was also determined. RESULTS: Between 1998 and 2008, sixty-three cases of confirmed meningococcal disease (36 meningitis, 26 sepsis and 1 conjunctivitis) were identified among hospitalized children. The average incidence rate of meningococcal disease was 11.6/100,000 (8/100,000 for meningitis and 3.7/100,000 for meningococcemia, respectively). There was a significant rise on the number of meningococcal disease cases in 2005 2006 that was sustained till the end of the surveillance period. Serogroup was determined for 43 of the 63 meningococcal disease cases: 38 serogroup W-135, 3 serogroup A and 2 serogroup Y. ST-11 was the most predominant sequence type and strongly associated with serogroup W-135. Two of the three serogroup A isolates were ST-1, and both serogroup Y isolates were ST-175. N. meningitidis remained highly susceptible to all antibiotics used for treatment in the country, although the presence of isolates presenting intermediate resistance to penicillin advocates for continued surveillance. CONCLUSIONS: Our data show a high rate of meningococcal disease in Manhica, Mozambique, mainly caused by serogroup W-135 ST 11 strains, and advocates for the implementation of a vaccination strategy covering serogroup W-135 meningococci in the country. PMID- 21695195 TI - Shortened telomere length is associated with increased risk of cancer: a meta analysis. AB - BACKGROUND: Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. A series of epidemiological studies have examined the association between shortened telomeres and risk of cancers, but the findings remain conflicting. METHODS: A dataset composed of 11,255 cases and 13,101 controls from 21 publications was included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and the relative telomere length. Heterogeneity among studies and their publication bias were further assessed by the chi(2)-based Q statistic test and Egger's test, respectively. RESULTS: The results showed that shorter telomeres were significantly associated with cancer risk (OR = 1.35, 95% CI = 1.14-1.60), compared with longer telomeres. In the stratified analysis by tumor type, the association remained significant in subgroups of bladder cancer (OR = 1.84, 95% CI = 1.38-2.44), lung cancer (OR = 2.39, 95% CI = 1.18-4.88), smoking-related cancers (OR = 2.25, 95% CI = 1.83-2.78), cancers in the digestive system (OR = 1.69, 95% CI = 1.53-1.87) and the urogenital system (OR = 1.73, 95% CI = 1.12 2.67). Furthermore, the results also indicated that the association between the relative telomere length and overall cancer risk was statistically significant in studies of Caucasian subjects, Asian subjects, retrospective designs, hospital based controls and smaller sample sizes. Funnel plot and Egger's test suggested that there was no publication bias in the current meta-analysis (P = 0.532). CONCLUSIONS: The results of this meta-analysis suggest that the presence of shortened telomeres may be a marker for susceptibility to human cancer, but single larger, well-design prospective studies are warranted to confirm these findings. PMID- 21695196 TI - Subtype specific elevated expression of hyaluronidase-1 (HYAL-1) in epithelial ovarian cancer. AB - BACKGROUND: Epithelial ovarian cancer (EOC) is morphologically heterogeneous being classified as serous, endometrioid, clear cell, or mucinous. Molecular genetic analysis has suggested a role for tumor suppressor genes located at chromosome 3p in serous EOC pathogenesis. Our objective was to evaluate the expression of HYAL1, located at chromosome 3p21.3, in these EOC subtypes, and to investigate its correlation with the expression of steroid hormone receptors. METHODOLOGY/PRINCIPAL FINDINGS: We determined the mRNA expression of HYAL1, estrogen receptor (ER)-alpha, ERbeta and progesterone receptor (PR) in EOC tumor samples and cell lines using quantitative RT-PCR. We also examined the expression of these genes in a publicly available microarray dataset. HYAL-1 enzyme activity was measured in EOC cell lines and in plasma samples from patients. We found that HYAL1 mRNA expression was elevated in clear cell and mucinous EOC tissue samples, but not in serous and endometrioid samples, normal ovaries or benign tumors. Similar results were obtained by two different techniques and with tissue sample cohorts from two independent institutions. Concordantly, HYAL1 mRNA levels and enzymatic activity were elevated only in EOC cell lines derived from clear cell and mucinous subtypes. We also showed that HYAL1 mRNA was inversely correlated to that of ERalpha specifically in clear cell and mucinous EOCs. Additionally, ectopic expression of ERalpha in a clear cell EOC cell line (ER- and PR-negative) induced 50% reduction of HYAL1 mRNA expression, supporting a role of ERalpha in HYAL1 gene regulation. Significantly, HYAL-1 activity was also high in the plasma of patients with these EOC subtypes. CONCLUSIONS/SIGNIFICANCE: This is the first report showing high HYAL-1 levels in EOC and demonstrating HYAL1 gene repression by ERalpha. Our results identify Hyaluronidase-1 as a potential target/biomarker for clear cell and mucinous EOCs and especially in tumors with low ERalpha levels. PMID- 21695197 TI - Population carrier rates of pathogenic ARSA gene mutations: is metachromatic leukodystrophy underdiagnosed? AB - BACKGROUND: Metachromatic leukodystrophy (MLD) is a severe neurometabolic disease caused mainly by deficiency of arylsulfatase A encoded by the ARSA gene. Based on epidemiological surveys the incidence of MLD per 100,000 live births varied from 0.6 to 2.5. Our purpose was to estimate the birth prevalence of MLD in Poland by determining population frequency of the common pathogenic ARSA gene mutations and to compare this estimate with epidemiological data. METHODOLOGY: We studied two independently ascertained cohorts from the Polish background population (N~3000 each) and determined carrier rates of common ARSA gene mutations: c.459+1G>A, p.P426L, p.I179S (cohort 1) and c.459+1G>A, p.I179S (cohort 2). PRINCIPAL FINDINGS: Taking into account ARSA gene mutation distribution among 60 Polish patients, the expected MLD birth prevalence in the general population (assuming no selection against homozygous fetuses) was estimated as 4.0/100,000 and 4.1/100,000, respectively for the 1(st) and the 2(nd) cohort with a pooled estimate of 4.1/100,000 (CI: 1.8-9.4) which was higher than the estimate of 0.38 per 100,000 live births based on diagnosed cases. The p.I179S mutation was relatively more prevalent among controls than patients (OR = 3.6, P = 0.0082, for a comparison of p.I179S frequency relative to c.459+1G>A between controls vs. patients). CONCLUSIONS/SIGNIFICANCE: The observed discrepancy between the measured incidence of metachromatic leukodystrophy and the predicted carriage rates suggests that MLD is substantially underdiagnosed in the Polish population. The underdiagnosis rate may be particularly high among patients with p.I179S mutation whose disease is characterized mainly by psychotic symptoms. PMID- 21695198 TI - Chlamydia pneumoniae infection induced allergic airway sensitization is controlled by regulatory T-cells and plasmacytoid dendritic cells. AB - Chlamydia pneumoniae (CP) is associated with induction and exacerbation of asthma. CP infection can induce allergic airway sensitization in mice in a dose- and time-dependent manner. Allergen exposure 5 days after a low dose (mild moderate), but not a high dose (severe) CP infection induces antigen sensitization in mice. Innate immune signals play a critical role in controlling CP infection induced allergic airway sensitization, however these mechanisms have not been fully elucidated. Wild-type, TLR2-/-, and TLR4-/- mice were infected intranasally (i.n.) with a low dose of CP, followed by i.n. exposure to human serum albumin (HSA) and challenged with HSA 2 weeks later. Airway inflammation, immunoglobulins, eosinophils, and goblet cells were measured. Low dose CP infection induced allergic sensitization in TLR2-/- mice, but not in TLR4-/- mice, due to differential Treg responses in these genotypes. TLR2-/- mice had reduced numbers of Tregs in the lung during CP infection while TLR4-/- mice had increased numbers. High dose CP infection resulted in an increase in Tregs and pDCs in lungs, which prevented antigen sensitization in WT mice. Depletion of Tregs or pDCs resulted in allergic airway sensitization. We conclude that Tregs and pDCs are critical determinants regulating CP infection-induced allergic sensitization. Furthermore, TLR2 and TLR4 signaling during CP infection may play a regulatory role through the modulation of Tregs. PMID- 21695199 TI - Illegal substance use among Italian high school students: trends over 11 years (1999-2009). AB - PURPOSE: To monitor changes in habits in drug use among Italian high school students. METHODS: Cross-sectional European School Survey Project on Alcohol and Other Drugs (ESPAD) carried out in Italy annually for 11 years (1999-2009) with representative samples of youth attending high school. The sample size considered ranges from 15,752 to 41,365 students and response rate ranged from 85.5% to 98.6%. Data were analyzed to obtain measures of life-time prevalence (LT), use in the last year (LY), use in the last 30 days (LM), frequent use. Comparisons utilized difference in proportion tests. Tests for linear trends in proportion were performed using the Royston p trend test. RESULTS: When the time-averaged value was considered, cannabis (30% LT) was the most, and heroin the least (2%) frequently used, with cocaine (5%), hallucinogens (2%) and stimulants (2%) in between. A clear gender gap is evident for all drugs, more obvious for hallucinogens (average M/F LY prevalence ratio 2, range 1.7-2.4, p<0.05), less for cannabis (average M/F LY prevalence ratio 1.3, range 1.2-1.5, p<0.05). Data shows a change in trend between 2005 and 2008; in 2006 the trend for cannabis use and availability dropped and the price rose, while from 2005 cocaine and stimulant use prevalence showed a substantial increase and the price went down. After 2008 use of all substances seems to have decreased. CONCLUSIONS: Drug use is widespread among students in Italy, with cannabis being the most and heroin the least prevalent. Girls are less vulnerable than boys to illegal drug use. In recent years, a decrease in heroin use is overbalanced by a marked rise in hallucinogen and stimulant use. PMID- 21695200 TI - A novel peptide ELISA for universal detection of antibodies to human H5N1 influenza viruses. AB - BACKGROUND: Active serologic surveillance of H5N1 highly pathogenic avian influenza (HPAI) virus in humans and poultry is critical to control this disease. However, the need for a robust, sensitive and specific serologic test for the rapid detection of antibodies to H5N1 viruses has not been met. METHODOLOGY/PRINCIPAL FINDINGS: Previously, we reported a universal epitope (CNTKCQTP) in H5 hemagglutinin (HA) that is 100% conserved in H5N1 human isolates and 96.9% in avian isolates. Here, we describe a peptide ELISA to detect antibodies to H5N1 virus by using synthetic peptide that comprises the amino acid sequence of this highly conserved and antigenic epitope as the capture antigen. The sensitivity and specificity of the peptide ELISA were evaluated using experimental chicken antisera to H5N1 viruses from divergent clades and other subtype influenza viruses, as well as human serum samples from patients infected with H5N1 or seasonal influenza viruses. The peptide ELISA results were compared with hemagglutinin inhibition (HI), and immunofluorescence assay and immunodot blot that utilize recombinant HA1 as the capture antigen. The peptide ELISA detected antibodies to H5N1 in immunized animals or convalescent human sera whereas some degree of cross-reactivity was observed in HI, immunofluorescence assay and immunodot blot. Antibodies to other influenza subtypes tested negative in the peptide-ELISA. CONCLUSION/SIGNIFICANCE: The peptide-ELISA based on the highly conserved and antigenic H5 epitope (CNTKCQTP) provides sensitive and highly specific detection of antibodies to H5N1 influenza viruses. This study highlighted the use of synthetic peptide as a capture antigen in rapid detection of antibodies to H5N1 in human and animal sera that is robust, simple and cost effective and is particularly beneficial for developing countries and rural areas. PMID- 21695201 TI - Molecular strategy for survival at a critical high temperature in Eschierichia coli. AB - The molecular mechanism supporting survival at a critical high temperature (CHT) in Escherichia coli was investigated. Genome-wide screening with a single-gene knockout library provided a list of genes indispensable for growth at 47 degrees C, called thermotolerant genes. Genes for which expression was affected by exposure to CHT were identified by DNA chip analysis. Unexpectedly, the former contents did not overlap with the latter except for dnaJ and dnaK, indicating that a specific set of non-heat shock genes is required for the organism to survive under such a severe condition. More than half of the mutants of the thermotolerant genes were found to be sensitive to H(2)O(2) at 30 degrees C, suggesting that the mechanism of thermotolerance partially overlaps with that of oxidative stress resistance. Their encoded enzymes or proteins are related to outer membrane organization, DNA double-strand break repair, tRNA modification, protein quality control, translation control or cell division. DNA chip analyses of essential genes suggest that many of the genes encoding ribosomal proteins are down-regulated at CHT. Bioinformatics analysis and comparison with the genomic information of other microbes suggest that E. coli possesses several systems for survival at CHT. This analysis allows us to speculate that a lipopolysaccharide biosynthesis system for outer membrane organization and a sulfur-relay system for tRNA modification have been acquired by horizontal gene transfer. PMID- 21695202 TI - Rising cyclin-CDK levels order cell cycle events. AB - BACKGROUND: Diverse mitotic events can be triggered in the correct order and time by a single cyclin-CDK. A single regulator could confer order and timing on multiple events if later events require higher cyclin-CDK than earlier events, so that gradually rising cyclin-CDK levels can sequentially trigger responsive events: the "quantitative model" of ordering. METHODOLOGY/PRINCIPAL FINDINGS: This 'quantitative model' makes predictions for the effect of locking cyclin at fixed levels for a protracted period: at low cyclin levels, early events should occur rapidly, while late events should be slow, defective, or highly variable (depending on threshold mechanism). We titrated the budding yeast mitotic cyclin Clb2 within its endogenous expression range to a stable, fixed level and measured time to occurrence of three mitotic events: growth depolarization, spindle formation, and spindle elongation, as a function of fixed Clb2 level. These events require increasingly more Clb2 according to their normal order of occurrence. Events occur efficiently and with low variability at fixed Clb2 levels similar to those observed when the events normally occur. A second prediction of the model is that increasing the rate of cyclin accumulation should globally advance timing of all events. Moderate (<2-fold) overexpression of Clb2 accelerates all events of mitosis, resulting in consistently rapid sequential cell cycles. However, this moderate overexpression also causes a significant frequency of premature mitoses leading to inviability, suggesting that Clb2 expression level is optimized to balance the fitness costs of variability and catastrophe. CONCLUSIONS/SIGNIFICANCE: We conclude that mitotic events are regulated by discrete cyclin-CDK thresholds. These thresholds are sequentially triggered as cyclin increases, yielding reliable order and timing. In many biological processes a graded input must be translated into discrete outputs. In such systems, expression of the central regulator is likely to be tuned to an optimum level, as we observe here for Clb2. PMID- 21695203 TI - Viral shedding in patients infected with pandemic influenza A (H1N1) virus in Kenya, 2009. AB - BACKGROUND: Understanding shedding patterns of 2009 pandemic influenza A (H1N1) (pH1N1) can inform recommendations about infection control measures. We evaluated the duration of pH1N1 virus shedding in patients in Nairobi, Kenya. METHODS: Nasopharyngeal (NP) and oropharyngeal (OP) specimens were collected from consenting laboratory-confirmed pH1N1 cases every 2 days during October 14 November 25, 2009, and tested at the Centers for Diseases Control and Prevention Kenya by real time reverse transcriptase polymerase chain reaction (rRT-PCR). A subset of rRT-PCR-positive samples was cultured. RESULTS: Of 285 NP/OP specimens from patients with acute respiratory illness, 140 (49%) tested positive for pH1N1 by rRT-PCR; 106 (76%) patients consented and were enrolled. The median age was 6 years (Range: 4 months-41 years); only two patients, both asthmatic, received oseltamivir. The median duration of pH1N1 detection after illness onset was 8 days (95% CI: 7-10 days) for rRT-PCR and 3 days (Range: 0-13 days) for viral isolation. Viable pH1N1 virus was isolated from 132/162 (81%) of rRT-PCR-positive specimens, which included 118/125 (94%) rRT-PCR-positive specimens collected on day 0-7 after symptoms onset. Viral RNA was detectable in 18 (17%) and virus isolated in 7/18 (39%) of specimens collected from patients after all their symptoms had resolved. CONCLUSIONS: In this cohort, pH1N1 was detected by rRT-PCR for a median of 8 days. There was a strong correlation between rRT-PCR results and virus isolation in the first week of illness. In some patients, pH1N1 virus was detectable after all their symptoms had resolved. PMID- 21695205 TI - 8-Chloro-cyclic AMP and protein kinase A I-selective cyclic AMP analogs inhibit cancer cell growth through different mechanisms. AB - Cyclic AMP (cAMP) inhibits the proliferation of several tumor cells. We previously reported an antiproliferative effect of PKA I-selective cAMP analogs (8-PIP-cAMP and 8-HA-cAMP) on two human cancer cell lines of different origin. 8 Cl-cAMP, another cAMP analog with known antiproliferative properties, has been investigated as a potential anticancer drug. Here, we compared the antiproliferative effect of 8-Cl-cAMP and the PKA I-selective cAMP analogs in three human cancer cell lines (ARO, NPA and WRO). 8-Cl-cAMP and the PKA I selective cAMP analogs had similarly potent antiproliferative effects on the BRAF positive ARO and NPA cells, but not on the BRAF-negative WRO cells, in which only 8-Cl-cAMP consistently inhibited cell growth. While treatment with the PKA I selective cAMP analogs was associated with growth arrest, 8-Cl-cAMP induced apoptosis. To further investigate the actions of 8-Cl-cAMP and the PKA I selective cAMP analogs, we analyzed their effects on signaling pathways involved in cell proliferation and apoptosis. Interestingly, the PKA I-selective cAMP analogs, but not 8-Cl-cAMP, inhibited ERK phosphorylation, whereas 8-Cl-cAMP alone induced a progressive phosphorylation of the p38 mitogen-activated protein kinase (MAPK), via activation of AMPK by its metabolite 8-Cl-adenosine. Importantly, the pro-apoptotic effect of 8-Cl-cAMP could be largely prevented by pharmacological inhibition of the p38 MAPK. Altogether, these data suggest that 8 Cl-cAMP and the PKA I-selective cAMP analogs, though of comparable antiproliferative potency, act through different mechanisms. PKA I-selective cAMP analogs induce growth arrest in cells carrying the BRAF oncogene, whereas 8-Cl cAMP induce apoptosis, apparently through activation of the p38 MAPK pathway. PMID- 21695204 TI - Targeting of voltage-gated calcium channel alpha2delta-1 subunit to lipid rafts is independent from a GPI-anchoring motif. AB - Voltage-gated calcium channels (Ca(v)) exist as heteromultimers comprising a pore forming alpha(1) with accessory beta and alpha(2)delta subunits which modify channel trafficking and function. We previously showed that alpha(2)delta-1 (and likely the other mammalian alpha(2)delta isoforms--alpha(2)delta-2, 3 and 4) is required for targeting Ca(v)s to lipid rafts, although the mechanism remains unclear. Whilst originally understood to have a classical type I transmembrane (TM) topology, recent evidence suggests the alpha(2)delta subunit contains a glycosylphosphatidylinositol (GPI)-anchor that mediates its association with lipid rafts. To test this notion, we have used a strategy based on the expression of chimera, where the reported GPI-anchoring sequences in the gabapentinoid sensitive alpha(2)delta-1 subunit have been substituted with those of a functionally inert Type I TM-spanning protein--PIN-G. Using imaging, electrophysiology and biochemistry, we find that lipid raft association of PIN alpha(2)delta is unaffected by substitution of the GPI motif with the TM domain of PIN-G. Moreover, the presence of the GPI motif alone is not sufficient for raft localisation, suggesting that upstream residues are required. GPI-anchoring is susceptible to phosphatidylinositol-phospholipase C (PI-PLC) cleavage. However, whilst raft localisation of PIN-alpha(2)delta is disrupted by PI-PLC treatment, this is assay-dependent and non-specific effects of PI-PLC are observed on the distribution of the endogenous raft marker, caveolin, but not flotillin. Taken together, these data are most consistent with a model where alpha(2)delta-1 retains its type I transmembrane topology and its targeting to lipid rafts is governed by sequences upstream of the putative GPI anchor, that promote protein-protein, rather than lipid-lipid interactions. PMID- 21695206 TI - Brain-computer interface based on generation of visual images. AB - This paper examines the task of recognizing EEG patterns that correspond to performing three mental tasks: relaxation and imagining of two types of pictures: faces and houses. The experiments were performed using two EEG headsets: BrainProducts ActiCap and Emotiv EPOC. The Emotiv headset becomes widely used in consumer BCI application allowing for conducting large-scale EEG experiments in the future. Since classification accuracy significantly exceeded the level of random classification during the first three days of the experiment with EPOC headset, a control experiment was performed on the fourth day using ActiCap. The control experiment has shown that utilization of high-quality research equipment can enhance classification accuracy (up to 68% in some subjects) and that the accuracy is independent of the presence of EEG artifacts related to blinking and eye movement. This study also shows that computationally-inexpensive bayesian classifier based on covariance matrix analysis yields similar classification accuracy in this problem as a more sophisticated Multi-class Common Spatial Patterns (MCSP) classifier. PMID- 21695207 TI - Characterization of two malaria parasite organelle translation elongation factor G proteins: the likely targets of the anti-malarial fusidic acid. AB - Malaria parasites harbour two organelles with bacteria-like metabolic processes that are the targets of many anti-bacterial drugs. One such drug is fusidic acid, which inhibits the translation component elongation factor G. The response of P. falciparum to fusidic acid was characterised using extended SYBR-Green based drug trials. This revealed that fusidic acid kills in vitro cultured P. falciparum parasites by immediately blocking parasite development. Two bacterial-type protein translation elongation factor G genes are identified as likely targets of fusidic acid. Sequence analysis suggests that these proteins function in the mitochondria and apicoplast and both should be sensitive to fusidic acid. Microscopic examination of protein-reporter fusions confirm the prediction that one elongation factor G is a component of parasite mitochondria whereas the second is a component of the relict plastid or apicoplast. The presence of two putative targets for a single inhibitory compound emphasizes the potential of elongation factor G as a drug target in malaria. PMID- 21695208 TI - Protective effects of positive lysosomal modulation in Alzheimer's disease transgenic mouse models. AB - Alzheimer's disease (AD) is an age-related neurodegenerative pathology in which defects in proteolytic clearance of amyloid beta peptide (Abeta) likely contribute to the progressive nature of the disorder. Lysosomal proteases of the cathepsin family exhibit up-regulation in response to accumulating proteins including Abeta(1-42). Here, the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK) was used to test whether proteolytic activity can be enhanced to reduce the accumulation events in AD mouse models expressing different levels of Abeta pathology. Systemic PADK injections in APP(SwInd) and APPswe/PS1DeltaE9 mice caused 3- to 8-fold increases in cathepsin B protein levels and 3- to 10-fold increases in the enzyme's activity in lysosomal fractions, while neprilysin and insulin-degrading enzyme remained unchanged. Biochemical analyses indicated the modulation predominantly targeted the active mature forms of cathepsin B and markedly changed Rab proteins but not LAMP1, suggesting the involvement of enhanced trafficking. The modulated lysosomal system led to reductions in both Abeta immunostaining as well as Abeta(x-42) sandwich ELISA measures in APP(SwInd) mice of 10-11 months. More extensive Abeta deposition in 20-22-month APPswe/PS1DeltaE9 mice was also reduced by PADK. Selective ELISAs found that a corresponding production of the less pathogenic Abeta(1-38) occurs as Abeta(1-42) levels decrease in the mouse models, indicating that PADK treatment leads to Abeta truncation. Associated with Abeta clearance was the elimination of behavioral and synaptic protein deficits evident in the two transgenic models. These findings indicate that pharmacologically-controlled lysosomal modulation reduces Abeta(1-42) accumulation, possibly through intracellular truncation that also influences extracellular deposition, and in turn offsets the defects in synaptic composition and cognitive functions. The selective modulation promotes clearance at different levels of Abeta pathology and provides proof-of-principle for small molecule therapeutic development for AD and possibly other protein accumulation disorders. PMID- 21695209 TI - The impact of economic crises on communicable disease transmission and control: a systematic review of the evidence. AB - There is concern among public health professionals that the current economic downturn, initiated by the financial crisis that started in 2007, could precipitate the transmission of infectious diseases while also limiting capacity for control. Although studies have reviewed the potential effects of economic downturns on overall health, to our knowledge such an analysis has yet to be done focusing on infectious diseases. We performed a systematic literature review of studies examining changes in infectious disease burden subsequent to periods of crisis. The review identified 230 studies of which 37 met our inclusion criteria. Of these, 30 found evidence of worse infectious disease outcomes during recession, often resulting from higher rates of infectious contact under poorer living circumstances, worsened access to therapy, or poorer retention in treatment. The remaining studies found either reductions in infectious disease or no significant effect. Using the paradigm of the "SIR" (susceptible-infected recovered) model of infectious disease transmission, we examined the implications of these findings for infectious disease transmission and control. Key susceptible groups include infants and the elderly. We identified certain high risk groups, including migrants, homeless persons, and prison populations, as particularly vulnerable conduits of epidemics during situations of economic duress. We also observed that the long-term impacts of crises on infectious disease are not inevitable: considerable evidence suggests that the magnitude of effect depends critically on budgetary responses by governments. Like other emergencies and natural disasters, preparedness for financial crises should include consideration of consequences for communicable disease control. PMID- 21695210 TI - Effect of seven-valent pneumococcal conjugate vaccine on Staphylococcus aureus colonisation in a randomised controlled trial. AB - BACKGROUND: Heptavalent pneumococcal conjugate vaccine (PCV7) shifts nasopharyngeal colonisation with vaccine serotype pneumococci towards nonvaccine serotypes. Because of the reported negative association of vaccine serotype pneumococci and Staphylococcus aureus in the nasopharynx, we explored the effect of PCV7 on nasopharyngeal colonisation with S. aureus in children and parents. METHODOLOGY/PRINCIPAL FINDINGS: This study was part of a randomised controlled trial on the effect of PCV7 on pneumococcal carriage, enrolling healthy newborns who were randomly assigned (1:1:1) to receive PCV7 (1) at 2 and 4 months of age (2) at 2, 4 and 11 months or (3) no PCV7 (controls). Nasopharyngeal colonisation of S. aureus was a planned secondary outcome. Nasopharyngeal swabs were obtained from all children over a 2-year period with 6-months interval and from one parent at the child's age of 12 and 24 months and cultured for Streptococcus pneumoniae and S. aureus. Between July 2005 and February 2006, 1005 children were enrolled and received either 2-doses of PCV7 (n = 336), 2+1-doses (336) or no dose (n = 333) before PCV7 implementation in the Dutch national immunization program. S. aureus colonisation had doubled in children in the 2+1-dose group at 12 months of age compared with unvaccinated controls (10.1% versus 5.0%; p = 0.019). A negative association for co-colonisation of S. pneumoniae and S. aureus was observed for both vaccine serotype (adjusted odds ratio (aOR) 0.53, 95% confidence interval (CI) 0.38-0.74) and nonvaccine serotype pneumococci (aOR 0.67, 95% CI 0.52-0.88). CONCLUSIONS/SIGNIFICANCE: PCV7 induces a temporary increase in S. aureus colonisation in children around 12 months of age after a 2+1-dose PCV7 schedule. The potential clinical consequences are unknown and monitoring is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT00189020. PMID- 21695211 TI - Prognostic association of YB-1 expression in breast cancers: a matter of antibody. AB - The literature concerning the subcellular location of Y-box binding protein 1 (YB 1), its abundance in normal and cancer tissues, and its prognostic significance is replete with inconsistencies. An explanation for this could be due in part to the use of different antibodies in immunohistochemical and immunofluorescent labeling of cells and tissues. The inconsistencies could also be due to poor resolution of immunohistochemical data. We analyzed two cohorts of breast tumours for both abundance and subcellular location of YB-1 using three different antibodies; two targeting N-terminal epitopes (AB-a and AB-b) and another (AB-c) targeting a C-terminal epitope. We also investigated stress-induced nuclear translocation of YB-1 in cell culture. We report that both AB-a and AB-c detected increased YB-1 in the cytoplasm of high-grade breast cancers, and in those lacking estrogen and progesterone receptors; however the amount of YB-1 detected by AB-a in these cancers is significantly greater than that detected by AB-c. We confirm our previously published findings that AB-b is also detecting hnRNP A1, and cannot therefore be used to reliably detect YB-1 by immunohistochemistry. We also report that AB-a detected nuclear YB-1 in some tumour tissues and stress treated cells, whereas AB-c did not. To understand this, cancer cell lines were analyzed using native gel electrophoresis, which revealed that the antibodies detect different complexes in which YB-1 is a component. Our data suggest that different YB-1 antibodies show different staining patterns that are determined by the accessibility of epitopes, and this depends on the nature of the YB-1 complexes. It is important therefore to standardize the protocols if YB-1 is to be used reproducibly as a prognostic guide for different cancers. PMID- 21695212 TI - The effect of viewing eccentricity on enumeration. AB - Visual acuity and contrast sensitivity progressively diminish with increasing viewing eccentricity. Here we evaluated how visual enumeration is affected by visual eccentricity, and whether subitizing capacity, the accurate enumeration of a small number (~3) of items, decreases with more eccentric viewing. Participants enumerated gratings whose (1) stimulus size was constant across eccentricity, and (2) whose stimulus size scaled by a cortical magnification factor across eccentricity. While we found that enumeration accuracy and precision decreased with increasing eccentricity, cortical magnification scaling of size neutralized the deleterious effects of increasing eccentricity. We found that size scaling did not affect subitizing capacities, which were nearly constant across all eccentricities. We also found that size scaling modulated the variation coefficients, a normalized metric of enumeration precision, defined as the standard deviation divided by the mean response. Our results show that the inaccuracy and imprecision associated with increasing viewing eccentricity is due to limitations in spatial resolution. Moreover, our results also support the notion that the precise number system is restricted to small numerosities (represented by the subitizing limit), while the approximate number system extends across both small and large numerosities (indexed by variation coefficients) at large eccentricities. PMID- 21695213 TI - Survival of civilian and prisoner drug-sensitive, multi- and extensive drug- resistant tuberculosis cohorts prospectively followed in Russia. AB - OBJECTIVE AND METHODS: A long-term observational study was conducted in Samara, Russia to assess the survival and risk factors for death of a cohort of non multidrug resistant tuberculosis (non-MDRTB) and multidrug resistant tuberculosis (MDRTB) civilian and prison patients and a civilian extensive drug-resistant tuberculosis (XDRTB) cohort. RESULTS: MDRTB and XDRTB rates of 54.8% and 11.1% were identified in the region. Half (50%) of MDRTB patients and the majority of non-MDRTB patients (71%) were still alive at 5 years. Over half (58%) of the patients died within two years of establishing a diagnosis of XDRTB. In the multivariate analysis, retreatment (HR = 1.61, 95%CI 1.04, 2.49) and MDRTB (HR = 1.67, 95%CI 1.17, 2.39) were significantly associated with death within the non MDR/MDRTB cohort. The effect of age on survival was relatively small (HR = 1.01, 95%CI 1.00, 1.02). No specific factor affected survival of XDRTB patients although median survival time for HIV-infected versus HIV-negative patients from this group was shorter (185 versus 496 days). The majority of MDRTB and XDRTB strains (84% and 92% respectively) strains belonged to the Beijing family. Mutations in the rpoB (codon 531 in 81/92; 88.8%), katG (mutation S315T in 91/92, 98.9%) and inhA genes accounted for most rifampin and isoniazid resistance respectively, mutations in the QRDR region of gyrA for most fluroquinolone resistance (68/92; 73.5%). CONCLUSIONS: Alarmingly high rates of XDRTB exist. Previous TB treatment cycles and MDR were significant risk factors for mortality. XDRTB patients' survival is short especially for HIV-infected patients. Beijing family strains comprise the majority of drug-resistant strains. PMID- 21695214 TI - Adherence to combination prophylaxis for prevention of mother-to-child transmission of HIV in Tanzania. AB - BACKGROUND: Since 2008, Tanzanian guidelines for prevention of mother-to-child transmission of HIV (PMTCT) recommend combination regimen for mother and infant starting in gestational week 28. Combination prophylaxis is assumed to be more effective and less prone to resistance formation compared to single-drug interventions, but the required continuous collection and intake of drugs might pose a challenge on adherence especially in peripheral resource-limited settings. This study aimed at analyzing adherence to combination prophylaxis under field conditions in a rural health facility in Kyela, Tanzania. METHODS AND FINDINGS: A cohort of 122 pregnant women willing to start combination prophylaxis in Kyela District Hospital was enrolled in an observational study. Risk factors for decline of prophylaxis were determined, and adherence levels before, during and after delivery were calculated. In multivariate analysis, identified risk factors for declining pre-delivery prophylaxis included maternal age below 24 years, no income-generating activity, and enrolment before 24.5 gestational weeks, with odds ratios of 5.8 (P = 0.002), 4.4 (P = 0.015) and 7.8 (P = 0.001), respectively. Women who stated to have disclosed their HIV status were significantly more adherent in the pre-delivery period than women who did not (P = 0.004). In the intra- and postpartum period, rather low drug adherence rates during hospitalization indicated unsatisfactory staff performance. Only ten mother-child pairs were at least 80% adherent during all intervention phases; one single mother-child pair met a 95% adherence threshold. CONCLUSIONS: Achieving adherence to combination prophylaxis has shown to be challenging in this rural study setting. Our findings underline the need for additional supervision for PMTCT staff as well as for clients, especially by encouraging them to seek social support through status disclosure. Prophylaxis uptake might be improved by preponing drug intake to an earlier gestational age. Limited structural conditions of a healthcare setting should be taken into serious account when implementing PMTCT combination prophylaxis. PMID- 21695215 TI - Variant G57E of mannose binding lectin associated with protection against tuberculosis caused by Mycobacterium africanum but not by M. tuberculosis. AB - Structural variants of the Mannose Binding Lectin (MBL) cause quantitative and qualitative functional deficiencies, which are associated with various patterns of susceptibility to infectious diseases and other disorders. We determined genetic MBL variants in 2010 Ghanaian patients with pulmonary tuberculosis (TB) and 2346 controls and characterized the mycobacterial isolates of the patients. Assuming a recessive mode of inheritance, we found a protective association between TB and the MBL2 G57E variant (odds ratio 0.60, confidence interval 0.4 0.9, P 0.008) and the corresponding LYQC haplotype (P(corrected) 0.007) which applied, however, only to TB caused by M. africanum but not to TB caused by M. tuberculosis. In vitro, M. africanum isolates bound recombinant human MBL more efficiently than did isolates of M. tuberculosis. We conclude that MBL binding may facilitate the uptake of M. africanum by macrophages, thereby promoting infection and that selection by TB may have favoured the spread of functional MBL deficiencies in regions endemic for M. africanum. PMID- 21695216 TI - Iwr1 protein is important for preinitiation complex formation by all three nuclear RNA polymerases in Saccharomyces cerevisiae. AB - BACKGROUND: Iwr1, a protein conserved throughout eukaryotes, was originally identified by its physical interaction with RNA polymerase (Pol) II. PRINCIPAL FINDINGS: Here, we identify Iwr1 in a genetic screen designed to uncover proteins involved in Pol III transcription in S. cerevisiae. Iwr1 is important for Pol III transcription, because an iwr1 mutant strain shows reduced association of TBP and Pol III at Pol III promoters, a decreased rate of Pol III transcription, and lower steady-state levels of Pol III transcripts. Interestingly, an iwr1 mutant strain also displays reduced association of TBP to Pol I-transcribed genes and of both TBP and Pol II to Pol II-transcribed promoters. Despite this, rRNA and mRNA levels are virtually unaffected, suggesting a post-transcriptional mechanism compensating for the occupancy defect. CONCLUSIONS: Thus, Iwr1 plays an important role in preinitiation complex formation by all three nuclear RNA polymerases. PMID- 21695217 TI - Importance of post-translational modifications for functionality of a chloroplast localized carbonic anhydrase (CAH1) in Arabidopsis thaliana. AB - BACKGROUND: The Arabidopsis CAH1 alpha-type carbonic anhydrase is one of the few plant proteins known to be targeted to the chloroplast through the secretory pathway. CAH1 is post-translationally modified at several residues by the attachment of N-glycans, resulting in a mature protein harbouring complex-type glycans. The reason of why trafficking through this non-canonical pathway is beneficial for certain chloroplast resident proteins is not yet known. Therefore, to elucidate the significance of glycosylation in trafficking and the effect of glycosylation on the stability and function of the protein, epitope-labelled wild type and mutated versions of CAH1 were expressed in plant cells. METHODOLOGY/PRINCIPAL FINDINGS: Transient expression of mutant CAH1 with disrupted glycosylation sites showed that the protein harbours four, or in certain cases five, N-glycans. While the wild type protein trafficked through the secretory pathway to the chloroplast, the non-glycosylated protein formed aggregates and associated with the ER chaperone BiP, indicating that glycosylation of CAH1 facilitates folding and ER-export. Using cysteine mutants we also assessed the role of disulphide bridge formation in the folding and stability of CAH1. We found that a disulphide bridge between cysteines at positions 27 and 191 in the mature protein was required for correct folding of the protein. Using a mass spectrometric approach we were able to measure the enzymatic activity of CAH1 protein. Under circumstances where protein N glycosylation is blocked in vivo, the activity of CAH1 is completely inhibited. CONCLUSIONS/SIGNIFICANCE: We show for the first time the importance of post translational modifications such as N-glycosylation and intramolecular disulphide bridge formation in folding and trafficking of a protein from the secretory pathway to the chloroplast in higher plants. Requirements for these post translational modifications for a fully functional native protein explain the need for an alternative route to the chloroplast. PMID- 21695218 TI - Defining global gene expression changes of the hypothalamic-pituitary-gonadal axis in female sGnRH-antisense transgenic common carp (Cyprinus carpio). AB - BACKGROUND: The hypothalamic-pituitary-gonadal (HPG) axis is critical in the development and regulation of reproduction in fish. The inhibition of neuropeptide gonadotropin-releasing hormone (GnRH) expression may diminish or severely hamper gonadal development due to it being the key regulator of the axis, and then provide a model for the comprehensive study of the expression patterns of genes with respect to the fish reproductive system. METHODOLOGY/PRINCIPAL FINDINGS: In a previous study we injected 342 fertilized eggs from the common carp (Cyprinus carpio) with a gene construct that expressed antisense sGnRH. Four years later, we found a total of 38 transgenic fish with abnormal or missing gonads. From this group we selected the 12 sterile females with abnormal ovaries in which we combined suppression subtractive hybridization (SSH) and cDNA microarray analysis to define changes in gene expression of the HPG axis in the present study. As a result, nine, 28, and 212 genes were separately identified as being differentially expressed in hypothalamus, pituitary, and ovary, of which 87 genes were novel. The number of down- and up regulated genes was five and four (hypothalamus), 16 and 12 (pituitary), 119 and 93 (ovary), respectively. Functional analyses showed that these genes involved in several biological processes, such as biosynthesis, organogenesis, metabolism pathways, immune systems, transport links, and apoptosis. Within these categories, significant genes for neuropeptides, gonadotropins, metabolic, oogenesis and inflammatory factors were identified. CONCLUSIONS/SIGNIFICANCE: This study indicated the progressive scaling-up effect of hypothalamic sGnRH antisense on the pituitary and ovary receptors of female carp and provided comprehensive data with respect to global changes in gene expression throughout the HPG signaling pathway, contributing towards improving our understanding of the molecular mechanisms and regulative pathways in the reproductive system of teleost fish. PMID- 21695219 TI - Cloning, characterization and analysis of cat and ben genes from the phenol degrading halophilic bacterium Halomonas organivorans. AB - BACKGROUND: Extensive use of phenolic compounds in industry has resulted in the generation of saline wastewaters that produce significant environmental contamination; however, little information is available on the degradation of phenolic compounds in saline conditions. Halomonas organivorans G-16.1 (CECT 5995(T)) is a moderately halophilic bacterium that we isolated in a previous work from saline environments of South Spain by enrichment for growth in different pollutants, including phenolic compounds. PCR amplification with degenerate primers revealed the presence of genes encoding ring-cleaving enzymes of the beta ketoadipate pathway for aromatic catabolism in H. organivorans. FINDINGS: The gene cluster catRBCA, involved in catechol degradation, was isolated from H. organivorans. The genes catA, catB, catC and the divergently transcribed catR code for catechol 1,2-dioxygenase (1,2-CTD), cis,cis-muconate cycloisomerase, muconolactone delta-isomerase and a LysR-type transcriptional regulator, respectively. The benzoate catabolic genes (benA and benB) are located flanking the cat genes. The expression of cat and ben genes by phenol and benzoic acid was shown by RT-PCR analysis. The induction of catA gene by phenol and benzoic acid was also probed by the measurement of 1,2-CTD activity in H. organivorans growth in presence of these inducers. 16S rRNA and catA gene-based phylogenies were established among different degrading bacteria showing no phylogenetic correlation between both genes. CONCLUSIONS/SIGNIFICANCE: In this work, we isolated and determined the sequence of a gene cluster from a moderately halophilic bacterium encoding ortho-pathway genes involved in the catabolic metabolism of phenol and analyzed the gene organization, constituting the first report characterizing catabolic genes involved in the degradation of phenol in moderate halophiles, providing an ideal model system to investigate the potential use of this group of extremophiles in the decontamination of saline environments. PMID- 21695220 TI - Long-term exposure to ambient air pollution and mortality due to cardiovascular disease and cerebrovascular disease in Shenyang, China. AB - BACKGROUND: The relationship between ambient air pollution exposure and mortality of cardiovascular and cerebrovascular diseases in human is controversial, and there is little information about how exposures to ambient air pollution contribution to the mortality of cardiovascular and cerebrovascular diseases among Chinese. The aim of the present study was to examine whether exposure to ambient-air pollution increases the risk for cardiovascular and cerebrovascular disease. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a retrospective cohort study among humans to examine the association between compound-air pollutants [particulate matter <10 um in aerodynamic diameter (PM(10)), sulfur dioxide (SO(2)) and nitrogen dioxide (NO(2))] and mortality in Shenyang, China, using 12 years of data (1998-2009). Also, stratified analysis by sex, age, education, and income was conducted for cardiovascular and cerebrovascular mortality. The results showed that an increase of 10 ug/m(3) in a year average concentration of PM(10) corresponds to 55% increase in the risk of a death cardiovascular disease (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.51 to 1.60) and 49% increase in cerebrovascular disease (HR, 1.49; 95% CI, 1.45 to 1.53), respectively. The corresponding figures of adjusted HR (95%CI) for a 10 ug/m(3) increase in NO(2) was 2.46 (2.31 to 2.63) for cardiovascular mortality and 2.44 (2.27 to 2.62) for cerebrovascular mortality, respectively. The effects of air pollution were more evident in female that in male, and nonsmokers and residents with BMI<18.5 were more vulnerable to outdoor air pollution. CONCLUSION/SIGNIFICANCE: Long-term exposure to ambient air pollution is associated with the death of cardiovascular and cerebrovascular diseases among Chinese populations. PMID- 21695221 TI - The retrograde IFT machinery of C. elegans cilia: two IFT dynein complexes? AB - We analyzed the relatively poorly understood IFT-dynein (class DYNC2)-driven retrograde IFT pathway in C. elegans cilia, which yielded results that are surprising in the context of current models of IFT. Assays of C. elegans dynein gene expression and intraflagellar transport (IFT) suggest that conventional IFT dynein contains essential heavy (CHE-3), light-intermediate (XBX-1), plus three light polypeptide chains that participate in IFT, but no "essential" intermediate chain. IFT assays of XBX-1::YFP suggest that IFT-dynein is transported as cargo to the distal tip of the cilium by kinesin-2 motors, but independent of the IFT particle/BBSome complexes. Finally, we were surprised to find that the subset of cilia present on the OLQ (outer labial quadrant) neurons assemble independently of conventional "CHE-3" IFT-dynein, implying that there is a second IFT-dynein acting in these cilia. We have found a novel gene encoding a dynein heavy chain, DHC-3, and two light chains, in OLQ neurons, which could constitute an IFT-dynein complex in OLQ neuronal cilia. Our results underscore several surprising features of retrograde IFT that require clarification. PMID- 21695222 TI - Microfabricated physical spatial gradients for investigating cell migration and invasion dynamics. AB - We devise a novel assay that introduces micro-architectures into highly confining microchannels to probe the decision making processes of migrating cells. The conditions are meant to mimic the tight spaces in the physiological environment that cancer cells encounter during metastasis within the matrix dense stroma and during intravasation and extravasation through the vascular wall. In this study we use the assay to investigate the relative probabilities of a cell 1) permeating and 2) repolarizing (turning around) when it migrates into a spatially confining region. We observe the existence of both states even within a single cell line, indicating phenotypic heterogeneity in cell migration invasiveness and persistence. We also show that varying the spatial gradient of the taper can induce behavioral changes in cells, and different cell types respond differently to spatial changes. Particularly, for bovine aortic endothelial cells (BAECs), higher spatial gradients induce more cells to permeate (60%) than lower gradients (12%). Furthermore, highly metastatic breast cancer cells (MDA-MB-231) demonstrate a more invasive and permeative nature (87%) than non-metastatic breast epithelial cells (MCF-10A) (25%). We examine the migration dynamics of cells in the tapered region and derive characteristic constants that quantify this transition process. Our data indicate that cell response to physical spatial gradients is both cell-type specific and heterogeneous within a cell population, analogous to the behaviors reported to occur during tumor progression. Incorporation of micro-architectures in confined channels enables the probing of migration behaviors specific to defined geometries that mimic in vivo microenvironments. PMID- 21695223 TI - Epigenetic patterns maintained in early Caenorhabditis elegans embryos can be established by gene activity in the parental germ cells. AB - Epigenetic information, such as parental imprints, can be transmitted with genetic information from parent to offspring through the germ line. Recent reports show that histone modifications can be transmitted through sperm as a component of this information transfer. How the information that is transferred is established in the parent and maintained in the offspring is poorly understood. We previously described a form of imprinted X inactivation in Caenorhabditis elegans where dimethylation on histone 3 at lysine 4 (H3K4me2), a mark of active chromatin, is excluded from the paternal X chromosome (Xp) during spermatogenesis and persists through early cell divisions in the embryo. Based on the observation that the Xp (unlike the maternal X or any autosome) is largely transcriptionally inactive in the paternal germ line, we hypothesized that transcriptional activity in the parent germ line may influence epigenetic information inherited by and maintained in the embryo. We report that chromatin modifications and histone variant patterns assembled in the germ line can be retained in mature gametes. Furthermore, despite extensive chromatin remodeling events at fertilization, the modification patterns arriving with the gametes are largely retained in the early embryo. Using transgenes, we observe that expression in the parental germline correlates with differential chromatin assembly that is replicated and maintained in the early embryo. Expression in the adult germ cells also correlates with more robust expression in the somatic lineages of the offspring. These results suggest that differential expression in the parental germ lines may provide a potential mechanism for the establishment of parent-of-origin epigenomic content. This content can be maintained and may heritably affect gene expression in the offspring. PMID- 21695224 TI - Comparative analysis of proteome and transcriptome variation in mouse. AB - The relationships between the levels of transcripts and the levels of the proteins they encode have not been examined comprehensively in mammals, although previous work in plants and yeast suggest a surprisingly modest correlation. We have examined this issue using a genetic approach in which natural variations were used to perturb both transcript levels and protein levels among inbred strains of mice. We quantified over 5,000 peptides and over 22,000 transcripts in livers of 97 inbred and recombinant inbred strains and focused on the 7,185 most heritable transcripts and 486 most reliable proteins. The transcript levels were quantified by microarray analysis in three replicates and the proteins were quantified by Liquid Chromatography-Mass Spectrometry using O(18)-reference-based isotope labeling approach. We show that the levels of transcripts and proteins correlate significantly for only about half of the genes tested, with an average correlation of 0.27, and the correlations of transcripts and proteins varied depending on the cellular location and biological function of the gene. We examined technical and biological factors that could contribute to the modest correlation. For example, differential splicing clearly affects the analyses for certain genes; but, based on deep sequencing, this does not substantially contribute to the overall estimate of the correlation. We also employed genome wide association analyses to map loci controlling both transcript and protein levels. Surprisingly, little overlap was observed between the protein- and transcript-mapped loci. We have typed numerous clinically relevant traits among the strains, including adiposity, lipoprotein levels, and tissue parameters. Using correlation analysis, we found that a low number of clinical trait relationships are preserved between the protein and mRNA gene products and that the majority of such relationships are specific to either the protein levels or transcript levels. Surprisingly, transcript levels were more strongly correlated with clinical traits than protein levels. In light of the widespread use of high throughput technologies in both clinical and basic research, the results presented have practical as well as basic implications. PMID- 21695225 TI - A new view of the bacterial cytosol environment. AB - The cytosol is the major environment in all bacterial cells. The true physical and dynamical nature of the cytosol solution is not fully understood and here a modeling approach is applied. Using recent and detailed data on metabolite concentrations, we have created a molecular mechanical model of the prokaryotic cytosol environment of Escherichia coli, containing proteins, metabolites and monatomic ions. We use 200 ns molecular dynamics simulations to compute diffusion rates, the extent of contact between molecules and dielectric constants. Large metabolites spend ~80% of their time in contact with other molecules while small metabolites vary with some only spending 20% of time in contact. Large non covalently interacting metabolite structures mediated by hydrogen-bonds, ionic and pi stacking interactions are common and often associate with proteins. Mg(2+) ions were prominent in NIMS and almost absent free in solution. Kappa(+) is generally not involved in NIMSs and populates the solvent fairly uniformly, hence its important role as an osmolyte. In simulations containing ubiquitin, to represent a protein component, metabolite diffusion was reduced owing to long lasting protein-metabolite interactions. Hence, it is likely that with larger proteins metabolites would diffuse even more slowly. The dielectric constant of these simulations was found to differ from that of pure water only through a large contribution from ubiquitin as metabolite and monatomic ion effects cancel. These findings suggest regions of influence specific to particular proteins affecting metabolite diffusion and electrostatics. Also some proteins may have a higher propensity for associations with metabolites owing to their larger electrostatic fields. We hope that future studies may be able to accurately predict how binding interactions differ in the cytosol relative to dilute aqueous solution. PMID- 21695226 TI - Genetic analysis of genome-scale recombination rate evolution in house mice. AB - The rate of meiotic recombination varies markedly between species and among individuals. Classical genetic experiments demonstrated a heritable component to population variation in recombination rate, and specific sequence variants that contribute to recombination rate differences between individuals have recently been identified. Despite these advances, the genetic basis of species divergence in recombination rate remains unexplored. Using a cytological assay that allows direct in situ imaging of recombination events in spermatocytes, we report a large (~30%) difference in global recombination rate between males of two closely related house mouse subspecies (Mus musculus musculus and M. m. castaneus). To characterize the genetic basis of this recombination rate divergence, we generated an F2 panel of inter-subspecific hybrid males (n = 276) from an intercross between wild-derived inbred strains CAST/EiJ (M. m. castaneus) and PWD/PhJ (M. m. musculus). We uncover considerable heritable variation for recombination rate among males from this mapping population. Much of the F2 variance for recombination rate and a substantial portion of the difference in recombination rate between the parental strains is explained by eight moderate- to large-effect quantitative trait loci, including two transgressive loci on the X chromosome. In contrast to the rapid evolution observed in males, female CAST/EiJ and PWD/PhJ animals show minimal divergence in recombination rate (~5%). The existence of loci on the X chromosome suggests a genetic mechanism to explain this male-biased evolution. Our results provide an initial map of the genetic changes underlying subspecies differences in genome-scale recombination rate and underscore the power of the house mouse system for understanding the evolution of this trait. PMID- 21695227 TI - Characterization of 9-nitrocamptothecin liposomes: anticancer properties and mechanisms on hepatocellular carcinoma in vitro and in vivo. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the third most common cause of cancer related mortality worldwide. 9-Nitrocamptothecin (9NC) is a potent topoisomerase-I inhibitor with strong anticancer effect. To increase the solubility and stability, we synthesized a novel 9NC loaded liposomes (9NC-LP) via incorporating 9NC into liposomes. In the present study, we determined the effects of 9NC and 9NC-LP on in vitro and in vivo, and the underlying mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We first analyzed the characteristics of 9NC-LP. Then we compared the effects of 9NC and 9NC-LP on the proliferation and apoptosis of HepG2, Bel-7402, Hep3B and L02 cells in vitro. We also investigated their anticancer properties in nude mice bearing HCC xenograft in vivo. 9NC-LP has a uniform size (around 190 nm) and zeta potential (~-11 mV), and exhibited a steady sustained-release pattern profile in vitro. Both 9NC and 9NC-LP could cause cell cycle arrest and apoptosis in a dose-dependent and p53-dependent manner. However, this effect was not ubiquitous in all cell lines. Exposure to 9NC-LP led to increased expression of p53, p21, p27, Bax, caspase-3, caspase-8, caspase-9 and apoptosis-inducing factor, mitochondrion-associated 1 and decreased expression of Bcl-2, cyclin E, cyclin A, Cdk2 and cyclin D1. Furthermore, 9NC-LP exhibited a more potent antiproliferative effect and less side effects in vivo. Western blot analysis of the xenograft tumors in nude mice showed similar changes in protein expression in vivo. CONCLUSIONS/SIGNIFICANCE: In conclusion, 9NC and 9NC-LP can inhibit HCC growth via cell cycle arrest and induction of apoptosis. 9NC-LP has a more potent anti-tumor effect and fewer side effects in vivo, which means it is a promising reagent for cancer therapy via intravenous administration. PMID- 21695228 TI - Statistical inference on the mechanisms of genome evolution. PMID- 21695230 TI - Specific SKN-1/Nrf stress responses to perturbations in translation elongation and proteasome activity. AB - SKN-1, the Caenorhabditis elegans Nrf1/2/3 ortholog, promotes both oxidative stress resistance and longevity. SKN-1 responds to oxidative stress by upregulating genes that detoxify and defend against free radicals and other reactive molecules, a SKN-1/Nrf function that is both well-known and conserved. Here we show that SKN-1 has a broader and more complex role in maintaining cellular stress defenses. SKN-1 sustains expression and activity of the ubiquitin proteasome system (UPS) and coordinates specific protective responses to perturbations in protein synthesis or degradation through the UPS. If translation initiation or elongation is impaired, SKN-1 upregulates overlapping sets of cytoprotective genes and increases stress resistance. When proteasome gene expression and activity are blocked, SKN-1 activates multiple classes of proteasome subunit genes in a compensatory response. SKN-1 thereby maintains UPS activity in the intestine in vivo under normal conditions and promotes survival when the proteasome is inhibited. In contrast, when translation elongation is impaired, SKN-1 does not upregulate proteasome genes, and UPS activity is then reduced. This indicates that UPS activity depends upon presence of an intact translation elongation apparatus; and it supports a model, suggested by genetic and biochemical studies in yeast, that protein synthesis and degradation may be coupled processes. SKN-1 therefore has a critical tissue-specific function in increasing proteasome gene expression and UPS activity under normal conditions, as well as when the UPS system is stressed, but mounts distinct responses when protein synthesis is perturbed. The specificity of these SKN-1-mediated stress responses, along with the apparent coordination between UPS and translation elongation activity, may promote protein homeostasis under stress or disease conditions. The data suggest that SKN-1 may increase longevity, not only through its well-documented role in boosting stress resistance, but also through contributing to protein homeostasis. PMID- 21695229 TI - A large gene network in immature erythroid cells is controlled by the myeloid and B cell transcriptional regulator PU.1. AB - PU.1 is a hematopoietic transcription factor that is required for the development of myeloid and B cells. PU.1 is also expressed in erythroid progenitors, where it blocks erythroid differentiation by binding to and inhibiting the main erythroid promoting factor, GATA-1. However, other mechanisms by which PU.1 affects the fate of erythroid progenitors have not been thoroughly explored. Here, we used ChIP-Seq analysis for PU.1 and gene expression profiling in erythroid cells to show that PU.1 regulates an extensive network of genes that constitute major pathways for controlling growth and survival of immature erythroid cells. By analyzing fetal liver erythroid progenitors from mice with low PU.1 expression, we also show that the earliest erythroid committed cells are dramatically reduced in vivo. Furthermore, we find that PU.1 also regulates many of the same genes and pathways in other blood cells, leading us to propose that PU.1 is a multifaceted factor with overlapping, as well as distinct, functions in several hematopoietic lineages. PMID- 21695231 TI - Exome sequencing identifies ZNF644 mutations in high myopia. AB - Myopia is the most common ocular disorder worldwide, and high myopia in particular is one of the leading causes of blindness. Genetic factors play a critical role in the development of myopia, especially high myopia. Recently, the exome sequencing approach has been successfully used for the disease gene identification of Mendelian disorders. Here we show a successful application of exome sequencing to identify a gene for an autosomal dominant disorder, and we have identified a gene potentially responsible for high myopia in a monogenic form. We captured exomes of two affected individuals from a Han Chinese family with high myopia and performed sequencing analysis by a second-generation sequencer with a mean coverage of 30* and sufficient depth to call variants at ~97% of each targeted exome. The shared genetic variants of these two affected individuals in the family being studied were filtered against the 1000 Genomes Project and the dbSNP131 database. A mutation A672G in zinc finger protein 644 isoform 1 (ZNF644) was identified as being related to the phenotype of this family. After we performed sequencing analysis of the exons in the ZNF644 gene in 300 sporadic cases of high myopia, we identified an additional five mutations (I587V, R680G, C699Y, 3'UTR+12 C>G, and 3'UTR+592 G>A) in 11 different patients. All these mutations were absent in 600 normal controls. The ZNF644 gene was expressed in human retinal and retinal pigment epithelium (RPE). Given that ZNF644 is predicted to be a transcription factor that may regulate genes involved in eye development, mutation may cause the axial elongation of eyeball found in high myopia patients. Our results suggest that ZNF644 might be a causal gene for high myopia in a monogenic form. PMID- 21695232 TI - Differential detection of potentially hazardous Fusarium species in wheat grains by an electronic nose. AB - Fungal infestation on wheat is an increasingly grave nutritional problem in many countries worldwide. Fusarium species are especially harmful pathogens due to their toxic metabolites. In this work we studied volatile compounds released by F. cerealis, F. graminearum, F. culmorum and F. redolens using SPME-GC/MS. By using an electronic nose we were able to differentiate between infected and non infected wheat grains in the post-harvest chain. Our electronic nose was capable of distinguishing between four wheat Fusaria species with an accuracy higher than 80%. PMID- 21695233 TI - Testing the ortholog conjecture with comparative functional genomic data from mammals. AB - A common assumption in comparative genomics is that orthologous genes share greater functional similarity than do paralogous genes (the "ortholog conjecture"). Many methods used to computationally predict protein function are based on this assumption, even though it is largely untested. Here we present the first large-scale test of the ortholog conjecture using comparative functional genomic data from human and mouse. We use the experimentally derived functions of more than 8,900 genes, as well as an independent microarray dataset, to directly assess our ability to predict function using both orthologs and paralogs. Both datasets show that paralogs are often a much better predictor of function than are orthologs, even at lower sequence identities. Among paralogs, those found within the same species are consistently more functionally similar than those found in a different species. We also find that paralogous pairs residing on the same chromosome are more functionally similar than those on different chromosomes, perhaps due to higher levels of interlocus gene conversion between these pairs. In addition to offering implications for the computational prediction of protein function, our results shed light on the relationship between sequence divergence and functional divergence. We conclude that the most important factor in the evolution of function is not amino acid sequence, but rather the cellular context in which proteins act. PMID- 21695234 TI - Mutual inactivation of Notch receptors and ligands facilitates developmental patterning. AB - Developmental patterning requires juxtacrine signaling in order to tightly coordinate the fates of neighboring cells. Recent work has shown that Notch and Delta, the canonical metazoan juxtacrine signaling receptor and ligand, mutually inactivate each other in the same cell. This cis-interaction generates mutually exclusive sending and receiving states in individual cells. It generally remains unclear, however, how this mutual inactivation and the resulting switching behavior can impact developmental patterning circuits. Here we address this question using mathematical modeling in the context of two canonical pattern formation processes: boundary formation and lateral inhibition. For boundary formation, in a model motivated by Drosophila wing vein patterning, we find that mutual inactivation allows sharp boundary formation across a broader range of parameters than models lacking mutual inactivation. This model with mutual inactivation also exhibits robustness to correlated gene expression perturbations. For lateral inhibition, we find that mutual inactivation speeds up patterning dynamics, relieves the need for cooperative regulatory interactions, and expands the range of parameter values that permit pattern formation, compared to canonical models. Furthermore, mutual inactivation enables a simple lateral inhibition circuit architecture which requires only a single downstream regulatory step. Both model systems show how mutual inactivation can facilitate robust fine-grained patterning processes that would be difficult to implement without it, by encoding a difference-promoting feedback within the signaling system itself. Together, these results provide a framework for analysis of more complex Notch-dependent developmental systems. PMID- 21695235 TI - Finished genome of the fungal wheat pathogen Mycosphaerella graminicola reveals dispensome structure, chromosome plasticity, and stealth pathogenesis. AB - The plant-pathogenic fungus Mycosphaerella graminicola (asexual stage: Septoria tritici) causes septoria tritici blotch, a disease that greatly reduces the yield and quality of wheat. This disease is economically important in most wheat growing areas worldwide and threatens global food production. Control of the disease has been hampered by a limited understanding of the genetic and biochemical bases of pathogenicity, including mechanisms of infection and of resistance in the host. Unlike most other plant pathogens, M. graminicola has a long latent period during which it evades host defenses. Although this type of stealth pathogenicity occurs commonly in Mycosphaerella and other Dothideomycetes, the largest class of plant-pathogenic fungi, its genetic basis is not known. To address this problem, the genome of M. graminicola was sequenced completely. The finished genome contains 21 chromosomes, eight of which could be lost with no visible effect on the fungus and thus are dispensable. This eight chromosome dispensome is dynamic in field and progeny isolates, is different from the core genome in gene and repeat content, and appears to have originated by ancient horizontal transfer from an unknown donor. Synteny plots of the M. graminicola chromosomes versus those of the only other sequenced Dothideomycete, Stagonospora nodorum, revealed conservation of gene content but not order or orientation, suggesting a high rate of intra-chromosomal rearrangement in one or both species. This observed "mesosynteny" is very different from synteny seen between other organisms. A surprising feature of the M. graminicola genome compared to other sequenced plant pathogens was that it contained very few genes for enzymes that break down plant cell walls, which was more similar to endophytes than to pathogens. The stealth pathogenesis of M. graminicola probably involves degradation of proteins rather than carbohydrates to evade host defenses during the biotrophic stage of infection and may have evolved from endophytic ancestors. PMID- 21695236 TI - Natural allelic variation defines a role for ATMYC1: trichome cell fate determination. AB - The molecular nature of biological variation is not well understood. Indeed, many questions persist regarding the types of molecular changes and the classes of genes that underlie morphological variation within and among species. Here we have taken a candidate gene approach based on previous mapping results to identify the gene and ultimately a polymorphism that underlies a trichome density QTL in Arabidopsis thaliana. Our results show that natural allelic variation in the transcription factor ATMYC1 alters trichome density in A. thaliana; this is the first reported function for ATMYC1. Using site-directed mutagenesis and yeast two-hybrid experiments, we demonstrate that a single amino acid replacement in ATMYC1, discovered in four ecotypes, eliminates known protein-protein interactions in the trichome initiation pathway. Additionally, in a broad screen for molecular variation at ATMYC1, including 72 A. thaliana ecotypes, a high frequency block of variation was detected that results in >10% amino acid replacement within one of the eight exons of the gene. This sequence variation harbors a strong signal of divergent selection but has no measurable effect on trichome density. Homologs of ATMYC1 are pleiotropic, however, so this block of variation may be the result of natural selection having acted on another trait, while maintaining the trichome density role of the gene. These results show that ATMYC1 is an important source of variation for epidermal traits in A. thaliana and indicate that the transcription factors that make up the TTG1 genetic pathway generally may be important sources of epidermal variation in plants. PMID- 21695237 TI - Spatial dynamics of human-origin H1 influenza A virus in North American swine. AB - The emergence and rapid global spread of the swine-origin H1N1/09 pandemic influenza A virus in humans underscores the importance of swine populations as reservoirs for genetically diverse influenza viruses with the potential to infect humans. However, despite their significance for animal and human health, relatively little is known about the phylogeography of swine influenza viruses in the United States. This study utilizes an expansive data set of hemagglutinin (HA1) sequences (n = 1516) from swine influenza viruses collected in North America during the period 2003-2010. With these data we investigate the spatial dissemination of a novel influenza virus of the H1 subtype that was introduced into the North American swine population via two separate human-to-swine transmission events around 2003. Bayesian phylogeographic analysis reveals that the spatial dissemination of this influenza virus in the US swine population follows long-distance swine movements from the Southern US to the Midwest, a corn rich commercial center that imports millions of swine annually. Hence, multiple genetically diverse influenza viruses are introduced and co-circulate in the Midwest, providing the opportunity for genomic reassortment. Overall, the Midwest serves primarily as an ecological sink for swine influenza in the US, with sources of virus genetic diversity instead located in the Southeast (mainly North Carolina) and South-central (mainly Oklahoma) regions. Understanding the importance of long-distance pig transportation in the evolution and spatial dissemination of the influenza virus in swine may inform future strategies for the surveillance and control of influenza, and perhaps other swine pathogens. PMID- 21695239 TI - Drift and genome complexity revisited. PMID- 21695238 TI - Meiosis-specific loading of the centromere-specific histone CENH3 in Arabidopsis thaliana. AB - Centromere behavior is specialized in meiosis I, so that sister chromatids of homologous chromosomes are pulled toward the same side of the spindle (through kinetochore mono-orientation) and chromosome number is reduced. Factors required for mono-orientation have been identified in yeast. However, comparatively little is known about how meiotic centromere behavior is specialized in animals and plants that typically have large tandem repeat centromeres. Kinetochores are nucleated by the centromere-specific histone CENH3. Unlike conventional histone H3s, CENH3 is rapidly evolving, particularly in its N-terminal tail domain. Here we describe chimeric variants of CENH3 with alterations in the N-terminal tail that are specifically defective in meiosis. Arabidopsis thaliana cenh3 mutants expressing a GFP-tagged chimeric protein containing the H3 N-terminal tail and the CENH3 C-terminus (termed GFP-tailswap) are sterile because of random meiotic chromosome segregation. These defects result from the specific depletion of GFP tailswap protein from meiotic kinetochores, which contrasts with its normal localization in mitotic cells. Loss of the GFP-tailswap CENH3 variant in meiosis affects recruitment of the essential kinetochore protein MIS12. Our findings suggest that CENH3 loading dynamics might be regulated differently in mitosis and meiosis. As further support for our hypothesis, we show that GFP-tailswap protein is recruited back to centromeres in a subset of pollen grains in GFP-tailswap once they resume haploid mitosis. Meiotic recruitment of the GFP-tailswap CENH3 variant is not restored by removal of the meiosis-specific cohesin subunit REC8. Our results reveal the existence of a specialized loading pathway for CENH3 during meiosis that is likely to involve the hypervariable N-terminal tail. Meiosis-specific CENH3 dynamics may play a role in modulating meiotic centromere behavior. PMID- 21695240 TI - The influenza virus protein PB1-F2 inhibits the induction of type I interferon at the level of the MAVS adaptor protein. AB - PB1-F2 is a 90 amino acid protein that is expressed from the +1 open reading frame in the PB1 gene of some influenza A viruses and has been shown to contribute to viral pathogenicity. Notably, a serine at position 66 (66S) in PB1 F2 is known to increase virulence compared to an isogenic virus with an asparagine (66N) at this position. Recently, we found that an influenza virus expressing PB1-F2 N66S suppresses interferon (IFN)-stimulated genes in mice. To characterize this phenomenon, we employed several in vitro assays. Overexpression of the A/Puerto Rico/8/1934 (PR8) PB1-F2 protein in 293T cells decreased RIG-I mediated activation of an IFN-beta reporter and secretion of IFN as determined by bioassay. Of note, the PB1-F2 N66S protein showed enhanced IFN antagonism activity compared to PB1-F2 wildtype. Similar observations were found in the context of viral infection with a PR8 PB1-F2 N66S virus. To understand the relationship between NS1, a previously described influenza virus protein involved in suppression of IFN synthesis, and PB1-F2, we investigated the induction of IFN when NS1 and PB1-F2 were co-expressed in an in vitro transfection system. In this assay we found that PB1-F2 N66S further reduced IFN induction in the presence of NS1. By inducing the IFN-beta reporter at different levels in the signaling cascade, we found that PB1-F2 inhibited IFN production at the level of the mitochondrial antiviral signaling protein (MAVS). Furthermore, immunofluorescence studies revealed that PB1-F2 co-localizes with MAVS. In summary, we have characterized the anti-interferon function of PB1-F2 and we suggest that this activity contributes to the enhanced pathogenicity seen with PB1-F2 N66S- expressing influenza viruses. PMID- 21695241 TI - Cross-neutralizing antibodies to pandemic 2009 H1N1 and recent seasonal H1N1 influenza A strains influenced by a mutation in hemagglutinin subunit 2. AB - Pandemic 2009 H1N1 influenza A virus (2009 H1N1) differs from H1N1 strains that circulated in the past 50 years, but resembles the A/New Jersey/1976 H1N1 strain used in the 1976 swine influenza vaccine. We investigated whether sera from persons immunized with the 1976 swine influenza or recent seasonal influenza vaccines, or both, neutralize 2009 H1N1. Using retroviral pseudovirions bearing hemagglutinins on their surface (HA-pseudotypes), we found that 77% of the sera collected in 1976 after immunization with the A/New Jersey/1976 H1N1 swine influenza vaccine neutralized 2009 H1N1. Forty five percent also neutralized A/New Caledonia/20/1999 H1N1, a strain used in seasonal influenza vaccines during the 2000/01-2006/07 seasons. Among adults aged 48-64 who received the swine influenza vaccine in 1976 and recent seasonal influenza vaccines during the 2004/05-2008/09 seasons, 83% had sera that neutralized 2009 H1N1. However, 68% of age-matched subjects who received the same seasonal influenza vaccines, but did not receive the 1976 swine influenza vaccine, also had sera that neutralized 2009 H1N1. Sera from both 1976 and contemporary cohorts frequently had cross neutralizing antibodies to 2009 H1N1 and A/New Caledonia/20/1999 that mapped to hemagglutinin subunit 2 (HA2). A conservative mutation in HA2 corresponding to a residue in the A/Solomon Islands/3/2006 and A/Brisbane/59/2007 H1N1 strains that circulated in the 2006/07 and 2007/08 influenza seasons, respectively, abrogated this neutralization. These findings highlight a cross-neutralization determinant influenced by a point mutation in HA2 and suggest that HA2 may be evolving under direct or indirect immune pressure. PMID- 21695242 TI - Coronavirus gene 7 counteracts host defenses and modulates virus virulence. AB - Transmissible gastroenteritis virus (TGEV) genome contains three accessory genes: 3a, 3b and 7. Gene 7 is only present in members of coronavirus genus a1, and encodes a hydrophobic protein of 78 aa. To study gene 7 function, a recombinant TGEV virus lacking gene 7 was engineered (rTGEV-Delta7). Both the mutant and the parental (rTGEV-wt) viruses showed the same growth and viral RNA accumulation kinetics in tissue cultures. Nevertheless, cells infected with rTGEV-Delta7 virus showed an increased cytopathic effect caused by an enhanced apoptosis mediated by caspase activation. Macromolecular synthesis analysis showed that rTGEV-Delta7 virus infection led to host translational shut-off and increased cellular RNA degradation compared with rTGEV-wt infection. An increase of eukaryotic translation initiation factor 2 (eIF2alpha) phosphorylation and an enhanced nuclease, most likely RNase L, activity were observed in rTGEV-Delta7 virus infected cells. These results suggested that the removal of gene 7 promoted an intensified dsRNA-activated host antiviral response. In protein 7 a conserved sequence motif that potentially mediates binding to protein phosphatase 1 catalytic subunit (PP1c), a key regulator of the cell antiviral defenses, was identified. We postulated that TGEV protein 7 may counteract host antiviral response by its association with PP1c. In fact, pull-down assays demonstrated the interaction between TGEV protein 7, but not a protein 7 mutant lacking PP1c binding motif, with PP1. Moreover, the interaction between protein 7 and PP1 was required, during the infection, for eIF2alpha dephosphorylation and inhibition of cell RNA degradation. Inoculation of newborn piglets with rTGEV-Delta7 and rTGEV wt viruses showed that rTGEV-Delta7 virus presented accelerated growth kinetics and pathology compared with the parental virus. Overall, the results indicated that gene 7 counteracted host cell defenses, and modified TGEV persistence increasing TGEV survival. Therefore, the acquisition of gene 7 by the TGEV genome most likely has provided a selective advantage to the virus. PMID- 21695243 TI - Pathogen recognition receptor signaling accelerates phosphorylation-dependent degradation of IFNAR1. AB - An ability to sense pathogens by a number of specialized cell types including the dendritic cells plays a central role in host's defenses. Activation of these cells through the stimulation of the pathogen-recognition receptors induces the production of a number of cytokines including Type I interferons (IFNs) that mediate the diverse mechanisms of innate immunity. Type I IFNs interact with the Type I IFN receptor, composed of IFNAR1 and IFNAR2 chains, to mount the host defense responses. However, at the same time, Type I IFNs elicit potent anti proliferative and pro-apoptotic effects that could be detrimental for IFN producing cells. Here, we report that the activation of p38 kinase in response to pathogen-recognition receptors stimulation results in a series of phosphorylation events within the IFNAR1 chain of the Type I IFN receptor. This phosphorylation promotes IFNAR1 ubiquitination and accelerates the proteolytic turnover of this receptor leading to an attenuation of Type I IFN signaling and the protection of activated dendritic cells from the cytotoxic effects of autocrine or paracrine Type I IFN. In this paper we discuss a potential role of this mechanism in regulating the processes of innate immunity. PMID- 21695244 TI - Molecular interactions that enable movement of the Lyme disease agent from the tick gut into the hemolymph. AB - Borrelia burgdorferi, the causative agent of Lyme disease, is transmitted to humans by bite of Ixodes scapularis ticks. The mechanisms by which the bacterium is transmitted from vector to host are poorly understood. In this study, we show that the F(ab)(2) fragments of BBE31, a B.burgdorferi outer-surface lipoprotein, interfere with the migration of the spirochete from tick gut into the hemolymph during tick feeding. The decreased hemolymph infection results in lower salivary glands infection, and consequently attenuates mouse infection by tick-transmitted B. burgdorferi. Using a yeast surface display approach, a tick gut protein named TRE31 was identified to interact with BBE31. Silencing tre31 also decreased the B. burgdorferi burden in the tick hemolymph. Delineating the specific spirochete and arthropod ligands required for B. burgdorferi movement in the tick may lead to new strategies to interrupt the life cycle of the Lyme disease agent. PMID- 21695245 TI - Bacteria-Induced Dscam Isoforms of the Crustacean, Pacifastacus leniusculus. AB - The Down syndrome cell adhesion molecule, also known as Dscam, is a member of the immunoglobulin super family. Dscam plays an essential function in neuronal wiring and appears to be involved in innate immune reactions in insects. The deduced amino acid sequence of Dscam in the crustacean Pacifastacus leniusculus (PlDscam), encodes 9(Ig)-4(FNIII)-(Ig)-2(FNIII)-TM and it has variable regions in the N-terminal half of Ig2 and Ig3 and the complete Ig7 and in the transmembrane domain. The cytoplasmic tail can generate multiple isoforms. PlDscam can generate more than 22,000 different unique isoforms. Bacteria and LPS injection enhanced the expression of PlDscam, but no response in expression occurred after a white spot syndrome virus (WSSV) infection or injection with peptidoglycans. Furthermore, PlDscam silencing did not have any effect on the replication of the WSSV. Bacterial specific isoforms of PlDscam were shown to have a specific binding property to each tested bacteria, E. coli or S. aureus. The bacteria specific isoforms of PlDscam were shown to be associated with bacterial clearance and phagocytosis in crayfish. PMID- 21695246 TI - Cooperative and antagonistic contributions of two heterochromatin proteins to transcriptional regulation of the Drosophila sex determination decision. AB - Eukaryotic nuclei contain regions of differentially staining chromatin (heterochromatin), which remain condensed throughout the cell cycle and are largely transcriptionally silent. RNAi knockdown of the highly conserved heterochromatin protein HP1 in Drosophila was previously shown to preferentially reduce male viability. Here we report a similar phenotype for the telomeric partner of HP1, HOAP, and roles for both proteins in regulating the Drosophila sex determination pathway. Specifically, these proteins regulate the critical decision in this pathway, firing of the establishment promoter of the masterswitch gene, Sex-lethal (Sxl). Female-specific activation of this promoter, Sxl(Pe), is essential to females, as it provides SXL protein to initiate the productive female-specific splicing of later Sxl transcripts, which are transcribed from the maintenance promoter (Sxl(Pm)) in both sexes. HOAP mutants show inappropriate Sxl(Pe) firing in males and the concomitant inappropriate splicing of Sxl(Pm)-derived transcripts, while females show premature firing of Sxl(Pe). HP1 mutants, by contrast, display Sxl(Pm) splicing defects in both sexes. Chromatin immunoprecipitation assays show both proteins are associated with Sxl(Pe) sequences. In embryos from HP1 mutant mothers and Sxl mutant fathers, female viability and RNA polymerase II recruitment to Sxl(Pe) are severely compromised. Our genetic and biochemical assays indicate a repressing activity for HOAP and both activating and repressing roles for HP1 at Sxl(Pe). PMID- 21695247 TI - Potential drug development candidates for human soil-transmitted helminthiases. AB - BACKGROUND: Few drugs are available for soil-transmitted helminthiasis (STH); the benzimidazoles albendazole and mebendazole are the only drugs being used for preventive chemotherapy as they can be given in one single dose with no weight adjustment. While generally safe and effective in reducing intensity of infection, they are contra-indicated in first-trimester pregnancy and have suboptimal efficacy against Trichuris trichiura. In addition, drug resistance is a threat. It is therefore important to find alternatives. METHODOLOGY: We searched the literature and the animal health marketed products and pipeline for potential drug development candidates. Recently registered veterinary products offer advantages in that they have undergone extensive and rigorous animal testing, thus reducing the risk, cost and time to approval for human trials. For selected compounds, we retrieved and summarised publicly available information (through US Freedom of Information (FoI) statements, European Public Assessment Reports (EPAR) and published literature). Concomitantly, we developed a target product profile (TPP) against which the products were compared. PRINCIPAL FINDINGS: The paper summarizes the general findings including various classes of compounds, and more specific information on two veterinary anthelmintics (monepantel, emodepside) and nitazoxanide, an antiprotozoal drug, compiled from the EMA EPAR and FDA registration files. CONCLUSIONS/SIGNIFICANCE: Few of the compounds already approved for use in human or animal medicine qualify for development track decision. Fast-tracking to approval for human studies may be possible for veterinary compounds like emodepside and monepantel, but additional information remains to be acquired before an informed decision can be made. PMID- 21695249 TI - Identification of novel SNPs in glioblastoma using targeted resequencing. AB - High-throughput sequencing opens avenues to find genetic variations that may be indicative of an increased risk for certain diseases. Linking these genomic data to other "omics" approaches bears the potential to deepen our understanding of pathogenic processes at the molecular level. To detect novel single nucleotide polymorphisms (SNPs) for glioblastoma multiforme (GBM), we used a combination of specific target selection and next generation sequencing (NGS). We generated a microarray covering the exonic regions of 132 GBM associated genes to enrich target sequences in two GBM tissues and corresponding leukocytes of the patients. Enriched target genes were sequenced with Illumina and the resulting reads were mapped to the human genome. With this approach we identified over 6000 SNPs, including over 1300 SNPs located in the targeted genes. Integrating the genome wide association study (GWAS) catalog and known disease associated SNPs, we found that several of the detected SNPs were previously associated with smoking behavior, body mass index, breast cancer and high-grade glioma. Particularly, the breast cancer associated allele of rs660118 SNP in the gene SART1 showed a near doubled frequency in glioblastoma patients, as verified in an independent control cohort by Sanger sequencing. In addition, we identified SNPs in 20 of 21 GBM associated antigens providing further evidence that genetic variations are significantly associated with the immunogenicity of antigens. PMID- 21695250 TI - Cryptic speciation in Brazilian Epiperipatus (Onychophora: Peripatidae) reveals an underestimated diversity among the peripatid velvet worms. AB - BACKGROUND: Taxonomical studies of the neotropical Peripatidae (Onychophora, velvet worms) have proven difficult, due to intraspecific variation and uniformity of morphological characters across this onychophoran subgroup. We therefore used molecular approaches, in addition to morphological methods, to explore the diversity of Epiperipatus from the Minas Gerais State of Brazil. METHODOLOGY/PRINCIPAL FINDINGS: Our analyses revealed three new species. While Epiperipatus diadenoproctussp. nov. can be distinguished from E. adenocryptussp. nov. and E. paurognostussp. nov. based on morphology and specific nucleotide positions in the mitochondrial cytochrome c oxidase subunit I (COI) and small ribosomal subunit RNA gene sequences (12S rRNA), anatomical differences between the two latter species are not evident. However, our phylogenetic analyses of molecular data suggest that they are cryptic species, with high Bayesian posterior probabilities and bootstrap and Bremer support values for each species clade. The sister group relationship of E. adenocryptussp. nov. and E. paurognostussp. nov. in our analyses correlates with the remarkable morphological similarity of these two species. To assess the species status of the new species, we performed a statistical parsimony network analysis based on 582 base pairs of the COI gene in our specimens, with the connection probability set to 95%. Our findings revealed no connections between groups of haplotypes, which have been recognized as allopatric lineages in our phylogenetic analyses, thus supporting our suggestion that they are separate species. CONCLUSIONS/SIGNIFICANCE: Our findings suggest high cryptic species diversity and endemism among the neotropical Peripatidae and demonstrate that the combination of morphological and molecular approaches is helpful for clarifying the taxonomy and species diversity of this apparently large and diverse onychophoran group. PMID- 21695251 TI - Mapping HIV-1 vaccine induced T-cell responses: bias towards less-conserved regions and potential impact on vaccine efficacy in the Step study. AB - T cell directed HIV vaccines are based upon the induction of CD8+ T cell memory responses that would be effective in inhibiting infection and subsequent replication of an infecting HIV-1 strain, a process that requires a match or near match between the epitope induced by vaccination and the infecting viral strain. We compared the frequency and specificity of the CTL epitope responses elicited by the replication-defective Ad5 gag/pol/nef vaccine used in the Step trial with the likelihood of encountering those epitopes among recently sequenced Clade B isolates of HIV-1. Among vaccinees with detectable 15-mer peptide pool ELISpot responses, there was a median of four (one Gag, one Nef and two Pol) CD8 epitopes per vaccinee detected by 9-mer peptide ELISpot assay. Importantly, frequency analysis of the mapped epitopes indicated that there was a significant skewing of the T cell response; variable epitopes were detected more frequently than would be expected from an unbiased sampling of the vaccine sequences. Correspondingly, the most highly conserved epitopes in Gag, Pol, and Nef (defined by presence in >80% of sequences currently in the Los Alamos database www.hiv.lanl.gov) were detected at a lower frequency than unbiased sampling, similar to the frequency reported for responses to natural infection, suggesting potential epitope masking of these responses. This may be a generic mechanism used by the virus in both contexts to escape effective T cell immune surveillance. The disappointing results of the Step trial raise the bar for future HIV vaccine candidates. This report highlights the bias towards less-conserved epitopes present in the same vaccine used in the Step trial. Development of vaccine strategies that can elicit a greater breadth of responses, and towards conserved regions of the genome in particular, are critical requirements for effective T-cell based vaccines against HIV-1. TRIAL REGISTRATION: ClinicalTrials.gov NCT00849680, A Study of Safety, Tolerability, and Immunogenicity of the MRKAd5 Gag/Pol/Nef Vaccine in Healthy Adults. PMID- 21695252 TI - Evolutionary history of the cancer immunity antigen MAGE gene family. AB - The evolutionary mode of a multi-gene family can change over time, depending on the functional differentiation and local genomic environment of family members. In this study, we demonstrate such a change in the melanoma antigen (MAGE) gene family on the mammalian X chromosome. The MAGE gene family is composed of ten subfamilies that can be categorized into two types. Type I genes are of relatively recent origin, and they encode epitopes for human leukocyte antigen (HLA) in cancer cells. Type II genes are relatively ancient and some of their products are known to be involved in apoptosis or cell proliferation. The evolutionary history of the MAGE gene family can be divided into four phases. In phase I, a single-copy state of an ancestral gene and the evolutionarily conserved mode had lasted until the emergence of eutherian mammals. In phase II, eight subfamily ancestors, with the exception for MAGE-C and MAGE-D subfamilies, were formed via retrotransposition independently. This would coincide with a transposition burst of LINE elements at the eutherian radiation. However, MAGE-C was generated by gene duplication of MAGE-A. Phase III is characterized by extensive gene duplication within each subfamily and in particular the formation of palindromes in the MAGE-A subfamily, which occurred in an ancestor of the Catarrhini. Phase IV is characterized by the decay of a palindrome in most Catarrhini, with the exception of humans. Although the palindrome is truncated by frequent deletions in apes and Old World monkeys, it is retained in humans. Here, we argue that this human-specific retention stems from negative selection acting on MAGE-A genes encoding epitopes of cancer cells, which preserves their ability to bind to highly divergent HLA molecules. These findings are interpreted with consideration of the biological factors shaping recent human MAGE-A genes. PMID- 21695254 TI - The changes in China's forests: an analysis using the Forest Identity. AB - Changes in forest carbon stocks are a determinant of the regional carbon budget. In the past several decades, China has experienced a pronounced increase in forest area and density. However, few comprehensive analyses have been conducted. In this study, we employed the Forest Identity concept to evaluate the changing status of China's forests over the past three decades, using national forest inventory data of five periods (1977-1981, 1984-1988, 1989-1993, 1994-1998, and 1999-2003). The results showed that forest area and growing stock density increased by 0.51% and 0.44% annually over the past three decades, while the conversion ratio of forest biomass to growing stock declined by 0.10% annually. These developments resulted in a net annual increase of 0.85% in forest carbon sequestration, which is equivalent to a net biomass carbon uptake of 43.8 Tg per year (1 Tg = 10(12) g). This increase can be attributed to the national reforestation/afforestation programs, environmentally enhanced forest growth and economic development as indicated by the average gross domestic product. PMID- 21695253 TI - Communication impairments in mice lacking Shank1: reduced levels of ultrasonic vocalizations and scent marking behavior. AB - Autism is a neurodevelopmental disorder with a strong genetic component. Core symptoms are abnormal reciprocal social interactions, qualitative impairments in communication, and repetitive and stereotyped patterns of behavior with restricted interests. Candidate genes for autism include the SHANK gene family, as mutations in SHANK2 and SHANK3 have been detected in several autistic individuals. SHANK genes code for a family of scaffolding proteins located in the postsynaptic density of excitatory synapses. To test the hypothesis that a mutation in SHANK1 contributes to the symptoms of autism, we evaluated Shank1(-/ ) null mutant mice for behavioral phenotypes with relevance to autism, focusing on social communication. Ultrasonic vocalizations and the deposition of scent marks appear to be two major modes of mouse communication. Our findings revealed evidence for low levels of ultrasonic vocalizations and scent marks in Shank1(-/ ) mice as compared to wildtype Shank1(+/+) littermate controls. Shank1(-/-) pups emitted fewer vocalizations than Shank1(+/+) pups when isolated from mother and littermates. In adulthood, genotype affected scent marking behavior in the presence of female urinary pheromones. Adult Shank1(-/-) males deposited fewer scent marks in proximity to female urine than Shank1(+/+) males. Call emission in response to female urinary pheromones also differed between genotypes. Shank1(+/+) mice changed their calling pattern dependent on previous female interactions, while Shank1(-/-) mice were unaffected, indicating a failure of Shank1(-/-) males to learn from a social experience. The reduced levels of ultrasonic vocalizations and scent marking behavior in Shank1(-/-) mice are consistent with a phenotype relevant to social communication deficits in autism. PMID- 21695255 TI - Mammalian target of rapamycin is a therapeutic target for murine ovarian endometrioid adenocarcinomas with dysregulated Wnt/beta-catenin and PTEN. AB - Despite the fact that epithelial ovarian cancers are the leading cause of death from gynecological cancer, very little is known about the pathophysiology of the disease. Mutations in the WNT and PI3K pathways are frequently observed in the human ovarian endometrioid adenocarcinomas (OEAs). However, the role of WNT/beta catenin and PTEN/AKT signaling in the etiology and/or progression of this disease is currently unclear. In this report we show that mice with a gain-of-function mutation in beta-catenin that leads to dysregulated nuclear accumulation of beta catenin expression in the ovarian surface epithelium (OSE) cells develop indolent, undifferentiated tumors with both mesenchymal and epithelial characteristics. Combining dysregulated beta-catenin with homozygous deletion of PTEN in the OSE resulted in development of significantly more aggressive tumors, which was correlated with inhibition of p53 expression and cellular senescence. Induced expression of both mTOR kinase, a master regulator of proliferation, and phosphorylation of its downstream target, S6Kinase was also observed in both the indolent and aggressive mouse tumors, as well as in human OEA with nuclear beta catenin accumulation. Ectopic allotransplants of the mouse ovarian tumor cells with a gain-of-function mutation in beta-catenin and PTEN deletion developed into tumors with OEA histology, the growth of which were significantly inhibited by oral rapamycin treatment. These studies demonstrate that rapamycin might be an effective therapeutic for human ovarian endometrioid patients with dysregulated Wnt/beta-catenin and Pten/PI3K signaling. PMID- 21695256 TI - Transcriptional regulation of BMP2 expression by the PTH-CREB signaling pathway in osteoblasts. AB - Intermittent application of parathyroid hormone (PTH) has well established anabolic effects on bone mass in rodents and humans. Although transcriptional mechanisms responsible for these effects are not fully understood, it is recognized that transcriptional factor cAMP response element binding protein (CREB) mediates PTH signaling in osteoblasts, and that there is a communication between the PTH-CREB pathway and the BMP2 signaling pathway, which is important for osteoblast differentiation and bone formations. These findings, in conjunction with putative cAMP response elements (CREs) in the BMP2 promoter, led us to hypothesize that the PTH-CREB pathway could be a positive regulator of BMP2 transcription in osteoblasts. To test this hypothesis, we first demonstrated that PTH signaling activated CREB by phosphorylation in osteoblasts, and that both PTH and CREB were capable of promoting osteoblastic differentiation of primary mouse osteoblast cells and multiple rodent osteoblast cell lines. Importantly, we found that the PTH-CREB signaling pathway functioned as an effective activator of BMP2 expression, as pharmacologic and genetic modulation of PTH-CREB activity significantly affected BMP2 expression levels in these cells. Lastly, through multiple promoter assays, including promoter reporter deletion, mutation, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA), we identified a specific CRE in the BMP2 promoter which is responsible for CREB transactivation of the BMP2 gene in osteoblasts. Together, these results demonstrate that the anabolic function of PTH signaling in bone is mediated, at least in part, by CREB transactivation of BMP2 expression in osteoblasts. PMID- 21695257 TI - Leucine-rich repeat kinase 2 modulates retinoic acid-induced neuronal differentiation of murine embryonic stem cells. AB - BACKGROUND: Dominant mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most prevalent cause of Parkinson's disease, however, little is known about the biological function of LRRK2 protein. LRRK2 is expressed in neural precursor cells suggesting a role in neurodevelopment. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, differential gene expression profiling revealed a faster silencing of pluripotency-associated genes, like Nanog, Oct4, and Lin28, during retinoic acid-induced neuronal differentiation of LRRK2-deficient mouse embryonic stem cells compared to wildtype cultures. By contrast, expression of neurotransmitter receptors and neurotransmitter release was increased in LRRK2+/- cultures indicating that LRRK2 promotes neuronal differentiation. Consistently, the number of neural progenitor cells was higher in the hippocampal dentate gyrus of adult LRRK2-deficient mice. Alterations in phosphorylation of the putative LRRK2 substrates, translation initiation factor 4E binding protein 1 and moesin, do not appear to be involved in altered differentiation, rather there is indirect evidence that a regulatory signaling network comprising retinoic acid receptors, let-7 miRNA and downstream target genes/mRNAs may be affected in LRRK2-deficient stem cells in culture. CONCLUSION/SIGNIFICANCE: Parkinson's disease-linked LRRK2 mutations that associated with enhanced kinase activity may affect retinoic acid receptor signaling during neurodevelopment and/or neuronal maintenance as has been shown in other mouse models of chronic neurodegenerative diseases. PMID- 21695258 TI - Murine missing in metastasis (MIM) mediates cell polarity and regulates the motility response to growth factors. AB - BACKGROUND: Missing in metastasis (MIM) is a member of the inverse BAR-domain protein family, and in vitro studies have implied MIM plays a role in deforming membrane curvature into filopodia-like protrusions and cell dynamics. Yet, the physiological role of the endogenous MIM in mammalian cells remains undefined. PRINCIPAL FINDINGS: We have examined mouse embryonic fibroblasts (MEFs) derived from mice in which the MIM locus was targeted by a gene trapping vector. MIM(-/-) MEFs showed a less polarized architecture characterized by smooth edges and fewer cell protrusions as compared to wild type cells, although the formation of filopodia-like microprotrusions appeared to be normal. Immunofluorescent staining further revealed that MIM(-/-) cells were partially impaired in the assembly of stress fibers and focal adhesions but were enriched with transverse actin filaments at the periphery. Poor assembly of stress fibers was apparently correlated with attenuation of the activity of Rho GTPases and partially relieved upon overexpressing of Myc-RhoA(Q63L), a constitutively activated RhoA mutant. MIM(-/-) cells were also spread less effectively than wild type cells during attachment to dishes and substratum. Upon treatment with PDGF MIM(-/-) cells developed more prominent dorsal ruffles along with increased Rac1 activity. Compared to wild type cells, MIM(-/-) cells had a slower motility in the presence of a low percentage of serum-containing medium but migrated normally upon adding growth factors such as 10% serum, PDGF or EGF. MIM(-/-) cells were also partially impaired in the internalization of transferrin, fluorescent dyes, foreign DNAs and PDGF receptor alpha. On the other hand, the level of tyrosine phosphorylation of PDGF receptors was more elevated in MIM depleted cells than wild type cells upon PDGF treatment. CONCLUSIONS: Our data suggests that endogenous MIM protein regulates globally the cell architecture and endocytosis that ultimately influence a variety of cellular behaviors, including cell polarity, motility, receptor signaling and membrane ruffling. PMID- 21695259 TI - Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance. AB - BACKGROUND: Insulin-degrading enzyme (IDE) is widely recognized as the principal protease responsible for the clearance and inactivation of insulin, but its role in glycemic control in vivo is poorly understood. We present here the first longitudinal characterization, to our knowledge, of glucose regulation in mice with pancellular deletion of the IDE gene (IDE-KO mice). METHODOLOGY: IDE-KO mice and wild-type (WT) littermates were characterized at 2, 4, and 6 months of age in terms of body weight, basal glucose and insulin levels, and insulin and glucose tolerance. Consistent with a functional role for IDE in insulin clearance, fasting serum insulin levels in IDE-KO mice were found to be ~3-fold higher than those in wild-type (WT) controls at all ages examined. In agreement with previous observations, 6-mo-old IDE-KO mice exhibited a severe diabetic phenotype characterized by increased body weight and pronounced glucose and insulin intolerance. In marked contrast, 2-mo-old IDE-KO mice exhibited multiple signs of improved glycemic control, including lower fasting glucose levels, lower body mass, and modestly enhanced insulin and glucose tolerance relative to WT controls. Biochemically, the emergence of the diabetic phenotype in IDE-KO mice correlated with age-dependent reductions in insulin receptor (IR) levels in muscle, adipose, and liver tissue. Primary adipocytes harvested from 6-mo-old IDE KO mice also showed functional impairments in insulin-stimulated glucose uptake. CONCLUSIONS: Our results indicate that the diabetic phenotype in IDE-KO mice is not a primary consequence of IDE deficiency, but is instead an emergent compensatory response to chronic hyperinsulinemia resulting from complete deletion of IDE in all tissues throughout life. Significantly, our findings provide new evidence to support the idea that partial and/or transient inhibition of IDE may constitute a valid approach to the treatment of diabetes. PMID- 21695261 TI - A genetically encoded tool kit for manipulating and monitoring membrane phosphatidylinositol 4,5-bisphosphate in intact cells. AB - BACKGROUND: Most ion channels are regulated by phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P(2)) in the cell membrane by diverse mechanisms. Important molecular tools to study ion channel regulation by PtdIns(4,5)P(2) in living cells have been developed in the past. These include fluorescent PH domains as sensors for Forster resonance energy transfer (FRET), to monitor changes in plasma membrane(.) For controlled and reversible depletion of PtdIns(4,5)P(2), voltage-sensing phosphoinositide phosphatases (VSD) have been demonstrated as a superior tool, since they are independent of cellular signaling pathways. Combining these methods in intact cells requires multiple transfections. We used self-cleaving viral 2A-peptide sequences for adenovirus driven expression of the PH-domain of phospholipase-Cdelta1 (PLCdelta1) fused to ECFP and EYFP respectively and Ciona intestinalis VSP (Ci-VSP), from a single open reading frame (ORF) in adult rat cardiac myocytes. METHODS AND RESULTS: Expression and correct targeting of ECFP-PH-PLCdelta1(,) EYFP-PH-PLCdelta1, and Ci-VSP from a single tricistronic vector containing 2A-peptide sequences first was demonstrated in HEK293 cells by voltage-controlled FRET measurements and Western blotting. Adult rat cardiac myocytes expressed Ci-VSP and the two fluorescent PH-domains within 4 days after gene transfer using the vector integrated into an adenoviral construct. Activation of Ci-VSP by depolarization resulted in rapid changes in FRET ratio indicating depletion of PtdIns(4,5)P(2) in the plasma membrane. This was paralleled by inhibition of endogenous G protein activated K(+) (GIRK) current. By comparing changes in FRET and current, a component of GIRK inhibition by adrenergic receptors unrelated to depletion of PtdIns(4,5)P(2) was identified. CONCLUSIONS: Expression of a FRET sensor pair and Ci-VSP from a single ORF provides a useful approach to study regulation of ion channels by phosphoinositides in cell lines and transfection-resistant postmitotic cells. Generally, adenoviral constructs containing self-cleaving 2A peptide sequences are highly suited for simultaneous transfer of multiple genes in adult cardiac myocytes. PMID- 21695260 TI - Phylogeny of parasitic parabasalia and free-living relatives inferred from conventional markers vs. Rpb1, a single-copy gene. AB - BACKGROUND: Parabasalia are single-celled eukaryotes (protists) that are mainly comprised of endosymbionts of termites and wood roaches, intestinal commensals, human or veterinary parasites, and free-living species. Phylogenetic comparisons of parabasalids are typically based upon morphological characters and 18S ribosomal RNA gene sequence data (rDNA), while biochemical or molecular studies of parabasalids are limited to a few axenically cultivable parasites. These previous analyses and other studies based on PCR amplification of duplicated protein-coding genes are unable to fully resolve the evolutionary relationships of parabasalids. As a result, genetic studies of Parabasalia lag behind other organisms. PRINCIPAL FINDINGS: Comparing parabasalid EF1alpha, alpha-tubulin, enolase and MDH protein-coding genes with information from the Trichomonas vaginalis genome reveals difficulty in resolving the history of species or isolates apart from duplicated genes. A conserved single-copy gene encodes the largest subunit of RNA polymerase II (Rpb1) in T. vaginalis and other eukaryotes. Here we directly sequenced Rpb1 degenerate PCR products from 10 parabasalid genera, including several T. vaginalis isolates and avian isolates, and compared these data by phylogenetic analyses. Rpb1 genes from parabasalids, diplomonads, Parabodo, Diplonema and Percolomonas were all intronless, unlike intron-rich homologs in Naegleria, Jakoba and Malawimonas. CONCLUSIONS/SIGNIFICANCE: The phylogeny of Rpb1 from parasitic and free-living parabasalids, and conserved Rpb1 insertions, support Trichomonadea, Tritrichomonadea, and Hypotrichomonadea as monophyletic groups. These results are consistent with prior analyses of rDNA and GAPDH sequences and ultrastructural data. The Rpb1 phylogenetic tree also resolves species- and isolate-level relationships. These findings, together with the relative ease of Rpb1 isolation, make it an attractive tool for evaluating more extensive relationships within Parabasalia. PMID- 21695262 TI - Impaired proteostasis contributes to renal tubular dysgenesis. AB - Protein conformational disorders are associated with the appearance, persistence, accumulation, and misprocessing of aberrant proteins in the cell. The etiology of renal tubular dysgenesis (RTD) is linked to mutations in the angiotensin converting enzyme (ACE). Here, we report the identification of a novel ACE mutation (Q1069R) in an RTD patient. ACE Q1069R is found sequestered in the endoplasmic reticulum and is also subject to increased proteasomal degradation, preventing its transport to the cell surface and extracellular fluids. Modulation of cellular proteostasis by temperature shift causes an extension in the processing time and trafficking of ACE Q1069R resulting in partial rescue of the protein processing defect and an increase in plasma membrane levels. In addition, we found that temperature shifting causes the ACE Q1069R protein to be secreted in an active state, suggesting that the mutation does not affect the enzyme's catalytic properties. PMID- 21695263 TI - Superhelical duplex destabilization and the recombination position effect. AB - The susceptibility to recombination of a plasmid inserted into a chromosome varies with its genomic position. This recombination position effect is known to correlate with the average G+C content of the flanking sequences. Here we propose that this effect could be mediated by changes in the susceptibility to superhelical duplex destabilization that would occur. We use standard nonparametric statistical tests, regression analysis and principal component analysis to identify statistically significant differences in the destabilization profiles calculated for the plasmid in different contexts, and correlate the results with their measured recombination rates. We show that the flanking sequences significantly affect the free energy of denaturation at specific sites interior to the plasmid. These changes correlate well with experimentally measured variations of the recombination rates within the plasmid. This correlation of recombination rate with superhelical destabilization properties of the inserted plasmid DNA is stronger than that with average G+C content of the flanking sequences. This model suggests a possible mechanism by which flanking sequence base composition, which is not itself a context-dependent attribute, can affect recombination rates at positions within the plasmid. PMID- 21695264 TI - Matrix metalloproteinase-8 mediates the unfavorable systemic impact of local irradiation on pharmacokinetics of anti-cancer drug 5-Fluorouracil. AB - Concurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for cancer treatment. However, the interactions between radiation and 5-FU remain unclear. Here, we evaluated the influence of local irradiation on the pharmacokinetics of 5-FU in rats. The single-fraction radiation was delivered to the whole pelvic fields of Sprague-Dawley rats after computerized tomography based planning. 5-FU at 100 mg/kg was prescribed 24 hours after radiation. A high performance liquid chromatography system was used to measure 5-FU in the blood. Matrix metalloproteinase-8 (MMP-8) inhibitor I was administered to examine whether or not RT modulation of 5-FU pharmacokinetic parameters could be blocked. Compared with sham-irradiated controls, whole pelvic irradiation reduced the area under the concentration versus time curve (AUC) of 5-FU in plasma and, in contrast, increased in bile with a radiation dose-dependent manner. Based on protein array analysis, the amount of plasma MMP-8 was increased by whole pelvic irradiation (2.8-fold by 0.5 Gy and 5.3-fold by 2 Gy) in comparison with controls. Pretreatment with MMP-8 inhibitor reversed the effect of irradiation on AUC of 5-FU in plasma. Our findings first indicate that local irradiation modulate the systemic pharmacokinetics of 5-FU through stimulating the release of MMP-8. The pharmacokinetics of 5-FU during concurrent chemoradiaiton therapy should be rechecked and the optimal 5-FU dose should be reevaluated, and adjusted if necessary, during CCRT. PMID- 21695265 TI - Boosting of synaptic potentials and spine Ca transients by the peptide toxin SNX 482 requires alpha-1E-encoded voltage-gated Ca channels. AB - The majority of glutamatergic synapses formed onto principal neurons of the mammalian central nervous system are associated with dendritic spines. Spines are tiny protuberances that house the proteins that mediate the response of the postsynaptic cell to the presynaptic release of glutamate. Postsynaptic signals are regulated by an ion channel signaling cascade that is active in individual dendritic spines and involves voltage-gated calcium (Ca) channels, small conductance (SK)-type Ca-activated potassium channels, and NMDA-type glutamate receptors. Pharmacological studies using the toxin SNX-482 indicated that the voltage-gated Ca channels that signal within spines to open SK channels belong to the class Ca(V)2.3, which is encoded by the Alpha-1E pore-forming subunit. In order to specifically test this conclusion, we examined the effects of SNX-482 on synaptic signals in acute hippocampal slices from knock-out mice lacking the Alpha-1E gene. We find that in these mice, application of SNX-482 has no effect on glutamate-uncaging evoked synaptic potentials and Ca influx, indicating that that SNX-482 indeed acts via the Alpha-1E-encoded Ca(V)2.3 channel. PMID- 21695266 TI - Action and emotion recognition from point light displays: an investigation of gender differences. AB - Folk psychology advocates the existence of gender differences in socio-cognitive functions such as 'reading' the mental states of others or discerning subtle differences in body-language. A female advantage has been demonstrated for emotion recognition from facial expressions, but virtually nothing is known about gender differences in recognizing bodily stimuli or body language. The aim of the present study was to investigate potential gender differences in a series of tasks, involving the recognition of distinct features from point light displays (PLDs) depicting bodily movements of a male and female actor. Although recognition scores were considerably high at the overall group level, female participants were more accurate than males in recognizing the depicted actions from PLDs. Response times were significantly higher for males compared to females on PLD recognition tasks involving (i) the general recognition of 'biological motion' versus 'non-biological' (or 'scrambled' motion); or (ii) the recognition of the 'emotional state' of the PLD-figures. No gender differences were revealed for a control test (involving the identification of a color change in one of the dots) and for recognizing the gender of the PLD-figure. In addition, previous findings of a female advantage on a facial emotion recognition test (the 'Reading the Mind in the Eyes Test' (Baron-Cohen, 2001)) were replicated in this study. Interestingly, a strong correlation was revealed between emotion recognition from bodily PLDs versus facial cues. This relationship indicates that inter-individual or gender-dependent differences in recognizing emotions are relatively generalized across facial and bodily emotion perception. Moreover, the tight correlation between a subject's ability to discern subtle emotional cues from PLDs and the subject's ability to basically discriminate biological from non biological motion provides indications that differences in emotion recognition may - at least to some degree - be related to more basic differences in processing biological motion per se. PMID- 21695267 TI - p53 Gene repair with zinc finger nucleases optimised by yeast 1-hybrid and validated by Solexa sequencing. AB - The tumor suppressor gene p53 is mutated or deleted in over 50% of human tumors. As functional p53 plays a pivotal role in protecting against cancer development, several strategies for restoring wild-type (wt) p53 function have been investigated. In this study, we applied an approach using gene repair with zinc finger nucleases (ZFNs). We adapted a commercially-available yeast one-hybrid (Y1H) selection kit to allow rapid building and optimization of 4-finger constructs from randomized PCR libraries. We thus generated novel functional zinc finger nucleases against two DNA sites in the human p53 gene, near cancer mutation 'hotspots'. The ZFNs were first validated using in vitro cleavage assays and in vivo episomal gene repair assays in HEK293T cells. Subsequently, the ZFNs were used to restore wt-p53 status in the SF268 human cancer cell line, via ZFN induced homologous recombination. The frequency of gene repair and mutation by non-homologous end-joining was then ascertained in several cancer cell lines, using a deep sequencing strategy. Our Y1H system facilitates the generation and optimisation of novel, sequence-specific four- to six-finger peptides, and the p53-specific ZFN described here can be used to mutate or repair p53 in genomic loci. PMID- 21695268 TI - The reconstruction of condition-specific transcriptional modules provides new insights in the evolution of yeast AP-1 proteins. AB - AP-1 proteins are transcription factors (TFs) that belong to the basic leucine zipper family, one of the largest families of TFs in eukaryotic cells. Despite high homology between their DNA binding domains, these proteins are able to recognize diverse DNA motifs. In yeasts, these motifs are referred as YRE (Yap Response Element) and are either seven (YRE-Overlap) or eight (YRE-Adjacent) base pair long. It has been proposed that the AP-1 DNA binding motif preference relies on a single change in the amino acid sequence of the yeast AP-1 TFs (an arginine in the YRE-O binding factors being replaced by a lysine in the YRE-A binding Yaps). We developed a computational approach to infer condition-specific transcriptional modules associated to the orthologous AP-1 protein Yap1p, Cgap1p and Cap1p, in three yeast species: the model yeast Saccharomyces cerevisiae and two pathogenic species Candida glabrata and Candida albicans. Exploitation of these modules in terms of predictions of the protein/DNA regulatory interactions changed our vision of AP-1 protein evolution. Cis-regulatory motif analyses revealed the presence of a conserved adenine in 5' position of the canonical YRE sites. While Yap1p, Cgap1p and Cap1p shared a remarkably low number of target genes, an impressive conservation was observed in the YRE sequences identified by Yap1p and Cap1p. In Candida glabrata, we found that Cgap1p, unlike Yap1p and Cap1p, recognizes YRE-O and YRE-A motifs. These findings were supported by structural data available for the transcription factor Pap1p (Schizosaccharomyces pombe). Thus, whereas arginine and lysine substitutions in Cgap1p and Yap1p proteins were reported as responsible for a specific YRE-O or YRE-A preference, our analyses rather suggest that the ancestral yeast AP-1 protein could recognize both YRE-O and YRE-A motifs and that the arginine/lysine exchange is not the only determinant of the specialization of modern Yaps for one motif or another. PMID- 21695269 TI - Novel arenavirus sequences in Hylomyscus sp. and Mus (Nannomys) setulosus from Cote d'Ivoire: implications for evolution of arenaviruses in Africa. AB - This study aimed to identify new arenaviruses and gather insights in the evolution of arenaviruses in Africa. During 2003 through 2005, 1,228 small mammals representing 14 different genera were trapped in 9 villages in south, east, and middle west of Cote d'Ivoire. Specimens were screened by pan-Old World arenavirus RT-PCRs targeting S and L RNA segments as well as immunofluorescence assay. Sequences of two novel tentative species of the family Arenaviridae, Menekre and Gbagroube virus, were detected in Hylomyscus sp. and Mus (Nannomys) setulosus, respectively. Arenavirus infection of Mus (Nannomys) setulosus was also demonstrated by serological testing. Lassa virus was not found, although 60% of the captured animals were Mastomys natalensis. Complete S RNA and partial L RNA sequences of the novel viruses were recovered from the rodent specimens and subjected to phylogenetic analysis. Gbagroube virus is a closely related sister taxon of Lassa virus, while Menekre virus clusters with the Ippy/Mobala/Mopeia virus complex. Reconstruction of possible virus-host co-phylogeny scenarios suggests that, within the African continent, signatures of co-evolution might have been obliterated by multiple host-switching events. PMID- 21695270 TI - Levels and determinants of inflammatory biomarkers in a Swiss population-based sample (CoLaus study). AB - OBJECTIVE: to assess the levels and determinants of interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF)-alpha and C-reactive protein (CRP) in a healthy Caucasian population. METHODS: population sample of 2884 men and 3201 women aged 35 to 75. IL-1beta, IL-6 and TNF-alpha were assessed by a multiplexed particle based flow cytometric assay and CRP by an immunometric assay. RESULTS: Spearman rank correlations between duplicate cytokine measurements (N = 80) ranged between 0.89 and 0.96; intra-class correlation coefficients ranged between 0.94 and 0.97, indicating good reproducibility. Among the 6085 participants, 2289 (37.6%), 451 (7.4%) and 43 (0.7%) had IL-1beta, IL-6 and TNF-alpha levels below detection limits, respectively. Median (interquartile range) for participants with detectable values were 1.17 (0.48-3.90) pg/ml for IL-1beta; 1.47 (0.71-3.53) pg/ml for IL-6; 2.89 (1.82-4.53) pg/ml for TNF-alpha and 1.3 (0.6-2.7) ng/ml for CRP. On multivariate analysis, greater age was the only factor inversely associated with IL-1beta levels. Male sex, increased BMI and smoking were associated with greater IL-6 levels, while no relationship was found for age and leisure-time PA. Male sex, greater age, increased BMI and current smoking were associated with greater TNF-alpha levels, while no relationship was found with leisure-time PA. CRP levels were positively related to age, BMI and smoking, and inversely to male sex and physical activity. CONCLUSION: Population-based levels of several cytokines were established. Increased age and BMI, and to a lesser degree sex and smoking, significantly and differentially impact cytokine levels, while leisure-time physical activity has little effect. PMID- 21695271 TI - Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway. AB - BACKGROUND: Phosphoinositide 3-kinase (PI3K)/Akt pathway is linked to the development of asthma. Anti-malarial drug artesunate is a semi-synthetic derivative of artemisinin, the principal active component of a medicinal plant Artemisia annua, and has been shown to inhibit PI3K/Akt activity. We hypothesized that artesunate may attenuate allergic asthma via inhibition of the PI3K/Akt signaling pathway. METHODOLOGY/PRINCIPAL FINDINGS: Female BALB/c mice sensitized and challenged with ovalbumin (OVA) developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and cytokine and chemokine levels. Lung tissues were examined for cell infiltration and mucus hypersecretion, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Artesunate dose-dependently inhibited OVA-induced increases in total and eosinophil counts, IL-4, IL-5, IL-13 and eotaxin levels in bronchoalveolar lavage fluid. It attenuated OVA-induced lung tissue eosinophilia and airway mucus production, mRNA expression of E-selectin, IL-17, IL-33 and Muc5ac in lung tissues, and airway hyperresponsiveness to methacholine. In normal human bronchial epithelial cells, artesunate blocked epidermal growth factor-induced phosphorylation of Akt and its downstream substrates tuberin, p70S6 kinase and 4E binding protein 1, and transactivation of NF-kappaB. Similarly, artesunate blocked the phosphorylation of Akt and its downstream substrates in lung tissues from OVA-challenged mice. Anti-inflammatory effect of artesunate was further confirmed in a house dust mite mouse asthma model. CONCLUSION/SIGNIFICANCE: Artesunate ameliorates experimental allergic airway inflammation probably via negative regulation of PI3K/Akt pathway and the downstream NF-kappaB activity. These findings provide a novel therapeutic value for artesunate in the treatment of allergic asthma. PMID- 21695272 TI - Endothelial and macrophage-specific deficiency of P38alpha MAPK does not affect the pathogenesis of atherosclerosis in ApoE-/- mice. AB - BACKGROUND: The p38alpha Mitogen-Activated Protein Kinase (MAPK) regulates stress and inflammation-induced cellular responses. Factors implicated in the development of atherosclerosis including modified low-density lipoprotein (LDL), cytokines and even shear stress induce p38 activation in endothelial cells and macrophages, which may be important for plaque formation. This study investigates the effects of endothelial- and macrophage-specific deficiency of p38alpha in atherosclerosis development, in Apolipoprotein E deficient (ApoE(-/-)) mice. METHODOLOGY/PRINCIPAL FINDINGS: ApoE(-/-) mice with macrophage or endothelial cell-specific p38alpha deficiency were fed a high cholesterol diet (HCD) for 10 weeks and atherosclerosis development was assessed by histological and molecular methods. Surprisingly, although p38alpha-deficiency strongly attenuated oxidized LDL-induced expression of molecules responsible for monocyte recruitment in endothelial cell cultures in vitro, endothelial-specific p38alpha ablation in vivo did not affect atherosclerosis development. Similarly, macrophage specific deletion of p38alpha did not affect atherosclerotic plaque development in ApoE(-/ ) mice. CONCLUSIONS: Although previous studies implicated p38alpha signaling in atherosclerosis, our in vivo experiments suggest that p38alpha function in endothelial cells and macrophages does not play an important role in atherosclerotic plaque formation in ApoE deficient mice. PMID- 21695273 TI - Prebiotic effects of wheat arabinoxylan related to the increase in bifidobacteria, Roseburia and Bacteroides/Prevotella in diet-induced obese mice. AB - BACKGROUND: Alterations in the composition of gut microbiota--known as dysbiosis- has been proposed to contribute to the development of obesity, thereby supporting the potential interest of nutrients targeting the gut with beneficial effect for host adiposity. We test the ability of a specific concentrate of water extractable high molecular weight arabinoxylans (AX) from wheat to modulate both the gut microbiota and lipid metabolism in high-fat (HF) diet-induced obese mice. METHODOLOGY/PRINCIPAL FINDINGS: Mice were fed either a control diet (CT) or a HF diet, or a HF diet supplemented with AX (10% w/w) during 4 weeks. AX supplementation restored the number of bacteria that were decreased upon HF feeding, i.e. Bacteroides-Prevotella spp. and Roseburia spp. Importantly, AX treatment markedly increased caecal bifidobacteria content, in particular Bifidobacterium animalis lactis. This effect was accompanied by improvement of gut barrier function and by a lower circulating inflammatory marker. Interestingly, rumenic acid (C18:2 c9,t11) was increased in white adipose tissue due to AX treatment, suggesting the influence of gut bacterial metabolism on host tissue. In parallel, AX treatment decreased adipocyte size and HF diet-induced expression of genes mediating differentiation, fatty acid uptake, fatty acid oxidation and inflammation, and decreased a key lipogenic enzyme activity in the subcutaneous adipose tissue. Furthermore, AX treatment significantly decreased HF induced adiposity, body weight gain, serum and hepatic cholesterol accumulation and insulin resistance. Correlation analysis reveals that Roseburia spp. and Bacteroides/Prevotella levels inversely correlate with these host metabolic parameters. CONCLUSIONS/SIGNIFICANCE: Supplementation of a concentrate of water extractable high molecular weight AX in the diet counteracted HF-induced gut dysbiosis together with an improvement of obesity and lipid-lowering effects. We postulate that hypocholesterolemic, anti-inflammatory and anti-obesity effects are related to changes in gut microbiota. These data support a role for wheat AX as interesting nutrients with prebiotic properties related to obesity prevention. PMID- 21695274 TI - A novel stress-associated protein 'AtSAP10' from Arabidopsis thaliana confers tolerance to nickel, manganese, zinc, and high temperature stress. AB - We describe here the functional characterization of a novel AtSAP10, a member of the Stress Associated Protein (SAP) gene family, from Arabidopsis thaliana ecotype Columbia. AtSAP10 contains an A20 and AN1 zinc-finger domain at the N- and C-terminal, respectively. Arabidopsis SAP10 showed differential regulation by various abiotic stresses such as heavy metals and metalloids (Ni, Cd, Mn, Zn, and As), high and low temperatures, cold, and ABA. Overexpression of AtSAP10 in Arabidopsis conferred strong tolerance to heavy metals such as Ni, Mn, and Zn and to high temperature stress. AtSAP10 transgenic plants under these stress conditions grew green and healthy, attained several-fold more biomass, and had longer roots as compared to wild type plants. Further, while these transgenic plants accumulated significantly greater amounts of Ni and Mn in both shoots and root tissues, there was no significant difference in the accumulation of Zn. AtSAP10 promoter-GUS fusion studies revealed a root and floral organ-specific expression of AtSAP10. Overexpression of AtSAP10-GFP fusion protein showed the localization in both nucleus and cytoplasm. Taken together, these results showed that AtSAP10 is a potentially useful candidate gene for engineering tolerance to heavy metals and to abiotic stress in cultivated plants. PMID- 21695275 TI - Large differences in publicly visible health behaviours across two neighbourhoods of the same city. AB - BACKGROUND: There are socioeconomic disparities in the likelihood of adopting unhealthy behaviours, and success at giving them up. This may be in part because people living in deprived areas are exposed to greater rates of unhealthy behaviour amongst those living around them. Conventional self-report surveys do not capture these differences in exposure, and more ethological methods are required in order to do so. METHODOLOGY/PRINCIPAL FINDINGS: We performed 12 hours of direct behavioural observation in the streets of two neighbourhoods of the same city which were similar in most regards, except that one was much more socioeconomically deprived than the other. There were large differences in the publicly visible health behaviours observed. In the deprived neighbourhood, we observed 266 more adults smoking (rate ratio 3.44), 53 more adults drinking alcohol (rate ratio not calculable), and 38 fewer adults running (rate ratio 0.23), than in the affluent neighbourhood. We used data from the Health Survey for England to calculate the differences we ought to expect to have seen given the individual-level socioeconomic characteristics of the residents. The observed disparities between the two neighbourhoods were considerably greater than this null model predicted. There were also different patterns of smoking in proximity to children in the two neighbourhoods. CONCLUSIONS/SIGNIFICANCE: The differences in observed smoking, drinking alcohol, and physical activity between these two neighbourhoods of the same city are strikingly large, and for smoking and running, their magnitude suggests substantial area effects above and beyond the compositional differences between the neighbourhoods. Because of these differences, individuals residing in deprived areas are exposed to substantially more smoking and public drinking, and less physical activity, as they go about their daily lives, than their affluent peers. This may have important implications for the initiation and maintenance of health behaviours, and the persistence of health inequalities. PMID- 21695276 TI - In cortical neurons HDAC3 activity suppresses RD4-dependent SMRT export. AB - The transcriptional corepressor SMRT controls neuronal responsiveness of several transcription factors and can regulate neuroprotective and neurogenic pathways. SMRT is a multi-domain protein that complexes with HDAC3 as well as being capable of interactions with HDACs 1, 4, 5 and 7. We previously showed that in rat cortical neurons, nuclear localisation of SMRT requires histone deacetylase activity: Inhibition of class I/II HDACs by treatment with trichostatin A (TSA) causes redistribution of SMRT to the cytoplasm, and potentiates the activation of SMRT-repressed nuclear receptors. Here we have sought to identify the HDAC(s) and region(s) of SMRT responsible for anchoring it in the nucleus under normal circumstances and for mediating nuclear export following HDAC inhibition. We show that in rat cortical neurons SMRT export can be triggered by treatment with the class I-preferring HDAC inhibitor valproate and the HDAC2/3-selective inhibitor apicidin, and by HDAC3 knockdown, implicating HDAC3 activity as being required to maintain SMRT in the nucleus. HDAC3 interaction with SMRT's deacetylation activation domain (DAD) is known to be important for activation of HDAC3 deacetylase function. Consistent with a role for HDAC3 activity in promoting SMRT nuclear localization, we found that inactivation of SMRT's DAD by deletion or point mutation triggered partial redistribution of SMRT to the cytoplasm. We also investigated whether other regions of SMRT were involved in mediating nuclear export following HDAC inhibition. TSA- and valproate-induced SMRT export was strongly impaired by deletion of its repression domain-4 (RD4). Furthermore, over expression of a region of SMRT containing the RD4 region suppressed TSA-induced export of full-length SMRT. Collectively these data support a model whereby SMRT's RD4 region can recruit factors capable of mediating nuclear export of SMRT, but whose function and/or recruitment is suppressed by HDAC3 activity. Furthermore, they underline the fact that HDAC inhibitors can cause reorganization and redistribution of corepressor complexes. PMID- 21695277 TI - Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials. AB - BACKGROUND: Adjuvant trastuzumab therapy has yielded conflicting results for overall survival, concerns about central nervous system (CNS) metastasis, and questions about optimal schedule. Therefore, we carried out a meta-analysis to assess the benefits of concurrent or sequential trastuzumab with adjuvant chemotherapy for early breast cancer patients with HER2-positive tumors. METHODS: Computerized and manual searches were performed to identify randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in HER2 positive early breast cancer patients. Odds ratios were used to estimate the association between the addition of trastuzumab to adjuvant chemotherapy and various survival outcomes. The fixed-effects or random-effects model was used to combine data. FINDINGS: With six eligible studies identified, this analysis demonstrated that patients with HER2-positive breast cancer derived benefit in disease-free survival, overall survival, locoregional recurrence and distant recurrence (all P<0.001) from the addition of trastuzumab to adjuvant chemotherapy, whereas trastuzumab did worse in CNS recurrence as compared to the control group (P = 0.018). Furthermore, concomitant use of trastuzumab significantly lowered the hazard of death (P<0.001) but bore a higher incidence of CNS recurrence (P = 0.010), while statistical significance failed to be discerned for either overall survival (P = 0.069) or CNS metastasis (P = 0.374) between the sequential and observation arms. CONCLUSION: This analysis verifies the efficacy of trastuzumab in the adjuvant setting. Additionally, our findings indirectly corroborate the superiority of concurrent trastuzumab to sequential use and also illuminate that prolonged survival is the possible reason for the higher incidence of CNS with trastuzumab versus observation. PMID- 21695278 TI - Mitochondrial DNA backgrounds might modulate diabetes complications rather than T2DM as a whole. AB - Mitochondrial dysfunction has been implicated in rare and common forms of type 2 diabetes (T2DM). Additionally, rare mitochondrial DNA (mtDNA) mutations have been shown to be causal for T2DM pathogenesis. So far, many studies have investigated the possibility that mtDNA variation might affect the risk of T2DM, however, when found, haplogroup association has been rarely replicated, even in related populations, possibly due to an inadequate level of haplogroup resolution. Effects of mtDNA variation on diabetes complications have also been proposed. However, additional studies evaluating the mitochondrial role on both T2DM and related complications are badly needed. To test the hypothesis of a mitochondrial genome effect on diabetes and its complications, we genotyped the mtDNAs of 466 T2DM patients and 438 controls from a regional population of central Italy (Marche). Based on the most updated mtDNA phylogeny, all 904 samples were classified into 57 different mitochondrial sub-haplogroups, thus reaching an unprecedented level of resolution. We then evaluated whether the susceptibility of developing T2DM or its complications differed among the identified haplogroups, considering also the potential effects of phenotypical and clinical variables. MtDNA backgrounds, even when based on a refined haplogroup classification, do not appear to play a role in developing T2DM despite a possible protective effect for the common European haplogroup H1, which harbors the G3010A transition in the MTRNR2 gene. In contrast, our data indicate that different mitochondrial haplogroups are significantly associated with an increased risk of specific diabetes complications: H (the most frequent European haplogroup) with retinopathy, H3 with neuropathy, U3 with nephropathy, and V with renal failure. PMID- 21695279 TI - Phos-tag-based analysis of myosin regulatory light chain phosphorylation in human uterine myocytes. AB - BACKGROUND: The 'phosphate-binding tag' (phos-tag) reagent enables separation of phospho-proteins during SDS-PAGE by impeding migration proportional to their phosphorylation stoichiometry. Western blotting can then be used to detect and quantify the bands corresponding to the phospho-states of a target protein. We present a method for quantification of data regarding phospho-states derived from phos-tag SDS-PAGE. The method incorporates corrections for lane-to-lane loading variability and for the effects of drug vehicles thus enabling the comparison of multiple treatments by using the untreated cellular set-point as a reference. This method is exemplified by quantifying the phosphorylation of myosin regulatory light chain (RLC) in cultured human uterine myocytes. METHODOLOGY/PRINCIPAL FINDINGS: We have evaluated and validated the concept that, when using an antibody (Ab) against the total-protein, the sum of all phosphorylation states in a single lane represents a 'closed system' since all possible phospho-states and phosphoisotypes are detected. Using this approach, we demonstrate that oxytocin (OT) and calpeptin (Calp) induce RLC kinase (MLCK)- and rho-kinase (ROK)-dependent enhancements in phosphorylation of RLC at T18 and S19. Treatment of myocytes with a phorbol ester (PMA) induced phosphorylation of S1 RLC, which caused a mobility shift in the phos-tag matrices distinct from phosphorylation at S19. CONCLUSION/SIGNIFICANCE: We have presented a method for analysis of phospho-state data that facilitates quantitative comparison to a reference control without the use of a traditional 'loading' or 'reference' standard. This analysis is useful for assessing effects of putative agonists and antagonists where all phospho-states are represented in control and experimental samples. We also demonstrated that phosphorylation of RLC at S1 is inducible in intact uterine myocytes, though the signal in the resting samples was not sufficiently abundant to allow quantification by the approach used here. PMID- 21695280 TI - Pathways of distinction analysis: a new technique for multi-SNP analysis of GWAS data. AB - Genome-wide association studies (GWAS) have become increasingly common due to advances in technology and have permitted the identification of differences in single nucleotide polymorphism (SNP) alleles that are associated with diseases. However, while typical GWAS analysis techniques treat markers individually, complex diseases (cancers, diabetes, and Alzheimers, amongst others) are unlikely to have a single causative gene. Thus, there is a pressing need for multi-SNP analysis methods that can reveal system-level differences in cases and controls. Here, we present a novel multi-SNP GWAS analysis method called Pathways of Distinction Analysis (PoDA). The method uses GWAS data and known pathway-gene and gene-SNP associations to identify pathways that permit, ideally, the distinction of cases from controls. The technique is based upon the hypothesis that, if a pathway is related to disease risk, cases will appear more similar to other cases than to controls (or vice versa) for the SNPs associated with that pathway. By systematically applying the method to all pathways of potential interest, we can identify those for which the hypothesis holds true, i.e., pathways containing SNPs for which the samples exhibit greater within-class similarity than across classes. Importantly, PoDA improves on existing single-SNP and SNP-set enrichment analyses, in that it does not require the SNPs in a pathway to exhibit independent main effects. This permits PoDA to reveal pathways in which epistatic interactions drive risk. In this paper, we detail the PoDA method and apply it to two GWAS: one of breast cancer and the other of liver cancer. The results obtained strongly suggest that there exist pathway-wide genomic differences that contribute to disease susceptibility. PoDA thus provides an analytical tool that is complementary to existing techniques and has the power to enrich our understanding of disease genomics at the systems-level. PMID- 21695281 TI - Towards an evolutionary model of transcription networks. AB - DNA evolution models made invaluable contributions to comparative genomics, although it seemed formidable to include non-genomic features into these models. In order to build an evolutionary model of transcription networks (TNs), we had to forfeit the substitution model used in DNA evolution and to start from modeling the evolution of the regulatory relationships. We present a quantitative evolutionary model of TNs, subjecting the phylogenetic distance and the evolutionary changes of cis-regulatory sequence, gene expression and network structure to one probabilistic framework. Using the genome sequences and gene expression data from multiple species, this model can predict regulatory relationships between a transcription factor (TF) and its target genes in all species, and thus identify TN re-wiring events. Applying this model to analyze the pre-implantation development of three mammalian species, we identified the conserved and re-wired components of the TNs downstream to a set of TFs including Oct4, Gata3/4/6, cMyc and nMyc. Evolutionary events on the DNA sequence that led to turnover of TF binding sites were identified, including a birth of an Oct4 binding site by a 2nt deletion. In contrast to recent reports of large interspecies differences of TF binding sites and gene expression patterns, the interspecies difference in TF-target relationship is much smaller. The data showed increasing conservation levels from genomic sequences to TF-DNA interaction, gene expression, TN, and finally to morphology, suggesting that evolutionary changes are larger at molecular levels and smaller at functional levels. The data also showed that evolutionarily older TFs are more likely to have conserved target genes, whereas younger TFs tend to have larger re-wiring rates. PMID- 21695282 TI - Two evolutionary histories in the genome of rice: the roles of domestication genes. AB - Genealogical patterns in different genomic regions may be different due to the joint influence of gene flow and selection. The existence of two subspecies of cultivated rice provides a unique opportunity for analyzing these effects during domestication. We chose 66 accessions from the three rice taxa (about 22 each from Oryza sativa indica, O. sativa japonica, and O. rufipogon) for whole-genome sequencing. In the search for the signature of selection, we focus on low diversity regions (LDRs) shared by both cultivars. We found that the genealogical histories of these overlapping LDRs are distinct from the genomic background. While indica and japonica genomes generally appear to be of independent origin, many overlapping LDRs may have originated only once, as a result of selection and subsequent introgression. Interestingly, many such LDRs contain only one candidate gene of rice domestication, and several known domestication genes have indeed been "rediscovered" by this approach. In summary, we identified 13 additional candidate genes of domestication. PMID- 21695283 TI - Aliskiren/amlodipine combination for the treatment of hypertension. AB - The challenge of managing hypertension is exemplified by the limited success of monotherapy and necessity for multiple drug regimens targeting complimentary pathways. Recent evidence suggests that combination therapy including angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs) provides blood pressure control while reducing cardiovascular mortality and morbidity over ACE inhibitor/diuretic therapy. However, CCBs, ACE inhibitors and angiotensin receptor blockers all increase plasma renin activity (PRA), promoting angiotensin I accumulation and angiotensin II production through alternative pathways. While the clinical ramifications of this and other compensatory pathways activating the renin-angiotensin-aldosterone system are unclear, the recently approved aliskiren/amlodipine antihypertensive combination pill has been shown to decrease PRA via aliskiren's direct inhibition of renin. The purpose of this monograph is to review the mechanisms of action, pharmacodynamics, and safety and efficacy profile of the aliskiren/amlodipine combination pill. PMID- 21695284 TI - Tesamorelin: a novel therapeutic option for HIV/HAART-associated increased visceral adipose tissue. AB - Metabolic complications are common in treated HIV patients. Their etiology is multifactorial and the development of increased abdominal fat contributes to cardiovascular risk and impaired quality of life. Treated patients with fat mass distribution changes have relative growth hormone deficiency. Both pharmacologic and physiologic doses of growth hormone reduce the increased visceral adipose tissue and improve the associated abnormal lipid profiles in short-term studies. However, impaired glucose homeostasis changes and significant musculoskeletal toxicity occurs. A novel growth hormone-releasing factor analogue, tesamorelin, provides a physiologic means of restoring a normal growth hormone secretion profile and reduces increased visceral adipose tissue, improving both abnormal lipid profiles and patients' quality of life. Glucose homeostasis is generally well maintained. Cessation of treatment with either growth hormone or tesamorelin results in a prompt return of truncal obesity. Management strategies for the long term maintenance of the reduced visceral adipose tissue have not yet been clarified and long-term effects on decreasing cardiovascular risks and improving clinical outcomes are uncertain. PMID- 21695285 TI - Biosimilars for the treatment of infectious diseases: the case of biosimilar interferons. AB - Biopharmaceuticals are the fastest-growing and the most expensive among prescription drugs. A biopharmaceutical drug can cost a patient between USD 25,000 and USD 120,000 a year. Such sophisticated medicines are critical options for many unmet medical needs where no sufficient therapies are available, and the demand for lower-cost biopharmaceuticals is tremendous. Biosimilars are similar to, but not the same as, innovative biopharmaceuticals. Since they are developed following patent expiration of innovative medicines, biosimilars represent a potentially lower-cost option to patients and healthcare providers. With a broad range of biopharmaceuticals going off patent, the biosimilars field became the focus of attention of drug developers, healthcare providers, patient advocate groups and politicians. Regulatory and marketing issues for biosimilars have been discussed in several recent reviews. The main focus of this article is the scientific spects of interferon-alpha biosimilars and next-generation interferons for the treatment of hepatitis C. PMID- 21695287 TI - COMT genetic variants and pain. AB - Catechol-O-methyltransferase (COMT) metabolizes catechol neurotransmitters dopamine, noradrenaline and adrenaline that are involved in various physiological functions including mood, cognition and stress response. Human pain is closely related to all these functions. The gene encoding the COMT enzyme (COMT) has functional polymorphisms that contribute to the interindividual variability in human pain phenotypes such as pain sensitivity, chronicity, severity and response to pain medicine. This review outlines pain symptoms and syndromes that are affected by COMT functional variation, summarizes findings of genetic association studies and provides critical outlook on reported results. Although the exact mechanism of the effect of COMT on human pain is currently uncertain, it has a clear potential to predict clinical outcomes and identify patients at risk for developing pain conditions. PMID- 21695286 TI - Nanotechnology in ocular delivery: current and future directions. AB - Our knowledge in the field of ocular drug delivery is rapidly expanding. An increase in the understanding of ocular drug absorption and disposition vis-a-vis developments in nanotechnology has led to the emergence of many of the nanotechnology-based ocular drug delivery systems including nanoparticles, microemulsions, liposomes, solid lipid nanoparticles, light-sensitive nanocarrier systems, etc. The need to develop effective treatments for posterior eye segment diseases is more important than surface delivery. Treatment of blinding diseases of the eye, such as proliferative retinopathy or macular degeneration, requires effective and safe delivery of drugs to posterior eye segment tissues, and recent advances in nanotechnology have demonstrated successful outcomes. Nanoscientists should focus their efforts on nano-ophthalmology. This review describes the current status and progress made so far, and the course that needs to be pursued in the future. PMID- 21695288 TI - A report from the 21st European Congress of Clinical Microbiology and Infectious Diseases and the 27th International Congress of Chemotherapy (May 7-10, 2011 - Milan, Italy). PMID- 21695289 TI - Aluminium complexes containing bidentate and symmetrical tridentate pincer type pyrrolyl ligands: synthesis, reactions and ring opening polymerization. AB - A series of aluminium derivatives containing substituted bidentate and symmetrical tridentate pyrrolyl ligands, [C(4)H(3)NH(2-CH(2)NH(t)Bu)] and [C(4)H(2)NH(2,5-CH(2)NH(t)Bu)(2)], in toluene or diethyl ether were synthesized. Their reactivity and application for the ring opening polymerization of epsilon caprolactone have been investigated. The reaction of AlMe(3) with one equiv. of [C(4)H(3)NH(2-CH(2)NH(t)Bu)] in toluene at room temperature affords [C(4)H(3)N(2 CH(2)NH(t)Bu)]AlMe(2) (1) in 70% yield by elimination of one equiv. of methane. Interestingly, while reacting AlMe(3) with one equiv. of [C(4)H(3)NH(2 CH(2)NH(t)Bu)] in toluene at 0 degrees C followed by refluxing at 100 degrees C, [{C(4)H(3)N(2-CH(2)N(t)Bu)}AlMe](2) (2) has been isolated via fractional recrystalliztion in 30% yield. Similarly, reacting AlMe(3) with two equiv. of C(4)H(3)NH(2-CH(2)NH(t)Bu) generates [C(4)H(3)N(2-CH(2)NH(t)Bu)](2)AlMe (3) in a moderate yield. Furthermore, complex 1 can be transformed to an aluminium alkoxide derivative, [C(4)H(3)N(2-CH(2)NH(t)Bu)][OC(6)H(2)(-2,6-(t)Bu(2)-4 Me)]AlMe (4) by reacting 1 with one equiv. of HOC(6)H(2)(-2,6-(t)Bu(2)-4-Me) in toluene via the elimination of one equiv. of methane. The reaction of AlR(3) with one equiv. of [C(4)H(2)NH(2,5-CH(2)NH(t)Bu)(2)] in toluene at room temperature affords [C(4)H(2)N(2,5-CH(2)NH(t)Bu)(2)]AlR(2) (5, R = Me; 6, R = Et) in moderate yield. Surprisingly, from the reaction of two equiv. of [C(4)H(2)NH(2,5 CH(2)NH(t)Bu)(2)] with LiAlH(4) in diethyl ether at 0 degrees C, a novel complex, [C(4)H(2)N(2-CH(2)N(t)Bu)(5-CH(2)NH(t)Bu)](2)AlLi (7) has been isolated after repeating re-crystallization. Furthermore, reacting one equiv. of C(4)H(2)NH(2,5-CH(2)NH(t)Bu)(2) with AlH(3).NMe(3) in diethyl ether generates an aluminium dihydride complex, [C(4)H(2)N(2,5-CH(2)NH(t)Bu)(2)]AlH(2) (8), in high yield. Additionally, treating 8 with one equiv. of HOC(6)H(2)(-2,6-(t)Bu(2)-4-Me) in methylene chloride produces [C(4)H(2)N(2,5-CH(2)NH(t)Bu)(2)][OC(6)H(2)(-2,6 (t)Bu(2)-4-Me)]AlH (9) with the elimination of one equiv. of H(2). The aluminium alkoxide complex 4 shows moderate reactivity toward the ring opening polymerization of epsilon-caprolatone in toluene. PMID- 21695290 TI - Using a co-culture microsystem for cell migration under fluid shear stress. AB - We have successfully developed a microsystem to co-cultivate two types of cells with a minimum defined gap of 50 MUm, and to quantitatively study the impact of fluid shear stress on the mutual influence of cell migration velocity and distance. We used the hydrostatic pressure to seed two different cells, endothelial cells (ECs) and smooth muscle cells (SMCs), on opposite sides of various gap sizes (500 MUm, 200 MUm, 100 MUm, and 50 MUm). After cultivating the cells for 12 h and peeling the co-culture microchip from the culture dish, we studied the impacts of gap size on the migration of either cell type in the absence or presence of fluid shear stress (7 dyne cm(-2) and 12 dyne cm(-2)) influence. We found that both gap size and shear stress have profound influence on cell migration. Smaller gap sizes (100 MUm and 50 MUm) significantly enhanced cell migration, suggesting a requirement of an effective concentration of released factor(s) by either cell type in the gap region. Flow-induced shear stress delayed the migration onset of either cell type in a dose-dependent manner regardless of the gap size. Moreover, shear stress-induced decrease of cell migration becomes evident when the gap size was 500 MUm. We have developed a co culture microsystem for two kinds of cells and overcome the conventional difficulties in observation and mixed culture, and it would have more application for bio-manipulation and tissue repair engineering. PMID- 21695291 TI - Optical imaging in tissue with X-ray excited luminescent sensors. AB - We report a high-spatial resolution imaging technique to measure optical absorption and detect chemical and physical changes on surfaces embedded in thick tissue. Developing sensors to measure chemical concentrations on implanted surfaces through tissue is an important challenge for analytical chemistry and biomedical imaging. Tissue scattering dramatically reduces the resolution of optical imaging. In contrast, X-rays provide high spatial resolution imaging through tissue but do not measure chemical concentrations. We describe a hybrid technique which uses a scanning X-ray beam to irradiate Gd(2)O(2)S scintillators and detect the resulting visible luminescence through the tissue. The amount of light collected is modulated by optical absorption in close proximity to the luminescence source. By scanning the X-ray beam, and measuring total amount of light collected, one can measure the local absorption near scintillators at a resolution limited by the width of luminescence source (i.e. the width of the X ray excitation beam). For proof of principle, a rectangular 1.7 mm scanning X-ray beam was used to excite a single layer of 8 MUm Gd(2)O(2)S particles, and detect the absorption of 5 nm thick silver island film through 10 mm of pork. Lifetime and spectroscopic measurements, as well changing the refractive index of the surroundings indicate that the silver reduces the optical signal through attenuated total internal reflection. The technique was used to image the dissolution of regions of the silver island film which were exposed to 1 mM of H(2)O(2) through 1 cm of pork tissue. PMID- 21695292 TI - PPh3-catalyzed synthesis of dicyano-2-methylenebut-3-enoates as efficient dienes in catalytic asymmetric inverse-electron-demand Diels-Alder reaction. AB - We present here the synthesis of dicyano-2-methylenebut-3-enoates as novel Diels Alder dienes through an efficient PPh(3)-catalyzed strategy, and an unprecedented PPh(3)-catalyzed addition/all-carbon-based asymmetric inverse-electron-demand Diels-Alder sequence reaction is disclosed for the first time. PMID- 21695293 TI - Influence of excited state aromaticity in the lowest excited singlet states of fulvene derivatives. AB - The absorption spectra and excited state dipole moments of four differently substituted fulvenes have been investigated both experimentally and computationally. The results reveal that the excited state dipole moment of fulvenes reverses in the first excited singlet state when compared to the ground state. The oppositely polarized electron density distributions, which dominate the ground state and the first excited singlet state of fulvenes, respectively, reflect the reversed pi-electron counting rules for aromaticity in the two states (4n + 2 vs. 4n, respectively). The results show that substituents indeed influence the polarity of fulvenes in the two states, however, cooperative interactions between the substituents and the fulvene moiety are most pronounced in the ground state. PMID- 21695294 TI - Synthesis of anatase TiO2 rods with dominant reactive {010} facets for the photoreduction of CO2 to CH4 and use in dye-sensitized solar cells. AB - Single crystalline anatase TiO(2) rods with dominant reactive {010} facets are directly synthesized by hydrothermally treating Cs(0.68)Ti(1.83)O(4)/H(0.68)Ti(1.83)O(4) particles. The nanosized rods show a comparable conversion efficiency in dye-sensitized solar cells (DSSCs), and a superior photocatalytic conversion of CO(2) into methane to the benchmark P25 TiO(2) nanocrystals. PMID- 21695295 TI - Adsorption of collagen onto single walled carbon nanotubes: a molecular dynamics investigation. AB - Classical molecular dynamics (MD) simulation has been carried out to understand the adsorption of collagen like peptides onto single walled carbon nanotubes (CNT) in an aqueous environment. It is observed that the triple helical structure of all the model collagen like peptides (CPs) has been unaltered upon adsorption onto CNT. The model CPs do not wrap around the CNT, however, the axis of the triple helix subtends a cross angle with respect to the axis of the CNT. The interaction between the CPs and CNT as well as that between the CPs and water molecules was observed by MD simulation snapshots. The inherent nature of the interaction of CPs with CNT facilitates the penetration of CPs into the water/CNT interface. During this process, water molecules trapped between the CPs and CNT are appreciably displaced. Although, hydrophobic-hydrophobic interaction is crucial for the interaction, the role of piR (R = OH and NH(2)) interactions are also observed from the geometrical parameters. The sequence specific interaction of CPs with CNT is evident from the results. It is found that the length of the CNT, curvature of the CNT and length of the CPs do not significantly influence interaction between the two systems. Overall the findings provide important information for the development of nanocomposite materials from collagen and CNT. PMID- 21695296 TI - New water-soluble Mn-porphyrin with catalytic activity for superoxide dismutation and peroxynitrite decomposition. AB - We have synthesized a new water-soluble cationic Mn-porphyrin with catalytic activity for both superoxide dismutation and peroxynitrite decomposition. The resulting Mn-porphyrin also showed higher stability for reactive oxygen species such as hydrogen peroxide and lower cytotoxicity, when compared with a control normal Mn-porphyrin. Furthermore, the new porphyrin recovered the viability of lipopolysaccharide-stimulated macrophage RAW 264.7 cells but the control Mn porphyrin did not. PMID- 21695307 TI - Direct observation and spectroscopy of nanoscaled carboxylated carbonaceous fragments coated on carbon nanotubes. AB - The coating of nanoscaled carboxylated carbonaceous fragments on carbon nanotubes (CNTs) has been directly observed in chemical imaging with a concurrent identification of their electronic structure by scanning transmission X-ray microscopy. The coating also shields the detection of the CNT/nanoparticle interaction. PMID- 21695306 TI - Direct analysis of camptothecin from Nothapodytes nimmoniana by desorption electrospray ionization mass spectrometry (DESI-MS). AB - Desorption electrospray ionization was employed for fast and direct ambient detection of the anti-tumor drug, camptothecin, and its derivative, 9 methoxycamptothecin in Nothapodytes nimmoniana. Different parts of the plant such as leaves, stems and bark were examined. The ion intensities suggest that the concentration in bark is higher than that in the leaves and stems. The method does not require any sample preparation or preseparation. The identity of the alkaloids was further confirmed by tandem mass spectrometry. PMID- 21695308 TI - Self-assembly of an iron(II)-based M5L6 metallosupramolecular cage. AB - A pentanuclear M(5)L(6) coordination cage is self-assembled in solution from a rigid linear heteroditopic phen-tpy ligand and an iron (II) salt. PMID- 21695309 TI - Discrimination between 5-hydroxymethylcytosine and 5-methylcytosine by a chemically designed peptide. AB - An artificial phosphopeptide recognized the difference between methylated and hydroxymethylated cytosines in DNA. The Sp1 zinc finger peptide substituted by phosphotyrosine effectively discriminated between 5-methylcytosine, 5 hydroxymethylcytosine ((hm)C) and unmethylated cytosine. The DNA recognition properties of the peptide differ from those of other chemicals that detect (hm)C. PMID- 21695310 TI - Ultrasensitive DNA detection based on Au nanoparticles and isothermal circular double-assisted electrochemiluminescence signal amplification. AB - We report here an ultrasensitive DNA detection approach which combines Au NPs enhanced electrochemiluminescence (ECL) of the CdS nanocrystal (NC) film with isothermal circular amplification reaction of polymerase and nicking endonuclease (NEase). By the double-signal amplification, this approach could sensitively respond down to 5 aM DNA. PMID- 21695311 TI - Ester hydrogenation catalyzed by Ru-CNN pincer complexes. AB - We report new Ru-CNN pincer catalysts for ester hydrogenation under mild conditions. PMID- 21695312 TI - Highly diastereo- and enantioselective synthesis of syn-beta-substituted tryptophans via asymmetric Michael addition of a chiral equivalent of nucleophilic glycine and sulfonylindoles. AB - The asymmetric synthesis of syn-beta-substituted tryptophan derivatives was carried out by the Michael addition of chiral equivalent of nucleophilic glycine with sulfonylindoles, and high diastereo- and enantioselectivities were achieved. The resulting adducts were readily converted to syn-beta-substituted tryptophans in 96% yield, indicating that the proposed method is a highly efficient route to chiral syn-beta-substituted tryptophans. PMID- 21695313 TI - Reversible hydrocarbon/perfluorocarbon phase-switching of [Ru(bipy)3]2+ driven by supramolecular heteromeric fluorous carboxylate-carboxylic acid H-bond interactions. AB - The Ru(bipy)(3) dication is efficiently and reversibly transferred into perfluorocarbons due to the formation of a highly fluorophillic hydrogen-bonded fluorous carboxylate-carboxylic acid counter-anion, whilst retaining key luminescence and photosensitizer characteristics, for example in singlet oxygen production. PMID- 21695314 TI - Ir-catalysed formation of C-F bonds. From allylic alcohols to alpha fluoroketones. AB - A novel iridium-catalysed tandem isomerisation/C-F bond formation from allylic alcohols and Selectfluor(r) to prepare alpha-fluorinated ketones as single constitutional isomers is reported. PMID- 21695315 TI - Direct substitution of the hydroxy group with highly functionalized nitrogen nucleophiles catalyzed by Au(III). AB - A direct catalytic substitution of various allylic and benzylic alcohols with synthetically useful, but acid-sensitive Boc, Bus, and Dios protected amine nucleophiles, which have not been well utilized for Lewis acid catalysis, with various functionalities (OTBS, OTHP, etc.) was efficiently catalyzed by 1 mol% of Au(III) under mild conditions. PMID- 21695316 TI - An amphiphilic pyrene sheet for selective functionalization of graphene. AB - We have demonstrated that the aromatic amphiphile consisting of a hydrophilic dendron and an aromatic segment with a planar conformation can selectively exfoliate graphite powder into single- and double-layer graphene sheets in aqueous solution through hydrophilic functionalization of graphene surfaces. PMID- 21695318 TI - Photoinduced work function changes by isomerization of a densely packed azobenzene-based SAM on Au: a joint experimental and theoretical study. AB - Responsive monolayers are key building blocks for future applications in organic and molecular electronics in particular because they hold potential for tuning the physico-chemical properties of interfaces, including their energetics. Here we study a photochromic SAM based on a conjugated azobenzene derivative and its influence on the gold work function (Phi(Au)) when chemisorbed on its surface. In particular we show that the Phi(Au) can be modulated with external stimuli by controlling the azobenzene trans/cis isomerization process. This phenomenon is characterized experimentally by four different techniques, kelvin probe, kelvin probe force microscopy, electroabsorption spectroscopy and ultraviolet photoelectron spectroscopy. The use of different techniques implies exposing the SAM to different measurement conditions and different preparation methods, which, remarkably, do not alter the observed work function change (Phi(trans)-Phi(cis)). Theoretical calculations provided a complementary insight crucial to attain a deeper knowledge on the origin of the work function photo-modulation. PMID- 21695317 TI - Shape switching of hollow layer-by-layer hydrogel microcontainers. AB - We present a novel type of ultrathin hydrogel microcapsules with pH-triggered shape switch. The capsules are produced as hollow hydrogel replicas of cubical inorganic templates and capable of keeping cubical geometries at neutral pH but transform into bulged structures at basic pH. PMID- 21695319 TI - Synthesis and structure of A4V6[Te2(4+)Te6+]O24 (A = K, Rb)-two new quaternary mixed-valent tellurium oxides. AB - Two new mixed-valent tellurium oxides with vanadium(V), A(4)V(6)[Te(2)(4+)Te(6+)]O(24) (A = K and Rb), have been synthesized by hydrothermal and conventional solid state techniques. Their structures were determined by single-crystal X-ray diffraction analysis. These two iso-structural compounds exhibit layered structural topologies consisting of [V(6)Te(3)O(24)](4 ) anionic units. In these anionic structural units, a Te(6+)O(6) octahedron is connected to six VO(4) tetrahedra by corner-sharing to generate a [V(6)TeO(24)] unit, and each of these [V(6)TeO(24)] units are interconnected by sharing two Te(4+)O(3) polyhedra to complete the infinite [V(6)Te(3)O(24)](4-) sheets. Infrared spectroscopy, UV-Visible diffuse reflectance spectroscopy, and thermogravimetric analysis were also performed on these two compounds. Crystal data: K(4)V(6)Te(3)O(24), trigonal, space group R 3c (No. 167) with a = b = 9.7075(6) A, c = 42.701(3) A, V = 3484.9(4) A(3), and Z = 6; Rb(4)V(6)Te(3)O(24), trigonal, space group R 3c (No. 167) with a = b = 9.8399(9) A, c = 43.012(4) A, V = 3606.6(6) A(3), and Z = 6. PMID- 21695320 TI - Naphthylthiourea-modified permethylcyclodextrin as a highly sensitive and selective "turn-on" fluorescent chemosensor for Hg2+ in water and living cells. AB - A naphthylthiourea-modified cyclodextrin (1) and its urea derivative (2) were synthesized, and their fluorescence behaviors in the presence of various metal ions were investigated. Significantly, 1 showed a highly sensitive and selective fluorescence sensing ability for Hg(2+) over other metal ions in both water and living cells. That is, the addition of Hg(2+) to an aqueous solution of 1 gave a significantly enhanced fluorescence at ~380 nm. In contrast, the addition of other metal ions induced negligible fluorescence changes. The possible mechanism may be due to the transformation of thiourea to urea by Hg(2+)-induced desulfurization in water. PMID- 21695321 TI - Recyclable heterogeneous copper oxide on alumina catalyzed coupling of phenols and alcohols with aryl halides under ligand-free conditions. AB - An efficient alumina-supported CuO-catalyzed O-arylation of phenols and aliphatic alcohols with various aryl as well as heteroaryl halides under ligand-free conditions are reported. This protocol provides a variety of diaryl ether and bis diaryl ether motifs by reacting different aryl/aliphatic halides with differently substituted phenols and saturated alcohols in the presence of a catalytic amount of CuO on alumina and KOH as a base at moderate temperature under nitrogen atmosphere. The described methodology is simple, straightforward and efficient to afford the cross-coupled products in high yields under ligand-free conditions. The explored catalyst is inexpensive, air-stable and recyclable up to three cycles. PMID- 21695322 TI - Chemically engineered papain as artificial formate dehydrogenase for NAD(P)H regeneration. AB - Organometallic complexes of the general formula [(eta(6)-arene)Ru(N?N)Cl](+) and [(eta(5)-Cp*)Rh(N?N)Cl](+) where N?N is a 2,2'-dipyridylamine (DPA) derivative carrying a thiol-targeted maleimide group, 2,2'-bispyridyl (bpy), 1,10 phenanthroline (phen) or ethylenediamine (en) and arene is benzene, 2-chloro-N-[2 (phenyl)ethyl]acetamide or p-cymene were identified as catalysts for the stereoselective reduction of the enzyme cofactors NAD(P)(+) into NAD(P)H with formate as a hydride donor. A thorough comparison of their effectiveness towards NAD(+) (expressed as TOF) revealed that the Rh(III) complexes were much more potent catalysts than the Ru(II) complexes. Within the Ru(II) complex series, both the N?N and arene ligands forming the coordination sphere had a noticeable influence on the activity of the complexes. Covalent anchoring of the maleimide functionalized Ru(II) and Rh(III) complexes to the cysteine endoproteinase papain yielded hybrid metalloproteins, some of them displaying formate dehydrogenase activity with potentially interesting kinetic parameters. PMID- 21695323 TI - "Multi-scan single shot" quantitative 2D NMR: a valuable alternative to fast conventional quantitative 2D NMR. AB - Quantitative Ultrafast (UF) 2D NMR is a very promising methodology enabling the acquisition of 2D spectra in a single scan. The analytical performances of UF 2D NMR have been highly increased in the last few years, however little is known about the sensitivity of ultrafast experiments versus conventional 2D NMR. A fair and relevant comparison has to consider the Signal-to-Noise Ratio (SNR) per unit of time, in order to answer the following question: for a given experiment time, should we run a conventional 2D experiment or is it preferable to accumulate ultrafast acquisitions? To answer this question, we perform here a systematic comparison between accumulated ultrafast experiments and conventional ones, for different experiment durations. Sensitivity issues and other analytical aspects are discussed for the COSY experiment in the context of quantitative analysis. The comparison is first carried out on a model sample, and then extended to model metabolic mixtures. The results highlight the high analytical performance of the "multi-scan single shot" approach versus conventional 2D NMR acquisitions. This result is attributed to the absence of t(1) noise in spatially encoded experiments. The multi-scan single shot approach is particularly interesting for quantitative applications of 2D NMR, whose occurrence in the literature has been greatly increasing in the last few years. PMID- 21695325 TI - Scalable weak aligning medium for enantiodiscrimination of water soluble chiral molecules. AB - The study reports the first indication of a lyotropic liquid crystalline phase of an aqueous solution of polysaccharide xanthan gum, as a physical parameter dependent scalable and reversible weak alignment medium, for enantiodiscrimination of water soluble chiral molecules. PMID- 21695324 TI - Tetris in monolayers: patterned self-assembly using side chain shape. AB - The "kinked" shapes of conjugated alkadiynes constrain chain packing in monolayers on HOPG. Centrally located diyne units permit assembly of 1,5 bis(alkadiyne)anthracene monolayers. Off-center diynes inhibit self-assembly. Shape matched pairs of off-center diyne chains direct self-assembly of compositionally patterned, two component monolayers. PMID- 21695326 TI - Isotope effects in hydrogen-bonded complexes. Calculation of geometrical and vibrational characteristics of asymmetric isotopologues of [F(HF)2]-. AB - The geometrical and vibrational characteristics of isolated H-bonded anionic complexes [FHFDF](-), [FHFTF](-), and [FDFTF](-) are calculated quantum mechanically. The four-dimensional anharmonic vibrational problems are solved by the variational method using the potential energy and dipole moment surfaces calculated in the MP2/6-311++G(3df,3pd) approximation with the basis set superposition error taken into account. Changes in the bond lengths of molecular fragments LF (L = H, D, T) and in the distances between the F(-) anion and the centers of mass of LF are used as the vibrational coordinates. For each isotopologue, the vibrational energy levels, the transition frequencies and absolute intensities for the H-bond and L-F stretching vibrations are determined. To study the isotope effects on the geometrical parameters, the values of internuclear separations and the asymmetry parameter of the F(-)...L-F bridges, averaged over the ground state and several excited vibrational states, are calculated, as well as their standard deviations. The calculations revealed an extremely strong influence of anharmonic coupling between different vibrations on the absorption intensities and a significant mass-dependence of spectroscopic and structural parameters. The geometry and harmonic frequencies of KH(2)F(3), KD(2)F(3), and KHDF(3) are also calculated at a lower ab initio level. The results obtained for [FHFDF](-), [FHFTF](-), and [FDFTF](-) are compared with the available experimental data and the results of earlier calculations of the symmetric complexes [F(HF)(2)](-), [F(DF)(2)](-), and [F(TF)(2)](-) and complexes containing a positive K-meson. PMID- 21695327 TI - The excited state dipole moments of betaine pyridinium investigated by an innovative solvatochromic analysis and TDDFT calculations. AB - This work reports on the solvatochromic properties of a simple heterocyclic betaine pyridinium, 2-(1-pyridinio)benzimidazolate (SBPa), having promising potentialities in non-linear optics. From advanced PCM-TDDFT calculations, the solvatochromism of SBPa was found to be unusual, involving two different electronic states for absorption (S(0)-> S(2)) and emission (S(1)->S'(0)). To account for this behavior, we developed an innovative physical treatment which consists in a non-linear fit of the solvatochromic data using the Bilot-Kawski theoretical model and visualizing the least-square coefficient chi(2) on a 2D map as a function of the solute polarizability and gas phase absorption energy. In parallel, Kamlet-Taft correlations were undertaken to select a propitious set of electrostatic solvents usable in this treatment. Protic solvents that lead to specific interactions and nonpolar solvents that favor dimerization processes were excluded. From a choice of aprotic solvents with sufficiently high polarity, 4 dipole moments MU(g)(S(0)) = +9.1 D, MU(e)(S(2)) = -1.5 D, MU(e)(S(1)) = 0 D and MU(g)(S'(0)) = +3.31 D were determined, the 3 former values being in close agreement with TDDFT values, although the solute polarizability values seem underestimated. Anyhow, disregarding this discrepancy, we evaluated the static hyperpolarizability to beta(0) = -64 * 10(-30) esu from the solvatochromic data in close agreement with DFT calculations. PMID- 21695328 TI - Benzotriazolate cage complexes of tin(II) and lithium: halide-influenced serendipitous assembly. AB - The one-pot reactions of the tin(II) halides SnX(2) (X = F, Cl, Br, I) with lithium hexamethyldisilazide, [Li(hmds)], and benzotriazole, (bta)H, produce contrasting outcomes. Tin(II) fluoride does not react with [Li(hmds)] and (bta)H, the outcome being the formation of insoluble [Li(bta)](infinity). Tin(II) chloride and tin(II) bromide react with [Li(hmds)] and (bta)H in toluene to produce the hexadecametallic tin(II)-lithium cages [(hmds)(8)Sn(8)(bta)(12)Li(8)X(4)].(n toluene) [X = Cl, 3.(8 toluene); X = Br, 4.(3 toluene)]. The reaction of tin(II) iodide with [Li(hmds)] and (bta)H in thf solvent produces the ion-separated species [{(thf)(2)Li(bta)}(3){Li(thf)}](2)[SnI(4)].(thf), [5](2)[SnI(4)].(thf), the structure of which contains a cyclic trimeric unit of lithium benzotriazolate and a rare example of the tetraiodostannate(II) dianion. PMID- 21695330 TI - Dissociative electron attachment to H2S probed by ion momentum imaging. AB - The dissociation dynamics of negative ion resonance states in H(2)S formed upon electron attachment are studied using momentum imaging of the fragment H(-) and S(-) ions and compared with similar resonances in water. The H(-) momentum images show that dissociation dynamics at the 5.2 eV resonance are very similar to those of the 6.5 eV (B(1)) resonance in water. Unlike the 8.5 eV resonance in water, which has A(1) symmetry but is found to display considerable deviation from the axial recoil approximation in the momentum distribution of H(-) ions, the distribution from the corresponding resonance in H(2)S at 7.5 eV is found to follow the axial recoil approximation fairly well. The resonance state with B(2) symmetry at 10 eV is found to decay via four dissociation channels viz.-H(-) + H + S, H(-) + SH(A(2)Sigma), H(-) + SH(X(2)Pi) and S(-) + H + H channels, similar to those that were seen in the B(2) resonance in water at 12 eV, including sequential fragmentation in the multiple fragmentation channels. However, the angular distributions for the fragment ions from this resonance are found to be distinctly different from those in water, even while displaying considerable deviation from the axial recoil approximation similar to that in water. PMID- 21695329 TI - Non-conventional hydrogen bonds: pterins-metal anions. AB - In this paper, we present an analysis of the interaction of metal ions (Cu, Ag and Au) with three different pterins (pterin, isoxanthopterin and sepiapterin) to provide insights concerning the formation of conventional and non-conventional H bonds. Density functional theory calculations were performed in order to reveal the optimized structures of pterin molecules, dimers and tetramers compounds, both with and without metal anions (M). The interaction with small metal clusters (M(3)) is also considered. The formation of different systems is characterized in terms of the structural parameters and hydrogen binding energies (HBE). The HBE values for pterin-M systems presented in this study lie between 22 and 60 kcal mol(-1) and can therefore be classified as strong conventional and strong non conventional hydrogen bonds. The HBE with small metal clusters (pterin-M(3)) are smaller than the HBE with metal atoms. Vertical electron detachment energies (VEDEs) are also reported in order to analyze the influence of the hydrogen bond on electronic properties. A direct correlation between VEDEs and HBE was found for pterin-M and pterin-M(3) complexes; i.e. as the VEDEs increase, the HBE also augment. The only exception is with Ag(3). The main conclusion derived from this study is that the strong non-conventional hydrogen bonds formed between pterins, dimers and tetramers do not affect the formation of conventional hydrogen bonds between pterins but they do influence the VEDEs. PMID- 21695331 TI - Passivity and electrocatalysis of nanostructured nickel encapsulated in carbon. AB - Metallic nickel is a powerful electrocatalyst in alkaline solution and is able to be used in the alkaline fuel cell. However, in acidic solution, electrocatalysis is impossible because the metal is subject to rapid corrosion at low pH for all potentials at which an acidic fuel cell would operate. Here we report the synthesis and passive nature of a nickel-carbon nanostructured material which shows electrocatalytic activity. A thin film composed of nickel and carbon prepared by co-sputtering a graphite target partially covered with a nickel foil shows remarkable passivity against corrosion when polarized in hot sulphuric acid. The film, which contains 21 atom-% nickel, also shows significant electrocatalysis of the hydrogen oxidation reaction, and therefore forms the basis of a new type of fuel cell anode catalyst. High-resolution transmission electron microscopy (HRTEM) reveals a nanostructure of carbon-encapsulated nickel nanocrystals of <=ca. 4 nm diameter. The passive nature of the material against corrosion is due to protection generated by the presence of a very thin carbon rich layer encapsulating the nanoparticulate catalyst: this is a new form of passivation. PMID- 21695332 TI - Recent developments of cyclopropene chemistry. AB - This critical review discusses recent developments in the field of cyclopropene chemistry. Although several excellent reviews that mainly focused on the thermolysis and pyrolysis as well as metal-mediated reactions of cyclopropenes have been published, significant new developments have also been achieved in recent years. This brand new review provides an overview of the progress from 2007 to 2011 on the syntheses and transformations of cyclopropenes as well as their related mechanistic studies (238 references). PMID- 21695333 TI - Tailoring nanoporous materials by atomic layer deposition. AB - Atomic layer deposition (ALD) is a cyclic process which relies on sequential self terminating reactions between gas phase precursor molecules and a solid surface. The self-limiting nature of the chemical reactions ensures precise film thickness control and excellent step coverage, even on 3D structures with large aspect ratios. At present, ALD is mainly used in the microelectronics industry, e.g. for growing gate oxides. The excellent conformality that can be achieved with ALD also renders it a promising candidate for coating porous structures, e.g. for functionalization of large surface area substrates for catalysis, fuel cells, batteries, supercapacitors, filtration devices, sensors, membranes etc. This tutorial review focuses on the application of ALD for catalyst design. Examples are discussed where ALD of TiO(2) is used for tailoring the interior surface of nanoporous films with pore sizes of 4-6 nm, resulting in photocatalytic activity. In still narrower pores, the ability to deposit chemical elements can be exploited to generate catalytic sites. In zeolites, ALD of aluminium species enables the generation of acid catalytic activity. PMID- 21695334 TI - Preparation and structure refinement of Eu3+ doped CaMoO4 nanoparticles. AB - The nanoparticles of CaMoO(4) : Eu(3+) (Eu(3+) = 0, 1, 3, 5, 7, 10 at. %) are prepared at low temperature (150 degrees C for 3 h) using urea hydrolysis in ethylene glycol. These are characterized by X-ray diffraction (XRD), infrared spectroscopy (IR) and transmission electron microscopy (TEM). From XRD study, it was found that the solubility limit of Eu(3+) ions at the Ca(2+) sites is up to 3 at. % and above this, phase segregation occurs. In combination with Rietveld analysis, its crystal structure was found to be tetragonal phase (space group I4(1)/a (88) and Z = 4 (number of CaMoO(4) formula units per unit cell). Unit cell parameters and bond distances are calculated. The average crystallite sizes of as-prepared, 500 and 900 degrees C heated samples are found to be 20, 35 and 70 nm, respectively. The lattice strain is found to be 0.003-0.005. From IR study, the bands at 820 and 441 cm(-1) are assigned to asymmetric stretching and bending vibrations of the MoO(4)(2-) tetrahedron, respectively. From TEM study, the shape of particle was found to be spherical. The high resolution TEM suggests a change in orientation of the crystal on annealing up to 900 degrees C. PMID- 21695335 TI - Luminescence properties of Eu3+ doped CaMoO4 nanoparticles. AB - When Eu(3+) ions occupy Ca(2+) sites of CaMoO(4), which has a body centered tetragonal structure with inversion symmetry, only the magnetic dipole transition ((5)D(0)->(7)F(1)) should be allowed according to Judd-Ofelt theory. Even if there are a few distortions in the Eu(3+) environment, its intensity should be more than that of the electric dipole transition ((5)D(0)->(7)F(2)). We report here the opposite effect experimentally and ascribe this to the polarizability effect of the MoO(4) tetrahedron, which is neighboring to EuO(8) (symmetric environment). The contribution of the energy transfer process from the Mo-O charge transfer band to Eu(3+) and the role of Eu(3+) over the surface of the particle could be distinguished when luminescence decay processes were measured at two different excitations (250 and 398 nm). Further, the luminescence intensities and lifetimes increase significantly with increasing heat-treatment temperature of the doped samples. This is attributed to the reduction of H(2)O from the surface of the particles and a non-radiative process after heat treatment. PMID- 21695336 TI - Synthesis of fluorinated Thomsen-Friedenreich antigens: direct deoxyfluorination of alphaGalNAc-threonine tert-butyl esters. AB - Selectively 6-fluorinated analogs of the tumor-associated T(N) antigen Fmoc Thr(alpha-O-GalNAc)-OtBu can be efficiently prepared using DAST-mediated de(hydr)oxyfluorination reactions of preformed and orthogonally protected glycosyl amino esters without affecting the labile protecting groups and O glycosidic linkages. The resulting mono- and difluorinated T(N) analogs are interesting building blocks for non-hydrolyzable mucin-type antigen mimetics, as illustrated by the unprecedented synthesis of two different multiply fluorinated Thomsen-Friedenreich derivatives. The reported deoxyfluoro antigen analogs represent important functional probes for carbohydrate-binding proteins and glycosyl-processing enzymes. PMID- 21695337 TI - Conjugated polymer nanoparticles for small interfering RNA delivery. AB - Loosely aggregated conjugated polymer nanoparticles (CPNs) were used as nontoxic and efficient small interfering RNA (siRNA) delivery vehicles with delivery visualization. A significant down regulation (94%) of a target gene was achieved by transfection of HeLa cells with the CPNs/siRNA complexes, supporting CPN as a promising siRNA delivery carrier. PMID- 21695338 TI - Dual-functional Au-Fe3O4 dumbbell nanoparticles for sensitive and selective turn on fluorescent detection of cyanide based on the inner filter effect. AB - We demonstrate for the first time that bifunctional Au-Fe(3)O(4) dumbbell nanoparticles can be used for sensitive and selective turn-on fluorescent detection of cyanide based on the inner filter effect, and a "magnetic concentration-washing process" is proposed to effectively reduce the interference of dye pollution. PMID- 21695339 TI - The MXCXXC class of metallochaperone proteins: model studies. AB - Transition metal ions can be both beneficial and harmful to biological systems if not carefully regulated. A family of proteins that include a conserved sequence in their binding site of MXCXXC is responsible for delivery and homeostasis of different metals. Model studies present an effective tool for studying the parameters governing metal affinity, selectivity and other mechanistic aspects. Small-molecule, peptide-based, and advanced models will be presented, as well as functional models of potential industrial applications. PMID- 21695340 TI - trans,trans-2,4-Hexadiene incorporation on enzymes for site-specific immobilization and fluorescent labeling. AB - Lipase B from Candida antarctica (CAL-B) has been site-directedly modified by the introduction of a trans,trans-hexadiene moiety onto lipase molecules, identified by MALDI-TOF. This modification on CAL-B permitted its immobilization on Q Sepharose supports in excellent yields (>95%) when native lipase was not immobilized at pH 7 and 25 degrees C. After the entire modification procedure, the catalytic activity of the protein on the solid support was surprisingly increased 2-fold. A tailor-made maleimide-fluorophore derivative was specifically covalently linked to the protein in high yield via a selective Diels-Alder reaction in aqueous media. Furthermore, the NBD-labeled-CAL-B was also immobilized on the ionic support, retaining around 80% of the specific activity. The preparation of this labeled-CAL-B was also possible by a Diels-Alder reaction on solid phase in excellent yields. PMID- 21695341 TI - A chiral metal-organic framework for sequential asymmetric catalysis. AB - A chiral metal-organic framework (MOF) of the lcy topology was constructed from the Mn-Salen derived dicarboxylic acid and the [Zn(4)(MU(4)-O)(O(2)CR)(6)] secondary building unit, and used in highly regio- and stereo-selective sequential alkene epoxidation/epoxide ring-opening reactions. PMID- 21695342 TI - Stem cell differentiation indicated by noninvasive photonic characterization and fractal analysis of subcellular architecture. AB - We hypothesised that global structural changes in stem cells would manifest with differentiation, and that these changes would be observable with light scattering microscopy. Analysed with a fractal dimension formalism, we observed significant structural changes in differentiating human mesenchymal stem cells within one day after induction, earlier than could be detected by gene expression profiling. Moreover, light scattering microscopy is entirely non-perturbative, so the same sample could be monitored throughout the differentiation process. We explored one possible mechanism, chromatin remodelling, to account for the changes we observed. Correlating with the staining of HP1alpha, a heterochromatin protein, we applied novel microscopy methods and fractal analysis to monitor the plastic dynamics of chromatin within stem cell nuclei. We showed that the level of chromatin condensation changed during differentiation, and provide one possible explanation for the changes seen with the light scattering method. These results lend physical insight into stem cell differentiation while providing physics based methods for non-invasive detection of the differentiation process. PMID- 21695343 TI - Surface-enhanced Raman study of the interactions between tripodal cationic polyamines and polynucleotides. AB - Raman and surface-enhanced Raman spectra of new DNA/RNA-binding compounds consisting of three imidazole (Im) and three pyridine (Py) rings connected by tripodal polyaminomethylene linkages were obtained by the near-infrared excitation at 1064 nm. Study of interactions of Im and Py polyamines with single stranded RNA polynucleotides (poly A, poly G, poly C, poly U), double-stranded DNA polynucleotides (poly dAdT-poly dAdT, poly dGdC-poly dGdC) and calf thymus DNA (ct-DNA) by surface-enhanced Raman spectroscopy (SERS) reveals unambiguous enhancement of the Raman scattering from the small molecules as well as appearance of new bands in spectra associated mainly with nucleobases. The SERS experiments point toward comparable interactions of Im and Py polyamines with single-stranded purine and pyrimidine polynucleotides. Furthermore, SERS experiments with double stranded polynucleotides reveal the base-pair dependent selectivity of Im and Py, whereby interactions within both, major and minor groove are indicated for poly dAdT-poly dAdT, at variance to preferred binding of Im and Py to only major groove of poly dGdC-poly dGdC. SERS spectra of Im and Py with ct-DNA imply that protonated amino groups of these compounds preferentially interact with N7 atoms (adenine, guanine) while nitrogen in aromatic rings of polyamines might be attracted to C6-NH(2) (adenine), all sites being located at the major groove of the DNA helix. Wavenumber downshift of the imidazole (Im) and pyridine (Py) ring vibrations supports aromatic stacking interactions of imidazole and pyridine aromatic moieties with DNA base-pairs. PMID- 21695344 TI - Development of a simple and stability-indicating RP-HPLC method for determining olanzapine and related impurities generated in the preparative process. AB - A simple and stability-indicating reverse phase high performance liquid chromatographic (RP-HPLC) method was developed and validated for the determination of olanzapine (OLN) and related impurities in bulk drugs. Eight impurities were characterized respectively, and particularly a new process impurity from OLN synthesis was structurally confirmed as 1-(5-methylthionphen-2 yl)-1H-benzimidazol-2(3H)-one (Imp-7) by X-ray single crystal diffraction, MS, (1)H NMR, (13)C NMR and HSQC. A mechanism of formation pathway for Imp-7 was proposed. Optimum separation for OLN and eight related impurities was carried out on an Agilent Octyldecyl silica column (TC-C(18), 4.6 mm * 250 mm, 5 MUm) using a gradient HPLC method. The method was validated with respect to specificity, linearity, accuracy, precision, LOD and LOQ. Regression analysis showed good correlation (r(2) > 0.9985) between the investigated component concentrations and their peak areas within the test ranges for OLN and eight impurities. The repeatability and intermediate precision, expressed as RSD, were less than 1.74%. The proposed stability-indicating method was suitable for routine quality control and drug analysis of OLN in bulk drugs. PMID- 21695345 TI - Catalytic decarboxylative alkylation of beta-keto acids with sulfonamides via the cleavage of carbon-nitrogen and carbon-carbon bonds. AB - An efficient decarboxylative alkylation reaction of beta-keto acids with N benzylic or N-allylic sulfonamides has been developed, for the first time, through sequential cleavage of carbon-nitrogen and carbon-carbon bonds in the presence of 10 mol% of FeCl(3). PMID- 21695346 TI - Rainbows and glories in the angular scattering of the state-to-state F + H2 reaction at E(trans)=0.04088 eV. AB - State-of-the-art differential cross sections (DCSs) have been reported by Wang et al. [Proc. Nat. Acad. Sci. (U.S.), 2008, 105, 6227] for the state-to-state F + H(2)-> FH + H reaction using fully quantum-state-selected crossed molecular beams. We theoretically analyze the angular scattering of this reaction, in order to quantitatively understand the physical content of structure in the DCSs. Three transitions are studied, v(i)=0, j(i)=0, m(i)=0 -> v(f)=3, j(f)=0, 1, 2, m(f)=0 at a translational energy of 0.04088 eV, where v, j, m are the vibrational, rotational and helicity quantum numbers respectively for the initial and final states. The input to our analyses consists of accurate quantum scattering (S) matrix elements computed for the Fu-Xu-Zhang potential energy surface, as used by Wang et al. in a computational simulation of their experimental DCSs. We prove that the pronounced peak at forward angles observed in the experimental and simulated DCSs for all three transitions is a glory. At larger angles, it is demonstrated that the 000 -> 300 and 000 -> 310 DCSs both possess a broad farside rainbow, which is accompanied by diffraction oscillations. We confirm the conjecture of Wang et al. that these diffraction oscillations arise from nearside farside (NF) interference. We find that the reaction is N dominant for all three transitions. The theoretical techniques used to analyze the angular scattering include uniform semiclassical theories of glory and of rainbow scattering. We also make the first application of a semiclassical formula that is uniform for both glory + rainbow scattering. In addition, structure in the DCSs is analyzed using NF theory and local angular momentum theory, in both cases with three resummations of the partial wave series for the scattering amplitude. We make the first explicit application of the Thiele rational interpolation formula to extract the position and residue of the leading Regge pole from a set of S matrix elements, thereby making contact with complex angular momentum theories of DCSs, which interpret the angular scattering in terms of Regge resonances. Our calculations complement the exit-valley vibrationally-adiabatic analysis of Wang et al. PMID- 21695347 TI - Chiral symmetry breaking via crystallization of the glycine and alpha-amino acid system: a mathematical model. AB - We introduce and numerically solve a mathematical model of the experimentally established mechanisms responsible for the symmetry breaking transition observed in the chiral crystallization experiments reported by I. Weissbuch, L. Addadi, L. Leiserowitz and M. Lahav, J. Am. Chem. Soc., 1988, 110, 561-567. The mathematical model is based on five basic processes: (1) the formation of achiral glycine clusters in solution, (2) the nucleation of oriented glycine crystals at the air/water interface in the presence of hydrophobic amino acids, (3) a kinetic orienting effect which inhibits crystal growth, (4) the enantioselective occlusion of the amino acids from solution, and (5) the growth of oriented host glycine crystals at the interface. We translate these processes into differential rate equations. We first study the model with the orienting process (2) without (3) and then combine both allowing us to make detailed comparisons of both orienting effects which actually act in unison in the experiment. Numerical results indicate that the model can yield a high percentage orientation of the mixed crystals at the interface and the consequent resolution of the initially racemic mixture of amino acids in solution. The model thus leads to separation of enantiomeric territories, the generation and amplification of optical activity by enantioselective occlusion of chiral additives through chiral surfaces of glycine crystals. PMID- 21695348 TI - Multichromophore light harvesting in hybrid solar cells. AB - A new technologically relevant method for multichromophore sensitizing of hybrid blend solar cells is presented. Two dyes having complementary absorption in the UV-visible regions are individually adsorbed on nanocrystalline TiO(2) powder. These dyed TiO(2) nanoparticles are blended with an organic hole-conductor (HC) Spiro-OMeTAD in desired compositions and applied on a conducting substrate by doctor-blading at room temperature to fabricate multichromophore-sensitized hybrid blend solar cells. The external quantum efficiency (EQE) of the single hybrid layer system fabricated with two dyes, that absorb mainly UV (TPD dye) and visible regions (Ru-TPA-NCS dye), exhibited a clear panchromatic response with the sum of the EQE characteristics of each single dye cell. The first results of a multichromophore-sensitized solid-state solar cell showed J(sc) of 2.1 mA cm( 2), V(oc) of 645 mV, FF of 47% and efficiency of 0.65% at AM 1.5 G, 100 mW cm(-2) illumination intensity. The J(sc) of the multichromophore cell is the sum of the individually dyed solar cells. The process described here is technically very innovative and very simple in procedure. It has potentials to be adopted for panchromatic sensitization using more than two dyes in a single hybrid layer or layer-wise fabrication of a tandem structure at room temperature. PMID- 21695349 TI - A sensitive colorimetric label-free assay for trypsin and inhibitor screening with gold nanoparticles. AB - Gold nanoparticles (Au-NPs) with negative charges aggregate in the presence of Arg(6) due to electrostatic interactions resulting in the red-shift of the plasmon absorption. But, after incubation of Arg(6) with trypsin the aggregation of Au-NPs can be prohibited. Accordingly, a newly designed-Au-NPs based colorimetric assay method for trypsin activity is established. Trypsin with a concentration as low as 1.6 ng mL(-1) can be assayed with this new colorimetric assay. This colorimetric label-free assay for trypsin can be performed in aqueous solution and both Au-NPs and Arg(6) are easily accessible. Thus, this assay method is useful for screening inhibitors of trypsin. PMID- 21695350 TI - New for old. Password to the thermodynamics of the protic ionic liquids. AB - Activity coefficients at infinite dilution of some common solvents in a protic ionic liquid ethylammonium nitrate have been measured using well established gas chromatography-method. This method was possible to apply due to extremely low vapour pressure of ethylammonium nitrate at temperatures below 100 degrees C. Activity coefficients and separation factors were compared with those for aprotic ionic liquids. A new window for intensive accumulation of thermodynamic properties of protic ionic liquids has been opened. PMID- 21695351 TI - Progesterone inhibits the growth of human neuroblastoma: in vitro and in vivo evidence. AB - We investigated the antitumorogenic effects of progesterone (P4) in a human neuroblastoma (SK-N-AS) cell line in vitro and in a mouse xenograft model of neuroblastoma. The safety of P4 was tested in rat primary cortical neurons and human foreskin fibroblasts (HFF-1). At high doses, P4 significantly (P < 0.05) decreased SK-N-AS cell viability in vitro, and this effect was not blocked either by 5alpha-reductase inhibitor, finasteride or the P4 receptor antagonist RU486. Even at very high doses, P4 did not induce any cell death in healthy primary cortical neurons or HFF-1. The bioavailability of P4 24 h after the last injection in the serum of treated animals was significantly (P < 0.05) higher (10 33 MUg/mL) than in untreated animals. In nude mice, P4 (50 and 100 mg/kg) inhibited neuroblastoma growth by ~50% over 8 d of treatment. No drug toxicity was observed in the mice, as measured by body weight and activity. P4 suppressed the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP-9, MMP-2), which are involved in tumor vascular development. High-dose P4 inhibited tumor growth by suppressing cell proliferation and inducing apoptosis, as evidenced by the expression of proliferating cell nuclear antigen and cleaved caspase-3. P4 significantly increased the expression of P4 receptor isoform-A and suppressed phospho-Akt (Ser437) expression. In conclusion, at high doses, P4 effectively inhibits the growth of solid neuroblastoma tumor and has high bioavailability, selective toxicity and a high margin of safety, making it a possible candidate for further study as a potential clinical treatment of neuroblastoma. PMID- 21695353 TI - Qualitative research in performing arts medicine. PMID- 21695352 TI - Peripheral administration of human adrenomedullin and its binding protein attenuates stroke-induced apoptosis and brain injury in rats. AB - Stroke is a leading cause of death and the primary medical cause of acquired adult disability worldwide. The progressive brain injury after acute stroke is partly mediated by ischemia-elicited inflammatory responses. The vasoactive hormone adrenomedullin (AM), upregulated under various inflammatory conditions, counterbalances inflammatory responses. However, regulation of AM activity in ischemic stroke remains largely unknown. Recent studies have demonstrated the presence of a specific AM binding protein (that is, AMBP-1) in mammalian blood. AMBP-1 potentiates AM biological activities. Using a rat model of focal cerebral ischemia induced by permanent middle cerebral artery occlusion (MCAO), we found that plasma levels of AM increased significantly, whereas plasma levels of AMBP-1 decreased significantly after stroke. When given peripherally early after MCAO, exogenous human AM in combination with human AMBP-1 reduced brain infarct volume 24 and 72 h after MCAO, an effect not observed after the treatment by human AM or human AMBP-1 alone. Furthermore, treatment of human AM/AMBP-1 reduced neuron apoptosis and morphological damage, inhibited neutrophil infiltration in the brain and decreased serum levels of S100B and lactate. Thus, human AM/AMBP-1 has the ability to reduce stroke-induced brain injury in rats. AM/AMBP-1 can be developed as a novel therapeutic agent for patients with ischemic stroke. PMID- 21695354 TI - How and why musicians are different from nonmusicians: a bibliographic review. AB - Musicians differ from nonmusicians in many ways; their many special skills reflect the fact that their brains are built differently and function differently. This review of 172 references from PAMA's bibliographic database reveals that most differences occur in the neurobiological realm, in contrast to those of gross anatomy and physiology. Gross changes occur in both cerebral and cerebellar hemispheres and in both gray and white matter. Neurophysiologic differences, measured by sophisticated imaging and electrophysiological techniques, are revealed in sound processing in general, as well as in multiple parameters of music perception, processing, and performance. Most of the neurological differences, both structural and functional, seem to be related to the early age of onset, intense degree, and prolonged duration of musical training and affect multiple, widespread areas of the brain. Training-related differences extend beyond the musical realm to speech, special senses, and general mental parameters and are seen in both instrumental and vocal musicians. A small percentage of reviewed papers demonstrated no appreciable differences between musicians and nonmusicians in a few parameters. PMID- 21695355 TI - Safety of subcutaneous microinjections (mesotherapy) in musicians. AB - OBJECTIVE: Determine the safety and tolerance of mesotherapy as a technique for the treatment of musculoskeletal complaints in musicians. METHOD: 67 patients (55.2% women) were subjected to a total of 267 mesotherapy sessions. A mesotherapy needle or normal needle was used randomly. The drugs employed were thiocolchicoside and diazepam as muscular relaxants, pentoxifylline or buflomedil as vasodilators, and piroxicam as an anti-inflammatory, as directed. A visual analogue scale was used to quantify the pain produced by the microinjections as well as the degree of immediate and midterm side effects as reported on a standard questionnaire. RESULTS: A mean of 155.5 microinjections were performed per session, of which 45.6% were perceived as painful by the patient with a mean severity of 4.3 out of 10. The pain reduced to 0.5 out of 10 after 24 hours. The most sensitive areas were the levator scapulae and splenius muscles. Systemic symptoms were reported by 5.99% of the musicians after the mesotherapy sessions (muscular weakness 1.5%, rash 1.5%, drowsiness 1.1% and itching 1.1%, being the most frequent). The mean severity of these symptoms was 2.77 out of 10. In all cases the symptoms had completely disappeared after 24 hours. No patient referred to signs of local or systemic infection. CONCLUSIONS: The application of drugs by means of subcutaneous injections (mesotherapy) in musicians is a technique that is safe, well tolerated, and without any severe complications. PMID- 21695356 TI - The lived experience of professional musicians with playing-related injuries: a phenomenological inquiry. AB - The purpose of this study was to understand the lived experience of professional instrumental musicians who have experienced playing-related injuries. The study used a hermeneutic phenomenological methodology developed to examine this lived experience. In-depth interviews were conducted with 10 professional musicians, followed by a focus group where preliminary findings were presented to participants and their feedback was sought. Other sources of lived experience included participant-observation by the researcher, who is a musician and has experienced injuries, and biographic and artistic representations of musical performance and its loss, including literature, films, and television. The findings were summarized in a visual representation unique to this study. The representation illustrates three roles-musician, worker, and teacher-that are participated in, and disrupted by, the experience of being injured. In addition, the experience of a playing-related injury takes place within the context of a healthcare system which was perceived as insufficient to meet their needs: specialized care was rarely available and, if available, was not local or timely; treatment operated on a fee-for-service model when many musicians had meagre incomes and lacked coverage for these services; and treatment provided often failed to allow musicians to continue to perform at the level they had previously achieved. Finally, the representation illustrated four existentials-lived time, space, body and social relations-that permeated the experience. This study suggests that improvements to healthcare delivery and education of musicians, music teachers, and healthcare professionals are needed. PMID- 21695357 TI - Evidence of noise-induced hearing loss in young people studying popular music. AB - The number of students studying popular music, music technology, and sound engineering courses at both school and university to has increased rapidly in the last few years. These students are generally involved in music-making/recording and listening to a high level, usually in environments with amplified music. Recent studies have shown that these students are potentially exposed to a high risk of noise-induced hearing loss (NIHL( and are not covered by the same regulatory framework as employees. This study examined the pure tone air conduction hearing thresholds of 50 undergraduate students, including recent school leavers, on a range of popular music courses, to assess if there was evidence of hearing loss. Forty-four percent of students showed evidence of audiometric notch at 4-6 kHz, and 16% were classified under the UK Occupational Health and Safety guidelines as exhibiting mild hearing loss. Instance of audiometric notch was considerably higher than reported from studies of the general population but was around the same level or lower than that reported from studies of "traditional" music courses and conservatoires, suggesting no higher risk for popular music students than for "classical" music students. No relationship with age was present, suggesting that younger students were as likely to exhibit audiometric notch as mature students. This indicates that these students may be damaging their hearing through leisure activities while still at school, suggesting a need for robust education measures to focus on noise exposure of young people. PMID- 21695358 TI - Music performance anxiety--part 1. A review of its epidemiology. AB - Music performance anxiety (MPA) affects many individuals regardless of age, gender, experience, and hours of practice. In order to better understand the epidemiology of MPA, a review of the literature was done. Sixteen articles, meeting EBM criteria, were identified and analyzed. Children rarely suffer from MPA, while adolescents show symptoms similar to adults. Females are generally more affected than males. There is no relation between professional experience and performance anxiety. Great musicians such as Pau Casals and Enrico Caruso suffered from MPA. Nevertheless, students affected by MPA may decide not to become professional musicians because of their inability to cope with the devastating effects of performance anxiety. Solo performances showed higher MPA scores than ensemble performances. Despite these conclusions, long-term cohort studies with larger, homogeneous groups of subjects would be desirable, according to the evidence-based medicine criteria. PMID- 21695359 TI - Long-term treatment effects of sensory motor retuning in a pianist with focal dystonia. AB - Here we present the case of a pianist suffering from unilateral focal hand dystonia for 10 yrs which affected his piano playing as well as other activities of daily life. The treatment applied was sensory motor retuning (SMR), a behavioral treatment for focal hand dystonia. Improvement was clearly achieved from the beginning of therapy. After 10 mos of treatment, performance levels were comparable to those before illness onset. The patient returned to high-level piano playing, and after 8 yrs of follow-up, performance remains normal. PMID- 21695360 TI - Oefening baart Kunst-"Exercise bears (gives birth to) art": symposium for and by the Allied Health Professions of the NVDMG, Medisch Centrum Haaglanden, Den Haag, February 5, 2011. PMID- 21695361 TI - Vitamin D deficiency contributed to Mozart's death. PMID- 21695362 TI - Retrospectively exploring the importance of items in the decision to leave the emergency medical services (EMS) profession and their relationships to life satisfaction after leaving EMS and likelihood of returning to EMS. AB - An exit survey was returned by a sample of 127 respondents in fully compensated positions who left the EMS profession, most within 12 months prior to filling out the exit survey. A very high percentage continued to work after leaving EMS. Respondents were asked to rate the importance of each of 17 items in affecting their decision to leave EMS. A higher than anticipated response to a "not applicable" response choice affected the usability of 8 of these items. Nine of the 17 items had at least 65 useable responses and were used for further analysis. Within these 9, stress/burnout and lack of job challenges had the highest importance in affecting the decision to leave EMS, while desire for better pay and benefits had the lowest importance. Desire for career change was positively related to life satisfaction after leaving EMS and negatively related to likelihood of returning to EMS. Stress/burnout was positively related to life satisfaction after leaving EMS. Study limitations and future research issues are briefly discussed. PMID- 21695363 TI - Peer review: Does it matter? AB - A time-honored principle observed in the domain of published journals in the health field is to rely upon the judgment of peers in making decisions about which manuscripts will be accepted and which will be rejected. A paper by Lipworth et al. that appeared in the April 2011 issue of Social Science & Medicine addresses many pros and cons of relying upon the peer-review process to ensure that only high-quality research is published (either by rejecting or improving substandard manuscripts) and also to increase the likelihood that the findings are disseminated to interested parties. The authors refer to many studies that support the points made in their paper. PMID- 21695364 TI - At the crossroad of higher education and health care. AB - Health care and higher education intersect in important fundamental ways. This essay focuses on the crossroad where the two entities meet, which may be envisioned as constituting two intersecting multilane highways complete with on ramps, off ramps, passing lanes, and breakdown lanes. Some lanes also may be characterized by the movement of vehicles that only can be sighted periodically. For example, federal budgets and decisions on appropriations usually are seen at specific intervals during the year. PMID- 21695365 TI - Attitudes toward management of decreased sexual desire in premenopausal women: a national survey of nurse practitioners and physician assistants. AB - Recent studies have determined that low sexual desire affects between one quarter to one third of adult premenopausal women, leading to distress. The prevalence of distress from low desire may suggest management gaps in the clinicians managing these patients, as recent studies have shown a reluctance to discuss sexual concerns. A survey based on the Theory of Planned Behavior, a predictive model linking attitudes and behavior, was designed to determine what factors influenced behavioral intent and behavior of nurse practitioners and physician assistants when managing decreased sexual desire and sexual concerns in premenopausal women. A path analysis found that attitudes and subjective norms were associated with behavioral intent in both groups and explained roughly one third of the intent to initiate a discussion about sexual health. In general, nurse practitioners and physician assistants had positive attitudes toward managing sexual concerns in female patients but were still at times reluctant to initiate sexual health discussions. This study shows that increased education is needed on female sexual dysfunction in the allied health professional community, as well as techniques for communicating with patients about their sexual concerns. PMID- 21695366 TI - A two-decades-long study of scholarship by clinical laboratory science faculty. AB - To compete successfully in academia, clinical laboratory science (CLS) faculty members must actively engage in research and scholarly activities. Without research, some CLS educators may experience difficulty in the promotion and tenure process or even find their educational programs threatened with closure. Thus began a national study, spanning the years 1985, 1996, and 2008: to compare CLS faculty demographics, their scholarship, and their perceptions of the research environment. Since 1985, faculty members with doctorates have increased from 26% to 52% and senior faculty at the rank of associate and full professors have improved from 38% to 54%. Over time, the data show CLS faculty are providing more refereed publications (in the 2008 study, 19% had 11 or more publications) and more presentations (in the 2008 study, 34% had 11 or more presentations). Grant monies garnered included $62 million in the latest study. On the other hand, there are more faculty in non-tenured track positions. In addition, in both the 1996 and 2008 studies, the average number of faculty per program remained the same (4), as did hours spent each week in teaching (22). For all three studies, faculty perceived the top two research environment characteristics the same: i.e., 1) research is important for promotion and tenure and 2) computer accessibility is present. The lowest ranked characteristic of the research environment for all these studies-time available for research. PMID- 21695367 TI - Health professions students' use of social media. AB - The internet is increasingly a part of everyday life by facilitating networking opportunities and offering ways to associate with others who have similar interests, values, or goals. An online survey was administered to 644 first-year students and 413 graduating students via Surveymonkey to investigate their media preferences, to gauge if they are active on social media sites, and to evaluate how they responded to advertisements. Students were in the following health professions: biotechnology, couple and family therapy, medicine, nursing, occupational therapy, physical therapy, public health, radiologic and imaging sciences, and pharmacy. Results indicate that students prefer online media as their primary source of information. The majority of students were using Facebook, and very few were using Twitter or LinkedIn or other social networking sites. Understanding social media usage has several implications for educating, connecting with, and researching health professions students from all stages of their academic career. PMID- 21695368 TI - Factors associated with enrollment in allied health education programs: development of a predictive scale. AB - The purpose of this study was to identify factors related to a student's decision to enroll in college/university allied health education programs. The secondary purpose was to create a scale that can be used by colleges and universities to assess decision-making among prospective and current allied health education students. METHODS: We identified factors and developed the scale in 4 stages: 1) review of the literature, 2) focus group studies, 3) pilot testing, and 4) administration of the scale and testing of measurement properties. Research participants (n = 1,123) were students enrolled in allied and non-allied health education programs in Tennessee. RESULTS: In exploratory and confirmatory factor analyses, this study identified six factors linked to the decision to enroll in allied health education programs: personal influence, social influence, academic preparation, career opportunity, individual aspiration, and self-efficacy. Discriminant function analyses further revealed that these factors predicted program enrollment status. CONCLUSION: Although this scale may not be generalizable to all allied health education fields, it may assist universities and colleges in targeting and recruiting students into their allied health education programs. PMID- 21695369 TI - Development of a hybrid distance occupational therapy program in Alaska. AB - There are shortages of health professionals in rural states. Correspondingly, health professions education programs often do not exist in these areas. Students from rural areas seeking health professions degrees frequently move out of state or to urban areas for education. To address the shortage of occupational therapists in Alaska, Creighton University, a private, Jesuit university partnered with the University of Alaska Anchorage, a public institution, to deliver a hybrid occupational therapy program to students residing near or in Anchorage, Alaska. Characteristics for a successful interorganizational partnership include effective communication, a common goal, mutual needs, and trust. This academic program was designed by applying these characteristics and using agreed-upon benchmarks for web-based programs as described by Phipps and Merisotis. The collaborative program demonstrates a model, which could be used between two disparate institutions to meet the challenges and needs of rural and underserved areas for access to health education programs. PMID- 21695370 TI - Examining change in emotional-social intelligence, caring, and leadership in health professions students. AB - PURPOSE: To describe and compare the development of emotional-social intelligence (ESI), caring, and leadership of nursing and physical therapy students from the beginning of their professional education until after their first clinical experiences. METHODS: At the beginning of their first professional year, 73 nursing students and 60 physical therapy students completed three self-report questionnaires: the BarOn Emotional Quotient Inventory Short (EQ-i:S) for ESI, the Caring Ability Inventory, and the Self-Assessment Leadership Instrument (SALI). For each instrument, higher scores represent higher levels of ESI, caring, or leadership, respectively. The students completed the questionnaires again after finishing their first clinical experiences. RESULTS: A two-way ANOVA with repeated measures (group vs time) revealed a significant interaction for the total score of the EQ-i:S. At both time periods, scores on the SALI were lower for the nursing students compared to the physical therapy students. There were no other significant time or group effects. CONCLUSION: Nursing and physical therapy students had little change in ESI, leadership, and caring between the start of their academic programs and completion of their first clinical affiliations. PMID- 21695371 TI - A conceptual framework for international service-learning course planning: promoting a foundation for ethical practice in the physical therapy and occupational therapy professions. AB - As physical therapy (PT) and occupational therapy (OT) educational programs endeavor to foster core values of social responsibility, justice, and altruism in an increasingly global community, the incorporation of local and international service-learning (ISL) into the curriculum is growing. Much of the research has focused on the measurement of student learning, with little written about the impact on the host community. Proponents of global health initiatives are calling for consideration of all stakeholders to ensure ethical practice. This paper explores the current literature related to PT and OT ISL and builds a conceptual framework for ISL course planning. The essential phases in the framework include: 1) pre-experience planning/preparation stage, 2) field immersion experience stage, and 3) postexperience stage. The essential elements are: 1) cultural competency training, 2) communication and coordination with community, 3) comprehensive assessment, and 4) strategic planning. The authors suggest this framework as a practical tool to structure ISL courses with an explicit emphasis on ethical concerns. Additionally, they seek to foster more dialogue and action related to the promotion of ethical practices in ISL in PT and OT education programs. PMID- 21695372 TI - Work strain in midlife and 28-year work ability trajectories. AB - OBJECTIVES: We investigated the 28-year development trajectories of work ability among initially middle-aged male and female municipal employees and the association of perceived mental and physical work strain in midlife by work ability trajectory groups. METHODS: The baseline data of the Finnish longitudinal study of municipal employees (FLAME) were collected in 1981 (N=6257) with follow ups in 1985, 1992, 1997, and 2009. Work ability was assessed in all the waves as present perceived work ability relative to lifetime best. Altogether, N=2690 had work ability data in 1981 and 2009, and at least for one wave in between these years, and were included in group-based semi-parametric mixture modeling trajectory analyses. Baseline differences in mental and physical work strain according to the work ability trajectories were assessed with MANCOVA (multivariate analysis of covariance). RESULTS: A five-group work ability trajectory model was identified for men and a four-group model for women. For the majority, a linear decline from excellent to moderate or moderate to poor work ability was observed while non-linear trajectories with sudden collapse and, in some cases, modest subsequent recovery of work ability were also observed. Individuals who maintained their work ability on an excellent-to-moderate level throughout the follow-up more often reported low mental and physical work strain in midlife. CONCLUSIONS: A substantial proportion of individuals seem to maintain their work ability on a moderate level from midlife to old age. Work strain may have far-reaching negative effects on individuals' work ability from midlife to old age, warranting vigilance in maintaining and promoting work ability throughout the lifespan. PMID- 21695373 TI - Systematic review of the epidemiology of gastroesophageal reflux disease in Japan. AB - BACKGROUND: Epidemiological studies of gastroesophageal reflux disease (GERD) in Japan vary in design. This systematic review examines the prevalence of GERD in Japan, distinguishing between study methodologies, and reports on changes over time and factors potentially associated with GERD. METHODS: PubMed and Embase searches identified studies reporting the prevalence of GERD in the general population, primary care patients, and individuals undergoing routine health checks. RESULTS: Of the twenty eligible studies, half excluded individuals taking acid-suppressive medication, so these studies would have been likely to have underestimated the prevalence by 2-3%. Nine studies reported the prevalence of at least weekly reflux symptoms (the definition closest to the Montreal definition): in seven studies this was 6.5-9.5%, but in two studies that included individuals who underwent upper gastrointestinal endoscopy the prevalence was 19.0 and 21.8%. Eight studies used symptom scores: prevalence estimates ranged from 10.2 to 29.0% in five studies using the Carlsson-Dent self-administered questionnaire (QUEST), and from 27.0 to 37.6% in three studies using the frequency scale for the symptoms of GERD. Prevalence estimates were 15.1-24.3% in three studies that reported the presence of reflux symptoms of undefined frequency. Six studies reported the prevalence of reflux esophagitis as 4.9-8.2%. Changes in prevalence over time and factors associated with reflux symptoms were inconsistent. CONCLUSIONS: Few studies have reported the prevalence of GERD in Japan using standardized criteria. Thus, prevalence estimates vary substantially, reflecting differences in study populations and GERD definitions. However, seven studies reported that the prevalence of at least weekly symptoms was 6.5-9.5%, a finding which approaches that reported in Western populations (10-20%). PMID- 21695375 TI - Effect of repetitive transcranial magnetic stimulation on rectal function and emotion in humans. AB - BACKGROUND: A previous brain imaging study demonstrated activation of the right dorsolateral prefrontal cortex (DLPFC) during visceral nociception, and this activation was associated with anxiety. We hypothesized that functional modulation of the right DLPFC by repetitive transcranial magnetic stimulation (rTMS) can reveal the actual role of right DLPFC in brain-gut interactions in humans. METHODS: Subjects were 11 healthy males aged 23.5 +/- 1.4 (mean +/- SE) years. Viscerosensory evoked potential (VEP) with sham (0 mA) or actual (30 mA) electrical stimulation (ES) of the rectum was taken after sham, low frequency rTMS at 0.1 Hz, and high frequency rTMS at 10 Hz to the right DLPFC. Rectal tone was measured with a rectal barostat. Visceral perception and emotion were analyzed using an ordinate scale, rectal barostat, and VEP. KEY RESULTS: Low frequency rTMS significantly reduced anxiety evoked by ES at 30 mA (p < 0.05). High frequency rTMS-30 mA ES significantly produced more phasic volume events than sham rTMS-30 mA ES (p < 0.05). CONCLUSIONS AND INFERENCES: We successfully modulated the gastrointestinal function of healthy individuals through rTMS to the right DLPFC. Thus, rTMS to the DLPFC appears to modulate the affective, but not direct, component of visceral perception and motility of the rectum. PMID- 21695374 TI - Haplotype in the IBD5 region is associated with refractory Crohn's disease in Slovenian patients and modulates expression of the SLC22A5 gene. AB - BACKGROUND: The IBD5 locus (OMIM ID 606348) on chromosome 5 was suggested to be one of the most important genetic factors involved in the pathogenesis of inflammatory bowel diseases (IBDs). However the main contributor from this region is still unknown. METHODS: We investigated the possible association of the IBD5 locus with IBD in Slovenian patients and correlation between disease-associated single nucleotide polymorphisms (SNPs) and quantitative gene expression (eQTL) of candidate genes from the IBD5 locus in peripheral blood lymphocytes and colon tissue biopsies from IBD patients. We genotyped SNPs from the IBD5 locus in 312 healthy controls and 632 IBD patients. RESULTS: We found statistically significant association of polymorphisms rs1050152 in gene SLC22A4 (p = 0.005, OR = 2.177, 95% CI = 1.270-3.526) and rs2631372 in gene SLC22A5 (p = 0.001, OR = 0.473, 95% CI = 0.307-0.731) and TC haplotype of both polymorphisms (p = 0.006, OR = 1,541, 95% CI = 1.130-2.100) with refractory Crohn's disease (CD) in Slovenian patients who do not respond to standard therapy, including patients who develop fistulas. We found decreased expression of SLC22A4 and SLC22A5 genes in peripheral blood lymphocytes from IBD patients compared to control group and decreased expression of SLC22A5 gene in inflamed tissue biopsies compared to noninflamed colon (p = 0.009). We found lower expression of SLC22A5 gene in IBD patients with disease-susceptible genotypes for both disease-associated SNPs. CONCLUSIONS: Our data suggest that SNPs and haplotype in the IBD5 SLC22A4/SLC22A5 region contribute to the development of particularly refractory Crohn's disease in the Slovenian population, and expression studies in blood lymphocytes and colon tissue biopsies and eQTL analysis suggest that SLC22A5 is the main gene in the IBD5 region contributing to the IBD pathogenesis. PMID- 21695376 TI - Inhibitory effect of delphinidin on monocyte-endothelial cell adhesion induced by oxidized low-density lipoprotein via ROS/p38MAPK/NF-kappaB pathway. AB - Monocyte adhesion to the vascular endothelium and their subsequent trans endothelial migration are pivotal early events in atherogenesis. In this study, the effect of delphinidin, belonging to the group of anthocyanin, on adhesion of monocytes to endothelial cells induced by ox-LDL was investigated. The results showed that the pre-treatment with delphinidin (50, 100, or 200 MUM) dose dependently decreased the ox-LDL-induced up-regulation of the expression of ICAM 1 and P-selectin, and the enhanced adhesion and transmigration of monocytes. To determine the role of ROS/p38MAPK/NF-kappaB pathway, intracellular ROS level, p38MAPK protein expression, NF-kappaB transcription activity and protein expression, IkappaB-alpha degradation, NADPH oxidase subunit (Nox2 and p22phox) protein, and mRNA expression were measured. The results showed that delphinidin attenuated ox-LDL-induced generation of ROS, p38MAPK protein expression, NF kappaB transcription activity and protein expression, IkappaB-alpha degradation, NADPH oxidase subunit (Nox2 and p22phox) protein and mRNA expression in endothelial cells in a dose-dependent manner. These results suggest that delphinidin attenuates ox-LDL induced expression of adhesion molecules (P selectin and ICAM-1) and the adhesion of monocytes to endothelial cells by inhibiting ROS/p38MAPK/NF-kappaB pathway. These findings provide a basis for the design of potent antiatherosclerotic agents that will have therapeutic potential in the prevention of AS. PMID- 21695377 TI - Collection and identification of human remains volatiles by non-contact, dynamic airflow sampling and SPME-GC/MS using various sorbent materials. AB - Human remains detection canines are used in locating deceased humans in diverse scenarios and environments based on odor produced during the decay process of the human body. It has been established that human remains detection canines are capable of locating human remains specifically, as opposed to living humans or animal remains, thus suggesting a difference in odor between the different sources. This work explores the collection and determination of such odors using a dynamic headspace concentration device. The airflow rate and three sorbent materials-Dukal cotton gauze, Johnson & Johnson cotton-blend gauze, and polyester material-used for odor collection were evaluated using standard compounds. It was determined that higher airflow rates and openly woven material, e.g., Dukal cotton gauze, yielded significantly less total volatile compounds due to compound breakthrough through the sorbent material. Collection from polymer- and cellulose based materials demonstrated that the molecular backbone of the material is a factor in compound collection as well. Volatiles, including cyclic and straight chain hydrocarbons, organic acids, sulfides, aldehydes, ketones, and alcohols, were collected from a population of 27 deceased bodies from two collection locations. The common compounds between the subjects were compared and the odor profiles were determined. These odor profiles were compared with those of animal remains and living human subjects collected in the same manner. Principal component analysis showed that the odor profiles of the three sample types were distinct. PMID- 21695379 TI - Post streptococcal myalgia: an under-recognized clinical syndrome. AB - Post streptococcal myalgia (PSM) is an under-recognized non-infectious sequelae of streptococcal infection in children. The authors report a case of PSM in an 11 year-old boy along with a review of previously reported cases. The diagnosis of PSM should be considered in children presenting with acute myalgia and high Anti Streptolysin O titres. PMID- 21695378 TI - Analytical in vitro approach for studying cyto- and genotoxic effects of particulate airborne material. AB - In the field of inhalation toxicology, progress in the development of in vitro methods and efficient exposure strategies now offers the implementation of cellular-based systems. These can be used to analyze the hazardous potency of airborne substances like gases, particles, and complex mixtures (combustion products). In addition, the regulatory authorities require the integration of such approaches to reduce or replace animal experiments. Although the animal experiment currently still has to provide the last proof of the toxicological potency and classification of a certain compound, in vitro testing is gaining more and more importance in toxicological considerations. This paper gives a brief characterization of the CULTEX(r) Radial Flow System exposure device, which allows the exposure of cultivated cells as well as bacteria under reproducible and stable conditions for studying cellular and genotoxic effects after the exposure at the air-liquid or air-agar interface, respectively. A commercial bronchial epithelial cell line (16HBE14o-) as well as Salmonella typhimurium tester strains were exposed to smoke of different research and commercial available cigarettes. A dose-dependent reduction of cell viability was found in the case of 16HBE14o- cells; S. typhimurium responded with a dose-dependent induction of revertants. The promising results recommend the integration of cellular studies in the field of inhalation toxicology and their regulatory acceptance by advancing appropriate validation studies. PMID- 21695380 TI - Fainting attacks in children. AB - Fainting attack or syncope in children is a common occurrence, with vasovagal syncope being the commonest cause for majority of pediatric syncope. The aim of emergency room evaluation is not to miss the rare serious underlying disorder causing syncope. A complete detailed history of the event followed by physical examination helps in categorising syncope into the three major categories neurally mediated, cardiovascular and non cardiovascular syncope. Investigations will remain normal in majority of the cases. A 12-lead ECG and standing test should be done in all the cases which helps in establishing the cause for syncope. Management varies depending upon the cause and majority of them do not require hospital admission. PMID- 21695381 TI - Management of childhood brain tumors: consensus report by the Pediatric Hematology Oncology (PHO) Chapter of Indian Academy of Pediatrics (IAP). AB - Brain tumors are the second most common childhood tumors and remain the leading cause of cancer related deaths in children. Appropriate diagnosis and management of these tumors are essential to improve survival. There are no clinical practical guidelines available for the management of brain tumors in India. This document is a consensus report prepared after a National Consultation on Pediatric Brain Tumors held in Delhi on 06 Nov 2008. The meeting was attended by eminent experts from all over the country, in the fields of Neurosurgery, Radiation Oncology, Pediatric Oncology, Neuropathology, Diagnostic Imaging, Pediatric Endocrinology and Allied Health Professionals. This article highlights that physicians looking after children with brain tumors should work as part of a multidisciplinary team to improve the survival, quality of life, neuro-cognitive outcomes and standards of care for children with brain tumors. Recommendations for when to suspect, diagnostic workup, initial management, long-term follow up and specific management of individual tumors are outlined. PMID- 21695382 TI - Central thickening of the donor posterior corneal disc in femtosecond-laser assisted Descemet's stripping endothelial keratoplasty. PMID- 21695383 TI - Cost-effectiveness of cataract surgery in Japan. AB - PURPOSE: To evaluate the cost-effectiveness of cataract surgery through measurement of the cost per quality-adjusted life-year (QALY) in Japan. METHODS: A total of 549 patients scheduled for cataract surgery at 12 clinical sites from November 2008 through February 2010 were included in the study. Prospective assessment of patient preference-based quality of life (utility) was performed before and after the surgery using the time tradeoff method, EuroQol, and Health Utilities Index Mark 3. Multiple regression analysis was used to determine the correlation between utility and visual acuity. The QALYs gained through cataract surgery were estimated, and cost-utility analysis was performed. RESULTS: The utilities significantly correlated with the visual acuity in the better seeing eye. In all the subgroups (first eye surgery, second eye surgery, and bilateral surgery), mean utility improvement was statistically significant. Average QALYs for unilateral cataract surgery and bilateral cataract surgery were 2.40 and 3.40, respectively. The cost per QALY gained from surgery was estimated at Y122,472 (US $1,307) for unilateral surgery and Y145,562 (US $1,553) for bilateral surgery. CONCLUSIONS: Routine cataract surgery in Japan is highly cost effective. Factors that contribute to this are the high clinical effectiveness of the surgery, the substantial improvement in patient-perceived quality of life, and the reasonable cost of the surgery. PMID- 21695384 TI - Dietary intake of fruit and vegetables and risk of non-Hodgkin lymphoma. AB - OBJECTIVE: Few studies have evaluated the potential association between consumption of fruit and vegetables and non-Hodgkin lymphoma (NHL) by histologic subtype, and the results of these studies have been inconsistent. METHODS: A detailed history of dietary practices and food preferences was collected using a food frequency questionnaire from 348 cases and 470 controls in a population based, case-control study conducted in Nebraska during 1999-2002. Risk for the highest versus lowest quartile or tertile of intake was estimated by odds ratios (ORs) and 95% confidence interval (CIs). RESULTS: A lower risk of overall NHL was associated with a high intake of green leafy vegetables (OR = 0.6; CI = 0.3-1.0) and cruciferous vegetables (OR = 0.7; CI = 0.4-1.0). Analysis by subtype showed that green leafy vegetable intake was associated with a lower risk of follicular lymphoma (OR = 0.5; CI = 0.3-0.8) and diffuse large B-cell lymphoma (DLBCL) (OR = 0.5; CI = 0.3-0.9), while consumption of cruciferous vegetables was associated with a lower risk of DLBCL (OR = 0.4; CI = 0.2-0.8). No association was found with intake of total vegetables, carotene-rich vegetables, or all fruit. For nutrients, the risk of NHL overall was inversely associated with a higher intake of beta-cryptoxanthin (OR = 0.6; CI = 0.4-0.9), magnesium (OR = 0.4; CI = 0.2 0.6), potassium (OR = 0.5; CI = 0.3-1.0), and fiber (OR = 0.6; CI = 0.3-1.0), but positively associated with a higher intake of retinol (OR = 1.7; CI = 1.1-2.8). Intakes of vitamin E, magnesium, and potassium were inversely associated with the risk of DLBCL. CONCLUSION: A higher intake of green leafy vegetables and cruciferous vegetables is associated with a lower risk of NHL overall, particularly follicular lymphoma and DLBCL. PMID- 21695385 TI - Male circumcision and penile cancer: a systematic review and meta-analysis. AB - OBJECTIVE: We systematically reviewed the evidence of an association between male circumcision and penile cancer. METHODS: Databases were searched using keywords and text terms for the epidemiology of penile cancer. Random effects meta analyses were used to calculate summary odds ratios (ORs) and 95% confidence intervals (CI). RESULTS: We identified eight papers which evaluated the association of circumcision with penile cancer, of which seven were case-control studies. There was a strong protective effect of childhood/adolescent circumcision on invasive penile cancer (OR = 0.33; 95% CI 0.13-0.83; 3 studies). In two studies, the protective effect of childhood/adolescent circumcision on invasive cancer no longer persisted when analyses were restricted to boys with no history of phimosis. In contrast, there was some evidence that circumcision in adulthood was associated with an increased risk of invasive penile cancer (summary OR = 2.71; 95% CI 0.93-7.94; 3 studies). There was little evidence for an association of penile intra-epithelial neoplasia and in situ penile cancer with circumcision performed at any age. CONCLUSIONS: Men circumcised in childhood/adolescence are at substantially reduced risk of invasive penile cancer, and this effect could be mediated partly through an effect on phimosis. Expansion of circumcision services in sub-Saharan Africa as an HIV prevention strategy may additionally reduce penile cancer risk. PMID- 21695386 TI - A novel repair of a perineal hernia with long-term follow-up. PMID- 21695387 TI - Association of OGG1 Ser326Cys polymorphism with colorectal cancer risk: a meta analysis. AB - INTRODUCTION: 8-Oxoguanine DNA glycosylase 1 (OGG1), a key protein involved in the base excision repair pathway, can recognize and excise several lesions from oligodeoxynucleotides with single DNA damage. A C/G polymorphism at 1,245 bp (C1245G) in exon 7 of the OGG1 (Ser326Cys, rs1052133) is found to have a lower enzymatic activity. A variety of case-control studies have been published evaluating the association between OGG1 Ser326Cys polymorphism and colorectal cancer (CRC), though their conclusions were always contradictory. MATERIALS AND METHODS: This meta-analysis enrolled 12 studies to estimate the overall risk of OGG1 Ser326Cys polymorphism associated with CRC. The pooled odds ratios (ORs) were performed for codominant model (Cys/Cys versus Ser/Ser; Ser/Cys versus Ser/Ser), dominant model (Ser/Cys + Cys/Cys versus Ser/Ser) and recessive model (Cys/Cys versus Ser/Cys + Ser/Ser). RESULTS: No significant associations were found for Cys/Cys versus Ser/Ser (OR = 1.19, 95% confidence interval (CI) 0.92 1.53), Ser/Cys versus Ser/Ser (OR = 1.04, 95% CI 0.95-1.13), Ser/Cys + Cys/Cys versus Ser/Ser (OR = 1.06, 95% CI 0.98-1.16) and Cys/Cys versus Ser/Cys + Ser/Ser (OR = 1.11, 95% CI 0.90-1.38); moreover, in the stratified analyses, no significantly increased risk was found for all genetic models. CONCLUSIONS: Our meta-analysis suggests that the OGG1 Ser326Cys polymorphism is not associated with CRC risk. PMID- 21695388 TI - Efficacy and safety of micafungin as an empirical therapy for invasive fungal infections in patients with hematologic disorders: a multicenter, prospective study. AB - This study was conducted as a prospective, multicenter trial to evaluate the efficacy and safety of micafungin as an empirical therapy for suspected invasive fungal infections (IFIs), including febrile neutropenia (FN), and to evaluate the usefulness of beta-D: -glucan (BG) and Aspergillus galactomannan (GM) antigen in patients with hematologic diseases. A total of 121 patients were enrolled and assessed for safety, and 119 were examined for clinical efficacy. The main underlying diseases were acute myeloid leukemia (38.0%), acute lymphoblastic leukemia (18.2%), and malignant lymphoma (18.2%). The median initial daily dose and duration of micafungin treatment were 150 mg/day and 13 days, respectively. The overall response rate for suspected IFIs (n = 119), based on four composite endpoints, including baseline IFI, breakthrough IFIs (proven and probable), survival, and premature discontinuation, was 79.0%. In addition, the response rate for FN (n = 81), based on these four endpoints as well as defervescence during neutropenia, was 39.5%. Breakthrough IFIs (proven, probable, and possible) occurred in five patients during micafungin treatment. All of these patients were positive for either BG or GM before the breakthrough IFIs. The incidence of adverse events (AEs) associated with micafungin was 10.7% and most were mild. The majority of AEs were liver dysfunction. These results indicate the effectiveness and safety of micafungin as an empirical therapy for suspected IFIs, including FN, and the usefulness of monitoring both BG and GM to detect breakthrough IFIs. PMID- 21695390 TI - Risk factors for caries incidence in a cohort of Flemish preschool children. AB - The main objective of this study was to identify the risk factors for the incidence of visible caries experience in a cohort of preschool children living in Flanders. Data were collected from 1,057 children; validated questionnaires on oral health-related behaviour were completed by parents at birth (2003-2004), at age 3 (2007) and 5 years (2009). At ages 3 and 5, the children were examined by trained dentists. Logistic regression analyses were performed with the following as outcome variables: visible caries experience at age 3 and increment in visible caries experience between ages 3 and 5. At ages 3 and 5, enamel and/or dentinal caries experience was observed in 22% and 41% of the cohort, respectively. The multivariable logistic regression analyses revealed that the presence of visible plaque accumulation on at least one primary tooth was a significant risk factor for visible caries experience at age 3 and for an increment in caries experience between ages 3 and 5. Children with previous caries experience at age 3 had significantly higher odds for new caries lesions at age 5. Presence of visible plaque and previous caries experience are confirmed as significant risk factors for visible caries experience in preschool children. Interventions aimed at caries prevention should focus on very young children and on the control of plaque accumulation. The presence of visible plaque accumulation as a screening tool to identify young children at risk for future caries experience shows high potential. PMID- 21695391 TI - "Minding the gap": imagination, creativity and human cognition. AB - Inquiry into the nature of mental images is a major topic in psychology where research is focused on the psychological faculties of imagination and creativity. In this paper, we draw on the work of L.S. Vygotsky to develop a cultural historical approach to the study of imagination as central to human cognitive processes. We characterize imagination as a process of image making that resolves "gaps" arising from biological and cultural-historical constraints, and that enables ongoing time-space coordination necessary for thought and action. After presenting some basic theoretical considerations, we offer a series of examples to illustrate for the reader the diversity of processes of imagination as image making. Applying our arguments to contemporary digital media, we argue that a cultural-historical approach to image formation is important for understanding how imagination and creativity are distinct, yet inter-penetrating processes. PMID- 21695392 TI - A moderate eclecticism: ontological and epistemological issues. AB - The principle of eclecticism is discussed with the point of departure in a definition of psychology and its subject areas. It is argued that eclecticism constitutes one of the key developmental conditions for science. The argument begins with an analysis of the distinction between real and recognized object and concludes that a scientific object always has an infinite number of aspects and that this fact is not reducible to a question of complexity. Next a differentiation between theoretical levels based on ontological arguments are introduced and it is concluded that it is necessary to accept positive eclectic processes in theories, and that development of theories is due to an eclectic relationship with other theories. A series of examples are given for different versions of the eclectic development of psychological disciplines and concepts, namely phenomenology, psychoanalysis, stress, and cognition. PMID- 21695389 TI - Hypothalamic control of energy and glucose metabolism. AB - The central nervous system (CNS), generally accepted to regulate energy homeostasis, has been implicated in the metabolic perturbations that either cause or are associated with obesity. Normally, the CNS receives hormonal, metabolic, and neuronal input to assure adequate energy levels and maintain stable energy homeostasis. Recent evidence also supports that the CNS uses these same inputs to regulate glucose homeostasis and this aspect of CNS regulation also becomes impaired in the face of dietary-induced obesity. This review focuses on the literature surrounding hypothalamic regulation of energy and glucose homeostasis and discusses how dysregulation of this system may contribute to obesity and T2DM. PMID- 21695393 TI - Acupuncture alleviates the affective dimension of pain in a rat model of inflammatory hyperalgesia. AB - Although studies demonstrate that electroacupuncture (EA) alleviates the sensory dimension of pain, they have not addressed EA's effect on the affective dimension. An inflammatory pain rat model, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a conditioned place avoidance test to determine EA's effects and its underpinning mechanism on the affective dimension of pain. CFA-injected rats showed place aversion, i.e. the affective dimension of pain, by spending less time in a pain-paired compartment after conditioning than before, while saline-injected rats did not. CFA rats given EA treatment at GB30 before a post-conditioning test showed no aversion to the pain-paired compartment, indicating that EA inhibited the affective response. Intra-rostral anterior cingulate cortex (rACC) administration of a kappa-, but not MU-opioid receptor antagonist, blocked EA action. These data demonstrate that EA activates opioid receptors in the rACC to inhibit the affective dimension of pain. PMID- 21695394 TI - Association between Na+,K+-ATPase activity and the vulnerability/resilience to mood disorders induced by early life experience. AB - There is increasing evidence that early life events can influence neurodevelopment and later susceptibility to disease. Chronic variable stress (CVS) has been used as a model of depression. The objective of this study was to evaluate the interaction between early experience and vulnerability to chronic variable stress in adulthood, analyzing emotional, metabolic and neurochemical aspects related to depression. Pups were (1) handled (10 min/day) or (2) left undisturbed from day 1 to 10 after birth. When the animals reached adulthood, the groups were subdivided and the rats were submitted or not to CVS, which consisted of daily exposure to different stressors for 40 days, followed by a period of behavioral tasks, biochemical (plasma corticosterone and insulin sensitivity) and neurochemical (Na+,K+-ATPase activity in hippocampus, amygdala and parietal cortex) measurements. Neonatally-handled rats demonstrated shorter immobility times in the forced swimming test, independently of the stress condition. There was no difference concerning basal corticosterone or insulin sensitivity between the groups. Na+,K+-ATPase activity was decreased in hippocampus and increased in the amygdala of neonatally-handled rats. CVS decreased the enzyme activity in the three structures, mainly in the non-handled group. These findings suggest that early handling increases the ability to cope with chronic variable stress in adulthood, with animals showing less susceptibility to neurochemical features associated with depression, confirming the relevance of the precocious environment to vulnerability to psychiatric conditions in adulthood. PMID- 21695396 TI - Components of a meaningful retirement life--a phenomenological study of the 1950s birth cohort in urban China. AB - This phenomenological study focuses on the 1950s birth cohort in urban China. The research purposes are to depict the dynamic picture of retirement experiences, capture the essence of the phenomenon, and discover the perceived (either experienced or anticipated) challenges in achieving a meaningful retirement life among this aging cohort. Ten face-to-face, semi-structured interviews were conducted in Xi'an City, Shaanxi Province, China. Four main themes emerged regarding the components of a meaningful retirement life: (1) cohort identification and formative experiences, (2) family-orientation with a special focus on the only-child, (3) pursuit of a balanced state of mind in the face of challenges, and (4) leisure without self-indulgence. The historical events, having occurred across participants' life courses, and traditional Chinese culture are shown to be the sources of meaning and the contexts linking the four themes. PMID- 21695395 TI - Acute study of clinical effectiveness of nesiritide in decompensated heart failure: nesiritide redux. AB - Nesiritide, a synthetic drug form of human B-type natriuretic peptide, is approved for the early treatment of dyspnea in acute decompensated heart failure. Meta-analyses suggested a risk of worsening renal insufficiency and mortality with its use. Therefore, the Acute Study of Clinical Effectiveness in Decompensated Heart Failure (ASCEND-HF) was designed as a prospective, multicenter, double-blind, randomized trial to examine the use of nesiritide in this common, morbid, and often lethal clinical condition. Two coprimary end points, dyspnea and 30-day hospital readmission or death, were chosen to examine symptomatic response and objective outcomes, respectively. Preliminary reports from ASCEND-HF investigators suggest no significant improvement in symptoms or clinical outcomes, although no adverse effect on mortality or renal function was noted. We recommend the continued use of nesiritide in acute decompensated heart failure as an individualized case-based therapy to those patients who meet criteria for treatment and are expected to receive benefit from its use. PMID- 21695397 TI - The health of the "older women" in Accra, Ghana: results of the Women's Health Study of Accra. AB - The health of women residing in the developing countries is not limited to reproductive health conditions or infectious diseases. While these illnesses remain serious threats to a healthy life, as the population ages, the prevalence of illnesses considered to be of significance only in industrialized nations also increasingly afflicts the residents of the developing worlds. The health and well being of the older women was evaluated in the 2003 Women's Health Study of Accra. This community based survey and clinical and laboratory examination of 1,328 women identified a significantly high prevalence of malaria and chronic, non communicable diseases in all age groups without regard to education level or income. Hypertension, diabetes and obesity are significantly prevalent in women age 50 years and older. The prevalence of conditions which adversely affect health and quality of life, including impaired visual acuity, poor dentition, pain and limitations with mobility is significant in the women age 50 years and older. While these data are specific to Ghana, they have the potential to be generalizable to women in other urban areas in transition. As the life expectancy is increasing in developing countries, an increased awareness and treatment of chronic health conditions in the older women is critical to ensure a healthy life as they enter their golden years. PMID- 21695399 TI - XXI International Symposium on Glycoconjugates, August 21-26, 2011, Vienna, Austria. Abstracts. PMID- 21695398 TI - Synthetic scaffold coating with adeno-associated virus encoding BMP2 to promote endogenous bone repair. AB - Biomaterial scaffolds functionalized to stimulate endogenous repair mechanisms via the incorporation of osteogenic cues offer a potential alternative to bone grafting for the treatment of large bone defects. We first quantified the ability of a self-complementary adeno-associated viral vector encoding bone morphogenetic protein 2 (scAAV2.5-BMP2) to enhance human stem cell osteogenic differentiation in vitro. In two-dimensional culture, scAAV2.5-BMP2-transduced human mesenchymal stem cells (hMSCs) displayed significant increases in BMP2 production and alkaline phosphatase activity compared with controls. hMSCs and human amniotic fluid-derived stem cells (hAFS cells) seeded on scAAV2.5-BMP2-coated three dimensional porous polymer Poly(epsilon-caprolactone) (PCL) scaffolds also displayed significant increases in BMP2 production compared with controls during 12 weeks of culture, although only hMSC-seeded scaffolds displayed significantly increased mineral formation. PCL scaffolds coated with scAAV2.5-BMP2 were implanted into critically sized immunocompromised rat femoral defects, both with or without pre-seeding of hMSCs, representing ex vivo and in vivo gene therapy treatments, respectively. After 12 weeks, defects treated with acellular scAAV2.5 BMP2-coated scaffolds displayed increased bony bridging and had significantly higher bone ingrowth and mechanical properties compared with controls, whereas defects treated with scAAV2.5-BMP2 scaffolds pre-seeded with hMSCs failed to display significant differences relative to controls. When pooled, defect treatment with scAAV2.5-BMP2-coated scaffolds, both with or without inclusion of pre-seeded hMSCs, led to significant increases in defect mineral formation at all time points and increased mechanical properties compared with controls. This study thus presents a novel acellular bone-graft-free endogenous repair therapy for orthotopic tissue-engineered bone regeneration. PMID- 21695400 TI - Biliary confocal laser endomicroscopy real-time detection of cholangiocarcinoma. PMID- 21695401 TI - Prodromal irritable bowel syndrome may be responsible for delays in diagnosis in patients presenting with unrecognized Crohn's disease and celiac disease, but not ulcerative colitis. AB - INTRODUCTION: We aimed to determine the prevalence and duration of prodromal periods in patients with celiac disease and inflammatory bowel disease (Crohn's disease and ulcerative colitis). Furthermore, we explored to what extent vague abdominal symptoms consistent with both disorders were attributed to irritable bowel syndrome (IBS) and if the presence of prodromal IBS (P-IBS) had an impact on prodrome duration. METHODS: In the study, 683 biopsy-proven patients (celiac n = 225, ulcerative colitis n = 228, Crohn's disease n = 230) completed a postal survey including an assessment of prodromal periods and IBS symptoms during both the prodrome and at present (achieved by completion of the ROME II criteria). Results were compared to age/sex-matched controls (n = 348). RESULTS: Crohn's disease patients had the highest prevalence of prodromes (94%) in comparison to ulcerative colitis (48%) and celiac disease (44%). However, Crohn's disease patients have the lowest prevalence of P-IBS (29%) in comparison to ulcerative colitis (38%) and celiac disease (67%). Prodrome duration in patients with P-IBS Crohn's disease was 4 years in comparison to 2 years without (p = 0.018). Prodrome duration in P-IBS celiac disease was 10 years in comparison to 7 years without (p = 0.046). Prodrome duration in patients with ulcerative colitis was not affected by P-IBS (p >= 0.05). Age and sex were not confounding factors. CONCLUSIONS: This is the first study to make direct comparisons of prodrome periods between celiac disease and IBD. Prodrome duration in celiac disease is significantly longer and more often characterized by P-IBS than IBD. In celiac disease and CD, P-IBS increases prodrome duration. This may represent a failure to understand the overlap between IBS and celiac disease/IBD. PMID- 21695402 TI - Acute liver failure in a pediatric patient with disseminated tuberculosis. PMID- 21695403 TI - Gastric juice prostaglandins and peptide growth factors as potential markers of chronic atrophic gastritis, intestinal metaplasia and gastric cancer: their potential clinical implications based on this pilot study. AB - BACKGROUND: Gastric secretion can provide valuable information especially when Helicobacter pylori (Hp) infection results in chronic atrophic gastritis (CAG) and intestinal metaplasia (IM) preceding adenocarcinoma (AdCa). AIMS: Looking for a potential biomarker of malignant transformation in the setting of chronic inflammation we studied the levels of prostaglandin E2 (PGE(2)), as well as peptide growth factors [epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha)], harbingers of injury and repair, in gastric juice aspirated at endoscopy from patients with CAG, CAG/IM, AdCa, and controls. METHODS: The PGE(2), EGF and TGFalpha concentrations in the gastric juice were measured using radioimmunoassays (RIAs). RESULTS: In patients with AdCa gastric juice PGE(2) increased fivefold versus controls (P < 0.01) and almost threefold versus patients with CAG (P < 0.05). The EGF levels in patients with AdCa were fourfold higher versus controls (P < 0.001) and almost threefold higher versus CAG (P < 0.05). In patients with CAG/IM the EGF levels were also almost 3 times higher versus controls. The TGFalpha levels in patients with AdCa were half the value of controls and CAG (P < 0.05). In patients with CAG/IM the levels were as low as 1/5 of controls or CAG (P < 0.05). CONCLUSIONS: Testing the gastric juice for PGE(2), EGF, and TGFalpha in patients with endoscopy and biopsy proven CAG, may be helpful in follow up of patients who may potentially progress to IM and ultimately AdCa. This could be considered as an adjunct to histologic assessment especially that even the best surveillance biopsy specimen regimens are inherited with sampling errors. PMID- 21695404 TI - Correlation of insulin resistance, beta cell function and insulin sensitivity with serum sFas and sFasL in newly diagnosed type 2 diabetes. AB - Pancreatic beta cell dysfunction and reduced insulin sensitivity are fundamental factors associated with glucotoxicity, lipotoxicity and oxidative stress in type 2 diabetic patients (T2DM). Diabetic milieu can induce apoptosis in several types of cells. The aim of present study was to compare circulating soluble apoptotic markers (sFas and sFas-L) with HOMA-IR, HOMA-%S, HOMA-%B in the serum of newly diagnosed T2DM and healthy subjects. For this study, 94 T2DM and 60 healthy subjects were enroled and evaluated for various parameters. Biochemical quantifications were performed with Syncron CX5 auto-analyzer. The levels of serum sFas-L, TNF-alpha and IL-6 were estimated by flowcytometry. The fasting serum insulin and sFas quantified by ELISA. HOMA-IR, HOMA-%S and HOMA-%B were calculated with HOMA calculator v2.2.2. The levels of TC, TG, LDL-C, VLDL-C were augmented and HDL declined significantly (P < 0.001) in diabetics. The levels of serum insulin, TNF-alpha, IL-6, sFas, HOMA-IR were raised (P < 0.001) and sFas-L, HOMA-%S and HOMA-%B were decreased significantly (P < 0.001) in T2DM subjects than healthy. In diabetics, serum sFas was positively correlated with HOMA-IR (r = 0.720, P < 0.001) and negatively with HOMA-%B (r = -0.642, P < 0.001) significantly while serum sFasL was negatively correlated with HOMA-IR (r = 0.483, P < 0.001) and positively with HOMA-%B (r = 0.466, P < 0.001) significantly. Further, the multivariate stepwise regression analysis shows that HOMA-IR contributes significantly to the variance of sFas and sFasL. Our findings suggest that the pancreatic beta cell dysfunction along with increased insulin resistance appears to be associated with apoptotic markers. PMID- 21695405 TI - Promoting physical activity with goal-oriented mental imagery: a randomized controlled trial. AB - Self-regulation theory and research suggests that different types of mental imagery can promote goal-directed behaviors. The present study was designed to compare the efficacy of approach imagery (attainment of desired goal states) and process imagery (steps for enacting behavior) in promoting physical activity among inactive individuals. A randomized controlled trial was conducted with 182 inactive adults who received one of four interventions for generating mental images related to physical activity over a 4-week period, with Approach Imagery (approach versus neutral) and Process Imagery (process versus no process) as the intervention strategies. Participants received imagery training and practiced daily. Repeated measures ANOVAs revealed that Approach Imagery: (1) increased approach motivations for physical activity at Week 4; (2) induced greater intentions post-session, which subsequently induced more action planning at Week 4; (3) enhanced action planning when combined with process images at post-session and Week 1; and (4) facilitated more physical activity at Week 4 via action planning. These findings suggest that inducing approach orientation via mental imagery may be a convenient and low-cost technique to promote physical activity among inactive individuals. PMID- 21695406 TI - Diagnostic thresholds in osteoporosis: how are they used in clinical trials? AB - Clinical trials are used to determine the efficacy and safety of a medication prior to approval for commercial use and to influence the prescribing habits of clinicians. The lack of uniformity in the diagnostic thresholds used in clinical trials on osteoporosis makes it difficult to compare the results of these trials. The use of placebo, different anatomical sites, T-score cutoff points, and risk factors precludes any meaningful comparison being made between the outcomes of clinical trials. Finally, the lack of uniform reporting format makes it difficult to retrieve important information to compare one medication to another. Because the diagnostic thresholds used affect the outcomes of these trials, health care providers need to be aware of these criteria to determine whether the results of a particular clinical trial can be applied to a particular patient. PMID- 21695408 TI - A convolution/superposition method using primary and scatter dose kernels formed for energy bins of X-ray spectra reconstructed as a function of off-axis distance: comparison of calculated and measured 10-MV X-ray doses in thorax-like phantoms. AB - We performed experimental studies on the convolution/superposition method reported in the former companion paper (Iwasaki in Radiol Phys Technol 4, 2011) using 10-MV X-ray beams from open-jaw-collimated fields. The method uses primary and scatter dose kernels formed for energy bins of X-ray spectra reconstructed as a function of off-axis distance. We made a comparison of calculations and measurements in water phantoms and thorax-like phantoms with respect to percentage depth dose curves, tissue-phantom ratio curves, and dose profiles. We made the dose calculation by taking into account the beam-hardening effect with depth and the off-axis radiation-softening effect. We found that the method could be used, in general, for performing accurate dose calculations. PMID- 21695407 TI - Osteopenia: a diagnostic and therapeutic challenge. AB - We discussed whether we are able to select a subgroup of patients with osteopenia having a high fracture risk, in which anti-osteoporotic drug treatment can be advocated. We concluded that in individuals in whom, based on clinical risk factors, a dual-energy x-ray absorptiometry (DXA) was performed in which osteopenia was diagnosed, anti-osteoporotic treatment should be prescribed in those patients with prevalent vertebral fractures, and in patients chronically using glucocorticoids, in a dosage of 7.5 mg per day or more. Although recent developments with regard to high-resolution imaging techniques (eg, peripheral quantitative computed tomography) seem to be promising, until now they do not provide substantial more reliable information than DXA in the prediction of fractures. We think that more data are urgently needed, since safe and effective drugs are available, but there is uncertainty to which patients with osteopenia these drugs should be prescribed. PMID- 21695410 TI - Ethical Dilemmas and End-of-Life Choices for Patients with Implantable Cardiac Devices: Decisions Regarding Discontinuation of Therapy. AB - OPINION STATEMENT: It is our belief that a well-designed cardiac device management program should include end-of-life patient and family planning, addressing potential decisions regarding withdrawal of pacemaker and/or implantable cardioverter defibrillator therapy. Guided by the basic ethical and legal principles outlined in the article, it is the responsibility of the electrophysiologist and other involved health care providers to introduce this topic to patients, provide guidance and resources for decision making, and honor both patient and family requests. PMID- 21695411 TI - The same, but different--a bird's-eye view on mitosis. PMID- 21695412 TI - Dexamethasone increases the phosphorylation of nephrin in cultured podocytes. AB - BACKGROUND: We reported that nephrin is phosphorylated at Y1204 and Y1228 under normal conditions and that the phosphorylation is decreased in puromycin nephrosis and in human minimal change nephrosis. These results indicate that the phosphorylation of nephrin is important for maintaining normal podocyte function. However, little is known about the regulation of nephrin phosphorylation. Here, we investigated whether glucocorticoid, a drug used to treat glomerular diseases with proteinuria, might affect the phosphorylation of nephrin. METHODS: Human cultured podocytes transiently expressing human nephrin were treated with dexamethasone (Dex), and the phosphorylation of nephrin was determined by immunoblot with the anti-pY1228 antibody. RESULTS: Dex treatment for 24 h increased the phosphorylation of nephrin; this increased phosphorylation was inhibited by the glucocorticoid receptor antagonist but not by the mineral corticoid receptor antagonist. A shorter incubation time (30 min) did not increase the phosphorylation, and actinomycin D and cycloheximide treatments abolished the increased phosphorylation. The activation of Src-family kinases was correlated with nephrin phosphorylation, both of which were abolished by small interfering RNA (siRNA) treatment for serum/glucocorticoid-induced kinase 1 (SGK1). CONCLUSIONS: These results clarify a novel action of glucocorticoid on nephrin phosphorylation through SGK1. Glucocorticoid treatment for human glomerulonephritis may exert its function by regulating the phosphorylation of nephrin. PMID- 21695413 TI - The pathogenesis and treatment of pediatric Henoch-Schonlein purpura nephritis. AB - Henoch-Schonlein purpura (HSP) is a systemic disorder characterized by leukocytoclastic vasculitis involving the capillaries and the deposition of IgA immune complexes. Renal involvement is the principal cause of morbidity and mortality in children with HSP. Thus, it is important to clarify the onset mechanism of Henoch-Schonlein purpura nephritis (HSPN) and to identify the most appropriate treatment. We herein review the pathogenesis and treatment of HSPN. As to the pathogenesis, several studies suggest that galactose-deficient IgA1 is recognized by anti-glycan antibodies, leading to the formation of circulating immune complexes and their mesangial deposition, thereby inducing renal injury. Aggressive therapies for the treatment of severe HSPN, including multiple drug combination therapy and plasmapheresis, have been shown to be effective in ameliorating proteinuria and histological severity. Nevertheless, detailed investigations of the pathogenesis of HSPN and double-blind randomized control studies on children with HSPN are still necessary. PMID- 21695414 TI - Urinary angiotensinogen as a predictive marker in patients with immunoglobulin A nephropathy. AB - BACKGROUND: The intrarenal renin-angiotensinogen system (RAS) plays a major role in the progression of chronic kidney disease. Urinary angiotensinogen (UAGT) provides a specific index of the intrarenal RAS status. This study was conducted to find the role of UAGT as a predictive marker in patients with immunoglobulin A nephropathy (IgAN). METHODS: Thirty-six patients with IgAN, 14 non-IgAN and 15 healthy controls were included. The UAGT concentration was measured using human ELISA kits and adjusted by urinary creatinine. RESULTS: UAGT levels were significantly higher in patients with IgAN and non-IgAN than in healthy subjects (104.96 vs. 6.71 ng/mgCr, p < 0.01). Using univariate regression analysis, UAGT was found to correlate with the urine protein-to-creatinine ratio (UPCR), serum creatinine, and systolic and diastolic blood pressure in patients with IgAN. Multivariate regression analysis revealed that UAGT correlated positively with UPCR. Patients with levels of UAGT >100 ng/mgCr showed higher serum creatinine after treatment than patients with UAGT levels <100 ng/mgCr. CONCLUSION: This study showed that UAGT levels are increased and correlate positively with the UPCR in IgAN. Patients with high levels of UAGT may have poor renal function following treatment. PMID- 21695415 TI - Incidence and risk factors for radiocontrast-induced nephropathy in patients with hepatocellular carcinoma undergoing transcatheter arterial chemoembolization. AB - BACKGROUND: Transcatheter arterial chemoembolization (TACE) is an effective treatment for unresectable hepatocellular carcinoma (HCC); however, large volumes of radiocontrast agents are used for TACE and may induce renal dysfunction. Most patients with HCC have coexisting liver cirrhosis (LC) at the time of diagnosis. Advanced cirrhosis is characterized by peripheral vasodilatation associated with decreased renal perfusion due to the activation of vasoconstrictor systems. We retrospectively investigated patients with HCC who had undergone TACE to determine the incidence and risk factors for radiocontrast-induced nephropathy (RCIN). METHODS: A total of 101 patients with HCC who underwent a combined 221 TACE treatment sessions were included. Follow-up serum creatinine levels within 96 h after TACE were confirmed in these patients. RCIN was defined as an increase of at least 25% in baseline serum creatinine levels between 48 and 96 h after TACE. RESULTS: RCIN developed in 20 (9%) of the 221 treatment sessions after TACE. A univariate analysis showed that the Child-Pugh score (6.0 +/- 1.3 vs. 6.7 +/- 1.9, P = 0.005), ascites (14.4 vs. 40%, P = 0.008), contrast medium volume (257.3 +/- 66.8 vs. 275.0 +/- 44.0 ml, P = 0.009), total bilirubin (1.3 +/- 1.7 vs. 3.4 +/- 8.0 mg/dl, P < 0.001), basal serum creatinine levels (0.9 +/- 0.3 vs. 1.0 +/- 0.5 mg/dl, P < 0.001) and glomerular filtration rate using the modification of diet in renal disease formula (90.5 +/- 21.8 vs. 88.4 +/- 29.6 ml/min, P = 0.015) were significantly associated with the development of RCIN. A multivariate analysis revealed that the Child-Pugh score was associated with RCIN [odds ratio (OR) 1.5; P = 0.015]. Overall, in-hospital mortality after TACE was 4.07% (with RCIN, 30%; without RCIN, 1.5%; P < 0.001). The multivariate analysis also showed that the Child-Pugh score and the occurrence of RCIN were associated with in-hospital mortality after TACE (OR 2.8; P = 0.001; OR 26.7, P = 0.002, respectively). CONCLUSIONS: RCIN after TACE was closely associated with the severity of LC. Effective preventive measures remain to be determined in patients with HCC and advanced LC who are undergoing TACE. PMID- 21695416 TI - Metabolomic profiling of the autosomal dominant polycystic kidney disease rat model. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disease characterized by renal cyst expansion, resulting in renal failure. With the progression of renal damage, the accumulation of uremic compounds is recently reported to subsequently cause further renal damage and hypertension. Finding uremic toxins and sensitive markers for detecting the early stage of ADPKD is necessary to clarify its pathophysiological process and to prevent its progression. The aim of this study was to analyze the profile of uremic retention solutes of ADPKD by capillary electrophoresis-mass spectrometry (CE-MS) using the Han:SPRD rat model. METHODS: Two hundred and ninety-seven cations and 190 anions were comprehensively analyzed by CE-MS in Han:SPRD rats and control rats. RESULTS: We found 21 cations and 19 anions that accumulated significantly in the heterozygous (Cy/+) ADPKD rat model compared with control rats. Among the compounds, increases in 5-methyl-2'-deoxycytidine, glucosamine, ectoine, allantoate, alpha-hydroxybenzoate, phenaceturate and 3-phenylpropionate and decreases in 2-deoxycytidine, decanoate and 10-hydroxydecanoate were newly identified in the ADPKD Cy/+ rats. CONCLUSION: We identified uremic retention solutes in ADPKD Cy/+ rats. Compounds related to ADPKD could be useful markers for detecting the early stage of ADPKD. PMID- 21695417 TI - Involvement of kynurenines in Huntington's disease and stroke-induced brain damage. AB - Several components of the kynurenine pathway of tryptophan metabolism are now recognised to have actions of profound biological importance. These include the ability to modulate the activation of glutamate and nicotinic receptors, to modify the responsiveness of the immune system to inflammation and infection, and to modify the generation and removal of reactive oxygen species. As each of these factors is being recognised increasingly as contributing to major disorders of the central nervous system (CNS), so the potentially fundamental role of the kynurenine pathway in those disorders is presenting a valuable target both for understanding the progress of those disorders and for developing potential drug treatments. This review will summarise some of the evidence for an important contribution of the kynurenines to Huntington's disease and to stroke damage in the CNS. Together with preliminary evidence from a study of kynurenine metabolites after major surgery, an important conclusion is that kynurenine pathway activation closely reflects cognitive function, and may play a significant role in cognitive ability. PMID- 21695418 TI - Is all cognitive impairment in Parkinson's disease "mild cognitive impairment"? AB - Cognitive impairment can be demonstrated in Parkinson's disease (PD) from the very beginning of the disease. Clinical manifestations range from slight deficits, only demonstrable by means of neuropsychological testing, up to dementia. If a linear involution is supposed for the cognitive worsening in PD, then the relatively subtle cognitive defects should be taken as the earliest signs of dementia implying that PD-MCI concept would be thoroughly equivalent to that used for the early prediction of other dementias among healthy population. Cognitive defects in PD, however, may not follow a normal distribution. While fronto-striatal deficits, such as working memory, set-shifting and free-recall verbal memory appear altered in most patients during long periods of time, certain functions depending on more posterior-cortical regions, such as copying or naming, usually characterize patients with dementia. Fronto-striatal and posterior-cortical cognitive defects may have a different pathophysiological substrates, evolution and prognosis. While fronto-striatal defects appear more related to dopaminergic defects, posterior-cortical defects may obey multiple neurotransmitter failure. Designing criteria to accurately diagnose PD-MCI is highly relevant for clinical treatment, research, care-giving and decision making. Besides quantitative defects, an operative definition of MCI in PD should clearly distinguish a "risky cognitive profile" among the broad cognitive defects intrinsic to PD. Thus, along with other possible biological markers, from a neuropsychological point of view, posterior-cortical defects probably represent the very syndrome of MCI in PD. PMID- 21695419 TI - Subthalamic nucleus versus pedunculopontine nucleus stimulation in Parkinson disease: synergy or antagonism? AB - Stimulation of the subthalamic nucleus (STN) improves the cardinal features of Parkinson disease (PD). However, its efficacy on gait disorders is less satisfying in the long term. In recent years, the pedunculopontine (PPN) nucleus has emerged as a possible promising deep brain stimulation target for gait disorders in PD. In this review, we examine whether STN and PPN act synergistically or antagonistically. Results suggest that the combination of STN and PPN stimulations leads to a significant further improvement in gait as compared with STN stimulation alone, but additive effects on the classical motor triad are questionable. Thus, they highlight the specificity of STN stimulation over PPN's for the PD cardinal features and the specificity of PPN stimulation over STN for gait disorders. In addition, low-frequency stimulation of the PPN may improve alertness. The additive rather than potentiating effects of STN and PPN stimulations suggest that they may be mediated by distinct pathways. Nevertheless, considering the inconsistencies in published results regarding the influence of PPN stimulation on gait disorders, work is still needed before one can know whether it will convert into a standard surgical treatment and to decipher its place beside STN stimulation. PMID- 21695420 TI - Copper ability to induce premature senescence in human fibroblasts. AB - Human diploid fibroblasts (HDFs) exposed to subcytotoxic concentrations of oxidative or stressful agents, such as hydrogen peroxide, tert butylhydroperoxide, or ethanol, undergo stress-induced premature senescence (SIPS). This condition is characterized by the appearance of replicative senescence biomarkers such as irreversible growth arrest, increase in senescence associated beta-galactosidase (SA beta-gal) activity, altered cell morphology, and overexpression of several senescence-associated genes. Copper is an essential trace element known to accumulate with ageing and to be involved in the pathogenesis of some age-related disorders. Past studies using either yeast or human cellular models of ageing provided evidence in favor of the role of intracellular copper as a longevity modulator. In the present study, copper ability to cause the appearance of senescent features in HDFs was assessed. WI-38 fibroblasts exposed to a subcytotoxic concentration of copper sulfate presented inhibition of cell proliferation, cell enlargement, increased SA beta-gal activity, and mRNA overexpression of several senescence-associated genes such as p21, apolipoprotein J (ApoJ), fibronectin, transforming growth factor beta-1 (TGF beta1), insulin growth factor binding protein 3, and heme oxygenase 1. Western blotting results confirmed enhanced intracellular p21, ApoJ, and TGF beta1 in copper-treated cells. Thus, similar to other SIPS-inducing agents, HDF exposure to subcytotoxic concentration of copper results in premature senescence. Further studies will unravel molecular mechanisms and the biological meaning of copper associated senescence and lead to a better understanding of copper-related disorder establishment and progression. PMID- 21695421 TI - Brain-derived neurotrophic factor (BDNF) gene: a gender-specific role in cognitive function during normal cognitive aging of the MEMO-Study? AB - Cognitive aging processes are underpinned by multiple processes including genetic factors. The brain-derived neurotrophic factor (BDNF) has been suggested to be involved in age-related cognitive decline in otherwise healthy individuals. The gender-specific role of the BDNF gene in cognitive aging remains unclear. The identification of genetic biomarkers might be a useful approach to identify individuals at risk of cognitive decline during healthy aging processes. The aim of this study was to investigate the associations between three single-nucleotide polymorphisms (SNPs) in the BDNF gene and domains of cognitive functioning in normal cognitive aging. The sample, comprising 369 participants (M = 72.7 years, SD = 4.45 years), completed an extensive neuropsychological test battery measuring memory, motor function, and perceptual speed. The relationships between the SNPs rs6265, rs7103411, and rs7124442 and cognitive domains were examined. While significant main effects of BDNF SNPs on cognitive function were found for the association between rs7103411 and memory performance, gender-specific analyses revealed for females significant main effects of rs7103411 for memory and of rs6265 for perceptual speed independent of the APOE*E4 status and education. The finding for the association between rs6265 and perceptual speed in females remained significant after Bonferroni correction for multiple comparisons. None of the analyses showed significant results for males. This study is the first to implicate that the SNPs rs6265 and rs7103411 affect cognitive function in the elderly in a gender-specific way. PMID- 21695422 TI - Exponential growth combined with exponential decline explains lifetime performance evolution in individual and human species. AB - The physiological parameters characterizing human capacities (the ability to move, reproduce or perform tasks) evolve with ageing: performance is limited at birth, increases to a maximum and then decreases back to zero at the day of death. Physical and intellectual skills follow such a pattern. Here, we investigate the development of sport and chess performances during the lifetime at two different scales: the individual athletes' careers and the world record by age class in 25 Olympic sports events and in grandmaster chess players. For all data sets, a biphasic development of growth and decline is described by a simple model that accounts for 91.7% of the variance at the individual level and 98.5% of the variance at the species one. The age of performance peak is computed at 26.1 years old for the events studied (26.0 years old for track and field, 21.0 years old for swimming and 31.4 years old for chess). The two processes (growth and decline) are exponential and start at age zero. Both were previously demonstrated to happen in other human and non-human biological functions that evolve with age. They occur at the individual and species levels with a similar pattern, suggesting a scale invariance property. PMID- 21695424 TI - The effect of nitric oxide on the pressure of the acutely obstructed ureter. AB - Acute ureteral obstruction leads to changes in pressure inside the ureter, interrupting ureter function. The aim of our study is to explore the relationship between nitric oxide (NO) concentration and pressure in the ureter and to observe the effects of nitric oxide on the revival of renal function. We created the animal models by embedding balloons in the lower ureters of anesthetized dogs and expanding them to simulate acute ureteral obstruction. First, the test animals were pre-treated intravenously with different doses of L-NAME (non-selective nitric oxide synthase inhibitor) to inhibit nitric oxide synthase (NOS), and 10 min later, each subject was administered an intravenous dose of isoproterenol (10 MUg/kg). We measured ureter pressure (UP), total and peak concentrations of NO (using an NO monitor, model inNO-T) in ureteral urine, and the volume of the urine (UFV) leaking from the balloon edge. After a certain amount of time had elapsed, it became clear that the dose of L-NAME was inversely related to the total and peak concentrations of NO, the rate of change in UP, and the volume of urine produced. We conclude that L-NAME prevents the NOS from inhibiting the release of NO, then inhibits the effect of isoproterenol reducing the pressure of the acute obstructive ureter. Inversely, we think that NO can reduce the pressure of the acute obstructive ureter and make the obstructive ureter recanalization. And when more the concentration of nitric oxide, the more the pressure will be reduced, and more urine will be collected. PMID- 21695423 TI - Klotho locus, metabolic traits, and serum hemoglobin in hospitalized older patients: a genetic association analysis. AB - Klotho (KL) gene has been involved in severe alterations of physiological biochemical parameters leading to premature aging-like phenotypes and strikingly shortening lifespan. KL participates to the regulation of a number of intracellular biochemical pathways, including lipid profile and glucose metabolism. Aim of this study was to investigate the possible association between KL locus and biological parameters commonly accepted as indicators of the clinical status in hospitalized older patients. We genotyped the single nucleotide polymorphisms (SNPs) rs9536314, rs1207568, and rs564481 at the KL locus in 594 hospitalized older patients (65-99 years), consecutively attending a geriatric ward, and tested the association of these KL variants with biological quantitative traits using analyses of covariance and genetic risk score models. Significant associations of rs9536314 with serum levels of hemoglobin, albumin, and high-density lipoprotein cholesterol (HDL-C) as well as significant associations of rs564481 with serum levels of hemoglobin, fasting insulin, and fasting glucose were observed. Gender-segregated analyses confirmed these associations, and suggested that the associations of KL genotypes with HDL-C, fasting glucose and fasting insulin levels may be driven by the female gender, while the association with serum levels of hemoglobin may be driven by the male gender. The association of KL genotypes with creatinine levels was found only in females, while the association with insulin-like growth factor-1 (IGF-1) and lymphocytes count (LC) was found only in males. The genetic risk score (GRS) models further confirmed significant associations among KL SNPs and hemoglobin, total cholesterol, and HDL-C. Gender-segregated analyses with the GRS-tagged approach confirmed the associations with HDL-C, fasting glucose, and fasting insulin levels in females, and with hemoglobin and LC in males. Our findings suggested that KL locus may influence quantitative traits such as serum levels of lipid, fasting glucose, albumin and hemoglobin in hospitalized older patients, with some gender differences suggested for creatinine, IGF-1 levels, and LC, thus being one of the genetic factors possibly contributing to age-related diseases and longevity. PMID- 21695427 TI - Genetic diversity and geographic differentiation analysis of duckweed using inter simple sequence repeat markers. AB - Duckweed, with rapid growth rate and high starch content, is a new alternate feedstock for bioethanol production. The genetic diversity among 27 duckweed populations of seven species in genus Lemna and Spirodela from China and Vietnam was analyzed by ISSR-PCR. Eight ISSR primers generating a reproducible amplification banding pattern had been screened. 89 polymorphic bands were scored out of the 92 banding patterns of 16 Lemna populations, accounting for 96.74% of the polymorphism. 98 polymorphic bands of 11 Spirodela populations were scored out of 99 banding patterns, and the polymorphism was 98.43%. The genetic distance of Lemna varied from 0.127 to 0.784, and from 0.138 to 0.902 for Spirodela, which indicated a high level of genetic variation among the populations studied. The unweighted pair group method with arithmetic average (UPGMA) cluster analysis corresponded well with the genetic distance. Populations from Sichuan China grouped together and so did the populations from Vietnam, which illuminated populations collected from the same region clustered into one group. Especially, the only one population from Tibet was included in subgroup A2 alone. Clustering analysis indicated that the geographic differentiation of collected sites correlated closely with the genetic differentiation of duckweeds. The results suggested that geographic differentiation had great influence on genetic diversity of duckweed in China and Vietnam at the regional scale. This study provided primary guidelines for collection, conservation, characterization of duckweed resources for bioethanol production etc. PMID- 21695426 TI - The genetic and physiological analysis of late-flowering phenotype of T-DNA insertion mutants of AtCAL1 and AtCAL2 in Arabidopsis. AB - The homozygous T-DNA mutants of AtCAL1 (Rat1) and AtCAL2 (Rat2) were obtained. The double mutant of Rat2/Rat1RNAi was constructed which showed obvious late flowering phenotype from others. The expression of various flowering-related genes was studied among mutants and wild-type plants by quantitative RT-PCR. The double mutant plants showed the shortest root length compared with T-DNA insertion mutants and wild type plants under red light, blue light, and white light. The double mutants showed hypersensitivity to NaCl and ABA. However, these mutants had no effect on stomatal closure by ABA. PMID- 21695425 TI - Late effects of childhood leukemia therapy. AB - As survival rates for children treated for childhood cancers become significantly better, the focus is increasingly on determining the late effects of treatments and the best ways to monitor for them and prevent their occurrence. This review focuses on recent literature discussing the late effects of treatment in patients treated for acute myeloid leukemia and acute lymphoblastic leukemia during childhood. The late effects of therapy for childhood leukemia include secondary malignancy, cardiotoxicity, obesity, endocrine abnormalities, reproductive changes, neurocognitive deficits, and psychosocial effects. As clinicians have become more aware of the late effects of therapy, treatment regimens have been changed to decrease late effects, but patients still require long-term follow-up for their prevention and treatment. PMID- 21695428 TI - Role of unusual CD4+ CD28- T cells in acute coronary syndrome. AB - Acute coronary syndrome (ACS) is a group of clinical symptoms that results from complete or partial occlusive thrombus, which is caused by coronary an atherosclerotic plaque rupture or erosion. According to a recent study, CD4(+) CD28(-) T cells are found in atherosclerotic plaques and the peripheral circulation blood in patients with ACS, these cells play an important role in plaque ruptures. CD4(+) CD28(-) T cells are an unusual subset of helper cells, which expand and have harmful effects in ACS. In this review, we discuss the current issues on the generation of CD4(+) CD28(-) T cells and focus on their phenotypic and functional characteristics relevant to the development of cardiovascular events. Targeting the CD4(+) CD28(-) T cells subset in ACS could provide novel therapeutic means to prevent acute life-threatening coronary events. PMID- 21695429 TI - Genetic diversity and effect of temperature and pH on the growth of Macrophomina phaseolina isolates from sunflower fields in Hungary. AB - The effects of temperature and pH on the growth of 45 Hungarian Macrophomina phaseolina isolates from different locations and hosts were compared on the basis of their genetic diversity. One Spanish and two Serbian isolates were also included in the experiment. The most favourable temperature regimes for the development of the isolates ranged between 25 and 35 degrees C. The optimal pH for the pathogen varied between 4.0 and 6.0, but growth was observed on potato dextrose agar even at pH values of 3.0, 7.0 and 8.0. RAPD analysis with 13 different primer pairs generated 148 unambiguous bands. RFLP analysis involving 8 different restriction endonucleases was performed on a 1550 bp fragment of the rDNA region containing internal transcribed spacers (ITS1, ITS2), the 5.8S rDNA and part of the 25S rDNA. The greatest genetic distance values were obtained for three isolates, two from Hungary and one from Spain, which had similar values, but were quite distinct from all the others. A strong positive correlation was observed between the genetic distances and the growth parameters measured at various temperatures, and between the geographical data and the growth data sets at different pH values, but the correlation was less strong in the latter case. While Hungarian M. phaseolina populations are thought to reproduce clonally, the present results indicate the coexistence of different haplotypes in this area, and besides the geographical dominance of a given haplotype it was found that a closer genetic relationship might exist between spatially distinct haplotypes. PMID- 21695430 TI - Study of the differential transcription in liver of growth hormone receptor (GHR), insulin-like growth factors (IGF1, IGF2) and insulin-like growth factor receptor (IGF1R) genes at different postnatal developmental ages in pig breeds. AB - The objective of this study was to determine hepatic expression levels of GHR, IGF1R, IGF1 and IGF2 genes in young growing gilts at different developmental ages (60-210 days) in five pig breeds: Polish Large White (PLW), Polish Landrace (PL), Pulawska (Pul), Duroc (Dur) and Pietrain (Pie). We studied the differences among pig breeds as well as within each breed for pigs in different developmental ages. Obtained results revealed major differences among breeds in hepatic gene expression of porcine GHR, IGF1R, IGF1 and IGF2 genes in different developmental ages. The differences among breeds of GHR expression were significantly higher in PLW, PL at the age of 60, 90, 120 days as compared to Pul, Dur and Pie. In turn, the highest level of IGF1R expression was observed in PL at age of 150, 180 and 210 days, whereas in case of IGF1 the highest level was recorded in Pie gilts at the age of 60 and 90 days. Moreover trait associated study revealed highly significant correlations between hepatic expressions of IGF1R and IGF2 genes and carcass composition traits (P < 0.01) The results of study suggest that porcine GHR, IGF1R, IGF1 and IGF2 genes may be potential candidate genes for postnatal growth and carcass composition traits. Therefore, the implementation of the hepatic expression of GH/IGF genes into the pig breeding and gene assisted selection program in different pig breeds should be considered. However, further population wide study is needed to clarify the hepatic expression association with economic traits, such as body growth, meat quality and carcass composition traits. PMID- 21695431 TI - Detection of double stranded RNA in phytopathogenic Macrophomina phaseolina causing charcoal rot in Cyamopsis tetragonoloba. AB - One hundred one isolates of Macrophomina phaseolina from various hosts and eco geographical locations were employed for elucidating relationships among genetic diversity and virulence. Highly pathogenic, moderately pathogenic, and hypovirulent cluster bean specific isolates were identified. In order to correlate respective phenotypes of plant pathogenic fungus multiple and complex patterns of dsRNA elements were analyzed. Double-stranded ribonucleic acids (dsRNA) are ubiquitous in all major groups and most of them have vast potential as biological control agents for fungi. Rate of virulence and its further association could ascertain by host plant and their fungal genotypes. Variability of the fungal genotypes decides the link between the complexity of dsRNA with different variants and the change in virulence pattern. Double-stranded RNA was identified in approximately 21.7% of M. phaseolina isolates from charcoal rot infected cluster bean varieties. After recurrent laboratory transfer on culture media, the preponderance of the isolates harboring dsRNAs developed degenerate culture phenotypes and showed reduced virulence (hypovirulence) to cluster bean. Macrophomina has successfully showed diversified and reproducible banding profile in dsRNA containing/free isolates. This is the first report of hypovirulence and detection of dsRNA in Macrophomina phaseolina isolates of cluster bean origin. PMID- 21695432 TI - Effects of FUT1 gene mutation on resistance to infectious disease. AB - Alpha-(1,2)-fucosyltransferase (FUT1) gene has been identified as a candidate gene for regulating the expression of Escherichia coli F18 receptor gene (ECF18R) which promotes adherence of Enterotoxigenic (ETEC) and Verotoxigenic (VTEC) Escherichia coli (E. coli) via F18 fimbriae. In order to illustrate the polymorphisms of FUT1 and their effects on resistance to natural infection by Porcine Respiratory and Reproductive Symdrome Virus (PRRSV) and Haemophilus parasuis, the distributions of different genotypes and the relative risks of disease incidence in pigs were investigated. A total of 1,041 pigs representing three European breeds (Duroc, Landrace and LargeWhite), five Chinese local breeds (Wild pig, Small MeiShan, QinPing, JinHua, and JianLi) and three commercial populations (LargeWhite * JianLi, Duroc * Landrace * LargeWhite and Duroc * wild pig) were selected to analyze the genotype of the FUT1 gene by PCR-RFLP. Only the GG genotype associated with susceptibility to ECF18 bacteria was detected in Chinese local pig breeds and a population of LargeWhite * JianLi, while the AA genotype which confers resistance to ECF18 was detected in two European breeds (Duroc and LargeWhite), two populations of Duroc * wild pig and Duroc * Landrace * LargeWhite. Regarding relative risk of incidence, Duroc * Landrace * LargeWhite with genotypes GG or AG showed greater relative risk (OR = 2.040, P = 0.025; OR = 1.750, P = 0.081, respectively) than those with genotype AA during natural infection by both PRRSV and Haemophilus parasuis. It can be concluded that the mutation of FUT1 gene might play a role in pig infection by multi-pathogens, and that AA may be a favourable genotype for increasing the resistance to disease. PMID- 21695433 TI - Cloning, structural characterization and expression analysis of a novel lipid storage droplet protein-1 (LSD-1) gene in Chinese honeybee (Apis cerana cerana). AB - Lipid storage droplet 1 (LSD-1), a PAT family protein located around lipid droplets in insects, is intimately linked to lipid droplets formation and lipid metabolism. Conjugated linoleic acid (CLA) and rosiglitazone (Rosi) have previously been shown to modulate the expression of several PAT family proteins through peroxisome proliferator-activated receptor-gamma (PPARgamma). In the present study, we isolated and characterized a novel LSD-1 gene, referred to AccLSD-1, from Chinese honeybee (Apis cerana cerana). Sequence analysis indicated that the central region of LSD-1 protein had significant sequence similarity and a typical LSD-1 gene was composed of 8 exons and 7 introns. Interestingly, the first intron of AccLSD-1 including several PPARgamma-response elements (PPREs) was located in 5' UTR. Analysis of 5'-flanking region of AccLSD-1 revealed a number of putative cis-acting elements, including three PPREs. Quantitative real time PCR showed that AccLSD-1 expressed ubiquitously from feeding larva to adult, and its expression level was highest at brown-eyed pupae (Pb) stage. The effect of CLA, Rosi and combination on AccLSD-1 expressions indicated 1% CLA and 0.5 mg/ml Rosi were considered as the suitable diets for rearing adult workers in laboratory, and AccLSD-1 was down-regulated by CLA whereas up-regulated by Rosi. Furthermore, the combination of CLA and Rosi remarkly rescued the suppression of AccLSD-1 expression by CLA alone. These results suggest that AccLSD-1 is associated with A. cerana cerana development, especially during pupal metamorphosis, and can be regulated by CLA or Rosi possibly via activating PPARgamma. PMID- 21695434 TI - Identifying patterns of recovery experiences and their links to psychological outcomes across one year. AB - PURPOSE: The main aim of this study was to examine patterns of recovery experiences (i.e., psychological detachment, relaxation, mastery and control during off-job time) and their links to psychological outcomes (job burnout, work engagement and sleep problems) across 1 year. METHODS: The study is based on 1 year longitudinal data collected among Finnish employees (n = 274) using questionnaires. First, patterns of recovery experiences, that is, subgroups of employees with unique and distinctive patterns of mean-level stability and change in recovery experiences across 1 year were identified using Latent Profile Analysis. Second, differences in psychological outcomes between the patterns identified were investigated by means of ANOVA/ANCOVA for repeated measures. RESULTS: Five patterns of recovery experiences were identified. Over 70% of the employees belonged to a pattern with reasonably high stable levels of all four recovery experiences across the 1-year follow-up. This pattern seemed to suffer least from job burnout and sleep problems. Of the four remaining patterns, those with experiences of high levels of mastery and control during off-job time had highest work engagement, and among those with decreasing levels of all recovery experiences job exhaustion increased across time. CONCLUSIONS: Patterns of recovery experiences play a significant role in maintaining long-term psychological well-being. PMID- 21695436 TI - Tendon lesions in the shoulder: tear and wear without push and pull? PMID- 21695437 TI - Occupational physical activity and mortality among Danish workers. AB - PURPOSE: The relationship between occupational physical activity (OPA) and mortality has mainly been studied among males and shows conflicting results. This study examines this relationship in a cohort of both male and female workers. METHODS: OPA was determined by 4 self-reported questions in a representative sample of 5,839 Danish workers aged 18-59 years at baseline. A 19-year follow-up on mortality was assessed by linkage with the national death registry. Gender stratified Cox regression models were used to determine the effect of high OPA on all-cause mortality while controlling for age, BMI, smoking, alcohol consumption, doctor-diagnosed disease, influence at work, and social class. RESULTS: Two hundred and sixty-two males (8.6%) and 174 females (6.2%) died during follow-up. Being in the highest quartile of OPA predicted an increased risk for all-cause mortality among male workers (HR: 1.79, CI: 1.19-2.70), but not among female workers (HR: 0.99, CI: 0.65-1.49) compared with workers in the lowest quartile of OPA. Among females, indications of a u-shaped relationship between occupational physical activity and all-cause mortality were found. CONCLUSIONS: The findings indicate that high occupational physical activity increases the risk for all cause mortality among male workers. Future studies need to further examine gender differences in the effects of OPA on mortality. PMID- 21695439 TI - Trans-vaginal repair of a recurrent pouch-vaginal fistula. PMID- 21695438 TI - Phase 1 trial of S-1 in combination with sorafenib for patients with advanced hepatocellular carcinoma. AB - PURPOSE: Sorafenib is a multi-kinase inhibitor, which was approved as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). We conducted a phase 1 study of sorafenib plus S-1 in patients with advanced HCC. EXPERIMENTAL DESIGN: We designed to escalate S-1 at 4 different dose levels with fixed dose of sorafenib. Four dose levels were as follows: level 1, D1-14 S-1 50 mg/m(2)/day + D1-21 sorafenib 400 mg bid; level 2, D1-14 S-1 60 mg/m(2)/day + D1-21 sorafenib 400 mg bid; level 3,, D1-14 S-1 70 mg/m(2)/day + D1-21 sorafenib 400 mg bid; level 4, D1-14 S-1 80 mg/m(2)/day + D1-21 sorafenib 400 mg bid. The treatment was repeated every 3 weeks. RESULTS: From August 2009 to July 2010, 20 patients with advanced HCC were enrolled. The median age was 48 years (range, 29-74). Eighteen (90%) patients had hepatitis B viral infection and 19 (95%) patients were rated as Child-Pugh class A. The dose-limiting toxicities were grade 4 infection and thrombocytopenia. After a median follow-up duration of 8.6 months (range, 3.7 14.2 months), median PFS was 3.9 months (95% CI, 0.8-7.0 months) and median OS was 10.4 months (95% CI, 0-22.4 months). In pharmacokinetic analysis, there was no statistically significant drug interaction between sorafenib and S-1. CONCLUSIONS: The combination of sorafenib and S-1 showed tolerable toxicity profile and modest clinical efficacy in patients with advanced HCC. The recommended dose of sorafenib and S-1 was 400 mg twice daily and 40 mg/m(2) twice daily, respectively. PMID- 21695440 TI - Agraffectomy after low rectal stapling procedures for hemorrhoids and rectocele. AB - BACKGROUND: Various sequelae which might lead to reintervention have been described after stapled rectal mucosectomy for hemorrhoids. One potential treatment modality for persistent complaints after stapled hemorrhoidopexy (SHP) or stapling for rectocele is the so-called agraffectomy (removal of the retained staples). This treatment option means a further procedure that can range from removal of the staples through the anoscope to removal of the entire staple line with the associated scar tissue. METHODS: In order to review the published literature, we conducted a search on Medline, Pubmed, and Embase using different terms for "agraffectomy." RESULTS: Overall, fourteen reports were found, dealing with agraffectomy for various conditions after low rectal stapling for hemorrhoids or rectocele. Agraffectomy is a rarely mentioned treatment option for conditions after SHP. In rectal stenosis with complete occlusion of the rectal lumen, the removal of the stenotic anastomosis and remaining staples seems to be reasonable. The same can be said of the removal of retained staples for rectal bleeding or in order to avoid penile injuries in anal intercourse. In contrast, the collected published reports on agraffectomy in this review only provide low level evidence that this procedure provides relief for other problems such as incontinence or chronic pain. CONCLUSIONS: There is no clear evidence that agraffectomy is indicated if not in case of rectal stenosis and hemorrhage caused by the staples. PMID- 21695441 TI - Local giant cell foreign body reaction after silicone injection for fecal incontinence in humans: two case reports. AB - Since the 1990s, one of the methods used for treating fecal incontinence due to internal anal sphincter defects has been the injection of bulking agents. The aim of this paper is to report two cases of local giant cell foreign body reaction after injection of PTQ(TM) in humans. To the best of the authors' knowledge, this is the first report of an adverse immune response to silicone injection in humans. PMID- 21695442 TI - Metastatic lymph node ratio (LNR) as a prognostic variable in colorectal cancer patients undergoing laparoscopic resection. AB - BACKGROUND: Lymph node ratio (LNR: the ratio of metastatic to total retrieved nodes) has shown prognostic significance in several tumors. Its role in patients with colorectal cancer submitted to laparoscopic resection is still not clearly defined. The aim of this study was to evaluate the impact of LNR on long-term outcome in patients undergoing curative laparoscopic resection. METHODS: Patients' data were retrieved from our prospective in-hospital collected data of patients that underwent laparoscopic surgery for curable colorectal cancer over a 6-year period. Long-term data were collected from our outpatient's clinic data and personal contact when necessary. RESULTS: Two hundred and five patients underwent laparoscopic resection for curable colorectal cancer in the study period. Sixty-five patients were node positive. Receiver operating characteristic (ROC) analysis selected 0.13 as the best LNR cutoff value in this group. Kaplan Meier 5-year survival analysis revealed a significant decrease in overall and disease-free survival in patients with an LNR above 0.13. Long-term outcome of patients with an LNR below 0.13 was similar to node-negative stage II patients. CONCLUSIONS: The lymph node ratio is a valuable prognostic factor in node positive colon cancer patients undergoing laparoscopic resection. Patients with an LNR below 0.13 have the same long-term outcome as stage II node-negative patients. The laparoscopic approach presents the same trends in terms of overall survival and disease-free survival as conventional open access when LNR is considered. PMID- 21695443 TI - Simultaneous caecal volvulus through a congenital mesenteric defect and proximal intussusception. PMID- 21695444 TI - The finite cell method for bone simulations: verification and validation. AB - Standard methods for predicting bone's mechanical response from quantitative computer tomography (qCT) scans are mainly based on classical h-version finite element methods (FEMs). Due to the low-order polynomial approximation, the need for segmentation and the simplified approach to assign a constant material property to each element in h-FE models, these often compromise the accuracy and efficiency of h-FE solutions. Herein, a non-standard method, the finite cell method (FCM), is proposed for predicting the mechanical response of the human femur. The FCM is free of the above limitations associated with h-FEMs and is orders of magnitude more efficient, allowing its use in the setting of computational steering. This non-standard method applies a fictitious domain approach to simplify the modeling of a complex bone geometry obtained directly from a qCT scan and takes into consideration easily the heterogeneous material distribution of the various bone regions of the femur. The fundamental principles and properties of the FCM are briefly described in relation to bone analysis, providing a theoretical basis for the comparison with the p-FEM as a reference analysis and simulation method of high quality. Both p-FEM and FCM results are validated by comparison with an in vitro experiment on a fresh-frozen femur. PMID- 21695445 TI - Socialization of social anxiety in adolescent crowds. AB - In this study, we looked at whether social anxiety is socialized, or influenced by peers' social anxiety, more in some peer crowds than others. Adolescents in crowds with eye-catching appearances such as Goths and Punks (here termed Radical), were compared with three comparison groups. Using data from 796 adolescents (353 girls and 443 boys; M ( age ) = 13.36) at three timepoints, the results show that adolescents affiliating with the Radical crowd tended to select peers from the same crowd group. Being a member of a crowd in itself did not predict socialization of social anxiety, but adolescents in the Radical crowd were more influenced by their peers' social anxiety than adolescents who did not affiliate with the Radical crowd group. The results suggest that through a bidirectional process, adolescents affiliating with Radical crowds may narrow their peer relationship ties in time, and in turn socialize each other's social anxiety. PMID- 21695446 TI - Inhibitory control and harsh discipline as predictors of externalizing problems in young children: a comparative study of U.S., Chinese, and Japanese preschoolers. AB - We examined associations between child inhibitory control, harsh parental discipline and externalizing problems in 120 4 year-old boys and girls in the US, China, and Japan. Individual differences in children's inhibitory control abilities, assessed using behavioral tasks and maternal ratings, were related to child externalizing problems reported by mothers. As predicted, both child inhibitory control and maternal harsh discipline made significant contributions to child externalizing problems in all three countries. Across countries, child inhibitory control and maternal harsh discipline made significant independent contributions to early externalizing problems, suggesting an additive model of association. Our findings supported the cross-cultural generalizability of child inhibitory control and parental harsh punishment as key contributors to disruptive behavior in young children. PMID- 21695448 TI - Automatic recognition of major fissures in human lungs. AB - PURPOSE: The major hurdle for three-dimensional display of lung lobes is the automatic recognition of lobar fissures, boundaries of lung lobes. Lobar fissures are difficult to recognize due to their variable shape and appearance, along with the low contrast and high noise inherent in computed tomographic (CT) images. An algorithm for recognizing the major fissures in human lungs was developed and tested. METHODS: The algorithm employs texture analysis and fissure appearance to mimic the way that surgeons/radiologists read CT images in clinical settings. The algorithm uses 3 stages to automatically find the major fissures in human lungs: (a) texture analysis, (b) fissure region analysis, and (c) fissure identification. RESULTS: The algorithm's feasibility was evaluated using isotropic CT images from 16 anonymous patients with varying pathologies. Compared with manual segmentation, the algorithm yielded mean distances of 1.92 +/- 2.07 and 2.07 +/- 2.37 mm, for recognizing the left and right major fissures, respectively. CONCLUSIONS: An automatic recognition algorithm for major fissures in human lungs is feasible, providing a foundation for the future development of a complete segmentation algorithm for lung lobes. PMID- 21695447 TI - Music and video as distractors for boys with ADHD in the classroom: comparison with controls, individual differences, and medication effects. AB - This study examined the effects of music and video on the classroom behavior and performance of boys with and without attention deficit hyperactivity disorder (ADHD) and examined the effects of 0.3 mg/kg methylphenidate (MPH). In one study, 41 boys with ADHD and 26 controls worked in the presence of no distractor, music, or video. Video produced significant distraction, particularly for the boys with ADHD, and MPH improved the performance of boys with ADHD across distractor conditions.There were individual differences in response to the music such that some boys were adversely affected and others benefited relative to no distractor.In a second study, music and MPH were assessed in an additional 86 boys with ADHD to examine further the music results. In the presence or absence of music, MPH improved performance relative to placebo. Similar individual differences were found as in Experiment 1. PMID- 21695449 TI - Investigating mechanisms of chronic kidney disease in mouse models. AB - Animal models of chronic kidney disease (CKD) are important experimental tools that are used to investigate novel mechanistic pathways and to validate potential new therapeutic interventions prior to pre-clinical testing in humans. Over the past several years, mouse CKD models have been extensively used for these purposes. Despite significant limitations, the model of unilateral ureteral obstruction (UUO) has essentially become the high-throughput in vivo model, as it recapitulates the fundamental pathogenetic mechanisms that typify all forms of CKD in a relatively short time span. In addition, several alternative mouse models are available that can be used to validate new mechanistic paradigms and/or novel therapies. Here, we review several models-both genetic and experimentally induced-that provide investigators with an opportunity to include renal functional study end-points together with quantitative measures of fibrosis severity, something that is not possible with the UUO model. PMID- 21695450 TI - Early steroid withdrawal in pediatric renal transplant: five years of follow-up. AB - This prospective, comparative trial investigated the impact on mean change in height standard deviation score (SDS), acute rejection rate, and renal function of early steroid withdrawal in 96 recipients with 5 years of follow-up. Recipients under basiliximab induction and steroid withdrawal (SW: TAC/MMF; n = 55) were compared with a matched steroid control group (SC: TAC/MMF/STEROID, n = 41). SW received steroids until Day 6, SC decreased to 10 mg/m(2) within 2 months post-transplant. Five years after SW, the longitudinal growth (SDS) gain was 1.4 +/- 0.4 vs. 1.1 +/- 0.3 for SC group (p < 0.02). Height benefits in prepubertal and pubertal status in both groups were demonstrated in the delta growth trends (mixed model; p < 0.01). Biopsy-proven acute rejection in SW was 11% and 17.5%, SC (p: ns). Mean eGFR (ml/min/1.73 m(2)) at 5 years post-transplant was SW 80.6 +/- 27.8 vs. 82.6 +/- 25.1 for SC (p: ns). The death-censored graft survival rate at 1 and 5 years was 99 and 90% for SW; 98 and 96% for SC (p = ns). PTLD incidence in SW 3.3 vs. 2.5% in SC (p: ns). Five years post-transplant, early steroid withdrawal showed positive impacts on growth, stable renal function without increased acute rejection risk, and PTLD incidence. PMID- 21695451 TI - Surgical management of vesicoureteral reflux in children. AB - Vesicoureteral reflux (VUR) is the most common uropathy affecting children. Compared to children without VUR, those with VUR have a higher rate of pyelonephritis and renal scarring following urinary tract infection (UTI). Options for treatment include observation with or without antibiotic prophylaxis and surgical repair. Surgical intervention may be necessary in patients with persistent reflux, renal scarring, and recurrent or breakthrough febrile UTI. Both open and endoscopic approaches to reflux correction are successful and reduce the occurrence of febrile UTI. Estimated success rates of open and endoscopic reflux correction are 98.1% (95% CI 95.1, 99.1) and 83.0% (95% CI 69.1, 91.4), respectively. Factors that affect the success of endoscopic injection include pre-operative reflux grade and presence of functional or anatomic bladder abnormalities including voiding dysfunction and duplicated collecting systems. Few studies have evaluated the long-term outcomes of endoscopic injection, and with variable results. In patients treated endoscopically, recurrent febrile UTI occurred in 0-21%, new renal damage in 9 12%, and recurrent reflux in 17-47.6% of treated ureters with at least 1 year follow-up. These studies highlight the need for standardized outcome reporting and longer follow-up after endoscopic treatment. PMID- 21695452 TI - Multicomponent reactions of ammonium thiocyanate, acyl chlorides, alkyl bromides, and enaminones: a facile one-pot synthesis of thiophenes. AB - An efficient synthesis of thiophene derivatives is described via one-pot reaction between ammonium thiocyanate, acyl chlorides, alpha-halocarbonyls, and enaminones under solvent-free conditions at 65 degrees C. The mild reaction conditions and high yields of the products exhibit the good synthetic advantage of these methods. PMID- 21695453 TI - Biotransformation of three pharmaceutical active compounds by the fungus Phanerochaete chrysosporium in a fed batch stirred reactor under air and oxygen supply. AB - White-rot fungi are a group of microorganisms capable of degrading xenobiotic compounds, such as polycyclic aromatic hydrocarbons or synthetic dyes, by means of the action of extracellular oxidative enzymes secreted during secondary metabolism. In this study, the transformation of three anti-inflammatory drugs: diclofenac, ibuprofen and naproxen were carried out by pellets of Phanerochaete chrysosporium in fed-batch bioreactors operating under continuous air supply or periodic pulsation of oxygen. The performance of the fungal reactors was steady over a 30-day treatment and the effect of oxygen pulses on the pellet morphology was evidenced. Complete elimination of diclofenac was achieved in the aerated and the oxygenated reactors, even with a fast oxidation rate in the presence of oxygen (77% after 2 h), reaching a total removal after 23 h. In the case of ibuprofen, this compound was completely oxidized under air and oxygen supply. Finally, naproxen was oxidized in the range of 77 up to 99% under both aeration conditions. These findings demonstrate that the oxidative capability of this microorganism for the anti-inflammatory drugs is not restricted to an oxygen environment, as generally accepted, since the fungal reactor was able to remove these compounds under aerated and oxygenated conditions. This result is very interesting in terms of developing viable reactors for the oxidation of target compounds as the cost of aeration can be significantly reduced. PMID- 21695454 TI - Corrosion behavior of carbon steel in the presence of two novel iron-oxidizing bacteria isolated from sewage treatment plants. AB - In this work, two novel iron oxidizing bacteria (IOB), namely Gordonia sp. MZ-89 and Enterobacter sp. M01101, were isolated from sewage treatment plants and identified by biochemical and molecular methods. Then, microbially influenced corrosion (MIC) of carbon steel in the presence of these bacteria was investigated. The electrochemical techniques such as potentiodynamic polarization measurements and electrochemical impedance spectroscopy (EIS) were used to measure the corrosion rate and observe the corrosion mechanism. The results showed that the existence of these microorganisms decreased the corrosion potential and enhanced the corrosion rate. Scanning electron microscopy (SEM) images revealed the ground boundary attacks and pitting on carbon steel samples in the presence of these bacteria after polarization. Corrosion scales were identified with X-ray diffraction (XRD). It was demonstrated that these bacteria can greatly affect the crystalline phase of corrosion products that also confirmed by SEM results. It was inferred that these bacteria were responsible for the corrosion of carbon steel, especially in the form of localized corrosion. PMID- 21695455 TI - ["War of the slings": when do I do what and which concept will endure?]. AB - The number of incontinence surgeries has drastically increased for female stress urinary incontinence requiring treatment. On the one hand, public perception of the problem has become widespread, increasingly removing the stigma of the condition, and on the other hand, newer surgical techniques and materials have been continually developed in the last 15 years. The use of tension-free vaginal slings for the treatment of stress incontinence is associated with high continence rates and minimal side effects and has meanwhile become the gold standard in the management of incontinence. PMID- 21695456 TI - [Urinary incontinence - topic nr. 1]. PMID- 21695457 TI - [Robotic medicine in Germany: quo vadis?]. AB - Today, one can hardly imagine the medical daily routine without computer-assisted systems, although their benefit usually is not investigated by prospective randomised trials. While in the industrial working environment computer-assisted systems are thoroughly accepted because of their precision and endurance, in medicine there are fierce debates about their use at considerably high costs. At least the perioperative advantages (e.g. less blood loss, shorter period of hospitalization), to a large extent, are beyond dispute. The high costs may be compensated by a higher volume of treated patients. Only the treatment of a higher volume of patients will lead to a reduction of infrastructure costs per case. On the other hand, only a large number of cases ensure the achievement of skills to handle such a complex system. This, in return, reduces the chance of the occurrence of complications and shorter operation times will lead to economic advantages. PMID- 21695458 TI - Targeting low molecular weight cyclin E (LMW-E) in breast cancer. AB - Low molecular weight cyclin E (LMW-E) plays an important oncogenic role in breast cancer. LMW-E, which is not found in normal tissue, can promote the formation of aggressive tumors and can lead to increased genomic instability and tumorigenesis. Additionally, breast cancer patients whose tumors express LMW-E have a very poor prognosis. Therefore, we investigated LMW-E as a potential specific target for treatment either alone or in combination therapy. We hypothesized that because LMW-E binds to CDK2 more efficiently than full length cyclin E, resulting in increased activity, CDK inhibitors could be used to target tumors with LMW-E bound to CDK2. To test the hypothesis, an inducible full length and LMW-E MCF7-Tet-On system was established. Cyclin E (full length (EL) or LMW E) is only expressed upon induction of the transgene. The doubling times of cells were unchanged when the transgenes were induced. However, upon induction, the kinase activity associated with LMW-E was much higher than that in the EL induced cells or any of the uninduced cells. Additionally only the LMW-E induced cells underwent chromosome aberrations and increased polyploidy. By examining changes in proliferation and survival in cells with induced full length and LMW-E, CDK inhibitors alone were determined to be insufficient to specifically inhibit LMW-E expressing cells. However, in combination with doxorubicin, the CDK inhibitor, roscovitine (seliciclib, CYC202), synergistically led to increased cell death in LMW-E expressing cells. Clinically, the combination of CDK inhibitors and chemotherapy such as doxorubicin provides a viable personalized treatment strategy for those breast cancer patients whose tumors express the LMW-E. PMID- 21695459 TI - Anti-cytokeratin CAM 5.2 (B.D. Biosciences) has a primary reactivity with CK 7 and CK 8 (48 and 52 kD) rather than with the smaller molecular weight keratin breakdown fractions (50, 43, and 38 kD). PMID- 21695460 TI - SerpinB3, a new prognostic tool in breast cancer patients treated with neoadjuvant chemotherapy. AB - It is unclear which patients with breast cancer benefit from anthracycline-based neoadjuvant chemotherapy and whether taxanes increase survival. Hsp70 and serpinB3 inhibit a lysosomal cell death pathway induced in anthracycline and taxane treated cells, which may be critical for breast cancer cell survival. Thus we evaluated serpinB3 and Hsp70 as putative prognostic biomarkers in breast cancer patients treated with neoadjuvant chemotherapy. SerpinB3 and Hsp70 were measured by immunohistochemistry in residual breast tumours of patients without a complete pathological response [pCR] (n = 250), from a retrospective cohort of 296 patients treated with anthracycline-based chemotherapy with or without sequential docetaxel prior to surgical resection. SerpinB3 (P = 0.02) and Hsp70 (P = 0.008) positivity in residual tumour were associated with a poor pathological response and serpinB3 was an independent prognostic biomarker (HR 2.1 (95% CI 1.2-3.8), P = 0.02). Docetaxel significantly improved overall survival of breast cancer patients treated with neoadjuvant chemotherapy. Furthermore, serpinB3 positivity predicted poor survival in patients treated with anthracycline-based chemotherapy alone (P = 0.02), but those with serpinB3 negative tumours had as equally good survival as those also treated with docetaxel (P = 0.7). Survival was independent of serpinB3 expression in patients who received sequential docetaxel. The Nottingham prognostic index (NPI), calculated at surgical resection, predicted overall survival in these neoadjuvantly treated patients (P < 0.001) and serpinB3 status segregated patients with a moderate NPI into distinct prognostic subgroups. The use of clinical (NPI) and molecular (serpinB3) biomarkers measured at surgical resection to provide accurate prognostication in patients who do not achieve a pCR following neoadjuvant chemotherapy could facilitate optimal post-operative clinical management of these patients and is of significant clinical value. Furthermore, serpinB3 status in residual tumour is a biomarker of neoadjuvant docetaxel benefit in patients not achieving a pCR and use of serpinB3 molecular subtyping for adjuvant docetaxel treatment planning warrants further investigation. PMID- 21695461 TI - Curcumin protects mice against concanavalin A-induced hepatitis by inhibiting intrahepatic intercellular adhesion molecule-1 (ICAM-1) and CXCL10 expression. AB - The effect of curcumin on liver injury caused by Concanavalin A (Con A) has not been carefully examined. This study was designed to evaluate the protective effect of curcumin on Con A-induced hepatitis in mice. Liver injured mice received curcumin by gavage at a dose of 200 mg/kg body weight before Con A intravenous administration. Curcumin was effective in reducing the elevated plasma levels of aminotransferases and the incidence of liver necrosis compared with Con A-injected control group. Enzyme-linked immunosorbent assay (ELISA) showed that curcumin suppressed proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-4 production in Con A-injected mice. The reduced severity of hepatitis in curcumin pretreated mice correlated with decrease in numbers of liver CD4(+) T cells but not CD8(+) T cells by immunohistochemical analysis. Furthermore, the expression levels of intercellular adhesion molecule-1 (ICAM-1) and the interferon-inducible chemokine CXCL10 in hepatic tissue were significantly decreased by curcumin pretreatment. In conclusion, curcumin pretreatment protects against T cell-mediated hepatitis in mice. PMID- 21695462 TI - Transforming growth factor-beta1 promotes lung adenocarcinoma invasion and metastasis by epithelial-to-mesenchymal transition. AB - Lung cancer is a highly malignant carcinoma, and most deaths of lung cancer are caused by metastasis. The alterations associated with epithelial-to-mesenchymal transition (EMT) may be related to the cancer cell metastasis. Nevertheless, the mechanism of lung cancer metastasis remains unclear. We conducted a study in vitro to investigate whether transforming growth factor-beta1 (TGF-beta1) could induce changes of, such as cell morphology, expression of relative protein markers, and cellular motile and invasive activities. In this research, the changes of cell morphology were first investigated under a phase contrast microscope, then western blotting was employed to detect the expression of E cadherin, vimentin, and fibronectin, and finally cell motility and invasion were evaluated by cell wound-healing as well as invasion assays. The data indicated that human lung adenocarcinoma cell lines, A-549 and PC-9 cells of epithelial cell characteristics, were induced to undergo EMT by TGF-beta1. Following TGF beta1 treatment, cells showed dramatic morphological changes assessed by phase contrast microscopy, accompanied by decreased epithelial marker E-cadherin and increased mesenchymal markers vimentin and fibronectin. More importantly, cell motility and invasion were also enhanced in the EMT process. These results indicated that TGF-beta1 may promote lung adenocarcinoma invasion and metastasis via the mechanism of EMT. PMID- 21695463 TI - Arthroscopic management and platelet-rich plasma therapy for avascular necrosis of the hip. AB - PURPOSE: The purpose is to describe a noninvasive arthroscopic procedure as an alternative to open surgery for avascular necrosis of the hip. METHODS: Patients with grade I or IIA avascular necrosis of the hip are treated by core decompression performed by drilling under fluoroscopic guidance. Liquid platelet rich plasma (PRP) is delivered through a trocar, saturating the necrotic area. In more severe conditions, the necrotic bone is decompressed and debrided, through a cortical window at the head-neck junction. A composite graft made of autologous bone and PRP is delivered by impactation through the core decompression track. Fibrin membranes are applied to enhance healing of the head-neck window and arthroscopic portals. Platelet-rich plasma is infiltrated in the central compartment. RESULTS: This arthroscopic approach aids in making diagnosis of the labrum and articular cartilage and permits intra-operative treatment decisions. Visual control permits the precise localization and treatment for the necrotic area allowing cartilage integrity to be preserved. CONCLUSIONS: Arthroscopic management of avascular necrosis of the femoral head is viable and has significant advantages. Clinical studies should justify the theoretical additional benefits of this approach. PMID- 21695464 TI - The fixation strength of tibial PCL press-fit reconstructions. AB - PURPOSE: A secure tibial press-fit technique in posterior cruciate ligament reconstructions is an interesting technique because no hardware is necessary. For anterior cruciate ligament (ACL) reconstruction, a few press-fit procedures have been published. Up to the present point, no biomechanical data exist for a tibial press-fit posterior cruciate ligament (PCL) reconstruction. The purpose of this study was to characterize a press-fit procedure for PCL reconstruction that is biomechanically equivalent to an interference screw fixation. METHODS: Quadriceps and hamstring tendons of 20 human cadavers (age: 49.2 +/- 18.5 years) were used. A press-fit fixation with a knot in the semitendinosus tendon (K) and a quadriceps tendon bone block graft (Q) were compared to an interference screw fixation (I) in 30 porcine femora. In each group, nine constructs were cyclically stretched and then loaded until failure. Maximum load to failure, stiffness, and elongation during failure testing and cyclical loading were investigated. RESULTS: The maximum load to failure was 518 +/- 157 N (387-650 N) for the (K) group, 558 +/- 119 N (466-650 N) for the (I) group, and 620 +/- 102 N (541-699 N) for the (Q) group. The stiffness was 55 +/- 27 N/mm (18-89 N/mm) for the (K) group, 117 +/- 62 N/mm (69-165 N/mm) for the (I) group, and 65 +/- 21 N/mm (49-82 N/mm) for the (Q) group. The stiffness of the (I) group was significantly larger (P = 0.01). The elongation during cyclical loading was significantly larger for all groups from the 1st to the 5th cycle compared to the elongation in between the 5th to the 20th cycle (P < 0.03). CONCLUSION: All techniques exhibited larger elongation during initial loading. Load to failure and stiffness was significantly different between the fixations. The Q fixation showed equal biomechanical properties compared to a pure tendon fixation (I) with an interference screw. All three fixation techniques that were investigated exhibit comparable biomechanical properties. Preconditioning of the constructs is critical. Clinical trials have to investigate the biological effectiveness of these fixation techniques. PMID- 21695465 TI - Collagen meniscus implantation: a systematic review including rehabilitation and return to sports activity. AB - PURPOSE: To determine collagen meniscus implant (CMI) efficacy for improving patient function, symptoms, and activity level. Study methodologies, rehabilitation, and return to sports guidelines were also reviewed. METHODS: MedLine, EMBASE, CINAHL, Life Science Citations, and Cochrane Central Register of Controlled Trials databases were searched from January 1995-May 2011 using the term collagen meniscal or meniscus implant. Only human studies with English language abstracts that reported patient outcomes were included. Modified Coleman Methodology criteria were used to score research quality. RESULTS: Eleven studies with 520 subjects (men = 428; women = 92; 17.7% women) of 38.2 +/- 3.7 years of age met the inclusion criteria. Of these subjects, 321 (men = 263, women = 58; 18.1% women) received a CMI. Based primarily on Lysholm Knee Score, Tegner Activity Scale, pain scales and self-assessment measurements knee function, symptoms, and activity level generally improved by 46.6 +/- 39.9 months post surgery. Rehabilitation was described in 9/11 (81.8%) studies and four released patients to full activities at 6 months post-surgery. No study described how advanced rehabilitation or function testing contributed to return to activity decision-making. Research quality was generally low (67.1 +/- 18.6) with widely ranging (29-97) scores. Reduced CMI size at last follow-up was reported in 6/11 (54.5%) studies, but the significance of this finding is unknown. CONCLUSIONS: Knee function, symptoms, and activity level generally improved following CMI use, but poor research report quality was common. Additional well-designed long-term prospective studies are needed to better determine knee osteoarthrosis prevention efficacy and appropriate patient selection. PMID- 21695466 TI - Estrogen and muscle stiffness have a negative relationship in females. AB - PURPOSE: Hormonal fluctuations are one potential reason why females might have a greater rate of noncontact ACL injury. The hamstrings are capable of limiting anterior cruciate ligament (ACL) loading. This study examined whether relationships existed between reproductive hormones (estradiol-beta-17, free testosterone, and progesterone) and hamstring neuromechanical variables (hamstring musculotendinous stiffness (MTS), rate of force production (RFP), time to 50% peak torque (T50%), and electromechanical delay (EMD)) in genders combined and independently. METHODS: Muscle properties of the hamstrings and reproductive hormones were evaluated in 30 subjects (15 males and 15 females) that were free from lower extremity injury and had no history of ACL injury. Females were tested 3-5 days after the onset of menses and were not using oral contraceptive. Pearson correlation coefficients were calculated for each hormone and muscle property. RESULTS: For genders combined, estrogen (mean = 46.0 +/- 28.2 pg/mL) was negatively correlated with RFP (mean = 758.8 +/- 507.6 N/kg s(-1), r = -0.43, P = 0.02) and MTS (mean = 12.8 +/- 2.6 N/cm, r = -0.43, P = 0.02). Free testosterone (mean = 13.2 +/- 13.0 pg/mL) was positively correlated with RFP (r = 0.56, P < 0.01) and MTS (r = 0.46, P = 0.01) but negatively correlated with T50% (mean = 114.7 +/- 38.9 ms, r = -0.43, P = 0.02). When gender was considered separately, females demonstrated negative correlation between estrogen (mean = 68.0 +/- 23.2 pg/mL) and MTS (mean = 11.7 +/- 1.5 N/cm, r = -0.53, P = 0.05) and free testosterone (mean = 1.5 +/- 0.6 pg/mL) and MTS (r = -0.52, P = 0.05). Males alone displayed no significant correlations between the selected hormones and muscle properties. CONCLUSIONS: Correlations exist between muscle properties and reproductive hormones. Females, however, may be more sensitive to reproductive hormones and their fluctuations. PMID- 21695467 TI - The arrangement and the attachment areas of three ACL bundles. AB - PURPOSE: Normal anterior cruciate ligament (ACL) can be divided into three fiber bundles-i.e., anteromedial (AM), intermediate (IM), and posterolateral (PL) bundles. However, their arrangement and attachment areas had remained unclear. The purpose of this study was to clarify the arrangement of these three ACL fiber bundles and their attachment sites, and to provide information on the tunnel placement in anatomical triple bundle ACL reconstruction. METHODS: Seven non embalmed human frozen knees were used. ACL fibers were bluntly divided into three bundles. A different-colored thread was wound around each fiber bundle in a spiral. Macroscopical investigation was performed to clarify the arrangement of three ACL bundles. Each fiber bundle was carefully detached from the femur and tibia, and then the distribution of attachment sites of each fiber bundle was observed. RESULTS: In knee extension, all bundles consisting of AM, IM and PL bundles ran parallel to each other in the lateral view from the medial side. The AM bundle overlapped with the IM bundle, whereas the PL bundle ran parallel to them on the distal aspects. As the knee flexion increased, the bundles became twisted around each other. On the tibial side, the attachment areas of three fiber bundles formed a triangular shape showing arrangements of AM, IM and PL bundles on the anteromedial, anterolateral and posterior aspects, respectively. On the femoral side, the PL bundle was attached on the distal-posterior areas; the IM bundle was attached distal-anterior to the AM bundle. They were arranged in a triangular shape on the tibia side as well. CONCLUSION: This study clarified the arrangement of three fiber bundles of ACL and detailed geographical locations of their attachment sites. The detailed anatomic description of the natural ACL attachment might suggest to surgeons where to make tunnels during anatomical double/triple bundle ACL reconstruction. PMID- 21695468 TI - Use of transtibial aimer via the accessory anteromedial portal to identify the center of the ACL footprint. AB - PURPOSE: To assess the ability of a transtibial aimer with a 7-mm off-set in a standardized position to reach the center of the ACL footprint on the femur through the AM portal. METHODS: Nineteen cadaveric knees were dissected, and the perimeter of the femoral ACL footprint was marked. The aimer was placed just superior to the medial joint line close to the medial condyle through the AM portal. The guide was rested upon the posterior cortex and placed in three different positions: (A) at zero degrees in frontal plane and 60 degrees in axial plane, (B) at 45 degrees in frontal and 45 degrees in axial, and (C) at the center of the ACL insertion site under direct visualization. A digital camera was used to take pictures on the axial plane, and Image J software was used for angle measurement. Aluminum beads were used to mark the three positions indicated by the aimer, and CT scans were performed. The distances from the true center of the ACL to each point were determined. RESULTS: Position A resulted in femoral tunnel placement furthest from the center of the ACL footprint (8.6 mm). Position B was at a distance of 3.2 mm, and position C was the most accurate, with an average distance of 2.0 mm. The angles required by Position C varied with an average of 54 degrees +/- 11 degrees in the frontal plane and an average of 44 degrees +/- 6 degrees in the axial plane. CONCLUSION: The 7-mm transtibial aimer was unable to reach the center of ACL footprint at a fixed orientation. PMID- 21695469 TI - In vivo microdialysis and electroencephalographic activity in freely moving guinea pigs exposed to organophosphorus nerve agents sarin and VX: analysis of acetylcholine and glutamate. AB - Organophosphorus nerve agents such as sarin (GB) and VX irreversibly inhibit acetylcholinesterase, causing a buildup of acetylcholine (ACh) in synapses and neuromuscular junctions, which leads to excess bronchial secretions, convulsions, seizures, coma, and death. Understanding the unique toxic characteristics of different nerve agents is vital in the effort to develop broad spectrum medical countermeasures. To this end, we employed a repeated measure multivariate design with striatal microdialysis collection and high-performance liquid chromatography analysis to measure changes in concentrations of several neurotransmitters (ACh, glutamate, aspartate, GABA) in the same samples during acute exposure to GB or VX in freely moving guinea pigs. Concurrent with microdialysis collection, we used cortical electrodes to monitor brain seizure activity. This robust double multivariate design provides greater fidelity when comparing data while also reducing the required number of subjects. No correlation between nerve agents' propensity for causing seizure and seizure-related lethality was observed. The GB seizure group experienced more rapid and severe cholinergic toxicity and lethality than that of the VX seizure group. Seizures generated from GB and VX exposure resulted in further elevation of ACh level and then a gradual return to baseline. Glutamate levels increased in the GB, but not in the VX, seizure group. There were no consistent changes in either aspartate or GABA as a result of either nerve agent. These observations reinforce findings with other nerve agents that seizure activity per se contributes to the elevated levels of brain ACh observed after nerve agent exposure. PMID- 21695470 TI - Creative mood swings: divergent and convergent thinking affect mood in opposite ways. AB - Increasing evidence suggests that emotions affect cognitive processes. Recent approaches have also considered the opposite: that cognitive processes might affect people's mood. Here we show that performing and, to a lesser degree, preparing for a creative thinking task induce systematic mood swings: Divergent thinking led to a more positive mood, whereas convergent thinking had the opposite effect. This pattern suggests that thought processes and mood are systematically related but the type of relationship is process-specific. PMID- 21695471 TI - Haptic identification of raised-line drawings: high visuospatial imagers outperform low visuospatial imagers. AB - It has been assumed (Lederman et al. 1990, Perception & psychophysics) that a visual imagery process is involved in the haptic identification of raised-line drawings of common objects. The finding of significant correlations between visual imagery ability and performance on picture-naming tasks was taken as experimental evidence in support of this assumption. However, visual imagery measures came from self-report procedures, which can be unreliable. The present study therefore used an objective measure of visuospatial imagery abilities in sighted participants and compared three groups of high, medium and low visuospatial imagers on their accuracy and response times in identifying raised line drawings by touch. Results revealed between-group differences on accuracy, with high visuospatial imagers outperforming low visuospatial imagers, but not on response times. These findings lend support to the view that visuospatial imagery plays a role in the identification of raised-line drawings by sighted adults. PMID- 21695472 TI - Body movement enhances the extraction of temporal structures in auditory sequences. AB - Auditory and motor systems interact in processing auditory rhythms. This study investigated the effect of intuitive body movement, such as head nodding or foot tapping, on listeners' ability to entrain to the pulse of an auditory sequence. A pulse-finding task was employed using an isochronous sequence of tones in which tones were omitted at pseudorandom positions. Musicians and non-musicians identified their subjectively fitting pulse either using periodic body movement or through listening only. The identified pulse was measured subsequently by finger tapping. Movement appeared to assist pulse extraction especially for non musicians. The chosen pulse tempi tended to be faster with movement. Additionally, movement led to higher synchronization stabilities of the produced pulse along the sequence, regardless of musical training. These findings demonstrated the facilitatory role of body movement in entraining to auditory rhythms and its interaction with musical training. PMID- 21695473 TI - Recurrence of posterior polymorphous corneal dystrophy is caused by the overgrowth of the original diseased host endothelium. AB - Posterior polymorphous corneal dystrophy (PPCD) is a rare, bilateral autosomal dominant disorder affecting primarily the corneal endothelium and descemet membrane (DM). The aim of this study was to establish the origin of abnormal endothelium in a patient with PPCD exhibiting cornea graft failure after keratoplasty surgery. A sex-mismatched graft obtained from a patient with PPCD who underwent repeat penetrating keratoplasty and the patient's original cornea were investigated. Combined fluorescent immunohistochemistry for cytokeratin (CK) 19 (a marker of aberrant PPCD endothelium) with fluorescence in situ hybridization (FISH) of the sex chromosomes were used in order to characterize the cells on the posterior graft surface. The pathological endothelium of the failed PPCD cornea revealed strong positivity for CK19 using fluorescent immunohistochemistry. In all the CK19-positive cells, both X and Y chromosomes were simultaneously detected using FISH. The results clearly showed the original cells of the patient (XY), within 3.5 years, almost totally overgrown the posterior corneal surface of the graft (XX). Moreover, an abnormal posterior collagenous layer populated by fibroblast-like cells was observed between DM and the endothelium in the failed graft, but its exact origin could not be established due to the low number of cells. Simultaneous detection of CK19 using fluorescent immunohistochemistry together with the detection of gonosomes using FISH was performed for the first time in the cornea and allowed us to prove that the recurrence of PPCD was caused by pathological abnormal proliferation and migration of recipient cells into donor graft. PMID- 21695474 TI - Clinical practice: Obstructive renal candidiasis in infancy. AB - Renal candidiasis is an increasingly common condition affecting predominantly premature infants receiving neonatal intensive care or term infants with urogenital tract anomalies. Multiple risk factors are usually present. Although rare, some infants develop an obstructive uropathy due to fungal balls, and this requires prompt detection and intervention to preserve kidney function. The management of obstructive renal bezoars is challenging and not well summarised in the past. This is mainly due to scarce literature confined to case reports or case series only. This review clarifies various definitions used in relation to renal candidiasis and identifies infants particularly at risk of obstruction. Clinical presentation, diagnosis and the role of imaging are discussed. A summary of the recent literature is provided to outline the range of existing treatment options available with published drug dosages and mode of delivery used. No single approach is successful in all cases and clinicians need to be aware of the different options available: apart from adequate urinary drainage and use of systemic +/- local antifungal agents, additional treatment with fibrinolytic agents and/or endoscopic or open surgical removal may be required. A new simplified algorithm for use in management is proposed. We hope this review will help clinicians in their management of patients presenting with this complex and challenging diagnosis. PMID- 21695475 TI - Perceived stress and team performance during a simulated resuscitation. AB - PURPOSE: Barriers to optimal performance of cardiopulmonary resuscitation may partly relate to human factors, such as stress and specific emotions. The aim of this study was to investigate whether mental stress and different perceived emotions have a negative impact on the performance of rescuers. METHODS: This prospective, observational study was conducted at the Simulator Center of the University Hospital Basel, Switzerland. A total of 120 medical students (70% female) participated in teams of three. They reported levels of perceived stress, feeling overwhelmed, motivation and specific emotions before, during, and after a simulated resuscitation. The association of stress/overload (index of stress and feeling overwhelmed), motivation, and specific emotions with resuscitation performance defined as hands-on time during the first 180 s after cardiac arrest was investigated. RESULTS: During resuscitation, levels of stress/overload, motivation, and negative emotions were significantly higher as compared to the periods before and after resuscitation. In contrast, positive emotions were highest before and after resuscitation and significantly lower during resuscitation. In general, females reported higher stress/overload and negative emotions, whereas males reported more positive emotions. A multivariate linear regression model showed negative associations of stress/overload (regression coefficient -18.12, 95% CI -30.73, -5.51, p = 0.006) and positive associations of motivation (regression coefficient 13.45, 95% CI 0.95, 25.95, p = 0.036) with resuscitation performance. CONCLUSION: A simulated cardiac arrest caused substantial perceived stress/overload and negative emotions, particularly in female students, which adversely impacted resuscitation performance. Further studies are required to expand our findings to more experienced medical professionals and investigate whether stress coping strategies improve resuscitation performance. PMID- 21695476 TI - The role of renal hypoperfusion in development of renal microcirculatory dysfunction in endotoxemic rats. AB - PURPOSE: To study the role of renal hypoperfusion in development of renal microcirculatory dysfunction in endotoxemic rats. METHODS: Rats were randomized into four groups: a sham group (n = 6), a lipopolysaccharide (LPS) group (n = 6), a group in which LPS administration was followed by immediate fluid resuscitation which prevented the drop of renal blood flow (EARLY group) (n = 6), and a group in which LPS administration was followed by delayed (i.e., a 2-h delay) fluid resuscitation (LATE group) (n = 6). Renal blood flow was measured using a transit time ultrasound flow probe. Microvascular perfusion and oxygenation distributions in the renal cortex were assessed using laser speckle imaging and phosphorimetry, respectively. Interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha were measured as markers of systemic inflammation. Furthermore, renal tissue samples were stained for leukocyte infiltration and inducible nitric oxide synthase (iNOS) expression in the kidney. RESULTS: LPS infusion worsened both microvascular perfusion and oxygenation distributions. Fluid resuscitation improved perfusion histograms but not oxygenation histograms. Improvement of microvascular perfusion was more pronounced in the EARLY group compared with the LATE group. Serum cytokine levels decreased in the resuscitated groups, with no difference between the EARLY and LATE groups. However, iNOS expression and leukocyte infiltration in glomeruli were lower in the EARLY group compared with the LATE group. CONCLUSIONS: In our model, prevention of endotoxemia-induced systemic hypotension by immediate fluid resuscitation (EARLY group) did not prevent systemic inflammatory activation (IL-6, IL-10, TNF-alpha) but did reduce renal inflammation (iNOS expression and glomerular leukocyte infiltration). However, it could not prevent reduced renal microvascular oxygenation. PMID- 21695477 TI - Genotype * environment interaction is weaker in genitalia than in mating signals and body traits in Enchenopa treehoppers (Hemiptera: Membracidae). AB - Theory predicts that selection acting across environments should erode genetic variation in reaction norms; i.e., selection should weaken genotype * environment interaction (G * E). In spite of this expectation, G * E is often detected in fitness-related traits. It thus appears that G * E is at least sometimes sustained under selection, a possibility that highlights the need for theory that can account for variation in the presence and strength of G * E. We tested the hypothesis that trait differences in developmental architecture contribute to variation in the expression of G * E. Specifically, we assessed the influence of canalization (robustness to genetic or environmental perturbations) and condition dependence (association between trait expression and prior resource acquisition or vital cellular processes). We compared G * E across three trait types expected to differ in canalization and condition-dependence: mating signals, body size related traits, and genitalia. Because genitalia are expected to show the least condition-dependence and the most canalization, they should express weaker G * E than the other trait types. Our study species was a member of the Enchenopa binotata species complex of treehoppers. We found significant G * E in most traits; G * E was strongest in signals and body traits, and weakest in genitalia. These results support the hypothesis that trait differences in developmental architecture (canalization and condition-dependence) contribute to variation in the expression of G * E. We discuss implications for the dynamics of sexual selection on different trait types. PMID- 21695478 TI - The presence and localization of melatonin receptors in the rat aorta. AB - Melatonin is involved in blood pressure modulation in rats and humans. Some of the effects of melatonin are presumably mediated via two G-protein-coupled receptors (MT(1) and MT(2)), but the distribution of MT(1) and MT(2) in the cardiovascular system remains to be explored comprehensively. We investigated the expression of both the receptors in the rat aorta on mRNA level by RT-PCR and real time RT-PCR as well as on protein level via western blotting and immunofluorescence microscopy. We verified MT(1) mRNA expression in the rat aorta and demonstrated the absence of MT(2) mRNA in this vessel type. MT(1) receptors were confirmed also at the protein level, and surprisingly they were preferentially localized to the tunica adventitia. Since no daily changes in MT(1) mRNA expression were detected, we suppose that the circadian changes in circulating melatonin concentrations are sufficient to mediate circadian effects of melatonin in the aorta. The localization of MT(1) in the tunica adventitia suggests an influence of melatonin on vasa vasorum function and signal transduction in the aorta wall. PMID- 21695479 TI - Anticonvulsive effect of folic acid in homocysteine thiolactone-induced seizures. AB - Numerous studies have linked folate deficiency and resultant elevated plasma homocysteine levels with an increased risk of neurodegenerative diseases and seizures. The aim of the present study was to examine the effect of acute folic acid administration on behavioural and electroencephalographic (EEG) characteristics of DL homocysteine thiolactone-induced seizures in adult rats. Adult male Wistar rats were divided into following groups: (1) saline-treated (C); (2) DL homocysteine thiolactone 8 mmol/kg, i.p. (H); (3) groups that received folic acid i.p. in doses: 5 mg/kg (F(5)), 10 mg/kg (F(10)) and 15 mg/kg (F(15)) and (4) F 30 min prior to H (F(5)H, F(10)H and F(15)H, respectively). Seizure behaviour was assessed by incidence, latency, number and intensity of seizure episodes. Seizure severity was described by a descriptive scale with grades 0-4. For EEG recordings, under pentobarbital anaesthesia three gold-plated recording electrodes were implanted into the skull. There were no behavioural and EEG signs of seizure activity in C, F(5), F(10) and F(15) groups. In F(15)H group, the incidence of seizures was significantly lower, and the latency significantly prolonged, comparing to the H. Pre-treatment with F did not affect median number and severity of seizure episodes in all FH groups. Administration of F decreased mean total spectral power density in all FH groups, in a dose dependent manner, in comparison with H. Our findings suggest that folic acid has anticonvulsive and antiepileptic effect on H-induced seizures in adult rats. PMID- 21695480 TI - Transcriptomic and nuclear architecture of immune cells after LPS activation. AB - Changes in the nuclear positioning of specific genes, depending on their expression status, have been observed in a large diversity of physiological processes. However, gene position is poorly documented for immune cells which have been subjected to activation following bacterial infection. Using a pig model, we focused our study on monocyte-derived macrophages and neutrophils, as they are the first lines of defence against pathogens. We examined whether changes in gene expression due to LPS activation imply that genes have repositioned in the nuclear space. We first performed a transcriptomic analysis to identify the differentially expressed genes and then analysed the networks involved during lypopolysaccharide/interferon gamma activation in monocyte derived macrophages. This allowed us to select four up-regulated (IL1beta, IL8, CXCL10 and TNFalpha) and four down-regulated (VIM, LGALS3, TUBA3 and IGF2) genes. Their expression statuses were verified by quantitative real-time RT-PCR before studying their behaviour in the nuclear space during macrophage activation by means of 3D fluorescence in situ hybridization. No global correlation was found between gene activity and radial positioning. Only TNFalpha belonging to the highly transcribed MHC region on chromosome 7 became more peripherally localized in relation to the less decondensed state of its chromosome territory (CT) in activated macrophages. The analysis of gene positioning towards their CT revealed that IL8 increases significantly its tendency to be outside its CT during the activation process. In addition, the gene to CT edge distances increase for the three up-regulated genes (IL8, CXCL10 and TNFalpha) among the four analysed. Contrarily, the four down-regulated genes did not change their position. The analysis of gene behaviour towards their CT was extended to include neutrophils for three (TNFalpha, IL8 and IL1beta) up- and two (IGF2 and TUBA3) down-regulated genes, and similar results were obtained. The analysis was completed by studying the four up-regulated genes in fibroblasts, not involved in immune response. Our data suggest that relocation in the nuclear space of genes that are differentially expressed in activated immune cells is gene and cell type specific but also closely linked to the entire up-regulation status of their chromosomal regions. PMID- 21695481 TI - Effects of etidronate on calcification of scales and ribs in the goldfish, Carassius auratus. AB - Effects of etidronate on the calcification of scales and ribs were investigated in goldfish. Daily intraperitoneal injections of etidronate at doses of 1 and 10 mgP/kg body weight for 2 weeks inhibited calcification of ontogenic scales and ribs without affecting the accretion of organic matrices. Removal of some scales induced their regeneration within the two-week period. Their newly formed organic matrix was fully uncalcified in fish treated with 10 mgP/kg, whereas in those treated with 1 mgP/kg, the regenerating scales were only partially calcified. Daily administration of etidronate 10 mgP/kg resulted in an increase of body weight. These results suggested that the inhibitory effect of etidronate on the calcification of osseous tissues in mammals can be expected also on comparable tissues in fishes. An appropriate dose of etidronate that inhibits hard tissue calcification but not affects the body growth in fish seemed to exist between 1 and 10 mgP/kg. PMID- 21695482 TI - Effects of Haematococcus pluvialis supplementation on antioxidant system and metabolism in rainbow trout (Oncorhynchus mykiss). AB - Effects of commercial source for astaxanthin (Haematococcus pluvialis) (H.p) on antioxidant power, specific marker enzymes, and some metabolites were examined in rainbow trout (Oncorhynchus mykiss). Fish were fed on diets containing 1, 3, and 10 g microalga kg(-1) feed for 30 days. Serum total antioxidant activity and lipid peroxidation product, indicated by malondialdehyde (MDA), significantly enhanced with different doses of administration, indicating the elevated antioxidant status in all treatment groups. In group fed with high dose of alga, significantly elevated aspartate aminotransferase activity (AST) was noted, indicating damage of normal liver function in this group. Alkaline phosphatase (ALP) and alanine aminotransferase (ALT) were not affected in all groups. Although serum total protein remained unaffected, serum glucose level was decreased significantly in lower doses of administration. Furthermore, triglyceride and cholesterol levels showed significant decrease in 3 g kg(-1) microalga group by modulation of lipid metabolism in this group. On the other hand, in highest dose, significant increase in lipids was observed, indicating the slight dysfunction in lipid metabolism in this treatment group. The present study suggests that Haematococcus pluvialis especially in dose of 3 g kg(-1) feed administration may effectively enhance the antioxidant system and some biochemical parameters in rainbow trout. PMID- 21695483 TI - Results of the clinical donor case and quality system case workshops of the European Association of Tissue Banks annual meeting 2009. AB - The European Association of Tissue Banks (EATB) Donor Case Workshop and Quality System Case workshop are forums held within the program of the EATB Annual Congress. These workshops offer an opportunity to discuss and evaluate approaches taken to challenging situations, regarding donor selection and quality issues, and strengthen the professional tissue banking and regulatory networks across Europe. This report reflects some of the discussion at the congress workshops and also subsequent correspondence between the various individuals who submitted cases for discussion. The cases presented to the workshops demonstrate that the findings, their interpretation, deducted actions and preventive measures in tissue banks are not predictable. The varied responses and lack of consensus corroborate this and clearly indicate that operating procedures cannot comprehensively cover or prepare for all eventualities. For many of the issues raised there is a lack of information in the published literature. The workshops actively engage participants, representing a wide array of international expertise, in an informal, secure and enjoyable setting, which facilitates learning from peers and provides potential solutions to those submitting cases. By publishing a summary of the discussions, we hope to reach a wider audience and to stimulate individuals to undertake full literature reviews or research on some of the discussed subjects. PMID- 21695485 TI - Using clinical cardiovascular risk scores to predict coronary artery plaque severity and stenosis detected by CT coronary angiography in asymptomatic Chinese subjects. AB - We aimed to determine whether the Framingham risk score (FRS), systematic coronary risk evaluation (SCORE), and Chinese multi-provincial cohort study (CMCS) could predict anatomic severity of coronary plaques. From January 2007 to October 2010, we performed a contrast-enhanced 64-slice or 256-slice multidetector computed tomography coronary angiography as part of a health check up protocol in 806 asymptomatic subjects (70.5% male, 56 +/- 9 year-old). Risk scores significantly correlated with calcium volume score, plaque stenosis score and plaque distribution score (P < 0.001). Of the 3 risk scores, the SCORE system showed the best correlation. Overall, 180 (22%) and 37 (5%) subjects were found to have stenosis of 50-69% and more than 70% in at-least one coronary artery segment, respectively. In the prediction of the presence of obstructive CAD (>= 50% diameter stenosis), all risk scores had similar discrimination. In the prediction of severe CAD (>= 70% diameter stenosis), FRS and CMCS had similar area under curves but SCORE discriminated better than FRS (P < 0.05). The optimal cutoff point to predict obstructive CAD was 9.54% for FRS, 1.05% for CMCS, and 0.95% for SCORE, whereas to predict severe CAD was 9.63, 1.05, 1.15% for FRS, CMCS, SCORE, respectively, with a sensitivity of 0.61-0.70 and a specificity of 0.55-0.66. Cardiovascular risk scores are associated with the severity and extent of coronary artery plaque. The stronger association might translate into a better discrimination using SCORE. These findings will aid in the appropriate selection or recalibration of the risk assessment system for cardiovascular disease screening. PMID- 21695484 TI - Three-dimensional analysis of interventricular septal curvature from cardiac magnetic resonance images for the evaluation of patients with pulmonary hypertension. AB - Although abnormal septal motion is a well-known sign of increased pulmonary arterial pressures, it is not routinely used to quantify the severity of pulmonary hypertension (PH). This determination relies on invasive measurements or Doppler echocardiographic estimation of right ventricular (RV) pressures, which is not always feasible or accurate in patients with PH. We hypothesized that dynamic 3D analysis of septal curvature from cardiac magnetic resonance (CMR) images may reveal differences between patients with different degrees of PH. Forty-four patients (14 controls; 30 PH patients who underwent right heart catheterization) were studied using CMR and echocardiography. CMR imaging was performed using Philips 1.5T scanner with a phased-array cardiac coil, in a retrospectively gated steady-state free precession cine mode at 30 frames per cardiac cycle. Patients were divided into 3 subgroups according to pulmonary arterial pressure. CMR images were used to reconstruct dynamic 3D left ventricular endocardial surfaces, which were analyzed to calculate septal curvature throughout the cardiac cycle. 3D curvature analysis was feasible in 88% patients. Septal curvature showed different temporal patterns in different groups. Curvature values progressively decreased with increasing severity of PH, and correlated well with invasive pressures (r-values 0.78-0.79), pulmonary vascular resistance (r = 0.83) and Doppler-derived RV peak-systolic pressure (r = 0.75). 3D analysis of septal curvature from CMR images may become a useful component in the CMR examination in patients with known or suspected PH. PMID- 21695486 TI - Enhancement of activity and selectivity of Candida rugosa lipase and Candida antarctica lipase A by bioimprinting and/or immobilization for application in the selective ethanolysis of fish oil. AB - Candida rugosa lipase (CRL) and Candida antarctica lipase A (CALA) with improved activity and selectivity were prepared for use in organic solvent media. CRL bioimprinted with fatty acids exhibited eightfold enhanced transesterification activity in hexane. Combination of bioimprinting and coating with lecithin or with immobilization did not improve the activity further. CALA was immobilized with and without bioimprinting, none of which improved the activity. All modified lipases were tested for selective ethanolysis of fish oil to concentrate omega-3 polyunsaturated fatty acids (PUFA). None of the preparations, except the immobilized ones catalysed ethanolysis. Immobilized CRL-catalyzed ethanolysis giving 27% (v/v) ethyl esters (EE) in 48 h, of which 43 mol% was oleic acid but no PUFA was detected in the EE fraction. Fatty acid selectivity of CALA was significantly improved by immobilization combined with bioimprinting, resulting in 5.5-fold lower omega-3 PUFA in EE. PMID- 21695487 TI - A highly stable Cu/Zn superoxide dismutase from Withania somnifera plant: gene cloning, expression and characterization of the recombinant protein. AB - A gene from Withania somnifera (winter cherry), encoding a highly stable chloroplastic Cu/Zn superoxide dismutase (SOD), was cloned and expressed in Escherichia coli. The recombinant enzyme (specific activity of ~4,200 U mg(-1)) was purified and characterized. It retained ~90 and ~70% residual activities after 1 h at 80 and 95 degrees C, respectively. At 95 degrees C, thermal inactivation rate constant (K (d)) of the enzyme was 2.46 * 10(-3) min(-1) and half-life of heat inactivation was 4.68 h. The enzyme was stable against a broad pH range (2.5-11.0). It also showed a high degree of resistance to detergent, ethanol and protease digestion. This recombinant Cu/Zn SOD could therefore have useful applications. PMID- 21695488 TI - Varenicline as a smoking cessation aid in schizophrenia: effects on smoking behavior and reward sensitivity. AB - RATIONALE: Smoking rates are up to five times higher in people with schizophrenia than in the general population, placing these individuals at high risk for smoking-related health problems. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, is a promising aid for smoking cessation in this population. To maximize treatment efficacy while minimizing risks, it is critical to identify reliable predictors of positive response to varenicline in smokers with schizophrenia. OBJECTIVES: Negative symptoms of schizophrenia are related to dysfunctions in the brain reward system, are associated with nicotine dependence, and may be improved by nicotine or nicotinic receptor agonists, suggesting that smoking cessation may be especially difficult for patients with substantial negative symptoms. The purpose of the study was to evaluate negative symptoms as predictors of response to varenicline. METHODS: Patients with schizophrenia (N = 53) completed a 12-week smoking cessation trial combining varenicline with cognitive behavioral therapy. Negative symptoms were assessed via the Scale for the Assessment of Negative Symptoms (Andreasen 1983). Outcomes included smoking abstinence as assessed by self-report and expired carbon monoxide. Change in performance on a probabilistic reward task was used as an index of change in reward sensitivity during treatment. RESULTS: At week 12, 32 participants met criteria for 14-day point-prevalence abstinence. Patients with lower baseline symptoms of affective flattening (more typical affect) were more likely to achieve smoking abstinence and demonstrated larger increases in reward sensitivity during treatment. CONCLUSIONS: These data suggest that affective flattening symptoms in smokers with schizophrenia may predict response to varenicline. PMID- 21695489 TI - Archaeal and bacterial diversity in hot springs on the Tibetan Plateau, China. AB - The diversity of archaea and bacteria was investigated in ten hot springs (elevation >4600 m above sea level) in Central and Central-Eastern Tibet using 16S rRNA gene phylogenetic analysis. The temperature and pH of these hot springs were 26-81 degrees C and close to neutral, respectively. A total of 959 (415 and 544 for bacteria and archaea, respectively) clone sequences were obtained. Phylogenetic analysis showed that bacteria were more diverse than archaea and that these clone sequences were classified into 82 bacterial and 41 archaeal operational taxonomic units (OTUs), respectively. The retrieved bacterial clones were mainly affiliated with four known groups (i.e., Firmicutes, Proteobacteria, Cyanobacteria, Chloroflexi), which were similar to those in other neutral-pH hot springs at low elevations. In contrast, most of the archaeal clones from the Tibetan hot springs were affiliated with Thaumarchaeota, a newly proposed archaeal phylum. The dominance of Thaumarchaeota in the archaeal community of the Tibetan hot springs appears to be unique, although the exact reasons are not yet known. Statistical analysis showed that diversity indices of both archaea and bacteria were not statistically correlated with temperature, which is consistent with previous studies. PMID- 21695491 TI - Physiology of the aging bone and mechanisms of action of bisphosphonates. AB - Fragility fractures, a major public health concern, are expected to further increase due to aging of the world populations because age remains a cardinal, independent determinant of fracture risk. With aging the balance between bone formation and resorption during the remodeling process becomes negative, with increased resorption and reduced formation. Bisphosphonates (BPs) are widely prescribed anti-resorptive agents that inhibit osteoclasts attachment to bone matrix and enhance osteoclast apoptosis. BPs can be divided into nitrogen containing (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). Both classes induce apoptosis but they evoke it differently. Several studies have examined the molecular mechanisms underlying BPs' effects on osteoclasts and bone remodeling. N-BPs (alendronate, risedronate, zoledronate) inhibit the intracellular mevalonate pathway and protein isoprenylation, via the enzyme farnesyl pyrophosphate synthase. N-BPs act by competition, binding to the natural substrate-binding site of the enzyme. The less potent non-N-BPs (etidronate, clodronate), do not inhibit the mevalonate pathway and protein isoprenylation, but are metabolized intracellularly to metabolites, which are cytotoxic analogs of ATP. N-BPs represent the first choice treatment for diseases associated with excessive bone resorption, such as fragility fractures (due to postmenopausal-, male, glucocorticoid- and transplant-induced osteoporosis), Paget's disease of bone, and bone metastasis. Better understanding of BPs' effects on osteoblasts/osteocytes (e.g., preventing apoptosis) and differential distribution may further help explain anti-fracture benefit and bone quality effects. Lower affinity BPs (e.g., risedronate) may allow better access to osteocyte network. Effects of BPs on bone senescence, cancer cells apoptosis and prevention of cardiovascular calcifications may open new avenues for biogerontological research. PMID- 21695490 TI - [Perioperative visual loss after nonocular surgery]. AB - Perioperative visual loss (POVL) after nonocular surgery is a rare but unexpected event and represents a devastating complication. It is most often associated with cardiac, spinal as well as head and neck surgery. The etiology of POVL remains incompletely understood. Any portion of the visual system may be involved, from the cornea to the occipital lobe. The most common site of permanent injury is, however, the optic nerve itself and ischemia is the most often presumed mechanism. Multiple factors have been proposed as risk factors for POVL, including long duration in the prone position, decreased ocular perfusion pressure, excessive blood loss and anemia, hypotension, hypoxia, excessive fluid replacement, elevated venous pressure, head positioning and a patient-specific vascular susceptibility which may be anatomic or physiologic. However, the risk factors for any given patient or procedure may vary. The underlying specific pathogenesis of these neuro-ophthalmic complications remains unknown and physicians should be alert to the potential for loss of vision in the postoperative period. This review updates readers on the incidence, suspected risk factors, diagnosis and treatment of POVL in the setting of nonocular surgery. PMID- 21695492 TI - In memoriam professor Corwin Hansch: birth pangs of QSAR before 1961. PMID- 21695493 TI - Properties and detection of two cryptoviruses from pepper (Capsicum annuum). AB - Pepper (Capsicum annuum L.) contains a range of endogenous dsRNA molecules resembling the genomes of cryptoviruses. In this work, we have completed the molecular characterization of Pepper cryptic virus 1 (PCV-1) from cv "Jalapeno M" and generated complete genomic sequences of another cryptovirus from cv "Hungarian Wax" designated Pepper cryptic virus 2 (PCV-2). The two viruses share limited identical amino acid content in both genomic segments and appear phylogenetically closer to cryptoviruses reported from other crops (i.e. Raphanus sativus cryptic virus 3, Black raspberry cryptic virus) than to each other. Two sets of virus-specific primers were successfully used in RT-PCR tests for the simultaneous and discriminative detection of these two viruses in pepper leaves and seeds. Both viruses were detected in several pepper cultivars tested, either as single or mixed infections. PMID- 21695494 TI - [Management of an HTLV-1 infected man in assisted reproductive technology]. AB - Management of people infected by HTLV-1 in assisted reproductive technology (ART) is a rare event. Since HTLV is sexually transmitted, HTLV serodiscordant couples have to systematically use condoms. The sperm processing (centrifugation on density gradient) performed for semen of HIV-infected men was applied. Detection of HTLV-1 provirus DNA was negative before and after sperm processing, allowing ART. PMID- 21695495 TI - [HIV and risk factors for the blood donors at the central hospital of Yaounde, Cameroon]. AB - The HIV/AIDS infection is in a permanent progress in Cameroon. Through this descriptive and analytical cross-sectional study, we aimed to compare the occurrence of the HIV by taking into account the risks factors that are significantly associated with HIV. The investigation was carried out from 1 January till 31 December 2009 in the Blood Bank of the Central Hospital of Yaounde in Cameroon. A structured questionnaire was proposed to collect socio demographic and risk behavioral information. Venous blood was collected for HIV antibody testing. Generalized estimating equation with logistic regression was used to analyze the risk factors for HIV infection. In all, 5 058 persons were included in this study. Serological examination revealed a total prevalence of 5.4% of HIV infection in the population studied. The family/replacement donors constituted the majority (69.5%) and showed a higher risk of seropositivity of HIV than the benevolent donors in raw analysis; but after adjustment, the family donors had the same risk of seropositivity of HIV than voluntary blood donors (aOR = 1.00). Variables such as homosexual intercourse (aOR = 1.61), to have already made a screening test of HIV (aOR = 1.83), mobility (aOR = 2.24), treatment and records of STI (aOR = 3.81), use of the condom (aOR = 6.63), more than one sexual partner (aOR = 8.40) remained significantly linked to the result of the HIV serology and constituted risk factors that will be emphasized during the selection of the donors. PMID- 21695496 TI - [Targeted screening for HTLV-1 in couples requesting medically assisted reproduction]. AB - Currently there are no guidelines for the targeting of HTLV-1 screening of couples requesting inclusion in an assisted fertility programme. These can be drawn up only if there is a multidisciplinary input allowing for specialist advice on the quantification of risk in the target populations offered help with fertility both in mainland France and the Antilles or French Guyana.In units offering Assisted Reproductive Technics (ART) targeted screening which might reveal a requirement for specific medical management, presents the opposing problems of the need for exhaustive questioning of the couple and that of non discrimination. If screening is arranged to take place before the couple is taken on for assisted reproduction, then the good practice which is currently recommended and applied for HIV, is a suitable reference model. It remains to define the expected benefits in this branch of medicine where medical responsibility in assisted conception is already highly regulated. Moreover, if any measures are applied in the context of assisted reproduction, this would suggest that similar guidelines should be established for natural conception. PMID- 21695498 TI - Diagnosis of diabetes diseases using an Artificial Immune Recognition System2 (AIRS2) with fuzzy K-nearest neighbor. AB - The use of expert systems and artificial intelligence techniques in disease diagnosis has been increasing gradually. Artificial Immune Recognition System (AIRS) is one of the methods used in medical classification problems. AIRS2 is a more efficient version of the AIRS algorithm. In this paper, we used a modified AIRS2 called MAIRS2 where we replace the K- nearest neighbors algorithm with the fuzzy K-nearest neighbors to improve the diagnostic accuracy of diabetes diseases. The diabetes disease dataset used in our work is retrieved from UCI machine learning repository. The performances of the AIRS2 and MAIRS2 are evaluated regarding classification accuracy, sensitivity and specificity values. The highest classification accuracy obtained when applying the AIRS2 and MAIRS2 using 10-fold cross-validation was, respectively 82.69% and 89.10%. PMID- 21695497 TI - [Viral infection risk in polytransfused adults: seroprevalence of seven viruses in central Tunisia]. AB - The aim of this study is to evaluate the prevalence of seven transfusion transmitted viruses in polytransfused adults and children comparatively with a group of healthy control subjects. We studied 107 polytransfused patients (59 adults and 48 children) and 160 control subjects (100 blood donors and 60 children). Immunoenzymatic tests were used for detection of HBs antigen (HBs Ag), antibodies against hepatitis C Virus (anti-HCV), and human immunodeficiency virus (anti-HIV), and IgG antibodies against human cytomegalovirus (IgG anti-CMV), human parvovirus B19 (IgG anti-PB19), and hepatitis E virus (IgG anti-HEV). An immunofluorescent assay was performed for the detection of human herpesvirus 8 antibodies (anti-HHV8). Prevalence of HBs Ag, anti-HCV, anti-HIV, IgG anti-CMV, IgG anti-PB19, IgG anti-HEV, and anti-HHV8 in polytransfused group was 8.4, 4.7, 0, 86.9, 60.7, 28.9, and 47.6%, respectively, and 1.8, 0.6, 0, 86.2, 53.1, 10, and 12.5%, respectively, in the control group. The difference in prevalence between the two groups was statistically significant for HBs Ag (P = 0.01), anti HCV (P = 0.03), IgG anti-HEV (P < 10(-4)), and IgG anti-HHV8 (P < 10(-4)). Categorization according to age showed that hepatitis B and C risk was limited in adult polytransfused group. HHV8 infection was higher in polytransfused subjects born before the use of leucocyte-depleted blood components. Our results corroborate literature data on the risk of HEV and HHV8 infection by blood transfusion. Hepatitis B vaccination and improvement in screening tests have an important role in reduction of hepatitis B and C risk in transfusion, especially in young polytransfused persons. However, a residual risk of transmitting viral infections persists, and efforts are needed to improve transfusion safety. PMID- 21695499 TI - Variable threshold method for ECG R-peak detection. AB - In this paper, a wearable belt-type ECG electrode worn around the chest by measuring the real-time ECG is produced in order to minimize the inconvenient in wearing. ECG signal is detected using a potential instrument system. The measured ECG signal is transmits via an ultra low power consumption wireless data communications unit to personal computer using Zigbee-compatible wireless sensor node. ECG signals carry a lot of clinical information for a cardiologist especially the R-peak detection in ECG. R-peak detection generally uses the threshold value which is fixed. There will be errors in peak detection when the baseline changes due to motion artifacts and signal size changes. Preprocessing process which includes differentiation process and Hilbert transform is used as signal preprocessing algorithm. Thereafter, variable threshold method is used to detect the R-peak which is more accurate and efficient than fixed threshold value method. R-peak detection using MIT-BIH databases and Long Term Real-Time ECG is performed in this research in order to evaluate the performance analysis. PMID- 21695500 TI - Positive illusions in adolescents: the relationship between academic self enhancement and depressive symptomatology. AB - Positive illusions are systematically inflated self-perceptions of competence, and are frequently seen in areas of great difficulty. Although these illusions have been extensively documented in children and adults, their role in typical adolescent emotion regulation is unclear. This study investigated the relationship between positive illusions, depressive symptomatology, and school stress in a sample of 71 school-based adolescents. Findings revealed that adolescents who were achieving slightly below average in math significantly overestimated their performance, but adolescents did not overestimate their performance in spelling. Positive illusions in math were negatively related to depressive symptomatology. Implications for positive illusions theory are discussed. PMID- 21695501 TI - Factors affecting encouragement of relatives among families with Lynch syndrome to seek medical assessment. AB - Lynch syndrome (HNPCC) is an autosomal dominant hereditary cancer syndrome, and members of affected families are at-risk for developing colorectal and other associated tumors. Such individuals should disseminate familial genetic information, so they can seek specific medical assessment or genetic testing to reduce mortality and morbidity rates by early detection. Since published results have been encouraging, we explored which factors influence the likelihood of good communication within families regarding medical assessment. We studied 40 individuals from 33 families who satisfied the Japanese clinical criteria for Lynch syndrome and their relatives at our hospital. We determined the status of relatives of the 40 individuals after genetic counseling and testing using questionnaires and semi-structured interviews based on pedigree charts. We also examined their knowledge or perception of colorectal cancer syndrome, levels of intimacy and whether or not they encouraged their relatives to have specific medical assessments. We found that 75% of the individuals advised their relatives to seek medical assessment, and any significant background factors that promoted such encouragement were observed. They tended to encourage first degree relatives and discuss the issue with other family members such as spouses before undertaking such attempts at encouragement. The reasons and methods of imparting encouragement were essentially identical. We also found that genetic testing for at-risk or more distant relatives was not encouraged so often. Therefore, providing individuals who have been tested for Lynch syndrome with opportunities for disseminating familial genetic information through appropriate genetic counseling is important. PMID- 21695502 TI - Electrical characterization of single cells using polysilicon wire ion sensor in an isolation window. AB - A polysilicon wire (PSW) sensor can detect the H(+) ion density (pH value) of the medium coated on its surface, and different cells produce different extracellular acidification and hence different H(+) ion densities. Based on this, we used a PSW sensor in combination with a mold-cast polydimethylsiloxane (PDMS) isolation window to detect the adhesion, apoptosis and extracellular acidification of single normal cells and single cancer cells. Single living human normal cells WI38, MRC5, and BEAS-2B as well as non-small-cell lung cancer (NSCLC) cells A549, H1299, and CH27 were cultivated separately inside the isolation window. The current flowing through the PSW channel was measured. From the PSW channel current change as a function of time, we determined the cell adhesion time by observing the time required for the current change to saturate, since a stable extracellular ion density was established after the cells were completely adhered to the PSW surface. The apoptosis of cells can also be determined when the channel current change drops to zero. We found that all the NSCLC cells had a higher channel current change and hence a lower pH value than the normal cells anytime after they were seeded. The corresponding average pH values were 5.86 for A549, 6.00 for H1299, 6.20 for CH27, 6.90 for BEAS-2B, 6.96for MRC5, and 7.02 for WI38, respectively, after the cells were completely adhered to the PSW surface. Our results show that NSCLC cells have a stronger cell-substrate adhesion and a higher extracellular acidification rate than normal cells. PMID- 21695503 TI - Hippocampal levels of GluR1 and GluR2 complexes are modulated by training in the Multiple T-maze in C57BL/6J mice. AB - A series of studies has shown the importance of AMPA-type glutamate receptors (AMPARs) for memory formation. The aim of the current study was to show whether GluR1 and GluR2 complexes rather than subunits in mouse hippocampus were involved in training in the multiple T-Maze (MTM). C57BL/6J mice were trained in the MTM and compared to yoked controls. 6 h following the completion of the fourth day training, mice were euthanized, hippocampi were taken and proteins extracted, run on blue native gels with subsequent immunoblotting with antibodies against mouse GluR1 and GluR2. On blue-native western blotting, GluR1 protein was represented by a single band at the apparent molecular weight of about 480 kDa probably indicating a tetrameric assembly. GluR2 protein was represented by a single band between apparent molecular weights of 480 and 720 kDa indicating a homo- or heteropolymer probably with other AMPAR or regulatory subunits. In mice trained in the MTM, protein levels for GluR1 were significantly increased while GluR2 levels were significantly decreased. On two-dimensional (2D) gel electrophoresis, the presence of GluR1 and GluR2 were identified by mass spectrometry, and 2D immunoblotting revealed several expression forms of these receptor subunits. Findings unequivocally show that GluR1 and GluR2 complexes are linked to training in the MTM in C57BL/6J mice. These results may not only form the basis for studying receptor complexes rather than receptor subunits in memory formation or mechanisms of potential cognitive enhancers but represent a tool for investigations into pharmacological studies including the use of glutamate receptor agonists and antagonists. PMID- 21695504 TI - Comparison of the anti-inflammatory and anti-nociceptive effects of cortistatin 14 and somatostatin-14 in distinct in vitro and in vivo model systems. AB - We showed that somatostatin (SST) exerts anti-inflammatory and anti-nociceptive effects through somatostatin receptor subtypes 4 and 1 (sst(4)/sst(1)). Since cortistatin (CST) is a structurally similar peptide, we aimed at comparing the sst(1)- and sst(4)-binding and activating abilities, as well as the effects of SST-14 and CST-14 on inflammatory and nociceptive processes. CST-14 concentration dependently displaced radiolabeled SST-14 binding, induced similar sst(1) and sst(4)-activation with a less potency, and exerted significantly greater inhibitory effect on endotoxin-stimulated interleukin (IL)-1beta production of murine peritoneal macrophages. Capsaicin-induced calcitonin gene-related peptide release from peripheral sensory nerve terminals of isolated rat tracheae was significantly decreased by 2 MUM CST and 100 nM SST, but concentration-response correlation was not found. Mustard oil-evoked acute neurogenic plasma protein extravasation in the rat hindpaw skin, carrageenan-induced mouse paw edema, mechanical hyperalgesia, and IL-1beta, tumor necrosis factor-alpha production, as well as mild heat injury-evoked thermal hyperalgesia were similarly attenuated by both peptides. In the latter case, i.pl. and i.p. injections exerted equal inhibitory actions. CST-14 and SST-14 similarly diminish both acute neurogenic and cellular inflammatory processes, as well as mechanical and heat hyperalgesia, in which their inhibitory effect on sensory nerve endings is likely to be involved. However, CST-14 exerts remarkably greater inhibition on cytokine production. PMID- 21695505 TI - Quantitative structure activity relationships of some pyridine derivatives as corrosion inhibitors of steel in acidic medium. AB - Quantum chemical calculations using the density functional theory (B3LYP/6-31G DFT) and semi-empirical AM1 methods were performed on ten pyridine derivatives used as corrosion inhibitors for mild steel in acidic medium to determine the relationship between molecular structure and their inhibition efficiencies. Quantum chemical parameters such as total negative charge (TNC) on the molecule, energy of highest occupied molecular orbital (E (HOMO)), energy of lowest unoccupied molecular orbital (E (LUMO)) and dipole moment (MU) as well as linear solvation energy terms, molecular volume (Vi) and dipolar-polarization (pi) were correlated to corrosion inhibition efficiency of ten pyridine derivatives. A possible correlation between corrosion inhibition efficiencies and structural properties was searched to reduce the number of compounds to be selected for testing from a library of compounds. It was found that theoretical data support the experimental results. The results were used to predict the corrosion inhibition of 24 related pyridine derivatives. PMID- 21695506 TI - Molecular docking and 3D-QSAR study on 4-(1H-indazol-4-yl) phenylamino and aminopyrazolopyridine urea derivatives as kinase insert domain receptor (KDR) inhibitors. AB - Vascular endothselial growth factor (VEGF) and its receptor tyrosine kinase VEGFR 2 or kinase insert domain receptor (KDR) have been identified as new promising targets for the design of novel anticancer agents. It is reported that 4-(1H indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives exhibit potent inhibitory activities toward KDR. To investigate how their chemical structures relate to the inhibitory activities and to identify the key structural elements that are required in the rational design of potential drug candidates of this class, molecular docking simulations and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods were performed on 78 4-(1H indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives as KDR inhibitors. Surflex-dock was used to determine the probable binding conformations of all the compounds at the active site of KDR. As a result, multiple hydrophobic and hydrogen-bonding interactions were found to be two predominant factors that may be used to modulate the inhibitory activities. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were developed based on the docking conformations. The CoMFA model produced statistically significant results with the cross-validated correlation coefficient q(2) of 0.504 and the non-cross-validated correlation coefficient r(2) of 0.913. The best CoMSIA model was obtained from the combination of steric, electrostatic and hydrophobic fields. Its q(2) and r(2) being 0.595 and 0.947, respectively, indicated that it had higher predictive ability than the CoMFA model. The predictive abilities of the two models were further validated by 14 test compounds, giving the predicted correction coefficients r (pred) (2) of 0.727 for CoMFA and 0.624 for CoMSIA, respectively. In addition, the CoMFA and CoMSIA models were used to guide the design of a series of new inhibitors of this class with predicted excellent activities. Thus, these models may be used as an efficient tool to predict the inhibitory activities and to guide the future rational design of 4-(1H-indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives-based novel KDR inhibitors with potent activities. PMID- 21695507 TI - Homology modeling of the structure of acyl coA:isopenicillin N-acyltransferase (IAT) from Penicillium chrysogenum. IAT interaction studies with isopenicillin-N, combining molecular dynamics simulations and docking. AB - In the last step of penicillin biosynthesis, acyl-CoA:isopenicillin N acyltransferase (IAT) (E.C. 2.3.1.164) catalyzes the conversion of isopenicillin N (IPN) to penicillin G. IAT substitutes the alpha-aminoadipic acid side chain of IPN by a phenylacetic acid phenolate group (from phenylacetyl-CoA). Having a three-dimensional (3D) structure of IAT helps to determine the steps involved in side chain exchange by identifying the atomic details of substrate recognition. We predicted the IAT 3-D structure (alpha- and beta-subunits), as well as the manner of IPN and phenylacetyl-CoA bind to the mature enzyme (beta-subunit). The 3D IAT prediction was achieved by homology modeling and molecular docking in different snapshots, and refined by molecular dynamic simulations. Our model can reasonably interpret the results of a number of experiments, where key residues for IAT processing as well as strictly conserved residues most probably involved with enzymatic activity were mutated. Based on the results of docking studies, energies associated with the complexes, and binding constants calculated, we identified a site located in the region generated by beta1, beta2 and beta5 strands, which forms part of the central structure of beta-subunit, as the potential binding site of IPN. The site comprises the amino acid residues Cys103, Asp121, Phe122, Phe123, Ala168, Leu169, His170, Gln172, Phe212, Arg241, Leu262, Asp264, Arg302, Ser309, and Arg310. Through hydrogen bonds, the IPN binding site establishes interactions with Cys103, Leu169, Gln172, Asp264 and Arg310. Our model is also validated by a recently revealed crystal structure of the mature enzyme. PMID- 21695508 TI - Essential metal (Cu, Zn) exposures alter the activity of ATPases in gill, kidney and muscle of tilapia Oreochromis niloticus. AB - An acute (96 h--0.1, 0.5, 1.0, 1.5 MUg/ml) and chronic (up to 30 days--0.05 MUg/ml) protocols of Cu and Zn were applied to freshwater fish Oreochromis niloticus to investigate these essential metal effects on the activities of gill, kidney and muscle Na(+)/K(+)-ATPase, Mg(2+)-ATPase and Ca(2+)-ATPase. In vitro effects of both metals (20 min--0.1, 0.5, 1.0, 1.5 MUg/ml) were also measured to be able to compare both exposure routes. Data showed that ATPase activities, in general, decreased following all the exposure conditions, though there were some increases especially in Mg(2+)-ATPase activity. Among the enzymes, Na(+)/K(+) ATPase and Ca(2+)-ATPase appeared to be more sensitive than Mg(2+)-ATPase to the metals. The data also indicated that effects of Cu on ATPase activity in the tissues of O. niloticus were stronger than the effects of Zn, possibly due to higher toxic effects of Cu. In vivo and in vitro exposures of metals showed similar trends with a few exceptions, especially in the gill. Variability of ATPase activity is determined by tissue type, metal species, concentration and duration. This work showed that even essential metals can alter significantly activities of ATPases in fish and thus suggests using them as a sensitive biomarker in metal contaminated waters. PMID- 21695509 TI - Acute effects of pure cylindrospermopsin on the activity and transcription of antioxidant enzymes in tilapia (Oreochromis niloticus) exposed by gavage. AB - The cyanobacterial toxin cylindrospermopsin (CYN) is a widely distributed contaminant of freshwater systems with the consequent risk for human and wildlife, particularly fish. However, CYN toxicity data on fish are still scarce. It is known that CYN inhibits glutathione synthesis and this could contribute to oxidative damage. In the present work tilapia (Oreochromis niloticus) were exposed by gavage to 200 and 400 MUg/kg bw of pure CYN and sacrificed after 24 h. The activity and relative mRNA expression by real-time PCR of antioxidant enzymes glutathione peroxidase (GPx) and soluble glutathione-S-transferases (sGST) and the sGST protein abundance by Western blot analysis were evaluated in liver and kidney. Also the induction of lipid peroxidation (LPO) was assayed. Results show an increase of LPO products in both organs. Moreover, CYN altered the activity, gene expression and protein abundance of the enzymes, indicating the importance of GPx and sGST in CYN pathogenicity. This is the first time that CYN is reported to affect these enzymes in fish and they have shown to be responsive biomarkers of CYN toxicity. PMID- 21695510 TI - Chronic zebrafish low dose decabrominated diphenyl ether (BDE-209) exposure affected parental gonad development and locomotion in F1 offspring. AB - Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants around the world. Because of large production volumes, widespread usage and persistence, PBDEs are now ubiquitous environmental pollutants detected in a wide variety of environment media and human samples and therefore pose a significant public health concern. Deca-PBDE (BDE-209) is the only commercial PBDE mixture still allowed for use at present, and has been recently detected at high levels in human samples. However, few studies explore its effect on development, reproduction or neurobehavior with animal models. In particular, studies with long-term chronic exposure at relatively low doses are lacking. In this study, we utilize the zebrafish model to explore the developmental, reproductive, and behavioral toxicities associated with long-term chronic exposure to deca-PBDE (BDE-209). Our findings revealed that long-term chronic exposure to low dose of deca-BDE (ranging from 0.001 to 1 MUM) affected overall fitness (measured by condition factor), gonad development, male gamete quantity and quality in F0 parental fish. For F1 offspring without continuous exposure to BDE-209, parental BDE treatment led to delayed hatch and motor neuron development, loose muscle fiber, slow locomotion behavior in normal conditions, and hyperactivity when subjected to light-dark photoperiod stimulation. In conclusion, parental chronic low dose BDE-209 exposure not only affects F0 growth and reproduction, but also elicits neurobehavior alternations in F1 offspring. PMID- 21695511 TI - Ecotoxicological diagnosis of striped dolphin (Stenella coeruleoalba) from the Mediterranean basin by skin biopsy and gene expression approach. AB - Mediterranean cetacean odontocetes are exposed to environmental stress, in particular to persistent organic pollutants, polycyclic aromatic hydrocarbons and trace elements. In the present study, the response of "gene-expression biomarkers" was evaluated in Mediterranean striped dolphin (Stenella coeruleoalba) skin biopsies collected in three sampling areas: Pelagos sanctuary (Ligurian sea), Ionian sea, and Strait of Gibraltar. The mRNA levels of five putative biomarker genes (aryl hydrocarbon receptor, E2F-1 transcription factor, cytochrome P450 1A, estrogen receptor 1, and heat shock protein 70) were measured for the first time by quantitative real-time PCR in cetacean skin biopsies. The different responses of most of the genes reflected contamination levels in the three sampling areas. Pelagos sanctuary dolphins appeared to be the most exposed to toxicological stress, having the highest up-regulation of CYP1A and AHR. Moreover, a cluster analysis distinguished the populations on the basis of the gene expression biomarker used in our study, showing different pattern between Mediterranean sea and Strait of Gibraltar. Our results suggest that this molecular approach applied to non-destructive biopsy material is a powerful diagnostic tool for evaluating ecotoxicological impact on cetacean populations. PMID- 21695512 TI - Lysenkoism in poland. AB - This article describes the impact of, and response to, Trofim D. Lysenko's anti genetics campaign in Poland between the years 1949 and 1956. It focuses particularly upon the response of three individuals - Teodor Marchlewski, Waclaw Gajewski, and Aleksandra Putrament - who were central figures in the controversy in Poland. In addition to examining the responses and motivations of these individuals, the article also addresses the question of why the Lysenko-era in Poland ended relatively earlier than in neighboring Soviet-allied states such as Hungary, East Germany or Czechoslovakia, as well as 9 years before Lysenko was forced from power in the USSR. I argue that conditions specific to Polish politics and Poland's relationship with the Soviet Union, during the Thaw after Stalin's death, provided the opponents of "Lysenkoism" in Poland with an opportunity to criticize Lysenko, and restore Polish genetics. These conditions are linked to the near-revolution in Poland following the strike in Poznan in June, 1956, and successful transition of power between Edward Ochab and Wladyslaw Gomulka the following October. PMID- 21695513 TI - Should esophageal resections for cancer be performed in high-volume centers only? AB - Esophageal resection remains the only curative option for esophageal cancer, and therefore, improving the outcome of surgery is the best method of reducing mortality. Several studies have evaluated the postoperative morbidity and mortality after esophageal resection, analyzing the relationship between volume or surgical experience and operative mortality. In this article, the evidence supporting the referral of esophageal surgery to centers with a greater experience (i.e., high-volume centers) is reviewed in order to establish the best practice. PMID- 21695514 TI - Familial Mediterranean fever and seronegative arthritis. AB - Familial Mediterranean fever (FMF) is characterized by recurrent, self-limited episodes of polyserositis, with articular involvement also being a common manifestation. The pattern and joint predilection of arthritis show many similarities to those of spondyloarthritis. Moreover, case series suggest an increased prevalence of ankylosing spondylitis or spondyloarthritis among FMF patients. FMF is caused by mutations in the MEFV gene encoding pyrin, which is believed to be involved in regulation of interelukin-1beta activation. Recent studies conducted in populations with a high background carrier rate of MEFV variants have reported an increased frequency of M694V among AS patients with no personal or family history of FMF. These findings are of interest, as both candidate gene and genome-wide association studies suggest that the interleukin-1 cytokine pathway may be implicated in the pathogenesis of ankylosing spondylitis. Therefore, association of M694V with ankylosing spondylitis can be recognized as a geographic region-specific risk factor affecting a common inflammatory pathway in the disease pathogenesis. PMID- 21695515 TI - Diagnostic utility of MRI in early spondyloarthritis. AB - The introduction of MRI in spondyloarthritis (SpA) constitutes a major advance and is increasingly being implemented in clinical practice in cases in which clinical suspicion of SpA is high yet pelvic radiography is equivocal. Recent studies and development of consensus by international experts support the routine use of specific MRI sequences and scanning protocols for the evaluation of the sacroiliac joints in diagnostic work-up. There is also agreement that the finding of bone marrow edema in the sacroiliac joints carries a high probability of SpA, and emerging data indicate that the finding of erosion may also be diagnostically helpful, even in preradiographic SpA. Recent studies suggest that the diagnostic role of MRI may be further enhanced through the study of additional MRI sequences and prospective studies using systematic methodologies aimed at further scrutiny of structural lesions and the contribution of spinal imaging. Interest in MRI for SpA is poised for substantial growth. PMID- 21695516 TI - Natural cycle IVF/IVM may be more desirable for poor responder patients after failure of stimulated cycles. AB - OBJECTIVE: To describe pregnancies and live births resulted from natural cycle IVF combined with in-vitro maturation (natural-cycle IVF/IVM) for three poor responder women after failure of stimulated cycles. METHODS: For case 1 and 2, the mature oocytes from aspirated follicles were inseminated by intracytoplasmic sperm injection (ICSI) immediately; immature oocytes were matured in vitro, and the embryos from mature and immature oocytes transferred on day 3 after oocyte retrieval. For case 3, 3 consecutive natural cycles were performed, in which the matured oocytes from in vivo or in vitro were vitrified in the first and second cycle, and warmed on the retrieval day of the third fresh cycle. Then the embryos resulted from vitrified-warmed and fresh oocytes were transferred. RESULTS: A total of 15 oocytes were obtained from the 7 retrieval cycles for the three cases. The case 1 was successfully pregnant at her first natural cycle, and case 2 was pregnant after two consecutive cycles. The two cases had successfully delivered and case 3 was in her ongoing pregnancy at the time of submission. CONCLUSION: These results demonstrate that natural-cycle IVF/IVM might be a reasonable and efficient treatment alternative for poor responder patients when stimulated cycle has failed. PMID- 21695517 TI - A review of breast imaging following mastectomy with or without reconstruction in an outpatient community center. AB - Despite developments in surgical technique, radiation treatment, and chemotherapeutic agents, tumor recurrence and distant disease have remained a major concern in breast cancer management. Breast imaging after mastectomy in the screening arena remains a controversial topic for breast imagers. Many feel the yield of finding a recurrent cancer with imaging in the asymptomatic patient is too low to be beneficial; others believe imaging should be performed on these patients as the risk of recurrence exists. Patients after a mastectomy procedure are considered high risk and, when they present with clinical symptoms, will require evaluation by the radiologist. In this diagnostic/symptomatic scenario, imaging becomes the routine and current imaging tools, such as mammography, ultrasound, and magnetic resonance imaging (MRI), can easily be incorporated to diagnose recurrent cancer. Our facility has a large population of patients that undergo mastectomy after a carcinoma diagnosis as well as a number of patients that have undergone a mastectomy procedure because of their high-risk status (whether family history or genetic predisposition). A certain percentage of these patients have proceeded to reconstructive surgery. We image these patients routinely as part of our screening protocol. Over the years we have become familiar with the appearance of remaining tissue along the chest wall after mastectomy as well as the reconstructed breasts. This familiarity is important as the imaging of these patients with mammography and other modalities available today can be challenging. This manuscript will discuss the benefits and some limitations surrounding imaging these patients, in both the asymptomatic and symptomatic scenarios, as well as what imaging protocols can be integrated within a facility's standard evaluation. PMID- 21695518 TI - Electroconvulsive therapy: a novel hypothesis for the involvement of purinergic signalling. AB - It is proposed that ATP is released from both neurons and glia during electroconvulsive therapy (ECT) and that this leads to reduction of depressive behaviour via complex stimulation of neurons and glia directly via P2X and P2Y receptors and also via P1 receptors after extracellular breakdown of ATP to adenosine. In particular, A(1) adenosine receptors inhibit release of excitatory transmitters, and A(2A) and P2Y receptors may modulate the release of dopamine. Sequential ECT may lead to changes in purinoceptor expression in mesolimbic and mesocortical regions of the brain implicated in depression and other mood disorders. In particular, increased expression of P2X7 receptors on glial cells would lead to increased release of cytokines, chemokines and neurotrophins. In summary, we suggest that ATP release following ECT involves neurons, glial cells and neuron-glial interactions acting via both P2 and after breakdown to adenosine via P1 receptors. We suggest that ecto-nucleotidase inhibitors (increasing available amounts of ATP) and purinoceptor agonists may enhance the anti depressive effect of ECT. PMID- 21695519 TI - Certification and licensing of clinical medical physicists in AFOMP countries. AB - In many countries the education and training of medical physicists has changed over the last few decades from being rather ad hoc to becoming structured with residency programs becoming quite common. These are often followed by formal certification by independent bodies, and medical physics professional organizations (MPPOs) affirming the quality of certified physicists and recognizing their competence and ability to practice independently. Policies on the training and education of medical physicists have been developed by the International Organization for Medical Physics (IOMP) and by the Asia-Oceania Federation of Organizations for Medical Physics (AFOMP). Currently nine countries in Asia-Oceania operate systems for the certification of clinical medical physicists and four others are planning or implementing such systems. The existing systems, which are described in this paper, generally conform to the policies. Licensing of medical physicists, which is primarily the responsibility of government bodies, is almost unknown in that region. PMID- 21695520 TI - Simulating waiting list management. AB - Patients' experiences of waiting for treatment have changed dramatically in recent years in the United Kingdom's National Health Service. There has been a substantial reduction in the mean wait but the characteristics of the distributions have also changed significantly, implying a change in priorities and waiting list management. Simulations are often used to assess proposals for investment and reorganisation that might affect waiting time. However, a more realistic model incorporating waiting list management behaviour is needed since empirical distributions of waiting times indicate that a first-in-first-out model is not valid. This study develops a model of waiting list management that includes an explicit measure of priority associated with the patient's wait compared to a specified target. The model can generate a range of behaviours, from the near negative exponential distributions associated with some historic examples of waiting list management, through to the well defined modes of a rigid first-in-first-out system. In one illustration of the use of the waiting list management model, the impact of the seasonal variations in demand and supply was explored. Simulation experiments demonstrated the consequent seasonality in waiting times, implying a need for care when monitoring progress towards any targets. PMID- 21695521 TI - Costing hospital resources for stroke patients using phase-type models. AB - Optimising resources in healthcare facilities is essential for departments to cope with the growing population's requirements. An aspect of such performance modelling involves investigating length of stay, which is a key performance indicator. Stroke disease costs the United Kingdom economy seven billion pounds a year and stroke patients are known to occupy long periods of time in acute and long term beds in hospital as well as requiring support from social services. This may be viewed as an inefficient use of resources. Thrombolysis is a therapy which uses a clot-dispersing drug which is known to decrease the institutionalisation of eligible stroke patients if administered 3 h after incident but it is costly to administer to patients. In this paper we model the cost of treating stroke patients within a healthcare facility using a mixture of Coxian phase type model with multiple absorbing states. We also discuss the potential benefits of increasing the usage of thrombolysis and if these benefits balance the expense of administering the drug. PMID- 21695522 TI - Computed tomographic analysis of the esophagus, left atrium, and pulmonary veins: implications for catheter ablation of atrial fibrillation. AB - PURPOSE: The aim of this study was to investigate the anatomic relationship around the left atrium (LA) and to provide clinical information to help avoid the risk of an atrio-esophageal fistula during atrial fibrillation (AF) ablation. METHODS: The multidetector spiral computed tomography images of 77 male patients (mean age, 54 +/- 9 years) with drug-refractory AF and 37 male control subjects (mean age, 50 +/- 11 years) were analyzed. We measured the following variables: (1) distance between the ostia of the pulmonary veins (PVs) and the ipsilateral esophageal border, (2) presence of a pericardial fat pad around each PV, and (3) contact width/length and presence of a fat pad between the LA and the esophagus. RESULTS: The distance between the esophagus and the ostia of right superior PV, right inferior PV (RIPV), left superior PV, and left inferior PV (LIPV) was 27.2 +/- 9.4 mm, 22.9 +/- 10.3 mm, 2.7 +/- 9.4 mm, and 7.1 +/- 8.8 mm, respectively. A fat pad between the esophagus and the superior PV was present in more than 90% of the subjects in both groups. However, the fat pad around inferior PV was present less frequently in the patients than in the control group (p = 0.011, RIPV; p < 0.001, LIPV). The average length of the LA-esophagus contact in the patients and the control group subjects was 26.2 +/- 10.4 and 18.5 +/- 5.1 mm, respectively (p < 0.001). CONCLUSION: Caution should be exercised when ablating the LIPV because the esophagus is located in close proximity to the left-sided PV and most of the inferior PVs in patients with AF are not covered with fat pads. PMID- 21695523 TI - Muscle ceramide content is similar after 3 weeks' consumption of fat or carbohydrate diet in a crossover design in patients with type 2 diabetes. AB - This study aimed at investigating the effect of prolonged adaptation to fat- or carbohydrate-rich diet on muscle ceramide in type 2 diabetes patients, using a longitudinal crossover study. Eleven type 2 diabetes patients consumed isocaloric fat- or carbohydrate-rich diet for 3 weeks in random order. After each dietary intervention period, muscle glycogen, triacylglycerol and ceramide content and plasma concentrations of insulin, adiponectin, glucose and FFA were determined. Insulin resistance was assessed by HOMA2 calculation. After the dietary period, plasma glucose and insulin, insulin sensitivity, muscle glycogen, triacylglycerol and ceramide content were similar. Plasma adiponectin concentration was significantly higher after fat compared with carbohydrate-rich diet. Results indicated that following fat-rich diet intake muscle ceramide and triacylglycerol concentrations were not different compared with that after carbohydrate-rich diet. Furthermore, plasma adiponectin concentration was higher after fat-rich compared with carbohydrate-rich diet, but insulin sensitivity remained similar despite the major difference in dietary macronutrient composition. PMID- 21695524 TI - Oxygen uptake efficiency plateau: physiology and reference values. AB - The relationship of oxygen uptake [Formula: see text] to ventilation [Formula: see text], i.e., oxygen uptake efficiency (OUE) is known to differ between normal subjects and patients with congestive heart failure. However, only the oxygen uptake efficiency slope (OUES, i.e., slope of [Formula: see text] has previously been reported. To understand the physiology and to improve the usefulness of OUE in assessing cardiovascular function, we analyzed the complete response pattern of OUE during entire incremental exercise tests and ascertained effect of age, body size, gender, fitness, and ergometer type on exercise OUE to generate reference values in normal healthy subjects. We investigated the effect of age, gender, and fitness on OUE using incremental cardiopulmonary exercise in 474 healthy subjects, age 17-78 years, of which 57 were highly fit. The final methods of OUE analysis were: (1) OUE plateau at the highest values (OUEP), (2) OUE at anaerobic threshold (OUE@AT), and (3) OUES using the entire exercise period. The OUEP and OUE@AT were similar, highly reproducible, less variable than the OUES (p < 0.0001), and unaffected by the study sites or types of ergometry. The resultant prediction equations from 417 normal subjects for men were OUEP (mL/L) = 42.18 - 0.189 * years + 0.036 * cm and OUES [L/min/log(L/min)] = -0.610 - 0.032 * years + 0.023 * cm + 0.008 * kg. For women, OUEP (mL/L) = 39.16 - 0.189 * years + 0.036 * cm and OUES [L/min/log(L/min)] = -1.178 - 0.032 * years + 0.023 * cm + 0.008 * kg. OUE@AT was similar to OUEP. Extreme fitness has a minimal effect on OUEP. OUEP is advantageous, since it measures maximal oxygen extraction from ventilated air but does not require high intensity exercise. The OUEP is a non-invasive parameter dependent only on age, gender, height, and cardiovascular health. PMID- 21695525 TI - Patients with left bundle branch block pattern and high cardiac risk myocardial SPECT: does the current management suffice? AB - INTRODUCTION: Myocardial perfusion SPECT (MPS) is frequently used for cardiovascular risk stratification. The significance of MPS in patients with abnormal electrical ventricular activation is often questionable. This review assesses the value of MPS for risk stratification of patients with intrinsic left bundle branch block or that due to right ventricular apical pacing. METHODS: We reviewed the literature by a search of the MEDLINE database (January 1980 to September 2010). The terms prognosis or prognostic value were combined with SPECT and LBBB or pacing or pacemakers. MPS was categorised as low and high risk according to the original definitions. RESULTS: We identified 11 studies suitable for review. A low-risk MPS is associated with a low risk of cardiac events whereas high-risk MPS carries a 4.8-fold increased risk, 95% CI [3.2 - 7.2] (p < 0.0001). Despite secondary prevention and an improved medical and interventional care, these figures have hardly changed over time. CONCLUSION AND CLINICAL IMPLICATIONS: A low-risk MPS permits a policy of watchful waiting whereas a high risk MPS requires further analysis and treatment. The persistent high cardiac death and acute myocardial infarction rate after a high-risk MPS suggest that the current management of these patients does not suffice and needs reconsideration. PMID- 21695526 TI - Isoproterenol-induced cardiomyopathy in rats: influence of Acorus calamus Linn.: A. calamus attenuates cardiomyopathy. AB - Acorus calamus has been used as a traditional remedy since ancient days but its cardioprotective effect is not yet well characterized. The aim of this study was to assess the effect of A. calamus rhizome extract in isoproterenol-induced cardiomyopathy in rats. Male Wistar rats were treated with normal saline (0.5 ml/kg, i.p.), isoproterenol (5 mg/kg, i.p.), A. calamus (100 and 200 mg/kg, respectively, by gavage) alone, amlodipine (9.0 mg/kg, by gavage) alone, A. calamus (100 and 200 mg/kg, respectively) + isoproterenol and amlodipine (9.0 mg/kg) + isoproterenol, single dose/day for 30 days, respectively. Isoproterenol induced cardiomyopathy was characterized by a significant (P < 0.001) increase in heart weigh/body weight ratio, calcineurin, nitric oxide, lactate dehydrogenase, and thiobarbituric acid-reactive substance levels as well as a significant (P < 0.001) decrease in reduced glutathione, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase levels. Treatment with A. calamus significantly (P < 0.05 and P < 0.01) attenuated isoproterenol-induced cardiomyopathy. No significant alteration was found in A. calamus-alone groups compared with the vehicle. Amlodipine is used as standard drug in this study. Thus, the result shows that A. calamus attenuates isoproterenol-induced cardiomyopathy. This could be due to attenuating calcineurin activity and oxidative stress. PMID- 21695527 TI - The unsaturation of phosphatidylglycerol in thylakoid membrane alleviates PSII photoinhibition under chilling stress. AB - Over-expression of chloroplast glycerol-3-phosphate acyltransferase gene (LeGPAT) in tomato increased cis-unsaturated fatty acid content in phosphatidylglycerol (PG) of the thylakoid membrane. Under chilling stress, the oxygen evolving activity, the maximal photochemical efficiency of PSII (F (v)/F (m)), and superoxide dismutase (SOD) and ascorbate peroxidase (APX) activities decreased less in sense lines than in antisense lines compared to wild-type (WT) plants. Consistently, the relative electric conductivity, O-2and H(2)O(2) contents in sense lines were lower than those of WT and antisense lines. The antisense lines with low level of unsaturated fatty acids in PG were extremely susceptible to photoinhibition of PSII and had a significant reduction in the D1 protein content of PSII reaction center under chilling stress. However, in the presence of streptomycin (SM), the degradation of D1 protein was faster in sense lines than in WT and antisense plants. These results suggested that, under chilling stress conditions, increasing cis-unsaturated fatty acids in PG through over-expression of LeGPAT can alleviate PSII photoinhibition by accelerating the repair of D1 protein and improving the activities of antioxidant enzymes in chloroplasts. PMID- 21695528 TI - Fluorescence in situ hybridization on plant extended chromatin DNA fibers for single-copy and repetitive DNA sequences. AB - The compactness of plant chromosomes and the structure of the plant cell wall and cytoplasm provide a great obstacle to fluorescence in situ hybridization (FISH) for single-copy or low-copy DNA sequences. Consequently, many new methods for improving spatial resolution via chromosomal stretching have been employed to overcome this technical challenge. In this article, a technique for extracting cell-wall free nuclei at mitotic interphase, then using these nuclei to prepare extended DNA fibers (EDFs) by the method of a receding interface, whereby slide mounted chromatin produces EDFs in concert with gravity-assisted buffer flow, was adopted as a result of the low frequency of EDF damage produced by this procedure. To examine the quality of these EDFs, we used single-copy gene encoding S-locus receptor kinase and multi-copy 5S rDNA (ribosomal DNA) as probes. The resulting EDFs proved suitable for high-resolution FISH mapping for repetitive DNA sequences, and the localization of a single-copy locus. PMID- 21695529 TI - Cancer screening in patients infected with HIV. AB - Non-AIDS-defining cancers are a rising health concern among HIV-infected patients. Cancer screening is now an important component of health maintenance in HIV clinical practice. The decision to screen an HIV-infected patient for cancer should include an assessment of individualized risk for the particular cancer, life expectancy, and the harms and benefits associated with the screening test and its potential outcome. HIV-infected patients are at enhanced risk of several cancers compared to the general population; anal cancer, hepatocellular carcinoma, Hodgkin's lymphoma, and lung cancer all have good evidence demonstrating an enhanced risk in HIV-infected persons. A number of cancer screening interventions have shown benefit for specific cancers in the general population, but data on the application of these tests to HIV-infected persons are limited. Here we review the epidemiology and background literature relating to cancer screening interventions in HIV-infected persons. We then use these data to inform a conceptual model for evaluating HIV-infected patients for cancer screening. PMID- 21695530 TI - Evolution of species trait through resource competition. AB - To understand the evolution of diverse species, theoretical studies using a Lotka Volterra type direct competition model had shown that concentrated distributions of species in continuous trait space often occurs. However, a more mechanistic approach is preferred because the competitive interaction of species usually occurs not directly but through competition for resource. We consider a chemostat type model where species consume resource that are constantly supplied. Continuous traits in both consumer species and resource are incorporated. Consumers utilize resource whose trait values are similar with their own. We show that, even when resource-supply has a continuous distribution in trait space, a positive continuous distribution of consumer trait is impossible. Self-organized generation of distinct species occurs. We also prove global convergence to the evolutionarily stable distribution. PMID- 21695531 TI - Visual depth from motion parallax and eye pursuit. AB - A translating observer viewing a rigid environment experiences "motion parallax", the relative movement upon the observer's retina of variously positioned objects in the scene. This retinal movement of images provides a cue to the relative depth of objects in the environment, however retinal motion alone cannot mathematically determine relative depth of the objects. Visual perception of depth from lateral observer translation uses both retinal image motion and eye movement. In Nawrot and Stroyan (Vision Res 49:1969-1978, 2009) we showed mathematically that the ratio of the rate of retinal motion over the rate of smooth eye pursuit mathematically determines depth relative to the fixation point in central vision. We also reported on psychophysical experiments indicating that this ratio is the important quantity for perception. Here we analyze the motion/pursuit cue for the more general, and more complicated, case when objects are distributed across the horizontal viewing plane beyond central vision. We show how the mathematical motion/pursuit cue varies with different points across the plane and with time as an observer translates. If the time varying retinal motion and smooth eye pursuit are the only signals used for this visual process, it is important to know what is mathematically possible to derive about depth and structure. Our analysis shows that the motion/pursuit ratio determines an excellent description of depth and structure in these broader stimulus conditions, provides a detailed quantitative hypothesis of these visual processes for the perception of depth and structure from motion parallax, and provides a computational foundation to analyze the dynamic geometry of future experiments. PMID- 21695532 TI - Postpartum impairment of pelvic floor muscle function: factors involved and association with prolapse. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study is to assess factors involved in the impairment of pelvic floor muscle (PFM) function from antepartum to 6 months postpartum. We also investigated whether reduced PFM strength was associated with pelvic organ prolapse (POP) postpartum. METHODS: This was a prospective cohort study including 319 primigravid women delivered vaginally. PFM function was assessed in pregnant women at term and 6 months postpartum by digital palpation and perineometry. Prolapse was explored using the POP quantification (POP-Q) system. RESULTS: Instrumental delivery, larger newborn head circumference, and older maternal age were independent risk factors for impaired PFM function postpartum. Women with POP-Q stage >= II postpartum had a significant decrease in PFM strength with respect to the antepartum period, and lower PFM strength than women without such prolapse. CONCLUSIONS: Both constitutional and obstetric factors are involved in impairment of PFM function postpartum. Reduced PFM strength is associated with prolapse in the postpartum period. PMID- 21695533 TI - Cell growth and P(3HB) accumulation from CO2 of a carbon monoxide-tolerant hydrogen-oxidizing bacterium, Ideonella sp. O-1. AB - Cell growth and accumulation of polyhydroxybutyric acid, P(3HB), from CO(2) in autotrophic condition of a newly isolated hydrogen-oxidizing bacterium, the strain O-1, was investigated. The bacterium, which was deposited in the Japan Collection of Microorganisms as JCM17105, autotrophically grows by assimilating H(2), O(2), and CO(2) as substrate. 16S rRNA gene sequence of the bacterium was the closest to Ideonella dechloratans (99%). Specific growth rate of the strain O 1 was faster than a hydrogen-oxidizing bacterium, Ralstonia eutropha, which is well-known P(3HB)-producing microorganism. The strain O-1 is tolerant to high O(2) concentration and it can grow above 30% (v/v) O(2), while the growth of R. eutropha and Alcaligenes latus was seriously inhibited. In culture medium containing 1 g/L (NH(4))(2)SO(4), cell concentration of the strain O-1 and P(3HB) increased to 6.75 and 5.26 g/L, respectively. The content of P(3HB) in the cells was 77.9% (w/w). The strain O-1 was very tolerant to carbon monoxide (CO) and it grew even at 70% (v/v) CO, while the growth of R. eutropha and A. latus were seriously inhibited at 5% (v/v) CO. From these results, it is expected that the strain O-1 will be useful in the manufacture of P(3HB) because the industrial exhaust gas containing CO(2), H(2), and CO can be directly used as the substrate in the fermentation process. PMID- 21695534 TI - A fast and robust method for automated analysis of axonal transport. AB - Cargo movement along axons and dendrites is indispensable for the survival and maintenance of neuronal networks. Key parameters of this transport such as particle velocities and pausing times are often studied using kymograph construction, which converts the transport along a line of interest from a time lapse movie into a position versus time image. Here we present a method for the automatic analysis of such kymographs based on the Hough transform, which is a robust and fast technique to extract lines from images. The applicability of the method was tested on simulated kymograph images and real data from axonal transport of synaptophysin and tetanus toxin as well as the velocity analysis of synaptic vesicle sharing between adjacent synapses in hippocampal neurons. Efficiency analysis revealed that the algorithm is able to detect a wide range of velocities and can be used at low signal-to-noise ratios. The present work enables the quantification of axonal transport parameters with high throughput with no a priori assumptions and minimal human intervention. PMID- 21695535 TI - Human bone material characterization: integrated imaging surface investigation of male fragility fractures. AB - The interrelation of calcium and phosphorus was evaluated as a function of bone material quality in femoral heads from male fragility fracture patients via surface analytical imaging as well as scanning microscopy techniques. A link between fragility fractures and increased calcium to phosphorus ratio was observed despite normal mineralization density distribution. INTRODUCTION: Bone fragility in men has been recently recognized as a public health issue, but little attention has been devoted to bone material quality and the possible efficacy in fracture risk prevention. Clinical routine fracture risk estimations do not consider the quality of the mineralized matrix and the critical role played by the different chemical components that are present. This study uses a combination of different imaging and analytical techniques to gain insights into both the spatial distribution and the relationship of phosphorus and calcium in bone. METHODS: X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry imaging techniques were used to investigate the relationship between calcium and phosphorus in un-embedded human femoral head specimens from fragility fracture patients and non-fracture age-matched controls. The inclusion of the bone mineral density distribution via backscattered scanning electron microscopy provides information about the mineralization status between the groups. RESULTS: A link between fragility fracture and increased calcium and decreased phosphorus in the femoral head was observed despite normal mineralization density distribution. Results exhibited significantly increased calcium to phosphorus ratio in the fragility fracture group, whereas the non fracture control group ratio was in agreement with the literature value of 1.66 M ratio in mature bone. CONCLUSIONS: Our results highlight the potential importance of the relationship between calcium and phosphorus, especially in areas of new bone formation, when estimating fracture risk of the femoral head. The determination of calcium and phosphorus fractions in bone mineral density measurements may hold the key to better fracture risk assessment as well as more targeted therapies. PMID- 21695536 TI - Inter-individual discount factor differences in reward prediction are topographically associated with caudate activation. AB - In general, humans tend to devalue a delayed reward. Such delay discounting is a theoretical and computational concept in which the discount factor influences the time scale of the trade-off between delay of reward and amount of reward. The discount factor relies on the individual's ability to evaluate the future reward. Using functional magnetic resonance imaging, we investigated brain mechanisms for reward valuation at different individual discount factors in a delayed reward choice task. In the task, participants were required to select small/immediate or large/delayed rewards to maximize the total reward over time. The discount factor for each participant individually was calculated from the behavioral data based on an exponential discounting model. The estimated value of a future reward increases as the expected delivery approaches, so the time course of these estimated values was computed based on each individual's discount factor; each was entered into the regression analysis as an explanatory (independent) variable. After the region of interest was narrowed anatomically to the caudate, a peak coordinate was detected in each individual. A correlation analysis revealed that the location of the peak along the dorsal-ventral axis in the right caudate was positively correlated with the discount factor. This implies that individuals who showed a larger discount factor had peak activations in a more dorsal part of the right caudate associated with future reward prediction. This evidence also suggests that a higher ability to delay reward prediction might be related to activation of the more dorsal caudate. PMID- 21695537 TI - SOMPNN: an efficient non-parametric model for predicting transmembrane helices. AB - Accurately predicting the transmembrane helices (TMH) in a helical membrane protein is an important but challenging task. Recent researches have demonstrated that statistics-based methods are promising routes to improve the TMH prediction accuracy. However, most of existing TMH predictors are parametric models and they have to make assumptions of several or even hundreds of adjustable parameters based on the underlying probability distribution, which is difficult when no a priori knowledge is available. Besides the performances of these parametric predictors significantly depend on the estimated parameters, some of them need to exploit the entire training dataset in the prediction stage, which will lead to low prediction efficiency and this problem will become even worse when dealing with large-scale dataset. In this paper, we propose a novel SOMPNN model for prediction of TMH that features by minimal parameter assumptions requirement and high computational efficiency. In the SOMPNN model, a self-organizing map (SOM) is used to adaptively learn the helices distribution knowledge hidden in the training data, and then a probabilistic neural network (PNN) is adopted to predict TMH segments based on the knowledge learned by SOM. Experimental results on two benchmark datasets show that the proposed SOMPNN outperforms most existing popular TMH predictors and is promising to be extended to deal with other complicated biological problems. The datasets and the source codes of SOMPNN are available at http://www.csbio.sjtu.edu.cn/bioinf/SOMPNN/. PMID- 21695538 TI - Modeling and optimization of trihalomethanes formation potential of surface water (a drinking water source) using Box-Behnken design. AB - PURPOSE: The present research aims to investigate the individual and interactive effects of chlorine dose/dissolved organic carbon ratio, pH, temperature, bromide concentration, and reaction time on trihalomethanes (THMs) formation in surface water (a drinking water source) during disinfection by chlorination in a prototype laboratory-scale simulation and to develop a model for the prediction and optimization of THMs levels in chlorinated water for their effective control. METHODS: A five-factor Box-Behnken experimental design combined with response surface and optimization modeling was used for predicting the THMs levels in chlorinated water. The adequacy of the selected model and statistical significance of the regression coefficients, independent variables, and their interactions were tested by the analysis of variance and t test statistics. RESULTS: The THMs levels predicted by the model were very close to the experimental values (R(2) = 0.95). Optimization modeling predicted maximum (192 MUg/l) TMHs formation (highest risk) level in water during chlorination was very close to the experimental value (186.8 +/- 1.72 MUg/l) determined in laboratory experiments. The pH of water followed by reaction time and temperature were the most significant factors that affect the THMs formation during chlorination. CONCLUSION: The developed model can be used to determine the optimum characteristics of raw water and chlorination conditions for maintaining the THMs levels within the safe limit. PMID- 21695539 TI - Spatial distribution and speciation of mercury and methyl mercury in the surface water of East River (Dongjiang) tributary of Pearl River Delta, South China. AB - PURPOSE: The distribution and speciation of mercury in surface water of East River, Guangdong province, China were investigated. METHODS: All told 63 water samples were collected during a bi-weekly sampling campaign from July 15th to 26th, 2009. RESULTS: Total mercury (THg) concentrations in water samples ranged from 11 to 49 ng/L. Maximum levels of THg were measured in the lower reaches of East River, where it passes through a major industrial area adjacent to Dongguang city. Higher ratios of dissolved mercury (THg (aq)) in proportion to THg were restricted to the downstream section of East River. Concentrations of the minor constituent methyl mercury varied in the range from 0.08 to 0.21 ng/L. On average, methyl mercury made up 0.8% and 0.56% of THg (aq) and THg, respectively. Dissolved species dominated the speciation of methyl mercury in proportions up to 81%, which may imply that methyl mercury is largely produced in situ within the river water. Environmental factors (such as water temperature, dissolved oxygen, etc.) are regarded to play an important role in Hg methylation processes were monitored and assessed. CONCLUSIONS: In an international perspective, East River must be classified as a polluted river with considerably sources within its industrial areas. The THg (aq) and particle mercury fluxes to the Pearl River Estuary by East River run-off were estimated to be 0.31 +/- 0.11 and 0.17 +/- 0.13 t/year, respectively. Hence, in total nearly 0.5 t Hg is annually released to the sea from the East River tributary. PMID- 21695540 TI - Very high gravity (VHG) ethanolic brewing and fermentation: a research update. AB - There have been numerous developments in ethanol fermentation technology since the beginning of the new millennium as ethanol has become an immediate viable alternative to fast-depleting crude reserves as well as increasing concerns over environmental pollution. Nowadays, although most research efforts are focused on the conversion of cheap cellulosic substrates to ethanol, methods that are cost competitive with gasoline production are still lacking. At the same time, the ethanol industry has engaged in implementing potential energy-saving, productivity and efficiency-maximizing technologies in existing production methods to become more viable. Very high gravity (VHG) fermentation is an emerging, versatile one among such technologies offering great savings in process water and energy requirements through fermentation of higher concentrations of sugar substrate and, therefore, increased final ethanol concentration in the medium. The technology also allows increased fermentation efficiency, without major alterations to existing facilities, by efficient utilization of fermentor space and elimination of known losses. This comprehensive research update on VHG technology is presented in two main sections, namely VHG brewing, wherein the effects of nutrients supplementation, yeast pitching rate, flavour compound synthesis and foam stability under increased wort gravities are discussed; and VHG bioethanol fermentation studies. In the latter section, aspects related to the role of osmoprotectants and nutrients in yeast stress reduction, substrates utilized/tested so far, including saccharide (glucose, sucrose, molasses, etc.) and starchy materials (wheat, corn, barley, oats, etc.), and mash viscosity issues in VHG bioethanol production are detailed. Thereafter, topics common to both areas such as process optimization studies, mutants and gene level studies, immobilized yeast applications, temperature effect, reserve carbohydrates profile in yeast, and economic aspects are discussed and future prospects are summarized. PMID- 21695541 TI - Expression and fermentation optimization of oxidized polyvinyl alcohol hydrolase in E. coli. AB - Oxidized polyvinyl alcohol (PVA) hydrolase (OPH) is a key enzyme in the degradation of PVA, suggesting that OPH has a great potential for application in textile desizing processes. In this study, the OPH gene from Sphingopyxis sp. 113P3 was modified, by artificial synthesis, for overexpression in Escherichia coli. The OPH gene, lacking the sequence encoding the original signal peptide, was inserted into pET-20b (+) expression vector, which was then used to transform E. coli BL21 (DE3). OPH expression was detected in culture medium in which the transformed E. coli BL21 (DE3) was grown. Nutritional and environmental conditions were investigated for improved production of OPH protein by the recombinant strain. The highest OPH activity measured was 47.54 U/mL and was reached after 84 h under optimal fermentation conditions; this level is 2.64-fold higher that obtained under sub-optimal conditions. The productivity of recombinant OPH reached 565.95 U/L/h. The effect of glycine on the secretion of recombinant OPH was examined by adding glycine to the culture medium to a final concentration of 200 mM. This concentration of glycine reduced the fermentation time by 24 h and increased the productivity of recombinant OPH to 733.17 U/L/h. Our results suggest that the recombinant strain reported here has great potential for use in industrial applications. PMID- 21695542 TI - The Guyon's canal in perspective: 3-T MRI assessment of the normal anatomy, the anatomical variations and the Guyon's canal syndrome. AB - PURPOSES: (1) To revisit the anatomical boundaries of the canal, its contents and its two channels, (2) to describe the anatomical variations of the canal's borders and the variations of its contents, and (3) to discuss the clinical relevance of the Guyon's canal syndrome. METHODS: Two hundred and fifty MR wrists examinations were reviewed. MR spin echo T1-weighted axial slices were used to analyze the Guyon's canal. The anatomical boundaries, the cross-sectional area and length of the canal were calculated. The anatomical variations of the canal's walls and contents and their prevalence were sought. Changes related to Guyon's canal syndrome were also evaluated. RESULTS: From the 250 wrists, the anatomy of the Guyon's canal was normal in 168 (67.2%) wrists; 73 (29.2%) wrists presented with anatomical variations; and 9 (3.6%) wrists had derangements causing Guyon's canal syndrome. The cross-sectional area of the canal was 33 +/- 11 mm2 proximally and 45 +/- 19 mm2 distally. The canal's length was approximately 40 +/ 4 mm. Among the 73 wrists with anatomical variations, there were aberrant muscles in 39 (53.4%) wrists, multiple ulnar nerve branching in 22 (30%) cases, increased amount of fat tissue inside the canal in 9 (12.3%) cases and hypoplastic hamulus in 3 (4.1%) cases. There were 9 (3.6%) symptomatic wrists with clinical and radiological features attributed to Guyon's canal syndrome. CONCLUSION: MRI is an excellent modality for the evaluation of the Guyon's canal. PMID- 21695543 TI - Can 11beta-hydroxysteroid dehydrogenase activity predict the sensitivity of bone to therapeutic glucocorticoids in inflammatory bowel disease? AB - In healthy individuals measures of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme activity predict the change in bone formation markers in response to therapeutic glucocorticoids. It is unclear whether these measures remain predictive in inflammatory disease. We therefore examined whether 11beta HSD1 activity predicts changes in bone markers and bone mineral density (BMD) in patients with inflammatory bowel disease (IBD) treated with therapeutic glucocorticoids. Prospective and cross-sectional studies were carried out in patients attending a gastroenterology clinic with active (n = 39) or clinically inactive (n = 34) IBD and healthy controls (n = 51). Urinary corticosteroid metabolite profiles were obtained on a spot urine sample and total corticosteroid metabolite excretion and 11beta-HSD1 activity (measured as the ratio of tetrahydrocortisol to tetrahydrocortisone metabolites, [THF+alloTHF]/THE) determined. Patients with active disease were treated with an 8-week reducing course of oral prednisolone. The (THF+alloTHF)/THE ratio was significantly increased in patients with IBD, even those in clinical remission. The baseline (THF+alloTHF)/THE ratio failed to predict the decrease in bone formation markers or hip BMD. Measures of 11beta-HSD activity do not predict bone loss during glucocorticoid treatment of active IBD, probably due to disease-related increases in 11beta-HSD1 activity. Our observation of elevated 11beta-HSD1 activity in clinically inactive IBD implicates gastrointestinal glucocorticoid activation in the maintenance of disease remission. PMID- 21695544 TI - Gastrointestinal tolerability and patterns of switching in patients treated for primary osteoporosis: the Swedish Adherence Register Analysis (SARA). AB - The objective of this study was to describe and analyze the gastrointestinal tolerability and medication switching in patients receiving treatment for primary osteoporosis in Sweden. The study was based on all patients starting therapy with alendronate, risedronate, strontium ranelate, and raloxifene in Sweden between 2005 and 2009. The primary outcome measure was start of treatment with a gastroprotective agent, and the secondary outcome was hospitalization for a gastrointestinal adverse event (GIAE). Switching was analyzed while patients were on treatment. The crude incidence of gastroprotective treatment during the first 6 months after initiation of osteoporosis therapy was 5.14%, 5.93%, 4.25%, and 2.86% for patients prescribed alendronate, risedronate, strontium ranelate, and raloxifene, respectively. Patients prescribed raloxifene had a significantly lower risk of filling a prescription for a gastroprotective agent compared with alendronate. There was no significant difference in the risk of hospitalization for GIAEs. Less than 3% switched therapy while on treatment. Patients prescribed risedronate, strontium ranelate, and raloxifene had a significantly higher risk of switching compared with patients taking alendronate. In conclusion, no significant difference in the incidence of GIAEs was found between patients prescribed alendronate, risedronate, and strontium ranelate. Individuals prescribed raloxifene had a significantly lower risk of GIAEs compared with patients prescribed alendronate. No significant difference was found in the frequency of hospitalization for GIAEs. Switching between osteoporosis medications and drug classes was uncommon. Prescribers should consider the real world gastrointestinal safety of osteoporosis drugs when choosing between treatment options to potentially improve medication adherence and consequently effectiveness. PMID- 21695545 TI - Dietary n-3 polyunsaturated fatty acids modify fatty acid composition in hepatic and abdominal adipose tissue of sucrose-induced obese rats. AB - The fatty acid profile of hepatocytes and adipocytes is determined by the composition of the dietary lipids. It remains unclear which fatty acid components contribute to the development or reduction of insulin resistance. The present work examined the fatty acid composition of both tissues in sucrose-induced obese rats receiving fish oil to determine whether the effect of dietary (n-3) polyunsaturated fatty acids (PUFAs) on the reversion of metabolic syndrome in these rats is associated to changes in the fatty acid composition of hepatocyte and adipocyte membrane lipids. Animals with metabolic syndrome were divided into a corn-canola oil diet group and a fish oil diet group, and tissues fatty acids composition were analyzed after 6 weeks of dietary treatment. Fatty acid profiles of the total membrane lipids were modified by the fatty acid composition of the diets fed to rats. N-3 PUFAs levels in animals receiving the fish oil diet plus sucrose in drinking water were significantly higher than in animals under corn canola oil diets. It is concluded that in sucrose-induced obese rats, consumption of dietary fish oil had beneficial effects on the metabolic syndrome and that such effects would be conditioned by the changes in the n-3 PUFAs composition in hepatic and adipose tissues because they alter membrane properties and modify the type of substrates available for the production of active lipid metabolites acting on insulin resistance and obesity. PMID- 21695546 TI - Within- and among-species variation in specific leaf area drive community assembly in a tropical cloud forest. AB - Specific leaf area (SLA) is a key functional trait reflecting the trade-off between resource capture and conservation, and has been identified as playing an important role in plant community assembly. Mechanistic models of community assembly state that the assemblage of species in a local community is controlled by environment filters operating on functional traits. We measured within- and among-species variation of SLA, and environmental conditions in a tropical cloud forest to explore how variation in this functional trait contributes to community assembly. SLA variation at the species level was also decomposed into alpha (within assemblage variation), and beta (across assemblage variation) values. SLA decreased with increasing solar irradiance (approximated using plant height) within the three study sites, and differed among the three sites both for within- and among-species comparisons. Mean plot SLA, accounting for both within and among species across the three sites, increased significantly in relation to air temperature but not local photosynthetic photon flux density and soil total phosphorus. Alpha SLA decreased with increasing solar irradiance within the three sites and beta SLA differed among the three sites. Our results clearly demonstrate that light and air temperature are key environmental factors involved in organizing plant species within and among communities in tropical cloud forests. The strong relationship between both intra- and interspecific variation in SLA and environmental conditions strongly confirms the role of trait variation in the assembly of plant species in tropical cloud forest communities via environment filtering related to light availability and air temperature. PMID- 21695547 TI - Patients whose GP knows complementary medicine tend to have lower costs and live longer. AB - BACKGROUND: Health economists have largely ignored complementary and alternative medicine (CAM) as an area of research, although both clinical experiences and several empirical studies suggest cost-effectiveness of CAM. OBJECTIVE: To explore the cost-effectiveness of CAM compared with conventional medicine. METHODS: A dataset from a Dutch health insurer was used containing quarterly information on healthcare costs (care by general practitioner (GP), hospital care, pharmaceutical care, and paramedic care), dates of birth and death, gender and 6-digit postcode of all approximately 150,000 insurees, for the years 2006 2009. Data from 1913 conventional GPs were compared with data from 79 GPs with additional CAM training in acupuncture (25), homeopathy (28), and anthroposophic medicine (26). RESULTS: Patients whose GP has additional CAM training have 0-30% lower healthcare costs and mortality rates, depending on age groups and type of CAM. The lower costs result from fewer hospital stays and fewer prescription drugs. DISCUSSION: Since the differences are obtained while controlling for confounders including neighborhood specific fixed effects at a highly detailed level, the lower costs and longer lives are unlikely to be related to differences in socioeconomic status. Possible explanations include selection (e.g. people with a low taste for medical interventions might be more likely to choose CAM) and better practices (e.g. less overtreatment, more focus on preventive and curative health promotion) by GPs with knowledge of complementary medicine. More controlled studies (replication studies, research based on more comprehensive data, cost-effectiveness studies on CAM for specific diagnostic categories) are indicated. PMID- 21695548 TI - Can we prevent or treat renal dysfunction in chronic heart failure? AB - We aimed to summarize the predictors of renal dysfunction and present strategies to prevent and/or treat renal dysfunction in Chronic Heart Failure (CHF). Several factors may predict renal dysfunction in CHF, including older age, comorbidities (anemia, hypertension, diabetes), severity of underlying heart disease (systolic and diastolic dysfunction, central venous pressure) as well as certain therapies in specific circumstances (diuretics, nonsteroid acute inflammatory drugs, and renine-angiotensin-aldosterone (RAAS) inhibitors). Thus, prevention of renal dysfunction is possible in CHF by treating comorbidities and underlying heart disease as well as by monitoring therapies with potential toxic renal effect. At present, there is no specific treatment for renal dysfunction, but several new entities are under investigation. In conclusion, prevention of renal dysfunction is possible in CHF, but treatment is still under investigation. New studies are necessary to establish whether a specific algorithm may be used to prevent renal dysfunction in CHF patients. PMID- 21695549 TI - New roles for renin and prorenin in heart failure and cardiorenal crosstalk. AB - The renin-angiotensin-aldosterone-system (RAAS) plays a central role in the pathophysiology of heart failure and cardiorenal interaction. Drugs interfering in the RAAS form the pillars in treatment of heart failure and cardiorenal syndrome. Although RAAS inhibitors improve prognosis, heart failure-associated morbidity and mortality remain high, especially in the presence of kidney disease. The effect of RAAS blockade may be limited due to the loss of an inhibitory feedback of angiotensin II on renin production. The subsequent increase in prorenin and renin may activate several alternative pathways. These include the recently discovered (pro-) renin receptor, angiotensin II escape via chymase and cathepsin, and the formation of various angiotensin subforms upstream from the blockade, including angiotensin 1-7, angiotensin III, and angiotensin IV. Recently, the direct renin inhibitor aliskiren has been proven effective in reducing plasma renin activity (PRA) and appears to provide additional (tissue) RAAS blockade on top of angiotensin-converting enzyme and angiotensin receptor blockers, underscoring the important role of renin, even (or more so) under adequate RAAS blockade. Reducing PRA however occurs at the expense of an increase plasma renin concentration (PRC). PRC may exert direct effects independent of PRA through the recently discovered (pro-) renin receptor. Additional novel possibilities to interfere in the RAAS, for instance using vitamin D receptor activation, as well as the increased knowledge on alternative pathways, have revived the question on how ideal RAAS-guided therapy should be implemented. Renin and prorenin are pivotal since these are at the base of all of these pathways. PMID- 21695550 TI - HLA class I allele promiscuity revisited. AB - The peptide repertoire presented on human leukocyte antigen (HLA) class I molecules is largely determined by the structure of the peptide binding groove. It is expected that the molecules having similar grooves (i.e., belonging to the same supertype) might present similar/overlapping peptides. However, the extent of promiscuity among HLA class I ligands remains controversial: while in many studies T cell responses are detected against epitopes presented by alternative molecules across HLA class I supertypes and loci, peptide elution studies report minute overlaps between the peptide repertoires of even related HLA molecules. To get more insight into the promiscuous peptide binding by HLA molecules, we analyzed the HLA peptide binding data from the large epitope repository, Immune Epitope Database (IEDB), and further performed in silico analysis to estimate the promiscuity at the population level. Both analyses suggest that an unexpectedly large fraction of HLA ligands (> 50%) bind two or more HLA molecules, often across supertype or even loci. These results suggest that different HLA class I molecules can nevertheless present largely overlapping peptide sets, and that "functional" HLA polymorphism on individual and population level is probably much lower than previously anticipated. PMID- 21695551 TI - Mannose-binding lectin 1 haplotypes influence serum MBL-A concentration, complement activity, and milk production traits in Chinese Holstein cattle. AB - Mannose-binding lectin (MBL) is a member of the collectin protein family that binds a broad range of microorganisms and activates the lectin-complement pathway of innate immunity. MBL deficiency is associated with an increased risk for various infections and arises from five polymorphisms in the promoter and first exon of the MBL gene in humans. In this study, three novel single-nucleotide polymorphisms (SNPs) in the promoter region and two previously reported SNPs in exon 2 of the MBL1 gene were detected using PCR single-strand conformation polymorphism, restriction fragment length polymorphism, and DNA sequencing in 537 cattle from three Chinese breeds. Analysis of the genotypes and haplotypes was used to investigate the polymorphisms and their possible implications, especially their association with serum MBL-A levels, complement activity (CH50 and ACH50), and milk production traits was investigated. The g.2651G > A SNP in exon 2 affected the serum MBL-A concentrations and the serum CH50 values, whereas the g. 1330G > A SNP significantly affected CH50 and the somatic cell scores (SCSs). Statistical analysis revealed that cows with the ATGGC/ACAAC combined genotype and those with the AAGGT/ACGGT combined genotype exhibited the lowest and highest SCSs, respectively. Serum antibacterial activities were also conducted to verify the effect of the SNPs on resistance to mastitis pathogens. Results of real-time PCR showed that the liver of cows with clinical mastitis exhibited a higher MBL1 expression compared with healthy ones (P < 0.05). Findings of this study indicate that the MBL1 gene possibly contributes to bacterial infection resistance and can be used as a molecular marker of milk production traits to control mastitis. PMID- 21695552 TI - Chronic homework in emerging borderlands of healthcare. AB - The task of caring for those with chronic illnesses has gained a new centrality in health care at a global level. We introduce the concept of "chronic homework" to offer a critical reflection on the treatment of chronic illnesses in three quite different national and local contexts: Uganda, Denmark, and the United States. A major challenge for clinicians, patients, and family caregivers is how to navigate the task of moving health care from clinic to home. By "chronic homework," we refer to the work patients and families are expected to carry out in their home contexts as part of the treatment of chronic conditions. Families and patients spend time receiving training by clinical experts in the various tasks they are to do at home. While this "colonization" of the popular domain could easily be understood from a Foucauldian perspective as yet another emerging mode of governmentality, this a conceptualization can oversimplify the way specific practices of homework are re-imagined and redirected by patients and significant others in their home surroundings. In light of this re-invention of homework in local home contexts, we foreground another conceptual trope, describing chronic homework as a borderland practice. PMID- 21695553 TI - [The 7th international congress on spondyloarthropathy: Gent, October 2010]. AB - At the Spondyloarthropathy (SpA) Congress 2010 new results were presented on the pathophysiology, imaging and therapy of this disease. With a better understanding in particular of the bone biology, the causes of the disease-specific alterations in bone could be explained in the future so that new therapy options can be developed. Magnetic resonance imaging is a milestone for a better understanding of the pathophysiology of SpA. Against the background of the pressure of increasing costs in the healthcare system and cost-intensive biologics it was discussed how well the therapeutic response to TNFalpha antagonists can be predicted. In connection with this it was critically commented that in the clinical routine time limited attempts at therapy in order to decide how the therapy should be continued depending on the response would be more useful than to make a strict selection of patients based on predictors. PMID- 21695554 TI - [Endoprosthetic replacement of rheumatoid finger joints]. AB - Resection arthroplasty, arthrodesis and prosthetic reconstruction are able to guarantee the maintenance of good functional ability of finger joints even in late stages and with severe destruction. Destruction of soft tissues of the finger joints cannot be corrected by prosthetic measures alone. A stabile situation of the wrist joint is one of the most important prerequisites for a normal performance of daily life activities. Silastic endoprostheses are still the gold standard for finger replacement in rheumatoid arthritis. PMID- 21695555 TI - [Total knee arthroplasty for rheumatoid arthritis]. AB - A total of 150,000 primary total knee arthroplasties are performed in Germany each year. There is only a limited amount of evidence-based data available on possible surgery-related differences between osteoarthritis (OA) and rheumatoid arthritis (RA) of the knee joint. The following review summarizes the recent literature on total knee arthroplasty with a focus on special features of RA patients. PMID- 21695556 TI - [Combined endoscopic treatment of Spigelian hernia : laparoscopy - total extraperitoneal patch plasty - laparoscopy]. AB - Spigelian hernias are rare forms of abdominal hernia but can lead to severe complications. Besides conventional techniques there are only a few reports on the successful use of minimally invasive surgery (MIS) techniques. In this paper the combination of laparoscopy and TEP (total extraperitoneal patch plasty) technique without mesh fixation is presented. In our opinion laparoscopy - TEP - laparoscopy is a logical, safe and beneficial method for treatment of Spigelian hernias. PMID- 21695557 TI - [Soft tissue sarcoma of the upper extremities. Analysis of factors relevant for prognosis in 160 patients]. AB - BACKGROUND: Soft tissue sarcomas (STS) are a rare entity with reduced prognosis due to their aggressive biology. For an optimal treatment of STS identification of independent prognostic factors is crucial in order to reduce tumor-related mortality and recurrence rates. The surgical oncological concept includes wide excisions with resection safety margins >1 cm which enables acceptable functional results and reduced rates of amputation of the lower extremities. In contrast, individual anatomy of the upper extremities, in particular of the hand, leads to an intentional reduction of resection margins in order to preserve the extremity and its function with the main intention of tumor-free resection margins. In this study, the oncological safety and outcome as well as functional results were validated by a retrospective analysis of survival rate, recurrence rate and potential prognostic factors. PATIENTS AND METHODS: A total of 160 patients who had been treated for STS of the upper extremities were retrospectively included. Independent prognostic factors were analyzed (primary versus recurrent tumor, tumor size, resection status, grade of malignancy, additional therapy, localization in the upper extremity). Kaplan-Meier analyses for survival rate and local control were calculated. Further outcome measures were functional results validated by the DASH score and rate of amputation. RESULTS: In 130 patients (81%) wide tumor excision (R0) was performed and in 19 patients (12%) an amputation was necessary. The 5-year overall survival rate was 70% and the 5-year survival rate in primary tumors was 81% whereas in recurrences 55% relapsed locally. The 10-year overall survival rate was 45% and the 5-year recurrence rate was 18% for primary STS and 43% for recurrent STS. Variance analysis revealed primary versus recurrent tumor, tumor size, resection status and grade of malignancy as independent prognostic factors. Analysis of functional results showed a median DASH score of 37 (0-100; 0=contralateral extremity). CONCLUSION: The 5-year survival and local recurrence rates are comparable to STS wide resections with safety margins >1 cm for the lower extremities and the trunk. Analysis of prognostic factors revealed resection status and the tumor-free resection margins to be the main goals in STS resection of upper extremity. PMID- 21695558 TI - ARTS binds to a distinct domain in XIAP-BIR3 and promotes apoptosis by a mechanism that is different from other IAP-antagonists. AB - ARTS (Sept4_i2), is a pro-apoptotic protein localized at the mitochondria of living cells. In response to apoptotic signals, ARTS rapidly translocates to the cytosol where it binds and antagonizes XIAP to promote caspase activation. However, the mechanism of interaction between these two proteins and how it is regulated remained to be explored. In this study, we show that ARTS and XIAP bind directly to each other, as recombinant ARTS and XIAP proteins co immunoprecipitate together. We also show that over expression of ARTS alone is sufficient to induce a strong down-regulation of XIAP protein levels and that this reduction occurs through the ubiquitin proteasome system (UPS). Using various deletion and mutation constructs of XIAP we show that ARTS specifically binds to the BIR3 domain in XIAP. Moreover, we found that ARTS binds to different sequences in BIR3 than other IAP antagonists such as SMAC/Diablo. Computational analysis comparing the location of the putative ARTS interface in BIR3 with the known interfaces of SMAC/Diablo and caspase 9 support our results indicating that ARTS interacts with residues in BIR3 that are different from those involved in binding SMAC/Diablo and caspase 9. We therefore suggest that ARTS binds and antagonizes XIAP in a way which is distinct from other IAP-antagonists to promote apoptosis. PMID- 21695559 TI - Parental coping with developmental disorders in adolescents within the ultraorthodox Jewish community in Israel. AB - This preliminary study compares the coping strategies used by 100 ultraorthodox Jewish parents and 100 secular Jewish parents for dealing with adolescent children with developmental disorders. The parents completed two questionnaires on the sense of stress-related personal growth and the sense of coherence. The ultraorthodox parents reported a higher sense of growth and a higher sense of coherence than the secular parents. In addition, there were associations found between demographic characteristics. Gender differences between mothers and fathers in the sense of growth and community differences between ultraorthodox fathers and secular fathers in the sense of coherence are discussed. The study highlights the uniqueness of the religious point of view in dealing with adolescent children with developmental disorders. PMID- 21695560 TI - The Subthreshold Autism Trait Questionnaire (SATQ): development of a brief self report measure of subthreshold autism traits. AB - The current study was motivated by a need for a self-report questionnaire that assesses a broad range of subthreshold autism traits, is brief and easily administered, and is relevant to the general population. An initial item pool was administered to 1,709 students. Structural validity analysis resulted in a 24 item questionnaire termed the Subthreshold Autism Trait Questionnaire (SATQ; Cronbach's alpha coefficient = .73, test-retest reliability = .79). An exploratory factor analysis suggested 5 factors. Confirmatory factor analysis indicated the 5 factor solution was an adequate fit and outperformed two other models. The SATQ successfully differentiated between an ASD and student group and demonstrated convergent validity with other ASD measures. Thus, the current study introduces and provides initial psychometric support for the SATQ. PMID- 21695561 TI - Novel integrin-targeted binding-triggered drug delivery system for methotrexate. AB - PURPOSE: To design a binding-induced conformation change drug delivery system for integrin-targeted delivery of methotrexate and prove the feasibility of using hairpin peptide structure for binding triggered drug delivery. METHODS: Methotrexate prodrugs were synthesized using solid phase peptide synthesis techniques by conjugating methotrexate to Arg-Gly-Asp (RGD) or a hairpin peptide, RWQYV(D)PGKFTVQRGD (hairpin-RGD). Levels of integrin alpha(V)beta(3) in HUVEC were up-regulated using adenoviral system and knocked down using siRNA. Stability of prodrugs and methotrexate release from prodrugs were evaluated in plasma, in presence or absence of integrin alpha(V)beta(3)-expressing cells. Molecular modeling was performed to support experimental results using MOE. RESULTS: Prodrugs recognized and bound to integrin alpha(V)beta(3)-expressing cells in integrin alpha(V)beta(3) expression level-dependent manner. Prodrug with hairpin peptide could resist Streptomyces griseus-derived glutamic acid-specific endopeptidase (SGPE) and plasma enzyme hydrolysis. Drug release was triggered in presence of HUVEC cells and SGPE. Analysis of conformation energy supported that conformational change in MTX-hairpin-RGD led to exposure of labile link upon binding to integrin alpha(V)beta(3)-expressing cells. CONCLUSIONS: Binding induced conformation change of hairpin peptide can be used to design integrin targeted drug delivery system. PMID- 21695562 TI - Psychosocial correlates of shape and weight concerns in overweight pre adolescents. AB - Shape and weight concerns among overweight pre-adolescents heighten risk for eating disorders and weight gain. Treatment and prevention efforts require consideration of psychosocial factors that co-occur with these concerns. This study involved 200 overweight pre-adolescents, aged 7-12 years (M age = 9.8; SD = 1.4), presenting for family-based weight control treatment. Hierarchical regression was used to examine the influence of pre-adolescents' individual characteristics and social experiences, and their parents' psychological symptoms, on shape and weight concerns as assessed by the Child Eating Disorder Examination. Findings revealed that higher levels of dietary restraint, greater feelings of loneliness, elevated experiences with weight-related teasing, and higher levels of parents' eating disorder symptoms predicted higher shape and weight concerns among overweight pre-adolescents. Interventions addressing overweight pre-adolescents' disordered eating behaviors and social functioning, as well as their parents' disordered eating behaviors and attitudes, may be indicated for those endorsing shape and weight concerns. PMID- 21695564 TI - Sequential bilateral upper extremity intravenous regional anesthesia with chloroprocaine. AB - PURPOSE: This case report describes the novel use of sequential bilateral upper extremity intravenous regional anesthesia with 2-chloroprocaine for bilateral endoscopic carpal tunnel decompression. CLINICAL FEATURES: A 49-yr-old female, American Society of Anesthesiologists physical status I, presented for outpatient bilateral carpal tunnel release. Sequential bilateral intravenous regional anesthesia was performed with 0.5% 2-chloroprocaine 30 mL per arm using a double upper arm tourniquet. Intraoperative sedation consisted of midazolam and fentanyl. Tourniquet times for the right and left arms were 28 and 19 min, respectively. After deflation of each tourniquet, mild limb twitching occurred but resolved immediately after administration of intravenous midazolam. The patient made a rapid recovery, and she was discharged home uneventfully. CONCLUSIONS: Bilateral sequential intravenous regional anesthesia with 2 chloroprocaine is effective for upper extremity surgery of short duration. Recommendations to minimize the risk of local anesthetic toxicity are reviewed. PMID- 21695563 TI - Lymphoceles, lymphorrhea, and lymphedema after laparoscopic and open endometrial cancer staging. AB - PURPOSE: To evaluate the incidence of lymphoceles, lymphorrhea, and lymphedema after systematic pelvic lymphadenectomy in patients who underwent laparoscopic or open abdominal staging for endometrial cancer. METHODS: A total of 138 consecutive women who underwent systematic laparoscopic pelvic lymphadenectomy for endometrial cancer staging were compared to 123 historical control subjects staged via an open approach. Postoperative screening for lymphadenectomy-related complications by ultrasound was consistently performed. RESULTS: The incidence of perioperative complications was lower in cases than in control subjects. Overall, lymphoceles were diagnosed in 19 (15.4%) and 2 (1.4%) patients who had open and laparoscopic staging, respectively (odds ratio 12.42; 95% confidence interval 2.82-54.55; P < 0.0001). Symptomatic lymphoceles were more frequent after open staging than after laparoscopy (P = 0.028). Lymphorrhea occurred in 1 and 4 patients after laparoscopic and open surgery (P = 0.19). No difference in the incidence of lymphedema was observed. CONCLUSIONS: Our findings suggest that laparoscopic endometrial cancer staging is associated with a lower occurrence of both asymptomatic and symptomatic lymphoceles compared to open surgery. PMID- 21695565 TI - Setting standards for simulation in anesthesia: the role of safety criteria in accreditation standards. AB - PURPOSE: In this article, we describe a critical event which occurred in a simulation centre, and we also review possible safety issues for participants and staff involved in medical simulation training. PRINCIPAL FINDINGS: The authors report an incident with the potential of harming trainees and staff which occurred during a full-scale simulation. The episode raised the question of training safety in simulation centres. In this instance, the computer program controlling the mannequin enabled a continuous and non-regulated outflow of carbon dioxide which led to an intense reaction in the soda lime canister. The absorbent canister became too hot to be touched (a temperature probe, later placed in the centre of the front canister, measured 53 degrees C). All activities involving the mannequin and anesthesia machine were stopped immediately. CONCLUSIONS: Simulation in healthcare is a valuable educational tool to train for a variety of clinical encounters in a safe environment without harming a patient. Due to technological progress and the use of authentic equipment recreating near real environments, simulation training has become exceedingly realistic. The Society for Simulation in Healthcare (SSH) has published revised accreditation standards for simulation centres which incorporate training safety sub-criteria to address and manage. By highlighting recommendations of other high-risk industries on this issue, SSH proposes a possible approach to enhance safety in medical simulation. PMID- 21695566 TI - Observations on effects of a neem seed extract (MiteStop(r)) on biting lice (mallophages) and bloodsucking insects parasitizing horses. AB - The hair of 300 horses belonging to short hair and long hair races had been routinely treated during the last 3 years with a neem seed extract (MiteStop(r)) in order to kill mallophages (e.g., specimens of the genus Werneckiella). It was found that in all cases, a hidden infestation with these biting lice had existed, which became visible when the product (diluted 1:20 with tap water) was brushed onto the hair. The mallophages left the body surface and became visible as a fine "wooly looking" layer at the tips of the hair. Furthermore, this treatment stopped the forming of dandruff of the skin of the horses, which, in case of heavy mallophage infestations, had looked like being powdered. Another interesting result of the treatment was reported by the riders. They described that the product had a considerable repellent effect on bloodsucking tabanids, mosquitoes, ceratopogonids, simuliids, as well as on licking flies. This repellency effect was noted to last for up to 7 days if the horses were not washed. PMID- 21695567 TI - Molecular characterization of Giardia duodenalis in dogs from Brazil. AB - The intestinal protozoan parasite Giardia duodenalis (syn. Giardia intestinalis and Giardia lamblia) is a widespread enteric pathogen in human and domestic animals. This organism is one of the most common parasites in domestic dogs in Brazil. In this study, we determined the occurrence and genetic characterization of G. duodenalis isolated from dogs from south-central Sao Paulo state, Brazil. A total of 300 fecal samples were collected. Fecal specimens were screened for the presence of G. duodenalis using microscopy (zinc sulfate solution flotation technique) and polymerase chain reaction (PCR) targeting the small subunit ribosomal (SSU-rDNA) and glutamate dehydrogenase (GDH) genes. Genetic characterization was performed using restriction fragment length polymorphisms (RFLP) and sequencing analysis of the GDH gene. In addition, selected samples were further characterized by RFLP and sequencing of the beta-giardin gene. The overall occurrence of G. duodenalis was 17.3% (52/300). The occurrence was higher in stray dogs (28%) than in household dogs (6.25%). Of the 36 PCR-positive samples that were selected for genotyping, only dog-specific genotype C (20 isolates), D (11 isolates) and mixed C + D (five isolates) isolates were detected in the study. This study provides current information on the infection rates of G. duodenalis genotypes in canine populations and describes for the first time the presence of mixed infections within host-specific C and D genotypes in dogs in Brazil. These genotypes were widespread and commonly found in domestic dogs living in urban and suburban environments of the studied area and confirmed the endemic status of Giardia in this region. PMID- 21695568 TI - In vitro efficacy of plant extracts and synthesized substances on Rhipicephalus (Boophilus) Microplus (Acari: Ixodidae). AB - Herbal drugs have been widely evaluated as an alternative method of parasite control, aiming to slow development of resistance and obtain low-cost biodegradable parasiticides. This study evaluated the in vitro efficacy on Rhipicephalus (Boophilus) microplus of extracts from Carapa guianensis seed oil, Cymbopogon martinii and Cymbopogon schoenanthus leaf essential oil, and Piper tuberculatum leaf crude extract and similar synthesized substances. In the immersion test, engorged females were evaluated in five dilutions ranging from 10% to 0.030625% concentration. In the larval test on impregnated filter paper, the concentration ranged from 10% to 0.02%. The treatments and controls were done in three replicates. Chemical analysis of the oils was performed by gas chromatography. The main compounds were oleic acid (46.8%) for C. guianensis and geraniol for C. martinii (81.4%), and C. schoenanthus (62.5%). The isolated and synthesized substances showed no significant effect on larvae and adult. C. martinii and P. tuberculatum showed the best efficacy on the engorged females. The LC(50) and LC(90) were 2.93% and 6.66% and 3.76% and 25.03%, respectively. In the larval test, the LC(50) and LC(90) obtained for C. martinii, P. tuberculatum, and C. schoenanthus were 0.47% and 0.63%, 0.41% and 0.79%, 0.57% and 0.96%, respectively. The fact that geraniol is present in greater quantities in C. martinii explains its higher activity in relation to C. shoenanthus. It is necessary to validate the in vivo use of safe and effective phytoparasiticidal substances. Efforts should be focused on developing formulations that enhance the efficacy in vivo and lengthen the residual period. PMID- 21695569 TI - Phylogenetic study of Setaria cervi based on mitochondrial cox1 gene sequences. AB - The objective of the present study was to examine the phylogenetic position of Setaria cervi based on sequences of mitochondrial cytochrome c oxidase subunit 1 (cox1) gene. A fragment of the cox1 gene from two morphologically identified S. cervi collected from red deer (Cervus elaphus) from Italy were amplified, sequenced, and compared with corresponding sequences of other filarioid nematode species. Phylogenetic studies using Bayesian analysis revealed S. cervi as monophyletic with other Setaria species, confirming S. cervi as a member of the Setaria genus. S. cervi appeared to be sister species to Setaria labiatopapillosa and Setaria digitata. Setaria tundra and Setaria equina, the other two Setaria species presented in the Italian fauna, formed a sister group to the clade consisting of S. cervi, S. labiatopapillosa, and S. digitata. In addition to phylogenetic clarification, our study is the first molecular identification of S. cervi, which may be useful for further molecular identification and differentiation of this filarial worm from other filarioid nematode species, especially in the earlier developmental stages of its life cycle. PMID- 21695571 TI - Chronic treatment with a glucagon receptor antagonist lowers glucose and moderately raises circulating glucagon and glucagon-like peptide 1 without severe alpha cell hypertrophy in diet-induced obese mice. AB - AIMS/HYPOTHESIS: Antagonism of the glucagon receptor (GCGR) represents a potential approach for treating diabetes. Cpd-A, a potent and selective GCGR antagonist (GRA) was studied in preclinical models to assess its effects on alpha cells. METHODS: Studies were conducted with Cpd-A to examine the effects on glucose-lowering efficacy, its effects in combination with a dipeptidyl peptidase 4 (DPP-4) inhibitor, and the extent and reversibility of alpha cell hypertrophy associated with GCGR antagonism in mouse models. RESULTS: Chronic treatment with Cpd-A resulted in effective and sustained glucose lowering in mouse models in which endogenous murine Gcgr was replaced with human GCGR (hGCGR). Treatment with Cpd-A also led to stable, moderate elevations in both glucagon and glucagon-like peptide 1 (GLP-1) levels, which were completely reversible and not associated with a hyperglycaemic overshoot following termination of treatment. When combined with a DPP-4 inhibitor, Cpd-A led to additional improvement of glycaemic control correlated with elevated active GLP-1 levels after glucose challenge. In contrast to Gcgr-knockout mice in which alpha cell hypertrophy was detected, chronic treatment with Cpd-A in obese hGCGR mice did not result in gross morphological changes in pancreatic tissue. CONCLUSIONS/INTERPRETATION: A GRA lowered glucose effectively in diabetic models without significant alpha cell hypertrophy during or following chronic treatment. Treatment with a GRA may represent an effective approach for glycaemic control in patients with type 2 diabetes, which could be further enhanced when combined with DPP-4 inhibitors. PMID- 21695570 TI - Effect of praziquantel prolonged administration on granuloma formation around Schistosoma japonicum eggs in lung of sensitized mice. AB - Schistosomiasis remains a major public health problem and it is an immune disease. The schistosome egg is the primary parasite factor responsible for the overt disease. The eggs release the soluble antigen, which induces intensive tissue reaction, a granulomatous reaction to the eggs. If granuloma formation could be suppressed, overt disease might not develop. Praziquantel is an effective antischistosomal drug especially for adult worms. However, whether praziquantel has a suppressing effect on granuloma formation around schistosome eggs directly remains unclear. The purpose of the present study was to investigate the effect of praziquantel, especially administered persistently, on granuloma formation around Schistosoma japonicum eggs in the lung of sensitized mice. Thirty-six mice were divided into three groups averagely. Group A was a control group. First, the mice were injected with schistosomal eggs hypodermically in abdomen, and 10 days later injected with schistosomal eggs intravenously via a tail vein. Group B was a praziquantel short administration group. In addition to the injections of schistosomal eggs as the same of Group A, the mice were administered with praziquantel in a daily dose of 300 mg/kg for 3 days, from 1 day before the intravenous injection of the eggs. Group C was a praziquantel prolonged administration group. In addition to the injections of schistosomal eggs as the same of Group A, the mice were administered with praziquantel in a daily dose of 150 mg/kg for 5 days weekly until the mice were sacrificed. Three mice of each group were sacrificed on days 7, 14, 28, and 56, respectively after the intravenous injection of the eggs, and the lung tissues were fixed with formalin and the slices were HE stained. The granulomas containing eggs in their centers were selected, and 25-30 granulomas from the animals of each group were measured at each time period. The mean areas of egg granulomas of each group were calculated, and the neutrophilic granulocytes, eosinocytes, lymphocytes, fibroblasts, and macrophages within the egg granulomas were counted. The mean numbers of them of each group were calculated. All the data of each group were analyzed and compared statistically. On day 56 after the intravenous injection of the eggs, the mean area of schistosomal egg granulomas in group B was (227.4 +/- 728.0) * 10(3) MUm(2), less than that of [(297.9 +/- 153.3) * 10(3) MUm(2)] in group A, and the suppression rate was 23.7% (P < 0.05). On days 7, 14, 28, and 56, the mean areas of schistosomal egg granulomas in group C were (575.8 +/- 155.6) * 10(3) MUm(2), (310.5 +/- 854.0) * 10(3) MUm(2), (267.7 +/- 513.3) * 10(3) MUm(2), and (214.9 +/- 446.4) * 10(3) MUm(2), respectively, significantly less than those of [(692.7 +/- 232.6) * 10(3) MUm(2), (439.4 +/- 165.0) * 10(3) MUm(2), (385.7 +/- 129.3) * 10(3) MUm(2), and (297.9 +/- 153.3) * 10(3) MUm(2)] in group A. The suppression rates were 16.9%, 29.3%, 30.6%, and 27.9%, respectively (P values <0.05). On day 56, the mean numbers of neutrophilic granulocytes were 11.4 +/- 5.0 in group A and 5.2 +/- 3.1 in group C, respectively, with the suppression rate of 54.4% in group C (P < 0.05). On day 56, the mean numbers of eosinocytes within the egg granulomas were 2.3 +/- 2.0, 0.1 +/- 0.3, and 0.3 +/- 0.6 in groups A, B, and C, respectively, with the suppression rate of 95.7% in group B and 87.0% in group C (P values <0.05). On day 56, the mean numbers of macrophages within egg granulomas were 14.3 +/- 6.9 in group C, compared with 18.6 +/- 8.2 in group A, the suppression rate was 23.1% (P < 0.05). On day 56, the mean numbers of fibroblasts within the egg granulomas were 6.6 +/- 4.4 and 5.8 +/- 2.6 in groups B and C, respectively, and compared with 14.3 +/- 7.8 in group A, the increasing extents decreased by 53.8% and 59.4%, respectively (P values <0.05). Therefore, the administration of praziquantel, especially the prolonged administration, can suppress the formation of schistosomal egg granulomas, including reduction in the areas of granulomas and suppression of the inflammatory cells and the hyperplasia of fibroblasts within granulomas. PMID- 21695572 TI - Genome-wide analysis of the beta-glucosidase gene family in maize (Zea mays L. var B73). AB - The hydrolysis of beta-D: -glucosidic bonds which is required for the liberation of many physiologically important compounds is catalyzed by the enzyme beta glucosidase (BGLU, EC 3.2.1.21). BGLUs are implicated in several processes in plants, such as the timely response to biotic and abiotic stresses through activation of phytohormones and defense compounds. We identified 26 BGLU isozymes in the genome of the maize inbred B73 and propose a standardized nomenclature for all Zea mays BGLU paralogs (Zmbglu1-Zmbglu26). We characterized their intron-exon structure, protein features, phylogenetic relationships, and measured their expression and activity in various tissues under different environmental conditions. Sequence alignments revealed some characteristic motifs (conserved amino acids) and specific differences among different isozymes. Analysis of putative signal peptides suggested that some BGLUs are plastidic, whereas others are mitochondrial, cytosolic, vacuolar or secreted. Microarray and RT-PCR analysis showed that each member of the Zmbglu family had a characteristic expression pattern with regard to tissue specificity and response to different abiotic conditions. The source of variance for gene expression was highest for the type of organ analyzed (tissue variance) than for the growth conditions (environmental variance) or genotype (genetic variance). Analysis of promoter sequences revealed that each Zmbglu paralog possesses a distinct set of cis elements and transcription factor binding sites. Since there are no two Zmbglu paralogs that have identical molecular properties, we conclude that gene subfunctionalization in maize occurs much more rapidly than gene duplication. PMID- 21695573 TI - How high is Hispanic/Mexican fertility in the united states? Immigration and tempo considerations. AB - In this article, I demonstrate that the apparently much higher fertility of Hispanic/Mexican women in the United States is almost exclusively the product of period estimates obtained for immigrant women and that period measures of immigrant fertility suffer from three serious sources of bias that together significantly overstate fertility levels: difficulties in estimating the size of immigrant groups; the tendency for migration to occur at a particular stage in life; and, most importantly, the tendency for women to have a birth soon after migration. When these sources of bias are taken into consideration, the fertility of native Hispanic/Mexican women is very close to replacement level. In addition, the completed fertility of immigrant women in the United States is dramatically lower than the level obtained from period calculations. Findings are consistent with classical theories of immigrant assimilation but are a striking departure from the patterns found in previous studies and published statistics. The main implication is that without a significant change in immigration levels, current projections based on the premise of high Hispanic fertility are likely to considerably exaggerate Hispanic population growth, its impact on the ethno racial profile of the country, and its potential to counteract population aging. PMID- 21695574 TI - The effect of repeated mild cold water immersions on the adaptation of the vasomotor responses. AB - There are several types of cold adaptation based on the alteration of thermoregulatory response. It has been thought that the temperature of repeated cold exposures during the adaptation period is one of the factors affecting the type of cold adaptation developed. This study tested the hypothesis that repeated mild cold immersions would induce an insulative cold adaptation but would not alter the metabolic response. Seven healthy male participants were immersed to their xiphoid process level repeatedly in 26 degrees C water for 60 min, 3 days every week, for 4 weeks. During the first and last exposure of this cold acclimation period, the participants underwent body immersion tests measuring their thermoregulatory responses to cold. Separately, they conducted finger immersion into 5 degrees C water for 30 min to assess their cold-induced vasodilation (CIVD) response before and after cold acclimation. During the immersion to xiphoid process, participants showed significantly lower mean skin temperature and skin blood flow in the forearm post-acclimation, while no adaptation was observed in the metabolic response. Additionally, blunted CIVD responses were observed after cold acclimation. From these results, it was considered that the participants showed an insulative-type of cold acclimation after the repeated mild cold immersions. The major finding of this study was the acceptance of the hypothesis that repeated mild cold immersion was sufficient to induce insulative cold adaptation but did not alter the metabolic response. It is suggested that the adaptation in the thermoregulatory response is specific to the response which is repeatedly stimulated during the adaptation process. PMID- 21695575 TI - Patient-to-patient variability in autologous pericardial matrix scaffolds for cardiac repair. AB - The pursuit of alternate therapies for end-stage heart failure post-myocardial infarction has led to the development of a variety of in situ gelling materials to be used as cellular or acellular scaffolds for cardiac repair. Previously, a protocol was established to decellularize human and porcine pericardia and process the extracellular matrix (ECM) into an injectable form. The resulting gels were found to retain components of the native extracellular matrix; cell infiltration was facilitated in vivo, and neovascularization was observed by 2 weeks. However, the assertion that an injectable form of human pericardial tissue could be a potentially autologous scaffold for myocardial tissue engineering requires assessment of the patient-to-patient variability. With this work, seven human pericardia from a relevant patient demographic are processed into injectable matrix materials that gel when brought to physiologic conditions. The resulting materials are compared with respect to their protein composition, glycosaminoglycan content, in vitro degradation, in vivo gelation, and microstructure. It is observed that a diminished collagen content in a subset of samples prevents in vitro gelation but not in vivo gelation at lower ECM concentrations. The structure is similarly fibrous and porous across all samples, implying the cell infiltration may be similarly facilitated. The biochemical composition as characterized by tandem mass spectrometry is comparable; basic ECM components are conserved across all samples, and the presence of a wide variety of ECM proteins and glycoproteins demonstrate the retention of biochemical complexity post-processing. It is concluded that the variability within human pericardial tissue specimens does not prevent them from being processed into injectable scaffolds; therefore, pericardial tissue offers a promising source as an autologous, injectable biomaterial scaffold. PMID- 21695576 TI - Isolated motor neglect following infarction of the posterior limb of the right internal capsule: a case study with diffusion tensor imaging-based tractography. AB - Motor neglect is an impairment in the ability to initiate movement not attributable to muscle weakness. The neural network of this syndrome is not precisely defined. We present the diffusion tensor imaging (DTI)-base tractography findings in an acute stroke patient presenting with isolated motor neglect following infarction in the posterior limb of the internal capsule within the anterior choroidal artery territory. A left-handed 17-year-old woman presented with an acute onset of motor neglect of her left arm. Motor tasks performed with the affected limb were awkward; however, the tasks could be accomplished with effort. Magnetic resonance imaging (MRI) including DTI of the brain were performed. DTI-based tractography extracted the fiber tracts originating from regions of interest placed on the ischemic lesion. MRI revealed an acute ischemic infarction at the posterior part of the posterior limb of the right internal capsule within the territory of the anterior choroidal artery. DTI based tractography showed fiber tracts projecting from the lesion to the posterior part of the supplementary motor area and some fiber tracts projecting to posterior aspects of the thalamus. DTI-based tractography may be a useful tool for visualizing white matter pathways in vivo following an acute infarction. Our case study supports the notion that fiber tracts connecting the posterior part of the posterior limb of the internal capsule, supplementary motor area, and posterior aspect of the thalamus are key areas of a neural network involved in motor neglect syndrome. PMID- 21695577 TI - Contribution of Glomus intraradices inoculation to nutrient acquisition and mitigation of ionic imbalance in NaCl-stressed Trigonella foenum-graecum. AB - The study aimed to investigate the effects of an AM fungus (Glomus intraradices Schenck and Smith) on mineral acquisition in fenugreek (Trigonella foenum graecum) plants under different levels of salinity. Mycorrhizal (M) and non mycorrhizal (NM) fenugreek plants were subjected to four levels of NaCl salinity (0, 50, 100, and 200 mM NaCl). Plant tissues were analyzed for different mineral nutrients. Leaf senescence (chlorophyll concentration and membrane permeability) and lipid peroxidation were also assessed. Under salt stress, M plants showed better growth, lower leaf senescence, and decreased lipid peroxidation as compared to NM plants. Salt stress adversely affected root nodulation and uptake of NPK. This effect was attenuated in mycorrhizal plants. Presence of the AM fungus prevented excess uptake of Na(+) with increase in NaCl in the soil. It also imparted a regulatory effect on the translocation of Na(+) ions to shoots thereby maintaining lower Na(+) shoot:root ratios as compared to NM plants. Mycorrhizal colonization helped the host plant to overcome Na(+)-induced Ca(2+) and K(+) deficiencies. M plants maintained favorable K(+):Na(+), Ca(2+):Na(+), and Ca(2+):Mg(2+) ratios in their tissues. Concentrations of Cu, Fe, and Zn(2+) decreased with increase in intensity of salinity stress. However, at each NaCl level, M plants had higher concentration of Cu, Fe, Mn(2+), and Zn(2+) as compared to NM plants. M plants showed reduced electrolyte leakage in leaves as compared to NM plants. The study suggests that AM fungi contribute to alleviation of salt stress by mitigation of NaCl-induced ionic imbalance thus maintaining a favorable nutrient profile and integrity of the plasma membrane. PMID- 21695578 TI - "Vest over pants" abdominoplasty in post-bariatric patients. AB - Obesity has become a worldwide metabolic disease, necessitating appropriate treatment. Conservative therapy has shown lack of success long term on managing weight loss and comorbidities. On the other hand, bariatric surgery has demonstrated effectiveness. Unfortunately, bariatric patients experience significant skin excess, laxity, and ptosis which may lead to postural, functional, hygienic, dermatologic, and aesthetic impairments. These can be corrected only with body-contouring surgery. Among these procedures, abdominoplasty is one of the most commonly performed operations. In 1977, Planas presented his "vest over pants" abdominoplasty, which had several advantages over the previous approaches. In this study, the technique was tested on post bariatric patients. From 2005 to 2008, subsequent to laparoscopic biliopancreatic diversion, a tummy tuck was performed on 35 patients (28 females; 7 males). The patients were followed up for a mean period of 5 years. After abdominal contouring, 22 patients had an uneventful recovery and local complications were reported in the other 13 patients. Several advantages of this abdominal lipectomy method were recorded: minimal infection rate and single flap weight; high vascular safety; excellent matching of the flaps' thickness and scar position on the abdomen; minimal cumbersome maneuver and traction of the tissues; relatively short operating and lead time; and discrete comfort for the assistants and surgeon. In conclusion, the "vest over pants" abdominoplasty in post-bariatric patients has been demonstrated to be effective, fast to perform, comfortable for the surgeon, and safe. PMID- 21695579 TI - Breast augmentation after Macrolane filler injections. PMID- 21695580 TI - Healthcare costs of methicillin resistant Staphylococcus aureus and Pseudomonas aeruginosa infections in veterans: role of vitamin D deficiency. AB - Methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (P. aeruginosa) infections are frequently associated with hospitalization and increased healthcare costs. Vitamin D deficiency may contribute to increased costs for patients with these infections and there is evidence that vitamin D may have an antimicrobial role. To evaluate the role of vitamin D deficiency in the costs incurred with these infections, we studied the relationship of serum 25(OH)D levels to healthcare costs in veterans in the southeastern United States. Patients with both infections were vitamin D deficient to a similar extent and so were combined for further analysis. Vitamin D deficient patients had higher costs and service utilization than those who were not vitamin D deficient. Those with vitamin D deficiency had higher inpatient costs compared to the non-deficient group, and this difference was across most categories except for the number of inpatient hospitalizations or total number of days as an inpatient. Vitamin D deficiency was not significantly related to outpatient cost or service utilization parameters. We conclude that vitamin D deficiency is intimately linked to adverse healthcare costs in veterans with MRSA and P. aeruginosa infections. Vitamin D status should be assayed in patients with these infections. PMID- 21695581 TI - Induction of oligodendrocyte differentiation from adult human fibroblast-derived induced pluripotent stem cells. AB - Induced pluripotent stem cells (iPSCs) prepared from somatic cells might become a novel therapeutic tool in regenerative medicine, especially for the central nervous system (CNS). In this study, we attempted to induce O4-positive (O4(+)) oligodendrocytes from adult human fibroblast-derived iPSCs in vitro. We used two adult human iPSC cell lines, 201B7 and 253G1. 201B7 was induced by four-gene transduction (oct4, sox2, klf4, c-myc), and 253G1 was induced by three-gene transduction (oct4, sox2, klf4). We treated these cells with two in vitro oligodendrocyte-directed differentiation protocols that were optimized for human embryonic stem cells. One protocol used platelet-derived growth factor as the major mitogen for oligodendrocyte lineage cells, and the other protocol used epidermal growth factor (EGF) as the mitogen. Although the differentiation efficiency was low (less than 0.01%), we could induce O4(+) oligodendrocytes from 253G1 cells using the EGF-dependent differentiation protocol. This is the first report of the in vitro induction of oligodendrocytes differentiation from human iPSCs. PMID- 21695582 TI - Establishment of a novel ovine kidney cell line for isolation and propagation of viruses infecting domestic cloven-hoofed animal species. AB - A sheep kidney-derived cell line, FLK-N3, was successfully established after serial (>100) passages. Persistent infection of this cell line with viruses and mycoplasma was not detected. The cells grew well and showed susceptibility to a wide variety of viruses derived from ovine, bovine, and porcine species, including orf virus, maedi visna virus, bovine herpesvirus 1, bovine parainfluenza virus 3, bovine viral diarrhea viruses 1 and 2, bovine coronavirus, bovine respiratory syncytial virus, bovine enterovirus, suid herpesvirus 1, and porcine enterovirus. These results suggest that the FLK-N3 cell line could be useful for isolation and propagation of viruses that affect cloven-hoofed animals. PMID- 21695583 TI - Pepsin detection in patients with laryngopharyngeal reflux before and after fundoplication. AB - BACKGROUND: Some patients with gastroesophageal reflux disease (GERD) suffer from laryngopharyngeal reflux (LPR). There is no reliable diagnostic test for LPR as there is for GERD. We hypothesized that detection of pepsin (a molecule only made in the stomach) in laryngeal epithelium or sputum should provide evidence for reflux of gastric contents to the larynx, and be diagnostic of LPR. We tested this hypothesis in a prospective study in patients with LPR symptoms undergoing antireflux surgery (ARS). METHODS: Nine patients undergoing ARS for LPR symptoms were studied pre- and postoperatively using a clinical symptom questionnaire, laryngoscopy, 24-h pH monitoring, biopsy of posterior laryngeal mucosa, and sputum collection for pepsin Western blot assay. RESULTS: The primary presenting LPR symptom was hoarseness in six, cough in two, and globus sensation in one patient. Pepsin was detected in the laryngeal mucosa in eight of nine patients preoperatively. There was correlation between biopsy and sputum (+/+ or -/-) in four of five patients, both analyzed preoperatively. Postoperatively, pH monitoring improved in all but one patient and normalized in five of eight patients. Eight of nine patients reported improvement in their primary LPR symptom (six good, two mild). Only one patient (who had negative preoperative pepsin) reported no response to treatment of the primary LPR symptom. Postoperatively, pepsin was detected in only one patient. CONCLUSIONS: Pepsin is often found on laryngeal epithelial biopsy and in sputum of patients with pH-test proven GERD and symptoms of LPR. ARS improves symptoms and clears pepsin from the upper airway. Detection of pepsin improves diagnostic accuracy in patients with LPR. PMID- 21695584 TI - Video: intrahepatic Glissonian approach for pure laparoscopic right hemihepatectomy. AB - AIM: To present a video of laparoscopic right hepatectomy using Glissonian technique. A new strategy for liver transection is presented. Liver is divided in three parts. The posterior part, containing short hepatic veins, is divided with stapler before liver transection. Anterior part is fully divided with harmonic scalpel, and the middle part, containing hepatic veins from segments 5 and 8, is the last part to be transected. PATIENT AND METHOD: A 41-year-old woman with right-sided hepatolithiasis and choledocholithiasis was referred for surgical treatment. Patient was positioned in left lateral position. Four trocars were used. Operation began with division of liver ligaments, right liver mobilization, and exposure of the retrohepatic vena cava. Cholecystectomy was performed, followed by intrahepatic access to the right Glissonian pedicle (containing arterial, portal, and bile duct branches of segments 5-8). Two small incisions were performed around hilar plate according to specific anatomic landmarks. A vascular clamp was introduced into those incisions, resulting in ischemic delineation of right liver. Clamp was replaced by a vascular stapler, and stapler was fired. Liver parenchyma was divided by harmonic scalpel combined with vascular stapler. The specimen was extracted through suprapubic incision. Intraoperative cholangiography confirmed a 2-cm common bile duct stone which was immediately removed by endoscopy (endoscopic retrograde cholangiopancreatography, ERCP). Falciform ligament was sutured to maintain the liver in its original anatomical position, avoiding hepatic vein kinking, and abdominal cavity was drained. RESULTS: Operative time was 180 min, with blood loss estimated at 50 ml, without need for transfusion. Postoperative recovery was uneventfully, and patient was discharged on the fourth postoperative day. CONCLUSION: Laparoscopic intrahepatic Glissonian approach is feasible and is a useful technique for rapid and safe control of the right liver pedicle, facilitating laparoscopic right hemihepatectomy. The special strategy described may help laparoscopic surgeons to safely perform this challenging procedure. PMID- 21695585 TI - Robotic versus laparoscopic surgery for rectal cancer and cost-effectiveness analysis. PMID- 21695587 TI - Dystroglycan is associated with tumor progression and patient survival in gastric cancer. AB - Previous reports had indicated that there was a possible correlation of dystroglycan (DG) with biological behavior of cancer cells and cancer patients' survival. However, the role of DG expression in gastric cancer was rarely studied. In this study, alpha-DG and beta-DG expression were determined by immunohistochemistry in specimens of primary cancer, metastatic lymph node, distal metastatic lesion, and their normal counterpart tissues in 20 gastric cancer patients. Correlations between alpha-DG and beta-DG expression and prognosis were retrospectively analyzed. Our results found that positive expression of alpha-DG in normal mucosa, paired primary tumor, metastatic lymph node and distal metastatic site was detected in 95%, 70%, 25%, and 5% specimens, individually. Regarding beta-DG,it was 70%, 55%, 10%, and 10%, individually. Patients who had lower alpha-DG expression in tumors than in normal counterparts showed poor survival (p = 0.002), whereas such a correlation was not found in the case of beta-DG (p = 0.079). Difference of alpha-DG between primary tumor and its normal counterparts was an independent prognostic factor in gastric cancer with distal metastasis. This study showed DG expression was gradually reduced during tumor progression. Different expression of alpha-DG, but not beta-DG, between primary tumor and normal specimen, correlated with patient survival, implicating a potential marker for gastric cancer prognosis. PMID- 21695589 TI - Exploring the role of religiosity and spirituality in amniocentesis decision making among Latinas. AB - Given the complex array of emotional and medical issues that may arise when making a decision about amniocentesis, women may find that their spiritual and/or religious beliefs can comfort and assist their decision-making process. Prior research has suggested that Latinas' spiritual and/or religious beliefs directly influence their amniocentesis decision. A more intimate look into whether Latinas utilize their beliefs during amniocentesis decision-making may provide an opportunity to better understand their experience. The overall goal of this study was to describe the role structured religion and spirituality plays in Latinas' daily lives and to evaluate how religiosity and spirituality influences health care decisions, specifically in prenatal diagnosis. Semi-structured interviews were conducted with eleven women who were invited to describe their religious beliefs and thoughts while considering the option of amniocentesis. All participants acknowledged the influence of religious and/or spiritual beliefs in their everyday lives. Although the women sought comfort and found validation in their beliefs and in their faith in God's will during their amniocentesis decision-making process, results suggest the risk of procedure-related complications played more of a concrete role than their beliefs. PMID- 21695588 TI - The use of transient elastography in the management of chronic hepatitis B. AB - There has been increasing interest in noninvasive methods of assessing liver fibrosis over the last decade. The use of transient elastography in measuring liver stiffness has become the forefront of a wide range of noninvasive tools. Most of the other methods are based on measurements of biomarkers associated with fibrosis. There are several reasons for its wide acceptance, including the ease of performing a scan, the short procedure time, the results being immediately available on completion of the examination, and its reproducibility. For chronic hepatitis B (CHB), the cut-off values for F3 and F4 fibrosis range between 7.5 12.0 and 11.0-13.4 kPa, respectively, although the cut-offs may be slightly lower in those with normal ALT. In addition to measuring liver fibrosis, recent studies have demonstrated several other roles for transient elastography, including selecting patients who will benefit from antiviral therapy, monitoring response to antiviral therapy, and predicting long-term outcomes. However, there are limitations associated with transient elastography, including the confounding effects of inflammatory activity, and to a lesser extent, steatosis, on liver stiffness. There is also reduced accuracy observed in lower fibrosis stages (F0 F2). Furthermore, the incidences of failed and unreliable scan have been reported to be ~ 3 and 16%, respectively. Although liver biopsy can be avoided in an estimated 50-60% using transient elastography, in situations where liver stiffness measurement is nondiagnostic or inconsistent with the clinical picture, a biopsy is still recommended. Further studies are needed to consolidate the role of transient elastography in the management of CHB, and for incorporation of this method into current treatment guidelines. PMID- 21695591 TI - Single incision laparoscopic cholecystectomy (SILC) versus laparoscopic cholecystectomy (LC)-a matched pair analysis. AB - INTRODUCTION: The aim of our study was to compare single incision laparoscopic cholecystectomy (SILC) and laparoscopic cholecystectomy (LC) with respect to complications, operating time, postoperative pain, use of analgesics, length of stay, return to work, rate of incisional hernia, and cosmetic outcome. METHODS: Sixty-seven patients underwent SILC. Of a cohort of 163 LC operated in the same time period, 67 patients were chosen for a matched pair analysis. Pairs were matched for age, gender, ASA, BMI, acuity, and previous abdominal surgery. In the SILC group, patient characteristics (gender, age, BMI, comorbidities, ASA, previous abdominal surgery, symptomatic cholecystolithiasis, cholecystitis) and perioperative data (surgeon, operation time, conversion rate and cause, intraoperative complications, postoperative complications, reoperation rate, VAS at 24 h, VAS at 48 h, use of analgesics according to WHO class, and length of stay) were collected prospectively. RESULTS: Follow-up in the SILC and LC group was completed with a minimum of 17 and a maximum of 26 months; data acquired were recovery time the patients needed until they were able to get back into the working process, long-term incidence of postoperative hernias, and satisfaction with cosmetic outcome. Operating time was longer for SILC (median 75 min, range 39-168 vs. 63, range 23-164, p = 0.039). There were no significant differences for SILC and LC with regard to postoperative pain measured by VAS at 24 h (median 3, range 0-8 vs. 2, range 0-8, p = 0.224), at 48 h (median 2, range 0-6 vs. 2, range 0-8, p = 0.571), use of analgesics, and length of stay (median 2 days, range 1-9 vs. 2, range 1-11, p = 0.098). There was no major complication in either group. The completion rate of SILC was 85.1% (57 of 67). Although there was a trend towards an earlier return to the working process in patients of the SILC group, this was not significant. The rate of incisional hernias was 1.9% (1/53) in the SILC and 2.1% (1/48) in the LC group indicating no significant difference. Self-assessment of satisfaction with the cosmetic outcome was not judged different by patients in both groups. CONCLUSION: SILC is associated with longer operating time, but equals LC with respect to safety, postoperative pain, use of analgesics, length of stay, return to work, rate of incisional hernia, and cosmetic outcome. PMID- 21695590 TI - Mood and anxiety disorders in a sample of Canadian perinatal women referred for psychiatric care. AB - Perinatal depression currently receives considerable attention, but not all perinatal women presenting for psychiatric care are depressed. The Edinburgh Postnatal Depression Scale (EPDS) is now routinely administered, but high scores are interpreted as evidence for depressive illness only. This study examined psychiatric diagnoses and mean EPDS scores among perinatal women at a tertiary center. Women accessing care between March 2006 and June 2008 completed a clinical diagnostic interview and the EPDS. Mean EPDS scores were calculated for each psychiatric diagnosis; sensitivity and specificity were calculated for major depressive episode (MDE) and generalized anxiety disorder (GAD). The majority of the sample (N = 91), 49.5%, had GAD comorbid with MDE or another anxiety disorder, followed by MDE (38.5%) comorbid with an anxiety disorder. One third (29.7%) met criteria for MDE and GAD. Only 3.3% had MDE alone and 5.5% had GAD alone. Half the sample (50.5%) had more than one psychiatric disorder. Mean EPDS scores exceeded 11 for the majority of diagnostic groups. Sensitivity of the EPDS for MDE was 0.78 and 0.70 for GAD. Most women had an anxiety disorder and met criteria for more than one psychiatric disorder. Mean EPDS scores were consistently high. Sensitivity of the EPDS for MDE and GAD was comparable. PMID- 21695592 TI - Outcome of transanal endorectal vs. transabdominal pull-through in patients with Hirschsprung's disease. AB - INTRODUCTION: Various outcomes have been reported in patients with Hirschsprung's disease (HD) following transanal endorectal (TERPT) or conventional transabdominal (ABD) pull-through procedures. This study examined postoperative complications and the long-term outcome of TERPT vs. ABD pull-through for HD. METHODS: Records were reviewed for 53 patients over 3 years of age in whom a pull through procedure was performed for HD (TERPT, n = 24; ABD, n = 29) between 1992 and 2007 at the Departments of Pediatric Surgery, University of Heidelberg and University Hospital of Mannheim, and their families were interviewed and scored via a thorough 15-item, post-pull-through, long-term outcome questionnaire. Total scores ranged from 0 to 40: 0 to 10, excellent; 11 to 20, good; 21 to 30, fair; and 31 to 40, poor. Two-sided Fisher's exact test and analysis of variance were used to compare different variables in patients in the two groups with significance set at p < 0.05. Results are expressed as mean and standard deviation (SD). RESULTS: Overall scores were similar (TERPT, n = 16, 7.3 +/- 6.6 vs. ABD, n = 23, 4.6 +/- 3.5, p = 0.11) and showed mainly excellent or good long term outcome for TERPT (93.8%) and ABD (99.7%) pull-through procedures. The incidence of incontinence in children older than 3 years was insignificantly lower in ABD group (TERPT 18.7% vs. ABD 4.3 %, p = 0.15). Regarding the soiling score, however, the soiling tended to be significantly more severe after TERPT than ABD. For the TERPT procedure, the appearance of postoperative constipation, enterocolitis, anastomotic dehiscence, and symptomatic anastomotic stricture was lower but this was not statistically significant. After TERPT, patients started to feed sooner (TERPT 2.8 days vs. ABD 4.4 days, p = 0.005) and operating time (TERPT 133.2 min vs. ABD 204 min, p < 0.001) and hospital stay (TERPT 9.8 days vs. ABD 17.7 days, p < 0.001) were significantly shorter. CONCLUSION: We employ the TERPT procedure as the first choice in children with rectosigmoid HD. PMID- 21695593 TI - Visual awareness of objects and their colour. AB - At any given moment, our awareness of what we 'see' before us seems to be rather limited. If, for instance, a display containing multiple objects is shown (red or green disks), when one object is suddenly covered at random, observers are often little better than chance in reporting about its colour (Wolfe, Reinecke, & Brawn, Visual Cognition, 14, 749-780, 2006). We tested whether, when object attributes (such as colour) are unknown, observers still retain any knowledge of the presence of that object at a display location. Experiments 1-3 involved a task requiring two-alternative (yes/no) responses about the presence or absence of a colour-defined object at a probed location. On this task, if participants knew about the presence of an object at a location, responses indicated that they also knew about its colour. A fourth experiment presented the same displays but required a three-alternative response. This task did result in a data pattern consistent with participants' knowing more about the locations of objects within a display than about their individual colours. However, this location advantage, while highly significant, was rather small in magnitude. Results are compared with those of Huang (Journal of Vision, 10(10, Art. 24), 1-17, 2010), who also reported an advantage for object locations, but under quite different task conditions. PMID- 21695594 TI - Correlates of quality of life in China rural-urban female migrate workers. AB - BACKGROUND: Rural-urban female migrant workers living in factories are a special majority group in the city of Shenzhen, China. These female workers came from different provinces of mainland China. The health-related issues and quality of life (QOL) of this migrator have become serious public health and social problems, which have not been well characterized. This study aimed to explore the QOL and related factors of rural-urban female migrant workers living in factories in China. METHODS: In total, 3,622 rural-urban female migrant workers completed the Health Survey Short Form (SF-36). Sociodemographic characteristics, health status and job satisfaction during the past 6 months were also collected. RESULTS: Subjects had an average of 2.53 +/- 1.93 (median = 2.00, quartile interval = 3.00) diseases. The two-week Morbidity Rate was 21.9%, and only 14.0% of the subjects were satisfied with their current job. Compared to Chinese female norms, the participants scored lower in seven concepts domains of SF-36 (role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health). Multiple stepwise linear regression analysis showed that after adjustment for age, education level, work duration and job satisfaction, two-week Morbidity Rate, anemia symptoms and muscular soreness proved to be significant predictors for all the 7 domains (except for physical functioning). Digestive system disease was a significant predictor in 5 out of 7 domains, while urinary system disease and gynecological disease were significant predictors in 4 out of 7 domains. CONCLUSIONS: In general, QOL in rural-urban female migrant workers was lower than Chinese female norms. Improving their job satisfaction and controlling job-related disease appears to be critical to improving their QOL. PMID- 21695595 TI - Continuous hypertonic saline for acute liver failure. AB - Acute liver failure (ALF) is a clinical condition with high mortality. The most common cause of death in ALF is cerebral edema. We present a 12-year-old boy with hepatitis A-related acute liver failure in grade IV hepatic encephalopathy successfully managed in the ICU using continuous hypertonic saline as the preferred osmotherapy. PMID- 21695596 TI - The nucleosome binding protein NSBP1 is highly expressed in human bladder cancer and promotes the proliferation and invasion of bladder cancer cells. AB - NSBP1 is a recently identified member of the HMGN protein family which binds to nucleosomes and regulates gene transcription through chromatin remodeling. In this study, we aimed to investigate the potential role of NSBP1 in human bladder cancer. We examined NSBP1 expression in 114 surgically removed bladder cancer specimens as well as 11 human bladder cell lines by immunohistochemistry and Western blot analysis, and found that NSBP1 level was correlated with the increased tumor grade and pathologic stage, and lymph node metastasis. RNAi mediated knockdown of NSBP1 in EJ cells, a bladder cancer cell line that overexpressed NSBP1, resulted in moderate decrease of cell viability, moderate blockage of cell cycle at G2/M phase, and decreased cyclin B1 expression, but had no effects on apoptosis. Moreover, NSBP1 knockdown led to reduced activity of MMP 9 but not MMP-2. Taken together, these results suggest that NSBP1 promotes the viability of bladder cancer cells through increased cell proliferation but not decreased apoptosis, and increases the invasion ability of metastatic bladder cancer cells through the upregulation of MMP-9 activity. Our findings not only provide a molecular understanding of the role of NSBP1 in bladder cancer, but also suggest NSBP1 RNAi as a novel therapeutic approach for bladder cancer. PMID- 21695597 TI - MHC region and risk of systemic lupus erythematosus in African American women. AB - The major histocompatibility complex (MHC) on chromosome 6p21 is a key contributor to the genetic basis of systemic lupus erythematosus (SLE). Although SLE affects African Americans disproportionately compared to European Americans, there has been no comprehensive analysis of the MHC region in relationship to SLE in African Americans. We conducted a screening of the MHC region for 1,536 single nucleotide polymorphisms (SNPs) and the deletion of the C4A gene in a SLE case control study (380 cases, 765 age-matched controls) nested within the prospective Black Women's Health Study. We also genotyped 1,509 ancestral informative markers throughout the genome to estimate European ancestry to control for population stratification due to population admixture. The most strongly associated SNP with SLE was the rs9271366 (odds ratio, OR = 1.70, p = 5.6 * 10(-5)) near the HLA-DRB1 gene. Conditional haplotype analysis revealed three other SNPs, rs204890 (OR = 1.86, p = 1.2 * 10(-4)), rs2071349 (OR = 1.53, p = 1.0 * 10(-3)), and rs2844580 (OR = 1.43, p = 1.3 * 10(-3)), to be associated with SLE independent of the rs9271366 SNP. In univariate analysis, the OR for the C4A deletion was 1.38, p = 0.075, but after simultaneous adjustment for the other four SNPs the odds ratio was 1.01, p = 0.98. A genotype score combining the four newly identified SNPs showed an additive risk according to the number of high-risk alleles (OR = 1.67 per high-risk allele, p < 0.0001). Our strongest signal, the rs9271366 SNP, was also associated with higher risk of SLE in a previous Chinese genome-wide association study (GWAS). In addition, two SNPs found in a GWAS of European ancestry women were confirmed in our study, indicating that African Americans share some genetic risk factors for SLE with European and Chinese subjects. In summary, we found four independent signals in the MHC region associated with risk of SLE in African American women. PMID- 21695598 TI - Sub-optimal asthma control in teenagers in the midland region of Ireland. AB - BACKGROUND: Internationally, many children with asthma are not attaining achievable asthma control. AIMS: To examine the prevalence of asthma in teenagers in four midland counties, their asthma control and the barriers, if any, to gaining control of asthma. METHODOLOGY: International Study of Asthma and Allergies in Children (ISAAC) methodology was used in a survey of Junior Cycle Year 2 second-level students. RESULTS: The prevalence of "wheeze ever" was 49.8%, "wheeze in the last 12 months" was 32.6% and "asthma ever" was 23.5%. Of teenagers with current asthma, 96% had evidence of sub-optimal asthma control during the previous year. For the majority of the teenagers with asthma, treatment was not guideline concordant; infrequent lung function testing, insufficient review after acute care and poor use of written asthma action plans. Barriers included lack of awareness of need for treatment. CONCLUSIONS: If asthma guidelines are implemented fully, these children may experience better health. PMID- 21695599 TI - Tubular anomalous bones found in both thighs of a long-tailed macaque (Macaca fascicularis). AB - Tubular anomalous bones were found in both thighs of a 6-year-old male long tailed macaque (Macaca fascicularis) bred in captivity. The bones had jagged ends and protruded from the skin. Radiographs showed that they developed in the femurs at the middle and elongated. They were removed with surgery under anesthesia. Histological analysis revealed that these bones had the same histological structure as the femur, though they were composed of primary and secondary osteon regions. This finding indicated that the new bones developed from the old bone piece(s), acquired a tubular shape, and elongated. It is suggested that the anomalous bones were produced not by the congenital deformity but by regeneration from fragments of the fractured femur that were embedded in the bone marrow; these acquired a tubular pattern and elongated. PMID- 21695604 TI - [Diseases of the orbit. From orbital tumors to orbital reconstruction]. PMID- 21695600 TI - An effective salvage treatment using ifosfamide, etoposide, cytarabine, dexamethasone, and rituximab (R-IVAD) for patients with relapsed or refractory aggressive B-cell lymphoma. AB - We evaluated the efficacy and toxicity of a new salvage regimen, consisting of rituximab (375 mg/m(2), day 1), ifosfamide (1500 mg/m(2) on days 3-7), etoposide (150 mg/m(2), days 3-5), cytarabine (100 mg/m(2), days 3-5) and dexamethasone (40 mg/body, days 3-5) (R-IVAD) for relapsed or refractory aggressive B-cell lymphoma. In this study, a total of 32 patients with a median age of 64 years (range 38-79) who received an average of 2.6 cycles of R-IVAD from 2001 to 2009 in our institution were retrospectively analyzed. R-IVAD was given every 3 weeks up to a total of three courses with support by granulocyte colony stimulating factor. The overall response rate was 72%, with 56% complete response. On a median follow-up of 16 months (range 2-99), estimated 2-year overall survival (OS) and event-free survival were 55% and 36%, respectively. Of these patients, 10 successfully proceeded to consolidating high-dose chemotherapy followed by autologous stem cell transplantation, accounting for 90% of the 2-year OS. No treatment-related mortality was observed during the investigation. We, therefore, conclude that R-IVAD regimen is a safe and efficacious alternative for patients with relapsed or refractory aggressive B-cell lymphoma. PMID- 21695605 TI - [Clinical and neuroradiological diagnostics of orbital tumors]. AB - Exophthalmus is the leading sign of space-occupying lesions of the orbit. Patients may further present with lid swelling, impaired ocular motility and optic neuropathy including a relative afferent pupillary defect, compressive optic disc edema or optic atrophy. Orbital tumors can be classified into various categories depending on the etiology, as lymphoproliferative lesions (in particular non-Hodgkin's lymphoma as the most common malignant orbital tumor of adulthood), optic nerve and meningeal lesions, lacrimal gland lesions, secondary orbital tumors which extend to the orbit from neighboring structures and metastases. Slightly less common are vasculogenic and cystic lesions including cavernous hemangioma as the most common benign orbital tumor of adulthood and dermoid cysts as the most common benign orbital tumor of childhood. Rhabdomyosarcoma is the most common malignant orbital tumor of childhood but has a low total incidence. Orbital tumors might not only cause symptoms like pain, diplopia and loss of visual acuity but may also lead to esthetically disfiguring changes. Particular attention should be paid to underlying systemic diseases and generalized tumor diseases. This article illustrates the approach to a detailed clinical and neuroradiological assessment which is mandatory for the care of orbital tumor patients. PMID- 21695606 TI - [Therapy of posterior orbital tumors]. AB - Tumors of the posterior orbit require different therapeutic modalities, depending on the histological entity. In the orbit all structures are in close relationship and the endocranium is in the direct proximity. This requires profound knowledge of topographic anatomy and high therapeutic precision. The surgical approach to the posterior orbit via a ventral intraorbital approach is strongly restricted due to the ocular bulb which consumes most space in the anterior orbit. Therefore if the bulb and vision are to be retained extraorbital surgical corridors are predominantly preferred. These are classified into extracranial and intracranial approaches. In detail, the former are medial transethmoidal orbitotomy, caudal transmaxillar orbitotomy and lateral orbitotomy. Frontolateral and frontotemporal orbitotomy as well as frontal, bifrontal and subfrontal orbitotomy are intracranial approaches. Apart from surgical methods there are several forms of radiotherapy which can be applied to orbital tumors under certain indications. Radiotherapy may be performed with external fractionated photon radiation or as stereotactic radiation, with heavy ions or protons or as brachytherapy. In this article various therapeutic interventions to the posterior orbit and the indications and potential side-effects are described. PMID- 21695607 TI - [Function-retaining reconstruction after orbital trauma]. AB - Precise anatomical reconstruction of extensive orbital fractures is a challenging procedure for surgeons. Computer-assisted technologies, anatomical preformed implants and the possibility of acquiring 3D images using cone beam computed tomography are considered as the new standards. In this short review these applications are presented. PMID- 21695608 TI - [Monochromatic aberration in accommodation. Dynamic wavefront analysis]. AB - BACKGROUND: Monochromatic aberrations may influence the visual acuity of the eye. They are not stable and can be affected by different factors. The subject of the following paper is the dynamic investigation of the changes in wavefront aberration with accommodation. METHOD: Dynamic measurement of higher and lower order aberrations was performed with a WASCA Wavefront Analyzer (Carl-Zeiss Meditec) and a specially constructed target device for aligning objects in far and near distances on 25 subjects aged from 15 to 27 years old. RESULTS: Wavefront aberrations showed some significant changes in accommodation. In addition to the characteristic sphere reaction accompanying miosis and changes in horizontal prism (Z(1) (1)) in the sense of a convergence movement of the eyeball also occurred. Furthermore defocus rose (Z(2) (0)) and astigmatism (Z(2) (-2)) changed. In higher-order aberrations a decrease in coma-like Zernike polynomials (Z(3) (-1), Z(3) (1)) was found. The most obvious change appeared in spherical aberration (Z(4) (0)) which increased and changed from positive to negative. In addition the secondary astigmatism (Z(4) (-2)) and quadrafoil (Z(4) (4)) rise also increased. The total root mean square (RMS), as well as the higher-order aberrations (RMS-HO) significantly increased in accommodation which is associated with a theoretical reduction of visual acuity. An analysis of the influence of pupil size on aberrations showed significant increases in defocus, spherical aberration, quadrafoil, RMS and RMS HO by increasing pupil diameter. By accommodation-associated miosis, the growing aberrations are partially compensated by focusing on near objects. Temporal analysis of the accommodation process with dynamic wavefront analysis revealed significant delays in pupil response and changing of prism in relation to the sphere reaction. In accommodation to near objects a discrete time ahead of third order aberrations in relation to the sphere response was found. CONCLUSION: Using dynamic wavefront measurement achieved a sequential analysis of aberrations during accommodation. Significant changes in the lower and higher-order aberrations could be detected. These are additionally varied by the associated pupillary response. Moreover, the synchronicity of wave front reaction in the accommodation process was proven. PMID- 21695609 TI - [Differences in the treatment of exudative age-related macular degeneration in Germany and Great Britain]. AB - The treatment of age-related macular degeneration with anti-VEGF medications has resulted not only in significant improvements in eye treatment but also in rising costs of ophthalmological therapy. This new treatment has been rapidly introduced into daily practice in Germany with its social security healthcare system and also in Great Britain with its National Health Service. In both countries the most prevalent treatment scheme currently includes three baseline injections of ranibizumab followed by additional injections depending on persisting disease activity. PMID- 21695612 TI - Traditional Chinese medicine in the new century. PMID- 21695610 TI - [Glaucoma with primary iris malformations. Axenfeld-Rieger syndromes, ICE syndromes (essential iris atrophy, Chandler's syndrome, Cogan-Reese syndrome), aniridia]. AB - Iris malformations are often associated with malformations of the entire eye and systemic diseases. Malformations of the anterior chamber angle can lead to juvenile glaucoma. Axenfeld-Rieger syndromes have autosomal dominant transmission and are associated with juvenile glaucoma in 50-60% of patients. Besides eye anomalies craniofacial malformations are also typical. The etiology of iridocorneal endothelial (ICE) syndrome is unclear but atypical endothelial cells lead to malformations of the entire anterior eye segment of the eye and glaucoma. Aniridia is a bilateral, congenital malformation which manifests sporadically and transmission is usually autosomal dominant. Glaucoma, malformations of the entire eye and systemic malformations are associated with aniridia. Conservative and microsurgical treatment of glaucoma of these syndromes need the cooperation of different medical subspecialties and are often ineffective. PMID- 21695613 TI - Metformin for cancer prevention. PMID- 21695614 TI - Construction of the vessel-collateral theory and its guidance for prevention and treatment of vasculopathy. AB - According to the self-discipline of traditional Chinese medicine, vessel collateral theory was constructed systematically, which was important to improving prevention and treatment level of vasculopathy. The hypothesis of "homeostasis (Cheng), compensatory auto-adaptation (Zhi), regulation (Tiao) and equilibrium (Ping)" based on the "qi-yin-yang-five elements" coupled with the ying (nutrients)-wei (defense) theory, has become the core content of the vessel collateral theory. Clinical and laboratory trials have been developed to further confirm the scientific connotations of the hypothesis, such as Tong Xin Luo capsule, as the representative drugs of vessel collateral theory, showed good efficacy in protecting the vascular endothelium, stabilizing the vulnerable plaque and reducing the blood vessel spasm. "Sou, ti, shu, tong" was the characteristics of Tong Xin Luo capsule in treating "microvascular damage" as the core mechanism of acute myocardial infarction, cerebral infarction and microvascular complications of diabetes. Shen Song Yang Xin capsules in the treatment of arrhythmia have made integrated adjustment advantage. Qi Li Qiang Xin capsules have been made treating both manifestation and root cause of chronic heart failure. These research have improved prevention and treatment level of major vascular system diseases. PMID- 21695615 TI - Practices, challenges, and opportunities: HIV/AIDS treatment with traditional Chinese medicine in China. AB - Traditional Chinese medicine (TCM) has become widely used in the treatment of acquired immune deficiency syndrome (AIDS) in China in recent years. In this article, we summarize the recent major developments in human immunodeficiency virus/AIDS (HIV/AIDS) treatment with TCM. The use of TCM is associated with preventing or alleviating HIV-related symptoms, reducing treatment side effects, and improving the quality of life. The potential beneficial effects of TCM should be confirmed through extensive and rigorous trials. PMID- 21695616 TI - Developments in cancer prevention and treatment using traditional Chinese medicine. AB - Through the joint efforts of several generations of practitioners in traditional Chinese medicine (TCM) and integrated medicine of oncology, we have made some achievements in cancer treatment using TCM in over 50 years, including treatment concepts, methods, and basic and clinical research. Currently, TCM plays an indispensable role in cancer prevention and treatment. However, we also clearly recognize that there are some issues that have yet to be resolved. In the future, cancer treated with TCM will face unprecedented opportunities and challenges. This article reviews the developments of TCM in the treatment of cancer. PMID- 21695618 TI - Acupuncture-related techniques for the treatment of opiate addiction: a case of translational medicine. AB - Drug addiction is a chronic brain disorder characterized by withdrawal symptoms that occur during drug abstinence and a high tendency of relapse. Compared with the currently available pharmacological interventions, acupuncture therapy has the potential to help drug addicts stay away from drugs without major adverse side effects. It has taken decades of research to optimize the parameters of electrical acupoint stimulation for detoxification and for relapse prevention, as well as to establish a safe and easy procedure by which drug addicts can use it on themselves. The discovery that acupuncture can trigger the release of opioid substances from the brain in the 1970s provided the inspiration. Following this, basic research on animals made it possible to understand the mechanisms of action and establish the procedure for treating drug addictions. This article reviews the past, present, and foreseeable future regarding the use of acupuncture related technique for the treatment of opiate addiction from the perspective of translational medicine. PMID- 21695617 TI - Clinical acupuncture research in the West. AB - In recent years, acupuncture has rapidly become part of mainstream medicine in the West, where new developments in acupuncture clinical research show extensive progress in evaluating the efficacy and safety of the modality in many categories of disease, especially in pain conditions. Although challenges and difficulties remain, the acupuncture research community has matured and its past experience may lead to even better methods and more innovative research. PMID- 21695619 TI - Mechanism of acupuncture regulating visceral sensation and mobility. AB - Chinese ancient medical scientists have long focused on the internal and external contacts between acupoints on the surface of the body and the viscera. The Miraculous Pivot (it is one of the earliest medical classics in China) stated, "Twelve regular channels belong to the zang-fu organs internally, and connect to the extremities and joints externally." Traditional Chinese medicine considers acupoints as defined areas where the Qi of viscera and meridians are transfused. These include the reaction points of visceral diseases on the body surface as well as the acupuncture trigger points that promote the flow of Qi and blood, and regulate visceral function. Chinese ancient medical scientists classified the specificity of the main acupoints in the body based on the meridian doctrine, which has been instructing clinical application for about 2000 years. Laws on the domino effect of acupoints have mainly focused on conclusions to clinical experiences. Indications of some acupoints exceed the practical paradigm since the excessive extension occurred during theory derivation. The current research direction on acupuncture focuses on three aspects: the effectiveness of acupuncture and moxibustion; the relevances and associations between meridians and viscera; and the physical and chemical properties and relevant physical basis of acupoints. The relevance between meridians and viscera is the central theory in the meridian doctrine, and acupoints are regarded as an important link in the relationship between meridians and viscera. Specific relationships between acupoints and target organs exist. Stimulating different acupoints on the body surface can help deal with different diseases, especially visceral diseases. In addition, acupoints have a dual function of reflecting and treating visceral diseases. There is no systemic research available on acupoint specificity, despite current knowledge and clinical experiences, which results in a weak foundation for acupuncture theory. This study focuses on the relevance and associations between meridians and viscera. A summary of the mechanisms of acupuncture regulating visceral sensation and mobility and the specific relationships between acupoints and their target organs are presented in this review. PMID- 21695620 TI - Exploring the methodology and application of clinical pathway in evidence-based Chinese medicine. AB - At present, clinical pathway has become one of the most important health care reform measures in many countries. In this study, the authors introduced basic concepts and explored the application of the clinical pathway of evidence-based Chinese medicine incorporated with the methodology from the concepts of management, evidence-based medicine, operational research and health economics. Such concepts provide examples and experiences, on which the application of clinical pathway in Chinese medicine practice in China can be based. PMID- 21695621 TI - Thinking and practice of accelerating transformation of traditional Chinese medicine from experience medicine to evidence-based medicine. AB - The gradual development of Chinese medicine is based on constant accumulation and summary of experience in clinical practice, but without the benefit of undergoing the experimental medicine stage. Although Chinese medicine has formed a systematic and unique theory system through thousands of years, with the development of evidence-based medicine, the bondage of the research methods of experience medicine to Chinese medicine is appearing. The rapid transition and transformation from experience medicine to evidence-based medicine have become important content in the development of Chinese medicine. According to the features of Chinese medicine, we propose the research idea of "taking two ways simultaneously," which is the study both in the ideal condition and in the real world. Analyzing and constructing the theoretical basis and methodology of clinical research in the real world, and building the stage for research technique is key to the effective clinical research of Chinese medicine. Only by gradually maturing and completing the clinical research methods of the real world could we realize "taking two ways simultaneously" and complementing each other, continuously produce scientific and reliable evidence of Chinese medicine, as well as transform and develop Chinese medicine from experience medicine to evidence-based medicine. PMID- 21695622 TI - Consolidated standards of reporting trials (CONSORT) for traditional Chinese medicine: current situation and future development. AB - The reporting standards for randomized controlled trials were first published in 1996 by a group of scientists under the name "CONSORT," which means consolidated standards of reporting trials. Revisions followed in 2001 and 2010. A draft of the CONSORT for traditional Chinese medicine (TCM) was published in both Chinese and English in 2007. After publication of the draft, comments were solicited from the medical community. Some papers did raise concerns about which items should be included in the CONSORT for TCM such as the rationale of the trial design, intervention, outcome assessment, and adverse events. We have now reached the next step which is the finalization of the CONSORT for TCM. Three tasks remain. First, the major changes in CONSORT statement 2010 should be integrated into the CONSORT for TCM. Second, Chinese drugs from minerals and animals should be included in the guidelines. Finally, agreement must be reached among the working groups. Once the draft is finalized, wide dissemination and co-publication will be considered. PMID- 21695623 TI - An introduction to the medicinal plant genome project. AB - In recent years, genomics has developed rapidly with the application of next generation sequencing technology. However, very few studies have been carried out on genomics for medicinal plants. This paper introduces the genome research of medicinal plants, including genome sequencing, assembly, annotation, and functional genomics, to set up the foundation for the development of natural medicines and the selection of cultivars with good agricultural traits. This study places the study on traditional Chinese medicine into the frontier field of life science. PMID- 21695624 TI - Top-geoherbs of traditional Chinese medicine: common traits, quality characteristics and formation. AB - Top-geoherbs used in China are always featured with high qualities, and they grow in specified areas with specific environment. Recently, researches on top geoherbs have attracted increasing attention in China and other countries. In order to have a thorough knowledge of top-geoherbs, this article reviews the concept, historical evolution, common trait and quality characteristics of top geoherbs, and explains the forming mechanism including genetic mechanism and environmental mechanism. In addition, it introduces the influence of human factors on the quality of top-geoherbs. Finally, it proposes some problems that should be paid attention to in the researches on top-geoherbs. PMID- 21695626 TI - Analysis on the distinguishing features of traditional Chinese therapeutics and related statistical issues. AB - Traditional Chinese medicine (TCM) is one of the rarely existing ancient traditional medicines that hold systematic theories as well as preventative and therapeutic methods for diseases in practice. From the 1950s, such research methods as mathematics, statistics, and data mining (DM) have been gradually introduced to TCM studies, making it more scientific. Meanwhile, the distinct features of TCM theories and diagnostic-model have constantly challenged the methodology of statistics. This paper introduces the following scientific features of traditional Chinese therapeutics: 1) its goal is to balance the functions and conditions of human body; 2) it emphasizes on holism and individualization; 3) it stresses the longitudinal regulation and evaluation mode, which is a circle of syndrome diagnosis, treatment and evaluation; 4) the interventions of TCM are abundant, compound and natural; and 5) humanistic thought is everywhere. Some statistical problems are raised based on these features. First, complex statistical methods that can analyze subjective indexes and latent variables, multidimensional and multistage data, non-equilibrium designed studies, and longitudinal data are required. Second, comprehensive evaluation on multiple-target mechanism has been brought in by combination treatment. Third, there is a need to analyze how humanity and related cultural factors may influence the effect of interventions. Thus, promoting implemented studies of statistics as well as carrying out the TCM scientific propositions have become the common expectations of both TCM and modern medicine. PMID- 21695625 TI - Overview of the quality standard research of traditional Chinese medicine. AB - Traditional Chinese medicine (TCM) has been widely used for the prevention and treatment of various diseases for a long time in China. Due to its proven efficacy, wide applications, and low side effect, TCM has increasingly attracted worldwide attention. However, one of the biggest challenges facing the clinical practice of TCM is the uncontrollable quality. In this review, the progress of the development and the current status of quality standard as well as new quality control techniques introduced in Chinese Pharmacopoeia (2010 edition), such as liquid chromatography hyphenated mass spectrometry (LC-MS), fingerprint, quantitative analysis of multicomponents by single-marker (QAMS), thin layer chromatography bio-autographic assay (TLC-BAA), and DNA molecular marker technique, are briefly overviewed. PMID- 21695627 TI - The fundamental theory of traditional Chinese medicine and the consideration in its research strategy. AB - Stressing the uniqueness and complexity of traditional Chinese medicine (TCM) theory system, this paper analyzes the characteristics of TCM as a discipline from four perspectives: scientific nature, fundamental theory, clinical practice, and pharmacological action. It suggests that when the research strategy of TCM theory is designed, the core theory of TCM should be emphasized on the theoretical research on TCM original thinking theory, TCM theory, Chinese materia medica and formulas, acupuncture and moxibustion, meridians and collaterals, and other related fields. Researchers and practitioners should ensure that the basic research on TCM theory is based on clinical practice, research methods (both traditional and contemporary) are exploited, and methodological innovation is underscored. The rule of TCM development should be followed and the characteristics and advantages of TCM carried forward. Meanwhile, the methods and theory of contemporary science and technology should be exploited to fulfill the goal of inheriting, enriching, and developing the fundamental theory of TCM. PMID- 21695628 TI - Protecting traditional knowledge of Chinese medicine: concepts and proposals. AB - With the development of the knowledge economy, knowledge has become one of the most important resources for social progress and economic development. Some countries have proposed measures for the protection of their own traditional knowledge. Traditional Chinese medicine belongs to the category of intangible cultural heritage because it is an important part of Chinese cultural heritage. Today the value of traditional knowledge of Chinese medicine has been widely recognized by the domestic and international public. This paper discusses the definition of traditional knowledge of Chinese medicine and its protection, and evaluates research on its classification. We review the present status of the protection of traditional knowledge of Chinese medicine and tentatively put forward some possible ideas and methods for the protection of traditional knowledge of Chinese medicine. Our goal is to find a way to strengthen the vitality of traditional Chinese medicine and consolidate its foundation. We believe that if we could establish a suitable sui generis(sui generis is a Latin term meaning "of its own kind" and is often used in discussions about protecting the rights of indigenous peoples. Here we use it to emphasize the fact that protection of traditional knowledge of Chinese medicine cannot be achieved through existing legal means of protection alone due to its unique characteristics) system for traditional knowledge, a more favorable environment for the preservation and development of traditional Chinese medicine will ultimately be created. PMID- 21695629 TI - Correlation between cold and hot pattern in traditional Chinese medicine and gene expression profiles in rheumatoid arthritis. AB - Clinical manifestations of rheumatoid arthritis (RA) are diversified, and based on the manifestations, the patients with RA could be classified into different patterns under traditional Chinese medicine. These patterns decide the selection of herbal prescription, and thus they can help find a subset of rheumatoid arthritis patients for a type of therapy. In the present study, we combine genome wide expression analysis with methods of systems biology to identify the functional gene networks for the sets of clinical symptoms that comprise the major information for pattern classification. Clinical manifestations in rheumatoid arthritis were clustered with factor analysis, and two factors (similar to cold and hot patterns in traditional Chinese medicine) were found. Microarray technology was used to reveal gene expression profiles in CD4(+) T cells from 21 rheumatoid arthritis patients. Protein-protein interaction information for these genes from databases and literature data was searched. The highly-connected regions were detected to infer significant complexes or pathways in this protein-protein interaction network. The significant pathways and function were extracted from these subnetworks using the Biological Network Gene Ontology tool. The genes significantly related to hot and cold patterns were identified by correlations analysis. MAPK signalling pathway, Wnt signaling pathway, and insulin signaling pathway were found to be related to hot pattern. Purine metabolism was related to both hot and cold patterns. Alanine, aspartate, and tyrosine metabolism were related to cold pattern, and histindine metabolism and lysine degradation were related to hot pattern. The results suggest that cold and hot patterns in traditional Chinese medicine were related to different pathways, and the network analysis might be used for identifying the pattern classification in other diseases. PMID- 21695630 TI - Reevaluation of the effect of Dianxianning on seizure rate of refractory epilepsy as additive treatment in clinical practice. AB - We observed the effect of Dianxianning, which was used as additive treatment to treat 206 epilepsy patients, on the epilepsy seizure rate. Based on a multicenter, prospective, randomized, and controlled clinical trial design, we used the seizure rate of epilepsy as the main index. For the treatment group comprising 137 patients, we combined Dianxianning with chemical medicine, which is the basic treatment. For the control group with 69 patients, we added placebo. The results showed that 1) Effect on seizure rate: After a three-month treatment, the seizure rate of the treatment group decreased by 37.84% on average, whereas that of the control group decreased by 13.18% on average. Statistically comparing the two groups, there was a significant difference between these groups (P < 0.05). 2) Effect on seizure frequency: As time passed, the frequency in each group gradually decreased. After a three-month treatment, there was a significant difference between the two groups (P < 0.05). 3) Comparison between the before and after treatment of each group: There was a very significant difference between the two groups (P < 0.0001). The results indicated that, as an additive treatment, Dianxianning has a good effect on controlling the epilepsy seizure rate and frequency management. It is more effective than using chemical medicine alone. PMID- 21695632 TI - Local and global epigenetic regulation of V(D)J recombination. AB - Despite using the same Rag recombinase machinery expressed in both lymphocyte lineages, V(D)J recombination of immunoglobulins only occurs in B cells and T cell receptor recombination is confined to T cells. This vital segregation of recombination targets is governed by the coordinated efforts of several epigenetic mechanisms that control both the general chromatin accessibility of these loci to the Rag recombinase, and the movement and synapsis of distal gene segments in these enormous multigene AgR loci, in a lineage and developmental stage-specific manner. These mechanisms operate both locally at individual gene segments and AgR domains, and globally over large distances in the nucleus. Here we will discuss the roles of several epigenetic components that regulate V(D)J recombination of the immunoglobulin heavy chain locus in B cells, both in the context of the locus itself, and of its 3D nuclear organization, focusing in particular on non-coding RNA transcription. We will also speculate about how several newly described epigenetic mechanisms might impact on AgR regulation. PMID- 21695633 TI - Introduction to fragment-based drug discovery. AB - Fragment-based drug discovery (FBDD) has emerged in the past decade as a powerful tool for discovering drug leads. The approach first identifies starting points: very small molecules (fragments) that are about half the size of typical drugs. These fragments are then expanded or linked together to generate drug leads. Although the origins of the technique date back some 30 years, it was only in the mid-1990s that experimental techniques became sufficiently sensitive and rapid for the concept to be become practical. Since that time, the field has exploded: FBDD has played a role in discovery of at least 18 drugs that have entered the clinic, and practitioners of FBDD can be found throughout the world in both academia and industry. Literally dozens of reviews have been published on various aspects of FBDD or on the field as a whole, as have three books (Jahnke and Erlanson, Fragment-based approaches in drug discovery, 2006; Zartler and Shapiro, Fragment-based drug discovery: a practical approach, 2008; Kuo, Fragment based drug design: tools, practical approaches, and examples, 2011). However, this chapter will assume that the reader is approaching the field with little prior knowledge. It will introduce some of the key concepts, set the stage for the chapters to follow, and demonstrate how X-ray crystallography plays a central role in fragment identification and advancement. PMID- 21695634 TI - Phosphodiesterase inhibitors: history of pharmacology. AB - The first pharmacological investigations of phosphodiesterase (PDE) inhibitors were developed with the clinical efficacies of drugs isolated from coffee, cacao and tea but only later their relevant ingredients were identified as xanthines that act as PDE. With its diuretic, inotropic and bronchodilating clinical efficacy, use of theophylline anticipated the clinical goals, which were later approached with the first-generation of weakly selective PDE inhibitors in the period from 1980 to 1990. Pharmacological and clinical research with these early compounds provided a vast pool of information regarding desired and adverse actions - although most of these new drugs had to be discontinued due to severe adverse effects. The pharmacological models for cardiac, vascular and respiratory indications were analysed for their PDE isoenzyme profiles, and when biochemical and molecular biological approaches expanded our knowledge of the PDE superfamily, the purified isoenzymes that were now available opened the door for more systematic studies of inhibitors and for generation of highly selective isoenzyme-specific drugs. The development of simple screening models and clinically relevant indication models reflecting the growing knowledge about pathomechanisms of disease are summarised here for today's successful application of highly selective PDE3, PDE4 and PDE5 inhibitors. The interplay of serendipitous discoveries, the establishment of intelligent pharmacological models and the knowledge gain by research results with new substances is reviewed. The broad efficacies of new substances in vitro, the enormous biodiversity of the PDE isoenzyme family and the sophisticated biochemical pharmacology enabled Viagra to be the first success story in the field of PDE inhibitor drug development, but probably more success stories will follow. PMID- 21695635 TI - Phosphodiesterase inhibitors: factors that influence potency, selectivity, and action. AB - Cyclic nucleotide phosphodiesterases (PDEs) are promising targets for pharmacological intervention. The presence of multiple PDE genes, diversity of the isoforms produced from each gene, selective tissue and cellular expression of the isoforms, compartmentation within cells, and an array of conformations of PDE proteins are some of the properties that challenge the development of drugs that target these enzymes. Nevertheless, many of the characteristics of PDEs are also viewed as unique opportunities to increase specificity and selectivity when designing novel compounds for certain therapeutic indications. This chapter provides a summary of the major concepts related to the design and use of PDE inhibitors. The overall structure and properties of the catalytic domain and conformations of PDEs are summarized in light of the most recent X-ray crystal structures. The distinctive properties of catalytic domains of different families as well as the technical challenges associated with probing PDE properties and their interactions with small molecules are discussed. The effect of posttranslational modifications and protein-protein interactions are additional factors to be considered when designing PDE inhibitors. PDE inhibitor interaction with other proteins needs to be taken into account and is also discussed. PMID- 21695636 TI - Pharmacology, clinical efficacy, and tolerability of phosphodiesterase-4 inhibitors: impact of human pharmacokinetics. AB - Since more than two decades anti-inflammatory effects of inhibitors of phosphodiesterase-4 have been described in numerous cellular and animal studies and were finally confirmed in clinical trials. The path from an early, pioneering study with Ro20-1724 showing reduction of psoriatric plaque size in 1979 to modern PDE4 inhibitors such as oral apremilast in development for psoriasis, the inhaled PDE4 inhibitor GSK256066 in development for asthma and COPD and finally roflumilast, the first PDE4 inhibitor approved and currently marketed as an oral, once-daily remedy for severe COPD was marked by large progress in chemical optimization based on improved understanding of PDE4 biology and drug-like properties determining the appropriate pharmacokinetic profile. In this chapter aspects of the pharmacology and clinical efficacy of PDE4 inhibitors, which have been in clinical development over the years are summarized with specific emphasis on their clinical pharmacokinetic properties. PMID- 21695637 TI - Structural insight into the substrate specificity of phosphodiesterases. AB - Cyclic nucleotide phosphodiesterases (PDEs) share a highly conserved catalytic domain that hydrolyzes cAMP, cGMP, or both nucleotides. However, the mechanism that allows the PDE catalytic sites to specifically recognize these nucleotides and distinguish between their subtle differences is still unclear. An early model, called the "glutamine switch", proposed that the side chain of an invariant glutamine adopts two different conformations to allow for formation of two hydrogen bonds with cAMP and cGMP, thereby differentiating these nucleotides. However, the structure of PDE4D2 in complex with cAMP shows that Gln369 forms only one hydrogen bond with the substrate. In addition, the structures of PDE10A in complex with cAMP and cGMP reveal that cAMP and cGMP bind to the active site in different orientations and have different interactions with PDE10A residues. These structures suggest that the invariant glutamine does not appear to be a key residue to differentiate between cAMP and cGMP, although it is important for substrate binding. The structure-based sequence alignment shows that most of the active site residues change across PDE families. These residues may not only contribute differently to the substrate specificity, but also generate slightly different shapes and sizes of the active sites in different PDE families. Therefore, the substrate specificity of PDEs is likely to be determined jointly by multiple elements at the active site, yet the detailed mechanism needs further study. PMID- 21695638 TI - A fission yeast-based platform for phosphodiesterase inhibitor HTSs and analyses of phosphodiesterase activity. AB - Fission yeast strains have been engineered so that their growth behavior reflects the activity of heterologous cyclic nucleotide phosphodiesterases (PDEs). These strains can be used in High-Throughput Screens (HTSs) for PDE inhibitors that possess "drug-like" characteristics, displaying activity in a growth stimulation assay over a 48-h period. Through three generations of development, a collection of strains expressing 10 of the 11 mammalian PDE families that is appropriate for small molecule inhibitor screening has been generated in our laboratory. Strains unable to synthesize cyclic nucleotides allow characterization of PDE activity in that the enzyme's potency is reflected in the amount of either cAMP or cGMP that must be added to the growth medium to stimulate cell growth. In the future, this system could be used to screen cDNA libraries for biological regulators of target PDEs and for the construction of strains that co-express PDEs and associated regulatory proteins to facilitate molecular and genetic studies of their functions and, in particular, to identify whether different PDE-partner protein complexes show distinct patterns of inhibitor sensitivity. PMID- 21695639 TI - The GAF-tandem domain of phosphodiesterase 5 as a potential drug target. AB - Classic PDE5 inhibitors interact with and block the catalytic site of PDE5. They have been clinically validated for treatment of erectile dysfunction as well as reduction of pulmonary arterial pressure, improvement of exercise capacity, quality of life, and arterial oxygenation in patients with secondary pulmonary hypertension. Minor side effects are visual disturbances, headache, migraine, back pain, and interaction with nitrates (hypotension). Some of those side effects presumably can be ameliorated by improving selectivity and pharmacokinetics; other side effects probably are target related due to inhibition of basic physiological processes. Target related side effects may be bypassed by using PDE5 inhibitors with a different mode of action: PDE5, like PDE2, PDE6, PDE10, and PDE11, is a multidomain protein with an N-terminal tandem GAF domain, which in case of PDE5, is allosterically activated by cGMP. Potential inhibitors acting at the PDE5 GAF domain would be expected to inhibit only pathophysiologically upregulated PDE5 activity, whereas basal activity of PDE5 would remain unaffected.Here, we summarize a high-throughput screening campaign to identify inhibitors of the regulatory GAF domain of human PDE5. To target the regulatory domain independently from the catalytic site, we used a chimeric reporter enzyme: The hPDE5 GAF-tandem domain functionally replaced the GAF domain in the cyanobacterial adenylyl cyclase CyaB1. We identified inhibitors that target the GAF domain and also inhibitors that target the bacterial cyclase.Compounds binding to the PDE5 GAF domain were reanalysed with native human PDE5 to demonstrate inhibition using capillary electrophoresis. This identified 16 compounds that act on the GAF domain of PDE5. Two compounds fulfilled the initial requirement to inhibit, exclusively, activated PDE5, but not basal PDE5 activity. PMID- 21695640 TI - Small molecule allosteric modulators of phosphodiesterase 4. AB - Phosphodiesterase 4 (PDE4) inhibitors have shown benefit in human clinical trials but dosing is limited by tolerability, particularly because of emesis. Novel cocrystal structures of PDE4 catalytic units with their regulatory domains together with bound inhibitors have revealed three different PDE4 conformers that can be exploited in the design of novel therapeutic agents. The first is an open conformer, which has been employed in the traditional approach to the design of competitive PDE4 inhibitors. The second is an asymmetric dimer in which a UCR2 regulatory helix from one monomer is placed in a closed conformation over the opposite active site in the PDE4 dimer (trans-capping). Only one active site can be closed by an inhibitor at a time with the consequence that compounds exploiting this conformer only partially inhibit PDE4 enzymatic activity while retaining potency in cellular and in vivo models. By placing an intrinsic ceiling on the magnitude of PDE4 inhibition, such compounds may better maintain spatial and temporal patterning of signaling in cAMP microdomains with consequent improved tolerability. The third is a symmetric PDE4 conformer in which helices from the C-terminal portion of the catalytic unit cap both active sites (cis capping). We propose that dual-gating of PDE4 activity may be further fine tuned by accessory proteins that recognize open or closed conformers of PDE4 regulatory helices. PMID- 21695641 TI - Regulation of endothelial barrier function by cyclic nucleotides: the role of phosphodiesterases. AB - The endothelium plays an important role in maintaining normal vascular function. Endothelial barrier dysfunction leading to increased permeability and vascular leakage is associated with several pathological conditions such as edema and sepsis. Thus, the development of drugs that improve endothelial barrier function is an active area of research. In this chapter, the current knowledge concerning the signaling pathways regulating endothelial barrier function is discussed with a focus on cyclic nucleotide second messengers (cAMP and cGMP) and cyclic nucleotide phosphodiesterases (PDEs). Both cAMP and cGMP have been shown to have differential effects on endothelial permeability in part due to the various effector molecules, crosstalk, and compartmentalization of cyclic nucleotide signaling. PDEs, by controlling the amplitude, duration, and localization of cyclic nucleotides, have been shown to play a critical role in regulating endothelial barrier function. Thus, PDEs are attractive drug targets for the treatment of disease states involving endothelial barrier dysfunction. PMID- 21695642 TI - Phosphodiesterases as targets for intermittent claudication. AB - Intermittent claudication (IC) is one of the most frequent forms of lower extremity peripheral arterial disease (PAD) and is most commonly caused by arterial atherosclerosis. Its clinical manifestation includes fatigue, discomfort, or pain occurring in limb muscles due to exercise-induced ischemia, thus limiting the ability of IC patients to walk and exercise. In addition to lifestyle changes (diet, exercise, and smoking cessation), pharmacological treatments are needed. Pathologically, atherosclerotic lesions cause a mismatch in oxygen supply and metabolic demand in the leg muscles during walking/exercise. This subjects the muscles to repeated ischemia and reperfusion injury that can alter structure and oxidative metabolism, resulting in insufficient utilization of oxygen supply. Despite extensive research efforts, cilostazol and pentoxifylline are the only drugs indicated for relieving the symptoms of IC, with cilostazol demonstrating significant improvement in walking distance and quality of life in these patients. Originally developed as a PDE3 inhibitor, cilostazol was later found to have several other pharmacological actions, and its success has been attributed to its multifactorial actions on platelets, endothelium, smooth muscle, and lipid profiles. Using cilostazol as an example, we discuss the rationales and pitfalls of targeting PDEs in IC, and potential strategies for the development of new and more effective pharmacological treatments. PMID- 21695643 TI - Phosphodiesterase inhibition in heart failure. AB - Compounds that inhibit the catalytic activity of cyclic nucleotide phosphodiesterases are used as therapeutic agents to increase intracellular cAMP and/or cGMP content in cells or tissues of interest. In patients with heart failure, inhibitors of enzymes in the PDE3 family of cyclic nucleotide phosphodiesterases are used to raise intracellular cAMP content in cardiac muscle, with inotropic actions. These drugs are effective in acute applications, but their long-term use has been complicated by an increase in cardiovascular mortality in clinical trials. Inhibitors of enzymes in the PDE5 family have been used to raise cGMP content in cardiac muscle in animal models of pressure overload, chronic beta-adrenergic receptor stimulation, ischemic injury, and doxorubicin toxicity, and have been shown to have antihypertrophic and cardioprotective actions. Recent experimental results raise some question as to the likely applicability of these findings to humans, in whose hearts PDE5 is present at much lower levels than those seen in animal models, and raise the possibility of PDE1, a dual-specificity phosphodiesterase present at high levels in human myocardium, as an alternative target for inotropic and cardioprotective actions. PMID- 21695645 TI - Role of phosphodiesterases in adult-onset pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is characterized by increased mean pulmonary artery pressure (mPAP) due to vasoconstriction and structural changes in the small pulmonary arteries (PAs); proliferation of pulmonary artery smooth muscle cells (PASMCs) contributes to the remodeling. The abnormal pathophysiology in the pulmonary vasculature relates to decreased cyclic nucleotide levels in PASMCs. Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, thereby PDE inhibitors are effective in vasodilating the PA and decreasing PASMC proliferation. Experimental studies support the use of PDE3, PDE5, and PDE1 inhibitors in PAH. PDE5 inhibitors such as sildenafil are clinically approved to treat different forms of PAH and lower mPAP, increase functional capacity, and decrease right ventricular hypertrophy, without decreasing systemic arterial pressure. New evidence suggests that the combination of PDE inhibitors with other therapies for PAH may be beneficial in treating the disease. Furthermore, inhibiting PDEs in the heart and the inflammatory cells that infiltrate the PA may offer new targets to reduce right ventricular hypertrophy and inhibit inflammation that is associated with and contributes to the development of PAH. This chapter summarizes the advances in the area and the future of PDEs in PAH. PMID- 21695646 TI - Treatment of erectile dysfunction and lower urinary tract symptoms by phosphodiesterase inhibitors. AB - To date, it is widely accepted that several disorders of the male and female urogenital tract, such as erectile dysfunction, bladder overactivity, urinary stone disease, the benign prostatic syndrome, as well as symptoms of female sexual arousal and orgasmic dysfunctions, can be therapeutically approached by influencing the function of the smooth musculature of the respective organs. To achieve a pronounced drug effect without significant adverse events, a certain degree of tissue selectivity is mandatory. Selective intervention in intracellular pathways regulating smooth muscle tone has become the most promising strategy to modulate tissue and organ function. Since the concept of taking a pill to relieve symptoms of lower urinary tract dysfunction is now widely accepted following the successes of phosphodiesterase 5 (PDE5) inhibitor treatment of erectile dysfunction, the treatment of urological diseases has focused on orally available drugs acting via influencing intracellular signaling pathways, thereby combining a high response rate with the advantage of an on demand intake. Specifically, the use of isoenzyme-selective PDE inhibitors offers great opportunities in the medical treatment of various genitourinary diseases. These agents are regarded to be safe and to be efficacious, i.e., having a fast onset of drug action and an improved effect-to-side-effect ratio. As experience with this class of compounds and their use in urology is rapidly growing, basic and clinical research in this field will most likely expand the pharmacological armamentarium of innovative treatment options in the next few years. The purpose of this review is to summarize current, as well as potential, upcoming indications for the use of PDE inhibitors in the pharmacotherapy of male erectile dysfunction and lower urinary tract symptoms. PMID- 21695644 TI - Phosphodiesterases: emerging therapeutic targets for neonatal pulmonary hypertension. AB - Pulmonary hypertension in the neonate is associated with multiple underlying problems such as respiratory distress syndrome, meconium aspiration syndrome, congenital diaphragmatic hernia, bronchopulmonary dysplasia, sepsis, or congenital heart disease. Because of the heterogeneous group of disorders, the therapeutic approach and response often depends on the underlying disease. In many of these conditions, there is evidence that cyclic nucleotide signaling and specifically phosphodiesterases (PDEs) are disrupted. PDE inhibitors represent an emerging class of pulmonary vasodilators in adults. Studies are now under way to evaluate the utility, efficacy, and safety of such therapies in infants with pulmonary hypertension. PMID- 21695648 TI - Phosphodiesterases as targets for modulating T-cell responses. AB - The cAMP-protein kinase A (PKA) signaling pathway is strongly involved in the regulation and modulation of immune responses, and cAMP is the most potent and acute inhibitor of T-cell activation. Thus, cAMP levels in the cell must be tightly regulated. Cyclic AMP-specific phosphodiesterases (PDEs) provide the only mechanism for degrading cAMP in cells, thereby functioning as key regulators of signaling. To obtain a complete immune response with optimal cytokine production and T-cell proliferation, ligation of both the T-cell receptor (TCR) and the CD28 receptor is required. However, engagement of the TCR in primary T cells is followed by rapid cAMP production in lipid rafts and activation of the cAMP- PKA Csk pathway inhibiting proximal T-cell signaling. In contrast, TCR/CD28 costimulation leads to the recruitment of a PDE4/beta-arrestin complex to rafts in a phosphatidylinositol 3-kinase (PI3K)-dependent manner, resulting in the downregulation of cAMP levels. Thus, the activities of both PKA and PDE4 seem to be important for regulation of TCR-induced signaling and T-cell function. The use of selective inhibitors has revealed that PDEs are important drug targets in several diseases with an inflammatory component where immune function is important such as asthma, chronic obstructive pulmonary disease (COPD), cardiovascular diseases, and neurological disorders. PDEs are also interesting drug targets in immunosuppression following transplantation and for modulation of immune responses. PMID- 21695647 TI - Evaluation of the therapeutic utility of phosphodiesterase 5A inhibition in the mdx mouse model of duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a devastating and ultimately fatal disease characterized by progressive muscle wasting and weakness. DMD is caused by the absence of a functional dystrophin protein, which in turn leads to reduced expression and mislocalization of dystrophin-associated proteins including neuronal nitric oxide (NO) synthase mu (nNOSMU). Disruption of nNOSMU signaling results in muscle fatigue and unopposed sympathetic vasoconstriction during exercise, thereby increasing contraction-induced damage in dystrophin-deficient muscles. The loss of normal nNOSMU signaling during exercise is central to the vascular dysfunction proposed over 40 years ago to be an important pathogenic mechanism in DMD. Recent preclinical studies focused on circumventing defective nNOSMU signaling in dystrophic skeletal and cardiac muscle by inhibiting phosphodiesterase 5A (PDE5A) have shown promising results. This review addresses nNOS signaling in normal and dystrophin-deficient muscles and the potential of PDE5A inhibition as a therapeutic approach for the treatment of cardiovascular deficits in DMD. PMID- 21695650 TI - Phosphodiesterase inhibitors in the treatment of inflammatory diseases. AB - Phosphodiesterase 4 (PDE4) belongs to a family of enzymes which catalyzes the breakdown of 3, 5'-adenosine cyclic monophosphate (cAMP) and is ubiquitously expressed in inflammatory cells. There is little evidence that inflammatory diseases are caused by increased expression of this isoenzyme, although human inflammatory cell activity can be suppressed by selective PDE4 inhibitors. Consequently, there is intense interest in the development of selective PDE4 inhibitors for the treatment of a range of inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, and psoriasis. Recent clinical trials with roflumilast in COPD have confirmed the therapeutic potential of targeting PDE4 and recently roflumilast has been approved for marketing in Europe and the USA, although side effects such as gastrointestinal disturbances, particularly nausea and emesis as well as headache and weight loss, may limit the use of this drug class, at least when administered by the oral route. However, a number of strategies are currently being pursued in attempts to improve clinical efficacy and reduce side effects of PDE4 inhibitors, including delivery via the inhaled route, development of nonemetic PDE4 inhibitors, mixed PDE inhibitors, and/or antisense biologicals targeted toward PDE4. PMID- 21695651 TI - Harnessing the clinical efficacy of phosphodiesterase 4 inhibitors in inflammatory lung diseases: dual-selective phosphodiesterase inhibitors and novel combination therapies. AB - Phosphodiesterase (PDE) 4 inhibitors have been in development as a novel anti inflammatory therapy for more than 20 years, with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, only one selective PDE4 inhibitor, roflumilast (Daxas ((r))), has been approved for use in humans and available in Canada and the European Union in 2011 for the treatment of a specific population of patients with severe COPD. In many other cases, the development of PDE4 inhibitors of various structural classes has been discontinued due to lack of efficacy and/or dose-limiting adverse events. Indeed, for many of these compounds, it is likely that the maximum tolerated dose is either subtherapeutic or at the very bottom of the efficacy dose-response curve. Thus, a significant ongoing challenge that faces the pharmaceutical industry is to synthesize compounds with therapeutic ratios that are superior to roflumilast. Several strategies are being considered, but clinically effective compounds with an optimal pharmacophore have not, thus far, been reported. In this chapter, alternative means of harnessing the clinical efficacy of PDE4 inhibitors are described. These concepts are based on the assumption that additive or synergistic anti-inflammatory effects can be produced with inhibitors that target either two or more PDE families or with a PDE4 inhibitor in combination with other anti-inflammatory drugs such as a glucocorticoid. PMID- 21695649 TI - Cyclic nucleotides and phosphodiesterases in monocytic differentiation. AB - Monocytes are immune cells that can differentiate into a number of cell types including macrophages, dendritic cells, and osteoclasts upon exposure to various cytokines. The phenotypes of these differentiated cells are highly heterogeneous and their differentiation can be affected by the cyclic nucleotides, 3'-5'-cyclic adenosine monophosphate (cAMP) and 3'-5'-cyclic guanosine monophosphate (cGMP). The intracellular levels of cAMP and cGMP are controlled through regulation of production by adenylyl and guanylyl cyclases and through degradation by cyclic nucleotide phosphodiesterases (PDEs). PDE inhibition and subsequent changes in cyclic nucleotide levels can alter the final phenotype of a differentiating monocyte with regards to surface marker expression, gene expression, or changes in secreted chemokine and cytokine levels. The differentiation process itself can also be either inhibited or augmented by changes in cyclic nucleotide levels, depending on the system being studied and the timing of cyclic nucleotide elevation. This chapter explores the effects of PDE inhibition and increases in cGMP and cAMP on monocytic differentiation into osteoclasts, dendritic cells, and macrophages. PMID- 21695652 TI - Phosphodiesterases in the central nervous system: implications in mood and cognitive disorders. AB - Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes that are involved in the regulation of the intracellular second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP) by controlling their rates of hydrolysis. There are 11 different PDE families and each family typically has multiple isoforms and splice variants. The PDEs differ in their structures, distribution, modes of regulation, and sensitivity to inhibitors. Since PDEs have been shown to play distinct roles in processes of emotion and related learning and memory processes, selective PDE inhibitors, by preventing the breakdown of cAMP and/or cGMP, modulate mood and related cognitive activity. This review discusses the current state and future development in the burgeoning field of PDEs in the central nervous system. It is becoming increasingly clear that PDE inhibitors have therapeutic potential for the treatment of neuropsychiatric disorders involving disturbances of mood, emotion, and cognition. PMID- 21695653 TI - Therapeutic potential of phosphodiesterase inhibitors in parasitic diseases. AB - Protozoan parasites of the order kinetoplastida are the causative agents of three of the world's most important neglected human diseases: African trypanosomiasis, American trypanosomiasis, and leishmaniasis. Current therapies are limited, with some treatments having serious and sometimes lethal side effects. The growing number of cases that are refractory to treatment is also of concern. With few new drugs in development, there is an unmet medical need for new, more effective, and safer medications. Recent studies employing genetic and pharmacological techniques have begun to shed light on the role of the cyclic nucleotide phosphodiesterases in the life cycle of these pathogens and suggest that these important regulators of cyclic nucleotide signaling may be promising new targets for the treatment of parasitic diseases. PMID- 21695654 TI - Pilot trial of simvastatin in the treatment of sporadic inclusion-body myositis. AB - Sporadic inclusion-body myositis (s-IBM) is a chronic progressive inflammatory myopathy leading to severe disability. It has been suggested that statins may benefit s-IBM patients based on their pleiotropic effects on autoimmunity and possible adverse influence of increased cholesterol on muscle pathological changes. We carried out a pilot, open-label trial to evaluate safety and tolerability of oral simvastatin in s-IBM patients. Fourteen patients were treated with 40 mg of simvastatin over 12 months. Primary outcome measures included the assessment tools proposed by International Myositis Outcome Assessment Collaborative Study group and the IBM-Functional Rating Scale. As additional data, we report the results obtained from muscle MRI, biopsy and oropharyngeal scintigraphy. Ten patients completed the trial and the treatment appeared safe and well tolerated. None of the patients showed a significant clinical improvement. Outcome measures used in this study proved to be valuable tools for global assessment of s-IBM patients. At present, we cannot recommend simvastatin as a treatment for s-IBM though our data may warrant a placebo controlled study. PMID- 21695656 TI - A progranulin mutation associated with cortico-basal syndrome in an Italian family expressing different phenotypes of fronto-temporal lobar degeneration. AB - Cortico-basal syndrome (CBS) is a rare neurodegenerative disease characterised by movement and cognitive disorders. It occurs along the spectrum of fronto-temporal lobar degeneration (FTLD), which also includes fronto-temporal dementia (FTD) and progressive supranuclear palsy (PSP). FTLD has recently been shown to be associated with mutations in GRN gene, coding for progranulin, a multifunctional secreted glycoprotein involved in cell cycle, inflammation and tissue repair. We describe the case of a 73-year-old man suffering from CBS with a family history of cognitive disorders belonging to the clinical spectrum of FTLD. Sequencing analysis of GRN in this patient revealed that the C157KfsX97 null mutation has been already described by Le Ber et al. in a French patient affected by an apparently sporadic form of FTD. This report confirms the variability of clinical phenotypes associated with the same mutation and emphasises the importance of genetic analysis in cases with a clear familiarity, as well as in apparently sporadic forms. PMID- 21695657 TI - Incidence and prognosis of stroke in young adults: a population-based study in Ferrara, Italy. AB - The reported annual incidence of juvenile stroke ranges from 9 to 47 cases per 100,000 inhabitants. We sought to estimate the incidence of first-ever stroke in young adults through a population-based stroke registry in a well-defined and stable population. We planned to collect all cases of new stroke in people aged 15-44 years in Ferrara, Italy, over the period 2002-2007. During the surveillance period, a first-ever stroke was diagnosed in 39 patients, giving a mean annual crude incidence rate of 12.1 cases per 100,000 person-years (95% CI 8.6-16.5), 9.1 when adjusted to the European population. The overall 30-day case fatality rate was 7.7, 21.4% for hemorrhagic stroke. The incidence rate was in the range of estimates detected in western countries. The case-fatality rate was lower than that reported in less recent studies. The stroke subtype predicted the probability of death and the outcome. PMID- 21695658 TI - Multimodal CT imaging of a posterior fossa stroke. PMID- 21695659 TI - Assessment of biocorrelates for brain involvement in female patients with rheumatoid arthritis. AB - Central nervous system (CNS) abnormalities are rare in patients with rheumatoid arthritis (RA). Direct studies done to investigate brain involvement in RA are few or even absent. We hypothesized that CNS is not excluded from the inflammatory disease process in RA. Thus we systematically investigated markers of brain involvement in 55 females with RA. We examined patients' cognition using battery of sensitive psychometric testing [Mini-Mental State Examination, Stanford-Binet test (fourth edition) and Wechsler Memory Scale-Revised] and by recording P300 component of event-related potentials, a neurophysiological analogue. We also measured the serum levels of S100B and neuron-specific enolase (NSE), markers of glial and neuronal cells. Compared to control subjects, lower scores in cognitive testing were reported in 71% of the patients (n=39) and abnormal P300 latency and amplitude (P<0.001, 0.050). Patients had higher levels of S100B (P<0.029) and higher levels of S100B were correlated with lower total scores of cognitive functions (P<0.01), P300 latency (P<0.05), and NSE concentrations (P<0.01). However, cognitive scores did not correlate with disease activity or severity. Although depression scores were significant in patients with RA (P<0.001), but they did not correlate with cognitive scores. Seven patients had white matter hyperintensities in MRI brain suggesting vasculitis, ischemic brain lesions and dots of demyelination, and all had higher levels of S100B. Results of this study directly indicate that the disease process (inflammation and demyelination) is associated with cognitive deficits observed with RA. PMID- 21695660 TI - [New epidemics, old questions]. PMID- 21695664 TI - [The UN Convention on the Rights of Persons with Disabilities--gaining a foothold in psychiatry's political seesaw?]. PMID- 21695661 TI - [New recommendations for contact tracing in tuberculosis]. AB - In 2007, the German Central Committee against Tuberculosis (DZK) published recommendations for contact tracing that introduced the new interferon gamma release assays (IGRAs). Meanwhile, substantial progress has been made in documenting the utility of IGRAs. Because IGRAs are usually superior to the tuberculin skin test (TST) in detecting latent TB infection (LTBI) with respect to sensitivity and specificity in adult contact populations that are at least partially BCG vaccinated, it is now recommended that instead of two-step testing only IGRAs be used.[nl]As the literature does not yet provide sufficient data on the accuracy of IGRAs in children younger than 5 years, the TST remains the method of choice in that age group. To date, also, no clear body of data exists to substantiate better performance for IGRAs than for the TST in older children, thus in this age group using of either test is recommended. The new recommendations also underscore the importance of a diligent preselection of close contacts in order to achieve a high probability that positive test results represent recent infection and to thus increase the benefit of chemopreventive treatment for those identified as requiring it. In a third point of update, it is noted that re-testing of contacts individuals found positive for LTBI may produce a considerable number of false-negative results and should thus be avoided in case of documented exposure. PMID- 21695665 TI - [Evidence-based medicine is gold standard for medical guidelines]. PMID- 21695666 TI - MSTN mRNA after varying exercise modalities in humans. AB - The aim of this study was to examine the effects of strength and endurance training on myostatin mRNA in the vastus lateralis muscle of healthy and physically active humans. 21 healthy and physically active sports students (static and dynamic knee extensor strength 33 +/- 4.5 N/kgBW; 1 185 +/- 170 W, respectively; maximum oxygen uptake 52.5 +/- 8 ml/kgBW/min) were recruited and randomly assigned to a moderate endurance training group (n=7), a strength training group (n=7) and a control group (n=7). Muscle biopsies were taken from the vastus lateralis muscle 3-5 days before the start as well as at the end of the 12 weeks' training period. Exercise-specific functional improvements after moderate endurance training and strength training were measured for submaximal endurance and for static and dynamic strength of the knee extensor muscles. None of the myostatin mRNA values showed significant pre-post differences or group specific differences. These results are in contrast to data with sedentary subjects, suggesting that myostatin is necessary for adaptations of skeletal muscle to exercise stress. We conclude that functional improvements after moderate endurance training and strength training can occur without alterations in myostatin mRNA in physically active humans. PMID- 21695667 TI - Hypermobility and dance: a review. AB - Joint hypermobility is defined as an excessive range of motion. Although the dance profession has often promoted hypermobility for aesthetic reasons, there is a belief amongst health professionals that potential risks associated with the condition may have been overlooked. The aims of this review were to examine the epidemiology of joint hypermobility in dancers; the effects on fatigue and bone health; the injury profile of hypermobile dancers; and the use of the Beighton score as a diagnostic tool. Depending on the criteria used, epidemiological studies suggest that hypermobility among dancers can be as high as 44%, especially in students. As hypermobility has been linked to fatigue in the general population, the hypermobile dancer should be careful given the association between fatigue and aetiology of injury in dance. Similarly, in light of research encouraging dancers to become fitter, this recommendation may not be appropriate for hypermobile dancers. In addition, the Beighton score used in most dance related studies may not be an appropriate measure of hypermobility in these populations. More research is necessary into this area to ascertain the reasons for the attrition rate from student to soloist/principal level and whether it is linked to dance health and injury issues. PMID- 21695668 TI - ACL injury mechanisms and related factors in male and female carving skiers: a retrospective study. AB - In recreational alpine skiing, ACL injury risk is 3 times greater in females. However, since the introduction of carving skis ACL injury risk seems to have decreased. No study has yet investigated the distribution of ACL injury mechanisms in male and female carving skiers. Therefore, the aim of the study was to investigate potential gender specific differences of ACL injury mechanisms and related factors among carving skiers. In total, 220 recreational carving skiers (59 males and 161 females) suffering from an ACL injury volunteered for this study. Demographic data, skiing ability, equipment related and environmental factors, circumstances and causes for the fall, and type of fall (injury mechanisms) were collected by questionnaire. The forward twisting fall is the most reported ACL injury mechanism in both gender (p=0.672) accounting for 54% of all injuries, although male and female skiers differed significantly with regard to circumstances of fall (p=0.001) and actions when ACL injury occurred (p=0.04). Bindings not releasing at the time point of accident occurred 2.6 times more with females than with males (p=0.005). The forward twisting fall seems to have become the dominant ACL injury mechanism both in male and female recreational skiers since the introduction of carving skis. PMID- 21695669 TI - Maternal body mass index: a poor diagnostic test for detection of abnormal fetal growths. AB - We sought to determine if maternal body mass index (BMI; kg/m (2)) identifies newborns with abnormal fetal growth (small for gestational age [SGA], large for gestational age [LGA], or macrosomia) at >=37 weeks. Singletons with reliable gestational age and without diabetes or hypertension were analyzed. Areas under the receiver-operating characteristic (AUC) curves were calculated for BMI (first visit, delivery, and the change during pregnancy) to identify abnormal growth. If the AUC was <=0.75 then the diagnostic test was not useful. Among 3582 cohorts, SGA occurred in 10%, LGA in 9%, and 11% were macrosomic. AUC indicates that BMI at delivery is significantly better than BMI at first visit for identification of aberrant growth, but their AUCs were less than 0.75, indicating it is not a useful diagnostic test. Maternal BMIs (at first visit, delivery, or the change during pregnancy) are poor predictors of abnormal fetal growth. PMID- 21695670 TI - [Quality of (socio-)medical advisory services and expertises in statutory social insurances]. PMID- 21695671 TI - Surgery for inflammatory tumor of the lung caused by pulmonary actinomycosis. AB - BACKGROUND: Actinomycosis is an uncommon chronic suppurative bacterial infection caused by anaerobic bacteria. Pulmonary actinomycosis is even more infrequent and generally simulates a wide variety of pulmonary disorders including tuberculosis and lung cancer. Therefore delayed diagnosis and misdiagnosis is common. Here, actinomycosis was initially confused with pulmonary carcinoma. METHODS: We report on three cases of inflammatory tumors caused by pulmonary actinomycosis. All three patients were male and had a history of alcoholism and poor oral hygiene associated with dental disease. Clinical symptoms were nonspecific and radiographic imaging showed tumor-like mass lesions not distinguishable from neoplasms. Preoperative bronchoscopy, sputum culture, laboratory tests and bronchoalveolar lavage neither confirmed an infectious disease nor ruled out lung cancer. Hence all patients underwent thoracotomy for both diagnosis and definitive treatment. Intraoperatively we encountered a necrotizing infection forming cavitary as well as tumorous lesions and a lobectomy was performed due to destroyed lung tissue. In one case the tumorous lesion involved the chest wall so that partial resection of the 3rd rib with the adjacent soft tissue was mandatory. RESULTS: Histological examination of the pulmonary specimen established the diagnosis of pulmonary actinomycosis. All patients recovered well and received antibiotic therapy with oral penicillin. CONCLUSIONS: The diagnosis of pulmonary actinomycosis remains challenging. In cases of an inflammatory tumor imitating lung cancer, surgical resection is mandatory, both to confirm the diagnosis and for the definitive treatment in cases with irreversible parenchymal destruction. Here, surgery in combination with medical treatment offered reliably excellent results. PMID- 21695672 TI - Cor triatriatum with tetralogy of Fallot and anomalous drainage of left superior vena cava: a case report and literature review. AB - Cor triatriatum is a rare malformation, especially in association with tetralogy of Fallot, and has only been reported a few times in the literature. Due to the complexity of this abnormality, careful intraoperative exploration and a good differential diagnosis are crucial to select the appropriate surgical procedure. Here, we report a case with this rare combination of anomalies, an abnormal membranous septum above the mitral valve, and anomalous drainage of the left superior vena cava. The patient was successfully treated and achieved excellent hemodynamic parameters. PMID- 21695673 TI - Lung segment geometry study: simulation of largest possible tumours that fit into bronchopulmonary segments. AB - BACKGROUND: Segmental resection in stage I non-small cell lung cancer (NSCLC) has been well described and is considered to have similar survival rates as lobectomy but with increased rates of local tumour recurrence due to inadequate parenchymal margins. In consequence, today segmentectomy is only performed when the tumour is smaller than 2 cm. METHODS: Three-dimensional reconstructions from 11 thin-slice CT scans of bronchopulmonary segments were generated, and virtual spherical tumours were placed over the segments, respecting all segmental borders. As a next step, virtual parenchymal safety margins of 2 cm and 3 cm were subtracted and the size of the remaining tumour calculated. RESULTS: The maximum tumour diameters with a 30-mm parenchymal safety margin ranged from 26.1 mm in right sided segments 7 + 8 to 59.8 mm in the left apical segments 1-3. CONCLUSIONS: Using a three-dimensional reconstruction of lung CT scans, we demonstrated that segmentectomy or resection of segmental groups should be feasible with adequate margins, even for larger tumours in selected cases. PMID- 21695674 TI - Lobar torsion after video-assisted thoracoscopic lobectomy: 2 case reports. AB - Lung torsion is a rare but potentially lethal complication after pulmonary resection. We report two cases of right middle lobar torsion after video-assisted thoracoscopic (VATS) right upper lobectomy in our unit. The two cases were diagnosed definitely 7 and 14 days after VATS surgery by computed tomography (CT) scan and bronchoscopy, respectively. Rethoracotomy and right middle lobectomy were performed in both patients. VATS lobectomy contributes to the development of lobar torsion so this complication should be considered. Carefully checking anatomical structures before thoracotomic closure and correctly suturing the middle lobe to the consecutive lobe are effective ways to prevent this complication. PMID- 21695675 TI - Coronary artery bypass as adequate treatment for entrapped coronary angioplasty catheter. AB - A 47-year-old man presenting with stable angina pectoris was admitted for elective coronary angioplasty. After balloon angioplasty and uneventful deployment of the stent in the right coronary artery, the angioplasty catheter became entrapped between the stent and the wall of the right coronary artery. During attempts at percutaneous retrieval of the retained catheter, it was inadvertently broken and became embedded near the stent. The patient was stable during the procedure with no electrocardiographic changes. He underwent emergency triple coronary artery bypass, leaving the piece of catheter in situ. He had an uneventful postoperative recovery. After six months, he was angina-free with no electrocardiographic changes. PMID- 21695676 TI - [Academic training for health care professionals]. PMID- 21695679 TI - Thermogenesis, muscle hyperplasia, and the origin of birds. PMID- 21695681 TI - Preparation of Al2O3/TiO2 composite sol-gel fiber for headspace solid-phase microextraction of chlorinated organic solvents from urine. AB - A new solid-phase microextraction fiber based on alumina/titania sol-gel-coated on copper wire for headspace sampling of chlorinated organic solvents (chloroform, carbon tetrachloride, trichloroethene, and tetrachloroethene) from urine samples is introduced. The influences of fiber coating composition and microextraction conditions (extraction temperature, extraction time, and ionic strength of the sample matrix) on the fiber performance were investigated. Also, the influence of temperature and time on desorption of analytes from fiber was studied. The proposed fiber has high capacity and demonstrates fast sampling of chlorinated organic solvents from urine samples with high sensitivity. The relative standard deviation (RSD, n=5) for all analytes was below 6.5%. PMID- 21695682 TI - Development of a UHPLC method for the assessment of the metabolic profile of cinitapride. AB - An ultra high-performance liquid chromatographic method was developed to study the cinitapride metabolism. Metabolites were generated from the incubation of cinitapride with human liver microsomes. Cinitapride and its metabolites were separated by reversed-phase mode using a formate aqueous solution (pH 6.5) and acetonitrile as the components of the mobile phase. Chromatographic conditions, including the establishment of an elution gradient, were optimized for obtaining the maximum number of resolved components in the minimum analysis time. Experimental design and multicriteria decision-making strategies were utilized to facilitate the optimization of chromatographic conditions. Figures of merit were evaluated with cinitapride standards and incubated samples. Limits of detection are about 0.03 MUmol/L, and repeatabilities are better than 0.06% for retention times and better than 3.5% for concentrations. The method was applied to characterize the in vitro cinitapride metabolism with human liver microsomes. PMID- 21695683 TI - Preparation of zwitterionic polymeric monolithic columns for hydrophilic interaction capillary liquid chromatography. AB - Porous zwitterionic monolithic columns based on photo-initiated copolymerization of N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl)ammonium betaine and poly(ethylene glycol) diacrylate in a binary porogen system comprising isopropanol and decanol were prepared in 75-MUm-id fused silica capillaries. The resulting monolith was evaluated by hydrophilic interaction chromatography. Inverse size-exclusion chromatography was used to characterize the pore structure of the resulting monolith. A typical hydrophilic interaction chromatography mechanism was observed when the organic content in the mobile phase was higher than 60%. Good separations of amides, phenols, and benzoic acids were achieved. An efficiency of 75,000 plates/m was obtained. The effects of mobile phase pH, salt concentration, and organic modifier content on retention were investigated. For polar-charged analytes, both hydrophilic interactions and electrostatic interactions contributed to the selectivity. PMID- 21695684 TI - Monolithic polymer layer with gradient of hydrophobicity for separation of peptides using two-dimensional thin layer chromatography and MALDI-TOF-MS detection. AB - Superhydrophobic monolithic porous polymer layers supported onto glass plates with a gradient of hydrophobicity have been prepared and used for 2-D thin layer chromatography of peptides. The 50 MUm-thin poly(glycidyl methacrylate-co ethylene dimethacrylate) layers prepared using UV-initiated polymerization in a simple mold were first hydrolyzed using dilute sulfuric acid and then hydrophilized via two-step grafting of poly(ethylene glycol) methacrylate to obtain superhydrophilic plates. The hydrophobicity was then formed by photografting of lauryl methacrylate. The exposure to UV light that initiates photografting was spatially controlled using moving shutter that enabled forming of the diagonal gradient of hydrophobicity. This new concept enables the solutes to encounter the gradient for each of the two sequential developments. Practical application of our novel plates was demonstrated with a rapid 2-D separation of a mixture of model peptides gly-tyr, val-tyr-val, leucine enkephalin, and oxytocin in dual reversed-phase mode using different mobile phases in each direction. Detection of fluorescent-labeled peptides was achieved through UV light visualization while separation of native leucine enkephalin and oxytocin was monitored directly using MALDI mass spectrometry. PMID- 21695685 TI - Application of pneumatic nebulization single-drop microextraction for the determination of organophosphorous pesticides by gas chromatography-mass spectrometry. AB - Organophosphorous pesticides (OPPs) including dichlorvos, diazinon, malathion, phenamiphos and chlorpyrifos, in water samples were extracted by pneumatic nebulization single-drop microextraction (PN-SDME) and then determined by gas chromatography-mass spectrometry (GC-MS). Experimental parameters affecting the performances of PN-SDME, such as flow rate of carrier gas, extraction time and microdrop volume, were examined and optimized. The limits of detection for the analytes were in the range of 0.0014-0.0019 MUg/mL. The linear range was 0.0050 0.50 MUg/mL, except dichlorvos (0.0070-0.50 MUg/mL). Water samples were analyzed and the recoveries of the analytes in the spiked water samples were from 75.2 to 105.3%. The relative standard deviations were lower than 12.7%. PMID- 21695686 TI - Liquid chromatography-electrospray ionization tandem mass spectrometry for the quantification of styraxlignolide A in rat plasma. AB - Styraxlignolide A is a pharmacologically active ingredient isolated from Styrax japonica Sieb. et Zucc. A rapid, selective, and sensitive liquid chromatographic method with electrospray ionization tandem mass spectrometry was developed for use in the quantification of styraxlignolide A in rat plasma. Styraxlignolide A was extracted from rat plasma using ethyl acetate at neutral pH. The analytes were separated on an Atlantis dC18 column using a mixture of methanol and ammonium formate (10 mM, pH 3.0) (70:30, v/v) and detected by tandem mass spectrometry in multiple reaction monitoring mode. The standard curve was linear (r(2) =0.9978) over the concentration range of 100-10000 ng/mL. The lower limit of quantification was 100 ng/mL using 50 MUL of plasma sample. The coefficient of variation and relative error for intra- and inter-assays at four QC levels were 1.6-8.3% and from -12.0 to -1.7%, respectively. The present method was applied successfully to the pharmacokinetic study of styraxlignolide A after intravenous administration of styraxlignolide A at a dose of 10 mg/kg in male Sprague-Dawley rats. PMID- 21695687 TI - Mid-scale free-flow electrophoresis with gravity-induced uniform flow of background buffer in chamber for the separation of cells and proteins. AB - A large-scale free-flow electrophoresis (LS-FFE) is often too large for cell separation of lab scale, whereas micro-FFE (MUFFE) has great difficulty in cell isolation due to easy blockage by cell accumulation in MUFFE. In this study, a mid-scale FFE (MS-FFE) is developed for cell and protein separations. The volume of the separation chamber (70*40*0.1-0.8 mm) is from 280 MUL to 2.24 mL, much lower than that in an LS-FFE but higher than that in a MUFFE. Gravity is used for uniform flow of the background buffer only via a single pump with 16 channels and the sample is injected via an adjuster originally used for clinical intravenous injection. The experiments reveal that the hydrodynamic and electrohydrodynamic flows are much stable, and the Joule heat can be effectively dispersed without obvious positive or negative deviation as shown by the omega plots. By the device, Escherichia coli and Staphylococcus aureus, which easily accumulate to block MUFFE and are separated with difficulty due to their same negative charges carried, can be well isolated under the conditions of 4.5 mM pH 8.5 Tris-boric buffer (4.5 mM Tris, 4.5 mM boric acid) with 0.10 mM ethylene diamine tetraacetic acid and 5% m/v sucrose, 200 MUL/min, 800 V, and sample injection via inlet 4. The mid-scale FFE device could also be used for the separation of three model proteins of horse heart cytochrome c, myoglobin and bovine serum albumin. The device has clear significance for mid-scale separation of cells and proteins. PMID- 21695688 TI - Effects of process parameters on supercritical CO2 extraction of total phenols from strawberry (Arbutus unedo L.) fruits: An optimization study. AB - The aim of this work was to optimize total phenolic yield of Arbutus unedo fruits using supercritical fluid extraction. A Box-Behnken statistical design was used to evaluate the effect of various values of pressure (50-300 bar), temperature (30-80 degrees C) and concentration of ethanol as co-solvent (0-20%) by CO2 flow rate of 15 g/min for 60 min. The most effective variable was co-solvent ratio (p<0.005). Evaluative criteria for both dependent variables (total phenols and radical scavenging activity) in the model were assigned maximum. Optimum extraction conditions were elicited as 60 bar, 48 degrees C and 19.7% yielding 25.72 mg gallic acid equivalent (GAE) total phenols/g extract and 99.9% radical scavenging capacity, which were higher than the values obtained by conventional water (24.89 mg/g; 83.8%) and ethanol (15.12 mg/g; 95.8%) extractions demonstrating challenges as a green separation process with improved product properties for industrial applications. PMID- 21695689 TI - Differential proteomic response of rice (Oryza sativa) leaves exposed to high- and low-temperature stress. AB - Global mean surface temperature has been predicted to increase by 1.8-4 degrees C within this century, accompanied by an increase in the magnitude and frequency of extreme temperature events. Developing rice cultivars better adapted to non optimal temperatures is essential to increase rice yield in the future and, hence, understanding the molecular response of rice to temperature stress is necessary. In this study, we investigated the proteomic responses of leaves of 24 day-old rice seedlings to sudden temperature changes. Rice seedlings grown at 28/20 degrees C (day/night) were subjected to 3-day exposure to 12/5 degrees C or 20/12 degrees C (day/night) for low-temperature stress, and 36/28 degrees C or 44/36 degrees C (day/night) for high-temperature stress, followed by quantitative label-free shotgun proteomic analysis on biological triplicates of each treatment. Out of over 1100 proteins identified in one or more temperature treatments, more than 400 were found to be responsive to temperature stress. Of these, 43, 126 and 47 proteins were exclusively found at 12/5, 20/12 and 44/36 degrees C (day/night), respectively. Our results showed that a greater change occurs in the rice leaf proteome at 20/12 degrees C (day/night) in comparison to other non-optimal temperature regimes. In addition, our study identified more than 20 novel stress-response proteins. PMID- 21695690 TI - Expression and biophysical analysis of a triple-transmembrane domain-containing fragment from a yeast G protein-coupled receptor. AB - Structural characterization of G protein-coupled receptors (GPCRs) is hindered by the inherent hydrophobicity, flexibility, and large size of these signaling proteins. Insights into conformational preferences and the three-dimensional (3D) structure of domains of these receptors can be obtained using polypeptide fragments of these proteins. Herein, we report the expression, purification, and biophysical characterization of a three-transmembrane domain-containing 131 residue fragment of the yeast alpha-factor receptor, Ste2p. Ste2p TM1-TM3 (G31 R161) was expressed as a TrpDeltaLE fusion protein in Escherichia coli. The expressed protein was subject to CNBr cleavage to remove the fusion tag and TM1 TM3 was purified by reverse-phased HPLC. The cleavage product was isolated in yields of up to 20 mg per liter of culture in both unlabeled and uniformly [15N] labeled and [15N, 13C, 2H]-labeled forms. The secondary structure of TM1-TM3 was determined to be helical in a number of membrane mimetic environments, including 2,2,2-trifluoroethanol (TFE):water and lysomyristoylphosphatidylglycerol (LMPG) detergent micelles by circular dichroism. Preliminary HSQC analysis in 50% TFE:water and LMPG micelles prepared in sodium phosphate and 4-(2-hydroxyethyl)-1 piperazine ethanesulfonic acid (HEPES) buffers revealed that this fragment is suitable for structural analysis by nuclear magnetic resonance (NMR). Complete backbone assignments and a detailed localization of the secondary structural elements of TM1-TM3 in 50% TFE:water have been achieved. PMID- 21695691 TI - Activating NK cell receptor expression/function (NKp30, NKp46, DNAM-1) during chronic viraemic HCV infection is associated with the outcome of combined treatment. AB - Specific NK cell killer inhibitory receptor (KIR):HLA haplotype combinations have been associated with successful clearance of acute and chronic HCV infection. Whether an imbalance of activating NK cell receptors also contributes to the outcome of treatment of chronic HCV infection, however, is not known. We studied peripheral NK cell phenotype and function in 28 chronically viraemic HCV genotype I treatment-naive patients who underwent treatment with pegylated IFN-alpha and ribavirin. At baseline, chronically infected patients with sustained virological response (SVR) had reduced CD56(bright) CD16(+/-) cell populations, increased CD56(dull) CD16(+) NK cell proportions, and lower expression of NKp30, DNAM-1, and CD85j. Similarly, reduced NK cell IFN-gamma production but increased degranulation was observed among nonresponding (NR) patients. After treatment, CD56(bright) CD16(+/-) NK cell numbers increased in both SVR and NR patients, with a parallel significant increase in activating NKp30 molecule densities in SVR patients only. In vitro experiments using purified NK cells in the presence of rIL-2 and IFN-alpha confirmed upregulation of NKp30 and also of NKp46 and DNAM 1 in patients with subsequent SVR. Thus, differences in patient NK cell receptor expression and modulation during chronic HCV-1 infection are associated with subsequent outcome of standard treatment. Individual activating receptor expression/function integrates with KIR:HLA genotype carriage to determine the clearance of HCV infection upon treatment. PMID- 21695694 TI - The classical CD14++ CD16- monocytes, but not the patrolling CD14+ CD16+ monocytes, promote Th17 responses to Candida albicans. AB - In the present study, we investigated the functional differences between cluster of differentiation (CD)14(++) CD16(-) and CD14(+) CD16(+) monocytes during anti Candida host defense. CD14(++) CD16(-) are the "classical" monocytes and represent the majority of circulating monocytes in humans, while CD14(+) CD16(+) monocytes patrol the vasculature for maintenance of tissue integrity and repair. Both monocyte subsets inhibited the germination of live Candida albicans, and there was no difference in their capacity to phagocytose and kill Candida. Although production of IL-6 and IL-10 induced by C. albicans was found to be similar between monocyte subsets, IL-1beta and prostaglandin E2 (PGE2) production was higher in CD14(++) CD16(-) compared with CD14(+) CD16(+) monocytes. In line with the increased production of IL-1beta and PGE2, central mediators for inducing Th17 responses, CD14(++) CD16(-) monocytes induced greater Th17 responses upon stimulation with heat-killed C. albicans yeast. The percentage of cells that expressed mannose receptor (MR) was higher in the CD14(++) CD16(-) monocyte subset, and MR-specific stimulation induced higher Th17 responses only in co-cultures of CD14(++) CD16(-) monocytes and CD4 lymphocytes. In conclusion, both monocyte subsets have potent innate antifungal properties, but only CD14(++) CD16(-) monocytes are capable of inducing a potent Th17 response to C. albicans, an important component of antifungal host defense. PMID- 21695695 TI - Particle aerosolisation and break-up in dry powder inhalers: evaluation and modelling of the influence of grid structures for agglomerated systems. AB - This study aimed to investigate the influence of grid structures on the break-up and aerosol performance of a model inhalation formulation through the use of standardised entrainment tubes in combination with computational fluid dynamics (CFD). A series of entrainment tubes with grid structures of different aperture size and wire diameters were designed in silico and constructed using three dimensional printing. The flow characteristics were simulated using CFD, and the deposition and aerosol performance of a model agglomerate system (496.3-789.2 um agglomerates containing 3.91 um median diameter mannitol particles) were evaluated by chemical analysis and laser diffraction, respectively. Analysis of the mannitol recovery from the assembly indicated that mass deposition was primarily on the grid structure with little before or after the grid. Mass deposition was minimal down to 532 um; however, for smaller grid apertures, significant blockage was observed at all airflow rates (60-140 L . min(-1)). Analysis of the particle size distribution exiting the impactor assembly suggested that mannitol aerosolisation was dependent on the void percentage of the grid structure. It is proposed that initial particle-grid impaction results in a shearing force causing agglomerate fragmentation followed by immediate re entrainment into the turbulent airstream within the grid apertures which causes further dispersion of the fine particles. Such observations have significant implications in the design of dry powder inhaler devices. PMID- 21695696 TI - Impact of extractables/leachables from filters on stability of protein formulations. AB - Aqueous extractables/leachables from three sterilizing-grade filter membranes [polyvinylidene fluoride (PVDF), polyethersulfone (PES), and mixed cellulose ester (MCE)] were found to significantly reduce the surface tension of aqueous solutions. To evaluate the effect of these extractables/leachables from filter membranes on stability of protein formulations, model IgG2 formulations (with or without added surfactant) were spiked with different levels of filter extractables from stock solutions as a stress study. The stock solutions of extractables were created by processing the filter membranes through autoclaving and soaking steps. The IgG2 formulations were subsequently subject to agitation and temperature stress. Extractables/leachables from the filters were found to have a significant protective (PVDF, PES) and destabilizing (MCE) impact on both visible and subvisible particulates formation under agitation stress for formulations that did not contain any additional surfactant such as polysorbate 80. The impact of filter extractables/leachables on chemical stability of the antibody formulation displayed a more complicated pattern, but was generally destabilizing, causing increases in aggregation, oxidation, and acidic species. In conclusion, extractables/leachables from filter membranes may have impact on protein formulation stability and caution should be exercised during protein filtration, especially when filtering small volumes and in preformulation or high throughput screening studies. PMID- 21695697 TI - The relationships between perioperative CEA, CA 19-9, and CA 72-4 and recurrence in gastric cancer patients after curative radical gastrectomy. AB - BACKGROUND AND OBJECTIVES: The correlation between perioperative CEA, CA 19-9, and CA 72-4 and recurrence of gastric cancer has not been clarified. The aim of this study was to investigate the relationships between perioperative CEA, CA 19 9, and CA 72-4 and recurrence of gastric cancer. METHODS: We retrospectively analyzed the relationships between the tumor markers CEA, CA 19-9, and CA 72-4 and recurrence of gastric cancer. RESULTS: In patients with early gastric cancer, the recurrence sensitivity of postoperative CEA, CA 19-9, and CA 72-4 was 40.0, 5.6, and 2.8%, respectively. And in patients with advanced gastric cancer, the recurrence sensitivity of postoperative CEA, CA 19-9, and CA 72-4 was 100.0, 68.2, and 51.3%, respectively. Multivariate analyses showed that an increase in postoperative CEA in early gastric cancer was an independent prognostic factor of recurrence. In patients with advanced gastric cancer, age >60 years, stage III, and postoperative CEA increase and CA 72-4 increase were independent prognostic factors of recurrence. CONCLUSIONS: For patients with advanced gastric cancer, CEA, CA 19-9, and CA 72-4 are considered useful for follow-up tests. Although, CEA is considered useful for follow-up test for patients with early gastric cancer, but CA19-9 and CA72-4 are less useful due to their low sensitivity. PMID- 21695698 TI - Can the CIMP status be used to stratify the colorectal cancer patients who respond to adjuvant chemotherapy? PMID- 21695699 TI - Minimally invasive esophagectomy for esophageal cancer: comparative analysis of open and hand-assisted laparoscopic abdominal lymphadenectomy with gastric conduit reconstruction. AB - BACKGROUND AND OBJECTIVES: Esophagectomy for esophageal cancer is an invasive procedure. Minimally invasive approaches such as hand-assisted laparoscopic surgery (HALS) might reduce surgical stress and improve postoperative course. METHODS: We retrospectively analyzed 216 consecutive patients who underwent esophagectomy for esophageal cancer through either HALS (109 patients) or open laparotomy (107 patients), through an abdominal approach. The peri- and postoperative outcomes were compared between the two groups. RESULTS: No significant difference was observed in physical and tumor status between the two groups. The mean operating time (HALS: 452 +/- 65, Open: 456 +/- 69 min) and mean number of resected lymph nodes (HALS: 19.3 +/- 7.1, Open: 20.8 +/- 8.3) were similar, while total blood loss was lower in HALS (HALS: 695 +/- 369, Open: 1,101 +/- 540 ml; P = 0.0001). The postoperative course showed marginally lower incidences of pulmonary (HALS: 6.4%, Open: 14.0%; P = 0.062) and overall complications (HALS: 23.9%, Open: 35.5%; P = 0.11), lower C-reactive protein level at postoperative days 1, 3, and 7, and shorter duration of systemic inflammatory response syndrome (HALS: 2.3 days, Open: 3.5 days; P = 0.0002) in HALS than in OPEN. The disease-free survival rates at 2 years were 65% in HALS and 53% in Open. CONCLUSIONS: The findings suggest that HALS is feasible and useful for patients with esophageal cancer. PMID- 21695700 TI - Is the sentinel node biopsy clinically applicable for limited lymphadenectomy and modified gastric resection in gastric cancer? A meta-analysis of feasibility studies. AB - BACKGROUND: Sentinel node biopsies (SNBs) have been clinically applied in melanoma and breast cancer for limited lymphadenectomy. However, the use of SNB remains controversial in gastric cancer due to unsatisfactory sensitivity and variability. This meta-analysis was performed to determine the sensitivity of SNB in gastric cancer and to identify factors that improve its sensitivity. METHODS: Feasibility studies on SNB in gastric cancer were searched for from 2001 to 2009 in Pubmed, Cochrane, and Embase. Forty-six reports, which included 2,684 patients, were found. Estimated sensitivities, detection rates, and negative (NPV), and positive predictive values (PPV) were calculated using a random effects model. Inter-study heterogeneity, meta-regression, and subgroup analysis for sensitivity was performed. RESULTS: The estimated sensitivity, detection rate, NPV, and PPV were 87.8%, 97.5%, 91.8%, and 38.0%, respectively, with significant inter-study heterogeneity (P < 0.0001). However, no significant contributor to heterogeneity was identified. By subgroup analysis, sensitivity was found to depend significantly on the number of SNs harvested. CONCLUSIONS: SNB in gastric cancer is probably not clinically applicable for limited lymphadenectomy due its unsatisfactory sensitivity and heterogeneity between practicing surgeons. To improve sensitivity, more than four SNs should be harvested, and a tumor specific SNB method should be developed. PMID- 21695701 TI - Patient-oriented functional results of total femoral endoprosthetic reconstruction following oncologic resection. AB - BACKGROUND AND OBJECTIVES: Functional outcomes following oncologic total femoral endoprosthetic reconstruction (TFR) are lacking. We compared patient-oriented functional results of TFRs to proximal femur and distal femur reconstructions (PFR and DFR). We also compared function and complications with regard to knee and hip componentry. METHODS: Fifty-four TFR patients were identified from three institutional prospective databases. Forty-one had fixed- and 13 had rotating hinge knees, 37 hemiarthroplasty and 17 total hip arthroplasty componentry. Toronto Extremity Salvage Scores (TESS) for n = 27 were compared between groups and to cohorts of PFR (n = 31) and DFR (n = 85) patients using the Mann-Whitney U test. RESULTS: Follow-up averaged 4 years. Mechanical complications included five hip dislocations and one femoral malrotation. Four dislocations were in fixed hinge implants, all in those lacking abductor reattachment. TESS averaged 69.3 +/ 17.8, statistically decreased from DFR (P = 0.002) and PFR patients (P = 0.036). No significant differences were detected between patients in the fixed-hinge (n = 18) and rotating-hinge (n = 9) groups (P = 0.944), or total hip (n = 8) and hemiarthroplasty (n = 19) groups (P = 0.633). CONCLUSIONS: TFR is reserved for extreme cases of limb salvage, portending a poor prognosis overall. Function reflects additive impairments from PFR and DFR. TFR outcomes differ little with rotating- or fixed-hinge, total hip or hemiarthroplasty implants. PMID- 21695702 TI - Wip1 over-expression correlated with TP53/p14(ARF) pathway disruption in human astrocytomas. AB - PURPOSE: Wip1 over-expression inhibits p53 function and reduces selection for TP53 mutations during cancer progression. To clarify the correlation of Wip1 with TP53/p14(ARF) pathway disruption in astyrocytomas, the expression of Wip1 and TP53/p14(ARF) pathway alterations have been investigated. METHODS: Tumor samples of 52 patients of astrocytomas were examined for TP53 mutations, p14(ARF) expression, and Wip1 expression. Direct sequencing of region from exons 5 to 8 of the TP53 gene was performed on the genomic DNA in each sample. The DNA methylation states of the CpG islands of the p14(ARF) gene were determined by MSP. The expression of Wip1 was analyzed by real-time quantitative PCR, Western blot, and immunohistochemical staining. RESULTS: Disruption of the TP53/p14ARF pathway was detected in 57.7% of samples. Among 22 cases without TP53 and p14ARF alterations, 11 (50%) had Wip1 mRNA over-expression. In tumors with wild-type TP53 and p14ARF, Wip1 mRNA was over-expressed only 1 case out of 30 (3.3%). Higher levels of Wip1 were associated with TP53 mutations but not with lower levels of expression of p14(ARF) or aberrant promoter hypermethylation of the p14(ARF) gene. CONCLUSION: Wip1 is selectively over-expressed in astyrocytomas without alterations in TP53 or p14(ARF). Wip1 may inhibit the TP53/p14(ARF) pathway. PMID- 21695704 TI - Multi scale modal decomposition of primary form, waviness and roughness of surfaces. AB - This article introduces an innovative method for the multi-scale analysis of high value-added surfaces, which consists of applying a method based on a new parameterization. This kind of surface parameterization refers to natural modes of vibration, and is therefore named modal parameterization. It allows us to characterize the form, waviness and roughness defects of a surface. This parameterization opens up new fields of analysis, such as the appearance quality of surfaces. It is thereby possible to decompose a measured surface in a vector basis, of which vectors are represented by plane natural eigenmodes sorted by frequency and complexity. Different filtering operations can then be produced, such as extracting the primary form of the surface. To analyze the perceived quality of surfaces, these investigations focus on two approaches: that appearance defects have small periodicity, and that there is a link between curvatures and the visual impact of an anomaly. This methodology is applied to two prestige lighters, whose surfaces were measured by extended field confocal microscopy. Moreover, a prospect of this work is to develop an augmented-reality type monitoring tool for sensory experts. PMID- 21695703 TI - Conversion of intratumoral regulatory T cells by human gastric cancer cells is dependent on transforming growth factor-beta1. AB - BACKGROUND AND OBJECTIVES: Regulatory T cells (Treg) inhibits immune responses mediated by T cells. This study aimed to investigate whether Treg are accumulated in human gastric cancer tissue and the mechanism of Treg induction by gastric cancer cells. METHODS: Tissue infiltrated leukocytes from gastric adenocarcinomas were subjected to flow cytometry and immunohistochemistry. Percentage, phenotype, function, and clinical relevance of Treg were analyzed. TGF-beta1 production by cancer cells was determined by Western blot and in vitro co-culture experiments were performed to mimic gastric cancer microenvironment. RESULTS: The percentages of CD4(+) Foxp3(+) T cells in gastric cancer tissues were significantly higher than those from adjacent non-tumor gastric tissues (P < 0.05). The results of classical Treg phenotype and proliferation assay supported that the elevated CD4(+) Foxp3(+) T cells represents a suppressive Treg population. High proportion of Treg is correlated to advance TNM stage and reduced survival. Primary gastric cancer cells produced abundance of TGF-beta1 which was responsible for conversion of Treg. CONCLUSION: The proportion of functional Treg is elevated in human gastric cancer and related to poor prognosis. Gastric cancer cells directly convert CD4(+) naive T cells to Treg by TGF-beta1, suggesting a possible mechanism through which tumor cells evade the immune system. PMID- 21695705 TI - ["Demarcation issues" - an unusual subject in Pharmazie in unserer Zeit? Not at all!]. PMID- 21695706 TI - A comparison of conventional Everhart-Thornley style and in-lens secondary electron detectors: a further variable in scanning electron microscopy. AB - The secondary electron (SE) imaging of several samples across a range of scanning electron microscopes (SEM) and SE detectors under matched operating conditions has generated a highly variable image data set. Using microanalytical conditions (10-15 kV), images from in-column SE detectors reveal the presence of surface films and contaminants that are invisible to conventional Everhart-Thornley SE detectors under the same conditions. Data from studying the effects of working distance, the image resolution derived through contrast transfer function analysis and electrostatic mirror imaging of the SE detectors in operation combine with other studies to suggest that the classically defined SE1 component can be separated from other SE components. SE images obtained by tailored mechanical design and energy-filtering will provide SE images with probe-sized resolution and dominated by surface detail currently only seen in low-voltage SEM, potentially even from thermionic-sourced columns. PMID- 21695707 TI - In vitro antitumor activity of broccolini seeds extracts. AB - Broccolini (Brassica oleracea Italica * Alboglabra) is a hybrid of broccoli and kai-lan, Chinese broccoli. To date, no report on antitumor activity of Broccolini (NOT Broccoli) is available. In this study, we evaluated the antiproliferative effects of broccolini seeds extract (BSE) on human lung and ovarian cancer cells. It was found that BSE induces A549 and OVCAR-3 cells apoptosis in a dose dependent manner by using MTT assay. The IC(50) values of BSE in A549 and OVCAR-3 cells were estimated to be 81.94 and 78.6 ug/ml, respectively. Furthermore, the phase contrast microscope showed that in high-dose group (90~120 ug/ml), the morphology structure of OVCAR-3 cells become irregular and exhibited characteristics of apoptosis such as cell membrane shrinkage, condensation and fragmentation of nuclear chromatin as well as formation of apoptotic bodies. PMID- 21695708 TI - Assessment of intermittent UMTS electromagnetic field effects on blood circulation in the human auditory region using a near-infrared system. AB - The aim of the present study was to assess the potential effects of intermittent Universal Mobile Telecommunications System electromagnetic fields (UMTS-EMF) on blood circulation in the human head (auditory region) using near-infrared spectroscopy (NIRS) on two different timescales: short-term (effects occurring within 80 s) and medium-term (effects occurring within 80 s to 30 min). For the first time, we measured potential immediate effects of UMTS-EMF in real-time without any interference during exposure. Three different exposures (sham, 0.18 W/kg, and 1.8 W/kg) were applied in a controlled, randomized, crossover, and double-blind paradigm on 16 healthy volunteers. In addition to oxy-, deoxy-, and total haemoglobin concentrations ([O(2) Hb], [HHb], and [tHb], respectively), the heart rate (HR), subjective well-being, tiredness, and counting speed were recorded. During exposure to 0.18 W/kg, we found a significant short-term increase in Delta[O(2) Hb] and Delta[tHb], which is small (~17%) compared to a functional brain activation. A significant decrease in the medium-term response of Delta[HHb] at 0.18 and 1.8 W/kg exposures was detected, which is in the range of physiological fluctuations. The medium-term DeltaHR was significantly higher (+1.84 bpm) at 1.8 W/kg than for sham exposure. The other parameters showed no significant effects. Our results suggest that intermittent exposure to UMTS-EMF has small short- and medium-term effects on cerebral blood circulation and HR. PMID- 21695709 TI - Analysis of three-dimensional SAR distributions emitted by mobile phones in an epidemiological perspective. AB - The three-dimensional distribution of the specific absorption rate of energy (SAR) in phantom models was analysed to detect clusters of mobile phones producing similar spatial deposition of energy in the head. The clusters' characteristics were described from the phones external features, frequency band and communication protocol. Compliance measurements with phones in cheek and tilt positions, and on the left and right side of a physical phantom were used. Phones used the Personal Digital Cellular (PDC), Code division multiple access One (CdmaOne), Global System for Mobile Communications (GSM) and Nordic Mobile Telephony (NMT) communication systems, in the 800, 900, 1500 and 1800 MHz bands. Each phone's measurements were summarised by the half-ellipsoid in which the SAR values were above half the maximum value. Cluster analysis used the Partitioning Around Medoids algorithm. The dissimilarity measure was based on the overlap of the ellipsoids, and the Manhattan distance was used for robustness analysis. Within the 800 MHz frequency band, and in part within the 900 MHz and the 1800 MHz frequency bands, weak clustering was obtained for the handset shape (bar phone, flip with top and flip with central antennas), but only in specific positions (tilt or cheek). On measurements of 120 phones, the three-dimensional distribution of SAR in phantom models did not appear to be related to particular external phone characteristics or measurement characteristics, which could be used for refining the assessment of exposure to radiofrequency energy within the brain in epidemiological studies such as the Interphone. PMID- 21695710 TI - Within-group social bonds in white-faced saki monkeys (Pithecia pithecia) display male-female pair preference. AB - White-faced saki monkeys (Pithecia pithecia) lack most of the behavioral and physical traits typical of primate monogamy [Fuentes, 1999]. In order to determine if social bonds in this species reflect patterns displayed by pair bonded groups or larger multimale-multifemale groups, we draw on 17 months of data collected on wild white-faced sakis at Brownsberg Nature Park, Suriname. We analyzed within-group social bonds for three habituated groups (one two-adult and two multiadult groups) by measuring grooming, proximity, and approach/leave patterns between adult and subadult group members. We found that both two-adult and multiadult groups showed significantly stronger social bonds between a single male-female dyad within each group (deemed "primary dyads"). In all three groups, primary dyads were composed of the oldest adult male and a breeding female. These pairs had significantly higher levels of grooming than other within-group dyads and were also in close proximity (<1 m) more often than nonprimary dyads. Grooming in primary dyads was nonreciprocal, and consistently biased toward female investment. Grooming patterns in nonprimary dyads varied, but were often more reciprocal. Grooming and proximity of the primary dyad also changed in relation to infant development. Our results suggest that while white-faced sakis do not show behavioral and physical traits typical of monogamy or pair-bonding, social bonds are strongest between a single male-female pair. Pitheciine social systems range from small group monogamy in Callicebus to large multimale multifemale groups in Chiropotes and Cacajao. As the middle taxon in this platyrrhine radiation, behavioral strategies of white-faced sakis provide a model for how social bonds and affiliation could be influenced by and affect the evolution of larger group size in primates. PMID- 21695711 TI - Identification of novel matrix metalloproteinase inhibitors by screening of phenol fragments library. AB - In the last 20 years, a great variety of synthetic, low molecular weight MMP inhibitors (MMPIs) have been synthesized and tested, although none has reached clinical utility. Exploration of novel ZBGs and development of non-hydroxamate MMPI has become a focus in current research. It's well-known that polyphenols can produce beneficial effects on human health by their antioxidant properties as well as they have the ability to block gelatinase activity. In this work we tested a series of selected phenols as MMP inhibitors. The most interesting hit (B6) shows sub-micromolar activity against MMP-2 (IC(50) 0.59 +/- 0.05 uM, LE = 1.07) and a fairly good selectivity spectrum. PMID- 21695712 TI - Synthesis of some triazolophthalazine derivatives for their anti-inflammatory and antimicrobial activities. AB - Several novel series of triazolophthalazine derivatives namely; pyrazolylethenyltriazolophthalazinones (4a-d), styryltriazolophthalazinones (5a,b), aryloxopropenyltriazolophthalazinones (7a,b), pyrazolinyl- (8a,b), (9a,b) and (10a-f), pyrazolyl- (11a-d), (1,2-oxazol-5-yl)-1,2,4-triazolo[3,4 a]phthalazin-6(5H)-ones (14a,b), triazolo[3,4-a]phthalazin-3-yl-pyridine-3 carbonitriles (12a,b), triazolo[3,4-a]phthalazin-3-yl)ethylthioacetic acids (13a,b) and 2-aryl-5-arylamino-1H,5H-pyrazolo[2",3"-1',5']imidazo[3',4'-1,5] 1,2,4-triazolo[3,4-a]phthalazin-12(13H)-ones (15a-c) have been synthesized. The anti-inflammatory activity of representative compounds has been studied. Compounds 8b, 10c, 10f, 11b, 12a, 13b, and 15a showed anti-inflammatory activities comparable to that of the reference standard, indomethacin. They exhibit also minimal ulcerogenic effect relevant to the reference standard and were found to be non-toxic up to 120 mg/kg orally or up to 75 mg/kg through parenteral route. Concerning the antimicrobial activity; compounds 12b and 13b were found to be equipotent to ampicillin against Staphylococcus aureus, while compounds 10a and 10f were found to be as potent as ampicillin against E. coli, whereas compound 14b exhibited equipotency to clotrimazole against Candida albicans. Compounds 8b, 10f, 11b, 12a, and 13b exhibited, besides their antimicrobial activity, moderate to potent anti-inflammatory profiles. This represents a fruitful matrix for the development of a new class of dual non acidic anti-inflammatory/antimicrobial agents. PMID- 21695713 TI - Cytotoxic and antimicrobial activities of Cu(II), Co(II), Pt(II) and Zn(II) Complexes with N,O-chelating heterocyclic carboxylates. AB - A series of Cu(II), Co(II), Pt(II) and Zn(II) coordination compounds has been prepared by the reaction of the metal chlorides with pyrazine-2-carboxylic acid, pyridine-2-carboxylic acid, imidazole-4-carboxylic acid, benzimidazole-2 carboxylic acid and 1-methylimidazole-2-carboxylic acid. The complexes were characterized by IR, UV-VIS, elemental analysis, and some by (1) H-NMR, X-ray crystallography, HPLC and LC/MS spectroscopy. All complexes consist of a 2:1 ratio of ligand to metal ion. IR and X-ray crystallography show that coordination is through the nitrogen and carboxylate oxygen donor atoms of the ligand to form chelating rings. DFT calculations predict that the trans-coordinated isomers are thermodynamically more stable than their cis-forms. Only one of five complexes studied by X-ray crystallography, Cu(II) complex of 1-methylimidazole-2 carboxylic acid showed a cis-configured metal ion center. HPLC analysis indicated that Pt(II) complex of 1-methylimidazole-2-carboxylic acid is dominated (>90%) by the trans-configured complex. All other complexes showed one isomer, presumably the trans-form. The cytotoxic activity was investigated in human cancer cell lines in vitro; only the Pt(II) complexes were active. The antimicrobial activity against four bacterial strains and one fungi was estimated by the MIC method and best results were found amongst the Co(II) complexes. These results indicate that trans-coordinated bischelating N,O-heterocyclic carboxylates of Pt(II) are an interesting new class of potential antitumor agents. PMID- 21695714 TI - A proline rich acidic protein PRAP identified from uterine luminal fluid of estrous mice is able to enhance the estrogen responsiveness of Ishikawa cells. AB - Using mice as experimental animals, proteins in the uterine luminal fluid (ULF) from both adults and diethylstilbestrol dipropionate (DES)-treated immature animals were resolved by 2D gel electrophoresis. Two of the protein spots, (a) and (b) around the positions of 18-20 kDa, in the adult ULF were not found in the DES-treated ULF. Automated Edman degradation established the same N-terminal sequences of AHQVPVKTKGKHVFP for the two protein spots. Two trypsin digests of spot (a) were analyzed using CID MS/MS to establish the peptide sequences DNQLGPLLPEPK and RPDAMTWVETEDILSHLR. These partial sequences were confirmed in the cDNA-deduced mouse proline rich acidic protein (PRAP). Using human Ishikawa cell line as a surrogate endometrial model, we demonstrated rapid entrance of exogenous PRAP into the cells and its ability to enhance alkaline phosphatase activity of the E(2) -stimulated cells. Further, the transcripts of five estrogen responsive genes, including ALPP (Placental alkaline phosphtase), ALPPL (placental alkaline phosphatase-like 2), TGF (transforming growth factor), PR (progesterone receptor), and Wnt7a, were measured after the cell incubation in modified Eagle medium containing 0.1 nM E(2) , or 0-25 uM PRAP, or both together at 37 degrees C for 48 h. As compared with the control, E(2) alone increased the transcripts of ALPP, ALPPL, TGF-alpha, and PR, and reduced the transcript of Wnt7a, whereas PRAP alone had a slight impact on their expression. E(2) together with PRAP greatly increased the E(2) -stimulated transcriptions of ALPP, ALPPL, TGF-alpha, and PR, and markedly reduced the E(2) -suppressed transcription of Wnt7a. PMID- 21695715 TI - Phytoglycoprotein (38 kDa) induces cell cycle (G0/G1) arrest and apoptosis in HepG2 cells. AB - Styrax japonica Siebold et al Zuccarini (SJSZ) has been used to heal inflammation and bronchitis as folk medicine in Korea. Firstly, glycoprotein isolated from SJSZ (SJSZ glycoprotein) has a molecular weight with 38 kDa and consists of carbohydrate (57.64%) and protein (42.35%). In the composition of SJSZ glycoprotein, carbohydrate mostly consists of glucose (28.17%), galactose (21.85%), and mannose (2.62%) out of 52.64%, respectively. The protein consists of Trp (W, 7.01%), Pro (P, 6.72%), and Ile (I, 5.42%) out of 42.35% as three major amino acids, while total amount of other amino acids is 23.20%. The purpose of this study is to know whether the SJSZ glycoprotein (38 kDa) induces the cell cycle arrest and apoptosis in HepG2 cells. Cytotoxicity was evaluated using MTT and lactate dehydrogenase assay and amount of intracellular reactive oxygen species (iROS) and nitric oxide (NO) was measured using fluorescence microplate reader. Activities of cell cycle-related proteins [p53, p21, p27, Cyclin D1, and cyclin-dependent kinase (CDK)4] and apoptosis-related factors [iNOS, Bid, Bcl 2/bax, cytochrome c, caspase-9, caspase-3, and poly-(ADP-ribose) polymerase (PARP)] were assessed by Western blot and fluorescence-activated cell sorter (FACS) analysis. In the cell cycle-related proteins, SJSZ glycoprotein (50 ug/ml) significantly enhances the expression of p53, p21, and p27, whereas it suppressed the activity of cyclin D1/CDK4. In the apoptosis-related factors, SJSZ glycoprotein (50 ug/ml) stimulates to increase iROS, and NO, to activate iNOS, Bid, Bcl-2/bax, cytochrome c, caspase-9, caspase-3, and PARP. SJSZ glycoprotein (50 ug/ml) has potent effect to arrest cell cycle from G(0) /G(1) to S and to induce apoptosis in HepG2 cells. PMID- 21695716 TI - shRNA-mediated silencing of Gli2 gene inhibits proliferation and sensitizes human hepatocellular carcinoma cells towards TRAIL-induced apoptosis. AB - Aberrant activation of the Hedgehog (Hh) signaling pathway has been reported in various cancer types including hepatocellular carcinoma (HCC). As a key effector of this signaling, Gli2 plays a crucial role in carcinogenesis, including the activation of genes encoding apoptosis inhibitors and cell-cycle regulators. In this study, we examined the role of Gli2 proliferation and survival of HCC cells. First, the expression levels of Hh pathway components were detected in a subset of HCC cell lines. To establish the role of Gli2 in maintaining the tumorigenic properties of HCC cells, we developed small hairpin RNA (shRNA) targeting Gli2 and transfected it into SMMC-7721 cell, which was selected with high level of Hh signaling expression. Next, effects of Gli2 gene silencing, on cell proliferation and on the expression of cell cycle-related proteins were evaluated, then, whether down-regulation of Gli2 renders HCC cell susceptible to TRAIL was examined in vitro. Knockdown of Gli2 inhibited cell proliferation and induced G1 phase arrest of cell cycle in SMMC-7721 cell through down-regulation of cyclin D1, cyclinE2, and up-regulation of p21-WAF1. Also, Gli2 gene siliencing sensitized SMMC-7721 cell to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by reducing the expression of the long and short isoform of c-FLIP and Bcl-2, and then augmented the activation of initiator caspases-8/-9 and effector caspases-3, which induces PARP cleavage. In conclusion, our data suggest that Gli2 plays a predominant role in the proliferation and apoptosis resistance of HCC cells, and that knockdown of Gli2 may be a novel anticancer strategy for the treatment of HCC. PMID- 21695717 TI - Commentary: participant differences and validity of jury studies. PMID- 21695718 TI - Detection of tumor glutamate metabolism in vivo using (13)C magnetic resonance spectroscopy and hyperpolarized [1-(13)C]glutamate. AB - Dynamic nuclear polarization can be used to increase the sensitivity of solution state (13)C magnetic resonance spectroscopy by four orders of magnitude. We show here that [1-(13)C]glutamate can be polarized to 28%, representing a 35,000-fold increase in its sensitivity to detection at 9.4 T and 37 degrees C. The metabolism of hyperpolarized glutamate to alpha-ketoglutarate, catalyzed by the enzyme alanine transaminase, was detected in vitro in human hepatoma cells (HepG2). Incubation of the cells with sodium pyruvate increased the level of the hyperpolarized label in the alpha-ketoglutarate pool, with an associated increase in the apparent rate constant describing flux of hyperpolarized (13)C label between glutamate and alpha-ketoglutarate. The metabolism of hyperpolarized glutamate was observed in vivo following coadministration of pyruvate in a murine lymphoma model. This represents a new method to probe glutamate metabolism and citric acid cycle activity in vivo; as glutamate is an endogenous molecule, it has the potential to be used in the clinic. PMID- 21695719 TI - Inflow-based vascular-space-occupancy (iVASO) MRI. AB - Vascular-space-occupancy (VASO) MRI, a blood nulling approach for assessing changes in cerebral blood volume (CBV), is hampered by low signal-to-noise ratio (SNR) because only 10-20% of tissue signal is recovered when using nonselective inversion for blood nulling. A new approach, called inflow-VASO (iVASO), is introduced in which only blood flowing into the slice has experienced inversion, thereby keeping tissue and cerebrospinal fluid (CSF) signal in the slice maximal and reducing CSF partial volume effects. SNR increases of 198% +/- 12% and 334% +/- 9% (mean +/- SD, n = 7) with respect to VASO were found at TR values of 5 s and 2 s, respectively. When using inflow approaches, data interpretation is complicated by the fact that signal changes are affected by vascular transit times. An optimal TR-range (1.5-2.5 s) was derived in which the iVASO response during activation predominantly reflects arterial/arteriolar CBV (CBV(a)) changes. In this TR-range, perfusion contributions to the signal change are negligible because arterial label has not yet undergone capillary exchange, and arterial and precapillary blood signals are nulled. For TR = 2 s, the iVASO signal change upon visual stimulation corresponded to a CBV(a) increase of 58% +/ 7%, in agreement with arteriolar CBV changes previously reported. The onset of the hemodynamic response for iVASO occurred 1.2 +/- 0.5 s (n = 7) faster than for conventional VASO. PMID- 21695720 TI - Echo-planar imaging with prospective slice-by-slice motion correction using active markers. AB - Head motion is a fundamental problem in functional magnetic resonance imaging and is often a limiting factor in its clinical implementation. This work presents a rigid-body motion correction strategy for echo-planar imaging sequences that uses micro radiofrequency coil "active markers" for real-time, slice-by-slice prospective correction. Before the acquisition of each echo-planar imaging-slice, a short tracking pulse-sequence measures the positions of three active markers integrated into a headband worn by the subject; the rigid-body transformation that realigns these markers to their initial positions is then fed back to dynamically update the scan-plane, maintaining it at a fixed orientation relative to the head. Using this method, prospectively-corrected echo-planar imaging time series are acquired on volunteers performing in-plane and through-plane head motions, with results demonstrating increased image stability over conventional retrospective image-realignment. The benefit of this improved image stability is assessed in a blood oxygenation level dependent functional magnetic resonance imaging application. Finally, a non-rigid-body distortion-correction algorithm is introduced to reduce the remaining signal variation. PMID- 21695721 TI - Diffusion imaging with prospective motion correction and reacquisition. AB - A major source of artifacts in diffusion-weighted imaging is subject motion. Slow bulk subject motion causes misalignment of data when more than one average or diffusion gradient direction is acquired. Fast bulk subject motion can cause signal dropout artifacts in diffusion-weighted images and results in erroneous derived maps, e.g., fractional anisotropy maps. To address both types of artifacts, a fully automatic method is presented that combines prospective motion correction with a reacquisition scheme. Motion correction is based on the prospective acquisition correction method modified to work with diffusion weighted data. The images to reacquire are determined automatically during the acquisition from the imaging data, i.e., no extra reference scan, navigators, or external devices are necessary. The number of reacquired images, i.e., the additional scan duration can be adjusted freely. Diffusion-weighted prospective acquisition correction corrects slow bulk motion well and reduces misalignment artifacts like image blurring. Mean absolute residual values for translation and rotation were <0.6 mm and 0.5 degrees . Reacquisition of images affected by signal dropout artifacts results in diffusion maps and fiber tracking free of artifacts. The presented method allows the reduction of two types of common motion related artifacts at the cost of slightly increased acquisition time. PMID- 21695722 TI - Real-time motion correction for high-resolution larynx imaging. AB - Motion--both rigid-body and nonrigid--is the main limitation to in vivo, high resolution larynx imaging. In this work, a new real-time motion compensation algorithm is introduced. Navigator data are processed in real time to compute the displacement information, and projections are corrected using phase modulation in k-space. Upon automatic feedback, the system immediately reacquires the data most heavily corrupted by nonrigid motion, i.e., the data whose corresponding projections could not be properly corrected. This algorithm overcomes the shortcomings of the so-called diminishing variance algorithm by combining it with navigator-based rigid-body motion correction. Because rigid-body motion correction is performed first, continual bulk motion no longer impedes nor prevents the convergence of the algorithm. Phantom experiments show that the algorithm properly corrects for translations and reacquires data corrupted by nonrigid motion. Larynx imaging was performed on healthy volunteers, and substantial reduction of motion artifacts caused by bulk shift, swallowing, and coughing was achieved. PMID- 21695723 TI - Temporal filtering effects in dynamic parallel MRI. AB - Autocalibrated parallel MRI methods such as TSENSE or k-t SENSE have been presented for dynamic imaging studies as they are able to provide images with high temporal resolution. One key element of these techniques is the temporal averaging of the undersampled raw data to obtain an unaliased image. This image represents the temporal average (also known as direct current, DC) and is used to derive the reconstruction parameters. In this work, we show that aliasing artifacts can be introduced in the DC signal obtained from the undersampled raw data. These artifacts lead to undesired temporal filtering effects when the DC signal is used for coil sensitivity calibration or when the DC signal is subtracted from the raw data. It is demonstrated that the temporal filtering effects can be reduced significantly by filtering the DC signal. PMID- 21695724 TI - Combination of complex-based and magnitude-based multiecho water-fat separation for accurate quantification of fat-fraction. AB - Multipoint water-fat separation techniques rely on different water-fat phase shifts generated at multiple echo times to decompose water and fat. Therefore, these methods require complex source images and allow unambiguous separation of water and fat signals. However, complex-based water-fat separation methods are sensitive to phase errors in the source images, which may lead to clinically important errors. An alternative approach to quantify fat is through "magnitude based" methods that acquire multiecho magnitude images. Magnitude-based methods are insensitive to phase errors, but cannot estimate fat-fraction greater than 50%. In this work, we introduce a water-fat separation approach that combines the strengths of both complex and magnitude reconstruction algorithms. A magnitude based reconstruction is applied after complex-based water-fat separation to removes the effect of phase errors. The results from the two reconstructions are then combined. We demonstrate that using this hybrid method, 0-100% fat-fraction can be estimated with improved accuracy at low fat-fractions. PMID- 21695725 TI - Respiratory self-gated multiple gradient recalled echo sequence for free breathing abdominal R2* mapping. AB - Abdominal effective transverse relaxation rate (R(2)*) mapping is critical for a wide range of applications. However, respiratory motion can lead to significant image quality deterioration and R(2)* overestimation. For this work, we explored the feasibility of combining respiratory self-gating techniques with a multiple gradient-recalled echo sequence for free-breathing abdominal R(2)* measurements. In a series of eight normal volunteers, respiratory self-gated-multiple gradient recalled echo methods effectively avoided motion artifacts to produce quantitative R(2)* measurements in liver, spleen, and kidneys that were comparable to R(2)* measurements produced while breath-holding. Respiratory self gated-multiple gradient-recalled echo methods demonstrated the potential to avoid the need for breath-holding during abdominal R(2)* mapping. For clinical application, respiratory self-gated-multiple gradient-recalled echo approaches could be particularly useful for R(2)* measurements in those patients unable or unwilling to sustain sufficiently long breath-holds to avoid motion artifacts. PMID- 21695726 TI - 16 T diffusion microimaging of fixed prostate tissue: preliminary findings. AB - Diffusion tensor microimaging was used to investigate the water diffusion properties of formalin-fixed prostate tissue at spatial resolution approaching the cellular scale. Diffusion tensor microimaging was performed at 16.4 T with 40 MUm isotropic voxels. Diffusion tensor microimaging clearly demonstrated distinct microscopic diffusion environments and tissue architecture consistent with that seen on light microscopy of the same tissue. The most restricted diffusion environment is the secretory epithelial cell layer (voxel bulk mean diffusivity, D = 0.4 +/- 0.1 * 10(-3) mm(2)/sec). Diffusion in the fibromuscular stromal matrix is relatively less restricted (D = 0.7 +/- 0.1 * 10(-3) mm(2)/sec). In tumor tissue (Gleason pattern 4+4) distinct glandular and ductal structures are absent in the diffusion-weighted images and diffusivity is low (D = 0.5 +/- 0.1 * 10(-3) mm(2)/sec). Distinct stromal and epithelial diffusion compartments are the most likely origin of biexponential diffusion decay observed in vivo. PMID- 21695727 TI - Comparison of lung T2* during free-breathing at 1.5 T and 3.0 T with ultrashort echo time imaging. AB - Assessment of lung effective transverse relaxation time (T(2)*) may play an important role in the detection of structural and functional changes caused by lung diseases such as emphysema and chronic bronchitis. While T(2)* measurements have been conducted in both animals and humans at 1.5 T, studies on human lung at 3.0 T have not yet been reported. In this work, ultrashort echo time imaging technique was applied for the measurement and comparison of T(2)* values in normal human lungs at 1.5 T and 3.0 T. A 2D ultrashort echo time pulse sequence was implemented and evaluated in phantom experiments, in which an eraser served as a homogeneous short T(2)* sample. For the in vivo study, five normal human subjects were imaged at both field strengths and the results compared. The average T(2)* values measured during free-breathing were 2.11(+/-0.27) ms at 1.5 T and 0.74(+/-0.1) ms at 3.0 T, respectively, resulting in a 3.0 T/1.5 T ratio of 2.9. Furthermore, comparison of the relaxation values at end-expiration and end inspiration, accomplished through self-gating, showed that during normal breathing, differences in T(2)* between the two phases may be negligible. PMID- 21695728 TI - Quantitative magnetization transfer studies of apoptotic cell death. AB - Magnetization transfer measurements were performed on samples of acute myeloid leukemia cells at early (36 h postcisplatin treatment) and late (48 h posttreatment) stages of apoptosis. Magnetization transfer ratio was calculated and a two-pool model was fitted to data at two powers and 16 offset frequencies of saturation pulse. No parameters changed significantly at early stages of apoptosis. At late stages, changes in magnetization transfer ratio were not significant, but quantitative model parameters showed a decrease in macromolecular proton fraction, M(0B), and an increase in the T(2) relaxation time of free water. Analysis also indicated an increase in the ratio R * M(0B)/R(1A), where R is the exchange rate between free water and macromolecular protons and R(1A) is the T(1) relaxation rate of free water. Changes in the magnetization transfer spectrum were largely attributable to differences in the free water pool and did not occur any earlier than changes in the average T(1) relaxation time, T(1obs). PMID- 21695729 TI - Traveling-wave RF shimming and parallel MRI. AB - At sufficiently high Larmor frequencies, traveling electromagnetic waves along a magnet bore can be used for remote magnetic resonance excitation and detection, effectively using the bore as a waveguide. So far, this approach has relied only on the lowest waveguide modes and thus has not supported multiple-channel operation for radiofrequency shimming and parallel imaging. In this work, this limitation is addressed by establishing a larger number of propagating modes and tapping their spatial field diversity with multiple waveguide ports. The number of available modes is increased by loading with dielectric inserts; the ports are implemented by stub and loop couplers at the end of a waveguide extension. The resulting traveling-wave array, operated at 298 MHz in a 7T whole-body magnet, is shown to enable radiofrequency shimming as well as parallel imaging with commonly used acceleration factors. The last part of the study concerns the amount of dielectric loading that is required. For the given Larmor frequency and bore dimensions, it is found that rather few water-filled inserts, occupying ~5% of the bore cross-section, are sufficient for effective parallel imaging. PMID- 21695730 TI - First image from a combined positron emission tomography and field-cycled MRI system. AB - Combining positron emission tomography and MRI modalities typically requires using either conventional MRI with a MR-compatible positron emission tomography system or a modified MR system with conventional positron emission tomography. A feature of field-cycled MRI is that all magnetic fields can be turned off rapidly, enabling the use of conventional positron emission tomography detectors based on photomultiplier tubes. In this demonstration, two photomultiplier tube based positron emission tomography detectors were integrated with a field-cycled MRI system (0.3 T/4 MHz) by placing them into a 9-cm axial gap. A positron emission tomography-MRI phantom consisting of a triangular arrangement of positron-emitting point sources embedded in an onion was imaged in a repeating interleaved sequence of ~1 sec MRI then 1 sec positron emission tomography. The first multimodality images from the combined positron emission tomography and field-cycled MRI system show no additional artifacts due to interaction between the systems and demonstrate the potential of this approach to combining positron emission tomography and MRI. PMID- 21695731 TI - Bone structure and fracture risk: do they go arm in arm? PMID- 21695732 TI - Reliability and validity of a new sexual function questionnaire (Nagoya Sexual Function Questionnaire) for schizophrenic patients taking antipsychotics. AB - OBJECTIVE: This study aims to validate a new user-friendly sexual function questionnaire (Nagoya Sexual Function Questionnaire [NSFQ]) for schizophrenic patients taking antipsychotics. METHODS: Schizophrenic outpatients (men = 30, women = 30) were asked to fill out the NSFQ at initial entry into the research program (Time1) and again 1 to 2 weeks later (Time2). To assess the convergent validity of the NSFQ, at Time1, subjects were asked to fill out the Japanese version of the Udvalg for Kliniske Undersogekser Side Effect Rating Scale (UKU). To assess the discriminant validity of the NSFQ, at Time1, subjects were also asked to fill out the Japanese version of Epworth Sleepiness Scale. RESULTS: Results from Cronbach's alpha analysis indicated that the NSFQ demonstrated excellent internal consistency and scale reliability. The NSFQ also demonstrated strong test-retest reliability. The NSFQ total score was highly correlated with the UKU total score. The NSFQ was shown to have good convergent validity with the UKU. The NSFQ total score was not correlated with the Japanese version of Epworth Sleepiness Scale total score. CONCLUSIONS: This study revealed the internal consistency, test-retest reliability, and convergent and discriminant validities of the NSFQ. PMID- 21695734 TI - Cannabinoid type 1 receptor gene polymorphisms are not associated with olanzapine induced weight gain. AB - BACKGROUND: Olanzapine is an atypical antipsychotic known to cause considerable weight gain. The cannabinoid type 1 receptor has been reported to be involved in energy balance control, appetite stimulation, and increases in body weight. METHODS: In the present study, we investigated three polymorphisms (rs1049353, rs806368, and rs4707436) in the cannabinoid type 1 receptor gene (CNR1) and weight gain in Korean patients with schizophrenia receiving olanzapine treatment. Weight and height were measured prior to starting olanzapine and again after long term treatment in 78 patients with schizophrenia. CNR1 polymorphisms were genotyped using PCR-RFLP methods. RESULTS: The three CNR1 polymorphisms were not associated with body weight changes from baseline to the endpoint after olanzapine treatment (p > 0.05). There were also no significant differences in genotype, allele, or haplotype frequencies between the high weight gain (at least 7%) and low weight gain (less than 7%) groups. CONCLUSION: Within the limitations imposed by the smallness of the clinical sample, our findings suggest that CNR1 polymorphisms are not associated with olanzapine-induced weight gain. PMID- 21695733 TI - Concomitant medication of psychoses in a lifetime perspective. AB - OBJECTIVE: Patients treated with antipsychotic drugs often receive concomitant psychotropic compounds. Few studies address this issue from a lifetime perspective. Here, an analysis is presented of the prescription pattern of such concomitant medication from the first contact with psychiatry until the last written note in the case history documents, in patients with a diagnosis of psychotic illness. METHODS: A retrospective descriptive analysis of all case history data of 66 patients diagnosed with schizophrenia or schizophrenia-like psychotic disorders. RESULTS: Benzodiazepines and benzodiazepine-related anxiolytic drugs had been prescribed to 95% of the patients, other anxiolytics, sedatives or hypnotic drugs to 61%, anti-parkinsonism drugs to 86%, and antidepressants to 56% of the patients. However, lifetime doses were small and most of the time patients had no concomitant medication. The prescribed lifetime dose of anti-parkinsonism drugs was associated with that of prescribed first generation but not second-generation antipsychotics. CONCLUSIONS: Most psychosis patients are sometimes treated with concomitant drugs but mainly over short periods. Lifetime concomitant add-on medication at the individual patient level is variable and complex but not extensive. PMID- 21695736 TI - Arithmetic and biologically-inspired computing using phase-change materials. PMID- 21695737 TI - Synthesis, characterization, and the photochromic, luminescence, metallogelation and liquid-crystalline properties of multifunctional platinum(II) bipyridine complexes. AB - A series of multifunctional platinum(II) bipyridine complexes were designed, synthesized, and characterized by (1)H NMR, fast atom bombardment mass spectrometry (FAB-MS), and elemental analysis. Their electrochemical and photophysical properties were investigated. The photochromic properties of the spironaphthoxazine-containing complexes were also studied. Some of these complexes were shown to be capable of forming stable thermoreversible metallogels in organic solvents. In contrast to typical thermotropic organogels and metallogels, one of the complexes could form metallogels in dodecane and is very stable towards external stimuli. The photochromic activation parameters for the bleaching reaction of a representative spironaphthoxazine-containing complex in a dodecane gel were determined through kinetic studies at various temperatures. Lamellar liquid-crystalline behavior was also observed in one of the complexes, and the liquid-crystalline properties were studied by thermogravimetry analysis (TGA), polarized optical microscopy (POM), differential scanning calorimetry (DSC), variable-temperature X-ray diffraction (XRD), and variable-temperature infrared (IR) spectroscopy. PMID- 21695738 TI - Preparation, structure, and ethylene (co)polymerization behavior of Group IV metal complexes with an [OSSO]-carborane ligand. AB - The synthesis of Group IV metal complexes that contain a tetradentate dianionic [OSSO]-carborane ligand [(HOC(6)H(2)tBu(2)-4,6)(2)(CH(2))(2)S(2)C(2 (B(10)H(10))] (1a) is described. Reactions of TiCl(4) and Ti(OiPr)(4) with the [OSSO]-type ligand 1a afford six-coordinated titanium complex [Ti(OC(6)H(2)tBu(2) 4,6)(2)(CH(2))(2)S(2)C(2)(B(10)H(10))Cl(2)] (2a) and four-coordinated titanium complex [Ti(OC(6)H(2)tBu(2)-4,6)(2)(CH(2))(2)S(2)C(2)(B(10)H(10))(OiPr)(2)] (2b), respectively. ZrCl(4) and HfCl(4) were treated with 1a to give six-coordinated zirconium complex [Zr(OC(6)H(2)tBu(2)-4,6)(2)(CH(2))(2)S(2)C(2)(B(10)H(10))Cl(2) (thf)(2)] (2c) and six-coordinated hafnium complex [Hf(OC(6)H(2)tBu(2) 4,6)(2)(CH(2))(2)S(2)C(2)(B(10)H(10))Cl(2)] (2d). All the complexes were fully characterized by IR, NMR spectroscopy, and elemental analysis. In addition, X-ray structure analyses were performed on complexes 2a and 2b and reveal the expected different coordination geometry due to steric hindrance effects. Extended X-ray absorption fine structure (EXAFS) spectroscopy was performed on complexes 2c and 2d to describe the coordination chemistry of this ligand around Zr and Hf. Six coordinated titanium complex 2a showed good activity toward ethylene polymerization as well as toward copolymerization of ethylene with 1-hexene in the presence of methylaluminoxane (MAO) as cocatalyst (up to 1060 kg[mol(Ti)](-1) h(-1) in the case of 10 atm of ethylene pressure). PMID- 21695735 TI - Synthesis and enantiopreferential DNA-binding profile of late 3d transition metal R- and S-enantiomeric complexes derived from N,N-bis-(1-benzyl-2-ethoxyethane): Validation of R-enantiomer of copper(II) complex as a human topoisomerase II inhibitor. AB - To evaluate the biological preference of chiral drug candidates for molecular target DNA, new potential metal-based chemotherapeutic agents 1-3 (a and b) of late 3d transition metals Ni(II), Cu(II), and Zn(II), respectively, derived from (R)- and (S)-2-amino-2-phenylethanol with ?CH(2) ?CH(2) ? linker were synthesized and thoroughly characterized. Interaction studies of 1-3 (a and b) with calf thymus DNA in Tris buffer were studied by electronic absorption titrations, luminescence titrations, cyclic voltammetry, and circular dichroism. The results reveal that the extent of DNA binding of R-enantiomer of copper 1a was highest in comparison to rest of the complexes via electrostatic interaction mode. The nuclease activity of 1(a and b) with supercoiled pBR322 DNA was further examined by gel electrophoresis, which reveals that complex 1a exhibits a remarkable DNA cleavage activity (concentration dependent) with pBR322DNA, and the cleavage activity of both enantiomers of complex 1 was significantly enhanced in the presence of activators. The activating efficiency follows the order Asc > H(2) O(2) > MPA for 1a, and reverse order was observed for 1b, because of the differences in enantioselectivity and conformation. Further, it was observed that cleavage reaction involves singlet oxygen species and superoxide radicals via oxidative cleavage mechanism. In addition, complex 1a exhibits significant inhibitory effects on the topoisomerase II (topo II) activity at a very low concentration ~24 MUM, which suggest that complex 1a is indeed catalytic inhibitor or (poison) of human topo II. PMID- 21695739 TI - (1-Alkynyl)dicarbonylcyclopentadienyliron complexes as electron-rich alkynes in organic synthesis: BF3-mediated [2+2] cycloaddition/ring-opening providing (2 alkenyl-1-imino)iron complexes. PMID- 21695740 TI - Telomerisation of buta-1,3-diene and methanol: superiority of chromanyl-type phosphines in the Dow process for the industrial production of 1-MOD. AB - Butadiene and methanol were telomerised in the presence of palladium catalysts with ligands containing 8-diphenylphosphinochromane-like substituents at phosphorus. MonoXantphos and monoSPANphos afforded the most active, stable and selective catalysts known to date under commercially relevant production conditions for 1-methoxyocta-2,7-diene, the precursor to oct-1-ene. PMID- 21695741 TI - Differential diagnosis of adnexal masses: sequential use of the risk of malignancy index and HistoScanning, a novel computer-aided diagnostic tool. AB - OBJECTIVE: To assess the value of ovarian Histo-Scanning(TM) , a novel computerized technique for interpreting ultrasound data, in combination with the risk of malignancy index (RMI) in improving triage for women with adnexal masses. METHODS: RMI indices were assessed in 199 women enrolled in a prospective study to investigate the use of HistoScanning. Ultrasound scores were obtained by blinded analysis of archived images. The following sequential test was developed: HistoScanning was modeled as a second-line test for RMI between a lower cut-off and an upper cut-off. The optimal combination of these cut-offs that together maximized the Youden index (Sensitivity + Specificity - 1) was determined. RESULTS: Using RMI at the standard cut-off value of 250 resulted in a sensitivity of 74% and a specificity of 86%. When RMI was combined with HistoScanning, the highest accuracy was achieved by using HistoScanning as a sequential second-line test for patients with RMI values between 105 and 2100. At these cut-off values, sequential use of RMI and HistoScanning resulted in mean sensitivity and specificity estimates of 88% and 95%, respectively. CONCLUSIONS: Our data suggest that HistoScanning may have the potential to improve the diagnostic accuracy of RMI, which could result in better triage for women with adnexal masses. Further prospective validation is warranted. PMID- 21695742 TI - Vitamin A dynamics in breastmilk and liver stores: a life history perspective. AB - OBJECTIVES: Newborns are dependent on breastmilk vitamin A for building hepatic stores of vitamin A that will become critical for survival after weaning. It has been documented that vitamin A concentrations in breastmilk decline across the first year postpartum in both well-nourished and malnourished populations. The reason for this decline has been assumed to be a sign of concurrently depleting maternal hepatic stores. This study investigates this assumption to clarify why the decline occurs, drawing on life history theory. METHODS: A cross sectional survey was conducted among lactating mothers in Kenya in 2006. Data were used to examine (1) the relationship between liver vitamin A and time, (2) if the relationship between milk and liver vitamin A varies by time, and (3) by maternal parity. RESULTS: The relationship between liver vitamin A and time fits the quadratic pattern with marginal significance (P = 0.071, n = 192); the liver vitamin A declined during early postpartum then recovered in late postpartum time, controlling covariates. The milk-liver vitamin A relationship varied by postpartum time periods (P = 0.03) and by maternal parity (P = 0.005). Mothers in earlier postpartum or higher parity had a stronger positive relationship between milk and liver vitamin A than mothers in later postpartum or lower parity. CONCLUSIONS: Our observations are consistent with life history tradeoffs and negate the assumption that maternal hepatic and milk vitamin A decline together. Rather, maternal liver vitamin A has a dynamic relationship with milk vitamin A, particularly depending on postpartum time and maternal parity. PMID- 21695744 TI - Anxiety, depression and quality of life after cancer diagnosis: what psychosocial variables best predict how patients adjust? AB - OBJECTIVE: Significant numbers of cancer patients suffer distress, reduced quality of life and various other psychological problems. Evidence regarding psychological predictors of these outcomes is inconsistent. This study explored a range of predictors using an established psychological framework to identify the most important predictors of cancer adjustment, and when these are best assessed for optimal outcome prediction. METHODS: One hundred sixty newly diagnosed breast, colorectal, lung and prostate cancer patients completed questionnaires after diagnosis and at 3- and 6-month follow-up. Measures included personality, illness cognitions, emotion, coping and outcome (anxiety, depression and quality of life). RESULTS: Between 47-74% of variance in psychosocial outcome was explained although large proportions were accounted for by clinical factors, demographics and earlier levels of anxiety, depression and quality of life. Of the psychological variables, cognitive appraisals featured more consistently then either emotions or coping. CONCLUSIONS: There are clear and consistent predictors of negative psychosocial outcome that could be used in clinical practice to risk assess and monitor patients for adjustment difficulties. The finding that appraisals were more predictive of outcome than emotions and coping may inform the development of psychological interventions for cancer patients. PMID- 21695743 TI - Neurons generated in senescence maintain capacity for functional integration. AB - Adult-born neurons in the dentate gyrus (DG) can survive for long periods, are capable of integrating into neuronal networks, and are important for hippocampus dependent learning. Neurogenesis is dramatically reduced during senescence, and it remains unknown whether those few neurons that are produced remain capable of network integration. The expression of Arc, a protein coupled to neuronal activity, was used to measure activity among granule cells that were labeled with BrdU 4 months earlier in young (9 months) and aged (25 months) Fischer344 rats. The results indicate that while fewer cells are generated in the senescent DG, those that survive are (a) more likely to respond to spatial processing by expressing Arc relative to the remainder of the granule cell population and (b) equally responsive to spatial exploration as granule cells of the same age from young animals. These findings provide compelling evidence that newborn granule cells in the aged DG retain the capacity for participation in functional hippocampal networks. PMID- 21695745 TI - Factors related to depressive symptoms among Chinese caregivers of cancer patients. AB - OBJECTIVE: Caregivers, assuming the responsibilities of caring for patients, are involved in significant emotional and physical caring which may lead to depressive symptoms. However, few studies are available pertaining to related factors of depressive symptoms among cancer caregivers in China. This study aims to evaluate the prevalence of depressive symptoms and to explore its predictive factors. METHODS: A face-to-face interview was conducted with 312 cancer caregivers in Shenyang. Depressive symptoms were assessed by the Center for Epidemiologic Studies Depression scale. Hierarchical multivariate regression analysis was used to explore the factors related to depressive symptoms. In the hierarchical regression, caregiver demographic characteristics were entered in the first step, patients' characteristics were entered in the second step, objective caregiving loads were entered in the third step, subjective caregiving burden was entered in the fourth step, and Sense of Coherence (SOC) was entered in the last step. RESULTS: The prevalence of caregivers' depressive symptoms was 63.5%. Regression analyses showed that demographic characteristics of caregivers and subjective caregiving burden explained most of the total variance, accounting for 28.5% and 14.6%, respectively. Subjective caregiving burden was positively associated with depressive symptoms, whereas SOC was negatively associated with depressive symptoms. CONCLUSIONS: Chinese caregivers of cancer patients experienced higher levels of depressive symptoms. Demographic characteristics of caregivers and subjective caregiving burden were the most significant predictors of depressive symptoms, whereas SOC could attenuate the levels of depressive symptoms. Caregiving burden should be decreased, and SOC is highly recommended to manage caregiving tasks in order to alleviate depressive symptoms. PMID- 21695746 TI - Physical and mental health status and health behaviors in male breast cancer survivors: a national, population-based, case-control study. AB - OBJECTIVE: Identify the current physical and mental health status and health behaviors of male breast cancer survivors. METHODS: Using data from the national, population-based, 2009 Behavioral Risk Factor Surveillance System (BRFSS) survey, 66 cases of male breast cancer were identified (mean age = 66.2 years, mean time since diagnosis = 12.0 years). Male breast cancer cases were matched with 198 male BRFSS respondents with no history of cancer (control group) on age, education, and minority status. The male breast cancer and control groups were compared on physical and mental health status and health behaviors, using t-test and logistic regression analyses. RESULTS: The male breast cancer group reported poorer physical and mental health than controls. Male breast cancer survivors were significantly (p < 0.05) more likely to be obese (Odds Ratio = 2.41) and reported more physical comorbidities (Effect Size = 0.45) and activity limitations (Odds Ratio = 3.17), poorer life satisfaction (Effect Size = 0.41) and general health (Effect Size = 0.40), and more days in the past month when mental health (Effect Size = 0.49), and physical health (Effect Size = 0.29) were not good. In contrast, the male breast cancer and control groups were similar with regard to current health behaviors, including tobacco and alcohol use, diet, exercise, and health care. CONCLUSIONS: The diagnosis and treatment of male breast cancer may be associated with clinically important and long-term deficits in physical and mental health status, deficits which may exceed those evidenced by long-term female breast cancer survivors. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21695747 TI - The psychosocial impact of an abnormal cervical smear result. AB - BACKGROUND: Data on the impact of abnormal cervical smear results on health related quality of life (HrQoL) are scarce. We aimed to (i) prospectively assess the HrQoL of women who were informed of an abnormal smear result; (ii) identify predictors of greater negative psychosocial impact of an abnormal result; and (iii) prospectively estimate the quality-adjusted life-years (QALYs) lost following an abnormal result. METHODS: Between 08/2006 and 08/2008, 492 women with an abnormal result and 460 women with a normal result, frequency matched for age and clinic, were recruited across Canada. HrQoL was measured at recruitment and 4 and 12 weeks later with the EuroQol, Short Form-12, short Spielberg State Trait Anxiety Inventory (STAI) and HPV Impact Profile. Three blocks of potential predictors of higher psychosocial impact were tested by hierarchical modeling: (i) socio-demographics; (ii) sexual activity; and (iii) smear result severity, communication, and understanding. RESULTS: Receiving an abnormal result significantly increased anxiety (STAI mean difference between both groups = 8.3). Initial anxiety decreased over time for the majority of women. However, 35% of women had clinically meaningful anxiety at 12 weeks (i.e. STAI scores >=0.5 standard deviation of the controls). These women reported a lower socio-economic level, did not completely understand the information about their result and perceived themselves at higher risk of cancer. QALY lost following an abnormal result were between 0.007 and 0.009. CONCLUSIONS: Receiving an abnormal smear has a statistically significant and clinically meaningful negative impact on mental health. However, this negative impact subsides after 12 weeks for the majority of women. PMID- 21695749 TI - Force-transformed free-energy surfaces and trajectory-shooting simulations reveal the mechano-stereochemistry of cyclopropane ring-opening reactions. PMID- 21695748 TI - Clinical features, prevalence and psychiatric complaints in subjects with fear of vomiting. AB - Specific phobia of vomiting (also known as emetophobia) is a relatively understudied phobia with respect to its aetiology, clinical features and treatment. In this stage, research is mostly based on people with self-reported fear of vomiting. This paper presents a survey on the clinical features of fear of vomiting of individuals. Self-reported vomit-fearful subjects from the Dutch community and from an Internet support group are included. Both vomit-fearful groups were characterized by high reports of fear, the presence of panic symptoms, and by extensive avoidance and safety behaviours. They also reported other psychiatric complaints, which were measured with a structured screening instrument. Vomiting complaints started mostly in late puberty. A significant proportion of the vomit-fearful participants had a treatment history. The prevalence rate of fear of vomiting in the community sample was established at 8.8% (female : male ratio = 4:1). Overall, results show that fear of vomiting is a common phenomenon, which can seriously impair daily functioning. Finally, clinical questions to be addressed in future research are formulated. KEY PRACTITIONER MESSAGE: Specific phobia of vomiting (also known as emetophobia) is among the least studied phobias. Most clinical data come from research with self described fear of vomiting. This paper presents data on the clinical features, prevalence and additional psychiatric complaints of fear of vomiting in two vomit fearful samples and one control sample with no fear of vomiting. Estimates of prevalence of fear of vomiting in a Dutch community sample were established at 1.8% for men and 7% for women. Evidence suggests that fear of vomiting is a chronic and disabling condition that may cause significant impairment in daily functioning. PMID- 21695750 TI - Rapid one-step low-temperature synthesis of nanocrystalline gamma-Al2O3. PMID- 21695751 TI - Feasibility of an exercise-based rehabilitation programme for chronic hip pain. AB - BACKGROUND: Chronic hip pain is prevalent and disabling and has considerable consequences for the individual, and health and social care. Evidence-based guidelines recommend that patients with chronic hip pain benefit from exercise, but these guidelines are predominantly based on the efficacy of knee rehabilitation programmes. Studies investigating hip rehabilitation programmes suggest that these may not be feasible, citing issues with case identification. This study evaluated the feasibility of an exercise-based rehabilitation programme in a primary care hospital. METHODS: Forty-eight participants with chronic hip pain were randomly allocated to receive a five-week exercise and self management programme or to continue under the management of their general practitioner (GP). Participants were assessed at baseline, six weeks and six months. Outcome measures included Western Ontario and McMaster Universities osteoarthritis index physical function subscale, pain, objective functional performance, self-efficacy, anxiety and depression. RESULTS: This programme was feasible, well tolerated and easily implemented into a primary healthcare facility. Adherence to the programme was high (81% attendance). Immediately following rehabilitation, all outcomes measures improved (effect sizes 0.2-0.4), although these improvements diminished at six months. There were no differences between the groups (all p > 0.05). CONCLUSIONS: An exercise-based rehabilitation programme was found to be feasible and well tolerated by people with chronic hip pain. The moderate effects in all outcomes immediately following rehabilitation suggested that it warrants further investigation. Issues with diagnosis and adaptations to the programme were identified and will be addressed in a randomized controlled trial. PMID- 21695752 TI - Matchstick-shaped Ag2S-ZnS heteronanostructures preserving both UV/blue and near infrared photoluminescence. PMID- 21695753 TI - Enantioseparation and electronic properties of a propeller-shaped triarylborane. PMID- 21695754 TI - Protein import into chloroplasts: dealing with the (membrane) integration problem. PMID- 21695755 TI - A chimeric GPCR model mimicking the ligand binding site of the human Y1 receptor studied by NMR spectroscopy. PMID- 21695756 TI - Small molecule modulates hairpin structures in CAG trinucleotide repeats. PMID- 21695757 TI - Life-cycle exposure to the estrogenic mycotoxin zearalenone affects zebrafish (Danio rerio) development and reproduction. AB - Zearalenone (ZON) is one of the worldwide most common mycotoxin and exhibits estrogenic activity in the range of natural steroid estrogens. The occurrence of ZON has been reported in soil, drainage water, wastewater effluents, and rivers, but its ecotoxicological effects on fish have hardly been investigated. The consequences of continuous long-term ZON exposure, including a subsequent depuration period, as well as transgenerational effects of F0 short-term exposure on F1 generation were investigated. Effects on growth, reproduction activity, physiology, and morphology of zebrafish (Danio rerio) were examined in a 182 day live-cycle experiment. Life-long exposure to ZON for 140 days increased wet weight, body length, and condition factor of female fish at 1000 ng/L, and sex ratio was shifted toward female from 320 ng/L ZON. Only females at 1000 ng/L ZON revealed a 1.5-fold induction of plasma vitellogenin (VTG). Relative fecundity at 1000 ng/L recovered significantly during the depuration period. An increased condition factor in adult female F1 fish implies that exposure of F0 generation to 1000 ng/L ZON affected growth of F1 generation. A negative correlation between relative fecundity in the F1 generation (all groups exposed to 320 ng/L ZON) and the nominal ZON concentrations of the F0 exposure might indicate an influence of F0 exposure on reproductive performance of F1 generation. No exposure scenario affected fertility, hatch, embryo survival, and gonad morphology of zebrafish. Evaluating the environmental relevance of this data, the risk for fish to be harmed by exposure to ZON solely seems rather marginal, but ZON might contribute to the overall estrogenicity in the environment. (c) 2011 Wiley Periodicals, Inc. Environ Toxicol 2013. PMID- 21695758 TI - Diallyl sulfide, diallyl disulfide, and diallyl trisulfide inhibit migration and invasion in human colon cancer colo 205 cells through the inhibition of matrix metalloproteinase-2, -7, and -9 expressions. AB - Diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) are major organosulfur compounds exiting in garlic (Allium sativum). These compounds are reported to exhibit various pharmacological properties such as antibacteria, antiangiogenesis, anticancer, and anticoagulation, and they also induce cytotoxicity and induction of apoptosis in human cancer cells. Although these compounds show wide spectrum of biological activities, there are no reports to show that DAS, DADS, and DATS affected migration and invasion of human colon cancer cells, and their exact molecular mechanisms are not well investigated. Therefore, the purpose of this study was to determine whether DAS, DADS, and DATS affected the invasion and migration abilities of colo 205 human colon cancer cells. The results indicate that DAS, DADS, and DATS at 10 and 25 MUM inhibited the migration and invasion of colo 205 cells in the order of DATS < DADS < DAS. DATS is the highest for inhibition of migration and invasion of colo 205 cells. DAS, DADS, and DATS induce downregulation expression of PI3K, Ras, MEKK3, MKK7, ERK1/2, JNK1/2, and p38 and then lead to the inhibition of MMP-2, -7, and -9. DAS, DADS, and DATS inhibited NF-kappaB and COX-2 for leading to the inhibition of cell proliferation. Taken together, these results demonstrated that application of DAS, DADS, and DATS might serve as potential antimetastatic drugs. PMID- 21695759 TI - Bioaccumulation of algal toxins and changes in physiological parameters in Mediterranean mussels from the North Adriatic Sea (Italy). AB - The Northwestern Adriatic Sea is a commercially important area in aquaculture, accounting for about 90% of the Italian mussel production, and it was subjected to recurring cases of mussel farm closures due to toxic algae poisoning. A spatial and temporal survey of four sites along the North Adriatic Sea coasts of Emilia Romagna (Italy) was undertaken to study the possible impairments of physiological parameters in Mytilus galloprovincialis naturally exposed to algal toxins. The sites were selected as part of the monitoring network for the assessment of algal toxins bioaccumulation by the competent Authority. Samples positive to paralytic shellfish toxins and to lipophilic toxins were detected through the mouse bioassay. Lipophilic toxins were assessed by HPLC. Decreasing yessotoxins (YTX) levels were observed in mussels from June to December, while homo-YTX contents increased concomitantly. Lysosome membrane stability (LMS), glutathione S-transferase and catalase activities, and multixenobiotic resistance (MXR)-related gene expressions were assessed as parameters related to the mussel health status and widely utilized in environmental biomonitoring. Levels of cAMP were also measured, as possibly involved in the algal toxin mechanisms of action. Low LMS values were observed in hemocytes from mussels positive to the mouse bioassay. MXR-related gene expressions were greatly inhibited in mussels positive to the mouse bioassay. Clear correlations were established between increasing homo-YTX contents (and decreasing YTX) and increasing cAMP levels in the tissues. Similarly, significant correlations were established between the increase of homo YTX and cAMP levels, and the expressions of three MXR-related genes at submaximal toxin concentrations. In conclusion, YTXs may affect mussel physiological parameters, including hemocyte functionality, gene expression and cell signaling. PMID- 21695760 TI - Small fibre neuropathy: role in the diagnosis of diabetic sensorimotor polyneuropathy. AB - Small fibres constitute 70-90% of peripheral nerve fibres and regulate several key functions such as tissue blood flow, temperature and pain perception as well as sweating, all of which are highly relevant to the clinical presentation and adverse outcomes associated with foot ulcerations in patients with diabetes. Recent studies demonstrated significant abnormalities in the small fibres in subjects with impaired glucose tolerance and diabetes, despite normal electrophysiology, suggesting that the earliest nerve fibre damage is to the small fibres. Unfortunately, guidelines and consensus statements focus on large fibres and continue to advocate electrophysiology as a diagnostic modality and as a primary end point for the assessment of therapeutic benefit. (In part, this reflects the difficulties in quantifying small fibre dysfunction and damage.) We have therefore critically assessed currently available techniques that measure small fibre dysfunction in diabetic neuropathy, using quantitative sensory and sudomotor testing. We have assessed the role of identifying structural damage by quantifying intraepidermal nerve fibre density in skin biopsies and corneal nerve morphology using corneal confocal microscopy. Finally, we propose a definition for diabetic neuropathy that incorporates small fibre damage. PMID- 21695761 TI - Methods of investigation for cardiac autonomic dysfunction in human research studies. AB - This consensus document provides evidence-based guidelines regarding the evaluation of diabetic cardiovascular autonomic neuropathy (CAN) for human research studies; the guidelines are the result of the work of the CAN Subcommittee of the Toronto Diabetic Neuropathy Expert Group. The subcommittee critically reviewed the limitations and strengths of the available diagnostic approaches for CAN and the need for developing new tests for autonomic function. It was concluded that the most sensitive and specific approaches currently available to evaluate CAN in clinical research are: (1) heart rate variability, (2) baroreflex sensitivity, (3) muscle sympathetic nerve activity, (4) plasma catecholamines, and (5) heart sympathetic imaging. It was also recommended that efforts should be undertaken to develop new non-invasive and safe CAN tests to be used in clinical research, with higher sensitivity and specificity, for studying the pathophysiology of CAN and evaluating new therapeutic approaches. PMID- 21695762 TI - Painful diabetic peripheral neuropathy: consensus recommendations on diagnosis, assessment and management. AB - Painful diabetic peripheral neuropathy (DPN) is common, is associated with significant reduction in quality of life and poses major treatment challenges to the practising physician. Although poor glucose control and cardiovascular risk factors have been proven to contribute to the aetiology of DPN, risk factors specific for painful DPN remain unknown. A number of instruments have been tested to assess the character, intensity and impact of painful DPN on quality of life, activities of daily living and mood. Management of the patient with DPN must be tailored to individual requirements, taking into consideration the co-morbidities and other factors. Pharmacological agents with proven efficacy for painful DPN include tricyclic anti-depressants, the selective serotonin and noradrenaline re uptake inhibitors, anti-convulsants, opiates, membrane stabilizers, the anti oxidant alpha-lipoic acid and topical agents including capsaicin. Current first line therapies for painful DPN include tricyclic anti-depressants, the serotonin and noradrenaline re-uptake inhibitor duloxetine and the anti-convulsants pregabalin and gabapentin. When prescribing any of these agents, other co morbidities and costs must be taken into account. Second-line approaches include the use of opiates such as synthetic opioid tramadol, morphine and oxycodone controlled release. There is a limited literature with regard to combination treatment. In extreme cases of painful DPN unresponsive to pharmacotherapy, occasional use of electrical spinal cord stimulation might be indicated. There are a number of unmet needs in the therapeutic management of painful DPN. These include the need for randomized controlled trials with active comparators and data on the long-term efficacy of agents used, as most trials have lasted for less than 6 months. Finally, there is a need for appropriately designed studies to investigate non-pharmacological approaches. PMID- 21695763 TI - Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. AB - Prior to a joint meeting of the Neurodiab Association and International Symposium on Diabetic Neuropathy held in Toronto, Ontario, Canada, 13-18 October 2009, Solomon Tesfaye, Sheffield, UK, convened a panel of neuromuscular experts to provide an update on polyneuropathies associated with diabetes (Toronto Consensus Panels on DPNs, 2009). Herein, we provide definitions of typical and atypical diabetic polyneuropathies (DPNs), diagnostic criteria, and approaches to diagnose sensorimotor polyneuropathy as well as to estimate severity. Diabetic sensorimotor polyneuropathy (DSPN), or typical DPN, usually develops on long standing hyperglycaemia, consequent metabolic derangements and microvessel alterations. It is frequently associated with microvessel retinal and kidney disease-but other causes must be excluded. By contrast, atypical DPNs are intercurrent painful and autonomic small-fibre polyneuropathies. Recognizing that there is a need to detect and estimate severity of DSPN validly and reproducibly, we define subclinical DSPN using nerve conduction criteria and define possible, probable, and confirmed clinical levels of DSPN. For conduct of epidemiologic surveys and randomized controlled trials, it is necessary to pre-specify which attributes of nerve conduction are to be used, the criterion for diagnosis, reference values, correction for applicable variables, and the specific criterion for DSPN. Herein, we provide the performance characteristics of several criteria for the diagnosis of sensorimotor polyneuropathy in healthy subject- and diabetic subject cohorts. Also outlined here are staged and continuous approaches to estimate severity of DSPN. PMID- 21695764 TI - Should waist circumference be replaced by index of central obesity (ICO) in definition of metabolic syndrome? AB - Waist circumference has been widely used as the parameter of central obesity in defining metabolic syndrome. Global consensus definition of metabolic syndrome has suggested various race- and gender-specific cutoffs of waist circumference for quantifying central obesity. We have earlier proposed that using index of central obesity (ICO), the need for race- and gender-specific cutoffs may be obviated. We propose that waist circumference be supplanted with index of central obesity in all definitions of metabolic syndrome. Using index of central obesity a common cutoff of 0.5 applicable across races and genders might be obtained. Moreover, it will enhance the sensitivity of definition by diagnosing subjects who are shorter than general population. Among 258 male and 242 female diabetic patients, subjects with metabolic syndrome (defined as per gender-specific waist circumference cutoffs), were found to have a common lower range of index of central obesity suggesting that a common cutoff of waist circumference may be obtained. In another study from National Health and Nutrition Examination Survey database, replacing index of central obesity with waist circumference was found to enhance the specificity and sensitivity of definition of metabolic syndrome. PMID- 21695765 TI - International Neuropathy Workshop of 2009: introduction to the final reports. AB - Neuropathies are amongst the most common of the long-term complications of diabetes, affecting up to 50% of patients. Their clinical features vary immensely and patients may present with a wide spectrum of specialties, from neurology to urology, for example, or from cardiology to podiatry. Neuropathies are typically characterized by a progressive loss of nerve fibres which may affect both of the principal divisions of the peripheral nervous system. The epidemiology and natural history of the diabetic neuropathies remain poorly defined. The International Consensus Workshop in Toronto in 2009 arose from the fact that at the moment there are no clear, universally accepted guidelines regarding the definition of diabetic neuropathies. This has resulted in a massive variation in how neuropathy is diagnosed in different centres and countries. A preliminary summary report of the Toronto meeting was published in 2010. The series of papers published in this issue of Diabetes/Metabolism Research and Reviews are the detailed reports that came from each sub-group of this Consensus panel. These reviews cover the problems with definitions and classification of neuropathy, the management of painful neuropathy and then the sub-group of small fibre neuropathies. There are also 3 papers on the autonomic neuropathies, covering cardiovascular autonomic neuropathies, as well as other areas of the autonomic neuropathies including gastrointestinal, urogenital and pseudomotor neuropathies. This series of papers will give the reader detailed information on the diverse aspects of diabetic neuropathies, their measurement and management, and will also assist in the selection of appropriate measures of both autonomic and somatic nerve function in clinical trials. This is clearly work in progress as diagnostic criteria for diabetic neuropathies are likely to evolve with developments in the field. PMID- 21695766 TI - Foods for the prevention of diabetes: how do they work? AB - With the diabetes epidemic reaching menacing proportions worldwide, there is an urgent need for the development of cost-efficient prevention strategies to be effective at the population level. Great potential in this direction lies in properly designed, large-scale dietary interventions. The macronutrient composition and the caloric content of our diet are major determinants of glucose homeostasis and there is a continuously growing list of foods, nutrients or individual compounds that have been associated with an increased or reduced incidence of diabetes mellitus. These include fat, carbohydrates, fibre, alcohol, polyphenols and other micronutrients or individual dietary compounds, which have been shown to either promote or prevent a progression towards a (pre-)diabetic state. This review aims to briefly summarize relevant epidemiological data linking foods to diabetes and to provide insights into the mechanisms through which these effects are mediated. These include improvement of insulin sensitivity or promotion of insulin resistance, regulation of inflammatory pathways, regulation of glucose transport and tissue glucose uptake, aggravation or attenuation of postprandial glycaemia/insulinaemia, interactions with hormonal responses and beta-cell-dependent mechanisms. PMID- 21695767 TI - Type 2 diabetes affects hippocampus volume differentially in men and women. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) has been shown to result in medical complications on several organ systems including the kidneys, eyes, cardiovascular system, and most recently described the brain, including the hippocampus. There is also evidence that females are disproportionately affected by these medical complications. Brain volume reductions have also been associated with chronic low-grade inflammation and dyslipidaemia. This study investigated the relationships among T2DM, gender, inflammation, dyslipidaemia, and hippocampal volumes. METHOD: Participant groups consisted of 40 obese adults with T2DM and 47 lean adults, group-matched on age, gender, race, and education. Each participant underwent medical examination including a standard panel of blood tests, a magnetic resonance imaging, and cognitive evaluation. RESULTS: We show that there is a gender difference in the association of T2DM and hippocampal volumes: diabetic women are most affected despite having better glucose control than their male counterparts. Although females with T2DM had disproportionately lower high density lipoprotein as well as better haemoglobin A1c, neither of these results explained why females with T2DM had the smallest hippocampal volumes. CONCLUSIONS: These important findings indicate that in addition to the higher rate of traditional medical complication, females with T2DM are likely to suffer more brain complications than males. These observations, if supported by larger studies, suggest that in the future gender could be considered when customizing diabetes treatment. PMID- 21695768 TI - Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. AB - The Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of the Toronto Consensus Panel on Diabetic Neuropathy worked to update CAN guidelines, with regard to epidemiology, clinical impact, diagnosis, usefulness of CAN testing, and management. CAN is the impairment of cardiovascular autonomic control in the setting of diabetes after exclusion of other causes. The prevalence of confirmed CAN is around 20%, and increases up to 65% with age and diabetes duration. Established risk factors for CAN are glycaemic control in type 1 and a combination of hypertension, dyslipidaemia, obesity, and glycaemic control in type 2 diabetes. CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy. Criteria for CAN diagnosis and staging are: (1) one abnormal cardiovagal test result identifies possible or early CAN; (2) at least two abnormal cardiovagal test results are required for definite or confirmed CAN; and (3) the presence of orthostatic hypotension in addition to abnormal heart rate test results identifies severe or advanced CAN. Progressive stages of CAN are associated with increasingly worse prognosis. CAN assessment is relevant in clinical practice for (1) diagnosis of CAN clinical forms, (2) detection and tailored treatment of CAN clinical correlates (e.g. tachycardia, orthostatic hypotension, non-dipping, QT interval prolongation), (3) risk stratification for diabetic complications and cardiovascular morbidity and mortality, and (4) modulation of targets of diabetes therapy. Evidence on the cost-effectiveness of CAN testing is lacking. Apart from the preventive role of intensive glycaemic control in type 1 diabetes, recommendations cannot be made for most therapeutic approaches to CAN. PMID- 21695769 TI - Diversity in diabetes: the role of insulin aspart. AB - Diabetes management is changing not only with novel treatments but also in patient demography. This presents clinical challenges and influences our view of diabetes therapies. Insulin analogues have been developed to overcome some of the limitations of traditional human insulins, with the aim of providing a more physiological pharmacokinetic/pharmacodynamic profile. The rapid-acting insulin analogue insulin aspart has been investigated in many clinical trials over the past 10 years and the aim of this review is to present the insulin aspart clinical trial data from across the spectrum of patients with diabetes. Five studies have looked at insulin aspart use (including continuous subcutaneous insulin infusion) in children and adolescents, where the analogue was as effective and well tolerated as soluble human insulin. One large-scale, randomized, controlled trial in pregnant women with type 1 diabetes observed trends towards a reduction in major hypoglycaemia, fewer preterm deliveries and lower birthweight with insulin aspart compared with soluble human insulin. Two 6 month, randomized, controlled, multicentre, multinational, parallel-group, open label trials reported significant reductions in haemoglobin A(1c) and major nocturnal hypoglycaemia with insulin aspart compared with soluble human insulins in patients with type 1 diabetes. There are fewer data involving insulin analogue use in hospitals and in elderly patients with diabetes, but some recent studies have investigated insulin aspart in the emergency department, intensive/non intensive care setting and in a pharmacokinetic/pharmacodynamic study in patients aged >= 65 years. In summary, the evidence would suggest that insulin aspart is suitable for use in a variety of patients with diabetes. PMID- 21695770 TI - Determination of diethylstilbestrol based on biotin-streptavidin-amplified time resolved fluoro-immunoassay. AB - A rapid and sensitive time-resolved fluoroimmunoassay (TR-FIA) based on the biotin-streptavidin amplification system was developed for the determination of diethylstilbestrol (DES). Europium-labelled streptavidin derivatives combined with europium and anhydride of diethylene triamine penta-acetic acid were used to label streptavidin; biotin was coupled with goat anti-rabbit IgG to form a biotin goat anti-rabbit IgG bridge between streptavidin-europium and the anti-DES antibody in the immunoassay. The DES assay was carried out by measuring the fluorescence of Eu(3+) -SA at 615 nm. The presented method produced a wide linear range, 0.001-1000.0 ng/mL, and a detection limit up to 0.81 pg/mL for DES. The method was applied to determine DES in serum samples, with recoveries of 97.4 107.8% and RSD 1.32-4.04%. The assay results by the present method showed that biotin-streptavidin amplified TR-FIA for DES detection; it may offer high sensitivity and promising alternative special methods in biological samples. PMID- 21695771 TI - Model for end-stage liver disease exceptions in the context of the French model for end-stage liver disease score-based liver allocation system. AB - Model for End-Stage Liver Disease (MELD) score-based allocation systems have been adopted by most countries in Europe and North America. Indeed, the MELD score is a robust marker of early mortality for patients with cirrhosis. Except for extreme values, high pretransplant MELD scores do not significantly affect posttransplant survival. The MELD score can be used to optimize the allocation of allografts according to a sickest first policy. Most often, patients with small hepatocellular carcinomas (HCCs) and low MELD scores receive extra points, which allow them appropriate access to transplantation comparable to the access of patients with advanced cirrhosis and high MELD scores. In addition to patients with advanced cirrhosis and HCC, patients with a number of relatively uncommon conditions have low MELD scores and a poor prognosis in the short term without transplantation but derive excellent benefits from transplantation. These conditions, which correspond to the so-called MELD score exceptions, justify the allocation of a specific score for appropriate access to transplantation. Here we report the conclusions of the French consensus meeting. The goals of this meeting were (1) to identify which conditions merit MELD score exceptions, (2) to list the criteria needed for defining each of these conditions, and (3) to define a reasonable time interval for organ allocation for each MELD exception in the general context of organ shortages. MELD exceptions were discussed in an attempt to reconcile the concepts of transparency, equity, justice, and utility. PMID- 21695772 TI - Optimization of the dosing regimen of mycophenolate mofetil in pediatric liver transplant recipients. AB - Mycophenolate mofetil (MMF) is now commonly used in pediatric liver transplant recipients, but no clear recommendations about the dosing regimen have been made for this population. The aim of this study was to determine the MMF dosage required for pediatric liver transplant recipients to achieve an area under the plasma concentration-time curve from 0 to 12 hours (AUC(0-12) ) for mycophenolic acid (MPA) greater than 30 mg hour/L. A pharmacokinetic study of 15 children (median age = 8.3 years, range = 1.1-15.2 years) was performed at a median of 11.0 months (range = 0.5-88.0 months) after liver transplantation. MMF was initially introduced at a median starting dose of 300 mg/m(2) twice a day (range = 186-554 mg/m(2) twice a day). Thirteen of the 15 patients had an MPA AUC(0-12) value less than 30 mg hour/L. The MMF dosage had to be increased in all patients except 1. The MMF dosage required to reach an MPA AUC(0-12) value greater than the defined target of 30 mg hour/L ranged from 371 to 1014 mg/m(2) /day. For 2 patients who received rifampin in addition to MMF, the MPA AUC(0-12) value remained low despite a 2-fold increase in the MMF dosage. In conclusion, an initial MMF dose of 600 mg/m(2) twice a day led to MPA AUC(0-12) values greater than the 30 mg hour/L threshold except when rifampin was coadministered. Because of the important interindividual variability of MPA pharmacokinetics, therapeutic drug monitoring is recommended for optimizing the daily MMF dosage. Furthermore, these results suggest that the coadministration of MPA with rifampin should be avoided. PMID- 21695774 TI - Forward light scatter is a simple measure of T-cell activation and proliferation but is not universally suited for doublet discrimination. AB - Following activation by antigen, T cells enter the cell cycle in stages that can be defined with flow cytometric markers. We show that these markers include the increase of forward light scatter width (FSC-W) signal and the ratio of FSC area/peak. This change in light scatter precedes the first cell division and may reflect blast transformation. We show that the FSC-W parameter can be used, alone or in combination with other activation markers, to monitor the relative and absolute numbers of T cells responding to a proliferative stimulus. In contrast to dye dilution assays, the FSC-W method does not allow discrimination between consecutive cell divisions, but it has several advantages and could complement the dye dilution assay. Our findings also show that the routine elimination of doublets based on FSC signals may exclude proliferating T cells from the analysis. PMID- 21695773 TI - Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence based analysis of 15 years of experience. PMID- 21695775 TI - An improved flow cytometric assay for detection and discrimination between malignant cells and atypical mesothelial cells, in serous cavity effusions. AB - BACKGROUND: The aim of this study was to evaluate a flow cytometric assay for the detection of malignant effusions. METHODS: During the last 4-year period, 125 effusions suspicious for malignancy were prospectively analyzed by flow cytometry and conventional cytology. A three-step flow cytometric assay was performed, beginning with an initial informative panel of two protocols, containing SYTO-16, 7-AAD, CD71-PE, CD45-ECD, and CD66abce-FITC, CD64-PE, CD45-ECD, CD16-PECy5, CD14 PECy7, respectively. This was followed by a basic immunophenotypic panel of seven three-color combinations, containing in the first position, EMA, Ber-EP4, CD66abce, CD56, and intracellular desmin-33, combined with CD71-PE and CD45-PeCy5 in each tube. Finally, a cytokeratin-FITC/propidium iodide DNA panel was conducted, for the detection of aneuploidy in cytokeratin positive cells. RESULTS: The sensitivity and specificity of flow cytometry were 85.1 and 97.8%, and of cytology 93.2 and 95.6%, respectively. A significant association was observed between the results of the two techniques (P < 0.001). Among eight atypical cases detected by cytology, five had been precisely characterized as malignant by flow cytometry. EMA and Ber-EP4 proved the most sensitive markers for malignancy diagnosis, while the detection of desmin-33 negative/cytokeratin positive cells had the simultaneous highest positive and negative predictive values. CD66abce was very specific, although nonsensitive, while DNA ploidy analysis was nonspecific, as hyperploidy was observed in reactive mesothelial cells. CONCLUSIONS: A flow cytometric assay of high sensitivity and specificity is proposed for the routine identification of carcinoma cells in effusions and their distinction from atypical mesothelial cells, as an ancillary to conventional cytology. PMID- 21695776 TI - Altered T cell differentiation associated with loss of CD27 and CD28 in HIV infected Indian individuals. AB - BACKGROUND: HIV-1 infection is associated with depletion of naive T cell subsets and skewed T cell differentiation and maturation, leading to accumulation of T cells at intermediate and end stages of differentiation. CD27 and CD28 expression have been utilized in assessing these population subsets. METHODS: We characterized T cell subsets based on expression of CD45RA, CCR7, CD27, and CD28 and compared these subsets in HIV-1 infected Indian subjects and uninfected controls. RESULTS: HIV-1 infection was associated with an increase in effector and memory T cell subsets and a concomitant decrease in naive T cells. HIV-1 infected subjects showed accumulation of intermediate CD8 T cell (CD27+CD28-) differentiation subsets, whereas CD4 T cells progressed to late stage differentiation (CD27-CD28-). These subsets were negatively associated with CD4 T cell counts and positively associated with plasma viremia. CD57, an immunosenescence marker, was also increased on T cell subsets from HIV-1 infected individuals. Antiretroviral therapy resulted in partial restoration of differentiation status. CONCLUSION: Persistent HIV-1 replication and chronic immune activation, along with altered cytokine secretion profile, lead to impaired T cell differentiation and maturation. Detailed understanding of factors associated with differentiation defects in HIV-1 infected Indian individuals will strongly assist in Indian HIV-1 vaccine efforts and add to our knowledge of HIV-1 subtype C pathogenesis. PMID- 21695777 TI - A new approach to prepare well-dispersed CaF(2) nanoparticles by spray drying technique. AB - Previously, nano-sized calcium fluoride (CaF2) particles were prepared using a spray drying method by simultaneously feeding Ca(OH)2 and NH4F solutions to a two liquid nozzle. The aim of the present study was to prepare better-dispersed nano CaF2 particles by co-forming a soluble salt, sodium chloride (NaCl). NaCl of various concentrations were added to the NH(4) F solution, leading to formation of (CaF2 +NaCl) composites with CaF2 /NaCl molar ratios of 4/1, 4/4, and 4/16. Pure nano-CaF2 was also prepared as the control. Powder X-ray diffraction analysis showed that the products contained crystalline CaF2 and NaCl. Scanning electron microscopy examinations showed that both the CaF2 /NaCl composite and pure CaF2 particles were about (50-800) nm in size and consisted of primary CaF2 particles of < 50 nm in size. BET surface area measurements showed similar primary particle sizes for all samples. Dynamic light scattering measurements showed that the washed (CaF2+NaCl) particles were much smaller than the pure CaF2 as the dissolution of NaCl "freed" most of the primary CaF2 particles, leading to a greater degree of particle dispersion. The well-dispersed nano-CaF2 may be expected to be a more effective anticaries agent than NaF by providing longer lasting elevations of fluoride concentrations in oral fluids. PMID- 21695778 TI - Effect of processing on silk-based biomaterials: reproducibility and biocompatibility. AB - Silk fibroin has been successfully used as a biomaterial for tissue regeneration. To prepare silk fibroin biomaterials for human implantation a series of processing steps are required to purify the protein. Degumming to remove inflammatory sericin is a crucial step related to biocompatibility and variability in the material. Detailed characterization of silk fibroin degumming is reported. The degumming conditions significantly affected cell viability on the silk fibroin material and the ability to form three-dimensional porous scaffolds from the silk fibroin, but did not affect macrophage activation or beta sheet content in the materials formed. Methods are also provided to determine the content of residual sericin in silk fibroin solutions and to assess changes in silk fibroin molecular weight. Amino acid composition analysis was used to detect sericin residuals in silk solutions with a detection limit between 1.0 and 10% wt/wt, while fluorescence spectroscopy was used to reproducibly distinguish between silk samples with different molecular weights. Both methods are simple and require minimal sample volume, providing useful quality control tools for silk fibroin preparation processes. PMID- 21695779 TI - Fibrin-targeted block copolymers for the prevention of postsurgical adhesions. AB - Despite advances in surgical methods, postsurgical adhesions (PSA) remain a significant clinical challenge affecting millions of patients each year. These permanent fibrous connections between tissues result from the bridging of wounded internal surfaces by an extended fibrin gel matrix (FGM). Adhesion formation is a result of a systems level convergence of wound healing pathways, complicating the design of materials that could inhibit their occurrence. In this study, a systematic approach that identifies key material properties required for functional performance optimization was used to design a new fibrin-targeted PSA prevention material. A series of multifunctional polymers with varied molecular architectures was synthesized to investigate the effect of changing polymer structural parameters on the ability to disrupt the formation of an extended FGM. Initial studies in a murine adhesion model demonstrated a statistically significant reduction in the degree of PSA formation, demonstrating the potential value of this systematic approach. PMID- 21695780 TI - Global identification of transcription start sites in the genome of Apis mellifera using 5'LongSAGE. AB - The precise identification of the transcription start sites (TSSs) of genes in the honeybee genome will be helpful for inferring start codons and for determining promoter elements. The 5'SAGE approach provides a powerful tool for identifying TSSs in the sequenced genome. The main purpose of this study is to identify the actual TSSs of expressed genes as well as the usage of different TSSs in the Apis mellifera genome. We performed a 5'LongSAGE (5'LS) analysis for the adult drone head, and the TSSs of the expressed genes were determined by mapping the 5'LS tag sequences to the honeybee genome. A total of 8,280 unique 19 bp 5'LS tag sequences were identified that corresponded to 3,655 predicted genes. Out of these tags, 4,998 tags (60.4%) were mapped to a region from -1,000 bp to +100 bp of the start codon of 2,301 reference coding sequences. Notably, we observed that 28-47% of the 3,655 honeybee genes initiated transcription from alternative TSSs. The TSS consensus pattern of the honeybee genes, DT(rich) PyPu(G(rich))(T/A)(T(rich))(3), was obtained by aligning the sequences flanking the 5'LS-TSSs. We also identified three new genes in the regions downstream of 5'LS tags and validated 21 TSSs using RT-PCR amplification. Additionally, 17 genes identified by the 5'LS tags were associated with the Gene Ontology term "behavior." Mapping of the 5'LS tags on the genome not only provided direct evidence of expression for in silico predicted genes but also allowed for the identification of previously unrecognized, novel exons and alternative TSSs. PMID- 21695782 TI - Polymer nanoneedle-mediated intracellular drug delivery. AB - Delivery of drugs into the cellular cytoplasm of target cells represents a major hurdle in treating various diseases. This challenge can be addressed by encapsulation of drugs onto or within nanoparticles, which can then be targeted to diseased cells. Here, needle-shaped particles are shown to exhibit substantially higher cytoplasmic delivery of drugs such as siRNA compared to their spherical counterparts. Furthermore, these needles are designed to lose their sharp tips over time and can render themselves ineffective over time, thereby offering control over their duration of activity and toxicity. Such polymer nanoneedles open new avenues for delivering drug molecules directly into the cytoplasm with low toxicity. PMID- 21695784 TI - Helical assemblies of gold nanoparticles. PMID- 21695783 TI - Wet nanoscale imaging and testing of polymersomes. PMID- 21695785 TI - An industrial perspective on bioreactor scale-down: what we can learn from combined large-scale bioprocess and model fluid studies. AB - For industrial bioreactor design, operation, control and optimization, the scale down approach is often advocated to efficiently generate data on a small scale, and effectively apply suggested improvements to the industrial scale. In all cases it is important to ensure that the scale-down conditions are representative of the real large-scale bioprocess. Progress is hampered by limited detailed and local information from large-scale bioprocesses. Complementary to real fermentation studies, physical aspects of model fluids such as air-water in large bioreactors provide useful information with limited effort and cost. Still, in industrial practice, investments of time, capital and resources often prohibit systematic work, although, in the end, savings obtained in this way are trivial compared to the expenses that result from real process disturbances, batch failures, and non-flyers with loss of business opportunity. Here we try to highlight what can be learned from real large-scale bioprocess in combination with model fluid studies, and to provide suitable computation tools to overcome data restrictions. Focus is on a specific well-documented case for a 30-m(3) bioreactor. Areas for further research from an industrial perspective are also indicated. PMID- 21695781 TI - More effective nanomedicines through particle design. AB - Nanomedicine is an emerging field that applies concepts in nanotechnology to develop novel diagnostics and therapies. Physical and chemical properties of particles, including size, shape, modulus, surface charge and surface chemistry, play an important role in determining particle-cell interactions, cellular trafficking mechanisms, biodistribution, and pharmacokinetics. This discussion focuses on both nanoparticles and microparticles since microparticles can also provide many insights for the development of drug carriers and possess advantages over nanoparticles in certain applications. This review covers recent major advancement in the nanomedicine field and also highlights studies using the PRINT technology. PMID- 21695786 TI - Green fluorescent protein (GFP) leakage from microbial biosensors provides useful information for the evaluation of the scale-down effect. AB - Mixing deficiencies can be potentially detected by the use of a dedicated whole cell microbial biosensor. In this work, a csiE promoter induced under carbon limited conditions was involved in the elaboration of such biosensor. The cisE biosensor exhibited interesting response after up and down-shift of the dilution rate in chemostat mode. Glucose limitation was accompanied by green fluorescent protein (GFP) leakage to the extracellular medium. In order to test the responsiveness of microbial biosensors to substrate fluctuations in large-scale, a scale-down reactor (SDR) experiment was performed. The glucose fluctuations were characterized at the single cell level and tend to decrease the induction of GFP. Simulations run on the basis of a stochastic hydrodynamic model have shown the variability and the frequencies at which biosensors are exposed to glucose gradient in the SDR. GFP leakage was observed to a great extent in the case of a culture operated in well-mixed fed-batch mode, by comparison with those operated in SDR. GFP leakage seems to be correlated to a higher membrane permeability, confirming previous studies highlighting a better cell viability in cultures operated in a fluctuating environment. Our results suggest that GFP leakage could be used in parallel to the normal GFP biosensor function in order to assess microbial viability in process conditions. PMID- 21695787 TI - The zero-sum game of pathway optimization: emerging paradigms for tuning gene expression. AB - With increasing price volatility and growing awareness of the lack of sustainability of traditional chemical synthesis, microbial chemical production has been tapped as a promising renewable alternative for the generation of diverse, stereospecific compounds. Nonetheless, many attempts to generate them are not yet economically viable. Due to the zero-sum nature of microbial resources, traditional strategies of pathway optimization are attaining minimal returns. This result is in part a consequence of the gross changes in host physiology resulting from such efforts and underscores the need for more precise and subtle forms of gene modulation. In this review, we describe alternative strategies and emerging paradigms to address this problem and highlight potential solutions from the emerging field of synthetic biology. PMID- 21695788 TI - Changes in the bacterial community structure and diversity during bamboo retting. AB - Microbial retting is a critical step in obtaining fiber bundles from bamboo culm using indigenous microorganisms. A cultivation-independent technique for monitoring the changes in bacteria community during bamboo retting was applied in this work. This technique involves genetic profiling of PCR-amplified small subunit rRNA and the single-strand conformation polymorphism (SSCP) gel analysis of the PCR-amplified 16S rDNA fragments. The study revealed that both the structure and the diversity of investigated communities varied with the incubation periods and sample locations. The bacteria bands from SCCP gel profiles related to Bacillus sp. decreased in intensity, and Phaeospirillum sp. and Azospirillum brasilense completely disappeared during the 4(th) and 5(th) month of incubation, while the bands related to the Sphingomonas japonica, Alphaproteobacterium Ellin335 and Microbacterium sp. increased. The bands closely related to Sphingomonads, Brevundimonas brasilense, Pseudoclavibacter sp., Agrococcus jenensis and Oxalophagus oxalicus remained dominant during the whole incubation period. This study showed that the use of PCR assay targeting 16S rRNA and SCCP profiling provided valuable information on monitoring the bacteria dynamic changes occurring in the bacteria community during bamboo retting, which is crucial for controlling the quality of the retting process and improving the retting efficiency, and thus benefits for fiber recovery. PMID- 21695789 TI - CNTs@SnO2@carbon coaxial nanocables with high mass fraction of SnO2 for improved lithium storage. PMID- 21695790 TI - Bis-cinnolines as n-type semiconducting material with high electron mobility and thermal stability and their application in organic photovoltaic cells. PMID- 21695791 TI - In situ X-ray spectromicroscopy investigation of the material stability of SOFC metal interconnects in operating electrochemical cells. AB - The present in situ study of electrochemically induced processes occurring in Cr/Ni bilayers in contact with a YSZ electrolyte aims at a molecular-level understanding of the fundamental aspects related to the durability of metallic interconnects in solid oxide fuel cells (SOFCs). The results demonstrate the potential of scanning photoelectron microspectroscopy and imaging to follow in situ the evolution of the chemical states and lateral distributions of the constituent elements (Ni, Cr, Zr, and Y) as a function of applied cathodic potential in a cell working at 650 degrees C in 10(-6) mbar O(2) ambient conditions. The most interesting findings are the temperature-induced and potential-dependent diffusion of Ni and Cr, and the oxidation-reduction processes resulting in specific morphology-composition changes in the Ni, Cr, and YSZ areas. PMID- 21695792 TI - Mechanisms of structure generation during plastic compression of nanofibrillar collagen hydrogel scaffolds: towards engineering of collagen. AB - Operator control of cell/matrix density of plastically compressed collagen hydrogel scaffolds critically depends on reproducibly limiting the extent of scaffold compaction, as fluid expulsion. A functional model of the compression process is presented, based on the idea that the main fluid-leaving surface (FLS) behaves as an ultrafiltration membrane, allowing fluid (water) out but retaining collagen fibrils to form a cake. We hypothesize that accumulation of collagen at the FLS produces anisotropic structuring but also increases FLS hydraulic resistance (R(FLS) ), in turn limiting the flux. Our findings show that while compressive load is the primary determinant of flux at the beginning of compression (load-dependent phase), increasing FLS collagen density (measured by X-ray attenuation) and increasing R(FLS) become the key determinants of flux as the process proceeds (flow-dependent phase). The model integrates these two phases and can closely predict fluid loss over time for a range of compressive loads. This model provides a useful tool for engineering cell and matrix density to tissue-specific levels, as well as generating localized 3D nano micro-scale structures and zonal heterogeneity within scaffolds. Such structure generation is important for complex tissue engineering and forms the basis for process automation and up-scaling. PMID- 21695793 TI - Retroviral expression of MIR2 decreases both surface MHC class I and the alloimmune CTL response. AB - The immune response to allogeneic cells in tissue-engineered constructs is a major barrier to their successful application in the treatment of many human diseases. Specifically, the T cell-mediated immune response, initiated through the recognition of cell surface MHCI molecules, is the primary cause of acute cellular allograft rejection. In this study, we altered expression of MHCI through viral immunomodulatory mechanisms to examine whether allogeneic cells could be made to 'mimic' viral evasion of a host CTL response. We demonstrate the successful application of a retroviral vector in vitro to overexpress the Kaposi's sarcoma-associated herpesvirus immunomodulatory protein, MIR2, in human monocyte-like myeloid progenitor cells. This approach led to differential downregulation of cell surface MHCI, ICAM-1 and B7-2 molecules. We also demonstrate that downregulation of immunoactive molecules has the functional effect of significantly reducing T cell-mediated cytotoxicity without altering NK mediated cytotoxicity in vitro. These results provide proof-of-concept that viral immune evasion strategies allow cell-based tissue-engineered constructs to delay or even prevent acute cellular immune rejection in vivo. Importantly, this methodology could facilitate the development of universal donor cells for tissue engineering applications. PMID- 21695794 TI - Advanced maturation by electrical stimulation: Differences in response between C2C12 and primary muscle progenitor cells. AB - Skeletal muscle tissue engineering still does not result in the desired functional properties and texture as preferred for regenerative medicine and meat production applications. Electrical stimulation has been appropriately used as a tool to advance muscle cell maturation in vitro, thereby simulating nerve stimulation, as part of the muscle cell niche in vivo. We first investigated the effects of electrical stimulation protocols in two-dimensional (2D) monolayers of C2C12 and translated these protocols to a three-dimensional (3D) model system, based on a collagen type I/Matrigel(TM) hydrogel. More importantly, we addressed the ongoing debate of the translation of results found in cell lines (C2C12) to a primary cell source [muscle progenitor cells (MPCs)] in our 3D system. Striking differences in maturation level were found between the different cell sources. Constructs with MPCs were much more mature than C2C12 constructs, based on developed cross-striations and expression levels of mature myosin heavy chain (MHC) isoforms. Overall, electrical stimulation, when optimally timed, accelerated sarcomere assembly in both 2D and 3D. In addition, MPC constructs were more susceptible to the electrical stimulus, resulting in a shift of MHC expression to slower isoforms. PMID- 21695795 TI - Basic fibroblast growth factor enhances osteogenic and chondrogenic differentiation of human bone marrow mesenchymal stem cells in coral scaffold constructs. AB - Temporomandibular joint (TMJ) disorders are commonly occurring degenerative joint diseases that require surgical replacement of the mandibular condyle in severe cases. Transplantation of tissue-engineered mandibular condyle constructs may solve some of the current surgical limitations to TMJ repair. We evaluated the feasibility of mandibular condyle constructs engineered from human bone marrow derived mesenchymal cells (BMSCs). Specifically, human BMSCs were transfected with basic FGF (bFGF) gene-encoding plasmids and induced to differentiate into osteoblasts and chondroblasts. The cells were seeded onto mandibular condyle shaped porous coral scaffolds and evaluated for osteogenic/chondrogenic differentiation, cell proliferation, collagen deposition and tissue vascularization. Transfected human BMSCs expressed bFGF and were highly proliferative. Osteogenesis was irregular, showing neovascularization around new bone tissue. There was no evidence of bilayered osteochondral tissue present in normal articulating surfaces. Collagen deposition, characteristic of bone and cartilage, was observed. Subcutaneous transplantation of seeded coral/hydrogel hyaluran constructs into nude mice resulted in bone formation and collagen type I and type II deposition. Neovascularization was observed around newly formed bone tissue; bFGF expression was detected in implanted constructs seeded with bFGF expressing hBMSCs. This report demonstrates that engineered porous coral constructs using bFGF gene-transfected human BMSCs may be a feasible option for surgical transplantation in TMJ repair. PMID- 21695797 TI - Characterization of electrospun poly(L-lactide) and gold nanoparticle composite scaffolds for skeletal muscle tissue engineering. AB - Traumatic injuries can interrupt muscle contraction by damaging the skeletal muscle and/or the peripheral nerves. The healing process results in scar tissue formation that impedes muscle function. Electrospinning and metal nanoparticles (Nps) can create a scaffold that will trigger muscle cell elongation, orientation, fusion, and striation. Poly(L-lactic acid) (PLLA) and gold (Au) Nps were electrospun to create three composite scaffolds, 7% Au-PLLA, 13% Au-PLLA and 21% Au-PLLA, and compared to PLLA alone. The scaffolds had a conductivity of 0.008 +/- 0.003 S/cm for PLLA, 0.053 +/- 0.015 S/cm for 7% Au-PLLA, 0.076 +/- 0.004 S/cm for 13% Au-PLLA and 0.094 +/- 0.037 S/cm for 21% Au-PLLA. Next, a cell study was conducted with rat primary muscle cells and all three Au-PLLA scaffolds. The first cell study showed low cell proliferation on all three of the Au-PLLA scaffolds; however, the second cell study showed that this was not due to Au Nps toxicity. Instead, low cell proliferation may be a marker for myotube differentiation and fusion. Values for the elastic modulus and yield stress for the Au-PLLA scaffolds on days 0, 7, 14, 21 and 28 were much higher than those for skeletal muscle tissue. Therefore, lower amounts of Au Nps may be utilized to create a biodegradable, biocompatible and conductive scaffold for skeletal muscle repair. PMID- 21695798 TI - Microfabrication of PDLLA scaffolds. AB - This study aimed to comprehend the potentialities of the microfabrication to produce tissue-engineering scaffolds. Structures presenting homogeneously distributed pores of size 100 and 200 um were fabricated through layer-by-layer deposition of filaments of poly(D,L-lactic acid) (PDLLA) prepared from dichloromethane/dimethylformamide solutions. Rheological tests on the solution and molecular weight distributions of PDLLA, solvent cast films and microfabricated scaffolds were performed to determine which material conditions are optimal for the microfabricated system and to identify any possible material modification induced by the process. In vitro qualitative preliminary cell culture studies were conducted using MG63 osteoblast cell lines after assuring the non-cytotoxicity of the scaffold material by the lactate dehydrogenase in vitro toxicology assay; biological evaluations were initially performed using scaffolds with the smaller (100 um) pore size. Scanning electron microscopy imaging was used to determine cell morphology distribution. A second cell culture test was performed, using the scaffold with the higher (200 um) porosity. Confocal laser microscopy (CLM) was utilized to examine cell morphology and growth behaviour. Cellular metabolic activity and viability were also examined using Alamar Blue assay and further verifications were performed using CLM. Cell culture studies indicated homogeneous distribution, high viability and metabolic activity. Pore dimension affects cell distribution: pores < 100 um acted as barrier structures for the MG63 osteoblast cell line; penetration inside the matrix was hindered and cells grew on the outer part. Increasing pore size resulted in a more homogeneous cell distribution and penetration of cells inside the structure was achieved. PMID- 21695796 TI - Biomechanical characteristics of regenerated cortical bone in the canine mandible. AB - To test the mechanical properties of regenerate cortical bone created using mandibular bone transport (MBT) distraction, five adult male American foxhound dogs underwent unilateral distraction of the mandible with a novel MBT device placed to linearly repair a 30-35 mm bone defect. The animals were sacrificed 12 weeks after the beginning of the consolidation period. Fourteen cylindrical specimens were taken from the inner (lingual) and outer (buccal) plates of the reconstructed mandible and 21 control specimens were removed from the contralateral aspect of the mandible. The mechanical properties of the 35 cylindrical cortical bone specimens were assessed by using a non-destructive pulse ultrasound technique. Results showed that all of the cortical mechanical properties exhibit higher numerical values on the control side than the MBT regenerate side. In addition, both densities and the elastic moduli in the direction of maximum stiffness of the regenerate cortical bone specimens are higher on the lingual side than the buccal side. Interestingly, there is no statistical difference between elastic modulus (E(1) and E(2) ) in orthogonal directions throughout the 35 cortical specimens. The data suggest that not only is the regenerate canine cortical bone heterogeneous, but the elastic mechanical properties tend to approximate transverse isotropy at a tissue level, as opposed to control cortical bone, which is orthotropic. In addition, the elastic mechanical properties are higher not only on the control side but also in the lingual anatomical position, suggesting a stress shielding effect from the presence of the reconstruction plate. PMID- 21695799 TI - Influence of pore size on the redifferentiation potential of human articular chondrocytes in poly(urethane urea) scaffolds. AB - The chemical and physical properties of scaffolds affect cellular behaviour, which ultimately determines the performance and outcome of tissue-engineered cartilage constructs. The objective of this study was to assess whether a degradable porous poly(urethane urea) scaffold could be a suitable material for cartilage tissue engineering. We also investigated whether the post-expansion redifferentiation and cartilage tissue formation of in vitro expanded adult human chondrocytes could be regulated by controlled modifications of the scaffold architecture. Scaffolds with different pore sizes, < 150 um, 150-300 um and 300 500 um, were seeded with chondrocytes and subjected to chondrogenic and osteogenic induction in vitro. The poly(urethane urea) scaffold with the smaller pore size enhanced the hyaline-like extracellular matrix and thus neocartilage formation. Conversely, the chondrocytes differentiated to a greater extent into the osteogenic pathway in the scaffold with the larger pore size. In conclusion, our results demonstrate that poly(urethane urea) may be useful as a scaffold material in cartilage tissue engineering. Furthermore, the chondrogenic and the osteogenic differentiation capacity of in vitro expanded human articular chondrocytes can be influenced by the scaffold architecture. By tailoring the pore sizes, the performance of the tissue-engineered cartilage constructs might be influenced and thus also the clinical outcome in the long run. PMID- 21695800 TI - Sensitivity of fine-needle aspiration for papillary carcinoma of the thyroid correlates with tumor size. AB - Fine-needle aspiration (FNA) of the thyroid for papillary carcinomas is highly sensitive. We sought to determine if the sensitivity of FNA for papillary carcinoma is correlated with the size of the tumor. We reviewed the results of thyroid resections for the last 12 years and correlated the findings with clinical and cytologic information. During the time period, a total of 1,331 resections were performed, and a total of 501 papillary carcinomas were identified, including 291 classic tumors, 65 follicular variants, and 145 "incidental" tumors. Sensitivity for all tumors was strongly correlated with tumor size and ranged from a sensitivity of 0-3% for tumors 2 mm or less, 90% for tumors 1-3 cm (220/244, P < 0.001) and 83% for tumors above 3 cm (47/59, P = 0.02). Abnormal FNAs of classic tumors were always recognized as papillary (262/262) compared to only 49% of follicular variants (32/65, P < 0.001). The sensitivity of FNA for papillary thyroid carcinoma is strongly correlated with tumor size. Tumors smaller than 0.5 cm and tumors larger than 3 cm may be more difficult to successfully aspirate on FNA, and the follicular variant may be more difficult to recognize as papillary. PMID- 21695801 TI - Rare example of the use of fine-needle aspiration cytology for periapical osseous dysplasia. AB - Osseous dysplasia (OD) is one of the fibro-osseous jaw lesions characterized by cellular fibrous tissue with hard tissue formation. We report a rare fine-needle aspiration cytology (FNAC) for periapical OD. A 34-year-old woman had well defined, round, mixed radiolucent lesions in the periapical regions of the bilateral mandibular canines. FNAC showed hypocellular with some multinucleated giant cells and a few clusters of fibroblastlike cells. These cells had bland nuclei, with no nuclear atypia or mitotic figures. No calcified materials or bony spicules were evident. Microscopically, the lesions consisted of cellular fibrous tissue and hard tissue. The final diagnosis was bilateral periapical OD. FNAC alone may not be an accurate procedure for definitive diagnosis of a fibro osseous lesion, but it can be a useful and reliable diagnostic method when used in conjunction with clinical and imaging findings. PMID- 21695802 TI - Fine needle aspiration cytology of malignant endovascular papillary angioendothelioma. AB - Here we described a rare case of malignant endovascular papillary angioendothelioma (Dabska tumor) in an adult female. On fine needle aspiration, the smear showed many small clusters of tumor cells with rosettoid arrangement along with papillary fragments with fibrovascular core and hobnail like arrangement of the cells. Histopathological examination revealed a vascular tumor in the form of papillary projection into the vascular lumina, lined by atypical endothelial cells. PMID- 21695804 TI - Microfilaria in liver aspiration cytology: an extremely rare finding. AB - Filariasis is a common public health problem in the Indian subcontinent. The diagnosis can be made conventionally by demonstrating microfilaria in peripheral blood smears. Despite its high incidence it is unusual to find microfilariae in fine-needle aspiration (FNA) cytology smears. Microfilariae have been reported in cytological specimens of various organs, but it is extremely rare to find microfilaria in fine FNA cytology of liver. We report seventh case of microfilaria in liver aspirate in a male patient suffering from gallbladder cancer. PMID- 21695805 TI - Orbital aspergillus infection diagnosed by FNAC. AB - Fungal infections of the orbit represent a small minority of orbital infections. However, due to the virulent nature of some of the fungal species, they can have a devastating effect on ocular functions. Most of these fungi are saprophytes, which cause opportunistic infections. Aspergillus is one such fungus that can cause infection at various sites in an immunosuppressed individual. Sinonasal aspergillus infection with orbital extension and orbital aspergillus infection progress relentlessly. They can have a precipitous clinical course resulting in total loss of vision. Fine needle aspiration cytology (FNAC) is rarely used as a preoperative diagnostic tool in the investigation of orbital mass lesions. Further, fungal infections of orbit are seldom diagnosed on FNAC. Two cases of fungal infection of the orbital and periorbital tissue diagnosed on FNAC are presented. A 50-year-old diabetic male presented with diminishing vision, pain, and forward protrusion of the left eye. On examination, he had upper eye lid fullness. A 55-year-old diabetic male presented with a swelling on the right upper eye lid. The patients were evaluated radiologically and then subjected to FNAC. The smears showed giant cells, histiocytes, epithelioid granulomas, and fungal hyphae. A diagnosis of fungal infection was arrived at which was subsequently confirmed by culture and biopsy. Orbital aspergillus infection can have a precipitous course. Computerized tomography and magnetic resonance imaging of the orbit provide crucial information. However, FNAC can help in making an early definitive diagnosis of fungal infection and thus obviate the need for a biopsy. PMID- 21695803 TI - Fine needle aspiration cytology of epithelioid sarcoma. AB - In this case report, we have described the fine needle aspiration cytology (FNAC) of epithelioid sarcoma (ES) in a 40-year-old female patient who presented with multiple nodular swellings over right forearm and single right axillary lymph node. The FNAC smear showed predominantly dispersed as well as three-dimensional clusters of malignant cells admixed with basement membrane like material. The individual cells were moderately pleomorphic with round to oval nuclei and moderate to abundant amount of cytoplasm. The neoplastic cells have well-defined cytoplasmic borders and intercellular spaces. The excision biopsy of the swelling of the forearm showed ES. The cytology features of ES are characteristic and a preoperative diagnosis is helpful for proper management of the case. PMID- 21695806 TI - Fine needle aspiration cytology of solid neuroendocrine carcinoma of the breast: a case report. AB - We report a case of neuroendcrine (NE) carcinoma in the right breast of a 67-year old female, ultrasonography revealed a lesion composed of irregular hypoechoic masses and mammography showed asymmetric breast tissue. Histopathologic examination of the surgical sample showed a solid to nested proliferation of plasmacytoid cells that showed immunocytochemical positivity for chromogranin A, synaptophysin, CD56, and estrogen receptor. Our case was diagnosed as solid NE carcinoma. Though the findings of fine needle aspiration cytology reflected the histological features, we were not able to cytopathologic grounds only to predict the NE nature of this tumor. We performed immunocytochemistry using Chromogranin A, Synaptophysin, and CD56 on our cytologic smear retrospectively with positive results for all of the markers. When the cytopathologic examination of a given breast neoplasm is suggestive of NE differentiation, immunocytochemical staining for NE markers is generally useful for a correct preoperative diagnosis. An acurate preoperative diagnosis of NE carcinoma on FNAC can be achieved based on its distinctive cytomorphologic and immunocytochemical features. PMID- 21695807 TI - Characterization of superporous cellulose matrix for high-throughput adsorptive purification of lysozyme. AB - Protein purification essentially requires macroporous adsorbents matrices, which can provide high efficiency in packed bed and expanded bed (EB) even at high flow rates on account of reduced pore diffusion resistance resulting from finite intraparticle flow in the superpores. Rigid spherical superporous adsorbent beads with high carboxyl group density were prepared by crosslinking of cellulose. The matrix (diameter: 100-300 MUm, mean pore size: 1-3 MUm, pore volume: 57-59%, and bulk density: ~1,438 kg/m3) could be used in packed bed as well as EB for purification of various biomolecules. Attempts were made to use indigenously developed rigid, superporous crosslinked cellulose adsorbent for high-throughput purification of lysozyme from chicken egg white's extract. A typical adsorption isotherm for lysozyme in crude was well correlated with the Langmuir isotherm model. Two maxima of binding capacity on celbeads bearing carboxymethyl (celbeads CM) group for lysozyme were observed at pH 4.5 and 7.5. Uptake kinetics showed that the diffusivity of lysozyme was 100 times higher than conventional matrices. Such superporous matrix can be used for high-throughput purification of proteins from crude feedstocks and is reflected in leveling off of height equivalent to theoretical plate vs. flow curve after threshold velocity. Optimization of binding and elution conditions resulted in overall purification of lysozyme in a high yield and purity of 98.22 and 98.8%, respectively, with purification factor of 51.54 in a single step. The overall productivity (14.21 kg/m3 h) and specific activity (2.2*10(5) U/mg) were higher than that obtained with traditional particulate resins. PMID- 21695808 TI - Protein extraction by Winsor-III microemulsion systems. AB - Proteins (bovine serum albumin (BSA), alpha-chymotrypsin, cytochrome c, and lysozyme) were extracted from 0.5 to 2.0 g L(-1) aqueous solution by adding an equal volume of isooctane solution that contained a surfactant mixture (Aerosol OT, or AOT, and a 1,3-dioxolane (or cyclic ketal) alkyl ethoxylate, CK-2,13 E5.6), producing a three-phase (Winsor-III) microemulsion with a middle, bicontinuous microemulsion, phase highly concentrated in protein (5-13 g L(-1)) and small in volume (12-20% of entire volume). Greater than 90% forward extraction was achieved within a few minutes. Robust W-III microemulsion systems were formulated at 40 degrees C, or at 25 degrees C by including a surfactant with shorter ethoxylate length, CK-2,13-E3 , or 1.5% NaCl (aq). Successful forward extraction correlated with high partitioning of AOT in the middle phase (>95%). The driving force for forward extraction was mainly electrostatic attractions imposed by the anionic surfactant AOT, with the exception of BSA at high ionic strength, which interacted via hydrophobic interactions. Through use of aqueous stripping solutions of high ionic strength (5.0 wt %) and/or pH 12.0 (to negate the electrostatic attractive driving force), cytochrome c and alpha chymotrypsin were back extracted from the middle phase at >75% by mass, with the specific activity of recovered alpha-chymotrypsin being >90% of its original value. PMID- 21695809 TI - Extracellular purine and pyrimidine catabolism in cell culture. AB - The presence of purines and pyrimidines bases, nucleosides, and nucleotides in the culture medium has shown to differently affect the growth of a Chinese hamster ovary (CHO) cell line producing the secreted form of the human placental alkaline phosphatase enzyme (SEAP; Carvalhal et al., Biotech Prog. 2003;19:69 83). CHO, BHK, as well as Sf9 cell growth was clearly reduced in the presence of purines but was not affected by pyrimidines at the concentrations tested. The knowledge about the mechanisms by which nucleotides exert their effect when present outside the cells remains very incomplete. The catabolism of both extracellular purines and pyrimidines was followed during the culture of CHO cells. Purines/pyrimidines nucleotides added at a concentration of 1 mM to the culture medium decreased to negligible concentrations in the first 2 days. Purine and pyrimidine catabolism originated only purinic and pyrimidic end-products, respectively. The comparison between AMP catabolism in serum-free cultures (CHO cells expressing Factor VII and Sf9 cells) and in cultures containing serum (CHO cells expressing SEAP and BHK cells expressing Factor VII) showed that AMP extracellular catabolism is mediated by both cells and enzymes present in the serum. This work shows that the quantification of purines and pyrimidines in the culture medium is essential in animal cell culture optimization. When using AMP addition as a chemical cell growth strategy for recombinant protein production improvement, AMP extracellular concentration monitoring allows the optimization of the multiple AMP addition strategy for a prolonged cell culture duration with high specific productivity. PMID- 21695810 TI - [Heart and tai chi; Viagra and mountaineering]. PMID- 21695811 TI - New studies of neurobehavioral evolution. Proceedings of a conference convened as a tribute to the life, work, and influence of Wally Welker. June 25-28, 2010. Washington, D.C., USA. PMID- 21695812 TI - Proceedings of the International Workshop on Adolescents and Young Adults with Cancer: Towards Better Outcomes in Canada. Toronto, Ontario, Canada. March 11-13, 2010. PMID- 21695813 TI - Abstracts of the Association of Breast Surgery Conference & AGM. May 16-17, 2011. PMID- 21695814 TI - Transcriptional unification of heart morphogenesis. Proceedings of the Second Annual Riley Heart Center Symposium on Cardiovascular Development. September 13 15, 2009. Indianapolis, Indiana, USA. PMID- 21695815 TI - Proceedings of the National Conference on Emerging Trends in Biochemistry and a Satellite Symposium of the Academy of Environmental Biology (AEB). January 23-24, 2010. Allahabad, India. PMID- 21695816 TI - Promoting health and development: closing the implementation gap. Proceedings of the 7th Global Conference on Health Promotion. October 26-30, 2009. Nairobi, Kenya. PMID- 21695817 TI - Info-fusion: utilization of multi-source data. Proceedings of the Twelfth Biennial Symposium on Statistical Methods. Decatur, Georgia, USA. April 6-8, 2009. PMID- 21695818 TI - Proceedings of the 14th International Conference on Research in Computational Molecular Biology (RECOMB 2010). August 12-15, 2010. Lisbon, Portugal. PMID- 21695819 TI - A life of its own: where will synthetic biology lead us? PMID- 21695820 TI - Nightmare scenario: can we learn to rewrite our bad dreams? PMID- 21695821 TI - Either/or: sports, sex, and the case of Caster Semenya. PMID- 21695822 TI - Unveil the potential function of CD in surfactant systems. AB - CDs may have promising functions in surfactant systems far beyond simply being disadvantageous to the formation of micelles. In this paper we review the recent literature and our work on the interesting effect of CDs on amphiphilic systems, especially on the concentrated single surfactant systems and catanionic surfactant mixed systems, both of them have been scarcely focused upon in the literature. In concentrated single surfactant systems, the 2:1 surfactant-CD inclusion complexes may form hierarchical self-assemblies such as lamellae, microtubes, and vesicles which are driven by hydrogen bonding. In nonstoichiometrically mixed catanionic surfactant systems, CDs behave as a stoichiometry booster that always selectively binds to the excess component so as to shift the mixing ratio to electro-neutral in the aggregates. In this way, CDs reduce the electrorepulsion in the aggregates and trigger their growth. Upon analysis of literature work and our own results, we expect that a new era focusing on the new function of CDs on surfactant systems will come. PMID- 21695823 TI - Culture evolves. Proceedings of a discussion meeting of the Royal Society and the British Academy. June 30, 2010. London, United Kingdom. PMID- 21695824 TI - Proceedings of the Fourteenth Adrenal Cortex Conference (Adrenal 2010) and Keith L. Parker Memorial Symposium. June 16-18, 2010. San Diego, California, USA. PMID- 21695825 TI - An update on ACL injury risk and prevention. Proceedings of the ACL Research Retreat V. March 25-27, 2010. Greensboro, North Carolina, USA. PMID- 21695826 TI - Proceedings of the Second World Congress of Agroforestry. August 2009. Nairobi, Kenya. PMID- 21695827 TI - Abstracts of the 17th Pediatric Rheumatology European Society Congress. Valencia, Spain. September 9-12, 2010. PMID- 21695828 TI - Special issue in memory of the life and legacy of William R. Markesbery, M.D. PMID- 21695829 TI - Proceedings of the 14th International Workshop on Quantitative Structure-Activity Relationships in Environmental and Health Sciences (Part 2). May 24-28, 2010. Montreal, Canada. PMID- 21695830 TI - Proceedings of the Threat-detection and Vigilance Workshop. June 17-20 2009. Stellenbosch, South Africa. PMID- 21695831 TI - Exploiting genome-wide association in oilseed Brassicas: a model for genetic improvement of major OECD crops for sustainable future farming. Proceedings of an international conference. November 9-12, 2009. Crawley, Western Australia, Australia. PMID- 21695832 TI - Mimicking red blood cells for drug delivery. PMID- 21695833 TI - Titania on the brain. PMID- 21695834 TI - Topical diclofenac for sprains? These doctors say No. PMID- 21695835 TI - Combining microfluidics with nanocrystals for clinical diagnostics. PMID- 21695836 TI - Viral hepatitis: progress and promise. PMID- 21695837 TI - Testing, testing: the health-care bill has no master plan for curbing costs. Is that a bad thing? PMID- 21695838 TI - Viral hepatitis: Impact of adherence to combination therapy for hepatitis C. AB - Combination therapy for chronic hepatitis C is associated with adverse effects that can lead to dose reduction or even discontinuation of treatment. A prospective, real-time, observational study by Marcellin and colleagues provides useful information for physicians regarding the role of patient adherence in tailoring patient management and optimizing treatment outcomes. PMID- 21695839 TI - The iceman: what the leader of the cryonics movement is really preserving. PMID- 21695840 TI - Russell bodies in light chain multiple myeloma. PMID- 21695841 TI - Managing patients with hepatitis-B-related or hepatitis-C-related decompensated cirrhosis. AB - Treatment of patients with hepatitis-B-related or hepatitis-C-related decompensated cirrhosis should focus on controlling the complications of cirrhosis, surveillance for hepatocellular carcinoma and, if applicable, preparation for orthotopic liver transplant. Interferon-based regimens for the treatment of hepatitis C have been somewhat successful in patients with cirrhosis, although treatment of patients with decompensated cirrhosis should be approached with caution. Given the potential for exacerbation of decompensation and poor tolerance of adverse effects, treatment should be reserved for those patients awaiting liver transplantation. Eradication of HCV before liver transplantation reduces the chances of recurrent hepatitis C infection after transplant. HBV can be treated with few adverse effects in patients with decompensated cirrhosis. This treatment is associated with improvement in decompensation in some patients. Hepatocellular carcinoma remains a significant risk in all patients with cirrhosis, and control of or eradication of HBV or HCV does not remove this risk. PMID- 21695842 TI - The plastic panic: how worried should we be about everyday chemicals? PMID- 21695843 TI - Medical biochemistry in everyday clinical praxis. PMID- 21695844 TI - Atlantic consumption of French rum and brandy and economic growth in the seventeenth- and eighteenth-century Caribbean. AB - Why did the production of rum in the French West Indies not achieve the same success within the French Atlantic as it did in the British Atlantic world? Surveying the history of rum production in the French Caribbean in the seventeenth and eighteenth centuries, this article contends that the reason why no regional trade in rum developed in French North America resulted from fierce industrial and institutional competition from brandy producers in metropolitan France. Rum, nevertheless, remained significant within the culture and economy of Native Americans and African Americans. This article seeks to add nuance to the wider debate of the ability of the trans-border diffusion of new ideas to stimulate and institutionalize industrial and economic growth in the Atlantic world. French entrepreneurs were no less 'entrepreneurial' than their British counterparts, but real constraints on consumption on both sides of the Atlantic created insufficient demand. PMID- 21695845 TI - "Measuring by the bushel": reweighing the Indian Ocean pepper trade. AB - Of all the oriental spices, black pepper was the most important until the eighteenth century. The historiography of the pepper trade is characterized by a strong focus on Europe in terms of both its economic significance in the ancient and medieval periods and the struggle for its control in the early modern period. This article, by contrast, seeks to situate the pepper trade firmly in its Asian contexts. It examines the Indian Ocean pepper trade from three perspectives. First, it places the trade in its supply-side context by focusing on the Malabar coast as the primary source of pepper. Second, it examines the relative importance of the different branches of Malabar's pepper trade and highlights the central role played by Muslim mercantile networks. Third, it considers the reconfiguration of these pepper networks in the sixteenth century in the face of aggressive competition from the Portuguese. In their sum, these arguments advocate the need for rethought balances of trade and a reweighted scholarly focus on the pepper trade in its global dimensions. PMID- 21695846 TI - [PCEA and IVPCA for acute postoperative pain management]. PMID- 21695847 TI - [Molecular mechanisms and clinical pharmacology of chronic pain]. PMID- 21695848 TI - [Update on acute lung injury]. PMID- 21695849 TI - [Potentials for differential block with local anesthetics]. PMID- 21695850 TI - [Understanding mechanism of upper airway obstruction]. PMID- 21695851 TI - Ask the doctor. A hospital in the area is advertising robotic surgery. Is it really any better than having a surgeon do the operation? PMID- 21695852 TI - Ask the doctor. For several years, I have been taking warfarin because of atrial fibrillation. I recently suffered several nosebleeds, which took two days to control. The trauma of those episodes makes me want to swear off warfarin, but I am not sure what other options I have. PMID- 21695853 TI - Ask the doctor. I think I may have cataracts. I heard somewhere that they need to be ripe before I get surgery. Is that true? PMID- 21695854 TI - Ask the doctor. I recently had a nuclear stress test and contrast agent got stuck in my gut, so the image couldn't be read. Is this a common problem, and is there anything that can be done about it? PMID- 21695855 TI - Ask the doctor. Why does the nose run in cold weather? PMID- 21695856 TI - Cut salt--it won't affect your iodine intake. Iodized salt provided only a small fraction of daily iodine intake. PMID- 21695857 TI - Specialized care improves stroke survival. If you are having a stroke, a stroke center may be the place to go. PMID- 21695858 TI - Weight-loss surgery can help--and harm--the heart. Understand the risks and limitations before embarking on this last-ditch option. PMID- 21695860 TI - The shape of cardiovascular risk. PMID- 21695859 TI - Who needs and implantable cardioverter-defibrillator? ICDs save lives, but sometimes medications and other options make more sense. PMID- 21695861 TI - Ask the doctor. One day while I was gardening, I either slipped, hit my head, and passed out, or I passed out, fell, and hit my head. Since we couldn't tell, my doctors recommended I get a defribillator as "insurance" in case a heart rhythm problem was the cause. I have had the defribillator for eight years now, and it has never gone off. The battery is almost done and my doctor wants to put in a new battery. At age 86, I'd rather not have the procedure, the routine checkups are a hassle, and all of this is expensive. Could I just let the battery run down, then either leave the device in place or have it taken out? PMID- 21695862 TI - Ask the doctor. My doctor told me I have pericardial effusion. I know it has something to do with fluid in the heart. Can you tell me more? PMID- 21695863 TI - [Public health practice in Croatia today]. PMID- 21695864 TI - [Public health policy in developing countries and international relations]. PMID- 21695865 TI - [Ebola and Marburg hemorrhagic fever viruses: update on filoviruses]. AB - The Ebola and Marburg viruses are the sole members of the Filoviridae family of viruses. They are characterized by a long filamentous form that is unique in the viral world. Filoviruses are among the most virulent pathogens currently known to infect humans. They cause fulminating disease characterized by acute fever followed by generalized hemorrhagic syndrome that is associated with 90% mortality in the most severe forms. Epidemic outbreaks of Marburg and Ebola viruses have taken a heavy toll on human life in Central Africa and devastated large ape populations in Gabon and Republic of Congo. Since their discovery in 1967 (Marburg) and 1976 (Ebola), more than 2,300 cases and 1,670 deaths have been reported. These numbers pale in comparison with the burden caused by malnutrition or other infectious disease scourges in Africa such as malaria, cholera, AIDS, dengue or tuberculosis. However, due to their extremely high lethality, association with multifocal hemorrhaging and specificity to the African continent, these hemorrhagic fever viruses have given rise to great interest on the part not only of the international scientific community but also of the general public because of their perceived potential as biological weapons. Much research has been performed on these viruses and major progress has been made in knowledge of their ecology, epidemiology and physiopathology and in development of vaccine candidates and therapeutic schemes. The purpose of this review is to present the main developments in these particular fields in the last decade. PMID- 21695866 TI - [Hydatid cyst of the heart: fatal outcome]. PMID- 21695867 TI - [Drainage basin of the the Senegal River, sanitary conditions in 2010. Part I: Illnesses directly linked to the water]. AB - Recent decades have seen an increase in the number of cases of waterborne illnesses involving humans and animals living in the Senegal River Basin. The "Senegal River Basin Development Authority" (French acronym, OMVS) decided to draft a "Water Development and Management Master Plan" (French acronym, SDAGE) for the Senegal drainage basin. The aim of ther plan is to avoid overuse of natural resources while allowing development of human activities in the area of the Senegal River. The SDAGE was designed to serve as a timetable and program for mobilizing resources and monitoring impact on the environment and local population until 2025. As part of the initial phase of the SDAGE, a study was carried out in 2009 to evaluate the status of waterborne illness in the Senegal River Basin. This study of the sanitary conditions was based on review of documents compiled from a bibliographic search. The purpose of this report is describe the main findings regarding diseases directly linked to water and national or regional programs for control of those disease in the study area. PMID- 21695868 TI - [Nifurtimox, a bright future for treatment of Chagas disease]. AB - Nifurtimox is one of the two molecules used for treatment of Chagas disease. Although posology has not yet been clearly defined, nifurtimox is increasingly used, especially in combination with eflonithin. Nifurtimox is perfectly suited to the WHO's Chagas disease eradication program. PMID- 21695869 TI - [Molecular diagnosis of acquired human immunodeficiency virus (HIV) in pooled plasma from blood donors at the Regional Blood Transfusion Center in Ouagadougou, Burkina Faso]. AB - STUDY OBJECTIVES: The aim of this pilot study was to investigate the use of viral genome diagnosis of HIV-1 infection in blood donors in the regional blood transfusion center in Ouagadougou, Burkina Faso. METHODOLOGY: This prospective study was carried out from August to December 2009 at the regional blood transfusion center in Ouagadougou (RBTC-O). Detection of HIV-1 was performed by RT-PCR on pooled plasma and individual samples from blood donors. Samples were selected based on reactivity with fourth generation ELISA. RESULTS: ELISA assays on 20 plasma pools demonstrated 10 negative samples, 8 positive and 2 undeterminable. All positive and negative ELISA tests were confirmed by RT-PCR. Findings of RT-PCR on individual samples confirmed those obtained on pooled plasma samples. For the two undeterminable pools, RT-PCR identified one as negative and the other as positive. Individual RT-PCR testing of donations contained in positive and negative pooled plasma samples confirmed negative or positive findings. CONCLUSIONS: Because of the high cost of RT-PCR, we recommend use first on minipools or individual samples from blood donors with questionable HIV-1 status to confirm status quickly and minimize loss of blood bags. PMID- 21695870 TI - [HIV prevalence, associated risk factors and evolution among truck drivers from 2001 to 2007 in Guinea]. AB - OBJECTIVE: The purpose of this study was to estimate correlation between HIV prevalence and behavior at risk for infection among truck drivers in Guinea and to report the trends of these indicators from 2001 to 2007. METHODS: A total of 313 truck drivers in 2001 and 600 in 2007 were selected, interviewed and then tested for HIV infection. Data were analyzed with SAS Windows 9.2. RESULTS: The prevalence HIV was 7.0% in 2001 and 5.3% in 2007 (p=0.30). Seroprevalence was positively correlated with monogamous marital status [prevalence ratio (PR)=10.00; p=0.02] in 2001, absence from home for longer than a month (PR=2.06; p=0.03), international hauls (PR=2.39; p=0.01), and alcohol consumption (RP=2.00; p=0.04) and negatively correlated with the ability to abstain in risk situations (PR=0.35; p=0.01) in 2007. Comparison of responses obtained in 2001 and 2007 showed a decrease in the number of casual sex partners (p<0.0001) and an increase in condom use (p<0.0001). Comparison also showed a decrease in the number of drivers who reported receiving counseling about HIV/AIDS from NGOs, state health care services and schools (p<0.0001). CONCLUSION: These two surveys showed high HIV prevalence among Guinean truck drivers in both 2001 and 2007. Condom use increased between 2001 and 2007 but remained inadequate. The correlation between monogamous marriage observed in 2001 was not found in 2007 but other risk factors such as alcohol consumption, prolonged absence from home, and international hauls were observed. The ability to abstain from sex in risk situations was associated with lower seroprevalence. During the study period, a decrease was observed in the number of truck drivers who reported receiving HIV/AIDS counseling from NGOs, state health care services, or schools. Prevention activities against HIV/AIDS must be reinforced in this high-risk population. PMID- 21695871 TI - [Impact of mid-level management and support on the performance of a district health system in the Democratic Republic of the Congo]. AB - INTRODUCTION: The aim of this study was to assess the contribution of mid-level management and support practices to the overall performance of a district healthcare system. METHODS: This case study was carried out in the North Kivu Province of the Democratic Republic of the Congo. It was based on analysis of (i) preventive and curative healthcare services and (ii) management and support practices provided from 2000 to 2008. RESULTS: In response to recurring sociopolitical unrest since 1992, the mid-level health system (provincial level) in North Kivu has strengthened management and support practices. The main goals have been to optimize allocation of interventions by external emergency organizations and integration of specialized program activities, to harmonize intervention techniques implemented by external partners, to standardize supervision of sanitary districts with regard to care provider skills, and to adapt strategic options defined by the Ministry of Health to the provincial level. Using this comprehensive approach, the performance of the North Kivu Province in terms of curative and preventive care has exceeded the national average since 2001. Between 2001 and 2008, use of curative services progressed from 0.36 to 0.50 new cases/capita/year. Positive results have also been recorded for infrastructure coverage, essential medicine stock, health information system, and emergency preparedness. CONCLUSION: Stronger mid-level management and support practices have improved care activities in the health district while protecting the population from unstructured interventions by emergency organizations or specialized programs. A comprehensive management approach has also improved the resilience of the district and increased its contribution to Millennium Development Goals. PMID- 21695872 TI - [Results of a survey to evaluate the efficacy of a regional awareness campaign on counterfeit street medicines in Bamako, Mali and Nouakchott, Mauritania]. AB - The purpose of the report is to describe the results of a survey conducted among schoolchildren in Mali and Mauritania to evaluate the efficacy of an awareness campaign (essentially poster-based) on illegal street medicines. Under teacher supervision, a total of 3,182 schoolchildren (n=) completed a written questionnaire. Analysis of responses demonstrated that campaign was effective since 61% of the pupils had seen the posters in pharmacies and 61% had spoken about them with their parents. More than 84% of the pupils had already heard about the dangers associated with illegal medicine. Despite a number of disparities especially with regard to the price and dangers of illegal street medicine, the schoolchildren were knowledgeable about rules of conservation and outlets for purchase of legal medicine. The responses obtained from schoolchildren from Nouakchott and those attending private schools were generally better than those obtained from schoolchildren from Bamako and those attending the public schools. PMID- 21695873 TI - [Epidemiologic and medico-clinical aspects of the cholera outbreak in the Littoral department of Benin in 2008]. AB - OBJECTIVE: The purpose of this study was to determine epidemiological and medico clinical features of the cholera outbreak that occurred in the Littoral department of Benin in 2008. METHODS: This cross-sectional descriptive analytic study was based on review of a total of 404 patient files. Study data included patient identity, clinical and therapeutic features and treatment outcome. Ten randomly selected patients participated in a focus group discussion. Decision makers in charge of managing the outbreak and medical personnel that provided care were thoroughly debriefed and 10 affected areas were visited. Data were analyzed using EPI INFO 3.3.2 and EXCEL 2007. RESULTS: The outbreak started in Cotonou on 26 July 2008 and lasted for 21 weeks. Mean patient age was 23.72 +/- 14.80 years. Attack rates per district ranged from 15.86 to 172.98 per 100.000. Attack rates in Agbodjedo, Hlacomey and Enagnon districts were significantly higher (p<10(-4)) than in other districts. The case fatality rate was 0.24 per 100. Crowded living conditions along the banks of the Cotonou lagoon along with poor sanitation and inadequate drinking water supply explain the endemicity of cholera in Cotonou. Vibrio cholerae O:1 was detected in 19 out of 36 stool samples. All strains were sensitive to ciprofloxacine but resistant to cotrimoxazole. Diarrhea was a consistent feature in all patients, along with vomiting in 88.11% and severe dehydration in 39.35%. Treatment involved oral rehydration, parenteral rehydration and antibiotherapy in 99.50%, 85% and 97.77% patients respectively. Antibiotherapy consisted of doxycycline for adult cases and amoxicilline for pregnant women and children. The duration of stay at the treatment center was significantly longer for patients with severe dehydration (p<10(-4)). CONCLUSION: Enhancing basic sanitation and access to drinking water and intensifying information campaigns on the need for healthy living behavior especially in districts located near the banks of Cotonou lagoon are needed to improve cholera prevention in the Littoral department in Benin. PMID- 21695874 TI - [Bacterial dermohypodermitis and necrotizing fascitis: 104-case series from Togo]. AB - The purpose of this retrospective study was to obtain data on the epidemiology, clinical features, and outcome of bacterial dermohypodermitis (BDH) observed in a hospital setting hospital in Lome, Togo. Cases of BDH treated in dermatology and internal medicine of the Lome university hospital center from January 1999 to December 2009 were reviewed. A total of 104 patients were hospitalized for BDH during the study period. Mean patient age was 42.9 +/- 16.1 years and sex ratio (M/F) was 0.89. Infection by HIV was detected in 10 of 37 patients in whom serology was performed. The site of erysipelas was located on the legs and feet in 93 cases (89.4%), entire lower limb in 4 (3.9%), upper limbs in 4 (3.9%), thighs in 2 (1.9%), and buttock in 1 (0.9%). The main local and systemic risk factors were existence of an entry site in 89 cases, use of depigmenting drugs in 11, HIV infection in 10, previous history of erysipelas in 9 cases, and lymphoedema in 8. First-line treatment used penicillin G in 90 cases. Seven patients presented necrotizing fasciitis. Necrotizing fasciitis was associated with HIV infection in 2 cases, use of non-steroidal anti-inflammatory drugs (NSAID) in 2, and use of depigmenting drugs in one. Two deaths were recorded in the necrotizing fasciitis group including one HIV-infected patient. Recurrence was observed in 8 patients and secondary complications such as lower limb elephantiasis occurred in 7 patients. PMID- 21695875 TI - [Early resumption of food intake after cesarean section in black African women: liquid versus solid food]. AB - OBJECTIVE: The purpose of this study was to compare the effects of early resumption of solid versus liquid food intake after emergency cesarean section in black African women, in terms of gastrointestinal complications and maternal satisfaction. PATIENTS AND METHOD: A total of 120 patients were randomly distributed into two groups of 60 each. In group L, liquid food intake in the form of sweetened citronella drink was allowed at will starting 6 six hours after the procedure but no solid food was allowed for 24 hours. In group S, normal solid food intake was resumed six hours after the procedure. The two study groups were not significantly different with regard to age, medical history, ASA class, obstetrical status, indications for cesarean section, anesthetic protocol, mean procedural duration, and postoperative analgesia. Study variables included tolerance of food intake, gastro-intestinal complications, time necessary to resume full activity and patient satisfaction. RESULTS: Overall, 6% of patients reported complications involving nausea, vomiting and bloating. There was no statistical difference between the two groups. Normal intestinal transit resumed earlier in group S but the difference was not significant. Auscultation of the abdomen at 16 hours after the procedure demonstrated presence of peristalsis in 59 patients in group S and 51 in group L (p = 0.008). The maternal satisfaction rate was 92% in group S and 43% in group L (p <0.01). All dissatisfied patients said that they would opt for solid food in case of future cesarean. CONCLUSION: Early solid food intake after cesarean in black African women is as well tolerated as early liquid feeding. Resumption of solid food intake allows earlier rehabilitation and improves patient satisfaction. PMID- 21695876 TI - [Detection of Mycobacterium ulcerans DNA in water bugs collected outside the aquatic environment in Benin]. AB - Hosting of Mycobacterium ulcerans by water bugs is now well established and their vectoring role has been demonstrated experimentally. These findings were recently corroborated by detection of viable bacilli in the saliva of wild water bugs. However, the extent of water bug involvement in M. ulcerans ecology remains unclear and difficult to evaluate due to lack of understanding about water bug biology. The purpose of this study is to describe the first detection of M. ulcerans DNA in the tissue of water bugs captured outside the aquatic environment. This finding supports the hypothesis that water bug migratory behavior contributes not only to the spread of M. ulcerans but also to transmission outside the aquatic environment. PMID- 21695877 TI - [Colonoscopic perforation: 6 cases in Abidjan, Cote d'Ivoire]. AB - OBJECTIVES: The purpose of this report is to describe diagnostic and therapeutic management of colonoscopic perforation and identify risk factors. MATERIAL AND METHODS: The charts of 6 patients who underwent surgery for colonoscopic perforation between January 2003 and December 2008 were reviewed. Study data included patient age, indication for colonoscopy, operative findings, repair technique, and outcome. RESULTS: All 6 perforations occurred during diagnostic colonoscopy. There were 5 females and 1 male. Endoscopy was performed by an experienced operator in 5 cases and by a training fellow in 1. Preparation of the colon was considered as good in 5 cases. The operator reported procedural problems in only 1 case. Diagnosis of perforation was immediate in 5 cases and delayed for 30 hours in 1. The lesion was located in the sigmoid colon in 5 cases and transverse colon in 1. All patients underwent laparotomy. The repair technique consisted of simple closure in 2 cases, closure with colostomy in one, and bowel resection with anastomosis (n=2). Two deaths occurred intraoperatively in I case and postoperatively in 1. The patient who died intraoperatively had not yet undergone repair when death occurred. In both patients who died, laparotomy was performed late in the presence of co-morbidity. CONCLUSION: Colonic perforation is a rare but severe iatrogenic complication following colonoscopic examination. Early recognition and treatment are essential to optimize outcome. Prevention depends on training to obtain skillful advancement technique. PMID- 21695878 TI - [Cryptococcal meningitis in children: description of 3 cases]. AB - Cryptococcal meningitis is much less common in children than adults. The purpose of this report is to describe 3 cases of cryptococcal meningitis observed in children admitted to the Neurology Department of the Fann University Hospital Center in Dakar, Senegal between July 2003 and November 2008. There were 2 girls whose ages were 8 and 15 years and one 9-year-old boy. All 3 patients presented acute or chronic meningoencephalitis. Diagnosis was based on direct microscopic examination of India ink preparations of cerebrospinal fluid (CSF) showing Cryptococcus neoformans at direct exam. Two patients were immunocompromised including one presenting severe protein-caloric malnutrition and one infected by HIV-1. The third patient was immunocompetent. All 3 patients were treated by intravenous Fluconazole. The immunocompetent boy died after 1 month of hospitalization due to cardiovascular and respiratory insufficiency. Both girls survived with severe neurosensory sequels. Cryptococcal meningitis that is relatively frequent in adulthood may be underestimated in children and should be tested for in any children presenting meningoencephalitis of undetermined cause. PMID- 21695879 TI - [Unusual presentation of mycetoma caused by Actinomadurella pelletieri on the scalp]. AB - INTRODUCTION: Mycetoma is chronic inflammatory process characterized by areas of tumefaction with draining sinus tracts. It affects the foot in 80% of cases. The purpose of this report is to describe a case that posed a diagnostic challenge due to unusual scalp location and clinical presentation. OBSERVATION: A 23-year old woman residing in a rural zone of Senegal consulted for indolent lesions ongoing on the scalp for 2 years. Physical examination showed two soft tumid lesions measuring about 3 cm in diameter on the vertex. The surface of the lesions was crusty but showed no sign of granules. Skull x-ray was normal. Skin biopsy demonstrated a polymorphous granulomatous infiltrate with foci of suppuration circumscribing small, irregular grains with radiating filaments. Mycological culture on Lowenstein medium demonstrated Actinomadurella pelletiere. Treatment with cotrimoxazole for 8 months led to significant regression of the lesions. DISCUSSION: The mycetoma described in this report posed a diagnostic challenge because of its unusual scalp location and especially its tumoral or pseudo-cystic presentation. This clinical form of mycetoma must be taken into account for diagnosis in any patient from endemic areas. PMID- 21695880 TI - [Acute respiratory distress syndrome caused by tropical eosinophilic lung disease: a case in Gabon]. AB - The purpose of this report is to describe the case of a 28-year-old woman in whom acute respiratory distress syndrome (ARDS) following cholecystectomy led to the discovery of eosinophilic lung disease. Outcome was favorable after oxygenotherapy and medical treatment using ivermectin and corticosteroids. The case shows that hypereosinophilic syndrome can be the underlying cause of ARDS. PMID- 21695881 TI - [Enterocutaneous fistula caused by strangulated groin hernia: five cases in Morocco]. AB - The purpose of this report is to describe 5 cases of strangulated hernia discovered in patients presenting with enterocutaneous fistula. Most patients were women with small femoral hernias. PMID- 21695882 TI - [Renal amyloidosis: uncommon complication of sickle cell disease]. AB - Type AA amyloidosis is a rare complication of sickle cell anemia. The purpose of this report is to describe the case of a 30-year-old man with heterozygous sickle cell disease who was referred to our unit with nephritic syndrome and microscopic hematuria. Light microscopy on a renal biopsy specimen demonstrated AA amyloidosis. After elimination of other causes, it was concluded that amyloidosis was the result of recurrent acute inflammation secondary to sickle cell disease. To our knowledge, this is the fifth that renal amyloidosis as a complication of sickle cell disease has been described in the literature. PMID- 21695883 TI - [Acute occlusion with fever in a Tunisian woman]. AB - The purpose of this report is to describe a case of idiopathic segmental infarction of the great omentum, in a Tunisian woman, who presented with acute right hypchondrial pain simulating cholecystitis. Abdominal CT scan is the modality of choice. If symptoms resist medical treatment or complications occur, laparoscopic excision is the best therapeutic technique. PMID- 21695884 TI - [Fatal erythroderma in a young Moroccan]. AB - The purpose of this report is to describe a case involving a young Moroccan who abruptly developed pruritic papulo-vesicular lesions with erythroderma. Secondary development of jaundice and tumoral syndrome lead to diagnosis of an acute form of adult T-cell leukemia/lymphoma associated with HTLV-1 infection. The patient died within three months. To o ur knowledge, this is the first such case reported in Morocco. PMID- 21695885 TI - [Socioeconomic impact of armed conflict on the health of women and children in the Democratic Republic of the Congo]. AB - Since 1996, the Democratic Republic of Congo (DRC) has been the theatre of armed conflict. More than 5.4 millions have died and 500,000 to 1,000,000 women have been raped. As a result of permanent insecurity including frequent massacres, burning of villages and plundering of personal property and crops, millions of Congolese people especially in eastern regions have been displaced with around 1.3 million in internal refugee camps. Rural populations have abandoned farming that was the main source of employment, food, and income. The purpose of this paper is to describe the socioeconomic impact of this armed conflict particularly on the health of women and children. Consequences include i) decreased food production, ii) worsening food insecurity and malnutrition, iii) reduced household income, and iv) inadequate health care leading to epidemic outbreaks of diseases such as cholera, measles, and meningitis. Food insecurity and poverty affect around 70% of the population. Chronic malnutrition and growth retardation affect 38% of children. The mortality rate for children under 5 has reached 205 per 1000 live births. Other than achieving lasting peace that is a prerequisite for development in the DRC, the main priority must be to provide victims with multiform assistance aimed at restarting the economy and ensuring food self sufficiency, thereby reducing both malnutrition and child mortality. Better access to healthcare and to psychosocial, medical, and legal services is also needed for rape victims. PMID- 21695886 TI - [Psychosocial treatment of psychological post trauma in post-conflict countries]. AB - Violence and armed conflict situations besetting numerous developing countries inflict a heavy toll on populations, especially in terms of posttraumatic mental disorders. In addition to upsetting the well-being and psychic balance of people, violent political instability prevents development of the country as a whole not only economically but also individually and socially. After being confronted with this reality for years, humanitarian workers have implemented actions aimed at treating and helping traumatized people to recover their mental health as a first step to achieving effective and durable development. However, despite the availability of effective low-cost treatment for post-traumatic mental disorders, officials in developing countries as well as in international organizations continue to ignore or neglect this crucial issue. This article is based on a study carried out by "Crisis prevention and post-conflict unit" of the Agence Francaise de Developpement. The purpose is to underline the need and describe available methods for management of post-traumatic stress disorders in populations of post-conflict countries, as prerequisite for sustainable reconstruction and development. PMID- 21695887 TI - [Viral markers of hepatitis B, C and D and HB vaccination status of a health care team in a rural district of Cameroon]. AB - Ninety-three health care workers (HCW) in the Tokombere sahelian district volunteered to participate in a trial to investigate viral markers of hepatitis B, C, and D and HB vaccination status. METHODS: . Sera were tested using the Vikia HBsAg kit followed by CMIA for detection of HBsAg, anti-HBs, anti-HBc, and anti-HCV. HBsAg-positive HCW were tested for HBV-DNA, anti-HDV, and, if positive for anti-HDV, HDV-RNA. RESULTS: Analysis of anti-HBc positivity indicated that 91% of HCW had been infected by HBV, regardless of vaccination history. Vikia HBsAg results were confirmed by chemiluminescent microparticle immunoassay (CMIA) in all HCW and were positive in 17 HCW with virus load >2000 IU/mL in 6 and HDV co-infection in 6. Anti-HCV was found in 6 HCW. Among the 55 HCW that had not been vaccinated, only 3 needed vaccination because of anti-HBc negativity. Among HCW considered for HBV treatment, one patient presenting HBV/HDV co-infection was excluded after diagnosis of hepatocarcinoma. CONCLUSION: Systematic HB vaccination of new HCW appears unnecessary in this rural region of Africa. Anti HBc screening is cost-effective for identifying HCW requiring vaccination. Vikia HBsAg is effective for point-of-care screening. We underline the need for universal early (preferably neonatal) HB vaccination and for availability of anti HBV drug in limited-resource countries. PMID- 21695888 TI - [Comparative study of two anti-antiretroviral protocols used for treatment of a cohort of HIV 1-positive patients followed at the Institute of Public Health and Hygiene in Dakar, Senegal]. AB - In the last ten years, the discovery of several antiretroviral drugs has greatly contributed to improving the survival and quality of life of HIV-infected persons. The purpose of this retrospective study was to compare the effectiveness and tolerance of two anti-retroviral combinations, i.e., Lamivudine + Zidovudine and Efavirenz versus Lamivudine + Zidovudine and Nevirapine. The files of HIV1 infected patients treated between July 2003 and December 2004 (18 months) and followed at the Institute of public health and hygiene in Dakar were reviewed. A total of 70 patients, i.e., 35 in each protocol group, were included. The following data were collected for each patient: age, sex, locality, elements to assess tolerance, and elements to assess effectiveness (CD4 count, viral load and opportunistic infection immuno-failure). Results indicated that the immunovirologic effectiveness of the two protocols was identical with regard to mean CD4 count, i.e., 327 cells/mm3 for AZT+3TC+EFV versus 334 cells/mm3 for AZT+ 3TC+NVP (p < 0.05). Immuno effectiveness was better for Lamivudine + Zidovudine + Efavirenz than Lamivudine + Zidovudine + Nevirapine. Significant therapeutic advances in recent years have improved survival and quality of life in patients under retroviral treatment. There are currently many anti-retroviral molecules available and several relatively well codified therapeutic protocols. PMID- 21695889 TI - [Guillain-Barre syndrome following type 4 dengue in Polynesia]. AB - Dengue fever is the most frequent arbrovirus infection in the world. It is endemic in French Polynesia where epidemic outbreaks sometimes occur. The most common clinical presentation is that of a flu-like illness but hemorrhagic dengue fever can be observed in severe cases. Association of dengue fever with Guillain Barre syndrome (GBS) has been reported in a few cases. The relationship between these two pathologies is unclear but autoimmune mechanisms are probably involved. PMID- 21695890 TI - [Occupational exposure to syphilis during venous ulcer curettage in Martinique]. AB - The purpose of this report is to describe the first case of occupational exposure to syphilis. This accident occurred during curettage of a venous ulcer in a 68 year-old woman in Martinique Island. The patient presented primary syphilis without HIV. This case points out the need for enhanced syphilis screening in epidemic areas. PMID- 21695891 TI - [Mortality of neonatal surgical emergencies at the Gynecology-Obstetric and Pediatric hospital of Yaounde, Cameroon]. AB - From July 2005 to November 2009, 38 neonates with surgical emergencies died in the neonatal unit of the Gyneco Obstetric and Pediatric Hospital Yaounde. The mortality rate of these emergencies was 43.1%, and those within the age group of 1 to 7 days were the most affected with a sex ratio of 1.2. The mean delay before consultation was 3.7 days. Half of the neonates had a birth weight of less than 2,500 g and 7 cases (18.4%) were premature. A medicalised ambulance was used for transfer to our unit in only half of the neonates. The main disorders were those affecting the digestive tract in 42.1% of our series. In 50% of our cases, there were associated malformations and 28 cases (73.7%) did not undergo surgery. Malnutrition and infection were the main complications in 60% of the cases. The authors discuss this deplorable situation and suggest recommendations for improvement. PMID- 21695892 TI - [Human rabies towards better communication between public health and veterinarian services]. PMID- 21695893 TI - [Changes of serum lipids after soy isoflavone and calcium supplementation in postmenopausal Chinese women with different ER-beta genotypes]. AB - OBJECTIVE: To observe the change of blood lipids after one-year of soy isoflavone and calcium supplementation in postmenopausal Chinese women with different ER beta genotypes. METHODS: Sixty postmenopausal women with normal serum lipid levels but with bone loss or even osteoporosis were selected from Wuhan. The ER beta genotypes of subjects were identified. The subjects were randomly divided into two groups, group I was given 440 mg/d calcium and VD 100 IU/d and group II was given calcium 440 mg/d, VD 100 IU/d and soy isoflavone 100mg/d for one year. Serum lipids, including TG, CHO, LDL and HDL were measured before and 12 months after intervention. RESULT: Total cholesterol was decreased both in group I and group II (P <0. 05). The change of serum TG was significantly different between group I and group II in subjects with Rr/rr genotype (0. 20 +/- 0. 41 and 0. 44 +/- 0. 93, P <0. 05). CONCLUSION: Rational intervention with calcium and soy isoflavone for postmenopausal women might be in favor of their health in bone and blood lipids metabolism, but the effects might be varied by different ER-beta genotypes. PMID- 21695894 TI - [Effect of phenethyl isothiocyanate given at different duration of gestation on the outcome of pregnancy in rats]. AB - OBJECTIVE: To investigate the effect of phenethyl isothiocyanate (PEITC) on fetal development and embryotoxicity in rats. METHODS: Acute oral toxicity was conducted by Horn method. PEITC suspended in Tween-80 water was administered orally once a day to pregnant rats in the gestation day 0 -6 (pre-implantation) and 7 - 16 (post-implantation) at the doses of 15, 60 and 120 mg/kg, respectively. On the gestation day 16 or 21, the number of live fetuses, reabsorbed fetuses and implanted sites were counted. The placental weights, fetal weights and organ weights were also recorded. RESULTS: The LD50 of PEITC for female rats was 1.47 g/kg. The maternial body weight gain and the number of implanted and live fetuses were decreased with the increase of PEITC dosage given during pre-implantation period. There was also a dose-dependent effect of PEITC given during post-implantation period on fetal weight/growth and placental weight. No toxicity on the organ weight of pregnant rats was observed. CONCLUSION: Phenethyl isothiocyanate given at different duration of gestation exhibited some embryo-toxicity on pregnant rats, and the no observable adverse effect level was 15 mg/kg. PMID- 21695895 TI - [Variability in tellurite resistance and the ter gene cluster among Escherichia coli O157 isolated in food from 2005 to 2007]. AB - OBJECTIVE: To investigate the presence of tellurite resistance (ter) gene cluster and its resistance in Escherichia coli 0157 strains collected by national foodborn disease surveillance system from 2005 to 2007. METHODS: The ter gene cluster was tested by PCR. Tellurite resistance was evaluated by plate dilution method. RESULTS: Of the investigated 89 E. coli strains,the presence of ter gene cluster was found in 51 strains. They were separately from 41 of 42 E. coli O157: H7 strains,all of 6 strains of O157 : NM (non-mobile flicH7 positive) and only 3 of 41 O157: NM (flicH7 negative)/O157: hund strains. The 51 strains with ter gene cluster were resistance to the high level of potassium tellurite. The MIC was from 64-512 microg/ml. In contrast, the MIC of most of 38 strains without ter gene cluster was from 2-16 microg/ml. Only one strain was 128 microg/ml. 28 of 29 stx-positive E. coli isolates contained the ter gene cluster and had the high levels of tellurite resistance. CONCLUSION: E. coli 0157 from food had the diversity levels of tellurite resistance. The presence of the ter gene cluster had significant associated with the high levels of tellurite resistance. PMID- 21695896 TI - [Evaluation on intervention project of mental health promotion in paid blood donors with HIV/AIDS infected adults in Anhui countryside]. AB - OBJECTIVE: To evaluate the effect of intervention project of mental health promotion in paid blood donors with AIDS/HIV infected adults in Anhui countryside. METHODS: About 41 HIV/AIDS infected adults were invited to take part in the intervention project. The project was put into practice by ways of multimedia course and group participation with the handbook of mental health promotion intervention for HIV/AIDS infected adults. All participants (41 intervention objects and 21 control objects) completed an anonymous questionnaire before and after the intervention. Depression, anxiety, self-esteem and coping style were evaluated by Center for Epidemiologic Studies Depression Scale, Self Rating Anxiety Scale, Self-Esteem Scale and Simplified Coping Style Questionnaire. RESULTS: There were 35.5% of the 62 blood donors without taking any education. There were 46.7% of them need to partially or completely rely on government grants and loans. Before intervention the rates of depression and anxiety, the scores of positive coping, negative coping and self-esteem were not significantly different between study group and control group (P > 0.05). After intervention the rates of depression and anxiety in study group were lower than those in control group and with significant difference. The scores of positive coping and self-esteem in study group were higher than those in control group, but the score of negative coping was contrary to them (P <0.05). The mental health promotion interventions for blood donors with HIV/AIDS in rural take an active effect on their anxiety symptoms, depressive symptoms, coping style and self-esteem (P <0.05). Age was the influence factor for the intervention on depression, negative coping. Level of education was the influence factor for the intervention on depression, anxiety and self-esteem intervention. Gender was the influence factor for the intervention on positive coping. All objects reported that they liked the intervention project of mental health promotion and liked the interactive form of education. CONCLUSION: Psychological intervention to improve the response capacity and mental health of paid blood donors with HIV/AIDS infected adults in countryside has a good effect. This intervention might be extend to similar population on HIV/AIDS in rural. The influence factor of intervention effect on different psychological character are difference. PMID- 21695897 TI - [Study of neutralization antibodie induced by DNA vaccine of HCV envelope protein 2 in mice]. AB - OBJECTIVE: To explore the feasibility of induction of neutralization antibodies against hepatitis C virus (HCV) infection by HCV envelope 2 protein (E2) DNA vaccines immunization. METHODS: Two kinds of expression plasmids of HCV envelope 2 protein, plasmid pCI-1b661 Delta encoding hydrophobic carboxyl terminal truncated E2 and pCI-1b661 Delta encoding E2 with deletion of hypervariable region 1 (HVR1) and carboxyl terminal, were constructed and respectively transfeted 293T cells, and truncated E2 protein in whole cell lysate and supernatant of 293T cells were analyzed by Western blot. After BALB/c mouse were intramuscularly immunized by the plasmids, sera antibodies against HVR1 were detected by ELISA and the neutralization activity of the antibodies were assayed with HCV pseudotype particle (HCVpp). RESULTS: Both plasmids could express secretary truncated E2 protein. All the mice immunized with plasmid pCI-1b661 produced HVR1 antibodies,while no HVR1 antibodies were detected in pCI-1b661 Delta immunized mice. The sera neutralization percentages against HCVpp in pCI1lb661 Delta and pCI-lb661 Delta immunized mice were (78.5 +/- 13.8)% and (38.7 +/- 6.5)%, respectively (P <0.01). Sera neutralization activity against HCVpp was positive correlated with the level of HVR1 antibodies in pCI-1b661 immunized mice (r = 0.967, P<0.01). CONCLUSION: DNA vaccines expressing truncated E2 protein could induce neutralization antibodies against HCV, and neutralization antibodies mainly was consisted of the antibodies against HVR1. PMID- 21695898 TI - [Effects of lanthanum on the phosphorylation of cAMP response element binding protein and expression of immediate early genes in the hippocampal CA3 area of rats]. AB - AOBJECTIVE: To study the effects of lanthanum (La) on calmodulin (CaM) activity, phosphorylation of CaM dependent protein kinase IV (CaMK IV), cAMP response element binding protein (CREB) and expression of c-fos, c-jun and egrl in the hippocampal CA3 area of rats. METHODS: Forty Wistar rats in pregnancy were divided randomly into four groups: control, 0.25%, 0.5% and 1.0% LaCl3 administrated groups. After birth,pups of LaC13-administrated groups were administrated with La by lactation before weaning, and then given with La by drinking water for one month. CaM activity was determined by phosphodiesterase. The protein expression levels of p-CaMK IV and p-CREB were measured by Western blotting,and c-fos,c-jun and egrl mRNA expression levels were detected by RT-PCR. RESULTS: CaM activity and protein expression levels of p-CaMK IV and p-CREB in the hippocampal CA3 area of three LaC13-administrated groups were lower significantly than those of control group, and presented dose-effect relationship to a certain extent. The expression levels of c-fos and c-jun mRNA in the hippocampal CA3 area of low and middle LaCl3-administrated groups were lower significantly than those of control group,and the expression levels of egrl mRNA in the hippocampal CA3 area of middle LaCl3-administrated group were lower significantly than those of control and low LaC13-administrated groups. The expression levels of c-fos, c-jun and egrl mRNA in the hippocampal CA3 area of high LaCl3-administrated group were lower significantly than those of control, low and middle LaCl3-administrated groups. CONCLUSION: La could decrease CaM activity, CaMK IV and CREB phosphorylation, c-fos, c-jun and egrl mRNA expression in the hippocampal CA3 area and therefore cause learning and memory impairment of rats. PMID- 21695899 TI - [Effect of subchronic fluoride exposure on pathologic change and beta-catenin expression in rat bone tissue]. AB - OBJECTIVE: To explore the effect of subchronic fluoride exposure on the expression of beta-catenin in the bone of rats and the role of beta-catenin in skeletal damage. METHODS: Wistar rats were randomly divided into four groups. The rats were treated at the doses of 50, 100 and 150 mg/L F- in drinking water, and control rats were drunk tap water. The contents of fluoride in bone and serum were determined after three month. The expressions of beta-catenin were analyzed by real-time RT-PCR and immunohistochemistry. RESULTS: HE staining indicated that the compact bone was thicker and the trabecular bone increased in fluoride treated group in comparison with control group. The hypertrophic chondrocytes accumulated and arranged disordered in fluoride-treated rats. The expressions of p-catenin mRNA and protein expressions in bones of fluoride-treated rats were higher than those of control group. Immunohistochemistry indicated that beta catenins were mainly expressed by osteoblast and osteoclast. There was also positive staining in hypertrophic chondrocyte. CONCLUSION: It was suggested that beta-catenin could play important role in bone sclerosis of subchronic fluoride exposure. PMID- 21695900 TI - [Effects of some membrane lipids on the hemolysis induced by hemolytic toxin from Karenia mikimotoi]. AB - OBJECTIVE: To explore the effects of some membrane lipids on the hemolysis induced by hemolytic toxin from Karenia mikimotoi. METHODS: Effects of exogenous membrane lipids such as lecithin, sphingomyelin, L-alpha-phosphatidic acid,cholesterol and gangliosides on the hemolysis induced by the hemolytic toxin were observed. The sensitivities of some erythrocytes from different animals such as rabbit, rat and fish to the hemolytic toxin were evaluated. The total gangliosides in different erythrocytes membrane were detected by colorimetry. RESULTS: Only gangliosides significantly inhibited the hemolysis of the hemolytic toxin from K. mikimotoi (P <0.05). Hemolytic percentages decreased to 16.05% after 10 min addition of ganglioside, while those of control were 35.65%. The rabbit red blood cell was the most sensitive to the hemolytic toxin. The hemolytic percentages of rabbit erythrocyte were higher than those of rat (P < 0.05) and fish (P < 0.01). The amounts of lipid-bind sialic acid (LBSA) on frozen dried membrane of rabbit were 672.08 microg/g,and were higher than those of rat (585.97 microg/g) (P < 0.05) and that of fish (431.52 microg/g) (P < 0.01). CONCLUSION: Exogenous gangliosides could have a potent inhibition on the hemolysis induced by hemolytic toxin from K. mikimotoi. There was a significant correlation between the sensitivities of different erythrocytes to the hemolytic toxin and the amount of ganglioside on different erythrocytes membrane. PMID- 21695901 TI - [Effect of bisphenol A exposure on sex hormone level in occupational women]. AB - OBJECTIVE: To explore the effect of bisphenol A (BPA) exposure on sex hormone levels in occupational women. METHODS: 51 women workers with at least a year of BPA exposure and 104 women workers without BPA exposure were chosen to do a case; control study. The information in general population characteristics, exposure, menstruation state, etc and the venous blood samples on an empty stomach were collected for the two groups. The endocrine hormones levels of follicle stimulating hormone (FSH), prolactin (PRL) , progesterone (P), estradiol (E2), luteinizing hormone (LH) were detected by RIA analysis. RESULT: The PRL level in the BPA exposure group was significantly higher to that in the control group (t = 2.127, P = 0.047). It was found that the proportion of abnormal PRL in the exposure group was significantly higher to the control group (chi2 = 4.924, P = 0. 026). In the age class of more than 30 years, the proportion of abnormal PRL in the exposure group was significantly higher to the control group (chi2 = 5.131, P = 0.023) and the proportion of abnormal progesterone in the exposure group was significantly to the control group (chi2 = 4.665, P = 0.031)in the same age class. In the people of no taking vitamin, the proportion of abnormal PRL in the exposure group was significantly higher to the control group (chi2 = 6.541, P = 0.011). The proportion of abnormal progesterone in the group of less than 5 years exposure was significantly higher to the group of more than 5 years exposure (chi2 = 3.938, P = 0. 047). The multivariate analysis found that BPA exposure was the independent risk factor to effect serum PRL (OR = 2.623, P = 0.030) of occupational women. Effect of BPA on FSH, E2, LH level couldn't be found through this study. CONCLUSION: BPA occupational exposure of women maked PRL level set up and effected progesterone level. After adjusting for age, exposure age and other potential confounding factors, BPA exposure is an independent risk factor to arise the level of serum PRL in occupational women. PMID- 21695902 TI - [Identification and investigation of disease-related peptides in sera from patients with chronic hepatitis B]. AB - OBJECTIVE: To investigate disease related or pathogenic short peptides in sera from patients with chronic hepatitis B (CHB). METHODS: Seventy-six serum samples, including 26 from patients with mild CHB, 19 with moderate CHB, 31 with severe CHB were tested using Matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF MS) analysis. Effects of the identified peptides on human stellate cell and human normal hepatic cell were tested using sera containing the peptides and synthesized peptides. Quantitive real-time PCR were used to assay the expression of transforming growth factor-beta (TGFbeta1) and collagen I (COLI). RESULTS: Among the distinguished proteins of serum proteomics profile, moleculars of 1779 Da, 1691 Da, 1450 Da, 1866 Da appeared stable. The 1866 Da protein, which was identified as complement C3f des-arginine (DRC3f) by Liquid chromatograph MS/MS (LC-MS/MS). The fresh sera or filtrated sera containing DRC3f (F = 55.715 and 26.325 respectively, P <0.01) , as well as the synthesized peptides of DRC3f and C3f, could stimulate proliferation of human hepatic cell (F = 40.004 and 89.685 respectively, P <0.01). DRC3f could decrease expression of TGFbeta1 and COLI in hepatic cells. CONCLUSION: The DRC3f identified in this study may serve as a biomarker for severe degree CHB. PMID- 21695903 TI - [Effect of calcium supplementation on the regain of BMD in Chinese lactating women with 4 major combined ER genotypes]. AB - OBJECTIVE: To observe the regain of bone mineral density (BMD) in Chinese lactating women with 4 major combined ER genotypes (defined as Pvu II and Xba I). METHODS: A total of 160 healthy lactating women was selected, 40 women with each of 4 genotypes (ppxx, Ppxx, PpXX or PPXx) were divided into a calcium supplement group received 600 mg calcium (as CaCO3) daily, and a control group. BMD of lumbar spine and left hip were measured by dual energy X-ray absorption bone densitometry on 3 months and one year after delivery. Calcium intake was calculated from a 3 days dietary recall. RESULTS: Whether supplementing calcium or not, the BMD of these women increased obviously (P <0.05).The less BMD regaining at hip was observed in women with ppxx genotype than those with Ppxx or PPXx genotype (P <0.05) when 600 mg calcium was given daily. Calcium supplementation and the duration of lactation were significantly related to hip BMD via a stepwise linear regression analysis (the standardized coefficient was 0.227, and P value was 0. 007). CONCLUSION: Although the dietary calcium intake was low in Wuhan lactating women, the BMD of lumbar spine or of left hip of women with some genotypes was increased greatly by calcium supplementation. PMID- 21695904 TI - [Correlation of band 3 protein in erythrocytes with physiological status of middle-aged and elderly people]. AB - OBJECTIVE: To analyze the correlation of band 3 protein of erythrocytes with physiological conditions of middle-aged and elderly people, and to investigate the expression of band 3 protein under different physiological status. METHODS: Cluster randomized sampling method for selecting subjects . Physical examination data and blood samples of 218 middle-aged and elderly people (80 males and 138 females) were collected. SDS-polyacrylamide gel electrophoresis was used to analyze band 3 protein in erythrocyte membrane. The difference of band 3 protein in different groups was analyzed by T Test and One-Way ANOVA. Correlation and regression of band 3 protein with physiological status was analyzed by Pearson correlation and linear regression. RESULTS: There was a significantly positive correlation (r =0.149) between the level of band 3 protein and physical activity (P <0.05), and a negative correlation (r = -0.156) between the level of band 3 protein and systolic blood pressure (P <0.05). The correlation of band 3 protein with gender, age, BMI and diastolic blood pressure (P >0.05) is not significant. The band 3 protein level of workers with medium activity was 24. 09% , which was significantly higher than that of light activity workers (23.42%) (P <0.05). The subjects with hypertension were proved to have a significantly lower level of band 3 protein (23.33%) than normal individuals (24.20%) (P < 0.05). CONCLUSION: The level of band 3 protein was positively correlated with physical activity and negatively correlated with systolic blood pressure. PMID- 21695905 TI - [Investigation on the feeding status of infants and young children in poor counties of Gansu Province]. AB - OBJECTIVE: To understand the feeding status and the current situation of complementary food supplement of infants and young children aged 6-23 months in Yongjing County and Yuzhong County, two of poorer counties in Gansu Province. METHODS: A study was conducted by cluster sampling. The status of breastfeeding and complementary food supplement was surveyed by using questionnaires. RESULTS: A total of 836 infants and young children aged 6-23 months were investigated. The results showed that 18. 2% of infants received breastfeeding in the first hour after birth. The breastfeeding rate reached up to 84.1%, while the percentage of continuous breastfeeding for 12-15 months and 20-23 months was only 29.6% and 8.7%, respectively. The percentage of almost exclusive breastfeeding,mixed feeding and artificial feeding attained 42.7%, 41.4% and 15.9% ,respectively during the first 6 months after birth. Besides, the complementary food not supplemented in time was in 68.7% of infants, among which, 35.2% of infants were supplemented too early and 33.5% not in time. The diversity of complementary foods in 6-11 month-old infants was less than that in 12-17 and 18-23 month-old young children. The situation of complementary food supplement for meeting the minimum acceptable dietary level in breastfeeding infants was lower than that in non-breastfeeding infants. CONCLUSION: The exclusive breastfeeding rate was relatively low. The inappropriate addition of complementary foods in time, category and frequency were the main issues to be concerned. It was suggested that publicizing knowledge on infant feeding should be strengthened. PMID- 21695906 TI - [Life style interventions study on the effects of impaired glucose regulations in Shanghai urban communities]. AB - OBJECTIVE: To access the effects of life style interventions on impaired glucose regulation (IGR) in Shanghai urban communities, China. METHOD: Two communities were randomly cluster-sampled to be carried out epidemiological intervention trial. Totally, 232 subjects with IGR were randomly allocated into 4 groups: control group,sports intervention group, diet intervention group, and sports and diet intervention group with the physical examinations in the baseline and end of this study respectively. Tests for fasting blood glucose, OGTT, HbA1c, total cholesterol,etc. were done. Data statistical analysis was occupied in SPSS 16.0. RESULTS: Compared to subjects of control group,fasting blood glucose, OGTT, HbAlc,total cholesterol,BMI,waist hip ratio and blood pressures were significantly decreased among subjects with three interventions (P < 0.05). Triglyceride were significantly decreased among subjects with sports intervention and sports and diet intervention (P < 0.05). High density lipids was significantly increased among subjects with sports and diet intervention (P < 0.05). There was a significant difference in 6 months cumulative incidence of diabetes mellitus between control group and interventions groups (8.6% vs. 0, Fisher' s exact P = 0.002), and the rate of transferring into normal blood glucose levels (fasting blood glucose < 5.6 mmol/L and 2 hours OGTT < 7.8 mmol/L) in control group was lower than those in three interventions group (3.4% vs. 8.6%, 14.0% and 16.9%, respectively) but only significant difference was observed between control group and sports and diet intervention group (OR = 5.74, 95% CI 1. 19-27. 64, P = 0.029). CONCLUSION: The life style interventions could decrease the risk of diabetes mellitus, help their transferring into normal blood glucose, and improve diabetic measures for the IGR population in Shanghai urban communities. PMID- 21695907 TI - [Effectiveness of social mobilization and social marketing in promoting NaFeEDTA fortified soya sauce in adult women]. AB - OBJECTIVE: To assess the effectiveness of social mobilization and social marketing in promoting NaFeEDTA-fortified soy sauce in an iron deficient population. METHOD: This study was an uncontrolled, community-based, before-after study, which was implemented in three counties of Shijiazhuang Municipality. The intervention was a social mobilization and social marketing strategy. Adult women older than 20 years of age participated in the evaluation protocol. The main outcomes included KAP relevant to IDA. Cross-sectional samples were used to assess the outcomes at baseline and 1 year later. RESULTS: Knowledge and attitudes of adult women had changed positively, and the percentage of women who had adopted NaFeEDTA-fortified soy sauce increased from 8.9% to 36.6% (P < 0.001). CONCLUSION: Social mobilization and social marketing had a positive impact on the KAP of adult women in the iron deficient population. PMID- 21695908 TI - [Study on the social support condition and its influence factors among people living with HIV/AIDS]. AB - OBJECTIVE: To explore the current status of social support and its influence factors among people living with HIV/AIDS (PLWHAS). METHOD: The status of social support was measured by Social Support Rating Scale (SSRS). Related factors were collected by self-designed questionnaire and analyzed by multiple stepwise regression. RESULTS: 294 PLWHAS were selected as the subjects, whose average overall scores of social support were 27.16 +/- 8.04, and were lower than those of the normal. Increased with the growth of the age, PLWHAS tended to obtain less social supports (beta = -0.119) ,and increased with the education level, PLWHAS tended to obtain more social supports (beta = 0.108). PLWHAS with annual income per capita being equal or greater than 3000 yuan got higher score than their opposites (beta = 0.141). Out of job (beta = - 0.166) and living alone (beta = 0.305) were risk factors, while good relationship with family (beta = 0.356) and a stable marriage (beta = 0. 252) were protective factors associated with social support. CONCLUSION: The social supports of PLWHAS were lower and affected by multiple factors, which involved age, employment,education,income, the mode of living,relation with family, etc. PMID- 21695909 TI - [Thallium content in adults older than 45 ages at Hezhang County of Guizhou Province]. AB - OBJECTIVE: To investigate the feature of Thallium content in adults of heavy metal contaminated district due to mining of Hezhang County, Guizhou Province. METHODS The subjects older than 45 ages were randomly recruited from the mineralized district (Magu village) and no-mineralized district (Salaxi viillage) , urine of villagers were collected and thallium content in urine were detected with ICP-MS. RESULTS: The average thallium contents in urine of Magu villagers were higner than those of Salaxi villagers,The urinary thallium contents of female were higner than those of male. The urinary thallium contents of residents in two districts were mostly under the upper limit of exposure in human bodies. CONCLUSION: There was no villager suffered from chronic poisoning of thallium in the two observing districts, the 95% upper limits of urinary thallium content for nonoccupational women older than 45 ages in Magu village was 8 microg/gCr and those for other nonoccupational subjects older than 45 ages was 5 microg/gCr. PMID- 21695910 TI - [Environmental hazard factors for respiratory tract and eye symptoms of women in Ankang rural, Shaanxi Province]. AB - OBJECTIVE: To investigate the relationship between environmental risk factors and respiratory and eye symptoms of women in rural areas, so as to provide baseline data for the intervention of indoor air pollution. METHOD: A household survey on the environmental risk factors and the health of 1575 rural women was analyzed. RESULTS: After age and income being adjusted, the OR of smoking, passive smoking, no ventilation indoors, using both coal and biomass versus respiratory symptoms were 2.42, 1.35, 1.52 and 1.44. The OR of cooking years and the age of beginning to cook versus respiratory symptoms were 1.44 and 0.92. The OR of no ventilation indoors, using both coal and biomass versus eye symptoms were 1.67 and 1.49. The OR of cooking years and the age of beginning to cook versus eye symptoms were 1.56 and 0.92. The OR of increasing cooking time everyday versus eye symptoms was 1.36. CONCLUSION: Exposure to indoor air pollution during cooking time was the most significant environmental risk factor for the respiratory and eye symptoms in rural women. PMID- 21695911 TI - [Comparison study of enrichment-PCR and traditional method for detection of Salmonella in poultry]. AB - OBJECTIVE: To compare the sensitivity, specificity and timeliness of Salmonella in poultry detected by enrichment-PCR and traditional method. METHOD: Salmonella specific primers (PsalF-PsalR) were chosen on the basis of invA gene. PCR method was developed and its specificity was proved by 30 Strains of Salmonella standard and isolates,and 18 strains of non-Salmonella. Refering to GB4789.4--2010, artificially contaminated experiment was done,six artificially-inoculated samples containing final concentration of salmonella CMCC50041 (1, 10, 10(2),10(3), 10(4), 10(5) and 10(6) CFU/25 g poultry samples) were preparated respectively, meanwhile one sample without inoculation was as control of background value. All the samples were incubated at 37 degrees C for 0, 4, 8, 12 and 18 h, and Iml of culture solutions were taken from the samples to extract DNA, respectively. PCR and traditional methods were applied to detect Salmonella bacteria. Sixteen samples of retail whole poultry were collected from markets in Beijing and detected by the above two methods after enriching for 12 h in SC at 37 degrees C. RESULTS: PCR method established was stable and specific, as 30 Salmonella were detected positive and 18 non-Salmonella were negative. PCR detection limit for artificially contaminated samples after enriching for 12h was 1 CFU/25 g sample. Traditional method detection limit was 10 CFU/25 g samples. The time limits of enrichment-PCR were 4-6 days, shorter than those of traditional method. The positive rate out of total 16 market-sold samples was 43.75% (7/16) for enrichment-PCR,while the rate was 31.25% (5/16) for traditional method. CONCLUSION: Enrichment-PCR was simple, rapid, sensitive and specific in comparition with traditional method. It could be applied in fast diagnosis of food poisoning and actual food samples screening. PMID- 21695912 TI - [Irradiation effect of 60Co gamma ray on Aspergillus flavus spores in normal saline and maize]. AB - OBJECTIVE: To observe irradiation effect of gamma ray on Aspergilllus flavus spores. METHODS: Aspergillus flavus spores of different concentration were prepared on two media and were exposed to gamma ray. D10 values and theoretical minimal sterilizing doses were calculated by colony counting results. Actual minimal sterilizing doses were verified according to theoretical dose. RESULTS: D10 value and minimal sterilizing dose of high concentration spore in normal saline were 0.39 kGy and 2.5 kGy. Those of low concentration spore in normal saline were 0.47 kGy and 1.5 kGy. Dl0 value and minimal sterilizing dose of high concentration spore in maize were 0.67 kGy and 3.0 kGy. Those of low concentration spore in maize were 0.72 kGy and 2.0 kGy. CONCLUSION: 3.0 Gy may be suitable for grain processing to sterilize Aspergillus flavus. PMID- 21695913 TI - [Determination of sennoside A and sennoside B simultaneously in health food by HPLC]. AB - OBJECTIVE: To develop an analytical method for determination of sennoside A and sennoside B simultaneously in health food by high performance liquid chromatography (HPLC). METHODS: Samples were extracted by ultrasound extraction and determined by HPLC with a UV detector. Using a Synergi Hydro-RP (250 mm x 4.6 mm, 4 microm) column and a mixture of CH3CN: 1.0% CH3COOH (17:83) as mobile phase for separation. The detection wavelength was at 270 nm. The contents were calculated with an external standard. RESULTS: The linearity was good in the ranges of 1.40 - 28.0 microg/ml for sennoside A and 1.45 - 29.0 microg/ml for sennoside B. The average recovery rates of sennoside A and sennoside B were 85.2% -97.2% and 86.1% -96.2%. The RSD was 7.5% and 6.8%, the limit of detection was 0.8 mg/kg and 0. 6 mg/kg, and the limit df quantification was 2.1 mg/kg and 2.0 mg/kg for sennoside A and sennoside B respectively. CONCLUSION: The method is simple, accurate and suitable for the determination of sennoside A and sennoside B in health food. PMID- 21695914 TI - [Rapid analysis of L-carnitine in health food by high performance anion exchange chromatography with pulsed amperometric detector]. AB - OBJECTIVE: A pulsed amperometric detector-high performance anion chromatography method for the determination of L-carnitine in health food was established. METHODS: After samples were dissolved and dispersed with ether, L-carnitine in samples was extracted with 0. 1 mmol/L HC1. Using 200 mmol/L NaOH as the mobile phase, amino PAC PA10 Amino acid-separation column as separation column and pulse ampere detector with An as working electrode throughout the experiment. RESULTS: The linear was good in the range of 0.08 - 1.00 mg/ml. The intra-day RSDs of peak area and retention time for L-carnitine standard solution were 3.97% and 0.62% and the inter-day RSDs were 5.66% and 0.69%, respectively. The average recoveries were 95.6% - 113.5% and the RSD of sample analysis was 7.34%. The results of the proposed method for the analysis of L-carnitine in health foods were satisfactory. CONCLUSION: The proposed method is simple, accurate and reproducible. One analysis can be completed within 15 min. The method is adaptive for the analysis of L-carnitine in health food. PMID- 21695915 TI - [Ten element contents and their distribution in fruits determinated by atomic absorption spectrometry]. AB - OBJECTIVE: To investigate the contents and distributions of the Zn, Cu, K, Ca, Mg, Mn, Pb, Cd, Cr and Se elements in the fruits. METHODS: The fruit samples were digested with wet method. Contents of zinc,copper, calcium,magnesium,potassium and manganese were determined by flame atomic absorption spectrometry (FAAS). Contents of lead, cadmium, chromium and selenium were determined by graphite furnace atomic absorption spectrometry (GFAAS). RESULTS: There existed differences for the element distribution in each part of the fruits. The contents of lead in the grapes, dried jujubes and papaya were close to the pollutant concentration limits, but their contents were lower than standard limits. The contents of chromium in the Guoguang apples, pears, dry jujubes and cherry tomatoes were higher than standard limits. Selenium was detected in the Guoguang apples, bananas, pears, dry jujubes, papaya and pomelo. The contents of copper in the grapes and dry jujubes exceeded standard limits. The contents of zinc were lower than standard limits. The calcium contents were the highest in the papaya. The contents of magnesium and manganese were the highest in the dry jujubes. The contents of potassium were higher in the dry jujubes, pomelo and cherry tomato. CONCLUSION: The highest levels of the elements were in the seeds,and the second levels were in the skin,the lowest levels were in the pulp. The element contents of the peel were higher than those the pulp. PMID- 21695916 TI - [Distribution and elimination of thiabendazole and its metabolite residue in laying hens]. AB - OBJECTIVE: To explore the distribution and elimination of thiabendazole and its metabolite 5-hydrothiabendazole residues in the hens tissues including liver, muscle, heart, fat, as well as in eggs. METHODS: Laying hens were orally administred thiabendazole for 5 consecutive days (100mg per hen daily) and then the hens were sacrificed at the times of 1 day, 3 days, 5 days and 7 days after the end of treatment. Eggs, liver,muscle,fat and heart tissues were collected and homogenized. The samples were extracted by acetonitrile, further concentrated and purified by an Oasis MCX cartridge, and then the contents of thiabendazole and 5 hydrothiabendazole in tissue homogenates determinated by liquid chromatography electrospray ionisation tandem mass spectrometry (UPLC-ESI-MS/MS). RESULTS: The major residues in the tissue homogenates was 5-hydroxythiabendazole, with more higher concentrations than thiabendazole. Egg samples presented the large majority of both drug residues. For the tissue homogenates,the total concentrations of thiabendazole and 5-hydrothiabendazole residues followed the order of liver > heart > muscle > fat at 1 day after the treatment. The withdrawal period of thiabendazole for eggs was about 7 days. CONCLUSION: Distribution and elimination of thiabendazole and its metabolite residues in laying hens were primarily studied in this study. PMID- 21695917 TI - [Biological change of normal human breast epithelial cells induced by B( a )P and NNK]. AB - OBJECTIVE: To explore the changes of biological characters of normal human epithelial cells treated chronicly with carcinogens. METHOD: At picomolar concentrations of NNK and B [ a ] P carcinogens, noncancerous MCF10A cells were repeatedly treated. Properties of biological target endpoint were studied in cells after 20 cycle's treatment. RESULTS: It was found that the treatment can induce cell acquisition of properties of reduced dependence on growth factors, anchorage-independent growth,and acinar-conformational disruption. CONCLUSION: MCF10A cells can acquire cancer-related properties after long-term,low concentration treatment with carcinogens. PMID- 21695918 TI - [Rapid method study of methicillin-resistant Staphylococcus aureus identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry]. AB - OBJECTIVE: To establish the method on rapid identification of Staphylococcus aureus and the performance of methicillin-resistance. METHODS: 40 isolation strains of staphylococcal were analyzed by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF-MS) and API Staph Ident system, and the performance of methicillin-resistance was tested by Disk Diffusion Susceptibility Testing. RESULTS: 34 isolation strains were identified by MALDI-TOF-MS as Staphylococcus aureus, and the result was uniform to the API Staph Ident system. 11 isolation strains were identified as methicillin-resistant Staphylococcus aureus (MRSA) and 23 isolation strains were methicillin susceptible to Staphylococcus aureus (MSSA). All the 34 isolation strains were clustered to 2 species identified by MALDI-TOF-MS. The result was uniform to the Disk Diffusion Susceptibility Testing. CONCLUSION: These results demonstrated that MALDI-TOF-MS could be a rapid technique for identification and discrimination of MRSA. PMID- 21695919 TI - [Simultaneous determination of 9 phenolic compounds in disinfectant by HPLC]. AB - OBJECTIVE: A high performance liquid chromatography method was established for determination of 9 phenolic compounds in the disinfectant. METHODS: on a C18 (4.6 mm x 250 mm, 5 microm) chromatography column, use the methol-0.22% sodium heptane solution (pH 3.5) as mobile phase ladder washing, under the following conditions: flow rate 1.0 ml/min, detection wave 280 nm, and the column temperature 25 degrees C. RESULTS: In this method, the linear range of each compound was 5 - 200 mg/L and the correlation coefficients was more than 0.9995. The detection limit was 1mg/L. The RSD was less than 4.8% and standard addition recovery varied from 97.6% to 108.2%. CONCLUSION: This method was easy to operate, fast and with high sensitivity. It was suitable for routine analysis for disinfectant and can be used for the quality control of effective compounds in disinfectant. PMID- 21695921 TI - [How to explain the decrease in coronary heart disease mortality]. PMID- 21695920 TI - [Do our patients with atrial fibrillation benefit from catheter ablation?]. PMID- 21695922 TI - [How to explain the decrease in coronary heart disease mortality]. PMID- 21695923 TI - [Idiopathic retroperitoneal fibrosis]. PMID- 21695924 TI - [Disturbance of synthesis of cholesterol and its precursors in clinically serious conditions]. AB - OBJECTIVE: The aim of the study was to elucidate the role and importance of hypocholesterolemia in clinically serious conditions. It was a monocentric, prospective clinical study. MATERIAL AND METHODS: Two groups of patients were recruited to the study--one group were patients with coronary heart disease (CHD), who underwent miniinvasive cardiosurgical operation without extracorporeal circulatio (n = 17) and one group of patients, who sustain polytrauma (n = 19). Thirty six patients were recruited into the study. We performed the determination of sterols (total cholesterol, HDL-cholesterol, LDL-cholesterol, triacylglycerols), and their precursors (beta-sitosterol, campesterol, lathosterol, skvalen), interleukin IL-6 and cortisol in the blood serum. The short version of ACTH stimulation test was performed. The oxidative burst of granulocytes was evaluated. The blood samples were taken on the day of admission, the first, the fourth and the eighth post-operative and post-traumatic day. RESULTS: There was a significant decline of total cholesterol (TC) and LDL cholesterol level with full recovery during observed period. There was a decline of cholesterol synthesis (lathosterol and lathosterol/cholesterol ratio) together with a decline of total cholesterol. There was a significantly negative correlation between IL-6 level and total cholesterol. Despite no confirmation of disturbance of adrenal function, there was a significantly positive correlation between lathosterol/cholesterol ratio (a de novo cholesterol synthesis marker) and cortisol level after the ACTH stimulation test. There was a significant breakdown of bactericidal function of granulocytes along with a decline of cholesterol level. CONCLUSION: There was decline of endogenous cholesterol synthesis in clinically serious conditions. The cholesterol synthesis rate is negatively influenced by IL-6 level. The rate of endogenous cholesterol synthesis positively correlated with cortisol production by the adrenals and with bactericidal function of granulocytes. PMID- 21695925 TI - [Treatment of critical limb ischemia and diabetic foot disease by the use of autologous stem cells]. AB - AIM: The aim of our study was to assess safety and effectiveness of therapy of critical limb ischaemia by autologous stem cells and evaluation of potential adverse events. METHODS: Fourteen patients were included into the study (11 men, 3 women, mean age 61.9 +/- 9.6 years, mean diabetes duration 23.5 +/- 11.1 years, mean glycated hemoglobin 6 +/- 1%). Eight patients were treated by bone marrow stromal cells, 6 patients by peripheral blood progenitor cells after stimulation by filgrastim. The suspension of stem cells was then applied into the muscles of ischemic limbs. We evaluated transcutaneous oxygen tension (TcPO2), subjective pain sensation assessed by Visual Analog Scale (VAS) and wound healing. RESULTS: TcPO2 significantly increased in all patients from 10 +/- 8.7 mm Hg before the treatment to 39.4 +/- 9.5 mm Hg after 6 months (p = 0.0005) after stem cell therapy. We also observed significant area defect reduction and pain decrease during the follow-up period. Median of area defect was reduced from 4.3 (0.7 - 31.7) before the treatment to 0.06 (0 - 0.5) cm2 after 6 months from the treatment (p = 0.0078). Decrease in rest pain was observed in all patients, mean VAS decreased from 5.3 +/- 1.8 to 1.1 +/- 1.3 after 6 months (p = 0.002). CONCLUSION: Our study suggests that stem cell therapy of diabetic foot disease is an effective therapeutic option with no adverse events for patients with severe peripheral arterial disease. This treatment leads to increase of transcutaneous oxygen tension, improves wound healing and decreases the rest pain. PMID- 21695926 TI - [Improvement of quality of life after ablation of longstanding persistent versus paroxysmal atrial fibrillation: results of 2-year follow-up]. AB - AIMS: The purpose of the study was to assess quality of life and socio-economic parameters in patients after ablation of paroxysmal versus longstanding persistent atrial fibrillation (AF). METHODS: The study included 89 patients with paroxysmal AF and 56 patients with longstanding persistent AF who underwent ablation within 1 year, and were afterwards prospectively followed up for 2 years. Quality of life was evaluated by the EQ-5D questionnaire before and every 6 months after ablation. RESULTS: Objective, respectively subjective quality of life at baseline was lower in patients with longstanding persistent AF (67 +/- 16 vs 71 +/- 10; p = 0.01, resp. 64 +/- 12 vs 67 +/- 16; p = 0.07); however, after 2 years, it exceeded that of the patients with paroxysmal AF (80 +/- 17 vs 75 +/- 18; p = 0.03; resp. 73 +/- 13 vs 70 +/- 17; p = 0.18). The baseline-2 year difference in improvement was higher in patients with longstanding persistent AF in both objective (p = 0.001) and subjective component (p = 0.05). Both groups displayed significant decrease in the days of hospitalization, and the days of working incapacity. CONCLUSION: Patients with longstanding persistent AF exhibit worse baseline quality of life than the patients with paroxysmal AF, and higher quality of life improvement after ablation. PMID- 21695927 TI - [Blood lipid changes at long-term antiretroviral treatment]. AB - The aim of study was to find the development trend of blood lipid concentration in a group of HIV positive patients treated by combination antiretroviral therapy (cART). We followed changes during the therapy and evaluated their aterogennic nature. METHODS: The group included 118 patients stepwise allocated to the AIDS Centre of the Faculty Hospital Brno, with the monitoring period being up to 1 month as the minimum and up to 17 years as the maximum. The patients were divided into cART treated patients and not treated patients. The following parameters were analysed: total cholesterol, triglycerides, HDL-cholesterol, apolipoprotein B, the total cholesterol/HDL-cholesterol index and non-HDL-cholesterol. RESULTS: Our group experienced a statistically significant increase of total cholesterol concentration already in the first months after cART initiation and this value continuously increased in the following years. The recommended target value for total cholesterol (5 mmol/l) was exceeded in the group of patients after 3-4 years of cART initiation. The triglyceride concentration showed a sudden increase already a few months after cART initiation, when the recommended optimum value of triglycerides (1.7 mmol/I) was exceeded. These changes had a further no statistic significance. The average triglyceride value was all around (slightly above) 1.7 mmol/l. Our group experienced a statistically significant increase of HDL cholesterol concentration in the first two years after cART initiation. A statistically significant change of HDL-cholesterol concentration was not found in the following years. The average HDL-cholesterol value was above optimal value HDL-Ch > 1.0 mmol/l for men (except initial category). A statistically significant change of apolipoprotein B concentration was found after 3-4 years of cART treatment. However, the average apolipoprotein B value did not exceed the target value in any of the followed categories. No statistically significant changes of the total cholesterol/HDL-cholesterol index were found. The resulting value was under 5 in all the followed categories. Statistically significant changes of non-HDL-cholesterol were found in patients with cART already a few months after treatment initiation and its concentration continually increased. However, the recommended target value of non-HDL-cholesterol (3.8 mmol/l) was exceeded only in the category of patients treated 4 - 5 years. The development trend of CD4+ lymphocyte count and HIV-1 RNA copies means high active of cART from standpoind of immunoregeneration (CD4+ lymphocyte count) and viral suppression (HIV-1 RNA copies) even in the group of treated patient with the longest monitoring period. CONCLUSION: Monitoring of our group of HIV-positive patients treated by combination antiretroviral therapy revealed a statistically significant increase of blood lipid concentrations (inclusive of HDL-cholesterol) during the treatment. However, these changes do not have an unequivocally aterogennic nature even in the group of treated patient with the longest monitoring period. PMID- 21695928 TI - [Cardiotoxicity of cancer therapy]. AB - Due to advances in oncological care, the number of patients exposed to and surviving after anticancer chemotherapy is steadily increasing. Anticancer agents, however, are often associated with side-effects including cardiotoxicity which has been identified as one of the most serious and potentially life threatening complications. Cardiotoxicity manifestations range from asymptomatic alterations of heart and vasculature function to arterial hypertension, myocardial ischemia, arrhythmias (including QT-prolongation) and overt heart failure. Post-chemotherapy cardiovascular impairment has been associated with increased morbidity and may also contribute to increased mortality in these patients, both early and late after chemotherapy. This review article describes pathophysiology, clinical manifestation, diagnostic algorithms, monitoring and therapy of cardiotoxicity caused by anticancer agents. We also outline and discuss a variety of problems associated with patient management from the viewpoint of clinical cardiology according to latest published findings. PMID- 21695929 TI - [Sorafenib in the treatment of hepatocellular carcinoma]. AB - Hepatocellular carcinoma (HCC) is the 5th most frequent tumour disease and, at the same time, the 3rd most frequent cause of death from cancer worldwide. More than 600 000 new patients are diagnosed every year and more than 80% are diagnosed at an advance stage where surgical treatment is not indicated and systemic chemotherapy does not provide longer survival time. Sorafenib is the first substance that provides proven significant prolongation of survival time of HCC patients. This is a multikinase inhibitor with anti-proliferative and anti angiogenic properties. Its efficacy was shown in the SHARP study that enabled licensing of sorafenib for the therapy of inoperable, metastasizing hepatocellular carcinoma, including patients with liver cirrhosis, functional class Child-Pugh A or B, in more than 60 countries worldwide, including the Czech Republic. The aim of this paper is to provide a comprehensive summary of the current treatment of HCC and, at the same time, to point out some new therapeutic approaches that, in the near future, shall certainly play a major role in the treatment of HCC. PMID- 21695930 TI - [Infectious complications in patients after cardiac arrest undergoing therapeutic hypothermia]. AB - Therapeutic hypothermia is currently recommended neuroprotective therapeutic measure for comatose patients after cardiac arrest. Hypothermia has been proven not only to affect the neurological outcomes but also the survival of patients after cardiac arrest. This communication summarizes the issue of early infectious complications in patients after cardiac arrest undergoing therapeutic hypothermia. Diagnosis of infectious events is complicated in patients after cardiac arrest not only by the physiological effects of therapeutic hypothermia but also by the consequences of reperfusion injury and development of postresuscitation disease associated with systemic inflammatory response syndrome. Furthermore, there are discussed limited diagnostic options of infectious complications. The significance of the usual symptoms of infections is reduced, as well as the value of laboratory markers such as procalcitonin and C reactive protein. Finally, the possibility of antibiotic treatment and eventual antibiotic prophylaxis during therapeutic hypothermia in patients after cardiac arrest outside hospitals is mentioned. PMID- 21695932 TI - [Internal medicine and cognitive decline in seniors]. AB - Authors show the situation in diagnostics and treatment of cognitive deterioration in elderly. There are stressed chronic diseases influencing significantly influencing the development of dementia. Adequate treatment of these diseases was proved as a factor delaying the cognitive decline. The relationship between different groups of medications and cognitive performance are discussed. The importance of nutrition of elderly and possible microelements deficits are mentioned--specially group B vitamines, polyunsaturated fatty acids etc. Special part of the article show the importance of physical and psychical activities from the cognition point of view. Depression is discussed as a potentiating factor of dementia development. The table of recommendations to preventive, prophylactical and diagnostic measures how to improve the management of cognitive deterioration in elderly. PMID- 21695931 TI - [The decrease in morbidity and mortality of patients with chronic forms of ischemic heart disease is the result of conservative treatment]. AB - Article presents actual comparison of therapeutic methods for patients with chronic coronary artery disease and their influence on morbidity and mortality. It calls attention to the insufficiently presented fact, that invasive methods, like percutaneous and surgical revascularization, despite great expectations, have not proved to lower morbidity and mortality in large randomized studies. In contrary several groups of drugs proved their efficiency many times. Paradoxically, the cheapest approach, life style intervention, seems to be the most efficient method for prognosis improvement of patients with chronic coronary artery disease. PMID- 21695933 TI - [Sulodexid and nephrotic syndrome in patients with diabetic nephropathy]. AB - Diabetic nephropathy (DN) is the most serious, life limited complication of both types of diabetes mellitus. Therefore the early identification and intensive treatment of DN is very important. DN involves the thickening of glomerular basement membrane (GBM) and the depletion of glycosaminoglycan (GAG) in the GBM with resultant diminution in the physiological electrostatic charge barrier. Additional mechanism in pathophysiology of DN is mesangial expansion. Sulodexide is glycosaminoglycan mixture of heparansulfate and dermatan sulfate. We present a 71-year old patient with severe nephrotic syndrome, probably caused by DN. AS patient refused renal biopsy, exact diagnosis of DN could not be confirmed. Since 2000 our patient was treated with sulodexide. More pronounced decrease of proteinuria was proved 1.5 year after the begin of this treatment (from 10.37 g/d to 4.8 g/d) and after 3 years was proteinuria negative. PMID- 21695934 TI - [Morbus Ormond (idiopatic retroperitoneal fibrosis)]. AB - Idiopathic retroperitoneal fibrosis (IRF) is a rare condition characterized by the development of fibrotic tissue around the abdominal aorta and iliac arteries and often involves structures as ureters and the inferior vena cava. The age at onset of signs and symptoms is between 40-60 years, males predominane over females. In most cases the clinical manifestation is presented as compressive syndrom of ureters, therefore the first known cases were described by urologists. In this report we present the case of 37-years old male examinated for persistent fever about 38 degrees C and high inflammatory activity in spite of empiric antibiotic therapy. Positron emission tomography (PET) showed locality of high metabolic activity of fluorodeoxyglucose with maximum paraaortal left. Microscopic examination of extracted mass showed presence of fibrous and inflammatory components. With clinical presentation, imaging and histological findings we made out the diagnosis of idiopathic retroperitoneal fibrosis--morbus Ormond. PMID- 21695935 TI - [The use of Dinoproston for induction of delivery]. AB - For the past decades induction of delivery is more often put in practice of modern obstetric. During the last couple of years it exceeds 20% of the vaginal deliveries. In the following study we have use Dinoprostone (Prepidil gel) as a remedy which stimulates labor. In 6 months 92 patients were selected. A 92 deliveries were stimulated with Prepidil gel. The results were satisfactory. Dinoprostone represents to be effective, safe and easy to use for induction of delivery. PMID- 21695936 TI - [Frequency of epidural analgesia for vaginal delivery]. AB - THE AIM: To establish the frequency of epidural analgesia for vaginal delivery. MATERIAL AND METHODS: The research includes 51 632 deliveries for 16 years period. RESULTS: Total frequency of vaginal delivery with EA, compared to total number of vaginal deliveries for period is 11.77%. DISCUSSION: The frequency shows tendency to slowly increase in the beginning of the period, probably because of getting experienced among some of the obstetricians, after then frequency stay relatively constant. Except care of somatic health of mother and foetus, modern obstetrics requires to ensure maximum comfort of parturient, to satisfy requirements of modern women for "painless" delivery and leave a positive memory of birth. That is why more frequently use of EA for vaginal delivery is necessary. CONCLUSION: EA is an approved method for anesthetizing vaginal delivery. It is established slowly increasing frequency of EA for anesthetizing vaginal delivery. The frequency of EA in University hospital "Maichin dom" is relatively low in comparison with mentioned in literature values, which raises the question of finding ways to further promote and increase the application of EA. PMID- 21695938 TI - [Modern kind of treatment for ovarian tumors with low malignant potential/summarized our and foreign experience]. AB - AIM: Our aim was to assess the ovarian tumors with low malignant potential. MATERIAL AND METHODS: We tried to summarize our and foreign experience for 10 years period (2000-2011) in this field. RESULTS: The method of choice is the surgical treatment with total cytoreduction if possible. Appendectomy is performed for the serous pathological types of ovarian tumors. CONCLUSIONS: In the early stages we try to spare the reproductive functions of the patients. In the advanced stages hysterectomy with BSO, omentecromy and appendectomy is performed. Systematic pelvic and paraaortal lymph node dissection is not recommended. Resection only of the suspected lymph nodes is performed. The chemotherapy has no prognostic significance. PMID- 21695937 TI - [Radical colpoparametrectomy after simple hysterectomy--operative treatment of patients with invasive cancer of the uterine corpus and cervix]. AB - INTRODUCTION: Diagnosis of invasive cervical carcinoma or residual tumor disease in patients who had previously simple hysterectomy means that the initial surgery is incomplete according to the oncological standards. One of the options in such cases is a second stage surgery--radical colpoparametrectomy (RC). MATERIAL AND METHODS: A retro- and prospective study during a period of Feb 1994-Jun 2010 enrolled a total of 28 patients that underwent RC after simple hysterectomy. Data were collected on demographics, tumor stage, histology, postoperative therapy, survival, complications. RESULTS: Median age of patients was 54.7 years. Invasive cervical carcinoma was diagnosed in 20 of 28 patients. Residual tumor disease was found in 5/28 patients who had simple hysterectomy for endometrial cancer. Uterine sarcoma was diagnosed in 3 cases. Histology revealed absence of tumor in 10/28 patients, lymph nodes, vaginal, and/or parametrial metastases in 18/28. Postoperative radiation and/or chemotherapy was arranged in 19/28 cases. Median follow up was 56 months with an overall 5-year survival of 88%. 11/28 patients had postoperative complications. CONCLUSION: RC is an alternative therapeutic approach for patients with invasive cancer of the uterine corpus and cervix who had simple hysterectomy. PMID- 21695939 TI - [Laparoscopic ovarian drilling and biopsy in women with polycystic ovaries (PCOS) and infertility]. AB - OBJECTIVES: To evaluate ovarian reserve according to results of biopsy of ovaries during laparoscopy. To investigate connections between hystologic results, drilling of ovaries and pregnancies. METHODS: We investigate prospectively 74 patients with polycystic ovaries (PCOS) and infertility. Operative laparoscopy have be done in 2006, 2008 and 2009 year in University Hospital "Maichin Dom" Sofia, Bulgaria. All patients had ovarian drilling and biopsy. RESULTS: Microscopic findings from biopsy of ovary in 74 women with PCOS were divided in 4 groups. In this investigation from 74 women with operative laparoscopy 33 patients (44.5%) were pregnant. CONCLUSION: The results of biopsy and registered pregnancies in PCOS patients is very difficult to analyse. Laparoscopic ovarian drilling and biopsy affect ovarian tissue. The ovary probably change own characteristics--ovarian metabolism and physiology are restored and this changes our clinical prognosis for a future pregnancies. PMID- 21695940 TI - [Neonatal complications of children born after in vitro fertilization]. AB - The purpose of this report is to compare the neonatal indices and the frequency of neonatal pathology in children, born after in vitro fertilization with those after natural conception. The study, which is a retrospective one, comprises all newborns from the three maternity hospitals of Pleven (University hospital, Saint Marina Obstetrical clinic, Avis-Medica Hospital) for the last 2 years. The comparative indices of the babies in the two groups are: birth weight and gestation age at birth, morbidity by separate nosological units: asphyxia, intraamniotic infection, intrauterine growth retardation, neonatal respiratory distress syndrome, congenital anomalies etc.), multiple births. The maternity age, delivery pattern, mean hospital stay and mortality are discussed too. The results are compared with other international data. PMID- 21695941 TI - [The very low birth weight and very low gestational age neonates--survival, prognosis and perspectives]. AB - The advances in perinatal medicine during the last decades lead to a reduction in neonatal mortality rates in risk newborns and a gradual lowering of the gestational age when survival is possible to 22 weeks of gestation. In the present survey we are making a review of the studies about the survival and the prognosis in neonates with very low birth weight and gestational age (VLBW, VLGA). Infants weighting more than 1000 g and with gestational age above 28 g.w. are with a good prognosis: low neonatal mortality and morbidity rates. In newborns with gestational age between 26 and 28 g.w. the neonatal mortality rates are relatively low, however the trend of further lowering has not changed during the last 15 years; morbidity rates varies between different centers and are relatively high. The greatest medical, social and ethical dilemmas represent the newborns with gestational age less than 25 g.w. In this group with an overall high neonatal mortality (with big variations between different centers), there is a significant high morbidity rate among survived babies. These are the infants at the border of perinatal viability, the "grey zone" of the neonatology, where further discussions are going on about the activity of the obstetric management, the intensity and the amount of neonatal resuscitation. PMID- 21695942 TI - [Scoring systems for assessing illness severity and predicting outcome in very low birth weight infants]. AB - The very low gestational age (VLGA) and birth weight (VLBW) in newborns and the related morbidities are one of the main causes of death in the neonatal period and during the first year of life. In the last two decades a number of neonatal scores for assessing the illness severity and the initial risk were developed. They are applied for different goals: to predict the risk of death and serious morbidity, to assure a more accurate evaluation of results between different NICU's, as a reliable basis for randomization of the patients in multicenter and longitudinal studies, for comparison of the effect when new therapeutic strategies are used. In this review we overview and discuss the most often used scoring systems for assessing of illness severity in VLBW infants: CRIB, SNAP, SNAPPE and their updates, NTISS, Berliner score, and some graphical models for predicting survival. In comparison to birth weight or gestational age alone they are more reliable tools for assessing the risk and comparing the results. PMID- 21695943 TI - [Trichinellosis and pregnancy--interpretation of immuneparasitologic results and possibilities for vertical transmission]. PMID- 21695944 TI - [Fetal meconium pseudocyst secondary to in utero perforation of colon transversum and meconium peritonitis]. AB - Fetal bowel intrauterine perforation causes sterile inflammation of the peritoneum, known as meconium peritonitis. In some cases the perforation closes spontaneously, thus forming a meconium pseudocyst between the intestinal loops and the omentum. Meconium peritonitis, complicated by pseudocyst formation, should always be considered when a fetal abdominal mass with diverse echogenicity and hyperechogenic calcifications is observed on prenatal ultrasound. Usually, this is associated with ascites and/or polyhydramnios. The differential diagnosis necessitates exclusion of all other fetal abdominal tumors. We present a case report of meconium pseudocyst diagnosed prenatally at 32 weeks of gestation which was successfully treated by surgery after birth. PMID- 21695945 TI - [Six-month follow-up of the effect of neomenor in patients with painful menstruation]. AB - Neomenor is herbal medication especially created to permanently relieve painful menstruation symptoms in girls and women with primary dysmenorrhea. It supplies the organism with substances essential for the metabolic processes that guarantee normal menstrual cycles. In some women these substances are out of balance, there is an excess of prostaglandins, which leads to painful periods, menstrual cramps and even migraine. Each NEOMENOR tablet contains 400 mg of standardized extracts from stalks of: Astragalus glycypyhyllos (Wild liquorice), Erodium cicutarium (Redstem Stork's Bill) and Geranium sanguineum (Bloody Cranesbill). Their biologically active substances inhibit the synthesis of prostaglandins and their secretion into the uterus, hence strong muscle contractions are reduced and menstrual cramps disappear. The aim of this short study is to gain personal impressions about the action of the preparation. We have tested 35 girls and women with middle-age--18.74 on (14-28 years) with menarche--average at 12.8, suffering of primary dysmenorrhea. We have watched following factors: degree of dysmenorrhea, duration of complaints, habitus, gynecological and mental status, used painkillers. As a result of three months treatment 63% of the patients with III-d and 37% with II-nd grade of dysmenorrhea transformed in 42% with II-nd and 45% with I-st grade of dysmenorrhea. Only in 4 patients (11%) therapy was without success. The monitoring continues. PMID- 21695946 TI - [Survival of probiotic microorganisms in the conditions in vitro imitating the process of human digestion]. AB - PURPOSE OF THE STUDY: Assessment of survival bifidobacteria and lactobacteria under the conditions in vitro, simulating digestion in human stomach and intestine, and study of survival probiotic and indigenous microorganisms in co cultivation on solid nutrient medium. MATERIALS AND METHODS: Probiotic microorganisms from commercial preparations Bifidobacterin and Lactobacterin, clinical isolates lactobacillus (Lactobacillus acidophilus No 1, L. brevis No 2) were used in experiments. Survival study of probiotic microorganisms was performed on a model in vitro, simulating the process of digestion in the human body. Assessment of the relationship of probiotic microorganisms and indigenous microorganisms was carried out in co-cultivation in vitro on solid nutrient medium. RESULTS: A significant reduction in the number of viable probiotic microorganisms during their incubation in model media was set as well as suppression of probiotic microorganisms growth by cultures of a clinical strains of lactobacillus, corresponding to biocompatibility by type "host against probiotic". CONCLUSION: While choosing probiotics in the treatment of dysbacterioses the character of relationship between probiotic microorganisms and indigenous microorganisms of a patient is recommended to be preliminarily tested. Also microorganisms of own microflora should be stimulated using modern prebiotics. PMID- 21695947 TI - [Reproductive disorders in women with celiac disease. Effect of the etiotropic therapy]. AB - Violation of reproductive function in patients with celiac disease can manifest as delayed puberty, infertility, amenorrhea, premature menopause, spontaneous abortion, low birth weight. The aim of the study was to establish the frequency and nature of reproductive function violation in patients with CD in the Russian Federation. MATERIALS AND METHODS: The study included 132 women (average age 38,5 +/- 1,17 years) with CD observed in CSRIG in the period from 2000 to 2010. Comparison group consisted 105 women (average age 38,7 +/- 1,6 years) with predominantly functional bowel disorders (irritable bowel syndrome, functional constipation, functional bloating, inert colon). Were took into account information regarding obstetric history, physical and laboratory signs of malabsorption syndrome (MS) study of antibodies to alpha-gliadin immunoglobulin (IG) A class (AGA) and tissue transglutaminase (AtTG). RESULTS: The average age of onset of menses was 14,3 +/- 1,4 years, and in the control group - 13,0 +/- 1,3 years (p > 0.05), half of patients with C (43.9%) had menstruation begun at age 15 years and older, while 7.6% of the women--aged 17 and older. In the comparison group menses beginning after 15 years was only at 13.3% of women. In 61.3% of patients with CD was irregular menstrual cycle while in the comparison group such violations were noted in 13.3% (p < 0.001). Prolonged periods of amenorrhea we observed in women with newly diagnosed GC 3 times more likely than the comparison group: 43.9% and 11.4% respectively (p < 0.01). They also had nearly 3 times more likely to occur spontaneous miscarriage: at 46.9% and 14.3% respectively (p < 0.01). The frequency of dead children birth was about the same: 2.3% and 1.9% respectively (p > 0.05). The frequency of reproductive disorders increased with the growth of the severity of MS. In 43% of women after 6-8 months of strict adherence to a gluten-free diet (GFD) had disappeared amenorrhea and there were regular menses. Three women of childbearing age, strictly abided the GFD and had a history of repeated spontaneous abortion during the year managed to get pregnant and give birth to healthy full-term baby. CONCLUSIONS: Reproductive disorders in women with celiac disease are significantly more likely than at women with functional bowel disease. One of the reasons of reproductive disorders in patients with CD can be malabsorption of necessary nutrients in the small intestine. The presence of reproductive disorders should be considered as a risk factor for celiac disease, so these women should be screened for celiac disease. PMID- 21695948 TI - [Importance of the immunogenetic factors in the development of glutensensitive celiac disease in adults of Moscow region]. AB - The study examined the genetic predisposition to the development of glutensensitive celiac disease (CD). Were analyzed samples of peripheral blood of 17 adult patients diagnosed with CD, as well as samples of umbilical cord blood of 1700 newborns of healthy children. HLA-typing was performed using two basic methods of molecular typing--SSO and SSP. The studies revealed the specificity of HLA-B*08; HLA-DRB1*2003; HLA-DRB1*07 and HLA-DQB1*02, which are the genetic markers of CD. Was identified a combination of HLA-markers of CD, each of which is a genetic marker for CD: HLA-B*08; HLA-DRB1*2003; HLA-DQB1*02 and HLA DRB1*2007; HLA-DQB1*02/HLADQB1*03. In addition, negative associations were identified with CD specificity of HLA-DQB1*05. Thus, the results indicate the possibility of individual risk predicting of CD developing in a healthy population and in families of patients with CD. PMID- 21695949 TI - [Bone mineral density in patients with celiac disease and medical treatment of the disorder]. AB - The article presents the results of a bone mineral density study in patients with glutensensitive celiac disease. Was discussed problem of malabsorption syndrome with clinical and pathogenetic point of view, which can lead to bone loss due to malabsorption of calcium and vitamin D for celiac disease. Also was take into account the effect of inflammatory cytokines and hormones on calcium regulating processes of bone remodeling. The role of adherence to a gluten-free diet in the formation of bone loss. The article is illustrated with three tables, one figure and two schedules. PMID- 21695950 TI - [Deficit of polyunsaturated fatty acids in patients with celiac disease]. AB - The aim--to study fatty acid composition of lipids in blood serum of patients with celiac disease, their role in metabolic processes and methods of therapy. MATERIALS AND METHODS: The study included 28 patients with celiac disease with malabsorption syndrome III degree: 20 women and 8 men aged 17 to 45 years. Was determined: steatorrhea with help of chemical quantitative method of Van de Kamer, fatty acids in blood serum lipids by thin layer and gas chromatography. RESULTS: There was a substantial steatorrhea in patients with celiac disease with malabsorption syndrome III in severity. Most patients with celiac disease were found to decrease the essential fatty acids, the most significant--arachidonic acid, which leads to disruption of the synthesis of prostaglandins, prostacyclin, a tendency to thrombosis. Parenteral administration of the drug essentiale helps normalize the fatty acid composition of serum. PMID- 21695951 TI - [Modern enteral nutrition as a treatment for gluten enteropathy]. PMID- 21695952 TI - [Biological treatment of refractory Crohn's disease: three years of observation]. PMID- 21695953 TI - [Pulmonary disorders in patients with chronic inflammatory bowel disease]. AB - The article devoted to respiratory pathology (RP) in patients with UC and CD with clinical-radiological and functional (a function of external respiration--ERF) methods. The study included 220 patients with IBD (164--with UC and 56--with CD), aged 18-76 years (average age 40.6 years). ERF was studied by spirograph and recording flow-volume curve of forced expiration using pnevmotaograph "Eton-1" (Russia), 11 patients underwent HDCT at on multislice computer tomograph Toshiba Aquilion-16 (Japan). The study found that RP was most often detected by pulmonary function tests (44.1%), with a targeted detection of respiratory symptoms (32.9%), especially during HDCT. Much less marked physical (8.6%) and radiological (12.3%), signs of pulmonary disease, which indicates the low sensitivity of standard X-ray study of the CO. Airflow obstruction in the majority (78.3%) patients were represented mainly by obstruction of small bronchus, while in 51.6% of patients with impaired respiratory functions had no respiratory complaints, and 79.4% of patients had no radiographic signs of RP. PMID- 21695954 TI - [Prevalence and risk factors of constipation in the adult population of Moscow (according to population-based study MUSA)]. AB - Aim was assessment prevalence of chronic constipation (CC) in adult Moscow population and associated prevalence/risk factors. MATERIAL & METHODS: Data was collected from 1189 randomly selected subjects older than 18 y. o. We used specially designed Questionnaire, which included questions for constipation, dietary habits, physical activity, obstetric history. RESULTS: 34.3% subjects said "yes" to question whether they had constipation, 16.5% had CC according to Rome III criteria. Female have significantly (p < 0.001) higher rate of 2 (as a minimum) symptoms of constipation: 29.8 (see symbol) 14.3% correspondently. Prevalence of CC has a tendency to increase with age reaching maximum 32.8% in subjects older 65 y. o. Factors associated with higher prevalence of CC are any number of deliveries in female, low level of dietary fiber and fluid intake and low physical activity (in male younger 55 y.o. with increased body mass index). CONCLUSION: CC is a common (especially in the elders) condition, associated with female gender, dietary habits, and physical activity. PMID- 21695955 TI - [Fructooligo- and fructopoly-saccharides in correction and prevention of intestinal microbiocenosis disorders in patients with bronchopulmonary pathology receiving antibacterial therapy]. AB - AIM: To evaluate the clinical efficacy BUD "Stimbifid (LLC In-MIN"/LLC ("MedStar", Russia), which contains inulin, oligofructose, vitamins (C, B1, B6, B12, E, PP, folic acid, pantothenic acid, biotin) and minerals (zinc, selenium) in the correction and prevention of violations of the microbiota in patients with chronic and acute diseases of the lungs in the background and after antibiotic therapy (ABT). Was examined total of 50 patients with bronchopulmonary pathology on the background and after antibiotic therapy (including 30 people at a "Stimbifid" reception). The criteria for evaluating the effectiveness were: the dynamics of clinical symptoms, while in transit through the intestines of activated carbon ("carbolex test"), bacteriological examination of feces before and after treatment, the definition of short-chain fatty acids in the faeces before and after treatment. Based on the results of complex research was established the high efficiency of "Stimbifida" in the correction of microbiota in patients with chronic and acute diseases of the lungs in the background and after antibiotic therapy. PMID- 21695956 TI - [Rifaximin application in the overgrowth bacterial syndrome in the small intestine in patients after cholecystectomy]. AB - The aim of the work was to determine the frequency of the overgrowth bacterial syndrome (OBS) in the small intestine in patients with postcholecystectomical syndrome (PHES) justify the need for correction of the microflora and to assess the effectiveness of rifaximin at a dose of 800 and 1200 mg/day. MATERIALS AND METHODS: With the help of the hydrogen breath test were examined 92 patients with PHES. 40 patients with OBS were treated with rifaximin, 20 of them received the drug at a dose of 800 mg and 20-1200 mg/day for 7 days. Effectiveness was determined by the dynamics of clinical symptoms and indicators of the hydrogen breath test. RESULTS AND DISCUSSION: OBS was detected in 76% of the patients with PHES, which justifies the holding of antibiotic therapy. Lack of acceleration of peristalsis of small intestine as a cause of diarrhea was confirmed by the study of the electromotive activity of the small intestine, which revealed no differences from the norm. In some patients on therapy at a dose of rifaximin 800 mg/day uncropped pain and dyspeptic symptoms and was not accompanied by normalization of the hydrogen breath test. In the treatment of rifaximin at a dose of 1200 mg/day was showed normalization of the hydrogen breath test parameters in 90% of patients and relief of clinical symptoms in most patients. CONCLUSION: Rifaximin at a dose of 1200 mg/day compared with a dose of 800 mg/day in patients with PHES associated with bacterial overgrowth in the small intestine, had a more pronounced clinical effect, as evidenced by positive dynamics in the form of relief of clinical symptoms and normalization of the hydrogen breath test. PMID- 21695957 TI - [Enterosan--perspective medications for patients with postinfection irritable bowel syndrome]. AB - The pathogenesis of PIBS matter transferred intestinal infections that lead to persistent intestinal dysbiosis. The aim of this study was to investigate the effectiveness of enterosana at PIBS. MATERIALS AND METHODS: A total of 37 patients with PIBS diarrhea included in the study group and 30 patients consisted the control group. Diagnosis PIBS installed in accordance with the criteria of the Rome Consensus II. To assess the intestinal microflora were sown feces and made hydrogen breath test. RESULTS: In the study group patients by the end of the 3-week course enterosan therapy was appeared stable clinical PIBS remission. In the reseeding of feces decreased levels of conditionally pathogenic microflora and increased to normal number of bifidobacteria and lactobacilli. Were normalized rates of hydrogen in exhaled air according to breath test, which reflects bacterial overgrowth in the lumen of the small intestine. CONCLUSION: Enterosan has good therapeutic effect in treating patients with PIBS, helps to restore normal intestinal microflora and improve intestinal digestion. PMID- 21695958 TI - [Effect of HP eradication on the development of gastroesophageal reflux disease: results of the prospective study]. AB - METHODS: Prospective post-eradication evaluations were conducted in 331 H. pylori positive patients with peptic ulcer diseases who were confirmed not to have GERD before eradication therapy. Endoscopic findings of reflux esophagitis were according to the Los Angeles classification system. Patients were categorized in the nonerosive reflux disease (NERD) subgroup by results of 24-hour ambulatory pH metry (reflux episodes, pathological oesophageal acid exposure, DeMeester score > 14.7). After that all patients received H. pylori eradication therapy. After eradication therapy, during follow-up for up to 5.0 years, endoscopies, 24-hour ambulatory pH-metries were performed on patients with occasions of acid regurgitation or heartburn. RESULTS: GERD developed in 79 of 280 (28%) patients cured of infection and in 6 of 51 (11.8%) patients who had persistent infection (p < 0.013, Pearson's test). The risk of developing GERD in patients cured of infection was still significantly higher than in the patients who had persistent infection (p < 0.036, log-rank test; Kaplan-Meier analysis). NERD and mild esophagitis were in mostly patients. Multivariate analysis with the Cox's Proportional-Hazards Regression identified cure of infection (hazard ratio, 2.294, 95% confidence interval, 1.043-5.494, p = 0.039), hiatal hernia (1.828, 1.177-2.838, p = 0.007), high body mass index (1,084, 1.019-1.152, p = 0.01), male gender (0.139, 0.034-0.567, p = 0.006) as significant factors for the risk of developing of gastroesophageal reflux disease. CONCLUSION: Eradication of H. pylori infection may increase the risk of developing reflux esophagitis in patients with peptic ulcer who were confirmed not to have GERD before eradication therapy. Hiatal hernia, high body mass index, male gender may be serve as additional risk factors. PMID- 21695959 TI - [Late diagnosis of celiac disease in a child with cystic fibrosis]. AB - Cystic fibrosis is frequent monogenic disorder inherited in an autosomal recessive manner and has a severe course and prognosis. Crucial for the patient's life are the nature and extent of lung injury, as well as the digestive system, especially the pancreas and liver. Since the late 1960's. appeared describing a combination of celiac disease and cystic fibrosis. Many authors believe their associated diseases. Cited the case of late diagnosis of celiac disease in patient with cystic fibrosis, diagnosed as late, which delayed the appointment of adequate therapy, severe violations of nutritional status and physical development of the child, the current weighting of the underlying disease. PMID- 21695960 TI - [Asymptomatic celiac disease in patient with chronic acalculous cholecystitis]. AB - We described a patient 40 years old, admitted to the clinic with periodic attacks of pain in the right upper quadrant. With ultrasound it was confirmed chronic acalculous cholecystitis, and at endoscopy and multiple biopsies revealed atrophy of the mucosa of the duodenum (DM), corresponding to celiac disease (stage III in the Marsh classification). Titer of antibodies to gliadin (AGA) and tissue transglutaminase (AtTG) were higher: 60 and 110 units/ml, respectively, at a rate of 10 units/ml. The patient was assigned a lifetime adherence to a gluten-free diet, serologic test and a control endoscopy with biopsy at 6 months. The important role of the doctor-endoscopist in the diagnosis of latent forms of celiac disease. The significance of DM atrophy in the pathogenesis of patients with chronic cholecystitis. PMID- 21695961 TI - [Diagnosis and treatment of the bacterial overgrowth syndrome in the small intestine]. PMID- 21695962 TI - [Serotonin regulation of motor function of the small intestine]. AB - The review described serotonergic regulation of motor function of the small intestine. Motor neurons of the enteric nervous system and cells--pacemakers (cells of Cajal) play an important role in the regulation of motor activity of the small intestine. Activated serotonin receptors expressed by neuronal and effector cells initiate the phase II and III of the migrating motor complex (MMC), changes the duration of the cycle and frequency of MMC. Serotonin, acting on 5-HT(2B) -, 5-HT(3) - and 5-HT(4)-receptors expressed by the Cajal cell, regulate the frequency of slow waves and amplitude of electromotor activity of the small intestine. PMID- 21695964 TI - [New horizons in the study of celiac disease: based on 18-th European Gastroenterology Week (23-27. 10. 2010)]. PMID- 21695963 TI - [Esophageal lesions in Crohn's disease and ulcerative colitis]. AB - This article reviews the literature about esophageal involvement of Crohn's disease and ulcerative colitis. The review highlights the incidence of IBD, clinical features and difficulties of diagnosis and treatment of patients with esophageal involvement of IBD. PMID- 21695965 TI - [Possibilities of transpapillary and laparoscopic methods of choledocholithiasis treatment]. AB - The results of surgical treatment of patients, suffering choledocholithiasis, were adduced. In 493 patients laparoscopic exploration of common biliary duct was accomplished, in 297 of them the choledocholithiasis diagnosis was definitely established while performing laparoscopic cholecystectomy (LCHE); in 136- endoscopic papillosphincterotomy (EPST) was done preoperatively, but the attempts to perform transpapillary lithoextraction and lithotripsy have failed; in 60--a residual choledocholithiasis was noted. In 930 patients EPST and lithoextraction were performed preoperatively and as a second stage--LCHE. PMID- 21695967 TI - [Application of transumbilical antibacterial therapy in patients with acute purulent cholangitis]. AB - In 2004 - 2010 yrs 75 patients were treated for an acute purulent cholangitis (APCH). In 42 (41.2%) patients (the main group), suffering an acute cholecystitis, choledocholithiasis, duodenal papilla magna (DPM) stenosis, obturation jaundice and APCH, transumbilical introduction of antibiotics (TUIA) and operative intervention were performed; in 33 (33.3%) patients (control group) antibiotics were administered intravenously. In APCH inflammatory reaction have disappeared faster while TUIA application. TUIA and endobiliary sanation application have secured achievement of high antibiotics concentration in biliary ducts, as well as an effective impact on microflora, prophilacting cholangiogenous infection generalization. TUIA owes significant advantages in comparison with conventional methods of antibacterial therapy. PMID- 21695966 TI - [Novel technologies in surgical treatment of cholelithiasis and benign ovarial tumours in ovarial polycystic syndrome using generator of automatic welding of the soft tissues]. AB - The results of operative treatment of 162 women, including 45 - for biliary calculous disease and 117 - for benign ovarial tumours with ovarial polycystosis syndrome, were analyzed. In 60 (20%) patients (control group) the operative interventions were performed, using monopolar and bipolar electrocoagulation, while in 102 (80%) patients (main group) - a generator of automatic biologic welding of soft tissues. While application of generator for biologic welding of soft tissues the hepatic tissue or ovarial follicular apparatus damage was noted, witnessing the ovarial reserve secure. PMID- 21695968 TI - [Diagnosis and treatment tactics for complicated pancreatic pseudocysts]. AB - Experience of 84 patients treatment for complicated pancreatic gland pseudocysts is presented. Tactics of diagnosis and treatment for complicated pancreatic gland pseudocysts was elaborated and substantiated. Individualized treatment-diagnosis approach provides, first of all, the complications elimination, an adequate surgical treatment of pancreatic gland pseudocyst is possible in late period. For complicated pancreatic pseudocysts treatment miniinvasive methods were used predominantly, when their application is impossible or fails the open procedure is performed. PMID- 21695969 TI - [Morphological substantiation for the surgical treatment of chronic hepatic abscess]. AB - The results of histological investigation, conducted in 27 patients, operated on for chronic hepatic abscess, are presented. Macroscopic and microscopic characteristic of all zones of hepatic affection is adduced, the mechanisms of formation of pyogenic membrane, zones of infiltration and fibrosis in chronic hepatic abscess formation are delineated. PMID- 21695970 TI - [Systemic inflammatory reaction and indices of the organ hepatic dysfunction in patients with abdominal sepsis]. AB - In 26 patients in complex of treatment of abdominal sepsis there was applied a 1.5% solution of reamberin intravenously in 400 ml dose during 5 days. The results of treatment were estimated, studying indices of systemic inflammatory reaction (SIR) and hepatic tests. Reamberin application have promoted rapid normalization of the parameters studied. The authors consider, that efficacy of reamberin is caused not only by positive impact on the SIR course, but by hepatoprotective action of the preparation as well. PMID- 21695971 TI - [The state of the vascular endothelium and histological changes of the muscular tissue in patients with chronic ischemia of the extremities]. AB - One of perspective trends of treatment in patients, suffering chronic ischemia of extremities, is application of a cellular technologies. This trend needs scientific confirmation, basing on investigations, which discover primary signs, characterizing chronic ischemic impact on the muscular tissue structure and ultrastructure of vascular endothelium in capillaries of the muscle. The results of investigations conducted witness the muscular tissue reconstruction occurrence under impact of chronic ischemia: restoration of muscular fascicles by connective tissue, spoiling young myons regeneration, the capillaries lumen obturation. In addition, in ischemic state the destruction of energetic organelles and endotheliocytes occurs. PMID- 21695972 TI - [Strategy of the metabolic acidosis correction and indices of coagulation profile in patients with severe traumatic shock]. AB - The strategy for correction of metabolic acidosis and coagulation profile disorders in severe traumatic shock was adduced. There was established, that severe traumatic shock is characterized by prominent metabolic acidosis, the bases deficiency reduction, the lactate content in arterial blood enhancement, as well as ionized calcium in the blood serum, significant enhancement of the partially activated thromboplastin time and protrombin time, what witnesses the prominent coagulation disorders presence on the metabolic acidosis background. The "Soda-buffer" (manufactured by "Yuriya Pharm", Ukraine) preparation application in a complex of infusion-transfusion therapy permits in early terms to correct effectively the metabolic acidosis and coagulopathy signs in the injured persons, suffering severe trauma. Effective correction of metabolic acidosis and disorders of coagulation profile permits to lower trustworthily the erythrocytic mass volume transfused as well as fresh-frozen plasm while the infusion-transfusion therapy conduction. PMID- 21695974 TI - [Pathogenetic aspects of complex treatment of Dupuytren's contracture in patients with chronic hepatitis]. AB - The results of Dupuytren's contracture treatment in patients, suffering chronic hepatitis with the hand deformity grade II and III, in the injured persons and liquidators of the Chernobyl disaster consequences, conducted in 2000-2010 yrs., were adduced. Beginning from the third week, when an active movements had emerged, the patients were treated locally, including lidase and solution, which consisted of dimexid, isotonic saline and furazolidon. PMID- 21695973 TI - [Complex treatment of pulmonary abscesses and pleural empyema in patients with severe thoracic trauma]. AB - The results of complex treatment of 40 injured persons with severe thoracic trauma, in whom pulmonary abscesses and pleural empyema had occurred postoperatively, were analyzed. Complex treatment of pulmonary abscesses and pleural empyema, using the methods of a local superhighfrequency irradiation of purulent foci have promoted their accelerated regression occurrence and reduction of a systemic inflammatory reactions severity, as well as prophylaxis of secondary purulent-septic complications, permitting to achieve lethality lowering and to escape practically reoperations performance. PMID- 21695975 TI - [Objective intraoperative estimation of state of the intestinal transplant prepared for placing into the perineum in experiment]. AB - The work is devoted to experimental investigation and practical application of the objective intraoperative diagnosis method for the intestinal transplant state estimation, which is prepared for descendence to perineum, using modified pulsoximetric data analyser in environment of experimental modelling of abdominoanal rectal resection, resulting in determination of objective indices of the intestinal transplant vital capacity. The method of operative intervention in experiment on laboratory animals is adduced. The expediency of application of modified pulsoximetric data analyser in colorectal surgery was established. PMID- 21695976 TI - [Differential diagnosis of abdominal tuberculosis and Crohn's disease]. PMID- 21695977 TI - [Elimination of the soft tissues defects in surgical treatment of giant nevuses using expander]. PMID- 21695978 TI - [Observation of penile head oleoma migration into the scrotum]. PMID- 21695979 TI - [Expression of Ki-67, p53, bcl-2, estrogen receptors alpha in patients with clear cell renal carcinoma and epidermal growth factor receptor mutation]. AB - Three hundred and thirty-six cases of clear-cell renal carcinoma (CCRC) were examined for epidermal growth factor receptor (EGFR) mutation: exon 19 deletion and L858R mutation in exon 21 of the EGFR gene. The expression of Ki-67, bcl-2, p53, and estrogen receptors alpha was studied in CCRC with EGFR mutation. There were 4 cases of CCRC with EGFR exon 19 deletion. The frequency of EGFR gene mutations was 1.2%. L858R missense mutations in exon 21 of the EGFR gene were absent. In CCRC, EGFR gene mutation (exon 19 deletion) was detected in 3 men and 1 woman with an age range of 50 to 60 years and Fuhrman differentiation grade 2 or 3. The Ki-67 index varied from 4 to 23%. The expression of bcl-2 and p53 was negative. A moderate estrogen receptor alpha expression was revealed in 1 of 4 cases. PMID- 21695980 TI - [The apoptosis inhibitor survivin in transitional cell carcinoma of the urinary bladder]. AB - Whether the expression of the apoptosis inhibitor survivin was correlated with the degree of differentiation and the stage of transitional cell carcinoma of the urinary bladder was studied. Sixty samples of surgical specimens from patients with urothelial carcinomas of various degrees of differentiation and different stages were examined. An immunohistochemical study using the monoclonal antibodies obtained by the authors was conducted. The high expression of survivin was shown to be correlated with the lower-grade differentiation of a tumor and its higher stage. PMID- 21695981 TI - [Differential diagnosis of precancerous and regenerative changes in the epithelium of the cervix uteri, by applying an immunohistochemical study]. AB - Precancerous changes in the epithelium of the cervix uteri include low- and high grade squamous intraepithelial lesions (LGSIL and HGSIL). Morphologically, these must be differentiated, among other conditions, immature squamous metaplasia (ISM) of the cervix uteri. MATERIALS AND METHODS: This study involved 119 cases divided into 3 groups: 1) LGSIL (n = 28); 2) HGSIL (n = 56); 3) ISM (n = 35). An immunohistochemical study was conducted using antibodies to p16INK4a, CK17, and Ki-67 according to the standard protocol. RESULTS: Ki-67 expression was mainly low and moderate in 67.9% of cases in the LGSIL group; it was seen in 100% of cases in the HGSIL group, being significant in 73.5%. In the ISM group, Ki-67 was identified in 65.7% of cases, most of which demonstrated a low-to-moderate expression. In the LGSIL group, the expression of p16INK4a was recorded in 46.4% of cases. In the HGSIL group, the reaction was observed in 73.2% of cases; of them 57.2% it was strong. In the ISM group, the reaction was chiefly low in 38.6% of cases. In the LGSIL group, CK17 expression was found in 17.9% of cases. In the HGSIL group, the reaction was recorded in 19.7% of cases, the expression being predominantly low. In the ISM group, the marker was detectable in 88.5% of cases; of them 51.4% showing a high expression. The expressions of p16NK4a and Ki-67 were statistically significantly higher in the HGSIL group (p < 0.05) than those in the LGSIL and ISM groups. On the contrary, the expression of CK1 7 was significantly higher in the ISM group (p < 0.05) than in the HGSIL and LGSIL groups. Thus, evaluation of p16INK4a, Ki-67, and CK17 expressions is a valuable diagnostic tool in the differential diagnosis of HGSIL, LGSIL, and ISM. PMID- 21695982 TI - [Coupling between the hemodynamic parameters and the morphological changes in the kidney in children with congenital hydronephrosis]. AB - The data of renal ultrasonographic and Doppler studies were comparatively assessed in children with congenital hydronephrosis. The degree of renal B-mode ultrasound hemodynamic parameters was used as the basis for grouping of the children. The resistance index (RI) of all branches of renal arteries receives attention. Morphological studies were carried out on renal biopsy specimens from 29 children from different groups and on 12 removed kidneys; the expression of TGF beta1 and alphaSMA was revealed using the streptavidin-biotin-peroxidase method. Morphological changes as hypoplasia or dysplasia became more pronounced from Group 1 to Group 3, RI increasing to peak in Group 3. Vascular changes were confined to compensatory processes following the pattern of remodeling that was manifested by vascular wall thickening and a gradual increase in RI. Failing compensatory processes resulted in the development of renal functional and hormonal decompensation and in the elevation of RI. There was a coupling between the magnitude of morphological changes and RI increases. A set of the findings emphasizes the undoubtedly important role of renal ultrasound study that makes it possible to judge the state of the vascular bed and to suggest renal structural problems in congenital hydronephrosis. PMID- 21695983 TI - [Immunohistochemical study of human fetal vomerona structures the nasal septum, by applying neuron-specific beta3-tubulin antibodies]. AB - The functioning of Jacobson's or vomeronasal organ (VNO) in man is the subject matter of discussion today. It is generally taken that VNO as an anatomic structure also remains in the adult; however, its receptor apparatus still degenerates in the fetal stage of ontogenesis. Nevertheless, the data available in the literature on the time and specific features of degenerative changes in the human fetal VNO are conflicting and ambiguous. The authors examined the human fetal nasal septum from the 8th week of development to birth, by applying the traditional histological procedures and neuron-specific beta3-tubulin antibodies. An immunohistochemical study could first show the receptor apparatus of the human fetal VNO at weeks 8-26 of development. The immunohistochemical study on a series of sections could reveal the regularities of spatial receptor distribution depending on the time of fetal development. In addition, the developed human fetal vomeronasal nerve and ganglion at weeks 8-26 were described, in human fetuses at weeks 8-26. The neuron-specific marker test has shown the nerve fibers departing directly from the VNO wall, which is inconsistent with the data available in the literature on vomeronasal nerve degeneration in this sign just after the 18th week of development. PMID- 21695984 TI - [Investigation of uterine scraping after non-progressive pregnancy due to HLA compatibility in married couples]. AB - Non-progressive pregnancy in the first trimester is one of the common and little studied causes of early habitual miscarriage. Pathohistological and immunohistochemical investigations of uterine scrapings were first carried out during laboratorily verified observations of HLA compatibility of two (12 patients) or more (12 patients) similar alleles. Stepwise degradation of decidual cells in the uteroplacental area and parietal endometrium was revealed as their pathomorphological equivalents due to the activation of local large granular lymphocytes and macrophages. These cells are characterized by a strong release of proteolytic enzymes and by cytolysis of surrounding decidual cells. Moreover, there was superficial cytotrophoblastic invasion, atrophy, and numerous villous epithelial defects with villous cytotrophoblast reduction. These pathological markers in the uterine scrapings are proposed to use for a further goal-oriented study of a married couple-HLA system. PMID- 21695985 TI - [The first experience of external quality control of immunohistochemical studies in the diagnosis of lymphoproliferative diseases]. AB - The paper presents the results of estimating the quality of immunohistochemical (IHC) staining in 36 pathologic laboratories of the Russian Federation. The results of IHC stains were assessed in 17 markers (CD3, CD5, CDIO, CD15, CD20, CD23, CD30, Bcl2, Bcl6, Pax5, TdT, Mum1, Cyclin D1, Ki-67, Kappa, Lambda, ALK), which are frequently used in the diagnosis of lymphoproliferative diseases, in the sections of specially formed tissue matrices. The study conducted in most participating laboratories has revealed the considerable IHC staining technology flaws that can critically affect the quality of diagnosis of lymphoproliferative diseases; the diagnostic capacities of some participating laboratories are inconsistent with the solved problems for a number of key antibodies being unavailable. PMID- 21695986 TI - [Control of the quality of tissue morphological diagnosis from the results of the Oncology.ru Pathology school]. AB - Two-year experience of the Oncology.ru Pathology school showed typical errors in the morphological diagnosis of complex cancer diseases, which were made in 7-67% of the examined cases. Inaccuracies in formulating morphological conclusions were made in 5-71% of the examined cases. The highest frequency of erroneous answers (67%) was noted in vaginal myxoid fibroma. Errors were relatively less common (31 45%) while diagnosing carcinoma of the perspiratory and sebaceous glands, neurofibroma, and Abrikosov's tumor of the skin. The average frequency of erroneous answers was in the range of 12-21% in cases of gastrointestinal stromal tumor of the esophagus, breast carcinoma in situ, placental hemangioma, vaginal botroid rhabdomyosarcoma, and malignant fibrous histiocytoma of the skin. The least frequency (7-10%) of errors was recorded when gastrointestinal carcinoid tumors, urothelial cancer of the bladder, cylindroma, and melanoma of the skin, and gastric MALT lymphoma were diagnosed. Retrospective analysis of these errors can be a real impetus to self-education and have great benefits to improve specialists' professional skills. It is extremely necessary to use of various education forms, including informal trainings, for continuous professional improvement of pathologists. PMID- 21695987 TI - [Chromophobic carcinoma of the kidney with intracytoplasmic tubules]. AB - The paper describes a rare case of chromophobic carcinoma (eosinophilic variant) of the kidney in a 72-year-old woman with the ultrastructural feature- intracellular tubules along with vesicular structures and mitochondria. Intracellular tubules are also seen during immunohistochemical study of the tumor. PMID- 21695988 TI - [Morphological study of ANCA-associated glomerulonephritis in children]. AB - The paper presents the results of a morphological study of ANCA-associated glomerulonephritis in children with different ANCA titers in the blood. Cellular and fibrotic crescents and tubulointerstitial fibrosis were noted when the blood ANCA values were low. On the contrary, destructive changes were prevalent in the glomerular loop and tubular walls when the blood ANCA values were high. PMID- 21695989 TI - [Hepatoid adenocarcinoma of the lung with multiple metastases to the small bowel]. AB - The authors describe a case of hepatoid adenocarcinoma of the lung with multiple metastases to the small bowel. An immunohistochemical study has been conducted. PMID- 21695990 TI - [Cardiac angiosarcoma]. AB - The paper outlines the authors'case of cardiac angiosarcoma. It provides the gross and microscopic characteristics of this tumor and procedures for its clinical and immunomorphological diagnosis. PMID- 21695991 TI - [Primary giant pulmonary leiomyosarcoma]. AB - The authors describe their case of primary giant pulmonary leiomyosarcoma as a rare cancer nosological entity. The specific features of the case were not only its rarity, the extent of lung and mediastinal involvement, and the pattern of tumor growth, but also the absence of metastases despite aggressive course. The size of the tumor and its specific growth pattern determined technical surgical treatment problems and early postoperative complications that resulted in death. PMID- 21695992 TI - [Telepathology in Uzbekistan]. AB - Since 2003, a system of teleconsultations by the specialists of regional postmortem bureaus (RPB) in various areas of pathology has been stepwisely set up on the basis of the Republican Postmortem Center in Uzbekistan. Each of 13 RPBs has at its disposal microscopes with digital photo and television cameras, and a fast-acting internet to transmit microscopic images of difficult cancer biopsies and autopsies, including cases of maternal deaths. The local specialists transmit these data to the Republican Postmortem Center (Tashkent). Such verified biopsies were more than 8000 in late 2008. The introduction of new information technologies in Uzbekistan has allowed a number of essential, organizational diagnostic problems to be solved. PMID- 21695993 TI - [Papillary thyroid carcinoma from tall and columnar cells]. AB - The paper analyzes the data available in the literature on the morphological and prognostic features of the relatively rare morphological types of papillary thyroid carcinoma from tall and columnar cells. It is shown that the poor prognostic tall cell variant may be successfully diagnosed in the cytological smears of preoperative fine-needle biopsy and by histological examination of surgically removed tumor tissue. The question of the borderline extent of tall cells in order to single out the tumor as an individual classification category remains open. Columnar cell carcinoma poses great difficulties in making cytological and histological diagnoses. The prognosis of nonencapsulated tumors is poor as compared with that of encapsulated analogs of this variant. PMID- 21695994 TI - [Disputable problems of the pathogenesis of implantation of the placenta into the uterine wall]. AB - The review analyzes publications on the clinical and pathomorphological diagnosis of implantation of the placenta (placenta accreta) (500 references). It characterizes the prevalence of placenta accreta in different countries of the world and a rapid increase in this indicator because of a rise in cesarean sections with further uterine scars. The clinical variants, major pathomorphological types, risk factors of this severe puerperal obstetric complication and the existing hypotheses of its pathogenesis are given. Promises for further studies of the mechanisms for implantation of villi and surrounding components of the uterine placental bed are denoted. PMID- 21695995 TI - [A pathologist's thoughts on the cytological diagnosis of thyroid neoplasias]. AB - Terminological and classification aspects are of great importance in the systems approach to managing endocrinological patients, including those with thyroid cancer. The 2007 Bethesda (USA) thyroid cytological study classification system contributes to the improvement of patient selection results for surgery for cancer evidence. Experience with more than 120000 cytological studies and more than 4500 examinations of intraoperative thyroid specimens could reveal some gap between the cytological interpretation of thyroid pathology and the evaluation of individual morphological phenomena that are particularly important in the differential diagnosis of follicular neoplasias, rare variants of papillary carcinoma. Among other things, there was evidence that it was inexpedient to use the term "dysplasia" in relation to the follicular epithelium and in both cytological and histological practice. Analysis of the results of consultations could reveal the most common diagnostic errors during morphological studies. PMID- 21695996 TI - [Lymphadenitis caused by nontuberculous mycobacteriae]. AB - Lymphadenitis caused by nontuberculous mycobacteriae has been increasingly seen in Finland since the cessation of universal BCG vaccination in 2006. An otherwise healthy child develops a slowly growing unilateral mass in the cervicofacial region. Without treatment, the lymphadenitis suppurates and forms a draining sinus, which dries after some weeks or months, leaving a scar. Surgical excision is curative treatment but cannot always be performed because of risk to the facial nerve or need of extensive surgery. In these cases, observation without antimicrobial treatment is usually recommended. The parents need professional information and support. PMID- 21695997 TI - [Personality disorders and working capacity]. AB - Personality disorders are common: some personality disorder is present in 6 to 10% of the populations. These disorders appear mostly together with some other psychiatric disorder which often has a larger impact on the working ability than the personality disorder. Because personality disorders appear particularly in interactive relationships, the patients may impose strain on their work community and jeopardize the working capacity of their workmates. Work itself is likely to improve the prognosis of personality disorders. Thus, for a person with personality disorder after losing his/her working capacity, primary objectives are active therapeutic approach, as short sick leave as possible and support for returning to work. PMID- 21695998 TI - [Pain caused by chronic pancreatitis]. AB - Pain is a predominant symptom in chronic pancreatitis. When diagnosing chronic pancreatitis it is important to exclude other causes of abdominal pain. Diagnostic evaluation can be started with upper abdominal ultrasound examination and fecal elastase-1 assay. Treatment of pancreatic pain should be actively carried out in order to prevent the pain to become chronic. If the pain cannot be managed with anti-inflammatory drugs and modifications of lifestyle, endoscopic, radiologic and surgical treatments have to be contemplated. PMID- 21695999 TI - [Are there enough medical scientists in Finland?]. AB - Discussion within the scientific society and hospital communities has raised concerns of the current status and future of clinical research in Finland. One of the crucial future challenges is whether there are enough medical scientists that are able to perform clinical research and comprehend and manage medicine as a whole. In the article, the authors present suggestions for solving the problematic issues. PMID- 21696000 TI - [Network-based continuing medical education]. AB - Network-based training can provide continuing medical education with methods, whose implementation by means of traditional training is difficult or practically impossible. By virtue of its chronological and geographical flexibility, educational application of the network may provide extra advantage for the trainee and the trainer. Implementation of network-based training is, however, demanding and laborious both technically and pedagogically, whereby organizations should strive for collaboration in organizing the training. In addition, the status of network-based continuing education in relation to the physician's working time should be clearly defined. PMID- 21696001 TI - [Congenital nephrotic syndrome of the Finnish type--key to the mechanisms of proteinuria]. AB - Congenital nephrotic syndrome of the Finnish type is a serious renal disease belonging to the Finnish disease heritage. It appears as substantial proteinuria, hypoproteinemia and edema in a newborn. Kidney transplantation is the only effective treatment. The cause of the disease is a mutation in the gene encoding the nephrin protein. Nephrin is produced by the epithelial cell (podocyte) of the glomerulus. It is expressed in the slit membrane connecting the pedicles of the podocyte. This finding has revolutionized the concept of glomerular filtration and set off active research on the pathogenetic mechanisms of proteinuria. PMID- 21696002 TI - [When should a patient be tested for HIV?]. AB - Thanks to current drug therapy, the prognosis of an early diagnosed HIV-positive patient is almost equivalent to the life expectancy of the general population. Because HIV-positive persons remain typically symptomless for years, suspicion of the infection should be remembered not only on the basis of symptoms compatible with the disease, but also on the basis of mere exposure. A symptomatic HIV patient may be encountered in any special field. The possibility of a symptomless HIV infection should be always kept in mind with patients having a known sexually transmitted disease or chronic viral hepatitis. Diagnosis of HIV is based on the demonstration of antibodies and/ or HIV antigen. PMID- 21696003 TI - [HaiPro--what was learned from patient safety incidents in Finnish health care units in 2007 to 2009?]. AB - Reports of the HaiPro reporting system are described and the role of reporting procedure aiming at internal development of the units and the possibilities of national development and monitoring of patient safety are discussed. The study material consisted of 64,405 reports of patient safety incidents accumulated from May 5, 2007 to December 31, 2009 to the HaiPro database from 36 user organizations. Of the reported incidents, 51% were associated with medicaments and the process of medication. The most common incidents were errors in registration, dispensing and administration of the drugs. PMID- 21696004 TI - [Fatal tick-borne encephalitis]. AB - The number of cases with tick-borne encephalitis in Europe has increased particularly in the 1990's, and new regions have become endemic. Ixodes persulcatus, i.e. the taiga tick, is found on the west coast of Finland along the Narpio-Simo axis. This tick has not been encountered in other parts of Western Europe. In Kokkola archipelago it transmits the Siberian subtype of tick-borne encephalitis virus. We describe the first and fatal case of tick-borne encephalitis transmitted by the "taiga tick" in Finland. PMID- 21696005 TI - [Update on current care guidelines: resuscitation]. AB - The Finnish national cardiopulmonary resuscitation guideline has been published as part of the Current Care, evidence-based guidelines series. This article gives a short overview of the main recommendations. Throughout, the guideline emphasises the quality of chest compressions. Intubation should be attempted only by a health care provider with adequate training and experience. Adrenaline and amiodarone are the only drugs used in cases of cardiac arrest. Patients at risk of cardiac arrest should be identified and preventative action taken. In health care facilities, do-not-attempt-resuscitation (DNAR) decisions should be done in advance for patients who would not survive from cardiac arrest. PMID- 21696006 TI - [Cooperation between hospitals and clinics in the treatment of inflammatory bowel diseases. A discussion]. PMID- 21696007 TI - Choices clinicians must make: when to intervene and how to help. PMID- 21696008 TI - [A voice]. PMID- 21696009 TI - [Killing and dignity of animals: a problem for veterinarians?]. AB - Killing of animals is an important task to be performed by veterinarians. Killing decisions and their implementation often raise ethical questions. As a result of an interdisciplinary workshop targeting the subject "killing of animals" with veterinarians and ethicists, a three-dimensional dimension scheme was developed. Whereas the first two dimensions are focused on the animal's past and future life and are discussed with regard to life quality and life accomplishment (the "telos"), the third dimension incorporates the reason to kill and may integrate the concept of dignity. This form of dignity and the weighing of interests are applied to example scenarios and the resulting responsibilities of veterinarians and society are discussed. PMID- 21696010 TI - Mesenchymal gene-expression profile identifies subgroup of glioblastoma patients that may be more responsive to dendritic cell vaccine. PMID- 21696011 TI - Amniotic fluid biomarkers are linked to oxidative stress in Down syndrome. PMID- 21696013 TI - Working with dental school admissions committees to enroll a more diverse student body. AB - The American Dental Education Association's Admissions Committee Workshop (ADEA ACW) was designed to challenge dental school administrators and admissions committee members to review their current admissions practices and to explore ways to attract a more diverse student body. Presented at the invitation of dental schools, this half-day interactive workshop provides opportunities for a dental school's administrators, staff, and admissions committee members to learn about the value of diversity in the educational environment and how to implement holistic admissions practices that take into consideration the experiences, attributes, and metrics of candidates for admission. This report explores the rationale for the development of the ADEA ACW, discusses lessons learned from presentation of the workshop at more than twenty-seven U.S. dental schools, and tracks enrollment trends of underrepresented minority students in dental schools where the workshop has been presented. PMID- 21696012 TI - [Hospital mortality after emergency surgery for perforated diverticulitis]. AB - OBJECTIVE: To assess which factors predict in-hospital mortality after emergency surgery for acute perforated diverticulitis. DESIGN: Multicenter retrospective study. METHOD: From 1995-2005 a total of 291 patients underwent surgery to treat perforated diverticulitis in five teaching hospitals in Rotterdam, the Netherlands. The relation to postoperative mortality of patient-related risk factors such as age, gender and classification according to the American Society of Anesthesiologists (ASA); disease severity factors such as Hinchey score and Mannheim peritonitis index (MPI); surgery-related risk factors, such as type of surgery, e.g. Hartmann's procedure (HP) or resection with primary anastomosis; surgeon, and time of operation were evaluated using multivariate analysis. RESULTS: The total postoperative in-hospital mortality was 29%. HP was performed 211 times and primary anastomosis was performed 75 times. HP was significantly more frequently performed in patients with higher values of age, ASA, Hinchey and MPI (all: p < 0.01). Multiple logistic regression analysis showed that age, ASA classification, Hinchey score, MPI and the absence of a specialist gastrointestinal surgeon during surgery, were important prognostic factors of mortality. Surgical technique was not related to postoperative mortality (adjusted odds ratio for mortality (HP versus primary anastomosis): 1.3; 95% CI: 0.6-2.9; p = 0.54). CONCLUSION: The type of surgery did not appear to be a risk factor for high postoperative mortality. As well as patient-related risk factors, including age, ASA and severity of disease scores, such as Hinchey score and MPI, the absence of a specialist gastrointestinal surgeon during surgery was found to be a factor associated with high mortality risk. PMID- 21696014 TI - National Vaccine Injury Compensation Program: revisions to the vaccine injury table. Final rule. AB - On September 13, 2010, the Secretary of Health and Human Services (the Secretary) published in the Federal Register a Notice of Proposed Rulemaking (NPRM) proposing changes to the regulations governing the National Vaccine Injury Compensation Program (VICP). Specifically, the Secretary proposed revisions to the Vaccine Injury Table (Table) to create distinct listings for hepatitis A, trivalent influenza, meningococcal, and human papillomavirus vaccines. The Secretary is now making this amendment to the Table by final rule; it is technical in nature. The four categories of vaccines described in this final rule are already covered vaccines under the VICP (starting in 2004) and are currently listed in a placeholder category (box XIII) in the Table. This final rule will list these vaccines as separate categories on the Table, with no associated injuries noted at this time, in order to help the public identify clearly that these vaccines are covered by the VICP. The changes implemented here are authorized by section 2114(e) of the Public Health Service Act (the Act). PMID- 21696015 TI - Evaluating the impact of the ADEA Admissions Committee Workshops. AB - Drawing on the interconnection of workforce diversity and oral health access, the American Dental Education Association (ADEA) is leading a novel approach to improve student body diversity in U.S. dental schools through an admissions committee development program. With funding provided by the Pipeline, Profession, and Practice: Community-Based Dental Education program and the Robert Wood Johnson Foundation, ten dental directors/deans of admissions from a cross-section of U.S. dental schools were selected through a competitive application process to participate in a Train-the-Trainers Admissions Committee Workshop. After completing intensive training that was built on legally sound admissions practices, these new trainers copresented ADEA Admissions Committee Workshops in two-member teams at six U.S. dental schools. This report summarizes the evaluation of both the train-the-trainers workshop and six workshops held in summer 2009. Also summarized are post-workshop outcomes relative to structural diversity at the participating schools. PMID- 21696016 TI - Advancement of women in dental education: expanding opportunities, enriching the pool. AB - In the recent past, we have seen both the dental student applicant and enrollment pools of women in the United States increase. There has been an increase in both women applicants and first-year enrollees from the year 2000. The advancement of women in advanced educational programs and into dental faculty positions has likewise seen a trend of increase. The challenge to dental education is to ensure that the recruitment and advancement of women to careers in dental education and research in the future are consistent with their talent, expertise, and career expectations. Within this pool of women are our future leaders, deans, and researchers. As we consider future faculty needs for all dental faculty members, we must consider the unique needs of women who must balance their careers with other societal demands related to their gender. PMID- 21696017 TI - Required warnings for cigarette packages and advertisements. Final rule. AB - The Food and Drug Administration (FDA) is amending its regulations to add a new requirement for the display of health warnings on cigarette packages and in cigarette advertisements. This rule implements a provision of the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) that requires FDA to issue regulations requiring color graphics, depicting the negative health consequences of smoking, to accompany the nine new textual warning statements required under the Tobacco Control Act. The Tobacco Control Act amends the Federal Cigarette Labeling and Advertising Act (FCLAA) to require each cigarette package and advertisement to bear one of nine new textual warning statements. This final rule specifies the color graphic images that must accompany each of the nine new textual warning statements. PMID- 21696018 TI - Colon and rectal surgery. PMID- 21696019 TI - Developmental-behavioral pediatrics. PMID- 21696020 TI - Addiction psychiatry. PMID- 21696022 TI - [Keypoints in psychiatric specialty training]. PMID- 21696021 TI - [Q & A. A patient brought in a comatose state, displaying acute hepatic disorder and an area of high absorption in the stomach in CT images]. PMID- 21696023 TI - [Training system and the current status of psychiatry specialist certification system]. PMID- 21696024 TI - [On the psychiatry residency program (specialist course) at Fukushima Prefectural Medical School Hospital]. PMID- 21696025 TI - [Acceptance of the psychiatry residency program at hospitals of local autonomous governments and general hospitals]. PMID- 21696026 TI - [Collaboration with psychiatrists--with special reference to examples]. PMID- 21696027 TI - [Collaboration with psychiatrists at hospitals--a viewpoint of a psychiatric nurse]. PMID- 21696028 TI - Cardiovascular Nursing: Scope and Standards of Practice (2008). PMID- 21696029 TI - Trend in lung transplantation in the U.S.: an analysis of the UNOS registry. AB - The number of lung transplants continues to increase in the U.S. The most significant change over the last decade occurred after the 2005 implementation of LAS. When the percentage of patients being transplanted increased even further, while time-to-transplant and the number of patients dying on the waiting list significantly declined. As a result of implementation of LAS in 2005, IPF recipients became the largest group to receive a lung transplant. And the number of transplants for patients age 60 and over has increased significantly. The number of DL transplants performed yearly increased while the number of SL transplants has remained relatively consistent throughout the last decade. Though the gender distribution of recipients has fluctuated each year, the proportion of females receiving lung transplant has decreased. Of the deceased-donor DL and SL transplant recipients, 69% had a cold ischemia time between 3-6 hrs. And 79% of primary DL and SL transplant recipients had a 0% PRA. 6. A higher number of HLA mismatches impacts unfavorably on graft survival rates; yet, surprisingly, zero HLA A-B-DR MM also have an unfavorable impact; Recipients with less than two hours of cold ischemia-time (n = 815, 4.3%) have the worst five-year graft survival; PRA levels greater than 25% have an unfavorable impact on graft survival. PMID- 21696030 TI - Simultaneous pancreas-kidney transplantation in the United States: an analysis of the UNOS registry. AB - The rate of chronic pancreas graft loss in simultaneous pancreas kidney transplantation has remained almost unchanged despite induction therapy. Since 1987, seven major immunosuppressive induction agents-basiliximab, daclizumab, ALG, eATG, OKT 3, alembuzumab, rATG-have been used as immunosuppressive induction agents. Those agents improved short-term survival by preventing acute rejection, but improvement of short-term survival has not translated into improved long-term graft survival. As with most solid organ transplants, there is a need for means to control chronic rejection to improve long-term graft survival. PMID- 21696031 TI - The current trend of induction and maintenance treatment in patient of different PRA levels: a report on OPTN/UNOS Kidney Transplant Registry data. AB - We investigate the status of sensitization in kidney transplant recipients and analyze the trend of induction and maintenance therapy in patients of different PRA levels. Despite the fact of the decreased percentages of kidney transplant recipients with presensitization history, the mean PRA levels of all kidney recipients has been increasing in the last 7 years, which is possibly due to the introduction of more sensitive antibody testing techniques or the tendency for kidney allocation organization and clinicians to give priority to patients with elevated PRA once a compatible donor kidney becomes available. The percentage of patients with treated rejection episodes within one year post-transplant were significantly higher in sensitized patients (PRA = 50-100:14.3%, and PRA = 1-49%: 13.9%) than in non-sensitized patients (12.4%). Both 1- and 5-yr graft survival rates have improved in the last 10 years; this was more significant in high PRA patients. Thymoglobulin was the most commonly used induction agent in last 10 years. Its users increased from 10% to 46% in non-sensitized patients, from 12% to 57% in PRA = 1-49% patients, and from 19% to 63% in PRA = 50-100% patients. The users of Campath, IVIg, and Rituximab have been increasing and reached 16%, 20%, and 11% in highly sensitized patients. In the last 5 years, steroid-free patients were 33-36%, 30-37%, and 10-25% for patients with PRA levels of 0, 1-49, and 50-100 respectively. Almost 90% of patients were on Prograf at discharge. Myfortic users have been increasing since 2005 and it may soon replace MMF if long-term follow-up study confirms its safety and efficacy. PMID- 21696032 TI - Organ allocation in the United Kingdom. AB - Organ allocation procedures in the United Kingdom are monitored on a regular basis. Changes are frequently made to improve equity of access and outcomes, based on the performance of a current scheme and simulations of alternatives. This article summarizes current arrangements for the allocation of kidneys, livers and cardiothoracic organs, and illustrates the monitoring process. A new national pancreas allocation scheme is outlined and forthcoming developments in the allocation of livers and DCD donor kidneys are summarized. PMID- 21696033 TI - 2010 report from the Center for International Blood and Marrow Transplant Research (CIBMTR): current uses and outcomes of hematopoietic cell transplants for blood and bone marrow disorders. AB - These data indicate increasing use of HCT for persons with blood and bone marrow disorders. Recent trends include increasing use of alternative donors including HLA-matched unrelated persons and of HLA-matched umbilical cord blood cells, increasing use of blood cell rather than bone marrow grafts and increasing use of reduced-intensity pretransplant conditioning regimens. Many of these shifts are driven by logistical considerations like the need for donors in persons without an HLA-identical sibling or expanding access to allotransplants to older patients. In other instances, like the shift from bone marrow to blood cell grafts or from conventional to reduced-intensity pretransplant conditioning regimens few randomized clinical trials have been reported to justify these shifts. More data are needed to critically-assess the impact of these changes. PMID- 21696034 TI - More than 1,000 kidney transplants in a single year by the "Hospital do Rim" Group in Sao Paulo - Brazil. AB - We describe the organization of a high-volume Brazilian kidney transplant program that performed 7,833 transplants in 12 years fulfilling government expectations without compromising the care of the patients. The annual number of kidney transplants increased from 428 in 1999 to 1,048 in 2010. In our Organ Procurement Organization (6.1 million inhabitants) brain death notifications increased from 196 to 468 in 2010 and 35% became actual donors. There are 5,011 patients on the waiting list and recipient selection is based on HLA matching. A significant proportion of the recipients is of black ethnicity and had been for long time on dialysis. Over 700 first appointments for living donation are done every year. After the transplant, the majority of patients are followed locally (200-250 appointments per day). The transplant outcome among living-donor recipients is comparable to large registries but inferior outcome have been observed among recipients of deceased donor organs, though consistent improvement has been seen in more recent years. We also discuss issues related to local regulations and solutions to improve efficiency and outcomes. PMID- 21696035 TI - Kidney transplantation at Necker Hospital: the most recent 5-year period (2004 2009). AB - The results of our last 5 years activity in kidney transplantation clearly show that it is possible to perform high-risk transplantations with very acceptable results: ECD kidneys, dual transplantation, recipients with DSAs. In depth statistical analysis of these data should allow a clearer definition of the best strategies to use in these situations. PMID- 21696036 TI - Long-term survival after renal transplantation: the influence of pretransplant bilateral nephrectomy. AB - The long-term survival of first successful renal transplants, along with overall patient survival, was studied retrospectively in 309 recipients at Belfast City Hospital between 1968 and 1986, of whom 155 had undergone prior bilateral nephrectomy (BN) and 154 had not (non-BN). The groups were comparable as regards mean age, gender, primary diagnoses, clinical status, pre-existing hypertension and pre-transplant dialysis and transfusion. There were 34 organs (BN 14, non-BN 20) from living related donors. Donor ages were comparable, as were histocompatibility findings. Recipients more than 60, with diabetic nephropathy, or with other co-morbidity were excluded. All recipients took azathioprine and low-dose steroid as maintenance antirejection, fewer than 3% switching to cyclosporine or other drugs during first graft survival. Mean BN graft survival was 15.9 years (95% CI 14.1-17.7) compared to 12.9 for non-BN (95% CI 11.3-14.5; p < 0.01). Mean BN patient survival was 19.4 years (95% CI 17.6-21.2) and non-BN was 14.9 years (95% CI 13.2-16.6; p < 0.01). Cumulative BN graft survival was 76.8% at 5 years, 61.6% at 10 years, and 37.4% at 20 years, compared to 67.1%, 53.5% and 27.0% for non-BN (p < 0.01). Overall BN patient survival was 84.5% at 5 years, 74.2% at 10 years and 51.6% at 20 years, with non-BN equivalents of 72.3%, 49.0% and 24.5%, respectively (p < 0.01). Long-term BN survivors also had less hypertension than non-BN (22.8% v 54.8% at 20 years; p < 0.05) which may be relevant to their better survival. Overall (BN plus non-BN) median graft (14.4 years) and patient (17.6 years) survival are testimony to the continuing long term success of the low-dose steroid regime followed in Belfast from 1968 to 1986. PMID- 21696037 TI - The 37-year kidney transplantation experience at Siriraj Hospital. AB - With 37-years of experience, a total of 801 kidney transplantations (59.4% were deceased donors and 40.6% were living donors) performed at Siriraj hospital were reported. The point system parallel to OPTN/UNOS for waitlists was utilized. Most of the recipients of deceased donor kidney transplantations had 3 HLA mismatches. Due to the point allocation system, none of them had 6 HLA mismatches. Extended criteria donor comprised 7.8% of all deceased donors. Mean duration of dialysis prior to deceased donor transplant was 53 +/- 34 months. Delayed graft function (DGF) was found in 54% of deceased donor kidney transplantation and resulted in significantly higher rate of 1 year biopsy-proven acute rejection, longer duration of kidney transplant admission, higher admission cost and lower patient survival compared to those with immediate graft function. Most of living donor kidney transplant recipient had 1 haplotype match. Mean donor age was 35.9 +/- 9.8 years. 95.6% of the recipients were on hemodialysis prior to transplantation. The current standard regimen includes calcineurin inhibitor, Mycophenolic acid and prednisolone. Interleukin-2 receptor monoclonal antibody has been used in the high immunological risk or high risk for DGF recipients that were 50% of the recipients. There was no statistically significant difference in the biopsy proven acute rejection (BPAR) free survival between deceased and living donor transplantation. Proportion of cases with the diagnosis of acute rejection according to Banff 2007 classification is as follows: 32.4% acute cellular rejection (ACR), 39.4% antibody-mediated rejection (AMR) and 21.1% mixed cellular and antibody-mediated rejection. Seventy two patients, 35 deceased donor and 37 living donor kidney transplant recipients, had biopsy-proven glomerular disease after transplantation which IgA nephropathy is the most common form of glomerulonephritis. Median graft survival was 7.6 and 13.2 years and median patient survival was 12.1 and 15.5 years for recipient of deceased and living donor transplant respectively. The follow up program of living donors was introduced in 2003 and there were not any donors who required renal replacement therapy. PMID- 21696038 TI - Outcomes for kidney transplants at the National University Health System: comparison with overseas transplants. AB - The 5-year and 10-year graft survivals for 186 deceased donor (DD) transplants performed at National University Health System (NUHS) were 79.9% and 58.4% respectively. 5-year and 10-year patient survivals for DD transplants performed at NUHS were 94.2% and 83.4%. The 5-year and 10-year graft survivals for 128 living donor (LD) transplants performed at NUHS were 90.2% and 72% respectively. 5-year and 10-year patient survivals for DD transplants performed at NUHS were 98.6% and 95.1%. The projected graft half lives were 14.6 and 20.6 years for DD and LD transplants respectively. These results compare favorably with the 10-year survival rates of 40% and 58% for DD and LD grafts reported by the United States Renal Data System (USRDS) in 2010. The younger age and the lower prevalence of diabetes and HLAmismatch in the DD and LD transplant study populations, in comparison to the USRDS population and perhaps better access and compliance to maintenance immunosuppression, could have contributed to these excellent outcomes. The 5-year and 10-year graft survivals for 162 transplants receiving what were likely deceased donor kidneys from China were 89.2% and 69.2% respectively. Although these survivals were apparently better than that for DD performed at NUHS, the advantage for China Tx disappeared when DD with primary non function or vascular thrombosis were excluded from analysis. The 5-year and 10-year patient survivals for 30 transplants receiving live non-related transplants from India were 82.3% and 60.1%. Both groups were considered to have received commercial transplants based on various aspects of history from the patients. Among those receiving China_Tx or India Tx, there were a disproportionate number of males and Chinese; and a significant proportion underwent pre-emptive transplant or transplant after only a short period of dialysis. Prevalence of post-transplant hepatitis B was significantly higher among China_Tx than their DD counterparts (7.7% vs. 1.2%, P = 0.005); likewise, post transplant hepatitis C was significantly higher for India_Tx than their LD counterparts (23.1% vs. 3.4%, P = 0.003). These results suggest that commercialization in transplant, results in inequities to access to transplantation and is associated with compromise in screening for infections among potential donors or in observing safety precautions during dialysis. PMID- 21696039 TI - Kidney transplantation at UCSF: 8,300 transplants and onward. AB - Overall, the kidney transplant experience at UCSF has been highly successful. The program has made significant contributions to the field of kidney transplantation with advancements in organ allocation, crossmatching, clinical trials, pediatric transplantation, organ preservation and transplantation in HIV-positive recipients, to name a few. The program was built on the shoulders of giants in kidney transplantation but continues to be innovative and bold and does not rely on past success to pave the future. The program is truly a tribute to the many surgeons, nephrologists, fellows and ancillary personnel who have made this program a premiere center for kidney transplantation over the past 40 years. PMID- 21696040 TI - One hundred percent three-year graft and patient survival: kidney transplantation at Saint Joseph Hospital of Orange. AB - We report 99 consecutive renal transplants between 7/1/04 and 6/30/07 with 100% 3 year graft survival, statistically higher than expected per the SRTR (p < 0.01). Ninety-eight patients had antibody induction of immunosuppression with either daclizumab (n = 52) or Thymoglobulin (n = 46). Steroids were minimized with nearly all patients tapered to prednisone 5 mg by discharge. Sixteen patients experienced early rejection. Twelve of the rejections were in 85 patients who received ABO compatible first transplants. Of these 12 rejections, 11 occurred in patients who had been induced with daclizumab and one with Thymoglobulin (p = 0.01). Immunosuppression, infection prophylaxis and surveillance, and all medical and social issues potentially impacting graft or patient survival were managed by the transplant center for the first year minimum, and as long as clinically indicated post-transplant. Patients were educated to have all subsequent medical and social issues triaged by the transplant center for the life of the transplant. PMID- 21696041 TI - The Liver Transplant Program at the Charite Berlin. AB - Liver transplantation is a well established procedure for patients in end-stage liver disease. The Liver Transplant Program at the Charit Berlin has 22 years of experience with over 2500 transplanted patients. Notwithstanding the progress in the field the overall outcome after liver transplantation has been challenged recently because of a rising demand for donor livers in the presence of a severe lack of suitable organs, rising numbers of extended criteria donors, and erroneous developments of allocation algorithms. In order to facilitate a just, transparent, and balanced allocation of a limited number of deceased donor livers, a MELD-based allocation system was imposed in the EUROTRANSPLANT-region in December 2006. Though waiting list mortality was successfully reduced from 20 to 10% since then, 1-year post-transplant patient outcome was impaired by a similar extent from 90% to below 80%. Concurrently, the allocation threshold rose significantly (Fig. 6); the mean match-MELD increased from 25 to 34 in Germany. Reasons for that are certainly multifactorial. However, inappropriate incentives on the basis of a rising economic pressure and a limitation of medical resources contribute significantly. In order to overcome these erroneous developments allocation algorithms and incentives should be modified. PMID- 21696042 TI - Liver transplantation at Cleveland Clinic. AB - This review describes our program and its outcomes and then provides an in-depth focuses into many of the unique aspects of our practice that have been important to the success of the program. These include a global appreciation for the impact and various presentations of chronic portal hypertension. We have sought to better understand and describe the various effects it can have on local allograft hemodynamics and graft survival. Intraoperative blood flow measurements of the hepatic artery and portal vein are important. Postoperative follow-up with Doppler ultrasound has been essential for both partial and whole grafts. A better understanding of systemic and graft hemodynamics has changed our clinical practice with regards to the intra- and post-operative management of the hepatic artery and portal vein. We have also focused on the issue of hepatocellular carcinoma, one of the major indications for liver transplantation. We have sought to better understand the heterogeneous clinical presentations of this disease and how to best approach them in a multidisciplinary fashion. Finally, we describe the various methods we have utilized to increase the number of hepatic grafts available for our patients. We have aggressively utilized all forms of grafts; living and deceased; partial and whole; and extended and standard criteria donors. We have done this with the focus on living donor safety and then concentrated on finding the best graft for the individual patient in the context of the national allocation systems in which we all work. PMID- 21696043 TI - Heart transplantation at the Deutsches Herzzentrum Berlin. AB - The Deutsches Herzzentrum Berlin is one of the largest transplant centers in Germany with more than 1700 transplant procedures, more than 170 being procedures in children, in patients from the beginning of life to 71 years of age. Survival rates during the early and intermediate follow-up are lower than in international data; however, long-term survival at 15 years or more is similar. Discrepant survival rates derive mainly from the organ shortage that resulted in the development of a different allocation system in Germany as compared to North America and in the increasing number of patients undergoing the bridge-to transplant concept to move the patient to transplantability. Thus, the patient at highest risk of death while on the waiting list, who according to the ISHLT registry is also the patient at highest risk of death early post-transplant, is the candidate most likely to undergo transplantation in Germany. Unfortunately, the myth persists of solving the donor organ shortage by increasing the "fairness" of organ allocation. Major goals of our transplant program are: the introduction of non-invasive cellular rejection screening with the intramyocardial electrogram (IMEG) and echocardiography; to characterize microvasculopathy in biopsy as a novel and easily diagnosed marker for poor prognosis; to identify Quilty as a determinant for poor prognosis; to propose classifications for microvasculopathy and epicardial vasculopathy that consider the diffuse character of the disease; and to provide insights into the therapeutic options and potential clinical benefits of novel immunosuppressive strategies. PMID- 21696044 TI - Lung transplantation at Barnes-Jewish Hospital and Washington University in St. Louis. AB - The lung transplant program at Washington University and Barnes-Jewish Hospital has performed more than 1,000 lung transplants since 1988. The most common operation during this time period has been bilateral-lung transplantation. The LAS has changed lung recipients' diagnoses nationally and at our center. IPF accounts for approximately 25% of recipients at our program and 33% of recipients nationally. Although more severely and acutely ill patients are now coming to transplantation, the long-term outcomes after transplantation have not changed substantially. The incidence of all forms of rejection is high after lung transplantation despite modern immunosuppressive regimens and surveillance techniques. Long-term survival after lung transplantation remains disappointing. In the most recent cohort, the 5-year survival is 64%, but this is significantly worse than survival after kidney, liver, and heart transplantation. PMID- 21696045 TI - Improving outcomes after intestinal transplantation at the University of California, Los Angeles. AB - This study summarizes a two decade experience with ITx at a single institution. It represents one of the largest such reports on the subject. Results indicate that a significant improvement in outcome has occurred since 2000. This improvement relates to center experience, induction immunotherapy, surgical techniques along with the reduction in CMV and EBV disease. Further advancements will require more focused analyses on outcomes after ITx. PMID- 21696046 TI - The HLA-matching effect in different cohorts of kidney transplant recipients: 10 years later. AB - Almost all the HLA-matching effects found by the 2000 analysis were confirmed by this study. The only HLA-matching effect found in the 2000 analysis that disappeared were those of "small matching effect" found in sub-populations of type I diabetes (PRA < 10%, donor age 20-35). The 2000 analysis found a lack of HLA matching effect in non-African American kidney transplant patients with type I diabetes between 1987 and 2000. The 2000 analysis found that a patients' ethnic group was a factor in graft survival; African American patients were found to have a significantly lower 10-year graft survival in the 5 or 6 mismatched group (27%) compared to Caucasian patients (40%). In addition, Asian patients (42%) had higher graft survival compared to that of Caucasian patients. In this study, we observe a similar pattern with death-censored graft analysis for all ethnic groups with 10-year graft survivals at 72.9% for Asians, 69.5% for Caucasians, and 49.3% for African Americans. There was an overall lack of HLA-matching effect on patient survival in the 2000 analysis. In our current analysis, the patient survivals remained virtually the same despite moderate increase in graft survival over the same period of time. The HLA-C locus mismatch was found to have additive effect to the 10-year graft survival trends observed in A and B mismatch cases. HLA-DQ mismatch on the other hand, showed limited HLA-matching effect and did not show the same additive effect as C. There are various possible issues in the DQ mismatch analysis, from the consistency of DQ typing results, lack of diversity in the DQ antigen, to the possibility of DQ mismatch having little effect on the graft survival. Utilizing kidney transplant cases performed from 1995 through 2000, the 2000 analysis projected 10-year survivals of 64% and 47% for the 0 ABDR mismatch and 5 or 6 ABDR mismatched cases respectively; the 2000 projection only missed actual death-censored survivals by 9% lower for the 0 mismatch and 17% lower for the 5 or 6 mismatch cases. Utilizing the transplant cases of 2005 through 2009, we projected their 10-year graft survivals for year 2020. The 10 year graft survival for 0 ABDR mismatched patients is expected to be over 85% and nearly 70% for 5 or 6 ABDR mismatched patients. The general upward trend of graft survival we have observed in the last 10 years has been dependent upon the development of novel transplant protocols and use of novel immunomodulatory reagents. This trend is likely to continue given the promise of new drugs and personalized healthcare. The decreasing range of the differences in the 10-year graft survival between best matched and worst matched HLA groups is also likely to continue. One interesting trend that is clearly evident is the increasing difference between the best and worst HLA-matching in terms of the associated graft half-life. The positive HLA-matching effect on long-term graft survival is clearly evident and should be taken into consideration for all kidney transplants. PMID- 21696047 TI - Impact of donor-specific HLA antibodies in transplantation, a review of the literature published in the last three years. AB - This chapter summarizes some of the recent findings published on the role in organ transplantation of HLA antibodies, and--more important--donor-specific HLA antibodies. The negative impact of both, preformed and de novo DSA is now better recognized in recipients of kidney, heart, lung, liver, pancreas, islet cells and bone marrow transplants. An appropriate design of a schedule to monitor HLA antibodies may identify patients at higher risk for immunological events earlier and allow interventions to avoid later graft loss. The value of strategies like preemptive treatment of antibodies and the use of new agents like bortezomib and eculizumab are of interest and need further investigation. PMID- 21696048 TI - Clinical management of renal transplant patients with donor-specific alloantibody: the state of the art. AB - Our understanding of the role of DSA in both early and late renal allograft injury has advanced significantly over the past decade. Novel protocols have been developed that have led to improved outcomes both in overcoming a positive crossmatch and in the treatment of early AMR. Early experience with bortezomib and eculizumab are encouraging and suggest the possibility of validation in controlled clinical trials. While alloantibody remains an extremely difficult clinical problem and it is unclear if overcoming early hurdles will only be followed by another major hurdle of chronic antibody mediated injury. However, it is clear that significant advances have occurred and if future studies can be designed appropriately, then our ability to control alloantibody in sensitized patients will continue to improve. PMID- 21696049 TI - Using HLA antibody detection, monitoring, and treatment to improve long-term allograft survival. AB - The evidence supporting HLA antibodies as a biomarker in transplant is substantial. It is becoming more clear that these patients represent a new phenotype of patient that is at the highest risk to rapidly progress to chronic damage. Therefore early detection of these high risk patients through serial screening is necessary. Additionally, once patients develop DSA positivity, IgG subclass testing may indicate how eminent his/her graft failure ensue. Moving forward, we should focus monitoring and treating at first detection of persistent antibodies. This may be the only reasonable way to have significant impact on long-term allograft survival. PMID- 21696050 TI - Alternatives for unsuccessful living donor kidney exchange pairs. AB - Living donor kidney exchange has become an efficient solution for recipients with incompatible donors. Here we describe the fate of all patients that were enrolled in our program during 2004-2010. METHODS: Data on registration, computerized matching, cross matching, and transplantations within or outside the program were collected. RESULTS: Between January 2004 and December 2010, 422 pairs were registered. To create new combinations a match procedure was run 28 times with a median input of 14 (7-22) new pairs and a median of 55 (16-92) participating pairs. Matches were found for 127/185 (69%) cross match-incompatible pairs and 91/237 (38%) ABO-incompatible pairs. 141 of the 218 matched pairs successfully donated and received kidneys in exchange. There were 77 transplants cancelled for medical or psychological reasons, and an alternative solution was found for 26 of these. So in total 167 (141 + 26) patients received a transplant. Of the remaining 51 cancelled transplants, 26 pairs dropped out, 22 patients found an alternative transplantation outside the program and 3 are still waiting. For the 204 unmatched couples, 46 are still in the program while 34 others dropped out, and 124 found an alternative living kidney donor. After 7 years, 39% of participants received a kidney within the exchange program, 35% were transplanted outside the program, 14% of the pairs were delisted and 12% are still waiting. Among the 146 patients who received a kidney outside the program, 47 were transplanted with a deceased donor kidney, 21 found another donor, 37 received an ABO-incompatible transplant and 41 were transplanted in a domino-paired procedure triggered by an non-directed donor. CONCLUSION: In the 7 years of our Living Donor Kidney Exchange Program 313/422 (74%) of the participating patients were transplanted. Approximately half of them (167/313, 53%) received a kidney through the exchange program, while 47 (15%) received a deceased donor kidney and 99 (32%) were transplanted through other living donation programs. The exchange program proved to be highly successful not only in its direct results but also indirectly by triggering alternative solutions. PMID- 21696051 TI - National Kidney Registry: 213 transplants in three years. AB - Since its establishment in 2008, the National Kidney Registry has facilitated 213 kidney transplants between unrelated living donors and recipients at 28 transplant centers. Rapid innovations in matching strategies, advanced computer technologies, good communication and an evolving understanding of the processes at participating transplant centers and histocompatibility laboratories are among the factors driving the success of the NKR. Virtual cross match accuracy has improved from 43% to 91% as a result of changes to the HLA typing requirements for potential donors and improved mechanisms to list unacceptable HLA antigens for sensitized patients. A uniform financial agreement among participating centers eliminated a major roadblock to facilitate unbalanced donor kidney exchanges among centers. The NKR transplanted 64% of the patients registered since 2008 and the average waiting time for those transplanted in 2010 was 11 months. PMID- 21696052 TI - Kidney paired donation: a single center approach to increase living donor transplantation. AB - Methodist Specialty and Transplant Hospital has performed a total of 125 KPD transplants from the onset of the program in Dec. 2007. With the addition of the KPD program, live donor transplants have increased annually by 35% demonstrating the ability to substantially increase access to transplantation utilizing this modality. Furthermore, KPD combined with selective desensitization has provided a means for individualized assessment and management of the highly sensitized patient. PMID- 21696053 TI - An update on antibody reduction and rejection reversal following bortezomib use: a report of 52 cases across 10 centers. AB - Based on the analysis of the 52 patient cases submitted for the Antibody Treatment Report of Clinical Transplants 2010, there is growing evidence that bortezomib is a viable option for antibody mediated rejection (AMR). Today, some centers have even chosen to use bortezomib as a first line agent in their AMR cases. In desensitization, from the current available data the use of bortezomib to desensitize patients is still under investigation. The optimal number of cycles as well as predictors of those who bortezomib may be useful still remain major questions. Continued data in this area is necessary and at this point bortezomib is a viable option and should be considered as part of some patients' desensitization regimen. Finally, in the area of chronic alloantibody mediated rejection (CAMR), there is exciting new data that bortezomib may have additional benefits and may provide a few more months of survival based on its effect to reduce proteinuria. However, in the CAMR cases it is clear that the damage that has already occurred due to persistent alloantibody is irreversible. This indicates that earlier treatment of alloantibodies in patients should occur to provide the best chance of allograft success. PMID- 21696054 TI - Bortezomib for desensitization of patients on a waiting list for deceased donor kidney transplant: experience in Mexico City. AB - Highly sensitized patients represent a challenge in all transplant programs. The use of bortezomib in combination with other strategies could be a real option for some patients. Unfortunately, one single cycle of four doses of bortezomib with 3 PP sessions may not be sufficient. With all the agents available to use in desensitization it is still not clear what is the best combination or who are the best candidates. We need more time and experience with its use to identify which patients could be the best candidate to receive it for desensitization. PMID- 21696055 TI - Bortezomib as an adjuvant to conventional therapy in the treatment of antibody mediated rejection (AMR): the full spectrum. AB - Antibody-mediated rejection (AMR) is a well-known complication of kidney transplantation. Its incidence is higher in HLA and ABO incompatible transplant recipients and in patients who develop de novo HLA antibodies. Different clinical and histological phenotypes of HLA-related AMR have been described with variable responses to conventional AMR treatment (Plasmapheresis, IVIG, thymoglobulin (ATG), and anti-CD20 antibodies). Regardless of the phenotype, once the HLA primed B cells have differentiated into antibody producing long-lived plasma cells, they become less vulnerable to conventional AMR treatment. Bortezomib (Velcade) is a proteasome inhibitor approved by the FDA for the treatment of multiple myeloma. It targets mature plasma cells, and hence it is intriguing to study its role in the suppression of long-lived plasma cells. Several previous reports have suggested effectiveness of Bortezomib in the treatment of AMR. We report our experience with Bortezomib as an adjuvant to conventional therapy in five distinct phenotypes of AMR: early acute AMR in the context of desensitization; subclinical acute AMR in the context of desensitization; late acute AMR due to de novo HLA antibody; late ACR and acute AMR due to de novo HLA antibody and chronic AMR due to de novo HLA antibody. PMID- 21696056 TI - Bortezomib for the treatment of chronic antibody-mediated kidney allograft rejection: a case report. AB - We report on a patient with chronic C4d-positive antibody-mediated rejection, who was subjected to treatment with bortezomib. Despite initial treatment with CD20 antibody rituximab and intravenous immunoglobulin, the patient presented with a steady increase in serum creatinine and de novo proteinuria. In an effort to directly target alloantibody-producing plasma cells and to prevent ongoing antibody-mediated graft injury, we applied treatment with a single cycle of bortezomib combined with dexamethasone. Treatment was associated with a > 50% decrease in DSA levels and disappearance of capillary C4d staining as detected in a follow-up biopsy. However, there were still profound glomerulitis, an unchanged degree of transplant glomerulopathy and a persistent discrete infiltration of the interstitium by CD138+ plasma cells. The clinical course was unfavorable: despite some decrease in urinary protein excretion, a further deterioration of kidney allograft function was noted. In summary, this case suggests distinct antihumoral efficacy of bortezomib also in the context of chronic AMR. Nevertheless, a major observation was that treatment failed to prevent deterioration of graft function. We speculate that, despite modulation of (complement-activating) DSA, advanced irreversible tissue injury in this late stage of rejection may have precluded a relevant clinical response. Together with other case studies, our results may provide a valuable basis for prospective trials designed to evaluate the efficacy of bortezomib in the prevention and treatment of earlier stages of chronic AMR, e.g. based on the results of early (protocol) biopsies and/or early post transplant antibody monitoring. PMID- 21696057 TI - Targeting alloantibody production with bortezomib: does it make more sense? AB - BACKGROUND: The effectiveness of current therapies for humoral rejection and decreasing antibody production directed against human leukocyte antigens (HLA) remains controversial. Standard regimens are unable to abrogate alloantibody production long term, most likely due to a lack of a direct effect on inhibiting and depleting mature plasma cells. Bortezomib (BZ) may be more effective at removing long-lived plasma cells compared to standard regimens that modulate alloantibody production by different mechanisms. METHODS: We report a kidney transplant recipient with several episodes of mixed antibody mediated and cellular rejection treated with numerous therapies including BZ. Monitoring included serial measurements of donor specific antibodies (DSA) by Luminex assay and repeated allograft biopsies. RESULTS: One cycle of BZ was able to reverse humoral rejection and graft dysfunction. DSA levels to multiple donor HLA antigens which were not affected by previous therapies were reduced to undetectable levels post BZ. Abrogation of DSA was only transient. Despite continued stable renal function post-BZ, the patient had a reemergence of DSA, and evidence of humoral rejection detected by allograft biopsy. CONCLUSIONS: Despite the promise of BZ as a therapy for humoral rejection, current data on how it should be used and its efficacy long-term remains limited. PMID- 21696058 TI - 1.7 year follow-up after bortezomib therapy for refractory antibody mediated rejection. AB - In summary, 1.7 years after transplantation, bortezomib rescue has been durably effective in salvaging our patient with refractory antibody mediated rejection. The only price has been persistently high levels of BK viruria. The presence of ongoing and even recurrent donor specific antibody has made it difficult to reduce immunosuppression further, and the concern that the high levels of BK viruria will eventually progress to viremia and nephropathy necessitates continued therapy with very low dose cidofovir and leflunomide. The absence of C1q binding DSA with stable renal function may provide some reserved optimism that the DSA that is detectable by convention Luminex assay may have reduced pathological implications. However, more data and prolonged follow-up are needed to determine whether or not non-complement binding DSA has an adverse pathological role. PMID- 21696059 TI - Bortezomib alone fails to decrease donor specific anti-HLA antibodies: even after one year post-treatment. AB - In a previous study we evaluated the in vivo efficacy of one cycle of Bortezomib (1.3 mg/m2 x 4 doses), used as the sole desensitization therapy, in four renal transplant recipients experiencing sub-acute antibody mediated rejection with persisting DSA. Bortezomib treatment did not significantly decrease DSA MFI within the 270-day posttreatment period in any patient. Here we reevaluate the patients' outcomes and bortezomib efficacy after one year post-treatment. The DSA levels remained stable or increased. In conclusion, one cycle of bortezomib alone does not decrease DSA levels in sensitized kidney transplant recipients. PMID- 21696060 TI - Bortezomib as rescue therapy for antibody mediated rejection: a single-center experience. AB - Case series have reported the use of bortezomib for treatment of primary and refractory treatment of cell-mediated acute rejection. The purpose of this article is to review a single-center experience with bortezomib used to treat humoral rejection in four transplant recipients. All patients received bortezomib after suffering antibody-mediated rejection refractory to intravenous immunoglobulin and plasmapheresis. Each patient had improved renal function after bortezomib treatment, biopsies became c4d negative in three of the four patients and the level of donor specific antibody reduction was mixed. Adverse drug events were not encountered, although two patients suffered infections, H1N1 pneumonia and cytomegalovirus colitis. In conclusion, these four cases demonstrate the promising use of bortezomib as rescue therapy for antibody mediated rejection. Future research is needed to explore the impact of bortezomib on HLA removal, histological reversal of rejection, and long-term graft function after transplantation. PMID- 21696061 TI - Reduction in proteinuria with bortezomib based therapy for antibody mediated rejection. PMID- 21696062 TI - Prognostic and predictive potential molecular biomarkers in colon cancer. AB - An important objective in nowadays research is the discovery of new biomarkers that can detect colon tumours in early stages and indicate with accuracy the status of the disease. The aim of our study was to identify potential biomarkers for colon cancer onset and progression. We assessed gene expression profiles of a list of 10 candidate genes (MMP-1, MMP-3, MMP-7, DEFA 1, DEFA-5, DEFA-6, IL-8, CXCL-1, SPP-1, CTHRC-1) by quantitative real time PCR in triplets of colonic mucosa (normal, adenoma, tumoral tissue) collected from the same patient during surgery for a group of 20 patients. Additionally we performed immunohistochemistry for DEFA1-3 and SPP1. We remarked that DEFA5 and DEFA6 are key factors in adenoma formation (p<0.05). MMP7 is important in the transition from a benign to a malignant status (p <0.01) and further in metastasis being a prognostic indicator for tumor transformation and for the metastatic potential of cancer cells. IL8, irrespective of tumor stage, has a high mRNA level in adenocarcinoma (p< 0.05). The level of expression for SPP1 is correlated with tumor level. We suggest that high levels of DEFAS, DEFA6 (key elements in adenoma formation), MMP7 (marker of colon cancer onset and progression to metastasis), SPP1 (marker of progression) and IL8 could be used to diagnose an early stage colon cancer and to evaluate the prognostic of progression for colon tumors. Further, if DEFA5 and DEFA6 level of expression are low but MMP7, SPP1 and IL8 level are high we could point out that the transition from adenoma to adenocarcinoma had already occurred. Thus, DEFA5, DEFA6, MMP7, IL8 and SPP1 consist in a valuable panel of biomarkers, whose detection can be used in early detection and progressive disease and also in prognostic of colon cancer. PMID- 21696063 TI - Pre-operative transthoracic real-time three-dimensional echocardiography for a better surgical strategy. AB - In this study we aimed to evaluate the three-dimensional (3D) transthoracic echocardiography (TTE) in the assessment of cardiac valve morphology. METHODS: Bidimensional (2D) and real-time 3D TTE was performed in 104 patients consecutive with cardiac catheterisation, prior to valve surgery. Using surgical findings as the gold standard, 2D and 3D TTE were compared for adequate recognition and accurate detection of morphology. A scoring protocol was used for recognition of the valvular segments (0= inadequate, 1 = adequate). RESULTS: Adequate echographic visualization of the valve segments was more frequently obtained by 3D than 2D TTE imaging (731/770 by 3D TTE vs. 693/770 by 2D TTE, p < 0.01). The valve leaflets segments were more clearly identified by 3D TTE rather than by 2D TTE (502/531 vs. 471/531, p <0.01). The assessment of commissures was similar by both methods (229/239 vs. 222/239, p=0.09). Total 3D TTE scores for mitral and aortic valves were significantly better than 2D ITE scores (mean score 12.91+/ 1.62 by 3D vs 11.58+/-1.02 by 2D, p=0.02). This superiority of 3D TTE was irrespective of rhythm (p <0.05 for both sinus rhythm and atrial fibrillation). Using surgical classification of valvular disease as gold standard, the sensibility and specificity were 91% and 84 % for 3D TTE, and 85% and 77% for 2D TTE, respectively. CONCLUSIONS: Real-time 3D was superior to 2D TTE forthe accurate localization and identification of valvular pathology, irrespective of heart rhythm. PMID- 21696064 TI - Craniofacial resection for malignant tumors of the paranasal sinuses. AB - OBJECTIVE: To review the experience with craniofacial resection for malignant tumors of the anterior skull base and analyze prognostic factors for survival. MATERIAL AND METHODS: Between 1996 and 2008, 64 consecutive patients with malignant tumors of the anterior skull base underwent craniofacial resection. Different parameters were analyzed to study their relationship with survival: age, sex, pathology, orbital involvement, dural involvement, status of the surgical margins, adjuvant radiotherapy, and whether the treatment was done before or after surgery. Survival analysis was carried out with the Kaplan-Meier product limit method and comparison between groups was performed by the log-rank test. Factors identified in the univariate analysis were then entered in the multivariate analysis using the Cox regression model in order to identify predictive factors of survival. RESULTS: For the entire group survival rates were 47% at 5 years. The highest survival was observed in patients with estesioneuroblastoma and the lowest in melanoma cases. Dural involvement and orbital clearance are predictors of poor survival. CONCLUSION: The improved survival and minimal morbidity associated with craniofacial resection make it the approach of choice for anterior skull base tumors. PMID- 21696065 TI - Carcinoid tumour of the appendix: problems of diagnosis and treatment. AB - Carcinoids (neuroendocrine tumours) are considered the most common primary appendiceal neoplasm. Primary appendiceal tumours are uncommon. Routine histopathological examination of appendicectomy specimens is justified given the not infrequent incidental finding of appendiceal tumours. In cases of appendicitis in the elderly, the index of suspicion for epithelial tumours of the appendix should be raised. Moreover, once the diagnosis of an adenomatous lesion is made, colonoscopic examination of the entire large bowel is mandatory given the frequency of synchronous colorectal neoplasia in our population. In our study, we review 3 cases of carcinoid tumor of the appendix and describe their presentation, treatment and outcome. They are often diagnosed incidentally after histopathological examination of the vermiform appendix submitted in the course of the management of another clinical diagnosis. Appendectomy is appropriate for lesions < 1 cm but for lesions over 2 cm in diameter there is a significant increase in metastatic spread and thus right hemicolectomy is required in such cases. Appendiceal carcinoid tumours are found in 0,3 - 0,9 per cent of patients undergoing appendicectomy. Controversy exists over the management following appendicectomy, especially with regard to the role of right hemicolectomy in patients with tumours smaller than 2 cm in diameter. PMID- 21696066 TI - Emergency laparoscopy combined with radiofrequency ablation for hemostasis after percutaneous liver biopsy. AB - There are no data in the literature on the use of radiofrequency ablation (RFA) in emergency laparoscopy as a means of hemostasis after liver biopsy. In this case report we have described a case of a patient with Waldenstrom macroglobulinemia and hypervascularised hepatic tumor who developed severe hepatic bleeding after liver biopsy. Innovative, minimally invasive treatment consisted in a laparoscopic approach with introduction of RFA needle into the biopsy site, followed by immediate hemostasis with no complications. Laparoscopic surgery with RFA avoids unnecessary laparotomy in case of severe bleeding from a known source. It is therefore the optimal choice, even in patients for whom percutaneous biopsy would be a high-risk procedure. PMID- 21696067 TI - Mucinous cystadenoma of the appendix. A diagnostic dilemma? AB - Mucocele of the appendix due to mucinous cystadenoma is a rare clinical finding. Approximately half of the patients are asymptomatic. It's defined as the dilatation of the appendiceal lumen due to abnormal accumulation of mucus in to it. The pseudomyxoma peritonei, as a result of rupture of the appendix, is the most dangerous complication. We present two case reports of patients that were presented in our Department with different clinical findings. The first patient was presented with symptoms of acute appendicitis, while the second patient showed with atypical symptoms such as abdominal pain, a palpable mass in the right iliac fossa and a diagnosed mucocele of the appendix with the use of computerized tomography. In both patients was performed an appendicectomy and the final histopathology diagnosis confirmed the presence of the mucinous cystadenoma of the appendix which caused the creation of the mucocele. In conclusion mucocele is a rare tumor which must be considered in the differential diagnosis of a mass in the right lower quadrant of the abdomen. PMID- 21696068 TI - Summary health statistics for the U.S. population: National Health Interview Survey, 2009. AB - OBJECTIVES: This report presents both age-adjusted and unadjusted health statistics from the 2009 National Health Interview Survey (NHIS) for the civilian noninstitutionalized population of the United States, classified by sex, age, race, Hispanic or Latino origin and race, education, family income, poverty status, health insurance coverage (where appropriate), place of residence, and region of residence. The topics covered are respondent-assessed health status, limitations in activities, special education or early intervention services, injury and poisoning episodes, health care access and utilization, and health insurance coverage. DATA SOURCE: NHIS is a household, multistage probability sample survey conducted annually by interviewers of the U.S. Census Bureau for the Centers for Disease Control and Prevention's National Center for Health Statistics. In 2009, household interviews were completed for 88,446 persons living in 33,856 households, reflecting a household response rate of 82.2%. SELECTED HIGHLIGHTS: Nearly 7 in 10 persons were in excellent or very good health in 2009. About 40 million persons (13%) were limited in their usual activities due to one or more chronic health conditions. About 4 million persons (2%) required the help of another person with activities of daily living, and about 9 million persons (4%) required the help of another person with instrumental activities of daily living. About 7% of children received special education or early intervention services. Among persons under age 65 years, about 46 million (18%) had no health insurance coverage. The most common reason for lacking health insurance was cost, followed by a change in employment. PMID- 21696069 TI - Assessment tool of Thai menopause-specific quality of life in Surat Thani Province, Thailand. AB - OBJECTIVE: To develop an assessment tool of Thai menopause-specific quality of life in Surat Thani Province, Thailand. MATERIAL AND METHOD: The present study divided research design into three phases. Phase I Concept clarification, a thorough study of related literature was conducted to search for the concept of menopause-specific quality of life and its existing instruments to guide developing instrument. Phase II Item development, in-depth interviews with 30 Thai menopausal women in Surat Thani was conducted and an initial pool of items relating to menopause-specific quality of life was generated to develop the instrument, then, tested with 399 menopausal women. Phase III psychometric test, the developed questionnaire was tested for validity and reliability with 402 menopausal women. RESULTS: The Thai Menopause-Specific Quality of Life instrument was well developed with 63 items, internal consistency reliability coefficient obtained 0.952, comprised of three domains including physic-psychological well being (51 items), sexual-socio-economic well-being (9 items) and vasomotor well being (3 items). CONCLUSION: The present study was directed to develop an effective instrument with integrity of psychometric property. This instrument was more meaningful to detect quality of life specific to Thai menopausal women. PMID- 21696070 TI - Reference range and characteristic of uterine artery Doppler in pregnant Thai women at 11-13(+6) gestational weeks. AB - OBJECTIVE: To determine uterine artery pulsatility index (PI) and to describe the characteristic of uterine artery Doppler velocimetry in pregnant Thai women at 11 13(+6) gestational weeks. MATERIAL AND METHOD: Between July 29, 2010 and September 30, 2010, 150 normal pregnant women at 11-13(+6) weeks of gestation who were attending at the antenatal care clinic, Department of Obstetrics and Genecology, Faculty of Medicine, Chulalongkorn University were recruited. Pulsatility index (PI) of the uterine artery was measured and mean PI was calculated and plotted against gestational age. Presence or absence of uterine notching in relation to laterality was also noted. RESULTS: The mean +/- SD uterine artery PI was 1.73 +/- 0.42. When segregated for gestation age, uterine artery PI was 1.78 +/- 0.41 at 11 weeks, 1.72 +/- 0.41 at 12 weeks, and 1.66 +/- 0.43 at 13 weeks' gestation. The uterine artery Pl was 1.84 +/- 0.37 with presence of notching and was 1.59 +/- 0.43 without notching. The uterine artery notching was presented in 29 (19.3%), 24 (16%), and 27 (18%) of the patients at 11, 12, and 13 weeks respectively. The uterine artery notching was absent in 27(18%), 23 (15.3%), and 20 (13.3%) of patients at 11, 12, and 13 weeks respectively. Thirty-nine patients (26%) demonstrated unilateral notch, 12 (8%) of the patients demonstrated ipsilateral notch, 19 patients (12.7%) demonstrated contralateral notch, and eight (5.3%) demonstrated unilateral notch with central placenta. CONCLUSION: Normal reference range and characteristics of uterine artery Doppler velocimetry in the presented population was established This may serve as a basis for a future study in patients with abnormal placental function. PMID- 21696071 TI - The efficacy of lower uterine segment compression for prevention of early postpartum hemorrhage after vaginal delivery. AB - OBJECTIVE: To determine the efficacy and amount of blood loss of the maneuver utilizing lower uterine segment compression (LUSC) for the prevention of early postpartum hemorrhage. MATERIAL AND METHOD: The present study enrolled 686 mothers with singleton pregnancy, gestational ages between 28 and 42 weeks, at the Department of Obstetrics and Gynecology, Charoenkrung Pracharak Hospital, Bangkok between July 2009 and March 2010. All subjects had no past medical history and delivered by vaginal route. They were divided into two groups, the experimental group and the control group. Mothers in both experimental and control groups were treated with the same methods, oxytocin administration before and after delivery, clamping and cutting umbilical cords within three minutes after birth of the newborns, and placental delivery done by controlled cord traction together with uterine massage at the fundus through the abdominal wall immediately. In addition, in the experimental group, the subjects were assisted by LUSC for 10 minutes. The amount of blood loss was measured and recorded two hours after delivery of the placentas in both experimental and control groups. RESULTS: Among 686 cases, nine cases were excluded from the present study. They were composed of five cases in the control group, with retained placenta, and four cases in the experimental group because of retained placenta, retained placental fragments, severe perineum tear, and vaginal hematoma. Subjects in the experimental group who were additionally assisted by LUSC were found to have lesser incidence of PPH with statistical significance in comparison to those in the control group (2.9% vs. 6.8%; relative risk 0.43, 95% confidence interval 0.21-0.90, p = 0.02). The amount of blood loss reduced by 29.26 ml (289.70 +/- 179.53 mlvs. 260.44 +/- 116.30 ml), p = 0.012). CONCLUSION: Lower uterine segment compression (LUSC) significantly reduced the rate of PPH and amount of blood loss after vaginal delivery The efficacy of this technique was over the conventional method in labor room care. Besides, LUSC was easy and safe. Neither anesthesia nor extra-expense was needed. LUSC was considered the innovation for management of postpartum hemorrhage. The maneuver was able to reduce the risk of maternal morbidity and mortality after the delivery of newborns. PMID- 21696072 TI - Intra-coronary bone marrow mononuclear cell transplantation in patients with ST elevation myocardial infarction: a randomized controlled study. AB - BACKGROUND: Stem cell transplantation is a potential treatment to improve left ventricular ejection fraction (LVEF) after ST elevation myocardial infarction (STEMI). However, the outcomes still are controversial. OBJECTIVE: To determine the 6-month LVEF of the patients who underwent intra-coronary bone marrow mononuclear cell (BMC) transplantation in patients with STEMI compared with controlled subjects. MATERIAL AND METHOD: After successful percutaneous coronary intervention (PCI) in STEMI patients who had LVEF was less than 50% were randomized to intra-coronary BMC transplantation or control. Bone marrow aspiration of 100 cc was performed in the morning. After cellprocessing for three hours, the suspension of BMC about 10 cc were infused to infracted area using standard PCI technique. Balloon occlusion for three minutes was performed during cell infusion. Cardiac magnetic resonance imaging was used to determine LVEF scar volume and LV volume before and six-month follow-up. RESULTS: Between September 2006 and July 2008, 23patients (11 in BMC group and 12 in control group) were enrolled. Mean BMC count before transplant was 420 x 10(6) cell with 96% viability. At six-month follow-up, New York Heart Association function class significantly improved in both groups (2.3 +/- 0.6 to 1.2 +/- 0. 4 for BMC and 2.3 +/- 0.7 to 1.3 +/- 0.5 for control group) but no difference was seen between groups. However, scar volume, wall motion score index, and LVEF did not show improvement after six months in both groups (33.7 +/- 7.7 to 33.5 +/- 7.6 for BMC and 31.1 +/- 7.1 to 32.6 +/- 8.3 for control group). No complication was observed during the procedure. CONCLUSION: BMC transplantation intra-coronary in patients with STEMI in KCMH was feasible and safe but LVEF improvement could not be demonstrated. PMID- 21696073 TI - Outcomes of antituberculosis treatments at 18 months follow-up in TB-HIV co infected patients on ART: a retrospective review of 166 cases. AB - OBJECTIVES: To study the outcomes of antituberculosis treatment in HIV/AIDS patients on antiretroviral therapy (ART). MATERIAL AND METHOD: This retrospective cohort study was performed by reviewing medical records of 166 patients co infected with tuberculosis (TB) and HIV in a hospital in Thailand seen between January 2005 and February 2008. These patients were treated with both antituberculosis (antiTB) and antiretroviral drugs (ART) and were followed for 18 months after the beginning of antiTB. RESULTS: Total 166 HIV patients with TB on ART and anti tuberculosis drugs were analyzed. The median age of patients was 36 years (20-72). Sixty-nine (41.6%) patients had pulmonary TB and 97 (58.4%) disseminated TB. Among them, 127 (76.5%) were cured and 15 (9.0%) had unsuccessful treatment. Median time for successful treatment was 10.8 months (6 32) during 18 months follow-up. There was no statistically significant difference in outcome of tuberculosis between the NVP and EFV base regimens in combination with rifampicin (5.4% vs. 10.8%, p = 0.751). CONCLUSION: Majority of HIV patients on ARTwith tuberculosis were successfully treated with antiTB drugs with median time of 10.8 months and no significant difference ofadverse events reported between NVP and EFV PMID- 21696074 TI - Prevalence of gastroesophageal reflux in Thai asthmatic patients. AB - BACKGROUND: Asthma is a chronic inflammatory disorder of airways and associated with airway hyperresponsiveness and reversible bronchoconstriction. Gastroesophageal reflux disease (GERD) is a disorder caused by the reflux of gastric content up into the esophagus. It has been proposed that GERD is one of the exacerbating factors in the patients with poor controlled asthma. OBJECTIVE: Determine the prevalence of GERD in asthmatic patients and the association between GERD and the level of asthma control in Thailand. MATERIAL AND METHOD: A cross-sectional descriptive study was conducted in 56 asthmatic patients at the King Chulalongkorn Memorial Hospital. They were performed twenty-four-hour esophageal pH monitoring. RESULTS: The prevalence of GERD in Thai asthmatic patients was 37.50%. Fifteen of 21 patients (71.43%) with GERD experienced reflux symptoms. The sensitivity specificity, positive predictive value and negative predictive value of reflux symptoms for diagnosis GERD were 71.43%, 77.14%, 65.22% and 81.82%, respectively. The prevalence of GERD was higher in uncontrolled asthmatic patients than partly controlled and controlled subjects. Among uncontrolled asthma, the prevalence of GERD was higher than those without GERD (57.17% and 25.72%, respectively, p = 0.028). Asthma Control Test (ACT) score of less than twenty (poor controlled asthma) was higher in the asthmatic patients with GERD than those without GERD (80.95% and 48.57%, respectively, p = 0.024). CONCLUSION: The authors concluded that the prevalence of GERD in Thai asthmatic patients was 37.50%. There was significant association between GERD and the level of asthma control. PMID- 21696075 TI - The efficacy of Jackson drain in the application to be a tunnel pleural catheter (TPC) in the management of malignant pleural effusion. AB - BACKGROUND: Malignant pleural effusion (MPE) is a common clinical problem in patients with advanced cancer and portends a poor prognosis, which means survival of less than six months. In June 1997, the US-FDA approved an indwelling TPC with a one-way drainage valve to be used in the management of MPE. Although popularity of this TPC has increased over the past few years, the experience with this device remains limited in Thai patients. One of the reasons is its high cost. OBJECTIVE: Assess the efficacy and the safety of customary indwelling TPC by using Jackson drain in the management of patients with symptomatic MPE. MATERIAL AND METHOD: Ten patients with symptomatic MPE were receiving these catheters (18 Fr Silicone catheters with 25 cm fenestrated length) to drain effusion via plastic vacuum bottles (250 ml) every other day or as needed to relieve dyspnea. The patient's dyspnic respiration, quality of life, and comfort during the catheter's application were quantified with a Borg score, the St. George Respiratory Disease Questionnaire (SGRQ), and the comfort's score, respectively. These parameters were recorded at initial (before insertion) and 2-week follow-up visit. Pain after 24 hours of each insertion was quantified by visual pain analogue scale (VPAS). Patients were followed until either death or catheter removal. RESULTS: The Borg score, SGRQ, and comfort's score showed significant improvement at 2-week visit (p < 0.05). Mean VPAS was 2.44. There was no early (2 week) complication, but the catheters were obstructed in three patients (mean = 60 days) and slipped out in two (day 18, day 50). CONCLUSION: This modified Jackson drain was effective in the treatment of MPE as a TPC without early complications. PMID- 21696076 TI - Validation of electronic medical database in patients with atrial fibrillation in community hospitals. AB - BACKGROUND: The electronic medical database (EMD) has been increasingly used for clinical research as it reflects a real-world practice with large and heterogeneous samples. However, few studies have reported on the validity of EMD from community hospitals for research purposes. OBJECTIVE: To assess the validity of EMD based on data from patients with atrial fibrillation (AF) receiving care from community hospitals in Phitsanulok Province, Thailand. MATERIAL AND METHOD: The validity of EMD was determined using hand-written out-patient medical records (OPMRs) as a criterion standard. One hundred ninety three records of patient with ICD-10 of AF (148) were retrieved from the EMD of two community hospitals between August 2007 and July 2008. For each patient, data of a randomly selected visit from the EMD was matched to data of the same visit from OPMRs, abstracted by a standardized data collection form. The EMD was cross-validated with OPMRs based on patient's diagnosis of AE co-morbidities (risk factors for stroke) and bleeding events. All data were tabulated in a 2 x 2 format to calculate sensitivity, specificity and the Cohen's Kappa. RESULTS: Out of 193 AF patients retrieved from the EMD, 169 (87.56%) were documented as having a diagnosis of AF in OPMRs. The EMD data on risk factors for stroke showed moderate to high sensitivity (range: 66.67-100%) and high specificity (range: 98.77-100%). The agreement between the two databases was considered good to very good (calculated kappa range: 0.7942-0.9681). The specificity based on major bleeding was 100%; however, sensitivity and the Cohens Kappa could not be determined as the major bleeding diagnosis was found in neither the EMD nor the OPMRs. CONCLUSION: The EMD of AF patients from community hospitals in Phitsanulok was valid and in good agreement with the OPMRs. The EMD from community hospitals appeared suitable for health research in patients with AF PMID- 21696078 TI - Marsupialization for simple fistula in ano: a randomized controlled trial. AB - BACKGROUND: Marsupialization of anal fistulotomy results in less raw-surface wound and may improve postoperative outcomes. The present study was designed to test the benefit of marsupialization for simple fistula in ano. MATERIAL AND METHOD: This was a randomized controlled study conducted at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Fifty patients with simple uncomplicated fistula in ano were allocated into either fistulotomy group or fistulotomy with marsupialization group. Patients with complex fistula in ano, prior incontinence, immuno-compromised status and bleeding tendency were excluded from the present study. The postoperative pain score, the pain score after the first defecation, total amount of the analgesic usage and complications were evaluated. Recurrence was also assessed RESULTS: There was no difference in the postoperative pain score between the treatment groups. However, there was a significant difference (p = 0.017) in the number of patients who needed pethidine injection (4 patients of the fistulotomy with marsupialization group versus 13 patients of the fistulotomy group). There was no statistical significant difference in the pain score after the first defecation and the amount of paracetamol usage in seven days. Five complications were found only in the fistulotomy group but the significant level was marginal (p = 0.0501). There was no recurrence of thefistula and none of the patients developed anal incontinence after the surgery. CONCLUSION: Marsupialization for anal fistulotomy is safe. This technique helps to improve the postoperative outcomes. PMID- 21696077 TI - Laparoscopic radical prostatectomy: perioperative outcomes and morbidity of 559 consecutive cases in Siriraj Hospital, Thailand. AB - OBJECTIVE: To evaluate perioperative outcomes and morbidity of laparoscopic radical prostatectomy in Siriraj Hospital during a 5-year experience. MATERIAL AND METHOD: Five hundred fifty nine patients who underwent laparoscopic radical prostatectomy (LRP) by seven surgeons at Siriraj Hospital between September 2004 and September 2009 were included in the study. Data of perioperative results and postoperative parameters were retrospectively evaluated. RESULTS: Mean operative time was 257 minutes SD 75 (range 125 to 680 min). The mean operative time of the first 100 cases was significantly higher than of the last 100 cases (307 ml/min SD 95 versus 223 ml/min SD 56; p-value = 0.001). Mean estimated blood loss was 779 ml SD 607 (range 40 to 6,000 ml). Of 559 patients, 148 patients (26.5%) had blood transfusions. The blood transfusion rate in the first 100 cases was significantly higher than those of the last 100 cases (36.5% versus 15%; p-value = 0.016). The median duration of catheterization time was 8 days. The mean time of drain insertion was 4.2 days SD 1.8 (range 2 to 18 days) postoperatively. Hospital stay was 8.8 days SD 7.6 (range 3 to 149 days). Overall perioperative complications rate was 17.1%. Of these patients, 13.4% were minor complication (Clavien 1, 2) and 3.7% were major complication (Clavien 3, 4). There were no mortalities. Late complication rate was 2.1%, which most of them were stricture of anastomosis. CONCLUSION: Perioperative outcomes and morbidity of LRP in a 5 year period were acceptable. Laparoscopic radical prostatectomy is technically demanding with an initially longer operative time and higher blood transfusion rate. The learning curve of the surgical team is needed to achieve good results. PMID- 21696079 TI - Short-term outcomes of two laparoscopic bariatric procedures. AB - OBJECTIVE: To compare the short term outcomes of laparoscopic Roux-Y gastric bypass (lap RYGB) and laparoscopic gastric banding (lap banding) for morbidly obese patients at a tertiary care hospital. MATERIAL AND METHOD: Medical records of patients who underwent laparoscopic bariatric surgery for morbid obesity between November 2003 and November 2008 were reviewed. Baseline data including demographics, anthropometric and biochemical measurements were recorded. Patients were followed postoperatively and the body weight was measured every three to six months. Follow-up biochemical measurements were also recorded. After approximately six months to one year after the initial operation, the Bariatric Analysis and Reporting Outcome System (BAROS) scores were obtained, and re evaluated every six months. RESULTS: There were 65 patients in the series, 31 underwent lap banding and 34 lap RYGB. There were 28 men (43%) and 37 women (57%), with an average age of 31.7 years (SD, 10.5 years). Patients were followed postoperatively for a period between six months and three years. The expected weight loss was 6% greater on the average for the lap RYGB group during the first two years of follow-up. Biochemical outcomes tended to marginally favor the lap RYGB group. There was no clear difference between groups in terms of the BAROS scores. CONCLUSION: Short- term differences between the two laparoscopic operations for morbid obesity tended to marginally favor lap RYGB. However, the BAROS scores were not clearly different between the two groups. These differences seemed to attenuate with time. The effects of the two operations were similar after two years. PMID- 21696080 TI - Prevalence of dyslipidemia in Thai schoolchildren. AB - OBJECTIVE: To evaluate the prevalence and risk factor of dyslipidemia in Thai schoolchildren. MATERIAL AND METHOD: A cross section- study of 348 schoolchildren aged 6-17.8 years in Nakork Nayok province, Thailand between May and June 2009 was conducted. Total cholesterol and triglyceride were measured from a 10-hour fasting blood. Dyslipidemia (hypercholesterolemia and/or hypertriglyceridemia) was defined according to the American Academy of Pediatrics AAP) guidelines. Demographic and anthropometric data were recorded. Odds ratio and 95% confidence interval were used to compare the prevalence of dyslipidemia. RESULTS: The prevalence of hypercholesterolemia and hypertriglyceridemia were 1.2% and 10.6%, respectively, with none of the children who simultaneously had high cholesterol and triglyceride levels. Overweight, obesity and thinness were defined in 34 (9.8%), 34 (9.8%) and 25 (7.2%) children, respectively. Odds ratio ofhaving dyslipidemia in overweight and/or obese children compared to non-obese children was 4.0 (95% CI 2.0-8.0). Odd ratios ofhaving dyslipidemia were not significant differences by other risk factors such as gender [1.2 (0.6-2.2)], age [1.3 (0.7 2.5)], hypertension [0.9 (0.2-4.2)], family history of dyslipidemia [2.4 (0.6 8.0)], family history of diabetes mellitus [0.5 (0.1-2.1)], presence ofa smoker in the family [1.5 (0.8-3.1)] and differentABO blood types. CONCLUSION: The overall prevalence of dyslipidemia in Thai schoolchildren was 11.8%. Overweight and/or obesity were the sole risk factor for dyslipidemia in Thai schoolchildren aged 6-17.8 years. PMID- 21696081 TI - A comparison of spinal isobaric levobupivacaine and racemic bupivacaine for lower abdominal and lower extremity surgery. AB - BACKGROUND: Levobupivacaine is a new long-acting local anesthetic, which is the isolated S-enantiomer of racemic bupivacaine with less cardiovascular and central nervous system toxicity than bupivacaine. Reports using levobupivacaine for epidural or brachial plexus anesthesia suggested equivalent clinical efficacy to bupivacaine. However, inadequate information for spinal anesthesia was found OBJECTIVE: To study the onset of motor block and other anesthetic efficacy of intrathecally administered racemic bupivacaine compared with levobupivacaine. MATERIAL AND METHOD: A prospective randomized double blind study at Srinagarind Hospital included seventy patients aged 18-65 years, ASA I-II, scheduled for elective lower abdominal and lower extremity surgery under spinal anesthesia was done. Exclusion criteria were known hypersensitivity to amide local anesthetics, contraindication against spinal anesthesia, morbid obesity, or patient unable to understand the study protocol. The patients were divided into two groups. They received either 0.5% isobaric racemic bupivacaine 3 mL or 0.5% isobaric levobupivacaine 3 mL for spinal anesthesia. The measurement included vital signs, peak block height, motor and sensory blockade and side effects. RESULTS: There was no significant difference between the two groups in the quality of motor and sensory block (p-value > 0.05). The median of peak block height of racemic bupivacaine and levobupivacaine group was T9 (T6-T12) and T9 (T4-T12) respectively Afew adverse events were detected and treated carefully with no clinically significant difference between groups. CONCLUSION: The present study indicated that 15 mg of isobaric racemic bupivacaine and levobupivacaine for spinal anesthesia had equivalent peak block height and showed equally effective efficacy regarding to both the onset time and duration of motor and sensory blockade. PMID- 21696082 TI - Current pattern treatment of hordeolum by ophthalmologists in Thailand. AB - OBJECTIVE: To assess the current pattern of treatment among ophthalmologists in Thailand. MATERIAL AND METHOD: A two-page Thai questionnaire was distributed to Thai ophthalmologists' annual meeting. Other questionnaires were sent to the eye institute or conducted by telephone interviews. RESULTS: Five hundred one physicians participated in the present study (49.17%). Warm compression usage was suggested (n = 459; 91.62%). The prescription before I & C was combined topical and oral antibiotics, only oral antibiotics (n = 12; 2.4%), or no oral antibiotics (n = 21; 4.19%). I & C was performed only in cases with flocculated mass in irrespective size (n = 271; 54%), mass size of 4.47 (range 2-10 mm) (n = 124; 24.76%), or requested by patients (n = 13; 2.59%). The prescription after I & C was combined topical and oral antibiotics, no oral antibiotics (n = 74; 14.77%), or no antibiotics at all (n = 14; 2.79%). CONCLUSION: Warm compression was commonly used. I&C was administered if there was flocculated mass. Antibiotics usage before and after I & C was the same. First choice antibiotics were combination of neomycin, polymyxin, and gramicidine eye drop, chloramphenicol eye ointment, and oral dicloxacillin. PMID- 21696083 TI - Bone mineral density: correlation between the lumbar spine, proximal femur and Radius in northern Thai women. AB - OBJECTIVE: To determine the correlation of bone mineral density (BMD) in lumbar spine, proximal femur and 1/3 radius in northern Thai women. MATERIALS AND METHOD: The data of this study was collected from the medical records and the BMD results of 885 perimenopausal and postmenopausal women who had the BMD measurement in Division of Nuclear Medicine, Department of Radiology, Faculty of Medicine, Chiang Mai University between January and December 2007. BMD was measured using dual-energy X-ray absorptiometry (Hologic, QDR-4500C). RESULTS: Mean age (+/- SD) was 58.7 +/- 9.9 year. The lowest T-score was found 51.6% at lumbar spine (LS), 29.2% at 1/3 radius, 13.8% at femoral neck (FN), 2.9% at total femur (TF) and 2.5% at trochanter region (TR). We found a significant correlation between age, BMI, duration of menopause, and BMD at the LS, TFE FN, TR and 1/3 radius (p < 0.01). The correlation between the BMD measures at LS and TF FN, TR and 1/3 radius were 0.708, 0.667, 0.721 and 0.633, respectively (p < 0 01). Women with perimenopausal status had higher height and BMD values at all five observed sites than postmenopausal women (p < 0.01). CONCLUSION: The present found a good correlation of the BMD from various skeletal sites. Interestingly, the correlation was found highest between the LS vs. TR and TF vs. TR region. Clearly, estrogen-deficient plays important role on the low BMD values in all skeletal sites. PMID- 21696084 TI - In vivo whole body dosimetry measurement technique of total body irradiation: a 12-year retrospective study result from one institute in Thailand. AB - OBJECTIVE: The main problem of total body irradiation (TBI) is how to maintain radiation dose homogeneity throughout the body during a treatment course. The simple set up treatment with non-complicated in vivo dosimetry measurement technique is the ideal method to solve this problem. For this reason, the authors have reported the results of in vivo dosimetry measurement method to prove the reliability of dose distribution from the authors' TBI technique. MATERIAL AND METHOD: The authors reviewed the data of dose measurement record from 53 patients' treatment files to report the uniformity of absorbed in vivo dose distribution throughout the whole body from TBI with semiconductor detectors and ionization chamber with the accepted homogeneity within +/- 10% of the prescribed dose. The result was reported in the term of mean and standard deviation of absorbed dose difference from the prescribed dose. RESULTS: The uniformity of radiation dose distribution throughout the whole body of all patients calculated from semiconductors was accepted with mean difference value of -3.2 +/- 2.5% from the prescribed dose and the difference of mean absorbed dose value at midline point between semiconductor and ionization chamber was 4 +/- 3.3%. CONCLUSION: This TBI dosimetry measurement technique has been proved to exhibit the reliability of dose homogeneity throughout the whole body within the accepted value. This could be applied for use at any institute that has some limitation in resources and small treatment room. PMID- 21696085 TI - Distribution of killer cell immunoglobulin-like receptor genes in Thai blood donors. AB - BACKGROUND: Killer cell Immunoglobulin-like Receptors (KIRs) are members of a group of molecules expressed on the surfaces of natural killer (NK) cells and some T cells. KIRs recognize MHC class I molecules on target cells. The interaction of these molecules regulates NK cell reactivity. The KIR gene cluster is highly polymorphic in individuals and different populations. OBJECTIVE: Determine the frequencies and diversities of KIR genes among the Thai population. RESULTS: Seventeen KIR genes and common subtypes were identified in 500 healthy Thai blood donors by PCR-SSP. The framework genes KIR2DL4, KIR3DL2, KIR3DL3, and KIR3DP1 were present in all individuals (100%). The observed frequencies of KIR genes vary in the presented population. The most frequent non-framework KIR gene was KIR2DLI (98.4%) while the least frequent was KIR2DL5B (24.2%). CONCLUSION: It was observed that the Thai population shows polymorphism of the KIR genes and the diversities of KIR genes in Thai differed from other populations. These data might be of benefit to future studies of the KIR gene and its association with diseases. PMID- 21696086 TI - Mature T-cell and NK-cell lymphomas in Thailand: an analysis of 71 cases. AB - OBJECTIVE: To identify the distribution of mature T-cell and NK-cell lymphomas in Siriraj Hospital and compare to the other world regions, using the latest WHO classification (2008). MATERIAL AND METHOD: Newly diagnosed cases of such lymphomas between January 1, 2004 and December 31, 2006 at Siriraj Hospital were recruited and reviewed. Additional immunohistochemical studies and/or EBV-encoded RNA (EBER) in situ hybridization were performed from the formalin-fixed paraffin embedded tissue. Then, lymphomas were reclassified according to the WHO classification (2008). RESULTS: Seventy-one cases including extranodal NK/T-cell lymphoma, nasal type (ENKTL, 31.0%), anaplastic large cell lymphoma (18.3%), angioimmunoblastic T-cell lymphoma (14.1%), peripheral T-cell lymphoma, not otherwise specified (12.7%), mycosis fungoides (MF, 8.5%), subcutaneous panniculitis-like T-cell lymphoma (SPTCL, 7.0%), primary cutaneous anaplastic large cell lymphoma (PCAL, 5.6%), primary cutaneous gamma-delta T-cell lymphoma (PCGDTL, 1.4%), and enteropathy-associated T-cell lymphoma (1.4%) were included in this study. In terms of changing version of the WHO classification from 2001 to 2008, only one case had the diagnosis changed from MF to PCGDTL, a newly proposed entity in the 2008 version. CONCLUSION: ENKTL was the most common in the present series and it had a significantly higher frequency than those reported in other previous studies. The frequency was relatively higher in SPTCL, PCAL, and MF when compared to the other series. Furthermore, changing the WHO classification from the 2001 version to the recently published2008 version may not affect the proportion of NK/T-cell lymphoma. PMID- 21696087 TI - A systematic review of the worldwide prevalence and incidence of Parkinson's disease. AB - BACKGROUND: A number of epidemiologic studies of Parkinson 's disease (PD) have been conducted worldwide over the years. Although every study reported the rise in prevalence and incidence rate of PD with the increasing age, the overall estimates were different across countries. The variation in reported data may partly be contributed by case ascertainment, case finding method, data collection, and most importantly different population structures. OBJECTIVE: Systematically review prevalence and incidence of PD and find the causes of variation in the results. MATERIAL AND METHOD: A literature search was conducted on Medline and EMBASE for studies worldwide investigating the prevalence and incidence of PD and included all adults, English and publication between 1965 and January 2010. The primary search of both databases yielded 5,330 results. After screening topics and abstracts, 168 relevant abstracts were tagged and saved for more thorough perusal. Ultimately, 40 papers were selected for review after applying the pre-specified inclusion criteria RESULTS: The worldwide prevalence of PD varies widely. One reason for the variation in prevalence estimates could be due to the differences in survival across countries. The use of epidemiological studies using medical records could be another reason for the variation in disease frequency. CONCLUSION: PD is common in the elderly. A number of descriptive epidemiologic studies have been conducted worldwide. Comparing the incidence and prevalence of Parkinson's disease is difficult. PMID- 21696088 TI - Topical antifungal agents for seborrheic dermatitis: systematic review and meta analysis. AB - OBJECTIVE: Assess the efficacy of topical antifungal agents for seborrheic dermatitis treatment. MATERIAL AND METHOD: A systematic review and meta-analysis of all relevant randomized vehicle-controlled trials of topical antifungal agents for seborrheic dermatitis treatment were searched. The quality of the enrolled studies was measured by criteria from Cochrane Collaboration, followed by data extraction. Two reviewers independently assessed the present study articles. When there was a disagreement between the two reviewers, a consensus was made by the third reviewer. Pooled relative risk (PRR) statistical analysis was used to determine the efficacy of treatment. RESULTS: One thousand ninety five studies were reviewed and nine studies were included. Four reports studied the efficacy of ketoconazole, two of metronidazole, two of ciclopirox, and one of bifonazole. Ketoconazole was more effective than vehicle [PRR is 5.78 (95% CI, 2.17-15.40)], as was metronidazole [PRR is 1.83 (95% CI: 1.05-3.17)] ciclopirox [PRR is 3.00 (95% CI, 1.86-4.84)], and bifonazole [PRR is 1.86 (95% CI: 0.96-3.59)]. CONCLUSION: The meta-analysis in the present study showed that the topical antifungal agents that demonstrated strong and moderate evidence of the efficacy for seborrheic dermatitis treatment were ketoconazole and ciclopirox, respectively. They could be used as an alternative treatment for seborrheic dermatitis. PMID- 21696089 TI - Advancing effectiveness science: an opportunity for nursing. PMID- 21696091 TI - The impact of nursing surveillance on failure to rescue. AB - Greater amounts of nursing surveillance is thought to decrease failure to rescue but studies to date have used nurse staffing levels as a proxy for nursing surveillance. The purpose of this nursing effectiveness study was to examine the unique treatment effect of nursing surveillance on failure to rescue. Data were abstracted from 9 electronic clinical data repositories including the nursing documentation system that used the Nursing Interventions Classification (NIC) to record nursing care. Nursing surveillance was quantified as "high use" when the subjects received it an average of 12 times per day or more. Propensity scores were used to match subjects who had received high-dose nursing surveillance with subjects who received low-dose nursing surveillance (average of less than 12 times a day). The results indicate that when nursing surveillance is performed an average of 12 times a day or greater, there is a significant (p = .0058) decrease in the odds of experiencing failure to rescue (odds ratio [OR] = 0.52) compared to when surveillance was delivered an average of less than 12 times a day. Additional unique variables included in this study are robust levels of nurse staffing based on hourly data, medical treatments, pharmaceutical treatments, and nursing treatments. The use of propensity scores helped determine the unique contribution of nursing surveillance on failure to rescue in this observational study. PMID- 21696090 TI - Measuring resource utilization in patient-oriented comparative effectiveness research: a psychometric study of the Resource Utilization Questionnaire. AB - In the United States, rising health care costs have led to discussion about bending the cost curve. To understand the true burden of disease and its treatment, costs of care, including those incurred by patients and their families, must be comprehensively assessed using psychometrically sound instruments. The Resource Utilization Questionnaire (RUQ) is a 21-item self report questionnaire first developed to measure the costs incurred by families of infants who had required intensive care during the newborn period. The purpose of this article is to describe the conceptualization of resource utilization and costs and other methodological issues in conducting economic analyses, the process of adapting the RUQ for use in children and families with Type 1 diabetes mellitus (T1DM), and the psychometric evaluation to establish content and criterion validity of the instrument. The finalized modified RUQ for T1DM (mRUQ T1DM) contained 25 items reflecting direct (5 items) and nondirect (3 items) health care, patient/family time (8 items), and patient/family productivity (9 items) costs using a 3-month recall. The mRUQ-T1DM validly measures cost incurred by children and families with T1DM and is easily completed by parents. Furthermore, the mRUQ-T1DM may be adapted for use in other populations using a similar process. PMID- 21696092 TI - Factors associated with falls during hospitalization in an older adult population. AB - BACKGROUND: Falls of hospitalized older adults are of concern for patients, family members, third-party payers, and caregivers. Falls are the most common safety incident among hospitalized patients with fall rates from 2.9-13 per 1,000 patient days. Little effectiveness research has been conducted on nursing interventions and other variables associated with falls of older adults during hospitalization. PURPOSE: The purpose of this exploratory outcomes effectiveness study was to examine variables associated with falls during hospitalization of older adults. METHOD: An effectiveness research model composed of patient characteristics, clinical conditions, nursing unit characteristics, medical, pharmacy, and nursing interventions was tested using generalized estimating equations (GEE) analysis. The sample consisted of 10,187 hospitalizations of 7,851 patients, aged 60 or older, admitted for acute care services over a 4-year period. Those included in the sample either had received the Nursing Interventions Classification (NIC) intervention of Fall Prevention (defined as "instituting special precautions with patient at risk for injury from falling" [Dochterman & Bulechek, 2004, p. 363]) or were at risk for falling as defined by a fall risk assessment scale. Data were obtained retrospectively from 9 clinical and administrative data repositories from 1 tertiary care hospital. DISCUSSION: Variables that were positively associated with falls, after controlling for other variables in the model, included several medical and nursing treatments; several types of medications including antidepressants, benzodiazepines, antipsychotic, and psychotropic agents; and several types of nursing treatments including restraints and neurologic monitoring (at low use rates of < 2 times a day). Variables inversely associated with falls included registered nurse (RN) skill mix, pressure ulcer care, pain management, and tube care. CONCLUSIONS: The study demonstrates the importance of conducting interdisciplinary effectiveness research that includes nursing care. Most of the variables associated with falls were interventions (medical, pharmacy, and nursing). Dose of nursing treatments and RN skill mix were also associated with falls. PMID- 21696093 TI - How clinical trials really work rethinking research ethics. AB - Despite prevalent concerns about the ethical conduct of clinical trials, little is known about the day-to-day work of trials and the ethical challenges arising in them. This paper reports on a study designed to fill this gap and demonstrates a need to refine the oversight system for trials to reflect an understanding of this day-to-day work. It also illuminates ethical challenges that cannot be addressed by the oversight system and so necessitate a rethinking of the ethics of clinical trials. PMID- 21696095 TI - Speaking of the value of life. AB - The phrase 'the value of life' is important in bioethics, particularly for those who hold the traditional views that life has intrinsic value and that the distinction between killing and allowing to die is valid. Ambiguities in the meaning of 'the value of life,' however, can lead to errors in medical ethical analysis by those who hold these traditional views. This essay notes three sources of such ambiguity: (1) three senses of the verb 'is,' (2) the difference between the transcendent and the transcendental, and (3) the difference between the transcendental and the empirical. On the basis of these distinctions, several conclusions are drawn: that the value of life is transcendental, not transcendent, both finite and priceless, that decisions to withhold or withdraw life-sustaining treatments are always judgments about the qualities of a person's life, so one cannot universally condemn "quality of life judgments," that the traditional distinction between killing and allowing to die tracks the distinction between the transcendental and the empirical, that "life itself" is not a benefit of treatment, and that foregoing treatments that are not futile can be consistent with respect for the value of life. PMID- 21696094 TI - A framework for risk-benefit evaluations in biomedical research. AB - Essentially all guidelines and regulations require that biomedical research studies have an acceptable risk-benefit profile. However, these documents offer little concrete guidance for implementing this requirement and determining when it is satisfied. As a result, those charged with risk-benefit evaluations currently assess the risk-benefit profile of biomedical research studies in unsystematic ways, raising concern that some research participants are not being protected from excessive risks and that some valuable studies involving acceptable risk are being rejected. The present paper aims to address this situation by delineating the first comprehensive framework, which is based on existing guidelines and regulations as well as the relevant literature, for risk benefit evaluations in biomedical research. PMID- 21696096 TI - Management of upper gastrointestinal bleeding in cirrhotic patients with documented esophageal varices evaluated at the Puerto Rico Medical Center. AB - Esophageal variceal bleeding is a frequent complication in patients with chronic liver disease. There is no published study that evaluates the management of this complication in Puerto Rico. Our study describes the management of patients with esophageal varices admitted to the emergency room of the Puerto Rico Medical Center from January 2002 to December 2004. Seventy-four patients were included, 50% of which presented stigmata of recent bleeding from esophageal varices. In patients who presented stigmata of recent esophageal variceal bleeding, larger varices were identified (65% vs. 27% p = 0.002). Significant bleeding and banding of esophageal varices was most common in patients with stigmata of recent bleed. Octreotide infusion and prophylactic antibiotics were received by the vast majority. The management of esophageal variceal bleeding in our institution is compliant with the American Association for the Study of Liver Diseases guidelines. PMID- 21696097 TI - Fistula-in-ano in children: a case series. AB - BACKGROUND: Fistula-in-ano is an abnormal connection between the inner surface of the anal canal and the perineal skin. METHODS: Between 2001 and 2010, seventeen patients with fistula-in-ano were surgically managed by a single surgeon within the University Pediatric Hospital and HIMA-San Pablo Hospital. RESULTS: There were 16 males and 1 female. The mean age at the time of operation was four years divided between infants (71%) and school children (29%). Fistulas were located on the midline right side in 5 patients, midline left side in 3 patients, midline bilaterally in 2 patients, in the anterior raphe in 4 patients and in the posterior raphe in 3 patients. Two patients of the infant group and two patients of the children group developed a perianal abscesses prior to the occurrence of fistula. All patients were managed with either fistulotomy or fistulectomy with six of them combined with Seton placement. There were no recurrence or complications. CONCLUSION: Fistulotomy is still considered the standard of care. PMID- 21696098 TI - Allergist role in asthma care in Puerto Rico. AB - INTRODUCTION: Puerto Ricans have one of the highest asthma prevalence and morbidity rates. However, limited information is available on asthma care and attitudes toward asthma treatment among Puerto Ricans living in the island. METHODS: We evaluated a cohort of subjects attending Ambulatory Health Screen Clinic in the two main cities in the north and south of the island during August of 2008. Subjects attending the clinic answered a survey about asthma care and attitudes toward asthma treatment. Approval was obtained from the Medical Sciences IRB and written informed consent obtained from all research subjects before enrollment. RESULTS: According to subject report, asthma care is primarily conducted by primary care physicians including pediatricians (35.8%), general practitioners (31.4%), and family physicians (4.3%). Pulmonary physicians conducted 23.3% of asthma care and allergists conduct 3.6%. Only 65.5 % reported using prescribed asthma medications. Fear of medication side effects (37.7%), lacks of health insurance coverage (26.4%), and medication cost (15.1%) were the most common causes reported for poor compliance. Subjects considered that physicians were one of the best sources (68.1%) for information on asthma, followed by the TV (23.7%) and the web (15.4%). CONCLUSIONS: Most asthma care in Puerto Rico is conducted by primary care providers. Subspecialists have a limited role and particularly allergists. Efforts to increased public and physician awareness of the role of allergists in asthma care in Puerto Rico are warranted. PMID- 21696099 TI - Clinical and thyroid ultrasound evaluation in an asymptomatic adult Puerto Rican population: The San Juan city hospital experience Coromoto A. Pale. AB - OBJECTIVES: to determine the prevalence of thyroid disease in an asymptomatic Puerto Rican adult population within an iodine sufficient area. Correlate the clinical thyroic features during palpation with thyroid sonographic findings. Relate gender, laboratory data, and family history with the presence or absence of thyroid pathology. METHODS: Cross-sectional, descriptive, comparative study performed during the period of February 2008-January 2009 in an asymptomatic Puerto Rican copulation. The study sample size consisted of 110 adult participants, employees of the San Juan City Hospital in apparent good health. A questionnaire emphasizing relevant personal and family thyroid pathology (benign and malignant) was obtained. A complete physical examination was performed emphasizing thyroid gland palpation, utilizing a posterior approach. for detection of any abnormal thyroid features. All participants underwent thyroid ultrasonographic (US) examination and blood sampling for ultrasensitive TSH and antiperoxidase antibodies. Subjects with thyroid nodules over one centimeter, found on thyroid US, were encouraged to undergo fine-needle aspiration biopsy (FNAB). RESULTS: The prevalence of thyroid pathology detected by palpation was 52.72% and 38.23% by US. The most frequent thyroid pathology found on palpation was goiter (41.37%) and multinodular goiter (64.85%). Twenty-four percent (24%) of the participants with normal findings on palpation had abnormal findings by US and 33.33% of those met criteria for FNAB. In sixteen patients with abnormal US, only six agreed to have FNAB, all were reported negative for malignancy. CONCLUSION: Our results suggest that routine thyroid US should be seriously considered for all patients with suspected thyroid disease. Statistical analysis demonstrated a significant correlation between palpation findings performed by an experience physician and thyroid ultrasonography results. Even in patients with negative family history of thyroid pathology, abnormal thyroid ultrasound abnormalities were detected in 35.73%. To our knowledge this is the first study done in Puerto Rico, comparing thyroid palpation and ultrasonographic findings. PMID- 21696100 TI - Pulmonary arterial hypertension: from pathophysiology to management. AB - Pulmonary arterial hypertension used to be considered an ultimately fatal disease despite the formerly available therapy. It is a disease characterized by progressive elevation of pulmonary vascular resistance and pulmonary arterial pressure, eventually resulting in right ventricular failure and death. The purpose of this article is to review the basic pathophysiologic processes involved in pulmonary arterial hypertension, to discuss patient presentation, classification, and diagnostic workup. Regarding treatment, all patients with PAH should be considered for standard therapy with anticoagulation, oxygen, and diuretics for management of right heart failure. Calcium channel blockers are only indicated for patients with a positive acute vasoreactivity test. Patients with a negative vasoreactivity test and considered low risk can be treated with oral agents such as endothelin receptor antagonists or PDE-5 inhibitor. Patients at high risk should be treated with prostacyclin analogs. Finally, a brief mention of new and future potential therapeutic strategies is also included. PMID- 21696102 TI - Uncommon cause of acute abdominal pain at the emergency room: epiploic appendagitis. AB - This is a case of 49 year-old-female with left lower quadrant pain. Initial diagnosis of acute diverticulitis entertained and treated accordingly. Diagnosis of epiploic appendagitis was done by abdominal CT-Scan. Epiploic appendagitis is commonly misdiagnosed as diverticulitis and appendicitis. Non-invasive studies may lead to early diagnosis avoiding unnecessary hospitalizations, antibiotic therapy and surgical intervention. PMID- 21696101 TI - Middle aged male with recurrent episodes of confusion, aggressive behavior and loss of consciousness. AB - We report a case of a 63 years-old-male with repeated bouts of confusion, aggressive behavior, dizziness and loss of consciousness occurring over a year. Such episodes increased in frequency and severity over time and were treated at the Emergency Room with intravenous dextrose solutions. Admitted at San Juan Bautista Medical Center due to severe hypoglycemia. Laboratory evaluation and prolong fasting ruled out an insulinoma or surreptitious administration of insulin or sulfonylurea. A CT scan of the abdomen and pelvis with oral contrast demonstrated a huge intra-abdominal mass invading the mesentery with herniated components laterally in the right lower quadrant. Patient underwent surgical resection of the abdominal mass. Histological description demonstrated a neoplastic pattern. Immunohistochemistry was compatible with an undifferentiated Synovial Sarcoma. PMID- 21696103 TI - Rib osteochondroma in a child: case report and review of literature. AB - Osteochondromas are the most common benign tumors of the skeleton. They usually arises from the metaphysial region of long bones. Only 10% of rib tumors are benign, and osteochondromas, account for half of these. These tumors typically begin to grow before puberty and continue until bone maturation is reached. We discuss a case of a 7-year-old boy found on physical examination to have a painless bony swelling arising as an outgrowth from the left fourth rib. Patient was taken to the operation room for a radical excision. CT scan and histopathological examination confirmed that the lesion was a non malignant osteochondroma. Costal osteochondroma is a rare but important condition to recognize due to its complications, such as reduced range of movement, pain, cosmetic abnormalities and bursitis. Costal osteochondromas tend to grow into the chest cavity and such lesions are rarely exophytic. There have been no previous reports of exophytic costal osteochondroma of this size in a child. PMID- 21696104 TI - Right lower quadrant abdominal pain in an immunocompromised patient: importance for an urgent diagnosis and treatment. AB - This is a case of a 34 years old male Hispanic patient with history of AIDS who presented to the ER with severe right lower quadrant abdominal pain of three days of evolution, associated with fever, chills, nausea, vomiting, watery diarrhea, weakness and general malaise. Acute appendicitis, Clostridium Difficile Colitis and Ischemic Colitis were the most important clinical conditions to consider in the differential diagnosis. Abdominal CT with IV contrast demonstrated thickening of the ascending colonic wall a finding highly suggestive of a transmural inflammatory necrotizing colitis of infectious etiology. Broad-spectrum antibiotic therapy, cancidas and ganciclovir were started with mark clinical improvement. IgG antibodies against CMV were elevated. Typhlitis is a serious illness that affects patients with impairment in immunity. It is important to include it in the differential diagnosis of an HIV/AIDS patient that presents with RLQ pain and fever. Contrast enhanced CT-Scan is mandatory to establish the diagnosis and to differentiate typhlitis from other intra-abdominal pathologies. Therapy needs to be individualized. PMID- 21696106 TI - What is a journal? PMID- 21696105 TI - An unusual cause of muscle weakness: a diagnostic challenge. AB - We report a case of 24 year-old-female presenting with bilateral leg heaviness sensation and difficult walking of one-day duration. Over the past three months she developed progressive and frequent tingling sensation on her hands accompanied by headache and increased thirst. Hypokalemia was identified and treated with resolution of symptoms. She was later found to have Graves' disease. After propranolol and radioiodine therapy no further episodes were reported. Thyrotoxic hypokalemic periodic paralysis is an alarming, potentially lethal, and rare complication of hyperthyroidism. The pathogenesis is uncertain. Because the condition is rare, it is frequently overlooked and misdiagnosed on presentation. It is important to recognize these clinical settings in hypokalemic patients in order to promptly start adequate medical therapy and avoid the lethal complications caused by prolonged sustained potassium depletion. PMID- 21696107 TI - A comparison of shear bond strength of immediate and delayed bonding of brackets to FRC bars using various orthodontic adhesives. AB - BACKGROUND: Fibre reinforced composite bars (FRC) have applications as bonded retainers, space maintainers and anchorage/movement units. However, the bond strength of attachments to FRC anchorage bars is unknown. AIMS: To compare the shear bond strengths of brackets bonded immediately to FRCs with different orthodontic adhesive systems and bonded with the same adhesives after a 48-hour delay, abraded with a diamond bur and etched with phosphoric acid. METHOD: One hundred and five recently extracted upper premolars were randomly assigned to seven groups (N = 15 teeth per group). FRCs were bonded to the buccal surfaces of the teeth and stainless steel orthodontic brackets were bonded to the FRCs with the following adhesive systems: Group 0 (Tetric Flow); Groups 1, 2 and 3 (Immediate bonding with chemically cured, no-mix and light cured composites, respectively, the bars covered with Tetric Flow); Groups 4, 5 and 6 (Bonding to FRCs delayed 48 hours, then bonded with chemically cured, no-mix and light cured composites, respectively, the bars covered with Tetric Flow). The FRC bars in Groups 4, 5 and 6 were abraded with a coarse-grit diamond bur before bonding the attachments to the bars. The shear bond strengths (SBS) were measured with a universal testing machine, and the adhesive remaining on the teeth after debonding was scored with the Adhesive Remnant Index (ARI). Data were analysed using analysis of variance (ANOVA), Duncan's post-hoc and Fisher's Exact test. RESULTS: There were no statistically significant SBS differences between Groups 0 (Mean SBS: 9.56 MPa), 1 (Mean SBS: 9.74 MPa), 2 (Mean SBS: 10.72 MPa) or 3 (Mean SBS: 9.54 MPa). Groups 4, 5 and 6 (Bonding delayed by 48 hours) had SBSs of 11.79 MPa, 11.63 MPa and 13.11 MPa, respectively, and were significantly higher than the SBSs in Groups 1, 2 and 3 (Immediate bonding). There were no significant differences in ARI scores among the groups. CONCLUSIONS: The mean SBSs in all groups fell within the clinically acceptable range (> 7 MPa). The combination of a 48-hour delay between placement of an FRC bar and bonding an attachment, abrading the FRC with a diamond bur and etching with phosphoric acid resulted in higher bond strengths. PMID- 21696108 TI - The effects of the pendulum distalising appliance and cervical headgear on the dentofacial structures. AB - BACKGROUND: Headgears are effective in distalising maxillary molars, but success depends on patient compliance and tolerance. Intra-oral distalising appliances are simple to construct and use and may be a better alternative for patients who are non-compliant or cannot tolerate headgear. AIMS: To compare the Pendulum (PEN) appliance and cervical headgear (CHG) on distal movement of maxillary first molars in patients requiring maxillary molar distalisation. METHODS: Thirty patients were randomly divided into two groups. Both groups had comparable occlusal and cephalometric characteristics before treatment. Fifteen patients (9 girls, 6 boys) with a mean age of 1 1.45 +/- 1.54 years (Range: 8.58-13.50 years) were treated with Pendulum appliances and 15 patients (10 girls, 5 boys) with a mean age of 11.72 + 1.24 years (Range: 9.58-13.33 years) were treated with a Ricketts-type CHG. A pilot study of four patients estimated that the time required to distalise the maxillary molars with the Pendulum appliance was five months. Therefore, the end of treatment records for the CHG group were taken after 4.96 +/- 0.35 months. Lateral and postero-anterior cephalometric radiographs were taken of both groups at the start (T1) and end of distalisation/treatment (T2). Changes in cephalometric measurements in the two groups were compared with Wilcoxon and Mann-Whitney U tests. RESULTS: Measurements indicated that U6-ANS distance, overjet and U1-APo distance increased, U6-PP angle and U6-PTV distance reduced, and the molar relationship improved more in the PEN group compared with the CHG group. Statistically, significant right molar - left molar differences were found between the two groups. Distalisation produced significant side effects, resulting in distal tipping of the first molars and an increase in overjet, whereas the CHG reduced the overjet. CONCLUSION: The Pendulum appliance was more effective than the CHG in distalising the maxillary first molars. PMID- 21696109 TI - Comparison of dietary intake between fixed orthodontic patients and control subjects. AB - BACKGROUND: Adolescence is a period of rapid physiological and psychological development which is associated with an increased demand in nutritional requirements. Orthodontic therapy is also commonly initiated during this phase of life and nutritional intake may also change during treatment. AIMS: To compare the nutrient intakes of adolescents wearing fixed orthodontic appliances and a control group matched for age and gender. METHOD: A total of 180 patients aged between 15 and 17 years participated in this study (90 in the study group and 90 controls). Demographic data were collected by questionnaire and dietary intake was assessed using a 24-hour memory recall and was analysed using Dietplan6 software (Forestfield Software Ltd, UK). Comparisons between groups were assessed by the Independent sample t-test dnd the SPSS was used for statistical analysis. RESULTS: Orthodontic patients consumed a similar number of total calories, protein and carbohydrate (p > 0.05); however, they had a greater intake of total fat, saturated fat, monosaturated fat, polysaturated fat, linolenic fat, linoleic fat and cholesterol and significantly lower intake of fibre, chromium and beta carotene (p < 0.05) compared with the Control group. The intake of other macro- and micro-nutrients did not differ significantly between groups. CONCLUSIONS: Adolescents receiving orthodontic treatment have an altered dietary intake that can be harmful to their health. As adolescents are at a critical stage of development and dietary intake is of particular importance, it is recommended that targeted nutritional guidance is provided to patients during orthodontic treatment. PMID- 21696110 TI - Evaluation of primary surgical outcomes in New Zealand patients with unilateral clefts of the lip and palate. AB - OBJECTIVE: To evaluate and compare the primary surgical outcomes of complete unilateral cleft lip and palate (UCLP) patients in two New Zealand cleft care centres. METHODS: This is a retrospective study of two providers of cleft care in New Zealand: Centre A in the North Island and Centre B in the South Island of New Zealand. Preorthodontic study models were evaluated from 28 UCLP patients from Centre A with primary surgical repairs performed between 1987-1999 and 31 UCLP patients from Centre B with primary surgical repairs performed between 1984-2000. Dental arch relationships were measured using the Goslon Yardstick. A Goslon score of 1 is considered to be an excellent outcome, whereas a score of 5 is a very poor treatment outcome. RESULTS: Intra- (Kappa: 0.84 - 0.93) and inter examiner (Kappa: 0.63 - 0.69) reliabilities revealed good to very good agreement between examiners using the Goslon Yardstick. The mean Goslon score for Centre A was 3.5, with no cases in Group 1, five cases in Group 2 (17.9 per cent), nine cases in Group 3 (32.1 per cent), 11 cases in Group 4 (39.3 per cent) and three cases in Group 5 (10.7 per cent). The mean score for Centre B was 3.1, with one case in Group 1 (3.2 per cent), nine cases in Group 2 (29.0 per cent), eight cases in Group 3 (25.8 per cent), 11 cases in Group 4 (35.5 per cent) and two cases in Group 5 (6.5 per cent). There were no statistically significant differences between the two centres (p > 0.05). CONCLUSIONS: The outcome scores from the two cleft centres, based on historic records, were disappointing and higher than expected. It is recommended that a review of primary surgical protocols be implemented to ensure outcomes comparable with international standards. The results provide useful benchmarks for future comparisons of treatment. PMID- 21696111 TI - The effects of various surface treatments on the shear bond strengths of stainless steel brackets to artificially-aged composite restorations. AB - OBJECTIVE: To compare the shear bond strengths (SBS) of stainless steel brackets bonded to artificially-aged composite restorations after different surface treatments. METHODS: Forty-five premolar teeth were restored with a nano-hybrid composite (Tetric EvoCeram), stored in deionised water for one week and randomly divided into three equal groups: Group I, he restorations were exposed to 5 per cent hydrofluoric acid for 60 seconds; Group II, the restorations were abraded with a micro-etcher (50 Iim alumina particles); Group III, the restorations were roughened with a coarse diamond bur. Similar premolar brackets were bonded to each restoration using the same resin adhesive and the specimens were then cycled in deionised water between 5 degrees C and 55 degrees C (500 cycles). The shear bond strengths were determined with a universal testing machine at a crosshead speed of 1 mm/min. The teeth and brackets were examined under a stereomicroscope and the adhesive remnants on the teeth scored with the adhesive remnant index (ARI). RESULTS: Specimens treated with the diamond bur had a significantly higher SBS (Mean: 18.45 +/- 3.82 MPa) than the group treated with hydrofluoric acid (Mean: 12.85 +/- 5.20 MPa). The mean SBS difference between the air-abrasion (Mean: 15.36 +/- 4.92 MPa) and hydrofluoric acid groups was not significant. High ARI scores occurred following abrasion with a diamond bur (100 per cent) and micro-etcher (80 per cent). In approximately two thirds of the teeth no adhesive was left on the restoration after surface treatment with hydofluoric acid. CONCLUSION: Surface treatment with a diamond bur resulted in a high bond strength between stainless steel brackets and artificially-aged composite restorations and was considered to be a safe and effective method of surface treatment. Most of the adhesive remained on the tooth following surface treatment with either the micro-etcher or the diamond bur. PMID- 21696112 TI - A systematic review of the association between appliance-induced labial movement of mandibular incisors and gingival recession. AB - OBJECTIVE: To determine if an association exists between appliance-induced labial movement of mandibular incisors and gingival recession. METHODS: Electronic databases were searched for studies with the terms: 'incisor', 'incisor proclination', 'tooth movement', 'orthodontic tooth movement', 'gingival recession' and 'orthodontic appliance'. The original articles and abstracts that met the initial inclusion criteria were retrieved, and their references hand searched for possible articles missed by the database searches. Inclusion criteria included human studies that suggested a link between labial movement of lower incisors produced by orthodontic treatment and gingival recession. Exclusion criteria included significant intrusion or extrusion of the mandibular incisors, periodontal disease, subjects taking medication that affects gingival health and subjects with systematic diseases. RESULTS: Seven articles fulfilled the selection criteria. Gingival recession after labial movement of lower incisors was assessed on dental casts, intra-oral slides, lateral cephalograms and gingival examination. The articles were analysed to determine the impact of their treatment methodology on the outcomes. CONCLUSIONS: No association between appliance-induced labial movement of mandibular incisors and gingival recession was found. Factors that may lead to gingival recession after orthodontic tipping and/or translation movement were identified as a reduced thickness of the free gingival margin, a narrow mandibular symphysis, inadequate plaque control and aggressive tooth brushing. PMID- 21696113 TI - Skeletal, dental and soft tissue changes in Class III patients treated with fixed appliances and lower premolar extractions. AB - BACKGROUND: Mild Class III malocciusions can be treated by upper incisor proclination and lower incisor retroclination following extraction of the lower first premolars. AIMS: To compare the skeletal, dental and soft tissue changes in Class III patients treated with fixed appliances, Class III traction and lower first premolar extractions with the changes in a group of untreated Class III patients. METHODS: The Treatment group consisted of 30 Class III patients (Mean age 13.69 +/- 1.48 years) who were treated by upper and lower fixed appliances, Class III intermaxillary traction and lower first premolar extractions for 2.88 +/- 1.12 years. The Control group consisted of 20 untreated Class III patients (Mean age 13.51 +/- 0.95) matched for age and gender. The T1 to T2 changes in the treated and untreated groups were compared using a paired t-test while differences between the two groups were compared with an independent t-test. RESULTS: During treatment, the upper incisors were proclined about 1 degree and the lower incisors were retroclined 8 degrees. Small, but statistically significant changes in SNB, Wits and the overlying soft tissues accompanied the changes in incisor inclination. At the end of treatment a positive overbite and overjet were achieved. The increase in lower facial height in the Treatment group was comparable with the change in the Control group. CONCLUSIONS: A range of mild to moderate Class III malocclusions can be treated by dentoalveolar compensation. PMID- 21696114 TI - Presence of cariogenic streptococci on various bracket materials detected by polymerase chain reaction. AB - OBJECTIVE: To determine the in vivo presence of Streptococcus mutans and Streptococcus sobrinus on different bracket materials and to correlate the prevalence with the Visible Plaque Index (VPI) and the Gingival Bleeding Index (GBI). METHODS: Orthodontic brackets made of different materials (stainless steel, gold, ceramic, plastic) were bonded to the upper and lower second premolars in 40 subjects receiving fixed orthodontic appliances. After 30 days, the brackets were debonded and the presence of S. mutans and S. sobrinus on the brackets was determined using the polymerase chain reaction (PCR) technique. The VPI and GBI were recorded and the relationship between the prevalence of the streptococci and the level of oral hygiene was calculated. RESULTS: There were fewer S. mutans and S. Sobrinus over the surface of gold and stainless steel brackets compared with the plastic and ceramic brackets. A statistically significant difference was observed in S. mutans and S. sobrinus prevalence between the metal brackets and the aesthetic brackets. However, there were no statistically significant differences in S. mutons and S. Sobrinus prevalence when the gold and stainless steel brackets were compared. Comparison between the plastic and ceramic brackets revealed a similar finding. Furthermore, a significant correlation was found between the in vivo prevalence of S. mutans and S.sobrinus and the oral hygiene indices (p < 0.05), suggesting that the oral hygiene indices could be a good indicator of S. mutans and S. sobrinus prevalence. CONCLUSIONS: Since microbial adhesion is greater on aesthetic brackets, good oral hygiene during treatment should be emphasised. PMID- 21696115 TI - Effectiveness and acceptability of Essix and Begg retainers: a prospective study. AB - BACKGROUND: Retainers vary in their effectiveness in maintaining teeth in their treated positions and in their acceptability by patients. AIMS: To compare the effectiveness and acceptability of Essix and Begg retainers. METHODS: Two hundred and twenty-four patients were randomly assigned to receive either upper and lower Essix or upper and lower Begg retainers. Subject acceptability was evaluated with seven questions related to chewing and biting, fit, speech, appearance, oral hygiene, comfort and maintenance recorded on a 1 O-point visual analogue scale. The effectiveness of the retainers to maintain alignment was assessed on study models taken on the day after debonding (T1), after three months retention (T2) and six months retention (T3) with the Peer Assessment Rating (PAR) and Irregularity Index (III). In addition to the upper and lower retainers, all subjects had bonded lower lingual retainers placed at the end of active treatment. RESULTS: There were small, but statistically significant, deteriorations in the PAR scores in both groups at T2 and T3. The T2-T1 and T3-T1 differences between the groups were statistically significant (Begg > Essix), but the differences did not exceed 2 points. For the Irregularity Index, the T3-T1 difference was statistically significant (Begg > Essix), but clinically insignificant as the difference was only 0.25 points. Subjects preferred the Begg retainer for chewing and biting (p = 0.000), and liked the appearance (p = 0.000) and comfort (p = 0.05) of the Essix retainers. The subjects in both groups reported both retainers had an acceptable fit. CONCLUSIONS: More subjects wearing Essix retainers considered their retainers were comfortable and had an acceptable appearance than subjects wearing Begg retainers, and more subjects with Begg retainers considered that their retainers were acceptable for biting and chewing than the subjects wearing Essix retainers. Both retainers allowed some relapse of teeth post-treatment, but the 6-month differences were small and may not be clinically significant. PMID- 21696116 TI - Orthodontic management of ectopic maxillary first permanent molars: a case report. AB - BACKGROUND: Ectopic position of a maxillary first permanent molar results in a local malocclusion within the mixed dentition and occurs when the tooth erupts more mesially to its normal path of eruption. The prevalence of ectopic maxillary first permanent molars has been reported at approximately 4 per cent. Possible treatment options include the extraction of the primary second molar and the placement of a space maintainer, extraction of the primary second molar and later regaining lost space during comprehensive treatment of the malocclusion or implementing interceptive treatment to disimpact the maxillary first permanent molar and preserving arch length. AIM: To describe the aetiology, classification and management of ectopic maxillary first permanent molars and to present two cases of intervention using simple orthodontic appliances. METHODS: A sectional fixed appliance and orthodontic separators were used to correct the ectopic maxillary first permanent molars. RESULTS: Successful disimpaction resulted in normal vertical eruption and arch length preservation. CONCLUSIONS: Management of ectopic maxillary first molars can be successfully achieved in the mixed dentition. PMID- 21696117 TI - Alignment of an ectopic canine with mini-implant anchorage: a case report. AB - AIMS: To describe the treatment of an ectopic maxillary left canine and Class II molar relationship in a 12 year-old girl. METHODS: A pendulum appliance was used in a first phase of treatment to distalise the maxillary molars to a Class I molar relationship. In the second phase of treatment, a mini-implant, inserted between the roots of the left maxillary central and lateral incisors, provided anchorage to move an ectopic maxillary left canine into position. RESULTS: The implant remained stable throughout treatment and a maxillary canine - first premolar transposition was corrected. Good overjet and overbite were achieved and have been maintained one year after completion of active treatment. PMID- 21696119 TI - Optimal force. PMID- 21696118 TI - Treatment of a Class III patient: a case report. AB - BACKGROUND: The skeletal Class III malocclusion may be characterised by mandibular prognathism, maxillary deficiency or both. AIM: To describe the early treatment of a skeletal Class Ill patient. METHODS: This case report presents a 10 year-old boy with a Class III malocclusion comprising a combination of maxillary deficiency and mandibular prognathism. Two treatment plans were considered. The first was to correct maxillary deficiency at an early age, while the second aimed to postpone treatment until after skeletal growth completion and then offer bimaxillary surgery. The case was treated early and a tongue appliance was used for maxillary protraction. RESULTS: The post-treatment SNA angle showed a 5 degree increase and a positive overbite and overjet were achieved after 23 months of active treatment. However, mandibular prognathism was still evident. CONCLUSION: Both treatment options have advantages and disadvantages which require informed clinical consideration. PMID- 21696120 TI - Control 21 'Stress-Breaking' Bracket. PMID- 21696121 TI - AVDC president's message. PMID- 21696122 TI - Oral examination results in rescued ferrets: clinical findings. AB - Ferrets have increased in popularity as pets, and a growing number are seen in companion animal practice. Domestic ferrets are commonly used as animal models for research of human oral conditions. The present study evaluated the prevalence of oral pathology in rescued ferrets which - to the authors' knowledge - has not yet been described in the scientific literature. Conscious oral examination was performed on 63 ferrets, of which 49 underwent general anesthesia for further examination. The most common clinical findings included malocclusion of mandibular second incisor teeth (95.2%); extrusion of canine teeth (93.7%); and abrasion and attrition of teeth (76.2%). Tooth fractures were exclusively associated with canine teeth and found in 31.7% of ferrets. Pulp exposure was confirmed in 60.0% of fractured teeth. The normal gingival sulcus depth measured < 0.5-mm in 87.8% of anesthetized ferrets. Clinical evidence of periodontal disease was present in 65.3% of anesthetized ferrets (gingivitis or probing depths > 0.5-mm), however advanced periodontal disease (i.e. periodontal pockets > 2-mm or stage 3 furcation exposure) was not found upon clinical examination. There was no evidence of tooth resorption, dental caries, stomatitis, or oral tumors in the examined group of ferrets. PMID- 21696123 TI - Dental eruption chronology in degus (Octodon degus). AB - The purpose of this study was to gain information concerning chronology of postnatal dental eruption in degus (Octodon degu). Specific findings pertain to the estimation of postnatal age at tooth emergence through the gingiva and to the age when a particular tooth is in functional occlusion. Fifty newborn degu pups were included in this study. The oral cavity endoscopy was carried out under isoflurane anesthesia in all animals 3 to 4 and 24-hours after birth, then at 1 day intervals until the age of 40-days, and subsequently at 2-day intervals until 75-days of age. Tooth emergence was considered to have occurred when any portion of the crown had penetrated the gingiva. The stage when the teeth come into occlusion was defined as the functional occlusion. The degus were born with completely erupted permanent incisors that were already in functional occlusion. All the premolar teeth and all the first molar teeth erupted on days 2 - 3 and 4 5 of life, respectively. The first signs offunctional occlusion ofall the first 2 cheek teeth were observed on days 9 - 11. Maxillary and mandibular second molar teeth emerged between days 17 - 19 and 18 - 20, respectively. First signs of functional occlusion were observed on days 30 - 31 and 31 - 33for maxillary and mandibular second molar teeth, respectively. Maxillary third molar teeth emerged on days 38 - 44 and erupted into occlusion on days 48 - 58. Mandibular third molar teeth emerged on days 39 - 46 and erupted into occlusion on days 58 - 72. PMID- 21696124 TI - Treatment of a periradicular lesion in an alpaca (Vicugna pacos). AB - This case report describes the diagnosis and surgical treatment of a cyst-like periradicular lesion in an alpaca. PMID- 21696125 TI - Nasopharyngeal tooth foreign body in a dog. AB - An 8-year-old Shih-tzu dog was presented with a 2-week history of cough and nasal discharge. Upon presentation, the dog had constant open-mouth breathing with stertor and blood-tinged mucopurulent nasal discharge. Oral examination revealed a missing right mandibular second premolar tooth and severe periodontal disease. Computed tomography showed a radiodense, retropharyngeal foreign body. The foreign body was removed using caudal rhinoscopy. The foreign body was the right mandibular second premolar covered by thick calculus. PMID- 21696126 TI - Treatment of oral abscesses in rodents and lagomorphs. PMID- 21696128 TI - Repair of secondary cleft palate in the dog. PMID- 21696127 TI - Oral examination and occlusal equilibration in rodents and lagomorphs. PMID- 21696129 TI - Rational design of a highly reactive ratiometric fluorescent probe for cyanide. AB - A novel highly reactive ratiometric fluorescent cyanide probe was judiciously designed based on 2-formylacrylonitrile moiety as a new cyanide reaction site. A DFT study was conducted to rationalize the extremely high reactivity nature of the ratiometric fluorescent cyanide probe. PMID- 21696130 TI - Evaluation of a microfabricated thermal modulator for comprehensive two dimensional microscale gas chromatography. AB - A microfabricated thermal modulator (MUTM) designed for ultimate use in a comprehensive two-dimensional microscale gas chromatography (MUGC * MUGC) system is evaluated. The 2-stage device measures 13 mm (l) * 6 mm (w) * 0.5 mm (h) and consists of two interconnected serpentine etched-Si microchannels suspended from a thin Pyrex cap and wall-coated with PDMS (polydimethylsiloxane). The chip is mounted within a few tens of micrometers of a thermoelectric cooler that maintains both stages at a baseline temperature between -35 and -20 degrees C in order to focus analytes eluting from an upstream separation column. Each stage is heated to 210 degrees C sequentially at a rate as high as 2400 degrees C/s by independent thin-film resistors to inject the analytes in consecutive fractions to a downstream column, and then cooled at a rate as high as -168 degrees C/s. The average power dissipation is only ~10 W for heating and 21 W for cooling without using consumable materials. In this study, the outlet of the MUTM is connected directly to a flame ionization detector to assess its performance. Following a demonstration of basic operation, the modulated peak amplitude enhancement (PAE) and full-width-at-half-maximum (fwhm) are evaluated for members of a series of n-alkanes (C(6)-C(10)) as a function of the rim and stage temperatures; modulation period, phase, and offset; analyte concentration; and carrier-gas flow rate. A PAE as high as 50 and a fwhm as narrow as 90 ms are achieved for n-octane under optimized conditions. PMID- 21696132 TI - Tale of a twist: magnetic and optical switching in copper(II) semiquinone complexes. AB - An intermediate (C) that is observed in both phenol hydroxylation and catechol oxidation with the side-on peroxide species [Cu(2)O(2)(DBED)(2)](2+) (DBED = N(1),N(2)-di-tert-butylethane-1,2-diamine) is identified as a copper(II) semiquinone species ([1](+)) through independent synthesis and characterization. The reaction of the redox-active 3,5-di-tert-butylquinone ligand with [(DBED)Cu(I)(MeCN)](+) yields a copper(II) semiquinone [1](+) complex with a singlet ground state and an intense purple chromophore (epsilon(580) ~ 3500 M(-1) cm(-1)). All other copper(II) semiquinone complexes characterized to date are paramagnetic and weakly colored (epsilon(800) ~ 500 M(-1) cm(-1)). Antiferromagnetic coupling between the Cu(II) center and the semiquinone radical in [1](+) is characterized by paramagnetic (1)H NMR and SQUID magnetometry. Comparative X-ray crystal structures along with density functional theory calculations correlate the geometric structures of copper(II) semiquinone complexes with their magnetic and optical properties. The unique observable properties of [1](+) originate from an increase in the overlap of the Cu 3d and semiquinone pi orbitals resulting from a large rhombic distortion in the structure with a twist of 51 degrees , attributable to the large isotropic demands of the tert-butyl substituents of the DBED ligand. Independent characterization of [1](+) allows the spectroscopic yields of intermediate C to be quantified in this intriguing hydroxylation reaction. PMID- 21696131 TI - Repair of the major lesion resulting from C5'-oxidation of DNA. AB - Oxidation of the C5'-position of DNA results in direct strand scission. The 3' fragments produced contain DNA lesions at their 5'-termini. The major DNA lesion contains an aldehyde at its C5'-position, but its nucleobase is unmodified. Excision of the lesion formed from oxidation of thymidine (T-al) is achieved by strand displacement synthesis by DNA polymerase beta (Pol beta) in the presence or absence of flap endonuclease 1 (FEN1). Pol beta displaces T-al and thymidine with comparable efficiency, but less so than a chemically stabilized abasic site analogue (F). FEN1 cleaves the flaps produced during strand displacement synthesis that are two nucleotides or longer. A ternary complex containing T-al is also a substrate for the bacterial UvrABC nucleotide excision repair system. The sites of strand scission are identical in ternary complexes containing T-al, thymidine, or F. UvrABC incision efficiency of these ternary complexes is comparable as well but significantly slower than a duplex substrate containing a bulky substituted thymidine. However, cleavage occurs only on the 5'-fragment and does not remove the lesion. These data suggest that unlike many lesions the redundant nature of base excision and nucleotide excision repair systems does not provide a means for removing the major damage product produced by agents that oxidize the C5'-position. This may contribute to the high cytotoxicity of drugs that oxidize the C5'-position in DNA. PMID- 21696133 TI - Dual molecular light switches for pH and DNA based on a novel Ru(II) complex. A non-intercalating Ru(II) complex for DNA molecular light switch. AB - A new Ru(II) complex of [Ru(phen)(2)(Hcdpq)](ClO(4))(2) {phen = 1,10 phenanthroline, Hcdpq = 2-carboxyldipyrido[3,2-f:2',3'-h]quinoxaline} was synthesized and characterized. The spectrophotometric pH and calf thymus DNA (ct DNA) titrations showed that the complex acted as a dual molecular light switch for pH and ct-DNA with emission enhancement factors of 17 and 26, respectively. It was shown to be capable of distinguishing ct-DNA from yeast RNA with this binding selectivity being superior to two well-known DNA molecular light switches of [Ru(bpy)(2)(dppz)](2+) {bpy =2,2'-bipyridine, and dppz = dipyrido-[3,2-a:2',3' c]phenazine}and ethidium bromide. The complex bond to ct-DNA probably in groove mode with a binding constant of (4.67 +/- 0.06) * 10(3) M(-1) in 5 mM Tris-HCl, 50 mM NaCl (pH = 7.10) buffer solution, as evidenced by UV-visible absorption and luminescence titrations, the dependence of DNA binding constants on NaCl concentrations, DNA competitive binding with ethidium bromide, and emission lifetime and viscosity measurements. To get insight into the light-switch mechanism, theoretical calculations were also performed by applying density functional theory (DFT) and time-dependent DFT. PMID- 21696134 TI - Low-temperature solvothermal approach to the synthesis of La4Ni3O8 by topotactic oxygen deintercalation. AB - A chimie douce solvothermal reduction method is proposed for topotactic oxygen deintercalation of complex metal oxides. Four different reduction techniques were employed to qualitatively identify the relative reduction activity of each including reduction with H(2) and NaH, solution-based reduction using metal hydrides at ambient pressure, and reduction under solvothermal conditions. The reduction of the Ruddlesden-Popper nickelate La(4)Ni(3)O(10) was used as a test case to prove the validity of the method. The completely reduced phase La(4)Ni(3)O(8) was produced via the solvothermal technique at 150 degrees C--a lower temperature than by other more conventional solid state oxygen deintercalation methods. PMID- 21696135 TI - Solid-state nanostructured materials from self-assembly of a globular protein polymer diblock copolymer. AB - Self-assembly of three-dimensional solid-state nanostructures containing approximately 33% by weight globular protein is demonstrated using a globular protein-polymer diblock copolymer, providing a route to direct nanopatterning of proteins for use in bioelectronic and biocatalytic materials. A mutant red fluorescent protein, mCherryS131C, was prepared by incorporation of a unique cysteine residue and site-specifically conjugated to end-functionalized poly(N isopropylacrylamide) through thiol-maleimide coupling to form a well-defined model protein-polymer block copolymer. The block copolymer was self-assembled into bulk nanostructures by solvent evaporation from concentrated solutions. Small-angle X-ray scattering and transmission electron microscopy illustrated the formation of highly disordered lamellae or hexagonally perforated lamellae depending upon the selectivity of the solvent during evaporation. Solvent annealing of bulk samples resulted in a transition toward lamellar nanostructures with mCherry packed in a bilayer configuration and a large improvement in long range ordering. Wide-angle X-ray scattering indicated that mCherry did not crystallize within the block copolymer nanodomains and that the beta-sheet spacing was not affected by self-assembly. Circular dichroism showed no change in protein secondary structure after self-assembly, while UV-vis spectroscopy indicated approximately 35% of the chromophore remained optically active. PMID- 21696136 TI - The absorption and translocation of polychlorinated biphenyl congeners by Cucurbita pepo ssp pepo. AB - The mobility of polychlorinated biphenyl (PCB) congeners within Cucurbita pepo ssp pepo cv. Howden (pumpkin), a PCB phytoextracting plant, was investigated through a comparison of field-weathered soil, root, shoot, and xylem sap congener profiles. This is the first study to show the presence of PCBs in xylem sap (range: 0.03-0.18 MUg.mL(-1)), confirming that PCB translocation throughout the plant occurs via this medium. A comparison of soil (5.2 +/- 2.5 MUg.g(-1)), root (27.1 +/- 2.1 MUg.g(-1)), shoot (range: 1.9 +/- 0.5 MUg.g(-1) - 8.2 +/- 1.4 MUg.g(-1)), and xylem sap (0.09 +/- 0.04 MUg.g(-1)) samples showed significant differences in congener profiles, with lower chlorinated congeners (predominately trichlorinated ones) found within xylem sap in higher amounts than higher chlorinated congeners. The total PCB concentrations of xylem sap samples collected at various lengths along the primary plant shoot were not significantly different from each other, while those of primary shoot tissue samples significantly decreased (two-sample t test, p = 0.01) as the distance from the plant base increased. PCA analysis of individual congeners in the roots, shoots and xylem sap indicated that movement of the PCB congeners in the plant was affected by the number of chlorines in the molecule, and hence possibly log K(ow) and molecular weight, but not by planarity. PMID- 21696139 TI - Role of conformation in pi-pi interactions and polymer/fullerene miscibility. AB - The origin of the miscibility between C(60) fullerene and a series of phenyl vinyl polymers has been investigated using a combination of wide-angle X-ray (WAXS) and neutron (WANS) scattering and density functional theory (DFT) computational modeling. The solubility limit of the C(60) in the polymers was found to increase nonlinearly with increasing phenyl rings in the side groups from 1 wt % in polystyrene (PS) to 12 wt % in poly(9-vinylphenanthrene) (P9VPh). The DFT calculations showed that the polymer interacts with the fullerene preferentially via the phenyl groups in these vinyl polymers. However, due to the backbone these phenyl groups are unable to form the energetically favorable T junction or planar pi-pi stacks with the fullerene and are randomly oriented to the cage. The nonlinear increase in solubility is believed to be associated with shape conformity of the three-ring phenanthrene to the curvature of the fullerene. PMID- 21696137 TI - Biomimetic chemical sensors using nanoelectronic readout of olfactory receptor proteins. AB - We have designed and implemented a practical nanoelectronic interface to G protein coupled receptors (GPCRs), a large family of membrane proteins whose roles in the detection of molecules outside eukaryotic cells make them important pharmaceutical targets. Specifically, we have coupled olfactory receptor proteins (ORs) with carbon nanotube transistors. The resulting devices transduce signals associated with odorant binding to ORs in the gas phase under ambient conditions and show responses that are in excellent agreement with results from established assays for OR-ligand binding. The work represents significant progress on a path toward a bioelectronic nose that can be directly compared to biological olfactory systems as well as a general method for the study of GPCR function in multiple domains using electronic readout. PMID- 21696140 TI - A novel strategy to assemble achiral ligands to chiral helical polyrotaxane structures. AB - Using the achiral N,N'-bis(2-pyridylmethyl)-1,6-hexanediamine ligand bearing two end pyridyl groups as the source of conformational chirality, a novel type of TMeQ[6]-based helical polyrotaxane was prepared and characterized by X-ray crystallography and (1)H NMR spectroscopy. The chirality of the polyrotaxane was generated from twisting of the hexylidene of the N,N'-bis(2-pyridylmethyl)-1,6 hexanediamine "string" when bound within the hydrophobic cavity of TMeQ[6]. Two opposite chiral helical polyrotaxanes crystallize as a racemic compound. PMID- 21696141 TI - Berberine, an isoquinoline alkaloid in herbal plants, protects pancreatic islets and serum lipids in nonobese diabetic mice. AB - Type 1 diabetes (T1D) damages pancreatic islets, gradually causing chronic complications. This study investigated the berberine effect on T1D in vivo. Nonobese diabetic (NOD) mice were grouped and administered 50, 150, and 500 mg of berberine/kg of body weight over 14 weeks using consecutive tube feeding. Changes in pancreatic islets, serum insulin, berberine, and lipid levels were determined. The results showed that berberine supplementation significantly (P < 0.05) increased the number of decreased islets and raised serum berberine levels in dose-dependent manners in experimental mice. Berberine supplementation also increased insulin levels, but decreased the ratio of low-density lipoprotein cholesterol (LDL-C)/total cholesterol (TC). Furthermore, serum berberine levels showed a significantly positive correlation with high-density lipoprotein cholesterol (HDL-C) levels and the HDL-C/TC ratio, but a negative correlation with the LDL-C/HDL-C ratio. This study suggests that berberine administration in vivo protects pancreatic islets and serum lipids in NOD mice. PMID- 21696142 TI - Refining the eosinophil cationic protein antibacterial pharmacophore by rational structure minimization. AB - Sequence analysis of eosinophil cationic protein (ECP), a ribonuclease of broad antimicrobial activity, allowed identification of residues 1-45 as the antimicrobial domain. We have further dissected ECP(1-45) with a view to defining the minimal requirements for antimicrobial activity. Structure-based downsizing has focused on both alpha-helices of ECP(1-45) and yielded analogues with substantial potency against Gram-negative and -positive strains. Analogues ECP(8 36) and ECP(6-17)-Ahx-(23-36) (Ahx, 6-aminohexanoic acid) involve 36% and 40% size reduction relative to (1-45), respectively, and display a remarkably ECP like antimicrobial profile. Both retain segments required for self-aggregation and lipolysaccharide binding, as well as the bacterial agglutination ability of parent ECP. Analogue (6-17)-Ahx-(23-36), in particular, is shown by NMR to preserve the helical traits of the native 8-16 (alpha1) and 33-36 (alpha2) regions and can be proposed as the minimal structure capable of reproducing the activity of the entire protein. PMID- 21696143 TI - New Raman-laser-induced breakdown spectroscopy identity of explosives using parametric data fusion on an integrated sensing platform. AB - The principal goal of sensors for the detection of explosives is to establish the identity of the interrogated target as a key to threat assessment and decision making. Despite the fact that both Raman spectroscopy and laser-induced breakdown spectroscopy (LIBS) have shown their capability in standoff detection of explosives, such techniques are not exempt from certain limitations, in terms of sensitivity and selectivity, to carry out this purpose when they are used individually. For this reason, the idea for the fusion of data reported by these orthogonal techniques, Raman and LIBS, has been around for a while. The present manuscript proposes an approach for the combination of the spectral outputs of Raman and LIBS sensors (data fusion strategy) in order to obtain knowledge about the identity of compounds better than that achieved when each technique acts alone. After simple mathematical treatment, a new pattern of identification (two dimensional, 2D, image) of several compounds (explosives, confusants, and supports) was generated from the assembly of their Raman and LIBS spectra. The efficiency of this strategy was evaluated by comparing the results obtained for differentiation between compounds using simple correlation coefficient values from the 2D images and those achieved using Raman and LIBS spectra separately. Additionally, the effect of two spectral pretreatments (autoscaling and normalization) on the generation of the 2D image was evaluated. The results derived from this study demonstrate that the 2D image improves the identification of compounds, mainly in those critical situations in which it is not easy to differentiate them when Raman spectroscopy or LIBS is used separately. PMID- 21696144 TI - Accelerating chemical database searching using graphics processing units. AB - The utility of chemoinformatics systems depends on the accurate computer representation and efficient manipulation of chemical compounds. In such systems, a small molecule is often digitized as a large fingerprint vector, where each element indicates the presence/absence or the number of occurrences of a particular structural feature. Since in theory the number of unique features can be exceedingly large, these fingerprint vectors are usually folded into much shorter ones using hashing and modulo operations, allowing fast "in-memory" manipulation and comparison of molecules. There is increasing evidence that lossless fingerprints can substantially improve retrieval performance in chemical database searching (substructure or similarity), which have led to the development of several lossless fingerprint compression algorithms. However, any gains in storage and retrieval afforded by compression need to be weighed against the extra computational burden required for decompression before these fingerprints can be compared. Here we demonstrate that graphics processing units (GPU) can greatly alleviate this problem, enabling the practical application of lossless fingerprints on large databases. More specifically, we show that, with the help of a ~$500 ordinary video card, the entire PubChem database of ~32 million compounds can be searched in ~0.2-2 s on average, which is 2 orders of magnitude faster than a conventional CPU. If multiple query patterns are processed in batch, the speedup is even more dramatic (less than 0.02-0.2 s/query for 1000 queries). In the present study, we use the Elias gamma compression algorithm, which results in a compression ratio as high as 0.097. PMID- 21696145 TI - Visualization of molecular fingerprints. AB - A visualization plot of a data set of molecular data is a useful tool for gaining insight into a set of molecules. In chemoinformatics, most visualization plots are of molecular descriptors, and the statistical model most often used to produce a visualization is principal component analysis (PCA). This paper takes PCA, together with four other statistical models (NeuroScale, GTM, LTM, and LTM LIN), and evaluates their ability to produce clustering in visualizations not of molecular descriptors but of molecular fingerprints. Two different tasks are addressed: understanding structural information (particularly combinatorial libraries) and relating structure to activity. The quality of the visualizations is compared both subjectively (by visual inspection) and objectively (with global distance comparisons and local k-nearest-neighbor predictors). On the data sets used to evaluate clustering by structure, LTM is found to perform significantly better than the other models. In particular, the clusters in LTM visualization space are consistent with the relationships between the core scaffolds that define the combinatorial sublibraries. On the data sets used to evaluate clustering by activity, LTM again gives the best performance but by a smaller margin. The results of this paper demonstrate the value of using both a nonlinear projection map and a Bernoulli noise model for modeling binary data. PMID- 21696146 TI - 1-Alkynyl- and 1-alkenyl-3-arylimidazo[1,5-a]pyridines: synthesis, photophysical properties, and observation of a linear correlation between the fluorescent wavelength and Hammett substituent constants. AB - 1-Alkynyl- and 1-alkenyl-3-arylimidazo[1,5-a]pyridines were synthesized. The Sonogashira coupling of 3-aryl-1-iodoimidazo[1,5-a]pyridines and various terminal alkynes with Pd(PPh(3))(2)Cl(2) (10 mol %) and CuI (10 mol %) in triethylamine at 80 degrees C for 12 h afforded the corresponding 1-alkenyl-3-arylimidazo[1,5 a]pyridines in good to excellent yields. The Mizoroki-Heck reaction of 3-aryl-1 iodoimidazo[1,5-a]pyridines and various styrene derivatives proceeded smoothly with Pd(OAc)(2) (5 mol %), IMes.HCl (10 mol %), and Cs(2)CO(3) (2 equiv) in DMA at 130 degrees C for 20 h to give the alkenylated imidazo[1,5-a]pyridines in moderate to high yields. The fluorescence maxima and fluorescence quantum yields of the alkynylated products were 458-560 nm and Phi(F) = 0.08-0.26 in chloroform solution, and those of the alkenylated imidazopyridines were 479-537 nm and Phi(F) = 0.03-0.13. The absorption behaviors of the obtained alkynylated and alkenylated imidazo[1,5-a]pyridines showed a good fit to the values predicted by TDDFT calculations at the B3LYP/6-311++G(d,p) level. In addition, the alkynylated imidazo[1,5-a]pyridines obtained showed linear correlations between the Hammett substituent constants of the substituents on the arylalkynyl group and their fluorescence wavelengths. PMID- 21696147 TI - Pyrolysis of phenethyl phenyl ether tethered in mesoporous silica. Effects of confinement and surface spacer molecules on product selectivity. AB - There has been expanding interest in exploring porous metal oxides as a confining environment for organic molecules resulting in altered chemical and physical properties including chemical transformations. In this paper, we examine the pyrolysis behavior of phenethyl phenyl ether (PPE) confined in mesoporous silica by covalent tethers to the pore walls as a function of tether density and the presence of cotethered surface spacer molecules of varying structure (biphenyl, naphthyl, octyl, and hexadecyl). The PPE pyrolysis product selectivity, which is determined by two competitive free-radical pathways cycling through the two aliphatic radical intermediates (PhCH.CH(2)OPh and PhCH(2)CH.OPh), is shown to be significantly different from that measured in the liquid phase as well as for PPE tethered to the exterior surface of nonporous silica nanoparticles. Tailoring the pore surface with spacer molecules further alters the selectivity such that the PPE reaction channel involving a molecular rearrangement (O-C phenyl shift in PhCH(2)CH.OPh), which accounts for 25% of the products in the liquid phase, can be virtually eliminated under pore confinement conditions. The origin of this change in selectivity is discussed in the context of steric constraints on the rearrangement path inside the pores, surface and pore confinement effects, pore surface curvature, and hydrogen bonding of PPE with residual surface silanols supplemented by nitrogen physisorption data and molecular dynamics simulations. PMID- 21696148 TI - Investigating the superhydrophobic behavior for underwater surfaces using impedance-based methods. AB - We have investigated the impedance behavior of immersed superhydrophobic (SH) polymethylene surfaces by tailoring the surface tension of the contacting liquid phase to gradually transition the surface from the Cassie to the Wenzel state. Control over the surface tension is accomplished by varying the ethanol content of the aqueous phase. To establish the mechanism of the transition, we imaged the interface of the film and identified three distinct events of this process: a nucleation event at low concentrations of ethanol in which small areas beneath the liquid phase transition into the Wenzel state, a propagation event characterized by the enlargement of the Wenzel domains and the lateral displacement of air, and a final event at higher concentrations of ethanol in which the thin air layer at the interface morphs into isolated pockets of air. Using this visualization of the transition, we characterized the Cassie and the Wenzel states by measuring the impedance at a frequency of 1 kHz for an initially SH film that changes its wetting behavior upon addition of ethanol. Establishment of the Cassie and Wenzel state conditions was based on concepts of electrochemical impedance spectroscopy (EIS) and quantitatively validated using both the Helmholtz theory and the analytical description of the electrochemical system in terms of the circuit model of a metal surface covered by a polymer film. Finally, we apply this strategy to determine the possibility for SH polymethylene (PM) films to reversibly transition between the Cassie and the Wenzel states. Results show that after rinsing and drying at ambient conditions for 24 h, the film recovers the SH state, suggesting the applicability of these SH films in outdoor environments with occasional periodic submersion in water. PMID- 21696149 TI - The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4. AB - Cells can respond to mechanical stress by gating mechanosensitive ion channels (MSCs). The cloning of Piezo1, a eukaryotic cation selective MSC, defines a new system for studying mechanical transduction at the cellular level. Because Piezo1 has electrophysiological properties similar to those of endogenous cationic MSCs that are selectively inhibited by the peptide GsMTx4, we tested whether the peptide targets Piezo1 activity. Extracellular GsMTx4 at micromolar concentrations reversibly inhibited ~80% of the mechanically induced current of outside-out patches from transfected HEK293 cells. The inhibition was voltage insensitive, and as seen with endogenous MSCs, the mirror image d enantiomer inhibited like the l. The rate constants for binding and unbinding based on Piezo1 current kinetics provided association and dissociation rates of 7.0 * 10(5) M(-1) s(-1) and 0.11 s(-1), respectively, and a K(D) of ~155 nM, similar to values previously reported for endogenous MSCs. Consistent with predicted gating modifier behavior, GsMTx4 produced an ~30 mmHg rightward shift in the pressure gating curve and was active on closed channels. In contrast, streptomycin, a nonspecific inhibitor of cationic MSCs, showed the use-dependent inhibition characteristic of open channel block. The peptide did not block currents of the mechanical channel TREK-1 on outside-out patches. Whole-cell Piezo1 currents were also reversibly inhibited by GsMTx4, and although the off rate was nearly identical to that of outside-out patches, differences were observed for the on rate. The ability of GsMTx4 to target the mechanosensitivity of Piezo1 supports the use of this channel in high-throughput screens for pharmacological agents and diagnostic assays. PMID- 21696150 TI - Fabrication of highly uniform nanoparticles from recombinant silk-elastin-like protein polymers for therapeutic agent delivery. AB - Here we generate silk-elastin-like protein (SELP) polymeric nanoparticles and demonstrate precise control over their dimensions using an electrospray differential mobility analyzer (ES-DMA). Electrospray produces droplets encompassing several polymer strands. Evaporation ensues, leading polymer strands to accumulate at the droplet interface, forming a hollow nanoparticle. The resulting nanoparticle size distributions, which govern particle yield, depend on buffer concentration to the -1/3 power, polymer concentration to the 1/3 power, and ratio of silk-to-elastin blocks. Three recombinantly tuned ratios of 8:16, 4:8, and 4:16, respectively named SELP-815K, SELP-47K, and SELP-415K, are employed, with the latter ratio resulting in a thinner shell and larger diameter for the nanoparticles than the former. The DMA narrows the size distribution by electrostatically classifying the aerosolized nanoparticles. These highly uniform nanoparticles have variations of 1.2 and 1.4 nm for 24.0 and 36.0 nm particles, respectively. Transmission electron microscopy reveals the nanoparticles to be faceted, as a buckling instability releases compression energy arising from evaporation after the shell has formed by bending it. A thermodynamic equilibrium exists between compression and bending energies, where the facet length is half the particle diameter, in agreement with experiments. Rod-like particles also formed from polymer-stabilized filaments when the viscous length exceeds the jet radius at higher solution viscosities. The unusual uniformity in composition and dimension indicates the potential of these nanoparticles to deliver bioactive and imaging agents. PMID- 21696151 TI - Dual effects of phloretin and phloridzin on the glycation induced by methylglyoxal in model systems. AB - In the present study, the dual effects of phloretin and phloridzin on methylglyoxal (MGO)-induced glycation were investigated in three N(alpha)-acetyl amino acid (arginine, cysteine, and lysine) models and three N-terminal polypeptide (PP01, PP02, and PP03 containing arginine, cysteine, and lysine, respectively) models. In both N(alpha)-acetyl amino acids and N-terminal polypeptides models, the arginine residue was confirmed as the major target for modification induced by MGO. Meanwhile, MGO modification was significantly inhibited by the addition of phloretin or phloridzin via their MGO-trapping abilities, with phloretin being more effective. Interestingly, the cysteine residue was intact when solely incubated with MGO, whereas the consumption of N(alpha)-acetylcysteine and PP02 was promoted by the addition of phloretin. Additional adducts, [N(alpha)-acetylcysteine + 2MGO + phloretin-H(2)O] and [2N(alpha)-acetylcysteine + 2MGO + phloretin-2H(2)O] were formed in the model composed of N(alpha)-acetylcysteine, MGO, and phloretin. Another adduct, [PP02 + 2MGO + phloretin-H(2)O] was observed in the model composed of PP02, MGO, and phloretin. The generation of adducts indicates that phloretin could directly participate in the modification of the cysteine residue in the presence of MGO. When creatine kinase (model protein) was exposed to MGO, the addition of phloridzin did not show a significant effect on retaining the activity of creatine kinase impaired by MGO, whereas the addition of phloretin completely inactivated creatine kinase. Results of the mass spectrometric analysis of intact creatine kinase in different models demonstrated that phloretin could directly participate in the reaction between creatine kinase and MGO, which would lead to the inactivation of creatine kinase. Furthermore, the addition of N(alpha) acetylcysteine was found to maintain the activity of creatine kinase incubated with phloretin and MGO. These results showed that phloretin and phloridzin could inhibit the modification of the arginine residue by MGO and that phloretin could directly participate in the reaction between the thiol group and MGO. PMID- 21696152 TI - Size-selective incorporation of DNA nanocages into nanoporous antimony-doped tin oxide materials. AB - A conductive nanoporous antimony-doped tin oxide (ATO) powder has been prepared using the sol-gel method that contains three-dimensionally interconnected pores within the metal oxide and highly tunable pore sizes on the nanoscale. It is demonstrated that these porous materials possess the capability of hosting a tetrahedral-shaped DNA nanostructure of defined dimensions with high affinity. The tunability of pore size enables the porous substrate to selectively absorb the DNA nanostructures into the metal oxide cavities or exclude them from entering the surface layer. Both confocal fluorescence microscopy and solution FRET experiments revealed that the DNA nanostructures maintained their integrity upon the size-selective incorporation into the cavities of the porous materials. As DNA nanostructures can serve as a stable three-dimensional nanoscaffold for the coordination of electron transfer mediators, this work opens up new possibilities of incorporating functionalized DNA architectures as guest molecules to nanoporous conductive metal oxides for applications such as photovoltaics, sensors, and solar fuel cells. PMID- 21696153 TI - Classifying molecules using a sparse probabilistic kernel binary classifier. AB - The central idea of supervised classification in chemoinformatics is to design a classifying algorithm that accurately assigns a new molecule to one of a set of predefined classes. Tipping has devised a classifying scheme, the Relevance Vector Machine (RVM), which is in terms of sparsity equivalent to the Support Vector Machine (SVM). However, unlike SVM classifiers, the RVM classifiers are probabilistic in nature, which is crucial in the field of decision making and risk taking. In this work, we investigate the performance of RVM binary classifiers on classifying a subset of the MDDR data set, a standard molecular benchmark data set, into active and inactive compounds. Additionally, we present results that compare the performance of SVM and RVM binary classifiers. PMID- 21696154 TI - Influence of dissolved organic carbon on methylmercury bioavailability across Minnesota stream ecosystems. AB - Stream ecosystems are widely contaminated by mercury (Hg) via atmospheric transport and deposition in watersheds. Dissolved organic carbon (DOC) is well known to be the dominant ligand for aqueous methylmercury (MeHg), the bioaccumulative form of Hg in aquatic food webs. However, it is less clear if and how the concentration and character (e.g., aromaticity) of DOC influences the availability of dissolved MeHg to stream food webs. In this work, we analyzed total-Hg and/or MeHg concentrations in water, seston, and macroinvertebrates (filter-feeding hydropsychid caddisflies), and other physiochemical properties in 30 streams along a south-north geographic gradient in eastern Minnesota that corresponds to substantial changes in dominant land cover (i.e., agriculture, urban, wetland, and forest). In general, MeHg concentrations in seston and hydropsychids were higher in watersheds with more forest and wetland coverage, and increased with dissolved MeHg concentration. However, we found that the efficiency of MeHg incorporation into the stream food webs (i.e., bioconcentration factors of MeHg in both seston and hydropsychids, BCF(MeHg) = solid MeHg / dissolved MeHg) decreased significantly with DOC concentration and aromaticity, suggesting that MeHg bioavailability to the base of food webs was attenuated at higher levels of terrestrial DOC. Therefore, our findings suggest that there is a dual role of DOC on MeHg cycling in streams: terrestrial DOC acts as the primary carrier ligand of dissolved MeHg for transport into surface waters, yet this aromatic DOC also attenuates dissolved MeHg uptake by aquatic food webs. Thus, consideration of MeHg bioavailability and its environmental regulation could help improve predictive models of MeHg bioaccumulation in stream ecosystems. PMID- 21696155 TI - Use of 5'-gamma-ferrocenyl adenosine triphosphate (Fc-ATP) bioconjugates having poly(ethylene glycol) spacers in kinase-catalyzed phosphorylations. AB - The 5'-gamma-ferrocenyl adenosine triphosphate (Fc-ATP) bioconjugates (3 and 4), containing the poly(ethylene glycol) spacers, were synthesized and compared to a hydrophobic analogue as co-substrates for the following protein kinases: sarcoma related kinase (Src), cyclin-dependent kinase (CDK), casein kinase II (CK2alpha), and protein kinase A (PKA). Electrochemical kinase assays indicate that the hydrophobic Fc-ATP analogue was an optimal co-substrate for which K(M) values were determined to be in the 30-200 MUM range, depending on the particular protein kinase. The luminescence kinase assay demonstrated the kinase utility for all Fc-ATP conjugates, which is in line with the electrochemical data. Moreover, Fc-ATP bioconjugates exhibit competitive behavior with respect to ATP. Relatively poor performance of the polar Fc-ATP bioconjugates as co-substrates for protein kinases was presumably due to the additional H-bonding and electrostatic interactions of the poly(ethylene glycol) linkers of Fc-ATP with the kinase catalytic site and the target peptides. Phosphorylation of the full-length protein, His-tagged pro-caspase-3, was demonstrated through Fc-phosphoamide transfer to the Ser residues of the surface-bound protein by electrochemical means. These results suggest that electrochemical detection of the peptide and protein Fc-phosphorylation via tailored Fc-ATP co-substrates may be useful for probing protein-protein interactions. PMID- 21696156 TI - Chromone, a privileged scaffold for the development of monoamine oxidase inhibitors. AB - Two series of novel chromone derivatives were synthesized and investigated for their ability to inhibit the activity of monoamine oxidase. The SAR data indicate that chromone derivatives with substituents in position 3 of gamma-pyrone nucleus act preferably as MAO-B inhibitors, with IC(50) values in the nanomolar to micromolar range. Almost all chromone 3-carboxamides display selectivity toward MAO-B. Identical substitutions on position 2 of gamma-pyrone nucleus result in complete loss of activity in both isoforms (chromones 2-12 except 3 and 5). Notably, chromone (19) exhibits an MAO-B IC(50) of 63 nM, greater than 1000-fold selectivity over MAO-A, and behaves as a quasi-reversible inhibitor. Docking experiments onto the MAO binding of the most active compound highlight different interaction patterns among the isoforms A and B. The differential analysis of the solvation effects among the chromone isomers gave additional insight about the superior outline of the 3-substituted chromone derivatives. PMID- 21696157 TI - High-valent uranium alkyls: evidence for the formation of U(VI)(CH2SiMe3)6. AB - Oxidation of [Li(DME)(3)][U(CH(2)SiMe(3))(5)] with 0.5 equiv of I(2), followed by immediate addition of LiCH(2)SiMe(3), affords the high-valent homoleptic U(V) alkyl complex [Li(THF)(4)][U(CH(2)SiMe(3))(6)] (1) in 82% yield. In the solid state, 1 adopts an octahedral geometry as shown by X-ray crystallographic analysis. Addition of 2 equiv of tert-butanol to [Li(DME)(3)][U(CH(2)SiMe(3))(5)] generates the heteroleptic U(IV) complex [Li(DME)(3)][U(O(t)Bu)(2)(CH(2)SiMe(3))(3)] (2) in high yield. Treatment of 2 with AgOTf fails to produce a U(V) derivative, but instead affords the U(IV) complex (Me(3)SiCH(2))Ag(MU-CH(2)SiMe(3))U(CH(2)SiMe(3))(O(t)Bu)(2)(DME) (3) in 64% yield. Complex 3 has been characterized by X-ray crystallography and is marked by a uranium-silver bond. In contrast, oxidation of 2 can be achieved via reaction with 0.5 equiv of Me(3)NO, producing the heteroleptic U(V) complex [Li(DME)(3)][U(O(t)Bu)(2)(CH(2)SiMe(3))(4)] (4) in moderate yield. We have also attempted the one-electron oxidation of complex 1. Thus, oxidation of 1 with U(O(t)Bu)(6) results in formation of a rare U(VI) alkyl complex, U(CH(2)SiMe(3))(6) (6), which is only stable below -25 degrees C. Additionally, the electronic properties of 1-4 have been assessed by SQUID magnetometry, while a DFT analysis of complexes 1 and 6 is also provided. PMID- 21696158 TI - Identification of the binding modes of N-phenylphthalimides inhibiting bacterial thymidylate synthase through X-ray crystallography screening. AB - To identify specific bacterial thymidylate synthase (TS) inhibitors, we exploited phenolphthalein (PTH), which inhibits both bacterial and human enzymes. The X-ray crystal structure of Lactobacillus casei TS (LcTS) that binds PTH showed multiple binding modes of the inhibitor, which prevented a classical structure-based drug design approach. To overcome this issue, we synthesized two phthalimidic libraries that were tested against TS enzymes and then we performed X-ray crystallographic screening of the active compounds. Compounds 6A, 8A, and 12A showed 40-fold higher affinity for bacterial TS than human TS. The X-ray crystallographic screening characterized the binding mode of six inhibitors in complexes with LcTS. Of these, 20A, 23A, and 24A showed a common unique binding mode, whereas 8A showed a different, unique binding mode. A comparative analysis of the LcTS X-ray complexes that were obtained with the pathogenic TS enabled the selection of compounds 8A and 23A as specific compounds and starting points to be exploited for the specific inhibition of pathogen enzymes. PMID- 21696159 TI - Effect of the Y955C mutation on mitochondrial DNA polymerase nucleotide incorporation efficiency and fidelity. AB - The human mitochondrial DNA polymerase (pol gamma) is responsible for the replication of the mitochondrial genome. Mutation Y955C in the active site of pol gamma results in early onset progressive external ophthalmoplegia, premature ovarian failure, and Parkinson's disease. In single-turnover kinetic studies, we show that the Y955C mutation results in a decrease in the maximal rate of polymerization and an increase in the K(m) for correct incorporation. The mutation decreased the specificity constant for correct incorporation of dGTP, TTP, and ATP to values of 1.5, 0.35, and 0.044 MUM(-1) s(-1), respectively, representing reductions of 30-, 110-, and 1300-fold, respectively, relative to the value for the wild-type enzyme. The fidelity of incorporation was reduced 6 130-fold, largely because of the significant decrease in the specificity constant for correct dATP:T incorporation. For example, k(cat)/K(m) for forming a TTP:T mismatch was decreased 10-fold from 0.0002 to 0.00002 MUM(-1) s(-1) by the Y955C mutant, but the 1300-fold slower incorporation of the correct dATP:T relative to that of the wild type led to a 130-fold lower fidelity. While correct incorporation of 8-oxo-dGTP was largely unchanged, the level of incorporation of 8-oxo-dG with dA in the template strand was reduced 500-fold. These results support a role for Y955 in stabilizing A:T base pairs at the active site of pol gamma and suggest that the severe clinical symptoms of patients with this mutation may be due, in part, to the reduced efficiency of incorporation of dATP opposite T, and that the autosomal dominant phenotype may arise from the resulting higher mutation frequency. PMID- 21696160 TI - Study of the flow field in the magnetic rod interfacial stress rheometer. AB - Several technological applications, consumer products, and biological systems derive their functioning from the presence of a complex fluid interface with viscoelastic interfacial rheological properties. Measurements of the "excess" rheological properties of such an interface are complicated by the intimate coupling of the bulk and interfacial flows. In the present work, analytical, numerical, and experimental results of the interfacial flow fields in a magnetic rod interfacial stress rheometer (ISR) are presented. Mathematical solutions are required to correct the experimentally determined apparent interfacial shear moduli and phase angles for the drag exerted by the surrounding phases, especially at low Boussinesq numbers. Starting from the Navier-Stokes equations and using the generalized Boussinesq-Scriven equation as a suitable boundary condition, the problem is solved both analytically and numerically. In addition, experimental data of the interfacial flow field are reported, obtained by following the trajectories of tracer particles at the interface with time. Good agreement is found between the three methods, indicating that both the analytical solution and the numerical simulations give an adequate description of the flow field and the resulting local interfacial shear rate at the rod. Based on these results, an algorithm to correct the experimental data of the ISR is proposed and evaluated, which can be extended to different types of interfacial shear rheometers and geometries. An increased accuracy is obtained and the measurement range of the ISR is expanded toward viscosities and elastic moduli of smaller magnitude. PMID- 21696161 TI - Trimethoxybenzene complexes of pentafluorophenylchlorocarbene. AB - Pentafluorophenylchlorocarbene, generated by laser flash photolysis (LFP) of pentafluorophenylchlorodiazirine, formed pi-type complexes with 1,3,5 trimethoxybenzene in pentane. The carbene and carbene complexes were in equilibrium with K = 3.21 * 10(5) M(-1) at 294 K. From the temperature dependence of K, DeltaH degrees = -10.2 kcal/mol, DeltaS degrees = -9.5 eu, and DeltaG degrees = -7.4 kcal/mol at 298 K. The carbene complexes were characterized by UV vis spectroscopy and computational analysis. PMID- 21696162 TI - Formation of a ruthenium(IV)-oxo complex by electron-transfer oxidation of a coordinatively saturated ruthenium(II) complex and detection of oxygen-rebound intermediates in C-H bond oxygenation. AB - A coordinatively saturated ruthenium(II) complex having tetradentate tris(2 pyridylmethyl)amine (TPA) and bidentate 2,2'-bipyridine (bpy), [Ru(TPA)(bpy)](2+) (1), was oxidized by a Ce(IV) ion in H(2)O to afford a Ru(IV)-oxo complex, [Ru(O)(H(+)TPA)(bpy)](3+) (2). The crystal structure of the Ru(IV)-oxo complex 2 was determined by X-ray crystallography. In 2, the TPA ligand partially dissociates to be in a facial tridentate fashion and the uncoordinated pyridine moiety is protonated. The spin state of 2, which showed paramagnetically shifted NMR signals in the range of 60 to -20 ppm, was determined to be an intermediate spin (S = 1) by the Evans' method with (1)H NMR spectroscopy in acetone-d(6). The reaction of 2 with various oraganic substrates in acetonitrile at room temperature afforded oxidized and oxygenated products and a solvent-bound complex, [Ru(H(+)TPA)(bpy)(CH(3)CN)], which is intact in the presence of alcohols. The oxygenation reaction of saturated C-H bonds with 2 proceeds by two step processes: the hydrogen abstraction with 2, followed by the dissociation of the alcohol products from the oxygen-rebound complexes, Ru(III)-alkoxo complexes, which were successfully detected by ESI-MS spectrometry. The kinetic isotope effects in the first step for the reaction of dihydroanthrathene (DHA) and cumene with 2 were determined to be 49 and 12, respectively. The second-order rate constants of C-H oxygenation in the first step exhibited a linear correlation with bond dissociation energies of the C-H bond cleavage. PMID- 21696163 TI - Multiple pathways of dissociative attachment: CH3Br on Si(100)-2*1. AB - We describe the dissociative attachment (DA) of methyl bromide to form chemisorbed CH(3) and Br on a Si(100)-2*1 surface at 270 K. The patterns of DA were studied experimentally by ultra-high vacuum scanning tunneling microscopy (STM) and interpreted by ab initio theory. The parent molecules were found to dissociate thermally by breaking the C-Br bond, attaching the resulting fragments CH(3) and Br at adjacent Si-atom sites. The observed DA resulted in three distinct attachment geometries: inter-row (IR, 88%), inter-dimer (ID, 11%), and on-dimer (OD, 1%). Ab initio computation agreed in predicting these three DA reaction pathways, with yields decreasing down the series, in accord with experiment. The three computed physisorption geometries, each of which correlated with a preferred outcome, IR, ID, or OD, exhibited similar heats of adsorption, the choice of pathway being governed by the energy barriers to DA chemisorption predicted to increase along the series: E(IR) = 0.48 eV, E(ID) = 0.57 eV, and E(OD) = 0.63 eV. PMID- 21696164 TI - Potential energy surface for (retro-)cyclopropanation: metathesis with a cationic gold complex. AB - The gas-phase cyclopropanation and apparent metathesis reactivity of ligand supported gold arylidenes with electron-rich olefins is explained by quantum chemical calculations. A deep potential minimum corresponding to a metal-bound cyclopropane adduct is in agreement with the measured absolute energies of the cyclopropanation and metathesis channels and is also consistent with previously reported electronic effects of arylidenes and supporting phosphorus ylid ligands on the product ratios. In the gas phase, the rate-determining step for the cyclopropanation is dissociation of the Lewis-acidic metal fragment, whereas the metathesis pathway features several rate-limiting transition states that are close in energy to the final product dissociation and hence contribute to the overall reaction rate. Importantly, the presented potential energy surface also accounts for the recently reported gold-catalyzed solution-phase retro cyclopropanation reactivity. PMID- 21696165 TI - Enhancing the Curie temperature of ferromagnetic semiconductor (Ga,Mn)As to 200 K via nanostructure engineering. AB - We demonstrate by magneto-transport measurements that a Curie temperature as high as 200 K can be obtained in nanostructures of (Ga,Mn)As. Heavily Mn-doped (Ga,Mn)As films were patterned into nanowires and then subject to low-temperature annealing. Resistance and Hall effect measurements demonstrated a consistent increase of T(C) with decreasing wire width down to about 300 nm. This observation is attributed primarily to the increase of the free surface in the narrower wires, which allows the Mn interstitials to diffuse out at the sidewalls, thus enhancing the efficiency of annealing. These results may provide useful information on optimal structures for (Ga,Mn)As-based nanospintronic devices operational at relatively high temperatures. PMID- 21696166 TI - Resistance to the third-generation cephalosporin ceftazidime by a deacylation deficient mutant of the TEM beta-lactamase by the uncommon covalent-trapping mechanism. AB - The Glu166Arg/Met182Thr mutant of Escherichia coli TEM(pTZ19-3) beta-lactamase produces a 128-fold increase in the level of resistance to the antibiotic ceftazidime in comparison to that of the parental wild-type enzyme. The single Glu166Arg mutation resulted in a dramatic decrease in both the level of enzyme expression in bacteria and the resistance to penicillins, with a concomitant 4 fold increase in the resistance to ceftazidime, a third-generation cephalosporin. Introduction of the second amino acid substitution, Met182Thr, restored enzyme expression to a level comparable to that of the wild-type enzyme and resulted in an additional 32-fold increase in the minimal inhibitory concentration of ceftazidime to 64 MUg/mL. The double mutant formed a stable covalent complex with ceftazidime that remained intact for the entire duration of the monitoring, which exceeded a time period of 40 bacterial generations. Compared to those of the wild type enzyme, the affinity of the TEM(pTZ19-3) Glu166Arg/Met182Thr mutant for ceftazidime increased by at least 110-fold and the acylation rate constant was augmented by at least 16-fold. The collective experimental data and computer modeling indicate that the deacylation-deficient Glu166Arg/Met182Thr mutant of TEM(pTZ19-3) produces resistance to the third-generation cephalosporin ceftazidime by an uncommon covalent-trapping mechanism. This is the first documentation of such a mechanism by a class A beta-lactamase in a manifestation of resistance. PMID- 21696167 TI - Liquid-gated ambipolar transport in ultrathin films of a topological insulator Bi2Te3. AB - Using ionic-liquid (IL) gating in electric-double-layer transistors (EDLTs), we investigate field-effect electrical transport properties of ultrathin epitaxial films of a topological insulator (TI), Bi(2)Te(3). Because of their extreme thinness, the Bi(2)Te(3) films show a band gap opening and resulting semiconducting transport properties. Near room temperature, an obvious ambipolar transistor operation with an ON-OFF ratio close to 10(3) was observed in the transfer characteristics of liquid-gated EDLTs and further confirmed by a sign change of the Hall coefficients. Modulation of the electronic states and a phase transition from a semiconducting conduction (dR(xx)/dT < 0) to a metallic transport (dR(xx)/dT > 0) were observed in the temperature-dependent resistance of the ultrathin Bi(2)Te(3) channel, demonstrating that the liquid gating is an effective way to modulate the electronic states of TIs. PMID- 21696168 TI - Graphene magnetoresistance device in van der Pauw geometry. AB - We have fabricated extraordinary magnetoresistance (EMR) device, comprising a monolayer graphene with an embedded metallic disk, that exhibits large room temperature magnetoresistance (MR) enhancement of up to 55,000% at 9 T. Finite element simulations yield predictions in excellent agreement with the experiment and show possibility for even better performance. Simplicity, ease of implementation and high sensitivity of this device imply great potential for practical applications. PMID- 21696169 TI - Effect of different vitamin D supplementations in poultry feed on vitamin D content of eggs and chicken meat. AB - According to a new European Union regulation, vitamin D(3) can be partially or totally substituted with 25-hydroxyvitamin D(3) (25-OH-D(3)) in hens' feed. The purpose of this study was to clarify how this regulation has affected the vitamin D content of commercial eggs and chicken meat. Another aim was to investigate how effectively 25-OH-D(3) is transferred from the hens' diet to egg yolk by analyzing eggs from farms using known commercial feeds and by conducting an animal study. Vitamin D determinations were made by HPLC methods. The vitamin D(3) contents of two commercial egg yolk pools were 4.9 +/- 0.14 and 4.0 +/- 0.10 MUg/100 g, and the 25-OH-D(3) contents were 1.3 +/- 0.19 and 1.0 +/- 0.07 MUg/100 g. The chicken meat pools contained 0.2-0.3 MUg of vitamin D(3)/100 g, whereas the content of 25-OH-D(3) was <=0.2 MUg/100 g. These results are comparable to earlier data. The animal and farm studies showed that 25-OH-D(3) was effectively transferred from the hens' diet to yolk. However, because the relative activity between 25-OH-D(3) and vitamin D(3) is unknown, it remains questionable whether the use of 25-OH-D(3) in hens' feed is beneficial to human vitamin D intake from eggs. PMID- 21696171 TI - Solvent effects on starch dissolution and gelatinization. AB - The disruption of starch granular structure during dissolution in varying concentrations of N-methyl morpholine N-oxide (NMMO) has been studied using three maize starches with varying ratios of amylose and amylopectin. Behavior in NMMO has been characterized by differential scanning calorimetry (DSC), microscopy, rapid viscosity analysis (RVA), and rheometry. Exothermic transitions were observed for the three starches in both 78 and 70% NMMO; the transition changed to an endotherm at 60 and 50% NMMO. Consistent with DSC, hot stage microscopy showed that starch granules dissolved at NMMO concentrations of 78 and 70%, whereas in 60 and 50% NMMO, gelatinization behavior similar to that found for starch in water was observed. Mechanical spectroscopy revealed the dominant viscous behavior (G" > G') of starch at NMMO concentrations of 70 and 78% and more elastic behavior (G' > G") at lower concentrations. Starch solutions in 78% NMMO obey the Cox-Merz rule, suggesting that the solutions are homogeneous on a molecular level. PMID- 21696170 TI - High-throughput screening of drug-lipid membrane interactions via counter propagating second harmonic generation imaging. AB - Here we report the use of counter-propagating second harmonic generation (SHG) to image the interactions between the local anesthetic tetracaine and a multicomponent planar supported lipid bilayer array in a label-free manner. The lipid bilayer arrays, prepared using a 3D continuous flow microspotter, allow the effects of lipid phase and cholesterol content on tetracaine binding to be examined simultaneously. SHG images show that tetracaine has a higher binding affinity to liquid-crystalline phase lipids than to solid-gel phase lipids. The presence of 28 mol % cholesterol decreased the binding affinity of tetracaine to bilayers composed of the mixed chain lipid, 1-steroyl-2-oleoyl-sn-glycero-3 phophocholine (SOPC), and the saturated lipids 1,2-dimyristoyl-sn-glycero-3 phophocholine (DMPC) and 1,2-dipamitoyl-sn-glycero-3-phophocholine (DPPC) while having no effect on diunsaturated 1,2-dioleoyl-sn-glycero-3-phophocholine (DOPC). The maximum surface excess of tetracaine increases with the degree of unsaturation of the phospholipids and decreases with cholesterol in the lipid bilayers. The paper demonstrates that SHG imaging is a sensitive technique that can directly image and quantitatively measure the association of a drug to a multicomponent lipid bilayer array, providing a high-throughput means to assess drug-membrane interactions. PMID- 21696172 TI - Piezotronic nanowire-based resistive switches as programmable electromechanical memories. AB - We present the first piezoelectrically modulated resistive switching device based on piezotronic ZnO nanowire (NW), through which the write/read access of the memory cell is programmed via electromechanical modulation. Adjusted by the strain-induced polarization charges created at the semiconductor/metal interface under externally applied deformation by the piezoelectric effect, the resistive switching characteristics of the cell can be modulated in a controlled manner, and the logic levels of the strain stored in the cell can be recorded and read out, which has the potential for integrating with NEMS technology to achieve micro/nanosystems capable for intelligent and self-sufficient multidimensional operations. PMID- 21696173 TI - The role of spontaneous polarization in the negative thermal expansion of tetragonal PbTiO3-based compounds. AB - PbTiO(3)-based compounds are well-known ferroelectrics that exhibit a negative thermal expansion more or less in the tetragonal phase. The mechanism of negative thermal expansion has been studied by high-temperature neutron powder diffraction performed on two representative compounds, 0.7PbTiO(3)-0.3BiFeO(3) and 0.7PbTiO(3)-0.3Bi(Zn(1/2)Ti(1/2))O(3), whose negative thermal expansion is contrarily enhanced and weakened, respectively. With increasing temperature up to the Curie temperature, the spontaneous polarization displacement of Pb/Bi (deltaz(Pb/Bi)) is weakened in 0.7PbTiO(3)-0.3BiFeO(3) but well-maintained in 0.7PbTiO(3)-0.3Bi(Zn(1/2)Ti(1/2))O(3). There is an apparent correlation between tetragonality (c/a) and spontaneous polarization. Direct experimental evidence indicates that the spontaneous polarization originating from Pb/Bi-O hybridization is strongly associated with the negative thermal expansion. This mechanism can be used as a guide for the future design of negative thermal expansion of phase-transforming oxides. PMID- 21696175 TI - Regioselective Suzuki coupling of dihaloheteroaromatic compounds as a rapid strategy to synthesize potent rigid combretastatin analogues. AB - Combretastatin A-4 (CA-4) is a potent tubulin depolymerizing agent able to inhibit tumor growth and with antivascular effects. Although it is in clinical trials, the search for novel analogues that may display better/different features is still ongoing. In this manuscript we describe the synthesis of novel constrained analogues of CA-4 obtained in only two synthetic steps exploiting a regioselective Suzuki coupling of dihalogenated heteroaromatic and alicyclic compounds. All the compounds synthesized have been evaluated for cytotoxicity and for their ability to inhibit tubulin assembly. One of them, 38, displayed low nanomolar cytotoxicity and proved to have a pharmacodynamic profile similar to that of CA-4 and a better pharmacokinetic profile, but most important of all, this synthetic strategy may pave the way for the easy and rapid generation of novel rigid analogues of combretastatins. PMID- 21696176 TI - Quantum transport in graphene nanonetworks. AB - The quantum transport properties of graphene nanoribbon networks are investigated using first-principles calculations based on density functional theory. Focusing on systems that can be experimentally realized with existing techniques, both in plane conductance in interconnected graphene nanoribbons and tunneling conductance in out-of-plane nanoribbon intersections were studied. The characteristics of the ab initio electronic transport through in-plane nanoribbon cross-points is found to be in agreement with results obtained with semiempirical approaches. Both simulations confirm the possibility of designing graphene nanoribbon-based networks capable of guiding electrons along desired and predetermined paths. In addition, some of these intersections exhibit different transmission probability for spin up and spin down electrons, suggesting the possible applications of such networks as spin filters. Furthermore, the electron transport properties of out-of-plane nanoribbon cross-points of realistic sizes are described using a combination of first-principles and tight-binding approaches. The stacking angle between individual sheets is found to play a central role in dictating the electronic transmission probability within the networks. PMID- 21696174 TI - Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. AB - Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound toward clinical candidate status. PMID- 21696177 TI - Studies of intrinsic hot phonon dynamics in suspended graphene by transient absorption microscopy. AB - Correlated transient absorption and atomic force microscopy (AFM) measurements have been performed for monolayer graphene, both free-standing and supported on a glass substrate. The AFM images allow us to locate regions of the suspended graphene. The transient absorption traces show a fast instrument response limited decay, followed by a slower intensity dependent decay. The fast decay is assigned to a combination of coupling between the excited charge carriers and the optical phonon modes of graphene and the substrate, and diffusion of the charge carrier out of the probe region. The slow decay is due to the hot phonon effect and reflects the lifetime of the intrinsic optical phonons of graphene. The time constant for the slow decay is longer for suspended graphene compared to substrate-supported graphene. This is attributed to interactions between the excited charge carriers and the surface optical phonon modes of the substrate, which supplies an additional relaxation channel for supported graphene. PMID- 21696178 TI - Nanoscale effects on heterojunction electron gases in GaN/AlGaN core/shell nanowires. AB - The electronic properties of heterojunction electron gases formed in GaN/AlGaN core/shell nanowires with hexagonal and triangular cross sections are studied theoretically. We show that at nanoscale dimensions, the nonpolar hexagonal system exhibits degenerate quasi-one-dimensional electron gases at the hexagon corners, which transition to a core-centered electron gas at lower doping. In contrast, polar triangular core/shell nanowires show either a nondegenerate electron gas on the polar face or a single quasi-one-dimensional electron gas at the corner opposite the polar face, depending on the termination of the polar face. More generally, our results indicate that electron gases in closed nanoscale systems are qualitatively different from their bulk counterparts. PMID- 21696179 TI - Evolution of packing parameters in the structural changes of silica mesoporous crystals: cage-type, 2D cylindrical, bicontinuous diamond and gyroid, and lamellar. AB - Cage-type, two-dimensional (2D) cylindrical hexagonal (C), bicontinuous diamond (D), bicontinuous gyroid (G), and one-dimensional (1D) lamellar (L) structures of silica mesoporous crystals (SMCs) were obtained by using the anionic surfactant N stearoyl-l-glutamic acid (C(18)GluA) as a template in the presence of the nonionic surfactant C(16)(EO)(10) (Brij-56). The mesostructures were controlled by the organic/inorganic interface curvature change induced by Brij-56. A synthesis-field diagram showed that the mesostructure changed in the sequence cage-type -> C -> intergrowth of C and D -> intergrowth of C and G -> D -> G -> L with increase of the amount of Brij-56. Mixed micelles were formed by the anionic and nonionic surfactants, the packing parameter g of which increased with increasing the addition amount of nonionic surfactant and the reaction temperature. The local g parameter was obtained from electron crystallography reconstruction results by calculating mean curvatures and Gaussian curvatures from the equi-electrostatic potential surface. The intergrowth of C and D and two kinds of intergrowth of C and G are also discussed. PMID- 21696180 TI - An investigation into the dissolution properties of celecoxib melt extrudates: understanding the role of polymer type and concentration in stabilizing supersaturated drug concentrations. AB - In this study, the dissolution properties of celecoxib (CX) solid dispersions manufactured from Eudragit 4155F and polyvinylpyrrolidone (PVP) were evaluated. Hot-melt extrusion (HME) technology was used to prepare amorphous solid dispersions of drug/polymer binary systems at different mass ratios. The drug concentrations achieved from the dissolution of PVP and Eudragit 4155F solid dispersions in phosphate buffer, pH 7.4 (PBS 7.4) were significantly greater than the equilibrium solubility of CX (1.58 MUg/mL). The degree of supersaturation increased significantly as the polymer concentration within the solid dispersion increased. The maximum drug concentration achieved by PVP solid dispersions did not significantly exceed the apparent solubility of amorphous CX. The predominant mechanism for achieving supersaturated CX concentrations in PBS 7.4 was attributed to stabilization of amorphous CX during dissolution. Conversely, Eudragit 4155F solid dispersions showed significantly greater supersaturated drug solutions particularly at high polymer concentrations. For example, at a drug/polymer ratio of 1:9, a concentration of 100 MUg/mL was achieved after 60 min that was stable (no evidence of drug recrystallization) for up to 72 h. This clearly identifies the potential of Eudragit 4155F to act as a solubilizing agent for CX. These findings were in good agreement with the results from solubility performed using PBS 7.4 in which Eudragit 4155F had been predissolved. In these tests, Eudragit 4155F significantly increased the equilibrium solubility of CX. Solution (1)H NMR spectra were used to identify drug/polymer interactions. Deshielding of CX aromatic protons (H-1a and H-1b) containing the sulfonamide group occurred as a result of dissolution of Eudragit 4155F solid dispersions, whereas deshielding of H-1a protons and shielding of H-1b protons occurred as a result of the dissolution of PVP solid dispersions. In principle, it is reasonable to suggest that the different drug/polymer interactions observed give rise to the variation in dissolution observed for the two polymer/drug systems. PMID- 21696181 TI - Co3O4-SiO2 nanocomposite: a very active catalyst for CO oxidation with unusual catalytic behavior. AB - A high surface area Co(3)O(4)-SiO(2) nanocomposite catalyst has been prepared by use of activated carbon as template. The Co(3)O(4)-SiO(2) composite, the surface of which is rich in silica and Co(II) species compared with normal Co(3)O(4), exhibited very high activity for CO oxidation even at a temperature as low as -76 degrees C. A rather unusual temperature-dependent activity curve, with the lowest conversion at about 80 degrees C, was observed with a normal feed gas (H(2)O content ~3 ppm). The U-shape of the activity curve indicates a negative apparent activation energy over a certain temperature range, which has rarely been observed for the heterogeneously catalyzed oxidation of CO. Careful investigation of the catalytic behavior of Co(3)O(4)-SiO(2) catalyst led to the conclusion that adsorption of H(2)O molecules on the surface of the catalyst caused the unusual behavior. This conclusion was supported by in situ diffuse reflectance Fourier transform infrared (DRIFT) spectroscopic experiments under both normal and dry conditions. PMID- 21696182 TI - Controlling heterojunction abruptness in VLS-grown semiconductor nanowires via in situ catalyst alloying. AB - For advanced device applications, increasing the compositional abruptness of axial heterostructured and modulation doped nanowires is critical for optimizing performance. For nanowires grown from metal catalysts, the transition region width is dictated by the solute solubility within the catalyst. For example, as a result of the relatively high solubility of Si and Ge in liquid Au for vapor liquid-solid (VLS) grown nanowires, the transition region width between an axial Si-Ge heterojunction is typically on the order of the nanowire diameter. When the solute solubility in the catalyst is lowered, the heterojunction width can be made sharper. Here we show for the first time the systematic increase in interface sharpness between axial Ge-Si heterojunction nanowires grown by the VLS growth method using a Au-Ga alloy catalyst. Through in situ tailoring of the catalyst composition using trimethylgallium, the Ge-Si heterojunction width is systematically controlled by tuning the semiconductor solubility within a metal Au-Ga alloy catalyst. The present approach of alloying to control solute solubilities in the liquid catalyst may be extended to increasing the sharpness of axial dopant profiles, for example, in Si-Ge pn-heterojunction nanowires which is important for such applications as nanowire tunnel field effect transistors or in Si pn-junction nanowires. PMID- 21696183 TI - Flexible visible-infrared metamaterials and their applications in highly sensitive chemical and biological sensing. AB - Flexible electronic and photonic devices have been demonstrated in the past decade, with significant promise in low-cost, light-weighted, transparent, biocompatible, and portable devices for a wide range of applications. Herein, we demonstrate a flexible metamaterial (Metaflex)-based photonic device operating in the visible-IR regime, which shows potential applications in high sensitivity strain, biological and chemical sensing. The metamaterial structure, consisting of split ring resonators (SRRs) of 30 nm thick Au or Ag, has been fabricated on poly(ethylene naphthalate) substrates with the least line width of ~30 nm by electron beam lithography. The absorption resonances can be tuned from middle IR to visible range. The Ag U-shaped SRRs metamaterials exhibit an electric resonance of ~542 nm and a magnetic resonance of ~756 nm. Both the electric and magnetic resonance modes show highly sensitive responses to out-of-plane bending strain, surrounding dielectric media, and surface chemical environment. Due to the electric and magnetic field coupling, the magnetic response gives a sensitivity as high as 436 nm/RIU. Our Metaflex devices show superior responses with a shift of magnetic resonance of 4.5 nm/nM for nonspecific bovine serum albumin protein binding and 65 nm for a self-assembled monolayer of 2 naphthalenethiol, respectively, suggesting considerable promise in flexible and transparent photonic devices for chemical and biological sensing. PMID- 21696184 TI - Noninvasive transdermal iontophoretic delivery of biologically active human basic fibroblast growth factor. AB - Human basic fibroblast growth factor (hbFGF; 17.4 kDa) has shown promise in the treatment of several dermatological conditions; symptomatic improvement was also observed in patients with peripheral arterial disease after arterial infusion. The objective of this study was to demonstrate the feasibility of using transdermal iontophoresis to deliver biologically active hbFGF noninvasively into and across the skin. The protein was cloned, expressed and purified in-house. Porcine skin was used to investigate transdermal iontophoretic transport of hbFGF as a function of current density (0.15, 0.3, and 0.5 mA/cm(2)); results were subsequently confirmed using human skin. Cumulative hbFGF permeation and skin deposition were quantified by ELISA. The absence of proteolytic degradation during skin transit was confirmed by SDS-PAGE. Biological activity postdelivery was determined using cell proliferation assays in human foreskin fibroblast (HFF) and NIH 3T3 cell lines. Confocal laser scanning microscopy (CLSM) was used to visualize the distribution of rhodamine-tagged hbFGF in the skin. Cumulative iontophoretic permeation at 0.3 mA/cm(2) was statistically superior to that at 0.15 mA/cm(2); however, there was no further improvement at 0.5 mA/cm(2). Significant skin deposition of hbFGF was observed, and this dominated transport; for example, after iontophoresis for 8 h at 0.5 mA/cm(2), skin deposition (77.74 +/- 37.36 MUg/cm(2)) was 4.4-fold higher than cumulative permeation (17.64 +/- 5.18 MUg/cm(2)). The superior skin deposition may be advantageous for dermatological applications. The HFF and NIH 3T3 cell proliferation assays confirmed that biological activity of hbFGF was retained postdelivery. Coiontophoresis of acetaminophen showed that the dominant transport mechanism switched from electroosmosis to electromigration upon increasing current density from 0.15 to 0.3 mA/cm(2). Experiments using human skin confirmed that iontophoretic permeation of hbFGF across porcine and human membranes was statistically equivalent. CLSM images of rhodamine-tagged hbFGF postiontophoresis indicated that the protein was evenly distributed throughout the epidermis and dermis. In conclusion, the results confirmed that transdermal iontophoresis was indeed able to deliver structurally intact, functional hbFGF noninvasively into and across the skin. The amounts of protein delivered were similar to those in reports from preclinical and clinical studies. PMID- 21696185 TI - Polymer swelling, drug mobilization and drug recrystallization in hydrating solid dispersion tablets studied by multinuclear NMR microimaging and spectroscopy. AB - Despite the advantages offered by solid dispersions, the marketed products based on this technology are few. The most frequent concern is the stability of the amorphous drug. The state of the drug in solid dispersions is, in general, poorly characterized as the number of characterization techniques available to monitor nanometer-sized drug particles embedded in a matrix are limited. Here we present a combination of localized NMR spectroscopic and NMR imaging techniques which allow in situ monitoring of the state of the drug during tablet disintegration and dissolution. (19)F NMR relaxation is shown to be sensitive to both the crystalline/amorphous state and the size of the model nanoparticles made of the drug substance flutamide. The time course of drug mobilization and recrystallization is detected with spatial resolution within swelling solid dispersion tablets. Comparing results from spatially resolved (19)F, (2)H and (1)H NMR experiments, recrystallization is related to its enabling factors such as local hydration level and local mobility of the polymer matrix. The initially amorphous drug may recrystallize either by nanoparticle coalescence or by ripening of crystalline grains. PMID- 21696186 TI - Quantifying defects in graphene via Raman spectroscopy at different excitation energies. AB - We present a Raman study of Ar(+)-bombarded graphene samples with increasing ion doses. This allows us to have a controlled, increasing, amount of defects. We find that the ratio between the D and G peak intensities, for a given defect density, strongly depends on the laser excitation energy. We quantify this effect and present a simple equation for the determination of the point defect density in graphene via Raman spectroscopy for any visible excitation energy. We note that, for all excitations, the D to G intensity ratio reaches a maximum for an interdefect distance ~3 nm. Thus, a given ratio could correspond to two different defect densities, above or below the maximum. The analysis of the G peak width and its dispersion with excitation energy solves this ambiguity. PMID- 21696187 TI - DNA cage delivery to mammalian cells. AB - DNA cages are nanometer-scale polyhedral structures formed by self-assembly from synthetic DNA oligonucleotides. Potential applications include in vivo imaging and the targeted delivery of macromolecules into living cells. We report an investigation of the ability of a model cage, a DNA tetrahedron, to enter live cultured mammalian cells. Cultured human embryonic kidney cells were treated with a range of fluorescently labeled DNA tetrahedra and subsequently examined using confocal microscopy and flow cytometry. Substantial uptake of tetrahedra into cells was observed both when the cells were treated with tetrahedra alone and when the cells were treated with a mixture of tetrahedra and a transfection reagent. Analysis of the subcellular localization of transfected tetrahedra using confocal microscopy and organelle staining indicates that the cages are located in the cytoplasm. FRET experiments indicate that the DNA cages remain substantially intact within the cells for at least 48 h after transfection. This is a first step toward the use of engineered DNA nanostructures to deliver and control the activity of cargoes within cells. PMID- 21696188 TI - Increasing the efficiency of single walled carbon nanotube amplification by Fe-Co catalysts through the optimization of CH4/H2 partial pressures. AB - Single walled carbon nanotubes (SWNTs) seeds are grown using Fe-Co nanoparticles on spin-on-glass. The relative efficiency of nucleation and amplification (versus etching) was investigated as a function of the CH(4)/H(2) feedstock ratio and growth temperature. At 900 degrees C, maximum amplification is obtained with CH(4)/H(2) ratio of 80:20 but 60:40 for nucleation. Amplification is further enhanced at 800 degrees C, compared with etching dominating at 1000 degrees C. Amplification of SWNTs is in equilibrium with etching; higher carbon feedstock pressure and decreased temperature increase the rate of amplification; the converse increases etching. PMID- 21696189 TI - Polymeric nanoparticles with precise ratiometric control over drug loading for combination therapy. AB - We report a novel approach for nanoparticle-based combination chemotherapy by concurrently incorporating two different types of drugs into a single polymeric nanoparticle with ratiometric control over the loading of the two drugs. By adapting metal alkoxide chemistry, we synthesize highly hydrophobic drug-poly-L lactide (drug-PLA) conjugates, of which the polymer has the same chain length while the drug may differ. These drug-polymer conjugates are then encapsulated into lipid-coated polymeric nanoparticles through a single-step nanoprecipitation method. Using doxorubicin (DOX) and camptothecin (CPT) as two model chemotherapy drugs, various ratios of DOX-PLA and CPT-PLA conjugates are loaded into the nanoparticles with over 90% loading efficiency. The resulting nanoparticles are uniform in size, size distribution and surface charge. The loading yield of DOX and CPT in the particles can be precisely controlled by simply adjusting the DOX PLA:CPT-PLA molar ratio. Cellular cytotoxicity results show that the dual-drug loaded nanoparticles are superior to the corresponding cocktail mixtures of single-drug loaded nanoparticles. This dual-drug delivery approach offers a solution to the long-standing challenge in ratiometric control over the loading of different types of drugs onto the same drug delivery vehicle. We expect that this approach can be exploited for many types of chemotherapeutic agents containing hydroxyl groups and thus enable codelivery of various drug combinations for combinatorial treatments of diseases. PMID- 21696190 TI - Characterization of CD44-mediated cancer cell uptake and intracellular distribution of hyaluronan-grafted liposomes. AB - Hyaluronan (HA) is a biocompatible and biodegradable linear polysaccharide which is of interest for tumor targeting through cell surface CD44 receptors. HA binds with high affinity to CD44 receptors, which are overexpressed in many tumors and involved in cancer metastasis. In the present study, we investigated the impact of HA molecular weight (MW), grafting density, and CD44 receptor density on endocytosis of HA-grafted liposomes (HA-liposomes) by cancer cells. Additionally, the intracellular localization of the HA-liposomes was determined. HAs of different MWs (5-8, 10-12, 175-350, and 1600 kDa) were conjugated to liposomes with varying degrees of grafting density. HA surface density was quantified using the hexadecyltrimethylammonium bromide turbidimetric method. Cellular uptake and subcellular localization of HA-liposomes were evaluated by flow cytometry and fluorescence microscopy. Mean particle sizes of HA-liposomes ranged from 120 to 180 nm and increased with increasing size of HA. HA-liposome uptake correlated with HA MW (5-8 < 10-12 < 175-350 kDa), grafting density, and CD44 receptor density and exceeded that obtained with unconjugated plain liposomes. HA liposomes were taken up into cells via lipid raft-mediated endocytosis, which is both energy- and cholesterol-dependent. Once within cells, HA-liposomes localized primarily to endosomes and lysosomes. The results demonstrate that cellular targeting efficiency of HA-liposomes depends strongly upon HA MW, grafting density, and cell surface receptor CD44 density. The results support a role of HA liposomes for targeted drug delivery. PMID- 21696191 TI - Assembly of polyethyleneimine in the hexagonal mesophase of nonionic surfactant: effect of pH and temperature. AB - We investigate the dispersion of a pH responsive polymer, polyethyleneimine, PEI, in a hexagonal (H(1)) mesophase of a nonionic surfactant, C(12)E(9), and water, at pH ranging from basic (pH = 12.8) to acidic (pH = 1). While the C(12)E(9)/H(2)O phase behavior is independent of pH, we demonstrate that, in the PEI/C(12)E(9)/H(2)O system, changing the pH influences PEI-C(12)E(9) interactions, and thus, influences the isotropic-H(1) phase transition. With decrease in pH, there is increasing protonation of the PEI chain, and consequently, the chain extends. We show, using a combination of SAXs, optical microscopy and visual experiments, that the inclusion of PEI in a 1:1 surfactant water mixture, lowers the hexagonal-isotropic transition temperature, T(HI). At higher pH = 12.8, T(HI) shows a pronounced decrease from 50 to 13 degrees C on addition of PEI, and the PEI/C(12)E(9)/H(2)O system forms a transparent gel. At pH = 1, we observe qualitatively different behavior and an opaque gel forms below T(HI) = 25 degrees C. The isotropic-H(1) transition, in turn, influences the phase separation of PEI chains from the C(12)E(9)/H(2)O system. 2D NMR ROESY data provides evidence that there are strong surfactant-PEI interactions at high pH that significantly reduce at lower pH. The NMR data is in accord with molecular dynamics simulations that show that surfactants strongly aggregate with unprotonated PEI chains, but not with fully protonated chains; thus, in this system, the pH controls a cascade of microstructural organization: increasing pH decreases chain protonation and increases polymer-surfactant interactions, resulting in suppression of the isotropic-H(1) transition to lower temperatures, thus, influencing the phase separation of PEI from the surfactant/water system. PMID- 21696194 TI - Copper-catalyzed aerobic oxidative intramolecular alkene C-H amination leading to N-heterocycles. AB - A copper-catalyzed aerobic oxidative intramolecular alkene C-H amination has been developed using readily available substituted 3-benzylidene-2-pyridin-2-ylmethyl 2,3-dihydro-isoindol-1-ones as the starting materials, and the corresponding N heterocycles were obtained in good to excellent yields. This method should provide a new and useful strategy for constructing N-heterocycles. PMID- 21696192 TI - Log-scale dose response of inhibitors on a chip. AB - We demonstrate the accommodation of log-scale concentration gradients of inhibitors on a single microfluidic chip with a semidirect dilution capability of reagents for the determination of the half-inhibitory concentration or IC(50). The chip provides a unique tool for hosting a wide-range of concentration gradient for studies that require an equal distribution of measuring points on a logarithmic scale. Using Matrix metalloproteinase IX and three of its inhibitors, marimastat, batimastat, and CP471474, we evaluated the IC(50) of each inhibitor with a single experiment. The present work could be applied to the systematic study of biochemical binding and inhibition processes particularly in the field of mechanistic enzymology and the pharmaceutical industry. PMID- 21696195 TI - Intramolecular Diels-Alder cycloaddition/rearrangement cascade of an amidofuran derivative for the synthesis of (+/-)-minfiensine. AB - An efficient synthesis of (+/-)-minfiensine has been accomplished employing an intramolecular Diels-Alder cycloaddition/rearrangement cascade of an amidofuran derivative. Thermal reorganization of the initially formed [4+2]-cycloadduct affords the critical tetrahydroiminoethanocarbazole skeleton of the alkaloid in high yield. PMID- 21696196 TI - Fabrication of nanowire electronics on nonconventional substrates by water assisted transfer printing method. AB - We report a simple, versatile, and wafer-scale water-assisted transfer printing method (WTP) that enables the transfer of nanowire devices onto diverse nonconventional substrates that were not easily accessible before, such as paper, plastics, tapes, glass, polydimethylsiloxane (PDMS), aluminum foil, and ultrathin polymer substrates. The WTP method relies on the phenomenon of water penetrating into the interface between Ni and SiO(2). The transfer yield is nearly 100%, and the transferred devices, including NW resistors, diodes, and field effect transistors, maintain their original geometries and electronic properties with high fidelity. PMID- 21696197 TI - Palladium-catalyzed direct arylation of thiophenes bearing SO2R substituents. AB - The palladium-catalyzed direct arylation of SO(2)R-substituted thiophene derivatives was found to proceed regioselectively at C5 and in high yields using a variety of aryl bromides and as low as 0.5-0.1 mol % of phosphine-free Pd(OAc)(2) as the catalyst. For these reactions, sulfonyls, sulfonamides, or even a sulfonic ester as the thiophene substituents were successfully employed. PMID- 21696198 TI - Regioselective cobalt-catalyzed addition of sulfides to unactivated alkenes. AB - A novel method to synthesize tertiary alkyl/aryl sulfides in a mild and regioselective manner from unactivated alkenes using cobalt catalysis is described. The methodology is compatible with sensitive functionalities and is successful with several different types of alkenes and sulfides. PMID- 21696199 TI - Adsorption of anionic and cationic surfactants on anionic colloids: supercharging and destabilization. AB - We present herein a study on the adsorption of anionic (SDS), cationic (CTAB), and nonionic (C(12)E(5)) surfactants onto anionic silica nanoparticles. The effects of this adsorption are studied by means of the static structure factor, S(q), and the collective diffusion coefficient, D(c), obtained from small-angle X ray scattering and dynamic light scattering measurements, respectively. The effective charge on the particles was determined also from classical electrophoresis and electroacoustic sonic-amplitude measurements. The surface tension of the sample was also investigated. Of particular note is the adsorption of SDS onto the silica nanoparticles, which leads to supercharging of the interface. This has interesting repercussions for structures obtained by the layer-by-layer (LbL) technique, because emulsions stabilized with supercharged and hydrophobized silica are perfect candidates for use in a multilayer system. PMID- 21696201 TI - Liquid phase separation of polyaromatics on [Cu2(BDC)2(dabco)]. AB - The porous coordination polymer (PCP) [Cu(2)(BDC)(2)(dabco)] is capable of selectively adsorbing up to 25 wt % of either 1-methylnaphthalene or 2 methylnaphthalene. Uptakes of unsubstituted naphthalene and 1,4 dimethylnaphthalene are significantly lower (7-13 wt %), suggesting that monomethyl substituted polyaromatics can be separated from the other fractions. Furthermore, this PCP can perform the difficult separation of 1-methylnaphthalene from 2-methylnaphthalene with separation factors as high as 2.6, proving that specific interactions of the methyl group with the lattice play an important role in determining the adsorption selectivity. PMID- 21696202 TI - Interfacial behavior of OEG-linear dendron monolayers: aggregation, nanostructuring, and electropolymerizability. AB - We report on the interesting interfacial behavior of oligoethylene glycol or OEGylated linear dendron monolayers at the air-water interface as a function of (a) carbazole dendron generation, (b) the length of the OEG units, and (c) the surface pressure applied upon compression. Surface pressure-area isotherms, hysteresis studies, and isobaric creep measurement revealed a structure-property relationship consistent with the hydrophilic-lipophilic balance of a linear dendron with the OEG group serving as the surface anchor to the water subphase. AFM studies revealed that all the OEGylated carbazole dendrons self-assemble into spherical morphology at low surface pressures but form ribbonlike structures as the surface pressure is increased. This nanostructuring is primarily imparted by the increase in van der Waals forces with increasing amount of carbazole units per dendron generation on a hydrophilic mica surface. Further, electrochemical cross-linking of the carbazole molecules by cyclic voltammetery (CV) on doped Si wafer has enabled the formation of an LB film monolayer with a secondary level of organization in the monolayer imparted by the inter- and intramolecular cross linking among the carbazole units. This study should provide a basis for monolayer film materials based on combining the LB technique and electrochemical cross-linking for nanostructuring superstructures at the air-water interface. PMID- 21696200 TI - 64Cu-labeled phosphonium cations as PET radiotracers for tumor imaging. AB - Alteration in mitochondrial transmembrane potential (DeltaPsi(m)) is an important characteristic of cancer. The observation that the enhanced negative mitochondrial potential is prevalent in tumor cell phenotype provides a conceptual basis for development of mitochondrion-targeting therapeutic drugs and molecular imaging probes. Since plasma and mitochondrial potentials are negative, many delocalized organic cations, such as rhodamine-123 and (3)H tetraphenylphosphonium, are electrophoretically driven through these membranes, and able to localize in the energized mitochondria of tumor cells. Cationic radiotracers, such as (99m)Tc-Sestamibi and (99m)Tc-Tetrofosmin, have been clinically used for diagnosis of cancer by single photon emission computed tomography (SPECT) and noninvasive monitoring of the multidrug resistance (MDR) transport function in tumors of different origin. However, their diagnostic and prognostic values are often limited due to their insufficient tumor localization (low radiotracer tumor uptake) and high radioactivity accumulation in the chest and abdominal regions (low tumor selectivity). In contrast, the (64)Cu-labeled phosphonium cations represent a new class of PET (positron emission tomography) radiotracers with good tumor uptake and high tumor selectivity. This review article will focus on our recent experiences in evaluation of (64)Cu-labeled phosphonium cations as potential PET radiotracers. The main objective is to illustrate the impact of radiometal chelate on physical, chemical, and biological properties of (64)Cu radiotracers. It will also discuss some important issues related to their tumor selectivity and possible tumor localization mechanism. PMID- 21696203 TI - Interfacial friction and adhesion of polymer brushes. AB - A bead-probe lateral force microscopy (LFM) technique is used to characterize the interfacial friction and adhesion properties of polymer brushes. Our measurements attempt to relate the physical structure and chemical characteristics of the brush to their properties as thin-film, tethered lubricants. Brushes are synthesized at several chain lengths and surface coverages from polymer chains of polydimethylsiloxane (PDMS), polystyrene (PS), and a poly(propylene glycol) poly(ethylene glycol) block copolymer (PPG/PEG). At high surface coverage, PDMS brushes manifest friction coefficients (COFs) that are among the lowest recorded for a dry lubricant film (MU ~ 0.0024) and close to 1 order of magnitude lower than the COF of a bare silicon surface. Brushes synthesized from higher molar mass chains exhibit higher friction forces than those created using lower molar mass polymers. Increased grafting density of chains in the brush significantly reduces the COF by creating a uniform surface of stretched chains with a decreased surface viscosity. Brushes with lower surface tension and interfacial shear stresses manifest the lowest COF. In particular, PDMS chains exhibit COFs lower than PS by a factor of 3.7 and lower than PPG/PEG by a factor of 4.7. A scaling analysis conducted on the surface coverage (sigma) in relation to the fraction (epsilon) of the friction force developing from adhesion predicts a universal relation epsilon ~ sigma(4/3), which is supported by our experimental data. PMID- 21696205 TI - Doped graphene sheets as anode materials with superhigh rate and large capacity for lithium ion batteries. AB - One great challenge in the development of lithium ion batteries is to simultaneously achieve high power and large energy capacity at fast charge and discharge rates for several minutes to seconds. Here we show that nitrogen- or boron-doped graphene can be used as a promising anode for high-power and high energy lithium ion batteries under high-rate charge and discharge conditions. The doped graphene shows a high reversible capacity of >1040 mAh g(-1) at a low rate of 50 mA g(-1). More importantly, it can be quickly charged and discharged in a very short time of 1 h to several tens of seconds together with high-rate capability and excellent long-term cyclability. For example, a very high capacity of ~199 and 235 mAh g(-1) was obtained for the N-doped graphene and B-doped graphene at 25 A g(-1) (about 30 s to full charge). We believe that the unique two-dimensional structure, disordered surface morphology, heteroatomic defects, better electrode/electrolyte wettability, increased intersheet distance, improved electrical conductivity, and thermal stability of the doped graphene are beneficial to rapid surface Li(+) absorption and ultrafast Li(+) diffusion and electron transport, and thus make the doped materials superior to those of pristine chemically derived graphene and other carbonaceous materials. PMID- 21696204 TI - Using free energy of binding calculations to improve the accuracy of virtual screening predictions. AB - Virtual screening of small molecule databases against macromolecular targets was used to identify binding ligands and predict their lowest energy bound conformation (i.e., pose). AutoDock4-generated poses were rescored using mean field pathway decoupling free energy of binding calculations and evaluated if these calculations improved virtual screening discrimination between bound and nonbound ligands. Two small molecule databases were used to evaluate the effectiveness of the rescoring algorithm in correctly identifying binders of L99A T4 lysozyme. Self-dock calculations of a database containing compounds with known binding free energies and cocrystal structures largely reproduced experimental measurements, although the mean difference between calculated and experimental binding free energies increased as the predicted bound poses diverged from the experimental poses. In addition, free energy rescoring was more accurate than AutoDock4 scores in discriminating between known binders and nonbinders, suggesting free energy rescoring could be a useful approach to reduce false positive predictions in virtual screening experiments. PMID- 21696206 TI - Mechanism of N/O bond scission of N2O by an unsaturated rhodium transient. AB - The mechanism of formation of triplet (PNP)RhO and (PNP)Rh(N(2)) (PNP = N(SiMe(2)CH(2)P(t)Bu(2))(2)) from reaction of two molecules of (PNP)Rh with N(2)O has been studied by DFT, evaluating mechanisms which (1) involve free N(2), and (2) which effect N/O bond scission in linearly coordinated (PNP)RhNNO. This work shows the variety of modes of binding N(2)O to this reducing, unsaturated metal fragment and also evaluates why a mechanism avoiding free N(2) is preferred. Comparisons are made to isoelectronic CO(2) in its reaction with (PNP)Rh. PMID- 21696208 TI - A toast to Jan Peter Toennies. PMID- 21696209 TI - Autobiography of Jan Peter Toennies. PMID- 21696213 TI - The dynamics of allyl radical dissociation. AB - Dissociation of the allyl radical, CH(2)CHCH(2), and its deuterated isotopolog, CH(2)CDCH(2), have been investigated using trajectory calculations on an ab initio ground-state potential energy surface calculated for 97,418 geometries at the coupled cluster single and double and perturbative treatment of triple excitations, with the augmented correlation consistent triple-zeta basis set level (CCSD(T)/AVTZ). At an excitation energy of 115 kcal/mol, corresponding to optical excitation at 248 nm, the primary channel is hydrogen loss with a quantum yield of 0.94 to give either allene or propyne in a ratio of 6.4:1. The total dissociation rate for CH(2)CHCH(2) is 6.3 * 10(10) s(-1), corresponding to a 1/e time of 16 ps. Methyl and C(2)H(2) are produced with a quantum yield of 0.06 by three different mechanisms: a 1,3 hydrogen shift followed by C-C cleavage to give methyl and acetylene, a double 1,2 shift followed by C-C cleavage to give methyl and acetylene, or a single 1,2 hydrogen shift followed by C-C cleavage to give methyl and vinylidene. In this last channel, the vinylidene eventually isomerizes to give internally excited acetylene, and the kinetic energy distribution is peaked at much lower energy (6.4 kcal/mol) than that for the other two channels (18 kcal/mol). The trajectory results also predict the v-J correlation, the anisotropy of dissociation, and distributions for the angular momentum of the fragments. The v-J correlation for the CH(3) + HCCH channel is strongest for high rotational levels of acetylene, where v is perpendicular to J. Methyl elimination is anisotropic, with beta = 0.66, whereas hydrogen elimination is nearly isotropic. In the hydrogen elimination channel, allene is rotationally excited with a total angular momentum distribution peaked near J = 17. In the methyl elimination channel, the peak of the methyl rotational distribution is at J ~ 12, whereas the peak of the acetylene rotational distribution is at J ~ 28. PMID- 21696214 TI - Highly sensitive proteome analysis of FACS-sorted adult colon stem cells. AB - In proteomics, multidimensional liquid chromatography combined with mass spectrometry has become a standard technique to reduce sample complexity and tackle the vast dynamic range. Such fractionation is necessary to obtain a comprehensive analysis of biological samples such as tissues and cell lines. However, extensive fractionation comes at the expense of sample losses, hampering the analysis of limited material. We previously described a highly sensitive multidimensional chromatographic strategy based on a combination of hydrophilic interaction liquid chromatography and reversed phase chromatography, which allows proteomic analysis with minimal sample losses. Here we apply this strategy to the analysis of a limited number of FACS-sorted colon stem cells extracted from mouse intestine, obtaining a proteome coverage comparable to current methods that generally require 100-fold more starting material. We propose that this alternative multidimensional chromatographic technology will find ample application such as in the analysis of distinct cellular populations obtained by laser microdissection. PMID- 21696215 TI - Allyl radical nature of a phenylcyclopentadienyl radical annelated with two homoadamantene frameworks. AB - 1-Phenylcyclopentadiene fused with two homoadamantene units at the 2,3- and 4,5 positions (4) was deprotonated with KH to lead to the quantitative formation of the corresponding cyclopentadienyl (Cp) anion 3(-). This anion was oxidized by AgCl to afford an orange crystalline solid consisting of Cp radical 3(*) and cyclopentadiene 4. The ESR spectrum in hexane exhibited approximately 15 lines, demonstrating that the two homoadamantene frameworks were equivalent and that the C1-C2(Ph)-C3 moiety of the five-membered ring formed a symmetrical allyl-like radical in agreement with the prediction by DFT calculation. The reaction of the Cp radical 3(*) with an oxygen molecule in the presence of Ag(+)SbF(6)(-) afforded the SbF(6)(-) salt of a phenylpyrylium ion annelated with two homoadamantene frameworks (8(+)SbF(6)(-)). PMID- 21696216 TI - Characterization of alginase and elicitor-active oligosaccharides from Gracilibacillus A7 in alleviating salt stress for Brassica campestris L. AB - Alginase was purified from Gracilibacillus A7 and evaluated for its ability to produce elicitor-active oligosaccharides. The optimum conditions for the alginase reaction are as follows: temperature, 40 degrees C; pH, 8.0; alginate content, 0.3-0.7%; and the presence of Na(+) and Mg(2+) metal ions. The degree of polymerization (DP) decreased as the reaction time of the alginase progressed, achieving values of 5.4 and 3.3 after 240 and 300 min, respectively. The relative root length (RRL) of the Brassica campestris L. increased with the addition of oligosaccharides with reduced DP values. The oligosaccharides with lower DP values are effective in reducing the effect of salt stress on the activity of the superoxide dismutase (SOD) and guaiacol peroxidase (POD), and oligosaccharides with moderate DP values can reduce the increase in lipid peroxidation activities (as malondialdehyde content) induced by salt stress. These results suggest that oligosaccharides may act as osmoprotective agents during the plant germination process. PMID- 21696218 TI - Biotite-brine interactions under acidic hydrothermal conditions: fibrous illite, goethite, and kaolinite formation and biotite surface cracking. AB - To ensure safe and efficient geologic CO(2) sequestration (GCS), it is crucial to have a better understanding of CO(2)-brine-rock interactions under GCS conditions. In this work, using biotite (K(Mg,Fe)(3)AlSi(3)O(10)(OH,F)(2)) as a model clay mineral, brine-biotite interactions were studied under conditions relevant to GCS sites (95 degrees C, 102 atm CO(2), and 1 M NaCl solution). After reaction for 3-17 h, fast growth of fibrous illite on flat basal planes of biotite was observed. After 22-70 h reaction, the biotite basal surface cracked, resulting in illite detaching from the surface. Later on (96-120 h), the cracked surface layer was released into solution, thus the inner layer was exposed as a renewed flat basal surface. The cracking and detachment of the biotite surface layer increased the surface area in contact with solution and accelerated biotite dissolution. On biotite edge surfaces, Al-substituted goethite and kaolinite precipitated. In control experiments with water under the same temperature and pressure, neither macroscopic fibrous illite nor cracks were observed. This work provides unique information on biotite-brine interaction under acidic hydrothermal conditions. PMID- 21696219 TI - Measuring and modeling adsorption of PAHs to carbon nanotubes over a six order of magnitude wide concentration range. AB - Understanding the interactions between organic contaminants and carbon nanomaterials is essential for evaluating the materials' potential environmental impact and their application as sorbent. Although a great deal of work has been published in the past years, data are still limited in terms of compounds, concentrations, and conditions investigated. We applied a passive sampling method employing polyoxymethylene (POM-SPE) to gain a better understanding of the interactions between polycyclic aromatic hydrocarbons (PAHs) and multiwalled carbon nanotubes (CNTs) over a 6 orders of magnitude wide concentration range. In the low-concentration range (pg-ng L(-1)), sorption of phenanthrene and pyrene was linear on a nonlogarithmic scale. Here, sorption could thus be described using a single sorption coefficient. Isotherm fits over the entire concentration range showed that (i) monolayer sorption models described the data very well, and (ii) the CNTs sorption capacity was directly related to their surface area. Sorption coefficients for 13 PAHs (11 of which have not been reported to date) were also measured at environmentally relevant low concentrations. No competition seemed to occur in the low-concentration range and sorption affinity was directly related to the solubility of the subcooled liquid of the compounds. PMID- 21696220 TI - An advance in proline ligation. AB - Native chemical ligation (NCL) is widely applicable for building proteins in the laboratory. Since the discovery of this method, many strategies have been developed to enhance its capability and efficiency. Because of the poor reactivity of proline thioesters, ligation at a C-terminal proline site is not readily accomplished. Here, we demonstrate that ligation at an N-terminal protein is feasible using the combined logic of NCL and metal-free dethiylation (MFD). PMID- 21696222 TI - Dual responsive supramolecular hydrogel with electrochemical activity. AB - Supramolecular materials with reversible responsiveness to environmental changes are of particular research interest in recent years. Inclusion complexation between cyclodextrin (CD) and ferrocene (Fc) is well-known and extensively studied because of its reversible association-dissociation controlled by the redox state of Fc. Although there are quite a few reported nanoscale materials incorporating this host-guest pair, polymeric hydrogels with electrochemical activity based on this interactive pair are still rare. Taking advantage of our previous reported hybrid inclusion complex (HIC) hydrogel structure, a new Fc-HIC was designed and obtained with beta-CD-modified quantum dots as the core and Fc ended diblock co-polymer p(DMA-b-NIPAM) as the shell, to achieve an electrochemically active hydrogel at elevated temperatures. Considering the two independent cross-linking strategies in the network structure, i.e., the interchain aggregation of pNIPAM and inclusion complexation between CD and Fc on the surface of the quantum dots, the hydrogel was fully thermo-reversible and its gel-sol transition was achieved after the addition of either an oxidizing agent or a competitive guest to Fc. PMID- 21696221 TI - Dityrosine, 3,4-dihydroxyphenylalanine (DOPA), and radical formation from tyrosine residues on milk proteins with globular and flexible structures as a result of riboflavin-mediated photo-oxidation. AB - Riboflavin-mediated photo-oxidative damage to protein Tyr residues has been examined to determine whether protein structure influences competing protein oxidation pathways in single proteins and protein mixtures. EPR studies resulted in the detection of Tyr-derived o-semiquione radicals, with this species suggested to arise from oxidation of 3,4-dihydroxyphenylalanine (DOPA). The yield of this radical was lower in samples containing beta-casein than in samples containing only globular proteins. Consistent with this observation, the yield of DOPA detected on beta-casein was lower than that on two globular proteins, BSA and beta-lactoglobulin. In contrast, samples with beta-casein gave higher yields of dityrosine than samples containing BSA and beta-lactoglobulin. These results indicate that the flexible structure of beta-casein favors radical-radical termination of tyrosyl radicals to give dityrosine, whereas the less flexible structure of globular proteins decreases the propensity for tyrosyl radicals to dimerize, with this resulting in higher yields of DOPA and its secondary radical. PMID- 21696223 TI - Thermodynamic heuristics with case-based reasoning: combined insights for RNA pseudoknot secondary structure. AB - The secondary structure of RNA pseudoknots has been extensively inferred and scrutinized by computational approaches. Experimental methods for determining RNA structure are time consuming and tedious; therefore, predictive computational approaches are required. Predicting the most accurate and energy-stable pseudoknot RNA secondary structure has been proven to be an NP-hard problem. In this paper, a new RNA folding approach, termed MSeeker, is presented; it includes KnotSeeker (a heuristic method) and Mfold (a thermodynamic algorithm). The global optimization of this thermodynamic heuristic approach was further enhanced by using a case-based reasoning technique as a local optimization method. MSeeker is a proposed algorithm for predicting RNA pseudoknot structure from individual sequences, especially long ones. This research demonstrates that MSeeker improves the sensitivity and specificity of existing RNA pseudoknot structure predictions. The performance and structural results from this proposed method were evaluated against seven other state-of-the-art pseudoknot prediction methods. The MSeeker method had better sensitivity than the DotKnot, FlexStem, HotKnots, pknotsRG, ILM, NUPACK and pknotsRE methods, with 79% of the predicted pseudoknot base-pairs being correct. PMID- 21696224 TI - Mechanism of antisense oligonucleotide interaction with natural RNAs. AB - Oligonucleotides find several numbers of applications: as diagnostic probes, RT and PCR primers and antisense agents due to their ability of forming specific interactions with complementary nucleotide sequences within nucleic acids. These interactions are strongly affected by accessibility of the target sequence in the RNA structure. In the present work the mechanism of invasion of RNA structure by oligonucleotide was investigated using a model system: yeast tRNA(Phe) and oligonucleotides complementary to the 3'-part of this molecule. Kinetics of interaction of oligonucleotides with in vitro transcript of yeast tRNAPhe was studied using stopped-flow technique with fluorescence quenching detection, 5' DABCYL labeled oligonucleotide was hybridized with 3'-fluorescein labeled tRNA(Phe). The results evidence for a four-step invasion process of the oligonucleotide-RNA complex formation. The process is initiated by formation of transition complexes with nucleotides in the T-loop and ACCA sequence. This complex formation is followed by RNA unfolding and formation of an extended heteroduplex with the oligonucleotide via strand displacement process. Computer modeling of oligonucleotide-tRNA(Phe) interaction revealed potential factors that could favor transition complexes formation and confirmed the proposed mechanism, showing the oligonucleotide to be a molecular "wedge". Our data evidence that oligonucleotide invasion into structured RNA is initiated by loop-single strand interactions, similar to the initial step of the antisense RNA-RNA interactions. The obtained results can be used for choosing efficient oligonucleotide probes. PMID- 21696225 TI - Intramolecular CH...O hydrogen bonds in the AI and BI DNA-like conformers of canonical nucleosides and their Watson-Crick pairs. Quantum chemical and AIM analysis. AB - The aim of this work is to cast some light on the H-bonds in double-stranded DNA in its AI and BI forms. For this purpose, we have performed the MP2 and DFT quantum chemical calculations of the canonical nucleoside conformers, relative to the AI and BI DNA forms, and their Watson-Crick pairs, which were regarded as the simplest models of the double-stranded DNA. Based on the atoms-in-molecules analysis (AIM), five types of the CH...O hydrogen bonds, involving bases and sugar, were detected numerically from 1 to 3 per a conformer: C2'H...O5', C1'H...O2, C6H...O5', C8H...O5', and C6H...O4'. The energy values of H-bonds occupy the range of 2.3-5.6 kcal/mol, surely exceeding the kT value (0.62 kcal/mol). The nucleoside CH...O hydrogen bonds appeared to "survive" turns of bases against the sugar, sometimes in rather large ranges of the angle values, pertinent to certain conformations, which points out to the source of the DNA lability, necessary for the conformational adaptation in processes of its functioning. The calculation of the interactions in the dA.T nucleoside pair gives evidence, that additionally to the N6H...O4 and N1...N3H canonical H-bonds, between the bases adenine and thymine the third one (C2H...O2) is formed, which, though being rather weak (about 1 kcal/mol), satisfies the AIM criteria of H bonding and may be classified as a true H-bond. The total energy of all the CH...O nontraditional intramolecular H-bonds in DNA nucleoside pairs appeared to be commensurable with the energy of H-bonds between the bases in Watson-Crick pairs, which implies their possible important role in the DNA shaping. PMID- 21696226 TI - From lipid transport to oxygenation of aromatic compounds: evolution within the Bet v1-like superfamily. AB - In absence of significant sequence similarity, remote homology between proteins can be confused with analogy and in such a case, shared ancestry can be inferred in light of certain unique and common features. In the present study, to understand the evolutionary origin of catalytic domain of large subunit of ring hydroxylating oxygenases (RHOs), belonging to the Bet v1-like superfamily, structure-based phylogenies have been derived from structural alignment of representative proteins of the superfamily. A careful inspection of the structural relatedness of RHOs with the rest of the families showed closest similarity between RHO catalytic domain and PA1206-like protein. In addition, phylogenetic relationship of the Rieske domain of the large subunit of RHOs with functionally and structurally similar proteins has also been elucidated so as to postulate the most possible events leading to the genesis of the large subunit of RHOs. PMID- 21696227 TI - Geometric parameters defining the structure of proteins--relation to early-stage folding step. AB - Two geometrical parameters describing the structure of a polypeptide: V-dihedral angle between two sequential peptide bond planes and R-radius of curvature are used for structural classification of polypeptide structure in proteins. The relation between these two parameters was the basis for the definition of the conformational sub-space for early-stage structural forms. The cluster analysis of V and lnR, applied to the selected proteins of well-defined secondary structure (according to DSSP classification) and to proteins without any introductory classified analysis, revealed that several of the discriminated groups of proteins agree with the assumed model of early-stage conformational sub space. This analysis shows that protein structures may be represented in VR space instead of Phi, Psi angles space, thus lowering the conformational space dimensionality. The VR model allows classification of traditional secondary structure elements as well as different Random Coil motifs, which broadens the range of recognized structural categories (compared to standard secondary structure elements). PMID- 21696228 TI - An analysis of the influence of protein intrinsic dynamical properties on its thermal unfolding behavior. AB - The influence of the protein topology-encoded dynamical properties on its thermal unfolding motions was studied in the present work. The intrinsic dynamics of protein topology was obtained by the anisotropic network model (ANM). The ANM has been largely used to investigate protein collective functional motions, but it is not well elucidated if this model can also reveal the preferred large-scale motions during protein unfolding. A small protein barnase is used as a typical case study to explore the relationship between protein topology-encoded dynamics and its unfolding motions. Three thermal unfolding simulations at 500 K were performed for barnase and the entire unfolding trajectories were sampled and partitioned into several windows. For each window, the preferred unfolding motions were investigated by essential dynamics analysis, and then associated with the intrinsic dynamical properties of the starting conformation in this window, which is detected by ANM. The results show that only a few slow normal modes imposed by protein structure are sufficient to give a significant overlap with the preferred unfolding motions. Especially, the large amplitude unfolding movements, which imply that the protein jumps out of a local energy basin, can be well described by a single or several ANM slow modes. Besides the global motions, it is also found that the local residual fluctuations encoded in protein structure are highly correlated with those in the protein unfolding process. Furthermore, we also investigated the relationship between protein intrinsic flexibility and its unfolding events. The results show that the intrinsic flexible regions tend to unfold early. Several early unfolding events can be predicted by analysis of protein structural flexibility. These results imply that protein structure-encoded dynamical properties have significant influences on protein unfolding motions. PMID- 21696229 TI - Molecular dynamics and docking studies on cardiac troponin C. AB - Cardiac troponin C (cTnC) is the Ca2+ dependent switch for contraction in heart muscle making it a potential target for drug research in the therapy of heart failure. Calcium binding on Troponin C (TnC) triggers a series of conformational changes exposing a hydrophobic pocket in the N-domain of TnC (cNTnC), which leads to force generation. Mutations and acidic pH have been related to altering the sensitivity of TnC affecting the efficiency of the heart. Bepridil, identified as a calcium sensitizer to TnC, has been experimentally found to bind to the N domain pocket of TnC but with negative cooperativity. Screening and de novo design were carried out using LUDI and AUTOLUDI programs in this work to identify and design potential ligands that can bind to the hydrophobic pocket of TnC. Two docking centers and multiple searching radii including 5 A, 5.5 A, 6 A, 6.5 A, 7.0 A and 7.5 A were used in LUDI to screen the ZINC database. Based on the LUDI docking results, 8 molecules were identified from the database with good potential to bind into the binding pocket and they were used as template molecules to generate a series of new molecules by AUTOLUDI design. Out of all the newly-designed molecules, 14 new ligands were recognized to be potential ligands that can bind and fit well into the binding pocket. These molecules can be used as starting molecules to develop TnC ligands. The binding stability and binding affinity of these molecules to the protein was further analyzed by molecular dynamics simulations. The results show that the binding energies, interactions and complex stabilities of 6 ligands are comparable to or better than bepridil. PMID- 21696230 TI - Studies on adaptability of binding residues and flap region of TMC-114 resistance HIV-1 protease mutants. AB - Drug resistant mutations have severely restricted the success of HIV therapy. These mutations frequently involve the aspartic protease encoded by the virus. Knowledge of the molecular mechanisms underlying the conformational changes of HIV-1 protease mutants may be useful in developing more effective and longer lasting treatment regimes. The flap regions of the protease are the target of a particular type of mutations occurring far from the active site, which are able to produce significant resistance against the anti-HIV drug TMC-114. We provide insight into the molecular basis of TMC-114 resistance major flap mutations (I50V and I54M) in HIV-1 protease. It reports the shape complementarity and receptor ligand interaction analysis supported by unrestrained all-atom molecular dynamics simulations of wild and major flap mutants of HIV-1 protease that sample large conformational changes of the flaps and active site binding residues. Both resistant flap mutants showed less atomic interaction toward TMC-114 and more structural deviation compared to wild HIV-protease. It is due to increasing flexibility at TMC-114 binding cavity and deviation of binding residues in 3-D space. Distortion in binding cavity and deviation in binding residues are the result of alteration in hydrogen bonding. Flap region also exhibited similar behaviour due to changes in number of hydrogen bonds during simulations. PMID- 21696231 TI - Biphasic association of T7 RNA polymerase and a nucleotide analogue, cibacron blue as a model to understand the role of initiating nucleotide in the mechanism of enzyme action. AB - T7 RNA polymerase (T7 RNAP) is an enzyme that utilizes ribonucleotides to synthesize the nascent RNA chain in a template-dependent manner. Here we have studied the interaction of T7 RNAP with cibacron blue, an anthraquinone monochlorotriazine dye, its effect on the function of the enzyme and the probable mode of binding of the dye. We have used difference absorption spectroscopy and isothermal titration calorimetry to show that the dye binds T7 RNAP in a biphasic manner. The first phase of the binding is characterized by inactivation of the enzyme. The second binding site overlaps with the common substrate-binding site of the enzyme. We have carried out docking experiment to map the binding site of the dye in the promoter bound protein. Competitive displacement of the dye from the high affinity site by labeled GTP and isothermal titration calorimetry of high affinity GTP bound enzyme with the dye suggests a strong correlation between the high affinity dye binding and the high affinity GTP binding in T7 RNAP reported earlier from our laboratory. PMID- 21696232 TI - Pharmacophore modeling and hybrid virtual screening for the discovery of novel IkappaB kinase 2 (IKK2) inhibitors. AB - IKK2 (IkappaB kinase 2) inhibitors have been identified as potential drug candidates in the treatment of various immune/inflammatory disorders as well as cancer. So far more than one hundred small molecule inhibitors against IKK2 have been reported publicly. In this investigation, pharmacophore modeling was carried out to clarify the essential structure-activity relationship for the known IKK2 inhibitors. One of the established pharmacophore hypotheses, namely Hypo8, which has the best prediction ability to an external test data set, was suggested as a template for virtual screening. Evaluation of the performances of Hypo8 and a hybrid method (Hypo81docking) in virtual screening indicated that the use of the hybrid virtual screening considerably increased the hit rate and enrichment factor. The hybrid method was therefore adopted for screening several commercially available chemical databases, including Specs, NCI, Maybridge and Chinese Nature Product Database (CNPD), for novel potent IKK2 inhibitors. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five. Finally some of the final hit compounds were selected and suggested for further experimental investigations. PMID- 21696233 TI - Investigations with spectroscopy, zeta potential and molecular modeling of the non-cooperative behaviour between cyclophosphamide hydrochloride and aspirin upon interaction with human serum albumin: binary and ternary systems from multi-drug therapy. AB - The interaction between cyclophosphamide hydrochloride (CYC) and aspirin (ASA) with human serum albumin (HSA) was studied by various kind of spectroscopic, zeta potential and molecular modeling under physiological conditions. The fluorescence data showed that the binding of drugs to proteins caused strong static fluorescence quenching. The analysis of the fluorescence quenching of HSA in the binary and ternary systems displayed that ASA was affected by the complex formed between CYC and HSA. Moreover, CYC was influenced by the HSA-ASA complex. The inherent binding information, including the quenching mechanism, binding constants, number of binding sites, effective quenching constant, fraction of the initial fluorescence and thermodynamic parameters were measured by the fluorescence quenching technique at various temperatures. In addition, according to the synchronous fluorescence spectra of HSA, the results showed that the fluorescence quenching of HSA originated from the Trp and Tyr residues, and indicated a conformational change of HSA with the addition of the drugs. Far-UV CD spectra of HSA were recorded before and after the addition of ASA and CYC as binary and ternary systems. An increase in intensity of the positive CD peak of HSA was observed in the presence of the drugs. The results were interpreted by excited interactions between the aromatic residues of the HSA binding sites and the drugs bound to them. The distance r between donor and acceptor was obtained by the Forster energy according to fluorescence resonance energy transfer (FRET) and found to be 2.35 nm and 1.78 nm for CYC and ASA, respectively. This confirmed the existence of static quenching for proteins in the presence of CYC and ASA. Furthermore, docking studies pointed at a reduction of the affinity of each of the drug compounds to the protein in the presence of the other in meaningful amounts. Pre-binding of any of the said compounds forced the second to bind in a non-optimized location and orientation. The potential at the electrokinetic shear surface of the protein-drug solution were measured at several concentrations of the drugs by the zeta potential technique, which confirmed experimental and theoretical results. PMID- 21696234 TI - Docking studies on the binding of quinoline derivatives and hematin to Plasmodium falciparum lactate dehydrogenase. AB - The literature has reported that ferriprotoporphyrin IX (hematin) intoxicates the malarial parasite through competition with NADH for the active site of the enzyme lactate dehydrogenase (LDH). In order to avoid this, the parasite polymerizes hematin to hemozoin. The quinoline derivatives are believed to form complexes with dimeric hematin, avoiding the formation of hemozoin and still inhibiting LDH. In order to investigate this hypothesis we calculated the docking energies of NADH and some quinoline derivatives (in the free forms and in complex with dimeric hematin) in the active site of the Plasmodium falciparum LDH (PfLDH). Ours results showed better docking score values to the complexes when compared to the free compounds, pointing them as more efficient inhibitors of Pf_LDH. Further we performed Molecular Dynamics (MD) simulations studies on the best docking conformation of the complex chloroquine-dimeric hematin with PfLDH. Our in silico results corroborate experimental data suggesting a possible action route for the quinoline derivatives in the inhibition of PfLDH. PMID- 21696217 TI - The metabolic serine hydrolases and their functions in mammalian physiology and disease. PMID- 21696235 TI - BetaDock: shape-priority docking method based on beta-complex. AB - This paper presents an approach and a software, BetaDock, to the docking problem by putting the priority on shape complementarity between a receptor and a ligand. The approach is based on the theory of the beta-complex. Given the Voronoi diagram of the receptor whose topology is stored in the quasi-triangulation, the beta-complex corresponding to water molecule is computed. Then, the boundary of the beta-complex defines the beta-shape which has the complete proximity information among all atoms on the receptor boundary. From the beta-shape, we first compute pockets where the ligand may bind. Then, we quickly place the ligand within each pocket by solving the singular value decomposition problem and the assignment problem. Using the conformations of the ligands within the pockets as the initial solutions, we run the genetic algorithm to find the optimal solution for the docking problem. The performance of the proposed algorithm was verified through a benchmark test and showed that BetaDock is superior to a popular docking software AutoDock 4. PMID- 21696236 TI - iSMART: an integrated cloud computing web server for traditional Chinese medicine for online virtual screening, de novo evolution and drug design. PMID- 21696237 TI - Turning round: multipotent stromal cells, a three-dimensional revolution? AB - Mesenchymal stromal cells (MSC) can be isolated from adult tissues and induced to differentiate into skeletal cells, such as osteoblasts, chondrocytes and adipocytes. Consequently, ex vivo MSC are valuable systems for studying the mechanisms that control tissue-context lineage commitment and may offer broad therapeutic applications in the orthopedic theater and beyond. To date, most of these studies have used MSC grown on two-dimensional (2-D) plastic surfaces. The use of three-dimensional (3-D) in vitro growth techniques for MSC may accelerate these areas of research by providing a more representative 'in vivo-like' environment, where cells interact with each other and their cellular products, rather than a plastic surface. We introduce some of the techniques used for 3-D in vitro cultures and how they relate to the MSC field. We will present evidence of how MSC grown as 3-D spheroids not only permits appropriate MSC-like behavior, but appears to promote their stem-cell attributes and therapeutic benefit in applications ranging from regenerative medicine to anti-inflammatory treatments and cancer therapy. 3-D culture techniques also allow de/reconstruction of the specialized in vivo niche of the tissue-resident stem cell where microenvironmental influences can be recognized. PMID- 21696238 TI - Neuronal plasticity of human Wharton's jelly mesenchymal stromal cells to the dopaminergic cell type compared with human bone marrow mesenchymal stromal cells. AB - BACKGROUND AIMS: Mesenchymal stromal cells (MSC) derived from Wharton's jelly (WJ) of the umbilical cord are increasingly gaining prominence as substitutes for bone marrow (BM) MSC. While MSC isolated from different tissue sources may share common mesenchymal properties, the difference in their plasticity to individual lineages is ill-defined. Thus the focus of this study was to estimate the neuronal plasticity of WJ MSC to the dopaminergic (DA) cell type in comparison with BM MSC. METHODS: For neuronal differentiation, MSC were exposed to developmentally relevant cues for midbrain DA neurons: sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF8), along with basic fibroblast growth factor (bFGF). RESULTS: Naive MSC from both sources constitutively expressed neuronal markers. Flow cytometry data revealed that the control WJ MSC shared a signature similar to BM MSC for early neuronal markers (nestin, musashi12 and A2B5) and DA specific markers [tyrosine hydroxylase (TH) and Nuclear Receptor related protein 1 (Nurr1) but differed for mature neuronal proteins [beta-tubulin III and microtubule-associated protein 2 (Map2ab)]. Similar populations of cells in both sources of MSC were positive for the SHH receptors [patched (PTCH) and smoothened (SMO)]. In induced BM and WJ MSC, real-time reverse transcriptase (RT)-polymerase chain reaction (PCR) analysis showed similar levels of DA-related transcription factors Nurr1 and Engrailed (En) 1. Immunocytochemical and flow cytometry analysis showed an increase in mature neuronal marker Map2ab. Kv4.2, a K(+) channel marker, was observed only in the induced MSC. Induced MSC also expressed several DA-specific markers, TH, dopamine and cyclic AMP regulated phosphoprotein (DARPP) 32, paired-like homeodomain transcription factor (PitX) 3 and vesicular monoamine transporter (VMAT) 2, in comparable levels between the two sources. The efficiency (c. 65%) of transdifferentiation of WJ MSC to TH-positive cells was similar to that of induced BM MSC. Constitutive and inducible release of dopamine was found to be similar between induced BM and WJ MSC, as measured by dopamine enzyme-linked immunosorbent assay (ELISA). Interestingly, an adenosine triphosphate (ATP)-stimulated change in intracellular Ca(2+) was observed in both control and induced MSC, but only the induced MSC was capable of releasing dopamine. CONCLUSIONS: Our data demonstrate that MSC from the two different sources respond similarly to inductive cues to differentiate terminally to a DA cell type, and the neuronal plasticity of human WJ MSC is comparable with that of BM MSC. PMID- 21696239 TI - Factors associated with perceived stigma among people living with HIV/AIDS in post-conflict northern Uganda. AB - HIV-related stigma continues to persist in several African countries including Uganda. This study quantified the burden of stigma and examined factors associated with stigma among 476 people living with HIV (PLHTV) in Gulu, northern Uganda. Data were collected between February and May 2009 using the HIV/AIDS Stigma Instrument-PLWA. Females more than males, respondents aged above 30 years, and those who had been on antiretroviral therapy for a longer time experienced higher levels of stigma. Verbal abuse and negative self-perception were more common forms of stigma. The association between antiretroviral therapy and stigma suggested that organizational aspects of antiretroviral delivery may lead to stigmatization of PLHIV. Interventions such as counseling of PLHIV, education of health workers and the community would lead to reductions in negative self perception and verbal abuse and in turn improve the quality of life for PLHIV in northern Uganda. PMID- 21696240 TI - Computer-facilitated rapid HIV testing in emergency care settings: provider and patient usability and acceptability. AB - Providers in emergency care settings (ECSs) often face barriers to expanded HIV testing. We undertook formative research to understand the potential utility of a computer tool, "CARE," to facilitate rapid HIV testing in ECSs. Computer tool usability and acceptability were assessed among 35 adult patients, and provider focus groups were held, in two ECSs in Washington State and Maryland. The computer tool was usable by patients of varying computer literacy. Patients appreciated the tool's privacy and lack of judgment and their ability to reflect on HIV risks and create risk reduction plans. Staff voiced concerns regarding ECS based HIV testing generally, including resources for follow-up of newly diagnosed people. Computer-delivered HIV testing support was acceptable and usable among low-literacy populations in two ECSs. Such tools may help circumvent some practical barriers associated with routine HIV testing in busy settings though linkages to care will still be needed. PMID- 21696241 TI - A multimodal behavioral intervention to impact adherence and risk behavior among perinatally and behaviorally HIV-infected youth: description, delivery, and receptivity of adolescent impact. AB - Secondary prevention programs are needed to help HIV-positive youth reduce risk behavior and improve adherence to HIV medications. This article provides an overview of Adolescent Impact, a secondary HIV prevention intervention, including its description, delivery, and receptivity among the two unique groups of participants. Adolescent Impact, a 12-session behavioral intervention incorporating individual and group components was designed to increase HIV knowledge, disease management and risk reduction skills, and motivate healthy lifestyles among HIV-infected adolescents. A standardized protocol was implemented at three sites in the northeastern United States. One hundred sixty six HIV-positive youth, aged 13-21 (mean = 16.8 years), enrolled in the study were randomized to receive either the intervention (n = 83) or standard of care (n = 83). Participants were predominantly of minority race/ethnicity (94% African American or Hispanic); 53% were female and 59.6% were perinatally infected. Perinatally infected youth were significantly more likely to be young, had experienced HIV Class C-related symptoms and had CD4-positive T lymphocyte counts of fewer than 200 cells (all p values < .01). The mean number of sessions attended was 9.4, with most (83.3%) participants attending at least half (>= 6) of the intervention sessions (86% perinatally infected, 78.6% behaviorally infected, p = .5). Participants' sociodemographic and clinical characteristics mirrored those of the larger HIV adolescent cohort in the United States Relatively high attendance rates suggest that youth were receptive to the program and its content. Through use of multiple intervention modalities, Adolescent Impact was able to accommodate a diverse group of clinic-attending HIV-positive youth and address the need for a compact intervention for use in the clinical setting. PMID- 21696242 TI - Exploring the sexual health priorities and needs of immigrant Latinas in the southeastern United States: a community-based participatory research approach. AB - Latinas living in the United States are disproportionately affected by HIV/AIDS and sexually transmitted infections. However, few effective interventions currently exist that are designed to meet the priorities and needs of recently arrived and less acculturated immigrant Latinas who are settling in the southeastern United States. To identify sexual health priorities, gaps in information and skills, and key intervention characteristics to improve sexual health among immigrant Latinas, a community-based participatory research partnership conducted four focus groups with Latinas, in central North Carolina. Findings revealed a lack of knowledge about sexual health, shame and embarrassment related to clinical exams and conversations about sex, multilevel barriers to sexual health, and disease transmission misinformation. Findings also suggested that interventions should include information about a broad range of sexual and reproductive health topics and skill building. Such interventions could serve to assist in diminishing health disparities experienced among this vulnerable population. PMID- 21696243 TI - Cruising for truckers on highways and the internet: sexual networks and infection risk. AB - Empirical evidence on the heterosexual partnerships of long-haul truckers suggests connections among occupational stressors, substance misuse, structural factors, and risk for sexually transmitted infections and HIV. Yet the potential risks associated with same-sex partnerships of truckers and truckchasers (men who specifically cruise for truckers) remain largely unknown. Drawing from diverse sources as well as primary and secondary data from 173 truckers and "truckchasers," we discuss how trucking and cruising contexts, in conjunction with Internet fora, jointly create a risk-enabling environment for truckers and their sex contacts. Findings point toward an elusive but extensive sexual network that spans across the Internet and highways and takes advantage of truckers' mobility as it bridges disparate epidemiological spaces and populations. The delineation of cruising within the hypermasculine occupational sector of trucking adds new insights to the study of sexual health, which is particularly important considering the riskladen sex contacts of truckers and truckchasers and potential for infection spread. PMID- 21696244 TI - HIV prevention for migrants in transit: developing and testing TRAIN. AB - This study was a pilot investigation of the feasibility, acceptability, and effects of TRAIN (Transit to Russia AIDS Intervention with Newcomers) a three session HIV preventive intervention for Tajik male labor migrants performed in transit. Sixty adult Tajik male labor migrants on the 5-day train ride from Dushanbe to Moscow were randomly assigned to either the intervention or a control condition. Each initially completed an in-person survey then another 3 days later (immediately postintervention), and participated in a cell phone survey three months later. All participants came to all intervention sessions, were satisfied with the program, and completed all postassessments. In comparison with the controls, the TRAIN group reported significant increases in condom use with sex workers and non-sex workers, condom knowledge, worry about HIV/AIDS, talking with persons about HIV/AIDS, talking with wife about HIV/AIDS, community activities, and religious activities. HIV/AIDS prevention performed in transit is feasible, accceptable, and potentially efficacious in diminishing HIV risk behaviors in labor migrants. PMID- 21696247 TI - Visual perception training on social skills and activity performance in low vision children. AB - The aim of this study was to evaluate the effect of two different visual perception training programmes on the social skills and activity performance of low-vision children. Forty children (aged 7-14 years) were randomly assigned into two groups with regard to the visual perception training performed: Group 1: aided paper and pen, and Group 2: with computer. The participants were evaluated before and after treatment using the Motor-Free Visual Perception Tests, Social Skills Assessment Tool for Children with Visual Impairments, and Canadian Occupational Performance Measurement. The training programmes were performed in the school for three months (two days/week and 45 minutes/day). In both groups, results of the social skills questionnaire showed significant differences before and after treatment (p < 0.01). Likewise, the results of the activity performance test indicated significant differences between the performance and total activity scores (p < 0.01). Both treatment programmes failed to show a significant relationship in respect of the increase in visual perception (p > 0.05). Based on these results, neither of the programmes tested appears to be superior to the other in low-vision children. PMID- 21696245 TI - The acceptance and feasibility of replacement feeding at 6 months as an HIV prevention method in Lilongwe, Malawi: results from the BAN study. AB - International guidelines recommend EBF to age 6 months among HIV-infected mothers choosing to breast-feed and cessation thereafter if replacement feeding is acceptable, feasible, affordable, sustainable, and safe. When mothers wean, they are challenged to provide an adequate replacement diet. This study investigates the use and acceptability of a lipid-based nutrient supplement (LNS) as a breast milk substitute when provided to infants (6-12 mo) of HIV-positive mothers, as part of the Breast-feeding, Antiretroviral, and Nutrition (BAN) Study. A sub sample of mothers (n = 45) participated in interviews that explored EBF, weaning, and strategies to feed LNS. Mothers reported several weaning strategies, including gradual reduction of breast-feeding, expressing breast-milk into a cup, and separation of mother and child. LNS, a peanut-based micronutrient fortified paste, was highly accepted and incorporated into the traditional diet. Weaning is a feasible HIV prevention method among this population in Malawi when supported by the provision of LNS as a breast-milk substitute. PMID- 21696248 TI - Intracranial tuberculomas in adults: a report of twelve consecutive patients in Houston, Texas. AB - BACKGROUND: Intracranial tuberculomas are rare manifestations of tuberculosis (TB). An extensive literature review revealed that no study of consecutive adults with intracranial tuberculoma has been conducted in the USA. METHODS: This retrospective study consisted of 12 adults consecutively identified with intracranial tuberculomas from 1995 to 2009 in Houston, Texas. Of the 12 cases, 8 had a histopathological diagnosis, while 4 had a probable diagnosis based on the following criteria: (1) Mycobacterium tuberculosis identified from a source outside the brain, (2) radiographic confirmation of an intracranial mass, (3) received chemotherapy with 2 or more anti-tuberculosis medications, and (4) clinical response at 1-y follow-up. RESULTS: Common clinical manifestations were altered mental status, fever, and night sweats. Four patients (25%) had a human immunodeficiency virus (HIV) infection. Nine patients (75%) had concomitant M. tuberculosis at at least 1 extracranial site, including 5 patients with pulmonary TB. The median duration of therapy was 11 months. Patients had a 1-y mortality rate of 16.7% and an overall morbidity rate of 20%. CONCLUSIONS: Intracranial tuberculomas in Houston, Texas, are rare. Hospital discharge predicted survival at 1 y, despite severe clinical presentations and invasive diagnostic procedures. However, tuberculoma cases are associated with higher mortality rates than non central nervous system TB cases. PMID- 21696249 TI - Effectiveness of entecavir in the management of acute hepatitis B developing in a patient with Hodgkin's lymphoma: a case report. AB - We describe a case of severe acute hepatitis B developing in a patient with Hodgkin's lymphoma after chemotherapy and before radiotherapy. Entecavir was administered leading to virological and biochemical response, which allowed the scheduled treatment to be completed. The patient had complete haematological remission and made a complete recovery from hepatitis B. PMID- 21696251 TI - Usefulness of the restriction-modification test plus staphylococcal cassette chromosome mec types and Panton-Valentine leukocidin encoding phages to identify Staphylococcus aureus methicillin-resistant clones. AB - We studied the usefulness of the restriction-modification (RM) test, staphylococcal cassette chromosome (SCC) mec types, and Panton-Valentine leukocidin (PVL)-encoding phages to identify Staphylococcus aureus methicillin resistant lineages and to differentiate clones that belong to the same lineage. A total of 108 methicillin-resistant S. aureus (MRSA) strains were characterized by pulsed-field gel electrophoresis (PFGE)--multi-locus sequence typing (MLST)--spa typing. The RM correctly identified the lineages CC5, CC8, CC30, and CC398, but not CC25 and CC72. The SCCmec and RM combined analysis allowed differentiation between MLST types within the same lineage. Only 5 MRSA strains were PVL positive. Four PVL-positive USA300 isolates carried elongated-head type PVL encoding phages, while the sequence type (ST)-30 strain carried an icosahedral head phage. The combination of the RM test method, SCCmec types, and PVL phage identification could be useful for MRSA typing purposes. PMID- 21696250 TI - Comparison of neutrophil volume distribution width to C-reactive protein and procalcitonin as a proposed new marker of acute infection. AB - BACKGROUND: The aim of this study was to assess the use of neutrophil distribution width (NDW) and to compare it to C-reactive protein (CRP) and procalcitonin (PCT), in the detection of early sepsis in the intensive care unit. METHODS: Subjects (N = 166) were divided into 4 groups: healthy, acute inflammatory non-infectious (AINI), localized infection, and systemic infection, according to clinical history and cultures. NDW, CRP, and PCT were compared among the different groups using multivariate analysis of variance (MANOVA). Diagnostic efficacy was assessed using receiver operating characteristic curves and areas under the curves (AUC). RESULTS: The lowest mean(NDW) was found in the healthy group (n = 41), followed by the AINI (n = 20), localized infection (n = 55), and systemic infection (n = 50) groups. AUC(NDW) was 0.877 for infected (localized + systemic) vs non-infected (healthy + AINI) groups, and 0.965 for systemic infection vs non-infected groups. A cut-off of 21.9 resulted in 90% sensitivity, 92% specificity, 90% positive predictive value, and 92% negative predictive value (AUC(NDW) = 0.965, 95% confidence interval 0.935-0.995). According to MANOVA, only NDW was able to differentiate an acute inflammatory process from early infection in postoperative patients, but not healthy from AINI subjects. CONCLUSIONS: NDW had the highest diagnostic accuracy and is available with the complete blood count with differential (CBC). It may be a promising parameter to aid in the diagnosis of acute infection in adults, provided the possibility of haematological disorders is first ruled out. PMID- 21696252 TI - Is linezolid a risk factor for Gram-negative bacillus infections in intensive care unit patients? A comparative study with vancomycin. AB - BACKGROUND: Linezolid is frequently used in critically ill patients with ventilator-associated pneumonia. Its potent activity against Gram-positive microorganisms and its high tissue penetration may favour Gram-negative colonization and infection. The aim of our study was to evaluate the risk for Gram-negative infections in critically ill patients treated with linezolid or vancomycin. METHODS: The cases of all patients admitted over an 18-month period to a hepatic intensive care unit for >= 1 week, and treated with linezolid or vancomycin, were retrospectively reviewed. The main clinical characteristics and infections due to Gram-negative bacteria in the month after starting linezolid or vancomycin were obtained. RESULTS: Seventy-one patients treated with linezolid and 68 treated with vancomycin fulfilled the inclusion criteria. Co-morbidities were similar in both groups. Patients on linezolid treatment had a longer stay in the ICU (mean +/- standard deviation 41 +/- 38 days vs 18.4 +/- 13 days), received this treatment later (14.3 +/- 15.1 days vs 6.3 +/- 6.5 days), had a higher mean serum creatinine concentration (1.71 +/- 1.18 mg/dl vs 1.04 +/- 1.04 mg/dl), more often required haemodiafiltration (29.6% vs 13.2%), and 30 day mortality was higher (42.3% vs 20.6%) than in patients receiving vancomycin. More than 95% in both groups received a broad-spectrum beta-lactam in addition to linezolid or vancomycin. The rate of Gram-negative infection during the following month was 28.2% in the linezolid group and 26.5% in the vancomycin group (p > 0.5). CONCLUSIONS: Linezolid was more frequently used in critically ill patients with longer ICU stay and renal failure. The rate of infection due to Gram negative microorganisms was similar in patients who received linezolid or vancomycin. PMID- 21696253 TI - Noroviruses as a major cause of acute gastroenteritis in children in Finland, 2009-2010. AB - Noroviruses are, after rotaviruses, the second most common cause of acute gastroenteritis in young children. In a prospective study conducted in 2009-2010 at the Tampere University Hospital, 195 stool specimens were collected from cases of acute gastroenteritis in children and examined for noroviruses, sapoviruses, and rotaviruses, using a reverse transcriptase polymerase chain reaction (RT PCR). Noroviruses were found in 49 (25%) of the cases and sapoviruses in 12 (6%). The norovirus genotype GII.4 dominated with a 76% share; other genotypes detected were GII.7/GII.6 (16%), GII.g/GII.12, GII.e/GII.4, and GII.7 (2% each). For comparison, 47 (24%) cases of rotavirus gastroenteritis were diagnosed in the same period. In conclusion, after the introduction of rotavirus vaccination in Finland in September 2009, noroviruses have become as common as rotaviruses as the causative agents of acute gastroenteritis in young children, and are likely to become the leading cause. Norovirus GII.4 continues to be the dominant genotype. PMID- 21696254 TI - Herpes simplex virus infection in the Croatian population. AB - BACKGROUND: Herpes simplex virus (HSV) infections are caused by 2 types of virus, HSV-1 and HSV-2. Both viruses are endemic worldwide. There are marked variations in the seroprevalences of HSV-1 and HSV-2 in Europe. The aim of this study was to determine the seroprevalence of HSV infections in Croatia. METHODS: During a 3-y period (2008-2010), a total of 1672 patients were tested for the presence of HSV 1 and HSV-2 antibodies using an enzyme-linked immunosorbent assay. RESULTS: The overall immunoglobulin G (IgG) seroprevalence rates were 72.5% for HSV-1 and 9.9% for HSV-2. There was no significant difference in seropositivity between males and females for HSV-1 (72.0% vs 73.0%) or HSV-2 (8.9% vs 10.7%). HSV-1 seroprevalence increased from 26.4% in those aged 6 months-9 y to 89.9% in those aged 40?49 y, and remained stable thereafter, ranging from 87.4% to 91.5% (p < 0.001). HSV-2 IgG seropositivity increased progressively from 5.7% in participants aged 20-29 y to 26.5% in participants aged >= 60 y (p < 0.001). HSV 1 seroprevalence did not differ between participants residing in urban and rural areas (72.5% vs 72.6%). Urban place of residence was a significant factor for HSV 2 seroprevalence in univariate analysis, but after standardization for age, it was no longer significant. CONCLUSIONS: Multiple logistic regression showed that age was a significant predictor of both HSV-1 and HSV-2 seropositivity, while female gender was a significant predictor of HSV-2 seropositivity. In pregnant women, obstetric history was not a significant predictor of either HSV-1 or HSV-2 seroprevalence. PMID- 21696255 TI - Performance and clinical significance of direct antimicrobial susceptibility testing on urine from hospitalized patients. AB - BACKGROUND: Urinary tract infections (UTIs) are common infections in the community and the hospital. With increasing antimicrobial resistance, specifically in the Gram-negative uropathogens, reliable, rapid antimicrobial susceptibility data would be useful to guide antimicrobial treatment. Direct antimicrobial susceptibility testing (DST) of urine with microscopic evidence of Gram-negative bacterial infection and its clinical significance was investigated in this study. METHODS: DST was performed by Kirby-Bauer disk diffusion method using undiluted urine as a non-standardized inoculum. Urine specimens with Gram negative bacteria on microscopy were included. DST results from growth of Gram negative bacteria were compared to routine antimicrobial susceptibility testing by Phoenix automated system (AST). Errors were scored as 'very major error' if susceptible by DST but resistant by AST and as 'major error' if resistant by DST but susceptible by AST. All other discrepancies were defined as 'minor error'. Discrepancies were resolved by determination of minimum inhibitory concentrations (MICs) using Etests. After discrepancy analysis, errors were scored as above using the Etest as the reference method. For analysis, specimens were divided into 3 categories: category A: 1 isolate found by DST as well as by routine culture; category B: 1 isolate detected by DST, but more than 1 isolate found on routine culture; category C: more than 1 isolate found by both DST and routine culture. The clinical significance of DST was determined prospectively by investigating the potential impact of DST on antimicrobial therapy. RESULTS: One hundred and sixteen urine specimens were included. For DST and AST there was agreement in 96% of 1152 comparisons in category A (n = 100), 88% of 41 comparisons in category B (n = 4), and 88% of 110 comparisons in category C (n = 12). The 64 discrepancies included 18 very major errors, 7 major errors, and 39 minor errors. Eight very major errors and 11 minor errors were not investigated because the isolates were not available. After Etest MIC determination for the 45 remaining discrepancies, DST showed 1 very major error, 1 major error, and 8 minor errors in category A, none in category B, and 5 major errors and 4 minor errors in category C. Antimicrobial therapy for UTI was prescribed for 53 patients. For 4 patients (8%) therapy was adjusted based on DST because of antimicrobial resistance and for 12 patients (23%) antimicrobial treatment could have been streamlined. CONCLUSIONS: DST on urine is reliable in monobacterial Gram-negative infections. With increasing antimicrobial resistance, DST can make an important contribution to patient management and reduce the use of broad spectrum antimicrobials. PMID- 21696256 TI - Ablative surgery and free flap reconstruction for elderly patients with oral or oropharyngeal cancer: oncologic and functional outcomes. AB - CONCLUSION: This was the first study to specifically demonstrate the validity of ablative surgery and free flap reconstruction for elderly patients with oral or oropharyngeal cancer in terms of oncologic and functional outcomes. OBJECTIVE: The aim of our study was to evaluate the impact of advanced age on oncologic and functional outcomes after ablative surgery and free flap reconstruction in patients with oral or oropharyngeal cancer. METHODS: We conducted a retrospective review of the medical records of all patients who underwent ablative surgery and reconstruction with free flap for primary oral or oropharyngeal cancer at our institution between 2000 and 2009. The impact of advanced age (>=70 years) on oncologic and functional outcomes was assessed in univariate and multivariate analyses. RESULTS: Advanced patient age had a worse impact on overall (p = 0.006), specific (p = 0.02) and disease-free (p = 0.03) survival in univariate analysis, but had only a worse impact on overall survival (p = 0.03) in multivariate analysis. In the elderly patients, overall, specific and disease free survival rates at 5 years were 43%, 51% and 49%, respectively. There was no significant difference in functional outcomes between elderly and young patients. PMID- 21696258 TI - Vulvar pythiosis in two captive camels (Camelus dromedarius). AB - Two camels (Camelus dromedarius), 3- and 4-years-old, respectively, from an eastern Tennessee wildlife farm presented with persistent weight loss and large vulvar masses. An initial biopsy of the vulvar mass of one of the camels performed by a local veterinarian showed eosinophilic dermatitis. An allergic or parasitic dermatitis was suspected. The two camels were treated with one dose of sodium iodide (66 mg/kg, in 1.0 L of normosolR, IV) and ivermectin 1% (200 ug/kg PO). Upon presentation at the Veterinary Teaching Hospital, University of Tennessee, additional biopsies of the masses again revealed eosinophilic dermatitis. Microscopic examination of a Gomori methenamine silver (GMS)-stained section prepared from the biopsy of one of the camels revealed the presence of fungal-like hyphae of a mold which was suspected to be Pythium insidiosum. The vulvar masses were surgically debulked in both animals and sodium iodide and Pythium-immunotherapy prescribed. Pythium insidiosum was isolated in culture and hyphae elements were detected in histological sections confirming the diagnosis of pythiosis in both animals. Despite signs of progressive healing of the vulvar surgical areas, postoperative persistent weight lost in one of the camels suggested the possibility of gastro intestinal (GI) tract pythiosis. This camel died 5 months after the first onset of clinical signs and unfortunately a necropsy was not performed. The other camel responded well to the combination of surgery, iodides, and immunotherapy and has currently rejoined the other members of the herd. PMID- 21696257 TI - Cochlin-tomoprotein (CTP) detection test identifies traumatic perilymphatic fistula due to penetrating middle ear injury. AB - CONCLUSIONS: The cochlin-tomoprotein (CTP) detection test can be used to make a definite, objective diagnosis of traumatic perilymphatic fistula (PLF), and therefore offers valuable information on patient selection for surgical treatment. OBJECTIVES: Penetrating middle ear injury can cause traumatic PLF, which is a surgically treatable otologic emergency. Recently, we have reported on CTP, a novel perilymph-specific protein. The purpose of this study was to determine if the CTP detection test is useful for the diagnosis of traumatic PLF. METHODS: This was a prospective study of CTP detection in penetrating middle ear injury cases with tympanic membrane perforation and hearing loss. RESULTS: A total of seven individuals were included in this study. CTP was detected in three of four cases with posterosuperior quadrant perforation of the tympanic membrane. In one of these three cases, even though the high resolution CT scan was not suggestive of PLF and the perilymph leakage could not be visualized intraoperatively, the CTP detection test was able to detect PLF. In two cases, the preoperative positive test results enabled us to make a diagnosis of PLF and a decision for surgical treatment. CTP was not detected in the cases with anterior or inferior tympanic membrane perforation. PMID- 21696259 TI - Epidemiology of Candida blood stream infections in patients with hematological malignancies or solid tumors. AB - Invasive Candida infections are associated with high morbidity and mortality. Due to an increased incidence in patients with hematological or oncological malignancies, fluconazole prophylaxis became a common practice in many centers in the late 1990s. Until recently, there was insufficient data on the effect of the use of azoles on the incidence of Candida blood stream infections and species distribution. Here we present a single center retrospective study of the epidemiology of Candida blood stream infections in hospitalized patients at a German university medical center from 2003-2009. Twenty-one Candida species were isolated in culture from blood specimens of 20 patients. The annual rate of candidemia approached 1.1 per thousand hospitalizations, during the first 5 years of the survey, but showed a significant increase after 2007. Candida albicans, although still the dominant species, was recovered as the responsible pathogen from only 28.6% of the cases. A high rate of fatal outcomes was noted at 30 days (56%) and 100 days (67%) after the first positive finding of Candida in blood culture. These results underline the clinical significance of this infectious complication, and the need for continuous monitoring for Candida blood stream infections in order to improve the clinical and therapeutic management of this specific patient population. PMID- 21696260 TI - Sulfosalicylate mediates improved vinorelbine loading into LUVs and antineoplastic effects. AB - Liposomal vinorelbine formulation is desirable, as it might improve the therapeutic activity of vinorelbine. However, because of its lipophilic and membrane-permeable properties, vinorelbine is hard to be formulated into liposomes using conventional drug-loading technologies. To improve vinorelbine retention, ammonium salts of several anionic agents were employed to prepare liposomal vinorelbine formulations. It was found that 5-sulfosalicylate (5ssa) could form stable complexes with vinorelbine and stabilize entrapped vinorelbine. The resultant vesicles had an in vitro release t(1/2) of ~12.49 hours in NH(3) containing media, which is longer than those of sulfate and phytate vesicles (~0.57 hours). The circulation half-life of vinorelbine after the injection of 5ssa vesicles into normal mice was ~13.01 hours, accounting for ~2-fold increase relative to that of sulfate vesicles. Improved drug retention correlated with enhanced antitumor efficacy. In the RM-1/c57 model, 5ssa vesicles were more efficacious than sulfate vesicles (P < 0.05). In RM-1/BDF1 and Lewis lung cancer/c57 models, antitumor efficacy was also considerably improved after vinorelbine encapsulation into 5ssa vesicles. For instance, in the RM/BDF1 model, liposomal vinorelbine was at least 4-fold more therapeutically active than free vinorelbine. Our results demonstrated that 5ssa could stabilize vinorelbine relative to other anions, resulting in the formulation with improved drug retention and efficacy. Improved vinorelbine retention might be associated with the formation of insoluble precipitate, which could be proved by precipitation study and decreased drug-release rate at a high D/L ratio. PMID- 21696261 TI - Toxicokinetics of ammonium perfluorohexanoate. AB - Excretion patterns and rates of ammonium perfluorohexanoate (APFHx) after administration of a single and multiple (14 days) oral dose(s) at 50 mg/kg to male and female mice and rats were examined. The test substance was [(14)C] labeled APFHx. After a single oral administration, total excretion was rapid, with mean recoveries of over 90% of the dose at 24 hours after administration, irrespective of gender or species. The major route of elimination was via the urine (means of percentage recovery between 73.0 and 90.2% of the dose), followed by the feces (means of percentage recovery between 7.0 and 15.5% of the dose). Elimination via expired air was negligible. For the multiple dose tests, multiple (13 daily doses) oral administration of APFHx was followed by a single oral administration of [(14)C]-APFHx. Excretion was rapid, with mean recoveries of over 90% of the administered dose (mean values >95% of the ultimately recovered material) at 24 hours after dosing, irrespective of gender or species. The major route of elimination was via the urine (means of percentage recovery between 77.8 and 83.4% of the dose), followed by the feces (means of percentage recovery between 9.6 and 12.9% of the dose). PMID- 21696262 TI - The complete genome sequence of Clostridium botulinum F str. 230613, insertion sites, and recombination of BoNT gene clusters. AB - The genomic DNA of Clostridium botulinum F str. 230613 includes a chromosome (3 993 083 bp, 3502 coding sequences (CDs)) and a plasmid (17 531 bp, 25 CDs). The arrangement of the botulinum neurotoxin serotype F (BoNT/F) gene cluster, a 15-kb (or longer) fragment including the bont gene and other relevant genes, and its different insertion sites in C. botulinum A2 and C. botulinum F were formulated. Mobile elements and virulence factors were analysed. We also found a cell adhesion and pectin lyase domain-containing protein, which may function in attaching to the host and as a pectin lyase. The nine BoNT gene clusters of group I C. botulinum strains were located at three sites in the chromosome of C. botulinum F str. 230613. This study showed the inserting inclination of BoNT/A1 tend to have gene clusters inserted at site 3, BoNT/F at site 2, and BoNT/A2 at site 1. Additionally, we found the recombination event between the BoNT gene clusters of sites 2 and 3, a mechanism that contributed to the diversity of the BoNT gene cluster arrangement. PMID- 21696263 TI - Chemotherapy-induced nausea and vomiting and antiemetic prophylaxis with palonosetron versus other 5-HT3 receptor antagonists in patients with cancer treated with low emetogenic chemotherapy in a hospital outpatient setting in the United States. AB - BACKGROUND: The incidence of overall (acute and delayed) chemotherapy-induced nausea and vomiting (CINV) events among patients treated with single- and multi day low emetogenic chemotherapy (LEC) is not well established. We studied a cohort of patients receiving LEC and antiemetic prophylaxis with palonosetron (Group 1) versus other 5-HT(3) receptor antagonists (5-HT(3)-RAs) (Group 2), to determine the overall rate of CINV and the proportion of patients experiencing delayed CINV (days 2-7 of a CT cycle) in a hospital outpatient setting. METHODS: Patients aged >=18 years with cancer diagnosis initiating single-day and multi day LEC for the first time between 4/1/2007 and 3/31/2009 were identified from the Premier Perspective database. CINV events (ICD-9-CM codes for nausea, vomiting, or volume depletion or CINV-related rescue medications) were assessed descriptively. A generalized linear multivariate regression model was developed, estimating the overall CINV event rate among Group 1 and 2 patients in the follow up period (first of eight chemotherapy [CT] cycles or 6 months). RESULTS: In the follow-up period, out of a total of 10,137 overall CINV events (single-day and multi-day LEC), 8783 events (86.6%) were identified in single-day LEC treated patients. Within single-day LEC treated events, in the first cycle, of 3184 events, 2996 (94.1%) events were delayed. Average number of delayed events per patient remained consistent throughout the eight cycles (3.1 [1st cycle] vs. 2.9 [8th cycle]; P = 0.842]). Among 2439 patients on antiemetic prophylaxis with a 5 HT(3)-RA, 10.1% (n = 247) initiated palonosetron. Regression analysis indicated that Group 1 patients (versus Group 2) had a 15.2% reduction in CINV event rate per CT cycle; P = 0.0403. Study limitations include potential lack of generalizability, absence of data on certain confounders including alcohol consumption and prior history of motion sickness, potential underestimation of incidence of uncontrolled CINV, and inability to draw conclusions pertaining to cause and effect relationship. CONCLUSION: In this retrospective analysis, delayed CINV comprised a major proportion of overall CINV among cancer diagnosed patients on single-day LEC. Additionally, palonosetron prophylaxis was associated with a significantly lower overall CINV event rate versus other 5-HT(3)-RA prophylaxis in single- and multi-day LEC treatment. PMID- 21696264 TI - Multidisciplinary pain education program (MPEP) for chronic pain patients: preliminary evidence for effectiveness and mechanisms of change. AB - OBJECTIVE: There is a need for effective brief interventions in chronic pain patients, and the identification of mechanisms of change. METHOD: In the present study, we tested the effectiveness of MPEP (Multidisciplinary Pain Education Program), a very brief, four-session cognitive-behaviorally based psycho educational intervention for chronic pain using a pre-and post-test design. In addition, pre- to post-treatment change scores were calculated to investigate factors associated with change in pain. Participants of the study were 53 patients with chronic non-cancer pain. Primary outcome measures were (1) pain severity, (2) health perception, and (3) severity of depression. Secondary outcome measures included factors that have been implicated in the maintenance of chronic pain and that might be associated with worse treatment outcome: (1) catastrophizing, (2) kinesiophobia, and (3) action-proneness. RESULTS: Findings provided preliminary evidence for the effectiveness of MPEP in that patients showed significant and clinically meaningful improvements in pain symptoms (F = 24.503, p < 0.001, d = 0.59) and action-proneness (F = 178.504, p < 0.001, d = 1.95), and small improvements in health perception (F = 7.116, p < 0.05, d = 0.30). Furthermore, results showed that changes in catastrophizing (beta = 0.455, p = 0.001) and severity of depression (beta = -0.300, p < 0.05) were independently and significantly associated with changes in pain. However, changes in health perception, kinesiophobia, and action-proneness were not significantly associated with changes in pain (beta = 0.203, ns; beta = 0.003, ns; and beta = 0.154, ns, respectively). Importantly, duration of chronic pain was not related to treatment outcome (beta = 0.070, ns). CONCLUSIONS: Overall, this study provides preliminary evidence for the effectiveness of MPEP and possible mechanisms through which MPEP is effective. Yet, further research is needed to investigate the efficacy of MPEP. PMID- 21696265 TI - Changes in schizophrenia-related hospitalization and ER use among patients receiving paliperidone palmitate: results from a clinical trial with a 52-week open-label extension (OLE). AB - BACKGROUND: Schizophrenia affects ~1.1% of the United States population, resulting in substantial direct, indirect and societal costs. OBJECTIVE: To evaluate hospitalization rates associated with use of paliperidone palmitate (PP). METHODS: Data were from a variable-duration double-blind (DB), randomized, relapse-prevention comparison (NCT00111189) of PP vs. placebo (Pbo), followed by a 1-year open-label extension (OLE). Between-phase change in schizophrenia related hospitalizations was evaluated using data from an investigator-completed questionnaire. Change in hospitalizations using patients before enrollment who participated in the OLE phase was also analyzed. Poisson regression was used to evaluate changes in incidence density within exposure category and by schizophrenia duration. RESULTS: A total of 160 patients in the PP-PP group and 153 in the Pbo-PP group from the DB to the OLE phase were included. Mean age (standard deviation [SD]), gender, and duration of schizophrenia were similar at the start of the DB phase (Pbo: 38.5 years [10.6], 51.0% male, 68.0% >=5 years' duration; PP: 37.3 years [11.4] (p = 0.342); 51.9% male (p = 0.874); 70.0% >=5 years' duration (p = 0.698), respectively. From the DB to the end of the OLE phase, the number of hospitalizations per person-year for patients treated during the DB phase with Pbo significantly declined from 0.27 to 0.06 (78% reduction; p = 0.005). A statistically nonsignificant difference was observed for PP patients treated during the DB phase with PP (0.11-0.04; 63.6% reduction; p = 0.076), compared with the OLE phase. Change from before enrollment to the end of the OLE phase (n = 381) produced similar results (0.35-0.04; 88.6% reduction; p < 0.001). Patients who enroll in a clinical trial may be different from the general population and this may affect the generalizability of results. CONCLUSION: From the double-blind to the open-label phase and from prior to the trial until the end of the open-label phase, hospitalizations significantly decreased for patients with schizophrenia treated with PP. PMID- 21696267 TI - Structured feedback to undergraduate medical students: 3 years' experience of an assessment tool. AB - BACKGROUND: There is a paucity of research on the effects of interactive feedback methods and sustained assessment strategies in formative assessment of students in the workplace. AIMS: To investigate the outcome of long-term use of an assessment tool. METHODS: Retrospective analysis of summarised assessment tools from 3 years of 464 final-year students in general practice. Quantitative data were analysed using non-parametric tests and a multi-level approach. Qualitative data were subjected to content analysis. RESULTS: Students' main deficiencies in the consultation were in the domains of working diagnoses and management plans; however, supervisors emphasised goals of patient-centred communication and structure of the medical interview. As a group, students underestimated their clinical performance, compared to supervisors' judgement. Most students were supplied with specific goals, 58% with specific follow-up feedback. The majority of students and supervisors were satisfied with the assessment strategy. Long term experience with the tool significantly increased the proportion of specific goals and feedback to students, supervisors' stringency of the assessment, and their satisfaction with the tool. CONCLUSIONS: The summarised assessment strategy proved feasible and acceptable with students and supervisors in a continuous attachment with assigned personal supervisors. However, there was room for improvement in supervisors' provision of specific follow-up feedback. PMID- 21696268 TI - Attitudes toward shared decision-making and risk communication practices in residents and their teachers. AB - BACKGROUND: Health professionals' attitudes toward shared decision-making (SDM) are an important facilitator of SDM, but information on these attitudes is limited. AIMS: The purpose of this study is to examine attitudes, education and practices around SDM and risk communication in residents and their teachers. METHOD: A questionnaire was mailed to residents in Swiss hospitals in postgraduate medical training programs assessing risk communication education and SDM. In an Internet survey, teachers of the medical training programs answered questions on SDM and risk communication practices. Data were analyzed with ANOVAs and paired samples t-tests. RESULTS: Significant differences in residents' and teachers' opinions regarding SDM were found between specialties and number of residents in a residency (1-3, 4-10, >=11 residents). Teachers showed a high use of verbal risk communication. Neither residents nor teachers expressed a strong feeling that they lacked the time for decision-making. Residents were significantly more negative about the ability of patients to participate in decision-making compared to their teachers. CONCLUSIONS: As residents are more negative about SDM compared to teachers and teachers do not always use the preferred and best methods for risk communication, more education for teachers and residents is needed to improve communication practices in the future. PMID- 21696266 TI - Impact of rosiglitazone therapy on the lipid profile, glycemic control, and medication costs among type 2 diabetes patients. AB - OBJECTIVE: To investigate the impact of rosiglitazone therapy on lipid profiles, glycemic control, and costs associated with cholesterol-lowering and diabetic medications among Type 2 diabetes mellitus (T2DM) patients in a standard practice setting. METHOD: This retrospective cohort study was conducted using data from the General Practice Research Database during 1999-2006. T2DM patients were classified based on the addition of rosiglitazone versus either metformin or a sulfonylurea ('comparison group') to pre-existing glucose lowering agents. After propensity score matching to control for differences in baseline patient characteristics, 1450 matched pairs were identified. The mean changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), glycosylated hemoglobin A1C (A1C), and daily medication costs were calculated. To investigate the incremental costs for lipid-lowering medications, a two-part model was utilized. RESULTS: The mean changes in TC and A1C for the rosiglitazone and metformin/sulfonylurea groups were 9 vs -10 mg/dL for TC, -2 vs -9 mg/dL for LDL C, and -0.8% vs. -1.2% for A1C, respectively. The mean changes in daily medication costs of glucose- and lipid-lowering drugs were $3.95 for rosiglitazone patients and $0.27 for metformin/sulfonylurea patients. For patients with positive incremental lipid-lowering costs, rosiglitazone use was significantly associated with costs eight times greater than metformin/sulfonylureas. Generalizability of the study is limited due to cost estimates using the national formulary and potential selection bias. CONCLUSIONS: Addition of rosiglitazone to an existing antidiabetic medication regimen improved glycemic control to a lesser extent than metformin/sulfonylurea, and also deteriorated patients' lipid profiles, leading to significantly greater daily costs. Economic evaluations of alternative therapies should consider such costs to estimate the full impact of different therapeutic approaches in diabetes. PMID- 21696269 TI - Improving written and verbal communication skills for international medical graduates: a linguistic and medical approach. AB - BACKGROUND: Adapting to UK communication styles can be difficult for International Medical Graduates (IMGs). Reache Northwest provides education, training and support for internationally trained refugee and asylum seeking health professionals who are looking to return to work in the UK. AIMS: A Safe and Effective Communication Skills course was designed by a team of language teachers and clinicians to provide IMGs with an understanding of the written, verbal and summarisation skills required in the UK work environment. METHODS: A series of language exercises adapted to clinical situations was developed. These increased in complexity to the practical application of language skills in clinical settings using simulated patients. The combination of language and clinical tutors meant that feedback could be given from a language teacher's perspective, the clinical perspective and the cultural context. RESULTS: The combination of language and clinical tutors meant that analysis of communication difficulties could be made from different perspectives and detailed, specific feedback could be given to each student in these areas. CONCLUSION: Using a combined linguistic and clinical approach can provide solutions to clinical communication problems that may otherwise be missed. This strategy could be extended to cover communication areas in other contexts. PMID- 21696270 TI - Assessing self-regulatory processes during clinical skill performance: a pilot study. AB - BACKGROUND: Self-regulated learning (SRL) is a cyclical process involving the proactive use of strategies and feedback to optimise performance. Previous research has used SRL microanalysis to assess and inform the training of athletic skills but there has been no previous research in clinical contexts. AIMS: The aim of this pilot study was to evaluate the use SRL microanalysis to assess the regulatory profiles of students who were successful and unsuccessful in a venipuncture task. METHOD: A SRL microanalysis protocol was administered to seven 3rd-year undergraduate medical students whilst they performed a venipuncture on a simulation mannequin arm. RESULTS: The use of SRL microanalytic questions had good inter-rater reliability. Students who were successful in venipuncture had high levels of strategic thinking before, during and after the clinical task, whereas the students who struggled on this task tended to focus on outcomes. CONCLUSIONS: The results shown in this study mirror the findings from previous research using SRL microanalysis. SRL microanalysis has strong potential as a structured assessment technique targeting the self-regulatory processes underlying clinical skill performance. Further research is recommended, especially on how the assessment of self-regulatory skills can be used to guide training for struggling students. PMID- 21696271 TI - Plagiarism: a case study of quality improvement in a taught postgraduate programme. AB - BACKGROUND: Plagiarism is a common issue in education. Software can detect plagiarism but little is known about prevention. AIMS: To identify ways to reduce the incidence of plagiarism in a postgraduate programme. METHODS: From 2006, all student assignments were monitored using plagiarism detection software (Turn It In) to produce percentage text matches for each assignment. In 2007, students were advised software was being used, and that plagiarism would result in penalties. In 2008, students attending a key module took part in an additional interactive seminar on plagiarism. A separate cohort of students did not attend the seminar, allowing comparison between attendees and non-attendees. RESULTS: Between 2006 and 2007, mean percentage text match values were consistent with a stable process, indicating advice and warnings were ineffective. Control chart analysis revealed that between 2007 and 2008, mean percentage text match changes showed a reduced text match in all nine modules, where students attended the interactive seminar, but none where students did not. This indicated that the interactive seminar had an effect. In 2008, there were no occurrences of plagiarism. Improvements were maintained in 2009. CONCLUSIONS: Advice and warnings against plagiarism were ineffective but a subsequent interactive seminar was effective at reducing plagiarism. PMID- 21696272 TI - Teaching conceptions and approaches to teaching of medical school faculty: the difference between how medical school teachers think about teaching and how they say that they do teach. AB - BACKGROUND: It is often assumed that the way teachers approach their teaching is determined by the way they think about learning. This study explores how teachers of an undergraduate medical programme (UMP) think about learning, how they approach teaching and whether their conceptions of learning relate to their teaching approaches. METHODS: Quantitative data of academic teachers involved in the undergraduate programme in medicine were collected and analysed. We used a questionnaire designed to measure teachers' conceptions of their own learning (COL) and of student learning as well as teachers' approaches to teaching (AT). RESULTS: Teachers of the medical undergraduate programme hold a variety of COL, of how students learn and their AT. No significant correlations were found between teachers' conceptions of learning and their AT. CONCLUSIONS: Although UMP teachers' ideas on learning and teaching are very diverse, some of their conceptions are interrelated. Teachers' ideas on their own learning is sometimes but not always - related to how they think about student learning. But most importantly, the way UMP teachers think about learning is not automatically converted into the way they approach teaching. PMID- 21696273 TI - The Ventriloscope(r) as an innovative tool for assessing clinical examination skills: appraisal of a novel method of simulating auscultatory findings. AB - BACKGROUND: Simulation is increasingly used as a teaching tool and in assessment. The Ventriloscope(r) (VS) is a new auscultation simulator. This modified stethoscope allows pre-recorded sounds (activated wirelessly) to be integrated with a simulated patient (SP, professional actor). AIMS: This study explores the instrument's potential for overcoming limitations of current objective structured clinical examination (OSCE) assessment by increasing validity while retaining reliability. METHODS: After training SPs to synchronise the device with their breathing (recreating abnormal signs), we evaluated the VS during a third year undergraduate medical student OSCE. Students (n = 385), examiners (n = 19) and SPs (n = 10) completed post-exam questionnaires which were analysed using a coding framework. OSCE performance data were analysed using Stata 10. RESULTS: When 'compared to their usual stethoscope' 40% of students found no difference in using the VS; 69% found it easier to identify sounds; 68% found examination with the VS very or fairly realistic when 'compared to examining a real patient'. Examination scores were comparable with other OSCE stations. CONCLUSIONS: The VS reliably provided consistent 'abnormal' auscultatory signs within an OSCE framework. Using a VS may increase OSCE validity, allowing examiners to assess students' application of knowledge in a realistically simulated setting. The VS can help bridge the gap between simulation and real patients. PMID- 21696274 TI - Patients' views on student participation in general practice consultations: a comprehensive review. AB - BACKGROUND: Recruiting general practitioners (GPs) to host students for their clerkship is difficult. GPs often assume patients dislike consulting a student doctor. AIM: To systematically review the evidence on patient satisfaction regarding the presence/participation of a student during a consultation in general practice. METHOD: Medline search (January 1990 to July 2010). One reviewer extracted data from the articles fulfilling the criteria which were set, and a second reviewer checked these for accuracy. Due to heterogeneity a quantitative synthesis could not be performed. RESULTS: Sixteen studies fulfilled the criteria. The majority of patients gave permission for the presence or participation of a student-doctor. Emotional problems and the need for an intimate examination were the main reasons for refusal. Satisfaction was high. Benefits the patients mentioned were: more time, a more thorough physical examination, better patient education and getting a second opinion. Altruism also played a role. CONCLUSION: In general, the attitude of patients towards student doctors is positive. There is a general reluctance to see a student-doctor for emotional or intimate problems. Future research should focus on the effect of the preceptor's presence in the latter case. Another interesting topic would be the effect on consent and appreciation of the student-doctor when there are differences in cultural background between patient and student. PMID- 21696275 TI - Integration of academic learning and service development through guided projects for rural practitioners in India. AB - BACKGROUND: Christian Medical College Vellore (CMC) aspired through its Fellowship in Secondary Hospital Medicine (FSHM), a 1-year distance-learning program, to integrate academic learning and service development through guided projects for junior doctors working in small rural hospitals. AIM: The purpose of this article is to report the evaluation of the effectiveness of the project work in the FSHM program. METHOD: Mixed method evaluation was done using focus group discussion with students, written surveys for students and faculty, and telephone interviews with students and medical superintendents. Evidence for validity was gathered for the written survey. Criteria for trustworthiness were applied for the qualitative data analysis. RESULTS: The major strengths of the project work identified were that students became aware of local health problems and how to deal with them, learned to work as a team, and had a sense of doing something useful. Recommendations for improvement were to have more interactions between guides and students. The benefits of projects to the hospital were providing improved clinical care, improved health systems, cost effective care management and benefits to the community. CONCLUSIONS: Service learning through guided project work should be incorporated into distance-learning educational programs for junior doctors working in rural hospitals. PMID- 21696276 TI - Tomorrow's curriculum for tomorrow's doctors. PMID- 21696277 TI - Developing a medical school: expansion of medical student capacity in new locations: AMEE Guide No. 55. AB - BACKGROUND: A concern about an impending shortage of physicians and a worry about the continued maldistribution of physicians to medically underserved areas have encouraged the expansion of medical school training places in many countries, either by the creation of new medical schools or by the creation of regional campuses. AIMS: In this Guide, the authors, who have helped create new regional campuses and medical schools in Australia, Canada, UK, USA, and Thailand share their experiences, triumphs, and tribulations, both from the views of the regional campus and from the views of the main Medical School campus. While this Guide is written from the perspective of building new regional campuses of existing medical schools, many of the lessons are applicable to new medical schools in any country of the world. Many countries in all regions of the world are facing rapid expansion of medical training facilities and we hope this Guide provides ideas to all who are contemplating or engaged in expanding medical school training places, no matter where they are. DESCRIPTION: This Guide comprises four sections: planning; getting going; pitfalls to avoid; and maturing and sustaining beyond the first years. While the context of expanding medical schools may vary in terms of infrastructure, resources, and access to technology, many themes, such as developing local support, recruiting local and academic faculty, building relationships, and managing change and conflict in rapidly changing environments are universal themes facing every medical academic development no matter where it is geographically situated. FURTHER INFORMATION: The full AMEE Guide, printed separately, in addition contains case examples from the authors' experiences of successes and challenges they have faced. PMID- 21696278 TI - Undergraduate medical education in Cyprus: the introduction of two medical schools. AB - BACKGROUND: Plans are underway to open the first two medical schools in Cyprus, a small island nation in the eastern Mediterranean. Two schools are planned: a private one which will offer graduate-only entry and provide a 4-year course and a state one which will admit school leavers for a 6-year course. AIM: The article aims to examine some of the arguments that led to this development and how this fits into the health education policy of Cyprus. METHOD: Information was gathered through searching PubMed, Google, international and local press using several keywords. The most recent search was in March 2011. Further information was sourced directly from publications and press releases from the relevant universities, institutions and regulatory bodies such as the Cyprus Medical Council and the Cyprus Statistical Service. DISCUSSION: Key questions discussed include the small size of the country, the size and number of medical schools and the impact on research. Comparisons are drawn with other countries and their experience. PMID- 21696279 TI - AMEE 2010 symposium: medical student education in the twenty-first century - a new Flexnerian era? AB - As we mark the 100th anniversary of the Flexner report which revolutionized the process of medical education, there is again concern that we face a critical need for change in the process of medical education in order to meet the needs of learners, teachers, and patients. In this symposium, panelists shared perspectives on medical education reform from throughout the world, including The Future of Medical Education in Canada, the role of regulators in contributing to reform, the evolution of accreditation standards, the current state of medical education in Southeast Asia, and the perspectives of a medical student on medical education reform. In the "Audience discussion" section, themes emerged surrounding medical education as a social good, the need for governmental support of medical education, the cost of medical education and the rise of for-profit medical schools, and embracing a broader view of health professional education. There remain remarkable parallels in calls for reform in medical education at the turn of the twentieth and twenty-first centuries but education which is patient centered and actively involves the voices of our patients and our students is likely to be a hallmark. PMID- 21696280 TI - Educating physicians for the future: Carnegie's calls for reform. AB - In both 1910 and 2010, The Carnegie Foundation for the Advancement of Teaching used existing educational innovations and learning theory to point the way to the future of medical education. Flexner's transformative report of 1910 was strongly influenced by the innovative curriculum at Johns Hopkins University School of Medicine and by educational principles of the Progressive Era. In 1912, Flexner wrote a similar critique of medical education in Europe. These two reports have powerfully shaped medical education for the past century. Yet much has changed since then, which prompted The Carnegie Foundation for the Advancement of Teaching to commission another report that was published in 2010. Drawing on contemporary educational innovations and research from the learning sciences, the authors make four recommendations for reform: (1) standardize on learning outcomes while individualizing the learning process, (2) integrate formal knowledge with clinical experience, (3) imbue habits of inquiry and improvement to achieve lifelong learning and excellence, and (4) explicitly cultivate the formation of professional identity. In this article, the author describes educational innovations and educational principles relevant to each of these four recommendations. PMID- 21696281 TI - The doctor we are educating for a future global role in health care. AB - Health care is deficient in many parts of the world, in money, facilities and manpower. In wealthy countries, the costs and complexity of health care are increasing unsustainably. Nevertheless, richer countries claim an ever escalating need for doctors, who migrate from poorer countries, with an ensuing global health workforce crisis. These political, social, demographic and international events necessitate a discussion on the roles and values of the doctor in the world today. The international mobility of both doctors and patients underlines the need for a global definition. Only when these roles and values are agreed in a global perspective, will medical education be capable of producing a professional equipped to fulfil that role. This doctor will then be useful both as a leader and as a member of health care teams with a flexible composition, related to resources and needs of particular regions, and at the same time be able to practise within any given health care system. An international task-force of the World Federation for Medical Education (WFME) is working to agree themes relevant to the role of the doctor globally, and developing a statement that can be used world-wide, and used to develop medical education policy. PMID- 21696282 TI - The curriculum for the doctor of the future: messages from the clinician's perspective. AB - BACKGROUND: Medical curricula should focus on the future of health care. Contemporary competency frameworks for curriculum design such as Canadian Medical Education Directions for Specialists (CanMEDS), ACGME and Tomorrow's Doctors share this vision by stressing generic competencies. AIM: The objective of this study was to investigate how well a contemporary competency framework fits in with clinicians' perspectives on future health care. METHODS: Using a strategic planning approach, a semi-structured open-ended questionnaire on the future of their profession was sent to 102 Dutch gynecologists. Through inductive analysis, a future perspective and its needed competencies were identified and compared to the CanMEDS framework. RESULTS: The 62 responses showed content validity for the CanMEDS roles. Additionally, two roles were identified: advanced technology user and entrepreneur. Within the role Communicator, the focus will change through more active patient participation. The roles Collaborator and Manager are predicted to change in focus because of an increase of complex interdisciplinary teamwork and leadership roles. CONCLUSION: By studying the Dutch gynecologists' perspective of the future in a strategic planning approach, two additional roles and focus areas within a contemporary competency framework were identified. The perspective of clinicians on future health care provides valuable messages on how to design future-proof curricula. PMID- 21696283 TI - Training healthcare professionals for the future: internationalism and effective inclusion of global health training. AB - There has been a continuing rise in recent years of the number of medical schools in the developed world offering 'global health' teaching to its students. Yet, the term itself is used in a number of contexts and as yet no clear consensus on what constitutes an appropriate or successful global health education programme has been reached. Approaches to sustainable internationalisation of medical curricula include the expansion of not only opportunities for training in specific global health topics, but also the development of broader generic graduate attributes including global citizenship and ethical, cultural and social responsibility. Key components for successful implementation of such an educational framework includes a breadth of educational approach to effect truly integrated and effective curricular internationalisation. That such programmes can offer benefits is appreciated by both faculty and students alike, but there is also a burgeoning concern about potential negative effects of socially and culturally insensitive programmes. We explore three potential pedagogic approaches to the subject; Model A: an 'additive' or contributory model of global health content (the commonest current approach), Model B: an 'integrated' approach and Model C: the more challenging 'transformative' approach requiring institutional as well as programme flexibility. PMID- 21696284 TI - Building expertise using the deliberate practice curriculum-planning model. AB - This article reviews critical shortcomings of the current system for the education of physicians. The authors propose and describe a deliberate practice curriculum-planning model for educating healthcare professionals to respond to the demands of modern healthcare. The model integrates contemporary educational philosophies, creating the curricular framework outlined as follows: (1) determine the overall competencies expected of learners at graduation from the program; (2) for program components, develop outcome-based objectives that stem from the overall competencies; (3) to fulfill the objectives, design appropriate content using a variety of learner-centered instructional methods; (4) stimulate acquisition of knowledge, skills, and attitudes through practice accompanied by formative assessment, reflection, and mentoring; (5) establish milestones for summative assessment accompanied by feedback, reflection, and mentoring. PMID- 21696285 TI - A patient perspective on the curriculum and training the future health professional. AB - Patients' expectations are explored through a personal reflection. The continuing mismatch between expectation and what is found in practice is highlighted. The author challenges the medical curriculum to put patient contact at its heart and to inspire future doctors to serve patients better in every way. PMID- 21696286 TI - The story of health care's Achilles' heel. AB - Medical education for future practice is addressed with the use of a narrative from the obstetric field. Medical expertise is present within the health care teams described. Due to inappropriate use of hierarchy and insufficient team work knowledge is not effectively being shared. A plea is made for a reappraisal of generic competencies in medical education and training. PMID- 21696287 TI - Asian perspectives for reflection. PMID- 21696288 TI - Saudi Meds: a competence specification for Saudi medical graduates. AB - A national competence framework has been developed by medical schools in the Kingdom of Saudi Arabia. The framework has seven domains - approach to daily Practice, Dr and patient, Dr and community, communication skills, professionalism, Dr and information technology, Dr and research. The framework will guide curriculum development and assessment in the Kingdom and ensure that medical education adapts to changing needs. The creation of a national framework promises the delivery of equivalent standards between medical schools while at the same time guaranteeing the schools' autonomy. PMID- 21696289 TI - Undergraduate education in trauma medicine: the students' verdict on current teaching. AB - BACKGROUND: Junior doctors are amongst the first healthcare professionals to assess and provide initial hospital care for multiply injured patients. Despite this, no requirements are placed upon UK medical schools for training undergraduates in aspects of trauma care. Medical students have increasingly been attending a number of student-organised extracurricular 'trauma conferences' in order to supplement their knowledge in this area. AIM: To provide insight into the quality and quantity of trauma medicine teaching currently received at the undergraduate level by directly eliciting the experiences of medical students. If a perceived lack of trauma teaching is driving students to seek extracurricular exposure to trauma education, what lessons can be gleaned for medical schools? METHODS: A voluntary, anonymous, quantitative questionnaire was used to collect data from 218 medical students from across the UK. RESULTS: Among our results, 60% of final-year students were shown to have received fewer than 5 h of teaching in trauma medicine. Basic cervical-spine immobilisation teaching had not been received by 62%, while a third had not received Basic Life Support (BLS) training. The majority of students believed their training in trauma medicine not to be adequate and would like to see more teaching offered by their respective medical schools. CONCLUSION: Students report a paucity of teaching in trauma medicine. Our findings corroborate previous concerns that junior doctors are under-prepared for managing trauma patients, and support the repeated calls made in the scientific literature to include organised teaching of trauma medicine in the undergraduate curriculum. PMID- 21696290 TI - Cost in assessment -important to examinees who are paying to sit and governments who are paying to set. PMID- 21696291 TI - eMedical Teacher. PMID- 21696293 TI - Green approach for nanoparticle biosynthesis by fungi: current trends and applications. AB - In recent years, the green approach of nanoparticle synthesis by biological entities has been gaining great interest over various other physico-chemical methods, which are laden with many disadvantages. The important challenging issues in current nanotechnology include the development of reliable experimental techniques for the synthesis of nanoparticles of different compositions and sizes along with high monodispersity. Biological systems offer unique promising features to tailor nanomaterials with predefined properties. Fungi are the favorite choice of microorganisms due to the wide variety of advantages they offer over bacteria, yeast, actinomycetes, plants, and other physico-chemical techniques. The use of microorganisms for the deliberate synthesis of nanoparticles is a fairly new and exciting area of research with considerable potential for further development. This review describes an overview of the current green approaches for the synthesis of nanoparticles with particular emphasis on fungi, which are gaining worldwide popularity as nano-factories for the green synthesis of nanoparticles. PMID- 21696295 TI - Marked response to single agent trastuzumab in a patient with metastatic HER-2 gene amplified rectal cancer. AB - Overexpression or HER-2 gene amplification occurs in approximately 25% of invasive breast cancers and predicts response to the targeting therapeutic antibody trastuzumab (1). In this report, trastuzumab was used in the treatment of a patient with metastatic colorectal cancer harboring HER-2 gene amplification and overexpression. There was a marked radiographic response to the trastuzumab. If a larger series confirms the efficacy of trastuzumab use in patients with colorectal cancers with HER-2 gene amplification, trastuzumab could help improve the outlook for patients with this unusual colorectal cancer variant. PMID- 21696294 TI - In vitro release characteristics and cellular uptake of poly(D,L-lactic-co glycolic acid) nanoparticles for topical delivery of antisense oligodeoxynucleotides. AB - The efficacy of antisense oligodeoxynucleotides (AsODNs) is compromised by their poor stability in biological fluids and the inefficient cellular uptake due to their size and negative charge. Since chemical modifications of these molecules have resulted in a number of non-antisense activities, incorporation into particulate delivery systems has offered a promising alternative. The aim of this study was to evaluate various poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles for AsODN entrapment and delivery. PLGA nanoparticles were prepared using the double emulsion solvent evaporation method. The influence of formulation parameters such as PLGA concentration and volume ratio of internal aqueous phase volume (Va1) to organic phase volume (Vo) to external aqueous phase volume (Va2) on particle size, polydispersity index (PDI) and zeta potential (ZP) was investigated using a full factorial study. The particle size increased with increasing PLGA concentrations and volume ratios, with an interaction detectable between the two factors. AsODN entrapment efficiencies ranged between 49.97% and 54.95% with no significant difference between various formulations. By fitting the in vitro release profiles to a dual first order release model it was shown that the AsODN release occurred via two processes: a diffusion controlled process in the early phase (25 to 32% within one day) and a PLGA degradation process in the latter (39 to 70% after 14 days). Cellular uptake studies using primary corneal epithelial cells suggested active transport of nanoparticles via endocytosis. PLGA nanoparticles therefore show potential to successfully entrap AsODNs, transport them into cells and release them over time due to polymer erosion. PMID- 21696296 TI - A phase II trial of panobinostat, a histone deacetylase inhibitor, in the treatment of patients with refractory metastatic renal cell carcinoma. AB - PURPOSE: To evaluate the activity of panobinostat in refractory renal carcinoma. PATIENTS AND METHODS: Patients with advanced clear cell renal carcinoma who had received previous therapy with at least one angiogenesis inhibitor and one mTOR inhibitor were treated with panobinostat 45 mg orally twice a week, and were reevaluated after 8 weeks. RESULTS: Twenty patients were treated with no objective responses. All patients progressed or stopped treatment prior to the 16 week reevaluation. Panobinostat was generally well-tolerated. CONCLUSION: Panobinostat had no activity in this group of patients with refractory renal carcinoma. Further development of panobinostat in renal carcinoma is not recommended. PMID- 21696297 TI - PTEN, pAKT, and pmTOR expression and subcellular distribution in primary renal cell carcinomas and their metastases. AB - The present study evaluated pAKT, pmTOR, and PTEN expression in a tissue microarray of primary renal cell carcinomas (PRCCs), their metastases, and normal renal parenchyma (NRP) (N = 45) by means of immunohistochemistry. Metastases in most subcellular compartments showed comparable and stronger expression for pAKT, pmTOR, and PTEN than PRCC and NRP, which was even more pronounced in patients with high-risk Memorial Sloan-Kettering Cancer Center (MSKCC) score. Furthermore, most subcellular compartments showed no differences between lymphogenous, haematogenous, synchronous, and metachronous metastases, which is interesting with regard to sensitivity to mTOR inhibitor therapy in metastasized RCCs with alterations in the PI3K/AKT pathway. PMID- 21696298 TI - Dehiscence and fenestration in skeletal Class I, II, and III malocclusions assessed with cone-beam computed tomography. AB - OBJECTIVE: To test the null hypothesis that the presence of dehiscence and fenestration was not different among patients with skeletal Class I, II, and III malocclusions. MATERIALS AND METHODS: In this retrospective study, a total of 123 cone-beam computed tomography (CBCT) images were obtained with an iCAT scanner (Imaging Sciences International, Hatfield, Pa). Patients with normal vertical patterns were classified according to dental malocclusion and ANB angle. Class I comprised 41 patients-21 girls and 20 boys (mean age, 22.4 +/- 4.5 years); Class II comprised 42 patients-22 girls and 20 boys (mean age, 21.5 +/- 4.2 years); and Class III comprised 40 subjects-22 girls and 18 boys (mean age, 22.1 +/- 4.5 years). A total of 3444 teeth were evaluated. Analysis of variance and Tukey's test were used for statistical comparisons at the P < .05 level. RESULTS: Statistical analysis indicated that the Class II group had a greater prevalence of fenestration than the other groups (P < .001). No difference was found in the prevalence of dehiscence among the three groups. Although fenestration had greater prevalence in the maxilla, more dehiscence was found in the mandible for all groups. In Class I, alveolar defects (dehiscence, fenestration) were matched relatively in both jaws. Furthermore, Class II and Class III subjects had more alveolar defects (41.11% and 45.02%, respectively) in the mandible. Dehiscences were seen with greater frequency in the mandibular incisors of all groups. CONCLUSION: The null hypothesis was rejected. Significant differences in the presence of fenestration were found among subjects with skeletal Class I, Class II, and Class III malocclusions. Fenestrations had greater prevalence in the maxilla, but more dehiscences were found in the mandible. PMID- 21696299 TI - Effect of redesigned Indian mixed meals on blood glucose and insulin levels in normal versus type 2 diabetic subjects--a comparative study. AB - This study reports the glycemic as well as insulinemic response of seven types of Indian vegetarian mixed meals (MMs). Each of the seven MMs was given at weekly intervals to both normal and type 2 diabetic subjects on the same day to reduce variations in food preparations. In this Indian study, each MM consisted of five to six food items with a low glycemic index (GI) ranging from 28.98 to 46.12%, glycemic load ranging from 15.58 to 23.8 g and energy value (calculated) from each test meal ranging from 403 to 502 kcal. All the seven meals were found to have postprandial glycemic control in normal subjects which ranged from 86 to 102.4 mg%, and a good postprandial glycemic control in type 2 diabetic subjects which ranged from 132.8 to 148.4 mg%, and hence appropriate for routine consumption by diabetic subjects. The glycemic and insulinemic pattern of all these MMs was similar in normal and diabetic subjects. Sustained intake of such low GI MMs by diabetic can result in good glycemic control. PMID- 21696300 TI - Estimation of exposure to furan in the Spanish population. AB - The presence of furan in foods has received recent attention because of its association with harmful effects to human health. This compound, which is originated as a consequence of thermal treatment, is mainly found in canned, jarred, toasted and fried foods. The aim of this study was to estimate the exposure to furan in the Spanish population and to study the evolution of furan content in the main categories of foods in recent years, taking into account changes in dietary patterns. With respect to exposure to furan in the Spanish population from 2001 to 2009, no large differences were found. The maximum furan exposure recorded in this study (1.95 MUg/kg bw/day) is lower than the 'no observable adverse effect level' of 0.08 mg/kg bw/day determined in the studies of experimental animals, and is close to the reported acceptable daily intake of 2 MUg/kg bw/day. PMID- 21696301 TI - Enhancement of nutritional value of finger millet-based food (Indian dosa) by co fermentation with horse gram flour. AB - Co-fermentation of finger millet with horse gram was carried out to produce inexpensive protein-rich food (dosa-an Indian breakfast food). Natural fermentation of finger millet-horse gram flour blend in different proportions (2:1, 3:1, 4:1 and 5:1) was performed for 24 h. Biochemical analysis showed reasonable drop in pH (6.6-4.2) and starch content (25.52%) with considerable augment in titratable acidity (0.168-1.046%), soluble proteins (1.1-fold) and free amino acids (2.6-fold) at 16 h. Lactic acid bacteria dominated yeast counts throughout the fermentation accompanied by a decrease in total soluble and reducing sugars. Total essential amino acids increased 1.1-fold at 16-h fermentation with protein containing 48.68% of essential amino acids over total amino acids. Lysine increased from 5.87 to 6.73 g of amino acid/100 g of total amino acids. Dosa, prepared from 16-h fermented batter, showed better sensory attributes for 4:1 ratio. The formulated new product might be used to overcome the protein-energy malnutrition problems. PMID- 21696303 TI - Videos in clinical medicine. Conscious sedation for minor procedures in adults. PMID- 21696302 TI - In-vitro neuroprotective properties of the Maydis stigma extracts from four corn varieties. AB - Neuroprotective effect of the ethyl acetate and ethanol extracts of the silks of four Zea mays L. varieties (var. intendata, var. indurata, var. everta and var. saccharata) was evaluated by acetylcholinesterase, butrylcholinesterase and tyrosinase inhibitions and by antioxidant activity tests against 2,2-diphenyl-1 picrylhydrazyl and superoxide as well as two iron-related antioxidant methods (iron-chelation capacity and ferric-reducing antioxidant power). Total phenol and flavonoid contents in the extracts were determined spectrophotometrically. PMID- 21696304 TI - Images in clinical medicine. Laryngopharyngeal edema. PMID- 21696305 TI - Front-of-package nutrition labeling--an abuse of trust by the food industry? PMID- 21696306 TI - Changes in diet and lifestyle and long-term weight gain in women and men. AB - BACKGROUND: Specific dietary and other lifestyle behaviors may affect the success of the straightforward-sounding strategy "eat less and exercise more" for preventing long-term weight gain. METHODS: We performed prospective investigations involving three separate cohorts that included 120,877 U.S. women and men who were free of chronic diseases and not obese at baseline, with follow up periods from 1986 to 2006, 1991 to 2003, and 1986 to 2006. The relationships between changes in lifestyle factors and weight change were evaluated at 4-year intervals, with multivariable adjustments made for age, baseline body-mass index for each period, and all lifestyle factors simultaneously. Cohort-specific and sex-specific results were similar and were pooled with the use of an inverse variance-weighted meta-analysis. RESULTS: Within each 4-year period, participants gained an average of 3.35 lb (5th to 95th percentile, -4.1 to 12.4). On the basis of increased daily servings of individual dietary components, 4-year weight change was most strongly associated with the intake of potato chips (1.69 lb), potatoes (1.28 lb), sugar-sweetened beverages (1.00 lb), unprocessed red meats (0.95 lb), and processed meats (0.93 lb) and was inversely associated with the intake of vegetables (-0.22 lb), whole grains (-0.37 lb), fruits (-0.49 lb), nuts (-0.57 lb), and yogurt (-0.82 lb) (P<=0.005 for each comparison). Aggregate dietary changes were associated with substantial differences in weight change (3.93 lb across quintiles of dietary change). Other lifestyle factors were also independently associated with weight change (P<0.001), including physical activity (-1.76 lb across quintiles); alcohol use (0.41 lb per drink per day), smoking (new quitters, 5.17 lb; former smokers, 0.14 lb), sleep (more weight gain with <6 or >8 hours of sleep), and television watching (0.31 lb per hour per day). CONCLUSIONS: Specific dietary and lifestyle factors are independently associated with long-term weight gain, with a substantial aggregate effect and implications for strategies to prevent obesity. (Funded by the National Institutes of Health and others.). PMID- 21696307 TI - Telaprevir for previously untreated chronic hepatitis C virus infection. AB - BACKGROUND: In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. METHODS: In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). RESULTS: Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. CONCLUSIONS: Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.). PMID- 21696309 TI - Clinical practice. Chronic hepatitis C infection. PMID- 21696310 TI - n-3 fatty acids in cardiovascular disease. PMID- 21696308 TI - Telaprevir for retreatment of HCV infection. AB - BACKGROUND: Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. METHODS: In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug. RESULTS: Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). CONCLUSIONS: Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.). PMID- 21696311 TI - Images in clinical medicine. Knuckle pads. PMID- 21696312 TI - Case records of the Massachusetts General Hospital. Case 19-2011. A 4-year-old Haitian boy with vomiting and diarrhea. PMID- 21696313 TI - Smokers with interstitial lung abnormalities. PMID- 21696314 TI - Smokers with interstitial lung abnormalities. PMID- 21696316 TI - Weight loss and exercise in obese older adults. PMID- 21696317 TI - Weight loss and exercise in obese older adults. PMID- 21696319 TI - Nurse staffing and inpatient hospital mortality. PMID- 21696320 TI - Nurse staffing and inpatient hospital mortality. PMID- 21696322 TI - Prevalence of smoking in China in 2010. PMID- 21696323 TI - Screening for increased protein thiol oxidation in oxidatively stressed muscle tissue. AB - Elevated oxidative stress can alter the function of proteins through the reversible oxidation of the thiol groups of key cysteine residues. This study evaluated a method to scan for reversible protein thiol oxidation in tissue by measuring reduced and oxidized protein thiols. It assessed the responsiveness of protein thiols to oxidative stress in vivo using a dystrophic (mdx) mouse model and compared the changes to commonly used oxidative biomarkers. In mdx mice, protein thiol oxidation was significantly elevated in the diaphragm, gastrocnemius and quadriceps muscles. Neither malondialdehyde nor degree of glutathione oxidation was elevated in mdx muscles. Protein carbonyl content was elevated, but changes in protein carbonyl did not reflect changes in protein thiol oxidation. Collectively, these data indicate that where there is an interest in protein thiol oxidation as a mechanism to cause or exacerbate pathology, the direct measurement of protein thiols in tissue would be the most appropriate screening tool. PMID- 21696324 TI - Telescoping the origins of obesity to women's bodies: how gender inequalities are being squeezed out of Barker's hypothesis. AB - AIM: This paper traces the genealogy of the Barker hypothesis and its intersections with popular representations of scientific discourses about pregnancy and maternal obesity. METHOD: Drawing on Foucault's genealogical method, this study examines the historical 'descent' of the developmental origins of adult disease and its initial grounding in structural factors of gender inequality and low socioeconomic status. RESULTS: In the more recent reproductive medicine literature, Barker's hypothesis has been used to understand the causes and consequences of foetal over-nutrition and has shifted its focus from social determinants to individual, gendered bodies. The print media has gainfully employed this conceptualization of obesity and, in doing so, placed women, and mothers in particular, as causal agents in the reproduction of obesity across generations. Such a 'common sense' understanding of obesity production and reproduction means that both the scientific literature and the public understanding of science has inadvertently assisted in putting women forward as the transmitters of obesity across generations. CONCLUSIONS: This powerful telescoping of the origins of obesity to women's bodies and their appetites is in stark contrast to earlier foci on gender inequalities and changing women's circumstances. PMID- 21696325 TI - Fat and muscle mass in different groups of pre-pubertal and pubertal rural children. Cross-cultural comparisons between Sahelian (rural Senegal) and Amazonian (Beni River, Bolivia) children. AB - BACKGROUND: An increase in fat accretion is essential for triggering the puberty spurt. Hence, nutritional constraints may influence puberty timing. AIM: To measure changes in fat and muscle mass in children living in natural environments but with different nutritional exposures. METHODS: Cross-comparisons of children from rural Senegal and lowland (Amazonian) Bolivia were carried out. Anthropometric measurements of stature, weight, four subcutaneous skin-folds (triceps, biceps, subscapular, supra-iliac) and arm circumference were made. Children were divided into two age groups (5-9.9-year-olds or 'pre pubescents' (n = 381) and 10-15-year-olds or 'pubescents' (n = 692)). RESULTS: Senegalese girls menstruated later than Bolivian girls and Senegalese boys also matured later than Bolivian boys. Bolivian children displayed more fat and muscle before puberty and during puberty than the Senegalese. They also had more fat deposited on the trunk. There were substantial differences in living conditions and nutritional patterns between both locations. In Senegal, nutritional stress is likely to appear early during in utero life and to persist throughout the growth period, including puberty. This leads to a deficit in fat accretion before and during puberty that is associated with a considerable delay in puberty occurrence. In Bolivia, such stress is far less severe. CONCLUSION: Variability in puberty should be analysed taking into account these differences. PMID- 21696326 TI - Socioeconomic status and body size among women in Honduran Miskito communities. AB - BACKGROUND: This study investigates evidence of the nutrition transition among women in Miskito communities on the northeastern coast of Honduras. AIM: The hypothesis that socioeconomic status (SES) is positively associated with body size and fatness is tested; and dietary and physical activity patterns are examined among SES groups. SUBJECTS AND METHODS: An anthropometric survey was conducted with 200 non-pregnant women following standard procedures. Dietary intake and physical activity data were collected using 24-hour recall methods. Women were categorized into three SES groups (high, medium and low) based on economic and social attributes. Differences in anthropometric measures, diet and physical activity among SES groups were analysed. RESULTS: More than 70% (n = 142) of women in the sample were overweight or obese. Mean height, weight, skin fold thicknesses, arm and calf circumferences, percentage body fat and upper-arm fat area were significantly greater among high SES women than low SES women. Women with high SES had lower rates of physical activity and higher rates of obesity, perceived food sufficiency, meat consumption, milk/dairy intake and general dietary diversity. CONCLUSION: High SES women were significantly fatter than low SES women; and variation observed among groups is likely related to different patterns of dietary intake and physical activity. PMID- 21696327 TI - Comparative effectiveness research and patients with multiple chronic conditions. PMID- 21696328 TI - Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. AB - BACKGROUND: We describe an outbreak of gastroenteritis and the hemolytic-uremic syndrome caused by Shiga-toxin-producing Escherichia coli in Germany in May, June, and July, 2011. The consumption of sprouts was identified as the most likely vehicle of infection. METHODS: We analyzed data from reports in Germany of Shiga-toxin-producing E. coli gastroenteritis and the hemolytic-uremic syndrome and clinical information on patients presenting to Hamburg University Medical Center (HUMC). An outbreak case was defined as a reported case of the hemolytic uremic syndrome or of gastroenteritis in a patient infected by Shiga-toxin producing E. coli, serogroup O104 or serogroup unknown, with an onset of disease during the period from May 1 through July 4, 2011, in Germany. RESULTS: A total of 3816 cases (including 54 deaths) were reported in Germany, 845 of which (22%) involved the hemolytic-uremic syndrome. The outbreak was centered in northern Germany and peaked around May 21 to 22. Most of the patients in whom the hemolytic-uremic syndrome developed were adults (88%; median age, 42 years), and women were overrepresented (68%). The estimated median incubation period was 8 days, with a median of 5 days from the onset of diarrhea to the development of the hemolytic-uremic syndrome. Among 59 patients prospectively followed at HUMC, the hemolytic-uremic syndrome developed in 12 (20%), with no significant differences according to sex or reported initial symptoms and signs. The outbreak strain was typed as an enteroaggregative Shiga-toxin-producing E. coli O104:H4, producing extended-spectrum beta-lactamase. CONCLUSIONS: In this outbreak, caused by an unusual E. coli strain, cases of the hemolytic-uremic syndrome occurred predominantly in adults, with a preponderance of cases occurring in women. The hemolytic-uremic syndrome developed in more than 20% of the identified cases. PMID- 21696329 TI - The relationship between binaural benefit and difference in unilateral speech recognition performance for bilateral cochlear implant users. AB - OBJECTIVE: The full benefit of bilateral cochlear implants may depend on the unilateral performance with each device, the speech materials, processing ability of the user, and/or the listening environment. In this study, bilateral and unilateral speech performances were evaluated in terms of recognition of phonemes and sentences presented in quiet or in noise. DESIGN: Speech recognition was measured for unilateral left, unilateral right, and bilateral listening conditions; speech and noise were presented at 0 degrees azimuth. The 'binaural benefit' was defined as the difference between bilateral performance and unilateral performance with the better ear. STUDY SAMPLE: Nine adults with bilateral cochlear implants participated. RESULTS: On average, results showed a greater binaural benefit in noise than in quiet for all speech tests. More importantly, the binaural benefit was greater when unilateral performance was similar across ears. As the difference in unilateral performance between ears increased, the binaural advantage decreased; this functional relationship was observed across the different speech materials and noise levels even though there was substantial intra- and inter-subject variability. CONCLUSIONS: The results indicate that subjects who show symmetry in speech recognition performance between implanted ears in general show a large binaural benefit. PMID- 21696330 TI - Voice gender discrimination provides a measure of more than pitch-related perception in cochlear implant users. AB - OBJECTIVES: (1) To investigate whether voice gender discrimination (VGD) could be a useful indicator of the spectral and temporal processing abilities of individual cochlear implant (CI) users; (2) To examine the relationship between VGD and speech recognition with CI when comparable acoustic cues are used for both perception processes. DESIGN: VGD was measured using two talker sets with different inter-gender fundamental frequencies (F(0)), as well as different acoustic CI simulations. Vowel and consonant recognition in quiet and noise were also measured and compared with VGD performance. STUDY SAMPLE: Eleven postlingually deaf CI users. RESULTS: The results showed that (1) mean VGD performance differed for different stimulus sets, (2) VGD and speech recognition performance varied among individual CI users, and (3) individual VGD performance was significantly correlated with speech recognition performance under certain conditions. CONCLUSIONS: VGD measured with selected stimulus sets might be useful for assessing not only pitch-related perception, but also spectral and temporal processing by individual CI users. In addition to improvements in spectral resolution and modulation detection, the improvement in higher modulation frequency discrimination might be particularly important for CI users in noisy environments. PMID- 21696331 TI - Cyclic adenosine monophosphate responsive element binding protein in post traumatic stress disorder. AB - OBJECTIVES: The cyclic adenosine monophosphate responsive element binding (CREB) protein is a transcription factor involved in different neural processes, such as learning, neuroplasticity and the modulation of stress response. Alterations in the CREB pathway have been observed in the brains and lymphocytes of patients affected by depression and alcohol abuse. Given the lack of information, our study aimed at investigating the levels of total and activated CREB protein in lympho-monocytes of 20 drug-free patients suffering from post-traumatic stress disorders (PTSD), as compared with 20 healthy control subjects. METHODS: Blood samples were collected from patients and healthy control subjects on the same time and lympho-monocytes were isolated according to standardized methods. CREB protein levels and activation were measured by means of immunoenzymatic techniques. RESULTS: The results showed that PTSD patients had statistically lower levels of total CREB protein in lympho-monocytes than healthy control subjects. On the contrary, no difference in the activated CREB protein was detected. CONCLUSIONS: These findings, albeit preliminary, would suggest that the CREB pathway might be involved in the pathophysiology of PTSD. Future studies should clarify if specific PTSD symptom clusters might be related to the CREB pathway. PMID- 21696332 TI - Use of Cordia dichotoma bark in the treatment of ulcerative colitis. AB - CONTEXT: The plant Cordia dichotoma Forst. f. (Boraginaceae) is commonly known as "Bhokar" in Marathi. This tree species has been of interest to researchers because traditionally its bark is reported in the treatment of ulcer and colic pain. OBJECTIVE: The present work was undertaken to validate its folk use in the treatment of ulcerative colitis (UC) by using scientific methods. MATERIALS AND METHODS: Dried bark powder was extracted with methanol and this crude methanol extract was fractionated using various solvents. These fractions were tested for effectiveness against UC. Macroscopical study and histopathology of the colon, level of myeloperoxidase (MPO) and malondialdehyde (MDA) in colon and blood were studied for the assessment of the activity. Antioxidant activity of these fractions was screened by using various methods. RESULTS: Animals treated with the methanol fraction of the crude methanol extract showed lower pathological scores and good healing. This fraction reduced MPO and MDA levels significantly in blood and tissue. It showed antioxidant potential [in DPPH (1,1-diphenyl-2 picrylhydrazyl) assay IC50 value is 26.25; trolox equivalent (TE) antioxidant capacity ug/ml TE/g of plant material on dry basis in ABTS (2,2'-azinobis[3 ethylbenzthiazoline]-6-sulfonic acid) and FRAP (ferric reducing antioxidant potential) assay is 2.03 and 2.45, respectively]. The fraction contains a high level of phenolics. DISCUSSION AND CONCLUSION: The methanol fraction of crude methanol extract of C. dichotoma bark is effective in the treatment of UC. PMID- 21696333 TI - The effect of Hypericum perforatum on isolated rat aorta. AB - CONTEXT: Different Hypericum species such as Hypericum perforatum (HP) L. and Hypericum triquetrifolium Turra are well known and widely used traditional medicine in Turkey. OBJECTIVES: We investigated the effect of standardized HP extract on endothelium and vascular function. MATERIALS AND METHODS: After suspending the aortas with endothelium in organ baths containing Krebs solution, contractile and relaxant responses were assessed in the absence and presence of HP (0.05 mg/ml). RESULTS: Although there were significant reductions in the contractile responses to phenylephrine (1113.73 +/- 164.11; 477.40 +/- 39.94; p < 0.05) and potassium chloride (745.58 +/- 66.73; 112.58 +/- 26.58; p < 0.05), no differences in the relaxant responses to acetylcholine (94.61 +/- 2.65; 87.79 +/- 9.40) and sodium nitroprusside (108.82 +/- 5.06; 106.43 +/- 7.45) were observed. DISCUSSION AND CONCLUSION: These data suggest that even the high dose of HP intervention does not bring any harmful effect on endothelium and smooth muscle function; meanwhile it might be beneficial on some of diseases accompanied with increased vascular contraction. PMID- 21696334 TI - Pre-formulation and chemical stability studies of penethamate, a benzylpenicillin ester prodrug, in aqueous vehicles. AB - Penethamate (PNT) is a diethylaminoethyl ester prodrug of benzylpenicillin used to treat bovine mastitis via the intramuscular route. Because of its instability, PNT products must be reconstituted before administration and the reconstituted injection has a short shelf life (7 days at 2-8 degrees C). The purpose of this paper was to investigate whether the stability of PNT can be improved in order to achieve a chemically stable ready-to-use aqueous-based PNT formulation or at least to extend the shelf life of the reconstituted suspension. A chemical stability study of PNT in aqueous-based solutions as a function of pH, buffer strength, solvent mixtures and temperature, supported by studies of its solubility in mixed solvents, allowed predictions of the shelf life of PNT solution and suspension formulations. PNT degraded in aqueous solutions by several pathways over the pH range 2.0-9.3 with a V-shaped pH-rate profile and a minimum pH of around 4.5. The stability of PNT solutions in mixed solvents was greater than in aqueous solutions. For example, in propylene glycol:citrate buffer (60:40, v/v, pH 4.5), the half-life of PNT was 4.3 days compared with 1.8 days in aqueous buffer. However, solubility of PNT in the mixed solvent was higher than that in aqueous solution and this had an adverse effect on the stability of suspensions. By judicious choosing of pH and mixed solvent, it is possible to achieve a storage life of a PNT suspension of 5.5 months at 5 degrees C, not sufficient for a ready-to-use product but a dramatic improvement in the storage life of the reconstituted product. PMID- 21696335 TI - Does diurnal rhythm have an impact on fetal biophysical profile? AB - OBJECTIVES: To investigate whether parameters in fetal biophysical profile (BPP) testing exhibit a diurnal rhythm and to discuss the probable factors associated with these variables. METHODS: Thirty healthy primigravid patients carrying pregnancies between 35 and 40 completed weeks were enrolled for the study. Fetal BPP testing was performed for each patient both in the early morning (08:00-10:00 am) and in the late evening (08:00-10:00 pm), and the scoring parameters were compared between morning and evening tests. RESULTS: BPP scores in the evening were significantly higher than that in the morning (p < 0.05). Deepest vertical amniotic pocket measurements and fetal breathing absence in the morning mostly contributed to this variation (p < 0.001). Fetal movement counts were also significantly lower in the morning tests (p < 0.001). CONCLUSIONS: The parameters of BPP exhibit circadian variations in healthy fetuses, which may be associated with many factors such as fetomaternal hormones. It is essential for the clinician to be aware of these changes when interpreting the results, as interventions based on false-positive results may have deleterious effects on both the mother and her fetus. PMID- 21696336 TI - The distribution and predictive value of Bishop scores in nulliparas between 37 and 42 weeks gestation. AB - OBJECTIVE: The natural distribution and predictive accuracy of Bishop scores was evaluated to predict cesarean delivery (CD) in nulliparas between 37 and 42 weeks gestation. STUDY DESIGN: Subjects underwent serial digital cervical examinations. The Bishop score was evaluated as a binary and continuous factor to predict CD at each gestational week beginning at 37 weeks. Bishop scores were categorized as <=5 or >5, and CD rates were compared across Bishop score categories using chi square or Fisher exact tests at each gestational week beginning at 37 weeks. RESULTS: In all, 171 patients were prospectively followed. The overall CD rate was 27.5%. The prevalence of unfavorable Bishop scores, categorized as <=5, decreased with increasing gestation age until 41 weeks. CD rates for the cohort with unfavorable Bishop scores was higher than those with favorable scores at each week. The likelihood ratio for CD was 1.35-2.00, depending on gestational age. The Bishop score that best predicted subsequent vaginal delivery following expectant management was >3 at 37 weeks and >5 at 39 weeks. CONCLUSION: A Bishop score <=5 between 37 and 39 weeks gestation predicts a higher CD rate compared to patients with a Bishop score >5 implying an intrinsically higher CD risk despite expectant management. PMID- 21696337 TI - Serum magnesium concentrations in polycystic ovary syndrome and its association with insulin resistance. AB - OBJECTIVE: It has been revealed that low serum magnesium (Mg) is often associated with insulin resistance (IR), cardiovascular problems, diabetes mellitus, and hypertension. Patients with polycystic ovary syndrome (PCOS) are known to have a high incidence of insulin resistance. This study was designed to determine whether women with PCOS exhibit serum magnesium deficiency and its potential association with IR. SUBJECTS AND METHODS: In this cross-sectional study, 103 cases with PCOS and 103 normal women who were matched for their age and body mass index (BMI) were included. Blood samples were collected after an overnight fast and concentrations of calcium, magnesium, testosterone, dehydroepianderosterone sulfate, insulin, fasting plasma glucose (FPG), triglyceride, total cholesterol, and HDL-cholesterol were measured. RESULTS: The risk of PCOS for subjects with Mg deficiency was 19 times greater than those who had normal serum Mg concentrations (p <= 0.0001). No correlation was found between Mg and insulin sensitivity or secretion, FPG, dyslipidemias, and also androgen concentrations. After adjustment for calcium concentration the role of magnesium to predict PCOS attenuated and became non-significant (beta:-1.9, p: 0.7). CONCLUSION: The present study provides the first evidence showing that magnesium deficiency is not associated with IR in PCOS. According the evidences of this study, serum calcium concentration is more potent predictor of PCOS than serum Mg and only calcium, not Mg, is related to insulin resistance in PCOS. PMID- 21696338 TI - Protruding labia minora: abnormal or just uncool? AB - There is a wide variety in the appearance of normal female external genitalia. Nevertheless a specific prototype is promoted by the media, leading to a false sense that all other appearances are abnormal. As adolescents become sexually aware at an earlier age, most of them are worried about the appearance of their genitalia, especially when labia minora protrude beyond labia majora. This is a prospective audit of adolescents presenting for assessment of their perceived abnormal genitalia. Sixteen girls aged 10.2 to 17.8 years presented between June 2009 and December 2010 to a specialist adolescent gynecology service. Their mean labial width was 36 mm (range: 20-55 mm). In six girls, the reason for attending the service was inequality of the size of labia ranging between 6 mm and 35 mm (mean of 20 mm). Among the remaining 10 girls, the concern had arisen through comparison with a prepubescent sibling (one case), change of genitalia during puberty (four cases), looking at internet pictures (four cases), and looking at an anatomy book (one case). Risks of Female Genital Cosmetic Surgery (FGCS) have not been adequately documented, especially with regards to sexual function and long-term patient satisfaction. External genitalia are likely to change during puberty and therefore, any genital operation in the absence of clear pathology should be deferred until adulthood. Even then, women should have clear expectations of what will be achieved with the operation in terms of appearance and function. PMID- 21696339 TI - Physically-based biodosimetry using in vivo EPR of teeth in patients undergoing total body irradiation. AB - PURPOSE: The ability to estimate individual exposures to radiation following a large attack or incident has been identified as a necessity for rational and effective emergency medical response. In vivo electron paramagnetic resonance (EPR) spectroscopy of tooth enamel has been developed to meet this need. MATERIALS AND METHODS: A novel transportable EPR spectrometer, developed to facilitate tooth dosimetry in an emergency response setting, was used to measure upper incisors in a model system, in unirradiated subjects, and in patients who had received total body doses of 2 Gy. RESULTS: A linear dose response was observed in the model system. A statistically significant increase in the intensity of the radiation-induced EPR signal was observed in irradiated versus unirradiated subjects, with an estimated standard error of dose prediction of 0.9 +/- 0.3 Gy. CONCLUSIONS: These results demonstrate the current ability of in vivo EPR tooth dosimetry to distinguish between subjects who have not been irradiated and those who have received exposures that place them at risk for acute radiation syndrome. Procedural and technical developments to further increase the precision of dose estimation and ensure reliable operation in the emergency setting are underway. With these developments EPR tooth dosimetry is likely to be a valuable resource for triage following potential radiation exposure of a large population. PMID- 21696340 TI - Microemulsions as vehicles for topical administration of voriconazole: formulation and in vitro evaluation. AB - This work was undertaken to investigate microemulsion (ME) as a topical delivery system for the poorly water-soluble voriconazole. Different ME components were selected for the preparation of plain ME systems with suitable rheological properties for topical use. Two permeation enhancers were incorporated, namely sodium deoxycholate or oleic acid. Drug-loaded MEs were evaluated for their physical appearance, pH, rheological properties and in vitro permeation studies using guinea pig skin. MEs based on polyoxyethylene(10)oleyl ether (Brij 97) as the surfactant showed pseudoplastic flow with thixotropic behavior and were loaded with voriconazole. Jojoba oil-based MEs successfully prolonged voriconazole release up to 4 h. No significant changes in physical or rheological properties were recorded on storage for 12 months at ambient conditions. The presence of permeation enhancers favored transdermal rather than dermal delivery. Sodium deoxycholate was more effective than oleic acid for enhancing the voriconazole permeation. Voriconazole-loaded MEs, with and without enhancers, showed significantly better antifungal activity against Candida albicans than voriconazole supersaturated solution. In conclusion, the studied ME formulae could be promising vehicles for topical delivery of voriconazole. PMID- 21696341 TI - Neonate antigen presenting cells within murine intestinal muscular layer. AB - The intestinal mucosa is exposed to a vast antigenic contact. Several antigen presenting cell (APCs) have been described within the gut associated lymphoid tissue (GALT) (Peyer's patches, lamina propria, mesenteric lymph nodes, muscular layer); however, this has been done almost exclusively in adult organisms. As there is no characterization of intestinal muscular layer's APCs during early neonate development we adapted the conventional technique used in adults, to the neonate intestine. We obtained the intestinal muscular layer from early neonates (days 0-3 upon birth) and from young mice (2 and 3 weeks after birth). A planar network of CD45(+), MHC-II(+), DEC-205(+) cells with irregular, some with prominent dendritic morphology was found at birth under basal physiological conditions, whereas Langerin(+) DCs appeared after two weeks. The variations seen in CD45(+), MHC-II(+) and DEC-205(+) cells along the early neonatal development, could be related to the new challenges by intestinal antigen exposure from the newborn diet (breast milk, solid food), and to important environmental changes (start walking, exploring the surroundings, etc). Our study reveals the presence of APCs in intestinal muscular layer at birth, and their subsequent changes in physiological, non-induced conditions, contributing basic information about these cells in the neonate intestinal immune system. PMID- 21696342 TI - MDMA & cannabis: a mini-review of cognitive, behavioral, and neurobiological effects of co-consumption. AB - Although the prevalence of co-use of cannabis and 3,4 methylenedioxymethamphetamine (MDMA) is very common among polydrug users in western societies, few studies have tested the consequences on behavior, cognition or neurobiology. This review examines 23 articles published between 2002 and 2010 with an explicit focus on the combination, or administration, of MDMA and cannabis or cannabinoid agents. The aim was to provide a short overview on the latest human research concerning cognitive effects of co-consumption of MDMA and cannabis, and a more elaborate picture of the state of knowledge about the interaction of cannabinoid agents and MDMA from animal studies. It was found that recent retrospective studies on cognitive functions in long-term drug abusers point to an additive negative effect on different types of memory, as well as a cannabis-independent decrease in learning and decision-making in MDMA users. Behavioral experiments in rodents and in vitro studies investigating the combined effect of MDMA and cannabinoid agents demonstrate modulator effects of acute co-administration on measures like body temperature, conditioned reinforcement, and presumed neurotoxicity. As neural mechanism underlying these changes, an interaction between the cannabinoid system, especially cannabinoid receptor 1, and the serotonergic and dopaminergic system in the prefrontal cortex, nucleus accumbens, and hippocampus is suggested. In conclusion, there are few and somewhat contradictory studies examining the effects of co-use of these drugs on cognitive measures like impulsivity, memory and executive functions or underlying neurobiological alterations, and a shortage of animal studies examining long-term effects of chronic co-administration. PMID- 21696343 TI - Immunotoxicity of cocaine and crack. AB - The toxicity of cocaine and crack was studied on the protozoan Tetrahymena pyriformis, using several endpoints, such as the DNA content of the macronuclei and the phagocytic ability. Both forms induced an increase in the DNA content of the protozoan, which indicates the stimulation of the mitotic process. In contrast, the phagocytic activity, of the protozoan was decreased after the administration of cocaine, an effect that was more extensive after the administration of crack. These results, derived from previous experiments, suggest a possible relationship between the observed immunosuppression in cocaine abusers and the immunosuppression found in the protozoan. This suppression subsequently may play a role in the development of other opportunistic infections in drug abusers. This paper, based on in vivo experiments with the protozoan Tetrahymena, suggests the compromised immune response in cocaine addicts and assures the reported effects of cocaine on immune cell function. PMID- 21696344 TI - Phosphodiesterase type 5 inhibitor abuse: a critical review. AB - Abuse of sildenafil has been reported since its introduction in 1999 and commonly documented in combination with illicit drugs among men and women of all ages. Increased risks of sexually transmissible diseases including HIV have been associated with sildenafil use in men who have sex with men. Recognizing the abuse potential of phosphodiesterase type 5 inhibitors (PDE5), we aim to summarize the current knowledge of this abuse. An investigation of EMBASE, PubMed, the Food and Drug Administration (FDA) website, MedWatch, and search engines was performed to evaluate information regarding sildenafil, tadalafil, and vardenafil abuse. The EMBASE search provided 46 articles fitting the search criteria and evaluation led to 21 separate publications with specific information regarding PDE5 abuse. A PubMed search found 10 additional publications. MedWatch reported 44 separate warnings since 2000, most of which reported contamination of herbal products with active drug components. Few reports of abuse were among the 14,818 reports in the FDA AERS for sildenafil. A search for "internet drug store" revealed 6.4 million hits and of 7000 internet pharmacies identified by the Verified Internet Pharmacy Practice Sites Program (VIPPS) only 4% were in proper compliance. The role internet pharmacies play in counterfeit PDE5 or abuse is not well documented; however based on easy access, direct patient marketing, and low advertised cost it is likely this role is underreported. Currently the best recommendation for providers is to recognize the possibility of abuse and to educate patients on risks of this behavior. PMID- 21696345 TI - Effect of the monoamine oxidase inhibition on rewarding effects of nicotine in rodents. AB - Nicotine, the primary psychoactive compound in tobacco, is responsible for the addictive effects of smoking; however, there is a paucity of information indicating whether the presence of other biological chemicals in tobacco alters nicotine's rewarding effects. It has been suggested that the addictive effects of smoking may be due, in part, to the inhibition of the pair of monoamine oxidase enzymes responsible for a significant fraction of monoamine metabolism, Monoamine Oxidase A and B (MAO-A and MAO-B). This paper reviews the current, limited literature examining the role of MAO inhibition on the rewarding effects of nicotine (e.g., self-administration) in rodents. Overall, studies with rats and mice do suggest that MAO plays a role in nicotine reward. However, results are mixed regarding the MAO subtype responsible for the rewarding effects of nicotine, most likely due to methodological variation across the limited number of studies. Important individual difference factors such as age, sex and genetics are discussed, along with relevant brain and neurotransmitter systems. Future research is needed that builds on the available literature to map out the relationship between MAO inhibition and nicotine reward. These data will enhance our understanding of the neuropharmacological effects of smoking and the value of implementing MAO inhibitors as pharmacotherapies for smoking cessation. PMID- 21696346 TI - A critical review of treatment approaches for gambling disorders. AB - This review presents the theoretical model, evidence base, and theoretical and methodological issues for seven treatment approaches to gambling disorders: 1) psychoanalytic and psychodynamic treatments, 2) Gamblers Anonymous, 3) behavioural treatments, 4) cognitive and cognitive-behavioural therapies, 5) brief, motivational, and self-directed interventions, 6) pharmacotherapies, and 7) family therapy approaches. Throughout the review, broader clinical and research issues are also discussed, including barriers to treatment-seeking, controlled gambling versus abstinence as a treatment goal, comorbidity, and the evaluation of treatment efficacy and effectiveness. PMID- 21696347 TI - Sports participation and alcohol use among adolescents: the impact of measurement and other research design elements. AB - INTRODUCTION: Sports participation, while offering numerous developmental benefits for adolescents, has been associated with alcohol use in prior research. However, the relationship between sports participation and alcohol use among adolescents remains unclear, particularly how research design elements impact evidence of this relationship. We reviewed the evidence regarding sports participation and alcohol use among adolescents, with a focus on examining the potential impact of research design elements on this evidence. METHODS: Studies were assessed for eligibility and coded based on research design elements including: study design, sampling method, sample size, and measures of sports participation and alcohol use. RESULTS: Fifty-four studies were assessed for eligibility, 29 of which were included in the review. Nearly two-thirds used a cross-sectional design and a random sampling method, with sample sizes ranging from 178 to 50,168 adolescents (Median = 1,769). Sixteen studies used a categorical measure of sports participation, while 7 applied an index-type measure and 6 employed some other measure of sports participation. Most studies assessed alcohol-related behaviors (n = 18) through categorical measures, while only 6 applied frequency only measures of alcohol use, 1 study applied quantity only measures, and 3 studies used quantity and frequency measures. CONCLUSIONS: Sports participation has been defined and measured in various ways, most of which do not differentiate between interscholastic and community-based contexts, confounding this relationship. Stronger measures of both sports participation and alcohol use need to be applied in future studies to advance our understanding of this relationship among youths. PMID- 21696348 TI - Nanodrug delivery systems in dentistry: a review on current status and future perspectives. AB - The present review provides an insight into various potential areas of dentistry that are being invaded by nanotechnology based drugs and drug delivery systems. Current treatments for diseases of dental and oral structures rely on the use of classical pharmacological agents which, in some cases are limited by low efficacy and lack of selectivity to target cells. However, various nanostructures in drug delivery and their challenges in the field of dentistry have not been reviewed so far in the literature. The different treatment opportunities of importance include caries control restorations, tooth remineralisation, management of dentinal hypersensitivity, dental caries vaccine, management of oral biofilm, root canal disinfection, local anaesthesia and periodontal infection. The authors have also identified few dental applications demanding extensive research to emerge as a promising therapeutic strategy. We conclude by claiming that dentistry should follow the trend of probing matter at nanoscale to achieve a predictable treatment outcome. PMID- 21696349 TI - Development of polysaccharide based colon targeted drug delivery system: design and evaluation of Assam Bora rice starch based matrix tablet. AB - The aim of this study was to develop a novel colon targeted matrix tablet containing Metronidazole (MTZ) as model drug. Matrix tablets were prepared using Assam Bora rice starch, which is essentially a natural polymer, by wet granulation technique. The granules prepared were subjected to evaluation for angle of repose, bulk density, compressibility index, Hausner's ratio, total porosity, and drug content. The developed tablets were also analysed for thickness, diameter, weight variation tests, tablet crushing strength, friability, and in vitro release studies. The granules displayed satisfactory flow properties, compressibility, Hausner's ratio and drug content. Almost all the tablet formulations showed acceptable pharmacotechnical properties and complied with the in-house developed specifications for the tested parameters. Drug release study confirmed to the initial fast release in the acidic environment of surface adhered drug followed by slow release in alkaline media subsequently leading to fast and major drug release in the caecal content. Furthermore, the release of drug was unaffected by the hostile environment of GIT which can be ascribed to microbial degradation, promptly followed by enzymatic degradation. Curve fitting proved that the drug release from the tablets followed the Higuchi model. In vitro bacterial inhibition studies illustrated that the released drugs were able to diffuse through agar medium, inhibiting MTZ sensitive Bacteroides fragilis. The selected MTZ matrix tablets (F1-F6) had zones of inhibition paralleling those of the marketed formulation. PMID- 21696350 TI - Local delivery of therapeutics for percutaneous coronary intervention. AB - Percutaneous coronary intervention (PCI) has become a highly effective alternative for the treatment of coronary artery disease. The use of stents has reduced the rates of restenosis by preventing elastic recoil and negative remodeling, however neointima formation still remains an issue. Local drug delivery is an attractive option to maintain effective drug concentrations at the site of arterial injury without risking systemic toxicity. Drug-eluting stents (DESs) are implanted to provide local drug delivery to combat neointima formation by slowing cell proliferation and migration. However, problems still remain with DES use including the non-specificity of therapeutics, incomplete endothelialization leading to late thrombosis, necessity for longer term anti platelet drug use, and local hypersensitivity to polymer delivery matrices. This review describes recent advances in local drug delivery for the prevention of restenosis. Many different drug therapeutics have been considered, as well as the material properties of the drug delivery systems. Systems for delivery include DESs, balloon catheters, polymeric cuffs and nanoparticles. Our own experience designing a controlled release device for a new therapeutic agent, Serp-1, an anti-inflammatory protein, is briefly presented. The release of Serp-1 can be extended using diffusion controlled release from physically crosslinked poly(vinyl alcohol) hydrogels, where its release properties can be tuned by the processing parameters of the hydrogel. PMID- 21696351 TI - Evidence for extensive non-endocytotic translocation of peptide nucleic acids across mammalian plasma membranes. AB - The ability of peptide nucleic acids (PNA) to enter and to cross filter-grown MDCK, HEK and CHO cells was studied by means of a protocol based on capillary electrophoresis combined with laser-induced fluorescence detection. The used approach avoided possible errors encountered in protocols based on confocal laserscanning microscopy and FACS analysis. In contradiction to the commonly anticipated unability of PNA to cross biomembranes, extensive translocation of unmodified PNA into and across the investigated cell types was found. The transport mode comprised a variety of energy dependent and -independent as well as temperature sensitive mechanisms being probably destined to natural substrates and hijacked by PNA. The presented results suggest active as well as passive export mechanisms rather than poor penetration into cells to be responsible for the only weak biological activity of unmodified PNA. PMID- 21696352 TI - In vitro and in vivo characterization of novel biomaterial for transdermal application. AB - Polymers have become an indispensable part in the design of a conventional as well as novel drug delivery system. Gum Copal (GC), a novel biomaterial obtained from Agathis species, is evaluated in the present study for its potential application as a matrix former in transdermal drug delivery systems. GC was initially characterized for various physicochemical properties and then mechanical characterization of the Plasticized films of GC was investigated. Verapamil hydrochloride (VH), owing to its pharmacokinetic properties, was selected as the model drug for the present work. Matrix type transdermal films of VH with GC, alone and in combination with polyvinyl pyrrolidone (PVP K-30), were developed and evaluated for various physicochemical properties. In-vitro drug release study was carried out using paddle over disk method and in-vitro skin permeation study was performed using human cadaver skin. On the basis of physicochemical properties, in-vitro drug release study and permeation performance, formulation F5 containing GC: PVP K-30 (60:40) was selected as an optimized formulation for in vivo study. Animal studies were carried out using Dawley rats and the data obtained from the plasma drug analysis showed that peak drug concentration of about 244.94 +/- 1.25 ng/mL was achieved in 6 h after the application of the patch and plasma drug concentration was maintained till 24 h. Skin irritancy test results proved the suitability of the biomaterial for transdermal application. The drug polymer interaction studies carried out using UV, FTIR and TLC analysis indicated that drug and polymer were compatible. Due to reasonably good mechanical properties, low water vapor transmission and sustained release capability, GC seems to be a promising film former for transdermal drug delivery. PMID- 21696353 TI - Quick-release bromocriptine for treatment of type 2 diabetes. AB - Quick-release bromocriptine (bromocriptine-QR) (Cycloset) was approved in 2009 for treatment of type 2 diabetes. The exact anti-diabetic mechanism of action of bromocriptine-QR has not been elucidated, but the drug may help resetting the circadian dopamine signal. Randomized placebo-controlled trials showed that the mean reduction in hemoglobin A1c (HbA1c) levels by bromocriptine-QR was 0.0-0.2% when compared to baseline and 0.4-0.5% when compared with placebo after 24 weeks of therapy. Withdrawal rates due to adverse effects in patients receiving bromocriptine-QR and placebo were 24% and 11%, respectively. The most common adverse effect of bromocriptine-QR was nausea reported by 32% of patients compared with 7% of patients randomized to placebo. The advantages of bromocriptine-QR were minimal risk of hypoglycemia, neutral effect on weight, and reassuring cardiovascular safety over 1 year of use. However, the drug had multiple drawbacks including modest efficacy, high rates of nausea, lack of long term efficacy and safety data, and considerable cost. Bromocriptine-QR may be used in patients with type 2 diabetes with mild hyperglycemia (HbA1c close to 7.5%) either as adjunctive treatment to metformin and sulfonylurea (SU) or as monotherapy in patients who are intolerant to both agents. PMID- 21696354 TI - Floating drug delivery systems for prolonging gastric residence time: a review. AB - Oral delivery of the drug is the most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in the formulations. Recent technological advancements have been made in controlled oral drug delivery systems by overcoming physiological difficulties, such as short gastric residence time and highly variable gastric emptying time. Gastroretentive dosage forms have been designed over the past three decades to overcome these difficulties. Several technical approaches are currently utilized in the prolongation of gastric residence time, including highdensity, swelling and expanding, polymeric mucoadhesive, ion-exchange, raft forming, magnetic and floating drug delivery systems (FDDS), as well as other delayed gastric emptying devices. In this review, the current technological developments of FDDS including patented delivery systems and marketed products, and their advantages and future potential for oral controlled drug delivery are discussed. PMID- 21696355 TI - Depot based drug delivery system for the management of depression. AB - Depression is a common mental disorder discerns with depressed mood, loss of interest, the primary treatment methods are drug therapy, electroconvulsive therapy, psychotherapy, light therapy, vagus nerve stimulation, etc. A number of innovative delivery systems have been developed to address suboptimal therapy outcomes by enhancing drug delivery, assuring efficacy of treatment, reducing side effects, improving compliance and drug targeting specific locations resulting in a higher efficiency. Depot delivery offers the advantage of a very high loading, controlled release of drug for an extended period of time and reduces frequency of dosing. The increase in AUC and decrease in Cmax reflects that the depot formulations could reduce the toxic complications and limitations of conventional and oral therapies. Products at preclinical and clinical stages include formulations of naltrexone and buprenorphine for alcoholism/drug abuse, GLP-1 peptides for diabetes, r-hFSH for fertility, dopamine for nerve growth, dexamethasone for ocular treatment, melanotan for cancer prevention, plasmid DNA for cancer prevention, a variety of vaccines, octreotide generics, etc. Most depot formulations are comprised of biodegradable polymer-excipients that control the rate of drug release and resorbs during/after drug release. The major advantage of depot antipsychotics over oral medication was facilitation of compliance in medication taking. One class of biodegradable polymers that has gained wide acceptance and still attractive today is lactide/glycolide polymers. The greatest advantage of these degradable polymers is that they are broken down into biologically acceptable molecules that are metabolized and removed from the body via normal metabolic pathways. This versatile delivery system offers the advantage of a very high loading and controlled release of various drug for an extended period of time compared with plain delivery system. New formulations of depression can offer advantages over older formulations in terms of convenience, side effect profiles, efficacy, and/or a fast onset of action. PMID- 21696356 TI - Enhanced delivery of topically-applied formulations following skin pre-treatment with a hand-applied, plastic microneedle array. AB - The purpose of this work is to characterize microchannels created by polymeric microneedles, applied by hand, and to demonstrate enhanced delivery of topically applied formulations of lidocaine hydrochloride and methylprednisolone sodium succinate (MPSS). 3M's Microstructured Transdermal System (MTS) arrays were applied to domestic swine to demonstrate reliability of penetration, depth of penetration and durability of the structures to repeat application and high force. Tissue levels of lidocaine and MPSS following topical application with and without microneedle pretreatment were determined by HPLC-MS analysis following digestion of biopsies. Almost all microneedles penetrate the stratum corneum upon hand force application. The depth of penetration varies from <100um to nearly 150um depending on the application force and the firmness of the underlying tissue. The arrays show excellent durability to repeated in-vivo application, with less than 5% of the structures evidencing even minimal tip bending after 16 applications. Under extreme force against a rigid surface, the microneedles bend but do not break. A lidocaine hydrochloride formulation applied topically in-vivo showed ~340% increase in local tissue levels when the MTS arrays were used to twice pre-treat the skin prior to applying the drug. Local delivery of a topically applied formulation of MPSS was over one order of magnitude higher when the application site was twice pre-treated with the MTS array. 3M's MTS array (marketed as 3M(TM) Microchannel Skin System) provides repeatable and robust penetration of the stratum corneum and epidermis and enhances delivery of some formulations such as lidocaine hydrochloride. PMID- 21696357 TI - Development of novel combined time and pH-dependent based drug delivery systems for targeting 5-fluorouracil to the colon. AB - The present work is aimed to develop new oral drug delivery systems of 5 fluorouracil for the treatment of colorectal cancer by using hydrophilic swellable polymer hydroxy propyl methyl cellulose (HPMC) and pH responsive soluble polymer Eudragit L100 (ED) as coating materials. Core tablets containing 50mg of 5-fluorouracil were prepared by direct compression. The core tablets compression coated with different ratios (9:1, 8:2, 7:3, 6:4 and 5:5) of HPMC and ED with a coat weight of 300 and 400mg. All the formulations were evaluated for the hardness, friability, drug content uniformity and in vitro drug release studies in media of different pH 1.2, 7.4 and 6.8. The formulations released 0 to 7% of the drug in physiological environment of stomach and small intestine depending upon proportion of HPMC and ED used in the coat. Among the different ratios used for coating with HPMC:ED combination, ratio 9:1 gave the best release profile with the coat weight of 300mg (1.34% in the initial 5h and 87% in 24 h). Further increase in the coat weight to 400mg with different ratios of 9:1, 8:2, 7:3, 6:4 and 5:5 led to drug release of 0%, 0%, 0%, 3.47% and 6.25%, respectively in the initial 5 h and 73.52%, 87.03%, 92.18%, 96.33% and 97.61%, respectively, in 24 h. Thus, based on the results of in vitro drug release studies, the ratio 7:3 with a coat weight of 400mg was found to be suitable for targeting 5 fluorouracil to the colon without being released in physiological environment of stomach and small intestine. The formulation showed no change in physical appearance, drug content or in vitro release pattern after storage at 40 degrees C / 75% RH for 3 months. The release of 5-fluorouracil from developed formulation was directly proportional to amount of ED used in the coat. The DSC and FTIR studies indicated no possibility of interaction between 5-fluorouracil and excipients. PMID- 21696358 TI - Asymmetric membrane capsules of phenylephrine hydrochloride: an osmotically controlled drug delivery system. AB - The aim of the current study was to develop osmotically controlled release system of freely water soluble drug phenylephrine hydrochloride by use of asymmetric membrane capsules to reduce the dosing frequency and consequently improve the patient compliance. Ethyl cellulose asymmetric membrane capsules were developed by phase inversion process and solubility modulation was accomplished by common ion effect wherein sodium chloride was included in the formulation that also served as an osmogen. The effect of formulation variables namely level of polymer (ethyl cellulose), level of pore former (glycerol) and level of osmogen (sodium chloride) on the in vitro release of the drug was evaluated by 2(3) factorial design. Effects of environmental factors on the release rate of the drug from asymmetric membrane capsules were also evaluated. Membrane characterization by scanning electron microscopy showed an outer dense region with less pores and inner porous region for the prepared asymmetric membrane. The dimensional analysis of asymmetric membrane capsule documented the capsules to be of uniform cap and body size comparable to commercial hard gelatin capsules. In vitro release studies results showed that incorporation of higher amount of osmogen not only increased the osmotic pressure but also controlled the drug release for a period of 12 hr. The drug release was inversely proportional to the level of polymer in asymmetric membrane capsule but directly related to the level of pore former in the membrane. The optimized asymmetric membrane capsule (F5) was able to provide zero order release of phenylephrine hydrochloride independent of agitation rate, intentional defect in the membrane and pH of dissolution medium but was dependent on the osmotic pressure gradient between inside and outside of the delivery system. PMID- 21696359 TI - Dark chocolate and blood pressure: a novel study from Jordan. AB - AIM: The goal of this study was to assess the effect of dark chocolate intake on cardiovascular parameters like blood pressure and heart rate values in a normotensive population. SUBJECTS AND METHODS: This is a randomized cross sectional study involving a total of 14,310 adults that were selected from various regions of Jordan. Well-trained pharmacy students interviewed participants in the outpatient settings. Participants reported their weekly intake of dark chocolate that has been further classified into mild (1-2 bars/week), moderate (3-4 bars/week), and high intake ( > 4 bars/week). For each participant, the systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate were measured three times with (10-15) minute intervals in the sitting position and the resting state. The arterial blood pressure (ABP) was calculated from the measured SBP and DBP values. RESULTS: All measured blood pressure values were significantly decreased for participants who reported higher dark chocolate consumption. Our results showed that heart rate values were not affected by variable intake of dark chocolate. In addition, increasing dark chocolate intake was associated with a significant decrease of blood pressure values in participants irrespective of the family history of hypertension or the age of the individual. However, heart rate values were unaffected. CONCLUSION: Higher intake of dark chocolate can be associated with lower values of blood pressure, while its effect on heart rate values was not consistent. PMID- 21696360 TI - Active tumor targeting of nanomaterials using folic acid, transferrin and integrin receptors. AB - Folic acid, transferrin and integrin alpha v beta 3 (alphavbeta3) receptors are overexpressed in various cancer cell lines. Ligands having high affinity for these receptors are often conjugated to nanocarriers to facilitate the tumor localization of therapeutic agents. In this review the use of these ligands for targeted delivery using liposomes, dendrimers and (N-(2-hydroxypropyl) methacrylamide) (HPMA) copolymers is discussed. Emphasis is placed on discussing drug delivery systems that have been optimized for in-vitro binding as well as in vivo pharmacokinetics. Our aim is to understand the various factors influencing the targeting ability of nanocarriers. PMID- 21696361 TI - FGF10 and FGF21 as regulators in adipocyte development and metabolism. AB - The FGF family comprises twenty-two evolutionarily related members with diverse functions in development, metabolism, and neuronal activities. FGF10 and FGF21 play unique roles in adipocyte development and metabolism, respectively. FGF10 mediates biological responses by activating FGF receptor 2b (FGFR2b) with heparin/heparan sulfate in a paracrine manner. In contrast, FGF21 mediates biological responses by activating FGFRs with betaKlotho in cultured cells. However, FGF21 acts in an autocrine manner via a beta Klotho-independent signaling pathway in mice. Fgf10 knockout mice die shortly after birth. Preadipocyte proliferation and adipogenesis are greatly impaired in Fgf10 knockout mouse embryos. FGF10 stimulates preadipocyte proliferation through the Ras/MAPK pathway followed by the cyclin D2-dependent phosphorylation of p130. FGF10 also stimulates adipogenesis by inducing the expression of pRb through the Ras/MAPK pathway. pRb binds C/EBPalpha. The pRb-C/EBPalpha complex induces adipogenesis. Fgf21 is abundantly expressed in the liver. Hepatic Fgf21 expression is markedly induced in mice by fasting. FGF21 exerts pharmacological effects on glucose and lipid metabolism in hepatocytes and adipocytes. However, the phenotypes of Fgf21 knockout mice, which are apparently normal and fertile, indicate FGF21 not to be a physiological regulator for hepatic functions. Hepatic FGF21 inhibits lipolysis in adipocytes, and so is a negative regulator of lipolysis during fasting. FGF21 may be a "thrifty factor". Serum FGF21 levels are increased in patients with metabolic diseases related with obesity, indicating potential roles of FGF21 in adipocyte metabolism. PMID- 21696362 TI - The role of PPARbeta/delta in the management of metabolic syndrome and its associated cardiovascular complications. AB - The association between metabolic syndrome and cardiovascular diseases raises important questions about the underlying pathological processes, especially for designing targeted therapeutic interventions. The Peroxisome Proliferators Activated Receptors (PPARs) are ligand-activated transcription factors that control lipid and glucose metabolism. Accumulating data suggest that PPARs may serve as potential targets for treating metabolic diseases and their cardiovascular complications. PPARs regulate gene expression by binding with RXR as a heterodimeric partner to specific DNA sequences, termed PPAR response elements. In addition, PPARs may modulate gene transcription also by directly interfering with other transcription factor pathways in a DNA-binding independent manner. To date, three different PPAR isoforms, designated alpha, beta/delta and gamma, have been identified. PPARalpha and PPARgamma are the most extensively examined and characterized, mainly because they are activated by compounds, such as fibrates and thiazolidinediones, that are in clinical use for the treatment of hypertriglyceridemia and insulin resistance, respectively. In contrast the role of PPARbeta/delta in metabolism has been less investigated. The recent availability of specific PPARbeta/delta agonists revealed that PPARbeta/delta plays a crucial role in fatty acid metabolism in several tissues. Besides, PPARbeta/delta activation exerts beneficial effects against organ-related ischemic events, such as myocardial and cerebral infarction, which are among the most critical cardiovascular complications evoked by metabolic dysregulation. This paper reviews the evidence and recent developments relating to the potential therapeutic effects of PPARbeta/delta agonists in the treatment of metabolic syndrome and its associated cardiovascular risk factors. PMID- 21696363 TI - The regulation of FoxP3-expressing regulatory T cells. AB - Regulatory T (Treg) cells play an important role in the maintenance of self tolerance and are involved in the prevention of autoimmune diseases and reduce/inhibit the progression of chronic inflammatory diseases. Forkhead box P3 (FoxP3) expression in Treg cells is believed to be a critical factor in the maintenance of Treg cells suppressive function. Multiple mechanisms of action of Treg cells have been proposed, including cell contact-dependent and cytokine dependent mechanisms. However, no clear picture is available to fully elucidate the regulation of FoxP3 gene expression in Treg cells and how FoxP3-expressing Treg cells mediate the immune response in vivo. This review will discuss the research advancements in Treg cell biology including the transcription factors and signaling pathways involved in the expression of FoxP3 gene as well as the advancements in the understanding of the factors involved in the Treg cell mediated suppressive mechanisms. PMID- 21696364 TI - The sphingolipid rheostat: a potential target for improving pancreatic islet survival and function. AB - Beta cell apoptosis and suboptimal islet function are implicated in the development of Type I (T1D) and Type II (T2D) diabetes, as well as the failure of the only current clinical beta cell replacement therapy for T1D, islet transplantation. Sphingosine kinase (SK) is a ubiquitous lipid kinase that controls the balance between prosurvival and proapoptotic precursors (e.g. sphingosine-1-phosphate (S1P) and ceramide, respectively), the so-called 'sphingolipid rheostat', in many cell types. S1P, a potent lipid mediator, acts intracellularly through second messengers and extracellularly through five G protein coupled receptors (S1P1-5), to promote calcium mobilization, intracellular signaling events, cytoskeleton rearrangements and mitogenesis. SK is important for revascularization responses, regulating the maturation of vascular endothelial progenitors and controlling cellular recruitment. The aim of this review is to highlight the sphingolipid rheostat in pancreatic biology as a therapeutic target for pharmacological and therapeutic intervention for diabetes and islet transplantation. SK and the sphingolipid rheostat are likely to be important for both islet function and beta cell survival and represent a common therapeutic target to protect the beta cell from diabetogenic insults and ultimately improve pancreatic islet function. A number of SK inhibitors and S1P receptor agonists/antagonists (including FTY720 (fingolimod) and its newer derivatives) have been recently described, with some now being used in the clinic. Recent developments in SK biochemistry and islet biology indicate the potential importance of the sphingolipid rheostat in determining islet survival and function. Pharmacological manipulation of this pathway represents a novel therapeutic strategy to prevent diabetes and improve islet transplantation outcomes. PMID- 21696365 TI - The impact of bacterial lipolysaccharides on the endothelial system: pathological consequences and therapeutic countermeasures. AB - Endothelial cells (ECs) express on their membrane Toll like receptor (TLR)-4 and, therefore, are able to interact with lipopolysaccharides (LPS) or endotoxins, major constituents of the gram-negative bacteria outer membrane. The impact of LPS on ECs can be either direct or mediated via release of cytokines and/or chemokines originated from monocytes/macrophages. In this review, the effect of the interaction between LPS and ECs on the outcome of various human diseases such as preeclampsia, hereditary haemorrhagic teleangiectasia, atherosclerosis and sepsis will be illustrated. Finally, the major therapeutic attempts aimed at neutralizing LPS and, therefore, their influence on ECs will be discussed. PMID- 21696366 TI - SLC41A1 Mg(2+) transport is regulated via Mg(2+)-dependent endosomal recycling through its N-terminal cytoplasmic domain. AB - SLC41A1 (solute carrier family 41, member A1) is a recently described vertebrate member of the MgtE family of Mg(2+) transporters. Although MgtE transporters are found in both prokaryotic and eukaryotic organisms, and are highly conserved, little is known about the regulation of their Mg(2+) transport function. In the present study, we have shown that endogenous SLC41A1 transporter expression is post-transcriptionally regulated by extracellular Mg(2+) in TRPM7 (transient receptor potential cation channel, subfamily M, member 7)-deficient cells, suggesting that SLC41A1 transporters underlie a novel plasma membrane Mg(2+) transport function. Consistent with this conclusion, structure-function analyses of heterologous SLC41A1 transporter expression demonstrate that SLC41A1 transporters exhibit the same plasma membrane orientation as homologous bacterial MgtE proteins, are capable of complementing growth of TRPM7-deficient cells only when the Mg(2+) transporting pore is intact, and require an N-terminal cytoplasmic domain for Mg(2+)-dependent regulation of lysosomal degradation and surface expression. Taken together, our results indicate that SLC41A1 proteins are a central component of vertebrate Mg(2+) transport systems, and that their Mg(2+) transport function is regulated primarily through an endosomal recycling mechanism involving the SLC41A1 N-terminal cytoplasmic domain. PMID- 21696368 TI - In this year of the veterinarian, we are including a series of papers on the history of veterinary medicine in Australia. AB - Disease control during the colonial period in Australia . Neurological diseases of ruminant livestock in Australia . Coxiella burnetii in beef cattle in Queensland . Desmotomy for flexural deformity in Thoroughbreds . Acute myeloid leukaemia in a Thoroughbred foal . Growth variants of Avibacterium paragallinarum . Volvulus in a dugong. PMID- 21696369 TI - Disease control during the colonial period in Australia. AB - The first permanent European settlers of Australia arrived in 1788 to establish a penal colony at Sydney, New South Wales (NSW). As the colony grew and wool production increased, more free settlers and emancipists developed farming in inland Australia. During the 1840s veterinarians commenced arriving in small numbers but they were not closely associated with the development and execution of disease control programs, which was left to lay inspectors of stock. The arrival of William Tyson Kendall and coordinated action with Graham Mitchell led to the establishment of a private veterinary college following the passage of veterinary surgeons legislation in Victoria. From this time, veterinarians came to be appointed to positions formerly occupied by lay inspectors and the veterinary profession was able to take up the role of planning and executing government-led disease control programs. From a colony relying on wool for export to the UK, technical advancements in meat freezing and pasture improvement widened the range and increased the quantity of exported products. Before the advent of veterinary advances, sheep scab was eradicated, a vaccine was developed for anthrax and glanders infection of horses was prevented entry to Australia. Graduates from the Melbourne Veterinary College spread across Australia and in this period a conservative quarantine policy was developed following inaction to control an outbreak of contagious bovine pleuropneumonia (CBPP) and the escape of rabbits to form a plague across the continent. Coordinated control of CBPP had to await the next century and advancement of technology increased our understanding of bacteriology and immunity of infectious diseases. Veterinary services were provided to the militia sent by the colonies to the Boer Wars in South Africa 1987-1901 and the veterinarians from Victoria were led by an Australian trained veterinarian. PMID- 21696367 TI - Autotaxin induces lung epithelial cell migration through lysoPLD activity dependent and -independent pathways. AB - Lung cell migration is a crucial step for re-epithelialization that in turn is essential for remodelling and repair after lung injury. In the present paper we hypothesize that secreted ATX (autotaxin), which exhibits lysoPLD (lysophospholipase D) activity, stimulates lung epithelial cell migration through LPA (lysophosphatidic acid) generation-dependent and -independent pathways. Release of endogenous ATX protein and activity was detected in lung epithelial cell culture medium. ATX with V5 tag overexpressed conditional medium had higher LPA levels compared with control medium and stimulated cell migration through G(alphai)-coupled LPA receptors, cytoskeleton rearrangement, phosphorylation of PKC (protein kinase C) delta and cortactin at the leading edge of migrating cells. Inhibition of PKCdelta attenuated ATX-V5 overexpressed conditional medium mediated phosphorylation of cortactin. In addition, a recombinant ATX mutant, lacking lysoPLD activity, or heat-inactived ATX also induced lung epithelial cell migration. Extracelluar ATX bound to the LPA receptor and integrin beta4 complex on A549 cell surface. Finally, intratracheal administration of LPS (lipopolysaccharide) into the mouse airway induced ATX release and LPA production in BAL (bronchoalveolar lavage) fluid. These results suggested a significant role for ATX in lung epithelial cell migration and remodelling through its ability to induce LPA production-mediated phosphorylation of PKCdelta and cortactin. In addition we also demonstrated association of ATX with the epithelial cell-surface LPA receptor and integrin beta4. PMID- 21696371 TI - Neurological diseases of ruminant livestock in Australia. I: general neurological examination, necropsy procedures and neurological manifestations of systemic disease, trauma and neoplasia. AB - Disease surveillance is an integral part of most veterinary practices in Australia. The aim of this series of invited reviews is to facilitate the differential and ultimately definitive diagnosis of some of the previously known, as well as the novel and emerging, neurological disorders of ruminant livestock, which is of particular importance in the surveillance for transmissible spongiform encephalopathies. General principles of a systematic neurological examination, necropsy procedures and the neurological manifestations of systemic disease, trauma and neoplasia are described here. PMID- 21696373 TI - Lethal genetic disorder in Poll Merino/Merino sheep in Australia. AB - OBJECTIVES: Characterise a lethal genetic disorder in Poll Merino/Merino sheep DESIGN: Pathological description of a new congenital multisystem disorder in a commercial sheep flock, and analysis of breeding data collected each lambing season between 2004 and mid-lambing season 2010. PROCEDURE: Necropsies were conducted on six affected lambs and the mode of inheritance of the disorder was determined by pedigree and segregation analyses. RESULTS: The affected lambs were dwarfs with multiple defects in several organs, including skeleton, heart, liver and kidneys. The disorder has been named brachygnathia, cardiomegaly and renal hypoplasia syndrome (BCRHS). Segregation analysis suggests the disorder is transmitted as an autosomal trait with a recessive mode of inheritance. An annual incidence of the disorder in the discovery flock of up to 2.5% was recorded. CONCLUSIONS: As a lethal disorder, the occurrence of BCRHS raises potential ethical and economic concerns for Merino breeders. The development of a DNA test would be useful to investigate its distribution in the Australian wool-sheep population. As the disorder affects both the skeleton and several critical organs, including the heart, it may provide a potential animal model for investigating key developmental processes in humans and other animals. PMID- 21696375 TI - Serological evidence of Coxiella burnetii infection in beef cattle in Queensland. AB - BACKGROUND: Queensland has the highest incidence of Q fever in Australia. The aim of this study was to undertake a cross-sectional seroprevalence survey of Coxiella burnetii, the causative agent of Q fever, in beef cattle in Queensland. METHODS: Serum samples were tested by ELISA for both phase II and phase I antigens of the organism using an Australian isolate. Blood samples were collected at an abattoir that processes beef cattle originating from northern and north-western Queensland, in addition to blood samples taken from beef cattle across Queensland as part of a second survey. RESULTS: Seropositivity was 16.8% (95% confidence interval 16.7-16.8%). CONCLUSION: Evidence of C. burnetii infection in beef cattle has public health implications for occupational exposure of primary producers and veterinarians and for the proximity of beef cattle properties to residential areas in regional Queensland. This study is the first known investigation of C. burnetii seroprevalence in beef cattle in Queensland and the first known use of an Australian C. burnetii isolate for screening using both phase II and phase I antigens. PMID- 21696376 TI - Retrospective study of outcome following desmotomy of the accessory ligament of the deep digital flexor tendon for type 1 flexural deformity in Thoroughbreds. AB - OBJECTIVE: Determine the long-term outcome for Thoroughbreds undergoing desmotomy of the accessory ligament of the deep digital flexor tendon (DAL-DDFT) for type 1 flexural deformity of the distal interphalangeal joint (DIPJ). DESIGN: Retrospective matched cohort study PROCEDURE: Medical records were retrieved over a 17-year period for Thoroughbreds that underwent DAL-DDFT for type 1 flexural deformity. Long-term outcome was determined by analysis of race records and comparison with maternal siblings. Comparisons between cases and controls included 2-year-old, 3-year-old and total career performance data. RESULTS: There were 46 cases of DAL-DDFT. The mean age at surgery was 151 days (median 118, range 2-562); 48% of case horses and 77% of 90 controls started in a race. For case horses that did race, the time to first race, total number of starts and prize money per race were not significantly different to maternal siblings. Age at the time of surgery did not alter the likelihood of starting a race. CONCLUSION: Thoroughbreds undergoing DAL-DDFT for type 1 flexural deformity of the DIPJ are less likely to race when compared with their maternal siblings. For those that do race, the time to first race, total races and earnings per race are not different from controls. There is no evidence to suggest that age at the time of surgery influences the likelihood of racing. PMID- 21696377 TI - Acute myeloid leukaemia (M6B: pure acute erythroid leukaemia) in a Thoroughbred foal. AB - A 10-week-old Thoroughbred filly was referred for anaemia of 4 weeks' duration. Haematology revealed severe anaemia and panleucopenia. Cytological examination of bone marrow smears revealed a myeloid to erythroid ratio <0.02:1 (reference range 0.5-2.4:1.0) and an abundance of erythroid precursor cells. The erythroid cell population included rubriblasts, prorubricytes and rubricytes, with only scant numbers of metarubricytes present. There were numerous mitotic erythroid cells, some of which were atypical and megaloblastic. These cytomorphological changes are consistent with pure acute erythroid leukaemia. No treatment was instituted and the filly died three days after presentation. This case illustrates the need to consider both haematology and bone marrow findings to establish a diagnosis of pure erythroid leukaemia. To our knowledge, there is no documented case of acute myeloproliferative disease in horses involving cells of erythroid lineage, but this condition should be considered a differential diagnosis for horses presenting with anaemia. PMID- 21696378 TI - Unusual growth variants of Avibacterium paragallinarum. AB - Two isolates of haemophilic bacteria originally isolated in the 1980s from chickens were re-examined. The addition of a 10% sterile filtrate from an overnight culture of Staphylococcus epidermidis allowed growth of both isolates in solid and liquid media that were otherwise not capable of supporting the growth of these isolates. Using the modified media, genotypic and serotypic studies were performed, which confirmed both isolates to be Avibacterium paragallinarum, with one isolate being serovar A and the other serovar C. The unusual growth requirements of these two isolates reinforces the need for careful interpretation by diagnostic laboratories examining chickens showing signs of upper respiratory tract disease. PMID- 21696379 TI - Small intestinal volvulus in a free-ranging female dugong (Dugong dugon). AB - An adult female dugong (Dugong dugon) was found dead and floating in Moreton Bay, Queensland, Australia. This animal was found to have a 360 degrees mesenteric volvulus with infarction of the associated segment of small intestine, and fibrinous peritonitis. Mortality was attributed to the volvulus and its sequelae. The cause was not apparent on gross or histological examination. PMID- 21696380 TI - Discussion of the paper of Ghosh, Taylor, and Sargent. PMID- 21696381 TI - Statistical modelling of network panel data: goodness of fit. AB - Networks of relationships between individuals influence individual and collective outcomes and are therefore of interest in social psychology, sociology, the health sciences, and other fields. We consider network panel data, a common form of longitudinal network data. In the framework of estimating functions, which includes the method of moments as well as the method of maximum likelihood, we propose score-type tests. The score-type tests share with other score-type tests, including the classic goodness-of-fit test of Pearson, the property that the score-type tests are based on comparing the observed value of a function of the data to values predicted by a model. The score-type tests are most useful in forward model selection and as tests of homogeneity assumptions, and possess substantial computational advantages. We derive one-step estimators which are useful as starting values of parameters in forward model selection and therefore complement the usefulness of the score-type tests. The finite-sample behaviour of the score-type tests is studied by Monte Carlo simulation and compared to t-type tests. PMID- 21696383 TI - Genotype-phenotype correlation in colorectal polyposis. AB - Familial adenomatous polyposis (FAP) has been divided into three clinical subtypes: mild, classical and severe. This study aimed to investigate for a correlation between genotype and phenotype. A codon-specific survival difference is unknown. A retrospective longitudinal study of 492 patients on the Manchester Polyposis Registry was conducted. Patients were grouped according to genotypes: 0, unknown mutation; 1, adenomatous polyposis coli (APC) 0-178 (and 312-412 of exon 9); 2, APC >1550; 3, APC 179-1249; 4, APC 1250-1549; and 5, MutYH. Date of onset of polyposis, incidence of colorectal cancer (CRC), survival and actuarial time to surgery were calculated. Median age of onset of polyposis for genotype 0 was 20.3 years, genotype 1 35.6 years, genotype 2 32.2, genotype 3 15.9 years, and genotype 4 14.8 years (p < 0.0001). Age of onset of CRC was similar between genotypes. Median survival for genotype 0 was 56.6 years, genotype 1 74.9 years, genotype 2 61.0 years, genotype 3 63.0 years, genotype 4 48.1 years, and genotype 5 69.7 years (p = 0.003). This survival difference was also seen when patients who underwent screening and those who did not were analysed separately. Survival in the screened population was 53.9 years in genotype 4 and 72.9 years in genotype 3. Patients with genotype 4 (APC 1249-1549) have a significantly worse survival despite screening and early prophylactic surgery. This analysis supports a genotype-phenotype correlation. Patients with a mutation APC 1249-1549 develop polyposis at an early age and have a worse survival. Patients with a mutation APC 0-178 or 312-412 develop polyposis later and have an improved survival. This survival difference has not previously been documented. PMID- 21696384 TI - High frequency of autosomal-recessive DFNB59 hearing loss in an isolated Arab population in Israel. AB - Autosomal-recessive non-syndromic hearing impairment (DFNB) is usually of prelingual onset with a moderate to profound degree of hearing loss. More than 70 DFNB loci have been mapped and ~40 causative genes have been identified. Non syndromic hearing impairment caused by mutations of DFNB59 (encoding pejvakin) has been described in a couple of families in which affected individuals presented with either auditory neuropathy or hearing loss of cochlear origin. We have identified and clinically evaluated three consanguineous families of Israeli Arab origin with prelingual non-syndromic hearing impairment and absent otoacoustic emissions in a total of eight affected individuals. All the families originate from the same village and bear the same family name. We have identified a c.406C>T (p.R136X) nonsense mutation in the DFNB59 gene in affected individuals from these families. Among the inhabitants of the village, we found an exceptionally high carrier frequency of ~1 in 12 individuals (7/85; 8.2%). The high prevalence of hearing impairment can be explained by a founder effect and the high consanguinity rate among the inhabitants of this village. PMID- 21696382 TI - Using Alzheimer's disease as a model for genetic risk disclosure: implications for personal genomics. AB - Susceptibility testing for common, complex adult-onset diseases is projected to become more commonplace as the rapid pace of genomic discoveries continues, and evidence regarding the potential benefits and harms of such testing is needed to inform medical practice and health policy. Apolipoprotein E (APOE) testing for risk of Alzheimer's disease (AD) provides a paradigm in which to examine the process and impact of disclosing genetic susceptibility for a prevalent, severe and incurable neurological condition. This review summarizes findings from a series of multi-site randomized clinical trials examining psychological and behavioral responses to various methods of genetic risk assessment for AD using APOE disclosure. We discuss challenges involved in disease risk estimation and communication and the extent to which participants comprehend and perceive utility in their genetic risk information. Findings on the psychological impact of test results are presented (e.g. distress), along with data on participants' health behavior and insurance purchasing responses (e.g. long-term care). Finally, we report comparisons of the safety and efficacy of intensive genetic counseling approaches to briefer models that emphasize streamlined processes and educational materials. The implications of these findings for the emerging field of personal genomics are discussed, with directions identified for future research. PMID- 21696385 TI - Smith-Lemli-Opitz syndrome among Arabs. AB - Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of variable presentation caused by the deficiency of the 3beta- hydroxycholesterol Delta(7) - reductase. Over the past 10 years, our biochemical laboratory has screened 191 plasma samples for possible SLOS, measuring the plasma cholesterol and 7 dehydrocholesterol using gas chromatography-mass spectrometry (GC-MS). The SLOS was confirmed in only five Arab patients with growth retardation, global developmental delay, dysmorphic features, and 2-3 toe syndactyly, among other findings. All cases represented moderate to severe form of SLOS. One patient had a unique cardiovascular malformation (cor triatriatum with significant obstruction of the right pulmonary veins). Two previously reported N287K (861 C>A) and R352Q (1055 G>A) and a novel R352L (1055 G>T) mutations were identified in the DHCR7 gene in these patients. The paper sheds light on this rare disease among Arabs and reviews all reported SLOS cases in the Arab population. PMID- 21696386 TI - A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome. AB - Although deficiency of complex I of the mitochondrial respiratory chain is a frequent cause of encephalopathy in children, only a few mutations have been reported in each of its subunits. In the absence of families large enough for conclusive segregation analysis and of robust functional testing, it is difficult to unequivocally show the causality of the observed mutations and to delineate genotype-phenotype correlations, making additional observations necessary. We observed two consanguineous siblings with an early-onset encephalopathy, medulla, brainstem and mesencephalon lesions on brain magnetic resonance imaging and death before 8 months of age, caused by a complex I deficiency. We used a homozygosity mapping approach and identified a missense mutation in the NDUFV1 gene. The mutation, p.Arg386His, affects a highly conserved residue, contiguous to a cysteine residue known to coordinate an Fe ion. This observation adds to our understanding of complex I deficiency disease. It validates the important role of Arg386 and therefore supports the current molecular model of iron-sulfur clusters in NDUFV1. PMID- 21696387 TI - De novo CDH1 mutation in a family presenting with early-onset diffuse gastric cancer. AB - In this report, we describe the first concluded case of a de novo germline mutation in CDH1 in a hereditary diffuse gastric cancer (HDGC) kindred. The incident case was a woman with a personal history of Hodgkin's lymphoma and diffuse gastric cancer, who was then confirmed to have a CDH1 mutation (c.1792 C>T (R598X)). The patient's mother was found to have the same CDH1 germline mutation; however, neither maternal grandparent was found to carry the mutation, thus leading to a conclusion that the proband's mother's mutation is of de novo origin. This case highlights the importance of recognition of the HDGC syndrome and of testing for CDH1 germline mutations in young individuals with diffuse gastric cancer without a family history of the disease. PMID- 21696388 TI - Novel mutation in ATP13A2 widens the spectrum of Kufor-Rakeb syndrome (PARK9). AB - Kufor-Rakeb syndrome (KRS) is a rare autosomal recessive inherited juvenile parkinsonian syndrome caused by mutations in ATP13A2. We describe six patients from a consanguineous Greenlandic Inuit family, homozygous for a novel frame shift mutation in exon 22 of ATP13A2 (c.2473C>AA, p.Leu825AsnfsX32). Disease onset varied from 10 to 29 years of age, the latest reported, and the clinical features were highly variable within a wide spectrum of an extrapyramidal pyramidal syndrome with cognitive/psychiatric features. Ataxia was seen in two patients and axonal neuropathy in one, features not previously related to KRS. Dopamine transporter scans showed symmetrical, severely reduced uptake in striatum in two patients. Magnetic resonance imaging was without atrophy in one patient despite disease duration of 17 years, and cerebral and cerebellar atrophy was seen in another patient after 4 years of disease duration. The molecular pathogenic mechanisms of ATP13A2 mutations are discussed. The observation that the mutant transcript is not degraded by nonsense-mediated RNA decay and the fact that none of the eight heterozygous carriers from the family have KRS symptoms suggest that the mutant protein does not interfere and destroy the function of the wild-type ATP13A2 protein. PMID- 21696389 TI - Relationship between dual-domain parameters and practical characterization data. AB - Dual-domain solute transport models produce significantly improved agreement to observations compared to single-domain (advection-dispersion) models when used in an a posteriori data fitting mode. However, the use of dual-domain models in a general predictive manner has been a difficult and persistent challenge, particularly at field-scale where characterization of permeability and flow is inherently limited. Numerical experiments were conducted in this study to better understand how single-rate mass transfer parameters vary with aquifer attributes and contaminant exposure. High-resolution reference simulations considered 30 different scenarios involving variations in permeability distribution, flow field, mass transfer timescale, and contaminant exposure time. Optimal dual domain transport parameters were empirically determined by matching to breakthrough curves from the high-resolution simulations. Numerical results show that mobile porosity increases with lower permeability contrast/variance, smaller spatial correlation length, lower connectivity of high-permeability zones, and flow transverse to strata. A nonzero non-participating porosity improves empirical fitting, and becomes larger for flow aligned with strata, smaller diffusion coefficient, and larger spatial correlation length. The non-dimensional mass transfer coefficient or Damkohler number tends to be close to 1.0 and decrease with contaminant exposure time, in agreement with prior studies. The best empirical fit is generally achieved with a combination of macrodispersion and first-order mass transfer. Quantitative prediction of ensemble-average dual domain parameters as a function of measurable aquifer attributes proved only marginally successful. PMID- 21696391 TI - The feasibility of Cryo In-SEM Raman microspectroscopy. AB - The combination of noninvasive compositional analysis by Raman microspectrometry with high-resolution imaging in the scanning electron microscope greatly expands the analytical capabilities of the electron microscope. However, the chemical preparation of scanning electron microscope (SEM) specimens, although adequate for low-resolution imaging of superficial detail, is not the true representation of the chemistry and composition of the sample, as extraction and aggregation artefacts as a result of dehydrating and cross-linking agents are abundant. The original chemical composition and ultrastructure is only preserved using cryo preparation methods. Therefore, a complete cryo transfer flange was designed and built to add cryogenic control of specimens to the configuration of the EMRAM instrument, a combined Raman spectrometer and XL-30 ESEM instrument. The Raman spectra of two model specimen, polystyrene beads and 2.3M sucrose were studied at ambient and cryogenic temperatures as well as during a heating ramp. Comparing the fingerprint regions of polystyrene and sucrose, both measured at ambient and at cryogenic conditions, only small spectral differences were observed for the main peaks of both molecules. A pronounced sharpening of the bands occurred in the 800-400 cm(-1) region, a result of the reduction of intermolecular interactions. The enhanced visibility of the lower frequency modes may offer interesting potential for more detailed interpretation of Raman spectra. PMID- 21696390 TI - Enzyme stability of microencapsulated Bifidobacterium animalis ssp. lactis Bb12 after freeze drying and during storage in low water activity at room temperature. AB - Stability of enzymes such as beta-galactosidase (beta-gal), beta-glucosidase (beta-glu), lactate dehydrogenase (LDH), pyruvate kinase (PK), hexokinase (HK), and ATPase of microencapsulated Bifidobacterium animalis ssp. lactis Bb12 after freeze-drying and after 10 wk of storage at low water activity (a(w)) at room temperature was studied. Bacteria were microencapsulated using alginate formulation with or without mannitol fortification (sodium alginate and mannitol [SAM] and sodium alginate [SA], respectively) by creating gel beads followed by freeze drying. Two types of dried gel beads were then stored at low a(w), such as 0.07, 0.1, and 0.2; storage in an aluminum foil was used as control. All storage was carried out at room temperature of 25 degrees C for 10 wk. Measurement of beta-gal, beta-glu, LDH, PK, HK, and ATPase (with or without exposure to pH 2.0 for 2 h) activities was carried out before freeze drying, after freeze drying, and after 10 wk of storage. There was a significant decrease in almost all enzyme activities, except that of PK. SAM and SA showed no different effect on maintaining enzyme activities during freeze drying. Storage for 10 wk at room temperature at various low a(w) using SAM and SA system had a significant effect on retention of most enzymes studied, except that of PK and LDH. Storage at a(w) of 0.07 and 0.1 was more effective in maintaining enzyme activities than storage at a(w) of 0.2 and in an aluminum foil. However, mannitol fortification into alginate system did not significantly improve retention of enzymes during 10 wk of storage. PMID- 21696392 TI - Spermatogonial stem cells alone are not sufficient to re-initiate spermatogenesis in the rat testis following adjudin-induced infertility. AB - The blood-testis barrier (BTB) is a unique ultrastructure in the testis, which creates a specialized microenvironment in the seminiferous epithelium known as the apical (or adluminal) compartment for post-meiotic germ-cell development and for maintenance of an immunological barrier. In this study, we have demonstrated unequivocally that a functional and intact BTB is crucial for the initiation of spermatogenesis, in particular, the differentiation of spermatogonial stem cells (SSCs). It was shown that adult rats (~300 g body weight, b.w.) treated with adjudin at 50 (low-dose) or 250 (high-dose) mg/kg b.w. by gavage led to germ-cell depletion from the seminiferous tubules and that >98% of the tubules were devoid of germ cells by ~2 week and rats became infertile in both groups after the sperm reserve in the epididymis was exhausted. While the population of SSC/spermatogonia in the seminiferous tubules from both groups was similar to that of normal rats, only rats from the low-dose group were capable of re initiating spermatogenesis; and by 20 weeks, greater than 75% of the tubules displayed normal spermatogenesis and the fertility of these rats rebounded. Detailed analysis by dual-labelled immunofluorescence analysis and a functional BTB integrity assay revealed that in both treatment groups, the BTB was disrupted from week 6 to week 12. However, the disrupted BTB 'resealed' in the low-dose group, but not in the high-dose group. Our findings illustrate that SSC/spermatogonia failed to differentiate into spermatocytes beyond A(aligned) spermatogonia in the high-dose group with a disrupted BTB. In short, these findings illustrate the critical significance of the BTB for re-initiation of spermatogenesis besides SSC and spermatogonia. PMID- 21696394 TI - Heterozygous deletion at the RLN1 locus in a family with testicular germ cell cancer identified by integrating copy number variation data with phenome and interactome information. AB - To search for disease-related copy number variations (CNVs) in families with a high frequency of germ cell tumours (GCT), we analysed 16 individuals from four families by array comparative genomic hybridization (aCGH) and applied an integrative systems biology algorithm that prioritizes risk-associated genes among loci targeted by CNVs. The top-ranked candidate, RLN1, encoding a Relaxin H1 peptide, although only detected in one of the families, was selected for further investigations. Validation of the CNV at the RLN1 locus was performed as an association study using qPCR with 106 sporadic testicular GCT patients and 200 healthy controls. Observed CNV frequencies of 1.9% among cases and 1.5% amongst controls were not significantly different and this was further confirmed by CNV data extracted from a genome-wide analysis of 189 cases and 380 controls, where similar frequencies of 2.2% were observed in both groups (p=1). Immunohistochemistry for Relaxin-H1 (RLN1), Relaxin-H2 (RLN2) and their cognate receptor, RXFP1, detected one, and in some cases both, of the relaxins in Leydig cells, Sertoli cells and a subset of neoplastic germ cells, whereas the receptor was present in Leydig cells and spermatids. Collectively, the findings show that a heterozygous loss at the RLN1 locus is not a genetic factor mediating high population-wide risk for testicular germ cell tumour, but do not exclude a contribution of this aberration in some cases of cancer. The preliminary expression data suggest a possible role of the relaxin peptides in spermatogenesis and warrant further studies. PMID- 21696393 TI - Bone morphogenetic protein signalling activity distinguishes histological subsets of paediatric germ cell tumours. AB - Germ cell tumours (GCTs) are cancers of the testis, ovary or extragonadal sites that occur in infants, children and adults. Testicular GCT is the most common cancer in young men aged 15-40 years. Abnormalities in developmental signalling pathways such as wnt/beta-catenin, TGF-beta/BMP and Hedgehog have been described in many childhood tumours. To date, however, the status of BMP signalling in GCTs has not been described. Herein, we examine BMP-SMAD signalling in a set of clinically-annotated paediatric GCTs. We find that BMP signalling activity is absent in undifferentiated tumours such as seminomas and dysgerminomas, but robustly present in most yolk sac tumours, a differentiated tumour type. Gene expression profiling of TGF-beta/BMP pathway genes in germinomas and yolk sac tumours reveals a set of genes that distinguish the two tumour types. There is significant intertumoural heterogeneity between tumours of the same histological subclass, implying that the BMP pathway can be differentially regulated in individual tumours. Finally, through miRNA expression profiling, we identify differential regulation of a set of miRNAs predicted to target the TGF-beta/BMP pathway at multiple sites. Taken together, these results suggest that the BMP signalling pathway may represent a new therapeutical target for childhood GCTs. PMID- 21696395 TI - Increased penile expression of transforming growth factor and elevated systemic oxidative stress in rabbits with chronic partial bladder outlet obstruction. AB - There is a growing body of evidence to support the direct link between obstructive bladder dysfunction and erectile dysfunction (ED). However, there have been few pathophysiological studies to determine the relationship between lower urinary tract syndrome (LUTS) and ED. As the transforming growth factor beta1 (TGF-beta1) that induces the synthesis of collagen in the penile tissues is critical for the development of ED, the first aim of this study was to investigate the expression of TGF-beta1 in the penis from male rabbits with chronic partial bladder outlet obstruction (PBOO). Besides, it has been suggested that oxidative stress plays a significant role in the pathophysiological mechanism of ED. Thus, the second aim of this study was to further investigate whether the urinary or serum oxidative stress markers are involved in chronic PBOO-induced penile dysfunction. A total of 16 male New Zealand White rabbits were separated equally into four groups: a control group and PBOO groups obstructed for 2, 4 and 8 weeks respectively. Using the RT-PCR and Western blot analysis, a progressive increase of TGF-beta1 in penis was found at 2, 4 and 8 weeks after obstruction. Moreover, the biomarkers for oxidative stress or oxidative damage were significantly detected in the penis of rabbits after PBOO, which include the enhancement of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine and plasma, plasma malondialdehyde (MDA) and total antioxidant capacity (TAC), as well as reduction of glutathione (GSH). On the basis of our results, the increase of TGF-beta1 and elevated systemic oxidative stress may play key roles to contribute to penile dysfunction after chronic PBOO. PMID- 21696396 TI - Foetal exposure to phthalate esters and anogenital distance in male newborns. AB - Phthalate esters, commonly used as plasticizers, show anti-androgenic activity and cause male reproductive malformation in experimental animals. However, the effects of prenatal exposure to phthalate esters in humans have not been extensively studied. The purpose of this study was to examine the relationship between prenatal exposure to phthalate esters and the anogenital distance (AGD) as a reproductive endpoint in human male newborns. Spot urine samples were collected from 111 Japanese pregnant women after obtaining their informed consent. Seven urinary phthalate ester metabolites were determined by high performance liquid chromatography-tandem mass spectrometry. Urinary isoflavones concentrations were measured as possible covariates because their oestrogenicities and high exposure levels among Japanese have the potential to affect male genital development. Birth outcomes and AGD, the distance from the centre of the anus to external genitalia, were measured for their male newborns. In a multiple regression model, the log-transformed mono-2-ethylhexyl phthalate concentration (specific gravity-corrected) was negatively significant, and maternal smoking status was positively significant, in explaining anogenital index (AGI) when potential covariates were controlled for. Urinary isoflavones did not significantly contribute to AGI in any models. Our results suggest that prenatal exposure to di(2-ethylhexyl) phthalate affects reproductive development in human males. PMID- 21696397 TI - Modest opposite associations of endogenous testosterone and oestradiol with left ventricular remodelling and function in healthy middle-aged men. AB - In healthy middle-aged men, endogenous testosterone does not seem to increase risk for cardiovascular disease (CVD). One explanation might be a differential effect of testosterone, and another, interference with oestradiol with respect to specific cardiovascular functions. To investigate these possibilities, we evaluated in a cross-sectional population of 1223 healthy men, aged 46 (6) years, associations between endogenous testosterone, oestradiol and left ventricular structure and function (echocardiography). Testosterone was inversely associated with ejection fraction (EF) and with more sensitive systolic tissue Doppler imaging indices. Oestradiol was positively associated with EF. These associations were confirmed by linear regression analyses, and consistent for calculated free as well as for total sex steroid concentrations. Standardized regression coefficients were -0.13 for testosterone (P < 0.01) and 0.12 for oestradiol (P < 0.01) for the association with EF, in a model which included height, waist circumference, triglycerides, glucose, systolic blood pressure, drug-treated hypertension, heart rate, haematocrit, current smoking, serum sampling time, age and excessive alcohol use. The study suggests an opposite link, albeit modestly, of testosterone and oestradiol with left ventricle systolic function in healthy middle-aged men. The finding provides a partial explanation for the overall neutral effect on CVD of testosterone in healthy middle-aged men. PMID- 21696398 TI - Screening of subfertile men for testicular carcinoma in situ by an automated image analysis-based cytological test of the ejaculate. AB - Testicular cancer (TC) is usually diagnosed after manifestation of an overt tumour. Tumour formation is preceded by a pre-invasive and asymptomatic stage, carcinoma in situ (CIS) testis, except for very rare subtypes. The CIS cells are located within seminiferous tubules but can be exfoliated and detected in ejaculates with specific CIS markers. We have built a high throughput framework involving automated immunocytochemical staining, scanning microscopy and in silico image analysis allowing automated detection and grading of CIS-like stained objects in semen samples. In this study, 1175 ejaculates from 765 subfertile men were tested using this framework. In 5/765 (0.65%) cases, CIS-like cells were identified in the ejaculate. Three of these had bilateral testicular biopsies performed and CIS was histologically confirmed in two. In total, 63 bilateral testicular biopsy were performed in conjunction with analysis of the ejaculates because of infertility work-up. Histological analysis of the biopsies for the presence of CIS yielded a test sensitivity of 0.67 and a specificity of 0.98. In addition, ejaculates from 45 patients with clinical signs of an overt TC were investigated and yielded a slightly lower sensitivity (0.51), possibly because of obstruction. We conclude that this novel non-invasive test combining automated immunocytochemistry and advanced image analysis allows identification of TC at the CIS stage with a high specificity, but a negative test does not completely exclude CIS. On the basis of the results, we propose that the assay could be offered to subfertile men and other patients who are at increased risk of TC. PMID- 21696399 TI - Are Caucasian-European men delaying fatherhood? Results of a 7 year observational study of infertile couples with male factor infertility. AB - This study was aimed at assessing presence and predictors of a trend towards more advanced paternal age at presentation in a cohort of 1283 Caucasian-European infertile couples with male factor infertility (MFI) over a short time frame. Multivariate linear regression analysis tested the association between predictors [namely, partners' age, length of infertility at first presentation, patients' comorbidities as scored with the Charlson Comorbidity Index (CCI) and educational status] and patient's age at presentation. Using anova, patient's age at presentation (F ratio: 2.43; p = 0.024) and patients' educational status (chi(2) trend: 142.38; p < 0.001) significantly increased over time. In contrast, length of infertility at first presentation, CCI and partners' age did not significantly change over time (all p >= 0.05). Linear regression analyses showed that CCI, educational status and year of presentation were not correlated with patients' age at presentation (all p >= 0.05), whereas partners' age (beta = 0.170; p < 0.001) and length of infertility (beta = 0.123; p = 0.004) were independent predictors of delayed fatherhood. These results showed a significant shift towards advanced paternal age, but a non-significant increase of maternal age at first presentation among Caucasian-European infertile couples with MFI over a short time frame. PMID- 21696400 TI - Male accessory gland infection and sperm parameters (review). AB - Male accessory gland infection (MAGI) has been identified among those diagnostic categories which have a negative impact on the reproductive function and fertility in males (Rowe et al., World Health Organization Manual for the Standardised Investigation and Diagnosis of the Infertile Couple, Cambridge University Press, Cambridge, 1993). MAGI is a hypernym which groups the following different clinical categories: prostatitis, prostate-vesiculitis and prostate vesiculo-epididymitis. Some of the characteristics they share are: common diseases, mainly have a chronic course, rarely cause obstruction of the seminal pathways, can have an unpredictable intracanicular spread to one or more sexual accessory glands of the reproductive tract, as well as to one or both sides. In this review, we show that all components involving the inflammatory response (from the agents which first trigger it to each component of the inflammatory response dynamic) can deteriorate conventional and/or non-conventional sperm parameters arising from one or more of the following mechanisms: altered secretory function of the epididymis, seminal vesicles, and prostate which reduce the antioxidant properties or scavenging role of the seminal plasma; deterioration of spermatogenesis; and (unilateral or bilateral) organic or functional sub-obstruction of the seminal tract. PMID- 21696401 TI - PPF microsphere depot sustains NSAID blood levels with infusion-like kinetics without 'burst'. AB - Management of pain is of paramount importance for a myriad of indications in human and animal health. Unfortunately, the administration of pain therapeutics is often complicated by insufficient control over pharmacokinetic profiles as a result of frequent oral dosing. Attempts to sustain and tightly control the concentration of these drugs in the blood via controlled release injectable formulations have typically resulted in drug 'burst', followed by marginal control over the ensuing pharmacokinetics. Here, precision particle fabrication (PPF) technology was used to produce uniform microspheres encapsulating the nonsteroidal anti-inflammatory drug meloxicam. After subcutaneous injection, plasma concentrations of meloxicam were held constant in canines for more than 2 weeks without initial drug burst. Pharmacokinetic profiles were accurately modeled using equations typically applied to steady-state infusion. PPF microsphere depots of pain therapeutics or other compounds may ultimately improve safety and sustain the efficacy of medications where such controlled uniform exposure would be therapeutically beneficial. PMID- 21696402 TI - Morphological and physiological differentiation of seedlings between dry and wet habitats in a tropical dry forest. AB - A common observation in tropical dry forests is the habitat preference of tree species along spatial soil water gradients. This pattern of habitat partitioning might be a result of species differentiation in their strategy for using water, along with competing functions such as maximizing water exploitation and tolerating soil water stress. We tested whether species from drier soil conditions exhibited a tolerance strategy compared with that of wet-habitat species. In a comparison of 12 morphophysiological traits in seedlings of 10 closely related dry and wet-habitat species pairs, we explored what trade-offs guide differentiation between habitats and species. Contrary to our expectations, dry-habitat species showed mostly traits associated with an exploitation strategy (higher carbon assimilation capacity, specific leaf area and leaf-specific conductivity and lower water-use efficiency). Strikingly, dry-habitat species tended to retain their leaves longer during drought. Additionally, we detected multiple strategies to live within each habitat, in part due to variation of strategies among lineages, as well as functional differentiation along the water storage capacity-stem density (xylem safety) trade-off. Our results suggest that fundamental trade-offs guide functional niche differentiation among tree species expressed both within and between soil water habitats in a tropical dry forest. PMID- 21696404 TI - Preliminary evaluation of the genotoxic potential of a hydrophilic polymer with three preservation systems. AB - This study compared the genotoxic potential of a polymeric associative thickener used in topically applied emulsions preserved with three different preservative systems. The method used for the assessment of genotoxicity is the in vitro micronucleus test [Organization for Economic Cooperation and Development (OECD) guideline number 487]. When changing an additive such as a preservation system in a raw material, it is crucial to re-evaluate its toxicity potential because this change may significantly alter its properties. This study shows that at the levels tested neither of the systems evaluated demonstrated any cytotoxic or genotoxic effects. Skin exposure must take into consideration factors such as duration, skin condition and metabolism, but most importantly concentration. Although preservatives can be toxic at high concentrations, they are usually safe at the concentrations used in cosmetic raw materials and formulations. If used to preserve raw materials, they undergo further dilution when added to the formulation. PMID- 21696403 TI - Leaf wax n-alkane deltaD values are determined early in the ontogeny of Populus trichocarpa leaves when grown under controlled environmental conditions. AB - The stable hydrogen isotope ratios (deltaD) of leaf wax n-alkanes record valuable information on plant and ecosystem water relations. It remains, however, unknown if leaf wax n-alkane deltaD values record only environmental variation during the brief period of time of leaf growth or if leaf wax n-alkane deltaD values are affected by environmental variability throughout the entire lifespan of a leaf. To resolve these uncertainties, we irrigated Populus trichocarpa trees with a pulse of deuterium-enriched water and used compound-specific stable hydrogen isotope analyses to test if the applied tracer could be recovered from leaf wax n alkanes of leaves that were at different stages of their development during the tracer application. Our experiment revealed that only leaf wax n-alkanes from leaves that had developed during the time of the tracer application were affected, while leaves that were already fully matured at the time of the tracer application were not. We conclude from our study that under controlled environmental conditions, leaf wax n-alkanes are synthesized only early in the ontogeny of a leaf. Our experiment has implications for the interpretation of leaf wax n-alkane deltaD values in an environmental context, as it suggests that these compounds record only a brief period of the environmental variability that a leaf experiences throughout its life. PMID- 21696405 TI - Eucalyptus increases ceramide levels in keratinocytes and improves stratum corneum function. AB - The objectives of this study were to identify a plant extract that would improve stratum corneum functions and to elucidate the mechanism(s) involved. Based on the information that stratum corneum functions depend on the level of ceramide in the stratum corneum, we identified a Eucalyptus extract that was able to increase the level of ceramide in human keratinocytes in culture and in human stratum corneum and that improves the stratum corneum water holding and barrier functions. Addition of the Eucalyptus extract to human keratinocytes in culture increased the level of ceramide in a dose-dependent manner and also increased the biosynthesis of ceramide, glucosylceramide and sphingomyelin. Topical application of the Eucalyptus extract on the dry skin of human subjects induced by acetone and diethylether treatment resulted in a significant increase in ceramide level in the stratum corneum, a significant improvement in its water-holding function and an improvement in its barrier function. The addition of macrocarpal A, one of the main components of the Eucalyptus extract, to human keratinocytes in culture increased the level of ceramide and the mRNA expression of serine palmitoyltransferase, acid sphingomyelinase, neutral sphingomyelinase, glucosylceramide synthase and glucocerebrosidase in a dose-dependent manner. Our results indicate that the increased content of ceramides in the stratum corneum may underlie the therapeutic effect of the Eucalyptus extract. Our results also indicate the possibility that macrocarpal A is the key component that stimulates the synthesis of ceramide in the stratum corneum. PMID- 21696406 TI - Use of an isothermal microcalorimetry assay to characterize microbial oxalotrophic activity. AB - Isothermal microcalorimetry (IMC) has been used in the past to monitor metabolic activities in living systems. A few studies have used it on ecological research. In this study, IMC was used to monitor oxalotrophic activity, a widespread bacterial metabolism found in the environment, and particularly in soils. Six model strains were inoculated in solid angle media with K-oxalate as the sole carbon source. Cupriavidus oxalaticus, Cupriavidus necator, and Streptomyces violaceoruber presented the highest activity (91, 40, and 55 MUW, respectively) and a maximum growth rate (MUmax h(-1) ) of 0.264, 0.185, and 0.199, respectively, among the strains tested. These three strains were selected to test the incidence of different oxalate sources (Ca, Cu, and Fe-oxalate salts) in the metabolic activity. The highest activity was obtained in Ca-oxalate for C. oxalaticus. Similar experiments were carried out with a model soil to test whether this approach can be used to measure oxalotrophic activity in field samples. Although measuring oxalotrophic activity in a soil was challenging, there was a clear effect of the amendment with oxalate on the metabolic activity measured in soil. The correlation between heat flow and growth suggests that IMC analysis is a powerful method to monitor bacterial oxalotrophic activity. PMID- 21696407 TI - Abundance and phylogenetic identity of archaeoplankton in the permanent oxygen minimum zone of the eastern tropical South Pacific. AB - We assessed the abundance and molecular phylogeny of archaeoplankton in the oxygen minimum zone (OMZ) of the eastern tropical South Pacific, using specific probe hybridization and phylogenetic analysis of the SSU-rRNA gene. Euryarchaea from Marine Group-II (MG-II) were most abundant in the surface oxic layer, representing 4.0+/-2.0% of the total picoplankton, while crenarchaea from Group I.1a (G-I.1a) peaked at the oxyclines, with a relative abundance of 8.1+/-4.3% (upper oxycline). In most of the stations, the abundance of both the groups decreased at the core of the OMZ, where a secondary maximum in cell density is commonly observed. The majority of the phylotypes affiliated with one of three groups: MG-II, euryarchaeal Marine Group-III (MG-III) and G-I.1a (75.9%, 12.8% and 10.3%, respectively). While MG-II phylotypes were found throughout the water column and G-I.1a ones were predominantly found within the oxyclines, MG-III phylotypes came almost exclusively from the OMZ core. Higher archaeal richness was found within the OMZ, with some of the exclusive lineages grouping with sequences from the deep ocean and hydrothermal vents. Moreover, G-I.1a sequences from the OMZ grouped into a different subcluster from the aerobic ammonium oxidizer Nitrosopumilus maritimus. Thus, the community structure of archaeoplankton in OMZs is rich and distinct, with G-I.1a members particularly prominent at the oxyclines. PMID- 21696408 TI - Comparison of phosphate uptake rates by the smallest plastidic and aplastidic protists in the North Atlantic subtropical gyre. AB - The smallest phototrophic protists (<3 MUm) are important primary producers in oligotrophic subtropical gyres - the Earth's largest ecosystems. In order to elucidate how these protists meet their inorganic nutrient requirements, we compared the phosphate uptake rates of plastidic and aplastidic protists in the phosphate-depleted subtropical and tropical North Atlantic (4-29 degrees N) using a combination of radiotracers and flow cytometric sorting on two Atlantic Meridional Transect cruises. Plastidic protists were divided into two groups according to their size (<2 and 2-3 MUm). Both groups of plastidic protists showed higher phosphate uptake rates per cell than the aplastidic protists. Although the phosphate uptake rates of protist cells were on average seven times (P<0.001) higher than those of bacterioplankton, the biomass-specific phosphate uptake rates of protists were one fourth to one twentieth of an average bacterioplankton cell. The unsustainably low biomass-specific phosphate uptake by both plastidic and aplastidic protists suggests the existence of a common alternative means of phosphorus acquisition - predation on phosphorus-rich bacterioplankton cells. PMID- 21696411 TI - LRRK2 expression in idiopathic and G2019S positive Parkinson's disease subjects: a morphological and quantitative study. AB - AIMS: Mutations in the gene encoding leucine-rich repeat kinase-2 (LRRK2) have been established as a common genetic cause of Parkinson's disease (PD). The distribution of LRRK2 mRNA and protein in the human brain has previously been described, although it has not been reported in PD cases with the common LRRK2 G2019S mutation. METHODS: To further elucidate the role of LRRK2 in PD, we determined the localization of LRRK2 mRNA and protein in post-mortem brain tissue from control, idiopathic PD (IPD) and G2019S positive PD cases. RESULTS: Widespread neuronal expression of LRRK2 mRNA and protein was recorded and no difference was observed in the morphological localization of LRRK2 mRNA or protein between control, IPD and G2019S positive PD cases. Using quantitative real-time polymerase chain reaction, we demonstrated that there is no regional variation in LRRK2 mRNA in normal human brain, but we have identified differential expression of LRRK2 mRNA with significant reductions recorded in limbic and neocortical regions of IPD cases compared with controls. Semi quantitative analysis of LRRK2 immunohistochemical staining demonstrated regional variation in staining intensity, with weak LRRK2 immunoreactivity consistently recorded in the striatum and substantia nigra. No clear differences were identified in LRRK2 immunoreactivity between control, IPD and G2019S positive PD cases. LRRK2 protein was identified in a small proportion of Lewy bodies. CONCLUSIONS: Our data suggest that widespread dysregulation of LRRK2 mRNA expression may contribute to the pathogenesis of IPD. PMID- 21696410 TI - Review: Contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates. AB - Professional boxers and other contact sport athletes are exposed to repetitive brain trauma that may affect motor functions, cognitive performance, emotional regulation and social awareness. The term of chronic traumatic encephalopathy (CTE) was recently introduced to regroup a wide spectrum of symptoms such as cerebellar, pyramidal and extrapyramidal syndromes, impairments in orientation, memory, language, attention, information processing and frontal executive functions, as well as personality changes and behavioural and psychiatric symptoms. Magnetic resonance imaging usually reveals hippocampal and vermis atrophy, a cavum septum pellucidum, signs of diffuse axonal injury, pituitary gland atrophy, dilated perivascular spaces and periventricular white matter disease. Given the partial overlapping of the clinical expression, epidemiology and pathogenesis of CTE and Alzheimer's disease (AD), as well as the close association between traumatic brain injuries (TBIs) and neurofibrillary tangle formation, a mixed pathology promoted by pathogenetic cascades resulting in either CTE or AD has been postulated. Molecular studies suggested that TBIs increase the neurotoxicity of the TAR DNA-binding protein 43 (TDP-43) that is a key pathological marker of ubiquitin-positive forms of frontotemporal dementia (FTLD-TDP) associated or not with motor neurone disease/amyotrophic lateral sclerosis (ALS). Similar patterns of immunoreactivity for TDP-43 in CTE, FTLD-TDP and ALS as well as epidemiological correlations support the presence of common pathogenetic mechanisms. The present review provides a critical update of the evolution of the concept of CTE with reference to its neuropathological definition together with an in-depth discussion of the differential diagnosis between this entity, AD and frontotemporal dementia. PMID- 21696412 TI - A quantitative study of the neuropathology of 32 sporadic and familial cases of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). AB - AIMS: To further characterize the neuropathology of the heterogeneous molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). METHODS: We quantified the neuronal cytoplasmic inclusions, glial inclusions, neuronal intranuclear inclusions, dystrophic neurites, surviving neurones, abnormally enlarged neurones, and vacuoles in regions of the frontal and temporal lobe using a phosphorylation-independent TDP-43 antibody in 32 cases of FTLD-TDP comprising sporadic and familial cases, with associated pathology such as hippocampal sclerosis (HS) or Alzheimer's disease (AD), and four neuropathological subtypes using TDP-43 immunohistochemistry. Analysis of variance (anova) was used to compare differences between the various groups of cases. RESULTS: These data from FTLD-TDP cases demonstrate quantitative differences in pathological features between: (i) regions of the frontal and temporal lobe; (ii) upper and lower cortex; (iii) sporadic and progranulin (GRN) mutation cases; (iv) cases with and without AD or HS; and (v) between assigned subtypes. CONCLUSIONS: The data confirm that the dentate gyrus is a major site of neuropathology in FTLD-TDP and that most laminae of the cerebral cortex are affected. GRN mutation cases are quantitatively different from sporadic cases, while cases with associated HS and AD have increased densities of dystrophic neurites and abnormally enlarged neurones respectively. There is little correlation between the subjective assessment of subtypes and the more objective quantitative data. PMID- 21696413 TI - Review: the architecture of inflammatory demyelinating lesions: implications for studies on pathogenesis. AB - Recent technological advances provided the chance to analyse the molecular events involved in the pathogenesis of lesions in human disease. A major prerequisite for such studies is, however, that the pathological material used is exactly defined and characterized. In multiple sclerosis (MS), this is difficult, as several types of active lesions exist, depending upon the stage of the disease, the age and location of these lesions and the inter-individual differences between patients. In addition, within an active lesion, different closely adjacent zones are present reflecting initial tissue injury, debris removal or repair. Here evidence is reviewed, showing that distinct subareas of active MS lesions reflect different pathological hallmarks of lesion evolution. These data provide the basis for our understanding of the pathogenesis of tissue injury in MS and imply that studies on MS pathogenesis have to rely on a clear definition of the lesions analysed and have to focus on specific lesion areas, isolated by microdissection. In addition, these data also imply that molecules, identified in these studies, must be confirmed and validated in the correct context of lesion initiation and/or progression. PMID- 21696414 TI - Neuropathological analysis of brain lesions in late-onset depression. PMID- 21696415 TI - BRAF-KIAA1549 fusion transcripts are less frequent in pilocytic astrocytomas diagnosed in adults. AB - AIM: Duplication of 7q34 resulting in generation of BRAF-KIAA1549 fusion transcripts is a characteristic event in pilocytic astrocytoma that may also aid distinction from diffuse astrocytic tumours. As data on BRAF-KIAA1549 fusion transcript status remain mainly limited to children, we aimed to examine the diagnostic value of BRAF-KIAA1549 fusion transcripts across all age groups. METHODS: BRAF-KIAA1549 fusion transcript status was examined using reverse transcription polymerase chain reaction on formalin-fixed paraffin-embedded samples of 105 primary pilocytic astrocytomas [median patient age: 17 years (1-74 years)]. RESULTS: Informative results (distinct wildtype BRAF bands detectable) were obtained in 105/124 cases (85%). Fusion transcripts were detected in 53 of cases (51%). They were more often encountered in tumours of infratentorial location [42/67 (63%) vs. 11/38 (29%)] and comprised KIAA1549-Ex16_BRAF-Ex9 (32 cases), KIAA1549-Ex15_BRAF-Ex9 (14 cases) and KIAA1549-Ex16_BRAF-Ex11 (seven cases). Fusion transcripts were present in 79% of tumours diagnosed in the first decade of life, but only in 51% of patients aged 11-20 years, 42% of patients aged 21-30 years, 30% of patients aged 31-40 years and 7% of patients older than 40 years. On multivariate logistic regression analysis, the association of fusion transcript status and age was confirmed adjusting for tumour location (P = 0.006). CONCLUSIONS: The frequency of BRAF-KIAA1549 fusion transcripts is significantly lower in adult patients with pilocytic astrocytoma, weakening the sensitivity of this specific diagnostic marker in that age group. PMID- 21696416 TI - Unmyelinated axons are more vulnerable to degeneration than myelinated axons of the cardiac nerve in Parkinson's disease. AB - AIMS: We recently demonstrated accumulation of alpha-synuclein aggregates of the cardiac sympathetic nerve in Parkinson's disease (PD) and a possible relationship between degeneration of the cardiac sympathetic nerve and alpha-synuclein aggregates. The aim of this study is to determine whether there is a difference in the degenerative process between unmyelinated and myelinated axons of the cardiac nerve. METHODS: We immunohistochemically examined cardiac tissues from four pathologically verified PD patients, nine patients with incidental Lewy body disease (ILBD) and five control subjects, using antibodies against neurofilament, myelin basic protein (MBP) and alpha-synuclein. First, we counted the number of neurofilament-immunoreactive axons not surrounded by MBP (unmyelinated axons) and those surrounded by MBP (myelinated axons). Next, we counted the number of unmyelinated and myelinated axons with alpha-synuclein aggregates. RESULTS: (i) The percentage of unmyelinated axons in PD (77.5 +/- 9.14%) was significantly lower compared to that in control subjects (92.2 +/- 2.40%). (ii) The ratio of unmyelinated axons with alpha-synuclein aggregates to total axons with alpha synuclein aggregates in ILBD ranged from 94.4 to 100 (98.2 +/- 2.18%). Among axons with alpha-synuclein aggregates, unmyelinated axons were the overwhelming majority, comprising 98.2%. CONCLUSION: These findings suggest that in PD unmyelinated axons are more vulnerable to degeneration than myelinated axons of the cardiac nerve, because alpha-synuclein aggregates accumulate much more abundantly in unmyelinated axons. PMID- 21696417 TI - Post-mortem findings in 10 patients with presumed normal-pressure hydrocephalus and review of the literature. AB - AIMS: Neuropathological features of idiopathic normal-pressure hydrocephalus (iNPH) are poorly characterized. Brain biopsy during life may help in the differential diagnosis of dementia, but post-mortem validation of biopsy findings is scarce. Here we review and report brain biopsy and post-mortem neuropathological findings in patients with presumed NPH. METHODS: We evaluated 10 patients initially investigated by intraventricular pressure monitoring and a frontal cortical biopsy for histological and immunohistochemical assessment as a diagnostic procedure for presumed NPH. RESULTS: Out of the 10 patients, eight were shunted and seven benefited. Until death, six had developed severe and two mild cognitive impairment. One was cognitively unimpaired, and one was mentally retarded. Three subjects displayed amyloid-beta (Abeta) aggregates in their frontal cortical biopsy obtained at the initial procedure. One of these patients developed Alzheimer's disease during a follow-up time of nearly 10 years. One patient with cognitive impairment and NPH suffered from corticobasal degeneration. In six patients various vascular lesions were seen at the final neuropathological investigation. Five of them were cognitively impaired, and in four vascular lesions were seen sufficient in extent to be considered as causative regarding their symptoms. CONCLUSIONS: The frequent finding of vascular pathology in NPH is intriguing, suggesting that vascular alterations might be causative of cognitive impairment in a notable number of patients with NPH and dementia. Brain biopsy can be used to detect Abeta aggregates, but neuropathological characteristics of iNPH as a distinct disease still need to be discovered. PMID- 21696418 TI - Septic metastatic encephalitis: coexistence of brain damage and repair. AB - AIMS: Septic metastatic encephalitis (SME) arises from systemic bacterial infections and is a severe complication of sepsis with a high mortality. In this study, we examined the neuropathological findings in humans suffering from SME including white matter pathology and proliferation of neural precursor cells in the hippocampal dentate gyrus. METHODS: The brains of 10 autopsy cases with SME and 10 control cases after sudden death from non-neurological causes were studied by means of immunohistochemistry. RESULTS: We found diffuse axonal injury and demyelination in the frontal cortex (P = 0.01) as well as increased numbers of recently generated TUC-4 expressing neurones in the hippocampal dentate gyrus in SME cases (P = 0.01). The median density of apoptotic granule cells in the dentate gyrus also was higher in SME cases, the difference, however, failed to reach statistical significance (P = 0.25). CONCLUSION: The coexistence of degenerative processes predominantly in the neocortex and regenerative activity in the hippocampal formation known from bacterial meningitis also characterizes the pathology of SME. PMID- 21696419 TI - Recurrent anaplastic meningioma treated by sunitinib based on results from quantitative proteomics. PMID- 21696420 TI - The HSPB8-BAG3 chaperone complex is upregulated in astrocytes in the human brain affected by protein aggregation diseases. AB - AIMS: HSPB8 is a small heat shock protein that forms a complex with the co chaperone BAG3. Overexpression of the HSPB8-BAG3 complex in cells stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, whose accumulation is a hallmark of many neurodegenerative disorders. HSPB8-BAG3 could thus play a protective role in protein aggregation diseases and might be specifically upregulated in response to aggregate-prone protein-mediated toxicity. Here we analysed HSPB8-BAG3 expression levels in post-mortem human brain tissue from patients suffering of the following protein conformation disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease and spinocerebellar ataxia type 3 (SCA3). METHODS: Western blotting and immunohistochemistry techniques were used to analyse HSPB8 and BAG3 expression levels in fibroblasts from SCA3 patients and post-mortem brain tissues, respectively. RESULTS: In all diseases investigated, we observed a strong upregulation of HSPB8 and a moderate upregulation of BAG3 specifically in astrocytes in the cerebral areas affected by neuronal damage and degeneration. Intriguingly, no significant change in the HSPB8-BAG3 expression levels was observed within neurones, irrespective of their localization or of the presence of proteinaceous aggregates. CONCLUSIONS: We propose that the upregulation of HSPB8 and BAG3 may enhance the ability of astrocytes to clear aggregated proteins released from neurones and cellular debris, maintain the local tissue homeostasis and/or participate in the cytoskeletal remodelling that astrocytes undergo during astrogliosis. PMID- 21696421 TI - S100beta as a novel and accessible indicator for the presence of monocyte-driven encephalitis in AIDS. AB - AIMS: The pathogenesis of human/simian immunodeficiency virus encephalitis (HIVE/SIVE) remains incompletely understood, but is associated with alterations in the blood-brain barrier. At present, it is not possible to easily determine if an individual has HIVE/SIVE before post mortem examination. METHODS: We have examined serum levels of the astroglial protein S100beta in SIV-infected macaques and show that it can be used to determine which animals have SIVE. We also checked for correlations with inflammatory markers such as CCL2/MCP-1, IL-6 and C reactive protein. RESULTS: We found that increased S100beta protein in serum correlated with decreased expression of the tight junction protein zonula occludens-1 on brain microvessels. Furthermore, the decrease in zonula occludens 1 expression was spatially related to SIVE lesions and perivascular deposition of plasma fibrinogen. There was no correlation between encephalitis and plasma levels of IL-6, MCP-1/CCL2 or C-reactive protein. CONCLUSIONS: Together, these data indicate that SIVE lesions are associated with vascular leakage that can be determined by S100beta protein in the periphery. The ability to simply monitor the presence of SIVE will greatly facilitate studies of the neuropathogenesis of AIDS. PMID- 21696422 TI - Utility of Ki67 immunostaining in the grading of pineal parenchymal tumours: a multicentre study. AB - AIMS: Pineal parenchymal tumours (PPTs) are rare neoplasms that are divided into pineocytoma (PC), pineoblastoma (PB) and PPT of intermediate differentiation (PPTID). Factors affecting the survival of patients with PPTs are morphological subtype and histological grading according to mitotic index and neurofilament immunostaining. Grading criteria to distinguish PPTIDs are difficult to define, particularly when using small specimens. The Ki67 labelling index (LI) might be helpful in distinguishing between grade II and III PPTIDs. Our study was performed to assess the predictive value of the Ki67 LI in a large cooperative series of PPTs and to evaluate whether inclusion of this data would improve and refine the World Health Organization classification. METHODS: A retrospective analysis of 33 PPTs was performed. The histological features of the tumours were reviewed and Ki67 LI scoring was evaluated by immunohistochemistry. Data were correlated with the patients' survival. RESULTS: The mean Ki67 LI was significantly different for tumour grades (0 in PC, 5.2 +/- 0.4 in PPTID grade II, 11.2 +/- 2.0 in PPTID grade III, 36.4 +/- 6.2 in PB; P < 0.0001). However, there was no statistically significant difference in either overall or disease free survival evaluated by the Kaplan-Meier method for patients with different grade tumours or Ki67 LI, possibly due to the different clinical management of patients in different centres. CONCLUSIONS: The Ki67 LI may be a useful additional tool for grading PPTs, more particularly in small tumour samples. PMID- 21696424 TI - Development and validation of a parenting assessment tool for Chinese parents. AB - OBJECTIVE: The objective of this study was to develop a parenting assessment tool (PAT) for parents of children aged 3 to 6 years to assess parenting attitudes and skills within the Chinese socio-cultural context. METHODS AND PARTICIPANTS: Focus group discussions were used to gather information for composing the PAT test items. Factor analysis was performed to build and refine the factor structure of PAT. Ten cities included in a larger programme, the Early Childhood Development Promotion Project carried out by the Capital Institute of Pediatrics in China, were chosen as the study area. Six hundred and twelve parents and their single children were chosen from those 10 cities by convenience sampling for the large scale investigation of PAT, and the results were used to test and validate the psychometric properties of PAT. RESULTS: The internal consistency of total PAT scores was 0.87, and those of the eight subscales ranged from 0.53 to 0.79. Test retest reliability over 2 weeks was also significant for the total scores and all subscales (range: 0.68-0.89). For the factor structure, an eight-factor solution accounting for 65.54% of the variance was most consistently fit. Concurrent validity was supported by significant positive correlations between total PAT scores and children's language ability, sociability and adaptive ability as assessed by the Developmental Diagnostic Scale of Children Aged 0-6 Years. CONCLUSIONS: The newly devised PAT test is a reliable instrument to assess the parenting skills and attitudes of parents of young children in urban China. PMID- 21696425 TI - Dying, death, disabled children and young people: how might we be better prepared? PMID- 21696423 TI - Neuropathological analysis of brainstem cholinergic and catecholaminergic nuclei in relation to rapid eye movement (REM) sleep behaviour disorder. AB - AIMS: Rapid eye movement sleep behaviour disorder (RBD) is characterized by loss of muscle atonia during rapid eye movement sleep and is associated with dream enactment behaviour. RBD is often associated with alpha-synuclein pathology, and we examined if there is a relationship of RBD with cholinergic neuronal loss in the pedunculopontine/laterodorsal tegmental nucleus (PPN/LDT), compared to catecholaminergic neurones in a neighbouring nucleus, the locus coeruleus (LC). METHODS: This retrospective study utilized human brain banked tissues of 11 Lewy body disease (LBD) cases with RBD, 10 LBD without RBD, 19 Alzheimer's disease (AD) and 10 neurologically normal controls. Tissues were stained with choline acetyl transferase immunohistochemistry to label neurones of PPN/LDT and tyrosine hydroxylase for the LC. The burden of tau and alpha-synuclein pathology was measured in the same regions with immunohistochemistry. RESULTS: Both the LC and PPN/LDT were vulnerable to alpha-synuclein pathology in LBD and tau pathology in AD, but significant neuronal loss was only detected in these nuclei in LBD. Greater cholinergic depletion was found in both LBD groups, regardless of RBD status, when compared with normals and AD. There were no differences in either degree of neuronal loss or burden of alpha-synuclein pathology in LBD with and without RBD. CONCLUSIONS: Whether decreases in brainstem cholinergic neurones in LBD contribute to RBD is uncertain, but our findings indicate these neurones are highly vulnerable to alpha-synuclein pathology in LBD and tau pathology in AD. The mechanism of selective alpha-synuclein-mediated neuronal loss in these nuclei remains to be determined. PMID- 21696426 TI - Children's and parents' beliefs regarding the value of walking: rehabilitation implications for children with cerebral palsy. AB - BACKGROUND: Walking for children with cerebral palsy (CP) has physiological and functional benefits, but also holds symbolic significance that largely remains unexplored. The aims of this pilot study were to describe beliefs about the value of walking held by children with CP and their parents, and to examine how these beliefs inform rehabilitation choices and perceptions of 'success'. METHODS: A critical qualitative design was employed. Six parents and six children with CP (Gross Motor Function Classification System III or IV, aged 9 to 18 years) each participated in a private interview. Analyses examined the relationship between dominant social beliefs regarding walking and participants' accounts. RESULTS: Parents' accounts revealed that all adopted a stance of doing something/trying anything as part of being a 'good parent' and maintaining hope. Tapering of walking interventions contributed to feelings of guilt and doubt. Children primarily viewed walking as exercise rather than functional. Their accounts also demonstrated how they internalized negative attitudes towards disability and judged themselves accordingly. CONCLUSIONS: The results of this pilot study provide provisional evidence regarding how dominant social values regarding walking and disability are taken up by parents and children. They suggest that rehabilitation programmes need to consider how they may unintentionally reinforce potentially harmful choices, and how best to engage families in discussions of their evolving values and treatment priorities. Further research is needed with a larger sample. PMID- 21696427 TI - The impact of childhood abuse history, domestic violence and mental health symptoms on parenting behaviour among mothers in Japan. AB - BACKGROUND: To assess the impact of childhood abuse history, domestic violence experiences and mental health symptoms on the parenting behaviour of mothers in Japan who have separated from violent husbands or partners. METHODS: A self administered questionnaire survey was conducted on a sample of mothers (n = 304) and their children (n = 498) residing in 83 mother-child homes in Japan. The survey assessed the mothers' childhood abuse history (physical, psychological and sexual abuse and neglect history), domestic violence experiences, current mental health symptoms (dissociative, depressive and traumatic symptoms) and parenting behaviours after moving into the homes to separate from a violent husband or partner. RESULTS: The mothers' childhood abuse history and experience of domestic violence were not associated with their not playing with their children. In contrast, the mothers' dissociative and depressive symptoms were significantly associated with not playing with their children. Although there was no association between the mothers' total childhood abuse history and not praising their children, their childhood physical abuse history was significantly associated with their not praising their children. The dissociative and depressive symptoms were also associated with no praise. Interestingly, the experience of domestic violence showed an inverse association with no praise. CONCLUSIONS: Mental health symptoms, more specifically dissociative and depressive symptoms, are associated with a decrease in parenting quality. Mothers who were physically abused as children are less likely to praise their own children, independent of maternal mental health symptoms. In contrast, mothers who experienced domestic violence but subsequently separated from their violent husbands or partners are more likely to praise their children. The treatment of mental health symptoms, particularly dissociative and depressive symptoms, therapy for childhood abuse history and separation from violent husbands or partners might be effective ways to enhance the quality of parenting in Japan. PMID- 21696428 TI - Comparisons of computed tomography, contrast-enhanced computed tomography and standing low-field magnetic resonance imaging in horses with lameness localised to the foot. Part 2: Lesion identification. AB - REASONS FOR PERFORMING STUDY: No previous study compares computed tomography (CT), contrast-enhanced computed tomography (CECT) and standing low-field magnetic resonance imaging (LFMRI) to detect lesions in horses with lameness localised to the foot. This study will help clinicians understand the limitations of these techniques. OBJECTIVES: To determine if CT, CECT and LFMRI would identify lesions within the distal limb and document discrepancies with lesion distribution and lesion classification. METHODS: Lesions in specific structures identified on CT and MR images of feet (31 limbs) from the same horse were reviewed and compared. Distributions of lesions were compared using a Chi-squared test and techniques analysed using the paired marginal homogeneity test for concordance. RESULTS: Lesions of the deep digital flexor tendon (DDFT) were most common and CT/CECT identified more lesions than LFMRI. Deep digital flexor tendon lesions seen on LFMRI only were frequently distal to the proximal extent of the distal sesamoid and DDFT lesions seen on CT/CECT only were frequently proximal to the distal sesamoid. Lesions identified on LFMRI only were core (23.3%) or splits (43.3%), whereas lesions identified only on CT were abrasions (29.8%), core (15.8%), enlargement (15.8%) or mineralisation (12.3%). Contrast-enhanced CT improved lesion identification at the DDFT insertion compared to CT and resulted in distal sesamoidean impar ligament and collateral sesamoidean ligament vascular enhancement in 75% of cases. Low-field MRI and CT/CECT failed to identify soft tissue mineralisation and bone oedema, respectively. CONCLUSIONS AND POTENTIAL RELEVANCE: Multiple lesions are detected with CT, CECT and LFMRI but there is variability in lesion detection and classification. LFMRI centred only on the podotrochlear apparatus may fail to identify lesions of the pastern or soft tissue mineralisation. Computed tomography may fail to identify DDFT lesions distal to the proximal border of the distal sesamoid. PMID- 21696429 TI - Identification of risk factors for traumatic injury in the general horse population of north-west England, Midlands and north Wales. AB - REASONS FOR PERFORMING STUDY: Traumatic injuries are a major cause of morbidity and mortality in the horse and consequently pose a serious threat to horses' wellbeing. To date, there have been no published studies assessing the frequency of injuries in the general horse population of the UK. OBJECTIVES: To obtain information regarding husbandry management strategies and injury prevalence in horses aged <=15 years, with the aim of identifying predisposing risk factors for injury. METHODS: A postal questionnaire was distributed to a randomly selected sample of horse owners across north-west England, Midlands and north Wales. Factors associated with injury were assessed using univariable and multivariable logistic regression analysis performed with the binary outcome variable defined as whether or not the horse had sustained an injury within the previous 12 months. RESULTS: A usable questionnaire response rate of 68% (652/953) was achieved. Forty percent of horses had sustained a traumatic injury within the past year, of which 62% occurred in the field and 13% during ridden exercise. Factors identified as being associated with an increased risk of traumatic injury included the following: breed other than cob or pony (P = 0.001), shorter duration of ownership (P = 0.002), being turned out with an increasing number of horses (P = 0.001), being used for competitive (P = 0.001) or Parelli (P = 0.006) purposes. Stabling at all times during the spring (P = 0.005), the use of wood fencing in paddocks (P = 0.05) and being prone to becoming distressed if left alone in a field (P = 0.04) were also found to be associated with an increased risk of injury. Stabling at all times during winter was associated with a decreased risk of injury (P = 0.006). CONCLUSIONS AND POTENTIAL RELEVANCE: Risk factors for sustaining injuries have been identified in association with management practices. This information may be used to educate owners regarding management of their horse(s) in order to prevent injury. PMID- 21696430 TI - A novel treatment for dynamic laryngeal collapse associated with poll flexion: the modified checkrein. AB - REASONS FOR PERFORMING THE STUDY: Dynamic laryngeal collapse (DLC) associated with poll flexion is a performance limiting dynamic upper airway disorder commonly diagnosed in Coldblooded trotters. An inspiratory obstruction occurs when affected horses are driven with tension on the reins, inducing poll flexion. To date, surgical treatment and conservative management have failed to improve racing performance in affected horses. OBJECTIVES: To test the efficacy of an external device, the modified checkrein, in limiting poll flexion, diminishing laryngeal collapse and improving airway mechanics when horses are driven on a treadmill with tension on the reins and test the hypothesis that the modified checkrein will limit poll flexion thereby improving endoscopic appearance of the larynx and reduce airway obstruction in harness racehorses affected with DLC. METHODS: Fourteen Norwegian Coldblooded trotter (NCT) racehorses previously diagnosed with DLC associated with poll flexion exercised on a high-speed treadmill at speeds that resulted in heart rate >200 beats/min. Upper airway videoendoscopy recordings, tracheal pressures and video recordings of the head and neck position were collected while horses exercised with the conventional checkrein on Day 1 and the modified checkrein on Day 2. RESULTS: The modified checkrein successfully limited poll flexion as measured by no change in head position parameters between phases of no rein tension and phases of rein tension. Endoscopic scores were significantly improved (arytenoids cartilage collapse P<0.0001; vocal fold collapse P<0.0001) and tracheal peak inspiratory pressures were significantly less negative (P = 0.0162) when horses were fitted with the modified checkrein compared to the conventional checkrein. CONCLUSIONS AND POTENTIAL RELEVANCE: The modified checkrein successfully limited poll flexion and also prevented upper airway obstruction in NCT horses affected with DLC associated with poll flexion. The modified checkrein seems promising in offering a method of conservative management in harness racehorses affected with this disorder. PMID- 21696431 TI - Low-field standing magnetic resonance imaging findings of the metacarpo/metatarsophalangeal joint of racing Thoroughbreds with lameness localised to the region: a retrospective study of 131 horses. AB - REASONS FOR PERFORMING STUDY: The metacarpo/metatarsophalangeal (MCP/MTP) joint is a common site of lameness in the Thoroughbred racehorse. Radiographs may fail to show pathology consistent with the degree of lameness. With a high incidence of stress fractures occurring in the distal third metacarpal/metatarsal (MC3/MT3) condyles and proximal phalanx, a definitive diagnosis as to the nature of the pathology is essential. OBJECTIVE: To describe the low-field magnetic resonance imaging (MRI) findings in Thoroughbred racehorses with MCP/MTP joint pain scanned under standing sedation. METHODS: The MR images and clinical records of all Thoroughbred racehorses undergoing MRI of the MCP/MTP joint between October 2006 and August 2010 were reviewed. A total of 168 joints from 131 horses were selected for inclusion. The MRI finding considered most significant in the lame (or lamest) limb was noted. RESULTS: Diagnostic quality images were obtainable in 97.8% of horses. The most common finding was palmar/plantar osteochondral disease in MC3/MT3 (54.9% of horses). Incomplete condylar fracture was diagnosed in 19.8% of horses, with the lateral condyle predominating. An incomplete sagittal fracure of P1 was diagnosed in 14.5% of horses and 11.4% were diagnosed with 'dorsal joint disease'. Other findings included transverse MC3 stress fractures (1.5%), soft tissue injuries (12.2%) and proximal phalangeal 'contusions' (3.8%). No significant bone/soft tissue injury was detected in 5.4% of cases. CONCLUSIONS: Standing MRI can detect a spectrum of disease within the MCP/MTP joints of racehorses. The procedure is well tolerated and may lead to a definitive diagnosis where radiographic imaging is inconclusive. POTENTIAL RELEVANCE: A total of 35.8% of cases had MRI findings consistent with fracture pathology, which could not be confirmed radiographically at the time of the MRI examination. This has important therapeutic and prognostic implications and may help to prevent catastrophic injury. PMID- 21696432 TI - Phacoemulsification and implantation of foldable +14 diopter intraocular lenses in five mature horses. AB - Presently, intraocular lenses (IOLs) are not routinely implanted after equine cataract surgery. Subsequently, horses are visual but markedly farsighted (hyperopic). This report describes the surgical results and visual status after phacoemulsification and implantation of IOLs in mature horses with spontaneous cataracts. Six eyes of 5 mature horses underwent phacoemulsification and implantation of a +14 diopter (D) foldable IOL. Recheck ocular examinations were performed at 1, 4 and 24 weeks post operatively. Refractive error was recorded at 4 weeks post operatively. Visual status, refractive error and anterior chamber depth were recorded 24 weeks post operatively: 5 of 6 operated eyes remained visual and the average refractive error was +0.4 +/- 1.1D. There was a significant difference between the 24 week post operative refractive error and the population mean of +10D (P<0.0001) for aphakic horses. The average post operative anterior chamber depth was 7.89 +/- 1.55 mm. One globe was enucleated 2 months post operatively. Phacoemulsification with IOL implantation resulted in a significant reduction in post operative refractive error and restored vision to within 0.4D of emmetropia in 5 of 6 operated eyes. Implantation of a +14D IOL ameliorated the hyperopia documented in aphakic horses and improved the post operative visual acuity. PMID- 21696433 TI - The timeline of metalloprotease events during oligofructose induced equine laminitis development. AB - REASON FOR PERFORMING STUDY: The role of matrix metalloproteases (MMPs) and the timeline of proteolysis during laminitis development are incompletely understood. OBJECTIVES: To determine the temporal progression of selected MMPs and protease regulators during laminitis development. METHODS: Five clinically normal Standardbred horses received, via nasogastric intubation, an oligofructose (OF) bolus (10 g/kg bwt). Laminitis induction proceeded for 48 h followed by euthanasia. Lamellar biopsies were obtained prior to dosing and at intervals during the treatment period for analysis (12, 18, 24, 30 and 36 h and at 48 h following euthanasia). Tissue samples were analysed by real-time PCR, zymography and western blotting. RESULTS: Activation of proMMP-2 occurs either simultaneously or at least 12 h following lamellar basement membrane (BM) damage, while no activation of proMMP-9 is seen during OF laminitis induction. Aggrecanase gene expression increased initially at 12-18 h post OF dosing, similar to BM changes. Gene expression of TIMP-2, a MMP regulator, decreases during laminitis development. CONCLUSIONS: The MMP-2/MT1-MMP complex may not play a major role in initiating lamellar BM damage. Aggrecanase and TIMP-2 gene expression appear related to BM lamellar changes. POTENTIAL RELEVANCE: MMPs, historically thought to cause laminitis, do not appear to play an initiating role in the lamellar lesion. Other host derived proteases and degradation of alternative lamellar matrix components need to be considered. PMID- 21696434 TI - Comparison of owner-reported health problems with veterinary assessment of geriatric horses in the United Kingdom. AB - REASONS FOR PERFORMING STUDY: Previous studies suggest that owners underestimate or incorrectly recognise or report health problems in geriatric horses. However, few studies have directly compared owner-reported and veterinary assessed disease. OBJECTIVES: To compare the findings of veterinary clinical examination of geriatric horses with owner-reported clinical signs and disease. METHODS: A total of 200 horses aged >= 15 years were randomly selected to receive a veterinary examination, from responses to a cross-sectional postal questionnaire survey. Veterinary examinations were performed within 2 months of questionnaire return, and agreement between owner-reported data and veterinary clinical findings was assessed. RESULTS: Owners under-reported many clinical signs and disease conditions detected on veterinary clinical examination. For example, dental abnormalities (detected in 95.4% of horses, reported by 24.5% of owners); cardiac murmurs (detected in 20% of horses, reported by 0.5% of owners); lameness (present in 50% of horses, reported by 23% of owners) and hoof abnormalities (detected in 80% of horses, reported by 27% of owners). Agreement between owner reported and veterinary assessed respiratory disease (Kappa 0.02-0.2), body condition score (Kappa 0.24) and coat abnormalities (Kappa 0.42) was poor, fair and moderate, respectively. Range of motion (ROM) of the tarsal and metacarpophalangeal joints was lower in horses with owner-reported osteoarthritis (P = 0.005 and <0.001, respectively). CONCLUSIONS AND POTENTIAL RELEVANCE: The low prevalence and relatively poor agreement of owner-reported disease compared to that detected on veterinary examination suggests inaccurate or under recognition, or inaccurate reporting of health problems by owners of geriatric horses, which could lead to a delay in presentation for veterinary treatment. Increased veterinary involvement and improved owner education in the care of geriatric horses should facilitate earlier identification of disease, particularly that which is not readily detectable by owners, and aid management of health and welfare problems. PMID- 21696435 TI - Cervical vertebral canal endoscopy in a horse with cervical vertebral stenotic myelopathy. AB - A 3-year-old Thoroughbred gelding presented with a history of neurological signs, including incoordination in his hindlimbs, of about 7 months' duration. On initial examination, the horse exhibited ataxia and paresis in all limbs with more severe deficits in the hindlimbs. Cervical radiographs displayed severe osteoarthritis of the articular processes between C5 and C6. On subsequent cervical myelography the dorsal contrast column was reduced by 90% at the level of the intervertebral space between C5 and C6. Cervical vertebral canal endoscopy, including epidural (epiduroscopy) and subarachnoid endoscopy (myeloscopy), was performed under general anaesthesia. A substantial narrowing of the subarachnoid space at the level between C6 and C7 was seen during myeloscopy, while no compression was apparent between C5 and C6. Epiduroscopy showed no abnormalities. After completion of the procedure, the horse was subjected to euthanasia and the cervical spinal cord submitted for histopathological examination. Severe myelin and axon degeneration of the white matter was diagnosed at the level of the intervertebral space between C6 and C7, with Wallerian degeneration cranially and caudally, indicating chronic spinal cord compression at this site. Myeloscopy was successfully used to identify the site of spinal cord compression in a horse with cervical vertebral stenotic myelopathy, while myelography results were misleading. PMID- 21696436 TI - Intravenous technetium-99m labelled PEG-liposomes in horses: a safety and biodistribution study. AB - REASONS FOR PERFORMING STUDY: Liposomes are phospholipid nanoparticles that extravasate at sites of increased vascular permeability. They have potential in equine medicine for targeted drug delivery and diagnostic imaging of infectious, inflammatory and neoplastic lesions. OBJECTIVES: This study evaluates the safety and biodistribution of i.v. polyethyleneglycol(PEG) liposomes in normal horses. METHODS: PEG-liposomes were prepared by the film hydration method and labelled using (99m) Tc-hexamethyl-propylene-amine-oxime. A single dose of 0.24 umol/kg bwt (99m) Tc-PEG-liposomes and 2.4 umol/kg bwt unlabelled PEG-liposomes was administered to 10 conscious horses via i.v. infusion at a rate of 6 umol/min for the first 15 min and 60 umol/min thereafter. Clinical parameters, haematology, plasma biochemistry and serum complement activity were monitored serially. Scintigraphic imaging was performed at 1, 12 and 21 h post infusion (PI). Six horses were subjected to euthanasia at 24 h PI. The percentage injected dose per kilogram of tissue was calculated for multiple organs. Results were analysed using repeated measures ANOVA. RESULTS: Horses did not demonstrate adverse reactions during or after liposome infusion. There was a significant elevation in heart rate and respiratory rate at 20 and 25 min PI. No significant complement consumption was detected, although a trend for decreased total haemolytic complement values at 20 min PI was present. Scintigraphic studies revealed a prolonged vascular phase that lasted to 21 h PI, with a reproducible pattern of organ distribution. Biodistribution studies revealed the highest concentrations of radiopharmaceutical within the lung, kidney, liver and spleen. CONCLUSIONS: Intravenous liposome administration appears to be safe in horses. When administered in combination with PEG-liposomes, (99m) Tc-PEG-liposomes have long circulating characteristics and a reproducible pattern of organ distribution in horses. POTENTIAL RELEVANCE: Radiolabelled liposomes may be useful for detecting infection, inflammation and neoplasia in the horse. Liposomes have significant potential for targeted drug delivery in the horse. This study establishes the scintigraphic findings and tissue distribution of 99mTc-PEG-liposomes after i.v. administration in healthy horses. PMID- 21696437 TI - Short-term temporal alterations in magnetic resonance signal occur in primary lesions identified in the deep digital flexor tendon of the equine digit. AB - REASONS FOR PERFORMING STUDY: Primary lesions of the deep digital flexor tendon (DDFT) within the digit are an important cause of lameness diagnosed using magnetic resonance imaging (MRI) but appearance of these lesions over time has not been documented. OBJECTIVES: To determine whether the magnetic resonance (MR) appearance of different primary DDFT lesions alter over a 6 month period and whether lesion type is a determinant of these changes. METHODS: Cases included had lameness attributable to a primary lesion involving the DDFT in the digit diagnosed on MRI. Lesions were typed into parasagittal, dorsal border and core lesions. Approximate volumes and intensities were quantified for each lesion type using T2* scan sequences. Follow-up examinations and measurements were repeated at 3 and 6 month periods following conservative management. RESULTS: Twenty-three horses fitted the inclusion criteria. Lesion distribution included: parasagittal (n = 7), dorsal border (n = 11) and core lesions (n = 5). No association was found between age of horse, degree of lameness and lesion type. Only dorsal border lesions showed statistically significant reduction both in volume (initial scan: 0.18 +/- 0.14 cm(3) ) at 3 months (0.11 +/- 0.10 cm(3) , P<0.05) and 6 months (0.05 +/- 0.05 cm(3) , P<0.01) and ratiometric intensity (initial scan: 4.06 +/- 1.54) at 6 months (2.00 +/- 0.43; P<0.01). Parasagittal and core lesions showed no difference in lesion volume or ratiometric intensity. Lameness improved in all lesion types following conservative management. CONCLUSIONS: Dorsal border lesions of the DDFT show reduction in both volume and intensity whereas parasagittal and core lesions do not. POTENTIAL RELEVANCE: Lesion typing may be important in predicting lesion behaviour and short-term outcome using MR imaging. PMID- 21696438 TI - Effects of acepromazine, butorphanol and buprenorphine on thermal and mechanical nociceptive thresholds in horses. AB - REASONS FOR PERFORMING STUDY: To investigate the antinociceptive effects of buprenorphine administered in combination with acepromazine in horses and to establish an effective dose for use in a clinical environment. OBJECTIVES: To evaluate the responses to thermal and mechanical stimulation following administration of 3 doses of buprenorphine compared to positive (butorphanol) and negative (glucose) controls. METHODS: Observer blinded, randomised, crossover design using 6 Thoroughbred geldings (3-10 years, 500-560 kg). Thermal and mechanical nociceptive thresholds were measured 3 times at 15 min intervals. Horses then received acepromazine 0.05 mg/kg bwt with one of 5 treatments i.v.: 5% glucose (Glu), butorphanol 100 ug/kg bwt (But) buprenorphine 5 ug/kg bwt (Bup5), buprenorphine 7.5 ug/kg bwt (Bup7.5) and buprenorphine 10 ug/kg bwt (Bup10). Thresholds were measured 15, 30, 45, 60, 90, 120, 150, 180, 230 min, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 24 h post treatment administration. The 95% confidence intervals for threshold temperature (DeltaT) for each horse were calculated and an antinociceptive effect defined as DeltaT, which was higher than the upper limit of the confidence interval. Duration of thermal antinociception was analysed using a within-subjects ANOVA and peak mechanical thresholds with a general linear model with post hoc Tukey tests. Significance was set at P<0.05. RESULTS: Mean (+/- s.d.) durations of thermal antinociception following treatment administration were: Glu 0.5 (1.1), But 2.9 (2.0), Bup5 7.4 (2.3), Bup7.5 7.8 (2.7) and Bup10 9.4 (1.1) h. B5, B7.5 and B10 were significantly different from Glu and But. No serious adverse effects occurred, although determination of mechanical thresholds was confounded by locomotor stimulation. CONCLUSIONS: Administration of acepromazine and all doses of buprenorphine produced antinociception to a thermal stimulus for significantly longer than acepromazine and either butorphanol or glucose. POTENTIAL RELEVANCE: This study suggests that buprenorphine has considerable potential as an analgesic in horses and should be examined further under clinical conditions and by investigation of the pharmacokinetic/pharmacodynamic profile. PMID- 21696439 TI - Increased plasma fructosamine concentrations in laminitic horses. AB - REASONS FOR PERFORMING STUDY: The use of plasma fructosamine concentration ([fructosamine]) as a marker of abnormal glucose homeostasis in laminitic horses has not been investigated. HYPOTHESIS: Plasma fructosamine concentration may be higher amongst laminitic horses than normal horses; this might relate to underlying insulin resistance. OBJECTIVES: 1) To compare [fructosamine] between laminitic and normal horses. 2) To investigate associations between [fructosamine] at presentation in laminitic horses with a) single sample markers of insulin resistance and b) outcome. METHODS: Plasma fructosamine concentration, fasting serum insulin concentration (insulin) and fasting plasma glucose concentration (glucose) were measured in 30 horses that presented with laminitis. Clinical details and follow-up data were recorded. Plasma fructosamine concentration was also measured in 19 nonlaminitic control horses. RESULTS: Laminitic horses had significantly higher mean [fructosamine] than normal horses (P<0.001). Thirteen of 30 laminitic horses had fasting hyperinsulinaemia, 2/30 had fasting hyperglycaemia. Statistically significant univariable correlations were identified between [fructosamine] and [glucose], [insulin] and the proxies RISQI and MIRG. Trends for association between [fructosamine] and negative outcome did not reach statistical significance. CONCLUSIONS AND POTENTIAL RELEVANCE: Increased mean [fructosamine] in laminitic horses may represent abnormal glycaemic control and [fructosamine] may become a clinically useful marker. PMID- 21696440 TI - Serum concentration of surfactant protein D in horses with lower airway inflammation. AB - REASONS FOR PERFORMING STUDY: Surfactant protein D (SP-D), mainly synthesised by alveolar type II cells and nonciliated bronchiolar cells, is one important component of innate pulmonary immunity. In man, circulating concentrations of SP D are routinely used as biomarkers for pulmonary injury. To date, serum SP-D levels have only been investigated in horses in an experimental model of bacterial airway infection. OBJECTIVES: To compare serum SP-D concentrations at rest and after exercise in horses with and without inflammatory airway disease (IAD). METHODS: Venous blood samples were collected from 42 Standardbred racehorses at rest and 60 min after performing a standardised treadmill exercise test. Tracheal wash and bronchoalveolar lavage fluid (BALF) samples were collected after exercise. Based on BALF cytology, 22 horses were defined as IAD affected and 20 classified as controls. Serum SP-D concentrations were assessed using a commercially available ELISA kit and statistically compared between groups of horses and sampling times. RESULTS: Serum concentrations of SP-D in IAD affected horses were significantly higher than those of control horses, both at rest and after exercise. Within the IAD-affected group, no significant correlation was found between serum SP-D concentrations and BALF cytology. Within each group of horses (IAD and control), no significant influence of exercise was found on serum SP-D levels. CONCLUSIONS: This is the first study determining serum SP-D concentrations in a noninfectious, naturally occurring form of lower airway inflammation in horses. The results highlight that IAD is associated with a detectable, though moderate, increase of circulating SP-D levels. POTENTIAL RELEVANCE: Serum concentration of surfactant protein D could represent a potentially valuable and readily accessible blood biomarker of equine lower airway inflammation. PMID- 21696441 TI - Glass fibre reinforced acrylic resin complete dentures: a 5-year clinical study. AB - BACKGROUND AND OBJECTIVES: The aim of the study was to establish the wear resistance of the glass fiber reinforced complete dentures comparative to the traditional acrylic complete dentures. MATERIALS AND METHODS: Complete new dentures were made to replace old fractured 'un'-reinforced acrylic dentures. The total number of dentures was 30 and woven E-glass fibre reinforcements were used in maxillary complete dentures. Unidirectional E-glass fibre reinforcements were used as partial fibre reinforcements in mandibular complete dentures. Ten complete acrylic un-reinforced dentures were used as control. The follow-up period was 5 years and the recalls were made at 6 months. RESULTS: After 5 years of wearing the new dentures, the control dentures suffered seven fractures. After 5 years all the mandibular reinforced dentures were in good shape. The maxillary complete reinforced dentures suffered four partial fractures. Fracture lines were restricted by the glass fibre net and the patients could still use their dentures. CONCLUSION: Pre-impregnated E-glass fibre nets and polymer pre impregnated E-glass unidirectional fibres are useful in reinforcing acrylic resin complete dentures especially were heavy occlusal forces are involved. Glass fibre reinforcement will be applied on the tension side in both cases (total fibre reinforcement and partial fibre reinforcement). The reinforcement cannot replace the necessary linings and occlusal adjustments. PMID- 21696442 TI - Oral health related quality of life of edentulous patients after denture relining with a silicone-based soft liner. AB - BACKGROUND: Knowledge of benefits caused by a treatment on quality of life is very relevant. Despite the wide use and acceptance of soft denture liners, it is necessary to evaluate the patient's response about the use of these materials with regard to improvement in oral health related quality of life (OHRQoL). OBJECTIVES: The aim of this study was to evaluate the influence of denture relining in the OHRQoL of edentulous patients. MATERIALS AND METHODS: Thirty-two complete denture wearers had their lower dentures relined with a silicone-based material (Mucopren soft, Kettenbach, Germany) according to chairside procedures. OHRQoL was assessed before and after 3 months of relining by means of OHIP-EDENT, and the median scores were compared by Wilcoxon test (p <= 0.05). RESULTS: After 3 months of relining, participants reported significant improvement of their OHRQoL (p <= 0.01). CONCLUSION: Denture relining with a soft liner may have a positive impact on the perceived oral health of edentulous patients. PMID- 21696443 TI - A case of hyporeninemic hypoaldosteronism in the dog. PMID- 21696444 TI - Infectious risk in xenotransplantation--what post-transplant screening for the human recipient? AB - Xenotransplantation may be associated with the transmission of pig microorganisms including viruses, bacteria, fungi, and parasites. As the recipient may be immunosuppressed, infection and pathologic consequences may be more pronounced compared to non-immunosuppressed individuals. Transmission of most microorganisms with exception of porcine endogenous retroviruses (PERV) may be prevented by screening the donor pig and qualified pathogen-free breeding. PERVs represent a special risk as they are present in the genome of all pigs and infect human cells in vitro. Until now, no PERV transmission was observed in experimental and clinical xenotransplantations as well as in numerous infection experiments. Nevertheless, several strategies have been developed to prevent PERV transmission. PMID- 21696445 TI - Clinical pig liver xenotransplantation: how far do we have to go? AB - As pigs are currently the preferred species for organ xenotransplantation, initial experience in liver xenotransplantation with wild-type (WT) pigs, advances in the development of genetically modified pigs, and recent studies using livers from them are reviewed. The xenotransplantation of livers from pigs transgenic for the human complement regulatory protein (CRP) CD55 or from alpha1,3-galactosyltransferase gene-knockout pigs+/- additionally transgenic for the CRP CD46 (GTKO/CD46 pigs) is associated with the survival of approximately 1 week. Satisfactory hepatic function has been documented, lending support to the concept that the pig liver might provide a bridge to allotransplantation. However, although significant features of rejection have not been documented, the development of an immediate thrombocytopenia after graft reperfusion is problematic and leads to spontaneous hemorrhage within the body cavities, native organs, and graft. Current studies are being directed to understand the factors causing the activation, aggregation, or phagocytosis of platelets, in particular the interaction between platelets and liver sinusoidal endothelial cells, hepatocytes, and Kupffer cells. If this problem can be resolved, a clinical trial of pig liver xenotransplantation as a bridge to allotransplantation may be both feasible and justified. PMID- 21696446 TI - Attitudinal study of organ xenotransplantation in patients on the kidney and liver transplant waiting list in a country with a high rate of deceased donation. AB - BACKGROUND: The organ transplant deficit is leading to an increase in the importance of solid organ xenotransplantation. However, the use of animals for human transplantation causes a certain amount of opposition in patients and the general public. The objective of this study was to analyze the attitude of patients on the kidney and liver waiting list toward xenotransplantation and the variables affecting this attitude. METHODS: Patients on the kidney and liver waiting list (January 2003 - December 2005) were surveyed. Attitude toward xenotransplantation was assessed using a psychosocial questionnaire about the donation of organs of animal origin administered by a healthcare professional from the Transplant Unit. RESULTS: A total of 373 patients were interviewed (kidney [n=214] and liver patients [n=158]). In the case of kidney patients, if the results of xenotransplantation were as effective as those attained using human organs, 76% (n=162) would be in favor. If the results were worse, only 8% (n=17) would be in favor. Two factors affected this attitude: a high level of education (P=0.007) and a positive attitude toward organ donation upon death (P< 0.001). In the case of liver patients, 67% (n=106) would be in favor if the results of xenotransplantation were as effective as those attained using human organs, decreasing to 16% (n=25) if the results were worse. Attitude toward deceased organ donation also affected the attitude of these patients (P<0.043). CONCLUSIONS: The attitude toward xenotransplantation of patients on the kidney and liver transplant waiting list was favorable and associated with a positive attitude toward human organ donation. PMID- 21696447 TI - Effect of alphaGal on corneal xenotransplantation in a mouse model. AB - BACKGROUND: It has been reported that hyperacute rejection (HAR) does not occur after pig-to-nonhuman corneal xenotransplantation. However, considering that immune privilege is already disrupted in most human corneal recipients, and the expression of alphaGal can be gradually reduced after pig-to-rat corneal transplantation, the long-term survival of corneal grafts from wild-type pigs cannot be guaranteed. Accordingly, we aimed to investigate the effect of alphaGal on the change in anti-Gal antibodies, using sensitized alpha1,3 galactosyltransferase gene-knockout (GTKO) mice recipients. METHODS: C57BL/6 (B6) and GTKO mice were divided into 5 groups and underwent orthotopically full thickness cormeal transplantation as follows (n=4 for each group): (1) group 1: B6 to B6; (2) group 2: fresh porcine posterior corneal lamella to B6; (3) fresh porcine posterior corneal lamella to GTKO; (4) group 4: decellularized porcine posterior corneal lamella to GTKO, and (5) group 5: B6 to GTKO. Before transplantation, all GTKO recipients were sensitized using intraperitoneal injections of rabbit blood cells. Median survival times (MST) for the corneal grafts of the different groups were compared and plasma concentrations of IgG/IgM anti-Gal antibodies were evaluated at 1 week, 2 weeks and 3 weeks post transplantation. RESULTS: There were no differences in MSTs between groups. Although there was no HAR of fresh porcine posterior corneal grafts even in sensitized GTKO recipients, alphaGal expression was induced in the transplanted fresh porcine corneal grafts and plasma concentration of IgG anti-Gal antibody was gradually increased in fresh porcine cornea-grafted GTKO recipients. On the contrary, alphaGal expression did not increase in the grafts and plasma concentration of anti-Gal antibodies did not change after transplantation using decellularized porcine corneas. CONCLUSIONS: Our findings suggest that alphaGal may affect the long-term survival of porcine corneal xenografts via antibody mediated rejection, although alphaGal does not have an effect on acute rejection and decellularized porcine corneas may enable the long-term survival of porcine corneal xenografts. PMID- 21696448 TI - Genetically-modified pig mesenchymal stromal cells: xenoantigenicity and effect on human T-cell xenoresponses. AB - BACKGROUND: Mesenchymal stromal cells (MSC) are being investigated as immunomodulatory therapy in the field of transplantation, particularly islet transplantation. While MSC can regenerate across species barriers, the immunoregulatory influence of genetically modified pig MSC (pMSC) on the human and non-human primate T-cell responses has not been studied. METHODS: Mesenchymal stromal cells from wild-type (WT), alpha1,3-galactosyltransferase gene knockout (GTKO) and GTKO pigs transgenic for the human complement-regulatory protein CD46 (GTKO/CD46) were isolated and tested for differentiation. Antibody binding and T cell responses to WT and GTKO pMSC in comparison with GTKO pig aortic endothelial cells (pAEC) were investigated. The expression of swine leukocyte antigen (SLA) class II (SLA II) was tested. Costimulatory molecules CD80 and CD86 mRNA levels were measured. Human T-cell proliferation and the production of pro-inflammatory cytokines in response to GTKO and GTKO/CD46 pMSC in comparison with human MSC (hMSC) were evaluated. RESULTS: alpha1,3-galactosyltransferase gene knockout and GTKO/CD46 pMSC isolation and differentiation were achieved in vitro. Binding of human antibodies and T-cell responses were lower to GTKO than those to WT pMSC. Human and baboon (naive and sensitized) antibody binding were significantly lower to GTKO pMSC than to GTKO pAEC. Before activation, <1% of GTKO pMSC expressed SLA II, compared with 2.5% of GTKO pAEC. After pig interferon-gamma (pIFN-gamma) activation, 99% of GTKO pAEC upregulated SLA II expression, compared with 49% of GTKO pMSC. Only 3% of GTKO pMSC expressed CD80 compared with 80% of GTKO pAEC without activation. After pIFN-gamma activation, GTKO pAEC upregulated CD86 mRNA level stronger than GTKO pMSC. The human CD4(+) T-cell response to GTKO pMSC was significantly weaker than that to GTKO pAEC, even after pIFN-gamma activation. More than 99% of GTKO/CD46 pMSC expressed hCD46. Human peripheral blood mononuclear cells and CD4(+) T-cell responses to GTKO and GTKO/CD46 pMSC were comparable with those to hMSC, and all were significantly lower than to GTKO pAEC. GTKO/CD46 pMSC downregulated human T-cell proliferation as efficiently as hMSC. The level of proinflammatory cytokines IL-2, IFN-gamma, TNF-alpha, and sCD40L correlated with the downregulation of T-cell proliferation by all types of MSC. CONCLUSION: Genetically modified pMSC is significantly less immunogenic than WT pMSC. GTKO/CD46 pMSC downregulates the human T-cell responses to pig antigens as efficiently as human MSC, which can be advantageous for therapeutic cell xenotransplantation. PMID- 21696449 TI - Adipose-derived stromal cells cultured in a low-serum medium, but not bone marrow derived stromal cells, impede xenoantibody production. AB - BACKGROUND: Although the immunomodulatory effects of mesenchymal stromal cells (MSC) on T cells have been elucidated, little is known about their effects on B cells. Recently, we have established a novel culture method for adipose-derived MSC (ASC) using low (2%) serum medium containing fibroblast growth factor-2. We showed that low serum-cultured ASC (LASC) was superior to high (20%) serum cultured ASC (HASC) when used in regenerative therapy. The aim of this study was to compare the action of LASC, HASC, and bone marrow-derived MSC (BM-MSC), on xenoantibody production by B cells. METHODS: Adipose-derived mesenchymal stromal cells and BM-MSC were obtained from humans or F344 rats and expanded in a low serum or a high-serum culture medium. Proliferation of human peripheral mononuclear cells (PBMC) or rat splenocytes was induced by phytohemagglutinin (PHA) or anti-IgM-antibody. These cells were then co-cultured with LASC, HASC, or BM-MSC, and cell proliferation was studied. Porcine red blood cells (pRBC) were intraperitoneally injected into Lewis rats, and LASC, HASC, or BM-MSC obtained from F344 rats were injected intravenously or intraperitoneally. The levels of antibodies (IgM and IgG) against pRBC were examined using flow cytometry. RESULTS: Human LASC suppressed PBMC proliferation more effectively than human HASC. Human LASC suppressed both T-cell and B-cell proliferation when incubated with PHA (a T-cell stimulus). However, human LASC did not suppress B-cell proliferation after incubation with anti-IgM-antibody (a T-cell-independent stimulus). Rat LASC suppressed PHA-stimulated splenocyte proliferation more effectively than rat HASC or rat BM-MSC. In vivo studies showed that intravenous injection of rat LASC significantly reduced the levels of IgG antibodies against pRBC, while intravenous administration of the other two types of MSC (rat HASC or rat BM-MSC) or intraperitoneal administration of rat LASC did not impede IgG production. A significant number of LASC were observed in the spleen when injected intravenously while only a few LASC were observed when given intraperitoneally. CONCLUSIONS: Administration of LASC effectively impeded xenoantibody production by B cells through the inhibition of T-cell function, while HASC or BM-MSC showed less promising effects. These results suggest that intravenous injection of LASC may be useful in attenuating antibody-mediated rejection. PMID- 21696450 TI - Xenotransplantation literature update, March-April 2011. PMID- 21696451 TI - Editorial comment to receptor dependent immobilization of spermatozoa by sperm immobilization factor isolated from Escherichia coli: proof of evidence. PMID- 21696452 TI - Halo naevi with associated vitiligo-like depigmentations: pathogenetic hypothesis. AB - BACKGROUND: In analogy with melanoma-associated leucoderma, halo naevi may trigger in some patients the development of additional depigmentations which are in distribution, extent and prognosis not in accordance with classic vitiligo. OBJECTIVE: The aim of this study was to support the hypothesis that in a subset of halo naevi patients vitiligo-like lesions develop directly linked to the halo phenomenon. METHODS: Forty-one patients with halo naevi were examined for the development of depigmentations not corresponding to typical vitiligo lesions. RESULTS: We identified a subset of five halo naevi patients with additional subtle depigmentations. After the occurrence of multiple halo naevi, they developed leucoderma that showed a different disease pattern than vitiligo (variable asymmetric distribution, limited extent and lack of progression). Moreover, the characteristics of these halo naevi patients with associated leucoderma were different from classic vitiligo patients (high number of halo naevi, absence of family history for vitiligo and absence of autoimmune diseases) and the timing of occurrence of the leucoderma suggested a direct relation with the halo phenomenon. CONCLUSIONS: In this article, we describe in a limited subset of patients with multiple halo naevi discrete depigmentations at distance from halo naevi which may result from a temporary autoimmune process directly linked to the halo phenomenon. This finding illustrates the collateral damage resulting from skin immunosurveillance and may have clinical consequences as the evolution pattern in this subset of patients is less progressive compared with vitiligo. We present clinical data that support this hypothesis and suggest to call it 'halo naevi-associated leucoderma'. PMID- 21696453 TI - Corrective eyeglasses and medial canthal basal cell carcinoma: a case-control study. AB - BACKGROUND: Corrective eyeglasses are frequently worn by adults, particularly at older ages. Their lenses and frames provide ultraviolet protection. Medial canthal basal cell carcinomas are infrequent (3-8%), and their relation with the use of corrective glasses was not yet investigated. OBJECTIVES: To assess the prevalence of corrective eyeglasses use in individuals with medial canthal basal cell carcinoma. METHODS: Case-control study using two controls matched by age, gender, and ethnicity for each case. Cases were patients with medial canthal basal cell carcinoma, and controls were patients with basal cell carcinoma elsewhere on the face. The prevalence of major risk variables was estimated and adjusted by conditional multiple logistic regression. RESULTS: Fifty cases and 100 controls were assessed. The mean patient age was 69.7 years, and 54% of the subjects were females. No difference regarding the eyeglasses use or use duration was found between groups. However, when visual defects were separately evaluated, eyeglasses for myopia correction were independently associated with lower risk of medial canthal basal cell carcinoma development (OR=0.26; P=0.03), what can be related to long term local photoprotection. CONCLUSION: The use of eyeglasses for myopia correction is associated with lower prevalence of medial cantal basal cell carcinoma. Risk-reducing mechanisms should be elucidated. PMID- 21696454 TI - Does MMF really slow down fibrosis of HCV recurrence in liver transplant recipients? PMID- 21696455 TI - Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation. AB - We describe the presumably first intentional ABO-incompatible deceased-donor kidney and pancreas transplantation with a severe antibody-mediated rejection during a rebound of isoagglutinins. Rejection was successfully treated with eculizumab, which inhibits the terminal pathway of complement. Complement analysis (C3, C3d,g, and a modified assay of classical complement-related hemolytic function) documented complement activation and confirmed that eculizumab completely blocked complement function. At 6 months, the patient had normal kidney and pancreas function, and histological evaluations revealed no evidence of sustained graft damage. This successful transplantation suggests that ABO barriers can safely be overcome without extensive preconditioning, when the complement inhibitor eculizumab is included. PMID- 21696456 TI - Complex regulation of the global regulatory gene csrA: CsrA-mediated translational repression, transcription from five promoters by Esigma70 and Esigma(S), and indirect transcriptional activation by CsrA. AB - CsrA of Escherichia coli is an RNA-binding protein that globally regulates gene expression by repressing translation and/or altering the stability of target transcripts. Here we explored mechanisms that control csrA expression. Four CsrA binding sites were predicted upstream of the csrA initiation codon, one of which overlapped its Shine-Dalgarno sequence. Results from gel shift, footprint, toeprint and in vitro translation experiments indicate that CsrA binds to these four sites and represses its own translation by directly competing with 30S ribosomal subunit binding. Experiments were also performed to examine transcription of csrA. Primer extension, in vitro transcription and in vivo expression studies identified two sigma70-dependent (P2 and P5) and two sigma(S) dependent (P1 and P3) promoters that drive transcription of csrA. Additional primer extension studies identified a fifth csrA promoter (P4). Transcription from P3, which is indirectly activated by CsrA, is primarily responsible for increased csrA expression as cells transition from exponential to stationary phase growth. Taken together, our results indicate that regulation of csrA expression occurs by a variety of mechanisms, including transcription from multiple promoters by two sigma factors, indirect activation of its own transcription, as well as direct repression of its own translation. PMID- 21696457 TI - The novel Pseudomonas aeruginosa two-component regulator BfmR controls bacteriophage-mediated lysis and DNA release during biofilm development through PhdA. AB - Biofilms are surface-adhered bacterial communities encased in an extracellular matrix composed of polysaccharides, proteins, and extracellular (e)DNA, with eDNA required for biofilm formation and integrity. Here we demonstrate that eDNA release is controlled by BfmR, a regulator essential for Pseudomonas aeruginosa biofilm development. Expression of bfmR coincided with localized cell death and DNA release, and could be stimulated by conditions resulting in membrane perturbation and cell lysis. DeltabfmR mutant biofilms demonstrated increased cell lysis and eDNA release suggesting BfmR to suppress, but not eliminate, these processes. Genome-wide transcriptional profiling indicated that BfmR was required for repression of genes associated with bacteriophage assembly and bacteriophage mediated lysis. Chromatin immunoprecipitation analysis of direct BfmR targets identified the promoter of PA0691, termed here phdA, encoding a previously undescribed homologue of the prevent-host-death (Phd) family of proteins. Lack of phdA expression coincided with impaired biofilm development and increased cell death, a phenotype comparable to DeltabfmR. Expression of phdA in DeltabfmR restored eDNA release, cell lysis and biofilm formation to wild-type levels, with phdA overexpression promoting resistance to the superinfective bacteriophage Pf4, detected only in biofilms. Therefore, we propose that BfmR regulates biofilm development by limiting bacteriophage-mediated lysis and thus, eDNA release, via PhdA. PMID- 21696458 TI - Bacitracin and nisin resistance in Staphylococcus aureus: a novel pathway involving the BraS/BraR two-component system (SA2417/SA2418) and both the BraD/BraE and VraD/VraE ABC transporters. AB - Two-component systems (TCSs) are key regulatory pathways allowing bacteria to adapt their genetic expression to environmental changes. Bacitracin, a cyclic dodecylpeptide antibiotic, binds to undecaprenyl pyrophosphate, the lipid carrier for cell wall precursors, effectively inhibiting peptidoglycan biosynthesis. We have identified a novel and previously uncharacterized TCS in the major human pathogen Staphylococcus aureus that we show to be essential for bacitracin and nisin resistance: the BraS/BraR system (Bacitracin resistance associated; SA2417/SA2418). The braRS genes are located immediately upstream from genes encoding an ABC transporter, accordingly designated BraDE. We have shown that the BraSR/BraDE module is a key bacitracin and nisin resistance determinant in S. aureus. In the presence of low antibiotic concentrations, BraSR activate transcription of two operons encoding ABC transporters: braDE and vraDE. We identified a highly conserved imperfect palindromic sequence upstream from the braDE and vraDE promoter sequences, essential for their transcriptional activation by BraSR, suggesting it is the likely BraR binding site. We demonstrated that the two ABC transporters play distinct and original roles in antibiotic resistance: BraDE is involved in bacitracin sensing and signalling through BraSR, whereas VraDE acts specifically as a detoxification module and is sufficient to confer bacitracin and nisin resistance when produced on its own. We show that these processes require functional BraD and VraD nucleotide-binding domain proteins, and that the large extracellular loop of VraE confers its specificity in bacitracin resistance. This is the first example of a TCS associated with two ABC transporters playing separate roles in signal transduction and antibiotic resistance. PMID- 21696459 TI - Hsp31 of Escherichia coli K-12 is glyoxalase III. AB - Hsp31 encoded by hchA is known as a heat-inducible molecular chaperone. Although structure studies revealed that Hsp31 has a putative catalytic triad consisting of Asp-214, His-186 and Cys-185, its enzymatic function, besides weak amino peptidase activity, is still unknown. We found that Hsp31 displays glyoxalase activity that catalyses the conversion of methylglyoxal (MG) to d-lactate without an additional cofactor. The glyoxalase activity was completely abolished in the hchA-deficient strain, confirming the relationship between the hchA gene and its enzymatic activity in vivo. Hsp31 exhibits Michaelis-Menten kinetics for substrates MG with K(m) and k(cat) of 1.43+/-0.12 mM and 156.9+/-5.5 min-1 respectively. The highest glyoxalase activity was found at 35-40 degrees C and pH of 6.0-8.0, and the activity was significantly inhibited by Cu2+, Fe3+ and Zn2+. Mutagenesis studies based on our evaluation of conserved catalytic residues revealed that the Cys-185 and Glu-77 were essential for catalysis, whereas His 186 was less crucial for enzymatic function, although it participates in the catalytic process. The stationary-phase Escherichia coli cells became more susceptible to MG when hchA was deleted, which was complemented by an expression of plasmid-encoded hchA. Furthermore, an accumulation of intracellular MG was observed in hchA-deficient strains. PMID- 21696460 TI - Genetic ablation of a Maurer's cleft protein prevents assembly of the Plasmodium falciparum virulence complex. AB - The malaria parasite Plasmodium falciparum assembles knob structures underneath the erythrocyte membrane that help present the major virulence protein, P. falciparum erythrocyte membrane protein-1 (PfEMP1). Membranous structures called Maurer's clefts are established in the erythrocyte cytoplasm and function as sorting compartments for proteins en route to the RBC membrane, including the knob-associated histidine-rich protein (KAHRP), and PfEMP1. We have generated mutants in which the Maurer's cleft protein, the ring exported protein-1 (REX1) is truncated or deleted. Removal of the C-terminal domain of REX1 compromises Maurer's cleft architecture and PfEMP1-mediated cytoadherance but permits some trafficking of PfEMP1 to the erythrocyte surface. Deletion of the coiled-coil region of REX1 ablates PfEMP1 surface display, trapping PfEMP1 at the Maurer's clefts. Complementation of mutants with REX1 partly restores PfEMP1-mediated binding to the endothelial cell ligand, CD36. Deletion of the coiled-coil region or complete deletion of REX1 is tightly associated with the loss of a subtelomeric region of chromosome 2, encoding KAHRP and other proteins. A KAHRP green fluorescent protein (GFP) fusion expressed in the REX1-deletion parasites shows defective trafficking. Thus, loss of functional REX1 directly or indirectly ablates the assembly of the P. falciparum virulence complex at the surface of host erythrocytes. PMID- 21696461 TI - ArsAB, a novel enzyme from Sporomusa ovata activates phenolic bases for adenosylcobamide biosynthesis. AB - In the homoacetogenic bacterium Sporomusa ovata, phenol and p-cresol are converted into alpha-ribotides, which are incorporated into biologically active cobamides (Cbas) whose lower ligand bases do not form axial co-ordination bonds with the cobalt ion of the corrin ring. Here we report the identity of two S. ovata genes that encode an enzyme that transfers the phosphoribosyl group of nicotinate mononucleotide (NaMN) to phenol or p-cresol, yielding alpha-O glycosidic ribotides. The alluded genes were named arsA and arsB (for alpha ribotide synthesis), arsA and arsB were isolated from a genomic DNA library of S. ovata. A positive selection strategy using an Escherichia coli strain devoid of NaMN:5,6-dimethylbenzimidazole (DMB) phosphoribosyltransferase (CobT) activity was used to isolate a fragment of S. ovata DNA that contained arsA and arsB, whose nucleotide sequences overlapped by 8 bp. SoArsAB was isolated to homogeneity, shown to be functional as a heterodimer, and to have highest activity at pH 9. SoArsAB also activated DMB to its alpha-N-glycosidic ribotide. Previously characterized CobT-like enzymes activate DMB but do not activate phenolics. NMR spectroscopy was used to confirm the incorporation of phenol into the cobamide, and mass spectrometry was used to identify SoArsAB reaction products. PMID- 21696462 TI - Characterization of DNA-binding sequences for CcaR in the cephamycin-clavulanic acid supercluster of Streptomyces clavuligerus. AB - RT-PCR analysis of the genes in the clavulanic acid cluster revealed three transcriptional polycistronic units that comprised the ceaS2-bls2-pah2-cas2, cyp fd-orf12-orf13 and oppA2-orf16 genes, whereas oat2, car, oppA1, claR, orf14, gcaS and pbpA were expressed as monocistronic transcripts. Quantitative RT-PCR of Streptomyces clavuligerus ATCC 27064 and the mutant S. clavuligerus ccaR::aph showed that, in the mutant, there was a 1000- to 10,000-fold lower transcript level for the ceaS2 to cas2 polycistronic transcript that encoded CeaS2, the first enzyme of the clavulanic acid pathway that commits arginine to clavulanic acid biosynthesis. Smaller decreases in expression were observed in the ccaR mutant for other genes in the cluster. Two-dimensional electrophoresis and MALDI TOF analysis confirmed the absence in the mutant strain of proteins CeaS2, Bls2, Pah2 and Car that are required for clavulanic acid biosynthesis, and CefF and IPNS that are required for cephamycin biosynthesis. Gel shift electrophoresis using recombinant r-CcaR protein showed that it bound to the ceaS2 and claR promoter regions in the clavulanic acid cluster, and to the lat, cefF, cefD-cmcI and ccaR promoter regions in the cephamycin C gene cluster. Footprinting experiments indicated that triple heptameric conserved sequences were protected by r-CcaR, and allowed identification of heptameric sequences as CcaR binding sites. PMID- 21696463 TI - Involvement of protein acetylation in glucose-induced transcription of a stress responsive promoter. AB - In eukaryotes, lysine acetylation is a well-established post-translational modification that has been implicated in virtually all aspects of eukaryotic physiology. Although homologues of the enzymes that catalyse protein acetylation are widely conserved and distributed among bacterial species, not much is known about the impact of protein acetylation on bacterial physiology. Here, we present evidence that the Gcn5-like acetyltransferase YfiQ and the sirtuin deacetylase CobB play crucial roles in the transcription regulation of the periplasmic stress responsive promoter cpxP when cells of Escherichia coli grow in the presence of glucose, an environment that induces protein acetylation. Under this growth condition, several acetylation sites were detected on three of the RNA polymerase subunits: beta, beta' and alpha. We focused on acetylations of the carboxy terminal domain (CTD) of alpha because of its relative small size and its limited acetylation. We determined that K298 of alpha is acetylated in a glucose and YfiQ dependent manner and that K298 is specifically required for glucose-induced cpxP transcription. Because the alphaCTD aids in promoter recognition by RNA polymerase, we propose its acetylation may influence bacterial physiology through effects on gene expression. PMID- 21696464 TI - The periplasmic membrane proximal domain of MacA acts as a switch in stimulation of ATP hydrolysis by MacB transporter. AB - Escherichia coli MacAB-TolC is a tripartite macrolide efflux transporter driven by hydrolysis of ATP. In this complex, MacA is the periplasmic membrane fusion protein that stimulates the activity of MacB transporter and establishes the link with the outer membrane channel TolC. The molecular mechanism by which MacA stimulates MacB remains unknown. Here, we report that the periplasmic membrane proximal domain of MacA plays a critical role in functional MacA-MacB interactions and stimulation of MacB ATPase activity. Binding of MacA to MacB stabilizes the ATP-bound conformation of MacB, whereas interactions with both MacB and TolC affect the conformation of MacA. A single G353A substitution in the C-terminus of MacA inactivates MacAB-TolC function by changing the conformation of the membrane proximal domain of MacA and disrupting the proper assembly of the MacA-MacB complex. We propose that MacA acts in transport by promoting MacB transition into the closed ATP-bound conformation and in this respect, is similar to the periplasmic solute-binding proteins. PMID- 21696466 TI - Simultaneous silencing of endo-beta-1,4 xylanase genes reveals their roles in the virulence of Magnaporthe oryzae. AB - Due to functional redundancy, it is often difficult to genetically analyse the biological function of fungal cell wall-degrading enzymes that belong to a gene family. To overcome this difficulty, we used RNAi to knock-down (KD) multiple xylanase genes to elucidate their roles in the pathogenicity of the blast fungus, Magnaporthe oryzae. To obtain the maximum average efficiency of gene silencing for the xylanase genes, we used the 'building blocks method', in which a 40 bp sequence was chosen from an endoxylanase gene, and 10 such sequences from 10 endoxylanases were combined to make an artificial RNAi trigger by synthetic DNA. Quantitative RT-PCR analysis revealed that the transcript levels of all the expressed xylanase genes were significantly reduced in KD mutants with the artificial RNAi trigger. Even though the KD mutants did not completely lose their pathogenicity to host plants, the number of lesions, rate of penetration and extent of infected cells were all reduced in KD mutant-infected leaves. The degree of pathogenicity reduction was associated with the silencing levels of xylanase mRNA and enzymatic activity in the KD mutants. Cytological analysis indicated that xylanases play significant roles in both vertical penetration and horizontal expansion of M. oryzae in infected plants. PMID- 21696465 TI - Two autonomous structural modules in the fimbrial shaft adhesin FimA mediate Actinomyces interactions with streptococci and host cells during oral biofilm development. AB - By combining X-ray crystallography and modelling, we describe here the atomic structure of distinct adhesive moieties of FimA, the shaft fimbrillin of Actinomyces type 2 fimbriae, which uniquely mediates the receptor-dependent intercellular interactions between Actinomyces and oral streptococci as well as host cells during the development of oral biofilms. The FimA adhesin is built with three IgG-like domains, each of which harbours an intramolecular isopeptide bond, previously described in several Gram-positive pilins. Genetic and biochemical studies demonstrate that although these isopeptide bonds are dispensable for fimbrial assembly, cell-cell interactions and biofilm formation, they contribute significantly to the proteolytic stability of FimA. Remarkably, FimA harbours two autonomous adhesive modules, which structurally resemble the Staphylococcus aureus Cna B domain. Each isolated module can bind the plasma glycoprotein asialofetuin as well as the polysaccharide receptors present on the surface of oral streptococci and epithelial cells. Thus, FimA should serve as an excellent paradigm for the development of therapeutic strategies and elucidating the precise molecular mechanisms underlying the interactions between cellular receptors and Gram-positive fimbriae. PMID- 21696467 TI - Antimicrobial peptide sensing and detoxification modules: unravelling the regulatory circuitry of Staphylococcus aureus. AB - Investigations into the resistance mechanisms of Firmicutes bacteria against antimicrobial peptides have revealed unique resistance modules comprised of an unusual type of ATP-binding cassette (ABC) transporter, paired with a two component regulatory system. In these systems, the ABC-transporter is not only involved in detoxification of the peptides, but also in their detection and resulting regulation of gene expression. The manuscript by Hiron et al. (2011) published in this issue describes an intriguing complexity of regulatory circuits and division of labour between the three paralogous modules in Staphylococcus aureus, providing important mechanistic insights and new perspectives for future investigations of these unique systems. PMID- 21696468 TI - Pervasive post-transcriptional control of genes involved in amino acid metabolism by the Hfq-dependent GcvB small RNA. AB - GcvB is one of the most highly conserved Hfq-associated small RNAs in Gram negative bacteria and was previously reported to repress several ABC transporters for amino acids. To determine the full extent of GcvB-mediated regulation in Salmonella, we combined a genome-wide experimental approach with biocomputational target prediction. Comparative pulse expression of wild-type versus mutant sRNA variants revealed that GcvB governs a large post-transcriptional regulon, impacting ~1% of all Salmonella genes via its conserved G/U-rich domain R1. Complementary predictions of C/A-rich binding sites in mRNAs and gfp reporter fusion experiments increased the number of validated GcvB targets to more than 20, and doubled the number of regulated amino acid transporters. Unlike the previously described targeting via the single R1 domain, GcvB represses the glycine transporter CycA by exceptionally redundant base-pairing. This novel ability of GcvB is focused upon the one target that could feedback-regulate the glycine-responsive synthesis of GcvB. Several newly discovered mRNA targets involved in amino acid metabolism, including the global regulator Lrp, question the previous assumption that GcvB simply acts to limit unnecessary amino acid uptake. Rather, GcvB rewires primary transcriptional control circuits and seems to act as a distinct regulatory node in amino acid metabolism. PMID- 21696470 TI - Germination proteins in the inner membrane of dormant Bacillus subtilis spores colocalize in a discrete cluster. AB - Dormant bacterial spores are extraordinarily resistant to environmental insults and are vectors of various illnesses. However, spores cannot cause disease unless they germinate and become vegetative cells. The molecular details of initiation of germination are not understood, but proteins essential in early stages of germination, such as nutrient germinant receptors (GRs) and GerD, are located in the spore inner membrane. In this study, we examine how these germination proteins are organized in dormant Bacillus subtilis spores by expressing fluorescent protein fusions that were at least partially functional and observing spores by fluorescence microscopy. We show that GRs and GerD colocalize primarily to a single cluster in dormant spores, reminiscent of the organization of chemoreceptor signalling complexes in Escherichia coli. GRs require all their subunits as well as GerD for clustering, and also require diacylglycerol addition to GerD and GRs' C protein subunits. However, different GRs cluster independently of each other, and GerD forms clusters in the absence of all the GRs. We predict that the clusters represent a functional germination unit or 'germinosome' in the spore inner membrane that is necessary for rapid and cooperative response to nutrients, as conditions known to block nutrient germination also disrupt the protein clusters. PMID- 21696469 TI - ppGpp in Sinorhizobium meliloti: biosynthesis in response to sudden nutritional downshifts and modulation of the transcriptome. AB - Sinorhizobium meliloti Rm2011 responds to sudden shifts to nitrogen or carbon starvation conditions by an accumulation of the stringent response alarmone ppGpp and remodelling of the transcriptome. The gene product of relA, Rel(Sm) , responsible for synthesis of ppGpp, shows functional similarities to E. coli SpoT. Using promoter-egfp gene fusions, we showed that in Rm2011 relA is expressed at a low rate, as a readthrough from the rpoZ promoter and from its own weak promoter. The low level of relA expression is physiologically relevant, since overexpression of Rel(Sm) inhibits ppGpp accumulation. The N-terminal portion of Rel(Sm) is required for ppGpp degradation in nutrient-sufficient cells and might be involved in regulation of the ppGpp synthase and hydrolase activities of the protein. Expression profiling of S. meliloti subjected to sudden nitrogen or carbon downshifts revealed that repression of 'house-keeping' genes is largely dependent on relA whereas activation of gene targets of the stress sigma factor RpoE2 occurred independently of relA. The regulatory genes nifA, ntrB, aniA and sinR, as well as genes related to modulation of protein biosynthesis and nucleotide catabolism, were induced in a relA-dependent manner. dksA was required for the majority of the relA-dependent regulations. PMID- 21696471 TI - Identification, localisation and functional implication of 26RFa orthologue peptide in the brain of zebra finch (Taeniopygia guttata). AB - Several neuropeptides with the C-terminal Arg-Phe-NH(2) (RFa) sequence have been identified in the hypothalamus of a variety of vertebrates. The present study was conducted to isolate novel RFa peptides from the zebra finch brain. Peptides were isolated by immunoaffinity purification using an antibody that recognises avian RFa peptides. The isolated peptide consisted of 25 amino acids with RFa at its C terminus. The sequence was SGTLGNLAEEINGYNRRKGGFTFRFa. Alignment of the peptide with vertebrate 26RFa has revealed that the identified peptide is the zebra finch 26RFa. We also cloned the precursor cDNA encoding this peptide. Synteny analysis of the gene showed a high conservation of this gene among vertebrates. In addition, we cloned the cDNA encoding a putative 26RFa receptor, G protein coupled receptor 103 (GPR103) in the zebra finch brain. GPR103 cDNA encoded a 432 amino acid protein that has seven transmembrane domains. In situ hybridisation analysis in the brain showed that the expression of 26RFa mRNA is confined to the anterior-medial hypothalamic area, ventromedial nucleus of the hypothalamus and the lateral hypothalamic area, the brain regions that are involved in the regulation of feeding behaviour, whereas GPR103 mRNA is distributed throughout the brain in addition to the hypothalamic nuclei. When administered centrally in free-feeding male zebra finches, 26RFa increased food intake 24 h after injection without body mass change. Diencephalic GPR103 mRNA expression was up-regulated by fasting for 10 h. Our data suggest that the hypothalamic 26RFa-its receptor system plays an important role in the central control of food intake and energy homeostasis in the zebra finch. PMID- 21696473 TI - Morphine-induced changes in opioid sensitivity in postpartum females: a unique progesterone response. AB - Opioid peptides play an important role in maternal behaviour, as well as in physiological and pathological phenomena involving motivation. Daily 3.5 mg/kg doses of morphine from days 17-21 of pregnancy are able to change the expression of maternal behaviour patterns. However, the role of hormones on such opioid behavioural actions remains to be determined. The present study investigated the endocrine responses to this morphine treatment. Corticosterone, progesterone, oestradiol and prolactin serum concentrations were measured after each morphine injection. No significant differences were found in corticosterone, oestradiol or prolactin serum concentrations. The results suggest that the treatment was unable to promote different effects, other than those caused by saline injections. In morphine-treated animals, however, progesterone concentrations were consistently and significantly increased from days 18-20 of treatment. Thus, because this behavioural meaningful opioidergic stimulation during late pregnancy affects progesterone levels, the findings of the present study raise the hypothesis that this hormone may play a role in morphine-induced changes in opioid sensitivity during late pregnancy and early lactation. PMID- 21696474 TI - Knowledge, attitude and practice towards blood donation in Iranian population. AB - BACKGROUND: The increase in demand for blood products because of new surgical and medical procedures seeks more research to find new ways to recruit people to donate blood. OBJECTIVE/AIM: To determine the level of people's knowledge about donating blood considering its relation with infectious and chronic diseases, drug abuse, unsafe sexual intercourse, menstruation and anaemia. In addition, their attitude towards blood donation regarding their previous behaviour and factors such as altruism, religion, family, fears and availability of blood donation centres has been evaluated. METHODS: This study was conducted in Tehran, Iran in 2009 on 1000 respondents. Data were collected through questionnaires that comprised 37 questions considering demographic and background characteristics, level of knowledge and positive and negative attitudes towards blood donation. Finally, data were analysed using SPSS software. RESULTS: Of 1000 in this study, 26% were donors, of whom 55% had donated blood more than once. The mean knowledge score of the participants was 8.6, which was associated with the subjects' gender and level of education (P = 0.031 and P < 0.001, respectively). Age, gender and level of education were significantly associated with one's attitude towards blood donation (P = 0.021, P < 0.001 and P = 0.003,respectively). Ninety-five percent of people have stated that their main motivation to donate blood was altruism. CONCLUSION: Altruism and being encouraged by others had the leading roles in peoples' positive attitude towards blood donation; whereas hard access to blood donation centres seemed to be the main inhibitory factor. PMID- 21696475 TI - Colony kin structure and breeding system in the ant genus Plagiolepis. AB - Relatedness is a central parameter in the evolution of sociality, because kin selection theory assumes that individuals involved in altruistic interactions are related. At least three reproductive characteristics are known to profoundly affect colony kin structure in social insects: the number of reproductive queens per colony, the relatedness among breeding queens and queen mating frequency. Both the occurrence of multiple queens (polygyny) and multiple mating (polyandry) decrease within-colony relatedness, while mating among sibs increases relatedness between the workers and the brood they rear. Using DNA microsatellites, we performed a detailed genetic analysis of the colony kin structure and breeding system in three ant species belonging to the genus Plagiolepis: P. schmitzii, P. taurica and P. maura. Our data show that queens of the three species mate multiply: queens of P. maura mate with 1-2 males, queens of P. taurica with 3-11 males and queens of P. schmitzii may have 1-14 different mates. Moreover, colonies are headed by multiple queens: P. taurica and P. maura are facultatively polygynous, while P. schmitzii is obligately polygynous. Despite polyandry and polygyny, relatedness within colonies remains high because all species are characterized by sib-mating, with a fixation index F(it) = 0.25 in P. taurica, 0.24 in P. schmitzii and 0.26 in P. maura, and because the male mates of a queen are on average closely related. PMID- 21696472 TI - Novel substrates for, and sources of, progestogens for reproduction. AB - Steroid hormones, such as progesterone, are typically considered to be primarily secreted by the gonads (albeit adrenals can also be a source) and to exert their actions through cognate intracellular progestin receptors (PRs). Through its actions in the midbrain ventral tegmental Area (VTA), progesterone mediates appetitive (exploratory, anxiety, social approach) and consummatory (social, sexual) aspects of rodents' mating behaviour. However, progesterone and its natural metabolites ('progestogens') are produced in the midbrain VTA independent of peripheral sources and midbrain VTA of adult rodents is devoid of intracellular PRs. One approach that we have used to understand the effects of progesterone and mechanisms in the VTA for mating is to manipulate the actions of progesterone in the VTA and to examine effects on lordosis (the posture female rodents assume for mating to occur). This review focuses on the effects and mechanisms of progestogens to influence reproduction and related processes. The actions of progesterone and its 5alpha-reduced metabolite and neurosteroid, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP; allopregnanolone) in the midbrain VTA to facilitate mating are described. The findings that 3alpha,5alpha THP biosynthesis in the midbrain occurs with mating are discussed. Evidence for the actions of 3alpha,5alpha-THP in the midbrain VTA via nontraditional steroid targets is summarised. The broader relevance of these actions of 3alpha,5alpha THP for aspects of reproduction, beyond lordosis, is summarised. Finally, the potential role of the pregnane xenobiotic receptor in mediating 3alpha,5alpha-THP biosynthesis in the midbrain is introduced. PMID- 21696477 TI - MC1R-dependent, melanin-based colour polymorphism is associated with cell mediated response in the Eleonora's falcon. AB - Colour polymorphism in vertebrates is usually under genetic control and may be associated with variation in physiological traits. The melanocortin 1 receptor (Mc1r) has been involved repeatedly in melanin-based pigmentation but it was thought to have few other physiological effects. However, recent pharmacological studies suggest that MC1R could regulate the aspects of immunity. We investigated whether variation at Mc1r underpins plumage colouration in the Eleonora's falcon. We also examined whether nestlings of the different morphs differed in their inflammatory response induced by phytohemagglutinin (PHA). Variation in colouration was due to a deletion of four amino acids at the Mc1r gene. Cellular immune response was morph specific. In males, but not in females, dark nestling mounted a lower PHA response than pale ones. Although correlative, our results raise the neglected possibility that MC1R has pleiotropic effects, suggesting a potential role of immune capacity and pathogen pressure on the maintenance of colour polymorphism in this species. PMID- 21696476 TI - Larval and nurse worker control of developmental plasticity and the evolution of honey bee queen-worker dimorphism. AB - Social evolution in honey bees has produced strong queen-worker dimorphism for plastic traits that depend on larval nutrition. The honey bee developmental programme includes both larval components that determine plastic growth responses to larval nutrition and nurse components that regulate larval nutrition. We studied how these two components contribute to variation in worker and queen body size and ovary size for two pairs of honey bee lineages that show similar differences in worker body-ovary size allometry but have diverged over different evolutionary timescales. Our results indicate that the lineages have diverged for both nurse and larval developmental components, that rapid changes in worker body ovary size allometry may disrupt queen development and that queen-worker dimorphism arises mainly from discrete nurse-provided nutritional environments, not from a developmental switch that converts variable nutritional environments into discrete phenotypes. Both larval and nurse components have likely contributed to the evolution of queen-worker dimorphism. PMID- 21696478 TI - Desiccation resistance and mating behaviour in laboratory populations of Drosophila simulans originating from the opposing slopes of Lower Nahal Oren (Israel). AB - Lower Nahal Oren in Northern Israel, often referred to as 'Evolution Canyon', has been proposed as a microscale model site for ecological evolution. However, conflicting stress resistance and mating assay results contribute to controversy over the Nahal Oren model. In this study, we further tested the Nahal Oren model, while extending its focus from Drosophila melanogaster to its sister species, Drosophila simulans. Using fly populations derived from the opposing canyon slopes and acclimated to laboratory conditions for 11-22 generations, we did not find a significant slope effect on desiccation resistance (P = 0.96) or body metabolic fuel content (P > 0.43), which would indicate a genetic basis for adaptation to local resource limitation. Multiple-choice mating assays (47-48% homotypic couples in two replicate populations) did not indicate divergence from a random mating pattern between north- and south-facing slope flies. In conclusion, our findings do not support divergence of D. simulans populations across Lower Nahal Oren. PMID- 21696479 TI - Sexual selection on male development time in the parasitoid wasp Nasonia vitripennis. AB - Mating systems are shaped by a species' ecology, which sets the stage for sexual selection. Males of the gregarious parasitoid wasp Nasonia vitripennis compete to mate virgin females at the natal site, before females disperse. Males could increase their fitness by being larger and monopolizing female emergence sites or by emerging earlier pre-empting access to females. We consider sexual selection on male body size and development time in Nasonia, and a potential trade-off between the two traits. We explored sex-specific patterns of larval and pupal development, finding that smaller wasps developed slower than their host-mates. Using competition experiments between brothers, we found that earlier eclosing males mated more females independently of absolute and relative body size. Our data explain the lack of relationship between fitness and body size in male Nasonia and reinforce the importance of protandry in mating systems where access to mates is time-limited. PMID- 21696480 TI - Genetic correlation between resting metabolic rate and exploratory behaviour in deer mice (Peromyscus maniculatus). AB - According to the 'pace-of-life' syndrome hypothesis, differences in resting metabolic rate (RMR) should be genetically associated with exploratory behaviour. A large number of studies reported significant heritability for both RMR and exploratory behaviour, but the genetic correlation between the two has yet to be documented. We used a quantitative genetic approach to decompose the phenotypic (co)variance of several metabolic and behavioural measures into components of additive genetic, common environment and permanent environment variance in captive deer mice. We found significant additive genetic variance for two mass independent metabolic measures (RMR and the average metabolic rate throughout the respirometry run) and two behavioural measures (time spent in centre and distance moved in a novel environment). We also detected positive additive genetic correlation between mass-independent RMR and distance moved (r(A) = 0.78 +/- 0.23). Our results suggest that RMR and exploratory behaviour are functionally integrated traits in deer mice, providing empirical support for one of the connections within the pace-of-life syndrome hypothesis. PMID- 21696481 TI - Parental rights and decision making regarding vaccinations: ethical dilemmas for the primary care provider. AB - PURPOSE: To discuss the ethical dilemma that a primary care nurse practitioner (NP) must face when parents refuse to have their children immunized. DATA SOURCES: Review of published literature on the topic. CONCLUSIONS: By listening carefully to their concerns, responding honestly, and providing clear information about the risks and benefits, NPs may be able to build trust and to convince once hesitant parents to have their children immunized. For those parents who refuse, NPs may feel uncertain on how to respond. By considering the ethical principles to which they are bound, autonomy, beneficence, and non-maleficence, NPs can work with the parents to decide what treatment is best for the child. IMPLICATIONS FOR PRACTICE: Providing truthful information to parents and utilizing public awareness through recent discussions in the media and on the Internet may be able to obviate many of the concerns of parents, which may be getting in the way of universal immunization. PMID- 21696482 TI - A journey to become a federally qualified health center. AB - PURPOSE: Since 1998, Integrated Health Care (IHC), an academic nurse-managed center of the University of Illinois at Chicago College of Nursing, has delivered primary and mental health care to people with serious and persistent mental illness who are enrolled in psychosocial rehabilitation. DATA SOURCES: Federal guidelines and experiences of the steering group. This article reports our journey of transformation to a achieve the status of a Federally Qualified Health Center (FQHC). CONCLUSIONS: Nurse-managed clinics (NMCs) have become important in the U.S. healthcare system with well documented positive impact. However, financial issues have placed may NMCs at risk for closure. Achieving FQHC status is seen as a viable option to increase revenue and therefore financial stability. IMPLICATIONS FOR PRACTICE: This discussion of the benefits of FQHC status, an overview of some common compliance issues with FQHC requirements, and the report of lessons learned along the way in meeting FQHC standards that we encountered can provide support and guidance for other NMCs in similar situations. PMID- 21696483 TI - Patient-provider partnership in a memory disorder center. AB - PURPOSE: The purpose of this article is to describe the patient-provider relationship that is embraced in a memory disorder center utlizing a nurse practitioner-based model of care delivery. DATA SOURCES: A case study approach was used to promote understanding of how this model could be used in practice. CONCLUSIONS: Establishing a partnership relationship with patients, families and other healthcare providers gave patients a greater voice in their care. Patients disclosed information to the practitioner that would otherwise have not been shared and practitioners' care management was more effective because it was based upon input from the patient and family as well as the practitioner's expertise. The interdisciplinary staff have learned to value one another's expertise and to call upon each other as the need arises. IMPLICATIONS FOR PRACTICE: Fostering patient-provider partnering increases the effectiveness of care as well as patient and family satisfaction with the care received. PMID- 21696484 TI - Access Carroll: community asthma education initiative. AB - PURPOSE: Grant funding from the American Academy of Nurse Practitioners Foundation was used to develop a community asthma education initiative for patients at Access Carroll. This initiative provided asthma education and supplies to current patients seen at the free healthcare clinic. While the focus was on patient education, the majority of funds were used to purchase supplies, including bronchodilators, spacer devices, nebulizers, and peak flow meters. DATA SOURCES: Using an asthma self-management and symptom control questionnaire, data were collected before and after the asthma education program. CONCLUSIONS: While on a small scale, this project was deemed successful by increasing patient asthma treatment awareness, improving patient quality of life, and reducing emergency department visits for the patients at Access Carroll. IMPLICATIONS FOR PRACTICE: Using specific tools to assess asthma treatment knowledge and current self perception of asthma control can help healthcare professionals quantify patients' symptoms and specify areas of augmentation in asthma understanding. PMID- 21696485 TI - Pre- and postassessment of nurse practitioners' knowledge of hereditary colorectal cancer. AB - PURPOSE: This study was part of an educational program conducted to describe nurse practitioners' (NPs') knowledge and perceived comfort level regarding the identification of hereditary colorectal cancer (CRC), specifically Lynch syndrome, also referred to as hereditary nonpolyposis CRC. DATA SOURCES: A 3-h workshop was developed that included a pretest to evaluate NPs' knowledge of hereditary CRC syndromes, educational program focusing on Lynch syndrome, and a posttest knowledge evaluation. Knowledge of hereditary CRC syndromes was assessed via a nine-item multiple choice self-report survey. Forty-two NPs participated in the study. CONCLUSION: Few NPs (39%) reported "comfortable" in identifying red flags "suspect" for Lynch syndrome. Percentage of NPs who responded correctly on each of the pretest items ranged from 17.0% to 57.1% (M = 26.2%; SD = 13.5%; 95% confidence intervals [CI] 14.9%, -37.5%). NPs who responded correctly to the same items after the educational program (posttest) ranged from 53.8% to 95% (M = 80.5%; SD = 15.3%; 95% CI 67.8%, -93.4%). IMPLICATIONS FOR PRACTICE: Genetic testing is widely available for Lynch syndrome. It is important that NPs are cognizant of the syndrome and identify patients at risk for hereditary cancer syndromes so appropriate referral and management can be instituted. PMID- 21696486 TI - Interaction goals in the primary care medical interview. AB - PURPOSE: To examine the extent to which nurse practitioners (NPs) pursue three supraordinate goals (instrumental, relational, and self-presentational) in their interactions with patients in the primary care medical interview. DATA SOURCES: One hundred three NPs representing a variety of specialties who responded to open ended survey. CONCLUSIONS: A content analysis of 590 goal statements listed by respondents resulted in the generation of seven basic level instrumental goals (global/general health care issues; diagnostic/assessment issues; treatment/plan of care issues; information-gathering; information-giving; information-verifying; and resource management); four basic level relational goals (relationship building; compliance-gaining; anxiety management; and identity management); and three basic level self-presentational goals (establishing expertise; demonstrating professionalism; and demonstrating compassion). IMPLICATIONS FOR PRACTICE: Primary care medical interviews are recurring events that can produce automatic or habitual communication that may not be optimal for patient care. Training sessions that enable NPs to observe themselves and others in interactions with patients can improve NP ability to recognize and attend to the multiple goals in effect at given point. Ultimately, this goal-oriented approach to interaction should generate more efficient, productive, and satisfying primary care medical interviews for both the NP and the patient. PMID- 21696487 TI - The impact of Tai Chi exercise on coronary heart disease: a systematic review. AB - PURPOSE: (a) To explore current studies on Tai Chi and its impact on coronary heart disease (CHD), (b) provide critique of existing studies, and (c) provide recommendations for clinical practice and future research. DATA SOURCES: Comprehensive review of literature. CONCLUSIONS: Tai Chi is a safe alternative exercise for patients who are at risk of CHD or with existing CHD. Implementing Tai Chi exercise may improve serum lipids, blood pressure, and heart rate. IMPLICATIONS FOR PRACTICE: Nurse practitioners (NPs) are in an ideal position to facilitate health promotion and disease prevention. NPs may prescribe Tai Chi as an alternative exercise therapy for their patients who are at risk for developing CHD and even for those with existing CHD. Tai Chi exercise may help prevent and even reverse the progression of cardiac disease. PMID- 21696488 TI - Understanding postdivorce coparenting families: integrative literature review. AB - PURPOSE: To perform a systematic review of the research literature on postdivorce coparenting relationships and improve practice through increasing providers' understanding of this dynamic relationship. DATA SOURCES: Health science and social science literatures were reviewed using the following databases: Cumulative Index of Nursing and Allied Health Literature (CINAHL), MEDLINE, PsycINFO, Google Scholar, PubMed, and Sociology Abstracts. CONCLUSIONS: Over 290 articles were found, although only 19 peer-reviewed articles met the inclusion criteria of research conducted with both postdivorce coparents. Researchers' priorities centered on quality and conflict in the postdivorce coparenting relationships. IMPLICATIONS FOR PRACTICE: This review may help improve the understanding of postdivorce families and the dynamics involved in their care. Based upon this review, areas of assessment and intervention for nurse practitioners are identified. PMID- 21696489 TI - Biomarkers in the diagnosis and therapy of CIDP: Proceedings of the Biomarkers Faculty Meeting; June 8-9, 2010, Athens, Greece. PMID- 21696490 TI - Current diagnosis of CIDP: the need for biomarkers. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic neuropathy characterized by symmetrical proximal and distal weakness, with large-fiber sensory loss, impaired balance, and areflexia. This condition is often underdiagnosed due to the frequent absence of these classical clinical features as well as abnormalities that arise during confirmatory tests. Current diagnostic tests involve the measurement of cerebrospinal fluid protein levels, nerve biopsy, electrodiagnostic testing, and treatment response. Due to the clinical heterogeneity of the condition and a lack of a consistent confirmatory test, a variety of diagnostic criteria were developed. At least 14 different sets of diagnostic criteria have been proposed that each have varying diagnostic sensitivities. Although the diagnostic tests used within these criteria are useful, they individually offer evidence to support, rather than definitively confirm, the diagnosis of CIDP. Currently, there is no biomarker that can reliably identify all patients with CIDP, but it is evident that such a biomarker is urgently needed to ensure effective disease management. PMID- 21696491 TI - Biomarkers of CIDP in patients with diabetes or CMT1. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease that targets the myelin sheaths in peripheral nerves. Primary demyelination can be detected by electrodiagnostic studies or nerve biopsy, but these do not distinguish between demyelination resulting from CIDP or from non-inflammatory causes such as diabetes or Charcot-Marie-Tooth type I. Consequently, the diagnosis of CIDP in such patients is often missed. Studies are needed to establish electrodiagnostic criteria for CIDP in patients with diabetes, and to identify biomarkers that distinguish between inflammatory and non-inflammatory causes of demyelinating neuropathy. PMID- 21696492 TI - Testing for anti-glycolipid IgM antibodies in chronic immune-mediated demyelinating neuropathies. AB - Antibodies to several nerve antigens have been reported in patients with chronic immune-mediated demyelinating neuropathies including chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and IgM paraproteinemic demyelinating polyneuropathy. The association of some reactivities with specific neuropathies, such as IgM antibodies to the myelin associated glycoprotein in neuropathy associated with IgM monoclonal gammopathy, permitted to cast some light in their pathogenetic mechanisms and introduced new useful tools in their diagnosis. Other antibodies have been variably associated with other forms of neuropathy or with neuropathy itself, casting some doubts on their diagnostic relevance in the workout of these neuropathies. This is particularly true for IgM antibodies to glycolipids, including ganglioside and sulfatides, whose possible role in immune-mediated neuropathies is still debated and will be here reviewed. PMID- 21696493 TI - Nerve biopsy in chronic inflammatory neuropathies: in situ biomarkers. AB - We collected the evidence for potential biomarkers in nerve biopsies that might be of use in diagnosis, assessment, or treatment response in chronic inflammatory demyelinating polyneuropathies (CIDPs). We performed a literature search in PubMed from 1965 to May 2010 using the key words (["chronic inflammatory polyneuropathy" or "polyradiculoneuritis" or {"chronic and neuritis"}] and "nerve biopsy") and searched manually within these references for relevant publications related to the subject. Twenty references gave information about potential biomarkers for CIDP. Evidence of demyelination alone is not specific for CIDP, but may support the diagnosis in the context of a typical clinical pattern. Although the total numbers of inflammatory cells do not distinguish well between CIDP and non-inflammatory neuropathies, the pattern of macrophage clusters around endoneurial vessels may be a simple marker of inflammation with good sensitivity and specificity. Immunohistochemistry for matrix metalloproteinase-9 may be useful for the distinction of inflammatory and non-inflammatory neuropathies. Microarrays which give a complex pattern of up- and downregulated genes also show promise for developing a biomarker. Immunohistochemistry on sural nerve biopsies has the potential to distinguish inflammatory from non-inflammatory neuropathies. More research is needed to establish the diagnostic validity of specific markers and of gene expression studies and to test whether they can distinguish between subtypes of inflammatory neuropathies. PMID- 21696494 TI - Differential gene expression in nerve biopsies of inflammatory neuropathies. AB - DNA microarray analysis is a powerful tool for simultaneous analysis and comparison of gene products expressed in normal and diseased tissues. We used this technique to identify differentially expressed genes (DEGs) in nerve biopsy samples of chronic inflammatory demyelinating polyneuropathy (CIDP) and vasculitic neuropathy (VAS) patients. We found novel previously uncharacterized genes of relevance to CIDP or VAS pathogenesis. Of particular interest in CIDP were tachykinin precursor 1, which may be involved in pain mediation, stearoyl-co enzyme A (CoA) desaturase, which may be a marker for remyelination, HLA-DQB1, CD69, an early T-cell activation gene, MSR1, a macrophage scavenger receptor, and PDZ and LIM domain 5 (PDLIM5), a factor regulating nuclear factor (NF)-kappa B activity. Genes upregulated in VAS included IGLJ3, IGHG3, IGKC, and IGL, which all function in B-cell selection or antigen recognition of B cells. Other upregulated genes included chemokines, such as CXCL9 and CCR2, as well as CPA3, a mast cell carboxypeptidase. Allograft inflammatory factor-1 (AIF-1), a modulator of immune response was upregulated both in CIDP and VAS. Microarray-based analysis of human sural nerve biopsies showed distinct gene expression patterns in CIDP and VAS. DEGs might provide clues to the pathogenesis of the diseases and be potential targets for therapeutics. PMID- 21696495 TI - Auto-immune polyradiculoneuropathy and a novel IgG biomarker in workers exposed to aerosolized porcine brain. AB - Twenty-four patients, all of whom were exposed to aerosolized porcine brain tissue through work-place environment (abattoir), developed a syndrome of immune mediated polyradiculoneuropathy; three also had central nervous system manifestations (transverse myelitis, meningoencephalitis, and aseptic meningitis). Patients had characteristic electrophysiological findings of very distal and proximal conduction slowing (prolonged distal and F-wave latencies, regions where the blood-nerve barrier is the most permeable) and all patients' serum contained a novel IgG immunofluorescence pattern. Nerve pathology, when available, showed mild changes of segmental demyelination, axonal degeneration, and inflammatory changes. Patients had meaningful improvement of symptoms and electrophysiologic findings with immune therapy and with removal of exposure to aerosolized brain tissue. We postulate that this outbreak is an auto-immune polyradiculoneuropathy triggered by occupational exposure to multiple aerosolized porcine neural tissue antigens that result in neural damage where the blood-nerve barrier is the least robust. PMID- 21696496 TI - Serum IgG levels as biomarkers for optimizing IVIg therapy in CIDP. AB - Intravenous immunoglobulin (IVIg) is a proven effective treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Guillain-Barre syndrome (GBS). In GBS, patients show a large variability in serum immunoglobulin G (IgG) levels after standard IVIg treatment and a large increase in serum IgG levels (DeltaIgG) was associated with a better outcome. Whether this is also the case in CIDP is not known. In contrast to GBS, most patients with CIDP need regular IVIg treatment for a prolonged period of time but the speed and magnitude of clinical response varies considerably between patients. Some patients with CIDP may need at least two IVIg courses before clinical signs of improvement become clear. At present, this clinical response is the only indicator used to adjust the IVIg dose and interval during maintenance treatment. Biomarkers reflecting disease activity or IVIg pharmacokinetics might be helpful to monitor patients and find the optimal dosage and frequency of IVIg treatment for individual patients. A recent prospective study in CIDP indicated that the increased DeltaIgG after standard IVIg dosage during maintenance treatment was relatively constant within individual patients, but differed considerably between patients who were treated with the same stable dosage and interval of IVIg. Further studies are required to determine whether this variation in pharmacokinetics of IVIg is related with clinical recovery and whether IgG levels can be used as biomarkers to monitor and to adjust the optimal IVIg dosage in individual patients with CIDP. PMID- 21696497 TI - Expression and function of the inhibitory Fcgamma-receptor in CIDP. AB - The inhibitory Fc-gamma receptor (FcgammaR) IIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and auto-immunity, and is required for the anti-inflammatory activity of intravenous immunoglobulin (IVIg) in various murine disease models. We found that treatment-naIve patients with chronic inflammatory demyelinating polyneuropathy (CIDP) showed an impaired expression of FcgammaIIB levels on naIve B cells, and failed to upregulate or to maintain upregulation of FcgammaIIB, as B cells progressed from the naIve to the memory compartment. The impaired expression of FcgammaRIIB was, at least partially, restored by clinically effective IVIg treatment. It remains to be determined whether FcgammaRIIB expression is a candidate for pre-treatment assessment and might thus be used as a prognostic marker of treatment response to IVIg. Nonetheless, our data suggest that new strategies specifically targeting FcgammaRIIB expression might have therapeutic merit in CIDP. PMID- 21696498 TI - Fas-mediated T-cell apoptosis in chronic inflammatory demyelinating polyneuropathy. AB - The Fas receptor is expressed by activated lymphocytes and is involved in switching off the immune response. Defective Fas function causes the autoimmune lymphoproliferative syndrome, but is also involved in common autoimmune disorders. Fas-mediated T-cell apoptosis is impaired in chronic inflammatory demyelinating polyneuropathy (CIDP), but not in Guillain-Barre syndrome (GBS). The defect seems to have a genetic component and involve the extrinsic apoptotic pathway mediated by caspase-8. The analysis of clinical features shows that Fas function is lower in CIDP patients with a progressive course and axonal damage, suggesting that defective Fas function favors not only CIDP development but also its aggressive evolution. Moreover, testing T-cell Fas function in patients with acute-onset demyelinating polyneuropathy can help in early discrimination between GBS and acute-onset CIDP. PMID- 21696499 TI - Polymorphism of CD1 and SH2D2A genes in inflammatory neuropathies. AB - In the quest for susceptibility factors of inflammatory neuropathies, many genes implicated in the pathogenesis of autoimmune diseases have been investigated with negative or conflicting results. We studied, with a gene candidate approach, the CD1 system specialized in capturing and presenting glycolipids to antigen specific T cells, and the SH2D2A gene encoding for a T-cell-specific adapter protein implicated in control of early T-cell activation. In Guillain-Barre syndrome, an initially positive association study with polymorphism of CD1A and CD1E genes was not confirmed. In chronic inflammatory demyelinating polyneuropathy, we did not find an association with CD1 genes, but we found an association with a homozygous genotype for a low repeat number of tandem GA in the SH2D2A gene. This genotype could result in defective control and elimination of autoreactive T cells. All the studies were performed on relatively small size populations. Confirmation in larger sized studies is required both for CD1 and SH2D2A genes. Considering the relative rarity of patients with inflammatory neuropathies, this can only be accomplished by international collaboration. PMID- 21696500 TI - Polymorphism of transient axonal glycoprotein-1 in chronic inflammatory demyelinating polyneuropathy. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterized by immune-mediated peripheral demyelination. Although corticosteroid, intravenous immunoglobulin (IVIg), and plasma exchange have been established as the most effective therapeutics, sub-populations of patients show little or no response to either of these therapies. We identified the clinical, electrophysiological, and genetic features related to IVIg responsiveness in CIDP by conducting a multi center study. Muscle atrophy and decreased compound muscle action potential (CMAP) were pronounced in IVIg non-responders, that is, features suggesting axonal dysfunction in peripheral nerves indicated IVIg unresponsiveness in CIDP. We then performed an association analysis using single nucleotide polymorphisms (SNPs) and haplotype studies between the IVIg responders and non-responders. We assessed SNPs of candidate genes that are particularly related to the function of Ranvier's node, paranode, or juxtaparanode. Two separate SNPs, corresponding to transient axonal glycoprotein-1 (TAG-1) and C-type lectin domain family 10, member A (CLEC10A), showed significant differences between responders and non responders. Haplotype analysis of a series of expanded SNPs, from TAG-1 or CLEC10A, showed that only TAG-1 included a significant haplotype within one linkage disequilibrium block that accommodates IVIg responsiveness. Diplotype analysis of TAG-1 also supported this observation. In conclusion, SNPs in TAG-1, which is a key molecule for axon-Schwann cell interactions and is distributed at the juxtaparanode, are related to the IVIg responsiveness of CIDP patients. PMID- 21696501 TI - Immune mechanisms in spontaneously occurring CIDP in NOD mice. AB - Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease affecting the peripheral nervous system (PNS) and is thought to involve both cellular and humoral immunity. Although its etiology remains to be fully elucidated, the use of animal models has provided some important information regarding its pathogenetic mechanisms. The development of a spontaneous autoimmune polyneuropathy (SAP) in B7-2 knockout non-obese diabetic (NOD) mice underscores the importance of co-stimulatory pathways such as B7-1/B7-2:CD28/CTLA 4 molecules in inflammatory neuropathies. These co-stimulatory molecules regulate the balance between pathogenic and regulatory T cells (Tregs). In SAP, pathogenic T cells are directed against myelin protein zero (P0), the most prominent PNS myelin protein that is a member of immunoglobulin gene superfamily. PMID- 21696502 TI - Biomarkers in experimental models of antibody-mediated neuropathies. AB - Autoimmune neuropathy models have been refined in animals over the past 50 years to enable links to be made between antibody signatures and disease pathogenesis; however, the application of these models to identify biomarkers has not been fully developed. Models for chronic inflammatory demyelinating polyneuropathy (CIDP) must ensure that adequate distinctions are made from variants of other neuropathic states such as Guillain-Barre syndrome (GBS) in order to be of greatest clinical use. One of the main hurdles to overcome is the diverse pathogenesis of CIDP, which must be reflected in any potential models. Some advances in the search for biomarkers of CIDP have been made with the elucidation of anti-glycolipid antibodies and myelin-associated proteins, but further research is needed for specific disease indicators. PMID- 21696503 TI - Potential biomarkers for monitoring therapeutic response in patients with CIDP. AB - Although the majority of patients with CIDP variably respond to intravenous immunoglobulin (IVIg), steroids, or plasmapheresis, 30% of them are unresponsive or insufficiently responsive to these therapies. The heterogeneity in therapeutic responses necessitates the need to search for biomarkers to determine the most suitable therapy from the outset and explore the best means for monitoring disease activity. The ICE study, which led to the first FDA-approved indication for IVIg in CIDP, has shown that maintenance therapy prevents relapses and axonal loss. In this paper, the multiple actions exerted by IVIg on the immunoregulatory network of CIDP are discussed as potential predictors of response to therapies. Emerging molecular markers, promising in identifying responders to IVIg from non responders, include modulation of FcgammaRIIB receptors on monocytes and genome wide transcription studies related to inflammatory mediators, demyelination, or axonal degeneration. Skin biopsies, Peripheral Blood Lymhocytes, CSF, and sera are accessible surrogate tissues for further exploring these molecules during therapies. PMID- 21696505 TI - Cytokine profile of a premature infant with early onset listeriosis. PMID- 21696506 TI - Development of Kawasaki syndrome in autoimmune neutropenia after treatment with granulocyte colony-stimulating factor. PMID- 21696507 TI - Blepharophimosis-ptosis-epicanthus inversus syndrome. PMID- 21696508 TI - Six-year-old girl with primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. PMID- 21696509 TI - Primary vulvar endodermal sinus tumor: a case report and review of the literature. PMID- 21696510 TI - A case of medullomyoblastoma. PMID- 21696511 TI - Fatal pulmonary veno-occlusive disease after chemotherapy for Burkitt's lymphoma. PMID- 21696512 TI - A surviving case of papillorenal syndrome with the phenotype of Potter sequence. PMID- 21696513 TI - Adenovirus serotype 31 infection in a newborn girl and review of the literature. PMID- 21696514 TI - Swine flu (H1N1) in children: preparing for future outbreaks. PMID- 21696515 TI - New mutation of CACNA1A gene in episodic ataxia type 2. PMID- 21696516 TI - Use of a flexible Blake(r) silicone drains for peritoneal dialysis in the neonatal intensive care unit. PMID- 21696518 TI - A set of five microsatellite markers linked to F8 gene can detect haemophilia A carriers across India. AB - Haemophilia A (HA) is an X-linked recessive bleeding disorder, primarily because of defects in the 186-kb long factor VIII gene (F8) affecting 1-2 men per 10,000 worldwide. Available markers for carrier detection are not effective in all populations, especially in India. In this study, we have chosen a set of five microsatellite markers, namely, DSX9897, DSX1073, intron 1 (GT)(n) , intron 22 (CA)(n) and intron 25 (CA)(n) , in and around the F8 gene to achieve better sensitivity for carrier detection. Each marker locus has been PCR amplified in the individual DNA samples using fluorescent markers followed by genotyping experiment in automated sequencer. Genotype calls have been made by GeneMapper Software (version 4). Allele frequency of each microsatellite marker was calculated manually. Heterozygosity was determined by counting the heterozygotes in the female subset. We have shown that in 253 normal individuals from 20 different ethnic groups of India, the heterozygosity for the markers ranged from 0.25 to 0.54; and for the entire subset of 102 female samples we could successfully discriminate between the two X-chromosomes using these five markers. These markers could also discriminate between the two X-chromosomes for each of 39 obligate carriers included in this study. In conclusion, this panel of five markers around the F8 locus can be used for carrier detection of HA with higher sensitivity across India for families affected with the disease. PMID- 21696519 TI - Exploring variation in pressure ulcer prevalence in Sweden and the USA: benchmarking in action. AB - AIM: To compare overall unit-level pressure ulcer (PU) prevalence, hospital acquired pressure ulcer (HAPU) prevalence and prevention strategies, as well as nurse staffing and workload in two hospitals in Sweden with data from the USA. METHODS: Medical and surgical units in a university hospital and a general hospital in Sweden were compared with 207 hospitals in the USA participating in the Collaborative Alliance for Nursing Outcomes (CALNOC) benchmarking registry. All adult inpatients in university hospital (n = 630), general hospital (n = 253) and CALNOC hospitals (n = 3506) were included in the study. Outcome indicators were pressure ulcer prevalence for all types (PU) and HAPU prevalence, specifically. Process indicators were risk assessment and PU prevention strategies. Structure indicators were nurse staffing (hours of care, and skill mix) and workload (admissions, discharges and transfers). RESULTS: The prevalence of PU (categories 1-4) was 17.6% (university hospital) and 9.5% (general hospital) compared with 6.3-6.7% in the CALNOC sample. The prevalence of full thickness HAPU (categories 3 and 4) was 2.7% (university hospital) and 2.0% (general hospital) compared with 0-0.5% in the CALNOC sample. Risk and skin assessment varied between 6% and 60% in the Swedish hospitals compared with 100% in the CALNOC sample. Total hours per patient day were 8.4 in both Swedish hospitals and 9.5 to 9.8 in the CALNOC hospitals CONCLUSIONS: The findings suggest a link between processes of care and outcomes that is exciting to observe internationally and suggest the opportunity to expedite performance improvement through global benchmarking. Using HAPU as a complement to point prevalence of PU in Sweden has revealed this indicator as a more valid measure for patient care quality. PMID- 21696520 TI - Evaluation of the physicians' approach to the diagnosis and treatment of patients with antituberculosis drug-induced hepatotoxicity. AB - OBJECTIVES: To describe the practices of physicians on the diagnosis and treatment of antituberculosis drug-induced hepatotoxicity (ATH), and to evaluate the concordance between these practices and the American Thoracic Society (ATS) 2006 guidelines. METHODS: Information was reviewed on 670 new cases of tuberculosis patients aged not less than 15 years and registered at the outpatient clinics of a large hospital in southern Thailand during October 2006 to September 2009. The patient was identified as having ATH if: (1) he/she was diagnosed as transaminitis, hepatitis or hepatotoxicity from antituberculosis (anti-TB) drugs; (2) their treatment regimen was subsequently modified by their attending physicians; and (3) their liver enzyme decreased after withdrawal of the suspected anti-TB drugs. Compliance with the ATS guidelines was considered on diagnosis, initial management, selection of alternative regimens, and a reintroduction strategy. RESULTS: The prevalence of ATH was 6.7%. The proportion of patients diagnosed as ATH in accordance with the ATS 2006 guidelines was 73.8%. For the initial management, isoniazid, rifampicin and pyrazinamide were concurrently stopped in 55.0% of patients. While waiting for normalization of liver enzymes, 28 patients (70.0%) were treated with alternative regimens and 12 patients (30.0%) took no drug. Only 47.5% of the ATH patients received a regimen in accordance with ATS guidelines, including three less hepatotoxic drugs (ethambutol, ofloxacin and streptomycin). Of 34 patients who discontinued the treatment, anti-TB drugs were reintroduced sequentially in 30 patients (88.2%). Of these, only 23.4% were firstly rechallenged with rifampicin as suggested by the ATS guidelines. CONCLUSIONS: The practice of physicians on the diagnosis and management of ATH varied. The practices of physicians on the diagnosis and rechallenged method were in high compliance with the ATS guidelines. For the initial management and selection of alternative regimens, the physicians' compliance was not good. PMID- 21696521 TI - Stop: the medical and human rights scandal in Bahrain. PMID- 21696523 TI - Role of silymarin to treat fibrosis development in non-alcoholic fatty liver disease. PMID- 21696524 TI - Hepatocellular carcinoma with portal vein tumor thrombosis: Improved treatment outcomes with external beam radiation therapy. AB - The treatment of advanced hepatocellular carcinoma (HCC) associated with portal vein tumor thrombosis (PVTT) is very challenging because of HCC's grave prognosis. Despite many efforts to improve the treatment results, patient survival has been limited to several months. In this situation, radiotherapy has been considered as an alternative treatment modality because of the growth of knowledge about the radiotolerance of normal tissue and the advances of radiotherapy techniques such as three dimensional conformal radiotherapy, intensity modulated radiotherapy, stereotactic body radiotherapy and proton therapy. More restoration of the liver function and longer survival of the patients can be achieved by the better response after radiotherapy. However, considering the high risk of intrahepatic advanced tumor or extrahepatic dissemination by PVTT at disease presentation, a combination of radiation therapy and systemic agents will be desirable. Therefore, performing prospective randomized clinical trials is important to assess the benefits of radiotherapy and to develop combination treatment strategies. PMID- 21696522 TI - Toll-like receptor signaling in liver regeneration, fibrosis and carcinogenesis. AB - Toll-like receptors (TLR) are the germline-coded pattern recognition receptors that sense microbial products. This signaling orchestrates complex signaling pathways that induce expression of inflammatory genes for host defense against invading microorganisms. Recent studies illustrate the role of TLR on non infectious inflammatory diseases. The liver has a unique anatomy bridging with the intestine by portal vein and bile ducts. This allows delivery of products from intestinal microflora directly into the liver. Subsequently, microbial products cause acute and chronic inflammation through TLR signaling in the liver. Not only exogenous products, but endogenous denatured products released from dying cells also facilitate inflammation even in sterile conditions. Consequently, these responses elicit tissue repairing including liver regeneration and fibrogenesis. An aberrant regenerative response may lead to hepatic carcinogenesis. In this review, we highlight the recently accumulated knowledge about TLR signaling in liver regeneration, fibrosis and carcinogenesis. PMID- 21696525 TI - The use of everolimus in pediatric liver transplant recipients: first experience in a single center. AB - The role of mTOR inhibitors, such as EVL, has not been established for pediatric liver transplant recipients up to now, although data from adult solid organ graft transplantation are very promising. Major complications following pediatric liver transplantation in the long-term course include chronic graft rejection and CNI derived nephrotoxicity. The purpose of our study was to report first results using EVL as a rescue therapy in pediatric liver transplant recipients for the following indications: chronic graft dysfunction n=12, suspected CNI toxicity n=3, hepatoblastoma n=2, and recurrence of primary sclerosing cholangitis post Ltx n=1. Four patients with chronic graft dysfunction developed completely normal liver function tests using EVL, six patients showed partial improvement, and two patients did not respond at all. One patient with CNI-induced nephropathy showed a slightly improved GFR. Both patients with hepatoblastoma did not develop any metastasis post-Ltx. First experience with EVL in pediatric liver transplant recipients shows promising results in patients with chronic graft failure when standard immunosuppression has failed. The future role of EVL in immunosuppressive protocols for children post-Ltx has to be proven by controlled clinical trials. PMID- 21696526 TI - Assessment of the roles of ordered lipid microdomains in post-endocytic trafficking of glycosyl-phosphatidylinositol-anchored proteins in mammalian fibroblasts. AB - We have used artificial phosphatidylethanolamine-polyethylene glycol (PE-PEG) anchored proteins, incorporated into living mammalian cells, to evaluate previously proposed roles for ordered lipid 'raft' domains in the post-endocytic trafficking of glycosylphosphatidylinositol (GPI)-anchored proteins in CHO and BHK cells. In CHO cells, endocytosed PE-PEG protein conjugates colocalized strongly with the internalized GPI-anchored folate receptor, concentrating in the endosomal recycling compartment, regardless of the structure of the hydrocarbon chains of the PE-PEG 'anchor'. However, internalized PE-PEG protein conjugates with long-chain saturated anchors recycled to the plasma membrane at a slow rate comparable to that measured for the GPI-anchored folate receptor, whereas conjugates with short-chain or unsaturated anchors recycled at a faster rate similar to that observed for the transferrin receptor. These findings support the proposal (Mayor et al. Cholesterol-dependent retention of GPI-anchored proteins in endosomes. EMBO J 1998;17:4628-4638) that the slow recycling of GPI proteins in CHO cells rests on their affinity for ordered lipid domains. In BHK cells, internalized PE-PEG protein conjugates with either saturated or unsaturated 'anchors' colocalized strongly with simultaneously endocytosed folate receptor and, like the folate receptor, gradually accumulated in late endosomes/lysosomes. These latter findings do not support previous suggestions that the sorting of GPI proteins to late endosomes in BHK cells depends on their association with lipid rafts. PMID- 21696527 TI - Onset of type 1 diabetes mellitus in two patients with maturity onset diabetes of the young. AB - The association between maturity onset diabetes of the young (MODY) and type 1 diabetes mellitus (T1DM) has been rarely described. We report two patients affected by MODY who developed T1DM. Case 1: a 4-yr-old girl referred for glycosuria presented hemoglobin A1c (HbA1c) of 6.6%. Islet cell antibodies (ICA) and anti-glutamic acid decarboxylase (GADA) were initially negative. As her father, uncle and grandmother showed mild hyperglycemia, they were screened for MODY 2. A novel mutation in glucokinase gene was found in the family. Few months later, her glycemic control worsened consistently and she required insulin treatment. A high titer of GADA and ICA was then detected. Six years afterwards insulin requirement is 0.8 U/kg and HbA1c 6.7%. Case 2: a 15-yr-old boy treated for growth hormone deficiency was found with a blood glucose level of 106 mg/dL. HbA1c was 7.2%, ICA and GADA were negative. Family history was positive for autoimmune diseases and type 2 diabetes mellitus. The patient was investigated for MODY 2 and MODY 3, and a mutation of hepatocyte nuclear factor-1 alpha gene was found. The same mutation was found in the mother who had never been referred for hyperglycemia. After 1 yr, due to an unjustified worsening of the metabolic control, autoimmunity was again investigated and a mild positivity was found. He then required insulin therapy and after 5 yr current HbA1c was 8.2%. The diagnosis of MODY does not exclude the risk of developing T1DM. Therefore autoimmunity should be investigated when ordinary treatments fail and metabolic control unexpectedly worsens. PMID- 21696528 TI - Predictors of the health-related quality of life of patients who are newly diagnosed with lung cancer in China. AB - The purpose of this study was to explore the level and predictors of the health related quality of life among patients who were newly diagnosed with lung cancer in China. A descriptive survey design was used to collect the data from 108 patients. The relationships among the variables were analyzed by using Pearson's correlation and multiple regression analyses. The results indicated that the patients in this sample had a poor quality of life in the physical, psychological, and environmental domains of the World Health Organization Quality of Life Questionnaire. Their age, annual family income, social support, and three dimensions of the health locus of control (internal, external, and chance) correlated significantly with the global quality of life. The stepwise multiple regressions showed that only the internal locus of control was statistically significant in predicting the patients' quality of life. The results suggest that healthcare professionals should pay particular attention to demographic characteristics, such as age and family income, and personal characteristics, such as the health locus of control and social support, when treating this patient group. PMID- 21696529 TI - Experiences of women who have a vaginal birth after requesting a cesarean section due to a fear of birth: a biographical, narrative, interpretative study. AB - A fear of childbirth is a reason for a Cesarean section on request without a medical indication. The law for patients' rights in Norway does not give women the opportunity to choose a Cesarean section, only the potential to participate in the decision-making process. This requires cooperation between health professionals and patients. The present study explores the experience of women who had a vaginal birth after requesting a Cesarean section due to a fear of birth. A biographical, narrative, interpretative method was used. Through five women's stories, it is evident that the practice of decision-making constitutes a challenge for both the women and the health professionals. The importance of a woman's right to be taken seriously, even if she does not want to understand the reason behind her fear of birth, is emphasized. An open mind from midwives and physicians is required, although this seems difficult to achieve. PMID- 21696530 TI - Life after cervical cancer: quality of life among Chinese women. AB - This study explored the meaning of "quality of life" among Chinese survivors of cervical cancer and the impact of cervical cancer survivorship on these women's quality of life. Written responses were used as the means of data collection. The qualitative data were analyzed by using a qualitative content analysis. The meaning of "quality of life", as perceived by 35 Chinese survivors of cervical cancer, included being free of disease, having a good standard of living, having a harmonious family atmosphere, and having a harmonious sex life. The impact of cervical cancer on the Chinese women's quality of life included physical and psychological sequelae, family distress, financial burden, and disruptions to their social functioning and sexual life. Nevertheless, there were positive gains that were reported by these survivors, including changes in their outlook on life, treasuring their life, and better family relationships. This study revealed that the Chinese survivors of cervical cancer identified their sexual life as one of the essential indicators of quality of life. It is necessary to raise nurses' awareness so that women's sexuality-related concerns are addressed. Health professionals also should provide relevant supportive care in order to address this target population's physical and psychosocial needs across the survivorship continuum. PMID- 21696531 TI - Amlodipine-induced gingival overgrowth: considerations in a geriatric patient. PMID- 21696532 TI - Rare case of asymptomatic mucous membrane pemphigoid. PMID- 21696533 TI - The category "animals" is more appropriate than the category "vegetables" to measure semantic category fluency. PMID- 21696534 TI - WRKY transcription factors: key components in abscisic acid signalling. AB - WRKY transcription factors (TFs) are key regulators of many plant processes, including the responses to biotic and abiotic stresses, senescence, seed dormancy and seed germination. For over 15 years, limited evidence has been available suggesting that WRKY TFs may play roles in regulating plant responses to the phytohormone abscisic acid (ABA), notably some WRKY TFs are ABA-inducible repressors of seed germination. However, the roles of WRKY TFs in other aspects of ABA signalling, and the mechanisms involved, have remained unclear. Recent significant progress in ABA research has now placed specific WRKY TFs firmly in ABA-responsive signalling pathways, where they act at multiple levels. In Arabidopsis, WRKY TFs appear to act downstream of at least two ABA receptors: the cytoplasmic PYR/PYL/RCAR-protein phosphatase 2C-ABA complex and the chloroplast envelope-located ABAR-ABA complex. In vivo and in vitro promoter-binding studies show that the target genes for WRKY TFs that are involved in ABA signalling include well-known ABA-responsive genes such as ABF2, ABF4, ABI4, ABI5, MYB2, DREB1a, DREB2a and RAB18. Additional well-characterized stress-inducible genes such as RD29A and COR47 are also found in signalling pathways downstream of WRKY TFs. These new insights also reveal that some WRKY TFs are positive regulators of ABA-mediated stomatal closure and hence drought responses. Conversely, many WRKY TFs are negative regulators of seed germination, and controlling seed germination appears a common function of a subset of WRKY TFs in flowering plants. Taken together, these new data demonstrate that WRKY TFs are key nodes in ABA responsive signalling networks. PMID- 21696535 TI - Improvement of spatial fibrin formation by the anti-TFPI aptamer BAX499: changing clot size by targeting extrinsic pathway initiation. AB - BACKGROUND: Tissue factor pathway inhibitor (TFPI) is a major regulator of clotting initiation and a promising target for pro- and anticoagulation therapy. The aptamer BAX499 (formerly ARC19499) is a high-affinity specific TFPI antagonist designed to improve hemostasis. However, it is not clear how stimulation of coagulation onset by inactivating TFPI will affect spatial and temporal clot propagation. OBJECTIVE: To examine the BAX499 effect on clotting in a spatial, reaction-diffusion experimental system in comparison with that of recombinant activated factor VII (rVIIa). METHODS: Clotting in plasma activated by immobilized tissue factor (TF) was monitored by videomicroscopy. RESULTS: BAX499 dose-dependently improved coagulation in normal and hemophilia A plasma activated with TF at 2 pmole m(-2) by shortening lag time and increasing clot size by up to ~2-fold. The effect was TFPI specific as confirmed by experiments in TFPI-depleted plasma with or without TFPI supplementation. Clotting improvement was half-maximal at 0.7 nm of BAX499 and reached a plateau at 10 nm, remaining there at concentrations up to 1000 nm. The BAX499 effect decreased with TF surface density increase. RVIIa improved clotting in hemophilia A plasma activated with TF at 2 or 20 pmole m(-2) , both by shortening lag time and increasing spatial velocity of clot propagation; its effects were strongly concentration dependent. CONCLUSIONS: BAX499 significantly improves spatial coagulation by inhibiting TFPI in a spatially localized manner that is different to that observed with rVIIa. PMID- 21696536 TI - Influenza vaccination and hemostasis: no sustainable procoagulant effects from 2009 H1N1 influenza vaccine in healthy healthcare workers. PMID- 21696537 TI - Randomized double-blind placebo-controlled crossover study to determine the effects of esomeprazole on inhibition of platelet function by clopidogrel. AB - BACKGROUND: Pharmacokinetic studies suggest that clopidogrel and esomeprazole are metabolized by similar hepatic enzymes; however, previous studies have not identified a biochemical interaction. OBJECTIVES: To determine whether addition of esomeprazole to patients receiving aspirin and clopidogrel reduces the antiplatelet effects of clopidogrel. PATIENT/METHODS: Patients with a history of an acute coronary syndrome who had previously received clopidogrel were recruited. Subjects were commenced on clopidogrel and randomized to one of two treatment arms (esomeprazole or placebo) for 6 weeks. Following a 2-week washout period for study medications, patients were crossed over onto the alternative treatment arm for a further 6 weeks. Platelet function tests were undertaken at baseline, following the first treatment period, after washout and following the second treatment period. RESULTS: Thirty-one patients were enrolled. Significant attenuation of clopidogrel's antiplatelet effects was seen with co-administration of esomeprazole compared with placebo. Vasodilator stimulated phosphoprotein (VASP), platelet aggregometry (area under the curve (AUC)) and VerifyNow results were 54.7% +/- 2.8 platelet reactivity index (PRI), 66.3 +/- 2.6 AUC units and 213.1 +/- 14.1 platelet reactivity units (PRU) with esomeprazole vs. 47% +/- 2.7 PRI, 59.7 +/- 3.7 AUC units and 181.4 +/- 14.6 PRU with placebo (P < 0.01 esomeprazole vs. placebo for all measures). There was no significant difference in platelet aggregometry (maximal aggregation) between the esomeprazole group (68.9% +/- 2.7 units) and placebo-treated group (64.5% +/- 4.1 units; P > 0.05). CONCLUSION: Esomeprazole when co-administered with aspirin and clopidogrel results in a significant attenuation of clopidogrel's antiplatelet effects. PMID- 21696538 TI - Prospective study of circulating soluble CD40 ligand concentrations and the incidence of cardiovascular disease in a nested prospective case-control study of older men and women. AB - BACKGROUND: CD40 ligand(CD40L) is implicated in atherosclerotic plaque formation. OBJECTIVES: We investigated prospective associations between circulating soluble CD40L and myocardial infraction (MI) or stroke in an older general population cohort, accounting for established and novel cardiovascular risk factors. METHODS: Baseline serum CD40L (sCD40L) was measured in incident MI (n = 368) and stroke (n = 304) cases and two controls per case, 'nested' in prospective UK studies of 4252 men and 4286 women aged 60-79 years, sampled from general practices in Britain in 1998-2000, with 7-year follow-up for fatal and non-fatal MI and stroke. RESULTS: sCD40L was higher in smokers and negatively associated with lung function and positively associated with total cholesterol and markers of inflammation, but not with other established cardiovascular disease (CVD) risk factors. Geometric mean sCD40L levels did not differ between MI cases and controls (5.94 ng mL(-1) vs. 5.82 ng mL(-1); P = 0.5) or between stroke cases and controls (5.61 ng mL(-1) vs. 5.28 ng mL(-1), P = 0.1). There was no strong evidence for elevated risk of MI or stroke in multivariable models comparing participants in the top to those in the bottom third of sCD40L. Age-adjusted odds ratios (ORs) were 1.39 [95% confidence interval (CI) 0.98, 1.96] for MI and 1.16 (0.78, 1.73) for stroke. These attenuated to 1.24 (95% CI 0.86, 1.79) and 1.18 (0.78, 1.78), respectively, after adjustment for established and novel CVD risk factors. CONCLUSIONS: sCD40L is associated with other inflammatory markers but is not itself a strong independent risk marker for either stroke or MI. PMID- 21696539 TI - Signaling role of CD36 in platelet activation and thrombus formation on immobilized thrombospondin or oxidized low-density lipoprotein. AB - BACKGROUND AND OBJECTIVE: Platelets abundantly express glycoprotein CD36 with thrombospondin-1 (TSP1) and oxidized low-density lipoprotein (oxLDL) as proposed ligands. How these agents promote platelet activation is still poorly understood. METHODS AND RESULTS: Both TSP1 and oxLDL caused limited activation of platelets in suspension. However, immobilized TSP1 and oxLDL, but not LDL, strongly supported platelet adhesion and spreading with a major role of CD36. Platelet spreading was accompanied by potent Ca(2+) rises, and resulted in exposure of P selectin and integrin activation, all in a CD36-dependent manner with additional contributions of alpha(IIb) beta(3) and ADP receptor stimulation. Signaling responses via CD36 involved activation of the protein tyrosine kinase Syk. In whole blood perfusion, co-coating of TSP1 or oxLDL with collagen enhanced thrombus formation at high-shear flow conditions, with increased expression on platelets of activated alpha(IIb) beta(3), P-selectin and phosphatidylserine, again in a CD36-dependent way. CONCLUSIONS: Immobilized TSP1 and oxLDL activate platelets partly via CD36 through a Syk kinase-dependent Ca(2+) signaling mechanism, which enhances collagen-dependent thrombus formation under flow. These findings provide novel insight into the role of CD36 in hemostasis. PMID- 21696541 TI - The effect of myosin RLC phosphorylation in normal and cardiomyopathic mouse hearts. AB - Phosphorylation of the myosin regulatory light chain (RLC) by Ca(2+)-calmodulin activated myosin light chain kinase (MLCK) is known to be essential for the inotropic function of the heart. In this study, we have examined the effects of MLCK-phosphorylation of transgenic (Tg) mouse cardiac muscle preparations expressing the D166V (aspartic acid to valine)-RLC mutation, identified to cause familial hypertrophic cardiomyopathy with malignant outcomes. Our previous work with Tg-D166V mice demonstrated a large increase in the Ca(2+) sensitivity of contraction, reduced maximal ATPase and force and a decreased level of endogenous RLC phosphorylation. Based on studies demonstrating the beneficial and/or protective effects of cardiac myosin phosphorylation for heart function, we hypothesized that an ex vivo phosphorylation of Tg-D166V cardiac muscle may rescue the detrimental contractile phenotypes observed earlier at the level of single myosin molecules and in Tg-D166V papillary muscle fibres. We showed that MLCK-induced phosphorylation of Tg-D166V cardiac myofibrils and muscle fibres was able to increase the reduced myofibrillar ATPase and reverse an abnormally increased Ca(2+) sensitivity of force to the level observed for Tg-wild-type (WT) muscle. However, in contrast to Tg-WT, which displayed a phosphorylation-induced increase in steady-state force, the maximal tension in Tg-D166V papillary muscle fibres decreased upon phosphorylation. With the exception of force generation data, our results support the notion that RLC phosphorylation works as a rescue mechanism alleviating detrimental functional effects of a disease causing mutation. Further studies are necessary to elucidate the mechanism of this unexpected phosphorylation-induced decrease in maximal tension in Tg-D166V skinned muscle fibres. PMID- 21696542 TI - 'It should be the most natural thing in the world': exploring first-time mothers' breastfeeding difficulties in the UK using audio-diaries and interviews. AB - Breastfeeding is a practice which is promoted and scrutinized in the UK and internationally. In this paper, we use interpretative phenomenological analysis to explore the experiences of eight British first-time mothers who struggled with breastfeeding in the early post-partum period. Participants kept audio-diary accounts of their infant feeding experiences across a 7-day period immediately following the birth of their infant and took part in related semi-structured interviews a few days after completion of the diary. The overarching theme identified was of a tension between the participants' lived, embodied experience of struggling to breastfeed and the cultural construction of breastfeeding as 'natural' and trouble-free. Participants reported particular difficulties interpreting the pain they experienced during feeds and their emerging maternal identities were threatened, often fluctuating considerably from feed to feed. We discuss some of the implications for breastfeeding promotion and argue for greater awareness and understanding of breastfeeding difficulties so that breastfeeding women are less likely to interpret these as a personal shortcoming in a manner which disempowers them. We also advocate the need to address proximal and distal influences around the breastfeeding dyad and, in particular, to consider the broader cultural context in the UK where breastfeeding is routinely promoted yet often constructed as a shameful act if performed in the public arena. PMID- 21696543 TI - Is home birth a marker for severe malnutrition in early infancy in urban communities of low-income countries? AB - This matched case-control study set out to determine the association between place of delivery and severe undernutrition in early infancy in a low-income country. All infants (aged 0-3 months) with severe undernutrition attending four well-child clinics for routine immunization in inner-city Lagos, Nigeria were matched for age and sex with well-nourished peers. The main outcome measures were the adjusted-matched-odds ratios from conditional logistic regression analysis of undernutrition based on z-scores below -3 for weight-for-age, height/length-for age and body-mass-index-for-age using current World Health Organization's Multicentre Growth Reference (WHO-MGR). From an eligible population of 7075 mother-infant pairs, 918 severely undernourished infants were enlisted as cases matched with 1836 controls. While there was no statistically significant difference between infants born outside hospitals as a group compared to those born in hospitals, infants delivered at residential homes compared to public hospitals had two-to-three fold odds of being severely underweight (p=0.002), severely stunted (p < 0.001) and severely wasted (p=0.008) after controlling for potential confounders. Infants delivered in private hospitals were also significantly associated with severe stunting (p=0.032). This study demonstrates that delivery in homes and private hospitals are potential markers for severe undernutrition in early infancy in this urban population and merits closer attention in any early nutritional intervention in comparable settings of low income countries. PMID- 21696544 TI - Glutamine stimulates the gene expression and processing of sterol regulatory element binding proteins, thereby increasing the expression of their target genes. AB - Here we show that the larger the amount of glutamine added to the medium, the more the expression of genes related to lipid homeostasis is promoted by the activation of sterol regulatory element binding proteins (SREBPs) at the transcriptional and post-translational levels in human hepatoma HepG2 cells. Glutamine increases the mRNA levels of several SREBP targets, including SREBP-2. The gene expression of SREBP-1a, a predominant form of SREBP-1 in most cultured cells and a target of the general transcription factor Sp1, is significantly augmented by glutamine via an increased binding of Sp1 to the SREBP-1a promoter. In contrast, the increased expression of SREBP targets including SREBP-2 is due to stimulation of the processing of SREBP proteins by glutamine. It is also shown that glutamine accelerates SREBP processing through increased transport of the SREBP/SREBP cleavage-activating protein complex from the endoplasmic reticulum to the Golgi apparatus. The processing of activating transcription factor 6 is activated by the same proteases as SREBPs in the Golgi in response to endoplasmic reticulum stress and is not induced by glutamine. Taken together, these results clearly demonstrate that glutamine brings about not only the induction of SREBP 1a transcription but also the stimulation of SREBP processing, thereby facilitating the gene expression of SREBP targets in cultured cells. PMID- 21696545 TI - Revealing the drug-resistant mechanism for diarylpyrimidine analogue inhibitors of HIV-1 reverse transcriptase. AB - Diaryltriazine (DATA) and diarylpyrimidine (DAPY) were two category inhibitors with highly potent activity for wild type (wt) and four principal mutant types (L100I, K103N, Y181C and Y188L) of HIV-1 reverse transcriptase (RT). We had revealed the drug-resistant mechanism of DATA analogue inhibitors with molecular dynamics simulation and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods. In this work, we investigated the drug-resistant mechanism of DAPY analogue inhibitors. It was found that DAPY analogue inhibitors form more hydrogen bonds and hydrophobic contacts with wild type and mutants of HIV-1 RT than DATA inhibitors. This could explain that DAPY analogue inhibitors are more potent than DATA for the wild type and mutants of HIV-1 RT. Then, 3D QSAR models were constructed for these inhibitors of wild type and four principal mutant types HIV-1 RT and evaluated by test set compounds. These combined models can be used to design new chemical entities and make quantitative prediction of the bioactivities for HIV-1 RT inhibitors before resorting to in vitro and in vivo experiment. PMID- 21696546 TI - Non-bisphosphonate inhibitors of isoprenoid biosynthesis identified via computer aided drug design. AB - The relaxed complex scheme, a virtual-screening methodology that accounts for protein receptor flexibility, was used to identify a low-micromolar, non bisphosphonate inhibitor of farnesyl diphosphate synthase. Serendipitously, we also found that several predicted farnesyl diphosphate synthase inhibitors were low-micromolar inhibitors of undecaprenyl diphosphate synthase. These results are of interest because farnesyl diphosphate synthase inhibitors are being pursued as both anti-infective and anticancer agents, and undecaprenyl diphosphate synthase inhibitors are antibacterial drug leads. PMID- 21696547 TI - Initial counseling prior to palliation for hypoplastic left heart syndrome. AB - OBJECTIVE: Multiple surgical approaches to the initial palliation of patients with hypoplastic left heart syndrome (HLHS) have been advocated throughout the years. We sought to examine what procedure, if any, is recommended for HLHS management in regard to physician preference, anatomical variations, and concomitant medical issues. PATIENTS AND METHODS: A Web-based survey of pediatric cardiologist subscribed to PediHeart was conducted. OUTCOME MEASURES: The types of palliation recommended (Norwood palliation, Sano modification, hybrid palliation, primary cardiac transplantation, or hospice care) for patients with HLHS with anatomic or comorbid variants were queried. Counseling provided by the physicians to families was also documented as regards survival and outcomes. RESULTS: Two hundred physicians (21% female) who averaged 12.3 years removed from training responded to the survey. US East Coast and Midwest respondents were more likely to recommend Norwood palliation (54% and 60%, respectively) and the US South and West respondents preferred Sano modification (73% and 82%, respectively). Norwood or Sano palliation was recommended over hospice care, hybrid palliation, or cardiac transplant for patients with an intact atrial septum (P < 0.05), moderate to severe tricuspid regurgitation (P < 0.05), or low birth weight defined as less than 2 kg (P < 0.05). Hospice was preferred in low birth-weight infants over hybrid palliation or cardiac transplantation (P < 0.05). Hospice was recommended over any other palliation for premature infants (less than 30 weeks gestation), chromosomal abnormalities, or end-organ dysfunction (P < 0.05). CONCLUSIONS: This survey demonstrates that different palliative options are primarily recommended by caretakers based upon institutional location and patient characteristics. Prospective comparative trials may force a rethinking of this approach over time. PMID- 21696548 TI - Pericardiocentesis of noncircumferential effusions using nonstandard catheter entry sites guided by echocardiography and fluoroscopy. AB - OBJECTIVE: Classically pericardiocentesis has been described and performed through the subxiphiod approach, which is feasible if the pericardial fluid is circumferential or collected inferior or anterior to the heart. However, not uncommonly, the collection of fluid is at the base of the heart or in the posterior or apical portion of the pericardium, necessitating a different approach. The purpose of this study is to describe echo and fluoroscopic guided pericardiocentesis to evacuate noncircumferential effusions, which are not accessible from the standard subcostal approach. METHODS: Retrospective review of all patients with localized/noncircumferential effusions at Rady Children's Hospital San Diego between May 2007 and February 2010 was performed. During these procedures, effusions were identified at the point closest to the skin. The pericardial drains were introduced, directed, and advanced under echocardiographic and fluoroscopic guidance while avoiding major organs. RESULTS: Ten patients were identified (age ranged from 20 days to 22 years, weight ranged from 1.6 kg to 94 kg). All procedures were successful in draining the pericardial effusions with minimal residual fluid and no complications. CONCLUSION: Echocardiographic and fluoroscopic guided pericardiocentesis is a feasible, relatively safe, and reliable technique to drain loculated pericardial effusions using nonstandard entry sites. PMID- 21696549 TI - Left ventricular noncompaction syndrome masquerading or misdiagnosed as congenital long QT syndrome: remember QT prolongation does not equal long QT syndrome. AB - Distinguishing congenital long QT syndrome from QT prolongation caused by drugs or a different underlying disease process is essential for selecting the proper treatment. Herein, we present a case of a patient referred for left cardiac sympathetic denervation as a last resort treatment option for her 19-year standing diagnosis of long QT syndrome with malignant ventricular fibrillation. However, based on her atypical clinical course and additional imaging studies, a diagnosis of left ventricular noncompaction, rather than long QT syndrome, was made. She left the clinic with a drastically different treatment plan and an improved quality of life. Because many cardiac and noncardiac diseases can demonstrate QT prolongation on electrocardiogram, all possible diagnoses should be considered before diagnosing a patient with congenital long QT syndrome especially with regard to the profound treatment implications and genetic follow up in family members. PMID- 21696550 TI - Atrial baffle problems following the Mustard operation in children and young adults with dextro-transposition of the great arteries: the need for improved clinical detection in the current era. AB - OBJECTIVE: Intraatrial Mustard baffle repair of dextro-transposition of the great arteries (d-TGA) is vulnerable to complications, typically obstruction and leaks. Because patients often require pacemakers or intracardiac electrophysiology studies (EPS)/ablation for arrhythmias, narrowed or obstructed baffles restrict cardiac access hindering intracardiac procedures. Current guidelines recommend clinical as well as comprehensive transthoracic echocardiographic/Doppler (TTE) studies to identify baffle problems. This study reviews the effectiveness of these guidelines in detection of baffle issues pre-EPS catheterization and need for ancillary vascular interventions. DESIGN: Data from all patients with repaired d-TGA referred for hemodynamic catheterization or EPS between 1995 and 2009 at our institution were reviewed, including symptoms and TTE findings. Obstruction was defined as either a disturbed color Doppler flow or mean velocity >1 m/s above the mitral valve or directly measured pressure gradient >4 mm Hg or more than 50% baffle diameter narrowing by venography. RESULTS: Of 59 patients (34 pacemaker, 9 ablation, 16 routine hemodynamic) ages 8-39 years (mean 22.8), only three (5%) had symptoms of obstruction. However, baffle complications were found in 33 patients (56%), some with more than one problem: superior vena cava (SVC) obstruction in 32, inferior VC in two and leak in four. Baffle stenting was required in 24 patients and leak closure in two. Precatheterization TTE was available in 51 patients and showed 34% sensitivity, 61% specificity, 63% negative predictive value, and only 37% positive predictive value in recognizing baffle complications when compared with the actual catheterization findings. CONCLUSION: This study reports that baffle complications in patients with d-TGA following Mustard operation are more common than previously reported. However, comprehensive TTE and clinical symptoms are not effective enough to recognize these complications. Suspicion of and better noninvasive imaging prior to catheterization is required. PMID- 21696551 TI - Impact of pharmacotherapy on interstage outcomes in single ventricle infants. AB - OBJECTIVE: To characterize the pharmacotherapeutic regimens used in infants with single ventricle heart disease and determine the influence of outpatient medications on interstage weight gain. DESIGN: Retrospective review. SETTING: Tertiary care pediatric hospital. PATIENTS: All patients discharged from our institution with single ventricle heart disease that underwent neonatal first stage surgical palliation between 2002 and 2009 were included. Patients who died prior to second stage palliation or underwent orthotopic heart transplantation were excluded. OUTCOME MEASURES: Outpatient medication regimens during the interstage period were reviewed. Medication regimens were compared between surgical eras and between patient groups experiencing different outcomes. A logistic regression model was developed to determine independent factors for an interstage increase in weight-for-age z-score (WAZ) and a linear regression model to determine medications significant for an increase in weight gain per day. RESULTS: The study cohort consisted of 161 patients (58% male). Most patients in this cohort had either hypoplastic left heart syndrome (51%) or unbalanced complete atrioventricular canal (29%). Patients were placed on a median of four medications (range 1-9) at discharge from first surgical palliation, with aspirin (79%), furosemide (79%), and angiotensin converting enzyme inhibitors (ACE-I) (73%) most commonly prescribed. A median of six medication doses per day (range 2 18) were prescribed at discharge. Most patients (71%) had a decrease in WAZ during the interstage period. Use of digoxin (P < 0.01) and high-dose furosemide (P = .02) were associated with a decrease in WAZ score during the interstage period. Additionally, the use of ACE-I, ranitidine, proton-pump inhibitors, or promotility agents was not associated with improved somatic growth during the interstage period. CONCLUSIONS: Infants with single ventricle heart disease have a high-medication burden during the interstage period. Despite the focused and intensified use of medications to improve feeding tolerance and somatic growth, current pharmacotherapeutic regimens appear to have little effect on interstage weight gain. PMID- 21696552 TI - Acquired left ventricular submitral aneurysms in the course of Takayasu arteritis in a child. AB - A 9-year-old black African boy was hospitalized for heart failure revealing a severe left ventricular dysfunction associated with dilated cardiomyopathy, two submitral aneurysms, occlusion of the circumflex artery and a giant coronary artery aneurysm on the proximal left anterior descending artery. The boy was coinfected with human immunodeficiency virus and Mycobacterium tuberculosis. Though rare, association of Takayasu arteritis and submitral aneurysm leads to rethinking the pathogenesis of submitral aneurysm and suggests that some of them may be acquired. In our case, a common inflammatory process, possibly triggered by tuberculosis or HIV, may underlie Takayasu and submitral aneurysms. PMID- 21696553 TI - Massive global right ventricular hypertrophy with both fixed and dynamic obstruction and pulmonary valve dysplasia. AB - Congenital pulmonary valvular dysplasia is an unusual condition typically associated with Noonan syndrome. Among its other cardiac manifestations, occasional patients with Noonan syndrome have been demonstrated to have hypertrophic nonobstructive cardiomyopathy, which may be biventricular. We report a unique case of pulmonary valvular dysplasia, dynamic right ventricular outflow tract obstruction and profound right ventricular hypertrophy with only mild left ventricular hypertrophy, in a patient without Noonan syndrome. PMID- 21696554 TI - Rhinomanometry in young patients with perennial allergic rhinitis with/without recent exposure to tobacco smoke. AB - OBJECTIVE: To assess the influence of environmental exposure to tobacco smoke on the nasal symptoms and nasal resistance of young patients with perennial allergic rhinitis. DESIGN: Cross-sectional study. SETTING: Tertiary referral centre. PARTICIPANTS: Fifty patients were evaluated (aged 10-19 years old): 25 patients with and 25 patients without recent exposure to tobacco smoke (confirmed by cotinine/creatinine ratio). MAIN OUTCOMES MEASURES: After a clinical evaluation, all the patients replied to a validated questionnaire of the severity of the nasal symptoms. Then total nasal airway resistance was recorded by active anterior rhinomanometry. RESULTS: Patients with exposure to tobacco smoke had a larger total resistance than patients without exposure (t-test, P < 0.01). No significant correlation was observed between the total score of the questionnaire of nasal symptoms and the nasal resistance. CONCLUSIONS: In young patients with perennial allergic rhinitis, exposure to tobacco smoke can be related to increased nasal resistance, which may not be recognised by the report of nasal symptoms. PMID- 21696555 TI - A 20-year retrospective study of tonsil cancer incidence and survival trends in South East England: 1987-2006. AB - BACKGROUND: There has been an increasing incidence of tonsil cancer worldwide. Documenting these changes is crucial to cancer prevention and control measures, resource allocation and understanding disease aetiology. OBJECTIVE: To analyse the changing epidemiology of tonsil cancer in South East England over a 20-year period between 1987 and 2006. DESIGN: A retrospective, quantitative study using secondary anonymised data obtained from the Thames Cancer Registry, London. Data were analysed using spss v.17 and survival analyses with Kaplan-Meier and Cox regression. SETTING: This study was conducted in South East of England comprising London, Kent, Surrey and Sussex counties with an average population of 12 million. This population increased from 10.7 to 11.8 million (a 10% increase) between 1987 and 2006. PARTICIPANTS: All patients with tonsil cancer in South East England registered with the Thames Cancer Registry (ICD-10 code C09) between 1987 and 2006. A total of 1794 patients' data were analysed. Ethical Considerations: Ethical approval was granted by the Kent Research Ethics Committee. MAIN OUTCOME MEASURES: Data were analysed for demographic trends including gender, age at diagnosis, yearly incidence and survival. RESULTS: Tonsil cancer incidence has increased significantly from 0.60 to 1.45 per 100,000 in the 20 years (P < 0.001). This increase is mainly amongst men and age groups 40-59 years with a significant reduction in age at diagnosis by 2 years from 61.6 years in the first decade to 59.6 years in the second decade (P < 0.001). Survival was worse in men, older age groups and in the presence of synchronous tumours (P < 0.001). There has been a statistically significant increase in median survival times from tonsil cancer by about 3 years from 2.7 years in the first decade to 5.7 years in the second decade of this study (P < 0.001). CONCLUSIONS: Tonsil cancer incidence has increased in the 20 years of this study in South East England, especially amongst men and age groups 40-59 years. There has also been significant reduction in the mean age at diagnosis and an increase in median survival times for tonsil cancer. Further studies are needed to explain these trends. PMID- 21696556 TI - Intrareader variability in mammographic diagnostic and perceptual performance amongst experienced radiologists in Australia. AB - INTRODUCTION: The purpose of this study was, for a group of experienced radiologists, to identify the magnitude of and statistical significance of intrareader variability in mammographic diagnostic performance or cancer diagnosis and mammographic perceptual performance or microcalcification detection. METHODS: Eight radiologist readers (8-30 years experience in radiology, five current BreastScreen readers) read a set of 100 digital mammograms on two separate reads with random case orders. Twenty-three of the 100 had proven malignancies, and 52 of the 100 had confirmed microcalcifications. The same mammograms were presented for both reads. The radiologists were requested to clear or call back cases and to indicate if any benign and malignant microcalcifications were present on the mammograms. Reading conditions were standardised. RESULTS: Intrareader variability in accuracy was demonstrated to be between 0% and 6% for the diagnostic task of breast cancer diagnosis and between 0% and 16% for the perceptual task of microcalcification detection. Intrareader agreement in the group of readers was high; between 75% and 93% (kappa=0.36-0.72) for cancer diagnosis and between 77.5% and 93% (kappa=0.17-0.77) for microcalcification detection. There was no correlation between reader's experience in radiology or being a BreastScreen reader and level of intrareader variability in cancer diagnosis and microcalcification detection. CONCLUSION: There exists intrareader variability in diagnostic and perceptual performance. Despite this variability, intrareader agreement remains high. PMID- 21696557 TI - Sixty-four multi-detector computerised tomography in the detection of lower gastrointestinal bleeding: A prospective study. AB - INTRODUCTION: Acute gastrointestinal bleeding (AGIB) is a serious and life threatening condition. Many diagnostic procedures and tests are being used to detect the site of bleeding with different success rates. The aim of our study is to prospectively evaluate accuracy of 64-slice multi-detector computerised tomography (MDCT) in the diagnosis of lower AGIB. METHODS: Between September 2007 and January 2009, patients with presumed lower AGIB were referred to the radiology department of our institution for 64-slice MDCT examination as part of the investigation for the lower AGIB. Any abnormalities to account for bleeding, such as tumours, bowel wall enhancement and increased intraluminal density, were recorded. RESULTS: Out of 139 patients with AGIB that were admitted to our casualty department, 27 patients (19 men and 8 women) in the age range of 24-88 years (mean age, 56 years) were suspected to have lower AGIB. Sixty-four-slice MDCT was performed and considered positive for bleeding in 19 (70%) cases, and in all the cases, the bleeding source was indentified in the arterial phase, showing a focal dense wall enhancement in 8 (42%) cases, circumferential wall enhancement in 4 (22%) cases and progressive increasing intraluminal density in 7 (36%) cases. The venous phase scan showed increased dispersion of the contrast within the lumen as an additional clue for active extravasation in 15 (79%) out of the 19 cases. Delayed 5-min scanning showed the same findings as venous phase in all the 19 positive cases and failed to depict any additional findings in the eight cases that were negative on arterial or venous phases. CONCLUSION: The study supports the high accuracy of 64-slice MDCT in locating the site of AGIB in patients thought to have a distal source of bleeding. Its accuracy in clinically proximal bleeding is not clear from this study, but MDCT is capable of showing such sources. PMID- 21696558 TI - Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) and morphologic MRI of cartilage in the long-term follow-up after Legg-Calve-Perthes disease (LCPD). AB - INTRODUCTION: The purpose of the present study was to evaluate the feasibility of delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) in the detection of cartilage changes versus morphologic imaging in the long-term course of Legg-Calve-Perthes disease (LCPD). METHODS: A total of 31 hips in 26 patients (mean age, 30.0years; range, 18-54years) who were diagnosed with LCPD in childhood were included. Twenty-one radiographically normal contralateral hips served as controls. dGEMRIC indices of femoral and acetabular cartilage in the weight-bearing zone. Cartilage morphology was classified on radial PD-weighted images according to the modified Outerbridge classification. RESULTS: Mean dGEMRIC values of cartilage were significantly lower in hips after LCPD than in the radiographically normal contralateral hips (513+/-100 ms vs. 579+/-103 ms; P=0.026). In 24 out of 31 LCPD hips and in 4 out of 21 radiographically normal contralateral hips, morphological cartilage changes were noted. Analysis of variance analysis revealed a significant influence of Outerbridge grading on decreased T1-values (P=0.031). CONCLUSION: Our results suggest that dGEMRIC at 1.5 T is suitable to assess cartilage quality changes in the long-term follow-up after LCPD. The evaluation of biochemical cartilage quality with dGEMRIC may provide additional information about early cartilage changes occurring without visible alterations of cartilage morphology. PMID- 21696559 TI - Diffusion-weighted MR-imaging for the detection of pulmonary nodules at 1.5 Tesla: intraindividual comparison with multidetector computed tomography. AB - INTRODUCTION: To investigate the feasibility of diffusion-weighted imaging (DWI) MRI for detecting pulmonary nodules at 1.5 Tesla in comparison with standard multidetector computed tomography (MDCT). METHODS: Twenty patients with disseminated cancer disease in which MDCT had assured the presence of at least one pulmonary nodule were examined using a respiratory-gated DWI MR-sequence. Grey scale inverted source images and coronal maximum intensity projection (MIP) images were consensually analysed by two experienced radiologists. Size and location of any nodule detected were assessed. Additionally, the readers evaluated each hemithorax for the presence of at least one nodule and applied a four-point conspicuity scale (1-hemithorax definitely affected; 4-hemithorax definitely not affected). MDCT data served as reference. RESULTS: At MDCT, a total of 71 pulmonary noduIes was found (size 3-5mm, n=16; 6-9mm, n=22; >=10mm, n=33). For the DWI MR-sequence, a sensitivity of 86.4% was calculated for nodules ranging 6-9mm and 97% for nodules >=10mm. In contrast, only 43.8% of lesions <=5mm was detected. The separate analysis of each hemithorax for the presence of at least one pulmonary nodule revealed a specificity rate, PPV and NPV of DWI-MR of 92.3%, 96% and 80%, respectively. CONCLUSIONS: The presented study is the first to confirm the diagnostic potential of DWI-MR in the detection of solid lung nodules. This technique allows for the detection of nodules >=6mm with reasonably high sensitivity rates (>86%). The observation of false positive findings decreases the accuracy of this approach compared with MDCT. PMID- 21696560 TI - Chest radiograph findings in children with laboratory confirmed pandemic H1N1 virus infection. AB - INTRODUCTION: Since its onset in the spring of 2009, the H1N1 pandemic has kept health-care professionals busy worldwide. Even though it often causes respiratory tract illness, reports describing the radiological manifestations in infected children are few. The purpose of this study was twofold: to review the chest radiograph findings in children with laboratory-confirmed pandemic (H1N1) 2009 influenza virus and compare them with the chest radiographic findings in children with the same symptoms but laboratory negative. METHODS: Informed consent was not required by the institutional review board for this retrospective study. We identified 151 children who were tested for pandemic H1N1 virus and had chest radiographs. Chest radiographs were evaluated for the presence of airway disease including hyperinflation, subsegmental atelectasis and peribronchial cuffing, airspace disease, pleural effusion or any combination of these, and compared for H1N1-positive and H1N1-negative children, for healthy and non-healthy children separately. RESULTS: No statistically significant difference between H1N1-tested positive children and H1N1-tested negative children was found for the proportion of abnormal chest rays (P=1 for healthy children, P=0.08 for children with chronic disease). For individual findings, there was no difference between H1N1 tested positive healthy children and H1N1-tested negative healthy children (P>0.083 for each finding) In children with chronic disease, there was significantly more subsegmental atelectasis (P=0.037) in the radiographs of H1N1 tested negative children. CONCLUSION: Chest radiographs have non-specific findings in cases of suspected swine flu in children and have limited value in distinguishing H1N1 from non-H1N1 viral infections for both healthy children and children with chronic disease. PMID- 21696561 TI - Pulmonary malignant focal ground-glass opacity nodules and solid nodules of 3cm or less: comparison of multi-detector CT features. AB - INTRODUCTION: To evaluate the different multi-detector computed tomography (MDCT) features between pulmonary malignant focal ground-glass opacity (fGGO) nodules and solid nodules of 3cm or less in diameter. METHODS: One hundred and five malignant solid nodules and 48 malignant fGGOs confirmed by pathology were retrospectively analysed with regard to the patient's demographic data, nodule size and MDCT features (shape, margin, interface, internal characteristics and adjacent structure). Differences were analysed using the Fisher exact test or Mann-Whitney U-test. RESULTS: The male to female ratio of patients with malignant solid nodules (60:45) was higher than that with malignant fGGOs (18:30) (P<0.05). There was no significant difference in either patient's age (P>0.05) or nodule size (P>0.05). The frequency of irregular shape (4% vs. 21%), spiculation (57% vs. 40%), vacuole sign (11% vs. 52%) and natural air bronchograms (0% vs. 24%) was significantly different between malignant solid nodules and fGGOs. No differences were found in the frequency of lobulation, cusp angle, spine-like process, interface and adjacent structure between the two groups (P>0.05). CONCLUSION: Malignant fGGOs and solid nodules showed mostly similar MDCT features. For malignant fGGOs, the frequency of irregular shape, vacuole sign and natural air bronchograms was higher than that in solid nodules, but the frequency of spiculation was lower than that in solid nodules. PMID- 21696562 TI - Isolated lipoma of filum terminale in adults: MRI findings and clinical correlation. AB - INTRODUCTION: Fat within the filum terminale is frequently seen on routine magnetic resonance imaging (MRI) of the lumbosacral spine (LSS), with prevalence of 1-5%. The objective of this study was to determine the prevalence and MRI features of isolated lipoma of filum terminale (LFT) in adult population and its correlation with the patient clinical presentations. METHODS: Prospective analysis of all lumbosacral MRI performed at King Abdullah University Hospital during a 21-month period. A total of 37 patients with LFT were included. Patients were divided into two groups. Group A patients have neurological deficit manifested by either motor, sensory or sphincter abnormality. Group B patients have normal neurological examination. Clinical findings were correlated with: A: thickness of LFT, B: length of LFT, C: distance of LFT from conus medullaris (CM), D: age of the patient. RESULTS: The prevalence of isolated LFT in our study was 3.2%. There was no significant correlation between the thickness or length of LFT and the presence of neurological deficit. The distance of LFT from CM was also not correlated with the patient clinical presentation. No significant difference in the age between the two groups. CONCLUSION: LFT in adult likely represent an incidental finding on routine lumbosacral MRI. Special attention for LFT in children is mandatory as it may indicate clinical tethering in otherwise normal appearing LSS. PMID- 21696563 TI - Multidetector row CT scan in hypersensitivity pneumonitis: contribution of minimum intensity projection reformation. AB - The objective of this pictorial essay is to highlight the key role of computed tomography scanning (CT scan), particularly minimum intensity projection (MinIP) reformation, with regards to the diagnosis of hypersensitivity pneumonitis (HP) and its contribution to patients' management. MinIP enhances detecting the characteristic CT scan features of HP, particularly air trapping and ground-glass opacities, features representing the bronchoalveolar lavage or biopsy core target zones to the clinician. PMID- 21696564 TI - Cervical pedicles: correcting a common misconception. AB - To bring to the attention of Australian radiologists in training, directors of training and radiologists in general, a commonly held erroneous misconception, specifically that of the plain radiographic appearance of the cervical spine pedicle and the transverse process in oblique projections. A human C5 vertebra was appropriately marked and radiographed in the oblique projection to demonstrate key anatomical structures and their relations. The rounded cortical contour overlying the vertebral body is commonly misinterpreted as a cervical transverse process but is the plain radiographic outline of the end-on ipsilateral pedicle. Because of the right-angle relationship of the transverse process long axis and the end-on pedicle long axis, the ipsilateral transverse process appears as a faint elongated corticated structure projecting beyond the vertebral body contour. It may also be obscured because of small size, relative osteopaenia and overlying soft tissue bulk. The end-on pedicle has been unequivocally demonstrated, as has the ipsilateral transverse process. The two lie at right angles to each other. The common misconception (amplified by an error in an earlier edition of a popular atlas) should be debunked by radiologists and should not be promulgated to Australian radiology trainees. PMID- 21696565 TI - Radiology of vernix caseosa peritonitis: case report and discussion. AB - Vernix caseosa peritonitis is a rare complication of pregnancy that can occur following Caesarean section. If fetal vernix enters the peritoneal cavity, it may incite an acute inflammatory response leading to peritonitis. This diagnosis should be considered when patients present with an acute abdomen pain following Caesarean section. Radiological imaging may identify lesions in the abdominal wall wound or peritoneal cavity, and the diagnosis can be made by image-guided biopsy. PMID- 21696566 TI - A comparison of ICRU point doses and volumetric doses of organs at risk (OARs) in brachytherapy for cervical cancer. AB - INTRODUCTION: In brachytherapy for cervix cancer, doses to organs at risk (OARs) are traditionally calculated using the ICRU-38 point doses to rectum and bladder. Three-dimensional image-guided brachytherapy allows assessment of OAR dose with dose volume histograms (DVHs). The purpose of this study was to analyse the correlation between DVHs and ICRU point doses. METHODS: Using the PLATOTM planning system, the bladder, rectum and sigmoid were retrospectively contoured on 62 CT datasets for 20 patients treated with definitive radiotherapy. The median external beam radiotherapy dose was 45 Gy. Brachytherapy was delivered using a CT-MRI compatible tandem and ovoids to a median dose of 24 Gy in three fractions. DVHs were calculated, and the minimum dose to 2 cc of tissue receiving the highest dose (D(2cc) ) was recorded and compared with the ICRU point doses (D(ICRU) ). RESULTS: The mean rectal D(ICRU) was 4.01 Gy compared with D(2cc) of 4.28 Gy. The mean bladder D(ICRU) was 6.74 Gy compared with D(2cc) of 8.65 Gy. The mean sigmoid D(2cc) was 4.58 Gy. The mean dose ratios (D(2cc) /D(ICRU) ) were 1.08 for rectum and 1.39 for bladder. D(ICRU) correlated with D(2cc) for rectum (r = 0.76, P = 0.001) and for bladder (r = 0.78, P = 0.01). CONCLUSION: OAR doses assessed by DVH criteria were higher than ICRU point doses. The significant correlation between D(2cc) and D(ICRU) has allowed us to set DVH dose constraints for CT-based brachytherapy and thus begin the transition from two-dimensional to three-dimensional image-guided brachytherapy planning. PMID- 21696567 TI - Does inverse-planned intensity-modulated radiation therapy have a role in the treatment of patients with left-sided breast cancer? AB - INTRODUCTION: The purpose of the study was to determine if multi-field inverse planned intensity-modulated radiation therapy (IMRT) improves on the sparing of organs at risk (heart, lungs and contralateral breast) when compared with field in-field forward-planned RT (FiF). METHODS: The planning CT scans of 10 women with left-sided breast cancer previously treated with whole-breast RT on an inclined breast board with both arms supported above the head were retrieved. The whole breast planning target volume (PTV) was defined by clinical mark-up and contoured on all relevant CT slices as were the organs at risk. For each patient, three plans were generated using FiF, five- and nine-field inverse-planned IMRT, all to a total dose of 50 Gy to the whole breast. Mean and maximum doses to the organs at risk and the homogeneity index (HI) of the whole-breast PTV were compared. RESULTS: The mean heart dose for the FiF plans was 2.63 Gy compared with 4.04 Gy for the five-field and 4.30 Gy for the nine-field IMRT plans, with no significant differences in the HI of the whole-breast PTV in all plans. The FiF plans resulted in a mean contralateral breast dose of 0.58 Gy compared with 0.70 and 2.08 Gy for the five- and nine-field IMRT plans, respectively. CONCLUSIONS: FiF resulted in a lower mean heart and contralateral breast dose with comparable HI of the whole-breast PTV in comparison with inverse-planned IMRT using five or nine fields. PMID- 21696568 TI - Establishing locoregional control of malignant pleural mesothelioma using high dose radiotherapy and (18) F-FDG PET/CT scan correlation. AB - INTRODUCTION: The management of malignant pleural mesothelioma represents one of the most challenging issues in oncology, as there is no proven long-term benefit from surgery, radiotherapy or chemotherapy alone or in combination. Locoregional progression remains the major cause of death, but radical surgical resection may produce major postoperative morbidity. While radical or postoperative radiotherapy using conventional techniques has resulted in severe toxicity with no impact on survival, recent advances in radiotherapy delivery may be more effective. METHODS: We treated patients with locally advanced mesothelioma whose tumours had been sub optimally resected with high-dose three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) to large volumes of one hemithorax, using CT and positron emission tomography (PET) scan-based treatment planning. Clinical outcomes were assessed by determining patterns of failure and metabolic changes in total glycolytic volume (TGV) between pre- and post-irradiation( 18) F-FDG PET/CT scans and by recording acute and late toxicity grades. RESULTS: Fourteen patients were analysed with 40 PET scans performed before and up to 4.5years after radiotherapy. Eleven patients had pleurectomy/decortications, one had an extrapleural pneumonectomy and two had no surgery. Four patients who received chemotherapy had all progressed prior to radiotherapy. After radiotherapy, the in-field local control rate was 71%. No progression occurred in two patients, one was salvaged with further radiotherapy to a new site, four recurred inside the irradiated volume all with concurrent distant metastases and the other seven had distant metastases only. The TGVs were reduced by an average of 67% (range 12-100%) after doses of 45 to 60Gy to part or all of one hemithorax. There were no serious treatment-related toxicities. Median survival was 25months from diagnosis and 17months after starting radiotherapy. CONCLUSIONS: We have established that mesothelioma can be locally controlled with high radiation doses using 3DCRT or IMRT, and that strict normal tissue dose constraints have limited radiation toxicities. Radiotherapy should be considered to prevent or delay the local manifestations of progressive disease in suitable patients after surgery including extrapleural pneumonectomy and pleurectomy/decortication. Higher radiation doses may allow more effective palliation. PMID- 21696569 TI - Safety and efficacy of radiation therapy as secondary prophylaxis for heterotopic ossification of non-hip joints. AB - INTRODUCTION: Prophylactic radiation therapy (RT) is an established adjuvant therapy for heterotopic ossification (HO) of the hip when delivered in the immediate pre- or postoperative setting. Its role in prevention of recurrence after excision of HO is supported by randomised trials for HO of the hip, but there is scant evidence to demonstrate the safety and efficacy of a similar approach in non-hip joints. In the current study, we evaluate radiological and functional outcomes after prophylactic RT for prevention of HO of the knee and upper extremity. METHODS: With institutional review board (IRB) approval, patients treated at our institution with prophylactic RT for non-hip HO from 1998 to 2009 were identified. Records were reviewed, including pre- and postoperative records, operative reports and radiography. The primary objectives were to determine the safety of RT and rate of treatment failure, as defined by need for further surgical intervention. RESULTS: A total of 30 patients received prophylactic RT for HO of the elbow (n=21), MCP joint (n=1) and knee (n=8). Twenty-nine of the 30 patients were treated within 24-48h postoperatively, and one patient was treated within 24h preoperatively. Based on institutional policy, only patients considered to be at high risk of recurrence were selected to receive prophylactic RT. Patients were treated to a dose of 7Gy in one fraction, with two parallel opposed. Complications following treatment included two patients with postoperative wound infections, one patient with a ruptured triceps tendon and one patient with a fracture within the treatment field. Follow-up information was available for 26 of 30 patients, with a median follow-up time of 16months (range, 2-143months). Recurrent HO, requiring surgical re-excision, developed in 10.5% (n=2) of patients who were followed for upper extremity HO (n=19). For patients followed after RT for HO of the knee (n=7), there were no recurrences of HO that required further intervention. CONCLUSION: In this group of patients at high risk for developing further HO, prophylactic RT appears to be a safe adjunct to surgery and is effective in prevention of HO recurrence. Results are similar to published reports of HO of the hip and support the use of surgical excision and perioperative, prophylactic RT for HO of non-hip joints. PMID- 21696570 TI - Management pathway for patients with cervical cancer in the Auckland region 2003 2007. AB - INTRODUCTION: This review was performed to describe the patient pathway and timelines involved in the treatment of FIGO (International Federation of Gynecology and Obstetrics) stage IB1 to IVA cervical cancer in a New Zealand cancer centre. METHODS: Retrospective audit of women with a new diagnosis of FIGO Stage IB1-IVA cervical cancer in the Auckland/Northland regions between 2003 and 2007. RESULTS: Two hundred and seven patients were identified. Median time from referral to first specialist assessment (FSA) was 10days, from FSA to decision to treat (DTT) 50days and from DTT to start of treatment 26days. Overall median time from referral to start of treatment was 97days. There was no difference in median time from referral to DTT for patients treated with primary surgery (48days) or radiotherapy (47days). On univariate analysis, factors associated with reduced time from referral to start of treatment were less socioeconomic deprivation (P=0.001), shorter time to completion of radiological investigations (P<0.0005) and private FSA (P<0.0005). Only private FSA remained significant on multivariate analysis. The greatest delay in the pathway was between FSA and DTT, encompassing presentation at multidisciplinary meeting, examination under anaesthetic and obtaining radiological investigations. Median overall treatment time (OTT) for patients treated with definitive radiotherapy was 56days and was increased by a median of 3days where there were delays accessing operating theatre time for brachytherapy insertions. CONCLUSION: Overall patient pathway and radiotherapy OTT were longer than optimal, and areas of delay potentially amenable to modification were identified. PMID- 21696572 TI - FoxP3 expression on melanoma cells is related to early visceral spreading in melanoma patients treated by electrochemotherapy. PMID- 21696573 TI - Temporal and sequential changes of glial cells and cytokine expression during neuronal degeneration after transient global ischemia in rats. AB - BACKGROUND: How glial cells and cytokines are associated with the progression of delayed neuronal death induced by transient global ischemia is still unclear. To further clarify this point, we studied morphological changes in glial cells (microglial cells and astrocytes), and cytokine protein levels, during the progression of neuronal cell loss in CA1 (Cornu Ammonis 1) of the hippocampus after transient global ischemia. METHODS: Morphological changes in glial cells were studied immuno-histochemically. Nine cytokines (IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma and TNF-alpha) were simultaneously measured by a multiplexed bead-based immunoassay from 6 h to day21 after transient four vessel occlusion (4VO) in rats. RESULTS: During the process of neuronal loss, we observed four distinct phases: (1) lag phase day0-2 (no NeuN+ cell loss observed), (2) exponential phase day2-7 (NeuN+ cells reduced in number exponentially), (3) deceleration phase day7-14 (reduction rate of NeuN+ cells became low), (4) stationary phase day14 onward (NeuN+ cell loss progressed no longer). In the lag phase, activated glial cells were observed in the entire hippocampus but later were gradually restricted to CA1. Cytokine protein levels in the lag and exponential phases were lower than in the deceleration and stationary phases. IL-1alpha, IL-1beta, IL-4, IL-6 and IFN-gamma in 4VO were significantly higher in all four phases than in sham. Compared with sham level, GM-CSF was significantly high in the deceleration phase. TNF-alpha was significantly high in both the deceleration and stationary phases. CONCLUSION: Ischemic stress in 4VO activated glial cells in areas beyond CA1 in the lag phase. Pyramidal neurons were injured in CA1 from the end of the lag phase and then neuronal cells reduced in CA1 in the exponential phase. After neuronal death began, the influence of dead cells on glial cells and cytokine expression gradually became stronger than the influence by ischemic stress. Therefore, from the deceleration phase, changes in glial cells and cytokine production were likely caused by dead cells. Cytokine interaction in the microenvironment may determine the functions of IL-1alpha, IL-1beta, IL-4, IL-6 and IFN-gamma in all four phases. The function of GM-CSF and TNF-alpha in the deceleration phase may be neurotrophic. PMID- 21696574 TI - New method for analysis of nonstationary signals. AB - BACKGROUND: Analysis of signals by means of symbolic methods consists in calculating a measure of signal complexity, for example informational entropy or Lempel-Ziv algorithmic complexity. For construction of these entropic measures one uses distributions of symbols representing the analyzed signal. RESULTS: We introduce a new signal characteristic named sequential spectrum that is suitable for analysis of the wide group of signals, including biosignals.The paper contains a brief review of analyses of artificial signals showing features similar to those of biosignals. An example of using sequential spectrum for analyzing EEG signals registered during different stages of sleep is also presented. CONCLUSIONS: Sequential spectrum is an effective tool for general description of nonstationary signals and it its advantage over Fourier spectrum. Sequential spectrum enables assessment of pathological changes in EEG-signals recorded in persons with epilepsy. PMID- 21696575 TI - Efficacy of vitamin D3-fortified-yogurt drink on anthropometric, metabolic, inflammatory and oxidative stress biomarkers according to vitamin D receptor gene polymorphisms in type 2 diabetic patients: a study protocol for a randomized controlled clinical trial. AB - BACKGROUND: Development of type 2 diabetes mellitus (T2DM) is determined by the interactions of genetic and environmental factors. This study was designed to evaluate the possible role of VDR single nucleotide polymorphisms (SNPs) on different aspects of diabetic host response (anthropometric, metabolic, oxidative stress and inflammatory) to daily intake of vitamin D through fortified yogurt drink for 12 weeks. METHODS/DESIGN: This study comprises two parts: (i) a case control study; and (ii) an intervention trial. In the first part, VDR polymorphisms (Taq1, FokI, Apa1, Bsm1, and Cdx2) are determined in 350 T2DM patients and 350 non-diabetic subjects. In the second part, the possible effects of daily intake of two servings of vitamin D3-fortified yogurt drink (FYD; 500 IU vitamin D/250 mL) on some selected metabolic (including insulin resistance), inflammatory and oxidative stress biomarkers in 135 T2DM patients are assessed. To relate the resulted changes in the biomarkers to vitamin D replenishment, another group of diabetic patients (n = 45) are also included in the study who receive 2 servings of plain yogurt drink (PYD) a day. The primary outcome is serum level of 25(OH) D, which it is expected to be elevated only in FYD group. Secondary outcomes include improvements in glycemic, metabolic, inflammatory and oxidative stress biomarkers in FYD group compared to PYD group. Three VDR FokI polymorphisms are determined only in FYD group followed by comparison of changes in the biomarkers among these genotypic variants. DISCUSSION: The present study, at least in part, elucidates the discrepancies in the results of different vitamin D-diabetes studies pertaining to the genetic variations of the population. If VDR polymorphisms are found to influence the response to our intervention, then knowing distribution of VDR polymorphisms in both diabetic and non-diabetic populations can give a picture of the proportion of the community in whom up to 1000 IU/d vitamin D may not be effective enough to improve insulin resistance and related morbidities. Therefore, they should ideally receive further nutritional support according to their genotype. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01236846. PMID- 21696576 TI - Constitutive phosphorylation of the FOXO1 transcription factor in gastric cancer cells correlates with microvessel area and the expressions of angiogenesis related molecules. AB - BACKGROUND: Although FOXO transcription factors may have an anti-angiogenic role, little is known about their role in tumor angiogenesis. The present study was performed to investigate the correlation between the constitutive expression of phosphorylated FOXO1 (pFOXO1) and angiogenesis in gastric cancer. METHODS: Immunohistochemistry was performed on tissue array slides containing 272 gastric carcinoma specimens, and the correlations between the cytoplasmic pFOXO1 expression in gastric cancer cells and CD34-immunopositive microvessel area (MVA) or the expressions of angiogenesis-related molecules were analyzed. In vitro analyses with Western blotting and semiquantitative reverse transcription polymerase chain reaction were performed using the stable SNU-638 gastric cancer cell line transfected with lentivirus-delivered FOXO1 short hairpin RNA. RESULTS: The cytoplasmic expression of pFOXO1 in tumor cells was observed in 85% of gastric carcinoma cases, and was found to be positively associated with higher MVA (P = 0.048). Moreover, pFOXO1 expression was positively correlated with the expressions of several angiogenesis-related proteins, including hypoxia inducible factor-1alpha (HIF-1alpha, P = 0.003), vessel endothelial growth factor (P = 0.004), phosphorylated protein kinase B (P < 0.001), and nuclear factor-kappaB (P = 0.040). In contrast, the expression of pFOXO1 was not correlated with that of phosphorylated signal transducer and activator of transcription 3 or beta catenin. In addition, cell culture experiments showed that FOXO1 suppression increased the mRNA and protein expressions of HIF-1alpha. CONCLUSION: Our results suggest that pFOXO1 expression in cancer cells plays a role in gastric cancer angiogenesis via mechanisms involving various angiogenesis-related molecules. Animal experiments are needed to confirm the anti-angiogenic role of FOXO1 in human gastric cancer. PMID- 21696577 TI - The dual role of academic surgeons as clinicians and researchers - an attempt to square the circle? PMID- 21696579 TI - Quantitative transcript analysis of the inducible expression system pSIP: comparison of the overexpression of Lactobacillus spp. beta-galactosidases in Lactobacillus plantarum. AB - BACKGROUND: Two sets of overlapping genes, lacLMReu and lacLMAci, encoding heterodimeric beta-galactosidases from Lactobacillus reuteri and Lactobacillus acidophilus, respectively, have previously been cloned and expressed using the pSIP vector system and Lactobacillus plantarum WCSF1 as host. Despite the high similarity between these lacLM genes and the use of identical cloning and expression strategies, strains harboring lacLMReu produced about twenty-fold more beta-galactosidase than strains containing lacLMAci. RESULTS: In this study, the plasmid copy numbers (PCN) of expression vectors pEH9R (lacLMReu) and pEH9A (lacLMAci) as well as the transcription levels of both lacLM genes were compared using quantitative PCR methods. Analyses of parallel fermentations of L. plantarum harboring either pEH9R or pEH9A showed that the expression plasmids were present in similar copy numbers. However, transcript levels of lacLM from L. reuteri (pEH9R) were up to 18 times higher than those of lacLM from L. acidophilus (pEH9A). As a control, it was shown that the expression levels of regulatory genes involved in pheromone-induced promoter activation were similar in both strains. CONCLUSION: The use of identical expression strategies for highly similar genes led to very different mRNA levels. The data indicate that this difference is primarily caused by translational effects that are likely to affect both mRNA synthesis rates and mRNA stability. These translational effects thus seem to be a dominant determinant for the success of gene expression efforts in lactobacilli. PMID- 21696578 TI - Vpx rescues HIV-1 transduction of dendritic cells from the antiviral state established by type 1 interferon. AB - BACKGROUND: Vpx is a virion-associated protein encoded by SIVSM, a lentivirus endemic to the West African sooty mangabey (Cercocebus atys). HIV-2 and SIVMAC, zoonoses resulting from SIVSM transmission to humans or Asian rhesus macaques (Macaca mulatta), also encode Vpx. In myeloid cells, Vpx promotes reverse transcription and transduction by these viruses. This activity correlates with Vpx binding to DCAF1 (VPRBP) and association with the DDB1/RBX1/CUL4A E3 ubiquitin ligase complex. When delivered experimentally to myeloid cells using VSV G-pseudotyped virus-like particles (VLPs), Vpx promotes reverse transcription of retroviruses that do not normally encode Vpx. RESULTS: Here we show that Vpx has the extraordinary ability to completely rescue HIV-1 transduction of human monocyte-derived dendritic cells (MDDCs) from the potent antiviral state established by prior treatment with exogenous type 1 interferon (IFN). The magnitude of rescue was up to 1,000-fold, depending on the blood donor, and was also observed after induction of endogenous IFN and IFN-stimulated genes (ISGs) by LPS, poly(I:C), or poly(dA:dT). The effect was relatively specific in that Vpx associated suppression of soluble IFN-beta production, of mRNA levels for ISGs, or of cell surface markers for MDDC differentiation, was not detected. Vpx did not rescue HIV-2 or SIVMAC transduction from the antiviral state, even in the presence of SIVMAC or HIV-2 VLPs bearing additional Vpx, or in the presence of HIV-1 VLPs bearing all accessory genes. In contrast to the effect of Vpx on transduction of untreated MDDCs, HIV-1 rescue from the antiviral state was not dependent upon Vpx interaction with DCAF1 or on the presence of DCAF1 within the MDDC target cells. Additionally, although Vpx increased the level of HIV-1 reverse transcripts in MDDCs to the same extent whether or not MDDCs were treated with IFN or LPS, Vpx rescued a block specific to the antiviral state that occurred after HIV-1 cDNA penetrated the nucleus. CONCLUSION: Vpx provides a tool for the characterization of a potent, new HIV-1 restriction activity, which acts in the nucleus of type 1 IFN-treated dendritic cells. PMID- 21696580 TI - Henoch Schonlein purpura associated with pulmonary adenocarcinoma. AB - INTRODUCTION: Henoch-Schonlein purpura is a common immunoglobulin A-mediated vasculitis syndrome in children. Henoch-Schonlein purpura can also affect adults and is probably related to malignancy. CASE PRESENTATION: We report the case of a 61-year-old Japanese man who presented for examination after an abnormal shadow was detected by chest radiography. He received a diagnosis of pulmonary adenocarcinoma, stage IV. Purpura on the legs, abdominal pain, diarrhea, hematuria and proteinuria developed at this time. Henoch-Schonlein purpura was diagnosed, base on the clinical symptoms and histological findings of biopsy specimens of the skin, which showed vasculitis with immunoglobulin A deposits. Our patient received chemotherapy with gemcitabine after successful steroid therapy for the Henoch-Schonlein purpura. CONCLUSION: Although hematological malignancies are well-known causes of vasculitides, cases of Henoch-Schonlein purpura associated with lung adenocarcinoma are rare. Our patient was treated with corticosteroid therapy, which cleared the purpura and cytotoxic chemotherapy for the non-small cell lung cancer. However, he died from heart failure due to cardiac tamponade. PMID- 21696581 TI - Multiple sexual partners and condom use among 10 - 19 year-olds in four districts in Tanzania: what do we learn? AB - BACKGROUND: Although some studies in Tanzania have addressed the question of sexuality and STIs among adolescents, mostly those aged 15 - 19 years, evidence on how multiple sexual partners influence condom use among 10 - 19 year-olds is limited. This study attempts to bridge this gap by testing a hypothesis that sexual relationships with multiple partners in the age group 10 - 19 years spurs condom use during sex in four districts in Tanzania. METHODS: Secondary analysis was performed using data from the Adolescents Module of the cross-sectional household survey on Maternal, Newborn and Child Health (MNCH) that was done in Kigoma, Kilombero, Rufiji and Ulanga districts, Tanzania in 2008. A total of 612 adolescents resulting from a random sample of 1200 households participated in this study. Pearson Chi-Square was used as a test of association between multiple sexual partners and condom use. Multivariate logistic regression model was fitted to the data to assess the effect of multiple sexual partners on condom use, having adjusted for potential confounding variables. STATA (10) statistical software was used to carry out this process at 5% two-sided significance level. RESULTS: Of the 612 adolescents interviewed, 23.4% reported being sexually active and 42.0% of these reported having had multiple (> 1) sexual partners in the last 12 months. The overall prevalence of condom use among them was 39.2%. The proportion using a condom at the last sexual intercourse was higher among those who knew that they can get a condom if they want than those who did not. No evidence of association was found between multiple sexual partners and condom use (OR = 0.77, 95% CI = 0.35 - 1.67, P = 0.504). With younger adolescents (10 - 14 years) being a reference, condom use was associated with age group (15 - 19: OR = 3.69, 95% CI = 1.21 - 11.25, P = 0.022) and district of residence (Kigoma: OR = 7.45, 95% CI = 1.79 - 31.06, P = 0.006; Kilombero: OR = 8.89, 95% CI = 2.91 - 27.21, P < 0.001; Ulanga: OR = 5.88, 95% CI = 2.00 - 17.31, P = 0.001), Rufiji being a reference category. CONCLUSION: No evidence of association was found between multiple sexual partners and condom use among adolescents in the study area. The large proportion of adolescents who engage in sexual activity without using condoms, even those with multiple partners, perpetuates the risk of transmission of HIV infections in the community. Strategies such as sex education and easing access to and making a friendly environment for condom availability are important to address the risky sexual behaviour among adolescents. PMID- 21696583 TI - Acute hepatitis in a woman following excessive ingestion of an energy drink: a case report. AB - INTRODUCTION: The consumption of energy drinks has increased significantly. We report the case of a patient who presented to our hospital with jaundice, abdominal pain, and markedly increased liver transaminases likely due to the increased consumption of an energy drink. To the best of our knowledge, this is the first case report in the literature linking the development of acute hepatitis to the consumption of an energy drink. CASE PRESENTATION: A 22-year-old Caucasian woman presented to our hospital with epigastric pain, nausea, vomiting, and low-grade fever. She had been drinking 10 cans of an energy drink daily for two weeks prior to presentation. Her physical examination revealed mild epigastric tenderness. Her initial blood tests revealed elevated alanine aminotransferase, aspartate aminotransferase, and total bilirubin. A computed tomographic scan of the abdomen and pelvis was normal, and the patient was discharged to home. She returned to the Emergency Department of our hospital with worsening pain and new-onset jaundice. This time her physical examination revealed epigastric tenderness and icteric sclera. Her aspartate aminotransferase, alanine aminotransferase, and international normalized ratio were markedly elevated. Further radiological studies were non-specific, and she was admitted to our hospital with a diagnosis of acute hepatitis. Her viral serology and toxicology screens were negative. The patient was treated supportively and was discharged after resolution of her symptoms and a marked decrease in her liver enzymes. CONCLUSION: The development of acute hepatitis in this patient was most likely due to the excessive ingestion of an energy drink, and we speculate that niacin was the culprit ingredient. PMID- 21696582 TI - Problematic internet usage in US college students: a pilot study. AB - BACKGROUND: Internet addiction among US college students remains a concern, but robust estimates of its prevalence are lacking. METHODS: We conducted a pilot survey of 307 college students at two US universities. Participants completed the Internet Addiction Test (IAT) as well as the Patient Health Questionnaire. Both are validated measures of problematic Internet usage and depression, respectively. We assessed the association between problematic Internet usage and moderate to severe depression using a modified Poisson regression approach. In addition, we examined the associations between individual items in the IAT and depression. RESULTS: A total of 224 eligible respondents completed the survey (73% response rate). Overall, 4% of students scored in the occasionally problematic or addicted range on the IAT, and 12% had moderate to severe depression. Endorsement of individual problematic usage items ranged from 1% to 70%. In the regression analysis, depressive symptoms were significantly associated with several individual items. Relative risk could not be estimated for three of the twenty items because of small cell sizes. Of the remaining 17 items, depressive symptoms were significantly associated with 13 of them, and three others had P values less than 0.10. There was also a significant association between problematic Internet usage overall and moderate to severe depression (relative risk 24.07, 95% confidence interval 3.95 to 146.69; P = 0.001). CONCLUSION: The prevalence of problematic Internet usage among US college students is a cause for concern, and potentially requires intervention and treatment amongst the most vulnerable groups. The prevalence reported in this study is lower than that which has been reported in other studies, however the at risk population is very high and preventative measures are also recommended. PMID- 21696584 TI - Learning curves and long-term outcome of simulation-based thoracentesis training for medical students. AB - BACKGROUND: Simulation-based medical education has been widely used in medical skills training; however, the effectiveness and long-term outcome of simulation based training in thoracentesis requires further investigation. The purpose of this study was to assess the learning curve of simulation-based thoracentesis training, study skills retention and transfer of knowledge to a clinical setting following simulation-based education intervention in thoracentesis procedures. METHODS: Fifty-two medical students were enrolled in this study. Each participant performed five supervised trials on the simulator. Participant's performance was assessed by performance score (PS), procedure time (PT), and participant's confidence (PC). Learning curves for each variable were generated. Long-term outcome of the training was measured by the retesting and clinical performance evaluation 6 months and 1 year, respectively, after initial training on the simulator. RESULTS: Significant improvements in PS, PT, and PC were noted among the first 3 to 4 test trials (p < 0.05). A plateau for PS, PT, and PC in the learning curves occurred in trial 4. Retesting 6 months after training yielded similar scores to trial 5 (p > 0.05). Clinical competency in thoracentesis was improved in participants who received simulation training relative to that of first year medical residents without such experience (p < 0.05). CONCLUSIONS: This study demonstrates that simulation-based thoracentesis training can significantly improve an individual's performance. The saturation of learning from the simulator can be achieved after four practice sessions. Simulation-based training can assist in long-term retention of skills and can be partially transferred to clinical practice. PMID- 21696585 TI - Effective implementation of research into practice: an overview of systematic reviews of the health literature. AB - BACKGROUND: The gap between research findings and clinical practice is well documented and a range of interventions has been developed to increase the implementation of research into clinical practice. FINDINGS: A review of systematic reviews of the effectiveness of interventions designed to increase the use of research in clinical practice. A search for relevant systematic reviews was conducted of Medline and the Cochrane Database of Reviews 1998-2009. 13 systematic reviews containing 313 primary studies were included. Four strategy types are identified: audit and feedback; computerised decision support; opinion leaders; and multifaceted interventions. Nine of the reviews reported on multifaceted interventions. This review highlights the small effects of single interventions such as audit and feedback, computerised decision support and opinion leaders. Systematic reviews of multifaceted interventions claim an improvement in effectiveness over single interventions, with effect sizes ranging from small to moderate. This review found that a number of published systematic reviews fail to state whether the recommended practice change is based on the best available research evidence. CONCLUSIONS: This overview of systematic reviews updates the body of knowledge relating to the effectiveness of key mechanisms for improving clinical practice and service development. Multifaceted interventions are more likely to improve practice than single interventions such as audit and feedback. This review identified a small literature focusing explicitly on getting research evidence into clinical practice. It emphasizes the importance of ensuring that primary studies and systematic reviews are precise about the extent to which the reported interventions focus on changing practice based on research evidence (as opposed to other information codified in guidelines and education materials). PMID- 21696586 TI - Effects of naturally-arising HIV Nef mutations on cytotoxic T lymphocyte recognition and Nef's functionality in primary macrophages. AB - BACKGROUND: Although HIV can infect several cellular subsets, such as CD4+ T lymphocytes and macrophages, it remains unclear whether an HIV infection in macrophages supports cytotoxic T lymphocyte (CTL) escape. Here, we tested two naturally-arising mutations located in the well-conserved polyproline region of Nef for their effects on CTL recognition, Nef's functionality, and viral replication capacity in macrophages. These mutations were selected because they are known to cause CTL escape in the context of T lymphocytes. FINDINGS: Monocyte derived macrophages (MDMs) infected with the wild-type virus, but not with variant viruses, were efficiently killed by CTL clones targeting Nef epitopes, VY8 (VPLRPMTY) and RY11 (RPQVPLRPMTY). The CTL-escape mutation, Arg75Thr, or Arg75Thr/Tyr85Phe double mutation, reduced the HLA class I down-regulation activity and, interestingly, increased the susceptibility of virus-infected MDMs to recognition by CTLs targeting a different epitope. The same mutations reduced the CCR5, but not CD4, down-regulation activity. Moreover, the Nef variants were impaired for Hck activation and enhancement of viral replication in MDMs. CONCLUSIONS: These results suggest that HIV-infected MDMs are killed by CTLs targeting Nef epitopes, contributing to selection and adaptation of CTL-escape viral variants. PMID- 21696587 TI - Field trial of three different Plasmodium vivax-detecting rapid diagnostic tests with and without evaporative cool box storage in Afghanistan. AB - BACKGROUND: Accurate parasitological diagnosis of malaria is essential for targeting treatment where more than one species coexist. In this study, three rapid diagnostic tests (RDTs) (AccessBio CareStart (CSPfPan), CareStart PfPv (CSPfPv) and Standard Diagnostics Bioline (SDBPfPv)) were evaluated for their ability to detect natural Plasmodium vivax infections in a basic clinic setting. The potential for locally made evaporative cooling boxes (ECB) to protect the tests from heat damage in high summer temperatures was also investigated. METHODS: Venous blood was drawn from P. vivax positive patients in Jalalabad, Afghanistan and tested against a panel of six RDTs. The panel comprised two of each test type; one group was stored at room temperature and the other in an ECB. RDT results were evaluated against a consensus gold standard based on two double read reference slides and PCR. The sensitivity, specificity and a measure of global performance for each test were determined and stratified by parasitaemia level and storage condition. RESULTS: In total, 306 patients were recruited, of which 284 were positive for P. vivax, one for Plasmodium malariae and none for Plasmodium falciparum; 21 were negative. All three RDTs were specific for malaria. The sensitivity and global performance index for each test were as follows: CSPfPan [98.6%, 95.1%], CSPfPv [91.9%, 90.5%] and SDBPfPv [96.5%, 82.9%], respectively. CSPfPv was 16% less sensitive to a parasitaemia below 5,000/MUL. Room temperature storage of SDBPfPv led to a high proportion of invalid results (17%), which reduced to 10% in the ECB. Throughout the testing period, the ECB maintained ~8 degrees C reduction over ambient temperatures and never exceeded 30 degrees C. CONCLUSIONS: Of the three RDTs, the CSPfPan test was the most consistent and reliable, rendering it appropriate for this P. vivax predominant region. The CSPfPv test proved unsuitable owing to its reduced sensitivity at a parasitaemia below 5,000/MUL (affecting 43% of study samples). Although the SDBPfPv device was more sensitive than the CSPfPv test, its invalid rate was unacceptably high. ECB storage reduced the proportion of invalid results for the SDBPfPv test, but surprisingly had no impact on RDT sensitivity at low parasitaemia. PMID- 21696588 TI - Ciliary neurotrophic factor promotes motor reinnervation of the musculocutaneous nerve in an experimental model of end-to-side neurorrhaphy. AB - BACKGROUND: It is difficult to repair nerve if proximal stump is unavailable or autogenous nerve grafts are insufficient for reconstructing extensive nerve damage. Therefore, alternative methods have been developed, including lateral anastomosis based on axons' ability to send out collateral sprouts into denervated nerve. The different capacity of a sensory or motor axon to send a sprout is controversial and may be controlled by cytokines and/or neurotrophic factors like ciliary neurotrophic factor (CNTF). The aim of the present study was to quantitatively assess collateral sprouts sent out by intact motor and sensory axons in the end-to-side neurorrhaphy model following intrathecal administration of CNTF in comparison with phosphate buffered saline (vehiculum) and Cerebrolysin. The distal stump of rat transected musculocutaneous nerve (MCN) was attached in an end-to-side fashion with ulnar nerve. CNTF, Cerebrolysin and vehiculum were administered intrathecally for 2 weeks, and all animals were allowed to survive for 2 months from operation. Numbers of spinal motor and dorsal root ganglia neurons were estimated following their retrograde labeling by Fluoro-Ruby and Fluoro-Emerald applied to ulnar and musculocutaneous nerve, respectively. Reinnervation of biceps brachii muscles was assessed by electromyography, behavioral test, and diameter and myelin sheath thickness of regenerated axons. RESULTS: Vehiculum or Cerebrolysin administration resulted in significantly higher numbers of myelinated axons regenerated into the MCN stumps compared with CNTF treatment. By contrast, the mean diameter of the myelinated axons and their myelin sheath thickness in the cases of Cerebrolysin- or CNTF treated animals were larger than were those for rats treated with vehiculum. CNTF treatment significantly increased the percentage of motoneurons contributing to reinnervation of the MCN stumps (to 17.1%) when compared with vehiculum or Cerebrolysin treatments (at 9.9 or 9.6%, respectively). Reduced numbers of myelinated axons and simultaneously increased numbers of motoneurons contributing to reinnervation of the MCN improved functional reinnervation of the biceps brachii muscle after CNTF treatment. CONCLUSION: The present experimental study confirms end-to-side neurorrhaphy as an alternative method for reconstructing severed peripheral nerves. CNTF promotes motor reinnervation of the MCN stump after its end-to-side neurorrhaphy with ulnar nerve and improves functional recovery of the biceps brachii muscle. PMID- 21696589 TI - Behavioural interventions for weight management in pregnancy: a systematic review of quantitative and qualitative data. AB - BACKGROUND: There is a rising prevalence of excessive weight gain in pregnancy and an increasing number of pregnant women who are overweight or obese at the start of the pregnancy. Excessive weight gain during pregnancy is associated with adverse maternal and neonatal consequences and increases the risk of long-term obesity. Pregnancy therefore may be a key time to prevent excessive weight gain and improve the health of women and their unborn child. This systematic review sought to assess the effectiveness of behavioural interventions to prevent excessive weight gain in pregnancy and explore the factors that influence intervention effectiveness. METHODS: We undertook a systematic review of quantitative and qualitative evidence. This included a meta-analysis of controlled trials of diet and physical activity interventions to prevent excessive weight gain during pregnancy and a thematic synthesis of qualitative studies that investigated the views of women on weight management during pregnancy. A thorough search of eleven electronic bibliographic databases, reference lists of included studies, relevant review articles and experts in the field were contacted to identify potentially relevant studies.Two independent reviewers extracted data. RevMan software was used to perform the meta-analyses. Qualitative data was subject to thematic analysis. Both quantitative and qualitative data were aligned using a matrix framework. RESULTS: Five controlled trials and eight qualitative studies were included. The overall pooled effect size found no significant difference in gestational weight gain amongst participants in the intervention group compared with the control group (mean difference -0.28 95% CI -0.64 to 0.09). The study designs, participants and interventions all varied markedly and there was significant heterogeneity within this comparison in the meta-analysis (I2 67%). Subgroup and sensitivity analysis did not identify contextual elements that influenced the effectiveness of the intervention.In a thematic analysis of the qualitative studies, three major themes emerged relating to women's views of weight management in pregnancy: pregnancy as a time of transition and change, conflicting and contradictory messages and a perceived lack of control. When the results of both quantitative and qualitative data were aligned it was clear that some of the barriers that women described in achieving healthy weight gain in pregnancy were not addressed by the interventions evaluated. This may have contributed to the limited effectiveness of the interventions. CONCLUSIONS: Despite intense and often tailored interventions there was no statistically significant effect on weight gain during pregnancy. Inadequate and often contradictory information regarding healthy weight management was reported by women in qualitative studies and this was addressed in the interventions but this in itself was insufficient to lead to reduced weight gain. Multiple types of interventions, including community based strategies are needed to address this complex health problem. PMID- 21696590 TI - Respiratory distress and chest pain: a perforated peptic ulcer with an unusual presentation. AB - BACKGROUND: Dyspnea and chest pain are common presenting complaints to the ED, and coupled together can present a challenging diagnostic dilemma in patients in extremis. A thoughtful evaluation is required, giving due diligence to the immediate life threats as well as multiple etiologies which can cause serious morbidity. A perforated peptic ulcer is one such possibility and requires rapid diagnosis and prompt intervention to avoid the associated high risk of morbidity and mortality. METHOD: We present a case report of a 54 year old man with respiratory distress and chest pain as the initial Emergency Department presentation of a perforated duodenal ulcer. RESULTS: We discuss an unusual presentation of a perforated duodenal ulcer that was recognized in the emergency department and treated promptly. The patient was surgically treated immediately, had a prolonged and complicated post-operative course, but is ultimately doing well. We also provide a brief literature review of the risk factors, imaging choices, and management decision required to treat a perforated ulcer. CONCLUSIONS: Perforated ulcers can have highly varied presentations and are occasionally difficult to diagnose in a complicated patient. Knowledge of the risk factors and a thorough history and physical can point to the diagnosis, but timely and appropriate imaging is often required because delays in diagnosis and treatment lead to poor outcomes. Early administration of antibiotics and immediate surgical repair are necessary to limit morbidity and mortality. PMID- 21696591 TI - Phylogeny and evolution of life-history strategies in the Sycophaginae non pollinating fig wasps (Hymenoptera, Chalcidoidea). AB - BACKGROUND: Non-pollinating Sycophaginae (Hymenoptera, Chalcidoidea) form small communities within Urostigma and Sycomorus fig trees. The species show differences in galling habits and exhibit apterous, winged or dimorphic males. The large gall inducers oviposit early in syconium development and lay few eggs; the small gall inducers lay more eggs soon after pollination; the ostiolar gall inducers enter the syconium to oviposit and the cleptoparasites oviposit in galls induced by other fig wasps. The systematics of the group remains unclear and only one phylogeny based on limited sampling has been published to date. Here we present an expanded phylogeny for sycophagine fig wasps including about 1.5 times the number of described species. We sequenced mitochondrial and nuclear markers (4.2 kb) on 73 species and 145 individuals and conducted maximum likelihood and Bayesian phylogenetic analyses. We then used this phylogeny to reconstruct the evolution of Sycophaginae life-history strategies and test if the presence of winged males and small brood size may be correlated. RESULTS: The resulting trees are well resolved and strongly supported. With the exception of Apocrytophagus, which is paraphyletic with respect to Sycophaga, all genera are monophyletic. The Sycophaginae are divided into three clades: (i) Eukoebelea; (ii) Pseudidarnes, Anidarnes and Conidarnes and (iii) Apocryptophagus, Sycophaga and Idarnes. The ancestral states for galling habits and male morphology remain ambiguous and our reconstructions show that the two traits are evolutionary labile. CONCLUSIONS: The three main clades could be considered as tribes and we list some morphological characters that define them. The same biologies re-evolved several times independently, which make Sycophaginae an interesting model to test predictions on what factors will canalize the evolution of a particular biology. The ostiolar gall-inducers are the only monophyletic group. In 15 Myr, they evolved several morphological adaptations to enter the syconia that make them strongly divergent from their sister taxa. Sycophaginae appears to be another example where sexual selection on male mating opportunities favored winged males in species with small broods and wingless males in species with large broods. However, some species are exceptional in that they lay few eggs but exhibit apterous males, which we hypothesize could be due to other selective pressures selecting against the re-appearance of winged morphs. PMID- 21696592 TI - Structural influence of gene networks on their inference: analysis of C3NET. AB - BACKGROUND: The availability of large-scale high-throughput data possesses considerable challenges toward their functional analysis. For this reason gene network inference methods gained considerable interest. However, our current knowledge, especially about the influence of the structure of a gene network on its inference, is limited. RESULTS: In this paper we present a comprehensive investigation of the structural influence of gene networks on the inferential characteristics of C3NET - a recently introduced gene network inference algorithm. We employ local as well as global performance metrics in combination with an ensemble approach. The results from our numerical study for various biological and synthetic network structures and simulation conditions, also comparing C3NET with other inference algorithms, lead a multitude of theoretical and practical insights into the working behavior of C3NET. In addition, in order to facilitate the practical usage of C3NET we provide an user-friendly R package, called c3net, and describe its functionality. It is available from https://r forge.r-project.org/projects/c3net and from the CRAN package repository. CONCLUSIONS: The availability of gene network inference algorithms with known inferential properties opens a new era of large-scale screening experiments that could be equally beneficial for basic biological and biomedical research with auspicious prospects. The availability of our easy to use software package c3net may contribute to the popularization of such methods. PMID- 21696593 TI - Fusion of metabolomics and proteomics data for biomarkers discovery: case study on the experimental autoimmune encephalomyelitis. AB - BACKGROUND: Analysis of Cerebrospinal Fluid (CSF) samples holds great promise to diagnose neurological pathologies and gain insight into the molecular background of these pathologies. Proteomics and metabolomics methods provide invaluable information on the biomolecular content of CSF and thereby on the possible status of the central nervous system, including neurological pathologies. The combined information provides a more complete description of CSF content. Extracting the full combined information requires a combined analysis of different datasets i.e. fusion of the data. RESULTS: A novel fusion method is presented and applied to proteomics and metabolomics data from a pre-clinical model of multiple sclerosis: an Experimental Autoimmune Encephalomyelitis (EAE) model in rats. The method follows a mid-level fusion architecture. The relevant information is extracted per platform using extended canonical variates analysis. The results are subsequently merged in order to be analyzed jointly. We find that the combined proteome and metabolome data allow for the efficient and reliable discrimination between healthy, peripherally inflamed rats, and rats at the onset of the EAE. The predicted accuracy reaches 89% on a test set. The important variables (metabolites and proteins) in this model are known to be linked to EAE and/or multiple sclerosis. CONCLUSIONS: Fusion of proteomics and metabolomics data is possible. The main issues of high-dimensionality and missing values are overcome. The outcome leads to higher accuracy in prediction and more exhaustive description of the disease profile. The biological interpretation of the involved variables validates our fusion approach. PMID- 21696594 TI - BioGraph: unsupervised biomedical knowledge discovery via automated hypothesis generation. AB - We present BioGraph, a data integration and data mining platform for the exploration and discovery of biomedical information. The platform offers prioritizations of putative disease genes, supported by functional hypotheses. We show that BioGraph can retrospectively confirm recently discovered disease genes and identify potential susceptibility genes, outperforming existing technologies, without requiring prior domain knowledge. Additionally, BioGraph allows for generic biomedical applications beyond gene discovery. BioGraph is accessible at http://www.biograph.be. PMID- 21696595 TI - "What families want - an assessment of family expectations in the ICU". AB - INTRODUCTION: Families of patients admitted in the intensive care units (ICUs) experience high levels of emotional stress. Access to information about patient's medical conditions and quality relationships with healthcare staff are high priority needs for these families and meeting these needs of the family members is a primary responsibility of ICU physicians and nurses. METHODOLOGY: Our objectives were to assess the expectations of ICU patients' families that can be fulfilled by physicians and nurses. The design was a descriptive, exploratory questionnaire based study over 6 months in the multidisciplinary ICU of a tertiary care hospital. RESULTS: Of 205 interviews, the median age of the patient was 28 years. One hundred and nineteen (58%) were male and Eighty six (42%) patients were female. 163 (79.5%) of the relatives were Next of kin, and 133 (64.9%) were male members. Of the family members, 20 (9.8%) were spouses. One hundred and forty two (69.3%) belonged to Middle income group. Ninety nine (48.3%) were Graduates of high school or above. Relation to patient, sex of relative, DNR status of patient and age of relative were statistically significant to make a difference to the satisfaction score. The majority of the relatives reached a score of 22-25. CONCLUSION: We conclude that families of critically ill patients were generally satisfied with communication in the ICU; however, our limitations are the cohort in our urban based tertiary care hospital may not adequately represent the majority of our population which is poor and illiterate and many other factors such as misunderstanding of medical knowledge and a more patriarchal attitude of physicians may affect family needs and satisfaction scores. PMID- 21696596 TI - Mesenteric panniculitis presenting with acute non-occlusive colonic ischemia. AB - BACKGROUND: The role of positron emission tomography (PET) of the mesentery as a diagnostic modality in cases of mesenteric panniculitis is unclear. CASE PRESENTATION: A 67-year-old woman presented with rectal bleeding due to nonocclusive colonic ischemia. Abdominal CT showed features of mesenteric panniculitis. PET-CT demonstrated no abnormal fluorine-18 fluordeoxyglucose uptake in the affected mesentery or any surrounding lymph nodes. Laparoscopic biopsies from a thickened segment of mesenteric fat excluded neoplastic infiltration. CONCLUSIONS: In cases of unexplained ischemic colitis, panniculitis should be considered a possible diagnosis. PET-CT may be negative for fluorine-18 fluordeoxyglucose uptake in this condition. As of known false-negative PET-CT results in mesenteric panniculitis, PET-CT has a limited role in the diagnostic work-up. PMID- 21696597 TI - Genome-wide deficiency screen for the genomic regions responsible for heat resistance in Drosophila melanogaster. AB - BACKGROUND: Temperature adaptation is one of the most important determinants of distribution and population size of organisms in nature. Recently, quantitative trait loci (QTL) mapping and gene expression profiling approaches have been used for detecting candidate genes for heat resistance. However, the resolution of QTL mapping is not high enough to examine the individual effects of various genes in each QTL. Heat stress-responsive genes, characterized by gene expression profiling studies, are not necessarily responsible for heat resistance. Some of these genes may be regulated in association with the heat stress response of other genes. RESULTS: To evaluate which heat-responsive genes are potential candidates for heat resistance with higher resolution than previous QTL mapping studies, we performed genome-wide deficiency screen for QTL for heat resistance. We screened 439 isogenic deficiency strains from the DrosDel project, covering 65.6% of the Drosophila melanogaster genome in order to map QTL for thermal resistance. As a result, we found 19 QTL for heat resistance, including 3 novel QTL outside the QTL found in previous studies. CONCLUSION: The QTL found in this study encompassed 19 heat-responsive genes found in the previous gene expression profiling studies, suggesting that they were strong candidates for heat resistance. This result provides new insights into the genetic architecture of heat resistance. It also emphasizes the advantages of genome-wide deficiency screen using isogenic deficiency libraries. PMID- 21696598 TI - Estimating and modelling cure in population-based cancer studies within the framework of flexible parametric survival models. AB - BACKGROUND: When the mortality among a cancer patient group returns to the same level as in the general population, that is, the patients no longer experience excess mortality, the patients still alive are considered "statistically cured". Cure models can be used to estimate the cure proportion as well as the survival function of the "uncured". One limitation of parametric cure models is that the functional form of the survival of the "uncured" has to be specified. It can sometimes be hard to find a survival function flexible enough to fit the observed data, for example, when there is high excess hazard within a few months from diagnosis, which is common among older age groups. This has led to the exclusion of older age groups in population-based cancer studies using cure models. METHODS: Here we have extended the flexible parametric survival model to incorporate cure as a special case to estimate the cure proportion and the survival of the "uncured". Flexible parametric survival models use splines to model the underlying hazard function, and therefore no parametric distribution has to be specified. RESULTS: We have compared the fit from standard cure models to our flexible cure model, using data on colon cancer patients in Finland. This new method gives similar results to a standard cure model, when it is reliable, and better fit when the standard cure model gives biased estimates. CONCLUSIONS: Cure models within the framework of flexible parametric models enables cure modelling when standard models give biased estimates. These flexible cure models enable inclusion of older age groups and can give stage-specific estimates, which is not always possible from parametric cure models. PMID- 21696599 TI - Substitution rate variation at human CpG sites correlates with non-CpG divergence, methylation level and GC content. AB - BACKGROUND: A major goal in the study of molecular evolution is to unravel the mechanisms that induce variation in the germ line mutation rate and in the genome wide mutation profile. The rate of germ line mutation is considerably higher for cytosines at CpG sites than for any other nucleotide in the human genome, an increase commonly attributed to cytosine methylation at CpG sites. The CpG mutation rate, however, is not uniform across the genome and, as methylation levels have recently been shown to vary throughout the genome, it has been hypothesized that methylation status may govern variation in the rate of CpG mutation. RESULTS: Here, we use genome-wide methylation data from human sperm cells to investigate the impact of DNA methylation on the CpG substitution rate in introns of human genes. We find that there is a significant correlation between the extent of methylation and the substitution rate at CpG sites. Further, we show that the CpG substitution rate is positively correlated with non CpG divergence, suggesting susceptibility to factors responsible for the general mutation rate in the genome, and negatively correlated with GC content. We only observe a minor contribution of gene expression level, while recombination rate appears to have no significant effect. CONCLUSIONS: Our study provides the first direct empirical support for the hypothesis that variation in the level of germ line methylation contributes to substitution rate variation at CpG sites. Moreover, we show that other genomic features also impact on CpG substitution rate variation. PMID- 21696600 TI - The impact of Metastasis Suppressor-1, MTSS1, on oesophageal squamous cell carcinoma and its clinical significance. AB - BACKGROUND: Metastasis suppressor-1 (MTSS1) has been proposed to function as a cytoskeletal protein with a role in cancer metastasis. Recent studies have demonstrated the clinical significance of MTSS1 in certain type of cancers, yet the clinical relevance of MTSS1 in oesophageal squamous cell carcinoma (ESCC) has not been reported. METHODS: In this study, we assessed the expression levels of MTSS1 in tumours and its matched adjacent non-tumour tissues obtained from 105 ESCC patients. We also used ESCC cells with differing MTSS1 expression and assessed the influence of MTSS1 on ESCC cells. RESULTS: Down-regulation of MTSS1 expression was observed both in oesophageal tumour tissues and ESCC cancer cell lines. We also reported that MTSS1 expression was associated with tumour grade (p = 0.024), lymph node metastasis (p = 0.010) and overall survival (p = 0.035). Patients with high levels of MTSS1 transcripts had a favorable prognosis in comparison with those who had reduced or absent expression levels. Using over expression and knockdown approach, we created sublines from ESCC cells and further demonstrated that MTSS1 expression in ESCC cells significantly influenced the aggressiveness of the oesophageal cancer cells, by reducing their cellular migration and in vitro invasiveness. CONCLUSION: MTSS1 serves as a potential prognostic indicator in human ESCC and may be an important target for cancer therapy. PMID- 21696601 TI - Unsuccessful therapy with adefovir and entecavir-tenofovir in a patient with chronic hepatitis B infection with previous resistance to lamivudine: a fourteen year evolution of hepatitis B virus mutations. AB - BACKGROUND: Complex mutants can be selected under sequential selective pressure by HBV therapy. To determine hepatitis B virus genomic evolution during antiviral therapy we characterized the HBV quasi-species in a patient who did no respond to therapy following lamivudine breakthrough for a period of 14 years. CASE PRESENTATION: The polymerase and precore/core genes were amplified and sequenced at determined intervals in a period of 14 years. HBV viral load and HBeAg/Anti HBe serological profiles as well as amino transferase levels were also measured. A mixture of lamivudine-resistant genotype A2 HBV strains harboring the rtM204V mutation coexisted in the patient following viral breakthrough to lamivudine. The L180M+M204V dominant mutant displayed strong lamivudine-resistance. As therapy was changed to adefovir, then to entecavir, and finally to entecavir-tenofovir the viral load showed fluctuations but lamivudine-resistant strains continued to be selected, with minor contributions to the HBV quasi-species composition of additional resistance-associated mutations. At the end of the 14-year follow up period, high viral loads were predominant, with viral strains harboring the lamivudine-resistance signature rtL180M+M204V. The precore/core frame A1762T and G1764A double mutation was detected before treatment and remaining in this condition during the entire follow-up. Specific entecavir and tenofovir primary resistance-associated mutations were not detected at any time. Plasma concentrations of tenofovir indicated adequate metabolism of the drug. CONCLUSIONS: We report the selection of HBV mutants carrying well-defined primary resistance mutations that escaped lamivudine in a fourteen-year follow-up period. With the exception of tenofovir resistance mutations, subsequent unselected primary resistance mutations were detected as minor populations into the HBV quasispecies composition during adefovir or entecavir monotherapies. Although tenofovir is considered an appropriate therapeutic alternative for the treatment of entecavir-unresponsive patients, its use was not effective in the case reported here. PMID- 21696602 TI - Dynamic reorganization of flotillins in chemokine-stimulated human T-lymphocytes. AB - BACKGROUND: Different types of membrane microdomains (rafts) have been postulated to be present in the rear and front of polarized migrating T-lymphocytes. Disruption of rafts by cholesterol sequestration prevents T-cell polarization and migration. Reggie/flotillin-1 and -2 are two highly homologous proteins that are thought to shape membrane microdomains. We have previously demonstrated the enrichment of flotillins in the uropod of human neutrophils. We have now investigated mechanisms involved in chemokine-induced flotillin reorganization in human T-lymphocytes, and possible roles of flotillins in lymphocyte polarization. RESULTS: We studied flotillin reorganization and lateral mobility at the plasma membrane using immunofluorescence staining and FRAP (fluorescence recovery after photobleaching). We show that flotillins redistribute early upon chemokine stimulation, and form very stable caps in the uropods of human peripheral blood T lymphocytes, colocalizing with the adhesion molecule PSGL-1 and activated ezrin/radixin/moesin (ERM) proteins. Chemokine-induced formation of stable flotillin caps requires integrity and dynamics of the actin cytoskeleton, but is not abolished by inhibitors suppressing Rho-kinase or myosin II activity. Tagged flotillin-2 and flotillin-1 coexpressed in T-lymphocytes, but not singly expressed proteins, colocalize in stable caps at the tips of uropods. Lateral mobility of coexpressed flotillins at the plasma membrane is already partially restricted in the absence of chemokine. Incubation with chemokine results in almost complete immobilization of flotillins. Capping is abolished when wild-type flotillin-1 is coexpressed with a mutant of flotillin-2 (G2A) that is unable to interact with the plasma membrane, or with a deletion mutant of flotillin-2 that lacks a putative actin-binding domain. Wild-type flotillin-2 in contrast forms caps when coexpressed with a mutant of flotillin-1 unable to interact with membranes. Transfection of T-lymphocytes with flotillin-2-G2A reduces cell polarization and uropod recruitment of endogenous flotillin-1 and PSGL-1. CONCLUSIONS: Our data suggest that stable flotillin cap formation in the rear of polarized T-lymphocytes requires flotillin heterooligomer formation, as well as direct F-actin interactions of flotillin-2 and raft/membrane association of flotillin-2, but not -1. Our data also implicate flotillin-rich actin-dependent membrane microdomains in T-lymphocyte uropod formation. PMID- 21696603 TI - Effect of acupuncture depth on muscle pain. AB - BACKGROUND: While evidence supports efficacy of acupuncture and/or dry needling in treating musculoskeletal pain, it is unclear which needling method is most effective. This study aims to determine the effects of depth of needle penetration on muscle pain. METHODS: A total of 22 healthy volunteers performed repeated eccentric contractions to induce muscle soreness in their extensor digital muscle. Subjects were assigned randomly to four groups, namely control group, skin group (depth of 3 mm: the extensor digital muscle), muscle group (depth of 10 mm: the extensor digital muscle) and non-segmental group (depth of 10 mm: the anterior tibial muscle). Pressure pain threshold and electrical pain threshold of the skin, fascia and muscle were measured at a point 20 mm distal to the maximum tender point on the second day after the exercise. RESULTS: Pressure pain thresholds of skin group (depth of 3 mm: the extensor digital muscle) and muscle group (depth of 10 mm: the extensor digital muscle) were significantly higher than the control group, whereas the electrical pain threshold at fascia of muscle group (depth of 10 mm: the extensor digital muscle) was a significantly higher than control group; however, there was no significant difference between the control and other groups. CONCLUSION: The present study shows that acupuncture stimulation of muscle increases the PPT and EPT of fascia. The depth of needle penetration is important for the relief of muscle pain. PMID- 21696604 TI - Decision curve analysis revisited: overall net benefit, relationships to ROC curve analysis, and application to case-control studies. AB - BACKGROUND: Decision curve analysis has been introduced as a method to evaluate prediction models in terms of their clinical consequences if used for a binary classification of subjects into a group who should and into a group who should not be treated. The key concept for this type of evaluation is the "net benefit", a concept borrowed from utility theory. METHODS: We recall the foundations of decision curve analysis and discuss some new aspects. First, we stress the formal distinction between the net benefit for the treated and for the untreated and define the concept of the "overall net benefit". Next, we revisit the important distinction between the concept of accuracy, as typically assessed using the Youden index and a receiver operating characteristic (ROC) analysis, and the concept of utility of a prediction model, as assessed using decision curve analysis. Finally, we provide an explicit implementation of decision curve analysis to be applied in the context of case-control studies. RESULTS: We show that the overall net benefit, which combines the net benefit for the treated and the untreated, is a natural alternative to the benefit achieved by a model, being invariant with respect to the coding of the outcome, and conveying a more comprehensive picture of the situation. Further, within the framework of decision curve analysis, we illustrate the important difference between the accuracy and the utility of a model, demonstrating how poor an accurate model may be in terms of its net benefit. Eventually, we expose that the application of decision curve analysis to case-control studies, where an accurate estimate of the true prevalence of a disease cannot be obtained from the data, is achieved with a few modifications to the original calculation procedure. CONCLUSIONS: We present several interrelated extensions to decision curve analysis that will both facilitate its interpretation and broaden its potential area of application. PMID- 21696605 TI - Reproducible gene targeting in recalcitrant Escherichia coli isolates. AB - BACKGROUND: A number of allele replacement methods can be used to mutate bacterial genes. For instance, the Red recombinase system of phage Lambda has been used very efficiently to inactivate chromosomal genes in E. coli K-12, through recombination between regions of homology. However, this method does not work reproducibly in some clinical E. coli isolates. FINDINGS: The procedure was modified by using longer homologous regions (85 bp and 500-600 bp), to inactivate genes in the uropathogenic E. coli strain UTI89. An lrhA regulator mutant, and deletions of the lac operon as well as the complete type 1 fimbrial gene cluster, were obtained reproducibly. The modified method is also functional in other recalcitrant E. coli, like the avian pathogenic E. coli strain APEC1. The lrhA regulator and lac operon deletion mutants of APEC1 were successfully constructed in the same way as the UTI89 mutants. In other avian pathogenic E. coli strains (APEC3E, APEC11A and APEC16A) it was very difficult or impossible to construct these mutants, with the original Red recombinase-based method, with a Red recombinase-based method using longer (85 bp) homologous regions or with our modified protocol, using 500 - 600 bp homologous regions. CONCLUSIONS: The method using 500-600 bp homologous regions can be used reliably in some clinical isolates, to delete single genes or entire operons by homologous recombination. However, it does not invariably show a greater efficiency in obtaining mutants, when compared to the original Red-mediated gene targeting method or to the gene targeting method with 85 bp homologous regions. Therefore the length of the homology regions is not the only limiting factor for the construction of mutants in these recalcitrant strains. PMID- 21696606 TI - YKL-40 levels are independently associated with albuminuria in type 2 diabetes. AB - OBJECTIVE AND DESIGN: YKL-40 is involved in inflammation and endothelial dysfunction, and is increased in patients with type 1 diabetes, with an independent association between increasing YKL-40 levels and increasing levels of albuminuria. YKL-40 is associated with atherosclerosis and an increased cardiovascular mortality in the general population. In the present study YKL-40 levels were examined in patients with type 2 diabetes (T2D) with increasing levels of albuminuria, known to be associated with an increased risk of cardiovascular disease. MATERIALS AND METHODS: One-hundred-five patients with T2D were examined: 49 with normoalbuminuria (N, U-albumin/creatinine < 2.5 mg/mmol), 35 with persistent microalbuminuria (MA, 2.5-25 mg/mmol) and 21 with persistent macroalbuminuria/diabetic nephropathy (DN, > 25 mg/mmol). The control group consisted of 20 healthy individuals (C). Groups were matched according to age, gender and known duration of diabetes. RESULTS: Median levels (interquartile range) of serum YKL-40 were significantly higher in N and MA vs. C (86 (55-137) ng/ml and 84 (71-147) ng/ml, respectively vs. 41 (33-55) ng/ml, p < 0.01) and even higher in patients with DN (120 (83-220) ng/ml, p < 0.001 for all comparisons). YKL-40 levels correlated with urinary albumin/creatinine-ratio in the total group of participants (r = 0.41, p < 0.001). Significant intercorrelations of YKL-40 were found with age, duration of diabetes, systolic blood pressure, lipid levels, HbA1c and HOMA-IR. After adjustment for significant covariates, albuminuria was significantly associated with YKL-40 levels (r = 0.32, p = 0.006). CONCLUSIONS: YKL-40 levels are elevated in patients with T2D with an independent association between increasing YKL-40 levels and increasing levels of albuminuria. The study suggests a role of YKL-40 in the progressing vascular complications in patients with T2D. PMID- 21696607 TI - Incident cervical infections with high- and low-risk human papillomavirus (HPV) infections among mothers in the prospective Finnish Family HPV Study. AB - BACKGROUND: The knowledge on type specificity and factors that increase or decrease the risk of incident HPV-infections is important to better understand the dynamics of HPV-infections. METHODS: A series of 329 pregnant women were enrolled in Finnish Family HPV Study at 3rd trimester of pregnancy and followed up for 6 years, during which 203 baseline HPV-negative women acquired incident HPV infection. Incidence times and incidence rates (IR) were calculated for 24 low-and high-risk HPV-types detected by Multiplex-HPV-genotyping at each visit. Poison regression was used to estimate predictors of incident HPV infections of species 7 and 9 HPV-genotypes. RESULTS: HPV16 was the most frequent (47.8%) incident genotype followed by multiple-type infections (25.1%), and single infection with HPV18, 70, 6 and 45. Actuarial mean times to incident event were longest for HPV31 (34.5 months) and HPV45 (32.8 months), while crude mean times were longest for HPV56 (42.4 months) and HPV16 (23.1 months). Actuarial IR was highest for HPV16 and multiple-type infections. Independent protective factors against incident infections were 1) > 2 life-time sexual partners (p = 0.014), 2) later initiation of oral contraceptives (age > 20 years) (p = 0.017) and 3) pregnancy at FU visit (p = 0.0001). CONCLUSIONS: Among newly delivered mothers, higher number of life-time sexual partners, initiation of OC use after age 20 and becoming pregnant during FU decreased the risk for incident species 7/9 HPV infections. PMID- 21696608 TI - A lack of association between hyperserotonemia and the increased frequency of serum anti-myelin basic protein auto-antibodies in autistic children. AB - BACKGROUND: One of the most consistent biological findings in autism is the elevated blood serotonin levels. Immune abnormalities, including autoimmunity with production of brain specific auto-antibodies, are also commonly observed in this disorder. Hyperserotonemia may be one of the contributing factors to autoimmunity in some patients with autism through the reduction of T-helper (Th) 1-type cytokines. We are the first to investigate the possible role of hyperserotonemia in the induction of autoimmunity, as indicated by serum anti myelin-basic protein (anti-MBP) auto-antibodies, in autism. METHODS: Serum levels of serotonin and anti-MBP auto-antibodies were measured, by ELISA, in 50 autistic patients, aged between 5 and 12 years, and 30 healthy-matched children. RESULTS: Autistic children had significantly higher serum levels of serotonin and anti-MBP auto-antibodies than healthy children (P < 0.001 and P < 0.001, respectively). Increased serum levels of serotonin and anti-MBP auto-antibodies were found in 92% and 80%, respectively of autistic patients. Patients with severe autism had significantly higher serum serotonin levels than children with mild to moderate autism (P < 0.001). Serum serotonin levels had no significant correlations with serum levels of anti-MBP auto-antibodies in autistic patients (P = 0.39). CONCLUSIONS: Hyperserotonemia may not be one of the contributing factors to the increased frequency of serum anti-MBP auto-antibodies in some autistic children. These data should be treated with caution until further investigations are performed. However, inclusion of serum serotonin levels as a correlate may be useful in other future immune studies in autism to help unravel the long-standing mystery of hyperserotonemia and its possible role in the pathophysiology of this disorder. PMID- 21696609 TI - Polyunsaturated fatty acids in various macroalgal species from North Atlantic and tropical seas. AB - BACKGROUND: In this study the efficacy of using marine macroalgae as a source for polyunsaturated fatty acids, which are associated with the prevention of inflammation, cardiovascular diseases and mental disorders, was investigated. METHODS: The fatty acid (FA) composition in lipids from seven sea weed species from the North Sea (Ulva lactuca, Chondrus crispus, Laminaria hyperborea, Fucus serratus, Undaria pinnatifida, Palmaria palmata, Ascophyllum nodosum) and two from tropical seas (Caulerpa taxifolia, Sargassum natans) was determined using GCMS. Four independent replicates were taken from each seaweed species. RESULTS: Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs), were in the concentration range of 2-14 mg/g dry matter (DM), while total lipid content ranged from 7-45 mg/g DM. The n-9 FAs of the selected seaweeds accounted for 3% 56% of total FAs, n-6 FAs for 3%-32% and n-3 FAs for 8%-63%. Red and brown seaweeds contain arachidonic (C20:4, n-6) and/or eicosapentaenoic acids (EPA, C20:5, n-3), the latter being an important "fish" FA, as major PUFAs while in green seaweeds these values are low and mainly C16 FAs were found. A unique observation is the presence of another typical "fish" fatty acid, docosahexaenoic acid (DHA, C22:6, n-3) at ~ 1 mg/g DM in S. natans. The n-6: n-3 ratio is in the range of 0.05-2.75 and in most cases below 1.0. Environmental effects on lipid bound FA composition in seaweed species are discussed. CONCLUSION: Marine macroalgae form a good, durable and virtually inexhaustible source for polyunsaturated fatty acids with an (n-6) FA: (n-3) FA ratio of about 1.0. This ratio is recommended by the World Health Organization to be less than 10 in order to prevent inflammatory, cardiovascular and nervous system disorders. Some marine macroalgal species, like P. palmata, contain high proportions of the "fish fatty acid" eicosapentaenoic acid (EPA, C20:5, n-3), while in S. natans also docosahexaenoic acid (DHA, C22:6, n-3) was detected. PMID- 21696610 TI - Pneumonia and poverty: a prospective population-based study among children in Brazil. AB - BACKGROUND: Children in developing country suffer the highest burden of pneumonia. However, few studies have evaluated associations between poverty and pneumonia. METHODS: A prospective population-based study on pneumonia was carried out as part of the Latin America Epidemiological Assessment of Pneumococcus (LEAP study). Chest x-rays were obtained for children one to 35 months old with suspected pneumonia presenting to emergency care centers and hospital emergency rooms in Goiania, Brazil. Chest radiographs were evaluated according to WHO guidelines. Clustering of radiologically-confirmed pneumonia were evaluated using a Poisson-based spatial scan statistic. Associations between census socioeconomic indicators and pneumonia incidence rates were analyzed using generalized linear models. RESULTS: From May, 2007 to May, 2009, chest radiographs were obtained from 11 521 children with clinical pneumonia; 3955 episodes were classified as radiologically-confirmed. Incidence rates were significantly higher in very low income areas (4825.2 per 105) compared to high income areas (1637.3 per 105). Spatial analysis identified clustering of confirmed pneumonia in Western (RR 1.78; p=0.001) and Southeast (RR 1.46; p=0.001) regions of the city, and clustering of hospitalized pneumonia in the Western region (RR 1.69; p=0.001). Lower income households and illiteracy were associated with pneumonia incidence. CONCLUSIONS: In infants the risk of developing pneumonia is inversely associated with the head of household income and with the woman educational level. Areas with deprived socioeconomic conditions had higher incidence of pneumonia and should be targeted for high vaccination coverage. PMID- 21696611 TI - Stromal upregulation of lateral epithelial adhesions: gene expression analysis of signalling pathways in prostate epithelium. AB - BACKGROUND: Stromal signalling increases the lateral cell adhesions of prostate epithelial cells grown in 3D culture. The aim of this study was to use microarray analysis to identify significant epithelial signalling pathways and genes in this process. METHODS: Microarray analysis was used to identify genes that were differentially expressed when epithelial cells were grown in 3D Matrigel culture with stromal co-culture compared to without stroma. Two culture models were employed: primary epithelial cells (ten samples) and an epithelial cell line (three experiments). A separate microarray analysis was performed on each model system and then compared to identify tissue-relevant genes in a cell line model. RESULTS: TGF beta signalling was significantly ranked for both model systems and in both models the TGF beta signalling gene SOX4 was significantly down regulated. Analysis of all differentially expressed genes to identify genes that were common to both models found several morphology related gene clusters; actin binding (DIAPH2, FHOD3, ABLIM1, TMOD4, MYH10), GTPase activator activity (BCR, MYH10), cytoskeleton (MAP2, MYH10, TMOD4, FHOD3), protein binding (ITGA6, CD44), proteinaceous extracellular matrix (NID2, CILP2), ion channel/ ion transporter activity (CACNA1C, CACNB2, KCNH2, SLC8A1, SLC39A9) and genes associated with developmental pathways (POFUT1, FZD2, HOXA5, IRX2, FGF11, SOX4, SMARCC1). CONCLUSIONS: In 3D prostate cultures, stromal cells increase lateral epithelial cell adhesions. We show that this morphological effect is associated with gene expression changes to TGF beta signalling, cytoskeleton and anion activity. PMID- 21696612 TI - Impact of exposure measurement error in air pollution epidemiology: effect of error type in time-series studies. AB - BACKGROUND: Two distinctly different types of measurement error are Berkson and classical. Impacts of measurement error in epidemiologic studies of ambient air pollution are expected to depend on error type. We characterize measurement error due to instrument imprecision and spatial variability as multiplicative (i.e. additive on the log scale) and model it over a range of error types to assess impacts on risk ratio estimates both on a per measurement unit basis and on a per interquartile range (IQR) basis in a time-series study in Atlanta. METHODS: Daily measures of twelve ambient air pollutants were analyzed: NO2, NOx, O3, SO2, CO, PM10 mass, PM2.5 mass, and PM2.5 components sulfate, nitrate, ammonium, elemental carbon and organic carbon. Semivariogram analysis was applied to assess spatial variability. Error due to this spatial variability was added to a reference pollutant time-series on the log scale using Monte Carlo simulations. Each of these time-series was exponentiated and introduced to a Poisson generalized linear model of cardiovascular disease emergency department visits. RESULTS: Measurement error resulted in reduced statistical significance for the risk ratio estimates for all amounts (corresponding to different pollutants) and types of error. When modelled as classical-type error, risk ratios were attenuated, particularly for primary air pollutants, with average attenuation in risk ratios on a per unit of measurement basis ranging from 18% to 92% and on an IQR basis ranging from 18% to 86%. When modelled as Berkson-type error, risk ratios per unit of measurement were biased away from the null hypothesis by 2% to 31%, whereas risk ratios per IQR were attenuated (i.e. biased toward the null) by 5% to 34%. For CO modelled error amount, a range of error types were simulated and effects on risk ratio bias and significance were observed. CONCLUSIONS: For multiplicative error, both the amount and type of measurement error impact health effect estimates in air pollution epidemiology. By modelling instrument imprecision and spatial variability as different error types, we estimate direction and magnitude of the effects of error over a range of error types. PMID- 21696613 TI - Diagnostic utility of C-reactive protein combined with brain natriuretic peptide in acute pulmonary edema: a cross sectional study. AB - INTRODUCTION: Discriminating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) from cardiogenic pulmonary edema (CPE) using the plasma level of brain natriuretic peptide (BNP) alone remains controversial. The aim of this study was to determine the diagnostic utility of combination measurements of BNP and C-reactive protein (CRP) in critically ill patients with pulmonary edema. METHODS: This was a cross-sectional study. BNP and CRP data from 147 patients who presented to the emergency department due to acute respiratory failure with bilateral pulmonary infiltrates were analyzed. RESULTS: There were 53 patients with ALI/ARDS, 71 with CPE, and 23 with mixed edema. Median BNP and CRP levels were 202 (interquartile range 95-439) pg/mL and 119 (62-165) mg/L in ALI/ARDS, and 691 (416-1,194) pg/mL (p < 0.001) and 8 (2-42) mg/L (p < 0.001) in CPE. BNP or CRP alone offered good discriminatory performance (C-statistics 0.831 and 0.887), but the combination offered greater one [C-statistics 0.931 (p < 0.001 versus BNP) (p = 0.030 versus CRP)]. In multiple logistic-regression, BNP and CRP were independent predictors for the diagnosis after adjusting for other variables. CONCLUSIONS: Measurement of CRP is useful as well as that of BNP for distinguishing ALI/ARDS from CPE. Furthermore, a combination of BNP and CRP can provide higher accuracy for the diagnosis. PMID- 21696614 TI - Road traffic accidents and posttraumatic stress disorder in an orthopedic setting in South-Eastern Nigeria: a controlled study. AB - BACKGROUND: Psychiatric liaison services are rare in trauma units of various hospitals in Nigeria and other sub-Saharan African countries. The occurrence of road traffic accidents (RTAs) resulting from low standard of road construction and inadequate maintenance have been on the increase in Nigeria. While the physical consequences of such RTAs are obvious, the psychological consequences are often not apparent. This study assessed the prevalence of posttraumatic stress disorder (PTSD) among victims of RTAs and compared same with controls drawn from a population who have not experienced RTAs. It also assessed the associated socio-demographic variables. METHOD: Study population consisted of one hundred and fifty RTA victims and two different control groups drawn from the population consisting of staffs of Federal Neuropsychiatric Hospital, Enugu, Nigeria and that of National Orthopedic Hospital, Enugu, Nigeria, 150 people in each control group were matched for age and sex with the RTA victims and they were interviewed with PTSD module of Mini International Neuropsychiatric Interview (MINI) and their socio-demographic variables obtained with socio demographic questionnaire. RESULTS: The prevalence of PTSD among RTA victims and the two control groups were 26.7%, 8.0% and 8.7% respectively. The difference in prevalence was statistically significant with RTA victims more likely to experience PTSD compared to the two control groups (X2 = 27.23, df = 2, p = 0.001). Gender influenced the prevalence of PTSD among victims of RTAs and the controls, with females more likely to experience PTSD when compared to the males. Among victims of RTAs, being gainfully employed prior to the accidents increased the likelihood of developing PTSD and this was statistically significant (X2 = 20.09, df = 1, p = 0.000). CONCLUSIONS: There is urgent need to pay more attention to developing consultation-liaison psychiatry services in trauma units of Nigerian hospitals, including orthopedic hospitals located in different geographical zones of the country. PMID- 21696615 TI - Individually integrated traditional Chinese medicine approach in the management of knee osteoarthritis: study protocol for a randomized controlled trial. AB - BACKGROUND: Knee osteoarthritis (OA) is considered a major public health issue causing chronic disability worldwide with the increasing number of aging people. In China and increasingly worldwide, many sufferers with knee OA are using complementary and alternative medicine including herbal drug, herbal patch, acupuncture and Tuina etc., to alleviate their symptoms. However, evidence gathered from systematic reviews or randomized controlled trials (RCT) has only validated acupuncture for the management of osteoarthritic pain. Moreover, such Traditional Chinese Medicine (TCM) methods above are commonly used in an integrative way. This trial is aimed to compare the efficacy of an individually integrated TCM approach in the management of knee OA with other single treatments as parallel randomized controls. METHODS/DESIGN: Five teaching hospitals will participate in this randomized controlled trial. 500 participants, 100 in each hospital, will be randomly assigned to receive oral administration of a Chinese herbal drug (counter osteophytes capsule), topical use of a Chinese herbal patch (Fufnag Zijin patch), acupuncture, Tuina and the individually integrated TCM approach. The individually integrated TCM approach consists of basic treatment of oral counter osteophytes capsule, variable use of Tuina, acupuncture and a herbal patch based on the severity of the patient's symptoms. The interventions are given for a period of 4 weeks. The primary outcome measure is the self-reported total score using the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcome measures include patient and investigator global assessment of response to treatment, patient and investigator global assessment of OA condition, WOMAC pain, stiffness, and physical function subscales, short form 36 (SF-36) and TCM assessment of OA condition measured by syndromes questionnaire. Mixed models and sensitivity analysis will be used for the statistical analysis. DISCUSSION: The trial is designed to test the hypothesis that an individually integrated TCM approach is more effective than four treatment modalities used separately. The major limitation of this study is lack of placebo control and of double blinding. TRIAL REGISTRATION: Chinese Cochrane Center ChiCTR-TRC-00000176. PMID- 21696616 TI - Identification of a truncated form of Methionine Sulfoxide Reductase A expressed in mouse embryonic stem cells. AB - BACKGROUND: Methionine Sulfoxide Reductase A (MsrA), an enzyme in the Msr gene family, is important in the cellular anti-oxidative stress defense mechanism. It acts by reducing the oxidized methionine sulfoxide in proteins back to sulfide and by reducing the cellular level of reactive oxygen species. MsrA, the only enzyme in the Msr gene family that can reduce the S-form epimers of methionine sulfoxide, has been located in different cellular compartments including mitochondria, cytosol and nuclei of various cell lines. METHODS: In the present study, we have isolated a truncated form of the MsrA transcript from cultured mouse embryonic stem cells and performed eGFP fusion protein expression, confocal microscopy and real time RT-PCR studies. RESULTS: Results show a different expression response of this truncated transcript to oxygen deprivation and reoxygenation treatments in stem cells, compared to the longer full length form. In addition, a different subcellular localization pattern was noted with most of the eGFP fusion protein detected in the cytosol. CONCLUSION: One possibility for the existence of a truncated form of the MsrA transcripts could be that with a smaller protein size, yet retaining a GCWFG action site, this protein might have easier access to oxidize methionine residues on proteins than the longer form of the MsrA protein, thus having an evolutionary selection advantage. This research opens the door for further study on the role and function of the truncated MsrA embryonic mouse stem cells. PMID- 21696617 TI - Pathological features of Breast Cancer seen in Northwestern Tanzania: a nine years retrospective study. AB - BACKGROUND: Breast cancer is more common in Western Countries compared to African populations. However in African population, it appears that the disease tends to be more aggressive and occurring at a relatively young age at the time of presentation. The aim of this study was to describe the trend of Breast Cancer in Northwestern Tanzania. METHODS: This was a retrospective study which involved all cases of breast cancer diagnosed histologically at Bugando Medical Center from 2002 to 2010. Histological results and slides were retrieved from the records in the Pathology department, clinical information and demographic data for patients were retrieved from surgical wards and department of medical records. Histology slides were re-evaluated for the histological type, grade (By modified Bloom Richardson score), and presence of necrosis and skin involvement. Data was entered and analyzed by SPSS computer software version 15. FINDINGS: There were 328 patients histologically confirmed to have breast cancer, the mean age at diagnosis was 48.7 years (+/- 13.1). About half of the patients (52.4%) were below 46 years of age, and this group of patients had significantly higher tendency for lymph node metastasis (p = 0.012). The tumor size ranged from 1 cm to 18 cm in diameter with average (mean) of 5.5 cm (+/- 2.5), and median size of 6 cm. Size of the tumor (above 6 cm in diameter) and presence of necrosis within the tumor was significantly associated with high rate of lymph node metastasis (p = 0.000). Of all patients, 64% were at clinical stage III (specifically IIIB) and 70.4% had lymph node metastasis at the time of diagnosis. Only 4.3% of the patients were in clinical stage I at the time of diagnosis. Majority of the patients had invasive ductal carcinoma (91.5%) followed by mucinous carcinoma (5.2%), Invasive lobular carcinoma (3%) and in situ ductal carcinoma (0.3%). In all patients, 185 (56.4%) had tumor with histological grade 3. CONCLUSION: Breast cancer in this region show a trend towards relative young age at diagnosis with advanced stage at diagnosis and high rate of lymph node metastasis. Poor Referral system, lack of screening programs and natural aggressive biological behavior of tumor may contribute to advanced disease at the time of diagnosis. PMID- 21696618 TI - Oestrogen deficiency modulates particle-induced osteolysis. AB - INTRODUCTION: Postmenopausal osteoporosis may modulate bone response to wear debris. In this article, we evaluate the influence of oestrogen deficiency on experimental particle-induced osteolysis. METHODS: Polyethylene (PE) particles were implanted onto the calvaria of normal controls, sham-ovariectomized (OVX), OVX mice and OVX mice supplemented with oestrogen (OVX+E). After 14 days, seven skulls per group were analyzed using a high-resolution micro-computed tomography (micro-CT) and histomorphometry, and for tartrate-specific alkaline phosphatase. Five calvariae per group were cultured for the assay of IL-1beta, IL-6, TNF-alpha and receptor activator of the nuclear factor kappaB (RANKL) secretion using quantitative ELISA. Serum IL-6 concentrations were obtained. The expression of RANKL and osteoprotegerin (OPG) mRNA were evaluated using real-time PCR. RESULTS: As assessed by MUCT and by histomorphometry, PE particles induced extensive bone resorption and an intense inflammatory reaction in normal controls, sham-OVX and OVX+E mice, but not in the OVX mice group. In normal controls, sham-OVX and OVX+E mice, PE particles induced an increase in serum IL-6, in TNF-alpha and RANKL local concentrations, and resulted in a significant increase in RANKL/OPG messenger RNA (mRNA) ratio. Conversely, these parameters remained unchanged in OVX mice after PE implantation. CONCLUSIONS: Oestrogen privation in the osteolysis murine model ultimately attenuated osteolytic response to PE particles, suggesting a protective effect. This paradoxical phenomenon was associated with a down-regulation of pro-resorptive cytokines. It is hypothesized that excessive inflammatory response was controlled, illustrated by the absence of increase of serum IL-6 in OVX mice after PE implantation. PMID- 21696619 TI - Does prolonged beta-lactam infusions improve clinical outcomes compared to intermittent infusions? A meta-analysis and systematic review of randomized, controlled trials. AB - BACKGROUND: The emergence of multi-drug resistant Gram-negatives (MDRGNs) coupled with an alarming scarcity of new antibiotics has forced the optimization of the therapeutic potential of available antibiotics. To exploit the time above the minimum inhibitory concentration mechanism of beta-lactams, prolonging their infusion may improve outcomes. The primary objective of this meta-analysis was to determine if prolonged beta-lactam infusion resulted in decreased mortality and improved clinical cure compared to intermittent beta-lactam infusion. METHODS: Relevant studies were identified from searches of MEDLINE, EMBASE, and CENTRAL. Heterogeneity was assessed qualitatively, in addition to I2 and Chi-square statistics. Pooled relative risks (RR) and 95% confidence intervals (CI) were calculated using Mantel-Haenszel random-effects models. RESULTS: Fourteen randomized controlled trials (RCTs) were included. Prolonged infusion beta lactams were not associated with decreased mortality (n=982; RR 0.92; 95% CI:0.61 1.37) or clinical cure (n=1380; RR 1.00 95% CI:0.94-1.06) compared to intermittent infusions. Subgroup analysis for beta-lactam subclasses and equivalent total daily beta-lactam doses yielded similar results. Most studies had notable methodological flaws. CONCLUSIONS: No clinical advantage was observed for prolonged infusion beta-lactams. The limited number of studies with MDRGNs precluded evaluation of prolonged infusion of beta-lactams for this subgroup. A large, multicenter RCT with critically ill patients infected with MDRGNs is needed. PMID- 21696620 TI - Correlation between endothelial function and carotid atherosclerosis in rheumatoid arthritis patients with long-standing disease. AB - INTRODUCTION: In this study, we aimed to determine the relationship between flow mediated endothelium-dependent vasodilatation (FMD) and carotid artery intima media wall thickness (IMT), two surrogate markers of atherosclerosis, in a series of Spanish patients with rheumatoid arthritis (RA) without clinically evident cardiovascular (CV) disease. METHODS: One hundred eighteen patients who fulfilled the 1987 American College of Rheumatology classification criteria for RA, had no history of CV disease and had at least one year of follow-up after disease diagnosis were randomly selected. Brachial and carotid ultrasonography were performed to determine FMD and carotid IMT, respectively. RESULTS: Carotid IMT values were higher and FMD percentages derived by performing ultrasonography were lower in individuals with a long duration from the time of disease diagnosis. Patients with a disease duration <= 7 years had significantly lower carotid IMT (mean +/- SD) 0.69 +/- 0.17 mm than those with long disease duration (0.81 +/- 0.12 mm in patients with >= 20 years of follow-up). Also, patients with a long disease duration had severe endothelial dysfunction (FMD 4.0 +/- 4.0% in patients with disease duration from 14.5 to 19.7 years) compared with those with shorter disease duration (FMD 7.4 +/- 3.8% in patients with disease duration <= 7 years). Linear regression analysis revealed that carotid IMT was unrelated to FMD in the whole sample of 118 patients. However, carotid IMT was negatively associated with FMD when the time from disease diagnosis ranged from 7.5 to 19.7 years (P = 0.02). CONCLUSIONS: In patients with RA without CV disease, endothelial dysfunction and carotid IMT increased with the duration of RA. The association between FMD and carotid IMT values was observed only in patients with long disease duration. PMID- 21696621 TI - Alternative health care consultations in Ontario, Canada: A geographic and socio demographic analysis. AB - BACKGROUND: An important but understudied component of Canada's health system is alternative care. The objective of this paper is to examine the geographic and socio-demographic characteristics of alternative care consultation in Ontario, Canada's largest province. METHODS: Data is drawn from the Canadian Community Health Survey (CCHS Cycle 3.1, 2005) for people aged 18 or over (n = 32,598) who had a consultation with an alternative health care provider. Four groups of consultations are examined: (1) all consultations (2) massage therapy (3) acupuncture, and (4) homeopath/naturopath. Descriptive statistics, mapping and logistic regression modeling are employed to analyze the data and to compare modalities of alternative health care use. RESULTS: In 2005, more than 1.2 million adults aged 18 or over consulted an alternative health care provider, representing about 13% of the total population of Ontario. The analysis revealed a varied geographic pattern of consultations across the province. Consultations were fairly even across the urban to rural continuum and rural residents were just as likely to consult a provider as their urban counterparts. From a health perspective, people with a chronic condition, lower health status and self perceived unmet health care needs were more likely to see an alternative health provider. Women with chronic conditions such as fibromyalgia, high blood pressure, chronic fatigue syndrome and chemical sensitivities were more likely to see an alternative provider if they felt their health care needs were not being met. CONCLUSIONS: The analysis revealed that geography is not a factor in determining alternative health care consultations in Ontario. By contrast, there is a strong association between these consultations and socio-demographic characteristics particularly age, sex, education, health and self-perceived unmet health care needs. The results underscore the importance of women's health needs as related to alternative care use. The paper concludes that there is a need for more place-specific research that explores the reasons why people use specific types of alternative health care as tied to socio-economic status, health, place of residence, and knowledge of these treatments. PMID- 21696622 TI - Relationship between care-givers' misconceptions and non-use of ITNs by under five Nigerian children. AB - BACKGROUND: Malaria has been a major public health problem in Nigeria and many other sub-Saharan African countries. Insecticide-treated nets have shown to be cost-effective in the prevention of malaria, but the number of people that actually use these nets has remained generally low. Studies that explore the determinants of use of ITN are desirable. METHODS: Structured questionnaires based on thematic areas were administered by trained interviewers to 7,223 care givers of under-five children selected from all the six geo-political zones of Nigeria. Bivariate analysis and multinomial logit model were used to identify possible determinants of use of ITN. RESULTS: Bivariate analysis showed that under-five children whose care-givers had some misconceptions about causes and prevention of malaria were significantly less likely to use ITN even though the household may own a net (p < 0.0001). Education and correct knowledge about modes of prevention of malaria, knowing that malaria is dangerous and malaria can kill were also significantly associated with use of ITN (p < 0.0001). Knowledge of symptoms of malaria did not influence use of ITN. Association of non-use of ITN with misconceptions about prevention of malaria persisted with logistic regression (Odds ratio 0.847; 95% CI 0.747 to 0.960). CONCLUSIONS: Misconceptions about causes and prevention of malaria by caregivers adversely influence the use ITN by under-five children. Appropriate communication strategies should correct these misconceptions. PMID- 21696623 TI - Review and application of group theory to molecular systems biology. AB - In this paper we provide a review of selected mathematical ideas that can help us better understand the boundary between living and non-living systems. We focus on group theory and abstract algebra applied to molecular systems biology. Throughout this paper we briefly describe possible open problems. In connection with the genetic code we propose that it may be possible to use perturbation theory to explore the adjacent possibilities in the 64-dimensional space-time manifold of the evolving genome. With regards to algebraic graph theory, there are several minor open problems we discuss. In relation to network dynamics and groupoid formalism we suggest that the network graph might not be the main focus for understanding the phenotype but rather the phase space of the network dynamics. We show a simple case of a C6 network and its phase space network. We envision that the molecular network of a cell is actually a complex network of hypercycles and feedback circuits that could be better represented in a higher dimensional space. We conjecture that targeting nodes in the molecular network that have key roles in the phase space, as revealed by analysis of the automorphism decomposition, might be a better way to drug discovery and treatment of cancer. PMID- 21696624 TI - Reconstruction of the acetabulum in THA using femoral head autografts in developmental dysplasia of the hip. AB - BACKGROUND: Severe acetabular deficiencies in cases of developmental dysplasia of the hip (DDH) often require complex reconstructive procedures in total hip arthroplasty (THA). The use of autologous femoral head grafts for acetabular reconstruction has been described, but few data is available about clinical results, the rates of non-union or aseptic loosening of acetabular components. METHODS: In a retrospective approach, 101 patients with 118 THA requiring autologous femoral head grafts to the acetabulum because of DDH were included. Six patients had died, another 6 were lost to follow-up, and 104 hips were available for clinical and radiological evaluation at a mean of 68 +/- 15 (13 to 159) months. RESULTS: The average Merle d'Aubigne hip score improved from 9 to 16 points. Seven implants had to be revised due to aseptic loosening (6.7%). The revisions were performed 90 +/- 34 (56 to 159) months after implantation. The other hips showed a stable position of the sockets without any signs of bony non union, severe radiolucencies at the implant-graft interface or significant resorption of the graft. CONCLUSION: The use of autologous femoral head grafts with cementless cups in primary THA can achieve promising short- to midterm results in patients with dysplastic hips. PMID- 21696625 TI - Health and human rights of women imprisoned in Zambia. AB - BACKGROUND: The healthcare needs and general experience of women in detention in sub-Saharan Africa are rarely studied and poorly understood. METHODS: A mixed methods study was conducted including in-depth interviews with 38 adult female prisoners and 21 prison officers in four Zambian prisons to assess the health and human rights concerns of female detainees. Key informant interviews with 46 officials from government and non-governmental organizations and a legal and policy review were also conducted. RESULTS: Despite special protection under international and regional law, incarcerated women's health needs-including prenatal care, prevention of mother-to-child transmission of HIV, and nutritional support during pregnancy and breastfeeding-are not being adequately met in Zambian prisons. Women are underserved by general healthcare programs including those offering tuberculosis and HIV testing, and reported physical and sexual abuse conducted by police and prison officers that could amount to torture under international law. CONCLUSIONS: There is an urgent need for women's healthcare services to be expanded, and for general prison health campaigns, including HIV and tuberculosis testing and treatment, to ensure the inclusion of female inmates. Abuses against women in Zambian police and prison custody, which violate their rights and compromise their health, must be halted immediately. PMID- 21696626 TI - Failure of fixation of trochanteric femur fractures: Clinical recommendations for avoiding Z-effect and reverse Z-effect type complications. AB - BACKGROUND: Z-effect and reverse Z-effect are complications that arise from the surgical treatment of pertrochanteric fractures of the femur with proximal femoral nails (PFN) comprising two interlocking head screws. Such complications are induced by the migration of screws in opposite directions, which may lead to failure of the osteosynthesis. FINDINGS: The paper describes three cases of pertrochanteric fractures that were treated with PFN with two interlocking screws that evolved to either Z-effect or reverse Z-effect. Literature-based explanations for this phenomenon are provided together with recommendations of how to avoid such complications. CONCLUSIONS: Although intramedullary fixation is an established method of treatment of femoral intertrochanteric and subtrochanteric fractures, the evolution of the procedure may include complications associated with the migration of the interlocking head screws. The occurrence of Z-effect and reverse Z-effect has not been completely elucidated, but the main causes of such complications are probably fracture fixation in varus position, severe medial comminution, inappropriate entry point of the nail and poor bone quality. PMID- 21696627 TI - A question of choice. AB - Women's reproductive rights, reproductive health, and constitutional privacy rights in the United States are addressed in light of the contemporary onslaught of the Christian Right. The misuse of State power by fundamentalist social forces in America is critiqued. The article also briefly reviews the question of State control over women's bodies. PMID- 21696628 TI - Physiologic and molecular consequences of endothelial Bmpr2 mutation. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is thought to be driven by dysfunction of pulmonary vascular microendothelial cells (PMVEC). Most hereditary PAH is associated with BMPR2 mutations. However, the physiologic and molecular consequences of expression of BMPR2 mutations in PMVEC are unknown. METHODS: In vivo experiments were performed on adult mice with conditional endothelial specific expression of the truncation mutation Bmpr2delx4+, with age-matched transactivator-only mice as controls. Phenotype was assessed by RVSP, counts of muscularized vessels and proliferating cells, and staining for thromboses, inflammatory cells, and apoptotic cells. The effects of BMPR2 knockdown in PMVEC by siRNA on rates of apoptosis were assessed. Affymetrix expression arrays were performed on PMVEC isolated and cultured from triple transgenic mice carrying the immortomouse gene, a transactivator, and either control, Bmpr2delx4+ or Bmpr2R899X mutation. RESULTS: Transgenic mice showed increased RVSP and corresponding muscularization of small vessels, with histologic alterations including thrombosis, increased inflammatory cells, increased proliferating cells, and a moderate increase in apoptotic cells. Expression arrays showed alterations in specific pathways consistent with the histologic changes. Bmpr2delx4+ and Bmpr2R899X mutations resulted in very similar alterations in proliferation, apoptosis, metabolism, and adhesion; Bmpr2delx4+ cells showed upregulation of platelet adhesion genes and cytokines not seen in Bmpr2R899X PMVEC. Bmpr2 mutation in PMVEC does not cause a loss of differentiation markers as was seen with Bmpr2 mutation in smooth muscle cells. CONCLUSIONS: Bmpr2 mutation in PMVEC in vivo may drive PAH through multiple, potentially independent, downstream mechanisms, including proliferation, apoptosis, inflammation, and thrombosis. PMID- 21696629 TI - Efficacy of integrated school based de-worming and prompt malaria treatment on helminths -Plasmodium falciparum co-infections: A 33 months follow up study. AB - BACKGROUND: The geographical congruency in distribution of helminths and Plasmodium falciparum makes polyparasitism a common phenomenon in Sub Saharan Africa. The devastating effects of helminths-Plasmodium co-infections on primary school health have raised global interest for integrated control. However little is known on the feasibility, timing and efficacy of integrated helminths Plasmodium control strategies. A study was conducted in Zimbabwe to evaluate the efficacy of repeated combined school based antihelminthic and prompt malaria treatment. METHODS: A cohort of primary schoolchildren (5-17 years) received combined Praziquantel, albendazole treatment at baseline, and again during 6, 12 and 33 months follow up surveys and sustained prompt malaria treatment. Sustained prompt malaria treatment was carried out throughout the study period. Children's infection status with helminths, Plasmodium and helminths-Plasmodium co infections was determined by parasitological examinations at baseline and at each treatment point. The prevalence of S. haematobium, S. mansoni, STH, malaria, helminths-Plasmodium co-infections and helminths infection intensities before and after treatment were analysed. RESULTS: Longitudinal data showed that two rounds of combined Praziquantel and albendazole treatment for schistosomiasis and STHs at 6 monthly intervals and sustained prompt malaria treatment significantly reduced the overall prevalence of S. haematobium, S. mansoni, hookworms and P. falciparum infection in primary schoolchildren by 73.5%, 70.8%, 67.3% and 58.8% respectively (p < 0.001, p < 0.001, p < 0.001, p < 0.001 respectively). More importantly, the prevalence of STH + schistosomes, P. f + schistosomes, and P. f + STHs + schistosomes co-infections were reduced by 68.0%, 84.2%, and 90.7%, respectively. The absence of anti-helminthic treatment between the 12 mth and 33 mth follow-up surveys resulted in the sharp increase in STHs + schistosomes co infection from 3.3% at 12 months follow up survey to 10.7%, slightly more than the baseline level (10.3%) while other co-infection combinations remained significantly low. The overall prevalence of heavy S. haematobium, S. mansoni and hookworms infection intensities were significantly reduced from: 17.9-22.4% to 2.6-5.1%, 1.6-3.3% to 0.0% and 0.0-0.7% to 0.0% respectively. CONCLUSION: Biannual Integrated school based antihelminthic and sustained prompt malaria treatment has a potential to reduce the burden of helminths-plasmodium co infections in primary school children. In areas of stable malaria transmission, active case finding is recommended to track and treat asymptomatic malaria cases as these may sustain transmission in the community. PMID- 21696630 TI - Protein kinase D1 (PKD1) activation mediates a compensatory protective response during early stages of oxidative stress-induced neuronal degeneration. AB - BACKGROUND: Oxidative stress is a key pathophysiological mechanism contributing to degenerative processes in many neurodegenerative diseases and therefore, unraveling molecular mechanisms underlying various stages of oxidative neuronal damage is critical to better understanding the diseases and developing new treatment modalities. We previously showed that protein kinase C delta (PKCdelta) proteolytic activation during the late stages of oxidative stress is a key proapoptotic signaling mechanism that contributes to oxidative damage in Parkinson's disease (PD) models. The time course studies revealed that PKCdelta activation precedes apoptotic cell death and that cells resisted early insults of oxidative damage, suggesting that some intrinsic compensatory response protects neurons from early oxidative insult. Therefore, the purpose of the present study was to characterize protective signaling pathways in dopaminergic neurons during early stages of oxidative stress. RESULTS: Herein, we identify that protein kinase D1 (PKD1) functions as a key anti-apoptotic kinase to protect neuronal cells against early stages of oxidative stress. Exposure of dopaminergic neuronal cells to H2O2 or 6-OHDA induced PKD1 activation loop (PKD1S744/748) phosphorylation long before induction of neuronal cell death. Blockade of PKCdelta cleavage, PKCdelta knockdown or overexpression of a cleavage-resistant PKCdelta mutant effectively attenuated PKD1 activation, indicating that PKCdelta proteolytic activation regulates PKD1 phosphorylation. Furthermore, the PKCdelta catalytic fragment, but not the regulatory fragment, increased PKD1 activation, confirming PKCdelta activity modulates PKD1 activation. We also identified that phosphorylation of S916 at the C-terminal is a preceding event required for PKD1 activation loop phosphorylation. Importantly, negative modulation of PKD1 by the RNAi knockdown or overexpression of PKD1S916A phospho-defective mutants augmented oxidative stress-induced apoptosis, while positive modulation of PKD1 by the overexpression of full length PKD1 or constitutively active PKD1 plasmids attenuated oxidative stress-induced apoptosis, suggesting an anti-apoptotic role for PKD1 during oxidative neuronal injury. CONCLUSION: Collectively, our results demonstrate that PKCdelta-dependent activation of PKD1 represents a novel intrinsic protective response in counteracting early stage oxidative damage in neuronal cells. Our results suggest that positive modulation of the PKD1-mediated compensatory protective mechanism against oxidative damage in dopaminergic neurons may provide novel neuroprotective strategies for treatment of PD. PMID- 21696631 TI - Sodium arsenite and hyperthermia modulate cisplatin-DNA damage responses and enhance platinum accumulation in murine metastatic ovarian cancer xenograft after hyperthermic intraperitoneal chemotherapy (HIPEC). AB - BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the USA. Recurrence rates are high after front-line therapy and most patients eventually die from platinum (Pt) - resistant disease. Cisplatin resistance is associated with increased nucleotide excision repair (NER), decreased mismatch repair (MMR) and decreased platinum uptake. The objective of this study is to investigate how a novel combination of sodium arsenite (NaAsO2) and hyperthermia (43 degrees C) affect mechanisms of cisplatin resistance in ovarian cancer. METHODS: We established a murine model of metastatic EOC by intraperitoneal injection of A2780/CP70 human ovarian cancer cells into nude mice. We developed a murine hyperthermic intraperitoneal chemotherapy model to treat the mice. Mice with peritoneal metastasis were perfused for 1 h with 3 mg/kg cisplatin +/- 26 mg/kg NaAsO2 at 37 or 43 degrees C. Tumors and tissues were collected at 0 and 24 h after treatment. RESULTS: Western blot analysis of p53 and key NER proteins (ERCC1, XPC and XPA) and MMR protein (MSH2) suggested that cisplatin induced p53, XPC and XPA and suppressed MSH2 consistent with resistant phenotype. Hyperthermia suppressed cisplatin-induced XPC and prevented the induction of XPA by cisplatin, but it had no effect on Pt uptake or retention in tumors. NaAsO2 prevented XPC induction by cisplatin; it maintained higher levels of MSH2 in tumors and enhanced initial accumulation of Pt in tumors. Combined NaAsO2 and hyperthermia decreased cisplatin-induced XPC 24 h after perfusion, maintained higher levels of MSH2 in tumors and significantly increased initial accumulation of Pt in tumors. ERCC1 levels were generally low except for NaAsO2 co-treatment with cisplatin. Systemic Pt and arsenic accumulation for all treatment conditions were in the order: kidney > liver = spleen > heart > brain and liver > kidney = spleen > heart > brain respectively. Metal levels generally decreased in systemic tissues within 24 h after treatment. CONCLUSION: NaAsO2 and/or hyperthermia have the potential to sensitize tumors to cisplatin by inhibiting NER, maintaining functional MMR and enhancing tumor platinum uptake. PMID- 21696632 TI - Temporal trends in serum concentrations of polychlorinated dioxins, furans, and PCBs among adult women living in Chapaevsk, Russia: a longitudinal study from 2000 to 2009. AB - BACKGROUND: The present study assessed the temporal trend in serum concentrations of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls (PCBs) among residents of a Russian town where levels of these chemicals are elevated due to prior industrial activity. METHODS: Two serum samples were collected from eight adult women (in 2000 and 2009), and analyzed with gas chromatography-high resolution mass spectrometry. RESULTS: The average total toxic equivalency (TEQ) decreased by 30% (from 36 to 25 pg/g lipid), and the average sum of PCB congeners decreased by 19% (from 291 to 211 ng/g lipid). Total TEQs decreased for seven of the eight women, and the sum of PCBs decreased for six of eight women. During this nine year period, larger decreases in serum TEQs and PCBs were found in women with greater increases in body mass index. CONCLUSIONS: This study provides suggestive evidence that average serum concentrations of dioxins, furans, and PCBs are decreasing over time among residents of this town. PMID- 21696633 TI - Visceral adiposity, insulin resistance and cancer risk. AB - BACKGROUND: There is a well established link between obesity and cancer. Emerging research is characterising this relationship further and delineating the specific role of excess visceral adiposity, as opposed to simple obesity, in promoting tumorigenesis. This review summarises the evidence from an epidemiological and pathophysiological perspective. METHODS: Relevant medical literature was identified from searches of PubMed and references cited in appropriate articles identified. Selection of articles was based on peer review, journal and relevance. RESULTS: Numerous epidemiological studies consistently identify increased risk of developing carcinoma in the obese. Adipose tissue, particularly viscerally located fat, is metabolically active and exerts systemic endocrine effects. Putative pathophysiological mechanisms linking obesity and carcinogenesis include the paracrine effects of adipose tissue and systemic alterations associated with obesity. Systemic changes in the obese state include chronic inflammation and alterations in adipokines and sex steroids. Insulin and the insulin-like growth factor axis influence tumorigenesis and also have a complex relationship with adiposity. There is evidence to suggest that insulin and the IGF axis play an important role in mediating obesity associated malignancy. CONCLUSIONS: There is much evidence to support a role for obesity in cancer progression, however further research is warranted to determine the specific effect of excess visceral adipose tissue on tumorigenesis. Investigation of the potential mechanisms underpinning the association, including the role of insulin and the IGF axis, will improve understanding of the obesity and cancer link and may uncover targets for intervention. PMID- 21696634 TI - Proteomic patterns of cervical cancer cell lines, a network perspective. AB - BACKGROUND: Cervical cancer is a major mortality factor in the female population. This neoplastic is an excellent model for studying the mechanisms involved in cancer maintenance, because the Human Papilloma Virus (HPV) is the etiology factor in most cases. With the purpose of characterizing the effects of malignant transformation in cellular activity, proteomic studies constitute a reliable way to monitor the biological alterations induced by this disease. In this contextual scheme, a systemic description that enables the identification of the common events between cell lines of different origins, is required to distinguish the essence of carcinogenesis. RESULTS: With this study, we sought to achieve a systemic perspective of the common proteomic profile of six cervical cancer cell lines, both positive and negative for HPV, and which differ from the profile corresponding to the non-tumourgenic cell line, HaCaT. Our objectives were to identify common cellular events participating in cancer maintenance, as well as the establishment of a pipeline to work with proteomic-derived results. We analyzed by means of 2D SDS-PAGE and MALDI-TOF mass spectrometry the protein extracts of six cervical cancer cell lines, from which we identified a consensus of 66 proteins. We call this group of proteins, the "central core of cervical cancer". Starting from this core set of proteins, we acquired a PPI network that pointed, through topological analysis, to some proteins that may well be playing a central role in the neoplastic process, such as 14-3-3zeta. In silico overrepresentation analysis of transcription factors pointed to the overexpression of c-Myc, Max and E2F1 as key transcription factors involved in orchestrating the neoplastic phenotype. CONCLUSIONS: Our findings show that there is a "central core of cervical cancer" protein expression pattern, and suggest that 14-3-3zeta is key to determine if the cell proliferates or dies. In addition, our bioinformatics analysis suggests that the neoplastic phenotype is governed by a non-canonical regulatory pathway. PMID- 21696635 TI - The mothers, Omega-3 and mental health study. AB - BACKGROUND: Major depressive disorder (MDD) during pregnancy and postpartum depression are associated with significant maternal and neonatal morbidity. While antidepressants are readily used in pregnancy, studies have raised concerns regarding neurobehavioral outcomes in exposed infants. Omega-3 fatty acid supplementation, most frequently from fish oil, has emerged as a possible treatment or prevention strategy for MDD in non-pregnant individuals, and may have beneficial effects in pregnant women. Although published observational studies in the psychiatric literature suggest that maternal docosahexaenoic acid (DHA) deficiency may lead to the development of MDD in pregnancy and postpartum, there are more intervention trials suggesting clinical benefit for supplementation with eicosapentaenoic acid (EPA) in MDD. METHODS/DESIGN: The Mothers, Omega-3 and Mental Health study is a double blind, placebo-controlled, randomized controlled trial to assess whether omega-3 fatty acid supplementation may prevent antenatal and postpartum depressive symptoms among pregnant women at risk for depression. We plan to recruit 126 pregnant women at less than 20 weeks gestation from prenatal clinics at two health systems in Ann Arbor, Michigan and the surrounding communities. We will follow them prospectively over the course of their pregnancies and up to 6 weeks postpartum. Enrolled participants will be randomized to one of three groups: a) EPA-rich fish oil supplement (1060 mg EPA plus 274 mg DHA) b) DHA-rich fish oil supplement (900 mg DHA plus 180 mg EPA; or c) a placebo. The primary outcome for this study is the Beck Depression Inventory (BDI) score at 6 weeks postpartum. We will need to randomize 126 women to have 80% power to detect a 50% reduction in participants' mean BDI scores with EPA or DHA supplementation compared with placebo. We will also gather information on secondary outcome measures which will include: omega-3 fatty acid concentrations in maternal plasma and cord blood, pro-inflammatory cytokine levels (IL-1beta, IL 6, and TNF-alpha) in maternal and cord blood, need for and dosage of antidepressant medications, and obstetrical outcomes. Analyses will be by intent to treat. DISCUSSION: This study compares the relative effectiveness of DHA and EPA at preventing depressive symptoms among pregnant women at risk. TRIAL REGISTRATION: CLINICAL TRIAL REGISTRATION NUMBER: NCT00711971. PMID- 21696636 TI - The re-identification risk of Canadians from longitudinal demographics. AB - BACKGROUND: The public is less willing to allow their personal health information to be disclosed for research purposes if they do not trust researchers and how researchers manage their data. However, the public is more comfortable with their data being used for research if the risk of re-identification is low. There are few studies on the risk of re-identification of Canadians from their basic demographics, and no studies on their risk from their longitudinal data. Our objective was to estimate the risk of re-identification from the basic cross sectional and longitudinal demographics of Canadians. METHODS: Uniqueness is a common measure of re-identification risk. Demographic data on a 25% random sample of the population of Montreal were analyzed to estimate population uniqueness on postal code, date of birth, and gender as well as their generalizations, for periods ranging from 1 year to 11 years. RESULTS: Almost 98% of the population was unique on full postal code, date of birth and gender: these three variables are effectively a unique identifier for Montrealers. Uniqueness increased for longitudinal data. Considerable generalization was required to reach acceptably low uniqueness levels, especially for longitudinal data. Detailed guidelines and disclosure policies on how to ensure that the re-identification risk is low are provided. CONCLUSIONS: A large percentage of Montreal residents are unique on basic demographics. For non-longitudinal data sets, the three character postal code, gender, and month/year of birth represent sufficiently low re identification risk. Data custodians need to generalize their demographic information further for longitudinal data sets. PMID- 21696637 TI - Repeat workers' compensation claims: risk factors, costs and work disability. AB - BACKGROUND: The objective of our study was to describe factors associated with repeat workers' compensation claims and to compare the work disability arising in workers with single and multiple compensation claims. METHODS: All initial injury claims lodged by persons of working age during a five year period (1996 to 2000) and any repeat claims were extracted from workers' compensation administrative data in the state of Victoria, Australia. Groups of workers with single and multiple claims were identified. Descriptive analysis of claims by affliction, bodily location, industry segment, occupation, employer and workplace was undertaken. Survival analysis determined the impact of these variables on the time between the claims. The economic impact and duration of work incapacity associated with initial and repeat claims was compared between groups. RESULTS: 37% of persons with an initial claim lodged a second claim. This group contained a significantly greater proportion of males, were younger and more likely to be employed in manual occupations and high-risk industries than those with single claims. 78% of repeat claims were for a second injury. Duration between the claims was shortest when the working conditions had not changed. The initial claims of repeat claimants resulted in significantly (p < 0.001) lower costs and work disability than the repeat claims. CONCLUSIONS: A substantial proportion of injured workers experience a second occupational injury or disease. These workers pose a greater economic burden than those with single claims, and also experience a substantially greater cumulative period of work disability. There is potential to reduce the social, health and economic burden of workplace injury by enacting prevention programs targeted at these workers. PMID- 21696638 TI - Identification of a novel SEREX antigen family, ECSA, in esophageal squamous cell carcinoma. AB - BACKGROUND: Diagnosis of esophageal squamous cell carcinoma (SCC) may improve with early diagnosis. Currently it is difficult to diagnose SCC in the early stage because there is a limited number of tumor markers available. RESULTS: Fifty-two esophageal SCC SEREX antigens were identified by SEREX (serological identification of antigens by recombinant cDNA expression cloning) using a cDNA phage library and sera of patients with esophageal SCC. Sequence analysis revealed that three of these antigens were similar in amino acid sequences, and they were designated as ECSA (esophageal carcinoma SEREX antigen)-1, -2 and -3. The ECSA family was also similar to an EST clone, hepatocellular carcinoma associated antigen 25a (HCA25a). Serum antibody levels to ECSA-1, -2 and -3 were significantly higher in patients with esophageal SCC than in healthy donors. Based on the conserved amino acid sequences, three peptides were synthesized and used for enzyme-linked immunosorbent assays (ELISA). The serum antibody levels against one of these peptides were significantly higher in patients with esophageal SCC. This peptide sequence was also conserved in FAM119A, GOSR1 and BBS5, suggesting that these are also ECSA family members. Reverse transcription followed by quantitative PCR analysis showed that the mRNA expression levels of ECSA-1, -2 and -3 and FAM119A but not of HCA25a, GOSR1 and BBS5 were frequently elevated in esophageal SCC tissues. CONCLUSIONS: We have identified a new gene family designated ECSA. Serum antibodies against the conserved domain of the ECSA family may be a promising tumor marker for esophageal SCC. PMID- 21696639 TI - Desmoplastic small round cell tumour in a 74 year old man: an uncommon cause of ascites (case report). AB - A rare case is provided of a 74 year old man who presented with ascites of unknown etiology. CT scan of the abdomen revealed extensive omental caking, and omental biopsy cytogenetics showed findings in keeping with a diagnosis of desmoplastic small round cell tumour (DSRCT). This case is unique in that it involves a significantly older patient, negative WT1 immunohistochemical staining, and negative cytology. Despite repeated paracenteses and fluid management, the patient died in hospital secondary to renal complications. PMID- 21696640 TI - Discrete derivative: a data slicing algorithm for exploration of sharing biological networks between rheumatoid arthritis and coronary heart disease. AB - BACKGROUND: One important concept in traditional Chinese medicine (TCM) is "treating different diseases with the same therapy". In TCM practice, some patients with Rheumatoid Arthritis (RA) and some other patients with Coronary Heart Disease (CHD) can be treated with similar therapies. This suggests that there might be something commonly existed between RA and CHD, for example, biological networks or biological basis. As the amount of biomedical data in leading databases (i.e., PubMed, SinoMed, etc.) is growing at an exponential rate, it might be possible to get something interesting and meaningful through the techniques developed in data mining. RESULTS: Based on the large data sets of Western medicine literature (PubMed) and traditional Chinese medicine literature (SinoMed), by applying data slicing algorithm in text mining, we retrieved some simple and meaningful networks. The Chinese herbs used in treatment of both RA and CHD, might affect the commonly existed networks between RA and CHD. This might support the TCM concept of treating different diseases with the same therapy. CONCLUSIONS: First, the data mining results might show the positive answer that there are biological basis/networks commonly existed in both RA and CHD. Second, there are basic Chinese herbs used in the treatment of both RA and CHD. Third, these commonly existed networks might be affected by the basic Chinese herbs. Forth, discrete derivative, the data slicing algorithm is feasible in mining out useful data from literature of PubMed and SinoMed. PMID- 21696641 TI - NS4A protein as a marker of HCV history suggests that different HCV genotypes originally evolved from genotype 1b. AB - BACKGROUND: The 9.6 kb long RNA genome of Hepatitis C virus (HCV) is under the control of RNA dependent RNA polymerase, an error-prone enzyme, for its transcription and replication. A high rate of mutation has been found to be associated with RNA viruses like HCV. Based on genetic variability, HCV has been classified into 6 different major genotypes and 11 different subtypes. However this classification system does not provide significant information about the origin of the virus, primarily due to high mutation rate at nucleotide level. HCV genome codes for a single polyprotein of about 3011 amino acids which is processed into structural and non-structural proteins inside host cell by viral and cellular proteases. RESULTS: We have identified a conserved NS4A protein sequence for HCV genotype 3a reported from four different continents of the world i.e. Europe, America, Australia and Asia. We investigated 346 sequences and compared amino acid composition of NS4A protein of different HCV genotypes through Multiple Sequence Alignment and observed amino acid substitutions C22, V29, V30, V38, Q46 and Q47 in NS4A protein of genotype 1b. Furthermore, we observed C22 and V30 as more consistent members of NS4A protein of genotype 1a. Similarly Q46 and Q47 in genotype 5, V29, V30, Q46 and Q47 in genotype 4, C22, Q46 and Q47 in genotype 6, C22, V38, Q46 and Q47 in genotype 3 and C22 in genotype 2 as more consistent members of NS4A protein of these genotypes. So the different amino acids that were introduced as substitutions in NS4A protein of genotype 1 subtype 1b have been retained as consistent members of the NS4A protein of other known genotypes. CONCLUSION: These observations indicate that NS4A protein of different HCV genotypes originally evolved from NS4A protein of genotype 1 subtype 1b, which in turn indicate that HCV genotype 1 subtype 1b established itself earlier in human population and all other known genotypes evolved later as a result of mutations in HCV genotype 1b. These results were further confirmed through phylogenetic analysis by constructing phylogenetic tree using NS4A protein as a phylogenetic marker. PMID- 21696643 TI - Protocol: An updated integrated methodology for analysis of metabolites and enzyme activities of ethylene biosynthesis. AB - BACKGROUND: The foundations for ethylene research were laid many years ago by researchers such as Lizada, Yang and Hoffman. Nowadays, most of the methods developed by them are still being used. Technological developments since then have led to small but significant improvements, contributing to a more efficient workflow. Despite this, many of these improvements have never been properly documented. RESULTS: This article provides an updated, integrated set of protocols suitable for the assembly of a complete picture of ethylene biosynthesis, including the measurement of ethylene itself. The original protocols for the metabolites 1-aminocyclopropane-1-carboxylic acid and 1 (malonylamino)cyclopropane-1-carboxylic acid have been updated and downscaled, while protocols to determine in vitro activities of the key enzymes 1 aminocyclopropane-1-carboxylate synthase and 1-aminocyclopropane-1-carboxylate oxidase have been optimised for efficiency, repeatability and accuracy. All the protocols described were optimised for apple fruit, but have been proven to be suitable for the analysis of tomato fruit as well. CONCLUSIONS: This work collates an integrated set of detailed protocols for the measurement of components of the ethylene biosynthetic pathway, starting from well-established methods. These protocols have been optimised for smaller sample volumes, increased efficiency, repeatability and accuracy. The detailed protocol allows other scientists to rapidly implement these methods in their own laboratories in a consistent and efficient way. PMID- 21696642 TI - Vitamin A decreases pre-receptor amplification of glucocorticoids in obesity: study on the effect of vitamin A on 11beta-hydroxysteroid dehydrogenase type 1 activity in liver and visceral fat of WNIN/Ob obese rats. AB - BACKGROUND: 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of inactive glucocorticoids to active glucocorticoids and its inhibition ameliorates obesity and metabolic syndrome. So far, no studies have reported the effect of dietary vitamin A on 11beta-HSD1 activity in visceral fat and liver under normal and obese conditions. Here, we studied the effect of chronic feeding of vitamin A-enriched diet (129 mg/kg diet) on 11beta-HSD1 activity in liver and visceral fat of WNIN/Ob lean and obese rats. METHODS: Male, 5-month-old, lean and obese rats of WNIN/Ob strain (n = 16 for each phenotype) were divided into two subgroups consisting of 8 rats of each phenotype. Control groups received stock diet containing 2.6 mg vitamin A/kg diet, where as experimental groups received diet containing 129 mg vitamin A/Kg diet for 20 weeks. Food and water were provided ad libitum. At the end of the experiment, tissues were collected and 11beta-HSD1 activity was assayed in liver and visceral fat. RESULTS: Vitamin A supplementation significantly decreased body weight, visceral fat mass and 11beta-HSD1 activity in visceral fat of WNIN/Ob obese rats. Hepatic 11beta-HSD1 activity and gene expression were significantly reduced by vitamin A supplementation in both the phenotypes. CCAAT/enhancer binding protein alpha (C/EBPalpha), the main transcription factor essential for the expression of 11beta-HSD1, decreased in liver of vitamin A fed-obese rats, but not in lean rats. Liver * receptor alpha (LXRalpha), a nuclear transcription factor which is known to downregulate 11beta-HSD1 gene expression was significantly increased by vitamin A supplementation in both the phenotypes. CONCLUSIONS: This study suggests that chronic consumption of vitamin A-enriched diet decreases 11beta HSD1 activity in liver and visceral fat of WNIN/Ob obese rats. Decreased 11beta HSD1 activity by vitamin A may result in decreased levels of active glucocorticoids in adipose tissue and possibly contribute to visceral fat loss in these obese rats. Studying the role of various nutrients on the regulation of 11beta-HSD1 activity and expression will help in the evolving of dietary approaches to treat obesity and insulin resistance. PMID- 21696644 TI - Menopausal symptoms. AB - INTRODUCTION: Menopause is a physiological event. In the UK, the median age for onset of menopausal symptoms is 45.5 to 47.5 years. Although endocrine changes are permanent, menopausal symptoms such as hot flushes, which are experienced by about 70% of women, usually resolve with time, although they can persist for decades in some women. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical treatments for menopausal symptoms? What are the effects of non-prescribed treatments for menopausal symptoms? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 79 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: agnus castus, antidepressants, black cohosh, clonidine, oestrogens, phyto-oestrogens, progestogens, testosterone, and tibolone. PMID- 21696645 TI - Delirium at the end of life. AB - INTRODUCTION: Delirium is common in the last weeks of life, occurring in 26% to 44% of people with advanced cancer in hospital, and in up to 88% of people with terminal illness in the last days of life. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions at the end of life in people with delirium caused by underlying terminal illness? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found three systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: artificial hydration; barbiturates; benzodiazepines; haloperidol; opioid switching; phenothiazines; and propofol. PMID- 21696646 TI - Athlete's foot. AB - INTRODUCTION: Around 15% to 25% of people are likely to have athlete's foot at any one time. The infection can spread to other parts of the body and to other people. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of topical treatments for athlete's foot? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: improved foot hygiene, including socks and hosiery; topical allylamines (naftifine and terbinafine); topical azoles (bifonazole, clotrimazole, econazole nitrate, miconazole nitrate, sulconazole nitrate, and tioconazole); and topical ciclopirox olamine. PMID- 21696647 TI - Headache (chronic tension-type). AB - INTRODUCTION: Chronic tension-type headache (CTTH) is a disorder that evolves from episodic tension-type headache, with daily or very frequent episodes of headache lasting minutes to days. It affects 4.1% of the general population in the USA, and is more prevalent in women (up to 65% of cases). METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for chronic tension type headache? What are the effects of non-drug treatments for chronic tension type headache? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 50 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acupuncture; amitriptyline; analgesics; anticonvulsant drugs; benzodiazepines; botulinum toxin; chiropractic and osteopathic manipulations; cognitive behavioural therapy (CBT); Indian head massage; mirtazapine; relaxation and electromyographic biofeedback; selective serotonin reuptake inhibitor antidepressants (SSRIs); and tricyclic antidepressants (other than amitriptyline). PMID- 21696648 TI - Opioid dependence. AB - INTRODUCTION: Dependence on opioids is a multifactorial condition involving genetic and psychosocial factors. There are three approaches to treating opioid dependence. Stabilisation is usually by opioid substitution treatments, and aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and independent of circumstances (such as finance and physical location). The next stage is to withdraw (detox) from opioids. The final aim is relapse prevention. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for stabilisation (maintenance) in people with opioid dependence? What are the effects of drug treatments for withdrawal in people with opioid dependence? What are the effects of drug treatments for relapse prevention in people with opioid dependence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: buprenorphine; clonidine; lofexidine; methadone; naltrexone; and ultra-rapid withdrawal regimes. PMID- 21696649 TI - Systemic lupus erythematosus. AB - INTRODUCTION: Systemic lupus erythematosus (SLE) occurs predominantly in young women, but also in children. The prevalence of SLE varies widely worldwide, ranging from about 1 in 3500 women (regardless of race) in the UK, to 1 in 1000 women in China, to 1 in 250 African-American women in the USA. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments on joint symptoms (arthralgia/arthritis) and other non-organ-threatening symptoms (such as serositis and fatigue) in people with systemic lupus erythematosus? What are the effects of interventions for cutaneous involvement in people with systemic lupus erythematosus? What are the effects of treatments in people with proliferative lupus nephritis (WHO grades 3-5)? What are the effects of treatments for neuropsychiatric involvement in people with systemic lupus nephritis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 11 systematic reviews or RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acitretin; antipsychotic drugs; chloroquine; combination corticosteroids plus immunosuppressants; corticosteroids; hydroxychloroquine; intravenous immunoglobulin; methotrexate; non-steroidal anti-inflammatory drugs (NSAIDs); plasmapheresis; and sunblock. PMID- 21696650 TI - Adult presentation of PHACES syndrome. AB - A significant percentage of children with hemangiomas may have PHACES syndrome which refers to the association of posterior fossa malformations, facial hemangiomas, arterial cerebrovascular abnormalities, cardiovascular anomalies, eye abnormalities and ventral defects like sternal clefting or supraumbilical raphe. A variety of factors have led to under diagnosis of PHACES syndrome in the past including lack of awareness and limited imaging modalities. Also, patients with PHACES syndrome with arterial cerebrovascular abnormalities can present with acute ischemic stroke. However, these patients usually present before one year of age. We describe a 29-year-old woman with no history of cerebrovascular disease who initially presented with symptoms of a stroke and was subsequently diagnosed to have PHACES syndrome exhibiting an array of multiple unusual imaging findings. We also discuss the current literature and recommendations about PHACES syndrome. PMID- 21696651 TI - Flow diversion in aneurysms trial: the design of the FIAT study. AB - Intracranial aneurysms, particularly large and giant, fusiform or recurrent aneurysms are increasingly treated with flow diverters (FDs), a recently introduced and approved neurovascular device. While some rare cases may not be treated any other way, in most patients a more conventional, conservative, or validated approach such as coiling, parent vessel occlusion, or surgical clipping exists. Only a randomized clinical trial can answer the question of which treatment option leads to better patient outcomes.We report the design of the FIAT study, a clinical care trial aiming to compare angiographic and clinical outcomes following treatment with a Flow-Diverter or with the best conventional treatment option. The FIAT study will include both a randomized and a registry portion. Patients will be proposed randomization to either FD stenting or best conventional treatment option (observation, coiling, stenting, or clipping) as determined by the treating physician. FIAT will recruit a total of 338 patients, to show that i) FD stenting can be performed with an 'acceptable' immediate complication rate of less than 15% morbidity and mortality (defined as mRS > 2); ii) FD stenting can increase from 75 to 90% the proportion of patients with a "good outcome", defined as complete or near-complete occlusion of the aneurysm AND a good clinical outcome (mRS >= 2) at one year, as compared to the best conventional option. The FIAT study provides a scientific and ethical context to care for patients eligible for flow-diversion therapy. PMID- 21696652 TI - Comparison of cerebral aneurysm volumes as determined by digitally measured 3D rotational angiography and approximation from three diameters. AB - This study compared digital measurement of aneurysm volume by 3D rotational angiography (3D-RA) with an approximation technique using three diameters of an aneurysm to re-interpret previously reported optimal packing densities (volume embolization ratio, VER) in coil embolization of intracranial aneurysms. Estimation of the volume of saccular aneurysms is important for calculation of the VER, which is in turn reported to be useful for prediction of coil compaction. The conventional formula for the volume estimation is V=4/3 pi(A/2) (B/2) (C/2), where A, B, and C are the aneurysmal height, length, and width measured on 3D-RA image respectively. Using 3D rotational angiography data from 74 aneurysms, the approximated volume generated using the conventional formula was directly compared with the digitally measured volume. The digitally measured volume varied from 0.003 ml to 7.935 ml, and the dome-to-neck ratio (D/N) from 0.79 up to 4.62. We found that the conventional formula almost systematically underestimated the volume by up to 50 %, particularly when the neck was large relative to the dome (D/N<2). On average, digitally measured volume was 1.26~1.29 times larger than the approximated volume obtained using the conventional formula.Conventional 2D angiography based aneurysm volume calculation tends to underestimate an aneurysm volume, so the so-called VER (volume embolization ratio) could be overestimated. PMID- 21696653 TI - Deliberate parent artery occlusion for non-saccular posterior cerebral artery aneurysms. AB - Posterior cerebral aneurysms are rare vascular lesions and usually present as non saccular or dissecting in nature. We present a retrospective review of our experience in the deliberate parent artery occlusion of posterior cerebral artery (PCA) aneurysms.From June 2006 to June 2010, 12 patients (seven men, five women) with posterior cerebral artery non-saccular aneurysms presented to our department and were treated by parent artery occlusion. There were eight (66.7%) aneurysms located at the P2 segment, two (16.7%) at the P2-3 junction, one (8.3%) at the P1 2 junction and one (8.3%) at the P3 segment. Ten of the 12 patients were treated by aneurysm together with parent artery occlusion and two were treated by proximal occlusion.The procedure was technically successful in all cases. Angiography was performed immediately after the procedure in all patients and showed occlusion of the parent vessel with no filling of the aneurysm. Only one patient (8.3%) developed procedure-related transient hemianopsia and recovered within one month. The other 11 patients showed no additional neurological symptoms after procedure. Deliberate parent artery occlusion by detachable coils appears to be well tolerated for P2 or distal segment of PCA in our limited case series. We propose that this technique could be a good treatment option in treating non-saccular aneurysms in this location. PMID- 21696654 TI - Intra-arterial nimodipine infusion for cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. AB - This study evaluated the efficacy of intra-arterial nimodipine infusion for symptomatic vasospasm in patients with aneurysmal subarachnoid hemorrhage (aSAH). Clinical data collected from 42 consecutive patients with symptomatic vasospasm after aSAH were retrospectively reviewed. Forty-two patients underwent 101 sessions of intra-arterial nimodipine infusion. Angiographic response, immediate clinical response, and clinical outcome were evaluated at discharge and six months later. Angiographic improvement was achieved in 82.2% of patients. The immediate clinical improvement rate was 68.3%, while the deterioration rate was 5.0%. A favorable clinical outcome was achieved in 76.2% at discharge and 84.6% six months. Vasospasm-related infarction occurred in 21.4%. There was no drug related complication. The nimodipine group showed satisfactory outcomes. Nimodipine can be recommended as an effective and safe intra-arterial agent for the treatment of symptomatic vasospasm after aSAH. PMID- 21696655 TI - Angiographic pitfall: duplicated tapered A1 segment of the anterior cerebral artery mimicking an anterior communicating artery aneurysm. AB - We describe a misleading case of a partially occluded A1 segment duplication that mimicked an ACoA aneurysm on computed tomography angiography and conventional angiography and led to surgical intervention. The location of such an anomaly at the ACoA on the side of least hemodynamic stress may provide a clue to recognizing this variant. PMID- 21696656 TI - Successful endosaccular coiling after a balloon occlusion test of the caudal channel of a double origin of the posterior inferior cerebellar artery originating from the aneurysm neck. AB - Therapeutic strategies for unruptured aneurysms in elective procedures must be carefully planned with respect to safety. We describe the case of a patient who presented with an unruptured aneurysm associated with a double origin of the posterior inferior cerebellar artery (DOPICA), a rare variant of aberrant origin. A three-dimensional rotational angiogram clearly showed that the aneurysm incorporated the origin of the DOPICA caudal channel, which was more dominant than the cranial one. The aneurysm was completely obliterated using detachable coils after a balloon occlusion test (BOT) of the caudal channel was conducted to confirm the tolerance of the patient following sudden interruption of the more prominent flow coming from the caudal channel of the DOPICA. This report affirms the need to suspect anomalies associated with a DOPICA that predispose to intracranial aneurysms and highlights the potential role of a BOT in pretreatment hemodynamic evaluations of unusual aneurysms accompanying a particular developmental anomaly. PMID- 21696657 TI - Myxomatous aneurysms: a case report and literature review. AB - Cardiac myxomas are benign tumors that may lead to neurological manifestations including ischemic stroke, aneurysms or metastases. We describe a patient with multiple intracranial aneurysms who presented with TIA-like symptoms following resection of an atrial myxoma, and review the clinical and imaging features of myxomatous aneurysms as reported in the literature. The most prominent imaging features of myxomatous aneurysms are their multiplicity, fusiform shape and distal location whereas from a clinical point of view they most often present with stroke like symptoms rather than with hemorrhage. These neurological manifestations may occur even after successful and complete surgical removal of the atrial myxoma. PMID- 21696659 TI - Cavernous redirection of venous drainage after partial transvenous coil occlusion of a sigmoid sinus dAVF: coil mass retrieval with flexible cysto-urethroscopy grasping forceps. a technical note. AB - We describe the case of a patient who presented with ocular symptoms (chemosis, proptosis, increased intra-ocular pressure, impaired visual acuity) eight months after the transvenous coil occlusion of an ipsilateral sigmoid sinus dural arteriovenous fistula (dAVF). Digital substraction angiography revealed a partial occlusion of the left sigmoid sinus with coils. Since the connection from the sigmoid sinus to the internal jugular vein was obliterated by coils without interrupting the arteriovenous shunt, the venous drainage was redirected into the inferior petrosal sinus, the cavernous sinus and the superior ophthalmic vein. The transjugular access to the inferior petrosal sinus was obstructed by a large coil mass in the jugular bulb. Several attempts to remove these coils with an Alligator retrieval device and a goose neck snare failed. The coil mass was withdrawn via a direct access to the internal jugular vein using flexible cysto urethroscopy grasping forceps, an urological device designed for the removal of kidney stones. After establishing anterograde drainage, the now accessible inferior petrosal sinus was occluded with fibered coils and the dAVF was completely obliterated. The ocular symptoms resolved within ten days. PMID- 21696658 TI - Mechanism of the formation of dural arteriovenous fistula: the role of the emissary vein. AB - Dural arteriovenous fistula (DAVF) can be separated into two types: DAVF which drains through an affected sinus (sinus type) and DAVF with direct reflux to the cortical vein (non-sinus type). The present report attempted to clarify the mechanism of formation and development of DAVF focusing on the emissary vein (EV) hypothesis.First, inflammation occurs at the penetrating point of the EV on the dura due to idiopathic or secondary causes. Local inflammatory reactions induce vessel dilatation and neovascularization, and subsequently create arteriovenous (AV) connections on the arteriole level. Although EV communicating with dural arteries might play a role as draining routes at first, they start to degrade due to compression of enlarged emissary arteries or to a hemodynamic shift to the drainage pathway of least resistance. Following the occlusion of drainage pathway through EV into the sinus or cortical veins may form, resulting in clinically detectable DAVF. The AV shunt then expands to the surrounding dura associated with recruitment of feeders from distant sites induced by expression of angiogenetic factors and a shift in the hemodynamic balance. In sinus type DAVF, the sinus is progressively compartmentalized and finally occludes due to thrombogenesis with activated coagulopathy or to hemodynamic hypertrophy of the sinus wall. This progression results in the mature, aggressive DAVF with drainage impairments. Previous mechanistic hypotheses focusing on sinus hypertension and sinus thromboses cannot explain the pathogenesis of non-sinus type of DAVF. Although the etiology of DAVF may be concerned by the thrombo-occlusive change of sinus, the unique theory presented in this report may enable an understanding of the common etiology of both types of DAVF. PMID- 21696660 TI - Intercavernous sinus dural arteriovenous fistula successfully treated with transvenous embolization. a case report. AB - The venous sinuses commonly found in the margins of the diaphragm and sella are venous interconnections between the bilateral cavernous dural sinuses and are termed intercavernous communications or intercavernous sinuses. They form a venous ring, a single "circular sinus" that extends throughout the skull base. We report the first case to our knowledge of an intercavernous sinus fistula. We emphasize the importance of thorough knowledge of lesion characteristics before considering any interventional procedure.An 84-year-old woman presented with alarming progressive orbital symptoms for one month affecting her left eye. A cerebral angiogram showed an intercavernous sinus fistula supplied by internal and external carotid arterial branches.Transvenous embolization through retrograde catheterization of the right inferior petrosal sinus allowed complete coil occlusion of the lesion. Cerebral angiography confirmed the absence of residual blood flow through the fistula.This report represents the first case of an intercavernous sinus dural arteriovenous fistula successfully treated with transvenous embolization. A detailed awareness of the regional anatomy is essential for treatment approach and favorable outcomes. PMID- 21696661 TI - Hydrocephalus secondary to hydrodynamic disequilibrium in an adult patient with a choroidal-type arteriovenous malformation. AB - We describe an adult patient with an unruptured choroidal-type arteriovenous malformation (AVM) associated with progressive hydrocephalus. There was no evidence of mechanical obstruction of the ventricular system by the AVM nidus itself or a draining vein. However significant reflux into periventricular and transmedullary veins was demonstrated. Following partial targeted embolization of the AVM, no further reflux was observed, the patient's clinical deficits resolved, and the hydrocephalus improved. We suggest a hydrodynamic disorder as a potential pathomechanism of hydrocephalus in this adult patient with an unruptured AVM. PMID- 21696662 TI - Arteriovenous fistula in a nerve root of the cauda equina fed by a proximal radiculo-medullary artery: a report of two cases. AB - While there have been a few reports on cases of intradural spinal arteriovenous fistula located on the filum terminale, no cases of its location in a nerve root of the cauda equina have been reported to date.We describe two such cases and describe the intraoperative findings. A 40-year-old man presented weakness of his left leg. Another 62-year-old man presented paraparesis dominantly in his left leg with urinary hesitation. In both cases, spinal T2-weighted magnetic resonance images showed edema of the spinal cord, indicating a flow void around it. Digital subtraction angiography disclosed an anterior radicular artery branching from the anterior spinal artery on the surface of the conus medullaris and a turnaround vein running in the opposite direction within the cauda equina. In the first patient, while the feeding artery running along a nerve root was detected, the draining vein and the fistula were not identified at first sight. An incision into the respective nerve root exposed their location within it. In the second patient, unlike the first case, the feeding artery and the fistula were buried in a nerve root, while the draining vein was running along the nerve's surface. In both cases, permanent clips were applied to the draining vein closest to the fistula. The recognition of a hidden fistulous point in a nerve root of the cauda equina is essential for successful obliteration of the fistula. PMID- 21696663 TI - Amplatzer vascular plug for occlusion of parent artery in carotid blowout with active extravasation. AB - Carotid blowout is a devastating complication in patients with head and neck malignancy. Various treatments including high risk surgery, carotid stenting or carotid occlusion using either coils or detachable balloons have been described. The key for any treatment is the rapidity at which it can be performed. We describe treatment of common carotid blowout secondary to neoplastic infiltration using four Amplatzer vascular plugs deployed in less than ten minutes. PMID- 21696664 TI - Achieving faster recanalization times by IA thrombolysis in acute ischemic stroke: where should we direct our efforts? AB - Faster recanalization correlates with better outcomes in acute ischemic stroke. We analyzed times from arrival in ER to end of treatment in patients undergoing endovascular treatment for acute ischemic stroke at our institution.We retrospectively studied patients who underwent IA procedures for stroke from 2005 to 2009 noting the times of arrival to ER, CT scan, arrival to DSA, arterial puncture and recanalization from our endovascular database. A subgroup analysis was performed based on administration of GA, use of mechanical devices and whether the procedure was performed during regular hours or after hours.Of 101 patients, 53 were male, with a median age of 66 years (range 18-87). There were 81 anterior circulation strokes. Median ER to CT time was 22 min (2-1025), CT to DSA arrival time 80 min (range 4-990), DSA arrival to puncture time 24 min (range 0-75) and puncture to recanalization time 84 min (range 11-206). 23.3% of patients had an ER to CT time interval of > 60 min and 71.3 % had a CT to DSA time interval of > 60 min contributing to significant in-hospital delays. For subgroup analysis the Mann-Whitney test was used. No significant differences in CT to DSA arrival (p=0.8), DSA arrival to puncture (p=0.1) and puncture to recanalization (p=0.59) times were noted between patients with and without GA. No significant difference was noted in puncture to recanalization times with or without device (p=0.78). 39 cases were done during regular (R) hours and 62 after (A) hours. Median ER to CT time (R=18 min, A = 27 min, p 0.02), CT to DSA arrival time (R=64 min, A=90 min, p 0.004) and DSA arrival to puncture time (R=18 min, A=25 min, p 0.003) was significantly higher after hours.ER to CT and CT to DSA arrival times in patients undergoing endovascular stroke therapy show wide variability and therefore, considerable scope for reduction. Time differences during regular and after hours should serve as a reminder to make efforts to reduce overall ischemic times in spite of staffing patterns and resource availability. PMID- 21696666 TI - Drug eluting stents for symptomatic intracranial and vertebral artery stenosis. AB - The use of bare metal stents (BMS) to prevent recurrent stroke due to stenosis of the cerebral vasculature is associated with high rates of restenosis. Drug eluting stents (DES) may decrease this risk. We evaluated the performance of DES in a cohort of patients treated at our institution.Consecutive patients treated with DES were identified by a case log and billing records; data regarding procedural details, clinical outcome and angiographic follow-up was obtained by retrospective chart review.Twenty-six patients (27 vessels; 14 vertebral origin (VO); 13 intracranial) were treated. Stenosis was reduced from mean 81% to 8% at the VO and 80% to 2% intracranially. No strokes occurred in the first 24 hours after stenting or at any time point in the VO group during a mean follow-up period of nine months. Among patients with intracranial stents, stroke with permanent disability occurred within 30 days in 1/12 (8%) and after 30 days in 1/11 (9%) with clinical follow-up (mean follow-up, 14 months). Follow-up catheter angiography was obtained in 14/14 (100%) in the VO group at mean eight months and in 8/11 surviving patients (73%) at a mean of ten months after stenting in the intracranial group. The restenosis rate was 21% at the VO (3/14) and 38% (3/8) for intracranial stents. Restenosis at the VO was less frequent than might have been expected from reports utilizing BMS, however, overall restenosis rates appeared higher than previously reported for patients with intracranial DES and comparable with restenosis rates for intracranial BMS. PMID- 21696665 TI - Early single center experience with the solitaire thrombectomy device for the treatment of acute ischemic stroke. AB - We report the immediate technical and clinical outcome of a new self-expanding fully retrievable stent in the treatment of acute ischemic stroke. Eleven consecutive patients with acute intracerebral artery occlusions were treated with a self-expandable fully retrievable intracranial stent (Solitaire AB). Four patients had an occlusion of the basilar artery, five had a middle cerebral artery occlusion and two had terminal carotid artery occlusions. Recanalization results were assessed by follow-up angiography immediately after the procedure. Neurologic status was evaluated before and after treatment (90-day follow-up) according to the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scales (mRS).Successful revascularization (TICI 2a/b and 3) was achieved in 11 of 11 (100%) patients, a TICI 3 state was accomplished in two (18%) patients, and partial recanalization or slow distal branch filling with filling of more than two-thirds of the vessel territory (TICI 2a/2b) was achieved in nine (82%) patients. The stent was removed in all patients. The mean time from stroke symptom onset to recanalization was 339 minutes (+/- 114.3 minutes). NIHSS on admission was 16.09 (+/- 4.7). Almost two-thirds of the patients (61.2%) improved by >6 points on the NIHSS at discharge, and 30% showed a mRS of <2 at 90 days. Mortality was 9%. One patient with a BA occlusion had a massive brain stem infarction and died two days after the procedure. There were no intracranial hemorrhages.The use of the Solitaire in ischemic stroke patients shows encouraging results. However, further prospective large randomized trials are mandatory to confirm these early results. PMID- 21696667 TI - Sinus thrombosis in a patient with intracranial hypotension: a suggested hypothesis of venous stasis. a case report. AB - We describe the case of a 26-year-old man with orthostatic headache. Cerebral angiography revealed thrombosis in the sagittal sinus. Spine MRI showed cerebrospinal fluid collection at the C1-2 level. We performed blood patch and the symptoms disappeared. We report a rare case of intracranial hypotension caused by CSF leak and describe our hypothesis that SIH can change the velocity of cerebral blood flow and cause thrombosis. PMID- 21696668 TI - Outcomes after endovascular treatment of symptomatic patients with Takayasu's arteritis. AB - We report our experience with endovascular treatment of supra-aortic arteries and follow-up results in patients with Takayasu's arteritis (TA) presenting with neurological symptoms. Of the 20 patients with TA who underwent cerebral angiography for neurological manifestations between May 2002 and May 2009, 12 (11 females, one male; mean age, 39 years; range 31-56 years) underwent endovascular treatment and evaluated outcome for 21 lesions, including nine common carotid arteries, four vertebral arteries, four subclavian arteries, two internal carotid arteries, and one brachiocephalic artery. Eight patients underwent multiple endovascular procedures for different lesions in single or multiple stages. Mean angiographic and clinical follow-up durations were 34 months (range, 11-79 months) and 39 months (range 11-91 months), respectively. Technical success was achieved for 20 procedures in 11 patients. One procedure failed, with 50% residual stenosis after stenting due to dense calcification of vessel walls. There were no procedure-related complications. Restenosis occurred at two lesions in two patients were treated by re-stenting. Asymptomatic occlusion occurred at two lesions in one patient. Ten patients remained in 0-1 on the modified Rankin scale (mRs) during mean 39 months. One patient, however, had a score of 3 on mRs due to a traumatic contusion during follow-up. One patient died from cardiac failure 36 months after successful angioplasty.Our data suggest that endovascular treatment of symptomatic supra-aortic lesions of TA is effective and durable in selected patients with neurologic symptoms. PMID- 21696670 TI - [Give to general practice the central role during the course of cancer]. PMID- 21696669 TI - Stretched and sheared microcatheter retained after onyx embolization of infantile myofibromatosis. AB - We describe a rare neurointerventional complication, namely a stretched and sheared microcatheter, extending 52 cm from its point of retention within an Onyx cast in an infant patient's neck mass, to the groin. The tumor was an unusual manifestation of infantile myofibromatosis and prior attempts at resection had proven impossible due to bleeding. Recommendations regarding microcatheter selection, diagnostic workup, and management of the ensuing complication are given. PMID- 21696671 TI - [The course of cancer in health care--time for a time out?]. PMID- 21696672 TI - [From symptoms to seeking doctor]. AB - 20-30% of patients diagnosed with cancer have delayed help-seeking for three months or longer. Misinterpretation of symptoms as benign is responsible for the long patient delay for some patients, but a number of psychosocial factors have also been identified as barriers for help-seeking. These include lack of social support, anxiety, avoidant coping, social risks, and the relationship between patient and physician. It has to be considered whether some of these factors are to be perceived as barriers or as basic conditions for interpretation of symptoms which cannot and should not be changed. PMID- 21696673 TI - [General practice and early cancer diagnosis]. AB - About 85% of cancer patients present with symptoms to general practice. The health care system should be organised in a way that GPs are able to refer patients to timely and early cancer diagnosis. The GP works in an area where symptoms most often are benign and cancer is rare. Only a minority of the symptoms in the population are presented to the GP. The GP must refer many of these knowing that generally the positive predictive value is 2-10%. To be able to ensure the best primary cancer diagnostic pathway we need much more research on symptoms, use of diagnostics and the way to organise this in a health care system where every third citizen will get cancer. PMID- 21696674 TI - [New and future cancer diagnostics]. AB - In patients with cancer the correct diagnosis is the basis for the correct treatment. Ultrasound, CT, MRI, SPECT and PET/CT are used for primary diagnosis, staging, evaluation of treatment effect, control, in patients with relapse and for planning of radiation therapy. The choice is made after diagnostic strategies based on sensitivity, specificity, side effects and price. Due to radiation ultrasound and MRI are preferred in children and adolescents. Denmark has a low use of diagnostic imaging, the challenge of tomorrow is to offer our patients the correct diagnostic imaging without delay and with high quality for both protocol and image interpretation. PMID- 21696675 TI - [Organisation of diagnosing patients with unspecific cancer symptoms]. AB - Danish cancer patients have more advanced cancer at the time of diagnosis than cancer patients in other Scandinavian countries, probably because of a delay in the diagnosis. Only 50% of the cancer patients have specific cancer symptoms when they initially contact their doctor. In Central Region, Denmark, a specific diagnosing program for patients with suspected serious disease that could be cancer without organ specific symptoms has been established at the Diagnostic Centre in Silkeborg. The diagnosing is planned as a parallel course instead of a serial course. A very close co-operation with all internal medical specialties, radiology, clinical biochemistry and gynecology is necessary. PMID- 21696676 TI - [Breakthroughs in cancer treatment]. AB - New possibilities for prevention and targeted medical treatment have resulted from the overwhelming progresses in cancer cell biology. Handling of enormous amounts of data with great velocity has made four dimensional radiotherapy possible. New techniques for creation of static and functional images of organs have improved the precision of localization of tumours. Accelerated and minimal invasive courses for patients along with better organization of surgical services will definitely improve outcomes of cancer surgery. Taken together these changes signify considerable improvements of the outlook for cancer patients in the coming decades. PMID- 21696677 TI - [Adult cancer rehabilitation]. AB - The aim of cancer rehabilitation is to enable patients to reach and maintain the physical and psychosocial functional levels needed to attain an independent and meaningful life. Rehabilitation should be integrated in cancer programs. Taking a systematic approach aiming to identify patients in need is essential and should include coordination amongst professionals. Research may add knowledge to the sparse evidence of the effect of the various interventions and the need of rehabilitation when living with cancer. Patient, organisational and economic perspectives are important. PMID- 21696678 TI - [Coherent palliative effort in health care]. AB - Effective palliative care requires continuous contact, exchange of information, and mutual professional respect between all the relevant health-care professionals. At least one of the professionals should coordinate care. Many patients with advanced cancer report uncovered palliative care needs. In order to assure that all cancer patients receive optimal palliative care, earlier initiation and better integration of basic palliative care (at hospitals and in primary care) and specialist palliative care teams are needed. PMID- 21696679 TI - [Culture-negative bacterial meningitis diagnosed with polymerase chain reaction]. AB - Aetiological diagnosis of patients with bacterial meningitis and possible secondary complications is crucial for the implementation of optimal treatment. Molecular biological methods such as polymerase chain reaction (PCR) can be used. We here present a clinical case in which the diagnosis of pneumococcal meningitis with a subsequent complication in the form of a secondary cerebral abscess was primarily made by real-time PCR after treatment had been initiated. PMID- 21696680 TI - [Necrotising fasciitis in a patient infected by Streptococcus pneumoniae]. AB - A 71 year-old male with interscapular pain was admitted on suspicion of an acute aortic dissection. The diagnosis was not supported by echocardiography or computed tomography (CT). Physical examination showed an erythematous area of the skin with crepitation between the scapulae, and the CT showed subcutaneous emphysema of the entire back region. Necrotising fasciitis was diagnosed and despite aggressive supportive therapy the patient died within hours. Blood cultures were positive for Streptococcus pneumoniae and this case adds to the list of reports of necrotising fasciitis related to pneumococci. PMID- 21696681 TI - Dermatology elective curriculum: Birdwatching list and travel guide. AB - Primary care physicians often see patients with dermatologic complaints, but do not perform as well as dermatologists in the diagnoses of common dermatologic conditions. This article describes a dermatology curriculum that aims to close the clinical practice gap by providing an efficient and effective way to teach dermatology to medical students and non-dermatology residents in the setting of a busy, outpatient dermatology practice. PMID- 21696682 TI - Feline-transmitted sporotrichosis: A case study from California. AB - We report a case of cat-associated sporotrichosis in an adult female in California. A retrospectively diagnosed cutaneous sporotrichosis infection in the patient's cat and the unusual site of the primary lesion in the patient contributed to delayed diagnosis and treatment. Here, we also review the English literature regarding the epidemiology of Sporothrix schenkii as a cat-associated zoonosis. PMID- 21696683 TI - Dermatomyofibroma mimicking granuloma annulare. AB - We report the case of a 9-year-old girl with a lesion on the posterior aspect of the neck, which was clinically compatible with granuloma annulare. An incisional biopsy was performed and the result of the biopsy was consistent with a fibrohistiocytic proliferation. After the total excision of the lesion, the definitive diagnosis of dermatomyofibroma was determined. Dermatomyofibroma is a benign and rare proliferation of myofibroblasts of the skin. Dermatomyofibroma is a solitary and slowly growing tumor. It is more common in adolescents and young adults, with a female preponderance. Dermatomyofibroma presents clinically as a papule or nodule. It may be slightly hyperpigmented. It is usually located on the upper trunk, axilla, upper arm, or neck. The treatment of choice is complete excision and the prognosis is excellent. PMID- 21696684 TI - Cutaneous findings leading to a diagnosis of superior vena cava syndrome: A case report and review of the literature. AB - Superior vena cava syndrome, which occurs in approximately 15,000 persons in the United States annually, consists of a collection of symptoms and signs resulting from the obstruction of the superior vena cava (SVC). An early and prominent symptom of this condition is a constellation of superficial, dilated, vertically oriented and tortuous cutaneous venules or veins above the ribcage margins, often presenting as a blanchable violaceous eruption. Herein, we report a case of superior vena cava syndrome diagnosed in our dermatology clinic. PMID- 21696685 TI - Atypical response to treatment in linear IgA bullous dermatosis of childhood: Revision of literature. AB - A three-year-old boy presented with 2 months of worsening skin lesions characterized by multiple clear vesicles and bullae. The histopathological and immunohistochemical examinations revealed changes consistent with linear IgA bullous dermatosis of childhood. Treatment with dapsone and prednisolone resulted in gradual clinical improvement. However, within a week of therapy he presented with diabetic ketoacidosis, the onset of type I diabetes mellitus. Since then, keeping this child asymptomatic has been a challenge. This case emphasizes the importance of close monitoring of patients taking systemic corticosteroids; the coexistence of other immune mediated conditions may influence the success of treatment. PMID- 21696686 TI - Biopsy of a 5 mm cystic lesion on the right heel of a 48-year-old woman. AB - An excisional biopsy of an asymptomatic cystic lesion that had been present for several years on the right heel of a 48-year-old woman revealed a subcutaneous cyst lined by ciliated columnar epithelium. On immunostaining, the epithelial cells were positive for Pan-cytokeratin (CK AE 1/3), estrogen receptor (ER) and progesterone receptor (PR), but negative for carcinoembryonic antigen (CEA), suggesting Mullerian type of epithelium. Cutaneous ciliated cyst of Mullerian type occurs almost exclusively on the lower extremity of premenopausal women. The lesion is benign and excision is curative. PMID- 21696687 TI - Syringocystadenoma papilliferum: Unusual location. AB - Syringocystadenocarcinoma papilliferum (SCAP) is rare. We describe a 55-year-old man with a partially eroded lesion on the trunk that developed over one year. Histopathological examination revealed syringocystadenoma papilliferum. A wide excision was performed to remove the tumor. The patient has been well without relapse or metastasis for 8 months. PMID- 21696688 TI - Amelanotic subungual melanoma after trauma: An unusual clinical presentation. AB - Amelanotic subungual melanoma (SUM) is difficult to clinically diagnose owing to its rarity and variable presentation. We describe a case of a 63-year-old gentleman with an amelanotic SUM that developed after local trauma and presented as a persistent non-healing ulcer which was initially mistaken for a chronic infection. Because amelanotic SUM can mimic other lesions, the physician should have a high index of suspicion for SUM when managing atypical nail lesions to ensure prompt recognition and treatment. The prior trauma to the nail also suggests that posttraumatic inflammation may play a role in SUM development. PMID- 21696689 TI - Verruca vulgaris in a plaque of acanthosis nigricans. AB - Warts are common cutaneous tumors, induced by different strains of the human papilloma virus. Many people develop one or more warts in their lifetime, most of which resolve spontaneously. We present a case of multiple warts within a plaque of acanthosis nigricans probably related to autoinoculation. PMID- 21696690 TI - Letter: Pemphigus herpetiformis of age of onset at 6 years. AB - INTRODUCTION: Pemphigus herpetiformis is a rare entity that combines the clinical features of dermatitis herpetiformis with the immunologic and histological features of pemphigus. It generally affects adults and pediatric cases are uncommon. We report a case of pemphigus herpetiformis in a 6-year-old girl treated successfully with dapsone. OBSERVATION: A 6-year-old girl presented with a pruritic, erythematous and vesiculous eruption. Histological examination showed acantholysis of the medial and superficial parts of the epidermis. Direct immunofluorescence study revealed cell surface immunoglobulin G and C3 deposits and staining on the dermo-epidermal junction. The child was diagnosed as having pemphigus herpetiformis. DISCUSSION: Pemphigus herpetiformis produces clinically a pruritic and atypical eruption that resembles dermatitis herpetiformis, with standard histology and immunofluorescence patterns recalling those of pemphigus. Considered to have a good prognosis, it responds well to dapsone and/or to low dose oral corticosteroids. The age range of onset varies from 31 to 81 years according to studies, without a male or female predilection. This is a report of a 6-year-old girl presenting with pemphigus herpetiformis, successfully treated with dapsone for two years with no relapse. PMID- 21696691 TI - Letter: A case of generalized guttate psoriasis induced by etanercept with relapse after abatacept. AB - Abatacept is the first in a new class of agents for the treatment of rheumatoid arthritis. We report a case of guttate psoriasis in a patient treated with abatacept for rheumatoid arthritis. This patient had the same reaction with etanercept in the past. PMID- 21696692 TI - Letter: Penile Kaposi sarcoma: A case of complete resolution with highly active antiretroviral therapy alone. AB - Kaposi sarcoma remains an important cause of morbidity in HIV-infected patients. Regardless of the recent pharmacological progress, treatment of this malignancy is still disappointing. We report the case of a patient with Kaposi sarcoma in an unusual localization, the penis, which completely resolved with highly active antiretroviral therapy alone. PMID- 21696693 TI - Letter: Necrobiotic xanthogranuloma of extremities in an elderly patient successfully treated with low-dose prednisolone. AB - We describe a 93-year-old Japanese woman who developed a painful yellowish plaque with reddish border on her left lower leg. Histological evaluation demonstrated hyaline necrobiosis and granulomatous lesions composed of histiocytes (some with foamy cytoplasm), multinucleated giant cells, and numerous cholesterol crystals. Serum electrophoresis displayed the presence of an M-peak with IgG lambda paraproteinemia. There was progressive ulcer formation in the location of the biopsy on the left leg. Multiple tender red dermal and subcutaneous skin nodules developed on her extremities. Oral administration of prednisolone 20 mg daily (0.5 mg/kg) was started. After 4 weeks, she obtained resolution of the skin lesions. PMID- 21696694 TI - How verbs can activate things: cross-language activation across word classes. AB - The present study explored whether language-nonselective access in bilinguals occurs across word classes in a sentence context. Dutch-English bilinguals were auditorily presented with English (L2) sentences while looking at a visual world. The sentences contained interlingual homophones from distinct lexical categories (e.g., the English verb spoke, which overlaps phonologically with the Dutch noun for ghost, spook). Eye movement recordings showed that depictions of referents of the Dutch (L1) nouns attracted more visual attention than unrelated distractor pictures in sentences containing homophones. This finding shows that native language objects are activated during second language verb processing despite the structural information provided by the sentence context. PMID- 21696695 TI - Processing of task-irrelevant natural scenes in social anxiety. AB - In this study, by manipulating perceptual load, we investigated whether socially anxious people process task-irrelevant, non-emotional, natural scenes. When attention was directed to letters and perceptual load was low, task-irrelevant natural scenes were processed, as evidenced by repetition priming effects, in both high and low socially anxious people. In the high perceptual load condition, repetition-priming effects decreased in participants with low social anxiety, but not in those with high social anxiety. The results were the same when attention was directed to pictures of animals: even in the high perceptual load condition, high socially anxious participants processed task-irrelevant natural scenes, as evidenced by flanker effects. However, when attention was directed to pictures of people, task-irrelevant natural scenes were not processed by participants in either anxiety group, regardless of perceptual load. These results suggest that high socially anxious individuals could not inhibit task-irrelevant natural scenes under conditions of high perceptual load, except when attention was focused on people. PMID- 21696696 TI - Crossmodal associations between flavoured milk solutions and musical notes. AB - A number of crossmodal associations have now been described in the context of food evaluation, such as between tastes or flavours and musical notes (Crisinel & Spence, 2010b). Here we extend these findings by presenting flavoured milk solutions of varying fat contents. The participants in the present study matched a series of milk samples to musical notes. They chose both the pitch and the class of instrument that they felt was most appropriate for each sample. Participants also rated various features of the samples, such as their pleasantness, bitterness, or familiarity. Consistent associations between flavours and both pitch and instruments were confirmed. However, fat content did not influence either the pitch or instrument chosen, although it did have an effect on pleasantness and intensity ratings. These results demonstrate that flavour-sound associations are not restricted to basic tastes and flavours presented individually, but are still present in the context of more complex food stimuli. The present study opens the way for further investigations into the nature and characteristics of crossmodal associations (or correspondences) between more complex stimuli, both in the auditory and gustatory/olfactory modalities. This novel approach could lead to new insights into the representation of chemosensory stimuli in humans. PMID- 21696697 TI - A novel EDA gene mutation in a Spanish family with X-linked hypohidrotic ectodermal dysplasia. AB - X-linked hypohidrotic ectodermal dysplasia (XLHED) is characterized by abnormal development of the hair, teeth, and sweat glands. It is caused by mutations in the EDA gene, which maps to the X chromosome and encodes a protein called ectodysplasin-A, a member of the tumor necrosis factor-related ligand family. Affected males typically exhibit all the typical features of HED, but heterozygous carriers may show mild to moderate clinical manifestations. We describe the case of a Spanish family in which a novel heterozygous c.733_734insGA mutation at the EDA gene was identified. It was located in exon 5 and consisted of a frame-shift mutation at codon 245, which gave rise to an abnormal protein with a premature stop codon after 35 residues. Genetic analyses in families with XLHED are useful for checking carrier status, but they also provide information for genetic counseling and prenatal diagnosis. PMID- 21696698 TI - Characteristics of periconus choroidal neovascularization in pathologic myopia. AB - PURPOSE: To examine the clinical characteristics of periconus choroidal neovascularizations (CNVs) in eyes with pathologic myopia. DESIGN: Retrospective observational case series. METHODS: We reviewed the medical records of 260 eyes of 254 patients with a myopic CNV and selected those with a periconus CNV. A periconus CNV was defined as a CNV that is located next to a myopic conus. To differentiate a periconus CNV from a subfoveal CNV that has expanded to the edge of the disc, eyes whose CNV involved the fovea were excluded. The data of the eyes with a subfoveal CNV were used for comparison. RESULTS: Eleven eyes (4.2%) of 11 patients had a periconus CNV. These CNVs had a triangular or oval shape whose base was directed toward the myopic conus. The eyes with a periconus CNV had a significantly larger myopic conus than eyes with a subfoveal myopic CNV. The degree of myopia and axial length were not significantly associated with the incidence of periconus CNV. In 5 of the 11patients, the periconus CNV had a spontaneous regression without treatment, and none had a recurrence. The other 6 patients received treatment and obtained an angiographic closure after a single treatment. A chorioretinal atrophy (ChRA) developed in 3 eyes, and the ChRA enlarged over the fovea in 2 of these eyes, which led to a significant decrease of vision. CONCLUSION: A periconus CNV is rare (4.2%) among the eyes with a myopic CNV and is more likely to develop in eyes with a large myopic conus. The absence of a significant association between the degree of myopia and incidence of periconus CNV suggests that the morphologic characteristics of the eye are not the causes of the periconus CNV. Although an angiographic closure can be easily attained with or without the treatment, the later development and progression of ChRA can impair vision. PMID- 21696699 TI - Update on idiopathic intracranial hypertension. AB - PURPOSE: To provide an update on various features of idiopathic intracranial hypertension. DESIGN: Perspective. METHODS: Selected articles on the epidemiology, clinical and imaging features, natural history, pathophysiology, and treatment of idiopathic intracranial hypertension were reviewed and interpreted in the context of the authors' clinical and research experience. RESULTS: Idiopathic intracranial hypertension primarily is a disease of obese women of childbearing age, but it can affect patients of any weight, sex, and age. Although a relatively rare disorder, idiopathic intracranial hypertension's associated costs in the United States entail hundreds of millions of dollars. Even after treatment, headaches frequently are persistent and may require the continued involvement of a neurologist. Quality-of-life reductions and depression are common among idiopathic intracranial hypertension patients. However, visual dysfunction, especially visual field abnormalities, represents the major morbidity of this disorder, and serial automated perimetry remains the primary method of patient monitoring. Patients who are men, black, very obese, or anemic are at higher risk of visual loss. Vitamin A metabolism, adipose tissue as an actively secreting endocrine tissue, and cerebral venous abnormalities are areas of active study regarding the pathophysiology of idiopathic intracranial hypertension. Treatment studies show that lumbar puncture is a valuable treatment (in addition to its crucial diagnostic role), and that weight management is critical. However, open questions remain regarding the efficacy of acetazolamide, cerebrospinal fluid diversion procedures, and cerebral venous stenting. CONCLUSIONS: Many questions remain unanswered about idiopathic intracranial hypertension. Ongoing studies, especially an ongoing National Institutes of Health-funded clinical trial of acetazolamide, should provide more insight into this important, yet poorly understood, syndrome of isolated intracranial hypertension. PMID- 21696700 TI - Racial differences in age-related macular degeneration rates in the United States: a longitudinal analysis of a managed care network. AB - PURPOSE: To compare the incidence, prevalence, and hazard of nonexudative and exudative age-related macular degeneration (AMD) among different races throughout the United States. DESIGN: Retrospective longitudinal cohort study. METHODS: Billing records of all encounters for 2 259 061 beneficiaries aged >=40 enrolled in a large, national US managed care network from 2001 through 2007 were reviewed and the incidence and prevalence of nonexudative and exudative AMD were determined and stratified by race. Cox regression analyses determined the hazard of nonexudative and exudative AMD for each race, with adjustment for confounders. RESULTS: During the study, 113 234 individuals (5.0%) were diagnosed with nonexudative and 17 181 (0.76%) with exudative AMD. After adjustment for confounders, blacks had a significantly reduced hazard of nonexudative (hazard ratio [HR]=0.75, 95% confidence interval [CI]: 0.71-0.79) and exudative AMD (HR=0.70, 95% CI: 0.59-0.83) at age 60 and a reduced hazard of nonexudative (HR=0.56, 95% CI: 0.52-0.60) and exudative AMD (HR=0.45, 95% CI: 0.37-0.54) at age 80 relative to whites. Similar comparisons for Latinos demonstrated an 18% reduced hazard for nonexudative AMD at age 80 (HR=0.82, 95% CI: 0.76-0.88) relative to whites. Asian Americans showed a 28% increased hazard for nonexudative AMD at age 60 (HR=1.28, 95% CI: 1.20-1.36) but a 46% decreased hazard for exudative AMD at age 80 (HR=0.54, 95% CI: 0.40-0.73). CONCLUSIONS: Racial minorities, including Latinos and Asian Americans, do not appear to have similar risks of developing nonexudative and exudative AMD as whites. Additional studies using other sources should be conducted to determine the generalizability of this study's findings to other groups. PMID- 21696701 TI - Risk factors for development of choroidal detachment after scleral buckling procedure. AB - PURPOSE: To determine risk factors of choroidal detachment after scleral buckling procedure for treatment of retinal detachment. DESIGN: Retrospective chart review. METHODS: The authors performed a retrospective study of 69 consecutive cases of retinal detachment from January 2007 to January 2008 treated by scleral buckling surgery. Two groups of patients were defined according to the absence or apparition of choroidal detachment, and a comparison of several parameters between these 2 groups was performed. RESULTS: Fifteen patients developed a choroidal detachment. The study found an average higher level of systolic blood pressure during surgery in the group with choroidal detachment than in the absence group (127.3 vs 119.1 mm Hg; P = .008). The authors also observed a statistically significant difference between the 2 groups when comparing the intraoperative peak value of systolic blood pressure (149.3 vs 138.5 mm Hg; P = .019). Finally, in the group that developed choroidal detachment, there were statistically more patients with high myopia (P = .02). CONCLUSION: This study highlights that the 2 main risk factors for development of choroidal detachment during scleral buckling surgery are high blood pressure during the intervention and the existence of high myopia. PMID- 21696702 TI - The relationship between macular sensitivity and retinal thickness in eyes with diabetic macular edema. AB - PURPOSE: To investigate relationship between macular sensitivity and retinal thickness in diabetic macular edema (DME). DESIGN: Prospective observational study. METHODS: settings: University-based retina practice. patients: Twenty-two eyes of 11 patients with DME. procedure: Fundus microperimetry and retinal thickness tomography were performed simultaneously using an automatic fundus perimetry/tomography system. main outcome measures: Quantification of macular sensitivity, fixation pattern, and relationship between macular sensitivity and retinal thickness. RESULTS: Fixation stability revealed that 21 eyes (95.4%) had stable fixation (>75% within central 2 degrees of point of fixation) and 1 eye (4.5%) had relatively unstable fixation (<75% of fixation points located within 2 degrees, >75% located within 4 degrees). Evaluation of fixation location revealed that 15 eyes (68.2%) had central (>50% of fixation points within 0.5 mm of fovea), 3 eyes (13.6%) pericentral (25% to 50% within 0.5 mm of fovea), and 4 eyes (18.2%) eccentric (<25% of fixation points within 0.5 mm of fovea) fixation location. Macular sensitivity increased by an average of 0.03 decibel (dB) (95% confidence interval [CI]: 0.00, 0.06) per 1-micron (MUm) increase in retinal thickness for thickness values <=280 MUm measured with the OPKO/OTI spectral domain OCT. The macular sensitivity decreased by an average 0.05 dB (95% CI: 0.08, -0.02) per 1-MUm increase in thickness for thickness values >280 MUm. CONCLUSIONS: In this pilot study, the majority of eyes with DME had stable, central fixation. Macular sensitivity varied depending on the thickness of the retina. Additional studies are needed to determine the role of microperimetry in eyes with DME. PMID- 21696703 TI - Comparison of comfort, discomfort, and continuum ratings of force levels and hand regions during gripping exertions. AB - The goal of this study was to compare three different evaluation systems of comfort, discomfort, and a continuum for the force levels and hand regions when gripping hand tools. Seventy-two participants were assigned to three groups, each group testing a different evaluation system. Each participant exerted ten levels of submaximal voluntary contractions on hand tools and used their assigned evaluation system to evaluate comfortable or uncomfortable feelings for the force levels and five different regions of the hand. The participants generally rated higher discomfort as required forces increased, but the discomfort and continuum evaluation systems were better than the comfort evaluation system because gripping exertion was related to the physical aspects of the hand tools and their users. Based on the results of the continuum evaluation system, the feeling changed from comfort to discomfort at 65% maximum voluntary contraction. The palm was the region of the hand with the most discomfort. Other design factors affecting comfort need to also be considered in order to better understand hand tool use. PMID- 21696704 TI - The effect of a new syringe design on the ability of rheumatoid arthritis patients to inject a biological medication. AB - Self-administration of new biological medications can be difficult for Rheumatoid Arthritis patients with functional impairment and hand and dexterity limitation. Twenty-three Rheumatoid Arthritis (RA) patients participated in this study to compare preferences and injection forces using a conventional syringe and a new ergonomically designed syringe. Injection force measurements were collected in two ways: a) isometric forces, with the syringes' plungers in fixed positions (depressed halfway and fully depressed), and b) forces exerted during injection of the medication. Subjects' grip and pinch strengths were measured. A perception questionnaire gauged subjects' impressions and preferences. Subjects were capable of exerting significantly higher isometric forces using the new syringe with the plunger fixed both halfway and fully depressed. During injection of the medication, peak and mean injection forces were significantly higher, and duration was shorter, when using the new syringe. Subjects rated the new syringe higher on all twenty attributes on preference and performance. Therefore, it is expected that the new syringe will benefit self-administration of medication injection for RA patients. PMID- 21696705 TI - Prophylactic effect of green tea and Nigella sativa extracts against fenitrothion induced toxicity in rat parotid gland. AB - OBJECTIVE: The aim of the present study was to compare between two antioxidant treatments in prevention of fenitrothion induced toxicity on rat parotid salivary gland. DESIGN: Forty adult male Wistar rats with an average weight of 120-150 g were randomised into 4 groups, control (group I), fenitrothion administration (group II), fenitrothion administration 1h after green tea extract or Nigella sativa oil extract administration (groups III and IV respectively). The rats were then sacrificed after 28 days. The submandibular salivary glands were examined histologically, immunohistochemically and ultrastructurally. RESULTS: Histopathologically the fenitrothion group showed sign of acini degeneration represented by loss of normal architecture (amalgamation). The nuclei of the acinar cells revealed different sizes and shape (polymorphism). The acini relatively preserved their shape in both prophylactic groups (III and IV). Histomorphometric analysis showed significant increase in the optical density of caspase-3 cleaved activity in all experimental groups (p=0.0001). A significant difference was observed between both prophylactic experimental groups III and IV (p=0.0039). Ultrastructurally, the nuclei of serous acini in group II appeared pyknotic with segregation of chromatin. Condensation of the chromatin at the periphery of the nucleus was observed in the nuclei of group III, Clumping of the chromatin with darkly stained pyknotic nucleus was detected in group IV. CONCLUSIONS: In a rat model the administration of natural antioxidants could be of beneficial effect on prevention of cytotoxicity induced by organophosphorous compounds. However, green tea showed more promising results than that of Nigella sativa. PMID- 21696706 TI - Ibuprofen inhibits neuroinflammation and attenuates white matter damage following hypoxia-ischemia in the immature rodent brain. AB - Damage to major white matter tracts is a hallmark mark feature of hypoxic ischemic (HI) brain injury in the preterm neonate. There is, however, no therapeutic intervention to treat this injury. Neuroinflammation is thought to play a prominent role in the pathogenesis of the HI-induced white matter damage but identification of the key mediators that constitute the inflammatory response remain to be fully elucidated. Cyclooxygenase enzymes (COX-1 and COX-2) are candidate neuroinflammatory mediators that may contribute to the HI-induced demise of early oligodendrocyte progenitors and myelination. We investigated whether ibuprofen, a non-steroidal anti-inflammatory drug that inhibits COX enzymes, can attenuate neuroinflammation and associated white matter damage incurred in a rodent model of preterm HI. On postnatal day 3 (P3), HI was produced (right carotid artery ligation and 30 min 6% O(2)). An initial dose of ibuprofen (100mg/kg, s.c.) was administered 2h after HI followed by a maintenance dose (50mg/kg, s.c.) every 24h for 6 days. Post-HI ibuprofen treatment significantly attenuated the P3 HI-induced increases in COX-2 protein expression as well as interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF alpha) levels in the brain. Ibuprofen treatment also prevented the HI-induced loss O4- and O1-positive oligodendrocyte progenitor cells and myelin basic protein (MBP)-positive myelin content one week after P3 HI. These findings suggest that a repeated, daily, ibuprofen treatment regimen administered after an HI insult may be a potential therapeutic intervention to prevent HI-induced damage to white matter progenitors and early myelination in the preterm neonate. PMID- 21696707 TI - Egocentric working memory impairment and dendritic spine plastic changes in prefrontal neurons after NMDA receptor blockade in rats. AB - Working memory may involve context-dependent allocentric or own movement dependent egocentric strategies. While allocentric working memory can be disrupted by N-methyl-D-aspartate (NMDA) blockage, the possible effects of NMDA receptor manipulation on the egocentric strategy have not been studied. Because dendritic spine plasticity in part underlies working memory-related behavioral efficiency, egocentric working memory performance was evaluated in adult rats following NMDA receptor blockade with 10mg/kg of the NMDA-receptor antagonist CPP, i.p. Dendritic spine density and the proportion of different spine types (thin, stubby, mushroom, wide, branched and double) were assessed in third-layer pyramidal neurons of the dorsomedial prefrontal cortex, after behavioral testing. Working memory was evaluated by challenging the rats to resolve twelve trials per day in a single-day session over five consecutive days, in a "cross-arm" maze and according to a delayed match-to-sample procedure. In control animals, the dendritic spine density remained unchanged after behavioral testing, although the proportion of mushroom spines decreased while that of the branched spines increased. NMDA receptor blockade impaired the behavioral performance of rats and resulted in a decrease in dendritic spine density when compared to the control animals, and dendritic spine types were unchanged. These results suggest that behavioral efficiency of egocentric working memory is dependent on NMDA receptor activation, and that plastic changes in spine cytoarchitecture may play a key role in behavioral performance. PMID- 21696708 TI - Nitric oxide has a role in attenuating the neuroendocrine response to anaphylactoid stress during lactation. AB - Stress increases nitric oxide (NO) production in the paraventricular nucleus of the hypothalamus (PVH). Lactation diminishes the response to stress and increases basal NO production markers in the PVH of the dam. This study investigated whether lactation modified the anaphylactic reaction to egg white (EW) injection, and if nitric oxide regulates the neuroendocrine response to this stressor. The activational response of PVH to EW was assessed by c-Fos immunohistochemistry, and NO production was determined by histological staining of NADPH-diaphorase and neuronal nitric oxide synthase (nNOS) and by measuring the concentration of total nitrates and nitrites (NOx) in the hypothalamus of lactating and diestrus rats. EW injection significantly increased the number of Fos-positive neurons in the parvocellular subdivision of the PVH in diestrus, but not in lactating rats. Similarly, EW injection increased the number of NADPH-diaphorase- and nNOS positive cells in the PVH of diestrus rats, but it did not alter the already increased basal number of NO-positive cells in lactating rats. Furthermore, the total concentration of NOx in the hypothalamus, the circulating level of corticosterone and interleukin-6 increased significantly after EW in diestrus, but not in lactating rats, compared to their corresponding controls. Intracerebral administration of L-NAME, a general NOS inhibitor, reversed the attenuation of the activational response to EW in the PVH of lactating rats. The present results show that lactation diminishes the anaphylactoid reaction to EW compared to that in diestrus rats. This attenuation was absent after L-NAME treatment, suggesting that sustained NO production in the PVH during lactation may limit the neuroendocrine response to stress. PMID- 21696709 TI - Non-invasive electrical stimulation of the brain (ESB) modifies the resting-state network connectivity of the primary motor cortex: a proof of concept fMRI study. AB - An innovative method to obtain fMRI resting-state network maps during non invasive electrical stimulation of the brain (ESB) was developed and tested. Five healthy volunteers participated in 2 fMRI sessions. In session one, a transcranial direct current stimulator (tDCS) was applied placing the positive electrode (31.5 cm(2)) over the right M1 of the cortex and the negative electrode (31.5 cm(2)) over the left supra-orbital area of the head. In session two, a monophasic pulsed current stimulator (tPCS) was applied using the identical electrode placement. Imaging was performed on a Siemens 3T Tim Trio scanner with a 12-channel head coil. At each session, five consecutive functional scans were obtained: 1) resting-state without stimulation (Rest-1), 2) a motor scan consisting of self-paced, bilateral finger-thumb opposition task, 3) resting state with ESB (Stim-1), 4) resting-state without stimulation (Rest-2), and 5) resting-state with ESB, replicating Stim-1 (Stim-2). Data were analyzed using AFNI and MATLAB. For motor task fMRI analysis, a general linear model (GLM) determined the voxels in the right and left M1 that were significantly correlated with the motor task paradigm. The resting-state time series from the voxels in the R-M1 were averaged and the resulting time series used as a regressor in a GLM analysis to identify M1 connectivity maps. Connectivity maps were quantified as R(2) values, and then combined to give overlap maps for each of the experimental conditions. Fourier analysis determined the energy in the normalized signal average time courses extracted from L-M1 and R-M1 for each of the resting-state scans. Both tDCS and tPCS lowered the R(2) values and energy of the averaged time course in the right and left M1 ROI. The effect of the tPCS appeared more pronounced and less variable among subjects. Applying non-invasive ESB during fMRI scanning may down regulate the motor cortex's resting-state network connectivity. PMID- 21696710 TI - Activity of three beta-1,4-galactanases on small chromogenic substrates. AB - beta-1,4-Galactanases belong to glycoside hydrolase family GH 53 and degrade galactan and arabinogalactan side chains of the complex pectin network in plant cell walls. Two fungal beta-1,4-galactanases from Aspergillus aculeatus, Meripileus giganteus and one bacterial enzyme from Bacillus licheniformis have been kinetically characterized using the chromogenic substrate analog 4 nitrophenyl beta-1,4-d-thiogalactobioside synthesized by the thioglycoligase approach. Values of k(cat)/K(m) for this substrate with A. aculeatus beta-1,4 galactanase at pH 4.4 and for M. giganteus beta-1,4-galactanase at pH 5.5 are 333M(-1)s(-1) and 62M(-1)s(-1), respectively. By contrast the B. licheniformis beta-1,4-galactanase did not hydrolyze 4-nitrophenyl beta-1,4-d thiogalactobioside. The different kinetic behavior observed between the two fungal and the bacterial beta-1,4-galactanases can be ascribed to an especially long loop 8 observed only in the structure of B. licheniformis beta-1,4 galactanase. This loop contains substrate binding subsites -3 and -4, which presumably cause B. licheniformis beta-1,4-galactanase to bind 4-nitrophenyl -1,4 beta-d-thiogalactobioside non-productively. In addition to their cleavage of 4 nitrophenyl -1,4-beta-d-thiogalactobioside, the two fungal enzymes also cleaved the commercially available 2-nitrophenyl-1,4-beta-d-galactopyranoside, but kinetic parameters could not be determined because of transglycosylation at substrate concentrations above 4mM. PMID- 21696711 TI - Montmorillonite K-10 clay-catalyzed Ferrier rearrangement of 2-C-hydroxymethyl-d glycals, 3,4,6-tri-O-alkyl-d-glycals, and 3,4-(dihydro-2H-pyran-5-yl)methanol: a few unexpected domino transformations. AB - Montmorillonite K-10 clay-catalyzed substitution reactions of 3,4,6-tri-O-alkyl-2 C-hydroxymethyl-d-glycals, 3,4,6-tri-O-acetyl-d-glycals, 3,4,6-tri-O-alkyl-d glycals, and 3,4-(dihydro-2H-pyran-5-yl)methanol with a few alcohols and phenols are described. The reactions of 2-C-hydroxymethyl-d-glycals with phenols were similar to those of 2-C-acetoxymethyl-d-glycals and afforded pyrano[2,3 b]benzopyrans. This montmorillonite K-10 clay-catalyzed transformation is facile both under ambient (Method 1) and microwave conditions (Method 2). Ferrier rearrangement of 3,4-(dihydro-2H-pyran-5-yl)methanol with p-cresol, 2,6-xylenol, and ethanol led to totally unexpected transformations. Reaction of 2-C hydroxymethyl-d-galactal with 2,6-dimethylphenol in the presence of montmorillonite K-10 led to a novel domino transformation affording 4-(5',6' dihydro-4H-pyran-3'-ylmethyl)-2,6-dimethylphenol. In contrast, 3,4,6-tri-O-acetyl d-glucal furnished the Ferrier rearrangement product, 2,6-dimethylphenyl 4,6-di-O acetyl-2,3-dideoxy-alpha-d-erythro-hex-2-enopyranoside. Also, isomerization of 3,4,6-tri-O-alkyl-d-glycals to products of allylic rearrangement, 2,3-unsaturated O-glycosides in good yields is reported. PMID- 21696713 TI - [A new revolution in the treatment of breast cancer?]. PMID- 21696712 TI - Combination treatment of mice with CRx-153 (nortriptyline and desloratadine) decreases the severity of experimental autoimmune encephalomyelitis. AB - Pro-inflammatory CD4(+) T cell-mediated autoimmune diseases, such as multiple sclerosis, are hypothesized to be initiated and maintained by self-reactive interferon-gamma (IFN-gamma) and interleukin-17 (IL-17) producing CD4(+) T cells. Previous studies have shown moderate to significant alterations in inflammatory T cell responses and potentially treatment of autoimmune disease by administration of antihistamine or tricyclic antidepressants alone. The goal of the present study was to determine if treatment of PLP(139-151)-induced relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) in SJL/J mice with a combination of two FDA approved drugs for other indications could decrease R-EAE disease. The findings show that combination treatment with desloratadine and nortriptyline decreases the mean clinical score, disease relapse frequency, and number of CD4(+) T cells infiltrating into the CNS. In addition, combination treatment of PLP(139-151) primed mice decreases the level of IFN-gamma and IL-17 secreted via a decrease in both the number of cells secreting and the amount of cytokine secreted per cell following PLP(139-151) reactivation ex vivo. This is in contrast to an increase in the level of IL-4 produced and the number of IL-4 secreting cells. The data also show that combination treatment with desloratadine and nortriptyline inhibits the production of IFN-gamma and IL-17 produced by naive CD4(+) T cells activated in the presence of Th1 cell- and Th17 cell promoting conditions, while increasing the level of IL-4 produced by naive CD4(+) T cells activated in the presence of Th2 cell-promoting conditions. The present findings suggest a novel method for the development of a putative autoimmune therapy. PMID- 21696715 TI - Increase in harm avoidance by genetic loading of schizophrenia. AB - BACKGROUND: Schizophrenia is highly familial neuropsychiatric disorder with heritability estimated at 60% to 90%. Even unaffected first-degree relatives of schizophrenia manifested some neuropsychologic abnormalities, neurologic soft sign, and morphologic anomalies. Because personality traits are under genetic influence and considerable heritability, we intended to evaluate temperament and character of first-degree relatives of schizophrenia and the influence of schizophrenia genetic loading on their temperament and character. METHODS: Temperament and Character Inventory was completed by 97 first-degree relatives of schizophrenia or schizoaffective disorder, 48 schizophrenic probands (44 patients with schizophrenia and 4 patients with schizoaffective disorder), and 106 control subjects. Within first-degree relatives, parents who have additional probands with schizophrenia spectrum disorder in their ascendant or collateral pedigree and siblings who have offspring with schizophrenia spectrum disorder were defined as presumed carriers (n = 20). Group differences in Temperament and Character Inventory scores were compared using a mixed-model analysis of variance with family as a random effect and age as a covariate. RESULTS: Harm avoidance (HA) scores increased in the order of control subjects, the first-degree relatives, and probands. Among the relatives, presumed carriers, but not presumed noncarriers, had higher HA compared with control subjects. In addition, probands showed significantly low reward dependence, low self-directedness, and low cooperativeness scores compared with the first-degree relatives and control subjects. Probands had also higher self-transcendence scores than the first degree relatives and had lower persistence scores than control subjects. CONCLUSIONS: Our findings that HA increases in proportion to the genetic loading of schizophrenia suggest that it may be a potential endophenotype of schizophrenia. PMID- 21696714 TI - Characteristics and comorbidity of ADHD sib pairs in the Central Valley of Costa Rica. AB - BACKGROUND: While genetic epidemiological studies demonstrate a substantial degree of genetic predisposition for attention-deficit/hyperactivity disorder (ADHD), they also suggest that the genetics are complex and may differ between populations or ethnic groups. OBJECTIVE: This study describes the phenomenology of siblings with ADHD from the genetically isolated population of the Central Valley of Costa Rica. METHODS: Rates of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-defined ADHD subtypes and comorbid conditions were calculated in a sample of 157 ADHD-affected children (probands and siblings) recruited for genetic studies using standardized approaches. Sib sib comparisons and logistic regressions were conducted to identify significant patterns of concordance. RESULTS: Combined-type ADHD (69.5%) was the most common subtype among probands, followed by the inattentive (27.4%), and hyperactive impulsive (3.2%) subtypes. Anxiety disorders were prevalent (55.9%), as were disruptive behavior disorders (30.9%) and Tourette disorder (17.0%). Probands and siblings showed high sib-sib concordance for anxiety disorders. CONCLUSIONS: ADHD in Costa Rica is similar in clinical and demographic characteristics to ADHD seen in other parts of the world, although the rates of co-occurring psychiatric disorders differ somewhat from those previously reported in Latin American samples. Comorbid anxiety is prevalent, with high rates of sib-sib concordance, and may represent a distinct, homogeneous subgroup suitable for genetic studies. PMID- 21696716 TI - The relationship between collisions and pseudoneglect: is it right? AB - When walking through narrow doorways people collide more frequently on the right side than on the left. This rightward collision bias has been attributed to pseudoneglect. Originally pseudoneglect was defined as leftward errors on a line bisection task; however, the term is used more broadly now to refer to the slight tendency to neglect the right side of space and attend more towards the left. Thus, rightward collisions are said to occur because the right side is neglected. In the present experiments, we examined this pseudoneglect hypothesis by assessing the influence of three factors (age, cuing, and motor activity) known to affect performance on traditional measures of pseudoneglect, such as line bisection tasks. Navigation and line bisection tasks were completed by younger and older adults performing a concurrent motor task (Experiment 1) and by younger adults performing no concurrent motor task (Experiment 2). In both experiments, attention was cued to the left, right, or both sides of space, or was uncued. In contrast to previous reports, in both experiments we found a leftward collision bias on the navigation task; this bias was relatively unaffected by age or cuing manipulations, and was attenuated by concurrent motor activity. In addition, we found no relation between performance on the navigation and line-bisection tasks, indicating that the leftward bias on the navigation task cannot be attributed to pseudoneglect. We provide alternative hypotheses that may explain differences between our results and those observed in others' studies. PMID- 21696717 TI - Emotion rendering in music: range and characteristic values of seven musical variables. AB - Many studies on the synthesis of emotional expression in music performance have focused on the effect of individual performance variables on perceived emotional quality by making a systematical variation of variables. However, most of the studies have used a predetermined small number of levels for each variable, and the selection of these levels has often been done arbitrarily. The main aim of this research work is to improve upon existing methodologies by taking a synthesis approach. In a production experiment, 20 performers were asked to manipulate values of 7 musical variables simultaneously (tempo, sound level, articulation, phrasing, register, timbre, and attack speed) for communicating 5 different emotional expressions (neutral, happy, scary, peaceful, sad) for each of 4 scores. The scores were compositions communicating four different emotions (happiness, sadness, fear, calmness). Emotional expressions and music scores were presented in combination and in random order for each performer for a total of 5 * 4 stimuli. The experiment allowed for a systematic investigation of the interaction between emotion of each score and intended expressed emotions by performers. A two-way analysis of variance (ANOVA), repeated measures, with factors emotion and score was conducted on the participants' values separately for each of the seven musical factors. There are two main results. The first one is that musical variables were manipulated in the same direction as reported in previous research on emotional expressive music performance. The second one is the identification for each of the five emotions the mean values and ranges of the five musical variables tempo, sound level, articulation, register, and instrument. These values resulted to be independent from the particular score and its emotion. The results presented in this study therefore allow for both the design and control of emotionally expressive computerized musical stimuli that are more ecologically valid than stimuli without performance variations. PMID- 21696718 TI - Phthalate exposure associated with self-reported diabetes among Mexican women. AB - BACKGROUND: Phthalates are ubiquitous industrial chemicals used as plasticizers in plastics made of polyvinyl chloride (PVC) to confer flexibility and durability. They are also present in products used for personal-care, industry and in medical devices. Phthalates have been associated with several adverse health effects, and recently it has been proposed that exposure to phthalates, could have an effect on metabolic homeostasis. This exploratory cross-sectional study evaluated the possible association between phthalate exposure and self reported diabetes among adult Mexican women. METHODS: As part of an on-going case control study for breast cancer, only controls were selected, which constituted 221 healthy women matched by age (+/-5 years) and place of residence with the cases. Women with diabetes were identified by self-report. Urinary concentrations of nine phthalate metabolites were measured by online solid phase extraction coupled to high performance liquid chromatography-isotope-dilution tandem mass spectrometry. RESULTS: Participants with diabetes had significantly higher concentrations of di(2-ethylhexyl) pththalate (DEHP) metabolites: mono(2-ethyl-5 hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) but lower levels of monobenzyl phthalate (MBzP) a metabolite of benzylbutyl phthalate, compared to participants without diabetes. A marginally significant positive associations with diabetes status were observed over tertiles with MEHHP (OR(T3 vs. T1)=2.66; 95% CI: 0.97 7.33; p for trend=0.063) and MEOHP (OR(T3 vs. T1)=2.27; 95% CI; 0.90-5.75; P for trend=0.079) even after adjusting for important confounders. CONCLUSIONS: The results suggest that levels of some phthalates may play a role in the genesis of diabetes. PMID- 21696719 TI - A broad framework to organize and compare ecological invasion impacts. AB - Invasive species have transformed local, regional and global biotas; however, few generalities about the mechanisms driving impacts of invaders have emerged. To explain variation in impacts among studies, we propose a broad framework that separates drivers of impacts into universal and unique attributes of the invasive species and the invaded habitat. Universal attributes are relevant to all invasions whereas unique attributes are distinct to a specific invasion. For example, impacts associated with the abundance of any invader or the properties of a specific invader (e.g., a rare toxin) represent a universal and unique impact attribute. Through meta-analyses of aquatic field experiments, we demonstrate the utility of our framework, documenting that both the abundance and the taxonomic identity of the invader significantly influence invasion outcomes for marine and freshwater plant and animal invaders. Our review also highlights that many more experiments are needed to test for universal attributes, such as priority effects, age and size, and how the attributes of the invaded habitat further modify invasion impacts. We hope that our framework will stimulate experimental invasion ecology and begin to reconcile the idiosyncrasies that currently impede the development of a unified framework for invasion impacts. PMID- 21696720 TI - [Chronic obstructive pulmonary disease and risk of fractures]. PMID- 21696721 TI - A bovine model for examining the effects of an aromatase inhibitor on ovarian function in women. AB - OBJECTIVE: To test the hypothesis that treatment with an aromatase inhibitor (letrozole) will terminate dominant ovarian follicle growth and result in the emergence of a new follicular wave, regardless of the stage of follicular development at the time of treatment. DESIGN: Prospective study. SETTING: Academic research center. ANIMAL(S): Postpubertal beef heifers. INTERVENTION(S): Randomized trial involving treatment with letrozole on days 1-3, 3-5, 5-7 (day 0 = pretreatment ovulation) or no treatment. MAIN OUTCOME MEASURE(S): Follicular development, corpus luteum (CL) development, hormone profiles, and plasma aromatase inhibitor concentration. RESULT(S): Multiple doses of letrozole lengthened the period of follicular dominance, delayed emergence of the next follicular wave, and resulted in a larger CL regardless of the stage of the follicular wave in which treatments were initiated. No effects on circulating FSH concentrations were detected, but the stimulatory effects on the dominant follicle and CL were associated with increased plasma concentrations of LH in letrozole-treated animals. Plasma P concentrations were numerically higher throughout the luteal phase in letrozole-treated versus control heifers, but differences were not significant. CONCLUSION(S): The results provide rationale for the hypothesis that the mechanism of action responsible for the stimulatory effect of aromatase inhibitors on ovarian function involves an elevation in circulating concentrations of LH rather than FSH. PMID- 21696722 TI - The impact of BMI on polytrauma outcome. AB - BACKGROUND: Varying results have been reported concerning the effect of body mass index (BMI) on polytrauma outcome. Although most studies focus on obesity and its associated preexisting medical diseases as a predictor for increased mortality rates, there is evidence that polytrauma patients with underweight also face an inferior outcome. METHODS: Records of 5766 trauma patients (minimum 18 years of age, Injury Severity Score >= 16, treated from 2004 to 2008) documented in the Trauma Registry of the German Society for Trauma Surgery were subclassified into 4 BMI groups and analysed to assess the impact of BMI on polytrauma outcome. RESULTS: Underweight (BMI Group I) as well as obesity (BMI Group IV) in polytraumatized patients are associated with significantly increased mortality by multivariate logistic regression analysis with hospital mortality as the target variable (adjusted odds ratio for BMI Group I, 2.1 (95% CI 1.2-3.8, p = 0.015); for BMI Group IV, 1.6 (95% CI 1.1-2.3, p = 0.009)). Simple overweight (BMI Group III) does not qualify as a predictor for increased mortality (odds ratio 1.0; 95% CI 0.8-1.3). CONCLUSIONS: There is a significant correlation between obesity, underweight, and increased mortality in polytraumatized patients. Efforts to promote optimal body weight may reduce not only the risk of chronic diseases but also the risk of polytrauma mortality amongst obese and underweight individuals. PMID- 21696723 TI - Chondrocytes or adult stem cells for cartilage repair: the indisputable role of growth factors. AB - Articular cartilage is easily injured but difficult to repair and cell therapies are proposed as tools to regenerate the defects in the tissue. Both differentiated chondrocytes and adult mesenchymal stem cells (MSCs) are regarded as cells potentially able to restore a functional cartilage. However, it is a complex process from the cell level to the tissue end product, during which growth factors play important roles from cell proliferation, extracellular matrix synthesis, maintenance of the phenotype to induction of MSCs towards chondrogenesis. Members of the TGF-beta superfamily, are especially important in fulfilling these roles. Depending on the cell type chosen to restore cartilage, the effect of growth factors will vary. In this review, the roles of these factors in the maintenance of the chondrocyte phenotype are discussed and compared with those of factors involved in the repair of cartilage defects, using chondrocytes or adult mesenchymal stem cells. PMID- 21696724 TI - Does the use of a "track and trigger" warning system reduce mortality in trauma patients? AB - INTRODUCTION: Despite the lack of robust evidence, numerous different "track and trigger" warning systems have been implemented. These have only been validated in an emergency medical admissions setting. The Modified Early Warning Score (MEWS) is the chosen track and trigger system used in the University Hospitals of Leicester trauma unit, but has not been validated in trauma patients. A considerable proportion of all trauma admissions are elderly patients with proximal femoral fractures and significant co-morbidities. Early recognition of physiological deterioration and prompt action could therefore be lifesaving in this patient group. AIM: To identify whether the implementation of the MEWS system coupled with a critical care outreach service resulted in a reduction in mortality in a busy trauma unit. METHOD: A retrospective study. The MEWS system was implemented in all trauma and orthopaedic wards at the Leicester Royal Infirmary in the summer of 2005. The numbers of emergency trauma inpatient admissions and deaths from January 2002 to December 2009 were obtained. The diagnosis, primary procedures and cause of death, if known, were noted. Comparisons were made pre- and post-MEWS. Student's t-test was used for statistical analysis. RESULTS: 32,149 patients were admitted (55% male; 45% female). Overall there were 889 deaths (77% female; 33% male, P<0.0001). The in hospital mortality rate for orthopaedic trauma patients was 2.8% throughout the 7 year study period. 61% of those who died were admitted with proximal femoral fractures. The modal age group with the highest mortality was 81-90 years. Overall, females had a considerably greater mortality rate than males. The mortality rate was lower post-MEWS in males (1.82-1.418%; P=0.214), females (4.871-3.364%; P=0.108) and all patients (3.215-2.294%; P=0.092), but this was not statistically significant. CONCLUSION: The use of a track and trigger warning system has not led to a statistically significant reduction in mortality in trauma patients. In view of the apparent lack of clinical effectiveness of the MEWS/outreach partnership, the cost effectiveness of this initiative needs to be questioned. Possible reasons for these findings include: failure of the MEWS to be correctly applied, inadequate action once the threshold is triggered, or unsuitability of this tool for this patient population. A better system for identifying and treating elderly, medically unwell trauma patients with co morbidities needs to be developed. PMID- 21696725 TI - Circulating cellular and humoral elements of immune function following splenic arterial embolisation or splenectomy in trauma patients. AB - BACKGROUND: Splenectomy impairs the ability to combat infection, especially with encapsulated organisms. However, there is limited understanding of the impact of splenic arterial embolisation on immune function. Our hypothesis was that embolisation would not impair systemic immune function. This study examines elements of cellular and humoral immunity in patients undergoing splenic embolisation or splenectomy for trauma. PATIENTS AND METHODS: Splenic embolisation (SE) and splenectomy patients (S) were compared to blunt trauma patients without splenic injury (NS). Lymphocyte counts, natural-killer cells, serum complement (C3, C4), and properdin levels were assayed. RESULTS: No significant differences in total, helper, or suppressor T-lymphocytes, complement (C3, C4), or properdin were found. B-lymphocyte counts were higher in S (602+/ 445cells/mm(3)) than SE (238+/-114cells/mm(3)) or NS (293+/-153cells/mm(3)) (p=.003 for pairwise comparisons). S also had more natural killer T-cells than NS (325+/-170cells/mm(3) vs. 174+/-116cells/mm(3), p=.004). CONCLUSION: Splenic embolisation does not alter the measured immunologic parameters. The absence of sensitive markers for splenic immune function limits the ability to assess the impact of embolisation for trauma. PMID- 21696726 TI - Determinants of patient satisfaction after cesarean delivery at a university teaching hospital in Nigeria. AB - OBJECTIVES: To assess the prevalence of satisfaction, and associated factors, among parturients who had recently delivered by cesarean. METHODS: In a descriptive cross-sectional study, women who delivered by cesarean at the University of Benin Teaching Hospital, Nigeria, were enrolled between April and July 2010. A simple, qualitative, semi-structured researcher-administered questionnaire was used for data collection. Data analysis was done via SPSS version 16. RESULTS: Among 220 women who delivered by cesarean, 211 women were enrolled in the study and were interviewed 2-5 days after delivery. The mean age was 30.8 +/- 5.1 years, and the median parity was 1. An initial negative reaction to the decision for cesarean delivery was reported by 76% of respondents, 19% were indifferent, and 5% reported an initial positive reaction. Satisfaction with delivery by cesarean was reported by 80% of the respondents. Satisfaction with cesarean delivery was significantly associated with age, level of education, initial reaction to the decision for cesarean delivery, and elective cesarean. CONCLUSION: Most parturients expressed overall satisfaction after delivery by cesarean. There is a need for in-depth studies in low-income countries to further evaluate satisfaction with regard to various aspects of the cesarean delivery experience. PMID- 21696727 TI - Gray-scale ultrasound versus CA-125 levels for predicting malignancy in adnexal masses. PMID- 21696728 TI - Maternal and perinatal outcomes of pregnancies associated with tuberculosis in eastern Sudan. PMID- 21696729 TI - Primary yolk sac tumor of the endometrium. PMID- 21696730 TI - The role of faith-based organizations in maternal and newborn health care in Africa. AB - BACKGROUND: Global disparities in maternal and newborn health represent one of the starkest health inequities of our times. Faith-based organizations (FBOs) have historically played an important role in providing maternal/newborn health services in African countries. However, the contribution of FBOs in service delivery is insufficiently recognized and mapped. OBJECTIVES: A systematic review of the literature to assess available evidence on the role of FBOs in the area of maternal/newborn health care in Africa. SEARCH STRATEGY: MEDLINE and EMBASE were searched for articles published between 1989 and 2009 on maternal/newborn health and FBOs in Africa. RESULTS: Six articles met the criteria for inclusion. These articles provided information on 6 different African countries. Maternal/newborn health services provided by FBOs were similar to those offered by governments, but the quality of care received and the satisfaction were reported to be better. CONCLUSION: Efforts to document and analyze the contribution of FBOs in maternal/newborn health are necessary to increase the recognition of FBOs and to establish stronger partnerships with them in Africa as an untapped route to achieving Millennium Development Goals 4 and 5. PMID- 21696731 TI - A study of maternal mortality in 8 principal hospitals in Pakistan in 2009. AB - OBJECTIVES: To determine maternal mortality to assess the achievement of Millennium Development Goal 5 in Pakistan and suggest remedial measures. METHODS: Throughout 2009, maternal deaths occurring in obstetrics and gynecology departments in 8 hospitals in Rawalpindi and Islamabad, Pakistan, were recorded. A data form was filled in by the duty registrar at the time of death. Data were analyzed via SPSS. RESULTS: During the study period, there were 47209 live births and 108 maternal deaths (age 17-45 years). Among those who died, 30% were primigravidas, 50% had a parity of 1-4, and 20% had a parity of 5 or more; 20.4% had not delivered, 40.7% had vaginal delivery, and 36.1% had cesarean delivery; 67.6% were unbooked and 32.4% were booked (14 under care of a consultant and 21 under care of a medical officer); 73%, 22%, and 5% died in the first, second, and third trimesters, respectively; 17.5% died prenatally, 4.6% during labor, and 78% postpartum; 73% were in a critical condition and 8% were dead on arrival. Eclampsia, postpartum hemorrhage, and sepsis caused 23, 13, and 13 deaths, respectively. CONCLUSION: Maternal death can be effectively managed by skilled care during pregnancy, childbirth, and the postnatal period. PMID- 21696733 TI - Impact of pH on the antifungal susceptibility of vaginal Candida albicans. AB - OBJECTIVE: To investigate the antifungal susceptibility at pH 7.0 and pH 4.0 of 5 antifungal agents against Candida albicans isolated from patients with vulvovaginal candidiasis. METHODS: Antifungal susceptibility testing at pH 7.0 and pH 4.0 was performed using the broth microdilution method (CLSI, document M27 A2). RESULTS: The minimal inhibitory concentrations (MICs) of miconazole, clotrimazole, fluconazole, and nystatin against C. albicans at pH 4.0 were significantly higher than those at pH 7.0 (0.25 vs 0.03 MUg/mL, 0.50 vs 0.03 MUg/mL, 0.50 vs 0.25 MUg/mL, and 32 vs 2 MUg/mL, respectively; P<0.001), whereas the MIC of itraconazole at pH 4.0 was lower than that at pH 7.0 (0.030 vs 0.125 MUg/mL; P<0.001). The susceptibility rate of C. albicans to itraconazole at pH 4.0 was significantly higher than at pH 7.0 (95.0% vs 51.7%; P<0.001). The susceptibility rate to itraconazole at pH 7.0 was significantly lower than the susceptibility rate to fluconazole (51.7% vs 100.0%; P<0.001), whereas the susceptibility rates to the 2 drugs were similar at pH 4.0 (95.0% and 96.7%, respectively). CONCLUSION: Media at different pH values should be used for sensitivity tests according to the environment of C. albicans. PMID- 21696732 TI - Comparison of single-dose and multiple-dose antibiotics for lower urinary tract infection in pregnancy. AB - OBJECTIVE: To compare the efficacy of fosfomycin trometamol, cefuroxime axetil, and amoxicillin clavulanate antibiotics, and to assess the difference in patient compliance, in the treatment of urinary tract infections during pregnancy. METHODS: Between September 2007 and May 2008, 90 out of 324 pregnant women with complaints of lower urinary tract infection, who were followed at the outpatient clinic or referred to the emergency department of Vakif Gureba Education and Research Hospital, were enrolled in a prospective study. Patients were randomized into 3 equal groups for treatment with single-dose fosfomycin trometamol, or 5 day courses of amoxicillin clavulanate or cefuroxime axetil. After follow-up, study data were obtained for 28, 27, and 29 patients, respectively. RESULTS: The treatment groups did not differ significantly in terms of demographics, clinical success rate, microbiological cure rate, or adverse effects. Significantly higher drug compliance was observed in the fosfomycin trometamol group than in the other 2 groups (P<0.05). CONCLUSION: Treatment with a single dose of fosfomycin trometamol was as effective for UTI as the standard course of treatment with amoxicillin clavulanate or cefuroxime axetil. Fosfomycin trometamol may be a preferable treatment for UTI because of its simpler use and better rates of compliance. PMID- 21696735 TI - Residents' experiences of interpersonal factors in nursing home care: a qualitative study. AB - BACKGROUND: With life expectancy lengthening, the number of those who will require care in a nursing home will increase dramatically in the next 20 years. Nursing home residents are frail older adults with complex needs, dependent on advanced nursing care. Long-term residents in nursing homes have long-term relationships with the nurses, which require a unique approach to the interpersonal aspects of nursing care. Understanding what is experienced as care quality, including quality of interpersonal processes, requires insight into the residents' perspectives for best value in care to be realized. OBJECTIVE: Main objective was to describe the nursing home residents' experience with direct nursing care, related to the interpersonal aspects of quality of care. DESIGN: A descriptive, exploratory design was used. SETTINGS: Four public municipal nursing homes in Norway with long-term residents were purposely selected for the study. PARTICIPANTS: Fifteen mentally lucid residents were included. The inclusion criteria were aged 65 and over, being a resident of the nursing home for one month or longer, and physical and mental capacity to participate in the interview. METHOD: In-depth interviews with the residents were performed. The transcribed interviews were analyzed using meaning categorizing. RESULTS: The residents emphasized the importance of nurses acknowledging their individual needs, which included need for general and specialized care, health promotion and prevention of complications, and prioritizing the individuals. The challenging balance between self-determination and dependency, the altered role from homeowner to resident, and feelings of indignity and depreciation of social status were key issues in which the residents perceived that their integrity was at risk in the patient-nurse interaction and care. Psychosocial well-being was a major issue, and the residents expressed an important role of the nursing staff helping them to balance the need for social contact and to be alone, and preserving a social network. CONCLUSIONS: Quality nursing care in nursing home implies a balanced, individual approach to medical, physical and psychosocial care, including interpersonal aspects of care. The interpersonal relationship between resident and nurse implies long-term commitment, reciprocal relationship on a personal level and interpersonal competence of the nurses to understand each resident's needs. PMID- 21696734 TI - A qualitative study to explore the impact of foot ulceration on health-related quality of life in patients with rheumatoid arthritis. AB - BACKGROUND: The overall prevalence of foot ulceration occurring in patients with rheumatoid arthritis is estimated at 10-13% in the UK, with a high rate of recurrence. In contrast with diabetes, there has been a lack of research in this area and the impact of the problem from a patient perspective is poorly understood. OBJECTIVE: To explore the added impact of foot ulceration on health related quality of life in non-diabetic patients with rheumatoid arthritis. DESIGN: Qualitative research design to elicit patient experiences. SETTINGS: Participants were recruited from hospital and community podiatry clinics in West Yorkshire (UK) between May 2008 and June 2009. PARTICIPANTS: A purposive sample of 23 adults with RA and open foot ulceration; patients with diabetes were excluded. METHODS: In-depth interviews were conducted with 23 participants using a topic guide. Framework analysis was employed to facilitate a case and theme based approach to identifying descriptive and explanatory accounts of the impact of foot ulceration on health-related quality of life. RESULTS: Participants indicated that foot ulceration impacted on their health-related quality of life across physical, social and psychological domains. Pain attributed to the ulcer was linked to new walking disability, affecting participants' lives in every domain. Pain and walking disability added to existing limitations in undertaking household tasks and personal care independently. Keeping the ulcer dry was a major problem for many in relation to personal hygiene. Participants described new restrictions in leisure activities which reduced social participation. Increased footwear/clothing restrictions affected self esteem and altered body image. An economic cost was attached to wound care and footwear alterations. Low mood, anxiety, frustration were attributed to the added impact of foot ulceration on their lives. Perceptions of impact fluctuated over time in relation to physical symptoms experienced by participants and the additional social limitations posed by the ulcer. CONCLUSION: Foot ulceration has an additional impact on health-related quality of life over and above the impact of rheumatoid arthritis in every domain. Whilst prevention is the ultimate goal, high rates of recurrence mean that clinicians need to consider ways to improve quality of life for affected patients throughout the patient journey. PMID- 21696736 TI - Plasma ferritin levels, genetic variations in HFE gene, and coronary heart disease in Chinese: a case-control study. AB - BACKGROUND: The association between body iron stores and coronary heart disease (CHD) was inconsistent. We sought to explore this association in Chinese Han population and further examine the association of the variations in hemochromatosis (HFE) gene and CHD risk. METHODS: We conducted a case-control study including 1334 CHD patients and 1334 age- and sex-frequency matched controls. The plasma ferritin levels were measured by enzyme linked immunosorbent assay. Genotypes of the tagging single nucleotide polymorphisms (tagSNPs) were determined by TaqMan SNP allelic discrimination. RESULTS: The plasma ferritin levels in CHD cases (197.9MUg/L [2.7-932.9MUg/L]) were higher than those in controls (179.9MUg/L [21.1-878.2MUg/L]; P=0.028). The odds ratios (ORs) across the tertiles of plasma ferritin levels were 1.0 (reference), 0.93 (0.76-1.13), and 1.23 (1.02-1.48; P for trend=0.028). Adjustment for the traditional risk factors attenuated the associations to null (P for trend=0.22). Compared with the TT genotype of tagSNP rs9366637, subjects with C allele had higher risk of CHD (OR=1.35 for TC and 1.76 for CC; P=0.001 and <0.001 respectively). After adjustment for the conventional risk factors the results remained unchanged. We did not find significantly different plasma ferritin levels among different genotypes of rs9366637 (P=0.52). CONCLUSIONS: The plasma ferritin levels were not significantly associated with CHD risk. However, the SNP rs9366637 in HFE gene was associated with higher CHD risk in Chinese Han population. The underlie mechanism remained to be elucidated in further studies. PMID- 21696737 TI - Antiatherogenic effects of newly developed apolipoprotein A-I mimetic peptide/phospholipid complexes against aortic plaque burden in Watanabe-heritable hyperlipidemic rabbits. AB - This study analyzed the antiatherogenic effects of newly developed apolipoprotein A-I (ApoA-I) mimetic peptide/phospholipid complexes (ETC-642) against the aortic plaque burden in vivo. We used human macrophage cells to analyze cholesterol efflux by ETC-642. Watanabe-heritable hyperlipidemic (WHHL) rabbits were divided into 3 groups: low- (15mg/kg) and high-dose ETC-642 (50mg/kg), and placebo. The test material was injected twice/week for 12 weeks. The aortic plaque burden was assessed by intravascular ultrasound (IVUS) at 0 and 12 weeks. Plasma lipid profiles were analyzed by capillary isotachophoresis every 4 weeks. ETC-642 had an effect on cholesterol efflux comparable to that of conventional rHDL. In WHHL rabbits, high-dose ETC-642 inhibited the progression of aortic atherosclerosis compared to placebo. There was no change in the percentage of plaque volume (%PV) in the high-dose group between before (30.9%) and after infusion (28.6%), whereas there was a significant increase in the control group from 27.8% to 37.9%. ETC 642 significantly reduced charge-modified low-density lipoprotein (LDL) by converting more negative-charged modified LDL to less negative-charged LDL, and reduced small dense (sd) LDL by converting it into large, buoyant (lb) LDL. Changes in the %PV were positively correlated with changes in negative-charged modified LDL (r=0.61, p<0.01) and sdLDL (r=0.59, p<0.01), and negatively correlated with changes in less negative-charged LDL (r=-0.43, p<0.01) and lbLDL (r=-0.57, p<0.01). In conclusion, the ETC-642-induced remodeling of sdLDL to large and lbLDL and the enhancement of cholesterol efflux may prevent progression of the aortic plaque burden. HDL-based therapy may be useful for preventing the progression of plaque volume. PMID- 21696738 TI - Macrophage cholesterol efflux to plasma and HDL in subjects with low and high homocysteine levels: a FIELD substudy. AB - OBJECTIVES: Increases of homocysteine (Hcy) by fenofibrate correlated inversely to changes in HDL-C and apoA-I in the FIELD study. This finding raised the question whether high Hcy may influence HDL function and counteract benefits of fenofibrate on cardiovascular outcomes. In a subset of the FIELD study we investigated whether fenofibrate therapy or high Hcy, separately or in concert, modulate: (1) ability of plasma or HDL to facilitate cholesterol efflux from THP 1 foam cells; (2) plasma potential to generate prebeta-HDL; (3) plasma phospholipid transfer protein (PLTP) activity, serum PON-1 mass and activity, HDL particle size and distribution. METHODS: We selected 33 subjects in the FIELD fenofibrate arm according to quartiles of Hcy at 5th year: 17 subjects were in the lowest (Low Hcy group) and 16 subjects were in the highest quartile (High Hcy group). In addition, 14 subjects allocated to placebo were matched by close-out Hcy levels to Low Hcy group. This design allowed us to examine the effects of both fenofibrate (comparison between placebo vs Low Hcy groups) and Hcy (comparison between close-out Low and High Hcy groups) on plasma and HDL ability to facilitate cellular cholesterol removal in the efflux assay in vitro using THP 1 foam cells. RESULTS: Hcy levels were 13.3+/-0.7 MUmol/L (placebo), 13.2+/-2 MUmol/L (Low Hcy) and 27.4+/-6.5 MUmol/L (High Hcy). Cholesterol efflux values to HDL and plasma, percentage of plasma prebeta-HDL, PLTP activity, serum PON-1 mass and HDL particle size and distribution were similar in both fenofibrate groups and comparable to those of the placebo group. CONCLUSIONS: In the present study cohort fenofibrate and high Hcy levels did not modulate HDL and plasma functions in the first step of reverse cholesterol transport, cholesterol efflux from foam cells. PMID- 21696739 TI - Relationship of coronary artery plaque composition to coronary artery stenosis severity: results from the prospective multicenter ACCURACY trial. AB - OBJECTIVES: The purpose of this study was to determine the relationship of coronary artery plaque composition as detected by coronary computed tomographic angiography (CCTA) to luminal diameter stenosis severity quantified by quantitative coronary angiography (QCA) in individuals without known coronary artery disease (CAD) presenting with stable chest pain syndrome. BACKGROUND: While CCTA has been previously evaluated for its ability to detect and exclude coronary artery stenosis, CCTA also permits assessment of other important plaque characteristics, including plaque composition. Identification of the relationship between plaque composition by CCTA and plaque severity by invasive angiography may provide valuable insight into the pathophysiology of coronary artery plaque. METHODS: Patients enrolled in the ACCURACY trial, a 16-site multicenter study of patients with stable chest pain syndrome but without known CAD undergoing both CCTA and invasive coronary angiography (ICA), comprised the study population. CCTAs were scored on a per-segment basis for plaque composition and graded as non calcified (>70% non-calcified), calcified (>70% calcified) or "mixed" (30-70% non calcified or calcified) by concordance of >= 2 of 3 readers. CCTAs were also scored on a per-patient basis, and individuals were categorized as possessing primarily non-calcified plaques, primarily calcified plaques or primarily mixed plaques. Quantitative coronary angiography (QCA) was performed in all patients, used as the reference standard for stenosis severity, and interpreted blinded to patient characteristics and CCTA results. RESULTS: 230 subjects comprised the study population (59.1% male, 57 +/- 10 years). QCA was performed in all subjects following CCTA (mean inter-test interval 5.9 +/- 4.3 days), and demonstrated obstructive CAD in 24.8% and 13.9% at the 50% and 70% stenosis severity threshold, respectively. On a per-segment based analysis, obstruction by QCA at both the 50% and 70% stenoses thresholds was more often for mixed composition plaques by CCTA (69.1% and 67.9%, respectively), as compared to non-calcified plaques (24.7% and 28.6%, respectively) and calcified plaques (6.1% and 3.6%, respectively) [p < 0.01 for comparisons]. On a per-patient basis, patients with mixed plaque or mixtures of plaque types more often exhibited obstructive coronary stenosis by QCA at the 50% level (39/96; 40.6%) compared to those with primarily non-calcified (12/43; 27.9%) or primarily calcified (4/29; 13.8%) plaques [p = 0.02]. CONCLUSIONS: In this multicenter trial of chest pain patients without known CAD, QCA-confirmed obstructive coronary stenosis was associated with mixed plaque composition by CCTA at both the per-segment and the per-patient levels. Coronary artery segments exhibiting calcified plaque were rarely associated with obstructive coronary stenosis. PMID- 21696740 TI - Thoracic aortic atherosclerosis in patients with aortic regurgitation. AB - OBJECTIVE: Hemodynamic forces are potential determinants of aortic atherosclerosis. Aortic regurgitation (AR) alters the flow pattern in the aorta. However, the association between AR and aortic atherosclerosis is not well known. METHODS: We assessed the presence, extent and distribution of atherosclerotic lesions in the aorta of 42 patients with chronic AR and compared them to 40 patients with similar risk factor profile for atherosclerosis and no valvular disease. RESULTS: There was no difference in the extent of atheroma in the ascending aorta and aortic arch between patients with and without AR. Descending aortic atheroma was evident in 25 patients with AR (60%) and 12 patients without AR (30%, p=0.01). AR was found to be the only predicting factor for the presence of aortic atherosclerosis in the descending aorta (odds ratio 4.1; 95% CI 1.2 14.3, p=0.03). CONCLUSIONS: There is an increased prevalence of descending aortic atherosclerosis in patients with significant AR. PMID- 21696741 TI - Turbulence downstream of subcoronary stentless and stented aortic valves. AB - Regions of turbulence downstream of bioprosthetic heart valves may cause damage to blood components, vessel wall as well as to aortic valve leaflets. Stentless aortic heart valves are known to posses several hemodynamic benefits such as larger effective orifice areas, lower aortic transvalvular pressure difference and faster left ventricular mass regression compared with their stented counterpart. Whether this is reflected by diminished turbulence formation, remains to be shown. We implanted either stented pericardial valve prostheses (Mitroflow), stentless valve prostheses (Solo or Toronto SPV) in pigs or they preserved their native valves. Following surgery, blood velocity was measured in the cross sectional area downstream of the valves using 10MHz ultrasonic probes connected to a dedicated pulsed Doppler equipment. As a measure of turbulence, Reynolds normal stress (RNS) was calculated at two different blood pressures (baseline and 50% increase). We found no difference in maximum RNS measurements between any of the investigated valve groups. The native valve had significantly lower mean RNS values than the Mitroflow (p=0.004), Toronto SPV (p=0.008) and Solo valve (p=0.02). There were no statistically significant differences between the artificial valve groups (p=0.3). The mean RNS was significantly larger when increasing blood pressure (p=0.0006). We, thus, found no advantages for the stentless aortic valves compared with stented prosthesis in terms of lower maximum or mean RNS values. Native valves have a significantly lower mean RNS value than all investigated bioprostheses. PMID- 21696742 TI - Numerical simulation of blood pulsatile flow in a stenosed carotid artery using different rheological models. AB - Symmetrical 30-60% stenosis in a common carotid artery under unsteady flow condition for Newtonian and six non-Newtonian viscosity models are investigated numerically. Results show power-law model produces higher deviations, in terms of velocity and wall shear stress in comparison with other models while generalized power-law and modified-Casson models are more prone to Newtonian state. Comparing separation length of recirculation region at different critical points of cardiac cycle confirms the necessity of considering blood flow in unsteady mode. Increasing stenosis intensity causes flow patterns more disturbed downstream of the stenosis and WSS appear to develop remarkably at the stenosis throat. PMID- 21696743 TI - On the derivation of passive 3D material parameters from 1D stress-strain data of hydrostats. AB - The present paper offers a novel equivalent-pressure approach to the derivation of isotropic passive muscle parameters from 1D stress-strain data sets. The approach aims specifically at the identification of material parameters in hydrostats, in which case the equivalent-force approach that is common for skeletal muscle generates suboptimal results. Instead, an equivalent-pressure hypothesis is formulated which provides more adequate boundary conditions for the concluding curve-fitting procedure. The choice of an appropriate constitutive description is decisive for the quality of the deduced parameter sets. Here, a Yeoh material law is chosen for the model of a squid tentacle. Parameters derived by both, equivalent-force and equivalent-pressure algorithms, are compared, illustrating the applicability limits of either. They are implemented in a finite element model of the tentacle. A prey-capture strike is simulated and compared to data from literature. The hydrostat-specific interpretation of the equivalent pressure hypothesis is shown to match the reference very well. PMID- 21696744 TI - Automatic recognition of falls in gait-slip training: Harness load cell based criteria. AB - Over-head-harness systems, equipped with load cell sensors, are essential to the participants' safety and to the outcome assessment in perturbation training. The purpose of this study was to first develop an automatic outcome recognition criterion among young adults for gait-slip training and then verify such criterion among older adults. Each of 39 young and 71 older subjects, all protected by safety harness, experienced 8 unannounced, repeated slips, while walking on a 7m walkway. Each trial was monitored with a motion capture system, bilateral ground reaction force (GRF), harness force, and video recording. The fall trials were first unambiguously indentified with careful visual inspection of all video records. The recoveries without balance loss (in which subjects' trailing foot landed anteriorly to the slipping foot) were also first fully recognized from motion and GRF analyses. These analyses then set the gold standard for the outcome recognition with load cell measurements. Logistic regression analyses based on young subjects' data revealed that the peak load cell force was the best predictor of falls (with 100% accuracy) at the threshold of 30% body weight. On the other hand, the peak moving average force of load cell across 1s period, was the best predictor (with 100% accuracy) separating recoveries with backward balance loss (in which the recovery step landed posterior to slipping foot) from harness assistance at the threshold of 4.5% body weight. These threshold values were fully verified using the data from older adults (100% accuracy in recognizing falls). Because of the increasing popularity in the perturbation training coupling with the protective over-head-harness system, this new criterion could have far reaching implications in automatic outcome recognition during the movement therapy. PMID- 21696745 TI - Simple complementary liquid chromatography and mass spectrometry approaches for the characterization of triacylglycerols in Pinus koraiensis seed oil. AB - A new simple strategy to identify triacylglycerols (TAGs) in oils and fats was performed using on line coupling of non aqueous reversed phase chromatography electrospray ionization-mass spectrometry (NARP-LC-ESI-MS(2)) with silver nitrate (AgNO(3)) as post-column additive, and chromatographic data (partition number information and both the graphs of log k vs. number of double bond (DBN) and carbon number (CN)). NARP liquid chromatography permitted to separate TAGs composed of Delta5 and Delta9 but not from Delta11 double bond location on alkyl chain of fatty acid residues. Silver cationization improved the sensitivity by a factor one hundred. MS(2) information gave unambiguously the nature of three fatty acid residues bonded to glyceryl backbone of TAGs while log k against DBN and CN curves discriminated between the same molecular mass TAG isomers (whose constitutive fatty acid residues are double bond position and configuration isomers). Combination of structural information given by MS with chromatographic retention laws led to the development of a general methodology for determination of the structure of TAGs in lipids. This methodology was applied to Pinus koraiensis seed oil for which some uncommon TAGs are present. It permitted the identification of 58 TAGs in this oil. The experimental proof of 29 uncommon TAGs as component of this oil is demonstrated. Among them 26 were minor constituents. PMID- 21696747 TI - Model simulation and experimental verification of a cation-exchange IgG capture step in batch and continuous chromatography. AB - The cation-exchange capture step of a monoclonal antibody (mAb) purification process using single column batch and multicolumn continuous chromatography (MCSGP) was modeled with a lumped kinetic model. Model parameters were experimentally determined under analytical and preparative conditions: porosities, retention factors and mass transfer parameters of purified mAb were obtained through a systematic procedure based on retention time measurements. The saturation capacity was determined through peak fitting assuming a Langmuir-type adsorption isotherm. The model was validated using linear batch gradient elutions. In addition, the model was used to simulate the start-up, cyclic steady state and shut down behavior of the continuous capture process (MCSGP) and to predict performance parameters. The obtained results were validated by comparison with suitable experiments using an industrial cell culture supernatant. Although the model was not capable of delivering quantitative information of the product purity, it proved high accuracy in the prediction of product concentrations and yield with an error of less than 6%, making it a very useful tool in process development. PMID- 21696746 TI - Membrane-assisted capillary isoelectric focusing coupling with matrix-assisted laser desorption/ionization-Fourier transform mass spectrometry for neuropeptide analysis. AB - Herein we report a highly efficient and reliable membrane-assisted capillary isoelectric focusing (MA-CIEF) system being coupled with MALDI-FTMS for the analysis of complex neuropeptide mixtures. The new interface consists of two membrane-coated joints made near each end of the capillary for applying high voltage, while the capillary ends were placed in the two reservoirs which were filled with anolyte (acid) and catholyte (base) to provide pH difference. Optimizations of CIEF conditions and comparison with conventional CIEF were carried out by using bovine serum albumin (BSA) tryptic peptides. It was shown that the MA-CIEF could provide more efficient, reliable and faster separation with improved sequence coverage when coupled to MALDI-FTMS. Analyses of orcokinin family neuropeptides from crabs Cancer borealis and Callinectes sapidus brain extracts have been conducted using the established MA-CIEF/MALDI-FTMS platform. Increased number of neuropeptides was observed with significantly enhanced MS signal in comparison with direct analysis by MALDI-FTMS. The results highlighted the potential of MA-CIEF as an efficient fractionation tool for coupling to MALDI MS for neuropeptide analysis. PMID- 21696748 TI - Electrolyte effect on adsorption and the phase transition from microstructures to nanostructures in ionic/ionic surfactants mixture. AB - The effect of salt concentration on intermicellar interactions and aggregate structures of anionic and cationic-rich mixtures of CTAB (cetyltrimethylammonium bromide) and SDS (sodium dodecyl sulfate) were investigated with conductometry, surface tension, zeta potential, cyclic voltammetry measurements and by determining the surfactant NMR self-diffusion coefficients. The critical aggregate concentration (CAC), surface excess (Gamma(max)), and mean molecular surface area (A(min)) were determined from plots of the surface tension (gamma) as a function of the log of total surfactant concentration. The electrochemical behavior of cationic-anionic (catanionic) mixed surfactant and self-assembled surfactant monomers at Pt wire electrode were studied by cyclic voltammetry (CV). A variation in the peak current versus the total concentration of surfactant allow us to evaluate the CAC and related parameters from regular solution theory along with the diffusion coefficient of the electroactive species. It was observed that, for both the planar air/aqueous interface and micellar systems, the nonideality decreased as the amount of electrolyte in the aqueous medium was increased. Finally, we investigated the variations of electrostatic, transfer and steric free energy in phase transition between mixed micelle and vesicle in the presence of electrolyte using the presented model by our groups. PMID- 21696750 TI - Effects of confinement on the molar enthalpy of argon adsorption in graphitic cylindrical pores: a grand canonical Monte Carlo (GCMC) simulation study. AB - Using a grand canonical Monte Carlo simulation, we study argon adsorption in graphitic cylindrical pores to investigate the differences between the isosteric heat and the integral molar enthalpy under subcritical and supercritical conditions and compare these results against those for a flat graphite surface to investigate the role of confinement on the enthalpy change of adsorption. The isosteric heat curve is finite under subcritical conditions, but for supercritical adsorption, it becomes infinite at the pressure where the excess concentration versus pressure is maximum. This can be circumvented using the integral molar enthalpy, which is a better variable to describe the energy change for supercritical adsorption. Finally, the effects of pore geometry (radius and length) on argon adsorption under subcritical and supercritical conditions are discussed. PMID- 21696749 TI - Computational methods for intramolecular electron transfer in a ferrous-ferric iron complex. AB - The limitations of common theoretical and molecular computational approaches for predicting electron transfer quantities were assessed, using an archetypal bridged ferrous-ferric electron transfer system in aqueous solution. The basis set effect on the magnitude of the electronic coupling matrix element computed using the quasi-diabatic method was carefully examined, and it was found that the error related to a poor basis set could exceed the thermal energy at room temperature. A range of approaches to determining the external (solvent) reorganization energy were also investigated. Significant improvements from the Marcus continuum model can be obtained by including dipolar Born-Kirkwood-Onsager correction. In this regard, we also found that Klamt's Conductor-Like Screening Model (COSMO) yields estimations of the external reorganization energy similar to those obtained with explicit solvent molecular dynamics simulations if the fast frequency modes are neglected, which makes it an attractive alternative to laborious umbrella sampling simulations. By using the COSMO model, we also confirm that a decrease in curvature of the potential energy surface is a manifestation of the dielectric saturation observed in the first solvation layer. The linearity of solvent response to the charge redistribution was assessed by analyzing the energy gap autocorrelation function as well as the solvent density and dipole moment fluctuations. Molecular dynamics was also used to evaluate the sign and magnitude of the solvent reorganization entropy and to determine its effect on the predicted electron transfer rate. Finally, we present a simple way of estimating the vibration frequency along the reaction coordinate, which also enables prediction of the mass-dependent isotopic signature of electron transfer reactions. PMID- 21696751 TI - Formation of uniform ferrocenyl-terminated monolayer covalently bonded to Si using reaction of hydrogen-terminated Si(111) surface with vinylferrocene/n decane solution by visible-light excitation. AB - Electrochemically active self-assembled monolayers (SAM) have been successfully fabricated with atomic-scale uniformity on a silicon (Si)(111) surface by immobilizing vinylferrocene (VFC) molecules through Si-C covalent bonds. The reaction of VFC with the hydrogen-terminated Si (H-Si)(111) surface was photochemically promoted by irradiation of visible light on a H-Si(111) substrate immersed in n-decane solution of VFC. We found that aggregation and polymerization of VFC was avoided when n-decane was used as a solvent. Voltammetric quantification revealed that the surface density of ferrocenyl groups was 1.4*10(-10) mol cm(-2), i.e., 11% in substitution rate of Si-H bond. VFC-SAMs were then formed by the optimized preparation method on n-type and p type Si wafers. VFC-SAM on n-type Si showed positive photo-responsivity, while VFC-SAM on p-type Si showed negative photo-responsivity. PMID- 21696752 TI - Ambient pressure effects on the electrokinetic potential of Zeonor-water interfaces. AB - Using phase-sensitive streaming potential experiments in a vacuum chamber, we demonstrate that lowering the ambient pressure of the air surrounding a hydrophobic, Zeonor microfluidic substrate results in a decrease in the time scale required for equilibration of the electrokinetic potential. At ambient air pressures below 0.74 atm, the electrokinetic potential changes from ~-84 mV to ~ 11 mV in 5 h, while the same decrease occurs in a period of over 200 h when the system is at 1 atm. Returning a sub-atmospheric system (where the electrokinetic potential had equilibrated to -11 mV) to atmospheric pressure did not result in any additional change in the electrokinetic potential. This can be described as a type of hysteresis of the electrokinetic potential with dissolved gas concentration. No time or pressure dependence was observed for the electrokinetic potential of hydrophilic (silica) substrates. PMID- 21696753 TI - Ventricular repolarization sequences on the epicardium and endocardium. Monophasic action potential mapping in healthy pigs. AB - To investigate repolarization sequence, monophasic action potentials were recorded from a mean of 153 +/- 54 left and right ventricular epicardial and endocardial sites in 10 pigs using the CARTO mapping system (Biosense Webster, Waterloo, Belgium). The activation time and end-of-repolarization (EOR) time were measured and 3-dimensional maps of activation and repolarization sequences constructed. RESULTS: In 8 of 9 pigs, both the activation and EOR times appeared first in the septum and last in the latero-basal areas on the endocardium, not on the epicardium. The EOR followed the activation sequence, both on the epicardium (in 8/9 pigs) and endocardium (in 8/8 pigs). The maximal EOR differences were 84 +/- 20 ms, whereas the local EOR differences between paired sites against each other on the left ventricular epicardium and endocardium were 11 +/- 9 ms in the apex and 12 +/- 12 ms in the anterior wall. CONCLUSION: The EOR follows the activation sequence both on the epicardium and endocardium. The apico-basal gradients are predominant repolarization gradients, as compared with the epicardial-endocardial gradients. PMID- 21696754 TI - Factors associated with failure to identify the culprit artery by the electrocardiogram in inferior ST-elevation myocardial infarction. AB - BACKGROUND: Right and left circumflex coronary artery occlusions cause inferior myocardial infarction. To improve the targeting of diagnostic and therapeutic measures individually, factors interfering with identification of the culprit artery by the electrocardiogram (ECG) were explored. METHODS: Patients with inferior preinfarction syndrome (n = 266) were included to the Danish Trial in Acute Myocardial Infarction-2 substudy. The culprit vessel was predicted by the ECG, and findings were correlated with angiography. Factors associated with false identification of the culprit artery by the ECG were examined. RESULTS: Electrocardiogram criteria for right coronary artery occlusion to predict coronary angiography findings had sensitivity, specificity, and positive and negative predictive values of 95%, 52%, 84%, and 81%. For left circumflex coronary artery occlusion, the corresponding values were 51%, 93%, 70%, and 85%, respectively. False ECG identification of the culprit artery was independently associated with left coronary dominance (P < .001; odds ratio [OR], 22.0; 95% confidence interval [CI], 7.2-67.0), multivessel disease (P = .035; OR, 2.2; 95% CI, 1.1-4.7), and absence of proximal occlusion pattern in the ECG (P = .003; OR, 4.0; 95% CI, 1.6-9.8). CONCLUSIONS: Left coronary artery dominance, multivessel disease, and absence of ECG signs of proximal culprit lesion are associated with failure to predict the culprit artery of inferior myocardial infarction by the 12 lead ECG. PMID- 21696755 TI - Pacemaker electrocardiogram with new large negative T waves: what is the cause? PMID- 21696756 TI - Ventricular fibrillation after exposure to air freshener-death just a breath away. AB - A case of ventricular fibrillation due to butane toxicity after unintentional inhalation of air freshener is reported for its rarity and to create awareness among practitioners and the public. A 25-year-old woman collapsed in the supermarket after unintended exposure to air freshener sprayed into her nostrils. Her husband started cardiopulmonary resuscitation immediately, and she was brought to the hospital. She had coarse ventricular fibrillation. Defibrillation with 360 J was given, and the rhythm reverted to normal sinus rhythm after the third shock. Epinephrine was not administered, and she was treated with esmolol infusion for ventricular ectopy. The patient recovered completely without any sequelae and was discharged on the fifth hospital day. On thin layer chromatography, the chemical content of the spray was identified to be isobutane. Avoiding epinephrine and administering beta-adrenergic blockers may protect the catecholamine-sensitized heart early during resuscitation in butane exposure cases. PMID- 21696757 TI - Skeletal muscle aldolase an overexpression in endotoxemic rats and inhibited by GSNO via potential role for S-nitrosylation in vitro. AB - BACKGROUND: Hepatic aldolase (ALD) A mRNA transcription and ALD B S-nitrosylation have been confirmed in endotoxemic rats and mice, respectively. In the present study we investigated whether the skeletal muscle ALD A shared potential for S nitrosylation to act as a hypoxia-related signaling mechanism in lipopolysaccharide (LPS) challenged rats. MATERIALS AND METHODS: Male Sprague Dawley rats were treated (i.p.) as follows, control group (n = 6) with 0.9% NaCl, tested group (n = 6) with a single dose of 2 mg/kg LPS. Protein S-nitrosylation was determined by biotin switch and dot blotting analysis. ALD A, hypoxia inducible factor 1alpha and vascular endothelial growth factor were determined by western blotting. ALD A catalytic activity treated with S-nitrosoglutathione (GSNO), an exogenous NO-donor, was examined in vitro. RESULTS: There were several S-nitrosylated proteins under basal conditions. ALD A was over-expressed in a hypoxia-related way in the skeletal muscle of LPS challenged rats. Importantly, treatment of ALD A with GSNO at concentration 50 MUmol/L ~ 1000 MUmol/L that inhibited catalytic activity, increased the number of S-nitrosylated bands and led to hyper-nitrosylation of basally S-nitrosylated proteins of ALD A. Quantization of enzyme S-nitrosothiol showed that a maximal of four cysteines per subunit was modified by S-nitrosylation in the presence of GSNO. CONCLUSIONS: These findings suggested that S-nitrosylation of ALD A might serve as a novel mechanism for controlling ALD A activity at the post-translational level in endotoxemic rats. PMID- 21696758 TI - Postoperative serum concentrations of high mobility group box chromosomal protein 1 correlates to the duration of SIRS and pulmonary dysfunction following gastrointestinal surgery. AB - OBJECTIVE: To clarify the time course of changes in the serum HMGB-1 concentrations in patients undergoing major gastrointestinal surgery, and to investigate whether the serum HMGB-1 levels correlate with the postoperative clinical course of the patients. METHODS: Twenty-eight patients with alimentary tract carcinoma who underwent elective gastrointestinal surgery were enrolled in this study. The correlation between the serum HMGB-1 levels and the postoperative clinical course were evaluated. RESULTS: Serum HMGB-1 concentrations in patients who underwent surgery for gastrointestinal cancer increased gradually during postoperative days, and reached peak concentrations on postoperative day 3 (POD3). There was a statistically significant positive correlation between the serum HMGB-1 levels on POD3 or POD5 and the duration of SIRS (r = 0.68, P < 0.001, r = 0.45, P < 0.05, respectively). A significantly positive correlation was found between the serum HMGB-1 levels on POD3 or POD5 and the heart rates on POD3 or POD5. Furthermore, there was a negative correlation between the serum HMGB-1 levels and PaO2/FiO2 ratio on POD3. CONCLUSIONS: Serum HMGB-1 levels increase after major gastrointestinal surgery, and the serum peak HMGB-1 levels correlate with the duration of SIRS and postoperative pulmonary dysfunction. PMID- 21696759 TI - The addition of lysostaphin dramatically improves survival, protects porcine biomesh from infection, and improves graft tensile shear strength. AB - BACKGROUND: Lysostaphin (LS), a naturally occurring Staphylococcal endopeptidase, has the ability to penetrate biofilm, and has been identified as a potential antimicrobial to prevent mesh infection. The goals of this study were to determine if LS adhered to porcine mesh (PM) can impact host survival, reduce the risk of long-term PM infection, and to analyze lysostaphin bound PM (LS-PM) mesh fascial interface in an infected field. METHODS: Abdominal onlay PMs measuring 3*3 cm were implanted in select groups of rats (n=75). Group assignments were based on bacterial inoculum and presence of LS on mesh. Explantation occurred at 60 d. Bacterial growth and mesh-fascial interface tensile strength were analyzed. Standard statistical analysis was performed. RESULTS: Only one out of 30 rats with bacterial inoculum not treated with LS survived. All 30 LS treated rats survived and had normal appearing mesh, including 20 rats with a bacterial inoculum (10(6) and 10(8) CFU). Mean tensile strength for controls and LS and no inoculum samples was 3.47+/-0.86 N versus 5.0+/-1.0 N (P=0.008). LS groups inoculated with 10(6) and 10(8) CFU exhibited mean tensile strengths of 4.9+/-1.5 N and 6.7+/-1.6 N, respectively (P=0.019 and P<0.001 compared with controls). CONCLUSION: Rats inoculated with S. aureus and not treated with LS had a mortality of 97%. By comparison, LS treated animals completely cleared S. aureus when challenged with bacterial concentrations of 1*10(6) and 1*10(8) with maintenance of mesh integrity at 60 d. These findings strongly suggest the clinical use of LS-treated porcine mesh in contaminated fields may translate into more durable hernia repair. PMID- 21696760 TI - Mesenchymal-specific inhibition of vascular endothelial growth factor (VEGF) attenuates growth in neonatal mice. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis and vasculogenesis. However, the role of VEGF in the regulation of neonatal mouse development is not completely defined. We sought to determine the effect of VEGF inhibition on the development of the neonatal mouse using a transgenic approach. MATERIALS AND METHODS: We generated triple transgenic mice that express the soluble VEGF receptor, (sFlt-1), specifically in the mesenchyme (dermo-1(Cre)- tetracycline reverse transcriptional activator (rtTA)(flox/flox) tet(0)-sflt-1). Mothers of the pups (transgenic and littermate controls) were fed doxycycline chow at birth for transgene activation via breast milk, and the pups were sacrificed at various time points. To test reversibility of the phenotype, mice from both groups (n = 6) were switched to normal chow at P50 and monthly weights were measured for 9 mo. RESULTS: Dermo-1(Cre)-rtTA(flox/flox)-tet(0)-sflt 1 mice were smaller compared with littermate controls at P21. There was a significant reduction in tissue VEGF levels following sFlt-1 expression. The rate of growth was reduced but did not impact overall survival after 1 y. A significant reduction in organ size as a percentage body weight was seen in the kidney and stomach, whereas the weight of the colon and spleen were relatively increased; however, no gross histologic difference was observed. After 6 mo on normal diet, the dermo-1(Cre)-rtTA(flox/flox)-tet(0)-sflt-1 mouse's weight doubled, indicating reversibility of phenotype. CONCLUSION: Mesenchymal-specific inhibition of VEGF in neonatal mice results in a severe but reversible arrest in somatic growth that does not affect overall survival at 1 yr. This mouse is a useful tool to test the function of VEGF in somatic growth. PMID- 21696761 TI - Macrophage genetic reprogramming during chronic peritonitis is augmented by LPS pretreatment. AB - BACKGROUND: Persistent and tertiary chronic peritonitis is a clinically challenging problem especially in those who are critically ill. This could be attributed to a state of immune-paralysis, known as microbial tolerance. Microbial tolerance is the diminished pro-inflammatory protein response following repeated stimulation by numerous pathogen-associated molecular patterns (PAMPs) of varying origins, which we have shown in this novel model of chronic peritonitis. We aimed in this study to investigate the molecular mechanisms behind microbial tolerance and the early innate immune response resolution in this model. METHODS: C57BL/6 mice were pretreated intra-peritoneally (IP) with saline or endotoxin LPS 10 mg/kg (LPS 10). Following pretreatment, peritonitis was induced 24 h later injecting 10(3)Klebsiella pneumonia CFU IP. Gentamicin was administered 4 h prior to infection and BID thereafter. Peritoneal exudate cells (PEC) were obtained through peritoneal lavage and RNA was isolated (n = 3) at 4, 24, and 48 h following infection. SA Biosciences(c) RT2-Profiler PCR array mouse Toll-like receptor signaling pathway (PAMM_018A) data were further analyzed by Ingenuity Pathway Inc. analysis (IPA). RESULTS: Of the 89 genes studied, 26 were significantly up-regulated (fold change > 1.2 and P value < 0.05) in the saline pretreated group at 4, 24, and 48 h after infection. There were no down-regulated genes. In the LPS-pretreated group, 35 genes were significantly up-regulated; of these genes, 13 were not increased in the saline pretreated infected mice. This left 22 up-regulated genes in both infected groups. At 4 h, 6 of these 22 genes (CHUK, HMGB1, HSPD1, IRAK2, LY96, and TLR4) were further 2-fold increased in the LPS pretreatment group compared with the saline pretreatment group. Only IRAK2 was 2-fold increased at 24 h. By 48 h, no LPS effect was seen. When applying IPA analysis, six main canonical pathways were constantly dysregulated in the same significance order in both the saline and LPS group at 4, 24, and 48 h. These were: Toll-like receptor and NF-kappaB signaling, hepatic cholestasis, interleukin-6, and LPS-mediated MAPK signaling pathways, and pattern recognition receptors of bacterial pathway. CONCLUSION: Peritonitis increased PEC gene expression associated with sepsis and a pro-inflammatory response, which was further augmented by LPS pretreatment over 24 h only. Prior exposure to LPS did not induce PEC gene tolerance to subsequent infection with Klebsiella at the mRNA level. Post-transcriptional modification as microRNA down-regulation of inflammatory cytokines could possibly explain such phenomena. PMID- 21696762 TI - Implementation of an Acuity Adaptable Patient Care Unit is associated with improved outcomes after major pulmonary resections. AB - BACKGROUND: Many centers have adapted an Acuity Adaptable Cardiothoracic Unit (AACU) to fast track cardiac surgery patients, yet few data exist on the impact of such a unit on general thoracic surgery outcomes. We examined the effects of implementing an Acuity Adaptable Cardiothoracic Unit on patients undergoing major pulmonary resections. METHODS: We reviewed data from an IRB-approved, prospective thoracic surgery database for patients during the 3-y periods pre- and post adoption of an Acuity Adaptable Cardiothoracic Unit. As surrogate endpoints to quality and cost, we examined length of stay, place of discharge, readmission rate, and 30-d mortality during these two time periods. RESULTS: A total of 488 patients underwent major pulmonary resections (416 lobectomies, 72 pneumonectomies) in this 6-y time period. Patients cared for in the AACU model had a shorter length of stay (LOS) compared with patients in a traditional ICU/general care model. The mean and median LOS for patients in the AACU model was 4.2 +/- 0.3 d and 3 d, and for the traditional ICU/general care model these were 7.8 +/- 1.2 d and 5 d, respectively (P < 0.001). Relative risk of readmission was 0.86 (95% CI = 0.45, 1.66, P = 0.392) and 30-d mortality was 0.49 (95% CI = 0.14, 1.68, P = 0.205) for patients in the AACU model compared with patients in the traditional ICU/general care unit. CONCLUSIONS: Implementation of an Acuity Adaptable Cardiothoracic Unit is associated with reduced length of hospital stay in patients undergoing major lung resections, without increased risk of readmission or 30-d mortality. Future studies will evaluate post operative events unique to an AACU model. PMID- 21696763 TI - A multidisciplinary cancer center maximizes surgeons' impact. AB - BACKGROUND: Colorectal cancer patients require care across different disciplines. Integration of multidisciplinary care is critical to accomplish excellent oncologic results. We hypothesized that the establishment of a dedicated colorectal cancer center (CRCC) around specialty-trained surgeons will lead to increased multidisciplinary management and improved outcomes in colorectal cancer patients. METHODS: We analyzed data from three periods: a baseline group, a period after the recruitment of specialty-trained surgeons, and a period after the creation of a dedicated multidisciplinary cancer center. Data analyzed included surrogate markers of surgical oncologic care, multidisciplinary integration, and oncologic outcomes. RESULTS: Recruitment of specialized surgeons led to improvements in surgical oncologic care; the establishment of the CRCC resulted in further improvements in surgical oncologic care and multidisciplinary integration. CONCLUSION: Our study suggests that although the recruitment of specialty-trained surgeons in a high volume center leads to improvement in surgical oncologic care, it is the establishment of a multidisciplinary center around the surgeons that leads to integrated care and improvements in oncologic outcomes. PMID- 21696764 TI - Metastatic invasive breast cancer recurrence following curative-intent therapy for ductal carcinoma in situ. AB - BACKGROUND: The development of an invasive breast cancer recurrence outside of the breast parenchyma following curative-intent therapy for ductal carcinoma in situ (DCIS) is rare. We describe the patient and tumor characteristics associated with such recurrences. METHODS: A retrospective review was conducted of 621 patients who were treated for DCIS between 2004 and 2009. Patient, tumor, and treatment characteristics were collected. Descriptive statistics were utilized for data summary and data were compared using chi(2), where appropriate. RESULTS: Of 621 patients who underwent curative-intent therapy for DCIS, 12 (1.9%) developed an invasive metastatic recurrence. Primary local therapy at the time of the initial DCIS diagnosis included 11 patients who underwent mastectomy and one who had lumpectomy and adjuvant radiotherapy. The metastatic recurrences were in chest wall and/or ipsilateral axillary lymph nodes only (n = 6) or distant sites with or without ipsilateral axillary or supraclavicular lymph nodes (n = 6). Of the 12 patients with invasive recurrence, eight had high grade DCIS with comedo necrosis at initial diagnosis. The biomarker profiles of the invasive recurrences included 55% estrogen receptor positivity, 45% progesterone receptor positivity, and 73% Her2/neu amplification. Patient age, tumor grade, presence of comedo necrosis, biomarker profile, and surgical treatment were not predictive of recurrence. CONCLUSION: Invasive metastatic recurrence following adequate local therapy for DCIS is uncommon and likely represents progression of unidentified invasive disease at the time of diagnosis. The majority of invasive recurrences were Her2/neu amplified. Further studies are necessary to determine if such a unique biomarker profile correlates with metastatic recurrence. PMID- 21696765 TI - Reoperative completion pancreatectomy for suspected malignant disease of the pancreas. AB - BACKGROUND: Completion pancreatectomy (CP) is a reoperative procedure to excise remnant pancreatic tissue after a prior pancreatic resection. In this study, we document our institution's experience with CP for recurrent malignant disease of the pancreas, describing indications for surgery, procedures performed, and patient outcomes. METHODS: We performed a retrospective review of 861 patients from the pancreatic surgery database in the Department of Surgery of Thomas Jefferson University from October 2005 to December 2010 to identify all cases of CP performed for suspected malignant disease. RESULTS: Eleven patients underwent reoperative CP at our institution from 2005 to 2010. The median time interval between the initial operation and CP was 32 mo. A combination of clinical symptoms, elevated tumor markers, and imaging studies were used for diagnosis of recurrent disease. Pancreatic ductal adenocarcinoma was the most common pathology, found in six patients. The postoperative complication rate was 18% and the median postoperative hospital length of stay was 6 d. There were no 30-d readmissions and no perioperative deaths. The 1-y survival rate following CP was 71% with an overall median survival of 17.5 mo. CONCLUSIONS: CP is a safe and effective option for a highly selected group of patients with suspected recurrent malignant disease of the remnant pancreas. Morbidity and mortality rates are within acceptable limits and similar to initial pancreatic resection. Eligibility depends heavily upon the absence of distant metastatic disease, technical factors for resection, and patient performance status. PMID- 21696766 TI - The surgical revolving door: risk factors for hospital readmission. AB - BACKGROUND: Unplanned hospital readmissions increase healthcare costs and patient morbidity. We sought to identify risk factors associated with early readmission in surgical patients. MATERIALS AND METHODS: All admissions from a mixed surgical unit during 2009 were retrospectively reviewed and unplanned readmissions within 30 d of discharge were identified. Demographic data, length of stay, pre-existing diagnoses, and complications during the index admission were evaluated. T-tests and Fisher exact tests were used to examine the relationship of independent variables with readmission. Univariate and multivariate regression analysis were performed. RESULTS: A total of 1808 index admissions occurred during the study period. In all, 51 (3%) patients were readmitted within 30 d of discharge. The majority of readmissions (53%) were for infectious reasons. On univariate analyses, DVT (P = 0.004) and acute renal failure (P = 0.002) were associated with increased risk of readmission. Readmitted patients were also more likely to have public insurance (63% versus 37%, P = 0.03) and have a longer stay in the hospital (8 d, range 4-14 d versus 3 d, range 2-7 d, P = 0.001). Initial admission after trauma evaluation was associated with a decreased risk of readmission (OR 0.374, P = 0.004). Other demographic variables and pre-existing conditions were not associated with increased readmission. On multivariate logistic regression only DVT (P = 0.039) and LOS (P = 0.014) remained significant. CONCLUSIONS: Increased LOS and the development of a DVT are risk factors for early unplanned hospital readmission. Admission following trauma is associated with a decreased risk of readmission, possibly due to proactive multidisciplinary discharge planning and geographically-based nurse practitioner involvement. PMID- 21696767 TI - Hemodilution is not critical in the pathogenesis of the acute coagulopathy of trauma. AB - BACKGROUND: The acute coagulopathy of trauma is multifactorial, but generally believed to be aggravated by coexisting acidosis, hypothermia, and hemodilution. While acidosis and hypothermia have been extensively evaluated, there is a paucity of data on the independent role of hemodilution in this scenario. We therefore hypothesized that hemodilution will impair coagulation following experimental trauma and hemorrhagic shock. METHODS: Adult male Spraque-Dawley rats underwent trauma and hemorrhagic shock, followed by resuscitation with 2 * SBV using normal saline (NS). Thrombelastography (TEG) was performed before and after shock. RESULTS: In this trauma model, resuscitation resulted in a hemodilution of 50% (43% +/- 4.05% versus 19.8% +/- 3.96% Hct pre-shock versus post-shock , P < 0.0001). Despite the substantial hemodilution, there was no significant change in clot strength (12.96 +/- 2.84 versus 11.79 +/- 1.28 dynes/cm(2) G pre-shock versus post-shock, P = 0.13). Similarly, the onset of coagulation (R time) was not impaired (1.68 +/- 1.74 s versus 1.75 +/- 0.63 s R time pre-shock versus post-shock, P = 0.45). CONCLUSION: In the absence of hypothermia and acidosis, hemodilution (<= 50%) has a trivial effect on coagulation following trauma and hemorrhagic shock. These data call to question the commonly held belief that hemodilution per se is critical in the development of post-injury coagulopathy. PMID- 21696768 TI - Pediatric negative appendectomy rate: trend, predictors, and differentials. AB - BACKGROUND: Appendectomy is one of the most commonly performed emergency operations in children. The diagnosis of appendicitis can be quite challenging, particularly in children. We set out to determine the accuracy of diagnosis of appendicitis by analyzing the trends in the negative appendectomy rate (NAR) using a national database. MATERIALS AND METHODS: Analysis of the Kids Inpatient Database (KID) was performed for the years 2000, 2003, and 2006 on children with appendectomy, excluding incidental appendectomies. Children (<18 y) without appendicitis but who underwent appendectomies were classified as negative appendectomies (NA), and those with appendicitis as positive appendectomies (PA). Comparisons were made between those with PA versus NA by demographic characteristics. The subset of patients with NA was then further analyzed. RESULTS: An estimated 250,783 appendectomies met the inclusion criteria. The NAR was 6.7%. Length of stay (LOS) was longer in NA versus PA (7 versus 3 d, P < 0.05). The NAR was increased in children under 5 y (21.1% versus 5.4% for among the 5-10 y versus 5.9% among the >10 y, P < 0.0001) and in females (9.3% versus 5.1%, P < 0.001). On multivariate analysis, increasing age was associated with lower odds of NA (OR = 0.92, P < 0.001). Females, rural hospitals, and Blacks were significantly more likely to experience NA. CONCLUSIONS: Younger age, female gender, Black ethnicity and rural hospitals are independent predictors of NA. These factors can be incorporated into diagnostic algorithms to improve the accuracy of diagnosis of appendicitis in children. PMID- 21696769 TI - A pulmonary hypertension model induced by continuous pulmonary air embolization. AB - BACKGROUND: Our goal was to create a clinically relevant large animal model of pulmonary hypertension to serve as a platform allowing preclinical risk/benefit assessment of innovative therapies including artificial lung prototypes. METHODS: Small amounts of filtered air were continuously infused into the pulmonary circulation of sheep (n = 4) for 8 wk. Hemodynamics and blood gases were measured daily. After termination of air embolization, the sheep were observed for 1 additional wk to assess the constancy of the pulmonary artery pressure changes. At the end of wk 9, all sheep were sacrificed and necropsy was performed. RESULTS: All animals survived the study and developed pulmonary hypertension by wk 5. Mean pulmonary artery pressures were elevated from 14 +/- 1 at baseline to 35 +/- 1 mmHg at wk 8 (P < 0.01) and remained unchanged throughout wk 9. A similar increase in pulmonary vascular resistance was observed. Systemic arterial pressure and PaO(2) dropped slightly compared with baselines but remained in safe ranges. Histologic evidence of severe pulmonary arterial remodeling and significant right ventricle hypertrophy was observed. CONCLUSIONS: We conclude that our 8-wk model of continuous air embolization produces reliable, chronic pulmonary hypertension in sheep with sustained hemodynamic changes, significant pulmonary vascular remodeling, and right ventricle hypertrophy. PMID- 21696770 TI - Impact of fundamentals of laparoscopic surgery training during medical school on performance by first year surgical residents. AB - BACKGROUND: Fundamentals of Laparoscopic Surgery (FLS) certification is a high stakes examination. The best training methods to enable successful certification are undetermined. We hypothesized that first year surgical residents (R01s) who had been pretrained as medical students would perform better during skills training than previously un-trained R01s. METHODS: This is an IRB-approved, retrospective review of FLS training data generated from a single surgical skills laboratory from July 2007 through June 2010. During the study period, there were 24 R01s with no previous FLS exposure (NOVICE group) and seven R01s who had undergone FLS task training while medical students (MS4 group). All R01s practiced the FLS skill tasks weekly for portions of the training sessions with informal feedback and teaching. Performance goals were proposed for each task based on local and national proficiency figures. The performance outcome measure was task completion time (TCT). Pretraining performance was designated iTCT and post-training fTCT. RESULTS: The MS4 group began with iTCTs for all four tasks that were significantly lower than the NOVICE iTCTs. At completion of the 16-wk training period, the MS4 group continued to demonstrate mean fTCTs that were lower for all four FLS skill tasks but only significantly for PEG, CIRCLE, and INTRA skill tasks. Both NOVICE and MS4 groups showed significant improvement for all four skill tasks (P < 0.05). CONCLUSIONS: In the current milieu of work-hour limitations, the integration of FLS skill training into medical school curriculum provided a durable advantage to the pretrained R01s, which was associated with higher levels of final performance. PMID- 21696771 TI - Transplant tolerance and regulatory T cells: let's get into specifics. PMID- 21696772 TI - Attitudes and behaviors on alcohol use and impaired driving in adolescents. AB - BACKGROUND: Underage drinking and driving is a national safety issue. We hypothesized students would have lenient thoughts and behaviors about drinking and driving. The aim of our study was to assess current adolescent behavior and attitudes on alcohol use and driving. METHODS: A survey of 40 multiple choice questions was administered to 11th and 12th grade students at an urban, public high school in Los Angeles, California. RESULTS: Of the 1282 upper class students, 302 completed the survey (127 eleventh graders and 175 twelfth graders; 31% response rate). Overall, 64.2% reported having used alcohol. Significantly more 12th graders than 11th graders had consumed alcohol (71.4% versus 54.3%; P = 0.002); irrespective of gender. Binge drinking was reported by 8.6% of students (11.4% 12th graders vs. 4.7% 11th graders; P = 0.06). Nearly one-half (49.7%) of students indicated they disapproved of binge drinking. Students were more willing to discuss alcohol issues with peers (63.2%) than parents (44.0%) or teachers/counselors (19.5%; P = < 0.001). Most students (88.1%) indicated they would not drive when they had consumed one to two drinks. CONCLUSIONS: Greater than 60% of respondents reported having used alcohol. Students expressed strong concern about alcohol-impaired driving. Binge drinking appears prevalent in high school-aged individuals and increases with age. The lack of communication between students and adults on the topic of alcohol offers opportunity for improvement. Since the number of young drivers injured in alcohol-related crashes remains unacceptably high, more effective prevention strategies are necessary. PMID- 21696773 TI - Limitations on surrogate decision-making for emergent liver transplantation. AB - BACKGROUND: Surrogate consent is an accepted form of promoting patient autonomy when patients cannot consent, but it can lead to surrogate duress and may be unreliable. Since consent for liver transplantation in patients with fulminant hepatic failure (FHF) is typically performed by surrogates and these patients typically regain decisional capacity, we chose this population to query patients' opinion on the surrogate consent process. MATERIALS AND METHODS: We developed a questionnaire that queried transplanted patients' experience and opinion on surrogate consent, suitability of surrogates, and return of decisional capacity. This survey was then sent to consecutive survivors of liver transplantation for FHF at our institution. RESULTS: Eleven of 14 patients eligible to participate completed the questionnaire. The mean follow-up for all survivors was 41 mo, with a range of survival since transplant of 5 mo to 10 y. Although 10/11 respondents agreed with their surrogates to consent to liver transplantation, all 11 patients thought that surrogates should not be able to decline liver transplantation for this condition. In distinction, 3/11 patients believed patients could decline liver transplantation. CONCLUSIONS: This is the first study to demonstrate that liver transplant patients do not think surrogate decision-makers should be permitted to contravene physician recommendations regarding transplant. In clinical settings when patients cannot speak for themselves, it may be appropriate for surrogates and clinicians to act together according to the patients' best interest rather than attempt to determine what the patient would want. This approach might reduce surrogate distress, better represent patient preferences, and improve the decision-making process for affected patients. PMID- 21696774 TI - Equal access to health care does not eliminate disparities in the management of adults with appendicitis. PMID- 21696775 TI - Cyclosporin-A does not prevent cold ischemia/reperfusion injury of rat livers. AB - Cyclosporin-A (CsA) has been reported to protect livers from warm ischemia/reperfusion (I/R) injury. To study if CsA has also a protective effect on cold I/R injury, two models were used: the isolated perfused rat liver (IPRL) and the orthotopic rat liver transplantation (ORLT). (1) IPRL: Livers were preserved for 24 h (5 degrees C) in University of Wisconsin (UW) solution alone (group 1), with CsA (400 nM) dissolved in dimethylsulfoxide (50 MUM) (group 2), and with dimethylsulfoxide (DMSO) alone (group 3). Livers were reperfused for 60 min (37 degrees C) (n = 8/group). Cell necrosis was evaluated by trypan blue uptake and apoptosis by laddering and terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay, and by caspase-3 activation. Marked and similar sinusoidal endothelial cell necrosis was found in the three groups while apoptosis was found similarly deceased in groups 2 and 3 compared with group 1. (2) ORLT: Donors received either CsA (5 mg/kg) or corn oil 24 h before transplantation. Recipients were sacrificed after 240 min; cell necrosis and apoptosis were then evaluated. No difference was found between treated and control groups. The current data strongly suggest that CsA has no protective effect on hepatic cold I/R injury. Hepatocyte apoptosis can be reduced by antioxidants, as occurred with DMSO, but introduction of CsA does not provide additional protective effect. PMID- 21696776 TI - Isolated intracranial Whipple's disease--report of a rare case and review of the literature. AB - INTRODUCTION: Whipple's disease (WD) is a rare multisystemic infectious disease that can involve a variety of organs namely the gastrointestinal tract, lymphatic system, heart and nervous system. Myorhythmia is a hallmark of WD. Isolated CNS involvement is very rare. CASE: We present a 50 year-old African-American woman with rapid cognitive decline, visual hallucinations, insomnia, dysarthria, and gait unsteadiness. She subsequently developed pendular nystagmus and gaze paresis. Serial brain MRI scans showed T2 hyperintense lesions in the left striatum and right parahippocampal gyrus. FDG-PET scan showed marked increase of glucose uptake in the left putamen. Serum and CSF PCR for Tropheryma whipplei was negative. Stereotactic biopsy of the lesion and tissue PCR was consistent with WD. REVIEW OF LITERATURE: A systematic review identified 24 cases of isolated intracranial presentation of WD since 1975. Cases with systemic and extracranial manifestations were excluded. DISCUSSION: In patients with rapidly progressive cognitive decline with negative workup for common etiologies, there should be a high index of suspicion for WD. Diagnosis of WD remains a challenge as traditional methods commonly fail to culture T. whipplei. PET scans can help in identifying areas of inflammation that can be biopsied. Our case proves that a negative serum and CSF PCR should not exclude CNS WD and a brain biopsy of the lesion with PCR assay should be performed when possible. PMID- 21696777 TI - Anorectal dysfunctions in Parkinson's disease. AB - Anorectal symptoms are frequently found in patients with Parkinson's disease (PD), mainly manifested as diffuse lower abdominal discomfort, constipation, and fecal incontinence. Among these symptoms, constipation may precede by years the motor manifestations of PD. Research has focused for decades on selection of a measurement method for detection of abnormalities and support of clinometric instruments for anorectal symptoms. We review those manifestations and their contribution to evaluation of the anorectal symptoms in patients with PD. PMID- 21696778 TI - Pathways of marine debris derived from trajectories of Lagrangian drifters. AB - Global set of trajectories of satellite-tracked Lagrangian drifters is used to study the dynamics of marine debris. A probabilistic model is developed to eliminate the bias in spatial distribution of drifter data due to heterogeneous deployments. Model experiments, simulating long-term evolution of initially homogeneous drifter array, reveal five main sites of drifter aggregation, located in the subtropics and maintained by converging Ekman currents. The paper characterizes the geography and structure of the collection regions and discusses factors that determine their dynamics. A new scale R(c)=(4k/|D|)(1/2) is introduced to characterize tracer distribution under competing effects of horizontal divergence D and diffusion k. Existence and locations of all five accumulation zones have been recently confirmed by direct measurements of microplastic at the sea surface. PMID- 21696779 TI - Effect of heavy oil on the development of the nervous system of floating and sinking teleost eggs. AB - Heavy oil (HO) on the sea surface penetrates into fish eggs and prevents the normal morphogenesis. To identify the toxicological effects of HO in the context of the egg types, we performed exposure experiments using floating eggs and sinking eggs. In the course of development, HO-exposed embryos of floating eggs showed abnormal morphology, whereas early larva of the sinking eggs had almost normal morphology. However, the developing peripheral nervous system of sinking eggs showed abnormal projections. These findings suggest that HO exposed fishes have problems in the developing neurons, although they have no morphological malformations. Through these observations, we conclude that HO is strongly toxic to floating eggs in the morphogenesis, and also affect the neuron development in both floating and sinking eggs. PMID- 21696780 TI - [Bariatric surgery for the treatment of type 2 diabetes mellitus]. AB - Weight loss can improve metabolic control in patients with type 2 diabetes mellitus but the results of conventional therapy in this respect have been discouraging. Besides achieving significant and sustained weight loss, bariatric surgery can improve or resolve type 2 diabetes mellitus in the majority of patients. Anatomical modifications and changes in the secretion of intestinal hormones can explain the superiority of malabsorptive techniques. Currently, bariatric surgery offers a therapeutic alternative for type 2 diabetes patients with severe obesity and poor metabolic control under conventional therapy. Ongoing research will provide insights regarding the effect of intestinal hormones, new surgery techniques and the possible benefits of bariatric surgery in non-obese patients. PMID- 21696781 TI - [Non-Hodgkin's lymphoma staging with PET-CT scan]. PMID- 21696782 TI - [Role of ecocardiogram in fever of unknown origin. Towards saturation of echocardiogram laboratories?]. PMID- 21696783 TI - [Pathogenic interactions between alcohol and hepatitis C]. PMID- 21696784 TI - [Acute coronary syndrome in patient treated with capecitabine]. PMID- 21696785 TI - [Telephone-based smoking cessation. Predictors of success]. AB - BACKGROUND AND OBJECTIVE: To identify the predictors of successful outcome in a telephone smoking cessation program. PATIENTS AND METHODS: Observational study in the context of clinical practice in a smoking cessation clinic. The smoking cessation program was carried out by phone over a period of 3 months and follow up for 6 months. Sociodemographic variables were analyzed, dependence, and comorbidity and the main variable was continuous abstinence at 24 weeks. RESULTS: 743 smokers, 43% male and 57% female, mean (SD) age: 41.9 (9.8) years. The continuous abstinence rate at 24 weeks was 37.3% (IC 95% 34.9-40.0).The multivariable model showed three variables with predictive value: no current psychiatric diagnosis, social support and the first item of Fagerstrom test (time to first cigarette in the morning). CONCLUSIONS: Treatment outcomes of this smoking cessation program was influenced by the following variables: nicotine dependence, psychiatric disorders and social support. PMID- 21696786 TI - [Quality of life in people with dementia: review of self-assessment specific scales]. AB - The aim of this paper is to review specific measures of Quality of Life (QoL) for dementia, in particular, those scales that can be self-reported by the person with dementia. Data from qualitative studies including persons with dementia, caregivers and professionals has allowed the construction of scales, mainly in the US and England. These scales share common domains related to activities of daily living, psychological aspects and social relations. These scales are being adapted and translated into other languages. This review, compared to previous ones, updates recent validations of these scales into Spanish. Assessment of QoL in persons with dementia contributes to reduce stigma, considers the subject as a person, and introduces a humanistic element on the health and social systems. PMID- 21696787 TI - [Comparison of the somatotype, nutritional assessment and food intake among university sport and sedentary students]. AB - BACKGROUND AND OBJECTIVE: The study of the somatotype and food intake among university students is important to carry out internal policies about the improvement of health and prevention of diseases. The aim of this study was to compare the somatotype, nutritional assessment and food intake of university sport and sedentary students. SUBJECTS AND METHOD: The sample were 1,299 university students (420 males and 879 females) from University of Valencia, during 2008-2009 and 2009-2010, who were evaluated for several anthropometric parameters, the somatotype and the nutritional and food intakes with a 7 day dietary diary. RESULTS: The somatotype was Endo-Mesomorph, Meso-Endomorph, Balanced Endomorph and Meso-Endomorph for sport and sedentary males, and sports and sedentary females, respectively. All groups had a high and low percentage of total calories in comparison with proteins plus lipids, and carbohydrates, respectively, as established in the nutritional objectives for the Spanish population. Low vitamin intakes, including E (in the sport males), A, D and E, folate and biotine (in the sedentary males) and A, D, E, folate and biotine (in the sport and sedentary females) were observed. All groups had a high intake of sodium and a deficit of potassium, calcium, iodine and magnesium. On the other hand, cereal groups were the most important in the energy dairy intake. CONCLUSIONS: Disequilibrium in macronutrients and micronutrients reflects the importance of developing food policies among University people to improve this situation. PMID- 21696788 TI - [Hospital at home: an opportunity for change]. AB - The purpose of this paper is to describe the hospital at home (HaH). The HaH is proposed as a tool of the hospital organization to provide a response to the increasing health care demands. It consists of providing hospital range clinical attention at the patient's home instead of institutional care. Patients depend on the hospital, and their health care professionals constitute the staff that provide care. The characteristics of the HaH are: willingness of the patient, a care provider at home, the task to be carried out must be hospital-based, and can be performed at the patient's home. The development of the HaH requires a prolonged clinical leadership as well as good relationship with the referring clinicians. The evaluation must be carried out as part of a continuum of services of the health system. Both clinical effects and repercussions on the hospital organization must be taken into account. The HaH can provide training and knowledge to physicians about real life patients as well as the opportunity to work alongside a multidisciplinary team. The research must always include a rigorous methodology. PMID- 21696790 TI - Site dependency of fatty acid composition in adipose triacylglycerol in rats and its absence as a result of high-fat feeding. AB - It is currently believed that metabolic syndrome, in general, and type 2 diabetes mellitus, in particular, depend more on visceral than on subcutaneous adipose tissue. However, the relationship between insulin resistance and fatty acid composition in visceral and subcutaneous adipose tissues remains to be clarified. In the present study, we extracted the triacylglycerol from visceral (epididymis and mesentery) and subcutaneous adipose tissues in normal and insulin-resistant, high-fat-fed (HFF) rats and determined the composition of each fatty acid. The concentrations of palmitoleic, docosapentaenoic, docosahexaenoic, dihomo-gamma linolenic, arachidonic, and docosatetraenoic acids were higher in epididymal adipose tissue than in mesenteric and subcutaneous adipose tissues; but no significant differences were detected between mesenteric and subcutaneous tissues in the normal group or among all the sites in the HFF rats. In the HFF group, stearic and oleic acid concentrations were higher, whereas n-3 and n-6 polyunsaturated ones were lower, than those in the normal group. Palmitoleic acid and some n-3 and n-6 polyunsaturated fatty acid compositions in adipose tissue triacylglycerol depend on anatomical location, which may affect the properties and/or function of adipose tissues. These results at least in part suggest that the properties of adipose tissue are difficult to distinguish based only on their "visceral" or "subcutaneous" sites. In addition, the absence of site dependence and/or difference in balance among saturated, monounsaturated, and polyunsaturated fatty acids may play an important role in the development of insulin resistance in the HFF rats. PMID- 21696791 TI - Incidence of malignancies in patients with diabetes mellitus and correlation with treatment modalities in a large Israeli health maintenance organization: a historical cohort study. AB - It has been hypothesized that incidence of and mortality from several malignancies are increased among diabetic patients. Whether certain treatment modalities, including use of metformin, sulfonylureas, or insulins, affect cancer incidence or mortality and whether use of long-acting insulin analogues glargine and detemir may increase cancer incidence more than traditional human insulins are debated. The objective was to investigate the association between specific glucose-lowering agents and cancer incidence in diabetic members of an Israeli health maintenance organization. We studied a cohort of 36,342 diabetic patients aged at least 18 years with no history of cancer or treatment with insulin as of January 1, 2003. For the period from January 2003 to December 2007, we searched pharmacy records for purchases of glucose-lowering agents, including metformin, sulfonylureas, human insulin, and analogue insulins. Incident cancer diagnoses were identified from the health maintenance organization cancer registry. We studied the association of cancer incidence with the use of specific glucose lowering agents, controlling for age, sex, and baseline glycohemoglobin measurement. Cancer was diagnosed in 6% of the study cohort during 164,652 person years of follow-up time. Cancer incidence increased with age and varied with medication purchasing patterns. On multivariate analysis, age (hazard ratio [HR], 1.049; confidence interval [CI], 1.045-1.052), male sex (HR, 1.16; CI, 1.065 1.264), and number of insulin purchases (HR, 1.007; CI, 1.001-1.012) were significantly associated with increased cancer risk, whereas number of metformin purchases was associated with reduced cancer risk (HR, 0.996; CI, 0.994-0.998). Male sex, age, and human insulin purchases were associated with increased cancer incidence, whereas metformin purchases were associated with decreased cancer risk. There was a trend for increased cancer incidence associated with use of long-acting insulin analogues, but the number of long-acting insulin analogue users was too small for risk estimates to be conclusive. PMID- 21696789 TI - [Therapy-related acute leukemia: study of 23 pacients]. AB - BACKGROUND AND OBJECTIVE: The growing use of antineoplastic treatments has led to an increase in the incidence of therapy-related leukemias (TRL). The objective was to describe the characteristics of TRL. PATIENTS AND METHODS: Twenty-three cases of TRL were registered. Chemotherapeutic agents used for the first tumor, time interval, clinical and biological characteristics, treatment and prognosis of the TRL were analyzed. RESULTS: Median age was 61 years. Cytotoxic agents used in previous neoplasm consisted of alkylating agents (17 patients), inhibitors of DNA topoisomerase II (14), antitubulin agents (12), radiotherapy (9, in 6 with radiotherapy) and antimetabolites (6). Median time from diagnosis of the first neoplasm to TRL was 3 years (range 1.2-15.8). Thirteen patients received intensive chemotherapy [with stem cell transplantation (SCT) in 3] and the other 10 received symptomatic treatment (median survival 3 years versus 0.079 years, P=0.004). CONCLUSIONS: In this study, TRL were associated with exposure to alkylating agents, antitubulin agents and topoisomerase II inhibitors. Response to treatment and prognosis were poor, although chemotherapy and SCT may prolong survival. PMID- 21696793 TI - [Evidence-based radiology for diagnostic imaging: what it is and how to practice it]. AB - Evidence-based radiology is defined as the decision that results from integrating clinical information to select the most appropriate imaging test on the basis of the best available evidence, the physician's experience, and the patient's expectations. The practice of evidence-based radiology consists of five steps: formulating the question, performing an efficient search of the literature, critically evaluating the literature, applying the results of the search and evaluation while taking into account our experience and the patient's values, and evaluating the results obtained within our own practice. In diagnostic imaging, the number of resources available for evidence-based radiology is increasing: apart from books, articles, and web pages on this subject, evidence-based radiology is receiving more attention at diagnostic imaging conferences. The principles of evidence-based radiology will help promote the appropriate use of resources, greatly benefiting patients (decreasing the use of examinations that use ionizing radiation), professionals (less overload), and managers (more efficient use of resources). PMID- 21696792 TI - Serum adipokine zinc alpha2-glycoprotein and lipolysis in cachectic and noncachectic heart failure patients: relationship with neurohormonal and inflammatory biomarkers. AB - Chronic heart failure is often complicated by the development of cachexia with the loss of fat mass. Zinc alpha2-glycoprotein (ZAG) is a serum adipokine with lipolytic effects in cancer cachexia. We evaluated in patients with advanced heart failure with (CxHF) or without cachexia (nCxHF) the relationship of ZAG with circulating free fatty acid (FFA), as an index of lipolysis, and with other neurohormonal and inflammatory biomarkers. Two groups, nCxHF (n = 46) and CxHF (n = 18), the latter having a documented, involuntary, edema-free loss of body weight of at least 7.5% in the previous 6 months, underwent plasma determination of FFA, ZAG, norepinephrine (NE), tumor necrosis factor-alpha, and natriuretic peptide levels (atrial natriuretic, B-type natriuretic peptide). The patients were compared with age-matched healthy controls (CTR) (n = 21). Zinc alpha2 glycoprotein, atrial natriuretic peptide, B-type natriuretic peptide, and tumor necrosis factor-alpha circulating levels were similarly greater in CxHF and nCxHF than in CTR. Free fatty acid and NE were higher in CxHF than in nCxHF. A positive correlation between FFA and NE was found in both CxHF (r = 0.73, P < .01) and nCxHF (r = 0.48, P < .01) but only in CxHF between ZAG and FFA (r = 0.54, P = .02) and between ZAG and NE (r = 0.70, P < .01). No correlations between natriuretic peptides and ZAG were found. Serum ZAG levels are increased in advanced heart failure patients compared with CTR, without differences between CxHF and nCxHF. Only in CxHF, ZAG levels are directly correlated to circulating levels of FFA and NE, suggesting a close interaction of ZAG with sympathetic mediated lipolysis. PMID- 21696794 TI - [The editorial process for Radiologia]. AB - Radiologia is the official journal of the Spanish Society of Diagnostic Imaging. It aims to contribute to the education of Spanish-speaking radiologists and to disseminate radiological research and knowledge in Spanish. The journal has an Editorial Board organized into areas or sections, and material published in the journal is chosen and improved through peer review. This article discusses the model of the scientific journal Radiologia and the characteristics of its Editorial Board, comparing Radiologia with official general radiology journals of other scientific societies. Moreover, the details of the journal's editorial process are revealed, including the editorial circuit, the reviewers' work, and the technical aspects of the final edition process. Finally, the article lists qualitative and quantitative data about the material that Radiologia receives and publishes. PMID- 21696795 TI - [CT colonography: what radiologists need to know]. AB - In 2008, CT colonography was approved by the American Cancer Society as a technique for screening for colorectal cancer. This approval should be considered an important step in the recognition of the technique, which although still relatively new is already changing some diagnostic algorithms. This update about CT colonography reports the quality parameters necessary for a CT colonographic study to be diagnostic and reviews the technical innovations and colonic preparation for the study. We provide a brief review of the signs and close with a discussion of the current indications for and controversies about the technique. PMID- 21696796 TI - [Thoracic vascular disease in oncologic patients]. AB - Patients with oncologic disease require frequent imaging tests (predominantly computed tomography) for follow-up. These patients may have thoracic vascular disease that can influence the diagnosis, treatment, and prognosis of their cancer. Primary vascular tumors can involve the thoracic vessels, like the pulmonary arteries (pulmonary artery sarcoma), and the neoplastic disease can extend locally (lung tumor) or remotely to the thoracic vessels (pulmonary tumor embolism and pulmonary tumor thrombotic microangiopathy). Oncologic treatment results in multiple complications that involve the thoracic vessels and can even compromise the patient's life in certain cases. CT, and especially multislice CT, makes it possible to evaluate neoplastic disease and associated thoracic vascular disease in oncologic patients. PMID- 21696797 TI - [Plenary conference of JNLF 2011: Freud, science and irrational]. PMID- 21696798 TI - Drosophila nucleoporin Nup154 controls cell viability, proliferation and nuclear accumulation of Mad transcription factor. AB - Nuclear Pore Complexes (NPCs) are involved in the regulation of nucleo cytoplasmic trafficking. Drosophila Nup154 encodes a nucleoporin component of the NPC that is expressed in high proliferating tissues such as germ cells. Hypomorphic mutations in this gene cause male and female sterility and reduction of cell proliferation in the adult fly. Here, we present evidences of a decrease in the number of spermatogonial cells in Nup154 mutants, caused both by increased cell death and reduced cell proliferation. Furthermore, we also found that RNAi mediated depletion of Nup154 in cultured cells prevented nuclear accumulation of the transcription factor Mothers against Dpp (Mad), suggesting a possible regulatory role for Nup154 in TGF-beta signal transduction. These results were confirmed in vivo on mutant testes where we observed a similar defect in the nuclear accumulation of the co-Smad Medea. PMID- 21696799 TI - A comparison of different approaches for measuring denitrification rates in a nitrate removing bioreactor. AB - Denitrifying woodchip bioreactors (denitrification beds) are increasingly used to remove excess nitrate (NO3-) from point-sources such as wastewater effluent or subsurface drains from agricultural fields. NO3- removal in these beds is assumed to be due to microbial denitrification but direct measurements of denitrification are lacking. Our objective was to test four different approaches for measuring denitrification rates in a denitrification bed that treated effluent discharged from a glasshouse. We compared these denitrification rates with the rate of NO3- removal along the length of the bed. The NO3- removal rate was 8.73 +/- 1.45 g m 3 d-1. In vitro acetylene inhibition assays resulted in highly variable denitrification rates (DR(AI)) along the length of the bed and generally 5 times greater than the measured (NO3--N removal rate. An in situ push-pull test, where enriched 15N-NO3- was injected into 2 locations along the bed, resulted in rates of 23.2 +/- 1.43 g N m-3 d-1 and 8.06 +/- 1.64 g N m-3 d-1. The denitrification rate calculated from the increase in dissolved N2 and N2O concentrations (DR(N2) along the length of the denitrification bed was 6.7 +/- 1.61 g N m-3 d-1. Lastly, denitrification rates calculated from changes in natural abundance measurements of delta15N-N2 and delta15N-NO3- along the length of the bed yielded a denitrification rate (DR(NA)) of 6.39 +/- 2.07 g m-3 d-1. Based on our experience, DR(N2) measurements were the easiest and most efficient approach for determining the denitrification rate and N2O production of a denitrification bed. However, the other approaches were useful for testing other hypotheses such as factors limiting denitrification or may be applied to determine denitrification rates in environmental systems different to our study site. DR(N2) does require very careful sampling to avoid atmospheric N2 contamination but could be used to rapidly determine denitrification rates in a variety of aquatic systems with high N2 production and even water flows. These measurements demonstrated that the majority of NO3- removal was due to heterotrophic denitrification. PMID- 21696800 TI - Advancing assessment and design of stormwater monitoring programs using a self organizing map: characterization of trace metal concentration profiles in stormwater runoff. AB - Stormwater runoff poses a great challenge to the scientific assessment of the effects of diffuse pollution sources on receiving waters. In this study, a self organizing map (SOM), a research tool for analyzing specific patterns in a large array of data, was applied to the monitoring data obtained from a stormwater monitoring survey to acquire new insights into stream water quality profiles under different rainfall conditions. The components of the input data vectors used by the SOM included concentrations of 10 metal elements, river discharge, and rainfall amount which were collected at the inlet and endpoint of an urban segment of the Yeongsan River, Korea. From the study, it was found that the SOM displayed significant variability in trace metal concentrations for different monitoring sites and rainfall events, with a greater impact of stormwater runoff on stream water quality at the upstream site than at the downstream site, except under low rainfall conditions (<= 4 mm). In addition, the SOM clearly determined the water quality characteristics for "non-storm" and "storm" data, where the parameters nickel and arsenic and the parameters chromium, cadmium, and lead played an important role in reflecting the spatial and temporal water quality, respectively. When the SOM was used to examine the efficacy of stormwater quality monitoring programs, between 34 and 64% of the sample size in the current data set was shown to be sufficient for estimating the stormwater pollutant loads. The observed errors were small, generally being below 10, 6, and 20% for load estimation, map resolution, and clustering accuracy, respectively. Thus, the method recommended may be used to minimize monitoring costs if both the efficiency and accuracy are further determined by examining a large existing data set. PMID- 21696801 TI - Poor efficacy of herbicides in biochar-amended soils as affected by their chemistry and mode of action. AB - We evaluated wheat straw biochar produced at 450 degrees C for its ability to influence bioavailability and persistence of two commonly used herbicides (atrazine and trifluralin) with different modes of action (photosynthesis versus root tip mitosis inhibitors) in two contrasting soils. The biochar was added to soils at 0%, 0.5% and 1.0% (w/w) and the herbicides were applied to those soil biochar mixes at nil, half, full, two times, and four times, the recommended dosage (H(4)). Annual ryegrass (Lolium rigidum) was grown in biochar amended soils for 1 month. Biochar had a positive impact on ryegrass survival rate and above-ground biomass at most of the application rates, and particularly at H(4). Within any given biochar treatment, increasing herbicide application decreased the survival rate and fresh weight of above-ground biomass. Biomass production across the biochar treatment gradient significantly differed (p<0.01) and was more pronounced in the case of atrazine than trifluralin. For example, the dose response analysis showed that in the presence of 1% biochar in soil, the value of GR(50) (i.e. the dose required to reduce weed biomass by 50%) for atrazine increased by 3.5 times, whereas it increased only by a factor of 1.6 in the case of trifluralin. The combination of the chemical properties and the mode of action governed the extent of biochar-induced reduction in bioavailability of herbicides. The greater biomass of ryegrass in the soil containing the highest biochar (despite having the highest herbicide residues) demonstrates decreased bioavailability of the chemicals caused by the wheat straw biochar. This work clearly demonstrates decreased efficacy of herbicides in biochar amended soils. The role played by herbicide chemistry and mode of action will have major implications in choosing the appropriate application rates for biochar amended soils. PMID- 21696802 TI - Mercury, lead and cadmium in human milk in relation to diet, lifestyle habits and sociodemographic variables in Madrid (Spain). AB - BACKGROUND: Although breastfeeding is the ideal way of nurturing infants, it can be a source of exposure to toxicants. This study reports the concentration of Hg, Pb and Cd in breast milk from a sample of women drawn from the general population of the Madrid Region, and explores the association between metal levels and socio demographic factors, lifestyle habits, diet and environmental exposures, including tobacco smoke, exposure at home and occupational exposures. METHODS: Breast milk was obtained from 100 women (20 mL) at around the third week postpartum. Pb, Cd and Hg levels were determined using Atomic Absorption Spectrometry. Metal levels were log-transformed due to non-normal distribution. Their association with the variables collected by questionnaire was assessed using linear regression models. Separate models were fitted for Hg, Pb and Cd, using univariate linear regression in a first step. Secondly, multivariate linear regression models were adjusted introducing potential confounders specific for each metal. Finally, a test for trend was performed in order to evaluate possible dose-response relationships between metal levels and changes in variables categories. RESULTS: Geometric mean Hg, Pb and Cd content in milk were 0.53 MUg L(-1), 15.56 MUg L(-1), and 1.31 MUg L(-1), respectively. Decreases in Hg levels in older women and in those with a previous history of pregnancies and lactations suggested clearance of this metal over lifetime, though differences were not statistically significant, probably due to limited sample size. Lead concentrations increased with greater exposure to motor vehicle traffic and higher potato consumption. Increased Cd levels were associated with type of lactation and tended to increase with tobacco smoking. CONCLUSIONS: Surveillance for the presence of heavy metals in human milk is needed. Smoking and dietary habits are the main factors linked to heavy metal levels in breast milk. Our results reinforce the need to strengthen national food safety programs and to further promote avoidance of unhealthy behaviors such as smoking during pregnancy. PMID- 21696803 TI - Radon hazard in shallow groundwaters II: dry season fracture drainage and alluvial fan upwelling. AB - 222Rn concentrations have been measured in a well located on the edge of a large Pleistocene-Holocene fan and belonging to the shallow pyroclastic aquifer of the Pietramelara Plain, southern Italy. The aim of this study has been both to characterise the hydrological inputs that determine the influx of 222Rn to the shallow aquifer and to understand the correlations between 222Rn, major ions, physical-chemical parameters and rainfall. Results obtained from the time series indicate that the studied well shows a 222Rn variability that is inconsistent with a mechanism of pure hydrological amplification, such as described in Radon hazard in shallow groundwaters: Amplification and long term variability induced by rainfall (De Francesco et al., 2010a). On the contrary, in this well hydrological amplification appears to be mainly tied to the upwelling of alluvial fan waters, rich in radon, in response to pistoning from recharge in the carbonate substrate. This upwelling of alluvial fan waters occurs during almost the whole period of the annual recharge and is also responsible of the constant increase in 222Rn levels during the autumn-spring period, when both the water table level and weekly rainfall totals drop. Furthermore, a rapid delivery mechanism for 222Rn likely operates through fracture drainage in concomitance with the very first late summer-early autumn rains, when rainfall totals appear largely insufficient to saturate the soil storage capacity. Results obtained from this study appear to be particularly significant in both radon hazard zoning in relation to the shallow aquifer and possibly also for indoor radon, owing to possible shallow aquifer-soil-building exchanges. Moreover, both the spike-like events and the long wave monthly scale background fluctuations detected can also have potential significance in interpreting 222Rn time series data as seismic and/or volcanic precursors. Finally, 222Rn has proved to be an excellent tracer for hydrological inputs to the shallow aquifer when combined with major ions, physical-chemical data and geological and geomorphological controls. PMID- 21696804 TI - Cola soft drinks for evaluating the bioaccessibility of uranium in contaminated mine soils. AB - There is a rising need for scientifically sound and quantitative as well as simple, rapid, cheap and readily available soil testing procedures. The purpose of this study was to explore selected soft drinks (Coca-Cola Classic(r), Diet Coke(r), Coke Zero(r)) as indicators of bioaccessible uranium and other trace elements (As, Ce, Cu, La, Mn, Ni, Pb, Th, Y, Zn) in contaminated soils of the Mary Kathleen uranium mine site, Australia. Data of single extraction tests using Coca-Cola Classic(r), Diet Coke(r) and Coke Zero(r) demonstrate that extractable arsenic, copper, lanthanum, manganese, nickel, yttrium and zinc concentrations correlate significantly with DTPA- and CaCl2-extractable metals. Moreover, the correlation between DTPA-extractable uranium and that extracted using Coca-Cola Classic(r) is close to unity (+0.98), with reduced correlations for Diet Coke(r) (+0.66) and Coke Zero(r) (+0.55). Also, Coca-Cola Classic(r) extracts uranium concentrations near identical to DTPA, whereas distinctly higher uranium fractions were extracted using Diet Coke(r) and Coke Zero(r). Results of this study demonstrate that the use of Coca-Cola Classic(r) in single extraction tests provided an excellent indication of bioaccessible uranium in the analysed soils and of uranium uptake into leaves and stems of the Sodom apple (Calotropis procera). Moreover, the unconventional reagent is superior in terms of availability, costs, preparation and disposal compared to traditional chemicals. Contaminated site assessments and rehabilitation of uranium mine sites require a solid understanding of the chemical speciation of environmentally significant elements for estimating their translocation in soils and plant uptake. Therefore, Cola soft drinks have potential applications in single extraction tests of uranium contaminated soils and may be used for environmental impact assessments of uranium mine sites, nuclear fuel processing plants and waste storage and disposal facilities. PMID- 21696805 TI - Distribution of vitamins A (retinol) and E (alpha-tocopherol) in polar bear kidney: Implications for biomarker studies. AB - Vitamins A and E content of inner organs, among these the kidneys, are increasingly being used as an indicator of adverse effects caused to the organism by e.g. environmental contaminants. In general, only a renal sub sample is used for analyses, and it is thus essential to know which part of the organ to sample in order to get a representative value for this important biomarker. The aim here was to assess the distribution of vitamins A (retinol) and E (alpha-tocopherol) within the polar bear multireniculate kidney (i.e. polar vs. medial position) and also within the cortex vs. medulla of each separate renculi. The results showed no significant difference between the medial and polar renculi with regards to either retinol (p=0.44) or alpha-tocopherol (p=0.75). There were, however, significant differences between cortex and medulla for both vitamins (retinol, p=0.0003; alpha-tocopherol, p<0.0001). The kidney cortex contained higher values of both vitamins than the medulla; on average 29% more retinol and 57% more alpha tocopherol. Mean concentrations in the medulla was 2.7 mg/kg for retinol and 116 mg/kg for alpha-tocopherol, and in the cortex 3.5 mg/kg for retinol and 182 mg/kg for alpha-tocopherol. These results clearly indicate that one should take precautions when analyzing retinol and alpha-tocopherol in polar bear kidneys. Prior to analysis, the renculi should be separated into medulla and cortex. The results indicated no significant differences between renculi from different parts of the kidney. PMID- 21696806 TI - Monitoring trends of urban development and environmental impact of Beijing, 1999 2006. AB - The high rates of environmental change and accelerated species loss in the urban development process should be quantified to rebalance the social and environmental dimensions of sustainability. In this study, an emergy-based environmental impact assessment model is designed according to the framework of the Eco-Indicator 99 for monitoring the negative effects on human well-being and ecosystem integrity in the urban development system of Beijing from 1999 to 2006. The environmental impact assessment model is based on the sustainability promotion perspective, and emphasizes the determinants of human health and ecosystem integrity in the urban development process. It is vital that the links among human health, ecosystem integrity and urban sustainability are therefore considered especially from the perspective of a supply-side environmental cost evaluation (including ecological service supply, ecological and economic losses and investment for treatment). Results suggest that: (1) out of all the pollutants, ecological services were mainly used to dilute sulfur dioxide and NH(3)-N; (2) nitrogen dioxide and greenhouse gases released by the urban system contribute heavily to both ecological and economic losses evaluated in emergy terms; and (3) emissions impact, mainly from airborne pollutants, with small contribution from waterborne emissions, generally increases from 1999 to 2006, undermining the sustainability of Beijing. The emergy synthesis proves to be very appropriate to account for large-scale and indirect costs generated by pollution as side effects of economic activity. Such knowledge is a necessary pre-requisite to perform a reliable cost-benefit evaluation of urban sustainability strategies, and provide guidance for policy decision making to maximize benefits and minimize negative impacts. PMID- 21696807 TI - Effect of doxazosin gastrointestinal therapeutic system 4 mg vs tamsulosin 0.2 mg on nocturia in Chinese men with lower urinary tract symptoms: a prospective, multicenter, randomized, open, parallel study. AB - OBJECTIVE: To compare the efficacy of the doxazosin gastrointestinal therapeutic system (doxazosin-GITS) 4 mg and tamsulosin 0.2 mg on nocturia in Chinese men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). METHODS: Data were analyzed from a prospective, multicenter, randomized, open, parallel study of Chinese men aged 50-84 years with LUTS/BPH. Two hundred patients were randomized to receive daily treatment with 4 mg doxazosin-GITS (n=100) or 0.2 mg tamsulosin (n=100) for 8 weeks. Nocturia was assessed by question 7 of the International Prostate Symptom Score (IPSS-question 7) and a frequency-volume chart (FVC) at weeks 4 and 8. Self-reported quality of sleep and quality of life by the last question of the IPSS questionnaire were also evaluated. RESULTS: A total of 189 patients (94 receiving doxazosin-GITS, 95 tamsulosin) completed the study. The reduction from baseline in mean nocturia was greater with doxazosin-GITS than tamsulosin by the FVC (1.7 vs 1.3 at week 4; 2.1 vs 1.7 at week 8, both P=.001) and by the IPSS-question 7 (1.5 vs 1.1 at 4 weeks, P=.001; 2.0 vs 1.6 at 8 weeks, P<.001). The patients who reported improved quality of sleep was significantly more with doxazosin-GITS than tamsulosin (43.6% vs 27.4% at 4 weeks, P=.020; 81.9% vs 67.4% at 8 weeks, P=.022), and quality of life was better with doxazosin-GITS (2.5 vs 2.8 at 4 weeks, P=.001; 2.1 vs 2.5 at 8 weeks, P<.001). CONCLUSION: In Chinese patients with LUTS/BPH, doxazosin-GITS is slightly better than tamsulosin in reducing the frequency of nocturia. PMID- 21696808 TI - Do silver alloy-coated catheters increase risk of urethral strictures after robotic-assisted laparoscopic radical prostatectomy? AB - OBJECTIVES: To evaluate whether the use of silver-coated catheters increased the risk of developing urethral stricture disease after robotic-assisted laparoscopic radical prostatectomy (RALP). Recently, silver alloy-coated Foley catheters have been shown to decrease the risk of catheter-associated urinary tract infections. Other than the increased cost, no disadvantages to the use of these catheters have been reported. MATERIAL AND METHODS: We switched to routine use of the Bardex I.C. silver alloy-coated Foley catheters for all urologic procedures on November 1, 2008. After institutional review board approval, we retrospectively reviewed the records of all consecutive patients who had undergone RALP 12 months before and after the catheter change. The primary outcome was the rate of urethral strictures after RALP. RESULTS: A total of 188 RALPs were performed during the 12 months before the catheter change. No patients who underwent RALP in the months before the catheter change had developed a new postoperative urethral stricture. In the 12 months after the change to the silver-coated catheters, 217 RALPs were performed. Six patients after RALP using silver-coated catheters developed new strictures, at a rate of 2.8% (P = .03). CONCLUSIONS: Silver alloy-coated urinary catheters might increase the risk of developing urethral strictures after RALP compared with standard noncoated catheters. Additional evaluation by a large randomized prospective trial is warranted to elucidate the true risk of stricture formation. PMID- 21696809 TI - Influence of obesity on urinary pH with respect to sex in healthy Koreans. AB - OBJECTIVES: To evaluate the association between urinary pH and metabolic risk factors, including obesity according to sex in a Korean population recruited through the health promotion center. METHODS: From 2008 to 2010, a total of 22 297 ostensibly healthy adult Koreans who visited our health promotion center were enrolled in the present study. The relationship between urinary pH and various metabolic risk factors, including obesity, were evaluated. RESULTS: The mean age +/- SD of the study population was 45.0 +/- 9.1 years. The men had a significantly greater body mass index and lower urinary pH than the women. Using multivariate logistic regression analysis, obesity significantly correlated with a lower urinary pH (<=5.5) only in men (odds ratio [OR] 1.095, P = .015) and not in women (OR 1.004, P = 0.945). Among the various factors examined, older age (>45 years), greater fasting blood glucose, and hyperuricemia were factors significantly associated with a lower urinary pH in both groups. Hypertriglyceridemia was a significant factor associated with lower urinary pH only in men, and a lower high-density lipoprotein cholesterol was the significant factor for a lower urinary pH in women. CONCLUSIONS: The results of the present study revealed that obesity is significantly correlated with lower urinary pH (<=5.5) only in men. PMID- 21696810 TI - Pathologic significance and prognostic value of phosphorylated cortactin expression in patients with sarcomatoid renal cell carcinoma. AB - OBJECTIVES: To clarify the clinical and prognostic significance of cortactin and phosphorylated cortactin in patients with sarcomatoid renal cell carcinoma (SRCC). METHODS: We retrospectively reviewed the data from 31 patients with SRCC and 33 with conventional renal cell carcinoma matched for clinicopathologic features. The immunoreactive score for cortactin, pY421 cortactin, and pY466 cortactin were measured using immunohistochemistry. The relationships between each immunoreactive score and the clinicopathologic features and survival were investigated. RESULTS: The immunoreactive score of p421 cortactin, but not that of cortactin and pY466 cortactin, was significantly greater in SRCC than in conventional renal cell carcinoma (P < .001). The expression of pY421 cortactin in SRCC correlated with the pT stage and metastasis (P < .001). The expression of pY466 cortactin showed a similar trend with pT stage (P = .043) but not with metastasis. Although both of pY421 cortactin and pY466 cortactin were identified as useful predictors for survival in univariate analyses, only pY421 cortactin expression was considered an independent predictor in patients with SRCC (odds ratio 4.53, 95% confidence interval 1.07-19.12, P = .040) in the multivariate analysis model, including pT stage and metastasis. CONCLUSIONS: Our results have demonstrated that phosphorylation of cortactin is a key process in malignant aggressiveness, and its expression is a useful predictor of cause-specific survival and could be a useful potential therapeutic target in patients with SRCC. PMID- 21696811 TI - Management trends in prenatally detected hydronephrosis: national survey of pediatrician practice patterns and antibiotic use. AB - OBJECTIVE: To assess the practice patterns of general pediatricians in the management of prenatally detected hydronephrosis. Hydronephrosis is the most common abnormality found on prenatal ultrasonography. The utility of prophylactic antibiotics in the postnatal management of this condition is controversial. No study has assessed the practice patterns of general pediatricians in the management of prenatally detected hydronephrosis. METHODS: An 18-question survey was sent to a random cross-section national sample of pediatricians from the American Medical Association Masterfile. The participants answered questions regarding practice location and type, practice experience, frequency of cases seen, familiarity with the published data, use of antibiotics, workup of hydronephrosis, and specialist referral. Multivariate logistic regression analysis was used to identify the factors associated with prescribing antibiotics. RESULTS: Of the 461 pediatricians, 244 (53%) responded. Of the respondents, 56% routinely prescribed antibiotics for prenatally detected hydronephrosis, and 57% performed the postnatal workup themselves. Of these, 98% routinely ordered ultrasound scans and ~40% routinely ordered voiding cystourethrograms. Of the respondents, 94% always had specialists readily available; however, only 41% always referred to a specialist. On multivariate logistic regression analysis, those who believe prophylactic antibiotics to be beneficial were significantly more likely to prescribe antibiotics than those who had not read the published data (odds ratio 6.1, 95% confidence interval 2-15). Those without specialist consultation readily available had an increased odds of starting prophylactic antibiotics compared with those who had consultation available (odds ratio 7.2, 95% confidence interval 1.3-39). CONCLUSION: Most pediatricians initiate postnatal management of prenatally detected hydronephrosis; therefore, pediatricians truly are the gatekeepers for children with this condition. Knowledge of the practice patterns is crucial for the dissemination of evidence-based information to the appropriate providers and will enable us to learn more about the utility of antibiotic prophylaxis in future studies. PMID- 21696812 TI - Both the variability and level of mouse allergen exposure influence the phenotype of the immune response in workers at a mouse facility. AB - BACKGROUND: The role of natural aeroallergen exposure in modulating allergen specific immune responses is not well understood. OBJECTIVE: We sought to examine relationships between mouse allergen exposure and mouse-specific immune responses. METHODS: New employees (n = 179) at a mouse facility underwent repeated assessment of mouse allergen exposure, skin prick tests (SPTs), and measurement of mouse-specific IgG levels. Relationships between the mean level of exposure, variability of exposure (calculated as log deviation), and time to development of immunologic outcomes were examined by using Cox proportional hazards models. RESULTS: By 24 months, 32 (23%) participants had experienced a positive SPT response, and 10 (8%) had mouse-specific IgG4. The incidence of a positive SPT response increased as levels of exposure increased from low to moderate, peaking at 1.2 ng/m3, and decreased beyond this point (P = .04). The more variable the exposure was across visits, the lower the incidence of a positive SPT response (hazard ratio [HR], 0.17; 95% CI, 0.07-0.41). Variability of exposure was an independent predictor of a positive SPT response in a model that included both exposure metrics. In contrast, the incidence of mouse-specific IgG4 increased with increasing levels of mouse allergen exposure (HR, 2.9; 95% CI, 1.4-6.0), and there was evidence of a higher risk of mouse-specific IgG4 with greater variability of exposure (HR, 6.3; 95% CI, 0.4-95.2). CONCLUSION: Both the level and variability of mouse allergen exposure influence the humoral immune response, with specific patterns of exposure associated with specific immunophenotypes. Exposure variability might be a more important predictor of a positive SPT response, whereas the average exposure level might be a more important predictor of mouse-specific IgG4. PMID- 21696814 TI - Effect of a partially hydrolyzed whey infant formula at weaning on risk of allergic disease in high-risk children: a randomized controlled trial. AB - BACKGROUND: Partially hydrolyzed whey formula (pHWF) has been recommended for infants with a family history of allergic disease at the cessation of exclusive breast-feeding to promote oral tolerance and prevent allergic diseases. OBJECTIVE: To determine whether feeding infants pHWF reduces their risk of allergic disease. METHODS: A single-blind (participant) randomized controlled trial was conducted to compare allergic outcomes between infants fed a conventional cow's milk formula, a pHWF, or a soy formula. Before birth, 620 infants with a family history of allergic disease were recruited and randomized to receive the allocated formula at cessation of breast-feeding. Skin prick tests to 6 common allergens (milk, egg, peanut, dust mite, rye grass, and cat dander) were performed at 6, 12, and 24 months. The primary outcome was development of allergic manifestations (eczema and food reactions) measured 18 times in the first 2 years of life. RESULTS: Follow-up was complete for 93% (575/620) at 2 years and 80% (495/620) at 6 or 7 years of age. There was no evidence that infants allocated to the pHWF (odds ratio, 1.21; 95% CI, 0.81-1.80) or the soy formula (odds ratio, 1.26; 95% CI, 0.84-1.88) were at a lower risk of allergic manifestations in infancy compared with conventional formula. There was also no evidence of reduced risk of skin prick test reactivity or childhood allergic disease. CONCLUSION: Despite current dietary guidelines, we found no evidence to support recommending the use of pHWF at weaning for the prevention of allergic disease in high-risk infants. PMID- 21696815 TI - Soybean isoflavones regulate dendritic cell function and suppress allergic sensitization to peanut. AB - BACKGROUND: Although peanut and soybean proteins share extensive amino acid sequence homology, the incidence and severity of allergic reactions to soy are much less than those to peanut. Soybeans are rich in anti-inflammatory isoflavones and are the most common source of isoflavones in the human food supply. OBJECTIVE: We hypothesized that the active isoflavones in the gut milieu are capable of modulating immune responses to dietary antigens by regulating dendritic cell (DC) function. METHODS: We tested this hypothesis in a murine model of peanut allergy and in human monocyte-derived dendritic cells (MDDCs). C3H/HeJ mice were fed a diet containing genistein and daidzein. The mice were sensitized and challenged with peanut, and the anaphylactic symptoms were compared with those of mice fed a soy-free diet. Human MDDCs were activated with cholera toxin in the presence of isoflavones. The surface expression of DC activation markers and DC-mediated effector functions were analyzed by means of flow cytometry. RESULTS: Dietary isoflavones significantly reduced the anaphylactic symptoms and mast cell degranulation in vivo after peanut challenge. Serum peanut-specific antibodies were markedly reduced in mice fed the isoflavone diet. Isoflavones inhibited cholera toxin-induced DC maturation in the mesenteric lymph nodes and human MDDCs and subsequent DC-mediated CD4(+) T-cell function in vitro. CONCLUSIONS: These data suggest that dietary isoflavones suppress allergic sensitization and protect against peanut allergy in vivo. Dietary supplementation of soybean isoflavones could be a novel strategy to prevent the development of allergic reactions to food. PMID- 21696816 TI - Brief report: how anxiously withdrawn preadolescents think about friendship. AB - Previous research suggests that anxiously withdrawn preadolescents demonstrate success in forming friendships, yet these friendships tend to be of lesser quality. Drawing on Selman's (1980) theory of interpersonal understanding, we compared levels of friendship understanding between anxiously withdrawn preadolescents and a sample of non-withdrawn age mates. Fifth graders (N = 116; 58% girls; mean age = 10.33 yrs) completed same-sex friendship and social behavior nominations, as well as a semi-structured clinical interview assessing understanding of various friendship issues in response to a hypothetical friendship dilemma. Results suggest that anxiously withdrawn preadolescents demonstrated lower levels of friendship understanding for some, but not all, friendship issues that may be related to friendship quality. The findings suggest that social cognitive assessments of friendship may be useful in understanding the friendship successes and difficulties of anxiously withdrawn preadolescents. PMID- 21696813 TI - Identification of ATPAF1 as a novel candidate gene for asthma in children. AB - BACKGROUND: Asthma is a common disease of children with a complex genetic origin. Understanding the genetic basis of asthma susceptibility will allow disease prediction and risk stratification. OBJECTIVE: We sought to identify asthma susceptibility genes in children. METHODS: A nested case-control genetic association study of children of Caucasian European ancestry from a birth cohort was conducted. Single nucleotide polymorphisms (SNPs, n = 116,024) were genotyped in pools of DNA samples from cohort children with physician-diagnosed asthma (n = 112) and normal controls (n = 165). A genomic region containing the ATPAF1 gene was found to be significantly associated with asthma. Additional SNPs within this region were genotyped in individual samples from the same children and in 8 independent study populations of Caucasian, African American, Hispanic, or other ancestries. SNPs were also genotyped or imputed in 2 consortia control populations. ATPAF1 expression was measured in bronchial biopsies from asthmatic patients and controls. RESULTS: Asthma was found to be associated with a cluster of SNPs and SNP haplotypes containing the ATPAF1 gene, with 2 SNPs achieving significance at a genome-wide level (P = 2.26 * 10(-5) to 2.2 * 10(-8)). Asthma severity was also found to be associated with SNPs and SNP haplotypes in the primary population. SNP and/or gene-level associations were confirmed in the 4 non-Hispanic populations. Haplotype associations were also confirmed in the non Hispanic populations (P = .045-.0009). ATPAF1 total RNA expression was significantly (P < .01) higher in bronchial biopsies from asthmatic patients than from controls. CONCLUSION: Genetic variation in the ATPAF1 gene predisposes children of different ancestries to asthma. PMID- 21696817 TI - XMRV and CFS--the sad end of a story. PMID- 21696818 TI - A comparison between adipose tissue and dental pulp as sources of MSCs for tooth regeneration. AB - In this study, several in vivo and in vitro comparisons were performed to test the possibility of using adipose-derived stem cells (ADSCs), a more convenient cell source than dental pulp stem cells (DPSCs), in tooth regeneration. Using an efficient, non-engineering implantation method, we first demonstrated that both implants of ADSCs and DPSCs were able to grow self-assembled new teeth in adult rabbit extraction sockets with high success rate. The stem cells were necessary because the implants grew no tooth without them. A stepwise comparison showed that the regenerated teeth from these two types of adult stem cells were living with nerves and vascular system and remarkably similar to a normal tooth in many details. Further strictly controlled, side-by-side comparisons between the two types of stem cells also showed that the expression patterns of gene markers and the broad differentiation potentials induced by specific methods in vitro were very similar. Although a few differences were found, they did not affect the tested tooth regeneration in vivo or differentiation in vitro. Furthermore, rabbit ADSCs had a higher growth rate and a better senescence resistance in culture. All these findings suggest that ADSCs, one of the richest adult stem cells in mammals, are very similar and useful as DPSCs for regenerative dentistry. PMID- 21696819 TI - Ambidextrous magnetic nanovectors for synchronous gene transfection and labeling of human MSCs. AB - The synchronization of gene expression and cell trafficking in transfected stem cells is crucial for augmentation of stem cell functions (differentiation and neurotropic factor secretion) and real time in vivo monitoring. We report a magnetic nanoparticle-based gene delivery system that can ensure simultaneous gene delivery and in vivo cell trafficking by high resolution MR imaging. The polar aprotic solvent soluble MnFe2O4 nanoparticles were enveloped using cationic polymers (branched polyethyleneimine, PEI) by the solvent shifting method for a gene loading. Using our magnetic nanovector system (PEI-coated MnFe2O4 nanoparticles), thus, we synchronized stem cell migration and its gene expression in a rat stroke model. PMID- 21696820 TI - The promotion of neural progenitor cells proliferation by aligned and randomly oriented collagen nanofibers through beta1 integrin/MAPK signaling pathway. AB - In regenerative medicine, accumulating evidence demonstrates that the property of substrates monitors neural stem cells behavior. However, how stem cells sense and interpret biochemical and topographical cues remains elusive. This study aimed to explore the mechanism how nanofibrous scaffold modulated stem cells behavior. Spinal cord derived neural progenitor cells (NPCs) were cultured on electrospun aligned and randomly oriented collagen nanofibrous scaffolds. A 30% increase in proliferation and an elevation of BrdU incorporation were observed in NPCs on collagen nanofibers, compared to that on collagen-coated surface. In particular, NPCs expanded faster on aligned nanofibers in comparison with that on randomly oriented nanofibers. Moreover, an alteration in cell cycle progression with a reduced percentage of cells in G0/G1 phase and increased cell proliferation index (S phase plus G2/M phase) was also detected in NPCs cultured on collagen nanofibers. Incubating NPCs with anti-beta1 integrin antibody or U1026 (an inhibitor of mitogen-activated protein kinase kinase, MEK) eliminated the altered cell cycle dynamics and BrdU incorporation induced by collagen nanofibers. In addition, cyclin D1 and cyclin dependent kinase 2 (CDK2), downstream genes of beta1 integrin/mitogen-activated protein kinase (MAPK) pathway that control G1/S phase transition, were correspondingly regulated by nanofibers. Collectively, these data suggested that the property of substrate modulated NPCs proliferation by promoting cell cycle through beta1 integrin/MAPK pathway. Our findings provide a better understanding of the interaction between NPCs and the substrate and therefore will pave way for regenerative medicine. PMID- 21696822 TI - SRY-specific cell free fetal DNA in maternal plasma in twin pregnancies throughout gestation. AB - OBJECTIVES: Levels of SRY-specific cell free fetal DNA (SRY-cffDNA) in maternal plasma were investigated in twin pregnancies with two male fetuses versus one male and one female fetus and singleton male pregnancies during second and third trimester. The aim was to evaluate at which gestational age the amount of SRY cffDNA reflects the number of fetuses and placentas respectively. METHODS: 251 venous blood samples were analyzed from a total of 178 women with male or mixed gender twin pregnancies and male singleton pregnancies in the second and the third trimester. The concentration of SRY-cffDNA was determined by quantitative real time PCR using the Y-chromosome specific SRY assay. For statistical analysis these three groups were divided into four subgroups according to their gestational age. RESULTS: During second trimester levels of SRY-cffDNA showed no differences between twin and singleton pregnancies. After 28 weeks SRY-cffDNA of male twin pregnancies was significantly increased compared to singleton male pregnancies and mixed-gender twin pregnancies with no differences between the latter two. CONCLUSION: The level of SRY-cffDNA in maternal serum of twin pregnancies reflects the number of fetuses only during the third trimester. Hence its use as a diagnostic tool for complications related to altered SRY-cffDNA levels in twin pregnancies should be evaluated at different weeks of gestation, especially during the second trimester. PMID- 21696821 TI - The hemocompatibility of a nitric oxide generating polymer that catalyzes S nitrosothiol decomposition in an extracorporeal circulation model. AB - Nitric oxide (NO) generating (NOGen) materials have been shown previously to create localized increases in NO concentration by the catalytic decomposition of blood S-nitrosothiols (RSNO) via copper (Cu)-containing polymer coatings and may improve extracorporeal circulation (ECC) hemocompatibility. In this work, a NOGen polymeric coating composed of a Cu0-nanoparticle (80 nm)-containing hydrophilic polyurethane (SP-60D-60) combined with the intravenous infusion of an RSNO, S- nitroso-N-acetylpenicillamine (SNAP), is evaluated in a 4 h rabbit thrombogenicity model and the anti-thrombotic mechanism is investigated. Polymer films containing 10 wt.% Cu0-nanoparticles coated on the inner walls of ECC circuits are employed concomitantly with systemic SNAP administration (0.1182 MUmol/kg/min) to yield significantly reduced ECC thrombus formation compared to polymer control + systemic SNAP or 10 wt.% Cu NOGen + systemic saline after 4 h blood exposure (0.4 +/- 0.2 NOGen/SNAP vs 4.9 +/- 0.5 control/SNAP or 3.2 +/- 0.2 pixels/cm2 NOGen/saline). Platelet count (3.9 +/- 0.7 NOGen/SNAP vs 1.8 +/- 0.1 control/SNAP or 3.0 +/- 0.2 * 108/ml NOGen/saline) and plasma fibrinogen levels were preserved after 4 h blood exposure with the NOGen/SNAP combination vs either the control/SNAP or the NOGen/saline groups. Platelet function as measured by aggregometry (51 +/- 9 NOGen/SNAP vs 49 +/- 3% NOGen/saline) significantly decreased in both the NOGen/SNAP and NOGen/saline groups while platelet P selectin mean fluorescence intensity (MFI) as measured by flow cytometry was not decreased after 4 h on ECC to ex vivo collagen stimulation (26 +/- 2 NOGen/SNAP vs 29 +/- 1 MFI baseline). Western blotting showed that fibrinogen activation as assessed by Agamma dimer expression was reduced after 4 h on ECC with NOGen/SNAP (68 +/- 7 vs 83 +/- 3% control/SNAP). These results suggest that the NOGen polymer coating combined with SNAP infusion preserves platelets in blood exposure to ECCs by attenuating activated fibrinogen and preventing platelet aggregation. These NO-mediated platelet changes were shown to improve thromboresistance of the NOGen polymer-coated ECCs when adequate levels of RSNOs are present. PMID- 21696823 TI - Identification of positions in the human neuropeptide Y/peptide YY receptor Y2 that contribute to pharmacological differences between receptor subtypes. AB - The members of the neuropeptide Y (NPY) family are key players in food-intake regulation. In humans this family consists of NPY, peptide YY (PYY) and pancreatic polypeptide (PP) which interact with distinct preference for the four receptors showing very low sequence identity, i.e. Y1, Y2, Y4 and Y5. The binding of similar peptides to these divergent receptors makes them highly interesting for mutagenesis studies. We present here a site-directed mutagenesis study of four amino acid positions in the human Y2 receptor. T(3.40) was selected based on sequence alignments both between subtypes and between species and G(2.68), L(4.60) and Q(6.55) also on previous binding studies of the corresponding positions in the Y1 receptor. The mutated receptors were characterized pharmacologically with the peptide agonists NPY, PYY, PYY(3-36), NPY(13-36) and the non-peptide antagonist BIIE0246. Interestingly, the affinity of NPY and PYY(3 36) increased for the mutants T(3.40)I and Q(6.55)A. Increased affinity was also observed for PYY to Q(6.55)A. PYY(3-36) displayed decreased affinity for G(2.68)N and L(4.60)A whereas binding of NPY(13-36) was unaffected by all mutations. The antagonist BIIE0246 showed decreased affinity for T(3.40)I, L(4.60)A and Q(6.55)A. Although all positions investigated were found important for interaction with at least one of the tested ligands the corresponding positions in hY1 seem to be of greater importance for ligand binding. Furthermore these data indicate that binding of the agonists and the antagonist differs in their points of interaction. The increase in the binding affinity observed may reflect an indirect effect caused by a conformational change of the receptor. These findings will help to improve the structural models of the human NPY receptors. PMID- 21696824 TI - HLA-G expression is irrelevant to prognosis in patients with acute myeloid leukemia. AB - Human leukocyte antigen (HLA)-G could contribute to escape of cancer cells from host anti-tumor responses, and its potential clinical relevance in various malignancies was also addressed. However, the prognostic value of HLA-G in acute myeloid leukemia (AML) remains debated. In this study, HLA-G expression in malignant blasts was analyzed from 77 de novo AML patients (AML-M2, n=26; AML-M3, n=24; AML-M4, n=10; AML-M5, n=17) with flow cytometry. The proportion of HLA-G expressing blasts varied from 0% to 93.96% (median: 0.42%; 95% CI: 0-89.0%). Blasts with 0.5% or fewer HLA-G expressing were defined as negative according to its expression in normal CD34(+)CD45(+) cells (n=20, range: 0-0.5%; median: 0.13%; 95% CI: 0-0.42%). HLA-G expression status on leukemic blasts was not associated with the clinical parameters such as patient age at diagnosis, sex, sub-type of AML, percentage of blasts at diagnosis. Survival analysis revealed that HLA-G expression status on leukemic blasts is unrelated to the prognosis (p=0.884). The mean overall survival time for the HLA-G negative and positive patients was 20.7 months (95% CI: 16.1-25.3) and 20.1 months (95% CI: 14.3-25.8), respectively. Taken together, our findings indicated that HLA-G expression is of no significance for the prognosis of patients with AML. PMID- 21696825 TI - CASP8AP2 is a promising prognostic indicator in pediatric acute lymphoblastic leukemia. AB - The prognostic significance of caspase 8 associated protein 2 (CASP8AP2) in pediatric ALL is controversial. We determined a cut-off of CASP8AP2 expression in bone marrow samples of 39 newly diagnosed patients, and found a significantly poor bone marrow relapse-free survival (p=0.019) in low-expression group and verified it in another cohort of 106 patients (p=0.002). Furthermore, as an independent prognostic factor, CASP8AP2 expression was correlated to minimal residual disease (MRD), and incorporating it with MRD would help to identify patients at greater risk of bone marrow relapse. We also developed an algorithm comprised of clinical risk and CASP8AP2 expression, which could predict bone marrow relapse more accurately. PMID- 21696826 TI - Outcome of older adults with cytogenetically normal AML (CN-AML) and FLT3 mutations. AB - AML patients under the age of 60 whose blasts harbor a FLT3 internal tandem duplication (ITD) mutation have a higher relapse rate and inferior survival compared to those without this mutation. To determine if FLT3ITD also carries a negative prognostic impact in older adults receiving therapies commonly used in this age group, we retrospectively analyzed outcomes of patients >=60 years with CN-AML according to FLT3 mutation status. We identified 91 newly diagnosed CN-AML patients, 55 with wild-type FLT3 and 36 with FLT3ITD. Of the 91 patients, 36 received supportive care and/or experimental therapies while the remaining 55 received induction chemotherapy, followed by allogeneic SCT in 17 of these patients. Based on univariate analysis, advanced age at diagnosis was significantly associated with shorter overall survival (OS) (p<.0001) while intensive therapies were associated with improved OS (p<.0001). In a multivariate analysis that accounted for type of treatment, patient age, gender, and WBC count, FLT3ITD was significantly associated with shorter OS compared to wtFLT3 [p=.001; hazard ratio (HR)=2.23; 95% CI: 1.35-3.70]. Our data support the negative prognostic impact of FLT3ITD in older adults with CN-AML. PMID- 21696827 TI - Concentrations and seasonal variations of polybrominated diphenyl ethers (PBDEs) in in- and out-house dust and human daily intake via dust ingestion corrected with bioaccessibility of PBDEs. AB - The objective of this study was to investigate the concentrations, seasonal variations, bioaccessibility, and associated human daily intake of polybrominated diphenyl ethers (PBDEs) in in- and out-house dust collected in Shanghai, China. The PBDE concentrations varied from 131.6 to 3,886.7 ng g(-1) (with an average of 948.2 ng g(-1)) in in-house dust and from 8.7 to 3,116.3 ng g(-1) (with an average of 290.8 ng g(-1)) in out-house dust during four seasons. The PBDE concentrations in the autumn were the lowest for both in- and out-house dust. Among the detected PBDEs, BDE209 was the predominant congener, accounting for more than 80% of the total PBDE amounts. The bioaccessibility of PBDEs, measured using a simulation system of human gastrointestinal tract, was determined as 14.2 66.4% depending on individual PBDE congeners and showed significant negative correlations with organic matter in dust. After corrected with the bioaccessibility of PBDEs, the human daily intake of PBDEs via dust ingestion was calculated to be 0.4-21.4 and 4.3-40.6 ng day(-1) for an average adult and child in Shanghai, respectively. The values were much lower than most estimates in the literature, in which the bioaccessibility of PBDEs were not taken into account, suggesting that the intake of PBDEs may have been overestimated. PMID- 21696828 TI - Identification and characterization of five transcription factors that are associated with evolutionarily conserved immune signaling pathways in the schistosome-transmitting snail Biomphalaria glabrata. AB - Innate immunity consists of humoral and cellular components that play a vital role in regulation of defense responses to various pathogens in vertebrates and invertebrates. Recent studies have shown that Rel/DIF (dorsal-related immunity factor), Relish, STAT (signal transducer and activator of transcription) and CREB (cAMP response element-binding protein) transcription factor associated pathways are evolutionarily conserved across the animal kingdom. Although the primary role and general structure of the pathways in immunity have been revealed in many invertebrates, particularly arthropods, almost nothing is known about these pathways in the freshwater snail Biomphalaria glabrata, the intermediate host of the human blood fluke Schistosoma mansoni, which is a causative agent of human schistosomiasis. Given the central role of transcription factors (TF) in controlling expression of effector genes, understanding the role of a given TF is essential to obtaining insight into the general function of the corresponding signaling pathway. To better understand the immunity of B. glabrata, we investigated five homologues of TFs that have been shown to be associated with multiple prominent immune signaling pathways based on the considerable data reported from a wide phylogenetic range of animals. In this study we identified and characterized cDNAs of five TFs from B. glabrata, designated BgRelish, BgRel, BgSTAT1, BgSTAT2 and BgCREB, for the first time. Among the five TFs, Relish is first reported in Lophotrochozoa, one of three superphyla in Metazoa. Our identification of class I (BgRelish) and II (BgRel) NF-kappaB in B. glabrata suggests the two pathways, Toll-like receptor (TLR) and immune deficiency (IMD) like pathways, are present in the superphylum Lophotrochozoa. Preliminarily expression studies indicate these TF-associated pathways may be involved in the snail's anti-schistosome response. This study not only advances our understanding of the snail's defenses, but also provides new perspectives about the evolution of animal immunity. PMID- 21696829 TI - Expression of CRH, CRH-related peptide and CRH receptor in the ovary and potential CRH signalling pathways. AB - Capacity to cope with stress is crucial for survival and also reproduction. The stress response differs in the various parts of an organism. Central corticotropin-releasing hormone (CRH) has been identified to be the main stress regulator. In the reproductive system, stress has a deleterious effect on reproduction and CRH is associated with dysfunction of the reproductive endocrine axis. Members of the CRH family have been detected in different reproductive organs of males and females. Ovarian CRH is probably involved in steroid biosynthesis and inflammatory like processes, ovulation and luteolysis. These effects are mediated via the CRH receptors CRH-R1 and CRH-R2. CRH-Rs are G protein-coupled receptors that drive different signalling pathways in the cell. In human, ligands for these receptors are CRH, urocortin 1, stresscopin-related peptide and stresscopin. This review gives an overview on the expression of the CRH family members in the ovary of mammals. Furthermore, potential CRH-induced signalling mechanisms in the ovary will be introduced. PMID- 21696830 TI - Medication adherence and attitudes in patients with bipolar disorder and current versus past substance use disorder. AB - We examined the impact of substance use disorder (SUD) history among patients with bipolar I disorder (BD) in regards to medication-taking behaviors and attitudes. Interviews were conducted with inpatients hospitalized for BD, which included diagnostic instruments and measures of attitudes concerning psychiatric medications. We compared patients with BD and no history of SUD (BD-NH), BD and past history of SUD (BD-PH), and BD and current SUD (BD-C). The primary outcome variable was a standardized medication adherence ratio (SMAR) of [medication taken]/[medication prescribed]. Fifty-four patients with a BD diagnosis participated, which included BD-NH (n=26), BD-PH (n=19), and BD-C (n=9). The SMAR was significantly different among the three groups; post-hoc analyses revealed the SMAR was significantly lower among BD-C (M=0.70) compared to BD-NH (M=0.90) and BD-PH (M=0.97) patients. This finding remained significant after controlling for numerous patient characteristics. Attitudes regarding medications, measured by the Drug Attitude Inventory (DAI), were positive among a significantly higher percentage of BD-PH (89.47%) and BD-NH (65.38%) compared to BD-C (44.44%) patients. In conclusion, patients with BD-C demonstrated poor medication adherence and attitudes concerning medication management. Helping patients with BD achieve remission from SUD may lead to a more successful course of BD pharmacotherapy. PMID- 21696831 TI - Positive erotic picture stimuli for emotion research in heterosexual females. AB - In most experimental studies, emotional pictures are widely used as stimulus material. However, there is still a lack of standardization of picture stimuli displaying erotic relationships, despite the association between a number of psychological problems and severe impairments and problems in intimate relationships. The aim of the study was to test a set of erotic stimuli, with the potential to be used in experimental studies, with heterosexual female subjects. Twenty International Affective Picture System (IAPS) pictures and an additional 100 pictures showing romantic but not explicitly sexual scenes and/or attractive single males were selected. All pictures were rated with respect to valence, arousal, and dominance by 41 heterosexual women and compared to pictures with negative, positive, and neutral emotional valence. Erotic IAPS pictures and our additional erotic pictures did not differ in any of the evaluation dimensions. Analyses of variance (ANOVAs) for valence, arousal, and dominance comparing different picture valence categories showed strong effects for category. However, valence was not significantly different between erotic and positive pictures, while arousal and control were not significantly different between positive and neutral pictures. The pictures of our new set are as positive for heterosexual women as highly positive IAPS pictures, but higher in arousal and dominance. The picture set can be used in experimental psychiatric studies requiring high numbers of stimuli per category. Limitations are the restriction of stimuli application to heterosexual females only and to self-report data. PMID- 21696832 TI - Measurement of systemic and local respiratory cell-mediated immunity after influenza infection in chickens. AB - The detection of ChIFN production after ex vivo antigenic-stimulation of T lymphocytes has been evaluated for the first time, as a tool to assess cell mediated immunity (CMI) after avian influenza (AI) infection in 10-day-old SPF chickens. Preliminarily, recall antigens have been produced either by concentrating and inactivating the whole virus or by dissociating the viral proteins. Biologically and structurally intact forms of the viral proteins were isolated by non-ionic detergents while heating, chemical agents and ionic detergent used for virus inactivation altered the antigenic viral components. The n-octyl-B-D-gluco-pyranoside treatment at low temperature was very efficient to produce AI antigenic proteins used for evaluation of ChIFN production after ex vivo antigenic-stimulation of splenic and peripheral lymphocytes. In addition, protocols to isolate lymphocytes from the respiratory tract - the trachea and the lung - have been adapted for local CMI evaluation after similar ex vivo recall assay. Specific AI CMI in the spleen, the blood and the lung was detected for 5 weeks after low pathogenic AI (LPAI) infection in chickens, while further development is needed for tracheal CMI measurement. PMID- 21696835 TI - Which symptoms can distinguish between subjective cognitive impairment (SCI) and mild cognitive impairment (MCI)? AB - The SCI, the MCI, and the Alzheimer's disease (AD) are on a spectrum of disease progression; therefore, identification of the earliest signs of cognitive deterioration is becoming a crucial issue. The goal of this study was to examine symptom characteristics and distinguish predictive symptoms in patients with MCI compared with SCI, using caregiver questionnaires. We assessed the Korean Dementia Screening Questionnaire (KDSQ) and Seoul Instrumental activities of Daily Living (S-IADL) of 344 subjects with SCI and 697 with MCI. Multivariate logistic regression analyses were conducted after adjusting for age, sex, and educational status. Common and rare symptoms were similar between the SCI and MCI groups. The most distinguishing features of KDSQ were 'Finds it hard to go somewhere on his/her own using public transportation' (odds ratio=OR=4.56, p<0.0001), 'Has difficulty in operating appliances' (OR=2.47, p=0.001), and 'Keeps repeating the same question' (OR=2.03, p<0.0001). In S-IADL, the most outstanding features were 'using household appliances' (OR=3.99, p<0.0001), 'taking medication' (OR=2.38, p=0.01), and 'using public transportation' (OR=1.94, p=0.04). The dysfunction in 'using household appliance' and 'using public transportation' reflect the possibility of MCI rather than SCI. Therefore, it is suggested that these symptoms also have a discriminative and predictive power in identifying SCI. PMID- 21696833 TI - Historical and current perspective on tobacco use and nicotine addiction. AB - Although the addictive influence of tobacco was recognized very early, the modern concepts of nicotine addiction have relied on knowledge of cholinergic neurotransmission and nicotinic acetylcholine receptors (nAChRs). The discovery of the 'receptive substance' by Langley, that would turn out to be nAChRs, and 'Vagusstoff' (acetylcholine) by Loewi, coincided with an exciting time when the concept of chemical synaptic transmission was being formulated. More recently, the application of more powerful techniques and the study of animal models that replicate key features of nicotine dependence have led to important advancements in our understanding of molecular, cellular and systems mechanisms of nicotine addiction. In this review, we present a historical perspective and overview of the research that has led to our present understanding of nicotine addiction. PMID- 21696836 TI - An alternative approach to understanding the pathophysiological mechanisms of chronic heart failure. AB - No single well established hypothesis for the mechanisms of heart failure currently exists. Those definitions that do exist are either not universally applicable or are not exclusive to heart failure. The pathogenesis of heart failure has been considered by some to be too complex to define with multiple pathophysiological processes being implicated. The many clinical and neurohumoral features of heart failure may be more dependent on the severity of the condition and its speed of onset rather than its etiology. This suggests a potential single common pathway or pathogenic mechanism in all forms of heart failure regardless of cause. This viewpoint uses the framework of myocardial mechanics and energetics to propose an alternative, simplified definition and unifying hypothesis for the pathogenesis of chronic heart failure. Chronic heart failure may be understood as follows. Cardiac output and stroke volume are determined by the tissues' requirements; the ejection fraction is determined by both myocardial shortening and degree of end-diastolic wall thickness; the end-diastolic volume is determined by the requirement to normalize stroke volume. We will argue that chronic heart failure can be viewed as a condition where the dominant compensatory mechanism is through regulation of ventricular end-diastolic volume. Consequently, in conditions where there is a fall in tissue perfusion, stroke volume and tissue perfusion are returned toward normal predominantly via this feedback mechanism. It is important for researchers, clinicians and their patients that we strive for a comprehensive, inclusive and unambiguous unifying hypothesis for pathophysiological mechanisms of heart failure. PMID- 21696837 TI - Cardioprotection of Asperosaponin X on experimental myocardial ischemia injury. AB - BACKGROUND: Asperosaponin X was isolated from the roots of Dipsacus asper. In this study, we investigated the anti-myocardial ischemia and reperfusion (I/R) injury effects of Asperosaponin X in vivo and elucidated the potential mechanism in vitro. RESULTS: Asperosaponin X significantly attenuated hypoxia-induced cytotoxicity in a concentration-dependent manner in H9c2 cells. Treatment of H9c2 cells with Asperosaponin X 5 MUM or 10 MUM blocked TNF-alpha-induced nuclear factor kappaB (NF-kappaB) phosphorylation by blocking HMGB1 expression. Treatment of rats with Asperosaponin X 10mg/kg, (i.v.) protected the animals from myocardial I/R injury as indicated by a decrease in infarct volume, improvement in hemodynamics and reduction of myocardial damage severity. Treatment with Asperosaponin X also lowered serum levels of pro-inflammatory factors and reduced High mobility group box-1 protein (HMGB1), phosphorylated IkappaB-alpha and NF kappaB expression in ischemic myocardial tissue. Additionally, continuous i.v. of Asperosaponin X 14 days attenuated cardiac remodeling. CONCLUSIONS: These protective effects suggested that Asperosaponin X may be due to block of myocardial inflammatory cascades through an HMGB1-dependent NF-kappaB signaling pathway. PMID- 21696834 TI - Neuroimaging markers for the prediction and early diagnosis of Alzheimer's disease dementia. AB - Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease. At the time of clinical manifestation of dementia, significant irreversible brain damage is already present, rendering the diagnosis of AD at early stages of the disease an urgent prerequisite for therapeutic treatment to halt, or at least slow, disease progression. In this review, we discuss various neuroimaging measures that are proving to have potential value as biomarkers of AD pathology for the detection and prediction of AD before the onset of dementia. Recent studies that have identified AD-like structural and functional brain changes in elderly people who are cognitively within the normal range or who have mild cognitive impairment (MCI) are discussed. A dynamic sequence model of changes that occur in neuroimaging markers during the different disease stages is presented and the predictive value of multimodal neuroimaging for AD dementia is considered. PMID- 21696838 TI - Subclinical diastolic dysfunction in type 2 diabetic patients with and without carotid atherosclerosis: relationship with glyco-oxidation, lipid-oxidation and antioxidant status. AB - OBJECTIVES: The aim of this study was to evaluate subclinical diastolic dysfunction in type 2 diabetic patients and its relationship with glyco oxidation, lipo-oxidation and antioxidant capacity in the presence or absence of carotid plaques. BACKGROUND: Subclinical diastolic dysfunction is the early stage of diabetic cardiomyopathy, the pathogenic mechanisms of which are still little known. In particular, few data are available on the role of glyco-oxidation, lipo oxidation and antioxidant status, factors known to be involved in the atherosclerotic process. METHODS: We assessed myocardial systolic and diastolic functions in 57 consecutive asymptomatic type 2 diabetic patients (24 patients with no carotid plaques; 33 with plaques) and 27 healthy volunteers using transthoracic echocardiography. Glyco-oxidation and lipo-oxidation parameters and antioxidant status were also evaluated in fasting venous blood samples. RESULTS: Systolic function was similar between diabetic patients and controls, while most of the diastolic parameters (A, e', E/A, E/e') differed significantly between diabetics and controls, being worse in the former. Among the diastolic parameters, only the peak late diastolic velocity A differed significantly between the two groups of diabetic patients with no carotid plaques and with plaques (0.72 +/- 0.16 m/s vs 0.84 +/- 0.25 m/s, p<0.05). The diastolic parameters A and E/e' related to glycemic control, glyco-oxidation and antioxidant capacity, and to LDL size and density. CONCLUSIONS: Glyco-oxidation and antioxidant status, combined with the presence of small, dense LDL correlate with subclinical diastolic dysfunction in type 2 diabetic patients. Atherosclerotic lesions are associated with an altered atrial function. PMID- 21696839 TI - Inequality and polarisation in health systems' responsiveness: a cross-country analysis. AB - The World Health Report 2000 proposed three fundamental goals for health systems encompassing population health, health care finance and health systems responsiveness. The goals incorporate both an efficiency and equity dimension. While inequalities in population health and health care finance have motivated two important strands of research, inequalities in responsiveness have received less attention in health economics. This paper examines inequality and polarisation in responsiveness, bridging this gap in the literature and contributing towards an integrated analysis of health systems performance. It uses data from the World Health Survey to measure and compare inequalities in responsiveness across 25 European countries. In order to respect the inherently ordinal nature of the responsiveness data, median-based measures of inequality and polarisation are employed. The results suggest that, in the face of wide differences in the health systems analysed, there exists large variability in inequality in responsiveness across countries. PMID- 21696840 TI - The impact of comparative effectiveness research on health and health care spending. AB - Comparative effectiveness research (CER) is thought to identify what works and does not work in health care. We interpret CER as infusing evidence on product quality into markets, shifting the relative demand for products in CER studies. We analyze how shifts in demand affect health and health care spending and demonstrate that CER may raise or lower overall health when treatments have heterogeneous effects, but payers respond with product-specific coverage policies. Among patients with schizophrenia, we calibrate that subsidy policies based on the clinical trial CATIE may have reduced overall health by inducing some patients to switch away from schizophrenia treatments that were effective for them towards winners of the CER. PMID- 21696841 TI - Epigenetics and diabetic cardiomyopathy. AB - Cardiovascular complications are a chief cause of mortality and morbidity in diabetic patients. Recent studies suggest that epigenetic changes which may arise as a consequence of environmental factors play an important role in predisposition to disease. Epigenetic mechanisms such as DNA methylation, chromatin remodeling and histone modifications regulate the gene expression in response to environmental signals. Role of epigenetics has been recognized in the pathology of diabetes, however its role in diabetic associated cardiomyopathy remains largely unexplored. In this article, we review current literature on the epigenetic mechanisms involved in diabetes and discuss recent evidence of epigenetic changes that may play an important role in pathophysiology of DCM. PMID- 21696842 TI - Are we treating enough elderly patients with early stage non-small cell lung cancer? AB - Despite the fact that non-small-cell lung cancer (NSCLC) is very common in the older population, these patients are frequently underrepresented in clinical trials evaluating new anti-cancer agents, and thus it is difficult to reach evidence-based recommendations for this special population. The purpose of the present paper is to present the currently available evidence regarding treatment of early-stages of NSCLC in older patients. Although, age is still considered as a negative factor influencing treatment decisions and curative cancer-directed surgery is often omitted in the older population several studies support that surgical resection is feasible in the older patient and that age per se is not a contraindication for various surgical procedures. Pneumonectomy is associated with a higher mortality in the older population and this issue should be taken into account when deciding whether a patient is suitable for pneumonectomy. Older patients should be considered for adjuvant chemotherapy after surgical resection although little information is available regarding the real benefit and tolerability of these regimens for patients over 75 years of age. Given the lack of demonstrated benefit for the use of adjuvant RT it is also not recommended in older population. PMID- 21696843 TI - The biodiversity benefits of botanic gardens. PMID- 21696844 TI - Arabidopsis mutant of AtABCG26, an ABC transporter gene, is defective in pollen maturation. AB - In plants, pollen is the male gametophyte that is generated from microspores, which are haploid cells produced after meiosis of diploid pollen mother cells in floral anthers. In normal maturation, microspores interact with the tapetum, which consists of one layer of metabolically active cells enclosing the locule in anthers. The tapetum plays several important roles in the maturation of microspores. ATP-binding cassette (ABC) transporters are a highly conserved protein super-family that uses the energy released in ATP hydrolysis to transport substrates. The ABC transporter gene family is more diverse in plants than in animals. Previously, we reported that an Arabidopsis half-size type ABC transporter gene, COF1/AtWBC11/AtABCG11, is involved in lipid transport for the construction of cuticle layers and pollen coats in normal organ formation, as compared to CER5/AtWBC12/AtABCG12. However, physiological functions of most other ABCG members are unknown. Here, we identified another family gene, AtABCG26, which is required for pollen development in Arabidopsis. An AtABCG26 mutant developed very few pollen grains, resulting in a male-sterile phenotype. By investigating microspore and pollen development in this mutant, we observed that there was a slight abnormality in tetrad morphology prior to the formation of haploid microspores. At a later stage, we could not detect exine deposition on the microspore surface. During pollen maturation, many grains in the mutant anthers got aborted, and surviving grains were found to be defective in mitosis. Transmission of the mutant allele through male gametophytes appeared to be normal in genetic transmission analysis, supporting the view that the pollen function was disturbed by sporophytic defects in the AtABCG26 mutant. AtABCG26 can be expected to be involved in the transport of substrates such as sporopollenin monomers from tapetum to microspores, which both are plant-specific structures critical to pollen development. PMID- 21696845 TI - Silicon delays Tobacco ringspot virus systemic symptoms in Nicotiana tabacum. AB - Soluble silicon (Si) provides protection to plants against a variety of abiotic and biotic stress. However, the effects of Si on viral infections are largely unknown. To investigate the role of Si in viral infections, hydroponic studies were conducted in Nicotiana tabacum with two pathogens: Tobacco ringspot virus (TRSV) and Tobacco mosaic virus (TMV). Plants grown in elevated Si showed a delay in TRSV systemic symptom formation and a reduction in symptomatic leaf area, compared to the non-supplemented controls. TRSV-infected plants showed significantly higher levels of foliar Si compared to mock-inoculated plants. However, the Si effect appeared to be virus-specific, since the element did not alter TMV symptoms nor did infection by this virus alter foliar Si levels. Hence, increased foliar Si levels appear to correlate with Si-modulated protection against viral infection. This is all the more intriguing since N. tabacum is classified as a low Si accumulator. PMID- 21696846 TI - [New treatments for diabetic retinopathy]. AB - Even if several studies have clearly demonstrated that a good control of glycemia and arterial pressure allow reducing the incidence and the progression of diabetic retinopathy, there is currently no drug treatment to prevent the incidence or progression of diabetic retinopathy. However, significant progress has been made in treating the complications of diabetic retinopathy, including diabetic macular edema. Ranibizumab is effective in improving visual acuity in diabetic macular edema, but at the cost of repeated injections and monthly follow ups. It has obtained a marketing authorization (MA) in this indication. Injections of intravitreal triamcinolone acetonide are also effective in reducing macular edema and in improving visual acuity but at the cost of significant side effects and without MA for intraocular use. The latter must be proposed after failure and/or injection of anti-VEGF or laser therapy. PMID- 21696847 TI - [Decreased visual acuity in young patients; Javal's ophthalmometer is still contributing]. AB - PURPOSE: The purpose of this study was to recall the advantages of the Javal ophthalmometer in screening keratoconus. PATIENTS AND METHODS: In three young patients with progressive visual loss, optic neuropathy was strongly suspected by their ophthalmologist despite a strictly normal neuro-ophthalmology record. The patients underwent an ophthalmic clinical examination at the Bordeaux University Hospital, which guided the paraclinical examination with corneal videotopography (Orbscan II((r)), Bausch and Lomb) and the biomechanical properties of the cornea with the ocular response analyzer (ORA((r)), Reichert). RESULTS: Visual acuity improved in all patients on the pinhole visual acuity test. The videotopography concluded in keratoconus in all three patients. The biomechanical parameters were abnormal. The patients were equipped successfully with hard contact lenses. CONCLUSION: Despite the latest technologies including videotopography and ORA((r)), examination of the cornea with the Javal ophthalmometer remains a landmark of the eye examination and can assist in screening some keratoconus conditions and avoiding diagnostic uncertainties as well as inappropriate and expensive paraclinical examinations. PMID- 21696848 TI - [Visante(r) OCT findings of Descemet membrane detachment after refractive lensectomy: A case report]. AB - Descemet membrane detachment (DMD) is a rare complication that occurs mainly after cataract surgery. We report the case of a 55-years-old woman who underwent refractive lensectomy. The Day-1 postoperative examination was unremarkable, the Day-7 examination showed corneal oedema related to DMD, which was confirmed by Visante((r)) OCT. An intracameral injection of SF6 expansive gas allowed the reapplication of the membrane and the receding of corneal oedema. Through this observation, we discuss the pathogenesis of this uncommon entity and the contribution of Visante((r)) OCT. PMID- 21696849 TI - [Efficacy assessment of Nutrilarm(r), a per os omega-3 and omega-6 polyunsaturated essential fatty acid dietary formulation versus placebo in patients with bilateral treated moderate dry eye syndrome]. AB - INTRODUCTION: Inflammation is one of the main mechanisms common to all forms of dry eye. Since polyunsaturated acids are known to show biological anti inflammatory properties, the aim of this study was to evaluate the efficacy of dietary n-6 and n-3 fatty acids in patients suffering from ocular dryness. PATIENTS AND METHODS: One hundred and eighty-one patients diagnosed with bilateral moderate dry eye who were already treated with lachrymal substitutes were randomized in a double-blind international study to receive placebo or Nutrilarm((r)) capsules (combination of omega-3 and omega-6), twice a day for 6 months. In all subjects, dryness feeling, overall subjective comfort, and ocular symptoms (burning, stinging, sandy and/or gritty sensation, light sensitivity, reflex tearing, and ocular fatigue) were evaluated at each visit. Furthermore, fluorescein tests (break-uptime and Oxford scheme) and lissamine green test were performed at each visit. The Schirmer test was performed at inclusion and after 6 months of treatment. RESULTS: After 6 months of supplementation with Nutrilarm((r)), both the BUT scores and ocular fatigue were significantly improved when compared with placebo (P=0.036 and P=0.044, respectively). There was a trend in favor of Nutrilarm((r)) in terms of the efficacy evaluated by the investigator (P=0.061). Fewer patients experienced a feeling of severe dryness with Nutrilarm((r)) compared with placebo after 6 months of treatment (2.5 and 9.3%, respectively), but the difference was not statistically significant. CONCLUSION: Oral administration of a double supplementation dietary n-6 and n-3 fatty acids present an additional therapeutic advantage in patients suffering from ocular dryness who were already treated with lachrymal substitutes. PMID- 21696850 TI - [Ocular Lyme disease occurring during childhood: five case reports]. AB - INTRODUCTION: Lyme borreliosis (LB) is the most common human tick-borne disease in the Northern hemisphere. The various ophthalmologic manifestations of Lyme borreliosis (LB) during childhood are discussed in this paper. PATIENTS AND METHODS: Six children with LB-associated ocular manifestations were treated between 2000 and 2010 in the ophthalmology department of Strasbourg University Hospital (an endemic area). Medical history, ocular and systemic clinical findings, determinations of antibodies related to Borrelia, as well as exclusion of other causes were the diagnosis criteria. RESULTS: Two cases of uveitis, two cases of abducens palsies, one case of optical neuropathy, and one case of orbital myositis associated with LB were diagnosed. Systemic findings, such as arthritis, rash, or erythema migrans were mentioned in all cases. Two children also complained of severe knee arthritis. Determination of antibodies was positive in all patients. They were all treated with antibiotics adjusted to individual circumstances and some of them (two cases of uveitis and one of optic neuropathy) also had anti-inflammatory treatment. Resolution of ocular signs, with no relapse, was observed in all patients within two to 12 weeks. CONCLUSION: For any unexplained ocular symptom, even in children, LB should be taken into account, especially in endemic areas. Such patients should undergo serological testing. If the clinical presentation is suggestive of LB, a course of oral antibiotics should be used. All in all, permanent defects are extremely rare during the childhood period, even following long-term manifestation at an early age. PMID- 21696851 TI - Direct immunofluorescence of plucked hair for evaluation of immunologic remission in pemphigus vulgaris. AB - BACKGROUND: Negative direct immunofluorescence (DIF) is a predictor of immunologic remission in pemphigus vulgaris. Recently, it has been shown that plucked hair can be used as substrate for DIF in the diagnosis of pemphigus. OBJECTIVE: We sought to compare hair DIF in patients with pemphigus vulgaris in clinical remission with conventional DIF for the assessment of immunologic remission. METHODS: A total of 55 patients with pemphigus vulgaris fulfilling the following inclusion criteria were enrolled: absence of any lesion and daily prednisolone dosage equal or less than 10 mg without adjuvant drug in the preceding 6 months. Biopsy specimen and plucked hair were processed for DIF. Intercellular deposition of IgG and/or C3 was considered positive. RESULTS: Conventional DIF and hair DIF were positive in 28 (50.9%) and 36 (65.5%) patients, respectively. Hair DIF had a sensitivity of 0.79 (95% confidence interval [CI] 0.59-0.92), a specificity of 0.48 (95% CI 0.29-0.68), a positive predictive value of 0.61 (95% CI 0.44-0.77), and a negative predictive value of 0.68 (95% CI 0.43-0.87). LIMITATIONS: Small sample size is the main limitation of this study. CONCLUSIONS: The sensitivity of hair DIF was not high enough to allow us to suggest it as a substitute for conventional DIF. On the other hand, one cannot disregard positive cases of hair DIF in the setting of negative biopsy DIF. As hair plucking is less invasive than biopsy, the following approach could be suggested: hair DIF may be repeated in patients in clinical remission until negative; then conventional DIF should be performed, too. The physician can decide to stop treatment only when DIF assays on both substrates are negative. PMID- 21696852 TI - Basosquamous cell carcinoma in organ transplant patients: a clinicopathologic study. AB - BACKGROUND: Basosquamous cell carcinoma (BSCC) is a poorly known tumor showing pathological features of both basal and squamous cell carcinomas. BSCC has never been specifically studied in organ transplant recipients (OTRs). OBJECTIVE: We sought to study the clinicopathologic features of BSCC in OTRs and compare them with BSCC from nongrafted patients. METHODS: Tumors diagnosed as BSCC were re evaluated pathologically and immunohistochemically for the expression of the human epithelial antigen to confirm the diagnosis. The clinicopathologic features of BSCC in OTRs were compared with 30 BSCC obtained from nongrafted patients. RESULTS: In our cohort of 3520 OTRs, 12 patients (0.34%) developed BSCC after a mean postgraft delay of 13.2 years, ie, later than other skin carcinomas. As compared with control patients, the age of OTRs with BSCC and the tumor thickness were significantly lower. BSCC were located on the head/neck in both groups in more than 75% of cases. No metastases developed in OTRs (mean follow-up 2.8 years). During the follow-up period (mean 16 years), OTRs with BSCC developed up to 220 additional premalignant and malignant skin tumors. After the diagnosis of BSCC, two patients developed lymph node metastasis of distinct squamous cell carcinoma. LIMITATIONS: This is a single-center, retrospective study. CONCLUSIONS: BSCC is a rare tumor, even in OTRs who are at high risk of carcinomas. Its incidence (0.34%) is comparable with that of cutaneous lymphomas and melanomas, and much lower than that of other nonmelanoma skin cancers. Contrary to previous reports, BSCC do not seem to behave more aggressively than other nonmelanoma skin cancers. PMID- 21696853 TI - Oral administration of a hydrophilic extract of Polypodium leucotomos for the prevention of polymorphic light eruption. AB - BACKGROUND: Polymorphic light eruption (PLE) is the most common idiopathic photodermatosis. Reactive oxygen species have been implicated in the pathogenesis of PLE. Polypodium leucotomos (PL) is a natural extract from tropical fern leaves with potent antioxidant and anti-inflammatory properties. OBJECTIVE: In this study we sought to evaluate whether a concentrated hydrophilic extract of PL might prevent or delay the photoinduction of typical PLE lesions by artificial ultraviolet (UV) radiation. METHODS: A total of 35 patients with long-standing PLE were included in this open, uncontrolled bicenter study. PLE was induced by photoprovocation with artificial UVB and UVA light, thereafter oral treatment with PL was initiated. Two weeks later a second photoprovocation was performed while the patients were still taking PL. RESULTS: Thirty patients developed PLE lesions after repeated irradiation with UVA. Of these, 18 patients also responded to UVB. After PL treatment, 9 (30%) and 5 (28%) patients, respectively, were unresponsive to repeated UVA and UVB exposure. In the remaining patients, the mean number of UVA and UVB irradiations required to elicit PLE increased significantly from 1.95 to 2.62 (P = .005) and from 2.38 to 2.92 (P = .047), respectively. LIMITATIONS: The study was open and uncontrolled and included a relatively small number of patients. CONCLUSION: Our data indicate that oral PL treatment might be beneficial for the prevention of PLE. PMID- 21696854 TI - Cutaneous Merkel cell carcinoma. AB - PURPOSE: The aim of this study was to describe the treatment outcomes of patients with cutaneous Merkel cell carcinoma managed with curative intent. MATERIALS AND METHODS: Between December 1984 and November 2009, 40 patients with previously untreated Merkel cell carcinoma were managed with curative intent with radiotherapy alone (3 patients) or combined with surgery (37 patients). Adjuvant chemotherapy was administered to 11 patients. Primary sites were the following: head and neck, 32 patients; extremities, 6 patients; and trunk, 2 patients. Patients were staged according to the Yiengpruksawan staging system: stage I, local disease; stage II, regional disease; and stage III, distant metastases. Twenty-four patients had stage I disease, and 16 patients had stage II disease. Median follow-up on all patients was 3.0 years (range, 0.6-15.6 years). Median follow-up on survivors was 4.2 years (range, 2.2-14.2 years). RESULTS: The 5-year outcomes were local control, 92%; regional control, 78%; local-regional control, 79%; distant metastasis-free survival, 57%; cause-specific survival, 45%; and overall survival, 36%. The 5-year outcomes for those with stage I vs stage II disease were the following: local-regional control, 87% and 67% (P = .1607); distant metastasis-free survival, 71% and 37% (P = .0073); cause-specific survival, 58% and 27% (P = .0090); and overall survival, 48% and 18% (P = .0037). Local-regional recurrences were observed in 6 patients; one patient was successfully salvaged. Severe complications were observed in 3 patients. CONCLUSIONS: Radiotherapy alone or combined with surgery results in a high local regional control rate. The main mode of recurrence is distant. Approximately one half of patients are cured. PMID- 21696855 TI - Superior oblique muscle palsy after frontal sinus mini-trephine. AB - OBJECTIVE: The aim of this study is to present a case of superior oblique muscle dysfunction after a frontal sinus mini-trephine. METHODS: This is a case report of an 18-year-old woman where a mini-trephination approach and endoscope were used to open and marsupialize a symptomatic, opacified type IV cell within the left frontal sinus. After surgery, the patient developed a persisting diplopia; a left superior oblique muscle palsy was diagnosed. Nine cadaveric dissections of the trochlea were undertaken to clarify mechanisms for potential trochlear damage. RESULTS: Cadaveric dissection reveals that the trochlea is more than a simple pulley; it is a complex structure in close proximity to the orbital rim. The superior oblique tendon telescopes and is surrounded by a vascular sheath that could be easily traumatized. CONCLUSION: Damage to the trochlea could occur, as the periosteum is elevated from bone or during healing. Alternatively, prolonged traction on soft tissue near the trochlea could cause swelling of the vascular sheath, fibrosis, and hypomobility of the superior oblique tendon. Careful siting of the incision for external frontal sinus surgery as well as careful retraction of skin flaps and periosteal elevation are all techniques used, which should reduce the risk of damage to the trochlea. PMID- 21696856 TI - Unique case of malignant transformation of a vestibular schwannoma after fractionated radiotherapy. AB - OBJECTIVE: Malignant transformation of vestibular schwannoma is considered a rare clinical entity. Radiotherapy, as a treatment option for vestibular schwannoma, is regarded as a potential risk factor for secondary malignancy. Recently, radiotherapy with dose fractionation has been proposed, intended to diminish the risk of radiation-induced neuropathy. CASE PRESENTATION: The aim of the present study is to report the first case, to the best of our knowledge, of malignant transformation of a residual vestibular schwannoma 19 years after fractionated radiotherapy, describing its characteristics with regard to those previously reported in the literature. CONCLUSIONS: The main purpose of the present work is to state that the knowledge of the iatrogenic potential pitfalls of any technique of radiotherapy in clinical oncology is becoming a necessity. Finally, our report demonstrates that the irradiated patients must be monitored for life because a secondary malignancy may appear after a very long delay. PMID- 21696857 TI - Intended single-modality management of T1 and T2 tonsillar carcinomas: retrospective comparison of radical tonsillectomy vs radiation from a single institution. AB - BACKGROUND: T1 and T2 tonsillar squamous cell cancer with limited neck disease can be managed with single-modality radiation or surgery. Over 11 years, 17 patients underwent radical tonsillectomies; and 33 patients underwent radiation based treatments for T1 and T2 and N0 to N2a tonsil cancer. Patients were intended to receive single-modality treatment based on presentation; however, some ultimately received adjuvant treatments. METHODS: A retrospective chart review to compare overall survival (OS), disease-specific survival (DSS), and locoregional control (LRC) between the groups was used. RESULTS: In surgical group, of 17 patients, 11 underwent surgery alone, 3 underwent surgery and radiation, and 3 underwent surgery with concurrent chemoradiation. Five-year OS for the surgical and radiation groups was 93% and 72%, respectively (no significance achieved). Five-year DSS rates (93% and 80%) and LRC (69% and 89%) similarly did not yield any significant difference. CONCLUSION: Surgery remains a viable option in the management of T1 and T2 tonsillar cancers with comparable LRC, OS, and DSS. PMID- 21696858 TI - Conventional and sharp safety devices in 6 hospitals in British Columbia, Canada. AB - BACKGROUND: Reengineered sharp safety devices have been recommended to reduce occupational percutaneous injury risk in health care facilities. We conducted this study just over 1 year after passage of legislation requiring the use of sharp safety medical devices to assess the frequency of safety and conventional sharp device use and whether safety features were being activated to cover sharp points after safety devices were used and before disposal. METHODS: Approximately equal numbers of sharps disposal containers from various wards in 6 nonprofit adult and pediatric British Columbia hospitals were audited by paired research assistants, wearing protective clothing. RESULTS: In the 699 audited sharps containers, 7% (1,690/25,910) of all devices were conventional devices, specifically 2% (96/4,702) of all phlebotomy devices, 7% (1,240/17,705) of all syringes, and 10% (354/3,503) of all intravenous catheters. In addition, 94% (4,344/4,602) of all safety phlebotomy devices, 95% (2,955/3,119) of all safety intravenous devices, and 80% (13,050/16,420) of all safety syringes had been activated before disposal. CONCLUSION: More than 1 year after legislation was passed mandating the use of sharp safety devices in British Columbia hospitals, the risk from sharps remains excessive because of the ongoing use of conventional sharp devices and nonactivation of safety devices. PMID- 21696859 TI - Hepatitis A antibody seroprevalence among medical school students. AB - A total of 324 first- to third-year medical school students were examined for anti-hepatitis A virus IgG. Of these 324 students, 37 were found to be anti hepatitis A virus IgG positive (11.4%). Mass screening of medical students for seropositivity and vaccination of nonimmune students should be considered before starting medical clerkships. PMID- 21696860 TI - [Robotic surgery: history and teaching impact]. AB - CONTEXT: The purpose of this article is to review the history of robotic surgery, its impact on teaching as well as a description of historical and current robots used in the medical arena. SUMMARY OF EVIDENCE: Although the history of robots dates back to 2000 years or more, the last two decades have seen an outstanding revolution in medicine, due to all the changes that robotic surgery has made in the way of performing, teaching and practicing surgery. CONCLUSIONS: Robotic surgery has evolved into a complete and self-contained field, with enormous potential for future development. The results to date have shown that this technology is capable of providing good outcomes and quality care for patients. PMID- 21696861 TI - [Pioneer experience in Spain with LSSS nephrectomy in living donor]. AB - INTRODUCTION: LESS surgery (Laparoendoscopic single site surgery) is a surgical technique that aims to perform intraabdominal surgery using a single site entry, allowing for reduction in the number and size of the incisions, achieving better esthetic results with at least the same functional outcomes as with the conventional laparoscopic surgery. MATERIAL AND METHODS: We present the first experience of LESS living donor nephrectomy carried out by a totally European team. To perform it, a Quadport(r) device was placed through a 4 cm long paraumbilical incision. RESULTS: The nephrectomy was performed using the standards of conventional laparoscopic surgery, with the use of a precurved instrument in the left hand and straight instruments in the right. After bagging the kidney, the artery and vein were sectioned after clipping, allowing for rapid extraction of the organ through the same incision, with warm ischemia of 3.30" and 2.47," respectively. CONCLUSION: Living donor nephrectomy using the LESS technique is feasible and can be considered a good option for obtaining live donor kidney grafts in males. The application of said surgical in living kidney donor can increase the rate of donation, by reducing morbidity and improving the esthetic results with the same outcome for the donor as for the recipient. PMID- 21696862 TI - [Reply to the article "Effectiveness of levetiracetam in the treatment of two cases of status myoclonicus due to hypoxic encephalopathy"]. PMID- 21696863 TI - [Detection of resistance phenotypes in gram-negative bacteria]. AB - Detecting resistance in gram-negative microorganisms has a strong clinical and epidemiological impact, but there is still a great deal of debate about the most sensitive phenotypic method and whether in vitro susceptibility results should be interpreted. The present work reviews the phenotypes and mechanisms of resistance to beta-lactams, quinolones and aminoglycosides in gram-negative bacilli and also revises the different phenotypic methods used for their detection. A clinical interpretation of in vitro susceptibility results is also discussed. Extended spectrum and inhibitor resistant beta-lactamases, AmpC type beta-lactamases and carbapenemases are thoroughly reviewed. As regards quinolones, the resistance mediated both by plasmids and by mutations in the DNA gyrase and the topoisomerase IV genes is also reviewed. This report includes resistance patterns to aminoglycosides caused by modifying enzymes. Phenotypic detection of beta lactam resistance in Neisseria spp. and Haemophilus influenzae is also reviewed in a separate section. PMID- 21696864 TI - [Progressive multifocal leukoencephalopathy in a patient with acute myeloid leukaemia after allogeneic hematopoietic-cell transplantation]. PMID- 21696865 TI - Biological evaluation of twenty-eight ferrocenyl tetrasubstituted olefins: cancer cell growth inhibition, ROS production and hemolytic activity. AB - The antiproliferative effects of twenty-eight tetrasubstituted olefins bearing a ferrocenyl group, including six never-reported compounds, were evaluated against SF-295 (human glioblastoma), HCT-8 (human colon cancer), MDA-MB-435 (human melanoma) and HL-60 (human promyelocytic leukemia) using the MTT test. IC(50) values were determined for twenty-three active compounds and of these, ten compounds had IC(50) values lower than 2 MUM on one or more cell lines. Of all the compounds, only two produced significant amounts of ROS on HL-60 cells, and ROS production and growth inhibition could not be correlated. The ten most antiproliferative compounds were tested for their hemolytic activity on mouse erythrocytes. Five compounds showing high antiproliferative activity and low hemolytic activity were thus identified for further study. PMID- 21696866 TI - Synthesis and biological evaluation of 1-substituted-3(5)-(6-methylpyridin-2-yl) 4-(quinoxalin-6-yl)pyrazoles as transforming growth factor-beta type 1 receptor kinase inhibitors. AB - A series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6 yl)pyrazoles 14a-d, 15a-d, 17a, 17b, 18a-d, 19a, and 19b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell based luciferase reporter assay. The 2-[3-(6-methylpyridin-2-yl)-4-(quinoxalin-6 yl)-1H-pyrazol-1-yl]-N-phenylethanethioamide (18a) inhibited ALK5 phosphorylation with an IC(50) value of 0.013 MUM and showed 80% inhibition at 0.1 MUM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct. PMID- 21696867 TI - Drug calculation skills - are we running scared? PMID- 21696868 TI - Effect of time interval between food intake and exercise on substrate oxidation during exercise in obese and lean children. AB - BACKGROUND & AIMS: Exercise induces adaptations in fat metabolism favourable to the treatment of obesity. However, time interval between meal and exercise alters substrate bioavailability and oxidation during exercise. The aim of this study was therefore to investigate the effect of time interval between food intake and exercise on substrate oxidation rates in obese and lean children. METHODS: The metabolic responses to exercise of nine obese children (10.3 +/- 1.8 years; %body fat: 36.1 +/- 6.1) and seven lean children (9.2 +/- 1.6 years; %body fat: 22.2 +/ 4.1) were compared 1 h (time interval 1, TI1) and 3 h (TI3) after a standardized breakfast. RESULTS: Despite significantly lower plasma glucose and insulin concentrations and large effect size suggesting a higher plasma FFA availability (lean, 1.43, obese 0.98), fat oxidation was not significantly increased in TI3 compared to TI1 in both lean and obese children. Fat oxidation contributed marginally to energy expenditure during exercise (<20%) in both conditions and groups but was moderately increased during TI3 compared to TI1 in lean children (effect size: 0.54). CONCLUSIONS: The low contribution of fat oxidation to energy expenditure during exercise in obese and lean children fed 3 h before exercise questions the efficacy of moderate intensity exercise to favourably affect fat balance. PMID- 21696869 TI - Intranasal immunization with recombinant PspA fused with a flagellin enhances cross-protective immunity against Streptococcus pneumoniae infection in mice. AB - Streptococcus pneumoniae is a major respiratory pathogen that causes high levels of mortality and morbidity in infants and the elderly. Despite the use of antibiotics and vaccines, fatal pneumococcal disease remains prevalent. Pneumococcal surface protein A (PspA), a highly immunogenic surface protein produced by all strains of S. pneumoniae, can elicit protective immunity against fatal pneumococcal infection. We have previously demonstrated that the Vibrio vulnificus FlaB, a bacterial flagellin protein and agonist of TLR5, has strong mucosal adjuvant activity and induces protective immunity upon co-administration with tetanus toxoid. In this study, we have tested whether intranasal immunization with recombinant fusion proteins consisted of PspA and FlaB (PspA FlaB and FlaB-PspA) is able to elicit more efficient protective mucosal immune responses against pneumococcal infection than immunization with PspA alone or with a stoichiometric mixture of PspA and FlaB. When mice were intranasally immunized with fusion proteins, significantly higher levels of anti-PspA IgG and IgA were induced in serum and mucosal secretions. The mice immunized intranasally with the FlaB-PspA fusion protein were the most protected from a lethal challenge with live S. pneumoniae, as compared to the mice immunized with PspA only, a mixture of PspA and FlaB, or the PspA-FlaB fusion protein. FlaB-PspA also induced a cross protection against heterologous capsular types. These results suggest that a FlaB-PspA fusion protein alone could be used as an anti-pneumococcal mucosal vaccine or as an effective partner protein for multivalent capsular polysaccharide conjugate vaccines. PMID- 21696870 TI - In vivo assessment of local effects after application of bone screws delivering bisphosphonates into a compromised cancellous bone site. AB - BACKGROUND: The primary stability of cancellous screw is difficult to obtain in bone of compromised quality and failure of screw fixation is common. To overcome this problem, it is proposed to locally deliver bisphosphonate from the screw. An in vivo validation of the increase in fixation of the cancellous screw is then needed in compromised bone. METHODS: In this study, we used an overdrilling procedure, which enables consistent modeling of reduced screw stability comparable to compromised cancellous bone. Forty eight adult NZW rabbits were used in this study and all animals underwent bilateral femur implantation. One leg was implanted with the screw containing the bisphosphonate (biocoated group) while the other was used as control (control group) with the screw only. Mechanical testing and micro-CT imaging were used to assess the effect of local drug delivery of Zoledronate on screws fixation at 5 time points. FINDINGS: At the early time points (1, 5, and 10 days), no significant difference could be seen between the biocoated and control groups. At 6 weeks, the bone volume fraction was significantly higher in the trabecular region of the biocoated group. However, this increase did not have a significant effect on the pull-out force. At the last time point, 11 weeks, both the bone volume fraction and the pull-out force were significantly higher in the biocoated group. INTERPRETATION: The results of this study suggest that, in compromised bone, local delivery of bisphosphonate enhances the stability of bone screws. PMID- 21696871 TI - Back extensor muscle fatigue at submaximal workloads assessed using frequency banding of the electromyographic signal. AB - BACKGROUND: Changes in the mean or median frequency of the electromyographic (EMG) power spectrum are often used to assess skeletal muscle fatigue. A more global analysis of the spectral changes using frequency banding may provide a more sensitive measure of fatigue than changes in mean or median frequency. So, the aim of the present study was to characterize changes in different power spectrum frequency bands and compare these with changes in median frequency. METHODS: Twenty male subjects performed isometric contractions of the back muscles in an isometric dynamometer at 30%, 40%, 50% and 60% of maximum voluntary contraction. During each contraction, surface EMG signals were recorded from the right and left longissimus thoracis muscles, and endurance time was measured. The EMG power spectra were divided into four frequency bands (20-50 Hz; 50-80 Hz; 80 110 Hz; 110-140 Hz) and changes in power in each band with fatigue were compared with changes in median frequency. FINDINGS: The percentage changes in 20-50 Hz band were greater than in all other and the rate of change in power, indicated by the slope, was also greatest in 20-50 Hz band. Also, 20-50 Hz band had a greater change in power than the median frequency. INTERPRETATION: Power in the low frequency part of the EMG power spectrum increases with fatigue in a load dependent manner. The rate of change in low frequency power may be a useful indicator of fatigue rate or "fatigability" in the back muscles. Also, changes in low frequency power are more evident than changes in the median frequency. PMID- 21696872 TI - In situ evaluation of cadmium biomarkers in green algae. AB - In situ measurements provide data that are the highly representative of the natural environment. In this paper, laboratory-determined biomarkers of Cd stress that were previously identified for the green alga Chlamydomonas reinhardtii, were tested in two French rivers: a contaminated site on the Riou Mort River and an "uncontaminated" reference site on the Lot River. Transcript abundance levels were determined by real time qPCR for biomarkers thought to be Cd sensitive. Transcript levels were significantly higher (>5 fold) for organisms exposed to the contaminated site as compared to those exposed at the uncontaminated site. Biomarker mRNA levels were best correlated to free Cd (Cd(2+)) rather than intracellular Cd, suggesting that they may be useful indicators of in situ stress. The paper shows that biomarker expression levels increased with time, were sensitive to metal levels and metal speciation and were higher in the "contaminated" as opposed to the "reference" site. PMID- 21696873 TI - Work-related critical incidents in hospital-based health care providers and the risk of post-traumatic stress symptoms, anxiety, and depression: a meta-analysis. AB - This meta-analysis reviewed existing data on the impact of work-related critical incidents in hospital-based health care professionals. Work-related critical incidents may induce post-traumatic stress symptoms or even post-traumatic stress disorder (PTSD), anxiety, and depression and may negatively affect health care practitioners' behaviors toward patients. Nurses and doctors often cope by working part time or switching jobs. Hospital administrators and health care practitioners themselves may underestimate the effects of work-related critical incidents. Relevant online databases were searched for original research published from inception to 2009 and manual searches of the Journal of Traumatic Stress, reference lists, and the European Traumatic Stress Research Database were conducted. Two researchers independently decided on inclusion and study quality. Effect sizes were estimated using standardized mean differences with 95% confidence intervals. Consistency was evaluated, using the I(2)-statistic. Meta analysis was performed using the random effects model. Eleven studies, which included 3866 participants, evaluated the relationship between work-related critical incidents and post-traumatic stress symptoms. Six of these studies, which included 1695 participants, also reported on the relationship between work related critical incidents and symptoms of anxiety and depression. Heterogeneity among studies was high and could not be accounted for by study quality, character of the incident, or timing of data collection. Pooled effect sizes for the impact of work-related critical incidents on post-traumatic stress symptoms, anxiety, and depression were small to medium. Remarkably, the effect was more pronounced in the longer than in the shorter term. In conclusion, this meta-analysis supports the hypothesis that work-related critical incidents are positively related to post-traumatic stress symptoms, anxiety, and depression in hospital based health care professionals. Health care workers and their supervisors should be aware of the harmful effects of critical incidents and take preventive measures. PMID- 21696874 TI - Sexuality and the limits of agency among South African teenage women: theorising femininities and their connections to HIV risk practices. AB - In South Africa, both HIV and gender-based violence are highly prevalent. Gender inequalities give men considerable relational power over young women, particularly in circumstances of poverty and where sex is materially rewarded. Young women are often described as victims of men, but this inadequately explains women's observed sexual agency. This paper takes a different approach. We use qualitative interviews and ethnographic observation among 16 young women from the rural Eastern Cape to explore ways young women construct their femininities and exercise agency. The data were collected as part of an evaluation of Stepping Stones, which is a participatory behavioural intervention for HIV prevention that seeks to be gender transformative. Agency was most notable in particular stages of the dating 'game', especially relationship initiation. Constructions of desirable men differed but generally reflected a wish to avoid violence, and a search for mutual respect, sexual pleasure, romance, modernity, status and money. Agency was constrained once relationships were consented to, as men expected to control their partners, using violent and non-violent methods. Women knew this and many accepted this treatment, although often expressing ambivalence. Many of the women expressed highly acquiescent femininities, with power surrendered to men, as a 'choice' that made their lives in cultural terms more meaningful. In marked contrast to this was a 'modern' femininity, centred around a desire to be 'free'. A visible third position, notably emerging after the Stepping Stones intervention, rested not on a feminist challenge to patriarchy, but on an accommodation with men's power whilst seeking to negotiate greater respect and non-violence within relations with men. These multiple and dynamic femininities open up possibilities for change. They demonstrate the need to engage with women, both as victims of patriarchy and active supporters of the gender order. The multiplicity of women's hopes and desires and circumstances of emotional and relational fulfillment provides potential for interventions with women that acknowledge existing gender inequalities, validate women's agency, reduce violence and prevent HIV. PMID- 21696875 TI - Domain or not domain? That is the question: longitudinal semantic deterioration in Alzheimer's disease. AB - Category specific semantic impairment (e.g. living versus nonliving things) has been reported in association with various pathologies, including herpes simplex encephalitis and semantic dementia. However, evidence is inconsistent regarding whether this effect exists in diseases progressively impacting diverse cortical regions, such as Alzheimer's disease (AD). Ceiling effects producing non-Gaussian distributions and poor control for confounds such as nuisance variables (e.g. familiarity) may contribute to this discrepancy. Fourteen AD patients were longitudinally studied examining category effects on three semantic tasks (picture naming, naming to description and word to picture matching) matched across domain on all known nuisance variables (NV). To address non-Gaussian distributions, we run bootstrap analyses to determine whether NV, semantic domain or control performance best predicted AD patient performance. Multiple hierarchical regression analyses revealed that, whilst NV accounted for most of the explained variance in patients in the three tasks, the influence of semantic domain was substantially lower. Individual logistic regression demonstrated a significant category effect in only a few patients and healthy controls. No significant qualitative changes were observed in patients over time. Our results confirm the importance of NVs as predictors of AD patient performance, suggesting that the role of semantic domain is not a useful predictor of the progressive deterioration in AD. PMID- 21696876 TI - [Prognostic value of epithelial growth factor receptor, vascular endothelial growth factor, E-cadherin, and p120 catenin in resected non-small cell lung carcinoma]. AB - INTRODUCTION: Several markers have been investigated to predict the prognosis of lung cancer. In the present study, the prognostic values of epithelial growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), E-cadherin, and p120 catenin expression were investigated by immunohistochemistry in patients with a surgically resected non-small cell lung carcinoma (NSCLC). PATIENTS AND METHOD: EGFR, VEGF, E-cadherin, and p120 catenin expression were prospectively determined in resected specimens from patients with NSCLC who had undergone surgery between 2003 and 2007. Patients' and disease-related general characteristics and survival rate were recorded. RESULTS: One hundred seventeen patients with a mean age of 61.3 years were included in the study. After a mean follow-up of 27.5 months, the median survival was determined to be 44.0 months and the 5-year survival was 46.2%. The 5-year survival in negative and positive staining groups were as follows; 32% and 66.7% for EGFR (p = 0.02), 37.8% and 50.7% for VEGF (p = 0.5), 41% and 66% for E-cadherin (p = 0.19), 46% and 50% for p120 catenin (p = 0.27). The differentiation, N status, stage and EGFR staining were variables significantly affecting survival (p = 0.001, 0.006, 0.03 and 0.02 respectively). In multivariate Cox analysis, the EGFR staining level and N status were variables those significantly affecting survival (p = 0.021 and p = 0.010). CONCLUSIONS: While negative staining of EGFR was related with poor survival, staining of VEGF, E-cadherin, and p120 catenin were not related with survival in patients with resected NSCLC. PMID- 21696877 TI - [Lung transplantation with uncontrolled non-heart-beating donors. Transplantation. Donor prognostic factor and immediate evolution post transplant]. AB - INTRODUCTION: Uncontrolled donation after cardiac death (DACD) has become an alternative to lung transplantation with encephalic-death donation. The main objective of this study is to describe the incidence of clinically relevant events in the period of thirty days after lung transplant with uncontrolled DACD and the influence of factors depending on the donor and donation process as well. PATIENTS AND METHODS: Historical cohort study of 33 lung transplant receivers at Hospital Puerta de Hierro and Hospital Marques de Valdecilla with 32 DACD from Hospital Clinico San Carlos from 2002 to 2008. We studied surgical and medical complications, primary graft dysfunction, acute rejection, pneumonia and mortality. We made an evaluation of the donor characteristics and donation procedure times (minutes). RESULTS: Median age of recipients was 50.5 years (interquartile range, 38.5-58). There were 28 males and 5 females. Cumulative incidence of events in the first month was: pneumonia 10 (31.3%); primary graft dysfunction 15 (46.9%); rejection 12 (37.5%); mortality 4 (12.1%); medical complications 25 (78.1%); and surgical complications 18 (56.3%). Median time of cardiac arrest was higher in those who presented pneumonia (15 vs. 7.5; p = 0.027). Median time of cold ischemia was higher in those who presented surgical complications and mortality (436 vs. 343.5; p = 0.04; 505 vs. 410; p = 0.033, respectively), and median of total ischemia times were longer in the recipients who died (828 vs. 695; p = 0.036). CONCLUSIONS: Uncontrolled DACD are a valid alternative for expanding the donor pool in order to mitigate the current shortage of lungs that are valid for transplantation. The incidence of complications is comparable with published data in the literature. PMID- 21696878 TI - [Initial experience with excimer laser-assisted pacemaker and defibrillator lead extraction]. AB - Explantation of chronically implanted pacemaker or defibrillator leads can be technically demanding. We present the results of the first 44 leads extracted with excimer laser sheaths in 25 patients with a median lead implantation time of 7 years (range: 2 to 20 years). Indications for extraction were lead fracture in 17 patients, pocket infection in 4, septicemia in 2, and lead endocarditis in 2 cases. Complete extraction was achieved in 43 leads (97.7%), while the lead tip (< 4 cm) was abandoned in 1 case. There was no in-hospital mortality. The excimer laser-assisted system is a safe and efficient alternative for pacemaker and defibrillator lead extraction. This technology has resulted in excellent outcomes in our series, allowing us to treat remarkably difficult cases. PMID- 21696880 TI - Cow's milk dependent exercise-induced urticaria after oral tolerance induction in an adolescent. PMID- 21696882 TI - Hotel water consumption at a seasonal mass tourist destination. The case of the island of Mallorca. AB - While it is true that tourism is one of the main driving forces behind economic growth in several world regions, it is also true that tourism can have serious negative environmental impacts, especially with regard to water resources. The tourist water demand can generate big problems of sustainability, mainly in those regions where water is scarce, as occurs in most coastal and small island destinations where a large part of world tourism is concentrated. Given the shortage of literature on the subject, further research into the tourist water demand is required, with particular attention to the hotel sector, since hotels are the most popular option for tourists, displaying higher levels of water consumption. The main purpose of this study is to develop a model to analyse hotel water consumption at a mature sun and sand destination with a strong seasonal pattern and scarcity of water; characteristics shared by some of the world's main tourist destinations. Our model includes a set of different hotel variables associated with physical, seasonal and management-related factors and it improves on the capacity to explain water consumption at such destinations. Following a hierarchical regression methodology, the model is empirically tested through a survey distributed to managers of a representative sample of hotels on the island of Mallorca. From the obtained results, interesting recommendations can be made for both hotel managers and policy makers. Among these, it should be highlighted that the strategic move contemplated by many mature destinations towards a higher quality, low-season model could have significant negative effects in terms of the sustainability of water resources. Our results also conclude that managerial decisions, like the system of accommodation that is offered (i.e. the proliferation of the "all-inclusive" formula, both at mature and new destinations), could give rise to the same negative effect. Development of water saving initiatives (usually introduced in response to demand-based factors), also reveals significant effects over water consumption. Finally, other key factor in explaining hotel water consumption is the management system under which the hotel is run. PMID- 21696881 TI - From steroid receptors to cytokines: the thermodynamics of self-associating systems. AB - Since 1987, the Gibbs Conference on Biothermodynamics has maintained a focus on understanding the quantitative aspects of gene regulatory systems. These studies coupled rigorous techniques with exact theory to dissect the linked reactions associated with bacterial and lower eukaryotic gene regulation. However, only in the last ten years has it become possible to apply this approach to clinically relevant, human gene regulatory systems. Here we summarize our work on the thermodynamics of human steroid receptors and their interactions with multi-site promoter sequences, highlighting results not available from more traditional biochemical and structural approaches. Noting that the Gibbs Conference has also served as a vehicle to promote the broader use of thermodynamics in understanding biology, we then discuss collaborative work on the hydrodynamics of a cytokine implicated in tumor suppression, prostate derived factor (PDF). PMID- 21696883 TI - SO2 gas adsorption by modified kaolin clays: influence of previous heating and time acid treatments. AB - Modified kaolin clays were used as adsorbents for SO(2) gas adsorptions. The clays were heated up to 900 degrees C previous to acid treatments with 0.5 N sulfuric acid solutions at boiling temperature during different times up to 1440 min. Equilibrium adsorption at 25 degrees C and 0.1 MPa was carried out by using a volumetric apparatus. The samples were characterized by chemical analysis, X ray diffraction and infrared analysis. The heating of the clays followed by acid treatment improved the adsorption capacity of the kaolin clays. The presence of amorphous silica and hydroxyl in the final products improved SO(2) adsorption capacity. Better properties for SO(2) adsorption were found in kaolin rich in not well ordered kaolinite clay mineral. PMID- 21696884 TI - Biocontainment of polychlorinated biphenyls (PCBs) on flat concrete surfaces by microbial carbonate precipitation. AB - In this study, a biosealant obtained from microbial carbonate precipitation (MCP) was evaluated as an alternative to an epoxy-coating system. A bacterium Sporosarcina pasteurii strain ATCC 11859, which metabolizes urea and precipitates calcite in a calcium-rich environment, was used in this study to generate the biosealant on a PCB-contaminated concrete surface. Concrete cylinders measuring 3 in (76.2 mm) by 6 in (152.4 mm) were made in accordance with ASTM C33 and C192 and used for this purpose. The PCB, urea, Ca(2+), and bacterial cell concentrations were set at 10 ppm, 666 mM, 250 mM, and about 2.1 * 10(8) cells mL(-1), respectively. The results indicate that the biosealed surfaces reduced water permeability by 1-5 orders of magnitude, and had a high resistance to carbonation. Since the MCP biosealant is thermally stable under temperatures of up to 840 degrees C, the high temperatures that normally exist in the surrounding equipment, which may contain PCB-based fluids, have no effect on the biosealed surfaces. Consequently, there is greater potential to obtain a stronger, coherent, and durable surface by MCP. No measurable amount of PCBs was detected in the permeating water, indicating that the leaching water, if any, will have a minimum impact on the surrounding environment. PMID- 21696885 TI - The orphan nuclear receptor EAR2 is overexpressed in colorectal cancer and it regulates survivability of colon cancer cells. AB - EAR2 is a member of the chick ovalbumin upstream promoter-transcription factors (COUP-TFs). COUP-TFs belong to orphan nuclear receptors and regulate many biological processes. Little is known regarding EAR2 in cancer, though much progress has been made in understanding the function of other COUP-TF members. The aim of this study is to investigate the expression and possible function of EAR2 in colorectal cancer. We determined expression of EAR2 in human primary colorectal malignant tumors and their paired adjacent normal colorectal tissues. We found that expression of EAR2 was upregulated in colorectal tumors. Knockdown of EAR2 induced apoptosis of colon cancer cells, suggesting that EAR2 may function to regulate survivability of colon cancer cells. In vivo tumor study demonstrated that knockdown of EAR2 inhibited the xenograft growth of colon cancer cells. We found that knockdown of EAR2 inhibited the expression of X linked inhibitor of apoptosis protein (XIAP), suggesting that EAR2 regulates cell survivability, at least partly, through XIAP. In this manuscript, we demonstrated that expression of EAR2 was elevated in colorectal cancer and knockdown of EAR2 reduced survivability and tumor growth of colon cancer cells. Our results suggest that EAR2 plays an important role in development of colorectal cancer. The findings also suggest that EAR2 may serve as a potential therapeutic target of colorectal cancer. PMID- 21696886 TI - Fuzzy modeling and simulation for lead removal using micellar-enhanced ultrafiltration (MEUF). AB - In the present paper, a three factor, three-level response surface design based on Box-Behnken design (BBD) was developed for maximizing lead removal from aqueous solution using micellar-enhanced ultrafiltration (MEUF). Due to extremely complexity and nonlinearity of membrane separation processes, fuzzy logic (FL) models have been driven to simulate MEUF process under a wide range of initial and hydrodynamic conditions. Instead of using mathematical model, fuzzy logic approach provides a simpler and easier approach to describe the relationships between the processing variables and the metal rejection and permeation flux. Statistical values, which quantify the degree of agreement between experimental observations and numerically calculated values, were found greater than 91% for all cases. The results show that predicted values obtained from the fuzzy model were in very good agreement with the reported experimental data. PMID- 21696887 TI - Effects of field-manure applications on stratified 17beta-estradiol concentrations. AB - The occurrence of the manure-borne estrogen, 17beta-estradiol (E2), was investigated in laboratory and field soils. In the laboratory, E2 was applied to soil to simulate concentrations found in swine (Sus scrofa domestica) manure (5000ngL(-1)). The aqueous-extracted E2 dissipated in the soil by 98% within 1h and was not significantly different from background concentrations (18ng L(-1)) for the duration of the experiment (64h). In the field study, soil cores were taken before and several dates after swine manure application. Equivalent porewater concentrations of water-extractable E2 were determined in 0.15-m increments down to the water table (0.70-2.00m deep). The average frequency of detection for 168 samples was 38% (average=40ng L(-1) porewater equivalents). Eleven days after manure application there was no significant effect on E2 detection frequency or concentration. However, E2 concentrations significantly increased by 6 months after manure application, and appeared to be related to precipitation. Concentrations then returned to original levels by 17 months after manure application. Manure did not have an immediate effect on E2 occurrence due to the capacity of the soil to rapidly sorb E2. However, it appears that soil may act as a long-term reservoir for E2 in the environment, which may be periodically released through desorption. PMID- 21696888 TI - Blunted autonomic reactivity and increased pain tolerance in somatoform patients. AB - Somatoform disorders are characterized by the presence of multiple somatic symptoms. Patients often experience different pain syndromes, and recent research suggests that sympathovagal balance is disturbed in somatoform patients, which could be related to alteration in pain sensitivity. This study analyzed how proposed sympathovagal imbalance interacts with objective pain assessment and the imagination of pain in somatoform disorders. Twenty-one patients (4 men) with diagnosed multisomatoform disorder were included in the study and matched to healthy control subjects. Autonomic measures and heart rate variability were assessed during baseline; pain perception was assessed by means of a pressure algometer and pain imagination. We found evidence for a sympathovagal imbalance in somatoform disorders characterized by low parasympathetic activation and high sympathetic activation during all conditions. Additionally, somatoform patients had reduced pain tolerance. Vagal withdrawal during pain assessment was more pronounced for healthy control subjects and correlated positively with assessed pain tolerance. During imagination somatoform, patients reported higher pain unpleasantness and higher pain intensity as compared to control subjects. We conclude that our data demonstrate an imbalance in sympathovagal activation and a hyposensitivity to pain tolerance stimuli in somatoform disorders. Parasympathetic reactivity might form crucial information when judging pain associated affective-motivational components. Our results might be attributable to a deficient detection of visceral signals and might be a pathogenetic mechanism for the development of emotional difficulties and increased everyday vulnerability in somatoform patients. PMID- 21696890 TI - Comments on Lee et al. 177 (2011) communication "Evaluation of a new...". PMID- 21696889 TI - Efficacy and safety of tanezumab in the treatment of chronic low back pain. AB - Increased nerve growth factor levels are associated with chronic pain conditions, including chronic low back pain (LBP). This study examined safety and analgesic efficacy of tanezumab, a humanized anti-nerve growth factor antibody, in adults with chronic LBP. Patients received intravenous tanezumab 200 MUg/kg plus oral placebo (n=88), intravenous placebo plus oral naproxen 500 mg twice a day (n=88), or intravenous placebo plus oral placebo (n=41). Primary outcome was average LBP intensity (aLBPI) at Week 6. Secondary outcomes were proportion of patients with >=30% or >=50% reduction in aLBPI, Roland-Morris Disability Questionnaire and Brief Pain Inventory-short form scores, Patients' Global Assessment of LBP, Patients' Global Evaluation of study medication, and rescue medication use. Mean aLBPI change from baseline to Week 6 was greater with tanezumab vs naproxen (P=0.004) and placebo (P<0.001). Greater proportions of patients reported >=30% and >=50% reduction in aLBPI with tanezumab vs naproxen (P<=0.013) and placebo (P<0.001), and greater improvements in Roland-Morris Disability Questionnaire (P<0.001) and other secondary outcomes except rescue medication use. Tanezumab was associated with adverse events (AEs) of abnormal peripheral sensation that were generally mild and resolved before study completion; however, there were no serious AEs. Nine patients (4 of whom were tanezumab-treated) discontinued due to AEs. In conclusion, tanezumab resulted in analgesic efficacy that was clinically and statistically superior to placebo and naproxen in patients with chronic LBP. Tanezumab clinical development is on regulatory hold due to AEs in osteoarthritis patients. PMID- 21696891 TI - Augmented bacterial elimination by Kupffer cells after IL-18 pretreatment via IFN gamma produced from NK cells in burn-injured mice. AB - We recently demonstrated that IL-18 injections following burn restored IFN-gamma production and increased mouse survival after bacterial infection. However, it has yet to be fully elucidated how the IL-18 therapy affects the function of phagocytic cells. We investigated the effect of IL-18 therapy on function and interaction of Kupffer cells and NK cells in burned mice. C57BL/6 mice received a 20% full-thickness burn, followed by multiple injections with IL-18. Although burn-injured mice had decreased expression of IL-18 receptors on the NK/NKT cells 5 days after injury, multiple IL-18 injections restored this expression. IL-18 treatment also augmented Kupffer cell phagocytosis. Although burn decreased the number of CD68(+) Kupffer cells with phagocytic activity, IL-18 treatment partially restored their proportion, and augmented phagocytosis-induced ROS production in CD68(+) Kupffer cells after the injection of heat-killed Escherichia coli. Consistently, IL-18 restored the impaired E. coli killing activity of Kupffer cells of burn-injured mice. Such Kupffer cell activation by IL-18 was abrogated by the deletion of NK cells or IFN-gamma. In conclusion, IL 18 therapy in burn-injured mice enhanced function of CD68(+) Kupffer cells via the activation of liver NK cells and augmentation of their IFN-gamma production, thereby improving survival after E. coli infection. PMID- 21696892 TI - Psychosocial stress exposure impairs memory retrieval in children. AB - Negative consequences of stress on working memory and delayed memory retrieval have been observed in adult humans. Little is known about the occurrence of similar effects in children. Forty-four German full-term children, aged 8-10 years, were randomly assigned to a stressful (Trier Social Stress Test for Children--TSST-C) or to a non-stressful control condition. Afterwards, delayed memory retrieval was tested using a computerized version of the well-known card game "Memory". It contained positive, neutral and negative stimuli. In addition, working memory of verbal and non-verbal material was assessed. The stressed children showed pronounced cortisol increases accompanied by a decrease in mood. Children exposed to the stressor performed poorer in the delayed memory retrieval test (memory card game). They committed more errors. No differences were found for working memory. The stress-induced memory retrieval impairment mirrors findings in adults. In contrast, the missing working memory effects could suggest developmental differences in stress sensitivity. PMID- 21696893 TI - The impact of short-term feeding of magnesium supplements on the quality of pork packaged in modified atmosphere. AB - This study compared the effect of dietary magnesium (Mg) supplementation on pork quality during 13 days of storage at 4+/-1 degrees C under modified atmosphere. The experiment was conducted with 40 gilts (Pietrain*(Landrace*Large White)) which were fed one of four diets five days prior to slaughter: 1) control diet; 2) Mg oxide; 3) Mg sulphate; or 4) Mg chelate. Dietary Mg supplementation did not affect 24-h pH, colour, and Warner-Bratzler shear force values. Pork from pigs fed the Mg chelate-supplemented diet had the lowest (P<=0.05) drip, exudative, and cooking losses. Furthermore, pork from pig supplemented with Mg oxide had the lowest TBARS values. Visual assessment of pork from pigs supplemented with Mg chelate received higher colour and lower exudative scores, as well as overall acceptability scores, throughout display. Thus, Mg chelated supplementation could be effective in improving pork quality during 13 days of storage under modified atmosphere conditions. PMID- 21696895 TI - QEEG norms for the first year of life. AB - BACKGROUND: QEEG allows a more objective evaluation of cerebral electrical activity as well as the production of topographical maps for easier comprehension. Here we have developed qEEG norms for the first year of life using methods previously published for other age ranges, including for example, regression for Gausssianity before Z transformation. These norms constitute a non invasive and low cost tool for the functional evaluation of the infant's brain. RESULTS: Developmental equations were obtained from 101 healthy infants recording at spontaneous quiet sleep stage II. Polynomial regression equations, with age as independent variable, were calculated for full Broad Band Spectral Parameters (BBSP) using the Least Squares technique. Interpolated maps of the BBSP values or their Z transformation were constructed for linked-ear reference, average reference and Laplacian montages. All montages produced similar tendency curves and Z maps of absolute and relative power, and mean frequency at all frequency bands. The norms obtained were validated against an independent group of 50 healthy infants and some pathological cases. 91-98% of cases were well classified as normal across all measures and montages. To exemplify, two pathological cases are presented of which their qEEG maps show resemblance to CT and MRI. CONCLUSIONS: These qEEG norms are highly useful as an aid to visual interpretation and for the study of pathology further evolution as well as for assessment of infants showing brain risk factors. To our knowledge this is the first normative qEEG study for the initial year of life with such large sample and validation-group. PMID- 21696896 TI - Health-related quality of life, emotional and behavioral problems in mild to moderate prematures at (pre-)school age. AB - BACKGROUND: There is a gap in the knowledge of longterm outcome of mild to moderate prematures compared to the extreme prematures or very low birth weight infants. AIM: Determine health-related quality of life (HRQoL) and prevalence of emotional and behavioral problems in (pre-)school age children born at 32 to 36 weeks' gestation. STUDY DESIGN: A descriptive cohort study in a non-Neonatal Intensive Care Unit. Patient characteristics, diagnoses, treatment and social economic status (SES) were analyzed. Study tools were the TNO-AZL Preschool Quality of Life (TAPQoL) and Child Behavior Checklist (CBCL). SUBJECTS: 362 children born between 32 and 36 weeks' gestation who had a follow-up evaluation at 2-5 years of age. OUTCOME MEASURE: Health-related quality of life and the occurrence of emotional and behavioral problems. RESULTS: Main characteristics (mean+/-SD) were: gestation 34.7+/-1 weeks and birth weight 2360+/-444 g. Most families were two-parent middle-class households with parents employed at their educational level. Questionnaire response rate was 62.7%. The 12-item TAPQoL showed significantly lower scores for stomach and liveliness, while scores for behavior, communication and sleep were significantly higher compared to the general population. The TAPQoL subscale score for lung problems was significantly lower for children who had received continuous positive airway pressure (CPAP). CBCL scores were within the validated normal range although the study-population scored higher on emotionally reactive, somatic complaints and attention problems compared to their full-term peers. CONCLUSION: Children born at 32 to 36 weeks' gestational age do not experience an overall lower HR-QoL at 2 to 5 years of age. CPAP results in lower HRQoL scores for lung problems. The overall occurrence of behavioral and emotional problems does not differ from the general term-born pediatric population. Several subitems need further attention. PMID- 21696894 TI - A double-blind, placebo-controlled assessment of the safety of potential interactions between intravenous cocaine, ethanol, and oral disulfiram. AB - BACKGROUND: A majority of cocaine addicts have a comorbid alcohol use disorder. Previous studies demonstrated efficacy of disulfiram in the treatment of cocaine dependence among patients with comorbid alcohol use disorder or opioid dependence. However, the cardiac risks of a disulfiram-ethanol reaction (DER) in individuals who drink, when coupled with the cardiac effects of cocaine, could result in significant toxicity or lethality due to the 3-way drug interaction. AIMS: This study examined the safety of combining cocaine (30 mg i.v.) and ethanol (0.4 g/kg i.v.) in disulfiram-treated (0, 250, and 500 mg/d, p.o.) cocaine-dependent research volunteers. RESULTS: The results showed that disulfiram did not enhance the cardiovascular effects of cocaine and may have reduced the subjective high from cocaine. In contrast, ethanol produced adverse ECG changes including QTc prolongation and a DER consisting of hypotension, tachycardia, nausea, and flushing in disulfiram-treated subjects. The severity of the DER was related to disulfiram dose and the trial with 500 mg/d was stopped prematurely due to safety concerns. The DER-related hypotension and tachycardia seen with ethanol infusion alone in disulfiram-treated subjects, was not exacerbated when combined with cocaine. In fact, cocaine tended to counteract the ethanol-related hypotension though it did exacerbate the tachycardia in two of seven subjects. CONCLUSIONS: Though conclusions are limited by the moderate doses of cocaine, ethanol, and disulfiram tested, the data do suggest that the risks of the moderate use of cocaine and ethanol in individuals treated with moderate doses of disulfiram (<= 250 mg/d) may not be as problematic as some may assume. PMID- 21696897 TI - Sodium Alginate (Gaviscon(r)) does not reduce apnoeas related to gastro oesophageal reflux in preterm infants. AB - BACKGROUND: Apnoea of prematurity (AOP) frequently recurs in preterm infants. We have previously shown that a significant but variable proportion of AOP is induced by gastro-oesophageal reflux (GOR). AIM: The aim of this study is to evaluate the efficacy of sodium alginate in reducing the frequency of GOR-related AOP. SUBJECTS: Twenty-eight preterm infants with AOP were studied by a six-hour recording of combined multichannel intraluminal impedance and pH monitoring and polysomnography, including two three-hour postprandial periods: sodium alginate was given after one single meal named as drug-given (DG) meal, while the other as drug-free (DF). RESULTS: During 165h of registration, 715 apnoeas were recorded, 368 after-DG and 347 after-DF (p=.99); furthermore, 851 GOR episodes were detected, 315 after-DG and 536 after-DF (p=.001). No differences in the number of AOP were found between DG and DF. A significant reduction in the number of acid GORs and in acid exposure was found during DG, while the administration of sodium alginate didn't influence non-acid GOR indexes. The frequency of GOR-related apnoeas didn't differ between DG and DF. DISCUSSION: Sodium alginate doesn't reduce the total number of AOP nor GOR-related apnoeas. On the other hand, it reduces acid GOR features, while it had no effect on non-acid GOR indexes. PMID- 21696898 TI - Early treatment of osteogenesis imperfecta: which drug to use? PMID- 21696899 TI - Testosterone levels and cognition in elderly men: a review. AB - Average testosterone levels and many cognitive functions show a decline with age. There is evidence to suggest that this association is not just age related. Results from cell culture and animal studies provide convincing evidence that testosterone could have protective effects on brain function. Alzheimer's disease (AD) is characterised by brain pathology affecting cognitive function and AD prevalence increases with age. Testosterone levels are lower in AD cases compared to controls, and some studies have suggested that low free testosterone (FT) may precede AD onset. Men with AD may show accelerated endocrinological ageing, characterised by an earlier lowering of thyroid stimulating hormone, an earlier increase in sex hormone binding globulin (SHBG), a subsequent earlier decrease in FT and an earlier increase in gonadotropin levels in response to this. Positive associations have been found between testosterone levels and global cognition, memory, executive functions and spatial performance in observational studies. However, non-significant associations were also reported. It may be that an optimal level of testosterone exists at which some cognitive functions are improved. This may be modified with an older age, with a shifting of the optimal testosterone curve to maintain cognition to the left and a lower optimal level thus needed to be beneficial for the brain. Genetic factors, such as APOE and CAG polymorphisms may further interact with testosterone levels in their effects on cognition. The roles of SHBG, gonadotropins, thyroid hormones and estrogens in maintaining cognitive function and preventing dementia in men are also not completely understood and should be investigated further. Hypogonadal men do not seem to benefit from testosterone supplementation but small scale, short term intervention studies in eugonadal men with and without cognitive impairments have shown promising results. Larger randomised, controlled trials are needed to further investigate testosterone treatment in protecting against cognitive decline and/or dementia. PMID- 21696900 TI - Evaluation of vapor profiles of explosives over time using ATASS (Automated Training Aid Simulation using SPME). AB - Despite numerous instrumental achievements, canines are still considered the most effective field method for explosive detection. However, due to strict explosive regulations and safety requirements, it can be a challenge for agencies with "bomb dogs" to train using neat explosive materials. This establishes a need for non-explosive canine training aids with the same volatile component profiles as the explosives that they represent. In order to compare mimic materials to their explosive counterparts, a technique must be established that not only allows for identification of volatile compounds but also can monitor changes in the headspace profile over time with respect to time and temperature. The Automated Training Aid Simulation using SPME (or ATASS) was developed for that purpose. As described, ATASS was used to observe changes in the volatile profile of three explosives (Composition C-4, 2,4-dinitrotoluene (DNT), and triacetone triperoxide (TATP)) and respective prototype training materials (0.1% by mass C-4, 1% by mass 2,4-DNT, and 1% by mass TATP). Samples were prepared in vials and metal tins within a gallon (~ 3785 mL) paint can to simulate common field techniques for canine training. Monitoring these materials in real time provides a better understanding of the major volatile components present and how the relative abundances of these components can change over time. The results presented indicate that ATASS successfully allows for a sufficient comparison between explosive and non-explosive training materials. PMID- 21696901 TI - WITHDRAWN: Disorders of BH4 metabolism and the treatment of patients with 6 pyruvoyl-tetrahydropterin synthase deficiency in Taiwan. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21696902 TI - Dual-energy CT-cholangiography in potential donors for living-related liver transplantation: improved biliary visualization by intravenous morphine co medication. AB - PURPOSE: To prospectively evaluate whether intravenous morphine co-medication improves bile duct visualization of dual-energy CT-cholangiography. MATERIALS AND METHODS: Forty potential donors for living-related liver transplantation underwent CT-cholangiography with infusion of a hepatobiliary contrast agent over 40 min. Twenty minutes after the beginning of the contrast agent infusion, either normal saline (n=20 patients; control group [CG]) or morphine sulfate (n=20 patients; morphine group [MG]) was injected. Forty-five minutes after initiation of the contrast agent, a dual-energy CT acquisition of the liver was performed. Applying dual-energy post-processing, pure iodine images were generated. Primary study goals were determination of bile duct diameters and visualization scores (on a scale of 0 to 3: 0--not visualized; 3--excellent visualization). RESULTS: Bile duct visualization scores for second-order and third-order branch ducts were significantly higher in the MG compared to the CG (2.9+/-0.1 versus 2.6+/-0.2 [P<0.001] and 2.7+/-0.3 versus 2.1+/-0.6 [P<0.01], respectively). Bile duct diameters for the common duct and main ducts were significantly higher in the MG compared to the CG (5.9+/-1.3 mm versus 4.9+/-1.3 mm [P<0.05] and 3.7+/-1.3 mm versus 2.6+/-0.5 mm [P<0.01], respectively). CONCLUSION: Intravenous morphine co medication significantly improved biliary visualization on dual-energy CT cholangiography in potential donors for living-related liver transplantation. PMID- 21696903 TI - Comprehensive chemical analysis of Venenum Bufonis by using liquid chromatography/electrospray ionization tandem mass spectrometry. AB - A rapid, sensitive and versatile liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method was developed for the comprehensive analyses of the chemical constituents contained in the Chinese medicine-Venenum Bufonis (VB, Chan' Su in Chinese). LC analysis was carried out on an Agilent Eclipse plus C18 RRHD column (2.1 * 150 mm, 1.8 MUm) with a linear gradient solvent system of water (0.1% formic acid) and acetonitrile (0.1% formic acid) as mobile phase. Detection and quantification were performed by multiple reaction monitoring (MRM) transitions via electrospray ionization (ESI) source operating in the positive ionization mode. Through "Molecular Feature Extraction" (MFE), more than 900 features were detected from VB extracts. Among them, a total of 97 components were identified using the Agilent METLIN accurate mass matching database (DB) established according to those reported in the literatures. Further more, 30 high quality matches were obtained by comparisons of their accurate mass and retention times (AMRT) with those imported out in the developed personal database (METLIN DB with AMRT). The characteristic fragmentation pathways were proposed for the tentative characterization of four representative types of bufadienolides in the present work. The targeted MS/MS experiment of the 30 major compounds was performed for their quantification and semi-quantification. And 7 of them were quantified over the assaying concentration range of 5.0-500 pg/MUL. The lowest limit of detection and quantification of them were 0.25-0.50 and 1.25 0.25 pg/MUL, respectively. The recoveries varied from 83 to 106% depending on the chemical types and different extraction solvents. The remained 23 bufosteroids were simultaneously semi-quantified using three representative standard compounds as their standard references, respectively. PMID- 21696904 TI - Quantification of cinacalcet by LC-MS/MS using liquid-liquid extraction from 50 MUL of plasma. AB - A simple and economical high-performance liquid chromatography-positive ion electrospray tandem mass spectrometry method was developed and validated for the quantification of cinacalcet in plasma. Following liquid-liquid extraction, the analyte was separated using an isocratic mobile phase on a reversed-phase column and analyzed by MS/MS in the multiple reaction monitoring mode using the respective [M+H]+ ions, m/z 358-155 for cinacalcet and m/z 310-148 for the internal standard. The assay exhibited a linear dynamic range of 0.1-200 ng/mL for cinacalcet in plasma. Acceptable precision (<10%) and accuracy (100+/-5%) were obtained for concentrations over the standard curve range. A run time of 3.5 min for each sample made it possible to analyze more than 250 samples per day. The method was successfully applied to quantify cinacalcet concentrations in a preclinical pharmacokinetic study after a single oral administration of cinacalcet at 10 mg/kg to rats. Following oral administration the maximum mean concentration in plasma (C(max); 160+/-56 ng/mL) was achieved at 1.0 h (T(max)), area under the curve (AUC) and half-life (t(1/2)) were 949+/-257 ng h/mL and 3.58+/-0.4 h, respectively. PMID- 21696905 TI - Targeted and non-targeted metabolic time trajectory in plasma of patients after acute coronary syndrome. AB - Metabolite fingerprinting (metabolomics/metabonomics) is perfectly suited for assessing the biological response following acute coronary syndrome (ACS) as relevant information can be identified in both the change and the absence of change in metabolite concentrations as time progresses post syndrome. During this study the metabolic pattern of plasma from patients at time points 0, four days, two months and six months after the onset of ACS were compared to controls using a non-targeted approach with gas chromatography mass spectrometry (GC-MS). Fatty acid profiles of the sample set were also analysed in a targeted way. The methods were employed with the aim to identify specific biomarkers, which vary with time. Using the non-targeted approach 27 statistically significant metabolites of interest were found: glucose, fructose, myoinositol, pyruvate, lactate, oxalate, citrate, isocitrate, succinate, malate, valine, alanine, serine, glycine, cysteine, threonine, aspartate, tryptophan, tyrosine, 4-hydroxyproline, 2 hydroxybutyrate, 2-aminobutyrate, 2,3,4-trihydroxybutyrate, 3-hydroxybutyrate, creatinine and aminomalonate. In addition, the targeted analysis of 21 fatty acids revealed patients within the group ACS at day 0 had the highest values for all 21. After 4 days, values decreased and were maintained at a lower level during the 6 months. Whereas the overall fatty acid profile did not change, different patterns of concentration trajectories over time were identified, which can reflect the underlying metabolic alterations as a result of the initial ACS, interestingly these levels had not fully reverted six months later. PMID- 21696906 TI - Practical use of GenoType(r) HelicoDR, a molecular test for Helicobacter pylori detection and susceptibility testing. AB - Compared to culture-based method, the sensitivity, specificity, positive, and negative predictive values of the GenoType((r)) HelicoDR for detecting Helicobacter pylori resistance were, respectively, 100, 86.2, 89.7%, and 100% to clarithromycin as well as 82.6, 95.1, 90.5%, and 90.7% to fluoroquinolones. This molecular assay detected a mixture of genotypes and could successfully analyze biopsies without transport/storage limitations. PMID- 21696907 TI - In vitro activity of a novel broad-spectrum antifungal, E1210, tested against Candida spp. as determined by CLSI broth microdilution method. AB - The in vitro activity of the novel antifungal agent E1210 and four comparators (caspofungin, fluconazole, posaconazole, and voriconazole) was determined against 90 clinical isolates of Candida using Clinical and Laboratory Standards Institute methods. The collection was composed of 21 Candida albicans, 20 C. glabrata, 25 C. parapsilosis, and 24 C. tropicals, and also included 21 fluconazole-resistant and 15 caspofungin-resistant strains. E1210 was highly active against all the species tested and was more potent than all comparators. The MIC(90) results (MUg/mL) for E1210, caspofungin, fluconazole, posaconazole, and voriconazole, respectively, were as follows by species: C. albicans (0.06, 4, >=64, 0.5, 0.5), C. glabrata (0.06, 2, 32, 1, 1), C. parapsilosis (0.06, 4, 16, 0.12, 0.25), and C. tropicalis (0.06, 4, >=64, 0.5, 2). E1210 was also the most active agent against fluconazole-resistant strains of C. albicans (MIC range, 0.015-0.12 MUg/mL), C. glabrata (0.06 MUg/mL), C. parapsilosis (MIC range, 0.06-0.05 MUg/mL), and C. tropicalis (MIC range, 0.008-0.06 MUg/mL), and was the most potent agent tested against caspofungin-resistant strains of C. albicans (MIC range, 0.008-0.12 MUg/mL), C. glabrata (MIC range, 0.03-0.06 MUg/mL), and C. tropicalis (MIC range, 0.015-0.06 MUg/mL). PMID- 21696908 TI - The landscape of postgraduate education in palliative care for general practitioners: results of a nationwide survey in Flanders, Belgium. AB - OBJECTIVE: To describe the offer of continuing medical education (CME) in palliative care in Flanders, Belgium and to explore the way providers of CME address the preferences of general practitioners (GP's) towards CME. METHODS: Questionnaire-survey among official providers of formal CME. RESULTS: The response rate was 43%, equally distributed over all 5 provinces of Flanders. Data show large content gaps, an under usage of appropriate educational techniques and an absence of evaluation of the impact of CME on clinical practice. Providers of CME explain how they take the preferences of GP's concerning education in palliative care into account. CONCLUSIONS: The present offer of CME is insufficient to educate GP's in palliative care. The absence of quality criteria and the lack of coordination between different providers results in an unattractive labyrinth of courses leaving GP's and their patients in the cold. PRACTICE IMPLICATIONS: A comprehensive offer of CME sessions should be installed in a coordination between all providers. This could render the use of means (logistics and speakers) more efficient. Further research could look into other ways of acquiring palliative care competences such as evaluating the learning effect of GP's working together with specialized palliative home care teams. PMID- 21696909 TI - Clinical communication training in continuing medical education: possible, do able and done? PMID- 21696910 TI - The prevalence of endocrinopathic laminitis among horses presented for laminitis at a first-opinion/referral equine hospital. AB - Endocrinopathic causes of laminitis may be a common underlying causative pathogenesis in first-opinion or field cases presenting with laminitis, as opposed to laminitis produced in inflammatory research models. This study aimed to determine whether evidence of an underlying endocrinopathy was present in horses presented for laminitis to a first-opinion/referral veterinary teaching hospital. A second aim was to compare the signalment of horses and ponies with laminitis with the equine hospital population during the same period. All horses presenting for laminitis at Helsinki University Equine Teaching Hospital, Finland, over a 16-month period were examined for an underlying endocrinopathy. Horses presenting for laminitis were compared with the hospitalized population over the same period. There were 36 horses presented for laminitis, and evidence of endocrinopathy was present in 89%. Of the horses showing an underlying endocrinopathy, one-third had a diagnosis of pituitary pars intermedia dysfunction, and two-thirds showed basal hyperinsulinemia indicative of insulin resistance, without evidence of hirsutism. Phenotypic indicators of obesity were present in 95% of horses with basal hyperinsulinemia without hirsutism. Compared with the hospital population during the same period, horses with laminitis associated with an underlying endocrinopathy were significantly older and more likely to be pony breeds. Our data support that endocrine testing should be performed on all cases of laminitis that do not have a clear inflammatory or gastrointestinal origin. PMID- 21696911 TI - Does clinician continuity over two brief motivational sessions improve outcomes in college students? AB - Previous research has shown that brief motivational interventions (BMIs) are an effective treatment approach for reducing college student alcohol use and associated negative consequences. The purpose of this study was to determine whether clinician continuity (having the same vs. a different clinician) across an initial BMI and follow-up booster session was related to differences in session satisfaction, self-reported alcohol use, and alcohol-related negative consequences. Participants included 358 undergraduate students who were part of a larger randomized clinical trial. Results revealed no significant differences in alcohol use and associated consequences at follow-up between participants who met with the same versus a different clinician. Clinician continuity was not significantly related to intervention fidelity in terms of BMI-consistent qualities, relevance of information presented, or session satisfaction. These findings suggest that clinician continuity across BMIs for college students is not related to participant satisfaction or intervention effectiveness, especially if the clinicians adhere to empirically supported techniques. PMID- 21696912 TI - Preliminary evaluation of extended-release naltrexone in Michigan and Missouri drug courts. AB - This pilot study, a retrospective case series analysis, examined the feasibility and effectiveness of treating alcohol dependence with extended-release naltrexone (XR-NTX) in the drug court setting. In two Michigan courts and in one Missouri court, 32 clients were treated with XR-NTX and were matched with 32 clients with standard care in an open-label, voluntary recruitment design. Treatment with XR NTX was associated with relative risk reductions (RRRs; p = ns) of 57% fewer missed drug court sessions, a 35% reduction in the monthly ratio of positive drug and alcohol tests to total tests, and 35% fewer individuals with greater than 25% overall positive alcohol or drug tests. In the principal end-point analysis of annualized number of new arrests, 26% of standard-care clients were rearrested versus 8% on XR-NTX (RRR = 69%; p < .05). Treatment with XR-NTX appeared to be feasible and was associated with a consistently large treatment effect across multiple outcomes relevant to the drug court setting. PMID- 21696913 TI - Risk of drug-related mortality during periods of transition in methadone maintenance treatment: a cohort study. AB - This study aims to identify periods of elevated risk of drug-related mortality during methadone maintenance treatment (MMT) in primary care using a cohort of 3,162 Scottish drug users between January 1993 and February 2004. Deaths occurring during treatment or within 3 days after last methadone prescription expired were considered as cases "on treatment." Fatalities occurring 4 days or more after leaving treatment were cases "off treatment." Sixty-four drug-related deaths were identified. The greatest risk of drug-related death was in the first 2 weeks of treatment (adjusted hazard ratio 2.60, 95% confidence interval 1.03 6.56). Risk of drug-related death was lower after the first 30 days following treatment cessation, relative to the first 30 days off treatment. History of psychiatric admission was associated with increased risk of drug-related death in treatment. Increasing numbers of treatment episodes and urine testing were protective. History of psychiatric admission, increasing numbers of urine tests, and coprescriptions of benzodiazepines increased the risk of mortality out of treatment. The risk of drug-related mortality in MMT is elevated during periods of treatment transition, specifically treatment initiation and the first 30 days following treatment dropout or discharge. PMID- 21696914 TI - Accuracy of sentinel lymph node biopsy after neo-adjuvant chemotherapy in patients with locally advanced breast cancer and clinically positive axillary nodes. AB - BACKGROUND: Feasibility and accuracy of sentinel node biopsy (SLNB) after the delivery of neo-adjuvant chemotherapy (NAC) is controversial. We here report our experience in NAC-treated patients with locally advanced breast cancer and clinically positive axillary nodes, and compare it with the results from our previous randomized trial assessing SLNB in early-stage breast cancer patients. PATIENTS AND METHODS: Sixty-four consecutive patients with large infiltrating tumor and clinically positive axillary nodes received NAC and subsequent lymphatic mapping, SLNB and complete axillary lymph node dissection (ALND). The status of the sentinel lymph node (SLN) was compared to that of the axilla. RESULTS: At least one SLN was identified in 60 of the 64 patients (93.8%). Among those 60 patients, 37 (61.7%) had one or more positive SLN(s) and 23 (38.3%) did not. Two of the patients with negative SLN(s) presented metastases in other non sentinel nodes. SLNB thus had a false-negative rate, a negative predictive value and an overall accuracy of 5.1%, 91.3% and 96.7%, respectively. All these values were similar to those we reported for SLNB in the settings of early-stage breast cancer. CONCLUSION: SLNB after NAC is safe and feasible in patients with locally advanced breast cancer and clinically positive nodes, and accurately predicts the status of the axilla. PMID- 21696915 TI - "Show me the money": the cost of atrial fibrillation. PMID- 21696916 TI - Disgust proneness and obsessive-compulsive symptoms in a clinical sample: structural differentiation from negative affect. AB - Although a growing body of research has revealed robust associations between disgust and obsessive-compulsive disorder (OCD) symptoms, there remains a paucity of research examining the specificity of this association in clinical samples. The present study employed structural equation modeling to differentiate disgust from negative affect in the prediction of OCD symptoms in a clinical sample (n=153). Results indicate that disgust and negative affect latent factors were independently related to OCD symptoms. However, when both variables were simultaneously modeled as predictors, latent disgust remained significantly associated with OCD symptoms, whereas the association between latent negative affect and OCD symptoms became nonsignificant. Multiple statistical tests of mediation converged in support of disgust as a significant intervening variable between negative affect and OCD symptoms. The implications of these findings for further delineating the role of individual differences in disgust proneness in the development of OCD are discussed. PMID- 21696917 TI - An analysis of functional communication training as an empirically supported treatment for problem behavior displayed by individuals with intellectual disabilities. AB - This paper examines the literature on the use of functional communication training (FCT) as a treatment for problem behavior displayed by individuals with intellectual disabilities (ID). Criteria for empirically supported treatments developed by Divisions 12 and 16 of the American Psychological Association (Kratochwill & Stoiber, 2002; Task Force, 1995) and adapted by Jennett and Hagopian (2008) for evaluation of single-case research studies were used to examine the support for FCT. Results indicated that FCT far exceeds criteria to be designated as a well-established treatment for problem behavior exhibited by children with ID and children with autism spectrum disorder, and can be characterized as probably efficacious with adults. PMID- 21696918 TI - Piaget's water-level task: the impact of vision on performance. AB - In the present study, the aim was to examine the differences in performance between children and adolescents with visual impairment and sighted peers in the water-level task. Twenty-eight individuals with visual impairments, 14 individuals with blindness and 14 individuals with low vision, and 28 sighted individuals participated in the present study. Fourteen sighted individuals participated blindfolded and 14 were able to use their sight. The findings indicate that use of vision can influence the performance in water-level task. However, in the restriction of visual ability (participants with blindfold), individuals with blindness might present better performance than blindfolded sighted participants. PMID- 21696919 TI - On the use of interaction error potentials for adaptive brain computer interfaces. AB - We propose an adaptive classification method for the Brain Computer Interfaces (BCI) which uses Interaction Error Potentials (IErrPs) as a reinforcement signal and adapts the classifier parameters when an error is detected. We analyze the quality of the proposed approach in relation to the misclassification of the IErrPs. In addition we compare static versus adaptive classification performance using artificial and MEG data. We show that the proposed adaptive framework significantly improves the static classification methods. PMID- 21696920 TI - Leiomyomatous hamartoma of the midline maxillary gingival presenting as a congenital epulis: a case report with an immunohistochemical study. AB - An otherwise-healthy 2-year-old Japanese female presented with a polyp-like lesion on the palatal surface at the incisive papilla. The appearance of the lesion was similar to that of a congenital epulis. The histological findings showed proliferating mesenchymal components that contained mainly smooth muscle admixed with collagen fibres, nerve fibres, small vessels and mucous salivary glands. The immunohistochemical staining findings for alpha-smooth-muscle actin, desmin and S-100 protein were all positive. The histological diagnosis was therefore leiomyomatous hamartoma, based on clinical microscopic observations. PMID- 21696921 TI - Dynamic component of sports is an important determinant factor of heart rate recovery. AB - OBJECTIVE: It is usually suggested that life expectancy of top athletes especially in endurance sports is longer than that of sedentary people. On the other hand, heart rate recovery (HRR) after exercise is an independent risk factor for cardiovascular disease and mortality, but differences in HRR between various top athletes are unclear. We examined HRR in various top athletes to clarify a role of HRR that may affect their life expectancy. METHODS: HRR was defined as the difference between the heart rate at peak exercise and that at 2 min after the finish of exercise using symptom-limited maximal graded bicycle ergometer exercise testing. The relationships between HRR with the grade of static and dynamic component of classification of sports, age, and body mass index (BMI) were estimated. SUBJECTS: The subjects were 720 male athletes participating in the National Sports Festival Japan in 2005-2008 and age-matched 28 sedentary controls. RESULTS: HRR was significantly correlated (p<0.0001) with the higher grade of dynamic component of sports, younger age, and lower BMI in both univariate and multivariate analysis. CONCLUSIONS: HRR of top athletes is predicted by increased dynamic component of sports, younger age, and lower BMI. PMID- 21696922 TI - Frontal areas contribute to reduced global coordination of resting-state gamma activities in drug-naive patients with schizophrenia. AB - Schizophrenia has been postulated to involve impaired neuronal cooperation in large-scale neural networks, including cortico-cortical circuitry. Alterations in gamma band oscillations have attracted a great deal of interest as they appear to represent a pathophysiological process of cortical dysfunction in schizophrenia. Gamma band oscillations reflect local cortical activities, and the synchronization of these activities among spatially distributed cortical areas has been suggested to play a central role in the formation of networks. To assess global coordination across spatially distributed brain regions, Omega complexity (OC) in multichannel EEG was proposed. Using OC, we investigated global coordination of resting-state EEG activities in both gamma (30-50 Hz) and below gamma (1.5-30 Hz) bands in drug-naive patients with schizophrenia and investigated the effects of neuroleptic treatment. We found that gamma band OC was significantly higher in drug-naive patients with schizophrenia compared to control subjects and that a right frontal electrode (F3) contributed significantly to the higher OC. After neuroleptic treatment, reductions in the contribution of frontal electrodes to global OC in both bands correlated with the improvement of schizophrenia symptomatology. The present study suggests that frontal brain processes in schizophrenia were less coordinated with activity in the remaining brain. In addition, beneficial effects of neuroleptic treatment were accompanied by improvement of brain coordination predominantly due to changes in frontal regions. Our study provides new evidence of improper intrinsic brain integration in schizophrenia by investigating the resting-state gamma band activity. PMID- 21696923 TI - Atypical antipsychotics and effects of muscarinic, serotonergic, dopaminergic and histaminergic receptor binding on insulin secretion in vivo: an animal model. AB - The atypical antipsychotics (AAPs) have been associated with increased risk of type-2 diabetes. Evidence suggests direct, drug-related effects independent of weight gain and although mechanisms underlying this phenomenon are unclear, it has been suggested that the heterogeneous receptor binding profile of the AAPs may influence receptors implicated in glucose metabolism. This study aimed to clarify weight gain-independent mechanisms of AAP-induced changes in insulin secretion by deconstructing their binding profile with representative antagonists. Healthy rats were pretreated with a single subcutaneous dose of darifenacin 6 mg/kg (n=10), a selective M(3) muscarinic antagonist; ketanserin 2mg/kg (n=10), a 5HT(2A) antagonist; raclopride 0.3mg/kg (n=11) a selective D(2)/D(3) antagonist; terfenadine 20mg/kg (n=9) a selective H(1) antagonist; or, vehicle (n=11). Hyperglycemic clamps were employed following injection, providing an index of secretory capacity of pancreatic beta-cells. Acute treatment with darifenacin and ketanserin significantly decreased insulin response to glucose challenge as compared to controls, which was confirmed in the darifenacin group by reduced C-peptide levels. Treatment with raclopride resulted in an increased insulin response and a strong tendency to increased C-peptide levels. H(1) blockade did not result in effects on insulin or C-peptide. Results suggest that the effects of antipsychotics on glucose dysregulation may be related to direct inhibitory effects of muscarinic (M(3)) and serotonergic (5HT(2)) antagonism on insulin secretion. Based on the expression of D(2)-like receptors in beta-cells, which mediate inhibition of insulin secretion, we propose that prolonged D(2) blockade with antipsychotics may predispose to depletion of insulin stores and an eventual defect in pancreatic compensation. PMID- 21696924 TI - Personality traits in attempted and completed suicide. AB - OBJECTIVE: Though widely used in clinical and biological studies, no investigation of the factor structure of the Karolinska Scales of Personality (KSP) has been performed in suicide attempters. There are very few studies of personality traits in suicide completers. The aim of the present study was to assess the factor structure of KSP in suicide attempters. A secondary aim was to examine whether the factor structure of the KSP was related to gender and/or to violent method of the suicide attempt or to suicide completion. METHOD: The factor structure of the KSP was analysed in data from 165 suicide attempters from the Suicide Prevention Clinic at the Karolinska University Hospital using principal component analysis and orthogonal varimax rotation for the factor extraction. The effect of gender and (1) used method in the suicide attempt (violent versus nonviolent), and (2) later completed suicide on the factors was assessed in two separate series of the two-way ANOVAs. RESULT: A four-factor solution appeared: (1) Neuroticism, (2) Nonconformity, (3) Psychoticism and (4) Extraversion. Men who later completed suicide reported more Extroversion than male survivors. CONCLUSION: The obtained factor structure is comparable to a previous factor structure in a group of twins from the population-based Swedish Twin Registry indicating that no specific personality structure characterized the current sample. Differences in personality traits between suicide completers and survivors indicate that these groups may have some distinct characteristics. PMID- 21696925 TI - Actigraphic daytime activity is reduced in patients with cognitive impairment and apathy. AB - OBJECTIVES: Apathy is a neuropsychiatric symptom in mild cognitive impairment (MCI) and dementia. This study examines correlations between Apathy Evaluation Scale (AES) ratings and actigraphic measures of daytime activity. The aim of this study is to determine the value of ambulatory actigraphy in the assessment of locomotor deficits as a correlate of apathy in geriatric patients with cognitive impairment. PATIENTS AND METHODS: In this cross-sectional study a total of 82 participants were recruited, 32 patients with dementia, 21 patients with MCI and 23 elderly controls. Rating scales for apathy (AES) and depression (Beck Depression Inventory, BDI) were completed. To measure daytime activity a wrist worn actigraph and an established protocol were used. A single measure of mean daytime activity per participant was calculated for further statistical analysis. RESULTS: In the two groups of patients with MCI and dementia, apathy is associated with reduced daytime activity, independent of diagnosis (no group by apathy interaction). AES scores correlate significantly with daytime activity. Cognitive impairment reduces daytime activity (effect greater in dementia than in MCI). Daytime activity is negatively correlated with memory deficits. CONCLUSION: Ambulatory actigraphy is a promising method to evaluate self-initiated action as a correlate of apathy in patients with cognitive impairment. PMID- 21696926 TI - Measuring self-harm in adults: a systematic review. AB - PURPOSE: To identify from the literature, and to critically evaluate, all validated instruments currently available to measure self-harming behaviour in adults. MATERIALS AND METHODS: Medline, Embase, PsycInfo, Health and Psychosocial Instruments and Google scholar were searched, grey literature was sought and the reference lists of relevant articles were checked to identify instruments. RESULTS: A total of seven validated instruments which met our inclusion criteria were identified and data were extracted regarding each instrument's format, administration method, psychometric properties and number of items and domains included. Considerable variation was observed in the overall quality of these instruments. Fourteen other instruments were identified which did not describe their psychometric properties or had not been published and were subsequently excluded from our review. DISCUSSION: Although many instruments were identified in our search, only a small number had been validated with published psychometric properties. Of the identified instruments, the Suicide Attempt Self-Injury Interview (SASII) appears to be the most robust and comprehensive instrument currently available. Despite the absence of psychometric data, numerous other instruments have been used in published studies, including clinical trials. CONCLUSION: Our results highlight the pressing need for a standardized, empirically validated and versatile measure of intentional self-harming behaviour for use in both clinical and research settings. The optimum characteristics of such an instrument are discussed. PMID- 21696927 TI - Seventeen-year clinical outcome of schizophrenia in Bali. AB - OBJECTIVE: To examine the 17-year clinical outcome of schizophrenia and its predictors in Bali. METHODS: Subjects were 59 consecutively admitted first episode schizophrenia patients. Their clinical outcome was evaluated by standardized symptomatic remission criteria based on Positive and Negative Syndrome Scale (PANSS) scores and operational functional remission criteria at 17 year follow-up. The standardized mortality ratio (SMR) over 17 years was also calculated as another index of clinical outcome. RESULTS: Among these 59 patients, 43 (72.9%) could be followed-up, 15 (25.4%) had died, and one (1.7%) was alive but refused to participate in the study. Combined remission (i.e. symptomatic and functional remission) was achieved in 14 patients (23.7% of original sample). Duration of untreated psychosis (DUP) was a significant baseline predictor of combined remission. Mean age at death of deceased subjects was 35.7, and SMR was 4.85 (95% CI: 2.4-7.3), indicating that deaths were premature. Longer DUP was associated with excess mortality. CONCLUSIONS: The long term outcome of schizophrenia in Bali was heterogeneous, demonstrating that a quarter achieved combined remission, half were in nonremission, and a quarter had died at 17-year follow-up. DUP was a significant predictor both for combined remission and mortality. PMID- 21696928 TI - Endogenous regulation of the growth-rate responses of a spring-dwelling strain of the freshwater alga, Chlorella minutissima, to light and temperature. AB - The paper presents a laboratory investigation of the temperature- and light- dependence of autotrophic growth of the alga Chlorella minutissima. It was isolated from the storage basin of a spring in the mountains of the Massif Central, France. The alga was grown at temperatures between (10 and 35 degrees C) and under irradiances from 30 to 550 MUmol m(-2) s(-1), under a light/dark cycle. The results were fitted to selected descriptive models, seeking to express, as far as possible, the observed physiological behaviour of the strain and the minimum irradiance required to sustain net growth. At all temperatures, the maximum rates of growth observed are strikingly slower than those of other Chlorella strains and of other small algae, reported in the literature, even when correction is made for continuous light. The Q10 statistic for growth at temperatures>20 degrees C rates is also noticeably lower than in other species, while the apparent threshold of any growth is about 8 degrees C. Growth rates are readily light-saturated at all temperatures but with little evidence of adaptation of photosynthesis to low photon-flux rates. No short-term flexibility in these properties (over a time-scale of days) was demonstrated during the course of our experiments. We deduce that the algal strain had become genetically adapted to the relatively constant, even-temperature and low-light conditions of the spring-water habitat whence it was originally isolated. PMID- 21696929 TI - Improving the accuracy of suicide attempter classification. AB - OBJECTIVE: Psychometrical questionnaires such as the Barrat's impulsiveness scale version 11 (BIS-11) have been used in the assessment of suicidal behavior. Traditionally, BIS-11 items have been considered as equally valuable but this might not be true. The main objective of this article is to test the discriminative ability of the BIS-11 and the international personality disorder evaluation screening questionnaire (IPDE-SQ) to predict suicide attempter (SA) status using different classification techniques. In addition, we examine the discriminative capacity of individual items from both scales. MATERIALS AND METHODS: Two experiments aimed at evaluating the accuracy of different classification techniques were conducted. The answers of 879 individuals (345 SA, 384 healthy blood donors, and 150 psychiatric inpatients) to the BIS-11 and IPDE SQ were used to compare the classification performance of two techniques that have successfully been applied in pattern recognition issues, Boosting and support vector machines (SVM) with respect to linear discriminant analysis, Fisher linear discriminant analysis, and the traditional psychometrical approach. RESULTS: The most discriminative BIS-11 and IPDE-SQ items are "I am self controlled" (Item 6) and "I often feel empty inside" (item 40), respectively. The SVM classification accuracy was 76.71% for the BIS-11 and 80.26% for the IPDE-SQ. CONCLUSIONS: The IPDE-SQ items have better discriminative abilities than the BIS 11 items for classifying SA. Moreover, IPDE-SQ is able to obtain better SA and non-SA classification results than the BIS-11. In addition, SVM outperformed the other classification techniques in both questionnaires. PMID- 21696930 TI - Non-invasive estimate of blood glucose and blood pressure from a photoplethysmograph by means of machine learning techniques. AB - OBJECTIVE: This work presents a system for a simultaneous non-invasive estimate of the blood glucose level (BGL) and the systolic (SBP) and diastolic (DBP) blood pressure, using a photoplethysmograph (PPG) and machine learning techniques. The method is independent of the person whose values are being measured and does not need calibration over time or subjects. METHODOLOGY: The architecture of the system consists of a photoplethysmograph sensor, an activity detection module, a signal processing module that extracts features from the PPG waveform, and a machine learning algorithm that estimates the SBP, DBP and BGL values. The idea that underlies the system is that there is functional relationship between the shape of the PPG waveform and the blood pressure and glucose levels. RESULTS: As described in this paper we tested this method on 410 individuals without performing any personalized calibration. The results were computed after cross validation. The machine learning techniques tested were: ridge linear regression, a multilayer perceptron neural network, support vector machines and random forests. The best results were obtained with the random forest technique. In the case of blood pressure, the resulting coefficients of determination for reference vs. prediction were R(SBP)(2)=0.91, R(DBP)(2)=0.89, and R(BGL)(2)=0.90. For the glucose estimation, distribution of the points on a Clarke error grid placed 87.7% of points in zone A, 10.3% in zone B, and 1.9% in zone D. Blood pressure values complied with the grade B protocol of the British Hypertension society. CONCLUSION: An effective system for estimate of blood glucose and blood pressure from a photoplethysmograph is presented. The main advantage of the system is that for clinical use it complies with the grade B protocol of the British Hypertension society for the blood pressure and only in 1.9% of the cases did not detect hypoglycemia or hyperglycemia. PMID- 21696931 TI - Sunflower cotyledons cope with copper stress by inducing catalase subunits less sensitive to oxidation. AB - Copper is an essential trace element for living organisms, in excess, can be toxic to the cell because of its capacity to generate reactive oxygen species (ROS). Catalase (CAT) catalyzes the dismutation of hydrogen peroxide into water and dioxygen and in plants it is located in peroxisomes and glyoxysomes. Different metals can induce changes in CAT activity, but the mechanism underlying its changes is unclear. After 4h of treatment with 5 and 10 MUM CuCl(2) a decrease in the specific CAT activity was detected in sunflower cotyledons of post-germinative heterotrophic seedlings. At 8h of treatment, 5 MUM Cu(2+) produced an induction of CAT activity while only a complete recovery to control values was observed for 10 MUM Cu(2+) treated seedlings. These activity variations were not related to the level of CAT protein expression, but they did correlate with the oxidative state of the CAT protein. This indicates that the mechanism of CAT inactivation by Cu(2+) involves oxidation of the protein structure. The level of the mRNA of CATA3 and CATA4 increased with the presence of the metal after 4h of exposure. These CAT genes code for the synthesis of CAT subunits less sensitive to oxidation, which would prevent the copper-induced oxidative inactivation of CAT. PMID- 21696932 TI - The management of accidental dural puncture and postdural puncture headache: a North American survey. AB - STUDY OBJECTIVE: To evaluate the management of accidental dural puncture (ADP) and postdural puncture headache (PDPH) among obstetric anesthesiologists practicing in North America. DESIGN: Questionnaire survey of individual members of the Society for Obstetric Anesthesia and Perinatology (SOAP). SETTING: University hospital. MEASUREMENTS: In June 2008, a 4-part, 83-item electronic survey was distributed to all North American members of SOAP. It contained questions about respondent demographics, epidural catheter and intrathecal catheter management after ADP, PDPH management, epidural blood patch (EBP) management, and patient follow-up. MAIN RESULTS: Of the 843 United States and Canadian members of SOAP who were surveyed, 160 responses were collected. Respondents reported placing an epidural 75% of the time and an intrathecal catheter 25% of the time following ADP. Common prophylactic and conservative treatment strategies included hydration, caffeine, and opioids by mouth; 76% of respondents leave an intrathecal catheter in place for 24 hours to reduce the frequency of headache. Epidural blood patches are placed by 81% of practitioners less than 24 hours after headache onset. CONCLUSIONS: Protocols for ADP management are rare. There is wide variation in catheter management after dural puncture, measures used to prevent and treat a resultant headache, and EBP management. PMID- 21696933 TI - The optimal dose of esmolol and nicardipine for maintaining cardiovascular stability during rapid-sequence induction. AB - STUDY OBJECTIVE: To determine the optimal dose of esmolol in combination with nicardipine in effectively blocking undesirable cardiovascular responses during rapid-sequence induction. DESIGN: Prospective, randomized clinical comparison study. SETTING: Operating room of a university hospital. PATIENTS: 200 ASA physical status 1 and 2 patients requiring general anesthesia with endotracheal tube placement. INTERVENTIONS: Patients were randomly allocated into one of 4 groups: Group E0 (no esmolol; control), Group E0.25 (esmolol 0.25 mg/kg), Group E0.5 (esmolol 0.5 mg/kg), and Group E1.0 (esmolol 1.0 mg/kg). All patients received 20 MUg/kg of nicardipine, and esmolol was then given according to group allocation. Ninety seconds later, thiopental sodium 5 mg/kg and succinylcholine 1.0 mg/kg were injected. Endotracheal intubation was performed 60 seconds after injection of the anesthetic agents. MEASUREMENTS: Systolic (SBP), diastolic (DBP), and mean arterial (MAP) pressures; heart rate (HR), and rate-pressure product (RPP) were measured 30 seconds before and after intubation, and at 1, 3, 5, and 10 minutes after intubation. Rate changes using baseline values as the standard [rate changes = measured value/baseline value * 100 (%)] were calculated. MAIN RESULTS: Significant attenuations in SBP, MAP, HR, and RPP after intubation were noted in the experimental groups as compared with the control group (P < 0.05). Rate changes in HR in Groups E0.5 and E1.0 were significantly lower than those in Group E0.25 immediately and one minute after intubation (P < 0.05). No difference in rate changes in HR were noted between the E0.5 and E1.0 groups. CONCLUSIONS: The combination of nicardipine 20 MUg/kg and esmolol 0.5 mg/kg most effectively attenuates the cardiovascular responses during rapid sequence induction. PMID- 21696934 TI - Effect of fluticasone propionate/salmeterol on arterial stiffness in patients with COPD. AB - BACKGROUND: COPD is associated with increased arterial stiffness which may in part explain the cardiovascular morbidity observed in the disease. A causal relationship between arterial stiffness and cardiovascular events has not been established, though their strong association raises the possibility that therapies that reduce arterial stiffness may improve cardiovascular outcomes. Prior studies suggest that fluticasone propionate/salmeterol (FSC) may improve cardiovascular outcomes in COPD and we hypothesized that FSC would reduce arterial stiffness in these patients. METHODS: This multicenter, randomized, double-blind, placebo-controlled study compared the effects of FSC 250/50 MUg twice-daily and placebo on aortic pulse wave velocity (aPWV) as determined by ECG gated carotid and femoral artery waveforms. The primary endpoint was aPWV change from baseline at 12-weeks (last measure for each patient). RESULTS: 249 patients were randomized; the mean FEV(1) in each group was similar (55% predicted) and 60% of patients reported a cardiovascular disorder. At 12-weeks, aPWV between FSC and placebo was -0.42 m/s (95%CI -0.88, 0.03; p = 0.065). A statistically significant reduction in aPWV between FSC and placebo was observed in those who remained on study drug throughout the treatment period [-0.49 m/s (95%CI -0.98, 0.01; p = 0.045)]. A post hoc analysis suggested the effect of FSC was greater in patients with higher baseline aPWV. CONCLUSION: FSC does not reduce aPWV in all patients with moderate to severe COPD, but may have effects in those with elevated arterial stiffness. Additional studies are required to determine if aPWV could serve as a surrogate for cardiovascular events in COPD. PMID- 21696935 TI - Spatial and temporal regulation of integrin signalling during cell migration. PMID- 21696936 TI - Analysing the Spanish smoke-free legislation of 2006: a new method to quantify its impact using a dynamic model. AB - BACKGROUND: There are many models that study aspects of smoking habits: the influence of price, tax, relapse time, and the effects of prohibition. There are also studies examining the effects of the Spanish smoke-free law. We wanted to build a model able to separate the effect of the law from the pre-law evolution of smoking habits. METHODS: Using data from the Spanish Ministry of Health and Social Policy, we developed a dynamic model of tobacco use. The model projects the evolution over time of the number of non-smokers, smokers and ex-smokers before 2006. Then, we compared the predictions of the model with data for the years after the law came into force, 2006 and 2009. RESULTS: We show that smoke free law has had a significant impact on different sub-populations. The number of ex-smokers increased significantly in 2006 and this increase was maintained in 2009. The number of smokers also decreased significantly in 2006, but in 2009 this returned to its value before the law. Simultaneously, the number of non smokers decreased in 2009. CONCLUSIONS: When the law came into force (2006), its restriction on smoking in public and work places made many smokers decide to give up smoking, decreasing the number of smokers and increasing the number of ex smokers. In 2009, the majority of those who succeeded in giving up smoking did not return to the habit. However, the smoke-free law had no effect on new smokers and the number of smokers returned to previous levels, whereas the number of non smokers decreased. Therefore, we can conclude that the law had a very positive effect in the first few years but this has dissipated over time, with the exception of ex-smokers, whose number is still higher than before the law. PMID- 21696937 TI - An estimation of the prevalence of opioid dependence in New Zealand. AB - BACKGROUND: An accurate prevalence estimate for opioid dependence in New Zealand, and hence the extent of unmet treatment need, is lacking. METHODS: Opioid users were recruited via snowball sampling, with participants initially recruited from opioid substitution treatment (OST) services and dedicated needle exchanges in Auckland, Tauranga and Christchurch. Participants estimated the number of people they knew personally who were receiving OST and who were not receiving OST, but were using opioids daily or almost daily. From these estimates a multiplier of the ratio between these two groups was derived and applied to the known number receiving OST in New Zealand to arrive at the total population estimate. RESULTS: The mean multiplier estimate, weighted for treatment site, for 84 recruited participants was 2.015. The multiplier was higher for Christchurch. Initial recruitment source did not influence the value of the multiplier estimate. When the multiplier was applied to the known size of the New Zealand OST treatment population the total opioid dependent population was estimated to be 9142 (95% CI: 8248-10036), of whom half were not receiving OST. CONCLUSION: This figure was lower than for previous less robust estimates, but still represents a substantial level of unmet need. Greater effort needs to be made to close this treatment gap. PMID- 21696938 TI - Solid-phase fluorescence spectroscopy to characterize organic wastes. AB - The production of solid organic waste (SOW) such as sewage sludge (SS) or municipal solid waste (MSW) has been continuously increasing in Europe since the beginning of the 1990'. Today, the European Union encourages the stabilization of these wastes using biologic processes such as anaerobic digestion and/or composting to produce bio-energy and organic fertilizers. However, the design and management of such biologic processes require knowledge about the quantity and quality of the organic matter (OM) contained in the SOW. The current methods to characterize SOW are tedious, time-consuming and often insufficiently informative. In this paper, we assess the potential of solid-phase fluorescence (SPF) spectroscopy to quickly provide a relevant characterization of SOW. First, we tested well known model compounds (tryptophan, bovine serum albumin, lignin and humic acid) and biologic matrix (Escherichia coli) in three dimensional solid phase fluorescence (3D-SPF) spectroscopy. We recorded fluorescence spectra from proteinaceous samples but we could not record the fluorescence emitted by lignin and humic acid powders. For SOW samples, fluorescence spectra were successfully recorded for MSW and most of its sub-components (foods, cardboard) but impossible for SS, sludge compost (SC) and ligno-cellulosic wastes. Based on visual observations and additional assays, we concluded that the presence of highly light-absorptive chemical structures in such dark-colored samples was responsible for this limitation. For such samples, i.e. lignin, humic acid, SS, SC and ligno cellulosic wastes, we show that laser induced fluorescence (LIF) spectroscopy enables the acquisition of 2D fluorescence spectra. PMID- 21696939 TI - Pricing landfill externalities: emissions and disamenity costs in Cape Town, South Africa. AB - The external (environmental and social) costs of landfilling (e.g. emissions to air, soil and water; and 'disamenities' such as odours and pests) are difficult to quantify in monetary terms, and are therefore not generally reflected in waste disposal charges or taken into account in decision making regarding waste management options. This results in a bias against alternatives such as recycling, which may be more expensive than landfilling from a purely financial perspective, but preferable from an environmental and social perspective. There is therefore a need to quantify external costs in monetary terms, so that different disposal options can be compared on the basis of their overall costs to society (financial plus external costs). This study attempts to estimate the external costs of landfilling in the City of Cape Town for different scenarios, using the benefits transfer method (for emissions) and the hedonic pricing method (for disamenities). Both methods (in particular the process of transferring and adjusting estimates from one study site to another) are described in detail, allowing the procedures to be replicated elsewhere. The results show that external costs are currently R111 (in South African Rands, or approximately US$16) per tonne of waste, although these could decline under a scenario in which energy is recovered, or in which the existing urban landfills are replaced with a new regional landfill. PMID- 21696940 TI - Environmental impact of APC residues from municipal solid waste incineration: reuse assessment based on soil and surface water protection criteria. AB - Waste management and environmental protection are mandatory requirements of modern society. In our study, air pollution control (APC) residues from municipal solid waste incinerators (MSWI) were considered as a mixture of fly ash and fine particulate solids collected in scrubbers and fabric filters. These are hazardous wastes and require treatment before landfill. Although there are a number of treatment options, it is highly recommended to find practical applications rather than just dump them in landfill sites. In general, for using a construction material, beyond technical specifications also soil and surface water criteria may be used to ensure environmental protection. The Dutch Building Materials Decree (BMD) is a valuable tool in this respect and it was used to investigate which properties do not meet the threshold criteria so that APC residues can be further used as secondary building material. To this end, some scenarios were evaluated by considering release of inorganic species from unmoulded and moulded applications. The main conclusion is that the high amount of soluble salts makes the APC residues a building material prohibited in any of the conditions tested. In case of moulding materials, the limits of heavy metals are complied, and their use in Category 1 would be allowed. However, also in this case, the soluble salts lead to the classification of "building material not allowed". The treatments with phosphates or silicates are able to solve the problem of heavy metals, but difficulties with the soluble salts are still observed. This analysis suggests that for APC residues to comply with soil and surface water protection criteria to be further used as building material at least a pre-treating for removing soluble salts is absolutely required. PMID- 21696941 TI - In-situ produced ascorbic acid as coreactant for an ultrasensitive solid-state tris(2,2'-bipyridyl) ruthenium(II) electrochemiluminescence aptasensor. AB - Herein, an ultrasensitive solid-state tris(2,2'-bipyridyl) ruthenium(II) (Ru(bpy)(3)(2+)) electrochemiluminescence (ECL) aptasensor using in-situ produced ascorbic acid as coreactant was successfully constructed for detection of thrombin. Firstly, the composite of Ru(bpy)(3)(2+) and platinum nanoparticles (Ru PtNPs) were immobilized onto Nafion coated glass carbon electrode, followed by successive adsorption of streptavidin-alkaine phosphatase conjugate (SA-ALP) and biotinylated anti-thrombin aptamer to successfully construct an ECL aptasensor for thrombin determination. In our design, Pt nanoparticles in Ru(bpy)(3)(2+) Nafion film successfully inhibited the migration of Ru(bpy)(3)(2+) into the electrochemically hydrophobic region of Nafion and facilitated the electron transfer between Ru(bpy)(3)(2+) and electrode surface. Furthermore, ALP on the electrode surface could catalyze hydrolysis of ascorbic acid 2-phosphate to in situ produce ascorbic acid, which co-reacted with Ru(bpy)(3)(2+) to obtain quite fast, stable and greatly amplified ECL signal. The experimental results indicated that the aptasensor exhibited good response for thrombin with excellent sensitivity, selectivity and stability. A linear range of 1 * 10(-15)-1 * 10(-8) M with an ultralow detection limit of 0.33 fM (S/N=3) was obtained. Thus, this procedure has great promise for detection of thrombin present at ultra-trace levels during early stage of diseases. PMID- 21696942 TI - Integration of silicon-via electrodes with different recording characteristics on a glass microprobe using a glass reflowing process. AB - Electrodes on planar type microelectromechanical system (MEMS) microprobes mainly record neurons on the top-side of probe shaft (called a top-side electrode). However, it is often necessary to record neurons other than those on the top-side of the probe shaft. This study uses the glass reflowing technique to embed silicon-vias in a glass probe to implement a microprobe capable of recording neurons around the shaft. The proposed technology makes it possible to fabricate, distribute, and integrate four types of electrodes on the shaft: top-side, back side, double-side, and sidewall electrodes. These electrodes have different recording characteristics. The in vitro and in vivo (using crayfish and rat brain) experiments in this study shows that the top-side and back-side electrodes are respectively more sensitive to neurons on the top-side and back-side of the probe shaft. In contrast, signals recorded by double-side electrode and sidewall electrode are equally sensitive to neurons around the probe shaft. This study enables the implementation and integration of these four types of electrodes, meeting the requirements of various neural applications. PMID- 21696943 TI - S-layer fusion proteins--construction principles and applications. AB - Crystalline bacterial cell surface layers (S-layers) are the outermost cell envelope component of many bacteria and archaea. S-layers are monomolecular arrays composed of a single protein or glycoprotein species and represent the simplest biological membrane developed during evolution. The wealth of information available on the structure, chemistry, genetics and assembly of S layers revealed a broad spectrum of applications in nanobiotechnology and biomimetics. By genetic engineering techniques, specific functional domains can be incorporated in S-layer proteins while maintaining the self-assembly capability. These techniques have led to new types of affinity structures, microcarriers, enzyme membranes, diagnostic devices, biosensors, vaccines, as well as targeting, delivery and encapsulation systems. PMID- 21696944 TI - Interactions between areas of the cortical grasping network. AB - Skilled grasp is a sensorimotor process requiring the brain to extract sensory cues from the environment to shape a motor command. Although a large body of literature has focused on which brain areas either integrate the visual object's properties or control the motor output, it is still unclear how grasp-related information is transferred from one area to another. Understanding interactions between brain areas is crucial for the study of visuomotor transformations. Recently, new advances in both human and non-human primates have shown it is possible to study cortico-cortical interactions during different task contexts. This sheds new light on how brain areas are integrated in a dynamic network for controlling grasping actions. PMID- 21696946 TI - Has there been progress in cancer care in Croatia? Assessing outcomes in a partially complete mortality follow-up setting. AB - BACKGROUND: We examine the possibility of assessing progress in cancer care with partially complete mortality follow-up information, and report outcomes from Croatia. METHODS: Follow-up based on death certificates indicating cancer as the cause of death was available from the Croatian National Cancer Registry. The effect of partially complete follow-up was first examined with data from the Saarland Cancer Registry by comparing absolute, relative, and cancer death certificate based survival estimates. Survival changes between 2000 and 2006 are reported for 21 common cancers amongst patients aged 15-49 and 50-59 in Croatia. RESULTS: Survival estimates based on cancer death specific follow-up could well approximate absolute and relative survival for patients aged 15-49, and relative survival for patients aged 50-59: overestimation by more than one standard error occurred 1 and 2 and 5 times, respectively, amongst 21 cancers. In Croatia, significant survival increases occurred for patients aged 15-59 with colorectal and breast cancers, patients aged 15-49 with thyroid cancer and patients aged 50 59 with malignant melanoma and prostate cancer. CONCLUSIONS: Outcome evaluation is limited with partially complete follow-up information. Internationally comparable cancer information continues to lack from South-Eastern Europe, and the provision thereof remains a highly important public health task. PMID- 21696945 TI - The role of a midbrain network in competitive stimulus selection. AB - A midbrain network interacts with the well-known frontoparietal forebrain network to select stimuli for gaze and spatial attention. The midbrain network, containing the superior colliculus (SC; optic tectum, OT, in non-mammalian vertebrates) and the isthmic nuclei, helps evaluate the relative priorities of competing stimuli and encodes them in a topographic map of space. Behavioral experiments in monkeys demonstrate an essential contribution of the SC to stimulus selection when the relative priorities of competing stimuli are similar. Neurophysiological results from the owl OT demonstrate a neural correlate of this essential contribution of the SC/OT. The multi-layered, spatiotopic organization of the midbrain network lends itself to the analysis and modeling of the mechanisms underlying stimulus selection for gaze and spatial attention. PMID- 21696947 TI - Systolic and diastolic dysfunction in long-term adult survivors of childhood cancer. AB - AIM: To assess systolic and diastolic function in adult childhood-cancer survivors (CCS) after treatment entailing potential cardiovascular toxicity. METHODS: The study cohort consisted of 277 adult CCS (median age 28 [range 18 48]years), who had been treated with anthracyclines, platinum, and/or radiotherapy between 1976 and 1999, along with 130 healthy sibling controls. The assessments included echocardiography, baroreflex sensitivity measurement, and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP). Echocardiography measurements were shortening fraction (SF) (abnormal<29%) for systolic function and tissue velocity imaging of early diastole (TVI Et) (abnormal<8.00)cm/sec for diastolic function; systolic function was also assessed by the wall motion score index (WMSI). RESULTS: At 18 (5-31)years post-treatment, the prevalence of both impaired SF and abnormal WMSI was increased in CCS compared to controls (p=0.003 and p<0.001, respectively). CCS also had an increased prevalence of diastolic dysfunction compared to the controls (12% versus 1%, p<0.001). Abnormal SF and/or abnormal diastolic function were found in 43% of CCS. NT-proBNP was higher in CCS and was associated to increased WMSI. Baroreflex sensitivity was lower in CCS and was associated with diastolic dysfunction. Systolic as well as diastolic dysfunction was associated with cumulative dose of anthracyclines and mediastinal irradiation. CONCLUSION: After treatment with potential cardiovascular toxic therapies, the risk of systolic and diastolic dysfunction in CCS is considerable. Since these abnormalities, in particular diastolic dysfunction, are age related, the observed effects might be considered a sign of precocious cardiac ageing. PMID- 21696949 TI - Light driven hydrogen production in protein based semi-artificial systems. AB - Photobiological hydrogen production has recently attracted interest in terms of being a potential source for an alternative energy carrier. Especially the natural light driven hydrogen metabolism of unicellular green algae appears as an attractive blueprint for a clean and potentially unlimited dihydrogen source. However, the efficiency of in vivo systems is limited by physiological and evolutionary constraints and scientists only begin to understand the regulatory networks influencing cellular hydrogen production. A growing number of projects aim at circumventing these limitations by focusing on semi-artificial systems. They reconstitute parts of the native electron transfer chains in vitro, combining photosystem I as a photoactive element with a proton reducing catalytic element such as hydrogenase enzymes or noble metal nanoparticles. This review summarizes various approaches and discusses limitations that have to be overcome in order to establish economically applicable systems. PMID- 21696948 TI - Pancreatoblastoma: a report from the European cooperative study group for paediatric rare tumours (EXPeRT). AB - BACKGROUND: Pancreatoblastoma is a very rare malignant tumour typically occurring in the early years of life. Due to its rarity, standardised diagnostic and therapeutic guidelines are not available for pancreatoblastoma. METHODS: The newborn cooperative group denominated EXPeRT - European cooperative study group for paediatric rare tumours - combined in a joint analysis of all cases registered between 2000 and 2009 by the national groups of Italy, France, United Kingdom, Poland and Germany. RESULTS: Twenty patients <18years old (median age 4years) were analysed: nine had distant metastases at diagnosis. Seventeen patients had tumour resection, at initial or delayed surgery. Eighteen received chemotherapy (response rate 73%), seven received radiotherapy. For the whole series, 5-year event-free survival and overall survival were 58.8% and 79.4%, respectively. Outcome did not correlate with tumour site and size, but was strongly influenced by the feasibility of tumour complete resection. CONCLUSIONS: This international study confirms the rarity of the disease, the critical role of surgical resection both as therapy and as a prognostic variable, and the potential efficacy of chemotherapy. The adoption of an intensive multidisciplinary approach is required, as well as the referral to highly experienced centres. Further international cooperation is needed to collect larger series and stimulate biological studies to improve our understanding of the biology and the natural history of PBL. PMID- 21696950 TI - Enhancement effect of hematite nanoparticles on fermentative hydrogen production. AB - The effects of hematite nanoparticles concentration (0-1600 mg/L) and initial pH (4.0-10.0) on hydrogen production were investigated in batch assays using sucrose fed anaerobic mixed bacteria at 35 degrees C. The optimum hematite nanoparticles concentration with an initial pH 8.48 was 200mg/L, with the maximum hydrogen yield of 3.21 mol H(2)/mol sucrose which was 32.64% higher than the blank test. At 200mg/L hematite nanoparticles concentration, further initial pH optimization experiments indicated that at pH 6.0 the maximum hydrogen yield reached to 3.57 mol H(2)/mol sucrose and hydrogen content was 66.1%. The slow release of hematite nanoparticles had been recorded by transmission electron microscopy (TEM). In addition, TEM analysis indicated that the hematite nanoparticles can affect the shape of bacteria, namely, its length increased from ca. 2.0-3.6 MUm to ca. 2.6 5.6 MUm, and width became narrower. PMID- 21696951 TI - Indolin-2-one p38alpha inhibitors I: design, profiling and crystallographic binding mode. AB - The use of structure-based design and molecular modeling led to the discovery of indolin-2-one derivatives as potent and selective p38alpha inhibitors. The predicted binding mode was confirmed by X-ray crystallography. PMID- 21696952 TI - Pyrazole-based sulfonamide and sulfamides as potent inhibitors of mammalian 15 lipoxygenase. AB - A series of inhibitors of mammalian 15-lipoxygenase (15-LO) based on a 3,4,5-tri substituted pyrazole scaffold is described. Replacement of a sulfonamide functionality in the lead series with a sulfamide group resulted in improved physicochemical properties generating analogs with enhanced inhibition in cell based and whole blood assays. PMID- 21696953 TI - Pyrrolo[2,3-c]azepine derivatives: a new class of potent protein tyrosine phosphatase 1B inhibitors. AB - A series of pyrrolo[2,3-c]azepine derivatives was designed, synthesized, and evaluated as a new class of inhibitors against protein tyrosine phosphatase 1B (PTP1B) in vitro. The results demonstrated that compounds bearing a biphenyl moiety were proved to markedly influence the potency of these inhibitors. Particularly, compounds 29, 35 and 36 showed interesting inhibition with IC(50) value of 16.36, 14.93 and 13.92MUM, respectively. PMID- 21696954 TI - Growth inhibitory activities of oxyprenylated and non-prenylated naturally occurring phenylpropanoids in cancer cell lines. AB - A series of 25 selected oxyprenylated natural phenylpropanoids were synthesized, and their growth inhibitory activities were evaluated in vitro together with 14 other commercially available non-alkylated compounds belonging to the same chemical series. The compounds were tested on six human cancer cell lines using MTT colorimetric assays. The data reveal that of the six chemical groups (G) studied, coumarins (G1), cinnamic and benzoic acids (G2), chalcones (G3), acetophenones (G4), anthraquinones (G5), and cinnamaldehydes and cinnamyl alcohols (G6), G2-related compounds displayed the weakest growth inhibitory activities in vitro, whereas G5-related compounds displayed the highest activities. Quantitative videomicroscopy analyses were then carried out on human U373 glioblastoma cells, which are characterized by various levels of resistance to different pro-apoptotic stimuli. These analyses revealed that compounds 20 (4,2',4'-trihydroxychalcone), and 30 and 31 (two cinnamaldehydes) were cytostatic and able to overcome the intrinsic resistance of U373 cancer cells to pro apoptotic stimuli. PMID- 21696955 TI - N-Acylhydrazones as inhibitors of PDE10A. AB - Cyclic nucleotide phosphodiesterases (PDEs) are represented by a large superfamily of enzymes. A series of hydrazone-based inhibitors was synthesized and shown to be novel, potent, and selective against PDE10A. Optimized compounds of this class were efficacious in animal models of schizophrenia and may be useful for the treatment of this disease. PMID- 21696956 TI - A novel HDAC inhibitor with a hydroxy-pyrimidine scaffold. AB - Histone deacetylases (HDACs) are enzymes involved in many important biological functions. They have been linked to a variety of cancers, psychiatric disorders, and other diseases. Since small molecules can serve as probes to study the relevant biological roles of HDACs, novel scaffolds are necessary to develop more efficient, selective drug candidates. Screening libraries of molecules may yield structurally diverse probes that bind these enzymes and modulate their functions in cells. Here we report a small molecule with a novel hydroxy-pyrimidine scaffold that inhibits multiple HDAC enzymes and modulates acetylation levels in cells. Analogs were synthesized in an effort to evaluate structure-activity relationships. PMID- 21696957 TI - Pathological and mammographic prognostic factors for screen detected cancers in a multi-centre randomised, controlled trial of mammographic screening in women from age 40 to 48 years. AB - AIM: To assess pathological and radiological prognostic factors for cancers detected by screening within a multi-centre RCT trial of mammographic screening of younger women. METHOD: The survival of 232 women with screen detected invasive cancer was ascertained. Data on invasive cancer size, histological grade, nodal status, vascular invasion, mammographic spiculation, comedo calcification and mammographic background were assessed. Kaplan-Meier and Cox proportional hazards methods were used to examine survival. RESULTS: Univariate analysis indicated that women with cancers with the following features had poorer survival; >= 30 mm, histologically grade 3, heavily node positive (4 or more positive nodes), vascular invasion positive and displaying mammographic comedo calcification. In a multivariate model survival remained poorer in women with four or more nodes positive (HR 8.36, 95% CI 2.31, 30.17) and in those with comedo calcification (HR 3.00,95% CI 1.13, 7.99). CONCLUSION: Nodal status and the presence of mammographic comedo calcification have independent prognostic significance in young women with screen detected cancer. PMID- 21696958 TI - Compensatory mechanisms of transtibial amputees during circular turning. AB - Turning plays a prominent role in daily living activities and requires the modulation of the ground reaction forces to accelerate the body's center-of-mass along the path of the turn. With the ankle plantarflexors being prominent contributors to the propulsive ground reaction forces, it is not clear how transtibial amputees perform turning tasks without these important muscles. The purpose of this study was to identify the compensatory mechanisms used by transtibial amputees during a simple turning task by analyzing the radial and anterior-posterior ground reaction impulses and sagittal, transverse and coronal joint work of the residual and intact legs. These quantities were analyzed with the residual leg on both the inside and outside of the turn and compared to non amputees. The analysis showed that amputees and non-amputees use different joint strategies to turn. Amputees rely primarily on sagittal plane hip joint work to turn while non-amputees rely primarily on ankle work in the sagittal plane and hip joint work in the coronal plane. Differences in strategies are most likely due to the minimal power output provided by the passive prosthetic feet used by amputees and perhaps a desire to minimize the risk of falling. Understanding these differences in turning strategies will aid in developing effective rehabilitation therapies and prosthetic devices that improve amputee mobility. PMID- 21696959 TI - Gaze strategies for avoiding obstacles: Differences between young and elderly subjects. AB - Visual input is highly relevant for safely stepping over obstacles. In this study, gaze-behaviour was investigated in elderly, middle-aged and young subjects as they walked on a treadmill repeatedly stepping over obstacles, which approached either on the right or left side. In between obstacle-steps, subjects visually fixated a target N or F located two or four steps ahead on the floor, respectively. An acoustic warning signal announced the obstacles, after which subjects were free to look wherever they wanted. Gaze-movements were measured by video-oculography. Four conditions with 20 obstacles were conducted (two with target N, two with target F). In two conditions, high-precision stepping was investigated by asking subjects to step with minimal foot-clearance over the obstacles, while receiving acoustic feedback about their performance. In the high precision conditions, more subjects (target N: 70%, F: 81%) turned their gaze on the obstacles and for a longer time than in unrestricted conditions. When fixating on the near target N and unrestricted stepping over the obstacles, significantly more elderly subjects (85%) turned their gaze on the obstacle compared to middle-aged (17%) and young subjects (29%). The elderly turned their gaze earlier and longer on the obstacle than middle-aged or young subjects. Our results reveal a different gaze-behaviour strategy of elderly subjects suggesting a greater dependency on visual inputs. PMID- 21696960 TI - Significance of increased signal intensity on MRI in prognosis after surgical intervention for cervical spondylotic myelopathy. AB - We aimed to examine whether increased signal intensity (ISI) on T2-weighted MRI can be used to predict the surgical outcome of patients with cervical spondylotic myelopathy (CSM). ISI on T2-weighted MRI are frequently observed but the relevance of this finding remains controversial in patients with CSM. Between September 2007 and February 2009, 52 patients with CSM who underwent surgery were studied prospectively. Preoperative and postoperative functional status was evaluated using the modified Japanese Orthopaedic Association (JOA) scoring system, and the recovery rate was calculated using the Hirabayashi method. An MRI was performed on all patients. For those with ISI on T2-weighted MRI, the ratio of the signal intensity on T2-weighted to T1-weighted MRI (T2:T1 ratio) at the same spinal cord level and of similar area was calculated. Although the clinical outcome of all patients had improved at final follow-up, there was a significant difference between patients with ISI and those without ISI in age, duration of symptoms, preoperative and postoperative JOA scores, and recovery rate. The preoperative and postoperative JOA scores and the recovery rate differed significantly (p<0.05) between the three groups: patients without a T2-weighted ISI, and those with different levels of a T2:T1 ratio. Patients with an ISI usually had a low preoperative JOA score and experienced less improvement in neurologic function after surgery. The T2:T1 ratio can be used to help predict surgical outcomes. PMID- 21696961 TI - Primary anaplastic solitary fibrous tumor of the tentorium cerebelli. AB - Meningeal solitary fibrous tumors (MSFT) have been described in about 80 patients as benign spindle-cell neoplasms, with few anaplastic variants. We report a 57 year-old male patient with a 4-month history of progressive headache caused by a primary anaplastic MSFT arising from the tentorium cerebelli. MRI revealed a tentorium-based tumor that extended into the occipital lobe superiorly and into the cerebellum inferiorly on the left. Following gross total resection of the tumor and postoperative radiotherapy, the patient experienced symptomatic improvement with no recurrence at the 12-month follow-up. The final tumor pathology was consistent with an anaplastic MSFT, with a Ki-67 proliferative index of 25%. PMID- 21696962 TI - Effects of single-bundle and double-bundle ACL reconstruction on tibiofemoral compressive stresses and joint kinematics during simulated squatting. AB - The purpose of this study was to compare tibiofemoral (TF) kinematics and TF compressive stresses between single bundle- (SB-) and double bundle-ACL reconstruction (DB-ACLR) during simulated squatting. Twelve matched pairs of fresh frozen cadaver knees were utilized. A simulated squat through 100 degrees of knee flexion was performed in the ACL-intact joint. The ACL was transected and SB- and DB-ACLR procedures were performed in one knee of each pair. The squat was repeated. Knee kinematics were measured using a motion tracking system and the TF compressive forces were measured using thin film pressure sensors. The posterior shifts of the tibia for SB- and DB-ACLR knees were significantly greater than the ACL-intact condition for knee flexion angles 0 degrees to 40 degrees (p<.05). However, there was no difference between the SB- and DB-ACLR knees at any flexion angle (0 degrees to 100 degrees ; p=.37). SB- and DB-ACLR knees had greater IE rotation than intact knees from 90 degrees through 50 degrees of flexion (p<.05), but not between 40 degrees and full extension. There was no difference between SB- and DB-ACLR knees (p=.68). The TF compressive stresses of the DB-ACLR were significantly lower than intact for all angles except 10 degrees (p=.06), whereas SB-ACLR knees did not differ from intact at flexion angles between 30 degrees and 50 degrees (p>.32). There were no significant differences between the two reconstruction conditions (p=.74). This study showed that there was no difference in the TF kinematics or compressive stresses between SB- and DB-ACLR, and only minor differences when compared to the intact state. PMID- 21696963 TI - Design, synthesis and biological evaluation of 2'-deoxy-2',2'-difluoro-5 halouridine phosphoramidate ProTides. AB - We report the synthesis of a series of novel 2'-deoxy-2',2'-difluoro-5 halouridines and their corresponding phosphoramidate ProTides. All compounds were evaluated for antiviral activity and for cellular toxicity. Interestingly, 2' deoxy-2',2'-difluoro-5-iodo- and -5-bromo-uridines showed selective activity against feline herpes virus replication in cell culture due to a specific recognition (activation) by the virus-encoded thymidine kinase. PMID- 21696964 TI - Generation of 'Unnatural Natural Product' library and identification of a small molecule inhibitor of XIAP. AB - Natural products have been utilized for drug discovery. To increase the source diversity, we generated a new chemical library consisting of chemically modified microbial metabolites termed 'Unnatural Natural Products' by chemical conversion of microbial metabolites in crude broth extracts followed by purification of reaction products with the LC-photo diode array-MS system. Using this library, we discovered an XIAP inhibitor, C38OX6, which restored XIAP-suppressed enzymatic activity of caspase-3 in vitro. Furthermore, C38OX6 sensitized cancer cells to anticancer drugs, whereas the unconverted natural product did not. These findings suggest that our library could be a useful source for drug seeds. PMID- 21696965 TI - Synthesis and antidepressant-like activity evaluation of sulphonamides and sulphonyl-hydrazones. AB - In this study a series of sulphonamides and sulphonyl hydrazones of maleimide, naphthalimide and phthalimide derivatives was synthesized. The antidepressant effect of these compounds was evaluated by the forced-swimming test in mice. The behavioural parameter observed in this test is a reduction in the immobility time, which is indicative of antidepressant activity. All compounds, except 8, 11 and 24, were active as antidepressants. The most active compound was the sulphonyl-hydrazone 10 which showed an activity of around 72.02% at 60 mg/kg, it thus being more active than imipramine (10mg/kg, ip), a commercial antidepressant. Other important results were obtained for the benzylnaphthalimide derivatives, the sulphonamides 21 and 22 showing activity of 64% at 10mg/kg, also being more active than imipramine. These results indicate that the sulphonamides and sulphonyl-hydrazone cyclic imide derivatives are potential compounds for use in the designing of new candidates for the treatment of depression. PMID- 21696966 TI - Interactions of the carrier ligands of antidiabetic metal complexes with human serum albumin: a combined spectroscopic and separation approach with molecular modeling studies. AB - The specific binding of carrier ligands of antidiabetic vanadium(IV) and zinc(II) complexes into drug binding pockets of human serum albumin (HSA) has been investigated via displacement reactions of site markers such as warfarin and dansylglycine by different spectroscopic (fluorescence, circular dichroism, NMR) and separation methods (capillary zone electrophoresis, ultrafiltration-UV). Conditional stability constants of the ligands were calculated for the binding at sites I and II of HSA. Binding site I was found to be the primary binding site for 2,6-pyridine dicarboxylic acid (dipic) and picolinic acid (pic), and site II for 6-methylpicolinic acid (6-Mepic) and maltol, although dipic, 6-Mepic and pic displace both site markers at differing extents. The experimental data is complemented by protein-ligand docking calculations for dipic and 6-Mepic which support the observations. PMID- 21696967 TI - The discovery of long-acting saligenin beta2 adrenergic receptor agonists incorporating hydantoin or uracil rings. AB - A series of novel, potent and selective human beta(2) adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of (R)-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12h in guinea pigs in vivo at its EC(90) 25 MUM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m. PMID- 21696969 TI - 18beta-Glycyrrhetinic acid derivatives induced mitochondrial-mediated apoptosis through reactive oxygen species-mediated p53 activation in NTUB1 cells. AB - Twenty six 18beta-glycyrrhetinic acid (GA) (1) derivatives 2-27 including twelve new GA derivatives 10, 11, 13-17, 21-25 were synthesized and evaluated for cytotoxicities against NTUB1 cells (human bladder cancer cell lines). seco Compounds 9, 25, and 27 are the most potent compounds of this series, inhibiting cell growth of human NTUB1 cells with an IC(50) values of 2.34 +/- 0.28, 4.76 +/- 1.15, and 3.31 +/- 0.61 MUM, respectively. Exposure of NTUB1 to 25 for 24h significantly increased the production of reactive oxygen species (ROS). Flow cytometric analysis exhibited that treatment of NTUB1 with 25 did not induce cell cycle arrest but accompanied by an increase of apoptotic cell death in a dose dependant manner after 24h. Mitochondrial membrane potential (MMP) decreased significantly in a dose-dependant manner when the NTUB1 cells were exposed to 25 for 24h. Marked collapse of the MMP suggested that dysfunction of the mitochondria may be involved in the oxidative burst and apoptosis induced by 25. Western blot analysis shows that NTUB1 cells treated with 25 increased the level of p-p53 in a dose-dependant manner. Further, NAC treatment prevented p53 phosphorylation stimulated by 25. These results suggested that 25 induced a mitochondrial-mediated apoptosis in NTUB1 cells through activation of p53, which are mainly mediated ROS generated by 25. PMID- 21696968 TI - Synthesis and evaluation of a radioiodinated trisaccharide derivative as a synthetic substrate for a sensitive N-acetylglucosaminyltransferase V radioassay. AB - N-acetylglucosaminyltransferase V (GnT-V) is one of the most relevant glycosyltransferases to tumor invasion and metastasis. Based on previous findings of molecular recognition between GnT-V and synthetic substrates, we designed and synthesized a p-iodophenyl-derivatized trisaccharide, 2-(4-iodophenyl)ethyl 6-O [2-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-alpha-d-mannopyranosyl]-beta-D glucopyranoside (IPGMG, 1) and its radiolabeled form, [(125)I]IPGMG ([(125)I]1), for use in assays of GnT-V activity in vitro. The tributyltin derivative, 2-[4-(n tributylstannyl)phenyl]ethyl 6-O-[2-O-(3,4,6-tri-O-acetyl-2-acetamido-2-deoxy beta-D-glucopyranosyl)-3,4,6-tri-O-acetyl-alpha-D-mannopyranosyl]-2,3,4-tri-O acetyl-beta-D-glucopyranoside (21), was synthesized as a precursor for the preparation of [(125)I]1. The iododestannylation of 21 using hydrogen peroxide as an oxidant followed by deacetylation yielded [(125)I]1. When [(125)I]1 was incubated in GnT-V-expressing cells with a UDP-GlcNAc donor, the production of beta1-6GlcNAc-bearing IPGMG (IPGGMG, 2) was confirmed by radio-HPLC. In kinetic analysis, 1 was found to be a good substrate with a K(m) of 23.7 MUM and a V(max) of 159 pmol/h. MUg protein. [(125)I]1 would therefore be a useful synthetic substrate for the quantitative determination of GnT-V activity. PMID- 21696970 TI - 3-bromohomofascaplysin A, a fascaplysin analogue from a Fijian Didemnum sp. ascidian. AB - A new fascaplysin analogue, 3-bromohomofascaplysin A (1), along with two known analogues, homofascaplysin A (2) and fascaplysin (3), were isolated from a Fijian Didemnum sp. ascidian. The absolute configurations of 3-bromohomofascaplysin A (1) and homofascaplysin A (2) were determined via experimental and theoretically calculated ECD spectra. The differential activities of 1-3 against different blood-borne life stages of the malaria pathogen Plasmodium falciparum were assessed. Homofascaplysin A (2) displayed an IC(50) of 0.55+/-0.11 nM against ring stage parasites and 105+/-38 nM against all live parasites. Given the stronger resistance of ring stage parasites against most current antimalarials relative to the other blood stages, homofascaplysin A (2) represents a promising agent for treatment of drug resistant malaria. PMID- 21696971 TI - Fe valence determination and Li elemental distribution in lithiated FeO0.7F1.3/C nanocomposite battery materials by electron energy loss spectroscopy (EELS). AB - Electron energy loss spectroscopy (EELS) is a powerful technique for studying Li ion battery materials because the valence state of the transition metal in the electrode and charge transfer during lithiation and delithiation processes can be analyzed by measuring the relative intensity of the transition metal L3 and L2 lines. In addition, the Li distribution in the electrode material can be mapped with nanometer scale resolution. Results obtained for FeO0.7F1.3/C nanocomposite positive electrodes are presented. The Fe average valence state as a function of lithiation (discharge) has been measured by EELS and results are compared with average Fe valence obtained from electrochemical data. For the FeO0.7F1.3/C electrode discharged to 1.5 V, phase decomposition is observed and valence mapping with sub-nanometer resolution was obtained by STEM/EELS analysis. For the lowest discharge voltage of 0.8 V, a surface electrolyte inter-phase (SEI) layer is observed and STEM/EELS results are compared with the Li-K edges obtained for various Li standard compounds (LiF, Li2CO3 and Li2O). PMID- 21696972 TI - Determination of carbon-14 in environmental level, solid reference materials. AB - An intercomparison exercise to determine the (14)C activity concentrations in a range of solid, environmental level materials was conducted between laboratories in the UK. IAEA reference materials, C2, C6 and C7, and an in-house laboratory QA material were dispatched in 2006 to ten laboratories comprising of members of the Analyst Informal Working Group (AIWG) and one other invited party. The laboratories performed the determinations using a number of techniques, and using the results each one was evaluated in terms of levels of precision, sensitivity and limits of detection. The results of the study show that all techniques are capable of successfully analysing (14)C in environmental level materials, however, a shortage of certified environmental reference materials exists. The suitability of the IAEA reference materials and other material for use as reference materials was also assessed. PMID- 21696973 TI - New insights on the barrel medic MtOGG1 and MtFPG functions in relation to oxidative stress response in planta and during seed imbibition. AB - In plants, 8-oxoguanine DNA glycosylase/lyase (OGG1) and formamidopyrimidine-DNA glycosylase (FPG) play similar roles within the base excision repair (BER) pathway involved in the removal of oxidized bases, e.g. 7,8-dihydro-8-oxoguanine (8-oxo-dG) and formamidopyrimidine (FAPy) lesions. To date, it is not clear why plants have retained both the OGG1 and FPG functions. In the present work, we have investigated the possible roles played in planta by MtOGG1 and MtFPG genes from Medicago truncatula Gaertn. (barrel medic). Bioinformatic investigation revealed the presence of putative mitochondrial and nuclear localization signals in the MtOGG1 and MtFPG amino acid sequences, respectively, thus suggesting for different subcellular fates. The expression profiles of both genes were evaluated by Quantitative Real-Time PCR (QRT-PCR) in barrel medic plantlets grown in vitro under oxidative stress conditions induced by copper (CuCl(2), 0.05, 0.1 and 0.2 mM) and polyethylene glycol (PEG6000, 50, 100 and 150 g L(-1)). The MtOGG1 and MtFPG genes were up-regulated in response to stress agents, at different levels, depending on treatment and tissue. As for copper, MtOGG1 showed significant up regulation (up to 1.2- and 1.7-fold) only in roots while the MtFPG mRNA significantly increased (up to 1.3- and 2.8-fold, respectively) in roots and aerial parts. In response to PEG, the MtOGG1 expression was significantly enhanced in aerial parts (up to 1.3-fold) while the MtFPG showed significant (1.2 fold) up-regulation in roots. The expression profiles of MtOGG1 and MtFPG genes were also evaluated during seed imbibition, a physiological process which is characterized by Reactive Oxygen Species (ROS) accumulation and requires active DNA repair. PMID- 21696974 TI - Assessment of changes in photosystem II structure and function as affected by water deficit in Amaranthus hypochondriacus L. and Amaranthus hybridus L. AB - The present study describes the behaviour of photosystem II (PSII) in Amaranthus hypochondriacus and Amaranthus hybridus under water stress conditions, assessed by the analyses of the polyphasic rise in chlorophyll a fluorescence (O-J-I-P). We determined the adaptive behaviour in relation to the regulation of the different functional and structural parameters of PSII, which was a direct and rapid response due to changes in soil water status indicated by a decrease in leaf water potential and relative water content. It allows for the identification of specific key or limiting chlorophyll fluorescence parameters which could be used to identify traits conveying tolerance. For the above partial processes of PSII function studied, it seems that A. hybridus remained the more stable upon water stress (after 17 days of withholding water), concerning the specific energy fluxes of absorption/reaction centre (ABS/RC) apparent (antenna size) and trapping/reaction centre (TR/RC) (maximum trapping flux), as well as the density of the reaction centres/cross section (RC/CS) and the phenomenological trapping flux/cross section (TR(o)/CS). It was clear that amaranth adjusts the non photochemical (k(n)) deactivation constant of PSII and to a less extend also the photochemical (k(p)) deactivation constant by means of photoregulation, which forms the basis of the quenching of chlorophyll a fluorescence. Although drought stress caused the deactivation of RCs leading to a decrease in the density of active RCs, the plants compensated by increasing the efficiency of the conversion of trapped excitation energy to electron transport beyond Q(A) (efficiency of exciton trapping/reaction centre: ET(o)/TR(o)). Subsequent damage to PSII might be the reason for the slow, or lack of recovery, for most of the parameters measured. PMID- 21696975 TI - The effect of ascorbic acid and dehydroascorbic acid on the root gravitropic response in Arabidopsis thaliana. AB - The effects of ascorbic acid (AA) and dehydroascorbic acid (DHA), one of products of the disproportionation of monodehydroascorbate (MDHA) by AA oxidase (AAO, EC 1.10.3.3), on the gravitropic curvature of Arabidopsis roots were characterized by biochemical and genetic approaches. Exogenously applied AA and DHA both stimulated root gravitropic responses in a concentration-dependent fashion. AA also changed the Indole-3-acetic acid (IAA) distribution in the roots after gravistimulation. In an effort to determine the relationship between AA and DHA in the gravitropic response, changes in the amount of reduced AA were evaluated in Arabidopsis under a variety of conditions. The expression level of an AAO gene (AAO1) was increased upon gravistimulation. Brassinolide (BL), indole-3-acetic acid (IAA), and AA also increased the transcript levels of this gene. Root elongation and the gravitropic response were both suppressed in the AA biosynthesis mutant, vtc1, which has a greatly reduced level of total AA. Furthermore, the line of AAO double mutants (aao1-1 X aao3-1, 41-21) showed a reduced gravitropic response and reduced root elongation. Taken together, the results of this study imply that both AA and DHA help to determine the redox environment for the root gravitropic response, but DHA, rather than AA, is a major player in the regulation of the gravitropic response mediated by AA in the roots of Arabidopsis thaliana. PMID- 21696976 TI - Expression analysis and functional characterization of apple MdVHP1 gene reveals its involvement in Na(+), malate and soluble sugar accumulation. AB - The vacuolar H(+)-pyrophosphatase (VHP) is a proton pump, which energizes transport across the tonoplast. The contributions of VHP to ion, organic acid and sugar storage are unclear in fruit. Here we characterized the role of an apple vacuolar H(+)-pyrophosphatase gene (MdVHP1) in Na(+), malate and soluble sugar accumulation. MdVHP1 expression was consistent with VHP activities in apple fruits at most developmental stages, and highly significantly correlated with Na(+) concentration during fruit development. In apple fruits treated in vitro (i.e., fruit-bearing branches were cultured in Hoagland solution containing each of salt, malate and sucrose, respectively, or irradiated by blue light), MdVHP1 expression was significantly correlated with Na(+) and malate transporter genes MdNHX1 and MdtDT, while subunit A of the vacuolar H(+)-ATPase (MdVHA-A) was significantly correlated with MdtDT and sucrose transporter gene (MdSUT1). In addition, MdVHP1 overexpression noticeably promoted Na(+) and malate accumulation, but slightly increased soluble sugar accumulation in transgenic apple callus and tomato fruit, partially by regulating transporter genes MdNHX1, MdtDT and MdSUT1. Taken together, it appears that MdVHP1 favorably contributes to Na(+), malate and soluble sugar accumulation in apple fruit. PMID- 21696977 TI - A simple method of substernal bar removal after the Nuss procedure. AB - The Nuss procedure for pectus excavatum is a well-known technique. Although there are numerous reports on the Nuss procedure, the reports on its removal are few. Removal has been done with many variations in the supine position, which involves bending the bar or bringing the bar beneath the operating table, which can prove to be troublesome and dangerous. Our simple technique allows easy removal of the substernal bar without bar bending. This technique was used in 21 patients without complication. PMID- 21696978 TI - An unusual fatal penetrating coronary artery injury with effective perioperative management. AB - We report here an uncommon anterior chest trauma with an unusual fatal penetrating coronary artery injury by pneumatic nail gun with effective perioperative management. While doing upholstery, a 32-year-old male patient accidentally stabbed by a pneumatic nail gun with injury to the anterior chest was brought to the emergency room of our hospital. Persistent chest pain with unstable vital signs and no external injury except for a faint ecchymosis on anterior chest were noted at arrival. Sixty-four-slice computed tomography (CT) scan revealed a foreign body completely embedded in the chest wall penetrating the left ventricle, with the coronary artery also suspected of being involved because of ST-T changes of V2 to V6 on electrocardiography. Three-dimensional reconstructive CT scans showed a penetrating injury to the left anterior descending coronary artery without complete transection. Thereafter, we performed the operation of nail removal with direct repair of coronary artery that was scheduled based on the image findings preoperatively, and the operation was smoothly performed without coronary artery cardiopulmonary bypass and grafting bypass effectively and simply. He was discharged uneventfully 14 days later. Another CT scan was performed which showed patency of repaired coronary artery 3 months later. PMID- 21696979 TI - Impact of UV-B irradiation on photosynthetic performance and chloroplast membrane components in Oryza sativa L. AB - The impact of UV-B radiation on photosynthetic related parameters was studied in Oryza sativa L. cv. Safari plants, after an UV-B irradiation performed 1h per day for 7days (between 8 and 14days after germination) with a ten narrow-band (lambda 311nm) that resulted in a total biological effective UV-B (UVB(BE)) of 2.975kJm( 2)day(-1) and a total of 20.825kJm(-2). Gas exchange measurements were severely affected, showing reductions higher than 80% in net photosynthesis (P(n)), stomatal conductance and photosynthetic capacity (A(max)), 1day after the end of the 7-days UV-B treatment. Similarly, several fluorescence parameters (F(o), F(v)/F(m), Fv'/Fm', phi(e), q(P) and q(E)) and thylakoid electron transport (involving both photosystems) were also severely reduced. Concomitantly, a decline of xanthophylls, carotenes, Chl a, Chl (a+b) and Chl (a/b) values was accompanied by the increase of the lipoperoxidation level in chloroplast membranes, altogether reflecting a loss of protection against oxidative stress. Seven days after of the end of UV-B treatment, most fluorescence parameters recovered, but in P(n), A(max), thylakoid electron transport rates, Chl a and lipid classes, as well as the level of lipoperoxidation, the impacts were even stronger than immediately after the end of stress, denoting a clear loss of performance of photosynthetic structures. However, only a moderate impact on total lipids was observed, accompanied by some changes in the relative weight of the major chloroplast membrane lipid classes, with emphasis on the decrease of MGDG and the increase of phospholipids. That suggested an ability to de novo lipid synthesis allowing qualitative changes in the lipid matrix. Notably, the leaves developed after the end of UV-B irradiation showed a much lower impact, with significantly decreased values only in P(n) and g(s), rises in several fluorescence parameters, thylakoid electron transport, photosynthetic pigments (xanthophylls and chls) and DEPS, while lipid classes presented values close to control. The results showed a global impact of UV-B in the photosynthetic structures and performance in irradiated leaves, but revealed also a low impairment extent in the leaves entirely developed after the end of the irradiation, reflecting a remarkable recovery of the plant after the end of stress, what could constitute an advantage under occasional UV-B exposure events in this vital worldwide staple food crop. PMID- 21696981 TI - Toll-like receptor-4 and vascular inflammation in diabetes: editorial. PMID- 21696980 TI - Burn-induced alterations in toll-like receptor-mediated responses by bronchoalveolar lavage cells. AB - Burn is associated with profound inflammation and activation of the innate immune system in multiple organ beds, including the lung. Similarly, toll-like receptors (TLR) are associated with innate immune activation. Nonetheless, it is unclear what impact burn has on TLR-induced inflammatory responses in the lung. METHODS: Male C57BL/6 mice were subjected to burn (3rd degree, 25% TBSA) or sham procedure and 1, 3 or 7 days thereafter, bronchoalveolar lavage (BAL) fluid was collected and cells were isolated and cultured in vitro with specific TLR agonists as follows: Zymosan (TLR-2), LPS (TLR-4) and CpG-ODN (TLR-9). Supernatants were collected 48 h later and assayed for inflammatory cytokine levels (IL-1beta, IL 6, IL-10, IL-17, TNF-alpha, KC, MCP-1, MIP-1alpha, MIP-1beta and RANTES) by Bioplex. RESULTS: BAL fluid from sham and burn mice did not contain detectable cytokine levels. BAL cells, irrespective of injury, were responsive to TLR-2 and TLR-4 activation. Seven days after burn, TLR-2 and TLR-4 mediated responses by BAL cells were enhanced as evidenced by increased production of IL-6, IL-17, TNF alpha, MCP-1, MIP-1beta and RANTES. CONCLUSIONS: Burn-induced changes in TLR-2 and TLR-4 reactivity may contribute to the development of post-burn complications, such as acute lung injury (ALI) and adult respiratory distress syndrome (ARDS). PMID- 21696983 TI - Critical appraisal of published smear layer-removal studies: methodological issues. AB - The smear layer phenomenon has been extensively addressed over the past 3 decades. However, there still are unanswered questions on this issue and the main responsible factor is the qualitative and nonreproducible character of most in vitro smear layer removal studies. The methodological reasons that led to the current lack of reliable conclusions on procedures aiming to remove the smear layer are comprehensively addressed. The limitations and outcomes related to different assessment methods are discussed as well. General speaking, the results by score-based conventional SEM studies are not trustworthy and reproducible. Computational routines able to automatically extract quantitative data of dentin morphology are necessary to minimize the human bias. An ideal experimental model should have a longitudinal observational character, in which a given dentin area can be observed at different times. The use of flat dentin samples should be avoided because of the influence of gravity as well as root canal anatomy on the final result of the chelating process. The experimental model also needs to take into consideration the amount and distribution of sclerotic dentin and irregular secondary dentin, otherwise the final results can be compromised. Inasmuch as there is a clear lack of scientific standard, simple comparative SEM evaluations are pointless at the present moment. The ideal experimental model to assess smear layer removal is not currently available. Therefore, further research efforts should be directed to the development of and testing of new methodological approaches to be used in the smear layer removal studies. The improvement of the experimental models is a requirement to draw up optimized clinical guidelines for the chemical treatment of the root dentin. PMID- 21696982 TI - Insights on the role of diabetes and geographic variation in patients with critical limb ischaemia. AB - BACKGROUND: Patients with critical limb ischaemia (CLI) unsuitable for revascularisation have a high rate of amputation and mortality (30% and 25% at 1 year, respectively). Localised gene therapy using plasmid DNA encoding acidic fibroblast growth factor (NV1FGF, riferminogene pecaplasmid) has showed an increased amputation-free survival in a phase II trial. This article provides the rationale, design and baseline characteristics of CLI patients enrolled in the pivotal phase III trial (EFC6145/TAMARIS). METHODS: An international, double blind, placebo-controlled, randomised study composed of 525 CLI patients recruited from 170 sites worldwide who were unsuitable for revascularisation and had non-healing skin lesions was carried out to evaluate the potential benefit of repeated intramuscular administration of NV1FGF. Randomisation was stratified by country and by diabetic status. RESULTS: The mean age of the study cohort was 70 +/- 10 years, and included 70% males and 53% diabetic patients. Fifty-four percent of the patients had previous lower-extremity revascularisation and 22% had previous minor amputation of the index leg. In 94% of the patients, the index leg had distal occlusive disease affecting arteries below the knee. Statins were prescribed for 54% of the patients, and anti-platelet drugs for 80%. Variation in region of origin resulted in only minor demographic imbalance. Similarly, while diabetic status was associated with a frequent history of coronary artery disease, it had little impact on limb haemodynamics and vascular lesions. CONCLUSIONS: Clinical characteristics and vascular anatomy of CLI patients with ischaemic skin lesions who were unsuitable for revascularisation therapy show little variations by region of origin and diabetic status. The findings from this large CLI cohort will contribute to our understanding of this disease process. This study is registered with ClinicalTrials.gov, number NCT00566657. PMID- 21696985 TI - Circulating cytokine concentrations in dogs with different degrees of myxomatous mitral valve disease. AB - Cytokines have been associated with the progression of congestive heart failure (CHF) in humans and may be implicated in the pathophysiology of myxomatous mitral valve disease (MMVD) in dogs. The aim of this study was to determine the serum concentrations of cytokines in dogs with MMVD. The study included 16 Cairn terriers with no or minimal mitral regurgitation (MR), 41 Cavalier King Charles Spaniels (CKCS) with different degrees of MR and 11 dogs of different breeds with CHF due to MMVD. Granulocyte-macrophage colony-stimulating factor, interferon gamma, interleukin (IL)-2, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, keratinocyte derived chemokine, interferon-gamma-induced protein and monocyte chemoattractant protein-1 (MCP-1) were measured using a canine-specific multiplex immunoassay. CHF dogs had significantly higher MCP-1 concentrations than dogs with no or minimal MR. Among the CKCS, IL-2 and IL-7 decreased with increasing left atrial size and IL-7 also decreased with increasing MR. IL-8 decreased with increasing left ventricular end-systolic internal dimensions. MCP-1 was increased in CHF dogs compared to healthy control dogs and IL-2, IL-7 and IL-8 decreased with increasing indices of disease severity. The results suggest a role for these cytokines in canine MMVD and CHF. PMID- 21696986 TI - Cytokine expression by pulmonary leukocytes from calves challenged with wild-type and leukotoxin-deficient Mannheimia haemolytica. AB - The objective of this study was to assess the role of leukotoxin (LKT) in modulating the pulmonary cytokine response of calves challenged with Mannheimia haemolytica. Thirty-six calves, seronegative to LKT and M. haemolytica whole cell antigen were divided into three groups (I, II and III). Calves in groups I and II were challenged by the intra-bronchial route with 25 mL of phosphate buffered saline (PBS) containing 0.44*10(9) cfu/mL of LKT deficient (lkt(-)) and 25 mL of PBS containing 0.31*10(9) cfu/mL of wild-type (wt) M. haemolytica serotype 1, respectively. Group III calves were challenged intra-bronchially with 25 mL of sterile PBS. Leukocytes were collected from broncho-alveolar lavage fluid (BALF) 4 days before and at 1, 3, and 6 days post-inoculation (p.i.). Expression of the following cytokines in the recovered leukocytes was measured using real-time PCR: interleukin (IL)-1beta, -8, -10, -12 (p40) and TNF-alpha. The amount of TNF-alpha produced was also quantified by ELISA. Although a statistically significant difference in the expression of these cytokines was not observed between groups challenged with the wt and lkt(-) strains, the wt infected group (II) did exhibit higher mean clinical scores. Overall, there was considerable variation in the composition of the BALF between the groups and by day 7 p.i., both lkt(-)- and wt challenged calves had seroconverted to M. haemolytica. PMID- 21696987 TI - Safety aspects of longitudinal administration of IGF-I/IGFBP-3 complex in neonatal mice. AB - OBJECTIVE: Very preterm birth is associated with a high risk of morbidity. Infants born very preterm have low serum levels of insulin-like growth factor I (IGF-I), that further decrease after birth. IGF-I is essential for brain development and low serum levels have been associated with retinopathy of prematurity. The present study aimed to investigate the effects of prolonged administration of a low dose of rhIGF-I/rhIGFBP-3 on glucose levels and total body weight, as well as liver, spleen and brain weights, and gray and subcortical white matter in newborn mice. DESIGN: The study was performed as three different trials. In all experiments C57BL/6N mice were injected with a rhIGF-I/rhIGFBP-3 complex or saline. In the first experimental trial, blood glucose levels were assessed 30 min, 1 h, 1.5 h, 3 h, 6 h, 24 h and 48 h after the rhIGF-I/rhIGFBP-3 or saline injection on postnatal day (PND) 6. In the second trial, mice were injected daily from PND 3 to 11 and sacrificed on PND 12 for analysis of IGF-I serum levels. In the third trial, body and organ weights and effects on gray and white matter were assessed on PND 18 after PND 3-11 treatments as above. Effects on gray and white matter were measured using immunoreactivity for microtubule associated protein-2 (MAP-2), myelin basic protein (MBP), 2',3'-cyclic nucleotide 3' phosphodiesterase (CNPase), neurofilament and oligodendrocyte lineage transcription factor 2 (Olig2). RESULTS: Blood glucose levels were unchanged in the rhIGF-I/rhIGFBP-3-treated group compared to baseline. In the control group glucose levels increased 30 min after the second saline injection; levels were not elevated at the subsequent time point. Three hours after the rhIGF-I/rhIGFBP 3 or saline, glucose levels were lower in rhIGF-I/rhIGFBP-3-treated animals than in saline treated (p=0.026). At PND 18, total body weight was higher in rhIGF I/rhIGFBP-3-treated mice compared with controls (p<0.05), but there were no differences between groups in brain, liver or spleen weights. No differences in gray matter area were found between groups. Analyses of white matter markers showed an increased number of Olig2-positive cells in rhIGF-I/rhIGFBP-3-treated mice compared with controls (p<0.001). There were no differences between groups in terms of MBP, CNPase or neurofilament immunoreactivity. CONCLUSIONS: Prolonged administration of rhIGF-I/rhIGFBP-3 did not have a negative impact on blood glucose levels and was beneficial for total body growth. PMID- 21696988 TI - The neurology of biotinidase deficiency. AB - Biotinidase deficiency is an autosomal recessively inherited metabolic disorder in which the enzyme, biotinidase, is defective and the vitamin, biotin, is not recycled. Individuals with biotinidase deficiency, if not treated with biotin, usually exhibit neurological and cutaneous abnormalities. Biotin treatment can ameliorate or prevent symptoms. Biotinidase deficiency meets the major criteria for inclusion in newborn screening programs. With the advent of universal newborn screening for the disorder, the "window-of-opportunity" to characterize the consequences of the untreated disease is essentially gone. To understand the neurology of biotinidase deficiency, we must depend on what is already known about symptomatic individuals with the disorder. Therefore, in this review, the neurological findings of symptomatic individuals with profound biotinidase deficiency have been compiled to catalog the characteristic features of the disorder and the consequences of biotin treatment on these findings. In addition, based on the available evidence, I have speculated on the cause of neurological problems associated with the disorder. Future studies in biotinidase-deficient animals should allow us to demonstrate more definitively if these speculations are correct. PMID- 21696989 TI - Acute melioid community-acquired pneumonia. AB - OBJECTIVES: To better understand the characteristics of patients with acute melioid community-acquired pneumonia (CAP) on emergency department (ED) arrival, and the risk factors in patients with acute melioid CAP that differ from those in patients with severe CAP of causes other than melioidosis. METHODS: This was a retrospective case-control study. RESULTS: During the study period, a total of 15 patients suffered from acute melioid CAP. Comparison with 60 patients with severe CAP of causes other than melioidosis, revealed that visit to the ED in the rainy season, shock on arrival, diabetes, poor sugar control with glycemia >=250mg/dl, chest radiograph with cavity formation, and poor clinical outcome, were significantly predominant in patients with acute melioid CAP. Multivariate logistic regression analysis indicated that poor sugar control with glycemia >=250mg/dl (odds ratio (OR) 38.3, 95% confidence interval (CI) 3.6-406.2; p<0.01), visiting the ED during the rainy season (OR 13.7, 95% CI 2.3-80.9; p<0.01), and shock on ED arrival (OR 18.7, 95% CI 1.8-192.8; p=0.01) were independent risk factors for patients with CAP caused by Burkholderia pseudomallei. CONCLUSIONS: Physicians in melioidosis endemic areas should administer antimicrobials covering B. pseudomallei to patients with CAP who visit the ED during the rainy season, who have poor sugar control with glycemia >=250mg/dl, and who are in shock on ED arrival, to facilitate timely, appropriate antibiotic therapy and lower the mortality rate. PMID- 21696990 TI - Clinicopathological features and the practice of diagnosing infectious cutaneous granulomas in Egypt. AB - OBJECTIVE: To present the clinicopathological features and the practice of diagnosing infectious cutaneous granulomas in Egypt. METHODS: This study included all cases diagnosed with infectious cutaneous granuloma during the period 2004 2010 at Al-Hussein University Hospital, Cairo. Clinical and histological features were recorded, along with the positivity rate (PR) for each diagnostic method. RESULTS: This study included 233 cases (150 males and 83 females) with a mean age of 47 years. Three groups of infection were recorded: bacterial infections (73.8% Mycobacterium and 3.9% non-Mycobacterium), parasitic infestations (16.7%), and deep fungal infections (5.6%). Tuberculosis cases formed the largest granuloma group (40.8%), followed by leprosy (31.7%) and leishmaniasis (15.9%). A total of 36 cases were diagnosed by direct smear (PR 15.5%), 61 cases by skin biopsy (PR 31.0%), 84 cases by intradermal test (PR 63.6%), 26 cases by serological tests (PR 60.5%), 18 cases by tissue culture (PR 69.2%), and eight cases by PCR (PR 100%). CONCLUSIONS: Mycobacterial infections constitute the most common infectious cutaneous granulomas among Egyptians. Routine methods such as direct smear, skin biopsy, and intradermal tests remain the most commonly applied and economical methods for diagnosis in developing countries, although specific methods such as tissue culture and PCR have higher positivity rates in the diagnosis. PMID- 21696991 TI - A novel statistical morphometry imaging method for differentiating long bone geometry: methodological development and application with adolescent idiopathic scoliosis (AIS) patients. AB - Non-invasive quantification of bone shape is crucial in orthopaedic research. The primary objective of this study was to develop an automated statistical morphometry method for comparing the cross-sectional images of normal and diseased bones. The secondary objective involved demonstrating the effectiveness of the proposed method in distinguishing AIS patients from normal controls. This framework is composed of bone segmentation followed by measurements of maximum and minimum bone diameters, inter-group and intra-group statistical morphometry, and statistical analysis of bone thickness. The proposed framework was applied to detect bone morphological abnormality in adolescent idiopathic scoliosis (AIS) patients. The forearm bones in cross-sectional peripheral quantitative computed tomography (pQCT) images from 23 AIS patients and 16 normal controls were analyzed. The radius outer contour was found to be rounder and the radius cortical bone was thinner in AIS patients compared to normal controls. PMID- 21696993 TI - SPES/SCOPA and MDS-UPDRS: formulas for converting scores of two motor scales in Parkinson's disease. AB - BACKGROUND: Motor impairment in Parkinson's disease (PD) can be evaluated with the Short Parkinson's Evaluation Scale/Scales for Outcomes in Parkinson's disease (SPES/SCOPA) and the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The aim of this study was to determine equation models for the conversion of scores from one scale to the other. METHODS: 148 PD patients were evaluated with the SPES/SCOPA-motor and the MDS-UPDRS motor examination. Linear regression was used to develop equation models. RESULTS: Scores on both scales were highly correlated (r = 0.88). Linear regression revealed the following equation models (explained variance: 78%): CONCLUSION: With the equation models identified in this study, scores from SPES/SCOPA-motor can be converted to scores from MDS-UPDRS motor examination and vice versa. PMID- 21696992 TI - Experimental and computational analysis of soft tissue stiffness in forearm using a manual indentation device. AB - A hand held stiffness meter can be used to measure indentation stiffness of human soft tissues, sensitively altered, e.g., by pathological tissue swelling. Under indentation load, the relative contribution of each soft tissue component (i.e., skin, adipose tissue and muscle) to the biomechanical response is not known. In the present study, we evaluated the biomechanical role of different soft tissues in relaxed, physically stressed and oedemic human forearm. Soft tissue stiffness of the forearms of nine healthy human subjects was measured under four different test protocols: (1) forearm at rest, (2) forearm under isometric flexor loading, (3) forearm under isometric extensor loading, and (4) forearm under venous occlusion. In (2) and (3) the loading forces were monitored using a dynamometer, and in (4) the soft tissue swelling was induced by venous occlusion using a pressure cuff. At the site of indentation, thickness of different tissue layers (skin, adipose tissue and muscle) was measured using B-mode ultrasound imaging. Layered, hyperelastic finite element (FE) model of the indentation measurement was created and the model response was matched with that of the stiffness meter to determine the elastic modulus for each tissue in the model. Optimized values of the elastic modulus for skin and adipose tissue at rest were 210 kPa and 1.9 kPa, respectively. Further, significance of the variations in stiffness of different tissues on the indentation response was tested. Experimentally, indentation stiffness of the forearm increased during isometric extensor and flexor loads as well as under venous occlusion by 53, 91 and 15%, respectively. The FE model could reproduce the experimental responses primarily by the increased modulus of skin; 112% (446 kPa), 210% (651 kPa) and 21% (254 kPa) under flexor and extensor loading as well as during venous occlusion, respectively. The indentation response was 9-16 times more sensitive to changes in the mechanical properties of skin than those of adipose tissue and muscle. In conclusion, the present stiffness meter may be used to quantify in vivo mechanical properties of soft tissues in the forearm, sensitively modulated by soft tissue swelling and muscle loading. PMID- 21696994 TI - Policy implications of neighbourhood effects on health research: towards an alternative to poverty deconcentration. AB - While researchers build an evidence that where one lives has an independent effect on their health, the work of translating this research into effective policies is impeded by problematic assumptions about urban poverty. In light of new experimental studies on the health effects of neighbourhoods using housing mobility programs, this paper addresses the politics of poverty deconcentration that implicitly undergirds much of this new research. By raising critiques of these programs that are rarely considered in the health literature, this paper challenges the central treatment of poverty dispersal in the new experimental literature. Poverty dispersal policies, without addressing the competitive urban structure, simply react to symptoms of poverty and ignore the underlying factors that shape the neighbourhood resources that structure health outcomes. These factors include municipal fragmentation, exclusionary land use planning, and municipal competition. Effective social policies aimed at improving neighbourhood influence on health must address the competitive and fragmented municipal structure that produces a patchwork of affluence and deprivation in today's urban America. PMID- 21696995 TI - Activity space environment and dietary and physical activity behaviors: a pilot study. AB - This study examined relationships among individual demographics, environmental features (e.g., fast food outlet density, park land use) of residential neighborhoods and activity spaces, and weight-related behaviors (diet, physical activity). Participants' movement was tracked for 7 days using global positioning systems (GPS). Two activity space measures (one standard deviation ellipse, daily path area) were derived from the GPS data. Activity spaces were generally larger than residential neighborhoods; environmental features of residential neighborhoods and activity spaces were weakly associated; and some activity space environmental features were related to dietary behaviors. Activity spaces may provide new insights into environmental influences on obesity-related behaviors. PMID- 21696996 TI - The hippocampus: hub of brain network communication for memory. AB - A complex brain network, centered on the hippocampus, supports episodic memories throughout their lifetimes. Classically, upon memory encoding during active behavior, hippocampal activity is dominated by theta oscillations (6-10Hz). During inactivity, hippocampal neurons burst synchronously, constituting sharp waves, which can propagate to other structures, theoretically supporting memory consolidation. This 'two-stage' model has been updated by new data from high density electrophysiological recordings in animals that shed light on how information is encoded and exchanged between hippocampus, neocortex and subcortical structures such as the striatum. Cell assemblies (tightly related groups of cells) discharge together and synchronize across brain structures orchestrated by theta, sharp waves and slow oscillations, to encode information. This evolving dynamical schema is key to extending our understanding of memory processes. PMID- 21696997 TI - Social effects of oxytocin in humans: context and person matter. AB - Building on animal research, the past decade has witnessed a surge of interest in the effects of oxytocin on social cognition and prosocial behavior in humans. This work has generated considerable excitement about identifying the neurochemical underpinnings of sociality in humans, and discovering compounds to treat social functioning deficits. Inspection of the literature, however, reveals that the effects of oxytocin in the social domain are often weak and/or inconsistent. We propose that this literature can be informed by an interactionist approach in which the effects of oxytocin are constrained by features of situations and/or individuals. We show how this approach can improve understanding of extant research, suggest novel mechanisms through which oxytocin might operate, and refine predictions about oxytocin pharmacotherapy. PMID- 21696998 TI - The human Turing machine: a neural framework for mental programs. AB - In recent years much has been learned about how a single computational processing step is implemented in the brain. By contrast, we still have surprisingly little knowledge of the neuronal mechanisms by which multiple such operations are sequentially assembled into mental algorithms. We outline a theory of how individual neural processing steps might be combined into serial programs. We propose a hybrid neuronal device: each step involves massively parallel computation that feeds a slow and serial production system. Production selection is mediated by a system of competing accumulator neurons that extends the role of these neurons beyond the selection of a motor action. Productions change the state of sensory and mnemonic neurons and iteration of such cycles provides a basis for mental programs. PMID- 21696999 TI - Plasma levels of vascular endothelial growth factor during and after radiotherapy in combination with celecoxib in patients with advanced head and neck cancer. AB - Celebrex and radiotherapy in advanced head and neck cancer. This phase I dose escalation study seeks to determine the phase II recommended dose of cyclooxygenase type 2 (COX-2) inhibitor in patients with locally advanced squamous cell head and neck (H&N) cancer, treated with accelerated radiotherapy. Anti-vasculogenic effect of this treatment on serum vascular endothelial growth factor (VEGF) is examined. Patients were irradiated with curative intent (72Gy in 6weeks). Celecoxib was administered throughout the radiotherapy course. Serum VEGF level were tested during radiotherapy and in follow-up. Tumor specimens were stained to quantify the COX-2 expression. Thirty-two patients completed the treatment. The dose of celecoxib was escalated (200, 400 and 800mg bid, then de escalated to 600mg bid). The acute toxicity related to the treatment in the first and second cohort did not reach grade III; in the third cohort three patients had grade III radiation toxicity and one had celecoxib-related toxicity. In the last fourth cohort the toxicity was acceptable. Significant VEGF level drop (p=0.011) was found between radiation day 1 and post-treatment visit. Significant decrease (p=0.022) of the VEGF level was shown in patients with high COX-2 expression in the tumor. Phase II recommended dose of celecoxib combined with accelerated radiotherapy in advanced H&N cancer was 600mg bid. A significant decrease of the post-treatment serum VEGF level compared to the initial level was noticed only in patients with high COX-2 expression in tumors. PMID- 21697000 TI - Prognostic significance of tumor-related genes hypermethylation detected in cancer-free surgical margins of oral squamous cell carcinomas. AB - Oral squamous cell carcinoma (OSCC) is characterized by high mortality rates. High incidence of local recurrences in the normal-appearing surgical margins of OSCC patients indicates the existence molecular alterations, including DNA methylation, which could not be detectable by histopathologic analysis. The objective of our study was to determine correlation of tumor-related genes hypermethylation detected in histopathologically negative surgical margins with clinical and prognostic parameters. The genes selected for methylation analysis covered a wide range cellular processes including cell cycle control (p16), apoptosis (DAPK and RASSF1A), Wnt signaling (APC, WIF1 and RUNX3), cell-cell adhesion (E-cad), and DNA repair (MGMT and hMLH1). All of 47 patients had histologically confirmed negative surgical margins. For each of patient, samples from primary malignant tissue and the two consecutive surgical margins were taken at the time of surgery. DNA methylation was determined by multiplex nested methylation-specific PCR. Twenty-seven patients were margin-positive for promoter hypermethylation of at least one gene under study. The presence of DAPK promoter hypermethylation detected in surgical margins was associated with the decreased overall survival (p=0.004, log rank test). Multivariate analysis revealed that DAPK promoter hypermethylation in surgical margins is an independent prognostic factor for overall survival, HR=4.105 (1.458-11.555, 95% CI, p=0.007). Hypermethylation of other tumor-related genes under study did not have prognostic significance. These results demonstrate that DNA hypermethylation in histologically negative surgical margins is a frequent event. Promoter hypermethylation of DAPK gene detected in surgical margins may be a useful molecular marker for the poor survival in OSCC patients. Further investigation into the therapeutic potential of these findings in OSCC is warranted. PMID- 21697001 TI - FT-IR, FT-Raman spectroscopy and computational study of (E)-4-((anthracen-9 ylmethylene)amino)-N-carbamimidoylbenzene sulfonamide. AB - The infrared and Raman spectra of (E)-4-((anthracen-9-ylmethylene)amino)-N carbamimidoylbenzene sulfonamide have been recorded and analysed. Geometry and harmonic vibrational wavenumbers were calculated theoretically using Gaussian03 set of quantum chemistry codes. The data obtained from vibrational wavenumber calculations are used to assign vibrational bands found in infrared and Raman spectra of the studied molecule. The red-shift of the NH stretching band in the infrared spectrum from the computed wavenumber indicates the weakening of the NH bond. The NH stretching band has split into a doublet in the IR spectrum owing to the Davydov coupling between neighbouring units. The geometrical parameters of the title compound are in agreement with the reported similar derivatives. The calculated first hyperpolarizability is comparable with the reported value of similar structures and may be an attractive object for further studies on non linear optics. The important thermodynamical parameters are also reported. PMID- 21697002 TI - Low-temperature phase transition in [Mn(OS(CH3)2)6](ClO4)2 studied by single crystal X-ray diffraction, infrared absorption and Raman scattering spectroscopies. AB - Single crystal X-ray diffraction studies of [Mn(OS(CH3)2)6](ClO4)2 have shown that the low temperature phase transition, detected by differential scanning calorimetry (DSC) at about 223 K, is associated with the crystal symmetry's reduction from an orthorhombic crystallographic system (Fdd2, No. 43) to a monoclinic one (Cc, No. 9). The analysis of the full width at half maximum of the bands connected with: deltad(OClO)F2 and rho(CH3) vibrational modes in the FT-IR and FT-RS spectra, respectively, registered in the function of temperature, proved that the reorientational motions of ClO4- anions and CH3 groups from (CH3)2SO ligands, began to slow down at temperatures below the phase transition at about 223K. Mean values of activation energy for ClO4- reorientation in the high temperature phase I and low temperature phase II are: Ea(I)~14 kJ mol(-1) and Ea(II)~10 kJ mol(-1), respectively. Analogous values for CH3 reorientation are: Ea(I)~23 kJ mol(-1) and Ea(II)~1 kJ mol(-1), respectively. PMID- 21697003 TI - Photoconductivity and photoluminescence of ZnO nanoparticles synthesized via co precipitation method. AB - Photoconductivity and photoluminescence studies of ZnO nanoparticles (NPs) synthesized by co-precipitation method capped with thioglycerol are carried out. The effect of annealing at 300 degrees C is also studied. The transmission electron micrograph (TEM) and X-ray diffraction (XRD) pattern confirm the hexagonal wurtzite structure of ZnO nanoparticles. The UV-vis absorption spectrum of ZnO NPs shows blue shift of absorption peak as compared to bulk ZnO. The photoluminescence (PL) spectra of as-synthesized ZnO NPs show band edge emission as well as blue-green emission. After annealing band edge emission is quenched. Photocurrent is found to vary super linearly at high voltage for both as synthesized as well as annealed ZnO NPs. Time resolved rise and decay photocurrent spectra are found to exhibit anomalous photoconductivity for as synthesized as well as annealed ZnO NPs wherein the photocurrent decreases even during steady illumination. PMID- 21697004 TI - Ionic liquid-based single drop microextraction of ultra-trace copper in food and water samples before spectrophotometric determination. AB - In this work, room temperature ionic liquid (RTIL) 1-butyl-3-methylimidazolium hexafluorophosphate ([C4mim]PF6) was used as extractant in single drop microextraction (SDME). The traditionally volatile organic extractants were substituted by this green reagent, which changed SDME preconcentration into environmentally friendly method, relatively. After this pretreatment, ultra-trace copper in water and food samples could be accurately detected by spectrophotometer. This study was focused on the improvement of the analytical performance of spectrophotometric determination, expanding its applications. The influence factors relevant to IL-SDME, such as absorption spectra of complex, drop volume of RTIL, stirring rate and time, concentration of chelating agent, pH, and salt effect were studied systematically. Under the optimal conditions, the limit of detection (LOD) was 0.15 MUg L(-1) with an enhancement factor (EF) of 33. The proposed method was green, simple, rapid, sensitive, and cost efficient. PMID- 21697005 TI - Solid phase extraction of gold(III) on attapulgite modified with triocarbohydrazide prior to its determination in environmental samples by ICP OES. AB - The first study on the high efficiency of triocarbohydrazide modified attapulgite as solid-phase extractant for preconcentration of trace Au(III) prior to the measurement by inductively coupled plasma optical emission spectrometry (ICP-OES) has been reported. Experimental conditions for effective adsorption of trace levels of Au(III) were optimized with respect to different experimental parameters using batch and column procedures in detail. At pH 3, Au(III) could be quantitatively adsorbed on the new sorbent, and the adsorbed Au(III) could be completely eluted from the sorbent surface by 2.0mL 1.0molL(-1) of HCl+2% CS(NH(2))(2) solution. An enrichment factor of 150 was accomplished. Moreover, common interfering ions did not interfere in both separation and determination. The maximum adsorption capacity of the sorbent for Au(III) was found to be 66.7mgg(-1). The detection limit (3sigma) of this method was 0.32MUgL(-1) and the relative standard deviation (RSD) was 3.3% (n=8). The method, with high selectivity, sensitivity and reproducibility, was validated using certified reference materials, and had been applied for the determination of trace Au(III) with satisfactory results. PMID- 21697006 TI - Evaluation of sericin/collagen membranes as prospective wound dressing biomaterial. AB - Sericin, a silk protein, has high potential for use in biomedical applications. In this study, wound dressing membranes of Sericin (S) and Collagen (C) were prepared by glutaraldehyde cross-linking at S/C; 2:1, 1:1, 1:2, and 0:1 weight ratios. They were stable in water for 4 weeks. However, increasing the proportion of sericin had decreasing effect on the membrane stability. Water swelling property of membranes was enhanced with sericin. The highest water swelling was obtained in 1:1 group (9.06 g/g), but increasing collagen or sericin content in the membranes had a diminishing effect. Highest water vapor transmission rate was obtained with 1:2 group (1013.80 g/m(2)/day). Oxygen permeability results showed that 1:2 (7.67 mg/L) and 2:1 (7.85 mg/L) S/C groups were better than the other groups. While sericin decreased the tensile strength and elongation of membranes, it increased modulus. Sericin also increased brittleness of membranes, but their UTS range (24.93-44.92 MPa) was still suitable for a wound dressing. Membranes were not penetrable to microorganisms. Cytotoxicity studies showed that fibroblasts and keratinocytes attached and gained their characteristic morphologies. They also proliferated on membranes significantly. After 1 week of subcutaneous implantation, a fibrous capsule formed around all membranes with an acute inflammation. Sericin containing membranes showed signs of degradation (at 2nd week), while collagen only membranes remained largely intact. Eventually, sericin containing membranes degraded in 3 weeks with moderate inflammatory response. Overall results suggest that sericin/collagen membranes would be favorable as wound dressing material when sericin ratio is less than or equal to the collagen component. PMID- 21697007 TI - Reduced sleep-associated consolidation of declarative memory in attention deficit/hyperactivity disorder. AB - OBJECTIVE: Sleep supports the consolidation of declarative memory. Patients with attention-deficit/hyperactivity disorder (ADHD) are not only characterized by sleep problems but also by declarative memory deficits. Given that the consolidation of declarative memory during sleep is supported by slow oscillations, which are predominantly generated by the prefrontal cortex, and that ADHD patients display low prefrontal brain activity, we assumed that ADHD patients show reduced sleep-associated consolidation of declarative memory. METHODS: The impact of sleep on the consolidation of declarative memory was examined with a picture recognition task. Twelve ADHD patients (10-16 years) and 12 healthy controls participated in two experimental conditions: in the sleep condition, learning was performed in the evening and picture recognition was tested after nocturnal sleep; in the wake condition, learning was conducted in the morning while retrieval took place after a day of wakefulness. RESULTS: Analyses of recognition accuracy revealed reduced sleep-associated enhancement of recognition accuracy in ADHD. While sleep-associated enhancement of recognition accuracy was correlated with slow oscillation power during non-REM sleep in healthy controls, no such correlations were observed in ADHD. CONCLUSIONS: These data indicate a deficit in sleep-associated consolidation of declarative memory in ADHD. Moreover, our results suggest reduced functionality of slow oscillations in sleep-associated consolidation of declarative memory in ADHD. PMID- 21697008 TI - Effects of adenotonsillectomy on R-R interval and brain natriuretic peptide levels in children with sleep apnea: a preliminary report. AB - OBJECTIVES: Obstructive sleep apnea is associated with decreased R-R interval length and overall R-R interval variability in the electrocardiogram along with increased morning brain natriuretic peptide (BNP) blood levels. These findings indicate enhanced sympathetic tone and cardiac strain. In this study, it was hypothesized that adenotonsillectomy (AT) in children with sleep apnea is accompanied by improvement in polysomnography indices, increase in length and variability of R-R interval, and reduction in BNP levels. METHODS: Polysomnography and measurements of morning BNP levels were performed before and 4-6months after AT. Mean and standard deviation of R-R interval were calculated from polysomnography electrocardiogram recordings. RESULTS: Twenty-one children were studied. Apnea-hypopnea index and log-transformed BNP levels decreased postoperatively from 8.4+/-7.6 episodes/h and 2.2+/-0.7, to 1.8+/-1.4 episodes/h and 1.9+/-0.3, respectively (p<0.05). Mean R-R interval increased from 703.2+/ 137.4ms (Stage 2), 699.3+/-135.8ms (Stage 3), 707.4+/-128.9ms (Stage 4) and 660.5+/-140.1ms (Stage REM), to 773.5+/-122.7ms (Stage 2), 765.7+/-73.7ms (Stage 3), 771.2+/-71.6ms (Stage 4), and 738.6+/-81.7ms (Stage REM), respectively (p<0.05 for comparisons pre- vs. post-operatively). Standard deviation of R-R in Stage 2 increased from 88.5+/-29.6 to 122.7+/-67ms (p=0.045). CONCLUSIONS: Increase in nocturnal length of R-R interval and decrease in BNP levels after AT for sleep apnea may reflect postoperative reduction in sympathetic tone and cardiac strain. PMID- 21697009 TI - Melanin concentrating hormone in central hypersomnia. AB - BACKGROUND: Narcolepsy with cataplexy (NC) is a disabling disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations, due to a deficient hypocretin/orexin neurotransmission. Melanin concentrating hormone (MCH) neurons involved in the homeostatic regulation of REM sleep are intact. We hypothesized that an increased release of MCH in NC would be partly responsible for the abnormal REM sleep manifestations. METHODS: Twenty-two untreated patients affected with central hypersomnia were included: 14 NC, six idiopathic hypersomnia with long sleep time, and two post-traumatic hypersomnia. Fourteen neurological patients without any sleep disorders were included as controls. Using radioimmunoassays, we measured hypocretin-1 and MCH levels in cerebrospinal fluid (CSF). RESULTS: The MCH level was slightly but significantly lower in patients with hypersomnia (98 +/- 32 pg/ml) compared to controls (118 +/ 20 pg/ml). After exclusion of patients affected with post-traumatic hypersomnia the difference became non-significant. We also failed to find any association between MCH level and hypocretin level, the severity of daytime sleepiness, the number of SOREMPs, the frequency of cataplexy, and the presence of hypnagogic hallucinations or sleep paralysis. CONCLUSION: This study reports the first measurement of MCH in CSF using radioimmunoassay technology. It appears to be a non-informative tool to differentiate etiologies of central hypersomnia with or without REM sleep dysregulation. PMID- 21697010 TI - Adaptation of Listeria monocytogenes to oxidative and nitrosative stress in IFN gamma-activated macrophages. AB - IFN-gamma-activated macrophages are considered to be the primary effector cells in host defense against Listeria monocytogenes infections. However despite the induction of the complex host defense mechanisms, survival of L. monocytogenes in activated macrophages is still observed. Here we used a whole genome-based transcriptome approach to examine for bacterial genes specifically induced in IFN gamma-activated macrophages. We demonstrated that cells activated by IFN-gamma had elevated oxidative and nitrosative stress levels in both the activated macrophages as well as in the intracellular replicating bacteria isolated from these infected cells. We found that a subset of 21 transcripts were specifically differentially regulated in bacteria growing in cells pretreated with IFN-gamma. Bioinformatics and functional analysis revealed that many of these genes have roles involved in overcoming oxidative stress and contribute to bacterial survival within activated macrophages. We detected increased transcription of the putative trpE gene of L. monocytogenes, encoding an anthranilate synthase, in bacteria growing in IFN-gamma cells indicating host cell metabolic restriction of bacterial growth. Indeed we found enhanced activation of host cell genes involved in the kynurenine pathway indicating an increased need of L. monocytogenes for tryptophan during replication in IFN-gamma-activated macrophages. PMID- 21697011 TI - Biofilms in drinking water and their role as reservoir for pathogens. AB - Most microorganisms on Earth live in various aggregates which are generally termed "biofilms". They are ubiquitous and represent the most successful form of life. They are the active agent in biofiltration and the carriers of the self cleaning potential in soils, sediments and water. They are also common on surfaces in technical systems where they sometimes cause biofouling. In recent years it has become evident that biofilms in drinking water distribution networks can become transient or long-term habitats for hygienically relevant microorganisms. Important categories of these organisms include faecal indicator bacteria (e.g., Escherichia coli), obligate bacterial pathogens of faecal origin (e.g., Campylobacter spp.) opportunistic bacteria of environmental origin (e.g., Legionella spp., Pseudomonas aeruginosa), enteric viruses (e.g., adenoviruses, rotaviruses, noroviruses) and parasitic protozoa (e.g., Cryptosporidium parvum). These organisms can attach to preexisting biofilms, where they become integrated and survive for days to weeks or even longer, depending on the biology and ecology of the organism and the environmental conditions. There are indications that at least a part of the biofilm populations of pathogenic bacteria persists in a viable but non-culturable (VBNC) state and remains unnoticed by the methods appointed to their detection. Thus, biofilms in drinking water systems can serve as an environmental reservoir for pathogenic microorganisms and represent a potential source of water contamination, resulting in a potential health risk for humans if left unnoticed. PMID- 21697012 TI - Improving human hemato-lymphoid-system mice by cytokine knock-in gene replacement. AB - Human hemato-lymphoid-system mice hold great promise for modeling and studying important human diseases in vivo, and to enable vaccine testing. Until now, several major limitations have restricted the utility of human hemato-lymphoid system mice in translational research. Recently, however, significant advances have been made in improving these mice, based on the delivery of human cytokines to create a better environment for human cells in the mouse host. In this review, we discuss the various approaches with a particular focus on improving human hemato-lymphoid-system mice by human cytokine knock-in gene replacement. PMID- 21697013 TI - Emerging Tim-3 functions in antimicrobial and tumor immunity. AB - T cell immunoglobulin-3 (Tim-3) has been identified as a marker of differentiated interferon-gamma-producing CD4(+) T helper type 1 and CD8(+) T cytotoxic type 1 cells. The interaction of Tim-3 with its ligand, galectin-9 (Gal-9), induces cell death, and in vivo blockade of this interaction results in exacerbated autoimmunity and abrogation of tolerance in experimental models, establishing Tim 3 as a negative regulatory molecule. Recent studies have uncovered additional mechanisms by which Tim-3 negatively regulates T cell responses, such as promoting the development of CD8(+) T cell exhaustion and inducing expansion of myeloid-derived suppressor cells. In contrast to this inhibitory effect on T cells, Tim-3-Gal-9 interaction promotes macrophage clearance of intracellular pathogens. Here, we focus on the emerging role for Tim-3 in tumor and antimicrobial immunity. PMID- 21697015 TI - Determinants of quality of life after epilepsy surgery: systematic review and evidence summary. AB - We systematically reviewed evidence-based determinants of health-related quality of life (QOL) in adults undergoing epilepsy surgery and assessed the effect of study methods. Medline, Embase, and the Cochrane library (1950-2008) were searched systematically. Two authors independently performed every step of the review. We obtained the proportion of studies reporting statistically significant positive or negative impact on QOL. Of 39 eligible studies, 32 assessed the impact of surgery on QOL and 29 (90.6%) found a significant positive effect. The most prevalent preoperative determinant was psychological function. Seizure freedom was the most prevalent postoperative determinant (80% of studies), followed by antiepileptic drug adverse events, employment status, and psychological function. Psychosocial (95%), physical (91%), and overall QOL (90%) domains improved most frequently, whereas role limitation (63%) and cognition (78%) improved least frequently. Methods, choice of instrument, and time of measurement influenced QOL outcomes and should be carefully chosen in future studies. PMID- 21697016 TI - Managing apathy. PMID- 21697014 TI - Microbiome influences on insect host vector competence. AB - Insect symbioses lack the complexity and diversity of those associated with higher eukaryotic hosts. Symbiotic microbiomes are beneficial to their insect hosts in many ways, including dietary supplementation, tolerance to environmental perturbations and maintenance and/or enhancement of host immune system homeostasis. Recent studies have also highlighted the importance of the microbiome in the context of host pathogen transmission processes. Here we provide an overview of the relationship between insect disease vectors, such as tsetse flies and mosquitoes, and their associated microbiome. Several mechanisms are discussed through which symbiotic microbes can influence the ability of their host to transmit pathogens, as well as potential disease control strategies that harness symbiotic microbes to reduce pathogen transmission through an insect vector. PMID- 21697019 TI - Presentation, diagnosis, and treatment of oesophageal motility disorders. AB - Whilst the current treatment of achalasia is well understood, the management of other oesophageal disorders is still debated, as these are rare and the literature on their clinical presentation and management is scarce. The following review describes the clinical presentation of oesophageal motility disorders, gives an overview of their diagnosis in light of the new advances in oesophageal motility testing, and provides an evidence-based approach to their management with different forms of treatment (medical, endoscopic, and minimally invasive). PMID- 21697018 TI - [Usefulness of genetic tests in familial hypocalciuric hypercalcemia with atypical clinical presentation]. AB - OBJECTIVES: Biochemical tests related to calcium and phosphorus metabolism have traditionally been considered as a reliable tool to differentiate familial hypocalciuric hypercalcemia (FHH) from primary hyperparathyroidism (PHPT). However, diagnosis may sometimes be difficult even for experienced clinicians. Our objective was to assess the accuracy of diagnostic tests in FHH and the circumstances in which genetic studies are required. PATIENTS AND METHODS: A descriptive study was conducted of two families with hypercalcemia and suspected atypical FHH. Urinary calcium excretion was measured in 24-hour urine using different tests (calcium excretion (CE), urinary calcium/creatinine clearance ratio (UCCR)), and serum PTH and 25-hydroxyvitamin D levels were tested. Index cases underwent genetic study. RESULTS: One patient from the first family showed overt, persistent hypercalciuria with values more consistent with PHPT than with FHH if we consider, as proposed by guidelines, a UCCR lower than 0.01 as diagnostic of FHH and a value higher than 0.02 as diagnostic of PHPT. The index case of the second family underwent surgery for a parathyroid adenoma. Both cases had a mutation c. 164C>T (Pro55Leu) in exon 2 in heterozygosis. CONCLUSIONS: According to current clinical guidelines, definitive diagnosis of FHH requires genetic confirmation, which allowed in our case for detection of two families with FHH and atypical clinical presentations. We think that rational use of genetic tests may avoid unnecessary surgery and excess monitoring costs. PMID- 21697017 TI - A phase II study of sagopilone (ZK 219477; ZK-EPO) in patients with breast cancer and brain metastases. AB - Treatments for women with recurrent brain metastases from breast cancer are limited. In this phase II study,we administered sagopilone to patients with breast cancer and brain metastases. We observed modest activity with a central nervous system objective response rate of 13.3%; however, median PFS was disappointing. Further studies should focus on other agents to treat this challenging clinical problem. BACKGROUND: Patients with progressive metastatic breast cancer to the central nervous system (CNS) have limited treatment options. PATIENTS AND METHODS: We conducted a phase II study of sagopilone, an epothilone B analogue that crosses the blood-brain barrier, in patients with breast cancer brain metastases. Women were treated with 16 mg/m(2) or 22 mg/m(2) intravenously every 21 days. The primary endpoint was CNS objective response rate (ORR). Secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). Using modified, high-resolution magnetic resonance angiography (MRA), we also evaluated changes in vessel tortuosity with treatment. RESULTS: Fifteen women were enrolled; all had progressive CNS disease despite whole-brain radiotherapy. Two patients achieved a partial response (ORR, 13.3%) and remained in the study for 6 cycles. Responses were not associated with normalization of tumor-associated vessels on correlative imaging studies. Median PFS and OS were 1.4 months and 5.3 months, respectively. The most common grade 3 toxicities were lymphopenia and fatigue. Enrollment was stopped prematurely because of limited observed activity and slow accrual. CONCLUSIONS: Sagopilone was associated with modest CNS activity in patients with breast cancer; however median PFS was disappointing. Further studies should examine other potentially active agents and/or combinations for this challenging clinical problem. PMID- 21697021 TI - Ibuprofen worsens Streptococcus pyogenes soft tissue infections in mice. AB - BACKGROUND: Group A streptococcus (GAS) is a common cause of soft tissue infection. Nonsteroidal anti-inflammatory drugs have been reported to worsen GAS soft tissue infections. METHODS: A mouse model of GAS soft tissue infection was developed. The extent of cutaneous lesions, tissue damage, release of inflammatory cytokines, and survival rates were compared between mice with and without ibuprofen administration after GAS soft tissue infection. RESULTS: All twelve mice without ibuprofen administration survived for at least 10 days. In contrast, mortality rate of 14 mice with ibuprofen therapy was 72.5%. Ibuprofen treated mice exhibited more evident macrophage infiltration and tissue damage in the GAS-infected soft tissues. In GAS-infected mice, tissue levels of interleukin 6 and tumor necrosis factor alpha were significantly higher in ibuprofen-treated mice than those in the control group. CONCLUSIONS: The results supported the concept that ibuprofen use in GAS soft tissue infections might induce the development of severe necrotizing infections and increase mortality rate. PMID- 21697020 TI - Multilocus sequence typing of invasive group B Streptococcus in central area of Taiwan. AB - BACKGROUND: Group B Streptococcus (GBS) (Streptococcus agalactiae) is an important pathogen in neonates, pregnant women, and adults with underlying disease. METHODS: Fifty clinical isolates were collected during the period 2001 2004 and analyzed by multilocus sequence typing and capsular serotyping. RESULTS: The six major sequence types (STs) identified by multilocus sequence typing were ST1, ST12, ST19, ST17, ST23, and ST10. Five major clonal complexes (CCs) and one single ST (ST61) from 11 different STs were found. CC1 (n=14) was the most common one, followed by CC12 (n=13), CC19 (n=9), CC17 (n=7), and CC23 (n=6). The most common serotypes were serotype III, followed by Ib, V, Ia, and IV. The most invasive strains in adults belonged to ST1 (CC1) and serotype V, and those in neonates belonged to ST17 (CC17) and serotype III. In addition, ST19 was distributed in adults and neonates. CONCLUSIONS: These results are similar to those of previous reports, but some geographic differences were found, suggesting that limited clonal lineages play important roles in GBS-associated diseases worldwide. Continued tracking of GBS in the population through clinical isolates is important for epidemiologic investigations and vaccine development. PMID- 21697022 TI - [Neurocutaneous melanosis]. PMID- 21697023 TI - [Fasting hyperglycaemia and polymorphism in glucokinase promoter (rs1799884)]. AB - Glucokinase is one of the most important regulators of fasting glucose levels. There are several mutations in the glucokinase gene (GCK) which are linked with monogenic diabetes. Recently, a polymorphism in its promoter has been described, which is associated with impaired fasting glucose levels. We present a 7 years and 7 months old boy with overweight and a familial background of diabetes in two previous generations. In the oral glucose tolerance test, he had impaired fasting glucose levels and after two hours, with a high insulin response. Laboratory abnormalities improved after weight loss, but he maintains a slight fasting hyperglycaemia. The molecular study of the most common monogenic diabetes forms, MODY subtypes 1, 2, and 3, was negative. The allelic variant G/A was however detected at the GCK promoter polymorphism rs1799884. PMID- 21697024 TI - [Paroxysmal autonomic dysfunction of neonatal onset and medulloblastoma]. PMID- 21697025 TI - Minimally invasive transplantation of Schwann cells into the peripheral nerve- preliminary results in rats. PMID- 21697026 TI - Peroneus quartus and functional ankle instability. AB - INTRODUCTION: Physical and rehabilitation medicine physicians commonly see patients with chronic functional ankle instability. The main anatomical structures involved in ankle stability are the peroneus (fibularis) brevis and peroneus longus muscles. Several anatomical muscle-tendon variations have been described in the literature as being sometimes responsible for this instability, the peroneus quartus muscle being the most frequent. The objective of this clinical study is to discuss the implication of the bilateral peroneus quartus muscle in functional ankle instability. CLINICAL CASE: This 26-year-old patient was seen in PM&R consultation for recurrent episodes of lateral ankle sprains. The clinical examination found a moderate hyperlaxity on the right side in bilateral ankle varus. We also noted a bilateral weakness of the peroneus muscles. Additional imaging examinations showed a supernumerary bilateral peroneus quartus. The electroneuromyogram of the peroneus muscles was normal. DISCUSSION: In the literature the incidence of a supernumerary peroneus quartus muscle varies from 0 to 21.7%. Most times this muscle is asymptomatic and is only fortuitously discovered. However some cases of chronic ankle pain or instability have been reported in the literature. It seems relevant to discuss, around the clinical case of this patient, the impact of this muscle on ankle instability especially when faced with lingering weakness of the peroneus brevis and longus muscles in spite of eccentric strength training and in the absence of any neurological impairment. One of the hypotheses, previously described in the literature, would be the overcrowding effect resulting in a true conflict by reducing the available space for the peroneal muscles in the peroneal sheath. PMID- 21697027 TI - Evaluation of the role of [18F]FDG-PET/CT and [68Ga]DOTATOC-PET/CT in differentiating typical and atypical pulmonary carcinoids. AB - Pulmonary carcinoids are histologically classified into typical and atypical. It is important to identify these preoperatively for treatment planning and prognosis. Structural imaging cannot conclusively differentiate between them. The aim of this study was to assess the possibility of differentiating the 2 variants using [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) and [68Ga]1,4,7,10-tetraazacyclododecane-N(I-IIII)-tetraacetic acid-(D)-Phe1-Thy3-octreotide (DOTATOC)-PET/CT. The imaging results of 20 patients with pulmonary carcinoids (13 typical, 7 atypical) on [18F]FDG-PET/CT and [68Ga]DOTATOC-PET/CT were assessed retrospectively. Six typical carcinoids failed to reveal significant uptake on [18F]FDG-PET/CT. All the atypical carcinoids revealed significant uptake on the [18F]FDG-PET/CT that was higher than that in typical carcinoids (standardized uptake value (SUV)max, 2.9-8.4, P = 0.001). The SUVmax in typical carcinoids on [68Ga]DOTATOC-PET/CT was significantly higher (SUVmax, 8.8-66) compared with atypical carcinoids (SUVmax, 1.1-18.5, P = 0.002). Ratios of SUVmax on [68Ga]DOTATOC-PET/CT to that on [18F]FDG-PET/CT were significantly higher (P < 0.001) in typical carcinoids compared with atypical carcinoids. The different uptake patterns on [18F]FDG and [68Ga]DOTATOC-PET/CT. and the ratio of SUVmax may be helpful in differentiating between typical and atypical carcinoids. PMID- 21697029 TI - Testing chemicals for effects on breast development, lactation, and cancer. PMID- 21697030 TI - Kyrgyzstan: Health system review. AB - Kyrgyzstan has undertaken wide-ranging reforms of its health system in a challenging socioeconomic and political context. The country has developed two major health reform programmes after becoming independent: Manas (1996 to 2006) and Manas Taalimi (2006 to 2010). These reforms introduced comprehensive structural changes to the health care delivery system with the aim of strengthening primary health care, developing family medicine and restructuring the hospital sector.Major service delivery improvements have included the introduction of new clinical practice guidelines, improvements in the provision and use of pharmaceuticals, quality improvements in the priority programmes for mother and child health, cardiovascular diseases, tuberculosis and HIV/AIDS, strengthening of public health and improvements in medical education. A Community Action for Health programme was introduced through new village health committees, enhancing health promotion and allowing individuals and communities to take more responsibility for their own health. Health financing reform consisted of the introduction of a purchaser provider split and the establishment of a single payer for health services under the state-guaranteed benefit package (SGBP). Responsibility for purchasing health services has been consolidated under the Mandatory Health Insurance Fund (MHIF), which pools general revenue and health insurance funding. Funds have been pooled at national level since 2006, replacing the previous pooling at oblast level. The transition from oblast-based pooling of funds to pooling at the national level allowed the MHIF to distribute funds more equitably for the SGBP and the Additional Drug Package. Although utilization of both primary care and hospital services declined during the 1990s and early 2000s, it is increasing again. There is increasing equality of access across regions, improved financial protection and a decline in informal payments, but more efforts will be required in these areas in the future. PMID- 21697028 TI - Environmental exposures and mammary gland development: state of the science, public health implications, and research recommendations. AB - OBJECTIVES: Perturbations in mammary gland (MG) development may increase risk for later adverse effects, including lactation impairment, gynecomastia (in males), and breast cancer. Animal studies indicate that exposure to hormonally active agents leads to this type of developmental effect and related later life susceptibilities. In this review we describe current science, public health issues, and research recommendations for evaluating MG development. DATA SOURCES: The Mammary Gland Evaluation and Risk Assessment Workshop was convened in Oakland, California, USA, 16-17 November 2009, to integrate the expertise and perspectives of scientists, risk assessors, and public health advocates. Interviews were conducted with 18 experts, and seven laboratories conducted an MG slide evaluation exercise. Workshop participants discussed effects of gestational and early life exposures to hormonally active agents on MG development, the relationship of these developmental effects to lactation and cancer, the relative sensitivity of MG and other developmental end points, the relevance of animal models to humans, and methods for evaluating MG effects. SYNTHESIS: Normal MG development and MG carcinogenesis demonstrate temporal, morphological, and mechanistic similarities among test animal species and humans. Diverse chemicals, including many not considered primarily estrogenic, alter MG development in rodents. Inconsistent reporting methods hinder comparison across studies, and relationships between altered development and effects on lactation or carcinogenesis are still being defined. In some studies, altered MG development is the most sensitive endocrine end point. CONCLUSIONS: Early life environmental exposures can alter MG development, disrupt lactation, and increase susceptibility to breast cancer. Assessment of MG development should be incorporated in chemical test guidelines and risk assessment. PMID- 21697031 TI - Autologous serum skin test vs autologous plasma skin test in patients with chronic urticaria: evaluation of reproducibility, sensitivity and specificity and relationship with disease activity, quality of life and anti-thyroid antibodies. AB - Recent concerns have arisen about the specificity and interpretation of the autologous serum skin test (ASST), suggesting that ASST might produce false positive results, and proposing the use of autologous plasma (APST) instead for intradermal testing in autoreactive urticaria. We investigated autoreactivity to autologous plasma and compared the results for reproducibility, sensitivity, specificity and accuracy and evaluated their association with quality of life and anti-TPO antibodies. 70 adults with chronic spontaneous urticaria (CU) and 62 controls underwent testing with ASST and APST and the tests were repeated two days after the first visit. Blood tests measured anti-TPO levels. Disease activity was assessed by urticaria activity score (UAS-7) and quality of life impairment was assessed by DLQI and CU-Q(2)oL. There were no statistically significant differences between ASST (+) and ASST (-) and also APST (+) and APST (-) patients with regard to disease duration, anti-TPO antibodies, urticaria activity scores, DLQI scores and CU-Q(2)oL scores. The results of first ASST and APST were well correlated with the results of second ASST and APST. The specificity of the two tests was similar, while ASST had a higher sensitivity and accuracy. Our results showed that there is no need to use autologous plasma instead of autologous serum for intradermal testing in CU. PMID- 21697032 TI - Combined treatment with etanercept 50 mg once weekly and narrow-band ultraviolet B phototherapy in chronic plaque psoriasis. AB - The combination of etanercept, a tumour necrosis factor alpha inhibitor, with narrow-band ultraviolet B (NB-UVB) phototherapy has recently been reported to be effective in moderate-to-severe plaque psoriasis, yielding better results than either monotherapy. To assess the efficacy and safety of this combined treatment using the lower approved etanercept dosage. In this single-arm open-label study patients received etanercept 50 mg once weekly combined with NB-UVB phototherapy three times weekly for 8 weeks, followed by etanercept alone until week 12. We evaluated the proportion of patients achieving 75%, 90% and 100% improvement of their initial PASI score (PASI75, PASI90, and PASI100, respectively). Patients were 19 men and 14 women, mean age 48.3 years +/- 12.1 standard deviation (SD) and mean baseline Psoriasis Area and Severity Index (PASI) score 22.5 +/- 7.5. On treatment weeks 4, 8, and 12, 24.2%, 66.7%, and 81.8% of patients achieved PASI75; 8.0%, 15.1%, and 57.6% reached PASI90, and 0%, 6.0%, and 24.2% attained PASI100, respectively. There were no severe side effects. Low-dosage etanercept combined with NB-UVB phototherapy is an effective, safe and economical approach to treat moderate-to-severe plaque psoriasis. Further studies are clearly required to assess its long-term efficacy and safety. PMID- 21697033 TI - Human papillomavirus 13 in a Mexican Mayan community with multifocal epithelial hyperplasia: could saliva be involved in household transmission? AB - Multifocal epithelial hyperplasia (MEH) is a disease of the oral mucosa. Human papillomaviruses 13 and 32 have been detected in these lesions. We describe the epidemiology and clinical characteristics of patients with MEH in a rural community in the Mayan area of Mexico with 53 cases and 54 controls. Clinical and epidemiological data were collected through a direct interview. Oral cell samples were collected with a cytobrush. Subjects collected their own saliva sample in a sterile bottle. All samples were tested for HPV 13 and 32 by polymerase chain reaction using specific primers. Of the 53 patients and 54 healthy subjects, 56% were < 12 years old, 25% were males and 75% females. Evolution of the lesions was between two months and 17 years. The lesions affected lips, jugal mucosa, and tongue, 96% had multiple lesions. From 53 patients, fifty samples of oral cells and 31 samples of saliva were analyzed. HPV 13 was detected in 100% oral cell and 100% saliva samples studied. 16 healthy subjects were HVP 13 positive. A highly significant association of HPV 13 infection and MEH was found, as determined by chi square test (p = 0.00) Household transmission of HPV 13 may happen through saliva and the shared use of contaminated objects. PMID- 21697034 TI - Halo angioma: a new clinical and dermoscopical description. PMID- 21697035 TI - Didymosis cesioanemica: an unusual counterpart of phacomatosis cesioflammea. PMID- 21697036 TI - Oral propranolol: an effective, safe treatment for infantile hemangiomas. AB - Infantile hemangiomas (IH) are the most common childhood tumors. In 2008, Labreze reported the serendipitous effect of oral propranolol on hemangioma and since then it has overshadowed the use of other therapeutic modalities in the treatment of IH. The aim of this prospective, clinical study was to assess the efficacy and safety profile of oral propranolol at a fixed dose of 2 mgkg(-1) in the treatment of 30 patients with problematic IH. Propranolol treatment continued for a duration of 2-14 months where 60% of the patients (n=18) showed a final excellent response with complete resolution of the lesion (P<0.001). 20% (n=6) showed a good response with more than 50% reduction in the size of the IH. 16.6% showed a fair response (n=5) with less than 50% reduction in the size of the IH. Only one patient (3.3%) was resistant to treatment. Five patients (17.24%) showed evidence of rebound growth after cessation of therapy and responded well to re treatment.We did not face any side effects related to the oral propranolol. In conclusion, propranolol therapy at a fixed dose of 2 mgkg(-1), given in three equally divided doses, is a very safe and effective regimen in the treatment of IH. PMID- 21697037 TI - Sarcoidosis presenting transepidermal elimination. PMID- 21697038 TI - Disseminated Mycobacterium intracellulare infection. PMID- 21697039 TI - Phacomatosis melanovascularis: a new example of non-allelic twin spotting. AB - We report an infant who had a combination of two rather common nevoid skin conditions, namely "telangiectatic nevus" or "capillary malformation", and "hyperpigmented mosaicism" or "segmental pigmentary disorder" in close apposition, occupying large areas of the body in a mosaic distribution. This association may be considered a further example of didymosis, for which we propose the term, "phacomatosis melanovascularis" to denote a possible non allelic twin spotting condition. To our knowledge, this is the first case reported in the literature. PMID- 21697040 TI - Frostbite as a complication of frozen gloves in the prevention of docetaxel induced onycholysis. PMID- 21697041 TI - The expression levels of thrombospondin-1 in dermatofibroma and dermatofibrosarcoma protuberans. AB - Dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) are benign or intermediate malignant fibrotic dermal tumors. The contribution of transforming growth factor beta (TGF-beta) in the progression of sclerosis in fibrotic diseases has been implicated. To clarify the involvement of TGF-beta signaling in the pathogenesis of DF or DFSP, we investigated the expression of thrombospondin 1 (TSP-1), which mediates TGF-beta1 activation, on those fibrotic tumors. In the present study, we examined the expression of TSP-1 in DF and DFSP using immunohistochemical analysis and immunoblotting. In immunohistochemical staining, the expression of TSP-1 was detected weakly on epidermis and epidermal appendages, and hardly in fibroblasts in normal skin sections. The expression levels of TSP-1 were elevated in DFSP cells in comparison to normal dermal sections or DF cells. On the other hand, there was no significant difference in the protein levels in vitro of TSP-1 among normal fibroblasts, DF cells, and DFSP cells. Although the contribution of TGF-beta signaling to DF or DFSP is still unknown, the expression patterns of TSP-1 in DF cells and DFSP cells may be helpful in differential diagnosis of these tumors. PMID- 21697042 TI - Linear porokeratosis with nail dystrophy. PMID- 21697043 TI - Deimination and expression of peptidylarginine deiminases during cutaneous wound healing in mice. AB - Deimination, the conversion of protein-bound arginines into citrullines, is a post-translational modification catalyzed by a peptidylarginine deiminase (Pad). In the epidermis, three Pads are expressed, namely Pad1, 2 and 3, and the major deiminated protein is filaggrin. Deimination of fibrin has been observed in various pathological inflammatory conditions. Here, we analyzed the expression of Pads and citrullination of proteins during cutaneous wound healing, i.e. in a physiological inflammatory condition. Full-thickness punches were performed on adult mouse back skin, and wound recovery was analyzed over 10 days by immunohistology and western blotting. Pad1 was immunodetected in all the neo epidermis. Pad3, normally expressed in the stratum granulosum, was not detected in the hyperproliferative tongue of the neo-epidermis, but was shown to be co localized with (pro)filaggrin in a large number of keratinocyte layers in its differentiating part. Deiminated proteins were detected in the stratum corneum of the neo-epidermis in the late phase of re-epithelialization, and in the clot and the clot-derived scab. In the clot where we only detected Pad4, one of the deiminated proteins was shown to be fibrin. Deimination of the clot proteins, and more generally wound healing and keratinocyte differentiation, seemed to be Pad2 independent, as shown using Padi2(-/-) mice. PMID- 21697044 TI - Oral verrucous carcinoma treated with imiquimod 5% cream and carbon dioxide laser. PMID- 21697045 TI - Efficacy of taxane regimens in patients with metastatic angiosarcoma. AB - The purpose of this study was to evaluate the efficacy of taxane regimens in patients with metastatic angiosarcoma. Forty-one patients with metastatic angiosarcoma treated at the National Cancer Center Hospital between January 1982 and January 2009 were retrospectively classified into 3 groups according to the treatment type: (i) taxane (n=11), (ii) non-taxane (n=14), and (iii) best supportive care (BSC; n=16) groups. The taxane group received paclitaxel (n=6), docetaxel (n=4), or albumin-bound paclitaxel (n=1), and the non-taxane group received mainly doxorubicin-containing regimens (n=12). The differences in progression-free survival (PFS) among the 3 groups were statistically significant (P<0.001). After adjusting for prognostic factors, the taxane group had significantly longer PFS than the non-taxane (hazard ratio=0.282; 95% confidence interval=0.086-0.923; P=0.036) and BSC (hazard ratio=0.015; 95% confidence interval = 0.003-0.083; P<0.001) groups. Overall survival was also significantly longer in the taxane group than in the other groups. A taxane regimen may be more effective than a non-taxane regimen for treating patients with metastatic angiosarcoma. PMID- 21697046 TI - Acquired bilateral nevoid telangiectasia syndrome with gastrointestinal involvement. PMID- 21697047 TI - Ramipril-induced drug reaction with eosinophilia and systemic symptoms (DRESS). PMID- 21697048 TI - Amicrobial pustulosis of the folds revealing asymptomatic autoimmune thyroiditis. PMID- 21697049 TI - Multiple milia and comedones as a skin manifestation of systemic amyloidosis. PMID- 21697050 TI - Acquired zinc deficiency due to long-term tube feeding. PMID- 21697051 TI - Successful treatment with narrowband UVB phototherapy in prurigo pigmentosa associated with pregnancy. PMID- 21697052 TI - Superimposed linear graft-versus-host disease and secondary cutaneous involvement of anaplastic large cell lymphoma. PMID- 21697053 TI - Maculopapular-type drug eruption caused by entecavir. PMID- 21697054 TI - Dermoscopy of solitary cylindroma. PMID- 21697055 TI - The diagnostic usefulness of dermoscopy for nevus depigmentosus. PMID- 21697056 TI - Keloid exacerbation associated with adult T-cell leukemia/lymphoma cell infiltration. PMID- 21697057 TI - Disseminated eruptive interstitial granuloma annulare mimicking lichen nitidus. PMID- 21697058 TI - Frontal fibrosing alopecia: a review of eleven patients. AB - BACKGROUND: Frontal fibrosing alopecia (FFA) is a primary lymphocytic cicatricial alopecia with a distinctive clinical pattern of progressive frontotemporal hairline recession. OBJECTIVES: Our purpose was to describe the clinical and histopathological features as well as the response to treatment of eleven cases of FFA diagnosed at the Trichology Consultation, over three years. METHODS: A retrospective case note review was performed of eleven adult patients with FFA. The clinical data as well the histopathologic findings and laboratory tests were accessed. The patients were treated with different drugs, depending on the stage of the disease. The age of onset of the alopecia ranged from 45 to 80 years. Ten patients (90.9%) were postmenopausal women. All patients had progressive and symmetrical alopecia localized to the frontal and temporal hairline. Seven patients (63.6%) had marked decreased to complete loss of eyebrows and in four patients axillar alopecia was also evident. Laboratory investigations were normal. Scalp biopsy specimens from the anterior hairline showed similar findings. No significant improvement was observed in the majority of cases. CONCLUSION: Differential diagnosis should take into account several other conditions. It seems there is no effective treatment proven with an appropriate level of evidence in the management of FFA. PMID- 21697059 TI - Peroxisome proliferator receptor (PPAR) beta/delta in psoriatic patients before and after two conventional therapeutic modalities: methotrexate and PUVA. AB - Peroxisome proliferator-activated receptor beta/delta is a member of the nuclear hormone receptor superfamily suggested to contribute to psoriasis pathogenesis. Methotrexate and PUVA mainly target the T cell-mediated immunopathology of psoriasis. Our work aimed at estimating PPARbeta/delta in psoriatic patients and investigating whether the standard therapeutic modalities (methotrexate and PUVA) exert their anti-psoriatic activity partially through altering PPARbeta/delta levels. RT-PCR was used to measure PPAR beta/delta mRNA levels in twenty four chronic plaque psoriasis patients. Patients were divided into two groups (12 patients each); group A received intramuscular methotrexate and group B was treated by PUVA 3 times/week in a PUVA 1000 cabin for ten weeks each, followed by measurement of PPAR beta/delta mRNA levels. Twelve healthy volunteers served as controls. PPAR beta/delta mRNA levels were significantly elevated in all patients and significantly decreased ten weeks after treatment, however, post treatment levels were still significantly elevated in comparison with those of controls. PPAR beta/delta mRNA levels showed a significant positive correlation with disease duration. PMID- 21697060 TI - Analysis of 6 cases of drug-induced pemphigus. AB - OBJECTIVES: To study clinical and laboratory characteristics of drug-induced pemphigus. METHODS: Using direct immunofluorescence (IF), indirect IF, ELISA and immunoblotting to characterize 6 patients with drug-induced pemphigus (DIP) and compared them with 20 cases of idiopathic pemphigus. RESULTS: All the 6 cases of DIP showed obvious itching (100%) and no damage to the oral mucosa. Five out of 6 DIP cases (83.33%) presented as pemphigus folicaeus (PF) since they contained circulating Dsg1-specific IgG, were sensitive to low doses of glucocorticoid, and had good prognosis. One case was showed as pemphigus vulgaris (PV). Dsg1-specific IgA was positive in peripheral blood of 4 cases (66.67%), and the antibody disappeared after treatment. In patients with idiopathic pemphigus, only 6 cases (30%) had mild itching, and 12 cases (60%) had oral mucosal lesions. Twelve cases (60%) were PV with anti-Dsg1 and -Dsg3 antibodies, and 8 cases (40%) were PF with anti-Dsg1 antibody only. One case (5%) had anti-Dsg1 IgA. CONCLUSION: Drug factors should be considered for pemphigus as some common antibiotics can cause pemphigus. PMID- 21697061 TI - Serum concentration of dehydroepiandrosterone sulfate (DHEA-S) in patients suffering from acute urticaria. PMID- 21697062 TI - Etanercept, childhood and long-term safety: a case of five years treatment. PMID- 21697063 TI - Elevated expression of activation-induced cytidine deaminase in T and NK cells from patients with chronic active Epstein-Barr virus infection. PMID- 21697064 TI - Demodicosis successfully treated with repeated doses of oral ivermectin and permethrin cream. PMID- 21697065 TI - Bullous dermatomyositis in China. PMID- 21697066 TI - Risk factors for early-onset basal cell carcinoma in a German institution. AB - BACKGROUND: Genetic predisposition and ultraviolet (UV) exposure are the most important risk factors for basal cell carcinoma (BCC). Recent reports have demonstrated an increasing incidence of BCC among younger patients. We investigated potential risk factors for sporadic BCC in a subset of young German patients. METHODS: Twenty-five patients with BCC at the age of 19 to 40 years (mean 34.4 years) were included in the study. They were selected from a total of 2,058 patients who received surgical treatment for BCC between December 2004 and November 2008. Patients were contacted by telephone interview and asked about sun habits, associated medical conditions, and lifestyle-related variables. Data were compared with interview results from sex-, age- and skin type-matched controls. RESULTS: We found 1.4% (29) of 2,058 BCC patients to be <=40 years of age. Four patients had Gorlin-Goltz syndrome and were excluded from further analysis. Multivariate analysis showed tanning bed use (OR= 25.0; IC95%: 2.26-277.36) and smoking (OR=13.34; IC95%: 1.56-113.8) to be the most significant independent risk factors for BCC, while sunscreen use had a protective effect. CONCLUSION: BCCs in young patients were only rarely related to hereditary syndromes, but were associated with environmental carcinogens, i.e. UV radiation and smoking. PMID- 21697067 TI - Relapsing polychondritis associated with psoriasis vulgaris and alopecia areata. PMID- 21697068 TI - Mesalazine-induced psoriasis in patients with inflammatory bowel diseases. PMID- 21697069 TI - Atypical cutaneous mycobacteriosis co-infection with pulmonary tuberculosis in an immunocompetent patient. PMID- 21697070 TI - Generalized granuloma annulare possibly associated with acute Epstein-Barr virus infection. PMID- 21697072 TI - Author response: incorrect citation. PMID- 21697073 TI - The inflammatory changes of adipose tissue in late pregnant mice. AB - The infiltration of classically activated macrophages (M1) and alternatively activated macrophages (M2) in subcutaneous adipose tissue (SAT) and parametrial adipose tissue (PAT) was analyzed to investigate whether local inflammatory change in adipose tissue occurs in late pregnancy. C57BL/6N female mice at 6 weeks of age were fed a normal chow diet for 4 weeks prior to mating at 10 weeks of age and were sampled on day 17 of pregnancy. The serum levels of adipokines and biochemical markers were measured using ELISA and enzymatic methods. The identification of M1 and M2 was analyzed by double immunofluorescence with anti F4/80 and anti-CD11c antibodies. The gene expression of adipokines in adipose tissues was analyzed by quantitative RT-PCR. The pregnant group showed adipocyte hypertrophy, higher macrophage infiltration, and higher M1/M2 in both SAT and PAT compared with the non-pregnant (NP) group. Serum levels of free fatty acids, tumor necrosis factor alpha (TNFalpha), interleukin 6 (IL6), and IL10 were higher, and serum levels of adiponectin were lower in the pregnant group than those in the NP group. The gene expressions of CD68, Itgax, CCR2, TNFalpha, and PAI1 in SAT during pregnancy were significantly higher than those in the NP group, as were the gene expressions of CD68, Emrl, Itgax, MCP1, TNFalpha, IL6, PAI1, adiponectin, and IL10 in PAT. These results suggest that the low-grade inflammation of adipose tissue indicated by increased macrophage infiltration occurs in late normal pregnancy. PMID- 21697074 TI - Maternal milk consumption, fetal growth, and the risks of neonatal complications: the Generation R Study. AB - BACKGROUND: Maternal cow-milk consumption may increase birth weight. Previous studies did not assess the association of maternal milk consumption with trimester-specific fetal growth. OBJECTIVE: The objective was to assess associations of first-trimester maternal milk consumption with fetal growth characteristics in different trimesters and the risk of neonatal complications. DESIGN: In total, 3405 mothers participating in a prospective cohort study completed a 293-item semiquantitative food-frequency questionnaire to obtain information about dairy consumption during the first trimester of pregnancy. Fetal head circumference, femur length, and weight were estimated in the second and third trimesters by ultrasonography. RESULTS: Maternal milk consumption of >3 glasses/d was associated with greater fetal weight gain in the third trimester of pregnancy, which led to an 88-g (95% CI: 39, 135 g) higher birth weight than that with milk consumption of 0 to 1 glass/d. In addition, head circumference tended to be 2.3 cm (95% CI: -0.0, 4.6 cm) larger when mothers consumed >3 glasses/d. Maternal milk consumption was not associated with length growth. Maternal protein intake (P for trend = 0.01), but not fat or carbohydrate intake, from dairy products was associated with higher birth weight. This association appeared to be limited to milk (P for trend < 0.01), whereas protein intake from nondairy food or cheese was not associated with birth weight. CONCLUSIONS: Maternal milk consumption is associated with greater fetal weight gain. The association seems to be due to milk protein, or milk components closely associated with protein, rather than to the fat or carbohydrate fraction of milk. PMID- 21697075 TI - Randomized trial of fortified milk and supplements to raise 25-hydroxyvitamin D concentrations in schoolchildren in Mongolia. AB - BACKGROUND: The optimal public health strategy for maintaining 25-hydroxyvitamin D [25(OH)D] concentrations in schoolchildren in Mongolia is unknown. OBJECTIVE: The objective was to compare the effectiveness of different supplement and fortified milk regimens to increase 25(OH)D concentrations in Mongolian schoolchildren. DESIGN: Twenty-one classrooms of 579 children aged 9-11 y were randomized to interventions with an equivalent content of vitamin D(3): 1) a one time seasonal supplement of 13,700 IU, 2) 300 IU/d from supplements, 3) 300 IU/d from fortified ultra-high-temperature pasteurized milk from the United States, 4) 300 IU/d from fortified pasteurized Mongolian milk, or 5) unfortified pasteurized Mongolian milk (control). RESULTS: In January, the mean (+/-SD) serum 25(OH)D concentration was 8 +/- 4 ng/mL (20 +/- 10 nmol/L), and 98% of the children had a concentration <20 ng/mL (50 nmol/L). In March, concentrations were 8 +/- 4 ng/mL after unfortified milk, 20 +/- 6 ng/mL after fortified Mongolian milk, 29 +/- 10 ng/mL after fortified US milk, 21 +/- 6 ng/mL after daily supplements, and 12 +/- 4 ng/mL after seasonal supplements (each greater than unfortified milk, P < 0.01). Seasonal supplementation was less effective than was daily supplementation (P < 0.0001). Despite consuming daily supplements or fortified milk, 41% of the children still had concentrations <20 ng/mL (50 nmol/L). Children with lower baseline 25(OH)D concentrations experienced slightly larger 25(OH)D responses to intervention than did children with higher concentrations (P = 0.002). CONCLUSIONS: In this population with extremely low vitamin D concentrations, delivery of 300 IU vitamin D/d via supplements or in fortified milk improved 25(OH)D concentrations but failed to raise concentrations uniformly to >20 ng/mL (50 nmol/L). The daily low-dose intervention was superior to the seasonal larger dose intervention. Higher doses may be needed to prevent deficiency in schoolchildren in Mongolia and at other northern latitudes. This trial is registered at clinicaltrials.gov as NCT00886379. PMID- 21697076 TI - A comparison of the National Center for Health Statistics and new World Health Organization growth references for school-age children and adolescents with the use of data from 11 low-income countries. AB - BACKGROUND: In 2007 new World Health Organization (WHO) growth references for children aged 5-19 y were introduced to replace the National Center for Health Statistics (NCHS) references. OBJECTIVE: This study aimed to compare the prevalence of stunting, wasting, and thinness estimated by the NCHS and WHO growth references. DESIGN: NCHS and WHO height-for-age z scores were calculated with the use of cross-sectional data from 20,605 schoolchildren aged 5-17 y in 11 low-income countries. The differences in the percentage of stunted children were estimated for each year of age and sex. The z scores of body mass index-for-age and weight-for-height were calculated with the use of the WHO and NCHS references, respectively, to compare differences in the prevalence of thinness and wasting. RESULTS: No systematic differences in mean z scores of height-for age were observed between the WHO and NCHS growth references. However, z scores of height-for-age varied by sex and age, particularly during early adolescence. In children for whom weight-for-height could be calculated, the estimated prevalence of thinness (WHO reference) was consistently higher than the prevalence of wasting (NCHS reference) by as much as 9% in girls and 18% in boys. CONCLUSIONS: In undernourished populations, the application of the WHO (2007) references may result in differences in the prevalence of stunting for each sex compared with results shown when the NCHS references are used as well as a higher estimated prevalence of thinness than of wasting. An awareness of these differences is important for comparative studies or the evaluation of programs. For school-age children and adolescents across all ranges of anthropometric status, the same growth references should be applied when such studies are undertaken. PMID- 21697077 TI - Fatty acids in the de novo lipogenesis pathway and risk of coronary heart disease: the Cardiovascular Health Study. AB - BACKGROUND: De novo lipogenesis (DNL) is an endogenous pathway whereby carbohydrates and proteins are converted to fatty acids. DNL could affect coronary heart disease (CHD) or sudden cardiac arrest (SCA) via generation of specific fatty acids. Whether these fatty acids are prospectively associated with SCA or other CHD events is unknown. OBJECTIVE: The objective was to investigate the relations of 4 fatty acids in the DNL pathway-palmitic acid (16:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and cis-vaccenic acid (18:1n-7)-with incident CHD, including fatal CHD, nonfatal myocardial infarction (NFMI), and SCA. DESIGN: A community-based prospective study was conducted in 2890 men and women aged >=65 y, who were free of known CHD at baseline and who were followed from 1992 to 2006. Cardiovascular disease risk factors and plasma phospholipid fatty acids were measured at baseline by using standardized methods. Incident CHD was ascertained prospectively and was centrally adjudicated by using medical records. Risk was assessed by using multivariable-adjusted Cox proportional hazards. RESULTS: During 29,835 person-years of follow-up, 631 CHD and 71 SCA events occurred. Both 18:1n-7 and 16:1n-9 were associated with a higher risk of SCA [multivariable-adjusted hazard ratio (95% CI) for the interquintile range: 7.63 (2.58, 22.6) for 18:1n-7 and 2.30 (1.16, 4.55) for 16:1n-9] but not of total CHD, fatal CHD, or NFMI. In secondary analyses censored to mid-follow-up (7 y) to minimize the effects of changes in concentrations over time, 16:1n-9 was also associated with a significantly higher risk of total CHD (2.11; 1.76, 2.54), including a higher risk of CHD death, NFMI, and SCA; 16:0 and 16:1n-7 were not associated with clinical CHD outcomes. CONCLUSION: Higher plasma phospholipid 18:1n-7 and 16:1n-9 concentrations were prospectively associated with an elevated risk of SCA but not of other CHD events, except in secondary analyses. PMID- 21697078 TI - Disrupted fat distribution and composition due to medium-chain triglycerides in mice with a beta-oxidation defect. AB - BACKGROUND: Because of the enhanced recognition of inherited long-chain fatty acid oxidation disorders by worldwide newborn screening programs, an increasing number of asymptomatic patients receive medium-chain triglyceride (MCT) supplements to prevent the development of cardiomyopathy and myopathy. OBJECTIVE: MCT supplementation has been recognized as a safe dietary intervention, but long term observations into later adulthood are still not available. We investigated the consequences of a prolonged MCT diet on abdominal fat distribution and composition and on liver fat. DESIGN: Mice with very-long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD(-/-)) were supplemented for 1 y with a diet in which MCTs replaced long-chain triglycerides without increasing the total fat content. The dietary effects on abdominal fat accumulation and composition were analyzed by in vivo (1)H- and (13)C-magnetic resonance spectroscopy (9.4 Tesla). RESULTS: After 1 y of MCT supplementation, VLCAD(-/-) mice accumulated massive visceral fat and had a dramatic increase in the concentration of serum free fatty acids. Furthermore, we observed a profound shift in body triglyceride composition, ie, concentrations of physiologically important polyunsaturated fatty acids dramatically decreased. (1)H-Magnetic resonance spectroscopy analysis and histologic evaluation of the liver also showed pronounced fat accumulation and marked oxidative stress. CONCLUSION: Although the MCT-supplemented diet has been reported to prevent the development of cardiomyopathy and skeletal myopathy in fatty acid oxidation disorders, our data show that long-term MCT supplementation results in a severe clinical phenotype similar to that of nonalcoholic steatohepatitis and the metabolic syndrome. PMID- 21697079 TI - A model for estimating the minimum number of offspring to sample in studies of reproductive success. AB - Molecular parentage permits studies of selection and evolution in fecund species with cryptic mating systems, such as fish, amphibians, and insects. However, there exists no method for estimating the number of offspring that must be assigned parentage to achieve robust estimates of reproductive success when only a fraction of offspring can be sampled. We constructed a 2-stage model that first estimated the mean (MU) and variance (v) in reproductive success from published studies on salmonid fishes and then sampled offspring from reproductive success distributions simulated from the MU and v estimates. Results provided strong support for modeling salmonid reproductive success via the negative binomial distribution and suggested that few offspring samples are needed to reject the null hypothesis of uniform offspring production. However, the sampled reproductive success distributions deviated significantly (chi(2) goodness-of-fit test p value < 0.05) from the known simulated reproductive success distribution at rates often >0.05 and as high as 0.24, even when hundreds of offspring were assigned parentage. In general, reproductive success patterns were less accurate when offspring were sampled from cohorts with larger numbers of parents and greater variance in reproductive success. Our model can be reparameterized with data from other species and will aid researchers in planning reproductive success studies by providing explicit sampling targets required to accurately assess reproductive success. PMID- 21697080 TI - Prevalence of velopharyngeal insufficiency in woodwind and brass students. AB - BACKGROUND: Velopharyngeal insufficiency (VPI) is a disorder in which air leaks out through the nose, reducing performance quality and capacity in wind and brass players. There have been limited studies on the prevalence of this potentially career-threatening disorder. AIMS: To identify the prevalence of VPI in a sample of conservatorium level woodwind and brass student instrumentalists in Australia. METHODS: Wind and brass students from four music institutions were recruited by email invitation to complete an online survey. Results from 77 musicians were analysed for their knowledge and experience of VPI. Musicians who had experienced VPI provided information on the characteristics, symptoms and treatment or advice sought for the disorder. RESULTS: Of the 77 musicians included in the analysis, 44% had heard of VPI, 30% were aware of other musicians who had experienced VPI and 39% had personally experienced VPI. CONCLUSIONS: The results suggest that VPI may be a common occurrence in wind and brass players. Informal discussions with colleagues and music teachers also suggest that VPI is a frequent phenomenon. This group of musicians represents the largest sample surveyed about VPI to date. PMID- 21697081 TI - Monoamine oxidase a expression is vital for embryonic brain development by modulating developmental apoptosis. AB - Monoamine oxidases (MAO-A, MAO-B) metabolize biogenic amines and have been implicated in neuronal apoptosis. Although apoptosis is an important process in embryo development, the role of MAO isoenzymes has not been investigated in detail. We found that expression of MAO-A and MAO-B can be detected early on during embryo development. Expression levels remained constant until around midgestation but then dropped to almost undetectable levels toward birth. Similar expression kinetics were observed in the brain. Isoform-specific expression silencing of MAO-A mediated by siRNA during in vitro embryogenesis induced developmental defects, as indicated by a reduction of the crown rump length and impaired cerebral development. These alterations were paralleled by elevated serotonin levels. Similar abnormalities were observed when embryos were cultured in the presence of the MAO-A inhibitor clorgyline or when the transcriptional inhibitor of MAO-A expression R1 was overexpressed. In contrast, no such alterations were detected when expression of MAO-B was knocked down. To explore the underlying mechanisms for the developmental abnormalities in MAO-A knockdown embryos, we quantified the degree of developmental apoptosis in the developing brain. MAO-A knockdown reduced the number of apoptotic cells in the neuroepithelium, which coincided with impaired activation of caspases 3 and 9. Moreover, we observed reduced cyclin D1 levels as an indicator of impaired cell proliferation in MAO-A knockdown embryos. This data highlights MAO-A as a vital regulator of embryonic brain development. PMID- 21697082 TI - Investigation of the molecular origins of protein-arginine methyltransferase I (PRMT1) product specificity reveals a role for two conserved methionine residues. AB - Protein-arginine methyltransferases aid in the regulation of many biological processes by methylating specific arginyl groups within targeted proteins. The varied nature of the response to methylation is due in part to the diverse product specificity displayed by the protein-arginine methyltransferases. In addition to site location within a protein, biological response is also determined by the degree (mono-/dimethylation) and type of arginine dimethylation (asymmetric/symmetric). Here, we have identified two strictly conserved methionine residues in the PRMT1 active site that are not only important for activity but also control substrate specificity. Mutation of Met-155 or Met-48 results in a loss in activity and a change in distribution of mono- and dimethylated products. The altered substrate specificity of M155A and M48L mutants is also evidenced by automethylation. Investigation into the mechanistic basis of altered substrate recognition led us to consider each methyl transfer step separately. Single turnover experiments reveal that the rate of transfer of the second methyl group is much slower than transfer of the first methyl group in M48L, especially for arginine residues located in the center of the peptide substrate where turnover of the monomethylated species is negligible. Thus, altered product specificity in M48L originates from the differential effect of the mutation on the two rates. Characterization of the two active-site methionines provides the first insight into how the PRMT1 active site is engineered to control product specificity. PMID- 21697084 TI - Crystal structure of plasminogen activator inhibitor-1 in an active conformation with normal thermodynamic stability. AB - The serpin plasminogen activator inhibitor-1 (PAI-1) is a crucial regulator in fibrinolysis and tissue remodeling. PAI-1 has been associated with several pathological conditions and is a validated prognostic marker in human cancers. However, structural information about the native inhibitory form of PAI-1 has been elusive because of its inherent conformational instability and rapid conversion to a latent, inactive structure. Here we report the crystal structure of PAI-1 W175F at 2.3 A resolution as the first model of the metastable native molecule. Structural comparison with a quadruple mutant (14-1B) previously used as representative of the active state uncovered key differences. The most striking differences occur near the region that houses three of the four mutations in the 14-1B PAI-1 structure. Prominent changes are localized within a loop connecting beta-strand 3A with the F helix, in which a previously observed 3(10)-helix is absent in the new structure. Notably these structural changes are found near the binding site for the cofactor vitronectin. Because vitronectin is the only known physiological regulator of PAI-1 that slows down the latency conversion, the structure of this region is important. Furthermore, the previously identified chloride-binding site close to the F-helix is absent from the present structure and likely to be artifactual, because of its dependence on the 14-1B mutations. Instead we found a different chlorine-binding site that is likely to be present in wild type PAI-1 and that more satisfactorily accounts for the chlorine stabilizing effect on PAI-1. PMID- 21697083 TI - Crystal structure of clustered regularly interspaced short palindromic repeats (CRISPR)-associated Csn2 protein revealed Ca2+-dependent double-stranded DNA binding activity. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) and their associated protein genes (cas genes) are widespread in bacteria and archaea. They form a line of RNA-based immunity to eradicate invading bacteriophages and malicious plasmids. A key molecular event during this process is the acquisition of new spacers into the CRISPR loci to guide the selective degradation of the matching foreign genetic elements. Csn2 is a Nmeni subtype-specific cas gene required for new spacer acquisition. Here we characterize the Enterococcus faecalis Csn2 protein as a double-stranded (ds-) DNA-binding protein and report its 2.7 A tetrameric ring structure. The inner circle of the Csn2 tetrameric ring is ~26 A wide and populated with conserved lysine residues poised for nonspecific interactions with ds-DNA. Each Csn2 protomer contains an alpha/beta domain and an alpha-helical domain; significant hinge motion was observed between these two domains. Ca(2+) was located at strategic positions in the oligomerization interface. We further showed that removal of Ca(2+) ions altered the oligomerization state of Csn2, which in turn severely decreased its affinity for ds-DNA. In summary, our results provided the first insight into the function of the Csn2 protein in CRISPR adaptation by revealing that it is a ds-DNA-binding protein functioning at the quaternary structure level and regulated by Ca(2+) ions. PMID- 21697085 TI - Pyrovanadolysis, a pyrophosphorolysis-like reaction mediated by pyrovanadate, Mn2+, and DNA polymerase of bacteriophage T7. AB - DNA polymerases catalyze the 3'-5'-pyrophosphorolysis of a DNA primer annealed to a DNA template in the presence of pyrophosphate (PP(i)). In this reversal of the polymerization reaction, deoxynucleotides in DNA are converted to deoxynucleoside 5'-triphosphates. Based on the charge, size, and geometry of the oxygen connecting the two phosphorus atoms of PP(i), a variety of compounds was examined for their ability to carry out a reaction similar to pyrophosphorolysis. We describe a manganese-mediated pyrophosphorolysis-like activity using pyrovanadate (VV) catalyzed by the DNA polymerase of bacteriophage T7. We designate this reaction pyrovanadolysis. X-ray absorption spectroscopy reveals a shorter Mn-V distance of the polymerase-VV complex than the Mn-P distance of the polymerase PP(i) complex. This structural arrangement at the active site accounts for the enzymatic activation by Mn-VV. We propose that the Mn(2+), larger than Mg(2+), fits the polymerase active site to mediate binding of VV into the active site of the polymerase. Our results may be the first documentation that vanadium can substitute for phosphorus in biological processes. PMID- 21697086 TI - Structural insights into recognition of triple-helical beta-glucans by an insect fungal receptor. AB - The innate ability to detect pathogens is achieved by pattern recognition receptors, which recognize non-self-components such as beta1,3-glucan. beta1,3 Glucans form a triple-helical structure stabilized by interchain hydrogen bonds. beta1,3-Glucan recognition protein (betaGRP)/gram-negative bacteria-binding protein 3 (GNBP3), one of the pattern recognition receptors, binds to long, structured beta1,3-glucan to initiate innate immune response. However, binding details and how specificity is achieved in such receptors remain important unresolved issues. We solved the crystal structures of the N-terminal beta1,3 glucan recognition domain of betaGRP/GNBP3 (betaGRP-N) in complex with the beta1,3-linked glucose hexamer, laminarihexaose. In the crystals, three structured laminarihexaoses simultaneously interact through six glucose residues (two from each chain) with one betaGRP-N. The spatial arrangement of the laminarihexaoses bound to betaGRP-N is almost identical to that of a beta1,3 glucan triple-helical structure. Therefore, our crystallographic structures together with site-directed mutagenesis data provide a structural basis for the unique recognition by such receptors of the triple-helical structure of beta1,3 glucan. PMID- 21697087 TI - Modulation of CCAAT/enhancer binding protein homologous protein (CHOP)-dependent DR5 expression by nelfinavir sensitizes glioblastoma multiforme cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). AB - Human glioblastoma multiforme cells demonstrate varying levels of sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Endoplasmic reticulum (ER) stress has been shown to trigger cell death through apoptosis. We therefore pursued a strategy of integrating clinically relevant investigational agents that cooperate mechanistically through the regulation of ER stress and apoptosis pathways. Nelfinavir belongs to the protease inhibitor class of drugs currently used to treat patients with HIV and is in clinical trials as an anti-tumor agent. We found that Nelfinavir treatment led to ER stress-induced up-regulation of the DR5 receptor. This transactivation was mediated by the transcription factor CCAAT/enhancer binding protein homologous protein (CHOP). We also determined that ER stress-induced ATF4 up regulation was responsible for modulation of CHOP. In contrast, DR4 receptor expression was unchanged by Nelfinavir treatment. Combining Nelfinavir with TRAIL led to a significantly enhanced level of apoptosis that was abrogated by siRNA silencing of DR5. We provide evidence that Nelfinavir-induced ER stress modulates DR5 expression in human glioblastoma multiforme cells and can enhance TRAIL efficacy. These studies provide a potential mechanistic rationale for the use of the Food and Drug Administration-approved agent Nelfinavir in combination with DR5 agonists to induce apoptosis in human malignancies. PMID- 21697088 TI - Enhanced epithelial-mesenchymal transition-like phenotype in N acetylglucosaminyltransferase V transgenic mouse skin promotes wound healing. AB - N-Acetylglucosaminyltransferase V (GnT-V) catalyzes the beta1,6 branching of N acetylglucosamine on N-glycans. GnT-V expression is elevated during malignant transformation in various types of cancer. However, the mechanism by which GnT-V promotes cancer progression is unclear. To characterize the biological significance of GnT-V, we established GnT-V transgenic (Tg) mice, in which GnT-V is regulated by a beta-actin promoter. No spontaneous cancer was detected in any organs of the GnT-V Tg mice. However, GnT-V expression was up-regulated in GnT-V Tg mouse skin, and cultured keratinocytes derived from these mice showed enhanced migration, which was associated with changes in E-cadherin localization and epithelial-mesenchymal transition (EMT). Further, EMT-associated factors snail, twist, and N-cadherin were up-regulated, and cutaneous wound healing was accelerated in vivo. We further investigated the detailed mechanisms of EMT by assessing EGF signaling and found up-regulated EGF receptor signaling in GnT-V Tg mouse keratinocytes. These findings indicate that GnT-V overexpression promotes EMT and keratinocyte migration in part through enhanced EGF receptor signaling. PMID- 21697089 TI - Structural and functional evolution of isopropylmalate dehydrogenases in the leucine and glucosinolate pathways of Arabidopsis thaliana. AB - The methionine chain-elongation pathway is required for aliphatic glucosinolate biosynthesis in plants and evolved from leucine biosynthesis. In Arabidopsis thaliana, three 3-isopropylmalate dehydrogenases (AtIPMDHs) play key roles in methionine chain-elongation for the synthesis of aliphatic glucosinolates (e.g. AtIPMDH1) and leucine (e.g. AtIPMDH2 and AtIPMDH3). Here we elucidate the molecular basis underlying the metabolic specialization of these enzymes. The 2.25 A resolution crystal structure of AtIPMDH2 was solved to provide the first detailed molecular architecture of a plant IPMDH. Modeling of 3-isopropylmalate binding in the AtIPMDH2 active site and sequence comparisons of prokaryotic and eukaryotic IPMDH suggest that substitution of one active site residue may lead to altered substrate specificity and metabolic function. Site-directed mutagenesis of Phe-137 to a leucine in AtIPMDH1 (AtIPMDH1-F137L) reduced activity toward 3 (2'-methylthio)ethylmalate by 200-fold, but enhanced catalytic efficiency with 3 isopropylmalate to levels observed with AtIPMDH2 and AtIPMDH3. Conversely, the AtIPMDH2-L134F and AtIPMDH3-L133F mutants enhanced catalytic efficiency with 3 (2'-methylthio)ethylmalate ~100-fold and reduced activity for 3-isopropylmalate. Furthermore, the altered in vivo glucosinolate profile of an Arabidopsis ipmdh1 T DNA knock-out mutant could be restored to wild-type levels by constructs expressing AtIPMDH1, AtIPMDH2-L134F, or AtIPMDH3-L133F, but not by AtIPMDH1 F137L. These results indicate that a single amino acid substitution results in functional divergence of IPMDH in planta to affect substrate specificity and contributes to the evolution of specialized glucosinolate biosynthesis from the ancestral leucine pathway. PMID- 21697090 TI - Snapshots of enzymatic Baeyer-Villiger catalysis: oxygen activation and intermediate stabilization. AB - Baeyer-Villiger monooxygenases catalyze the oxidation of carbonylic substrates to ester or lactone products using NADPH as electron donor and molecular oxygen as oxidative reactant. Using protein engineering, kinetics, microspectrophotometry, crystallography, and intermediate analogs, we have captured several snapshots along the catalytic cycle which highlight key features in enzyme catalysis. After acting as electron donor, the enzyme-bound NADP(H) forms an H-bond with the flavin cofactor. This interaction is critical for stabilizing the oxygen activating flavin-peroxide intermediate that results from the reaction of the reduced cofactor with oxygen. An essential active-site arginine acts as anchoring element for proper binding of the ketone substrate. Its positively charged guanidinium group can enhance the propensity of the substrate to undergo a nucleophilic attack by the flavin-peroxide intermediate. Furthermore, the arginine side chain, together with the NADP(+) ribose group, forms the niche that hosts the negatively charged Criegee intermediate that is generated upon reaction of the substrate with the flavin-peroxide. The fascinating ability of Baeyer Villiger monooxygenases to catalyze a complex multistep catalytic reaction originates from concerted action of this Arg-NADP(H) pair and the flavin subsequently to promote flavin reduction, oxygen activation, tetrahedral intermediate formation, and product synthesis and release. The emerging picture is that these enzymes are mainly oxygen-activating and "Criegee-stabilizing" catalysts that act on any chemically suitable substrate that can diffuse into the active site, emphasizing their potential value as toolboxes for biocatalytic applications. PMID- 21697091 TI - Truncation, randomization, and selection: generation of a reduced length c-Jun antagonist that retains high interaction stability. AB - The DNA binding activity of the transcriptional regulator activator protein-1 shows considerable promise as a target in cancer therapy. A number of different strategies have been employed to inhibit the function of this protein with promise having been demonstrated both in vitro and in vivo. Peptide-based therapeutics have received renewed interest in the last few years, and a number of 37-amino acid peptides capable of binding to the coiled coil dimerization domain of Jun and Fos have been derived. Here, we demonstrate how truncation and semi-rational library design, followed by protein-fragment complementation, can be used to produce a leucine zipper binding peptide by iterative means. To this end, we have implemented this strategy on the FosW peptide to produce 4hFosW. This peptide is truncated by four residues with comparably favorable binding properties and demonstrates the possibility to design progressively shorter peptides to serve as leucine zipper antagonists while retaining many of the key features of the parent peptide. Whether or not the necessity for low molecular weight antagonists is required from the perspective of druggability and efficacy is subject to debate. However, antagonists of reduced length are worthy of perusal from the point of view of synthetic cost as well as identifying the smallest functional unit that is required for binding. PMID- 21697092 TI - Structural basis of multifunctionality in a vitamin B12-processing enzyme. AB - An early step in the intracellular processing of vitamin B(12) involves CblC, which exhibits dual reactivity, catalyzing the reductive decyanation of cyanocobalamin (vitamin B(12)), and the dealkylation of alkylcobalamins (e.g. methylcobalamin; MeCbl). Insights into how the CblC scaffold supports this chemical dichotomy have been unavailable despite it being the most common locus of patient mutations associated with inherited cobalamin disorders that manifest in both severe homocystinuria and methylmalonic aciduria. Herein, we report structures of human CblC, with and without bound MeCbl, which provide novel biochemical insights into its mechanism of action. Our results reveal that CblC is the most divergent member of the NADPH-dependent flavin reductase family and can use FMN or FAD as a prosthetic group to catalyze reductive decyanation. Furthermore, CblC is the first example of an enzyme with glutathione transferase activity that has a sequence and structure unrelated to the GST superfamily. CblC thus represents an example of evolutionary adaptation of a common structural platform to perform diverse chemistries. The CblC structure allows us to rationalize the biochemical basis of a number of pathological mutations associated with severe clinical phenotypes. PMID- 21697093 TI - Nicotinamide phosphoribosyltransferase is essential for interleukin-1beta mediated dedifferentiation of articular chondrocytes via SIRT1 and extracellular signal-regulated kinase (ERK) complex signaling. AB - Although much is known about interleukin (IL)-1beta and its role as a key mediator of cartilage destruction in osteoarthritis, only limited information is available on IL-1beta signaling in chondrocyte dedifferentiation. Here, we have characterized the molecular mechanisms leading to the dedifferentiation of primary cultured articular chondrocytes by IL-1beta treatment. IL-1beta or lipopolysaccharide, but not phorbol 12-myristate 13-acetate, retinoic acid, or epidermal growth factor, induced nicotinamide phosphoribosyltransferase (NAMPT) expression, showing the association of inflammatory cytokines with NAMPT regulation. SIRT1, in turn, was activated NAMPT-dependently, without any alteration in the expression level. Activation or inhibition of SIRT1 oppositevely regulates IL-1beta-mediated chondrocyte dedifferentiation, suggesting this protein as a key regulator of chondrocytes phenotype. SIRT1 activation promotes induction of ERK and p38 kinase activities, but not JNK, in response to IL-1beta. Subsequently, ERK and p38 kinase activated by SIRT1 also induce SIRT1 activation, forming a positive feedback loop to sustain downstream signaling of these kinases. Moreover, we found that the SIRT1-ERK complex, but not SIRT1-p38, is engaged in IL-1beta-induced chondrocyte dedifferentiation via a Sox-9-mediated mechanism. JNK is activated by IL-1beta and modulates dedifferentiation of chondrocytes, but this pathway is independent on NAMPT-SIRT1 signaling. Based on these findings, we propose that IL-1beta induces dedifferentiation of articular chondrocytes by up-regulation of SIRT1 activity enhanced by both NAMPT and ERK signaling. PMID- 21697094 TI - The Escherichia coli DinD protein modulates RecA activity by inhibiting postsynaptic RecA filaments. AB - Escherichia coli dinD is an SOS gene up-regulated in response to DNA damage. We find that the purified DinD protein is a novel inhibitor of RecA-mediated DNA strand exchange activities. Most modulators of RecA protein activity act by controlling the amount of RecA protein bound to single-stranded DNA by affecting either the loading of RecA protein onto DNA or the disassembly of RecA nucleoprotein filaments bound to single-stranded DNA. The DinD protein, however, acts postsynaptically to inhibit RecA during an on-going DNA strand exchange, likely through the disassembly of RecA filaments. DinD protein does not affect RecA single-stranded DNA filaments but efficiently disassembles RecA when bound to two or more DNA strands, effectively halting RecA-mediated branch migration. By utilizing a nonspecific duplex DNA-binding protein, YebG, we show that the DinD effect is not simply due to duplex DNA sequestration. We present a model suggesting that the negative effects of DinD protein are targeted to a specific conformational state of the RecA protein and discuss the potential role of DinD protein in the regulation of recombinational DNA repair. PMID- 21697095 TI - Bone morphogenetic protein-1 processes insulin-like growth factor-binding protein 3. AB - The bone morphogenetic protein-1 (BMP1)-like metalloproteinases play key roles in extracellular matrix formation, by converting precursors into mature functional proteins involved in forming the extracellular matrix. The BMP1-like proteinases also play roles in activating growth factors, such as BMP2/4, myostatin, growth differentiation factor 11, and transforming growth factor beta1, by cleaving extracellular antagonists. The extracellular insulin-like growth factor-binding proteins (IGFBPs) are involved in regulating the effects of insulin-like growth factors (IGFs) on growth, development, and metabolism. Of the six IGFBPs, IGFBP3 has the greatest interaction with the large pool of circulating IGFs. It is also produced locally in tissues and is itself regulated by proteolytic processing. Here, we show that BMP1 cleaves human and mouse IGFBP3 at a single conserved site, resulting in markedly reduced ability of cleaved IGFBP3 to bind IGF-I or to block IGF-I-induced cell signaling. In contrast, such cleavage is shown to result in enhanced IGF-I-independent ability of cleaved IGFBP3 to block FGF-induced proliferation and to induce Smad phosphorylation. Consistent with in vivo roles for such cleavage, it is shown that, whereas wild type mouse embryo fibroblasts (MEFs) produce cleaved IGFBP3, MEFs doubly null for the Bmp1 gene and for the Tll1 gene, which encodes the related metalloproteinase mammalian Tolloid-like 1 (mTLL1), produce only unprocessed IGFBP3, thus demonstrating endogenous BMP1 related proteinases to be responsible for IGFBP3-processing activity in MEFs. Similarly, in zebrafish embryos, overexpression of Bmp1a is shown to reverse an Igfbp3-induced phenotype, consistent with the ability of BMP1-like proteinases to cleave IGFBP3 in vivo. PMID- 21697096 TI - Novel functions of lipid-binding protein 5 in Caenorhabditis elegans fat metabolism. AB - The lipid-binding protein (LBP) family is conserved from Caenorhabditis elegans to mammals and essential for fatty acid homeostasis. RNAi-mediated knockdown of nine C. elegans lbp family members revealed that lbp-5 regulates fat accumulation. C. elegans LBP-5 bound directly to various fatty acids with varying affinities. lbp-5 expression in nhr-49(nr2041) worms was much lower than in N2 worms. Nhr-49 transcriptional activity also decreased with lbp-5 deletion, suggesting that they may work together as functional partners in fat metabolism. In support of this notion, LBP-5 translocated into nuclei, where it appeared to influence C. elegans NHR-49 target genes involved in energy metabolism. Interestingly, LBP-5 is required for stearic acid-induced transcription of NHR-49 target genes. Thus, this knowledge could help identify therapeutic targets to treat obesity and diseases associated with nematode-host interactions. PMID- 21697097 TI - Bioengineering anabolic vitamin D-25-hydroxylase activity into the human vitamin D catabolic enzyme, cytochrome P450 CYP24A1, by a V391L mutation. AB - CYP24A1 is a mitochondrial cytochrome P450 (CYP) that catabolizes 1alpha,25 dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) to different products: calcitroic acid or 1alpha,25-(OH)(2)D(3)-26,23-lactone via multistep pathways commencing with C24 and C23 hydroxylation, respectively. Despite the ability of CYP24A1 to catabolize a wide range of 25-hydroxylated analogs including 25-hydroxyvitamin D(3), the enzyme is unable to metabolize the synthetic prodrug, 1alpha hydroxyvitamin D(3) (1alpha-OH-D(3)), presumably because it lacks a C25-hydroxyl. In the current study we show that a single V391L amino acid substitution in the beta3a-strand of human CYP24A1 converts this enzyme from a catabolic 1alpha,25 (OH)(2)D(3)-24-hydroxylase into an anabolic 1alpha-OH-D(3)-25-hydroxylase, thereby forming the hormone, 1alpha,25-(OH)(2)D(3). Furthermore, because the mutant enzyme retains its basal ability to catabolize 1alpha,25-(OH)(2)D(3) via C24 hydroxylation, it can also make calcitroic acid. Previous work has shown that an A326G mutation is responsible for the regioselectivity differences observed between human (primarily C24-hydroxylating) and opossum (C23-hydroxylating) CYP24A1. When the V391L and A326G mutations were combined (V391L/A326G), the mutant enzyme continued to form 1alpha,25-(OH)(2)D(3) from 1alpha-OH-D(3), but this initial product was diverted via the C23 hydroxylation pathway into the 26,23-lactone. The relative position of Val-391 in the beta3a-strand of a homology model and the crystal structure of rat CYP24A1 is consistent with hydrophobic contact of Val-391 and the substrate side chain near C21. We interpret that the substrate specificity of V391L-modified human CYP24A1 toward 1alpha-OH-D(3) is enabled by an altered contact with the substrate side chain that optimally positions C25 of the 1alpha-OH-D(3) above the heme for hydroxylation. PMID- 21697099 TI - Ongoing GC-biased evolution is widespread in the human genome and enriched near recombination hot spots. AB - Fast evolving regions of many metazoan genomes show a bias toward substitutions that change weak (A,T) into strong (G,C) base pairs. Single-nucleotide polymorphisms (SNPs) do not share this pattern, suggesting that it results from biased fixation rather than biased mutation. Supporting this hypothesis, analyses of polymorphism in specific regions of the human genome have identified a positive correlation between weak to strong (W->S) SNPs and derived allele frequency (DAF), suggesting that SNPs become increasingly GC biased over time, especially in regions of high recombination. Using polymorphism data generated by the 1000 Genomes Project from 179 individuals from 4 human populations, we evaluated the extent and distribution of ongoing GC-biased evolution in the human genome. We quantified GC fixation bias by comparing the DAFs of W->S mutations and S->W mutations using a Mann-Whitney U test. Genome-wide, W->S SNPs have significantly higher DAFs than S->W SNPs. This pattern is widespread across the human genome but varies in magnitude along the chromosomes. We found extreme GC biased evolution in neighborhoods of recombination hot spots, a significant correlation between GC bias and recombination rate, and an inverse correlation between GC bias and chromosome arm length. These findings demonstrate the presence of ongoing fixation bias favoring G and C alleles throughout the human genome and suggest that the bias is caused by a recombination-associated process, such as GC-biased gene conversion. PMID- 21697098 TI - Differential loss and retention of cytoglobin, myoglobin, and globin-E during the radiation of vertebrates. AB - If rates of postduplication gene retention are positively correlated with levels of functional constraint, then gene duplicates that have been retained in a restricted number of taxonomic lineages would be expected to exhibit relatively low levels of sequence conservation. Paradoxical patterns are presented by gene duplicates that have been retained in a small number of taxa but which are nonetheless subject to strong purifying selection relative to paralogous members of the same multigene family. This pattern suggests that such genes may have been co-opted for novel, lineage-specific functions. One possible example involves the enigmatic globin-E gene (GbE), which appears to be exclusively restricted to birds. Available data indicate that this gene is expressed exclusively in the avian eye, but its physiological function remains a mystery. In contrast to the highly restricted phyletic distribution of GbE, the overwhelming majority of jawed vertebrates (gnathostomes) possess copies of the related cytoglobin (Cygb) and myoglobin (Mb) genes. The purpose of the present study was 1) to assess the phyletic distribution of the Cygb, Mb, and GbE genes among vertebrates, 2) to elucidate the duplicative origins and evolutionary histories of these three genes, and 3) to evaluate the relative levels of functional constraint of these genes based on comparative sequence analysis. To accomplish these objectives, we conducted a combined phylogenetic and comparative genomic analysis involving taxa that represent each of the major lineages of gnathostome vertebrates. Results of synteny comparisons and phylogenetic topology tests revealed that GbE is clearly not the product of a recent, bird-specific duplication event. Instead, GbE originated via duplication of a proto-Mb gene in the stem lineage of gnathostomes. Unlike the Mb gene, which has been retained in all major gnathostome lineages other than amphibians, the GbE gene has been retained only in the lineage leading to modern birds and has been independently lost in at least four major lineages: teleost fish, amphibians, mammals, and nonavian reptiles. Despite the restricted phyletic distribution of this gene, our results indicate that GbE is one of the most highly conserved globins in the avian genome. PMID- 21697105 TI - Learning disability and contraceptive decision-making. PMID- 21697106 TI - "He seized her in his manly arms and bent his lips to hers...". The surprising impact that romantic novels have on our work. PMID- 21697100 TI - Dynamics of gene duplication in the genomes of chlorophyll d-producing cyanobacteria: implications for the ecological niche. AB - Gene duplication may be an important mechanism for the evolution of new functions and for the adaptive modulation of gene expression via dosage effects. Here, we analyzed the fate of gene duplicates for two strains of a novel group of cyanobacteria (genus Acaryochloris) that produces the far-red light absorbing chlorophyll d as its main photosynthetic pigment. The genomes of both strains contain an unusually high number of gene duplicates for bacteria. As has been observed for eukaryotic genomes, we find that the demography of gene duplicates can be well modeled by a birth-death process. Most duplicated Acaryochloris genes are of comparatively recent origin, are strain-specific, and tend to be located on different genetic elements. Analyses of selection on duplicates of different divergence classes suggest that a minority of paralogs exhibit near neutral evolutionary dynamics immediately following duplication but that most duplicate pairs (including those which have been retained for long periods) are under strong purifying selection against amino acid change. The likelihood of duplicate retention varied among gene functional classes, and the pronounced differences between strains in the pool of retained recent duplicates likely reflects differences in the nutrient status and other characteristics of their respective environments. We conclude that most duplicates are quickly purged from Acaryochloris genomes and that those which are retained likely make important contributions to organism ecology by conferring fitness benefits via gene dosage effects. The mechanism of enhanced duplication may involve homologous recombination between genetic elements mediated by paralogous copies of recA. PMID- 21697108 TI - A touch of the vapours... PMID- 21697109 TI - The pen is dead. Long live the pen. PMID- 21697113 TI - Improving the clarity and consistency of advice on missed contraceptive pills in the UK. PMID- 21697114 TI - Injectable local anaesthetic for IUD/IUS fittings: author's response. PMID- 21697115 TI - Early medical abortion at home. PMID- 21697116 TI - Option of local anaesthetic for IUD fittings. PMID- 21697117 TI - Preventing teenage pregnancies and abortions: is it attainable? PMID- 21697119 TI - Mirena(r) removal from a nulliparous woman. PMID- 21697122 TI - Identification of novel transcripts in annotated genomes using RNA-Seq. AB - SUMMARY: We describe a new 'reference annotation based transcript assembly' problem for RNA-Seq data that involves assembling novel transcripts in the context of an existing annotation. This problem arises in the analysis of expression in model organisms, where it is desirable to leverage existing annotations for discovering novel transcripts. We present an algorithm for reference annotation-based transcript assembly and show how it can be used to rapidly investigate novel transcripts revealed by RNA-Seq in comparison with a reference annotation. AVAILABILITY: The methods described in this article are implemented in the Cufflinks suite of software for RNA-Seq, freely available from http://bio.math.berkeley.edu/cufflinks. The software is released under the BOOST license. CONTACT: cole@broadinstitute.org; lpachter@math.berkeley.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21697123 TI - In-depth annotation of SNPs arising from resequencing projects using NGS-SNP. AB - SUMMARY: NGS-SNP is a collection of command-line scripts for providing rich annotations for SNPs identified by the sequencing of whole genomes from any organism with reference sequences in Ensembl. Included among the annotations, several of which are not available from any existing SNP annotation tools, are the results of detailed comparisons with orthologous sequences. These comparisons can, for example, identify SNPs that affect conserved residues, or alter residues or genes linked to phenotypes in another species. AVAILABILITY: NGS-SNP is available both as a set of scripts and as a virtual machine. The virtual machine consists of a Linux operating system with all the NGS-SNP dependencies pre installed. The source code and virtual machine are freely available for download at http://stothard.afns.ualberta.ca/downloads/NGS-SNP/. CONTACT: stothard@ualberta.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21697124 TI - MetaABC--an integrated metagenomics platform for data adjustment, binning and clustering. AB - SUMMARY: MetaABC is a metagenomic platform that integrates several binning tools coupled with methods for removing artifacts, analyzing unassigned reads and controlling sampling biases. It allows users to arrive at a better interpretation via series of distinct combinations of analysis tools. After execution, MetaABC provides outputs in various visual formats such as tables, pie and bar charts as well as clustering result diagrams. AVAILABILITY: MetaABC source code and documentation are available at http://bits2.iis.sinica.edu.tw/MetaABC/ CONTACT: dywang@gate.sinica.edu.tw; hktsai@iis.sinica.edu.tw SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21697125 TI - GeneNetWeaver: in silico benchmark generation and performance profiling of network inference methods. AB - MOTIVATION: Over the last decade, numerous methods have been developed for inference of regulatory networks from gene expression data. However, accurate and systematic evaluation of these methods is hampered by the difficulty of constructing adequate benchmarks and the lack of tools for a differentiated analysis of network predictions on such benchmarks. RESULTS: Here, we describe a novel and comprehensive method for in silico benchmark generation and performance profiling of network inference methods available to the community as an open source software called GeneNetWeaver (GNW). In addition to the generation of detailed dynamical models of gene regulatory networks to be used as benchmarks, GNW provides a network motif analysis that reveals systematic prediction errors, thereby indicating potential ways of improving inference methods. The accuracy of network inference methods is evaluated using standard metrics such as precision recall and receiver operating characteristic curves. We show how GNW can be used to assess the performance and identify the strengths and weaknesses of six inference methods. Furthermore, we used GNW to provide the international Dialogue for Reverse Engineering Assessments and Methods (DREAM) competition with three network inference challenges (DREAM3, DREAM4 and DREAM5). AVAILABILITY: GNW is available at http://gnw.sourceforge.net along with its Java source code, user manual and supporting data. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. CONTACT: dario.floreano@epfl.ch. PMID- 21697126 TI - ontoCAT: an R package for ontology traversal and search. AB - MOTIVATION: There exist few simple and easily accessible methods to integrate ontologies programmatically in the R environment. We present ontoCAT-an R package to access ontologies in widely used standard formats, stored locally in the filesystem or available online. The ontoCAT package supports a number of traversal and search functions on a single ontology, as well as searching for ontology terms across multiple ontologies and in major ontology repositories. AVAILABILITY: The package and sources are freely available in Bioconductor starting from version 2.8: http://bioconductor.org/help/bioc views/release/bioc/html/ontoCAT.html or via the OntoCAT website http://www.ontocat.org/wiki/r. CONTACT: natalja@ebi.ac.uk; natalja@ebi.ac.uk. PMID- 21697127 TI - A procedure to statistically evaluate agreement of differential expression for cross-species genomics. AB - MOTIVATION: Animal models play a pivotal role in translation biomedical research. The scientific value of an animal model depends on how accurately it mimics the human disease. In principle, microarrays collect the necessary data to evaluate the transcriptomic fidelity of an animal model in terms of the similarity of expression with the human disease. However, statistical methods for this purpose are lacking. RESULTS: We develop the agreement of differential expression (AGDEX) procedure to measure and determine the statistical significance of the similarity of the results of two experiments that measure differential expression across two groups. AGDEX defines a metric of agreement and determines statistical significance by permutation of each experiment's group labels. Additionally, AGDEX performs a comprehensive permutation-based analysis of differential expression for each experiment, including gene-set analyses and meta-analytic integration of results across studies. As an example, we show how AGDEX was recently used to evaluate the similarity of the transcriptome of a novel model of the brain tumor ependymoma in mice to that of a subtype of the human disease. This result, combined with other observations, helped us to infer the cell of origin of this devastating human cancer. AVAILABILITY: An R package is currently available from www.stjuderesearch.org/site/depts/biostats/agdex and will shortly be available from www.bioconductor.org. PMID- 21697128 TI - Metab: an R package for high-throughput analysis of metabolomics data generated by GC-MS. AB - MOTIVATION: The Automated Mass Spectral Deconvolution and Identification System (AMDIS) is freeware extensively applied in metabolomics. However, datasets processed by AMDIS require extensive data correction, filtering and reshaping to create reliable datasets for further downstream analysis. Performed manually, these processes are laborious and extremely time consuming. Furthermore, manual corrections increase the chance of human error and can introduce additional technical variability to the data. Thus, an automated pipeline for curating GC-MS data is urgently needed. RESULTS: We present the Metab R package designed to automate the pipeline for analysis of metabolomics GC-MS datasets processed by AMDIS. AVAILABILITY: The Metab package, the AMDIS library and the reference ion library are available at www.metabolomics.auckland.ac.nz/index.php/downloads. CONTACT: k.ruggiero@auckland.ac.nz. PMID- 21697129 TI - JSBML: a flexible Java library for working with SBML. AB - SUMMARY: The specifications of the Systems Biology Markup Language (SBML) define standards for storing and exchanging computer models of biological processes in text files. In order to perform model simulations, graphical visualizations and other software manipulations, an in-memory representation of SBML is required. We developed JSBML for this purpose. In contrast to prior implementations of SBML APIs, JSBML has been designed from the ground up for the Java programming language, and can therefore be used on all platforms supported by a Java Runtime Environment. This offers important benefits for Java users, including the ability to distribute software as Java Web Start applications. JSBML supports all SBML Levels and Versions through Level 3 Version 1, and we have strived to maintain the highest possible degree of compatibility with the popular library libSBML. JSBML also supports modules that can facilitate the development of plugins for end user applications, as well as ease migration from a libSBML-based backend. AVAILABILITY: Source code, binaries and documentation for JSBML can be freely obtained under the terms of the LGPL 2.1 from the website http://sbml.org/Software/JSBML. PMID- 21697130 TI - SNPman: a program for genotype calling using run data from TaqMan allelic discrimination. AB - SUMMARY: The SNPman program calls the genotypes of single nucleotide polymorphisms (SNP) from TaqMan allelic discrimination assays. It utilizes the fluorescence data collected over the whole PCR run, rather than relying on the end point fluorescence measurements that is the basis of the genotype calling process in most software solutions sold with the real-time instruments. This inspection of run data facilitates genotype calls in difficult sample sets, especially in those containing various concentrations of DNA or inhibitors, as indicated by results of a reanalysis of 3738 genotyping samples. The program works with data from three different widely used PCR instruments. AVAILABILITY: The compiled program is available online at http://sourceforge.net/projects/snpman/files/, along with its user documentation and demonstration data files. It is free of charge for non-commercial users. CONTACT: Ondrej.Cinek@Lfmotol.cuni.cz SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21697131 TI - Response to "Comments on 'Bayesian variable selection for disease classification using gene expression data'". PMID- 21697132 TI - SEAL: a distributed short read mapping and duplicate removal tool. AB - SUMMARY: SEAL is a scalable tool for short read pair mapping and duplicate removal. It computes mappings that are consistent with those produced by BWA and removes duplicates according to the same criteria employed by Picard MarkDuplicates. On a 16-node Hadoop cluster, it is capable of processing about 13 GB per hour in map+rmdup mode, while reaching a throughput of 19 GB per hour in mapping-only mode. AVAILABILITY: SEAL is available online at http://biodoop seal.sourceforge.net/. PMID- 21697133 TI - Full-length transcriptome analysis of human retina-derived cell lines ARPE-19 and Y79 using the vector-capping method. AB - PURPOSE. To collect an entire set of full-length cDNA clones derived from human retina-derived cell lines and to identify full-length transcripts for retinal preferentially expressed genes. METHODS. The full-length cDNA libraries were constructed from a retinoblastoma cell line, Y79, and a retinal pigment epithelium cell line, ARPE-19, using the vector-capping method, which generates a genuine full-length cDNA. By single-pass sequencing of the 5'-end of cDNA clones and subsequent mapping to the human genome, the authors determined their transcriptional start sites and annotated the cDNA clones. RESULTS. Of the 23,616 clones isolated from Y79-derived cDNA libraries, 19,229 full-length cDNA clones were identified and classified into 4808 genes, including genes of >10 kbp. Of the 7067 genes obtained from the Y79 and ARPE-19 libraries, the authors selected 72 genes that were preferentially expressed in the eye, of which 131 clones corresponding to 57 genes were fully sequenced. As a result, we discovered many variants that were produced by different transcriptional start sites, alternative splicing, and alternative polyadenylation. CONCLUSIONS. The bias-free, full length cDNA libraries constructed using the vector-capping method were shown to be useful for collecting an entire set of full-length cDNA clones for these retinal cell lines. Full-length transcriptome analysis of these cDNA libraries revealed that there were, unexpectedly, many transcript variants for each gene, indicating that obtaining the full-length cDNA for each variant is indispensable for analyzing its function. The full-length cDNA clones (approximately 80,000 clones each for ARPE-19 and Y79) will be useful as a resource for investigating the human retina. PMID- 21697134 TI - Role of adenosine in the control of choroidal blood flow during changes in ocular perfusion pressure. AB - PURPOSE: The purpose of the present study was to investigate whether the nucleoside adenosine is involved in the regulatory processes of choroidal blood flow (ChBF) during an experimental decrease in ocular perfusion pressure (OPP). METHODS: In this randomized, double-masked, placebo-controlled, two-way crossover study, 14 subjects received either intravenous adenosine or placebo on two different study days. The suction cup method was used for a stepwise increase in intraocular pressure (IOP). Subfoveal ChBF was measured by laser Doppler flowmetry. Mean arterial pressure (MAP) and IOP were measured noninvasively. Ocular perfusion pressure was calculated as OPP = 2/3MAP - IOP. RESULTS: Adenosine increased ChBF significantly versus placebo before application of the suction cup (P < 0.05). When the suction cup was applied, a significant decrease in OPP was observed. This effect was comparable on all study days. The decrease in OPP was paralleled by a significant decrease in ChBF (maximum between -43% and -52%) which was less pronounced than the decrease in OPP (maximum between -62% and -64%). Neither placebo nor adenosine influenced the ChBF increase during suction cup-induced changes in OPP. CONCLUSIONS: The data of the present study confirm that the human choroid shows some regulatory capacity during a decrease in OPP. Adenosine influences basal vascular tone in the choroid but is not involved in the regulatory mechanisms during an increase in IOP. (ClinicalTrials.gov number, NCT00712764.). PMID- 21697135 TI - Mitochondria-targeted peptide MTP-131 alleviates mitochondrial dysfunction and oxidative damage in human trabecular meshwork cells. AB - PURPOSE: To investigate the antioxidative ability of a novel mitochondria targeted peptide MTP-131 in immortalized human trabecular meshwork (iHTM) and glaucomatous human trabecular meshwork (GTM(3)) cell lines. METHODS: Cultured iHTM and GTM(3) cells were pretreated with MTP-131 for 1 hour, and sustained oxidative stress was induced by subjecting TM cells to 200 MUM hydrogen peroxide (H(2)O(2)) for 24 hours. Untreated cells and cells incubated with H(2)O(2) alone were used as controls. Lactate dehydrogenase (LDH) assay was used to determine cell viability. Changes of mitochondrial membrane potential (DeltaPsim) and generation of intracellular reactive oxygen species (ROS) were analyzed by flow cytometry and confocal microscopy. Activation of caspase 3 was quantified by Western blotting, and apoptosis was measured by flow cytometry. Release of cytochrome c and changes in cytoskeleton were analyzed by confocal microscopy. Data were analyzed with commercial data analysis software and P < 0.05 was considered to be statistically significant. RESULTS: In both iHTM and GTM(3) cells, decrease of DeltaPsim and elevation of intracellular ROS were detected after sustained oxidative stress induced by H(2)O(2). When cells were pretreated with MTP-131, the H(2)O(2)-induced mitochondrial depolarization was prevented; intracellular ROS, LDH release, and apoptosis were significantly decreased; release of cytochrome c from mitochondria to cytoplasm and activation of caspase 3 were inhibited. In addition, cytoskeleton changes caused by H(2)O(2) were also alleviated by MTP-131. CONCLUSIONS: Mitochondria-targeted peptide MTP-131 could prevent both iHTM and GTM(3) cells from sustained oxidative stress induced by H(2)O(2). PMID- 21697136 TI - Proteomic profiling of inflammatory signaling molecules in the tears of patients on chronic glaucoma medication. AB - PURPOSE: To identify the tear proteins associated with the long-term use of glaucoma medication by using proteomic analysis and to compare these proteins to those previously reported in primary dry eye disease. METHODS: Eighteen patients treated with topical antiglaucoma medications and 10 normal age-matched subjects with no prior topical treatment were recruited for the study. Tears were collected by using Schirmer's strip and analyzed by iTRAQ (isobaric tag for relative and absolute quantitation) for tear proteins by mass spectrometry. Conjunctival samples were collected and RNA expression determined by PCR. RESULTS: Of the 124 identified tear proteins (99% confidence, ProtScore >= 2.0), we found that the tear levels of S100-A8, S100-A9, mammaglobin B, and 14-3-3 zeta/delta were significantly increased in the medicated group compared with levels in the nonmedicated group (P < 0.05). For S100-A9, mammaglobin B, and 14-3 3 zeta/delta, use of topical medication for less than 1 year did not reach statistical significance compared with that in the nonmedicated group. Eyes on topical medication for less than 1 year showed a decrease in proline-rich 4 protein tear level (P = 0.0049) compared to nonmedicated group. The tear proteins detected in the medicated group differed from those in the primary dry eye group. CONCLUSIONS: Treatment with topical antiglaucoma medications for longer than 1 year may start to induce ocular surface inflammation. The inflammatory tear protein profile present in chronically medicated glaucomatous eyes appears to be different from that found in primary dry eye. Identification of tear proteins specific to medicated glaucomatous eyes will help to specifically develop targeted screening modalities and therapeutic agents different from current conventional dry eye management. PMID- 21697137 TI - Surgical resection of highly suspicious pulmonary nodules without a tissue diagnosis. AB - OBJECTIVE: The safety and efficacy of surgical resection of lung nodule without tissue diagnosis is controversial. We evaluated direct surgical resection of highly suspicious pulmonary nodules and the clinical and radiological predictors of malignancy. METHODS: Retrospective analyses were performed on 113 patients who underwent surgical resection without prior tissue diagnosis for highly suspicious pulmonary nodules. Clinical and radiological characteristics were compared between histologically proven benign and malignant nodules after resection. Total costs, length of hospitalization and waiting time to surgery were compared with those of patients who had tissue diagnosis prior to surgery. RESULTS: Among 280 patients with pulmonary nodules suspicious for lung cancer, 113 (40.4%) underwent operation without prior tissue diagnosis. Lung nodules were diagnosed as malignant in 96 (85%) of the 113 patients. Except for forced expiratory volume in 1 s, clinical characteristics were not significantly different according to the pathologic results. Forty-five (90%) of 50 patients with ground-glass opacity nodules had a malignancy. Mixed ground-glass opacity, bubble lucency, irregular margin and larger size correlated with malignancy in ground-glass opacity nodules (P<0.05). Fifty-one (81%) of 67 patients with solid nodules had a malignancy. Spiculation, pre-contrast attenuation and contrast enhancement significantly correlated with malignancy in solid nodules (P<0.05). Surgical resection without tissue diagnosis significantly decreased total costs, hospital stay and waiting time (P<0.05). CONCLUSIONS: Direct surgical resection of highly suspicious pulmonary nodules can be a valid procedure. However, careful patient selection and further investigations are required to justify direct surgical resection. PMID- 21697138 TI - Empirical correlates of low scores on MMPI-2/MMPI-2-RF restructured clinical scales in a sample of university students. AB - In the present study, the authors explored the meaning of low scores on the MMPI 2/MMPI-2-RF restructured clinical (RC) scales. Using responses of a sample of university students (N = 811), the authors examined whether low (T < 39), within normal-limits (T = 39-64), and high (T > 65) score levels on the RC scales are differentially associated with multidimensional personality questionnaire (MPQ) defined personality descriptions. Eleven primary MPQ scales and three higher order MPQ scales (negative emotionality, positive emotionality, and constraint) were used to yield these descriptions. MANOVAs were conducted for each RC scale and followed up by univariate ANOVAs and post hoc Dunnett T3 tests to identify reliable RC-scale-defined group differences for the individual MPQ scales. For those cases that exhibited significant differences between the low and within normal subgroups on the Dunnett T3 tests, effect sizes were computed. The authors identified and discussed meaningful MPQ-based personality characteristics of the low scoring subjects. PMID- 21697140 TI - Symptom prevalence in advanced cancer: age, gender, and performance status interactions. AB - Age, gender, and performance status (PS) are important patient characteristics which might influence to cancer symptom profile. We conducted a secondary analysis of a symptom database to examine any interaction of these factors on symptom prevalence. 38 symptoms were assessed in 1000 consecutive patients with advanced cancer. The association of the three demographic factors with each symptom was examined using logistic regression analysis. Eight symptoms were associated with more than one of the three factors. Model-based estimates of symptom prevalence were calculated for 30 groups based on combinations of age, gender, and ECOG PS (0-4). Prevalence differences between various groups >10% were empirically classified as clinically relevant. The frequency of all eight symptoms (pain, constipation, sleep problems, nausea, anxiety, vomiting, sedation, and blackouts) was associated with more than one of the demographic characteristics of age, gender, and PS level. The prevalence of all eight decreased with older age. Females had more nausea, anxiety, and vomiting than males; males greater sleep problems. The prevalence of constipation, sedation, and blackouts was higher with worse PS, whereas pain and anxiety became less common with worse PS. Age, gender, and PS appeared to be associated with variations in the prevalence of eight gastrointestinal and neuropsychological symptoms in cancer patients. They should be included as important variables in clinical practice symptom research data. PMID- 21697139 TI - Item banks for measuring emotional distress from the Patient-Reported Outcomes Measurement Information System (PROMIS(r)): depression, anxiety, and anger. AB - The authors report on the development and calibration of item banks for depression, anxiety, and anger as part of the Patient-Reported Outcomes Measurement Information System (PROMIS(r)). Comprehensive literature searches yielded an initial bank of 1,404 items from 305 instruments. After qualitative item analysis (including focus groups and cognitive interviewing), 168 items (56 for each construct) were written in a first person, past tense format with a 7 day time frame and five response options reflecting frequency. The calibration sample included nearly 15,000 respondents. Final banks of 28, 29, and 29 items were calibrated for depression, anxiety, and anger, respectively, using item response theory. Test information curves showed that the PROMIS item banks provided more information than conventional measures in a range of severity from approximately -1 to +3 standard deviations (with higher scores indicating greater distress). Short forms consisting of seven to eight items provided information comparable to legacy measures containing more items. PMID- 21697141 TI - Explanations of AD in ethnic minority participants undergoing cognitive screening. AB - The purpose of this study was to describe and compare explanations of Alzheimer's disease (AD) of African American, Afro-Caribbean, and European American older adults undergoing cognitive screening. Participants were asked a series of open ended questions regarding what they knew about AD and if they were experiencing memory problems. Responses were coded and quantized for analysis. Forty percent reported experiencing memory problems. Afro-Caribbeans made significantly more incorrect statements about AD and were less likely to identify memory loss as a symptom. Half the participants said they would seek their physician's advice if the screening was positive; none mentioned a memory disorder center. Misconceptions about AD included the effect of aluminum, brain collapse, relaxed brain, shaking, tremors, and physical illness. More Afro-Caribbeans, all of whom were first generation, had misconceptions about AD. Campaigns to educate the public about AD need to provide culturally sensitive and appropriate information to ethnic minority populations. PMID- 21697142 TI - Treating sleep problems in dementia caregivers based on parent-child interventions. AB - BACKGROUND: Interventions developed for improving sleep in parents of young children or in developmentally delayed children might also prove effective for persons with dementia and their caregivers. METHODS: We selectively reviewed the literature for interventions effective in improving sleep in parents of young children or in developmentally delayed children. RESULTS: Graduated extinction and adult fading have been minimally explored in dementia populations. They are fairly brief and could be administered during primary care or dementia clinic visits. Combination strategies such as extinction and sleep-enhancing medication are very effective and may be applicable for persons with dementia and their caregivers. Physical capabilities and degree of cognitive decline of patients with dementia must be considered, and medical staff and caregivers should adjust behavioral strategies to maximize the use of patients' intact cognitive abilities. CONCLUSIONS: Interventions for divergent populations prone to similar problems as those of patients with dementia might be effective and advance existing research. PMID- 21697143 TI - Mattis Dementia Rating Scale 2: screening for MCI and dementia. AB - Identifying patients at higher risk of developing dementia is important. The usefulness of the Mattis Dementia Rating scale-Second Edition (MDRS-2) to detect and differentiate between patients with amnestic mild cognitive impairment (A MCI), Parkinson's disease and MCI (PD-MCI), PD with dementia (PDD), and Alzheimer's disease (AD) was investigated. In all, 22 healthy controls (HC), 22 A MCI, 22 PD-MCI, 16 PDD, and 22 AD patients were evaluated using an extensive neuropsychological battery, including the MDRS-2. The MDRS-2 total standardized score detected all groups of patients. The dementia groups performed worse than HC on the 5 MDRS-2 subscales. Alzheimer's disease patients scored higher than PDD on MDRS-2 conceptualization and lower on memory. Healthy controls were better than PD-MCI on MDRS-2 initiation/perseveration and memory and better than A-MCI on memory. No difference was found between the MCI groups. The MDRS-2 is a suitable short scale for MCI and dementia screening but is not specific enough to differentiate between A-MCI and PD-MCI. PMID- 21697144 TI - Experiences and perceptions of culturally and linguistically diverse family carers of people with dementia. AB - Dementia incidence rates are rapidly increasing among culturally and linguistically diverse (CALD) Australians, and there is very little local research to inform practice. In response, a qualitative study employing focus group methods was undertaken with carers from 4 CALD communities-Arabic-speaking, Chinese-speaking, Italian-speaking and, Spanish-speaking. The study examined the experiences and perceptions of these family carers with regard to their caregiving for a person living with dementia (PLWD). Analysis revealed that while considerable similarities exist across the experiences and perceptions of carers from all 4 CALD communities, there were nevertheless some important distinctions across the different groups. These study findings have significant implications for those working with CALD communities. PMID- 21697146 TI - Segment-specific differences in the inward rectifier K(+) current along the renal interlobular artery. AB - AIMS: We investigated the role of the inward rectifier K(+) channel (K(IR)) in the renal interlobular artery (ILA). The ILA supplies the afferent arteriole and ranges in diameter from >100 um near its origin at the arcuate artery to <30 um at its most distal segment. METHODS AND RESULTS: Vasodilatory responses to elevated extracellular K(+) (15 mmol/L) and vasoconstrictor responses due to K(IR) blockade by Ba(2+) (10-100 umol/L) were assessed in in vitro perfused hydronephrotic rat kidneys. The distal ILA (26 +/- 1 um) exhibited K(+)-induced dilation and Ba(2+)-induced vasoconstriction, whereas neither response was observed in the proximal ILA (108 +/- 3 um). The intermediate ILA (55 +/- 1 um) exhibited a modest K(+)-induced vasodilatation, but no Ba(2+)-induced vasoconstriction. The K(+)-induced dilations were blocked by Ba(2+), but not by ouabain. Ba(2+)-induced depolarization, measured in ILA segments from normal kidneys, decreased with the increasing diameter. Patch-clamp studies demonstrated that the K(IR) current (I(KIR)) density also was inversely correlated with ILA segment diameter. Myocytes from afferent arterioles and distal ILAs exhibited similarly large I(KIR), whereas this current was absent in proximal ILA myocytes. Finally, we found that Ba(2+) attenuated myogenic vasoconstriction, suggesting an involvement of I(KIR). The previously shown pattern of myogenic reactivity of the ILA (distal > intermediate > proximal) mirrors the distribution of I(KIR) reported in the present study, further supporting a role for I(KIR). CONCLUSION: Our findings indicate differences in the magnitude of I(KIR) along the ILA and suggest that the influence of K(IR) on reactivity increases as vessel diameter decreases from proximal to distal regions. PMID- 21697147 TI - Photosynthetic responses of field-grown Pinus radiata trees to artificial and aphid-induced defoliation. AB - The phloem-feeding aphid Essigella californica represents a potential threat to the productivity of Pinus radiata plantations in south-eastern Australia. Five- and nine-year-old field trials were used to characterize the effects of artificial and natural aphid-induced (E. californica) defoliation, respectively, on shoot photosynthesis and growth. Photosynthetic capacity (A(max)) was significantly greater following a 25% (D25) (13.8 umol m(-2) s(-1)) and a 50% (D50) (15.9 umol m(-2) s(-1)) single-event upper-crown artificial defoliation, 3 weeks after defoliation than in undefoliated control trees (12.9 umol m(-2) s( 1)). This response was consistently observed for up to 11 weeks after the defoliation event; by Week 16, there was no difference in A(max) between control and defoliated trees. In the D50 treatment, this increased A(max) was not sufficient to fully compensate for the foliage loss as evidenced by the reduced diameter increment (by 15%) in defoliated trees 36 weeks after defoliation. In contrast, diameter increment of trees in the D25 treatment was unaffected by defoliation. The A(max) of trees experiencing upper-crown defoliation by natural and repeated E. californica infestations varied, depending on host genotype. Despite clear differences in defoliation levels between resistant and susceptible genotypes (17 vs. 35% of tree crown defoliated, respectively), growth of susceptible genotypes was not significantly different from that of resistant genotypes. The observed increases in A(max) in the lower crown of the canopy following attack suggested that susceptible genotypes were able to partly compensate for the loss of foliage by compensatory photosynthesis. The capacity of P. radiata to regulate photosynthesis in response to natural aphid-induced defoliation provides evidence that the impact of E. californica attack on stem growth will be less than expected, at least for up to 35% defoliation. PMID- 21697145 TI - NCX is an important determinant for premature ventricular activity in a drug induced model of Andersen-Tawil syndrome. AB - AIMS: Andersen-Tawil syndrome (ATS1)-associated ventricular arrhythmias are initiated by premature ventricular activity (PVA) resulting from diastolic Ca(2+) (Ca(D)) accumulation. We hypothesized that relatively high Na(+)-Ca(2+) exchanger (NCX) expression coupled with slower Ca(2+) uptake may constitute an arrhythmogenic substrate during drug-induced ATS1 (DI-ATS1). METHODS AND RESULTS: DI-ATS1 was induced with 10 umol/L BaCl(2) and 2 mmol/L [K(+)](o). Ca(2+) transients and action potentials were optically mapped from Langendorff-perfused guinea pig ventricles. Intracellular Ca(2+) handling was modulated by either direct NCX inhibition with 5 umol/L KB-R7943 or by sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) inhibition with cyclopiazonic acid (CPA). During DI-ATS1, PVA was more frequent in left ventricular (LV)-base (LVB) vs. LV-apex (LVA) (2.2 +/- 0.8 vs. 0.6 +/- 0.3 PVA/10 min), consistent with greater Ca(D) (1.65 +/- 0.13 vs. 1.42 +/- 0.09 normalized-Ca(D) units) and western blot-assessed NCX protein expression (81.2 +/- 30.9%) in LVB relative to LVA. Further, regions of high NCX (LVB) evidenced a shorter PVA coupling interval relative to regions of low NCX expression (LVA, 67.7 +/- 3.5 vs. 78.5 +/- 3.6%). Inhibiting NCX during DI-ATS1 lowered the incidence of ventricular tachycardias (VTs, 0 vs. 25%) and PVA (1.5 +/- 0.4 vs. 4.3 +/- 1.4 PVA/10 min), but it did not affect PVA coupling intervals in LVB nor LVA (70.8 +/- 4.3 vs. 73.8 +/- 2.5%). Conversely, inhibition of SERCA2a with CPA, thereby increasing the role of NCX in Ca(2+) handling, significantly increased the incidence of VTs and PVA relative to DI-ATS1 alone, while decreasing the PVA coupling interval in all regions. CONCLUSION: PVA preferentially occurs in regions of enhanced NCX expression with relatively slower Ca(2+) uptake and during perfusion of CPA which further reduces sarcoplasmic reticular Ca(2+) uptake. PMID- 21697148 TI - Differentiation in light energy dissipation between hemiepiphytic and non hemiepiphytic Ficus species with contrasting xylem hydraulic conductivity. AB - Hemiepiphytic Ficus species (Hs) possess traits of more conservative water use compared with non-hemiepiphytic Ficus species (NHs) even during their terrestrial growth phase, which may result in significant differences in photosynthetic light use between these two growth forms. Stem hydraulic conductivity, leaf gas exchange and chlorophyll fluorescence were compared in adult trees of five Hs and five NHs grown in a common garden. Hs had significantly lower stem hydraulic conductivity, lower stomatal conductance and higher water use efficiency than NHs. Photorespiration played an important role in avoiding photoinhibition at high irradiance in both Hs and NHs. Under saturating irradiance levels, Hs tended to dissipate a higher proportion of excessive light energy through thermal processes than NHs, while NHs dissipated a larger proportion of electron flow than Hs through the alternative electron sinks. No significant difference in maximum net CO2 assimilation rate was found between Hs and NHs. Stem xylem hydraulic conductivity was positively correlated with maximum electron transport rate and negatively correlated with the quantum yield of non-photochemical quenching across the 10 studied Ficus species. These findings indicate that a canopy growth habit during early life stages in Hs of Ficus resulted in substantial adaptive differences from congeneric NHs not only in water relations but also in photosynthetic light use and carbon economy. The evolution of epiphytic growth habit, even for only part of their life cycle, involved profound changes in a suite of inter-correlated ecophysiological traits that persist to a large extent even during the later terrestrial growth phase. PMID- 21697149 TI - Posttraumatic growth of injured patients after motor vehicle accidents: an interpretative phenomenological analysis. AB - This study aimed to explore the process of posttraumatic growth of injured patients after a motor vehicle accident in China. Semi-structured interviews were conducted with six patients. Transcripts were analyzed using interpretative phenomenological analysis. Four main super-ordinate themes emerged: construction of meaning; perception of self; perception of connection; and perception of life philosophy. These themes describe growth and emotional distress which may well coexist. Posttraumatic growth can be seen as one outcome of a process of struggling with traumatic injuries. Some strategies for facilitating posttraumatic growth are discussed. Health-care providers may help the recovery of injured patients by facilitating posttraumatic growth. PMID- 21697150 TI - Social cognitive impairments and psychotic symptoms: what is the nature of their association? AB - Social cognitive deficits are associated with psychotic symptoms, but the nature of this association remains unknown. This study uses a genetically sensitive cross-trait cross-sibling design to investigate the nature of the overlap between both phenotypes. A sample of 1032 patients, 1017 of their healthy siblings, and 579 control subjects were recruited within the Dutch Genetic Risk and Outcome in Psychosis (GROUP) study. Participants completed a battery of cognitive tests, including 2 social cognitive tests on theory of mind (ToM) and emotion recognition. Within siblings, symptoms were assessed with the Structured Interview for Schizotypy--Revised. The Positive and Negative Syndrome Scale was used to assess patients' symptoms. Within patients, social cognitive performance was consistently and significantly associated with disorganized and, to a lesser degree, with negative symptoms. Associations with positive symptoms were significant, but smaller. Suggestive of a shared etiology, both social cognitive factors showed significant familial clustering. The associations between patients' ToM and subclinical symptoms in siblings were nonsignificant, suggesting that their overlap within patients is due to individual rather than shared familial factors. Indicative of a shared etiology, familial covariation was present between patients' emotion recognition ability and disorganized and, albeit to a lesser degree, positive but not negative subclinical symptoms in siblings. PMID- 21697151 TI - Artefacts in CBCT: a review. AB - Artefacts are common in today's cone beam CT (CBCT). They are induced by discrepancies between the mathematical modelling and the actual physical imaging process. Since artefacts may interfere with the diagnostic process performed on CBCT data sets, every user should be aware of their presence. This article aims to discuss the most prominent artefacts identified in the scientific literature and review the existing knowledge on these artefacts. We also briefly review the basic three-dimensional (3D) reconstruction concept applied by today's CBCT scanners, as all artefacts are more or less directly related to it. PMID- 21697152 TI - Clinical research and diagnostic efficacy studies in the oral and maxillofacial radiology literature: 1996-2005. AB - OBJECTIVES: The aim of this study was to determine the level of evidence that is published in the oral and maxillofacial radiology (OMR) literature. METHODS: OMR papers published in Dentomaxillofacial Radiology and Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology between 1996 and 2005 were classified using epidemiological study design and diagnostic efficacy hierarchies. The country of origin and number of authors were noted. RESULTS: Of the 725 articles, 384 could be classified with the epidemiological study design hierarchy: 155 (40%) case reports/series and 207 (54%) cross-sectional studies. The distribution of study designs was not statistically significant across time (Fisher's exact test, P = 0.06) or regions (P = 0.89). The diagnostic efficacy hierarchy was applicable to 246 articles: 71 (29%) technical efficacy and 166 (67%) diagnostic accuracy studies. The distribution of efficacy levels was not statistically significant across time (P = 0.22) but was significant across regions (P < 0.01). Authors from Japan produced 26% of the papers with a mean +/- standard deviation of 5.78 +/- 1.98 authors per paper (APP); American authors, 23% (3.78 +/- 1.72 APP); and all others, 51% (3.76 +/- 1.51 APP). CONCLUSION: The OMR literature consisted mostly of case reports/series, cross-sectional, technical efficacy and diagnostic accuracy studies. Such studies do not provide strong evidence for clinical decision making nor do they address the impact of diagnostic imaging on patient care. More studies at the higher end of the study design and efficacy hierarchies are needed in order to make wise choices regarding clinical decisions and resource allocations. PMID- 21697153 TI - Fibrous dysplasia--a 13-year retrospective radiographic analysis in a south Indian population. AB - OBJECTIVE: The aim of this study was to examine the clinical and radiographic presentation of fibrous dysplasia through a 13-year retrospective study in patients who reported to the outpatient unit of Government Dental College, Trivandrum. METHODS: The clinical file records and radiographs of the patients who reported to the outpatient clinic in the Department of Oral Medicine and Radiology were retrospectively reviewed for histopathologically diagnosed fibrous dysplasia. A detailed analysis of the clinical and radiographic features of the 24 cases retrieved was carried out. RESULTS: The male-to-female ratio of incidence was approximately 1:1. Most of the patients were in the second or third decade of life. Almost all the patients presented with a complaint of swelling on the side of the face. The mandible was more frequently involved than the maxilla. The most common radiographic pattern observed was the "ground-glass" appearance. Most of the patients exhibited expansion of the involved bone and loss of lamina dura of associated teeth. CONCLUSION: The awareness of protean features of fibrous dysplasia evident through this study is essential in the accurate diagnosis and proper treatment planning of such lesions. PMID- 21697154 TI - Detection of dental root fractures by using cone-beam computed tomography. AB - OBJECTIVES: The purpose of this study was to compare the diagnostic accuracy of cone beam CT (CBCT) with that of conventional dental radiography in the detection of root fractures and to evaluate the influence of root canal fillings on root fracture detection. METHODS: We investigated 128 patients with clinically suspected root fractures in 135 teeth. These patients underwent conventional dental radiography, CBCT and eventually surgical exploration. Among the 135 teeth, 86 were non-endodontically treated teeth and 49 were endodontically treated teeth. Two oral radiologists independently analysed the dental radiographs and CBCT images of each patient and reached a consensus. The CBCT findings of root fractures were set as the detection of a separation of the adjacent root segments on at least two contiguous sections and on at least two of the three-dimensional (3D) planes. RESULTS: Root fracture was intraoperatively detected in 95 of the 135 teeth. The sensitivity and specificity of root fractures diagnosed on the basis of the consensus between the 2 evaluators were 26.3% and 100%, respectively, for dental radiography and 89.5% and 97.5%, respectively, for CBCT. CBCT was significantly more accurate than dental radiography in detecting root fractures (P < 0.001). The sensitivity of CBCT was reduced in the presence of root canal fillings but its specificity remained unaffected. Both the sensitivity and specificity of dental radiography were not influenced by the presence of root canal fillings. CONCLUSIONS: CBCT appears to be more accurate than conventional dental radiography in the detection of root fractures. PMID- 21697155 TI - Accuracy of linear measurement in the Galileos cone beam computed tomography under simulated clinical conditions. AB - OBJECTIVES: The aim of this study was to determine the geometric accuracy of cone beam CT (CBCT)-based linear measurements of bone height obtained with the Galileos CBCT (Sirona Dental Systems Inc., Bensheim, Hessen, Germany) in the presence of soft tissues. METHODS: Six embalmed cadaver heads were imaged with the Galileos CBCT unit subsequent to placement of radiopaque fiduciary markers over the buccal and lingual cortical plates. Electronic linear measurements of bone height were obtained using the Sirona software. Physical measurements were obtained with digital calipers at the same location. This distance was compared on all six specimens bilaterally to determine accuracy of the image measurements. RESULTS: The findings showed no statistically significant difference between the imaging and physical measurements (P > 0.05) as determined by a paired sample t test. The intraclass correlation was used to measure the intrarater reliability of repeated measures and there was no statistically significant difference between measurements performed at the same location (P > 0.05). CONCLUSIONS: The Galileos CBCT image-based linear measurement between anatomical structures within the mandible in the presence of soft tissues is sufficiently accurate for clinical use. PMID- 21697156 TI - Accuracy of scanography using storage phosphor plate systems and film for assessment of mandibular third molars. AB - OBJECTIVES: The aim of this study was to compare the diagnostic accuracy of two digital photostimulable storage phosphor (PSP) systems and film for assessment of mandibular third molars before surgery. METHODS: 110 patients were referred to have both their mandibular third molars removed. Each patient underwent a radiographic examination with scanography using either Digora (Soredex, Helsinki, Finland) and film or VistaScan (Durr Dental, Beitigheim-Bissingen, Germany) and film in a randomized paired design. Two observers examined the following variables on the scanograms: bone coverage, angulation of the tooth in the bone, number of roots, root morphology and the relationship to the mandibular canal. In 75 of the pairs (Digora/film pair = 38 and Vista/film pair = 37) both third molars were eventually removed. During and after surgery the same variables were assessed, which served as reference standard for the radiographic assessments. The Wilcoxon signed-rank test tested differences in accuracy (radiographic compared with surgical findings) between Digora/film and between Vista/film. RESULTS: There was no statistically significant difference between the diagnostic accuracy of film and either of the two digital receptors for assessment of mandibular third molars before surgery (P > 0.05), although Digora obtained a higher accuracy than film. CONCLUSIONS: Scanography is a valuable method for examination of mandibular third molars before removal and the PSP digital receptors in this study were equal to film for this purpose. PMID- 21697158 TI - 18F-DOPA PET/CT unravels malignant paraganglioma mimicking temporomandibular joint disorder. AB - This report presents a 29-year-old patient with severe temporomandibular joint (TMJ) pain. Anamnesis and clinical examination led us to the diagnosis of TMJ disorder. He was also in control for a malignant paraganglioma originating from the right carotid body. After initial surgery 8.5 years ago and the removal of metastases 2 years ago he was deemed disease free. An (18)F-3,4 dihydroxyphenylalanine (DOPA) positron emission tomography (PET)/CT scan was obtained during follow-up 6 months before he was presented to our clinic. Suspicious of a connection between the actual pain and the tumour, we scrutinized these images. We found a tiny pathological tracer uptake in the right jugular foramen but no correlating finding in the matching CT. We repeated the DOPA PET/CT and found several metastases including the previously detected lesion. Further thin-slice CT and MRI showed a 5 mm paraganglioma located anteriorly to the jugular bulb within the jugular foramen. The lesion was in close relation to the Arnold's nerve, a branch of the vagus nerve which carries sensory information from the external tympanic membrane, external auditory canal and the external ear and explained the severe pain in our patient. He then underwent radiotherapy (45 Gy) during which the pain diminished considerably. In a variety of neuroendocrine tumours, including paraganglioma, DOPA PET/CT allows primary diagnosis, staging and restaging with a higher detection rate than conventional radiological imaging. Owing to low anatomical resolution however, high resolution contrast enhanced CT and MRI are necessary to complete the investigations. PMID- 21697157 TI - Chemical genoprotection: reducing biological damage to as low as reasonably achievable levels. AB - OBJECTIVES: The aim of this study was to evaluate the antioxidant substances present in the human diet with an antimutagenic protective capacity against genotoxic damage induced by exposure to X-rays in an attempt to reduce biological damage to as low a level as reasonably possible. METHODS: Ten compounds were assessed using the lymphocyte cytokinesis-block micronucleus (MN) cytome test. The compounds studied were added to human blood at 25 MUM 5 min before exposure to irradiation by 2 Gy of X-rays. RESULTS: The protective capacity of the antioxidant substances assessed was from highest to lowest according to the frequency of the MN generated by X-ray exposure: rosmarinic acid = carnosic acid = delta-tocopherol = l-acid ascorbic = apigenin = amifostine (P < 0.001) > green tea extract = diosmine = rutin = dimetylsulfoxide (P < 0.05) > irradiated control. The reduction in genotoxic damage with the radiation doses administered reached 58%, which represents a significant reduction in X-ray-induced chromosomal damage (P < 0.001). This degree of protection is greater than that obtained with amifostine, a radioprotective compound used in radiotherapy and which is characterised by its high toxicity. CONCLUSION: Several antioxidant substances, common components of the human diet and lacking toxicity, offer protection from the biological harm induced by ionizing radiation. Administering these protective substances to patients before radiological exploration should be considered, even in the case of small radiation doses and regardless of the biological damage expected. PMID- 21697159 TI - Secondary chondrosarcoma in the mandibular condyle. AB - We report the case of a woman who had secondary chondrosarcoma in an osteochondroma in the left mandibular condyle, presenting as a large lobulated bone density mass in the left condyle process, to illustrate the clinical characteristics and imaging findings. PMID- 21697161 TI - Why should we insist patients remove all jewellery? PMID- 21697160 TI - Ameloblastic fibro-odontosarcoma of the mandible: imaging findings. AB - We report a histologically verified case of ameloblastic fibro-odontosarcoma (AFOS) affecting the right mandible. CT scanning showed an expansile intraosseous mass with ill-defined borders and slightly dense opacities. PMID- 21697162 TI - The cost of a bodyguard. AB - Host manipulation by parasites not only captures the imagination but has important epidemiological implications. The conventional view is that parasites face a trade-off between the benefits of host manipulation and their costs to fitness-related traits, such as longevity and fecundity. However, this trade-off hypothesis remains to be tested. Dinocampus coccinellae is a common parasitic wasp of the spotted lady beetle Coleomegilla maculata. Females deposit a single egg in the haemocoel of the host, and during larval development the parasitoid feeds on host tissues. At the prepupal stage, the parasitoid egresses from its host by forcing its way through the coccinellid's abdominal segments and begins spinning a cocoon between the ladybird's legs. Remarkably, D. coccinellae does not kill its host during its development, an atypical feature for parasitoids. We first showed under laboratory conditions that parasitoid cocoons that were attended by a living and manipulated ladybird suffered less predation than did cocoons alone or cocoons under dead ladybirds. We then demonstrated that the length of the manipulation period is negatively correlated with parasitoid fecundity but not with longevity. In addition to documenting an original case of bodyguard manipulation, our study provides the first evidence of a cost required for manipulating host behaviour. PMID- 21697163 TI - Multi-variate models are essential for understanding vertebrate diversification in deep time. AB - Statistical models are helping palaeontologists to elucidate the history of biodiversity. Sampling standardization has been extensively applied to remedy the effects of uneven sampling in large datasets of fossil invertebrates. However, many vertebrate datasets are smaller, and the issue of uneven sampling has commonly been ignored, or approached using pairwise comparisons with a numerical proxy for sampling effort. Although most authors find a strong correlation between palaeodiversity and sampling proxies, weak correlation is recorded in some datasets. This has led several authors to conclude that uneven sampling does not influence our view of vertebrate macroevolution. We demonstrate that multi variate regression models incorporating a model of underlying biological diversification, as well as a sampling proxy, fit observed sauropodomorph dinosaur palaeodiversity best. This bivariate model is a better fit than separate univariate models, and illustrates that observed palaeodiversity is a composite pattern, representing a biological signal overprinted by variation in sampling effort. Multi-variate models and other approaches that consider sampling as an essential component of palaeodiversity are central to gaining a more complete understanding of deep time vertebrate diversification. PMID- 21697164 TI - Sibling bullying during infancy does not make wimpy adults. AB - Despite frequent suggestions that dominance-subordination relationships in infancy can affect subsequent agonistic potential during adult life, to our knowledge no explicit test has been made. Experiments have shown that adverse conditions during early development can have long-term effects on a variety of traits ranging from growth to competitive behaviour. In many vertebrate species, the main social setting in which the infant develops is a sibling group where competition is often mediated by a dominance hierarchy. Here, we show in a long lived marine bird that subordination to an aggressive sibling throughout infancy does not compromise aggressiveness years later during adult life. Former junior and senior chicks of the blue-footed booby, whose typical brood of two chicks exhibits a consistent dominance-subordination relationship with strong 'trained winner' and 'trained loser' conditioning effects, did not differ in their aggressiveness while defending their nest against a conspecific intruder stimulus. Our results suggest that aggressive subordination and associated food deprivation, poor growth and elevated stress hormone during infancy do not prejudice aggressiveness of adult boobies during at least the first 13 years of life. Development of important traits such as aggressive tendencies may be buffered against the normal and predictable challenges of infancy. PMID- 21697165 TI - African grey parrots (Psittacus erithacus) use inference by exclusion to find hidden food. AB - Exclusion allows the detection of hidden food when confronted with the choice between an empty and a potentially baited food location. However, exclusion may be based on avoidance of the empty location without drawing inferences about the presence of the food in the baited location. So far, such inferences have been demonstrated in the great apes only: after seeing an experimenter eating one of two food types, which both had been hidden previously in two boxes, the apes were able to choose the box that still contained the other food type. African grey parrots are capable of exclusion, and we here assessed if they are capable of inference by exclusion. In our task, two different but equally preferred food items were hidden in full view of the birds under two opaque cups. Then, an experimenter secretly removed one food type and showed it to the bird. Similarly to the apes, one out of seven parrots significantly preferred the baited cup; control conditions rule out that its choice was based on associative learning or the use of olfactory cues. Thus, we conclude that-like the apes-some grey parrots are able to infer the location of a hidden food reward. PMID- 21697166 TI - Experimental evidence that women's mate preferences are directly influenced by cues of pathogen prevalence and resource scarcity. AB - When choosing a mate, women are thought to face a trade-off between genetic and parental quality. Recent research suggests that this trade-off is influenced by environmental factors such as pathogen prevalence and resource scarcity, which affect the relative value of genetic and parental quality to offspring fitness. To further investigate these findings, the current study primed 60 women with pathogen prevalence, resource scarcity or an irrelevant threat, before administering a forced trade-off task that assessed mate preferences for traits thought to be indicative of genetic or parental quality. Women primed with pathogen prevalence revealed greater preferences for traits indicative of genetic quality at the expense of traits indicative of parental quality. The reverse was found for women primed with resource scarcity. These findings suggest that environmental factors may directly influence women's mate preferences owing to evolved plasticity, such that mate preferences are flexible in response to environmental factors. PMID- 21697167 TI - Modelling the effects of past and future climate on the risk of bluetongue emergence in Europe. AB - Vector-borne diseases are among those most sensitive to climate because the ecology of vectors and the development rate of pathogens within them are highly dependent on environmental conditions. Bluetongue (BT), a recently emerged arboviral disease of ruminants in Europe, is often cited as an illustration of climate's impact on disease emergence, although no study has yet tested this association. Here, we develop a framework to quantitatively evaluate the effects of climate on BT's emergence in Europe by integrating high-resolution climate observations and model simulations within a mechanistic model of BT transmission risk. We demonstrate that a climate-driven model explains, in both space and time, many aspects of BT's recent emergence and spread, including the 2006 BT outbreak in northwest Europe which occurred in the year of highest projected risk since at least 1960. Furthermore, the model provides mechanistic insight into BT's emergence, suggesting that the drivers of emergence across Europe differ between the South and the North. Driven by simulated future climate from an ensemble of 11 regional climate models, the model projects increase in the future risk of BT emergence across most of Europe with uncertainty in rate but not in trend. The framework described here is adaptable and applicable to other diseases, where the link between climate and disease transmission risk can be quantified, permitting the evaluation of scale and uncertainty in climate change's impact on the future of such diseases. PMID- 21697168 TI - Modelling human balance using switched systems with linear feedback control. AB - We are interested in understanding the mechanisms behind and the character of the sway motion of healthy human subjects during quiet standing. We assume that a human body can be modelled as a single-link inverted pendulum, and the balance is achieved using linear feedback control. Using these assumptions, we derive a switched model which we then investigate. Stable periodic motions (limit cycles) about an upright position are found. The existence of these limit cycles is studied as a function of system parameters. The exploration of the parameter space leads to the detection of multi-stability and homoclinic bifurcations. PMID- 21697169 TI - Hypertension management 2011: optimal combination therapy. AB - Raised levels of blood pressure result from the complex interplay of environmental and genetic factors. The complexity of blood pressure control mechanisms has major implications for individual responsiveness to antihypertensive drugs. The underlying haemodynamic disorder in the majority of cases is a rise in peripheral vascular resistance. This observation led to the discovery and development of increasingly sophisticated and targeted vasodilators, although many of the earlier antihypertensive drugs, by virtue of their actions blocking the sympathetic nervous system, had a vasodilator component to their mode of action. A recent meta-analysis of placebo controlled trials of monotherapy in unselected hypertensives, reports average (placebo corrected) blood pressure responses to single agents of 9.1 mmHg systolic and 5.5 mmHg diastolic pressure. These average values disguise the extremely wide ranging responses in individuals across a fall of 20-30 mmHg systolic at one extreme, to no effect at all, or even a small rise in blood pressure at the other. The second factor determining individual responses to monotherapy is the extent to which initial falls in pressure are opposed by reflex responses in counter regulatory mechanisms that are activated following the blood pressure reduction. Thus, a satisfactory blood pressure response is rarely reached with monotherapy alone. What then is the next step if blood pressure is not a goal after the patient has been treated with monotherapy for a few weeks? Should you uptitrate, substitute or combine? PMID- 21697170 TI - Comparison of coronary bypass surgery with drug-eluting stenting for the treatment of left main and/or three-vessel disease: 3-year follow-up of the SYNTAX trial. AB - AIMS: Long-term randomized comparisons of percutaneous coronary intervention (PCI) to coronary artery bypass grafting (CABG) in left main coronary (LM) disease and/or three-vessel disease (3VD) patients have been limited. This analysis compares 3-year outcomes in LM and/or 3VD patients treated with CABG or PCI with TAXUS Express stents. METHODS AND RESULTS: SYNTAX is an 85-centre randomized clinical trial (n= 1800). Prospectively screened, consecutive LM and/or 3VD patients were randomized if amenable to equivalent revascularization using either technique; if not, they were entered into a registry. Patients in the randomized cohort will continue to be followed for 5 years. At 3 years, major adverse cardiac and cerebrovascular events [MACCE: death, stroke, myocardial infarction (MI), and repeat revascularization; CABG 20.2% vs. PCI 28.0%, P< 0.001], repeat revascularization (10.7 vs. 19.7%, P< 0.001), and MI (3.6 vs. 7.1%, P= 0.002) were elevated in the PCI arm. Rates of the composite safety endpoint (death/stroke/MI 12.0 vs. 14.1%, P= 0.21) and stroke alone (3.4 vs. 2.0%, P= 0.07) were not significantly different between treatment groups. Major adverse cardiac and cerebrovascular event rates were not significantly different between arms in the LM subgroup (22.3 vs. 26.8%, P= 0.20) but were higher with PCI in the 3VD subgroup (18.8 vs. 28.8%, P< 0.001). CONCLUSIONS: At 3 years, MACCE was significantly higher in PCI- compared with CABG-treated patients. In patients with less complex disease (low SYNTAX scores for 3VD or low/intermediate terciles for LM patients), PCI is an acceptable revascularization, although longer follow-up is needed to evaluate these two revascularization strategies. PMID- 21697173 TI - On valuing patches: estimating contributions to metapopulation growth with reverse-time capture-recapture modelling. AB - Metapopulation ecology has historically been rich in theory, yet analytical approaches for inferring demographic relationships among local populations have been few. We show how reverse-time multi-state capture-recapture models can be used to estimate the importance of local recruitment and interpopulation dispersal to metapopulation growth. We use 'contribution metrics' to infer demographic connectedness among eight local populations of banner-tailed kangaroo rats, to assess their demographic closure, and to investigate sources of variation in these contributions. Using a 7 year dataset, we show that: (i) local populations are relatively independent demographically, and contributions to local population growth via dispersal within the system decline with distance; (ii) growth contributions via local survival and recruitment are greater for adults than juveniles, while contributions involving dispersal are greater for juveniles; (iii) central populations rely more on local recruitment and survival than peripheral populations; (iv) contributions involving dispersal are not clearly related to overall metapopulation density; and (v) estimated contributions from outside the system are unexpectedly large. Our analytical framework can classify metapopulations on a continuum between demographic independence and panmixia, detect hidden population growth contributions, and make inference about other population linkage forms, including rescue effects and source-sink structures. Finally, we discuss differences between demographic and genetic population linkage patterns for our system. PMID- 21697171 TI - The structure and function of cardiac t-tubules in health and disease. AB - The transverse tubules (t-tubules) are invaginations of the cell membrane rich in several ion channels and other proteins devoted to the critical task of excitation-contraction coupling in cardiac muscle cells (cardiomyocytes). They are thought to promote the synchronous activation of the whole depth of the cell despite the fact that the signal to contract is relayed across the external membrane. However, recent work has shown that t-tubule structure and function are complex and tightly regulated in healthy cardiomyocytes. In this review, we outline the rapidly accumulating knowledge of its novel roles and discuss the emerging evidence of t-tubule dysfunction in cardiac disease, especially heart failure. Controversy surrounds the t-tubules' regulatory elements, and we draw attention to work that is defining these elements from the genetic and the physiological levels. More generally, this field illustrates the challenges in the dissection of the complex relationship between cellular structure and function. PMID- 21697172 TI - Mate choice for major histocompatibility complex genetic divergence as a bet hedging strategy in the Atlantic salmon (Salmo salar). AB - Major histocompatibility complex (MHC)-dependent mating preferences have been observed across vertebrate taxa and these preferences are expected to promote offspring disease resistance and ultimately, viability. However, little empirical evidence linking MHC-dependent mate choice and fitness is available, particularly in wild populations. Here, we explore the adaptive potential of previously observed patterns of MHC-dependent mate choice in a wild population of Atlantic salmon (Salmo salar) in Quebec, Canada, by examining the relationship between MHC genetic variation and adult reproductive success and offspring survival over 3 years of study. While Atlantic salmon choose their mates in order to increase MHC diversity in offspring, adult reproductive success was in fact maximized between pairs exhibiting an intermediate level of MHC dissimilarity. Moreover, patterns of offspring survival between years 0+ and 1+, and 1+ and 2+ and population genetic structure at the MHC locus relative to microsatellite loci indicate that strong temporal variation in selection is likely to be operating on the MHC. We interpret MHC-dependent mate choice for diversity as a likely bet-hedging strategy that maximizes parental fitness in the face of temporally variable and unpredictable natural selection pressures. PMID- 21697174 TI - Impact of epistasis and pleiotropy on evolutionary adaptation. AB - Evolutionary adaptation is often likened to climbing a hill or peak. While this process is simple for fitness landscapes where mutations are independent, the interaction between mutations (epistasis) as well as mutations at loci that affect more than one trait (pleiotropy) are crucial in complex and realistic fitness landscapes. We investigate the impact of epistasis and pleiotropy on adaptive evolution by studying the evolution of a population of asexual haploid organisms (haplotypes) in a model of N interacting loci, where each locus interacts with K other loci. We use a quantitative measure of the magnitude of epistatic interactions between substitutions, and find that it is an increasing function of K. When haplotypes adapt at high mutation rates, more epistatic pairs of substitutions are observed on the line of descent than expected. The highest fitness is attained in landscapes with an intermediate amount of ruggedness that balance the higher fitness potential of interacting genes with their concomitant decreased evolvability. Our findings imply that the synergism between loci that interact epistatically is crucial for evolving genetic modules with high fitness, while too much ruggedness stalls the adaptive process. PMID- 21697175 TI - Measuring the cost of plasticity: a problem of statistical non-independence. PMID- 21697177 TI - Spectral tuning and evolution of primate short-wavelength-sensitive visual pigments. AB - The peak sensitivities (lambda(max)) of the short-wavelength-sensitive-1 (SWS1) pigments in mammals range from the ultraviolet (UV) (360-400 nm) to the violet (400-450 nm) regions of the spectrum. In most cases, a UV or violet peak is determined by the residue present at site 86, with Phe conferring UV sensitivity (UVS) and either Ser, Tyr or Val causing a shift to violet wavelengths. In primates, however, the tuning mechanism of violet-sensitive (VS) pigments would appear to differ. In this study, we examine the tuning mechanisms of prosimian SWS1 pigments. One species, the aye-aye, possesses a pigment with Phe86 but in vitro spectral analysis reveals a VS rather than a UVS pigment. Other residues (Cys, Ser and Val) at site 86 in prosimians also gave VS pigments. Substitution at site 86 is not, therefore, the primary mechanism for the tuning of VS pigments in primates, and phylogenetic analysis indicates that substitutions at site 86 have occurred at least five times in primate evolution. The sole potential tuning site that is conserved in all primate VS pigments is Pro93, which when substituted by Thr (as found in mammalian UVS pigments) in the aye-aye pigment shifted the peak absorbance into the UV region with a lambda(max) value at 371 nm. We, therefore, conclude that the tuning of VS pigments in primates depends on Pro93, not Tyr86 as in other mammals. However, it remains uncertain whether the initial event that gave rise to the VS pigment in the ancestral primate was achieved by a Thr93Pro or a Phe86Tyr substitution. PMID- 21697178 TI - Vancomycin-resistant enterococcal bacteraemia and daptomycin: are higher doses necessary? AB - BACKGROUND: The MIC corresponding to daptomycin susceptibility for vancomycin resistant enterococci (VRE) is <= 4 mg/L. Based on the concentration-dependent killing properties of daptomycin, there may be concern about achieving adequate concentrations when the MIC approaches the upper end of the susceptible range (3 4 mg/L). Higher doses of daptomycin may be needed to treat VRE isolates with higher MICs. METHODS: We conducted a single-centre retrospective chart review of adult cases with VRE bacteraemia who received daptomycin as initial therapy. The primary outcome was time to microbiological cure (TMC) between standard doses (<= 6 mg/kg) and high doses (> 6 mg/kg) of daptomycin and whether TMC differed based on MICs. The secondary outcome evaluated the daptomycin MIC distribution and assessed whether recent exposure to vancomycin was associated with higher daptomycin MICs. RESULTS: Forty-six cases were included in the primary analysis and 60.9% of patients were neutropenic. The two dose groups differed in the baseline characteristics of age, body mass index, blood culture source and catheter removal. Median TMC was 2 days for both dose groups. There was no significant difference in TMC between MIC subgroups of <= 2 mg/L versus >2 and <= 4 mg/L. For the secondary analysis 227 VRE isolates were evaluated and 62% had daptomycin MICs of 3-4 mg/L. Each daptomycin MIC group had a similar incidence of prior vancomycin exposure. CONCLUSIONS: Based on this retrospective review we did not observe a difference in TMC based on daptomycin dose and MIC; however, there were various limitations to this study, and the study was not powered to detect a difference in TMC. Also, prior vancomycin exposure did not appear to influence daptomycin MICs. The frequency of daptomycin MICs of 3-4 mg/L reported in this study is higher than those reported in the literature. PMID- 21697179 TI - Leakage of emerging clinically relevant multidrug-resistant Salmonella clones from pig farms. AB - OBJECTIVES: To assess the presence of multidrug-resistant (MDR) Salmonella with human clinical relevance in pig farms from different regions of Portugal and to analyse their mobile genetic elements associated with antibiotic resistance. METHODS: Seventy-nine samples were collected from six piggeries and analysed for the presence of Salmonella. All isolates were examined for susceptibility to antimicrobial agents and representative isolates for resistance genes and class 1 integrons (PCR/restriction fragment length polymorphism). Clonality was determined by PFGE and multilocus sequence typing (MLST). Plasmid analysis included determination of size, content and characterization of the incompatibility group (rep-PCR and I-CeuI/S1-hybridization). RESULTS: Sixty Salmonella isolates were recovered from five samples (two manure, two waste lagoons and one animal feed) in half of the piggeries studied. All isolates were resistant to at least one antibiotic (tetracycline) and 97% to at least four antibiotics from different families. In 10 isolates representing different serogroup and resistance phenotype combinations a diversity of resistance genes and integrons was detected. These isolates belonged to the internationally widespread Salmonella Rissen (ST469) and Salmonella Typhimurium DT104 (ST19) clones, as well as to the emerging Salmonella Typhimurium monophasic variant with examples of Spanish (carrying a sul3-atypical integron within IncA/C plasmids, here assigned to ST19) and European (ASSuT phenotype, assigned to ST34) clones. CONCLUSIONS: This is one of the few studies reporting emerging MDR Salmonella clones and the first one detecting Salmonella Typhimurium monophasic variant in the pig production setting. The survival of these strains in manure and waste lagoons is of concern, since these environments might allow spread of MDR bacteria beyond pig farms' boundaries. PMID- 21697180 TI - Induced radioactivity in and around high-energy particle accelerators. AB - Particle accelerators and their surroundings are locations of residual radioactivity production that is induced by the interaction of high-energy particles with matter. This paper gives an overview of the principles of activation caused at proton accelerators, which are the main machines operated at Conseil Europeen pour la Recherche Nucleaire. It describes the parameters defining radio-nuclide production caused by beam losses. The second part of the paper concentrates on the analytic calculation of activation and the Monte Carlo approach as it is implemented in the FLUKA code. Techniques used to obtain, on the one hand, estimates of radioactivity in Becquerel and, on the other hand, residual dose rates caused by the activated material are discussed. The last part of the paper focuses on experiments that allow for benchmarking FLUKA activation calculations and on simulations used to predict activation in and around high energy proton machines. In that respect, the paper addresses the residual dose rate that will be induced by proton-proton collisions at an energy of two times 7 TeV in and around the Compact Muon Solenoid (CMS) detector. Besides activation of solid materials, the air activation expected in the CMS cavern caused by this beam operation is also discussed. PMID- 21697182 TI - Prognostic value of a tissue Doppler-derived index of left ventricular filling pressure on composite morbidity after off-pump coronary artery bypass surgery. AB - BACKGROUND: The ratio of early transmitral flow velocity to early diastolic velocity of the mitral annulus (E/e') is an indicator of diastolic function that correlates well with left ventricular (LV) filling pressure and is relatively independent of systolic function and rhythm abnormalities. We prospectively evaluated the predictive value of E/e' for postoperative outcome in patients undergoing off-pump coronary artery bypass graft surgery (OPCAB). METHODS: Patients undergoing OPCAB were classified into three groups according to their E/e' ratio: (i) normal E/e' <8; (ii) undetermined E/e' >=8 and <=15; and (iii) elevated E/e' >15. Among those with E/e' between 8 and 15, patients with elevated LV filling pressure were further identified by comprehensive Doppler examination. These patients were classified as having a high LV filling pressure, together with patients who had E/e' ratios >15. Univariate and multivariate regression analyses were used to evaluate the relationship between preoperative variables and composite endpoints for morbidity. RESULTS: In univariate analysis, diabetes mellitus, recent myocardial infarction, chronic obstructive pulmonary disease, serum creatinine (sCr) concentration, E/e' >15, high LV filling pressure, LV ejection fraction, New York Heart Association class III and IV, and use of diuretics were significant risk factors for postoperative morbidity. In multivariate regression analysis of these variables, only sCr (odds ratio 1.4) and E/e' >15 (odds ratio 2.4) or high LV filling pressure (odds ratio 2.8) remained as independent risk factors. CONCLUSIONS: E/e' ratio >15 was a significant predictor of composite endpoints of postoperative morbidity. We suggest that E/e' ratio should be included in the routine preoperative assessment of patients presenting for OPCAB. PMID- 21697183 TI - Optimized method for correct left-sided central venous catheter placement under electrocardiographic guidance. AB - BACKGROUND: Central venous catheter (CVC) placement under ECG guidance in the left thoracocervical area can lead to catheter misplacement. The aim of this study was to identify the cause and quantify the magnitude of this error. METHODS: CVCs were sited in either the left or right internal jugular (IJ), subclavian (SC), or innominate (brachiocephalic) vein using the Seldinger technique and a total of 227 insertions were studied. The position of the catheter tip was confirmed with two different intra-atrial ECG monitoring methods (Seldinger's wire vs 10% saline solution). Measurements were compared between the two methods and correlated to the different access sites. RESULTS: All right sided CVC had the line tip in the optimal position and both intra-atrial ECG recording by Seldinger's wire or 10% saline delivered correct results. For left sided lines, however, the two methods gave significantly different results regarding the position of the line tip for each insertion site. When using the Seldinger wire as intravascular ECG lead, the results differed from the saline method by a mean of 21 mm for the IJ and 10 mm for the SC. CONCLUSIONS: CVC placement under ECG guidance is a reliable method to site the line tip at the optimal position. However, when using a left-sided thoracocervical access point, the Seldinger wire-conducted ECG delivered a constant error. This could be adjusted for by advancing the CVC 20 mm in addition to the wire-based measurement of the insertion depth at the left IJ vein and 10 mm at the left SC vein. PMID- 21697181 TI - Contribution of persistent C-Jun N-terminal kinase activity to the survival of human vestibular schwannoma cells by suppression of accumulation of mitochondrial superoxides. AB - Vestibular schwannomas (VSs) result from inactivating mutations in the merlin tumor suppressor gene. The merlin protein suppresses a variety of progrowth kinase-signaling cascades, including extracellular regulated kinase/mitogen activated protein kinase (ERK/MAPK), c-Jun N-terminal kinase (JNK), and phosphatidyl-inositol 3-kinase (PI3-K)/Akt. Recent studies indicate that ERKs and Akt are active in human VSs, and here we show that JNKs are also persistently active in human VS cells. With use of cultures of human VSs, we investigated the contribution of each of these signals to the proliferative and survival response of VS cells. Inhibition of ERK or Akt signaling reduced VS cell proliferation but did not increase apoptosis, whereas inhibition of JNK with SP600125, I-JIP, or siRNA knock-down reduced VS cell proliferation and survival by inducing apoptosis. By contrast, JNK activity promotes apoptosis in normal Schwann cells. Inhibition of JNK increased the fluorescence intensity of VS cells loaded with 5 (and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (H(2)DCFDA), a fluorescent probe for reactive oxygen species (ROS). Furthermore, ebselen, a ROS scavenger, rescued VS cells with suppressed JNK from apoptosis, suggesting that JNK activity protects VS cells from apoptosis by limiting accumulation of ROS. VS cultures treated with JNK inhibitors demonstrated significantly higher levels of MitoSOX Red fluorescence, implying that persistent JNK activity specifically suppresses superoxide production in the mitochondria. Overexpression of superoxide dismutase 2 (MnSOD; mitochondrial SOD) prevented apoptosis in VS cells with suppressed JNK signaling. Taken together, these results indicate that persistent JNK activity enhances VS cell survival, at least in part, by suppressing accumulation of mitochondrial superoxides. PMID- 21697184 TI - Point-of-care assessment of platelet aggregation in paediatric open heart surgery. AB - BACKGROUND: Congenital heart disease (CHD) is associated with complex coagulation abnormalities. Platelet aggregability has not been investigated in detail in children with acyanotic and cyanotic malformations undergoing open heart surgery. The method of whole-blood multiple electrode aggregometry (MEA) appears suitable for rapid platelet analysis in children, for example, because of small sample volumes. We investigated perioperative evolution of platelet aggregation by means of MEA in children with CHD. METHODS: Fifty children with acyanotic or cyanotic malformations were included in a prospective observational study. Laboratory testing was assessed before anaesthesia, and during and after surgery until the fifth postoperative day. MEA was performed in hirudin-anticoagulated blood using adenosine diphosphate (ADP), arachidonic acid, and thrombin receptor-activating peptide for platelet activation. Surgical variables, bleeding volumes, and transfusion requirements were documented during hospital stay. RESULTS: Mean platelet count was within the normal range in all patients with no intergroup differences. Before surgery, aggregation to all agonists was within the age adjusted normal range in cyanotic children and was statistically significantly higher compared with acyanotic children. Platelet aggregation decreased significantly during surgery in both groups followed by a slow recovery not reaching baseline levels. Bleeding and platelet transfusions were higher in the cyanotic group. Transfusion requirements correlated with ADP-induced platelet aggregation. CONCLUSIONS: These results indicate higher blood loss, despite better platelet aggregation in cyanotic patients compared with acyanotic patients. MEA alone might not be suitable for predicting increased perioperative blood loss. PMID- 21697185 TI - Alcoholic and non-alcoholic fatty liver in adolescents: a worrisome convergence. PMID- 21697186 TI - Subjective measures of binge drinking, suboptimal subjective health and alcohol specific hospitalizations among working-aged adults: a prospective cohort study. AB - AIMS: The purpose of this prospective study was to determine how subjective measures of binge drinking predict suboptimal subjective health. In order to contribute to the understanding of potential causal mechanisms, we also aimed to determine the factors through which subjective health predicts alcohol-specific hospitalizations. METHODS: A total of 16,111 alcohol-drinking men and women, aged 20-54 years, participated in the Health and Social Support baseline postal survey in 1998, and also responded to the repeated measurement 5 years later in 2003 (T2). Suboptimal subjective health was defined as self-reported overall health status being fair, rather poor or poor. Subjective measures of binge drinking were frequency of subjective intoxications/drunkenness, frequency of hangovers and frequency of alcohol-induced pass-outs. RESULTS: Frequency of intoxications, hangovers and alcohol-induced pass-outs, all predicted suboptimal subjective health regardless of several potential confounders, including beverage-specific total intake. Those reporting suboptimal subjective health at baseline had a 5 fold odds ratio (5.08, 95% confidence interval: 3.43, 6.48) for alcohol-related hospitalizations, compared with those rating their health above fair, when gender and age were controlled. Binge drinking, together with concurrent symptoms of depression, explained over 50% of this relationship, and when additionally taking into account smoking, over two-thirds of this relation was explained. CONCLUSION: Mental health is an important mediating factor between binge drinking, suboptimal subjective health and alcohol-specific hospitalizations, and symptoms of depression should therefore be taken into account in prevention of alcohol related adverse health outcomes. PMID- 21697187 TI - Outbreak of type C botulism in laying hens. PMID- 21697188 TI - Clinical veterinary students' perceptions of a 'Day one' skills guide. AB - Veterinary schools in the UK are required by the Royal College of Veterinary Surgeons to ensure that their students have attained essential 'Day one' skills (DOS) by graduation. To aid students' understanding of how they could satisfy this requirement, the Royal Veterinary College produced a DOS guide, which was distributed in the 2007 to 2008 academic year to students in the third and fourth years of the professional veterinary course. The same students were surveyed towards the end of the 2008 to 2009 session about the guide, when they were in the fourth and final years, to rate its usefulness and to indicate their perceived levels of competence, both currently and expected at graduation. Focus group discussions were subsequently conducted to explore the findings of the survey. Responses from 88 fourth-year (39 per cent) and 174 (87 per cent) final year students revealed that while almost all respondents were aware of the DOS guide, their use of it was low. Final-year students rated themselves as being more competent than fourth-year students, but were less optimistic about their expected level of competence regarding several invasive procedures, which some students considered to be 'unattainable' by graduation, despite the apparent value of extramural studies and intramural rotations in providing opportunities for learning. PMID- 21697189 TI - Squirrel adenovirus type 1 in red squirrels (Sciurus vulgaris) in Germany. PMID- 21697190 TI - Alterations in peripheral circulation in dogs with cardiac tamponade. PMID- 21697191 TI - Epizootic of dolphin morbillivirus on the Catalonian Mediterranean coast in 2007. PMID- 21697192 TI - Prevalence of Johne's disease among cattle in Orkney. PMID- 21697193 TI - An investigation into social information processing in young people with Asperger syndrome. AB - Deficits in social functioning are a core feature of autistic spectrum disorders (ASD), being linked to various cognitive and developmental factors, but there has been little attempt to draw on normative models of social cognition to understand social behaviour in ASD. The current study explored the utility of Crick and Dodge's (1994) information processing model to studying social cognition in ASD, and examined associations between social information processing patterns, theory of mind skills and social functioning. A matched-group design compared young people with Asperger syndrome with typically developing peers, using a social information processing interview previously designed for this purpose. The Asperger syndrome group showed significantly different patterns of information processing at the intent attribution, response generation and response evaluation stages of the information processing model. Theory of mind skills were found to be significantly associated with parental ratings of peer problems in the Asperger syndrome group but not with parental ratings of pro-social behaviour, with only limited evidence of an association between social information processing and measures of theory of mind and social functioning. Overall, the study supports the use of normative social information processing approaches to understanding social functioning in ASD. PMID- 21697194 TI - The daily lives of adolescents with an autism spectrum disorder: discretionary time use and activity partners. AB - This study explores the daily lives, particularly discretionary time, of adolescents with an autism spectrum disorder (ASD). We describe the activities and activity partners of adolescents, the factors associated with their discretionary time use, and the impact of time use on their autism symptoms. Mothers of 103 adolescents with an ASD completed two 24-hour time diaries to describe their adolescent's activity participation during the third wave of a longitudinal study. Adolescents with an ASD spent considerable time in discretionary activities, with watching television and using a computer as the most frequent activities. They most frequently spent discretionary time alone or with their mothers. They spent little time engaged in conversations or doing activities with peers. Age, gender, the presence of intellectual disability, severity of autism symptoms and maladaptive behaviors, the number of siblings, maternal education, marital status, and family income were associated with adolescent time use. Notably, greater time spent in conversation and reading predicted future decreases in severity of social impairment. The way that adolescents with an ASD spend their free time may have implications for their development and the course of their autism symptoms. PMID- 21697196 TI - Biomechanical models in the study of lower limb amputee kinematics: a review. AB - BACKGROUND: Optoelectronic motion capture may provide a platform for the development of objective biomechanical outcome measures applicable to the young, active individual with lower limb loss. In order to create valid and robust tools, the modelling strategy applied must adequately represent both natural and prosthetic segments and joints. OBJECTIVES: To explore existing usage of optoelectronic motion capture and modelling strategies for the analysis of amputee function. STUDY DESIGN: Literature review. METHODS: Systematic search of Medline (OVID) and keyword search of the Journal of Prosthetics and Orthotics. RESULTS: Over 60% (n = 32) of the 51 studies extracted adopted a conventional three degree-of-freedom modelling approach. Linear segment representation (15%) and six degree-of-freedom techniques (19%) were employed in the remaining papers. Prosthetic modelling strategies were poorly reported. Landmarks were estimated from corresponding positions on the contralateral intact limb, mechanical joint centres and regression equations. No model defined the residuum and socket independently. CONCLUSIONS: In the absence of a definitive solution, it is essential that the limitations of any model are understood in the development and establishment of reliable outcome measures for this population using motion capture technology. Poor reporting and a lack of consistency make comparison of results between studies and institutions impractical. CLINICAL RELEVANCE: Standard modelling techniques may not consistently represent the body and prosthesis adequately to produce valid results for the analysis of function of persons with lower limb loss. Variation in modelling techniques limits the utility of findings reported in the literature. Development and application of a uniform, robust modelling strategy would benefit research and clinical practice. PMID- 21697197 TI - Dynamic input to determine hip joint moments, power and work on the prosthetic limb of transfemoral amputees: ground reaction vs knee reaction. AB - BACKGROUND: Calculation of lower limb kinetics is limited by floor-mounted force plates. OBJECTIVES: Comparison of hip joint moments, power and mechanical work on the prosthetic limb of a transfemoral amputee calculated by inverse dynamics using either the ground reactions (force-plates) or knee reactions (transducer). STUDY DESIGN: Comparative analysis. METHODS: Kinematics, ground reaction and knee reaction data were collected using a motion analysis system, two force-plates, and a multi-axial transducer mounted below the socket, respectively. RESULTS: The inverse dynamics using ground reaction underestimated the peaks of hip energy generation and absorption occurring at 63% and 76% of the gait cycle (GC) by 28% and 54%, respectively. This method also overestimated by 24% a phase of negative work at the hip (37%-56% GC), and underestimated the phases of positive (57%-72% GC) and negative (73%-98%GC) work at the hip by 11% and 58%, respectively. CONCLUSIONS: A transducer mounted within the prosthesis has the capacity to provide more realistic kinetics of the prosthetic limb because it enables assessment of multiple consecutive steps and a wide range of activities without the issue of foot placement on force-plates. CLINICAL RELEVANCE: The hip is the only joint an amputee controls directly to set the prosthesis in motion. Hip joint kinetics are associated with joint degeneration, low back pain, risk of falls, etc. Therefore, realistic assessment of hip kinetics over multiple gait cycles and a wide range of activities is essential. PMID- 21697198 TI - Mobility function of a prosthetic knee joint with an automatic stance phase lock. AB - BACKGROUND: There is a need for a prosthetic knee joint design that is technologically and functionally appropriate for use in developing countries. OBJECTIVES: To develop and clinically evaluate a new type of stance phase controlled prosthetic knee joint that provides stance phase stability without inhibiting swing phase flexion. STUDY DESIGN: A crossover repeated measures study design comparing the new knee joint to the participant's conventional low- or high-end prosthetic knee joint. METHODS: The new knee joint was fitted to fourteen individuals aged 15 to 67 years with unilateral lower limb amputations. Walk tests were performed to measure walking speed. Energy expenditure was estimated using the physiological cost index (PCI). RESULTS: Walking speeds with the new knee joint were on average 0.14 m/s faster than conventional low-end knees (p < 0.0001), but 0.07 m/s slower than conventional high-end prosthetic knees (p = 0.008). The PCI was similar across all three knee joint technologies (p = 0.276). CONCLUSIONS: Mobility function with the new knee joint, in terms of walking speed, was more closely matched to high-end than low-end prosthetic knee joints. Therefore, given its relatively simple design, the new stance phase control mechanism may offer a functional and cost effective solution for active transfemoral amputees. CLINICAL RELEVANCE: This paper describes a new type of prosthetic knee joint mechanism that is intended to be cost-effective while providing high-level stance phase function to active individuals with a transfemoral amputation. Initial clinical testing suggests that the new knee joint may have some functional advantages over existing technologies in this category. PMID- 21697199 TI - Postural asymmetries in transfemoral amputees. AB - BACKGROUND: Postural asymmetries are thought to lead to impairment of body structure and function such as muscle imbalance, gait asymmetry and possible chronic conditions, which result in limitation of mobility and restriction of daily activity for transfemoral amputees (TFAs). Despite the potential clinical impact, postural asymmetries have not been confirmed or quantified in TFAs. OBJECTIVES: To identify the presence of postural asymmetries in TFAs utilizing clinical evaluation measures. STUDY DESIGN: An observational cross-sectional study in which participants were evaluated at a single time point without intervention or follow-up. METHODS: Forty-seven unilateral TFAs were measured for standing limb length, pelvic innominate inclination (PII), lateral trunk flexion and hip extension. RESULTS: Limb length discrepancy was present in 66% of participants and 57% had a short prosthetic limb. PII was greater than has been reported in the literature, and the shorter the prosthetic lower limb, the greater the PII on the amputated side (r = -0.422, p = 0.004). Limb length discrepancy and decreased lateral trunk flexion accounted for 26% of the variance in amputated side PII. CONCLUSION: Three postural measurements, namely leg length, pelvic innominate inclination and hip extension, were found to differ between the intact and amputated limb in this study sample. CLINICAL RELEVANCE: Clinicians should include postural assessment as part of their routine evaluation of TFAs in an effort to achieve postural symmetry and reduce the risk of chronic conditions associated with impairment of body structure and function. PMID- 21697200 TI - Effects of joint alignment and type on mechanical properties of thermoplastic articulated ankle-foot orthosis. AB - BACKGROUND: Articulated or hinged ankle-foot orthosis (AFO) allow more range of motion. However, quantitative investigation on articulated AFO is still sparse. OBJECTIVE: The objective of the study was to quantitatively investigate effects of alignment and joint types on mechanical properties of the thermoplastic articulated AFO. STUDY DESIGN: Tamarack dorsiflexion assist flexure joints with three durometers (75, 85 and 95) and free motion joint were tested. The AFO joint was aligned with the center of the motor shaft (surrogate ankle joint), 10 mm superior, inferior, anterior and posterior with respect to the motor shaft center. METHODS: The AFO was passively moved from 20 degrees plantar flexion to 15 degrees dorsiflexion at a speed of 10 degrees /s using a motorized device. Mechanical properties including index of hysteresis, passive resistance torque and quasi-static stiffness (at neutral, 5 degrees , 10 degrees and 15 degrees in plantar flexion) were quantified. RESULTS: Significant effects of joint types and joint alignment on the mechanical properties of an articulated thermoplastic AFO were revealed. Specifically, center alignment showed minimum resistance and stiffness while anterior and posterior alignment showed significantly higher resistance and stiffness. The dorsiflexion assist torques at neutral position ranged from 0.69 +/- 0.09 to 1.88 +/- 0.10 Nm. CONCLUSIONS: Anterior and posterior alignment should be avoided as much as possible. CLINICAL RELEVANCE: The current study suggested that anterior and posterior alignment be avoided as much as possible in clinical practice due to potential skin irritation and increase in stress around the ankle joint. PMID- 21697201 TI - Osseointegration amputation prostheses on the upper limbs: methods, prosthetics and rehabilitation. AB - BACKGROUND: The osseointegration programme for upper extremity amputation started in Sweden in 1990, when a titanium fixture was first implanted into a thumb. This method has since been used for transhumeral and below-elbow amputation. The treatment involves two surgical procedures. During the first a titanium fixture is surgically attached to the skeleton, and a second procedure six months later involves a skin penetrating abutment to which the prosthesis is attached. OBJECTIVES: To describe the osseointegration procedure for surgery, prosthetics and rehabilitation. METHODS: Patients with short stumps and previous problems with prosthetic fitting were selected. From 1990 to April 2010, 37 upper limb cases were treated and fitted with prosthesis: 10 thumbs, 1 partial hand, 10 transradial and 16 transhumeral amputations. Of these, 7 patients are currently not prosthetic users. RESULTS: Patients indicated that function and quality of life had improved since osseointegration. CONCLUSION: Osseointegration is an important platform for present and future prosthetic technology. The prosthetic situation is improved due to the stable fixation, freedom of motion and functionality. CLINICAL RELEVANCE: The two-stage osseointegration procedure has the potential to change the rehabilitation strategy for selected upper limb amputees. The method eliminates the need for a socket and the prosthesis will always fit. The stable prosthetic fixation and increased freedom of motion generates improved function. Specially designed components and rehabilitation procedures have been developed. PMID- 21697202 TI - Reliability and construct validity of the Turkish version of the Trinity Amputation and Prosthetic Experience Scales (TAPES) in lower limb amputees. AB - BACKGROUND: In Turkey there is no amputee-specific instrument to measure health related quality of life in lower limb amputees. OBJECTIVES: To evaluate the validity and reliability of a Turkish version of the Trinity Amputation and Prosthesis Experience Scales (TAPES). STUDY DESIGN: Outcome study to determine test-retest reliability and construct validity of the adapted Turkish version of the TAPES. METHODS: After translation/retranslation of the TAPES, the Turkish version of the TAPES was applied to 47 amputees. A quality of life evaluation (Nottingham Health Profile), a satisfaction evaluation (Satisfaction with Prosthesis), and a functional assessment tool (Amputee Mobility Predictor) were also performed and analysed. RESULTS: On the basis of retesting, the Turkish version of the TAPES was observed to be reliable. The first domain of the Turkish version, which includes psychosocial adjustment, activity restriction and satisfaction with the prosthesis, was found to be valid. However, the validity of the second domain could not be analysed. CONCLUSIONS: The Turkish version of the multidimensional TAPES survey is valid and reliable in Turkish unilateral lower limb amputees and may be used in clinical situations to assess the needs of amputees. CLINICAL RELEVANCE: The Turkish version of the TAPES quality-of-life measurement tool for amputees is a valid instrument for assessing the effectiveness of rehabilitation and clinical applications. PMID- 21697203 TI - My prosthesis as a part of me: a qualitative analysis of living with an osseointegrated prosthetic limb. AB - BACKGROUND: Bone-anchored prosthesis is still a rather unusual treatment for patients with limb loss. OBJECTIVES: The aim of this study was to improve our understanding about the experience of living with an osseointegrated prosthesis (OI-prosthesis) compared to one suspended with a socket, through the use of qualitative research methodology. STUDY DESIGN: A qualitative phenomenological research method. METHODS: Thirteen Swedish patients (37-67 years) with unilateral upper or lower limb amputation (10 transfemoral, 2 transhumeral, 1 transradial), who had been using OI-prostheses for 3 to 15 years, were recruited by means of purposive sampling. An audio-taped in-depth interview was performed. The guiding question was 'How do you experience living with your osseointegrated prosthesis compared to your earlier prostheses suspended with sockets?'. The empirical phenomenological psychological method was used for data analysis. RESULTS: The results showed that all participants described living with an OI-prosthesis as a revolutionary change. These experiences were described in terms of three typologies, called 'Practical prosthesis', 'Pretend limb' and 'A part of me'. CONCLUSIONS: The most important finding was that the change went beyond the functional improvements, integrating the existential implications in the concept of quality of life. CLINICAL RELEVANCE: This qualitative in-depth interview study on patients using bone-anchored prosthetic limbs showed that all described a revolutionary change in their lives as amputees and the meaning of that change went beyond the functional improvements, integrating existential implications in the concept of quality of life. PMID- 21697204 TI - Survey of upper limb prosthesis users in Sweden, the United Kingdom and Canada. AB - BACKGROUND: As part of the process of improving prosthetic arms, it is important to obtain the opinions of the user population. OBJECTIVES: To identify factors that should be focused on to improve prosthesis provision. STUDY DESIGN: Postal questionnaire. METHODS: The questionnaire was sent to 292 adults (aged 18 to 70 years) with upper-limb loss or absence at five centres (four in Europe) Participants were identified as regular attendees of the centres. RESULTS: This questionnaire received a response from 180 users (response rate 62%) of different types of prosthetic devices. Responses showed that the type of prosthesis generally used was associated with gender, level of loss and use for work (Pearson chi-square, p-values below 0.05). The type of prosthesis was not associated with cause, side, usage (length per day, sports or driving) or reported problems. The findings did not identify any single factor requiring focus for the improvement of prostheses or prosthetic provision. CONCLUSIONS: Every part of the process of fitting a prosthesis can be improved, which will have an effect for some of the population who use their devices regularly. There is, however, no single factor that would bring greater improvement to all users. CLINICAL RELEVANCE: Based on information gained from a broad range of prosthesis users, no single aspect of prosthetic provision will have a greater impact on the use of upper limb prostheses than any other. Efforts to improve the designs of prosthetic systems can cover any aspect of provision. PMID- 21697207 TI - Introductory paragraph. PMID- 21697209 TI - Common carotid intima-media thickness in cardiovascular risk stratification of older people: the Rotterdam Study. AB - AIM: Non-invasive measures of atherosclerosis, such as carotid intima-media thickness (cIMT), may improve global cardiovascular risk prediction. The aim of this study was to determine whether common carotid IMT in addition to traditional risk factors improves risk classification in a general population of older people. METHODS AND RESULTS: A group of 3580 non-diabetic people aged 55-75 years and free of cardiovascular disease at baseline were followed for a median time of 12.2 years. Compared to models based on Framingham risk factors, we studied the ability of common cIMT measurement to better classify people into categories of low (<10%), intermediate (10-20%) and high (>20%) 10-year risk of hard coronary heart disease (CHD) and stroke. In older men, addition of cIMT to Framingham risk factors did not improve prediction of hard CHD or stroke. In older women, addition of cIMT to Framingham risk factors significantly improved risk classification. cIMT improved the C-statistic of the model for hard CHD from 0.711 to 0.719 and for stroke from 0.712 to 0.721, at good calibration. Reclassification was least in the majority of women classified as low risk (4% (n = 76) for hard CHD and 3% (n = 62) for stroke) and most substantial in women at intermediate risk (43% (n = 70) for hard CHD and 28% (n = 76) for stroke). The net reclassification improvement in women was 8.2% (p = 0.03) for hard CHD and 8.0% (p = 0.06) for stroke. CONCLUSION: cIMT had some additional value beyond traditional risk factors in the cardiovascular risk stratification of older women, but not of older men. PMID- 21697208 TI - Supporting community-based exercise in long-term neurological conditions: experience from the Long-term Individual Fitness Enablement (LIFE) project. AB - BACKGROUND: Patients with long-term neurological conditions often have low levels of physical activity and participation in exercise. Exercise referral schemes have been introduced in the UK to encourage physical activity in sedentary and clinical populations but typically exclude patients with long-term neurological conditions. We have developed and evaluated an exercise support system for people with long-term neurological disability, called the Physical Activity Support System, to enable them to use local gym facilities safely and effectively. The intervention: We describe the Physical Activity Support System for people with long-term neurological conditions and provide data on the use of this system in a phase II randomized controlled study trial. The system has five key components: access and transport advice, the fitness instructor, the gym, health professional support and how to exercise safely. RESULTS: Ninety-nine patients with a range of long-term neurological conditions used six different community exercise facilities in Oxfordshire and Birmingham. Average gym attendance was one session per week for 12 weeks. Participants required an average of three 1-hour face-to face physiotherapy contacts to achieve this. The average direct cost for the support system was L275. CONCLUSIONS: The scheme achieved comparable exercise participation to standard GP exercise referral schemes operating in the same centres and offers a relatively cheap, practical and feasible system for supporting people with long-term neurological conditions. PMID- 21697212 TI - Acupuncture for restless legs syndrome in patients previously treated with dopaminergic drugs. PMID- 21697210 TI - Exercise training improves neurovascular control and functional capacity in heart failure patients regardless of age. AB - BACKGROUND: Exercise training is a non-pharmacological strategy for treatment of heart failure. Exercise training improves functional capacity and quality of life in patients. Moreover, exercise training reduces muscle sympathetic nerve activity (MSNA) and peripheral vasoconstriction. However, most of these studies have been conducted in middle-aged patients. Thus, the effects of exercise training in older patients are much less understood. The present study was undertaken to investigate whether exercise training improves functional capacity, muscular sympathetic activation and muscular blood flow in older heart failure patients, as it does in middle-aged heart failure patients. DESIGN: Fifty-two consecutive outpatients with heart failure from the database of the Unit of Cardiovascular Rehabilitation and Physiology Exercise were divided by age (middle aged, defined as 45-59 years, and older, defined as 60-75 years) and exercise status (trained and untrained). METHODS: MSNA was recorded directly from the peroneal nerve using the microneurography technique. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Functional capacity was evaluated by cardiopulmonary exercise test. RESULTS: Exercise training significantly and similarly increased FBF and peak VO(2) in middle-aged and older heart failure patients. In addition, exercise training significantly and similarly reduced MSNA and forearm vascular resistance in these patients. No significant changes were found in untrained patients. CONCLUSION: Exercise training improves neurovascular control and functional capacity in heart failure patients regardless of age. PMID- 21697213 TI - Repeated application of low-frequency electroacupuncture improves high-fructose diet-induced insulin resistance in rats. AB - BACKGROUND: Insulin resistance is frequently present in obesity and during the development of type 2 diabetes mellitus. OBJECTIVE: The purpose of the present study was to investigate the effect of electroacupuncture (EA) on high-fructose diet (HFD)-induced insulin resistance. METHODS: Male Wistar rats were fed HFD for 4 weeks and developed insulin resistance. Insulin sensitivity was assessed by clamp. The number of animals was seven, eight and seven in the control, HFD and HFD+EA groups, respectively. AMP-activated protein kinase (AMPK) and glucose transporter 4 (GLUT4) in skeletal muscle were measured by Western blotting analysis (n=7 in each group). EA stimulation was carried out 12 times over 4 weeks at an intensity of 1-3 mA and a frequency of 2/15 Hz in a conscious state without restraint. RESULTS: There was no significant difference in mean body weight and fasting blood glucose concentration between groups at the end of the experiment. The mean glucose infusion rate during the clamp was significantly lower in the HFD group than in controls (p<0.05). There was no significant difference in expression of GLUT4 in skeletal muscle in the control and each group. Phosphorylated AMPKalpha (Thr172) in skeletal muscle showed a significant increase immediately after the final EA stimulation when compared with the control group (p<0.05). CONCLUSION: Repeated application of EA is capable of improving diet-induced insulin resistance, probably through activation of AMPK signalling pathways in skeletal muscle. These results suggest that repeated application of EA may have beneficial effects on diet-induced insulin resistance. PMID- 21697215 TI - Of swords, ploughshares, and climate change. PMID- 21697214 TI - Predicting risk of osteoporotic and hip fracture in the United Kingdom: prospective independent and external validation of QFractureScores. AB - OBJECTIVE: To evaluate the performance of the QFractureScores for predicting the 10 year risk of osteoporotic and hip fractures in an independent UK cohort of patients from general practice records. DESIGN: Prospective cohort study. SETTING: 364 UK general practices contributing to The Health Improvement Network (THIN) database. PARTICIPANTS: 2.2 million adults registered with a general practice between 27 June 1994 and 30 June 2008, aged 30-85 (13 million person years), with 25,208 osteoporotic fractures and 12,188 hip fractures. MAIN OUTCOME MEASURES: First (incident) diagnosis of osteoporotic fracture (vertebra, distal radius, or hip) and incident hip fracture recorded in general practice records. RESULTS: Results from this independent and external validation of QFractureScores indicated good performance data for both osteoporotic and hip fracture end points. Discrimination and calibration statistics were comparable to those reported in the internal validation of QFractureScores. The hip fracture score had better performance data for both women and men. It explained 63% of the variation in women and 60% of the variation in men, with areas under the receiver operating characteristic curve of 0.89 and 0.86, respectively. The risk score for osteoporotic fracture explained 49% of the variation in women and 38% of the variation in men, with corresponding areas under the receiver operating characteristic curve of 0.82 and 0.74. QFractureScores were well calibrated, with predicted risks closely matching those across all 10ths of risk and for all age groups. CONCLUSION: QFractureScores are useful tools for predicting the 10 year risk of osteoporotic and hip fractures in patients in the United Kingdom. PMID- 21697216 TI - 2020health. PMID- 21697217 TI - Think tank criticises payment by results for treating drug addicts as "seriously misguided". PMID- 21697218 TI - Development of ovarian hyperstimulation syndrome: interrogation of key proteins and biological processes in human follicular fluid of women undergoing in vitro fertilization. AB - Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication and potentially life-threatening condition resulting from excessive ovarian stimulation during assisted reproductive technologies. Our aim was to identify candidate proteins in follicular fluid (FF) using various proteomic approaches which may help to identify patients at risk of OHSS. We analysed the proteome alterations in FF from patients suffering from severe forms of OHSS (OHSS+) compared with a control group of women without or with only mild signs of OHSS (OHSS-). The 12 abundant proteins of FF were removed using an immunoaffinity system. Pools of remaining depleted proteins were applied to the two-dimensional (2D) electrophoresis and 2D liquid chromatography and proteins in differentially expressed protein spots/fractions were identified by mass spectrometry. Among a total of 19 candidate proteins differentially expressed (P< 0.05) between OHSS+ and OHSS- FF samples, three proteins, namely ceruloplasmin, complement C3 and kininogen-1, were found using both 2D techniques. Computer modelling highlighted the important role of kininogen-1 as an anchor for mediated interactions with other identified proteins including ferritin light chain and ceruloplasmin, hepatocyte growth factor-like protein, as well as complement C3 and gelsolin, thus linking various biological processes including inflammation and angiogenesis, iron transport and storage, blood coagulation, innate immunity, cell adhesion and actin filament polymerization. The delineation of such processes may allow the development of informed corrective therapeutic intervention in patients at risk of OHSS and a set of key proteins of the FF may be helpful as potential biomarkers for monitoring IVF therapy. PMID- 21697219 TI - Azithromycin, Ureaplasma and chronic lung disease of prematurity: a case study for neonatal drug development. AB - Chronic lung disease of prematurity (CLD) remains a major cause of morbidity and mortality in preterm infants. Ureaplasma has received intermittent attention over the last two decades as a possible contributory factor. In addition, pulmonary inflammation is associated with the development of CLD. The macrolide azithromycin provides an attractive option to determine if it can decrease the development of CLD as it has both anti-inflammatory and anti-infective properties. In this article, the authors review the evidence for the role of Ureaplasma in the development of CLD and the obstacles faced in the development of a drug before it reaches clinical practice. PMID- 21697224 TI - The demise of cultured doctors is bad for everyone. PMID- 21697220 TI - No longer lost in translation: the art and science of sports injury prevention implementation research. AB - It is now understood that sports injury interventions will not have significant public health impact if they are not widely accepted and adopted by target sports participants. Although there has been increasing recognition of the need for intervention studies conducted within the real-world context of sports delivery, very few studies have been conducted in this important area. A major reason for this is that there are significant challenges in conducting implementation research; the more traditional sports medicine approaches may not be fully appropriate and new ways of thinking about how to design, conduct and report such research is needed. Moreover, real-world implementation of sports injury interventions and evaluation of their effectiveness needs to start to take into account the broad ecological context in which they are introduced, as well as considering the best way to translate this knowledge to reach the audiences who most need to benefit from such research. This overview paper provides perspectives and guidance on the design, conduct and evaluation of sports injury intervention implementation studies, including better understanding of the complexity of the ecological settings for intervention delivery. Some conceptual approaches that could be adopted in future implementation studies are discussed; particular emphasis is given to intervention mapping as a tool to assist intervention development, diffusion of innovations theory to guide the planning of intervention strategies and the RE-AIM (reach, effectiveness, adoption, implementation and maintenance) framework for programme evaluation and programme design. Finally, a broad agenda for this emerging important field of sports medicine research is outlined. PMID- 21697225 TI - Commentary: Heading for a therapeutic stalemate. PMID- 21697226 TI - Dangers of research into chronic fatigue syndrome. PMID- 21697227 TI - Commentary: Living with CFS/ME. PMID- 21697228 TI - Watching the detectives: tracking the source of Europe's latest E coli outbreak. PMID- 21697229 TI - Doctor doctor. PMID- 21697230 TI - Assisted dying: are doctors in denial? PMID- 21697231 TI - WHO issues its first guidelines on HIV in men who have sex with men. PMID- 21697232 TI - Cardiologist wins right to exclude hearsay evidence against him. PMID- 21697233 TI - A limping child. PMID- 21697234 TI - It is all in the history, or is it? PMID- 21697235 TI - Kasabach-Merritt syndrome in a term neonate. PMID- 21697236 TI - Chorioamnionitis as a risk factor for bronchopulmonary dysplasia: a systematic review and meta-analysis. AB - OBJECTIVE: To conduct a systematic review of the association between chorioamnionitis (CA) and bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: The authors searched Medline, Embase, CINAHL, Science Citation Index and PubMed, reviewed reference lists and contacted the primary authors of relevant studies. Studies were included if they had a comparison group, examined preterm or low birthweight infants, and provided primary data. Two reviewers independently screened the search results, applied inclusion criteria and assessed methodological quality. One reviewer extracted data and a second reviewer checked data extraction. Studies were combined with an OR using a random effects model. Meta-regression was used to explore potential confounders. RESULTS: 3587 studies were identified; 59 studies (15 295 patients) were included. The pooled unadjusted OR showed that CA was significantly associated with BPD (OR 1.89, 95% CI 1.56 to 2.3). Heterogeneity was substantial (I(2)=66.2%) and may be partially explained by the type of CA. Infants exposed to CA were significantly younger and lighter at birth. The pooled adjusted OR was 1.58 (95% CI 1.11 to 2.24); heterogeneity was substantial (I(2)=65.1%) which may be due to different variables being controlled in each study. There was strong evidence of publication bias which suggests potential overestimation of the measure of association between CA and BPD. CONCLUSIONS: Unadjusted and adjusted analyses showed that CA was significantly associated with BPD; however, the adjusted results were more conservative in the magnitude of association. The authors found strong evidence of publication bias. Despite a large body of evidence, CA cannot be definitively considered a risk factor for BPD. PMID- 21697237 TI - The growing role of the Hippo--NDR kinase signalling in neuronal development and disease. AB - The nuclear Dbf2-realted (NDR) family members are highly conserved serine/threonine protein kinases that function in concert with the Hippo signalling pathway to play crucial roles in regulation of cell proliferation and survival in non-neuronal cells. Recent studies employing a range of animal models have implicated NDR kinases as regulators of multiple aspects of development in post-mitotic neurons including progenitor proliferation, fate specification and circuit formation, all of which are crucial for neuronal functions. This review summarizes the recent advances in our understanding of the neuronal functions of NDR kinases and discusses their association with neuronal diseases. PMID- 21697238 TI - Ouabain activates the Na-K-ATPase signalosome to induce autosomal dominant polycystic kidney disease cell proliferation. AB - The Na-K-ATPase is part of a cell signaling complex, the Na-K-ATPase signalosome, which upon activation by the hormone ouabain regulates the function of different cell types. We previously showed that ouabain induces proliferation of epithelial cells derived from renal cysts of patients with autosomal dominant polycystic kidney disease (ADPKD cells). Here, we investigated the signaling pathways responsible for mediating the effects of ouabain in these cells. Incubation of ADPKD cells with ouabain, in concentrations similar to those found in blood, stimulated phosphorylation of the epidermal growth factor receptor (EGFR) and promoted its association to the Na-K-ATPase. In addition, ouabain activated the kinase Src, but not the related kinase Fyn. Tyrphostin AG1478 and PP2, inhibitors of EGFR and Src, respectively, blocked ouabain-dependent ADPKD cell proliferation. Treatment of ADPKD cells with ouabain also caused phosphorylation of the caveolar protein caveolin-1, and disruption of cell caveolae with methyl beta-cyclodextrin prevented Na-K-ATPase-EGFR interaction and ouabain-induced proliferation of the cells. Downstream effects of ouabain in ADPKD cells included activation of B-Raf and MEK and phosphorylation of the extracellular regulated kinase ERK, which translocated into the ADPKD cell nuclei. Finally, ouabain reduced expression of the cyclin-dependent kinase inhibitors p21 and p27, which are suppressors of cell proliferation. Different from ADPKD cells, ouabain showed no significant effect on B-Raf, p21, and p27 in normal human kidney epithelial cells. Altogether, these results identify intracellular pathways of ouabain dependent Na-K-ATPase-mediated signaling in ADPKD cells, including EGFR-Src-B-Raf MEK/ERK, and establish novel mechanisms involved in ADPKD cell proliferation. PMID- 21697240 TI - Stressed podocytes fail to fold: a potential new role of ER in FSGS. PMID- 21697239 TI - Attenuated renal vascular responses to acute angiotensin II infusion in smooth muscle-specific Na+/Ca2+ exchanger knockout mice. AB - Recent studies in smooth muscle-specific Na(+)/Ca(2+) exchanger-1 knockout (NCX1(sm-/-)) mice reveal reduced arterial pressure and impaired myogenic responses compared with heterozygous littermates. In this study, we determined renal function in male anesthetized NCX1(sm-/-) mice and NCX1 heterozygous (NCX1(+/-)) littermates before and during acute ANG II infusions. Systolic blood pressure in awake mice was lower in NCX1(sm-/-) mice compared with NCX1(+/-) mice (119 +/- 4 vs. 131 +/- 3 mmHg, P < 0.05). Acute ANG II infusions (5 ng.min(-1).g( 1) body wt) increased mean arterial pressure in anesthetized NCX1(+/-) (109 +/- 2 to 134 +/- 3 mmHg, P < 0.001, n = 8) and NCX1(sm-/-) (101 +/- 8 to 129 +/- 8 mmHg, P < 0.01, n = 6) mice to a similar extent (Delta25 +/- 1 vs. Delta28 +/- 4 mmHg, P > 0.05). In response to ANG II infusions, PAH clearance (C(PAH)) decreased from 1.39 +/- 0.27 to 0.98 +/- 0.22 ml.min(-1).g(-1) (P < 0.05) and glomerular filtration rate (GFR) was reduced from 0.50 +/- 0.09 to 0.32 +/- 0.06 ml.min(-1).g(-1) (P < 0.05) in NCX1(+/-) mice. In contrast, the NCX1(sm-/-) did not exhibit significant reductions in either C(PAH) (1.16 +/- 0.30 to 1.22 +/- 0.34 ml.min(-1).g(-1), P > 0.05) or GFR (0.48 +/- 0.08 to 0.41 +/- 0.05 ml.min( 1).g(-1), P > 0.05) during acute ANG II infusions. Using flometry to measure renal blood flow continuously, NCX1(sm-/-) mice had significantly attenuated responses to ANG II infusions (-34.2 +/- 3.9%, P < 0.05) compared with those in NCX1(+/-) mice (-48 +/- 2%) or in wild-type mice (-69 +/- 7%). These data indicate that renal vascular responses to ANG II are attenuated in NCX1(sm-/-) mice compared with NCX1(+/-) mice and that NCX1 contributes to the renal vasoconstriction response to acute ANG II infusions. PMID- 21697241 TI - Physiology: found in translation. PMID- 21697244 TI - Advances in the diagnosis of pleural disease in lung cancer. AB - Pleural disease in lung cancer can be benign or malignant with the latter carrying a grave prognosis. In this review, we describe and discuss the advances in pleural imaging, procedures, and biomarkers for the diagnosis of pleural diseases in lung cancer. Ultrasound and computed tomography are increasingly applied in the planning of pleural procedures to enhance diagnostic accuracy and safety whilst pleuroscopy gives excellent yield in excess of 93% in the evaluation of cytology negative pleural effusions. Invasion beyond the elastic layer of the visceral pleura upstages lung cancer, and may indicate a need for adjuvant chemotherapy. Biomarkers isolated from pleural fluid or tissue may aid in diagnosis and guide treatment in the future. Magnetic resonance imaging, positron emission tomography, narrow band imaging of the pleura and autofluorescence thoracoscopy are technologies that require further evaluation to better define their respective roles in the diagnostic algorithms of pleural diseases in lung cancer. PMID- 21697242 TI - Effects of cytochrome P-450 metabolites of arachidonic acid on the epithelial sodium channel (ENaC). AB - Sodium reabsorption via the epithelial Na(+) channel (ENaC) in the aldosterone sensitive distal nephron plays a central role in the regulation of body fluid volume. Previous studies have indicated that arachidonic acid (AA) and its metabolite 11,12-EET but not other regioisomers of EETs inhibit ENaC activity in the collecting duct. The goal of this study was to investigate the endogenous metabolism of AA in cultured mpkCCD(c14) principal cells and the effects of these metabolites on ENaC activity. Liquid chromatography/mass spectrometry analysis of the mpkCCD(c14) cells indicated that these cells produce prostaglandins, 8,9-EET, 11,12-EET, 14,15-EET, 5-HETE, 12/8-HETE, and 15-HETE, but not 20-HETE. Single channel patch-clamp experiments revealed that 8,9-EET, 14,15-EET, and 11,12-EET all decrease ENaC activity. Neither 5-, 12-, nor 15-HETE had any effect on ENaC activity. Diclofenac and ibuprofen, inhibitors of cyclooxygenase, decreased transepithelial Na(+) transport in the mpkCCD(c14) cells. Inhibition of cytochrome P-450 (CYP450) with MS-PPOH activated ENaC-mediated sodium transport when cells were pretreated with AA and diclofenac. Coexpression of CYP2C8, but not CYP4A10, with ENaC in Chinese hamster ovary cells significantly decreased ENaC activity in whole-cell experiments, whereas 11,12-EET mimicked this effect. Thus both endogenously formed EETs and their exogenous application decrease ENaC activity. Downregulation of ENaC activity by overexpression of CYP2C8 was PKA dependent and was prevented by myristoylated PKI treatment. Biotinylation experiments and single-channel analysis revealed that long-term treatment with 11,12-EET and overexpression of CYP2C8 decreased the number of channels in the membrane. In contrast, the acute inhibitory effects are mediated by a decrease in the open probability of the ENaC. We conclude that 11,12-EET, 8,9-EET, and 14,15 EET are endogenously formed eicosanoids that modulate ENaC activity in the collecting duct. PMID- 21697243 TI - Regional and systemic hemodynamic responses following the creation of a murine arteriovenous fistula. AB - The study of hemodynamic alterations following the creation of an arteriovenous fistula (AVF) is relevant to vascular adaptive responses and hemodialysis access dysfunction. This study examined such alterations in a murine AVF created by anastomosing the carotid artery to the jugular vein. AVF blood flow was markedly increased due to reduced AVF vascular resistance. Despite such markedly increased basal blood flow, AVF blood flow further increased in response to acetylcholine. This AVF model exhibited increased cardiac output and decreased systemic vascular resistance; the kidney, in contrast, exhibited decreased blood flow and increased vascular resistance. Augmentation in AVF blood flow was attended by increased arterial heme oxygenase-1 (HO-1) mRNA and protein expression, the latter localized to smooth muscle cells of the AVF artery; AVF blood flow was substantially reduced in HO-1(-/-) mice compared with HO-1(+/+) mice. Finally, in a murine model of a representative disease known to exhibit impaired hemodynamic responses (sickle cell disease), the creation of an AVF was attended by decreased AVF flow and impaired AVF function. We conclude that this AVF model exhibits markedly increased AVF blood flow, a vasodilatory reserve capacity, increased cardiac output, decreased renal blood flow, and a dependency on intact hemodynamic responses, in general, and HO-1 expression, in particular, in achieving and maintaining AVF blood flow. We suggest that these findings support the utility of this model in investigating the basis for and the consequences of hemodynamic stress, including shear stress, and the pathobiology of hemodialysis AVF dysfunction. PMID- 21697245 TI - The effects of acculturation on obesity rates in ethnic minorities in England: evidence from the Health Survey for England. AB - OBJECTIVES: To investigate the extent of generational differences in adult health related lifestyles and socio-economic circumstances, and explore whether these differences might explain changing patterns of obesity in ethnic minorities in England. METHODS: Seven ethnic minority groups were selected from the ethnically boosted 1999 and 2004 Health Survey for England (Indian n = 1580; Pakistani n = 1858; Bangladeshi n = 1549; Black Caribbean n = 1472; Black African n = 587; Chinese n = 1559; and Irish n = 889). Age and sex adjusted odds of being obese in the second generation when compared with the first were estimated before and after adjusting for generational differences in health-related behaviours (snacking, eating cakes and fried foods, low levels of physical exercise, any drinking, current smoker, etc.) and socio-economic factors (social class, equivalized income and highest qualification). RESULTS: Indian [OR: 1.76 (1.14 2.71)] and Chinese [OR: 3.65 (1.37-9.78)] groups were more likely to be obese in the second generation than the first after adjusting for age and sex, with no significant differences observed in all other groups. However, the risk of obesity in all groups converged between generations to the risk observed in the White reference group, with exception to the Black Caribbean group. Adjusting independently for the mixed patterns of acculturative changes and the uniform upward social mobility in all groups increased the risk of obesity in the second generation. CONCLUSIONS: Obesity converged to the risk in the majority population following acculturation. Future research needs to consider generation and trans cultural identities as a fundamental variable in determining the causes of ethnic health inequalities. PMID- 21697246 TI - The economic cost to households of childhood malaria in Papua New Guinea: a focus on intra-country variation. AB - BACKGROUND: We compare direct and indirect household costs associated with malaria treatment for children<3 years in two provinces of Papua New Guinea. In particular, we explore the role of uncertainty around mean household costs and whether assuming a normal distribution for household costs limits the accuracy of any direct cost comparisons. METHODS: Exit surveys were undertaken at inpatient and outpatient health facilities. In order to handle uncertainty and facilitate comparisons, parametric and non-parametric bootstrap methods were used to estimate direct and indirect costs at the individual data level. The inpatient and outpatient incremental costs from Madang and Maprik health facilities were compared and significant differences between provinces were identified. RESULTS: Differences were noted between provinces for both inpatient and outpatient household costs. Total arithmetic mean costs for an outpatient malaria episode were US$7.54 in Madang and US$9.20 in Maprik. Total mean inpatient malaria episode costs were US$25.20 in Madang and US$14.08 in Maprik. As cost distributions were not normal, non-parametric bootstrap techniques were used for cost comparisons. Total household costs per outpatient episode of malaria were lower, although not significantly, in Maprik than in Madang (incremental cost of US$ -1.67; 95% CI -4.16, 0.31), while total household costs per inpatient episode were significantly higher in Madang than in Maprik (difference of US$11.16; 95% CI 5.47, 25.33). A difference was noted between provinces in the proportion of indirect costs in total household costs for an outpatient visit: 76% in Madang vs 94% in Maprik. The proportion for indirect costs associated with inpatient visits varied less: 63% in Madang vs 68% in Maprik. CONCLUSIONS: Intra-country differences need to be considered in estimating household costs for both outpatient and inpatient malaria treatment. Our findings suggest that it is important to recognize the impact of both direct and indirect costs on individuals' capacity to afford treatment. Certain indirect costs are difficult to measure accurately, particularly respondents' interpretations of their productive versus non-productive time. Despite this, exploring intra-country cost variation can provide important information to health policy makers. PMID- 21697247 TI - A survival analysis approach to modeling human fecundity. AB - Understanding conception probabilities is important not only for helping couples to achieve pregnancy but also in identifying acute or chronic reproductive toxicants that affect the highly timed and interrelated processes underlying hormonal profiles, ovulation, libido, and conception during menstrual cycles. Currently, 2 statistical approaches are available for estimating conception probabilities depending upon the research question and extent of data collection during the menstrual cycle: a survival approach when interested in modeling time to-pregnancy (TTP) in relation to women or couples' purported exposure(s), or a hierarchical Bayesian approach when one is interested in modeling day-specific conception probabilities during the estimated fertile window. We propose a biologically valid discrete survival model that unifies the above 2 approaches while relaxing some assumptions that may not be consistent with human reproduction or behavior. This approach combines both the survival and the hierarchical models allowing investigators to obtain the distribution of TTP and day-specific probabilities during the fertile window in a single model. Our model allows for the consideration of covariate effects at both the cycle and the daily level while accounting for daily variation in conception. We conduct extensive simulations and utilize the New York State Angler Prospective Pregnancy Cohort Study to illustrate our approach. We also provide the code to implement the model in R software in the supplemental section of the supplementary material available at Biostatistics online. PMID- 21697248 TI - Polyamines are increased in obese children and are related to markers of oxidative/nitrosative stress and angiogenesis. AB - CONTEXT: Polyamines (putrescine, spermidine, and spermine) are polycationic amines derived from arginine, which is the precursor of nitric oxide (NO). Due to the close relationship between the metabolism of polyamines and NO metabolism, the alteration in polyamine homeostasis can affect the NO bioavailability at the endothelium. OBJECTIVES: The objective of the study was to test the hypothesis that childhood obesity is associated with a significant modification of blood polyamines and to investigate the presence of correlation between these molecules, circulating markers of oxidative and nitrosative stress, and endothelial dysfunction. DESIGN AND SETTING: This was an observational analytical case-control study conducted at one tertiary care center. PATIENTS AND METHODS: The study was performed with 102 children aged 7-14 yr (60 obese, 42 nonobese). Blood polyamines were measured by HPLC. Metabolites of the NO pathway, oxidative stress parameters, inflammatory markers, adhesion molecules, and adipocytokines were also determined. RESULTS: Polyamine levels were significantly higher in obese children. Among them, spermine was the polyamine with the more discriminatory power, taking into account the obesity. In all children, spermine levels were related to biomarkers of oxidative/nitrosative stress, inflammation, and leptin and to adhesion molecules, soluble E-selectin, and soluble intercellular adhesion molecule-1. Only in obese children was there a positive correlation with vascular endothelial growth factor and a negative correlation with 3'-nitrotyrosine levels. CONCLUSIONS: Polyamine levels are increased in childhood obesity and correlated to markers of oxidative/nitrosative stress and angiogenesis. This finding implicates polyamine metabolism in the complications of obesity. Their potential utility as a clinical tool remains to be elucidated. PMID- 21697249 TI - Hippocampal size and memory functioning in children and adolescents with congenital hypothyroidism. AB - BACKGROUND: Despite early diagnosis and treatment of congenital hypothyroidism (CH) after newborn screening, selective and persistent neurocognitive weaknesses may be seen. One area of particular weakness is memory, especially on tasks known to be mediated by the hippocampus. However, the hippocampus has not been directly studied in this population. OBJECTIVE: Our objective was to use magnetic resonance imaging to determine whether children and adolescents with CH have reduced hippocampal size and abnormal hippocampal growth patterns relative to peers and whether reduced hippocampal volumes in CH predict poor memory performance. METHODS: Studied were 35 CH and 44 typically developing controls aged 9-15 yr. All were assessed using standardized tests of intelligence and verbal and visual memory and received an magnetic resonance imaging scan. Parents completed a questionnaire of their everyday memory functioning (EMF). Right and left hippocampal volumes were measured by manual tracing. RESULTS: CH subjects scored significantly below controls on indices of verbal but not visual memory as well as aspects of EMF. CH subjects also had smaller hippocampal volumes, particularly on the left side. Unlike controls, who showed a positive relationship between age and hippocampal volumes, age was unrelated to hippocampal size in CH. Structure-function correlations revealed significant relationships between hippocampal volumes and EMF in controls and modest correlations between hippocampal volumes and memory test scores but not EMF in CH. CONCLUSIONS: Compromised hippocampal development in CH may contribute to some of the memory weaknesses observed in this population. PMID- 21697250 TI - Cholecalciferol plus calcium suppresses abnormal PBMC reactivity in patients with multiple sclerosis. AB - CONTEXT: The active metabolite of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D], is a potent modulator of immune cells in vitro. OBJECTIVE: Our objective was to determine whether the sun-dependent nutrient, cholecalciferol, can alter disease-associated cellular immune abnormalities in patients with multiple sclerosis (MS). DESIGN: This was an open-label, 12-month, randomized controlled trial. SETTING: Patients with MS were recruited from the MS Clinic at St. Michael's Hospital, Toronto. PATIENTS: Forty-nine patients were matched (for age, sex, disease duration, disease-modifying drug, and disability) and enrolled (treated n = 25; control n = 24). Four patients were lost to follow-up (n = 2 from each group). INTERVENTION: Treated patients received increasing doses of cholecalciferol (4,000-40,000 IU/d) plus calcium (1200 mg/d), followed by equilibration to a moderate, physiological intake (10,000 IU/d). Control patients did not receive supplements. MAIN OUTCOME MEASURES: At enrollment and at 12 months, peripheral blood mononuclear cell (PBMC) proliferative responses to disease-associated, MS-relevant, and control antigens were measured, along with selected serum biochemical markers. RESULTS: At 12 months, mean serum 25 hydroxyvitamin D [25(OH)D] concentrations were 83 +/- 35 nmol/liter and 179 +/- 76 nmol/liter in control and treated participants, respectively (paired t, P < 0.001). Serum 1,25(OH)(2)D did not differ between baseline and 1 yr. In treated patients, 12-month PBMC proliferative responses to neuron antigens myelin basic protein and exon-2 were suppressed (P = 0.002). In controls, there were no significant changes in disease-associated PBMC responsiveness. There were no significant differences between groups in levels of selected biomarkers. INTERPRETATION: MS-associated, abnormal T cell reactivities were suppressed in vivo by cholecalciferol at serum 25(OH)D concentrations higher than 100 nmol/liter. PMID- 21697252 TI - Treatment of congenital hyperinsulinism with lanreotide acetate (Somatuline Autogel). AB - CONTEXT: Congenital hyperinsulinism (CH) may be treated conservatively in many children with octreotide given by multiple sc injections or via an insulin pump. OBJECTIVE: We describe two children treated with a once-monthly injection of a long-acting somatostatin analog. PATIENTS AND METHODS: Both patients presented with hypoglycemia 30 min after birth and were subsequently diagnosed with CH. Patients were initially treated with diazoxide, hydrochlorothiazide, frequent feedings, and octreotide via an insulin pump. With this therapy, they were normoglycemic with a good growth rate, normal weight gain, and excellent neurodevelopment. Treatment with the long-acting somatostatin analog lanreotide acetate (Somatuline Autogel), administered by deep sc injection of 30 mg once a month, was started at the ages of 41/2 and 4 yr, respectively. Octreotide infusion was gradually weaned over 1 month. Continuous glucose monitoring after discontinuation of pump therapy showed normoglycemia. The first patient has now been treated with the lanreotide acetate for over 5 yr, and the second for 3 yr. Treatment is well-tolerated, and both the patients and their parents are satisfied with the transition from pump therapy to once-a-month injection and prefer it to pump therapy. CONCLUSION: Lanreotide acetate may be a safe and effective alternative to octreotide pump therapy in patients with CH, offering an improved quality of life. Longer follow-up of a larger patient group is needed. PMID- 21697251 TI - Sexual dimorphism in the early life programming of serum leptin levels in European adolescents: the HELENA study. AB - AIM: The aim of this study was to test the hypothesis that a lower birth weight, as an indicator of adverse intrauterine environment, is associated with higher serum leptin levels in European adolescents. We also examined the possible sexual dimorphism in this relationship. METHODS: Fasting serum leptin was measured in 757 European born at term adolescents (429 females) aged 14.6 +/- 1.2 yr. We measured weight and height, and body mass index was calculated. Birth weight, duration of pregnancy, and duration of breast-feeding were obtained from parental records. Duration of pregnancy and breast-feeding, pubertal status, center, body mass index, and physical activity were entered as confounders in the analyses. RESULTS: There was a significant interaction effect between sex and birth weight on serum leptin levels (P = 0.044). We observed that body weight at birth was negatively and significantly associated with serum leptin levels only in female adolescents (beta = -0.109; adjusted P = 0.008). The association persisted after further controlling for physical activity (beta = -0.115; adjusted P = 0.016). CONCLUSIONS: These findings provide further evidence for a sex-specific programming effect of birth weight on serum leptin levels. Our results also contribute to explain the detrimental health effects associated with lower birth weight, such as long-term increased risk of developing obesity and type 2 diabetes. PMID- 21697253 TI - Telomerase-driven expression of the sodium iodide symporter (NIS) for in vivo radioiodide treatment of cancer: a new broad-spectrum NIS-mediated antitumor approach. AB - CONTEXT: Telomerase promoters (hTERT and hTR) are useful for transcriptional targeting in gene therapy models of cancer. Telomerase-driven expression of the sodium iodide symporter (NIS) in tumor cells has been successfully used as a reporter gene in vivo using positron emission tomography (PET) imaging. OBJECTIVE: The aim of this study was to investigate the NIS-mediated therapeutic effect of telomerase promoters in a wide variety of human cancer cell lines. DESIGN AND METHODS: Promoter fragments from either hTERT or hTR were used to drive the expression of NIS in cell lines derived from melanoma (M14), breast (MDA-MB-231), colon (HT-29), lung (H460), ovarian (OVCAR-3), and thyroid (TPC-1) carcinomas. Iodide uptake assays, protein immunodetection, and clonigenic assays were used to confirm NIS functional expression and the (131)I-mediated cytopathic effect. Tumor xenografts in mice were infected with hTERT and hTR and then treated using radioiodide. RESULTS: Both promoters were selectively active in cancer cells that were effectively killed by exposure to (131)I. One single dose of 1 mCi (131)I markedly suppressed tumor growth of melanoma-derived tumor xenografts compared with controls. This effect was more modest in colon cancer derived xenografts in part due to the reduced infectivity and the tumor cystic nature. The therapeutic effect of hTR promoter was found to be stronger than that of hTERT promoter. CONCLUSIONS: These results demonstrate that telomerase-driven expression of NIS could potentially have applications for (131)I therapy of a wide variety of cancers. Additionally, this is the first study to report NIS mediated (131)I therapy of melanoma tumors in vivo. PMID- 21697254 TI - Preservation of beta-cell function: the key to diabetes prevention. AB - CONTEXT: The Centers for Disease Control and Prevention estimates that there are approximately 79,000,000 individuals in the United States with prediabetes [impaired glucose tolerance (IGT) and/or impaired fasting glucose] and that approximately 40-50% will progress to type 2 diabetes mellitus (T2DM) during their lifetime. Therefore, treatment of high-risk IGT individuals to prevent T2DM has important medical, economic, social, and human implications. Individuals in the upper tertile of IGT are maximally/near-maximally insulin resistant, have lost 70-80% of their beta-cell function, and have approximately a 10% incidence of diabetic retinopathy. Therefore, preservation of the remaining 20-30% of beta cell function is critical to prevent future development of T2DM. EVIDENCE ACQUISITION: We searched MEDLINE from 2000 to the present to identify placebo controlled trials in which individuals with IGT received pharmacological therapy to prevent progression to diabetes. EVIDENCE SYNTHESIS: Lifestyle modification reduces IGT conversion to T2DM, but it is difficult to implement and maintain. Moreover, 40-50% of IGT subjects progress to T2DM despite weight loss. In contrast, pharmacological intervention with medications that reverse known pathophysiological abnormalities (beta-cell dysfunction and insulin resistance) uniformly prevents IGT progression to T2DM. Thiazolidinediones reduce IGT conversion to diabetes by approximately 50-70%. Metformin in the U.S. Diabetes Prevention Program reduced the development of T2DM by 31% and has been recommended by the American Diabetes Association. Because glucagon-like peptide-1 analogs augment insulin secretion, preserve beta-cell function, and promote weight loss, they may be efficacious in preventing IGT progression to T2DM. CONCLUSION: Pharmacological intervention with a variety of agents (thiazolidinediones, metformin, acarbose, glucagon-like peptide-1 analogs) consistently reduces the rate of conversion of IGT to T2DM. PMID- 21697256 TI - Metropolitan-level racial residential segregation and black-white disparities in hypertension. AB - Few studies have examined geographic variation in hypertension disparities, but studies of other health outcomes indicate that racial residential segregation may help to explain these variations. The authors used data from 8,071 black and white participants in the National Health and Nutrition Examination Survey (1999 2006) who were aged 25 years or older to investigate whether black-white hypertension disparities varied by level of metropolitan-level racial residential segregation and whether this was explained by race differences in neighborhood poverty. Racial segregation was measured by using the black isolation index. After adjustment for demographics and individual-level socioeconomic position, blacks had 2.74 times higher odds of hypertension than whites (95% confidence interval (CI): 2.32, 3.25). However, race differences were significantly smaller in low- than in high-segregation areas (P(interaction) = 0.006). Race differences in neighborhood poverty did not explain this heterogeneity, but poverty further modified race disparities: Race differences were largest in segregated, low poverty areas (odds ratio = 4.14, 95% CI: 3.18, 5.38) and smallest in nonsegregated, high-poverty areas (odds ratio = 1.24, 95% CI: 0.77, 2.01). These findings suggest that racial disparities in hypertension are not invariant and are modified by contextual levels of racial segregation and neighborhood poverty, highlighting the role of environmental factors in the genesis of disparities. PMID- 21697255 TI - Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. AB - CONTEXT: Reference ranges are essential for partitioning testosterone levels into low or normal and making the diagnosis of androgen deficiency. We established reference ranges for total testosterone (TT) and free testosterone (FT) in a community-based sample of men. METHODS: TT was measured using liquid chromatography tandem mass spectrometry in nonobese healthy men, 19-40 yr old, in the Framingham Heart Study Generation 3; FT was calculated. Values below the 2.5th percentile of reference sample were deemed low. We determined the association of low TT and FT with physical dysfunction, sexual symptoms [European Male Aging Study (EMAS) only], and diabetes mellitus in three cohorts: Framingham Heart Study generations 2 and 3, EMAS, and the Osteoporotic Fractures in Men Study. RESULTS: In a reference sample of 456 men, mean (sd), median (quartile), and 2.5th percentile values were 723.8 (221.1), 698.7 (296.5), and 348.3 ng/dl for TT and 141. 8 (45.0), 134.0 (60.0), and 70.0 pg/ml for FT, respectively. In all three samples, men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs, or frailty and diabetes than those with normal levels. In EMAS, men with low TT and FT were more likely to report sexual symptoms than men with normal levels. Men with low TT and FT were more likely to have at least one of the following: sexual symptoms (EMAS only), physical dysfunction, or diabetes. CONCLUSION: Reference ranges generated in a community based sample of men provide a rational basis for categorizing testosterone levels as low or normal. Men with low TT or FT by these criteria had higher prevalence of physical dysfunction, sexual dysfunction, and diabetes. These reference limits should be validated prospectively in relation to incident outcomes and in randomized trials. PMID- 21697257 TI - Breast cancer screening: a 35-year perspective. AB - Screening for breast cancer has been evaluated by 9 randomized trials over 5 decades and recommended by major guideline groups for more than 3 decades. Successes and lessons for cancer screening from this history include development of scientific methods to evaluate screening, by the Canadian Task Force on the Periodic Health Examination and the U.S. Preventive Services Task Force; the importance of randomized trials in the past, and the increasing need to develop new methods to evaluate cancer screening in the future; the challenge of assessing new technologies that are replacing originally evaluated screening tests; the need to measure false-positive screening test results and the difficulty in reducing their frequency; the unexpected emergence of overdiagnosis due to cancer screening; the difficulty in stratifying individuals according to breast cancer risk; women's fear of breast cancer and the public outrage over changing guidelines for breast cancer screening; the need for population scientists to better communicate with the public if evidence-based recommendations are to be heeded by clinicians, patients, and insurers; new developments in the primary prevention of cancers; and the interaction between improved treatment and screening, which, over time, and together with primary prevention, may decrease the need for cancer screening. PMID- 21697259 TI - In vivo-transmigrated human neutrophils are resistant to antiapoptotic stimulation. AB - Neutrophils respond to microbial invasion or injury by transmigration from blood to tissue. Transmigration involves cellular activation and degranulation, resulting in altered levels of surface receptors and changed responsiveness to certain stimuli. Thus, fundamental functional changes are associated with neutrophil transmigration from blood to tissue. Neutrophils isolated from peripheral blood spontaneously enter apoptosis, a process that can be accelerated or delayed by different pro- or antiapoptotic factors. How tissue neutrophils that have transmigrated in vivo regulate cell death is poorly understood. In this study, in vivo-transmigrated neutrophils (tissue neutrophils) were collected using a skin chamber technique and compared with blood neutrophils from the same donors with respect to regulation of cell death. Skin chamber fluid contained a variety of cytokines known to activate neutrophils and regulate their lifespan. Freshly prepared tissue neutrophils had elevated activity of caspase 3/7 but were fully viable; spontaneous cell death after in vitro culture was also similar between blood and tissue neutrophils. Whereas apoptosis of cultured blood neutrophils was delayed by soluble antiapoptotic factors (e.g., TLR ligands), tissue neutrophils were completely resistant to antiapoptotic stimulation, even though receptors were present and functional. In vitro transmigration of blood neutrophils into skin chamber fluid did not fully confer resistance to antiapoptotic stimulation, indicating that a block of antiapoptotic signaling occurs specifically during in vivo transmigration. We describe a novel, functional alteration that takes place during in vivo transmigration and highlights the fact that life and death of neutrophils may be regulated differently in blood and tissue. PMID- 21697258 TI - The OsNRAMP1 iron transporter is involved in Cd accumulation in rice. AB - Cadmium (Cd) is a heavy metal toxic to humans and the accumulation of Cd in the rice grain is a major agricultural problem, particularly in Asia. The role of the iron transporter OsNRAMP1 in Cd uptake and transport in rice was investigated here. An OsNRAMP1:GFP fusion protein was localized to the plasma membrane in onion epidermal cells. The growth of yeast expressing OsNRAMP1 was impaired in the presence of Cd compared with yeast transformed with an empty vector. Moreover, the Cd content of OsNRAMP1-expressing yeast exceeded that of the vector control. The expression of OsNRAMP1 in the roots was higher in a high Cd accumulating cultivar (Habataki) than a low Cd-accumulating cultivar (Sasanishiki) regardless of the presence of Cd, and the amino acid sequence of OsNRAMP1 showed 100% identity between Sasanishiki and Habataki. Over-expression of OsNRAMP1 in rice increased Cd accumulation in the leaves. These results suggest that OsNRAMP1 participates in cellular Cd uptake and Cd transport within plants, and the higher expression of OsNRAMP1 in the roots could lead to an increase in Cd accumulation in the shoots. Our results indicated that OsNRAMP1 is an important protein in high-level Cd accumulation in rice. PMID- 21697260 TI - Technical advance: Langerhans cells derived from a human cell line in a full thickness skin equivalent undergo allergen-induced maturation and migration. AB - In this report, the construction of a functional, immunocompetent, full-thickness skin equivalent (SE) is described, consisting of an epidermal compartment containing keratinocytes, melanocytes, and human LCs derived from the MUTZ-3 cell line (MUTZ-LC) and a fibroblast-populated dermal compartment. The CD1a(+)Langerin(+)HLA-DR(+) MUTZ-LCs populate the entire epidermis at a similar density to that found in native skin. Exposure of the SE to subtoxic concentrations of the allergens NiSO(4) and resorcinol resulted in LC migration out of the epidermis toward the fibroblast-populated dermal compartment. A significant dose-dependent up-regulation of the DC maturation-related CCR7 and IL 1beta transcripts and of CD83 at the protein level upon epidermal exposure to both allergens was observed, indicative of maturation and migration of the epidermally incorporated LC. We have thus successfully developed a reproducible and functional full-thickness SE model containing epidermal MUTZ-LC. This model offers an alternative to animal testing for identifying potential chemical sensitizers and for skin-based vaccination strategies and provides a unique research tool to study human LC biology in situ under controlled in vitro conditions. PMID- 21697261 TI - An uncertain future: the unchanging views of care home residents about living and dying. AB - BACKGROUND: Older people living in a care home have a limited life expectancy, and care homes are an important setting for end-of-life care provision. AIM: This research aimed to explore the views, experiences and expectations of end-of-life care among care home residents to understand if key events or living in a residential environment influenced their views. DESIGN: The research used a prospective design. The paper draws on the qualitative interviews of 63 care home residents who were interviewed up to three times over a year. This was a sub sample of the larger data set of 121 care home residents. SETTING/PARTICIPANTS: The residents were recruited from six care homes (providing personal care with no on-site nursing) in the UK. RESULTS: Four main themes were identified; Living in the Past, Living in the Present, Thinking about the Future and Actively Engaged with planning the future. Many residents said they had not spoken to the care staff about end-of-life care; many assumed their family or General Practitioner would take responsibility. CONCLUSIONS: Core to the older person's ability to discuss end-of-life care is their acceptance of being in a care home, the involvement of family members in making decisions and the extent to which they believed they could influence decision making within their everyday lives. Advance care plans should document ongoing dialogue. These findings can inform how primary health and palliative care services introduce, discuss and tailor existing frameworks and programmes of end-of-life care. PMID- 21697262 TI - Predictors of non-remission of depression in a palliative care population. AB - BACKGROUND: Prospective studies of depression in palliative care are rare. Two studies that examine depression prospectively in patients with advanced disease have not looked at predictors of remission. AIMS: to explore prospective predictors of non-remission of depression in palliative care. DESIGN AND PARTICIPANTS: The study design comprised two data collections: initial assessment on referral to a palliative care service in South London, UK, and a four-week follow-up. Seventy six participants met the criteria for 'any depressive syndrome' at the time 1 assessment, using the PRIME-MD, who also participated at time 2. The outcome measure was remission (N = 39) or non-remission (N = 37) of depression by time 2. RESULTS: The findings showed that reporting low social support from family and friends at time of referral was the most powerful risk factor for non-remission. There was also a strong association between improved physical symptoms, from time 1 to 2, and remission of depression. CONCLUSIONS: This study in palliative care is the first of which we are aware to explore factors associated with non-remission of depression. Depressed patients identified with low social support on referral to palliative care services might particularly benefit from additional psychosocial care in the treatment of their depression. This study provides evidence that effective physical symptom management in palliative care may be a valuable intervention for depressive symptoms. PMID- 21697263 TI - End-of-life care in hospitalized adults with complex congenital heart disease: care delayed, care denied. AB - Adults with congenital heart disease represent a growing patient population. Notwithstanding dramatic improvements in survival and life expectancy over recent decades, many of these patients remain at risk of premature death from progressive heart disease and would benefit from the principles of palliative and end-of-life care. Data on end-of-life care in this patient group are, however, lacking. We report a retrospective study of 48 patients with congenital heart disease who died while admitted to our hospital (mean age at death 37 +/- 14 years). We describe circumstances of death, end-of-life discussions, and the provision of end-of-life care. The majority of patients had complex congenital heart disease and were considered to be in the end stage of their disease. Despite this, only a minority of patients had documented end-of-life discussions prior to their terminal admission and most received continuing aggressive medical treatment up to their demise. Advanced palliative and end-of-life care strategies should be developed for and provided to this group of patients, with the dual aims of reduction of unwarranted therapies and enhancement of the quality of death and dying. PMID- 21697264 TI - Place of death related to demographic factors for hospice patients in Wellington, Aotearoa New Zealand. AB - BACKGROUND: Because socioeconomic and cultural factors contribute to where one dies, it is important to document place of death determinants in diverse societies. AIM: The purpose of this study was to describe where persons in an Aotearoa New Zealand hospice die, and to identify factors that are associated with place of death. DESIGN: A retrospective chart review was conducted. SETTING/PARTICIPANTS: Data were extracted from the charts of all patients receiving services from one hospice (i.e. secondary care) for whom death occurred during 2006-2008; 1268 cases for whom place of death was recorded comprise this sample. RESULTS: For close to half (47%), death occurred in the hospice inpatient unit, whereas 29% died at home, 8% died in an acute hospital setting, and 17% died in an aged/residential care facility. Bivariate analyses showed that persons who die in an aged/residential care facility are more likely to be aged 65 or older, unmarried, have a non-cancer diagnosis, and are likely poorer. Asians, those aged less than 65, those with cancer, and those admitted initially to hospice for respite care tended to die in the hospice inpatient unit. Multinominal logistic regression indicated that dying at home was only predicted by being from a Pacific Island. CONCLUSIONS: Age, economics, diagnosis, ethnicity, marital status, and whether one enters a hospice service for (at least in part) respite were all associated to a certain extent with where one dies. These findings contribute to the growing evidence linking various factors, especially ethnic groups, with place of death. PMID- 21697265 TI - What is the methodological rigour of palliative care research in long-term care facilities in Europe? A systematic review. AB - BACKGROUND: The European population is rapidly ageing, resulting in increasing numbers of older people dying in long-term care facilities. There is an urgent need for palliative care in long-term care facilities. AIM: The aim of this study was to systematically review the literature on palliative care research in long term care facilities in Europe with respect to how the palliative care populations were described, and to determine the study designs and patient outcome measures utilized. METHODS: We used a systematic literature review. The search strategy included searches of PubMed, Embase and PsychINFO databases from 2000 up to May 2010, using search terms related to 'palliative care' and 'end-of life care' combined with search terms related to 'long-term care'. We selected articles that reported studies on patient outcome data of palliative care populations residing in a long-term care facility in Europe. RESULTS: This review demonstrated that there are few, and mainly descriptive, European studies on palliative care research in long-term care facilities. Fourteen studies were retained in the review, of which eight were conducted in the Netherlands. None of these studies described their study population specifically as a palliative care or end-of-life care population. Retrospective and prospective designs were applied using many different measurement instruments. Most instruments were proxy ratings. Symptom (management) was the most frequently measured outcome. CONCLUSION: To improve future research on palliative care in long-term care facilities, agreement on what can be considered as palliative care in long-term care facilities and, the availability of well-developed and tested measurement instruments is needed to provide more evidence, and to make future research more comparable. PMID- 21697266 TI - Opioid switching to methadone: a pharmacoepidemiological study from a national prescription database. AB - BACKGROUND: Opioid switching to methadone is reported frequently to improve pain control in patients with an unacceptable balance between pain control and side effects during treatment with first line opioids, but carries a risk of drug accumulation and respiratory depression. To justify this risk it is required that less risky treatments are tried beforehand and that a sufficiently large proportion of patients experience a long-lasting improvement in pain control. RESEARCH QUESTIONS: How large was the proportion of patients remaining on long term methadone treatment after a switch from a strong opioid to methadone? How long had the patients been treated with opioids before the switch to methadone? METHODS: Longitudinal pharmacoepidemiological study from the complete national Norwegian Prescription Database. RESULTS: One hundred and thirty (77%) cancer patients received more than one dispensed prescription of methadone. Forty-nine (40%) chronic non-malignant pain (CNMP) patients continued to have methadone prescriptions dispensed more than 6 months after the switch. Of 168 cancer patients, 48 (29%) had tried two strong opioids prior to the switch to methadone whereas 21 (12.5%) had tried three or more strong opioids. Similar numbers for 124 CNMP patients were 26 (21%) and 34 (27%), respectively. INTERPRETATION: Opioid switching to methadone appears to provide a long lasting improvement in pain control in a significant proportion of patients. However, the study raises concerns that treatment options with less risk are not being exhausted prior to switching to methadone. PMID- 21697268 TI - The oncologist Chinese edition: a global mission, a unifying bond. PMID- 21697267 TI - Are we heading in the same direction? European and African doctors' and nurses' views and experiences regarding outcome measurement in palliative care. AB - OBJECTIVE: To examine and compare doctors' and nurses' views and experiences regarding outcome measurement in palliative care, including patient-reported outcome measures (PROMs). METHODS: A web-based survey developed through expert review and piloting was conducted in Europe and Africa with palliative care professionals working in clinical care, audit and research. RESULTS: The overall participation rate was 42% (663/1592) and the overall completion rate was 59% (392/663). Of these respondents, 196 were doctors (51% male, mean 47 years) and 104 were nurses (84% female, mean 45 years). Doctors' most common reported reasons for not using tools were time constraints followed by lack of training. For nurses, it was lack of training followed by time constraints. Provision of information and guidance influenced willingness to use measures. For those that used tools, most reported favourable outcome measurement experiences. Both prioritized brief PROMs, and measures that included physical and psychological domains. For clinical purposes, the main advantage for doctors was assessment/screening, and clinical decision making for nurses. For research, doctors were most influenced by a measure's comparability with national/international literature followed by its validation in palliative care. For nurses, validation in palliative care was followed by tool access. CONCLUSION: Overall these respondents shared similar views and experiences, and both were influenced by similar factors. Multidisciplinary outcome measurement education and training is feasible and required. Multidimensional and brief PROMs that include physical and psychological domains need to be prioritized, and access to freely available, validated and translated tools is needed to ensure cross-national comparisons and coordination of international research. PMID- 21697272 TI - Effects of wire-bottom caging on heart rate, activity and body temperature in telemetry-implanted rats. AB - Some experimental procedures are associated with placement of animals in wire bottom cages. The goal of this study was to evaluate stress-related physiological parameters (heart rate [HR], body temperature [BT], locomotor activity [LA], body weight [BW] and food consumption) in rats under two housing conditions, namely in wire-bottom cages and in bedding-bottom cages. Telemetry devices were surgically implanted in male Sprague-Dawley rats. HR, BT and LA were recorded at 5 min intervals. Analysis under each housing condition was performed from 16:00 to 08:00 h of the following day (4 h light, 12 h dark). During almost all of the light phase, the HR of rats housed in wire-bottom cages remained high (371 +/- 35 bpm; mean +/- SD; n = 6) and was significantly different from that of rats housed in bedding-bottom cages (340 +/- 29 bpm; n = 6; P < 0.001; Student's t-test). In general, BT was similar under the two housing conditions. However, when rats were in wire-bottom cages, BT tended to fluctuate more widely during the dark phase. LA decreased when animals were housed in wire-bottom cages, in particular during the dark phase. Moreover, there was a significant difference with respect to the gain in BW: BW of rats housed in bedding-bottom cages increased 12 +/- 2 g, whereas that of rats in wire-bottom cages decreased by 2 +/- 3 g (P < 0.001). Our results demonstrate that housing rats in wire-bottom cages overnight leads to immediate alterations of HR, BW and LA, which might be related to a stress response. PMID- 21697274 TI - Multiple actions of the anthracycline daunorubicin on cardiac ryanodine receptors. AB - Our aim was to examine the molecular basis for acute effects of the anthracycline daunorubicin on cardiac ryanodine receptor (RyR2) channels and cardiac calsequestrin (CSQ2). Cardiotoxic effects of anthracyclines preclude their chemotherapeutic use in patients with pre-existing heart conditions. To address this significant problem, the mechanisms of anthracycline toxicity must be defined but at present are poorly understood. RyR2 channel activity was assessed by measuring Ca2+ release from cardiac sarcoplasmic reticulum vesicles and by examining single RyR2 channels inserted into artificial lipid bilayers. We show that 0.5 to 10 MUM daunorubicin increases the activity of RyR2 channels after 5 to 10 min and that activity then declines to very low levels when channels are exposed to daunorubicin concentrations of >= 2.5 MUM for a further 10 to 20 min. Extensive dissection of these effects shows for the first time that the activation results from a redox-independent binding of daunorubicin to the RyR2 complex. Novel data include the demonstration of daunorubicin binding to RyR2. We provide compelling evidence that RyR2 channel inhibition is due to the oxidation of free SH groups. The oxidation reaction is prevented by the presence of 1 mM dithiothreitol. We also present novel data showing that CSQ2 modifies the response of RyR2 to daunorubicin, but that the response of RyR2 is not dependent on daunorubicin binding to CSQ2. We suggest that binding of daunorubicin to RyR2 and CSQ2, and oxidation of RyR2, are all likely to contribute to anthracycline induced cardiotoxicity during chemotherapy. PMID- 21697273 TI - Resveratrol restores Nrf2 level and prevents ethanol-induced toxic effects in the cerebellum of a rodent model of fetal alcohol spectrum disorders. AB - In humans, ethanol exposure during pregnancy produces a wide range of abnormalities in infants collectively known as fetal alcohol spectrum disorders (FASD). Neuronal malformations in FASD manifest as postnatal behavioral and functional disturbances. The cerebellum is particularly sensitive to ethanol during development. In a rodent model of FASD, high doses of ethanol (blood ethanol concentration 80 mM) induces neuronal cell death in the cerebellum. However, information on potential agent(s) that may protect the cerebellum against the toxic effects of ethanol is lacking. Growing evidence suggests that a polyphenolic compound, resveratrol, has antioxidant and neuroprotective properties. Here we studied whether resveratrol (3,5,4'-trihydroxy-trans stilbene), a phytoalexin found in red grapes and blueberries, protects the cerebellar granule neurons against ethanol-induced cell death. In the present study, we showed that administration of resveratrol (100 mg/kg) to postnatal day 7 rat pups prevents ethanol-induced apoptosis by scavenging reactive oxygen species in the external granule layer of the cerebellum and increases the survival of cerebellar granule cells. It restores ethanol-induced changes in the level of transcription factor nuclear factor-erythroid derived 2-like 2 (nfe2l2, also known as Nrf2) in the nucleus. This in turn retains the expression and activity of its downstream gene targets such as NADPH quinine oxidoreductase 1 and superoxide dismutase in cerebellum of ethanol-exposed pups. These studies indicate that resveratrol exhibits neuroprotective effects in cerebellum by acting at redox regulating proteins in a rodent model of FASD. PMID- 21697275 TI - EZH2 promotes malignant phenotypes and is a predictor of oral cancer development in patients with oral leukoplakia. AB - Oral leukoplakia (OL) is the most common premalignancy in the oral cavity. A small proportion of OLs progresses to oral squamous cell carcinoma (OSCC). To assess OSCC risk of OLs, we investigated the role of the transcriptional repressor enhancer of zeste homolog 2 (EZH2) in oral tumorigenesis and its clinical implication as an OSCC risk predictor. Immunohistochemistry was used to measure EZH2 expression in OLs from 76 patients, including 37 who later developed OSCC and 39 who did not. EZH2 expression was associated with clinicopathologic parameters and clinical outcomes. To determine the biological role of EZH2 in OL, EZH2 level was reduced using EZH2 siRNAs in Leuk-1 cells, its impact on cell cycle, anchorage-dependent/independent growth, and invasion was assessed. We observed strong EZH2 expression in 34 (45%), moderate expression in 26 (34%), and weak/no expression in 16 (21%) of the OLs. The higher EZH2 levels were strongly associated with dysplasia (P < 0.001) and OSCC development (P < 0.0001). Multivariate analysis indicated that EZH2 expression was the only independent factor for OSCC development (P < 0.0001). At 5 years after diagnosis, 80% of patients whose OLs expressed strong EZH2 developed OSCC whereas only 24% patients with moderate and none with weak/no EZH2 expression did so (P < 0.0001). In Leuk 1 cells, EZH2 downregulation resulted in G(1) arrest; decreased invasion capability, decreased anchorage-independent growth; downregulation of cyclin D1 and upregulation of p15(INK4B). Our data suggest that EZH2 plays an important role in OL malignant transformation and may be a biomarker in predicting OSCC development in patients with OLs. PMID- 21697276 TI - Metabolic syndrome and risks of colon and rectal cancer: the European prospective investigation into cancer and nutrition study. AB - Metabolic syndrome (MetS) is purportedly related to risk of developing colorectal cancer; however, the association of MetS, as defined according to recent international criteria, and colorectal cancer has not been yet evaluated. In particular, it remains unclear to what extent the MetS components individually account for such an association. We addressed these issues in a nested case control study that included 1,093 incident cases matched (1:1) to controls by using incidence density sampling. Conditional logistic regression was used to estimate relative risks (RR) and 95% CIs. MetS was defined according to the criteria of the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII), the International Diabetes Federation (IDF), and the 2009 harmonized definition. Among individual components, abdominal obesity (RR = 1.51; 95% CI: 1.16-1.96) was associated with colon cancer, whereas abnormal glucose metabolism was associated with both colon (RR = 2.05; 95% CI: 1.57-2.68) and rectal cancer (RR = 2.07; 95% CI: 1.45-2.96). MetS, as defined by each of the definitions, was similarly associated with colon cancer (e.g., RR = 1.91; 95% CI: 1.47-2.42 for MetS by NCEP/ATPIII), whereas MetS by NCEP/ATPIII, but not IDF or harmonized definition, was associated with rectal cancer (RR = 1.45; 95% CI: 1.02 2.06). Overall, these associations were stronger in women than in men. However, the association between MetS and colorectal cancer was accounted for by abdominal obesity and abnormal glucose metabolism such that MetS did not provide risk information beyond these components (likelihood ratio test P = 0.10 for MetS by NCEP/ATPIII). These data suggest that simple assessment of abnormal glucose metabolism and/or abdominal obesity to identify individuals at colorectal cancer risk may have higher clinical utility than applying more complex MetS definitions. PMID- 21697277 TI - ADP-ribosylarginine hydrolase regulates cell proliferation and tumorigenesis. AB - Protein ADP-ribosylation is a reversible posttranslational modification of uncertain significance in cancer. In this study, we evaluated the consequences for cancer susceptibility in the mouse of a genetic deletion of the enzyme responsible for removing mono-ADP-ribose moieties from arginines in cellular proteins. Specifically, we analyzed cancer susceptibility in animals lacking the ADP-ribosylarginine hydrolase (ARH1) that cleaves the ADP ribose-protein bond. ARH1(-/-) cells or ARH1(-/-) cells overexpressing an inactive mutant ARH1 protein (ARH1(-/-)+dm) had higher proliferation rates than either wild-type ARH1(+/+) cells or ARH1(-/-) cells engineered to express the wild-type ARH1 enzyme. More significantly, ARH1(-/-) and ARH1(+/-) mice spontaneously developed lymphomas, adenocarcinomas, and metastases more frequently than wild-type ARH1(+/+) mice. In ARH1(+/-) mice, we documented in all arising tumors mutation of the remaining wild-type allele (or loss of heterozygosity), illustrating the strict correlation that existed between tumor formation and absence of ARH1 gene function. Our findings show that proper control of protein ADP-ribosylation levels affected by ARH1 is essential for cancer suppression. PMID- 21697278 TI - A novel tumor antigen derived from enhanced degradation of bax protein in human cancers. AB - Cancer cells frequently exhibit defects in apoptosis, which contribute to increased survival and chemotherapeutic resistance. For example, genetic mutations or abnormal proteasomal degradation can reduce expression of Bax which limits apoptosis. In cancers where abnormal proteasomal degradation of Bax occurs, we hypothesized that Bax peptides that bind to human leukocyte antigen (HLA) class I molecules would be generated for presentation to CD8(+) T cells. To test this hypothesis, we generated T cells against pooled Bax peptides, using the blood of healthy human donors. Although T-cell responses were of low frequency (0.15%), a CD8(+) T-cell clone (KSIVB17) was isolated that optimally recognized Bax(136-144) peptide (IMGWTLDFL) presented by HLA-A*0201. KSIVB17 was able to recognize and kill a variety of HLA-matched cancer cells including primary tumor cells from chronic lymphocytic leukemia (CLL). No reactivity was seen against HLA matched, nontransformed cells such as PHA blasts and skin fibroblasts. Furthermore, KSIVB17 reactivity corresponded with the proteasomal degradation patterns of Bax protein observed in cancer cells. Taken together, our findings suggest a new concept for tumor antigens based on regulatory proteins that are ubiquitously expressed in normal cells, but that have abnormally enhanced degradation in cancer cells. Bax degradation products offer candidate immune antigens in cancers such as CLL in which increased Bax degradation correlates with poor clinical prognosis. PMID- 21697279 TI - Antibody-dependent cell cytotoxicity synapses form in mice during tumor-specific antibody immunotherapy. AB - Antibody-dependent cell cytotoxicity (ADCC) plays a critical role in monoclonal antibody (mAb)-mediated cancer therapy. ADCC, however, has not been directly shown in vivo but inferred from the requirement for IgG Fc receptors (FcgammaR) in tumor rejection in mice. Here, we investigated the mechanism of action of a Tn antigen-specific chimeric mAb (Chi-Tn), which binds selectively to a wide variety of carcinomas, but not to normal tissues, in both humans and mice. Chi-Tn mAb showed no direct toxicity against carcinomas cell lines in vitro but induced the rejection of a murine breast tumor in 80% to 100% of immunocompetent mice, when associated with cyclophosphamide. Tumor rejection was abolished in Fc receptors associated gamma chain (FcR-gamma)-deficient mice, suggesting a role for ADCC. Indeed, tumor cells formed stable conjugates in vivo with FcR-gamma chain expressing macrophages and neutrophils in Chi-Tn mAb-treated but not in control mAb-treated mice. The contact zone between tumor cells and ADCC effectors accumulated actin, FcgammaR and phospho-tyrosines. The in vivo formed ADCC synapses were organized in multifocal supra-molecular activation clusters. These results show that in vivo ADCC mediated by macrophages and neutrophils during tumor rejection by Chi-Tn mAb involves a novel type of multifocal immune synapse between effectors of innate immunity and tumor cells. PMID- 21697280 TI - Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer. AB - In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patients. In the tumor and malignant ascites, CD4(+)CD123(+)BDCA2(+) pDC were the most abundant dendritic cell subset; however, they were profoundly depleted in peripheral blood. The presence of pDC in primary ovarian cancer, but not ascites, was an independent prognostic factor associated with early relapse. Following chemotherapy, we observed a partial restoration of blood pDC levels in patients in complete remission. These findings show preferential recruitment of pDC into tumors where they express a partially mature phenotype that may reflect an in situ activation. Importantly, compared with pDC found in ascites or blood, tumor associated pDC (TApDC) produced less IFN-alpha, TNF-alpha, IL-6, macrophage inflammatory protein-1beta, and RANTES in response to toll-like receptor stimulation, and alterations in pDC functions were mainly mediated through tumor derived TNF-alpha and TGF-beta. Unlike ascites-derived pDC, TApDC induced IL-10 production from allogeneic naive CD4(+) T lymphocytes, suggesting the existence of a paracrine immunosuppressive loop. Taken together, our findings indicate that both local and systemic dysfunction of pDC play a critical role in the progression of ovarian cancer via induction of immune tolerance. PMID- 21697281 TI - Systemic cancer therapy with a small molecule agonist of toll-like receptor 7 can be improved by circumventing TLR tolerance. AB - Topical application of small molecule Toll-like receptor 7 (TLR7) agonists is highly effective for the treatment of skin tumors, whereas their systemic application has been largely unsuccessful for cancer therapy. One reason may be that repeated systemic application of TLR ligands can induce a state of immune unresponsiveness, termed TLR tolerance. We show here that a single injection of the TLR7 agonist R848 in mice induces a short period of increased response to TLR stimulation followed by a state of hyporesponsiveness lasting several days. This state is characterized by inhibited secretion of the key cytokines interleukin (IL)-12p70 and IL-6 as well as by a block in IFN-alpha production. We show for the first time that at the cellular level, TLR7 tolerance occurs in both plasmacytoid and myeloid dendritic cells, two cell populations that play a critical role in the initiation and amplification of antitumor immune responses. We further show that TLR7 tolerance in plasmacytoid dendritic cells is accompanied by downregulation of the adaptor protein IL-1 receptor-associated kinase 1. On the basis of these findings, we have designed a novel strategy for the treatment of tumors by using cycles of repeated R848 injections separated by treatment-free intervals. We show in CT26 tumor-bearing mice that this protocol circumvents TLR7 tolerance and improves the efficacy of cancer immunotherapy. PMID- 21697282 TI - Api6/AIM/Spalpha/CD5L overexpression in alveolar type II epithelial cells induces spontaneous lung adenocarcinoma. AB - Chronic inflammation is an important contributor to the development of lung cancers, one of the most common malignancies worldwide, but the underlying molecular mechanisms of inflammation that specifically cue cancer risk remain poorly understood. Apoptosis inhibitor 6 (Api6, also known as AIM, Sp-alpha, and CD5L) is a downstream target gene of neutral lipids and peroxisome proliferator activated receptor gamma in lung alveolar type II (AT II) epithelial cells. An association among increased expression of Api6 in certain settings of pathogenic lung inflammation in mice prompted us to hypothesize a possible role in cancer. Here, we report that Api6 promotes malignant transformation by limiting lung epithelial cell apoptosis and promoting immune escape. The specific function of Api6 in AT II cells was determined by using a doxycycline-inducible Api6 mouse model. Api6 overexpression inhibited apoptosis and activated oncogenic signaling in AT II lung epithelial cells, inducing emphysema and adenocarcinoma. In addition, Api6 overexpression in AT II cells increased the concentrations of proinflammatory cytokines/chemokines in bronchoalveolar lavage fluid and serum, promoting expansion of myeloid-derived suppressor cells (MDSC) in lung and blood but not in bone marrow or spleen. Lung MDSCs suppressed T-cell proliferation and activity in vitro and reduced levels of T cells in vivo following doxycycline treatment to activate Api6. Together, our findings establish that Api6 promotes lung tumorigenesis by blocking a mechanism of epithelial apoptosis that would normally support immunosurveillance. PMID- 21697283 TI - Indirubins decrease glioma invasion by blocking migratory phenotypes in both the tumor and stromal endothelial cell compartments. AB - Invasion and proliferation in neoplasia require the cooperation of tumor cell and endothelial compartments. Glycogen synthase kinase-3 (GSK-3) is increasingly recognized as a major contributor to signaling pathways that modulate invasion and proliferation. Here we show that GSK-3 inhibitors of the indirubin family reduce invasion of glioma cells and glioma-initiating cell-enriched neurospheres both in vitro and in vivo, and we show that beta-catenin signaling plays an important role in mediating these effects. Indirubins improved survival in glioma bearing mice in which a substantial decrease in blood vessel density was seen in treated animals. In addition, indirubins blocked migration of endothelial cells, suggesting that anti-invasive glioma therapy with GSK-3 inhibitors in vivo not only inhibits invasion of tumor cells, but blocks migration of endothelial cells, which is also required for tumor angiogenesis. Overall, our findings suggest that indirubin inhibition of GSK-3 offers a novel treatment paradigm to target 2 of the most important interacting cellular compartments in heterotypic models of cancer. PMID- 21697284 TI - A drug resistance screen using a selective MET inhibitor reveals a spectrum of mutations that partially overlap with activating mutations found in cancer patients. AB - The emergence of drug resistance is a primary concern in any cancer treatment, including with targeted kinase inhibitors as exemplified by the appearance of Bcr Abl point mutations in chronic myeloid leukemia (CML) patients treated with imatinib. In vitro approaches to identify resistance mutations in Bcr-Abl have yielded mutation spectra that faithfully recapitulated clinical observations. To predict resistance mutations in the receptor tyrosine kinase MET that could emerge during inhibitor treatment in patients, we conducted a resistance screen in BaF3 TPR-MET cells using the novel selective MET inhibitor NVP-BVU972. The observed spectrum of mutations in resistant cells was dominated by substitutions of tyrosine 1230 but also included other missense mutations and partially overlapped with activating MET mutations that were previously described in cancer patients. Cocrystallization of the MET kinase domain in complex with NVP-BVU972 revealed a key role for Y1230 in binding of NVP-BVU972, as previously reported for multiple other selective MET inhibitors. A second resistance screen in the same format with the MET inhibitor AMG 458 yielded a distinct spectrum of mutations rich in F1200 alterations, which is consistent with a different predicted binding mode. Our findings suggest that amino acid substitutions in the MET kinase domain of cancer patients need to be carefully monitored before and during treatment with MET inhibitors, as resistance may preexist or emerge. Compounds binding in the same manner as NVP-BVU972 might be particularly susceptible to the development of resistance through mutations in Y1230, a condition that may be addressed by MET inhibitors with alternative binding modes. PMID- 21697286 TI - Automated multi-level pathology identification techniques for abnormal retinal images using artificial neural networks. AB - AIM: To automatically classify abnormal retinal images from four different categories using artificial neural networks with a high degree of accuracy in minimal time to assist the ophthalmologist in subsequent treatment planning. METHODS: We used 420 abnormal retinal images from four different categories (non proliferative diabetic retinopathy, central retinal vein occlusion, central serous retinopathy and central neo-vascularisation membrane). Green channel extraction, histogram equalisation and median filtering were used as image pre processing techniques, followed by texture-based feature extraction. The application of Kohonen neural networks for pathology identification was also explored. RESULTS: The approach described yielded an average classification accuracy of 97.7% with +/-0.8% deviation for individual categories. The average sensitivity and the specificity values are 96% and 98%, respectively. The time taken by the Kohonen neural network to achieve these accurate results was 300+/ 40 s for the 420 images. CONCLUSION: This study suggests that the approach described can act as a diagnostic tool for retinal disease identification. Simultaneous multi-level classification of abnormal images is possible with high accuracy using artificial neural networks. The results also suggest that the approach is time-efficient, which is essential for ophthalmologic applications. PMID- 21697287 TI - Idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis is a progressive lung disease that carries a poor prognosis and for which there are no effective therapies. Although the excessive deposition of extracellular matrix, combined with evidence of recurrent injury to the alveolar epithelium, are well-described there is a pressing need to understand these processes better at a molecular level and thus to identify potential therapeutic targets in this intractable disease. This review considers some recent advances published in Thorax and elsewhere that have improved our understanding of the pathophysiology of idiopathic pulmonary fibrosis, using data both from human cells and tissue and from animal models of pulmonary fibrosis. The studies particularly address the fate of the alveolar epithelial cell and mechanisms of fibrogenesis, and identify mechanistic pathways shared with co existing conditions such as lung cancer and pulmonary hypertension. The concepts of physiological biomarkers of disease progression and prognosis are also discussed. PMID- 21697285 TI - IGFBP-3 is a metastasis suppression gene in prostate cancer. AB - The insulin-like growth factor binding protein IGFBP-3 is a proapoptotic and antiangiogenic protein in prostate cancer (CaP). Epidemiologic studies suggest that low IGFBP-3 is associated with greater risk of aggressive, metastatic prostate cancers, but in vivo functional data are lacking. Here we show that mice that are genetically deficient in IGFBP-3 exhibit weaker growth of primary prostate tumors but higher incidence of metastatic disease. Prostates in IGFBP-3 knockout mice (IGFBP-3KO mice) failed to undergo apoptosis after castration. Spontaneous prostate tumors did not develop in IGFBP-3KO mice, but splenic lymphomas occurred in 23% of female IGFBP-3KO mice by 80 weeks of age. To assess the effects of IGFBP-3 deficiency on prostate cancer development, we crossed IGFBP-3KO mice with a c-Myc-driven model of CaP that develops slow-growing, nonmetastatic tumors. By 24 weeks of age, well-differentiated prostate cancers were observed in all mice regardless of IGFBP-3 status. However, by 80 weeks of age IGFBP-3KO mice tended to exhibit larger prostate tumors than control mice. More strikingly, lung metastases were observed at this time in 55% of the IGFBP 3KO mice but none in the control animals. Cell lines established from IGFBP 3KO:Myc tumors displayed more aggressive phenotypes in proliferation, invasion, and colony formation assays, relative to control Myc tumor cell lines. In addition, Myc:IGFBP-3KO cells exhibited evidence of epithelial-mesenchymal transition. Our findings established a function for IGFBP-3 in suppressing metastasis in prostate cancer, and they also offered the first reported transgenic model of spontaneous metastatic prostate cancer for studies of this advanced stage of disease. PMID- 21697288 TI - Immunochemical properties and pathological relevance of anti-beta2-glycoprotein I antibodies of different avidity. AB - Despite available treatment, there is still significant morbidity and mortality present among patients with the autoimmune thrombophilic condition termed 'antiphospholipid syndrome' (Espinosa, G. and Cervera, R. 2009. Morbidity and mortality in the antiphospholipid syndrome. Curr. Opin. Pulm. Med. 15:413.). High avidity (HAv) anti-beta(2)-glycoprotein I (anti-beta(2)GPI) antibodies, shown to correlate with thrombotic events in patients, could represent the much needed improved prognostic marker. By studying their effect on crystalline annexin A5 shield on phospholipid surfaces (one of proposed pathogenic mechanisms), with the use of atomic force microscopy, the pathogenic potential of HAv anti-beta(2)GPI antibodies was confirmed. Furthermore, by using surface plasmon resonance and enzyme-linked immunosorbent assays, unique binding characteristics of HAv antibodies in comparison with low avidity antibodies were established. HAv anti beta(2)GPI were confirmed to (i) recognize beta(2)-glycoprotein I in a solution, (ii) interact predominantly monovalently (much lower dependency on the antigen density) and (iii) form more stable complexes with the antigen. Since enzyme linked immunosorbent assays currently used in routine diagnostics detect anti beta(2)GPI antibodies of unknown avidity, our observations are potentially useful for the development of improved diagnostic tests capable of detecting clinically relevant antibodies. PMID- 21697290 TI - Current practice patterns among pathologists in the assessment of venous invasion in colorectal cancer. AB - AIMS: Venous invasion (VI) is a known independent prognostic indicator of recurrence and survival in colorectal cancer. The guidelines of the Royal College of Pathologists (RCPath) state that, in a series of resections, extramural VI should be detected in at least 25% of specimens. However, there is widespread variability in the reported incidence, and this may affect patient access to adjuvant therapy. This study aims to clarify the current practice patterns of pathologists regarding the assessment of VI and to identify factors associated with an increased self-reported VI detection rate. METHODS: A population-based survey was mailed to 361 pathologists in the province of Ontario, Canada. RESULTS: The overall response rate was 64.9%. Most pathologists were practicing in community-based centres (66.2%) and approximately half had been in practice for over 15 years (53.5%). A subspecialist interest in gastrointestinal (GI) pathology was declared by 27.3% of pathologists. The majority of pathologists (70.2%) reported that they detected VI in less than 10% of resection specimens, with only 9.1% reporting VI detection rates above 20%. Standardised reporting criteria were applied by 62.1%. Special stains were employed by 57.6% if VI was suspected on H&E-stained sections. Practice in a university-affiliated centre, a subspecialist interest in GI pathology and the acceptance of the 'orphan arteriole' sign were all independently associated with a self-reported VI detection rate above 10% on multivariate analysis. CONCLUSIONS: Self-reported VI detection rates are low among most pathologists. Even among specialist GI pathologists practicing in university-affiliated centres, few reported a detection rate close to that recommended by the RCPath. Strategies to increase the detection of VI may be required. PMID- 21697289 TI - Converging pathways lead to overproduction of IL-17 in the absence of vitamin D signaling. AB - Multiple pathways converge to result in the overexpression of T(h)17 cells in the absence of either vitamin D or the vitamin D receptor (VDR). CD4(+) T cells from VDR knockout (KO) mice have a more activated phenotype than their wild-type (WT) counterparts and readily develop into T(h)17 cells under a variety of in vitro conditions. Vitamin D-deficient CD4(+) T cells also overproduced IL-17 in vitro and 1,25 dihydroxyvitamin D(3) inhibited the development of T(h)17 cells in CD4(+) T-cell cultures. Conversely, the induction of inducible (i) Tregs was lower in VDR KO CD4(+) T cells than WT and the VDR KO iTregs were refractory to IL-6 inhibition. Host-specific effects of the VDR were evident on in vivo development of naive T cells. Development of naive WT CD4(+) T cells in the VDR KO host resulted in the overexpression of IL-17 and more severe experimental inflammatory bowel disease (IBD). The increased expression of T(h)17 cells in the VDR KO mice was associated with a reduction in tolerogenic CD103(+) dendritic cells. The data collectively demonstrate that T(h)17 and iTreg cells are direct and indirect targets of vitamin D. The increased propensity for development of T(h)17 cells in the VDR KO host results in more severe IBD. PMID- 21697291 TI - ICU nurses' acceptance of electronic health records. AB - OBJECTIVE: To assess intensive care unit (ICU) nurses' acceptance of electronic health records (EHR) technology and examine the relationship between EHR design, implementation factors, and nurse acceptance. DESIGN: The authors analyzed data from two cross-sectional survey questionnaires distributed to nurses working in four ICUs at a northeastern US regional medical center, 3 months and 12 months after EHR implementation. MEASUREMENTS: Survey items were drawn from established instruments used to measure EHR acceptance and usability, and the usefulness of three EHR functionalities, specifically computerized provider order entry (CPOE), the electronic medication administration record (eMAR), and a nursing documentation flowsheet. RESULTS: On average, ICU nurses were more accepting of the EHR at 12 months as compared to 3 months. They also perceived the EHR as being more usable and both CPOE and eMAR as being more useful. Multivariate hierarchical modeling indicated that EHR usability and CPOE usefulness predicted EHR acceptance at both 3 and 12 months. At 3 months postimplementation, eMAR usefulness predicted EHR acceptance, but its effect disappeared at 12 months. Nursing flowsheet usefulness predicted EHR acceptance but only at 12 months. CONCLUSION: As the push toward implementation of EHR technology continues, more hospitals will face issues related to acceptance of EHR technology by staff caring for critically ill patients. This research suggests that factors related to technology design have strong effects on acceptance, even 1 year following the EHR implementation. PMID- 21697292 TI - Automated concept-level information extraction to reduce the need for custom software and rules development. AB - OBJECTIVE: Despite at least 40 years of promising empirical performance, very few clinical natural language processing (NLP) or information extraction systems currently contribute to medical science or care. The authors address this gap by reducing the need for custom software and rules development with a graphical user interface-driven, highly generalizable approach to concept-level retrieval. MATERIALS AND METHODS: A 'learn by example' approach combines features derived from open-source NLP pipelines with open-source machine learning classifiers to automatically and iteratively evaluate top-performing configurations. The Fourth i2b2/VA Shared Task Challenge's concept extraction task provided the data sets and metrics used to evaluate performance. RESULTS: Top F-measure scores for each of the tasks were medical problems (0.83), treatments (0.82), and tests (0.83). Recall lagged precision in all experiments. Precision was near or above 0.90 in all tasks. Discussion With no customization for the tasks and less than 5 min of end-user time to configure and launch each experiment, the average F-measure was 0.83, one point behind the mean F-measure of the 22 entrants in the competition. Strong precision scores indicate the potential of applying the approach for more specific clinical information extraction tasks. There was not one best configuration, supporting an iterative approach to model creation. CONCLUSION: Acceptable levels of performance can be achieved using fully automated and generalizable approaches to concept-level information extraction. The described implementation and related documentation is available for download. PMID- 21697293 TI - How to improve the delivery of medication alerts within computerized physician order entry systems: an international Delphi study. AB - OBJECTIVES: To determine what information can be helpful in prioritizing and presenting medication alerts according to the context of the clinical situation. To assess the usefulness of different ways of delivering medication alerts to the user. DESIGN: An international Delphi study with two quantitative rounds. 69 researchers with expertise in computerized physician order entry (CPOE) systems were asked to estimate the usefulness of 20 possible context factors, and to assess the potential impact of six innovative ways of delivering alert information on adverse drug event (ADE) rates. RESULTS: Participants identified the following top five context information items (in descending order of usefulness): (1) severity of the effect of the ADE the alert refers to; (2) clinical status of the patient; (3) probability of occurrence of the ADE the alert refers to; (4) risk factors of the patient; and (5) strength of evidence on which the alert is built. The ways of delivering alert information with the highest estimated ADE reduction potential are active alerting, proactive prescription simulation and a patient medication module that gives patient oriented alert information. LIMITATIONS: Most participants had a research oriented focus; therefore the results may not reflect the opinions of CPOE users or CPOE implementers. CONCLUSION: The study results may provide CPOE system developers and healthcare institutions with information on how to design more effective alert mechanisms. PMID- 21697294 TI - Is the commercialisation of human tissue and body material forbidden in the countries of the European Union? AB - The human body and its parts are widely perceived as matters beyond commercial usage. This belief is codified in several national and European documents. This so-called 'no-property rule' is held to be the default position across the countries of the European Union. However, a closer look at the most pertinent national and European documents, and also current practices in the field, reveals a gradual model of commercialisation of human tissue. In particular, we will argue that the ban on commercialisation of body material is not as strict as it may appear at first sight, leaving room for the commercial practice of tissue procurement and transfer. We argue for more transparent information for patients and tissue donors, an intensified ethical debate on commercialisation practices, and a critical review of current normative principles. PMID- 21697295 TI - Innovative surgery: the ethical challenges. AB - Innovative surgery raises four kinds of ethical challenges: potential harms to patients; compromised informed consent; unfair allocation of healthcare resources; and conflicts of interest. Lack of adequate data on innovations and lack of regulatory oversight contribute to these ethical challenges. In this paper these issues and the extent to which problems may be resolved by better evidence-gathering and more comprehensive regulation are explored. It is suggested that some ethical issues will be more resistant to resolution than others, owing to special features of both surgery and innovation. PMID- 21697296 TI - Predictors of hospitalised patients' preferences for physician-directed medical decision-making. AB - BACKGROUND: Although medical ethicists and educators emphasise patient-centred decision-making, previous studies suggest that patients often prefer their doctors to make the clinical decisions. OBJECTIVE: To examine the associations between a preference for physician-directed decision-making and patient health status and sociodemographic characteristics. METHODS: Sociodemographic and clinical information from all consenting general internal medicine patients at the University of Chicago Medical Center were examined. The primary objectives were to (1) assess the extent to which patients prefer an active role in clinical decision-making, and (2) determine whether religious service attendance, the importance of religion, self-rated spirituality, Charlson Comorbidity Index, self reported health, Vulnerable Elder Score and several demographic characteristics were associated with these preferences. RESULTS: Data were collected from 8308 of 11,620 possible participants. Ninety-seven per cent of respondents wanted doctors to offer them choices and to consider their opinions. However, two out of three (67%) preferred to leave medical decisions to the doctor. In multiple regression analyses, preferring to leave decisions to the doctor was associated with older age (per year, OR=1.019, 95% CI 1.003 to 1.036) and frequently attending religious services (OR=1.5, 95% CI 1.1 to 2.1, compared with never), and it was inversely associated with female sex (OR=0.6, 95% CI 0.5 to 0.8), university education (OR=0.6, 95% CI 0.4 to 0.9, compared with no high school diploma) and poor health (OR=0.6, 95% CI 0.3 to 0.9). CONCLUSIONS: Almost all patients want doctors to offer them choices and to consider their opinions, but most prefer to leave medical decisions to the doctor. Patients who are male, less educated, more religious and healthier are more likely to want to leave decisions to their doctors, but effects are small. PMID- 21697297 TI - Prenatal zinc supplementation of zinc-adequate rats adversely affects immunity in offspring. AB - We previously showed that zinc (Zn) supplementation of Zn-adequate dams induced immunosuppressive effects that persist in the offspring after weaning. We investigated whether the immunosuppressive effects were due to in utero exposure and/or mediated via milk using a cross-fostering design. Pregnant rats with adequate Zn nutriture were supplemented with either Zn (1.5 mg Zn in 10% sucrose) or placebo (10% sucrose) during pregnancy (3 times/wk). At postnatal d 3, 4 pups of Zn-supplemented dams (Zn-P) were exchanged with 4 of placebo-supplemented dams (P-Zn). The remaining pups continued with their biological mothers (Zn-Zn and P P). Pups were orally immunized with dinitrophenol ovalbumin-BSA and/or cholera toxin B subunit (CTB), and serum Zn concentrations and cellular and humoral responses were assessed. Pups of Zn-supplemented dams had higher serum Zn when fostered either by placebo- or Zn-supplemented dams compared to pups of placebo supplemented dams (P < 0.01). Postnatal Zn exposure reduced the number of Peyer's patches in both the Zn-Zn and P-Zn groups (P < 0.01). Prenatal Zn exposure suppressed CTB- (P = 0.05) and BSA-specific proliferation response of Peyer's Patch lymphocytes (P = 0.07). Prenatal Zn exposure effects on the splenocyte cytokine response were differently influenced by fostering mothers' Zn status. Antigen presenting cell (APC) activity of splenocytes was lower in the Zn-Zn group than in the P-P group (P < 0.08). In conclusion, prenatal Zn exposure increases serum Zn levels in pups and suppresses antigen-specific proliferation and antibody responses and APC function, whereas postnatal exposure may suppress the mucosal immune reservoir. PMID- 21697298 TI - Diet, environmental factors, and lifestyle underlie the high prevalence of vitamin D deficiency in healthy adults in Scotland, and supplementation reduces the proportion that are severely deficient. AB - Vitamin D deficiency has recently been implicated as a possible risk factor in the etiology of numerous diseases, including nonskeletal conditions. In humans, skin synthesis following exposure to UVB is a potent source of vitamin D, but in regions with low UVB, individuals are at risk of vitamin D deficiency. Our objectives were to describe the prevalence of vitamin D deficiency and to investigate determinants of plasma 25-hydroxyvitamin D (25-OHD) concentrations in a high northern latitude country. Detailed dietary, lifestyle, and demographic data were collected for 2235 healthy adults (21-82 y) from Scotland. Plasma 25 OHD was measured by liquid chromatography-tandem MS. Among study participants, 34.5% were severely deficient (25-OHD <25 nmol/L) and 28.9% were at high risk of deficiency (25-40 nmol/L). Only 36.6% of participants were at low risk of vitamin D deficiency or had adequate levels (>40 nmol/L). Among participants who were taking supplements, 21.3% had a May-standardized 25-OHD concentration >50 nmol/L, 54.2% had 25-50 nmol/L, and 24.5% had <25 nmol/L, whereas this was 15.6, 43.3, and 41%, respectively, among those who did not take supplements (P < 0.0001). The most important sources of vitamin D were supplements and fish consumption. Vitamin D deficiency in Scotland is highly prevalent due to a combination of insufficient exposure to UVB and insufficient dietary intake. Higher dietary vitamin D intake modestly improved the plasma 25-OHD concentration (P = 0.02) and reduced the proportion of severely deficient individuals (P < 0.0001). In regions with low UVB exposure, dietary and supplement intake may be much more important than previously thought and consideration should be given to increasing the current recommended dietary allowance of 0-10 MUg/d for adults in Scotland. PMID- 21697299 TI - Folate intake, MTHFR genotype, and sex modulate choline metabolism in mice. AB - Choline and folate are interrelated in 1-carbon metabolism, mostly because of their shared function as methyl donors for homocysteine remethylation. Folate deficiency and mutations of methylenetetrahydrofolate reductase (MTHFR) reduce the availability of a major methyl donor, 5-methyltetrahydrofolate, which in turn may lead to compensatory changes in choline metabolism. This study investigated the hypothesis that reductions in methyl group supply, either due to dietary folate deficiency or Mthfr gene deletion, would modify tissue choline metabolism in a sex-specific manner. Mthfr wild type (+/+) or heterozygous (+/-) knockout mice were randomized to a folate-deficient or control diet for 8 wk during which time deuterium-labeled choline (d9-choline) was consumed in the drinking water (~10 MUmol/d). Mthfr heterozygosity did not alter brain choline metabolite concentrations, but it did enhance their labeling in males (P < 0.05) and tended to do so in females (P < 0.10), a finding consistent with greater turnover of dietary choline in brains of +/- mice. Dietary folate deficiency in females yielded 52% higher (P = 0.027) hepatic glycerophosphocholine, which suggests that phosphatidylcholine (PtdCho) degradation was enhanced. Labeling of the hepatic PtdCho in d3 form was also reduced (P < 0.001) in females, which implies that fewer of the dietary choline-derived methyl groups were used for de novo PtdCho biosynthesis under conditions of folate insufficiency. Males responded to folate restriction with a doubling (P < 0.001) of hepatic choline dehydrogenase transcripts, a finding consistent with enhanced conversion of choline to the methyl donor, betaine. Collectively, these data show that several adaptations in choline metabolism transpire as a result of mild perturbations in folate metabolism, presumably to preserve methyl group homeostasis. PMID- 21697300 TI - A high antioxidant spice blend attenuates postprandial insulin and triglyceride responses and increases some plasma measures of antioxidant activity in healthy, overweight men. AB - There is much interest in the potential of dietary antioxidants to attenuate in vivo oxidative stress, but little characterization of the time course of plasma effects exists. Culinary spices have demonstrated potent in vitro antioxidant properties. The objective of this study was to examine whether adding 14 g of a high antioxidant spice blend to a 5060-kJ (1200 kcal) meal exerted significant postprandial effects on markers of plasma antioxidant status and metabolism. Healthy overweight men (n = 6) consumed a control and spiced meal in a randomized crossover design with 1 wk between testing sessions. Blood was sampled prior to the meal and at 30-min intervals for 3.5 h (total of 8 samples). Mixed linear models demonstrated a treatment * time interaction (P < 0.05) for insulin and TG, corresponding with 21 and 31% reductions in postprandial levels with the spiced meal, respectively. Adding spices to the meal significantly increased the ferric reducing antioxidant power, such that postprandial increases following the spiced meal were 2-fold greater than after the control meal (P = 0.009). The hydrophilic oxygen radical absorbance capacity (ORAC) of plasma also was increased by spices (P = 0.02). There were no treatment differences in glucose, total thiols, lipophilic ORAC, or total ORAC. The incorporation of spices into the diet may help normalize postprandial insulin and TG and enhance antioxidant defenses. PMID- 21697301 TI - Low serum vitamin D is associated with high risk of diabetes in Korean adults. AB - Vitamin D may play a role in glucose metabolism. A low vitamin D level has been associated with increased risk of diabetes mellitus, but the association has not been confirmed in Asians. Our objective was to examine the association of serum 25-hydroxyvitamin D [25(OH)D] levels with insulin resistance and diabetes mellitus in Korean adults based on a large population-based survey. Cross sectional analyses were carried out on 5787 Korean adults (2453 men and 3334 women) who were 20 y or older and participated in the Fourth Korea NHANES conducted in 2008. Diabetes mellitus was defined as fasting plasma glucose >=7 mmol/L or current use of oral hypoglycemic agents or insulin. Insulin resistance was estimated by homeostatic model assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI). Compared to individuals with a sufficient serum 25(OH)D concentration >=75 nmol/L, the OR (95% CI) for diabetes mellitus were 1.73 (1.09-2.74), 1.30 (0.91-1.84), and 1.40 (0.99-1.98) for serum 25(OH)D concentrations <25, 25 to <50, and 50 to <75 nmol/L, respectively, after multiple adjustments (P-trend < 0.0001). Furthermore, the serum 25(OH)D level was inversely associated with HOMA-IR (beta = -0.061; P = 0.001) and positively associated with QUICKI (beta = 0.059; P = 0.001) in overweight or obese participants. In conclusion, a low serum vitamin D concentration is associated with a high risk of diabetes mellitus in Korean adults and the concentration is inversely associated with insulin resistance in those who are overweight or obese. PMID- 21697302 TI - A lutein-enriched diet prevents cholesterol accumulation and decreases oxidized LDL and inflammatory cytokines in the aorta of guinea pigs. AB - Lutein has been shown to be protective against age-related macular degeneration; however, the antiinflammatory and antioxidant effects of this carotenoid in aortas are less known. Guinea pigs were fed a hypercholesterolemic diet (0.25 g cholesterol/100 g) and randomly allocated to a control group (n = 9) or a lutein group (n = 10) (0.01 g/100 g lutein) [corrected] and fed the experimental diets for 12 wk. Plasma LDL cholesterol and TG did not differ between groups; however, the lutein group had lower concentrations of medium size LDL (P < 0.05). As expected, guinea pigs from the lutein group had higher concentrations of plasma and liver lutein than those from the control group (P < 0.0001). Aortic cholesterol and malondialdehyde concentrations were lower in the lutein group (9.6 +/- 2.8 mmol/g and 1.69 +/- 1.35 nmol/mg protein) compared to the control group (15.5 +/- 2.3 mmol/g and 2.98 +/- 1.45 nmol/mg protein) (P < 0.05). Hematoxilin and eosin staining indicated that aortas from the control group presented focal intimal thickening, whereas either less thickness or no visible thickness was present in aortas from the lutein group. Oxidized LDL (oxLDL) was lower both in plasma and aorta in the lutein group compared to the control group (P < 0.001). Aortic cytokines were also lower in the lutein group (P < 0.05). Plasma lutein and oxLDL (r = -0.79; P < 0.0001) and plasma lutein and aortic oxLDL (r = -0.64; P < 0.0001) were negatively correlated. These data suggest that lutein exerts potent antioxidant and antiinflammatory effects in aortic tissue that may protect against development of atherosclerosis in guinea pigs. PMID- 21697303 TI - Americans with diet-related chronic diseases report higher diet quality than those without these diseases. AB - Large health disparities exist in the U.S. across ethnic and socioeconomic status groups. Using nationally representative data, we tested whether American patients with diet-related chronic diseases had higher diet quality than nonpatients. We also tested whether nutrition knowledge and beliefs (NKB) and food label (FL) use were associated with the observed differences. The 1994-1996 Continuing Survey of Food Intake by Individuals, and the Diet and Health Knowledge Survey were examined for 4356 U.S. adults. Dietary intakes were assessed using 2 nonconsecutive 24-h recalls and diet quality was assessed by using the USDA 2005 Healthy Eating Index (HEI). Patients' mean HEI was higher than that of nonpatients (mean +/- SE: 53.6 +/- 0.5 vs. 51.8 +/- 0.4; P < 0.001). Among patients, blacks were 92% more likely to report low diet quality (HEI < 20th percentile) than whites. The positive association between chronic diseases and HEI was observed only for patients with good NKB [OR = 1.80 (95% CI = 1.34, 2.43)]. The diabetes-HEI association was stronger among FL users [OR = 2.24 (95% CI = 1.08, 4.63)] than non-FL users [OR = 1.33 (95% CI = 0.65, 2.73)]. Hypertensive patients' and nonpatients' diet quality did not significantly differ; linear regression models showed no difference in their HEI (beta +/- SE: 0.6 +/- 0.6; P > 0.05) or sodium intake (-18.6 +/- 91.4 g/d; P > 0.05) between them. In conclusion, U.S. adults with diet-related chronic diseases reported somewhat higher diet quality than nonpatients, especially among those patients with good NKB and use of FL. Efforts are needed to promote healthy eating among Americans with diet-related chronic diseases; nutrition education and promotion of FL use may help. PMID- 21697305 TI - Getting to yes: the fate of neuroradiology manuscripts rejected by radiology over a 2-year period. PMID- 21697304 TI - Pilot study of FPPRGD2 for imaging alpha(v)beta(3) integrin--how integral are integrins? AB - Mittra et al (1) describe a new positron emission tomographic (PET) radiopharmaceutical, fluorine 18 ((18)F) 2-fl uoropropionyl labeled PEGylated dimeric RGD peptide (FPPRGD2), a marker of alpha(v)beta(3) integrin expression, which they tested in fi ve healthy volunteers. No adverse events were encountered, and the biodistribution suggested both a renal and a hepatobiliary excretory route. This early safety testing paves the way for future studies of patients with cancer who are undergoing antiangiogenic therapies. (18)F-FPPRGD2 represents one of several integrin imaging agents that are moving closer to clinical reality. PMID- 21697306 TI - Shoulder US: anatomy, technique, and scanning pitfalls. AB - The accuracy of shoulder ultrasonography (US) is largely dependent on the US examination technique. It is essential that the individual performing the US examination has an understanding of pertinent anatomy, such as bone surface anatomy and tendon orientation. It is also important to be familiar with imaging pitfalls related to US technique, such as anisotropy. In this article, shoulder US scanning technique, as well as related anatomy and scanning pitfalls, will be reviewed. The use of a protocol-driven shoulder US examination is important to ensure a comprehensive and efficient evaluation. An on-line video tutorial demonstrating a shoulder US also accompanies this article. PMID- 21697307 TI - Imaging of pulmonary viral pneumonia. AB - Imaging and clinical manifestations of viral pneumonia are protean and not reliably predictive of its origin. All patients with neutropenic fever and normal findings at chest radiography should undergo thin-section computed tomography to determine whether parenchyma abnormalities are present. Although the radiologic manifestations of viral pneumonia are nonspecific and difficult to differentiate from those of other infections, it is important to consider viral infection when confronted with a rapidly progressive pneumonia in patients with risk factors for infection. Although definitive diagnosis cannot be made on the basis of imaging features alone, the use of a combination of clinical and radiographic findings can substantially improve the accuracy of diagnosis in this disease. PMID- 21697309 TI - Case 171: facial nerve hemangioma. PMID- 21697310 TI - CT colonography after colorectal cancer resection: a one-stop assessment of metachronous mucosal lesions, local recurrence, and distant metastases. PMID- 21697311 TI - Diffusion-weighted MR imaging in placental insufficiency: erroneous units and inaccurate apparent diffusion coefficient measurements. PMID- 21697312 TI - MR imaging in pulmonary embolism during pregnancy. PMID- 21697313 TI - This radiologist is visible. PMID- 21697314 TI - Searching for the holy grail: the pretense and fallacy of measuring CT radiation exposure in an individual patient. PMID- 21697315 TI - Management of patients with palpitations: a position paper from the European Heart Rhythm Association. PMID- 21697317 TI - Clinical and microbiological characteristics of community-acquired Staphylococcus lugdunensis infections in Southern Taiwan. AB - Most Staphylococcus lugdunensis strains (49/59, 83%) were related to clinical infections, were susceptible to most antimicrobial agents with an overall oxacillin-resistant rate of 5% (3/58), and carried relatively great genetic diversity. Community-acquired infections (41/49, 84%) were dominant, often developed in patients with comorbidity, and had rather benign clinical courses without mortality. PMID- 21697316 TI - Aeromonas aquariorum is widely distributed in clinical and environmental specimens and can be misidentified as Aeromonas hydrophila. AB - Genotypic characterization of 215 Aeromonas strains (143 clinical, 52 environmental, and 20 reference strains) showed that Aeromonas aquariorum (60 strains, 30.4%) was the most frequently isolated species in clinical and water samples and could be misidentified as Aeromonas hydrophila by phenotypic methods. PMID- 21697318 TI - High-resolution genotyping of Chlamydia trachomatis by use of a novel multilocus typing DNA microarray. AB - Typing of Chlamydia trachomatis is important to understanding its epidemiology. Currently used methods such as DNA sequencing of the ompA gene and multilocus sequence typing (MLST) either offer limited epidemiological resolution or are laborious and expensive, or both. DNA microarray technology using the ArrayStrip format is an affordable alternative for genotyping. In this study, we developed a new multilocus typing (MLT) DNA microarray, based on the target regions of a high resolution MLST system as well as software for easy analysis. Validation of the array was done by typing 80 previously MLST-typed clinical specimens from unselected adolescents in school. The MLT array showed 100% specificity and provided 2.4-times-higher resolution than ompA sequencing, separating the commonly predominating ompA E/Bour genotype into 7 MLT array genotypes. The MLT array reproduced epidemiological findings revealed by the MLST system and showed sufficient sensitivity to work with clinical specimens. Compared to MLST analysis, the expenses needed for testing a sample with the MLT array are considerably lower. Moreover, testing can be completed within 1 working day rather than 3 or 4 days, with data analysis not requiring highly specialized personnel. The present MLT array represents a powerful alternative in C. trachomatis genotyping. PMID- 21697319 TI - Prosthetic joint infection caused by Mycobacterium alvei in an elderly patient. AB - We report the first case of prosthetic joint infection caused by Mycobacterium alvei, which was identified by PCR-restriction fragment length polymorphism and verified by analysis of nucleotide sequences of its amplified 16S ribosomal DNA. The pathogen was susceptible to linezolid, amikacin, ciprofloxacin, tigecycline, and trimethoprim-sulfamethoxazole. The clinical implications are discussed. PMID- 21697320 TI - Sequence analysis of the p1 adhesin gene of Mycoplasma pneumoniae in clinical isolates collected in Beijing in 2008 to 2009. AB - The p1 genes of 60 Mycoplasma pneumoniae clinical isolates were sequenced and compared to previously reported p1 gene sequences. An AGT trinucleotide variable number tandem repeat was identified that ranged in copy number from 5 to 14 among the isolates. In addition, a novel p1 gene variant named 2c was identified in 6 of the isolates. PMID- 21697321 TI - Collaborative evaluation of an erythromycin-clindamycin combination well for detection of inducible clindamycin resistance in beta-hemolytic streptococci by use of the CLSI broth microdilution method. AB - Constitutive or inducible clindamycin resistance can occur in beta-hemolytic streptococci due to the presence of an erm gene. The Clinical and Laboratory Standards Institute (CLSI) has recommended a disk approximation test (D-zone test) with erythromycin and clindamycin disks and a single-well broth test combining erythromycin and clindamycin for detection of inducible clindamycin resistance in staphylococci, but only a disk approximation test for the beta hemolytic streptococci. This collaborative study assessed two different erythromycin and clindamycin concentration combinations in single wells (1 MUg/ml + 0.25 MUg/ml [erythromycin plus clindamycin] and 1 MUg/ml + 0.5 MUg/ml) with three different brands of Mueller-Hinton broth supplemented with 3% lysed horse blood for testing of frozen panels prepared for this study. All labs performed the D-zone test as described by the CLSI. A total of 155 nonduplicate streptococcal isolates (50 group A, 48 group B, 28 group C, and 29 group G isolates) were tested; 99 isolates showed inducible resistance by the D-zone test. There were some differences noted based upon the test medium. The sensitivity of the erythromycin plus clindamycin combination of 1 MUg/ml + 0.25 MUg/ml was 91 to 100%, while the sensitivity of the combination of 1 MUg/ml + 0.5 MUg/ml was 95 to 100%. Specificity overall was 98%. The slightly higher sensitivity of the combination of 1 MUg/ml + 0.5 MUg/ml is recommended. This study has demonstrated that a single-well microdilution test incorporating erythromycin and clindamycin in combination is a sensitive and specific indicator of inducible clindamycin resistance and could be included in routine test panels. PMID- 21697322 TI - Evaluation of matrix-assisted laser desorption ionization-time of flight mass spectrometry for rapid identification of Beta-hemolytic streptococci. AB - This study was undertaken to evaluate matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) for the rapid identification of beta-hemolytic streptococci. We compared Bruker Biotyper 2.0 with Vitek2 coupled to the agglutination test. MALDI-TOF MS analysis of 386 beta-hemolytic streptococcal isolates yielded high-confidence identification to the species level for all 386 isolates. The Vitek2 gave high-confidence identification to the species level for 88% of Streptococcus agalactiae isolates (n = 269/306), 92% of Streptococcus pyogenes isolates (n = 48/52), and 39% of isolates of Streptococcus dysgalactiae serogroups C and G (n = 11/28). PMID- 21697323 TI - Comparative evaluation of three automated systems for DNA extraction in conjunction with three commercially available real-time PCR assays for quantitation of plasma Cytomegalovirus DNAemia in allogeneic stem cell transplant recipients. AB - Limited data are available on the performance of different automated extraction platforms and commercially available quantitative real-time PCR (QRT-PCR) methods for the quantitation of cytomegalovirus (CMV) DNA in plasma. We compared the performance characteristics of the Abbott mSample preparation system DNA kit on the m24 SP instrument (Abbott), the High Pure viral nucleic acid kit on the COBAS AmpliPrep system (Roche), and the EZ1 Virus 2.0 kit on the BioRobot EZ1 extraction platform (Qiagen) coupled with the Abbott CMV PCR kit, the LightCycler CMV Quant kit (Roche), and the Q-CMV complete kit (Nanogen), for both plasma specimens from allogeneic stem cell transplant (Allo-SCT) recipients (n = 42) and the OptiQuant CMV DNA panel (AcroMetrix). The EZ1 system displayed the highest extraction efficiency over a wide range of CMV plasma DNA loads, followed by the m24 and the AmpliPrep methods. The Nanogen PCR assay yielded higher mean CMV plasma DNA values than the Abbott and the Roche PCR assays, regardless of the platform used for DNA extraction. Overall, the effects of the extraction method and the QRT-PCR used on CMV plasma DNA load measurements were less pronounced for specimens with high CMV DNA content (>10,000 copies/ml). The performance characteristics of the extraction methods and QRT-PCR assays evaluated herein for clinical samples were extensible at cell-based standards from AcroMetrix. In conclusion, different automated systems are not equally efficient for CMV DNA extraction from plasma specimens, and the plasma CMV DNA loads measured by commercially available QRT-PCRs can differ significantly. The above findings should be taken into consideration for the establishment of cutoff values for the initiation or cessation of preemptive antiviral therapies and for the interpretation of data from clinical studies in the Allo-SCT setting. PMID- 21697324 TI - Rapid genoserotyping tool for classification of Salmonella serovars. AB - We have developed a Salmonella genoserotyping array (SGSA) which rapidly generates an antigenic formula consistent with the White-Kauffmann-Le Minor scheme, currently the gold standard for Salmonella serotyping. A set of 287 strains representative of 133 Salmonella serovars was assembled to validate the array and to test the array probes for accuracy, specificity, and reproducibility. Initially, 76 known serovars were utilized to validate the specificity and repeatability of the array probes and their expected probe patterns. The SGSA generated the correct serovar designations for 100% of the known subspecies I serovars tested in the validation panel and an antigenic formula consistent with that of the White-Kauffmann-Le Minor scheme for 97% of all known serovars tested. Once validated, the SGSA was assessed against a blind panel of 100 Salmonella enterica subsp. I samples serotyped using traditional methods. In summary, the SGSA correctly identified all of the blind samples as representing Salmonella and successfully identified 92% of the antigens found within the unknown samples. Antigen- and serovar-specific probes, in combination with a pepT PCR for confirmation of S. enterica subsp. Enteritidis determinations, generated an antigenic formula and/or a serovar designation consistent with the White-Kauffmann-Le Minor scheme for 87% of unknown samples tested with the SGSA. Future experiments are planned to test the specificity of the array probes with other Salmonella serovars to demonstrate the versatility and utility of this array as a public health tool in the identification of Salmonella. PMID- 21697325 TI - Multiplex real-time PCR assay for detection of methicillin-resistant Staphylococcus aureus and associated toxin genes. AB - We describe a real-time PCR assay for the detection of methicillin-resistant Staphylococcus aureus and genes encoding toxic shock syndrome toxin 1 and Panton Valentine leukocidin. Rapid screening and detection of toxins is a useful tool for surveillance studies and outbreak investigations involving large numbers of isolates. PMID- 21697326 TI - Multilaboratory evaluation of real-time PCR tests for hepatitis B virus DNA quantification. AB - The performance characteristics of four different assays for hepatitis B virus (HBV) quantification were assessed: the Abbott RealTime HBV IUO, the Roche Cobas AmpliPrep/Cobas TaqMan HBV test, the Roche Cobas TaqMan HBV test with HighPure system, and the Qiagen artus HBV TM ASR. Limit of detection (LOD), linear range, reproducibility, and agreement were determined using a serially diluted plasma sample from a single chronically infected subject. Each assay was tested by at least three laboratories. The LOD of the RealTime and two TaqMan assays was approximately 1.0 log(10) IU/ml; for artus HBV (which used the lowest volume of extracted DNA), it was approximately 1.5 log(10) IU/ml. The linear range spanned 1.0 to at least 7.0 log(10) IU/ml for all assays. Median values were consistently lowest for artus HBV and highest for Cobas AmpliPrep/Cobas TaqMan HBV. Assays incorporating automated nucleic acid extraction were the most reproducible; however, the overall variability was minor since the standard deviations for the means of all tested concentrations were <=0.32 log(10) IU/ml for all assays. False-positive results were observed with all assays; the highest rates occurred with tests using manual nucleic acid extraction. The performance characteristics of these assays suggest that they are useful for management and therapeutic monitoring of chronic HBV infection. PMID- 21697327 TI - Use of filter paper as a transport medium for laboratory diagnosis of cholera under field conditions. AB - Confirmation of a cholera epidemic is based on bacteriological identification of the agent and requires the sending of samples to a culture laboratory, often in countries with limited resources. Comparison of the use of filter paper with the use of Cary-Blair reference medium for stool transport showed that this simple transport medium is appropriate for the recovery of Vibrio cholerae. PMID- 21697328 TI - Impact of clinical symptoms on interpretation of diagnostic assays for Clostridium difficile infections. AB - Asymptomatic Clostridium difficile colonization is common in hospitalized patients. Existing C. difficile assay comparisons lack data on severity of diarrhea or patient outcomes, limiting the ability to interpret their results in regard to the diagnosis of C. difficile infection (CDI). The objective of this study was to measure how including patient presentation with the C. difficile assay result impacted assay performance to diagnose CDI. Stool specimens from 150 patients that met inclusion and exclusion criteria were selected. Nine methods to detect C. difficile in stool were evaluated. All patients were interviewed prospectively to assess diarrhea severity. We then assessed how different reference standards, with and without the inclusion of patient presentation, impact the sensitivity, specificity, and positive and negative predictive values of the assays to diagnose CDI. There were minimal changes in sensitivity; however, specificity was significantly lower for the assays Tox A/B II, C. diff Chek-60, BD GeneOhm Cdiff, Xpert C. difficile, and Illumigene C. difficile and for toxigenic culture (P was <0.01 for all except Tox A/B II from fresh stool, for which the P value was 0.016) when the reference standard was recovery of toxigenic C. difficile from stool plus the presence of clinically significant diarrhea compared to when the reference standard was having at least four assays positive while ignoring diarrhea severity. There were 15 patients whose assay result was reported as negative but subsequently found to be positive by at least four assays in the comparison. None suffered from any CDI-related adverse events. In conclusion, clinical presentation is important when interpreting C. difficile diagnostic assays. PMID- 21697330 TI - Extensive horizontal gene transfer in ureaplasmas from humans questions the utility of serotyping for diagnostic purposes. AB - Ureaplasma parvum and Ureaplasma urealyticum are sexually transmitted, opportunistic pathogens of the human urogenital tract. There are 14 known serovars distributed between the two species. For decades, it has been postulated based upon limited data that virulence is related to serotype specificity. The results were often inconclusive due to the small sample size and extensive cross reactivity between certain serovars. We developed real-time quantitative PCRs that allow reliable differentiation of the two species and type strains of each of the 14 serovars. To investigate species and serovar distributions, we typed 1,061 clinical isolates of human ureaplasmas from diverse patient populations. There was only a tenuous association between individual Ureaplasma serovars and certain patient populations. This may in part be explained by the fact that almost 40% of the isolates were genetic mosaics, apparently arising from the recombination of multiple serovars. This explains the extensive cross-reactivity based upon serotyping and the lack of consistent association of given serotypes with disease. PMID- 21697331 TI - Wide dispersion of ST175 clone despite high genetic diversity of carbapenem nonsusceptible Pseudomonas aeruginosa clinical strains in 16 Spanish hospitals. AB - During the COMParative Activity of Carbapenems Testing (COMPACT) surveillance study, 448 Pseudomonas aeruginosa clinical isolates were obtained from 16 Spanish hospitals. Nonsusceptibility (EUCAST breakpoints) to imipenem (35%), meropenem (33%), and/or doripenem (33%) was observed with 175 isolates (39%). Simultaneous resistance to these three drugs was observed with 126 of the 175 isolates (72%). Except for colistin, high resistance rates were observed among noncarbapenem antibiotics. Clonal relatedness was investigated by pulsed-field gel electrophoresis (PFGE) with SpeI, discriminating 68 patterns. Multilocus sequence typing (MLST) was performed on 84 isolates representing different PFGE types and all participating hospitals. Thirty-nine sequence types (STs) could be distinguished, and of these, ST175 (48 isolates, 10 hospitals), ST646 (16 isolates, 4 hospitals), ST532 (13 isolates, 3 hospitals), and ST111 (13 isolates, 7 hospitals) were the most frequently encountered. Minimum-spanning tree analysis confirmed a wide dissemination of different clones among participant hospitals, particularly ST175. PFGE pattern comparison within the four most frequent STs revealed that ST175 isolates were relatively uniform, while ST646, ST532, and ST111 isolates were highly diverse, with almost every isolate belonging to a unique pulsotype, even when originating from the same center. The population of carbapenem-nonsusceptible P. aeruginosa isolates from 16 hospitals is highly diverse, with one ST (ST175) representing a highly conserved clone disseminated in 10 of the 16 participant hospitals. This ST175 clone should be added to the list of P. aeruginosa clones at high risk for epidemic spread, such as the Liverpool, Manchester, and Melbourne clones previously found in cystic fibrosis patients and ST235 in the nosocomial setting. PMID- 21697332 TI - Preanalytical delay reduces sensitivity of QuantiFERON-TB gold in-tube assay for detection of latent tuberculosis infection. AB - The effects of incubation delays on the accuracy of the QuantiFERON-TB gold in tube assay (QFT-GIT) were measured. Compared to immediate incubation, 6- and 12 hour delays resulted in positive-to-negative reversion rates of 19% (5/26) and 22% (5/23), respectively. These findings underscore the need for standardizing QFT-GIT preanalytical practices. PMID- 21697333 TI - Group B streptococci causing neonatal infections in barcelona are a stable clonal population: 18-year surveillance. AB - We analyzed 212 group B streptococci (GBS) from newborns with invasive infections in the area of Barcelona, Spain, between 1992 and 2009, with the aim of documenting changes in the prevalences of serotypes, antimicrobial resistance, and genetic lineages and evaluating their associations with either early-onset disease (EOD) or late-onset disease (LOD). Serotypes III (n = 118) and Ia (n = 47) together accounted for nearly 78% of the isolates. All isolates carried an alpha or alpha-like protein gene, and specific associations between genes and serotypes, such as serotype Ib and bca, serotype II and bca, serotype III and rib, and serotype V and alp3, reflected the presence of particular genetic lineages. Macrolide resistance (14.2%) was significantly associated with serotype V. Pulsed-field gel electrophoresis (PFGE) clustering was an excellent predictor of serotype and antibiotic resistance. The combination of PFGE and multilocus sequence typing revealed a large number of genetically distinct lineages. Still, specific lineages were dominant in our collection, particularly the serotype III/ST17/rib lineage, which had enhanced potential to cause LOD. Serotype Ia was concentrated in a single PFGE cluster composed of two genetic lineages: ST23/eps and ST24/bca. The ST24/bca sublineage of serotype Ia, which is found infrequently elsewhere, may be emerging as an important cause of neonatal invasive infections in the Mediterranean region. In spite of the introduction of prophylaxis, resulting in a pronounced decline in the frequency of EOD, the study revealed a remarkably stable clonal structure of GBS causing neonatal infections in Barcelona over a period of 18 years. PMID- 21697334 TI - A synonymous change in the influenza A virus neuraminidase gene interferes with PCR-based subtyping and oseltamivir resistance mutation detection. PMID- 21697329 TI - Identification of HIV superinfection in seroconcordant couples in Rakai, Uganda, by use of next-generation deep sequencing. AB - HIV superinfection, which occurs when a previously infected individual acquires a new distinct HIV strain, has been described in a number of populations. Previous methods to detect superinfection have involved a combination of labor-intensive assays with various rates of success. We designed and tested a next-generation sequencing (NGS) protocol to identify HIV superinfection by targeting two regions of the HIV viral genome, p24 and gp41. The method was validated by mixing control samples infected with HIV subtype A or D at different ratios to determine the inter- and intrasubtype sensitivity by NGS. This amplicon-based NGS protocol was able to consistently identify distinct intersubtype strains at ratios of 1% and intrasubtype variants at ratios of 5%. By using stored samples from the Rakai Community Cohort Study (RCCS) in Uganda, 11 individuals who were HIV seroconcordant but virally unlinked from their spouses were then tested by this method to detect superinfection between 2002 and 2005. Two female cases of HIV intersubtype superinfection (18.2%) were identified. These results are consistent with other African studies and support the hypothesis that HIV superinfection occurs at a relatively high rate. Our results indicate that NGS can be used for detection of HIV superinfection within large cohorts, which could assist in determining the incidence and the epidemiologic, virologic, and immunological correlates of this phenomenon. PMID- 21697335 TI - Computational analysis of the structural mechanism of inhibition of chemokine receptor CXCR4 by small molecule antagonists. AB - Understanding the structural mechanism of receptor-ligand interactions for the chemokine receptor CXCR4 is essential for determining its physiological and pathological functions and for developing new therapies targeted to CXCR4. We have recently reported a structural mechanism for CXCR4 antagonism by a novel synthetic CXCR4 antagonist RCP168 and compared its effectiveness against the natural agonist SDF-1alpha. In the present study, using molecular docking, we further investigate the binding modes of another seven small molecules known to act as CXCR4 antagonists. The predicted binding modes were compared with previously published mutagenesis data for two of these (AMD3100 and AMD11070). Four antagonists, including AMD3100, AMD11070, FC131 and KRH-1636, bound in a similar fashion to CXCR4. Two important acidic amino acid residues (Asp262 and Glu288) on CXCR4, previously found essential for AMD3100 binding, were also involved in binding of the other ligands. These four antagonists use a binding site in common with that used by RCP168, which is a novel synthetic derivative of vMIP-II in which the first 10 residues are replaced by D-amino acids. Comparison of binding modes suggested that this binding site is different from the binding region occupied by the N-terminus of SDF-1alpha, the only known natural ligand of CXCR4. These observations suggest the presence of a ligand-binding site (site A) that co-exists with the agonist (SDF-1alpha) binding site (site B). The other three antagonists, including MSX123, MSX202 and WZ811, are smaller in size and had very similar binding poses, but binding was quite different from that of AMD3100. These three antagonists bound at both sites A and B, thereby blocking both binding and signaling by SDF-1alpha. PMID- 21697336 TI - Regulation of prolactin secretion during the estrus in rats: possible role of glucocorticoids. AB - Mifepristone (MIF) administration to cycling rats at proestrus induces hypersecretion of prolactin (PRL) at the following estrus. We aimed to assess whether this effect is due to the antiprogesterone or antiglucocorticoid action of MIF and to help underscore the nature of the circulating hormone(s) regulating PRL secretion at estrus. Female cycling rats in proestrus were treated with vehicle; the progesterone (Pg) and glucocorticoid receptor antagonists, MIF (5 mg/kg) or ORG-33628 (5 mg/kg); the glucocorticoid agonist dexamethasone (DEX; 27 mg/kg)+/-MIF; or the inhibitor of steroid synthesis aminoglutethimide (AG; 150 mg/kg)+/-MIF. The animals' blood was sampled the same day at 1800 h and at 1800 h of the following day to assess for circulating PRL and Pg levels. To distinguish antiglucocorticoid from antiprogesterone effects of MIF, we administered a highly specific neutralizing antibody against Pg. None of the antagonists modified serum PRL values at proestrus but increased PRL levels at estrus. DEX decreased the secretion of PRL at proestrus, yet the effect was entirely blocked by MIF. Furthermore, DEX decreased PRL at estrus in a MIF-reversible manner, suggesting that adrenal corticoids during proestrous may regulate PRL secretion at estrus. AG increased PRL secretion at estrus, whereas its association with MIF produced an even higher response. PRL concentration at estrus was not modified by the antiprogesterone antibody, suggesting that the effect of MIF is a consequence of its antiglucocorticoid effect and not due to its antiprogesterone properties. In conclusion, PRL secretion in the afternoon of the estrus is most likely regulated by glucocorticoids through an inhibitory action. PMID- 21697337 TI - Comparison of memory B cell, antibody-secreting cell, and plasma antibody responses in young children, older children, and adults with infection caused by Vibrio cholerae O1 El Tor Ogawa in Bangladesh. AB - Children bear a large component of the global burden of cholera. Despite this, little is known about immune responses to cholera in children, especially those under 5 years of age. Cholera vaccine studies have demonstrated lower long-term protective efficacy in young children than in older children and adults. Memory B cell (MBC) responses may correlate with duration of protection following infection and vaccination. Here we report a comparison of immune responses in young children (3 to 5 years of age; n = 17), older children (6 to 17 years of age; n = 17), and adults (18 to 60 years of age; n = 68) hospitalized with cholera in Dhaka, Bangladesh. We found that young children had lower baseline vibriocidal antibody titers and higher fold increases in titer between day 2 and day 7 than adults. Young children had higher baseline IgG plasma antibody levels to Vibrio cholerae antigens, although the magnitudes of responses at days 7 and 30 were similar across age groups. As a surrogate marker for mucosal immune responses, we assessed day 7 antibody-secreting cell (ASC) responses. These were comparable across age groups, although there was a trend for older age groups to have higher levels of lipopolysaccharide-specific IgA ASC responses. All age groups developed comparable MBC responses to V. cholerae lipopolysaccharide and cholera toxin B subunit at day 30. These findings suggest that young children are able to mount robust vibriocidal, plasma antibody, ASC, and MBC responses against V. cholerae O1, suggesting that under an optimal vaccination strategy, young children could achieve protective efficacy comparable to that induced in adults. PMID- 21697338 TI - Multisite comparison of high-sensitivity multiplex cytokine assays. AB - The concentrations of cytokines in human serum and plasma can provide valuable information about in vivo immune status, but low concentrations often require high-sensitivity assays to permit detection. The recent development of multiplex assays, which can measure multiple cytokines in one small sample, holds great promise, especially for studies in which limited volumes of stored serum or plasma are available. Four high-sensitivity cytokine multiplex assays on a Luminex (Bio-Rad, BioSource, Linco) or electrochemiluminescence (Meso Scale Discovery) platform were evaluated for their ability to detect circulating concentrations of 13 cytokines, as well as for laboratory and lot variability. Assays were performed in six different laboratories utilizing archived serum from HIV-uninfected and -infected subjects from the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS) and commercial plasma samples spanning initial HIV viremia. In a majority of serum samples, interleukin-6 (IL 6), IL-8, IL-10, and tumor necrosis factor alpha were detectable with at least three kits, while IL-1beta was clearly detected with only one kit. No single multiplex panel detected all cytokines, and there were highly significant differences (P < 0.001) between laboratories and/or lots with all kits. Nevertheless, the kits generally detected similar patterns of cytokine perturbation during primary HIV viremia. This multisite comparison suggests that current multiplex assays vary in their ability to measure serum and/or plasma concentrations of cytokines and may not be sufficiently reproducible for repeated determinations over a long-term study or in multiple laboratories but may be useful for longitudinal studies in which relative, rather than absolute, changes in cytokines are important. PMID- 21697339 TI - Vibrio cholerae O1 infection induces proinflammatory CD4+ T-cell responses in blood and intestinal mucosa of infected humans. AB - Vibrio cholerae O1 is a noninvasive enteric pathogen and serves as a model for studies of mucosal immunity. Although symptomatic V. cholerae infection induces durable protection against subsequent disease, vaccination with oral killed whole cell V. cholerae stimulates less long-lasting protection against cholera. In this study, we demonstrated that cholera induces an early proinflammatory cellular immune response that results in priming of Th1- and Th17-type cytokine responses to ex vivo antigenic stimulation and an increase in the ratio of Th1 to Th2 CD4(+) T-cell responses. Comparable priming of Th1 and Th17 responses, with an increased ratio of Th1 to Th2 CD4(+) T-cell responses, was not observed in subjects who received two doses of the oral cholera vaccine Dukoral (a whole-cell cholera toxin B subunit containing [WC-CTB] vaccine). These findings suggest that natural V. cholerae infection induces an early, proinflammatory cellular immune response, despite the apparent lack of clinical signs of inflammation. The failure of the WC-CTB vaccine to activate equivalent, CD4(+) T-cell responses is a potential explanation for the shorter duration of protection following immunization with this vaccine. Additional studies are needed to determine whether these early T-cell-mediated events predict the subsequent duration of immunologic memory. PMID- 21697341 TI - Varicella-zoster virus (VZV) glycoprotein E is a serological antigen for detection of intrathecal antibodies to VZV in central nervous system infections, without cross-reaction to herpes simplex virus 1. AB - Herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV) cause serious central nervous system (CNS) diseases that are diagnosed with PCR using samples of cerebrospinal fluid (CSF) and, during later stages of such infections, with assays of intrathecal IgG antibody production. However, serological diagnoses have been hampered by cross-reactions between HSV-1 and VZV IgG antibodies and are commonly reported in patients with herpes simplex encephalitis (HSE). In this study we have evaluated VZV glycoprotein E (gE) as a new antigen for serological diagnosis of VZV-induced CNS infections. Paired samples of CSF and serum from 29 patients with clinical diagnosis of VZV CNS infection (n = 15) or HSE (n = 14), all confirmed by PCR, were analyzed. VZV gE and whole VZV were compared as antigens in enzyme-linked immunosorbent assays (ELISAs) for serological assays in which the CSF/serum sample pairs were diluted to identical IgG concentrations. With the gE antigen, none of the HSE patients showed intrathecal IgG antibodies against VZV, compared to those shown by 11/14 patients using whole-VZV antigen (P < 0.001). In the patients with VZV infections, significantly higher CSF/serum optical density (OD) ratios were found in the VZV patients using the VZV gE antigen compared to those found using the whole-VZV antigen (P = 0.001). These results show that gE is a sensitive antigen for serological diagnosis of VZV infections in the CNS and that this antigen was devoid of cross-reactivity to HSV 1 IgG in patients with HSE. We therefore propose that VZV gE can be used for serological discrimination of CNS infections caused by VZV and HSV-1. PMID- 21697340 TI - A novel Lawsonia intracellularis autotransporter protein is a prominent antigen. AB - Investigation of antigenic determinants of the microaerophilic obligate intracellular bacterium Lawsonia intracellularis using a mass spectrometry approach identified a novel bacterial protein present in an extract of cell culture medium aspirated from heavily infected in vitro cell cultures. Western immunoblotting analysis of SDS-PAGE-resolved proteins using immune sera pooled from L. intracellularis-infected pigs revealed the presence of a strongly immunoreactive band of ~ 72 kDa. Liquid chromatography-electrospray ionization tandem mass spectrometry analysis of this component and database mining using a fully annotated L. intracellularis genome sequence and the comprehensive GenBank prokaryotic genomic database highlighted the presence of a protein that shares little sequence similarity with other prokaryotic proteins and appears to be highly species specific. Detailed bioinformatic analyses identified the protein as member of the autotransporter protein family of surface-exposed proteins, and the designation LatA (Lawsonia autotransporter protein A) is suggested. Recognition of recombinant LatA on Western blots by a panel of sera from infected and control pigs corresponded 100% with a commercial serodiagnostic that relies on in vitro culture of this fastidious organism. LatA therefore represents a potential candidate for the development of a rapid and species-specific serodiagnostic reagent. PMID- 21697342 TI - Monoclonal antibodies specific for immunorecessive epitopes of glucuronoxylomannan, the major capsular polysaccharide of Cryptococcus neoformans, reduce serotype bias in an immunoassay for cryptococcal antigen. AB - Immunoassay for detection of glucuronoxylomannan (GXM), the major capsular polysaccharide of Cryptococcus neoformans, is an important tool for diagnosis of cryptococcosis. However, immunoassays that are based solely or in part on detection with polyclonal antibodies may show serotype bias in detection of GXM, particularly limited sensitivity for serotype C. In this study, we describe detection of GXM in an antigen capture sandwich enzyme-linked immunosorbent assay (ELISA) that used a cocktail of two monoclonal antibodies (MAbs). MAb F12D2 was previously produced by immunization with GXM that had been treated to remove O acetyl groups, a major source of serotype specificity. MAb F12D2 has a high degree of reactivity with GXM of serotypes A, B, C, and D, but the reactivity with serotype D was less than was found with other MAbs. MAb 339 is highly reactive with GXM of serotypes A and D. Use of a combination of the two MAbs produced an immunoassay that had the best properties of both MAbs, including good reactivity with serotype C, which is an emerging threat in sub-Saharan Africa. These results suggest that next-generation immunoassays for diagnosis of cryptococcosis may be formulated by (i) use of immunization and hybridoma screening strategies that are designed to prospectively meet the needs of immunoassay performance and (ii) careful selection of MAbs that span the expected polysaccharide serotypes in the subject patient population. PMID- 21697344 TI - Human endogenous retrovirus transcription profiles of the kidney and kidney derived cell lines. AB - The human genome comprises approximately 8-9 % of human endogenous retroviruses (HERVs) that are transcribed with tissue specificity. However, relatively few organs have been examined in detail for individual differences in HERV transcription pattern, nor have tissue-to-cell culture comparisons been frequently performed. Using an HERV-specific DNA microarray, a core HERV transcription profile was established for the human kidney comparing 10 tissue samples. This core represents HERV groups expressed uniformly or nearly so in non tumour kidney tissue. The profiles obtained from non-tumour tissues were compared to 10 renal tumour tissues (renal cell carcinoma, RCC) derived from the same individuals and additionally, to 22 RCC cell lines. No RCC cell line or tumour specific differences were observed, suggesting that HERV transcription is not altered in RCC. However, when comparing tissue transcription to cell line transcription, there were consistent differences. The differences were irrespective of cancer state and included cell lines derived from non-tumour kidney tissue, suggesting that a specific alteration of HERV transcription occurs when establishing cell lines. In contrast to previous publications, all known HERV-derived tumour antigens, including those identified in RCC, were expressed both in multiple RCC cell lines and several non-tumour tissue-derived cell lines, a result that contrasts with findings from patient samples. The results establish the core kidney transcription pattern of HERVs and reveal differences between cell culture lines and tissue samples. PMID- 21697343 TI - Comprehensive linker-scanning mutagenesis of the hepatitis C virus E1 and E2 envelope glycoproteins reveals new structure-function relationships. AB - Despite extensive research, many details about the structure and functions of hepatitis C virus (HCV) glycoproteins E1 and E2 are not fully understood, and their crystal structure remains to be determined. We applied linker-scanning mutagenesis to generate a panel of 34 mutants, each containing an insertion of 5 aa at a random position within the E1E2 sequence. The mutated glycoproteins were analysed by using a range of assays to identify regions critical for maintaining protein conformation, E1E2 complex assembly, CD81 receptor binding, membrane fusion and infectivity. The results, while supporting previously published data, provide several interesting new findings. Firstly, insertion at amino acid 587 or 596 reduced E1E2 heterodimerization without affecting reactivity with some conformation-sensitive mAbs or with CD81, thus implicating these residues in glycoprotein assembly. Secondly, insertions within a conserved region of E2, between amino acid residues 611 and 631, severely disrupted protein conformation and abrogated binding of all conformation-sensitive antibodies, suggesting that the structural integrity of this region is critical for the correct folding of E2. Thirdly, an insertion at Leu-682 specifically affected membrane fusion, providing direct evidence that the membrane-proximal 'stem' of E2 is involved in the fusion mechanism. Overall, our results show that the HCV glycoproteins generally do not tolerate insertions and that there are a very limited number of sites that can be changed without dramatic loss of function. Nevertheless, we identified two E2 insertion mutants, at amino acid residues 408 and 577, that were infectious in the murine leukemia virus-based HCV pseudoparticle system. PMID- 21697345 TI - prM-antibody renders immature West Nile virus infectious in vivo. AB - West Nile virus (WNV) is a member of the family Flaviviridae and is a neurotropic pathogen responsible for severe human disease. Flavivirus-infected cells release virus particles that contain variable numbers of precursor membrane (prM) protein molecules at the viral surface. Consequently, antibodies are produced against the prM protein. These antibodies have been shown to activate the infectious potential of fully immature flavivirus particles in vitro. Here, we provide in vivo proof that prM antibodies render immature WNV infectious. Infection with antibody-opsonized immature WNV particles caused disease and death of mice, and infectious WNV was found in the brains and sera. PMID- 21697346 TI - Common marmoset (Callithrix jacchus) as a primate model of dengue virus infection: development of high levels of viraemia and demonstration of protective immunity. AB - Dengue virus (DENV) causes a wide range of illnesses in humans: dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Animal models that constantly develop high levels of viraemia are required for the development of protective and preventive measures. Common marmosets (Callithrix jacchus) demonstrated high levels of viraemia after inoculation with clinical isolates of four serotypes of DENV; in particular, over 10(6) genome copies ml( 1) after inoculation with DENV-2. Non-structural protein 1 and DENV-specific IgM and IgG antibodies were consistently detected. The DENV-2 genome was detected in lymphoid organs including the lymph nodes, spleen and thymus, and also in non lymphoid organs. DENV antigen was detected by immunohistochemistry in the liver and spleen from inoculated marmosets. Four marmosets were reinoculated with DENV 2 at 33 weeks after primary inoculation with DENV-2. The DENV-2 genome was not detected in any of these marmosets, indicating protection from a secondary infection. The results indicate that common marmosets are highly sensitive to DENV infection, and suggest that marmosets could be a reliable primate model for the evaluation of candidate vaccines. PMID- 21697347 TI - Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor-2 inhibits type 1 interferon signalling by targeting interferon-stimulated gene factor-3. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) encodes four viral interferon regulatory factors (vIRF-1-4). We investigated the mechanism and consequences of vIRF-2-mediated inhibition of interferon-response element signalling following type I interferon (IFN) induction. Western blot and electrophoretic mobility shift assays identified the interferon-stimulated gene factor-3 (ISGF-3) components STAT1 and IRF-9 as the proximal targets of vIRF-2 activity. The biological significance of vIRF-2 inhibition of ISGF-3 was demonstrated by vIRF-2 mediated rescue of the replication of the IFN-sensitive virus encephalomyocarditis virus. This study provides both a mechanism and evidence for KSHV vIRF-2-mediated suppression of the consequences of type 1 IFN-induced signalling. PMID- 21697348 TI - Restrictions that control herpes simplex virus type 1 infection in mouse brain ex vivo. AB - Elucidating the cellular and molecular factors governing herpes simplex virus type 1 (HSV-1) neurotropism is a prerequisite for understanding HSV-1 encephalitis and for targeting HSV-1-derived vectors for gene transfer to the brain. Earlier we had described an ex vivo system of mouse brain slices and demonstrated a selective and unique infection pattern, mostly around the ventricles. Here, we examined tissue factors controlling HSV-1 infection of brain slices. We demonstrated that heparan sulphate, while an important factor, does not determine the infection pattern. Hyaluronic acid, but not collagen, appears to enhance HSV-1 brain infection. To investigate whether tissue distribution of viral receptors determines the infection pattern, we examined transcription of herpes virus entry mediator and nectin-1 receptor genes in infected and uninfected brain regions. Both the infected and the uninfected regions express the receptors. We also explored the influence of intra-cellular factors. HSV-1 does not preferentially infect proliferating cells in the brain slices, despite its predilection to the ventricular zones. To delineate the step at which the HSV 1 infection cascade is restricted, mRNA was isolated following tissue infection, and transcription of the immediate-early and late viral genes was evaluated. The results indicated that HSV-1 genes are not expressed in regions that do not express a viral reporter gene. Therefore, we conclude that tissue resistance to infection is associated with a block at or prior to the immediate-early mRNA synthesis. Taken together, using the ex vivo system of organotypic culture we describe here extra-cellular and intra-cellular restriction levels of HSV-1 brain infection. PMID- 21697349 TI - Serine/arginine-rich protein 30c activates human papillomavirus type 16 L1 mRNA expression via a bimodal mechanism. AB - Two splice sites on the human papillomavirus type 16 (HPV-16) genome are used exclusively by the late capsid protein L1 mRNAs: SD3632 and SA5639. These splice sites are suppressed in mitotic cells. This study showed that serine/arginine rich protein 30c (SRp30c), also named SFRS9, activated both SD3632 and SA5639 and induced production of L1 mRNA. Activation of HPV-16 L1 mRNA splicing by SRp30c required an intact arginine/serine-repeat (RS) domain of SRp30c. In addition to this effect, SRp30c could enhance L1 mRNA production indirectly by inhibiting the early 3'-splice site SA3358, which competed with the late 3'-splice site SA5639. SRp30c bound directly to sequences downstream of SA3358, suggesting that SRp30c inhibited the enhancer at SA3358 and caused a redirection of splicing to the late 3'-splice site SA5639. This inhibitory effect of SRp30c was independent of its RS domain. These results suggest that SRp30c can activate HPV-16 L1 mRNA expression via a bimodal mechanism: directly by stimulating splicing to late splice sites and indirectly by inhibiting competing early splice sites. PMID- 21697350 TI - Predicting antigenic sites on the foot-and-mouth disease virus capsid of the South African Territories types using virus neutralization data. AB - Foot-and-mouth disease virus (FMDV) outer capsid proteins 1B, 1C and 1D contribute to the virus serotype distribution and antigenic variants that exist within each of the seven serotypes. This study presents phylogenetic, genetic and antigenic analyses of South African Territories (SAT) serotypes prevalent in sub Saharan Africa. Here, we show that the high levels of genetic diversity in the P1 coding region within the SAT serotypes are reflected in the antigenic properties of these viruses and therefore have implications for the selection of vaccine strains that would provide the best vaccine match against emerging viruses. Interestingly, although SAT1 and SAT2 viruses displayed similar genetic variation within each serotype (32 % variable amino acids), antigenic disparity, as measured by r(1)-values, was less pronounced for SAT1 viruses compared with SAT2 viruses within our dataset, emphasizing the high antigenic variation within the SAT2 serotype. Furthermore, we combined amino acid variation and the r(1)-values with crystallographic structural data and were able to predict areas on the surface of the FMD virion as antigenically relevant. These sites were mostly consistent with antigenic sites previously determined for types A, O and C using mAbs and escape mutant studies. Our methodology offers a quick alternative to determine antigenic relevant sites for FMDV field strains. PMID- 21697351 TI - Infection of hepatocytes with 17-D vaccine-strain yellow fever virus induces a strong pro-inflammatory host response. AB - Yellow fever virus (YFV) causes serious disease in endemic areas of South America and Africa, even though a very well tolerated vaccine is available. YFV primarily targets the liver where as many as 80 % of hepatocytes may be involved during infection. The objective of this project was to compare and contrast the cytokine response from hepatocytes infected with either wild-type (Asibi) or vaccine (17-D 204) strains of YFV, with the goal of identifying responses that might be correlated with disease severity or vaccine efficacy. We report here that PH5CH8 hepatocytes support a productive infection with both wild-type and vaccine-strain YFV. Infection with either virus resulted in elevated expression of several pro- and anti-inflammatory cytokines [interleukin (IL)-1beta, IL-4, IL-6, IL-8, IL-10 and tumour necrosis factor-alpha) with a corresponding increase in transcription. Hepatocytes infected with vaccine virus had a more profound response than did cells infected with wild-type virus. Pre-stimulation of hepatocytes with IL-6 resulted in reduced viral titres, elevated concentrations of cytokines released from Asibi virus-infected cells and improved cell viability in cells infected with 17-D virus. Data reported here suggest that 17-D virus stimulates an appropriate antiviral inflammatory response in hepatocytes, while Asibi virus can attenuate the host response. These data identify potential mechanisms that are associated with increased virulence in wild-type virus infections and also provide clues towards potential immune-response limitations that may be associated with vaccine-related adverse events. PMID- 21697352 TI - Identification of an antibody-binding epitope on the rotavirus A non-structural protein NSP2 using phage display analysis. AB - The non-structural protein 2 (NSP2) of rotavirus has important roles in rotavirus replication associated with RNA binding, hydrolysis of NTPs and RNA, and helix destabilizing properties. A cell-culture assay using an NSP2-specific mAb and polyclonal antiserum to block virus replication showed a 73 and 96 % reduction in the amount of virus produced during replication, respectively. Phage display technology was used to identify the antibody-binding region on the NSP2 protein with the motif (244)T-(Y/F)-O-O-O-X-K-O-G(252), where O is a hydrophilic residue and X is any amino acid. This region was mapped to the three-dimensional NSP2 crystal structure to visualize the epitope. Analysis revealed identity to a region on NSP2 that mapped to a site exposed on the surface of the protein, which could possibly interfere with a functionally important region of the protein. Antibody binding to this region could disrupt the essential roles of NSP2, such as the formation of viroplasms with NSP5 or the interaction with viral RNA, thereby indicating a possible mechanism for the observed inhibition of virus replication. Genetic analysis of the putative binding region of NSP2 revealed a high level of conservation, suggesting that the region is under strict control. PMID- 21697353 TI - Analytical evaluation of a high-sensitivity troponin T assay and its clinical assessment in acute coronary syndrome. AB - BACKGROUND: The recently developed, highly sensitive cardiac troponin T (hs-cTnT) immunoassay improves the detection of acute myocardial infarction (AMI). However, this assay requires further analytical and clinical evaluation. METHODS: Imprecision, linearity, limits of quantification and interferences were evaluated; hs-cTnT was compared with a conventional cardiac troponin I assay (cTnI), performed on an X-pand((r))HM, in a population of patients with suspected AMI. Finally, the 99th percentile cut-off point for a reference population was explored in 213 healthy control subjects. RESULTS: Imprecision analysis demonstrated coefficients of variation (CVs) below 4%, linearity showed a 0.999 coefficient of correlation, with excellent recovery (99.9%) and a limit of quantification (10%CV) was found at 9.2 ng/L. A negative interference (>20%) with haemolysis was observed when supplemental haemoglobin was above 0.25 g/dL. Patients with suspected AMI more frequently displayed an increased hs-cTnT (83%) than an increased cTnI (55%, P < 0.01). Unstable angina was present in 63% of patients with an increased hs-cTnT associated with no increase in cTnI. The 99th percentile value for our reference population was 16.9 ng/L. In 213 healthy blood donors, hs-cTnT levels were significantly correlated with age (P < 0.0001), and were higher in men than in women (P < 0.0001). CONCLUSIONS: The analytical performance of hs-cTnT complied with the international guidelines for AMI detection. Determining the degree of haemolysis in a sample is of paramount importance to the interpretation of hs-cTnT results. The 99th percentile value of our reference population was established. PMID- 21697355 TI - Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model. AB - AIMS: A routine secondary pharmacology screen indicated that reversibly binding oral P2Y(12) receptor antagonist ticagrelor could inhibit adenosine uptake in human erythrocytes, suggesting that ticagrelor may potentiate adenosine-mediated responses in vivo. The aim of this study was to further characterize the adenosine uptake inhibition in vitro and study possible physiological consequences of adenosine uptake inhibition by ticagrelor in an anesthetized dog model of coronary blood flow compared to dipyridamole. METHODS AND RESULTS: We measured [2-3H]adenosine uptake in purified human erythrocytes and several cell lines in the presence of ticagrelor or the known uptake inhibitor dipyridamole as a comparator. Using an open-chest dog model (beagles), we measured the left anterior descending (LAD) coronary artery blood flow during reactive hyperemia after 1 minute occlusion or intracoronary infusion of adenosine before and after administration of vehicle, ticagrelor, or dipyridamole (each n = 8). Ticagrelor concentration-dependently inhibited adenosine uptake in human erythrocytes and in cell lines of rat, canine, or human origin. In the dog model, ticagrelor and dipyridamole dose-dependently augmented reactive hyperemia after LAD occlusion, as assessed by percentage repayment of flow debt relative to control (both Ps < .05). Ticagrelor and dipyridamole also dose-dependently augmented intracoronary adenosine-induced increases in LAD blood flow relative to control (both Ps < .05). CONCLUSION: Ticagrelor inhibits adenosine uptake in vitro and subsequently augments cardiac blood flow in a canine model of reactive hypoxia- or adenosine induced blood flow increases. These findings suggest that ticagrelor may have additional benefits in patients with acute coronary syndrome beyond inhibition of platelet aggregation. PMID- 21697354 TI - Diverse environmental stresses elicit distinct responses at the level of pre-mRNA processing in yeast. AB - Gene expression in eukaryotic cells is profoundly influenced by the post transcriptional processing of mRNAs, including the splicing of introns in the nucleus and both nuclear and cytoplasmic degradation pathways. These processes have the potential to affect both the steady-state levels and the kinetics of changes to levels of intron-containing transcripts. Here we report the use of a splicing isoform-specific microarray platform to investigate the effects of diverse stress conditions on pre-mRNA processing. Interestingly, we find that diverse stresses cause distinct patterns of changes at this level. The responses we observed are most dramatic for the RPGs and can be categorized into three major classes. The first is characterized by accumulation of RPG pre-mRNA and is seen in multiple types of amino acid starvation regimes; the magnitude of splicing inhibition correlates with the severity of the stress. The second class is characterized by a rapid decrease in both pre- and mature RPG mRNA and is seen in many stresses that inactivate the TORC1 kinase complex. These decreases depend on nuclear turnover of the intron-containing pre-RNAs. The third class is characterized by a decrease in RPG pre-mRNA, with only a modest reduction in the mature species; this response is observed in hyperosmotic and cation-toxic stresses. We show that casein kinase 2 (CK2) makes important contributions to the changes in pre-mRNA processing, particularly for the first two classes of stress responses. In total, our data suggest that complex post-transcriptional programs cooperate to fine-tune expression of intron-containing transcripts in budding yeast. PMID- 21697356 TI - Characterizing the involvement of rostrolateral prefrontal cortex in prospective memory. PMID- 21697357 TI - Time course of classically conditioned Purkinje cell response is determined by initial part of conditioned stimulus. AB - Classical conditioning of a motor response such as eyeblink is associated with the development of a pause in cerebellar Purkinje cell firing that is an important driver of the overt response. This conditioned Purkinje cell response is adaptively timed and has a specific temporal profile that probably explains the time course of the overt behavior. It is generally assumed that the temporal properties of the conditioned Purkinje cell response are determined by the temporal pattern of the parallel fiber impulses generated by the conditioned stimulus at the time of the conditioned response. We show here in the decerebrate ferret preparation that a very brief conditioned stimulus, consisting of only one or two impulses in the mossy fibers, can be sufficient to elicit a full conditioned Purkinje cell response with normal time course. The finding suggests that parallel fiber input to the Purkinje cell influences the firing rate several hundred milliseconds later. It poses a serious challenge to the standard view of the role of parallel fiber impulses in response timing. PMID- 21697358 TI - Constant darkness induces IL-6-dependent depression-like behavior through the NF kappaB signaling pathway. AB - Substantial experimental evidence indicates a major role for the circadian system in mood disorders. Additionally, proinflammatory cytokines have been proposed to be involved in the pathogenesis of depression. However, the molecular elements determining the functional interplay between these two systems in depression have not been described as yet. Here we investigate whether long-term light deprivation in the constant darkness (DD) paradigm affects depression-like behavior in mice and concomitantly modulates the levels of proinflammatory cytokines. We find that after 4 weeks of DD, mice display depression-like behavior, which is paralleled by reduced hippocampal cell proliferation. This chronobiologically induced depressive state is associated with elevated levels of plasma IL-6 (interleukin-6) and IL-6 and Il1-R1 (interleukin 1 receptor, type I) protein levels in the hippocampus and also alters hippocampal protein levels of the clock genes per2 and npas2. Using pharmacological blockers of the NF-kappaB pathway, we provide evidence that the effects of DD on depression-like behavior, on hippocampal cell proliferation, on altered expressional levels of brain and plasma IL-6, and on the modulation of clock gene expression are mediated through NF-kappaB signaling. Moreover, NF-kappaB activity is enhanced in hippocampal tissue of DD mice. Mice with a deletion of IL-6, one of the target genes of NF kappaB, are resistant to DD-induced depression-like behavior, which suggests a pivotal role for this cytokine in the constant darkness mouse model of depression. We here first describe some of the molecular elements bridging chronobiological and inflammatory processes in the constant darkness mouse model of depression. PMID- 21697360 TI - Differential control of presynaptic CaMKII activation and translocation to active zones. AB - The release of neurotransmitters, neurotrophins, and neuropeptides is modulated by Ca(2+) mobilization from the endoplasmic reticulum (ER) and activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Furthermore, when neuronal cultures are subjected to prolonged depolarization, presynaptic CaMKII redistributes from the cytoplasm to accumulate near active zones (AZs), a process that is reminiscent of CaMKII translocation to the postsynaptic side of the synapse. However, it is not known how presynaptic CaMKII activation and translocation depend on neuronal activity and ER Ca(2+) release. Here these issues are addressed in Drosophila motoneuron terminals by imaging a fluorescent reporter of CaMKII activity and subcellular distribution. We report that neuronal excitation acts with ER Ca(2+) stores to induce CaMKII activation and translocation to a subset of AZs. Surprisingly, activation is slow, reflecting T286 autophosphorylation and the function of presynaptic ER ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP3Rs). Furthermore, translocation is not simply proportional to CaMKII activity, as T286 autophosphorylation promotes activation, but does not affect translocation. In contrast, RNA interference-induced knockdown of the AZ scaffold protein Bruchpilot disrupts CaMKII translocation without affecting activation. Finally, RyRs comparably stimulate both activation and translocation, but IP3Rs preferentially promote translocation. Thus, Ca(2+) provided by different presynaptic ER Ca(2+) release channels is not equivalent. These results suggest that presynaptic CaMKII activation depends on autophosphorylation and global Ca(2+) in the terminal, while translocation to AZs requires Ca(2+) microdomains generated by IP3Rs. PMID- 21697362 TI - Coordination of uncoupled bimanual movements by strictly timed interhemispheric connectivity. AB - Independent use of both hands is characteristic of human action in daily life. By nature, however, in-phase bimanual movements, for example clapping, are easier to accomplish than anti-phase movements, for example playing the piano. It is commonly agreed that interhemispheric interactions play a central role in the coordination of bimanual movements. However, the spatial, temporal, and physiological properties of the interhemispheric signals that coordinate different modes of bimanual movements are still not completely understood. More precisely, do individual interhemispheric connectivity parameters have behavioral relevance for bimanual rapid anti-phase coordination? To address this question, we measured movement-related interhemispheric interactions, i.e., inhibition and facilitation, and correlated them with the performance during bimanual coordination. We found that movement-related facilitation from right premotor to left primary motor cortex (rPMd-lM1) predicted performance in anti-phase bimanual movements. It is of note that only fast facilitation during the preparatory period of a movement was associated with success in anti-phase movements. Modulation of right to left primary motor interaction (rM1-lM1) was not related to anti-phase but predicted bimanual in-phase and unimanual behavior. These data suggest that strictly timed modulation of interhemispheric rPMd-lM1 connectivity is essential for independent high-frequency use of both hands. The rM1-lM1 results indicate that adjustment of connectivity between homologous M1 may be important for the regulation of homologous muscle synergies. PMID- 21697361 TI - Central representation of postingestive chemosensory cues in mice that lack the ability to taste. AB - The gustatory nerves of mice lacking P2X2 and P2X3 purinergic receptor subunits (P2X-dblKO) are unresponsive to taste stimulation (Finger et al., 2005). Surprisingly, P2X-dblKO mice show residual behavioral responses to concentrated tastants, presumably via postingestive detection. Therefore, the current study tested whether postingestive signaling is functional in P2X-dblKO mice and if so, whether it activates the primary viscerosensory nucleus of the medulla, the nucleus of the solitary tract (nTS). Like WT animals, P2X-dblKO mice learned to prefer a flavor paired with 150 mm monosodium glutamate (MSG) over a flavor paired with water. This preference shows that, even in the absence of taste sensory input, postingestive cues are detected and associated with a flavor in P2X-dblKO mice. MSG-evoked neuronal activation in the nTS was measured by expression of the immediate early gene c-Fos [c-Fos-like immunoreactivity (Fos LI)]. In rostral, gustatory nTS, P2X-dblKO animals, unlike WT animals, showed no taste quality-specific labeling of neurons. Furthermore, MSG-evoked Fos-LI was significantly less in P2X-dblKO mice compared with WT animals. In contrast, in more posterior, viscerosensory nTS, MSG-induced Fos-LI was similar in WT and P2X dblKO mice. Together, these results suggest that P2X-dblKO mice can form preferences based on postingestive cues and that postingestive detection of MSG does not rely on the same purinergic signaling that is crucial for taste. PMID- 21697359 TI - A novel role of the WNT-dishevelled-GSK3beta signaling cascade in the mouse nucleus accumbens in a social defeat model of depression. AB - Based on earlier gene expression and chromatin array data, we identified the protein, dishevelled (DVL)-2, as being regulated in the nucleus accumbens (NAc), a key brain reward region, in the mouse social defeat model of depression. Here, we validate these findings by showing that DVL2 mRNA and protein levels are downregulated in NAc of mice susceptible to social defeat stress, effects not seen in resilient mice. Other DVL isoforms, DVL1 and DVL3, show similar patterns of regulation. Downregulation of DVL was also demonstrated in the NAc of depressed humans examined postmortem. Interestingly, several members of the WNT (Wingless)-DVL signaling cascade, including phospho-GSK3beta (glycogen synthase kinase-3beta), also show significant downregulation in the NAc of susceptible, but not resilient, mice, demonstrating concerted regulation of this pathway in the NAc due to social defeat stress. By using viral-mediated gene transfer to overexpress a dominant-negative mutant of DVL in NAc, or by using a pharmacological inhibitor of DVL administered into this brain region, we show that blockade of DVL function renders mice more susceptible to social defeat stress and promotes depression-like behavior in other assays. Similar prodepression-like effects were induced upon overexpressing GSK3beta in the NAc, while overexpressing a dominant-negative mutant of GSK3beta promoted resilience to social defeat stress. These findings are consistent with the knowledge that downregulation of DVL and phospho-GSK3beta reflects an increase in GSK3beta activity. These studies reveal a novel role for the DVL-GSK3beta signaling pathway, acting within the brain's reward circuitry, in regulating susceptibility to chronic stress. PMID- 21697363 TI - Prior expectation mediates neural adaptation to repeated sounds in the auditory cortex: an MEG study. AB - Repetition suppression, the phenomenon that the second presentation of a stimulus attenuates neural activity, is typically viewed as an automatic consequence of repeated stimulus presentation. However, a recent neuroimaging study has suggested that repetition suppression may be driven by top-down expectations. Here we examined whether and when repetition suppression can be modulated by top down expectation. Participants listened to auditory stimuli in blocks where tone repetitions were either expected or unexpected, while we recorded ongoing neural activity using magnetoencephalography. We found robust repetition suppression in the auditory cortex for repeated tones. Interestingly, this reduction was significantly larger for expected than unexpected repetitions, both in terms of evoked activity and gamma-band synchrony. These findings indicate a role of top down expectation in generating repetition suppression and are in line with predictive coding models of perception, in which the difference between expected and actual input is propagated from lower to higher cortical areas. PMID- 21697370 TI - First spike latency code for interaural phase difference discrimination in the guinea pig inferior colliculus. AB - First spike latency has been suggested as a source of the information required for fast discrimination tasks. However, the accuracy of such a mechanism has not been analyzed rigorously. Here, we investigate the utility of first spike latency for encoding information about the location of a sound source, based on the responses of inferior colliculus (IC) neurons in the guinea pig to interaural phase differences (IPDs). First spike latencies of many cells in the guinea pig IC show unimodal tuning to stimulus IPD. We investigated the discrimination accuracy of a simple latency code that estimates stimulus IPD from the preferred IPD of the single cell that fired first. Surprisingly, despite being based on only a single spike, the accuracy of the latency code is comparable to that of a conventional rate code computed over the entire response. We show that spontaneous firing limits the capacity of the latency code to accumulate information from large neural populations. This detrimental effect can be overcome by generalizing the latency code to estimate the stimulus IPD from the preferred IPDs of the population of cells that fired the first n spikes. In addition, we show that a good estimate of the neural response time to the stimulus, which can be obtained from the responses of the cells whose response latency is invariant to stimulus identity, limits the detrimental effect of spontaneous firing. Thus, a latency code may provide great improvement in response speed at a small cost to the accuracy of the decision. PMID- 21697365 TI - Memory modulates journey-dependent coding in the rat hippocampus. AB - Neurons in the rat hippocampus signal current location by firing in restricted areas called place fields. During goal-directed tasks in mazes, place fields can also encode past and future positions through journey-dependent activity, which could guide hippocampus-dependent behavior and underlie other temporally extended memories, such as autobiographical recollections. The relevance of journey dependent activity for hippocampal-dependent memory, however, is not well understood. To further investigate the relationship between hippocampal journey dependent activity and memory, we compared neural firing in rats performing two mnemonically distinct but behaviorally identical tasks in the plus maze: a hippocampus-dependent spatial navigation task and a hippocampus-independent cue response task. While place, prospective, and retrospective coding reflected temporally extended behavioral episodes in both tasks, memory strategy altered coding differently before and after the choice point. Before the choice point, when discriminative selection of memory strategy was critical, a switch between the tasks elicited a change in a field's coding category, so that a field that signaled current location in one task coded pending journeys in the other task. After the choice point, however, when memory strategy became irrelevant, the fields preserved coding categories across tasks, so that the same field consistently signaled either current location or the recent journeys. Additionally, on the start arm, firing rates were affected at comparable levels by task and journey; on the goal arm, firing rates predominantly encoded journey. The data demonstrate a direct link between journey-dependent coding and memory and suggest that episodes are encoded by both population and firing rate coding. PMID- 21697369 TI - A large-scale analysis of odor coding in the olfactory epithelium. AB - Mammals can perceive and discriminate myriad volatile chemicals as having a distinct odor. Odorants are initially detected by odorant receptors (ORs) on olfactory sensory neurons (OSNs) in the nose. In the mouse, each OSN expresses one of ~1000 different OR genes. Although OSNs and their expressed ORs constitute the fundamental units of sensory input to the brain, a comprehensive understanding of how they encode odor identities is still lacking. To gain a broader and more detailed understanding of odorant recognition and odor coding at this level, we tested the responses of 3000 mouse OSNs to 125 odorants with diverse structures and perceived odors. These studies revealed extraordinary diversity, but also bias, in odorant recognition by the OSN, and thus OR, repertoire. They indicate that most OSNs are narrowly tuned to detect a subset of odorants with related structures and often related odors, but that the repertoire also includes broadly tuned components. Strikingly, the vast majority of odorants activated a unique set of OSNs, usually two or more in combination. The resulting combinatorial codes varied in size among odorants and sometimes contained both narrowly and broadly tuned components. While many OSNs recognized multiple odorants, some appeared specific for a given pheromone or other animal-associated compound, or for one or more odorants with a particular odor quality, raising the possibility that signals derived from some OSNs and ORs might elicit an innate behavior or convey a specific odor quality. PMID- 21697364 TI - Corticothalamic feedback controls sleep spindle duration in vivo. AB - Spindle oscillations are commonly observed during stage 2 of non-rapid eye movement sleep. During sleep spindles, the cerebral cortex and thalamus interact through feedback connections. Both initiation and termination of spindle oscillations are thought to originate in the thalamus based on thalamic recordings and computational models, although some in vivo results suggest otherwise. Here, we have used computer modeling and in vivo multisite recordings from the cortex and the thalamus in cats to examine the involvement of the cortex in spindle oscillations. We found that although the propagation of spindles depended on synaptic interaction within the thalamus, the initiation and termination of spindle sequences critically involved corticothalamic influences. PMID- 21697366 TI - The locus ceruleus responds to signaling molecules obtained from the CSF by transfer through tanycytes. AB - Neurons can access signaling molecules through two principal pathways: synaptic transmission ("wiring transmission") and nonsynaptic transmission ("volume transmission"). Wiring transmission is usually considered the far more important mode of neuronal signaling. Using embryonic chick locus ceruleus (LoC) as a model, we quantified and compared routes of delivery of the neurotrophin nerve growth factor (NGF), either through a multisynaptic axonal pathway or via the CSF. We now show that the axonal pathway from the eye to the LoC involves axo axonic transfer of NGF with receptor switching (p75 to trkA) in the optic tectum. In addition to the axonal pathway, the LoC of chick embryos has privileged access to the CSF through a specialized glial/ependymal cell type, the tanycyte. The avian LoC internalizes from the CSF in a highly specific fashion both NGF and the hormone urotensin (corticotropin-releasing factor family ligand). Quantitative autoradiography at the ultrastructural level shows that tanycytes transcytose and deliver NGF to LoC neurons via synaptoid contacts. The LoC-associated tanycytes express both p75 and trkA receptors. The NGF extracted by tanycytes from the CSF has physiological effects on LoC neurons, as evidenced by significantly altered nuclear diameters in both gain-of-function and loss-of-function experiments. Quantification of NGF extraction shows that, compared with multisynaptic axonal routes of NGF trafficking to LoC, the tanycyte route is significantly more effective. We conclude that some clinically important neuronal populations such as the LoC can use a highly efficient "back door" interface to the CSF and can receive signals via this tanycyte-controlled pathway. PMID- 21697367 TI - Nuclear factor-kappaB contributes to neuron-dependent induction of glutamate transporter-1 expression in astrocytes. AB - The glutamate transporter-1 [GLT-1 (excitatory amino acid transporter 2)] subtype of glutamate transporter ensures crisp excitatory signaling and limits excitotoxicity in the CNS. Astrocytic expression of GLT-1 is regulated during development, by neuronal activity, and in neurodegenerative diseases. Although neurons activate astrocytic expression of GLT-1, the mechanisms involved have not been identified. In the present study, astrocytes from transgenic mice that express enhanced green fluorescent protein (eGFP) under the control of a bacterial artificial chromosome (BAC) containing a very large region of DNA surrounding the GLT-1 gene (BAC GLT-1 eGFP mice) were used to assess the role of nuclear factor-kappaB (NF-kappaB) in neuron-dependent activation of the GLT-1 promoter. We provide evidence that neurons activate NF-kappaB signaling in astrocytes. Transduction of astrocytes from the BAC GLT-1 eGFP mice with dominant negative inhibitors of NF-kappaB signaling completely blocked neuron-dependent activation of a NF-kappaB reporter construct and attenuated induction of eGFP. Exogenous expression of p65 and/or p50 NF-kappaB subunits induced expression of eGFP or GLT-1 and increased GLT-1-mediated transport activity. Using wild-type and mutant GLT-1 promoter reporter constructs, we found that NF-kappaB sites at 583 or -251 relative to the transcription start site were required for neuron dependent reporter activation. Electrophoretic mobility shift and supershift assays reveal that p65 and p50 interact with these same sites ex vivo. Finally, chromatin immunoprecipitation showed that p65 and p50 interact with these sites in adult cortex, but not in kidney (a tissue that expresses no detectable GLT-1). Together, these studies strongly suggest that NF-kappaB contributes to neuron dependent regulation of astrocytic GLT-1 transcription. PMID- 21697373 TI - Flight activity alters velocity tuning of fly motion-sensitive neurons. AB - Sensory neurons are mostly studied in fixed animals, but their response properties might change when the animal is free to move. Indeed, recent studies found differences between responses of sensory neurons in resting versus moving insects. Since the dynamic range of visual motion stimuli strongly depends on the speed at which an animal is moving, we investigated whether the visual system adapts to such changes in stimulus dynamics as induced by self-motion. Lobula plate tangential cells of flies lend themselves well to study this question because they are known to code for ego-motion based on optic-flow. We recorded the responses of the lobula plate tangential cell H1 to a visual pattern moving at different velocities under three different conditions: fixed flies before and after application of the octopamine agonist chlordimeform (CDM) and tethered flying flies. CDM has been previously shown to induce arousal in flies. We found that flying as well as the application of CDM significantly broadens the velocity tuning of H1 toward higher velocities. PMID- 21697368 TI - Role of the CaMKII/NMDA receptor complex in the maintenance of synaptic strength. AB - During long-term potentiation (LTP), synapses undergo stable changes in synaptic strength. The molecular memory processes that maintain strength have not been identified. One hypothesis is that the complex formed by the Ca(2+)/calmodulin dependent protein kinase II (CaMKII) and the NMDA-type glutamate receptor (NMDAR) is a molecular memory at the synapse. To establish a molecule as a molecular memory, it must be shown that interfering with the molecule produces a persistent reversal of LTP. We used the CN class of peptides that inhibit CaMKII binding to the NR2B subunit in vitro to test this prediction in rat hippocampal slices. We found that CN peptides can reverse saturated LTP, allowing additional LTP to be induced. The peptide also produced a persistent reduction in basal transmission. We then tested whether CN compounds actually affect CaMKII binding in living cells. Application of CN peptide to slice cultures reduced the amount of CaMKII concentrated in spines, consistent with delocalization of the kinase from a binding partner in the spine. To more specifically assay the binding of CaMKII to the NMDAR, we used coimmunoprecipitation methods. We found that CN peptide decreased synaptic strength only at concentrations necessary to disrupt the CaMKII/NMDAR complex, but not at lower concentrations sufficient to inhibit CaMKII activity. Importantly, both the reduction of the complex and the reduction of synaptic strength persisted after removal of the inhibitor. These results support the hypothesis that the CaMKII/NMDAR complex has switch-like properties that are important in the maintenance of synaptic strength. PMID- 21697371 TI - Cortical glial fibrillary acidic protein-positive cells generate neurons after perinatal hypoxic injury. AB - Glial fibrillary acidic protein-positive (GFAP(+)) cells give rise to new neurons in the neurogenic niches; whether they are able to generate neurons in the cortical parenchyma is not known. Here, we use genetic fate mapping to examine the progeny of GFAP(+) cells after postnatal hypoxia, a model for the brain injury observed in premature children. After hypoxia, immature cortical astroglia underwent a shift toward neuronal fate and generated cortical excitatory neurons that appeared synaptically integrated into the circuitry. Fate-mapped cortical GFAP(+) cells derived ex vivo from hypoxic, but not normoxic, mice were able to form pluripotent, long-term self-renewing neurospheres. Similarly, exposure to low oxygen conditions in vitro induced stem-cell-like potential in immature cortical GFAP(+) cells. Our data support the conclusion that hypoxia promotes pluripotency in GFAP(+) cells in the cortical parenchyma. Such plasticity possibly explains the cognitive recovery found in some preterm children. PMID- 21697372 TI - Target-dependent control of synaptic inhibition by endocannabinoids in the thalamus. AB - Inhibitory neurons in the thalamic reticular nucleus (TRN) play a critical role in controlling information transfer between thalamus and neocortex. GABAergic synapses formed by TRN neurons contact both thalamic relay cells and neurons within TRN. These two types of synapses are thought to have distinct roles for the generation of thalamic network activity, but their selective regulation is poorly understood. In many areas throughout the brain, retrograde signaling mediated by endocannabinoids acts to dynamically regulate synaptic strength over both short and long time scales. However, retrograde signaling has never been demonstrated in the thalamus. Here, we show that depolarization-induced suppression of inhibition (DSI) is prominent at inhibitory synapses interconnecting TRN neurons. DSI is completely abolished in the presence of a cannabinoid receptor 1 (CB1R) antagonist and in mice lacking CB1Rs. DSI is prevented by DAG lipase inhibitors and prolonged by blocking the 2 arachidonoylglycerol (2-AG) degradation enzyme monoacylglycerol lipase, indicating that it is mediated by the release of 2-AG from TRN neurons. By contrast, DSI is not observed at TRN synapses targeting thalamic relay neurons. A combination of pharmacological and immunohistochemical data indicate that the differences in endocannabinoid signaling at the two synapses are mediated by a synapse-specific targeting of CB1Rs, as well as differences in endocannabinoid release between the two target neurons. Together, our results show that endocannabinoids control transmitter release at specific thalamic synapses, and could dynamically regulate sensory information processing and thalamus-mediated synchronous oscillations. PMID- 21697374 TI - A model of interval timing by neural integration. AB - We show that simple assumptions about neural processing lead to a model of interval timing as a temporal integration process, in which a noisy firing-rate representation of time rises linearly on average toward a response threshold over the course of an interval. Our assumptions include: that neural spike trains are approximately independent Poisson processes, that correlations among them can be largely cancelled by balancing excitation and inhibition, that neural populations can act as integrators, and that the objective of timed behavior is maximal accuracy and minimal variance. The model accounts for a variety of physiological and behavioral findings in rodents, monkeys, and humans, including ramping firing rates between the onset of reward-predicting cues and the receipt of delayed rewards, and universally scale-invariant response time distributions in interval timing tasks. It furthermore makes specific, well-supported predictions about the skewness of these distributions, a feature of timing data that is usually ignored. The model also incorporates a rapid (potentially one-shot) duration learning procedure. Human behavioral data support the learning rule's predictions regarding learning speed in sequences of timed responses. These results suggest that simple, integration-based models should play as prominent a role in interval timing theory as they do in theories of perceptual decision making, and that a common neural mechanism may underlie both types of behavior. PMID- 21697376 TI - Controlling specific locomotor behaviors through multidimensional monoaminergic modulation of spinal circuitries. AB - Descending monoaminergic inputs markedly influence spinal locomotor circuits, but the functional relationships between specific receptors and the control of walking behavior remain poorly understood. To identify these interactions, we manipulated serotonergic, dopaminergic, and noradrenergic neural pathways pharmacologically during locomotion enabled by electrical spinal cord stimulation in adult spinal rats in vivo. Using advanced neurobiomechanical recordings and multidimensional statistical procedures, we reveal that each monoaminergic receptor modulates a broad but distinct spectrum of kinematic, kinetic, and EMG characteristics, which we expressed into receptor-specific functional maps. We then exploited this catalog of monoaminergic tuning functions to devise optimal pharmacological combinations to encourage locomotion in paralyzed rats. We found that, in most cases, receptor-specific modulatory influences summed near algebraically when stimulating multiple pathways concurrently. Capitalizing on these predictive interactions, we elaborated a multidimensional monoaminergic intervention that restored coordinated hindlimb locomotion with normal levels of weight bearing and partial equilibrium maintenance in spinal rats. These findings provide new perspectives on the functions of and interactions between spinal monoaminergic receptor systems in producing stepping, and define a framework to tailor pharmacotherapies for improving neurological functions after CNS disorders. PMID- 21697375 TI - Prefrontal and monoaminergic contributions to stop-signal task performance in rats. AB - Defining the neural and neurochemical substrates of response inhibition is of crucial importance for the study and treatment of pathologies characterized by impulsivity such as attention-deficit/hyperactivity disorder and addiction. The stop-signal task (SST) is one of the most popular paradigms used to study the speed and efficacy of inhibitory processes in humans and other animals. Here we investigated the effect of temporarily inactivating different prefrontal subregions in the rat by means of muscimol microinfusions on SST performance. We found that dorsomedial prefrontal cortical areas are important for inhibiting an already initiated response. We also investigated the possible neural substrates of the selective noradrenaline reuptake inhibitor atomoxetine via its local microinfusion into different subregions of the rat prefrontal cortex. Our results show that both orbitofrontal and dorsal prelimbic cortices mediate the beneficial effects of atomoxetine on SST performance. To assess the neurochemical specificity of these effects, we infused the alpha2-adrenergic agonist guanfacine and the D(1)/D(2) antagonist alpha-flupenthixol in dorsal prelimbic cortex to interfere with noradrenergic and dopaminergic neurotransmission, respectively. Guanfacine, which modulates noradrenergic neurotransmission, selectively impaired stopping, whereas blocking dopaminergic receptors by alpha-flupenthixol infusion prolonged go reaction time only, confirming the important role of noradrenergic neurotransmission in response inhibition. These results show that, similar to humans, distinct networks play important roles during SST performance in the rat and that they are differentially modulated by noradrenergic and dopaminergic neurotransmission. This study advances our understanding of the neuroanatomical and neurochemical determinants of impulsivity, which are relevant for a range of psychiatric disorders. PMID- 21697377 TI - Spontaneous age-related neurite branching in Caenorhabditis elegans. AB - The analysis of morphological changes that occur in the nervous system during normal aging could provide insight into cognitive decline and neurodegenerative disease. Previous studies have suggested that the nervous system of Caenorhabditis elegans maintains its structural integrity with age despite the deterioration of surrounding tissues. Unexpectedly, we observed that neurons in aging animals frequently displayed ectopic branches and that the prevalence of these branches increased with time. Within age-matched populations, the branching of mechanosensory neurons correlated with decreased response to light touch and decreased mobility. The incidence of branching was influenced by two pathways that can affect the rate of aging, the Jun kinase pathway and the insulin/IGF-1 pathway. Loss of Jun kinase signaling, which slightly shortens lifespan, dramatically increased and accelerated the frequency of neurite branching. Conversely, inhibition of the daf-2 insulin/IGF-1-like signaling pathway, which extends lifespan, delayed and suppressed branching, and this delay required DAF 16/FOXO activity. Both JNK-1 and DAF-16 appeared to act within neurons in a cell autonomous manner to influence branching, and, through their tissue-specific expression, it was possible to disconnect the rate at which branching occurred from the overall rate of aging of the animal. Old age has generally been associated with the decline and deterioration of different tissues, except in the case of tumor cell growth. To our knowledge, this is the first indication that aging can potentiate another form of growth, the growth of neurite branches, in normal animals. PMID- 21697379 TI - Competition for visual selection in the oculomotor system. AB - During behavior, the oculomotor system is tasked with selecting objects from an ever-changing visual field and guiding eye movements to these locations. The attentional priority given to visual targets during selection can be strongly influenced by external stimulus properties or internal goals based on previous experience. Although these exogenous and endogenous drivers of selection are known to operate across partially overlapping timescales, the form of their interaction over time remains poorly understood. Using a novel choice task that simultaneously manipulates stimulus- and goal-driven attention, we demonstrate that exogenous and endogenous attentional biases change linearly as a function of time after stimulus onset and have an additive influence on the visual selection process in rhesus macaques (Macaca mulatta). We present a family of computational models that quantify this interaction over time and detail the history dependence of both processes. The computational models reveal the existence of a critical 140-180 ms attentional "switching" time, when stimulus- and goal-driven processes simultaneously favor competing visual targets. These results suggest that the brain uses a linear sum of attentional biases to guide visual selection. PMID- 21697378 TI - Functional NMDA receptors at axonal growth cones of young hippocampal neurons. AB - NMDA receptors (NMDARs) are critical to the development of the nervous system, although their roles at axonal growth cones are unclear. We examined NMDAR localization and function at axonal growth cones of young hippocampal neurons. Our immunocytochemical data showed that native and transfected NMDAR subunits are expressed in axons and growth cones of young (days in vitro 3-6) hippocampal rat neurons. Moreover, immunogold electron microscopy showed that NR1 is expressed in growth cones of postnatal day 2 rat hippocampus. Local application of NMDAR agonists to growth cones of voltage-clamped neurons evoked inward currents that were blocked by bath application of an NMDAR antagonist (dl-APV), indicating that these NMDARs are functional. In addition, calcium imaging experiments indicated that NMDARs present in growth cones mediate calcium influx. Calcium transients in growth cones persisted despite pharmacological blockade of voltage-sensitive calcium channels and depletion of intracellular calcium stores. Our findings reveal the presence of functional NMDARs in axons and growth cones of young neurons, suggesting a role for these receptors in axonal guidance and synapse formation during neuronal development. PMID- 21697380 TI - Neurobiology of value integration: when value impacts valuation. AB - Everyday choice options have advantages (positive values) and disadvantages (negative values) that need to be integrated into an overall subjective value. For decades, economic models have assumed that when a person evaluates a choice option, different values contribute independently to the overall subjective value of the option. However, human choice behavior often violates this assumption, suggesting interactions between values. To investigate how qualitatively different advantages and disadvantages are integrated into an overall subjective value, we measured the brain activity of human subjects using fMRI while they were accepting or rejecting choice options that were combinations of monetary reward and physical pain. We compared different subjective value models on behavioral and neural data. These models all made similar predictions of choice behavior, suggesting that behavioral data alone are not sufficient to uncover the underlying integration mechanism. Strikingly, a direct model comparison on brain data decisively demonstrated that interactive value integration (where values interact and affect overall valuation) predicts neural activity in value sensitive brain regions significantly better than the independent mechanism. Furthermore, effective connectivity analyses revealed that value-dependent changes in valuation are associated with modulations in subgenual anterior cingulate cortex-amygdala coupling. These results provide novel insights into the neurobiological underpinnings of human decision making involving the integration of different values. PMID- 21697382 TI - The second-generation active Abeta immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. AB - Immunization against amyloid-beta (Abeta) can reduce amyloid accumulation in vivo and is considered a potential therapeutic approach for Alzheimer's disease. However, it has been associated with meningoencephalitis thought to be mediated by inflammatory T-cells. With the aim of producing an immunogenic vaccine without this side effect, we designed CAD106 comprising Abeta1-6 coupled to the virus like particle Qbeta. Immunization with this vaccine did not activate Abeta specific T-cells. In APP transgenic mice, CAD106 induced efficacious Abeta antibody titers of different IgG subclasses mainly recognizing the Abeta3-6 epitope. CAD106 reduced brain amyloid accumulation in two APP transgenic mouse lines. Plaque number was a more sensitive readout than plaque area, followed by Abeta42 and Abeta40 levels. Studies with very strong overall amyloid reduction showed an increase in vascular Abeta, which atypically was nonfibrillar. The efficacy of Abeta immunotherapy depended on the Abeta levels and thus differed between animal models, brain regions, and stage of amyloid deposition. Therefore, animal studies may not quantitatively predict the effect in human Alzheimer's disease. Our studies provided no evidence for increased microhemorrhages or inflammatory reactions in amyloid-containing brain. In rhesus monkeys, CAD106 induced a similar antibody response as in mice. The antibodies stained amyloid deposits on tissue sections of mouse and human brain but did not label cellular structures containing APP. They reacted with Abeta monomers and oligomers and blocked Abeta toxicity in cell culture. We conclude that CAD106 immunization is suited to interfere with Abeta aggregation and its downstream detrimental effects. PMID- 21697381 TI - Attentional templates in visual working memory. AB - Most theories of attention propose that we maintain attentional templates in visual working memory to control what information is selected. In the present study, we directly tested this proposal by measuring the contralateral-delay activity (CDA) of human event-related potentials during visual search tasks in which the target is cued on each trial. Here we show that the CDA can be used to measure the maintenance of attentional templates in visual working memory while processing complex visual scenes. In addition, this method allowed us to directly observe the shift from working memory to long-term memory representations controlling attention as learning occurred and experience accrued searching for the same target object. Our findings provide definitive support for several critical proposals made in theories of attention, learning, and automaticity. PMID- 21697383 TI - Chondroitinase combined with rehabilitation promotes recovery of forelimb function in rats with chronic spinal cord injury. AB - Chondroitinase ABC (ChABC) in combination with rehabilitation has been shown to promote functional recovery in acute spinal cord injury. For clinical use, the optimal treatment window is concurrent with the beginning of rehabilitation, usually 2-4 weeks after injury. We show that ChABC is effective when given 4 weeks after injury combined with rehabilitation. After C4 dorsal spinal cord injury, rats received no treatment for 4 weeks. They then received either ChABC or penicillinase control treatment followed by hour-long daily rehabilitation specific for skilled paw reaching. Animals that received both ChABC and task specific rehabilitation showed the greatest recovery in skilled paw reaching, approaching similar levels to animals that were treated at the time of injury. There was also a modest increase in skilled paw reaching ability in animals receiving task-specific rehabilitation alone. Animals treated with ChABC and task specific rehabilitation also showed improvement in ladder and beam walking. ChABC increased sprouting of the corticospinal tract, and these sprouts had more vGlut1(+ve) presynaptic boutons than controls. Animals that received rehabilitation showed an increase in perineuronal net number and staining intensity. Our results indicate that ChABC treatment opens a window of opportunity in chronic spinal cord lesions, allowing rehabilitation to improve functional recovery. PMID- 21697384 TI - Functional correlates of the anterolateral processing hierarchy in human auditory cortex. AB - Converging evidence supports the hypothesis that an anterolateral processing pathway mediates sound identification in auditory cortex, analogous to the role of the ventral cortical pathway in visual object recognition. Studies in nonhuman primates have characterized the anterolateral auditory pathway as a processing hierarchy, composed of three anatomically and physiologically distinct initial stages: core, belt, and parabelt. In humans, potential homologs of these regions have been identified anatomically, but reliable and complete functional distinctions between them have yet to be established. Because the anatomical locations of these fields vary across subjects, investigations of potential homologs between monkeys and humans require these fields to be defined in single subjects. Using functional MRI, we presented three classes of sounds (tones, band passed noise bursts, and conspecific vocalizations), equivalent to those used in previous monkey studies. In each individual subject, three regions showing functional similarities to macaque core, belt, and parabelt were readily identified. Furthermore, the relative sizes and locations of these regions were consistent with those reported in human anatomical studies. Our results demonstrate that the functional organization of the anterolateral processing pathway in humans is largely consistent with that of nonhuman primates. Because our scanning sessions last only 15 min/subject, they can be run in conjunction with other scans. This will enable future studies to characterize functional modules in human auditory cortex at a level of detail previously possible only in visual cortex. Furthermore, the approach of using identical schemes in both humans and monkeys will aid with establishing potential homologies between them. PMID- 21697385 TI - Bulk loading of calcium indicator dyes to study astrocyte physiology: key limitations and improvements using morphological maps. AB - Calcium signaling has been studied in astrocyte cell bodies using bulk loading of calcium indicator dyes, and astrocytes are known to display intracellular calcium transients. An assumption in recent data on the neuronal impact of somatic astrocyte calcium transients has been that bulk loading reflects signaling in relevant astrocyte compartments such as processes. We assessed bulk loading using Sholl analysis (Sholl, 1953) of astrocytes loaded with common calcium indicator dyes and compared these data with Sholl analysis of astrocyte morphology. In the CA1 region of the hippocampus from rats, we found that bulk loading of calcium indicator dyes only reports on calcium signals within the soma and in the most proximal processes, leaving ~90% of the area of an astrocyte and its extensive processes unsampled. By using morphological reconstructions as "maps" after the imaging session, we present simple procedures that remedy these shortfalls and permit reliable detection of calcium transients in distal astrocyte processes. The data thus reveal limitations in the interpretation of astrocyte calcium imaging data gathered with bulk loading and provide refinements to minimize these shortcomings. PMID- 21697386 TI - Not all desensitizations are created equal: physiological evidence that AMPA receptor desensitization differs for kainate and glutamate. AB - AMPA receptor-mediated responses to the agonist kainate differ from those of glutamate in two important respects. Glutamate is a full agonist that elicits strongly desensitizing responses, whereas kainate is a partial agonist with responses that are often described as weakly desensitizing or non-desensitizing. The efficacy of kainate relative to glutamate has previously been shown to be increased by mutations in the AMPA receptor ligand-binding cleft (Mano et al., 1996) and by coexpression with the auxiliary subunit stargazin (Tomita et al., 2005; Turetsky et al., 2005), but much less is known about factors that affect kainate desensitization. We therefore designed experiments to compare kainate and glutamate desensitization and efficacy in wild-type and mutant AMPA receptors expressed with and without stargazin in HEK293 cells. Desensitization to the two agonists was differentially affected by mutations in the helices participating in bonds between two subunits in the active state of the receptor (Sun et al., 2002), indicating that the protein interactions maintaining the stability of the dimer interface differ depending on which agonist is bound. Kainate efficacy was affected by factors distinct from ligand-binding cleft closure, including mutations in the dimer interface and channel vestibule as well as receptor composition. The increase in kainate responses for AMPA receptors coexpressed with stargazin was the result of both reduced kainate desensitization and increased kainate efficacy. These results provide critical new insights into the agonist dependence of both AMPA receptor activation and desensitization and the mechanism of the effects of stargazin on responses of partial agonists. PMID- 21697387 TI - Specification of a Foxj1-dependent lineage in the forebrain is required for embryonic-to-postnatal transition of neurogenesis in the olfactory bulb. AB - Establishment of a neural stem cell niche in the postnatal subependymal zone (SEZ) and the rostral migratory stream (RMS) is required for postnatal and adult neurogenesis in the olfactory bulbs (OB). We report the discovery of a cellular lineage in the SEZ-RMS-OB continuum, the specification of which is dependent on the expression of the forkhead transcription factor Foxj1 in mice. Spatially and temporally restricted Foxj1+ neuronal progenitors emerge during embryonic periods, surge during perinatal development, and are active only for the first few postnatal weeks. We show that the development of the unique Foxj1-derived lineage is dependent on Foxj1 expression and is required for overall postnatal neurogenesis in the OB. Strikingly, the production of neurons from Foxj1+ progenitors significantly declines after the early postnatal weeks, but Foxj1 derived neurons in the OB persist during adult periods. For the first time, our study identifies the time- and region-specific activity of a perinatal progenitor domain that is required for transition and progression of OB neurogenesis from the embryonic-to-postnatal periods. PMID- 21697388 TI - A stable sparse fear memory trace in human amygdala. AB - Pavlovian fear conditioning is highly conserved across species, providing a powerful model of aversive learning. In rodents, fear memory is stored and reactivated under the influence of the amygdala. There is no evidence for an equivalent mechanism in primates, and an opposite mechanism is proposed whereby primate amygdala contributes only to an initial phase of aversive learning, subsequently ceding fear memory to extra-amygdalar regions. Here, we reexamine this question by exploiting human high-resolution functional magnetic resonance imaging in conjunction with multivariate methods. By assuming a sparse neural coding, we show it is possible, at an individual subject level, to discriminate responses to conditioned (CS+ and CS-) stimuli in both basolateral and centro cortical amygdala nuclei. The strength of this discrimination increased over time and was tightly coupled to the behavioral expression of fear, consistent with an expression of a stable fear memory trace. These data highlight that the human basolateral and centro-cortical amygdala support initial learning as well more enduring fear memory storage. A sparse neuronal representation for fear, here revealed by multivariate pattern classification, resolves why an enduring memory trace has proven elusive in previous human studies. PMID- 21697390 TI - Unesterified cholesterol accumulation in late endosomes/lysosomes causes neurodegeneration and is prevented by driving cholesterol export from this compartment. AB - While unesterified cholesterol (C) is essential for remodeling neuronal plasma membranes, its role in certain neurodegenerative disorders remains poorly defined. Uptake of sterol from pericellular fluid requires processing that involves two lysosomal proteins, lysosomal acid lipase, which hydrolyzes C esters, and NPC1 (Niemann-Pick type C1). In systemic tissues, inactivation of either protein led to sterol accumulation and cell death, but in the brain, inactivation of only NPC1 caused C sequestration and neurodegeneration. When injected into the CNS of the npc1(-/-) mouse, 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), a compound known to prevent this C accumulation, diffused throughout the brain and was excreted with a t(½) of 6.5 h. This agent caused suppression of C synthesis, elevation of C esters, suppression of sterol regulatory-binding protein 2 (SREBP2) target genes, and activation of liver X receptor-controlled genes. These findings indicated that HP-beta-CD promoted movement of the sequestered C from lysosomes to the metabolically active pool of C in the cytosolic compartment of cells in the CNS. The ED(50) for this agent in the brain was ~0.5 mg/kg, and the therapeutic effect lasted >7 d. Continuous infusion of HP-beta-CD into the ventricular system of npc1(-/-) animals between 3 and 7 weeks of age normalized the biochemical abnormalities and completely prevented the expected neurodegeneration. These studies support the concept that neurons continuously acquire C from interstitial fluid to permit plasma membrane turnover and remodeling. Inactivation of NPC1 leads to lysosomal C sequestration and neurodegeneration, but this is prevented by the continuous, direct administration of HP-beta-CD into the CNS. PMID- 21697389 TI - Stimulus selectivity and spatial coherence of gamma components of the local field potential. AB - The gamma frequencies of the local field potential (LFP) provide a physiological correlate for numerous perceptual and cognitive phenomena and have been proposed to play a role in cortical function. Understanding the spatial extent of gamma and its relationship to spiking activity is critical for interpreting this signal and elucidating its function, but previous studies have provided widely disparate views of these properties. We addressed these issues by simultaneously recording LFPs and spiking activity using microelectrode arrays implanted in the primary visual cortex of macaque monkeys. We find that the spatial extent of gamma and its relationship to local spiking activity is stimulus dependent. Small gratings, and those masked with noise, induce a broadband increase in spectral power. This signal is tuned similarly to spiking activity and has limited spatial coherence. Large gratings, however, induce a gamma rhythm characterized by a distinctive spectral "bump," which is coherent across widely separated sites. This signal is well tuned, but its stimulus preference is similar across millimeters of cortex. The preference of this global gamma rhythm is sensitive to adaptation, in a manner consistent with its magnifying a bias in the neuronal representation of visual stimuli. Gamma thus arises from two sources that reflect different spatial scales of neural ensemble activity. Our results show that there is not a single, fixed ensemble contributing to gamma and that the selectivity of gamma cannot be used to infer its spatial extent. PMID- 21697391 TI - Modular realignment of entorhinal grid cell activity as a basis for hippocampal remapping. AB - Hippocampal place fields, the local regions of activity recorded from place cells in exploring rodents, can undergo large changes in relative location during remapping. This process would appear to require some form of modulated global input. Grid-cell responses recorded from layer II of medial entorhinal cortex in rats have been observed to realign concurrently with hippocampal remapping, making them a candidate input source. However, this realignment occurs coherently across colocalized ensembles of grid cells (Fyhn et al., 2007). The hypothesized entorhinal contribution to remapping depends on whether this coherence extends to all grid cells, which is currently unknown. We study whether dividing grid cells into small numbers of independently realigning modules can both account for this localized coherence and allow for hippocampal remapping. To do this, we construct a model in which place-cell responses arise from network competition mediated by global inhibition. We show that these simulated responses approximate the sparsity and spatial specificity of hippocampal activity while fully representing a virtual environment without learning. Place-field locations and the set of active place cells in one environment can be independently rearranged by changes to the underlying grid-cell inputs. We introduce new measures of remapping to assess the effectiveness of grid-cell modularity and to compare shift realignments with other geometric transformations of grid-cell responses. Complete hippocampal remapping is possible with a small number of shifting grid modules, indicating that entorhinal realignment may be able to generate place field randomization despite substantial coherence. PMID- 21697393 TI - Retraction. Synaptic metaplasticity through NMDA receptor lateral diffusion. PMID- 21697392 TI - The outermost region of the developing cortical plate is crucial for both the switch of the radial migration mode and the Dab1-dependent "inside-out" lamination in the neocortex. AB - Mammalian neocortex has a laminated structure that develops in a birth-date dependent "inside-out" pattern. This layered structure is established by neuronal migration with sequential changes of the migratory mode regulated by several signaling cascades, including the Reelin-Disabled homolog 1 (Dab1) pathway. Although the importance of "locomotion," the major migratory mode, has been well established, the physiological significance of the mode change from locomotion to "terminal translocation," the final migratory mode, is unknown. In this study, we found that the outermost region of the mouse cortical plate has several histologically distinct features and named this region the primitive cortical zone (PCZ). Time-lapse analyses revealed that "locomoting" neurons paused transiently just beneath the PCZ before migrating into it by "terminal translocation." Furthermore, whereas Dab1-knockdown (KD) neurons could reach beneath the PCZ, they failed to enter the PCZ, suggesting that the Dab1-dependent terminal translocation is necessary for entry of the neurons into the PCZ. Importantly, sequential in utero electroporation experiments directly revealed that failure of the Dab1-dependent terminal translocation resulted in disruption of the inside-out alignment within the PCZ and that this disrupted pattern was still preserved in the mature cortex. Conversely, Dab1-KD locomoting neurons could pass by both wild-type and Dab1-KD predecessors beneath the PCZ. Our data indicate that the PCZ is a unique environment, passage of neurons through which involves molecularly and behaviorally different migratory mechanisms, and that the migratory mode change from locomotion to terminal translocation just beneath the PCZ is critical for the Dab1-dependent inside-out lamination in the mature cortex. PMID- 21697396 TI - Linear chain PEGylated recombinant Bacillus thiaminolyticus thiaminase I enzyme has growth inhibitory activity against lymphoid leukemia cell lines. AB - Cancer cells acquire abnormalities in energy metabolism, collectively known as the Warburg effect, affecting substrate availability of thiamine-dependent enzymes. To investigate a strategy to exploit abnormal cancer-associated metabolism related to thiamine, we tested the cytotoxicity of native Bacillus thiaminolyticus thiaminase I enzyme, which digests thiamine, in the NCI60 cell line drug cytotoxicity screening program and found that leukemia cell lines were among the most sensitive to thiaminase I. We obtained additional lymphoid leukemia cell lines and confirmed that native thiaminase I and linear chain PEGylated thiaminase I enzyme (LCPTE) have cytotoxic activity in these cell lines. In addition, the IC(50) of 3 of the 5 leukemia cell lines (Reh, RS4, and Jurkat) were at least 1,000-fold more sensitive than Molt-4 cells, which in turn, were among the most sensitive in the NCI60 panel. The 3 LCPTE-sensitive leukemia cell lines were also sensitive to removal of thiamine from the medium, thus suggesting the mechanism of action of LCPTE involves extracellular thiamine starvation. Surprisingly, rapamycin showed a protective effect against LCPTE toxicity in the 3 LCPTE-sensitive cell lines but not in the other 2 cell lines, suggesting involvement of an mTOR-dependent pathway. Immunoblot analysis of the LCPTE-sensitive cell lines after LCPTE exposure revealed changes in mTOR pathway phosphorylation. Nude mice bearing RS4 leukemia xenografts showed both tumor growth delay and prolonged survival after a single dose of LCPTE. Therefore, disruption of thiamine-dependent metabolism may be a novel therapeutic approach to target altered energy metabolism in leukemia and other cancers. PMID- 21697394 TI - Histone deacetylase cytoplasmic trapping by a novel fluorescent HDAC inhibitor. AB - Inhibitors of histone deacetylases (HDAC) are an important emerging class of drugs for the treatment of cancers. HDAC inhibitors are currently under evaluation in clinical trials as single agents and as sensitizers in combinations with chemotherapies and radiation therapy. Although these drugs have important effects on cancer cell growth and functions, the mechanisms underlying HDAC inhibitor activities remain to be fully defined. By using rational drug design, compound 2, a fluorescent class II HDAC targeting inhibitor, was synthesized and observed to accumulate in the cytoplasmic compartments of treated cells, but not in the nuclei. Furthermore, immunostaining of inhibitor exposed cells for HDAC4 showed accumulation of this enzyme in the cytoplasmic compartment with concomitant increased acetylation of tubulin and nuclear histones. These observations support a mechanism by which nuclear histone acetylation is increased as a result of HDAC4 trapping and sequestration in the cytoplasm after binding to compound 2. The HDAC inhibitor offers potential as a novel theranostic agent, combining diagnostic and therapeutic properties in the same molecule. PMID- 21697397 TI - Transformation-dependent silencing of tumor-selective apoptosis-inducing TRAIL by DNA hypermethylation is antagonized by decitabine. AB - TNF-related apoptosis-inducing ligand (TRAIL) kills tumor cells selectively. We asked how emerging tumor cells escape elimination by TRAIL and how tumor-specific killing by TRAIL could then be restored. We found that TRAIL expression is consistently downregulated in HRAS(G12V)-transformed cells in stepwise tumorigenesis models derived from four different tissues due to DNA hypermethylation of CpG clusters within the TRAIL promoter. Decitabine de silenced TRAIL, which remained inducible by interferon, while induction of TRAIL by blocking the HRAS(G12V)-activated mitogen-activated protein kinase pathway was subordinated to epigenetic silencing. Decitabine induced apoptosis through upregulation of endogenous TRAIL in cooperation with favorable regulation of key players acting in TRAIL-mediated apoptosis. Apoptosis induction by exogenously added TRAIL was largely increased by decitabine. In vivo treatment of xenografted human HRAS(G12V)-transformed human epithelial kidney or syngenic mice tumors by decitabine blocked tumor growth induced TRAIL expression and apoptosis. Our results emphasize the potential of decitabine to enhance TRAIL-induced apoptosis in tumors and thus provide a rationale for combination therapies with decitabine to increase tumor-selective apoptosis. PMID- 21697395 TI - Discovery of a small molecule targeting IRA2 deletion in budding yeast and neurofibromin loss in malignant peripheral nerve sheath tumor cells. AB - Malignant peripheral nerve sheath tumor (MPNST) is a life-threatening complication of neurofibromatosis type 1 (NF1). NF1 is caused by mutation in the gene encoding neurofibromin, a negative regulator of Ras signaling. There are no effective pharmacologic therapies for MPNST. To identify new therapeutic approaches targeting this dangerous malignancy, we developed assays in NF1(+/+) and NF1(-/-) MPNST cell lines and in budding yeast lacking the NF1 homologue IRA2 (ira2Delta). Here, we describe UC1, a small molecule that targets NF1(-/-) cell lines and ira2Delta budding yeast. By using yeast genetics, we identified NAB3 as a high-copy suppressor of UC1 sensitivity. NAB3 encodes an RNA binding protein that associates with the C-terminal domain of RNA Pol II and plays a role in the termination of nonpolyadenylated RNA transcripts. Strains with deletion of IRA2 are sensitive to genetic inactivation of NAB3, suggesting an interaction between Ras signaling and Nab3-dependent transcript termination. This work identifies a lead compound and a possible target pathway for NF1-associated MPNST, and shows a novel model system approach to identify and validate target pathways for cancer cells in which NF1 loss drives tumor formation. PMID- 21697398 TI - Evolution of foot and ankle specialist. PMID- 21697399 TI - Hammer toe, mallet toe, and claw toe. PMID- 21697403 TI - eComment: Hemodynamic monitoring with LiDCOplus system in the patients supported by isolated right ventricular assist device. PMID- 21697401 TI - eComment: About the localization techniques of solitary pulmonary nodules. PMID- 21697402 TI - eComment: Multimodal approach for blood conservation in cardiac surgery and the importance of avoiding hemodilution. PMID- 21697405 TI - eComment: Tricuspid valve replacement with vacuum-assisted venous drainage. PMID- 21697404 TI - eComment: Trans-pericardial extra-anatomic aortic bypass for coarctation of the aorta. PMID- 21697406 TI - Spino-renal fistula due to gunshot injury. AB - A 22-year-old female patient was treated for spino-renal fistula as a result of a high-velocity gunshot injury to her abdomen. The patient presented with meningeal signs, a headache and right monoparesis. A CT scan of her abdomen revealed a leak of contrast from the right kidney into the perirenal space and tracking further into the thecal sac. An MRI scan showed a stable fracture of L3 with slight compression of the thecal sac and features of cord contusion caused by the shockwave of the bullet. To the best of our knowledge a spino-renal fistula of traumatic origin has not previously been reported in the English language literature. PMID- 21697408 TI - Variant ventral intrahepatic course of inferior vena cava: volume-rendering and maximum intensity projection CT findings. AB - Anatomically, the inferior vena cava (IVC) courses through the liver posteriorly and drains into the right atrium. We describe an extremely rare case of the anterior intrahepatic course of the IVC that drained into the right atrium seen on a CT scan of a healthy 26-year-old female who presented to the emergency room with abdominal pain. The anterior intrahepatic segment was bridged to the posteroinferior portion of the IVC by an oblique segment. Associated renal and arterial anomalies were also observed in our patient. PMID- 21697407 TI - Nodular regenerative hyperplasia of the liver: coral atoll-like lesions on ultrasound are characteristic in predisposed patients. AB - Nodular regenerative hyperplasia (NRH) is an uncommon liver disease characterised histologically by numerous small hyperplastic nodules that are not separated by fibrotic tissue. It is thought to be the result of obliterative vasculopathy, and it has been associated with chronic use of medications, toxic substances and a wide variety of systemic diseases. Imaging diagnosis of early-stage NRH remains problematic. The nodules are rarely discerned and their appearance and behaviour before and after contrast medium administration are heterogeneous and not specific. A review of the literature shows that ultrasound has succeeded on occasion in revealing small focal liver lesions in patients with NRH. To our knowledge, there has been no published data on the performance in this setting of last-generation ultrasound scanners and techniques such as contrast-enhanced ultrasound (CEUS). The question is an important one because abdominal ultrasound is widely used as a first-line imaging technique for the evaluation of liver disease, and this makes it particularly suitable as a potential tool for the early diagnosis of NRH. Owing to the prolonged subclinical period and the limited help provided by imaging, the diagnosis in vivo of NRH is currently frequently missed, and it is still made exclusively on the basis of liver biopsy. In conclusion, this report describes 4 cases of biopsy-proven NRH that have been diagnosed over the past 2 years by our group. All were characterised by known comorbidities that confer a predisposition to NRH and by a peculiar parenchymal ultrasound pattern that we refer to as the "atoll sign". PMID- 21697409 TI - Isolated intracranial Rosai-Dorfman disease mimicking meningioma in a child: a case report and review of the literature. AB - We report the first case of extensive involvement of isolated intracranial Rosai Dorfman's disease (RDD) in a child. Our case is unique because it presents with involvement of the middle cranial fossa, cavernous sinus, pituitary gland, orbit, ethmoid and sphenoid sinuses. Previous cases of intracranial RDD in children have reported separate involvement of cavernous sinus, suprasellar region, and frontal and petroclival regions. Involvement of the pituitary gland has so far not been reported. A 14-year-old male presented with a medical history of loss of vision, raised erythrocyte sedimentation rate (ESR), and abnormal prolactin and cortisol levels. Radiologically the diagnosis was meningioma. The histopathological diagnosis was RDD with emperipolesis and S-100 positivity. RDD is a histiocytic proliferation of unknown aetiology, which commonly affects lymph nodes. Uncommonly it involves the extranodal sites and rarely the central nervous system (CNS). 80 cases of RDD involving CNS have been reported in the literature, and only 5 were in children. Although the definitive diagnosis of RDD disease is based on the histopathology report, it should be included in the differentials of a lesion mimicking meningioma especially in children. PMID- 21697411 TI - Haemorrhagic low-grade fibromyxoid sarcoma: MR findings in two young women. AB - Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue sarcoma characterised by a deceptively bland histological appearance and a paradoxically aggressive behaviour. LGFMS usually presents in young-to-middle-aged adults as a painless, slow-growing mass with the potential for local recurrence and metastasis despite low-grade histology. Several case reports have described variable MR findings of LGFMS without haemorrhage or necrosis. We report here on the MR findings in two young women with haemorrhagic LGFMS in the thigh. PMID- 21697410 TI - Identification of the primary tumour with the help of diffusion-weighted MRI in a patient with autosomal dominant polycystic kidney disease and metastatic renal cell carcinoma. AB - We report the case of a 47-year-old patient with autosomal dominant polycystic kidney disease, who became symptomatic owing to a painful metastasis of a renal cell carcinoma. Abdominal sonography, multiphase CT and MRI were performed in order to localise and resect the primary tumour, but its identification was severely hampered owing to multiple renal cysts. In addition to standard MRI protocol, a spin-echo, single-shot echo planar diffusion-weighted imaging sequence was performed. The mean apparent diffusion coefficient (ADC) of renal cysts was 2.66+/-0.12 * 10(-3) mm(2) s(-1), 1.76+/-0.19 * 10(-3) mm(2) s(-1) of renal parenchyma in and 1.26+/-0.18 * 10(-3) mm(2) s(-1) of a suspicious soft tissue mass at the midsection of the right kidney, indicating an area of higher cellularity. This value was significant lower than the ADC obtained for renal parenchyma (p<0.0001). Right-sided nephrectomy was performed and the pathological diagnosis of the suspicious lesion was clear cell renal carcinoma. PMID- 21697414 TI - Normal variants of the accessory hemiazygos vein. AB - This short communication describes two normal variants of the accessory hemiazygous vein in a 15-year-old female. The article demonstrates that knowledge of the aberrant venous anatomy and the collateral pathway is important for the practising radiologist. PMID- 21697413 TI - Distribution of brain metastases: implications for non-uniform dose prescriptions. AB - OBJECTIVES: The aim of this study was to determine the disease-specific distribution of brain metastases and, using radiobiological modelling, estimate how these anatomical tendencies might be exploited when delivering prophylactic whole-brain radiotherapy for small cell lung cancer in complete remission. METHODS: Disease-specific brain metastasis atlases were created by mapping brain metastases to a standard image set from a database of patients who were to receive external beam radiation therapy. The specific diseases investigated included lung (both small cell and non-small cell), breast, renal and gynaecological cancers as well as melanoma. Radiobiological modelling was used to estimate how much improvement, in terms of the metastasis-free rate at 3 years, might be possible with non-uniform dose distributions if there are spatial biases in the incidence of micrometastases from small cell lung cancer. RESULTS: For lung and breast cancer, there was an increased probability of cerebellar metastases compared with what would be predicted based solely on brain volume. This trend was not evident for renal cancer, gynaecological malignancies or melanoma. CONCLUSION: Radiobiological models suggest that if there is a non uniform distribution of microscopic brain metastases in patients with small cell lung cancer, higher population-based metastasis-free rates might be achievable with non-uniform irradiation compared with the same integral whole-brain dose delivered as a uniform prescription. PMID- 21697415 TI - MRI in lung cancer: a pictorial essay. AB - Imaging studies play a critical role in the diagnosis and staging of lung cancer. CT and 18-fluorodeoxyglucose positron emission tomography CT (PET/CT) are widely and routinely used for staging and assessment of treatment response. Many radiologists still use MRI only for the assessment of superior sulcus tumours, and in cases where invasion of the spinal cord canal is suspected. MRI can detect and stage lung cancer, and this method could be an excellent alternative to CT or PET/CT in the investigation of lung malignancies and other diseases. This pictorial essay discusses the use of MRI in the investigation of lung cancer. PMID- 21697412 TI - High-resolution CT of complications of idiopathic fibrotic lung disease. AB - Idiopathic pulmonary fibrosis (IPF) has a more variable clinical course than has been traditionally recognised. Many patients will remain stable over time while others experience relatively rapid deterioration. The prognosis and clinical course of patients with other fibrosing lung diseases is also variable. A number of conditions may complicate the clinical course of the idiopathic fibrosing lung diseases, which results in morbidity and mortality, but also represents potentially treatable causes of worsening symptoms. Infection and malignancy have a long-recognised association with IPF while other conditions, particularly pulmonary hypertension and acute exacerbation of IPF, are being increasingly recognised in this patient population. Many of these patients have serial high resolution CT (HRCT) examinations that may demonstrate one or more of these supervening conditions. In this article we review the more common conditions that may complicate the course of idiopathic fibrosing lung disease with an emphasis on the HRCT appearance, which the reporting radiologist should be aware of. PMID- 21697416 TI - Anterior knee pain. PMID- 21697417 TI - Letter to the editor: Post-thoracocentesis chest radiograph - is it time for a change in practice? PMID- 21697418 TI - Letter to the editor: Diagnostic procedures and case related information in ICM induced hypersensitivity. PMID- 21697421 TI - Movements of Rana catesbeiana tadpoles in weak current flows resemble a directed random walk. AB - Current flow is an important biological stimulus for larval anuran amphibians, but little is known about how it is perceived. We quantified behavioral responses to controlled water flow in the bullfrog tadpole (Rana catesbeiana) at developmental stages prior to metamorphic climax, and examined the contribution of a functioning lateral line system to these behaviors. Tadpoles at these developmental stages show a significant preference for the sides and bottom of a flow tank. In response to water flow at three different rates, they exhibit a significant, time-dependent tendency to move downstream, away from the source of the flow, and to remain in areas where flow is minimized. The consistency of these behaviors at all tested flow rates suggests that the animals are not simply passively pushed by the current; instead, they actively swim away from the current source. Tadpoles do not exhibit positive rheotaxis towards the source of the flow at any flow rate but as a group are randomly oriented. Treatment with cobalt chloride, a known blocker of superficial neuromast function, significantly reduces the tendency to move downstream, but does not alter the preference for the sides and bottom of the tank. Tadpoles' movements under flow are consistent with a model of locomotion based on a directed random walk. PMID- 21697423 TI - Plasma-accessible carbonic anhydrase at the tissue of a teleost fish may greatly enhance oxygen delivery: in vitro evidence in rainbow trout, Oncorhynchus mykiss. AB - During a generalized acidosis in rainbow trout, catecholamines are released into the blood, activating red blood cell (RBC) Na(+)/H(+) exchange (betaNHE), thus protecting RBC intracellular pH (pH(i)) and subsequent O(2) binding at the gill. Because of the presence of a Root effect (a reduction in oxygen carrying capacity of the blood with a reduction in pH), the latter could otherwise be impaired. However, plasma-accessible carbonic anhydrase (CA) at the tissues (and absence at the gills) may result in selective short-circuiting of RBC betaNHE pH regulation. This would acidify the RBCs and greatly enhance O(2) delivery by exploitation of the combined Bohr-Root effect, a mechanism not previously proposed. As proof-of principle, an in vitro closed system was developed to continuously monitor extracellular pH (pH(e)) and O(2) tension (P(O(2))) of rainbow trout blood. In this closed system, adding CA to acidified, adrenergically stimulated RBCs short circuited betaNHE pH regulation, resulting in an increase in P(O(2)) by >30 mmHg, depending on the starting Hb-O(2) saturation and degree of initial acidification. Interestingly, in the absence of adrenergic stimulation, addition of CA still elevated P(O(2)), albeit to a lesser extent, a response that was absent during general NHE inhibition. If plasma-accessible CA-mediated short-circuiting is operational in vivo, the combined Bohr-Root effect system unique to teleost fishes could markedly enhance tissue O(2) delivery far in excess of that in vertebrates possessing a Bohr effect alone and may lead to insights about the early evolution of the Root effect. PMID- 21697422 TI - Glucocorticoid and mineralocorticoid receptors regulate paracellular permeability in a primary cultured gill epithelium. AB - The role of corticosteroid receptors (CRs) in the regulation of gill permeability was examined using a primary cultured trout gill epithelium. The epithelium expressed both glucocorticoid receptors (GR1 and GR2) and a mineralocorticoid receptor (MR), and cortisol treatment significantly increased transepithelial resistance (TER) and decreased paracellular [(3)H]PEG-4000 flux. Epithelial permeability was unaffected by deoxycorticosterone or aldosterone. The GR antagonist RU486 as well as MR antagonists spironolactone and RU26752 significantly reduced, but did not completely block, the effects of cortisol. The MR antagonist eplerenone was without effect. Only RU486 + spironolactone or RU486 + RU26752 treatment completely suppressed the effects of cortisol. On its own, RU486 had cortisol-like effects which could be blocked by spironolactone, suggesting that although RU486 is a GR antagonist, in this system it may also have agonistic properties that are mediated through the MR. The GR agonist dexamethasone increased TER and reduced [(3)H]PEG-4000 flux across cultured epithelia and was unaffected by MR antagonists. Therefore, alterations in transcript abundance of select tight junction (TJ) proteins were examined in response to cortisol, dexamethasone (a GR agonist) and RU486 (as a MR agonist). Occludin and claudin-7, -8d, -12 and -31 mRNA were significantly elevated in response to cortisol, dexamethasone or RU486 treatment. Claudin-3a mRNA was significantly elevated in response to cortisol or dexamethasone only, and claudin 28b and -30 mRNA were significantly altered following cortisol or RU486 treatment only. The data support a role for the GRs and MR in regulating gill permeability and suggest that TJ proteins are responsive to cortisol through both or individual CR types. PMID- 21697424 TI - Temperature-induced maternal effects and environmental predictability. AB - Maternal effects could influence the persistence of species under environmental change, but the adaptive significance of many empirically estimated maternal effects remains unclear. Inferences about the adaptive significance of maternal effects depend on the correlation between maternal and offspring environments, the relative importance of frequency- or density-dependent selection and whether absolute or relative fitness measures are used. Here, we combine the monitoring of the environment over time with a factorial experiment where we manipulated both the maternal and offspring environment in a marine bryozoan (Bugula neritina). We focused on temperature as our environmental variable as temperature commonly varies over short time scales in nature. We found that offspring from mothers kept in warmer water were smaller and more variable in size, but had increased dispersal potential and higher metamorphic success than offspring from mothers kept in cooler water. Our results suggest that, under frequency- or density-independent selection, mothers that experienced higher temperatures compared with lower temperatures were favoured. Under frequency- or density dependent selection, there were indications that mothers that experienced higher temperatures would be favoured only if their offspring encountered similar (warmer) temperatures, though these results were not statistically significant. Analysis of time series data on temperature in the field shows that the maternal thermal environment is a good predictor of the temperatures offspring are likely to experience early in life. We suggest that future studies on maternal effects estimate environmental predictability and present both absolute and relative estimates of maternal fitness within each offspring environment. PMID- 21697425 TI - Transepithelial D-glucose and D-fructose transport across the American lobster, Homarus americanus, intestine. AB - Transepithelial transport of dietary D-glucose and d-fructose was examined in the lobster Homarus americanus intestine using D-[(3)H]glucose and D-[(3)H]fructose. Lobster intestines were mounted in a perfusion chamber to determine transepithelial mucosal to serosal (MS) and serosal to mucosal (SM) transport mechanisms of glucose and fructose. Both MS glucose and fructose transport, as functions of luminal sugar concentration, increased in a hyperbolic manner, suggesting the presence of mucosal transport proteins. Phloridizin inhibited the MS flux of glucose, but not that of fructose, suggesting the presence of a sodium dependent (SGLT1)-like glucose co-transporter. Immunohistochemical analysis, using a goat anti-rabbit GLUT5 polyclonal antibody, revealed the localization of a brush border GLUT5-like fructose transport protein. MS fructose transport was decreased in the presence of mucosal phloretin in warm spring/summer animals, but the same effect was not observed in cold autumn/winter animals, suggesting a seasonal regulation of sugar transporters. Mucosal phloretin had no effect on MS glucose transport. Both SM glucose and SM fructose transport were decreased in the presence of increasing concentrations of serosal phloretin, providing evidence for the presence of a shared serosal GLUT2 transport protein for the two sugars. The transport of d-glucose and d-fructose across lobster intestine is similar to sugar uptake in mammalian intestine, suggesting evolutionarily conserved absorption processes for these solutes. PMID- 21697428 TI - Jumping mechanisms and performance of snow fleas (Mecoptera, Boreidae). AB - Flightless snow fleas (snow scorpion flies, Mecoptera, Boreidae) live as adults during northern hemisphere winters, often jumping and walking on the surface of snow. Their jumping mechanisms and performance were analysed with high speed imaging. Jumps were propelled by simultaneous movements of both the middle and hind pairs of legs, as judged by the 0.2 ms resolution afforded by image rates of 5000 frames s(-1). The middle legs of males represent 140% and the hindlegs 187% of the body length (3.4 mm), and the ratio of leg lengths is 1:1.3:1.7 (front:middle:hind). In preparation for a jump the middle legs and hindlegs were rotated forwards at their coxal joints with the fused mesothorax and metathorax. The first propulsive movement of a jump was the rotation of the trochantera about the coxae, powered by large depressor muscles within the thorax. The acceleration time was 6.6 ms. The fastest jump by a male had a take-off velocity of 1 m s(-1), which required 1.1 MUJ of energy and a power output of 0.18 mW, and exerted a force about 16 times its body weight. Jump distances of about 100 mm were unaffected by temperature. This, and the power per mass of muscle requirement of 740 W kg(-1), suggests that a catapult mechanism is used. The elastic protein resilin was revealed in four pads at the articulation of the wing hinge with the dorsal head of the pleural ridge of each middle leg and hindleg. By contrast, fleas, which use just their hindlegs for jumping, have only two pads of resilin. This, therefore, provides a functional reference point for considerations about the phylogenetic relationships between snow fleas and true fleas. PMID- 21697427 TI - The broad range of contractile behaviour of the avian pectoralis: functional and evolutionary implications. AB - Wing-assisted incline running (WAIR) in birds combines the use of the wings and hindlimbs to ascend otherwise insurmountable obstacles. It is a means of escape in precocial birds before they are able to fly, and it is used by a variety of juvenile and adult birds as an alternative to flight for exploiting complex three dimensional environments at the interface of the ground and air. WAIR and controlled flapping descent (CFD) are the bases of the ontogenetic-transitional wing hypothesis, wherein WAIR and CFD are proposed to be extant biomechanical analogs for incremental adaptive stages in the evolutionary origin of flight. A primary assumption of the hypothesis is that work and power requirements from the primary downstroke muscle, the pectoralis, incrementally increase from shallow- to steep-angled terrestrial locomotion, and between terrestrial and aerial locomotion. To test this assumption, we measured in vivo force, electromyographic (EMG) activity and length change in the pectoralis of pigeons (Columba livia) as the birds engaged in shallow and steep WAIR (65 and 85 deg, respectively) and in three modes of slow flight immediately following take-off: ascending at 80 deg, level and descending at -60 deg. Mean EMG amplitude, muscle stress, strain, work and power were minimal during shallow WAIR and increased stepwise from steep WAIR to descending flight and level flight to reach the highest levels during ascending flight. Relative to resting length of the pectoralis, fractional lengthening (maximum muscle strain) was similar among behaviors, but fractional shortening (minimum muscle strain) was absent during WAIR such that the pectoralis did not shorten to less than the resting length. These data dramatically extend the known range of in vivo contractile behavior for the pectoralis in birds. We conclude that WAIR remains a useful extant model for the evolutionary transition from terrestrial to aerial locomotion in birds because work and power requirements from the pectoralis increase incrementally during WAIR and from WAIR to flight. PMID- 21697426 TI - Variation in metabolic rate of Anopheles gambiae and A. arabiensis in a Sahelian village. AB - In the Sahel, the Anopheles gambiae complex consists of Anopheles arabiensis and the M and S molecular forms of A. gambiae sensu stricto. However, the composition of these malaria vectors varies spatially and temporally throughout the region and is thought to be linked to environmental factors such as rainfall, larval site characteristics and duration of the dry season. To examine possible physiological divergence between these taxa, we measured metabolic rates of mosquitoes during the wet season in a Sahelian village in Mali. To our knowledge, this study provides the first measurements of metabolic rates of A. gambiae and A. arabiensis in the field. The mean metabolic rate of A. arabiensis was higher than that of M-form A. gambiae when accounting for the effects of female gonotrophic status, temperature and flight activity. However, after accounting for their difference in body size, no significant difference in metabolic rate was found between these two species (whilst all other factors were found to be significant). Thus, body size may be a key character that has diverged in response to ecological differences between these two species. Alternatively, these species may display additional differences in metabolic rate only during the dry season. Overall, our results indicate that changes in behavior and feeding activity provide an effective mechanism for mosquitoes to reduce their metabolic rate, and provide insight into the possible strategies employed by aestivating individuals during the dry season. We hypothesize that female mosquitoes switch to sugar feeding while in dormancy because of elevated metabolism associated with blood digestion. PMID- 21697429 TI - Anterior lateral eyes of Lycosa tarantula (Araneae: Lycosidae) are used during orientation to detect changes in the visual structure of the substratum. AB - Previous studies in the wolf spider Lycosa tarantula (Linnaeus 1758) have shown that homing is carried out by path integration and that, in the absence of information relative to the sun's position or any pattern of polarized light, L. tarantula obtains information as to the angle it must turn to home through the anterior lateral eyes (ALEs). In the present study, spiders were trained to walk over a black-and-white grating and afterwards tested either over a white substratum, the same substratum used for training or the same substratum rotated 90 deg (two groups: ALEs covered and only ALEs uncovered; they were tested first without their eyes covered and then with their eyes covered). The directional bearing was measured both in training and test conditions. Under the white or the same substratum in test conditions, the directional bearing had the same mean direction and a distribution similar to that of the training sessions. When the substratum was rotated 90 deg, the directional bearing had the same mean direction but the distribution was significantly different from that of the training sessions. Moreover, if ALEs were covered, spiders behaved as if the substratum had not been rotated and the directional bearing distribution was similar to that of the training sessions. But, if ALEs were the only eyes uncovered, spiders behaved as if no eyes were covered and directional bearing distribution was similar to that of the test condition. It is suggested that, when homing, L. tarantula uses both idiothetic information and visual information gathered through ALEs. These findings present the first evidence that spiders can use the visual structure of the substratum to return home. PMID- 21697430 TI - Building a robotic link between muscle dynamics and hydrodynamics. AB - This study used a novel feedback approach to control a robotic foot using force and length signals transmitted from an isolated Xenopus laevis frog muscle. The foot's environment (inertial versus hydrodynamic), gearing (outlever/inlever) and size were changed to alter the muscle's load. Upon nerve stimulation (250 Hz, 80 ms train duration), variation in loading generated a range of muscle stress (19.8+/-5.3 to 66.0+/-22.5 kPa), work (1.89+/-0.67 to 6.87+/-2.96 J kg(-1) muscle) and power (12.4+/-7.5 to 64.8+/-28.3 W kg(-1) muscle; mean +/- s.d., N=6 frogs). Inertial versus hydrodynamic loading dramatically shifted contractile dynamics. With the foot in water, the muscle generated ~30% higher force, yet shortened slower, producing lower power than inertial loading. Power increased in air from 22.6+/-5.8 to 63.6+/-27.2 W kg(-1) muscle in response to doubling the gear ratio, but did not increase in water. Surprisingly, altering foot size diminished muscle performance in water, causing power to drop significantly from 41.6+/-11.1 to 25.1+/-8.0 W kg(-1) muscle as foot area was doubled. Thus, morphological modifications influenced muscle dynamics independently of neural control; however, changes in loading environment and gearing affected contractile output more strongly than changes in foot size. Confirming recent theory, these findings demonstrate how muscle contractile output can be modulated solely by altering the mechanical environment. PMID- 21697431 TI - Hyperbaric computed tomographic measurement of lung compression in seals and dolphins. AB - Lung compression of vertebrates as they dive poses anatomical and physiological challenges. There has been little direct observation of this. A harbor and a gray seal, a common dolphin and a harbor porpoise were each imaged post mortem under pressure using a radiolucent, fiberglass, water-filled pressure vessel rated to a depth equivalent of 170 m. The vessel was scanned using computed tomography (CT), and supported by a rail and counterweighted carriage magnetically linked to the CT table movement. As pressure increased, total buoyancy of the animals decreased and lung tissue CT attenuation increased, consistent with compression of air within the lower respiratory tract. Three-dimensional reconstructions of the external surface of the porpoise chest showed a marked contraction of the chest wall. Estimation of the volumes of different body compartments in the head and chest showed static values for all compartments except the lung, which showed a pressure-related compression. The depth of estimated lung compression ranged from 58 m in the gray seal with lungs inflated to 50% total lung capacity (TLC) to 133 m in the harbor porpoise with lungs at 100% TLC. These observations provide evidence for the possible behavior of gas within the chest of a live, diving mammal. The estimated depths of full compression of the lungs exceeds previous indirect estimates of the depth at which gas exchange ceases, and concurs with pulmonary shunt measurements. If these results are representative for living animals, they might suggest a potential for decompression sickness in diving mammals. PMID- 21697432 TI - A tale of three taxes: photo-gyro-gravitactic bioconvection. AB - The term bioconvection encapsulates the intricate patterns in concentration, due to hydrodynamic instabilities, that may arise in suspensions of non-neutrally buoyant, biased swimming microorganisms. The directional bias may be due to light (phototaxis), gravity (gravitaxis), a combination of viscous and gravitational torques (gyrotaxis) or other taxes. The aim of this study is to quantify experimentally the wavelength of the initial pattern to form from an initially well-mixed suspension of unicellular, swimming green algae as a function of concentration and illumination. As this is the first such study, it is necessary to develop a robust and meticulous methodology to achieve this end. The phototactic, gyrotactic and gravitactic alga Chlamydomonas augustae was employed, with various red or white light intensities from above or below, as the three not altogether separable taxes were probed. Whilst bioconvection was found to be unresponsive to changes in red light, intriguing trends were found for pattern wavelength as a function of white light intensity, depending critically on the orientation of the illumination. These trends are explored to help unravel the mechanisms. Furthermore, comparisons are made with theoretical predictions of initial wavelengths from a recent model of photo-gyrotaxis, encouragingly revealing good qualitative agreement. PMID- 21697433 TI - Audiogram of a stranded Blainville's beaked whale (Mesoplodon densirostris) measured using auditory evoked potentials. AB - Quantifying and understanding the impact of anthropogenic sound on marine mammals has been the focus of many researchers both in laboratory settings as well as in the field. This study presents the audiogram of a sub-adult Blainville's beaked whale that stranded in Hawaii. The hearing measurements were conducted using the non-invasive auditory brainstem response technique. A total of 11 sinusoidally amplitude modulated tones were tested ranging from 5.6 to 160 kHz. The audiogram data indicated that the region of best hearing was found between 40 and 50 kHz with thresholds below 50 dB. This frequency range partially overlaps with the frequency modulated upsweep that Blainville's beaked whales have been reported to use during echolocation. These results match the frequency range obtained from the hearing measurements of a Gervais' beaked whale previously tested using contact acoustic stimulation and emphasize the importance of obtaining rapid hearing measurements on live stranded animals to improve the understanding of poorly known species. PMID- 21697434 TI - How do tiger moths jam bat sonar? AB - The tiger moth Bertholdia trigona is the only animal in nature known to defend itself by jamming the sonar of its predators - bats. In this study we analyzed the three-dimensional flight paths and echolocation behavior of big brown bats (Eptesicus fuscus) attacking B. trigona in a flight room over seven consecutive nights to determine the acoustic mechanism of the sonar-jamming defense. Three mechanisms have been proposed: (1) the phantom echo hypothesis, which states that bats misinterpret moth clicks as echoes; (2) the ranging interference hypothesis, which states that moth clicks degrade the bats' precision in determining target distance; and (3) the masking hypothesis, which states that moth clicks mask the moth echoes entirely, making the moth temporarily invisible. On nights one and two of the experiment, the bats appeared startled by the clicks; however, on nights three through seven, the bats frequently missed their prey by a distance predicted by the ranging interference hypothesis (~15-20 cm). Three-dimensional simulations show that bats did not avoid phantom targets, and the bats' ability to track clicking prey contradicts the predictions of the masking hypothesis. The moth clicks also forced the bats to reverse their stereotyped pattern of echolocation emissions during attack, even while bats continued pursuit of the moths. This likely further hinders the bats' ability to track prey. These results have implications for the evolution of sonar jamming in tiger moths, and we suggest evolutionary pathways by which sonar jamming may have evolved from other tiger moth defense mechanisms. PMID- 21697435 TI - A model for group-size-dependent behaviour decisions in insects using an oscillator network. AB - Aggressive behaviour within pairs of male crickets leads to the establishment of a dominance hierarchy. Defeated males avoid their victorious adversaries for several hours before regaining aggressiveness. However, the defeated male does not regain aggressiveness if repeated fighting occurs. Loss of individual aggressiveness is limited by group size, which constrains the number of crickets fighting at any given time. Thus, group aggressive behaviour is modulated by an environmental factor, group size, which is ultimately determined by individual actions, i.e. fighting between two individuals. We developed a robot model to elucidate the mechanism of group-size-dependent behaviour alternation in crickets. The behaviour of individual robots was evaluated experimentally with mobile robots and the group behaviour of the robots was evaluated by computer simulation. We demonstrated that the group-size-dependent strategy in crickets could be generated by local interactions between robots, where the behaviour was governed by an oscillator and memory of the outcome of previous fights. PMID- 21697436 TI - Changes in gill H+-ATPase and Na+/K+-ATPase expression and activity during freshwater acclimation of Atlantic salmon (Salmo salar). AB - Few studies have examined changes in salmon gill ion transporter expression during the transition from seawater to freshwater, a pivotal moment in the salmonid life cycle. Seawater-acclimated Atlantic salmon were transferred to freshwater and blood and gill tissue were sampled over 30 days of acclimation. Salmon held in seawater had stable plasma osmolality and sodium and chloride levels throughout the experiment. Following freshwater exposure, plasma sodium and chloride levels and total osmolality decreased significantly before returning towards control levels over time. Gill H(+)-ATPase activity increased by more than 45% 14 days after exposure to freshwater, whereas H(+)-ATPase mRNA levels were not affected by the salinity change. Within 4 days of freshwater exposure, gill Na(+)/K(+)-ATPase activity increased ~43% over control levels, remaining significantly higher until the 30 day sampling group when it declined back to control levels. This increase in activity was associated with a more than 7-fold increase in Na(+)/K(+)-ATPase isoform alpha1a mRNA level and a ~60% decrease in Na(+)/K(+)-ATPase isoform beta1b mRNA level. The mRNA levels of Na(+)/K(+)-ATPase isoforms alpha1c and alpha3 did not change as a result of freshwater exposure. The time courses for mRNA expression of the small membrane protein FXYD 11 and the beta1-subunit were very similar, with levels increasing significantly 7 days following freshwater exposure before subsiding back to control levels at 30 days. Taken together, these data suggest an important role for Na(+)/K(+)-ATPase in freshwater acclimation in Atlantic salmon. PMID- 21697437 TI - Electrolocation based on tail-bending movements in weakly electric fish. AB - Weakly electric fish generate an electric field with their electric organ to navigate in space, detect objects and communicate with conspecifics. Several studies have examined how electric fish identify objects with their electroreceptors and use electric images for electrolocation. It has been argued that sensor readings from electroreceptors along the rostrocaudal line allow fish to determine the location of a target object. It is well known that the ratio between the maximal slope and the maximal amplitude of the electric image can allow the discrimination of object distances, regardless of object size and conductivity. In order to understand the temporal pattern of electric images, we used a model of electric field perturbation. Using the model, we suggest that the temporal pattern generated at an electrosensor during tail bending is another cue that can be used by the fish to discriminate object distances. The time course of electric sensor signals from a specific electroreceptor when tail-bending movements are applied can provide information about the lateral distance of a target object. PMID- 21697438 TI - Learning to breathe and sing: development of respiratory-vocal coordination in young songbirds. AB - How do animals with learned vocalizations coordinate vocal production with respiration? Songbirds such as the zebra finch learn their songs, beginning with highly variable babbling vocalizations known as subsong. After several weeks of practice, zebra finches are able to produce a precisely timed pattern of syllables and silences, precisely coordinated with expiratory and inspiratory pulses (Franz M, Goller F. J Neurobiol 51: 129-141, 2002). While respiration in adult song is well described, relatively little is known about respiratory patterns in subsong or about the processes by which respiratory and vocal patterns become coordinated. To address these questions, we recorded thoracic air sac pressure in juvenile zebra finches prior to the appearance of any consistent temporal or acoustic structure in their songs. We found that subsong contains brief inspiratory pulses (50 ms) alternating with longer pulses of sustained expiratory pressure (50-500 ms). In striking contrast to adult song, expiratory pulses often contained multiple (0-8) variably timed syllables separated by expiratory gaps and were only partially vocalized. During development, expiratory pulses became shorter and more stereotyped in duration with shorter and fewer nonvocalized parts. These developmental changes eventually resulted in the production of a single syllable per expiratory pulse and a single inspiratory pulse filling each gap, forming a coordinated sequence similar to that of adult song. To examine the role of forebrain song-control nuclei in the development of respiratory patterns, we performed pressure recordings before and after lesions of nucleus HVC (proper name) and found that this manipulation reverses the developmental trends in measures of the respiratory pattern. PMID- 21697439 TI - Nucleus accumbens shell, but not core, tracks motivational value of salt. AB - To appropriately respond to an affective stimulus, we must be able to track its value across changes in both the external and internal environment. The nucleus accumbens (NAc) is a critical component of reward circuitry, but recent work suggests that the NAc encodes aversion as well as reward. It remains unknown whether differential NAc activity reflects flexible changes in stimulus value when it is altered due to a change in physiological state. We measured the activity of individual NAc neurons when rats were given intraoral infusions of a hypertonic salt solution (0.45 M NaCl) across multiple sessions in which motivational state was manipulated. This normally nonpreferred taste was made rewarding via sodium depletion, which resulted in a strong motivation to seek out and consume salt. Recordings were made in three conditions: while sodium replete (REP), during acute sodium depletion (DEP), and following replenishment of salt to normal sodium balance (POST). We found that NAc neurons in the shell and core subregions responded differently across the three conditions. In the shell, we observed overall increases in NAc activity when the salt solution was nonpreferred (REP) but decreases when the salt solution was preferred (DEP). In the core, overall activity was significantly altered only after sodium balance was restored (POST). The results lend further support to the selective encoding of affective stimuli by the NAc and suggest that NAc shell is particularly involved in flexibly encoding stimulus value based on motivational state. PMID- 21697440 TI - Slow oscillating population activity in developing cortical networks: models and experimental results. AB - During early development neuronal networks express slow oscillating synchronized activity. The activity can be driven by several, not necessarily mutually exclusive, mechanisms. Each mechanism might have distinctive consequences for the phenomenology, formation, or sustainment of the early activity pattern. Here we study the emergence of the oscillatory activity in three computational models and multisite extracellular recordings that we obtained from developing cortical networks in vitro. The modeled networks consist of leaky integrate-and-fire neurons with adaptation coupled via depressing synapses, which were driven by neurons that are intrinsically bursting, intrinsically random spiking, or driven by spontaneous synaptic activity. The activity of model networks driven by intrinsically bursting cells best matched the phenomenology of 1-wk-old cultures, in which early oscillatory activity has just begun. Intrinsically bursting neurons were present in cortical cultures, but we found them only in those cultures that were younger than 3 wk in vitro. On the other hand, synaptically dependent random spiking was highest after 3 wk in vitro. In conclusion, model networks driven by intrinsically bursting cells show a good approximation of the emergent recurrent population activity in young networks, whereas the activity of more mature networks seems to be better explained by spontaneous synaptic activity. Moreover, similar to previous experimental observations, distributed stimulation in the model was more effective in suppressing population bursts than repeated stimulation of the same neurons. This observation can be explained by an effective depression of a larger fraction of synapses by distributed stimulation. PMID- 21697441 TI - Smooth changes in the EMG patterns during gait transitions under body weight unloading. AB - During gradual speed changes, humans exhibit a sudden discontinuous switch from walking to running at a specific speed, and it has been suggested that different gaits may be associated with different functioning of neuronal networks. In this study we recorded the EMG activity of leg muscles at slow increments and decrements in treadmill belt speed and at different levels of body weight unloading. In contrast to normal walking at 1 g, at lower levels of simulated gravity (<0.4 g) the transition between walking and running was generally gradual, without systematic abrupt changes in either intensity or timing of EMG patterns. This phenomenon depended to a limited extent on the gravity simulation technique, although the exact level of the appearance of smooth transitions (0.4 0.6 g) tended to be lower for the vertical than for the tilted body weight support system. Furthermore, simulations performed with a half-center oscillator neuromechanical model showed that the abruptness of motor patterns at gait transitions at 1 g could be predicted from the distinct parameters anchored already in the normal range of walking and running speeds, whereas at low gravity levels the parameters of the model were similar for the two human gaits. A lack of discontinuous changes in the pattern of speed-dependent locomotor characteristics in a hypogravity environment is consistent with the idea of a continuous shift in the state of a given set of central pattern generators, rather than the activation of a separate set of central pattern generators for each distinct gait. PMID- 21697442 TI - Of mice and intrinsic excitability: genetic background affects the size of the postburst afterhyperpolarization in CA1 pyramidal neurons. AB - As the use of genetically engineered mice has become increasingly prevalent in neurobiological research, evidence has steadily accumulated that substantial differences exist between strains. Although a number of studies have reported effects of genetic background on behavior, few have focused on differences in neurophysiology. The postburst afterhyperpolarization (AHP) is an important determinant of intrinsic neuronal excitability and has been suggested to play a critical role in the cellular mechanisms underlying learning and memory. Using whole cell current-clamp recordings of CA1 pyramidal neurons, we examined the magnitude of different phases of the AHP (peak, medium, and slow) in two commonly used genetic backgrounds, C57BL/6 (B6) and 129SvEv (129), as well as in an F2 hybrid B6:129 background (F2). We found that neurons from B6 and F2 animals exhibited a significantly larger AHP compared with 129 animals and that this difference was consistent across all phases. Furthermore, our recordings revealed a marked dichotomy in the shape of the AHP waveform, which was independent of genetic background. Approximately 60% of cells exhibited an AHP with a sharp transition between the peak AHP and medium AHP, whereas the remaining 40% exhibited a more gradual transition. Our data add to the growing body of work suggesting that genetic background can affect neuronal function as well as behavior. In addition, these results highlight the innate heterogeneity of CA1 pyramidal neurons, even within a single genetic background. These differences should be taken into consideration during the analysis and comparison of experimental results. PMID- 21697444 TI - Effects of wrist tendon vibration on arm tracking in people poststroke. AB - The goal of this study was to evaluate the influence of wrist tendon vibration on a multijoint elbow/shoulder tracking task. We hypothesized that tendon vibration applied at the wrist musculature would improve upper arm tracking performance in chronic stroke survivors through increased, Ia-afferent feedback to the central nervous system (CNS). To test this hypothesis, 10 chronic stroke and 5 neurologically intact subjects grasped the handle of a planar robot as they tracked a target through a horizontal figure-8 pattern. A total of 36 trials were completed by each subject. During the middle trials, 70-Hz tendon vibration was applied at the wrist flexor tendons. Position, velocity, and electromyography data were evaluated to compare the quality of arm movements before, during, and after trials with concurrent vibration. Despite tracking a target that moved at a constant velocity, hand trajectories appeared to be segmented, displaying alternating intervals of acceleration and deceleration. Segments were identifiable in tangential velocity data as single-peaked, bell-shaped speed pulses. When tendon vibration was applied at the wrist musculature, stroke subjects experienced improved tracking performance in that hand path lengths and peak speed variability decreased, whereas movement smoothness increased. These performance improvements were accompanied by decreases in the muscle activity during movement. Possible mechanisms behind improved movement control in response to tendon vibration may include improved sensorimotor integration or improved cortical modulation of spinal reflex activity. PMID- 21697443 TI - The human prefrontal cortex mediates integration of potential causes behind observed outcomes. AB - Prefrontal cortex has long been implicated in tasks involving higher order inference in which decisions must be rendered, not only about which stimulus is currently rewarded, but also which stimulus dimensions are currently relevant. However, the precise computational mechanisms used to solve such tasks have remained unclear. We scanned human participants with functional MRI, while they performed a hierarchical intradimensional/extradimensional shift task to investigate what strategy subjects use while solving higher order decision problems. By using a computational model-based analysis, we found behavioral and neural evidence that humans solve such problems not by occasionally shifting focus from one to the other dimension, but by considering multiple explanations simultaneously. Activity in human prefrontal cortex was better accounted for by a model that integrates over all available evidences than by a model in which attention is selectively gated. Importantly, our model provides an explanation for how the brain determines integration weights, according to which it could distribute its attention. Our results demonstrate that, at the point of choice, the human brain and the prefrontal cortex in particular are capable of a weighted integration of information across multiple evidences. PMID- 21697445 TI - The mechanism of ethanol action on midbrain dopaminergic neuron firing: a dynamic clamp study of the role of I(h) and GABAergic synaptic integration. AB - Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are expressed in dopaminergic (DA) neurons of the ventral tegmental area (VTA) as well as in DA and GABAergic neurons of the substantia nigra (SN). The excitation of DA neurons induced by ethanol has been proposed to result from its enhancing HCN channel current, I(h). Using perforated patch-clamp recordings in rat midbrain slices, we isolated I(h) in these neurons by voltage clamp. We showed that ethanol reversibly increased the amplitude and accelerated the activation kinetics of I(h) and caused a depolarizing shift in its voltage dependence. Using dynamic-clamp conductance injection, we injected artificial I(h) and fluctuating GABAergic synaptic conductance inputs into neurons following block of intrinsic I(h). This demonstrated directly a major role of I(h) in promoting rebound spiking following phasic inhibition, which was enhanced as the kinetics and amplitude of I(h) were changed in the manner induced by ethanol. Similar effects of ethanol were observed on I(h) and firing rate in non-DA, putatively GABAergic interneurons, indicating that in addition to its direct effects on firing, ethanol will produce large changes in the inhibition and disinhibition (via GABAergic interneurons) converging on DA neurons. Thus the overall effects of ethanol on firing of DA cells of the VTA and SN in vivo, and hence on phasic dopamine release in the striatum, appear to be determined substantially by its action on I(h) in both DA cells and GABAergic interneurons. PMID- 21697446 TI - Contributions of Kv7-mediated potassium current to sub- and suprathreshold responses of rat layer II/III neocortical pyramidal neurons. AB - After block of Kv1- and Kv2-mediated K(+) currents in acutely dissociated neocortical pyramidal neurons from layers II/III of rat somatosensory and motor cortex, the remaining current is slowly activating and persistent. We used whole cell voltage clamp to show that the Kv7 blockers linopirdine and XE-991 blocked a current with similar kinetics to the current remaining after combined block of Kv1 and Kv2 channels. This current was sensitive to low doses of linopirdine and activated more slowly and at more negative potentials than Kv1- or Kv2-mediated current. The Kv7-mediated current decreased in amplitude with time in whole cell recordings, but in most cells the current was stable for several minutes. Current in response to a traditional M-current protocol was blocked by muscarine, linopirdine, and XE-991. Whole cell slice recordings revealed that the Q10 for channel deactivation was ~2.5. Sharp electrode current-clamp recordings from adult pyramidal cells demonstrated that block of Kv7-mediated current with XE-991 reduced rheobase, shortened the latency to firing to near rheobase current, induced more regular firing at low current intensity, and increased the rate of firing to a given current injection. XE-991 did not affect single action potentials or spike frequency adaptation. Application of XE-991 also eliminated subthreshold voltage oscillations and increased gain for low-frequency inputs (<10 Hz) without affecting gain for higher frequency inputs. These data suggest important roles for Kv7 channels in subthreshold regulation of excitability, generation of theta-frequency subthreshold oscillations, regulation of interspike intervals, and biasing selectivity toward higher frequency inputs. PMID- 21697448 TI - Neural correlates of cognitive control of reaching movements in the dorsal premotor cortex of rhesus monkeys. AB - Canceling a pending movement is a hallmark of voluntary behavioral control because it allows us to quickly adapt to unattended changes either in the external environment or in our thoughts. The countermanding paradigm allows the study of inhibitory processes of motor acts by requiring the subject to withhold planned movements in response to an infrequent stop-signal. At present the neural processes underlying the inhibitory control of arm movements are mostly unknown. We recorded the activity of single units in the rostral and caudal portion of the dorsal premotor cortex (PMd) of monkeys trained in a countermanding reaching task. We found that among neurons with a movement-preparatory activity, about one third exhibit a modulation before the behavioral estimate of the time it takes to cancel a planned movement. Hence these neurons exhibit a pattern of activity suggesting that PMd plays a critical role in the brain networks involved in the control of arm movement initiation and suppression. PMID- 21697447 TI - Effects of persistent inward currents, accommodation, and adaptation on motor unit behavior: a simulation study. AB - Motor neurons are often assumed to generate spikes in proportion to the excitatory synaptic input received. There are, however, many intrinsic properties of motor neurons that might affect this relationship, such as persistent inward currents (PICs), spike-threshold accommodation, or spike-frequency adaptation. These nonlinear properties have been investigated in reduced animal preparation but have not been well studied during natural motor behaviors because of the difficulty in characterizing synaptic input in intact animals. Therefore, we studied the influence of each of these intrinsic properties on spiking responses and muscle force using a population model of motor units that simulates voluntary contractions in human subjects. In particular, we focused on the difference in firing rate of low-threshold motor units when higher threshold motor units were recruited and subsequently derecruited, referred to as DeltaF. Others have used DeltaF to evaluate the extent of PIC activation during voluntary behavior. Our results showed that positive DeltaF values could arise when any one of these nonlinear properties was included in the simulations. Therefore, a positive DeltaF should not be considered as exclusive evidence for PIC activation. Furthermore, by systematically varying contraction duration and speed in our simulations, we identified a means that might be used experimentally to distinguish among PICs, accommodation, and adaptation as contributors to DeltaF. PMID- 21697449 TI - Comparative posthearing development of inhibitory inputs to the lateral superior olive in gerbils and mice. AB - Interaural intensity differences are analyzed in neurons of the lateral superior olive (LSO) by integration of an inhibitory input from the medial nucleus of the trapezoid body (MNTB), activated by sound from the contralateral ear, with an excitatory input from the ipsilateral cochlear nucleus. The early postnatal refinement of this inhibitory MNTB-LSO projection along the tonotopic axis of the LSO has been extensively studied. However, little is known to what extent physiological changes at these inputs also occur after the onset of sound-evoked activity. Using whole-cell patch-clamp recordings of LSO neurons in acute brain stem slices, we analyzed the developmental changes of inhibitory synaptic currents evoked by MNTB fiber stimulation occurring after hearing onset. We compared these results in gerbils and mice, two species frequently used in auditory research. Our data show that neither the number of presumed input fibers nor the conductance of single fibers significantly changed after hearing onset. Also the amplitude of miniature inhibitory currents remained constant during this developmental period. In contrast, the kinetics of inhibitory synaptic currents greatly accelerated after hearing onset. We conclude that tonotopic refinement of inhibitory projections to the LSO is largely completed before the onset of hearing, whereas acceleration of synaptic kinetics occurs to a large part after hearing onset and might thus be dependent on proper auditory experience. Surprisingly, inhibitory input characteristics, as well as basic membrane properties of LSO neurons, were rather similar in gerbils and mice. PMID- 21697450 TI - Inhibitory-excitatory synaptic balance is shifted toward increased excitation in magnocellular neurosecretory cells of heart failure rats. AB - Despite the well-established contribution of neurohumoral activation to morbidity and mortality in heart failure (HF) patients, relatively little is known about the underlying central nervous system mechanisms. In this study, we aimed to determine whether changes in GABAergic inhibitory and glutamatergic excitatory synaptic function contribute to altered hypothalamic magnocellular neurosecretory cell (MNC) activity in HF rats. Patch-clamp recordings were obtained from MNCs in brain slices from sham and HF rats. Glutamate excitatory (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs) were simultaneously recorded, and changes in their strengths, as well as their interactions, were evaluated. We found a diminished GABAergic synaptic strength in MNCs of HF rats, reflected as faster decaying IPSCs and diminished mean IPSC charge transfer. Opposite changes were observed in glutamate EPSC synaptic strength, resulting in a shift in the GABA-glutamate balance toward a relatively stronger glutamate influence in HF rats. The prolongation of glutamate EPSCs during HF was mediated, at least in part, by an enhanced contribution of AMPA receptor desensitization to the EPSC decay time course. EPSC prolongation, and consequently increased unitary strength, resulted in a stronger AMPA receptor-mediated excitatory drive to firing discharge in MNCs of HF rats. Blockade of GABA(A) synaptic activity diminished the EPSC waveform variability observed among events in sham rats, an effect that was blunted in HF rats. Together, our results suggest that opposing changes in postsynaptic properties of GABAergic and glutamatergic synaptic function contribute to enhanced magnocellular neurosecretory activity in HF rats. PMID- 21697451 TI - Hindlimb immobilization in a wheelchair alters functional recovery following contusive spinal cord injury in the adult rat. AB - BACKGROUND: Locomotor training of rats with thoracic contusion spinal cord injuries can induce task-specific changes in stepping but rarely results in improved overground locomotion, possibly due to a ceiling effect. Thus, the authors hypothesize that incompletely injured rats maximally retrain themselves while moving about in their cages over the first few weeks postinjury. OBJECTIVE: To test the hypothesis using hindlimb immobilization after mild thoracic contusion spinal cord injury in adult female rats. A passive stretch protocol was included as an independent treatment. METHODS: Wheelchairs were used to hold the hindlimbs stationary in an extended position leaving the forelimbs free. The wheelchairs were used for 15 to 18 hours per day, 5 days per week for 8 weeks, beginning at 4 days postinjury. A 20-minute passive hindlimb stretch therapy was applied to half of the animals. RESULTS: Hindlimb locomotor function of the wheelchair group was not different from controls at 1 week postinjury but declined significantly over the next 4 weeks. Passive stretch had no influence on wheelchair animals but limited functional recovery of normally housed animals, preventing them from regaining forelimb-hindlimb coordination. Following 8 weeks of wheelchair immobilization and stretch therapy, only the wheelchair group displayed an improvement in function when returned to normal housing but retained significant deficits in stepping and coordination out to 16 weeks. CONCLUSION: Hindlimb immobilization and passive stretch may hinder or conceal the normal course of functional recovery of spinal cord injured rats. These observations have implications for the management of acute clinical spinal cord injuries. PMID- 21697453 TI - Extrahypothalamic effects of leptin: a therapeutic for depression and dementia? PMID- 21697452 TI - Goal setting education and counseling practices of diabetes educators. AB - PURPOSE: The purpose of this study was to identify goal setting education practices used by diabetes educators working with type 2 diabetes patients. METHODS: Data were collected by a mail questionnaire with 179 diabetes educators purposively selected from the 2008 American Association of Diabetes Educators membership listing. RESULTS: Many diabetes educators (52%) reported that more than 75% of their patients set goals for diabetes control. Independent factor patterns for the frequency of information collected from the patient for the first diabetes education session showed that educators either focused on patients' self-management practices (exercise and dietary practices, knowledge, and social impacts of diabetes) or issues with learning about self-management, such as understanding the patient's learning style and motivation for managing diabetes. Factor patterns overall showed diverse approaches to working with patients, including strategies used with patients struggling with dietary goals and the importance of tasks to complete during the first patient session. CONCLUSION: Although most educators reported practices that were largely patient centered as promoted by the American Diabetes Association (ADA) and models of chronic disease management, patterns of practice suggest that diabetes educators vary considerably in how they apply education practices, especially with dietary self-management education. PMID- 21697454 TI - Reporter zebrafish: endocrine disruption meets estrogen signaling. PMID- 21697455 TI - The novel costimulatory programmed death ligand 1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo. AB - The programmed death ligand 1 (PDL1)/programmed death 1 (PD1) costimulatory pathway plays an important role in the inhibition of alloimmune responses as well as in the induction and maintenance of peripheral tolerance. It has been demonstrated recently that PDL1 also can bind B7.1 to inhibit T cell responses in vitro. Using the bm12 into B6 heart transplant model, we investigated the functional significance of this interaction in alloimmune responses in vivo. PD1 blockade unlike PDL1 blockade failed to accelerate bm12 allograft rejection, suggesting a role for an additional binding partner for PDL1 other than PD1 in transplant rejection. PDL1 blockade was able to accelerate allograft rejection in B7.2-deficient recipients but not B7.1-deficient recipients, indicating that PDL1 interaction with B7.1 was important in inhibiting rejection. Administration of the novel 2H11 anti-PDL1 mAb, which only blocks the PDL1-B7.1 interaction, aggravated chronic injury of bm12 allografts in B6 recipients. Aggravated chronic injury was associated with an increased frequency of alloreactive IFN-gamma-, IL 4-, and IL-6-producing splenocytes and a decreased percentage of regulatory T cells in the recipients. Using an in vitro cell culture assay, blockade of the interaction of PDL1 on dendritic cells with B7.1 on T cells increased IFN-gamma production from alloreactive CD4(+) T cells, whereas blockade of dendritic cell B7.1 interaction with T cell PDL1 did not. These data indicate that PDL1 interaction with B7.1 plays an important role in the inhibition of alloimmune responses in vivo and suggests a dominant direction for PDL1 and B7.1 interaction. PMID- 21697457 TI - Human NK cells display important antifungal activity against Aspergillus fumigatus, which is directly mediated by IFN-gamma release. AB - Despite the strong interest in the NK cell-mediated immunity toward malignant cells and viruses, there is a relative lack of data on the interplay between NK cells and filamentous fungi, especially Aspergillus fumigatus, which is the major cause of invasive aspergillosis. By studying the in vitro interaction between human NK cells and A. fumigatus, we found only germinated morphologies to be highly immunogenic, able to induce a Th1-like response, and capable of upregulating cytokines such as IFN-gamma and TNF-alpha. Moreover, priming NK cells with human rIL-2 and stimulating NK cells by direct NK cell-pathogen contact were essential to induce damage against A. fumigatus. However, the most interesting finding was that NK cells did not mediate anti-Aspergillus cytotoxicity through degranulation of their cytotoxic proteins (perforin, granzymes, granulysine), but via an alternative mechanism involving soluble factor(s). To our knowledge, our study is the first to demonstrate that IFN gamma, released by NK cells, directly damages A. fumigatus, attributing new properties to both human NK cells and IFN-gamma and suggesting them as possible therapeutic tools against IA. PMID- 21697458 TI - P2X7 receptor-dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome. AB - The ATP-gated P2X(7) receptor (P2X(7)R) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL-1beta processing and release. Trichinella spiralis-infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome. In this study, we used P2X(7)R knockout mice (P2X(7)R(-/-)) to investigate the role of P2X(7)R activation in the in vivo production of IL-1beta and the development of postinflammatory visceral hypersensitivity in the T. spiralis-infected mouse. During acute nematode infection, IL-1beta-containing cells and P2X(7)R expression were increased in the jejunum of wild-type (WT) mice. Peritoneal and serum IL-1beta levels were also increased, which was indicative of elevated IL-1beta release. However, in the P2X(7)R(-/-) animals, we found that infection had no effect upon intracellular, plasma, or peritoneal IL-1beta levels. Conversely, infection augmented peritoneal TNF-alpha levels in both WT and P2X(7)R(-/-) animals. Infection was also associated with a P2X(7)R-dependent increase in extracellular peritoneal lactate dehydrogenase, and it triggered immunological changes in both strains. Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X(7)R(-/-) animals. Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli; however, this did not develop in postinfected P2X(7)R(-/-) animals. Therefore, our results demonstrated that P2X(7)Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity. PMID- 21697456 TI - The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. AB - Programmed death-1 ligand 1 (PD-L1) is a coinhibitory molecule that negatively regulates multiple tolerance checkpoints. In the NOD mouse model, PD-L1 regulates the development of diabetes. PD-L1 has two binding partners, programmed death-1 and B7-1, but the significance of the PD-L1:B7-1 interaction in regulating self reactive T cell responses is not yet clear. To investigate this issue in NOD mice, we have compared the effects of two anti-PD-L1 Abs that have different blocking activities. Anti-PD-L1 mAb 10F.2H11 sterically and functionally blocks only PD-L1:B7-1 interactions, whereas anti-PD-L1 mAb 10F.9G2 blocks both PD-L1:B7 1 and PD-L1:programmed death-1 interactions. Both Abs had potent, yet distinct effects in accelerating diabetes in NOD mice: the single-blocker 10F.2H11 mAb was more effective at precipitating diabetes in older (13-wk-old) than in younger (6- to 7-wk-old) mice, whereas the dual-blocker 10F.9G2 mAb rapidly induced diabetes in NOD mice of both ages. Similarly, 10F.2H11 accelerated diabetes in recipients of T cells from diabetic, but not prediabetic mice, whereas 10F.9G2 was effective in both settings. Both anti-PD-L1 mAbs precipitated diabetes in adoptive transfer models of CD4(+) and CD8(+) T cell-driven diabetes. Taken together, these data demonstrate that the PD-L1:B7-1 pathway inhibits potentially pathogenic self reactive effector CD4(+) and CD8(+) T cell responses in vivo, and suggest that the immunoinhibitory functions of this pathway may be particularly important during the later phases of diabetogenesis. PMID- 21697459 TI - Akt-mediated proinflammatory response of mononuclear phagocytes infected with Burkholderia cenocepacia occurs by a novel GSK3beta-dependent, IkappaB kinase independent mechanism. AB - The environmental bacterium Burkholderia cenocepacia causes opportunistic lung infections in immunocompromised individuals, particularly in patients with cystic fibrosis. Infections in these patients are associated with exacerbated inflammation leading to rapid decay of lung function, and in some cases resulting in cepacia syndrome, which is characterized by a fatal acute necrotizing pneumonia and sepsis. B. cenocepacia can survive intracellularly in macrophages by altering the maturation of the phagosome, but very little is known on macrophage responses to the intracellular infection. In this study, we have examined the role of the PI3K/Akt signaling pathway in B. cenocepacia-infected monocytes and macrophages. We show that PI3K/Akt activity was required for NF kappaB activity and the secretion of proinflammatory cytokines during infection with B. cenocepacia. In contrast to previous observations in epithelial cells infected with other Gram-negative bacteria, Akt did not enhance IkappaB kinase or NF-kappaB p65 phosphorylation, but rather inhibited GSK3beta, a negative regulator of NF-kappaB transcriptional activity. This novel mechanism of modulation of NF-kappaB activity may provide a unique therapeutic target for controlling excessive inflammation upon B. cenocepacia infection. PMID- 21697461 TI - Human epidermal Langerhans cells replenish skin xenografts and are depleted by alloreactive T cells in vivo. AB - Epidermal Langerhans cells (LC) are potent APCs surveying the skin. They are crucial regulators of T cell activation in the context of inflammatory skin disease and graft-versus-host disease (GVHD). In contrast to other dendritic cell subtypes, murine LC are able to reconstitute after local depletion without the need of peripheral blood-derived precursors. In this study, we introduce an experimental model of human skin grafted to NOD-SCID IL2Rgamma(null) mice. In this model, we demonstrate that xenografting leads to the transient loss of LC from the human skin grafts. Despite the lack of a human hematopoietic system, human LC repopulated the xenografts 6 to 9 wk after transplantation. By staining of LC with the proliferation marker Ki67, we show that one third of the replenishing LC exhibit proliferative activity in vivo. We further used the skin xenograft as an in vivo model for human GVHD. HLA-disparate third-party T cells stimulated with skin donor-derived dendritic cells were injected intravenously into NOD-SCID IL2Rgamma(null) mice that had been transplanted with human skin. The application of alloreactive T cells led to erythema and was associated with histological signs of GVHD limited to the transplanted human skin. The inflammation also led to the depletion of LC from the epidermis. In summary, we provide evidence that human LC are able to repopulate the skin independent of blood-derived precursor cells and that this at least partly relates to their proliferative capacity. Our data also propose xeno-transplantation of human skin as a model system for studying the role of skin dendritic cells in the efferent arm of GVHD. PMID- 21697460 TI - Obstructive jaundice expands intrahepatic regulatory T cells, which impair liver T lymphocyte function but modulate liver cholestasis and fibrosis. AB - Although obstructive jaundice has been associated with a predisposition toward infections, the effects of bile duct ligation (BDL) on bulk intrahepatic T cells have not been clearly defined. The aim of this study was to determine the consequences of BDL on liver T cell phenotype and function. After BDL in mice, we found that bulk liver T cells were less responsive to allogeneic or syngeneic Ag loaded dendritic cells. Spleen T cell function was not affected, and the viability of liver T cells was preserved. BDL expanded the number of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg), which were anergic to direct CD3 stimulation and mediated T cell suppression in vitro. Adoptively transferred CD4(+)CD25(-) T cells were converted into Treg within the liver after BDL. In vivo depletion of Treg after BDL restored bulk liver T cell function but exacerbated the degrees of inflammatory cytokine production, cholestasis, and hepatic fibrosis. Thus, BDL expands liver Treg, which reduce the function of bulk intrahepatic T cells yet limit liver injury. PMID- 21697462 TI - Comparing the kinetics of NK cells, CD4, and CD8 T cells in murine cytomegalovirus infection. AB - NK cells recognize virus-infected cells with germline-encoded activating and inhibitory receptors that do not undergo genetic recombination or mutation. Accordingly, NK cells are often considered part of the innate immune response. The innate response comprises rapid early defenders that do not form immune memory. However, there is increasing evidence that experienced NK cells provide increased protection to secondary infection, a hallmark of the adaptive response. In this study, we compare the dynamics of the innate and adaptive immune responses by examining the kinetic profiles of the NK and T cell response to murine CMV infection. We find that, unexpectedly, the kinetics of NK cell proliferation is neither earlier nor faster than the CD4 or CD8 T cell response. Furthermore, early NK cell contraction after the peak of the response is slower than that of T cells. Finally, unlike T cells, experienced NK cells do not experience biphasic decay after the response peak, a trait associated with memory formation. Rather, NK cell contraction is continuous, constant, and returns to below endogenous preinfection levels. This indicates that the reason why Ag experienced NK cells remain detectable for a prolonged period after adoptive transfer and infection is in part due to the high precursor frequency, slow decay rate, and low background levels of Ly49H(+) NK cells in recipient DAP12-deficient mice. Thus, the quantitative contribution of Ag-experienced NK cells in an endogenous secondary response, with higher background levels of Ly49H(+) NK cells, may be not be as robust as the secondary response observed in T cells. PMID- 21697463 TI - Evaluation of CYP2C8 inhibition in vitro: utility of montelukast as a selective CYP2C8 probe substrate. AB - Understanding the potential for cytochrome P450 (P450)-mediated drug-drug interactions is a critical step in the drug discovery process. Although in vitro studies with CYP3A4, CYP2C9, and CYP2C19 have suggested the presence of multiple binding regions within the P450 active site based on probe substrate-dependent inhibition profiles, similar studies have not been performed with CYP2C8. The ability to understand CYP2C8 probe substrate sensitivity will enable appropriate in vitro and in vivo probe selection. To characterize the potential for probe substrate-dependent inhibition with CYP2C8, the inhibition potency of 22 known inhibitors of CYP2C8 were measured in vitro using four clinically relevant CYP2C8 probe substrates (montelukast, paclitaxel, repaglinide, and rosiglitazone) and amodiaquine. Repaglinide exhibited the highest sensitivity to inhibition in vitro. In vitro phenotyping indicated that montelukast is an appropriate probe for CYP2C8 inhibition studies. The in vivo sensitivities of the CYP2C8 probe substrates cerivastatin, fluvastatin, montelukast, pioglitazone, and rosiglitazone were determined in relation to repaglinide on the basis of clinical drug-drug interaction (DDI) data. Repaglinide exhibited the highest sensitivity in vivo, followed by cerivastatin, montelukast, and pioglitazone. Finally, the magnitude of in vivo CYP2C8 DDI caused by gemfibrozil-1-O-beta-glucuronide was predicted. Comparisons of the predictions with clinical data coupled with the potential liabilities of other CYP2C8 probes suggest that montelukast is an appropriate CYP2C8 probe substrate to use for the in vivo situation. PMID- 21697464 TI - Complete genome analysis of three novel picornaviruses from diverse bat species. AB - Although bats are important reservoirs of diverse viruses that can cause human epidemics, little is known about the presence of picornaviruses in these flying mammals. Among 1,108 bats of 18 species studied, three novel picornaviruses (groups 1, 2, and 3) were identified from alimentary specimens of 12 bats from five species and four genera. Two complete genomes, each from the three picornaviruses, were sequenced. Phylogenetic analysis showed that they fell into three distinct clusters in the Picornaviridae family, with low homologies to known picornaviruses, especially in leader and 2A proteins. Moreover, group 1 and 2 viruses are more closely related to each other than to group 3 viruses, which exhibit genome features distinct from those of the former two virus groups. In particular, the group 3 virus genome contains the shortest leader protein within Picornaviridae, a putative type I internal ribosome entry site (IRES) in the 5' untranslated region instead of the type IV IRES found in group 1 and 2 viruses, one instead of two GXCG motifs in 2A, an L->V substitution in the DDLXQ motif in 2C helicase, and a conserved GXH motif in 3C protease. Group 1 and 2 viruses are unique among picornaviruses in having AMH instead of the GXH motif in 3C(pro). These findings suggest that the three picornaviruses belong to two novel genera in the Picornaviridae family. This report describes the discovery and complete genome analysis of three picornaviruses in bats, and their presence in diverse bat genera/species suggests the ability to cross the species barrier. PMID- 21697465 TI - The ribonucleotide reductase R1 subunits of herpes simplex virus 1 and 2 protect cells against poly(I . C)-induced apoptosis. AB - We recently provided evidence that the ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 (HSV-1 and -2) protect cells against tumor necrosis factor alpha- and Fas ligand-induced apoptosis by interacting with caspase 8. Double-stranded RNA (dsRNA) is a viral intermediate known to initiate innate antiviral responses. Poly(I . C), a synthetic analogue of viral dsRNA, rapidly triggers caspase 8 activation and apoptosis in HeLa cells. Here, we report that HeLa cells after HSV-1 and HSV-2 infection were quickly protected from apoptosis caused by either extracellular poly(I . C) combined with cycloheximide or transfected poly(I . C). Cells infected with the HSV-1 R1 deletion mutant ICP6Delta were killed by poly(I . C), indicating that HSV-1 R1 plays a key role in antiapoptotic responses to poly(I . C). Individually expressed HSV R1s counteracted caspase 8 activation by poly(I . C). In addition to their binding to caspase 8, HSV R1s also interacted constitutively with receptor-interacting protein 1 (RIP1) when expressed either individually or with other viral proteins during HSV infection. R1(1-834)-green fluorescent protein (GFP), an HSV-2 R1 deletion mutant protein devoid of antiapoptotic activity, did not interact with caspase 8 and RIP1, suggesting that these interactions are required for protection against poly(I . C). HSV-2 R1 inhibited the interaction between the Toll/interleukin-1 receptor domain-containing adaptor-inducing beta interferon (IFN-beta) (TRIF) and RIP1, an interaction that is essential for apoptosis triggered by extracellular poly(I . C) plus cycloheximide or TRIF overexpression. TRIF silencing reduced poly(I . C)-triggered caspase 8 activation in mock- and ICP6Delta-infected cells, confirming that TRIF is involved in poly(I . C)-induced apoptosis. Thus, by interacting with caspase 8 and RIP1, HSV R1s impair the apoptotic host defense mechanism prompted by dsRNA. PMID- 21697466 TI - The rhesus rotavirus gene encoding VP4 is a major determinant in the pathogenesis of biliary atresia in newborn mice. AB - Biliary atresia (BA) is a devastating disease of childhood for which increasing evidence supports a viral component in pathogenesis. The murine model of BA is induced by perinatal infection with rhesus rotavirus (RRV) but not with other strains of rotavirus, such as TUCH. To determine which RRV gene segment(s) is responsible for pathogenesis, we used the RRV and TUCH strains to generate a complete set of single-gene reassortants. Eleven single-gene "loss-of-function" reassortants in which a TUCH gene replaced its RRV equivalent and 11 single-gene "gain-of-function" reassortants in which an RRV gene replaced its TUCH equivalent were generated. Newborn BALB/c mice were inoculated with the reassortants and were monitored for biliary obstruction and mortality. In vitro, the ability to bind to and replicate within cholangiocytes was analyzed. Infection of mice with the "loss-of-function" reassortant R(T(VP4)), where gene 4 from TUCH was placed on an RRV background, eliminated the ability of RRV to cause murine BA. In a reciprocal fashion, the "gain-of-function" reassortant T(R(VP4)) resulted in murine BA with 88% mortality. Compared with those for RRV, R(T(VP4)) binding and titers in cholangiocytes were significantly attenuated, while T(R(VP4)) binding and titers were significantly increased over those for TUCH. Reassortants R(T(VP3)) and T(R(VP3)) induced an intermediate phenotype. RRV gene segment 4 plays a significant role in governing tropism for the cholangiocyte and the ability to induce murine BA. Gene segment 3 did not affect RRV infectivity in vitro but altered its in vivo effect. PMID- 21697467 TI - Binding of the mannose-specific lectin, griffithsin, to HIV-1 gp120 exposes the CD4-binding site. AB - The glycans on HIV-1 gp120 play an important role in shielding neutralization sensitive epitopes from antibody recognition. They also serve as targets for lectins that bind mannose-rich glycans. In this study, we investigated the interaction of the lectin griffithsin (GRFT) with HIV-1 gp120 and its effects on exposure of the CD4-binding site (CD4bs). We found that GRFT enhanced the binding of HIV-1 to plates coated with anti-CD4bs antibodies b12 and b6 or the CD4 receptor mimetic CD4-IgG2. The average enhancement of b12 or b6 binding was higher for subtype B viruses than for subtype C, while for CD4-IgG2, it was similar for both subtypes, although lower than observed with antibodies. This GRFT-mediated enhancement of HIV-1 binding to b12 was reflected in synergistic neutralization for 2 of the 4 viruses tested. The glycan at position 386, which shields the CD4bs, was involved in both GRFT-mediated enhancement of binding and neutralization synergism between GRFT and b12. Although GRFT enhanced CD4bs exposure, it simultaneously inhibited ligand binding to the coreceptor binding site, suggesting that GRFT-dependent enhancement and neutralization utilize independent mechanisms. This study shows for the first time that GRFT interaction with gp120 exposes the CD4bs through binding the glycan at position 386, which may have implications for how to access this conserved site. PMID- 21697468 TI - Binding of avian coronavirus spike proteins to host factors reflects virus tropism and pathogenicity. AB - The binding of viruses to host cells is the first step in determining tropism and pathogenicity. While avian infectious bronchitis coronavirus (IBV) infection and avian influenza A virus (IAV) infection both depend on alpha2,3-linked sialic acids, the host tropism of IBV is restricted compared to that of IAV. Here we investigated whether the interaction between the viral attachment proteins and the host could explain these differences by using recombinant spike domains (S1) of IBV strains with different pathogenicities, as well as the hemagglutinin (HA) protein of IAV H5N1. Protein histochemistry showed that S1 of IBV strain M41 and HA of IAV subtype H5N1 displayed sialic acid-dependent binding to chicken respiratory tract tissue. However, while HA bound with high avidity to a broad range of alpha2,3-linked sialylated glycans, M41 S1 recognized only one particular alpha2,3-linked disialoside in a glycan array. When comparing the binding of recombinant IBV S1 proteins derived from IBV strains with known differences in tissue tropism and pathogenicity, we observed that while M41 S1 displayed binding to cilia and goblet cells of the chicken respiratory tract, S1 derived from the vaccine strain H120 or the nonvirulent Beaudette strain had reduced or no binding to chicken tissues, respectively, in agreement with the reduced abilities of these viruses to replicate in vivo. While the S1 protein derived from the nephropathogenic IBV strain B1648 also hardly displayed binding to respiratory tract cells, distinct binding to kidney cells was observed, but only after the removal of sialic acid from S1. In conclusion, our data demonstrate that the attachment patterns of the IBV S proteins correlate with the tropisms and pathogenicities of the corresponding viruses. PMID- 21697469 TI - SH2-containing inositol 5'-phosphatase inhibits transformation of Abelson murine leukemia virus. AB - v-Abl protein tyrosine kinase encoded by Abelson murine leukemia virus (Ab-MLV) transforms pre-B cells. Transformation requires the phosphatidylinositol 3-kinase (PI3K) pathway. This pathway is antagonized by SH2-containing inositol 5' phosphatase (SHIP), raising the possibility that v-Abl modulates PI3K signaling through SHIP. Consistent with this, we show that v-Abl expression reduces levels of full-length p145 SHIP in a v-Abl kinase activity-dependent fashion. This event requires signals from the Abl SH2 domain but not the carboxyl terminus. Forced expression of full-length SHIP significantly reduces Ab-MLV pre-B-cell transformation. Therefore, reduction of SHIP protein by v-Abl is a critical component in Ab-MLV transformation. PMID- 21697470 TI - Potyviral VPg enhances viral RNA Translation and inhibits reporter mRNA translation in planta. AB - Viral protein genome-linked (VPg) plays a central role in several stages of potyvirus infection. This study sought to answer questions about the role of Potato virus A (PVA; genus Potyvirus) VPg in viral and host RNA expression. When expressed in Nicotiana benthamiana leaves in trans, a dual role of VPg in translation is observed. It repressed the expression of monocistronic luciferase (luc) mRNA and simultaneously induced a significant upregulation in the expression of both replicating and nonreplicating PVA RNAs. This enhanced viral gene expression was due at least to the 5' untranslated region (UTR) of PVA RNA, eukaryotic initiation factors 4E and iso 4E [eIF4E/eIF(iso)4E], and the presence of a sufficient amount of VPg. Coexpression of VPg with viral RNA increased the viral RNA amount, which was not the case with the monocistronic mRNA. Both mutations at certain lysine residues in PVA VPg and eIF4E/eIF(iso)4E depletion reduced its ability to upregulate the viral RNA expression. These modifications were also involved in VPg-mediated downregulation of monocistronic luc expression. These results suggest that VPg can titrate eIF4Es from capped monocistronic RNAs. Because VPg-mediated enhancement of viral gene expression required eIF4Es, it is possible that VPg directs eIF4Es to promote viral RNA expression. From this study it is evident that VPg can serve as a specific regulator of PVA expression by boosting the viral RNA amounts as well as the accumulation of viral translation products. Such a mechanism could function to protect viral RNA from being degraded and to secure efficient production of coat protein (CP) for virion formation. PMID- 21697471 TI - Poliovirus switches to an eIF2-independent mode of translation during infection. AB - Inhibition of translation is an integral component of the innate antiviral response and is largely accomplished via interferon-activated phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha). To successfully infect a host, a virus must overcome this blockage by either controlling eIF2alpha phosphorylation or by utilizing a noncanonical mode of translation initiation. Here we show that enterovirus RNA is sensitive to translation inhibition resulting from eIF2alpha phosphorylation, but it becomes resistant as infection progresses. Further, we show that the cleavage of initiation factor eIF5B during enteroviral infection, along with the viral internal ribosome entry site, plays a role in mediating viral translation under conditions that are nonpermissive for host cell translation. Together, these results provide a mechanism by which enteroviruses evade the antiviral response and provide insight into a noncanonical mechanism of translation initiation. PMID- 21697472 TI - Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen reduces interleukin-8 expression in endothelial cells and impairs neutrophil chemotaxis by degrading nuclear p65. AB - Latency-associated nuclear antigen 1 (LANA-1) of Kaposi's sarcoma-associated herpesvirus (KSHV) is the major viral latent protein and functions as a multifaceted protein. Here, we report that LANA-1 attenuates the endothelial response to tumor necrosis factor alpha (TNF-alpha) stimulation and inhibits consequent neutrophil chemotaxis. Reporter assays showed that LANA-1 constantly repressed nuclear factor (NF)-kappaB transactivity upon TNF-alpha stimulation. We also found that LANA-1 decreased nuclear p65 protein levels through enhancement of polyubiquitylation-mediated p65 degradation and that an elongin B/elongin C cullin 5-LANA-1-p65 complex assembled by LANA-1 was responsible for this enhanced p65 degradation. In telomerase-immortalized human umbilical vein endothelial cells, LANA-1 was demonstrated to repress interleukin-8 expression, which was involved in neutrophil recruitment to the inflammatory site. Through an in vitro transmigration assay, we determined a suppressive effect of LANA-1 on neutrophil chemotaxis. Our work suggests that KSHV LANA-1 is a negative modulator of acute inflammation and sheds light on a new mechanism by which KSHV during the latent life cycle evades the host innate immune response. PMID- 21697473 TI - The E7 open reading frame acts in cis and in trans to mediate differentiation dependent activities in the human papillomavirus type 16 life cycle. AB - Human papillomaviruses (HPVs) are the causative agents of several important genital and other mucosal cancers. The HPV16 E7 gene encodes a viral oncogene that is necessary for the continued growth of cancer cells, but its role in the normal, differentiation-dependent life cycle of the virus is not fully understood. The function of E7 in the viral life cycle was examined using a series of mutations of E7 created in the context of the complete HPV16 genome. The effect of these E7 mutations on key events of the viral life cycle, including immortalization, episomal maintenance, late promoter activation, and infectious virion synthesis, was examined. Our studies show that the pRb binding domain is indispensable for early viral activities, whereas the C-terminal zinc finger domain contributed primarily to very late events. Mutations of the casein kinase II phosphorylation site caused a complex phenotype involving both the function of E7 protein and a cis element necessary for the activation of the late promoter, identifying for the first time a promoter element important for late promoter function in the context of the viral genome. All mutant genomes tested showed reduced viral titers following growth in organotypic raft cultures. These studies clarify the role of E7 as a regulator of late events in the differentiation dependent HPV life cycle. PMID- 21697474 TI - Effective antiviral treatment of systemic orthopoxvirus disease: ST-246 treatment of prairie dogs infected with monkeypox virus. AB - Smallpox preparedness research has led to development of antiviral therapies for treatment of serious orthopoxvirus infections. Monkeypox virus is an emerging, zoonotic orthopoxvirus which can cause severe and transmissible disease in humans, generating concerns for public health. Monkeypox virus infection results in a systemic, febrile-rash illness closely resembling smallpox. Currently, there are no small-molecule antiviral therapeutics approved to treat orthopoxvirus infections of humans. The prairie dog, using monkeypox virus as a challenge virus, has provided a valuable nonhuman animal model in which monkeypox virus infection closely resembles human systemic orthopoxvirus illness. Here, we assess the efficacy of the antiorthopoxvirus compound ST-246 in prairie dogs against a monkeypox virus challenge of 65 times the 50% lethal dose (LD(50)). Animals were infected intranasally and administered ST-246 for 14 days, beginning on days 0, 3, or after rash onset. Swab and blood samples were collected every 2 days and analyzed for presence of viral DNA by real-time PCR and for viable virus by tissue culture. Seventy-five percent of infected animals that received vehicle alone succumbed to infection. One hundred percent of animals that received ST-246 survived challenge, and animals that received treatment before symptom onset remained largely asymptomatic. Viable virus and viral DNA were undetected or at greatly reduced levels in animals that began treatment on 0 or 3 days postinfection, compared to control animals or animals treated post-rash onset. Animals treated after rash onset manifested illness, but all recovered. Our results indicate that ST-246 can be used therapeutically, following onset of rash illness, to treat systemic orthopoxvirus infections. PMID- 21697475 TI - Alteration of the chronic wasting disease species barrier by in vitro prion amplification. AB - Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of cervids now detected in 19 states of the United States, three Canadian provinces, and South Korea. Whether noncervid species can be infected by CWD and thereby serve as reservoirs for the infection is not known. To investigate this issue, we previously used serial protein misfolding cyclic amplification (sPMCA) to demonstrate that CWD prions can amplify in brain homogenates from several species sympatric with cervids, including prairie voles (Microtus ochrogaster) and field mice (Peromyscus spp.). Here, we show that prairie voles are susceptible to mule deer CWD prions in vivo and that sPMCA amplification of CWD prions in vole brain enhances the infectivity of CWD for this species. Prairie voles inoculated with sPMCA products developed clinical signs of TSE disease approximately 300 days prior to, and more consistently than, those inoculated with CWD prions from deer brain. Moreover, the deposition patterns and biochemical properties of protease-resistant form of PrP (PrP(RES)) in the brains of affected voles differed from those in cervidized transgenic (CerPrP) mice infected with CWD. In addition, voles inoculated orally with sPMCA products developed clinical signs of TSE and were positive for PrP(RES) deposition, whereas those inoculated orally with deer-origin CWD prions did not. These results demonstrate that transspecies sPMCA of CWD prions can enhance the infectivity and adapt the host range of CWD prions and thereby may be useful to assess determinants of prion species barriers. PMID- 21697476 TI - Cellular transcription factor Oct-1 interacts with the Epstein-Barr virus BRLF1 protein to promote disruption of viral latency. AB - The Epstein-Barr virus (EBV) latent-to-lytic switch is an essential part of the viral life cycle, but the cellular factors that promote viral reactivation are not well defined. In this report, we demonstrate that the cellular transcription factor Oct-1 cooperates with the EBV immediate-early protein BRLF1 (R, Rta) to induce lytic viral reactivation. We show that cotransfected Oct-1 enhances the ability of BRLF1 to activate lytic gene expression in 293 cells stably infected with a BRLF1-defective EBV mutant (BRLF1-stop) and that Oct-1 increases BRLF1 mediated activation of lytic EBV promoters in reporter gene assays. We find that Oct-1 interacts directly with BRLF1 in vitro and that a mutant BRLF1 protein (the M140A mutant) attenuated for the ability to interact with Oct-1 in vitro is also resistant to Oct-1-mediated transcriptional enhancement in 293 BRLF1-stop cells. Furthermore, we show that cotransfected Oct-1 augments BRLF1 binding to a variety of lytic EBV promoters in chromatin immunoprecipitation (ChIP) assays (including the BZLF1, BMRF1, and SM promoters) and that BRLF1 tethers Oct-1 to lytic EBV promoters. In addition, we demonstrate that an Oct-1 mutant defective in DNA binding (the S335D mutant) still retains the ability to enhance BRLF1 transcriptional effects. Finally, we show that knockdown of endogenous Oct-1 expression reduces the level of constitutive lytic EBV gene expression in both EBV-positive B-cell and EBV-positive epithelial cell lines. These results suggest that Oct-1 acts as a positive regulator of EBV lytic gene expression and that this effect is at least partially mediated through its interaction with the viral protein BRLF1. PMID- 21697477 TI - Ebolavirus delta-peptide immunoadhesins inhibit marburgvirus and ebolavirus cell entry. AB - With the exception of Reston and Lloviu viruses, filoviruses (marburgviruses, ebolaviruses, and "cuevaviruses") cause severe viral hemorrhagic fevers in humans. Filoviruses use a class I fusion protein, GP(1,2), to bind to an unknown, but shared, cell surface receptor to initiate virus-cell fusion. In addition to GP(1,2), ebolaviruses and cuevaviruses, but not marburgviruses, express two secreted glycoproteins, soluble GP (sGP) and small soluble GP (ssGP). All three glycoproteins have identical N termini that include the receptor-binding region (RBR) but differ in their C termini. We evaluated the effect of the secreted ebolavirus glycoproteins on marburgvirus and ebolavirus cell entry, using Fc tagged recombinant proteins. Neither sGP-Fc nor ssGP-Fc bound to filovirus permissive cells or inhibited GP(1,2)-mediated cell entry of pseudotyped retroviruses. Surprisingly, several Fc-tagged Delta-peptides, which are small C terminal cleavage products of sGP secreted by ebolavirus-infected cells, inhibited entry of retroviruses pseudotyped with Marburg virus GP(1,2), as well as Marburg virus and Ebola virus infection in a dose-dependent manner and at low molarity despite absence of sequence similarity to filovirus RBRs. Fc-tagged Delta-peptides from three ebolaviruses (Ebola virus, Sudan virus, and Tai Forest virus) inhibited GP(1,2)-mediated entry and infection of viruses comparably to or better than the Fc-tagged RBRs, whereas the Delta-peptide-Fc of an ebolavirus nonpathogenic for humans (Reston virus) and that of an ebolavirus with lower lethality for humans (Bundibugyo virus) had little effect. These data indicate that Delta-peptides are functional components of ebolavirus proteomes. They join cathepsins and integrins as novel modulators of filovirus cell entry, might play important roles in pathogenesis, and could be exploited for the synthesis of powerful new antivirals. PMID- 21697478 TI - Campylobacter jejuni group III phage CP81 contains many T4-like genes without belonging to the T4-type phage group: implications for the evolution of T4 phages. AB - CP81 is a virulent Campylobacter group III phage whose linear genome comprises 132,454 bp. At the nucleotide level, CP81 differs from other phages. However, a number of its structural and replication/recombination proteins revealed a relationship to the group II Campylobacter phages CP220/CPt10 and to T4-type phages. Unlike the T4-related phages, the CP81 genome does not contain conserved replication and virion modules. Instead, the respective genes are scattered throughout the phage genome. Moreover, most genes for metabolic enzymes of CP220/CPt10 are lacking in CP81. On the other hand, the CP81 genome contains nine similar genes for homing endonucleases which may be involved in the attrition of the conserved gene order for the virion core genes of T4-type phages. The phage apparently possesses an unusual modification of C or G bases. Efficient cleavage of its DNA was only achieved with restriction enzymes recognizing pure A/T sites. Uncommonly, phenol extraction leads to a significant loss of CP81 DNA from the aqueous layer, a property not yet described for other phages belonging to the T4 superfamily. PMID- 21697479 TI - In vivo comparison of chronic wasting disease infectivity from deer with variation at prion protein residue 96. AB - Chronic wasting disease (CWD) is a prion disease of cervids that causes neurodegeneration and death. Susceptibility to prion infections, including CWD, can be dependent on the amino acid sequence of the host prion protein (PrP). Here, CWD agent obtained from a deer expressing the 96SS genotype, associated with partial resistance to CWD, was used to infect transgenic (tg) mice expressing either 96GG or 96SS deer PrP. Transgenic mice expressing 96GG deer PrP succumbed to this agent, but tg mice expressing 96SS deer PrP did not. Additional studies using inocula from 96GG deer showed no transmission to 96SS PrP mice and delayed disease in 96GS mice. Thus, 96S PrP played an inhibitory role in disease progression in tg mice. PMID- 21697480 TI - Disulfide bond formation contributes to herpes simplex virus capsid stability and retention of pentons. AB - Disulfide bonds reportedly stabilize the capsids of several viruses, including papillomavirus, polyomavirus, and simian virus 40, and have been detected in herpes simplex virus (HSV) capsids. In this study, we show that in mature HSV-1 virions, capsid proteins VP5, VP23, VP19C, UL17, and UL25 participate in covalent cross-links, and that these are susceptible to dithiothreitol (DTT). In addition, several tegument proteins were found in high-molecular-weight complexes, including VP22, UL36, and UL37. Cross-linked capsid complexes can be detected in virions isolated in the presence and absence of N-ethylmaleimide (NEM), a chemical that reacts irreversibly with free cysteines to block disulfide formation. Intracellular capsids isolated in the absence of NEM contain disulfide cross-linked species; however, intracellular capsids isolated from cells pretreated with NEM did not. Thus, the free cysteines in intracellular capsids appear to be positioned such that disulfide bond formation can occur readily if they are exposed to an oxidizing environment. These results indicate that disulfide cross-links are normally present in extracellular virions but not in intracellular capsids. Interestingly, intracellular capsids isolated in the presence of NEM are unstable; B and C capsids are converted to a novel form that resembles A capsids, indicating that scaffold and DNA are lost. Furthermore, these capsids also have lost pentons and peripentonal triplexes as visualized by cryoelectron microscopy. These data indicate that capsid stability, and especially the retention of pentons, is regulated by the formation of disulfide bonds in the capsid. PMID- 21697481 TI - Emergence of genotype I of Japanese encephalitis virus as the dominant genotype in Asia. AB - Japanese encephalitis virus (JEV), a mosquito-borne zoonotic pathogen, is one of the major causes of viral encephalitis worldwide. Previous phylogenetic studies based on the envelope protein indicated that there are four genotypes, and surveillance data suggest that genotype I is gradually replacing genotype III as the dominant strain. Here we report an evolutionary analysis based on 98 full length genome sequences of JEV, including 67 new samples isolated from humans, pigs, mosquitoes, midges. and bats in affected areas. To investigate the relationships between the genotypes and the significance of genotype I in recent epidemics, we estimated evolutionary rates, ages of common ancestors, and population demographics. Our results indicate that the genotypes diverged in the order IV, III, II, and I and that the genetic diversity of genotype III has decreased rapidly while that of genotype I has increased gradually, consistent with its emergence as the dominant genotype. PMID- 21697483 TI - Enhanced sialic acid-dependent endocytosis explains the increased efficiency of infection of airway epithelia by a novel adeno-associated virus. AB - We previously used directed evolution in human airway epithelia to create adeno associated virus 2.5T (AAV2.5T), a highly infectious chimera of AAV2 and AAV5 with one point mutation (A581T). We hypothesized that the mechanism for its increased infection may be a higher binding affinity to the surface of airway epithelia than its parent AAV5. Here, we show that, like AAV5, AAV2.5T, uses 2,3N linked sialic acid as its primary receptor; however, AAV2.5T binds to the apical surface of human airway epithelia at higher levels and has more receptors than AAV5. Furthermore, its binding affinity is similar to that of AAV5. An alternative hypothesis is that AAV2.5T interaction with 2,3N-linked sialic acid may instead be required for cellular internalization. Consistent with this, AAV2.5T binds but fails to be internalized by CHO cells that lack surface expression of sialic acid. Moreover, whereas AAV2.5T binds similarly to human (rich in 2,3N-linked sialic acid) and pig airway epithelia (2,6N-linked sialic acid), significantly more virus was internalized by human airway. Subsequent transduction correlated with the level of internalized rather than surface-bound virus. We also found that human airway epithelia internalized significantly more AAV2.5T than AAV5. These data suggest that AAV2.5T has evolved to utilize specific 2,3N-linked sialic acid residues on the surface of airway epithelia that mediate rapid internalization and subsequent infection. Thus, sialic acid serves as not just an attachment factor but is also required for AAV2.5T internalization, possibly representing an important rate-limiting step for other viruses that use sialic acids. PMID- 21697482 TI - Adenovirus type 5 early region 1B 55K oncoprotein-dependent degradation of cellular factor Daxx is required for efficient transformation of primary rodent cells. AB - Early region 1B 55K (E1B-55K) from adenovirus type 5 (Ad5) is a multifunctional regulator of lytic infection and contributes in vitro to complete cell transformation of primary rodent cells in combination with Ad5 E1A. Inhibition of p53 activated transcription plays a key role in processes by which E1B-55K executes its oncogenic potential. Nevertheless, additional functions of E1B-55K or further protein interactions with cellular factors of DNA repair, transcription, and apoptosis, including Mre11, PML, and Daxx, may also contribute to the transformation process. In line with previous results, we performed mutational analysis to define a Daxx interaction motif within the E1B-55K polypeptide. The results from these studies showed that E1B-55K/Daxx binding is not required for inhibition of p53-mediated transactivation or binding and degradation of cellular factors (p53/Mre11). Surprisingly, these mutants lost the ability to degrade Daxx and showed reduced transforming potential in primary rodent cells. In addition, we observed that E1B-55K lacking the SUMO-1 conjugation site (SCS/K104R) was sufficient for Daxx interaction but no longer capable of E1B-55K-dependent proteasomal degradation of the cellular factor Daxx. These results, together with the observation that E1B-55K SUMOylation is required for efficient transformation, provides evidence for the idea that SUMO-1 conjugated E1B-55K-mediated degradation of Daxx plays a key role in adenoviral oncogenic transformation. We assume that the viral protein contributes to cell transformation through the modulation of Daxx-dependent pathways. This further substantiates the assumption that further mechanisms for efficient transformation of primary cells can be separated from functions required for the inhibition of p53-stimulated transcription. PMID- 21697484 TI - Characterization of H1N1 swine influenza viruses circulating in Canadian pigs in 2009. AB - The 2009 pandemic H1N1 (pH1N1), of apparent swine origin, may have evolved in pigs unnoticed because of insufficient surveillance. Consequently, the need for surveillance of influenza viruses circulating in pigs has received added attention. In this study we characterized H1N1 viruses isolated from Canadian pigs in 2009. Isolates from May 2009 were comprised of hemagglutinin and neuraminidase (NA) genes of classical SIV origin in combination with the North American triple-reassortant internal gene (TRIG) cassette, here termed contemporary SIV (conSIV) H1N1. These conSIV H1N1 viruses were contiguous with the North American alphaH1 cluster, which was distinct from the pH1N1 isolates that were antigenically more related to the gammaH1 cluster. After the initial isolation of pH1N1 from an Alberta pig farm in early May 2009, pH1N1 was found several times in Canadian pigs. These pH1N1 isolates were genetically and antigenically homogeneous. In addition, H1N1 viruses bearing seasonal human H1 and N1 genes together with the TRIG cassette and an NA encoding an oseltamivir resistance marker were isolated from pigs. The NS gene of one of these seasonal human-like SIV (shSIV) H1N1 isolates was homologous to pH1N1 NS, implicating reassortment between the two strains. Antigenic cross-reactivity was observed between pH1N1 and conSIV but not with shSIV H1N1. In summary, although there was cocirculation of pH1N1 with conSIV and shSIV H1N1 in Canadian pigs after May 2009, there was no evidence supporting the presence of pH1N1 in pigs prior to May 2009. The possibility for further reassortants being generated exists and should be closely monitored. PMID- 21697485 TI - Cleavage of the adaptor protein TRIF by enterovirus 71 3C inhibits antiviral responses mediated by Toll-like receptor 3. AB - Enterovirus 71 (EV71) causes hand-foot-and-mouth disease and neurological complications in young children. Although the underlying mechanisms remain obscure, impaired or aberrant immunity is thought to play a role. In infected cells, EV71 suppresses type I interferon responses mediated by retinoid acid inducible gene I (RIG-I). This involves the EV71 3C protein, which disrupts the formation of a functional RIG-I complex. In the present study, we report that EV71 inhibits the induction of innate immunity by Toll-like receptor 3 (TLR3) via a distinct mechanism. In HeLa cells stimulated with poly(I . C), EV71 inactivates interferon regulatory factor 3 and drastically suppresses interferon-stimulated gene expression. Notably, EV71 specifically downregulates a TRIF, TIR domain containing adaptor inducing beta interferon (IFN-beta). When expressed alone in mammalian cells, EV71 3C is capable of exhibiting these activities. EV71 3C associates with and induces TRIF cleavage in the presence of Z-VAD-FMK, a caspase inhibitor. TRIF cleavage depends on its amino acid pair Q312-S313, which resembles a proteolytic site of picornavirus 3C proteases. Further, site-specific 3C mutants with a defective protease activity bind TRIF but fail to mediate TRIF cleavage. Consequently, these 3C mutants are unable to inhibit NF-kappaB and IFN beta promoter activation. TRIF cleavage mediated by EV71 may be a mechanism to impair type I IFN production in response to Toll-like receptor 3 (TLR3) activation. PMID- 21697486 TI - Development and application of hepatitis C reporter viruses with genotype 1 to 7 core-nonstructural protein 2 (NS2) expressing fluorescent proteins or luciferase in modified JFH1 NS5A. AB - To facilitate genotype-specific high-throughput studies of hepatitis C virus (HCV), we have developed reporter viruses using JFH1-based recombinants expressing core-nonstructural protein 2 (NS2) of genotype 1 to 7 prototype isolates. We introduced enhanced green fluorescent protein (EGFP) into NS5A domain III of the genotype 2a virus J6/JFH1 [2a(J6)]. During Huh7.5 cell culture adaptation, 2a(J6)-EGFP acquired a 40-amino-acid (aa) (Delta40) or 25-aa (Delta25) deletion in NS5A domain II, rescuing the impairment of viral assembly caused by the EGFP insertion. Delta40 conferred efficient growth characteristics to 2a(J6) tagged with EGFP, DsRed-Express2, mCherry, or Renilla luciferase (RLuc), yielding peak supernatant infectivity titers of 4 to 5 log(10) focus forming units (FFU)/ml. 2a(J6) with Delta40 or Delta25 was fully viable in Huh7.5 cells. In human liver chimeric mice, 2a(J6)-EGFPDelta40 acquired various deletions in EGFP, while 2a(J6)Delta40 did not show an impaired viability. We further developed panels of JFH1-based genotype 1 to 7 core-NS2 recombinants expressing EGFP- or RLuc-NS5ADelta40 fusion proteins. In cell culture, the different EGFP recombinants showed growth characteristics comparable to those of the nontagged recombinants, with peak infectivity titers of 4 to 5 log(10) FFU/ml. RLuc recombinants showed slightly less efficient growth characteristics, with peak infectivity titers up to 10-fold lower. Overall, the EGFP and RLuc recombinants were genetically stable after one viral passage. The usefulness of these reporter viruses for high-throughput fluorescence- and luminescence-based studies of HCV-receptor interactions and serum-neutralizing antibodies was demonstrated. Finally, using RLuc viruses, we showed that the genotype-specific core-NS2 sequence did not influence the response to alfa-2b interferon (IFN-alfa 2b) and that genotype 1 to 7 viruses all responded to treatment with p7 ion channel inhibitors. PMID- 21697487 TI - Hepatitis C virus stimulates the phosphatidylinositol 4-kinase III alpha dependent phosphatidylinositol 4-phosphate production that is essential for its replication. AB - Phosphatidylinositol 4-kinase III alpha (PI4KA) is an essential cofactor of hepatitis C virus (HCV) replication. We initiated this study to determine whether HCV directly engages PI4KA to establish its replication. PI4KA kinase activity was found to be absolutely required for HCV replication using a small interfering RNA transcomplementation assay. Moreover, HCV infection or subgenomic HCV replicons produced a dramatic increase in phosphatidylinositol 4-phosphate (PI4P) accumulation throughout the cytoplasm, which partially colocalized with the endoplasmic reticulum. In contrast, the majority of PI4P accumulated at the Golgi bodies in uninfected cells. The increase in PI4P was not observed after infection with UV-inactivated HCV and did not reflect changes in PI4KA protein or RNA abundance. In an analysis of U2OS cell lines with inducible expression of the HCV polyprotein or individual viral proteins, viral polyprotein expression resulted in enhanced cytoplasmic PI4P production. Increased PI4P accumulation following HCV protein expression was precluded by silencing the expression of PI4KA, but not the related PI4KB. Silencing PI4KA also resulted in aberrant agglomeration of viral replicase proteins, including NS5A, NS5B, and NS3. NS5A alone, but not other viral proteins, stimulated PI4P production in vivo and enhanced PI4KA kinase activity in vitro. Lastly, PI4KA coimmunoprecipitated with NS5A from infected Huh-7.5 cells and from dually transfected 293T cells. In sum, these results suggest that HCV NS5A modulation of PI4KA-dependent PI4P production influences replication complex formation. PMID- 21697488 TI - Direct inhibition of tombusvirus plus-strand RNA synthesis by a dominant negative mutant of a host metabolic enzyme, glyceraldehyde-3-phosphate dehydrogenase, in yeast and plants. AB - The replication of plus-strand RNA viruses depends on many cellular factors. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an abundant metabolic enzyme that is recruited to the replicase complex of Tomato bushy stunt virus (TBSV) and affects asymmetric viral RNA synthesis. To further our understanding on the role of GAPDH in TBSV replication, we used an in vitro TBSV replication assay based on recombinant p33 and p92(pol) viral replication proteins and cell-free yeast extract. We found that the addition of purified recombinant GAPDH to the cell extract prepared from GAPDH-depleted yeast results in increased plus-strand RNA synthesis and asymmetric production of viral RNAs. Our data also demonstrate that GAPDH interacts with p92(pol) viral replication protein, which may facilitate the recruitment of GAPDH into the viral replicase complex in the yeast model host. In addition, we have identified a dominant negative mutant of GAPDH, which inhibits RNA synthesis and RNA recruitment in vitro. Moreover, this mutant also exhibits strong suppression of tombusvirus accumulation in yeast and in virus-infected Nicotiana benthamiana. Overall, the obtained data support the model that the co opted GAPDH plays a direct role in TBSV replication by stimulating plus-strand synthesis by the viral replicase. PMID- 21697489 TI - Antiviral activity of salmonid gamma interferon against infectious pancreatic necrosis virus and salmonid alphavirus and its dependency on type I interferon. AB - We investigated the antiviral activity and gene induction properties of interferon gamma (IFN-gamma) compared to type I IFN (IFNa1) in Atlantic salmon. IFN-gamma protected salmon cells against infectious pancreatic necrosis virus (IPNV)-induced cytopathic effect (CPE), reduced virus titers, and inhibited the synthesis of the viral structural protein VP3. Moreover, IFN-gamma showed potent antiviral activity against salmonid alphavirus 3 (SAV3) measured as a reduction in virus nsP1 transcripts. IFN-gamma (a type II IFN) had less specific antiviral activity against IPNV than IFNa1, showing a half-maximal effective concentration of 1.6 ng/ml versus 31 pg/ml determined in the CPE reduction assay. Compared to IFNa1, IFN-gamma was a more effective inducer of the antiviral protein GBP, several interferon regulatory transcription factors (IRFs), and the chemokine IP 10. The antiviral activity of IFN-gamma may also in part be ascribed to upregulation of Mx, ISG15, and viperin. These are typical type I IFN-induced genes in mammals and were also more strongly induced by IFNa1 than by IFN-gamma in salmon cells. Fish and mammalian IFN-gamma thus show strikingly similar gene induction properties. Interestingly, the antiviral activity of IFN-gamma against IPNV and SAV3 and its ability to induce Mx and ISG15 markedly decreased in the presence of neutralizing antiserum against IFNa1. In contrast, antiIFNa1 had no effect on the induction of IRF-1 and IP-10 by IFN-gamma. This suggests that the antiviral activity of IFN-gamma is partially dependent on IFNa induction. However, because antiIFNa1 could not abolish the IFN-gamma-mediated induction of Mx and ISG15 completely, IFN-gamma may possibly also induce such genes directly. PMID- 21697490 TI - Inhibition of HIV-1 Tat-mediated transcription by a coumarin derivative, BPRHIV001, through the Akt pathway. AB - The human immunodeficiency virus type 1 (HIV-1)-encoded RNA-binding protein Tat is known to play an essential role in viral gene expression. In the search for novel compounds to inhibit Tat transactivity, one coumarin derivative, BPRHIV001, was identified, with a 50% effective concentration (EC(50)) against HIV-1 at 1.3 nM. BPRHIV001 is likely to exert its effects at the stage after initiation of RNAPII elongation since Tat protein expression and the assembly of the Tat/P-TEFb complex remained unchanged. Next, a reduction of the p300 protein level, known to modulate Tat function through acetylation, was observed upon BPRHIV001 treatment, while the p300 mRNA level was unaffected. A concordant reduction of phosphorylated Akt, which was shown to be closely related to p300 stability, was observed in the presence of BPRHIV001 and was accompanied by a decrease of phosphorylated PDPK1, a well-known Akt activator. Furthermore, the docking analysis revealed that the reduced PDPK1 phosphorylation likely resulted from the allosteric effect of interaction between BPRHIV001 and PDPK1. With strong synergistic effects with current reverse transcriptase inhibitors, BPRHIV001 has the potential to become a promising lead compound for the development of a novel therapeutic agent against HIV-1 infection. PMID- 21697491 TI - The left half of the XMRV retrovirus is present in an endogenous retrovirus of NIH/3T3 Swiss mouse cells. AB - Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus found in association with human prostate cancer and chronic fatigue syndrome, although these associations are controversial. XMRV shows at most 94% identity to known mouse retroviruses. Here we used XMRV-specific PCR to search for a more closely related source of XMRV in mice. While we could not find a complete copy, we did find a 3,600-bp region of XMRV in an endogenous retrovirus present in NIH/3T3 cells. These results show that XMRV has clear ancestors in mice and highlight another possible source of contamination in PCR assays for XMRV. PMID- 21697492 TI - Hepatitis C virus infection promotes hepatic gluconeogenesis through an NS5A mediated, FoxO1-dependent pathway. AB - Chronic hepatitis C virus (HCV) infection is often associated with type 2 diabetes. However, the precise mechanism underlying this association is still unclear. Here, using Huh-7.5 cells either harboring HCV-1b RNA replicons or infected with HCV-2a, we showed that HCV transcriptionally upregulated the genes for phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), the rate-limiting enzymes for hepatic gluconeogenesis. In this way, HCV enhanced the cellular production of glucose 6-phosphate (G6P) and glucose. PEPCK and G6Pase gene expressions are controlled by the transcription factor forkhead box O1 (FoxO1). We observed that although neither the mRNA levels nor the protein levels of FoxO1 expression were affected by HCV, the level of phosphorylation of FoxO1 at Ser319 was markedly diminished in HCV-infected cells compared to the control cells, resulting in an increased nuclear accumulation of FoxO1, which is essential for sustaining its transcriptional activity. It was unlikely that the decreased level of FoxO1 phosphorylation was mediated through Akt inactivation, as we observed an increased phosphorylation of Akt at Ser473 in HCV-infected cells compared to control cells. By using specific inhibitors of c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS), we demonstrated that HCV infection induced JNK activation via increased mitochondrial ROS production, resulting in decreased FoxO1 phosphorylation, FoxO1 nuclear accumulation, and, eventually, increased glucose production. We also found that HCV NS5A mediated increased ROS production and JNK activation, which is directly linked with the FoxO1-dependent increased gluconeogenesis. Taken together, these observations suggest that HCV promotes hepatic gluconeogenesis through an NS5A-mediated, FoxO1 dependent pathway. PMID- 21697493 TI - Cutaneous human papillomavirus type 38 E7 regulates actin cytoskeleton structure for increasing cell proliferation through CK2 and the eukaryotic elongation factor 1A. AB - We previously reported that the oncoproteins E6 and E7 from cutaneous human papillomavirus type 38 (HPV38) can immortalize primary human keratinocytes in vitro and sensitize transgenic mice to develop skin cancer in vivo. Immunofluorescence staining revealed that human keratinocytes immortalized by HPV38 E6 and E7 display fewer actin stress fibers than do control primary keratinocyte cells, raising the possibility of a role of the viral oncoproteins in the remodeling of the actin cytoskeleton. In this study, we show that HPV38 E7 induces actin stress fiber disruption and that this phenomenon correlates with its ability to downregulate Rho activity. The downregulation of Rho activity by HPV38 E7 is mediated through the activation of the CK2-MEK-extracellular signal regulated kinase (ERK) pathway. In addition, HPV38 E7 is able to induce actin fiber disruption by binding directly to eukaryotic elongation factor 1A (eEF1A) and abolishing its effects on actin fiber formation. Finally, we found that the downregulation of Rho activity by HPV38 E7 through the CK2-MEK-ERK pathway facilitates cell growth proliferation. Taken together, our data support the conclusion that HPV38 E7 promotes keratinocyte proliferation in part by negatively regulating actin cytoskeleton fiber formation through the CK2-MEK-ERK Rho pathway and by binding to eEF1A and inhibiting its effects on actin cytoskeleton remodeling. PMID- 21697494 TI - Chimeric Chikungunya viruses are nonpathogenic in highly sensitive mouse models but efficiently induce a protective immune response. AB - Chikungunya virus (CHIKV) is an important pathogen causing outbreaks of highly debilitating and often chronic, arthralgic human disease. We have designed chimeric alphaviruses encoding CHIKV-specific structural proteins but no structural or nonstructural proteins capable of interfering with development of cellular antiviral response. These chimeras demonstrate a highly attenuated phenotype in both immunocompetent and immunocompromised (A129) mice. However, after a single vaccination, they induced protective immune response against subsequent CHIKV challenge, characterized by high titers of neutralizing antibodies. The rational design of alphavirus genomes provides a strong basis for the development of new recombinant alphaviruses with irreversible, highly attenuated, cell type-restricted phenotypes. PMID- 21697495 TI - Mutational analysis of the zippering reaction during flavivirus membrane fusion. AB - The current model of flavivirus membrane fusion is based on atomic structures of truncated forms of the viral fusion protein E in its dimeric prefusion and trimeric postfusion conformations. These structures lack the two transmembrane domains (TMDs) of E as well as the so-called stem, believed to be involved in an intra- and intermolecular zippering reaction within the E trimer during the fusion process. In order to gain experimental evidence for the functional role of the stem in flavivirus membrane fusion, we performed a mutagenesis study with recombinant subviral particles (RSPs) of tick-borne encephalitis virus, which have fusion properties similar to those of whole infectious virions and are an established model for viral fusion. Mutations were introduced into the stem as well as that part of E predicted to interact with the stem during zippering, and the effect of these mutations was analyzed with respect to fusion peptide interactions with target cells, E protein trimerization, trimer stability, and membrane fusion in an in vitro liposome fusion assay. Our data provide evidence for a molecular interaction between a conserved phenylalanine at the N-terminal end of the stem and a pocket in domain II of E, which appears to be essential for the positioning of the stem in an orientation that allows zippering and the formation of a structure in which the TMDs can interact as required for efficient fusion. PMID- 21697496 TI - cis-Acting effects on RNA processing and Drosha cleavage prevent Epstein-Barr virus latency III BHRF1 expression. AB - In Epstein-Barr virus (EBV) latency III (LTIII) infection, BHRF1 encodes three microRNAs (miRNAs). Herein we report that Drosha cleavage of LTIII BHRF1 RNA and cis-acting splicing effects inhibit splicing and inhibit BHRF1 RNA and protein expression. Evidence shown here supports the view that Drosha cleavage to generate mature miRNAs and cis-acting sequences that prevent mRNA maturation are independent processes that prevent LTIII BHRF1 expression in lymphoblastoid cell lines. PMID- 21697497 TI - Type I interferon contributes to CD4+ T cell depletion induced by infection with HIV-1 in the human thymus. AB - Persistent induction of type 1 interferon (IFN) is associated with human immunodeficiency virus type 1 (HIV-1) infection. We report here that the pathogenic HIV strain R3A (HIV-R3A) induced high levels of type 1 IFN, while the nonpathogenic HIV-R3B showed no significant induction in human fetal thymus organ culture (HFTOC). We found that IFN contributed to the depletion of human T cells by HIV-R3A in a fusion-independent fashion. The R3B recombinant with the R3A Env V1V2 domain (R3B/A-V1V2) was able to induce type 1 IFN, which contributed to the increased depletion of T cells. Therefore, type 1 IFN induction plays a significant role in HIV-induced T cell depletion in the human thymus. PMID- 21697498 TI - APOBEC3 has not left an evolutionary footprint on the HIV-1 genome. AB - It is known that the human immune proteins APOBEC3G and -F (hA3G/F) can inhibit Vif-deficient HIV by G-to-A mutation; however, the roles of these enzymes in the evolution of HIV are debated. We argue that if evolutionary pressure from hA3G/F exists there should be evidence of their imprint on the HIV genome in the form of (i) underrepresentation of hA3G/F target motifs (e.g., TGGG [targeted position is underlined]) and overrepresentation of product motifs (e.g., TAGG) and/or (ii) an increase in the ratio of nonsynonymous to synonymous (NS/S) G-to-A changes among hA3G/F target motifs and a decrease of NS/S A-to-G changes among hA3G/F product motifs. To test the first hypothesis, we studied the representation of hA3G/F target and product motifs in 1,932 complete HIV-1 genomes using Markov models. We found that the highly targeted motifs are not underrepresented and their product motifs are not overrepresented. To test the second hypothesis, we determined the NS/S G<->A changes among the hA3G/F target and product motifs in 1,540 complete sets of nine HIV-1 genes. The NS/S changes did not show an increasing/decreasing trend within the target/product motifs, but the NS/S changes within the motif AG was exceptionally low. We observed the same pattern by analyzing 740 human genes. Given that hA3G/F do not act on the human genome, this suggests a small NS/S change within AG has arisen by other mechanisms. We therefore find no evidence of an evolutionary footprint of hA3G/F. We postulate several mechanisms to explain why the HIV-1 genome does not contain the hA3G/F footprint. PMID- 21697499 TI - Oxidized LDL and the risk of coronary heart disease: results from the MONICA/KORA Augsburg Study. AB - BACKGROUND: Oxidative stress plays a critical role in the initiation and progression of atherosclerosis. Oxidized LDL (oxLDL) is a marker of oxidative stress. We prospectively investigated whether increased serum oxLDL concentrations are associated with incident coronary heart disease (CHD). METHODS: We conducted a prospective population-based case-cohort study within the MONICA/KORA Augsburg studies. Serum oxLDL concentrations were measured in 333 case individuals with incident CHD and in 1727 noncase individuals selected from a source population of 9300 middle-aged, healthy men and women. The mean (SD) follow-up time was 10.8 (4.6) years. RESULTS: Baseline oxLDL concentrations were higher in case individuals than in noncase individuals (P < 0.001). After adjustment for age, sex, survey, smoking status, systolic blood pressure, physical activity, diabetes, body mass index, parental history of myocardial infarction, and alcohol consumption, the hazard ratio (HR) for comparing the first and third tertiles was 1.87 (95% CI, 1.33-2.64; P < 0.001). Additional adjustment for lipid parameters, inflammatory markers, and markers of endothelial dysfunction attenuated the association (HR, 1.29; 95% CI, 0.88-1.89; P = 0.087). We observed no significant interactions between oxLDL and sex or being overweight. CONCLUSIONS: Increased oxLDL concentrations were associated with an increased risk for incident CHD. Nevertheless, because this effect became nonsignificant after adjustment for covariates, particularly the ratio of total cholesterol to HDL cholesterol, it may be mediated primarily by lipid parameters. Further studies are warranted to clarify this issue. PMID- 21697500 TI - Association of telomere length in older men with mortality and midlife body mass index and smoking. AB - BACKGROUND: Leukocyte telomere length has been taken as a measure of biological age but several inconsistencies exist. METHODS: We investigated associations between leukocyte telomere length in old age, midlife risk factors, and mortality. The Helsinki Businessmen Study (a cohort of mainly business executives, born 1919-1934) had baseline assessments of cardiovascular risk factors including body mass index between 1964 and 1973 at a mean age of 40. Leukocyte telomere length and proportion of short telomeres were measured from DNA samples collected in 2002-2003 (n = 622, mean age 78 years). Body mass index and smoking in old age were assessed from questionnaires. Total mortality was verified from registers through January 2010. Main outcome measures were relationships between telomeres, body mass index, smoking, and mortality. RESULTS: Leukocyte telomere length and notably proportion of short telomeres (<5kb) in old age were significantly (p =. 008 after full adjustments) and in a graded manner associated with midlife overweight and smoking. The associations were independent of age and cardiovascular risk factors including postload glucose. Associations with body mass index and smoking were nonsignificant in old age, and telomere length did not predict 7-year total mortality. CONCLUSIONS: We conclude that smoking and overweight in midlife, irrespective of glucose, cholesterol and blood pressure, are related to shorter leukocyte telomeres in old men. Telomere length in old age did not predict total mortality possibly due to competing causes. PMID- 21697501 TI - Clinical meaningfulness of the changes in muscle performance and physical function associated with testosterone administration in older men with mobility limitation. AB - CONTEXT: Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trial's Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participant's perception of change. METHODS: Men aged 65 years and older, with mobility limitation, total testosterone 100-350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared. RESULTS: Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change. CONCLUSIONS: Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this population. PMID- 21697502 TI - bop5 Mutations reveal new roles for the IC138 phosphoprotein in the regulation of flagellar motility and asymmetric waveforms. AB - I1 dynein, or dynein f, is a highly conserved inner arm isoform that plays a key role in the regulation of flagellar motility. To understand how the IC138 IC/LC subcomplex modulates I1 activity, we characterized the molecular lesions and motility phenotypes of several bop5 alleles. bop5-3, bop5-4, and bop5-5 are null alleles, whereas bop5-6 is an intron mutation that reduces IC138 expression. I1 dynein assembles into the axoneme, but the IC138 IC/LC subcomplex is missing. bop5 strains, like other I1 mutants, swim forward with reduced swimming velocities and display an impaired reversal response during photoshock. Unlike mutants lacking the entire I1 dynein, however, bop5 strains exhibit normal phototaxis. bop5 defects are rescued by transformation with the wild-type IC138 gene. Analysis of flagellar waveforms reveals that loss of the IC138 subcomplex reduces shear amplitude, sliding velocities, and the speed of bend propagation in vivo, consistent with the reduction in microtubule sliding velocities observed in vitro. The results indicate that the IC138 IC/LC subcomplex is necessary to generate an efficient waveform for optimal motility, but it is not essential for phototaxis. These findings have significant implications for the mechanisms by which IC/LC complexes regulate dynein motor activity independent of effects on cargo binding or complex stability. PMID- 21697503 TI - Role of Hsc70 binding cycle in CFTR folding and endoplasmic reticulum-associated degradation. AB - The Hsp/c70 cytosolic chaperone system facilitates competing pathways of protein folding and degradation. Here we use a reconstituted cell-free system to investigate the mechanism and extent to which Hsc70 contributes to these co- and posttranslational decisions for the membrane protein cystic fibrosis transmembrane conductance regulator (CFTR). Hsc70 binding to CFTR was destabilized by the C-terminal domain of Bag-1 (CBag), which stimulates client release by accelerating ADP-ATP exchange. Addition of CBag during CFTR translation slightly increased susceptibility of the newly synthesized protein to degradation, consistent with a profolding function for Hsc70. In contrast, posttranslational destabilization of Hsc70 binding nearly completely blocked CFTR ubiquitination, dislocation from the endoplasmic reticulum, and proteasome mediated cleavage. This effect required molar excess of CBag relative to Hsc70 and was completely reversed by the CBag-binding subdomain of Hsc70. These results demonstrate that the profolding role of Hsc70 during cotranslational CFTR folding is counterbalanced by a dominant and essential role in posttranslational targeting to the ubiquitin-proteasome system. Moreover, the degradative outcome of Hsc70 binding appears highly sensitive to the duration of its binding cycle, which is in turn governed by the integrated expression of regulatory cochaperones. PMID- 21697504 TI - The spindle checkpoint protein Mad2 regulates APC/C activity during prometaphase and metaphase of meiosis I in Saccharomyces cerevisiae. AB - In many eukaryotes, disruption of the spindle checkpoint protein Mad2 results in an increase in meiosis I nondisjunction, suggesting that Mad2 has a conserved role in ensuring faithful chromosome segregation in meiosis. To characterize the meiotic function of Mad2, we analyzed individual budding yeast cells undergoing meiosis. We find that Mad2 sets the duration of meiosis I by regulating the activity of APC(Cdc20). In the absence of Mad2, most cells undergo both meiotic divisions, but securin, a substrate of the APC/C, is degraded prematurely, and prometaphase I/metaphase I is accelerated. Some mad2Delta cells have a misregulation of meiotic cell cycle events and undergo a single aberrant division in which sister chromatids separate. In these cells, both APC(Cdc20) and APC(Ama1) are prematurely active, and meiosis I and meiosis II events occur in a single meiotic division. We show that Mad2 indirectly regulates APC(Ama1) activity by decreasing APC(Cdc20) activity. We propose that Mad2 is an important meiotic cell cycle regulator that ensures the timely degradation of APC/C substrates and the proper orchestration of the meiotic divisions. PMID- 21697505 TI - Arp2/3 promotes junction formation and maintenance in the Caenorhabditis elegans intestine by regulating membrane association of apical proteins. AB - It has been proposed that Arp2/3, which promotes nucleation of branched actin, is needed for epithelial junction initiation but is less important as junctions mature. We focus here on how Arp2/3 contributes to the Caenorhabditis elegans intestinal epithelium and find important roles for Arp2/3 in the maturation and maintenance of junctions in embryos and adults. Electron microscope studies show that embryos depleted of Arp2/3 form apical actin-rich microvilli and electron dense apical junctions. However, whereas apical/basal polarity initiates, apical maturation is defective, including decreased apical F-actin enrichment, aberrant lumen morphology, and reduced accumulation of some apical junctional proteins, including DLG-1. Depletion of Arp2/3 in adult animals leads to similar intestinal defects. The DLG-1/AJM-1 apical junction proteins, and the ezrin-radixin-moesin homologue ERM-1, a protein that connects F-actin to membranes, are required along with Arp2/3 for apical F-actin enrichment in embryos, whereas cadherin junction proteins are not. Arp2/3 affects the subcellular distribution of DLG-1 and ERM-1. Loss of Arp2/3 shifts both ERM-1 and DLG-1 from pellet fractions to supernatant fractions, suggesting a role for Arp2/3 in the distribution of membrane associated proteins. Thus, Arp2/3 is required as junctions mature to maintain apical proteins associated with the correct membranes. PMID- 21697506 TI - Golgi localization of ERManI defines spatial separation of the mammalian glycoprotein quality control system. AB - The Golgi complex has been implicated as a possible component of endoplasmic reticulum (ER) glycoprotein quality control, although the elucidation of its exact role is lacking. ERManI, a putative ER resident mannosidase, plays a rate limiting role in generating a signal that targets misfolded N-linked glycoproteins for ER-associated degradation (ERAD). Herein we demonstrate that the endogenous human homologue predominantly resides in the Golgi complex, where it is subjected to O-glycosylation. To distinguish the intracellular site where the glycoprotein ERAD signal is generated, a COPI-binding motif was appended to the N terminus of the recombinant protein to facilitate its retrograde translocation back to the ER. Partial redistribution of the modified ERManI was observed along with an accelerated rate at which N-linked glycans of misfolded alpha1-antitrypsin variant NHK were trimmed. Despite these observations, the rate of NHK degradation was not accelerated, implicating the Golgi complex as the site for glycoprotein ERAD substrate tagging. Taken together, these data provide a potential mechanistic explanation for the spatial separation by which glycoprotein quality control components operate in mammalian cells. PMID- 21697507 TI - Assembly and sorting of the tonoplast potassium channel AtTPK1 and its turnover by internalization into the vacuole. AB - The assembly, sorting signals, and turnover of the tonoplast potassium channel AtTPK1 of Arabidopsis (Arabidopsis thaliana) were studied. We used transgenic Arabidopsis expressing a TPK1-green fluorescent protein (GFP) fusion or protoplasts transiently transformed with chimeric constructs based on domain exchange between TPK1 and TPK4, the only TPK family member not located at the tonoplast. The results show that TPK1-GFP is a dimer and that the newly synthesized polypeptides transiently interact with a thus-far unidentified 20-kD polypeptide. A subset of the TPK1-TPK4 chimeras were unable to assemble correctly and these remained located in the endoplasmic reticulum where they interacted with the binding protein chaperone. Therefore, TPK1 must assemble correctly to pass endoplasmic reticulum quality control. Substitution of the cytosolic C terminus of TPK4 with the corresponding domain of TPK1 was sufficient to allow tonoplast delivery, indicating that this domain contains tonoplast sorting information. Pulse-chase labeling indicated that TPK1-GFP has a half-life of at least 24 h. Turnover of the fusion protein involves internalization into the vacuole where the GFP domain is released. This indicates a possible mechanism for the turnover of tonoplast proteins. PMID- 21697508 TI - Cell wall modifications in maize pulvini in response to gravitational stress. AB - Changes in cell wall polysaccharides, transcript abundance, metabolite profiles, and hormone concentrations were monitored in the upper and lower regions of maize (Zea mays) pulvini in response to gravistimulation, during which maize plants placed in a horizontal position returned to the vertical orientation. Heteroxylan levels increased in the lower regions of the pulvini, together with lignin, but xyloglucans and heteromannan contents decreased. The degree of substitution of heteroxylan with arabinofuranosyl residues decreased in the lower pulvini, which exhibited increased mechanical strength as the plants returned to the vertical position. Few or no changes in noncellulosic wall polysaccharides could be detected on the upper side of the pulvinus, and crystalline cellulose content remained essentially constant in both the upper and lower pulvinus. Microarray analyses showed that spatial and temporal changes in transcript profiles were consistent with the changes in wall composition that were observed in the lower regions of the pulvinus. In addition, the microarray analyses indicated that metabolic pathways leading to the biosynthesis of phytohormones were differentially activated in the upper and lower regions of the pulvinus in response to gravistimulation. Metabolite profiles and measured hormone concentrations were consistent with the microarray data, insofar as auxin, physiologically active gibberellic acid, and metabolites potentially involved in lignin biosynthesis increased in the elongating cells of the lower pulvinus. PMID- 21697509 TI - Striatal origin of the pathologic beta oscillations in Parkinson's disease. AB - Enhanced oscillations at beta frequencies (8-30 Hz) are a signature neural dynamic pathology in the basal ganglia and cortex of Parkinson's disease patients. The mechanisms underlying these pathological beta oscillations remain elusive. Here, using mathematical models, we find that robust beta oscillations can emerge from inhibitory interactions between striatal medium spiny neurons. The interaction of the synaptic GABAa currents and the intrinsic membrane M current promotes population oscillations in the beta frequency range. Increased levels of cholinergic drive, a condition relevant to the parkinsonian striatum, lead to enhanced beta oscillations in the striatal model. We show experimentally that direct infusion of the cholinergic agonist carbachol into the striatum, but not into the neighboring cortex, of the awake, normal rodent induces prominent beta frequency oscillations in the local field potential. These results provide evidence for amplification of normal striatal network dynamics as a mechanism responsible for the enhanced beta frequency oscillations in Parkinson's disease. PMID- 21697510 TI - MicroRNA regulation of homeostatic synaptic plasticity. AB - Homeostatic mechanisms are required to control formation and maintenance of synaptic connections to maintain the general level of neural impulse activity within normal limits. How genes controlling these processes are co-coordinately regulated during homeostatic synaptic plasticity is unknown. MicroRNAs (miRNAs) exert regulatory control over mRNA stability and translation and may contribute to local and activity-dependent posttranscriptional control of synapse-associated mRNAs. However, identifying miRNAs that function through posttranscriptional gene silencing at synapses has remained elusive. Using a bioinformatics screen to identify sequence motifs enriched in the 3'UTR of rapidly destabilized mRNAs, we identified a developmentally and activity-regulated miRNA (miR-485) that controls dendritic spine number and synapse formation in an activity-dependent homeostatic manner. We find that many plasticity-associated genes contain predicted miR-485 binding sites and further identify the presynaptic protein SV2A as a target of miR-485. miR-485 negatively regulated dendritic spine density, postsynaptic density 95 (PSD-95) clustering, and surface expression of GluR2. Furthermore, miR 485 overexpression reduced spontaneous synaptic responses and transmitter release, as measured by miniature excitatory postsynaptic current (EPSC) analysis and FM 1-43 staining. SV2A knockdown mimicked the effects of miR-485, and these effects were reversed by SV2A overexpression. Moreover, 5 d of increased synaptic activity induced homeostatic changes in synaptic specializations that were blocked by a miR-485 inhibitor. Our findings reveal a role for this previously uncharacterized miRNA and the presynaptic protein SV2A in homeostatic plasticity and nervous system development, with possible implications in neurological disorders (e.g., Huntington and Alzheimer's disease), where miR-485 has been found to be dysregulated. PMID- 21697511 TI - Cyclin-dependent kinase subunit (Cks) 1 or Cks2 overexpression overrides the DNA damage response barrier triggered by activated oncoproteins. AB - Cyclin-dependent kinase subunit (Cks) proteins are small cyclin-dependent kinase interacting proteins that are frequently overexpressed in breast cancer, as well as in a broad spectrum of other human malignancies. However, the mechanistic link between Cks protein overexpression and oncogenesis is still unknown. In this work, we show that overexpression of Cks1 or Cks2 in human mammary epithelial and breast cancer-derived cells, as well as in other cell types, leads to override of the intra-S-phase checkpoint that blocks DNA replication in response to replication stress. Specifically, binding of Cks1 or Cks2 to cyclin-dependent kinase 2 confers partial resistance to the effects of inhibitory tyrosine phosphorylation mediated by the intra-S-phase checkpoint, allowing cells to continue replicating DNA even under conditions of replicative stress. Because many activated oncoproteins trigger a DNA damage checkpoint response, which serves as a barrier to proliferation and clonal expansion, Cks protein overexpression likely constitutes one mechanism whereby premalignant cells can circumvent this DNA damage response barrier, conferring a proliferative advantage under stress conditions, and therefore contributing to tumor development. PMID- 21697513 TI - Mouse embryos stressed by physiological levels of osmolarity become arrested in the late 2-cell stage before entry into M phase. AB - Preimplantation mouse embryos of many strains become arrested at the 2-cell stage if the osmolarity of culture medium that normally supports development to blastocysts is raised to approximately that of their normal physiological environment in the oviduct. Arrest can be prevented if molecules that serve as "organic osmolytes" are present in the medium, because organic osmolytes, principally glycine, are accumulated by embryos to provide intracellular osmotic support and regulate cell volume. Medium with an osmolarity of 310 mOsM induced arrest of approximately 80% of CF1 mouse embryos at the 2-cell stage, in contrast to the approximately 100% that progressed beyond the 2-cell stage at 250 or 301 mOsM with glycine. The nature of this arrest induced by physiological levels of osmolarity is unknown. Arrest was reversible by transfer to lower-osmolarity medium at any point during the 2-cell stage, but not after embryos would normally have progressed to the 4-cell stage. Cessation of development likely was not due to apoptosis, as shown by lack of external annexin V binding, detectable cytochrome c release from mitochondria, or nuclear DNA fragmentation. Two-cell embryos cultured at 310 mOsM progressed through the S phase, and zygotic genome activation markers were expressed. However, most embryos failed to initiate the M phase, as evidenced by intact nuclei with decondensed chromosomes, low M-phase promoting factor activity, and an inactive form of CDK1, although a few blastomeres were arrested in metaphase. Thus, embryos become arrested late in the G(2) stage of the second embryonic cell cycle when stressed by physiological osmolarity in the absence of organic osmolytes. PMID- 21697512 TI - A general strategy for the evolution of bond-forming enzymes using yeast display. AB - The ability to routinely generate efficient protein catalysts of bond-forming reactions chosen by researchers, rather than nature, is a long-standing goal of the molecular life sciences. Here, we describe a directed evolution strategy for enzymes that catalyze, in principle, any bond-forming reaction. The system integrates yeast display, enzyme-mediated bioconjugation, and fluorescence activated cell sorting to isolate cells expressing proteins that catalyze the coupling of two substrates chosen by the researcher. We validated the system using model screens for Staphylococcus aureus sortase A-catalyzed transpeptidation activity, resulting in enrichment factors of 6,000-fold after a single round of screening. We applied the system to evolve sortase A for improved catalytic activity. After eight rounds of screening, we isolated variants of sortase A with up to a 140-fold increase in LPETG-coupling activity compared with the starting wild-type enzyme. An evolved sortase variant enabled much more efficient labeling of LPETG-tagged human CD154 expressed on the surface of HeLa cells compared with wild-type sortase. Because the method developed here does not rely on any particular screenable or selectable property of the substrates or product, it represents a powerful alternative to existing enzyme evolution methods. PMID- 21697515 TI - Quantitative investigations on the effects of exposure durations to the combined cryoprotective agents on mouse oocyte vitrification procedures. AB - Vitrification by using two-step exposures to combined cryoprotective agents (CPAs) has become one of the most common methods for oocyte cryopreservation. By quantitatively examining the status of oocytes during CPA additions and dilutions, we can analyze the degree of the associated osmotic damages. The osmotic responses of mouse MII oocyte in the presence of the combined CPAs (ethylene glycol, EG, and dimethyl sulfoxide, DMSO) were recorded and analyzed. A two-parameter model was used in the curve-fitting calculation to determine the values of hydraulic conductivity (L(p)) and permeability (P(s)) to the combined CPAs at 25 degrees C and 37 degrees C. The effects of exposure durations and the exposure temperatures on the cryopreservation in terms of frozen-thawed cell survival rates and subsequent development were examined in a series of cryopreservation experiments. Mouse MII oocytes were exposed to pretreatment solution (PTS) and vitrification solution (VS) at specific temperatures. The PTS used in our experiment was 10% EG and 10% DMSO dissolved in modified PBS (mPBS), and the VS was EDFS30 (15% EG, 15% DMSO, 3 * 10(-3) M Ficoll, and 0.35 M sucrose in mPBS).The accumulative osmotic damage (AOD) and intracellular CPA concentrations were calculated under the different cryopreservation conditions, and for the first time, the quantitative interactions between survival rates, subsequent development rates, and values of AOD were investigated. PMID- 21697516 TI - Generation of viable embryos and embryonic stem cell-like cells from cultured primary follicles in mice. AB - Primary follicles retrieved from B6CBAF1 prepubertal mice were cultured in a stepwise manner in an alpha-minimum essential medium-based medium to generate viable embryos and embryonic stem cell (ESC)-like cells. A significant increase in follicle growth and oocyte maturation accompanied by increased secretion of 17beta-estradiol and progesterone was achieved by exposing primary follicles to 100 or 200 mIU of follicle-stimulating hormone (FSH) during culture. More oocytes developed into blastocysts following in vitro fertilization (IVF) or parthenogenetic activation after culture with 200 mIU of FSH during the entire culture period than with 100 mIU. Eleven ESC-like cell lines, consisting of four heterozygotic and seven homozygotic phenotypes, were established from 25 trials of primary follicle culture combined with IVF or parthenogenetic activation. In conclusion, primary follicles can potentially yield developmentally competent oocytes, which produce viable embryos and ESC-like cell lines following in vitro manipulation. We suggest a method to utilize immature follicles, which are most abundant in ovaries, to improve reproductive efficiency and for use in regenerative medicine. PMID- 21697517 TI - Large differences in peak oxygen uptake do not independently alter changes in core temperature and sweating during exercise. AB - The independent influence of peak oxygen uptake (Vo(2 peak)) on changes in thermoregulatory responses during exercise in a neutral climate has not been previously isolated because of complex interactions between Vo(2 peak), metabolic heat production (H(prod)), body mass, and body surface area (BSA). It was hypothesized that Vo(2 peak) does not independently alter changes in core temperature and sweating during exercise. Fourteen males, 7 high (HI) Vo(2 peak): 60.1 +/- 4.5 ml.kg-1.min-1; 7 low (LO) Vo(2 peak): 40.3 +/- 2.9 ml.kg-1.min-1 matched for body mass (HI: 78.2 +/- 6.1 kg; LO: 78.7 +/- 7.1 kg) and BSA (HI: 1.97 +/- 0.08 m2; LO: 1.94 +/- 0.08 m2), cycled for 60-min at 1) a fixed heat production (FHP trial) and 2) a relative exercise intensity of 60% Vo(2 peak) (REL trial) at 24.8 +/- 0.6 degrees C, 26 +/- 10% RH. In the FHP trial, H(prod) was similar between the HI (542 +/- 38 W, 7.0 +/- 0.6 W/kg or 275 +/- 25 W/m2) and LO (535 +/- 39 W, 6.9 +/- 0.9 W/kg or 277 +/- 29 W/m2) groups, while changes in rectal (T(re): HI: 0.87 +/- 0.15 degrees C, LO: 0.87 +/- 0.18 degrees C, P = 1.00) and aural canal (T(au): HI: 0.70 +/- 0.12 degrees C, LO: 0.74 +/- 0.21 degrees C, P = 0.65) temperature, whole-body sweat loss (WBSL) (HI: 434 +/- 80 ml, LO: 440 +/- 41 ml; P = 0.86), and steady-state local sweating (LSR(back)) (P = 0.40) were all similar despite relative exercise intensity being different (HI: 39.7 +/- 4.2%, LO: 57.6 +/- 8.0% Vo(2 peak); P = 0.001). At 60% Vo(2 peak), H(prod) was greater in the HI (834 +/- 77 W, 10.7 +/- 1.3 W/kg or 423 +/- 44 W/m2) compared with LO (600 +/- 90 W, 7.7 +/- 1.4 W/kg or 310 +/- 50 W/m2) group (all P < 0.001), as were changes in T(re) (HI: 1.43 +/- 0.28 degrees C, LO: 0.89 +/- 0.19 degrees C; P = 0.001) and T(au) (HI: 1.11 +/- 0.21 degrees C, LO: 0.66 +/- 0.14 degrees C; P < 0.001), and WBSL between 0 and 15, 15 and 30, 30 and 45, and 45 and 60 min (all P < 0.01), and LSR(back) (P = 0.02). The absolute esophageal temperature (T(es)) onset for sudomotor activity was ~0.3 degrees C lower (P < 0.05) in the HI group, but the change in T(es) from preexercise values before sweating onset was similar between groups. Sudomotor thermosensitivity during exercise were similar in both FHP (P = 0.22) and REL (P = 0.77) trials. In conclusion, changes in core temperature and sweating during exercise in a neutral climate are determined by H(prod), mass, and BSA, not Vo(2 peak). PMID- 21697514 TI - Xenobiotic effects on ovarian preantral follicles. AB - Women are born with a finite population of ovarian follicles, which are slowly depleted during their reproductive years until reproductive failure (menopause) occurs. The rate of loss of primordial follicles is determined by genetic and environmental influences, but certain toxic exposures can accelerate this process. Ionizing radiation reduces preantral follicle numbers in rodents and humans in a dose-dependent manner. Cigarette smoking is linked to menopause occurring 1-4 yr earlier than with nonsmokers, and components of smoke, polycyclic aromatic hydrocarbons, can cause follicle depletion in rodents or in ovaries in vitro. Chemotherapeutic agents, such as alkylating drugs and cisplatin, also cause loss of preantral ovarian follicles. Effects depend on dose, type, and reactivity of the drug, and the age of the individual. Evidence suggests DNA damage may underlie follicle loss induced by one common alkylating drug, cyclophosphamide. Occupational exposures have also been linked to ovarian damage. In an industrial setting, 2-bromopropane caused infertility in men and women, and it can induce ovarian follicle depletion in rats. Solvents, such as butadiene, 4-vinylcyclohexene, and their diepoxides, can also cause specific preantral follicle depletion. The mechanism(s) underlying effects of the latter compound may involve alterations in apoptosis, survival factors such as KIT/Kit Ligand, and/or the cellular signaling that maintains primordial follicle dormancy. Estrogenic endocrine disruptors may alter follicle formation/development and impair fertility or normal development of offspring. Thus, specific exposures are known or suspected of detrimentally impacting preantral ovarian follicles, leading to early ovarian failure. PMID- 21697519 TI - Effect of pulmonary TNF-alpha overexpression on mouse isolated skeletal muscle function. AB - TNF-alpha is a proinflammatory cytokine that is involved in numerous pathological processes including chronic obstructive pulmonary disease (COPD). In the present study, we used a transgenic mouse model that overexpresses TNF-alpha in the lung (Tg(+)) to test the hypothesis that chronic exposure to TNF-alpha (as seen in COPD) reduces skeletal muscle force production and fatigue resistance, particularly under low Po(2) conditions. At 7-12 mo, body and muscle weight of both extensor digitorum longus (EDL) and soleus were significantly smaller in Tg(+) compared with littermate wild-type (WT) mice; however, the body-to-muscle weight ratio was not different between groups. EDL and soleus muscles were subjected to in vitro fatiguing contractile periods under high (~550 Torr) and low Po(2) (~40 Torr). Although all muscles were less fatigue-resistant during low Po(2) compared with high Po(2), only the soleus fatigued more rapidly in Tg(+) mice (~12%) compared with WT at high Po(2). The maximal tension of EDL was equally reduced in Tg(+) mice (28-34% decrease from WT under both Po(2) conditions); but for soleus this parameter was smaller only under low Po(2) in Tg(+) mice (~31% decrease from WT). The peak rate of relaxation and the peak rate of contraction were both significantly reduced in Tg(+) EDL muscles compared with WT EDL under low Po(2) conditions, but not in soleus. These results demonstrate that TNF-alpha upregulation in the lung impairs peripheral skeletal muscle function but affects fast- and slow-twitch muscles differentially at high and low Po(2). PMID- 21697518 TI - Acamprosate-responsive brain sites for suppression of ethanol intake and preference. AB - Acamprosate suppresses alcohol intake and craving in recovering alcoholics; however, the central sites of its action are unclear. To approach this question, brain regions responsive to acamprosate were mapped using acamprosate microimplants targeted to brain reward and circadian areas implicated in alcohol dependence. mPer2 mutant mice with nonfunctional mPer2, a circadian clock gene that gates endogenous timekeeping, were included, owing to their high levels of ethanol intake and preference. Male wild-type (WT) and mPer2 mutant mice received free-choice (15%) ethanol/water for 3 wk. The ethanol was withdrawn for 3 wk and then reintroduced to facilitate relapse. Four days before ethanol reintroduction, mice received bilateral blank or acamprosate-containing microimplants releasing ~50 ng/day into reward [ventral tegmental (VTA), peduculopontine tegmentum (PPT), and nucleus accumbens (NA)] and circadian [intergeniculate leaflet (IGL) and suprachiasmatic nucleus (SCN)] areas. The hippocampus was also targeted. Circadian locomotor activity was measured throughout. Ethanol intake and preference were greater in mPer2 mutants than in wild-type (WT) mice (27 g.kg( 1).day(-1) vs. 13 g.kg(-1).day(-1) and 70% vs. 50%, respectively; both, P < 0.05). In WTs, acamprosate in all areas, except hippocampus, suppressed ethanol intake and preference (by 40-60%) during ethanol reintroduction. In mPer2 mutants, acamprosate in the VTA, PPT, and SCN suppressed ethanol intake and preference by 20-30%. These data are evidence that acamprosate's suppression of ethanol intake and preference are manifest through actions within major reward and circadian sites. PMID- 21697520 TI - beta-Hydroxy-beta-methylbutyrate reduces myonuclear apoptosis during recovery from hind limb suspension-induced muscle fiber atrophy in aged rats. AB - beta-Hydroxy-beta-methylbutyrate (HMB) is a leucine metabolite shown to reduce protein catabolism in disease states and promote skeletal muscle hypertrophy in response to loading exercise. In this study, we evaluated the efficacy of HMB to reduce muscle wasting and promote muscle recovery following disuse in aged animals. Fisher 344*Brown Norway rats, 34 mo of age, were randomly assigned to receive either Ca-HMB (340 mg/kg body wt) or the water vehicle by gavage (n = 32/group). The animals received either 14 days of hindlimb suspension (HS, n = 8/diet group) or 14 days of unloading followed by 14 days of reloading (R; n = 8/diet group). Nonsuspended control animals were compared with suspended animals after 14 days of HS (n = 8) or after R (n = 8). HMB treatment prevented the decline in maximal in vivo isometric force output after 2 wk of recovery from hindlimb unloading. The HMB-treated animals had significantly greater plantaris and soleus fiber cross-sectional area compared with the vehicle-treated animals. HMB decreased the amount of TUNEL-positive nuclei in reloaded plantaris muscles (5.1% vs. 1.6%, P < 0.05) and soleus muscles (3.9% vs. 1.8%, P < 0.05). Although HMB did not significantly alter Bcl-2 protein abundance compared with vehicle treatment, HMB decreased Bax protein abundance following R, by 40% and 14% (P < 0.05) in plantaris and soleus muscles, respectively. Cleaved caspase-3 was reduced by 12% and 9% (P < 0.05) in HMB-treated reloaded plantaris and soleus muscles, compared with vehicle-treated animals. HMB reduced cleaved caspase-9 by 14% and 30% (P < 0.05) in reloaded plantaris and soleus muscles, respectively, compared with vehicle-treated animals. Although, HMB was unable to prevent unloading-induced atrophy, it attenuated the decrease in fiber area in fast and slow muscles after HS and R. HMB's ability to protect against muscle loss may be due in part to putative inhibition of myonuclear apoptosis via regulation of mitochondrial-associated caspase signaling. PMID- 21697521 TI - Neurokinin 3 receptor forms a complex with acetylated histone H3 and H4 in hypothalamic neurons following hyperosmotic challenge. AB - The neurokinin 3 receptor (NK3R) is a G protein-coupled receptor that is expressed in brain and is highly expressed by magnocellular vasopressinergic neurons in both the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus. Hyperosmolarity causes a ligand-mediated internalization of NK3Rs to the cytoplasm and to the nuclei of vasopressinergic PVN neurons. This receptor activation-dependent pathway is presumed to be a means to directly transmit synaptic signals from the cell membrane to the nucleus. The present study evaluated in vivo the subnuclear domains that associate with NK3R. Rats were administered 2 M NaCl (intragastric) or no intragastric load, and 40 min later, the PVN was dissected and nuclei were isolated. Using double-immuno-transmission electron microscopy (TEM), we show that, compared with controls, hyperosmolarity causes a significant increase in NK3R Immunogold beads in the nucleus of PVN neurons. Furthermore, NK3R spatially colocalized with histone H4 and with highly acetylated H4 in nuclei isolated from the PVN of rats administered 2 M NaCl, but not in nuclei from control rats. Next, coimmunoprecipitation experiments showed that acetylated H4, as well as acetylated H3, were pulled down with NK3R in the PVN nuclear enriched fraction from rats treated with 2 M NaCl, but not from control rats. In response to hyperosmolarity, NK3R is transported to the nucleus of PVN neurons and associates with transcriptionally active chromatin, where it may influence the transcription of genes. PMID- 21697522 TI - Effects of chronic dietary salt loading on the renin angiotensin and adrenergic systems of rainbow trout (Oncorhynchus mykiss). AB - Previous studies have demonstrated that chronic dietary salt loading causes hypertension and a decreased sensitivity of the systemic vasculature to alpha adrenergic stimulation and other hypertensive stimuli (e.g. hypercapnia) in rainbow trout (Oncorhynchus mykiss). This reduced sensitivity to hypertensive stimuli is consistent with a possible blunting of homeostatic responses normally aimed at raising blood pressure. To test this idea, we examined the consequences of long-term salt feeding and the associated hypertension on the interactive capacities of the renin angiotensin system (RAS) and adrenergic systems to elevate blood pressure in trout. Secretion of catecholamines in response to a range of doses of homologous ANG II in vivo and in situ (using a perfused posterior cardinal vein preparation) was reduced in the salt-fed fish. The reduced sensitivity to ANG II could not be explained by alterations in stored catecholamine (adrenaline or noradrenaline) levels or the general responsiveness of the chromaffin cells to depolarizing stimuli (60 mmol/l KCl). Despite the decreased responsiveness of the chromaffin cells to ANG II, plasma catecholamines were increased to a greater extent in the salt-fed fish during acute hypoxia (a condition that activates the RAS). Interestingly, the pressor effects of ANG II in vivo were actually heightened in the salt-fed fish. The increased pressor response to exogenous ANG II was likely attributable to its direct interaction with vascular ANG II receptors because the effect persisted even after blockade of alpha-adrenergic receptors. Treating fish with the vascular smooth muscle relaxant papaverine caused similar reductions in blood pressure and increases in plasma ANG II levels regardless of diet. Similarly, inhibition of angiotensin converting enzyme with lisinopril reduced blood pressure equally in control and salt-fed fish. These results indicate that, while long-term dietary salt loading blunts the response of trout chromaffin cells to ANG II, the RAS itself appears to be unaffected. Indeed, the capacity of ANG II to elevate blood pressure is not compromised nor do fish exhibit a reduced capacity to mount an acute humoral adrenergic stress response during acute hypoxia. PMID- 21697524 TI - Local network regulation of orexin neurons in the lateral hypothalamus. AB - Obesity and inadequate sleep are among the most common causes of health problems in modern society. Thus, the discovery that orexin (hypocretin) neurons play a pivotal role in sleep/wake regulation, energy balance, and consummatory behaviors has sparked immense interest in understanding the regulatory mechanisms of these neurons. The local network consisting of neurons and astrocytes within the lateral hypothalamus and perifornical area (LH/PFA), where orexin neurons reside, shapes the output of orexin neurons and the LH/PFA. Orexin neurons not only send projections to remote brain areas but also contribute to the local network where they release multiple neurotransmitters to modulate its activity. These neurotransmitters have opposing actions, whose balance is determined by the amount released and postsynaptic receptor desensitization. Modulation and negative feedback regulation of excitatory glutamatergic inputs as well as release of astrocyte-derived factors, such as lactate and ATP, can also affect the excitability of orexin neurons. Furthermore, distinct populations of LH/PFA neurons express neurotransmitters with known electrophysiological actions on orexin neurons, such as melanin-concentrating hormone, corticotropin-releasing factor, thyrotropin-releasing hormone, neurotensin, and GABA. These LH/PFA specific mechanisms may be important for fine tuning the firing activity of orexin neurons to maintain optimal levels of prolonged output to sustain wakefulness and stimulate consummatory behaviors. Building on these exciting findings should shed further light onto the cellular mechanisms of energy balance and sleep-wake regulation. PMID- 21697523 TI - MU-Opioid modulation in the rostral solitary nucleus and reticular formation alters taste reactivity: evidence for a suppressive effect on consummatory behavior. AB - The neural control of feeding involves many neuromodulators, including the endogenous opioids that bind MU-opioid receptors (MORs). Injections of the MOR agonist, Damgo, into limbic and hypothalamic forebrain sites increase intake, particularly of palatable foods. Indeed, forebrain Damgo injections increase sucrose-elicited licking but reduce aversive responding (gaping) to quinine, suggesting that MOR activation may enhance taste palatability. A MU-opioid influence on taste reactivity has not been assessed in the brain stem. However, MORs are present in the first-order taste relay, the rostral nucleus of the solitary tract (rNST), and in the immediately subjacent reticular formation (RF), a region known to be essential for consummatory responses. Thus, to evaluate the consequences of rNST/dorsal RF Damgo in this region, we implanted rats with intraoral cannulas, electromyographic electrodes, and brain cannulas aimed at the ventral border of the rNST. Licking and gaping elicited with sucrose, water, and quinine were assessed before and after intramedullary Damgo and saline infusions. Damgo slowed the rate, increased the amplitude, and decreased the size of fluid induced lick and gape bouts. In addition, the neutral stimulus water, which typically elicits licks, began to evoke gapes. Thus, the current results demonstrate that MU-opioid activation in the rNST/dorsal RF exerts complex effects on oromotor responding that contrast with forebrain effects and are more indicative of a suppressive, rather than a facilitatory effect on ingestion. PMID- 21697525 TI - Visual consciousness revisited: magnocellular and parvocellular contributions to conscious and nonconscious vision. AB - Current theoretical approaches to consciousness and vision associate the dorsal cortical pathway, in which magnocellular (M) input is dominant, with nonconscious visual processing and the ventral cortical pathway, in which parvocellular (P) input is dominant, with conscious visual processing. We explored the known differences between M and P contrast-response functions to investigate the roles of these channels in vision. Simulations of contrast-dependent priming revealed that priming effects obtained with unmasked, visible primes were best modeled by equations characteristic of M channel responses, whereas priming effects obtained with masked, invisible primes were best modeled by equations characteristic of P channel responses. In the context of current theoretical approaches to conscious and nonconscious processing, our results indicate a surprisingly significant role of M channels in conscious vision. In a broader discussion of the role of M channels in vision, we propose a neurophysiologically plausible interpretation of the present results: M channels indirectly contribute to conscious object vision via top-down modulation of reentrant activity in the ventral object-recognition stream. PMID- 21697527 TI - Leveraging crowdsourcing to facilitate the discovery of new medicines. AB - Gloomy predictions about the future of pharma have forced the industry to investigate alternative models of drug discovery. Public-private partnerships (PPPs) have the potential to revitalize the discovery and development of first-in class therapeutics. The new PPP Arch2POCM hopes to foster biomedical innovation through precompetitive validation of pioneer therapeutic targets for human diseases. In this meeting report, we capture insights garnered from the April 2011 Arch2POCM conference. PMID- 21697528 TI - Broken barriers: a new take on sepsis pathogenesis. AB - Despite intense research into the pathogenesis of sepsis, the current therapy for this devastating syndrome is primarily supportive and mortality remains high. The paucity of specific therapies is not for lack of effort; countless clinical trials in sepsis patients have failed despite promising preclinical data obtained from in vitro and animal models. Human sepsis is characterized by diffuse microvascular leak and tissue edema-features that have been largely ignored in animal models. Moreover, there have been no clinical trials of agents designed to prevent or treat leaky vasculature. Recent compelling evidence suggests that the breakdown in endothelial barrier function plays a crucial role in the pathogenesis of sepsis. In particular, these data suggest that preventing vascular leak can reduce mortality from sepsis. In this Perspective, we highlight the endothelial barrier as a new target for sepsis therapeutics, examining three potential strategies: enhancement of endothelial junctions; reinforcement of the endothelial cytoskeleton; and modulation of endothelial activation. PMID- 21697529 TI - Endoplasmic reticulum stress enters a Nogo zone. AB - The debilitating disease pulmonary arterial hypertension (PAH) is characterized by an elevation in blood pressure in the lung arteries caused by vessel-blocking vascular-cell proliferation. This vascular remodeling is thought to result in part from defects in the endoplasmic reticulum stress response and mitochondrial dysfunction in pulmonary artery smooth muscle cells. In this issue of Science Translational Medicine, Sutendra et al. show that the vascular remodeling protein Nogo-B plays a role in the development of PAH in response to hypoxia-induced stress. The new findings finger Nogo-B as a possible therapeutic target for PAH. PMID- 21697530 TI - Dosage thresholds for AAV2 and AAV8 photoreceptor gene therapy in monkey. AB - Gene therapy is emerging as a therapeutic modality for treating disorders of the retina. Photoreceptor cells are the primary cell type affected in many inherited diseases of retinal degeneration. Successfully treating these diseases with gene therapy requires the identification of efficient and safe targeting vectors that can transduce photoreceptor cells. One serotype of adeno-associated virus, AAV2, has been used successfully in clinical trials to treat a form of congenital blindness that requires transduction of the supporting cells of the retina in the retinal pigment epithelium (RPE). Here, we determined the dose required to achieve targeting of AAV2 and AAV8 vectors to photoreceptors in nonhuman primates. Transgene expression in animals injected subretinally with various doses of AAV2 or AAV8 vectors carrying a green fluorescent protein transgene was correlated with surgical, clinical, and immunological observations. Both AAV2 and AAV8 demonstrated efficient transduction of RPE, but AAV8 was markedly better at targeting photoreceptor cells. These preclinical results provide guidance for optimal vector and dose selection in future human gene therapy trials to treat retinal diseases caused by loss of photoreceptors. PMID- 21697532 TI - Immunogenicity of the tuberculosis vaccine MVA85A is reduced by coadministration with EPI vaccines in a randomized controlled trial in Gambian infants. AB - New tuberculosis vaccines are urgently needed to curtail the current epidemic. MVA85A is a subunit vaccine that could enhance immunity from BCG vaccination. To determine MVA85A safety and immunogenicity as well as interactions with other routine vaccines administered in infancy, we randomized healthy 4-month-old infants who had received Bacille Calmette-Guerin at birth to receive Expanded Program on Immunization (EPI) vaccines alone, EPI and MVA85A simultaneously, or MVA85A alone. Adverse events were monitored throughout. Blood samples obtained before vaccination and at 1, 4, and 20 weeks after vaccination were used to assess safety and immunogenicity. The safety profile of both low and standard doses was comparable, but the standard dose was more immunogenic and therefore was selected for the second stage of the study. In total, 72 (first stage) and 142 (second stage) infants were enrolled. MVA85A was safe and well tolerated and induced a potent cellular immune response. Coadministration of MVA85A with EPI vaccines was associated with a significant reduction in MVA85A immunogenicity, but did not affect humoral responses to the EPI vaccines. These results provide important information regarding timing of immunizations, which is required for the design of infant efficacy trials with MVA85A, and suggest that modifications to the standard EPI schedule may be required to incorporate a new generation of T cell-inducing vaccines. PMID- 21697533 TI - Eusorbents and eusorption: a review of physiological events to therapeutic concepts. AB - Eusorbents are considered the exogenous substances that facilitate and enhance intestinal absorption. Eusorption is the process by which eusorbents affect the mechanisms of intestinal absorption. These 2 concepts should be distinguished from the well-known probiotics and prebiotics that may also play a role in benefiting the host. This review covers the eusorption paradigm in the optimization of oral rehydration and the treatment of diarrhea. The various factors that influence the validity of eusorbents to facilitate the eusorption were considered (i.e., viscosity, hydrating agents, and minerals such as zinc). The role of surface tension in solute absorption was addressed. The possible effects that eusorbents could play in the gene activation of the intestinal mucosa were also considered. This review should contribute to the understanding of absorptive enhancements of specific substances and their properties that facilitate the desired effects in health and disease. PMID- 21697531 TI - The role of Nogo and the mitochondria-endoplasmic reticulum unit in pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) is caused by excessive proliferation of vascular cells, which occlude the lumen of pulmonary arteries (PAs) and lead to right ventricular failure. The cause of the vascular remodeling in PAH remains unknown, and the prognosis of PAH remains poor. Abnormal mitochondria in PAH PA smooth muscle cells (SMCs) suppress mitochondria-dependent apoptosis and contribute to the vascular remodeling. We hypothesized that early endoplasmic reticulum (ER) stress, which is associated with clinical triggers of PAH including hypoxia, bone morphogenetic protein receptor II mutations, and HIV/herpes simplex virus infections, explains the mitochondrial abnormalities and has a causal role in PAH. We showed in SMCs from mice that Nogo-B, a regulator of ER structure, was induced by hypoxia in SMCs of the PAs but not the systemic vasculature through activation of the ER stress-sensitive transcription factor ATF6. Nogo-B induction increased the distance between the ER and mitochondria and decreased ER-to-mitochondria phospholipid transfer and intramitochondrial calcium. In addition, we noted inhibition of calcium-sensitive mitochondrial enzymes, increased mitochondrial membrane potential, decreased mitochondrial reactive oxygen species, and decreased mitochondria-dependent apoptosis. Lack of Nogo-B in PASMCs from Nogo-A/B-/- mice prevented these hypoxia-induced changes in vitro and in vivo, resulting in complete resistance to PAH. Nogo-B in the serum and PAs of PAH patients was also increased. Therefore, triggers of PAH may induce Nogo-B, which disrupts the ER-mitochondria unit and suppresses apoptosis. This could rescue PASMCs from death during ER stress but enable the development of PAH through overproliferation. The disruption of the ER-mitochondria unit may be relevant to other diseases in which Nogo is implicated, such as cancer or neurodegeneration. PMID- 21697534 TI - Folic acid effects on s-adenosylmethionine, s-adenosylhomocysteine, and DNA methylation in patients with intermediate hyperhomocysteinemia. AB - OBJECTIVE: Folic acid (FA) supplementation decreases homocysteine (tHcy) levels. However, little is known about the effects of FA treatment on DNA methylation or plasma S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy) concentrations. The purpose of this study was to investigate the effects of FA supplementation on AdoMet, AdoHcy, and genomic DNA methylation in hyperhomocysteinemic subjects without end-stage renal disease. METHODS: To evaluate the effects of 5 mg FA/d for 8 weeks, we recruited 7 hyperhomocysteinemic MTHFR677TT patients (tHcy >30 MUmol/L) with normal renal function. RESULTS: FA supplementation induced a decrease in tHcy (from 51.1 +/- 21 at baseline to 26.1 +/- 27 MUmol/L after folate supplementation; p < 0.01). A parallel increase was seen in plasma AdoMet concentrations and the AdoMet/AdoHcy ratio (p < 0.05). However, FA supplementation had no effect on global DNA methylation levels in the present study. CONCLUSIONS: Supraphysiologic FA supplementation can modulate biochemical markers in one-carbon metabolism such as tHcy, AdoMet, and the AdoMet/AdoHcy ratio in hyperhomocysteinemic subjects. However, the reduction in homocysteinemia and the increased availability of methyl compounds provided by vitamin supplementation may not be sufficient to affect genomic DNA methylation. PMID- 21697535 TI - CLA does not impair endothelial function and decreases body weight as compared with safflower oil in overweight and obese male subjects. AB - OBJECTIVE: Conjugated linoleic acid (CLA) showed a wide range of beneficial biological effects with relevance for cardiovascular health in animal models and humans. Most human studies used olive oil as a reference. This study assessed the effect of CLA as compared with safflower oil on endothelial function and markers of cardiovascular risk in overweight and obese men. Heated safflower oil and olive oil were given for additional descriptive control. METHODS: Eighty-five overweight men (aged 45-68 years, body mass index 25-35 kg/m(2)) were randomized to receive 4.5 g/d of the CLA isomeric mixture, safflower oil, heated safflower oil, or olive oil in a 4-week double-blind study. Endothelial function was assessed by peripheral arterial tonometry (PAT) index determination in the fasting and postprandial state (i.e., 4 hours after consumption of a fat- and sucrose-rich meal). RESULTS: CLA as compared with safflower oil consumption did not impair fasting or postprandial PAT index but decreased body weight. CLA as compared with safflower oil did not change total, low-density lipoprotein (LDL), or high-density lipoprotein (HDL) cholesterol; triglycerides; insulin sensitivity indices; C-reactive protein; soluble adhesion molecules; oxidized LDL; lipoprotein a (Lp[a]); paraoxonase; or platelet-activating factor acetylhydrolase (PAF-AH) activity, but significantly reduced arylesterase activity and increased concentrations of the F(2)-isoprostane 8-iso-prostaglandin F (PGF)(2alpha). CONCLUSION: CLA did not impair endothelial function. Other parameters associated with metabolic syndrome and oxidative stress were not changed or were slightly improved. Results suggest that CLA does not increase cardiovascular risk. Increased F(2)-isoprostane concentrations in this context may not indicate increased oxidative stress. PMID- 21697536 TI - Insulin dynamics of breast- or formula-fed overweight and obese children. AB - OBJECTIVE: The aim of the present study was to evaluate the association between the type of early feeding and indices of insulin metabolism in 8-year-old overweight and obese children. METHODS: The sample included 350 overweight (body mass index [BMI] >=1.036 standard deviation score [SDS]) and obese (BMI >=1.645 SDS) children and 33 normal-weight control subjects who had been exclusively breast-fed or formula-fed for 4 months or longer. Parameters of insulin sensitivity and secretion were derived from 120-minute oral glucose tolerance tests. RESULTS: Overweight and obese formula-fed children (N = 165) were more insulin resistant than breast-fed individuals (N = 185; Whole-Body Insulin Sensitivity Index 5.1 +/- 2.3 vs 6.6 +/- 2; p < 0.0001) despite having the same degree of obesity (BMI z-score 1.8 +/- 0.4 vs 1.7 +/- 0.4 SDS; p = 0.5). They compensated for enhanced insulin resistance by augmenting insulin secretion (Insulinogenic Index 6.8 +/- 3.6 vs 5.2 +/- 2.5 MUIU/mL * mg/mL(-1); p < 0.0001). Thus, they presented with a disposition index similar to that of breast-fed children (34.6 +/- 15 vs 30.8 +/- 19.2; p = 0.4), Formula feeding was associated with greater catch-up growth in the first month (odds ratio 2.49, 95% confidence interval 1.97 to 3.01; p < 0.0001) and between months 6 and 12 of life (odds ratio 4.62, 95% confidence interval 3.58 to 5.67; p < 0.0001). CONCLUSIONS: In comparison with breast-feeding, formula feeding seems to be associated with reduced insulin sensitivity and increased insulin secretion in overweight and obese children. PMID- 21697537 TI - Survey on eating disorder-related thoughts, behaviors, and their relationship with food intake and nutritional status in female high school students in Taiwan. AB - OBJECTIVE: Eating disorders are now a global health problem for adolescents and young female adults. The level of eating disorders among young female adults is growing in Asian countries. Therefore, the purpose of this study was to investigate body image, weight concerns, eating attitudes, dietary intake, and nutritional status related to eating disorders of female high school students in Taiwan. METHODS: A total of 1605 female high school students participated in this study. The written questionnaire included respondents' demographics and weight concerns, the Eating Attitudes Test-26 (EAT-26), and 24-hour dietary recall. Blood chemistry data were also collected. The data were analyzed using a Student t test, chi(2) analysis, and logistic regression. RESULTS: Disturbed eating attitudes and behaviors were found in 17.11% of participants (measured by an EAT 26 score >=20). Logistic regression analyses showed that disturbed eating attitudes/behaviors were significantly associated with overestimation of body weight, unrealistic body weight goal, dissatisfaction with body weight, and weight loss experiences. The reported intakes of energy, protein, carbohydrate, zinc, and vitamins B6 and B12 were significantly lower in participants with disturbed eating patterns than in participants without disturbance issues. Conversely, participants with disturbed eating patterns had higher dietary and crude fiber intake than participants without disturbed eating issues. The percentage of participants with abnormal values of total iron-binding capacity and serum iron was significantly higher in those with disturbed eating patterns than in those without disturbed eating patterns. CONCLUSION: Disturbed eating attitudes/behaviors exist among female adolescents in Taiwan, and these behaviors jeopardize their nutritional status. The possibility of using the EAT-26 as a reference to predict the quality and quantity of food intake among female adolescents is worthy of further study. PMID- 21697538 TI - Effects of encapsulated fruit and vegetable juice powder concentrates on oxidative status in heavy smokers. AB - OBJECTIVE: Long-term cigarette smoking has negative effects on oxidative status, promoting low-density lipoprotein (LDL) oxidation and formation of lipid peroxides. We evaluated the effects of 2 different encapsulated formulas, consisting primarily of mixed juice powder concentrate, on oxidative status compared with placebo. METHODS: This randomized, double-blind, placebo-controlled study was performed on 101 apparently healthy heavy smokers (>20 cigarettes/d, duration >10 years; median age 47 years, range 41-57 years; 54 M) before and after 3 months' supplementation. Subjects were randomized into 3 groups, well matched for sex and age: (1) placebo; (2) fruit/vegetable (FV); and (3) fruit/vegetable/berry (FVB). Analysis of oxidative status was performed on 75 (46 M) compliant subjects (>95% of assigned capsules). Changes in lipid panel parameters, oxidative-INDEX (Oxy-I, calculated on the basis of serum hydroperoxides and total antioxidant capacity measured by spectrophotometric methods), oxidized-LDL (ox-LDL; enzyme-linked immunosorbent assay [ELISA] method), and malondialdehyde (MDA; gas chromatography-mass spectrometry method) in free (fMDA), bound (bMDA), and total (tMDA = fMDA + bMDA) forms are reported. Statistical analysis was performed with R statistical software. RESULTS: After supplementation, compared with placebo, both FV and FVB groups showed a significant decrease in total cholesterol (p < 0.05), ox-LDL (p = 0.03), and fMDA levels (p = 0.004) accompanied by a slight increase in bMDA concentrations, possibly as the result of fMDA conjugation. Moreover, a significant decrease in Oxy-I was found in both active groups compared with placebo (p < 0.001). CONCLUSION: Intervention with both nutraceutical formulations resulted in improvement in some oxidative alterations attributed to long-term cigarette smoking. PMID- 21697539 TI - Regional body composition changes during lactation in Indian women from the low income group and their relationship to the growth of their infants. AB - BACKGROUND: Increased energy requirement during lactation may lead to maternal tissue depletion in women from poor subsistence communities. OBJECTIVES: To examine the regional body composition changes in undernourished lactating women and to assess the relationship of maternal body composition changes with weight gain of the infants. SUBJECTS AND METHODS: Body composition was assessed using dual energy x-ray absorptiometry in 35 lactating women at 4 time points: within 1 month after delivery (baseline) and at 6, 12, and 18 months postpartum. RESULTS: The mean age, height, and body mass index of the women were 23.5 years, 150.7 cm, and 20.0 kg/m(2), respectively. There were no significant differences in body weight or whole-body lean as well as fat mass at 4 time points, but the percentage fat decreased significantly during lactation. There was selective mobilization of fat mass from the leg region, whereas the appendicular skeletal mass (ASM) increased significantly. When the growth of the infants in the first 6 months (proxy for the lactation performance) was assessed in relation to the maternal body composition changes during that period, it was observed that the change in fat mass had a negative relationship to the weight gain of the infant. Change in the ASM during this period, however, had a significant positive relationship with the weight gain of the infants. CONCLUSION: There were important differences in the lactation-related changes in the regional body composition parameters of these undernourished women. Regional body composition changes may be related to the weight gain of the breast-fed infants. PMID- 21697540 TI - Impact of a resistant dextrin with a prolonged oxidation pattern on day-long ghrelin profile. AB - OBJECTIVES: The effects of a new resistant dextrin ingested at breakfast on day long metabolic parameters and ghrelin profile at subsequent lunch were investigated. METHODS: In this randomized, single-blinded, crossover study, 12 healthy men ingested a standardized breakfast with 50 g of NUTRIOSE 10, a resistant dextrin (RD), or of maltodextrin (Malto) and a standardized lunch 5 hours later. Both products (RD and Malto) were derived from corn naturally rich in (13)C to follow their metabolic fate (by using stable isotope analysis). Oxidation and fermentation patterns were assessed by simultaneous (13)CO(2)/H(2) breath testing. The appearance of exogenous (13)C-glucose in plasma, glycemia, insulinemia, nonesterified fatty acids (NEFAs), and ghrelin concentrations were measured for 10 hours following breakfast ingestion. RESULTS: With RD, H(2) excretion (fermentation) was significantly enhanced compared with Malto, whereas the appearance of (13)CO(2) (oxidation) was significantly prolonged (p < 0.0001). Following breakfast, ghrelin secretion was significantly less inhibited and NEFA concentration was higher with RD (p < 0.05), but unexpectedly, both remained lower after lunch and up to T600 minutes. According to the reduced bioavailability of RD compared with Malto, the appearance of (13)C-glucose in plasma (p < 0.0001) and glycemic and insulinemic responses to breakfast (p < 0.05) were significantly reduced. CONCLUSIONS: Ingestion of this new resistant dextrin at breakfast decreased ghrelin concentrations in response to the subsequent lunch, even if the caloric load ingested at breakfast was lower. This effect may be linked to the prolonged fermentation/oxidation pattern seen in the late postprandial phase (up to 10 hours after ingestion at breakfast), and thus prolonged energy release with the resistant dextrin. PMID- 21697541 TI - High dietary sodium intake among young children in Vancouver, British Columbia. AB - OBJECTIVE: To determine the intake distribution and food sources of sodium among young children. METHODS: Dietary intake was determined for 190 children, 16 months to 6 years of age, using a food frequency questionnaire completed by interviewing a parent. Dietary intake of all nutrients, including dietary sodium, was analyzed. The major food sources of sodium were assessed by grouping foods into categories based on Canada's Food Guide, with subsequent subdivision into food type categories. RESULTS: Dietary sodium intakes were skewed, with a median intake of 2021 mg/d and 5th-95th percentile range of 888-3975 mg/d. The sodium intake of 91.6% of children was above the recommended 1000 or 1200 mg/d for children 1-3 or 3-6 years, respectively, and 85% and 54% had intakes above the tolerable upper limits of 1500 and 1900 mg/d, respectively. The 5 food sources providing the highest amount of sodium were soups, processed/fast foods, dairy products, breads, and processed meats. CONCLUSION: Children are vulnerable to high sodium intake as a result of their food patterns and the high sodium content of these foods. This report demonstrates that Canadian children have high sodium intakes. Knowledge of feeding practices involving high-sodium foods can assist parents and caregivers in reducing the high sodium intake of young children. PMID- 21697542 TI - ABCA1 increases extracellular ATP to mediate cholesterol efflux to ApoA-I. AB - ATP-binding cassette protein A1 (ABCA1) is a key plasma membrane protein required for the efflux of cellular cholesterol to extracellular acceptors, particularly to apolipoprotein A-I (apoA-I). This process is essential to maintain cholesterol homeostasis in the body. The detailed molecular mechanisms, however, are still insufficiently understood. Also, the molecular identity of ABCA1, i.e., channel, pump, or flippase, remains unknown. In this study we analyzed extracellular ATP levels in the medium of ABCA1-expressing BHK cells and RAW macrophages and compared them to the medium of nonexpressing cells. We found that extracellular ATP concentrations are significantly elevated when cells express ABCA1. Importantly, a dysfunctional ABCA1 mutant (A937V), when expressed similarly as wild-type ABCA1, is unable to raise extracellular ATP concentration, which suggests a casual relationship between functional ABCA1 and elevated extracellular ATP. To explore the physiological role of extracellular ATP, we analyzed ABCA1-mediated cholesterol efflux under conditions where extracellular ATP levels were modulated. We found that increasing extracellular ATP within the physiological range, i.e., =0.70. There are two other phase boundaries which occur around 0.05=0.6 T and below 0.5 K. The observed MU(+) spin-lattice relaxation rates reveal persisting spin dynamics across the whole phase diagram, reflect the various phase boundaries and are interpreted to arise in the AF and FIM phases from the Ce3 sublattice (the Ce ions are located on three different sublattices) and in the intermediate phase, viewed as a short range ordered (SRO) state, also from the Ce1 and Ce2 sublattices with slower fluctuation rates. In the paramagnetic regime the Ce1 sublattice displays the slowest spin dynamics. In the FIM phase the fraction of relaxing MU(+) appears to shrink with rising B, evidencing a possible phase separation. PMID- 21697569 TI - Nano-scale distribution of ZnO free exciton luminescence in ZnO:Zn microcrystals and its modification under electron beam excitation. AB - The dependences of cathodoluminescence (CL) from ZnO:Zn phosphor powder upon local space, accelerating voltage and beam current have been investigated at room temperature. Ultraviolet (UV) luminescence, which is hard to be observed in photoluminescence (PL) at room temperature, has been clearly observed in CL as well as green luminescence. The intensity ratio of the UV luminescence to the green one varies from point to point. From the comparison with PL, the UV luminescence is attributed to the recombination of ZnO free excitons. The UV luminescence is little observed at low accelerating voltage where, similar to the excitation light for PL measurement, the electron beam penetrates into only the surface depletion layer where free excitons are unstable due to the surface electric field. However, the UV luminescence from the depletion layer becomes observable at large beam current because of the suppression of the electric field in the depletion layer caused by injected electrons. PMID- 21697570 TI - Physical and chemical properties of sputter-deposited TaC(x)N(y) films. AB - The structural, electronic, optical, and mechanical properties of stoichiometric TaC(x)N(y = 1-x) were simulated using an ab initio calculation based on density functional theory (DFT) within the generalized gradient approximation. The calculations revealed the theoretical lattice parameter, density of states, refractive index, and elastic constants as a function of carbon and nitrogen content. TaC(x)N(y) films were subsequently produced on Si wafers using unbalanced magnetron sputtering. The structural, optical, and mechanical properties were measured using x-ray diffraction/transmission electron microscopy, vacuum ultraviolet spectroscopic ellipsometry, and nanoindentation, respectively. The computational and experimental properties were compared. The lattice parameter, the energy of the 2p bands in the density of states, and the energy of the interband transitions were found to decrease with increasing C content. No significant changes in the elastic constants were observed as a result of substituting N atoms with C atoms. The hardness and the elastic modulus were in the 40 and 380 GPa range, respectively. The experimental Young's modulus was much smaller than the computational one and this discrepancy was attributed to the nanocrystalline nature of the films. Also, the elastic constants were found to decrease dramatically for over-stoichiometric films. PMID- 21697571 TI - Effect of Fibonacci modulation on superconductivity. AB - We have studied finite-sized single band models with short-range pairing interactions between electrons in the presence of diagonal Fibonacci modulation in one dimension. Two models, namely the attractive Hubbard model and the Penson Kolb model, have been investigated at half-filling at zero temperature by solving the Bogoliubov-de Gennes equations in real space within a mean-field approximation. The competition between 'disorder' and the pairing interaction leads to a suppression of superconductivity (of usual pairs with zero centre-of mass momenta) in the strong-coupling limit while an enhancement of the pairing correlation is observed in the weak-coupling regime for both models. However, the dissimilarity of the pairing mechanisms in these two models brings about notable differences in the results. The extent to which the bond-ordered wave and the eta paired (of pairs with centre-of-mass momenta = pi) phases of the Penson-Kolb model are affected by the disorder has also been studied in the present calculation. Some finite size effects are also identified. PMID- 21697572 TI - A numerical study of transport and shot noise in 2D hopping. AB - We have used modern supercomputer facilities to carry out extensive Monte Carlo simulations of 2D hopping (at negligible Coulomb interaction) in conductors with a completely random distribution of localized sites in both space and energy, within a broad range of the applied electric field E and temperature T, both within and beyond the variable-range hopping region. The calculated properties include not only dc current and statistics of localized site occupation and hop lengths, but also the current fluctuation spectrum. Within the calculation accuracy, the model does not exhibit 1/f noise, so that the low-frequency noise at low temperatures may be characterized by the Fano factor F. For sufficiently large samples, F scales with conductor length L as (L(c)/L)(alpha), where alpha = 0.76 +/- 0.08<1, and parameter L(c) is interpreted as the average percolation cluster length. At relatively low E, the electric field dependence of parameter L(c) is compatible with the law [Formula: see text] which follows from directed percolation theory arguments. PMID- 21697573 TI - A numerical study of Coulomb interaction effects on 2D hopping transport. AB - We have extended our supercomputer-enabled Monte Carlo simulations of hopping transport in completely disordered 2D conductors to the case of substantial electron-electron Coulomb interaction. Such interaction may not only suppress the average value of hopping current, but also affect its fluctuations rather substantially. In particular, the spectral density S(I)(f) of current fluctuations exhibits, at sufficiently low frequencies, a 1/f-like increase which approximately follows the Hooge scaling, even at vanishing temperature. At higher f, there is a crossover to a broad range of frequencies in which S(I)(f) is nearly constant, hence allowing characterization of the current noise by the effective Fano factor [Formula: see text]. For sufficiently large conductor samples and low temperatures, the Fano factor is suppressed below the Schottky value (F = 1), scaling with the length L of the conductor as F = (L(c)/L)(alpha). The exponent alpha is significantly affected by the Coulomb interaction effects, changing from alpha = 0.76 +/- 0.08 when such effects are negligible to virtually unity when they are substantial. The scaling parameter L(c), interpreted as the average percolation cluster length along the electric field direction, scales as [Formula: see text] when Coulomb interaction effects are negligible and [Formula: see text] when such effects are substantial, in good agreement with estimates based on the theory of directed percolation. PMID- 21697574 TI - Possible existence of a band of extended states induced by inter-Landau-band mixing in a quantum Hall system. AB - The mixing of states with opposite chiralities in a quantum Hall system is shown to have a delocalization effect. It is possible that extended states may form bands because of this mixing, as is shown through a numerical calculation on a two-channel network model. Based on this result, a new phase diagram with a narrow metallic phase separating two adjacent QH phases and/or separating a QH phase from the insulating phase is proposed. The data from recent non-scaling experiments are reanalysed and it is shown that they seem to be consistent with the new phase diagram. However, due to finite-size effects, further study on large system size is still needed to conclude whether there are extended state bands in the thermodynamic limit. PMID- 21697575 TI - Spectroscopy of Tm and Ho in KYF(4) single crystals. AB - We report on the spectroscopic characterization of Tm :KYF(4) and Ho :KYF(4) single crystals. The energy level splittings are given, as well as the Judd-Ofelt parameters, the polarized absorption and emission cross sections and the energy transfer coefficients. This allows to have a deeper understanding of the Tm-Ho codoped KYF(4) system and shows KYF(4) to be a promising material for widely tunable and efficient 2 um laser operation. PMID- 21697576 TI - Defect-induced homogeneous amorphization of silicon: the role of defect structure and population. AB - Molecular dynamics based on the environment-dependent interatomic potential is used to investigate the influence of the nature and distribution of defects on solid state, homogeneous amorphization of Si. To this end, different kinds of defects, including single interstitials and vacancies (both uncorrelated and correlated distributions), bond defects, and small interstitial and vacancy clusters, have been considered. It is shown that the threshold defect concentration for amorphization depends on the defect type, and, in the case of single defects, on the degree of correlation between interstitial and vacancy distributions. The threshold varies within the interval [0.18-0.28] atomic fraction, the upper value corresponding to the case of bond defects, the lower to the uncorrelated distributions of single [Formula: see text] split interstitials plus compensating vacancies. PMID- 21697577 TI - Valence and magnetic ordering in intermediate valence compounds: TmSe versus SmB(6). AB - The intermediate valence systems TmSe and SmB(6) have been investigated up to 16 and 18 GPa by ac microcalorimetry with a pressure (p) tuning realized in situ at low temperature. For TmSe, the transition from an antiferromagnetic insulator for p<3 GPa to an antiferromagnetic metal at higher pressure has been confirmed. A drastic change in the p variation of the Neel temperature (T(N)) is observed at 3 GPa. In the metallic phase (p>3 GPa), T(N) is found to increase linearly with p. A similar linear p increase of T(N) is observed for the quasitrivalent compound TmS, which is at ambient pressure equivalent to TmSe at p~7 GPa. In the case of SmB(6) long range magnetism has been detected above p~8 GPa, i.e. at a pressure slightly higher than the pressure of the insulator to metal transition. However a homogeneous magnetic phase occurs only above 10 GPa. The magnetic and electronic properties are related to the renormalization of the 4f wavefunction either to the divalent or the trivalent configurations. As observed in SmS, long range magnetism in SmB(6) occurs already far below the pressure where a trivalent Sm(3+) state will be reached. It seems possible to describe roughly the physical properties of the intermediate valence equilibrium by assuming formulae for the Kondo lattice temperature depending on the valence configuration. Comparison is also made with the appearance of long range magnetism in cerium and ytterbium heavy fermion compounds. PMID- 21697578 TI - Magnetoelastic effects in Jahn-Teller distorted CrF2 and CuF2 studied by neutron powder diffraction. AB - We have studied the temperature dependence of the crystal and magnetic structures of the Jahn-Teller distorted transition metal difluorides CrF2 and CuF2 by neutron powder diffraction in the temperature range 2-280 K. The lattice parameters and the unit cell volume show magnetoelastic effects below the Neel temperature. The lattice strain due to the magnetostriction effect couples with the square of the order parameter of the antiferromagnetic phase transition. We also investigated the temperature dependence of the Jahn-Teller distortion, which does not show any significant effect at the antiferromagnetic phase transition but increases linearly with increasing temperature for CrF2, and remains almost independent of temperature in CuF2. The magnitude of magnetovolume effect seems to increase with the low temperature saturated magnetic moment of the transition metal ions but the correlation is not at all perfect. PMID- 21697579 TI - Phonon-drag thermopower in an armchair graphene nanoribbon. AB - We calculate the phonon-drag thermopower S(g) of an armchair graphene nanoribbon (AGNR) in the boundary scattering regime of phonons. S(g) is studied as a function of temperature, Fermi energy and width of the AGNR. At very low temperatures T, S(g) is exponentially suppressed and an activated behavior is observed which is characteristic of one-dimensional carriers. This is in contrast to the power law dependence in graphene in the Bloch-Gruneisen regime. However, at higher T, S(g) in the AGNR levels off. S(g) also shows strong dependence on Fermi energy and width of the AGNR. The magnitude of S(g) in the AGNR is compared with that in single-wall carbon nanotube and graphene. PMID- 21697580 TI - TiO2 nanorod arrays functionalized with In2S3 shell layer by a low-cost route for solar energy conversion. AB - We report the fabrication and characterization of a TiO(2)-In(2)S(3) core-shell nanorod array structure for application of semiconductor-sensitized solar cells. Hydrothermally synthesized TiO(2) nanorod arrays on FTO glass substrates are functionalized with a uniform In(2)S(3) shell layer by using the successive ion layer adsorption and reaction (SILAR) method. This low-cost technique promotes a uniform deposition of In(2)S(3) nanoshells on the surface of TiO(2) nanorods, thus forming an intact interface between the In(2)S(3) shell and TiO(2) core. Results show that the thickness of In(2)S(3) shell layers as well as the visible light absorption threshold can be effectively controlled by varying the coating cycles during the SILAR process. The best reproducible performance of the sandwich solar cell using the TiO(2)-In(2)S(3) core-shell nanorod arrays as photoelectrodes was obtained after 30 SILAR cycles, exhibiting a short-circuit current (I(sc)) of 2.40 mA cm(-2), an open-circuit voltage (V(oc)) of 0.56 V, a fill factor (ff) of 0.40 and a conversion efficiency (eta) of 0.54%, respectively. These results demonstrate a feasible and controllable route towards In(2)S(3) coating on a highly structured substrate and a proof of concept that such TiO(2)-In(2)S(3) core-shell architectures are novel and promising photoelectrodes in nanostructured solar cells. PMID- 21697581 TI - Aligned nanowires and nanodots by directed block copolymer assembly. AB - The directed self-assembly of block copolymers (BCPs) is a promising route to generate highly ordered arrays of sub-10 nm features. Ultradense arrays of a monolayer of spherical microdomains or cylindrical microdomains oriented parallel to the surface have been produced where the lateral ordering is guided by surface patterning and the lattice defined by the patterning can be commensurate or incommensurate with the natural period of the BCP. Commensurability between the two can be used to elegantly manipulate the lateral ordering and orientation of the BCP microdomains so as to form well-aligned arrays of 1D nanowires or 2D addressable nanodots. No modification of the substrate surface, aside from the patterning, was used, making the influence of lattice mismatch and pattern amplification on the size, shape and pitch of the BCP microdomains more transparent. A skew angle between incommensurate lattices, defining a stretching or compression of the BCP chains to compensate for the lattice mismatch, is presented. PMID- 21697582 TI - Design and characterization of nanoknife with buffering beam for in situ single cell cutting. AB - A novel nanoknife with a buffering beam is proposed for single-cell cutting. The nanoknife was fabricated from a commercial atomic force microscopy (AFM) cantilever by focused-ion-beam (FIB) etching technique. The material identification of the nanoknife was determined using the energy dispersion spectrometry (EDS) method. It demonstrated that the gallium ion pollution of the nanoknife can be ignored during the etching processes. The buffering beam was used to measure the cutting force based on its deformation. The spring constant of the beam was calibrated based on a referenced cantilever by using a nanomanipulation approach. The tip of the nanoknife was designed with a small edge angle 5 degrees to reduce the compression to the cell during the cutting procedure. For comparison, two other nanoknives with different edge angles, i.e. 25 degrees and 45 degrees , were also prepared. An in situ single-cell cutting experiment was performed using these three nanoknives inside an environmental scanning electron microscope (ESEM). The cutting force and the sample slice angle for each nanoknife were evaluated. It showed the compression to the cell can be reduced when using the nanoknife with a small edge angle 5 degrees . Consequently, the nanoknife was capable for in situ single-cell cutting tasks. PMID- 21697583 TI - Host-guest energetic nanocomposites based on self-assembly of multi-nitro organic molecules in nanochannels of mesoporous materials. AB - Host-guest energetic nanocomposites have been synthesized by self-assembly of the high energy density compound HNIW in nanometer-scale channels of an ordered mesoporous material SBA-15. The complete impregnation of HNIW can be achieved in acetone solvent at ambient temperature, and the maximum amount was around 70 wt%. Structural characterizations were systematically provided by XRD, TEM, N(2) adsorption, TG, (13)C solid-state NMR and FT-IR. The tendency of multi-nitro organic molecules to self-assemble when the solvent evaporated has been described. Hydrogen bond interactions were considered as the main driving force, so the choices of matched host matrix and guest organic compounds were pivotal for implementing this process. The thermal properties of nanocomposites were measured by DSC analysis. Compared with pure HNIW and a physical mixture, the decomposition peak temperature of the confined crystals decreased about 11 degrees C, while the total amount of heat released slightly increased. This strategy can also be expanded to other similar host-guest systems. PMID- 21697584 TI - Top-down fabrication of vertical silicon nano-rings based on Poisson diffraction. AB - Vertical Si nano-rings with a uniform thickness of about 100 nm have been fabricated by conventional optical photolithography with a low cost based on Poisson diffraction. Moreover, the roughness of the Si nano-rings can be effectively reduced by sacrificial oxidation. In order to increase the density of the nano-rings, coaxial twin Si nano-rings have been fabricated by the Poisson diffraction method combined with the spacer technique. The thickness of both the inner and outer Si nano-rings is about 60 nm, and the gap between the twin nano rings is about 100 nm. PMID- 21697585 TI - Combined effect of quantum size and disorder in a two-dimensional armchair graphene nanoribbon with s-wave pairing. AB - We investigate the quantum size effect combined with the disorder effect on an armchair graphene nanoribbon with s-wave pairing. In the framework of the Bogoliubov-de Gennes equation, the spatial distribution of the pairing potential is self-consistently determined for both pure and disordered systems. The dependence of the order parameter on the chemical potential is calculated for the zero-disordered case and a gap-like structure with two peaks is found. The relationship of the average pairing potential to the width of ribbon is discussed. Moreover, the disorder effect on the associated behavior is studied. PMID- 21697586 TI - A new 13C breath test to detect vitamin B12 deficiency: a prevalent and poorly diagnosed health problem. AB - Vitamin B12 deficiency is emerging as a growing public health problem. The most commonly used diagnostic tests are limited in accuracy, sensitivity, and are non specific for B12 deficiency. The aim of this study was to develop a simple B12 breath test (BBT) to more accurately evaluate vitamin B12 status as an alternative to the most common diagnostic test, serum B12 levels. The breath test is based on the metabolism of sodium 1-(13)C-propionate to (13)CO(2) which requires B12 as a cofactor. We initially compared the BBT to current B12 diagnostic methods in 58 subjects. Subjects also received a second BBT 1-3 days after initial testing to evaluate reproducibility of results. Propionate dosage, fasting times, and collection periods were compared, respectively. The dose of sodium 1-(13)C-propionate (10-50 mg) gave equivalent results while an 8 h fast was essential. Statistical analysis revealed that breath collection times could be reduced to just a baseline and 10 and 20 min following propionate dosing. We also measured the incidence of B12 deficiency with the BBT in 119 patients with chronic pancreatitis, Crohn's disease, small intestinal bacterial overgrowth, and subjects over 65 years of age. The BBT results agreed with previous publications showing a higher incidence of B12 deficiency in these patients. The BBT may provide clinicians with a non-invasive, accurate, reliable, and reproducible diagnostic test to detect vitamin B12 deficiency. PMID- 21697587 TI - Hemispatial neglect reflected on visual memory. AB - PURPOSE: Recent studies of hemispatial neglect have revealed both lateralized and nonlateralized attention mechanisms contributing to the syndrome. In addition, neglect patients show impaired spatial working memory and diminished working memory capacity. The aim of this study was to investigate, how neglect would be reflected in their performances in commonly used clinical visual memory tests. METHODS: Twelve patients with right hemisphere lesions and left neglect and twelve matched controls were assessed with the Behavioural Inattention Test, the visual reproduction of the WMS-R, the object memory test, the Rey figure test and the list learning test. Visuo-spatial span was explored with the Corsi block test. RESULTS: The severity of neglect was significantly associated with the naming of objects from the left side, with the copying of the Rey figure and with the immediate visual reproduction of the WMS-R. In comparison to the matched controls, the patients named and copied fewer items from both sides and showed impaired immediate and delayed recall of visual material, more so from the left side. After recovery, patients were still impaired in their visual search, whereas their immediate reproduction of visual material was no longer significantly different from the control subjects. The deficit in delayed recall of visual material persisted and was lateralized to the left side of the recollected memories. The role of hemianopia was analyzed. CONCLUSIONS: Patients with neglect exhibited spatial working memory bias and diminished nonlateralized attention capacity in encoding and immediate recall. The deficit in delayed recall was lateralized to the left side of memorized material. PMID- 21697588 TI - Activation changes in sensorimotor cortex during improvement due to CIMT in chronic stroke. AB - PURPOSE: The integrity of the pyramidal tract (PT) does not seem to influence clinical improvement after two weeks of Constraint-Induced Movement Therapy (CIMT). However, when PT is intact, improvement is associated with a decrease of fMRI-activation in primary sensorimotor cortex (SMC) and when affected, with an increase of activation in SMC. The aim was to observe the long-term effect of CIMT, depending on the integrity of the PT, and to correlate improvement with changes in fMRI-activation. SUBJECTS AND METHODS: Twelve new chronic stroke patients were treated with CIMT and integrity of PT was measured with transcranial magnetic stimulation. Before therapy, after therapy, and after 6 months, changes in motor function were correlated with differential and percent fMRI signal changes. RESULTS: All patients improved after two weeks of therapy, but only those with intact PT maintained improvement after 6 months. When PT was intact, improvement correlated with first a decrease of activation in SMC and after 6 months with an increase. When PT was affected, improvement consistently correlated with an increase in a lateral extension of SMC. Percent changes of activation were surrounded by differential changes. CONCLUSIONS: An intact PT might be advantageous for lasting improvement after CIMT and subregions in the SMC seem to behave differently during recovery. PMID- 21697589 TI - Virtual reality based rehabilitation speeds up functional recovery of the upper extremities after stroke: a randomized controlled pilot study in the acute phase of stroke using the rehabilitation gaming system. AB - PURPOSE: Given the incidence of stroke, the need has arisen to consider more self managed rehabilitation approaches. A promising technology is Virtual Reality (VR). Thus far, however, it is not clear what the benefits of VR systems are when compared to conventional methods. Here we investigated the clinical impact of one such system, the Rehabilitation Gaming System (RGS), on the recovery time course of acute stroke. RGS combines concepts of action execution and observation with an automatic individualization of training. METHODS. Acute stroke patients (n = 8) used the RGS during 12 weeks in addition to conventional therapy. A control group (n = 8) performed a time matched alternative treatment, which consisted of intense occupational therapy or non-specific interactive games. RESULTS. At the end of the treatment, between-group comparisons showed that the RGS group displayed significantly improved performance in paretic arm speed that was matched by better performance in the arm subpart of the Fugl-Meyer Assessment Test and the Chedoke Arm and Hand Activity Inventory. In addition, the RGS group presented a significantly faster improvement over time for all the clinical scales during the treatment period. CONCLUSIONS. Our results suggest that rehabilitation with the RGS facilitates the functional recovery of the upper extremities and that this system is therefore a promising tool for stroke neurorehabilitation. PMID- 21697590 TI - Isometric contraction interferes with transcranial direct current stimulation (tDCS) induced plasticity: evidence of state-dependent neuromodulation in human motor cortex. AB - BACKGROUND AND PURPOSE: Neuroplastic alterations of cortical excitability and activity represent the likely neurophysiological foundation of learning and memory formation. Beyond their induction, alterations of these processes by subsequent modification of cortical activity, termed metaplasticity, came into the focus of interest recently. Animal slice experiments demonstrated that neuroplastic excitability enhancements, or diminutions, can be abolished by consecutive subthreshold stimulation. These processes, termed de-potentiation, and de-depression, have so far not been explored in humans. METHODS: We combined neuroplasticity induction by transcranial direct current stimulation (tDCS) applied to the hand area of primary motor cortex (M1), which can be used to induce long-lasting excitability enhancements or reductions, dependent on the polarity of stimulation, with short-lasting voluntary muscle contraction (VMC), which itself does not induce plastic cortical excitability changes. Corticospinal and intra-cortical M1 excitability were monitored by different transcranial magnetic stimulation (TMS) protocols. RESULTS: VMC reduced or tended to reverse the anodal tDCS-driven motor cortical excitability enhancement and the cathodal tDCS-induced excitability diminution. Our findings thus demonstrate de potentiation- and de-depression-like phenomena at the system level in the human motor cortex. CONCLUSION: This neurophysiological study may contribute to a better understanding of the balance between induction and reversal of plasticity associated with motor learning and rehabilitation processes. PMID- 21697592 TI - Treatment with nerve grafts and aFGF attenuates allodynia caused by cervical root transection injuries. AB - PURPOSE: Nerve root traction injuries induce spinal cord inflammation and lead to neuronal death within days. In the present study, we examined the inflammatory response one week after multiple cervical root transections. METHODS: In the transection group, the left cervical roots (C6-8) of rats were cut at the spinal cord junction. In the repair group, transected roots were repaired with nerve grafts and the subsequent application of aFGF and fibrin glue. A sham group had nerve roots exposed without transection. Mechanical allodynia and spinal glial responses were evaluated. RESULTS: Allodynia did not differ between the treatment groups on day 2. Rats with transected spinal nerve roots had significantly more allodynia by 7 days, which was associated with IL-1beta expression in dorsal and ventral horn astrocytes, and microglia activation. Repair of nerve roots with autologous intercostal nerve grafts and FGF in fibrin glue attenuated the allodynia, reduced IL-1beta expression in astroctyes and reduced microglia activation, along with a significant increase in arginase I expression. CONCLUSION: This study demonstrated a correlation between an increased number of IL-1beta-positive astrocytes and the development of allodynia. Our treatment significantly decreased IL-1beta-positive astrocytes, thus preventing the occurrence of neuropathic pain following multiple cervical root injuries. PMID- 21697591 TI - Horizontal ladder task-specific re-training in adult rats with contusive thoracic spinal cord injury. AB - PURPOSE: Using the horizontal ladder task, we examined some issues that need to be resolved before task-specific rehabilitative training can be employed clinically for the frequent contusive spinal cord injury (SCI). We hypothesized that improving recovery in task performance after contusive thoracic SCI requires frequent re-training and initiating the re-training early during spontaneous recovery. METHODS: Contusive SCI was produced at the adult female Sprague Dawley rat T10 vertebra. Task re-training was initiated one week later when occasional weight-supported plantar steps were taken overground (n = 8). It consisted of 2 repetitions each day, 5 days each week, for 3 weeks. Task performance and overground locomotion were assessed weekly. Neurotransmission through the SCI ventrolateral funiculus was examined. SCI morphometry was determined. RESULTS: Re training did not improve task performance recovery compared to untrained Controls (n = 7). Untrained overground locomotion and neurotransmission through the SCI did not change. Lesion area at the injury epicenter as a percentage of the total spinal cord area as well as total tissue, lesion, and spared tissue, white matter, or gray matter volumes did not differ. CONCLUSIONS: For the horizontal ladder task after contusive thoracic SCI, earlier re-training sessions with more repetitions and critical neural circuitry may be necessary to engender a rehabilitation effect. PMID- 21697593 TI - Neural correlates of somatosensory processing in patients with neglect. AB - PURPOSE: Recent evidence from neuroimaging studies using visual tasks suggests that the right superior parietal cortex plays a pivotal role for the recovery of neglect. Importantly, neglect-related deficits are not limited to the visual system and have a rather multimodal nature. We employed somatosensory stimulation in patients with neglect in order to analyze activity changes in networks that are presumably associated with this condition. METHODS: Eleven chronic neglect patients with right hemispherical stroke were investigated with a fMRI paradigm in which the affected and unaffected hand were passively moved. RESULTS: Brain activation was correlated with the performance in clinical neglect tests. Significant positive correlations with brain activation were found for the lesion duration, the performance in bells and letter cancellation tests and the line bisection test. These activated areas formed a distributed pattern in the right superior parietal cortex. CONCLUSIONS: The results suggest a shared representation of visual and somatosensory networks in the right superior parietal cortex in patients with right hemispherical strokes and neglect. The spatial pattern of activity in the superior parietal cortex points out to a different representation of changes related to lesion duration and neglect. PMID- 21697594 TI - Hypoglossal-facial anastomosis (HFA) over a 10 mm gap bridged by a Y-tube-conduit enhances neurite regrowth and reduces collateral axonal branching at the lesion site. AB - PURPOSE: The outcome of severe peripheral nerve injuries requiring surgical repair (transection and suture) is usually poor. Recent work suggests that direct suture of nerves increases collagen production and provides unfavourable conditions for a proper axonal regrowth. We tested whether entubulation of the hypoglossal nerve into a Y-tube conduit connecting it with the zygomatic and buccal facial nerve branches would improve axonal pathfinding at the lesion site, quality of muscle reinnervation and recovery of vibrissal whisking. METHODS: For hypoglossal-facial anastomosis (HFA) over a Y-tube (HFA-Y-tube) the proximal stump of the hypoglossal nerve was entubulated and sutured into the long arm of a Y-tube (isogeneic abdominal aorta with its bifurcation). The zygomatic and buccal facial branches were entubulated and sutured to the short arms of the Y-tube. Restoration of vibrissal motor performance, degree of collateral axonal branching at the lesion site and quality of neuro-muscular junction (NMJ) reinnervation were compared to animals receiving HFA-Coaptation (no entubulation) after 4 months. RESULTS: HFA-Y-tube reduced collateral axonal branching. However it failed to reduce the proportion of polyinnervated NMJ and did not improve functional outcome when compared to HFA-Coaptation. CONCLUSION: Elimination of compression by tightly opposed nerve fragments improved axonal pathfinding. However, biometric analysis of vibrissae movements did not show positive effects suggesting that polyneuronal reinnervation - rather than collateral branching - may be the critical limiting factor. Since polyinnervation of muscle fibers is activity-dependent and can be manipulated, the present findings raise hopes that clinically feasible and effective therapies after HFA could be soon designed and tested. PMID- 21697595 TI - Coadministration of epidermal growth factor and growth hormone releasing peptide 6 improves clinical recovery in experimental autoimmune encephalitis. AB - PURPOSE: Multiple sclerosis is a complex and devastating autoimmune disease of the central nervous system. Up to now, a constellation of candidate drugs have been evaluated with no major success. Experimental Autoimmune Encephalitis (EAE) is the animal counterpart that reproduces critical features of the human MS process. The aim of the present work is to study a possible therapeutic effect of epidermal growth factor (EGF) and growth hormone releasing peptide-6 (GHRP(6)) coadministration in mild and severe EAE. METHODS: Mild and severe forms of EAE were generated immunizing rats and mice with xenogeneic spinal cord homogenate and with the encephalitogenic peptide MOG(p35-35), respectively. EGF and GHRP(6) alone or combined were administered in therapeutic and prophylactic schedules. A clinical score was established to follow-up the animals during the disease period. Malondialdehyde (MDA) serum concentration and insulin like growth factor 1 (IGF-1) relative level from brain tissue were determined. RESULTS: Only the combined EGF+GHRP(6) therapy reduced the clinical score in mild as well in severe EAE forms. The combination also improved the survival rate in nearly 100% of the severe EAE animals. In addition to these effects, there was an increase in the brain IGF-1 transcript and a decrease of serum MDA. CONCLUSIONS: EGF+GHRP(6) proved to be effective in improving the natural course of both mild and severe EAE. Accordingly, the treatment reduces inflammatory infiltration and microvascular damage, which may be associated to the attenuation of the lipid peroxidation process and the transcriptional enhancement of IGF-1, a major pro survival factor for brain cells. PMID- 21697596 TI - Stem cell survival and functional outcome after traumatic brain injury is dependent on transplant timing and location. AB - PURPOSE: Recent work indicates that transplanted neural stem cells (NSCs) can survive, migrate to the injury site, and facilitate recovery from traumatic brain injury (TBI). The present study manipulated timing and location of NSC transplants following controlled cortical impact injury (CCI) in mice to determine optimal transplant conditions. METHODS: In Experiment 1 (timing), NSCs (E14.5 mouse) were injected into the host striatum, ipsilateral to the injury, at 2, 7, or 14 days. In Experiment 2 (location), NSCs or vehicle were injected into the mouse striatum (7 days post-CCI) either ipsilateral or contralateral to the injury and cognitive and motor abilities were assessed from weeks 1-8 post transplant. Histological measures of NSC survival, migration, and differentiation were taken at 6 and 8 weeks post-transplant. RESULTS: The results demonstrate that: (1) 2-7 days post-injury is the optimal time-range for delivering NSCs; (2) time of transplantation does not affect short-term phenotypic differentiation; (3) transplant location affects survival, migration, phenotype, and functional efficacy; and (4) NSC-mediated functional recovery is not contingent upon NSC migration or phenotypic differentiation. CONCLUSIONS: These findings provide further support for the idea that mechanisms other than the replacement of damaged neurons or glia, such as NSC-induced increases in protective neurotrophic factors, may be responsible for the functional recovery observed in this model of TBI. PMID- 21697597 TI - Crystallographic determination of the disease-associated T1184R variant of complement regulator factor H. AB - The soluble 155 kDa glycoprotein factor H (FH) protects host tissue from damage by the human complement system. It accelerates decay of the alternative-pathway C3 convertase, C3bBb, and is a cofactor for factor I-mediated cleavage of the opsonin C3b. Numerous mutations and single-nucleotide polymorphisms (SNPs) occur in the gene encoding FH and the resulting missense mutations and truncation products result in altered functionality that predisposes to the development of the serious renal condition atypical haemolytic uraemic syndrome (aHUS). Other polymorphisms are linked to membranoproliferative glomerulonephritis and macular degeneration. The two C-terminal modules of FH (FH19-20) harbour numerous aHUS associated mutations that disrupt the ability of factor H to protect host cells from complement-mediated damage. In this work, the crystal structure of an aHUS associated T1184R variant of FH19-20 at a resolution of 1.52 A is described. It is shown that this mutation has negligible structural effects but causes a significant change in the electrostatic surface of these two domains. Mechanisms are discussed by which this mutation may alter FH-ligand interactions, particularly with regard to the extension of a region of this molecule within module 20 that has been associated with the binding of glycosaminoglycans (GAGs) or sialic acid residues. PMID- 21697598 TI - High-resolution X-ray structure of the rabbit histidine triad nucleotide-binding protein 1 (rHINT1)-adenosine complex at 1.10 A resolution. AB - Histidine triad nucleotide-binding protein 1 (HINT1) represents the most ancient and widespread branch in the histidine-triad protein superfamily. HINT1 plays an important role in various biological processes and has been found in many species. Here, the first complete structure of the rabbit HINT1-adenosine complex is reported at 1.10 A resolution, which is one of the highest resolutions obtained for a HINT1 structure. The final structure has an R(cryst) of 14.25% (R(free) = 16.77%) and the model exhibits good stereochemical qualities. A detailed analysis of the atomic resolution data allowed an update of the details of the protein structure in comparison to previously published data. PMID- 21697599 TI - Simultaneous X-ray diffraction from multiple single crystals of macromolecules. AB - The potential in macromolecular crystallography for using multiple crystals to collect X-ray diffraction data simultaneously from assemblies of up to seven crystals is explored. The basic features of the algorithms used to extract data and their practical implementation are described. The procedure could be useful both in relation to diffraction data obtained from intergrown crystals and to alleviate the problem of rapid diffraction decay arising from the effects of radiation damage. PMID- 21697600 TI - Structure analysis of Entamoeba histolytica enolase. AB - Entamoeba histolytica enolase (EhENO) reversibly interconverts 2-phosphoglyceric acid (2-PGA) and phosphoenolpyruvic acid (PEP). The crystal structure of the homodimeric EhENO is presented at a resolution of 1.9 A. In the crystal structure EhENO presents as an asymmetric dimer with one active site in the open conformation and the other active site in the closed conformation. Interestingly, both active sites contain a copurified 2-PGA molecule. While the 2-PGA molecule in the closed active site closely resembles the conformation known from other enolase-2-PGA complexes, the conformation in the open active site is different. Here, 2-PGA is shifted approximately 1.6 A away from metal ion I, most likely representing a precatalytic situation. PMID- 21697601 TI - Processing incommensurately modulated protein diffraction data with Eval15. AB - Recent challenges in biological X-ray crystallography include the processing of modulated diffraction data. A modulated crystal has lost its three-dimensional translational symmetry but retains long-range order that can be restored by refining a periodic modulation function. The presence of a crystal modulation is indicated by an X-ray diffraction pattern with periodic main reflections flanked by off-lattice satellite reflections. While the periodic main reflections can easily be indexed using three reciprocal-lattice vectors a*, b*, c*, the satellite reflections have a non-integral relationship to the main lattice and require a q vector for indexing. While methods for the processing of diffraction intensities from modulated small-molecule crystals are well developed, they have not been applied in protein crystallography. A recipe is presented here for processing incommensurately modulated data from a macromolecular crystal using the Eval program suite. The diffraction data are from an incommensurately modulated crystal of profilin-actin with single-order satellites parallel to b*. The steps taken in this report can be used as a guide for protein crystallographers when encountering crystal modulations. To our knowledge, this is the first report of the processing of data from an incommensurately modulated macromolecular crystal. PMID- 21697602 TI - Isothiazolidinone (IZD) as a phosphoryl mimetic in inhibitors of the Yersinia pestis protein tyrosine phosphatase YopH. AB - Isothiazolidinone (IZD) heterocycles can act as effective components of protein tyrosine phosphatase (PTP) inhibitors by simultaneously replicating the binding interactions of both a phosphoryl group and a highly conserved water molecule, as exemplified by the structures of several PTP1B-inhibitor complexes. In the first unambiguous demonstration of IZD interactions with a PTP other than PTP1B, it is shown by X-ray crystallography that the IZD motif binds within the catalytic site of the Yersinia pestis PTP YopH by similarly displacing a highly conserved water molecule. It is also shown that IZD-based bidentate ligands can inhibit YopH in a nonpromiscuous fashion at low micromolar concentrations. Hence, the IZD moiety may represent a useful starting point for the development of YopH inhibitors. PMID- 21697603 TI - Development of high-performance X-ray transparent crystallization plates for in situ protein crystal screening and analysis. AB - X-ray transparent crystallization plates based upon a novel drop-pinning technology provide a flexible, simple and inexpensive approach to protein crystallization and screening. The plates consist of open cells sealed top and bottom by thin optically, UV and X-ray transparent films. The plates do not need wells or depressions to contain liquids. Instead, protein drops and reservoir solution are held in place by rings with micrometre dimensions that are patterned onto the bottom film. These rings strongly pin the liquid contact lines, thereby improving drop shape and position uniformity, and thus crystallization reproducibility, and simplifying automated image analysis of drop contents. The same rings effectively pin solutions containing salts, proteins, cryoprotectants, oils, alcohols and detergents. Strong pinning by rings allows the plates to be rotated without liquid mixing to 90 degrees for X-ray data collection or to be inverted for hanging-drop crystallization. The plates have the standard SBS format and are compatible with standard liquid-handling robots. PMID- 21697604 TI - Mycobacterium tuberculosis acyl carrier protein synthase adopts two different pH dependent structural conformations. AB - The crystal structures of acyl carrier protein synthase (AcpS) from Mycobacterium tuberculosis (Mtb) and Corynebacterium ammoniagenes determined at pH 5.3 and pH 6.5, respectively, are reported. Comparison of the Mtb apo-AcpS structure with the recently reported structure of the Mtb AcpS-ADP complex revealed that AcpS adopts two different conformations: the orthorhombic and trigonal space-group structures show structural differences in the alpha2 helix and in the conformation of the alpha3-alpha4 connecting loop, which is in a closed conformation. The apo-AcpS structure shows electron density for the entire model and was obtained at lower pH values (4.4-6.0). In contrast, at a higher pH value (6.5) AcpS undergoes significant conformational changes, resulting in disordered regions that show no electron density in the AcpS model. The solved structures also reveal that C. ammoniagenes AcpS undergoes structural rearrangement in two regions, similar to the recently reported Mtb AcpS-ADP complex structure. In vitro reconstitution experiments show that AcpS has a higher post-translational modification activity between pH 4.4 and 6.0 than at pH values above 6.5, where the activity drops owing to the change in conformation. The results show that apo AcpS and AcpS-ADP adopt different conformations depending upon the pH conditions of the crystallization solution. PMID- 21697605 TI - Additive effects of beta-blockers on renin-angiotensin system inhibitors for patients after acute myocardial infarction treated with primary coronary revascularization. AB - BACKGROUND: Although some beta-blockers are effective for patients after acute myocardial infarction (AMI), few studies have compared their additive effects on renin-angiotensin system inhibitors (RAS-Is). METHODS AND RESULTS: The 251 consecutive AMI patients administered angiotensin-converting-enzyme inhibitors (ACE-Is) or angiotensin-II receptor blockers (ARBs) were retrospectively investigated and divided into 2 groups: treated without beta-blockers (no-beta blocker group, n=80) or treated with beta-blockers before discharge (beta-blocker group, n=171; carvedilol [n=91] or bisoprolol [n=80]). The doses of RAS-Is used for patients in the no-beta-blocker group were at least double those used in the beta-blocker group. No significant differences between the 2 groups were observed with regard to baseline characteristics. After a 12-month follow-up, the survival and cardiac event-free rates in the beta-blocker group were significantly higher than those in the no-beta-blocker group. The percent change in blood pressure did not significantly differ between the 2 groups, but the levels of brain natriuretic peptide, metalloproteinase-2, and metalloproteinase-9 and the left ventricular ejection fraction improved significantly in the beta-blocker group compared with the no-beta-blocker group. Regarding the 2 beta-blockers, carvedilol treatment produced more favorable outcomes than bisoprolol. CONCLUSIONS: The data suggest that treatment with RAS-I in combination with beta blocker is more effective for patients after AMI than treatment with RAS-I alone. PMID- 21697606 TI - Cardioscopic detection of left ventricular thrombi. -With special reference to a comparison with left ventriculography and echocardiography-. AB - BACKGROUND: Thrombosis occurs in the left ventricle and causes ischemic cerebral attacks. However, differences in the incidence of left ventricular thrombi (LVT) among various categories of heart diseases are not known. METHODS AND RESULTS: From April 2000 to 31 March 2008, 258 patients (104 females and 154 males; age 63 +/- 6 years) with a heart disease underwent cardioscopy of the left ventricle. LVT were detected by cardioscopy in 78 of 258 patients; 12.5% of 57 patients with stable angina, 0% of 9 with unstable angina, 45.2% of 42 with acute myocardial infarction, 23.2% of 43 with old myocardial infarction, 61.9% of 21 with idiopathic acute myocarditis, 44.3% of 68 with idiopathic chronic myocarditis, 33.3% of 6 with rheumatic valvular disease, 25.7% of 31 with idiopathic dilated cardiomyopathy and in 8.0% of 12 with idiopathic hypertrophic cardiomyopathy. Nine of 78 thrombi were globular and 69 were mural. The detection rate of LVT by cardioscopy, left venticulography, non-contrast and contrast echocardiography was 30.2%, 2.7%, 1.9% and 7.0%, respectively. CONCLUSIONS: LVT were frequently detected by cardioscopy in patients with heart diseases. Although invasive, cardioscopy was more sensitive in detecting LVT than left ventriculography, and non-contrast and contrast echocardiography. PMID- 21697607 TI - Thrombus attached to the left atrial septal pouch assessed on 3-dimensional transesophageal echocardiography. PMID- 21697608 TI - Transmural perfusion gradient in adenosine triphosphate stress myocardial perfusion computed tomography. AB - BACKGROUND: The aim of the present study was to assess semi-quantification of myocardial perfusion using adenosine triphosphate (ATP)-stress myocardial perfusion computed tomography (MPCT) in patients with coronary artery disease (CAD). METHODS AND RESULTS: Seventeen patients with CAD underwent ATP-stress MPCT, stress myocardial perfusion scintigraphy (MPS) and coronary angiography (CAG). With ATP loading (0.16 mg.kg-1.min-1, 5 min) and slow infusion of contrast medium (2 ml/s, 100 ml), stress images were acquired using prospective electrocardiogram-gated 64-slice CT. Stress MPCT images were analyzed according to the transmural perfusion gradient (TMPG; difference between subendocardial and epicardial attenuation, divided by wall thickness; Hounsfield units [HU]/mm) per segment, and summed TMPG was compared with those of stress MPS and CAG per territory and patient, respectively. There were 36 CAG-proved stenotic vessels in 51 (17 * 3) territories. There were significant correlations between TMPG and MPS stress score per segment, per territory and per patient, respectively (P<0.05). Summed TMPG in territories with and without >70% coronary stenosis was 32.3HU/mm (-1.9~90.9) and 14.5 HU/mm (-5.6~38.4; P<0.05). For detecting coronary artery stenosis, sensitivity, specificity, positive and negative predictive values using the summed TMPG were 72%, 87%, 93% and 57%, in comparison with summed MPS (64%, 73%, 85%, and 46%). CONCLUSIONS: Semi-quantification of myocardial perfusion using TMPG has great potential to evaluate the severity of myocardial ischemia, similarly to MPS score. PMID- 21697609 TI - Effect of limb ischemic preconditioning on myocardial injury in patients undergoing mitral valve replacement surgery. -A randomized controlled trial-. AB - BACKGROUND: Whether limb ischemic preconditioning (LIPC) is beneficial for patients undergoing mitral valve replacement (MVR) surgery is unknown. METHODS AND RESULTS: Seventy-five adult patients undergoing MVR surgery were randomly assigned to 3 groups: control group (n=25), LIPC group I (3 * 5-min cycles of right upper arm ischemia and 5-min reperfusion; n=25) and LIPC group II (3 * 5 min cycles of right upper arm ischemia and 5-min reperfusion combined with 2 * 10 min cycles of right upper leg ischemia and 10-min reperfusion; n=25). Cardiopulmonary bypass (CPB) time, cross-clamp time, cardiac index, cumulative postoperative dosage of dobutamine, intensive care stay, postoperative hospital stay were not statistically different. Although the cumulative postoperative dosage of dobutamine was not different, there was a significantly lower inotropic requirement in LIPC II compared with the control group at 4 and 8h after surgery. Plasma levels of cardiac troponin-I in the 3 groups significantly increased during CPB and peaked at 4h after surgery. Levels of cTnI in LIPC II were significantly lower than in the control group at each time point after surgery. CONCLUSIONS: Myocardial injury is obvious after MVR surgery. LIPC can protect the myocardium from ischemia-reperfusion injury and decrease the inotropic requirement after surgery. The data also confirmed the requirement for the preconditioning stimulus to cross a threshold. PMID- 21697610 TI - Relationship between biological variation in B-type natriuretic peptide and plasma renin concentration in stable outpatients with dilated cardiomyopathy. AB - BACKGROUND: The aim of the present study was to interpret B-type natriuretic peptide (BNP) level in outpatients with stable chronic heart failure (CHF); it is important to clarify whether the change in BNP represents disease progression or a range of biological variation. METHODS AND RESULTS: To compare biological variation in BNP and biological variation in factors of the renin-angiotensin aldosterone system (RAS) in stable CHF patients with dilated cardiomyopathy (DCM), the BNP plasma levels and RAS factors were measured in 115 stable outpatients with DCM. According to stepwise multivariate analysis, plasma BNP at baseline (P=0.005), presence of atrial fibrillation (P=0.015), and a high biological variation in plasma renin concentration (PRC; P=0.002) were significant independent dominant factors related to a high biological variation in BNP. Although there was no change in body weight or blood pressure during the 2-month study period, the % change in hematocrit was negatively correlated with % change in BNP (r=-0.327, P=0.0008), and positively correlated with % change in PRC (r=0.671, P=0.001). CONCLUSIONS: There was a significant relationship between biological variation in BNP and biological variation in PRC, suggesting that the physiological interaction between the natriuretic peptide system and RAS may contribute to the biological variation in plasma BNP in stable outpatients with DCM. PMID- 21697611 TI - Epidemiology and predictors of short-term mortality in symptomatic venous thromboembolism. AB - BACKGROUND: The epidemiology of symptomatic venous thromboembolism (VTE) in Taiwan has not been well investigated. The aim of this study was to report on the epidemiology and short-term prognosis of symptomatic VTE. METHODS AND RESULTS: This nationwide population-based cohort study used the Taiwanese National Health Insurance claims databases to identify adults older than 18 years of age with symptomatic VTE diagnosed in 2002. We investigated the clinical features of VTE and determined independent risk factors of 1-month mortality. A total of 2,774 patients were identified with a mean age of 62.8 years and the female-to-male ratio was 1.15:1. The crude incidence of symptomatic VTE was 16.5 per 100,000 persons, which steadily increased with age, ranging from 4 per 100,000 in patients <40 years old to 108 per 100,000 in patients >= 80 years. We observed no seasonal and meteorological variations in the incidence of VTE. The overall 1 month mortality rate was 8.8%, with 7.1% in deep venous thrombosis and 12.9% in pulmonary embolism. Multivariate analysis demonstrated that pulmonary embolism, cancer, neurologic disease with extremity paresis or paralysis, older age, longer hospital stay, and major abdominal and thoracic surgery in the 3 months preceding VTE were independent predictors of 1-month death. CONCLUSIONS: Although the incidence of VTE was lower in Taiwanese populations than in Western ones, short term mortality rates were high in specific populations. These findings suggest optimal treatment is needed in higher-risk patients. PMID- 21697612 TI - Inhibitory effect of caffeic acid on human organic anion transporters hOAT1 and hOAT3: a novel candidate for food-drug interaction. AB - Several kinds of food have been shown to influence the absorption and metabolism of drugs, although there is little information about their effect on the renal excretion of drugs. In this study, we performed uptake experiments using Xenopus laevis oocytes to assess the inhibitory effects of chlorogenic acid, caffeic acid and quinic acid, which are contained in coffee, fruits and vegetables, on human organic anion transporters hOAT1 and hOAT3; these transporters mediate renal tubular uptake of anionic drugs from blood. Injection of hOAT1 and hOAT3 cRNA into oocytes stimulated uptake of typical substrates of hOAT1 and hOAT3 (p aminohippurate and estrone sulfate, respectively); among the three compounds tested, caffeic acid most strongly inhibited these transporters. The apparent 50% inhibitory concentrations of caffeic acid were estimated to be 16.6 uM for hOAT1 and 5.4 uM for hOAT3. Eadie-Hofstee plot analysis showed that caffeic acid inhibited both transporters in a competitive manner. In addition to the transport of p-aminohippurate and estrone sulfate, that of antifolates and antivirals was inhibited by caffeic acid. These findings show that caffeic acid has inhibitory potential against hOAT1 and hOAT3, suggesting that renal excretion of their substrates could be affected in patients consuming a diet including caffeic acid. PMID- 21697613 TI - Absence of excretion of the active moiety of bisacodyl and sodium picosulfate into human breast milk: an open-label, parallel-group, multiple-dose study in healthy lactating women. AB - The aim of this study was to determine whether administration of the prodrugs bisacodyl (Bisa) and sodium picosulfate (SPS) leads to excretion of their common active metabolite, bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM), in breast milk. Two groups of 8 healthy lactating women who had stopped breast feeding received multiple doses of Bisa or SPS. Plasma, urine, and breast milk were collected and concentrations of free and total BHPM were determined using validated liquid chromatography/mass spectrometry methods. BHPM remained below the limits of detection in breast milk following single- and multiple-dose administration of Bisa and SPS. First, BHPM plasma concentrations were observed after a lag time of about 3 to 4 h and 4 to 5 h following Bisa and SPS administration, respectively. C(max) was attained approximately 5 h after dosing of Bisa and 9 h after dosing of SPS. BHPM did not accumulate after multiple administrations of Bisa and only slightly accumulated following multiple doses of SPS. About 12% and 13% of Bisa and SPS was excreted as BHPM into urine at steady state. BHPM, the active moiety of Bisa and SPS, was not excreted into human breast milk. Hence, use of Bisa or SPS to treat constipation of breast-feeding women is considered well tolerated with regard to exposing infants to BHPM via breast milk. PMID- 21697614 TI - Organic solvent use in enterprises in Japan. AB - This study was initiated to elucidate possible changes in types of organic solvents (to be called solvents in short) used in enterprises in Japan through comparison of current solvent types with historical data since 1983. To investigate current situation in solvent use in enterprises, surveys were conducted during one year of 2009 to 2010. In total, workroom air samples in 1,497 unit workplaces with solvent use were analyzed in accordance with regulatory requirements. Typical use pattern of solvents was as mixtures, accounting for >70% of cases. Adhesives spreading (followed by adhesion) was relatively common in small-scale enterprises, whereas printing and painting work was more common in middle-scale ones, and solvent use for testing and research purpose was basically in large-scaled enterprises. Through-out printing, painting, surface coating and adhesive application, toluene was most common (being detected in 49 to 82% of workplaces depending on work types), whereas isopropyl alcohol was most common (49%) in degreasing, cleaning and wiping workplaces. Other commonly used solvents were methyl alcohol, ethyl acetate and acetone (33 to 37%). Comparison with historical data in Japan and literature retrieved data outside of Japan all agreed with the observation that toluene is the most commonly used solvent. Application of trichloroethylene and 1,1,1 trichloroethane, once common in 1980s, has ceased to exist in recent years. PMID- 21697615 TI - Tractor controls actuating force limits for Indian operators. AB - In four-wheel tractors, proper design of controls is important for comfortable and safe operation of the tractor. The design involves location and dimensions of controls as well as strength limits for operating these controls. The present study was aimed to quantify human strength for operation of tractor controls and to recommend the maximum control actuating forces for normal operation of tractors based on strength capability of 3,423 Indian male agricultural workers. The 5th percentile values of strength parameters i.e. leg strength sitting (left and right), foot strength sitting (right), torque strength (both hands) sitting, push strength (left hand and right hand) sitting and pull strength (left hand and right hand) sitting of agricultural workers collected using a strength measurement set-up were taken into consideration for the study. It was recommended that the maximum actuating forces for normal operation of frequently operated brake and clutch pedals of tractors should not exceed 260 N and 125 N based on 5th percentile values of right and left leg strength of male agricultural workers, respectively. The maximum actuating force required in steering wheel operation should not exceed 51 N based on 5th percentile value of torque strength (both hands) sitting of workers. The maximum actuating forces required for operating frequently operated levers viz. gear selection, speed selection, hydraulic control and hand throttle of Indian tractors should not exceed 46 N, 46 N, 25 N and 25 N, respectively. It may be concluded that the maximum actuating force limits as given in Bureau of Indian Standards IS 10703 are very high as compared to the findings of the study based on strength data of Indian male operators, which highlight the need to revise the standard. PMID- 21697616 TI - Musculoskeletal disorder costs and medical claim filing in the US retail trade sector. AB - The average costs of Musculoskeletal Disorder (MSD) and odds ratios for filing medical claims related to MSD were examined. The medical claims were identified by ICD 9 codes for four US Census regions within retail trade. Large private firms' medical claims data from Thomson Reuters Inc. MarketScan databases for the years 2003 through 2006 were used. Average costs were highest for claims related to lumbar region (ICD 9 Code: 724.02) and number of claims were largest for low back syndrome (ICD 9 Code: 724.2). Whereas the odds of filing an MSD claim did not vary greatly over time, average costs declined over time. The odds of filing claims rose with age and were higher for females and southerners than men and non southerners. Total estimated national medical costs for MSDs within retail trade were $389 million (2007 USD). PMID- 21697617 TI - Estimation of the prevalence of latent abnormalities in the lung and the accuracy of indirect chest x-ray examination among Japanese workers of different age groups. AB - It is considered that annual chest x-ray (CXR) examination can be restricted to workers by age; however, adequate epidemiological evidence is needed regarding the difference in the effectiveness of CXR examination between younger and older age groups. This study attempted to estimate the prevalence of latent abnormalities (P) in the lung and the false negative rate (F) and false positive rate (G) of examinations among workers of different age groups. 112,482 subjects who were screened for three consecutive years with no findings at the first screening, were selected. The proportion of positive findings at the second screening and the proportion of negative findings at the third screening were incorporated into a stochastic model, and 5-yr-age-specific P, F, and G were estimated. P tended to increase with increasing age. F was 40-45% in <45-yr-old subjects and was only 10% in the older age groups. G showed a steady increase with increasing age. This study indicates that the nature of findings differs between younger and older age groups, and this difference affects the accuracy of examination. In Japan, the age of workers should be considered when a CXR examination is performed. PMID- 21697618 TI - Conflicts at work--the relationship with workplace factors, work characteristics and self-rated health. AB - Few studies have considered the work environment in relation to workplace conflicts and those who have been published have included relatively few psychosocial work environment factors. Little research has been published on the consequences of workplace conflicts in terms of employee health. In this study, the statistical relationships between work and workplace characteristics on one hand and conflicts on the other hand are examined. In addition, the relationship between conflicts at work and self-rated health are described. The study population was derived from the Swedish Longitudinal Occupational Survey of Health (SLOSH) 2006; n=5,141. Among employees at workplaces with more than 20 employees (n=3,341), 1,126 (33.7%) responded that they had been involved in some type of conflict during the two years preceding the survey. Among the work and workplace characteristics studied, the following factors were independently associated with increased likelihood of ongoing conflicts: Conflicting demands, emotional demands, risk of transfer or dismissal, poor promotion prospects, high level of employee influence and good freedom of expression. Factors that decreased the likelihood of ongoing conflicts were: Good resources, good relations with management, good confidence in management, good procedural justice (fairness of decisions) and good social support. After adjustment for socioeconomic conditions the odds ratio for low self-rated health associated with ongoing conflict at work was 2.09 (1.60-2.74). The results provide a good starting point for intervention and prevention work. PMID- 21697619 TI - Characterization of wood dust from furniture by scanning electron microscopy and energy-dispersive x-ray analysis. AB - Study characterized and analyzed form factor, elementary composition and particle size of wood dust, in order to understand its harmful health effects on carpenters in Quindio (Colombia). Once particle characteristics (size distributions, aerodynamic equivalent diameter (D(alpha)), elemental composition and shape factors) were analyzed, particles were then characterized via scanning electron microscopy (SEM) in conjunction with energy dispersive X-ray analysis (EDXRA). SEM analysis of particulate matter showed: 1) cone-shaped particle ranged from 2.09 to 48.79 um D(alpha); 2) rectangular prism-shaped particle from 2.47 to 72.9 um D(alpha); 3) cylindrically-shaped particle from 2.5 to 48.79 um D(alpha); and 4) spherically-shaped particle from 2.61 to 51.93 um D(alpha). EDXRA reveals presence of chemical elements from paints and varnishes such as Ca, K, Na and Cr. SEM/EDXRA contributes in a significant manner to the morphological characterization of wood dust. It is obvious that the type of particles sampled is a complex function of shapes and sizes of particles. Thus, it is important to investigate the influence of particles characteristics, morphology, shapes and D(alpha) that may affect the health of carpenters in Quindio. PMID- 21697620 TI - Postures and movements in the most common tasks of power line workers. AB - The repair and maintenance of electrical power lines involves awkward postures, which are known risk factors for developing musculoskeletal disorders. The aim of the present study was to quantify postures and movements of upper arm, head, upper back and neck in the main tasks performed by line workers. Posture of twelve right-handed line workers was recorded by inclinometry and presented as percentiles of angular and angular velocity distributions. All tasks involved considerable upper-arm elevation, ranging from 73 degrees to 115 degrees for the 90th percentile. Upper-arm elevation showed significant differences between tasks, but no consistent differences between right and left sides. Regarding velocity, the right arm presented higher levels than the left arm. All tasks required significant extension of head, upper back and neck, ranging from 7 degrees to 67 degrees for head (10th percentile). All tasks, except the one performed with a continuous extension, also involved pronounced flexion, ranging from 33 degrees to 60 degrees for the head (90th percentile). Work which required highly elevated arms also required significant head extension (r(2)=0.56). Awkward postures of upper arms, head, upper back and neck were identified by inclinometry, demonstrating the need for preventative interventions to reduce musculoskeletal disorders among line workers. PMID- 21697621 TI - Vitamin D deficiency and seasonal and inter-day variation in circulating 25 hydroxyvitamin D and parathyroid hormone levels in indoor daytime workers: a longitudinal study. AB - Seasonal variation in circulating 25-hydroxyvitamin D (25OHD) levels related to seasonal and inter-day fluctuation in sunlight ultraviolet irradiation, may lead to misjudgments concerning 25OHD status in individual workers around threshold levels. Here, to examine seasonal and inter-day variations in plasma 25OHD, we conducted a longitudinal study involving indoor daytime workers. Subjects were four male indoor daytime workers aged 32-57 yr working in Kawasaki City, Japan. Blood samples were obtained on six days within two two-week periods in February and October, 2008. Plasma 25OHD, serum intact parathyroid hormone (PTH) and 1alpha,25-dihydroxyvitamin D [1alpha,25(OH)(2)D] were measured. Individual monthly mean 25OHD levels were 16-56% higher in October than in February (p=0.03), while individual monthly mean intact PTH levels were 15-41% lower in October (p=0.09). No seasonal change was observed in 1alpha,25(OH)(2)D (p=0.62). Notably, nearly all measured 25OHD levels in February were lower than the reference value of 20 ng/ml. Our study identified the occurrence of seasonal variation in circulating 25OHD and intact PTH levels, even after accounting for inter-day variability, and hypovitaminosis D in wintertime in indoor daytime male workers in Japan. Due to this variability, single spot measurements of 25OHD may lead to misjudgment of workers' vitamin D status. PMID- 21697622 TI - Subjective symptoms of female workers sorting goods in summer. AB - Subjective musculoskeletal symptoms are more frequently complained about in cold store work and in related conditions than those experienced in normal temperature work. This cross sectional study was undertaken to evaluate the effects of indoor cooling and cold storage goods on the prevalence of subjective symptoms in summer. Female workers sorting cold storage goods (exposed group) were the main subjects of this study (n=47). We also included a group of female workers engaged sorting dry goods as the unexposed to cold group (n=86). Work load for the two groups were estimated according to the recommended criteria. A self-administered questionnaire covering age, occupational career, smoking, alcohol drinking and physical exercise, present or past history of diseases, individual protective measures against cold or heat, and subjective symptoms (60 items) was used. The air temperature of the site at the start of working time for the workers sorting cold storage goods was 22.2C which was significantly lower than those measured for the other two work places (25.4C and 25.4C) of the unexposed to cold group. Environmental temperatures at the foot level at the sorting workshop of cold storage goods and dry goods were ca.16C and 26C all day, respectively. The surface temperatures of cold storage goods were between -2.8C and 9.4C. The surface temperature of dry goods was 26.5C. Among the working characteristic items, only daily working hours in the exposed group (5.6 +/- 0.6 h) were significantly longer than those in the unexposed to cold group (4.6 +/- 0.9 h) (p<0.01). The prevalence rates of finger cold sensation, stiffness in the fingers, pain in the wrist, pain in the elbow, back dullness, back pain, low-back cold sensation, foot cold sensation and pain in the foot in the exposed group were significantly higher than those in the unexposed to cold group (p<0.05 or p<0.01). Pain in the fingers, numbness in the fingers, pain in the foot and foot numbness due to the cold in the exposed group were significantly higher than those in the unexposed to cold group (p<0.05 or p<0.01). These results suggest that indoor cooling and/or job activities related to cold storage goods could, to some extent, affect peripheral circulatory disturbances; and it could be regarded as a factor related to musculoskeletal symptoms among the exposed workers. PMID- 21697623 TI - Mental health, suicidal ideation, and related factors among workers from medium sized business establishments in northern Japan: comparative study of sex differences. AB - A questionnaire survey was conducted among 3,233 workers (2,442 males and 791 females) from 17 medium-sized business establishments in northern Japan with respect to GHQ-12 score, suicidal ideation, sociodemographic characteristics, work-associated factors, and attitude toward mental health resources. Sex differences were assessed for each questionnaire item, and logistic regression analyses were performed separately for males and females. Significant correlations between common mental disorder (CMD: GHQ-12 score>=3) and the following factors were found for both sexes: short sleep, irregular working schedule, working in specific businesses, and attitude toward mental health resources. Associations between CMD and excess workload were significant only in male workers. While correlations between suicidal ideation and demand for mental health resources were observed in both sexes, significant correlations were observed between suicidal ideation and use of mental health resources for female workers alone. These results suggest that screening of a high-risk population and provision of mental health resources contribute to suicide prevention as a part of mental health promotion measures in medium-sized business establishments. They also suggest the need for identification of business/job type-specific stressors while considering sex differences in lifestyle factors, working environment, and help-seeking behavior. PMID- 21697624 TI - Effect of cold conditions on manual performance while wearing petroleum industry protective clothing. AB - The purpose of this study was to investigate manual performance and thermal responses during low work intensity in persons wearing standard protective clothing in the petroleum industry when they were exposed to a range of temperatures (5, -5, -15 and -25C) that are relevant to environmental conditions for petroleum industry personnel in northern regions. Twelve men participated in the study. Protective clothing was adjusted for the given cold exposure according to current practices. The subjects performed manual tests five times under each environmental condition. The manual performance test battery consisted of four different tests: tactile sensation (Semmes-Weinstein monofilaments), finger dexterity (Purdue Pegboard), hand dexterity (Complete Minnesota dexterity test) and grip strength (grip dynamometer). We found that exposure to -5C or colder lowered skin and body temperatures and reduced manual performance during low work intensity. In conclusion the current protective clothing at a given cold exposure is not adequate to maintain manual performance and thermal balance for petroleum workers in the high north. PMID- 21697625 TI - Factors of working conditions and prolonged fatigue among teachers at public elementary and junior high schools. AB - Prolonged fatigue among elementary and junior high school teachers not only damages their health but also affects the quality of education. The aim of this study was to determine the factors of working conditions associated with prolonged fatigue among teachers at public elementary and junior high schools. We distributed a self-reported, anonymous questionnaire to 3,154 teachers (1,983 in elementary schools, 1,171 in junior high schools) working in public schools in a city in Japan. They were asked to assess 18 aspects of their working conditions using a seven-point Likert scale. Prolonged fatigue was measured using the Japanese version of the checklist individual strength questionnaire. Multiple regression analysis was used to examine the association between working conditions and prolonged fatigue. Gender, age, and school type were introduced as confounders. In all, 2,167 teachers participated in this study. Results showed that qualitative and quantitative workload (time pressure due to heavy workload, interruptions, physically demanding job, extra work at home), communication with colleagues (poor communication, lack of support), and career factors (underestimation of performance by the board of education or supervisors, occupational position not reflecting training, lack of prospects for work, job insecurity) were associated with prolonged fatigue. PMID- 21697626 TI - Relationship between autonomic nervous system activity during sleep and fasting glucose in Japanese workers. AB - Although autonomic nervous system activity is reportedly related to diurnal glucose tolerance impairment, the relationship with glucose tolerance during sleep is unclear. Since work styles have recently diversified, it is important to assess the effect of sleep on workers' health. Elucidation of the relationship between autonomic nervous system activity during sleep and glucose tolerance in workers may facilitate preventive measures against diabetes using non pharmacological means (e.g., sleep hygiene education, relaxation techniques and stress management). We examined whether autonomic nervous system activity during sleep is related to fasting glucose or glycated hemoglobin (HbA1c) in individuals with either normal or impaired fasting glucose tolerance. The subjects were 77 apparently healthy Japanese workers with normal or impaired fasting glucose. We used high frequency (HF) and the ratio of low frequency to high frequency (LF/HF) obtained by pulse wave analysis to estimate autonomic nervous system activity. The data were analyzed using a generalized estimating equation adjusted for potential confounders (age, gender, engagement in shift work, sleep duration, and body mass index). Fasting glucose was significantly negatively related to HF, the parasympathetic component during sleep. Our results suggest that parasympathetic activity during sleep is associated with fasting glucose in apparently healthy Japanese workers. PMID- 21697627 TI - Organic solvent use in research institutions in Japan. AB - In 2008-2009, types of organic solvents used and air-borne vapor concentrations were surveyed in 1909 laboratories in four large research institutions in accordance with current regulations. The results were classified into 5 groups in terms of research fields (agriculture, biology, medicine, natural science, and technology and engineering) and evaluated after the regulatory rules. Laboratory air analyses by gas chromatography identified 5 and 20 solvents out of 7 Group 1 solvents and 40 Group 2 solvents, respectively; 10 solvents were used in more than 10% of the laboratories in each of the 5 research fields. The use of unmixed single solvent appeared to be unique in research laboratories in contrast to use of solvent mixtures in industrial facilities for production. Laboratories of technology and engineering fields used more various organic solvents more frequently, whereas use of xylenes appeared to be more specific to laboratories of bio-medical fields. Among the commonly used solvents, chloroform was the leading solvent to induce poorer results in regulatory classification (i.e., Class 3 in Administrative Control Classes) typically when applied in high pressure liquid chromatography which was too voluminous to be accommodated in a local exhaustion chamber. PMID- 21697628 TI - Quantitative evaluation of distortion in sketching under mono and dual axes whole body vibration. AB - Performance of sedentary activities such as reading and writing, in trains is known to be affected by the vibrations. An experimental study was therefore initiated to investigate the interference perceived in sketching task under low frequency random vibration in both mono and dual axes. Thirty healthy male subjects participated in the study. Random vibration stimuli were excited in various axes in frequency range of 1-20 Hz at magnitudes of 0.4, 0.8 and 1.2 m/s(2). The task required the subjects to sketch the given geometric figures such as circle, rectangle and triangle under vibration environment in two subject postures (sketch pad on lap and on table). Three performance methods were used to measure the effect of vibration stimuli and posture. They consisted of two specifically designed objective methods for percentage distortion measurement and one subjective method using Borg CR10 scale. The results revealed that the percentage distortion and difficulty in sketching increased with an increase in vibration magnitude and was found to be higher for vibration in Y- and Z-axis. Similar trend was observed for percentage distortion and difficulty in sketching for dual axes also. The perceived difficulty and impairment in sketching performance was greater while sketching on lap for X-axis, while the effect was just the reverse for other axes. PMID- 21697629 TI - The mechanical effect of anterior pelvic tilt taping on slump sitting by seated workers. AB - The objectives of this study were to determine whether there is a change in the pelvic inclination after about 30 min of slump sitting by seated workers, and if so, to determine whether these changes can be prevented by the application of anterior pelvic tilt taping (APTT). The subjects who consented to participate in the experiment were randomly allocated to two groups: no-APTT group and APTT group. The no-APTT group performed slump sitting for 30 min, and the both pelvic inclinations were remeasured. In the APTT group, the both pelvic inclinations were measured immediately after the application of the APTT, and then again after 30 min of slump sitting. The both pelvic inclinations in the no-APTT group were significantly decreased (p<0.05) after they returned to the upright standing posture. The both pelvic inclinations in the APTT group were significantly increased immediately after the APTT (p<0.05), and this increase was maintained when returning to the upright standing posture after 30 min of slump sitting (p>0.05). We suggest that APTT can be applied as an auxiliary treatment method for preventing changes in pelvic inclination and musculoskeletal problems of low back area by awkward sitting posture in the seated worker. PMID- 21697630 TI - Increased lipid accumulation in liver and white adipose tissue in aging in the SAMP10 mouse. AB - The population of elderly persons has increased worldwide. However, few studies have examined age-dependent changes in lipid and carbohydrate metabolism related to age-related diseases. The number of cases of metabolic syndrome is increasing worldwide and prevention of lifestyle diseases may lead to prolongation of lifespan. In this study, we examined age-dependent changes in lipid and carbohydrate metabolism in the senescence-accelerated (SAM) P10 mouse. Tissue weights and biochemical parameters in plasma and liver were examined in SAMP10 mice aged 3, 6, 9, and 12 mo. White adipose tissue weight and the levels of liver triacylglycerol, plasma free fatty acids, and plasma insulin all showed increases with aging of the mice. To examine this mechanism in detail, aging-related changes in mRNA expression of genes related to lipid and carbohydrate metabolism were examined by DNA microarray analysis. The mRNA level for Hsd11b1 (hydroxysteroid 11-beta dehydrogenase 1), which increases insulin secretion and resistance, was elevated with aging in the liver of SAMP10 mice. These results show that lipid accumulation in liver and white adipose tissue is promoted by aging in SAMP10 mice through an increase in plasma insulin levels. PMID- 21697631 TI - Elevated maternal serum folate in the third trimester and reduced fetal growth: a longitudinal study. AB - This study aimed to examine the association of fetal growth and elevated third trimester maternal serum folate due to folic acid (FA) supplement intake. Dietary intake, use of FA supplements, weight, and blood biomarkers of B-vitamins (serum folate, pyridoxal, vitamin B(12), and plasma total homocysteine) were observed in 33 healthy pregnant women at the third trimester (average gestational age 35 wk). Birth outcomes were assessed through hospital birth records. Infant anthropometry and maternal blood biomarkers were followed up at 1 mo postpartum. Fourteen women were taking FA supplements at the third trimester. Dietary intake was similar among FA users and non-users, but serum folate and pyridoxal were significantly higher in users (11.6+/-6.7 vs. 6.1+/-3.2 ng/mL, and 13.8+/-21.7 vs. 3.2+/-1.4 ng/mL, respectively). Plasma total homocystein (tHcy) was higher in non-users compared to users, but not significantly. Nine FA users and eight non-users had low serum vitamin B(12) values (<203 pg/mL). Nine FA users and all non-users had low serum pyridoxal values (<7.0 ng/mL). Infant birthweight was significantly lower in users compared to non-users (2,894+/-318 vs. 3,154+/-230 g). At 1 mo postpartum, infant weight and length were similar between FA users and non-users, but infant weight gain was larger in users. Higher serum folate values due to FA use in the third trimester was related to reduced fetal size. Excess FA under low vitamin B(6) and B(12) status may affect fetal growth. PMID- 21697632 TI - Dietary medium-chain triglycerides attenuate hepatic lipid deposition in growing rats with protein malnutrition. AB - The objective of this study was to investigate the effects of dietary medium chain triglycerides (MCT) on hepatic lipid accumulation in growing rats with protein malnutrition. Weaning rats were fed either a low-protein diet (3%, LP) or control protein diet (20%, CP), in combination with or without MCT. The four groups were as follows: CP-MCT, CP+MCT, LP-MCT, and LP+MCT. Rats in the CP-MCT, CP+MCT and LP+MCT groups were pair-fed their respective diets based on the amount of diet consumed by the LP-MCT group. Rats were fed each experimental diet for 30 d. Four weeks later, the respiratory quotient was higher in the LP-MCT group than those in the other groups during the fasting period. Hepatic triglyceride content increased in the LP groups compared with the CP groups. Hepatic triglyceride content in the LP+MCT group, however, was significantly decreased compared with that in the LP-MCT group. Levels of carnitine palmitoyltransferase (CPT) 1a mRNA and CPT2 mRNA were significantly decreased in the livers of the LP-MCT group, as compared with corresponding mRNA levels of the other groups. These results suggest that ingestion of a low-protein diet caused fatty liver in growing rats. However, when rats were fed the low-protein diet with MCT, hepatic triglyceride deposition was attenuated, and mRNA levels encoding CPT1a and CPT2 were preserved at the levels of rats fed control protein diets. PMID- 21697633 TI - Dietary taurine reduces hepatic secretion of cholesteryl ester and enhances fatty acid oxidation in rats fed a high-cholesterol diet. AB - We investigated the fate of exogenous fatty acid in connection with decreased hepatic accumulation and secretion of cholesteryl esters in rats fed diets containing taurine. Providing taurine as 5% of the diet for 14 d significantly decreased concentrations of cholesterol, especially cholesteryl esters in both serum and liver. Ketone body production and incorporation of exogenous [1 (14)C]oleate into ketone bodies in liver perfusate were consistently higher during a 4-h perfusion period in taurine-fed rats than in control rats. The elevation was accompanied by increased activity of liver mitochondrial carnitine palmitoyltransferase, a rate-limiting enzyme for fatty acid oxidation. Dietary taurine significantly reduced hepatic secretion of cholesteryl ester and decreased incorporation of exogenous oleic acid substrate into this lipid molecule. Further, the extent of reduction in hepatic secretion of cholesteryl ester was closely related to its diminished accumulation in the liver. The conversion pattern of exogenous [1-(14)C]oleic acid substrate suggested a decreased esterification-to-oxidation ratio in the taurine group compared with the control. These results suggest that taurine-induced reduction in hepatic accumulation of cholesteryl ester was associated with reduced hepatic secretion of this lipid molecule, and was inversely related to enhanced ketone body production and fatty acid oxidation. PMID- 21697634 TI - Association between dietary folate intake and blood status of folate and homocysteine in Malaysian adults. AB - Folate is of prime interest among investigators in nutrition due to its multiple roles in maintaining health, especially in preventing neural tube defects and reducing the risk of cardiovascular diseases. We investigated the effect of dietary folate intake on blood folate, vitamin B(12), vitamin B(6), and homocysteine status. One hundred subjects consisting of Chinese and Malay subjects volunteered to participate in this cross-sectional study. Dietary folate intake was assessed by 24-h dietary recall and a food-frequency questionnaire (FFQ). Serum and red blood cell folate were analyzed using a microbiological assay, while serum vitamin B(12) was determined by electrochemiluminescence immunoassay (ECLIA), and high-performance liquid chromatography (HPLC) was used for the determination of serum vitamin B(6) and homocysteine. The mean folate intake, serum folate, RBC folate, serum vitamin B(12), and B(6), were higher in female subjects, with the exception of serum homocysteine. The Chinese tended to have higher folate intake, serum folate, RBC folate, and vitamin B(12). A positive association was found between folate intake and serum folate while a negative association was found between folate intake and serum homocysteine. Stepwise linear regression of serum folate showed a significant positive coefficient for folate intake whilst a significant negative coefficient was found for serum homocysteine when controlling for age, gender, and ethnicity. In conclusion, high dietary folate intake helps to increase serum folate and to lower the homocysteine levels. PMID- 21697635 TI - Rats allowed to self-select zinc-deficient lard and fish-oil diets did not develop a preference for fish-oil diet. AB - Zinc (Zn)-deficiency causes a reduction in food intake and alters adipose metabolism. The effect of zinc restriction in rats on the selection of fish-oil and lard was studied during a period of reduced appetite. The reduction of appetite was caused by an experimentally induced Zn-deficiency. Four-week-old male rats were divided into three dietary treatment groups: Zn-adequate (ZnA, 30.9 mg Zn/kg), marginal Zn-deficient (ZnM, 5.9 mg Zn/kg) or Zn-deficient (ZnD, 0.9 mg Zn/kg). The three groups were placed on a self-selection regimen of the ZnA-fish-oil diet (ZnA-FD) and the ZnA-lard diet (ZnA-LD), the ZnM-FD and the ZnM LD or the ZnD-FD and the ZnD-LD, respectively for 24 d. The amount of the FD intake in the ZnD group decreased to 0.5 g/d after day 4-6 of self-selecting on the LD and the FD and no significant increase in the FD intake in the group was observed during the self-selection period. However, after day 7-9 and 13-15, the FD intake of the ZnA and the ZnM groups increased, respectively, and at the end of the self-selection period the ZnM and the ZnA rats consumed about 2.0 g FD/d and 4.5 g FD/d, respectively. The FD intake ratio [FD intake (g)/total intake (g)] in the ZnD rats during the self-selection period was the lowest and that in the ZnA rats was the highest of three groups. In conclusion, we showed that zinc status alters fish-oil and lard selection patterns and ZnD rats did not show a preference for fish-oil. PMID- 21697636 TI - Jejunal induction of SI and SGLT1 genes in rats by high-starch/low-fat diet is associated with histone acetylation and binding of GCN5 on the genes. AB - The intestinal expression of genes involved in carbohydrate digestion and absorption, such as sucrase-isomaltase (SI) and sodium-dependent glucose cotransporter (SGLT1), is higher in rodents fed a high-starch/low-fat (HS) diet than in those fed a low-starch/high-fat (LS) diet. In the present study, we investigated whether the HS diet-induced induction of SI and SGLT1 in the rat jejunum is coordinately regulated by nuclear transcription factors, histone acetylation, or histone acetyltransferases. HS diet intake induced jejunal expression of a histone acetyltransferase, general control of amino acid synthesis (GCN5), concurrently with the SI and SGLT1 genes; however, gene expression of nuclear transcription factors such as hepatocyte nuclear factor-1, caudal type homeobox-2, and GATA-binding protein-4 was unaffected by the HS diet. Acetylation of histones H3/H4 and binding of acetyltransferase GCN5 on the promoter/enhancer and transcribed regions of SI and SGLT1 genes were significantly higher in HS diet-fed rats than in LS diet-fed rats, but transcription factor binding was not affected by the HS diet. Our results suggest that the concomitant induction of SI and SGLT1 genes in the jejunum by the HS diet is closely associated with the binding of GCN5 and acetylation of histones H3/H4 on these genes. PMID- 21697637 TI - Rapid rehydration and moderate plasma glucose elevation by fluid containing enzymatically synthesized glycogen. AB - Enzymatically synthesized glycogen (ESG) has high solubility and its solution has low osmotic pressure. Therefore ESG solution could be rapidly absorbed and could be adequate for water rehydration and carbohydrate supplementation during exercise. The object of this study was to evaluate the gastric emptying time and plasma glucose elevation after an administration of ESG solution in comparison with another carbohydrate solution by using a laboratory animal. Male BALB/c mice were administered 10% w/v solution of glucose, maltodextrin, starch, naturally synthesized glycogen (NSG) and ESG at a dose of 20 uL/g body weight for the measurement of gastric emptying rate (Experiment 1) and 10 uL/g body weight for the measurement of plasma glucose elevation (Experiment 2). The osmolarity of gastric content was lower in the ESG and maltodextrin group than the other carbohydrate group. Weight of gastric fluid was significantly lower in the ESG and water group than the glucose group (p<0.01). Plasma glucose level was significantly lower in the ESG group than the glucose group from 0 to 60 min after administration (p<0.01), whereas plasma glucose level was same from 60 to 120 min for the ESG and glucose group (p=0.948). In Experiment 3, BALB/c mice ran on a treadmill for 2 h and were administered 8% of ESG or glucose solution (1.75, 3.5 or 7.0 uL/g body weight) every 20 min during running. There was no difference in post-exercise muscle glycogen level. These data suggest that 1) ESG beverage does not disturb water absorption because of its short gastric emptying time and 2) ESG slowly elevates plasma glucose level and maintains it for a prolonged time compared to the glucose solution. PMID- 21697638 TI - Naringenin in combination with vitamins C and E potentially protects oxidative stress-mediated hepatic injury in cadmium-intoxicated rats. AB - Cadmium (Cd)-induced oxidative stress and hepatic injury is one of the major outcomes of chronic Cd toxicity, which can be ameliorated by numerous antioxidants. The present study was undertaken to find the therapeutic efficacy of naringenin (NGN) plus vitamins C and E on Cd-induced oxidative hepatotoxicity in Wistar rats. It has been noticed that Cd intoxication significantly elevates the levels of serum hepatic marker enzymes such as alanine amino transferase, aspartate amino transferase, alkaline phosphatase, lactate dehydrogenase, gamma glutamyl transferase, total bilirubin, and hepatic thiobarbituric acid reactive substances, lipid hydroperoxides, conjugated dienes and protein carbonyls. In addition, Cd also decreases the activities of hepatic enzymatic antioxidants superoxide dismutase, catalase, glutathione peroxidase, glutathione S transferase, glutathione reductase and glucose-6-phosphate dehydrogenase and the levels of non-enzymatic antioxidants total sulphydryl groups, reduced glutathione, vitamins C and E and histopathological changes in liver. Treatment with NGN and vitamins C and E in combination more significantly improved the altered biochemical and histopathological changes in the liver of Cd-intoxicated rats than the NGN or vitamins C and E treatment alone. CONCLUSION: The present data suggest that combined administration of NGN with vitamins C and E proved to be more beneficial in the treatment of Cd-hepatotoxicity than NGN treatment alone. PMID- 21697639 TI - Spirulina prevents memory dysfunction, reduces oxidative stress damage and augments antioxidant activity in senescence-accelerated mice. AB - Spirulina has proven to be effective in treating certain cancers, hyperlipidemia, immunodeficiency, and inflammatory processes. In this study, we aimed to investigate the effects of Spirulina on memory dysfunction, oxidative stress damage and antioxidant enzyme activity. Three-month-old male senescence accelerated prone-8 (SAMP8) mice were randomly assigned to either a control group or to one of two experimental groups (one receiving daily dietary supplementation with 50 mg/kg BW and one with 200 mg/kg BW of Spirulina platensis water extract). Senescence-accelerated-resistant (SAMR1) mice were used as the external control. Results showed that the Spirulina-treated groups had better passive and avoidance scores than the control group. The amyloid beta-protein (Abeta) deposition was significantly reduced at the hippocampus and whole brain in both Spirulina groups. The levels of lipid peroxidation were significantly reduced at the hippocampus, striatum, and cortex in both Spirulina groups, while catalase activity was significantly higher only in the 200 mg/kg BW Spirulina group than in the control group. Glutathione peroxidase activity was significantly higher only in the cortex of the 200 mg/kg group than in that of the SAMP8 control group. However, superoxide dismutase activity in all parts of the brain did not significantly differ among all groups. In conclusion, Spirulina platensis may prevent the loss of memory possibly by lessening Abeta protein accumulation, reducing oxidative damage and mainly augmenting the catalase activity. PMID- 21697640 TI - Adenosine thiamine triphosphate (AThTP) inhibits poly(ADP-ribose) polymerase-1 (PARP-1) activity. AB - Overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) has been demonstrated to result in various stress-related diseases, including diabetes mellitus. Deficiency of cellular nicotinamide adenine dinucleotide (NAD(+)) content, consumed by PARP-1 to add ADP-ribose moieties onto target proteins, contributes to pathophysiological conditions. Adenosine thiamine triphosphate (AThTP) exists in small amounts in mammals; however, the function(s) of this metabolite remains unresolved. The structure of AThTP resembles NAD(+). Recent experimental studies demonstrate beneficial impacts of high-dose thiamine treatment of diabetic complications. These findings have led us to hypothesize that AThTP may modulate the activity of PARP-1. We have chemically synthesized AThTP and evaluated the effect of AThTP on recombinant PARP-1 enzyme activity. AThTP inhibited the PARP-1 activity at 10 uM, and a structural model of the PARP-1-AThTP complex highlighted the AThTP binding site. The results provide new insights into the pharmacological importance of AThTP as an inhibitor of PARP-1. PMID- 21697641 TI - Different recovery responses from dietary zinc-deficiency in the distribution of rat granulocytes. AB - The purpose of this study was to elucidate the effects of the recovery from dietary zinc-deficiency on the number of total white blood cells (WBCs), neutrophils, eosinophils and basophils, and plasma zinc and corticosterone concentrations in weanling male Sprague Dawley rats. Rats (n=34) of the zinc deficient diet (0.6 mg zinc/kg diet) and control diet (35.2 mg zinc/kg diet) groups were fed for 4 wk, and then rats of both groups were fed with the control diet for 3 wk. Zinc-deficiency increased duration-dependently and clearly the number of total WBCs, neutrophils and eosinophils, and the increased numbers of these cells recovered to the control levels in week 2 of the recovery. On the other hand, the number of basophils increased by the zinc-deficiency recovered to the control levels in week 1 of the recovery. Zinc-deficiency significantly decreased plasma zinc concentrations by 85%, and markedly increased plasma corticosterone concentrations by 317%, as compared with the control group. In the recovery period, plasma zinc and corticosterone concentrations recovered to the control levels in week 2 of the recovery. These results suggest that zinc deficiency and its recovery responses in the number of granulocytes and total WBCs are reversible, and their recovery rates depend on the subsets of granulocytes in rats. PMID- 21697642 TI - The quality of cryopreserved sperm collected from feline caudal epididymides stored at room temperature. AB - On the assumption that animals of wild feline species died in the field, caudal epididymal sperm were cryopreserved following storage of the feline epididymides at 20 degrees C for 0-24 hr, and their qualities were observed. Compared to the qualities at 0 hr, no significant differences were noted following 12 hr of storage at 20 degrees C. On comparison of the qualities between caudal sperm cryopreserved after 24 hr storage at 4 degrees C and after 12 hr at 20 degrees C followed by 12 hr storage at 4 degrees C, no significant differences were noted. These findings suggest that the cryopreserved sperm collected from epididymides of dead animals might be useful for artificial insemination if cryopreservation was performed within 12 hr exposure to ambient temperature. PMID- 21697643 TI - Neutropenia associated with osteomyelitis due to Hepatozoon canis infection in a dog. AB - A 4-year-old, intact male Shiba dog was referred to Yamaguchi University Animal Medical Center, Yamaguchi, Japan, for the following complaints: anorexia, lethargy, intermittent fever, gingival bleeding and abdominal purpura. The dog presented with persistent neutropenia. Histopathological examination of a bone marrow sample revealed round to oval structures that resembled Hepatozoon micromerozoites and formed a "wheel-spoke" pattern. Furthermore, mature neutrophils were observed around these structures. PCR and sequencing using bone marrow aspirate confirmed Hepatozoon canis (H. canis) infection. These findings suggest that the neutropenia observed in this case was associated with osteomyelitis due to H. canis infection. This is the first report of neutropenia associated with H. canis infection. H. canis infection can be included in the differential diagnosis in canine cases of neutropenia in areas where the disease is endemic. PMID- 21697645 TI - Glucosamine induces cell death via proteasome inhibition in human ALVA41 prostate cancer cell. AB - Glucosamine, a naturally occurring amino monosaccharide, has been reported to play a role in the regulation of apoptosis more than half century. However the effect of glucosamine on tumor cells and the involved molecular mechanisms have not been thoroughly investigated. Glucosamine enters the hexosamine biosynthetic pathway (HBP) downstream of the rate-limiting step catalyzed by the GFAT (glutamine:fluctose- 6-phosphate amidotransferase), providing UDPGlcNAc substrates for O-linked beta-N-acetylglucosamine (O-GlcNAc) protein modification. Considering that O-GlcNAc modification of proteasome subunits inhibits its activity, we examined whether glucosamine induces growth inhibition via affecting proteasomal activity. In the present study, we found glucosamine inhibited proteasomal activity and the proliferation of ALVA41 prostate cancer cells. The inhibition of proteasomal activity results in the accumulation of ubiquitinated proteins, followed by induction of apoptosis. In addition, we demonstrated that glucosamine downregulated proteasome activator PA28gamma and overexpression of PA28gamma rescued the proteasomal activity and growth inhibition mediated by glucosamine. We further demonstrated that inhibition of O-GlcNAc abrogated PA28gamma suppression induced by glucosamine. These findings suggest that glucosamine may inhibit growth of ALVA41 cancer cells through downregulation of PA28gamma and inhibition of proteasomal activity via O-GlcNAc modification. PMID- 21697646 TI - Growth hormone deficiency in the transition period: body composition and gonad function. AB - Recombinant GH therapy is normally administered to GH-deficient children in order to achieve a satisfactory height - the main target during childhood and adolescence. However, the role of GH does not end once final height has been reached, but continues during the so-called transition period. In this phase of life, the body undergoes several changes, both physical and psychological, that culminate in adulthood. During this period, GH has a part in numerous metabolic functions. These include the lipid profile, where it increases HDL and reduces LDL, with the global effect of cardiovascular protection. It also has important effects on body composition (improved muscle strength and lean body mass and reduced body fat), the achievement of proper peak bone density, and gonad maturation. Retesting during the transition period, involving measurement of IGF I plus a provocative test (insulin tolerance test or GHRH + arginine test), is thus necessary to establish any persistent GH deficiency requiring additional replacement therapy. The close cooperation of the medical professionals involved in the patient's transition from a pediatric to an adult endocrinologist is essential. The aim of this review is to point out the main aspects of GH treatment on body composition, metabolic and gonad functions in the transition period. PMID- 21697647 TI - Role of the energy sensor adenosine monophosphate-activated protein kinase in the regulation of immature gonadotropin-releasing hormone neuron migration. AB - BACKGROUND: The 5'-AMP-activated protein kinase (AMPK) plays a fundamental role in regulating energy homeostasis as well as feeding and metabolism, through central and peripheral actions. AMPK is activated by conditions causing ATP depletion and by different metabolic molecules, such as adiponectin and AMPK agonist, such as 5-aminoimidazole- 4-carboxamide-1-beta-D-ribofuranoside (AICAR). AMPK activation has also been shown to affect the migration of different cell types and to participate in the central control of reproductive function, although information concerning AMPK and the development of the hypothalamic reproductive compartment is lacking. AIM: To explore whether AMPK activation by globular adiponectin (gAdipo) and AICAR may affect the migratory ability of GnRH neurons. MATERIALS AND METHODS: We used GN11 immature GnRH neurons (in vitro model system), RT-PCR and Western blot analysis, and Boyden's chamber assay. RESULTS: gAdipo did not affect FBS-stimulated migration of GN11 cells and activated AMPK through the mandatory phosphorylation of extracellular signal regulated kinase 1 and 2 (ERK1/2) and Akt, which also interact one to each other. AICAR treatment inhibited FBS-stimulated GN11 cell migration, through a long lasting activation of AMPK. A downstream activation of ERK1/2 by AICAR was also observed and inhibition of ERK1/2 amplified AICAR-induced inhibition of migration. CONCLUSIONS: The direct, but not the indirect, activation of AMPK appears to negatively affect FBSinduced GN11 cell migration, suggesting that the final balance between pro-migratory and anti-migratory actions may also depend upon the specific sequence of intracellular signals activated by one agent. PMID- 21697648 TI - Cadmium-induced apoptosis and necrosis in human osteoblasts: role of caspases and mitogen-activated protein kinases pathways. AB - Cadmium is a widespread environmental pollutant which induces severe toxic alterations, including osteomalacia and osteoporosis, likely by estrogen receptor dependent mechanisms. Indeed, cadmium has been described to act as an endocrine disruptor and its toxicity is exerted both in vivo and in vitro through induction of apoptosis and/or necrosis by not fully clarified intracellular mechanism(s) of action. Aim of the present study was to further investigate the molecular mechanism by which cadmium might alter homeostasis of estrogen target cells, such as osteoblast homeostasis, inducing cell apoptosis and/or necrosis. Human osteoblastic cells (hFOB 1.19) in culture were used as an in vitro model to characterize the intracellular mechanisms induced by this heavy metal. Cells were incubated in the presence/ absence of 10-50 MUM cadmium chloride at different times and DNA fragmentation and activation of procaspases- 8 and -3 were induced upon CdCl(2) treatment triggering apoptotic and necrotic pathways. Addition of caspase-8 and -3 inhibitors (Z-IETD-FMK and Z-DQMD-FMK) partially blocked these effects. No activation of procaspase-9 was observed. To determine the role of mitogen-activated protein kinases (MAPK) in these events, we investigated c-jun N terminal kinase (JNK), p38 and extracellular signal-regulated protein kinase (ERK1/2) phosphorylation which were activated by 10 MUM CdCl(2). Chemical inhibitors of JNK, p38, and ERK1/2, SP600125, SB202190, and PD98059, significantly reduced the phosphorylation of the kinases and blunted apoptosis. In contrast, caspase inhibitors did not reduce the cadmium-induced MAPK phosphorylation, suggesting an independent activation of these pathways. In conclusion, at least 2 pathways appear activated by cadmium in osteoblasts: a direct induction of caspase-8 followed by activation of caspase-3 and an indirect induction by phosphorylation of ERK1/2, p38, and JNK MAPK triggering activation of caspase-8 and -3. PMID- 21697649 TI - Assessment of biochemical control of acromegaly during treatment with somatostatin analogues by oral glucose load and insulin-like growth factor I. AB - BACKGROUND: The use of oral glucose tolerance test (OGTT) in evaluating biochemical control in acromegalic patients on somatostatin analogues (SSA) has recently been questioned. AIM: To gain further insights into this topic, we analyzed basal and nadir GH levels during OGTT in acromegalic patients on SSA. SUBJECTS AND METHODS: Basal IGF-I and GH values, as well as GH levels along the test, were analyzed in 115 standard OGTT performed in 33 acromegalic patients followed up between 1993 and 2009. All patients were on SSA at the time of the study; 22 of them had previously undergone unsuccessful surgery. No patient had undergone radiotherapy. GH suppression was considered normal when the hormonal value fell to <1 MUg/l during OGTT. Diagnostic accuracy was analyzed by receiver operating characteristic (ROC) curves. RESULTS: ROC analysis showed that the GH basal value yielding the best specificity (100%) was 3.9 MUg/l. All patients with basal GH>3.9 MUg/l displayed lack of GH suppression after OGTT and 80% also displayed high IGF-I. Conversely, patients with basal GH<3.9 MUg/l presented a variable biochemical pattern with half of them failing to suppress GH after OGTT and 36.6% displaying high IGF-I levels. CONCLUSIONS: Our results show that baseline GH levels >3.9 MUg/l are predictive of absent OGTT-dependent GH suppression; however, 20% of these patients display partial biochemical control (normal IGF-I levels). On the other hand, basal GH values <3.9 MUg/l are not predictive of GH suppressibility by glucose and are often discordant with IGF-I levels. PMID- 21697650 TI - Manifesto for the current understanding and management of traumatic brain injury induced hypopituitarism. AB - Traumatic brain injury (TBI)-induced hypopituitarism remains a relevant medical problem, because it may affect a significant proportion of the population. In the last decade important studies have been published investigating pituitary dysfunction after TBI. Recently, a group of experts gathered and revisited the topic of TBI-induced hypopituitarism. During the 2-day meeting, the main issues of this topic were presented and discussed, and current understanding and management of TBI-induced hypopituitarism are summarized here. PMID- 21697651 TI - Multilevel coordination of phosphate and sulfate homeostasis in plants. AB - Phosphate and sulfate are two macro-elements essential for plant growth and development. Both elements play a central role in numerous aspects of plant metabolism and their deficiencies have profound effects on the transcriptome as well as on numerous metabolic pathways. The research emphasis so far has been on elucidating the molecular physiology of these individual nutritive elements. Recent data proved the existence of complex connections between the various regulatory layers of the homeostasis of these elements, but the molecular bases and biological significance of such interconnections remains poorly understood. This review provides an update on recent advances to identify the components involved in phosphate and sulfate homeostasis crosstalk. In light of this case study, developing a comprehensive understanding of the coordination of the ion homeostasis and identifying genes which can be used as good molecular markers for monitoring the "integrative ionic status" of plants is not only of great scientific interest, but also crucial for biotechnological and agronomic applications. PMID- 21697652 TI - MicroRNA-9: functional evolution of a conserved small regulatory RNA. AB - The functional significance of microRNA-9 (miR-9) during evolution is evidenced by its conservation at the nucleotide level from flies to humans but not its diverse expression patterns. Recent studies in several model systems reveal that miR-9 can regulate neurogenesis through its actions in neural or non-neural cell lineages. In vertebrates, miR-9 exerts diverse cell-autonomous effects on the proliferation, migration, and differentiation of neural progenitor cells by modulating different mRNA targets. In some developmental contexts, miR-9 suppresses apoptosis and is misregulated in several types of cancer cells, influencing proliferation or metastasis formation. Moreover, downregulation of miR-9 in postmitotic neurons is also implicated in some neurodegenerative diseases. Thus, miR-9 is emerging as an important regulator in development and disease through its ability to modulate different targets in a manner dependent on the developmental stage and the cellular context. PMID- 21697655 TI - Retracted manuscript: "Arginine methylation in interferon signaling: new light on an old story". PMID- 21697656 TI - The use of a mobile application to track process workflow in perioperative services. AB - This article discusses the data collection tool developed to investigate how patient flow is affected by the delivery of different types of care within Perioperative Services. To better understand the Perioperative Services processes, this study tracked staff members as they perform their activities. A challenging aspect of documenting the processes observed while tracking the Perioperative Services staff is to record the specific times and order in which the activities took place. The Perioperative Services is a fast-paced, dynamic environment where the staff members often perform multiple tasks that may also be interrupted, and each staff member may perform these tasks in their own sequence. To meet the needs of accurate data gathering, an iPhone/iPod Touch application was developed. It provides several advantages over the traditional paper/pencil method: (1) time stamps are instantaneous and consistent among the data collectors, (2) activities are entered via swipe-and-click capability, (3) multiple active tasks and interruptions can be tracked, and (4) collected data can be output to Microsoft Excel or Access for analysis. The "app" has proven to be useful in capturing data for our study. This technology can be customized and applied to similar settings at other hospitals. PMID- 21697654 TI - Development of an Fn14 agonistic antibody as an anti-tumor agent. AB - TWEAK, a TNF family ligand with pleiotropic cellular functions, was originally described as capable of inducing tumor cell death in vitro. TWEAK functions by binding its receptor, Fn14, which is up-regulated on many human solid tumors. Herein, we show that intratumoral administration of TWEAK, delivered either by an adenoviral vector or in an immunoglobulin Fc-fusion form, results in significant inhibition of tumor growth in a breast xenograft model. To exploit the TWEAK-Fn14 pathway as a therapeutic target in oncology, we developed an anti-Fn14 agonistic antibody, BIIB036. Studies described herein show that BIIB036 binds specifically to Fn14 but not other members of the TNF receptor family, induces Fn14 signaling, and promotes tumor cell apoptosis in vitro. In vivo, BIIB036 effectively inhibits growth of tumors in multiple xenograft models, including colon (WiDr), breast (MDA-MB-231), and gastric (NCI-N87) tumors, regardless of tumor cell growth inhibition response observed to BIIB036 in vitro. The anti-tumor activity in these cell lines is not TNF-dependent. Increasing the antigen-binding valency of BIB036 significantly enhances its anti-tumor effect, suggesting the contribution of higher order cross-linking of the Fn14 receptor. Full Fc effector function is required for maximal activity of BIIB036 in vivo, likely due to the cross-linking effect and/or ADCC mediated tumor killing activity. Taken together, the anti tumor properties of BIIB036 validate Fn14 as a promising target in oncology and demonstrate its potential therapeutic utility in multiple solid tumor indications. PMID- 21697657 TI - On being present: a Zen perspective. PMID- 21697653 TI - Emerging antibody combinations in oncology. AB - The use of monoclonal antibodies (mAbs) has become a general approach for specifically targeting and treating human disease. In oncology, the therapeutic utility of mAbs is usually evaluated in the context of treatment with standard of care, as well as other small molecule targeted therapies. Many anti-cancer antibody modalities have achieved validation, including the targeting of growth factor and angiogenesis pathways, the induction of tumor cell killing or apoptosis, and the blocking of immune inhibitory mechanisms to stimulate anti tumor responses. But, as with other targeted therapies, few antibodies are curative because of biological complexities that underlie tumor formation and redundancies in molecular pathways that enable tumors to adapt and show resistance to treatment. This review discusses the combinations of antibody therapeutics that are emerging to improve efficacy and durability within a specific biological mechanism (e.g., immunomodulation or the inhibition of angiogenesis) and across multiple biological pathways (e.g., inhibition of tumor growth and induction of tumor cell apoptosis). PMID- 21697658 TI - Magnet status--does it promote holistic health care? AB - It was a harrowing experience for the patient (we'll call her Amy). She developed many iatrogenic problems, in spite of specific and strong advocacy from her children aimed at protecting her. These types of situations happen all of the time in hospitals, but often patients and family members do not realize that the problems occur because of the interventions, not because of the patient's own health condition or body system responses. Oftentimes, patients do not survive these types of events, and family members often have no way to know that the disastrous outcomes could have been prevented. Here is a summary of what happened to Amy, and sequelae of these events. PMID- 21697659 TI - Curriculum as environment: a focus group study. AB - Curricula development is critical for the advancement and evolution of holistic nursing education. Although the American Holistic Nurses Association offers advanced practice board certification for graduate nurses, there is a scarcity of available graduate holistic nursing courses and curricula. The researchers developed a curriculum for an advanced holistic nursing program at a university college of nursing in South Florida. The curriculum and process of development were presented at a workshop during a national holistic nursing conference. A portion of the workshop included an opportunity for attendees to voluntarily participate in a focus group research study. The specific aim of the research was to determine the best approaches for the development of curricula for the promotion of graduate holistic nurse education based on the insights of holistic nurses, nurse educators, nurse practitioners, and scholars. A content analysis identified 3 themes that addressed holistic nursing curriculum: (1) consider curriculum as an evolving blueprint for personal and professional growth; (2) embrace the uniqueness of students; and (3) encourage faculty to co-create the learning environment. PMID- 21697660 TI - Use of the Serenity Prayer among adults with type 2 diabetes: a pilot study. AB - The incidence of type 2 diabetes is rising rapidly with significant associated morbidity and mortality. Treatment efforts are focused on control of serum blood glucose levels. It was anticipated that the use of the Serenity Prayer would assist those who need to gain control over their physiological symptoms. A pilot study of the effect of daily recitation of the Serenity Prayer for 6 weeks on serum blood glucoses in patients with uncontrolled type 2 diabetes was implemented. Thirty-six participants were enrolled in the study; there was a very high attrition rate over the course of the study. Serum blood glucose levels over the duration of the study were analyzed. At 4 to 6 weeks, time 2, there were 2 participants who had lower serum blood glucose levels, 2 had increased serum blood glucose levels, and 4 had no change. Challenges in completing this research and specific recommendations for future research are addressed. PMID- 21697662 TI - Finding meaning in suffering. AB - Nurses commonly encounter pain and suffering, and alleviation of pain and suffering is a focus of the nurse's job. Spirituality and religion may assist patients who are suffering, and understanding the relationship between spiritual influences and suffering can help nurses better care for patients. Finding meaning in suffering has been described as a transcendent experience. Nurses can help patients find meaning through interventions such as listening to and witnessing suffering, connecting suffering and spirituality, creating a healing environment, and inviting reflections on suffering. Patients are "wounded story tellers" who can use their stories to make sense of their illness. Little research however has looked at patients' stories and caregivers' response in relation to patients' suffering. This article describes how patients find meaning in suffering and how nursing interventions can assist suffering patients. The process of caring for a suffering person is painful for the nurse and requires exceptional effort on the nurse's part, but the very act that drains the nurse can also create the fuel for compassionate care. PMID- 21697661 TI - Biofield therapies in cardiovascular disease management: a brief review. AB - Though there have been advances over the last 30 years in the therapeutic approaches to cardiovascular disease (CVD), heart disease and stroke remain the leading cause of mortality and morbidity worldwide. Many medical therapies for CVD are associated with a number of side effects, often leading patients to seek non-pharmacological treatments to complement standard care. Referred to as complementary and alternative medicine (CAM), these therapies consist of a heterogeneous group of modalities used in addition to conventional health care. Biofield therapies exist within this CAM domain and involve the direction of healing energy to facilitate general health and well-being by modifying the energy field. What follows is a brief overview of three biofield therapies developed or used within the field of nursing (Therapeutic Touch, Reiki, and Healing Touch), surveying the use of these interventions for individuals with CVD, and outcomes that may impact CVD risk factors and health-related quality of life. PMID- 21697663 TI - The hidden challenges in role transitions and how leadership coaching can help new leaders find solid ground. AB - Leadership coaching is becoming an increasingly important intervention that helps individual nurse executives and managers develop and use the best of their strengths, gifts, and talents. As the need for leadership in nursing becomes urgent and brave souls move into the positions of greater authority and potential impact, they will face challenges as they move up in rank. This article identifies the hidden and often-overlooked challenges that are faced by new leaders as they transition into roles of increased responsibility, and it demonstrates how leadership coaching can help new leaders make successful transitions. As the current health care crisis creates opportunity for new leaders, those who opt for promotions and lateral shifts encounter both expected and surprising challenges. The expected challenges include mastering new content skills, learning new organizational structures, and getting to know new teams. The less obvious stressors include issues of self-esteem, assertiveness, self consciousness, self-criticism, perfectionism, new boundaries, changing identities, and finding one's own leadership style. These important issues are often kept out of conscious awareness and overlooked at great cost to the individual leader and her institution. Leadership coaching can provide support and practical strategies for managing and overcoming these hidden challenges. PMID- 21697664 TI - African mango (IGOB131): a proprietary seed extract of Irvingia gabonensis is found to be effective in reducing body weight and improving metabolic parameters in overweight humans. PMID- 21697666 TI - Making sense of block "success" in ambulatory anesthesia practice. PMID- 21697667 TI - Acute pain on and off the battlefield: what we do, what we know, and future directions. PMID- 21697668 TI - The WAKE(c) score: patient-centered ambulatory anesthesia and fast-tracking outcomes criteria. PMID- 21697669 TI - Managing neural dysfunction after regional anesthesia: experience in a walk-in follow-up clinic. PMID- 21697670 TI - Complications associated with peripheral nerve blocks: lessons from the ASA Closed Claims Project. PMID- 21697671 TI - Economics: projecting costs and revenue for an interventional pain service in the ambulatory setting. PMID- 21697672 TI - Updated guide to billing for regional anesthesia (United States). PMID- 21697673 TI - Getting the best value for consumable supplies in regional anesthesia. PMID- 21697674 TI - The progression of regional anesthesia into acute and perioperative pain medicine. PMID- 21697677 TI - Comment on: Recurrence rate in vulvar carcinoma in relation to pathological margin distance [Groenen SMA, Timmers PJ, Burger CW. Int J Gynecol Cancer. 2010;20:869-873]. PMID- 21697678 TI - Considering early detection of relapsed ovarian cancer: a review of the literature. AB - INTRODUCTION: Patients treated for ovarian cancer with curative intent receive an intensive follow-up program in the years after treatment. However, the aimed improved survival through early detection of recurrence is subject to debate. Theoretically, the survival benefit depends on the lead time and the preclinical detection rate and on the effectiveness of recurrence treatment. This systematic review aimed at determining the effectiveness of early detection of recurrent ovarian cancer. METHODS: A systematic literature search in PubMed, EMBASE, MEDLINE, and the Cochrane Library was performed for articles published in 1985 to 2009 in English, German, or Dutch, excluding editorials, letters, and case reports. RESULTS: In total, 67 articles were included. Of 4 observational studies and 1 randomized controlled trial, only 1 observational study reported a better survival for patients who attended routine follow-up compared with those who did not. The sensitivity of cancer antigen 125 for a preclinical recurrence, based on 38 articles using 35 U/mL as a cutoff level, was 65%, with a median lead time of 3 months (range, 1-7 months). Seven studies showed that, on average, 67% (ranging from 20% to 80%) of the 798 relapsed patients had no clinical symptoms when recurrent ovarian cancer was diagnosed. CONCLUSIONS: Routine follow-up may detect 2 of 3 recurrences asymptomatically with a lead time of 3 months. Recurrence treatment may extend survival by several months, but published studies did not show a survival advantage of early detection by routine follow-up examinations. Therefore, the content and aims of routine follow-up should be reconsidered, whereas routine cancer antigen 125 testing with the aim to improve life expectancy should be omitted. PMID- 21697679 TI - Adjuvant chemotherapy for endometrial cancer. AB - OBJECTIVE: To review the role of adjuvant chemotherapy in endometrial cancer and to identify the groups of patients who were most likely to have benefit from adjuvant chemotherapy. METHODS: Bibliographic search was conducted for randomized trials involving chemotherapy given in an adjuvant setting for early stage endometrial cancer or advanced stage with minimal residual disease after surgery. The search included the National Library of Medicine's MEDLINE/PubMed database, studies cited in the reports, proceedings of international conferences, and registered clinical trials. Details of each trial were explored and summarized. RESULTS: Seven reports from 8 randomized trials were identified. Two trials were reported together with separate and combined statistical analyses. Characteristic features of the patients and diseases, details of surgical treatment including lymph node resection, types and pattern of radiation and chemotherapy, and the results from each trial varied. Only 2 trials showed significant survival improvement in patients who had adjuvant chemotherapy alone or chemotherapy after radiation compared with radiation alone. Data from these trials showed that the patients who were likely to have survival benefit from adjuvant chemotherapy were those with the following high risk features: did not have or had limited lymph node surgical evaluation, metastatic nodal involvement, tumors of high-grade or aggressive histology, stage IC, stage II or IIIA with 50% or greater myometrial invasion, and stage IIIC to IV. CONCLUSIONS: The results from trials were inconsistent regarding a survival benefit of adjuvant chemotherapy in comparison to radiation alone or in addition to radiation. Only certain groups of patients with high risk features were likely to gain survival advantage from adjuvant chemotherapy. The physician must carefully evaluate risk features of each patient and her disease to select one who is most likely to gain advantage from chemotherapy. PMID- 21697680 TI - Detection and genotyping of human papilloma virus in cervical cancer specimens from Saudi patients. AB - OBJECTIVE: To determine the rates and types of human papilloma virus (HPV) infection in cervical cancer specimens from Saudi patients. METHODS: One hundred specimens were randomly selected and retrieved from the achieved samples stored in the pathology department accessioned under the diagnosis of cervical cancer and carcinoma in situ between the years 1997 and 2007. Human papilloma virus in the clinical samples was detected using polymerase chain reaction amplification methods. Two primer systems are commonly used: the MY09-MY11 primers and the GP5+ GP6+ that amplify a wide range of HPV genotypes. Human papilloma virus isolates were genotyped using DNA sequencing and reverse line blot hybridization assay to identify the high-risk HPV genotypes. RESULTS: Ninety cases fulfilled the diagnostic criteria and were analyzed. The rate of HPV genotype detection among cervical cancer samples was 95.5%. The most common HPV genotype detected by both methods was HPV-16 (63.4%), followed by HPV-18 (11.1%), HPV-45 (4.5%), HPV-33 (3.3%), and HPV-31, HPV-52, HPV-53, HPV-58, HPV-59, and HPV-66 with 2.2% prevalence rate each. CONCLUSIONS: Prevalence of HPV genotypes among patients with cervical cancer in Saudi Arabia is comparable to the international rates. The use of the reverse line blot hybridization assay genotyping method could be useful for classifying oncogenic HPV-positive women. It is relatively inexpensive and reliable and can be performed in routine practice or epidemiological study compared with the available standard commercial kits. PMID- 21697681 TI - Differentiating squamous cell carcinoma of the cervix and epithelioid trophoblastic tumor. AB - BACKGROUND: Epithelioid trophoblastic tumor (ETT) is a recently described subtype of gestational trophoblastic neoplasia (GTN). Its diagnosis requires a high level of suspicion because it is often mistaken for more common cervical or uterine corpus epithelial neoplasms. CASE: This is a 39-year-old woman who presented with a cervical mass and positive human chorionic gonadotropin and was diagnosed with both locally advanced squamous cell cervical carcinoma and nonmetastatic GTN. She was treated unsuccessfully with concurrent intravenous cisplatin plus pelvic radiation and single-agent intravenous methotrexate. A retrospective review of the cervical biopsy using immunohistochemistry as well as genotyping of the tumor changed the original diagnosis to ETT. It is known that ETT is relatively unresponsive to chemotherapy compared with most other types of GTN; therefore, surgery would have been the optimal treatment. She died despite multiple salvage chemotherapies. CONCLUSIONS: Malignant GTN is one of the most curable gynecologic malignancies; however, its correct diagnosis is critical for the appropriate treatment. It can be easily misdiagnosed as a carcinoma because of their morphologic similarity. Genetic fingerprinting and immunohistochemistry are potentially valuable tools to confirm the diagnosis of ETT. PMID- 21697682 TI - Should uterine tandem applicators ever be placed without ultrasound guidance? No: a brief report and review of the literature. AB - BACKGROUND: Brachytherapy is an integral component of the curative treatment of locally advanced cervical cancer. Optimal applicator placement is associated with improvements in local control and treatment-related toxicity. Uterine perforation by the tandem is common and often undetected by orthogonal radiographs. The role of ultrasound in guiding tandem placement remains controversial. METHODS: A 55 year-old woman with International Federation of Gynecology and Obstetrics stage IIB cervix cancer underwent placement of a Fletcher-Suit-Delcos tandem and ovoids applicator. Postoperative computed tomography was used for treatment planning. RESULTS: The applicator appeared to be appropriately placed on clinical exam and orthogonal radiographs. Postoperative computed tomography revealed the tandem had perforated the anterior uterine wall. In a second procedure, the tandem was placed correctly under intraoperative ultrasonography. CONCLUSIONS: A review of the literature finds a relatively high rate of uterine perforation of the uterus that is undetected by orthogonal radiographs or clinical examination. Multiple reports support the use of real-time ultrasound for patients with especially challenging anatomy. As this report illustrates, uterine perforation is possible in any patient. Therefore, routine real-time ultrasonography should be considered for all uterine tandem insertions. PMID- 21697683 TI - Clinical practice guidelines for the management of patients with endometrial cancer in France: recommendations of the Institut National du Cancer and the Societe Francaise d'Oncologie Gynecologique. AB - INTRODUCTION: Endometrial cancer is the most common gynecological malignancy in France, with more than 6500 new cases in 2010. The French National Cancer Institute has been leading a clinical practice guidelines (CPG) project since 2008. This project involves the development and updating of evidence-based CPG in oncology. OBJECTIVE: To develop CPG for diagnosis, treatment, and follow-up for patients with endometrial cancer. METHODS: The guideline development process is based on systematic literature review and critical appraisal by experts, with feedback from specialists in cancer care delivery. The recommendations are thus based on the best available evidence and expert agreement. RESULTS: Main recommendations include a routine pelvic magnetic resonance imaging in association with magnetic resonance imaging exploration of the para-aortic lymph nodes for locoregional staging, surgical treatment based on total hysterectomy with bilateral salpingo-oophorectomy with or without lymphadenectomy, and clinical examination for the follow-up. The initial laparoscopic surgical approach is recommended for stage I tumors. Lymphadenectomy and postoperative external radiotherapy are recommended for patients with high risk of recurrence but are restricted for patients with low or intermediate risk. If brachytherapy is indicated, it should be given at a high-dose rate rather than a low-dose rate. Routine imaging, biologic tests, and vaginal smears are not indicated for follow up. PMID- 21697684 TI - Recommendations of the Fertility Task Force of the European Society of Gynecologic Oncology about the conservative management of ovarian malignant tumors. AB - In young patients with borderline ovarian tumor a conservative treatment approach does not seem to have a significant impact on survival, and the outcome regarding fertility is good in general. It can be considered even if noninvasive peritoneal implants are discovered at the time of the initial surgery. In contrast, in patients with epithelial ovarian cancer, conservative surgery should be considered only in adequately staged patients, with a stage IA grade 1 (and probably 2) serous, mucinous or an endometrioid tumor, including a careful follow up. Such an approach could also probably be discussed in stage IC grade 1 disease.In patients with nonepithelial malignant ovarian tumors, conservative surgery is also feasible, particularly in patients with malignant germ cell tumors because of their high chemosensitivity leading to an excellent prognosis in general. PMID- 21697686 TI - Pain: more than just a number. PMID- 21697687 TI - Anatomy and clinical implications of the ultrasound-guided subsartorial saphenous nerve block. AB - BACKGROUND: We evaluated the anatomic basis and the clinical results of an ultrasound-guided saphenous nerve block close to the level of the nerve's exit from the inferior foramina of the adductor canal. METHODS: The anatomic study was conducted in 11 knees of formalin-preserved cadavers in which the saphenous nerve was dissected from near its exit from the inferior foramina of the adductor canal. The clinical study was conducted in 23 volunteers. Using a linear probe, the femoral vessels and the sartorius muscle were depicted in short-axis view at the level where the saphenous nerve exits the inferior foramina of the adductor canal. Ten milliliters of 1.5% lidocaine was injected into the compartment structured by the sartorius muscle and the femoral artery. RESULTS: The saphenous nerve was found to exit the adductor canal from its inferior foramina in 9 (81.8%) of 11 and at a more proximal level in 2 (18.2%) of 11 of the anatomic specimens. In a single specimen (9%), the saphenous nerve was formed by the anastomosis of 2 branches. In all the dissections, the saphenous nerve, after exiting the adductor canal, passed between the sartorius muscle and the femoral artery. Of the 23 volunteers, 22 responded with a complete sensory block, whereas a single volunteer demonstrated no sensory blockade. None of the volunteers experienced a motor block of the hip flexors and knee extensors. CONCLUSIONS: Ultrasound-guided injection directly caudally from the inferior foramina of the adductor canal, between the sartorius muscle and the femoral artery, seems to be an effective approach for saphenous nerve block. PMID- 21697688 TI - Recognition of an incidental abscess and a hematoma during ultrasound-guided femoral nerve block. AB - Ultrasound guidance for femoral nerve blockade allows visualization of normal and abnormal anatomy. Two cases of femoral nerve blockade under ultrasound guidance are presented where a major perineural pathologic lesion was incidentally revealed. These pathologic lesions, an abscess and a hematoma, resulted in significant adaptations in clinical care and have not been reported previously. We review and discuss incidental pathologic lesions that can be found in the femoral region. Identification of these 2 pathologic lesions facilitated our perioperative management strategies in two separate cases. PMID- 21697690 TI - Is there really a cause-effect relationship between steroid dose, pain management practices, joint injected (sacroiliac joint), and infection? PMID- 21697691 TI - Incidence of phrenic nerve block after interscalene brachial plexus block. PMID- 21697692 TI - A venous structure anterior to the brachial plexus in the supraclavicular region. PMID- 21697694 TI - Side-lobe artifact observed during ultrasound-guided peripheral nerve blocks of the upper limb. PMID- 21697695 TI - Perineural catheters: ultrasound guidance or assistance? PMID- 21697696 TI - Atypical "corner pocket" for ultrasound-guided supraclavicular block. PMID- 21697697 TI - Human cadaver model for teaching ultrasound-guided neuraxial interventions. PMID- 21697698 TI - Regional anesthetic techniques for video-assisted thoracoscopic surgery. PMID- 21697699 TI - Vulvar manifestations of Crohn's disease. AB - Crohn's disease is an inflammatory bowel disorder with several well-known extraintestinal manifestations, such as erythema nodosum, uveitis, and arthritis. Less commonly observed are vulvar manifestations, which have primarily been discussed in case reports or small case series. These cases generally highlight patients with histopathology limited to noncaseating granulomas. As these histological findings are identified in bowel biopsies from only approximately 50% of patients with gastrointestinal Crohn's disease, there is likely an under recognition and underdiagnosis of vulvar lesions as Crohn's disease manifestations. We describe the largest case series to date involving patients with vulvar Crohn's disease, discuss the varied clinical presentations, and describe the histopathological findings, which include noncaseating granulomas, ulcerations, lymphatic lesions, and even dysplasia and carcinoma. Our findings underscore the importance of keeping vulvar Crohn's disease on the differential diagnosis when faced with a range of vulvar symptoms and suggest that regular gynecological surveillance in patients with Crohn's disease may be of benefit. PMID- 21697700 TI - Distinction of melanoma in situ from solar lentigo on sun-damaged skin using morphometrics and MITF immunohistochemistry. AB - Distinction between melanoma in situ (MIS) and solar lentigo (SL) on chronically sun-damaged skin (CSDS) by hematoxylin and eosin (H&E) criteria alone can be difficult and in frozen section (FS) material, may be virtually impossible without immunohistochemistry (IHC). In this study, we used microphthalmia associated transcription factor (MITF) IHC-directed image analysis to compare melanocyte nuclear morphometrics of MIS, SL, and sections of sun-damaged skin from redundant tissue acquired during Mohs micrographic surgery. The mean nuclear diameter and melanocytic density figures for MIS were greater than those for SL and CSDS by both independent t-test and analysis of variance statistics. No significant differences in these parameters were found between SL and sun-damaged skin. Cutoff values that favored MIS over SL included melanocyte density >=10 nuclei per 200 MUm, nuclear diameter >=9 MUm, and a product of density and diameter of 80 or more, as each of these values was associated with 100% specificity of MIS diagnosis. Our results suggest that image analysis of melanocytes labeled with MITF IHC can be used to produce morphometric data that distinguish MIS from SL and CSDS. The study was conducted using permanent sections, but previous studies with FSs indicate that the findings would apply to FSs as well. Quantitative assessment of melanocytic parameters using image analysis will likely become increasingly important as an adjunct to conventional histopathology for the diagnosis and surgical management of MIS on sun-damaged skin. PMID- 21697701 TI - Wilms tumor 1 expression in vascular neoplasms and vascular malformations. AB - BACKGROUND: Wilms tumor 1 (WT1) protein is expressed during angiogenesis and malignant transformation of endothelial cells and can be helpful to distinguish between proliferative and malformative vascular lesions. METHODS: We evaluated retrospectively 117 vascular neoplasms and 50 vascular malformations. Vascular neoplasms included infantile hemangioma (n = 87), noninvoluting congenital hemangioma (n = 5), rapidly involuting congenital hemangioma (n = 3), tufted angioma (n = 8), pyogenic granuloma (n = 13), and spindle cell hemangioma (n = 1). Vascular malformations were lymphatic malformations (n = 28), venous malformations (n = 16), capillary malformation (n = 1), and stage II arteriovenous malformations (n = 5). Immunohistochemical stains for WT1 and GLUT1 were performed in all lesions. RESULTS: All 117 vascular neoplasms showed positive expression of WT1, whereas all vascular malformations in our study were completely negative for WT1 except in arteriovenous malformations, where WT1 expression was positive. CONCLUSIONS: The comparison between vascular neoplasms and vascular malformations showed that GLUT1 expression is positive only in infantile hemangiomas, whereas WT1 positivity is found in all vascular neoplasms and in arteriovenous malformations. WT1 antibody is an ancillary test that can be helpful to differentiate vascular neoplasms from most vascular malformations. PMID- 21697703 TI - Features of plexiform fibrohistiocytic tumor in skin punch biopsies: a retrospective study of 6 cases. AB - Plexiform fibrohistiocytic tumor (PFHT) is a mesenchymal neoplasm of intermediate malignant potential, which typically presents as a dermal or subcutaneous nodule, and is therefore often sampled by skin punch biopsy where diagnostic features may be subtle or absent. We retrospectively analyzed a series of 6 cases of PFHT to highlight for dermatopathologists the features of PFHTs useful to distinguish it from the other entities in the differential diagnosis. On the basis of the proportion of spindled fibroblastic cells to histiocytoid nodules in the biopsy specimen, we divided PFHT into 3 histologic variants: cellular, fibrous, and mixed. The biopsies also were compared with the final resection specimens, in an attempt to determine which histologic features in the original biopsies were most helpful in establishing a diagnosis. Clinical follow-up and immunohistochemistry were performed on all cases. The cellular and mixed variants were a lesser diagnostic challenge inasmuch as the distinctive features were more easily identifiable in small punch biopsy specimens. The fibrous variant proved more difficult to diagnose. Features most helpful in the diagnosis of PFHT were biphasic appearance with small, cellular, histiocytoid aggregates and accompanying plump spindled cells in the deep dermis and subcutis. Negative staining for CD34, NK1/C3, factor XIIIa, and beta-catenin by immunohistochemistry proved useful in excluding some of its mimics. PMID- 21697702 TI - Cutaneous mixed tumor, eccrine variant: a clinicopathologic and immunohistochemical study of 50 cases, with emphasis on unusual histopathologic features. AB - Mixed tumor, eccrine type, is a rare cutaneous adnexal neoplasm, mostly reported as isolated case reports. A systematic analysis of its histopathologic and immunohistochemical features has not previously been performed on a large series. The purpose of our investigation was to study a large number of cutaneous eccrine mixed tumors so as to fully characterize the entire spectrum of changes in the epithelial and stromal components, with an emphasis on unusual histopathologic features that may represent a diagnostic pitfall. This article reports a light microscopic and immunohistochemical study of 50 cases of eccrine mixed tumor, complemented by a literature review. Our study identified some unusual histopathologic features, thus extending the morphologic spectrum of this neoplasm. These included prominent cribriform areas, clear cell change, pseudorosette structures, prominent osseous metaplasia, and physaliphorous-like cells. Most of these features have not been previously recorded in eccrine mixed tumors and may represent a potential diagnostic pitfall. PMID- 21697704 TI - Blood pressure and forearm blood flow after multiple sets of a resistive exercise for the lower limbs. AB - PURPOSE: Postexercise hypotension after resistive exercises has been described, but its underlying mechanisms are not well known. This study observed the blood pressure (BP) and vascular conductance after multiple sets of a lower-body resistive exercise. METHODS: BP and forearm blood flow (FBF; venous occlusion plethysmography) were assessed at rest and during reactive hyperemia, before and during postexercise recovery (10 and 60 min) in 16 men assigned to experimental (EG; n=9) and control (CG; n=7) groups. The EG performed the bilateral knee extension (10 sets of 15 repetitions with 90% of 15 repetitions maximum), whereas CG stayed at rest. RESULTS: No between-group differences were detected at rest in any of the variables (P>0.13). In EG, the systolic BP (mmHg) assessed 10 min after the exercise was significant compared with rest condition (104.4+/-1.5 vs. 111.3+/-2.0; P=0.011). The FBF (ml/100 ml/min/mmHg) and the forearm vascular conductance (FVC; ml/min/mmHg) in the postexercise recovery were lower than at rest in EG (FBF: rest=3.08+/-1.03, 10 min=2.21+/-0.68, P=0.007 and 60 min=2.33+/ 0.47, P=0.018; FVC: rest=0.039+/-0.014, 10 min=0.029+/-0.008, P=0.02 and 60 min=0.030+/-0.006, P=0.03), but not in CG (FBF: resting=2.80+/-0.52, 10 min=2.87+/-0.53, P=0.22 and 60 min=2.97+/-0.73, P=0.14; FVC: resting=0.035+/ 0.006, 10 min=0.029+/-0.010, P=0.32 and 60 min=0.029+/-0.013, P=0.13). No within group (P=0.67) or between-group (P=0.11) changes were found in FBF and FVC during reactive hyperemia along postexercise recovery. CONCLUSION: Multiple sets of a single-resistance exercise induced postexercise hypotension and decreased FBF, albeit vasodilatation capacity was probably preserved. PMID- 21697705 TI - Patient-provider internet portals--patient outcomes and use. AB - An important emerging information technology tool is the electronic health record with a patient-provider Internet portal. Patient-provider Internet portals offer a venue for providing patient access to personal health data. In this study, we conducted a cross-sectional secondary data analysis to describe the types of diabetes patients who utilize the patient-provider Internet portal and examine any preliminary differences in patient outcomes. Data from this study suggest that a significant portion of patients (29.7%) with diabetes utilize the portal. Clinical outcome results indicated that portal use was not a significant predictor of low-density lipoprotein and total cholesterol levels. However, portal use was a statistically significant predictor of glycosylated hemoglobin (HbA1c) (P < .001). As patient-provider Internet portals are increasingly implemented and utilized across the nation, both clinical and nonclinical impacts must be evaluated. Patient-provider Internet portals have the ability to provide patients with the opportunity tobe increasingly involved in their own care,enhance patient-provider communication, and potentially reduce inequity, improve clinical outcomes, and increase access to care. PMID- 21697707 TI - A transdisciplinary approach to developing a web-based nursing experiential log system for advanced practice nursing clinical experiences. AB - This article describes a transdisciplinary project between the computer information systems department and the graduate nursing department of a higher education institution. The project is the planning, development, and implementation of a Web-based nursing experiential log system for advanced practice nursing clinical experiences, which was funded by a Nursing Education Practice and Retention grant from the Health Resources and Services Administration. The article explains the concept and benefits of the transdisciplinary nature of the project. The design team, project leadership, and roles within the team are reviewed, including the role of end-user faculty in the design process. The article describes the focus and scope of the Web-based experiential log system database that is used to document and track advanced practice nursing student clinical experiences, as well as a summary of the design process used to develop the log system and the specific functionality of the database system. The implementation process, including end-user training, pilot implementation, and modifications, lessons learned, and future directions of the project are addressed. The article concludes with the benefits to the clinical experience and graduate nursing program that have been noted since the implementation of the system. PMID- 21697706 TI - Evaluation of satisfaction and use of electronic intervention for behavior change. AB - This report describes use and satisfaction of a tailored intervention delivered via Web site and handheld computer. All participants used both delivery methods. Healthy women (N = 74) aged 40 to 60 years participated in this mixed-method descriptive study. Satisfaction was measured via Computer Satisfaction Questionnaire and open-ended comments. Data on use of the handheld computer were embedded into program and captured real time. Unique Internet provider addresses tracked Web site use from March 2007 through August 2008. Results indicate 80% of participants were very to extremely satisfied. There was no significant relationship between use and satisfaction. Knowledge but not self-efficacy scores differed over time. Usage was not related to knowledge scores. Handheld computer was used most frequently during the first week, with use decreasing over 7 weeks. Personal assessment of calcium intake and feedback sections were used most frequently. Handheld computer was used by 71% of participants for 4 weeks, 55% for 6 weeks, and 29% for the full 8 weeks. Participants commented on intervention content and positive and negative aspects of the devices and keyboard. This study presented an opportunity to examine data related to actual use. This dimension of intervention fidelity is more readily available in eHealth applications than with printed information. PMID- 21697708 TI - Internet addiction among students of the medical university of bialystok. AB - The objective of this research was to assess Internet addiction among students of the Faculty of Health Prevention at the Medical University of Bialystok. The present study included 358 students-nursing (n = 232), midwifery (n = 71), and medical rescue (n = 55). The following instruments were administered to the participants:the Young test, a test of the intensity of the abstinence syndrome, and a test of "online" addiction. Students who did not have a computer at home spent 3 hours a day on the Internet; students who did have a computer at home spent 0.5 to 8hours. On average, all respondents spent 1.8 +/- 1.3 hours daily online. Internet addiction was confirmed among 24 (10.3%) nursing, 7 (9.9%) midwifery, and 5(9.1%) medical rescue students. The abstinence syndrome was noted among 11 (4.7%) nursing, 7(9.9%) obstetrics, and 7 (12.7%) medical rescue students. Several students had both an Internet addiction and the abstinence syndrome. PMID- 21697709 TI - Association between self-assessed attention and objective neuropsychological tests in parkinson disease. AB - OBJECTIVE: To examine the relationship between self-assessed attentional skills and objective neuropsychological measures of attention in Parkinson disease (PD) and controls. BACKGROUND: The reliable self-assessment of one's own cognitive skills and deficits is an important but difficult task, especially in a chronic neurological condition like PD. Theories point out that brain structures involved in a realistic self-appraisal might be affected in PD. No study directly examined the association between self-assessed attentional skills and objective neuropsychological measures of attention in PD. METHODS: We applied a case control design with 54 participants in the PD group and 54 healthy controls. PD patients and controls completed questionnaires on depression and self-assessed attention and were examined with computerized tests of attention. RESULTS: PD patients differed from controls in subjective and objective assessment of attention. Depression and self-assessed attention share a significant amount of variance, but are unrelated to objective measures of attention in both groups. In PD patients, there are no associations between functional outcome and objective and subjective measures of attention. CONCLUSIONS: Conscious reports in PD patients and controls are based on different processes rather than actual attentional performance. These processes are not differentially affected in PD. Nevertheless, patients' self-assessments are not an accurate indicator of their level of objective attentional functioning. Without a definite validity criterion, it cannot be decided whether the objective or subjective assessment of attention is more valid. Therefore, a multidimensional approach integrating different sources of information is most adequate in the assessment of attentional capacities and their meaning for everyday life in PD patients. PMID- 21697710 TI - Regional brain atrophy and impaired decision making on the balloon analog risk task in behavioral variant frontotemporal dementia. AB - OBJECTIVE: The goal of this study was 2-fold, first, to compare decision making in behavioral variant frontotemporal dementia (bvFTD) patients and healthy adults using the Balloon Analog Risk Task (BART), and, second, to identify the regions of gray matter atrophy associated with bvFTD patients' BART performance. BACKGROUND: Stimulus-reinforcement learning is required to evaluate the results of previously chosen actions to improve future decisions. Although there is a well established literature suggesting altered decision making in FTD patients and data from lesion studies suggest orbitofrontal cortex (OFC) involvement in decision making, there is very little research looking at the brain correlates of decision making in FTD populations specifically. METHOD: Twenty-seven bvFTD patients and 19 age-matched and education-matched normal controls completed the BART. Voxel-based morphometry analysis was performed on the magnetic resonance imaging scans of a subset of patients. RESULTS: Compared with healthy controls, the bvFTD patients did not learn and pumped less to inflate a balloon to receive a reward, indicating altered stimulus-reinforcement learning. The voxel-based morphometry analysis indicated that bvFTD patients' impaired BART performance was related to atrophy in the right lateral OFC. CONCLUSIONS: The right lateral OFC is crucial for stimulus-reinforcement learning required for the adjustment of behavior under changing reward contingencies. PMID- 21697712 TI - How many functional brains in developmental dyslexia? When the history of language delay makes the difference. AB - BACKGROUND: Clinical manifestations of developmental dyslexia (DD) are greatly variable, suggesting complex underlying mechanisms. It was recently advanced that the characteristics of DD in Italian, a language with shallow orthography, are influenced by a positive history for language delay. OBJECTIVE: We explored this hypothesis by studying in Italian individuals with DD (i) the brain representation of phonological processing with functional magnetic resonance imaging and (ii) the correlation between the patterns of activation and the presence/absence of previous language delay. METHOD: Thirteen individuals with DD and 13 controls participated in the functional magnetic resonance imaging experiment consisting of a rhyme-generation task. RESULTS: Individuals with DD showed a reduced activation of phonological processing areas of the left hemisphere, such as the middle frontal gyrus, the precuneus, and the inferior parietal lobule, and in particular the superior temporal gyrus. Furthermore, patients with a history of language delay had reduced activation in the left inferior and medial frontal gyrus, that was associated with worse reading and phonological accuracy than patients with normal language development. CONCLUSIONS: Neurofunctional profiles of Italian individuals with DD are correlated to the history of language delay, suggesting that the relatively better behavioral profiles observed in individuals without a history of language delay are associated with a major activation of frontal networks normally involved in phonological working memory. PMID- 21697713 TI - Simultaneous Descemet stripping automated endothelial keratoplasty and aphakic iris-fixated intraocular lens implantation: a case series. AB - PURPOSE: To report 3 cases of simultaneous Descemet stripping automated endothelial keratoplasty (DSAEK) and aphakic iris-fixated intraocular lens (IOL) implantation in patients with aphakia and bullous keratopathy. METHODS: We retrospectively documented the clinical characteristics of patients before and after simultaneous DSAEK and aphakic iris-fixated IOL implantation undergoing operation between November 2008 and September 2009. RESULTS: None of the cases showed any intraoperative complications. During the postoperative period, the corneal lenticule was clear and well-attached, and the iris-fixated IOL was well positioned. CONCLUSIONS: Simultaneous DSAEK and aphakic iris-fixated IOL implantation can be used successfully and simultaneously in patients with aphakia and bullous keratopathy. PMID- 21697711 TI - Anti-saccade performance predicts executive function and brain structure in normal elders. AB - OBJECTIVE: To assess the neuropsychological and anatomical correlates of anti saccade (AS) task performance in normal elders. BACKGROUND: The AS task correlates with neuropsychological measures of executive function and frontal lobe volume in neurological diseases, but has not been studied in a well characterized normal elderly population. Because executive dysfunction can indicate an increased risk for cognitive decline in cognitively normal elders, we hypothesized that AS performance might be a sensitive test of age-related processes that impair cognition. METHOD: The percentage of correct AS responses was evaluated in 48 normal elderly subjects and associated with neuropsychological test performance using linear regression analysis and gray matter volume measured on magnetic resonance imaging scans using voxel-based morphometry. RESULTS: The percentage of correct AS responses was associated with measures of executive function, including modified trails, design fluency, Stroop inhibition, abstraction, and backward digit span, and correlated with gray matter volume in 2 brain regions involved in inhibitory control: the left inferior frontal junction and the right supplementary eye field. The association of AS correct responses with neuropsychological measures of executive function was strongest in individuals with fewer years of education. CONCLUSIONS: The AS task is sensitive to executive dysfunction and frontal lobe structural alterations in normal elders. PMID- 21697714 TI - Recurrent corneal hypertrophic scar after laser-assisted subepithelial keratectomy with mitomycin C treatment. AB - PURPOSE: To report recurrent corneal hypertrophic scar after laser-assisted subepithelial keratectomy (LASEK) with mitomycin C treatment. METHODS: Two patients experienced decreased visual acuity in 1 eye arising from elevated corneal opacity about 12 months after uneventful LASEK with intraoperative mitomycin C application. The elevated opacities were easily removed mechanically. RESULTS: Pathologic examinations showed irregular arrangement of collagen fibers and myofibroblasts, diagnosed as hypertrophic scars. The lesions recurred at about 4-month intervals, despite repeated debridement with and without prophylactic mitomycin C treatment. CONCLUSIONS: Recurrent corneal hypertrophic scar may be a rare complication after LASEK treatment with mitomycin C application. PMID- 21697715 TI - Investigation of the actions taken by adults who failed a telephone-based hearing screen. AB - OBJECTIVES: Hearing impairment constitutes a highly prevalent chronic health condition among older adults worldwide which negatively impacts on communication and health-related quality of life. Irrespective of this, the majority of older adults do not seek professional help for hearing impairment and/or do not obtain hearing aids. Therefore, a new approach for detecting and promoting help-seeking for hearing impairment is needed. The purpose of this study was to investigate the actions taken by those who failed Telscreen, a telephone-based screening tool for hearing loss, and to increase our understanding of factors that influence taking action. DESIGN: A cohort of 193 participants (112 females, 81 males; age range 24-93 yr) who had failed Telscreen participated in a follow-up telephone interview 4 to 5 mo later. Participants were asked why they called Telscreen, about their hearing ability, their Telscreen result, and what action they had taken toward hearing rehabilitation. One outcome measure was identified: decision to seek professional help for hearing impairment (yes/no). Given that the outcome measure was dichotomized, a logistic regression model for binary outcomes was fitted to the data. RESULTS: Of the 193 participants who failed Telscreen, only 36% sought help from a range of sources (e.g., audiologist, hearing service or hearing aid provider, and family doctor). Results of the logistic regression analysis indicated that individuals who had considered hearing aids before calling Telscreen and/or who recalled their Telscreen result were significantly more likely to seek professional help for their hearing impairment. Nineteen participants who sought help for their hearing impairment had hearing aid fitting recommended to them. Eight participants had aid/s fitted, and of these, six reported a successful outcome. CONCLUSIONS: For every 100 individuals who fail a hearing screening, only 36 seek help. Of these 36 individuals who take some action, 13 are recommended hearing aids, approximately half of whom follow this advice and obtain hearing aids. Approximately three-quarters of these individuals use and value their hearing aids. Provided that the screening is automated and low cost, hearing screening via telephone has proven to change the lives of 5% of individuals who decided to seek professional help for hearing impairment at little cost to the other 95% of individuals. Suggestions for future research based on the present research findings are discussed. PMID- 21697716 TI - Pigment epithelium-derived factor: a not so sympathetic regulator of insulin resistance? AB - Pigment epithelium-derived factor (PEDF), an adipokine, is a regulator of oxidative stress, inflammation, angiogenesis, and insulin sensitivity. Contrary to animal and cell culture data, inhibition of the sympathoadrenal system does not affect serum PEDF in humans. However, during acute beta-adrenergic receptor stimulation serum PEDF concentration is decreased. PEDF may be involved in cross talk between adipose tissue and skeletal muscle. PMID- 21697717 TI - Overcoming barriers to progress in exercise genomics. AB - This commentary focuses on the issues of statistical power, the usefulness of hypothesis-free approaches such as in genome-wide association explorations, the necessity of expanding the research beyond common DNA variants, the advantage of combining transcriptomics with genomics, and the complexities inherent to the search for links between genotype and phenotype in exercise genomics research. PMID- 21697718 TI - Type V collagen genotype and exercise-related phenotype relationships: a novel hypothesis. AB - We have shown that a variant within COL5A1, which encodes a subunit of type V collagen, is associated with injury and performance phenotypes. Although seemingly unrelated, these phenotypes are associated directly or indirectly with the mechanical properties of musculoskeletal soft tissue. We therefore hypothesize that variants in the COL5A1 gene alter fibril architecture and structure and, thereby, mechanical properties. PMID- 21697719 TI - Understanding hospital performance: the role of network ties and patterns of competition. AB - BACKGROUND: To improve efficiency and quality, a number of policies have recently been implemented to increase competition and cooperation within the health systems of many countries. We theorize how hospital performance, measured as productivity, is contingent upon network embeddedness, the extent to which a hospital is involved in a network of interconnected interorganizational relationships. PURPOSE: The aim of this study was to explore the effects on hospital productivity resulting from both collaborative network ties and competitive relationships between providers. METHODOLOGY: We used panel data collected between 2003 and 2007 from 35 hospitals in Abruzzo, one of the most populated regions of central Italy. We used secondary data of hospital activities regarding both clinical and administrative aspects. For each year, we examined the intensity of interhospital competition and the unique position each provider has within a larger network of relationships with other hospitals. Other idiosyncratic organizational characteristics were examined as well. FINDINGS: Our results show that hospital productivity is negatively related to the degree of competition that a hospital faces and positively related to the degree with which hospitals establish collaborative relationships. We also found that the negative impact on hospital productivity due to competition was lessened when hospitals were more likely to create cooperative network ties. PRACTICE IMPLICATIONS: Because interhospital collaboration and competition are related to hospital productivity, they should constitute a core element in the strategic planning of a hospital's operation. Health administrators should implement policies that favor collaborative network ties at the regional level and mitigate interorganizational rivalries when establishing collaborative relationships with local competitors. PMID- 21697720 TI - Transformational leadership and workplace injury and absenteeism: analysis of a National Nursing Assistant Survey. AB - BACKGROUND: Transformational leadership (TL) has long been popular among management scholars and health services researchers, but no research studies have empirically tested the association of TL with workplace injuries and absenteeism among nursing assistants (NAs). PURPOSE: This cross-sectional study seeks to explore whether TL is associated with workplace injuries and absenteeism among NAs. METHODOLOGY: We analyzed the 2004 National Nursing Assistant Survey data (n = 2,882). A multivariate logistic regression analysis was performed to test the role of TL in the context of workplace performances. PRINCIPAL FINDINGS: Results reveal that the TL model was positively linked to workplace injury in the level of NAs. Injury-related absenteeism was also associated with the TL style, indicating that TL behaviors may help address workplace absence among NAs. PRACTICE IMPLICATIONS: Findings suggest that introducing TL practices may benefit NAs in improving workplace performances. PMID- 21697721 TI - Urocortin 3 inhibits cardiac sympathetic nerve activity in conscious sheep. AB - There is an increasing body of evidence suggesting a role for the urocortin (Ucn) peptides in blood pressure regulation and in the pathophysiology of cardiovascular disease. Both Ucn1 and Ucn2 have recently been shown to inhibit cardiac sympathetic nerve activity (CSNA) in sheep. However, there are few studies reporting the effects of Ucn3 on the sympathetic nervous system. Hence, this study performed in normal conscious sheep examines the effects of Ucn3 on CSNA. Intravenous Ucn3 (administered at doses of 25 and 100 MUg) caused transient falls in arterial pressure (P = 0.025), more prolonged rises in heart rate (P < 0.001), and falls in stroke volume (P < 0.001) and peripheral resistance (P = 0.018). CSNA, measured as burst area and burst incidence, fell in a dose dependent manner after Ucn3 bolus (all P < 0.001). CSNA burst frequency tended to be reduced after high-dose Ucn3. Ucn3 had no significant effect on plasma catecholamine levels. In conclusion, this study reports for the first time that Ucn3 induces potent inhibition of sympathetic traffic directed toward the heart. This provides further support for a role for Ucn3 in pressure and volume homeostasis and suggests that further investigation of potential therapeutic applications for Ucn3 in cardiovascular disease is warranted. PMID- 21697722 TI - Organic cation transporter 3: expression in failing and nonfailing human heart and functional characterization. AB - The organic cation transporter 3 (OCT3, SLC22A3) contributes to the control of cardiac catecholamine concentrations and is important for the disposition and action of cationic drugs, such as metformin, in the myocardium. We sought to characterize the regulation of OCT3 in failing human hearts and to study commonly prescribed drugs for their potential to interact with OCT3-dependent uptake of metformin. SLC22A3 was expressed high in the human heart with strongest OCT3 immunoreactivity in vascular endothelial cells. SLC22A3/OCT3 expression was not changed in failing human left ventricular myocardium compared with nonfailing control tissues and thus is not involved in altered catecholamine homeostasis generally observed in failing hearts. Michaelis-Menten kinetics of OCT3-mediated uptake of prototypical OCT substrates 1-methyl-4-phenylpyridinium and metformin were studied in human embryonic kidney 293 cells stably overexpressing OCT3. The affinity of 1-methyl-4-phenylpyridinium for OCT3 was much higher (Km 157 +/- 16 MUM) than the affinity of metformin (Km 2.46 +/- 0.36 mM; P < 0.01), whereas maximum transport rate of 1-methyl-4-phenylpyridinium was significantly lower than that of metformin. Verapamil, carvedilol, imipramine, and cimetidine were competitive inhibitors of OCT3-mediated metformin uptake (Ki 3.6-15.8 MUM). Altogether, OCT3 might be important for the cardiac disposition of cationic drugs, and OCT3-dependent interaction with concomitantly administered compounds may limit their disposition and effect. PMID- 21697723 TI - Attenuation of atherogenesis via the anti-inflammatory effects of the selective estrogen receptor beta modulator 8beta-VE2. AB - BACKGROUND: Recent studies suggest that modulation of estrogen receptor beta (ERbeta) may play a crucial role in maintaining vascular homeostasis. We hypothesized that selective ERbeta activation will attenuate atherogenesis via anti-inflammatory mechanisms. METHODS AND RESULTS: Atherosclerosis-prone apoE mice were ovariectomized and then fed a high-cholesterol diet with daily subcutaneous injections of the highly selective and potent ERbeta agonist (8beta VE2) for 5 weeks. Compared with controls, treatment with 8beta-VE2 reduced aortic arch atherosclerotic lesion areas by 34% of total and 75% of dense lesions, while not altering the serum lipid profile. We attribute these observed vascular effects solely to ERbeta modulation as (1) treatment with the nonselective ER antagonist ICI 182,780 completely abrogated the beneficial vascular effects of 8beta-VE2 and (2) uterine weight (a sensitive indicator of ERalpha modulation) did not change with 8beta-VE2 treatment. Moreover, mice treated with 8beta-VE2 had reduced serum interleukin 1beta and tumor necrosis factor alpha levels. Finally, treatment of macrophages in vitro with 8beta-VE2 blocked the uptake of acetylated low-density lipoprotein, suppressed the extracellular levels of the inflammatory cytokine tumor necrosis factor alpha, and enhanced the extracellular levels of the antiatherogenic/anti-inflammatory protein heat shock protein 27. CONCLUSIONS: Selective ERbeta activation by 8beta-VE2 attenuates atherogenesis and is associated with favorable modulation of vascular inflammation. PMID- 21697724 TI - Nitric oxide-mediated relaxation to lactate of coronary circulation in the isolated perfused rat heart. AB - The objective of this study was to analyze the effects of lactate on coronary circulation. Rat hearts were perfused in a Langendorff preparation, and the coronary response to lactate (3-30 mM) was recorded after precontracting coronary vasculature with 11-dideoxy-1a,9a-epoxymethanoprostaglandin F2alpha (U46619), in the presence or the absence of the inhibitor of nitric oxide synthesis, N-omega nitro-l-arginine methyl ester (l-NAME, 10 M), the blocker of Ca-dependent potassium channels, tetraethylammonium (TEA, 10 M), or the blocker of adenosine triphosphate-sensitive potassium channels, glybenclamide (10 M). The effects of lactate were also studied in isolated segments of rat coronary arteries that were precontracted with U46619, with or without endothelium. In perfused hearts, lactate induced concentration-dependent coronary vasodilatation and a reduction in myocardial contractility (left ventricular developed pressure and dP/dt) without altering the heart rate. Coronary vasodilatation in response to lactate was reduced by l-NAME but unaffected by TEA or glybenclamide. The effects of lactate on myocardial contractility were unchanged by l-NAME, TEA, or glybenclamide. In isolated coronary artery segments, lactate also produced relaxation, an effect attenuated by removing the endothelium. Together these findings suggest that lactate exerts coronary vasodilatory effects through the release of endothelial nitric oxide, independently of potassium channels. These findings may be relevant for the regulation of coronary circulation when lactate levels are elevated. PMID- 21697726 TI - Does the aminopeptidase A have prognostic and diagnostic value in Chagas disease and other dilated cardiomyopathies? AB - Chagas disease (CD), which is caused by the protozoan Trypanosoma cruzi, is a major cause of heart failure in Latin America. We investigated if plasma activity of one of the enzymes being part of the renin-angiotensin system, aminopeptidase A (APA), has diagnostic and prognostic potency in patients with CD and dilated cardiomyopathies (DCMs) due to other causes. Blood samples were taken from 94 patients with CD, 46 patients with DCM, and 34 healthy control subjects. Plasma APA activity was determined by fluorometry assays. The average follow-up time was 39 months; by the end of study, 33 patients had died and another 13 received heart transplant. There was no significant alteration in plasma APA activity in the patients with CD or DCM, as compared with that in controls. The Pearson correlation of echocardiographic data with plasma APA activity in patients with CD and DCM did not reveal any significant correlation with left-ventricular ejection fraction or other echocardiographic parameters. APA activity was unable to predict mortality or the need for heart transplant. Detection of APA activity in plasma may not prove suitable for prognosis in patients with heart failure and is unable to screen or diagnose asymptomatic patients with CD for early therapy. PMID- 21697725 TI - Regulation of kinase cascade activation and heat shock protein expression by poly(ADP-ribose) polymerase inhibition in doxorubicin-induced heart failure. AB - Cardiomyopathy is one of the most severe side effects of the chemotherapeutic agent doxorubicin (DOX). The formation of reactive oxygen species plays a critical role in the development of cardiomyopathies, and the pathophysiological cascade activates nuclear enzyme poly(ADP-ribose) polymerase (PARP), and kinase pathways. We characterized the effects of the PARP-inhibitor and kinase-modulator compound L-2286 in DOX-induced cardiac injury models. We studied the effect of the established superoxide dismutase-mimic Tempol and compared the effects of this agent with those of the PARP inhibitor. In the rat H9C2 cardiomyocytes, in which DOX-induced poly(ADP-ribosyl)ation, L-2286 protected them from the DOX induced injury in a concentration-dependent manner. In the in vivo studies, mice were pretreated (for 1 week) with L-2286 or Tempol before the DOX treatment. Both the agents improved the activation of cytoprotective kinases, Akt, phospho specific protein kinase C ϵ, zeta/lambda and suppressed the activity of cell death promoting kinases glycogen synthase kinase-3beta, JNK, and p38 mitogen activated protein kinase, but the effect of PARP inhibitor was more pronounced and improved the survival as well. L-2286 activated the phosphorylation of proapoptotic transcription factor FKHR1 and promoted the expression of Hsp72 and Hsp90. These data suggest that the mode of the cytoprotective action of the PARP inhibitor may include the modulation of kinase pathways and heat shock protein expression. PMID- 21697727 TI - The functional role of PI3K in maintenance of blood pressure and baroreflex suppression in (mRen2)27 and mRen2.Lewis rat. AB - The phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway in brain of spontaneously hypertensive rats, but not Wistar-Kyoto (WKY) rats, contributes to elevated mean arterial pressure (MAP). The role of PI3K in the regulation of blood pressure or autonomic function in the nucleus tractus solitarii (NTS) is yet to be established in other Ang II-dependent models of hypertension. Thus, we microinjected PI3K inhibitors, wortmannin or LY294002, into the NTS, and measured MAP, baroreflex sensitivity (BRS) for heart rate (HR) control, and HR variability (HRV) in mRen2.Lewis congenic and (mRen2)27 transgenic rats. Bilateral NTS microinjections of wortmannin (100 nmol/L; 50 nL) reduced MAP in (mRen2)27 and mRen2.Lewis rats (33 +/- 5 mm Hg, n = 7, and 32 +/- 6 mm Hg, n = 9, respectively) for approximately 90 minutes. Spectral and sequence analysis showed improvements in spontaneous BRS and HRV (50%-100%) after treatment in both hypertensive strains. Injections of wortmannin into NTS of Hannover Sprague-Dawley or Lewis control rats failed to alter MAP, BRS, or HRV. In mRen2.Lewis, but not in control Lewis rats, LY294002 (50 MUmole/L) reduced MAP and increased BRS and HRV similar to wortmannin. Thus, the pharmacologic blockade of the PI3K signaling pathway in NTS reveals an important contribution to resting MAP and BRS in rats with overexpression of the Ren2 gene. PMID- 21697728 TI - Cost-effectiveness of levosimendan in patients with acute heart failure. AB - Heart failure is a major public health problem because of its high prevalence and impact on mortality, morbidity, quality of life, and social costs. The aim of this analysis was to estimate the effects of the novel inodilator levosimendan versus standard inotropic therapy (ST) of dobutamine in acute heart failure. A study population of 292 patients with acute heart failure was derived from an observational registry of patients referred to our department. Of these, 147 patients received iv levosimendan (0.05-0.1 MUg.kg.min for 24 hours), and 145 patients were treated with ST. Duration of hospitalization, survival at 1 month, and the rehospitalization rate during the year after the index hospitalization were evaluated. Cost-effectiveness analysis was performed. The mean length of hospitalization was 12.08 and 13.57 days in the levosimendan and ST groups, respectively (P < 0.05). Rehospitalization rates were lower in the levosimendan group at 6 months (1.44% vs. 2.3%; P < 0.05) and 12 months (7.6% vs. 14.3%; P < 0.05). Mortality rate at 1 month was 2.1% versus 6.9% in the levosimendan and ST groups, respectively (P < 0.05). The per-capita cost of treatment with levosimendan was ?78.86 higher than that with ST during the first hospitalization but ?280.22 lower when the rehospitalization rate was considered. PMID- 21697729 TI - Selective blockade of P2Y12 receptors by prasugrel inhibits myocardial infarction induced by thrombotic coronary artery occlusion in rats. AB - We evaluated the effects of prasugrel, a third-generation thienopyridyl prodrug, on P2Y12 receptors, adenosine 5'-diphosphate (ADP)-induced platelet aggregation, and myocardial infarction (MI) in rats. Oral administration of prasugrel (0.3-3 mg/kg) resulted in the dose-related inhibition of washed platelet aggregation induced by ADP (1-10 MUM). Ex vivo [H]-2-MeS-ADP binding to platelet P2Y12 receptors was also inhibited by prasugrel in a similar dose range. The antiaggregatory effects of prasugrel correlated strongly with P2Y12 blockade with correlation coefficients of 0.85-0.92, suggesting that the antiaggregatory activity of prasugrel largely reflected P2Y12 blockade achieved in vivo. We further examined the effects of the in vivo P2Y12 inhibition by prasugrel (1-10 mg/kg, po) on MI induced by thrombotic coronary artery occlusion in rats. In surviving rats, infarct size at 24 hours after photoirradiation was evaluated. In the vehicle group, necrosis area/total left ventricular area was 37.9% +/- 6.8% (mean +/- SE, n = 7). At all prasugrel doses tested (n = 7 for each dose), necrosis area/total left ventricular area was significantly smaller than that in the vehicle group: 14.4% +/- 4.0% for 1 mg/kg (P < 0.01), 19.8% +/- 4.5% for 3 mg/kg (P < 0.05), and 14.8% +/- 3.6% for 10 mg/kg (P < 0.01). At the highest administered dose of prasugrel (10 mg/kg), blood pressure and heart rate were unchanged. Arrhythmia was observed in 5 of 7 animals in the vehicle group at 24 hours after irradiation; in contrast, no arrhythmia was found in the group treated with prasugrel (10 mg/kg). Taken together, these results demonstrate that prasugrel is a selective P2Y12 inhibitor in vivo, providing effective inhibition of platelet aggregation and MI in rats. PMID- 21697730 TI - Metabolic disorders and oxidative stress programming in offspring of rats fed a high-fat diet during lactation: effects of a vinifera grape skin (ACH09) extract. AB - This study examined the effect of Vitis vinifera grape skin ACH09 extract (ACH09) on metabolic disorders and oxidative stress in adult offspring of rats fed a high fat diet (HF) during lactation. Four groups of female rats were fed: control diet (7% fat); ACH09 (7% fat + 200 mg.kg.d ACH09 orally); HF (24% fat); HF+ ACH09 (24% fat + 200 mg.kg.d ACH09 orally) during lactation. From weaning onward, all female offspring were fed a control diet and killed when they were 90 or 180 days old. Systolic blood pressure was increased in adult offspring of HF-fed dams, and ACH09 prevented hypertension. Increased adiposity, plasma triglyceride, glucose levels, and insulin resistance were observed in offspring from both ages, and these changes were reversed by ACH09. The plasma oxidative damage assessed by malondialdehyde levels was increased, and nitrite levels decreased in the HF group of both ages, which were reversed by ACH09. In addition, ACH09 restored the decreased plasma and mesenteric artery antioxidant activities of superoxide dismutase, catalase, and glutathione peroxidase in the HF group. In conclusion, ACH09 protected normally fed offspring of HF-fed dams during lactation from phenotypic and metabolic characteristics of metabolic syndrome providing an alternative nutritional resource for the prevention of metabolic syndrome. PMID- 21697731 TI - Xuezhikang, extract of red yeast rice, inhibited tissue factor and hypercoagulable state through suppressing nicotinamide adenine dinucleotide phosphate oxidase and extracellular signal-regulated kinase activation. AB - Xuezhikang, extract of red yeast rice, is a traditional Chinese medicine with multiple cardioprotective effect. It contains a family of naturally occurring statins, such as lovastatin. Tissue factor (TF) is overexpressed in macrophages of lipid core plaques, which display high procoagulant activity and seem to be a potentially target for anti-atherothrombosis. Therefore, the purpose of this study was to explore the effect and possible molecular mechanisms of xuezhikang on inhibiting TF expression and hypercoagulable state and the differences compared with lovastatin. Our results showed that xuezhikang significantly suppressed oxidized low-density lipoprotein-induced TF expression in macrophages in a concentration-dependent manner. Xuezhikang reduced nicotinamide adenine dinucleotide phosphate oxidase activity by decreasing membrane translocation of p47 through inhibition of extracellular signal-regulated kinase 1/2 activation. Nicotinamide adenine dinucleotide phosphate inhibitor (diphenyleneiodonium) also inhibited the oxidized low-density lipoprotein-induced TF expression, similar to the effects of xuezhikang. Furthermore, consistent with the severity of aortic atherosclerosis, xuezhikang (300 mg.kg.d) significantly reduced blood coagulation activation and TF expression in high-cholesterol diet-induced atherosclerotic rats. In addition, xuezhikang was more potent than lovastatin on inhibiting the expression of TF and nicotinamide adenine dinucleotide phosphate oxidase activation. These observations provide evidences that inhibition of xuezhikang on hypercoagulation and TF expression may partly account for its cardioprotective benefits. PMID- 21697733 TI - Atorvastatin worsens left ventricular diastolic dysfunction and endothelial dysfunction of epicardial coronary arteries in normocholesterolemic porcine with left ventricular hypertrophy. AB - Statins have pleiotropic effects that can reverse endothelial dysfunction and prevent the development of left ventricular hypertrophy (LVH). The goal of this study was to assess the effect of treatment with atorvastatin on the endothelial dysfunction of epicardial coronary arteries and the development of LVH in a porcine model. LVH was induced through 2 months of aortic banding (AB) of the ascending aorta. Experimental groups were (1) sham untreated: without AB, (2) LVH untreated: with AB, and (3,4) LVH treated: with AB treated with 40 and 80 mg of atorvastatin, respectively, for 60 days, and (5) sham treated: without AB treated with 80 mg of atorvastatin for 60 days. Vascular reactivity studies were performed in organ chambers experiments. NO bioavailability was assessed using cyclic guanosine monophosphate quantification. Oxidative stress levels were measured by quantifying angiotensin II) and nitrite/nitrate levels. LVH and LV diastolic function were evaluated using echocardiography. Atorvastatin decreased endothelium-dependent relaxations and cyclic guanosine monophosphate levels in all treated animals. Angiotensin II levels were increased, whereas nitrite levels were similar among groups (P > 0.05). LV diastolic dysfunction and LVH were significantly greater in all treated animals (P < 0.01). High-density lipoprotein levels and low-density lipoprotein levels were significantly decreased in animals receiving atorvastatin (P < 0.05). In this swine model of LVH, atorvastatin did not prevent LVH development or coronary endothelial dysfunction and resulted in worsening of the LV diastolic dysfunction. PMID- 21697732 TI - Anti-inflammation therapy by activation of prostaglandin EP4 receptor in cardiovascular and other inflammatory diseases. AB - Prostaglandin E2 constitutes a major cyclooxygenase-2-derived prostanoid produced at inflammatory sites. In vitro and in vivo data support its role as a modulator of inflammation. Prostaglandin E2 exerts anti-inflammatory effects by binding to one of its receptors, the prostaglandin E receptor 4 (EP4), thereby modulating macrophage and T lymphocyte functions that participate crucially in innate and adaptive immunity and tissue remodeling and repair. The activation of EP4 suppresses the release of cytokines and chemokines from macrophages and T cells, inhibits the proliferation and the activation of T cells, and induces T-cell apoptosis. Lack of EP4 in bone marrow-derived cells accelerates local inflammation in atherosclerotic and aneurysm lesions and increases the prevalence of aneurysm formation. An EP4 agonist promotes graft survival in allograft cardiac transplantation and dampens tissue damage after myocardial ischemia. Anti inflammatory actions of EP4 agonism may benefit other inflammatory disorders, including colitis and gastric ulcers. By contrast, EP4 acts as a proinflammatory mediator in encephalomyelitis, skin inflammation, and arthritis by promoting T helper (Th) 1 differentiation and Th17 expansion. Overall, EP4 activation produces powerful anti-inflammatory responses in many experimental diseases, rendering EP4 agonists attractive agents to attenuate syndromes associated with inflammation. PMID- 21697734 TI - Disruption of chronic cariporide treatment abrogates myocardial ion homeostasis during acute ischemia reperfusion. AB - Cariporide, an Na/H exchanger inhibitor, is a drug with cardioprotective properties. However, chronic treatment with cariporide may modify the protein phenotype of the cardiomyocytes. Disruption of the equilibrium between a cariporide-modified phenotype and the supply of cariporide could be deleterious. The aim of this study was to test the effects of this equilibrium rupture (EqR) on cardiac function at baseline and acute ischemia reperfusion. Rats were chronically treated with cariporide (2.5 mg.kg.d) or with placebo for 21 days, after which isolated Langendorff-mode heart perfusion experiments utilized cariporide-free buffer. During this type of perfusion, the drug is rapidly cleared from the cellular environment. After 30 minutes of stabilization, the hearts were subjected to global zero-flow ischemia (25 minutes) followed by reperfusion (45 minutes). Measures of mechanical function, oxygen consumption, lactate plus pyruvate, CO2 and proton release into the coronary effluent were determined. The gene and protein expression of proton extruders was also evaluated. Chronic cariporide administration followed by EqR reduced the expression of the Na/H exchanger, increased the expression of the HCO3 or Na exchanger, decreased monocarboxylate/H carrier expression, reduced the lactate plus pyruvate release but did not change the glucose oxidation rate and mechanical function compared with baseline conditions. The resulting low glycolytic rate was associated with a stronger contracture during ischemia. During reperfusion, the early release of acidic forms was higher and redirected toward the use of the Na/H and HCO3 /Na exchangers to the detriment of the safe monocarboxylate/H carrier. Both phenomena were assumed to increase the Na uptake and activate the Na/Ca exchanger, resulting in Na and Ca overload and further cellular damage. This explains the impaired recovery of the contractile function observed in the EqR group during reperfusion. In conclusion, although cariporide is usually cardioprotective, a disruption of its chronic treatment followed by an ischemia/reperfusion event can become deleterious. PMID- 21697735 TI - "Exposure" is not absorption. PMID- 21697736 TI - Protecting workers in large-scale emergency responses: NIOSH Experience in the Deepwater Horizon response. PMID- 21697737 TI - Physical activity, sedentary behavior, and melatonin among rotating shift nurses. AB - OBJECTIVE: To determine the effect of physical activity and sedentary behavior on melatonin levels in a group of rotating shift nurses. METHODS: Physical activity and sedentary behaviors for 118 nurses were recorded during both a day shift and a night shift using activity diaries, and concentrations of urinary 6 sulfatoxymelatonin were analyzed for each shift. RESULTS: During the day shift, energy expended in moderate- and vigorous-intensity physical activity between 3 PM and 7 AM was negatively associated with melatonin levels (P = 0.024). During the night shift, energy expended in sedentary behaviors was negatively associated with melatonin levels (P = 0.008). CONCLUSIONS: Physical activity and energy expended in sedentary behavior are inversely associated with morning urinary melatonin concentrations. Nevertheless, energy expenditure explains a relatively small amount of melatonin variation, perhaps suggesting that peak melatonin is minimally affected by these patterns of physical activity. PMID- 21697738 TI - Law enforcement officer versus non-law enforcement officer status as a longitudinal predictor of traditional and emerging cardiovascular risk factors. AB - OBJECTIVE: To determine whether law enforcement officer (LEO) status and perceived stress are longitudinal predictors of traditional and inflammatory cardiovascular (CV) risk factors. METHOD: Linear hierarchical regression was employed to investigate the longitudinal (more than 7 years) relationship between occupational category (LEO vs non-LEO) and perceived stress scale scores, and traditional and inflammatory CV risk factors in an all-male sample of 105 LEOs and 65 non-LEOs. RESULTS: The occupational status of LEOs, compared with that of non-LEOs, predicted higher levels of C-reactive protein, systolic blood pressure, body mass index, and waist circumference. Perceived stress across occupational categories was directly associated with diastolic blood pressure and waist circumference and inversely with fibrinogen. Perceived stress did not interact with occupational category to predict any risk factor. CONCLUSION: Traditional and inflammatory risk factors, but not perceived stress, appear to contribute to elevated CV risk among LEOs. PMID- 21697740 TI - Extra-articular malunions of the scapula: a comparison of functional outcome before and after reconstruction. AB - OBJECTIVE: To assess surgical and functional results after corrective reconstruction of malunited, scapula neck or body fractures in patients who presented with chronic pain, limited range of motion, weakness, and gross deformity of the shoulder. DESIGN: Case series. SETTING: Level I teaching trauma center. PATIENTS: Between 2000 and 2008, five patients (mean age, 44 years) underwent operative reconstruction of a malunited, scapula neck and/or body fracture. Mean time from injury to surgery was 15 months (range, 8-41 months). All patients presented with debilitating pain and weakness and were unable to return to work. When measured on three-dimensional computed tomographic scan, mean preoperative fracture deformity included 3.0 cm (range, 1.7-4.2 cm) of medial/lateral displacement, 25 degrees (range, 10 degrees -40 degrees ) of angular deformity, and a 25 degrees (range, 19 degrees -29 degrees ) glenopolar angle. INTERVENTION: Surgical osteotomy and reorientation of scapula neck and/or body, with fixation using 2.7- or 3.5-mm implants and autogenous graft, through a posterior Judet approach. MAIN OUTCOMES MEASURES: Pre- and postoperative functional measures of range of motion and strength testing and patient-based outcome scores (Disabilities of the Arm, Shoulder and Hand and Short Form-36). RESULTS: Mean follow-up was 39 months (range, 18-101 months). All patients united radiographically, were pain-free with regard to the shoulder, and expressed satisfaction with their result. Four of five patients returned to their original occupation and activities. Mean Disabilities of the Arm, Shoulder and Hand score improved from 39 (range, 27-58) preoperatively to 10 (range, 0-35) postoperatively. There were no complications. CONCLUSIONS: Malunion after nonoperative treatment of a displaced scapula fracture may be associated with poor functional and cosmetic outcomes. Operative reconstruction can yield good surgical and functional results. PMID- 21697739 TI - A new technique for removing intramedullary cement. AB - Treatment of infected long bone fractures or nonunions requires stability for bony union, yet retained implants can lead to persistent infection. Antibiotic cement intramedullary nails, in addition to external fixation, are commonly used to deliver intramedullary antibiotics in infected long bone fractures and provide temporary stability. However, the retrieval of these nails can result in debonding of antibiotic cement, which can require significant time and effort to remove. A variety of methods, including intramedullary hooks, reverse curettes, flexible osteotomes, and stacked guide rods, are commonly used to remove cement fragments. When these methods fail to allow access to the entire length of the canal, the Reamer Irrigator Aspirator system (Synthes, Paoli, PA) serves as an effective method for removing retained intramedullary cement. The surgical technique is described, and three cases illustrate the successful use of the Reamer Irrigator Aspirator system for removal of an antibiotic cement intramedullary nail. PMID- 21697741 TI - Screw depth sounding in proximal humerus fractures to avoid iatrogenic intra articular penetration. AB - Unstable and displaced proximal humerus fractures remain a treatment challenge. The use of locked plates has improved construct stability, but complication rates remain high. Biomechanical studies have emphasized the importance of anchoring screws in the subchondral bone of the humeral head to improve implant stability. However, the spherical shape of the proximal humerus and the limited tactile sensation of its soft cancellous bone make determining accurate screw length difficult, and reported rates of intraoperative screw penetration are high. Iatrogenic screw penetration, even if recognized and corrected before leaving the operating room, may lead to late failure. We present a simple technique of quickly and safely determining screw length using a blunt-tipped Kirschner wire and instruments found in basic orthopaedic sets. PMID- 21697742 TI - Maternal psychopathology and psychomotor development of children with GERD. AB - OBJECTIVES: The relation between gastroesophageal reflux disease (GERD) and maternal psychopathology as well as the role of impairments in mother-child interactions in the perpetuation of feeding problems in children with GERD was previously implicated but not confirmed. The present study aimed to study the relation between maternal psychopathology and feeding problems in children with GERD and the effects of GERD on the psychomotor development of children. SUBJECTS AND METHODS: The case group included 39 children with GERD and their mothers and the comparison group included 39 healthy children and their mothers. The groups were matched for age, gestational age, socioeconomic status, and sex. Scales used for the psychiatric assessment of mothers were the Beck Anxiety Inventory, Hamilton Rating Scale for Depression, Eating Attitudes Test, and Experiences in Close Relationships-Revised. The children's developmental levels were assessed by the Brunet-Lezine Revised test. RESULTS: Maternal Beck Anxiety Inventory, Hamilton Rating Scale for Depression, Eating Attitudes Test, and Experiences in Close Relationships-Revised scores were significantly higher in the case group. Forced feeding and maternal thoughts of the child's feeding as insufficient were associated with a high level of maternal attachment-related anxiety and avoidance. Children with GERD had significantly lower Brunet-Lezine-Revised scores. CONCLUSIONS: Maternal psychopathology, especially insecure attachment, may play a role in the feeding problems in children with GERD. Children with GERD should be examined for maternal psychopathology and feeding problems so that maladaptive feeding behaviors can receive appropriate intervention before the development of negative reinforcement to feeding. The psychomotor development of children should be kept in mind. PMID- 21697743 TI - Early developing celiac disease in children with cerebral palsy. AB - OBJECTIVES: We have reported on increased levels of antibodies against gliadin and/or transglutaminase 2 (TG2) in children with cerebral palsy (CP) but without having increased prevalence of celiac disease (CD). The aim of the present study was to evaluate whether these children have mucosal signs of early developing CD, human leukocyte antigen (HLA)-DQ2/DQ8, and antibodies against deamidated gliadin peptides (DGP). PATIENTS AND METHODS: Stored blood samples from 16 children with CP were analyzed regarding HLA-DQ2/DQ8 and anti-DGP antibodies. HLA-DQ2/DQ8 were analyzed by polymerase chain reaction sequence-specific oligonucleotide probes. Anti-DGP antibodies were analyzed with enzyme-linked immunosorbent assay. Small bowel biopsies from 15 of these children were available for immunohistochemistry regarding IgA colocalized with TG2, densities of alpha/beta+ and gamma/delta+ intraepithelial lymphocytes. RESULTS: Mucosal immunoglobulin A (IgA) deposits colocalized with TG2 were found in the small-bowel biopsy from 1 patient with serum IgA-class anti-TG2 antibodies, HLA-DQ2, and gastrointestinal complaints. Another 2 children had slightly increased numbers of mucosal alpha/beta+ and/or gamma/delta+ intraepithelial lymphocytes. In total, 10 of 16 children were HLA DQ2 and/or DQ8-positive. Anti-DGP antibodies were detected in sera from 4 of 16 children. CONCLUSIONS: In the present study, 1 child with CP had IgA colocalizing with TG2 in the small-bowel mucosa, suggesting CD at an early stage. Although the majority of children with CP and elevated levels of CD-related seromarkers are HLA-DQ2 and/or DQ8-positive, they have neither classical nor early developing CD. PMID- 21697744 TI - Biochemical parameters and anthropometry predict NAFLD in obese children. AB - The aim of the present study was to build a predictive model of nonalcoholic fatty liver disease (NAFLD) in obese children. Fifty-six obese 10-year-old children underwent blood tests for biochemical measures and magnetic resonance imaging for NAFLD diagnosis. A model combining waist-to-height ratio, homeostasis model assessment of insulin resistance, adiponectin, and alanine aminotransferase was accurate in predicting NAFLD (AUROC = 0.94 [95% confidence interval 0.89 0.99], P < 10). When adiponectin was not included in the model, the discrimination accuracy was still good (AUROC = 0.88 [95% confidence interval 0.79-0.97], P < 10). In conclusion, a predictive equation combining routinely available variables may allow physicians to identify obese children at the highest risk of NAFLD. PMID- 21697745 TI - Abdominal pain-predominant functional gastrointestinal diseases in children and adolescents: prevalence, symptomatology, and association with emotional stress. AB - BACKGROUND AND OBJECTIVE: Functional gastrointestinal disorders (FGD) are common among children, but little is known regarding their prevalence in developing countries. We assessed the prevalence of abdominal pain-predominant FGD, in addition to the predisposing factors and symptomatology, in Sri Lankan children. PATIENTS AND METHODS: A cross-sectional survey was conducted among a randomly selected group of 10- to 16-year-olds in 8 randomly selected schools in 4 provinces in Sri Lanka. A validated, self-administered questionnaire was completed by children independently in an examination setting. FGD were diagnosed using Rome III criteria. RESULTS: A total of 2180 questionnaires were distributed and 2163 (99.2%) were included in the analysis (1189 [55%] boys, mean age 13.4 years, standard deviation 1.8 years). Of them, 270 (12.5%) had at least 1 abdominal pain-predominant FGD. Irritable bowel syndrome (IBS) was seen in 107 (4.9%), functional dyspepsia in 54 (2.5%), functional abdominal pain in 96 (4.4%), and abdominal migraine (AM) in 21 (1.0%) (2 had AM and functional dyspepsia, 6 had AM and IBS). Extraintestinal symptoms were more common among affected children (P < 0.05). Abdominal pain-predominant FGD were higher in girls and those exposed to stressful events (P < 0.05). Prevalence negatively correlated with age (r = -0.05, P = 0.02). CONCLUSIONS: Abdominal pain predominant FGD affects 12.5% of children ages 10 to 16 years and constitutes a significant health problem in Sri Lanka. IBS is the most common FGD subtype present. Abdominal pain-predominant FGD are higher in girls and those exposed to emotional stress. Prevalence of FGD decreased with age. Extraintestinal symptoms are more frequent in affected children. PMID- 21697746 TI - Friends and physical activity during the transition from primary to secondary school. AB - PURPOSE: The study's purpose was to examine whether friendship factors predict discretionary physical activity after the transition to secondary school. METHODS: Data represent a secondary analysis of the Personal and Environmental Associations with Children's Health Study. Outcomes were minutes of moderate to vigorous physical activity (MVPA) obtained after school (3:30-8:30 p.m.) and for weekends. Data were collected at the end of primary and the start of secondary school. Exposures were self-reported number of friends, friend support for physical activity, and friend sedentary preferences. Change (secondary--primary) was calculated for all variables. RESULTS: Boys' after-school MVPA declined by 16% after the move from primary to secondary school with a 12% decline for girls. Both boys' (24%) and girls' (17%) weekend MVPA increased after the move to secondary school. Regression analysis indicated that an increase in the number of friends between primary and secondary school was associated with increased after school and weekend MVPA. Inspection of the coefficients indicated that each additional friend was associated with 3.7 more minutes of MVPA after school and 9.8 min of MVPA during the weekend for girls. Similarly, each additional unit on a four-item friend support for physical activity scale was associated with 1.8 more minutes of after-school MVPA and 6.0 more minutes of weekend MVPA among girls. Although friend support was cross-sectionally associated with boys' MVPA during primary school, neither the number of friends nor friend support for physical activity was associated with change in boys' after-school or weekend MVPA. CONCLUSIONS: Increased number of friends and friend support for physical activity were associated with increases in girls' MVPA after the move to secondary school. Strategies to foster friend support for physical activity may be important for helping girls be active. PMID- 21697747 TI - Effect of resistance, endurance, and concurrent training on TNF-alpha, IL-6, and CRP. AB - PURPOSE: The aim of the present study was to evaluate the effects of 16 wk of resistance training (RT), endurance training (ET), and concurrent training (CT) on inflammatory markers, C-reactive protein (CRP), and functional capacity in sedentary middle-age men. METHODS: Healthy subjects were randomized into RT (n = 11), ET (n = 12), CT (n = 11), and a control group (n = 13). The subjects performed three weekly sessions lasting about 60 min for 16 wk. Maximal strength was tested in bench press and leg press. The peak oxygen uptake (VO2peak) was measured in an incremental exercise test. Plasma tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6), and CRP levels were determined by an enzyme-linked immunosorbent assay. RESULTS: Maximal strength was increased after 16 wk, with no differences between RT and CT. VO2peak increased in ET and CT comparing before and after training. There were no significant differences in TNF-alpha, IL-6, and CRP comparing before and after training. CONCLUSIONS: Sixteen weeks of RT, ET, or CT in middle-age healthy men has not affected low and moderate IL-6, TNF-alpha, and CRP levels. CT performed in the same weekly frequency and session duration of ET and RT was effective in increasing both maximal strength and VO2peak, in addition to improvements in lipid profile. PMID- 21697748 TI - Pilot study of granulocyte-macrophage colony-stimulating factor and interleukin-2 as immune adjuvants for a melanoma peptide vaccine. AB - Thus far, peptide vaccines used to stimulate tumor-specific immune responses in patients with melanoma have been largely unsuccessful. Granulocyte-macrophage colony-stimulating factor and interleukin-2 are immune-potentiating cytokines that have improved vaccine responses in preclinical models. We hypothesized that higher doses of granulocyte-macrophage colony-stimulating factor and addition of low-dose interleukin-2 might augment responses to vaccine antigens. Patients with resected stage II, III, or IV melanoma were treated with vaccines containing three melanoma-associated peptides [MART-1a, gp100(207-217), and survivin], along with 300 or 500 mcg granulocyte-macrophage colony-stimulating factor in Montanide ISA. Cohorts of patients received low-dose subcutaneous interleukin-2 on days 7 20 after vaccination. Induction of a response was defined as either doubling of cytotoxic T lymphocyte frequency from baseline or increase in frequency from undetectable (<0.05%) to detectable. Leukocyte subsets and plasma cytokines were analyzed before and after vaccination. Cytotoxic T lymphocyte responses to MART 1a, gp100(207-217), and survivin were induced in 11, 16, and 14 of 19 patients, respectively. Responses were not higher in patients receiving 500 mcg granulocyte macrophage colony-stimulating factor or low-dose interleukin-2 than in patients receiving 300 mcg granulocyte-macrophage colony-stimulating factor only. Interleukin-2 treatment (in nine patients) led to increases in natural killer cells and T regulatory cells compared with no interleukin-2 treatment (nine patients). Multiple plasma cytokines were transiently induced during vaccination. Neither increasing the dose of granulocyte-macrophage colony-stimulating factor nor addition of low-dose interleukin-2 resulted in an increase in the frequency of vaccine-specific cytotoxic T lymphocytes to a melanoma peptide vaccine. The increase in T regulatory cells associated with interleukin-2 treatment suggests that interleukin-2 may be immunosuppressive in this setting. PMID- 21697749 TI - Histaminergic modulation of acetylcholine-induced gamma oscillations in rat hippocampus. AB - We investigated the interaction between ambient histamine and acetylcholine by studying gamma oscillations in rat hippocampus, induced by bath application of acetylcholine (10 uM combined with 2 uM physostigmine). The power of gamma was significantly increased by the H1 antagonist, fexofenadine, and H2 receptor agonist, dimaprit, and reduced by the H2 receptor antagonist, cimetidine. These effects suggest an interference with ambient histamine. Depletion of histamine from their fibers by hypoxia and blockade of histamine uptake resulted in loss of the fexofenadine-mediated and cimetidine-mediated effects on acetylcholine induced gamma. We conclude that acetylcholine can cause histamine release from histaminergic fibers and thereby can influence attentional states by augmenting gamma. This effect is likely due to activation of H2 receptors by histamine and thereby might contribute to the previously described enhancement of working memory. PMID- 21697751 TI - Does intraoperative computed tomography obviate the need for postoperative imaging studies in deep brain stimulation surgery? PMID- 21697753 TI - Stereotactic radiosurgery with or without embolization for intracranial dural arteriovenous fistulae. PMID- 21697754 TI - Transcranial Doppler as an initial screening tool for patients with mild to moderate traumatic brain injury. PMID- 21697755 TI - Diffusion tensor imaging and colored fractional anisotropy mapping of the ventralis intermedius nucleus of the thalamus. AB - BACKGROUND: The ventralis intermedius (VIM) nucleus of the thalamus is the primary surgical target for treatment of tremor. Most centers rely on indirect targeting based on atlas-defined coordinates rather than patient-specific anatomy, making intraoperative physiological mapping critical. Detailed identification of this target based on patient-specific anatomic features can help optimize the surgical treatment of tremor. OBJECTIVE: To study colored fractional anisotropic images and diffusion tensor imaging (DTI) tractography to identify characteristic magnetic resonance appearances of the VIM nucleus. METHODS: Four patients undergoing stereotactic surgery for essential tremor (ET) were retrospectively studied with analysis of magnetic resonance imaging-based colored fractional anisotropy (FA) images and fiber tractography. All were scanned with a 1.5-T magnetic resonance imaging unit, and all sequences were obtained before frame placement. Because the goal of this study was to identify the DTI characteristics of physiologically defined VIM nucleus, we selected and studied patients who had undergone DTI and had efficacious tremor control with intraoperative microlesioning effect and tremor reduction with less than 2.0-V stimulation. RESULTS: Analysis of color FA maps, which graphically illustrate fiber directionality, revealed consistent anatomic patterns. The region of the VIM nucleus can be seen as an intermediate region where there is a characteristic transition of color. Presumptive VIM nucleus interconnectivity with sensorimotor cortex and cerebellum was identified via the internal capsule and the superior cerebellar peduncle, respectively. FA maps could also be used to distinguish segments of gray matter, white matter, and gray-white matter boundaries. CONCLUSION: Analysis of DTI and FA maps on widely available 1.5-T magnetic resonance imaging yields clear identification of various structures key to neurosurgical targeting. Prospective evaluation of integrating DTI into neurosurgical planning may be warranted. PMID- 21697756 TI - Silicone spacer repair of medial rectus after iatrogenic orbit fracture. AB - A 51-year-old woman underwent endoscopic nasal polypectomy and ethmoidectomy with accidental entry into the right orbit causing enophthalmos and transection of the medial rectus muscle (MR). The repair of a fracture and of a damaged MR is technically challenging, particularly when large portions of bone and muscle are missing. We report a rare case of repair of the bony defect with an implant and reattachment of the MR with a silicone retina band, through a combined transcaruncular and transconjunctival approach. Postoperatively, the patient had residual enophthalmos and strabismus; further surgical options are discussed. PMID- 21697757 TI - Comparing pericanalicular sutures with direct canalicular wall sutures for canalicular laceration. AB - PURPOSE: To determine whether a statistically significant difference exists between direct canalicular wall sutures (DCs) and pericanalicular sutures (PCs) in the repair of traumatic canalicular lacerations. METHODS: The medical records of 63 patients who underwent primary repairs for traumatic canalicular lacerations were retrospectively reviewed. Patients were divided in 2 groups according to the suturing techniques used: the DC group (n = 41) and the PC group (n = 22). Anatomic results were compared between these 2 groups. A successful result was determined by attempted irrigation and probing of the injured canaliculus at the last follow-up visit. RESULTS: There were 6 failed procedures among the patients who underwent pericanalicular repair and 1 failed procedure among the patients who underwent direct canalicular wall repair (p = 0.024). CONCLUSIONS: These data support the higher success rates in patients treated with direct canalicular repair compared with pericanalicular repair. PMID- 21697758 TI - Orbital perineurioma in the setting of dacryocystitis. AB - A benign orbital perineurioma was discovered just posterior to the lacrimal sac during surgery for recurrent bacterial dacryocystitis in an 83-year-old woman. The tumor was circumscribed but nonencapsulated and located exterior to the lacrimal sac mucosa. It was composed of cytologically bland spindle cells organized in graceful, elongated, and twisted bundles reminiscent of a storiform pattern. Immunohistochemical staining displayed a diagnostic pattern of Claudin 1, GLUT-1, and epithelial membrane antigen positivity. Malignant transformation is virtually unknown, even with incomplete excision. The differential diagnosis includes neurofibroma, schwannoma, leiomyoma, solitary fibrous tumor (CD34 positive), and low-grade fibromyxoid sarcoma. PMID- 21697759 TI - Intraorbital false (thrombosed) aneurysm of the meningolacrimal branch of the middle meningeal artery: a case report and an appraisal of anatomy. AB - PURPOSE: To describe a rare case of a thrombosed (false) aneurysm of the meningolacrimal branch of the middle meningeal artery. METHODS: Interventional case report. RESULTS: A 36-year-old man presented with unilateral proptosis of sudden onset after minor head trauma. Imaging showed an apical oval mass interposed between the superior and lateral rectii muscles in close proximity to a vessel about 0.5 mm in diameter. On carotid angiography, the mass did not fill with contrast material, but the adjacent artery proved to be the meningolacrimal branch of the middle meningeal artery. This pseudoaneurysm was successfully evacuated surgically, and the overlying vessel was ligated. CONCLUSION: Orbital aneurysms are exceedingly rare and almost exclusively derived from the ophthalmic artery. To the best of our knowledge, this is the first reported case of an intraorbital aneurysm arising from the meningolacrimal branch of the middle meningeal artery which was successfully managed surgically. PMID- 21697760 TI - Impact of curcumin, raspberry extract, and neem leaf extract on rel protein regulated cell death/radiosensitization in pancreatic cancer cells. AB - OBJECTIVES: Nuclear factor kappaB (NF-kappaB) plays an intrinsic role in promoting growth, angiogenesis, and metastasis in pancreatic cancer (PC) and serves as a mechanism underlying therapeutic resistance. Accordingly, we investigated the efficacy of bioactive phytochemicals in inhibiting radiotherapy (RT)-induced NF-kappaB activity, signaling, and NF-kappaB-dependent regulation of cell death. METHODS: Panc-1, BxPC-3, and MIA PaCa-2 cells exposed to 10 Gy (single high dose [SDR]) or 2 Gy/d for 5 days (fractionated radiation [FIR]) with or without curcumin (CUR), neem leaf extract (NLE), or black raspberry extract (RSE) were analyzed. RESULTS: Radiotherapy profoundly induced NF-kappaB-DNA binding activity with relatively robust activation after FIR. Curcumin, NLE, and RSE significantly inhibited both constitutive and RT-induced NF-kappaB. Furthermore, quantitative polymerase chain reaction profiling of 88 NF-kappaB pathway molecules demonstrated that CUR, NLE, and RSE comprehensively, yet differentially inhibited FIR/SDR-induced genes. Functionally, CUR, NLE, and RSE markedly conferred RT-inhibited cell viability/survival, robustly activated caspase-3/7 activity, and subsequent cell death. More importantly, NF-kappaB overexpression and silencing studies demonstrate that these compounds potentiate RT-induced cell death by targeting RT-induced NF-kappaB. CONCLUSIONS: These data strongly imply that CUR, NLE, and RSE may serve as effective "deliverables" to potentiate RT in PC cure and further throw light that these phytochemicals induced cell killing may involve selective regulation of RT-induced NF-kappaB. PMID- 21697761 TI - Evaluating the characteristics and the management of patients with neuroendocrine tumors receiving octreotide LAR during a 6-year period. AB - OBJECTIVE: This retrospective study evaluated physician practice patterns in the medical management of patients with neuroendocrine tumors (NETs) treated with octreotide LAR. METHODS: Data were collected from the medical charts of 392 patients diagnosed with NET and treated with octreotide LAR for 4 months or longer. RESULTS: Approximately 72% (n = 284) of patients had metastatic disease with carcinoid syndrome (CS). Of these, 92% (n = 260) had CS at diagnosis and 8% (n = 24) developed CS after diagnosis. Of the patients studied, 89% received octreotide LAR, and the most common octreotide LAR doses were 30 mg (45% of all regimens), 20 mg (32%), and 40 mg (11%). After 12 months of treatment with octreotide LAR, symptom resolution or improvement was seen in 60%, 48%, 48%, and 30% of patients with flushing, diarrhea, bronchoconstriction, and carcinoid heart disease, respectively. Approximately 57% of patients treated with octreotide LAR demonstrated stable disease; with rates of 57% at 20 mg, 57% at 30 mg, 55% at 40 mg, and 50% at 60 mg. CONCLUSIONS: This retrospective study has added to the wealth of evidence demonstrating the efficacy and safety of octreotide LAR in the treatment of patients with NET. The review highlights the importance of regular patient monitoring and clinical management. PMID- 21697762 TI - Transforming growth factor beta1 contributes to the invasiveness of pancreatic ductal adenocarcinoma cells through the regulation of CD24 expression. AB - OBJECTIVES: The aim of this study was to investigate the role of CD24 in the invasiveness of pancreatic ductal adenocarcinoma (PDAC). METHODS: We used 2 human PDAC cell lines containing large numbers of CD24-positive (CD24) cells (>65%; AsPC-1 cells) or few CD24 cells (<20%; CFPAC-1 cells). Invasiveness was estimated using the Matrigel invasion assay. The role of CD24 in invasiveness was evaluated using small interference RNA against CD24 mRNA. RESULTS: The invasive ability of CD24 cells collected by cell sorter was higher than that of CD24-negative (CD24) cells. On the other hand, silencing of CD24 decreased the invasive ability of CD24 cells. Importantly, considerable amount of CD24 cells was converted to CD24 cells within 24 hours under in vitro culture condition. Transforming growth factor beta1 significantly inhibited this conversion and consequently maintained the high invasiveness of CD24 cells. CONCLUSIONS: Our data show that CD24 contributes to the invasive ability of PDAC and also suggest that transforming growth factor beta1 may contribute to the invasiveness of PDAC by suppressing the conversion from CD24 cells to CD24 cells at the tumor site. PMID- 21697763 TI - Identification of HLA-A*0201- and A*2402-restricted epitopes of mucin 5AC expressed in advanced pancreatic cancer. AB - OBJECTIVES: Mucin 5AC (MUC5AC) was previously identified as being expressed in most pancreatic ductal adenocarcinomas. We studied the significance of MUC5AC expression for the development of pancreatic ductal adenocarcinoma and the possibility of using MUC5AC as a target for immunotherapy for pancreatic cancer. METHODS: We immunohistochemicaly tested MUC5AC expression in 134 specimens. To assess the possibility of using the MUC5AC protein to develop an anticancer vaccine, we examined MUC5AC for possible peptide epitopes to elicit cytotoxic T lymphocytes (CTLs). RESULTS: In immunohistochemical analysis, MUC5AC was absent from all cell types of the normal pancreas but was expressed de novo in 79% of invasive ductal adenocarcinoma. Clinicopathologically, primary tumors with lymph node metastasis had a significantly higher expression of MUC5AC. Next, we successfully established CTL clones stimulated by the MUC5AC-A02-1398 (FLNDAGACV) and MUC5AC-A24-716 (TCQPTCRSL) peptides, which have specific cytotoxicity against the corresponding HLA-A*0201- and A*2402-positive target cells pulsed with the candidate peptide. Each CTL clone also demonstrated its cytotoxic activity toward pancreatic cancer cells endogenously expressing MUC5AC. CONCLUSIONS: Our results suggest that MUC5AC is a novel tumor-associated antigen that has potential application as a vaccine against pancreatic cancer. PMID- 21697764 TI - Susceptibility locus for lung cancer at 15q25.1 is not associated with risk of pancreatic cancer. AB - OBJECTIVES: Four genome-wide association (GWA) studies have found that variation in a region of strong linkage disequilibrium on the long arm of chromosome 15 (15q24-25.1) containing nicotinic acetylcholine receptor genes contributes to lung cancer risk. Because cigarette smoking is a major risk factor for developing both lung cancer and pancreatic cancer, we hypothesized that variation in this region may also modify individual susceptibility to pancreatic cancer. METHODS: We conducted a case-control study of 523 patients with pathologically confirmed pancreatic adenocarcinoma and 1046 age-, sex-, ethnicity-, and smoking behavior matched cancer-free controls. RESULTS: We found that 2 risk single nucleotide polymorphisms reported in the lung cancer GWA studies-rs8034191: A>G and rs1051730: G>A, located in this 15q24-25.1 region-were not associated with risk of pancreatic cancer. CONCLUSIONS: The results of our study suggest that the 2 single nucleotide polymorphisms at 15q25.1 do not modify pancreatic cancer risk. PMID- 21697765 TI - Characterization of intestinal and pancreatic dysfunction in VPAC1-null mutant mouse. AB - OBJECTIVES: These studies examined the effect of homozygous deletion of vasoactive intestinal peptide receptor type 1 (VPAC1) on development and function of intestines and pancreas. METHODS: Genetically engineered VPAC1-null mutant mice were monitored for growth, development, and glucose homeostasis. Expression of VPAC1 was examined during embryonic development using VPAC1 promoter-driven beta-galactosidase transgenic mice. RESULTS: Homozygous deletion of VPAC1 resulted in fetal, neonatal, and postweaning death owing to failure to thrive, intestinal obstruction, and hypoglycemia. Histological findings demonstrated disorganized hyperproliferation of intestinal epithelial cells with mucus deposition and bowel wall thickening. The pancreas demonstrated small dysmorphic islets of Langerhans containing alpha, beta, and delta cells. Expression of a VPAC1 promoter-driven transgene was observed in E12.5 and E14.5 intestinal epithelial and pancreatic endocrine cells. Vasoactive intestinal peptide receptor type 1-null mutant animals had lower baseline blood glucose levels compared to both heterozygous and wild-type littermates. Vasoactive intestinal peptide receptor type 1-deficient mice responded to oral glucose challenge with normal rise in blood glucose followed by rapid hypoglycemia and failure to restore baseline glucose levels. Insulin challenge resulted in profound hypoglycemia and inadequate glucose homeostasis in VPAC1-null mutant animals. CONCLUSIONS: These observations support a role for VPAC1 during embryonic and neonatal development of intestines and endocrine pancreas. PMID- 21697766 TI - Mitochondrial impact of human immunodeficiency virus and antiretrovirals on infected pediatric patients with or without lipodystrophy. AB - We determined the mitochondrial status of a group of HIV-infected children, some with body fat abnormalities (BFA). We included 24 controls, 16 HIV-infected untreated, 26 HIV-infected treated, 6 BFA-untreated, and 21 BFA-treated patients. Genetic, translational, and functional mitochondrial values were measured. As compared with controls, mitochondrial DNA depletion and a reduction in functionality were found in BFA groups. PMID- 21697768 TI - Angle measurement reproducibility using EOS three-dimensional reconstructions in adolescent idiopathic scoliosis treated by posterior instrumentation. AB - STUDY DESIGN: A reproducibility study was conducted in preoperative and postoperative three-dimensional (3D) measurements for patients operated for adolescent idiopathic scoliosis (AIS). OBJECTIVE: To assess the reliability of preoperative and postoperative 3D reconstructions using EOS in patients operated for AIS. SUMMARY OF BACKGROUND DATA: No prior reliability study of 3D measurements has been performed in the literature for severe scoliosis and for operated patients. METHODS: This series included 24 patients (62 degrees +/- 11) operated for Lenke 1 or 2 AIS, using either all-pedicle screw constructs (group 1) or hybrid constructs, with universal clamps at thoracic levels (group 2). All patients underwent low-dose standing biplanar radiographs, pre- and postoperatively. Three operators performed the 3D reconstruction process two times preoperatively and two times postoperatively (total 288 reconstructions). Intraoperator repeatability and interoperator reproducibility were calculated and compared between groups. RESULTS: The preoperative reproducibility was between 4 degrees and 6.5 degrees for parameters dedicated to scoliosis (Cobb and apical vertebral rotation), between 4 degrees and 7 degrees for kyphosis and lordosis values, and between 1 degrees and 5 degrees for pelvic measurements. The postoperative reproducibility was between 5 degrees and 8 degrees for values of kyphosis and lordosis, between 1 degrees and 5.5 degrees for pelvic parameters, and between 6.5 degrees and 10.5 degrees for the scoliotic parameters. The reproducibility of the scoliotic parameters was slightly better in the hybrid construct group, but the difference was not significant (P = 0.8). No difference was found between groups for the other parameters. CONCLUSION: 3D postoperative reconstructions are as reproducible as preoperative ones. The reproducibility is not influenced by the type of implant used for correction. Mean difference between operator was higher than previously reported for the apical rotation measurement, but this difference can be explained by the severity of the curves and the lower visibility of the anatomical landmarks due to the implants. PMID- 21697767 TI - In vivo intervertebral disc characterization using magnetic resonance spectroscopy and T1rho imaging: association with discography and Oswestry Disability Index and Short Form-36 Health Survey. AB - STUDY DESIGN: An in vivo study of intervertebral disc degeneration by using quantitative magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). OBJECTIVE: To quantify water and proteoglycan (PG) content in the intervertebral disc by using in vivo MRS and to evaluate the relationship between MRS-quantified water/PG content, T1rho, Pfirrmann score, clinical self assessment, and discography. SUMMARY OF BACKGROUND DATA: Previous in vitro studies have investigated the relationship between MRS-quantified water/PG content and degenerative grade by using cadaveric intervertebral discs. T1rho has been shown to relate to Pfirrmann grade and clinical self-assessment. However, the associations between MRS-quantified water/PG content, MRI-based T1rho, self assessment of health status, and clinical response to discography have not been studied in vivo. METHODS: MRS and MRI were performed in 26 patients (70 discs) with symptomatic intervertebral degenerative disc (IVDD) and 23 controls (41 discs). Patients underwent evaluation of intervertebral discs with provocative discography. All subjects completed the Short Form-36 Health Survey and Oswestry Disability Index questionnaires. RESULTS: The water/PG peak area ratio was significantly elevated in (a) patients (compared with controls) and in (b) discs with positive discography (compared with negative discography). Magnetic resonance (MR) T1rho exhibited similar trends. A significant association was found between T1rho and normalized PG content (R = 0.61, P < 0.05) but not between T1rho and normalized water content (R = 0.24, P > 0.05). The water/PG peak area ratio, normalized water, normalized PG, and Pfirrmann grade were significantly associated with patient self-assessment of disability and physical composite score, while disc height was not. CONCLUSION: This study demonstrated a relationship between in vivo MRS spectroscopy (water content and PG content), imaging parameters (T1rho and Pfirrmann grade), discography results, and clinical self-assessment, suggesting that MRS-quantified water, PG, and MR T1rho relaxation time may potentially serve as biomarkers of symptomatic IVDD. PMID- 21697769 TI - Investigation of dichotomizing sensory nerve fibers projecting to the lumbar multifidus muscles and intervertebral disc or facet joint or sacroiliac joint in rats. AB - STUDY DESIGN: Immunohistological analysis of dichotomizing sensory nerve fibers projecting to the lumbar multifidus muscles and intervertebral disc (IVD), facet joint (FJ), or sacroiliac joint (SIJ) in rats. OBJECTIVE: To elucidate dichotomizing sensory nerve fibers projecting to the lumbar multifidus muscles and to IVDs, FJs, or SIJs. SUMMARY OF BACKGROUND DATA: Clinically, the origin of low back pain remains unknown. Multiple studies have identified lumbar muscles, IVDs, FJs, and SIJs as sources of low back pain. Pain may originate directly from lumbar muscles or be referred from the spine, or both. Dorsal root ganglion (DRG) neurons with dichotomizing axons have been reported in several species and are thought to be related to referred pain. METHODS: We used 2 neurotracers, 1,1' dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) and fluorogold (FG), in this double-labeling study involving 30 Sprague Dawley rats. DiI was applied to lumbar multifidus muscles in all rats. Simultaneously, FG was applied to the anterior left portion of L5-L6 IVDs in the IVD group (n = 10), to the left L5-L6 FJs in the FJ group (n = 10), and to the left SIJs in the SIJ group (n = 10). Fourteen days after surgery, left DRGs from L1 to L6 were harvested, sectioned, and observed under a fluorescence microscope. RESULTS: We verified the existence of double-labeled DRG neurons (i.e., dichotomizing sensory nerve fibers) projecting to lumbar multifidus muscles and to IVDs, FJs, or SIJs, depending on the group. The proportion of double-labeled cells in all DiI-labeled DRG neurons was higher in the FJ group (6.8%) and SIJ group (7.1%) than in the IVD group (3.1%) (P < 0.05). CONCLUSION: Our results document the presence of dichotomizing sensory nerve fibers projecting to lumbar multifidus muscles and to IVDs, FJs, and SIJs. Referred low back muscle pain may reflect disorders of lumbar posterior structures, such as FJs and SIJs, rather than disorders of lumbar anterior structures, such as IVDs. PMID- 21697771 TI - Unknown case: part 1. PMID- 21697770 TI - Disparities in rates of spine surgery for degenerative spine disease between HIV infected and uninfected veterans. AB - STUDY DESIGN: Retrospective analysis of nationwide Veterans Health Administration clinical and administrative data. OBJECTIVE: Examine the association between HIV infection and the rate of spine surgery for degenerative spine disease. SUMMARY OF BACKGROUND DATA: Combination antiretroviral therapy has prolonged survival in HIV-infected patients, increasing the prevalence of chronic conditions such as degenerative spine disease that may require spine surgery. METHODS: We studied all HIV-infected patients under care in the Veterans Health Administration from 1996 to 2008 (n = 40,038) and uninfected comparator patients (n = 79,039) matched on age, sex, race, year, and geographic region. The primary outcome was spine surgery for degenerative spine disease, defined by International Classification of Diseases, Ninth Revision procedure and diagnosis codes. We used a multivariate Poisson regression to model spine surgery rates by HIV infection status, adjusting for factors that might affect suitability for surgery (demographics, year, comorbidities, body mass index, combination antiretroviral therapy, and laboratory values). RESULTS: Two hundred twenty-eight HIV-infected and 784 uninfected patients underwent spine surgery for degenerative spine disease during 700,731 patient-years of follow-up (1.44 surgeries per 1000 patient-years). The most common procedures were spinal decompression (50%) and decompression and fusion (33%); the most common surgical sites were the lumbosacral (50%) and cervical (40%) spine. Adjusted rates of surgery were lower for HIV-infected patients (0.86 per 1000 patient-years of follow-up) than for uninfected patients (1.41 per 1000 patient-years; incidence rate ratio 0.61, 95% confidence interval: 0.51-0.74, P < 0.001). Among HIV-infected patients, there was a trend toward lower rates of spine surgery in patients with detectable viral load levels (incidence rate ratio 0.76, 95% confidence interval: 0.55-1.05, P = 0.099). CONCLUSION: In the Veterans Health Administration, HIV-infected patients experience significantly reduced rates of surgery for degenerative spine disease. Possible explanations include disease prevalence, emphasis on treatment of nonspine HIV-related symptoms, surgical referral patterns, impact of HIV on surgery risk-benefit ratio, patient preferences, and surgeon bias. PMID- 21697772 TI - Statistical issues in the interpretation of Pearson et al's study of lumbar intervertebral measurements. PMID- 21697774 TI - Therapeutic efficacy of polyclonal tregs does not require rapamycin in a low-dose irradiation bone marrow transplantation model. AB - BACKGROUND: Mixed chimerism is an effective strategy for the induction of transplantation tolerance but the toxicity of recipient conditioning makes current bone marrow (BM) transplantation (BMT) protocols unsuitable for widespread clinical application. Therapies promoting BM engraftment under minimal conditioning would facilitate translation of this concept to the clinic. Recently, we have shown that regulatory T cell (Treg) therapy has potent engraftment-enhancing effects in an irradiation-free noncytotoxic BMT protocol, but only if it is combined with rapamycin treatment. METHODS: Here, we investigated whether polyclonal Treg therapy is effective in promoting chimerism and tolerance in an otherwise unsuccessful BMT protocol using low-dose total body irradiation (1 Gy) and costimulation blockade and determined whether Tregs do so on their own without rapamycin. RESULTS: The application of polyclonal FoxP3 transduced recipient Tregs led to durable multilineage chimerism and donor specific skin graft tolerance whereas recipients receiving costimulation blockade alone or green flourescent protein (GFP)-transduced cells failed to develop chimerism. Infused Tregs had a limited life span as indicated by polymerase chain reaction analysis but rather contribute to de novo induction of subsequent Treg generations. Deletion of donor-reactive T cells was observed but progressed more slowly over time compared with recipients of a nonmyeloablative BMT protocol using 3 Gy total body irradiation. CONCLUSIONS: In conclusion, Treg therapy promotes BM engraftment on its own in a low-dose irradiation BMT protocol, leading to chimerism and tolerance maintained through deletional and nondeletional mechanisms. PMID- 21697773 TI - Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study. AB - BACKGROUND: Benefits of conversion from calcineurin inhibitor (CNI) to mammalian target of rapamycin inhibitor-based immunosuppression in long-term kidney transplant patients remain uncertain. METHODS: ASCERTAIN was a 24-month, open label, multicenter study. Kidney transplant patients more than 6 months posttransplant receiving CNI (baseline glomerular filtration rate [GFR] 30-70 mL/min/1.73 m) were randomized to everolimus with CNI elimination (n=127) or CNI minimization (n=144), or continued CNI unchanged (controls, n=123) to assess the effect on measured GFR at month 24 after randomization. RESULTS: Renal function was stable in all groups to month 24. Mean measured GFR at month 24, the primary endpoint, was 48.0+/-22.0 mL/min/1.73 m, 46.6+/-21.1 mL/min/1.73 m, and 46.0+/ 20.4 mL/min/1.73 m in the CNI elimination, CNI minimization, and control groups, respectively. Differences between CNI elimination (1.12 mL/min/1.73 m, 95% confidence interval [CI] -3.51 to 5.76, P=0.63) and CNI minimization (0.59 mL/min/1.73 m, 95% CI -3.88 to 5.07, P=0.79) versus controls at month 24 were nonsignificant that is, the primary endpoint was not met. No efficacy endpoint differed significantly between groups. Post hoc analyses showed that patients with baseline creatinine clearance (CrCl) more than 50 mL/min had a significantly greater increase in measured GFR after CNI elimination versus controls (difference 11.4 mL/min/1.73 m, 95% CI 2.1 to 20.8 mL/min/1.73 m, P=0.017). Adverse events resulted in discontinuation in 36 (28.3%) CNI elimination patients, 24 (16.7%) CNI minimization patients, and 5 (4.1%) controls (P<0.001 vs. CNI elimination; P=0.020 vs. CNI minimization). CONCLUSION: Conversion to everolimus with CNI elimination or minimization a mean of 5.6 years after kidney transplantation had no overall renal benefit and was associated with more frequent adverse events and discontinuations. Patients with CrCl more than 50 mL/min may benefit from a change in therapy more than 6 months after renal transplantation. PMID- 21697775 TI - Synthesis of some novel pyrazolo[1,5-a]pyrimidine derivatives and their application as disperse dyes. AB - A series of novel monoazo-disperse dyes containing pyrazolo[1,5-a]pyrimidine structures were synthesized starting with the coupling reaction between ethyl cyanoacetate and 4-hydroxybenzenediazonium chloride, followed by treatment of the resulting hydrazone product with hydrazine hydrate. The pyrazolohydrazone 6 is then treated with either 2,4-pentandione and enaminonitrile or aryl-substituted enaminoketones to give the target pyrazolo[1,5-a]pyrimidine dyes 7 and 15a-d. Structural assignments to the dyes were made using NMR spectroscopic methods. A new high temperature method, using microwave heating, was employed to apply these dyes to polyester fibers. Most of the dyed fabrics tested displayed moderate light fastness and excellent washing fastness properties. PMID- 21697776 TI - Microwave-assisted solution-phase synthesis and DART-mass spectrometric monitoring of a combinatorial library of indolin-2,3-dione schiff bases with potential antimycobacterial activity. AB - A combinatorial library composed of eleven hydrazides A-K and eleven indolin-1,2 dione derivatives 1-11 has been designed to formally generate sublibraries of 22 mixtures, M(1)-M(22) comprising of 121 Schiff bases, A-K(1-11). The designed library has been synthesized by the solution-phase method and microwave-assisted synthetic techniques. The formation of individual compounds of each mixture was confirmed by Direct Analysis in Real Time (DART) as ionization technique connected to an Ion Trap as a mass detector. The synthesized mixtures were evaluated for their antimycobacterial activity against four Mycobacterium strains; M. intercellulari, M. xenopi, M. cheleneoi and M. smegmatis. Variable antimycobacterial activity was revealed with the investigated mixtures and maximum activity was shown by M(8), M(10), M(11), and M(15) with MIC values of 1.5, 3.1, 6.2 and 0.09 MUg/mL, respectively. Application of the indexed method of analysis on these active mixtures revealed that compounds D(8), D(10) and D(11) may contribute to the activity of the tested mixtures. PMID- 21697777 TI - Synthesis and characterization of (Z)-5-arylmethylidene-rhodanines with photosynthesis-inhibiting properties. AB - A series of rhodanine derivatives was prepared. The synthetic approach, analytical and spectroscopic data of all synthesized compounds are presented. Lipophilicity of all the discussed rhodanine derivatives was analyzed using the RP-HPLC method. The compounds were tested for their ability to inhibit photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts and reduce chlorophyll content in freshwater alga Chlorella vulgaris. Structure-activity relationships between the chemical structure, physical properties and biological activities of the evaluated compounds are discussed. For majority of the tested compounds the lipophilicity of the compound and not electronic properties of the R1 substituent were decisive for PET inhibiting activity. The most potent PET inhibitor was (5Z)-5-(4 bromobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (IC(50) = 3.0 MUmol/L) and the highest antialgal activity was exhibited by (5Z)-5-(4-chlorobenzylidene)-2-thioxo 1,3-thiazolidin-4-one (IC(50) = 1.3 MUmol/L). PMID- 21697778 TI - Maleimido-functionalized NOTA derivatives as bifunctional chelators for site specific radiolabeling. AB - Two basic and simple synthetic routes for mono- and bis-maleimide bearing 1,4,7 triazacyclononane-N,N',N''-triacetic acid (NOTA) chelators as new bifunctional chelators are described. The syntheses are characterized by their simplicity and short reaction times, as well as practical purification methods and acceptable to very good chemical yields. The usefulness of these two synthetic pathways is demonstrated by the preparation of a set of mono- and bis-maleimide functionalized NOTA derivatives. In conclusion, these two methods can easily be expanded to the syntheses of further tailored maleimide-NOTA chelators for diverse applications. PMID- 21697780 TI - Which is the best technique for CABG; OPCAB, on-pump arrest CABG or on-pump beating CABG? PMID- 21697781 TI - Treatment of T4 esophageal cancer. Definitive chemo-radiotherapy vs chemo radiotherapy followed by surgery. AB - The outcome of patients with T4 esophageal cancer, defined as a tumor that invades neighboring structures (e.g., aorta, trachea, bronchus, and lung), is extremely poor. Despite recent advances in surgical techniques, these tumors are usually considered inoperable. Two distinct therapeutic options are currently available for T4 esophageal cancers: chemo-radiotherapy followed by surgery (CRT S), which comprises esophagectomy following down-staging of the tumor by CRT, and definitive chemo-radiotherapy (D-CRT), which is designed to avoid esophagectomy by using maximum doses of irradiation. CRT-S is superior to D-CRT with respect to local control and short-term survival although CRT-S is associated with relatively higher perioperative mortality and morbidity. On the other hand, it is sometimes difficult to achieve local control with D-CRT and the treatment often results in fistula formation, though a complete response to CRT is often associated with better prognosis. Admittedly, the difference in the survival rate between the two modalities is marginal at long-term follow-up due to operative morbidity and inadequate control of distant metastasis in CRT-S. Changes in perioperative management and intensive systemic chemotherapy may enhance the outcome. Randomized controlled trials involving large population samples are needed to define the standard treatment for T4 esophageal cancer. PMID- 21697782 TI - Extent of lung resection in non-small lung cancer with interlobar lymph node involvement. AB - BACKGROUND: Optimal resection type for non-small cell lung cancer (NSCLC) with interlobar lymph node involvement (ILNI) has seldom been reported. To completely resect a NSCLC with ILNI, some surgeons believe that a pneumonectomy is needed. METHODS: We retrospectively studied 151 patients (147 men, 4 women; mean age 58 +/- 8 years, range 34-79) with non-small lung cancer without mediastinal or hilar lymph node metastasis who underwent an anatomic lung resection with systematic lymph node dissection between January 1995 and November 2006. All patients had involvement of the surgical-pathologic interlobar (#11) lymph node: 8 patients had a T1 tumor; 95, T2; 39, T3; and 9, T4. We evaluated the effect of resection type (pneumonectomy in 90 patients versus lobectomy in 61) on their prognosis by univariate and multivariate analyses. RESULTS: The 5-year survival rate of patients was 61% for the lobectomy and 35% for the pneumonectomy (p = 0.04). We did not find statistically significant differences in sex, median age, distributions of tumor site, histology and differentiation, complete resection rate, N1 involvement status, morbidity and mortality. Patients who underwent the pneumonectomy had larger tumors and more T3 tumors. The T status, multiple levels N1 involvement and histology did not affect survival in the univariate analysis. Multivariate analysis revealed resection type as a significant prognostic factor. CONCLUSIONS: Pneumonectomy was not necessary in patients with NSCLC and interlobar lymph node involvement that we had discovered intraoperatively. PMID- 21697783 TI - Efficacy of convex probe endobronchial ultrasound (CP-EBUS) assisted transbronchial needle aspiration for mediastinal staging in non-small cell lung cancer cases with mediastinal lymphadenopathy. AB - BACKGROUND AND OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a sampling method for the patients with non-small cell lung cancer (NSCLC) that have enlarged mediastinal lymph nodes that are detected with computed tomography (CT). We aimed to investigate the value of EBUS-TBNA in sampling enlarged mediastinal lymph nodes in the patient with NSCLC. PATIENTS AND METHOD: From January 2007 to May 2009, patients were diagnosed NSCLC with CT scans showing enlarged lymph nodes (node >1 cm) or a positron emission tomography (PET/CT) finding of the mediastinum underwent EBUS-TBNA. RESULTS: EBUS-TBNA was successfully performed in all 52 patients (mean age, 52 years; 45 men) from 93 mediastinal lymph nodes. EBUS detected lymph node metastasis in 40 patients (77%). 12 patients (23%) with negative lymph node samples were underwent mediastinoscopy. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EBUS-TBNA in the detection of mediastinal metastasis were 95 %, 100%, 100%, 83%, and 96%, respectively. EBUS TBNA was uneventful, and there were no complications. CONCLUSION: EBUS-TBNA is an effective, safe and minimally invasive procedure following PET/CT or CT scanning in the mediastinal staging of potentially operable NSCLC. PMID- 21697784 TI - Improving survival results after surgical management of malignant pleural mesothelioma: an Australian institution experience. AB - BACKGROUND: There has been an evolving role of surgery for malignant pleural mesothelioma (MPM) over the past 25 years. The objective of this study was to investigate whether the survival results for MPM patients after surgery have improved within this time period by an analysis of a prospective cohort of 540 patients. METHODS: Five hundred and forty consecutive patients with MPM were treated by a thoracic surgical team. These patients were categorized into two groups: Group I (before September 1999, n = 270) and Group II (after September 1999, n = 270). The two groups were compared for clinicopathologic data and survival results. The statistical analyses of all prognostic parameters used overall survival as the endpoint. RESULTS: Group II had higher proportions of epithelial tumors and patients who had preoperative PET scan, extrapleural pneumonectomy (EPP), postoperative radiotherapy and pemetrexed chemotherapy. The overall survival results were significantly better in Group II compared with Group I (p = 0.004). Four factors were found to be independently associated with an improved survival in multivariate analysis: epithelial subtype (p <0.001); surgeon's experience with >100 cases (p = 0.006), patients who underwent EPP (p = 0.001) and those who received pemetrexed chemotherapy (p = 0.016). The median survival for patients selected for EPP was 20 months, as compared to 9 months for pleurodesis/decortication and pleurodesis. CONCLUSIONS: Significant improvement of overall survival results has been achieved in the more recent 270 MPM patients through accumulated experience in a specialist treatment center. PMID- 21697785 TI - When is transthoracic approach indicated in retrosternal goiters? AB - PURPOSE: It is critical to differentiate among pathologies of substernal thyroid gland diseases because surgical approaches (i.e., median sternotomy or thoracotomy) might also include a cervical incision. The aim of this study was to analyze the features of patients with goiter who underwent a thyroidectomy via a cervical incision and a median sternotomy or thoracotomy. METHODS: We reviewed 9 cases of thyroid disease in patients undergoing thoracic incisions with or without a cervical incision for varying indications between March 2003 and Jun 2009 were reviewed. Thyroidal masses were removed via a median sternotomy in six patients and thoracotomy in three patients. Split median sternotomy combining thoracotomy was performed in 1 patient. Cervical incision was added in all patients. RESULTS: Pathologic examination revealed multinodular goiter in 5 patients, thyroid carcinoma in 3, and reidel thyroiditis in 1. All patients were extubated in the early postoperative period. There was no postoperative mortality or morbidity. The mean hospital stay was 8.6 days (range, 4-11 days), and mean follow-up was 24.3 months (range, 4-39 months). CONCLUSIONS: We recommend the use of transthoracic approaches, such as median sternotomy and thoracotomy for retrosternal goiter for surgical exposure, because they provide a wide exposure and facilitate removal of the mass. By using median sternotomy and thoracotomy, we can avoid catastrophic results, such as hemorrhage, as well as completely remove malignancies. PMID- 21697786 TI - Surgical treatment of achalasia: transabdominal versus transthoracic cardiomyotomy. AB - BACKGROUND: Achalasia is a primary esophageal motor disorder involving the body of the esophagus and lower esophageal sphincter. The mechanism is destruction of the myenteric plexus after a viral infection. Multiple methods of treatment with variable results induced in achalasia. MATERIALS AND METHODS: We analyzed 70 patients with achalasia that underwent surgical treatment with transabdominal or transthoracic cardiomyotomy from 1982 to 2008 in Mashhad (Ghaem and Omid) hospital and at least 2 years follow up for evaluated result of surgery. RESULTS: The mean age was 39.2 +/- 9.42 years and the M/F = 0.89. The most common symptom was dysphagia (100%). The interval between beginnings of symptoms to a definitive diagnosis was 10.6 +/- 8.3 month. The ratio between the two techniques was 35/35 = 1. In 67.1% of patients, a previous history of pneumatic dilation was reported. Long-term good results after surgery were seen in 77.2% of patients. Recurrence after surgical treatment was seen in 22.8%. A comparison of the two techniques (with or without antireflux surgery), showed a greater failure rate in transabdominal cardiomyotomy without the antireflux protocol (8/15 = 40%), but by the chi- square test, the difference was not statistically significant (P = 0.107). The most common complication after surgery was esophageal leakage (2.85%), and mortality was zero. In recurrence, most patients underwent pneumatic dilation (9/16 = 56.2%), and if surgery was needed, all patients underwent a transthoracic approach with antireflux treatment. CONCLUSION: Based on the good, long-term results with the surgical treatment of achalasia, surgery is recommended in most patients. A transthoracic or transabdominal approach had good, long-term results, but a transthoracic approach had better results and usually did not need antireflux surgery. PMID- 21697787 TI - In vitro evaluation of the effect of cardiac surgery on cancer cell proliferation. AB - OBJECTIVE: Operative stress of cardiovascular surgery can alter the blood levels of various physiologically active substances (e.g., cytokines, growth factors), and thus potentially affect cancer cell proliferation. How the combination of changes in blood levels of these substances affects cancer cells has not been adequately addressed. We investigated the stimulatory capacity on cancer cells of serum from patients after cardiovascular surgery, using a novel in vitro assay method. METHODS: The subjects were 22 patients undergoing cardiovascular surgery, consisting of 11 off-pump and 11 on-pump procedures. Blood was sampled from each subject immediately before surgery, immediately after surgery, and after transfer to the intensive care unit. Human lung cancer cells were exposed to the serum of each blood sample from each patient, and an MTT assay was conducted to evaluate cell proliferation. RESULTS: Serum samples of all patients showed an inhibitory effect for lung cancer cell proliferation. This inhibitory effect was lower in postoperative serum compared with serum samples before surgery. As a result, lung cancer cell proliferation was better with postoperative serum samples than preoperative serum samples. The proliferation rate after surgery, when it was compared with preoperative serum, was significantly higher in patients with on pump procedures than in patients with off-pump procedures. CONCLUSION: The results of this study suggest that the operative stress of cardiovascular surgery induces changes in serum to make it less inhibitory for the cancer cell proliferation. This phenomenon is greater in patients with extracorporeal circulation. PMID- 21697788 TI - Coronary artery bypass grafting for acute myocardial infarction in stent ERA. AB - PURPOSE: We evaluated a treatment strategy for acute myocardial infarction (AMI) that percutaneous coronary intervention (PCI) is performed on a culprit lesion unless the culprit is an unprotected left main trunk. Emergent coronary artery bypass grafting (CABG) is done when the culprit is a left main trunk and a mechanical complication exists. METHODS: From 1997 to 2008, 22 and 232 patients underwent CABG for AMI and non-AMI, respectively. Of the 22 patients of AMI, PCI was performed in 12 patients and not performed in 10 patients before surgery. We investigated complication, intubation period, in-hospital mortality and hospitalization period. RESULTS: No in-hospital mortality was observed in all 22 AMI patients. There was no difference in in-hospital mortality and complication between the AMI and the non-AMI patients. No significant difference was found in hospital stay, complication, intubation period, in-hospital mortality and hospitalization period between patients who received preceding PCI and not. CONCLUSIONS: These results suggest that our treatment strategy is reasonable. Further studies will be warranted to clarify the role of preceding PCI. PMID- 21697789 TI - A hybrid approach to cardiac resynchronization therapy. AB - BACKGROUND: CRT (atrial-synchronized bi-ventricular pacing) has been shown to significantly improve the quality of life and exercise tolerance in patients with moderate-severe heart failure and an interventricular conduction delay (>120 msec) when compared to controls. Traditionally it has been performed by cardiologists in electrophysiology laboratories. In the event that the left ventricular lead cannot be positioned percutaneously the procedure is aborted and the cardiac surgeon consulted. The subsequent intervention by the surgeon, typically on another day, requires reexploration of the pocket, a thoracotomy, which results in an increase in length of stay (LOS), and an increase in infection risk. The objective of this study was to demonstrate that CRT could routinely be performed in a surgical operating room (OR) as a single rather than a staged procedure. METHODS: Between 1/1/06 and 7/1/06 18 patients (17 male and 1 female) with an average age of 56 years (range 36-79) underwent CRT. Transthoracic echo (TTE) revealed that all had left ventricular ejection fractions (LVEF) <30% (range 8%-28%). Five of the 18 had moderate-severe mitral regurgitation (MR). The etiology of the cardiomyopathies was ischemia in 4 and non-ischemia in 14. All had QRS intervals >120 msec (range 120-200 msec) and all were maintained preoperatively on their conventional therapy for heart failure (B blockers, +/- diuretic, +/- ACE-I or ARB) and all were either New York Heart Association (NYHA) functional class III or IV. Every case was performed under general anesthesia with an arterial line and Foley catheter in the semi right lateral decubitous position. Nine of the 18 patients underwent a left anterolateral mini-thoracotomy for epicardial left ventricular (LV) lead placement. All hardware included defibrillation technology (ICD). RESULTS: All 18 patients left the OR with successful bi-ventricular pacing in an average time of 170 minutes (range 140-200 min). The average epicardial lead pacing threshold was 0.9v (range 0.4-1.5v) while the average endocardial (transvenous) threshold was 0.4v (range 0.2-0.7v) at a pulse width of 0.5 msec. TTE at 1 month demonstrated an improvement in LVEF in 14/18 patients with an average increase of 5% (range 2% 9%). Four of the 5 patients with moderate-severe MR were reduced to mild. The average length of stay (LOS) following the procedure, in those patients who did not undergo a thoracotomy, was 4 days (range 3-6 days) while it was 7 days (range 6-10 days) in those who underwent a thoracotomy. CONCLUSION: These data clearly indicate that CRT can be successfully performed as a single-staged procedure in a cardiac OR. Although transvenous LV lead placement avoids a thoracotomy, the epicardial LV lead thresholds, in this series, are competitive with the transvenous results. We propose that in the spirit of cost containment, fee bundling, decreasing reimbursement, pay-for-performance, and infection control, these complex interventions should be performed in multipurpose interdisciplinary hybrid cardiac OR's, now available in most major medical centers, with designated time limitations and role assignments. PMID- 21697790 TI - Cystatin C in diabetics as a marker of mild renal insufficiency after CABG. AB - PURPOSE: The purpose of this study was to evaluate the accuracy of plasma cystatin C in acute impairment in renal function; plasma cystatin C was compared to plasma creatinine in two hundred patients undergoing elective CABG surgery. METHODS: We performed a prospective clinical study of two hundred patients undergoing coronary bypass surgery. Plasma creatinine and cystatin C were measured preoperatively and on the first and fourth days after surgery. Estimated glomerular filtration rate (GFR) was calculated using one creatinine-based and two cystatin C-based equations. RESULTS: There were 144 non-diabetic and 56 diabetic patients. The need for furosemide was more common among diabetics (80.4% of the patients vs. 53.9%, p = 0.024). Changes in cystatin C-based GFR with both equations were significantly greater in the group of diabetics (-14.3 +/- 28.0 and -11.2 +/- 19.3 ml/min/1.73 m(2) vs. -4.3 +/- 26.9 and -3.1 +/- 20.5 ml/min/1.73 m(2), p = 0.025 and 0.016, respectively). Changes in creatinine-based GFR did not differ between the diabetics and the non-diabetics. CONCLUSION: Cystatin C and cystatin C-based estimation of GFR may be useful and more sensitive than creatinine in detecting mild acute renal insufficiency in diabetic patients. PMID- 21697791 TI - Pleomorphic adenoma of the subglottis mistreated as chronic obstructive pulmonary disease, report of a case. AB - Upper airway obstruction due to subglottic mass can be misdiagnosed. We report the case of a 66-year-old man who was treated for chronic obstructive pulmonary disease (COPD) before a diagnosis of pleomorphic adenoma of the subglottis was made. According to the history of chronic cough and exertional dyspnea, he was treated with inhaled corticosteroids for COPD. Bronchoscopy and computed tomography (CT) revealed a mass occupying the subglottic cavity. After the excision operation, all symptoms disappeared. Histological evaluation revealed the diagnosis of pleomorphic adenoma. This case report emphasizes that not all chronic cough and dyspnea are attributable to COPD. PMID- 21697792 TI - Reoperation for mid-term failure of a freestyle bioprosthesis using a full root technique --a surgical case--. AB - The aortic root of a 30-year-old man was replaced with a Freestyle stentless aortic bioprosthesis for aortic regurgitation associated with annuloaortic ectasia. His clinical course was uneventful, and he was discharged without complications. Three years and six months after surgery, he presented with a high fever. Four years after surgery, transthoracic echocardiography revealed severe aortic regurgitation. We performed exploratory surgery and discovered a torn left coronary cusp of the Freestyle bioprosthesis. Organized vegetation was adherent to the left coronary cusp leaflet. The non-coronary cusp and the right coronary cusp were normal. The diagnosis was aortic regurgitation due to valve failure related to infective endocarditis. Consequently, we reconstructed the aortic root with a composite graft (26-mm Valsalva graft and a 21-mm ON-X mechanical valve). PMID- 21697793 TI - A case of diffused malignant pleural mesothelioma forming small multiple disseminations with intraoperatively suspicious carcinoid tumors. AB - A 65-year-old male, having symptoms suggestive of pulmonary malignant tumor, underwent video-assisted thoracic surgery (VATS). Surgery revealed a solid tumor originating from the thoracic wall, with many small solid tumors in the thoracic wall and diaphragm near the tumor. The intraoperative observation of a frozen section typed the tumor as carcinoid; however, hematoxylin-eosin staining and immunohistological findings provided the definitive diagnosis of diffused, malignant pleural mesothelioma (MPM). PMID- 21697794 TI - Solitary fibrous tumor of the pleura suddenly induced hypoglycemia before surgical treatment. AB - We present a case of a solitary fibrous tumor of the pleura with sudden onset, recurrent hypoglycemia. A 76-year-old smoking male with type-II diabetes mellitus admitted to our hospital for dyspnea and general malaise. Radiological findings revealed a large tumor occupying the right hemithorax. After bronchoscopic examination, the patient developed a fever and began to wheeze. Treatment with antibiotics and several other drugs improved his symptoms. Percutaneous needle biopsy confirmed the diagnosis. After these medical interventions, the patient suddenly developed recurrent hypoglycemia. After the right pneumonectomy, the patient never experienced hypoglycemia again. We should consider the possible relation between hypoglycemia and solitary fibrous tumor of the pleura, even when the patient is not hypoglycemic during the initial examination. PMID- 21697795 TI - Example of evoked potential monitoring for a neurogenic tumor positioned high in the mediastinum. AB - Excision of a neurogenic tumor of the brachial plexus positioned high in the mediastinal space could potentially result in a functional disorder of the arm. We report on a case in which we performed evoked potential monitoring on a tumor located high in the mediastinum. We found large potential changes in the median and ulnar nerve areas and had a concern that the excision might injure the brachial plexus. We did a biopsy and intraoperative rapid histological diagnosis, which promptly revealed that the tumor was not malignant. Thus, we decided not to excise the tumor because the procedure could possibly injure nerves in the arm. PMID- 21697796 TI - Spontaneous hemothorax associated with von Recklinghausen's disease: report of a case. AB - A 59-year-old woman with a history of von Recklinghausen's disease (VRD) suffered sudden chest pain. Enhanced chest computed tomography showed massive hemothorax, but no evidence of tumors or an obvious bleeding point in the thorax. After we had ensured a stable hemodynamic condition, we performed video-assisted thoracic surgery to remove the hematoma. The bleeding point was in a branch of the right subclavian artery. We performed direct surgical ligation of the bleeding vessel with a fibrin tissue-adhesive collagen fleece. Recovery was uneventful, and the patient is now doing well with no evidence of re-bleeding, 12 months postoperatively. Spontaneous hemothorax in patients with von Recklinghausen's disease represents a critical event, and exploratory video-assisted thoracic surgery appears useful in the removal of clotted blood and reinforcement of fragile arteries for the prevention of re-bleeding. We should recognize this rare and critical condition in patients with von Recklinghausen's disease. PMID- 21697797 TI - Dual-phase FDG-PET imaging shows suspected malignancy that histological examination later confirmed as sclerosing mediastinitis: report of a case. AB - Sclerosing mediastinitis is a rare, benign disorder that is often indistinguishable from malignancy by conventional imaging techniques. The value of fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in the diagnosis of this disorder has not been elucidated. Recently, a few studies have reported the use of dual-phase FDG-PET imaging in the diagnosis of malignancies. The dual phase contains early- and late- phase images. The maximum standard uptake value (SUVmax) of late phase images of malignant lesions tends to be higher than those of early phase images. The present case showed that early-phase SUVmax was 5.93, and late phase, 8.92. We strongly suspected malignancy from the results of this new imaging technique, though the histological examination of the surgical samples provided the definitive diagnosis of sclerosing mediastinitis, Flieder stage II. This report describes the uncommon use of dual-phase FDG-PET computed tomography in the preliminary diagnosis of sclerosing mediastinitis. It is thought that current imaging studies are insufficient for the diagnosis of sclerosing mediastinitis, and the rarity of this disorder may prevent the development of imaging techniques. Histological confirmation is still essential for the definitive diagnosis of this disorder. PMID- 21697798 TI - Postoperative elongation of the xiphoid process --report of a case--. AB - We report a case of a 66-year-old man who presented with an abnormal sensation, tenderness, and pain in the middle of his chest in May 2006, two years after a mitral valve replacement for severe mitral regurgitation and a MAZE operation for chronic atrial fibrillation elective cardiac. He was immediately admitted, and the x-ray examination revealed an abnormal elongation of the xiphoid process. At the time of discharge after the initial operation in 2004, x-rays indicated that the length of the xiphoid process was 3 cm; however, in 2006 it had elongated to 6 cm and was prominent in the anterior view. The patient underwent surgical extirpation of the xiphoid process while he was under local anesthesia. Histological examination of the resected xiphoid process revealed no signs of neoplastic or maligant change. The cause of the elongation of the xiphoid process was believed to be distraction tissue neogenesis. The xiphoid process, which fractured and separated from the sternum at the initial operation, was pulled down inferiorly by the rectus abdominis muscles, following which the xiphoid process became elongated and reconnected with the sternum. In cases of a fractured or amputated xiphoid process after median sternotomy, the xiphoid process should be resected to avoid its neogenesis. PMID- 21697799 TI - Inter-aorta-caval located tumor: a case report. AB - A paraganglioma is a rare tumor that develops out of extra-adrenal chromaffin cells and pheochromocytomas originating from the adrenal medulla. Early diagnosis and surgical planning are crucial, since the tumor secretes catecholamine and is adjacent to large vessels in the abdomen. Furthermore, since complete resection improves the prognosis, we recommend a meticulous surgical technique. Here, we present a case of paraganglioma in a 32-year-old male patient who initially presented with a stomachache. After conducting the required tests, we resected the tumor that was pressing against the vena cava in the interaortocaval region. PMID- 21697800 TI - Infection of pacemaker lead by penicillin-resistant Streptococcus Pneumoniae. AB - Penicillin-resistant Streptococcus pneumoniae (PRSP) infections have steadily increased worldwide; however, there are only a few reports of permanent pacemaker related infections caused by PRSP. Here, we describe a patient who developed 7 episodes of endocarditis and sepsis from PRSP infection of the pacemaker lead in the right atrium. By periodic administration of vancomycin and extraction of both leads, we resolved the infection. PMID- 21697801 TI - Aortic valve replacement and graft replacement of the ascending aorta using deep hypothermic circulatory arrest in a patient with myelodysplastic syndrome. AB - A 73-year-old woman with a 10-year history of myelodysplastic syndrome (MDS) had severe aortic regurgitation (AR) and an ascending thoracic aortic aneurysm (TAA) with a maximum diameter of 55 mm. By retrograde cerebral perfusion (RCP) in the patient under deep hypothermic circulatory arrest (DHCA), we replaced the ascending aorta graft and aortic valve. After surgery, we periodically administered granulocyte colony-stimulating factor (GCSF) with platelet aggregation. On postoperative day 20, the patient had a duodenal ulcer. On postoperative day 22, she had a subarachnoid hemorrhage, which was treated, nonoperatively, with a hemostatic agent. On postoperative day 126, she was discharged without sequelae, and 1.5 years after the surgery, she has had neither heart failure nor deterioration of MDS. PMID- 21697802 TI - Totally arterial off-pump coronary artery bypass grafting after pneumonectomy. AB - We report the case of an 82-year-old man who underwent triple coronary artery bypass grafting with arterial grafts, who 20 years previously underwent left pneumonectomy for lung cancer. Computed tomography (CT) presented a marked shift of the heart and great vessels into the left hemithorax. Off-pump coronary artery bypass grafting was performed through a left thoracotomy, in which the left internal thoracic, right gastroepiploic, and radial arteries were used. He was extubated 1 hour post-operatively and had an uneventful recovery. PMID- 21697803 TI - Pseudoaneurysm of ascending aorta 16 years after coronary artery bypass grafting. AB - Pseudoaneurysm of the ascending aorta after cardiac surgery is a rare but life threatening complication, which can result in rupture. Pseudoaneurysms are usually related to the aortic cannulation, the proximal site of graft anastomosis, or the suture line of aortotomy, and often occur after mediastinal infection. We report a case of pseudoaneurysm of the ascending aorta associated with aortic cannulation and the proximal anastomosis of a saphenous vein graft without an obvious history of mediastinal infection. PMID- 21697804 TI - Results of the Expanded HIV Testing Initiative--25 jurisdictions, United States, 2007-2010. AB - Approximately 20% of the estimated 1.2 million persons living with human immunodeficiency virus (HIV) infection in the United States at the end of 2008 were not aware of their infection. Testing, diagnosis, medical care, treatment with highly active antiretroviral therapy (HAART), and access to prevention services soon after HIV infection can prevent morbidity and mortality and reduce a person's risk for transmitting HIV. In 2006, CDC recommended screening patients aged 13--64 years for HIV infection in health-care settings that have a prevalence of undiagnosed HIV infection of >=0.1%. In October 2007, CDC initiated the Expanded HIV Testing Initiative (ETI), through which it funded 25 health departments to facilitate HIV screening and increase diagnoses of HIV infections and linkage to care among populations disproportionately affected by HIV, especially non-Hispanic blacks. This report describes the results of that effort. Annual progress reports designed to provide data specific to ETI indicated that 2,786,739 HIV tests were conducted, of which 29,503 (1.1%) were positive and 18,432 (0.7%) resulted in new HIV diagnoses. Blacks accounted for 1,411,780 (60%) of tests and 11,638 (70%) of new HIV diagnoses. Clinical settings comprised at least 75% of the 1,331 testing venues and accounted for 90% of all tests and 81% of all new HIV diagnoses. Based on follow-up data available for 16,885 persons with new HIV diagnoses, 12,711 (75.3%) were linked successfully to HIV primary care. Through expanded HIV testing activities, substantial numbers of persons previously unaware of their HIV infection were identified and linked to care. Health departments should continue to partner with clinical-care providers to provide routine HIV screening, especially in populations disproportionately affected by HIV. PMID- 21697805 TI - HIV screening of male inmates during prison intake medical evaluation- Washington, 2006-2010. AB - Since 2006, CDC has recommended routine, opt-out human immunodeficiency virus (HIV) screening for patients in health-care settings with a prevalence of undiagnosed HIV infection of >=0.1%. Before September 2007, the Washington State Department of Corrections (WADOC) only provided HIV testing to inmates on request. In September 2007, WADOC began routine HIV opt-in screening in which inmates were notified that HIV screening would be performed during the prison intake medical evaluation if they consented. In March 2010, WADOC switched to a routine opt-out HIV screening model in which inmates are notified that HIV screening will be performed unless they decline. To assess the proportion of inmates screened and the number of infections diagnosed during the use of the three HIV testing policies, WADOC reviewed HIV testing data for male inmates undergoing intake medical evaluation during January 2006--December 2010. From January 1, 2006, to August 31, 2007, 5% of 12,202 incoming inmates were tested for HIV at their request during the intake medical evaluation, and three (0.50%) of those tested had newly diagnosed HIV infection. From September 1, 2007, to March 15, 2010, 72% of 16,908 inmates agreed to opt-in HIV screening, and 13 (0.11%) tested positive for HIV. From March 16, 2010, to December 31, 2010, 90% of 5,168 inmates agreed to opt-out HIV screening, and six (0.13%) tested positive for HIV. Compared with routine opt-in HIV screening, opt-out HIV screening was associated with a greater proportion of inmates tested, without decreasing the rate of case detection. PMID- 21697806 TI - Ten great public health achievements--worldwide, 2001-2010. AB - Worldwide, a child born in 1955 had an average life expectancy at birth of only 48 years. By 2000, the average life expectancy at birth had increased to 66 years and, if past trends continue, is projected to rise to 73 years by 2025. These improvements in longevity have resulted from improved living conditions overall, advances in medical science, and a number of population-level interventions. However, major disparities persist. During the past decade, in low-income countries, average life expectancy at birth increased from 55 to 57 years (3.6%), while increasing from 78 to 80 years (2.6%) in high-income countries. Analogous to the recent MMWR report highlighting 10 public health achievements that occurred in the United States over the first 10 years of the new century, this report describes global public health achievements during the same period. Experts in global public health were asked to nominate noteworthy public health achievements that occurred outside of the United States during 2001-2010. From them, 10 have been summarized in this report. As with the previous report, the 10 global public health achievements are not ranked in any order. Additional information regarding these achievements is available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6019a5_addinfo.htm. PMID- 21697807 TI - Phosphoproteomic analysis of AT1 receptor-mediated signaling responses in proximal tubules of angiotensin II-induced hypertensive rats. AB - The signaling mechanisms underlying the effects of angiotensin II in proximal tubules of the kidney are not completely understood. Here we measured signal protein phosphorylation in isolated proximal tubules using pathway-specific proteomic analysis in rats continuously infused with pressor or non-pressor doses of angiotensin II over a 2-week period. Of the 38 phosphoproteins profiled, 14 were significantly altered by the pressor dose. This included increased phosphorylation of the protein kinase C isoenzymes, PKCalpha and PKCbetaII, and the glycogen synthase kinases, GSK3alpha and GSK3beta. Phosphorylation of the cAMP-response element binding protein 1 and PKCdelta were decreased, whereas PKCE remained unchanged. By contrast, the phosphorylation of only seven proteins was altered by the non-pressor dose, which increased that of PKCalpha, PKCdelta, and GSKalpha. Phosphorylation of MAP kinases, ERK1/2, was not increased in proximal tubules in vivo by the pressor dose, but was in proximal tubule cells in vitro. Infusion of the pressor dose decreased, whereas the non-pressor dose of angiotensin II increased the phosphorylation of the sodium and hydrogen exchanger 3 (NHE-3) in membrane fractions of proximal tubules. Losartan largely blocked the signaling responses induced by the pressor dose. Thus, PKCalpha and PKCbetaII, GSK3alpha and GSK3beta, and cAMP-dependent signaling pathways may have important roles in regulating proximal tubular sodium and fluid transport in Ang II-induced hypertensive rats. PMID- 21697808 TI - Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy. AB - Transplant glomerulopathy (TG) has received much attention in recent years as a symptom of chronic humoral rejection; however, many cases lack C4d deposition and/or circulating donor-specific antibodies (DSAs). To determine the contribution of other causes, we studied 209 consecutive renal allograft indication biopsies for chronic allograft dysfunction, of which 25 met the pathological criteria of TG. Three partially overlapping etiologies accounted for 21 (84%) cases: C4d-positive (48%), hepatitis C-positive (36%), and thrombotic microangiopathy (TMA)-positive (32%) TG. The majority of patients with confirmed TMA were also hepatitis C positive, and the majority of hepatitis C-positive patients had TMA. DSAs were significantly associated with C4d-positive but not with hepatitis C-positive TG. The prevalence of hepatitis C was significantly higher in the TG group than in 29 control patients. Within the TG cohort, those who were hepatitis C-positive developed allograft failure significantly earlier than hepatitis C-negative patients. Thus, TG is not a specific diagnosis but a pattern of pathological injury involving three major overlapping pathways. It is important to distinguish these mechanisms, as they may have different prognostic and therapeutic implications. PMID- 21697809 TI - Pattern of resistance to erythropoietin-stimulating agents in chronic kidney disease. AB - Routine administration of erythropoietin (EPO)-stimulating agents (ESAs) for the control of anemia has improved the quality of life of subjects with chronic kidney disease (CKD). However, a wide variation in individual response to ESA is often observed. The reasons for EPO resistance include demographic variables such as age and gender distribution, morbidity pattern, and modality of dialysis. Despite suggestions by observational data, there is no biological characteristic that puts children at a disadvantage for adequate response to ESA. On the contrary, children possess a superior capacity for red cell production, including extramedullary erythropoiesis. The reasons for larger requirement of ESA in children (than in adults) are greater inflammatory burden, disproportionate blood loss, and greater EPO dosing by pediatric physicians. To minimize the harmful (including fatal) consequences of EPO resistance, surveillance programs must replenish nutrient (for example, iron and folate) stores, minimize oxidative hemolysis, control hyperparathyroidism, avoid catheter infection, and optimize uremic clearance. This clinical approach is justified by the inadequacy of laboratory diagnosis of pertinent etiological factors. Indeed, the best proof for functional nutrient deficiency is often a therapeutic trial. Finally, there are upcoming therapeutic agents that exploit the capacity for an endogenous EPO synthesis in CKD subjects, and may therefore minimize the off-target effect of excess dosages. PMID- 21697810 TI - Novel inflammatory mechanisms of accelerated atherosclerosis in kidney disease. AB - A substantial body of evidence has accumulated linking an increased incidence of cardiovascular disease in patients with acute kidney injury (AKI), chronic kidney disease (CKD), and end-stage renal disease (ESRD). A multitude of novel risk factors related to decreased kidney function might interact with the renal and systemic immune systems involved in renal injury and repair to participate in accelerated atherogenesis (Immune inflammation-Renal injury-Atherosclerosis--the IRA Paradigm). In this review, we will discuss several of these novel risk factors and present the potential for the role of the immune-inflammatory system in accelerated atherosclerosis of kidney disease. PMID- 21697811 TI - High doses of epoetin do not lower mortality and cardiovascular risk among elderly hemodialysis patients with diabetes. AB - A randomized trial had suggested that high doses of erythropoiesis-stimulating agents (ESAs) might increase the risk of cardiovascular outcomes in predialysis diabetic patients. To evaluate this risk in diabetic patients receiving dialysis, we used data from 35,593 elderly Medicare patients on hemodialysis in the US Renal Data System of whom 19,034 were diabetic. A pooled logistic model was used to estimate the monthly probability of mortality and a composite cardiovascular end point. Inverse probability weighting was used to adjust for measured time dependent confounding by indication, estimated separately for diabetic and non diabetic cohorts. The adjusted 9-month mortality risk, significantly different between an ESA dose of 45,000 and 15,000 U/week, was 13% among diabetics and 5% among non-diabetics. In diabetic patients, the hazard ratio (HR) for more than 40,000 U/week was 1.32 for all-cause mortality and 1.26 for a composite end point of death and cardiovascular events compared with patients receiving 20,000 to 30,000 U/week. The corresponding HRs in non-diabetic patients were 1.06 and 1.10, respectively. A smaller effect of dose was found in non-diabetic patients. Thus, higher ESA doses, which are often necessary to achieve high hemoglobin levels, are not beneficial, and possibly harmful, to diabetic patients receiving dialysis. Our findings support a Food and Drug Administration advisory recommending that the lowest possible ESA dose be used to treat hemodialysis patients. PMID- 21697812 TI - Olfactory function improves following hemodialysis. AB - Olfactory function has been shown to be affected in chronic kidney disease; however, studies are contradictory and little is known on the effects of dialysis. To resolve these issues we tested olfactory function in 24 healthy controls and in 28 patients with chronic kidney disease receiving hemodialysis (20 patients) or peritoneal dialysis (the other 8). As assays for olfactory function we measured smell identification, n-butanol and acetic acid thresholds, Kt/V urea, percentage reduced urea, and weights before and after dialysis. Olfactory function was also self-rated by the participants. Compared to healthy controls, predialysis olfactory function was moderately but significantly decreased in the two dialysis groups, with hemodialysis patients being more affected. Patients self-rated olfactory function similar to that of healthy controls, suggesting that patients are unaware of the olfactory decrease. Olfactory function was significantly improved by one hemodialysis session. Neither body mass index, total volume loss, nor any other dialysis parameter correlated with olfactory function or its restitution following hemodialysis. The observed pattern of improvement suggests underlying mixed peripheral and central mechanisms. Thus, olfactory dysfunction in patients with chronic kidney disease is readily reversible by hemodialysis. PMID- 21697813 TI - Exome sequencing identified MYO1E and NEIL1 as candidate genes for human autosomal recessive steroid-resistant nephrotic syndrome. AB - To identify gene loci associated with steroid-resistant nephrotic syndrome (SRNS), we utilized homozygosity mapping and exome sequencing in a consanguineous pedigree with three affected siblings. High-density genotyping identified three segments of homozygosity spanning 33.6 Mb on chromosomes 5, 10, and 15 containing 296 candidate genes. Exome sequencing identified two homozygous missense variants within the chromosome 15 segment; an A159P substitution in myosin 1E (MYO1E), encoding a podocyte cytoskeletal protein; and an E181K substitution in nei endonuclease VIII-like 1 (NEIL1), encoding a base-excision DNA repair enzyme. Both variants disrupt highly conserved protein sequences and were absent in public databases, 247 healthy controls, and 286 patients with nephrotic syndrome. The MYO1E A159P variant is noteworthy, as it is expected to impair ligand binding and actin interaction in the MYO1E motor domain. The predicted loss of function is consistent with the previous demonstration that Myo1e inactivation produces nephrotic syndrome in mice. Screening 71 additional patients with SRNS, however, did not identify independent NEIL1 or MYO1E mutations, suggesting larger sequencing efforts are needed to uncover which mutation is responsible for the phenotype. Our findings demonstrate the utility of exome sequencing for rapidly identifying candidate genes for human SRNS. PMID- 21697814 TI - TWEAK, a multifunctional cytokine in kidney injury. AB - Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a cytokine of the TNF superfamily that activates the Fn14 receptor. TWEAK may regulate cell proliferation, cell death, cell differentiation, and inflammation. TWEAK and Fn14 are constitutively present in the kidney. Sources of TWEAK and Fn14 include intrinsic renal cells and infiltrating leukocytes. Basal Fn14 expression is low, but Fn14 is greatly upregulated during kidney injury. TWEAK contributes to kidney inflammation promoting chemokine secretion by renal cells through canonical and non-canonical NFkappaB activation. TWEAK also promotes tubular cell proliferation. However, TWEAK induces mesangial and tubular cell apoptosis under proinflammatory conditions. These data indicate that TWEAK is a multifunctional cytokine in the kidney, the actions of which are modulated by the cell microenvironment. Confirmation of the role of TWEAK in kidney injury came from functional studies in experimental animal models. The TWEAK/Fn14 pathway contributed to cell death and interstitial inflammation during acute kidney injury, to glomerular injury in lupus nephritis, to hyperlipidemia-associated kidney injury, and to tubular cell hyperplasia following unilateral nephrectomy. Circulating soluble TWEAK (sTWEAK) levels are a potential biomarker of adverse outcomes in chronic kidney disease and urinary sTWEAK is a potential biomarker of lupus nephritis activity. The available evidence suggests that TWEAK may provide diagnostic information and be a therapeutic target in renal injury. Its role in human kidney disease should be further explored. PMID- 21697815 TI - Biomarkers in chronic kidney disease: a review. AB - Chronic kidney disease (CKD) is a major public health problem. The classification of CKD by KDOQI and KDIGO and the routine eGFR reporting have resulted in increased identification of CKD. It is important to be able to identify those at high risk of CKD progression and its associated cardiovascular disease (CVD). Proteinuria is the most sensitive marker of CKD progression in clinical practice, especially when combined with eGFR, but these have limitations. Hence, early, more sensitive, biomarkers are required. Recently, promising biomarkers have been identified for CKD progression and its associated CVD morbidity and mortality. These may be more sensitive biomarkers of kidney function, the underlying pathophysiological processes, and/or cardiovascular risk. Although there are some common pathways to CKD progression, there are many primary causes, each with its own specific pathophysiological mechanism. Hence, a panel measuring multiple biomarkers including disease-specific biomarkers may be required. Large, longitudinal observational studies are needed to validate candidate biomarkers in a broad range of populations prior to implementation into routine CKD management. Recent renal biomarkers discovered include neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and liver-type fatty acid-binding protein. Although none are ready for use in clinical practice, it is timely to review the role of such biomarkers in predicting CKD progression and/or CVD risk in CKD. PMID- 21697816 TI - Insufficient vitamin D intakes among pregnant women. AB - Vitamin D has an important role in pregnancy in promoting fetal skeletal health. Maternal dietary intake is a key factor influencing both maternal and fetal status. There are limited data available on food groups contributing to vitamin D intake in pregnancy. The aim of this study was to determine dietary intakes of vitamin D throughout pregnancy in 64 women and to determine the main food groups contributing to vitamin D intake. Results showed that median dietary intakes of vitamin D ranged from 1.9-2.1 MUg/d during pregnancy, and were 80% below the current recommendation. The principal food groups contributing to vitamin D intake were meat, egg and breakfast cereal groups. Oily fish, the best dietary source of vitamin D, was consumed by <25% of women. These data call for more education; they question the role of vitamin D supplementation and highlight the contribution of other food groups more frequently consumed, namely, breakfast cereals, meat and eggs. PMID- 21697817 TI - Development of international criteria for a front of package food labelling system: the International Choices Programme. AB - BACKGROUND: A global push to reduce the amount of saturated and trans-fatty acids, added salt and sugar in processed food, and to enhance fruit, vegetable and whole grain intake, while limiting energy intake, exists for most populations. OBJECTIVES: To redesign the International Choices Program (note: this is unrelated to the US Smart Choices Program), initially Netherlands focused, by an international board of scientists to create a generic, global front-of-pack nutrition logo system that helps consumers make healthier food choices and stimulates product reformulation. METHODS: The Programme is a product group-specific-nutrient-profiling approach with a distinction between basic and discretionary foods. The basic product groups are main contributors of essential and beneficial nutrients, and are based on food-based dietary guidelines from more than 20 countries across the globe. Generic criteria are derived from international nutrient recommendations for trans-fatty acids, saturated fatty acids, sodium, added sugar, fibre and energy, and evaluated against food composition data from 12 countries across Europe and market reality (actual foods on the market). Selected debates such as the source of fibre are also presented. RESULTS: Generic criteria and a decision framework were developed to further define food categories, so as to meet the unique country- and region-specific dietary needs. The result is a complete set of criteria that is evaluated on a regular basis to ensure its alignment with international dietary patterns, new scientific insights and current developments within the food market. CONCLUSIONS: These guidelines are currently used in a number of countries across the globe, and are being evaluated for effectiveness. Completed studies have demonstrated an increase in consumer awareness, a positive effect on product innovation and a potential impact on nutrient intakes. PMID- 21697818 TI - Dietary factors and their associations with socioeconomic background in Finnish girls and boys 6-8 years of age: the PANIC Study. AB - BACKGROUND/OBJECTIVES: To study nutrient intake, food consumption and meal pattern, and their associations with socioeconomic background in Finnish children. SUBJECTS/METHODS: The subjects were a population sample of 424 children (211 girls, 213 boys) 6-8 years of age. Nutrient intake and meal pattern were measured by food records, and food intake and socioeconomic characteristics were assessed by questionnaires. RESULTS: Intakes of saturated fat, sucrose and salt were higher, and intakes of vitamin D, iron and fibre and unsaturated-to saturated fat ratio lower than recommended. Less than 5% of children consumed vegetables, fruit and berries as recommended. Children with highest parental education more likely ate fish (odds ratio (OR) 2.20, 95% confidence interval (CI) 1.06-4.54), fibre-rich bread (OR 5.06, 95% CI 1.80-14.29) and main meals (OR 2.54, 95% CI 1.34-4.83), but less likely used soft margarine (OR 0.43, 95% CI 0.20-0.94) as recommended than children with lowest parental education. Children with highest household income more likely consumed skimmed milk (OR 2.43, 95% CI 1.21-4.88) and fish (OR 2.21, 95% CI 1.12-4.36) as recommended than children with lowest household income. Only 34% of girls and 45% of boys ate all main meals daily. Snacks provided as much as 42% of total energy intake. CONCLUSIONS: Children do not meet recommendations in all important nutrients. Children from lowest socioeconomic position least likely consumed fish, skimmed milk and fibre rich bread and ate main meals, but most likely used soft margarine as recommended. Less than half of children ate all main meals daily. PMID- 21697819 TI - Effect of functional yogurt NY-YP901 in improving the trait of metabolic syndrome. AB - BACKGROUND/OBJECTIVES: This study was aimed to assess the beneficial effects on metabolic syndrome of functional yogurt NY-YP901 (Namyang Dairy Product Co. Ltd and Nutra R&BT Inc., Seoul, Korea) supplemented with mixture of Streptococcus thermophilus, Lactobacillus acidophilus, Bifidobacterium infantis and extra ingredients containing Bifidobacterium breve (CBG-C2), Enterococcus faecalis FK 23, fibersol-2 and so on. SUBJECTS/METHODS: This study was designed as an 8-week randomized, double-blind, placebo-controlled, parallel study. Treatment and control groups consumed a functional yogurt NY-YP901 (150 ml) and a placebo yogurt twice a day, respectively, for 8 weeks. Body weight and body mass index (BMI), blood pressure, lipid profiles, fasting glucose with HbA1C and waist circumference were measured before and after treatment. Inclusion criteria were healthy individuals between the ages 20-65 years old who submitted an informed consent. RESULTS: During the period August 2009 to December 2009, 101 healthy participants (31 males and 70 females) finished the study. Treatment group were 53 individuals, and the control group were 48 individuals. In the treatment group consuming NY-YP901, statistically significant beneficial changes were observed in body weight (treatment group vs control group=-0.24+/-1.50 vs +0.64+/-1.39 kg, P<0.05), BMI (-0.10+/-0.58 vs +0.24+/-0.50 kg/m(2), P<0.05 ) and low-density lipoprotein (LDL)-cholesterol (-7.71+/-14.14 vs -0.43+/-15.32 mg/dl, P<0.05) after 8 weeks. The change in other parameters was not different between the treatment and the control groups. CONCLUSIONS: The functional yogurt NY-YP901 reduced LDL-cholesterol, body weight and BMI in the subjects at a 300-ml consumption daily for 8 weeks. From these findings, regular intake of functional yogurt NY-YP901 may be consequently related to improve metabolic syndrome. PMID- 21697820 TI - Pragmatic study of orlistat 60 mg on abdominal obesity. AB - BACKGROUND/OBJECTIVES: It is well established that combining a reduced calorie, low-fat diet with the lipase inhibitor orlistat results in significantly greater weight loss than placebo plus diet. This weight loss is accompanied by changes in adipose tissue (AT) distribution. As 60 mg orlistat is now available as an over the-counter medication, the primary objective of this study was to determine whether 60 mg orlistat is effective as a weight loss option in a free-living community population with minimal professional input. METHODS: AT and ectopic lipid content were measured using magnetic resonance imaging and (1)H MR spectroscopy, respectively, in 27 subjects following 3 months treatment with orlistat 60 mg and a reduced calorie, low-fat diet. RESULTS: Significant reductions in intra-abdominal AT (-10.6%, P=0.023), subcutaneous (-11.7% P<0.0001) and pericardial fat (-9.8%, P=0.034) volumes and intrahepatocellular lipids (-43.3%, P=0.0003) were observed. These changes in body fat content and distribution were accompanied by improvements in plasma lipids and decreases in blood pressure and heart rate. CONCLUSION: These findings suggest that over-the counter 60 mg orlistat, in combination with the type of advice a subject could expect to be given when obtaining 60 mg orlistat in a community setting, does indeed result in potentially clinically beneficial changes in body composition and risk factors for metabolic diseases. PMID- 21697821 TI - Correlates of dietary resilience among socioeconomically disadvantaged adolescents. AB - BACKGROUND/OBJECTIVES: Despite increased risk for unhealthy diets, some socioeconomically disadvantaged adolescents manage to consume a healthy diet, thereby showing 'dietary resilience'. This investigation aimed to describe the vegetable and fruit intakes of socioeconomically disadvantaged adolescents, and explore the intrapersonal, social and environmental factors associated with more favourable dietary intakes among socioeconomically disadvantaged adolescents. SUBJECTS/METHODS: The present investigation draws on data from 1014 socioeconomically disadvantaged adolescents (55% girls), a sub-sample of 3264 adolescents aged 12-15 years recruited from 37 secondary schools in Victoria, Australia. The adolescents completed an online survey in 2004-2005 comprising an FFQ and questions pertaining to intrapersonal, social and environmental factors informed by the Social Cognitive Theory (SCT). Frequent vegetable and fruit intake was defined as ?2 times per day and ?1 time per day, respectively. RESULTS: Approximately one-third of socioeconomically disadvantaged adolescents frequently consumed vegetables and fruit (boys, 29% and 27% respectively; girls, 29% and 36% respectively). Greater perceived importance of health, and frequently being served vegetables with dinner, were associated with frequent intakes. Friends' support for healthy eating was associated with boys' frequent vegetable intake. Less stringent adherence to family meal-time rules was associated with frequent intakes; however, the opposite was observed when girls were expected to eat all foods served. CONCLUSIONS: Nutrition promotion messages targeting socioeconomically disadvantaged adolescents could focus on fostering appreciation for health and providing families with strategies to increase meal-time vegetable availability. Friends could be encouraged to support healthy eating among boys. Family meal-time rules warrant further investigation. PMID- 21697822 TI - Energy expenditure in chronic obstructive pulmonary disease-evaluation of simple measures. AB - BACKGROUND/OBJECTIVES: Almost 50% of all chronic obstructive pulmonary disease (COPD) patients become underweight. One possible reason for nutritional treatment to fail could be miscalculation of patients' energy requirements. The aim of this study was, therefore, to evaluate simple measures that may be used to assess the energy requirement of COPD patients. SUBJECTS/METHODS: This cross-sectional evaluation study includes 68 COPD patients (42 women). Resting metabolic rate (RMR) was assessed by indirect calorimetry, while total energy expenditure (TEE) was assessed by a 7-day monitoring using the ActiReg. Simple measures to evaluate was body weight (kg) multiplied by 125 kJ (30 kcal), predicted RMR multiplied by 1.7 and two simple questionnaires. RESULTS: Mean physical activity level (PAL) from the ActiReg was 1.46. Calculation of energy expenditure multiplying body weight with 125 kJ resulted in a TEE of 8614 kJ compared with ActiReg 8317 kJ (P=0.10). To multiply predicted RMR by 1.7 resulted in a statistically significant overestimation of 1335 kJ (P<0.01). Both questionnaires showed a clear 'dose-response' regarding PAL from ActiReg in the different activity categories. CONCLUSIONS: This study shows that simple measures of energy expenditure could, on group level, assess COPD patient's energy needs. However, for individual assessment of energy need, more thorough procedures are necessary. PMID- 21697823 TI - Changes in core food intake among Australian children between 1995 and 2007. AB - BACKGROUND/OBJECTIVES: To assess the changes in the consumption of core foods among Australian children between the 1995 National Nutrition Survey (1995 NNS) and the 2007 Australian National Children's Nutrition and Physical Activity Survey (2007 Children's Survey). SUBJECTS/METHODS: Core food consumption was analysed using 24-h recall data from 2-16 year old children using the 1995 NNS (n=2435) and the 2007 Children's Survey (n=4380). Differences in percent consuming, amounts consumed and percent energy contribution were assessed. RESULTS: The consumption of core foods increased significantly between the 1995 and 2007 surveys, including per-capita consumption and percent energy contribution (both P?0.001). Core foods contributed to 59% of energy intake in 1995 compared with 65% in 2007. The types of core foods consumed also changed during this time period with more children reporting eating healthy options such as wholemeal bread, reduced-fat milk, reduced-fat cheese and fruit in the 2007 Children's Survey. Conversely, the consumption of white bread, full-fat milk and low-fibre breakfast cereals was lower in 2007. CONCLUSIONS: Overall, reported dietary intake had improved from 1995 to 2007 among Australian children with an increase in the amounts of core foods consumed and healthier types of foods being chosen. Continued health-promotion activities and monitoring of food consumption are highly warranted. PMID- 21697824 TI - D2 receptor block abolishes theta burst stimulation-induced neuroplasticity in the human motor cortex. AB - Dopamine (DA) is a neurotransmitter with an important influence on learning and memory, which is thought to be due to its modulatory effect on plasticity at central synapses, which in turn depends on activation of D1 and D2 receptors. Methods of brain stimulation (transcranial direct current stimulation, tDCS; paired associative stimulation, PAS) lead to after-effects on cortical excitability that are thought to resemble long-term potentization (LTP)/long-term depression (LTD) in reduced preparations. In a previous study we found that block of D2 receptors abolished plasticity induced by tDCS but had no effect on the facilitatory plasticity induced by PAS. We postulated that the different effect of D2 receptor block on tDCS- and PAS-induced plasticity may be due to the different focality and associativity of the stimulation techniques. However, alternative explanations for this difference could not be ruled out. tDCS also differs from PAS in other aspects, as tDCS induces plasticity by subthreshold neuronal activation, modulating spontaneous activity, whereas PAS induces plasticity via phasic suprathreshold stimulation. The present study in 12 volunteers examined effects of D2 receptor blockade (sulpiride (SULP) 400 mg), on the LTP/LTD-like effects of theta burst transcranial magnetic stimulation (TBS), which has less restricted effects on cortical synapses than that of PAS, and does not induce associative plasticity, similar to tDCS, but on the other hand induces cortical excitability shifts by suprathreshold (rhythmic) activation of cortical neurons similarly to PAS. Administration of SULP blocked both the excitatory and inhibitory effects of intermittent (iTBS) and continuous TBS (cTBS), respectively. As the reduced response to TBS following SULP resembles its effect on tDCS, the results support an effect of DA on plasticity, which might be related to the focality and associativity of the plasticity induced. PMID- 21697825 TI - Structure of the human histamine H1 receptor complex with doxepin. AB - The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H(1) receptor (H(1)R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H(1)R complex with doxepin, a first-generation H(1)R antagonist. Doxepin sits deep in the ligand binding pocket and directly interacts with Trp 428(6.48), a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H(1)R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys 191(5.39) and/or Lys 179(ECL2), both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H(1)R antagonist specificity against H(1)R. PMID- 21697827 TI - XUTs are a class of Xrn1-sensitive antisense regulatory non-coding RNA in yeast. AB - Non-coding (nc)RNAs are key players in numerous biological processes such as gene regulation, chromatin domain formation and genome stability. Large ncRNAs interact with histone modifiers and are involved in cancer development, X chromosome inactivation and autosomal gene imprinting. However, despite recent evidence showing that pervasive transcription is more widespread than previously thought, only a few examples mediating gene regulation in eukaryotes have been described. In Saccharomyces cerevisiae, the bona-fide regulatory ncRNAs are destabilized by the Xrn1 5'-3' RNA exonuclease (also known as Kem1), but the genome-wide characterization of the entire regulatory ncRNA family remains elusive. Here, using strand-specific RNA sequencing (RNA-seq), we identify a novel class of 1,658 Xrn1-sensitive unstable transcripts (XUTs) in which 66% are antisense to open reading frames. These transcripts are polyadenylated and RNA polymerase II (RNAPII)-dependent. The majority of XUTs strongly accumulate in lithium-containing media, indicating that they might have a role in adaptive responses to changes in growth conditions. Notably, RNAPII chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) analysis of Xrn1 deficient strains revealed a significant decrease of RNAPII occupancy over 273 genes with antisense XUTs. These genes show an unusual bias for H3K4me3 marks and require the Set1 histone H3 lysine 4 methyl-transferase for silencing. Furthermore, abolishing H3K4me3 triggers the silencing of other genes with antisense XUTs, supporting a model in which H3K4me3 antagonizes antisense ncRNA repressive activity. Our results demonstrate that antisense ncRNA-mediated regulation is a general regulatory pathway for gene expression in S. cerevisiae. PMID- 21697830 TI - A salt-water reservoir as the source of a compositionally stratified plume on Enceladus. AB - The discovery of a plume of water vapour and ice particles emerging from warm fractures ('tiger stripes') in Saturn's small, icy moon Enceladus raised the question of whether the plume emerges from a subsurface liquid source or from the decomposition of ice. Previous compositional analyses of particles injected by the plume into Saturn's diffuse E ring have already indicated the presence of liquid water, but the mechanisms driving the plume emission are still debated. Here we report an analysis of the composition of freshly ejected particles close to the sources. Salt-rich ice particles are found to dominate the total mass flux of ejected solids (more than 99 per cent) but they are depleted in the population escaping into Saturn's E ring. Ice grains containing organic compounds are found to be more abundant in dense parts of the plume. Whereas previous Cassini observations were compatible with a variety of plume formation mechanisms, these data eliminate or severely constrain non-liquid models and strongly imply that a salt-water reservoir with a large evaporating surface provides nearly all of the matter in the plume. PMID- 21697833 TI - Biofuels. PMID- 21697831 TI - Tracking apex marine predator movements in a dynamic ocean. AB - Pelagic marine predators face unprecedented challenges and uncertain futures. Overexploitation and climate variability impact the abundance and distribution of top predators in ocean ecosystems. Improved understanding of ecological patterns, evolutionary constraints and ecosystem function is critical for preventing extinctions, loss of biodiversity and disruption of ecosystem services. Recent advances in electronic tagging techniques have provided the capacity to observe the movements and long-distance migrations of animals in relation to ocean processes across a range of ecological scales. Tagging of Pacific Predators, a field programme of the Census of Marine Life, deployed 4,306 tags on 23 species in the North Pacific Ocean, resulting in a tracking data set of unprecedented scale and species diversity that covers 265,386 tracking days from 2000 to 2009. Here we report migration pathways, link ocean features to multispecies hotspots and illustrate niche partitioning within and among congener guilds. Our results indicate that the California Current large marine ecosystem and the North Pacific transition zone attract and retain a diverse assemblage of marine vertebrates. Within the California Current large marine ecosystem, several predator guilds seasonally undertake north-south migrations that may be driven by oceanic processes, species-specific thermal tolerances and shifts in prey distributions. We identify critical habitats across multinational boundaries and show that top predators exploit their environment in predictable ways, providing the foundation for spatial management of large marine ecosystems. PMID- 21697834 TI - Lignocellulose: A chewy problem. PMID- 21697836 TI - Perspective: Don't foul the water. PMID- 21697835 TI - Algae: The scum solution. PMID- 21697837 TI - Local benefits: The seeds of an economy. PMID- 21697838 TI - Introduction: Next generation biofuels. PMID- 21697839 TI - Perspective: A new hope for Africa. PMID- 21697840 TI - Policy: Fuelling politics. PMID- 21697842 TI - Agriculture: Beyond food versus fuel. PMID- 21697841 TI - Perspective: Lessons from Brazil. PMID- 21697843 TI - Fuel options: The ideal biofuel. PMID- 21697844 TI - Measuring impact. PMID- 21697845 TI - The best we have: by Christian Martin. PMID- 21697847 TI - Solar energy: the thermoelectric alternative. PMID- 21697848 TI - Organic spintronics: filtering spins with molecules. PMID- 21697849 TI - Material witness: sink or swim. PMID- 21697850 TI - Polymer electrolyte membranes: diffusion realigned. PMID- 21697851 TI - Potential mechanisms in angiotensin II-induced EPCs senescence. PMID- 21697854 TI - Advances in depression research: 2011. PMID- 21697852 TI - Chronic kidney disease and subclinical lacunar infarction are independently associated with frontal lobe dysfunction in community-dwelling elderly subjects: the Sefuri brain MRI study. AB - Although recent studies have found that chronic kidney disease (CKD) is an independent risk factor for cognitive impairment in population-based cohorts, the mechanisms of cognitive impairment in subjects with CKD are unclear. We examined 503 elderly subjects (mean age: 72.4 years), who were living independently at home without apparent dementia, using MRI. The subject was judged as having frontal lobe dysfunction if the scores on the modified Stroop test were higher than the fifth quintile for each given decade. Serum creatinine values, measured by the enzymatic method, were used for the Japanese equation of estimated glomerular filtration rate (eGFR). Subjects in the frontal lobe dysfunction group tended to have higher blood pressure, lower eGFR and more lacunar infarcts, and were less educated. When possible confounders were entered into the multivariate logistic regression model, the independent predictors of frontal lobe dysfunction were eGFR (odds ratio 0.854; 95% confidence interval (CI) 0.743-0.983 per 10 ml min(-1) per 1.73 m(2)) and the number of lacunar infarction (odds ratio 1.460; 95% CI 1.127-1.892). The mean of the logarithmically transformed Stroop test scores in the eGFR<60 ml min(-1) per 1.73 m(2) group was 1.376 (95% CI 1.301 1.451), which was significantly higher than that (1.250) for the eGFR 60-89 ml min(-1) per 1.73 m(2) group (95% CI 1.215-1.285) (P=0.009) and tended to be higher than that (1.264) for the eGFR >=90 ml min(-1) per 1.73 m(2) group (95% CI 1.188-1.340) (analysis of covariance, adjusted for age). The present study showed that CKD and subclinical lacunar infarction independently contributed to frontal lobe dysfunction in healthy elderly subjects. PMID- 21697855 TI - Fatal viral infection-associated encephalopathy in two Chinese boys: a genetically determined risk factor of thermolabile carnitine palmitoyltransferase II variants. AB - Influenza-associated encephalopathy (IAE) is a potentially fatal neurological complication of influenza infection usually in the presence of high and persistent fever. Thermolabile carnitine palmitoyltransferase II enzyme (CPT-II) predisposes IAE, so far only described in Japanese. As the genetic origins of Japanese and Chinese are alike, similar genetic risk factors in CPT-II are expected. We report the first two unrelated Chinese patients of thermolabile CPT II variants that underlain the persistent high fever-triggered viral infection associated encephalopathy, multi-organ failure and death. Elevated (C16:0+C18:1)/C2 acylcarnitines ratio and the CPT2 susceptibility variant allele [p.Phe352Cys; p.Val368Ile] were detected. The asymptomatic family members of one patient also had abnormal long-chain acylcarnitines. In our experience of biochemical genetics, the elevated (C16:0+C18:1)/C2 acylcarnitines ratio is unusual and specific for thermolabile CPT-II variants. Allele frequency of [p.Phe352Cys; p.Val368Ile] among Hong Kong Chinese was 0.104, similar to Japanese data, and [p.Phe352Cys] has not been reported in Caucasians. This may explain the Asian-specific phenomenon of thermolabile CPT-II-associated IAE. We successfully demonstrated the thermolabile CPT-II variants in patients with viral infection associated encephalopathy in another Asian population outside Japanese. The condition is likely under-recognized. With our first cases, it is envisaged that more cases will be diagnosed in subsequent years. The exact pathogenic mechanism of how other factors interplay with thermolabile CPT-II variants and high fever leading to IAE, is yet to be elucidated. Fasting and decreased intake during illness may aggravate the disease. Further studies including high risk and neonatal screening are warranted to investigate its expressivity, penetrance and temperature-dependent behaviors in thermolabile CPT-II carriers. This may lead to discovery of the therapeutic golden window by aggressive antipyretics and L carnitine administration in avoiding the high mortality and morbidity of IAE. PMID- 21697856 TI - Novel and recurrent EMD mutations in patients with Emery-Dreifuss muscular dystrophy, identify exon 2 as a mutation hot spot. AB - Emery-Dreifuss muscular dystrophy (EDMD) is a neuromuscular disorder exhibiting a cardiomyopathy with cardiac conduction defects. X-linked EDMD arises from mutations in the EMD gene, which encodes for a nuclear membrane protein termed emerin. In this study, we describe novel and recurrent EMD mutations identified in 18 probands and three carriers from a cohort of 255 North American patients referred for EDMD genetic mutation analysis. Eight of these mutations are novel including six frameshift mutations (p.D9GfsX24, p.F39SfsX17, p.R45KfsX16, p.F190YfsX19, p.R203PfsX34 and p.R204PfsX7) and two non-sense mutations (p.S143X, p.W200X). Our data augment the number of EMD mutations by 13.8%, equating to an increase of 5.2% in the total known EMD mutations and to an increase of 6.0% in the number of different mutations. Analysis of the exon distribution of mutations within the EMD gene, suggests a nonrandom distribution, with exon 2 as a hot spot. This phenomenon may be due to its high GC content, which at 60% is the most GC-rich exon in the EMD gene. PMID- 21697857 TI - Clinical utility gene card for: Usher syndrome. PMID- 21697858 TI - Effects of sertraline on brain current source of the high beta frequency band: analysis of electroencephalography during audiovisual erotic stimulation in males with premature ejaculation. AB - To identify the effects of sertraline, a selective serotonin reuptake inhibitor, for the treatment of premature ejaculation (PE), changes in brain current-source density (CSD) of the high beta frequency band (22-30 Hz) induced by sertraline administration were investigated during audiovisual erotic stimulation. Eleven patients with PE (36.9+/-7.8 yrs) and 11 male volunteers (24.2+/-1.9 years) were enrolled. Scalp electroencephalography (EEG) was conducted twice: once before sertraline administration and then again 4 h after the administration of 50 mg sertraline. Statistical non-parametric maps were obtained using the EEG segments to detect the current-density differences in the high beta frequency bands (beta 3, 22-30 Hz) between the EEGs before and after sertraline administration in the patient group and between the patient group and controls after the administration of sertraline during the erotic video sessions. Comparing between before and after sertraline administration in the patients with PE, the CSD of the high beta frequency band at 4 h after sertraline administration increased significantly in both superior frontal gyri and the right medial frontal gyrus (P<0.01). The CSD of the beta-3 band of the patients with PE were less activated significantly in the middle and superior temporal gyrus, lingual and fusiform gyrus, inferior occipital gyrus and cuneus of the right cerebral hemisphere compared with the normal volunteers 4 h after sertraline administration (P<0.01). In conclusion, sertraline administration increased the CSD in both the superior frontal and right middle temporal gyrus in patients with PE. The results suggest that the increased neural activity in these particular cerebral regions after sertraline administration may be associated with inhibitory effects on ejaculation in patients with PE. PMID- 21697859 TI - Effects of ginsenoside on large-conductance K(Ca) channels in human corporal smooth muscle cells. AB - Ginseng was known to be an effective natural product that enhances penile erection. However, the precise biological function and mechanisms of action of ginseng with regard to erectile function remain unknown. The principal objective of this study was to identify ginsenoside (principal molecular ingredients of ginseng)-induced activation of large-conductance K(Ca) channel in human corporal smooth muscle cells, and to determine ginseng's mechanism of action on penile erection. Electrophysiological studies using cultured human corporal smooth muscle cells were conducted. We evaluated the effects of total ginsenosides (TGS) and ginsenoside Rg3 on large-conductance K(Ca) channel by determining whole-cell currents and single-channel activities. There was an increase in outward current dependent on TGS concentration (at +60 mV, 1 MUg ml(-1); 168.3+/-59.3%, n=6, P<0.05, 10 MUg ml(-1); 173.2+/-36.8%, n=4, P<0.05, 50 MUg ml(-1); 295.3+/-62.3%, n=19, P<0.001, 100 MUg ml(-1); and 462.3+/-97.1%, n=5, P<0.001) and Rg3 concentration (at +60 mV, 1 MUM (0.78 MUg ml(-1)); 222.8+/-64.8%, n=11, P<0.0001, 10 MUM; 672.6+/-137.1%, n=10, P<0.0001, 50 MUM; and 1713.3+/-234.7%, n=15, P<0.001) in the solution that was blocked completely by tetraethylammonium (TEA). Channel opening in cell-attached mode and channel activity in the inside-out membrane patches was also increased significantly by 50 MUg of TGS or 10 MUM of Rg3. The results of this study suggested that the activation of large-conductance K(Ca) channels by ginsenoside could be one mechanism of ginsenoside-induced relaxation in corporal smooth muscle. PMID- 21697860 TI - Emerging concepts in erectile preservation following radical prostatectomy: a guide for clinicians. AB - Radical prostatectomy (RP) is a commonly performed procedure for the management of prostate cancer. While documented oncologic outcome for early stage disease is excellent, functional impairments such as incontinence and erectile dysfunction (ED) are common after the procedure. Recent evidence has implicated cavernous nerve damage and subsequent corporal oxygen deprivation, as well as corporal inflammation, in the pathogenesis of post-RP ED. Targeted therapies such as oral phosphodiesterase-5 inhibitors, mechanical vacuum erection devices, local alprostadil delivery and testosterone replacement (for hypogonal patients) have demonstrated some efficacy in the management of post-RP ED. This review aggregates much of the recent data in support of these therapies and critically reviews them. The article then presents tools to assess patients and partner sexual function to aid in identifying and monitoring post-RP ED. Finally, the article describes a protocol in use at Baylor College of Medicine as a guide toward the development of a protocol for erectile preservation (EP). The purpose of this work is to educate clinicians on emerging concepts in EP and provide an implementable protocol for use in practice. PMID- 21697861 TI - Expression and distribution of key enzymes of the cyclic GMP signaling in the human clitoris: relation to phosphodiesterase type 5 (PDE5). AB - The clitoris contributes to the normal female sexual response cycle. A significance of cyclic guanosine monophosphate (GMP) has been assumed in the control of clitoral vascular smooth muscle. As only a few investigations on the physiology of the vascular and non-vascular clitoral tissue have been carried out, knowledge on the mechanisms controlling this particular female genital organ is still vague. It has been suggested that human clitoral corpus cavernosum smooth muscle is regulated by nitric oxide (NO)/cyclic GMP and related key enzymes, such as NO synthases (NOSs) and the phosphodiesterase type 5 (PDE5). The present study evaluated in the human clitoris, by means of immunohistochemistry, the expression and distribution of key enzymes of the cyclic GMP pathway, such as the endothelial NOS, PDE2, PDE11 and cyclic GMP-dependent protein kinase type I (cGKI) in relation to the PDE5. Immunohistochemistry revealed the presence of PDE2, PDE5 and cGKI in the smooth muscle wall of blood vessels transversing the supepithelial and stromal space. Immunosignals specific for PDE2 were also identified in interstitial-like cells located in the basal epithelial layer. Staining for PDE11A was observed in single nerve trunks located in the clitoral stroma. The results are in favor of a role of the cyclic GMP signaling in the control of clitoral blood flow. It seems likely that PDE2 and PDE11 are also involved in the mechanism of local (neuro)transmission in the clitoris. PMID- 21697862 TI - The two-week sabbatical. PMID- 21697866 TI - Oxygen-reduction catalysts: picking perovskites. PMID- 21697867 TI - Nitrogen fixation: nitrido complexes step up. PMID- 21697868 TI - Atmospheric photochemistry: roaming in the dark. PMID- 21697869 TI - Polymer synthesis: making the gradient. PMID- 21697870 TI - Coordination chemistry: all square for high-spin iron(II). PMID- 21697871 TI - Contemporary strategies for peptide macrocyclization. AB - Peptide macrocycles have found applications that range from drug discovery to nanomaterials. These ring-shaped molecules have shown remarkable capacity for functional fine-tuning. Such capacity is enabled by the possibility of adjusting the peptide conformation using the techniques of chemical synthesis. Cyclic peptides have been difficult, and often impossible, to prepare using traditional synthetic methods. For macrocyclization to occur, the activated peptide must adopt an entropically disfavoured pre-cyclization conformation before forming the desired product. Here, we review recent solutions to some of the major challenges in this important area of contemporary synthesis. PMID- 21697872 TI - Nitrenium ions as ligands for transition metals. AB - Unlike N-heterocyclic carbenes (NHCs), which are now used ubiquitously in metal based chemistry, the nitrogen-derived analogue (in which a carbon is replaced with the isoelectronic nitrogen cation, a nitrenium ion) has remained elusive as a ligand for metals. This is especially intriguing, because several other main group analogues of NHCs have been prepared, and have been shown to coordinate with transition-metal complexes. Here, we describe the preparation of several N heterocyclic nitrenium ions that are isoelectronic and isostructural to NHCs, and study their ligand properties. The formation of relatively strong nitrenium-metal bonds is unambiguously confirmed, in solution by selective (15)N-labelling experiments, and in the solid state by X-ray crystallography. Experimental and computational studies of the electronic properties of this novel type of ligand suggest that they are poor sigma-donors and good pi-acceptors. PMID- 21697873 TI - Ammonia formation by metal-ligand cooperative hydrogenolysis of a nitrido ligand. AB - Bioinspired hydrogenation of N(2) to ammonia at ambient conditions by stepwise nitrogen protonation/reduction with metal complexes in solution has experienced remarkable progress. In contrast, the highly desirable direct hydrogenation with H(2) remains difficult. In analogy to the heterogeneously catalysed Haber-Bosch process, such a reaction is conceivable via metal-centred N(2) splitting and unprecedented hydrogenolysis of the nitrido ligands to ammonia. We report the synthesis of a ruthenium(IV) nitrido complex. The high nucleophilicity of the nitrido ligand is demonstrated by unusual N-C coupling with pi-acidic CO. Furthermore, the terminal nitrido ligand undergoes facile hydrogenolysis with H(2) at ambient conditions to produce ammonia in high yield. Kinetic and quantum chemical examinations of this reaction suggest cooperative behaviour of a phosphorus-nitrogen-phosphorus pincer ligand in rate-determining heterolytic hydrogen splitting. PMID- 21697874 TI - Strong exchange and magnetic blocking in N23--radical-bridged lanthanide complexes. AB - Single-molecule magnets approach the ultimate size limit for spin-based devices. These complexes can retain spin information over long periods of time at low temperature, suggesting possible applications in high-density information storage, quantum computing and spintronics. Notably, the success of most such applications hinges upon raising the inherent molecular spin-inversion barrier. Although recent advances have shown the viability of lanthanide-containing complexes in generating large barriers, weak or non-existent magnetic exchange coupling allows fast relaxation pathways that mitigate the full potential of these species. Here, we show that the diffuse spin of an N(2)(3-) radical bridge can lead to exceptionally strong magnetic exchange in dinuclear Ln(III) (Ln = Gd, Dy) complexes. The Gd(III) congener exhibits the strongest magnetic coupling yet observed for that ion, while incorporation of the high-anisotropy Dy(III) ion gives rise to a molecule with a record magnetic blocking temperature of 8.3 K at a sweep rate of 0.08 T s(-1). PMID- 21697875 TI - An efficient synthesis of loline alkaloids. AB - Loline (1) is a small alkaloid that, in spite of its simple-looking structure, has posed surprising challenges to synthetic chemists. It has been known for more than a century and has been the subject of extensive biological investigations, but only two total syntheses have been achieved to date. Here, we report an asymmetric total synthesis of loline that, with less then ten steps, is remarkably short. Our synthesis incorporates a Sharpless epoxidation, a Grubbs olefin metathesis and an unprecedented transannular aminobromination, which converts an eight-membered cyclic carbamate into a bromopyrrolizidine. The synthesis is marked by a high degree of chemo- and stereoselectivity and gives access to several members of the loline alkaloid family. It delivers sufficient material to support a programme aimed at studying the complex interactions between plants, fungi, insects and bacteria brokered by loline alkaloids. PMID- 21697876 TI - Design principles for oxygen-reduction activity on perovskite oxide catalysts for fuel cells and metal-air batteries. AB - The prohibitive cost and scarcity of the noble-metal catalysts needed for catalysing the oxygen reduction reaction (ORR) in fuel cells and metal-air batteries limit the commercialization of these clean-energy technologies. Identifying a catalyst design principle that links material properties to the catalytic activity can accelerate the search for highly active and abundant transition-metal-oxide catalysts to replace platinum. Here, we demonstrate that the ORR activity for oxide catalysts primarily correlates to sigma-orbital (e(g)) occupation and the extent of B-site transition-metal-oxygen covalency, which serves as a secondary activity descriptor. Our findings reflect the critical influences of the sigma orbital and metal-oxygen covalency on the competition between O(2)(2-)/OH(-) displacement and OH(-) regeneration on surface transition metal ions as the rate-limiting steps of the ORR, and thus highlight the importance of electronic structure in controlling oxide catalytic activity. PMID- 21697877 TI - Facile removal of stabilizer-ligands from supported gold nanoparticles. AB - Metal nanoparticles that comprise a few hundred to several thousand atoms have many applications in areas such as photonics, sensing, medicine and catalysis. Colloidal methods have proven particularly suitable for producing small nanoparticles with controlled morphologies and excellent catalytic properties. Ligands are necessary to stabilize nanoparticles during synthesis, but once the particles have been deposited on a substrate the presence of the ligands is detrimental for catalytic activity. Previous methods for ligand removal have typically involved thermal and oxidative treatments, which can affect the size or morphology of the particles, in turn altering their catalytic activity. Here, we report a procedure to effectively remove the ligands without affecting particle morphology, which enhances the surface exposure of the nanoparticles and their catalytic activity over a range of reactions. This may lead to developments of nanoparticles prepared by colloidal methods for applications in fields such as environmental protection and energy production. PMID- 21697878 TI - Synthesis of 3-O-sulfonated heparan sulfate octasaccharides that inhibit the herpes simplex virus type 1 host-cell interaction. AB - Cell surface carbohydrates play significant roles in a number of biologically important processes. Heparan sulfate, for instance, is a ubiquitously distributed polysulfated polysaccharide that is involved, among other things, in the initial step of herpes simplex virus type 1 (HSV-1) infection. The virus interacts with cell-surface heparan sulfate to facilitate host-cell attachment and entry. 3-O Sulfonated heparan sulfate has been found to function as an HSV-1 entry receptor. Achieving a complete understanding of these interactions requires the chemical synthesis of such oligosaccharides, but this remains challenging. Here, we present a convenient approach for the synthesis of two irregular 3-O-sulfonated heparan sulfate octasaccharides, making use of a key disaccharide intermediate to acquire different building blocks for the oligosaccharide chain assembly. Despite substantial structural differences, the prepared 3-O-sulfonated sugars blocked viral infection in a dosage-dependent manner with remarkable similarity to one another. PMID- 21697879 TI - Light-induced spin-crossover magnet. AB - The light-induced phase transition between the low-spin (LS) and high-spin (HS) states of some transition-metal ions has been extensively studied in the fields of chemistry and materials science. In a crystalline extended system, magnetically ordering the HS sites of such transition-metal ions by irradiation should lead to spontaneous magnetization. Previous examples of light-induced ordering have typically occurred by means of an intermetallic charge transfer mechanism, inducing a change of valence of the metal centres. Here, we describe the long-range magnetic ordering of the extended Fe(II)(HS) sites in a metal organic framework caused instead by a light-induced excited spin-state trapping effect. The Fe-Nb-based material behaves as a spin-crossover magnet, in which a strong superexchange interaction (magnetic coupling through non-magnetic elements) between photo-produced Fe(II)(HS) and neighbouring Nb(IV) atoms operates through CN bridges. The magnetic phase transition is observed at 20 K with a coercive field of 240 Oe. PMID- 21697880 TI - Selenium stories. PMID- 21697882 TI - Virulence gene expression in Malassezia spp from individuals with seborrheic dermatitis. PMID- 21697881 TI - Microbial symbiosis with the innate immune defense system of the skin. AB - Skin protects itself against infection through a variety of mechanisms. Antimicrobial peptides (AMPs) are major contributors to cutaneous innate immunity, and this system, combined with the unique ionic, lipid, and physical barrier of the epidermis, is the first-line defense against invading pathogens. However, recent studies have revealed that our skin's innate immune system is not solely of human origin. Staphylococcus epidermidis, a major constituent of the normal microflora on healthy human skin, acts as a barrier against colonization of potentially pathogenic microbes and against overgrowth of already present opportunistic pathogens. Our resident commensal microbes produce their own AMPs, act to enhance the normal production of AMPs by keratinocytes, and are beneficial to maintaining inflammatory homeostasis by suppressing excess cytokine release after minor epidermal injury. These observations indicate that the normal human skin microflora protects skin by various modes of action, a conclusion supported by many lines of evidence associating diseases such as acne, atopic dermatitis, psoriasis, and rosacea with an imbalance of the microflora even in the absence of classical infection. This review highlights recent observations on the importance of innate immune systems and the relationship with the normal skin microflora to maintain healthy skin. PMID- 21697883 TI - Matrix metalloproteinase-8 is involved in dermal nerve growth: implications for possible application to pruritus from in vitro models. AB - Cutaneous nerve density is related to abnormal itch perception in dermatoses, such as atopic dermatitis and xerosis. However, the mechanisms underlying the elongation of dermal nerve fibers within the interstitial collagen (CoL) matrix are poorly understood. In this study, a culture system of rat dorsal root ganglion neurons consisting of type I CoL and a Boyden chamber containing a nerve growth factor (NGF) concentration gradient was used. Nerve fibers penetrating into type I CoL gel were observed in the presence of the NGF concentration gradient. Levels of matrix metalloproteinase-8 (MMP-8) mRNA and protein were increased in the cultured neurons and the conditioned medium, respectively. The nerve fiber penetration was dose dependently inhibited by MMP-8 blockers. Moreover, MMP-8 immunoreactivity was partially localized at growth cones in NGF responsive nerve fibers. Semaphorin 3A stimulation also showed the opposite effects on these NGF-dependent events. Intriguingly, MMP-8 expression was upregulated by type I and III CoLs, which are substrates for this enzyme. These results suggested that MMP-8 is involved in sensory nerve growth within the interstitial CoL matrix through modulation by the axonal guidance molecules and/or extracellular matrix components. These findings provide insight into the development of pruritus involving skin nerve density. PMID- 21697884 TI - Diversity of the human skin microbiome early in life. AB - Within days after birth, rapid surface colonization of infant skin coincides with significant functional changes. Gradual maturation of skin function, structure, and composition continues throughout the first years of life. Recent reports have revealed topographical and temporal variations in the adult skin microbiome. Here we address the question of how the human skin microbiome develops early in life. We show that the composition of cutaneous microbial communities evolves over the first year of life, showing increasing diversity with age. Although early colonization is dominated by Staphylococci, their significant decline contributes to increased population evenness by the end of the first year. Similar to what has been shown in adults, the composition of infant skin microflora appears to be site specific. In contrast to adults, we find that Firmicutes predominate on infant skin. Timely and proper establishment of healthy skin microbiome during this early period might have a pivotal role in denying access to potentially infectious microbes and could affect microbiome composition and stability extending into adulthood. Bacterial communities contribute to the establishment of cutaneous homeostasis and modulate inflammatory responses. Early microbial colonization is therefore expected to critically affect the development of the skin immune function. PMID- 21697885 TI - Proteolytic activation cascade of the Netherton syndrome-defective protein, LEKTI, in the epidermis: implications for skin homeostasis. AB - Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is the defective protein of the ichthyosiform condition Netherton syndrome (NS). Strongly expressed in the most differentiated epidermal layers, LEKTI is a serine protease inhibitor synthesized as three different high-molecular-weight precursors, which are rapidly processed into shorter fragments and secreted extracellularly. LEKTI polypeptides interact with several proteases to regulate skin barrier homeostasis as well as inflammatory and/or immunoallergic responses. Here, by combining antibody mapping, N-terminal sequencing, and site-specific mutagenesis, we defined the amino-acid sequence of most of the LEKTI polypeptides physiologically generated in human epidermis. We also identified three processing intermediates not described so far. Hence, a proteolytic cascade model for LEKTI activation is proposed. We then pinpointed the most effective fragments against the desquamation-related kallikreins (KLKs) and we proved that LEKTI is involved in stratum corneum shedding as some of its polypeptides inhibit the KLK-mediated proteolysis of desmoglein-1. Finally, we quantified the individual LEKTI fragments in the uppermost epidermis, showing that the ratios between LEKTI polypeptides and active KLK5 are compatible with a fine-tuned inhibition. These findings are relevant both to the understanding of skin homeostasis regulation and to the design of novel therapeutic strategies for NS. PMID- 21697886 TI - Negative regulation of dermal fibroblasts by enlarged adipocytes through release of free fatty acids. AB - Subcutaneous adipose tissue lies just beneath the dermal layer, but the interaction between the two types of tissue remains obscure. Recently, we reported that obesity is associated with decreased dermal elasticity. To investigate the mechanism of the adipose tissue/dermal interaction, fibroblasts were cocultured with small or enlarged adipocytes, using a membrane insert to prevent direct contact. Enlarged adipocytes reduced 3T3-L1 fibroblast proliferation and gene expression of collagen (I)-alpha1 (col (I)-alpha1) and elastin while increasing gene expression of matrix metalloproteinase 13 (MMP13). In contrast, small adipocytes had no such effects. These results indicate that factors secreted by enlarged adipocytes influence dermal condition. As enlarged adipocytes are known to release free fatty acids (FFAs), the effects of these acids on 3T3-L1 fibroblasts were examined. Palmitic acid decreased fibroblast proliferation, reduced gene expressions of col (I)-alpha1 and elastin, and increased MMP13. Similar effects were observed in human dermal fibroblasts. The influence of palmitic acid on fibroblasts was inhibited by eicosapentaenoic acid (EPA), an inhibitor of Toll-like receptors (TLRs). Furthermore, EPA inhibited the effects of enlarged adipocytes on fibroblasts in the coculture system. These data indicate that enlarged adipocytes negatively control the function of dermal fibroblasts through the activation of TLRs by secreted FFAs. PMID- 21697887 TI - Erythroid differentiation regulator 1, an interleukin 18-regulated gene, acts as a metastasis suppressor in melanoma. AB - Erythroid differentiation regulator (Erdr1) was first discovered in mouse leukemia cell lines and functions as a stress-related survival factor. This study investigated whether Erdr1 regulates murine melanoma progression, as well as the mechanism involved in Erdr1-regulated metastasis. The expression of Erdr1 is negatively correlated with IL-18 expression, which has a pro-cancer effect in melanoma. To study the role of Erdr1 as an anti-cancer factor, cell migration, invasion, and proliferation were measured. Erdr1 overexpression markedly inhibited the level of cell migration, invasion, and proliferation in B16F10 cells in vitro. In addition, Erdr1 overexpression significantly suppressed melanoma lung colonization, metastasis, and tumor growth in vivo. To identify the factors involved in Erdr1-reduced metastasis, heat shock protein 90 (HSP90), a well-known stress protein and contributor to tumor metastasis, was examined. We found that HSP90 was significantly decreased in Erdr1-overexpressing cells. Functional analysis demonstrated that HSP90 small-interfering RNA transfection reduced the migration ability and metastasis of melanoma. In conclusion, Erdr1 shows a powerful anti-metastasis effect that leads to the ability to reduce the metastatic potential of murine malignant melanoma cells. Erdr1 is an anti metastatic factor that may be a possible therapeutic target for treatment of melanoma. PMID- 21697888 TI - Huntingtin-interacting protein 1: a Merkel cell carcinoma marker that interacts with c-Kit. AB - Merkel cell carcinoma (MCC) is a neoplasm thought to originate from the neuroendocrine Merkel cells of the skin. Although the prevalence of MCC has been increasing, treatments for this disease remain limited because of a paucity of information regarding MCC biology. We have found that the endocytic oncoprotein Huntingtin-interacting protein 1 (HIP1) is expressed at high levels in ~90% of MCC tumors and serves as a more reliable histological cytoplasmic stain than the gold standard, cytokeratin 20. Furthermore, high anti-HIP1 antibody reactivity in the sera of a cohort of MCC patients predicts the presence of metastases. Another protein that is frequently expressed at high levels in MCC tumors is the stem cell factor (SCF) receptor tyrosine kinase, c-Kit. In working toward an understanding of how HIP1 might contribute to MCC tumorigenesis, we have discovered that HIP1 interacts with SCF-activated c-Kit. These data not only identify HIP1 as a molecular marker for management of MCC patients but also show that HIP1 interacts with and slows the degradation of c-Kit. PMID- 21697889 TI - Correction of dog dystrophic epidermolysis bullosa by transplantation of genetically modified epidermal autografts. AB - Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin blistering condition caused by mutations in the gene coding for collagen type VII. Genetically engineered RDEB dog keratinocytes were used to generate autologous epidermal sheets subsequently grafted on two RDEB dogs carrying a homozygous missense mutation in the col7a1 gene and expressing baseline amounts of the aberrant protein. Transplanted cells regenerated a differentiated and vascularized auto-renewing epidermis progressively repopulated by dendritic cells and melanocytes. No adverse immune reaction was detected in either dog. In dog 1, the grafted epidermis firmly adhered to the dermis throughout the 24-month follow up, which correlated with efficient transduction (100%) of highly clonogenic epithelial cells and sustained transgene expression. In dog 2, less efficient (65%) transduction of primary keratinocytes resulted in a loss of the transplanted epidermis and graft blistering 5 months after transplantation. These data provide the proof of principle for ex vivo gene therapy of RDEB patients with missense mutations in collagen type VII by engraftment of the reconstructed epidermis, and demonstrate that highly efficient transduction of epidermal stem cells is crucial for successful gene therapy of inherited skin diseases in which correction of the genetic defect confers no major selective advantage in cell culture. PMID- 21697890 TI - Hemoglobin A1c predicts healing rate in diabetic wounds. AB - Lower-extremity wounds are a major complication of diabetes. Hemoglobin A1c (HbA1c) reflects glycemia over 2-3 months and is the standard measure used to monitor glycemia in diabetic patients, but results from studies have not shown a consistent association of HbA1c with wound healing. We hypothesized that elevated HbA1c would be most associated with poor wound healing. To test this hypothesis, we conducted a retrospective cohort study of 183 diabetic individuals treated at the Johns Hopkins Wound Center. Our primary outcome was wound-area healing rate (cm(2) per day). Calibrated tracings of digital images were used to measure wound area. We estimated coefficients for healing rate using a multiple linear regression model controlling for clustering of wounds within individuals and other common clinic variables. The study population was 45% female and 41% African American, with a mean age of 61 years. Mean HbA1c was 8.0%, and there were 2.3 wounds per individual (310 wounds total). Of all measures assessed, only HbA1c was significantly associated with wound-area healing rate. In particular, for each 1.0% point increase in HbA1c, the daily wound-area healing rate decreased by 0.028 cm(2) per day (95% confidence interval: 0.003, 0.0054, P = 0.027). Our results suggest that glycemia, as assessed by HbA1c, may be an important biomarker in predicting wound-healing rate in diabetic patients.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub. PMID- 21697891 TI - Upregulation of Fanconi anemia DNA repair genes in melanoma compared with non melanoma skin cancer. PMID- 21697892 TI - Demonstration of epitope-spreading phenomena in bullous pemphigoid: results of a prospective multicenter study. AB - Bullous pemphigoid (BP), the most common autoimmune subepidermal bullous disease, is associated with an autoantibody response to BP180 and BP230, two components of junctional adhesion complexes in human skin promoting dermo-epidermal cohesion. Retrospective analyses demonstrated that these autoantigens harbor several epitopes targeted by autoaggressive B and T cells. The aim of this prospective multicenter study was to assess the evolution of IgG autoantibodies in 35 BP patients over a 12-month observation period. Epitope-spreading (ES) events were detected in 17 of 35 BP patients (49%). They preferentially occurred in an early stage of the disease and were significantly related to disease severity at diagnosis. Moreover, in three patients, spreading of IgG reactivity to intracellular epitopes of BP180 and BP230 was preceded by recognition of the BP180 ectodomain. Finally, IgG reactivity with extracellular epitopes of BP180 and intracellular epitopes of BP230 correlated with the severity of BP in disease course. These findings support the idea that IgG recognition of the BP180 ectodomain is an early and crucial event in BP disease, followed by variable intra- and intermolecular ES events, which likely shape the individual course of BP. PMID- 21697893 TI - Visualizing the neutrophil response to sterile tissue injury in mouse dermis reveals a three-phase cascade of events. AB - Neutrophil granulocytes traffic into sites of organ injury in which they may not only participate in tissue repair and pathogen clearance but may also contribute to collateral cell damage through the release of noxious mediators. The dynamics and mechanisms of neutrophil migration in the extravascular space toward loci of tissue damage are not well understood. Here, we have used intravital multi-photon microscopy to dissect the behavior of neutrophils in response to tissue injury in the dermis of mice. We found that, following confined physical injury, initially rare scouting neutrophils migrated in a directional manner toward the damage focus. This was followed by the attraction of waves of additional neutrophils, and finally stabilization of the neutrophil cluster around the injury. Although neutrophil migration in the steady state and during the scouting phase depended on pertussis toxin-sensitive signals, the amplification phase was sensitive to interference with the cyclic adenosine diphosphate ribose pathway. We finally demonstrated that neutrophil scouts also transit through the non-inflamed dermis, suggesting immunosurveillance function by these cells. Together, our data unravel a three-step cascade of events that mediates the specific accumulation of neutrophils at sites of sterile tissue injury in the interstitial space. PMID- 21697894 TI - Impact of passive vibration on pressure pulse wave characteristics. AB - The augmentation index (AIx), a marker of wave reflection, decreases following acute leg exercise. Passive vibration (PV) causes local vasodilation that may reduce AIx. This study investigated the effects of acute PV on wave reflection and aortic hemodynamics. In a crossover fashion 20 (M=9, F=11) healthy young (22+/-3 year) participants were randomized to 10 min PV or no vibration control (CON) trials. Subjects rested in the supine position with their legs over a vibration platform for the entire session. Radial waveforms were obtained by applanation tonometry before and after 3 min (Post-3) and 30 min (Post-30) of PV (~5.37 G) or CON. No change in parameters was found at Post-3. We found significant time-by-trial interactions (P<0.01) at Post-30 for augmented pressure, AIx and second systolic peak pressure (P2), such that these parameters significantly (P<0.05) decreased (-2.3+/-3.0 mm Hg, -7.2+/-6.9% and -1.5+/-3.5 mm Hg, respectively) after PV but not after CON. These findings suggest that acute PV applied to the legs decreases AIx owing to a decrease in wave reflection magnitude (P2). Further research is warranted to evaluate the potential clinical application of PV in populations at an increased cardiovascular risk who are unable to perform conventional exercise. PMID- 21697895 TI - Developmental origins of health and disease: experimental and human evidence of fetal programming for metabolic syndrome. AB - The concept of developmental origins of health and disease has been defined as the process through which the environment encountered before birth, or in infancy, shapes the long-term control of tissue physiology and homeostasis. The evidence for programming derives from a large number of experimental and epidemiological observations. Several nutritional interventions during diverse phases of pregnancy and lactation in rodents are associated with fetal and neonatal programming for metabolic syndrome. In this paper, recent experimental models and human epidemiological studies providing evidence for the fetal programming associated with the development of metabolic syndrome and related diseases are revisited. PMID- 21697896 TI - Telomere length and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. AB - Short telomeres are associated with aging and age-related diseases. Our aim was to determine whether short leukocyte telomere length is associated with risk factors and cardiovascular diseases in a high-risk hypertensive population. We measured leukocyte telomere lengths at recruitment in 1271 subjects with hypertension and left ventricular hypertrophy (LVH) participating in the Lifestyle Interventions and Independence for Elders (LIFE) study. At baseline, short mean telomere length was associated with coronary artery disease in males (odds ratio (OR) 0.61, 95% confidence interval (CI) 0.39-0.95), and transient ischemic attack in females (OR 0.62 95% CI 0.39-0.99). Proportion of short telomeres (shorter than 5 kb) was associated with Framingham risk score (r=0.07, P<0.05), cerebrovascular disease (OR 1.18, 95% CI 1.01-1.15) and type 2 diabetes in men (OR 1.07, 95% CI 1.02-1.11). During follow-up, proportion of short telomeres was associated with combined cardiovascular mortality, stroke or angina pectoris (hazard ratio 1.04, 95% CI 1.01-1.07). Telomere length was not associated with smoking, body mass index, pulse pressure or self-reported use of alcohol. Our data suggest that reduced leukocyte telomere length is associated with cardiovascular risk factors and diseases as well as type 2 diabetes, and is a predictor of cardiovascular disease in elderly patients with hypertension and LVH. PMID- 21697897 TI - Cell migration: An ABC of the RHO subfamily. PMID- 21697900 TI - The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function. AB - Podosomes and invadopodia are actin-based dynamic protrusions of the plasma membrane of metazoan cells that represent sites of attachment to - and degradation of - the extracellular matrix. The key proteins in these structures include the actin regulators cortactin and neural Wiskott-Aldrich syndrome protein (N-WASP), the adaptor proteins Tyr kinase substrate with four SH3 domains (TKS4) and Tyr kinase substrate with five SH3 domains (TKS5), and the metalloprotease membrane type 1 matrix metalloprotease (MT1MMP; also known as MMP14). Many cell types can produce these structures, including invasive cancer cells, vascular smooth muscle and endothelial cells, and immune cells such as macrophages and dendritic cells. Recently, progress has been made in our understanding of the regulatory and functional aspects of podosome and invadopodium biology and their role in human disease. PMID- 21697903 TI - Mismeasure for mismeasure. PMID- 21697904 TI - Poetry in motion. PMID- 21697905 TI - Damned if they do. PMID- 21697902 TI - Mechanisms of nuclear reprogramming by eggs and oocytes: a deterministic process? AB - Differentiated cells can be experimentally reprogrammed back to pluripotency by nuclear transfer, cell fusion or induced pluripotent stem cell technology. Nuclear transfer and cell fusion can lead to efficient reprogramming of gene expression. The egg and oocyte reprogramming process includes the exchange of somatic proteins for oocyte proteins, the post-translational modification of histones and the demethylation of DNA. These events occur in an ordered manner and on a defined timescale, indicating that reprogramming by nuclear transfer and by cell fusion rely on deterministic processes. PMID- 21697901 TI - Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. AB - The proper regulation of apoptosis is essential for the survival of multicellular organisms. Furthermore, excessive apoptosis can contribute to neurodegenerative diseases, anaemia and graft rejection, and diminished apoptosis can lead to autoimmune diseases and cancer. It has become clear that the post-translational modification of apoptotic proteins by ubiquitylation regulates key components in cell death signalling cascades. For example, ubiquitin E3 ligases, such as MDM2 (which ubiquitylates p53) and inhibitor of apoptosis (IAP) proteins, and deubiquitinases, such as A20 and ubiquitin-specific protease 9X (USP9X) (which regulate the ubiquitylation and degradation of receptor-interacting protein 1 (RIP1) and myeloid leukaemia cell differentiation 1 (MCL1), respectively), have important roles in apoptosis. Therapeutic agents that target apoptotic regulatory proteins, including those that are part of the ubiquitin-proteasome system, might afford clinical benefits. PMID- 21697906 TI - Supreme Court ruling is good, bad and ugly. PMID- 21697918 TI - Vaccine trial's ethics criticized. PMID- 21697919 TI - Open access comes of age. PMID- 21697920 TI - City living marks the brain. PMID- 21697921 TI - Worth a dam? PMID- 21697922 TI - Researchers tweet technical talk. PMID- 21697923 TI - Drug buddies. PMID- 21697925 TI - Culturomics: Word play. PMID- 21697926 TI - Hidden depths. PMID- 21697927 TI - US and China need contact, not cold war. PMID- 21697932 TI - Promoting science careers in Brazil. PMID- 21697933 TI - Don't base Spanish funding on citations. PMID- 21697934 TI - Community is key to REDD success. PMID- 21697935 TI - Reward research that informs policy. PMID- 21697936 TI - Is China producing too many PhDs? PMID- 21697937 TI - Social neuroscience: Stress and the city. PMID- 21697938 TI - Materials science: Graphene moire mystery solved? PMID- 21697939 TI - Metabolism: A lipid for fat disorders. PMID- 21697940 TI - Quantum physics: Correlations without parts. PMID- 21697942 TI - Aerodynamics: The cost of flight in flocks. PMID- 21697943 TI - Organic chemistry: Triumph for unnatural synthesis. PMID- 21697944 TI - Regioselective reactions for programmable resveratrol oligomer synthesis. AB - Although much attention has been devoted to resveratrol, a unique polyphenol produced by plants and credited as potentially being responsible for the 'French paradox'--the observation that French people have a relatively low incidence of coronary heart disease, even though their diet is high in saturated fats--the oligomers of resveratrol have been largely ignored despite their high biological activity. Challenges in achieving their isolation in sufficient quantity from natural sources, coupled with an inability to prepare them easily synthetically, are seen as the main obstacles. Here we report a programmable, controlled and potentially scalable synthesis of the resveratrol family via a three-stage design. The synthetic approach requires strategy- and reagent-guided chemical functionalizations to differentiate two distinct cores possessing multiple sites with the same or similar reactivity, ultimately leading to five higher-order natural products. This work demonstrates that challenging, positionally selective functionalizations of complex materials are possible where biosynthetic studies have indicated otherwise, it provides materials and tools with which to unlock the full biochemical potential of this family of natural products, and it affords an intellectual framework within which other oligomeric families could potentially be accessed. PMID- 21697945 TI - Experimental non-classicality of an indivisible quantum system. AB - In contrast to classical physics, quantum theory demands that not all properties can be simultaneously well defined; the Heisenberg uncertainty principle is a manifestation of this fact. Alternatives have been explored--notably theories relying on joint probability distributions or non-contextual hidden-variable models, in which the properties of a system are defined independently of their own measurement and any other measurements that are made. Various deep theoretical results imply that such theories are in conflict with quantum mechanics. Simpler cases demonstrating this conflict have been found and tested experimentally with pairs of quantum bits (qubits). Recently, an inequality satisfied by non-contextual hidden-variable models and violated by quantum mechanics for all states of two qubits was introduced and tested experimentally. A single three-state system (a qutrit) is the simplest system in which such a contradiction is possible; moreover, the contradiction cannot result from entanglement between subsystems, because such a three-state system is indivisible. Here we report an experiment with single photonic qutrits which provides evidence that no joint probability distribution describing the outcomes of all possible measurements--and, therefore, no non-contextual theory--can exist. Specifically, we observe a violation of the Bell-type inequality found by Klyachko, Can, Binicioglu and Shumovsky. Our results illustrate a deep incompatibility between quantum mechanics and classical physics that cannot in any way result from entanglement. PMID- 21697946 TI - Flying in a flock comes at a cost in pigeons. AB - Flying birds often form flocks, with social, navigational and anti-predator implications. Further, flying in a flock can result in aerodynamic benefits, thus reducing power requirements, as demonstrated by a reduction in heart rate and wingbeat frequency in pelicans flying in a V-formation. But how general is an aerodynamic power reduction due to group-flight? V-formation flocks are limited to moderately steady flight in relatively large birds, and may represent a special case. What are the aerodynamic consequences of flying in the more usual 'cluster' flock? Here we use data from innovative back-mounted Global Positioning System (GPS) and 6-degrees-of-freedom inertial sensors to show that pigeons (1) maintain powered, banked turns like aircraft, imposing dorsal accelerations of up to 2g, effectively doubling body weight and quadrupling induced power requirements; (2) increase flap frequency with increases in all conventional aerodynamic power requirements; and (3) increase flap frequency when flying near, particularly behind, other birds. Therefore, unlike V-formation pelicans, pigeons do not gain an aerodynamic advantage from flying in a flock. Indeed, the increased flap frequency, whether due to direct aerodynamic interactions or requirements for increased stability or control, suggests a considerable energetic cost to flight in a tight cluster flock. PMID- 21697947 TI - City living and urban upbringing affect neural social stress processing in humans. AB - More than half of the world's population now lives in cities, making the creation of a healthy urban environment a major policy priority. Cities have both health risks and benefits, but mental health is negatively affected: mood and anxiety disorders are more prevalent in city dwellers and the incidence of schizophrenia is strongly increased in people born and raised in cities. Although these findings have been widely attributed to the urban social environment, the neural processes that could mediate such associations are unknown. Here we show, using functional magnetic resonance imaging in three independent experiments, that urban upbringing and city living have dissociable impacts on social evaluative stress processing in humans. Current city living was associated with increased amygdala activity, whereas urban upbringing affected the perigenual anterior cingulate cortex, a key region for regulation of amygdala activity, negative affect and stress. These findings were regionally and behaviourally specific, as no other brain structures were affected and no urbanicity effect was seen during control experiments invoking cognitive processing without stress. Our results identify distinct neural mechanisms for an established environmental risk factor, link the urban environment for the first time to social stress processing, suggest that brain regions differ in vulnerability to this risk factor across the lifespan, and indicate that experimental interrogation of epidemiological associations is a promising strategy in social neuroscience. PMID- 21697949 TI - The Bcl-2 repertoire of mesothelioma spheroids underlies acquired apoptotic multicellular resistance. AB - Three-dimensional (3D) cultures are a valuable platform to study acquired multicellular apoptotic resistance of cancer. We used spheroids of cell lines and actual tumor to study resistance to the proteasome inhibitor bortezomib in mesothelioma, a highly chemoresistant tumor. Spheroids from mesothelioma cell lines acquired resistance to bortezomib by failing to upregulate Noxa, a pro apoptotic sensitizer BH3-only protein that acts by displacing Bim, a pro apoptotic Bax/Bak-activator protein. Surprisingly, despite their resistance, spheroids also upregulated Bim and thereby acquired sensitivity to ABT-737, an inhibitor of anti-apoptotic Bcl-2 molecules. Analysis using BH3 profiling confirmed that spheroids acquired a dependence on anti-apoptotic Bcl-2 proteins and were 'primed for death'. We then studied spheroids grown from actual mesothelioma. ABT-737 was active in spheroids grown from those tumors (5/7, ~70%) with elevated levels of Bim. Using immunocytochemistry of tissue microarrays of 48 mesotheliomas, we found that most (33, 69%) expressed elevated Bim. In conclusion, mesothelioma cells in 3D alter the expression of Bcl-2 molecules, thereby acquiring both apoptotic resistance and sensitivity to Bcl-2 blockade. Mesothelioma tumors ex vivo also show sensitivity to Bcl-2 blockade that may depend on Bim, which is frequently elevated in mesothelioma. Therefore, mesothelioma, a highly resistant tumor, may have an intrinsic sensitivity to Bcl 2 blockade that can be exploited therapeutically. PMID- 21697950 TI - Axotomy induces axonogenesis in hippocampal neurons through STAT3. AB - After axotomy of embryonic hippocampal neurons in vitro, some of the axotomized axons lose their identity, and new axons arise and grow. This axotomy-induced axonogenesis requires importin, suggesting that some injury-induced signals are transported via axons to elicit axonogenesis after axotomy. In this study, we show that STAT3 is activated in response to axotomy. Because STAT3 was co immunoprecipitated with importin beta in the axotomized neurons, we suggest that STAT3 is retrogradely transported as molecular cargo of importin alpha/beta heterodimers. Indeed, inhibition of importin alpha binding with STAT3 resulted in the attenuation of axonogenesis. Silencing STAT3 blocked the axonogenesis, demonstrating that STAT3 is necessary for axotomy-induced axonogenesis. Furthermore, the overexpression of STAT3 enhanced axotomy-induced axonogenesis. Taken together, these results demonstrate that activation and retrograde transport of STAT3 in injured axons have key roles in the axotomy-induced axonogenesis of hippocampal neurons. PMID- 21697951 TI - New therapeutic targets in Alzheimer's disease: brain deregulation of calcium and zinc. AB - The molecular determinants of Alzheimer's (AD) disease are still not completely known; however, in the past two decades, a large body of evidence has indicated that an important contributing factor for the disease is the development of an unbalanced homeostasis of two signaling cations: calcium (Ca(2+)) and zinc (Zn(2+)). Both ions serve a critical role in the physiological functioning of the central nervous system, but their brain deregulation promotes amyloid-beta dysmetabolism as well as tau phosphorylation. AD is also characterized by an altered glutamatergic activation, and glutamate can promote both Ca(2+) and Zn(2+) dyshomeostasis. The two cations can operate synergistically to promote the generation of free radicals that further intracellular Ca(2+) and Zn(2+) rises and set the stage for a self-perpetuating harmful loop. These phenomena can be the initial steps in the pathogenic cascade leading to AD, therefore, therapeutic interventions aiming at preventing Ca(2+) and Zn(2+) dyshomeostasis may offer a great opportunity for disease-modifying strategies. PMID- 21697955 TI - Regulation of gene expression in prostate cancer cells with an artificially constructed promoter responsive to radiation. AB - A promoter library was developed that is composed of DNA fragments constructed by randomly elongating the cis-acting elements of transcription factors presumably activated in prostate cancer by radiation, and linking to the TATA-box sequence. One promoter with the strongest reactivity to X-ray in the LNCap cells of the library was chosen and improved by the introduction of random mutations. The resultant promoter was designated clone 880-8, showing the highest dose-dependent activity enhancement with X-ray irradiation (X-irradiation). A recombinant retrovirus expressing the luciferase gene under the control of clone 880-8 was infected into LNCap cells that showed 9.12+/-0.36-fold enhancement of luciferase activity 12 h after X-irradiation at 10 Gy. When the infected cells were inoculated onto nude mice, enhancement of luciferase expression was 4.27+/-1.36 fold 12 h after X-irradiation at 10 Gy. When LNCap was infected with another recombinant carrying the fcy::fur gene downstream from clone 880-8, fcy::fur expression was enhanced by X-irradiation. It was also shown to increase the dose dependent cell killing ratio with 5-FC as compared with a counterpart without X irradiation. These results suggest that the method used in this study is effective to construct a promoter responsive to stimulation. Such promoters can be used for stimulation-controlled gene therapies. PMID- 21697953 TI - Efficient cochlear gene transfection in guinea-pigs with adeno-associated viral vectors by partial digestion of round window membrane. AB - The auditory portion of the inner ear, the cochlea, is an ideal organ for local gene transfection owing to its relative isolation. Various carriers have been tested for cochlear gene transfection. To date, viral vectors appear to have much higher transfection efficacy than non-viral mechanisms. Among these vectors, recombinant adeno-associated virus (rAAV) vectors have several advantages such as being non-pathogenic and the ability to produce prolonged gene expression in various cell types. However, rAAV vectors cannot pass through the intact round window membrane (RWM), otherwise a very attractive approach to access the human inner ear. In this study, performed in guinea-pigs, we describe a method to increase the permeability of RWM to rAAV vectors by partial digestion with collagenase solution. Elevated delivery of rAAV across the partially digested RWM increased transfection efficacy to a satisfactory level, even though it was still lower than that achieved by direct cochleostomy injection. Functional tests (auditory brainstem responses) showed that this enzymatic manipulation did not cause permanent hearing loss if applied appropriately. Morphological observations suggested that the damage to RWM caused by partial digestion healed within four weeks. Taken together, these findings suggest that partial digestion of the RWM is a safe and effective method for increasing the transfection of cochlear sensory cells with rAAV. PMID- 21697954 TI - Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. AB - Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs. PMID- 21697956 TI - Experimental autoimmune hearing loss is exacerbated in IL-10-deficient mice and reversed by IL-10 gene transfer. AB - Interleukin-10 (IL-10) has an important role in the homeostatic regulation of autoreactive T-cell repertoire. We hypothesized that endogenous IL-10 would regulate the severity of beta-tubulin-induced experimental autoimmune hearing loss (EAHL) and that exogenous IL-10 would abrogate it. BALB/c wild-type (WT) and homozygous IL-10-deficient mice (IL-10(-/-)) underwent beta-tubulin immunization to develop EAHL; some IL-10 mice with EAHL were administered IL-10 DNA at the peak of EAHL. Auditory brainstem responses were examined over time. EAHL developed progressively in both WT and IL-10(-/-) mice. However, the severity of hearing loss in the IL-10(-/-) mice was significantly greater than that in WT animals. Moreover, disease severity was associated with a significantly enhanced interferon-gamma level and loss of hair cells in IL-10(-/-) mice. IL-10 administered to EAHL IL-10(-/-) mice promoted IL-10 expression. Consequently, hearing significantly improved by protecting hair cells in established EAHL. Importantly, IL-10 treatment suppressed proliferation of antigen-specific T helper type 1 (Th1) cells, and the suppression can be attributed to inducing IL 10-secreting regulatory T cells that suppressed autoreactive T cells. We demonstrated that the lack of IL-10 exacerbated hearing loss, and the exogenous administration of IL-10 improved hearing. Mechanistically, our results indicate that IL-10 is capable of controlling autoimmune reaction severity by suppressing Th1-type proinflammatory responses and inducing IL-10-secreting regulatory T cells. PMID- 21697957 TI - Gold nanoparticle-mediated gene delivery induces widespread changes in the expression of innate immunity genes. AB - The unique properties of oligonucleotide (and small interfering RNA)-modified gold nanoparticle conjugates make them promising intracellular gene regulation agents. We found that gold nanoparticles stably functionalized with covalently attached oligonucleotides activate immune-related genes and pathways in human peripheral blood mononuclear cells, but not an immortalized, lineage-restricted cell line. These findings have strong implications for the application of oligonucleotide-modified gold nanoparticle conjugates in translational research and in the development of therapeutics and gene delivery systems. PMID- 21697958 TI - The significance of nitrogen cost minimization in proteomes of marine microorganisms. AB - Marine microorganisms thrive under low levels of nitrogen (N). N cost minimization is a major selective pressure imprinted on open-ocean microorganism genomes. Here we show that amino-acid sequences from the open ocean are reduced in N, but increased in average mass compared with coastal-ocean microorganisms. Nutrient limitation exerts significant pressure on organisms supporting the trade off between N cost minimization and increased average mass of amino acids that is a function of increased A+T codon usage. N cost minimization, especially of highly expressed proteins, reduces the total cellular N budget by 2.7-10%; this minimization in combination with reduction in genome size and cell size is an evolutionary adaptation to nutrient limitation. The biogeochemical and evolutionary precedent for these findings suggests that N limitation is a stronger selective force in the ocean than biosynthetic costs and is an important evolutionary strategy in resource-limited ecosystems. PMID- 21697959 TI - Dimorphism in methane seep-dwelling ecotypes of the largest known bacteria. AB - We present evidence for a dimorphic life cycle in the vacuolate sulfide-oxidizing bacteria that appears to involve the attachment of a spherical Thiomargarita-like cell to the exteriors of invertebrate integuments and other benthic substrates at methane seeps. The attached cell elongates to produce a stalk-like form before budding off spherical daughter cells resembling free-living Thiomargarita that are abundant in surrounding sulfidic seep sediments. The relationship between the attached parent cell and free-living daughter cell is reminiscent of the dimorphic life modes of the prosthecate Alphaproteobacteria, but on a grand scale, with individual elongate cells reaching nearly a millimeter in length. Abundant growth of attached Thiomargarita-like bacteria on the integuments of gastropods and other seep fauna provides not only a novel ecological niche for these giant bacteria, but also for animals that may benefit from epibiont colonization. PMID- 21697960 TI - Analysis of bacterial core communities in the central Baltic by comparative RNA DNA-based fingerprinting provides links to structure-function relationships. AB - Understanding structure-function links of microbial communities is a central theme of microbial ecology since its beginning. To this end, we studied the spatial variability of the bacterioplankton community structure and composition across the central Baltic Sea at four stations, which were up to 450 km apart and at a depth profile representative for the central part (Gotland Deep, 235 m). Bacterial community structure was followed by 16S ribosomal RNA (rRNA)- and 16S rRNA gene-based fingerprints using single-strand conformation polymorphism (SSCP) electrophoresis. Species composition was determined by sequence analysis of SSCP bands. High similarities of the bacterioplankton communities across several hundred kilometers were observed in the surface water using RNA- and DNA-based fingerprints. In these surface communities, the RNA- and DNA-based fingerprints resulted in very different pattern, presumably indicating large difference between the active members of the community as represented by RNA-based fingerprints and the present members represented by the DNA-based fingerprints. This large discrepancy changed gradually over depth, resulting in highly similar RNA- and DNA-based fingerprints in the anoxic part of the water column below 130 m depth. A conceivable mechanism explaining this high similarity could be the reduced oxidative stress in the anoxic zone. The stable communities on the surface and in the anoxic zone indicate the strong influence of the hydrography on the bacterioplankton community structure. Comparative analysis of RNA- and DNA based community structure provided criteria for the identification of the core community, its key members and their links to biogeochemical functions. PMID- 21697961 TI - Community ecology of hot spring cyanobacterial mats: predominant populations and their functional potential. AB - Phototrophic microbial mat communities from 60 degrees C and 65 degrees C regions in the effluent channels of Mushroom and Octopus Springs (Yellowstone National Park, WY, USA) were investigated by shotgun metagenomic sequencing. Analyses of assembled metagenomic sequences resolved six dominant chlorophototrophic populations and permitted the discovery and characterization of undescribed but predominant community members and their physiological potential. Linkage of phylogenetic marker genes and functional genes showed novel chlorophototrophic bacteria belonging to uncharacterized lineages within the order Chlorobiales and within the Kingdom Chloroflexi. The latter is the first chlorophototrophic member of Kingdom Chloroflexi that lies outside the monophyletic group of chlorophototrophs of the Order Chloroflexales. Direct comparison of unassembled metagenomic sequences to genomes of representative isolates showed extensive genetic diversity, genomic rearrangements and novel physiological potential in native populations as compared with genomic references. Synechococcus spp. metagenomic sequences showed a high degree of synteny with the reference genomes of Synechococcus spp. strains A and B', but synteny declined with decreasing sequence relatedness to these references. There was evidence of horizontal gene transfer among native populations, but the frequency of these events was inversely proportional to phylogenetic relatedness. PMID- 21697962 TI - Metatranscriptomic analyses of chlorophototrophs of a hot-spring microbial mat. AB - The phototrophic microbial mat community of Mushroom Spring, an alkaline siliceous hot spring in Yellowstone National Park, was studied by metatranscriptomic methods. RNA was extracted from mat specimens collected at four timepoints during light-to-dark and dark-to-light transitions in one diel cycle, and these RNA samples were analyzed by both pyrosequencing and SOLiD technologies. Pyrosequencing was used to assess the community composition, which showed that ~84% of the rRNA was derived from members of four kingdoms Cyanobacteria, Chloroflexi, Chlorobi and Acidobacteria. Transcription of photosynthesis-related genes conclusively demonstrated the phototrophic nature of two newly discovered populations; these organisms, which were discovered through metagenomics, are currently uncultured and previously undescribed members of Chloroflexi and Chlorobi. Data sets produced by SOLiD sequencing of complementary DNA provided >100-fold greater sequence coverage. The much greater sequencing depth allowed transcripts to be detected from ~15,000 genes and could be used to demonstrate statistically significant differential transcription of thousands of genes. Temporal differences for in situ transcription patterns of photosynthesis related genes suggested that the six types of chlorophototrophs in the mats may use different strategies for maximizing their solar-energy capture, usage and growth. On the basis of both temporal pattern and transcript abundance, intra guild gene expression differences were also detected for two populations of the oxygenic photosynthesis guild. This study showed that, when community-relevant genomes and metagenomes are available, SOLiD sequencing technology can be used for metatranscriptomic analyses, and the results suggested that this method can potentially reveal new insights into the ecophysiology of this model microbial community. PMID- 21697963 TI - Thermophilic anaerobic oxidation of methane by marine microbial consortia. AB - The anaerobic oxidation of methane (AOM) with sulfate controls the emission of the greenhouse gas methane from the ocean floor. AOM is performed by microbial consortia of archaea (ANME) associated with partners related to sulfate-reducing bacteria. In vitro enrichments of AOM were so far only successful at temperatures <=25 degrees C; however, energy gain for growth by AOM with sulfate is in principle also possible at higher temperatures. Sequences of 16S rRNA genes and core lipids characteristic for ANME as well as hints of in situ AOM activity were indeed reported for geothermally heated marine environments, yet no direct evidence for thermophilic growth of marine ANME consortia was obtained to date. To study possible thermophilic AOM, we investigated hydrothermally influenced sediment from the Guaymas Basin. In vitro incubations showed activity of sulfate dependent methane oxidation between 5 and 70 degrees C with an apparent optimum between 45 and 60 degrees C. AOM was absent at temperatures >=75 degrees C. Long-term enrichment of AOM was fastest at 50 degrees C, yielding a 13-fold increase of methane-dependent sulfate reduction within 250 days, equivalent to an apparent doubling time of 68 days. The enrichments were dominated by novel ANME-1 consortia, mostly associated with bacterial partners of the deltaproteobacterial HotSeep-1 cluster, a deeply branching phylogenetic group previously found in a butane-amended 60 degrees C-enrichment culture of Guaymas sediments. The closest relatives (Desulfurella spp.; Hippea maritima) are moderately thermophilic sulfur reducers. Results indicate that AOM and ANME archaea could be of biogeochemical relevance not only in cold to moderate but also in hot marine habitats. PMID- 21697964 TI - Human cadaver brain infusion skull model for neurosurgical training. AB - BACKGROUND: Microsurgical technique and anatomical knowledge require extensive laboratory training. Human cadaver models are especially valuable as they supply a good microsurgical training environment simultaneously providing authentic brain anatomy. We developed the "skull infusion model" as an extension of our previous "brain infusion model" taking it a step further maintaining simplicity but enhancing realism. METHODS: Four human cadaveric brains donated for educational purposes were explanted at autopsy. The specimens were prepared cannulating carotid and vertebral arteries with plastic tubings, flushed with abundant water and fixed for 1 month in formaldehyde. They were then enclosed with white silk clothing (emulating the dura mater) and inserted into human skulls cut previously into two pieces. Tap water at a flow rate of 10 L/h was infused through the arterial tubings. RESULTS: Diverse microsurgical procedures were performed by two trainees, including craniotomies with microsurgical approaches and techniques such as sylvian fissure exposure, extra-intracranial and intra-intracranial bypass, approaches to the ventricles and choroidal fissure opening. The water infusion fills the arterial system, leaking into the interstitial and cisternal space and finally moistening the whole specimen. This makes vascular microsurgical techniques become extremely realistic, increasing its compliance making manipulations easier and more authentic. CONCLUSIONS: Standard microsurgical laboratories frequently have difficulties to work with decapitated human cadaver heads but could have human brains readily available. Using the infusion model and inserting it in a human skull makes the environment much more realistic. Its simplicity and inexpensiveness make it a good alternative for developing microsurgical techniques. PMID- 21697965 TI - Histiocytosis X: Characteristics, behavior, and treatments as illustrated in a case series. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) is a proliferative disorder predominantly found in children. It often presents with pain in calvarium or spine and may cause neuroendocrine symptoms. The gold standard for diagnosing LCH is the detection of Birbeck Granules by EM. Here, we describe two unique presentations of LCH and we review current treatment guidelines. CASE DESCRIPTION: The first patient was a 23-year-old man who presented with progressive swelling and redness of the left eye. MRI revealed a left retrobulbar lesion extending into the middle cranial fossa with no signal abnormality in the brain parenchyma. The lesion was resected and pathological analysis revealed LCH. Bone scans were negative and the patient was discharged soon after. He later underwent fractionated radiotherapy (cumulative dose 26 Gy). Follow-up MRIs show no disease at 24 months post-op. The second patient was a 56-year-old man with left frontal skull pain for 5 months. Imaging showed a solitary osteolytic lesion extending into both dura and scalp with no signal abnormality of the parenchyma. Excisional biopsy revealed LCH. Surgery was well tolerated and follow-up imaging shows no recurrence at 24 months post-op. CONCLUSION: We demonstrate that LCH, though uncommon, must remain on the differential when osteolytic lesions present in the adult. Although LCH often has the clinical and radiographical presentation of an abscess, pathology analysis can successfully diagnose LCH based on markers and morphological characteristics. LCH has an excellent prognosis when treated aggressively with surgical resection and radiotherapy as both of our patients were and are now disease free at 2 year follow-up. PMID- 21697966 TI - Pediatric traumatic putamenal strokes: Mechanisms and prognosis. AB - BACKGROUND: Studies have shown that nearly 3% of closed head injuries result in basal ganglia hemorrhages and that this may be a more frequent occurrence in pediatric patients. Various mechanisms based on shearing forces have been implicated in the injury; however, the underlying mechanism leading to the increased incidence in pediatric patients has not been well described. Angiographic data suggest that putamenal perforators in children are more severely stretched at acute angles compared to those in adults, which may be a contributing factor to the increased incidence. CASE DESCRIPTION: We discuss a series of five relatively benign cases of traumatic putamenal strokes in children and review their presentations, mechanism of injury, neurological deficits, and management with reference to available literature. CONCLUSION: Although generally an alarming situation, benign presentations of putamenal strokes may be seen in pediatric populations after closed head injuries. In such cases, conservative management with subsequent rehabilitation and physical therapy is recommended. PMID- 21697967 TI - A rare case of greater petrosal nerve schwannoma. AB - BACKGROUND: Facial nerve schwannomas include only 0.8% of all intrapetrous mass lesions, and schwannomas originating exclusively from the greater petrosal nerve (GPN) are extremely rare. To date, only 13 reports have been described. In this case, the tumor was thought to originate from the GPN on the basis of clinical, radiological, and operative findings. CASE DESCRIPTION: A 23-year-old girl presented an acute left facial palsy, a disturbance in tear secretion of the ipsilateral eye, and a left-sided conductive hypoacusia. Computed tomography (CT) scan and magnetic resonance imaging (MRI) showed an extradural mass in the left middle fossa. A subtemporal approach was performed and the lesion, originating from the proximal portion of the GPN, was excised. The post-operative course was satisfactory, except for a xerophtalmia, which was treated with artificial teardrops. CONCLUSION: GPN schwannomas can originate anywhere alongside the course of the nerve, from its proximal segment near the facial hiatus to its distal segment near the foramen lacerum. For these reasons, it requires differential diagnosis with trigeminal nerve schwannomas or with injuries arising from the geniculate ganglion, because it can be easily confused with those lesions. However, in less severe cases, an early diagnosis can be able to preserve the function of the facial nerve by reducing iatrogenic injuries caused by surgical maneuvers. PMID- 21697969 TI - Recombinant human bone morphogenetic protein 2 labeled use in spinal surgery and sexual dysfunction. PMID- 21697968 TI - Virtual reality training in neurosurgery: Review of current status and future applications. AB - BACKGROUND: Over years, surgical training is changing and years of tradition are being challenged by legal and ethical concerns for patient safety, work hour restrictions, and the cost of operating room time. Surgical simulation and skill training offer an opportunity to teach and practice advanced techniques before attempting them on patients. Simulation training can be as straightforward as using real instruments and video equipment to manipulate simulated "tissue" in a box trainer. More advanced virtual reality (VR) simulators are now available and ready for widespread use. Early systems have demonstrated their effectiveness and discriminative ability. Newer systems enable the development of comprehensive curricula and full procedural simulations. METHODS: A PubMed review of the literature was performed for the MESH words "Virtual reality, "Augmented Reality", "Simulation", "Training", and "Neurosurgery". Relevant articles were retrieved and reviewed. A review of the literature was performed for the history, current status of VR simulation in neurosurgery. RESULTS: Surgical organizations are calling for methods to ensure the maintenance of skills, advance surgical training, and credential surgeons as technically competent. The number of published literature discussing the application of VR simulation in neurosurgery training has evolved over the last decade from data visualization, including stereoscopic evaluation to more complex augmented reality models. With the revolution of computational analysis abilities, fully immersive VR models are currently available in neurosurgery training. Ventriculostomy catheters insertion, endoscopic and endovascular simulations are used in neurosurgical residency training centers across the world. Recent studies have shown the coloration of proficiency with those simulators and levels of experience in the real world. CONCLUSION: Fully immersive technology is starting to be applied to the practice of neurosurgery. In the near future, detailed VR neurosurgical modules will evolve to be an essential part of the curriculum of the training of neurosurgeons. PMID- 21697970 TI - Rarest of the rare: Chordoid glioma infiltrating the optic chiasm. AB - BACKGROUND: Chordoid glioma is a rare brain tumor typically located within the anterior third ventricle. It is a well-circumscribed, non-infiltrative tumor that grows as a mass within the ventricle. CASE DESCRIPTION: We present the case of a 50-year-old woman with a chordoid glioma located in the anterior third ventricle. Unusually, MRI revealed an enlarged optic chiasm. Histological sampling of the chiasm revealed tumor invasion. CONCLUSION: Involvement of the optic apparatus is generally thought to be an imaging feature that can be used to distinguish chordoid gliomas from optic/hypothalamic gliomas. This case provides the first reported exception to this dogma. PMID- 21697971 TI - Balloon-assisted coiling of the proximal lobule of a paraophthalmic aneurysm causing panhypopituitarism: Technical case report. AB - BACKGROUND: We describe an intra-aneurysmal balloon-assisted technique to limit the coil volume in a large bilobulated paraophthalmic aneurysm. Our intent was to reduce the mass effect and presenting symptoms of diabetes insipidus (DI) with hypopituitarism. CASE DESCRIPTION: A 32-year-old woman presented with symptoms of DI and her work-up demonstrated hypopituitarism and partial bitemporal visual field defects. Cerebral angiography revealed a large paraophthalmic aneurysm with two distinctive lobules, projecting toward the pituitary fossa. The patient declined craniotomy but consented for endovascular treatment. The plan was to limit the embolization to the proximal lobule only. Initially, we used a dual microcatheter technique with a microcatheter in each lobule. A framing coil in the distal lobule did not prevent coil migration from the proximal lobule. Instead, we elected to use a Hyperform balloon in the distal lobule and were able to successfully coil the proximal lobule only. Her 3-year follow-up angiogram revealed a completely occluded aneurysm. The patient experienced resolution of the DI and improvement of her visual fields. However, she remained in hypopituitarism. CONCLUSION: Intra-aneurysmal balloon-assisted coiling of proximal aneurysmal lobules might be an alternative for the reduction of mass effect related to the coil mass. Careful follow-up is needed because subtotal occlusion carries a future risk of growth, recanalization and rupture. Unruptured intracranial carotid aneurysms can present with reversible DI and usually permanent pituitary disturbances. PMID- 21697972 TI - Amebic encephalitis. AB - BACKGROUND: Amebic encephalitis (granulomatous amebic encephalitis, GAE) an extremely rare disease occurring in immunocompromised patients. Presentation and early imaging findings are nonspecific. In GAE, enhancement may or may not be seen on imaging studies despite the presence of an aggressive, necrotizing, parasitic infection. CASE DESCRIPTION: The patient was a 79-year-old man with ill defined autoimmune hepatitis. He was on mild immunosuppression with 6-MP and low dose prednisone. He presented with an acute febrile illness and obtundation. Imaging revealed a nonenhancing mass lesion of the frontal lobe. The patient briefly improved on high-dose steroids, then deteriorated again, with repeat imaging showing enlargement of the edematous brain lesion and herniation. The patient underwent craniotomy for evacuation of a necrotic brain lesion. His condition did not improve. Frozen section revealed only necrosis. Permanent pathology revealed GAE caused by Acanthamoeba. CONCLUSION: Neurosurgeons should remain aware of this rare disease. Imaging is variable and may not show enhancement or necrosis despite large areas of parasitic infection. PMID- 21697973 TI - Acute formation of a pseudoaneurysm adjacent to a previously clipped anterior communicating artery aneurysm. AB - BACKGROUND: Cerebral pseudoaneurysms, especially of the anterior communicating artery (ACoA), are rare. CASE DESCRIPTION: Herein, the authors report a 66-year old patient who underwent successful clip ligation of a small ruptured ACoA aneurysm. Eighteen days after surgery, he suffered from another episode of subarachnoid hemorrhage due to the rupture of a newly formed pseudoaneurysm adjacent to the previously clipped aneurysm. This pseudoaneurysm was treated through clip ligation as well. CONCLUSION: A pseudoaneurysm may rarely form adjacent to a previously clipped cerebral aneurysm and should be included in the differential diagnosis of recurrent subarachnoid hemorrhage. Potential mechanisms of formation and management strategies for this challenging problem will be discussed. PMID- 21697974 TI - Endoscopic endonasal removal of a cavernous hemangioma of the orbital apex. AB - BACKGROUND: Cavernous hemangioma are the most common benign lesions of the orbit. Their surgical resection is still challenging and several surgical approaches have been proposed. CASE DESCRIPTION: We present the case of a 59-year-old woman with a cavernous hemangioma of the orbital apex, which was diagnosed incidentally. The hemangioma was extraconal and involved mainly the medial orbital apex; it also extended to the pterygoid fossa, to the middle fossa, to the maxillary and sphenoid sinuses. The surgical resection was performed by a pure endoscopic transphenoidal, transmaxillary, transethmoidal approach, achieving a total removal. The patient had a transient and incomplete paresis of the VI cranial nerve on the left side and did not experience other postoperative complications. CONCLUSION: The endoscopic endonasal approach proved successful in the management of this case and it should be considered in the surgical management of extraconal orbital apex lesions with medial or inferior extension. PMID- 21697975 TI - Clusters of nucleotide substitutions and insertion/deletion mutations are associated with repeat sequences. AB - The genome-sequencing gold rush has facilitated the use of comparative genomics to uncover patterns of genome evolution, although their causal mechanisms remain elusive. One such trend, ubiquitous to prokarya and eukarya, is the association of insertion/deletion mutations (indels) with increases in the nucleotide substitution rate extending over hundreds of base pairs. The prevailing hypothesis is that indels are themselves mutagenic agents. Here, we employ population genomics data from Escherichia coli, Saccharomyces paradoxus, and Drosophila to provide evidence suggesting that it is not the indels per se but the sequence in which indels occur that causes the accumulation of nucleotide substitutions. We found that about two-thirds of indels are closely associated with repeat sequences and that repeat sequence abundance could be used to identify regions of elevated sequence diversity, independently of indels. Moreover, the mutational signature of indel-proximal nucleotide substitutions matches that of error-prone DNA polymerases. We propose that repeat sequences promote an increased probability of replication fork arrest, causing the persistent recruitment of error-prone DNA polymerases to specific sequence regions over evolutionary time scales. Experimental measures of the mutation rates of engineered DNA sequences and analyses of experimentally obtained collections of spontaneous mutations provide molecular evidence supporting our hypothesis. This study uncovers a new role for repeat sequences in genome evolution and provides an explanation of how fine-scale sequence contextual effects influence mutation rates and thereby evolution. PMID- 21697976 TI - Expression of thioredoxin-1 and hypoxia inducible factor-1alpha in cerebral arteriovenous malformations: Possible role of redox regulatory factor in neoangiogenic property. AB - BACKGROUND: Recently it is reported that proliferative activity remains in vascular walls of cerebral arteriovenous malformations (AVMs). These reports indicate that endothelial cells in AVMs have the neoangiogenic property. In this study, we assess the role of thioredoxin-1 (Trx-1) and hypoxia-inducible factor 1a (HIF-1alpha) in AVMs. These factors are reported to play a role in neoangiogenesis. METHODS: We analyzed the expressions of Trx1 in the specimens of human cerebral AVMs. In addition, we also analyzed the expression of HIF-1alpha in these specimens by immunohistochemical method and RT-PCR. Furthermore, we assessed the effect of redox state and expression of Trx-1 during neoangiogenesis using in vitro angiogenesis assay. FINDINGS: Trx-1 and HIF-1alpha immunoreactivity was detected in almost all 17 specimens of AVMs. Trx-1 and HIF 1alpha immunoreactive cells were distributed mainly endothelium of intranidal arteries and enlarged veins with thickened vascular walls. Double staining shows that Trx-1 and VEGF (vascular endothelial growth factor) immunoreactivity were colocalized in the same cells. These cells were considered to be endothelial cells. HIF-1alpha immunoreactivity was also colocalized with VEGF immunoreactivity in endothelium. As for influencing factors, the presence of deep drainers and convulsion significantly associated with HIF-1alpha expression. Trx 1 assessed by western blotting decreased at 6 hours and 12 hours after plating on Matrigel, which is a model of angiogenesis. CONCLUSIONS: We have shown that the endothelial induction of Trx-1 and HIF-1alpha in cerebral AVMs. Based on all findings obtained in this study, Trx-1 may affect the neoangiogenic property of cerebral AVMs. PMID- 21697977 TI - Delayed intracranial and bony metastasis of paraganglioma. AB - BACKGROUND: Paragangliomas are tumors of neural crest origin that arise from the extra-adrenal paraganglia. In contrast with the often quoted 10% rule of malignancy for pheochromocytomas, the rate of malignancy as defined by local invasion or distant metastasis has been reported to be from 20% to as high as 50% in some case series with the most common sites of distant metastases being the liver, lungs, and bones. Here we present the case of a patient who presented with a rare case of intracranial metastasis from abdominal paraganglioma. CASE DESCRIPTION: Our patient was a 48-year-old male with a distant history of multiple resections of abdominal paraganglioma in 1975 who presented with left shoulder, and left occipital metastasis 35 years after his original paraganglioma operations. CONCLUSIONS: Intracranial metastasis of paraganglioma is rare. There are unfortunately no known criteria to assess the risk of metastatic potential and given the long possible latency period between the resection of the primary tumor and the discovery of metastatic disease, patients with paragangliomas require lifelong monitoring. The optimal interval of monitoring has not been elucidated but follow-up every 5-10 years seems warranted. PMID- 21697978 TI - Neuroscience research fails to support claims that excessive pornography consumption causes brain damage. PMID- 21697979 TI - Near-infrared spectroscopy monitoring of cerebral oxygen during assisted ventilation. AB - BACKGROUND: Changes in the arterial partial pressure of CO(2) (PaCO(2)) has a direct though transient effect on the cerebral vasculature and cerebral circulation. Decreased PaCO(2) levels lead to vasoconstriction and can result in dangerously low levels of cerebral perfusion that resolve in 4-6 h. It is currently believed that perfusion abnormalities contribute to intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) in the neonate. PaCO(2) induced vasoconstriction may contribute to the pathology of IVH and PVL. METHODS: Near-infrared spectroscopy [NIRS; (INVOS cerebral/somatic oximeter; Somanetics Corporation, Troy, MI, USA)] was utilized to determine changes in regional oxygenation (rSO(2)) of the brain in response to changes in ventilation in isoflurane anesthetized newborn piglets. RESULTS: Changes in cerebral rSO(2) correlated significantly with end-tidal CO(2) levels and to blood flow in the common carotid artery. This correlation was significant during baseline conditions, after periods of CO(2) loading and during periods of hypothermia. CONCLUSIONS: The results of the study demonstrate the utility of NIRS to accurately reflect changes in cerebral oxygenation and flow to the brain in response to changes in CO(2) levels in anesthetized, ventilated neonatal piglets. The use of NIRS may provide an early alert of low levels of cerebral blood flow and brain oxygenation, potentially helping in preventing the progression of IVH or PVL in the neonate. PMID- 21697980 TI - Surgical excision of filum terminale arteriovenous fistulae after lumbar fusion: Value of indocyanine green and theory on origins (a technical note and report of two cases). AB - BACKGROUND: Intradural filum terminale arteriovenous fistulas (AVFs) are uncommon. We report two cases of this rare entity in which we used indocyanine green (ICG) videoangiography to identify the fistulous connection of each lesion. CASE DESCRIPTION: Two male patients presented with unresolved lower extremity weakness and paresthesias following lumbar fusion surgery. In each case, angiography showed an AVF between the filum terminale artery (FTA), the distal segment of the anterior spinal artery (ASA), and an accompanying vein of the filum terminale. A magnetic resonance image (MRI) obtained before lumbar fusion was available in one of these cases and demonstrated evidence of the preexisting vascular malformation. Surgical obliteration of each fistulous connection was facilitated by the use of ICG videoangiography. This emerging technology was instrumental in pinpointing fistula anatomy and in choosing the exact segment of the filum for disconnection. CONCLUSION: Our findings indicate that intradural filum terminale AVFs may have a congenital origin and that ICG is a useful tool in their successful surgical management. As these cases demonstrate, spine surgeons should remain vigilant in evaluating patients based on their clinical symptomatology, even in the presence of obvious lumbar pathology. PMID- 21697981 TI - Safety and cost effectiveness of early discharge following microscopic trans sphenoidal resection of pituitary lesions. AB - BACKGROUND: Inpatient hospitalization following trans-sphenoidal resection of a pituitary neoplasm has traditionally involved a hospital stay of 2 days or more. It has been the policy of the senior pituitary neurosurgeon (GSA) since February 2008 to allow discharge home on postoperative day (POD) 1 if thirst mechanism is intact and the patient is tolerating oral hydration. The goal of this study was to evaluate the safety and cost-effectiveness of this practice. METHODS: We reviewed the charts of 30 patients, designated the early discharge group, who consecutively underwent microscopic trans-sphenoidal resection from February 2008 to December 2009. We then reviewed the charts of 30 patients, designated the standard discharge group, who consecutively underwent trans-sphenoidal resection from May 2007 to February 2008 before discharge home on POD1 was considered an appropriate option. Safety and cost-effectiveness of the two patient groups were retrospectively evaluated. RESULTS: Patients in the early discharge group went home, on average, on POD 1.3. Following exclusion of two outliers, the average date of discharge of patients in the standard discharge group was POD 2.2. The policy of early discharge saved an average of $1,949 per patient-approximately 4% the total cost of the procedure. Trends toward decreased costs did not reach statistical significance. While no patient suffered any measurable morbidity as a result of early discharge home, 1 in 3 patients in the early discharge group required unscheduled postoperative re-evaluation-a figure significantly higher than the standard discharge group. CONCLUSIONS: At a dedicated pituitary center with the resources to closely monitor outpatient endocrinological and postsurgical issues, early discharge home following trans-sphenoidal surgery is a safe option that is associated with an increase in the number of unscheduled postoperative visits and a trend toward lower costs. PMID- 21697982 TI - Multichannel near-infrared spectroscopy as a tool for assisting intra-arterial fasudil therapy for diffuse vasospasm after subarachnoid hemorrhage. AB - BACKGROUND: Diffuse cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) refractory to medical management can be treated with intra arterial administration of vasodilators, but valid bedside monitoring for the diagnosis and therapeutic assessment is poorly available. We demonstrate the successful application of regional cerebral oxygen saturation (rSO(2)) monitoring with multichannel near-infrared spectroscopy (NIRS) in assisting intra-arterial infusions of fasudil hydrochloride to a patient suffering from post-SAH vasospasm in the distal vascular territories. CASE DESCRIPTION: A 63-year-old man presented with SAH and intracerebral hematoma due to ruptured right middle cerebral artery aneurysm developed aphasia and right-sided weakness on day 9 after SAH onset. Delayed cerebral ischemia attributable to diffuse vasospasm in the distal territories of the left anterior and middle cerebral arteries was suspected. Since the symptoms persisted despite maximal hyperdynamic therapy with dobutamine, intra-arterial fasudil treatment in the setting of rSO(2) monitoring including the spasm-affected vascular territory with four-channel flexible NIRS sensors was subsequently performed. Decreased and fluctuating rSO(2) in angiographically documented vasospastic territories increased immediately after intra-arterial fasudil infusion in accordance with relief of vasospasm that correlated with neurological improvement. The procedure was repeated on day 11 since the effect was transient and neurological deterioration and reduction of rSO(2) recurred. The deficits resolved accompanied by uptake and maintenance of rSO (2) following the intra-arterial fasudil, resulting in favorable functional outcome. CONCLUSION: Continuous rSO(2) monitoring with multichannel NIRS is a feasible strategy to assist intraarterial fasudil therapy for detecting and treating the focal ischemic area exposed to diffuse vasospasm. PMID- 21697984 TI - Tentorial branch of the superior cerebellar artery. AB - BACKGROUND: The tentorial branch of the superior cerebellar artery (SCA) is not well known and is underreported in the literature. In the present study, the authors report and describe a dural branch arising from the SCA that was encountered during the surgical treatment of a tentorial dural arteriovenous fistula (DAVF). The clinical relevance of this branch is discussed. CASE DESCRIPTION: A 53-year-old patient suffered a third recurrent right thalamic hemorrhage within 2 weeks rendering him comatose. Computed tomography scan revealed a right thalamic hematoma extending into the ventricles, producing acute hydrocephalus and midline shift. Cerebral angiography revealed a right-sided tentorial Borden type III DAVF fed primarily by the tentorial artery of Bernasconi and Cassinari and, to a lesser extent, the petrous branch of the middle meningeal artery. A small dural feeder originating from the SCA was suspected. Venous drainage was via the lateral mesencephalic vein, through an aneurysmal dilated basal vein of Rosenthal, to the straight sinus. The DAVF was approached surgically via a right subtemporal approach. Intraoperatively, after division of the tentorium, a tentorial branch originating from the SCA was identified. This artery was sectioned while preserving the SCA. The draining vein was ligated adjacent to the sinus. Postoperatively, the patient's neurological status improved and postoperative angiography demonstrated complete obliteration of the tentorial DAVF. CONCLUSION: Knowledge of the tentorial branch of the SCA is important as it may potentially be sectioned during division of the tentorium or avulsed from its origin in the SCA during surgical manipulation in the ambient cistern. PMID- 21697985 TI - Monitoring of brain oxygenation in surgery of ruptured middle cerebral artery aneurysms. AB - BACKGROUND: The occurrence of brain ischemic lesions, due to temporary arterial occlusion or incorrect placement of the definitive clip, is a major complication of aneurysm surgery. Temporary clipping is a current technique during surgery and there is no reliable method of predicting the possibility of ischemia due to extended regional circulatory interruption. Even with careful inspection, misplacement of the definitive clip can be difficult to detect. Brain tissue oxygen concentration (PtiO(2)) was monitored during surgery of middle cerebral artery (MCA) aneurysm presenting with subarachnoid hemorrhage (SAH), for detection of changes in brain oxygenation due to reduced blood flow, as a predictor of ischemic events, during temporary clipping and after definitive clipping. METHODS: PtiO(2) was monitored during surgery of 13 patients harboring MCA aneurysms presenting with SAH, using a polarographic microcatheter (Licox, GMS, Kiel, Germany) placed in the territory of MCA. RESULTS: A decrease in PtiO(2) values was verified in every period of temporary clipping. Brain infarction occurred in 2 patients; in both cases, there was a decrease in PtiO(2) greater than 80% from basal value, a minimum value of less than 2 mmHg persisting for 2 or more minutes during temporary clipping, and an incomplete recovery of PtiO(2) after definitive clipping. In 2 patients, incomplete recovery of values after definitive clipping led to verification of inappropriate placement and repositioning of the clip. CONCLUSION: The results suggest that intraoperative monitoring of PtiO(2) may be a useful method of detection of changes in brain tissue oxygenation during MCA aneurysm surgery. Postoperative infarction in the territory of MCA developed in cases with an abrupt decrease of PtiO(2) and a very low and persistent minimum value, during temporary clipping, and an incomplete recovery after definitive clipping. Verification of clip position should be considered when there is an incomplete recovery or a persistent fall in PtiO(2) after definitive clipping. PMID- 21697983 TI - Endovascular implantation of covered stents in the extracranial carotid and vertebral arteries: Case series and review of the literature. AB - BACKGROUND: Covered stents are used endovascularly to seal arterial wall defects while preserving vessel patency. This report describes our experience with the use of covered stents to treat cervical pathology, and a review of the literature in regards to this topic is presented. CASE DESCRIPTION: Two patients presenting with the carotid blowout syndrome and one patient with a vertebrojugular fistula were treated with covered stents. This allowed for preservation of the vessel and was a treatment alternative to cerebral bypass. CONCLUSION: Covered stents provide a viable means of preserving the cervical vessels in selected patients; however, long-term follow-up is necessary to determine stent patency and permanency of hemostasis. PMID- 21697986 TI - Dissecting peripheral superior cerebellar artery aneurysms: Report of two cases and review of the literature. AB - BACKGROUND: Only a limited number of dissecting aneurysms of the peripheral cerebellar arteries have been previously described, and very few of these cases involve the superior cerebellar artery (SCA). Due to the rarity of these lesions, there is little consensus regarding prognosis and management. We describe our experience with two cases of complex peripheral SCA dissecting aneurysms and review the existing literature on this fascinating entity. CASE DESCRIPTION: Two patients, both with SCA dissecting aneurysms not amenable to endovascular treatment underwent microsurgical clipping, one with the associated removal of a tentorial meningioma. In each procedure a combined subtemporal, presigmoidal approach was performed. Surgical clips were utilized to reconstruct the aneurysms, and both patients were discharged without complication. Surgical management of complex distal SCA fusiform aneurysm is challenging and options include wrap/clip reconstruction, proximal occlusion, trapping, and distal outflow occlusion. When possible, preservation of the parent artery is preferred to mitigate the risk of brainstem infarction. If proximal occlusion or trapping are employed, we have advocated for the use of combined distal revascularization techniques to prevent permanent ischemic damage of the brainstem and cerebellar hemisphere. CONCLUSIONS: Peripherally dissecting aneurysm of the SCA is an uncommon entity. Management of these lesions is best handled by an experienced neuro-endovascular team combined with a neurovascular surgeon skilled in skull base approaches. PMID- 21697987 TI - Cranioplasty with subcutaneously preserved autologous bone grafts in abdominal wall-Experience with 75 cases in a post-war country Kosova. AB - BACKGROUND: The study is to show the advantages of preservation of a calvarial bone flap in the abdominal pocket after decompressive craniotomy. Decompressive craniectomy is an option in the surgical management of refractory hypertension when maximal medical treatment (sedation, drainage of cerebrospinal fluid, moderate cooling, etc) has failed to control refractory high intracranial pressure. METHODS: We have prospectively analyzed 82 consecutively operated cases decompressive craniotomies done at the University Neurosurgical Clinic in Prishtina/KOSOVA over a period of eight years (June 1999 to Aug 2008). Of the 75 who had their grafts replaced (7 patient died before replacement of bone graft), 62 patients had hemicraniectomy (fronto-parieto-temporal) 7 of them were bilateral. RESULTS: In 66 out of 75 patients was achieved a satisfactory and cosmetically reconstruction, in 9 cases was required augmentation with methyl methacrylate to achieve cosmetic needs. Two patients had infection and the bone was removed; 6 months later these patients had cranioplasty with methyl methacrylate. The duration of storage of calvarial bone in abdominal pouch before reimplantation was 14 - 232 days (range 56 days). CONCLUSION: We think that storage of the patients own bone flap in the abdominal pocket is a safe, easy, cheap, sterile, histocompatible, and better cosmetic results. PMID- 21697988 TI - The metabolic syndrome: prevalence, associated factors, and impact on survival among older persons in rural Bangladesh. AB - OBJECTIVES: To describe the prevalence of the metabolic syndrome (MetS) among older persons in rural Bangladesh, to investigate whether the prevalence varies by age, sex, literacy, marital status, nutritional status and socio-economic status, and to assess the impact of MetS on survival. METHODS: The study consisted of 456 persons who were aged >=60 years living in a rural area of Bangladesh during July 2003-March 2004. Data were collected through interview, clinical examination, and laboratory tests, and their survival status until 30(th) June 2009 was ascertained through the Matlab surveillance system. We defined MetS following the NCEP ATP III criteria, with minor modifications, i.e., presence of any three of the following: hypertension (BP >=130/85 mm Hg); random blood glucose (RBG) level >=7.0 mmol/L; hyper-triglyceridemia (>=2.28 mmol/L); low level of HDL-cholesterol (<1.04 mmol/L for men and <1.29 mmol/L for women); and BMI >=25.0 kg/m(2). Data were analysed with logistic regressions for the influential factors of MetS, and with Cox models for the association of MetS with the survival status. FINDINGS: The overall prevalence of MetS was 19.5%, 20.8% in women, and 18.0% in men. Asset-index and nutritional status were independently associated with MetS. During 4.93 years of follow-up, 18.2% died. In the presence of high RBG, MetS has a significant negative effect on survival (69.4% vs 95.2%, log rank p = 0.02). CONCLUSION: This study highlights the importance of the metabolic syndrome in rural Bangladesh. Our findings suggest that there is a need for screening programmes involving the metabolic syndrome to prevent diabetes and cardiovascular diseases. PMID- 21697990 TI - Sex ratio at birth in India, its relation to birth order, sex of previous children and use of indigenous medicine. AB - OBJECTIVE: Sex-ratio at birth in families with previous girls is worse than those with a boy. Our aim was to prospectively study in a large maternal and child unit sex-ratio against previous birth sex and use of traditional medicines for sex selection. MAIN OUTCOME MEASURES: Sex-ratio among mothers in families with a previous girl and in those with a previous boy, prevalence of indigenous medicine use and sex-ratio in those using medicines for sex selection. RESULTS: Overall there were 806 girls to 1000 boys. The sex-ratio was 720:1000 if there was one previous girl and 178:1000 if there were two previous girls. In second children of families with a previous boy 1017 girls were born per 1000 boys. Sex-ratio in those with one previous girl, who were taking traditional medicines for sex selection, was 928:1000. CONCLUSION: Evidence from the second children clearly shows the sex-ratio is being manipulated by human interventions. More mothers with previous girls tend to use traditional medicines for sex selection, in their subsequent pregnancies. Those taking such medication do not seem to be helped according to expectations. They seem to rely on this method and so are less likely use more definitive methods like sex selective abortions. This is the first such prospective investigation of sex ratio in second children looked at against the sex of previous children. More studies are needed to confirm the findings. PMID- 21697989 TI - Extensive geographic mosaicism in avian influenza viruses from gulls in the northern hemisphere. AB - Due to limited interaction of migratory birds between Eurasia and America, two independent avian influenza virus (AIV) gene pools have evolved. There is evidence of low frequency reassortment between these regions, which has major implications in global AIV dynamics. Indeed, all currently circulating lineages of the PB1 and PA segments in North America are of Eurasian origin. Large-scale analyses of intercontinental reassortment have shown that viruses isolated from Charadriiformes (gulls, terns, and shorebirds) are the major contributor of these outsider events. To clarify the role of gulls in AIV dynamics, specifically in movement of genes between geographic regions, we have sequenced six gull AIV isolated in Alaska and analyzed these along with 142 other available gull virus sequences. Basic investigations of host species and the locations and times of isolation reveal biases in the available sequence information. Despite these biases, our analyses reveal a high frequency of geographic reassortment in gull viruses isolated in America. This intercontinental gene mixing is not found in the viruses isolated from gulls in Eurasia. This study demonstrates that gulls are important as vectors for geographically reassorted viruses, particularly in America, and that more surveillance effort should be placed on this group of birds. PMID- 21697991 TI - Evolutionary Implications and Physicochemical Analyses of Selected Proteins of Type III Polyketide Synthase Family. AB - Type III polyketide synthases have a substantial role in the biosynthesis of various polyketides in plants and microorganisms. Comparative proteomic analysis of type III polyketide synthases showed evolutionarily and structurally related positions in a compilation of amino acid sequences from different families. Bacterial and fungal type III polyketide synthase proteins showed <50% similarity but in higher plants, it exhibited >80% among chalcone synthases and >70% in the case of non-chalcone synthases. In a consensus phylogenetic tree based on 1000 replicates; bacterial, fungal and plant proteins were clustered in separate groups. Proteins from bryophytes and pteridophytes grouped immediately near to the fungal cluster, demonstrated how evolutionary lineage has occurred among type III polyketide synthase proteins. Upon physicochemical analysis, it was observed that the proteins localized in the cytoplasm and were hydrophobic in nature. Molecular structural analysis revealed comparatively stable structure comprising of alpha helices and random coils as major structural components. It was found that there was a decline in the structural stability with active site mutation as prophesied by the in silico mutation studies. PMID- 21697992 TI - How Fitch-Margoliash Algorithm can Benefit from Multi Dimensional Scaling. AB - Whatever the phylogenetic method, genetic sequences are often described as strings of characters, thus molecular sequences can be viewed as elements of a multi-dimensional space. As a consequence, studying motion in this space (ie, the evolutionary process) must deal with the amazing features of high-dimensional spaces like concentration of measured phenomenon.TO STUDY HOW THESE FEATURES MIGHT INFLUENCE PHYLOGENY RECONSTRUCTIONS, WE EXAMINED A PARTICULAR POPULAR METHOD: the Fitch-Margoliash algorithm, which belongs to the Least Squares methods. We show that the Least Squares methods are closely related to Multi Dimensional Scaling. Indeed, criteria for Fitch-Margoliash and Sammon's mapping are somewhat similar. However, the prolific research in Multi Dimensional Scaling has definitely allowed outclassing Sammon's mapping.Least Square methods for tree reconstruction can now take advantage of these improvements. However, "false neighborhood" and "tears" are the two main risks in dimensionality reduction field: "false neighborhood" corresponds to a widely separated data in the original space that are found close in representation space, and neighbor data that are displayed in remote positions constitute a "tear". To address this problem, we took advantage of the concepts of "continuity" and "trustworthiness" in the tree reconstruction field, which limit the risk of "false neighborhood" and "tears". We also point out the concentration of measured phenomenon as a source of error and introduce here new criteria to build phylogenies with improved preservation of distances and robustness.The authors and the Evolutionary Bioinformatics Journal dedicate this article to the memory of Professor W.M. Fitch (1929-2011). PMID- 21697993 TI - Role of clinical questionnaires in optimizing everyday care of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of disability in all its stages, and death in patients with moderate or severe obstruction. At present, COPD is suboptimally managed; current health is often not measured properly and hardly taken into account in management plans, and the future risk for patients with regard to health status and quality of life is not being evaluated. This review addresses the effect of COPD on the lives of patients and examines ways in which existing assessment tools meet physicians' needs for a standardized, simple method to measure consistently the full impact of COPD on patients in routine clinical practice. Current assessment of COPD severity tends to focus on airflow limitation, but this does not capture the full impact of the disease and is not well correlated with patient perception of symptoms and health related quality of life. Qualitative studies have demonstrated that patients usually consider COPD impact in terms of frequency and severity of symptoms, and physical and emotional wellbeing. However, patients often have difficulty expressing their disease burden and physicians generally have insufficient time to collect this information. Therefore, it is important that methods are implemented to help generate a more complete understanding of the impact of COPD. This can be achieved most efficiently using a quick, reliable, and standardized measure of disease impact, such as a short questionnaire that can be applied in daily clinical practice. Questionnaires are precision instruments that contribute sensitive and specific information, and can potentially help physicians provide optimal care for patients with COPD. Two short, easy-to-use, specific measures, ie, the COPD Assessment Test and the Clinical COPD Questionnaire, enable physicians to assess patients' health status accurately and improve disease management. Such questionnaires provide important measurements that can assist primary care physicians to capture the impact of COPD on patients' daily lives and wellbeing, and improve long-term COPD management. PMID- 21697994 TI - Measuring the impact of a live, case-based, multiformat, interactive continuing medical education program on improving clinician knowledge and competency in evidence-based COPD care. AB - BACKGROUND: Major clinical gaps impede the evidence-based treatment of chronic obstructive pulmonary disease (COPD) in the primary care setting. Studies are needed to measure the effectiveness of continuing medical education (CME) on improving physician competency and performance toward evidence-based COPD care. METHODS: Between September 26, 2009 and December 12, 2009, 769 primary care physicians participated in a series of 12 regional, live, interactive, case based, multiformat, half-day CME programs on COPD. A subgroup of randomly selected participants (n = 50) and demographically matched nonparticipants (n = 50) completed surveys that included case vignettes, a validated tool for measuring physician performance in clinical practice. Cohen's d was used to calculate the magnitude of difference between participants and nonparticipants in the delivery of evidence-based care. RESULTS: Physicians who participated in CME programs were 50% more likely to provide evidence-based COPD care than physicians who did not participate. Compared with nonparticipants, participating physicians were more likely to recognize COPD correctly in a patient presenting with dyspnea (74% versus 94%, P = 0.007), recognize that women may have a greater susceptibility than men to the toxic effects of smoking (54% versus 90%, P < 0.001), and identify the mechanisms of action of emerging therapies (33% versus 65%, P = 0.003). CONCLUSION: Physicians who participated in a half-day regional CME program on COPD diagnosis, staging, and treatment were significantly more likely than nonparticipants to deliver evidence-based COPD care. With multiformat, interactive, focused educational interventions, physicians can make diagnostic and therapeutic choices in the primary care setting that align more closely with current guidelines and clinical evidence in COPD management. PMID- 21697995 TI - Induction of the unfolded protein response by cigarette smoke is primarily an activating transcription factor 4-C/EBP homologous protein mediated process. AB - PURPOSE: Cigarette smoke is the major risk factor associated with the development of chronic obstructive pulmonary disease (COPD). Recent studies propose a link between endoplasmic reticulum (ER) stress and emphysema, demonstrated by increased ER stress markers under smoking conditions. Here, we investigate whether cigarette smoke-induced ER stress is cell specific and correlates with acute and chronic cigarette smoke exposure. METHODS: Gene and protein expression changes in human primary lung cell cultures following cigarette smoke extract (CSE) exposure were monitored by qPCR and Western blot analysis. Mice and guinea pigs were exposed to cigarette smoke and ER stress markers examined in whole lung homogenates. Inflammatory cells from the bronchoalveolar lavage fluid of 10 days smoke exposed mice were also examined. RESULTS: Cigarette smoke induced a trend increase in the ER stress response through an activating transcription factor 4 (ATF4) mediated induction of C/EBP homologous protein (CHOP) in primary small airway epithelial cells. Bronchial epithelial cells and macrophages responded similarly to CSE. Wild-type mice and guinea pigs exposed to acute levels of cigarette smoke exhibited increased levels of CHOP but not at significant levels. However, after long-term chronic cigarette smoke exposure, CHOP expression was reduced. Interestingly, inflammatory cells from smoke exposed mice had a significant increase in CHOP/ATF4 expression. CONCLUSION: A trend increase in CHOP levels appear in multiple human lung cell types following acute cigarette smoke exposure in vitro. In vivo, inflammatory cells, predominately macrophages, demonstrate significant cigarette smoke-induced ER stress. Early induction of CHOP in cigarette smoke may play a pivotal role in early induction of lung disease, however in vivo long-term cigarette smoke exposure exhibited a reduction in the ER stress response. PMID- 21697996 TI - Geographic disparities in chronic obstructive pulmonary disease (COPD) hospitalization among Medicare beneficiaries in the United States. AB - BACKGROUND: Hospitalizations for persons with chronic obstructive pulmonary disease (COPD) result in significant health care resource use and excess expenditures. Despite well-documented sociodemographic disparities in COPD outcomes, no study has characterized geographic variations in COPD hospitalization across the US. METHODS: Almost 3.8 million COPD hospitalization records were extracted from Medicare claims for 1995-2006, and the total population of eligible Medicare beneficiaries was extracted from the Medicare enrollment records to calculate COPD hospitalization rates by Health Service Area (HSA), (n = 949). Spatial cluster analysis and Bayesian hierarchical spatial modeling were used to characterize the geography of COPD hospitalizations. RESULTS: The overall COPD hospitalization rate was 11.30 per 1,000 beneficiaries for the aggregated period 1995-2006. HSA-level COPD hospitalization rates had a median of 11.7 and a range of 3.0 (Cache, UT) to 76.3 (Pike, KY). Excessive hospitalization risk was concentrated in Appalachia, the southern Great Lakes, the Mississippi Delta, the Deep South, and west Texas. In the Bayesian spatial mixture model, 73% of variability of COPD hospitalization relative risk was attributed to unidentified regional social and physical environments shared by HSAs rather than to unique local HSA factors (27%). CONCLUSION: We discovered distinct geographic patterns in COPD hospitalization rates and risks attributed to both regionally-shared environmental risk factors and HSA-unique environmental contexts. The correlates of these geographic patterns remain to be determined. Geographic comparisons of COPD hospitalization risk provide insights for better public health practice, policies, and programs for COPD prevention. PMID- 21697997 TI - Comparative efficacy of indacaterol 150 MUg and 300 MUg versus fixed-dose combinations of formoterol + budesonide or salmeterol + fluticasone for the treatment of chronic obstructive pulmonary disease--a network meta-analysis. AB - OBJECTIVE: To compare efficacy of indacaterol to that of fixed-dose combination (FDC) formoterol and budesonide (FOR/BUD) and FDC salmeterol and fluticasone (SAL/FP) for the treatment of chronic obstructive pulmonary disease (COPD) based on the available randomized clinical trials (RCTs). METHODS: Fifteen placebo controlled RCTs were included that evaluated: indacaterol 150 MUg (n = 5 studies), indacaterol 300 MUg (n = 4), FOR/BUD 9/160 MUg (n = 2), FOR/BUD 9/320 MUg (n = 3), SAL/FP 50/500 MUg (n = 5), and SAL/FP 50/250 MUg (n = 1). Outcomes of interest were trough forced expiratory volume in 1 second (FEV(1)), total scores for St. George's Respiratory Questionnaire (SGRQ), and transition dyspnea index (TDI). All trials were analyzed simultaneously using a Bayesian network meta-analysis and relative treatment effects between all regimens were obtained. Treatment-by-covariate interactions were included where possible to improve the similarity of the trials. RESULTS: Indacaterol 150 MUg resulted in a higher change from baseline (CFB) in FEV(1) at 12 weeks compared to FOR/BUD 9/160 MUg (difference in CFB 0.11 L [95% credible intervals: 0.08, 0.13]) and FOR/BUD 9/320 MUg (0.09 L [0.06, 0.11]) and was comparable to SAL/FP 50/250 MUg (0.02 L [-0.04, 0.08]) and SAL/FP 50/500 MUg (0.03 L [0.00, 0.06]). Similar results were observed for indacaterol 300 MUg at 12 weeks and indacaterol 150/300 MUg at 6 months. Indacaterol 150 MUg demonstrated comparable improvement in SGRQ total score at 6 months versus FOR/BUD (both doses), and SAL/FP 50/500 MUg (-2.16 point improvement [-4.96, 0.95]). Indacaterol 150 and 300 MUg demonstrated comparable TDI scores versus SAL/FP 50/250 MUg (0.21 points (-0.57, 0.99); 0.39 [-0.39, 1.17], respectively) and SAL/FP 50/500 MUg at 6 months. CONCLUSION: Indacaterol monotherapy is expected to be at least as good as FOR/BUD (9/320 and 9/160 MUg) and comparable to SAL/FP (50/250 and 50/500 MUg) in terms of lung function. Indacaterol is also expected to be comparable to FOR/BUD (9/320 and 9/160 MUg) and SAL/FP 50/500 MUg in terms of health status and to SAL/FP (50/250 and 50/500 MUg) in terms of breathlessness. PMID- 21697998 TI - Protective effects of Morus alba leaves extract on ocular functions of pups from diabetic and hypercholesterolemic mother rats. AB - Phytotherapy is frequently considered to be less toxic and free from side effects than synthetic drugs. Hence, the present study was designed to investigate the protective use of crude water extract of Morus alba leaves on ocular functions including cataractogenesis, biochemical diabetic and hypercholesterolemic markers, retinal neurotransmitters and retinopathy of rat pups maternally subjected to either diabetes and/or hypercholesterolemia. Application of crude water extract of Morus alba resulted in amelioration of the alterations of maternal serum glucose, LDL, HDL, total cholesterol and creatine phosphokinase activity as well as retinal neurotransmitters including acetylcholine (ACE), adrenaline (AD), nor-adrenaline (NAD), serotonin (5-HT), histamine (HS), dopamine (DA) and gamma amino butyric acid (GABA). The retina of pups of either diabetic and/or hypercholesterolemia mothers exhibited massive alterations of retinal neurotransmitters. The alterations of retinal neurotransmitters were correlated with the observed pathological alterations of retinal pigmented epithelium, photoreceptor inner segment and ganglion cells and increased incidence of DNA fragmentation and apoptosis cell death. However, protection with Morus alba extract led to amelioration of the pathological alterations of retinal neurons and estimated neurotransmitters. Furthermore, a striking incidence of cataract was detected in pups of either diabetic and/or hypercholesterolemic mothers. Highest cataractogenesis was observed in pups of combined -treated groups. Our data indicate that experimental maternal diabetes alone or in combination with hypercholesterolemia led to alteration in the ocular structures of their pups, with an increasing incidence of cataract and retinopathy, and the effects of the extract might be attributed to the hypoglycaemic, antihypercholesterolemic and anti-oxidative potential of flavonoids, the major components of the plant extract. PMID- 21697999 TI - Purification and characterization of gigantoxin-4, a new actinoporin from the sea anemone Stichodactyla gigantea. AB - A new Cytolysin, termed as Gigantoxin-4, was isolated from the sea anemone Stichodactyla gigantea and found to be highly homologous with Cytolysin-3 (HMg III) from Heteractis magnifica, RTX-A from Radianthus macrodactylus, and Sticholysin-1 (St I) and Sticholysin-2 (St II) from Stichodactyla helianthus (homology 82%, 86%, 82% and 86% respectively). Its 20 N-terminal residues were identified and the full-length cDNA sequence was obtained by reverse transcription-polymerase chain reaction (RT-PCR). Multiple sequence alignments with other Cytolysins of the actinoporin family clearly indicated that Gigantoxin 4 belongs to this protein family. SDS-PAGE electrophoresis showed that this new actinoporin had a molecular mass of about 19 kDa, and possessed a high hemolytic activity to human erythrocytes (HA(50)= 40 ng/ml), which was inhibited by pre incubation with sphingomyelin (SM) or SM-cholesterol mixtures. Our in vivo experiments showed that Gigantoxin-4 had wide toxicity to the rat cardiovascular system and the respiratory system. A concentration of 30 MUg/kg Gigantoxin-4, i.v. produced a positive inotropic effect on the rat heart although final cardiovascular failure was inevitable, and 60 MUg/kg Gigantoxin-4 caused respiratory arrest rapidly resulting in rat death. HE staining indicated pathological changes in various organs and tissues after i.v. administration of Gigantoxin-4. PMID- 21698000 TI - Microcystin-LR (MCLR) induces a compensation of PP2A activity mediated by alpha4 protein in HEK293 cells. AB - Protein phosphatase 2A (PP2A) is a major protein phosphatase with important cell functions. Known and utilized as a potent inhibitor of PP2A, microcystin-LR (MCLR) targets PP2A as a core element that affects numerous cellular mechanisms. But apart from direct inhibition, the exact effect of MCLR on PP2A in cell is largely unknown, specifically with regard to cellular response and autoregulation. Here, we show that a low concentration of MCLR stimulates, rather than inhibits, PP2A activity in HEK293 cells. Immunoprecipitation and immunofluorescence assays reveal that the catalytic subunit and a regulatory subunit of PP2A, termed alpha4, dissociate from inactive complex upon MCLR exposure, suggesting that the released catalytic subunit regains activity and thereby compensates the activity loss. At high concentrations of MCLR, PP2A activity decreases along with dissociation of the core enzyme and altered post translational modification of its catalytic subunit. In addition, the dissociation of alpha4 and PP2A may contribute to destabilization of HEK293 cells cytoskeleton architecture, detachment to extracellular matrix and further anoikis. Our data provide a novel PP2A upregulation mechanism and challenge the recognition of MCLR only as a PP2A inhibitor in cells. PMID- 21698002 TI - Identification of MicroRNAs involved in hypoxia- and serum deprivation-induced apoptosis in mesenchymal stem cells. AB - The use of bone marrow mesenchymal stem cell- (MSC) transplantation therapy for cardiac diseases is limited due to poor survival of implanted cells. MicroRNAs (miRNAs) have been reported to be involved in regulating almost all cellular processes, including apoptosis. In this study, we found that the miRNA profile was altered during apoptosis induced by hypoxia and serum deprivation (hypoxia/SD). We further revealed that over-expression of miR-21, miR-23a and miR 210 could promote the survival of MSCs exposed to hypoxia/SD. In contrast, down regulation of miR-21, miR-23a and miR-503 aggravated apoptosis of MSCs. It was indicated that these miRNAs may play important roles during MSC apoptosis induced by hypoxia/SD. PMID- 21698004 TI - Mouse phenotyping with near-infrared fluorescence lymphatic imaging. AB - We demonstrate the ability to non-invasively and quantitatively image lymphatic architecture and contractile function using dynamic near-infrared (NIR) fluorescence imaging with injection of indocyanine green in normal and transgenic mice. Unlike normal mice, which showed well defined lymphatic drainage patterns and orthograde propagation of contraction waves, we observed tortuous and mispatterned lymphatic vessels and persistent retrograde lymph flow in mice with deficiency in Prox1, a transcription factor essential for lymphatic vascular development. NIR fluorescence imaging provides a method for quantifying lymphatic function for future studies designed to discern differences in lymphatic function in murine models of human lymphatic disease. PMID- 21698001 TI - Temporal expression of mutant LRRK2 in adult rats impairs dopamine reuptake. AB - Parkinson's disease (PD) results from progressive degeneration of dopaminergic neurons. Most PD cases are sporadic, but some have pathogenic mutation in the individual genes. Mutation of the leucine-rich repeat kinase-2 (LRRK2) gene is associated with familial and sporadic PD, as exemplified by G2019S substitution. While constitutive expression of mutant LRRK2 in transgenic mice fails to induce neuron death, transient expression of the disease gene by viral delivery causes a substantial loss of dopaminergic neurons in mice. To further assess LRRK2 pathogenesis, we created inducible transgenic rats expressing human LRRK2 with G2019S substitution. Temporal overexpression of LRRK2(G2019S) in adult rats impaired dopamine reuptake by dopamine transporter (DAT) and thus enhanced locomotor activity, the phenotypes that were not observed in transgenic rats constitutively expressing the gene throughout life time. Reduced DAT binding activity is an early sign of dopaminergic dysfunction in asymptomatic subjects carrying pathogenic mutation in LRRK2. Our transgenic rats recapitulated the initiation process of dopaminergic dysfunction caused by pathogenic mutation in LRRK2. Inducible transgenic approach uncovered phenotypes that may be obscured by developmental compensation in constitutive transgenic rats. Finding in inducible LRRK2 transgenic rats would guide developing effective strategy in transgenic studies: Inducible expression of transgene may induce greater phenotypes than constitutive gene expression, particularly in rodents with short life time. PMID- 21698003 TI - Investigating the pathogenic role of PADI4 in oesophageal cancer. AB - PADI4 post-translationally converts peptidylarginine to citrulline. PADI4 can disrupt the apoptotic process via the citrullination of histone H3 in the promoter of p53-target genes. The current study focused on PADI4 expression in various subtypes of oesophageal carcinoma (EC) by immunohistochemistry, western blotting and real time PCR. The study also investigated the effect of bile acid deoxycholate (DCA) on PADI4 expression in Eca-109 cells that originated from EC. Apoptosis and DCA-induced toxicity were analyzed by TUNEL, MTT assay and flow cytometry. Additionally, the present study investigated the correlation between single nucleotide polymorphism (SNP) in PADI4 gene and EC risk in Chinese population using Illumina GoldenGate assay. Compared with paraneoplastic tissues, the transcriptional and translational levels of PADI4 were significantly elevated in oesophageal squamous cell carcinoma (ESCC, n=9) and oesophageal adenocarcinoma (EAC, n=5) tissues. Immunolabeling detected expression of PADI4 in ESCC tissues (98.56%, n=139), EAC samples (87.5%, n=16) and oesophageal small cell undifferentiated carcinoma (91.7%, n=12) but not in normal tissues (0%, n=16). Furthermore, PADI4 levels is positively correlated with the pathological classification of ESCC (p=0.009). PADI4 expression levels were consistent with the number of apoptotic cells in the induced Eca-109 cells. rs10437048 [OR= 0.012831; 95% CI, 0.001746~0.094278; p=1.556*10(-12)] were significantly associated with decreased risk of EC, whereas rs41265997 [OR=12.7; 95% CI, 0.857077~33.207214; p=3.896*10(-8)] were significantly associated with increased risk of EC. rs41265997 in exon 3 of PADI4 gene is non-synonymous and converts ACG to ATG resulting in a threonine /methionine conversion at position 274 of the protein. Haplotypes GC that carries the variant alleles for rs2501796 and rs2477134 was significantly associated with increased risk of EC (frequency=0.085, p=0.0256, OR=2.7). The results suggest that PADI4 expression is related to the tumorigenic process of EC and the DCA-induced apoptosis. The PADI4 gene may be a valid EC susceptibility gene. PMID- 21698005 TI - Comprehensive volumetric confocal microscopy with adaptive focusing. AB - Comprehensive microscopy of distal esophagus could greatly improve the screening and surveillance of esophageal diseases such as Barrett's esophagus by providing histomorphologic information over the entire region at risk. Spectrally encoded confocal microscopy (SECM) is a high-speed reflectance confocal microscopy technology that can be configured to image the entire distal esophagus by helically scanning the beam using optics within a balloon-centering probe. It is challenging to image the human esophagus in vivo with balloon-based SECM, however, because patient motion and anatomic tissue surface irregularities decenter the optics, making it difficult to keep the focus at a predetermined location within the tissue as the beam is scanned. In this paper, we present a SECM probe equipped with an adaptive focusing mechanism that can compensate for tissue surface irregularity and dynamic focal variation. A tilted arrangement of the objective lens is employed in the SECM probe to provide feedback signals to an adaptive focusing mechanism. The tilted configuration also allows the probe to obtain reflectance confocal data from multiple depth levels, enabling the acquisition of three-dimensional volumetric data during a single scan of the probe. A tissue phantom with a surface area of 12.6 cm(2) was imaged using the new SECM probe, and 8 large-area reflectance confocal microscopy images were acquired over the depth range of 56 MUm in 20 minutes. Large-area SECM images of excised swine small intestine tissue were also acquired, enabling the visualization of villous architecture, epithelium, and lamina propria. The adaptive focusing mechanism was demonstrated to enable acquisition of in-focus images even when the probe was not centered and the tissue surface was irregular. PMID- 21698006 TI - Analysis of individual cone-photoreceptor directionality using scanning laser ophthalmoscopy. AB - Scanning laser ophthalmoscopy has been used to measure individual cone photoreceptor directionalities in the living human eye. The directionality is determined at different retinal eccentricities where it is expected that cones have diameters ranging between 5-10MUm, comparable to the spot size of the incident beam. Individual cone directionality values are compared with the predicted directionalities obtained by using the waveguide model of light coupling to and from photoreceptors for the case of a focused incident beam. PMID- 21698007 TI - Vaporization of perfluorocarbon droplets using optical irradiation. AB - Micron-sized liquid perfluorocarbon (PFC) droplets are currently being investigated as activatable agents for medical imaging and cancer therapy. After injection into the bloodstream, superheated PFC droplets can be vaporized to a gas phase for ultrasound imaging, or for cancer therapy via targeted drug delivery and vessel occlusion. Droplet vaporization has been previously demonstrated using acoustic methods. We propose using laser irradiation as a means to induce PFC droplet vaporization using a method we term optical droplet vaporization (ODV). In order to facilitate ODV of PFC droplets which have negligible absorption in the infrared spectrum, optical absorbing nanoparticles were incorporated into the droplet. In this study, micron-sized PFC droplets loaded with silica-coated lead sulfide (PbS) nanoparticles were evaluated using a 1064 nm laser and ultra-high frequency photoacoustic ultrasound (at 200 and 375 MHz). The photoacoustic response was proportional to nanoparticle loading and successful optical droplet vaporization of individual PFC droplets was confirmed using photoacoustic, acoustic, and optical measurements. A minimum laser fluence of 1.4 J/cm(2) was required to vaporize the droplets. The vaporization of PFC droplets via laser irradiation can lead to the activation of PFC agents in tissues previously not accessible using standard ultrasound-based techniques. PMID- 21698008 TI - Retinal image contrast obtained by a model eye with combined correction of chromatic and spherical aberrations. AB - Correcting spherical and chromatic aberrations in vitro in human eyes provides substantial visual acuity and contrast sensitivity improvements. We found the same improvement in the retinal images using a model eye with/without correction of longitudinal chromatic aberrations (LCAs) and spherical aberrations (SAs). The model eye included an intraocular lens (IOL) and artificial cornea with human ocular LCAs and average human SAs. The optotypes were illuminated using a D65 light source, and the images were obtained using two-dimensional luminance colorimeter. The contrast improvement from the SA correction was higher than the LCA correction, indicating the benefit of an aspheric achromatic IOL. PMID- 21698009 TI - Epidural needle with embedded optical fibers for spectroscopic differentiation of tissue: ex vivo feasibility study. AB - Epidural injection is commonly used to provide intraoperative anesthesia, postoperative and obstetric analgesia, and to treat acute radicular pain. Identification of the epidural space is typically carried out using the loss of resistance (LOR) technique, but the usefulness of this technique is limited by false LOR and the inability to reliably detect intravascular or subarachnoid needle placement. In this study, we present a novel epidural needle that allows for the acquisition of optical reflectance spectra from tissue close to the beveled surface. This needle has optical fibers embedded in the cannula that deliver and receive light. With two spectrometers, light received from tissue is resolved across the wavelength range of 500 to 1600 nm. To determine the feasibility of optical tissue differentiation, spectra were acquired from porcine tissues during a post mortem laminectomy. The spectra were processed with an algorithm that derives estimates of the hemoglobin and lipid concentrations. The results of this study suggest that the optical epidural needle has the potential to improve the accuracy of epidural space identification. PMID- 21698010 TI - In vivo photoacoustic micro-imaging of microvascular changes for Achilles tendon injury on a mouse model. AB - Since neovascularization has been reported that it is associated with tendinopathy, assessments of vascularity are important for both diagnosis and treatment estimation. Photoacoustic imaging, taking the advantages of good ultrasonic resolution and high optical absorption contrast, has been shown a promising tool for vascular imaging. In this study, we explore the feasibility of photoacoustic micro-imaging in noninvasive monitoring of microvascular changes in Achilles tendon injuries on a mouse model in vivo. During collagenase-induced tendinitis, a 25-MHz photoacoustic microscope was used to image microvascular changes in Achilles tendons of mice longitudinally up to 23 days. In addition, complementary tissue structural information was revealed by collateral 25-MHz ultrasound microscopy. Morphological changes and proliferation of new blood vessels in Achilles tendons were observed during and after the acute inflammation. Observed microvascular changes during tendinitis were similar to the findings in the literatures. This study demonstrates that photoacoustic imaging can potentially be a complementary tool for high sensitive diagnosis and assessment of treatment performance in tendinopathy. PMID- 21698011 TI - Real-time full field laser Doppler imaging. AB - We present a full field laser Doppler imaging instrument, which enables real-time in vivo assessment of blood flow in dermal tissue and skin. This instrument monitors the blood perfusion in an area of about 50 cm(2) with 480 * 480 pixels per frame at a rate of 12-14 frames per second. Smaller frames can be monitored at much higher frame rates. We recorded the microcirculation in healthy skin before, during and after arterial occlusion. In initial clinical case studies, we imaged the microcirculation in burned skin and monitored the recovery of blood flow in a skin flap during reconstructive surgery indicating the high potential of LDI for clinical applications. Small animal imaging in mouse ears clearly revealed the network of blood vessels and the corresponding blood perfusion. PMID- 21698012 TI - Experimental investigation of NIRS spatial sensitivity. AB - Near infrared spectroscopy (NIRS) is regarded as a potential medical diagnostic technique for investigation of hemodynamic changes. However, uncertainties pertaining to the origin of NIRS signals have hampered its clinical interpretation. The uncertainities in NIRS measurements especially in case of living tissues are due to lack of rigorous combined theoretical-experimental studies resulting in clear understanding of the origin of NIRS signals. For their reliable interpretation it is important to understand the relationship between spatial changes in optical properties and corresponding changes in the NIRS signal. We investigated spatial sensitivity of near infrared optical measurements using an experimental approach. It uses a liquid optical phantom as tissue equivalent, which is explored under robot-control by a small, approximately point like perturbation of desired optical properties, and a NIRS instrument for trans illumination/reflection measurements. The experimentally obtained sensitivity has been analyzed and compared with numerical simulations. In preliminary experiments we investigated the influence of various optical properties of the medium and of source/detector distances on the spatial sensitivity distribution. The acquired sensitivity maps can be used to define characteristic parameters. As an example, we used a 25% threshold to define a penetration depth measure which provides values in good accordance with published ones. To the best of our knowledge this is the first experimental study of NIRS spatial sensitivity. The presented method will allow in depth experimental investigation of the influence of various conditions pertaining to medium such as optical properties of tissue (scattering and absorption) and of the source/detector configuration. PMID- 21698013 TI - Two-photon excited autofluorescence imaging of freshly isolated frog retinas. AB - The purpose of this study was to investigate cellular sources of autofluorescence signals in freshly isolated frog (Rana pipiens) retinas. Equipped with an ultrafast laser, a laser scanning two-photon excitation fluorescence microscope was employed for sub-cellular resolution examination of both sliced and flat mounted retinas. Two-photon imaging of retinal slices revealed autofluorescence signals over multiple functional layers, including the photoreceptor layer (PRL), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), inner plexiform layer (IPL), and ganglion cell layer (GCL). Using flat mounted retinas, depth-resolved imaging of individual retinal layers further confirmed multiple sources of autofluorescence signals. Cellular structures were clearly observed at the PRL, ONL, INL, and GCL. At the PRL, the autofluorescence was dominantly recorded from the intracellular compartment of the photoreceptors; while mixed intracellular and extracellular autofluorescence signals were observed at the ONL, INL, and GCL. High resolution autofluorescence imaging clearly revealed mosaic organization of rod and cone photoreceptors; and sub cellular bright autofluorescence spots, which might relate to connecting cilium, was observed in the cone photoreceptors only. Moreover, single-cone and double cone outer segments could be directly differentiated. PMID- 21698014 TI - In vivo volumetric imaging of human retinal circulation with phase-variance optical coherence tomography. AB - We present in vivo volumetric images of human retinal micro-circulation using Fourier-domain optical coherence tomography (Fd-OCT) with the phase-variance based motion contrast method. Currently fundus fluorescein angiography (FA) is the standard technique in clinical settings for visualizing blood circulation of the retina. High contrast imaging of retinal vasculature is achieved by injection of a fluorescein dye into the systemic circulation. We previously reported phase variance optical coherence tomography (pvOCT) as an alternative and non-invasive technique to image human retinal capillaries. In contrast to FA, pvOCT allows not only noninvasive visualization of a two-dimensional retinal perfusion map but also volumetric morphology of retinal microvasculature with high sensitivity. In this paper we report high-speed acquisition at 125 kHz A-scans with pvOCT to reduce motion artifacts and increase the scanning area when compared with previous reports. Two scanning schemes with different sampling densities and scanning areas are evaluated to find optimal parameters for high acquisition speed in vivo imaging. In order to evaluate this technique, we compare pvOCT capillary imaging at 3x3 mm(2) and 1.5x1.5 mm(2) with fundus FA for a normal human subject. Additionally, a volumetric view of retinal capillaries and a stitched image acquired with ten 3x3 mm(2) pvOCT sub-volumes are presented. Visualization of retinal vasculature with pvOCT has potential for diagnosis of retinal vascular diseases. PMID- 21698015 TI - Wide-field imaging of fluorescent deoxy-glucose in ex vivo malignant and normal breast tissue. AB - Rapid in situ determination of surgical resection margins during breast cancer surgery would reduce patient time under anesthesia. We present preliminary data supporting the use of a fluorescent glucose analog (2-NBDG) as an optical contrast agent to differentiate freshly excised breast tissue containing cancerous cells from normal breast tissue. Multi-spectral images of 14 breast cancer specimens acquired before and after incubation with 2-NBDG demonstrated increased fluorescent signal in all of the malignant tissue due to increased 2 NBDG consumption. We demonstrate that 2-NBDG has potential as an optical contrast agent to differentiate cancerous from non-cancerous tissue. PMID- 21698016 TI - Robust automatic segmentation of corneal layer boundaries in SDOCT images using graph theory and dynamic programming. AB - Segmentation of anatomical structures in corneal images is crucial for the diagnosis and study of anterior segment diseases. However, manual segmentation is a time-consuming and subjective process. This paper presents an automatic approach for segmenting corneal layer boundaries in Spectral Domain Optical Coherence Tomography images using graph theory and dynamic programming. Our approach is robust to the low-SNR and different artifact types that can appear in clinical corneal images. We show that our method segments three corneal layer boundaries in normal adult eyes more accurately compared to an expert grader than a second grader-even in the presence of significant imaging outliers. PMID- 21698017 TI - Total retinal blood flow measurement with ultrahigh speed swept source/Fourier domain OCT. AB - Doppler OCT provides depth-resolved information on flow in biological tissues. In this article, we demonstrate ultrahigh speed swept source/Fourier domain OCT for visualization and quantitative assessment of retinal blood flow. Using swept laser technology, the system operated in the 1050-nm wavelength range at a high axial scan rate of 200 kHz. The rapid imaging speed not only enables volumetric imaging with high axial scan densities, but also enables measurement of high flow velocities in the central retinal vessels. Deep penetration in the optic nerve and lamina cribrosa was achieved by imaging at 1-um wavelengths. By analyzing en face images extracted from 3D Doppler data sets, absolute flow in single vessels as well as total retinal blood flow was measured using a simple and robust protocol that does not require measurement of Doppler angles. The results from measurements in healthy eyes suggest that ultrahigh speed swept source/Fourier domain OCT could be a promising technique for volumetric imaging of retinal vasculature and quantitation of retinal blood flow in a wide range of retinal diseases. PMID- 21698018 TI - Laser speckle imaging in the spatial frequency domain. AB - Laser Speckle Imaging (LSI) images interference patterns produced by coherent addition of scattered laser light to map subsurface tissue perfusion. However, the effect of longer path length photons is typically unknown and poses a limitation towards absolute quantification. In this work, LSI is integrated with spatial frequency domain imaging (SFDI) to suppress multiple scattering and absorption effects. First, depth sensitive speckle contrast is shown in phantoms by separating a deep source (4 mm) from a shallow source (2 mm) of speckle contrast by using a high spatial frequency of illumination (0.24 mm(-1)). We develop an SFD adapted correlation diffusion model and show that with high frequency (0.24 mm(-1)) illumination, doubling of absorption contrast results in only a 1% change in speckle contrast versus 25% change using a planar unmodulated (0 mm(-1)) illumination. Similar absorption change is mimicked in vivo imaging a finger occlusion and the relative speckle contrast change from baseline is 10% at 0.26 mm(-1) versus 60% at 0 mm(-1) during a finger occlusion. These results underscore the importance of path length and optical properties in determining speckle contrast. They provide an integrated approach for simultaneous mapping of blood flow (speckle contrast) and oxygenation (optical properties) which can be used to inform tissue metabolism. PMID- 21698019 TI - Integrated holographic system for all-optical manipulation of developing embryos. AB - We demonstrate a system for the combined optical injection and trapping of developing embryos. A Ti:sapphire femtosecond laser in tandem with a spatial light modulator, is used to perform fast and accurate beam-steering and multiplexing. We show successful intracellular delivery of a range of impermeable molecules into individual blastomeres of the annelid Pomatoceros lamarckii embryo by optoinjection, even when the embryo is still enclosed in a chorion. We also demonstrate the ability of the femtosecond laser optoinjection to deliver materials into inner layers of cells in a well-developed embryo. By switching to the continuous wave mode of the Ti:sapphire laser, the same system can be employed to optically trap and orient the 60 MUm sized P. lamarckii embryo whilst maintaining its viability. Hence, a complete all-optical manipulation platform is demonstrated paving the way towards single-cell genetic modification and cell lineage mapping in emerging developmental biology model species. PMID- 21698020 TI - In vivo and ex vivo epi-mode pump-probe imaging of melanin and microvasculature. AB - We performed epi-mode pump-probe imaging of melanin in excised human pigmented lesions and both hemoglobin and melanin in live xenograft mouse melanoma models to depths greater than 100 um. Eumelanin and pheomelanin images, which have been previously demonstrated to differentiate melanoma from benign lesions, were acquired at the dermal-epidermal junction with cellular resolution and modest optical powers (down to 15 mW). We imaged dermal microvasculature with the same wavelengths, allowing simultaneous acquisition of melanin, hemoglobin and multiphoton autofluorescence images. Molecular pump-probe imaging of melanocytes, skin structure and microvessels allows comprehensive, non-invasive characterization of pigmented lesions. PMID- 21698021 TI - Nanoshells for photothermal therapy: a Monte-Carlo based numerical study of their design tolerance. AB - The optimization of the coated metallic nanoparticles and nanoshells is a current challenge for biological applications, especially for cancer photothermal therapy, considering both the continuous improvement of their fabrication and the increasing requirement of efficiency. The efficiency of the coupling between illumination with such nanostructures for burning purposes depends unevenly on their geometrical parameters (radius, thickness of the shell) and material parameters (permittivities which depend on the illumination wavelength). Through a Monte-Carlo method, we propose a numerical study of such nanodevice, to evaluate tolerances (or uncertainty) on these parameters, given a threshold of efficiency, to facilitate the design of nanoparticles. The results could help to focus on the relevant parameters of the engineering process for which the absorbed energy is the most dependant. The Monte-Carlo method confirms that the best burning efficiency are obtained for hollow nanospheres and exhibit the sensitivity of the absorbed electromagnetic energy as a function of each parameter. The proposed method is general and could be applied in design and development of new embedded coated nanomaterials used in biomedicine applications. PMID- 21698022 TI - Ultrasmall spot size scanning laser ophthalmoscopy. AB - An ultrasmall spot size scanning laser ophthalmoscope has been developed that employs an annular aberration-corrected incident beam to increase the effective numerical aperture of the eye thereby reducing the width of the probing light spot. Parafovea and foveal cone photoreceptor visibility determined from small area retinal image scans are discussed from the perspective of mode matching between the focused incident beam and the waveguide modes of individual cones. The cone visibility near the fovea centralis can be increased with the annular illumination scheme whereas the visibility of larger parafovea cones drops significantly as a consequence of poorer mode match. With further improvements of the implemented wavefront correction technology it holds promise for individual cone-photoreceptor imaging at the fovea centralis and for optical targeting of the retina with increased resolution. PMID- 21698023 TI - Near-IR fluorescence and reflectance confocal microscopy for imaging of quantum dots in mammalian skin. AB - Understanding the skin penetration of nanoparticles (NPs) is an important concern due to the increasing presence of NPs in consumer products, including cosmetics. Technical challenges have slowed progress in evaluating skin barrier and NP factors that contribute to skin penetration risk. To limit sampling error and other problems associated with histological processing, many researchers are implementing whole tissue confocal or multiphoton microscopies. This work introduces a fluorescence and reflectance confocal microscopy system that utilizes near-IR excitation and emission to detect near-IR lead sulfide quantum dots (QDs) through ex vivo human epidermis. We provide a detailed prediction and experimental analysis of QD detection sensitivity and demonstrate detection of QD skin penetration in a barrier disrupted model. The unique properties of near-IR lead-based QDs will enable future studies that examine the impact of further barrier-disrupting agents on skin penetration of QDs and elucidate mechanistic insight into QD tissue interactions at the cellular level. PMID- 21698024 TI - Cramer-Rao analysis of steady-state and time-domain fluorescence diffuse optical imaging. AB - Using a Cramer-Rao analysis, we study the theoretical performances of a time and spatially resolved fDOT imaging system for jointly estimating the position and the concentration of a point-wide fluorescent volume in a diffusive sample. We show that the fluorescence lifetime is a critical parameter for the precision of the technique. A time resolved fDOT system that does not use spatial information is also considered. In certain cases, a simple steady-state configuration may be as efficient as this time resolved fDOT system. PMID- 21698025 TI - Analysis of the chicken retina with an adaptive optics multiphoton microscope. AB - The structure and organization of the chicken retina has been investigated with an adaptive optics multiphoton imaging microscope in a backward configuration. Non-stained flat-mounted retinal tissues were imaged at different depths, from the retinal nerve fiber layer to the outer segment, by detecting the intrinsic nonlinear fluorescent signal. From the stacks of images corresponding to the different retinal layers, volume renderings of the entire retina were reconstructed. The density of photoreceptors and ganglion cells layer were directly estimated from the images as a function of the retinal eccentricity. The maximum anatomical resolving power at different retinal eccentricities was also calculated. This technique could be used for a better characterization of retinal alterations during myopia development, and may be useful for visualization of retinal pathologies and intoxication during pharmacological studies. PMID- 21698026 TI - Customized eye models for determining optimized intraocular lenses power. AB - We have developed a new optical procedure to determine the optimum power of intraocular lenses (IOLs) for cataract surgery. The procedure is based on personalized eye models, where biometric data of anterior corneal shape and eye axial length are used. A polychromatic exact ray-tracing through the surfaces defining the eye model is performed for each possible IOL power and the area under the radial MTF is used as a metric. The IOL power chosen by the procedure maximizes this parameter. The IOL power for 19 normal eyes has been determined and compared with standard regression-based predictions. The impact of the anterior corneal monochromatic aberrations and the eye's chromatic aberration on the power predictions has been studied, being significant for those eyes with severe monochromatic aberrations, such as post-LASIK cataract patients, and for specific IOLs with low Abbe numbers. PMID- 21698027 TI - Critical comparison of diffuse reflectance spectroscopy and colorimetry as dermatological diagnostic tools for acanthosis nigricans: a chemometric approach. AB - Quantification of skin changes due to acanthosis nigricans (AN), a disorder common among insulin-resistant diabetic and obese individuals, was investigated using two optical techniques: diffuse reflectance spectroscopy (DRS) and colorimetry. Measurements were obtained from AN lesions on the neck and two control sites of eight AN patients. A principal component/discriminant function analysis successfully differentiated between AN lesion and normal skin with 87.7% sensitivity and 94.8% specificity in DRS measurements and 97.2% sensitivity and 96.4% specificity in colorimetry measurements. PMID- 21698028 TI - Integrated adaptive optics optical coherence tomography and adaptive optics scanning laser ophthalmoscope system for simultaneous cellular resolution in vivo retinal imaging. AB - We describe an ultrahigh-resolution (UHR) retinal imaging system that combines adaptive optics Fourier-domain optical coherence tomography (AO-OCT) with an adaptive optics scanning laser ophthalmoscope (AO-SLO) to allow simultaneous data acquisition by the two modalities. The AO-SLO subsystem was integrated into the previously described AO-UHR OCT instrument with minimal changes to the latter. This was done in order to ensure optimal performance and image quality of the AO- UHR OCT. In this design both imaging modalities share most of the optical components including a common AO-subsystem and vertical scanner. One of the benefits of combining Fd-OCT with SLO includes automatic co-registration between two acquisition channels for direct comparison between retinal structures imaged by both modalities (e.g., photoreceptor mosaics or microvasculature maps). Because of differences in the detection scheme of the two systems, this dual imaging modality instrument can provide insight into retinal morphology and potentially function, that could not be accessed easily by a single system. In this paper we describe details of the components and parameters of the combined instrument, including incorporation of a novel membrane magnetic deformable mirror with increased stroke and actuator count used as a single wavefront corrector. We also discuss laser safety calculations for this multimodal system. Finally, retinal images acquired in vivo with this system are presented. PMID- 21698029 TI - Measurement of the reduced scattering coefficient of turbid media using single fiber reflectance spectroscopy: fiber diameter and phase function dependence. AB - This paper presents a relationship between the intensity collected by a single fiber reflectance device (R(SF)) and the fiber diameter (d(fib)) and the reduced scattering coefficient ( MUs') and phase function (p(theta)) of a turbid medium. Monte Carlo simulations are used to identify and model a relationship between R(SF) and dimensionless scattering ( MUs'dfib). For MUs'dfib > 10 we find that R(SF) is insensitive to p(theta). A solid optical phantom is constructed with MUs' ~ 220 mm-1 and is used to convert R(SF) of any turbid medium to an absolute scale. This calibrated technique provides accurate estimates of MUs' over a wide range ([0.05 - 8] mm(-1)) for a range of d(fib) ([0.2 - 1] mm). PMID- 21698030 TI - Narrow-band pass filter array for integrated opto-electronic spectroscopy detectors to assess esophageal tissue. AB - A strategy for spectroscopy tissue diagnosis using a small number of wavelengths is reported. The feasibility to accurately quantify tissue information using only 16 wavelengths is demonstrated with several wavelength reduction simulations of the existing esophageal data set. These results are an important step for the development of a miniaturized, robust and low-cost spectroscopy system. This system is based on a sub-millimeter high-selective filter array that offers prospects for a simplified miniature spectrographic detector for a future diagnostic tool to improve the diagnosis of dysplasia. Several thin-film optical filters are optimized and fabricated and its spectral performance is shown to be sufficient for the selection of specific wavelength bands. PMID- 21698031 TI - Label-free classification of cultured cells through diffraction imaging. AB - Automated classification of biological cells according to their 3D morphology is highly desired in a flow cytometer setting. We have investigated this possibility experimentally and numerically using a diffraction imaging approach. A fast image analysis software based on the gray level co-occurrence matrix (GLCM) algorithm has been developed to extract feature parameters from measured diffraction images. The results of GLCM analysis and subsequent classification demonstrate the potential for rapid classification among six types of cultured cells. Combined with numerical results we show that the method of diffraction imaging flow cytometry has the capacity as a platform for high-throughput and label-free classification of biological cells. PMID- 21698032 TI - Investigating the distance limit of a metal nanoparticle based spectroscopic ruler. AB - Conventional Forster resonance energy transfer (FRET) processes involving a pair of fluorophore and organic quencher are restricted to an upper distance limit of ~10 nm. The application of a metal nanoparticle as a quencher can overcome the distance barrier of the traditional FRET technique. However, no standard distance dependence of this resonance energy transfer (RET) process has been firmly established. We have investigated the nonradiative energy transfer process between an organic donor (fluorescein) and gold nanoparticle quencher connected by double stranded (ds) DNA. The quenching efficiency of the gold nanoparticle as a function of distance between the donor and acceptor was determined by time resolved lifetime analyses of the donor. Our results showed a 1/d(4) distance dependence for the RET process for longer distances (>10 nm) and 1/d(6) distance dependence for shorter distances (<10 nm). Our results clearly indicate the applicability of metal nanoparticle based quenchers for studying systems that exceed the 10 nm FRET barrier. PMID- 21698033 TI - Deriving visual field loss based upon OCT of inner retinal thicknesses of the macula. AB - Using a multiple linear regression method, a derived visual field (VF) was obtained from retinal ganglion cell and retinal nerve fiber layer (RNFL) thicknesses measured with frequency-domain, optical coherence tomography (OCT) macular scans. 138 eyes from 92 glaucoma patients or suspects and 58 healthy eyes were included. The derived VF was compared to the VF measured with standard automated perimetry (SAP). The median agreement between the derived and observed VFs was 90%. As the derived and observed VFs should be independent, they can be combined to potentially increase the sensitivity/specificity of a test for glaucoma. PMID- 21698034 TI - Automated segmentation by pixel classification of retinal layers in ophthalmic OCT images. AB - Current OCT devices provide three-dimensional (3D) in-vivo images of the human retina. The resulting very large data sets are difficult to manually assess. Automated segmentation is required to automatically process the data and produce images that are clinically useful and easy to interpret. In this paper, we present a method to segment the retinal layers in these images. Instead of using complex heuristics to define each layer, simple features are defined and machine learning classifiers are trained based on manually labeled examples. When applied to new data, these classifiers produce labels for every pixel. After regularization of the 3D labeled volume to produce a surface, this results in consistent, three-dimensionally segmented layers that match known retinal morphology. Six labels were defined, corresponding to the following layers: Vitreous, retinal nerve fiber layer (RNFL), ganglion cell layer & inner plexiform layer, inner nuclear layer & outer plexiform layer, photoreceptors & retinal pigment epithelium and choroid. For both normal and glaucomatous eyes that were imaged with a Spectralis (Heidelberg Engineering) OCT system, the five resulting interfaces were compared between automatic and manual segmentation. RMS errors for the top and bottom of the retina were between 4 and 6 MUm, while the errors for intra-retinal interfaces were between 6 and 15 MUm. The resulting total retinal thickness maps corresponded with known retinal morphology. RNFL thickness maps were compared to GDx (Carl Zeiss Meditec) thickness maps. Both maps were mostly consistent but local defects were better visualized in OCT-derived thickness maps. PMID- 21698035 TI - Reflective afocal broadband adaptive optics scanning ophthalmoscope. AB - A broadband adaptive optics scanning ophthalmoscope (BAOSO) consisting of four afocal telescopes, formed by pairs of off-axis spherical mirrors in a non-planar arrangement, is presented. The non-planar folding of the telescopes is used to simultaneously reduce pupil and image plane astigmatism. The former improves the adaptive optics performance by reducing the root-mean-square (RMS) of the wavefront and the beam wandering due to optical scanning. The latter provides diffraction limited performance over a 3 diopter (D) vergence range. This vergence range allows for the use of any broadband light source(s) in the 450-850 nm wavelength range to simultaneously image any combination of retinal layers. Imaging modalities that could benefit from such a large vergence range are optical coherence tomography (OCT), multi- and hyper-spectral imaging, single- and multi-photon fluorescence. The benefits of the non-planar telescopes in the BAOSO are illustrated by resolving the human foveal photoreceptor mosaic in reflectance using two different superluminescent diodes with 680 and 796 nm peak wavelengths, reaching the eye with a vergence of 0.76 D relative to each other. PMID- 21698036 TI - True logarithmic amplification of frequency clock in SS-OCT for calibration. AB - With swept source optical coherence tomography (SS-OCT), imprecise signal calibration prevents optimal imaging of biological tissues such as coronary artery. This work demonstrates an approach using a true logarithmic amplifier to precondition the clock signal, with the effort to minimize the noises and phase errors for optimal calibration. This method was validated and tested with a high speed SS-OCT. The experimental results manifest its superior ability on optimization of the calibration and improvement of the imaging performance. Particularly, this hardware-based approach is suitable for real-time calibration in a high-speed system where computation time is constrained. PMID- 21698037 TI - History of the Department of Cell Biology at Yale School of Medicine, 1813-2010. AB - The Department of Cell Biology at the Yale University School of Medicine was established in 1983. It was preceded by the Section of Cell Biology, which was formed in 1973 when George E. Palade and collaborators came to Yale from the Rockefeller University. Cell Biology at Yale had its origins in the Department of Anatomy that existed from the beginning of classes at the Medical Institution of Yale College in 1813. This article reviews the history of the Department of Anatomy at Yale and its evolution into Cell Biology that began with the introduction of histology into the curriculum in the 1860s. The formation and development of the Section and Department of Cell Biology in the second half of the 20th century to the present time are described. Biographies and research activities of the chairs and key faculty in anatomy and cell biology are provided. PMID- 21698038 TI - Putting together the pieces of polio: how Dorothy Horstmann helped solve the puzzle. AB - Dr. Dorothy Horstmann, epidemiologist, virologist, clinician, and educator, was the first woman appointed as a professor at the Yale School of Medicine. Horstmann made significant contributions to the fields of public health and virology, her most notable being the demonstration that poliovirus reached the central nervous system via the bloodstream, upsetting conventional wisdom and paving the way for polio vaccines. In 1961, she was appointed a professor at Yale School of Medicine, and in 1969, she became the first woman at Yale to receive an endowed chair, which was named in honor of her mentor, Dr. John Rodman Paul. In this review, the major scientific contributions of Dr. Dorothy Horstmann will be highlighted from her more than 50-year tenure at Yale School of Medicine. PMID- 21698039 TI - Harvey Cushing's ghosts: death and hauntings in modern medicine. AB - The passing of Yale School of Medicine's 2010 Bicentennial occasions a moment of reflecting on the past, present, and future of medical education and research at Yale and beyond. Last June, a ribbon-cutting ceremony inaugurated the opening of the Cushing Center in the Cushing-Whitney Medical Library. Named after Harvey Cushing, an early 20th-century neurosurgeon and former Yale College alum, the dual education/exhibition space now houses hundreds of gross brain specimens constituting the Cushing Tumor Registry. Originally a personal collection, Cushing donated his numerous medical specimens, photographs, and other medical relics from his deathbed, relinquishing the brains to Yale only under the condition that a suitable space be erected to preserve the many specimens. Some 70 years later and after nearly being destroyed, Cushing's wish is fully realized: The once desiccated, hidden brains have been painstakingly restored and are now on view in the Cushing Center. The brains express Cushing's singular and spectral worldview as a surgeon, artist, athlete, soldier, book collector, and historian. PMID- 21698040 TI - Close to home: a history of Yale and Lyme disease. AB - Yale scientists played a pivotal role in the discovery of Lyme disease and are credited as the first to recognize, name, characterize, and treat the affliction. Today, Lyme disease is the most commonly reported vector-borne illness in the United States, affecting approximately 20,000 people each year, with the incidence having doubled in the past 10 years [1]. Lyme disease is the result of a bacterial infection transmitted to humans through the bite of an infected deer tick, which typically results in a skin rash at the site of attack. While most cases, when caught early, are easily treated by antibiotic therapy, delayed treatment can lead to serious systemic side effects involving the joints, heart, and central nervous system. Here we review Yale's role in the discovery and initial characterization of Lyme disease and how those early discoveries are crucial to our current understanding of the disease. PMID- 21698041 TI - Pioneering studies of the "morning-after" pill. AB - Yale School of Medicine produced the first proof-of-concept study on the viability of a "morning-after" pill for human use. This study was a result of a fruitful collaboration between a pair of Yale scientists, Drs. John M. Morris and Gertrude van Wagenen, who sought a non-abortion, post-coital contraceptive. They tested a variety of hormones, hormone-based synthetic drugs, and other compounds in monkeys in an effort to uncover a compound that was non-toxic but highly effective. Unfortunately, although they were unable to identify such a drug, their initial studies inspired other scientists to further pursue the concept of a "morning-after" pill, leading to the development of Food and Drug Administration (FDA)-approved emergency contraceptives. PMID- 21698042 TI - The legacy of a founding father of modern cell biology: George Emil Palade (1912 2008). AB - George Emil Palade's scientific contributions significantly advanced the field of modern cell biology. He pioneered a multidisciplinary approach, combining cell fractionation, biochemistry, and electron microscopy, which led to the identification of the ribosome as the site of protein synthesis and elucidated the eukaryotic secretory pathway. For these accomplishments, Palade, along with Albert Claude and Christian de Duve, won the 1974 Nobel Prize in Physiology or Medicine. This article provides an overview of Palade's seminal research in the context of the early developments in the field. PMID- 21698043 TI - Genetic engineering of a mouse: Dr. Frank Ruddle and somatic cell genetics. AB - Genetic engineering is the process of modifying an organism's genetic composition by adding foreign genes to produce desired traits or evaluate function. Dr. Jon W. Gordon and Sterling Professor Emeritus at Yale Dr. Frank H. Ruddle were pioneers in mammalian gene transfer research. Their research resulted in production of the first transgenic animals, which contained foreign DNA that was passed on to offspring. Transgenic mice have revolutionized biology, medicine, and biotechnology in the 21st century. In brief, this review revisits their creation of transgenic mice and discusses a few evolving applications of their transgenic technology used in biomedical research. PMID- 21698044 TI - The 2009 Nobel Prize in Chemistry: Thomas A. Steitz and the structure of the ribosome. AB - Over the past 200 years, there have been countless groundbreaking discoveries in biology and medicine at Yale University. However, one particularly noteworthy discovery with profoundly important and broad consequences happened here in just the past two decades. In 2009, Thomas Steitz, the Sterling Professor of Molecular Biophysics & Biochemistry, was awarded the Nobel Prize in Chemistry for "studies of the structure and function of the ribosome," along with Venkatraman Ramakrishnan of the MRC Laboratory of Molecular Biology and Ada E. Yonath of the Weizmann Institute of Science. This article covers the historical context of Steitz's important discovery, the techniques his laboratory used to study the ribosome, and the impact that this research has had, and will have, on the future of biological and medical research. PMID- 21698045 TI - Toward a modern synthesis of immunity: Charles A. Janeway Jr. and the immunologist's dirty little secret. AB - This essay chronicles the major theoretical and experimental contributions made by Charles A. Janeway, Jr. (1943-2003), Howard Hughes Medical Institute investigator and Yale Professor of Immunobiology, who established the fundamental role of the innate immune system in the induction of the adaptive arm. PMID- 21698046 TI - Saving our future: James Comer and the School Development Program. AB - Since the founding of the School Development Program (SDP) by Dr. James Comer in 1968, the manner in which child development is addressed in many schools has changed drastically. By working together using the SDP model, schools, parents, and child development experts are able to foster healthy social, emotional, and academic development in children, resulting in improvement in all areas. This review briefly describes the creation and implementation of the SDP model by Dr. James Comer. PMID- 21698047 TI - Reflections of a member of the bicentennial class on the Bicentennial Symposium. AB - This perspective piece explores what it means to be a first-year medical student at Yale School of Medicine during its bicentennial year. At first, it seemed like a hefty burden to bear. However, upon listening to Dr. Eric Kandel speak at the Bicentennial Symposium at Yale on April 28, 2011, it became clear what it means to be a part of the future of science and medicine at Yale. PMID- 21698048 TI - Creating the unforgettable: the short story of mapping long-term memory. Bicentennial Symposium. AB - Memory is a binary process relying on a short-term form lasting minutes to forge and communicate with a long-term form lasting years. Yale's Bicentennial Symposium opened with a lecture elucidating the obscure process of long-term memory formation. From his decades of research, Nobel Laureate Eric Kandel offered insight into the molecular framework that is long term-memory. PMID- 21698049 TI - Intelligent discussion on HIV vaccine serves as a small consolation for slow progress. Bicentennial Symposium. AB - Despite great public interest and desperate need, progress toward a viable human immunodeficiency virus (HIV) vaccine remains incredibly slow. Since Merck began its HIV vaccine research in 1985, the pharmaceutical company has yet to produce a vaccine capable of passing Phase II testing. Merck Laboratories President Peter S. Kim recently delivered a speech at Yale University that detailed his company's previous attempts to create an HIV vaccine and outlined a possible strategy for the future. By Kim's own admission, Merck will not produce a viable vaccine in the near future. However, the speech served as an important endorsement for HIV vaccine development from a highly respected leader in the pharmaceutical industry, which, historically, has produced drugs aimed at management rather than prevention. PMID- 21698050 TI - Tobacco-related disease burden and preventive initiatives in China. Global health and the chronic diseases: perspective, policy and practice. AB - The burden of chronic diseases in global health is a surging area of research. The Global Health Initiative at the National Heart, Lung, and Blood Institute brings together investigators from developing countries with those from the developed world to study these diseases. In China, approximately 83 percent of all deaths in 2000 were attributed to chronic illnesses, which are the research focuses of the Chinese center of the Global Health Initiative. Tobacco use as well as passive smoking are modifiable risk factors in a large number of such chronic conditions. The prevalence of smoking in China is extensive and has inseparable ties to the economy, with tobacco taxes making up a large portion of government revenue in poorer provinces. Methods of smoking prevention have been piloted in some Chinese schools, which have mitigated the increase in smoking rate but have not resulted in a primary preventive effect. Efforts by the Yale Global Health Initiative and the Yale-China Association are bringing researchers together to address chronic disease in China as Yale School of Medicine enters its 200th year. PMID- 21698051 TI - Harmonic medicine: the influence of music over mind and medical practice. AB - The Yale Medical Orchestra displayed exceptional talent and inspiration as it performed a timeless composition to celebrate Yale School of Medicine's bicentennial anniversary during a December 2010 concert. Under the leadership of musical directors Robert Smith and Adrian Slywotzky, the richly emotional meditations of Mendelssohn, Dvorak, Schubert, and Yale's own Thomas C. Duffy filled the minds and hearts of an audience as diverse as the orchestra. I intend to retrace the steps of that melodic journey in this essay, fully aware of the limits imposed on me to recreate the aural art form through the medium of text. While these symbols can be pale representations of the beauty and complexity of the music, I hope they will be the building blocks for the emotional experience of the audience. I describe the works' inception and their salient musical features and then review what we know about the effects of melody, meter, and timbre on our brains. My intentions are to provide evidence to encourage the further use of music as a tool in medical practice, provide interest in the works explored by the Yale orchestra, support the orchestra itself, and investigate a personal passion. PMID- 21698052 TI - The birth of chemotherapy at Yale. Bicentennial lecture series: Surgery Grand Round. AB - Chemotherapy, one of the mainstays of cancer treatment today, was pioneered at Yale during World War II. Last year, two Yale surgeons, Drs. John Fenn and Robert Udelsman, sought to unearth the mystery surrounding the discovery of chemotherapy and its first use at Yale. The first chemotherapy patient is known only as JD in the literature, and without a name, date of birth, or medical record number, a search for his record seemed futile. However, persistence coupled with sheer fortune led them to JD's chart, where they found information that differed from previous accounts. The riveting personal story of JD, an immigrant patient with lymphosarcoma, was revealed for the first time by Drs. Fenn and Udelsman on January 19, 2011, at a special Surgical Grand Rounds celebrating the bicentennial of Yale School of Medicine. PMID- 21698053 TI - Emulsified isoflurane preconditioning reduces lung injury induced by hepatic ischemia/reperfusion in rats. AB - OBJECTIVE: To investigate whether emulsified isoflurane preconditioning could reduce lung injury induced by hepatic I/R in rats and its mechanism. MATERIALS AND METHODS: 32 pentobarbital-anesthetized Sprague-Dawley rats were equally randomized into four groups: laparotomy group (Sham group), hepatic I/R and normal saline infusion group (I/R+S group), I/R and lipid vehicle infusion (I/R+V group), or I/R and 8% emulsified isoflurane infusion (I/R+E group) at the rate of 8 ml.kg(-1).h(-1) for 30 min. Blood supply of the hepatic artery and portal vein to the left and the median liver lobes was occluded for 90 min after 30-min washout time. Reperfusion was allowed to proceed for 4 h before sacrifice of the animals. Lung injury was observed histologically. Neutrophil infiltration and TNF alpha concentration in serum and lung were measured. Changes of wet-to-dry weight ratios in lung tissue, ICAM-1 expression and NF-kappaB activity in lung after hepatic I/R were determined. RESULTS: Compared with I/R+S or I/R+V group, emulsified isoflurane preconditioning reduced hepatic I/R-induced lung histologic injury and inhibited the increase of myeloperoxidase (MPO) activity in the lung tissue markedly (5.5+/-1.37 and 5.22+/-1.33 vs 3.81+/-1.62 U/g, P<0.05). In addition, both serum and lung tissue TNF-alpha levels were reduced in I/R+E group (104.58+/-31.40 and 94.60+/-22.23 vs 72.44+/-17.28 pg/ml, P<0.05; 393.51+/-88.22 and 405.46+/-102.87 vs 292.62+/-74.56 pg/ml, P<0.01). Emulsified isoflurane preconditioning also inhibited the increase of ICAM-1 expression (0.79+/-0.17 and 0.84+/-0.24 vs 0.62+/-0.21, P<0.05) and NF-kappaB translocation (4.93+/-0.48 and 4.76+/-0.57 vs 4.01+/-0.86, P<0.05) in the lung tissue markedly. CONCLUSIONS: Emulsified isoflurane preconditioning markedly attenuated hepatic I/R-induced lung injury in rats, which may be hopefully applied to the clinical treatment of organ injury caused by hepatic surgery, transplantation or hemorrhagic shock. PMID- 21698054 TI - The versatile use of temporoparietal fascial flap. AB - BACKGROUND: The pedicled or free temporoparietal fascial has been used in many areas, especially in head and neck reconstruction. This thin, pliable, highly vascularized flap may be also transferred as a carrier of subjacent bone or overlying skin. OBJECTIVE: The aim of this study is to report our experience in versatile use of temporoparietal fascial flap (TPFF) and discuss the surgical anatomy and technique. PATIENTS AND METHODS: A total number of 57 TPFFs have been used in periorbital, mid-facial, auricular, and tracheal reconstruction due to tumor resection, trauma, and congenital ear deformities. RESULTS: All the flaps were successfully transferred without any major complication. The cosmetic results were quite satisfactory to all patients. CONCLUSION: The advantages and minimal donor site morbidity of TPPF makes this flap a good choice in many reconstructive procedures. PMID- 21698055 TI - The association among lipoprotein-associated phospholipase A2 levels, total antioxidant capacity and arousal in male patients with OSA. AB - BACKGROUND: The mechanisms of the increased cardiac and vascular events in patients with OSA are not well understood. Arousal which is an important component of OSA was associated with increased sympathetic activation and electrocardiographic changes which prone to arrhythmias. We planned to examine the association among arousal, circulating Lp-PLA2 and total antioxidant capacity in male patients with OSA. METHODS: Fifty male patients with newly diagnosed OSA were enrolled the study. A full-night polysomnography was performed and arousal index was obtained. Lp-PLA2 concentrations were measured in serum samples with the PLAC Test. Total antioxidant capacity in patients was determined with Antioxidant Assay Kit. RESULTS: Arousal was positively correlated with LP-PLA2 levels (r=0.43, p=0.002) and was negatively correlated with total antioxidant capacity (r= -0.29, p=0.04). Elevated LP-PLA2 levels and decreased total antioxidant activities were found in the highest arousal quartile compared with the lowest and 2nd quartiles (p=0.02, p=0.05, respectively). LP-PLA2 was an independently predictor of arousal index in regression model (beta=0.357, p=0.002) CONCLUSIONS: This study demonstrated a moderate linear relationship between arousal and LP-PLA2 levels. Also, total antioxidant capacities were decreased in the higher arousal index. Based on the study result, the patients with higher arousal index may be prone to vascular events. PMID- 21698056 TI - Surgical treatment of depressed scar: a simple technique. AB - Scar formation is a process consequent to the healing of soft tissues after a trauma. However, abnormal or disturbed collagen production can cause anomalies of the cutaneous surface and textural irregularities. In the presence of a depressed scar in deep tissue, we began to use a new simple technique. In the presence of adherent scars, a small incision is performed so that an undermining scissor can enter inside. The entire cicatricial area is undermined on a subcutaneous plane which, by separating the deep scar from the superficial one, completely frees it from the present adhesions so that the existing depression is totally eliminated. In order to avoid the recreation of relapses, stitches formed in a U-shape are made in Nylon or Monocril 2-3/0 are made with a large needle and are placed close together so that a wide aversion is achieved at the margins of the scar and a deep wound closure is obtained by adhering to the undermined tissue. These stitches will then be removed about 2 weeks later. PMID- 21698057 TI - Prevention of pleural adhesions using a membrane containing polyethylene glycol in rats. AB - BACKGROUND: Recurrent thoracotomies regardless of the cause are not a rare occurrence. However, each thoracotomy results in adhesion to some extent. This adhesions increase morbidity and mortality presents a significant inconvenience for surgeons and prolongs the length of operations. OBJECTIVE: We investigated the efficacy of Prevadh(r), an anti-adhesion agent to prevent intrapleural adesions following thoracotomy in a rat model. METHODS: Twenty male adult Wistar Albino rats were divided into a sham group (Group A, n = 4), a control group (Group B, n = 8), and a study group (Group C, n = 8). Only left thoracotomy was performed in Group A. Group B underwent left thoracotomy, induction of adhesion, and 1 ml saline solution was administered to the thoracic cavity. However, in Group C underwent left thoracotomy, induction of adhesion, and Prevadh(r) was placed between the pleura and the lung. The rats were sacrificed on day 21, and adhesions were analyzed using both macroscopic and histopathological methods. The results were statistically analyzed. A value of P<0.05 was considered statistically significant. RESULTS: Mean lengths of adhesion differed statistically significantly among all three groups, while mean intensity of adhesion differed between Group A and Group B, and between Group B and Group C (P>0.05). There was also a statistically significant difference between Group A and Group C in mesothelium proliferation score (P>0.05). No statistically significant differences were found among the groups in terms of pleural thickness, macrophage and mononuclear cell infiltration (P>0.05). CONCLUSIONS: Prevadh(r) was shown in a rat model to effectively prevent post-thoracotomy adhesions. PMID- 21698058 TI - Models of care for early-stage breast cancer in Canada. AB - There is growing evidence that follow-up for patients with early breast cancer (ebc) can be effectively carried out by the primary health care provider if a plan is in place. Here, we present data from a recent survey conducted in Ontario indicating that a shared-care model could work if communication between all health professionals involved in the care of ebc patients were to be improved. Patients and primary care providers benefit when the specialist provides written information about what their roles are and what to expect. Primary care providers need to have easy access to the specialist to discuss areas of concern. Patients also need to share responsibility for their care, ensuring that they attend follow-up visits on a regular basis and that they discuss areas of concern with their primary health care provider. A shared-care model has the potential to provide the best care for the least cost to the health system. PMID- 21698059 TI - Patient adherence to aromatase inhibitor treatment in the adjuvant setting. AB - Improvements in adjuvant systemic therapy and detection of early disease have resulted in a decline of breast cancer death rates across all patient age groups in Canada. Non-adherence to adjuvant hormonal therapy in the setting of early breast cancer may significantly affect patient outcome. Factors associated with medication adherence are complex and may be patient-related, therapy-related, and health care provider-related. To date, there is a gap in the literature concerning a comprehensive understanding of factors related to medication adherence with anti-estrogen therapy in the adjuvant setting. The literature suggests that strategies for improving adherence should focus on education of patients, assessment of the ability of patients to understand their disease and related recurrence factors, and facilitation of adherence by patients by providing adequate support and strategies for good self-management. However, more research is needed to better understand how health care providers can support women with breast cancer on oral therapy in the adjuvant setting. PMID- 21698061 TI - ? PMID- 21698060 TI - ? PMID- 21698062 TI - Social isolation-induced aggression potentiates anxiety and depressive-like behavior in male mice subjected to unpredictable chronic mild stress. AB - BACKGROUND: Accumulating epidemiological evidence shows that life event stressors are major vulnerability factors for psychiatric diseases such as major depression. It is also well known that social isolation in male mice results in aggressive behavior. However, it is not known how social isolation-induced aggression affects anxiety and depressive-like behavior in isolated male mice subjected to unpredictable chronic mild stress (CMS), an animal model of depression. METHODOLOGY/PRINCIPAL FINDINGS: C57/B6 male mice were divided into 3 groups; non-stressed controls, in Group I; isolated mice subjected to the CMS protocol in Group II and aggression by physical contact in socially isolated mice subjected to the CMS protocol in Group III. In the sucrose intake test, ingestion of a 1% sucrose solution by mice in Groups II and III was significantly lower than in Group I. Furthermore, intake of this solution in Group III mice was significantly lower than in Group II mice. In the open field test, mice in Group III, showed reduced locomotor activity and reduced entry and retention time in the central zone, compared to Groups I and II mice. Moreover, the distances moved in 1 hour by Group III mice did not differ between night and morning. In the light/black box test, Groups II and III animals spent significantly less time in the light box compared to Group I animals. In the tail suspension test (TST) and forced swimming test (FST), the immobility times of Group II and Group III mice were significantly longer than in Group I mice. In addition, immobility times in the FST were significantly longer in Group III than in Group II mice. CONCLUSIONS/SIGNIFICANCE: These findings show that social isolation-induced aggression could potentiate anxiety and depressive-like behaviors in isolated male mice subjected to CMS. PMID- 21698063 TI - Energy metabolism in human pluripotent stem cells and their differentiated counterparts. AB - BACKGROUND: Human pluripotent stem cells have the ability to generate all cell types present in the adult organism, therefore harboring great potential for the in vitro study of differentiation and for the development of cell-based therapies. Nonetheless their use may prove challenging as incomplete differentiation of these cells might lead to tumoregenicity. Interestingly, many cancer types have been reported to display metabolic modifications with features that might be similar to stem cells. Understanding the metabolic properties of human pluripotent stem cells when compared to their differentiated counterparts can thus be of crucial importance. Furthermore recent data has stressed distinct features of different human pluripotent cells lines, namely when comparing embryo derived human embryonic stem cells (hESCs) and induced pluripotent stem cells (IPSCs) reprogrammed from somatic cells. METHODOLOGY/PRINCIPAL FINDINGS: We compared the energy metabolism of hESCs, IPSCs, and their somatic counterparts. Focusing on mitochondria, we tracked organelle localization and morphology. Furthermore we performed gene expression analysis of several pathways related to the glucose metabolism, including glycolysis, the pentose phosphate pathway and the tricarboxylic acid (TCA) cycle. In addition we determined oxygen consumption rates (OCR) using a metabolic extracellular flux analyzer, as well as total intracellular ATP levels by high performance liquid chromatography (HPLC). Finally we explored the expression of key proteins involved in the regulation of glucose metabolism. CONCLUSIONS/FINDINGS: Our results demonstrate that, although the metabolic signature of IPSCs is not identical to that of hESCs, nonetheless they cluster with hESCs rather than with their somatic counterparts. ATP levels, lactate production and OCR revealed that human pluripotent cells rely mostly on glycolysis to meet their energy demands. Furthermore, our work points to some of the strategies which human pluripotent stem cells may use to maintain high glycolytic rates, such as high levels of hexokinase II and inactive pyruvate dehydrogenase (PDH). PMID- 21698065 TI - A new species of Pandanaceae from northern Madagascar, Pandanus ankaranensis. AB - A new species, Pandanus ankaranensis Callm. & Laivao (Pandanaceae), is described from the karst region of Ankarana in northern Madagascar. It resembles P. grallatus B. C. Stone, another member of Pandanus sect. Mammillares H. St. John occurring in the area. The new taxon can be distinguished by its larger and wider leaves that are persistent on the branches, the stipe often lying on the rocks where plants grow, and its larger syncarps. Pandanus ankaranensis is classified as Vulnerable based on the IUCN Red List criteria. PMID- 21698064 TI - Malagasy Dracaena Vand. ex L. (Ruscaceae): an investigation of discrepancies between morphological features and spatial genetic structure at a small evolutionary scale. AB - Malagasy Dracaena (Ruscaceae) are divided into four species and 14 varieties, all of them showing a high level of morphological diversity and a putatively artefactual circumscription. In order to reveal relationships between those entangled entities, a span of Malagasy Dracaena were sampled and analyzed using cpDNA sequences and AFLP. The cpDNA analyses resolved three biogeographic clades that are mostly inconsistent with morphology, since similar phenotypes are found across the three clades. Bayesian inference clustering analyses based on the AFLP were not in accordance with the cpDNA analysis. This result might be explained by (1) a recent origin of the Malagasy species of Dracaena with an incomplete sorting of chloroplast lineages; (2) a high amount of hybridizations; (3) a complex migration pattern. Interestingly, when the AFLP are analyzed using the parsimony criterion, a trend towards a directional evolution of inflorescence types and ecological features was observed. This might be considered either as phenotypic plasticity and/or as the result of fast evolution in flower characters according to habitat preferences. Overall, our results point to the difficulty of defining evolutionarily significant units in Malagasy Dracaena, emphasizing the complex speciation processes taking place in tropical regions. PMID- 21698066 TI - The Primate Life History Database: A unique shared ecological data resource. AB - The importance of data archiving, data sharing, and public access to data has received considerable attention. Awareness is growing among scientists that collaborative databases can facilitate these activities.We provide a detailed description of the collaborative life history database developed by our Working Group at the National Evolutionary Synthesis Center (NESCent) to address questions about life history patterns and the evolution of mortality and demographic variability in wild primates.Examples from each of the seven primate species included in our database illustrate the range of data incorporated and the challenges, decision-making processes, and criteria applied to standardize data across diverse field studies. In addition to the descriptive and structural metadata associated with our database, we also describe the process metadata (how the database was designed and delivered) and the technical specifications of the database.Our database provides a useful model for other researchers interested in developing similar types of databases for other organisms, while our process metadata may be helpful to other groups of researchers interested in developing databases for other types of collaborative analyses. PMID- 21698067 TI - Adolescent Self-reported Alcohol/other Drug Use Consequences: Moderators of Self and Parent Agreement. AB - While the reliability of assessment instruments designed for use with adults is well established, much less is known about the adequacy of these instruments for adolescent substance abusers. As part of a comprehensive intake evaluation, the Inventory of Drug Use Consequences (InDUC) was administered both to forty adolescents assigned to a probationary substance abuse treatment program and to one of their parents. The correlation was statistically significant between Parent and Adolescent InDUC score(s), but the interrater reliability was relatively low. IQ scores and level of substance use were considered as moderator variables, but neither showed a significant effect. History of head injury, however, significantly moderated this relationship; those adolescents reporting no history of head injury showed little correspondence with Parent InDUC Score(s), whereas those adolescents with a history of head injury showed significant correlations with parent InDUC scores. This suggests that a history of head injury may affect the way in which adolescents perceive substance-related consequences. PMID- 21698068 TI - Religious and Spiritual Responses to 9/11: Evidence from the Add Health Study* AB - Despite a great deal of public discourse concerning the effect of the September 11(th) attacks on Americans' religious and spiritual lives, social scientists know very little about the nature, size, and duration of this effect. Using panel data from the National Longitudinal Study of Adolescent Health, this study analyzes the influence of 9/11 on the religious and spiritual lives of American young adults. The results suggest that the 9/11 attacks exerted only modest and short-lived effects on various aspects of young adults' religiosity and spirituality, and these effects were variable across different groups. These findings suggest that no remarkable religious revival occurred among young adults after September 11(th), and researchers interested in analyzing religious development across the life course or religious change over time need not worry about sea changes in religiosity and spirituality brought on by 9/11. PMID- 21698069 TI - ASSESSMENT OF TISSUE OPTICAL CLEARING AS A FUNCTION OF GLUCOSE CONCENTRATION USING OPTICAL COHERENCE TOMOGRAPHY. AB - One of the major challenges in imaging biological tissues using optical techniques, such as optical coherence tomography (OCT), is the lack of light penetration due to highly turbid structures within the tissue. Optical clearing techniques enable the biological samples to be more optically homogeneous, allowing for deeper penetration of light into the tissue. This study investigates the effect of optical clearing utilizing various concentrations of glucose solution (10%, 30%, and 50%) on porcine skin. A gold-plated mirror was imaged beneath the tissue and percentage clearing was determined by monitoring the change in reflected light intensity from the mirror over time. The ratio of percentage clearing per tissue thickness for 10%, 30% and 50% glucose was determined to be 4.7 +/- 1.6% mm(-1) (n = 6), 10.6 +/- 2.0% mm(-1) (n = 7) and 21.8 +/- 2.2% mm(-1) (n = 5), respectively. It was concluded that while higher glucose concentration has the highest optical clearing effect, a suitable concentration should be chosen for the purpose of clearing, considering the osmotic stress on the tissue sample. PMID- 21698070 TI - WHEN AND WHY DO HEDGEHOGS AND FOXES DIFFER? AB - Philip E. Tetlock's finding that "hedgehog" experts (those with one big theory) are worse predictors than "foxes" (those with multiple, less comprehensive theories) offers fertile ground for future research. Are experts as likely to exhibit hedgehog- or fox-like tendencies in areas that call for explanatory, diagnostic, and skill-based expertise-as they did when Tetlock called on experts to make predictions? Do particular domains of expertise curtail or encourage different styles of expertise? Can we trace these different styles to childhood? Finally, can we nudge hedgehogs to be more like foxes? Current research can only grope at the answers to these questions, but they are essential to gauging the health of expert political judgment. PMID- 21698071 TI - Potential Role of Dentin Sialoprotein by Inducing Dental Pulp Mesenchymal Stem Cell Differentiation and Mineralization for Dental Tissue Repair. AB - INTRODUCTION: Dentin sialoprotein (DSP) is a dentin extracellular matrix protein, a unique marker of dentinogenesis and plays a vital role in odontoblast differentiation and dentin mineralization. Recently, studies have shown that DSP induces differentiation and mineralization of periodontal ligament stem cells and dental papilla mesenchymal cells in vitro and rescues dentin deficiency and increases enamel mineralization in animal models. THE HYPOTHESIS: DSP as a nature therapeutic agent stimulates dental tissue repair by inducing endogenous dental pulp mesenchymal stem/progenitor cells into odontoblast-like cells to synthesize and to secrete dentin extracellular matrix forming new tertiary dentin as well as to regenerate a functional dentin-pulp complex. As DSP is a nature protein, and clinical procedure for DSP therapy is easy and simple, application of DSP may provide a new avenue for dentists with additional option for the treatment of substantially damaged vital teeth. EVALUATION OF THE HYPOTHESIS: Dental caries is the most common dental disease. Deep caries and pulp exposure have been treated by various restorative materials with limited success. One promising approach is dental pulp stem/progenitor-based therapies to regenerate dentin-pulp complex and restore its functions by DSP induction in vivo. PMID- 21698073 TI - Gene networks driving bovine mammary protein synthesis during the lactation cycle. AB - A crucial role for both insulin and mTOR in the regulation of milk protein synthesis is emerging. Bovine mammary biopsies harvested during late-pregnancy through end of subsequent lactation were used to evaluate via quantitative PCR the expression of 44 genes involved in pathways of insulin, mTOR, AMPK, and Jak2 Stat5 signalling and also glucose and amino acid (AA) transporters. We observed an increased expression during lactation of ELF5, AA and glucose transporters, insulin signaling pathway components, MAPK14, FRAP1, EIF4EBP2, GSK3A and TSC1 among mTOR signaling-related genes. Among ribosomal components RPL22 was down regulated. The overall data support a central role of AA and glucose transporters and insulin signaling through mTOR for the regulation of protein synthesis in bovine mammary gland. Furthermore, the existence of translational competition favoring the translation of milk protein transcripts was inferred from the combined dataset. PMID- 21698072 TI - Mouse retinal development: a dark horse model for systems biology research. AB - The developing retina is an excellent model to study cellular fate determination and differentiation in the context of a complex tissue. Over the last decade, many basic principles and key genes that underlie these processes have been experimentally identified. In this review, we construct network models to summarize known gene interactions that underlie determination and fundamentally affect differentiation of each retinal cell type. These networks can act as a scaffold to assemble subsequent discoveries. In addition, these summary networks provide a rational segue to systems biology approaches necessary to understand the many events leading to appropriate cellular determination and differentiation in the developing retina and other complex tissues. PMID- 21698074 TI - Mitotic and antiapoptotic effects of nanoparticles coencapsulating human VEGF and human angiopoietin-1 on vascular endothelial cells. AB - BACKGROUND: Research towards the application of nanoparticles as carrier vehicles for the delivery of therapeutic agents is increasingly gaining importance. The angiogenic growth factors, human vascular endothelial growth factor (VEGF) and human angiopoietin-1 are known to prevent vascular endothelial cell apoptosis and in fact to stimulate human vascular endothelial cell (HUVEC) proliferation. This paper aims to study the combined effect of these bioactive proteins coencapsulated in human serum albumin nanoparticles on HUVECs and to evaluate the potential application of this delivery system towards therapeutic angiogenesis. METHODS AND RESULTS: The angiogenic proteins, human VEGF and human angiopoietin 1, were coencapsulated in albumin nanoparticles for better controlled delivery of the proteins. The application of a nanoparticle system enabled efficient and extended-release kinetics of the proteins. The size of the nanoparticles crosslinked with glutaraldehyde was 101.0 +/- 0.9 nm and the zeta potential was found to be -18 +/- 2.9 mV. An optimal concentration of glutaraldehyde for the nanoparticle coating process was determined, and this provided stable and less toxic nanoparticles as protein carriers. The results of the study indicate that nanoparticles crosslinked with glutaraldehyde produced nanoparticles with tolerable toxicity which provided efficient and controlled release of the coencapsulated proteins. The nanoparticles were incubated for two weeks to determine the release profiles of the proteins. At the end of the two-week incubation period, it was observed that 49% +/- 1.3% of human angiopoietin-1 and 59% +/- 2.1% of human VEGF had been released from the nanoparticles. The proliferation and percent apoptosis of the HUVECs in response to released proteins was observed. CONCLUSION: The results indicate that the released proteins were biologically active and the combined application of both the proteins demonstrated a significant highly proliferative and antiapoptotic effect on HUVECs as compared with the effect demonstrated by the individual proteins released. These studies could serve as a basis to encourage further research into the potential in vivo application of these protein-loaded nanoparticles in the field of therapeutic angiogenesis. PMID- 21698075 TI - Improvement of adenoviral vector-mediated gene transfer to airway epithelia by folate-modified anionic liposomes. AB - Despite remarkable progress in the development of both viral and nonviral gene delivery vectors for airway disease treatment, poor gene transfer efficiency to the airway epithelium is a major obstacle in clinical application. To take advantage of the unique features of viral and nonviral vectors, we have developed complexes of adenovirus vector and anionic liposomes (AL-Ad5) by the calcium induced phase change method. In the current study, based on the fact that there are overexpressed folate receptors on the surface of airway epithelia, we further modified the AL-Ad5 complexes with folate (F-AL-Ad5) to improve the transduction ability of Ad5 in airway epithelia. The transduction efficiencies of the obtained F-AL-Ad5 and AL-Ad5 complexes were assessed in primary-cultured airway epithelia in vitro. Our results indicated that compared with naked adenovirus vector, both AL-Ad5 and F-AL-Ad5 could significantly enhance the gene transduction efficiency of adenovirus vector in primary-cultured airway epithelial cells. Moreover, the enhancement mediated by F-AL-Ad5 was more dramatic than that by AL-Ad5. These results suggested that F-AL-Ad5 may be a useful strategy to deliver therapeutic genes to the airway epithelia and is promising in clinical application. PMID- 21698076 TI - Spray deposition of live cells throughout the electrospinning process produces nanofibrous three-dimensional tissue scaffolds. AB - Compared with traditional in-vitro cell culture materials, three-dimensional nanofibrous scaffolds provide a superior environment for promoting cell functions. Since nanofibrous scaffolds have nanometer pore sizes, cells are unable to penetrate on their own, so must be incorporated into the scaffold during fabrication to ensure proper cell distribution. In this study, biodegradable and cytocompatible poly(DL-lactide-co-glycolide) (PLGA) nanofibers were produced using an electrospinning process. As a model cell line, fibroblasts were periodically sprayed from a pump-action spray bottle onto the developing scaffold. The viability of cells before and after spraying, and also after incorporation into the scaffold, was compared. Results indicated that cell spraying and the scaffold fabrication process did not significantly reduce cell viability. These findings, thus, contribute to the understanding of how to produce more physiological relevant cell-seeded nanofibrous scaffolds, an important element for the future of nanotechnology and tissue engineering. PMID- 21698077 TI - Optimizing supercritical antisolvent process parameters to minimize the particle size of paracetamol nanoencapsulated in L-polylactide. AB - BACKGROUND: The aim of this study was to optimize the different process parameters including pressure, temperature, and polymer concentration, to produce fine small spherical particles with a narrow particle size distribution using a supercritical antisolvent method for drug encapsulation. The interaction between different process parameters was also investigated. METHODS AND RESULTS: The optimized process parameters resulted in production of nanoencapsulated paracetamol in L-polylactide with a mean diameter of approximately 300 nm at 120 bar, 30 degrees C, and a polymer concentration of 16 ppm. Thermogravimetric analysis illustrated the thermal characteristics of the nanoparticles. The high electrical charge on the surface of the nanoparticles caused the particles to repel each other, with the high negative zeta potential preventing flocculation. CONCLUSION: Our results illustrate the effect of different process parameters on particle size and morphology, and validate results obtained via RSM statistical software. Furthermore, the in vitro drug-release profile is consistent with a Korsmeyer-Peppas kinetic model. PMID- 21698079 TI - Study of pharmacokinetics and tissue distribution of liposomal brucine for dermal administration. AB - OBJECTIVE: To evaluate the pharmacokinetics and tissue distribution of liposomal brucine (LB) for dermal application. METHODS: Pharmacokinetics and tissue distribution were studied by in vivo animal testing. High performance liquid chromatography (HPLC) was used to detect the concentration of brucine in rats' skin, plasma and various tissues. RESULTS: After dermal administration, LB was absorbed rapidly in the skin and could be detected after 0.5 hours. After 36 hours, levels were too low to be detected. In plasma, levels were also too low to be detected after 36 hours. The concentration of LB reached 50% of the maximum in all tissues except the brain, peaking after 1.5 hours but still detectable after 12 hours. CONCLUSION: The concentration of LB was high in skin at the application site. LB was quickly absorbed into tissues through the blood circulation and widely distributed throughout the whole body. There was no obvious toxicity and LB did not readily accumulate in tissues and organs. It showed local potency but low overall systemic toxicity. PMID- 21698080 TI - Nanotoxicology and nanoparticle safety in biomedical designs. AB - Nanotechnology has wide applications in many fields, especially in the biological sciences and medicine. Nanomaterials are applied as coating materials or in treatment and diagnosis. Nanoparticles such as titania, zirconia, silver, diamonds, iron oxides, carbon nanotubes, and biodegradable polymers have been studied in diagnosis and treatment. Many of these nanoparticles may have toxic effects on cells. Many factors such as size, inherent properties, and surface chemistry may cause nanoparticle toxicity. There are methods for improving the performance and reducing toxicity of nanoparticles in medical design, such as biocompatible coating materials or biodegradable/biocompatible nanoparticles. Most metal oxide nanoparticles show toxic effects, but no toxic effects have been observed with biocompatible coatings. Biodegradable nanoparticles are also used in the efficient design of medical materials, which will be reviewed in this article. PMID- 21698081 TI - Zinc oxide nanoparticles as selective killers of proliferating cells. AB - BACKGROUND: It has recently been demonstrated that zinc oxide nanoparticles (ZnO NPs) induce death of cancerous cells whilst having no cytotoxic effect on normal cells. However, there are several issues which need to be resolved before translation of zinc oxide nanoparticles into medical use, including lack of suitable biocompatible dispersion protocols and a better understanding being needed of the mechanism of their selective cytotoxic action. METHODS: Nanoparticle dose affecting cell viability was evaluated in a model of proliferating cells both experimentally and mathematically. The key issue of selective toxicity of ZnO NPs toward proliferating cells was addressed by experiments using a biological model of noncancerous cells, ie, mesenchymal stem cells before and after cell differentiation to the osteogenic lineage. RESULTS: In this paper, we report a biocompatible protocol for preparation of stable aqueous solutions of monodispersed zinc oxide nanoparticles. We found that the threshold of intracellular ZnO NP concentration required to induce cell death in proliferating cells is 0.4 +/- 0.02 mM. Finally, flow cytometry analysis revealed that the threshold dose of zinc oxide nanoparticles was lethal to proliferating pluripotent mesenchymal stem cells but exhibited negligible cytotoxic effects to osteogenically differentiated mesenchymal stem cells. CONCLUSION: Results confirm the ZnO NP selective cytotoxic action on rapidly proliferating cells, whether benign or malignant. PMID- 21698083 TI - Laser-fabricated castor oil-capped silver nanoparticles. AB - Silver nanoparticles were fabricated by ablation of a pure silver plate immersed in castor oil. A Nd:YAG-pulsed Q-switch laser with 1064-nm wavelength and 10-Hz frequency was used to ablate the plate for 10 minutes. The sample was characterized by ultraviolet-visible, atomic absorption, Fourier transform infrared spectroscopies, and transmission electron microscopy. The results of the fabricated sample showed that the nanoparticles in castor oil were about 5-nm in diameter, well dispersed, and showed stability for a long period of time. PMID- 21698084 TI - The relationship between cellular adhesion and surface roughness in polystyrene modified by microwave plasma radiation. AB - BACKGROUND: Surface modification of medical polymers can improve biocompatibility. Pure polystyrene is hydrophobic and cannot provide a suitable environment for cell cultures. The conventional method for surface modification of polystyrene is treatment with plasma. In this study, conventional polystyrene was exposed to microwave plasma treatment with oxygen and argon gases for 30, 60, and 180 seconds. METHODS AND RESULTS: Attenuated total reflection Fourier transform infrared spectra investigations of irradiated samples indicated clearly the presence of functional groups. Atomic force microscopic images of samples irradiated with inert and active gases indicated nanometric surface topography. Samples irradiated with oxygen plasma showed more roughness (31 nm) compared with those irradiated with inert plasma (16 nm) at 180 seconds. Surface roughness increased with increasing duration of exposure, which could be due to reduction of the contact angle of samples irradiated with oxygen plasma. Contact angle analysis showed reduction in samples irradiated with inert plasma. Samples irradiated with oxygen plasma showed a lower contact angle compared with those irradiated by argon plasma. CONCLUSION: Cellular investigations with unrestricted somatic stem cells showed better adhesion, cell growth, and proliferation for samples radiated by oxygen plasma with increasing duration of exposure than those of normal samples. PMID- 21698085 TI - Progressive fluid removal can avoid electrolyte disorders in severely burned patients. AB - INTRODUCTION: Extensive burn injury has systemic consequences due to capillary leak. After restoration of cellular integrity, infused fluid volume has to be removed partially. This can provoke electrolyte disorders. PURPOSE: We investigated the effect of progressive fluid removal on serum sodium level. METHOD: Retrospective study. Patients admitted to a burn unit were analyzed and separated in two groups without (Group A) or with (Group B) prolonged hypernatremia. Daily infusion-diuresis-ratio (IDR) was analyzed. RESULTS: Fourty (12 female; 28 male) patients with a mean age of 47+/-19 years, a total burn surface area (TBSA) of 26+/-12%, and a mean abbreviated burned severity index (ABSI) score of 7.3+/-2 were included. In Group A 25 patients with a mean age of 47+/-18 years, a mean TBSA of 23+/-11%, and a mean ABSI score of 6.9+/-2.1 were summarized. In Group B 15 patients with a mean age of 47+/-22 years, a mean TBSA of 30+/-13%, and a mean ABSI score of 8.1+/-1.7 were included. Hypernatremia occurred on day 5+/-1.4. There was no significant difference between both groups for fluid resuscitation amount within the first 24 hours. Statistical analysis of the first 7 days after burn injury showed a significantly higher percentage of removed fluid in Group B for day 3, day 4, day 5, day 6 and day 7. CONCLUSIONS: Amount and velocity of fluid removal regimen after burn injury can provoke electrolyte disorders. Serum sodium concentration can be used to calculate need of fluid resuscitation for fluid maintenance. There is a need of an established fluid removal strategy. PMID- 21698086 TI - Ascaris lumbricoides causing infarction of the mesenteric lymph nodes and intestinal gangrene in a child: a case report. AB - Ascaris lumbricoides or round worm infestation is quite common in the developing world. It affects all age groups but is more common in children. Most of the cases remain asymptomatic. The usual presentation is an intestinal obstruction. The physicians should be aware of this condition and consider it in the differential diagnosis when faced with such a case. The rare fatal complications include bleeding, perforation and gangrene. PMID- 21698087 TI - Isolated central nervous system relapse of systemic lymphoma (SCNSL): clinical features and outcome of a retrospective analysis. AB - We analyzed clinical outcome of patients with an isolated central nervous system lymphoma (CNSL) relapse after systemic non-Hodgkin's lymphoma (NHL). All 23 patients with an isolated secondary CNSL (SCNSL) treated at two institutions from 04/2003-12/2007 were included into this analysis. At cerebral relapse, 15/23 patients were treated with a regimen consisting of high-dose methotrexate (Bonn protocol). After a median follow-up of 6.5 months (range 1-68), 15/23 (65%) patients with SCNSL had relapsed or progressed. HD (high-dose)- methotrexate (MTX) chemotherapy according to the Bonn protocol is effective concerning response rates; however, overall survival of patients with SCNSL seems to be impaired in comparison to relapses in primary CNSL (PCNSL). PMID- 21698089 TI - The influence of neuroticism and psychological symptoms on the assessment of images in three-dimensional emotion space. AB - OBJECTIVE: The present study investigated the influence of neuroticism (NEO Five Factor Inventory (NEO-FFI)) and psychological symptoms (Brief Symptom Inventory (BSI)) on pleasure, arousal, and dominance (PAD) ratings of the International Affective Picture System (IAPS). METHODS: The subjects (N=131) were presented with images from the IAPS (30 images) and new images (30 images). The influence of neuroticism and BSI (median split: high vs. low) on the assessment of pleasure, arousal and dominance of the images was examined. Correlations of pleasure, arousal and dominance were presented in a 3-D video animation. RESULTS: Subjects with high scores (compared to subjects with low scores by median split) of neuroticism and psychological symptoms of the BSI rated the presented emotional images more negative in the valence dimension (pleasure), higher in arousal and less dominant. CONCLUSION: Neuroticism and psychological symptoms influence the subjective emotional evaluation of emotional images. Therefore the location in the three-dimensional emotion space depends on individual differences. Such differences must be kept in mind, if correlations between emotion ratings and other variables like psychobiological measures are analyzed. PMID- 21698088 TI - Fluid resuscitation protocols for burn patients at intensive care units of the United Kingdom and Ireland. AB - INTRODUCTION: The objective of this study was to determine the thermal injury fluid resuscitation protocols at intensive care units (ICUs) in the United Kingdom and Ireland. MATERIALS AND METHODS: A telephone questionnaire was designed to survey the fluid resuscitation protocols of ICUs at all hospitals with plastic/burn surgery departments in the British Isles in 2010. The feedback from the questionnaire was from the senior nurse in charge of the ICUs. RESULTS: 32/64 (50%) of these ICUs had provided care to burns patients. A 100% response from these 32 units was obtained. 71.4% commence fluid resuscitation at 15% total body surface area burn (TBSA), 21.4% at 20% TBSA and 7.1% at 10% TBSA in adults. The estimated resuscitation volume was most often calculated using the Parkland/Modified Parkland formula (87.5%) or the Muir and Barclay formula (12.5%). Interestingly, of the ICUs using formulae, two had recently moved from using the Muir and Barclay formula to Parkland formula and one had recently moved from using the Parkland formula to Muir and Barclay formula. Despite this, 37.5% of ICUs using a formula did not rigidly follow it exactly. The most commonly used resuscitation fluid was Ringer's lactate solution (46.9%) and Human Albumin Solution was used in 12.5%. No ICU used red cell concentrate as a first line fluid. 18.8% used a central line. 40.6% ICUs considered changing the IV solution during resuscitation. 78.1% ICUs consider urine output to be the most important factor in modifying resuscitation volumes. 59.4% ICUs calculate a maintenance fluid rate after completion of resuscitation. The endpoint for resuscitation was at 24 h in 46.9% ICUs and at 36 h in 9.4%. 5/32 (16%) felt their protocol gave too little and 6/32 (19%) felt their protocol gave too much. 59.3% ICUs gave oral/enteral fluids by naso-gastric or naso-jejenal tubes. 21.9% felt that oral/enteral resuscitation worked. Exactly half of the units believed that the formula that they used provided approximately the right amount of fluid, with 25% believing that it provided too much and 21.9% that it provided too little. DISCUSSION AND CONCLUSION: There is substantial variation in the fluid resuscitation protocols for burns of ICUs in the British Isles. The different practices demonstrated in this survey may have important consequences as inadequate fluid resuscitation can limit perfusion to potentially recoverable burns, grafted tissue and body organs not directly injured. PMID- 21698090 TI - A monte carlo method for assessing the quality of duplication-aware alignment algorithms. AB - The increasing availability of high throughput sequencing technologies poses several challenges concerning the analysis of genomic data. Within this context, duplication-aware sequence alignment taking into account complex mutation events is regarded as an important problem, particularly in light of recent evolutionary bioinformatics researches that highlighted the role of tandem duplications as one of the most important mutation events. Traditional sequence comparison algorithms do not take into account these events, resulting in poor alignments in terms of biological significance, mainly because of their assumption of statistical independence among contiguous residues. Several duplication-aware algorithms have been proposed in the last years which differ either for the type of duplications they consider or for the methods adopted to identify and compare them. However, there is no solution which clearly outperforms the others and no methods exist for assessing the reliability of the resulting alignments. This paper proposes a Monte Carlo method for assessing the quality of duplication-aware alignment algorithms and for driving the choice of the most appropriate alignment technique to be used in a specific context.The applicability and usefulness of the proposed approach are demonstrated on a case study, namely, the comparison of alignments based on edit distance with or without repeat masking. PMID- 21698091 TI - Structurama: bayesian inference of population structure. AB - Structurama is a program for inferring population structure. Specifically, the program calculates the posterior probability of assigning individuals to different populations. The program takes as input a file containing the allelic information at some number of loci sampled from a collection of individuals. After reading a data file into computer memory, Structurama uses a Gibbs algorithm to sample assignments of individuals to populations. The program implements four different models: The number of populations can be considered fixed or a random variable with a Dirichlet process prior; moreover, the genotypes of the individuals in the analysis can be considered to come from a single population (no admixture) or as coming from several different populations (admixture). The output is a file of partitions of individuals to populations that were sampled by the Markov chain Monte Carlo algorithm. The partitions are sampled in proportion to their posterior probabilities. The program implements a number of ways to summarize the sampled partitions, including calculation of the 'mean' partition-a partition of the individuals to populations that minimizes the squared distance to the sampled partitions. PMID- 21698092 TI - Functional organization of locomotor interneurons in the ventral lumbar spinal cord of the newborn rat. AB - Although the mammalian locomotor CPG has been localized to the lumbar spinal cord, the functional-anatomical organization of flexor and extensor interneurons has not been characterized. Here, we tested the hypothesis that flexor and extensor interneuronal networks for walking are physically segregated in the lumbar spinal cord. For this purpose, we performed optical recordings and lesion experiments from a horizontally sectioned lumbar spinal cord isolated from neonate rats. This ventral hemi spinal cord preparation produces well-organized fictive locomotion when superfused with 5-HT/NMDA. The dorsal surface of the preparation was visualized using the Ca(2+) indicator fluo-4 AM, while simultaneously monitoring motor output at ventral roots L2 and L5. Using calcium imaging, we provided a general mapping view of the interneurons that maintained a stable phase relationship with motor output. We showed that the dorsal surface of L1 segment contains a higher density of locomotor rhythmic cells than the other segments. Moreover, L1 segment lesioning induced the most important changes in the locomotor activity in comparison with lesions at the T13 or L2 segments. However, no lesions led to selective disruption of either flexor or extensor output. In addition, this study found no evidence of functional parcellation of locomotor interneurons into flexor and extensor pools at the dorsal-ventral midline of the lumbar spinal cord of the rat. PMID- 21698093 TI - Primary hyperparathyroidism influences the expression of inflammatory and metabolic genes in adipose tissue. AB - BACKGROUND: Primary hyperparathyroidism (PHPT) is characterised by increased production of parathyroid hormone (PTH) resulting in elevated serum calcium levels. The influence on bone metabolism with altered bone resorption is the most studied clinical condition in PHPT. In addition to this, patients with PHPT are at increased risk of non-skeletal diseases, such as impaired insulin sensitivity, arterial hypertension and increased risk of death by cardiovascular diseases (CVD), possibly mediated by a chronic low-grade inflammation. The aim of this study was to investigate whether adipose tissue reflects the low-grade inflammation observed in PHPT patients. METHODOLOGY/PRINCIPAL FINDINGS: Subcutaneous fat tissue from the neck was sampled from 16 non-obese patients with PHPT and from 16 patients operated for benign thyroid diseases, serving as weight matched controls. RNA was extracted and global gene expression was analysed with Illumina BeadArray Technology. We found 608 differentially expressed genes (q value<0.05), of which 347 were up-regulated and 261 were down-regulated. Gene ontology analysis showed that PHPT patients expressed increased levels of genes involved in immunity and defense (e.g. matrix metallopeptidase 9, S100 calcium binding protein A8 and A9, CD14, folate receptor 2), and reduced levels of genes involved in metabolic processes. Analysis of transcription factor binding sites present in the differentially expressed genes corroborated the up-regulation of inflammatory processes. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that PHPT strongly influences gene regulation in fat tissue, which may result in altered adipose tissue function and release of pathogenic factors that increase the risk of CVD. PMID- 21698094 TI - Information generated by the moving pinnae of Rhinolophus rouxi: tuning of the morphology at different harmonics. AB - Bats typically emit multi harmonic calls. Their head morphology shapes the emission and hearing sound fields as a function of frequency. Therefore, the sound fields are markedly different for the various harmonics. As the sound field provides bats with all necessary cues to locate objects in space, different harmonics might provide them with variable amounts of information about the location of objects. Also, the ability to locate objects in different parts of the frontal hemisphere might vary across harmonics. This paper evaluates this hypothesis in R. rouxi, using an information theoretic framework. We estimate the reflector position information transfer in the echolocation system of R. rouxi as a function of frequency. This analysis shows that localization performance reaches a global minimum and a global maximum at the two most energetic frequency components of R. rouxi call indicating tuning of morphology and harmonic structure. Using the fundamental the bat is able to locate objects in a large portion of the frontal hemisphere. In contrast, using the 1st overtone, it can only locate objects, albeit with a slightly higher accuracy, in a small portion of the frontal hemisphere by reducing sensitivity to echoes from outside this region of interest. Hence, different harmonic components provide the bat either with a wide view or a focused view of its environment. We propose these findings can be interpreted in the context of the foraging behaviour of R. rouxi, i.e., hunting in cluttered environments. Indeed, the focused view provided by the 1st overtone suggests that at this frequency its morphology is tuned for clutter rejection and accurate localization in a small region of interest while the finding that overall localization performance is best at the fundamental indicates that the morphology is simultaneously tuned to optimize overall localization performance at this frequency. PMID- 21698095 TI - Mimicking the neurotrophic factor profile of embryonic spinal cord controls the differentiation potential of spinal progenitors into neuronal cells. AB - Recent studies have indicated that the choice of lineage of neural progenitor cells is determined, at least in part, by environmental factors, such as neurotrophic factors. Despite extensive studies using exogenous neurotrophic factors, the effect of endogenous neurotrophic factors on the differentiation of progenitor cells remains obscure. Here we show that embryonic spinal cord derived progenitor cells express both ciliary neurotrophic factor (CNTF) and brain derived neurotrophic factor (BDNF) mRNA before differentiation. BDNF gene expression significantly decreases with their differentiation into the specific lineage, whereas CNTF gene expression significantly increases. The temporal pattern of neurotrophic factor gene expression in progenitor cells is similar to that of the spinal cord during postnatal development. Approximately 50% of spinal progenitor cells differentiated into astrocytes. To determine the effect of endogenous CNTF on their differentiation, we neutralized endogenous CNTF by administration of its polyclonal antibody. Neutralization of endogenous CNTF inhibited the differentiation of progenitor cells into astrocytes, but did not affect the numbers of neurons or oligodendrocytes. Furthermore, to mimic the profile of neurotrophic factors in the spinal cord during embryonic development, we applied BDNF or neurotrophin (NT)-3 exogenously in combination with the anti CNTF antibody. The exogenous application of BDNF or NT-3 promoted the differentiation of these cells into neurons or oligodendrocytes, respectively. These findings suggest that endogenous CNTF and exogenous BDNF and NT-3 play roles in the differentiation of embryonic spinal cord derived progenitor cells into astrocytes, neurons and oligodendrocytes, respectively. PMID- 21698096 TI - Comparison of life history characteristics of the genetically modified OX513A line and a wild type strain of Aedes aegypti. AB - The idea of implementing genetics-based insect control strategies modelled on the traditional SIT (Sterile Insect Technique), such as RIDL (Release of Insects carrying a Dominant Lethal), is becoming increasingly popular. In this paper, we compare a genetically modified line of Aedes aegypti carrying a tetracycline repressible, lethal positive feedback system (OX513A) with a genetically similar, unmodified counterpart and their respective responses to increasing larval rearing density using a constant amount of food per larva. The parameters that we examined were larval mortality, developmental rate (i.e., time to pupation), adult size and longevity. Analysis revealed some statistically significant differences between the life history traits we examined. The genetically modified OX513A line overall showed 5% lower larval survival as well as reduced adult longevity (20 vs 24 days mean lifespan) compared to the unmodified line. Furthermore, the OX513A line pupated about one day sooner, which could be advantageous in mass-rearing, but produced somewhat smaller adults than the unmodified line; this effect was more pronounced in females than in males. Increasing the larval rearing density delayed pupation, decreased adult longevity and reduced adult size in both lines. While the delay in pupation and the decrease in longevity were similar between the two lines, the decrease in adult size was more pronounced for OX513A males.Our study shows that in a controlled laboratory situation the transgenic sterile OX513A line may have somewhat reduced performance compared to its unmodified counterpart and that high rearing densities may further reduce performance. Laboratory-based cage trials as well as field trials are necessary to assess how the differences in life history traits documented here impact the males' success upon release. Furthermore, this paper highlights the potential value of optimisation of mass-rearing systems as optimised rearing methods may be able to alleviate performance issues associated with specific lines or with lab-adapted lines in general. PMID- 21698097 TI - A multi-label classifier for predicting the subcellular localization of gram negative bacterial proteins with both single and multiple sites. AB - Prediction of protein subcellular localization is a challenging problem, particularly when the system concerned contains both singleplex and multiplex proteins. In this paper, by introducing the "multi-label scale" and hybridizing the information of gene ontology with the sequential evolution information, a novel predictor called iLoc-Gneg is developed for predicting the subcellular localization of gram-positive bacterial proteins with both single-location and multiple-location sites. For facilitating comparison, the same stringent benchmark dataset used to estimate the accuracy of Gneg-mPLoc was adopted to demonstrate the power of iLoc-Gneg. The dataset contains 1,392 gram-negative bacterial proteins classified into the following eight locations: (1) cytoplasm, (2) extracellular, (3) fimbrium, (4) flagellum, (5) inner membrane, (6) nucleoid, (7) outer membrane, and (8) periplasm. Of the 1,392 proteins, 1,328 are each with only one subcellular location and the other 64 are each with two subcellular locations, but none of the proteins included has pairwise sequence identity to any other in a same subset (subcellular location). It was observed that the overall success rate by jackknife test on such a stringent benchmark dataset by iLoc-Gneg was over 91%, which is about 6% higher than that by Gneg-mPLoc. As a user-friendly web-server, iLoc-Gneg is freely accessible to the public at http://icpr.jci.edu.cn/bioinfo/iLoc-Gneg. Meanwhile, a step-by-step guide is provided on how to use the web-server to get the desired results. Furthermore, for the user's convenience, the iLoc-Gneg web-server also has the function to accept the batch job submission, which is not available in the existing version of Gneg-mPLoc web-server. It is anticipated that iLoc-Gneg may become a useful high throughput tool for Molecular Cell Biology, Proteomics, System Biology, and Drug Development. PMID- 21698099 TI - Impact of cellular miRNAs on circulating miRNA biomarker signatures. AB - Effective diagnosis and surveillance of complex multi-factorial disorders such as cancer can be improved by screening of easily accessible biomarkers. Highly stable cell free Circulating Nucleic Acids (CNA) present as both RNA and DNA species have been discovered in the blood and plasma of humans. Correlations between tumor-associated genomic/epigenetic/transcriptional changes and alterations in CNA levels are strong predictors of the utility of this biomarker class as promising clinical indicators. Towards this goal microRNAs (miRNAs) representing a class of naturally occurring small non-coding RNAs of 19-25 nt in length have emerged as an important set of markers that can associate their specific expression profiles with cancer development. In this study we investigate some of the pre-analytic considerations for isolating plasma fractions for the study of miRNA biomarkers. We find that measurement of circulating miRNA levels are frequently confounded by varying levels of cellular miRNAs of different hematopoietic origins. In order to assess the relative proportions of this cell-derived class, we have fractionated whole blood into plasma and its ensuing sub-fractions. Cellular miRNA signatures in cohorts of normal individuals are catalogued and the abundance and gender specific expression of bona fide circulating markers explored after calibrating the signal for this interfering class. A map of differentially expressed profiles is presented and the intrinsic variability of circulating miRNA species investigated in subsets of healthy males and females. PMID- 21698098 TI - Variation in human recombination rates and its genetic determinants. AB - BACKGROUND: Despite the fundamental role of crossing-over in the pairing and segregation of chromosomes during human meiosis, the rates and placements of events vary markedly among individuals. Characterizing this variation and identifying its determinants are essential steps in our understanding of the human recombination process and its evolution. STUDY DESIGN/RESULTS: Using three large sets of European-American pedigrees, we examined variation in five recombination phenotypes that capture distinct aspects of crossing-over patterns. We found that the mean recombination rate in males and females and the historical hotspot usage are significantly heritable and are uncorrelated with one another. We then conducted a genome-wide association study in order to identify loci that influence them. We replicated associations of RNF212 with the mean rate in males and in females as well as the association of Inversion 17q21.31 with the female mean rate. We also replicated the association of PRDM9 with historical hotspot usage, finding that it explains most of the genetic variance in this phenotype. In addition, we identified a set of new candidate regions for further validation. SIGNIFICANCE: These findings suggest that variation at broad and fine scales is largely separable and that, beyond three known loci, there is no evidence for common variation with large effects on recombination phenotypes. PMID- 21698100 TI - A randomized placebo-controlled trial of acetaminophen for prevention of post vaccination fever in infants. AB - BACKGROUND: Fever is common following infant vaccinations. Two randomized controlled trials demonstrated the efficacy of acetaminophen prophylaxis in preventing fever after whole cell pertussis vaccination, but acetaminophen prophylaxis has not been evaluated for prevention of fever following contemporary vaccines recommended for infants in the United States. METHODS: Children six weeks through nine months of age were randomized 1:1 to receive up to five doses of acetaminophen (10-15 mg per kg) or placebo following routine vaccinations. The primary outcome was a rectal temperature >=38 degrees C within 32 hours following the vaccinations. Secondary outcomes included medical utilization, infant fussiness, and parents' time lost from work. Parents could request unblinding of the treatment assignment if the child developed fever or symptoms that would warrant supplementary acetaminophen treatment for children who had been receiving placebo. RESULTS: A temperature >=38 degrees C was recorded for 14% (25/176) of children randomized to acetaminophen compared with 22% (37/176) of those randomized to placebo but that difference was not statistically significant (relative risk [RR], 0.63; 95% CI, 0.40-1.01). Children randomized to acetaminophen were less likely to be reported as being much more fussy than usual (10% vs 24%) (RR, 0.42; 95% CI, 0.25-0.70) or to have the treatment assignment unblinded (3% vs 9%) (RR, 0.31; 95% CI, 0.11-0.83) than those randomized to placebo. In age-stratified analyses, among children >=24 weeks of age, there was a significantly lower risk of temperature >=38 degrees C in the acetaminophen group (13% vs. 25%; p = 0.03). CONCLUSION: The results of this relatively small trial suggest that acetaminophen may reduce the risk of post-vaccination fever and fussiness. TRIAL REGISTRATION: Clinicaltrials.gov NCT00325819. PMID- 21698101 TI - Design, synthesis and characterization of a highly effective inhibitor for analog sensitive (as) kinases. AB - Highly selective, cell-permeable and fast-acting inhibitors of individual kinases are sought-after as tools for studying the cellular function of kinases in real time. A combination of small molecule synthesis and protein mutagenesis, identified a highly potent inhibitor (1-Isopropyl-3-(phenylethynyl)-1H pyrazolo[3,4-d]pyrimidin-4-amine) of a rationally engineered Hog1 serine/threonine kinase (Hog1(T100G)). This inhibitor has been successfully used to study various aspects of Hog1 signaling, including a transient cell cycle arrest and gene expression changes mediated by Hog1 in response to stress. This study also underscores that the general applicability of this approach depends, in part, on the selectivity of the designed the inhibitor with respect to activity versus the engineered and wild type kinases. To explore this specificity in detail, we used a validated chemogenetic assay to assess the effect of this inhibitor on all gene products in yeast in parallel. The results from this screen emphasize the need for caution and for case-by-case assessment when using the Analog-Sensitive Kinase Allele technology to assess the physiological roles of kinases. PMID- 21698102 TI - Mutational patterns in RNA secondary structure evolution examined in three RNA families. AB - The goal of this work was to study mutational patterns in the evolution of RNA secondary structure. We analyzed bacterial tmRNA, RNaseP and eukaryotic telomerase RNA secondary structures, mapping structural variability onto phylogenetic trees constructed primarily from rRNA sequences. We found that secondary structures evolve both by whole stem insertion/deletion, and by mutations that create or disrupt stem base pairing. We analyzed the evolution of stem lengths and constructed substitution matrices describing the changes responsible for the variation in the RNA stem length. In addition, we used principal component analysis of the stem length data to determine the most variable stems in different families of RNA. This data provides new insights into the evolution of RNA secondary structures and patterns of variation in the lengths of double helical regions of RNA molecules. Our findings will facilitate design of improved mutational models for RNA structure evolution. PMID- 21698103 TI - A controlled trial of the knowledge impact of tuberculosis information leaflets among staff supporting substance misusers: pilot study. AB - BACKGROUND: Information leaflets are widely used to increase awareness and knowledge of disease. Limited research has, to date, been undertaken to evaluate the efficacy of these information resources. This pilot study sought to determine whether information leaflets developed specifically for staff working with substance mis-users improved knowledge of tuberculosis (TB). METHOD: Staffs working with individuals affected by substance mis-use were recruited between January and May 2008. All participants were subjectively allocated by their line manager either to receive the TB-specific leaflet or a control leaflet providing information on mental health. Level of knowledge of TB was assessed using questionnaires before and after the intervention and data analysed using McNemar's exact test for matched pairs. RESULTS: The control group showed no evidence of a change in knowledge of TB, whereas the TB questionnaire group demonstrated a significant increase in knowledge including TB being curable (81% correct before to 100% correct after), length of treatment required (42% before to 73% after), need to support direct observation (18% to 62%) and persistent fever being a symptom (56% to 87%). Among key workers, who have a central role in implementing a care plan, 88% reported never receiving any TB awareness-raising intervention prior to this study, despite 11% of all respondents having TB diagnosed among their clients. CONCLUSION: Further randomized controlled trials are required to confirm the observed increase in short-term gain in knowledge and to investigate whether knowledge gain leads to change in health status. PMID- 21698104 TI - Identification of replication competent murine gammaretroviruses in commonly used prostate cancer cell lines. AB - A newly discovered gammaretrovirus, termed XMRV, was recently reported to be present in the prostate cancer cell line CWR22Rv1. Using a combination of both immunohistochemistry with broadly-reactive murine leukemia virus (MLV) anti-sera and PCR, we determined if additional prostate cancer or other cell lines contain XMRV or MLV-related viruses. Our study included a total of 72 cell lines, which included 58 of the 60 human cancer cell lines used in anticancer drug screens and maintained at the NCI-Frederick (NCI-60). We have identified gammaretroviruses in two additional prostate cancer cell lines: LAPC4 and VCaP, and show that these viruses are replication competent. Viral genome sequencing identified the virus in LAPC4 and VCaP as nearly identical to another known xenotropic MLV, Bxv-1. We also identified a gammaretrovirus in the non-small-cell lung carcinoma cell line EKVX. Prostate cancer cell lines appear to have a propensity for infection with murine gammaretroviruses, and we propose that this may be in part due to cell line establishment by xenograft passage in immunocompromised mice. It is unclear if infection with these viruses is necessary for cell line establishment, or what confounding role they may play in experiments performed with these commonly used lines. Importantly, our results suggest a need for regular screening of cancer cell lines for retroviral "contamination", much like routine mycoplasma testing. PMID- 21698105 TI - The oldest anatomically modern humans from far southeast Europe: direct dating, culture and behavior. AB - BACKGROUND: Anatomically Modern Humans (AMHs) are known to have spread across Europe during the period coinciding with the Middle to Upper Paleolithic transition. Whereas their dispersal into Western Europe is relatively well established, evidence of an early settlement of Eastern Europe by modern humans are comparatively scarce. METHODOLOGY/PRINCIPAL FINDING: Based on a multidisciplinary approach for the study of human and faunal remains, we describe here the oldest AMH remains from the extreme southeast Europe, in conjunction with their associated cultural and paleoecological background. We applied taxonomy, paleoecology, and taphonomy combined with geomorphology, stratigraphy, archeology and radiocarbon dating. More than 160 human bone remains have been discovered. They originate from a well documented Upper Paleolithic archeological layer (Gravettian cultural tradition) from the site of Buran-Kaya III located in Crimea (Ukraine). The combination of non-metric dental traits and the morphology of the occipital bones allow us to attribute the human remains to Anatomically Modern Humans. A set of human and faunal remains from this layer has been radiocarbon dated by Accelerator Mass Spectrometry. The direct-dating results of human bone establish a secure presence of AMHs at 31,900+240/-220 BP in this region. They are the oldest direct evidence of the presence of AMHs in a well documented archeological context. Based on taphonomical observations (cut marks and distribution of skeletal elements), they represent the oldest Upper Paleolithic modern humans from Eastern Europe, showing post-mortem treatment of the dead as well. CONCLUSION/SIGNIFICANCE: These findings are essential for the debate on the spread of modern humans in Europe during the Upper Paleolithic, as well as their cultural behaviors. PMID- 21698106 TI - Efficacy study of novel diamidine compounds in a Trypanosoma evansi goat model. AB - Three diamidines (DB 75, DB 867 and DB 1192) were selected and their ability to cure T. evansi experimentally infected goats was investigated. A toxicity assessment and pharmacokinetic analysis of these compounds were additionally carried out. Goats demonstrated no signs of acute toxicity, when treated with four doses of 1 mg/kg/day (total dose 4 mg/kg). Complete curative efficacy of experimentally infected goats was seen in the positive control group treated with diminazene at 5 mg/kg and in the DB 75 and DB 867 groups treated at 2.5 mg/kg. Drug treatment was administered once every second day for a total of seven days. Complete cure was also seen in the group of goats treated with DB 75 at 1.25 mg/kg. DB 1192 was incapable of curing goats at either four-times 2.5 mg/kg or 1.25 mg/kg. Pharmacokinetic analysis clearly demonstrated that the treatment failures of DB 1192 were due to sub-therapeutic compound levels in goat plasma, whilst compound levels for DB 75 and DB 867 remained well within the therapeutic window. In conclusion, two diamidine compounds (DB 75 and DB 867) presented comparable efficacy at lower doses than the standard drug diminazene and could be considered as potential clinical candidates against T. evansi infection. PMID- 21698107 TI - Proteomic analysis of the secretory response of Aspergillus niger to D-maltose and D-xylose. AB - Fungi utilize polysaccharide substrates through extracellular digestion catalyzed by secreted enzymes. Thus far, protein secretion by the filamentous fungus Aspergillus niger has mainly been studied at the level of individual proteins and by genome and transcriptome analyses. To extend these studies, a complementary proteomics approach was applied with the aim to investigate the changes in secretome and microsomal protein composition resulting from a shift to a high level secretion condition. During growth of A. niger on D-sorbitol, small amounts of D-maltose or D-xylose were used as inducers of the extracellular amylolytic and xylanolytic enzymes. Upon induction, protein compositions in the extracellular broth as well as in enriched secretory organelle (microsomal) fractions were analyzed using a shotgun proteomics approach. In total 102 secreted proteins and 1,126 microsomal proteins were identified in this study. Induction by D-maltose or D-xylose resulted in the increase in specific extracellular enzymes, such as glucoamylase A on D-maltose and beta-xylosidase D on D-xylose, as well as of microsomal proteins. This reflects the differential expression of selected genes coding for dedicated extracellular enzymes. As expected, the addition of extra D-sorbitol had no effect on the expression of carbohydrate-active enzymes, compared to addition of D-xylose or D-maltose. Furthermore, D-maltose induction caused an increase in microsomal proteins related to translation (e.g., Rpl15) and vesicular transport (e.g., the endosomal cargo receptor Erv14). Millimolar amounts of the inducers D-maltose and D-xylose are sufficient to cause a direct response in specific protein expression levels. Also, after induction by D-maltose or D-xylose, the induced enzymes were found in microsomes and extracellular. In agreement with our previous findings for D xylose induction, D-maltose induction leads to recruitment of proteins involved in proteasome-mediated degradation. PMID- 21698108 TI - Patterns of chemical diversity in the Mediterranean sponge Spongia lamella. AB - The intra-specific diversity in secondary metabolites can provide crucial information for understanding species ecology and evolution but has received limited attention in marine chemical ecology. The complex nature of diversity is partially responsible for the lack of studies, which often target a narrow number of major compounds. Here, we investigated the intra-specific chemical diversity of the Mediterranean sponge Spongia lamella. The chemical profiles of seven populations spreading over 1200 km in the Western Mediterranean were obtained by a straightforward SPE-HPLC-DAD-ELSD process whereas the identity of compounds was assessed by comparison between HPLC-MS spectra and literature data. Chemical diversity calculated by richness and Shannon indexes differed significantly between sponge populations but not at a larger regional scale. We used factor analysis, analysis of variance, and regression analysis to examine the chemical variability of this sponge at local and regional scales, to establish general patterns of variation in chemical diversity. The abundance of some metabolites varied significantly between sponge populations. Despite these significant differences between populations, we found a clear pattern of increasing chemical dissimilarity with increasing geographic distance. Additional large spatial scale studies on the chemical diversity of marine organisms will validate the universality or exclusivity of this pattern. PMID- 21698109 TI - Pax6 expression is sufficient to induce a neurogenic fate in glial progenitors of the neonatal subventricular zone. AB - BACKGROUND: The forebrain subventricular zone (SVZ) of neonatal mammals contains a large, heterogeneous population of migratory and proliferating precursors of interneurons and glia. These cell types are produced in large numbers in the immediate postnatal period, the glioblasts populating the hemispheres with astrocytes and oligodendrocytes, the neuroblasts migrating to the olfactory bulb to become interneurons. How cell fate decisions are determined or stabilized in this mixed population is not clear, although previous studies indicate the importance of two transcription factors, Pax6 in neurons and Olig2 in glia, and suggest there may be reciprocal repression between these genes. METHODOLOGY/PRINCIPAL FINDINGS: In examining the SVZ of neonatal mouse and rat brain, we find that the very large majority of SVZ cells express either Pax6 or Olig2, but few express both. We have used in vivo retro- and lenti-virus injections into the neonatal SVZ and in vitro gene transfer to demonstrate that pax6 over-expression is sufficient to down-regulate olig2 and to promote a neuronal lineage development and migration pattern in olig2-expressing cells. Furthermore, we provide evidence that Pax6 binds to the olig2 promoter and that an HEB sequence in the promoter is required for the Pax6 repression of olig2 transcription. Lastly, we constructed a lentivirus to target olig2-expressing cells in the SVZ to trace their fates, and found that the very large majority developed into glia. CONCLUSIONS/SIGNIFICANCE: We provide evidence for a direct repression of olig2 by Pax6. Since SVZ cells can display developmental plasticity in vitro, the cross-repression promotes a stabilization of cell fates. This repression may be critical in a germinal zone in which immature cells are highly migratory and are not organized into an epithelium. PMID- 21698111 TI - Inferring ecological processes from taxonomic, phylogenetic and functional trait beta-diversity. AB - Understanding the influences of dispersal limitation and environmental filtering on the structure of ecological communities is a major challenge in ecology. Insight may be gained by combining phylogenetic, functional and taxonomic data to characterize spatial turnover in community structure (beta-diversity). We develop a framework that allows rigorous inference of the strengths of dispersal limitation and environmental filtering by combining these three types of beta diversity. Our framework provides model-generated expectations for patterns of taxonomic, phylogenetic and functional beta-diversity across biologically relevant combinations of dispersal limitation and environmental filtering. After developing the framework we compared the model-generated expectations to the commonly used "intuitive" expectation that the variance explained by the environment or by space will, respectively, increase monotonically with the strength of environmental filtering or dispersal limitation. The model-generated expectations strongly departed from these intuitive expectations: the variance explained by the environment or by space was often a unimodal function of the strength of environmental filtering or dispersal limitation, respectively. Therefore, although it is commonly done in the literature, one cannot assume that the strength of an underlying process is a monotonic function of explained variance. To infer the strength of underlying processes, one must instead compare explained variances to model-generated expectations. Our framework provides these expectations. We show that by combining the three types of beta-diversity with model-generated expectations our framework is able to provide rigorous inferences of the relative and absolute strengths of dispersal limitation and environmental filtering. Phylogenetic, functional and taxonomic beta-diversity can therefore be used simultaneously to infer processes by comparing their empirical patterns to the expectations generated by frameworks similar to the one developed here. PMID- 21698110 TI - Sustained fixation induced changes in phoria and convergence peak velocity. AB - PURPOSE: This study sought to investigate the influence of phoria adaptation on convergence peak velocity from responses located at different initial vergence positions. METHODS: Symmetrical 4 degrees convergence step responses and near dissociated phoria (measured at 40 cm from the subject's midline) were recorded from six subjects with normal binocular vision using an infrared limbus tracking system with a haploscope. Two different sustained fixations (1 degrees and 16 degrees convergent rotation along the subject's midline) were used to study whether phoria had an influence on the peak velocity of convergence responses located at two initial vergence positions (1 degrees or 'far' steps and 12 degrees or 'near' steps). RESULTS: Phoria was significantly adapted after a sustained fixation task at near (16 degrees ) and far (1 degrees ) (p<0.002). A repeated measures ANOVA showed that convergence far steps were significantly faster than the near steps (p<0.03). When comparing convergence steps with the same initial vergence position, steps measured after near phoria adaptation were faster than responses after far adaptation (p<0.02). A regression analysis demonstrated that the change in phoria and the change in convergence peak velocity were significantly correlated for the far convergence steps (r = 0.97, p = 0.001). A weaker correlation was observed for the near convergence steps (r = 0.59, p = 0.20). CONCLUSION: As a result of sustained fixation, phoria was adapted and the peak velocity of the near and far convergence steps was modified. This study has clinical considerations since prisms, which evoke phoria adaptation, can be prescribed to help alleviate visual discomfort. Future investigations should include a systematic study of how prisms may influence convergence and divergence eye movements for those prescribed with prisms within their spectacles. PMID- 21698112 TI - Anchored design of protein-protein interfaces. AB - BACKGROUND: Few existing protein-protein interface design methods allow for extensive backbone rearrangements during the design process. There is also a dichotomy between redesign methods, which take advantage of the native interface, and de novo methods, which produce novel binders. METHODOLOGY: Here, we propose a new method for designing novel protein reagents that combines advantages of redesign and de novo methods and allows for extensive backbone motion. This method requires a bound structure of a target and one of its natural binding partners. A key interaction in this interface, the anchor, is computationally grafted out of the partner and into a surface loop on the design scaffold. The design scaffold's surface is then redesigned with backbone flexibility to create a new binding partner for the target. Careful choice of a scaffold will bring experimentally desirable characteristics into the new complex. The use of an anchor both expedites the design process and ensures that binding proceeds against a known location on the target. The use of surface loops on the scaffold allows for flexible-backbone redesign to properly search conformational space. CONCLUSIONS AND SIGNIFICANCE: This protocol was implemented within the Rosetta3 software suite. To demonstrate and evaluate this protocol, we have developed a benchmarking set of structures from the PDB with loop-mediated interfaces. This protocol can recover the correct loop-mediated interface in 15 out of 16 tested structures, using only a single residue as an anchor. PMID- 21698113 TI - Isopods failed to acclimate their thermal sensitivity of locomotor performance during predictable or stochastic cooling. AB - Most organisms experience environments that vary continuously over time, yet researchers generally study phenotypic responses to abrupt and sustained changes in environmental conditions. Gradual environmental changes, whether predictable or stochastic, might affect organisms differently than do abrupt changes. To explore this possibility, we exposed terrestrial isopods (Porcellio scaber) collected from a highly seasonal environment to four thermal treatments: (1) a constant 20 degrees C; (2) a constant 10 degrees C; (3) a steady decline from 20 degrees to 10 degrees C; and (4) a stochastic decline from 20 degrees to 10 degrees C that mimicked natural conditions during autumn. After 45 days, we measured thermal sensitivities of running speed and thermal tolerances (critical thermal maximum and chill-coma recovery time). Contrary to our expectation, thermal treatments did not affect the thermal sensitivity of locomotion; isopods from all treatments ran fastest at 33 degrees to 34 degrees C and achieved more than 80% of their maximal speed over a range of 10 degrees to 11 degrees C. Isopods exposed to a stochastic decline in temperature tolerated cold the best, and isopods exposed to a constant temperature of 20 degrees C tolerated cold the worst. No significant variation in heat tolerance was observed among groups. Therefore, thermal sensitivity and heat tolerance failed to acclimate to any type of thermal change, whereas cold tolerance acclimated more during stochastic change than it did during abrupt change. PMID- 21698114 TI - Over-expression of human lipoprotein lipase in mouse mammary glands leads to reduction of milk triglyceride and delayed growth of suckling pups. AB - BACKGROUND: The mammary gland is a conserved site of lipoprotein lipase expression across species and lipoprotein lipase attachment to the luminal surface of mammary gland vascular endothelial cells has been implicated in the direction of circulating triglycerides into milk synthesis during lactation. PRINCIPAL FINDINGS: Here we report generation of transgenic mice harboring a human lipoprotein lipase gene driven by a mammary gland-specific promoter. Lipoprotein lipase levels in transgenic milk was raised to 0.16 mg/ml, corresponding to an activity of 8772.95 mU/ml. High lipoprotein lipase activity led to a significant reduction of triglyceride concentration in milk, but other components were largely unchanged. Normal pups fed with transgenic milk showed inferior growth performances compared to those fed with normal milk. CONCLUSION: Our study suggests a possibility to reduce the triglyceride content of cow milk using transgenic technology. PMID- 21698115 TI - Biophysics of malarial parasite exit from infected erythrocytes. AB - Upon infection and development within human erythrocytes, P. falciparum induces alterations to the infected RBC morphology and bio-mechanical properties to eventually rupture the host cells through parasitic and host derived proteases of cysteine and serine families. We used previously reported broad-spectrum inhibitors (E64d, EGTA-AM and chymostatin) to inhibit these proteases and impede rupture to analyze mechanical signatures associated with parasite escape. Treatment of late-stage iRBCs with E64d and EGTA-AM prevented rupture, resulted in no major RBC cytoskeletal reconfiguration but altered schizont morphology followed by dramatic re-distribution of three-dimensional refractive index (3D RI) within the iRBC. These phenotypes demonstrated several-fold increased iRBC membrane flickering. In contrast, chymostatin treatment showed no 3D-RI changes and caused elevated fluctuations solely within the parasitophorous vacuole. We show that E64d and EGTA-AM supported PV breakdown and the resulting elevated fluctuations followed non-Gaussian pattern that resulted from direct merozoite impingement against the iRBC membrane. Optical trapping experiments highlighted reduced deformability of the iRBC membranes upon rupture-arrest, more specifically in the treatments that facilitated PV breakdown. Taken together, our experiments provide novel mechanistic interpretations on the role of parasitophorous vacuole in maintaining the spherical schizont morphology, the impact of PV breakdown on iRBC membrane fluctuations leading to eventual parasite escape and the evolution of membrane stiffness properties of host cells in which merozoites were irreversibly trapped, recourse to protease inhibitors. These findings provide a comprehensive, previously unavailable, body of information on the combined effects of biochemical and biophysical factors on parasite egress from iRBCs. PMID- 21698116 TI - Analysis of proteasomal proteolysis during the in vitro metacyclogenesis of Trypanosoma cruzi. AB - Proteasomes are large protein complexes, whose main function is to degrade unnecessary or damaged proteins. The inhibition of proteasome activity in Trypanosoma cruzi blocks parasite replication and cellular differentiation. We demonstrate that proteasome-dependent proteolysis occurs during the cellular differentiation of T. cruzi from replicative non-infectious epimastigotes to non replicative and infectious trypomastigotes (metacyclogenesis). No peaks of ubiquitin-mediated degradation were observed and the profile of ubiquitinated conjugates was similar at all stages of differentiation. However, an analysis of carbonylated proteins showed significant variation in oxidized protein levels at the various stages of differentiation and the proteasome inhibition also increased oxidized protein levels. Our data suggest that different proteasome complexes coexist during metacyclogenesis. The 20S proteasome may be free or linked to regulatory particles (PA700, PA26 and PA200), at specific cell sites and the coordinated action of these complexes would make it possible for proteolysis of ubiquitin-tagged proteins and oxidized proteins, to coexist in the cell. PMID- 21698117 TI - An improved transplantation strategy for mouse mesenchymal stem cells in an acute myocardial infarction model. AB - To develop an effective therapeutic strategy for cardiac regeneration using bone marrow mesenchymal stem cells (BM-MSCs), the primary mouse BM-MSCs (1(st) BM MSCs) and 5(th) passage BM-MSCs from beta-galactosidase transgenic mice were respectively intramyocardially transplanted into the acute myocardial infarction (AMI) model of wild type mice. At the 6(th) week, animals/tissues from the 1(st) BM-MSCs group, the 5(th) passage BM-MSCs group, control group were examined. Our results revealed that, compared to the 5(th) passage BM-MSCs, the 1(st) BM-MSCs had better therapeutic effects in the mouse MI model. The 1(st) BM-MSCs maintained greater differentiation potentials towards cardiomocytes or vascular endothelial cells in vitro. This is indicated by higher expressions of cardiomyocyte and vascular endothelial cell mature markers in vitro. Furthermore, we identified that 24 proteins were down-regulated and 3 proteins were up regulated in the 5(th) BM-MSCs in comparison to the 1(st) BM-MSCs, using mass spectrometry following two-dimensional electrophoresis. Our data suggest that transplantation of the 1(st) BM-MSCs may be an effective therapeutic strategy for cardiac tissue regeneration following AMI, and altered protein expression profiles between the 1(st) BM-MSCs and 5(th) passage BM-MSCs may account for the difference in their maintenance of stemness and their therapeutic effects following AMI. PMID- 21698118 TI - Poly(I:C) enhances the susceptibility of leukemic cells to NK cell cytotoxicity and phagocytosis by DC. AB - alpha active specific immunotherapy aims at stimulating the host's immune system to recognize and eradicate malignant cells. The concomitant activation of dendritic cells (DC) and natural killer (NK) cells is an attractive modality for immune-based therapies. Inducing immunogenic cell death to facilitate tumor cell recognition and phagocytosis by neighbouring immune cells is of utmost importance for guiding the outcome of the immune response. We previously reported that acute myeloid leukemic (AML) cells in response to electroporation with the synthetic dsRNA analogue poly(I:C) exert improved immunogenicity, demonstrated by enhanced DC-activating and NK cell interferon-gamma-inducing capacities. To further invigorate the potential of these immunogenic tumor cells, we explored their effect on the phagocytic and cytotoxic capacity of DC and NK cells, respectively. Using single-cell analysis, we assessed these functionalities in two- and three party cocultures. Following poly(I:C) electroporation AML cells become highly susceptible to NK cell-mediated killing and phagocytosis by DC. Moreover, the enhanced killing and the improved uptake are strongly correlated. Interestingly, tumor cell killing, but not phagocytosis, is further enhanced in three-party cocultures provided that these tumor cells were upfront electroporated with poly(I:C). Altogether, poly(I:C)-electroporated AML cells potently activate DC and NK cell functions and stimulate NK-DC cross-talk in terms of tumor cell killing. These data strongly support the use of poly(I:C) as a cancer vaccine component, providing a way to overcome immune evasion by leukemic cells. PMID- 21698119 TI - Photodynamic antimicrobial chemotherapy in aquaculture: photoinactivation studies of Vibrio fischeri. AB - BACKGROUND: Photodynamic antimicrobial chemotherapy (PACT) combines light, a light-absorbing molecule that initiates a photochemical or photophysical reaction, and oxygen. The combined action of these three components originates reactive oxygen species that lead to microorganisms' destruction. The aim was to evaluate the efficiency of PACT on Vibrio fischeri: 1) with buffer solution, varying temperature, pH, salinity and oxygen concentration values; 2) with aquaculture water, to reproduce photoinactivation (PI) conditions in situ. METHODOLOGY/PRINCIPAL FINDINGS: To monitor the PI kinetics, the bioluminescence of V. fischeri was measured during the experiments. A tricationic meso substituted porphyrin (Tri-Py(+)-Me-PF) was used as photosensitizer (5 uM in the studies with buffer solution and 10-50 uM in the studies with aquaculture water); artificial white light (4 mW cm(-2)) and solar irradiation (40 mW cm(-2)) were used as light sources; and the bacterial concentration used for all experiments was ~10(7) CFU mL(-1) (corresponding to a bioluminescence level of 10(5) relative light units--RLU). The variations in pH (6.5-8.5), temperature (10-25 degrees C), salinity (20-40 g L(-1)) and oxygen concentration did not significantly affect the PI of V. fischeri, once in all tested conditions the bioluminescent signal decreased to the detection limit of the method (~7 log reduction). The assays using aquaculture water showed that the efficiency of the process is affected by the suspended matter. Total PI of V. fischeri in aquaculture water was achieved under solar light in the presence of 20 uM of Tri-Py(+)-Me-PF. CONCLUSIONS/SIGNIFICANCE: If PACT is to be used in environmental applications, the matrix containing target microbial communities should be previously characterized in order to establish an efficient protocol having into account the photosensitizer concentration, the light source and the total light dose delivered. The possibility of using solar light in PACT to treat aquaculture water makes this technology cost-effective and attractive. PMID- 21698120 TI - MIP/Aquaporin 0 represents a direct transcriptional target of PITX3 in the developing lens. AB - The PITX3 bicoid-type homeodomain transcription factor plays an important role in lens development in vertebrates. PITX3 deficiency results in a spectrum of phenotypes from isolated cataracts to microphthalmia in humans, and lens degeneration in mice and zebrafish. While identification of downstream targets of PITX3 is vital for understanding the mechanisms of normal ocular development and human disease, these targets remain largely unknown. To isolate genes that are directly regulated by PITX3, we performed a search for genomic sequences that contain evolutionarily conserved bicoid/PITX3 binding sites and are located in the proximity of known genes. Two bicoid sites that are conserved from zebrafish to human were identified within the human promoter of the major intrinsic protein of lens fiber, MIP/AQP0. MIP/AQP0 deficiency was previously shown to be associated with lens defects in humans and mice. We demonstrate by both chromatin immunoprecipitation and electrophoretic mobility shift assay that PITX3 binds to MIP/AQP0 promoter region in vivo and is able to interact with both bicoid sites in vitro. In addition, we show that wild-type PITX3 is able to activate the MIP/AQP0 promoter via interaction with the proximal bicoid site in cotransfection experiments and that the introduction of mutations disrupting binding to this site abolishes this activation. Furthermore, mutant forms of PITX3 fail to produce the same levels of transactivation as wild-type when cotransfected with the MIP/AQP0 reporter. Finally, knockdown of pitx3 in zebrafish affects formation of a DNA-protein complex associated with mip1 promoter sequences; and examination of expression in pitx3 morphant and control zebrafish revealed a delay in and reduction of mip1 expression in pitx3-deficient embryos. Therefore, our data suggest that PITX3 is involved in direct regulation of MIP/AQP0 expression and that the alteration of MIP/AQP0 expression is likely to contribute to the lens phenotype in cataract patients with PITX3 mutations. PMID- 21698121 TI - Genetic variations in the regulator of G-protein signaling genes are associated with survival in late-stage non-small cell lung cancer. AB - The regulator of G-protein signaling (RGS) pathway plays an important role in signaling transduction, cellular activities, and carcinogenesis. We hypothesized that genetic variations in RGS gene family may be associated with the response of late-stage non-small cell lung cancer (NSCLC) patients to chemotherapy or chemoradiotherapy. We selected 95 tagging single nucleotide polymorphisms (SNPs) in 17 RGS genes and genotyped them in 598 late-stage NSCLC patients. Thirteen SNPs were significantly associated with overall survival. Among them, rs2749786 of RGS12 was most significant. Stratified analysis by chemotherapy or chemoradiation further identified SNPs that were associated with overall survival in subgroups. Rs2816312 of RGS1 and rs6689169 of RGS7 were most significant in chemotherapy group and chemoradiotherapy group, respectively. A significant cumulative effect was observed when these SNPs were combined. Survival tree analyses identified potential interactions between rs944343, rs2816312, and rs1122794 in affecting survival time in patients treated with chemotherapy, while the genotype of rs6429264 affected survival in chemoradiation-treated patients. To our knowledge, this is the first study to reveal the importance of RGS gene family in the survival of late-stage NSCLC patients. PMID- 21698122 TI - Impact of microscopic motility on the swimming behavior of parasites: straighter trypanosomes are more directional. AB - Microorganisms, particularly parasites, have developed sophisticated swimming mechanisms to cope with a varied range of environments. African Trypanosomes, causative agents of fatal illness in humans and animals, use an insect vector (the Tsetse fly) to infect mammals, involving many developmental changes in which cell motility is of prime importance. Our studies reveal that differences in cell body shape are correlated with a diverse range of cell behaviors contributing to the directional motion of the cell. Straighter cells swim more directionally while cells that exhibit little net displacement appear to be more bent. Initiation of cell division, beginning with the emergence of a second flagellum at the base, correlates to directional persistence. Cell trajectory and rapid body fluctuation correlation analysis uncovers two characteristic relaxation times: a short relaxation time due to strong body distortions in the range of 20 to 80 ms and a longer time associated with the persistence in average swimming direction in the order of 15 seconds. Different motility modes, possibly resulting from varying body stiffness, could be of consequence for host invasion during distinct infective stages. PMID- 21698123 TI - Integrative analysis of many weighted co-expression networks using tensor computation. AB - The rapid accumulation of biological networks poses new challenges and calls for powerful integrative analysis tools. Most existing methods capable of simultaneously analyzing a large number of networks were primarily designed for unweighted networks, and cannot easily be extended to weighted networks. However, it is known that transforming weighted into unweighted networks by dichotomizing the edges of weighted networks with a threshold generally leads to information loss. We have developed a novel, tensor-based computational framework for mining recurrent heavy subgraphs in a large set of massive weighted networks. Specifically, we formulate the recurrent heavy subgraph identification problem as a heavy 3D subtensor discovery problem with sparse constraints. We describe an effective approach to solving this problem by designing a multi-stage, convex relaxation protocol, and a non-uniform edge sampling technique. We applied our method to 130 co-expression networks, and identified 11,394 recurrent heavy subgraphs, grouped into 2,810 families. We demonstrated that the identified subgraphs represent meaningful biological modules by validating against a large set of compiled biological knowledge bases. We also showed that the likelihood for a heavy subgraph to be meaningful increases significantly with its recurrence in multiple networks, highlighting the importance of the integrative approach to biological network analysis. Moreover, our approach based on weighted graphs detects many patterns that would be overlooked using unweighted graphs. In addition, we identified a large number of modules that occur predominately under specific phenotypes. This analysis resulted in a genome-wide mapping of gene network modules onto the phenome. Finally, by comparing module activities across many datasets, we discovered high-order dynamic cooperativeness in protein complex networks and transcriptional regulatory networks. PMID- 21698124 TI - Generation of diverse biological forms through combinatorial interactions between tissue polarity and growth. AB - A major problem in biology is to understand how complex tissue shapes may arise through growth. In many cases this process involves preferential growth along particular orientations raising the question of how these orientations are specified. One view is that orientations are specified through stresses in the tissue (axiality-based system). Another possibility is that orientations can be specified independently of stresses through molecular signalling (polarity-based system). The axiality-based system has recently been explored through computational modelling. Here we develop and apply a polarity-based system which we call the Growing Polarised Tissue (GPT) framework. Tissue is treated as a continuous material within which regionally expressed factors under genetic control may interact and propagate. Polarity is established by signals that propagate through the tissue and is anchored in regions termed tissue polarity organisers that are also under genetic control. Rates of growth parallel or perpendicular to the local polarity may then be specified through a regulatory network. The resulting growth depends on how specified growth patterns interact within the constraints of mechanically connected tissue. This constraint leads to the emergence of features such as curvature that were not directly specified by the regulatory networks. Resultant growth feeds back to influence spatial arrangements and local orientations of tissue, allowing complex shapes to emerge from simple rules. Moreover, asymmetries may emerge through interactions between polarity fields. We illustrate the value of the GPT-framework for understanding morphogenesis by applying it to a growing Snapdragon flower and indicate how the underlying hypotheses may be tested by computational simulation. We propose that combinatorial intractions between orientations and rates of growth, which are a key feature of polarity-based systems, have been exploited during evolution to generate a range of observed biological shapes. PMID- 21698126 TI - Elemental profiling of single bacterial cells as a function of copper exposure and growth phase. AB - The elemental composition of single cells of Nitrosomonas europaea 19718 was studied via synchrotron X-ray fluorescence microscopy (XFM) as a function of inhibition by divalent copper (Cu(II)) and batch growth phase. Based on XFM, the intracellular Cu concentrations in exponential phase cultures of N. europaea exposed to Cu(II) were statistically higher than in stationary phase cultures at the 95% confidence interval (alpha = 0.05). However, the impact of Cu inferred from specific oxygen uptake rate (sOUR) measurements at the two physiological states was statistically not dissimilar at the Cu(II) doses tested, except at 1000 uM Cu(II), at which exponential phase cultures were significantly more inhibited. Furthermore, the elemental composition in uninhibited exponential and stationary phase N. europaea cultures was similar. Notably, the molar fractions of Cu and Fe, relative to other elements in N. europaea cultures were statistically higher than those recently reported in Pseudomonas fluorescens possibly owing to the preponderance of metal cofactor rich catalytic enzymes (such as ammonia monooxygenase) and electron transport mechanisms in N. europaea. PMID- 21698125 TI - Surveillance of transmitted antiretroviral drug resistance among HIV-1 infected women attending antenatal clinics in Chitungwiza, Zimbabwe. AB - The rapid scale-up of highly active antiretroviral therapy (HAART) and use of single dose Nevirapine (SD NVP) for prevention of mother-to-child transmission (pMTCT) have raised fears about the emergence of resistance to the first line antiretroviral drug regimens. A cross-sectional study was conducted to determine the prevalence of primary drug resistance (PDR) in a cohort of young (<25 yrs) HAART-naive HIV pregnant women attending antenatal clinics in Chitungwiza, Zimbabwe. Whole blood was collected in EDTA for CD4 counts, viral load, serological estimation of duration of infection using the BED Calypte assay and genotyping for drug resistance. Four hundred and seventy-one women, mean age 21 years; SD: 2.1 were enrolled into the study between 2006 and 2007. Their median CD4 count was 371cells/uL; IQR: 255-511 cells/uL. Two hundred and thirty-six samples were genotyped for drug resistance. Based on the BED assay, 27% were recently infected (RI) whilst 73% had long-term infection (LTI). Median CD4 count was higher (p<0.05) in RI than in women with LTI. Only 2 women had drug resistance mutations; protease I85V and reverse transcriptase Y181C. Prevalence of PDR in Chitungwiza, 4 years after commencement of the national ART program remained below WHO threshold limit (5%). Frequency of recent infection BED testing is consistent with high HIV acquisition during pregnancy. With the scale up of long-term ART programs, maintenance of proper prescribing practices, continuous monitoring of patients and reinforcement of adherence may prevent the acquisition and transmission of PDR. PMID- 21698127 TI - Assessing nutritional diversity of cropping systems in African villages. AB - BACKGROUND: In Sub-Saharan Africa, 40% of children under five years in age are chronically undernourished. As new investments and attention galvanize action on African agriculture to reduce hunger, there is an urgent need for metrics that monitor agricultural progress beyond calories produced per capita and address nutritional diversity essential for human health. In this study we demonstrate how an ecological tool, functional diversity (FD), has potential to address this need and provide new insights on nutritional diversity of cropping systems in rural Africa. METHODS AND FINDINGS: Data on edible plant species diversity, food security and diet diversity were collected for 170 farms in three rural settings in Sub-Saharan Africa. Nutritional FD metrics were calculated based on farm species composition and species nutritional composition. Iron and vitamin A deficiency were determined from blood samples of 90 adult women. Nutritional FD metrics summarized the diversity of nutrients provided by the farm and showed variability between farms and villages. Regression of nutritional FD against species richness and expected FD enabled identification of key species that add nutrient diversity to the system and assessed the degree of redundancy for nutrient traits. Nutritional FD analysis demonstrated that depending on the original composition of species on farm or village, adding or removing individual species can have radically different outcomes for nutritional diversity. While correlations between nutritional FD, food and nutrition indicators were not significant at household level, associations between these variables were observed at village level. CONCLUSION: This study provides novel metrics to address nutritional diversity in farming systems and examples of how these metrics can help guide agricultural interventions towards adequate nutrient diversity. New hypotheses on the link between agro-diversity, food security and human nutrition are generated and strategies for future research are suggested calling for integration of agriculture, ecology, nutrition, and socio-economics. PMID- 21698128 TI - Amino acid substitutions at the major insertion loop of Candida albicans sterol 14alpha-demethylase are involved in fluconazole resistance. AB - BACKGROUND: In the fungal pathogen Candida albicans, amino acid substitutions of 14alpha-demethylase (CaErg11p, CaCYP51) are associated with azole antifungals resistance. This is an area of research which is very dynamic, since the stakes concern the screening of new antifungals which circumvent resistance. The impact of amino acid substitutions on azole interaction has been postulated by homology modeling in comparison to the crystal structure of Mycobacterium tuberculosis (MT CYP51). Modeling of amino acid residues situated between positions 428 to 459 remains difficult to explain to date, because they are in a major insertion loop specifically present in fungal species. METHODOLOGY/PRINCIPAL FINDING: Fluconazole resistance of clinical isolates displaying Y447H and V456I novel CaErg11p substitutions confirmed in vivo in a murine model of disseminated candidiasis. Y447H and V456I implication into fluconazole resistance was then studied by site-directed mutagenesis of wild-type CaErg11p and by heterogeneously expression into the Pichia pastoris model. CLSI modified tests showed that V447H and V456I are responsible for an 8-fold increase in fluconazole MICs of P. pastoris mutants compared to the wild-type controls. Moreover, mutants showed a sustained capacity for producing ergosterol, even in the presence of fluconazole. Based on these biological results, we are the first to propose a hybrid homology structure-function model of Ca-CYP51 using 3 different homology modeling programs. The variable position of the protein insertion loop, using different liganded or non-liganded templates of recently solved CYP51 structures, suggests its inherent flexibility. Mapping of recognized azole-resistant substitutions indicated that the flexibility of this region is probably enhanced by the relatively high glycine content of the consensus. CONCLUSIONS/SIGNIFICANCE: The results highlight the potential role of the insertion loop in azole resistance in the human pathogen C. albicans. This new data should be taken into consideration for future studies aimed at designing new antifungal agents, which circumvent azole resistance. PMID- 21698129 TI - Development of an efficient recombinant mosquito densovirus-mediated RNA interference system and its preliminary application in mosquito control. AB - The Aedes aegypti densovirus (AeDNV) has potential as a delivery vector for foreign nucleic acids into mosquito cells. In this study, we investigated the ability of plasmids containing recombinant viral transducing genome to induce RNA interference (RNAi) effects in C6/C36 cells. We then evaluated the efficiency of a recombinant AeDNV vector to induce RNAi in Aedes albopictus larvae. We found that the expression of V-ATPase was inhibited by up to 90% at 96 h post transfection in transfected C6/C36 cells. In addition, the bioinsecticidal activities of various RNAi-expressing AeDNV vectors used to infect Ae. albopictus larvae were also tested. We found that when Ae. albopictus larvae were infected with recombinant AeDNV, expression of V-ATPase was downregulated by nearly 70% compared to controls. Furthermore, the median survival time bioassays demonstrated that recombinant AeDNV caused more serious pathogenic effects than the wild type virus. This is the first report showing that recombinant virus plasmid and corresponding recombinant AeDNV can be used as an effective in vitro and in vivo RNAi delivery system, respectively. PMID- 21698130 TI - Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance. AB - Genomic instability is a hallmark of human cancer cells. To prevent genomic instability, chromosomal DNA is faithfully duplicated in every cell division cycle, and eukaryotic cells have complex regulatory mechanisms to achieve this goal. Here, we show that untimely activation of replication origins during the G1 phase is genotoxic and induces genomic instability in the budding yeast Saccharomyces cerevisiae. Our data indicate that cells preserve a low level of the initiation factor Sld2 to prevent untimely initiation during the normal cell cycle in addition to controlling the phosphorylation of Sld2 and Sld3 by cyclin dependent kinase. Although untimely activation of origin is inhibited on multiple levels, we show that deregulation of a single pathway can cause genomic instability, such as gross chromosome rearrangements (GCRs). Furthermore, simultaneous deregulation of multiple pathways causes an even more severe phenotype. These findings highlight the importance of having multiple inhibitory mechanisms to prevent the untimely initiation of chromosome replication to preserve stable genome maintenance over generations in eukaryotes. PMID- 21698131 TI - Chromosomal macrodomains and associated proteins: implications for DNA organization and replication in gram negative bacteria. AB - The Escherichia coli chromosome is organized into four macrodomains, the function and organisation of which are poorly understood. In this review we focus on the MatP, SeqA, and SlmA proteins that have recently been identified as the first examples of factors with macrodomain-specific DNA-binding properties. In particular, we review the evidence that these factors contribute towards the control of chromosome replication and segregation by specifically targeting subregions of the genome and contributing towards their unique properties. Genome sequence analysis of multiple related bacteria, including pathogenic species, reveals that macrodomain-specific distribution of SeqA, SlmA, and MatP is conserved, suggesting common principles of chromosome organisation in these organisms. This discovery of proteins with macrodomain-specific binding properties hints that there are other proteins with similar specificity yet to be unveiled. We discuss the roles of the proteins identified to date as well as strategies that may be employed to discover new factors. PMID- 21698132 TI - High-resolution analysis of parent-of-origin allelic expression in the Arabidopsis Endosperm. AB - Genomic imprinting is an epigenetic phenomenon leading to parent-of-origin specific differential expression of maternally and paternally inherited alleles. In plants, genomic imprinting has mainly been observed in the endosperm, an ephemeral triploid tissue derived after fertilization of the diploid central cell with a haploid sperm cell. In an effort to identify novel imprinted genes in Arabidopsis thaliana, we generated deep sequencing RNA profiles of F1 hybrid seeds derived after reciprocal crosses of Arabidopsis Col-0 and Bur-0 accessions. Using polymorphic sites to quantify allele-specific expression levels, we could identify more than 60 genes with potential parent-of-origin specific expression. By analyzing the distribution of DNA methylation and epigenetic marks established by Polycomb group (PcG) proteins using publicly available datasets, we suggest that for maternally expressed genes (MEGs) repression of the paternally inherited alleles largely depends on DNA methylation or PcG-mediated repression, whereas repression of the maternal alleles of paternally expressed genes (PEGs) predominantly depends on PcG proteins. While maternal alleles of MEGs are also targeted by PcG proteins, such targeting does not cause complete repression. Candidate MEGs and PEGs are enriched for cis-proximal transposons, suggesting that transposons might be a driving force for the evolution of imprinted genes in Arabidopsis. In addition, we find that MEGs and PEGs are significantly faster evolving when compared to other genes in the genome. In contrast to the predominant location of mammalian imprinted genes in clusters, cluster formation was only detected for few MEGs and PEGs, suggesting that clustering is not a major requirement for imprinted gene regulation in Arabidopsis. PMID- 21698133 TI - SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. AB - The N-Myc oncoprotein is a critical factor in neuroblastoma tumorigenesis which requires additional mechanisms converting a low-level to a high-level N-Myc expression. N-Myc protein is stabilized when phosphorylated at Serine 62 by phosphorylated ERK protein. Here we describe a novel positive feedback loop whereby N-Myc directly induced the transcription of the class III histone deacetylase SIRT1, which in turn increased N-Myc protein stability. SIRT1 binds to Myc Box I domain of N-Myc protein to form a novel transcriptional repressor complex at gene promoter of mitogen-activated protein kinase phosphatase 3 (MKP3), leading to transcriptional repression of MKP3, ERK protein phosphorylation, N-Myc protein phosphorylation at Serine 62, and N-Myc protein stabilization. Importantly, SIRT1 was up-regulated, MKP3 down-regulated, in pre cancerous cells, and preventative treatment with the SIRT1 inhibitor Cambinol reduced tumorigenesis in TH-MYCN transgenic mice. Our data demonstrate the important roles of SIRT1 in N-Myc oncogenesis and SIRT1 inhibitors in the prevention and therapy of N-Myc-induced neuroblastoma. PMID- 21698134 TI - Trait variation in yeast is defined by population history. AB - A fundamental goal in biology is to achieve a mechanistic understanding of how and to what extent ecological variation imposes selection for distinct traits and favors the fixation of specific genetic variants. Key to such an understanding is the detailed mapping of the natural genomic and phenomic space and a bridging of the gap that separates these worlds. Here we chart a high-resolution map of natural trait variation in one of the most important genetic model organisms, the budding yeast Saccharomyces cerevisiae, and its closest wild relatives and trace the genetic basis and timing of major phenotype changing events in its recent history. We show that natural trait variation in S. cerevisiae exceeds that of its relatives, despite limited genetic variation, and follows the population history rather than the source environment. In particular, the West African population is phenotypically unique, with an extreme abundance of low-performance alleles, notably a premature translational termination signal in GAL3 that cause inability to utilize galactose. Our observations suggest that many S. cerevisiae traits may be the consequence of genetic drift rather than selection, in line with the assumption that natural yeast lineages are remnants of recent population bottlenecks. Disconcertingly, the universal type strain S288C was found to be highly atypical, highlighting the danger of extrapolating gene-trait connections obtained in mosaic, lab-domesticated lineages to the species as a whole. Overall, this study represents a step towards an in-depth understanding of the causal relationship between co-variation in ecology, selection pressure, natural traits, molecular mechanism, and alleles in a key model organism. PMID- 21698135 TI - Recurrent chromosome 16p13.1 duplications are a risk factor for aortic dissections. AB - Chromosomal deletions or reciprocal duplications of the 16p13.1 region have been implicated in a variety of neuropsychiatric disorders such as autism, schizophrenia, epilepsies, and attention-deficit hyperactivity disorder (ADHD). In this study, we investigated the association of recurrent genomic copy number variants (CNVs) with thoracic aortic aneurysms and dissections (TAAD). By using SNP arrays to screen and comparative genomic hybridization microarrays to validate, we identified 16p13.1 duplications in 8 out of 765 patients of European descent with adult-onset TAAD compared with 4 of 4,569 controls matched for ethnicity (P = 5.0 * 10-5, OR = 12.2). The findings were replicated in an independent cohort of 467 patients of European descent with TAAD (P = 0.005, OR = 14.7). Patients with 16p13.1 duplications were more likely to harbor a second rare CNV (P = 0.012) and to present with aortic dissections (P = 0.010) than patients without duplications. Duplications of 16p13.1 were identified in 2 of 130 patients with familial TAAD, but the duplications did not segregate with TAAD in the families. MYH11, a gene known to predispose to TAAD, lies in the duplicated region of 16p13.1, and increased MYH11 expression was found in aortic tissues from TAAD patients with 16p13.1 duplications compared with control aortas. These data suggest chromosome 16p13.1 duplications confer a risk for TAAD in addition to the established risk for neuropsychiatric disorders. It also indicates that recurrent CNVs may predispose to disorders involving more than one organ system, an observation critical to the understanding of the role of recurrent CNVs in human disease and a finding that may be common to other recurrent CNVs involving multiple genes. PMID- 21698136 TI - How chromatin is remodelled during DNA repair of UV-induced DNA damage in Saccharomyces cerevisiae. AB - Global genome nucleotide excision repair removes DNA damage from transcriptionally silent regions of the genome. Relatively little is known about the molecular events that initiate and regulate this process in the context of chromatin. We've shown that, in response to UV radiation-induced DNA damage, increased histone H3 acetylation at lysine 9 and 14 correlates with changes in chromatin structure, and these alterations are associated with efficient global genome nucleotide excision repair in yeast. These changes depend on the presence of the Rad16 protein. Remarkably, constitutive hyperacetylation of histone H3 can suppress the requirement for Rad7 and Rad16, two components of a global genome repair complex, during repair. This reveals the connection between histone H3 acetylation and DNA repair. Here, we investigate how chromatin structure is modified following UV irradiation to facilitate DNA repair in yeast. Using a combination of chromatin immunoprecipitation to measure histone acetylation levels, histone acetylase occupancy in chromatin, MNase digestion, or restriction enzyme endonuclease accessibility assays to analyse chromatin structure, and finally nucleotide excision repair assays to examine DNA repair, we demonstrate that global genome nucleotide excision repair drives UV-induced chromatin remodelling by controlling histone H3 acetylation levels in chromatin. The concerted action of the ATPase and C3HC4 RING domains of Rad16 combine to regulate the occupancy of the histone acetyl transferase Gcn5 on chromatin in response to UV damage. We conclude that the global genome repair complex in yeast regulates UV-induced histone H3 acetylation by controlling the accessibility of the histone acetyl transferase Gcn5 in chromatin. The resultant changes in histone H3 acetylation promote chromatin remodelling necessary for efficient repair of DNA damage. Recent evidence suggests that GCN5 plays a role in NER in human cells. Our work provides important insight into how GG-NER operates in chromatin. PMID- 21698137 TI - A Genome-Wide RNAi Screen for Factors Involved in Neuronal Specification in Caenorhabditis elegans. AB - One of the central goals of developmental neurobiology is to describe and understand the multi-tiered molecular events that control the progression of a fertilized egg to a terminally differentiated neuron. In the nematode Caenorhabditis elegans, the progression from egg to terminally differentiated neuron has been visually traced by lineage analysis. For example, the two gustatory neurons ASEL and ASER, a bilaterally symmetric neuron pair that is functionally lateralized, are generated from a fertilized egg through an invariant sequence of 11 cellular cleavages that occur stereotypically along specific cleavage planes. Molecular events that occur along this developmental pathway are only superficially understood. We take here an unbiased, genome-wide approach to identify genes that may act at any stage to ensure the correct differentiation of ASEL. Screening a genome-wide RNAi library that knocks-down 18,179 genes (94% of the genome), we identified 245 genes that affect the development of the ASEL neuron, such that the neuron is either not generated, its fate is converted to that of another cell, or cells from other lineage branches now adopt ASEL fate. We analyze in detail two factors that we identify from this screen: (1) the proneural gene hlh-14, which we find to be bilaterally expressed in the ASEL/R lineages despite their asymmetric lineage origins and which we find is required to generate neurons from several lineage branches including the ASE neurons, and (2) the COMPASS histone methyltransferase complex, which we find to be a critical embryonic inducer of ASEL/R asymmetry, acting upstream of the previously identified miRNA lsy-6. Our study represents the first comprehensive, genome-wide analysis of a single neuronal cell fate decision. The results of this analysis provide a starting point for future studies that will eventually lead to a more complete understanding of how individual neuronal cell types are generated from a single-cell embryo. PMID- 21698138 TI - A novel approach to selectively target neuronal subpopulations reveals genetic pathways that regulate tangential migration in the vertebrate hindbrain. AB - Vertebrate genes often play functionally distinct roles in different subsets of cells; however, tools to study the cell-specific function of gene products are poorly developed. Therefore, we have established a novel mouse model that enables the visualization and manipulation of defined subpopulations of neurons. To demonstrate the power of our system, we dissected genetic cascades in which Pax6 is central to control tangentially migrating neurons of the mouse brainstem. Several Pax6 downstream genes were identified and their function was analyzed by over-expression and knock-down experiments. One of these, Pou4f2, induces a prolonged midline arrest of growth cones to influence the proportion of ipsilaterally versus contralaterally settling neurons. These results demonstrate that our approach serves as a versatile tool to study the function of genes involved in cell migration, axonal pathfinding, and patterning processes. Our model will also serve as a general tool to specifically over-express any gene in a defined subpopulation of neurons and should easily be adapted to a wide range of applications. PMID- 21698139 TI - Within-genome evolution of REPINs: a new family of miniature mobile DNA in bacteria. AB - Repetitive sequences are a conserved feature of many bacterial genomes. While first reported almost thirty years ago, and frequently exploited for genotyping purposes, little is known about their origin, maintenance, or processes affecting the dynamics of within-genome evolution. Here, beginning with analysis of the diversity and abundance of short oligonucleotide sequences in the genome of Pseudomonas fluorescens SBW25, we show that over-represented short sequences define three distinct groups (GI, GII, and GIII) of repetitive extragenic palindromic (REP) sequences. Patterns of REP distribution suggest that closely linked REP sequences form a functional replicative unit: REP doublets are over represented, randomly distributed in extragenic space, and more highly conserved than singlets. In addition, doublets are organized as inverted repeats, which together with intervening spacer sequences are predicted to form hairpin structures in ssDNA or mRNA. We refer to these newly defined entities as REPINs (REP doublets forming hairpins) and identify short reads from population sequencing that reveal putative transposition intermediates. The proximal relationship between GI, GII, and GIII REPINs and specific REP-associated tyrosine transposases (RAYTs), combined with features of the putative transposition intermediate, suggests a mechanism for within-genome dissemination. Analysis of the distribution of REPs in a range of RAYT-containing bacterial genomes, including Escherichia coli K-12 and Nostoc punctiforme, show that REPINs are a widely distributed, but hitherto unrecognized, family of miniature non autonomous mobile DNA. PMID- 21698140 TI - Trade-off between bile resistance and nutritional competence drives Escherichia coli diversification in the mouse gut. AB - Bacterial diversification is often observed, but underlying mechanisms are difficult to disentangle and remain generally unknown. Moreover, controlled diversification experiments in ecologically relevant environments are lacking. We studied bacterial diversification in the mammalian gut, one of the most complex bacterial environments, where usually hundreds of species and thousands of bacterial strains stably coexist. Herein we show rapid genetic diversification of an Escherichia coli strain upon colonisation of previously germ-free mice. In addition to the previously described mutations in the EnvZ/OmpR operon, we describe the rapid and systematic selection of mutations in the flagellar flhDC operon and in malT, the transcriptional activator of the maltose regulon. Moreover, within each mouse, the three mutant types coexisted at different levels after one month of colonisation. By combining in vivo studies and determination of the fitness advantages of the selected mutations in controlled in vitro experiments, we provide evidence that the selective forces that drive E. coli diversification in the mouse gut are the presence of bile salts and competition for nutrients. Altogether our results indicate that a trade-off between stress resistance and nutritional competence generates sympatric diversification of the gut microbiota. These results illustrate how experimental evolution in natural environments enables identification of both the selective pressures that organisms face in their natural environment and the diversification mechanisms. PMID- 21698141 TI - Differential effects of MYH9 and APOL1 risk variants on FRMD3 Association with Diabetic ESRD in African Americans. AB - Single nucleotide polymorphisms (SNPs) in MYH9 and APOL1 on chromosome 22 (c22) are powerfully associated with non-diabetic end-stage renal disease (ESRD) in African Americans (AAs). Many AAs diagnosed with type 2 diabetic nephropathy (T2DN) have non-diabetic kidney disease, potentially masking detection of DN genes. Therefore, genome-wide association analyses were performed using the Affymetrix SNP Array 6.0 in 966 AA with T2DN and 1,032 non-diabetic, non nephropathy (NDNN) controls, with and without adjustment for c22 nephropathy risk variants. No associations were seen between FRMD3 SNPs and T2DN before adjusting for c22 variants. However, logistic regression analysis revealed seven FRMD3 SNPs significantly interacting with MYH9-a finding replicated in 640 additional AA T2DN cases and 683 NDNN controls. Contrasting all 1,592 T2DN cases with all 1,671 NDNN controls, FRMD3 SNPs appeared to interact with the MYH9 E1 haplotype (e.g., rs942280 interaction p-value = 9.3E-7 additive; odds ratio [OR] 0.67). FRMD3 alleles were associated with increased risk of T2DN only in subjects lacking two MYH9 E1 risk haplotypes (rs942280 OR = 1.28), not in MYH9 E1 risk allele homozygotes (rs942280 OR = 0.80; homogeneity p-value = 4.3E-4). Effects were weaker stratifying on APOL1. FRMD3 SNPS were associated with T2DN, not type 2 diabetes per se, comparing AAs with T2DN to those with diabetes lacking nephropathy. T2DN-associated FRMD3 SNPs were detectable in AAs only after accounting for MYH9, with differential effects for APOL1. These analyses reveal a role for FRMD3 in AA T2DN susceptibility and accounting for c22 nephropathy risk variants can assist in detecting DN susceptibility genes. PMID- 21698142 TI - Parallel adaptive divergence among geographically diverse human populations. AB - Few genetic differences between human populations conform to the classic model of positive selection, in which a newly arisen mutation rapidly approaches fixation in one lineage, suggesting that adaptation more commonly occurs via moderate changes in standing variation at many loci. Detecting and characterizing this type of complex selection requires integrating individually ambiguous signatures across genomically and geographically extensive data. Here, we develop a novel approach to test the hypothesis that selection has favored modest divergence at particular loci multiple times in independent human populations. We find an excess of SNPs showing non-neutral parallel divergence, enriched for genic and nonsynonymous polymorphisms in genes encompassing diverse and often disease related functions. Repeated parallel evolution in the same direction suggests common selective pressures in disparate habitats. We test our method with extensive coalescent simulations and show that it is robust to a wide range of demographic events. Our results demonstrate phylogenetically orthogonal patterns of local adaptation caused by subtle shifts at many widespread polymorphisms that likely underlie substantial phenotypic diversity. PMID- 21698143 TI - The role of response elements organization in transcription factor selectivity: the IFN-beta enhanceosome example. AB - What is the mechanism through which transcription factors (TFs) assemble specifically along the enhancer DNA? The IFN-beta enhanceosome provides a good model system: it is small; its components' crystal structures are available; and there are biochemical and cellular data. In the IFN-beta enhanceosome, there are few protein-protein interactions even though consecutive DNA response elements (REs) overlap. Our molecular dynamics (MD) simulations on different motif combinations from the enhanceosome illustrate that cooperativity is achieved via unique organization of the REs: specific binding of one TF can enhance the binding of another TF to a neighboring RE and restrict others, through overlap of REs; the order of the REs can determine which complexes will form; and the alternation of consensus and non-consensus REs can regulate binding specificity by optimizing the interactions among partners. Our observations offer an explanation of how specificity and cooperativity can be attained despite the limited interactions between neighboring TFs on the enhancer DNA. To date, when addressing selective TF binding, attention has largely focused on RE sequences. Yet, the order of the REs on the DNA and the length of the spacers between them can be a key factor in specific combinatorial assembly of the TFs on the enhancer and thus in function. Our results emphasize cooperativity via RE binding sites organization. PMID- 21698144 TI - Mechanisms for the evolution of a derived function in the ancestral glucocorticoid receptor. AB - Understanding the genetic, structural, and biophysical mechanisms that caused protein functions to evolve is a central goal of molecular evolutionary studies. Ancestral sequence reconstruction (ASR) offers an experimental approach to these questions. Here we use ASR to shed light on the earliest functions and evolution of the glucocorticoid receptor (GR), a steroid-activated transcription factor that plays a key role in the regulation of vertebrate physiology. Prior work showed that GR and its paralog, the mineralocorticoid receptor (MR), duplicated from a common ancestor roughly 450 million years ago; the ancestral functions were largely conserved in the MR lineage, but the functions of GRs-reduced sensitivity to all hormones and increased selectivity for glucocorticoids-are derived. Although the mechanisms for the evolution of glucocorticoid specificity have been identified, how reduced sensitivity evolved has not yet been studied. Here we report on the reconstruction of the deepest ancestor in the GR lineage (AncGR1) and demonstrate that GR's reduced sensitivity evolved before the acquisition of restricted hormone specificity, shortly after the GR-MR split. Using site-directed mutagenesis, X-ray crystallography, and computational analyses of protein stability to recapitulate and determine the effects of historical mutations, we show that AncGR1's reduced ligand sensitivity evolved primarily due to three key substitutions. Two large-effect mutations weakened hydrogen bonds and van der Waals interactions within the ancestral protein, reducing its stability. The degenerative effect of these two mutations is extremely strong, but a third permissive substitution, which has no apparent effect on function in the ancestral background and is likely to have occurred first, buffered the effects of the destabilizing mutations. Taken together, our results highlight the potentially creative role of substitutions that partially degrade protein structure and function and reinforce the importance of permissive mutations in protein evolution. PMID- 21698145 TI - Fish oil enhances recovery of intestinal microbiota and epithelial integrity in chronic rejection of intestinal transplant. AB - BACKGROUND: The intestinal chronic rejection (CR) is the major limitation to long term survival of transplanted organs. This study aimed to investigate the interaction between intestinal microbiota and epithelial integrity in chronic rejection of intestinal transplantation, and to find out whether fish oil enhances recovery of intestinal microbiota and epithelial integrity. METHODS/PRINCIPAL FINDINGS: The luminal and mucosal microbiota composition of CR rats were characterized by DGGE analysis at 190 days after intestinal transplant. The specific bacterial species were determined by sequence analysis. Furthermore, changes in the localization of intestinal TJ proteins were examined by immunofluorescent staining. PCR-DGGE analysis revealed that gut microbiota in CR rats had a shift towards Escherichia coli, Bacteroides spp and Clostridium spp and a decrease in the abundance of Lactobacillales bacteria in the intestines. Fish oil supplementation could enhance the recovery of gut microbiota, showing a significant decrease of gut bacterial proportions of E. coli and Bacteroides spp and an increase of Lactobacillales spp. In addition, CR rats showed pronounced alteration of tight junction, depicted by marked changes in epithelial cell ultrastructure and redistribution of occuldin and claudins as well as disruption in TJ barrier function. Fish oil administration ameliorated disruption of epithelial integrity in CR, which was associated with an improvement of the mucosal structure leading to improved tight junctions. CONCLUSIONS/SIGNIFICANCE: Our study have presented novel evidence that fish oil is involved in the maintenance of epithelial TJ integrity and recovery of gut microbiota, which may have therapeutic potential against CR in intestinal transplantation. PMID- 21698146 TI - The association between household socioeconomic position and prevalent tuberculosis in Zambia: a case-control study. AB - BACKGROUND: Although historically tuberculosis (TB) has been associated with poverty, few analytical studies from developing countries have tried to: 1. assess the relative impact of poverty on TB after the emergence of HIV; 2. explore the causal mechanism underlying this association; and 3. estimate how many cases of TB could be prevented by improving household socioeconomic position (SEP). METHODS AND FINDINGS: We undertook a case-control study nested within a population-based TB and HIV prevalence survey conducted in 2005-2006 in two Zambian communities. Cases were defined as persons (15+ years of age) culture positive for M. tuberculosis. Controls were randomly drawn from the TB-free participants enrolled in the prevalence survey. We developed a composite index of household SEP combining variables accounting for four different domains of household SEP. The analysis of the mediation pathway between household SEP and TB was driven by a pre-defined conceptual framework. Adjusted Population Attributable Fractions (aPAF) were estimated. Prevalent TB was significantly associated with lower household SEP [aOR = 6.2, 95%CI: 2.0-19.2 and aOR = 3.4, 95%CI: 1.8-7.6 respectively for low and medium household SEP compared to high]. Other risk factors for prevalent TB included having a diet poor in proteins [aOR = 3.1, 95%CI: 1.1-8.7], being HIV positive [aOR = 3.1, 95%CI: 1.7-5.8], not BCG vaccinated [aOR = 7.7, 95%CI: 2.8-20.8], and having a history of migration [aOR = 5.2, 95%CI: 2.7-10.2]. These associations were not confounded by household SEP. The association between household SEP and TB appeared to be mediated by inadequate consumption of protein food. Approximately the same proportion of cases could be attributed to this variable and HIV infection (aPAF = 42% and 36%, respectively). CONCLUSIONS: While the fight against HIV remains central for TB control, interventions addressing low household SEP and, especially food availability, may contribute to strengthen our control efforts. PMID- 21698147 TI - Up-regulated Dicer expression in patients with cutaneous melanoma. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs (18-24 nucleotides) that have recently been shown to regulate gene expression during cancer progression. Dicer, a central enzyme in the multi-component miRNA biogenesis pathway, is involved in cutting precursor miRNAs to functionally mature forms. Emerging evidence shows that Dicer expression is deregulated in some human malignancies and it correlates with tumor progression, yet this role has not yet been investigated in skin cancers. METHODS AND FINDINGS: Using an anti-human monoclonal antibody against Dicer and immunohistochemistry, we compared the expression of Dicer protein among 404 clinically annotated controls and skin tumors consisting of melanocytic nevi (n = 71), a variety of melanomas (n = 223), carcinomas (n = 73) and sarcomas (n = 12). Results showed a cell-specific up regulated Dicer in 81% of cutaneous, 80% of acrolentiginous and 96% of metastatic melanoma specimens compared to carcinoma or sarcoma specimens (P<0.0001). The expression of Dicer was significantly higher in melanomas compared to benign melanocytic nevi (P<0.0001). In patients with cutaneous melanomas, Dicer up regulation was found to be significantly associated with an increased tumor mitotic index (P = 0.04), Breslow's depth of invasion (P = 0.03), nodal metastasis (P = 0.04) and a higher American Joint Committee on Caner (AJCC) clinical stage (P = 0.009). Using western blot analysis, we confirmed the cell specific up-regulation of Dicer protein in vitro. A pooled-analysis on mRNA profiling in cutaneous tumors showed up-regulation of Dicer at the RNA level in cutaneous melanoma, also showing deregulation of other enzymes that participate in the biogenesis and maturation of canonical miRNAs. CONCLUSIONS: Increased Dicer expression may be a clinically useful biomarker for patients with cutaneous melanoma. Understanding deregulation of Dicer and its influence on miRNA maturation is needed to predict the susceptibility of melanoma patients to miRNA based therapy in the future. PMID- 21698148 TI - Hydrogen bonding penalty upon ligand binding. AB - Ligand binding involves breakage of hydrogen bonds with water molecules and formation of new hydrogen bonds between protein and ligand. In this work, the change of hydrogen bonding energy in the binding process, namely hydrogen bonding penalty, is evaluated with a new method. The hydrogen bonding penalty can not only be used to filter unrealistic poses in docking, but also improve the accuracy of binding energy calculation. A new model integrated with hydrogen bonding penalty for free energy calculation gives a root mean square error of 0.7 kcal/mol on 74 inhibitors in the training set and of 1.1 kcal/mol on 64 inhibitors in the test set. Moreover, an application of hydrogen bonding penalty into a high throughput docking campaign for EphB4 inhibitors is presented, and remarkably, three novel scaffolds are discovered out of seven tested. The binding affinity and ligand efficiency of the most potent compound is about 300 nM and 0.35 kcal/mol per non-hydrogen atom, respectively. PMID- 21698149 TI - Significantly longer envelope V2 loops are characteristic of heterosexually transmitted subtype B HIV-1 in Trinidad. AB - BACKGROUND: In Trinidad and the wider Caribbean, subtype B Human Immunodeficiency Virus-type 1 (HIV-1B) overwhelmingly accounts for HIV infection among heterosexuals; this contrasts with the association of HIV-1B with homosexual transmission and injecting drug use globally. The HIV envelope contains genetic determinants of cell tropism and evasion from immune attack. In this study we investigate the genetic properties of the env V1-C4 of HIV-1B soon after transmission to Trinidadian heterosexuals. This will reveal distinctive genetic features of the strains that cause the HIV-1B epidemic in Trinidad and generate insights to better understand their properties. METHODOLOGY/PRINCIPAL FINDINGS: Quasispecies sampling was performed on the env V1-C4 of HIV-1B strains soon after transmission to heterosexual Trinidadians in a cohort of seroconverters. Phylogenetic relationships were determined for these quasispecies and the length and number of asparagine (N) linked glycosylation sites (NLGS) in their variable loops compared to that for HIV-1B globally. Signature amino acids within the constant domains of the env V1-C4 were identified for heterosexually transmitted HIV-1B from Trinidad relative to HIV-1B globally. HIV-1B obtained from Trinidadian heterosexuals soon after seroconversion had significantly longer V2 loops with one more glycosylation site, shorter V3 loops and no significant difference in V1 or V4 when compared to HIV-1B obtained soon after seroconversion from infected individuals in the rest of the world. HIV-1B soon after seroconversion and during chronic infection of Trinidadians was not significantly different, suggesting that distinctly long V2 loops are characteristic of HIV-1B in Trinidad. A threonine deletion at position 319 (T319-) along with the substitutions R315K and S440R were found to be distinctly associated with HIV-1B from Trinidad compared to HIV-1B globally. CONCLUSIONS: This finding of distinctive genetic features that are characteristic of HIV-1B strains from Trinidad is consistent with the Trinidad epidemic being established by a founder strain or closely related founder strains of HIV-1B. PMID- 21698150 TI - The IFN-gamma-inducible GTPase, Irga6, protects mice against Toxoplasma gondii but not against Plasmodium berghei and some other intracellular pathogens. AB - Clearance of infection with intracellular pathogens in mice involves interferon regulated GTPases of the IRG protein family. Experiments with mice genetically deficient in members of this family such as Irgm1(LRG-47), Irgm3(IGTP), and Irgd(IRG-47) has revealed a critical role in microbial clearance, especially for Toxoplasma gondii. The in vivo role of another member of this family, Irga6 (IIGP, IIGP1) has been studied in less detail. We investigated the susceptibility of two independently generated mouse strains deficient in Irga6 to in vivo infection with T. gondii, Mycobacterium tuberculosis, Leishmania mexicana, L. major, Listeria monocytogenes, Anaplasma phagocytophilum and Plasmodium berghei. Compared with wild-type mice, mice deficient in Irga6 showed increased susceptibility to oral and intraperitoneal infection with T. gondii but not to infection with the other organisms. Surprisingly, infection of Irga6-deficient mice with the related apicomplexan parasite, P. berghei, did not result in increased replication in the liver stage and no Irga6 (or any other IRG protein) was detected at the parasitophorous vacuole membrane in IFN-gamma-induced wild type cells infected with P. berghei in vitro. Susceptibility to infection with T. gondii was associated with increased mortality and reduced time to death, increased numbers of inflammatory foci in the brains and elevated parasite loads in brains of infected Irga6-deficient mice. In vitro, Irga6-deficient macrophages and fibroblasts stimulated with IFN-gamma were defective in controlling parasite replication. Taken together, our results implicate Irga6 in the control of infection with T. gondii and further highlight the importance of the IRG system for resistance to this pathogen. PMID- 21698152 TI - CCL21/CCR7 promotes G2/M phase progression via the ERK pathway in human non-small cell lung cancer cells. AB - C-C chemokine receptor 7 (CCR7) contributes to the survival of certain cancer cell lines, but its role in the proliferation of human non-small cell lung cancer (NSCLC) cells remains vague. Proliferation assays performed on A549 and H460 NSCLC cells using Cell Counting Kit-8 indicated that activation of CCR7 by its specific ligand, exogenous chemokine ligand 21 (CCL21), was associated with a significant linear increase in cell proliferation with duration of exposure to CCL21. The CCL21/CCR7 interaction significantly increased the fraction of cells in the G(2)/M phase of the cell cycle as measured by flow cytometry. In contrast, CCL21/CCR7 had no significant influence on the G(0)/G(1) and S phases. Western blot and real-time PCR indicated that CCL21/CCR7 significantly upregulated expression of cyclin A, cyclin B1, and cyclin-dependent kinase 1 (CDK1), which are related to the G(2)/M phase transition. The expression of cyclin D1 and cyclin E, which are related to the G(0)/G(1) and G(1)/S transitions, was not altered. The CCL21/CCR7 interaction significantly enhanced phosphorylation of extracellular signal-regulated kinase (P-ERK) but not Akt, as measured by Western blot. LY294002, a selective inhibitor of PI3K that prevents activation of the downstream Akt, did not weaken the effect of CCL21/CCR7 on P-ERK. Coimmunoprecipitation further confirmed that there was an interaction between P ERK and cyclin A, cyclin B1, or CDK1, particularly in the presence of CCL21. CCR7 small interfering RNA or PD98059, a selective inhibitor of MEK that disrupts the activation of downstream ERK, significantly abolished the effects of exogenous CCL21. These results suggest that CCL21/CCR7 contributes to the time-dependent proliferation of human NSCLC cells by upregulating cyclin A, cyclin B1, and CDK1 potentially via the ERK pathway. PMID- 21698151 TI - The loss of the p53 activator HIPK2 is responsible for galectin-3 overexpression in well differentiated thyroid carcinomas. AB - BACKGROUND: Galectin-3 (Gal-3) is an anti-apoptotic molecule involved in thyroid cells transformation. It is specifically overexpressed in thyroid tumour cells and is currently used as a preoperative diagnostic marker of thyroid malignancy. Gal-3 expression is downregulated by wt-p53 at the transcriptional level. In well differentiated thyroid carcinomas (WDTCs) there is an unexplained paradoxical concomitant expression of Gal-3 and wt-p53. HIPK2 is a co-regulator of different transcription factors, and modulates basic cellular processes mainly through the activation of wt-p53. Since we demonstrated that HIPK2 is involved in p53 mediated Gal-3 downregulation, we asked whether HIPK2 deficiency might be responsible for such paradoxical Gal-3 overexpression in WDTC. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed HIPK2 protein and mRNA levels, as well as loss of heterozygosity (LOH) at the HIPK2 locus (7q32-34), in thyroid tissue samples. HIPK2 protein levels were high in all follicular hyperplasias (FHs) analyzed. Conversely, HIPK2 was undetectable in 91.7% of papillary thyroid carcinomas (PTCs) and in 60.0% of follicular thyroid carcinomas (FTCs). HIPK2 mRNA levels were upregulated in FH compared to normal thyroid tissue (NTT), while PTC showed mean HIPK2 mRNA levels lower than FH and, in 61.5% of cases, also lower than NTT. We found LOH at HIPK-2 gene locus in 37.5% of PTCs, 14.3% of FTCs and 18.2% of follicular adenomas. To causally link these data with Gal-3 upregulation, we performed in vitro experiments, using the PTC-derived K1 cells, in which HIPK2 expression was manipulated by RNA interference (RNAi) or plasmid mediated overexpression. HIPK2 RNAi was associated with Gal-3 upregulation, while HIPK2 overexpression with Gal-3 downregulation. CONCLUSIONS/SIGNIFICANCE: Our results indicate that HIPK2 expression and function are impaired in WDTCs, in particular in PTCs, and that this event explains Gal-3 overexpression typically observed in these types of tumours. Therefore, HIPK2 can be considered as a new tumour suppressor gene for thyroid cancers. PMID- 21698153 TI - Alpha hemolysin induces an increase of erythrocytes calcium: a FLIM 2-photon phasor analysis approach. AB - alpha-Hemolysin (HlyA) from Escherichia coli is considered as the prototype of a family of toxins called RTX (repeat in toxin), a group of proteins that share genetic and structural features. HlyA is an important virulence factor in E. coli extraintestinal infections, such as meningitis, septicemia and urinary infections. High concentrations of the toxin cause the lysis of several cells such as erythrocytes, granulocytes, monocytes, endothelial and renal epithelial cells of different species. At low concentrations it induces the production of cytokines and apoptosis. Since many of the subcytolytic effects in other cells have been reported to be triggered by the increase of intracellular calcium, we followed the calcium concentration inside the erythrocytes while incubating with sublytic concentrations of HlyA. Calcium concentration was monitored using the calcium indicator Green 1, 2-photon excitation, and fluorescence lifetime imaging microscopy (FLIM). Data were analyzed using the phasor representation. In this report, we present evidence that, at sublytic concentrations, HlyA induces an increase of calcium concentration in rabbit erythrocytes in the first 10 s. Results are discussed in relation to the difficulties of measuring calcium concentrations in erythrocytes where hemoglobin is present, the contribution of the background and the heterogeneity of the response observed in individual cells. PMID- 21698154 TI - A dual infection pseudorabies virus conditional reporter approach to identify projections to collateralized neurons in complex neural circuits. AB - Replication and transneuronal transport of pseudorabies virus (PRV) are widely used to define the organization of neural circuits in rodent brain. Here we report a dual infection approach that highlights connections to neurons that collateralize within complex networks. The method combines Cre recombinase (Cre) expression from a PRV recombinant (PRV-267) and Cre-dependent reporter gene expression from a second infecting strain of PRV (PRV-263). PRV-267 expresses both Cre and a monomeric red fluorescent protein (mRFP) fused to viral capsid protein VP26 (VP26-mRFP) that accumulates in infected cell nuclei. PRV-263 carries a Brainbow cassette and expresses a red (dTomato) reporter that fills the cytoplasm. However, in the presence of Cre, the dTomato gene is recombined from the cassette, eliminating expression of the red reporter and liberating expression of either yellow (EYFP) or cyan (mCerulean) cytoplasmic reporters. We conducted proof-of-principle experiments using a well-characterized model in which separate injection of recombinant viruses into the left and right kidneys produces infection of neurons in the renal preautonomic network. Neurons dedicated to one kidney expressed the unique reporters characteristic of PRV-263 (cytoplasmic dTomato) or PRV-267 (nuclear VP26-mRFP). Dual infected neurons expressed VP26-mRFP and the cyan or yellow cytoplasmic reporters activated by Cre mediated recombination of the Brainbow cassette. Differential expression of cyan or yellow reporters in neurons lacking VP26-mRFP provided a unique marker of neurons synaptically connected to dual infected neurons, a synaptic relationship that cannot be distinguished using other dual infection tracing approaches. These data demonstrate Cre-enabled conditional reporter expression in polysynaptic circuits that permits the identification of collateralized neurons and their presynaptic partners. PMID- 21698155 TI - Enduring fluoride health hazard for the Vesuvius area population: the case of AD 79 Herculaneum. AB - BACKGROUND: The study of ancient skeletal pathologies can be adopted as a key tool in assessing and tracing several diseases from past to present times. Skeletal fluorosis, a chronic metabolic bone and joint disease causing excessive ossification and joint ankylosis, has been only rarely considered in differential diagnoses of palaeopathological lesions. Even today its early stages are misdiagnosed in endemic areas. METHODOLOGY/PRINCIPAL FINDINGS: Endemic fluorosis induced by high concentrations of fluoride in water and soils is a major health problem in several countries, particularly in volcanic areas. Here we describe for the first time the features of endemic fluorosis in the Herculaneum victims of the 79 AD eruption, resulting from long-term exposure to high levels of environmental fluoride which still occur today. CONCLUSIONS/SIGNIFICANCE: Our observations on morphological, radiological, histological and chemical skeletal and dental features of this ancient population now suggest that in this area fluorosis was already endemic in Roman times. This evidence merged with currently available epidemiologic data reveal for the Vesuvius area population a permanent fluoride health hazard, whose public health and socio-economic impact is currently underestimated. The present guidelines for fluoridated tap water might be reconsidered accordingly, particularly around Mt Vesuvius and in other fluoride hazard areas with high natural fluoride levels. PMID- 21698156 TI - M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis. AB - Heparan sulfate proteoglycans (HSPGs) play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS) mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1alpha, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis. PMID- 21698157 TI - Genome-wide linkage scan to identify loci associated with type 2 diabetes and blood lipid phenotypes in the Sikh Diabetes Study. AB - In this investigation, we have carried out an autosomal genome-wide linkage analysis to map genes associated with type 2 diabetes (T2D) and five quantitative traits of blood lipids including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and triglycerides in a unique family-based cohort from the Sikh Diabetes Study (SDS). A total of 870 individuals (526 male/344 female) from 321 families were successfully genotyped using 398 polymorphic microsatellite markers with an average spacing of 9.26 cM on the autosomes. Results of non-parametric multipoint linkage analysis using S(all) statistics (implemented in Merlin) did not reveal any chromosomal region to be significantly associated with T2D in this Sikh cohort. However, linkage analysis for lipid traits using QTL-ALL analysis revealed promising linkage signals with p<=0.005 for total cholesterol, LDL cholesterol, and HDL cholesterol at chromosomes 5p15, 9q21, 10p11, 10q21, and 22q13. The most significant signal (p = 0.0011) occurred at 10q21.2 for HDL cholesterol. We also observed linkage signals for total cholesterol at 22q13.32 (p = 0.0016) and 5p15.33 (p = 0.0031) and for LDL cholesterol at 10p11.23 (p = 0.0045). Interestingly, some of linkage regions identified in this Sikh population coincide with plausible candidate genes reported in recent genome-wide association and meta-analysis studies for lipid traits. Our study provides the first evidence of linkage for loci associated with quantitative lipid traits at four chromosomal regions in this Asian Indian population from Punjab. More detailed examination of these regions with more informative genotyping, sequencing, and functional studies should lead to rapid detection of novel targets of therapeutic importance. PMID- 21698158 TI - Oncogenic CagA promotes gastric cancer risk via activating ERK signaling pathways: a nested case-control study. AB - BACKGROUND: CagA cellular interaction via activation of the ERK signaling pathway may be a starting point in the development of gastric cancer. This study aimed to evaluate whether genes involved in ERK downstream signaling pathways activated by CagA are susceptible genetic markers for gastric cancer. METHODS: In the discovery phase, a total of 580 SNPs within +/-5 kbp of 30 candidate genes were genotyped to examine an association with gastric cancer risk in the Korean Multi center Cancer Cohort (100 incident gastric cancer case-control sets). The most significant SNPs (raw or permutated p value<0.02) identified in the discovery analysis were re-evaluated in the extension phase using unconditional logistic regression model (400 gastric cancer case-control sets). Combined analyses including pooled- and meta-analysis were conducted to summarize all the results. RESULTS: 24 SNPs in eight genes (ERK, Dock180, C3G, Rap1, Src, CrkL, Mek and Crk) were significantly associated with gastric cancer risk in the individual SNP analyses in the discovery phase (p<0.05). In the extension analyses, ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 showed marginally significant gene dose effects for gastric cancer. Consistently, final combined analysis presented the SNPs as significantly associated with gastric cancer risk (OR = 1.56, [95% CI: 1.19-2.06], OR = 0.61, [95% CI: 0.43-0.87], OR = 0.59, [95% CI: 0.54-0.76], respectively). CONCLUSIONS: Our findings suggest that ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 are genetic determinants in gastric carcinogenesis. PMID- 21698160 TI - The composite insect trap: an innovative combination trap for biologically diverse sampling. AB - Documentation of insect diversity is an important component of the study of biodiversity, community dynamics, and global change. Accurate identification of insects usually requires catching individuals for close inspection. However, because insects are so diverse, most trapping methods are specifically tailored to a particular taxonomic group. For scientists interested in the broadest possible spectrum of insect taxa, whether for long term monitoring of an ecosystem or for a species inventory, the use of several different trapping methods is usually necessary. We describe a novel composite method for capturing a diverse spectrum of insect taxa. The Composite Insect Trap incorporates elements from four different existing trapping methods: the cone trap, malaise trap, pan trap, and flight intercept trap. It is affordable, resistant, easy to assemble and disassemble, and collects a wide variety of insect taxa. Here we describe the design, construction, and effectiveness of the Composite Insect Trap tested during a study of insect diversity. The trap catches a broad array of insects and can eliminate the need to use multiple trap types in biodiversity studies. We propose that the Composite Insect Trap is a useful addition to the trapping methods currently available to ecologists and will be extremely effective for monitoring community level dynamics, biodiversity assessment, and conservation and restoration work. In addition, the Composite Insect Trap will be of use to other insect specialists, such as taxonomists, that are interested in describing the insect taxa in a given area. PMID- 21698159 TI - Heat stress causes spatially-distinct membrane re-modelling in K562 leukemia cells. AB - Cellular membranes respond rapidly to various environmental perturbations. Previously we showed that modulations in membrane fluidity achieved by heat stress (HS) resulted in pronounced membrane organization alterations which could be intimately linked to the expression and cellular distribution of heat shock proteins. Here we examine heat-induced membrane changes using several visualisation methods. With Laurdan two-photon microscopy we demonstrate that, in contrast to the enhanced formation of ordered domains in surface membranes, the molecular disorder is significantly elevated within the internal membranes of cells preexposed to mild HS. These results were compared with those obtained by anisotropy, fluorescence lifetime and electron paramagnetic resonance measurements. All probes detected membrane changes upon HS. However, the structurally different probes revealed substantially distinct alterations in membrane heterogeneity. These data call attention to the careful interpretation of results obtained with only a single label. Subtle changes in membrane microstructure in the decision-making of thermal cell killing could have potential application in cancer therapy. PMID- 21698161 TI - Lipid-induced peroxidation in the intestine is involved in glucose homeostasis imbalance in mice. AB - BACKGROUND: Daily variations in lipid concentrations in both gut lumen and blood are detected by specific sensors located in the gastrointestinal tract and in specialized central areas. Deregulation of the lipid sensors could be partly involved in the dysfunction of glucose homeostasis. The study aimed at comparing the effect of Medialipid (ML) overload on insulin secretion and sensitivity when administered either through the intestine or the carotid artery in mice. METHODOLOGY/PRINCIPAL FINDINGS: An indwelling intragastric or intracarotid catheter was installed in mice and ML or an isocaloric solution was infused over 24 hours. Glucose and insulin tolerance and vagus nerve activity were assessed. Some mice were treated daily for one week with the anti-lipid peroxidation agent aminoguanidine prior to the infusions and tests. The intestinal but not the intracarotid infusion of ML led to glucose and insulin intolerance when compared with controls. The intestinal ML overload induced lipid accumulation and increased lipid peroxidation as assessed by increased malondialdehyde production within both jejunum and duodenum. These effects were associated with the concomitant deregulation of vagus nerve. Administration of aminoguanidine protected against the effects of lipid overload and normalized glucose homeostasis and vagus nerve activity. CONCLUSIONS/SIGNIFICANCE: Lipid overload within the intestine led to deregulation of gastrointestinal lipid sensing that in turn impaired glucose homeostasis through changes in autonomic nervous system activity. PMID- 21698162 TI - Zebrafish reproduction: revisiting in vitro fertilization to increase sperm cryopreservation success. AB - Although conventional cryopreservation is a proven method for long-term, safe storage of genetic material, protocols used by the zebrafish community are not standardized and yield inconsistent results, thereby putting the security of many genotypes in individual laboratories and stock centers at risk. An important challenge for a successful zebrafish sperm cryopreservation program is the large variability in the post-thaw in vitro fertilization success (0 to 80%). But how much of this variability was due to the reproductive traits of the in vitro fertilization process, and not due to the cryopreservation process? These experiments only assessed the in vitro process with fresh sperm, but yielded the basic metrics needed for successful in vitro fertilization using cryopreserved sperm, as well. We analyzed the reproductive traits for zebrafish males with a strict body condition range. It did not correlate with sperm volume, or motility (P>0.05), but it did correlate with sperm concentration. Younger males produced more concentrated sperm (P<0.05). To minimize the wastage of sperm during the in vitro fertilization process, 10(6) cells/ml was the minimum sperm concentration needed to achieve an in vitro fertilization success of >= 70%. During the in vitro process, pooling sperm did not reduce fertilization success (P>0.05), but pooling eggs reduced it by approximately 30 to 50% (P<0.05). This reduction in fertilization success was due not to the pooling of the females' eggs, but to the type of tools used to handle the eggs. Recommendations to enhance the in vitro process for zebrafish include: 1) using males of a body condition closer to 1.5 for maximal sperm concentration; 2) minimizing sperm wastage by using a working sperm concentration of 10(6) motile cells/ml for in vitro fertilization; and 3) never using metal or sharp-edged tools to handle eggs prior to fertilization. PMID- 21698163 TI - Informational gene phylogenies do not support a fourth domain of life for nucleocytoplasmic large DNA viruses. AB - Mimivirus is a nucleocytoplasmic large DNA virus (NCLDV) with a genome size (1.2 Mb) and coding capacity ( 1000 genes) comparable to that of some cellular organisms. Unlike other viruses, Mimivirus and its NCLDV relatives encode homologs of broadly conserved informational genes found in Bacteria, Archaea, and Eukaryotes, raising the possibility that they could be placed on the tree of life. A recent phylogenetic analysis of these genes showed the NCLDVs emerging as a monophyletic group branching between Eukaryotes and Archaea. These trees were interpreted as evidence for an independent "fourth domain" of life that may have contributed DNA processing genes to the ancestral eukaryote. However, the analysis of ancient evolutionary events is challenging, and tree reconstruction is susceptible to bias resulting from non-phylogenetic signals in the data. These include compositional heterogeneity and homoplasy, which can lead to the spurious grouping of compositionally-similar or fast-evolving sequences. Here, we show that these informational gene alignments contain both significant compositional heterogeneity and homoplasy, which were not adequately modelled in the original analysis. When we use more realistic evolutionary models that better fit the data, the resulting trees are unable to reject a simple null hypothesis in which these informational genes, like many other NCLDV genes, were acquired by horizontal transfer from eukaryotic hosts. Our results suggest that a fourth domain is not required to explain the available sequence data. PMID- 21698164 TI - Trial-by-trial changes in a priori informational value of external cues and subjective expectancies in human auditory attention. AB - BACKGROUND: Preparatory activity based on a priori probabilities generated in previous trials and subjective expectancies would produce an attentional bias. However, preparation can be correct (valid) or incorrect (invalid) depending on the actual target stimulus. The alternation effect refers to the subjective expectancy that a target will not be repeated in the same position, causing RTs to increase if the target location is repeated. The present experiment, using the Posner's central cue paradigm, tries to demonstrate that not only the credibility of the cue, but also the expectancy about the next position of the target are changed in a trial by trial basis. Sequences of trials were analyzed. RESULTS: The results indicated an increase in RT benefits when sequences of two and three valid trials occurred. The analysis of errors indicated an increase in anticipatory behavior which grows as the number of valid trials is increased. On the other hand, there was also an RT benefit when a trial was preceded by trials in which the position of the target changed with respect to the current trial (alternation effect). Sequences of two alternations or two repetitions were faster than sequences of trials in which a pattern of repetition or alternation is broken. CONCLUSIONS: Taken together, these results suggest that in Posner's central cue paradigm, and with regard to the anticipatory activity, the credibility of the external cue and of the endogenously anticipated patterns of target location are constantly updated. The results suggest that Bayesian rules are operating in the generation of anticipatory activity as a function of the previous trial's outcome, but also on biases or prior beliefs like the "gambler fallacy". PMID- 21698165 TI - Predator-induced demographic shifts in coral reef fish assemblages. AB - In recent years, it has become apparent that human impacts have altered community structure in coastal and marine ecosystems worldwide. Of these, fishing is one of the most pervasive, and a growing body of work suggests that fishing can have strong effects on the ecology of target species, especially top predators. However, the effects of removing top predators on lower trophic groups of prey fishes are less clear, particularly in highly diverse and trophically complex coral reef ecosystems. We examined patterns of abundance, size structure, and age based demography through surveys and collection-based studies of five fish species from a variety of trophic levels at Kiritimati and Palmyra, two nearby atolls in the Northern Line Islands. These islands have similar biogeography and oceanography, and yet Kiritimati has ~10,000 people with extensive local fishing while Palmyra is a US National Wildlife Refuge with no permanent human population, no fishing, and an intact predator fauna. Surveys indicated that top predators were relatively larger and more abundant at unfished Palmyra, while prey functional groups were relatively smaller but showed no clear trends in abundance as would be expected from classic trophic cascades. Through detailed analyses of focal species, we found that size and longevity of a top predator were lower at fished Kiritimati than at unfished Palmyra. Demographic patterns also shifted dramatically for 4 of 5 fish species in lower trophic groups, opposite in direction to the top predator, including decreases in average size and longevity at Palmyra relative to Kiritimati. Overall, these results suggest that fishing may alter community structure in complex and non-intuitive ways, and that indirect demographic effects should be considered more broadly in ecosystem based management. PMID- 21698166 TI - Genomic analysis of individual differences in ethanol drinking: evidence for non genetic factors in C57BL/6 mice. AB - Genetic analysis of factors affecting risk to develop excessive ethanol drinking has been extensively studied in humans and animal models for over 20 years. However, little progress has been made in determining molecular mechanisms underlying environmental or non-genetic events contributing to variation in ethanol drinking. Here, we identify persistent and substantial variation in ethanol drinking behavior within an inbred mouse strain and utilize this model to identify gene networks influencing such "non-genetic" variation in ethanol intake. C57BL/6NCrl mice showed persistent inter-individual variation of ethanol intake in a two-bottle choice paradigm over a three-week period, ranging from less than 1 g/kg to over 14 g/kg ethanol in an 18 h interval. Differences in sweet or bitter taste susceptibility or litter effects did not appreciably correlate with ethanol intake variation. Whole genome microarray expression analysis in nucleus accumbens, prefrontal cortex and ventral midbrain region of individual animals identified gene expression patterns correlated with ethanol intake. Results included several gene networks previously implicated in ethanol behaviors, such as glutamate signaling, BDNF and genes involved in synaptic vesicle function. Additionally, genes functioning in epigenetic chromatin or DNA modifications such as acetylation and/or methylation also had expression patterns correlated with ethanol intake. In verification for the significance of the expression findings, we found that a histone deacetylase inhibitor, trichostatin A, caused an increase in 2-bottle ethanol intake. Our results thus implicate specific brain regional gene networks, including chromatin modification factors, as potentially important mechanisms underlying individual variation in ethanol intake. PMID- 21698167 TI - Activated TLR signaling in atherosclerosis among women with lower Framingham risk score: the multi-ethnic study of atherosclerosis. AB - BACKGROUND: Atherosclerosis is the leading cause of cardiovascular disease (CVD). Traditional risk factors can be used to identify individuals at high risk for developing CVD and are generally associated with the extent of atherosclerosis; however, substantial numbers of individuals at low or intermediate risk still develop atherosclerosis. RESULTS: A case-control study was performed using microarray gene expression profiling of peripheral blood from 119 healthy women in the Multi-Ethnic Study of Atherosclerosis cohort aged 50 or above. All participants had low (<10%) to intermediate (10% to 20%) predicted Framingham risk; cases (N = 48) had coronary artery calcium (CAC) score >100 and carotid intima-media thickness (IMT) >1.0 mm, whereas controls (N = 71) had CAC<10 and IMT <0.65 mm. We identified two major expression profiles significantly associated with significant atherosclerosis (odds ratio 4.85; P<0.001); among those with Framingham risk score <10%, the odds ratio was 5.30 (P<0.001). Ontology analysis of the gene signature reveals activation of a major innate immune pathway, toll-like receptors and IL-1R signaling, in individuals with significant atherosclerosis. CONCLUSION: Gene expression profiles of peripheral blood may be a useful tool to identify individuals with significant burden of atherosclerosis, even among those with low predicted risk by clinical factors. Furthermore, our data suggest an intimate connection between atherosclerosis and the innate immune system and inflammation via TLR signaling in lower risk individuals. PMID- 21698168 TI - Human papillomavirus infection and anxiety: analyses in women with low-grade cervical cytological abnormalities unaware of their infection status. AB - BACKGROUND: Women testing positive for human papillomavirus (HPV) infection experience increased levels of anxiety that have been attributed to fears of stigmatization and developing cervical cancer. The objective of this study was to investigate the association between HPV infection and anxiety in women who were unaware they had been tested specifically for HPV, to determine if any anxiety experienced by HPV-positive women could be due to causes other than learning of test results. METHODS: This study was nested within a randomised controlled trial of management of women with abnormal cervical cytology conducted in the United Kingdom with recruitment between 1999 and 2002. At baseline, prior to having a sample taken for HPV testing, the results of which were not disclosed, women were assessed for anxiety using the Hospital Anxiety and Depression Scale and asked about fears of developing cervical cancer ("cancer worries"); this assessment was repeated at 12, 18, 24, and 30 months of follow-up. Logistic regression and generalized estimating equations were used for the cross-sectional (baseline) and longitudinal analyses, respectively. RESULTS: Among the 2842 participants, there was no association between HPV status and anxiety among white women. Among non white women, however, anxiety was less common among HPV-positive than HPV negative women (adjusted odds ratio 0.41, 95% confidence interval 0.22 to 0.77). Among non-smokers, cancer worry was more common in HPV-positive than HPV-negative women; the opposite association was observed among ex-smokers. CONCLUSIONS: Associations between HPV status and anxiety may be explained by factors other than learning of test results and may vary by ethnicity and lifestyle factors. PMID- 21698169 TI - Nontypable Haemophilus influenzae displays a prevalent surface structure molecular pattern in clinical isolates. AB - Non-typable Haemophilus influenzae (NTHi) is a gram negative pathogen that causes acute respiratory infections and is associated with the progression of chronic respiratory diseases. Previous studies have established the existence of a remarkable genetic variability among NTHi strains. In this study we show that, in spite of a high level of genetic heterogeneity, NTHi clinical isolates display a prevalent molecular feature, which could confer fitness during infectious processes. A total of 111 non-isogenic NTHi strains from an identical number of patients, isolated in two distinct geographical locations in the same period of time, were used to analyse nine genes encoding bacterial surface molecules, and revealed the existence of one highly prevalent molecular pattern (lgtF+, lic2A+, lic1D+, lic3A+, lic3B+, siaA-, lic2C+, ompP5+, oapA+) displayed by 94.6% of isolates. Such a genetic profile was associated with a higher bacterial resistance to serum mediated killing and enhanced adherence to human respiratory epithelial cells. PMID- 21698170 TI - The temporal development of fatty infiltrates in the neck muscles following whiplash injury: an association with pain and posttraumatic stress. AB - BACKGROUND: Radiological findings associated with poor recovery following whiplash injury remain elusive. Muscle fatty infiltrates (MFI) in the cervical extensors on magnetic resonance imaging (MRI) in patients with chronic pain have been observed. Their association with specific aspects of pain and psychological factors have yet to be explored longitudinally. MATERIALS AND FINDINGS: 44 subjects with whiplash injury were enrolled at 4 weeks post-injury and classified at 6 months using scores on the Neck Disability Index as recovered, mild and moderate/severe. A measure for MFI and patient self-report of pain, loss of cervical range of movement and posttraumatic stress disorder (PTSD) were collected at 4 weeks, 3 months and 6 months post-injury. The effects of time and group and the interaction of time by group on MFI were determined. We assessed the mediating effect of posttraumatic stress and cervical range of movement on the longitudinal relationship between initial pain intensity and MFI. There was no difference in MFI across all groups at enrollment. MFI values increased in the moderate/severe group and were significantly higher in comparison to the recovered and mild groups at 3 and 6 months. No differences in MFI values were found between the mild and recovered groups. Initial severity of PTSD symptoms mediated the relationship between pain intensity and MFI at 6 months. Initial ROM loss did not. CONCLUSIONS: MFI in the cervical extensors occur soon following whiplash injury and suggest the possibility for the occurrence of a more severe injury with subsequent PTSD in patients with persistent symptoms. PMID- 21698172 TI - Attentional window set by expected relevance of environmental signals. AB - The existence of an attentional window--a limited region in visual space at which attention is directed--has been invoked to explain why sudden visual onsets may or may not capture overt or covert attention. Here, we test the hypothesis that observers voluntarily control the size of this attentional window to regulate whether or not environmental signals can capture attention. We have used a novel approach to test this: participants eye-movements were tracked while they performed a search task that required dynamic gaze-shifts. During the search task, abrupt onsets were presented that cued the target positions at different levels of congruency. The participant knew these levels. We determined oculomotor capture efficiency for onsets that appeared at different viewing eccentricities. From these, we could derive the participant's attentional window size as a function of onset congruency. We find that the window was small during the presentation of low-congruency onsets, but increased monotonically in size with an increase in the expected congruency of the onsets. This indicates that the attentional window is under voluntary control and is set according to the expected relevance of environmental signals for the observer's momentary behavioral goals. Moreover, our approach provides a new and exciting method to directly measure the size of the attentional window. PMID- 21698171 TI - Phytosulfokine-alpha controls hypocotyl length and cell expansion in Arabidopsis thaliana through phytosulfokine receptor 1. AB - The disulfated peptide growth factor phytosulfokine-alpha (PSK-alpha) is perceived by LRR receptor kinases. In this study, a role for PSK signaling through PSK receptor PSKR1 in Arabidopsis thaliana hypocotyl cell elongation is established. Hypocotyls of etiolated pskr1-2 and pskr1-3 seedlings, but not of pskr2-1 seedlings were shorter than wt due to reduced cell elongation. Treatment with PSK-alpha did not promote hypocotyl growth indicating that PSK levels were saturating. Tyrosylprotein sulfotransferase (TPST) is responsible for sulfation and hence activation of the PSK precursor. The tpst-1 mutant displayed shorter hypocotyls with shorter cells than wt. Treatment of tpst-1 seedlings with PSK alpha partially restored elongation growth in a dose-dependent manner. Hypocotyl elongation was significantly enhanced in tpst-1 seedlings at nanomolar PSK-alpha concentrations. Cell expansion was studied in hypocotyl protoplasts. WT and pskr2 1 protoplasts expanded in the presence of PSK-alpha in a dose-dependent manner. By contrast, pskr1-2 and pskr1-3 protoplasts were unresponsive to PSK-alpha. Protoplast swelling in response to PSK-alpha was unaffected by ortho-vanadate, which inhibits the plasma membrane H(+)-ATPase. In maize (Zea mays L.), coleoptile protoplast expansion was similarly induced by PSK-alpha in a dose dependent manner and was dependent on the presence of K(+) in the media. In conclusion, PSK-alpha signaling of hypocotyl elongation and protoplast expansion occurs through PSKR1 and likely involves K(+) uptake, but does not require extracellular acidification by the plasma membrane H(+)-ATPase. PMID- 21698173 TI - Proximity of transmembrane segments 5 and 8 of the glutamate transporter GLT-1 inferred from paired cysteine mutagenesis. AB - BACKGROUND: GLT-1 is a glial glutamate transporter which maintains low synaptic concentrations of the excitatory neurotransmitter enabling efficient synaptic transmission. Based on the crystal structure of the bacterial homologue Glt(Ph), it has been proposed that the reentrant loop HP2, which connects transmembrane domains (TM) 7 and 8, moves to open and close access to the binding pocket from the extracellular medium. However the conformation change between TM5 and TM8 during the transport cycle is not clear yet. We used paired cysteine mutagenesis in conjunction with treatments with Copper(II)(1,10-Phenanthroline)(3) (CuPh), to verify the predicted proximity of residues located at these structural elements of GLT-1. METHODOLOGY/PRINCIPAL FINDINGS: To assess the proximity of transmembrane domain (TM) 5 relative to TM8 during transport by the glial glutamate transporter GLT-1/EAAT2, cysteine pairs were introduced at the extracellular ends of these structural elements. A complete inhibition of transport by Copper(II)(1,10-Phenanthroline)(3) is observed in the double mutants I295C/I463C and G297C/I463C, but not in the corresponding single mutants. Glutamate and potassium, both expected to increase the proportion of inward facing transporters, significantly protected against the inhibition of transport activity of I295C/I463C and G297C/I463C by CuPh. Transport by the double mutants I295C/I463C and G297C/I463C also was inhibited by Cd(2+). CONCLUSIONS/SIGNIFICANCE: Our results suggest that TM5 (Ile-295, Gly-297) is in close proximity to TM8 (Ile-463) in the mammalian transporter, and that the spatial relationship between these domains is altered during the transport cycle. PMID- 21698174 TI - Role of meprins to protect ileal mucosa of Crohn's disease patients from colonization by adherent-invasive E. coli. AB - Ileal lesions in Crohn's disease (CD) patients are colonized by pathogenic adherent-invasive Escherichia coli (AIEC) able to adhere to and invade intestinal epithelial cells (IEC), and to survive within macrophages. The interaction of AIEC with IEC depends on bacterial factors mainly type 1 pili, flagella, and outer membrane proteins. In humans, proteases can act as host defence mechanisms to counteract bacterial colonization. The protease meprin, composed of multimeric complexes of the two subunits alpha and beta, is abundantly expressed in IECs. Decreased levels of this protease correlate with the severity of the inflammation in patients with inflammatory bowel disease. The aim of the present study was to analyze the ability of meprin to modulate the interaction of AIEC with IECs. In patients with ileal CD we observed decreased levels of meprins, in particular that of meprin beta. Dose-dependent inhibition of the abilities of AIEC strain LF82 to adhere to and invade intestinal epithelial T84 cells was observed when bacteria were pre-treated with both exogenous meprin alpha and meprin beta. Dose dependent proteolytic degradation of type 1 pili was observed in the presence of active meprins, but not with heat-inactivated meprins, and pretreatment of AIEC bacteria with meprins impaired their ability to bind mannosylated host receptors and led to decreased secretion of the pro-inflammatory cytokine IL-8 by infected T84 cells. Thus, decreased levels of protective meprins as observed in CD patients may contribute to increased AIEC colonization. PMID- 21698176 TI - Potential misinterpretation of treatment effects due to use of odds ratios and logistic regression in randomized controlled trials. AB - BACKGROUND: In randomized controlled trials (RCTs), the odds ratio (OR) can substantially overestimate the risk ratio (RR) if the incidence of the outcome is over 10%. This study determined the frequency of use of ORs, the frequency of overestimation of the OR as compared with its accompanying RR in published RCTs, and we assessed how often regression models that calculate RRs were used. METHODS: We included 288 RCTs published in 2008 in five major general medical journals (Annals of Internal Medicine, British Medical Journal, Journal of the American Medical Association, Lancet, New England Journal of Medicine). If an OR was reported, we calculated the corresponding RR, and we calculated the percentage of overestimation by using the formula . RESULTS: Of 193 RCTs with a dichotomous primary outcome, 24 (12.4%) presented a crude and/or adjusted OR for the primary outcome. In five RCTs (2.6%), the OR differed more than 100% from its accompanying RR on the log scale. Forty-one of all included RCTs (n = 288; 14.2%) presented ORs for other outcomes, or for subgroup analyses. Nineteen of these RCTs (6.6%) had at least one OR that deviated more than 100% from its accompanying RR on the log scale. Of 53 RCTs that adjusted for baseline variables, 15 used logistic regression. Alternative methods to estimate RRs were only used in four RCTs. CONCLUSION: ORs and logistic regression are often used in RCTs and in many articles the OR did not approximate the RR. Although the authors did not explicitly misinterpret these ORs as RRs, misinterpretation by readers can seriously affect treatment decisions and policy making. PMID- 21698175 TI - Bayesian comparison of neurovascular coupling models using EEG-fMRI. AB - Functional magnetic resonance imaging (fMRI), with blood oxygenation level dependent (BOLD) contrast, is a widely used technique for studying the human brain. However, it is an indirect measure of underlying neuronal activity and the processes that link this activity to BOLD signals are still a topic of much debate. In order to relate findings from fMRI research to other measures of neuronal activity it is vital to understand the underlying neurovascular coupling mechanism. Currently, there is no consensus on the relative roles of synaptic and spiking activity in the generation of the BOLD response. Here we designed a modelling framework to investigate different neurovascular coupling mechanisms. We use Electroencephalographic (EEG) and fMRI data from a visual stimulation task together with biophysically informed mathematical models describing how neuronal activity generates the BOLD signals. These models allow us to non-invasively infer the degree of local synaptic and spiking activity in the healthy human brain. In addition, we use Bayesian model comparison to decide between neurovascular coupling mechanisms. We show that the BOLD signal is dependent upon both the synaptic and spiking activity but that the relative contributions of these two inputs are dependent upon the underlying neuronal firing rate. When the underlying neuronal firing is low then the BOLD response is best explained by synaptic activity. However, when the neuronal firing rate is high then both synaptic and spiking activity are required to explain the BOLD signal. PMID- 21698177 TI - Quinpramine ameliorates rat experimental autoimmune neuritis and redistributes MHC class II molecules. AB - Activation of inflammatory cells is central to the pathogenesis of autoimmune demyelinating diseases of the peripheral nervous system. The novel chimeric compound quinpramine--generated from imipramine and quinacrine--redistributes cholesterol rich membrane domains to intracellular compartments. We studied the immunological and clinical effects of quinpramine in myelin homogenate induced Lewis rat experimental autoimmune neuritis (EAN), a model system for acute human inflammatory neuropathies, such as the Guillain-Barre syndrome. EAN animals develop paresis of all limbs due to autoimmune inflammation of peripheral nerves. Quinpramine treatment ameliorated clinical disease severity of EAN and infiltration of macrophages into peripheral nerves. It reduced expression of MHC class II molecules on antigen presenting cells and antigen specific T cell proliferation both in vitro and in vivo. Quinpramine exerted its anti proliferatory effect on antigen presenting cells, but not on responder T cells. Our data suggest that quinpramine represents a candidate pharmaceutical for inflammatory neuropathies. PMID- 21698179 TI - The effect of bacterial infection on the biomechanical properties of biological mesh in a rat model. AB - BACKGROUND: The use of biologic mesh to repair abdominal wall defects in contaminated surgical fields is becoming the standard of practice. However, failure rates and infections of these materials persist clinically. The purpose of this study was to determine the mechanical properties of biologic mesh in response to a bacterial encounter. METHODS: A rat model of Staphylococcus aureus colonization and infection of subcutaneously implanted biologic mesh was used. Samples of biologic meshes (acellular human dermis (ADM) and porcine small intestine submucosa (SIS)) were inoculated with various concentrations of methicillin-resistant Staphylococcus aureus [10(5), 10(9) colony-forming units] or saline (control) prior to wound closure (n = 6 per group). After 10 or 20 days, meshes were explanted, and cultured for bacteria. Histological changes and bacterial recovery together with biomechanical properties were assessed. Data were compared using a 1-way ANOVA or a Mann-Whitney test, with p<0.05. RESULTS: The overall rate of staphylococcal mesh colonization was 81% and was comparable in the ADM and SIS groups. Initially (day 0) both biologic meshes had similar biomechanical properties. However after implantation, the SIS control material was significantly weaker than ADM at 20 days (p = 0.03), but their corresponding modulus of elasticity were similar at this time point (p>0.05). After inoculation with MRSA, a time, dose and material dependent decrease in the ultimate tensile strength and modulus of elasticity of SIS and ADM were noted compared to control values. CONCLUSION: The biomechanical properties of biologic mesh significantly decline after colonization with MRSA. Surgeons selecting a repair material should be aware of its biomechanical fate relative to other biologic materials when placed in a contaminated environment. PMID- 21698178 TI - Mutation D816V alters the internal structure and dynamics of c-KIT receptor cytoplasmic region: implications for dimerization and activation mechanisms. AB - The type III receptor tyrosine kinase (RTK) KIT plays a crucial role in the transmission of cellular signals through phosphorylation events that are associated with a switching of the protein conformation between inactive and active states. D816V KIT mutation is associated with various pathologies including mastocytosis and cancers. D816V-mutated KIT is constitutively active, and resistant to treatment with the anti-cancer drug Imatinib. To elucidate the activating molecular mechanism of this mutation, we applied a multi-approach procedure combining molecular dynamics (MD) simulations, normal modes analysis (NMA) and binding site prediction. Multiple 50-ns MD simulations of wild-type KIT and its mutant D816V were recorded using the inactive auto-inhibited structure of the protein, characteristic of type III RTKs. Computed free energy differences enabled us to quantify the impact of D816V on protein stability in the inactive state. We evidenced a local structural alteration of the activation loop (A-loop) upon mutation, and a long-range structural re-organization of the juxta-membrane region (JMR) followed by a weakening of the interaction network with the kinase domain. A thorough normal mode analysis of several MD conformations led to a plausible molecular rationale to propose that JMR is able to depart its auto inhibitory position more easily in the mutant than in wild-type KIT and is thus able to promote kinase mutant dimerization without the need for extra-cellular ligand binding. Pocket detection at the surface of NMA-displaced conformations finally revealed that detachment of JMR from the kinase domain in the mutant was sufficient to open an access to the catalytic and substrate binding sites. PMID- 21698181 TI - How DNA barcodes complement taxonomy and explore species diversity: the case study of a poorly understood marine fauna. AB - BACKGROUND: The species boundaries of some venerids are difficult to define based solely on morphological features due to their indistinct intra- and interspecific phenotypic variability. An unprecedented biodiversity crisis caused by human activities has emerged. Thus, to access the biological diversity and further the conservation of this taxonomically muddling bivalve group, a fast and simple approach that can efficiently examine species boundaries and highlight areas of unrecognized diversity is urgently needed. DNA barcoding has proved its effectiveness in high-volume species identification and discovery. In the present study, Chinese fauna was chosen to examine whether this molecular biomarker is sensitive enough for species delimitation, and how it complements taxonomy and explores species diversity. METHODOLOGY/PRINCIPAL FINDINGS: A total of 315 specimens from around 60 venerid species were included, qualifying the present study as the first major analysis of DNA barcoding for marine bivalves. Nearly all individuals identified to species level based on morphological traits possessed distinct barcode clusters, except for the specimens of one species pair. Among the 26 individuals that were not assigned binomial names a priori, twelve respectively nested within a species genealogy. The remaining individuals formed five monophyletic clusters that potentially represent species new to science or at least unreported in China. Five putative hidden species were also uncovered in traditional morphospecies. CONCLUSIONS/SIGNIFICANCE: The present study shows that DNA barcoding is effective in species delimitation and can aid taxonomists by indicating useful diagnostic morphological traits, informing needful revision, and flagging unseen species. Moreover, the BOLD system, which deposits barcodes, morphological, geographical and other data, has the potential as a convenient taxonomic platform. PMID- 21698182 TI - Renal HIV expression is unaffected by serum LPS levels in an HIV transgenic mouse model of LPS induced kidney injury. AB - Acute kidney injury (AKI) is associated with increased rates of mortality. For unknown reasons, HIV infected individuals have a higher risk of AKI than uninfected persons. We tested our hypothesis that increased circulating LPS increases renal expression of HIV and that HIV transgenic (Tg26) mice have increased susceptibility to AKI. Tg26 mice harbor an HIV transgene encoding all HIV genes except gag and pol, and develop a phenotype analogous to HIVAN. Mice were used at 4-6 weeks of age before the onset of gross renal disease. Mice were injected i.p. with LPS or sterile saline. Renal function, tubular injury, cytokine expression, and HIV transcription were evaluated in Tg26 and wild type (WT) mice. LPS injection induced a median 60.1-fold increase in HIV expression in spleen but no change in kidney. There was no significant difference in renal function, cytokine expression, or tubular injury scores at baseline or 24 hours after LPS injection. HIV transcription was also analyzed in vitro using a human renal tubular epithelial cell (RTEC) line. HIV transcription increased minimally in human RTEC, by 1.47 fold, 48 hours after LPS exposure. We conclude that Tg26 mice do not increase HIV expression or have increased susceptibility to LPS induced AKI. The increased risk of AKI in HIV infected patients is not mediated via increased renal expression of HIV in the setting of sepsis. Moreover, renal regulation of HIV transcription is different to that in the spleen. PMID- 21698180 TI - Resistance of a rodent malaria parasite to a thymidylate synthase inhibitor induces an apoptotic parasite death and imposes a huge cost of fitness. AB - BACKGROUND: The greatest impediment to effective malaria control is drug resistance in Plasmodium falciparum, and thus understanding how resistance impacts on the parasite's fitness and pathogenicity may aid in malaria control strategy. METHODOLOGY/PRINCIPAL FINDINGS: To generate resistance, P. berghei NK65 was subjected to 5-fluoroorotate (FOA, an inhibitor of thymidylate synthase, TS) pressure in mice. After 15 generations of drug pressure, the 2% DT (the delay time for proliferation of parasites to 2% parasitaemia, relative to untreated wild-type controls) reduced from 8 days to 4, equalling the controls. Drug sensitivity studies confirmed that FOA-resistance was stable. During serial passaging in the absence of drug, resistant parasite maintained low growth rates (parasitaemia, 15.5%+/-2.9, 7 dpi) relative to the wild-type (45.6%+/-8.4), translating into resistance cost of fitness of 66.0%. The resistant parasite showed an apoptosis-like death, as confirmed by light and transmission electron microscopy and corroborated by oligonucleosomal DNA fragmentation. CONCLUSIONS/SIGNIFICANCE: The resistant parasite was less fit than the wild-type, which implies that in the absence of drug pressure in the field, the wild-type alleles may expand and allow drugs withdrawn due to resistance to be reintroduced. FOA resistance led to depleted dTTP pools, causing thymineless parasite death via apoptosis. This supports the tenet that unicellular eukaryotes, like metazoans, also undergo apoptosis. This is the first report where resistance to a chemical stimulus and not the stimulus itself is shown to induce apoptosis in a unicellular parasite. This finding is relevant in cancer therapy, since thymineless cell death induced by resistance to TS-inhibitors can further be optimized via inhibition of pyrimidine salvage enzymes, thus providing a synergistic impact. We conclude that since apoptosis is a process that can be pharmacologically modulated, the parasite's apoptotic machinery may be exploited as a novel drug target in malaria and other protozoan diseases of medical importance. PMID- 21698183 TI - Comprehensive analysis of cellular galectin-3 reveals no consistent oncogenic function in pancreatic cancer cells. AB - Galectin-3 (Gal-3), a 31 kDa member of the family of beta-galactoside-binding proteins, has been implicated in the progression of different human cancers. However, the proposed roles differ widely, ranging from tumor-promoting cellular functions and negative impact on patient prognosis to tumor-suppressive properties and positive prognostic impact. We and others have previously identified Gal-3 as overexpressed in pancreatic cancer as compared to chronic pancreatitis and normal pancreatic tissue. The purpose of this study was thus the comprehensive analysis of putative cellular functions of Gal-3 by transient as well as stable silencing or overexpression of Gal-3 in a panel of 6 well established pancreatic cancer cell lines. Our results confirm that galectin-3 is upregulated at the mRNA level in pancreatic cancer and strongly expressed in the majority of pancreatic cancer cell lines. In individual cell lines, transient knockdown of Gal-3 expression resulted in moderate inhibitory effects on proliferation, migration or anchorage-independent growth of the cells, but these effects were not consistent across the spectrum of analyzed cell lines. Moreover, functional effects of the modulation of Gal-3 expression were not observed in stable knockdown or overexpression approaches in vitro and did not alter the growth characteristics of nude mouse xenograft tumors in vivo. Our data thus do not support a direct functional role of Gal-3 in the malignant transformation of pancreatic epithelial cells, although paracrine or systemic effects of Gal-3 expression are not excluded. PMID- 21698184 TI - Mice with a targeted deletion of the type 2 deiodinase are insulin resistant and susceptible to diet induced obesity. AB - BACKGROUND: The type 2 iodothyronine deiodinase (D2) converts the pro-hormone thyroxine into T3 within target tissues. D2 is essential for a full thermogenic response of brown adipose tissue (BAT), and mice with a disrupted Dio2 gene (D2KO) have an impaired response to cold. BAT is also activated by overfeeding. METHODOLOGY/PRINCIPAL FINDINGS: After 6-weeks of HFD feeding D2KO mice gained 5.6% more body weight and had 28% more adipose tissue. Oxygen consumption (V0(2)) was not different between genotypes, but D2KO mice had an increased respiratory exchange ratio (RER), suggesting preferential use of carbohydrates. Consistent with this, serum free fatty acids and beta-hydroxybutyrate were lower in D2KO mice on a HFD, while hepatic triglycerides were increased and glycogen content decreased. Neither genotype showed glucose intolerance, but D2KO mice had significantly higher insulin levels during GTT independent of diet. Accordingly, during ITT testing D2KO mice had a significantly reduced glucose uptake, consistent with insulin resistance. Gene expression levels in liver, muscle, and brown and white adipose tissue showed no differences that could account for the increased weight gain in D2KO mice. However, D2KO mice have higher PEPCK mRNA in liver suggesting increased gluconeogenesis, which could also contribute to their apparent insulin resistance. CONCLUSIONS/SIGNIFICANCE: We conclude that the loss of the Dio2 gene has significant metabolic consequences. D2KO mice gain more weight on a HFD, suggesting a role for D2 in protection from diet-induced obesity. Further, D2KO mice appear to have a greater reliance on carbohydrates as a fuel source, and limited ability to mobilize and to burn fat. This results in increased fat storage in adipose tissue, hepatic steatosis, and depletion of liver glycogen in spite of increased gluconeogenesis. D2KO mice are also less responsive to insulin, independent of diet-induced obesity. PMID- 21698186 TI - Disruption of LRRK2 does not cause specific loss of dopaminergic neurons in zebrafish. AB - Mutations in LRRK2 are genetically linked to Parkinson's disease (PD) but its normal biological function is largely unknown. Sheng et al. recently reported that deletion of the WD40 domain of LRRK2 in zebrafish specifically causes PD like loss of neurons and behavior defect. However, our similar early study and recent confirming experiments using the same reagents reported by Sheng et al. failed to reproduce the phenotype of the loss of dopaminergic neurons, although the mRNA of LRRK2 was molecularly disrupted. Our study suggests that function of LRRK2 and its usefulness to generate zebrafish PD model needs further evaluation. PMID- 21698185 TI - Overexpression of microRNAs from the miR-17-92 paralog clusters in AIDS-related non-Hodgkin's lymphomas. AB - BACKGROUND: Individuals infected by HIV are at an increased risk for developing non-Hodgkin's lymphomas (AIDS-NHL). In the highly active antiretroviral therapy (HAART) era, there has been a significant decline in the incidence of AIDS associated primary central nervous system lymphoma (PCNSL). However, only a modest decrease in incidence has been reported for other AIDS-NHL subtypes. Thus, AIDS-NHLs remain a significant cause of morbidity and mortality in HIV infected individuals. Recently, much attention has been directed toward the role of miRNAs in cancer, including NHL. Several miRNAs, including those encoded by the miR-17 92 polycistron, have been shown to play significant roles in B cell tumorigenesis. However, the role of miRNAs in NHL in the setting of HIV infection has not been defined. METHODOLOGY/PRINCIPAL FINDINGS: We used quantitative realtime PCR to assess the expression of miRNAs from three different paralog clusters, miR-17-92, miR-106a-363, and miR-106b-25 in 24 cases of AIDS-NHLs representing four tumor types, Burkitt's lymphoma (BL, n = 6), diffuse large B cell lymphoma (DLBCL, n = 8), primary central nervous system lymphoma (PCNSL, n = 5), and primary effusion lymphoma (PEL, n = 5). We also used microarray analysis to identify a differentiation specific miRNA signature of naive, germinal center, and memory B cell subsets from tonsils (n = 4). miRNAs from the miR-17-92 paralog clusters were upregulated by B cells, specifically during the GC differentiation stage. We also found overexpression of these miRNA clusters in all four AIDS-NHL subtypes. Finally, we also show that select miRNAs from these clusters (miR-17, miR-106a, and miR-106b) inhibited p21 in AIDS-BL and DLBCL cases, thus providing a mechanistic role for these miRNAs in AIDS-NHL pathogenesis. CONCLUSION: Dysregulation of miR-17-92 paralog clusters is a common feature of AIDS associated NHLs. PMID- 21698187 TI - Natural images from the birthplace of the human eye. AB - Here we introduce a database of calibrated natural images publicly available through an easy-to-use web interface. Using a Nikon D70 digital SLR camera, we acquired about six-megapixel images of Okavango Delta of Botswana, a tropical savanna habitat similar to where the human eye is thought to have evolved. Some sequences of images were captured unsystematically while following a baboon troop, while others were designed to vary a single parameter such as aperture, object distance, time of day or position on the horizon. Images are available in the raw RGB format and in grayscale. Images are also available in units relevant to the physiology of human cone photoreceptors, where pixel values represent the expected number of photoisomerizations per second for cones sensitive to long (L), medium (M) and short (S) wavelengths. This database is distributed under a Creative Commons Attribution-Noncommercial Unported license to facilitate research in computer vision, psychophysics of perception, and visual neuroscience. PMID- 21698188 TI - Identification and functional analysis of epigenetically silenced microRNAs in colorectal cancer cells. AB - Abnormal microRNA (miRNA) expression has been linked to the development and progression of several human cancers, and such dysregulation can result from aberrant DNA methylation. While a small number of miRNAs is known to be regulated by DNA methylation, we postulated that such epigenetic regulation is more prevalent. By combining MBD-isolated Genome Sequencing (MiGS) to evaluate genome wide DNA methylation patterns and microarray analysis to determine miRNA expression levels, we systematically searched for candidate miRNAs regulated by DNA methylation in colorectal cancer cell lines. We found 64 miRNAs to be robustly methylated in HCT116 cells; eighteen of them were located in imprinting regions or already reported to be regulated by DNA methylation. For the remaining 46 miRNAs, expression levels of 18 were consistent with their DNA methylation status. Finally, 8 miRNAs were up-regulated by 5-aza-2'-deoxycytidine treatment and identified to be novel miRNAs regulated by DNA methylation. Moreover, we demonstrated the functional relevance of these epigenetically silenced miRNAs by ectopically expressing select candidates, which resulted in inhibition of growth and migration of cancer cells. In addition to reporting these findings, our study also provides a reliable, systematic strategy to identify DNA methylation regulated miRNAs by combining DNA methylation profiles and expression data. PMID- 21698189 TI - Predicting protein folds with fold-specific PSSM libraries. AB - Accurately assigning folds for divergent protein sequences is a major obstacle to structural studies. Herein, we outline an effective method for fold recognition using sets of PSSMs, each of which is constructed for different protein folds. Our analyses demonstrate that FSL (Fold-specific Position Specific Scoring Matrix Libraries) can predict/relate structures given only their amino acid sequences of highly divergent proteins. This ability to detect distant relationships is dependent on low-identity sequence alignments obtained from FSL. Results from our experiments demonstrate that FSL perform well in recognizing folds from the "twilight-zone" SABmark dataset. Further, this method is capable of accurate fold prediction in newly determined structures. We suggest that by building complete PSSM libraries for all unique folds within the Protein Database (PDB), FSL can be used to rapidly and reliably annotate a large subset of protein folds at proteomic level. The related programs and fold-specific PSSMs for our FSL are publicly available at: http://ccp.psu.edu/download/FSLv1.0/. PMID- 21698190 TI - Enhanced cellular immunity in shrimp (Litopenaeus vannamei) after 'vaccination'. AB - It has long been viewed that invertebrates rely exclusively upon a wide variety of innate mechanisms for protection from disease and parasite invasion and lack any specific acquired immune mechanisms comparable to those of vertebrates. Recent findings, however, suggest certain invertebrates may be able to mount some form of specific immunity, termed 'specific immune priming', although the mechanism of this is not fully understood (see Textbox S1). In our initial experiments, either formalin-inactivated Vibrio harveyi or sterile saline were injected into the main body cavity (haemocoel) of juvenile shrimp (Litopenaeus vannamei). Haemocytes (blood cells) from V. harveyi-injected shrimp were collected 7 days later and incubated with a 1:1 mix of V. harveyi and an unrelated gram positive bacterium, Bacillus subtilis. Haemocytes from 'vaccinated' shrimp showed elevated levels of phagocytosis of V. harveyi, but not B. subtilis, compared with those from saline-injected (non-immunised) animals. The increased phagocytic activity was characterised by a significant increase in the percentage of phagocytic cells. When shrimp were injected with B. subtilis rather than vibrio, there was no significant increase in the phagocytic activity of haemocytes from these animals in comparison to the non-immunised (saline injected) controls. Whole haemolymph (blood) from either 'immunised' or non immunised' shrimp was shown to display innate humoral antibacterial activity against V. harveyi that was absent against B. subtilis. However, there was no difference in the potency of antibacterial activity between V. harveyi-injected shrimp and control (saline injected) animals showing that 'vaccination' has no effect on this component of the shrimp's immune system. These results imply that the cellular immune system of shrimp, particularly phagocytosis, is capable of a degree of specificity and shows the phenomenon of 'immune priming' reported by other workers. However, in agreement with other studies, this phenomenon is not universal to all potential pathogens. PMID- 21698191 TI - Modeling light adaptation in circadian clock: prediction of the response that stabilizes entrainment. AB - Periods of biological clocks are close to but often different from the rotation period of the earth. Thus, the clocks of organisms must be adjusted to synchronize with day-night cycles. The primary signal that adjusts the clocks is light. In Neurospora, light transiently up-regulates the expression of specific clock genes. This molecular response to light is called light adaptation. Does light adaptation occur in other organisms? Using published experimental data, we first estimated the time course of the up-regulation rate of gene expression by light. Intriguingly, the estimated up-regulation rate was transient during light period in mice as well as Neurospora. Next, we constructed a computational model to consider how light adaptation had an effect on the entrainment of circadian oscillation to 24-h light-dark cycles. We found that cellular oscillations are more likely to be destabilized without light adaption especially when light intensity is very high. From the present results, we predict that the instability of circadian oscillations under 24-h light-dark cycles can be experimentally observed if light adaptation is altered. We conclude that the functional consequence of light adaptation is to increase the adjustability to 24-h light dark cycles and then adapt to fluctuating environments in nature. PMID- 21698192 TI - A histone-like protein of mycobacteria possesses ferritin superfamily protein like activity and protects against DNA damage by Fenton reaction. AB - Iron is an essential metal for living organisms but its level must be strictly controlled in cells, because ferrous ion induces toxicity by generating highly active reactive oxygen, hydroxyl radicals, through the Fenton reaction. In addition, ferric ion shows low solubility under physiological conditions. To overcome these obstacles living organisms possess Ferritin superfamily proteins that are distributed in all three domains of life: bacteria, archaea, and eukaryotes. These proteins minimize hydroxyl radical formation by ferroxidase activity that converts Fe(2+) into Fe(3+) and sequesters iron by storing it as a mineral inside a protein cage. In this study, we discovered that mycobacterial DNA-binding protein 1 (MDP1), a histone-like protein, has similar activity to ferritin superfamily proteins. MDP1 prevented the Fenton reaction and protects DNA by the ferroxidase activity. The K(m) values of the ferroxidase activity by MDP1 of Mycobacterium bovis bacillus Calmette-Guerin (BCG-3007c), Mycobacterium tuberculosis (Rv2986c), and Mycobacterium leprae (ML1683; ML-LBP) were 0.292, 0.252, and 0.129 mM, respectively. Furthermore, one MDP1 molecule directly captured 81.4+/-19.1 iron atoms, suggesting the role of this protein in iron storage. This study describes for the first time a ferroxidase-iron storage protein outside of the ferritin superfamily proteins and the protective role of this bacterial protein from DNA damage. PMID- 21698194 TI - Jumping without using legs: the jump of the click-beetles (Elateridae) is morphologically constrained. AB - To return to their feet, inverted click-beetles (Elateridae) jump without using their legs. When a beetle is resting on its dorsal side, a hinge mechanism is locked to store elastic energy in the body and releases it abruptly to launch the beetle into the air. While the functional morphology of the jumping mechanism is well known, the level of control that the beetle has over this jumping technique and the mechanical constraints governing the jumps are not entirely clear. Here we show that while body rotations in air are highly variable, the jumps are morphologically constrained to a constant "takeoff" angle (79.9 degrees +/-1.56 degrees , n = 9 beetles) that directs 98% of the jumping force vertically against gravity. A physical-mathematical model of the jumping action, combined with measurements from live beetle, imply that the beetle may control the speed at takeoff but not the jumping angle. In addition, the model shows that very subtle changes in the exact point of contact with the ground can explain the vigorous rotations of the body seen while the beetle is airborne. These findings suggest that the evolution of this unique non-legged jumping mechanism resulted in a jumping technique that is capable of launching the body high into the air but it is too constrained and unstable to allow control of body orientation at landing. PMID- 21698193 TI - Transgene optimization, immunogenicity and in vitro efficacy of viral vectored vaccines expressing two alleles of Plasmodium falciparum AMA1. AB - BACKGROUND: Apical membrane antigen 1 (AMA1) is a leading candidate vaccine antigen against blood-stage malaria, although to date numerous clinical trials using mainly protein-in-adjuvant vaccines have shown limited success. Here we describe the pre-clinical development and optimization of recombinant human and simian adenoviral (AdHu5 and ChAd63) and orthopoxviral (MVA) vectors encoding transgene inserts for Plasmodium falciparum AMA1 (PfAMA1). METHODOLOGY/PRINCIPAL FINDINGS: AdHu5-MVA prime-boost vaccination in mice and rabbits using these vectors encoding the 3D7 allele of PfAMA1 induced cellular immune responses as well as high-titer antibodies that showed growth inhibitory activity (GIA) against the homologous but not heterologous parasite strains. In an effort to overcome the issues of PfAMA1 antigenic polymorphism and pre-existing immunity to AdHu5, a simian adenoviral (ChAd63) vector and MVA encoding two alleles of PfAMA1 were developed. This antigen, composed of the 3D7 and FVO alleles of PfAMA1 fused in tandem and with expression driven by a single promoter, was optimized for antigen secretion and transmembrane expression. These bi-allelic PfAMA1 vaccines, when administered to mice and rabbits, demonstrated comparable immunogenicity to the mono-allelic vaccines and purified serum IgG now showed GIA against the two divergent strains of P. falciparum encoded in the vaccine. CD8(+) and CD4(+) T cell responses against epitopes that were both common and unique to the two alleles of PfAMA1 were also measured in mice. CONCLUSIONS/SIGNIFICANCE: Optimized transgene inserts encoding two divergent alleles of the same antigen can be successfully inserted into adeno- and pox-viral vaccine vectors. Adenovirus-MVA immunization leads to the induction of T cell responses common to both alleles, as well as functional antibody responses that are effective against both of the encoded strains of P. falciparum in vitro. These data support the further clinical development of these vaccine candidates in Phase I/IIa clinical trials. PMID- 21698195 TI - Author self-citation in the general medicine literature. AB - BACKGROUND: Author self-citation contributes to the overall citation count of an article and the impact factor of the journal in which it appears. Little is known, however, about the extent of self-citation in the general clinical medicine literature. The objective of this study was to determine the extent and temporal pattern of author self-citation and the article characteristics associated with author self-citation. METHODOLOGY/PRINCIPAL FINDINGS: We performed a retrospective cohort study of articles published in three high impact general medical journals (JAMA, Lancet, and New England Journal of Medicine) between October 1, 1999 and March 31, 2000. We retrieved the number and percentage of author self-citations received by the article since publication, as of June 2008, from the Scopus citation database. Several article characteristics were extracted by two blinded, independent reviewers for each article in the cohort and analyzed in multivariable linear regression analyses. Since publication, author self-citations accounted for 6.5% (95% confidence interval 6.3-6.7%) of all citations received by the 328 articles in our sample. Self citation peaked in 2002, declining annually thereafter. Studies with more authors, in cardiovascular medicine or infectious disease, and with smaller sample size were associated with more author self-citations and higher percentage of author self-citation (all p<=0.01). CONCLUSIONS/SIGNIFICANCE: Approximately 1 in 15 citations of articles in high-profile general medicine journals are author self-citations. Self-citation peaks within about 2 years of publication and disproportionately affects impact factor. Studies most vulnerable to this effect are those with more authors, small sample size, and in cardiovascular medicine or infectious disease. PMID- 21698196 TI - Genetic susceptibility for individual cooperation preferences: the role of monoamine oxidase A gene (MAOA) in the voluntary provision of public goods. AB - In the context of social dilemmas, previous research has shown that human cooperation is mainly based on the social norm of conditional cooperation. While in most cases individuals behave according to such a norm, deviant behavior is no exception. Recent research further suggests that heterogeneity in social behavior might be associated with varying genetic predispositions. In this study, we investigated the relationship between individuals' behavior in a public goods experiment and the promoter-region functional repeat polymorphism in the monoamine oxidase A gene (MAOA). In a dynamic setting of increasing information about others' contributions, we analyzed differences in two main components of conditional cooperation, namely the players' own contribution and their beliefs regarding the contribution of other players. We showed that there is a significant association between individuals' behavior in a repeated public goods game and MAOA. Our results suggest that male carriers of the low activity alleles cooperate significantly less than those carrying the high activity alleles given a situation where subjects had to rely on their innate beliefs about others' contributions. With increasing information about the others' cooperativeness, the genetic effect diminishes. Furthermore, significant opposing effects for female subjects carrying two low activity alleles were observed. PMID- 21698197 TI - Cten is targeted by Kras signalling to regulate cell motility in the colon and pancreas. AB - CTEN/TNS4 is an oncogene in colorectal cancer (CRC) which enhances cell motility although the mechanism of Cten regulation is unknown. We found an association between high Cten expression and KRAS/BRAF mutation in a series of CRC cell lines (p = 0.03) and hypothesised that Kras may regulate Cten. To test this, Kras was knocked-down (using small interfering (si)RNA) in CRC cell lines SW620 and DLD1 (high Cten expressors and mutant for KRAS). In each cell line, Kras knockdown was mirrored by down-regulation of Cten Since Kras signals through Braf, we tested the effect of Kras knockdown in CRC cell line Colo205 (which shows high Cten expression and is mutant for BRAF but wild type for KRAS). Cten levels were unaffected by Kras knockdown whilst Braf knockdown resulted in reduced Cten expression suggesting that Kras signals via Braf to regulate Cten. Quantification of Cten mRNA and protein analysis following proteasome inhibition suggested that regulation was of Cten transcription. Kras knockdown inhibited cell motility. To test whether this could be mediated through Cten, SW620 cells were co-transfected with Kras specific siRNAs and a Cten expression vector. Restoring Cten expression was able to restore cell motility despite Kras knockdown (transwell migration and wounding assay, p<0.001 for both). Since KRAS is mutated in many cancers, we investigated whether this relationship could be demonstrated in other tumour models. The experiments were repeated in the pancreatic cancer cell lines Colo357 & PSN-1(both high Cten expressors and mutant for KRAS). In both cell lines, Kras was shown to regulate Cten and forced expression of Cten was able to rescue loss of cell motility following Kras knockdown in PSN-1 (transwell migration assay, p<0.001). We conclude that, in the colon and pancreas, Cten is a downstream target of Kras and may be a mechanism through which Kras regulates of cell motility. PMID- 21698198 TI - Antimetastatic effects of Phyllanthus on human lung (A549) and breast (MCF-7) cancer cell lines. AB - BACKGROUND: Current chemotherapeutic drugs kill cancer cells mainly by inducing apoptosis. However, they become ineffective once cancer cell has the ability to metastasize, hence the poor prognosis and high mortality rate. Therefore, the purpose of this study was to evaluate the antimetastatic potential of Phyllanthus (P. niruri, P. urinaria, P. watsonii, and P. amarus) on lung and breast carcinoma cells. METHODOLOGY/PRINCIPAL FINDINGS: Cytotoxicity of Phyllanthus plant extracts were first screened using the MTS reduction assay. They were shown to inhibit MCF 7 (breast carcinoma) and A549 (lung carcinoma) cells growth with IC(50) values ranging from 50-180 ug/ml and 65-470 ug/ml for methanolic and aqueous extracts respectively. In comparison, they have lower toxicity on normal cells with the cell viability percentage remaining above 50% when treated up to 1000 ug/ml for both extracts. After determining the non-toxic effective dose, several antimetastasis assays were carried out and Phyllanthus extracts were shown to effectively reduce invasion, migration, and adhesion of both MCF-7 and A549 cells in a dose-dependent manner, at concentrations ranging from 20-200 ug/ml for methanolic extracts and 50-500 ug/ml for aqueous extracts. This was followed by an evaluation of the possible modes of cell death that occurred along with the antimetastatic activity. Phyllanthus was shown to be capable of inducing apoptosis in conjunction with its antimetastastic action, with more than three fold increase of caspases-3 and -7, the presence of DNA-fragmentation and TUNEL positive cells. The ability of Phyllanthus to exert antimetastatic activities is mostly associated to the presence of polyphenol compounds in its extracts. CONCLUSIONS/SIGNIFICANCE: The presence of polyphenol compounds in the Phyllanthus plant is critically important in the inhibition of the invasion, migration, and adhesion of cancer cells, along with the involvement of apoptosis induction. Hence, Phyllanthus could be a valuable candidate in the treatment of metastatic cancers. PMID- 21698199 TI - Widespread secondary contact and new glacial refugia in the halophilic rotifer Brachionus plicatilis in the Iberian Peninsula. AB - Small aquatic organisms harbour deep phylogeographic patterns and highly structured populations even at local scales. These patterns indicate restricted gene flow, despite these organisms' high dispersal abilities, and have been explained by a combination of (1) strong founder effects due to rapidly growing populations and very large population sizes, and (2) the development of diapausing egg banks and local adaptation, resulting in low effective gene flow, what is known as the Monopolization hypothesis. In this study, we build up on our understanding of the mitochondrial phylogeography of the halophilic rotifer Brachionus plicatilis in the Iberian Peninsula by both increasing the number of sampled ponds in areas where secondary contact is likely and doubling sample sizes. We analyzed partial mitochondrial sequences of 252 individuals. We found two deep mitochondrial DNA lineages differing in both their genetic diversity and the complexity of their phylogeographic structure. Our analyses suggest that several events of secondary contact between clades occurred after their expansion from glacial refugia. We found a pattern of isolation-by-distance, which we interpret as being the result of historical colonization events. We propose the existence of at least one glacial refugium in the SE of the Iberian Peninsula. Our findings challenge predictions of the Monopolization hypothesis, since coexistence (i.e., secondary contact) of divergent lineages in some ponds in the Iberian Peninsula is common. Our results indicate that phylogeographic structures in small organisms can be very complex and that gene flow between diverse lineages after population establishment can indeed occur. PMID- 21698200 TI - Relationship between a novel polymorphism of the C5L2 gene and coronary artery disease. AB - BACKGROUND: C5L2 has been demonstrated to be a functional receptor of acylation stimulating protein (ASP), which is a stimulator of triglyceride synthesis or glucose transport. However, little is known about the variations in the coding region of the C5L2 gene and their association with coronary artery disease (CAD). METHODOLOGY/PRINCIPAL FINDINGS: We identified a novel single nucleotide polymorphism (SNP), 698C>T (P233L), in exon 2 using a polymerase chain reaction direct-sequencing method. This nucleotide change causes the amino-acid order from proline to leucine at codon 233. We examined the role of this SNP for CAD using two independent case-control studies: one was in the Han population (492 CAD patients and 577 control subjects) and the other was in the Uygur population (319 CAD patients and 554 control subjects). Heterozygote carriers of the 698CT genotype were more frequent among CAD patients than among controls not only in the Han population (7.3% versus 1.7%) but also in the Uygur population (4.7% versus 1.6%). The odds ratio (OR) for carriers of the 698CT genotype for CAD was 4.484 (95% confidence interval (CI): 2.197-9.174) in the Han group and 2.989 (95% CI: 1.292-6.909) in the Uygur population. After adjustment of confounding factors such as sex, age, smoking, alcohol consumption, hypertension, diabetes, as well as serum levels of triglyceride, total cholesterol, high-density lipoprotein, the difference remained significant in the Han group (P<0.001, OR = 6.604, 95% CI: 2.776-15.711) and in the Uygur group (P = 0.047, OR = 2.602, 95% CI: 1.015 6.671). CONCLUSION/SIGNIFICANCE: The 698CT genotype of C5L2 may be a genetic maker of CAD in the Han and Uygur population in western China. PMID- 21698201 TI - Acyl homoserine lactones from culture supernatants of Pseudomonas aeruginosa accelerate host immunomodulation. AB - The virulence of Pseudomonas aeruginosa is multifactorial and under the control of quorum sensing signals, such as acyl homoserine lactones (AHLs). The importance of these molecules in the establishment of infection has been previously reported. These molecules either improve the virulence potential of P. aeruginosa or modulate the host immune response. To establish the immune modulating potential of quorum sensing signal molecules, previous studies have only used synthetic AHLs. However, there can be differences in the biological properties of synthetic and natural AHLs. The use of naturally extracted AHLs from the culture supernatant of P. aeruginosa is likely to simulate natural conditions more than the use of synthetic AHLs. Therefore, in the present study, the immune modulating potential of synthetic and naturally extracted AHLs was compared using a thymidine uptake assay, immunophenotyping and sandwich ELISA in order to assess mouse T-cell proliferation and production of Th1 and Th2 cytokines. Natural AHLs were able to suppress T-cell proliferation, even at low concentrations, compared to synthetic AHLs. The majority of cells undergoing proliferation were CD4+, as revealed by immunophenotyping. The inhibition of T cells was stronger with natural AHLs compared to synthetic AHLs. Moreover, the natural AHLs were also able to shift immune responses away from host protective Th1 responses to pathogen protective Th2 responses. PMID- 21698202 TI - ER stress induces anabolic resistance in muscle cells through PKB-induced blockade of mTORC1. AB - BACKGROUND: Anabolic resistance is the inability to increase protein synthesis in response to an increase in amino acids following a meal. One potential mediator of anabolic resistance is endoplasmic reticulum (ER) stress. The purpose of the present study was to test whether ER stress impairs the response to growth factors and leucine in muscle cells. METHODS: Muscle cells were incubated overnight with tunicamycin or thapsigargin to induce ER stress and the activation of the unfolded protein response, mTORC1 activity at baseline and following insulin and amino acids, as well as amino acid transport were determined. RESULTS: ER stress decreased basal phosphorylation of PKB and S6K1 in a dose dependent manner. In spite of the decrease in basal PKB phosphorylation, insulin (10-50 nM) could still activate both PKB and S6K1. The leucine (2.5-5 mM)-induced phosphorylation of S6K1 on the other hand was repressed by low concentrations of both tunicamycin and thapsigargin. To determine the mechanism underlying this anabolic resistance, several inhibitors of mTORC1 activation were measured. Tunicamycin and thapsigargin did not change the phosphorylation or content of either AMPK or JNK, both increased TRB3 mRNA expression and thapsigargin increased REDD1 mRNA. Tunicamycin and thapsigargin both decreased the basal phosphorylation state of PRAS40. Neither tunicamycin nor thapsigargin prevented phosphorylation of PRAS40 by insulin. However, since PKB is not activated by amino acids, PRAS40 phosphorylation remained low following the addition of leucine. Blocking PKB using a specific inhibitor had the same effect on both PRAS40 and leucine-induced phosphorylation of S6K1. CONCLUSION: ER stress induces anabolic resistance in muscle cells through a PKB/PRAS40-induced blockade of mTORC1. PMID- 21698203 TI - Modulation of immunoglobulin production by invariant Valpha19-Jalpha33 TCR bearing cells. AB - We have previously shown that invariant Valpha19-Jalpha33 TCR(+) (Valpha19i T) cells suppress the disease progress in some models for organ specific autoimmune diseases and type IV allergy that deteriorate along with decline to excess in Th1 or Th17- immunity. In this study, we examined the effects of over-generation of Valpha19i T cells on the Th2-controlled immunoglobulin isotype production in the models for type I allergy. IgE production by invariant Valpha19-Jalpha33 TCR transgenic (Tg) mice was suppressed compared with that by non-Tg controls following administration with goat anti-mouse IgD antiserum or OVA, while IgG2a production was not influenced by the introduction of the transgene into the recipients. IgE production by wild type mice was similarly reduced when they were subjected to adoptive transfer with invariant Valpha19-Jalpha33 TCR Tg(+) but not Tg(-) cells prior to immunization. Furthermore, the suppression of IgE production by these recipients was enhanced when they were previously administered with a Valpha19i T cell activator, one of the modified alpha-mannosyl ceramides. In summary, it is suggested that Valpha19i T cells have potential to participate in the homeostasis of immunity and that they suppress disease progression resulting from not only Th1- but also Th2- immunity excess. PMID- 21698204 TI - The evolution of enzyme specificity in the metabolic replicator model of prebiotic evolution. AB - The chemical machinery of life must have been catalytic from the outset. Models of the chemical origins have attempted to explain the ecological mechanisms maintaining a minimum necessary diversity of prebiotic replicator enzymes, but little attention has been paid so far to the evolutionary initiation of that diversity. We propose a possible first step in this direction: based on our previous model of a surface-bound metabolic replicator system we try to explain how the adaptive specialization of enzymatic replicator populations might have led to more diverse and more efficient communities of cooperating replicators with two different enzyme activities. The key assumptions of the model are that mutations in the replicator population can lead towards a) both of the two different enzyme specificities in separate replicators: efficient "specialists" or b) a "generalist" replicator type with both enzyme specificities working at less efficiency, or c) a fast-replicating, non-enzymatic "parasite". We show that under realistic trade-off constraints on the phenotypic effects of these mutations the evolved replicator community will be usually composed of both types of specialists and of a limited abundance of parasites, provided that the replicators can slowly migrate on the mineral surface. It is only at very weak trade-offs that generalists take over in a phase-transition-like manner. The parasites do not seriously harm the system but can freely mutate, therefore they can be considered as pre-adaptations to later, useful functions that the metabolic system can adopt to increase its own fitness. PMID- 21698205 TI - The lineage contribution and role of Gbx2 in spinal cord development. AB - BACKGROUND: Forging a relationship between progenitors with dynamically changing gene expression and their terminal fate is instructive for understanding the logic of how cell-type diversity is established. The mouse spinal cord is an ideal system to study these mechanisms in the context of developmental genetics and nervous system development. Here we focus on the Gastrulation homeobox 2 (Gbx2) transcription factor, which has not been explored in spinal cord development. METHODOLOGY/PRINCIPAL FINDINGS: We determined the molecular identity of Gbx2-expressing spinal cord progenitors. We also utilized genetic inducible fate mapping to mark the Gbx2 lineage at different embryonic stages in vivo in mouse. Collectively, we uncover cell behaviors, cytoarchitectonic organization, and the terminal cell fate of the Gbx2 lineage. Notably, both ventral motor neurons and interneurons are derived from the Gbx2 lineage, but only during a short developmental period. Short-term fate mapping during mouse spinal cord development shows that Gbx2 expression is transient and is extinguished ventrally in a rostral to caudal gradient. Concomitantly, a permanent lineage restriction boundary ensures that spinal cord neurons derived from the Gbx2 lineage are confined to a dorsal compartment that is maintained in the adult and that this lineage generates inhibitory interneurons of the spinal cord. Using lineage tracing and molecular markers to follow Gbx2-mutant cells, we show that the loss of Gbx2 globally affects spinal cord patterning including the organization of interneuron progenitors. Finally, long-term lineage analysis reveals that the presence and timing of Gbx2 expression in interneuron progenitors results in the differential contribution to subtypes of terminally differentiated interneurons in the adult spinal cord. CONCLUSIONS/SIGNIFICANCE: We illustrate the complex cellular nature of Gbx2 expression and lineage contribution to the mouse spinal cord. In a broader context, this study provides a direct link between spinal cord progenitors undergoing dynamic changes in molecular identity and terminal neuronal fate. PMID- 21698206 TI - Genome-wide analysis reveals a major role in cell fate maintenance and an unexpected role in endoreduplication for the Drosophila FoxA gene Fork head. AB - Transcription factors drive organogenesis, from the initiation of cell fate decisions to the maintenance and implementation of these decisions. The Drosophila embryonic salivary gland provides an excellent platform for unraveling the underlying transcriptional networks of organ development because Drosophila is relatively unencumbered by significant genetic redundancy. The highly conserved FoxA family transcription factors are essential for various aspects of organogenesis in all animals that have been studied. Here, we explore the role of the single Drosophila FoxA protein Fork head (Fkh) in salivary gland organogenesis using two genome-wide strategies. A large-scale in situ hybridization analysis reveals a major role for Fkh in maintaining the salivary gland fate decision and controlling salivary gland physiological activity, in addition to its previously known roles in morphogenesis and survival. The majority of salivary gland genes (59%) are affected by fkh loss, mainly at later stages of salivary gland development. We show that global expression of Fkh cannot drive ectopic salivary gland formation. Thus, unlike the worm FoxA protein PHA-4, Fkh does not function to specify cell fate. In addition, Fkh only indirectly regulates many salivary gland genes, which is also distinct from the role of PHA-4 in organogenesis. Our microarray analyses reveal unexpected roles for Fkh in blocking terminal differentiation and in endoreduplication in the salivary gland and in other Fkh-expressing embryonic tissues. Overall, this study demonstrates an important role for Fkh in determining how an organ preserves its identity throughout development and provides an alternative paradigm for how FoxA proteins function in organogenesis. PMID- 21698207 TI - Exposure to apoptotic activated CD4+ T cells induces maturation and APOBEC3G mediated inhibition of HIV-1 infection in dendritic cells. AB - Dendritic cells (DCs) are activated by signaling via pathogen-specific receptors or exposure to inflammatory mediators. Here we show that co-culturing DCs with apoptotic HIV-infected activated CD4(+) T cells (ApoInf) or apoptotic uninfected activated CD4(+) T cells (ApoAct) induced expression of co-stimulatory molecules and cytokine release. In addition, we measured a reduced HIV infection rate in DCs after co-culture with ApoAct. A prerequisite for reduced HIV infection in DCs was activation of CD4(+) T cells before apoptosis induction. DCs exposed to ApoAct or ApoInf secreted MIP-1alpha, MIP-1beta, MCP-1, and TNF-alpha; this effect was retained in the presence of exogenous HIV. The ApoAct-mediated induction of co-stimulatory CD86 molecules and reduction of HIV infection in DCs were partially abrogated after blocking TNF-alpha using monoclonal antibodies. APOBEC3G expression in DCs was increased in co-cultures of DCs and ApoAct but not by apoptotic resting CD4(+) T cells (ApoRest). Silencing of APOBEC3G in DC abrogated the HIV inhibitory effect mediated by ApoAct. Sequence analyses of an env region revealed significant induction of G-to-A hypermutations in the context of GG or GA dinucleotides in DNA isolated from DCs exposed to HIV and ApoAct. Thus, ApoAct-mediated DC maturation resulted in induction of APOBEC3G that was important for inhibition of HIV-infection in DCs. These findings underscore the complexity of differential DC responses evoked upon interaction with resting as compared with activated dying cells during HIV infection. PMID- 21698208 TI - Dynamics of antibiotic resistant Mycobacterium tuberculosis during long-term infection and antibiotic treatment. AB - For an infecting bacterium the human body provides several potential ecological niches with both internally (e.g. host immunity) and externally (e.g. antibiotic use) imposed growth restrictions that are expected to drive adaptive evolution in the bacterium, including the development of antibiotic resistance. To determine the extent and pattern of heterogeneity generated in a bacterial population during long-term antibiotic treatment, we examined in a monoclonal Mycobacterium tuberculosis infection antibiotic resistant mutants isolated from one patient during a 9-years period. There was a progressive accumulation of resistance mutations in the infecting clone. Furthermore, apparent clonal sweeps as well as co-existence of different resistant mutants were observed during this time, demonstrating that during treatment there is a high degree of dynamics in the bacterial population. These findings have important implications for diagnostics and treatment of drug resistant tuberculosis infections. PMID- 21698209 TI - Lineage relationship of direct-developing melanocytes and melanocyte stem cells in the zebrafish. AB - Previous research in zebrafish has demonstrated that embryonic and larval regeneration melanocytes are derived from separate lineages. The embryonic melanocytes that establish the larval pigment pattern do not require regulative melanocyte stem cell (MSC) precursors, and are termed direct-developing melanocytes. In contrast, the larval regeneration melanocytes that restore the pigment pattern after ablation develop from MSC precursors. Here, we explore whether embryonic melanocytes and MSCs share bipotent progenitors. Furthermore, we explore when fate segregation of embryonic melanocytes and MSCs occurs in zebrafish development. In order to achieve this, we develop and apply a novel lineage tracing method. We first demonstrate that Tol2-mediated genomic integration of reporter constructs from plasmids injected at the 1-2 cell stage occurs most frequently after the midblastula transition but prior to shield stage, between 3 and 6 hours post-fertilization. This previously uncharacterized timing of Tol2-mediated genomic integration establishes Tol2-mediated transposition as a means for conducting lineage tracing in zebrafish. Combining the Tol2-mediated lineage tracing strategy with a melanocyte regeneration assay previously developed in our lab, we find that embryonic melanocytes and larval regeneration melanocytes are derived from progenitors that contribute to both lineages. We estimate 50-60 such bipotent melanogenic progenitors to be present in the shield-stage embryo. Furthermore, our examination of direct-developing and MSC-restricted lineages suggests that these are segregated from bipotent precursors after the shield stage, but prior to the end of convergence and extension. Following this early fate segregation, we estimate approximately 100 embryonic melanocyte and 90 MSC-restricted lineages are generated to establish or regenerate the zebrafish larval pigment pattern, respectively. Thus, the dual strategies of direct-development and MSC-derived development are established in the early gastrula, via fate segregation of the two lineages. PMID- 21698210 TI - Molecular cloning of a new immunomodulatory protein from Anoectochilus formosanus which induces B cell IgM secretion through a T-independent mechanism. AB - An immunomodulatory protein (IPAF) was purified and cloned from Anoectochilus formosanus, an Orchidaceae herbal plant in Asia. The major targeting immune cells of IPAF and its modulating effects toward B lymphocytes were investigated. Rapid amplification of cDNA ends (RACE) was conducted to clone the IPAF gene, and the obtained sequence was BLAST compared on the NCBI database. MACS-purified mouse T and B lymphocytes were stimulated with IPAF and the cell proliferation, activation, and Igs production were examined. IPAF comprised a 25 amino acids signal peptide and a 138 amino acids protein which was homologous to the lectins from Orchidaceae plant. IPAF selectively induced the cell proliferation in mouse splenic B lymphocytes but not T lymphocytes. The IPAF-induced B cells exhibited increased CD69 and MHC class II expression, and a dose- and time-dependent enhancement in IgM production. These results suggested potential benefits of IPAF to strengthen the humoral immunity. PMID- 21698211 TI - Control of CydB and GltA1 expression by the SenX3 RegX3 two component regulatory system of Mycobacterium tuberculosis. AB - Two component regulatory systems are used widely by bacteria to coordinate changes in global gene expression profiles in response to environmental signals. The SenX3-RegX3 two component system of Mycobacterium tuberculosis has previously been shown to play a role in virulence and phosphate-responsive control of gene expression. We demonstrate that expression of SenX3-RegX3 is controlled in response to growth conditions, although the absolute changes are small. Global gene expression profiling of a RegX3 deletion strain and wild-type strain in different culture conditions (static, microaerobic, anaerobic), as well as in an over-expressing strain identified a number of genes with changed expression patterns. Among those were genes previously identified as differentially regulated in aerobic culture, including ald (encoding alanine dehydrogenase) cyd,encoding a subunit of the cytochrome D ubiquinol oxidase, and gltA1, encoding a citrate synthase. Promoter activity in the upstream regions of both cydB and gltA1 was altered in the RegX3 deletion strain. DNA-binding assays confirmed that RegX3 binds to the promoter regions of ald, cydB and gltA1 in a phosphorylation dependent manner. Taken together these data suggest a direct role for the SenX RegX3 system in modulating expression of aerobic respiration, in addition to its role during phosphate limitation. PMID- 21698212 TI - Targeted delivery of mutant tolerant anti-coxsackievirus artificial microRNAs using folate conjugated bacteriophage Phi29 pRNA. AB - BACKGROUND: Myocarditis is the major heart disease in infants and young adults. It is very commonly caused by coxsackievirus B3 (CVB3) infection; however, no specific treatment or vaccine is available at present. RNA interference (RNAi) based anti-viral therapy has shown potential to inhibit viral replication, but this strategy faces two major challenges; viral mutational escape from drug suppression and targeted delivery of the reagents to specific cell populations. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we designed artificial microRNAs (AmiRs) targeting the 3'untranslated region (3'UTR) of CVB3 genome with mismatches to the central region of their targeting sites. Antiviral evaluation showed that AmiR-1 and AmiR-2 reduced CVB3 (Kandolf and CG strains) replication approximately 100-fold in both HeLa cells and HL-1 cardiomyocytes. To achieve specific delivery, we linked AmiRs to the folate-conjugated bacterial phage packaging RNA (pRNA) and delivered the complexes into HeLa cells, a folate receptor positive cancer cells widely used as an in vitro model for CVB3 infection, via folate-mediated specific internalization. We found that our designed pRNA-AmiRs conjugates were tolerable to target mutations and have great potential to suppress viral mutational escape with little effect on triggering interferon induction. CONCLUSION/SIGNIFICANCE: This study provides important clues for designing AmiRs targeting the 3'UTR of viral genome. It also proves the feasibility of specific deliver of AmiRs using conjugated pRNA vehicles. These small AmiRs combined with pRNA-folate conjugates could form a promising system for antiviral drug development. PMID- 21698213 TI - Morning and evening efficacy evaluation of rupatadine (10 and 20 mg), compared with cetirizine 10 mg in perennial allergic rhinitis: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: A circadian rhythm of symptoms has been reported in allergic rhinitis (AR). Severity of all major symptoms of AR, including runny nose, sneezing, and nasal congestion, is typically at its peak in the morning. The objective of this study was to explore the efficacy of the antihistamine and platelet activating factor (PAF) antagonist rupatadine in the morning and evening and to evaluate whether rupatadine provides effective symptom relief throughout the 24-hour dosing interval. METHODS: A total of 308 patients >=18 years of age with PAR was randomly assigned to once-daily rupatadine 10 mg, rupatadine 20 mg, or cetirizine 10 mg for 4 weeks in a placebo-controlled, double-blind study. The main outcome was the morning/evening reflective total symptom score (5TSS) over the treatment period. Secondary endpoints included morning/evening reflective nasal total symptom score (4NTSS), individual symptoms, Pdmax1 as percentage of days with daily severest symptom score <=1, and subject/investigator evaluation of therapeutic response. RESULTS: All active groups were significantly more effective than placebo in improving morning and evening evaluations of 5TSS (P < 0.001) and 4NTSS (P < 0.001) at 2 or 4 weeks. At morning evaluation, there was a significant reduction from baseline for 5TSS with rupatadine 10 mg (-36.8%, P < 0.01) and 20 mg (-46.3%, P < 0.01) compared with placebo. Similarly, 4NTSS was reduced significantly more with rupatadine 10 mg (-34%, P < 0.05) and 20 mg ( 41%, P < 0.01) compared with placebo. In the cetirizine 10 mg group, the reduction was -32.7% and -32.2% for 5TSS and 4NTSS, respectively, but this reduction was not significant compared with placebo. The percentage reduction was greater at evening than at morning evaluation. 5TSS reduction with rupatadine 10 mg (-40.7%, P < 0.05) and 20 mg (-49.9%, P < 0.01) and cetirizine 10 mg (-40.1%, P < 0.05) was significantly better than with placebo. 4NTSS values for active groups were also significantly improved versus placebo. When individual symptoms were assessed, statistically significant differences for rhinorrhea (P < 0.01), nasal itching (P < 0.01), and sneezing (P < 0.01) were shown in all active groups compared with placebo at morning and evening evaluations. Pdmax1 index was significantly improved for all active groups and the overall efficacy assessed by patients or investigators showed a significant improvement (P < 0.01) versus placebo at 2 and 4 weeks. The incidence of somnolence was significantly greater in all active groups versus placebo. CONCLUSION: The sustained 24-hour action of rupatadine 10 mg provides an effective control of morning and evening symptoms in patients with PAR treated for up to 4 weeks. PMID- 21698214 TI - Effectiveness of inhaler types for real-world asthma management: retrospective observational study using the GPRD. AB - PURPOSE: Results of randomized controlled trials may not predict effectiveness of inhaled corticosteroids (ICS) in real-world clinical practice, where inhaler technique and device characteristics can influence effectiveness. We compared asthma outcomes for ICS delivered via three different inhaler devices: pressurized metered-dose inhaler (pMDI), breath-actuated MDI (BAI), and dry powder inhaler (DPI). PATIENTS AND METHODS: This retrospective database study evaluated 1-year outcomes for primary care patients with asthma aged 5-60 years prescribed their first ICS (initiation population) by pMDI (n = 39,746), BAI (n = 9809), or DPI (n = 6792), or their first ICS dose increase (step-up population) by pMDI (n = 6245), BAI (n = 1388), or DPI (n = 1536). Co-primary outcome measures were composite proxy measures of asthma control (no hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory infection) and severe exacerbations (unscheduled hospital admission, emergency room attendance, or oral corticosteroids). Outcomes were adjusted for potential confounding factors identified during a baseline year. RESULTS: In the initiation population, adjusted odds ratios (95% confidence intervals [CI]) for asthma control, as compared with pMDIs, were significantly better for BAIs (1.08 [1.02 1.14]) and DPIs (1.13 [1.06-1.21]), while adjusted exacerbation rate ratios (95% CI) were 1.00 (0.93-1.08) and 0.88 (0.81-0.95), respectively. In the step-up population, adjusted odds of asthma control were 1.21 (1.05-1.39) for BAIs and 1.13 (0.99-1.29) for DPIs; adjusted exacerbation rate ratios were 0.83 (0.71 0.98) for BAIs and 0.85 (0.74-0.98) for DPIs, compared with pMDIs. CONCLUSION: Inhaler device selection may have a bearing on clinical outcomes. Differences in real-world effectiveness among these devices require closer evaluation in well designed prospective trials. PMID- 21698215 TI - Identification of DNA-damage DNA-binding protein 1 as a conditional essential factor for cytomegalovirus replication in interferon-gamma-stimulated cells. AB - The mouse cytomegaloviral (MCMV) protein pM27 represents an indispensable factor for viral fitness in vivo selectively, antagonizing signal transducer and activator of transcription 2 (STAT2)-mediated interferon signal transduction. We wished to explore by which molecular mechanism pM27 accomplishes this effect. We demonstrate that pM27 is essential and sufficient to curtail the protein half life of STAT2 molecules. Pharmacologic inhibition of the proteasome restored STAT2 amounts, leading to poly-ubiquitin-conjugated STAT2 forms. PM27 was found in complexes with an essential host ubiquitin ligase complex adaptor protein, DNA damage DNA-binding protein (DDB) 1. Truncation mutants of pM27 showed a strict correlation between DDB1 interaction and their ability to degrade STAT2. SiRNA mediated knock-down of DDB1 restored STAT2 in the presence of pM27 and strongly impaired viral replication in interferon conditioned cells, thus phenocopying the growth attenuation of M27-deficient virus. In a constructive process, pM27 recruits DDB1 to exploit ubiquitin ligase complexes catalyzing the obstruction of the STAT2-dependent antiviral state of cells to permit viral replication. PMID- 21698216 TI - High affinity nanobodies against the Trypanosome brucei VSG are potent trypanolytic agents that block endocytosis. AB - The African trypanosome Trypanosoma brucei, which persists within the bloodstream of the mammalian host, has evolved potent mechanisms for immune evasion. Specifically, antigenic variation of the variant-specific surface glycoprotein (VSG) and a highly active endocytosis and recycling of the surface coat efficiently delay killing mediated by anti-VSG antibodies. Consequently, conventional VSG-specific intact immunoglobulins are non-trypanocidal in the absence of complement. In sharp contrast, monovalent antigen-binding fragments, including 15 kDa nanobodies (Nb) derived from camelid heavy-chain antibodies (HCAbs) recognizing variant-specific VSG epitopes, efficiently lyse trypanosomes both in vitro and in vivo. This Nb-mediated lysis is preceded by very rapid immobilisation of the parasites, massive enlargement of the flagellar pocket and major blockade of endocytosis. This is accompanied by severe metabolic perturbations reflected by reduced intracellular ATP-levels and loss of mitochondrial membrane potential, culminating in cell death. Modification of anti VSG Nbs through site-directed mutagenesis and by reconstitution into HCAbs, combined with unveiling of trypanolytic activity from intact immunoglobulins by papain proteolysis, demonstrates that the trypanolytic activity of Nbs and Fabs requires low molecular weight, monovalency and high affinity. We propose that the generation of low molecular weight VSG-specific trypanolytic nanobodies that impede endocytosis offers a new opportunity for developing novel trypanosomiasis therapeutics. In addition, these data suggest that the antigen-binding domain of an anti-microbial antibody harbours biological functionality that is latent in the intact immunoglobulin and is revealed only upon release of the antigen binding fragment. PMID- 21698217 TI - Plasmodium falciparum merozoite invasion is inhibited by antibodies that target the PfRh2a and b binding domains. AB - Plasmodium falciparum, the causative agent of the most severe form of malaria in humans invades erythrocytes using multiple ligand-receptor interactions. The P. falciparum reticulocyte binding-like homologue proteins (PfRh or PfRBL) are important for entry of the invasive merozoite form of the parasite into red blood cells. We have analysed two members of this protein family, PfRh2a and PfRh2b, and show they undergo a complex series of proteolytic cleavage events before and during merozoite invasion. We show that PfRh2a undergoes a cleavage event in the transmembrane region during invasion consistent with activity of the membrane associated PfROM4 protease that would result in release of the ectodomain into the supernatant. We also show that PfRh2a and PfRh2b bind to red blood cells and have defined the erythrocyte-binding domain to a 15 kDa region at the N-terminus of each protein. Antibodies to this receptor-binding region block merozoite invasion demonstrating the important function of this domain. This region of PfRh2a and PfRh2b has potential in a combination vaccine with other erythrocyte binding ligands for induction of antibodies that would block a broad range of invasion pathways for P. falciparum into human erythrocytes. PMID- 21698219 TI - How abnormal is the behaviour of captive, zoo-living chimpanzees? AB - BACKGROUND: Many captive chimpanzees (Pan troglodytes) show a variety of serious behavioural abnormalities, some of which have been considered as possible signs of compromised mental health. The provision of environmental enrichments aimed at reducing the performance of abnormal behaviours is increasing the norm, with the housing of individuals in (semi-)natural social groups thought to be the most successful of these. Only a few quantitative studies of abnormal behaviour have been conducted, however, particularly for the captive population held in zoological collections. Consequently, a clear picture of the level of abnormal behaviour in zoo-living chimpanzees is lacking. METHODS: We present preliminary findings from a detailed observational study of the behaviour of 40 socially housed zoo-living chimpanzees from six collections in the United States of America and the United Kingdom. We determined the prevalence, diversity, frequency, and duration of abnormal behaviour from 1200 hours of continuous behavioural data collected by focal animal sampling. RESULTS, CONCLUSION AND SIGNIFICANCE: Our overall finding was that abnormal behaviour was present in all sampled individuals across six independent groups of zoo-living chimpanzees, despite the differences between these groups in size, composition, housing, etc. We found substantial variation between individuals in the frequency and duration of abnormal behaviour, but all individuals engaged in at least some abnormal behaviour and variation across individuals could not be explained by sex, age, rearing history or background (defined as prior housing conditions). Our data support a conclusion that, while most behaviour of zoo-living chimpanzees is 'normal' in that it is typical of their wild counterparts, abnormal behaviour is endemic in this population despite enrichment efforts. We suggest there is an urgent need to understand how the chimpanzee mind copes with captivity, an issue with both scientific and welfare implications. PMID- 21698218 TI - Sporangiospore size dimorphism is linked to virulence of Mucor circinelloides. AB - Mucor circinelloides is a zygomycete fungus and an emerging opportunistic pathogen in immunocompromised patients, especially transplant recipients and in some cases otherwise healthy individuals. We have discovered a novel example of size dimorphism linked to virulence. M. circinelloides is a heterothallic fungus: (+) sex allele encodes SexP and (-) sex allele SexM, both of which are HMG domain protein sex determinants. M. circinelloides f. lusitanicus (Mcl) (-) mating type isolates produce larger asexual sporangiospores that are more virulent in the wax moth host compared to (+) isolates that produce smaller less virulent sporangiospores. The larger sporangiospores germinate inside and lyse macrophages, whereas the smaller sporangiospores do not. sexMDelta mutants are sterile and still produce larger virulent sporangiospores, suggesting that either the sex locus is not involved in virulence/spore size or the sexP allele plays an inhibitory role. Phylogenetic analysis supports that at least three extant subspecies populate the M. circinelloides complex in nature: Mcl, M. circinelloides f. griseocyanus, and M. circinelloides f. circinelloides (Mcc). Mcc was found to be more prevalent among clinical Mucor isolates, and more virulent than Mcl in a diabetic murine model in contrast to the wax moth host. The M. circinelloides sex locus encodes an HMG domain protein (SexP for plus and SexM for minus mating types) flanked by genes encoding triose phosphate transporter (TPT) and RNA helicase homologs. The borders of the sex locus between the three subspecies differ: the Mcg sex locus includes the promoters of both the TPT and the RNA helicase genes, whereas the Mcl and Mcc sex locus includes only the TPT gene promoter. Mating between subspecies was restricted compared to mating within subspecies. These findings demonstrate that spore size dimorphism is linked to virulence of M. circinelloides species and that plasticity of the sex locus and adaptations in pathogenicity have occurred during speciation of the M. circinelloides complex. PMID- 21698220 TI - Environmental constraints guide migration of malaria parasites during transmission. AB - Migrating cells are guided in complex environments mainly by chemotaxis or structural cues presented by the surrounding tissue. During transmission of malaria, parasite motility in the skin is important for Plasmodium sporozoites to reach the blood circulation. Here we show that sporozoite migration varies in different skin environments the parasite encounters at the arbitrary sites of the mosquito bite. In order to systematically examine how sporozoite migration depends on the structure of the environment, we studied it in micro-fabricated obstacle arrays. The trajectories observed in vivo and in vitro closely resemble each other suggesting that structural constraints can be sufficient to guide Plasmodium sporozoites in complex environments. Sporozoite speed in different environments is optimized for migration and correlates with persistence length and dispersal. However, this correlation breaks down in mutant sporozoites that show adhesion impairment due to the lack of TRAP-like protein (TLP) on their surfaces. This may explain their delay in infecting the host. The flexibility of sporozoite adaption to different environments and a favorable speed for optimal dispersal ensures efficient host switching during malaria transmission. PMID- 21698221 TI - Increased sensitivity to broadly neutralizing antibodies of end-stage disease R5 HIV-1 correlates with evolution in Env glycosylation and charge. AB - BACKGROUND: Induction of broadly neutralizing antibodies, such as the monoclonal antibodies IgGb12, 2F5 and 2G12, is the objective of most antibody-based HIV-1 vaccine undertakings. However, despite the relative conserved nature of epitopes targeted by these antibodies, mechanisms underlying the sensitivity of circulating HIV-1 variants to broadly neutralizing antibodies are not fully understood. Here we have studied sensitivity to broadly neutralizing antibodies of HIV-1 variants that emerge during disease progression in relation to molecular alterations in the viral envelope glycoproteins (Env), using a panel of primary R5 HIV-1 isolates sequentially obtained before and after AIDS onset. PRINCIPAL FINDINGS: HIV-1 R5 isolates obtained at end-stage disease, after AIDS onset, were found to be more sensitive to neutralization by TriMab, an equimolar mix of the IgGb12, 2F5 and 2G12 antibodies, than R5 isolates from the chronic phase. The increased sensitivity correlated with low CD4(+) T cell count at time of virus isolation and augmented viral infectivity. Subsequent sequence analysis of multiple env clones derived from the R5 HIV-1 isolates revealed that, concomitant with increased TriMab neutralization sensitivity, end-stage R5 variants displayed envelope glycoproteins (Envs) with reduced numbers of potential N-linked glycosylation sites (PNGS), in addition to increased positive surface charge. These molecular changes in Env also correlated to sensitivity to neutralization by the individual 2G12 monoclonal antibody (mAb). Furthermore, results from molecular modeling suggested that the PNGS lost at end-stage disease locate in the proximity to the 2G12 epitope. CONCLUSIONS: Our study suggests that R5 HIV-1 variants with increased sensitivity to broadly neutralizing antibodies, including the 2G12 mAb, may emerge in an opportunistic manner during severe immunodeficiency as a consequence of adaptive molecular Env changes, including loss of glycosylation and gain of positive charge. PMID- 21698222 TI - The intrinsic antiviral defense to incoming HSV-1 genomes includes specific DNA repair proteins and is counteracted by the viral protein ICP0. AB - Cellular restriction factors responding to herpesvirus infection include the ND10 components PML, Sp100 and hDaxx. During the initial stages of HSV-1 infection, novel sub-nuclear structures containing these ND10 proteins form in association with incoming viral genomes. We report that several cellular DNA damage response proteins also relocate to sites associated with incoming viral genomes where they contribute to the cellular front line defense. We show that recruitment of DNA repair proteins to these sites is independent of ND10 components, and instead is coordinated by the cellular ubiquitin ligases RNF8 and RNF168. The viral protein ICP0 targets RNF8 and RNF168 for degradation, thereby preventing the deposition of repressive ubiquitin marks and counteracting this repair protein recruitment. This study highlights important parallels between recognition of cellular DNA damage and recognition of viral genomes, and adds RNF8 and RNF168 to the list of factors contributing to the intrinsic antiviral defense against herpesvirus infection. PMID- 21698223 TI - Signs of mood and anxiety disorders in chimpanzees. AB - BACKGROUND: In humans, traumatic experiences are sometimes followed by psychiatric disorders. In chimpanzees, studies have demonstrated an association between traumatic events and the emergence of behavioral disturbances resembling posttraumatic stress disorder (PTSD) and depression. We addressed the following central question: Do chimpanzees develop posttraumatic symptoms, in the form of abnormal behaviors, which cluster into syndromes similar to those described in human mood and anxiety disorders? METHODOLOGY/PRINCIPAL FINDINGS: In phase 1 of this study, we accessed case reports of chimpanzees who had been reportedly subjected to traumatic events, such as maternal separation, social isolation, experimentation, or similar experiences. We applied and tested DSM-IV criteria for PTSD and major depression to published case reports of 20 chimpanzees identified through PrimateLit. Additionally, using the DSM-IV criteria and ethograms as guides, we developed behaviorally anchored alternative criteria that were applied to the case reports. A small number of chimpanzees in the case studies met DSM-IV criteria for PTSD and depression. Measures of inter-rater reliability, including Fleiss' kappa and percentage agreement, were higher with use of the alternative criteria for PTSD and depression. In phase 2, the alternative criteria were applied to chimpanzees living in wild sites in Africa (n = 196) and chimpanzees living in sanctuaries with prior histories of experimentation, orphanage, illegal seizure, or violent human conflict (n = 168). In phase 2, 58% of chimpanzees living in sanctuaries met the set of alternative criteria for depression, compared with 3% of chimpanzees in the wild (p = 0.04), and 44% of chimpanzees in sanctuaries met the set of alternative criteria for PTSD, compared with 0.5% of chimpanzees in the wild (p = 0.04). CONCLUSIONS/SIGNIFICANCE: Chimpanzees display behavioral clusters similar to PTSD and depression in their key diagnostic criteria, underscoring the importance of ethical considerations regarding the use of chimpanzees in experimentation and other captive settings. PMID- 21698224 TI - Induction of Noxa-mediated apoptosis by modified vaccinia virus Ankara depends on viral recognition by cytosolic helicases, leading to IRF-3/IFN-beta-dependent induction of pro-apoptotic Noxa. AB - Viral infection is a stimulus for apoptosis, and in order to sustain viral replication many viruses are known to carry genes encoding apoptosis inhibitors. F1L, encoded by the orthopoxvirus modified vaccinia virus Ankara (MVA) has a Bcl 2-like structure. An MVA mutant lacking F1L (MVADeltaF1L) induces apoptosis, indicating that MVA infection activates and F1L functions to inhibit the apoptotic pathway. In this study we investigated the events leading to apoptosis upon infection by MVADeltaF1L. Apoptosis largely proceeded through the pro apoptotic Bcl-2 family protein Bak with some contribution from Bax. Of the family of pro-apoptotic BH3-only proteins, only the loss of Noxa provided substantial protection, while the loss of Bim had a minor effect. In mice, MVA preferentially infected macrophages and DCs in vivo. In both cell types wt MVA induced apoptosis albeit more weakly than MVADeltaF1L. The loss of Noxa had a significant protective effect in macrophages, DC and primary lymphocytes, and the combined loss of Bim and Noxa provided strong protection. Noxa protein was induced during infection, and the induction of Noxa protein and apoptosis induction required transcription factor IRF3 and type I interferon signalling. We further observed that helicases RIG-I and MDA5 and their signalling adapter MAVS contribute to Noxa induction and apoptosis in response to MVA infection. RNA isolated from MVA infected cells induced Noxa expression and apoptosis when transfected in the absence of viral infection. We thus here describe a pathway leading from the detection of viral RNA during MVA infection by the cytosolic helicase-pathway, to the up-regulation of Noxa and apoptosis via IRF3 and type I IFN signalling. PMID- 21698225 TI - Functional analysis of host factors that mediate the intracellular lifestyle of Cryptococcus neoformans. AB - Cryptococcus neoformans (Cn), the major causative agent of human fungal meningoencephalitis, replicates within phagolysosomes of infected host cells. Despite more than a half-century of investigation into host-Cn interactions, host factors that mediate infection by this fungal pathogen remain obscure. Here, we describe the development of a system that employs Drosophila S2 cells and RNA interference (RNAi) to define and characterize Cn host factors. The system recapitulated salient aspects of fungal interactions with mammalian cells, including phagocytosis, intracellular trafficking, replication, cell-to-cell spread and escape of the pathogen from host cells. Fifty-seven evolutionarily conserved host factors were identified using this system, including 29 factors that had not been previously implicated in mediating fungal pathogenesis. Subsequent analysis indicated that Cn exploits host actin cytoskeletal elements, cell surface signaling molecules, and vesicle-mediated transport proteins to establish a replicative niche. Several host molecules known to be associated with autophagy (Atg), including Atg2, Atg5, Atg9 and Pi3K59F (a class III PI3-kinase) were also uncovered in our screen. Small interfering RNA (siRNA) mediated depletion of these autophagy proteins in murine RAW264.7 macrophages demonstrated their requirement during Cn infection, thereby validating findings obtained using the Drosophila S2 cell system. Immunofluorescence confocal microscopy analyses demonstrated that Atg5, LC3, Atg9a were recruited to the vicinity of Cn containing vacuoles (CnCvs) in the early stages of Cn infection. Pharmacological inhibition of autophagy and/or PI3-kinase activity further demonstrated a requirement for autophagy associated host proteins in supporting infection of mammalian cells by Cn. Finally, systematic trafficking studies indicated that CnCVs associated with Atg proteins, including Atg5, Atg9a and LC3, during trafficking to a terminal intracellular compartment that was decorated with the lysosomal markers LAMP-1 and cathepsin D. Our findings validate the utility of the Drosophila S2 cell system as a functional genomic platform for identifying and characterizing host factors that mediate fungal intracellular replication. Our results also support a model in which host Atg proteins mediate Cn intracellular trafficking and replication. PMID- 21698227 TI - Functional evolution of leptin of Ochotona curzoniae in adaptive thermogenesis driven by cold environmental stress. AB - BACKGROUND: Environmental stress can accelerate the directional selection and evolutionary rate of specific stress-response proteins to bring about new or altered functions, enhancing an organism's fitness to challenging environments. Plateau pika (Ochotona curzoniae), an endemic and keystone species on Qinghai Tibetan Plateau, is a high hypoxia and low temperature tolerant mammal with high resting metabolic rate and non-shivering thermogenesis to cope in this harsh plateau environment. Leptin is a key hormone related to how these animals regulate energy homeostasis. Previous molecular evolutionary analysis helped to generate the hypothesis that adaptive evolution of plateau pika leptin may be driven by cold stress. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis, recombinant pika leptin was first purified. The thermogenic characteristics of C57BL/6J mice injected with pika leptin under warm (23+/-1 degrees C) and cold (5+/-1 degrees C) acclimation is investigated. Expression levels of genes regulating adaptive thermogenesis in brown adipose tissue and the hypothalamus are compared between pika leptin and human leptin treatment, suggesting that pika leptin has adaptively and functionally evolved. Our results show that pika leptin regulates energy homeostasis via reduced food intake and increased energy expenditure under both warm and cold conditions. Compared with human leptin, pika leptin demonstrates a superior induced capacity for adaptive thermogenesis, which is reflected in a more enhanced beta-oxidation, mitochondrial biogenesis and heat production. Moreover, leptin treatment combined with cold stimulation has a significant synergistic effect on adaptive thermogenesis, more so than is observed with a single cold exposure or single leptin treatment. CONCLUSIONS/SIGNIFICANCE: These findings support the hypothesis that cold stress has driven the functional evolution of plateau pika leptin as an ecological adaptation to the Qinghai-Tibetan Plateau. PMID- 21698226 TI - What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. AB - BACKGROUND: Resveratrol is a natural compound suggested to have beneficial health effects. However, people are consuming resveratrol for this reason without having the adequate scientific evidence for its effects in humans. Therefore, scientific valid recommendations concerning the human intake of resveratrol based on available published scientific data are necessary. Such recommendations were formulated after the Resveratrol 2010 conference, held in September 2010 in Helsingor, Denmark. METHODOLOGY: Literature search in databases as PUBMED and ISI Web of Science in combination with manual search was used to answer the following five questions: (1)Can resveratrol be recommended in the prevention or treatment of human diseases?; (2)Are there observed "side effects" caused by the intake of resveratrol in humans?; (3)What is the relevant dose of resveratrol?; (4)What valid data are available regarding an effect in various species of experimental animals?; (5)Which relevant (overall) mechanisms of action of resveratrol have been documented? CONCLUSIONS/SIGNIFICANCE: The overall conclusion is that the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources. On the other hand, animal data are promising in prevention of various cancer types, coronary heart diseases and diabetes which strongly indicate the need for human clinical trials. Finally, we suggest directions for future research in resveratrol regarding its mechanism of action and its safety and toxicology in human subjects. PMID- 21698228 TI - Productive parvovirus B19 infection of primary human erythroid progenitor cells at hypoxia is regulated by STAT5A and MEK signaling but not HIFalpha. AB - Human parvovirus B19 (B19V) causes a variety of human diseases. Disease outcomes of bone marrow failure in patients with high turnover of red blood cells and immunocompromised conditions, and fetal hydrops in pregnant women are resulted from the targeting and destruction of specifically erythroid progenitors of the human bone marrow by B19V. Although the ex vivo expanded erythroid progenitor cells recently used for studies of B19V infection are highly permissive, they produce progeny viruses inefficiently. In the current study, we aimed to identify the mechanism that underlies productive B19V infection of erythroid progenitor cells cultured in a physiologically relevant environment. Here, we demonstrate an effective reverse genetic system of B19V, and that B19V infection of ex vivo expanded erythroid progenitor cells at 1% O(2) (hypoxia) produces progeny viruses continuously and efficiently at a level of approximately 10 times higher than that seen in the context of normoxia. With regard to mechanism, we show that hypoxia promotes replication of the B19V genome within the nucleus, and that this is independent of the canonical PHD/HIFalpha pathway, but dependent on STAT5A and MEK/ERK signaling. We further show that simultaneous upregulation of STAT5A signaling and down-regulation of MEK/ERK signaling boosts the level of B19V infection in erythroid progenitor cells under normoxia to that in cells under hypoxia. We conclude that B19V infection of ex vivo expanded erythroid progenitor cells at hypoxia closely mimics native infection of erythroid progenitors in human bone marrow, maintains erythroid progenitors at a stage conducive to efficient production of progeny viruses, and is regulated by the STAT5A and MEK/ERK pathways. PMID- 21698229 TI - "Rational vaccine design" for HIV should take into account the adaptive potential of polyreactive antibodies. PMID- 21698230 TI - Increased expression of the dyslexia candidate gene DCDC2 affects length and signaling of primary cilia in neurons. AB - DCDC2 is one of the candidate susceptibility genes for dyslexia. It belongs to the superfamily of doublecortin domain containing proteins that bind to microtubules, and it has been shown to be involved in neuronal migration. We show that the Dcdc2 protein localizes to the primary cilium in primary rat hippocampal neurons and that it can be found within close proximity to the ciliary kinesin-2 subunit Kif3a. Overexpression of DCDC2 increases ciliary length and activates Shh signaling, whereas downregulation of Dcdc2 expression enhances Wnt signaling, consistent with a functional role in ciliary signaling. Moreover, DCDC2 overexpression in C. elegans causes an abnormal neuronal phenotype that can only be seen in ciliated neurons. Together our results suggest a potential role for DCDC2 in the structure and function of primary cilia. PMID- 21698231 TI - Intestinal activation of Notch signaling induces rapid onset hepatic steatosis and insulin resistance. AB - Here we investigate the effects of expressing an activated mutant of Notch (ICD E) in an inducible transgenic mouse model. Hepatic expression of ICD-E in adult animals has no detectable phenotype, but simultaneous induction of ICD-E in both the liver and small intestine results in hepatic steatosis, lipogranuloma formation and mild insulin resistance within 96 hours. This supports work that suggests that fatty liver disease may result from disruption of the gut-liver axis. In the intestine, ICD-E expression is known to produce a transient change in the proportion of goblet cells followed by shedding of the recombinant epithelium. We report additional intestinal transcriptional changes following ICD E expression, finding significant transcriptional down-regulation of rpL29 (ribosomal protein L29), which is implicated in the regulation of intestinal flora. These results provide further evidence of a gut-liver axis in the development of fatty liver disease and insulin resistance and validate a new model for future studies of hepatic steatosis. PMID- 21698232 TI - Node vulnerability under finite perturbations in complex networks. AB - A measure to quantify vulnerability under perturbations (attacks, failures, large fluctuations) in ensembles (networks) of coupled dynamical systems is proposed. Rather than addressing the issue of how the network properties change upon removal of elements of the graph (the strategy followed by most of the existing methods for studying the vulnerability of a network based on its topology), here a dynamical definition of vulnerability is introduced, referring to the robustness of a collective dynamical state to perturbing events occurring over a fixed topology. In particular, we study how the collective (synchronized) dynamics of a network of chaotic units is disrupted under the action of a finite size perturbation on one of its nodes. Illustrative examples are provided for three systems of identical chaotic oscillators coupled according to three distinct well-known network topologies. A quantitative comparison between the obtained vulnerability rankings and the classical connectivity/centrality rankings is made that yields conclusive results. Possible applications of the proposed strategy and conclusions are also discussed. PMID- 21698234 TI - Fractal characteristics of May-Grunwald-Giemsa stained chromatin are independent prognostic factors for survival in multiple myeloma. AB - BACKGROUND: The use of computerized image analysis for the study of nuclear texture features has provided important prognostic information for several neoplasias. Recently fractal characteristics of the chromatin structure in routinely stained smears have shown to be independent prognostic factors in acute leukemia. In the present study we investigated the influence of the fractal dimension (FD) of chromatin on survival of patients with multiple myeloma. METHODOLOGY: We analyzed 67 newly diagnosed patients from our Institution treated in the Brazilian Multiple Myeloma Study Group. Diagnostic work-up consisted of peripheral blood counts, bone marrow cytology, bone radiograms, serum biochemistry and cytogenetics. The International Staging System (ISS) was used. In every patient, at least 40 digital nuclear images from diagnostic May-Grunwald Giemsa stained bone marrow smears were acquired and transformed into pseudo-3D images. FD was determined by the Minkowski-Bouligand method extended to three dimensions. Goodness-of-fit of FD was estimated by the R(2) values in the log-log plots. The influence of diagnostic features on overall survival was analyzed in Cox regressions. Patients that underwent autologous bone marrow transplantation were censored at the day of transplantation. PRINCIPAL FINDINGS: Median age was 56 years. According to ISS, 14% of the patients were stage I, 39% were stage II and 47% were stage III. Additional features of a bad prognosis were observed in 46% of the cases. When stratifying for ISS, both FD and its goodness-of-fit were significant prognostic factors in univariate analyses. Patients with higher FD values or lower goodness-of-fit showed a worse outcome. In the multivariate Cox regression, FD, R(2), and ISS stage entered the final model, which showed to be stable in a bootstrap resampling study. CONCLUSIONS: Fractal characteristics of the chromatin texture in routine cytological preparations revealed relevant prognostic information in patients with multiple myeloma. PMID- 21698233 TI - MMP-2 siRNA inhibits radiation-enhanced invasiveness in glioma cells. AB - BACKGROUND: Our previous work and that of others strongly suggests a relationship between the infiltrative phenotype of gliomas and the expression of MMP-2. Radiation therapy, which represents one of the mainstays of glioma treatment, is known to increase cell invasion by inducing MMP-2. Thus, inhibition of MMP-2 provides a potential means for improving the efficacy of radiotherapy for malignant glioma. METHODOLOGY/PRINCIPAL FINDINGS: We have tested the ability of a plasmid vector-mediated MMP-2 siRNA (p-MMP-2) to modulate ionizing radiation induced invasive phenotype in the human glioma cell lines U251 and U87. Cells that were transfected with p-MMP-2 with and without radiation showed a marked reduction of MMP-2 compared to controls and pSV-transfected cells. A significant reduction of proliferation, migration, invasion and angiogenesis of cells transfected with p-MMP-2 and in combination with radiation was observed compared to controls. Western blot analysis revealed that radiation-enhanced levels of VEGF, VEGFR-2, pVEGFR-2, p-FAK, and p-p38 were inhibited with p-MMP-2-transfected cells. TUNEL staining showed that radiation did not induce apoptosis in U87 and U251 cells while a significant increase in TUNEL-positive cells was observed when irradiated cells were simultaneously transfected with p-MMP-2 as compared to controls. Intracranial tumor growth was predominantly inhibited in the animals treated with p-MMP-2 alone or in combination with radiation compared to controls. CONCLUSION/SIGNIFICANCE: MMP-2 inhibition, mediated by p-MMP-2 and in combination with radiation, significantly reduced tumor cell migration, invasion, angiogenesis and tumor growth by modulating several important downstream signaling molecules and directing cells towards apoptosis. Taken together, our results demonstrate the efficacy of p-MMP-2 in inhibiting radiation-enhanced tumor invasion and progression and suggest that it may act as a potent adjuvant for radiotherapy in glioma patients. PMID- 21698235 TI - Genome-wide transcriptomic analysis of intestinal tissue to assess the impact of nutrition and a secondary nematode challenge in lactating rats. AB - BACKGROUND: Gastrointestinal nematode infection is a major challenge to the health and welfare of mammals. Although mammals eventually acquire immunity to nematodes, this breaks down around parturition, which renders periparturient mammals susceptible to re-infection and an infection source for their offspring. Nutrient supplementation reduces the extent of periparturient parasitism, but the underlying mechanisms remain unclear. Here, we use a genome wide approach to assess the effects of protein supplementation on gene expression in the small intestine of periparturient rats following nematode re-infection. METHODOLOGY/PRINCIPAL FINDINGS: The use of a rat whole genome expression microarray (Affymetrix Gene 1.0ST) showed significant differential regulation of 91 genes in the small intestine of lactating rats, re-infected with Nippostrongylus brasiliensis compared to controls; affected functions included immune cell trafficking, cell-mediated responses and antigen presentation. Genes with a previously described role in immune response to nematodes, such as mast cell proteases, and intelectin, and others newly associated with nematode expulsion, such as anterior gradient homolog 2 were identified. Protein supplementation resulted in significant differential regulation of 64 genes; affected functions included protein synthesis, cellular function and maintenance. It increased cell metabolism, evident from the high number of non-coding RNA and the increased synthesis of ribosomal proteins. It regulated immune responses, through T-cell activation and proliferation. The up-regulation of transcription factor forkhead box P1 in unsupplemented, parasitised hosts may be indicative of a delayed immune response in these animals. CONCLUSIONS/SIGNIFICANCE: This study provides the first evidence for nutritional regulation of genes related to immunity to nematodes at the site of parasitism, during expulsion. Additionally it reveals genes induced following secondary parasite challenge in lactating mammals, not previously associated with parasite expulsion. This work is a first step towards defining disease predisposition, identifying markers for nutritional imbalance and developing sustainable measures for parasite control in domestic mammals. PMID- 21698236 TI - Neurite outgrowth of mature retinal ganglion cells and PC12 cells requires activity of CK1delta and CK1epsilon. AB - Mature retinal ganglion cells (RGCs) do not normally regenerate severed axons after optic nerve injury and show only little neurite outgrowth in culture. However, RGCs can be transformed into an active regenerative state after lens injury (LI) enabling these neurons to regrow axons in vitro and in vivo. In the current study we investigated the role of CK1delta and CK1epsilon activity in neurite outgrowth of LI stimulated RGCs and nerve growth factor (NGF) stimulated PC12 cells, respectively. In both cell types CK1delta and epsilon were localized in granular particles aligned at microtubules in neurites and growth cones. Although LI treatment did not measurably affect the expression of CK1delta and epsilon, it significantly elevated the specific kinase activity in the retina. Similarly, CK1delta/epsilon specific kinase activity was also elevated in NGF treated PC12 cells compared with untreated controls. Neurite extension in PC12 cells was associated with a change in the activity of CK1delta C-terminal targeting kinases, suggesting that activity of these kinases might be necessary for neurite outgrowth. Pharmacological inactivation of CK1delta and epsilon markedly compromised neurite outgrowth of both, PC12 cells and LI stimulated RGCs in a concentration dependent manner. These data provide evidence for a so far unknown, but essential role of CK1 isoforms in neurite growth. PMID- 21698237 TI - TLR2 signaling contributes to rapid inflammasome activation during F. novicida infection. AB - BACKGROUND: Early detection of microorganisms by the innate immune system is provided by surface-expressed and endosomal pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs). Detection of microbial components by TLRs initiates a signaling cascade leading to the expression of proinflammatory cytokines including IL-6 and IL-1beta. Some intracellular bacteria subvert the TLR response by rapidly escaping the phagosome and entering the cytosol. However, these bacteria may be recognized by the inflammasome, a multi-protein complex comprised of a sensor protein, ASC and the cysteine protease caspase-1. Inflammasome activation leads to release of the proinflammatory cytokines IL 1beta and IL-18 and death of the infected cell, an important host defense that eliminates the pathogen's replicative niche. While TLRs and inflammasomes are critical for controlling bacterial infections, it is unknown whether these distinct host pathways cooperate to activate defenses against intracellular bacteria. METHODOLOGY/SIGNIFICANT FINDINGS: Using the intracellular bacterium Francisella novicida as a model, we show that TLR2(-/-) macrophages exhibited delayed inflammasome activation compared to wild-type macrophages as measured by inflammasome assembly, caspase-1 activation, cell death and IL-18 release. TLR2 also contributed to inflammasome activation in response to infection by the cytosolic bacterium Listeria monocytogenes. Components of the TLR2 signaling pathway, MyD88 and NF-kappaB, were required for rapid inflammasome activation. Furthermore, TLR2(-/-) mice exhibited lower levels of cell death, caspase-1 activation, and IL-18 production than wild-type mice upon F. novicida infection. CONCLUSIONS/SIGNIFICANCE: These results show that TLR2 is required for rapid inflammasome activation in response to infection by cytosolic bacterial pathogens. In addition to further characterizing the role of TLR2 in host defense, these findings broaden our understanding of how the host integrates signals from spatiotemporally separated PRRs to coordinate an innate response against intracellular bacteria. PMID- 21698238 TI - Replication of putative susceptibility loci from genome-wide association studies associated with coronary atherosclerosis in Chinese Han population. AB - BACKGROUND: Coronary atherosclerosis, the main cause of cardiovascular disease, is a progressive disease. Recent Genome Wide Association Studies (GWASs) discovered several novel loci associated with coronary artery disease (CAD) or its main complication myocardial infarction (MI). In this study, we investigated the associations between previously reported CAD- and MI-associated variants and coronary atherosclerosis in Chinese Han population. METHODOLOGY/PRINCIPAL FINDINGS: We performed a case-control association study with 2,335 coronary atherosclerosis patients and 1,078 controls undergoing coronary angiography of Chinese Han from China. Fourteen single nucleotide polymorphisms (SNPs), located at 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21.3, 10q11.21 and 15q22.33, were genotyped in our sample collection. Six SNPs at 9p21 were associated with coronary atherosclerosis susceptibility (P(trend)<0.05) and rs10757274 showed the most significant association (P = 2.38*10(-08), OR = 1.34). These associations remained significant after adjustment for multiple comparisons. Rs17465637 at 1q41 (P(trend) = 6.83*10(-03), OR = 0.86) also showed significant association with coronary atherosclerosis, but the association was not significant after multiple comparisons. Additionally, rs501120 (P = 8.36*10(-03), OR = 0.80) at 10q11.21 was associated with coronary atherosclerosis in females, but did not show association in males and all participants. Variants at 1p13.3, 2q36.3, 6q25.1 and 15q22.33 showed no associations with coronary atherosclerosis and main cardiovascular risk factors in our data. CONCLUSIONS/SIGNIFICANCE: Our findings indicated variants at 9p21 were significantly associated with coronary atherosclerosis in Han Chinese. Variants at 1q41 showed suggestive evidence of association and variants at 10q11.21 showed suggestive evidence of association in females, which warrant further study in a larger sample. PMID- 21698239 TI - Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. AB - Natural killer (NK) cell-based adoptive immunotherapy is a promising treatment approach for many cancers. However, development of protocols that provide large numbers of functional NK cells produced under GMP conditions are required to facilitate clinical studies. In this study, we translated our cytokine-based culture protocol for ex vivo expansion of NK cells from umbilical cord blood (UCB) hematopoietic stem cells into a fully closed, large-scale, cell culture bioprocess. We optimized enrichment of CD34(+) cells from cryopreserved UCB units using the CliniMACS system followed by efficient expansion for 14 days in gas permeable cell culture bags. Thereafter, expanded CD34(+) UCB cells could be reproducibly amplified and differentiated into CD56(+)CD3(-) NK cell products using bioreactors with a mean expansion of more than 2,000 fold and a purity of >90%. Moreover, expansion in the bioreactor yielded a clinically relevant dose of NK cells (mean: 2*10(9) NK cells), which display high expression of activating NK receptors and cytolytic activity against K562. Finally, we established a versatile closed washing procedure resulting in optimal reduction of medium, serum and cytokines used in the cell culture process without changes in phenotype and cytotoxic activity. These results demonstrate that large numbers of UCB stem cell-derived NK cell products for adoptive immunotherapy can be produced in closed, large-scale bioreactors for the use in clinical trials. PMID- 21698240 TI - Holistic processing of words modulated by reading experience. AB - Perceptual expertise has been studied intensively with faces and object categories involving detailed individuation. A common finding is that experience in fulfilling the task demand of fine, subordinate-level discrimination between highly similar instances is associated with the development of holistic processing. This study examines whether holistic processing is also engaged by expert word recognition, which is thought to involve coarser, basic-level processing that is more part-based. We adopted a paradigm widely used for faces- the composite task, and found clear evidence of holistic processing for English words. A second experiment further showed that holistic processing for words was sensitive to the amount of experience with the language concerned (native vs. second-language readers) and with the specific stimuli (words vs. pseudowords). The adoption of a paradigm from the face perception literature to the study of expert word perception is important for further comparison between perceptual expertise with words and face-like expertise. PMID- 21698241 TI - Simplivariate models: uncovering the underlying biology in functional genomics data. AB - One of the first steps in analyzing high-dimensional functional genomics data is an exploratory analysis of such data. Cluster Analysis and Principal Component Analysis are then usually the method of choice. Despite their versatility they also have a severe drawback: they do not always generate simple and interpretable solutions. On the basis of the observation that functional genomics data often contain both informative and non-informative variation, we propose a method that finds sets of variables containing informative variation. This informative variation is subsequently expressed in easily interpretable simplivariate components.We present a new implementation of the recently introduced simplivariate models. In this implementation, the informative variation is described by multiplicative models that can adequately represent the relations between functional genomics data. Both a simulated and two real-life metabolomics data sets show good performance of the method. PMID- 21698242 TI - Statistical quantification of methylation levels by next-generation sequencing. AB - BACKGROUND/AIMS: Recently, next-generation sequencing-based technologies have enabled DNA methylation profiling at high resolution and low cost. Methyl-Seq and Reduced Representation Bisulfite Sequencing (RRBS) are two such technologies that interrogate methylation levels at CpG sites throughout the entire human genome. With rapid reduction of sequencing costs, these technologies will enable epigenotyping of large cohorts for phenotypic association studies. Existing quantification methods for sequencing-based methylation profiling are simplistic and do not deal with the noise due to the random sampling nature of sequencing and various experimental artifacts. Therefore, there is a need to investigate the statistical issues related to the quantification of methylation levels for these emerging technologies, with the goal of developing an accurate quantification method. METHODS: In this paper, we propose two methods for Methyl-Seq quantification. The first method, the Maximum Likelihood estimate, is both conceptually intuitive and computationally simple. However, this estimate is biased at extreme methylation levels and does not provide variance estimation. The second method, based on bayesian hierarchical model, allows variance estimation of methylation levels, and provides a flexible framework to adjust technical bias in the sequencing process. RESULTS: We compare the previously proposed binary method, the Maximum Likelihood (ML) method, and the bayesian method. In both simulation and real data analysis of Methyl-Seq data, the bayesian method offers the most accurate quantification. The ML method is slightly less accurate than the bayesian method. But both our proposed methods outperform the original binary method in Methyl-Seq. In addition, we applied these quantification methods to simulation data and show that, with sequencing depth above 40-300 (which varies with different tissue samples) per cleavage site, Methyl-Seq offers a comparable quantification consistency as microarrays. PMID- 21698243 TI - Planktonic microbes in the Gulf of Maine area. AB - In the Gulf of Maine area (GoMA), as elsewhere in the ocean, the organisms of greatest numerical abundance are microbes. Viruses in GoMA are largely cyanophages and bacteriophages, including podoviruses which lack tails. There is also evidence of Mimivirus and Chlorovirus in the metagenome. Bacteria in GoMA comprise the dominant SAR11 phylotype cluster, and other abundant phylotypes such as SAR86-like cluster, SAR116-like cluster, Roseobacter, Rhodospirillaceae, Acidomicrobidae, Flavobacteriales, Cytophaga, and unclassified Alphaproteobacteria and Gammaproteobacteria clusters. Bacterial epibionts of the dinoflagellate Alexandrium fundyense include Rhodobacteraceae, Flavobacteriaceae, Cytophaga spp., Sulfitobacter spp., Sphingomonas spp., and unclassified Bacteroidetes. Phototrophic prokaryotes in GoMA include cyanobacteria that contain chlorophyll (mainly Synechococcus), aerobic anoxygenic phototrophs that contain bacteriochlorophyll, and bacteria that contain proteorhodopsin. Eukaryotic microalgae in GoMA include Bacillariophyceae, Dinophyceae, Prymnesiophyceae, Prasinophyceae, Trebouxiophyceae, Cryptophyceae, Dictyochophyceae, Chrysophyceae, Eustigmatophyceae, Pelagophyceae, Synurophyceae, and Xanthophyceae. There are no records of Bolidophyceae, Aurearenophyceae, Raphidophyceae, and Synchromophyceae in GoMA. In total, there are records for 665 names and 229 genera of microalgae. Heterotrophic eukaryotic protists in GoMA include Dinophyceae, Alveolata, Apicomplexa, amoeboid organisms, Labrynthulida, and heterotrophic marine stramenopiles (MAST). Ciliates include Strombidium, Lohmaniella, Tontonia, Strobilidium, Strombidinopsis and the mixotrophs Laboea strobila and Myrionecta rubrum (ex Mesodinium rubra). An inventory of selected microbial groups in each of 14 physiographic regions in GoMA is made by combining information on the depth-dependent variation of cell density and the depth dependent variation of water volume. Across the entire GoMA, an estimate for the minimum abundance of cell-based microbes is 1.7*10(25) organisms. By one account, this number of microbes implies a richness of 10(5) to 10(6) taxa in the entire water volume of GoMA. Morphological diversity in microplankton is well-described but the true extent of taxonomic diversity, especially in the femtoplankton, picoplankton and nanoplankton--whether autotrophic, heterotrophic, or mixotrophic, is unknown. PMID- 21698244 TI - Transcriptome profiling of whole blood cells identifies PLEK2 and C1QB in human melanoma. AB - BACKGROUND: Developing analytical methodologies to identify biomarkers in easily accessible body fluids is highly valuable for the early diagnosis and management of cancer patients. Peripheral whole blood is a "nucleic acid-rich" and "inflammatory cell-rich" information reservoir and represents systemic processes altered by the presence of cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: We conducted transcriptome profiling of whole blood cells from melanoma patients. To overcome challenges associated with blood-based transcriptome analysis, we used a PAXgeneTM tube and NuGEN OvationTM globin reduction system. The combined use of these systems in microarray resulted in the identification of 78 unique genes differentially expressed in the blood of melanoma patients. Of these, 68 genes were further analyzed by quantitative reverse transcriptase PCR using blood samples from 45 newly diagnosed melanoma patients (stage I to IV) and 50 healthy control individuals. Thirty-nine genes were verified to be differentially expressed in blood samples from melanoma patients. A stepwise logit analysis selected eighteen 2-gene signatures that distinguish melanoma from healthy controls. Of these, a 2-gene signature consisting of PLEK2 and C1QB led to the best result that correctly classified 93.3% melanoma patients and 90% healthy controls. Both genes were upregulated in blood samples of melanoma patients from all stages. Further analysis using blood fractionation showed that CD45(-) and CD45(+) populations were responsible for the altered expression levels of PLEK2 and C1QB, respectively. CONCLUSIONS/SIGNIFICANCE: The current study provides the first analysis of whole blood-based transcriptome biomarkers for malignant melanoma. The expression of PLEK2, the strongest gene to classify melanoma patients, in CD45(-) subsets illustrates the importance of analyzing whole blood cells for biomarker studies. The study suggests that transcriptome profiling of blood cells could be used for both early detection of melanoma and monitoring of patients for residual disease. PMID- 21698245 TI - Formalin fixation at low temperature better preserves nucleic acid integrity. AB - Fixation with formalin, a widely adopted procedure to preserve tissue samples, leads to extensive degradation of nucleic acids and thereby compromises procedures like microarray-based gene expression profiling. We hypothesized that RNA fragmentation is caused by activation of RNAses during the interval between formalin penetration and tissue fixation. To prevent RNAse activation, a series of tissue samples were kept under-vacuum at 4 degrees C until fixation and then fixed at 4 degrees C, for 24 hours, in formalin followed by 4 hours in ethanol 95%. This cold-fixation (CF) procedure preserved DNA and RNA, so that RNA segments up to 660 bp were efficiently amplified. Histological and immunohistochemical features were fully comparable with those of standard fixation. Microarray-based gene expression profiles were comparable with those obtained on matched frozen samples for probes hybridizing within 700 bases from the reverse transcription start site. In conclusion, CF preserves tissues and nucleic acids, enabling reliable gene expression profiling of fixed tissues. PMID- 21698246 TI - Preferential activation of SMAD1/5/8 on the fibrosa endothelium in calcified human aortic valves--association with low BMP antagonists and SMAD6. AB - BACKGROUND: Aortic valve (AV) calcification preferentially occurs on the fibrosa side while the ventricularis side remains relatively unaffected. Here, we tested the hypothesis that side-dependent activation of bone morphogenic protein (BMP) pathway in the endothelium of the ventricularis and fibrosa is associated with human AV calcification. METHODS AND RESULTS: Human calcified AVs obtained from AV replacement surgeries and non-calcified AVs from heart transplantations were used for immunohistochemical studies. We found SMAD-1/5/8 phosphorylation (a canonical BMP pathway) was higher in the calcified fibrosa than the non-calcified fibrosa while SMAD-2/3 phosphorylation (a canonical TGFbeta pathway) did not show any difference. Interestingly, we found that BMP-2/4/6 expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both calcified and non-calcified AV cusps; however, BMP antagonists (crossvienless-2/BMPER and noggin) expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both disease states. Moreover, significant expression of inhibitory SMAD-6 expression was found only in the non-calcified ventricularis endothelium. CONCLUSIONS: SMAD-1/5/8 is preferentially activated in the calcified fibrosa endothelium of human AVs and it correlates with low expression of BMP antagonists and inhibitory SMAD6. These results suggest a dominant role of BMP antagonists in the side-dependent calcification of human AVs. PMID- 21698247 TI - Inconsistent results of diagnostic tools hamper the differentiation between bee and vespid venom allergy. AB - BACKGROUND: Double sensitization (DS) to bee and vespid venom is frequently observed in the diagnosis of hymenoptera venom allergy, but clinically relevant DS is rare. Therefore it is sophisticated to choose the relevant venom for specific immunotherapy and overtreatment with both venoms may occur. We aimed to compare currently available routine diagnostic tests as well as experimental tests to identify the most accurate diagnostic tool. METHODS: 117 patients with a history of a bee or vespid allergy were included in the study. Initially, IgE determination by the ImmunoCAP, by the Immulite, and by the ADVIA Centaur, as well as the intradermal test (IDT) and the basophil activation test (BAT) were performed. In 72 CAP double positive patients, individual IgE patterns were determined by western blot inhibition and component resolved diagnosis (CRD) with rApi m 1, nVes v 1, and nVes v 5. RESULTS: Among 117 patients, DS was observed in 63.7% by the Immulite, in 61.5% by the CAP, in 47.9% by the IDT, in 20.5% by the ADVIA, and in 17.1% by the BAT. In CAP double positive patients, western blot inhibition revealed CCD-based DS in 50.8%, and the CRD showed 41.7% of patients with true DS. Generally, agreement between the tests was only fair and inconsistent results were common. CONCLUSION: BAT, CRD, and ADVIA showed a low rate of DS. However, the rate of DS is higher than expected by personal history, indicating that the matter of clinical relevance is still not solved even by novel tests. Furthermore, the lack of agreement between these tests makes it difficult to distinguish between bee and vespid venom allergy. At present, no routinely employed test can be regarded as gold standard to find the clinically relevant sensitization. PMID- 21698248 TI - Neuronal assembly detection and cell membership specification by principal component analysis. AB - In 1949, Donald Hebb postulated that assemblies of synchronously activated neurons are the elementary units of information processing in the brain. Despite being one of the most influential theories in neuroscience, Hebb's cell assembly hypothesis only started to become testable in the past two decades due to technological advances. However, while the technology for the simultaneous recording of large neuronal populations undergoes fast development, there is still a paucity of analytical methods that can properly detect and track the activity of cell assemblies. Here we describe a principal component-based method that is able to (1) identify all cell assemblies present in the neuronal population investigated, (2) determine the number of neurons involved in ensemble activity, (3) specify the precise identity of the neurons pertaining to each cell assembly, and (4) unravel the time course of the individual activity of multiple assemblies. Application of the method to multielectrode recordings of awake and behaving rats revealed that assemblies detected in the cerebral cortex and hippocampus typically contain overlapping neurons. The results indicate that the PCA method presented here is able to properly detect, track and specify neuronal assemblies, irrespective of overlapping membership. PMID- 21698250 TI - Translational database selection and multiplexed sequence capture for up front filtering of reliable breast cancer biomarker candidates. AB - Biomarker identification is of utmost importance for the development of novel diagnostics and therapeutics. Here we make use of a translational database selection strategy, utilizing data from the Human Protein Atlas (HPA) on differentially expressed protein patterns in healthy and breast cancer tissues as a means to filter out potential biomarkers for underlying genetic causatives of the disease. DNA was isolated from ten breast cancer biopsies, and the protein coding and flanking non-coding genomic regions corresponding to the selected proteins were extracted in a multiplexed format from the samples using a single DNA sequence capture array. Deep sequencing revealed an even enrichment of the multiplexed samples and a great variation of genetic alterations in the tumors of the sampled individuals. Benefiting from the upstream filtering method, the final set of biomarker candidates could be completely verified through bidirectional Sanger sequencing, revealing a 40 percent false positive rate despite high read coverage. Of the variants encountered in translated regions, nine novel non synonymous variations were identified and verified, two of which were present in more than one of the ten tumor samples. PMID- 21698249 TI - Equine torovirus (BEV) induces caspase-mediated apoptosis in infected cells. AB - Toroviruses are gastroenteritis causing agents that infect different animal species and humans. To date, very little is known about how toroviruses cause disease. Here, we describe for the first time that the prototype member of this genus, the equine torovirus Berne virus (BEV), induces apoptosis in infected cells at late times postinfection. Observation of BEV infected cells by electron microscopy revealed that by 24 hours postinfection some cells exhibited morphological characteristics of apoptotic cells. Based on this finding, we analyzed several apoptotic markers, and observed protein synthesis inhibition, rRNA and DNA degradation, nuclear fragmentation, caspase-mediated cleavage of PARP and eIF4GI, and PKR and eIF2alpha phosphorylation, all these processes taking place after peak virus production. We also determined that both cell death receptor and mitochondrial pathways are involved in the apoptosis process induced by BEV. BEV-induced apoptosis at late times postinfection, once viral progeny are produced, could facilitate viral dissemination in vivo and contribute to viral pathogenesis. PMID- 21698251 TI - Neonatal astrocyte damage is sufficient to trigger progressive striatal degeneration in a rat model of glutaric acidemia-I. AB - BACKGROUND: We have investigated whether an acute metabolic damage to astrocytes during the neonatal period may critically disrupt subsequent brain development, leading to neurodevelopmental disorders. Astrocytes are vulnerable to glutaric acid (GA), a dicarboxylic acid that accumulates in millimolar concentrations in Glutaric Acidemia I (GA-I), an inherited neurometabolic childhood disease characterized by degeneration of striatal neurons. While GA induces astrocyte mitochondrial dysfunction, oxidative stress and subsequent increased proliferation, it is presently unknown whether such astrocytic dysfunction is sufficient to trigger striatal neuronal loss. METHODOLOGY/PRINCIPAL FINDINGS: A single intracerebroventricular dose of GA was administered to rat pups at postnatal day 0 (P0) to induce an acute, transient rise of GA levels in the central nervous system (CNS). GA administration potently elicited proliferation of astrocytes expressing S100beta followed by GFAP astrocytosis and nitrotyrosine staining lasting until P45. Remarkably, GA did not induce acute neuronal loss assessed by FluoroJade C and NeuN cell count. Instead, neuronal death appeared several days after GA treatment and progressively increased until P45, suggesting a delayed onset of striatal degeneration. The axonal bundles perforating the striatum were disorganized following GA administration. In cell cultures, GA did not affect survival of either striatal astrocytes or neurons, even at high concentrations. However, astrocytes activated by a short exposure to GA caused neuronal death through the production of soluble factors. Iron porphyrin antioxidants prevented GA-induced astrocyte proliferation and striatal degeneration in vivo, as well as astrocyte-mediated neuronal loss in vitro. CONCLUSIONS/SIGNIFICANCE: Taken together, these results indicate that a transient metabolic insult with GA induces long lasting phenotypic changes in astrocytes that cause them to promote striatal neuronal death. Pharmacological protection of astrocytes with antioxidants during encephalopatic crisis may prevent astrocyte dysfunction and the ineluctable progression of disease in children with GA-I. PMID- 21698252 TI - So small, so loud: extremely high sound pressure level from a pygmy aquatic insect (Corixidae, Micronectinae). AB - To communicate at long range, animals have to produce intense but intelligible signals. This task might be difficult to achieve due to mechanical constraints, in particular relating to body size. Whilst the acoustic behaviour of large marine and terrestrial animals has been thoroughly studied, very little is known about the sound produced by small arthropods living in freshwater habitats. Here we analyse for the first time the calling song produced by the male of a small insect, the water boatman Micronecta scholtzi. The song is made of three distinct parts differing in their temporal and amplitude parameters, but not in their frequency content. Sound is produced at 78.9 (63.6-82.2) SPL rms re 2.10(-5) Pa with a peak at 99.2 (85.7-104.6) SPL re 2.10(-5) Pa estimated at a distance of one metre. This energy output is significant considering the small size of the insect. When scaled to body length and compared to 227 other acoustic species, the acoustic energy produced by M. scholtzi appears as an extreme value, outperforming marine and terrestrial mammal vocalisations. Such an extreme display may be interpreted as an exaggerated secondary sexual trait resulting from a runaway sexual selection without predation pressure. PMID- 21698253 TI - Marital status and survival in pancreatic cancer patients: a SEER based analysis. AB - BACKGROUND: Recent findings suggest that marital status affects survival in patients with different types of cancer. However, its role in the survival of patients with pancreatic ductal adenocarcinoma is unknown. In this study, we investigated whether there was an association between marital status and overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Adult patients diagnosed with PDAC between 1998 and 2003 with known marital statuses were identified from the Surveillance, Epidemiology, and End Results registry of the National Cancer Institute. OS for these patients was plotted using the Kaplan-Meier method. Comparative risks of mortality were evaluated by using univariate and multivariate-adjusted Cox regression models. RESULTS: Using Kaplan-Meier analysis, we found that the median overall survival of patients was 4 months and 3 months (p<0.001) for married and unmarried patients, respectively. Subgroup analysis on patients with cancer-directed surgery showed that the median survival was 16 months and 13 months (P<0.0005) for married and unmarried groups, respectively. Multivariate analysis adjusting for age, race, sex, stage, year of diagnosis, radiation therapy and cancer-directed surgery showed that patients who were married at the time of diagnosis had a significantly decreased risk of death at both 2 months (15% risk reduction) and 3 years (13% risk reduction) post diagnosis. CONCLUSIONS: Marital status is an independent prognostic factor of both perioperative and long-term survival in patients with PDAC. This observation may suggest a suboptimally met psychosocial need among PDAC patients that is partially fulfilled by the support system provided by marriage. PMID- 21698254 TI - The Saccharomyces cerevisiae histone chaperone Rtt106 mediates the cell cycle recruitment of SWI/SNF and RSC to the HIR-dependent histone genes. AB - BACKGROUND: In Saccharomyces cerevisiae, three out of the four histone gene pairs (HTA1-HTB1, HHT1-HHF1, and HHT2-HHF2) are regulated by the HIR co-repressor complex. The histone chaperone Rtt106 has recently been shown to be present at these histone gene loci throughout the cell cycle in a HIR- and Asf1-dependent manner and involved in their transcriptional repression. The SWI/SNF and RSC chromatin remodeling complexes are both recruited to the HIR-dependent histone genes; SWI/SNF is required for their activation in S phase, whereas RSC is implicated in their repression outside of S phase. Even though their presence at the histone genes is dependent on the HIR complex, their specific recruitment has not been well characterized. In this study we focused on characterizing the role played by the histone chaperone Rtt106 in the cell cycle-dependent recruitment of SWI/SNF and RSC complexes to the histone genes. METHODOLOGY/PRINCIPAL FINDINGS: Using GST pull-down and co-immunoprecipitation assays, we showed that Rtt106 physically interacts with both the SWI/SNF and RSC complexes in vitro and in vivo. We then investigated the function of this interaction with respect to the recruitment of these complexes to HIR-dependent histone genes. Using chromatin immunoprecipitation assays (ChIP), we found that Rtt106 is important for the recruitment of both SWI/SNF and RSC complexes to the HIR-dependent histone genes. Furthermore, using synchronized cell cultures, we showed by ChIP assays that the Rtt106-dependent SWI/SNF recruitment to these histone gene loci is cell cycle regulated and restricted to late G1 phase just before the peak of histone gene expression in S phase. CONCLUSIONS/SIGNIFICANCE: Overall, these data strongly suggest that the interaction between the histone chaperone Rtt106 and both the SWI/SNF and RSC chromatin remodeling complexes is important for the cell cycle regulated recruitment of these two complexes to the HIR-dependent histone genes. PMID- 21698255 TI - Motor unit abnormalities in Dystonia musculorum mice. AB - Dystonia musculorum (dt) is a mouse inherited sensory neuropathy caused by mutations in the dystonin gene. While the primary pathology lies in the sensory neurons of dt mice, the overt movement disorder suggests motor neurons may also be affected. Here, we report on the contribution of motor neurons to the pathology in dt(27J) mice. Phenotypic dt(27J) mice display reduced alpha motor neuron cell number and eccentric alpha motor nuclei in the ventral horn of the lumbar L1 spinal cord region. A dramatic reduction in the total number of motor axons in the ventral root of postnatal day 15 dt(27J) mice was also evident. Moreover, analysis of the trigeminal nerve of the brainstem showed a 2.4 fold increase in number of degenerating neurons coupled with a decrease in motor neuron number relative to wild type. Aberrant phosphorylation of neurofilaments in the perikaryon region and axonal swellings within the pre-synaptic terminal region of motor neurons were observed. Furthermore, neuromuscular junction staining of dt(27J) mouse extensor digitorum longus and tibialis anterior muscle fibers showed immature endplates and a significant decrease in axon branching compared to wild type littermates. Muscle atrophy was also observed in dt(27J) muscle. Ultrastructure analysis revealed amyelinated motor axons in the ventral root of the spinal nerve, suggesting a possible defect in Schwann cells. Finally, behavioral analysis identified defective motor function in dt(27J) mice. This study reveals neuromuscular defects that likely contribute to the dt(27J) pathology and identifies a critical role for dystonin outside of sensory neurons. PMID- 21698256 TI - Reliability of serum metabolite concentrations over a 4-month period using a targeted metabolomic approach. AB - Metabolomics is a promising tool for discovery of novel biomarkers of chronic disease risk in prospective epidemiologic studies. We investigated the between- and within-person variation of the concentrations of 163 serum metabolites over a period of 4 months to evaluate the metabolite reliability expressed by the intraclass-correlation coefficient (ICC: the ratio of between-person variance and total variance). The analyses were performed with the BIOCRATES AbsoluteIDQTM targeted metabolomics technology, including acylcarnitines, amino acids, glycerophospholipids, sphingolipids and hexose in 100 healthy individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study who had provided two fasting blood samples 4 months apart. Overall, serum reliability of metabolites over a 4-month period was good. The median ICC of the 163 metabolites was 0.57. The highest ICC was observed for hydroxysphingomyelin C14:1 (ICC = 0.85) and the lowest was found for acylcarnitine C3:1 (ICC = 0). Reliability was high for hexose (ICC = 0.76), sphingolipids (median ICC = 0.66; range: 0.24-0.85), amino acids (median ICC = 0.58; range: 0.41-0.72) and glycerophospholipids (median ICC = 0.58; range: 0.03-0.81). Among acylcarnitines, reliability of short and medium chain saturated compounds was good to excellent (ICC range: 0.50-0.81). Serum reliability was lower for most hydroxyacylcarnitines and monounsaturated acylcarnitines (ICC range: 0.11-0.45 and 0.00-0.63, respectively). For most of the metabolites a single measurement may be sufficient for risk assessment in epidemiologic studies with healthy subjects. PMID- 21698257 TI - SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. AB - Short chain fatty acids (SCFAs) have recently attracted attention as potential mediators of the effects of gut microbiota on intestinal inflammation. Some of these effects have been suggested to occur through the direct actions of SCFAs on the GPR43 receptor in neutrophils, though the precise role of this receptor in neutrophil activation is still unclear. We show that mouse bone marrow derived neutrophils (BMNs) can chemotax effectively through polycarbonate filters towards a source of acetate, propionate or butyrate. Moreover, we show that BMNs move with good speed and directionality towards a source of propionate in an EZ Taxiscan chamber coated with fibrinogen. These effects of SCFAs were mimicked by low concentrations of the synthetic GPR43 agonist phenylacetamide-1 and were abolished in GPR43(-/-) BMNs. SCFAs and phenylacetamide-1 also elicited GPR43 dependent activation of PKB, p38 and ERK and these responses were sensitive to pertussis toxin, indicating a role for Gi proteins. Phenylacetamide-1 also elicited rapid and transient activation of Rac1/2 GTPases and phosphorylation of ribosomal protein S6. Genetic and pharmacological intervention identified important roles for PI3Kgamma, Rac2, p38 and ERK, but not mTOR, in GPR43 dependent chemotaxis. These results identify GPR43 as a bona fide chemotactic receptor for neutrophils in vitro and start to define important elements in its signal transduction pathways. PMID- 21698258 TI - Pedestrian injury and human behaviour: observing road-rule violations at high incident intersections. AB - BACKGROUND: Human behaviour is an obvious, yet under-studied factor in pedestrian injury. Behavioural interventions that address rule violations by pedestrians and motorists could potentially reduce the frequency of pedestrian injury. In this study, a method was developed to examine road-rule non-compliance by pedestrians and motorists. The purpose of the study was to examine the potential association between violations made by pedestrians and motorists at signalized intersections, and collisions between pedestrians and motor-vehicles. The underlying hypothesis is that high-incident pedestrian intersections are likely to vary with respect to their aetiology, and thus are likely to require individualized interventions- based on the type and rate of pedestrian and motorist violation. METHODS: High incident pedestrian injury intersections in Vancouver, Canada were identified using geographic information systems. Road-rule violations by pedestrians and motorists were documented at each incident hotspot by a team of observers at several different time periods during the day. RESULTS: Approximately 9,000 pedestrians and 18,000 vehicles were observed in total. In total for all observed intersections, over 2000 (21%) pedestrians committed one of the observed pedestrian road-crossing violations, while approximately 1000 (5.9%) drivers committed one of the observed motorist violations. Great variability in road-rule violations was observed between intersections, and also within intersections at different observation periods. CONCLUSIONS: Both motorists and pedestrians were frequently observed committing road-rule violations at signalized intersections, suggesting a potential human behavioural contribution to pedestrian injury at the study sites. These results suggest that each intersection may have unique mechanisms that contribute to pedestrian injury, and may require targeted behavioural interventions. The method described in this study provides the basis for understanding the relationship between violations and pedestrian injury risk at urban intersections. Findings could be applied to targeted prevention campaigns designed to reduce the number of pedestrian injuries at signalized intersections. PMID- 21698259 TI - Shared epitope alleles remain a risk factor for anti-citrullinated proteins antibody (ACPA)--positive rheumatoid arthritis in three Asian ethnic groups. AB - BACKGROUND: To investigate the associations between HLA-DRB1 shared epitope (SE) alleles and rheumatoid arthritis in subsets of rheumatoid arthritis defined by autoantibodies in three Asian populations from Malaysia. METHODS: 1,079 rheumatoid arthritis patients and 1,470 healthy controls were included in the study. Levels of antibodies to citrullinated proteins (ACPA) and rheumatoid factors were assessed and the PCR-SSO method was used for HLA-DRB1 genotyping. RESULTS: The proportion of ACPA positivity among Malay, Chinese and Indian rheumatoid arthritis patients were 62.9%, 65.2% and 68.6%, respectively. An increased frequency of SE alleles was observed in ACPA-positive rheumatoid arthritis among the three Asian ethnic groups. HLA-DRB1*10 was highly associated with rheumatoid arthritis susceptibility in these Asian populations. HLA DRB1*0405 was significantly associated with susceptibility to rheumatoid arthritis in Malays and Chinese, but not in Indians. HLA-DRB1*01 did not show any independent effect as a risk factor for rheumatoid arthritis in this study and HLA-DRB1*1202 was protective in Malays and Chinese. There was no association between SE alleles and ACPA- negative rheumatoid arthritis in any of the three Asian ethnic groups. CONCLUSION: The HLA-DRB1 SE alleles increase the risk of ACPA-positive rheumatoid arthritis in all three Asian populations from Malaysia. PMID- 21698260 TI - P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating. AB - Tauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. To understand the relationship between tau pathology and behavioral impairments, we comprehensively assessed behavioral abnormalities in a mouse tauopathy model expressing the human P301S mutant tau protein in the early stage of disease to detect its initial neurological manifestations. Behavioral abnormalities, shown by open field test, elevated plus-maze test, hot plate test, Y-maze test, Barnes maze test, Morris water maze test, and/or contextual fear conditioning test, recapitulated the neurological deficits of human tauopathies with dementia. Furthermore, we discovered that prepulse inhibition (PPI), a marker of sensorimotor gating, was enhanced in these animals concomitantly with initial neuropathological changes in associated brain regions. This finding provides evidence that our tauopathy mouse model displays neurofunctional abnormalities in prodromal stages of disease, since enhancement of PPI is characteristic of amnestic mild cognitive impairment, a transitional stage between normal aging and dementia such as Alzheimer's disease (AD), in contrast with attenuated PPI in AD patients. Therefore, assessment of sensorimotor gating could be used to detect the earliest manifestations of tauopathies exemplified by prodromal AD, in which abnormal tau protein may play critical roles in the onset of neuronal dysfunctions. PMID- 21698261 TI - Determination of real-time efflux phenotypes in Escherichia coli AcrB binding pocket phenylalanine mutants using a 1,2'-dinaphthylamine efflux assay. AB - To evaluate the importance of phenylalanine residues for substrate transport in the Escherichia coli efflux pump protein AcrB, we subjected Phe-to-Ala binding pocket mutants to a real-time efflux assay with the novel near-infrared lipophilic membrane probe 1,2'-dinaphthylamine (1,2'-DNA). All mutations, with the exception of F617A, led to considerable retardation of efflux. F610A was the point mutation with the most pronounced impact, followed by F628A, F615A, F136A, and F178A. This is the first study to demonstrate the importance of single phenylalanine residues within the AcrB binding pocket for real-time substrate transport. PMID- 21698263 TI - Preparation of TiO2 anatase nanocrystals by TiCl4 hydrolysis with additive H2SO4. AB - A new methodology was developed to synthesize uniform titania anatase nanocrystals by the hydrolysis of titanium chloride in sulfuric acid aqueous solutions at 0-90 degrees C. The samples were characterized by Raman spectroscopy, UV-visible spectroscopy, transmission electron microscopy (TEM), electron diffraction (ED), and an Energy dispersive X-ray spectroscopy (EDS). The effects of the reaction temperature, mole ratio of SO(4)(2-) to Ti(4+), and the calcinations temperature on the particle size and crystal phase were investigated. Depending on the acidity, the hydrolysis temperature, and the calcination temperature, rhombic anatase nanocrystals sizes in the range of 10 nm to 50 nm were obtained. In the additive of sulfuric acid, Raman spectra and electron diffraction confirmed that the nanoparticles are composed of anatase TiO(2). No other titania phases, such as rutile or brookite, were detected. PMID- 21698262 TI - Basolateral sorting of syntaxin 4 is dependent on its N-terminal domain and the AP1B clathrin adaptor, and required for the epithelial cell polarity. AB - Generation of epithelial cell polarity requires mechanisms to sort plasma membrane proteins to the apical and basolateral domains. Sorting involves incorporation into specific vesicular carriers and subsequent fusion to the correct target membranes mediated by specific SNARE proteins. In polarized epithelial cells, the SNARE protein syntaxin 4 localizes exclusively to the basolateral plasma membrane and plays an important role in basolateral trafficking pathways. However, the mechanism of basolateral targeting of syntaxin 4 itself has remained poorly understood. Here we show that newly synthesized syntaxin 4 is directly targeted to the basolateral plasma membrane in polarized Madin-Darby canine kidney (MDCK) cells. Basolateral targeting depends on a signal that is centered around residues 24-29 in the N-terminal domain of syntaxin 4. Furthermore, basolateral targeting of syntaxin 4 is dependent on the epithelial cell-specific clathrin adaptor AP1B. Disruption of the basolateral targeting signal of syntaxin 4 leads to non-polarized delivery to both the apical and basolateral surface, as well as partial intercellular retention in the trans Golgi network. Importantly, disruption of the basolateral targeting signal of syntaxin 4 leads to the inability of MDCK cells to establish a polarized morphology which suggests that restriction of syntaxin 4 to the basolateral domain is required for epithelial cell polarity. PMID- 21698264 TI - Regulating cytoplasmic calcium homeostasis can reduce aluminum toxicity in yeast. AB - Our previous study suggested that increased cytoplasmic calcium (Ca) signals may mediate aluminum (Al) toxicity in yeast (Saccharomyces cerevisiae). In this report, we found that a yeast mutant, pmc1, lacking the vacuolar calcium ion (Ca(2+)) pump Ca(2+)-ATPase (Pmc1p), was more sensitive to Al treatment than the wild-type strain. Overexpression of either PMC1 or an anti-apoptotic factor, such as Bcl-2, Ced-9 or PpBI-1, decreased cytoplasmic Ca(2+) levels and rescued yeast from Al sensitivity in both the wild-type and pmc1 mutant. Moreover, pretreatment with the Ca(2+) chelator BAPTA-AM sustained cytoplasmic Ca(2+) at low levels in the presence of Al, effectively making the cells more tolerant to Al exposure. Quantitative RT-PCR revealed that the expression of calmodulin (CaM) and phospholipase C (PLC), which are in the Ca(2+) signaling pathway, was down regulated under Al stress. This effect was largely counteracted when cells overexpressed anti-apoptotic Ced-9 or were pretreated with BAPTA-AM. Taken together, our results suggest that the negative regulation of Al-induced cytoplasmic Ca signaling is a novel mechanism underlying internal resistance to Al toxicity. PMID- 21698265 TI - miR-16 and miR-21 expression in the placenta is associated with fetal growth. AB - BACKGROUND: Novel research has suggested that altered miRNA expression in the placenta is associated with adverse pregnancy outcomes and with potentially harmful xenobiotic exposures. We hypothesized that aberrant expression of miRNA in the placenta is associated with fetal growth, a measurable phenotype resulting from a number of intrauterine factors, and one which is significantly predictive of later life outcomes. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed 107 primary, term, human placentas for expression of 6 miRNA reported to be expressed in the placenta and to regulate cell growth and development pathways: miR-16, miR-21, miR-93, miR-135b, miR-146a, and miR-182. The expression of miR-16 and miR-21 was markedly reduced in infants with the lowest birthweights (p<0.05). Logistic regression models suggested that low expression of miR-16 in the placenta predicts an over 4-fold increased odds of small for gestational age (SGA) status (p = 0.009, 95% CI = 1.42, 12.05). Moreover, having both low miR-16 and low miR 21 expression in the placenta predicts a greater increase in odds for SGA than having just low miR-16 or miR-21 expression (p<0.02), suggesting an additive effect of both of these miRNA. CONCLUSIONS/SIGNIFICANCE: Our study is one of the first to investigate placental miRNA expression profiles associated with birthweight and SGA status. Future research on miRNA whose expression is associated with in utero exposures and markers of fetal growth is essential for better understanding the epigenetic mechanisms underlying the developmental origins of health and disease. PMID- 21698266 TI - Generation of human female reproductive tract epithelium from human embryonic stem cells. AB - BACKGROUND: Recent studies have identified stem/progenitor cells in human and mouse uterine epithelium, which are postulated to be responsible for tissue regeneration and proliferative disorders of human endometrium. These progenitor cells are thought to be derived from Mullerian duct (MD), the primordial female reproductive tract (FRT). METHODOLOGY/PRINCIPAL FINDINGS: We have developed a model of human reproductive tract development in which inductive neonatal mouse uterine mesenchyme (nMUM) is recombined with green fluorescent protein (GFP) tagged human embryonic stem cells (hESCs); GFP-hESC (ENVY). We demonstrate for the first time that hESCs can be differentiated into cells with a human FRT epithelial cell phenotype. hESC derived FRT epithelial cells emerged from cultures containing MIXL1(+) mesendodermal precursors, paralleling events occurring during normal organogenesis. Following transplantation, nMUM treated embryoid bodies (EBs) generated epithelial structures with a typical MD phenotype that expressed the MD markers PAX2, HOXA10. Functionally, the hESCs derived FRT epithelium responded to exogenous estrogen by proliferating and secreting uterine specific glycodelin A (GdA). CONCLUSIONS/SIGNIFICANCE: These data show nMUM can induce differentiation of hESC to form the FRT epithelium. This may provide a model to study early developmental events of the human FRT. PMID- 21698267 TI - OSBP-related protein 8 (ORP8) regulates plasma and liver tissue lipid levels and interacts with the nucleoporin Nup62. AB - We earlier identified OSBP-related protein 8 (ORP8) as an endoplasmic reticulum oxysterol-binding protein implicated in cellular lipid homeostasis. We now investigated its action in hepatic cells in vivo and in vitro. Adenoviral overexpression of ORP8 in mouse liver induced a decrease of cholesterol, phospholipids, and triglycerides in serum (-34%, -26%, -37%, respectively) and liver tissue (-40%, -12%, -24%), coinciding with reduction of nuclear (n)SREBP-1 and -2 and mRNA levels of their target genes. Consistently, excess ORP8 reduced nSREBPs in HuH7 cells, and ORP8 overexpression or silencing by RNA interference moderately suppressed or induced the expression of SREBP-1 and SREBP-2 target genes, respectively. In accordance, cholesterol biosynthesis was reduced by ORP8 overexpression and enhanced by ORP8 silencing in [(3)H]acetate pulse-labeling experiments. ORP8, previously shown to bind 25-hydroxycholesterol, was now shown to bind also cholesterol in vitro. Yeast two-hybrid, bimolecular fluorescence complementation (BiFC), and co-immunoprecipitation analyses revealed the nuclear pore component Nup62 as an interaction partner of ORP8. Co-localization of ORP8 and Nup62 at the nuclear envelope was demonstrated by BiFC and confocal immunofluorescence microscopy. Furthermore, the impact of overexpressed ORP8 on nSREBPs and their target mRNAs was inhibited in cells depleted of Nup62. Our results reveal that ORP8 has the capacity to modulate lipid homeostasis and SREBP activity, probably through an indirect mechanism, and provide clues of an entirely new mode of ORP action. PMID- 21698268 TI - Finding your mate at a cocktail party: frequency separation promotes auditory stream segregation of concurrent voices in multi-species frog choruses. AB - Vocal communication in crowded social environments is a difficult problem for both humans and nonhuman animals. Yet many important social behaviors require listeners to detect, recognize, and discriminate among signals in a complex acoustic milieu comprising the overlapping signals of multiple individuals, often of multiple species. Humans exploit a relatively small number of acoustic cues to segregate overlapping voices (as well as other mixtures of concurrent sounds, like polyphonic music). By comparison, we know little about how nonhuman animals are adapted to solve similar communication problems. One important cue enabling source segregation in human speech communication is that of frequency separation between concurrent voices: differences in frequency promote perceptual segregation of overlapping voices into separate "auditory streams" that can be followed through time. In this study, we show that frequency separation (DeltaF) also enables frogs to segregate concurrent vocalizations, such as those routinely encountered in mixed-species breeding choruses. We presented female gray treefrogs (Hyla chrysoscelis) with a pulsed target signal (simulating an attractive conspecific call) in the presence of a continuous stream of distractor pulses (simulating an overlapping, unattractive heterospecific call). When the DeltaF between target and distractor was small (e.g., <=3 semitones), females exhibited low levels of responsiveness, indicating a failure to recognize the target as an attractive signal when the distractor had a similar frequency. Subjects became increasingly more responsive to the target, as indicated by shorter latencies for phonotaxis, as the DeltaF between target and distractor increased (e.g., DeltaF = 6-12 semitones). These results support the conclusion that gray treefrogs, like humans, can exploit frequency separation as a perceptual cue to segregate concurrent voices in noisy social environments. The ability of these frogs to segregate concurrent voices based on frequency separation may involve ancient hearing mechanisms for source segregation shared with humans and other vertebrates. PMID- 21698269 TI - Habitat-specific morphological variation among threespine sticklebacks (Gasterosteus aculeatus) within a drainage basin. AB - Habitat-specific morphological variation, often corresponding to resource specialization, is well documented in freshwater fishes. In this study we used landmark based morphometric analyses to investigate morphological variation among threespine sticklebacks (Gasterosteus aculeatus L.) from four interconnected habitat types within a single lowland drainage basin in eastern England. These included the upper and lower reaches of the river, the estuary, a connected ditch network and a coastal salt marsh. We found significant habitat-specific differences in morphology, with three axes of variation describing differences in orbit diameter, body depth, caudal peduncle shape and pectoral fin positioning as well as variation in relative dorsal and pelvic spine size. Interestingly, the ditch system, an artificial and heavily managed habitat, is populated by sticklebacks with a characteristic morphology, suggesting that human management of habitats can in some circumstances lead to morphological variation among the animals that inhabit them. We discuss the mechanisms that conceivably underlie the observed morphological variation and the further work necessary to identify them. Finally, we consider the implications of habitat-specific body shape variation for the behavioural ecology of this ecologically generalist species. PMID- 21698270 TI - Oxidative stress in the developing brain: effects of postnatal glucocorticoid therapy and antioxidants in the rat. AB - In premature infants, glucocorticoids ameliorate chronic lung disease, but have adverse effects on long-term neurological function. Glucocorticoid excess promotes free radical overproduction. We hypothesised that the adverse effects of postnatal glucocorticoid therapy on the developing brain are secondary to oxidative stress and that antioxidant treatment would diminish unwanted effects. Male rat pups received a clinically-relevant tapering course of dexamethasone (DEX; 0.5, 0.3, and 0.1 mg x kg(-1) x day(-1)), with or without antioxidant vitamins C and E (DEXCE; 200 mg x kg(-1) x day(-1) and 100 mg x kg(-1) x day(-1), respectively), on postnatal days 1-6 (P1-6). Controls received saline or saline with vitamins. At weaning, relative to controls, DEX decreased total brain volume (704.4+/-34.7 mm(3) vs. 564.0+/-20.0 mm(3)), the soma volume of neurons in the CA1 (1172.6+/-30.4 um(3) vs. 1002.4+/-11.8 um(3)) and in the dentate gyrus (525.9+/-27.2 um(3) vs. 421.5+/-24.6 um(3)) of the hippocampus, and induced oxidative stress in the cortex (protein expression: heat shock protein 70 [Hsp70]: +68%; 4-hydroxynonenal [4-HNE]: +118% and nitrotyrosine [NT]: +20%). Dexamethasone in combination with vitamins resulted in improvements in total brain volume (637.5+/-43.1 mm(3)), and soma volume of neurons in the CA1 (1157.5+/-42.4 um(3)) and the dentate gyrus (536.1+/-27.2 um(3)). Hsp70 protein expression was unaltered in the cortex (+9%), however, 4-HNE (+95%) and NT (+24%) protein expression remained upregulated. Treatment of neonates with vitamins alone induced oxidative stress in the cortex (Hsp70: +67%; 4-HNE: +73%; NT: +22%) and in the hippocampus (NT: +35%). Combined glucocorticoid and antioxidant therapy in premature infants may be safer for the developing brain than glucocorticoids alone in the treatment of chronic lung disease. However, antioxidant therapy in healthy offspring is not recommended. PMID- 21698271 TI - Garlic extract diallyl sulfide (DAS) activates nuclear receptor CAR to induce the Sult1e1 gene in mouse liver. AB - Constituent chemicals in garlic extract are known to induce phase I and phase II enzymes in rodent livers. Here we have utilized Car(+/+) and Car(-/-) mice to demonstrate that the nuclear xenobiotic receptor CAR regulated the induction of the estrogen sulfotransferase Sult1e1 gene by diallyl sulfide (DAS) treatment in mouse liver. DAS treatment caused CAR accumulation in the nucleus, resulting in a remarkable increase of SULT1E1 mRNA (3,200 fold) and protein in the livers of Car(+/+) females but not of Car(-/-) female mice. DAS also induced other CAR regulated genes such as Cyp2b10, Cyp3a11 and Gadd45beta. Compared with the rapid increase of these mRNA levels, which began as early as 6 hours after DAS treatment, the levels of SULT1E1 mRNA began increasing after 24 hours. This slow response to DAS suggested that CAR required an additional factor to activate the Sult1e1 gene or that this activation was indirect. Despite the remarkable induction of SULT1E1, there was no decrease in the serum levels of endogenous E2 or increase of estrone sulfate while the clearance of exogenously administrated E2 was accelerated in DAS treated mice. PMID- 21698273 TI - Demand for Zn2+ in acid-secreting gastric mucosa and its requirement for intracellular Ca2+. AB - BACKGROUND AND AIMS: Recent work has suggested that Zn(2+) plays a critical role in regulating acidity within the secretory compartments of isolated gastric glands. Here, we investigate the content, distribution and demand for Zn(2+) in gastric mucosa under baseline conditions and its regulation during secretory stimulation. METHODS AND FINDINGS: Content and distribution of zinc were evaluated in sections of whole gastric mucosa using X-ray fluorescence microscopy. Significant stores of Zn(2+) were identified in neural elements of the muscularis, glandular areas enriched in parietal cells, and apical regions of the surface epithelium. In in vivo studies, extraction of the low abundance isotope, (70)Zn(2+), from the circulation was demonstrated in samples of mucosal tissue 24 hours or 72 hours after infusion (250 ug/kg). In in vitro studies, uptake of (70)Zn(2+) from media was demonstrated in isolated rabbit gastric glands following exposure to concentrations as low as 10 nM. In additional studies, demand of individual gastric parietal cells for Zn(2+) was monitored using the fluorescent zinc reporter, fluozin-3, by measuring increases in free intracellular concentrations of Zn(2+) {[Zn(2+)](i)} during exposure to standard extracellular concentrations of Zn(2+) (10 uM) for standard intervals of time. Under resting conditions, demand for extracellular Zn(2+) increased with exposure to secretagogues (forskolin, carbachol/histamine) and under conditions associated with increased intracellular Ca(2+) {[Ca(2+)](i)}. Uptake of Zn(2+) was abolished following removal of extracellular Ca(2+) or depletion of intracellular Ca(2+) stores, suggesting that demand for extracellular Zn(2+) increases and depends on influx of extracellular Ca(2+). CONCLUSIONS: This study is the first to characterize the content and distribution of Zn(2+) in an organ of the gastrointestinal tract. Our findings offer the novel interpretation, that Ca(2+) integrates basolateral demand for Zn(2+) with stimulation of secretion of HCl into the lumen of the gastric gland. Similar connections may be detectable in other secretory cells and tissues. PMID- 21698272 TI - Genomic polymorphism of the pandemic A (H1N1) influenza viruses correlates with viral replication, virulence, and pathogenicity in vitro and in vivo. AB - The novel pandemic A (H1N1) virus was first identified in Mexico in April 2009 and quickly spread worldwide. Like all influenzas, the H1N1 strain-specific properties of replication, virulence, and pathogenicity are a result of the particular genomic sequence and concerted expression of multiple genes. Thus, specific mutations may support increased virulence and may be useful as biomarkers of potential threat to human health. We performed comparative genomic analysis of ten strains of the 2009 pandemic A (H1N1) influenza viruses to determine whether genotypes associated with clinical phenotypes, which ranged from mild to severe illness and up to lethal. Virus replication capacity was tested for each strain in vitro using cultured epithelial cells, while virulence and pathogenicity were investigated in vivo using the BALB/c mouse model. The results indicated that A/Sichuan/1/2009 strain had significantly higher replication ability and virulence than the other strains, and five unique non synonymous mutations were identified in important gene-encoding sequences. These mutations led to amino acid substitutions in HA (L32I), PA (A343T), PB1 (K353R and T566A), and PB2 (T471M), and may be critical molecular determinants for replication, virulence, and pathogenicity. Our results suggested that the replication capacity in vitro and virulence in vivo of the 2009 pandemic A (H1N1) viruses were not associated with the clinical phenotypes. This study offers new insights into the transmission and evolution of the 2009 pandemic A (H1N1) virus. PMID- 21698274 TI - Astragalus polysaccharides attenuate postburn sepsis via inhibiting negative immunoregulation of CD4+ CD25(high) T cells. AB - BACKGROUND: Astragalus polysaccharides (APS) isolated from one of the Chinese herbs, Astragalus mongholicus, are known to have a variety of immunomodulatory activities. However, it is not yet clear whether APS can exert an effect on the immune functions of regulatory T cells (Tregs). This study was carried out to investigate the effect of APS on the immune function of peripheral blood Tregs in postburn sepsis. METHODOLOGY/PRINCIPAL FINDINGS: BALB/C mice were randomly divided into six groups as follows: sham burn group, burn control (burn without infection animals) group, burn plus P. aeruginosa group, burn plus P. aeruginosa with APS (50 mg/kg) treatment group, burn plus P. aeruginosa with APS (100 mg/kg) treatment group, and burn plus P. aeruginosa with APS (200 mg/kg) treatment group, and they were sacrificed on postburn day 1, 3, 5, and 7, respectively, with seven animals at each time point. Magnetic microbeads were used to isolate peripheral blood Tregs and CD4(+) T cells. Phenotypes were analyzed by flow cytometry, and cytokine levels were determined with ELISA. In the burn plus P. aeruginosa group, forkhead/winged helix transcription factor p3 (Foxp3) expression on CD4(+)CD25(+)Tregs were strongly enhanced in comparison to the sham group, and the capacity of CD4(+)CD25(+)Tregs to produce interleukin (IL)-10 was markedly increased. Administration of APS to inhibit CD4(+)CD25(+)Tregs could significantly decrease expression of Foxp3 on CD4(+)CD25(+)Tregs, and IL-10 production in burned mice with P. aeruginosa infection. At the same time, proliferative activity and expression of IL-2 and IL-2Ralpha on CD4(+) T cells were restored. In contrast, anti-Toll-like receptor 4 (TLR4) antibody could block the effect of APS on Tregs immune function. CONCLUSION: APS might suppress CD4(+)CD25(+)Treg activity, at least in part, via binding TLR4 on Tregs and trigger a shift of Th2 to Th1 with activation of CD4(+) T cells in burned mice with P. aeruginosa infection. PMID- 21698275 TI - Khat use is associated with impaired working memory and cognitive flexibility. AB - RATIONALE: Khat consumption has increased during the last decades in Eastern Africa and has become a global phenomenon spreading to ethnic communities in the rest of the world, such as The Netherlands, United Kingdom, Canada, and the United States. Very little is known, however, about the relation between khat use and cognitive control functions in khat users. OBJECTIVE: We studied whether khat use is associated with changes in working memory (WM) and cognitive flexibility, two central cognitive control functions. METHODS: Khat users and khat-free controls were matched in terms of sex, ethnicity, age, alcohol and cannabis consumption, and IQ (Raven's progressive matrices). Groups were tested on cognitive flexibility, as measured by a Global-Local task, and on WM using an N back task. RESULT: Khat users performed significantly worse than controls on tasks tapping into cognitive flexibility as well as monitoring of information in WM. CONCLUSIONS: The present findings suggest that khat use impairs both cognitive flexibility and the updating of information in WM. The inability to monitor information in WM and to adjust behavior rapidly and flexibly may have repercussions for daily life activities. PMID- 21698277 TI - Cognitive flexibility and clinical severity in eating disorders. AB - OBJECTIVES: The aim of this study was to explore cognitive flexibility in a large dataset of people with Eating Disorders and Healthy Controls (HC) and to see how patient characteristics (body mass index [BMI] and length of illness) are related to this thinking style. METHODS: A dataset was constructed from our previous studies using a conceptual shift test--the Brixton Spatial Anticipation Test. 601 participants were included, 215 patients with Anorexia Nervosa (AN) (96 inpatients; 119 outpatients), 69 patients with Bulimia Nervosa (BN), 29 Eating Disorder Not Otherwise Specified (EDNOS), 72 in long-term recovery from AN (Rec AN) and a comparison group of 216 HC. RESULTS: The AN and EDNOS groups had significantly more errors than the other groups on the Brixton Test. In comparison to the HC group, the effect size decrement was large for AN patients receiving inpatient treatment and moderate for AN outpatients. CONCLUSIONS: These findings confirm that patients with AN have poor cognitive flexibility. Severity of illness measured by length of illness does not fully explain the lack of flexibility and supports the trait nature of inflexibility in people with AN. PMID- 21698276 TI - The relationship between asthma and depression in primary care patients: a historical cohort and nested case control study. AB - BACKGROUND AND OBJECTIVES: Asthma and depression are common health problems in primary care. Evidence of a relationship between asthma and depression is conflicting. OBJECTIVES: to determine 1. The incidence rate and incidence rate ratio of depression in primary care patients with asthma compared to those without asthma, and 2. The standardized mortality ratio of depressed compared to non-depressed patients with asthma. METHODS: A historical cohort and nested case control study using data derived from the United Kingdom General Practice Research Database. PARTICIPANTS: 11,275 incident cases of asthma recorded between 1/1/95 and 31/12/96 age, sex and practice matched with non-cases from the database (ratio 1:1) and followed up through the database for 10 years. 1,660 cases were matched by date of asthma diagnosis with 1,660 controls. MAIN OUTCOME MEASURES: number of cases diagnosed with depression, the number of deaths over the study period. RESULTS: The rate of depression in patients with asthma was 22.4/1,000 person years and without asthma 13.8 /1,000 person years. The incident rate ratio (adjusted for age, sex, practice, diabetes, cardiovascular disease, cerebrovascular disease, smoking) was 1.59 (95% CI 1.48-1.71). The increased rate of depression was not associated with asthma severity or oral corticosteroid use. It was associated with the number of consultations (odds ratio per visit 1.09; 95% CI 1.07-1.11). The age and sex adjusted standardized mortality ratio for depressed patients with asthma was 1.87 (95% CI: 1.54-2.27). CONCLUSIONS: Asthma is associated with depression. This was not related to asthma severity or oral corticosteroid use but was related to service use. This suggests that a diagnosis of depression is related to health seeking behavior in patients with asthma. There is an increased mortality rate in depressed patients with asthma. The cause of this needs further exploration. Consideration should be given to case-finding for depression in this population. PMID- 21698278 TI - Collective dynamics of gene expression in cell populations. AB - The phenotypic state of the cell is commonly thought to be determined by the set of expressed genes. However, given the apparent complexity of genetic networks, it remains open what processes stabilize a particular phenotypic state. Moreover, it is not clear how unique is the mapping between the vector of expressed genes and the cell's phenotypic state. To gain insight on these issues, we study here the expression dynamics of metabolically essential genes in twin cell populations. We show that two yeast cell populations derived from a single steady state mother population and exhibiting a similar growth phenotype in response to an environmental challenge, displayed diverse expression patterns of essential genes. The observed diversity in the mean expression between populations could not result from stochastic cell-to-cell variability, which would be averaged out in our large cell populations. Remarkably, within a population, sets of expressed genes exhibited coherent dynamics over many generations. Thus, the emerging gene expression patterns resulted from collective population dynamics. It suggests that in a wide range of biological contexts, gene expression reflects a self organization process coupled to population-environment dynamics. PMID- 21698279 TI - A DNMT3B alternatively spliced exon and encoded peptide are novel biomarkers of human pluripotent stem cells. AB - A major obstacle in human stem cell research is the limited number of reagents capable of distinguishing pluripotent stem cells from partially differentiated or incompletely reprogrammed derivatives. Although human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) express numerous alternatively spliced transcripts, little attention has been directed at developing splice variant-encoded protein isoforms as reagents for stem cell research. In this study, several genes encoding proteins involved in important signaling pathways were screened to detect alternatively spliced transcripts that exhibited differential expression in pluripotent stem cells (PSCs) relative to spontaneously differentiated cells (SDCs). Transcripts containing the alternatively spliced exon 10 of the de novo DNA methyltransferase gene, DNMT3B, were identified that are expressed in PSCs. To demonstrate the utility and superiority of splice variant specific reagents for stem cell research, a peptide encoded by DNMT3B exon 10 was used to generate an antibody, SG1. The SG1 antibody detects a single DNMT3B protein isoform that is expressed only in PSCs but not in SDCs. The SG1 antibody is also demonstrably superior to other antibodies at distinguishing PSCs from SDCs in mixed cultures containing both pluripotent stem cells and partially differentiated derivatives. The tightly controlled down regulation of DNMT3B exon 10 containing transcripts (and exon 10 encoded peptide) upon spontaneous differentiation of PSCs suggests that this DNMT3B splice isoform is characteristic of the pluripotent state. Alternatively spliced exons, and the proteins they encode, represent a vast untapped reservoir of novel biomarkers that can be used to develop superior reagents for stem cell research and to gain further insight into mechanisms controlling stem cell pluripotency. PMID- 21698280 TI - A novel synthetic smoothened antagonist transiently inhibits pancreatic adenocarcinoma xenografts in a mouse model. AB - BACKGROUND: Hedgehog (Hh) signaling is over-activated in several solid tumors where it plays a central role in cell growth, stroma recruitment and tumor progression. In the Hh signaling pathway, the Smoothened (SMO) receptor comprises a primary drug target with experimental small molecule SMO antagonists currently being evaluated in clinical trials. PRINCIPAL FINDINGS: Using Shh-Light II (Shh L2) and alkaline phosphatase (AP) based screening formats on a "focused diversity" library we identified a novel small molecule inhibitor of the Hh pathway, MS-0022 (2-bromo-N-(4-(8-methylimidazo[1,2-a]pyridin-2 yl)phenyl)benzamide). MS-0022 showed effective Hh signaling pathway inhibition at the level of SMO in the low nM range, and Hh pathway inhibition downstream of Suppressor of fused (SUFU) in the low uM range. MS-0022 reduced growth in the tumor cell lines PANC-1, SUIT-2, PC-3 and FEMX in vitro. MS-0022 treatment led to a transient delay of tumor growth that correlated with a reduction of stromal Gli1 levels in SUIT-2 xenografts in vivo. SIGNIFICANCE: We document the in vitro and in vivo efficacy and bioavailability of a novel small molecule SMO antagonist, MS-0022. Although MS-0022 primarily interferes with Hh signaling at the level of SMO, it also has a downstream inhibitory effect and leads to a stronger reduction of growth in several tumor cell lines when compared to related SMO antagonists. PMID- 21698281 TI - Differential proteomics in dequeened honeybee colonies reveals lower viral load in hemolymph of fertile worker bees. AB - The eusocial societies of honeybees, where the queen is the only fertile female among tens of thousands sterile worker bees, have intrigued scientists for centuries. The proximate factors, which cause the inhibition of worker bee ovaries, remain largely unknown; as are the factors which cause the activation of worker ovaries upon the loss of queen and brood in the colony. In an attempt to reveal key players in the regulatory network, we made a proteomic comparison of hemolymph profiles of workers with completely activated ovaries vs. rudimentary ovaries. An unexpected finding of this study is the correlation between age matched worker sterility and the enrichment of Picorna-like virus proteins. Fertile workers, on the other hand, show the upregulation of potential components of the immune system. It remains to be investigated whether viral infections contribute to worker sterility directly or are the result of a weaker immune system of sterile workers. PMID- 21698282 TI - Dogs discriminate identical twins. AB - Earlier studies have shown variation among experimental attempts to establish whether human monozygotic twins that are genetically identical also have identical individual scents. In none of the cases were the dogs able to distinguish all the individual scents of monozygotic twins living in the same environment if the scents were presented to them separately. Ten specially trained police German Shepherd dogs of three Czech Republic Police Regional Headquarters were used for scent identification in our study. The dogs were supposed to match scents of two monozygotic pairs (5 and 7 years old) and two dizygotic twin pairs (8 and 13 years old). Scents were collected on cotton squares stored in glass jars. Dog handlers were blind to the experiment details. In each trial (line-up), one scent was used as a starting scent and the dog was then sent to determine if any of the 7 presented glass jars contained a matching scent. Scents of children of similar ages were used as distractors. In the matching procedure, the dogs matched correctly the scent of one twin with the other, as well as two scents collected from every single identical and non identical twin to prove their efficacy and likewise, the presence of the matching twin scent in any given glass jar. All dogs in all trials distinguished correctly the scents of identical as well as non-identical twins. All dogs similarly matched positively two scents collected from the same individuals. Our findings indicated that specially trained German Shepherd dogs are able to distinguish individual scents of identical twins despite the fact that they live in the same environment, eat the same food and even if the scents are not presented to them simultaneously. PMID- 21698284 TI - When models interact with their subjects: the dynamics of model aware systems. AB - A scientific model need not be a passive and static descriptor of its subject. If the subject is affected by the model, the model must be updated to explain its affected subject. In this study, two models regarding the dynamics of model aware systems are presented. The first explores the behavior of "prediction seeking" (PSP) and "prediction avoiding" (PSP) populations under the influence of a model that describes them. The second explores the publishing behavior of a group of experimentalists coupled to a model by means of confirmation bias. It is found that model aware systems can exhibit convergent random or oscillatory behavior and display universal 1/f noise. A numerical simulation of the physical experimentalists is compared with actual publications of neutron life time and mass measurements and is in good quantitative agreement. PMID- 21698283 TI - Early mortality and AIDS progression despite high initial antiretroviral therapy adherence and virologic suppression in Botswana. AB - BACKGROUND: Adverse outcomes occurring early after antiretroviral therapy (ART) initiation are common in sub-Saharan Africa, despite reports of high levels of ART adherence in this setting. We sought to determine the relationship between very early ART adherence and early adverse outcomes in HIV-infected adults in Botswana. METHODS: This prospective cohort study of 402 ART-naive, HIV-infected adults initiating ART at a public HIV clinic in Gaborone, Botswana evaluated the relationship between suboptimal early ART adherence and HIV treatment outcomes in the initial months after ART initiation. Early adherence during the interval between initial ART dispensation and first ART refill was calculated using pill counts. In the primary analysis patients not returning to refill and those with adherence <0.95 were considered to have suboptimal early adherence. The primary outcome was death or loss to follow-up during the first 6 months of ART; a secondary composite outcome included the primary outcome plus incident opportunistic illness (OIs) and virologic failure. We also calculated the percent of early adverse outcomes theoretically attributable to suboptimal early adherence using the population attributable risk percent (PAR%). RESULTS: Suboptimal early adherence was independently associated with loss to follow-up and death (adjusted OR 2.3, 95% CI 1.1-4.8) and with the secondary composite outcome including incident OIs and virologic failure (adjusted OR 2.6, 95% CI 1.4 4.7). However, of those with early adverse outcomes, less than one-third had suboptimal adherence and approximately two-thirds achieved virologic suppression. The PAR% relating suboptimal early adherence and primary and secondary outcomes were 14.7% and 17.7%, respectively. CONCLUSIONS: Suboptimal early adherence was associated with poor outcomes, but most early adverse outcomes occurred in patients with optimal early adherence. Clinical care and research efforts should focus on understanding early adverse outcomes that occur despite optimal adherence. PMID- 21698285 TI - A distinct urinary biomarker pattern characteristic of female Fabry patients that mirrors response to enzyme replacement therapy. AB - Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naive female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2% sensitivity and 97.8% specificity when tested in an independent validation cohort consisting of 17 treatment-naive Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy. PMID- 21698286 TI - Integration of expressed sequence tag data flanking predicted RNA secondary structures facilitates novel non-coding RNA discovery. AB - Many computational methods have been used to predict novel non-coding RNAs (ncRNAs), but none, to our knowledge, have explicitly investigated the impact of integrating existing cDNA-based Expressed Sequence Tag (EST) data that flank structural RNA predictions. To determine whether flanking EST data can assist in microRNA (miRNA) prediction, we identified genomic sites encoding putative miRNAs by combining functional RNA predictions with flanking ESTs data in a model consistent with miRNAs undergoing cleavage during maturation. In both human and mouse genomes, we observed that the inclusion of flanking ESTs adjacent to and not overlapping predicted miRNAs significantly improved the performance of various methods of miRNA prediction, including direct high-throughput sequencing of small RNA libraries. We analyzed the expression of hundreds of miRNAs predicted to be expressed during myogenic differentiation using a customized microarray and identified several known and predicted myogenic miRNA hairpins. Our results indicate that integrating ESTs flanking structural RNA predictions improves the quality of cleaved miRNA predictions and suggest that this strategy can be used to predict other non-coding RNAs undergoing cleavage during maturation. PMID- 21698287 TI - Molecular cloning, characterization and expression analysis of two members of the Pht1 family of phosphate transporters in Glycine max. AB - BACKGROUND: Phosphorus is one of the macronutrients essential for plant growth and development. The acquisition and translocation of phosphate are pivotal processes of plant growth. In a large number of plants, phosphate uptake by roots and translocation within the plant are presumed to occur via a phosphate/proton cotransport mechanism. PRINCIPAL FINDINGS: We cloned two cDNAs from soybean (Glycine max), GmPT1 and GmPT2, which show homology to the phosphate/proton cotransporter PHO84 from the budding yeast Saccharomyces cerevisiae. The amino acid sequence of the products predicted from GmPT1 and GmPT2 share 61% and 63% identity, respectively, with the PHO84 in amino acid sequence. The deduced structure of the encoded proteins revealed 12 membrane-spanning domains with a central hydrophilic region. The molecular mass values are ~58.7 kDa for GmPT1 and ~58.6 kDa for GmPT2. Transiently expressed GFP-protein fusions provide direct evidence that the two Pi transporters are located in the plasma membrane. Uptake of radioactive orthophosphate by the yeast mutant MB192 showed that GmPT1 and GmPT2 are dependent on pH and uptake is reduced by the addition of uncouplers of oxidative phosphorylation. The K(m) for phosphate uptake by GmPT1 and GmPT2 is 6.65 mM and 6.63 mM, respectively. A quantitative real time RT-PCR assay indicated that these two genes are expressed in the roots and shoots of seedlings whether they are phosphate-deficient or not. Deficiency of phosphorus caused a slight change of the expression levels of GmPT1 and GmPT2. CONCLUSIONS: The results of our experiments show that the two phosphate transporters have low affinity and the corresponding genes are constitutively expressed. Thereby, the two phosphate transporters can perform translocation of phosphate within the plant. PMID- 21698288 TI - Binocular onset rivalry at the time of saccades and stimulus jumps. AB - Recent studies suggest that binocular rivalry at stimulus onset, so called onset rivalry, differs from rivalry during sustained viewing. These observations raise the interesting question whether there is a relation between onset rivalry and rivalry in the presence of eye movements. We therefore studied binocular rivalry when stimuli jumped from one visual hemifield to the other, either through a saccade or through a passive stimulus displacement, and we compared rivalry after such displacements with onset and sustained rivalry. We presented opponent motion, orthogonal gratings and face/house stimuli through a stereoscope. For all three stimulus types we found that subjects showed a strong preference for stimuli in one eye or one hemifield (Experiment 1), and that these subject specific biases did not persist during sustained viewing (Experiment 2). These results confirm and extend previous findings obtained with gratings. The results from the main experiment (Experiment 3) showed that after a passive stimulus jump, switching probability was low when the preferred eye was dominant before a stimulus jump, but when the non-preferred eye was dominant beforehand, switching probability was comparatively high. The results thus showed that dominance after a stimulus jump was tightly related to eye dominance at stimulus onset. In the saccade condition, however, these subject-specific biases were systematically reduced, indicating that the influence of saccades can be understood from a systematic attenuation of the subjects' onset rivalry biases. Taken together, our findings demonstrate a relation between onset rivalry and rivalry after retinal shifts and involvement of extra-retinal signals in binocular rivalry. PMID- 21698289 TI - Influenza A virus nucleoprotein exploits Hsp40 to inhibit PKR activation. AB - BACKGROUND: Double-stranded RNA dependent protein kinase (PKR) is a key regulator of the anti-viral innate immune response in mammalian cells. PKR activity is regulated by a 58 kilo Dalton cellular inhibitor (P58(IPK)), which is present in inactive state as a complex with Hsp40 under normal conditions. In case of influenza A virus (IAV) infection, P58(IPK) is known to dissociate from Hsp40 and inhibit PKR activation. However the influenza virus component responsible for PKR inhibition through P58(IPK) activation was hitherto unknown. PRINCIPAL FINDINGS: Human heat shock 40 protein (Hsp40) was identified as an interacting partner of Influenza A virus nucleoprotein (IAV NP) using a yeast two-hybrid screen. This interaction was confirmed by co-immunoprecipitation studies from mammalian cells transfected with IAV NP expressing plasmid. Further, the IAV NP-Hsp40 interaction was validated in mammalian cells infected with various seasonal and pandemic strains of influenza viruses. Cellular localization studies showed that NP and Hsp40 co-localize primarily in the nucleus. During IAV infection in mammalian cells, expression of NP coincided with the dissociation of P58(IPK) from Hsp40 and decrease PKR phosphorylation. We observed that, plasmid based expression of NP in mammalian cells leads to decrease in PKR phosphorylation. Furthermore, inhibition of NP expression during influenza virus replication led to PKR activation and concomitant increase in eIF2alpha phosphorylation. Inhibition of NP expression also led to reduced IRF3 phosphorylation, enhanced IFN beta production and concomitant reduction of virus replication. Taken together our data suggest that NP is the viral factor responsible for P58(IPK) activation and subsequent inhibition of PKR-mediated host response during IAV infection. SIGNIFICANCE: Our findings demonstrate a novel role of IAV NP in inhibiting PKR mediated anti-viral host response and help us understand P58(IPK) mediated inhibition of PKR activity during IAV infection. PMID- 21698290 TI - Diaphragm muscle weakness in an experimental porcine intensive care unit model. AB - In critically ill patients, mechanisms underlying diaphragm muscle remodeling and resultant dysfunction contributing to weaning failure remain unclear. Ventilator induced modifications as well as sepsis and administration of pharmacological agents such as corticosteroids and neuromuscular blocking agents may be involved. Thus, the objective of the present study was to examine how sepsis, systemic corticosteroid treatment (CS) and neuromuscular blocking agent administration (NMBA) aggravate ventilator-related diaphragm cell and molecular dysfunction in the intensive care unit. Piglets were exposed to different combinations of mechanical ventilation and sedation, endotoxin-induced sepsis, CS and NMBA for five days and compared with sham-operated control animals. On day 5, diaphragm muscle fibre structure (myosin heavy chain isoform proportion, cross-sectional area and contractile protein content) did not differ from controls in any of the mechanically ventilated animals. However, a decrease in single fibre maximal force normalized to cross-sectional area (specific force) was observed in all experimental piglets. Therefore, exposure to mechanical ventilation and sedation for five days has a key negative impact on diaphragm contractile function despite a preservation of muscle structure. Post-translational modifications of contractile proteins are forwarded as one probable underlying mechanism. Unexpectedly, sepsis, CS or NMBA have no significant additive effects, suggesting that mechanical ventilation and sedation are the triggering factors leading to diaphragm weakness in the intensive care unit. PMID- 21698291 TI - Conformational changes of rBTI from buckwheat upon binding to trypsin: implications for the role of the P(8)' residue in the potato inhibitor I family. AB - BWI-1 (buckwheat trypsin inhibitor), a member of the potato inhibitor I family, suppresses the growth of T-acute lymphoblastic leukemia cells and induces apoptosis in human solid tumor cell lines. Here, we report the crystal structure of rBTI (recombinant buckwheat trypsin inhibitor), a recombinant protein of BWI 1, at 1.84 A resolution and the structure of rBTI in complex with bovine trypsin at 2.26 A resolution. A conformational change of Trp53 at the P(8)' position in rBTI was observed upon its binding to trypsin, which is not seen in other members of the potato inhibitor I family reported previously. The role of the P(8)' residue in the potato inhibitor I family was examined by measuring the association and dissociation rates of four rBTI mutants with different substitutions at the P(2) and P(8)' positions when binding to trypsin. One of the mutants, P44T, was found to be a much stronger inhibitor than wild-type rBTI, with a picomolar (pM) dissociation constant. Our results could provide valuable insights for designing a new rBTI-based antitumor drug in the future. PMID- 21698292 TI - In vitro megakaryocyte differentiation and proplatelet formation in Ph-negative classical myeloproliferative neoplasms: distinct patterns in the different clinical phenotypes. AB - BACKGROUND: Ph-negative myeloproliferative neoplasms (MPNs) are clonal disorders that include primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET). Although the pathogenesis of MPNs is still incompletely understood, an involvement of the megakaryocyte lineage is a distinctive feature. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the in vitro megakaryocyte differentiation and proplatelet formation in 30 PMF, 8 ET, 8 PV patients, and 17 healthy controls (CTRL). Megakaryocytes were differentiated from peripheral blood CD34(+) or CD45(+) cells in the presence of thrombopoietin. Megakaryocyte output was higher in MPN patients than in CTRL with no correlation with the JAK2 V617F mutation. PMF-derived megakaryocytes displayed nuclei with a bulbous appearance, were smaller than ET- or PV-derived megakaryocytes and formed proplatelets that presented several structural alterations. In contrast, ET- and PV-derived megakaryocytes produced more proplatelets with a striking increase in bifurcations and tips compared to both control and PMF. Proplatelets formation was correlated with platelet counts in patient peripheral blood. Patients with pre-fibrotic PMF had a pattern of megakaryocyte proliferation and proplatelet formation that was similar to that of fibrotic PMF and different from that of ET. CONCLUSIONS/SIGNIFICANCE: In conclusion, MPNs are associated with high megakaryocyte proliferative potential. Profound differences in megakaryocyte morphology and proplatelet formation distinguish PMF, both fibrotic and prefibrotic, from ET and PV. PMID- 21698293 TI - Adenylate kinase 3 sensitizes cells to cigarette smoke condensate vapor induced cisplatin resistance. AB - BACKGROUND: The major established etiologic risk factor for bladder cancer is cigarette smoking and one of the major antineoplastic agents used for the treatment of advanced bladder cancer is cisplatin. A number of reports have suggested that cancer patients who smoke while receiving treatment have lower rates of response and decreased efficacy of cancer therapies. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the effect of cigarette smoke condensate (CSC) vapor on cisplatin toxicity in urothelial cell lines SV-HUC-1 and SCaBER cells. We showed that chronic exposure to CSC vapor induced cisplatin resistance in both cell lines. In addition, we found that the expression of mitochondrial-resident protein adenylate kinase-3 (AK3) is decreased by CSC vapor. We further observed that chronic CSC vapor-exposed cells displayed decreased cellular sensitivity to cisplatin, decreased mitochondrial membrane potential (DeltaPsim) and increased basal cellular ROS levels compared to unexposed cells. Re-expression of AK3 in CSC vapor-exposed cells restored cellular sensitivity to cisplatin. Finally, CSC vapor increased the growth of the tumors and also curtail the response of tumor cells to cisplatin chemotherapy in vivo. CONCLUSIONS/SIGNIFICANCE: The current study provides evidence that chronic CSC vapor exposure affects AK3 expression and renders the cells resistant to cisplatin. PMID- 21698294 TI - SLXL1, a novel acrosomal protein, interacts with DKKL1 and is involved in fertilization in mice. AB - BACKGROUND: Spermatogenesis is a complex cellular developmental process which involves diverse families of genes. The Xlr (X-linked, lymphocyte regulated) family includes multiple members, only a few of which have reported functions in meiosis, post-meiotic maturation, and fertilization of germ cells. Slx-like1 (Slxl1) is a member of the Xlr family, whose expression and function in spermatogenesis need to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: The mRNA and protein expression and localization of Slxl1 were investigated by RT-PCR, Western blotting and immunohistochemistry in different tissues and at different stages of spermatogenesis. The interacting partner of SLXL1 was examined by co immunoprecipitation and co-localization. Assessment of the role of SLXL1 in capacitation, acrosome reaction, zona pellucida binding/penetration, and fertilization was carried out in vitro using blocking antisera. The results showed that Slxl1 mRNA and protein were specifically expressed in the testis. SLXL1 was exclusively located in the acrosome of post-meiotic germ cells and interacts with DKKL1 (Dickkopf-like1), which is an acrosome-associated protein and plays an important role in fertilization. The rates of zona pellucida binding/penetration and fertilization were significantly reduced by the anti SLXL1 polyclonal antiserum. CONCLUSIONS/SIGNIFICANCE: SLXL1 is the first identified member of the XLR family that is associated with acrosome and is involved in zona pellucid binding/penetration and subsequent fertilization. These results, together with previous studies, suggest that Xlr family members participate in diverse processes from meiosis to fertilization during spermatogenesis. PMID- 21698295 TI - Effect of smoke-free legislation on adult smoking behaviour in England in the 18 months following implementation. AB - BACKGROUND: Comprehensive smoke-free legislation covering all enclosed public places and workplaces was implemented in England on 1 July 2007. This study examines the impact of this legislation on smoking prevalence, number of cigarettes smoked and location of smoking, controlling for secular trends through the end of 2008. METHOD AND FINDINGS: Repeat cross sectional survey using nationally representative data from the Health Survey for England (HSE). In total there are 54,333 respondents from 2003-2008. Logit and linear regression models were used to examine the effect of the legislation on smoking prevalence and the number of cigarettes smoked daily among continuing smokers which took the underlying trend into account. Our finding suggest that smoking prevalence (current smoker) decreased from 25% in 2003 to 21% in 2008 (AOR = 0.96 per year, 95% CI = 0.95-0.98, P<0.01) and the mean number of cigarettes consumed daily by smokers decreased from 14.1 in 2003 to 13.1 in 2008 (coefficient for time trend = -0.28+/-0.06 SE cig/day per year, P<0.01). After adjusting for these trends the introduction of smoke-free legislation was not associated with additional reductions in smoking prevalence (AOR = 1.02, 95% CI = 0.94-1.11, P = 0.596) or daily cigarette use in smokers (0.42+/-0.28 SE; P = 0.142). The percentage of respondents reporting smoking 'at work' and 'inside pubs or bars' decreased significantly from 14% to 2% (p<0.001) and from 34% to 2% (p<0.001), respectively, after the legislation. The percentage reporting smoking 'inside restaurants, cafes, or canteens' decreased significantly from 9% to 1% (p<0.001) and 'inside their home' decreased significantly from 65% to 55% (p<0.01). CONCLUSION: There is widespread compliance with the smoke-free legislation in England, which has led to large drops in indoor smoking in all venues, including at home. Declines in smoking prevalence and consumption continued along existing trends; they did not accelerate during the 18 months immediately following implementation. PMID- 21698296 TI - C-terminus of progranulin interacts with the beta-propeller region of sortilin to regulate progranulin trafficking. AB - Progranulin haplo-insufficiency is a main cause of frontotemporal lobar degeneration (FTLD) with TDP-43 aggregates. Previous studies have shown that sortilin regulates progranulin trafficking and is a main determinant of progranulin level in the brain. In this study, we mapped the binding site between progranulin and sortilin. Progranulin binds to the beta-propeller region of sortilin through its C-terminal tail. The C-terminal progranulin fragment is fully sufficient for sortilin binding and progranulin C-terminal peptide displaces progranulin binding to sortilin. Deletion of the last 3 residues of progranulin (QLL) abolishes its binding to sortilin and also sortilin dependent regulation of progranulin trafficking. Since progranulin haplo-insufficiency results in FTLD, these results may provide important insights into future studies of progranulin trafficking and signaling and progranulin based therapy for FTLD. PMID- 21698297 TI - Male germ cell apoptosis and epigenetic histone modification induced by Tripterygium wilfordii Hook F. AB - Multiglycosides of Tripterygium wilfordii Hook f (GTW), a Chinese herb-derived medicine used as a remedy for rheumatoid arthritis, are considered to be a reversible anti-fertility drug affecting the mammalian spermatids. However, the mechanism behind this effect is still unknown. To study the possible mechanism behind the impact of GTW on spermatogenesis, we administered 4 groups of 4-week old male mice with different doses of GTW. We found a dose-dependent decrease in the number of germ cells after 40 days of GTW treatment, and an increase in apoptotic cells from the low-dose to the high-dose group. During this same period the dimethylated level of histone H3 lysine 9 (H3K9me2) in GTW-treated testes germ cells declined. Additionally, spermatogonial stem cells (SSCs) from 6-day old mice were isolated to evaluate the possible effect of GTW or triptolide on development of SSCs. We found a significantly higher incidence of apoptosis and lower dimethylation level of H3K9me2 in the SSCs of GTW or triptolide treatment than in controls. Thus, these data suggest that the GTW-induced apoptosis might be responsible for the fertility impairment in mice. This damage could be traced back to the early stages of spermatogenesis. GTW also affected the epigenetic modification of H3K9 in spermatogenesis. Molecular dynamics simulation suggested that triptolide and dimethylated or trimethylated H3K9 might have similar interaction mechanisms with EED (embryonic ectoderm development). These candidate activation mechanisms provide the first glimpse into the pathway of GTW-induced gonad toxicity, which is crucial for further research and clinical application. PMID- 21698298 TI - The role of asymmetric interactions on the effect of habitat destruction in mutualistic networks. AB - Plant-pollinator mutualistic networks are asymmetric in their interactions: specialist plants are pollinated by generalist animals, while generalist plants are pollinated by a broad range involving specialists and generalists. It has been suggested that this asymmetric--or disassortative--assemblage could play an important role in determining the observed equal susceptibility of specialist and generalist plants under habitat destruction. At the core of the analysis of the phenomenon lies the observation that specialist plants, otherwise candidates to extinction, could cope with the disruption thanks to their interaction with a few generalist pollinators. We present a theoretical framework that supports this thesis. We analyze a dynamical model of a system of mutualistic plants and pollinators, subject to the destruction of their habitat. We analyze and compare two families of interaction topologies, ranging from highly assortative to highly disassortative ones, as well as real pollination networks. We found that several features observed in natural systems are predicted by the mathematical model. First, there is a tendency to increase the asymmetry of the network as a result of the extinctions. Second, an entropy measure of the differential susceptibility to extinction of specialist and generalist species show that they tend to balance when the network is disassortative. Finally, the disappearance of links in the network, as a result of extinctions, shows that specialist plants preserve more connections than the corresponding plants in an assortative system, enabling them to resist the disruption. PMID- 21698299 TI - Novel murine infection models provide deep insights into the "menage a trois" of Campylobacter jejuni, microbiota and host innate immunity. AB - BACKGROUND: Although Campylobacter jejuni-infections have a high prevalence worldwide and represent a significant socioeconomic burden, it is still not well understood how C. jejuni causes intestinal inflammation. Detailed investigation of C. jejuni-mediated intestinal immunopathology is hampered by the lack of appropriate vertebrate models. In particular, mice display colonization resistance against this pathogen. METHODOLOGY/PRINCIPAL FINDINGS: To overcome these limitations we developed a novel C. jejuni-infection model using gnotobiotic mice in which the intestinal flora was eradicated by antibiotic treatment. These animals could then be permanently associated with a complete human (hfa) or murine (mfa) microbiota. After peroral infection C. jejuni colonized the gastrointestinal tract of gnotobiotic and hfa mice for six weeks, whereas mfa mice cleared the pathogen within two days. Strikingly, stable C. jejuni colonization was accompanied by a pro-inflammatory immune response indicated by increased numbers of T- and B-lymphocytes, regulatory T-cells, neutrophils and apoptotic cells, as well as increased concentrations of TNF alpha, IL-6, and MCP-1 in the colon mucosa of hfa mice. Analysis of MyD88(-/-), TRIF(-/-), TLR4(-/-), and TLR9(-/-) mice revealed that TLR4- and TLR9-signaling was essential for immunopathology following C. jejuni-infection. Interestingly, C. jejuni-mutant strains deficient in formic acid metabolism and perception induced less intestinal immunopathology compared to the parental strain infection. In summary, the murine gut flora is essential for colonization resistance against C. jejuni and can be overcome by reconstitution of gnotobiotic mice with human flora. Detection of C. jejuni-LPS and -CpG-DNA by host TLR4 and TLR9, respectively, plays a key role in immunopathology. Finally, the host immune response is tightly coupled to bacterial formic acid metabolism and invasion fitness. CONCLUSION/SIGNIFICANCE: We conclude that gnotobiotic and "humanized" mice represent excellent novel C. jejuni-infection and -inflammation models and provide deep insights into the immunological and molecular interplays between C. jejuni, microbiota and innate immunity in human campylobacteriosis. PMID- 21698300 TI - Potential involvement of LOX-1 in functional consequences of endothelial senescence. AB - Numerous studies have described the process of senescence associated with accumulation of oxidative damage, mutations and decline in proliferative potential. Although the changes observed in senescent cells are likely to result in significant phenotypic alterations, the studies on consequences of endothelial senescence, especially in relation to aging-associated diseases, are scarce. We have analyzed effects of senescence on the functions of endothelial cells relevant to the development of atherosclerosis including angiogenesis, adhesion, apoptosis and inflammation. In the course of progressing through the passages, human umbilical vein endothelial cells (HUVECs) displayed significant increase in size (+36% passage 12 vs. passage 4 , p<0.001) and reduction in both basal and VEGF-stimulated tube formation. The analysis of a scavenger receptor LOX-1, a key molecule implicated in atherogenesis, revealed a significant decline of its message (mRNA) and protein content in senescent endothelial cells (-33%) and in aortas of 50 wk (vs. 5 wk) old mice (all p<0.01). These effects were accompanied by a marked reduction of the basal expression of VCAM-1 and ICAM-1. Compared to early cultures, late passage HUVECs also exhibited nuclear translocation of NF kappaB (p65) and reciprocal shifts in BAX and BCL2 protein content resulting in almost 2-fold increase in BAX/BCL2 ratio and 3-fold increase in apoptotic response to TNFalpha exposure (p<0.04). These changes in senescent endothelial cells are suggestive of aberrant responses to physiological stimuli resulting in a less permissive environment for tissue remodeling and progression of diseases requiring angiogenesis and cell adhesion in elderly, possibly, mediated by LOX-1. PMID- 21698303 TI - Gas-phase study of new organozinc reagents by IRMPD-spectroscopy, computational modelling and tandem-MS. AB - An extensive set of organozinc iodides, useful for Negishi-type cross-coupling reactions, are investigated as respective cations after formal loss of iodide in the gas phase. Firstly, two new alkylzinc compounds derived from Tyrosine (Tyr) and Tryptophan (Trp) are closely examined. Secondly, the influence of specific protecting groups on the subtle balance between intra- and intermolecular coordination of zinc in these reagents is probed through trifluoroacetyl (TFA) derivatized alkylzinc compounds. Finally, the influence of the strongly coordinating bidentate ligand N,N,N',N'-tetramethylethylenediamine (TMEDA) on the structure of alkylzinc cations is further explored in order to better understand the stability of the respective complexes towards water. A combination of electrospray (ESI)-MS/MS, accurate ion mass measurements, infrared multiple photon dissociation (IRMPD) spectroscopy and computational modelling allowed the full characterisation of all dimethylformamide (DMF)-solvated and TMEDA coordinated alkylzinc cations in the gas phase. The calculations indicate that the zinc cation in gas-phase alkylzinc-DMF or TMEDA-complex ions preferentially adopts a tetrahedral coordination sphere with four ligands. Additionally, conformers with only three binding partners bound to zinc but with effectively combined hydrogen-bond interactions are also found. Collision induced dissociation (CID) patterns demonstrate that the zinc-DMF interaction in tetrahedral four-coordinate mono-DMF-zinc complex ions as well as the interaction between TMEDA and zinc in the corresponding complex ions is even stronger than typical covalent bonds. In most cases, all major features of the IRMPD spectra are consistent with only a single major isomer, allowing secured identification and assignment. PMID- 21698302 TI - Optical and electronic properties of polyaniline sulfonic acid-ribonucleic acid gold nanobiocomposites. AB - Finely fibrillar polyaniline sulfonic acid (PSA)/ribonucleic acid (RNA) hybrids are developed by wrapping PSA with RNA from a mixture of aqueous PSA (P) and RNA (R) solutions of different compositions. FTIR spectra suggest H-bonding and pi-pi interactions in the hybrids and dedoping of self doped PSA during hybrid formation. UV-vis spectra exhibit a blue shift of the pi-band to polaron band transition of PSA from 870 to 581 nm due to dedoping. The PR hybrids show enhanced PL-properties when excited at 540 nm relative to PSA which also exhibits rectification behavior in current (I)-voltage (V) curves. Gold nanoparticles (Au NPs) grown on these PR hybrids by the reduction of Au(3+) by PSA show different morphologies with varying composition. FTIR spectra of the nanobiocomposites indicate that Au NPs are stabilized by the co-ordination of the nitrogen atoms of -N=Q=N- bonds of PSA (Q = quinonoid ring). The intensity of the Au plasmon band gradually decreases with time but the PL-intensities of the PAu/PRAu nanocomposites increase with time. The PL-intensity of the nanocomposites is higher than that of PSA and PR hybrids. The DC-conductivity of the PR hybrids increases by an order of magnitude on addition of Au NPs. I-V curves of the nanobiocomposites show negative differential resistance (NDR) in PSA rich systems with a stable NDR ratio of 7 in the PRAu21 and PRAu11 hybrids. Possible reasons from the accumulation of charges on the Au NPs and its stabilization through the pi-clouds of RNA bases are discussed. The PRAu11 system also exhibits rectification properties with a rectification ratio of 14. PMID- 21698301 TI - Therapeutic potential and challenges of targeting receptor tyrosine kinase ROR1 with monoclonal antibodies in B-cell malignancies. AB - BACKGROUND: Based on its selective cell surface expression in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), receptor tyrosine kinase ROR1 has recently emerged as a promising target for therapeutic monoclonal antibodies (mAbs). To further assess the suitability of ROR1 for targeted therapy of CLL and MCL, a panel of mAbs was generated and its therapeutic utility was investigated. METHODOLOGY AND PRINCIPAL FINDINGS: A chimeric rabbit/human Fab library was generated from immunized rabbits and selected by phage display. Chimeric rabbit/human Fab and IgG1 were investigated for their capability to bind to human and mouse ROR1, to mediate antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and internalization, and to agonize or antagonize apoptosis using primary CLL cells from untreated patients as well as MCL cell lines. A panel of mAbs demonstrated high affinity and specificity for a diverse set of epitopes that involve all three extracellular domains of ROR1, are accessible on the cell surface, and mediate internalization. The mAb with the highest affinity and slowest rate of internalization was found to be the only mAb that mediated significant, albeit weak, ADCC. None of the mAbs mediated CDC. Alone, they did not enhance or inhibit apoptosis. CONCLUSIONS AND SIGNIFICANCE: Owing to its relatively low cell surface density, ROR1 may be a preferred target for armed rather than naked mAbs. Provided is a panel of fully sequenced and thoroughly characterized anti-ROR1 mAbs suitable for conversion to antibody-drug conjugates, immunotoxins, chimeric antigen receptors, and other armed mAb entities for preclinical and clinical studies. PMID- 21698304 TI - pH-oscillations in a closed chemical system of CaSO3-H2O2-HCO3(-). AB - Long-lasting large amplitude periodic change of the pH is measured in an aqueous suspension of CaSO(3)-H(2)O(2)-HCO(3)(-) at 2.0-10.0 degrees C in a closed reactor. The amplitude can be as large as 2 pH units between pH 5 and 7. The observed phenomenon is explained and simulated by taking into account a slow dissolution of CaSO(3), which serves as a continuous supply of HSO(3)(-) for a H(+)-producing autocatalytic composite reaction between H(2)O(2) and HSO(3)(-). Protonation of HCO(3)(-) to form CO(2) in a reversible reaction provides for the necessary negative feedback in [H(+)]. PMID- 21698306 TI - Diameter-dependent internal gain in ZnO micro/nanowires under electron beam irradiation. AB - We observed a conductivity gain in intrinsic ZnO micro/nanowires at characteristic diameter scales from nanoscale to microscale by employing metal semiconductor-metal structures with ohmic contacts under electron beam irradiation. The conductivity is enhanced under electron beam illumination and the magnitude is inversely proportional to the micro/nanowire diameter from 400 nm to 1300 nm at constant radiation intensity. We also introduced a model to simulate the diameter-dependent electric potential distribution. We attribute these observations to the variation of the effective electron carrier density upon varying diameters of ZnO micro/nanowires, as a result of field effects from the diameter-dependent population of the surface-trapped holes. PMID- 21698305 TI - Poly(dimethylsiloxane) cross-linked carbon paste electrodes for microfluidic electrochemical sensing. AB - Recently, the development of electrochemical biosensors as part of microfluidic devices has garnered a great deal of attention because of the small instrument size and portability afforded by the integration of electrochemistry in microfluidic systems. Electrode fabrication, however, has proven to be a major obstacle in the field. Here, an alternative method to create integrated, low cost, robust, patternable carbon paste electrodes (CPEs) for microfluidic devices is presented. The new CPEs are composed of graphite powder and a binder consisting of a mixture of poly(dimethylsiloxane) (PDMS) and mineral oil. The electrodes are made by filling channels molded in previously cross-linked PDMS using a method analogous to screen printing. The optimal binder composition was investigated to obtain electrodes that were physically robust and performed well electrochemically. After studying the basic electrochemistry, the PDMS-oil CPEs were modified with multi-walled carbon nanotubes (MWCNT) and cobalt phthalocyanine (CoPC) for the detection of catecholamines and thiols, respectively, to demonstrate the ease of electrode chemical modification. Significant improvement of analyte signal detection was observed from both types of modified CPEs. A nearly 2-fold improvement in the electrochemical signal for 100 MUM dithiothreitol (DTT) was observed when using a CoPC modified electrode (4.0 +/- 0.2 nA (n = 3) versus 2.5 +/- 0.2 nA (n = 3)). The improvement in signal was even more pronounced when looking at catecholamines, namely dopamine, using MWCNT modified CPEs. In this case, an order of magnitude improvement in limit of detection was observed for dopamine when using the MWCNT modified CPEs (50 nM versus 500 nM). CoPC modified CPEs were successfully used to detect thiols in red blood cell lysate while MWCNT modified CPEs were used to monitor temporal changes in catecholamine release from PC12 cells following stimulation with potassium. PMID- 21698312 TI - Dissociation techniques in mass spectrometry-based proteomics. AB - The field of proteomics, the large-scale analysis of proteins, has undergone a huge expansion over the past decade. Mass spectrometry-based proteomics relies on the dissociation of peptide and/or protein ions to provide information on primary sequence and sites of post-translational modifications. Fragmentation techniques include collision-induced dissociation, electron capture dissociation and electron transfer dissociation. Here, we describe each of these techniques and their use in proteomics. The principles, advantages, limitations, and applications are discussed. PMID- 21698311 TI - Liquid phase ion mobility spectrometry. AB - A novel analytical method, called Liquid Phase Ion Mobility Spectrometry (LiPIMS) was demonstrated, where aqueous phase analytes were ionized and introduced into non-aqueous liquids, transported by an external electric field from the point of generation to a collection electrode. Ions were produced from a unique liquid phase ionization process, called Electrodispersion Ionization. Spectra of analyte ions illustrated the potential of LiPIMS as a new separation technique. Experimental data showed that electrodispersion ionization was effective in generating nanoampere level of ion current in hexane and benzene from aqueous samples. By controlling the ionization voltage in relation to the sample flow rate, it was possible to operate the electrodispersion ionization source in both continuous and pulsed ionization modes. Unique LiPIMS spectra of aqueous samples of tetramethylammonium bromide, tetrabutylammonium bromide and bradykinin were presented and their respected liquid phase ion mobility values were determined. PMID- 21698313 TI - Structural control of surface layer proteins at electrified interfaces investigated by in situ Fourier transform infrared spectroscopy. AB - In situ Fourier Transform Infrared (FTIR) Spectroscopy complemented by Electrochemical Quartz Microbalance (EQMB) investigations allowed a detailed insight into the influence of the electrode potential on competing adsorption processes and bonding mechanisms of buffer ions and S-layer protein molecules of Lysinibacillus sphaericus CCM2177 at an electrified liquid/gold interface. The S layer proteins adsorb on gold polarized positively of the point of zero charge by displacing perchlorate anions in the Helmholtz plane by their carboxylate groups. This is indicated by an increase of the peptide and carboxylate infrared absorption signals accompanied by a decrease of the perchlorate signal. S-layers interlinked laterally with Ca(2+) ions, positive of the point of zero charge, resulted in the formation of a crystalline layer participating in the Helmholtz layer. In contrast to the absence of the Ca(2+)-linkers, S-layers remain structurally intact also in the negative polarization domain where the Helmholtz layer is solely sustained by mainly solvated cations without participation of the negatively charged protein carboxylate functions. PMID- 21698314 TI - Carotenoid composition in Rhinacanthus nasutus (L.) Kurz as determined by HPLC-MS and affected by freeze-drying and hot-air-drying. AB - Rhinacanthus nasutus (L.) Kurz (Trade name: Bai he ling zhi), a traditional medicinal herb, has been reported to possess anticancer and antioxidant activities. However, the composition of the major functional compounds, carotenoids, remains uncertain. The objectives of this study were to develop a high performance liquid chromatography-mass spectrometry (HPLC-MS) method for carotenoid composition determination in R. nasutus and for carotenoid change by freeze-drying and hot-air-drying. A total of 24 carotenoids were separated within 54 min by using a YMC C(30) column and a gradient mobile phase of methanol acetonitrile-water (82 : 14 : 4, v/v/v) (A) and methylene chloride (100%) (B): 100% A initially, maintained for 10 min, decreased to 95% A in 25 min, 84% A in 30 min, 75% A in 37 min, 68% A in 40 min, 65% A in 47 min, and 55% A in 50 min with flow rate at 1 mL min(-1) and detection wavelength at 450 nm. The various carotenoids were identified by comparing the retention time, absorption spectra, Q-ratio and mass spectra of unknown peaks with reference standards as well as photoisomerized standards. Quantitation was carried out using an internal standard beta-apo-8'-carotenal, with all-trans-lutein and its cis isomers being present in the largest amount (862 MUg g(-1)) in freeze-dried R. nasutus, followed by all-trans-violaxanthin (494 MUg g(-1)), all-trans-beta-carotene and its cis isomers (479 MUg g(-1)), all-trans-neoxanthin and its cis isomers (251 MUg g(-1)), all-trans-alpha-carotene and its cis isomers (85.2 MUg g(-1)), luteoxanthin (14.3 MUg g(-1)), all-trans-zeaxanthin (3.94 MUg g(-1)), beta carotene-5,6-epoxide (3.45 MUg g(-1)) and all-trans-beta-cryptoxanthin (1.03 MUg g(-1)). Comparatively, some more carotenoids including cis-violaxanthin, luteoxanthin, cis-neoxanthin, neochrome, 13- or 13'-cis-lutein, 9- or 9'-cis lutein, beta-carotene-5,6-epoxide, 9- or 9'-cis-beta-carotene, 13- or 13'-cis beta-carotene, 15- or 15'-cis-beta-carotene and 13- or 13'-cis-alpha-carotene were generated in R. nasutus during hot-air-drying. PMID- 21698316 TI - Cholate-derived amphiphilic molecular baskets as glucose transporters across lipid membranes. AB - With introverted polar groups and hydrophobic exteriors, cholate-derived amphiphilic molecular baskets were efficient transporters of glucose across lipid membranes. PMID- 21698315 TI - Modified peptide monolayer binding His-tagged biomolecules for small ligand screening with SPR biosensors. AB - A peptide self-assembled monolayer (SAM) was designed to bind His-tagged biomolecules for surface plasmon resonance (SPR) bioanalysis, which was applied for the determination of K(d) for small ligand screening against CD36. Nonspecific adsorption could be minimized using penta- and hexa-peptide monolayers. In particular, monolayers consisting of 3-mercaptopropionyl-leucinyl histidinyl-aspartyl-leucinyl-histidinyl-aspartic acid (3-Mpa-LHDLHD) exhibited little (12 ng cm(-2)) nonspecific adsorption in crude serum. Modification of this peptide monolayer with Nalpha,Nalpha-bis(carboxymethyl)-L-lysine gave a surface competent for binding His-tagged proteins, as demonstrated using enzyme (human dihydrofolate reductase), protein/antibody and receptor (CD36) examples. Immobilization featured chelation of copper and the His-tagged protein by the peptide monolayer, which could be recycled by removing the copper using imidazole washes prior to reuse. PMID- 21698317 TI - Addition of a cyclopropyl alkyne to tetramesityldigermene: evidence for a biradical intermediate. AB - The reaction pathway for the addition of alkynes to tetramesityldigermene was examined using a cyclopropyl alkyne mechanistic probe. The results obtained indicate that the reaction is stepwise and involves biradical intermediates. PMID- 21698318 TI - Selective labeling of the endoplasmic reticulum in live cells with silicon quantum dots. AB - A simple and novel approach was developed to obtain water-dispersible silicon quantum dots (Si-QDs) of low toxicity that were able to selectively label the endoplasmic reticulum (ER) in live cells. A block copolymer (Pluronic F127) was used to coat the surface of Si-QDs. Si-QDs form aggregates with diameters of 20 40 nm and show an outstanding optical stability upon UV irradiation. Our F127 treated Si-QDs would be a powerful tool for long-term real-time observation of the ER in live cells. PMID- 21698319 TI - Phenomenological model of spin crossover in molecular crystals as derived from atom-atom potentials. AB - The method of atom-atom potentials, previously applied to the analysis of pure molecular crystals formed by either low-spin (LS) or high-spin (HS) forms (spin isomers) of Fe(II) coordination compounds (Sinitskiy et al., Phys. Chem. Chem. Phys., 2009, 11, 10983), is used to estimate the lattice enthalpies of mixed crystals containing different fractions of the spin isomers. The crystals under study were formed by LS and HS isomers of Fe(phen)(2)(NCS)(2) (phen = 1,10 phenanthroline), Fe(btz)(2)(NCS)(2) (btz = 5,5',6,6'-tetrahydro-4H,4'H-2,2'-bi 1,3-thiazine), and Fe(bpz)(2)(bipy) (bpz = dihydrobis(1-pyrazolil)borate, and bipy = 2,2'-bipyridine). For the first time the phenomenological parameters Gamma pertinent to the Slichter-Drickamer model (SDM) of several materials were independently derived from the microscopic model of the crystals with use of atom atom potentials of intermolecular interaction. The accuracy of the SDM was checked against the numerical data on the enthalpies of mixed crystals. Fair semiquantitative agreement with the experimental dependence of the HS fraction on temperature was achieved with use of these values. Prediction of trends in Gamma values as a function of chemical composition and geometry of the crystals is possible with the proposed approach, which opens a way to rational design of spin crossover materials with desired properties. PMID- 21698320 TI - A statistical approach to inelastic electron tunneling spectroscopy on fullerene terminated molecules. AB - We report on the vibrational fingerprint of single C(60) terminated molecules in a mechanically controlled break junction (MCBJ) setup using a novel statistical approach manipulating the junction mechanically to address different molecular configurations and to monitor the corresponding vibrational modes. In the IETS spectra, the vibrations of the anchoring C(60) dominate the spectra; thus information on the unit anchored with C(60) to the electrodes is masked by the modes arising from the anchoring groups. However, we have identified the additional modes from the fluorene backbone optically. PMID- 21698321 TI - A cryogenic beam of refractory, chemically reactive molecules with expansion cooling. AB - Cryogenically cooled buffer gas beam sources of the molecule thorium monoxide (ThO) are optimized and characterized. Both helium and neon buffer gas sources are shown to produce ThO beams with high flux, low divergence, low forward velocity, and cold internal temperature for a variety of stagnation densities and nozzle diameters. The beam operates with a buffer gas stagnation density of ~10(15)-10(16) cm(-3) (Reynolds number ~1-100), resulting in expansion cooling of the internal temperature of the ThO to as low as 2 K. For the neon (helium) based source, this represents cooling by a factor of about 10 (2) from the initial nozzle temperature of about 20 K (4 K). These sources deliver ~10(11) ThO molecules in a single quantum state within a 1-3 ms long pulse at 10 Hz repetition rate. Under conditions optimized for a future precision spectroscopy application [A. C. Vutha et al., J. Phys. B: At., Mol. Opt. Phys., 2010, 43, 074007], the neon-based beam has the following characteristics: forward velocity of 170 m s(-1), internal temperature of 3.4 K, and brightness of 3 * 10(11) ground state molecules per steradian per pulse. Compared to typical supersonic sources, the relatively low stagnation density of this source and the fact that the cooling mechanism relies only on collisions with an inert buffer gas make it widely applicable to many atomic and molecular species, including those which are chemically reactive, such as ThO. PMID- 21698322 TI - Adhesive lithography for fabricating organic electronic and optoelectronics devices. AB - Improvements in organic electronic materials have led to novel device applications, ranging from large-area flexible displays to lightweight plastic electronics. Progress on these applications would benefit from development of low cost fabrication techniques for organic semiconductors. In this review, several fabrication processes based on adhesion force (i.e. van der Waals forces, thiol metal reactions, and cold welding) are introduced. These patterning techniques are dry patterning techniques, i.e., the electronic materials are patterned from the raised regions of molds onto a substrate directly by additive or subtractive patterning methods. Patterning of organic small molecule, polymer thin films and metal electrodes by adhesive lithography is demonstrated. The operating properties of patterned organic light-emitting diodes (OLEDs) and organic thin film transistors (OTFTs) are comparable with the performance of devices fabricated by conventional evaporation deposition methods. PMID- 21698323 TI - Programmable peptide-directed two dimensional arrays of various nanoparticles on graphene sheets. AB - In this research, we report an innovative, chemical strategy for the in situ synthesis and direct two-dimensional (2D) arraying of various nanoparticles (NPs) on graphenes using both programmed-peptides as directing agents and graphenes as pre-formed 2D templates. The peptides were designed for manipulating the enthalpic (coupled interactions) constraint of the global system. Along with the functionalization of graphene for the stable dispersion, peptides directed the growth and array of NPs in a controllable manner. In particular, the sequences of peptides were encoded by the combination of glutamic acid (E), glycine (G), and phenylalanine (F) amino acids as follows: (E-G-F)(3)-G, with E for the interaction with NPs and F and G for the interaction with graphenes. For the entropic (restricted geometry) constraint, graphene was used as a 2D scaffold to tune the size, density, and position of NPs, while maintaining the intrinsic properties for electrochemical applications. The excellent quality of the resultant hybrids was demonstrated by their high electrocatalytic activity in the electrooxidation of methanol. This synergistic combination of peptides and graphenes allowed for a uniform 2D array and spontaneous organization of various NPs (i.e., Pt, Au, Pd, and Ru), which would greatly expand the utility and versatility of this approach for the synthesis and array of the advanced nanomaterials. PMID- 21698324 TI - Facile synthesis of hydroxyapatite nanoparticles, nanowires and hollow nano structured microspheres using similar structured hard-precursors. AB - A facile strategy was developed to delicately control the morphologies of hydroxyapatite materials from simple 0D morphologies to complicated 3D architectures using hard-precursors with similar structures. The present study provides a new platform for hydroxyapatite materials to be efficiently synthesized and manipulated. PMID- 21698325 TI - Dark-field microscopy studies of polarization-dependent plasmonic resonance of single gold nanorods: rainbow nanoparticles. AB - Orientation sensors require the monitoring of polarization-dependent surface plasmons of single nanoparticles. Herein, we present both the longitudinal and transverse surface plasmonic resonance from a single gold nanorod (AuNR) using conventional dark-field microscopy. The relative peak intensities of the transverse and longitudinal surface plasmons of a single AuNR can be successfully tuned by polarized excitation, which is an important step towards the use of transverse plasmon resonance of single AuNRs without photo-induced reshaping of nanoparticles. More interestingly, compared with AuNRs with small diameters, unique optical properties from AuNRs with diameters greater than 30 nm are revealed. As a result, optical images with different colors, rainbow nanoparticles (sea green, brown, red, yellow and green), depending on the polarization angle, can be revealed by a single AuNR. This result holds great promise for polarization-controlled colorimetric nanomaterials and single particle tracers in living cells and microfluidic flows. PMID- 21698326 TI - Nanoscale semiconductor-insulator-metal core/shell heterostructures: facile synthesis and light emission. AB - Controllably constructing hierarchical nanostructures with distinct components and designed architectures is an important theme of research in nanoscience, entailing novel but reliable approaches of bottom-up synthesis. Here, we report a facile method to reproducibly create semiconductor-insulator-metal core/shell nanostructures, which involves first coating uniform MgO shells onto metal oxide nanostructures in solution and then decorating them with Au nanoparticles. The semiconductor nanowire core can be almost any material and, herein, ZnO, SnO(2) and In(2)O(3) are used as examples. We also show that linear chains of short ZnO nanorods embedded in MgO nanotubes and porous MgO nanotubes can be obtained by taking advantage of the reduced thermal stability of the ZnO core. Furthermore, after MgO shell-coating and the appropriate annealing treatment, the intensity of the ZnO near-band-edge UV emission becomes much stronger, showing a 25-fold enhancement. The intensity ratio of the UV/visible emission can be increased further by decorating the surface of the ZnO/MgO nanowires with high-density plasmonic Au nanoparticles. These heterostructured semiconductor-insulator-metal nanowires with tailored morphologies and enhanced functionalities have great potential for use as nanoscale building blocks in photonic and electronic applications. PMID- 21698327 TI - Lasing of CdSe/SiO2 nanocables synthesized by the facile chemical vapor deposition method. AB - Semiconductor nanocables are good candidates for developing robust and environmental stable nanolasers. In this work, high-quality CdSe/SiO(2) nanocables were synthesized by the facile chemical vapor deposition method. The as-synthesized nanocables were characterized by scanning electron microscopy, high-resolution transmission electron microscopy, and energy-dispersive X-ray spectroscopy. The results confirm that the cores in the nanocables are single crystalline hexagonal CdSe nanowires (NWs) with the growth direction of [0001], and the shells are amorphous SiO(2). Room-temperature lasing properties of single nanocables were reported for the first time by fabricating the nanocables into Fabry-Perot cavities. The finite element method was employed to simulate the electromagnetic field distributions inside and outside the nanocable optical resonant cavities. Both the theoretical and experimental results show that there exists a strong dependence of the photonic mode confinement on the core diameter of the nanocable. PMID- 21698329 TI - Capture and dissociation in the complex-forming CH(v = 0,1) + D2 -> CHD + D, CD2 + H, CD + HD reactions and comparison with CH(v = 0,1) + H2. AB - Rate coefficients for the CH(v = 0,1) + D(2) reaction have been determined for all possible channels (T: 200-1200 K), using the quasiclassical trajectory method and a suitable treatment of the zero point energy. Calculations have also been performed on the CH(v = 1) + H(2) reaction and the CH(v = 1) + D(2) -> CH(v = 0) + D(2) process. Most of the results can be understood considering the key role played by the deep minimum of the potential energy surface (PES), the barrierless character of the PES, the energy of the reaction channels, and the kinematics. The good agreement found between theory and experiment for the rate coefficients of the capture process of CH(v = 0) + D(2), the total reactivity of CH(v = 1) + D(2), H(2), as well as the good agreement observed for the related CH(v = 0) + H(2) system (capture and abstraction), gives confidence on the theoretical rate coefficients obtained for the capture processes of CH(v = 1) + D(2), H(2), the individual reactive processes of CH(v = 1) + D(2), H(2), the abstraction and abstraction-exchange reactions for CH(v = 0) + D(2), and the inelastic process mentioned above, for which there are no experimental data available, and that can be useful in combustion chemistry and astrochemistry. PMID- 21698328 TI - Excited state dependent electron transfer of a rhenium-dipyridophenazine complex intercalated between the base pairs of DNA: a time-resolved UV-visible and IR absorption investigation into the photophysics of fac-[Re(CO)3(F2dppz)(py)]+ bound to either [poly(dA-dT)]2 or [poly(dG-dC)]2. AB - The transient species formed following excitation of fac [Re(CO)(3)(F(2)dppz)(py)](+) (F(2)dppz = 11,12-difluorodipyrido[3,2-a:2',3' c]phenazine) bound to double-stranded polynucleotides [poly(dA-dT)](2) or [poly(dG-dC)](2) have been studied by transient visible and infra-red spectroscopy in both the picosecond and nanosecond time domains. The latter technique has been used to monitor both the metal complex and the DNA by monitoring the regions 1900-2100 and 1500-1750 cm(-1) respectively. These data provide direct evidence for electron transfer from guanine to the excited state of the metal complex, which proceeds both on a sub-picosecond time scale and with a lifetime of 35 ps, possibly due to the involvement of two excited states. No electron transfer is found for the [poly(dA-dT)](2) complex, although characteristic changes are seen in the DNA-region TRIR consistent with changes in the binding of the bases in the intercalation site upon excitation of the dppz complex. PMID- 21698330 TI - Chemoselectivity in the Cu-catalyzed O-arylation of phenols and aliphatic alcohols. AB - An orthogonal set of Cu-catalysts for the selective mono-arylation of alkyl aryl diols using aryl iodides is presented. Picolinic acid ligated copper catalyst provided phenol O-arylation only, while alkyl aryl ethers are generated by ligand free copper catalyst in the presence of 2 equivalents NaOt-Bu. PMID- 21698331 TI - A model of cyclic transcriptomic behavior in the cyanobacterium Cyanothece sp. ATCC 51142. AB - Systems biology attempts to reconcile large amounts of disparate data with existing knowledge to provide models of functioning biological systems. The cyanobacterium Cyanothece sp. ATCC 51142 is an excellent candidate for such systems biology studies because: (i) it displays tight functional regulation between photosynthesis and nitrogen fixation; (ii) it has robust cyclic patterns at the genetic, protein and metabolomic levels; and (iii) it has potential applications for bioenergy production and carbon sequestration. We have represented the transcriptomic data from Cyanothece 51142 under diurnal light/dark cycles as a high-level functional abstraction and describe development of a predictive in silico model of diurnal and circadian behavior in terms of regulatory and metabolic processes in this organism. We show that incorporating network topology into the model improves performance in terms of our ability to explain the behavior of the system under new conditions. The model presented robustly describes transcriptomic behavior of Cyanothece 51142 under different cyclic and non-cyclic growth conditions, and represents a significant advance in the understanding of gene regulation in this important organism. PMID- 21698332 TI - Visible light-induced intramolecular cyclization reactions of diamines: a new strategy to construct tetrahydroimidazoles. AB - A new and efficient synthesis of highly substituted tetrahydroimidazole derivatives by means of visible light-induced intramolecular cyclization reactions has been described. This photoredox catalytic reaction exhibited high diastereoselectivity and afforded the desired products in good yields. PMID- 21698333 TI - Flow conditions in the vicinity of microstructured interfaces studied by holography and implications for the assembly of artificial actin networks. AB - Microstructured fluidic devices have successfully been used for the assembly of free standing actin networks as mechanical model systems on the top of micropillars. The assembly occurs spontaneously at the pillar heads when preformed filaments are injected into the channel. In order to reveal the driving mechanism of this localization, we studied the properties of the flow profile by holographic tracking. Despite the strong optical disturbances originating from the pillar field, 2 MUm particles were traced with digital in-line holographic microscopy (DIHM). Trajectories in the pillar free region and local alterations of the flow profile induced by the channel structure in the pillar decorated region can be distinguished. Velocity histograms at different z-positions reveal that the laminar flow profile across the channel shows a difference between the minimum in the z-component of the velocity field and the maximum of the overall velocity. This minimum drag in vertical direction is present at the top of the pillars and explains why biopolymer networks readily assemble in this region instead of forming a homogeneous three-dimensional network in between the pillars. On the basis of the observations we propose a new mechanism for actin network formation on top of the microstructures. PMID- 21698334 TI - The boron-boron single bond in diborane(4) as a non-classical electron donor for hydrogen bonding. AB - An ab initio study of an isomer of diborane(4) [B(2)H(4)] has been carried out at MP2/aug-cc-pVTZ to investigate the ground-state properties of this unusual molecule, a derivative of which has been described in the recent literature. The geometric, electronic and orbital characteristics of B(2)H(4)(4) have been analyzed using AIM, NBO, and ELF methodologies. A region with a high concentration of electron density is located near and along the B-B bond, on the opposite side of this bond relative to the bridging H atoms. This site serves as an electron-donor site to electrophiles, resulting in hydrogen-bonded complexes of B(2)H(4) with proton donors HF, HNC, HCl, HCN, and HCCH, and a van der Waals complex with H(2). These complexes have C(2v) symmetry and stabilization energies that vary from 2 to 27 kJ mol(-1). The SAPT2 energy decomposition analysis shows that the relative importance of the various terms that contribute to the interaction energy depends on the strength of the interaction. PMID- 21698335 TI - High-resolution NMR spectroscopy under the fume hood. AB - This work reports the possibility to acquire high-resolution (1)H NMR spectra with a fist-sized NMR magnet directly installed under the fume hood. The small NMR sensor based on permanent magnets was used to monitor the trimerization of propionaldehyde catalyzed by indium trichloride in real time by continuously circulating the reaction mixture through the magnet bore in a closed loop with the help of a peristaltic pump. Thanks to the chemical selectivity of NMR spectroscopy the progress of the reaction can be monitored on-line by determining the concentrations of both reactant and product from the area under their respective lines in the NMR spectra as a function of time. This in situ measurement demonstrates that NMR probes can be used in chemistry laboratories, e.g. for reaction optimization, or installed at specific points of interest along industrial process lines. Therefore, it will open the door for the implementation of feedback control based on spectroscopic NMR data. PMID- 21698336 TI - The iFly tracking system for an automated locomotor and behavioural analysis of Drosophila melanogaster. AB - The use of animal models in medical research provides insights into molecular and cellular mechanisms of human disease, and helps identify and test novel therapeutic strategies. Drosophila melanogaster--the common fruit fly--is one of the most well-established model organisms, as its study can be performed more readily and with far less expense than for other model animal systems, such as mice, fish, or primates. In the case of fruit flies, standard assays are based on the analysis of longevity and basic locomotor functions. Here we present the iFly tracking system, which enables to increase the amount of quantitative information that can be extracted from these studies, and to reduce significantly the duration and costs associated with them. The iFly system uses a single camera to simultaneously track the trajectories of up to 20 individual flies with about 100 MUm spatial and 33 ms temporal resolution. The statistical analysis of fly movements recorded with such accuracy makes it possible to perform a rapid and fully automated quantitative analysis of locomotor changes in response to a range of different stimuli. We anticipate that the iFly method will reduce very considerably the costs and the duration of the testing of genetic and pharmacological interventions in Drosophila models, including an earlier detection of behavioural changes and a large increase in throughput compared to current longevity and locomotor assays. PMID- 21698337 TI - Hydrodynamics from statistical mechanics: combined dynamical-NEMD and conditional sampling to relax an interface between two immiscible liquids. AB - We present a method to study hydrodynamic phenomena from atomistic simulations. In statistical mechanics, these fields are computed as the ensemble average over the time dependent probability density function corresponding to the time evolution of an initial conditional probability density function consistent with some initial conditions. These initial conditions typically consist in constraints on some macroscopic fields, e.g. the density field. We show how these processes can be studied by combining the dynamical approach to non-equilibrium molecular dynamics with the restrained simulation approach. As an illustration of our method, we study the relaxation to the equilibrium of an interface between two immiscible liquids. We show that, at a variance with the local time average method, the standard atomistic approach used in this field, our method is able to produce (macroscopic) fields satisfying the symmetry conditions of the problem. PMID- 21698338 TI - On-demand controlled release of docetaxel from a battery-less MEMS drug delivery device. AB - We report the development of a magnetically controlled MEMS device capable of on demand release of defined quantities of an antiproliferative drug, docetaxel (DTX). Controlled release of DTX with a dosage suitable for the treatment of diabetic retinopathy has been achieved for 35 days. The device consists of a drug loaded microreservoir (O6 mm *~550 MUm), sealed by an elastic magnetic PDMS (polydimethylsiloxane) membrane (O6 mm * 40 MUm) with a laser-drilled aperture (~100 * 100 MUm(2)). By applying a magnetic field, the magnetic PDMS membrane deforms, causing the discharge of the drug solution from the device. Controlled DTX release at a rate of 171 +/- 16.7 ng per actuation interval has been achieved for 35 days using a 255 mT magnetic field. The background leakage of drug solution through the aperture was negligible at 0.053 +/- 0.014 ng min(-1). The biological activity of the released drug was investigated using a cytotoxicity assay (cell apoptosis) for two cell lines, HUVEC (human umbilical vein endothelial cells) and PC3 (prostate cancer) cells. Reproducible release rates have been achieved and DTX within the PDMS MEMS reservoir maintains full pharmacological efficacy for more than two months. This device is a proof-of concept development for targeted delivery of hydrophobic drugs such as DTX and other taxane-based agents that require accurate delivery in nanomolar concentrations. PMID- 21698339 TI - In situ self-assembly of mild chemical reduction graphene for three-dimensional architectures. AB - Three-dimensional (3D) architectures of graphene are of interest in applications in electronics, catalysis devices, and sensors. However, it is still a challenge to fabricate macroscopic all-graphene 3D architectures under mild conditions. Here, a simple method for the preparation of 3D architectures of graphene is developed via the in situ self-assembly of graphene prepared by mild chemical reduction at 95 degrees C under atmospheric pressure without stirring. No chemical or physical cross-linkers or high pressures are required. The reducing agents include NaHSO(3), Na(2)S, Vitamin C, HI, and hydroquinone. Both graphene hydrogels and aerogels can be prepared by this method, and the shapes of the 3D architectures can be controlled by changing the type of reactor. The 3D architectures of graphene have low densities, high mechanical properties, thermal stability, high electrical conductivity, and high specific capacitance, which make them candidates for potential applications in supercapacitors, hydrogen storage and as supports for catalysts. PMID- 21698340 TI - Speed-dependent treadmill training is effective to improve gait and balance performance in patients with sub-acute stroke. AB - OBJECTIVE: To compare the effects of speed-dependent treadmill training on gait and balance performance in patients with sub-acute stroke. DESIGN: Single-blinded randomized controlled trial. SUBJECTS: A total of 26 patients with sub-acute stroke were randomly assigned to experimental (n = 13) and control (n = 13) groups. METHODS: Subjects in the experimental group underwent short interval walking trials with stepwise increases in treadmill speed (speed-dependent treadmill training), following the principles of sprint training. Control subjects received gait training on the treadmill at a steady speed. Gait speed, stride length, cadence, and Berg's Balance Score were recorded and analysed before and after the 10 training sessions. RESULTS: Results of 2-way repeated measures analysis of variance showed significant group*time interactions for gait speed and stride length (p < 0.05). Within each subject group there were improvements in all gait parameters and Berg's Balance Score after the training programme. In addition, the experimental group showed significantly larger increases in gait speed (mean 0.15 m/s, 95% confidence interval 0.04-0.26) and stride length (mean 0.16 m, 95% confidence interval 0.02-0.30) than the control subjects. CONCLUSION: Speed-dependent treadmill training in patients with sub acute stroke resulted in larger gains in gait speed and stride length compared with steady speed. The positive findings provide evidence for clinical practice of speed-dependent treadmill training in enhancing gait function after stroke. PMID- 21698341 TI - Clinical profiles as a function of level and type of impulsivity in a sample group of at-risk and pathological gamblers seeking treatment. AB - Level and type of impulsivity are essential variables to be taken into consideration during the initial evaluation of a pathological gambler. The aim of this study was to measure the score for 4 impulsivity-related traits (Urgency, (lack of) Premeditation, (lack of) Perseverance and Sensation seeking) in a sample group of at-risk and pathological gamblers, and to highlight any links with certain elements of clinical data. The UPPS Impulsive Behaviour Scale was administered to 84 problem gamblers seeking treatment. The severity of gambling disorders was evaluated using the diagnostic criteria of the DSM-IV. Psychiatric and addictive comorbidities were also explored. The results indicated that the score for the Urgency facet had a positive correlation with the severity of gambling disorders. It appeared that participants displayed different clinical profiles according to the level and type of impulsivity. Several of the UPPS scales were identified as risk factors for mood disorders, risk of suicide, alcohol use disorders, and Attention Deficit/Hyperactivity Disorder (ADHD). The results confirm both the complexity of the multi-dimensional concept of impulsivity and the reason why the UPPS is of interest for a more in-depth study of the subject. PMID- 21698342 TI - Is executive cognitive function associated with youth gambling? AB - Our objectives for this report were to identify trajectories of youth gambling behavior, and to examine their relation to executive cognitive function (ECF) and associated problem behaviors. Philadelphia school children, enrolled at ages 10 12 years (n = 387; 49% male), completed three annual assessments of risk behaviors, ECF, impulsivity, problem behaviors and demographics. Across ages 10 15 years, using methods from Nagin et al., two groups were identified: Early Gamblers (n = 111) initiated early and continued in later assessments, and Later Gamblers (n = 276) initiated at later ages and gambled less. Betting money on cards and sports were the most frequently reported gambling behaviors. Using gambling group as outcome, final backward selection logistic regression model showed Early Gamblers are more likely male (P = 0.001), report more active coping (P = 0.042), impulsive behaviors (P <= 0.008), and have friends who gamble (P = 0.001). Groups were similar in ECF, parental monitoring, marital status, SES, and race. Early Gamblers had higher incidence of problem behaviors and drug use (all P <= 0.006). Two gambling groups were identified in early adolescence with Early Gamblers showing higher levels of impulsivity and comorbid problems but similar levels of ECF compared to Late Gamblers. As more gambling groups are identified through later adolescence, ECF may emerge as a relevant precursor of problem gambling at this later time. PMID- 21698343 TI - An intranucleolar body associated with rDNA. AB - The nucleolus is the subnuclear organelle responsible for ribosome subunit biogenesis and can also act as a stress sensor. It forms around clusters of ribosomal DNA (rDNA) and is mainly organised in three subcompartments, i.e. fibrillar centre, dense fibrillar component and granular component. Here, we describe the localisation of 21 protein factors to an intranucleolar region different to these main subcompartments, called the intranucleolar body (INB). These factors include proteins involved in DNA maintenance, protein turnover, RNA metabolism, chromatin organisation and the post-translational modifiers SUMO1 and SUMO2/3. Increase in the size and number of INBs is promoted by specific types of DNA damage and depends on the functional integrity of the nucleolus. INBs are abundant in nucleoli of unstressed cells during S phase and localise in close proximity to rDNA with heterochromatic features. The data suggest the INB is linked with regulation of rDNA transcription and/or maintenance of rDNA. PMID- 21698344 TI - [CT urography in women with primary or recurrent pelvic tumors : background and initial experiences]. AB - Malignant tumors of the female pelvis account for 12-13% of newly diagnosed solid neoplasms among women in the USA and Germany. German guidelines advocate diagnostic imaging for local recurrence and metastasis while there are no recommendations for primary tumors. As excretory urography has been replaced by the excretory phase of computed tomography urography (CTU) in many institutions, two independent observers retrospectively evaluated CTUs of primary or recurrent female pelvic tumors to rule out associations between CTU findings and subsequent urologic measures. Among 31 CTUs of 27 women (age 29-84 years, mean 57 years) with 15 primary and 13 recurrent tumors, 83-100% of unremarkable proximal, middle and distal ureter segments were completely delineated in the excretory phase (delay 6-29 min, mean 16 min). The most common pathological findings included distal ureter obstruction (n=19, 61%), bladder compression (n=13, 42%) and bladder invasion (n=8, 26%). Out of 20 pathologically altered urinary tracts 8 were subsequently subjected to urologic measures (2-tailed Fisher exact test, p=0.0215) but none of the 10 unremarkable urinary tracts were treated. It appears that CTU is a sensible pre-therapeutic test for the urinary tract for primary and recurrent female pelvic tumors. PMID- 21698345 TI - [Ultrasonographic clarification of adnexal findings]. AB - The most important diagnostic test for clarification of an adnexal mass is ultrasonographic evaluation. The prognostic value of an ultrasonographic examination is higher in combination with the patient history and clinical findings. In order to achieve high diagnostic accuracy certain requirements are mandatory. Firstly a high level of expertise, meticulousness and patience of the examiner is crucial. Secondly the use of a high-end ultrasound machine is essential. Thirdly a thorough evaluation and interpretation of sonomorphologic findings are necessary. Furthermore, these skills have to be trained continuously. This is fundamental for subjective, sonographic pattern recognition and the successful use of tumor scores resulting in a correct classification of adnexal tumors. Most adnexal tumors (approximately 75%) can be correctly (sensitivity 95% and specificity 91%) classified as benign or malignant using a set of simple rules. Tumors which cannot be classified (approximately 25%) can be differentiated by ultrasound examination by an expert examiner on the basis of subjective evaluation in about 90% of cases. PMID- 21698347 TI - Yeast screening from avermectins wastewater and investigation on the ability of its fermentation. AB - Wastewater from avermectin production is refractory with high output, high chemical oxygen demand (COD) concentration and high cost further. The current wastewater treatment technology, with little reuse of the organic material, needs high dilution ratio during treatment. Yeast single cell protein was produced from the wastewater of avermectins fermentation in this research. First, the yeast strain (H-1) which show enough tolerance to avermectins residue was screened from the wastewater, and it was identified as being most closely related to Candida tropicalis (100%, EF120592.1) using 18S rDNA gene sequence analysis. Second, its growth characteristics in the avermectins wastewater were studied. The dry biomass reached the maximal point of 10 g/L, the COD removal was up to 66.67%, and avermectins removal in the wastewater was 99.48% at the optimal condition that it was liquid volume 50 ml (250 ml flask), pH 4.0, temperature 30 degrees C, inoculum volume 10% (V/V) and fermentation period 20 h. Third, the nutritional contents of dry yeast powder were determined, in which the water content was 8.12%, ash content was 5.18% and the crude protein was 40.02%. The dry yeast powder from avermectin waste liquor was promising to be used as a raw material or nitrogen source for commercial production of avermectins. The project was economically feasible by primary cost accounting. PMID- 21698346 TI - Maohuoside A promotes osteogenesis of rat mesenchymal stem cells via BMP and MAPK signaling pathways. AB - Osteoporosis is becoming a more prevalent health problem with the aging of the population around the world. Epimedium koreanum Nakai is one of the most used herbs in East Asia for curing osteoporosis, with its major ingredient, icariin, mostly explored by researchers. In this article, maohuoside A (MHA), a single isolated compound from the herb, was identified to be more potent than icariin in promoting osteogenesis of rat bone marrow-derived mesenchymal stem cells (rMSCs) (increasing by 16.6, 33.3, and 15.8% on D3, D7, and D11, respectively). Alkaline phosphatase (ALP) assay and calcium content measurement were assigned to quantify the promoted osteogenesis and alizarin red S (ARS) staining was conducted to visualize it. Quantitative real-time PCR (Q-PCR) was assayed to evaluate the mRNA expression of marker genes in osteogenesis and master regulators in BMP pathway. Moreover, PD98059 (PD) and SB203580 (SB), inhibitor of ERK1/2 and p38 MAPK pathway, were administered to assess the involvement of MAPK pathway in the promotion process. In conclusion, MHA pronouncedly enhanced the osteogenesis of rMSC, plausibly via the BMP and MAPK signaling pathways. PMID- 21698348 TI - Ionization constants and solubility of compounds involved in enzymatic synthesis of aminopenicillins and aminocephalosporins. AB - The article deals with experimental determination of ionization constants and solubility for the compounds (target products, initial beta-lactams, acylating agents and by-products) involved in enzymatic synthesis of some therapeutically used aminopenicillins and aminocephalosporins, namely ampicillin, amoxicillin, cephalexin, cephadroxil, cephaloglycin, cefaclor, cefprozil, cefatrizine. Methodology of investigations and the evaluation of experimental data for the determination of ionization constants and solubility of the different type electrolytes are presented. Applications of the methods based on acid-base potentiometric titration and on determination of solubility-pH dependence of assayed substances are discussed. The original data on ionization constants and solubility of amoxicillin, cefprozil, cefatrizine, cephadroxil and initial beta lactams for production of cefaclor, cefprozil and cefatrizine, as well as solubility of by-product D-(-)-p-hydroxyphenylglycine are presented. Experimentally determined parameters and constants available in the literature for all abovementioned aminopenicillins and aminocephalosporins are collected. These data might be used for choice of the conditions of both processes: the enzymatic synthesis and the isolation of the product from reaction mixture. PMID- 21698350 TI - Factors associated with reduced compliance of children to dental preventive measures. AB - The aim of this study was to record self-reported factors for non-compliance to 'dental home' preventive measures among pediatric patients, and to clarify whether number or frequency of recall appointments increases their long-term compliance to dental home. Children attending recall appointments in a pediatric dental clinic were interviewed regarding their compliance as well as factors for non-compliance with the previously recommended preventive measures. Files of 651 children were analyzed. A significant positive correlation was found between compliance with regular teeth brushing twice a day (p < 0.0001), using correct fluoride concentration toothpaste (p < 0.0001), drinking water between meals (p < 0.0001), using Elmex gel (p < 0.0001), flossing (p < 0.002) and number of recall appointments. The most common factor for non-compliance to 'dental home' was 'I forgot'. Not flossing was commonly justified by performance difficulty while non compliance to Elmex gel or to mouth rinses was attributed mainly to 'bad taste'. Additional common reasons were 'it was finished', 'my parents did not purchase', 'I did not find it at home', 'I did not know I need to'. Frequency and number of recall appointments might improve compliance with dental preventive measures. Referring to the specific factors of personal non-compliance may increase compliance. PMID- 21698349 TI - Dilatation of the ascending aorta and serum alpha 1-antitrypsin level in patients with bicuspid aortic valve. AB - Predictors of aortic dilatation are not well described in patients with bicuspid aortic valves (BAV). This study sought to examine the relationship between proximal aortic dilatation and matrix metalloproteinase-9 (MMP-9) and alpha 1 antitrypsin (alpha1AT) levels in patients with BAV. All patients underwent echocardiography using a standard protocol, and aortic measurements were taken in end-diastole. We studied 82 patients with BAV and categorized them into two groups according to aortic dimensions corrected for body surface area and age. The plasma level of alpha1AT was routinely determined using a BN ProSpec analyzer (Siemens Healthcare Diagnostics, Marburg, Germany), and that of MMP-9 were determined by ELISA (RayBiotech Inc. Norcross, GA, USA). Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS; SPSS Inc., Chicago, IL, USA) software for Windows version 12. This study included patients with BAV with no or mild valvular impairment. There were no significant differences between groups in terms of gender, body surface area, associated hypertension, diabetes mellitus, hyperlipidemia, or smoking. The mean ascending aortic diameter was 4.38 +/- 0.5 mm in group 1 and 3.34 +/- 0.35 mm in group 2 (p < 0.001). Plasma concentration of alpha1AT in patients with ascending aortic dilatation was significantly lower than that in the non-dilated group (1.32 +/- 0.27 and 1.49 +/- 0.25 g/l, respectively; p = 0.005). However, no significant difference was found in the MMP-9 level between the two groups (336.49 +/- 233.11 and 336.39 +/- 268.072 pg/ml, respectively; p = 0.96). We observed a significantly negative correlation between ascending aortic diameter and alpha1AT level (r = -0.300, p = 0.006) and a positive correlation between ascending aortic diameter and age (r = 0.413, p < 0.001). No significant correlation was found between plasma MMP-9 concentration and ascending aortic diameter (r = -0.008, p = 0.94). A multiple linear regression analysis was performed, including age, alpha1AT level, MMP-9 level, and left ventricular diastolic diameter. In this analysis, alpha1AT level and age were the independent predictors of aortic dilatation (p = 0.03 and p = 0.02, respectively). PMID- 21698351 TI - Opening a new era of ABA research. PMID- 21698352 TI - Endometrioid adenocarcinoma arising from colonic endometriosis in a Lynch syndrome patient. PMID- 21698353 TI - Protein biomarkers in exfoliated cells collected from the human rectal mucosa: implications for colorectal disease detection and monitoring. AB - PURPOSE: Colorectal disease biomarkers in stool are actively explored, but instability of biomolecules in faeces constitutes a problem. Collection of exfoliated cells from the surface of the rectal mucosa provides an alternative to stool-based methods. We aimed to develop an original approach allowing preservation and quantification of protein biomarkers in exfoliated material and tested it in a pilot clinical study. METHODS: A novel method of cell and protein preservation in ammonium sulphate-rich buffers was developed using cultured human cells and applied to exfoliated cell samples collected from 139 faecal occult blood test (FOBT)-positive patients prior to colonoscopies. Protein biomarkers comprising calprotectin, eosinophil-derived neurotoxin (EDN), dimeric pyruvate kinase type M2 (M2PK), soluble cytokeratin-18, d-dimer and glyceraldehyde 3 phosphate dehydrogenase were quantified using enzyme-linked immunosorbent assays with parallel cytological and immunocytochemical analysis. RESULTS: Long-term preservation of cells and their protein constituents at ambient temperature was achieved using buffers containing saturated ammonium sulphate. Application of this approach to exfoliated cell samples allowed consistent protein quantification. Calprotectin, EDN, M2PK, soluble cytokeratin 18 and d-dimer showed dramatic increase in a few cases of inflammatory bowel disease (IBD) detected among trial participants. Cytological signs of inflammation were also present in these samples. CONCLUSIONS: Application of exfoliated cells collected from the surface of the rectal mucosa provides a reliable method for quantifying protein biomarkers of gastrointestinal diseases. Our preliminary results obtained in a limited number of cases indicate that the approach might be especially useful for IBD diagnosis and monitoring, but further studies are needed to assess its diagnostic value. PMID- 21698354 TI - Fetal liver cell transplantation as a potential alternative to whole liver transplantation? AB - Because organ shortage is the fundamental limitation of whole liver transplantation, novel therapeutic options, especially the possibility of restoring liver function through cell transplantation, are urgently needed to treat end-stage liver diseases. Groundbreaking in vivo studies have shown that transplanted hepatocytes are capable of repopulating the rodent liver. The two best studied models are the urokinase plasminogen activator (uPA) transgenic mouse and the fumarylacetoacetate hydrolase (FAH)-deficient mouse, in which genetic modifications of the recipient liver provide a tissue environment in which there is extensive liver injury and selection pressure favoring the proliferation and survival of transplanted hepatocytes. Because transplanted hepatocytes do not significantly repopulate the (near-)normal liver, attention has been focused on finding alternative cell types, such as stem or progenitor cells, that have a higher proliferative potential than hepatocytes. Several sources of stem cells or stem-like cells have been identified and their potential to repopulate the recipient liver has been evaluated in certain liver injury models. However, rat fetal liver stem/progenitor cells (FLSPCs) are the only cells identified to date that can effectively repopulate the (near-)normal liver, are morphologically and functionally fully integrated into the recipient liver, and remain viable long-term. Even though primary human fetal liver cells are not likely to be routinely used for clinical liver cell repopulation in the future, using or engineering candidate cells exhibiting the characteristics of FLSPCs suggests a new direction in developing cell transplantation strategies for therapeutic liver replacement. This review will give a brief overview concerning the existing animal models and cell sources that have been used to restore normal liver structure and function, and will focus specifically on the potential of FLSPCs to repopulate the liver. PMID- 21698355 TI - Pancreatic cancer stem cells: new insights and perspectives. AB - Since the identification of self-renewing cells in the hematopoietic system several decades ago, stem cells have changed the way we study biology and medicine. Solid tumors contain a distinct subpopulation of cells that have stem cell characteristics and are exclusively responsible for tumorigenicity. This discovery has led to the development of the stem cell concept of cancer, which proposes that a subpopulation of self-renewing tumor cells, also termed cancer stem cells, is responsible for tumorigenesis and metastasis. This contrasts with the stochastic model of tumor development, which holds that all tumor cells are capable of tumor initiation. Different subpopulations of cancer stem cells have been identified in pancreatic ductal adenocarcinoma, based on the use of combinations of surface markers that allow their isolation, propagation, and further characterization. Importantly, cancer stem cells are not only capable of self-renewal and differentiation, but may also confer virulence via immune system evasion and multidrug resistance, and potentially via vasculogenic mimicry and transition to migratory and metastasizing derivatives. Therapeutic targeting of this subset of cells and the pathways defining their virulence holds great promise for the development of more effective strategies for the amelioration and eradication of this most lethal form of cancer. PMID- 21698356 TI - Targeting myeloma-osteoclast interaction with Vgamma9Vdelta2 T cells. AB - Multiple myeloma (MM) cells stimulate osteoclastogenesis, and osteoclasts (OCs) in turn enhance MM growth and drug resistance, resulting in a vicious cycle. Vgamma9Vdelta2 T cells exert potent anti-tumor effects, making T cell-based immunotherapies using these cells attractive candidates for currently incurable malignancies, such as MM. However, the impact of such treatments on the MM-OC interaction is largely unknown. We demonstrate here that Vgamma9Vdelta2 T cells expanded by zoledronic acid and IL-2 exerted potent cytotoxic effects on both MM cells and OCs, even in coculture settings, but showed no such effect on bone marrow stromal cells. Vgamma9Vdelta2 T cells marginally affected colony formation from normal hematopoietic progenitors, and furthermore migrated toward osteopontin and MIP-1alpha, factors produced by the MM-OC interaction. These results suggest that Vgamma9Vdelta2 T cells expanded by zoledronic acid and IL-2 are able to migrate to MM bone lesions and preferentially target OCs as well as MM cells, thereby inhibiting both tumor expansion and bone destruction. PMID- 21698357 TI - Effects of anti-osteoporosis medications on fracture healing. AB - A number of fractures are complicated by impaired healing. This is prevalent in certain risk groups such as elderly, osteoporotics, postmenopausal women, and in people with malnutrition. At present, no pharmacologic treatments are available. Thus, there is an unmet need for medications that can stimulate bone healing. Parathyroid hormone (PTH) is the first bone anabolic drug approved for the treatment of osteoporosis and, intriguingly, a number of animal studies prove the ability of PTH to induce fracture healing. PTH may therefore be a potential novel treatment option in humans with impaired healing. However, more randomized clinical trials documenting the clinical efficacy of PTH as a promoter of fracture healing in the clinical setting are warranted. Also, strontium ranelate seems to have beneficial effects on fracture healing under conditions with impaired healing. However, no clinical studies are available so far, and such studies are warranted before any conclusions can be drawn. In contrast, bisphosphonates-which are the most widely used drug for treating osteoporosis delay the healing process slightly, although apparently not clinically relevant. Finally, a number of newer antiresorptive agents are available, but very few studies have addressed their effects on bone healing. PMID- 21698358 TI - Minor, major, low-trauma, and high-trauma fractures: what are the subsequent fracture risks and how do they vary? AB - Osteoporosis is a leading health problem worldwide due to the morbidity and mortality associated with fractures. However, a large number of fractures occur in persons without osteoporosis, when defined by bone mineral density alone. Numerous studies have shown that the risk of subsequent fracture is increased following fractures at most sites, and the increased risk is not limited to prior hip and vertebral fractures only. In addition, the amount of trauma present at the time of a fracture event appears to have limited impact on future fracture risk. Thus, even fractures that occur in the presence of high trauma should be recognized as evidence of possible bone fragility. Further methods to better identify persons at risk of future fracture are needed, such as through evaluation of other indicators of bone strength or recognition of modifiable, non bone factors. Any initial fracture event is important for patients and caregivers to recognize as an implication for future fracture risk. PMID- 21698359 TI - Pharmacokinetic characterization of a natural product-inspired novel MEK1 inhibitor E6201 in preclinical species. AB - PURPOSE: E6201 is a natural product-inspired novel inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 (MEK1) and other kinases and is currently under development as an anticancer (parenteral administration) and antipsoriasis agent (topical application). In vitro and in vivo preclinical studies were performed to characterize the pharmacokinetics of E6201. Allometric scaling was applied to predict human pharmacokinetics of E6201. METHODS: In vitro metabolism studies for CYP induction and CYP inhibition were conducted using human hepatocytes and microsomes, respectively. Metabolic stability using microsomes and protein-binding studies using pooled plasma were performed for mice, rats, dogs, and human. Pharmacokinetics of E6201 and its isomeric metabolite, ER-813010, in mice, rats, and dogs was determined following single IV administration of E6201 at three dose levels. Bioanalysis was performed using LC/MS/MS. Pharmacokinetic parameters were determined using non compartmental analysis, and allometric scaling with a two-compartment model was used to predict E6201 pharmacokinetics in humans. RESULTS: E6201 showed high plasma protein binding (>95%), and metabolic stability half-life ranged from 36 to 89 min across species. In vitro CYP inhibition (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A) and CYP induction (CYP1A, 3A, 2C9, and 2C19) suggested no inhibitory or induction effect on the tested human CYPs up to 10 MUM of E6201. Pharmacokinetics of E6201 in mice, rats, and dogs was characterized by mean clearance ranging from 3.45 to 10.92 L/h/kg, distribution volume ranging from 0.63 to 13.09 L/kg, and elimination half-life ranging from 0.4 to 1.6 h. ER-813010 was detected in all species with metabolite to parent exposure ratio (AUC(R)) ranging from 3.1 to 33.4% and exhibited fast elimination (<3 h). The allometry predicted high clearance and large volume of distribution of E6201 in humans and was in general in good agreement with the observed first human subject pharmacokinetics. CONCLUSIONS: E6201 exhibited high clearance, high to moderate distribution, and fast elimination in preclinical species. In vitro results suggested that E6201 has low risk of drug-drug interactions due to CYP inhibition and induction in humans. In the first-in-man study, E6201 exhibited high clearance, which was well predicted by allometric scaling. PMID- 21698360 TI - Predicting regional space-time variation of PM2.5 with land-use regression model and MODIS data. AB - PURPOSE: Existing land-use regression (LUR) models use land use/cover, population, and traffic information to predict long-term intra-urban variation of air pollution. These models are limited to explaining spatial variation of air pollutants, and few of them are capable of addressing temporal variability. This article proposes a space-time LUR model at a regional scale by incorporating aerosol optical depth (AOD) data from the Moderate Resolution Imaging Spectroradiometer (MODIS). METHODS: A multivariate regression model was established to predict the distribution of particle matters less than 2.5 MUm in aerodynamic diameter (PM(2.5)) in Florida, USA. Monthly PM(2.5) averages at 34 monitoring sites in the year 2005 were used as the dependent variable, while independent variables include land-use patterns, population, traffic, and topographic characteristics. In addition, a monthly AOD variable derived from the MODIS data was integrated into the regression as a space-time predictor. Cross validation procedures were conducted to validate this AOD-enhanced LUR model. RESULTS: The final regression model yields a coefficient of determination (R (2)) of 0.63, which is comparable to other studies that employ aerodynamic/meteorological models. The cross validation indicated a good agreement between the observed and predicted PM(2.5) with a mean residual of 0.02 MUg/m(3). The distance to heavy-traffic roads is negatively associated with the concentrations of PM(2.5), while agricultural land use is positively correlated. PM(2.5) tends to concentrate in high-latitude areas of Florida and during summer/fall seasons. The monthly AOD has a significant contribution to explaining the variation of PM(2.5) and remarkably enhances the model performance. CONCLUSIONS: This research is the first attempt to improve current LUR models by integrating remote sensing technologies. The integrative model approach offers an effective means to estimate air pollution over time and space, and could be an alternative to the classic meteorological approach. The model results would provide adequate measurements for epidemiological studies, particularly for chronic health effects in large populations. PMID- 21698361 TI - Polychlorinated biphenyls and their hydroxylated metabolites in placenta from Madrid mothers. AB - INTRODUCTION: Concentrations and congener profiles of polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OH-PCBs) in placenta samples from a Madrid population (Spain) are reported. Structure dependent retentions of OH-PCBs are known to occur in both humans and wildlife, making it of interest to assess placental transfer of both parent compounds and their metabolites to the developing foetus. RESULTS: The SigmaPCB concentrations found in placenta samples were in the range 943-4,331 pg/g fresh weight (f.w.), and their hydroxylated metabolites showed a 20-time lower concentration level (53-261 pg/g f.w.). The PCB profiles were surprisingly dominated by CB-52 and CB-101 accounting for more than 44% of the total PCB concentration. This is indicating a source of exposure that is not yet identified. The OH-PCB profiles were dominated by 4-OH-CB187 and 4-OH-CB146, representing >50% of the SigmaOH-PCB concentration of the placenta samples. Statistical analysis of the data revealed strong correlations between the PCB congeners, among some OH-PCBs, and between OH-PCB metabolites with a meta and para- substitution pattern. Both PCB and OH-PCB concentrations presented homogeneous distribution, what allowed the establishment of a partial least squares model that correlated the concentrations of OH-PCB with those of PCBs in placenta samples. In addition, causal correlations were observed between the concentrations of OH-PCBs and those of their corresponding PCB precursors. PMID- 21698362 TI - Optimization of electro-oxidation process for the treatment of Reactive Orange 107 using response surface methodology. AB - INTRODUCTION: Textile industries release large amount of wastewater to the environment which alters the clarity of water, interfere with light penetration, and pose toxicity to microbes and fish species. In order to remove the dye from wastewater, this study aimed to optimize electro-oxidation process for the degradation of textile dye C.I. Reactive Orange 107 in wastewater using a statistical tool. METHODOLOGY: The wastewater was synthetically prepared and experiments were designed as the function of variables such as pH (X(1)), NaCl concentration (X(2)), and electrolysis time (X(3)). Graphite electrode was used for all experiments and current was fixed at 34.96 mA cm(-2). The response color and chemical oxygen demand (COD) were measured. UV-visible spectra were recorded at different time intervals and the intermediate was analyzed using FTIR spectrum. RESULTS AND DISCUSSION: The relevant quadratic and interaction terms of factors were investigated. The coefficient of determination (R(2)) value of 0.8227 and 0.9265 for color and COD removal, respectively, indicate the adequacy of the model. The variables such as X(2) and X(3) are significant for color and X(3) is significant for COD removal. CONCLUSION: The electro-oxidation process efficiently removes color and COD from the Reactive Orange 107 contaminated wastewater. The optimum conditions obtained from the statistical analysis at pH 9.4, NaCl concentration of 0.08 M, and electrolysis time of 16.0 min show maximum color and COD removal of 98%, and 90%, respectively. UV-visible spectrum confirms the decoloration and FTIR spectra show the formation of intermediates. PMID- 21698363 TI - The clinical relevance of bifid and trifid mandibular canals. AB - BACKGROUND: Bifid mandibular canals (BMC) and trifid mandibular canals (TMC) are variations on the normal anatomy with incidences ranging from 0.08% to 65.0%. Such aberrations have an important clinical impact. For example, an extra mandibular canal may explain inadequate anesthesia, especially when two mandibular foramina are involved. Furthermore, during mandibular surgery, a second, or even third, neurovascular bundle may be damaged causing paresthesia, neuroma development, or bleeding. CASE REPORT: Two cases are presented in this article. One patient had a BMC on both sites, and the other patient had a TMC on one site and a BMC on the other site. DISCUSSION: Initial screening for the presence of a BMC or TMC can be executed by conventional panoramic radiography. BMCs or TMCs are diagnosed, before executing mandibular surgery; additional CBCT scanning is indicated. PMID- 21698364 TI - High mobility group box-1 induces migration of vascular smooth muscle cells via TLR4-dependent PI3K/Akt pathway activation. AB - High mobility group box-1 (HMGB1), a potent mediator of inflammation, is known to regulate cellular events through binding to the multiple cell-surface receptors, including RAGE and TLRs. However, the role of TLR4 and details of HMGB1 signaling in vascular smooth muscle cells (VSMCs) migration has not been reported so far. The present study was designed to investigate the hypothesis that HMGB1-induced VSMCs migration is mediated via activation of phosphoinositide 3-kinase/Akt (PI3K/Akt) signalling pathway through TLR4. VSMCs from rat thoracic aorta were studied. HMGB1 (0.1-1000 ng/ml) stimulated VSMCs migration in a dose-dependent manner, with the highest value (about 3.5-fold increase). Incubation of VSMCs with 100 ng/ml caused a rapid increase in PI3K activity and Akt phosphorylation. Migration of VSMCs toward HMGB1 was significantly inhibited by silencing of TLR4 (P < 0.05). We also found pretreated cells with TLR4 siRNA or the PI3 K inhibitor LY294002 could markedly block PI3K/Akt pathway activation and VSMCs migration mediated by HMGB1 (P both <0.05). In conclusion, HMGB1 induces migration of VSMCs through a TLR4-dependent PI3 K/Akt signaling pathway, which suggests a possible molecular mechanism for HMGB1 may contribute to neointima formation in restenosis after vascular damage. PMID- 21698365 TI - Polymorphisms of KiSS-1 and GPR54 genes and their relationships with litter size in sheep. AB - The KiSS-1 and GPR54 genes were studied as candidate genes for the prolificacy in sheep. Four pairs of primers were designed to detect single nucleotide polymorphisms of exon 1 of KiSS-1 gene and exon 1, exon 2 and partial exon 5 of GPR54 gene in high fecundity breeds (Small Tail Han and Hu sheep) and low fecundity breeds (Dorset, Texel and Corriedale sheep) by PCR-SSCP. Polymorphisms in exon 1 of KiSS-1 gene were detected in prolific Small Tail Han sheep (AA, AB and BB genotypes) and Hu sheep (AA and CC genotypes), no polymorphism was found in low fecundity sheep breeds (only AA genotype). Polymorphisms in exon 2 of GPR54 gene were detected in prolific Hu sheep (DD and EE genotypes) and no polymorphism was found in prolific Small Tail Han sheep and low fecundity sheep breeds (only DD genotype). No polymorphism was detected in exon 1 and partial exon 5 of GPR54 gene in five sheep breeds. The polymorphic genotypes were sequenced. While compared the BB genotype with the AA genotype, one nucleotide mutation (G1035A) was detected, which resulted in amino acid change, Val25Met. Five nucleotide mutations were detected from AA to CC genotype (C981T, C996T, T997C, C1034G, C1039T), and among them four caused amino acid changes, that is, Arg7Trp, Phe12Leu, Asn24Lys, Ala26Val. While compared the EE genotype with the DD genotype, two nucleotide mutations (T2360C, A2411C) were detected, which gave rise to amino acid changes, Met90Thr and Asp107Ala, respectively. Genotype frequencies of AA, BB and AB were 0.62, 0.05 and 0.33 in Small Tail Han sheep, respectively. The Small Tail Han sheep ewes with genotype BB or AB had 0.88 (P < 0.05) or 0.51 (P < 0.05) lambs more than those with genotype AA; the Small Tail Han sheep ewes with genotype BB had 0.37 (P > 0.05) lambs more than those with genotype AB. These results preliminarily indicated that the KiSS-1 gene may have some association with prolificacy in sheep. PMID- 21698366 TI - Intron retention and 3'-UTR analysis of Arabidopsis Dicer-like 2 transcripts. AB - Arabidopsis thaliana Dicer-like protein 2 (AtDCL2) plays an essential role in the RNA interference pathway. The function of AtDCL2 and other DCLs has been much studied but little has been done to characterize the DCLs transcripts before they are translated into proteins. Here, we investigated AtDCL2 transcripts and showed that all 21 introns of AtDCL2 except intron 9, 18, 20 and 21 could be retained although spliced sequences usually predominated. Intron 10 was more frequently retained and transient expression assays in Nicotiana benthamiana leaves showed that when AG/C at the 3' splicing site of the intron was changed to AG/G, the intron was more frequently spliced out. Conversely, a high retention of intron 18 was obtained if the AG/G at the 3' splicing site was changed to AG/C. These results suggest that the sequence at the 3' splicing site affects the efficiency of intron splicing. The 3'-UTRs of AtDCL2 had lengths between 54 and 154 nts, and the different 3'-UTRs differentially affected the transcriptional levels of fused GFP expressed transiently in N. benthamiana. Further comparisons and mutation experiments suggested that a putative SBF-1 binding site and an AU-rich element in the 3'-UTR both down-regulated expression of the upstream GFP fused to the 3' UTR. Conversely, a second poly(A) consensus signal sequence in one 3'-UTR up regulated gene expression. Our results provide insight into the character of AtDCL2 transcripts and demonstrate the potential complexity of factors that affect the frequency and patterns of alternative splicing. PMID- 21698367 TI - Effect of LEPR Gln223Arg polymorphism on breast cancer risk in different ethnic populations: a meta-analysis. AB - Leptin and leptin receptor have been implicated in processes leading to breast cancer initiation and progression. An A to G transition mutation in codon 223, in exon 6 of the leptin receptor gene (LEPR) can result in glutamine to arginine substitution (Gln223Arg). A variety of case-control studies have been published evaluating the association between LEPR Gln223Arg polymorphism and breast cancer. However, published studies have yielded contradictory conclusions. This meta analysis enrolled eight studies to estimate the overall risk of LEPR Gln223Arg polymorphism associated with breast cancer. The pooled ORs were performed for codominant model (Arg/Arg versus Gln/Gln; Arg/Gln versus Gln/Gln), dominant model (Arg/Arg + Arg/Gln versus Gln/Gln), recessive model (Arg/Arg versus Arg/Gln + Gln/Gln). Overall significantly elevated breast cancer risk was found for recessive model (OR 1.32, 95% CI 1.03-1.69) and for genotype Arg/Gln versus Gln/Gln (OR 1.16, 95% CI 1.01-1.34). In the stratified analysis by ethnicity, significantly increased risks were also found among Africans for genotype Arg/Arg versus Gln/Gln: OR 1.86, 95% CI 1.28-2.71, Arg/Gln versus Gln/Gln: OR 1.48, 95% CI 1.10-1.99, dominant model: OR 1.60, 95% CI 1.21-2.11 and recessive model: OR 1.48, 95% CI 1.07-2.05; for Asians, Arg/Arg versus Gln/Gln: OR 6.79, 95% CI 3.42 13.47 and dominant model: OR 2.03, 95% CI 1.42-2.90. However, no significantly increased risk was found among Europeans for all genetic models. In conclusion, the LEPR 223Arg is a low-penetrant risk for developing breast cancer, especially for black African women. PMID- 21698369 TI - Drug-induced autoimmune-like hepatitis: a case of chronic course after drug withdrawal. PMID- 21698368 TI - Recommendations for post-polypectomy surveillance in community practice. AB - BACKGROUND: After colon cancer screening, large numbers of persons discovered with colon polyps may receive post-polypectomy surveillance with multiple colonoscopy examinations over time. Decisions about surveillance interval are based in part on polyp size, histology, and number. AIMS: To learn physicians' recommendations for post-polypectomy surveillance from physicians' office charts. METHODS: Among 322 physicians performing colonoscopy in 126 practices in N. Carolina, offices of 152 physicians in 55 practices were visited to extract chart data, for each physician, on 125 consecutive persons having colonoscopy in 2003. Subjects included persons with first-time colonoscopy and no positive family history or other indication beyond colonoscopy findings that might affect post polypectomy surveillance recommendations. Data were extracted about demographics, reason for colonoscopy, family history, symptoms, bowel prep, extent of examination, and features of each polyp including location, size, histology. Recommendations for post-polypectomy surveillance were noted. RESULTS: Among 10,089 first-time colonoscopy examinations, hyperplastic polyps were found in 4.5% of subjects, in whom follow-up by 4-6 years was recommended in 24%, sooner than recommended in guidelines. Of the 6.6% of persons with only small adenomas, 35% were recommended to return in 1-3 years (sooner than recommended in some guidelines) and 77% by 6 years. Surveillance interval tended to be shorter if colon prep was less than "excellent." Prep quality was not reported for 32% of examinations. CONCLUSIONS: Surveillance intervals after polypectomy of low-risk polyps may be more aggressive than guidelines recommend. The quality of post polypectomy surveillance might be improved by increased attention to guidelines, bowel prep, and reporting. PMID- 21698371 TI - Interaction of inorganic mercury with CoA-SH and acyl-CoAs. AB - Sulfur containing biomolecules are involved in complexes with mercury. CoA is an important cofactor for many enzymes involved in metabolic processes. Fatty acyl CoA-thioesters, substrates of mitochondrial beta-oxidation, are sulfur containing compounds and potential mercury ligands. The CoA-Hg(2+) complex can be easily assessed by UV-Vis spectroscopy or indirectly by antibacterial tests that reconfirmed the protective role of CoA on E. coli. The characteristics of these complexes were determined by means of FTIR spectroscopy. The reverse phase liquid chromatography combined with electrospray ionization tandem mass spectrometry was used for detection of the side-product that resulted through the cleavage of thioesters in the presence of mercury. An unexpected result was the detection of octathioic acid as a product. Our study shows that mitochondrial beta-oxidation can be affected by thioesters depletion assisted by Hg(2+). The GC-MS technique could be used to detect some possible mitochondrial injuries due to the heavy metal ions. PMID- 21698372 TI - Effect of diquat-induced oxidative stress on iron metabolism in male Fischer-344 rats. AB - Diquat toxicity causes iron-mediated oxidative stress; however, it remains unclear how diquat affects iron metabolism. Here, we examined the effect of diquat-induced oxidative stress on iron metabolism in male Fischer-344 rats, with particular focus on gene expression. Hepatic nonheme iron content was unchanged until 20 h after diquat treatment. Hepatic free iron levels increased markedly in the early stages following treatment and remained elevated for at least 6 h, resulting in severe hepatotoxicity, until returning to control levels at 20 h. The level of hepatic ferritin, especially the H-subunit, increased 20 h after diquat treatment due to elevated hepatic ferritin-H mRNA expression. These results indicate that early elevated levels of free iron in the liver of diquat treated rats cause hepatotoxicity, and that this free iron is subsequently sequestered by ferritin synthesized under conditions of oxidative stress, thus limiting the pro-oxidant challenge of iron. The plasma iron concentration decreased at 6 and 20 h after diquat treatment, whereas the level of plasma interleukin-6 increased markedly at 3 h and remained high until 20 h. In the liver of diquat-treated rats, expression of hepcidin mRNA was markedly upregulated at 3 and 6 h, whereas ferroportin mRNA expression was downregulated slightly at 20 h. Transferrin receptor 1 mRNA expression was significantly upregulated at 3, 6, and 20 h. These results indicate that inhibition of iron release from iron-storage tissues, through stimulation of the interleukin-6 hepcidin-ferroportin axis, and enhanced iron uptake into hepatocytes, mediated by transferrin receptor 1, cause hypoferremia. PMID- 21698373 TI - Cemented fixed-bearing PFC total knee arthroplasty: survival and failure analysis at 12-17 years. AB - BACKGROUND: Total knee arthroplasty (TKA) is the appropriate treatment for degenerative pathology of the knee. Implant surveillance is mandatory to improve clinical results. We present the long-term results of a series of consecutive TKA Press Fit Condylar (J&J), cemented fixed bearing with selective patellar resurfacing in nonselected patients. MATERIALS AND METHODS: In this prospective case series, 223 TKA were clinically and radiographically evaluated using the Hospital for Special Surgery (HSS) knee score and the Knee Society Roentgenographic Evaluation and Scoring System. RESULTS: There were 197 patients, with an average age of 68.4 years [95% confidence interval (CI) 52.7-84.1 years]; 49 arthroplasties were implanted in men (21.1%) and 184 (78.9%) in women. The average follow-up was approximately 13.5 years (162.1 months; 95% CI 132.3 191.9), and it was possible to evaluate 179 implants (76.8% of the implanted prosthesis) in 176 patients. The average HSS score increased from 61.5 (95% CI 60.4-62.7) to 89.4 (95% CI 87.7-.93.5) points. The cumulative average survival rate at 15 years (the endpoint being failure with revision) was 90.6% +/- 2% standard deviation. Resurfacing the patella did not make a difference in terms of implant survival. Progressive radiolucent lines were observed around 20 implants (14.3%); all were revised. CONCLUSIONS: The PFC system is an excellent prosthetic solution. Early clinical complications, mechanical axis and patellar resurfacing do not correlate with implant failure, whereas progressive radiolucent lines do. PMID- 21698374 TI - The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation. AB - PURPOSE: In children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients. METHODS: Data were retrospectively collected describing tacrolimus disposition, age, CYP3A5 and ABCB1 genotype, and pediatric risk of mortality (PRISM) scores for up to 14 days post-transplant in children receiving liver and renal transplants. Initial TAC dosing was equal in all patients and adjusted using therapeutic drug monitoring. We determined the relationship between covariates and tacrolimus disposition. RESULTS: Forty-eight kidney and 42 liver transplant recipients (median ages 11.5 and 1.5 years, ranges 1.5-17.7 and 0.05-14.8 years, respectively) received TAC post-transplant. In both transplant groups, younger children (<5 years) needed higher TAC doses than older children [kidney: 0.15 (0.07-0.35) vs. 0.09 (0.02-0.20) mg/kg/12h, p = 0.046, liver: 0.12 (0.04-0.32) vs. 0.09 (0.01-0.18) mg/kg/12h, p = 0.038]. In kidney but not liver transplants, CYP3A5 expressors needed significantly higher TAC doses than nonexpressors [0.15 (0.07-0.20) vs. 0.09 (0.02-0.35) mg/kg/12h, P = 0.001]. In these patients, age and CYP3A5 genotype were independently associated with TAC dosing requirement. In liver, but not kidney transplant patients, homozygous ABCB1 T-T-T haplotype carriers needed higher TAC doses than noncarriers [0.26 (0.15-0.32) vs. 0.11 (0.01-0.25) mg/kg/12h, p = 0.013]. CONCLUSION: CYP3A5 genotype may explain variation in tacrolimus disposition early after transplant in pediatric kidney recipients, independent of age-related variation. In contrast, in pediatric liver recipients, variation in tacrolimus disposition appears related to age and ABCB1 genotype. These findings illustrate the importance of the interplay among age, genotype, and transplant organ on tacrolimus disposition. PMID- 21698375 TI - Practice variation in a longitudinal perspective: a multilevel analysis of the prescription of simvastatin in general practices between 2003 and 2009. AB - PURPOSE: The Dutch national guideline for Cardiovascular Risk Management advised in 2006 initiation of statin therapy in new patients with simvastatin. After the introduction of this guideline several measures were taken to increase the prescription of simvastatin in general practice. The aim of this paper is to describe the trend and interpractice variation in the relative share of simvastatin in statin prescription over a 7-year period (2003-2009) in Dutch general practices. METHODS: Data were used from the National Registration Network of General Practice (LINH) in the Netherlands. We used multilevel logistic regression analysis with individuals nested within practices. We evaluated the variance at different time points by the intra-class correlation (ICC). RESULTS: The share of simvastatin prescriptions of all statin prescriptions increased from 40% in 2003 to 82% in 2009. While the ICC was above 20% during the periods 2005 to 2007, it decreased rapidly from 25% in 2007 to only 9% in 2009. CONCLUSION: Our results indicate that a combination of several intervention measures seems to have been successful. While it seems like the implementation of the guidelines alone had some effect, there was an additional effect when reimbursement measures were implemented. Furthermore, the practice seemed to have affected the adoption of the national CVRM guideline as the variation initially increased after the guideline implementation. By including information on both the proportion of simvastatin prescribed and interpractice variation, we achieved a more complete evaluation of how simvastatin prescription developed over time and how it was related to the different measures taken. PMID- 21698378 TI - Simple defined autoinduction medium for high-level recombinant protein production using T7-based Escherichia coli expression systems. AB - Protein production under the control of lac operon regulatory elements using autoinduction is based on diauxic growth of Escherichia coli on lactose after consumption of more preferred carbon substrates. A novel simple and cost effective defined autoinduction medium using a mixture of glucose, glycerol, and lactose as carbon substrate and NH(4)(+) as sole nitrogen source without any supplementation of amino acids and vitamins was developed for T7-based E. coli expression systems. This medium was successfully employed in 96-well microtiter plates, test tubes, shake flasks, and 15-L bioreactor cultivations for production of different types of proteins achieving an average yield of 500 mg L(-1) product. Cell-specific protein concentrations and solubility were similar as during conventional isopropyl beta-D-1-thiogalactopyranoside induction using Luria-Bertani broth. However, the final yield of target proteins was about four times higher, as a higher final biomass was achieved using this novel defined autoinduction broth. PMID- 21698376 TI - Sequencing technologies and genome sequencing. AB - The high-throughput - next generation sequencing (HT-NGS) technologies are currently the hottest topic in the field of human and animals genomics researches, which can produce over 100 times more data compared to the most sophisticated capillary sequencers based on the Sanger method. With the ongoing developments of high throughput sequencing machines and advancement of modern bioinformatics tools at unprecedented pace, the target goal of sequencing individual genomes of living organism at a cost of $1,000 each is seemed to be realistically feasible in the near future. In the relatively short time frame since 2005, the HT-NGS technologies are revolutionizing the human and animal genome researches by analysis of chromatin immunoprecipitation coupled to DNA microarray (ChIP-chip) or sequencing (ChIP-seq), RNA sequencing (RNA-seq), whole genome genotyping, genome wide structural variation, de novo assembling and re assembling of genome, mutation detection and carrier screening, detection of inherited disorders and complex human diseases, DNA library preparation, paired ends and genomic captures, sequencing of mitochondrial genome and personal genomics. In this review, we addressed the important features of HT-NGS like, first generation DNA sequencers, birth of HT-NGS, second generation HT-NGS platforms, third generation HT-NGS platforms: including single molecule HeliscopeTM, SMRTTM and RNAP sequencers, Nanopore, Archon Genomics X PRIZE foundation, comparison of second and third HT-NGS platforms, applications, advances and future perspectives of sequencing technologies on human and animal genome research. PMID- 21698379 TI - The effect of mixotrophy on microalgal growth, lipid content, and expression levels of three pathway genes in Chlorella sorokiniana. AB - Nannochloropsis oculata CCMP 525, Dunaliella salina FACHB 435, and Chlorella sorokiniana CCTCC M209220 were compared in mixotrophic and photoautotrophic cultures in terms of growth rate, protein, and lipid content. Growth improved in glucose, and the biomass productivities of N. oculata, D. salina, and C. sorokiniana were found to be 1.4-, 2.2- and 4.2-fold that observed photoautotrophically. However, biomass and lipid production decreased at the highest glucose concentrations. Meanwhile, the content of protein and lipid were significantly augmented for mixotrophic conditions at least for some species. C. sorokiniana was found to be well suited for lipid production based on its high biomass production rate and lipid content reaching 51% during mixotrophy. Expression levels of accD (heteromeric acetyl-CoA carboxylase beta subunit), acc1 (homomeric acetyl-CoA carboxylase), rbcL (ribulose 1, 5-bisphosphate carboxylase/oxygenase large subunit) genes in C. sorokiniana were studied by real time PCR. Increased expression levels of accD reflect the increased lipid content in stationary phase of mixotrophic growth, but expression of the acc1 gene remains low, suggesting that this gene may not be critical to lipid accumulation. Additionally, reduction of expression of the rbcL gene during mixotrophy indicated that utilization of glucose was found to reduce the role of this gene and photosynthesis. PMID- 21698377 TI - Application of the bacteriophage Mu-driven system for the integration/amplification of target genes in the chromosomes of engineered Gram negative bacteria--mini review. AB - The advantages of phage Mu transposition-based systems for the chromosomal editing of plasmid-less strains are reviewed. The cis and trans requirements for Mu phage-mediated transposition, which include the L/R ends of the Mu DNA, the transposition factors MuA and MuB, and the cis/trans functioning of the E element as an enhancer, are presented. Mini-Mu(LR)/(LER) units are Mu derivatives that lack most of the Mu genes but contain the L/R ends or a properly arranged E element in cis to the L/R ends. The dual-component system, which consists of an integrative plasmid with a mini-Mu and an easily eliminated helper plasmid encoding inducible transposition factors, is described in detail as a tool for the integration/amplification of recombinant DNAs. This chromosomal editing method is based on replicative transposition through the formation of a cointegrate that can be resolved in a recombination-dependent manner. (E-plus)- or (E-minus)-helpers that differ in the presence of the trans-acting E element are used to achieve the proper mini-Mu transposition intensity. The systems that have been developed for the construction of stably maintained mini-Mu multi integrant strains of Escherichia coli and Methylophilus methylotrophus are described. A novel integration/amplification/fixation strategy is proposed for consecutive independent replicative transpositions of different mini-Mu(LER) units with "excisable" E elements in methylotrophic cells. PMID- 21698380 TI - Synthesis and properties of a novel biosuperabsorbent from alkali soluble Rhizomucor pusillus proteins. AB - A novel biosuperabsorbent protein hydrogel was prepared from protein-rich alcoholic-alkali soluble parts of zygomycete Rhizomucor pusillus biomass. The fungal protein content was 46.8%, and the lipid content was 13.1%. Extraction of protein from this microorganism through the method applied prevents protein decomposition, resulting in maximum yield. After alcoholic-alkaline extraction, the proteins from the biomass were acylated using ethylenediaminetetraacetic dianhydride and subsequently treated with glutaraldehyde as a crosslinker for further experiments. Thermal consistency was investigated by means of two different methods: thermal denaturation via differential scanning calorimetry and thermal decomposition study via thermogravimetric analysis. The swelling behaviour of the crosslinked hydrogel was measured in deionised water, 0.9% NaCl solution and synthetic urine, which were 87.6, 43 and 38.6 g/g water after 24 h, respectively. Moreover, the isoelectric point (pI) of the hydrogel was determined as pH = 8 by studying swelling behaviour at different pHs. In addition, the dependencies of the swelling behaviour with regard to the chemical modification, the ionic strength, the degree of crosslinking, as well as water absorbency with or without load were studied. PMID- 21698381 TI - Real-time monitoring of cell viability using direct electrical measurement with a patch-clamp microchip. AB - Real-time tagless monitoring of cell viability using patch-clamp microchips is reported and validated by using fluorescence imaging techniques for the first time. Specifically, four human breast cancer cell lines (MDA-MB231, MDA-MB231 brain metastatic subline (abbreviated as MB231-BR), MB231-BR over-expressing HER2 gene (MB231-BR-HER2), and MB231-BR-vector control for the HER2 (MB231-BR-vector)) have been used for these studies. Systematic experiments on these cells found that the seal impedance/resistance of cells captured by the micro-pipettes always decreases during the process when the cell loses its viability, and therefore it is a valid indicator of live or dead cells. Systematic experiments also found that the Mega-seal of patch-clamp microchip is sufficient for monitoring cell viability. Given its simplicity of direct electrical measurement of cells without fluorescence labeling, this technology may provide an efficient technical platform to monitor the drug effects on cells, thereby significantly benefiting high throughput drug screening and discovery process. PMID- 21698382 TI - Design and integration of a generic disposable array-compatible sensor housing into an integrated disposable indirect microfluidic flow injection analysis system. AB - We describe an integration strategy for arbitrary sensors intended to be used as biosensors in biomedical or bioanalytical applications. For such devices ease of handling (by a potential end user) as well as strict disposable usage are of importance. Firstly we describe a generic array compatible polymer sensor housing with an effective sample volume of 1.55 MUl. This housing leaves the sensitive surface of the sensor accessible for the application of biosensing layers even after the embedding. In a second step we show how this sensor housing can be used in combination with a passive disposable microfluidic chip to set up arbitrary 8 fold sensor arrays and how such a system can be complemented with an indirect microfluidic flow injection analysis (FIA) system. This system is designed in a way that it strictly separates between disposable and reusable components- by introducing tetradecane as an intermediate liquid. This results in a sensor system compatible with the demands of most biomedical applications. Comparative measurements between a classical macroscopic FIA system and this integrated indirect microfluidic system are presented. We use a surface acoustic wave (SAW) sensor as an exemplary detector in this work. PMID- 21698383 TI - A portable pressure pump for microfluidic lab-on-a-chip systems using a porous polydimethylsiloxane (PDMS) sponge. AB - In this paper, we propose a novel portable and disposable pressure pump using a porous polydimethylsiloxane (PDMS) sponge and demonstrate its application to a microfluidic lab-on-a-chip. The porous PDMS sponge was simply fabricated by a sugar leaching technique based on capillary suction of pre-cured PDMS into lumps of sugar, thereby enabling us to achieve the porous PDMS sponge composed of interconnected micropores. To indicate the characteristics of the porous PDMS sponge and pump, we measured the average porosities of them whose values were 0.64 and 0.34, respectively. A stress-strain relationship of the fabricated portable pressure pump represented a linear behavior in the compressive strain range of 0 to 20%. Within this range, a pumping volume of the pressure pump could be linearly controlled by the compressed strain. Finally, the fabricated porous PDMS pump was successfully demonstrated as a portable pressure pump for a disposable microfluidic lab-on-a-chip for efficient detection of agglutination. The proposed portable pressure pump can be potentially applicable to various disposable microfluidic lab-on-a-chip systems. PMID- 21698384 TI - Continuous high-throughput phosphopeptide enrichment using microfluidic channels modified with aligned ZnO/TiO(2) nanorod arrays. AB - A capillary microchannel (CM) containing TiO(2)-coated ZnO nanorod arrays was applied as a novel microfluidic device to selectively bind and enrich phosphopeptides. The device was prepared by pumping a TiO(2) sol into a CM containing preformed ZnO nanorod arrays. Different thicknesses of the TiO(2) coating were obtained by controlling the flow duration of TiO(2) sol. The modified CM achieved uninterrupted high-throughput introduction, capture and enrichment of phosphopeptides using continuous-flow operation. The microfluidic device based on the modified CM showed great selectivity, sensitivity and durability for the enrichment of phosphopeptides from tryptic protein digests. These results suggest that microfluidic chips employing this strategy can be used for rapid and high-throughput enrichment of phosphopeptides from complex mixtures. PMID- 21698385 TI - Metachromatic leukodystrophy: natural course of cerebral MRI changes in relation to clinical course. AB - OBJECTIVE: Metachromatic Leukodystrophy (MLD) is a rare disorder leading to demyelination and neurological impairment. A natural history study within the German leukodystrophy network analyzed MRI changes with respect to the clinical course. METHODS: 113 MR images of 68 patients (33 late-infantile, 35 juvenile) were studied cross-sectionally and longitudinally. MRI and motor deterioration were assessed using standardized scoring systems. RESULTS: The temporal and spatial patterns of MR severity scores differed between the late-infantile and juvenile form. Although early (involving central white matter, corpus callosum) and late signs (involving pons, cerebellum, cerebral atrophy) were similar, high MRI scores (mean 18, SD 1.2, p < 0.001) were evident in the juvenile form already at the onset of first symptoms and even in presymptomatic patients. The progression rate of the MRI score was clearly higher and more uniform in the late infantile (on average 8 per year, p < 0.0001) than in the juvenile patients (on average 0.4 per year, p < 0.08). In late-infantile patients, MRI changes correlated highly with motor deterioration (rho = 0.73, p < 0.001), this was less remarkable in the juvenile form (rho = 0.50, p < 0.01). Severe motor dysfunction was associated with U-fiber involvement and cerebellar changes (p < 0.05). CONCLUSIONS: MRI showed a typical spatial pattern, which evolved gradually and uniformly during disease progression in late-infantile MLD. In juvenile MLD MRI changes were already observed at disease onset and temporal patterns were more variable. As therapeutic options for MLD are evolving, these findings are not only important for patient counseling but also for the evaluation of therapeutic interventions. PMID- 21698387 TI - Diurnal and nocturnal drooling in Parkinson's disease. AB - Drooling as symptom of Parkinson's disease (PD) has thus far been poorly defined. This uncertainty is reflected by high variations in published prevalence rates. The aim of this study was to investigate the prevalence of saliva loss versus accumulation of saliva as a possible preliminary stage, and diurnal drooling versus nocturnal drooling. In addition, we evaluated the association between drooling severity and the severity of facial and oral motor disorders. We collected age, disease duration, UPDRS III and Hoehn & Yahr stage from 104 consecutive outpatients with PD. Diurnal and nocturnal drooling was evaluated with a validated questionnaire (ROMP-saliva). A speech pathologist, blinded for drooling severity, rated facial expression, involuntary mouth opening and difficulty with nose breathing and also interviewed patients about sleeping position and nose-breathing during the night. Thirty patients (29%) had no complaints with saliva control ('non-droolers'), 45 patients (43%) experienced accumulation of saliva or only nocturnal drooling ('pre-droolers'), and 29 (28%) had diurnal drooling (24 of which also drooled during the night; 'droolers'). The droolers had longer disease duration (10 vs. 7 years, p = 0.01) and drooling was independently associated with involuntary mouth opening (OR = 2.0; 95% CI 1.02 3.99) and swallowing complaints (OR = 1.2; 95% CI 1.03-1.31). Diurnal drooling defined as dribbling of saliva while awake-is present in about 28% of PD patients. This is less than usually reported. Diurnal drooling typically appeared later in the disease course. The association with oral motor behavior should encourage the development of behavioral treatment approaches. PMID- 21698388 TI - News on the pathomechanism of migraine: spreading depression, a vascular factor, and cortical excitability. PMID- 21698389 TI - Robotic system for MRI-guided prostate biopsy: feasibility of teleoperated needle insertion and ex vivo phantom study. AB - PURPOSE: Magnetic Resonance Imaging (MRI) combined with robotic assistance has the potential to improve on clinical outcomes of biopsy and local treatment of prostate cancer. METHODS: We report the workspace optimization and phantom evaluation of a five Degree of Freedom (DOF) parallel pneumatically actuated modular robot for MRI-guided prostate biopsy. To shorten procedure time and consequently increase patient comfort and system accuracy, a prototype of a MRI compatible master-slave needle driver module using piezo motors was also added to the base robot. RESULTS: Variable size workspace was achieved using appropriate link length, compared with the previous design. The 5-DOF targeting accuracy demonstrated an average error of 2.5 mm (STD = 1.37 mm) in a realistic phantom inside a 3T magnet with a bevel-tip 18G needle. The average position tracking error of the master-slave needle driver was always below 0.1 mm. CONCLUSION: Phantom experiments showed sufficient accuracy for manual prostate biopsy. Also, the implementation of teleoperated needle insertion was feasible and accurate. These two together suggest the feasibility of accurate fully actuated needle placement into prostate while keeping the clinician supervision over the task. PMID- 21698390 TI - Modulation of adipokine production, glucose uptake and lactate release in human adipocytes by small changes in oxygen tension. AB - Adipose tissue becomes hypoxic in obesity, and cell culture studies have demonstrated that hypoxia leads to major changes in adipocyte function. Studies on the response of adipocytes to low O2 tension have employed marked hypoxia (1% O2). Here, we have examined the effects of modest hypoxia, utilising differing concentrations of O2 (1-21%), on adipokine production and glucose uptake by human adipocytes. Incubation with 10% O2 (24 h) increased expression of the leptin, vascular endothelial growth factor (VEGF) and Angptl4 genes, while leptin expression was elevated even at 15% O2 (compared to 'normoxia'-21% O2). Overall, there was a concentration-dependent increase in the expression of these genes as O2 fell, with the highest mRNA level evident at 1% O2. Parallel changes were observed in the secretion of leptin, VEGF and IL-6 into the medium, an increased release being evident at 10% O2 (15% O(2) for leptin). Adiponectin gene expression was reduced at 15% O2 and below, while adiponectin release was significantly reduced at 5% O2. Both 2-deoxy-D: -glucose uptake and lactate release showed progressive increases as O2 concentration fell, being significantly raised at 10% and 5% O2, respectively. The alterations in substrate transport were accompanied by parallel changes in transporter gene expression, GLUT1 and MCT1 mRNA level increasing from 15% and 10% O2, respectively. These results indicate that marked responses to reduced O2 concentration are exhibited by human adipocytes at O2 levels well above those associated with hypoxia and employed in cell culture studies. Adipocytes are sensitive to small changes in O2 tension. PMID- 21698391 TI - Voltage-dependent potassium currents in feline sino-atrial node myocytes. AB - We characterized the properties of the voltage-dependent K(+) currents I (to), I (Kr), and I (Ks) in isolated feline sino-atrial node (SAN) myocytes. I (to) activated rapidly and then inactivated with a single exponential and voltage independent time course. Recovery from inactivation of I (to) followed a single exponential time course with tau = 21.1 +/- 2.5 ms, at -80 mV. Steady-state inactivation relationship showed a V1/2 of inactivation at -47.9 +/- 2.3 mV. These biophysical properties are similar to the fast I (to) phenotype of other mammals. I (Kr) exhibited typical negative slope conductance at test potentials > 0 mV and slow deactivation. I (Ks) activated very slowly. The functional contribution of I (to), I (Kr), and I (Ks) to the sustained pacemaking activity of feline SAN myocytes was analyzed. Similar to other mammals, I (to) underlies the initial repolarization phase of the SAN action potential, whereas I (Kr) and I (Ks) mediate repolarization back to the maximal diastolic potential. I (Kr) and I (Ks) also contribute to diastolic depolarization because of their slow deactivation kinetics. The I (Kr) specific blocker E-4031 and the I (Ks) blocker HMR 1556 significantly increased action potential duration, but had negligible effects on the maximum diastolic potential and only modest effects on the frequency of spontaneous activity, suggesting that each one of these two currents itself is capable of supporting action potential repolarization in the feline sinus node. PMID- 21698392 TI - Interactive digital slides with heat maps: a novel method to improve the reproducibility of Gleason grading. AB - Our aims were to analyze reporting of Gleason pattern (GP) 3 and 4 prostate cancer with the ISUP 2005 Gleason grading and to collect consensus cases for standardization. We scanned 25 prostate biopsy cores diagnosed as Gleason score (GS) 6-7. Fifteen genitourinary pathologists graded the digital slides and circled GP 4 and 5 in a slide viewer. Grading difficulty was scored as 1-3. GP 4 components were classified as type 1 (cribriform), 2 (fused), or 3 (poorly formed glands). A GS of 5-6, 7 (3 + 4), 7 (4 + 3), and 8-9 was given in 29%, 41%, 19%, and 10% (mean GS 6.84, range 6.44-7.36). In 15 cases, at least 67% of observers agreed on GS groups (consensus cases). Mean interobserver weighted kappa for GS groups was 0.43. Mean difficulty scores in consensus and non-consensus cases were 1.44 and 1.66 (p = 0.003). Pattern 4 types 1, 2, and 3 were seen in 28%, 86%, and 67% of GP 4. All three coexisted in 16% (11% and 23% in consensus and non consensus cases, p = 0.03). Average estimated and calculated %GP 4/5 were 29% and 16%. After individual review, the experts met to analyze diagnostic difficulties. Areas of GP 4 and 5 were displayed as heat maps, which were helpful for identifying contentious areas. A key problem was to agree on minimal criteria for small foci of GP 4. In summary, the detection threshold for GP 4 in NBX needs to be better defined. This set of consensus cases may be useful for standardization. PMID- 21698393 TI - A library of cortical morphology analysis tools to study development, aging and genetics of cerebral cortex. AB - Sharing of analysis techniques and tools is among the main driving forces of modern neuroscience. We describe a library of tools developed to quantify global and regional differences in cortical anatomy in high resolution structural MR images. This library is distributed as a plug-in application for popular structural analysis software, BrainVisa (BV). It contains tools to measure global and regional gyrification, gray matter thickness and sulcal and gyral white matter spans. We provide a description of each tool and examples for several case studies to demonstrate their use. These examples show how the BV library was used to study cortical folding process during antenatal development and recapitulation of this process during cerebral aging. Further, the BV library was used to perform translation research in humans and non-human primates on the genetics of cerebral gyrification. This library, including source code and self-contained binaries for popular computer platforms, is available from the NIH-Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC) resource ( http://www.nitrc.org/projects/brainvisa_ext ). PMID- 21698394 TI - Map-based cloning proves qGC-6, a major QTL for gel consistency of japonica/indica cross, responds by Waxy in rice (Oryza sativa L.). AB - In this study, one major QTL affecting gel consistency (GC) of japonica/indica cross was identified on chromosome 6 using a DH population. To understand the molecular mechanism that regulates GC in rice grains, the major QTL (qGC-6) was isolated through a map-based cloning approach utilizing chromosome segment substitution lines (CSSLs). Using 64 plants with extremely soft GC that were selected on recombinant break points between two SSR markers, RM540 and RM8200 in a BC4F2 population, qGC-6 was mapped to a 60-kb DNA region between two STS markers, S26 and S27. These two markers were then used to further identify recombination break points. Finally, qGC-6 was delimited in an interval of a 11 kb region. Gene prediction analysis of the 11-kb DNA sequence containing qGC-6 identified only one putative ORF, which encodes granule-bound starch synthesis protein (Wx protein). Results of sequencing analysis and complementation experiment confirmed that this candidate ORF is responsible for rice GC. Genetic evidences revealed that Wx might contribute equally to the grain amylose content controlling gene as well as gel consistency. This new information is important to breed rice varieties with improved grain quality. PMID- 21698395 TI - Thalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage immunomodulatory therapy in patients with relapsed and refractory multiple myeloma. AB - The treatment of patients with multiple myeloma usually includes many drugs including thalidomide, lenalidomide and bortezomib. Lovastatin and other inhibitors of HMG-CoA reductase demonstrated to exhibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines. We treated 91 patients with relapsed or refractory multiple myeloma with thalidomide, dexamethasone and lovastatin (TDL group, 49 patients) or thalidomide and dexamethasone (TD group, 42 patients). A clinical response defined of at least 50% reduction of monoclonal band has been observed in 32% of TD patients and 44% of TDL patients. Prolongation of overall survival and progression-free survival in the TDL group as compared with the TD group has been documented. The TDL regimen was safe and well tolerated. The incidence of side effects was comparable in both groups. Plasma cells have been cultured in vitro with thalidomide and lovastatin to assess the impact of both drugs on the apoptosis rate of plasma cells. In vitro experiments revealed that the combination of thalidomide and lovastatin induced higher apoptosis rate than apoptosis induced by each drug alone. Our results suggest that the addition of lovastatin to the TD regimen may improve the response rate in patients with relapsed or refractory myeloma. PMID- 21698396 TI - Validated instruments in the evaluation and treatment outcomes of stress urinary incontinence in women. AB - Urinary incontinence is a highly prevalent condition. Although there are commonly used tools for the evaluation of urinary incontinence and measurement of treatment outcomes, there is no universally accepted standard. However, there are several validated instruments currently available and in use for assessment of patient-reported outcomes. Such an emphasis on patient-reported outcomes is key because there can be discrepancies between a physician's and a patient's perception of symptom severity and outcome. PMID- 21698397 TI - Retropubic and transobturator slings: still useful or should all patients be treated with mini-slings? AB - Traditional retropubic and transobturator midurethral slings are reliable, safe, and effective treatments for stress urinary incontinence. Unfortunately, they also are associated with rare but severe complications, such as bladder or bowel perforation, vascular injury, nerve damage, and/or groin muscle pain that can occur with the blind passage of trocars. To maintain efficacy and patient satisfaction while avoiding such complications, minimally invasive mini-slings have been developed. These smaller mini-slings can be placed through a single vaginal incision at the level of the midurethra without trocars. Mini-slings often are performed as an outpatient surgery, with minimal morbidity, pain, and quick patient recovery. With continued refinement and surgeon experience, mini slings potentially may be performed safely in the office setting under local anesthesia while maintaining the efficacy of traditional slings. PMID- 21698398 TI - Prevalence and diagnostic outcome relating to vitamin D deficiency in new patients presenting to an early arthritis clinic over 12 months. PMID- 21698399 TI - Rheumatologic manifestations of benign and malignant haematological disorders. AB - Diseases of blood and lymphoreticular system can have multisystem manifestations. Rheumatologic involvement has been reported in association with many benign and malignant haematological disorders; these patients are equally likely to present to both clinical rheumatologists and haematologists. This review focuses on the well-described rheumatologic features, other occasionally reported rheumatologic manifestations and unusual musculoskeletal complications related to the treatment in patients with underlying haematological conditions. The aim of this review is to help increase the awareness of rheumatologic manifestations seen in the blood disorders and to highlight the potential diagnostic pitfalls. PMID- 21698400 TI - Transcutaneous bilirubinometry: comparison of two multiwavelength devices in healthy term newborns. PMID- 21698401 TI - Elevated ground-level O(3) changes the diversity of anoxygenic purple phototrophic bacteria in paddy field. AB - The knowledge of the impact of elevated ground-level O(3) below ground the agro ecosystem is limited. A field experiment in China Ozone Free-Air Concentration Enrichment (FACE-O(3)) facility on a rice-wheat rotation system was carried out to investigate responses of anoxygenic phototrophic purple bacteria (AnPPB) to elevated ground-level O(3). AnPPB community structures and sizes in paddy soil were monitored by molecular approaches including PCR-DGGE and real-time quantitative PCR based upon the pufM gene on three typical rice growth stages. Repetitive sequence-based PCR (rep-PCR) in combination with culture-reliant method was conducted to reveal changes in genotypic diversity. Elevated ground level O(3) statistically reduce AnPPB abundance and percentage in total bacterial community in flooded rice soil via decreasing their genotypic diversity and metabolic versatility. Concomitantly, their community composition changed after rice anthesis stage under elevated ground-level O(3). Our results from AnPPB potential responses imply that continuously elevated ground-level O(3) in the future would eventually harm the health of paddy ecosystem through negative effect on soil microorganisms. PMID- 21698402 TI - Phylogenetic and gene expression analysis of cyanobacteria and diatoms in the twilight waters of the temperate northeast Pacific Ocean. AB - In this study, to explore the microbial community structure and its functionality in the deep-sea environments, we initially performed a 16S ribosomal RNA (rRNA) based community structure analyses for microbial communities in the sea water collected from sites of 765-790 m in depth in the Pacific Ocean. Interestingly, in the clone library we detected the presence of both photoautotrophic bacteria such as cyanobacteria and photoheterotrophic bacteria, such as Chloroflexus sp. To further explore the existence and diversity of possible light-utilizing microorganisms, we then constructed and analyzed a 23S rRNA plastid gene cloning library. The results showed that the majority of this cloning library was occupied by oxygenic photoautotrophic organisms, such as diatoms Thalassiosira spp. and cyanobacterium Synechococcus sp. In addition, the diversity of these oxygenic photoautotrophic organisms was very limited. Moreover, both reverse transcription PCR and quantitative reverse-transcription PCR approaches had been employed to detect expression of the genes involved in protein synthesis and photosynthesis of photoautotrophic organisms, and the positive results were obtained. The possible mechanisms underlying the existence of very limited diversity of photosynthetic organisms at this depth of ocean, as well as the positive detection of rRNA and mRNA of diatom and cyanobacteria, were discussed. PMID- 21698403 TI - Bacterial community composition of biological degreasing systems and health risk assessment for workers. AB - Biological degreasing system is a new technology based on the degradation capabilities of microorganisms to remove oil, grease, or lubricants from metal parts. No data is available about the potential biological health hazards in such system. Thus, a health risk assessment linked to the bacterial populations present in this new degreasing technology is, therefore, necessary for workers. We performed both cultural and molecular approaches in several biological degreasing systems for various industrial contexts to investigate the composition and dynamics of bacterial populations. These biological degreasing systems did not work with the original bacterial populations. Indeed, they were colonized by a defined and restricted group of bacteria. This group replaced the indigenous bacterial populations known for degrading complex substrates. Klebsiella pneumoniae, Klebsiella oxytoca, Pseudomonas aeruginosa, and Pantoea agglomerans were important members of the microflora found in most of the biological degreasing systems. These bacteria might represent a potential health hazard for workers. PMID- 21698404 TI - In vitro evaluation of phospholipase, proteinase, and esterase activities of Candida parapsilosis and Candida metapsilosis. AB - The aim of this study is to characterize extracellular phospholipase, proteinase, and esterase activities of Candida parapsilosis and C. metapsilosis isolated from clinical sources. Using PCR-restriction fragment length polymorphism (PCR-RFLP) of the secondary alcohol dehydrogenase (SADH) gene fragment, we identified 20 as C. parapsilosis and 11 as C. metapsilosis from 31 isolates of C. parapsilosis species complex. No C. orthopsilosis was identified. A significantly high isolation frequency of C. metapsilosis (35.5%) was observed. Subsequent evaluation of enzymatic profile showed that 90.5% of C. parapsilosis and 91.7% of C. metapsilosis isolates were phospholipase producers. No difference in phospholipase activity was observed between two species. In terms of proteinase, 81.0% of C. parapsilosis and 83.3% of C. metapsilosis isolates were positive. A higher level of proteinase activity was detected in C. parapsilosis. A remarkably high proportion of both C. parapsilosis and C. metapsilosis isolates exhibited strong phospholipase and proteinase activities, suggesting that the production of these two enzymes might be common for them. On the other hand, both species similarly displayed rare esterase activity, with only one C. parapsilosis and two C. metapsilosis isolates being positive. Our data may further add to the confusion concerning the hydrolytic enzymatic activities of the C. parapsilosis complex, and a wider collection of isolates and standardized methods may help to address the issue. PMID- 21698405 TI - A model of non-elemental olfactory learning in Drosophila. AB - The pathways for olfactory learning in the fruitfly Drosophila have been extensively investigated, with mounting evidence that that the mushroom body is the site of the olfactory associative memory trace (Heisenberg, Nature 4:266-275, 2003; Gerber et al., Curr Opin Neurobiol 14:737-744, 2004). Heisenberg's description of the mushroom body as an associative learning device is a testable hypothesis that relates the mushroom body's function to its neural structure and input and output pathways. Here, we formalise a relatively complete computational model of the network interactions in the neural circuitry of the insect antennal lobe and mushroom body, to investigate their role in olfactory learning, and specifically, how this might support learning of complex (non-elemental; Giurfa, Curr Opin Neuroethol 13:726-735, 2003) discriminations involving compound stimuli. We find that the circuit is able to learn all tested non-elemental paradigms. This does not crucially depend on the number of Kenyon cells but rather on the connection strength of projection neurons to Kenyon cells, such that the Kenyon cells require a certain number of coincident inputs to fire. As a consequence, the encoding in the mushroom body resembles a unique cue or configural representation of compound stimuli (Pearce, Psychol Rev 101:587-607, 1994). Learning of some conditions, particularly negative patterning, is strongly affected by the assumption of normalisation effects occurring at the level of the antennal lobe. Surprisingly, the learning capacity of this circuit, which is a simplification of the actual circuitry in the fly, seems to be greater than the capacity expressed by the fly in shock-odour association experiments (Young et al. 2010). PMID- 21698406 TI - Pregnancy after breast cancer: if you wish, ma'am. AB - A growing number of young breast cancer survivors consider reproductive health issues, including subsequent fertility and pregnancy, of great importance, but many questions regarding safety remain unanswered. We conducted a comprehensive literature search and review of published articles, control-matched, population based, and co-operative group reports that addressed various aspects of pregnancy after breast cancer (patients' expectations, fertility damage, assessment and preservation, maternal and fetal outcome, breast feeding). Overall, available data support pregnancy and breast feeding after breast cancer as safe and feasible for women at low risk of recurrence. This retrospective and population based evidence is, however, frequently incomplete; usually not representative of the entire population, it can be biased by patients' related effects or underpowered and is often not controlled for biological factors and risk determinants in the statistical model used. Before making any definitive assumption on this delicate and fundamental aspect of a woman's life after breast cancer, we should demonstrate without any reasonable doubt that the scattered information available today is scientifically sound. The Breast International Group and North American Breast Cancer Group are planning a global prospective study in young women with endocrine responsive, early breast cancer who desire pregnancy, to assess both patients' and pregnancy outcomes. The trial will include an observational phase investigating the feasibility and impact of a temporary treatment interruption to allow conception and an experimental phase investigating the optimal duration of the subsequent endocrine treatment after delivery or the last failed attempt to get pregnant. PMID- 21698407 TI - Co-amplification of the HER2 gene and chromosome 17 centromere: a potential diagnostic pitfall in HER2 testing in breast cancer. AB - Co-amplification of the centromere on chromosome 17 (CEP17) and HER2 can occur in breast cancer. Such aberrant patterns (clusters) on CEP17 can be misleading to calculate the HER2/CEP17 ratio, and thus underreporting of HER2 amplification. We identified 14 breast cancers retrospectively with HER2/CEP17 co-amplification and performed FISH (fluorescence in situ hybridization) with additional chromosome 17 probes (17p11.1-q11.1, 17p11.2-p12, TP53 on 17p13.1, RARA on 17q21.1-3 and TOP2 on 17q21.3-22) to characterize the spanning of the amplicon in these cases. Furthermore, the HER2 status was analyzed by means of HER2 silver in situ hybridization (SISH) and immunohistochemistry (IHC). The co-amplification of HER2/CEP17 was compared between the three institutions. TP53 was eusomic in all cases, 17p11.2-p12 in 79% (11/14), whereas 17p11.1-q11.1 showed chromosomal gain in all cases. RARA was amplified in 10/14 cases (71%) and TOP2 in 3/14 cases (21%). HER2 was amplified with FISH/SISH in all 14 cases. 9/14 tumors were 3+ IHC positive (64%) and 3 cases were 2+ IHC positive. In our cohort the CEP17 amplicon almost always involves the HER2 but not the TOP2 locus. Overall agreement on HER2/CEP17 ratio (when applying ASCO/CAP guidelines) was only 64% (9/14 cases) between the institutions. Discrepant ratios varied from 1.1 to 14.3. The HER2/CEP17 co-amplification is not defined in the ASCO/CAP guidelines, and may result in inaccurate HER2-FISH/SISH status, particularly if only the calculated HER2/CEP17 ratio is reported. It is recommended to report separate CEP17 and HER2 signals in complex HER2/CEP17 patterns. PMID- 21698408 TI - Correlation between docetaxel-induced skin toxicity and the use of steroids and H2 blockers: a multi-institution survey. AB - Steroids and H(2) blockers are commonly used as supportive care for taxane containing chemotherapy, but they also affect docetaxel's primary metabolizer, cytochrome P(450) 3A4. This retrospective observational study was performed to better understand the effects of these compounds on docetaxel-induced skin toxicities, specifically hand-foot syndrome (HFS) and facial erythema (FE), a relationship that is currently poorly understood. Member institutions of the Japan Breast Cancer Research Group were invited to complete a questionnaire on the occurrence of grade 2 or higher HFS and FE among patients treated between April 2007 and March 2008 with docetaxel as an adjuvant or neoadjuvant chemotherapeutic treatment for breast cancer. We obtained data for 993 patients from 20 institutions. Twenty percent received H(2) blockers, and all patients received dexamethasone. Univariate and multivariate analyses revealed that H(2) blockers are associated with a significantly higher incidence of both HFS and FE. The incidence of FE was significantly higher for the docetaxel + cyclophosphamide (TC) regimen than for non-TC regimens combined. Dexamethasone usage did not affect the incidence of either HFS or FE. In conclusion, use of H(2) blockers as premedication in breast cancer patients receiving docetaxel significantly increases the risk of both HFS and FE. PMID- 21698409 TI - Biopsy sampling of breast lesions: comparison of core needle- and vacuum-assisted breast biopsies. AB - Needle biopsy is now the initial investigation of choice for the pre-operative diagnosis of breast lesions. This includes core needle biopsy (CNB) and vacuum assisted biopsy (VAB) with or without radiologic assistance. The performance indices of both of these biopsy techniques were evaluated. In a large cohort of patients with breast lesions including 464 cases (285 CNB and 179 VAB), with confirmed outcomes, the diagnostic accuracy was compared using parameters including quantitation of the sampling based on the total number of cores taken, cores containing breast parenchyma, and cores with lesion; and non-epithelial changes including necrosis and calcification. CNB showed a 99% PPV, 94% NPV, 96% sensitivity, and 99% specificity, whereas VAB demonstrated a 100% PPV, 100% NPV, 100% sensitivity, and 100% specificity. The correct diagnosis in CNB was proportional to the number of cores extracted, whereas accuracy of VAB was independent of the total number of cores taken. There was a positive correlation between the presence of calcification and malignancy in CNB, but not detected under VAB. CNB and VAB were equally efficient in palpable lesions, in detecting necrosis, and calcification. Large calcification was found to be associated with malignancy in both CNB and VAB. In non-palpable lesions, VAB was more effective in the detection of calcification. The diagnostic accuracy of VAB appeared to be independent of number of cores sampled, whereas CNB required a minimum of 3-4 cores to achieve high diagnostic accuracy. PMID- 21698410 TI - HER2 discordance between primary breast cancer and its paired metastasis: tumor biology or test artefact? Insights through meta-analysis. AB - The proto-oncogene, HER2, has prognostic and predictive relevance in invasive breast cancer (IBC). HER2 testing of primary IBC guides treatment selection and is assumed to reflect HER2 status of associated metastases, although HER2 discordance between IBC and metastasis has been reported. Systematic review and meta-analysis of HER2 status in IBC and its paired loco-regional or distant metastasis were done. Quality appraisal considered whether (within-subject) testing conditions were maintained for paired primary and metastasis. Random effects logistic regression models were used to estimate pooled within-subject HER2 discordant proportions and to examine study-level covariates, including tumor-related and testing-related variables, potentially associated with HER2 discordance differences across (between) studies. Modelled paired HER2 data for primary and metastatic cancer (2520 subjects, 26 studies) showed a pooled HER2 discordance of 5.5% (3.6-8.5%). Sensitivity analysis, excluding the only study not maintaining same conditions for paired testing, gave a pooled estimate of 5.2% (3.5-7.8%). Pooled discordant proportion was not associated with differences between studies in test type, test scoring or interpretation criteria, subjects' median age, study time-frame, or HER2 positivity in primary cancer (all P > 0.05). However, type of metastasis was significantly associated with estimated HER2 discordance (P = 0.0017): studies of primary tumor paired with distant metastases had higher discordance [11.5% (6.9-18.6%)] than studies of primary paired with lymph node metastases only [4.1% (2.4-7.2%)], or those paired with nodal or various metastases [3.3% (2.0-5.6%)]; P < 0.01. HER2 discordant proportion was higher where paired metastases were metachronous relative to synchronous to primary IBC (P = 0.0024). Sensitivity analysis provided weak evidence (P = 0.074) that discordance in the direction of change from HER2 negative primary cancer to HER2-positive paired metastasis was more likely than the reverse. Study-level meta-analysis suggests factors associated with the type of metastasis as underlying mechanisms for observed HER2 discordance between primary IBC and paired metastasis. Test-related factors did not account for differences across studies in the HER2 discordant proportion. PMID- 21698411 TI - Time for a re-evaluation of mammography in the young? Results of an audit of mammography in women younger than 40 in a resource restricted environment. AB - Mammography in younger women is considered to be of limited value. In a resource restricted environment without access to magnetic resonance imaging (MRI) and with a high incidence of breast cancer in the young, mammography remains an important diagnostic tool. Recent technical advances and better regulation of mammography make a reassessment of its value in these conditions necessary. Data of all the mammograms performed at a tertiary hospital and private breast clinic between January 2003 and July 2009 in women less than 40 years of age were collected. Indications were the presence of a mass, follow-up after primary cancer therapy, and screening for patients perceived at high risk due to a family history or the presence of atypical hyperplasia. Data acquired were as follows: Demographics, prior breast surgery, indication for mammography, outcome of mammography, diagnostic procedures, and their results. Of 2,167 mammograms, 393 were performed for a palpable mass, diagnostic mammography. In these, the overall cancer detection rate was 40%. If the mammography was reported as breast imaging reporting and data system (BIRADS((r))) 5 versus BIRADS((r)) 3 and 4 versus BIRADS((r)) 1 and 2, a final diagnosis of malignancy was established in 96, 48, and 5%, respectively. Of 367 mammograms done for the follow-up after primary treatment of breast cancer, seven cancers were diagnosed for a detection rate of 1.9%. Of 1,312 mammograms performed for screening, the recall rate was 4%; the biopsy rate 2%, and the cancer diagnosis rate 3/1,000 examinations. In contrast to past series, this series has shown that recent advances in mammography have made it a useful tool in the management of breast problems in young women, notably in a resource-restricted environment. Women for screening should be selected carefully. PMID- 21698412 TI - Adult attention-deficit/hyperactivity disorder treatment and cardiovascular implications. AB - Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder afflicting adults worldwide. This article is an update on the evidence supporting medications for adult ADHD, with particular emphasis on cardiovascular implications. Relevant clinical literature was sought using PubMed searches, with an emphasis on new reports from April 2009 to April 2011. This review describes the efficacy and general tolerability of stimulant and nonstimulant medications for adults with ADHD as seen in contemporary clinical trials. Cardiovascular response to medications for ADHD is primarily seen in heart rate and blood pressure elevations, while less is known about the etiology of rare cardiovascular events or long-term sequelae. Further research is indicated to delineate clinical and functional outcomes for adults with ADHD, as well as long term safety of medication treatment. PMID- 21698413 TI - Total 18F-dopa PET tumour uptake reflects metabolic endocrine tumour activity in patients with a carcinoid tumour. AB - PURPOSE: Positron emission tomography (PET) using 6-[18F]fluoro-L dihydroxyphenylalanine (18F-dopa) has an excellent sensitivity to detect carcinoid tumour lesions. 18F-dopa tumour uptake and the levels of biochemical tumour markers are mediated by tumour endocrine metabolic activity. We evaluated whether total 18F-dopa tumour uptake on PET, defined as whole-body metabolic tumour burden (WBMTB), reflects tumour load per patient, as measured with tumour markers. METHODS: Seventy-seven consecutive carcinoid patients who underwent an 18F-dopa PET scan in two previously published studies were analysed. For all tumour lesions mean standardised uptake values (SUVs) at 40% of the maximal SUV and tumour volume on 18F-dopa PET were determined and multiplied to calculate a metabolic burden per lesion. WBMTB was the sum of the metabolic burden of all individual lesions per patient. The 24-h urinary serotonin, urine and plasma 5 hydroxindoleacetic acid (5-HIAA), catecholamines (nor)epinephrine, dopamine and their metabolites, measured in urine and plasma, and serum chromogranin A served as tumour markers. RESULTS: All but 1 were evaluable for WBMTB; 74 patients had metastatic disease. 18F-dopa PET detected 979 lesions. SUVmax on 18F-dopa PET varied up to 29-fold between individual lesions within the same patients. WBMTB correlated with urinary serotonin (r=0.51) and urinary and plasma 5-HIAA (r=0.78 and 0.66). WBMTB also correlated with urinary norepinephrine, epinephrine, dopamine and plasma dopamine, but not with serum chromogranin A. CONCLUSION: Tumour load per patient measured with 18F-dopa PET correlates with tumour markers of the serotonin and catecholamine pathway in urine and plasma in carcinoid patients, reflecting metabolic tumour activity. PMID- 21698416 TI - Integration of a smoking cessation program in the treatment protocol for patients with head and neck and lung cancer. AB - Smoking is the main causative factor for development of head and neck and lung cancer. In addition, other malignancies such as bladder, stomach, colorectal, kidney and pancreatic cancer have a causative relation with smoking. Continued smoking after having been diagnosed with cancer has many negative consequences: effectiveness of radiotherapy is diminished, survival time is shortened and risks of recurrence, second primary malignancies and treatment complications are increased. In view of the significant health consequences of continued smoking, therefore, additional support for patients to stop smoking seems a logical extension of the present treatment protocols for smoking-related cancers. For prospectively examining the effect of nursing-delivered smoking cessation programme for patients with head and neck or lung cancer, 145 patients with head and neck or lung cancer enrolled into this programme over a 2-year period. Information on smoking behaviour, using a structured, programme specific questionnaire, was collected at baseline, and after 6 and 12 months. At 6 months, 58 patients (40%) had stopped smoking and at 12 months, 48 patients (33%) still had refrained from smoking. There were no differences in smoking cessation results between patients with head and neck and lung cancer. The only significant factor predicting success was whether the patient had made earlier attempts to quit smoking. A nurse-managed smoking cessation programme for patients with head and neck or lung cancer shows favourable long-term success rates. It seems logical, therefore, to integrate such a programme in treatment protocols for smoking-related cancers. PMID- 21698415 TI - Combined therapy with 131I and retinoic acid in Korean patients with radioiodine refractory papillary thyroid cancer. AB - PURPOSE: The aim of this study was to assess the clinical outcome of redifferentiation therapy using retinoic acid (RA) in combination with 131I therapy, and to identify biological parameters that predict therapeutic response in Korean patients with radioiodine-refractory papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: A total of 47 patients (13 men, 34 women; age 54.2+/-13.6 years) with radioiodine-refractory PTC underwent therapy consisting of consecutive treatment with 131I and RA. Each 131I/RA treatment cycle involved the administration of oral isotretinoin for 6 weeks at 1-1.5 mg/kg daily followed by a single oral dose of 131I (range 5.5-16.7 GBq). Therapeutic responses were determined using serum thyroglobulin (Tg) levels and the change in tumour size 6 months after completing the 131I/RA therapy. Biological parameters and pathological parameters before and after combined therapy were compared. RESULTS: After completing 131I/RA therapy, 1 patient showed a complete response, 9 partial response, 9 stable disease, and 28 progressive disease, representing an overall response rate of 21.3%. Univariate analysis revealed that an age of <45 years and a persistently high serum Tg level were related to a good response. No clinical response was achieved when metastases showing no iodine uptake were present. Multivariate regression analysis showed that an age of <45 years was significantly associated with a good response. Of the 24 patients with well differentiated carcinoma, 5 (20.8%) responded to 131I/RA therapy, whereas all 6 patients with poorly differentiated carcinoma failed to respond. CONCLUSION: 131I/RA therapy was found to elicit a response rate of 21.3% among patients with radioiodine-refractory PTC, and an age of <45 years was found to be significantly associated with a good response. PMID- 21698414 TI - PET molecular imaging in stem cell therapy for neurological diseases. AB - Human neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal cord injury and multiple sclerosis are caused by loss of different types of neurons and glial cells in the brain and spinal cord. At present, there are no effective therapies against these disorders. Discovery of the therapeutic potential of stem cells offers new strategies for the treatment of neurological diseases. Direct assessment of stem cells' survival, interaction with the host and impact on neuronal functions after transplantation requires advanced in vivo imaging techniques. Positron emission tomography (PET) is a potential molecular imaging modality to evaluate the viability and function of transplanted tissue or stem cells in the nervous system. This review focuses on PET molecular imaging in stem cell therapy for neurological diseases. PMID- 21698417 TI - Universal newborn hearing screening, a revolutionary diagnosis of deafness: real benefits and limitations. AB - The finding that early detection of permanent congenital childhood hearing loss produces worthwhile benefit in terms of improved speech and language provides the rationale for the universal screening of newborns. The aim of the present study is to collect the current evidence with regard to the efficacy, the results and outcomes of universal hearing screening programs. An extensive search of the literature was performed in Medline and other available database sources. Study selection was based on the evaluation of the protocols used and the assessment of their efficacy in the early diagnosis of congenital hearing impairment. The initial referral rate and the rate of false positives were also evaluated. A total of 676,043 screened children have been identified in 20 studies. The average initial referral rate in these studies was 3.89%. The initial referral rate varied from 0.6 to 16.7%. The lost-to-follow-up rates varied from 3.7 to 65%. Although universal hearing screening is now widely adopted, there are still some serious drawbacks and limitations. False positives rates remain considerably high when newborns are screened with TEOAE's. The combination of TEOAE's and a ABR provides a significantly reduced referral rate. Close cooperation between audiological centres and maternity units and a dedicated secretariat team are of paramount importance with regard to the reliability and efficacy of universal hearing screening. PMID- 21698418 TI - Dietary restriction improves systemic and muscular oxidative stress in type 2 diabetic Goto-Kakizaki rats. AB - Type 2 diabetes is a heterogeneous metabolic disease characterized by insulin resistance and beta-cell dysfunction leading to hyperglycaemia and dyslipidaemia. Dietary intervention seems to improve some of these cellular complications, namely insulin resistance. Our aim was to evaluate the effects of dietary restriction on systemic and skeletal muscle oxidative stress and insulin resistance in normal Wistar rats and Goto-Kakizaki (GK) rats, a non-obese type 2 diabetic animal model. Four-month-old normal and diabetic rats were separated in four groups. One group of each strain was maintained with ad libitum standard diet, and the other group was submitted to a dietary restriction (50% of control animals daily food intake), during 2 months. Metabolic profile, insulin resistance indexes and muscle lipids were determined. Oxidative stress parameters were also measured at systemic and muscle levels: protein carbonyl, 8-hydroxy-2' deoxyguanosine and free 8-isoprostane. Dietary restriction improved lipid profile in both strains and urinary free 8-isoprostane and plasma carbonyl compounds in diabetic rats. An improvement of muscle triglycerides accumulation and 8 isoprostane concentration and a reduction of insulin resistance were also observed in GK rats. Our data show that dietary restriction ameliorates systemic and skeletal muscle oxidative stress state in type 2 diabetes, which is associated with improved insulin resistance. PMID- 21698420 TI - Surgical margin status of specimen and oncological outcomes after laparoscopic radical prostatectomy: experience after 400 procedures. AB - PURPOSE: To analyse the surgical margins status of prostatic glands, resected by laparoscopic radical prostatectomy (LRP) for prostate cancer, and to correlate it with biochemical free survival rate (BFSR). METHODS: Data were collected prospectively from 405 patients undergoing LRP from 2000 to 2009 at a single institution. Patients undergoing neoadjuvant and/or adjuvant therapy were excluded from the study. Three hundred patients matched all the criteria: 232 of these had negative surgical margins (NSM) and 68 positive surgical margins (PSM). The median follow-up was 62 months. PSM were classified based on the following: (a) the number of margins, monofocal and multifocal, (b) the location, apical or non-apical and (c) the extension, <=2.8 mm or >2.8 mm. These data were then entered into a multivariate analysis. RESULTS: Overall BFSR rate was 67.6% in PSM group and 88.8% in NSM group (P < 0.001). We registered a HR of 3.78 in multivariate analysis (P < 0.001). In terms of the extension, BFSR in univariate survival analysis was 77.8% in <=2.8 mm PSM and 38.9% in >2.8 mm PSM (P = 0.003), with a HR of 5.68 (P = 0.011) in multivariate analysis. BFSR was 59% for apical margins and 77% for non-apical margins (P = 0.038). In monofocal margins, BFSR was 73%, while 53% in multifocal (P = 0.014). CONCLUSIONS: We recommend careful evaluation of patients with PSM following LRP, especially if they are more than 2.8 mm, and in these cases, adjuvant therapy should be considered after radical surgery. PMID- 21698419 TI - Betaine prevents ethanol-induced oxidative stress and reduces total homocysteine in the rat cerebellum. AB - Oxidative stress is a hypothesis for the association of reactive oxygen species with cerebrovascular and neurodegenerative diseases. Thus, we examined whether oral betaine can act as a preventive agent in ethanol-induced oxidative stress on the cerebellum of rats. Thirty-two adult male Sprague-Dawley rats were divided into four equal groups (control, ethanol, betaine, and betaine plus ethanol) with different dietary regimens and were followed up for 1 month. Total homocysteine (tHcy) of plasma and cerebellum homogenate was determined by an Axis((r)) homocysteine EIA kit, and antioxidant enzyme (glutathione peroxidase (GPx), SOD, and CAT) activities of cerebellum homogenate were measured chemically by a spectrophotometer. Lipid peroxidation of cerebellum was shown by the measurement of thiobarbituric reactive substances (TBARS) via a spectrophotometer. Ethanol induced hyperhomocysteinemia was manifested by an increase in the concentrations of tHcy in the plasma and cerebellum homogenates of the ethanol group, while ethanol-induced oxidative stress was indicated via an increase in lipid peroxidation marker (TBARS) in cerebellum homogenates of ethanol-treated rats. In contrast, betaine prevented hyperhomocysteinemia and oxidative stress in the betaine plus ethanol group as well as the betaine group. The results of the present investigation indicated that the protective effect of betaine is probably related to its ability to strengthen the cerebellum membrane cells by enhancement of antioxidant enzyme activity principally GPx, while the methyl donor effect of betaine to reduce hyperhomocysteinemia has been explained previously and confirmed in the present study. PMID- 21698421 TI - Aberrant promoter methylation and inactivation of PTEN gene in cervical carcinoma from Indian population. AB - PURPOSE: PTEN, a tumor-suppressor gene located on chromosome 10q23.3 is implicated in multiple tumors including cervical carcinoma. METHODS: We examined 135 cervical cancer specimens for PTEN gene expression and promoter methylation using methylation-specific PCR and immunohistochemistry and also studied the mutation in PTEN gene through PCR-single-stranded conformational polymorphism. PTEN expression and its methylation status were also correlated with clinicopathologic parameters. RESULTS: The results showed an abnormal band on exon 5 and exon 9 of the PTEN gene. In PTEN gene, 61% specimen showed methylation. PTEN methylation was found in 39% cases of stage I, 60% of stage II, and 75% of stages III-IV. The correlation between PTEN methylation and clinical stage was found to be statistically significant (P = 0.003). Nuclear PTEN expression was detected in 84 of 135 (62%) cases of cervical carcinoma, and the remaining 51 of 135 (38%) cases were observed as expressional loss. The loss of PTEN expression was significantly correlated clinical stage (P = 0.001). Loss of PTEN expression was observed in 34 (41%) cases among 83 methylation positive cases, whereas among 52 methylation-negative cases, only 13 (25%) cases were seen as immunostaining negative with the statistically significant value (P = 0.05). CONCLUSION: Promoter methylation and loss of PTEN expression occur frequently in carcinoma of uterine cervix. Our results suggest that PTEN plays an important role in the carcinogenesis of cervical cancer. PMID- 21698422 TI - Expected benefits of streamlining undergraduate medical education by early commitment to specific medical specialties. AB - Undergraduate medical education is too long; it does not meet the needs for physicians' workforce; and its content is inconsistent with the job characteristics of some of its graduates. In this paper we attempt to respond to these problems by streamlining medical education along the following three reforms. First, high school graduates would be eligible for undergraduate medical education programs of 4 years duration. Second, medical school applicants would be required to commit themselves to a medical specialty and choose one of four undergraduate paths: (1) "Interventions/consultations" path that would prepare its graduates for residencies in secondary and tertiary specialties, such as cardiology and surgery, (2) "continuous patient care" path for primary care specialties, such as family medicine and psychiatry, (3) "diagnostic laboratory medicine and biomedical research" path that would prepare for either laboratory based careers, such as pathology, biochemistry and bacteriology, or research in e.g., immunology and molecular genetics, and (4) "epidemiology and public health" path that would include population-based research, preventive medicine and health care administration. Third, the content of each of these paths would focus on relevant learning outcomes, and medical school graduates would be eligible for residency training only in specialties included in their path. Hopefully, an early commitment to a medical specialty will reduce the duration of medical education, improve the regulation of physicians' workforce and adapt the curricular content to the future job requirements from medical school graduates. PMID- 21698423 TI - Additional prognostic factors in right colon cancer staging. AB - Based on the theory--which is now acknowledged-of a clinical difference between proximal and distal colon cancer and on the results of recent genetic and microbiological studies, a minority of authors have assumed that also in the sphere of right-sided colon cancer, tumors at three different locations, namely, the cecum and ascending and transverse colon, can be considered to be biologically different. These studies have provided the basis for a retrospective study carried out on 50 patients admitted to our department from 1996 to 2008 for tumor pathology of the right colon. The tumor was considered to be a unified biological entity and assessed in relation to the three above-mentioned locations. The results verify that the aggressive of the tumor increases from the cecum to the transverse, with a higher percentage of cecal tumors being in I stage, more tumors in the ascending colon being in II stage, and more transverse tumors, with the largest percentage of N+ and M+, in stages III and IV. This difference in biological behavior for the three tumor locations has been also found in terms of sensitiveness, both pre- and post-operation, of tumor markers CEA, TPA, and CA19-9. Clinical data revealed a binary relationship between the transverse, cecum, and ascending tumors, which ultimately affects patient mortality, which increases in a directly proportional way from the cecum to the transverse-in the case of a tumor at one of these locations. PMID- 21698424 TI - How lysenkoism became pseudoscience: dobzhansky to velikovsky. AB - At some point in America in the 1940s, T. D. Lysenko's neo-Lamarckian hereditary theories transformed from a set of disputed doctrines into a prime exemplar of "pseudoscience." This paper explores the context in which this theory acquired this pejorative status by examining American efforts to refute Lysenkoism both before and after the famous August 1948 endorsement of Lysenko's doctrines by the Stalinist state, with particular attention to the translation efforts of Theodosius Dobzhansky. After enumerating numerous tactics for combating perceived pseudoscience, the Lysenko case is then juxtaposed with another American case of alleged pseudoscience: the notorious 1950 scandal surrounding Immanuel Velikovsky's Worlds in Collision (1950, Worlds in Collision. New York: Macmillan). On several levels, the characterization of Lysenkoism as pseudoscientific served as a template for casting other rejected theories, including Velikovsky's, in the same light. PMID- 21698425 TI - [Treatment strategy for carpometacarpal fracture dislocation]. AB - Carpometacarpal (CMC) fracture dislocations of the 2nd through 5th ray are rare injuries whose extent is regularly underestimated in the initial radiographic evaluation of the hand. Obtaining a computed tomography scan is imperative due to the radiographic underrepresentation of the full bone and joint injury. Restoration of bone and joint anatomy of the affected region is of paramount import to prevent joint deterioration and loss of hand durability and dexterity. Early surgical intervention can lead to good functional results. Different operative treatment strategies exist with a common approach being Kirschner wire, screw or plate fixation after closed or open fracture reduction and joint relocation. PMID- 21698426 TI - Nickel allergies: paying the Toll for innate immunity. AB - Allergic contact hypersensitivity responses to the transition metal nickel (Ni(2+)) affect millions of people worldwide despite extensive legislatory efforts to ban the use of Ni(2+) in products coming into direct contact with the skin. Like other contact allergens, Ni(2+) triggers a T lymphocyte-driven delayed type hypersensitivity reaction that is characterized by leukocyte infiltration at sites of allergen exposure. The last years have revealed that besides a hapten specific T cell response, Ni(2+) can also directly trigger an innate immune response in resident skin cells that is necessary for mounting an allergic hypersensitivity reaction to Ni(2+). Recently, the receptor for the bacterial membrane component lipopolysaccharide, Toll-like receptor 4, has been identified as the crucial mediator of the innate immune response to Ni(2+), demonstrating that Ni(2+) employs signaling components of the bacterial defense system to elicit its allergic reactions. Here, we provide an overview of Ni(2+)-induced signaling events that have been implicated in contributing to the hypersensitivity response to this transition metal. We briefly review the causes and genetic predisposition fostering allergic responses to Ni(2+) and discuss potential therapeutic and prophylactic strategies and chances evolving from the novel insights into the molecular basis of this disease. PMID- 21698427 TI - Cancer suicide gene therapy with TK.007: superior killing efficiency and bystander effect. AB - Suicide gene therapy is a promising concept in oncology. We have recently introduced a novel suicide gene, TK.007, which was shown to excel established herpes simplex virus thymidine kinase (HSVtk) variants when used for donor lymphocyte modification in adoptive immunotherapy models. Here, the potential of TK.007 in killing cancer cells was studied. Initially, we transduced tumour cell lines derived from different neoplasias (glioblastoma, melanoma, lung cancer, colon cancer) with lentiviral LeGO vectors encoding TK.007 or the splice corrected (sc)HSVtk together with an eGFP/Neo-marker. Based on direct in vitro comparison, we found that TK.007 facilitates more efficient tumour cell killing at significantly lower ganciclovir doses in all tumour cell lines tested. Also, using different readout systems, we found a significantly stronger bystander effect of TK.007 as compared to scHSVtk. Importantly, in vitro data were confirmed in vivo using a subcutaneous G62 glioblastoma model in NOD/SCID mice. In mice transplanted with scHSVtk-positive tumours, treatment with low (10 mg/kg) or standard (50 mg/kg) ganciclovir doses resulted only in short-term growth inhibition or transient tumour remission, respectively. In striking contrast, in the TK.007 group, all animals achieved continuous complete remission after both standard and low-dose ganciclovir. Finally, a substantial bystander effect for TK.007 was also confirmed with the G62 model in vivo, where significantly prolonged survival for mice bearing tumours containing only 10% or 50% TK.007 expressing cells was observed. In summary, our data indicate strongly improved anti-tumour activity of TK.007 as compared to conventional HSVtk. We therefore suppose that TK.007 is an excellent candidate for cancer suicide gene therapy. PMID- 21698428 TI - Use and efficacy of bone morphogenetic proteins in fracture healing. AB - PURPOSE: This review evaluates the application of bone morphogenetic proteins (BMPs) in delayed bone repair, aiming at a broad audience from clinicians to scientists. Next to an overview of the role of the different BMPs, their antagonists and their current applications, special attention is focused on new scientific developments improving the effects of BMP-based therapy for bone repair. METHODS: Publication searches in PubMed and Embase revealed 850 relevant articles on the criteria 'BMP' AND 'bone repair' (as of May 2011). The abstracts were carefully reviewed and papers were selected according to the content. RESULTS: The resulting publications showed that BMP-2 and BMP-7 are clearly the most extensively evaluated BMPs, in general with positive results on bone healing, comparable to the use of unspecific preparations such as autologous bone grafts or platelet-rich plasma. CONCLUSIONS: Although the efficacy of BMPs as stimulators of bone repair has been demonstrated in model systems and clinical studies, the use of BMPs to enhance fracture healing in the clinical setting is still controversial. Issues such as when, where and how much of which BMP is the most effective and profitable to use still have to be elucidated. But optimisation of the BMP products used in combination with cheaper production methods will inevitably stimulate the clinical use of BMPs for bone fracture healing in the near future. PMID- 21698429 TI - Internal versus external fixation for unstable distal radius fractures: an up-to date meta-analysis. AB - PURPOSE: Our aim was to compare the effect of internal vs external fixation for unstable distal radius fractures regarding postoperative complications, clinical results and radiological outcomes. METHODS: We selected PubMed; Cochrane Library; EMBASE; BIOSIS; Ovid and the relevant English orthopaedic journals and pooled data from ten eligible randomised controlled trials containing 738 patients to conduct a subgroup analysis according to different periods of follow-up. Our aim was to summarise the best available evidence. RESULTS: Results showed that compared with external fixation, internal fixation led to significantly fewer total surgical complications [95% confidence interval (CI) 0.39-0.81, P = 0.002] and reduced the incidence of pin-track infections (95% CI 0.08-0.46, P = 0.0002) after a one year follow-up. For clinical results, grip strength (95% CI 1.59 8.25, P = 0.004), supination (95% CI 13.99-48.83, P = 0.0004) and pronation (95% CI 5.61-26.09, P = 0.002) were superior in the internal fixation group six weeks postoperatively, and the same results were obtained three months postoperatively for grip strength (95% CI 3.21-13.47, P = 0.001) and supination (95% CI 3.61 16.01, P = 0.002). Meanwhile, the Disabilities of the Arm, Shoulder and Hand (DASH) score was superior in the internal fixation group at three months (95% CI 20.62 to -2.07, P = 0.02) and after one year (95% CI -14.37 to -2.32, P = 0.007) follow-up. CONCLUSIONS: We suggest that the final results are significant and there is some evidence supporting the use of open reduction and internal fixation. PMID- 21698430 TI - Primary total hip arthroplasty with dual mobility socket to prevent dislocation: a 22-year follow-up of 240 hips. AB - PURPOSE: The longest follow-up dual mobility series from inventor Gilles Bousquet focussing on implant survival and the incidence of dislocation. METHODS: This was a retrospective study from 1985 to 1990, on 240 hips using a PF(r) modular femoral stem and a dual mobility Novae(r) tripodal socket (SERF). RESULTS: The 22 year follow-up global survival rate was 74%. No dislocation occurred, 41 hips were revised, including ten retentive failures (RF), 12 hips were lost to follow up, 87 patients (99 hips) died without revision, and 90 hips were still in situ. CONCLUSION: The dual mobility socket global survival rate is comparable to similar series. The 0% dislocation rate demonstrates the success of dual mobility with regard to implant stability. The main issues were cup fixation, which might be improved by the use of macrostructures and HA coating, and osteolytic lesions, caused by polyethylene wear. Traditionally suitable for patients older than 60 years, dual mobility might be extended for use in patients over 50. PMID- 21698433 TI - [3rd European Consensus Meeting for testicular cancer]. PMID- 21698432 TI - Outlier detection in high-density surface electromyographic signals. AB - Recently developed techniques allow the analysis of surface EMG in multiple locations over the skin surface (high-density surface electromyography, HDsEMG). The detected signal includes information from a greater proportion of the muscle of interest than conventional clinical EMG. However, recording with many electrodes simultaneously often implies bad-contacts, which introduce large power line interference in the corresponding channels, and short-circuits that cause near-zero single differential signals when using gel. Such signals are called 'outliers' in data mining. In this work, outlier detection (focusing on bad contacts) is discussed for monopolar HDsEMG signals and a new method is proposed to identify 'bad' channels. The overall performance of this method was tested using the agreement rate against three experts' opinions. Three other outlier detection methods were used for comparison. The training and test sets for such methods were selected from HDsEMG signals recorded in Triceps and Biceps Brachii in the upper arm and Brachioradialis, Anconeus, and Pronator Teres in the forearm. The sensitivity and specificity of this algorithm were, respectively, 96.9 +/- 6.2 and 96.4 +/- 2.5 in percent in the test set (signals registered with twenty 2D electrode arrays corresponding to a total of 2322 channels), showing that this method is promising. PMID- 21698431 TI - Identification and analysis of Phytophthora cactorum genes up-regulated during cyst germination and strawberry infection. AB - The oomycete Phytophthora cactorum can cause economically important diseases on numerous host plants worldwide, such as crown rot on strawberry. To explore the molecular mechanisms underlying the pathogenicity of P. cactorum on strawberry, transcriptional analysis of P. cactorum during strawberry infection and cyst germination was performed by applying suppression subtractive hybridization (SSH) and effector-specific differential display (ESDD) techniques. Two SSH cDNA libraries were generated, enriched for P. cactorum genes expressed during infection or during cyst germination, respectively, and 137 unique differentially expressed genes were identified. To specifically select RxLR effector genes from P. cactorum, ESDD was performed using RxLR and EER motif-based degenerate primers. Eight RxLR effector candidate genes as well as 67 other genes were identified out of 124 selected fragments. The expression levels of 20 putatively up-regulated genes were further analyzed using real-time RT-PCR, showing that, indeed 19 of these 20 genes were up-regulated during at least one of the studied developmental stages or during strawberry crown invasion, relative to the mycelium. This study provides a first overview of P. cactorum genes that are up regulated immediately prior to or during strawberry infection and also provides a novel method for selecting RxLR effector genes from the unsequenced genome of P. cactorum. PMID- 21698435 TI - Correlation of chronic kidney disease, diabetes and peripheral artery disease with cardiovascular events in patients using stress myocardial perfusion imaging. AB - OBJECTIVE: Normal stress myocardial perfusion imaging (MPI) studies generally suggest an excellent prognosis for cardiovascular events. Chronic kidney disease (CKD), diabetes and peripheral artery disease (PAD) have been established as the risk factors for cardiovascular events. However, whether these risk factors significantly predict cardiovascular events in patients with normal stress MPI is unclear. The purpose of this study was to evaluate the prognostic value of these risk factors in patients with normal stress MPI. METHODS: Patients with normal stress MPI (n = 372, male = 215 and female = 157, age = 69 years, CKD without hemodialysis = 95, diabetes = 99, PAD = 19, previous coronary artery disease = 116) were followed up for 14 months. Normal stress MPI was defined as a summed stress score of <4 and a summed difference score of <2. CKD was defined by an estimated glomerular filtration rate of <60 ml/min/1.73 m(2) and/or persistent proteinuria. Cardiovascular events included cardiac death, non-fatal myocardial infarction and congestive heart failure requiring hospitalization. RESULTS: Cardiovascular events occurred in 20 of 372 patients (5.4%). In univariate Cox regression analysis, PAD, diabetes, diabetic retinopathy, insulin use, anemia, hypoalbuminemia, CKD, left ventricular ejection fraction and pharmacological stress tests were significant predictors of cardiovascular events. In multivariate Cox regression analysis, PAD, diabetes and CKD were independent and significant predictors for cardiovascular events, and their number was the strongest predictor for cardiovascular events (hazard ratio = 21.7, P < 0.001). CONCLUSIONS: PAD, diabetes and CKD are coexisting, independent and significant risk factors for cardiovascular events, CKD being the strongest predictor. The number of coexisting risk factors is important in predicting cardiovascular events in patients with normal stress MPI. PMID- 21698434 TI - [Limits of pain treatment: medical and judicial aspects]. AB - Medical principles of pain treatment are generally in line with the judicial principles. To relieve pain is one of the fundamentals of medicine and this has also been acknowledged by the Federal Court in Germany. It is criminal bodily harm, when a physician denies a possible pain treatment. Whereas courts clearly see an obligation to basic and continuing education in pain diagnosis and therapy, pain is still not represented in the German licensing regulations for physicians. Only palliative medicine has been added to the obligatory curriculum. Very similar pain is not mandatory in many clinical disciplines leaving physicians without the needed knowledge to treat pain. The need for interdisciplinary treatment is not yet acknowledged sufficiently, although meanwhile chronic pain is regarded as a bio-psycho-social illness.Since 2009 the advance directive is regulated by law. However, still many physicians are unaware that not only the position of the patient but also of the relatives have been strengthened. In 2010 the Federal Court has pronounced a judgment allowing "passive euthanasia" in certain conditions but prohibiting any active handling even in line with the patient's will. This is also in line with the European Human Rights Convention. The judicial unpunished assisted suicide has provoked an ethical discussion within the medical profession. However, what is not illegal is not automatically accepted as ethical handling for physicians. Palliative medicine is at least one alternative in this discussion. PMID- 21698436 TI - Quantification of myocardial perfusion SPECT using freeware package (cardioBull). AB - OBJECTIVE: We have developed freeware package for automatically quantifying myocardial perfusion and (123)I-labeled radiopharmaceutical single-photon emission computed tomography (SPECT), which is called "cardioBull". We aim to evaluate diagnostic performance of the detection of coronary artery disease (CAD) on the developed software in comparison with commercially available software package [Quantitative Perfusion SPECT (QPS)]. METHODS: Stress-rest (99m)Tc sestamibi myocardial perfusion SPECT was performed in 36 patients with CAD and 35 control patients. A >= 75% stenosis in the coronary artery was identified by coronary angiography in the CAD group. Segmental perfusion defect score was automatically calculated by both cardioBull and QPS software. Summed stress score (SSS) was obtained to detect CAD by the receiver operator characteristic (ROC) analysis. Areas under the ROC curves (AUC) were calculated in patient-based and coronary-based analyses. RESULTS: Mean SSSs showed no significant difference between cardioBull and QPS (6.0 +/- 7.1 vs. 5.6 +/- 7.0). The AUC for cardioBull was equivalent to that for QPS (0.91 +/- 0.04 vs. 0.87 +/- 0.04, p = n.s.). Sensitivity, specificity, and accuracy for cardioBull were 89, 74, and 82%, respectively. For the regional detection of CAD, the AUC showed largest value in left anterior descending coronary artery (LAD) territory (0.86 +/- 0.06 for cardioBull, 0.87 +/- 0.06 for QPS, p = n.s.). Sensitivity, specificity and accuracy of cardioBull were 70, 88, and 83% for the LAD; 91, 62, and 66% for the left circumflex coronary artery (LCx); and 78, 69, and 70% for the right coronary artery (RCA), respectively. CONCLUSIONS: The AUC, sensitivity, specificity and accuracy for the detection of CAD showed high diagnostic performance on the developed software. In addition, the developed software provided comparable diagnostic performance to the commercially available software package. PMID- 21698438 TI - Changes in cortical slow wave activity in healthy aging. AB - A number of studies have demonstrated enhanced slow wave activity associated with pathological brain function e.g. in stroke patients, schizophrenia, depression, Morbus Alzheimer, and post-traumatic stress disorder. However, the association between slow wave activity and healthy aging has remained largely unexplored. This study examined whether the frequency at which focal generators of delta waves appear in the healthy cerebral cortex changes with age and whether this measure relates to cognitive performance. We investigated 53 healthy individuals aged 18 to 89 years and assessed MEG during a resting condition. Generators of focal magnetic slow waves were localized. Results showed a significant influence of age: dipole density decreases with increasing age. The relationship between cognitive performance and delta dipole density was not significant. The results suggest that in healthy aging slow waves decrease with aging and emphasize the importance of age-matched control groups for further studies. Increased appearance of slow waves as a marker for pathological stages can only be detected in relation to a control group of the same age. PMID- 21698437 TI - Incidence and risk factors for reoperation of surgically treated pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: The objective of our study was to estimate the incidence and to identify the risk factors for reoperation of surgically treated pelvic organ prolapse (POP). METHODS: We conducted a nested case-control study among 1,811 women who underwent POP surgery from January 1988 to June 2007. Cases (n = 102) were women who required reoperation for POP following the first intervention through December 2008. Controls (n = 226) were women randomly selected from the same cohort who did not require reoperation. RESULTS: The incidence of POP reoperation was 5.1 per 1,000 women-years. The cumulative incidence was 5.6%. Risk factors included preoperative prolapse in more than two vaginal compartments (adjusted OR 5.2; 95% CI 2.8-9.7), history of surgery for POP and/or urinary incontinence (adjusted OR 3.2; 95% CI 1.5-7.1), and sexual activity (adjusted OR 2.0; 95% CI 1.0-3.7). CONCLUSIONS: The risk of POP reoperation is relatively low and is associated with preexisting weakness of pelvic tissues. PMID- 21698439 TI - Testing the utility of a modified organ donation model among African American adults. AB - African Americans are overrepresented on the organ transplant waiting list because they are disproportionately impacted by certain health conditions that potentially warrant a life-saving transplant. While the African American need for transplantation is considerably high, organ and tissue donation rates are comparatively low, resulting in African Americans spending more than twice the amount of time on the national transplant waiting list as compared to people of other racial/ethnic backgrounds. There are a multitude of factors that contribute to the reluctance expressed by African Americans with respect to organ donation. This study proposes the use of an adaptation of the Organ Donation Model to explore the ways in which knowledge, trust in the donation/allocation process, and religious beliefs impact African American donation decision making. Bivariate and path analyses demonstrated that alignment with religious beliefs was the greatest driving factor with respect to attitudes towards donation; attitudes were significantly associated with donation intentions; and knowledge is directly associated with intentions to serve as a potential deceased organ donor. The significance of these variables speaks to the importance of their inclusion in a model that focuses on the African American population and offers new direction for more effective donation education efforts. PMID- 21698440 TI - Communication strategies for enhancing understanding of the behavioral implications of genetic and biomarker tests for disease risk: the role of coherence. AB - Individuals frequently have difficulty understanding how behavior can reduce genetically-conferred risk for diseases such as colon cancer. With increasing opportunities to purchase genetic tests, communication strategies are needed for presenting information in ways that optimize comprehension and adaptive behavior. Using the Common-Sense Model, we tested the efficacy of a strategy for providing information about the relationships (links) among the physiological processes underlying disease risk and protective action on understanding, protective action motivations, and willingness to purchase tests. We tested the generalizability of the strategy's effects across varying risk levels, for genetic tests versus tests of a non-genetic biomarker, and when using graphic and numeric risk formats. In an internet-based experiment, 749 adults from four countries responded to messages about a hypothetical test for colon cancer risk. Messages varied by Risk Action Link Information (provision or no provision of information describing how a low-fat diet reduces risk given positive results, indicating presence of a gene fault), Risk Increment (20%, 50%, or 80% risk given positive results), Risk Format (numeric or graphic presentation of risk increments), and Test Type (genetic or enzyme). Providing risk-action link information enhanced beliefs of coherence (understanding how a low-fat diet reduces risk) and response efficacy (low-fat diets effectively reduce risk) and lowered appraisals of anticipated risk of colon cancer given positive results. These effects held across risk increments, risk formats, and test types. For genetic tests, provision of risk action link information reduced the amount individuals were willing to pay for testing. Brief messages explaining how action can reduce genetic and biomarker detected risks can promote beliefs motivating protective action. By enhancing understanding of behavioral control, they may reduce the perceived value of genetic risk information. PMID- 21698441 TI - The Canadian Clean Air Regulatory Agenda Mercury Science Program. AB - The Clean Air Regulatory Agenda (CARA) Mercury Science Program was developed to provide scientific information to support regulatory activities and accountability pertaining to atmospheric emissions of mercury in Canada. The first phase of the science program, entitled "Setting-the-Baseline", sought to achieve the following: identify key indicators of the state-of-the-Canadian environment with respect to the transport, fate and effects of mercury; define these indicators; and, understand the processes that relate these indicators to anthropogenic emissions of mercury. To achieve these outcomes, a consultative process was used to identify the scientific needs of the agenda for mercury; understand Canada's scientific capacity; and, develop a plan to fulfill these scientific needs. The science plan that emerged from this process was structured around the themes of atmospheric monitoring, landscape-based risk assessment, ecological risk assessment, ecosystem modeling, and trends. Implementation of the science plan necessitated a multi-disciplinary and extensively partnered program. To date, the CARA Mercury Science Program is producing coordinated science at the national-scale that aims to directly assess the effectiveness of the CARA for mercury and for many of Canada's other mercury-related policies. PMID- 21698442 TI - Mercury levels of Nelson's and saltmarsh sparrows at wintering grounds in Virginia, USA. AB - Nelson's and saltmarsh sparrows (Ammodramus nelsoni and A. caudacutus) have recently been recognized as separate species, and because of their limited distributions and the susceptibility of their wetland habitats to climate change, these two new species are of conservation concern. Both species are known to bioaccumulate mercury at breeding sites in New England, USA where their ranges overlap, with the saltmarsh sparrow reported to have twice the concentration of blood total mercury. In this study we sampled both species on their shared wintering grounds, and documented that mercury exposure is lower than that reported for the breeding range, with saltmarsh sparrow blood mercury 2.6 times higher than in Nelson's sparrow. Feather mercury, which is incorporated on the breeding grounds, confirmed that saltmarsh sparrows had incorporated 2.3 times more mercury than Nelson's sparrows during the previous breeding season. A comparison of stable isotopes of nitrogen and carbon suggests that the higher exposure of saltmarsh sparrows may be not due to feeding at a higher trophic level, as previously hypothesized, but rather could be related to a difference in the carbon source at the base of each species' food chain. This study, along with recently published data from both species on additional breeding and wintering grounds, provides a more complete picture of relative mercury exposure. Saltmarsh sparrows are exposed to mercury levels that warrant concern, with the highest exposure being during the breeding season. Areas set aside for the long-term conservation of this species should be carefully assessed for mercury bioaccumulation. PMID- 21698443 TI - Heavy-metal concentrations in soft tissues of the burrowing crab Neohelice granulata in Bahia Blanca estuary, Argentina. AB - Copper (Cu), cadmium (Cd), and chromium (Cr) in soft tissues of male and female burrowing crab Neohelice granulate, as well as their eggs, were measured in two different locations in the Bahia Blanca estuary, a moderately polluted ecosystem, from October 2008 to August 2009. Differences between sexes, sites, and seasonality were assessed. Furthermore, metal levels in eggs were compared with metal levels in female crabs. The results showed no significant differences for Cu and Cd between sexes (Student t test p > 0.25 for both sites) and sites (two way analysis of variance: Cu p = 0.82 and Cd p = 0.29). Nevertheless, seasonality was found, with winter having significantly lower concentrations for both metals. The range of Cu concentrations was between 96.92 and 152.18 MUg g(-1) dry weight (dw), and the range of Cd concentrations was between 6.09 and 10.41 MUg g(-1) dw. Cr concentrations could not be assessed because most of the values were lower than the detection limit. Although heavy metals in sediments were not measured in this study, a bioaccumulation process may be occurring for Cd because levels found during the entire sampling period were greater than levels in sediment from previous years. For Cu, a regulation process may be occurring considering that this is an essential metal and levels of Cu in N. granulata found in this study were between 1 and 2 orders of magnitude greater than levels in sediments. Finally, Cu and Cd levels in eggs were detectable, but they were lower than levels in female crabs. The importance of these findings is linked to the fact that metal accumulation seems to be occurring before hatch. The presence of heavy metals in soft tissues as well as in eggs of N. granulata is of great importance considering that this is a key species within the Bahia Blanca estuary; therefore, it plays a major role in the transference of pollutants to greater trophic levels. PMID- 21698444 TI - Lymphoepithelial carcinoma: two case reports and a systematic review of oral and sinonasal cases. AB - Lymphoepithelial carcinoma (LEC) is a rare malignancy. Histologically, it is an undifferentiated carcinoma with an intermixed reactive lymphoplasmacytic infiltrate. Herein, we report two cases of LEC in the head and neck region that presented to Oulu University Hospital. Our first case is a 30-year-old man with LEC in the left maxillary sinus. The second case is a 49-year-old man with LEC in the soft palate and uvula with regional lymph node metastases at diagnosis. In addition, a systematic review of the literature from 1980 to 2010 was performed with MEDLINE and cross-references were searched manually. Case reports and clinical series of oral, oropharyngeal, nasal, and paranasal sinus LECs were reviewed revealing a total of 110 cases. Most of the oral cases were found in the tonsils (n = 29), oropharynx (n = 19), and in oral mucosa (n = 18), while sinonasal cases (n = 40) were mainly in the paranasal sinuses and nasal cavity. From 37 case reports, including ours, the median age was 58 and 62 years for sinonasal and oral/oropharyngeal LECs, respectively. Oral and oropharyngeal LECs have a 70.0% tendency to metastasize and 16.6% spread locally. In contrast, none of the nasal and paranasal LECs metastasized, but 60% spread locally. Epstein Barr virus (EBV) had been detected in 87.5% of all tested LEC cases. Treatment of LECs, during the last decade, has largely consisted of surgery, combined with radiotherapy or chemoradiation. Although local spread or nodal metastases are fairly common at the time of diagnosis, the mortality rate of adequately treated LEC patients is low. PMID- 21698445 TI - Homologous overexpression of omcZ, a gene for an outer surface c-type cytochrome of Geobacter sulfurreducens by single-step gene replacement. AB - The electron transfer pathway of Geobacter sulfurreducens has been intensively studied because of its ability of electron transfer to extracellular electron acceptors, such as Fe(III) and on electrode. However, the absence of overexpression system of G. sulfurreducens is one of the main obstacles for studying the physiology of G. sulfurreducens. OmcZ, an outer membrane-related c type cytochrome of G. sulfurrducens, was homologously overexpressed via genomic integration. Quantitative RT-PCR analysis showed that the omcZ transcript in the knock-in strain was sixfold more abundant than in the wild type. Notably, omcZ expression appears to downregulate the expression level of OmcS, another outer membrane-related c-type cytochrome of G. sulfurreducens, based on the comparisons of total protein and transcript levels. This is the first report of the successful genetic overexpression system for studying functional genomics of G. sulfurreducens. PMID- 21698446 TI - Sleeping Beauty-mediated knockdown of sheep myostatin by RNA interference. AB - Myostatin is a negative regulator of skeletal muscle growth. Myostatin dysfunction therefore offers a strategy for promoting animal muscle growth in livestock production. Knockdown of myostatin was achieved by combining RNA interference and the Sleeping Beauty (SB) transposon system in sheep cells. Four targeting sites of sheep myostatin were designed and measured for myostatin silencing in sheep fetal fibroblasts by real-time PCR. The sh3 construct induced significant decrease of myostatin gene expression by 90% (P<0.05). Myostatin silencing induced by SB-mediated sh3 was further tested in stably transfected cells. SB transposition increased the integration frequency of genes into sheep genomes and mediated a more efficient myostatin knockdown than random integration of sh3. We suggest that SB-mediated shRNA provides a novel potential tool for gene knockdown in the donor cells of animal cloning. PMID- 21698447 TI - [How can the shift of refraction due to vitreous substitutes be avoided? Posterior chamber intraocular lens for patients suffering from diabetic retinopathy]. AB - Silicone filling of pseudophakic eyes usually results in strong unilateral hyperopia and binocularity is severely disturbed. This problem can be avoided by designing a concave posterior lens surface with the centre of curvature in the macula (Acri.Lyc 59RET(r), haptics in capsular bag, body in vitreous cavity). The prospective study on 40 eyes with idiopathic macular foramen yields a mean refraction difference of 0.22 D with and without oil. The A-constant of the lens was found to be 115.7. Clinically relevant aniseikonia did not occur. The main indication is cataracts combined with diabetic retinopathy. PMID- 21698448 TI - [Cataract in a young patient]. AB - Myotonic dystrophy Curschmann-Steinert is a genetic disease which is inherited in an autosomal dominant pattern. Patients usually suffer from myotonia, muscular atrophy and weakness and myopathic facies. Furthermore, patients often present with ophthalmological symptoms with subcapsular cataract and bilateral ptosis being the most frequent ones. Therefore the ophthalmologist can help to detect patients suspected of having this disease and initiate further investigations. Despite clinically distinct findings, the disease is often overlooked because of the diversity of symptoms and clinical manifestations. PMID- 21698449 TI - Comparison of placental pathology between severe preeclampsia and HELLP syndrome. AB - OBJECTIVE: This study was performed to evaluate and compare the placental pathology in patients with severe pre-eclampsia (PE) and HELLP syndrome. Moreover, neonatal birth weight was compared between the two groups. MATERIALS AND METHODS: This cross-sectional prospective study was conducted in Alzahra and Beheshti Hospitals (Isfahan, Iran) between 2007 and 2009. Placentas from 32 patients having severe pre-eclampsia without HELLP (referred to as preeclampsia group) and 25 patients having severe preeclampsia with HELLP syndrome (referred to as HELLP group) were evaluated. The studied parameters included placental weight, chorioamnionitis (either acute or chronic), retroplacental hematoma, placental infarction, intervillous thrombosis, and decidual arteriopathy. Birth weight adjusted for gestational age was also compared between the two groups. RESULTS: We found statistically more significant frequency of retroplacental hematoma in the PE group compared to the HELLP group (P value 0.00). Despite the relatively high frequency of accelerated villous maturation and decidual arteriopathy in both groups, the difference between the two groups regarding these two parameters was not statistically significant. Other placental features did not show any significant difference between the two groups either. The frequency of small for gestational age births showed no statistically significant difference between the two groups. CONCLUSION: Retroplacental hematoma was the only placental pathology that showed statistically significant different frequencies between the two groups. Although this may suggest different underlying pathogenetic mechanisms in these two conditions, further studies are needed to confirm this hypothesis. PMID- 21698450 TI - Pregnancy management in women within the bladder-exstrophy-epispadias complex (BEEC) after continent urinary diversion. AB - BACKGROUND: Management of operative delivery in pregnant women after reconstruction of the bladder-exstrophy-epispadias complex (BEEC) using bowel segments remains a challenge. PATIENTS AND METHODS: We report urological history, pregnancy and delivery course of two BEEC patients after previous abdominal bowel surgeries. One had an ileocecal pouch after previously failed reconstruction, and the other had an ileum augmentation and a catheterizable Mitrofanoff stoma after functional reconstruction of the exstrophic bladder. RESULTS: Frequent bacteriuria and hydronephrosis warranted low-dose prophylaxis throughout pregnancy in one female, bilateral mild upper tract dilatation sonographic monitoring in both patients. Both were successfully delivered by cesarean section. No complications or clinical and sonographic signs for prolapse occurred. However, our operative experience revealed the importance of the abdominal incision type after different reconstructed reservoirs. CONCLUSION: Though care should be intense in pregnant BEEC individuals, patients should not be discouraged to have own children. To facilitate successful pregnancy outcome operative delivery should be done as a interdisciplinary team work and emergency situations should be avoided by meticulous planning and counseling of the BEEC patients. PMID- 21698451 TI - Inhibitory effect of Epigallocatechin gallate on ovarian cancer cell proliferation associated with aquaporin 5 expression. AB - OBJECTIVE: Abnormal expression of aquaporin 5 (AQP5) is associated with ovarian cancer infiltration, metastasis and angiogenesis. AQP 5 expression and apoptosis have been shown to be closely related to nuclear transcription factor NF-kappaB. In this study, we investigated the inhibition of cell proliferation and the induction of apoptosis by Epigallocatechin gallate (EGCG), a potential anti cancer drug, in the ovarian cancer cell line SKOV3 as well as the effect of EGCG on AQP5 expression and its possible mechanisms. METHODS: SKOV3 cells were treated with different concentrations of EGCG and the NF-kappaB-specific inhibitor pyrrolidine dithiocarbamate (PDTC) for different times. Cell proliferation was determined using the MTT assay, cell apoptosis was evaluated using the DNA ladder assay, the expression of AQP5, NF-kappaB p65 and IkappaBalpha was detected by immunohistochemistry, western blot analysis and RT-PCR, and the correlation of these protein expression was analyzed. RESULTS: With increasing concentrations of EGCG and prolonged treatment times, the growth inhibition rate of SKOV3 cells gradually increased in a dose- and time-dependent manner. The expression of AQP5 and nuclear p65 and IkappaBalpha was significantly decreased (P < 0.01). The cytoplasmic expression of IkappaBalpha gradually increased (P < 0.05), and the apoptosis of SKOV3 cells was induced as evidenced by typical fragmentation pattern in a DNA ladder assay. With increasing concentrations of PDTC and prolonged treatment times, the protein and mRNA levels of AQP5 in SKOV3 cells decreased (P < 0.01). In addition, the growth inhibition rate of SKOV3 cells significantly increased in a dose- and time-dependent manner. CONCLUSIONS: EGCG inhibited the proliferation and induced the apoptosis of ovarian cancer SKOV3 cells. EGCG also down-regulated expression of AQP5, which may inhibit tumor growth and be associated with nuclear transcription factor NF-kappaB. PMID- 21698452 TI - Spontaneous uterine rupture at the 21st week of gestation caused by placenta percreta. AB - PURPOSE: To describe the management of a ruptured uterus caused by placenta percreta in the 21st week of gestation. METHODS: We present a case report of a 33 year-old patient with a ruptured uterus in the 21st week of gestation who presented at the Department of Gynecology and Obstetrics, University of Schleswig Holstein, Campus Luebeck. Therapeutic management was performed by laparoscopy, and consecutive laparotomy and hysterectomy. RESULTS: A 33-year-old patient presented with severe abdominal pain in the 21st week of gestation at the department of abdominal surgery. A laparoscopy was performed to exclude appendicitis. There was about one liter of blood in the peritoneal cavity and a small, bleeding lesion in the fundus uteri was found which was coagulated. The blood was evacuated and the patient returned to department of gynecology. One hour after the first operation, the patient developed signs of hypovolemic shock and ultrasound showed absent fetal heart beat. An immediate laparotomy was performed and a ruptured uterus was detected. The fetus was removed and a hysterectomy performed. Pathology results showed a placenta percreta. After a few days in hospital and transfusion of 4 liters of blood the patient was discharged in a healthy condition. CONCLUSIONS: In a pregnant woman with severe abdominal pain even in the 21st week of gestation a placenta percreta has to be considered as a differential diagnosis. If there is no evidence of other causes, laparoscopy may help to confirm the diagnosis and hysterectomy is a life saving intervention. PMID- 21698454 TI - Bone mineral density in young women on methadone substitution. AB - Little is known about bone mineral density (BMD) in patients with heroin addiction and subsequent methadone substitution. The goal of this study was to compare bone mass density of young HIV-negative women on long-term methadone treatment to a local group of young healthy women. Eleven women (aged 20-29) with previous heroin dependence and current methadone substitution (20-140 mg, median 60, daily) for 1.5-9 (median 3) years were compared to 30 healthy women (aged 20 28). Participants were examined with dual-energy X-ray absorptiometry of the lumbar spine (L2-L4), of the total proximal hip area, and of the femoral neck. Patients and controls had neither current nor lifetime underweight condition, had comparable ages at menarche, and did not differ significantly in current body mass index (21.9 +/- 4.0, respectively, 20.5 +/- 1.5 kg/m(2)) in spite of a largely unhealthy lifestyle (cigarette, alcohol, and cocaine consumption in patients). Patients' total-hip parameters were marginally lower than those of controls (BMD P = 0.054, T score P = 0.049), whereas the femoral neck and lumbar spine parameters did not differ significantly between the two groups. Long-term methadone substitution in HIV-negative women seems to slightly affect bone mass density. PMID- 21698453 TI - Multi-dimensional MR spectroscopy: towards a better understanding of hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is normally diagnosed by neuropsychological (NP) tests. The goals of this study were to quantify cerebral metabolites, separate glutamate (Glu) from glutamine (Gln) in patients with minimal hepatic encephalopathy (MHE) as well as healthy subjects using the prior-knowledge fitting (ProFit) algorithm on data acquired by two-dimensional (2D) localized correlated spectroscopy (L-COSY) on two different MR scanners, and to correlate the metabolite changes with neuropsychological (NP) tests. We studied 14 MHE patients and 18 healthy controls using a GE 1.5 T Signa MR scanner. Another group of 16 MHE patients and 18 healthy controls were studied using a Siemens 1.5 T Avanto MR scanner. The following parameters were used for L-COSY: TR/TE = 2 s/30 ms, 3 * 3 * 3 cm(3) voxel size, 96 Deltat(1) increments with 8 averages per Deltat(1). Using the ProFit algorithm, we were able to differentiate Gln from Glu on the GE 1.5 T data in the medial frontal white/gray matter. The ratios of myo inositol (mI), Glu, total choline, scyllo-inositol (sI), phosphoethanolamine (PE), and total N-acetyl aspartate (NAA) showed statistically significant decline in HE patients compared to healthy controls, while the ratio of Gln was significantly increased. Similar trend was seen in the ProFit quantified Siemens 1.5 T data in the frontal and occipito-parietal white/gray regions. Among the NP domain scores, motor function, cognitive speed, executive function and the global scores showed significant differences. Excellent correlations between various NP domains and metabolite ratios were also observed. ProFit based cerebral metabolite quantitation enhances the understanding and basis of the current hypothesis of MHE. PMID- 21698455 TI - MKP-1 knockout does not prevent glucocorticoid-induced bone disease in mice. AB - Glucocorticoid-induced osteoporosis (GCOP) is predominantly caused by inhibition of bone formation, resulting from a decrease in osteoblast numbers. Employing mouse (MBA-15.4) and human (MG-63) osteoblast cell lines, we previously found that the glucocorticoid (GC) dexamethasone (Dex) inhibits cellular proliferation as well as activation of the MAPK/ERK signaling pathway, essential for mitogenesis in these cells, and that both these effects could be reversed by the protein tyrosine phosphatase (PTP) inhibitor vanadate. In a rat model of GCOP, the GC-induced changes in bone formation, mass, and strength could be prevented by vanadate cotreatment, suggesting that the GC effects on bone were mediated by one or more PTPs. Employing phosphatase inhibitors, qRT-PCR, Western blotting, and overexpression/knockdown experiments, we concluded that MKP-1 was upregulated by Dex, that this correlated with the dephosphorylation of ERK, and that it largely mediated the in vitro effects of GCs on bone. To confirm the pivotal role of MKP-1 in vivo, we investigated the effects of the GC methylprednisolone on the quantitative bone histology of wild-type (WT) and MKP-1 homozygous knockout (MKP 1(-/-)) mice. In WT mice, static bone histology revealed that GC administration for 28 days decreased osteoid surfaces, volumes, and osteoblast numbers. Dynamic histology, following time-spaced tetracycline labeling, confirmed a significant GC-induced reduction in osteoblast appositional rate and bone formation rate. However, identical results were obtained in MKP-1 knockout mice, suggesting that in these animals upregulation of MKP-1 by GCs cannot be regarded as the sole mediator of the GC effects on bone. PMID- 21698456 TI - Accurate prediction of protein structural class using auto covariance transformation of PSI-BLAST profiles. AB - Computational prediction of protein structural class based solely on sequence data remains a challenging problem in protein science. Existing methods differ in the protein sequence representation models and prediction engines adopted. In this study, a powerful feature extraction method, which combines position specific score matrix (PSSM) with auto covariance (AC) transformation, is introduced. Thus, a sample protein is represented by a series of discrete components, which could partially incorporate the long-range sequence order information and evolutionary information reflected from the PSI-BLAST profile. To verify the performance of our method, jackknife cross-validation tests are performed on four widely used benchmark datasets. Comparison of our results with existing methods shows that our method provides the state-of-the-art performance for structural class prediction. A Web server that implements the proposed method is freely available at http://202.194.133.5/xinxi/AAC_PSSM_AC/index.htm. PMID- 21698457 TI - Serum insulin-like growth factor-I and insulin-like growth factor binding protein 3 levels with risk of malignant melanoma. AB - We examined the relationship of insulin-like growth factor-I (IGF-I) and its primary growth factor, IGF binding protein-3 (IGFBP-3) with malignant melanoma using interview data and sera from cases (n = 286) and controls (n = 289) in a population-based case-control study conducted in 1986-1992 on Oahu, Hawaii. Serum IGF-I and IGFBP-3 concentrations were measured by ELISA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression and adjusting for age, sex, education, number of blistering sunburns, ability to tan, hair color, energy intake, BMI, height, smoking status, and drinking status. An inverse relationship was found between IGF-I concentration and melanoma (OR for upper vs. lower tertile: 0.44, 95% CI: 0.25-0.79), but clear associations were not observed between malignant melanoma and upper tertiles of IGFBP-3 and the IGF-1/IGFBP-3 molar ratio. The inverse association with IGF-I was strongest among subjects who did not report a history of non-melanoma skin cancer (NMSC) (OR for >= vs. < median: 0.39, 95% CI: 0.24-0.65), and a positive association was found among those with such a history (OR: 3.6, 95% CI: 1.0-13; p (interaction) = 0.0035). Our findings observed here between serum IGF-I and malignant melanoma warrants replication in studies with a larger sample size and a prospective design. PMID- 21698458 TI - Overexpression of the trehalose-6-phosphate synthase gene OsTPS1 enhances abiotic stress tolerance in rice. AB - Trehalose plays an important role in metabolic regulation and abiotic stress tolerance in a variety of organisms. In plants, its biosynthesis is catalyzed by two key enzymes: trehalose-6-phosphate synthase (TPS) and trehalose-6-phosphate phosphatase (TPP). The genome of rice (Oryza sativa) contains 11 OsTPS genes, and only OsTPS1 shows TPS activity. To demonstrate the physiological function of OsTPS1, we introduced it into rice and found that OsTPS1 overexpression improved the tolerance of rice seedling to cold, high salinity and drought treatments without other significant phenotypic changes. In transgenic lines overexpressing OsTPS1, trehalose and proline concentrations were higher than in the wild type and some stress-related genes were up-regulated, including WSI18, RAB16C, HSP70, and ELIP. These results demonstrate that OsTPS1 may enhance the abiotic stress tolerance of plants by increasing the amount of trehalose and proline, and regulating the expression of stress-related genes. Furthermore, we found that overexpression of some Class II TPSs also enhanced plant tolerance of abiotic stress. This work will help to clarify the role of trehalose metabolism in abiotic stress response in higher plants. PMID- 21698460 TI - Attitudes on DNA ancestry tests. AB - The DNA ancestry testing industry is more than a decade old, yet details about it remain a mystery: there remain no reliable, empirical data on the number, motivations, and attitudes of customers to date, the number of products available and their characteristics, or the industry customs and standard practices that have emerged in the absence of specific governmental regulations. Here, we provide preliminary data collected in 2009 through indirect and direct participant observation, namely blog post analysis, generalized survey analysis, and targeted survey analysis. The attitudes include the first available data on attitudes of those of individuals who have and have not had their own DNA ancestry tested as well as individuals who are members of DNA ancestry-related social networking groups. In a new and fluid landscape, the results highlight the need for empirical data to guide policy discussions and should be interpreted collectively as an invitation for additional investigation of (1) the opinions of individuals purchasing these tests, individuals obtaining these tests through research participation, and individuals not obtaining these tests; (2) the psychosocial and behavioral reactions of individuals obtaining their DNA ancestry information with attention given both to expectations prior to testing and the sociotechnical architecture of the test used; and (3) the applications of DNA ancestry information in varying contexts. PMID- 21698459 TI - Unique cell wall abnormalities in the putative phosphoinositide phosphatase mutant AtSAC9. AB - SAC9 is a putative phosphoinositide phosphatase in Arabidopsis thaliana involved in phosphoinositide signaling. sac9-1 plants have a constitutively stressed phenotype with shorter roots which notably accumulate phosphatidylinositol 4,5 bisphosphate and its hydrolysis product inositol trisphosphate. We investigated the primary roots of sac9-1 seedlings at the cytological and ultrastructural level to determine the structural basis for this altered growth. Despite the normal appearance of organelles and cytoplasmic elements, our studies reveal extreme abnormalities of cell wall and membrane structures in sac9-1 primary root cells, regardless of cell type, position within the meristematic area, and plane of section. Cell wall material was deposited locally and in a range of abnormal shapes, sometimes completely fragmenting the cell. Simple protuberances, broad flanges, diffuse patches, elaborate folds, irregular loops and other complex three-dimensional structures were found to extend randomly from the pre-existing cell wall. Abundant vesicles and excessive membrane material were associated with these irregular wall structures. We argue that a perturbed phosphoinositide metabolism most likely induces these observed abnormalities and hypothesize that a disorganized cytoskeleton and excessive membrane trafficking mediate the cell wall defects. PMID- 21698462 TI - PET-MRI in the head and neck area: challenges and new directions. PMID- 21698461 TI - Identification of genes necessary for wild-type levels of seed phytic acid in Arabidopsis thaliana using a reverse genetics approach. AB - The majority of phosphorus (P) in seeds is found in phytic acid (InsP(6)) which accumulates as the mixed salt phytate. InsP(6) is generally considered to be an anti-nutrient and the development of low phytic acid (lpa) seed crops is of significant interest. We have employed a reverse genetics approach to examine the impact of disrupting genes involved in inositol phosphate metabolism on Arabidopsis seed InsP(6) levels. Our analysis revealed that knockout mutations in three genes (AtITPK1, AtITPK4, and AtMIK/At5g58730) reduced seed InsP(6) in addition to knockouts of four previously reported genes (AtIPK1, AtIPK2beta, AtMRP5, and At5g60760). Seeds of these lpa mutants also exhibited reduced germination under various stress conditions. The greatest reduction in InsP(6) (>70%) was observed in atmrp5 seeds which were also among the least sensitive to the stresses examined. Expression analysis of the lpa genes revealed three distinct patterns in developing siliques consistent with their presumed roles. Disruption of each lpa gene resulted in changes in the expression in some of the other lpa genes indicating that transcription of lpa genes is modulated by other constituents of InsP(6) metabolism. While all the lpa genes represent possible targets for genetic engineering of low phytate seed crops, mutations in AtMRP5, AtMIK, and At5g60760 may be most successful for conventional approaches such as mutation breeding. PMID- 21698463 TI - Malignant versus benign mediastinal lesions: quantitative assessment with diffusion weighted MR imaging. AB - OBJECTIVES: We aimed to evaluate the performance of diffusion-weighted magnetic resonance imaging in differentiating malignant from benign mediastinal lesions. METHODS: Fifty-three mediastinal lesions were examined with T1- and T2-weighted (W) conventional images. Then, two diffusion-weighted images were obtained with b = 0 and 1000 s/mm2 values and apparent diffusion coefficients (ADC) were calculated. The statistical significance of differences between measurements was tested using the Student-t test. RESULTS: The mean ADC of malignant lesions was significantly lower than that of the benign masses (p < 0.001). The cut-off value of <= 1.39 * 10(-3) mm2/s indicated a malignant lesion with a sensitivity of 95% and specificity of 87%. CONCLUSION: Diffusion-weighted imaging may be helpful in differentiating benign from malignant mediastinal masses. PMID- 21698464 TI - Letter to the editor re: contrast enhanced ultrasound in the detection of liver metastases: a prospective multi-centre dose testing study using a perfluorobutane microbubble contrast agent (NC100100). PMID- 21698465 TI - Making renal stones change size-impact of CT image post processing and reader variability. AB - OBJECTIVES: The objectives of this study were to quantify the impact of image post-processing parameters on the apparent renal stone size, and to quantify the intra- and inter-reader variability in renal stone size estimation. METHODS: Fifty CT datasets including a renal or ureteral stone were included retrospectively during a prospective inclusion period. Each of the CT datasets was post-processed in different ways regarding slice thickness, slice increment and window setting. In the first part of the study a single reader repeated size estimations for the renal stones using different post-processing parameters. In the intra-reader variability experiment one reader reported size estimations for the same images with a one-week interval. The inter-reader variability data were obtained from 11 readers reporting size estimations for the same renal stones. RESULTS: The apparent stone size differed according to image post-processing parameters with the largest mean differences seen with regard to the window settings experiment (1.5 mm, p < 0.001) and slice thickness (0.8 mm, p < 0.001). Changes in parameters introduced a bias and a pseudo-random variability. The inter-reader variability was considerably larger than the intra-reader variability. CONCLUSION: Our results indicate a need for the standardisation of making measurements on CT images. PMID- 21698468 TI - Walk to me when I smile, step back when I'm angry: emotional faces modulate whole body approach-avoidance behaviors. AB - Facial expressions are potent social cues that can induce behavioral dispositions, such as approach-avoidance tendencies. We studied these tendencies by asking participants to make whole-body forward (approach) or backward (avoidance) steps on a force plate in response to the valence of social cues (happy or angry faces) under affect-congruent and incongruent mappings. Posturographic parameters of the steps related to automatic stimulus evaluation, step initiation (reaction time), and step execution were determined and analyzed as a function of stimulus valence and stimulus-response mapping. The main result was that participants needed more time to initiate a forward step towards an angry face than towards a smiling face (which is evidence of a congruency effect), but with backward steps, this difference failed to reach significance. We also found a reduction in spontaneous body sway prior to the step with the incongruent mapping. The results provide a crucial empirical link between theories of socially induced action tendencies and theories of postural control and suggest a motoric basis for socially guided motivated behavior. PMID- 21698467 TI - Visual attention affects temporal estimation in anticipatory motor actions. AB - The production of accurate motor actions requires successful extraction of relevant information about the target of that action. By the same token, it also requires the successful exclusion of potentially distracting, irrelevant information. This study sought to determine the impact of transient visual distractions on performance in an anticipatory timing task, in particular the temporal and spatial relationship between distractor and target at which maximal distraction occurs. The results support the notion of a critical temporal and spatial window of distraction which provides insight into the visuomotor processes underlying distraction. PMID- 21698469 TI - VEGF-C differentially regulates VEGF-A expression in ocular and cancer cells; promotes angiogenesis via RhoA mediated pathway. AB - Vascular angiogenesis is regulated by a number of cytokines of which vascular endothelial growth factor (VEGF)-A/and its receptor vascular endothelial growth factor receptor 2 (VEGFR2) play an indisputable role. Similarly lymphangiogenesis is regulated by VEGF-C and its receptor VEGFR3. Currently for treating vasculogenesis diseases such as proliferative retinopathies and cancer, a number of anti-VEGF-A therapies are approved for clinical use. Although clinical efficacies achieved are remarkable, they are found to be transitory in nature, followed by restoration of anti-VEGF therapy resistant angiogenesis. Recently the regulatory role of VEGF-C in initiating and potentiating neo-angiogenesis has been uncovered. Although the interactive nature of VEGF-A and C is known, the dynamics of their expression under knockdown conditions is yet to be established. Here in this study we have utilized siRNA to knockdown both VEGF-A and C either independently or in combination. Analysis of VEGF-A and C expression (only in cancer cell lines MCF7, A549 and H460 but not in the ocular cell line RPE19) has shown enhanced expression levels of VEGF-C with increase in knockdown of VEGF-A. However, VEGF-C knockdown has resulted in decreased expression levels of VEGF-A both in RPE19 and MCF7 cells in a dose dependent manner. In addition, VEGF-C knockdown also resulted in decreased expression of RhoA. Further, knockdown studies of RhoA even with supplementation of VEGF-C or A has resulted in decreased endothelial cell proliferation and stress fiber formation, indicating that VEGF-C does promote angiogenesis via RhoA mediated pathway. PMID- 21698470 TI - Comparison of neurosphere-like cell clusters derived from dental follicle precursor cells and retinal Muller cells. AB - Unrelated cells such as dental follicle precursor cells (DFPCs) and retinal Muller cells (MCs) make spheres after cultivation in serum-replacement medium (SRM). Until today, the relation and molecular processes of sphere formation from different cell types remain undescribed. Thus in this study we compared proteomes of spheres derived from MCs and DFPCs. 73% of 676 identified proteins were similar expressed in both cell types and many of them are expressed in the brain (55%). Moreover proteins are overrepresented that are associated with pathways for neural diseases such as Huntington disease or Alzheimer disease. Interestingly up-regulated proteins in DFPCs are involved in the biosynthesis of glycosphingolipids. These lipids are components of gangliosides such as GD3, which is a novel neural stem cell marker. In conclusion spheres from different types of cells have highly similar proteomes. These proteomes probably show essential cellular processes in neurosphere-like cell clusters. PMID- 21698471 TI - Protein-sparing effect of dietary lipid in practical diets for blunt snout bream (Megalobrama amblycephala) fingerlings: effects on digestive and metabolic responses. AB - This study aimed to evaluate the protein-sparing effect of dietary lipid on digestive and metabolic responses of fingerling Megalobrama amblycephala. Fish were fed nine practical diets with three protein levels (270, 310 and 350 g kg( 1)) and three lipid levels (40, 70 and 100 g kg(-1)) for 8 weeks. Weight gain was significantly affected only by dietary lipid levels with the highest found in fish fed 70 g kg(-1) lipid. Relative feed intake and whole-body protein content showed little difference among all the treatments. Activities of intestine lipase and amylase increased significantly as dietary lipid levels increased, whereas little difference was observed in protease activities. Liver lipid content was significantly affected only by protein levels with the lowest found in fish fed 310 g kg(-1) protein. Liver aspartate aminotransferase (GOT) activities increased significantly with decreasing lipid levels, whereas the highest GOT activity was obtained in fish fed 310 g kg(-1) protein in terms of dietary protein levels. Activities of liver lipoprotein lipase, total lipase and plasma cholesterol concentration of fish fed 350 g kg(-1) protein were significantly lower than that of the other groups, whereas the same was true for plasma 3, 5, 3' triiodothyronine level of fish fed 270 g kg(-1) protein. The results indicated that an increase of dietary lipid content from 40 to 70 g kg(-1) can enhance the growth and digestive enzyme activities of this species and reduce the proportion of dietary protein catabolized for energy without inducing hepatic steatosis; meanwhile, decreasing protein level from 350 to 310 g kg(-1) leads to the increase of lipase activities both in intestine and liver coupled with the reduced liver lipid content. PMID- 21698472 TI - Results of a haplotype-based GWAS for recurrent laryngeal neuropathy in the horse. AB - Recurrent laryngeal neuropathy (RLN) is a major upper-airway disease of horses that causes abnormal respiratory noise during exercise and can impair performance. Etiopathogenesis remains unclear but genetic factors have been suspected for many decades. The objective of this study was to identify risk loci associated with RLN. To that end we genotyped 234 cases (196 Warmbloods, 20 Trotters, 14 Thoroughbreds, and 4 Draft horses), 228 breed-matched controls, and 69 parents with the Illumina Equine SNP50 BeadChip. Using these data, we quantified population structure and performed single-marker and haplotype-based association studies, as well as family-based linkage analyses. We accounted for population stratification by modeling a random polygenic background effect with covariance structure estimated from genome-wide SNP data. Using the haplotype based approach, we identified two genome-wide suggestive loci in Warmbloods, respectively on chromosomes 21 (p = 1.62 * 10(-6)) and 31 (p = 1.69 * 10(-5)). The two signals were driven by the enrichment of a "protective" haplotype in controls compared to cases. PMID- 21698473 TI - [Is it possible to compare different studies on efficacy of biologicals in patients with rheumatoid arthritis? : mixed treatment comparison as a new tool for indirect comparison of clinical studies]. AB - Head-to-head studies as randomized, double blind clinical studies are the best method for directly comparing the efficacy of different therapeutic strategies. However, at the moment no such studies are available for biological agents in the treatment of patients with rheumatoid arthritis. Therefore it is only possible to compare different treatment strategies by indirect comparisons, for example by adjusted indirect comparison or mixed treatment comparison (MTC). The MTC is accepted by European authorities as supportive clinical evidence. As with the case of meta-analyses the quality of an indirect comparison is determined by the homogeneity of the studies included in the analysis.A short review of eight published indirect comparisons of the efficacy of biological agents in the treatment of patients with rheumatoid arthritis showed that the results with respect to tumor necrosis factor (TNF) blockers are similar and that there are differences in the efficacy of non-TNF biological agents. PMID- 21698474 TI - [Is fibromyalgia a viral disease?]. AB - Are viruses responsible for the pain in patients with fibromyalgia? Are viruses the trigger for rheumatoid arthritis? Is chronic fatigue syndrome a viral disease? There are many open questions with few or controversial answers. According to the current state of knowledge on the origin of the pain in fibromyalgia the varied symptomatic of fibromyalgia is triggered by peripheral as well as central mechanisms. Despite the broad spectrum of symptoms the disease is a specific entity which is mainly treated with dual reuptake inhibitors, anticonvulsives, tramadol, selective serotonin reuptake inhibitors, gamma hydroxybutyrate and dopamine agonists in individually selected combinations. PMID- 21698475 TI - [Education and training in pediatric and adolescent rheumatology - survey results : Gerd Horneff on behalf of the Committee for Undergraduate Training of the German Society for Rheumatology (DGRh)]. AB - In child and adolescent medicine pediatric rheumatology does not carry great weight. This fact is contrasted by the frequent occurrence of symptoms concerning the musculoskeletal system in childhood and adolescence. The obviously low interest in pediatric rheumatology probably has its roots in the education of undergraduates just as the often delayed diagnosis and inadequate therapy can possibly be credited to the content of specialist's training. The improvement of the educational situation is both concern and task of the German Society for Rheumatology (DGRh) and the German Society for Pediatric and Adolescent Rheumatology (GKJR). PMID- 21698476 TI - [New criteria for the classification of rheumatoid arthritis: significance for child and adolescent rheumatology?]. PMID- 21698477 TI - [Shoulder arthroplasty for primary synovial diseases]. AB - Shoulder arthroplasty has become an essential component of the standard surgical repertoire for the treatment of severe primary and secondary glenohumeral arthritis and has been shown to provide reliable long-term pain relief with satisfactory functional results. In most cases, in particular in patients with rheumatoid arthritis (RA), the indications for arthroplasty are primarily based on pain, which often includes severe pain at rest. Despite poor bone stock and impaired soft tissue quality in RA which frequently results in massive, irreparable rotator cuff tears, shoulder arthroplasty has been shown to be an effective means of improving shoulder function. Several different types of prostheses are now available for different indications determined by age, functional demand, etiology and structural deficits. For optimal outcome, the most suitable type of prosthesis needs to be selected by an experienced shoulder surgeon who is familiar with the entire spectrum of treatment options. PMID- 21698478 TI - Neurocysticercosis: local and systemic immune-inflammatory features related to severity. AB - Neurocysticercosis (NC) is caused by the establishment of Taenia solium cysticerci in the central nervous system. Previous studies have established that neuroinflammation plays a key role in the severity of the disease. However, the relationship between peripheral and local immune response remains inconclusive. This work studies the peripheral and local immune-inflammatory features and their relationships, toward the identification of potential peripheral immunologic features related to severity. A panel of cytokines was measured in paired cerebrospinal fluid (CSF) and in the supernatant of antigen-specific stimulated peripheral blood mononuclear cells samples (SN) in a total of 31 untreated inflammatory and non-inflammatory NC patients. Increased clinical and radiologic severity was associated with an increased cerebrospinal fluid cell count. A peripheral proliferative depression that negatively correlates with CSF cellularity and TNFalpha and that positively correlates with SN IL5 was observed in severe NC patients. These results provide evidences to support the systemic proliferative response as a biomarker to monitor the level of neuroinflammation, of possible value in the patients' follow-up during treatment. PMID- 21698479 TI - A proteomic approach for identification and localization of the pericellular components of chondrocytes. AB - Although the pericellular matrix (PCM) plays a central role in the communication between chondrocytes and extracellular matrix, its composition is largely unknown. In this study, the PCM was investigated with a proteomic approach using chondrons, which are enzymatically isolated constructs including the chondrocyte and its surrounding PCM. Chondrons and chondrocytes alone were isolated from human articular cartilage. Proteins extracted from chondrons and chondrocytes were used for two-dimensional electrophoresis. Protein spots were quantitatively compared between chondron and chondrocyte gels. Cellular proteins, which had similar density between chondron and chondrocyte gels, did not proceed for analysis. Since chondrons only differ from chondrocytes in association of the PCM, protein spots in the chondron gels that had higher quantity than that in the chondrocyte gels were selected as candidates of the PCM components and processed for mass spectrometry. Among 15 identified peptides, several were fragments of the three type VI collagen chains (alpha-1, alpha-2, and alpha-3). Other identified PCM proteins included triosephosphate isomerase, transforming growth factor-beta induced protein, peroxiredoxin-4, ADAM (A disintegrin and metalloproteinases) 28, and latent-transforming growth factor beta-binding protein-2. These PCM components were verified with immunohisto(cyto)chemistry for localization in the PCM region of articular cartilage. The abundance of type VI collagen in the PCM emphasizes its importance to the microenvironment of chondrocytes. Several proteins were localized in the PCM of chondrocytes for the first time and that warrants further investigation for their functions in cartilage biology. PMID- 21698482 TI - [Study of the incidence of malaria in febrile patients and among schoolchildren in the region of Trarza, Islamic Republic of Mauritania]. AB - A study was performed to appreciate the importance of malaria in the low valley of the Senegal River North Bank in Mauritania. The malaria incidence was assessed among patients visiting the regional hospital of Rosso (Trarza region) for a "presumptive malaria", a diagnosis assigned by the clinicians based on fever and other suggestive symptoms of malaria. The malaria prevalence rate was also measured in schoolchildren. A total of 1431 febrile outpatients were sampled for thick and thin blood films, between December 2004 and March 2005, August and November 2005, and April and July 2006. The average malaria prevalence rate was 2.5% (36/1431). It varied from 0.7% (4/576) for the period from December 2004 to March 2005 to 3.8% (18/475) from August to November 2005 and 2.1% (8/380) from April to July 2006. Of the 1040 school children of 6 to 14 years of age, the average malaria parasite prevalence rate was 0.9% (9/1040). It was 0.4% (1/224), 1.7% (7/413) and 0.2% (1/402), Respectively, in February 2004 (cold and dry season), October 2005 (rainy season) and June 2006 (hot and dry season). These very low levels of malaria endemicity and incidence are comparable with those recorded in the same area on the (South) bank of the river in Senegal. In this context of unstable malaria, characterized by the absence or a low level of natural immunity of the population, an effective monitoring is essential for an early detection and a damming up of the malaria epidemic blazes that likely occur. PMID- 21698480 TI - The effect of repeated restraint stress in pain-related behavior induced by nucleus pulposus applied on the nerve root in rats. AB - INTRODUCTION: Chronic pain has an impact on psychological and social factors. It is known that stress influences physiological and behavioral changes and affects several neurotransmitter and hormonal systems. It is also known that corticosterone is increased by stress. The role of chronic stress in sciatica in lumbar disc herniation (LDH) in rats has not been investigated. The aim of this study was to investigate the effect of the restraint stress (RS) on pain-related behavior induced by application of nucleus pulposus (NP) in rats. MATERIALS AND METHODS: Adult female Sprague-Dawley rats were divided into six experimental groups (naive group; naive + RS; sham group; sham + RS; autologous nucleus pulposus [NP] applied on the left L5 nerve root [NP group]; and NP + RS group). Von Frey tests were used to test pain-related behavior. Concentrations of plasma corticosterone were measured to assess changes in levels of endogenous corticosterone caused by RS. Expression of ATF-3 in the left L5 DRG was examined by immunohistochemical analyses in each group. RESULTS: Mechanical withdrawal thresholds of the NP and NP + RS groups were significantly decreased after surgery compared with the naive group. Although the thresholds in the NP group recovered after 28 days, the thresholds in the NP + RS group were significantly decreased during the 42 days after surgery. RS increased the concentration of plasma corticosterone at 21 and 42 days after surgery. In the NP and the NP + RS groups, the expression of ATF-3 was significantly increased at 7 days after surgery. The expression of ATF-3 was sustained for 21 days by RS. CONCLUSION: Concentrations of plasma corticosterone were increased in three groups that underwent RS. The pain-related behavior persisted for the long term in the LDH model. The expression of ATF-3 in DRG neurons increased for 21 days by RS. These results suggest that RS plays a role in the chronicity of pain-related behavior in the LDH rats. PMID- 21698483 TI - [A rare case of huge aspergilloma developed within a lesion of pulmonary fibrosis secondary with a systemic scleroderma in an immunocompetent patient in Madagascar]. AB - We report a rare case of a huge aspergilloma developed within a bronchiectasis due to pulling by a pulmonary fibrosis of systemic scleroderma. The patient is a 58-year-old woman presenting a deterioration of the general state associated with repeating hemoptysis, dyspnea, dysphagia, sclerodactylia, generalized cutaneous sclerosis and Raynaud's phenomenon. There was no antecedent pulmonary tuberculosis. The patient had a pulmonary arterial hypertension complicated by a chronic pulmonary heart at the stage of right cardiac decompensation. Aspergillosis serology was positive and the immunological assessment confirmed scleroderma. The computed tomography showed a huge oblong opacity in a small round bell shape ("signe du grelot", Monad's sign) in the left upper lobe developed within a bronchiectasis, and a bilateral pulmonary fibrosis. Although surgery remains the recommended treatment of an aspergilloma, the management of our patient was medical in front of contra-indication for surgery. The evolution was marked by repeating hemoptysis and stability of the pulmonary lesions 2 years later. The management of this entity remains difficult and complicated; the prognosis is in general unfavourable and depends at the same time on the evolution of scleroderma and the aspergilloma infection. PMID- 21698484 TI - Prediction of incident type 2 diabetes mellitus based on a twenty-year follow-up of the Ventimiglia heart study. AB - A novel algorithm to predict incident type 2 diabetes mellitus (iT2DM) is presented considering data from a 20-year prospective study in a Southern Italy population. Eight hundred and fifty-eight out of 1,351 subjects (24-85 years range of age) were selected. Incident type 2 diabetes was diagnosed in 103 patients in a 20-year follow-up. The Finnish Diabetes Risk Score (FINDRISC) and the Framingham Offspring Study simple clinical model (FOS) have been used as reference algorithms. Two custom algorithms have been created using Cox parametric hazard models followed by PROBIT analyses: the first one (VHSRISK) includes all the study subjects and the second one (VHS95RISK) evaluates separately subjects with baseline fasting blood glucose (FBG) above/below 5.2 mmol/L (95 mg/dL). The 44 iT2DM cases below 5.2 mmol/L of baseline FBG were predicted by high LDL cholesterol, metabolic syndrome (ATPIII criteria), BMI > 30 kg/m(2), and high factor VII activity. The 59 cases above the FBG threshold were predicted by FBG classes, hypertension, and age. ROC areas for iT2DM prediction were: FINDRISC = 0.759, FOS = 0.762, VHSRISK = 0.789, and VHS95RISK = 0.803. In a Mediterranean population, the use of a custom generated algorithm evaluating separately low/high FBG subjects improves the prediction of iT2DM in subjects classified at lower risk by common estimation algorithms. PMID- 21698485 TI - Women recover faster than men after standard knee arthroplasty. AB - BACKGROUND: Specific anatomic differences are believed to account for gender specific function and health-related quality of life after TKA. However, there are conflicting data in the literature regarding these gender-specific outcomes, especially as woman appear to have surgery later in the course of the disease compared with men. QUESTIONS/PURPOSES: We asked whether (1) women had worse knee function and health-related quality of life after TKA compared with men, (2) lower improvements in scores, and (3) slower recovery after surgery. METHODS: Using a cohort study design, we retrospectively analyzed prospectively collected data from three multicenter randomized controlled trials evaluating rehabilitation measures after standard unisex knee arthroplasty in 494 patients (141 men and 353 women). The primary outcome was self-reported physical function as measured by the WOMAC at 3, 6, 12, and 24 months after surgery. Secondary outcomes included the pain and stiffness scales of the WOMAC and the physical and mental component summaries of the SF-36. At the time of surgery, the women were on average older (70.8 versus 67.8 years), had lower mean physical function (55 versus 47), higher mean pain scores (54 versus 48), and greater stiffness (54 versus 46) as measured by the WOMAC. RESULTS: At the 3-, 6-, 12-, and 24-month followups, men and women had similar WOMAC scores. Improvements were greater for women compared with men for WOMAC function and pain subscale scores at the 3 month (function, 28 versus 23; pain, 32 versus 25) and 6-month followups (function, 32 versus 27; pain, 36 versus 31). At the 12- and 24-month followups we noted no differences in improvement between men and women. CONCLUSION: Although women had greater functional limitations at the time of surgery than men, they recover faster early after standard TKA although function is similar at 12 and 24 months. Women also had greater improvement of WOMAC scores after standard TKA than men. LEVEL OF EVIDENCE: Level II, prognostic study. See the guidelines for authors for a complete description of levels of evidence. PMID- 21698486 TI - Improvement of robustness and ethanol production of ethanologenic Saccharomyces cerevisiae under co-stress of heat and inhibitors. AB - Bioethanol is an attractive alternative to fossil fuels. Saccharomyces cerevisiae is the most important ethanol producer. However, yeast cells are challenged by various environmental stresses during the industrial process of ethanol production. The robustness under heat, acetic acid, and furfural stresses was improved for ethanologenic S. cerevisiae in this work using genome shuffling. Recombinant yeast strain R32 could grow at 45 degrees C, and resist 0.55% (v/v) acetic acid and 0.3% (v/v) furfural at 40 degrees C. When ethanol fermentation was conducted at temperatures ranging from 30 to 42 degrees C, recombinant strain R32 always gave high ethanol production. After 42 h of fermentation at 42 degrees C, 187.6 +/- 1.4 g/l glucose was utilized by recombinant strain R32 to produce 81.4 +/- 2.7 g/l ethanol, which were respectively 3.4 and 4.1 times those of CE25. After 36 h of fermentation at 40 degrees C with 0.5% (v/v) acetic acid, 194.4 +/- 1.2 g/l glucose in the medium was utilized by recombinant strain R32 to produce 84.2 +/- 4.6 g/l of ethanol. The extent of glucose utilization and ethanol concentration of recombinant strain R32 were 6.3 and 7.9 times those of strain CE25. The ethanol concentration produced by recombinant strain R32 was 8.9 times that of strain CE25 after fermentation for 48 h under 0.2% (v/v) furfural stress at 40 degrees C. The strong physiological robustness and fitness of yeast strain R32 support its potential application for industrial production of bioethanol from renewable resources such as lignocelluloses. PMID- 21698487 TI - The reductionist paradox: are the laws of chemistry and physics sufficient for the discovery of new drugs? AB - Reductionism is alive and well in drug-discovery research. In that tradition, we continually improve experimental and computational methods for studying smaller and smaller aspects of biological systems. Although significant improvements continue to be made, are our efforts too narrowly focused? Suppose all error could be removed from these methods, would we then understand biological systems sufficiently well to design effective drugs? Currently, almost all drug research focuses on single targets. Should the process be expanded to include multiple targets? Recent efforts in this direction have lead to the emerging field of polypharmacology. This appears to be a move in the right direction, but how much polypharmacology is enough? As the complexity of the processes underlying polypharmacology increase will we be able to understand them and their inter relationships? Is "new" mathematics unfamiliar in much of physics and chemistry research needed to accomplish this task? A number of these questions will be addressed in this paper, which focuses on issues and questions not answers to the drug-discovery conundrum. PMID- 21698488 TI - Overexpression of a homogeneous oligosaccharide with 13C labeling by genetically engineered yeast strain. AB - This report describes a novel method for overexpression of (13)C-labeled oligosaccharides using genetically engineered Saccharomyces cerevisiae cells, in which a homogeneous high-mannose-type oligosaccharide accumulates because of deletions of genes encoding three enzymes involved in the processing pathway of asparagine-linked oligosaccharides in the Golgi complex. Using uniformly (13)C labeled glucose as the sole carbon source in the culture medium of these engineered yeast cells, high yields of the isotopically labeled Man(8)GlcNAc(2) oligosaccharide could be successfully harvested from glycoprotein extracts of the cells. Furthermore, (13)C labeling at selected positions of the sugar residues in the oligosaccharide could be achieved using a site-specific (13)C-enriched glucose as the metabolic precursor, facilitating NMR spectral assignments. The (13)C-labeling method presented provides the technical basis for NMR analyses of structures, dynamics, and interactions of larger, branched oligosaccharides. PMID- 21698489 TI - [Treatment of fingertips]. AB - OBJECTIVE: The goal of excision of a subcutaneous abscess in the distal pulp of the fingertip is the fast and complete removal of the infected and devitalized tissue. INDICATIONS: Every acute infection of the fingertip. CONTRAINDICATIONS: Atypical infections, e.g., Herpes, Orf's disease, mycobacterial infections. SURGICAL TECHNIQUE: Excision of the infected area in the fingertip without damaging the digital nerves and their branches. POSTOPERATIVE MANAGEMENT: The wound is left open and is covered with a moist dressing. RESULTS: Early targeted incision brings good functional and cosmetic results. PMID- 21698490 TI - [Treatment of paronychia]. AB - OBJECTIVE: The procedure is selected based on the stage of infection with careful removal of the focal infection in the area of the nail fold. INDICATIONS: All infections of the periungual area. CONTRAINDICATIONS: Herpes infections [1, 12]. All purulent infections of the periungual area should be eliminated. SURGICAL TECHNIQUE: Opening of the abscess, excision of the eponychium, mobilization of the nail barrier away from the nail plate, inzision of the nail barrier at a defined place, necrosectomy, irrigation, and drainage. POSTOPERATIVE MANAGEMENT: Moist dressings and fingerbaths in the first few days. RESULTS: In most cases, the infection heals completely without substantial scar formation. PMID- 21698491 TI - Insertional anatomy and clinical relevance of the distal biceps tendon. AB - PURPOSE: This study was undertaken to evaluate the incidence of bifurcated distal biceps tendons and the tendon's insertional footprint on the radial tuberosity. METHODS: Twenty-five embalmed cadaveric specimens were dissected. The relationships and orientation of the muscle bellies and distal biceps tendon were examined. The insertional length, width, and footprint area of the distal biceps tendon on the radial tuberosity were evaluated. RESULTS: In 12 specimens (48%), the distal biceps tendon was in 2 distinct, easily separated parts. The average footprint length, width, and area of the tendon's insertion on the radial tuberosity were 20.5 mm +/- 2.0 mm, 9.7 mm +/- 1.3 mm, and 156.3 mm(2) +/- 29.4 mm(2), respectively. We calculated that the tendon's insertion occupied approximately 35.9% of the area of the radial tuberosity. In the specimens with a bifurcated distal biceps tendon, the long head of the tendon inserted at the posterosuperior portion of the radial tuberosity, and the average area was 71.4 mm(2) +/- 11.3 mm(2). The short head of the distal biceps tendon inserted at the anteroinferior portion, and the average area was 88.3 mm(2) +/- 24.1 mm(2). CONCLUSION: This study confirmed that bifurcated distal biceps tendon insertion is not a rare anatomical variation, showed by recent investigations, and found that the short head of the distal biceps tendon was inserted more anteriorly than the long head on the radial tuberosity. These findings may allow functional independence and isolated rupture of each portion. It can make correct diagnosis possible and allow for a more anatomical orientation of the tendon during surgical repair. PMID- 21698493 TI - Effects of creatine in a rat intestinal model of ischemia/reperfusion injury. AB - PURPOSE: Creatine belongs to a buffering system of cellular ATP level and has been reported to display direct antioxidant activity. Aim of this work was to investigate whether creatine treatment could ameliorate the antioxidant response of intestinal cells and limit the oxidative injury induced by anoxia and subsequent reoxygenation. METHODS: Jejunal and ileal tracts of rat intestine were everted and incubated in vitro under normoxic, anoxic and reoxygenation conditions in the absence and in the presence of 10 mM creatine. (Na+, K+) ATPase, gamma-GT and antioxidant enzymes activities were determined in mucosal homogenate, as well as malondialdehyde production and HSP70 expression. RESULTS: Both in jejunum and ileum, creatine treatment increases (Na+, K+)-ATPase activity; gamma-GT is unaffected in jejunum but stimulated in ileum. In both tissues, creatine does not alter the antioxidant activities or malondialdehyde level. HSP70 expression is increased only in jejunum. Anoxic conditions stimulate antioxidant activities to a greater extent in jejunum compared to ileum; reoxygenation does not evoke further effects, but enhances malondialdehyde production in both tracts. The protective action of creatine, in reoxygenation, is more marked in jejunum as for its stimulation of antioxidant activities; however, in jejunum, a prooxidant action of creatine is suggested, since malondialdehyde production is enhanced by its presence; on the contrary in ileum, where HSP70 is overexpressed in reoxygenation, peroxidation level is significantly reduced. CONCLUSIONS: The presence of creatine seems to potentiate the defensive response of both tissues, in jejunum by means of cell antioxidant equipment, in ileum by the involvement of HSP70. PMID- 21698492 TI - Fathers' intentions to accept human papillomavirus vaccination for sons and daughters: exploratory findings from rural Honduras. AB - OBJECTIVES: Little is known about fathers' attitudes toward human papillomavirus (HPV) vaccination in low-resource settings. We sought to determine the awareness of HPV vaccination among Honduran fathers, and to assess their intention to accept HPV vaccination for their sons and daughters. METHODS: We conducted 100 structured interviews of fathers recruited from medical and business settings between May 2007 and June 2008. After assessing baseline knowledge, fathers received a brief explanation of HPV infection, cervical cancer, genital warts, and HPV vaccination. They were then asked whether they would accept HPV vaccination for their sons and daughters. RESULTS: Prior to receiving information about HPV, 85% of fathers believed that cervical cancer was preventable, over two thirds could correctly name some form of prevention, 22% of fathers had heard of HPV, and 17% had heard of HPV vaccination. After receiving HPV-related information, 100% of fathers intended to accept HPV vaccination for their sons and 94% intended to accept HPV vaccination for their daughters. CONCLUSIONS: Few Honduran fathers were aware of HPV or HPV vaccination, but after receiving information, most would accept HPV vaccination for their sons and daughters. PMID- 21698494 TI - Plant polyphenols attenuate hepatic injury after hemorrhage/resuscitation by inhibition of apoptosis, oxidative stress, and inflammation via NF-kappaB in rats. AB - PURPOSE: Oxidative stress and inflammation contribute to hepatic injury after hemorrhage/resuscitation (H/R). Natural plant polyphenols, i.e., green tea extract (GTE) possess high anti-oxidant and anti-inflammatory activities in various models of acute inflammation. However, possible protective effects and feasible mechanisms by which plant polyphenols modulate pro-inflammatory, apoptotic, and oxidant signaling after H/R in the liver remain unknown. Therefore, we investigated the effects of GTE and its impact on the activation of NF-kappaB in the pathogenesis of hepatic injury induced by H/R. METHODS: Twenty four female LEWIS rats (180-250 g) were fed a standard chow (ctrl) or a diet containing 0.1% polyphenolic extracts (GTE) from Camellia sinensis starting 5 days before H/R. Rats were hemorrhaged to a mean arterial pressure of 30 +/- 2 mmHg for 60 min and resuscitated (H/R and GTE H/R groups). Control groups (sham, ctrl, and GTE) underwent surgical procedures without H/R. Two hours after resuscitation, tissues were harvested. RESULTS: Plasma alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) increased 3.5-fold and fourfold, respectively, in vehicle-treated rats as compared to GTE-fed rats. Histopathological analysis revealed significantly decreased hepatic necrosis and apoptosis in GTE-fed rats after H/R. Real-time PCR showed that GTE diminished gene expression of pro-apoptotic caspase-8 and Bax, while anti-apoptotic Bcl-2 was increased after H/R. Hepatic oxidative (4-hydroxynonenal) and nitrosative (3 nitrotyrosine) stress as well as systemic IL-6 level and hepatic IL-6 mRNA were markedly reduced in GTE-fed rats compared with controls after H/R. Plant polyphenols also decreased the activation of both JNK and NFkappaB. CONCLUSIONS: Taken together, GTE application blunts hepatic damage, apoptotic, oxidative, and pro-inflammatory changes after H/R. These results underline the important roles of JNK and NF-kappaB in inflammatory processes after H/R and the beneficial impact of plant polyphenols in preventing their activation. PMID- 21698495 TI - In vitro evaluation of the performance of Granada selective enrichment broth for the detection of group B streptococcal colonization. AB - A broth for the screening of group B streptococcal (GBS) carriage during pregnancy is about to be introduced. Simulating conditions in everyday practice, we have compared the sensitivity of this Granada tube broth (GT) with that of classical Amies transport medium (AT) in vitro. A total of 1,485 GT and 1,485 AT were tested with 33 well-characterized GBS strains in three different concentrations, five different incubation times, and three different temperatures. After initial incubation at room temperature (RT) or 4 degrees C, GT were placed at 37 degrees C. GT were scored for the presence of orange pigment. GT and AT were subcultured on blood agar (BA). Pigment was observed in 98% of GT incubated at 37 degrees C. GBS could be cultured in 91%, 73%, and 55% of GT incubated at 37 degrees C, RT, or 4 degrees C, respectively. For AT, these percentages were only 20% at 37 degrees C, 52% at RT, and 59% at 4 degrees C. When GT initially incubated at RT or 4 degrees C were subsequently incubated at 37 degrees C, the sensitivity improved significantly. We conclude that GT is a more sensitive GBS transport and culture medium than the conventional method, especially for low inocula and prolonged transport/incubation times. GT does not exclude the presence of GBS, and should always be incubated at 37 degrees C and subcultured on solid agar for optimal sensitivity. PMID- 21698496 TI - Rapid identification of bacteria in positive blood culture by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. AB - Blood culture is probably the most significant specimen used for the diagnosis of bacterial infections, especially for bloodstream infections. In the present study, we compared the resin-containing BD BACTECTM Plus-Aerobic (Becton Dickinson), non-charcoal-containing BacT/Alert((r)) SA (bioMerieux), and charcoal containing BacT/Alert((r)) FA (bioMerieux) blood culture bottles with direct identification by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). A total of 103 bacterial isolates, from clinical blood cultures, representing the most frequent 13 genera and 24 species were examined. Bacteria were extracted from positive blood culture broth by density centrifugation and then subjected to identification by MALDI-TOF MS using two different volumes and chemical treatments. Overall, correct identification by MALDI-TOF MS was obtained for the BD BACTECTM Plus-Aerobic, BacT/Alert((r)) SA, and BacT/Alert((r)) FA blood culture bottles in 72%, 45.6%, and 23%, respectively, for gram-negative bacteria in 86.6%, 69.2%, and 47.1%, respectively, and for gram-positive bacteria in 60.0%, 28.8%, and 5.4%, respectively. The lack of identification was observed mainly with viridans streptococci. Depending on the blood culture bottles used in routine diagnostic procedures and the protocol for bacterial preparation, the applied MALDI-TOF MS represents an efficient and rapid method for direct bacterial identification. PMID- 21698497 TI - The numerical distance effect is task dependent. AB - Number comparison tasks produce a distance effect e.g., Moyer & Landauer (Nature 215: 1519-1520, 1967). It has been suggested that this effect supports the existence of semantic mental representations of numbers. In a matching task, a distance effect also appears, which suggests that the effect has an automatic semantic component. Recently, Cohen (Psychonomic Bulletin & Review 16: 332-336, 2009) suggested that in both automatic and intentional tasks, the distance effect might reflect not a semantic number representation, but a physical similarity between digits. The present article (1) compares the distance effect in the automatic matching task with that in the intentional number comparison task and suggests that, in the latter, the distance effect does include an additional semantic component; and (2) indicates that the distance effect in the standard automatic matching task is questionable and that its appearance in previous matching tasks was based on the specific analysis and design that were applied. PMID- 21698498 TI - Brief report: relationship between self-awareness of real-world behavior and treatment outcome in autism spectrum disorders. AB - The aim of the present study was to investigate the influence of self-awareness of real-world behavior on treatment outcome in adolescents with ASD. For this purpose we followed 28 adolescents with ASD during their first year of specialized treatment. Results showed that better self-awareness at start of treatment was related with an increase in clinician-reported social functioning after 1 year of treatment. Additionally, an increase in self-awareness during treatment was related with a decrease of parent-reported problems in daily functioning. However, an increase in self-awareness was also related to an increase of self-reported daily and psychological problems. It is discussed that lowered self-awareness may result in an overestimation of personal real-world functioning and consequently may influence treatment course. PMID- 21698499 TI - Teachers' perceptions regarding the management of children with autism spectrum disorders. AB - This study examines Greek teachers' perceptions related to the nature and management of autistic children. To investigate these issues, a statistically reliable number of questionnaires (n = 228) was distributed to a diversified teacher population. The questionnaire responses were analyzed statistically to identify the explanatory power of critical independent variables. The research findings support that teachers' specialized training and working experience are critical inputs to improve teachers' perceptions and efficient serving of autistic children. A cumulative joint effect of teachers' previous specialized education and working experience working with autistic children was also indicated. This could be supportive of teachers upgrading their active leading role in team working with specialized scientific staff, parents and institutions on autistic children. PMID- 21698501 TI - Is port site resection necessary in the surgical management of gallbladder cancer? AB - BACKGROUND: In selected patients with incidental gallbladder carcinoma (GBCA) diagnosed after laparoscopic cholecystectomy (LC), definitive resection is warranted. Port site excision has been advocated but remains controversial. METHODS: Patients with GBCA were identified through institutional/departmental databases. The subset of patients with incidental tumors identified after LC and submitted to definitive surgical therapy were selected. Those subjected to port site resection were compared with patients who underwent resection without port site removal and analyzed for differences in recurrence patterns and survival. RESULTS: From 1992 to 2009, 113 patients with incidental GBCA presented for definitive resection after LC; 69 patients had port site resection and 44 did not. In the resected port site group, depth of tumor invasion was T1b = 6, T2 = 35, T3 = 28, and 13 (19%) had port site metastases. Port site disease was seen only in patients with T2 or T3 tumors and correlated with the development of peritoneal metastases (P = 0.01). Median survival of patients with T2/T3 tumors without port site metastases was 42 months compared to 17 months in patients with port site disease (P = 0.005). When only R0 resected patients were compared and adjusted for T and N stage, port site resection was not associated with overall survival (P = 0.23) or recurrence-free survival (P = 0.69). CONCLUSIONS: In patients with incidental GBCA, port site metastases were associated with peritoneal disease and decreased survival. Port site resection was not associated with improved survival or disease recurrence and should not be considered mandatory during definitive surgical treatment. PMID- 21698502 TI - Should we promote "increasing donor body weight to prevent small-for-size syndrome in living donor liver transplantation"? PMID- 21698503 TI - Adjuvant transcatheter arterial chemoembolization for intrahepatic cholangiocarcinoma after curative surgery: retrospective control study. AB - BACKGROUND: Effects of adjuvant transcatheter arterial chemoembolization (TACE) for intrahepatic cholangiocarcinoma (ICC) radical surgery have never been evaluated. METHODS: A retrospective analysis was conducted on 125 ICC patients who had undergone operations with curative intent in Shanghai Eastern Hepatobiliary Surgery Hospital from July 2002 to December 2003. Of these patients, 53 underwent adjuvant TACE (TACE group) and 72 did not (non-TACE group). Adjuvant TACE was performed one time 1.5-2.0 months after the operation. RESULTS: Follow-up was performed at a median of 18 months (range 3-96 months). There was no significant recurrence-free survival (RFS) difference between the TACE and non-TACE groups (P = 0.659). The 1-, 3-, and 5-year overall survival (OS) rates were 69.8, 37.7, and 28.3%, respectively, for the TACE group and 54.2, 25.0, and 20.8%, respectively, for the non-TACE group (P = 0.045). Among 54 patients with a recurrence time of <= 3 months, the OS rate of the TACE group was better than that of the non-TACE group (P < 0.001). For 59 patients with a recurrence time later than the median RFS, no significant RFS difference was found between the TACE and non-TACE groups (P = 0.681). These results indicate that TACE could not delay recurrence but could prolong the OS of patients with early recurrence. CONCLUSIONS: Adjuvant TACE after radical surgery was associated with better survival among the ICC patients with early recurrence. PMID- 21698504 TI - Quantification of plasma phospholipids by ultra performance liquid chromatography tandem mass spectrometry. AB - We describe a fast and robust ultra performance liquid chromatography tandem mass spectrometry method for the quantification of phospholipid (PL) species in EDTA plasma samples. We quantified total phosphatidylcholine (PC), phosphatidylethanolamine (PE), lysophosphatidylcholine (LPC), and sphingomyelin (SM) and several species within these classes using one or two external calibrators and one internal standard for each class. Inter-assay coefficients of variation were <10% for the most abundant species and <20% for all quantified PC, LPC, and SM species and the three most abundant PE species. Coefficients of linear regression were R(2) > 0.98. Mean recoveries were between 83% and 123%. The limits of detection were 0.37 MUmol/L for PC, 4.02 MUmol/L for LPC, 3.75 MUmol/L for PE, and 0.86 MUmol/L for SM. Quantification was linear over the physiological ranges for PE, LPC, and SM and up to 500 MUmol/L for PC. The concentrations of PLs in the plasma of healthy donors yielded results that were comparable with those of previous works. PMID- 21698505 TI - Antiplatelet and anticoagulant drugs in interventional radiology. AB - In treating peripheral arterial disease, a profound knowledge of antiplatelet and anticoagulative drug therapy is helpful to assure a positive clinical outcome and to anticipate and avoid complications. Side effects and drug interactions may have fatal consequences for the patient, so interventionalists should be aware of these risks and able to control them. Aspirin remains the first-line agent for antiplatelet monotherapy, with clopidogrel added where dual antiplatelet therapy is required. In case of suspected antiplatelet drug resistance, the dose of clopidogrel may be doubled; prasugrel or ticagrelor may be used alternatively. Glycoprotein IIb/IIIa inhibitors (abciximab or eptifibatide) may help in cases of hypercoagulability or acute embolic complications. Desmopressin, tranexamic acid, or platelet infusions may be used to decrease antiplatelet drug effects in case of bleeding. Intraprocedurally, anticoagulant therapy treatment with unfractionated heparin (UFH) still is the means of choice, although low molecular weight heparins (LMWH) are suitable, particularly for postinterventional treatment. Adaption of LMWH dose is often required in renal insufficiency, which is frequently found in elderly patients. Protamine sulphate is an effective antagonist for UFH; however, this effect is less for LMWH. Newer antithrombotic drugs, such as direct thrombin inhibitors or factor X inhibitors, have limited importance in periprocedural treatment, with the exception of treating patients with heparin-induced thrombocytopenia (HIT). Nevertheless, knowing pharmacologic properties of the newer drugs facilitate correct bridging of patients treated with such drugs. This article provides a comprehensive overview of antiplatelet and anticoagulant drugs for use before, during, and after interventional radiological procedures. PMID- 21698506 TI - Isolation and characterisation of acaricidal and larvicidal novel compound (2S,5R,6R)-2-hydroxy-3,5,6-trimethyloctan-4-one from Streptomyces sp. against blood-sucking parasites. AB - The aim of the present study was to assess the acaricidal and larvicidal property of marine actinobacterial compound (2S,5R,6R)-2-hydroxy-3,5,6-trimethyloctan-4 one extracted and isolated from Streptomyces sp. VITDDK3 tested against the larvae of Rhipicephalus (Boophilus) microplus Canestrini (Acari: Ixodidae), Anopheles subpictus Grassi and Culex quinquefasciatus Say (Diptera: Culicidae). The isolate was taxonomically characterised, identified and designated as Streptomyces sp. VITDDK3. The crude compound was loaded on silica gel column and eluted with chloroform-methanol-water. The purity of the compound isolated was analysed by thin layer chromatography using chloroform and methanol as the solvent system and confirmed by high-performance liquid chromatography. The structure of the purified compound was established from infrared, ultraviolet, (1)H-nuclear magnetic resonance (NMR), (13)C-NMR and mass spectral data. The chemical shift assignments obtained for the aliphatic compound from (1)H-NMR corresponding to the molecular formula C(11)H(22)O(2). Bioassay-guided fractionation led to the isolation of compound, which was identified as (2S,5R,6R)-2-hydroxy-3,5,6-trimethyloctan-4-one. In the present study, Streptomyces sp. VITDDK3 crude extract and different fractions were tested against the larvae of parasites at a concentration of 1,000 ppm. Those fractions showing 100% mortality in 24 h alone was selected for further column chromatographic separation. The purified compound (2S,5R,6R)-2-hydroxy-3,5,6 trimethyloctan-4-one was tested in the concentrations of 250, 200, 150, 100 and 50 ppm and observed the per cent mortality of 100, 88, 62, 50 and 36 against R. microplus; 100, 100, 87, 62 and 39 against A. subpitcus; and 100, 94, 79, 51 and 33 against C. quinquefasciatus, respectively. The crude extract showed parasitic effects after 24 h of exposure at 1,000 ppm, and parasite mortality was observed against the larvae of R. microplus (LC(50) = 88.74 ppm; r (2) = 0.865) against the larvae of A. subpictus (LC(50) = 162.59 ppm; r (2) = 0.817) and against C. quinquefasciatus (LC(50) = 120.15 ppm; r (2) = 0.782), respectively. The maximum efficacy was observed in purified marine actinobacterial compound (2S,5R,6R)-2 hydroxy-3,5,6-trimethyloctan-4-one with LC(50) and r (2) values against the larvae of R. microplus (94.49 ppm; 0.982) and A. subpictus (69.65 ppm; 0.906) and against C. quinquefasciatus (82.82 ppm; 0.957), respectively. The control (distilled water) showed nil mortality in the concurrent assay. PMID- 21698507 TI - Neuroprotective effects of white tea against oxidative stress-induced toxicity in striatal cells. AB - Tea is one of the most widely consumed beverages in the world and represents an important source of antioxidants mainly catechins that confer beneficial effects in reducing the risk of cardiovascular diseases, age-related disorders or cancer. In the central nervous system, oxidative stress caused by increased production of reactive oxygen and nitrogen species represents an important mechanism for neuronal dysfunction and cell loss in different neurodegenerative disorders. The neuroprotective effects of green-tea-derived polyphenols have extensively been demonstrated in different models of neurotoxicity. However, few data have been reported on the antioxidant activity of white tea extracts in the nervous system. In the present study, we demonstrate that white tea extracts protect striatal cell lines against oxidative stress-mediated cell death. The effects of white tea on protection of striatal cell cultures are likely associated with the antioxidant properties of white tea components since neuronal cell loss induced by nonoxidative insults such as D1 dopamine receptor activation cannot be prevented by pre-treatment with white tea. Altogether our results suggest that regular consumption of white tea may contribute to reduce oxidative stress associated with brain injury and be clinically useful for treating age-related and neurodegenerative disorders. PMID- 21698508 TI - Utility of prepuncture ultrasound for localization of the thoracic epidural space. AB - BACKGROUND: Ultrasound has been shown to facilitate accurate identification of the intervertebral level and to predict skin-to-epidural depth in the lumbar epidural space with reliable precision. We hypothesized that we could accurately predict the skin-to-epidural depth and the intervertebral level in the thoracic spine with the use of ultrasound. METHODS: Twenty patients presenting for thoracic surgery were included in a feasibility study. The skin-to-epidural depth was measured using prepuncture ultrasound in the paramedian window, and the predicted depth was compared with the actual needle depth and the depth as measured by computed tomography. In addition, the intervertebral levels were identified by ultrasound using the "counting up" method, and the results were compared with the levels identified by anesthesiologists. RESULTS: The ultrasound based depth measurements displayed a bias of 3.21 mm with 95% limits of agreement from -7.47 to 13.9 mm compared with the clinically determined needle depth. The intervertebral levels identified by the anesthesiologists and the sonographer matched in only 40% of cases. CONCLUSION: Ultrasound-based measurements of skin to-epidural depth show acceptable agreement with the actual depth observed during epidural catheterization; however, the limits of agreement are wide, which restricts the predictive value of ultrasound-based measurements. Further study is required to delineate the role of ultrasound in thoracic epidural catheterizations. PMID- 21698509 TI - Anesthetic management of patients with Brugada syndrome: a case series and literature review. AB - PURPOSE: To review the anesthetic management and perioperative outcomes of patients diagnosed with Brugada syndrome (BrS) who were treated at a single centre and to compare those results with a comprehensive review of the existing literature. CLINICAL FEATURES: A retrospective chart review of anesthesia records from patients diagnosed with BrS at the Mayo Clinic was undertaken with the emphasis on administered drugs, ST segment changes, and occurrence of complications, including death, hemodynamic instability, and dysrhythmias. Eight patients were identified who underwent a total of 17 operative procedures from 2000 through 2010. A total of 20 significant ST segment elevations were recorded in four patients, several of which occurred in close temporal relation to anesthetic drug administration. These elevations resolved uneventfully. There were no recorded dysrhythmias, and recovery from anesthesia proceeded uneventfully. A literature review of patients with BrS yielded 52 anesthetics in 43 patients. The only recorded complications included unmasking of a Brugada ECG pattern, one episode of polymorphic ventricular tachycardia, which converted spontaneously to sinus rhythm, and one episode of postoperative ventricular fibrillation in the setting of epidural anesthesia. CONCLUSIONS: In this series and in the literature, BrS patients tolerated anesthesia without untoward disease related complications. Propofol and local anesthetics carry a theoretical risk of arrhythmogenic potential in BrS patients, but clear evidence is lacking. However, awareness of their potential to induce arrhythmias warrants caution, especially with propofol infusions. Factors that might exacerbate ST segment elevations and subsequently lead to dysrhythmias (e.g., hyperthermia, bradycardia, and electrolyte imbalances, such as hyper- and hypokalemia and hypercalcemia) should be avoided or corrected. PMID- 21698510 TI - Conflict adaptation in time: foreperiods as contextual cues for attentional adjustment. AB - Interference evoked by distractor stimulus information, such as flankers in the Eriksen task, is reduced when the proportion of conflicting stimuli is increased. This modulation is sensitive to contextual cues such as stimulus location or color, suggesting attentional adjustment to conflict contingencies on the basis of context information. In the present study, we explored whether conflict adjustment is modulated by temporal variation of conflict likelihood. To this end, we associated low and high proportions of conflict stimuli with foreperiods of different lengths. Flanker interference was higher with foreperiods associated with low conflict proportions, suggesting that participants use the foreperiod as a contextual cue for attentional adjustment. We conjecture that participants initially adopt the strategy useful for conflict contingencies associated with short foreperiods, and then readjust during the trial, in the absence of any additional exogenous cue, when the imperative stimulus has not occurred during a certain time interval. PMID- 21698511 TI - Qualitative and quantitative determination of ten iridoids and secoiridoids in Gentiana straminea Maxim. by LC-UV-ESI-MS. AB - A simple and accurate HPLC-UV/MS method was developed for the simultaneous determination of ten iridoids and secoiridoids in the roots of Gentiana straminea Maxim. Separations were performed on a Kromasil-C18 column by gradient elution using methanol and water containing phosphoric acid. Analytes were identified by HPLC coupled with ESI-MS experiments. The chromatographic method was validated for selectivity, linearity, precision, limit of detection, limit of quantification, accuracy, and stability. The developed assay could be considered as a suitable quality control method for G. straminea and other "Qinjiao" herbs. PMID- 21698513 TI - Pressure immobilization bandages not indicated in the pre-hospital management of North American snakebites. PMID- 21698512 TI - Pretreatment with morin, a flavonoid, ameliorates adenosine triphosphatases and glycoproteins in isoproterenol-induced myocardial infarction in rats. AB - The aim of this investigation was to evaluate the preventive role of morin, a flavonoid, on cardiac marker enzymes such as aspartate transaminase, lactate dehydrogenase, creatine kinase and creatine kinase-MB, membrane-bound enzymes such as sodium potassium-dependent adenosine triphosphatase, calcium-dependent adenosine triphosphatase and magnesium-dependent adenosine triphosphatase, and glycoproteins such as hexose, hexosamine, fucose and sialic acid in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Male albino Wistar rats were pretreated with morin (20, 40 and 80 mg/kg) daily for a period of 30 days. After the treatment period, ISO (85 mg/kg) was subcutaneously injected into the rats at an interval of 24 h for 2 days. ISO-induced rats showed significantly (P < 0.05) increased activities of cardiac marker enzymes in serum and decreased activities in the heart, and increased activities of calcium-dependent adenosine triphosphatase and magnesium-dependent adenosine triphosphatase in the heart, and the activity of sodium potassium-dependent adenosine triphosphatase decreased in the heart. ISO induction also showed a significant increase in the levels of glycoproteins in serum and the heart. Pretreatment with morin (40 mg/kg) daily for a period of 30 days exhibited significant (P < 0.05) effects and altered these biochemical parameters positively compared to the other two doses. Thus, our study shows that morin has a protective role in ISO-induced MI in rats. The observed effects might be due to the free radical-scavenging, antioxidant and membrane-stabilising properties of morin. PMID- 21698514 TI - Development of microporous self-expanding stent grafts for treating cerebral aneurysms: designing micropores to control intimal hyperplasia. AB - Treatment of large (diameter 12-25 mm) or giant (diameter >25 mm) cerebral aneurysms with a broad neck in the cranio-cervical area is difficult and carries relatively high risks, even with surgical and/or endovascular methods. To this end, we have been developing a high-performance, self-expanding stent graft which consists of a commercially available NiTi stent (diameter 5 mm, length 20 mm) initially covered with a thin microporous segmented polyurethane membrane fabricated by the dip-coating method. Micropores are then created by the excimer laser ablation technique, and the outer surface is coated with argatroban. There are 2 types of micropore patterns: circular-shaped pore type (pore: diameter 100 MUm, opening ratio 12.6%) and the bale-shaped pore type (pore: size 100 * 268 MUm, opening ratio 23.6%). This self-expanding stent graft was tested on side wall aneurysms of both canine carotid arteries that were experimentally induced using the venous pouches from the external jugular veins, with the self-expanding stent graft on one side and a bare self-expanding stent on the other side. All carotid arteries were patent and free of marked stenosis after 1 month. All aneurysms were occluded by stent grafts, while patent in those treated with bare stents. Histologically, the stent grafts with bale-shaped micropores and a high opening ratio were associated with less intimal hyperplasia (187 +/- 98 MUm) than the bare stents (341 +/- 146 MUm) or the stent grafts with circular micropores and a low opening ratio (441 +/- 129 MUm). A pore ratio of 23.6% was found to control intimal growth. PMID- 21698516 TI - Inpatient consultations to an orthopaedic service: the hidden workload. AB - BACKGROUND: While the quality and efficiency of out-patient orthopaedic referrals are well documented in the literature, there is little on the standard and appropriateness of inpatient orthopaedic consultations. AIM: To prospectively audit the pattern of inpatient consultations to an orthopaedic service. METHODS: Data were prospectively collected on all inpatients referred to the orthopaedic service over a 4-month period. RESULTS: Sixty-eight consultations were received in the study period. The average age was 68 years (range 20-86 years). Seventy two percent of consultations were from medical services, 25% from other surgical specialties and the remainder (3%) from the psychiatric department. Eight (12%) patients required surgical intervention. Twenty patients (29%) had previously been seen in the outpatient department. CONCLUSIONS: Inpatient orthopaedic consultations generate a significant workload and the majority of such patients could be seen as outpatients. Clear and explicit guidelines on appropriate referral pathways, as well as enhanced education in the management of musculoskeletal disorders and available services may optimise delivery of patient care in the inpatient setting. PMID- 21698515 TI - Cytokine balance in hepatosplanchnic system during thoracoabdominal aortic aneurysm repair. AB - While prolonged visceral ischemia seems to be a potential source of elevated proinflammatory cytokines during thoracoabdominal aortic aneurysm (TAAA) repair, the underlying mechanisms are unclear. We have investigated the production of cytokines and fatty acid binding proteins (FABPs) in the hepatosplanchnic system during TAAA repair. Arterial and hepatic venous levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL) -6, -8, and -10, and liver- and intestinal type FABPs (L-FABP, I-FABP) were measured at four time points in ten patients undergoing TAAA repair. Visceral arteries were perfused through either a side-arm of distal aortic perfusion or an individual circuit using an independent pump, or both, without measuring perfusion pressure or blood flow. The postoperative courses of all patients were uneventful. During visceral perfusion, the levels of arterial IL-6, -8, and -10, and L-FABP elevated significantly (P = 0.0077, 0.0051, 0.0077, 0.0077, respectively), and these elevated levels persisted up to skin closure, with the exception of L-FABP (P = 0.0051 each). In contrast, there were only subtle increases in TNF-alpha and I-FABP levels. The production ratio through the hepatosplanchnic system of TNF-alpha, L-FABP, and I-FABP showed a pronounced peak during visceral perfusion, but only the peak of L-FABP was significant compared with baseline (P = 0.0077). All production ratios returned to baseline level at skin closure. The production ratio of IL-6 was negative throughout the operation and that of IL-8 and IL-10 remained at baseline during visceral perfusion. In conclusion, a portion of the TNF-alpha, L-FABP, and I-FABP might be produced temporarily in the hepatosplanchnic system during TAAA repair. Systemic elevation of IL-6, IL-8, and IL-10 might be modulated by inflammatory response to extracorporeal circulation or surgical stress. Thus, our simple visceral perfusion techniques may indeed be justified. PMID- 21698517 TI - Lobectomy versus total thyroidectomy in children with post-Chernobyl thyroid cancer: a 15 year follow-up. AB - In 1994, 21 Belarus children presenting papillary thyroid cancer (PTC) diagnosed after the Chernobyl disaster, and already submitted to subtotal surgery, underwent thyroid re-operation and post-operative radioiodine (131(I)) therapy. All were re-evaluated after a 15-year follow-up, to evaluate the results of partial versus total thyroidectomy. Nineteen out of 21 children (mean age 9.2 years) had previously undergone a lobectomy. All cases underwent re-operation in 1994. Histology revealed a PTC in the residual lobe in three cases, three had lymph node metastases. After surgery, 20 patients underwent 131(I) therapy. The post-131(I) whole body scan was negative in seven cases, showed neck node metastases in five, lung metastases in three, multiple associated metastases in six. The follow-up was performed with rhTSH-stimulated serum thyroglobulin (Tg) evaluation and ultrasonography. Twenty patients showed Tg <1 ng/ml and negative ultrasonography; the patient who refused 131(I) therapy showed a thyroid remnant and a Tg of 32 ng/ml. Chi-square analysis showed significantly higher prevalences of residual cancer in the neck or lung, lymph node metastases, and re-operations (before completion) in patients who had undergone lobectomy than in those who had undergone completion thyroidectomy and 131(I) therapy. The surgical complications after lobectomy were similar to those after completion thyroidectomy. A less-than total thyroidectomy should not be indicated in patients with radiation-induced PTC, due to the high risk of residual cancer in the thyroid left in situ. The results of this study favor total thyroidectomy as the initial treatment for thyroid cancer in children exposed to fallout radiation. PMID- 21698518 TI - The distinct role of comparative risk perceptions in a breast cancer prevention program. AB - BACKGROUND: Comparative risk perceptions may rival other types of information in terms of effects on health behavior decisions. PURPOSE: We examined associations between comparative risk perceptions, affect, and behavior while controlling for absolute risk perceptions and actual risk. METHODS: Women at an increased risk of breast cancer participated in a program to learn about tamoxifen which can reduce the risk of breast cancer. They reported comparative risk perceptions of breast cancer and completed measures of anxiety, knowledge, and tamoxifen-related behavior intentions. Three months later, the women reported their behavior. RESULTS: Comparative risk perceptions were positively correlated with anxiety, knowledge, intentions, and behavior 3 months later. After controlling for participants' actual risk of breast cancer and absolute risk perceptions, comparative risk perceptions predicted anxiety and knowledge, but not intentions or behavior. CONCLUSIONS: Comparative risk perceptions can affect patient outcomes like anxiety and knowledge independently of absolute risk perceptions and actual risk information. PMID- 21698519 TI - Higher prevalence of chronic kidney disease and shorter renal survival in patients with chronic hepatitis C virus infection. AB - BACKGROUND: The role of hepatitis C virus infection (HCV) in the etiology and progression of chronic kidney disease (CKD) is controversial. AIM: To measure the prevalence of CKD and evaluate its course in patients with chronic HCV infection. METHODS: A retrospective analysis was done after excluding patients with nephrolithiasis, structural kidney disease, and those with missing clinical information on 552 anti-HCV-positive patients and 313 patients without known HCV infection matched for age, race, and gender. CKD was defined as estimated glomerular filtration rate value of <60 mL/min/1.73 m(2) and/or persistence of proteinuria (>3 months) on urine analysis by dipstick. Viral load obtained during the initial evaluation was defined as "baseline viral load". RESULTS: The prevalence of CKD in the anti-HCV-positive group was significantly higher compared to control group [53 (9.6%) vs. 16 (5.1%), P = 0.02]. On multivariate regression analysis, higher age, hypertension, HCV PCR > 7 * 10(5) cps/mL, and diabetes mellitus were significant independent positive predictors, whereas history of interferon treatment was significant independent negative predictor for CKD. Male gender, human immunodeficiency virus status, body weight, intravenous drug use, and HCV genotype were not predictors of CKD. Analysis of renal survival through Kaplan-Meyer curves revealed significantly shorter time to develop CKD (74 vs. 84 months, P < 0.001; log rank) and end-stage renal disease (79.9 vs. 86.5 months, P = 0.005; log rank) in the HCV group compared to the control group. CONCLUSION: Chronic HCV infection was associated with a significantly higher prevalence of CKD compared with controls, as well as significantly shorter renal survival. A higher baseline viral load is an independent predictor of CKD. PMID- 21698520 TI - Selenium and copper status of camels in Al-Jouf area (Saudi Arabia). AB - In order to understand the changes in copper and selenium status in camel dam and calf around the calving period, blood samples were collected in 26 she-camel before delivery and after as well as their calves after birth. The mean values for the mother and their newborn were respectively 70.3 +/- 19.8 and 58.6 +/- 13.9 MUg/100 ml for copper, 5.3 +/- 3.7 and 4.6 +/- 1.7 MUg/100 ml for selenium. No change was observed for copper, but selenium increased after parturition in 81% of the case. The selenium status of camel calf was correlated with those of its mother, but not the copper. As the whole the correlation between selenium and copper was significantly positive. The selenium status was improved in camel receiving diet enriched with barley. The maternal transfer to milk has to be investigated. PMID- 21698521 TI - Improvement of trivalent leptospira vaccine by removal of anaphylactic agents. AB - The anaphylactic reactions in cattle following leptospira vaccination mostly booster dose in different parts of Iran have been reported. The serum proteins as allergic substances are components of liquid phase of the vaccine. Therefore, the vaccine was modified by washing the whole cultures by centrifugations. The modified vaccine was safe in laboratory animals and cattle as well as under field conditions. Microagglutination test revealed a similar pattern of antibody response to the three Leptospira interrogans serovars (Canicola, Grippotyphosa, and Sejro hardjo) in all vaccinated cattle groups while was higher than the response of control animals. The results of the present investigation revealed that we can minimize postvaccination shock in vaccinated cattle populations with removing the shock proteins. PMID- 21698522 TI - Transdisciplinary training in cancer prevention: reflections on two decades of training. AB - Education in cancer prevention and control calls for training that spans disciplines to bring a broad range of skills together to develop future leaders who can speed research and delivery of effective prevention and control programs. We review the history of the Harvard Cancer Prevention Education Program as one example and summarize approaches to transdisciplinary training from the early 1990s onwards. From backgrounds in traditional public health disciplines (epidemiology, behavioral science, health policy, decision sciences, biostatistics, and environmental health) and clinical training, we encouraged common vocabulary, teamwork, and application of knowledge to the prevention of cancer with a population health perspective. While the evaluation of training programs is necessarily tied to the career trajectories of trainees, spanning decades, we present some early evidence of broad applications of training across research and delivery in government and not for profit sectors. PMID- 21698524 TI - Clinical significance of Rho GDP dissociation inhibitor 2 in colorectal carcinoma. AB - BACKGROUND: Small GTPase proteins, including RhoA, RhoB, RhoC, Rac1, and cdc42, are important molecules for linking cell shape and cell-cycle progression because of their role in both cytoskeletal arrangements and mitogenic signaling. Over expression of wild-type or constitutively active forms of RhoA has been shown to induce invasive behavior in non-invasive rat hepatoma cells in vitro. In addition, over-expression of RhoC has been found in melanoma cells with increasing metastatic activity as well as inflammatory breast cancer. These results indicate that overexpression of Rho proteins contributes to cancer cell invasion and metastasis. Rho GDP dissociation inhibitor 2 (RhoGDI2) was recently shown to act as a metastasis suppressor gene in bladder cancer. The purpose of this study was to clarify the clinical significance of this gene expression in patients with colorectal carcinoma. METHODS: Fifty pairs of normal mucosa and cancer specimens obtained at the time of surgery from patients with colorectal cancer (CRC) were subjected to reverse transcription-polymerase chain reaction for RhoGDI2. RESULTS: No patients with RhoGDI2-higher expression tumors had liver metastasis (0 in 8 cases); however, 33.3% (14 in 42 cases) of patients with RhoGDI2-lower expression tumors had liver metastasis. With regard to outcome in relation to RhoGDI2-positivity, RhoGDI2-higher expression tumors had a significant correlation with superior relapse-free survival (RFS) time as compared to RhoGDI2-lower expression tumors in stage III CRC (log-rank test, P < 0.05). Moreover, multivariate analysis indicated that RhoGDI2 was an independent prognostic factor for RFS. CONCLUSION: RhoGDI2 is a novel predictor of RFS in patients with colorectal carcinoma. PMID- 21698525 TI - The metabolic effects of prolonged starvation and refeeding in sturgeon and rainbow trout. AB - The present study examines the particular metabolic strategies of the sturgeon Acipenser naccarii in facing a period of prolonged starvation (72 days) and subsequent refeeding (60 days) compared to the trout Oncorhynchus mykiss response under similar conditions. Plasma metabolites, endogenous reserves, and the activity of intermediate enzymes in liver and white muscle were evaluated. This study shows the mobilization of tissue reserves during a starvation period in both species with an associated enzymatic response. The sturgeon displayed an early increase in hepatic glycolysis during starvation. The trout preferentially used lactate for gluconeogenesis in liver and white muscle. The sturgeon had higher lipid-degradation capacity and greater synthesis of hepatic ketone bodies than the trout, although this latter species also showed strong synthesis of ketone bodies during starvation. During refeeding, the metabolic activity present before starvation was recovered in both fish, with a reestablishment of tissue reserves, plasmatic parameters (glucemia and cholesterol), and enzymatic activities in the liver and muscle. A compensatory effect in enzymes regarding lipids, ketone bodies, and oxidative metabolism was displayed in the liver of both species. There are metabolic differences between sturgeon and trout that support the contention that the sturgeon has common characteristics with elasmobranchs and teleosts. PMID- 21698526 TI - Factors affecting plasticity in whole-organism thermal tolerance in common killifish (Fundulus heteroclitus). AB - We characterized the degree of plasticity in thermal tolerance (assessed as critical thermal maxima; CTMax) and the relationship between thermal tolerance and underlying physiological and biochemical factors in two subspecies of a teleost fish, Fundulus heteroclitus. CTMax was not affected by repeated daily heat shock, but increased within a few days in response to warm acclimation. Loss of tolerance with acclimation to lowered temperatures occurred more slowly. Exposure to hypoxia decreased CTMax, and hyperoxia had no effect. CTMax showed a daily rhythm in both subspecies. Thermal acclimation changed the value of CTMax but did not affect the amplitude of the rhythm. Exposure to altered photoperiod had complex effects with a summer photoperiod producing a daily rhythm at higher CTMax than a spring photoperiod, and a winter photoperiod removing the rhythm. There was no daily rhythm in routine metabolic rate in either subspecies. There was no relationship between CTMax and the protein levels of the constitutive 70 and 90 kDa heat shock proteins (HSC70, HSP90beta) in gill, or with mRNA levels of hsc70 in liver. There was a daily rhythm in the basal levels of the inducible hsp70-2 mRNA. Induction of hsp70-2 mRNA with mild heat shock occurred only in the evening and at night, and not during the day. These results demonstrate that there is substantial plasticity of thermal tolerance in killifish, and that this plasticity does not differ between subspecies. CTMax has a complex relationship with physiological and biochemical mechanisms that have been hypothesized to affect thermal tolerance. PMID- 21698527 TI - Culture-expanded human dermal stem cells exhibit donor to donor differences in cAMP generation. AB - Stem cell techniques have facilitated a number of potential uses for such cells in cell therapy and drug development. Studies of the cAMP/protein kinase A (PKA) pathway are widely employed to investigate the effects of a large variety of substances. We assayed the cAMP pathway in human skin-derived mesenchymal stem cells (S-MSC) to evaluate donor to donor variations in response to pharmacological manipulations in vitro. Immunophenotyping of S-MSC revealed that, in general, 95% of S-MSCs were positive for CD90, CD73 and CD105 and negative for the expression of haemopoetic markers CD14, CD45 and human leukocyte antigen-DR (HLA-DR). Nevertheless, fluctuations occurred in basal cAMP levels from 5 pmol/mg to 18 pmol/mg. Total cAMP response element binding protein (CREB) concentrations ranged from 0.8 ng/ml to 1 ng/ml, whereas the proportions of phospho-CREB versus total CREB differed between the cell lines. Basic fibroblast growth factor (FGF 2) and epidermal growth factor (EGF) stimulated cAMP generation, whereas leukaemia inhibiting factor reduced some of their effects. Forskolin (0.05 and 1 mM) acted in synergy with FGF-2 and EGF; however, it caused pronounced donor to donor differences in the increase of cAMP and phospho-CREB levels. Additionally, dibutyryl-cAMP caused significant donor to donor variations in cell proliferation, possibly indicating a change of cell differentiation status. We speculate that similar donor diversity might be observed after cell stimulation with various G(s)-protein-coupled receptor ligands. Heterogeneity of donor cell responses to stimulation of the cAMP pathway indicates the need for wide safety margins for S-MSC use in drug screening; nevertheless, knowledge of this heterogeneity might be useful for the design of donor-specific cell therapy. PMID- 21698528 TI - N-myristoyltransferase in the leukocytic development processes. AB - The lipidic modification of proteins has recently been shown to be of immense importance, although many of the roles of these modifications remain as yet unidentified. One of such key modifications occurring on several proteins is the covalent addition of a 14-carbon long saturated fatty acid, a process termed myristoylation. Myristoylation can occur during both co-translational protein synthesis and posttranslationally, confers lipophilicity to protein molecules, and controls protein functions. The protein myristoylation process is catalyzed by the enzyme N-myristoyltransferase (NMT), which exists as two isoforms: NMT1 and NMT2. NMT1 is essential for growth and development, during which rapid cellular proliferation is required, in a variety of organisms. NMT1 is also reported to be elevated in many cancerous states, which also involve rapid cellular growth, albeit in an unwanted and uncontrolled manner. The delineation of myristoylation-dependent cellular functions is still in a state of infancy, and many of the roles of the myristoylated proteins remain to be established. The development of cells of the leukocytic lineage represents a phase of rapid growth and development, and we have observed that NMT1 plays a role in this process. The current review outlines the roles of NMT1 in the growth and differentiation of the cells of leukocytic origin. The described studies clearly demonstrate the roles of NMT1 in the regulation of the developmental processes of the leukocytes cells and provide a basis for further research with the aim of unraveling the roles of protein myristoylation in both cellular and physiological context. PMID- 21698529 TI - [Advanced therapy medicinal products : Scientific, medical, economic, and ethical aspects]. PMID- 21698530 TI - [Potential of hematopoietic stem cells as the basis for generation of advanced therapy medicinal products]. AB - Individualized, (stem) cell-based therapies of congenital and acquired illnesses are among the most exciting medical challenges of the twenty-first century. Before the full potential of such therapies can be achieved, many basic scientific and biotechnological questions remain to be answered. What is the ideal source for the generation of such cellular drugs is one of those issues. In many respects, hematopoietic stem cells fulfill the requirements for stem cells as starting material for novel cellular therapeutics, including the simple access to large amounts of stem cells, the availability of good phenotypic markers for their prospective isolation, and an extensive body of knowledge about the in vitro manipulation of these cells. This manuscript discusses the general and specific usability of hematopoietic stem cells as starting material for novel cellular therapeutics and presents some examples of hematological and nonhematological therapeutic approaches which are based on hematopoietic stem cells. PMID- 21698531 TI - [Use of human progenitor cells in the treatment of cartilage damage]. AB - Articular cartilage defects have virtually no self-healing capacity. As a consequence, a surgical approach for symptomatic grade III/IV defects is required. The application of bone marrow-stimulating techniques (Pridie drilling, microfracture) is only able to reproduce mechanically inferior fibrous cartilage tissue. The minimally invasive surgical technique and low cost with acceptable results in the medium term are the main reasons for the application of these techniques. The combination of microfracture and biomaterials, i.e., the AMIC technique, has not yet proved that the disadvantages of the marrow stimulation techniques can be overcome. At present, only laboratory cultivated autologous chondrocytes are able to restore a biomechanically superior cartilage layer. By selecting the appropriate cell fraction in conjunction with the controlled release of differentiating growth factors, sufficient cartilage regeneration also appears to be achievable on the basis of bone marrow aspirate. This is the subject of experimental studies of bone marrow aspirates and autologous growth factors with encouraging initial results. PMID- 21698532 TI - [Regulatory framework of innovative therapies : From bench to bedside]. AB - Novel therapies, e.g., cell and gene therapy or tissue engineering, are summarized in the European Union as advanced therapy medicinal products (ATMPs). In terms of composition and product properties, ATMPs are highly complex, and given their multiple potential actions they are subject to continuously developing regulatory requirements. Due to promising basic research findings, there are high expectations by the society toward the therapeutic potential of ATMPs. It is of utmost importance to develop a scientifically sound preclinical and clinical development plan before entering into the first clinical trial. Due to the complex features of ATMPs, this development plan should be discussed early with the regulatory authorities to define the specifics and challenges of each individual product. For planning as well as operational realization of the initial clinical trial involving ATMPs, specific requirements that need to be addressed are discussed in this paper. PMID- 21698533 TI - The advanced therapy classification procedure. Overview of experience gained so far. AB - The classification procedure, introduced by the European Regulation on advanced therapy medicinal products (ATMPs), has received a tremendous interest from companies, academic and public sponsors developing ATMPs. This procedure gives companies the opportunity to verify whether or not the product they are developing can be considered an ATMP and can therefore benefit from the new regulatory pathway introduced in the European Union for these types of medicinal products. This procedure is optional, free of charge and may take place at any stage of the development of an ATMP in advance of applying for a marketing authorisation. In case of doubt, briefing meetings organised by the European Medicines Agency Innovation Task Force may help preparing for an ATMP classification and are a starting point for the interactions between the Agency and the developers of ATMPs. This article reviews the advantages of the classification procedure for both the developers of ATMPs and the European regulatory network. Since the introduction of this procedure and up to 10 November 2010, the Committee for Advanced Therapies (CAT) has finalised 38 applications for classification. PMID- 21698534 TI - [The certification of advanced therapy medicinal products. A quality label for product development in small and medium-sized enterprises]. AB - Advanced therapy medicinal products (ATMPs) are gene therapy, cell therapy, and tissue engineered products. To gain access to the market within the European Union, ATMPs must be authorized by the European Commission (EC). Especially for small and medium-sized enterprises (SMEs), the European centralized procedure of marketing authorization that is conducted by the European Medicines Agency (EMA) constitutes a major challenge, because SMEs often have little experience with regulatory procedures and many have limited financial possibilities. To tackle these challenges, a certification procedure exclusively for SMEs and their ATMP development was introduced by the EC. Independently from a marketing authorization application, development and/or production processes can be certified. An issued certificate demonstrates that the respective process meets the current regulatory and scientific requirements of the EMA, representing a valuable milestone for putative investors and licensees. This article highlights the background, the detailed procedure, the minimum requirements, as well as the costs of certification, while giving further noteworthy guidance for interested parties. PMID- 21698535 TI - [Report from the Committee for Advanced Therapies (CAT). Pitfalls on the way from concept to medical treatment with advanced therapy medicinal products]. AB - Advanced therapy medicinal products (ATMP) are highly innovative and complex medicines. They comprise gene therapy medicinal products, somatic cell therapy medicinal products, and tissue-engineered products (TEP). With the European Regulation on ATMP that came into force in 2008, a consolidated regulatory framework was created, where the Committee for Advanced Therapies (CAT) at the European Medicines Agency (EMA) plays a central role. This article discusses pitfalls and challenges that the CAT has experienced in its discussions of various procedures. Often ATMPs are developed by small and medium-sized enterprises (SME) which also face nonscientific challenges. The CAT wishes to meet these challenges on a scientific and regulatory level during its 2010-2015 work program. PMID- 21698536 TI - [European Marketing Authorisation: a long process. Experiences of small biotech companies with the ATMP regulation]. AB - On 30 December 2008, the Regulation (EC) 1394/2007 on advanced therapy medicinal products (ATMPs) entered into force. Herewith the first EU-wide regulatory framework for ATMPs was established. It requires a central marketing authorisation application to the EMA (European Medicinal Agency). This new framework especially changes the code of regulatory practice for tissue engineered products (TEPs), as no registration procedure had been previously required for autologous TEPs. This also meant that no clinical proof of efficacy achieved by a pivotal clinical trial was necessary. Difficulties and their background as well as the vast requirements for product development that have to be addressed by small companies within a very short time frame are presented. Hereby, it is obvious that regulatory experience which is required to identify and implement the resulting implications was not in place yet and still had to be established. The lack of regulatory experience also resulted in difficulties with scientific advice preparation, expectations toward regulatory agencies, consultants, and transformation of regulatory requirements. Addressing the regulatory requirements within the transition period is even more difficult for entrepreneurs with products which are assigned for indications resulting in complex challenges to the trial design. Due to the enormous time pressure to generate data and due to the implied financial pressure, different adaptation strategies are evolving. In Germany the "hospital exemption" according to S4b AMG (German Medicinal Products Law) is of major importance. A reorientation toward acellular products and a slow down in development of new ATMP products is expected. PMID- 21698537 TI - Participation of patients in the development of advanced therapy medicinal products. AB - An increasing number of advanced therapy medicinal products (ATMPs) are under development and in clinical trials. Patients are central to this progress. In research, patients have funded, catalysed, coordinated and led projects. In regulation, patient groups have contributed to the creation of the political momentum for regulation of ATMPs, contributed to the debate and now participate in the regulatory process. Once licensed, patients will have a role in the pharmacovigilance, health technology assessment and reimbursement arrangements for these products. Patient groups contribute valuably as equal stakeholders at every step of the development of an ATMP. PMID- 21698538 TI - [A comprehensive assessment of ATMP. Difficulties and approaches]. AB - Advanced therapy medicinal products (ATMP) are associated with high expectations because they offer new opportunities for the treatment of diseases, e.g., the possibility of regenerating damaged or lost tissue. What the products (gene therapy, somatic cell therapy, and tissue engineered products) have in common is an innovative and complex development process that combines science and engineering. At the same time, this field of research is becoming increasingly interdisciplinary and requires international cooperation. A comprehensive assessment of ATMP has to take these issues into account. The application of Beauchamp and Childress' Four Principles (Principle-Based Ethics) as well as Discourse Ethics as a framework may lead to a broader consideration of medical ethics issues. PMID- 21698539 TI - [Reimbursement of new medical therapy]. AB - Medical progress poses a new financial challenge for the German statutory health insurance. In order to assure the stability of the German statutory health insurance all services have to be economical, but on the other hand the health care system allows access to new therapy in the ambulant and in-patient sector. This article describes in detail how new therapies are reimbursed. PMID- 21698540 TI - [The Innovation Office of the Paul-Ehrlich-Institut. Regulatory support during the scientific development of ATMP]. AB - In conformity with Regulation (EC) No. 1394/2007, advanced therapy medicinal products (ATMP) are now subject to the centralized marketing authorization procedure. This also applies to most medicinal products in regenerative medicine. ATMP that have been marketed in a member state by the end of 2008 must be centrally authorized by the end of 2012 at the latest. In exceptional cases, a national authorization is acceptable. Developers of these medicinal products are usually academic institutions or small- and medium-sized enterprises (SME). They focus on scientific aspects and usually have little experience with pharmaceutical law. The Innovation Office of the Paul-Ehrlich-Institut (PEI) is designed to support developers of medicinal products in the areas between research and development, on the one hand, and regulatory requirements, on the other. Its main role is supportive advice in the regulatory field with an emphasis on ATMP. For this purpose, the Innovation Office makes use of core competences from various experts at the PEI in order to provide a quality consulting service to those companies who are seeking advice as early as possible and hand in hand with the development process. The aim is to support the developer to identify the appropriate regulatory pathway and to provide advice for each individual medicinal product at its corresponding stage of development in order to develop a high-quality ATMP manufactured on the basis of positive nonclinical results and appropriate clinical studies that meet all the necessary requirements for the application of a marketing authorization. PMID- 21698541 TI - [Timely registration of fatalities in the state of Hessen. Experiences during the influenza A/H1N1 pandemic]. AB - Timely registration of fatalities is important for the assessment of course, extent, risk of age groups, and magnitude or severity of health threats. Nevertheless, timely data of casualties are not available on the state or national level. The current paper describes the implementation and structure of a surveillance system for the timely registration of casualties in the state of Hesse (Germany) and the experience obtained during the pandemic 2009/10. The delay of the case-based registration appears tolerable and after 2 weeks more than 80% of all deaths for a given week are registered. In 2008, the forwarding of the electronically registered data from the registry offices (95% of all cases) to the state statistical office (HSL) had been accelerated from a monthly to a weekly base. The HSL provides--on a weekly basis--this case-based data in accordance with data protection rules to the Hesse State Health Office (HLPUG, "Hessischer Landesprufungs- und Untersuchungsamt im Gesundheitswesen"). During the pandemic, the data allowed assessment of the excess mortality with a delay of 2 weeks. No significant excess mortality was apparent; however, a slight increase was observed in the age groups 15-34, 35-49, and 50-59. Correlation of time with the severity of the A/H1N1v epidemic was not very strong. Hence, the data did not indicate an excess significantly exceeding the number of death cases registered with the mandatory reporting system of 21 cases for Hesse. PMID- 21698542 TI - [Integrated bulletin for the automated surveillance of notifiable communicable diseases in Schleswig-Holstein (IBISSH). A spatiotemporal early warning system]. AB - The program package "Integrated Bulletin for Infectious disease Surveillance for Schleswig-Holstein" (IBIS(SH)) was introduced in 2008 for the automated data analysis of notifiable infectious diseases in Schleswig-Holstein, Germany. The Java-based IBIS(SH) software supports access to the national SurvNet@RKI reporting data via Access and MS SQL. The aim of the IBIS(SH) system is early warning and interpretation of clusters and monitoring of trends. One module of the system permits the analysis of temporal aberration by comparison of data from previous years. The interpretation system is based on the weekly median and on percentile values from previous years. The extent of an aberration is assessed by a five-step score magnitude scale. Another module permits the detection of regional clusters by the weekly assessment of a population-based risk analysis. IBIS(SH) automatically generates tables and graphs for the weekly bulletin and their allocation in the Internet. Data for the most relevant pathogens in Schleswig-Holstein are presented for the year 2009. The performance of the automated temporal and the regional detection systems are compared to outbreak detection by local health authorities. PMID- 21698543 TI - [Health after Fukushima. A current perspective]. AB - This short paper reflects on the current situation after the Fukushima nuclear accident and the potential health consequences of the disaster. We discuss perspectives related to radiation protection activities as well as to epidemiologic monitoring and research in the affected regions in order to assess long-term effects of the accident. PMID- 21698544 TI - [Dengue fever virus (DENV). Position of the Hematologic Working Group of the Federal Ministry of Health]. PMID- 21698545 TI - Immunoediting and persistence of antigen-specific immunity in patients who have previously been vaccinated with NY-ESO-1 protein formulated in ISCOMATRIXTM. AB - BACKGROUND: NY-ESO-1 protein formulated in ISCOMATRIXTM results in CD4+, CD8+ T cell and antibody-mediated immunity. We evaluated persistence of immunity, relapse-free survival and tumour antigen expression upon relapse in patients vaccinated in an earlier trial. METHODS: Immunity was measured in 28 patients with resected NY-ESO-1-expressing tumours (melanoma 25, breast 3) 252-1,155 days (median = 681) after vaccination. In the earlier vaccination, trial patients received NY-ESO-1 with ISCOMATRIXTM adjuvant at three protein doses 10 MUg, 30 MUg or 100 MUg (n = 14); 100 MUg NY-ESO-1 protein (n = 8) or placebo (n = 6), together with 1 MUg of intradermal (ID) NY-ESO-1 protein twice for DTH skin testing. Immune responses assessed in the current study included antibody titres, circulating NY-ESO-1-specific T cells and DTH reactivity 2 days after DTH skin testing with NY-ESO-1 protein (1 MUg) or peptides (10 MUg). Relapse-free survival was determined for 42 melanoma patients. On relapse NY-ESO-1 and HLA, class I was assessed by immunohistochemistry in 17. RESULTS: Persisting anti-NY-ESO-1 immunity was detected in 10/14 recipients who had previously received vaccine with ISCOMATRIXTM adjuvant. In contrast, immunity only persisted in 3/14 who received 100 MUg un-adjuvanted NY-ESO-1 protein (3/8) or 2 MUg DTH protein (0/6) P = 0.02. Hence, persisting NY-ESO-1 immunity was associated with prior adjuvant. Tumour NY-ESO-1 or HLA class I was downregulated in participants who relapsed suggesting immunoediting had occurred. CONCLUSION: Immunoediting suggests that a signal of anti-tumour activity was observed in high-risk resected melanoma patients vaccinated with NY-ESO-1/ISCOMATRIXTM. This was associated with measurable persisting immunity in the majority of vaccinated subjects tested. A prospective randomised trial has been undertaken to confirm these results. PMID- 21698546 TI - Analysis of the surface proteins of Acidithiobacillus ferrooxidans strain SP5/1 and the new, pyrite-oxidizing Acidithiobacillus isolate HV2/2, and their possible involvement in pyrite oxidation. AB - Two strains of rod-shaped, pyrite-oxidizing acidithiobacilli, their cell envelope structure and their interaction with pyrite were investigated in this study. Cells of both strains, Acidithiobacillus ferrooxidans strain SP5/1 and the moderately thermophilic Acidithiobacillus sp. strain HV2/2, were similar in size, with slight variations in length and diameter. Two kinds of cell appendages were observed: flagella and pili. Besides a typical Gram-negative cell architecture with inner and outer membrane, enclosing a periplasm, both strains were covered by a hitherto undescribed, regularly arranged 2-D protein crystal with p2 symmetry. In A. ferrooxidans, this protein forms a stripe-like structure on the surface. A similar surface pattern with almost identical lattice vectors was also seen on the cells of strain HV2/2. For the surface layer of both bacteria, a direct contact to pyrite crystals was observed in ultrathin sections, indicating that the S-layer is involved in maintaining this contact site. Observations on an S-layer-deficient strain show, however, that cell adhesion does not strictly depend on the presence of the S-layer and that this surface protein has an influence on cell shape. Furthermore, the presented data suggest the ability of the S-layer protein to complex Fe3+ ions, suggesting a role in the physiology of the microorganisms. PMID- 21698547 TI - Transfer of 14C-photosynthate to the sporocarp of an ectomycorrhizal fungus Laccaria amethystina. AB - Sporocarps of ectomycorrhizal fungi are strong carbon sinks for the source in host trees, but the details of carbon transfer from the host to the sporocarp are unknown. In this study, single seedlings of Japanese red pine (Pinus densiflora) colonised by Laccaria amethystina were grown on floral foam plates fitted in rhizoboxes, resulting in fruiting on the substrate. The seedlings were photosynthetically labelled with (14)CO(2); (14)C-labelled photosynthate transfer from leaves to sporocarps was then chased using a time-course autoradiography technique. (14)C was transferred to healthy, fresh sporocarps in a purple colour ranging from primordial to elongate sporocarps, but hardly to senesced ones that had faded to white or grey, or browned. This suggested that C is transferred only to physiologically active sporocarps. Two seedlings associated with a growing sporocarp were labelled again 7 and 16 days after the first labelling, respectively. (14)C accumulation in the sporocarps rose in a stepwise manner after the second labelling, indicating that sporocarps mainly used recently rather than previously photosynthesised C. PMID- 21698548 TI - Sex parties among young gay, bisexual, and other men who have sex with men in New York City: attendance and behavior. AB - Very little information exists with regard to sex party behaviors in young men who have sex with men (YMSM), often defined as men ranging in age from 13 to 29 years. The current analysis examines sex party attendance and behavior in a sample of 540 emergent adult gay, bisexual, and other YMSM in New York City, ages 18-29 years. Findings indicate that 8.7% (n = 47) of the sample had attended a sex party 3 months prior to assessment. Sex party attendees reported that parties included both HIV-positive and HIV-negative men; attendees also reported unprotected sex and limited access to condoms and lubricant. As compared with those who did not attend sex parties, those who did indicated significantly more lifetime and recent (last 3 months) casual sex partners, drug use (both number of different drugs used and total lifetime use), psychosocial burden (history of partner violence and number of arrests), and total syndemic burden (a composite of unprotected anal sex, drug use and psychosocial burden). These results indicate that while only a small percentage of the overall sample attended sex parties, the intersection of both individual risk factors coupled with risk factors engendered within the sex party environment itself has the potential to be a catalyst in the proliferation of the HIV/AIDS epidemic in urban settings. Lastly, given that sex parties are different than other sex environments, commercial and public, with regard to how they are accessed, public health strategies may need to become more tailored in order to reach this potentially highly risky group. PMID- 21698549 TI - Plateauing of oxygen intake. PMID- 21698551 TI - Time to delivery after the first course of antenatal corticosteroids: a cohort study. AB - The optimal time interval between administration of antenatal corticosteroids and delivery is 1 to 7 days. This study evaluates the timing of the first course of antenatal corticosteroids in clinical practice. We performed a retrospective cohort study of consecutive women who had received antenatal corticosteroids and/or delivered between 24 and 34 weeks of gestation. Time between administration of corticosteroids and delivery was compared between women with different causes of anticipated preterm deliveries: symptomatic preterm labor with intact membranes; preterm premature rupture of the membranes; (pre)eclampsia; hemolysis, elevated liver enzymes, and low platelet count; intrauterine growth restriction; vaginal blood loss; and suspected fetal distress. We included 439 women of whom 348 (79%) completed the course of corticosteroids. In women with a complete course, 143 (41%) delivered within 7 days. The median interval between the course and delivery was 11 days and varied between 41 days in women with vaginal blood loss, 25 days in women with spontaneous preterm labor with intact membranes, and 8 days in women with preeclampsia ( P < 0.001). In women with spontaneous preterm labor with intact membranes and in women with vaginal blood loss, we can benefit substantially from a more accurate discrimination of women who need corticosteroids immediately and women who do not. PMID- 21698552 TI - Fetal gastroschisis: epidemiological characteristics and pregnancy outcomes in Mississippi. AB - We describe the epidemiological characteristics and identify maternal-fetal outcomes in pregnancies complicated by gastroschisis. We retrospectively reviewed 115 cases of gastroschisis at the University of Mississippi Medical Center. The incidence of gastroschisis trended upward between 2000 and 2008. Significant proportions of mothers were nonobese, nulliparous, teenagers, smokers, and nonconsumers of alcohol. Infants delivered at > 36 weeks or without sepsis had shorter hospital stay (HS) and interval to full enteral feeding (FEF). The rates of low birth weight (LBW), fetal growth restriction, and spontaneous preterm birth (PTB) were 63%, 45%, and 24%, respectively. Bowel atresia was noted in 9%. Rates of primary closure (25%), neonatal sepsis (29%), fetal death (2%), and infant mortality (4%) were notable. Median HS and interval to FEF were 40 and 30 days, respectively. The incidence of gastroschisis is increasing in Mississippi. Sepsis, LBW, and PTB are key determinants of poor infant outcomes. PMID- 21698553 TI - Excessive gestational weight gain in women with gestational and pregestational diabetes. AB - We sought to determine the frequency of excessive gestational weight gain (GWG) and its impact on perinatal outcomes in women with gestational (GDM) and pregestational diabetes mellitus (DM). A retrospective cohort of diabetic women was studied. GWG was categorized by the 2009 Institute of Medicine guidelines. Perinatal outcomes were compared between those women with and without excessive GWG. There were 153 women who met study criteria. There was no difference in excessive GWG between women with GDM and pregestational DM (44.4% versus 38.5%, P = 0.51) or based on White's class ( P = 0.17). After adjusting for confounders, excessive GWG was not associated with an increased rate of adverse perinatal outcomes (odds ratio 1.49, 95% confidence interval 0.56 to 2.35) and had similar associations with both pregestational DM and GDM. Although excessive GWG was common in our diabetic population, it was not associated with an increased rate of adverse perinatal outcomes. PMID- 21698554 TI - Assessing preventability for obstetric hemorrhage. AB - We sought to determine preventability for cases of obstetric hemorrhage, identify preventable factors, and compare differences between levels of hospital. We retrospectively reviewed a 1-year cohort of severe and near-miss obstetric hemorrhage in an urban perinatal network. An expert panel, using a validated preventability model, reviewed all cases. Preventability and distribution of preventability factors were compared between levels of hospital care. Sixty-three severe and near-miss obstetric hemorrhage cases were identified from 11 hospitals; 54% were deemed potentially preventable. Overall preventability was not statistically different by level of hospital, and 88% were provider related. The only treatment-related preventability factors were significantly different between levels of hospital and significantly less common in level III hospitals (p < 0.01). The majority of obstetric hemorrhage was preventable. The most common potentially preventable factor was provider treatment error, and this was significantly more common in level II hospitals. New interventions should be focused on decreasing providers' treatment errors. PMID- 21698555 TI - Incidence of intussusception in early infancy: a capture-recapture estimate for Germany. AB - BACKGROUND: Rotavirus (RV) vaccination with the first generation vaccine (Rotashield) has been associated with intussusception (IS). Reliable age specific baseline incidence data for children <=6 months of age in particular is fundamental for further post marketing monitoring of potential effects of recently introduced new RV vaccines. METHODS: IS incidence was estimated by a 2 source capture-recapture calculation (CRC) based on ESPED (German Paediatric Surveillance Unit) reports and on hospital discharge records for 2006 and 2007. ESPED as well as hospital records were validated according to the Brighton Collaboration's Group definition for definite IS. PATIENTS: Children that have been treated for IS in a hospital in one of two states of Germany (North-Rhine Westphalia and Bavaria). RESULTS: The annual IS incidence for infants <1 year in Germany calculated with the CRC estimate in Germany was 61.7/100 000 (95% CI: 54.5-70.1). However, the incidence appeared to vary by month of age over a range of 19.2/100 000 cases (95% CI: 12.5-30.4) in the first 3 months of life to 98.5/100 000 cases (95% CI: 80.9-120.6) during the 6 (th) to 8 (th) month. The male to female ratio for infants was 1.7:1 (95%CI: 1.6-1.8). CONCLUSION: The average incidence estimate for IS in infants (< 1 year) confirms previous estimates in Germany and Switzerland. However, age specific baseline incidence estimates for IS substantially vary during the first year of life. This has to be taken into account when analysing episodes of IS potentially associated with RV vaccination. PMID- 21698556 TI - Criteria for the differential indication of asthma education versus asthma instruction for families of preschoolers: results from the randomized DIAT2 study (Differential Indication of Asthma Trainings in Toddlers). AB - BACKGROUND: Asthma management of preschoolers is more improved by a family oriented psycho-educational program provided by a multi-professional team than by a short instruction alone. For some families however an instruction could be sufficient. Criteria to assign education or instruction to asthmatic schoolchildren (DIA) have been evaluated . This paper describes the use of those criteria in the Preschoolers' and parents' asthma education trial (P (2)AET) . PATIENTS: DIA at study entry were available of 233 children (aged 2-5 [mean 3.9] years) participating in the randomised controlled P (2)AET (education, instruction, waiting group). Children had been included after having at least 3 obstructive episodes in their life plus chronic or recurrent wheeze in the 6 months before the start of the study. 74 % were on inhaled corticosteroids. METHODS: Logistic regression procedures were used to assess the predictive value of DIA and possible confounders on the success of the interventions (education and instruction). RESULTS: Regarding the outcome "better in asthma management test" education is superior to instruction (OR 5.2; CI 1.7-16). DIA "quarrel about inhalation" indicates an even greater advantage of education (OR 19; CI 2 176). An equal high advantage was found, when there was NO "need for peer support" (OR 11; CI 2-64). CONCLUSION: Families with asthmatic preschoolers displaying dysfunctional interaction, which can only be corrected in an educational process, should be provided with the psycho-educational program promptly. PMID- 21698557 TI - Three different causes of hypercalciuria. AB - Hypercalciuria is defined as urinary calcium excretion >=0.1 mmol/kg/24 h, and can be a result of various disease states. The most frequent clinical signs of hypercalciuria include hematuria, abdominal pain, urolithiasis, nephrocalcinosis, dysuria, enuresis, and urinary tract infection. 3 case reports of children with hypercalciuria of different origin are presented, with final diagnoses of (1)idiopathic hypercalciuria, (2)familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and (3)metabolic bone disease of prematurity, respectively. Assessment of hypercalciuria is essential in all children with urolithiasis and nephrocalcinosis, or demineralization of bone. It should be also a part of differential diagnostic procedure in hematuria, recurrent abdominal pain, urinary tract infection and enuresis in childhood. PMID- 21698558 TI - [Autism spectrum disorders - an overview of the current research status]. PMID- 21698559 TI - [Lack of blood pressure rise and blood pressure fall during ergometry]. PMID- 21698560 TI - [Severe pancytopenia and stomatitis in a patient treated with low-dose methostraxate]. AB - A 68-year-old female patient presented at the emergency room with episodes of epistaxis, dysphagia and malaise. The patient had acute prerenal renal failure, probably in association with previous infection of the airways and treatment with NSAID's. Laboratory values revealed greatly decreased leukocyte and platelet counts as well as anemia. The patient had a diagnosis of a seronegative arthritis since 9 months and, therefore, was treated with low dose methotrexate (MTX) 10 mg/week. After exclusion of other causes, myelosupression was considered to be associated with low-dose MTX. After stopping MTX and treatment with folic acid leucocyte and platelet counts returned to normal and stomatitis recovered as well within nine days. We discuss the pharmacology of low-dose MTX and in particular the risk factors and prophylaxis of its toxicity. Renal function needs special attention in patients treated with low-dose MTX. PMID- 21698562 TI - [Can family practice become transparent?]. PMID- 21698563 TI - [Vocational training of future GPs in Swiss hospitals: the view of chief physicians]. AB - BACKGROUND: We sought to assess the way future general practitioners are promoted by their chief physicians. METHODS: Semi quantitative questionnaires sent to 54 chief physicians (hospitals in cantons Zurich and Berne). RESULTS: 42 (77.8%) questionnaires were returned. 41 (97.6%) chief physicians asked the assistant physicians about their intended career. 23 (54.8%) discussed with future general practitioners (GPs) specific learning objectives. 32 (76.2%) chief physicians would have appreciated an official catalogue of learning objectives for future GPs. A GP-specific traineeship was lacking in most of the hospitals. CONCLUSIONS: The upcoming shortage of future GPs could be inhibited by an appropriate GP curriculum during the vocational training. PMID- 21698564 TI - [Periprosthetic joint infections - a review for general practitioners]. AB - The number of prosthetic joint implantation is continuously increasing. Periprosthetic joint infection is a rare but serious complication. The correct diagnosis is essential for successful treatment. It requires the close collaboration between general practitioners, orthopaedic surgeons and infectious disease specialists. A delayed diagnosis sets hurdles to the medical and surgical treatment. Also, antimicrobial treatment without proper microbiological sampling must be avoided. Swabs from wounds are not helpful, because the results represent the skin flora, but not the causative pathogen of infection. The general practitioner is the first physician that patients contact and has, therefore, a central role in diagnosing and managing periprosthetic joint infections. In this review, classification, diagnostic means and treatment concepts of periprosthetic joint infections are presented. PMID- 21698565 TI - [Macromastia (large breasts): references for breast reduction]. PMID- 21698566 TI - [Ethanol, sugar, acid and coma]. AB - We report on a 46-year-old female patient with chronic alcoholism, who presented with a severe metabolic acidosis and an increased anion gap despite repeated vomiting. In face of a dramatically increased serum-beta-hydroxybutyrate and after ruling out more common causes of acidosis, we were able to diagnose an alcoholic ketoacidosis. The epidemiology, pathophysiology, clinics and treatment of this often forgotten and misunderstood disorder of acid-base balance are discussed. PMID- 21698567 TI - [Beware of unconspicious cerebro spinal fluid]. AB - Nowadays with a lot of diagnostic facilities it is also difficult to find the right diagnose of herpes encephalitis. The aim of this case report was to give an overview about strategies of diagnostic and therapy of the herpes encephalitis. PMID- 21698568 TI - [Not Available]. PMID- 21698569 TI - [Not Available]. PMID- 21698573 TI - Hip resurfacing and metal-on-metal total hip arthroplasty. PMID- 21698574 TI - Hip resurfacing and pseudotumour. AB - Metal on metal hip resurfacing has been used widely over the last ten years but there has been recent concern about destructive soft tissue reactions, which have been called pseudotumours by some authors. This has generated considerable controversy. This review explains why pseudotumours occur after resurfacing and how they can be prevented. It also supports the continued use of resurfacing in appropriate patients by appropriately trained surgeons. PMID- 21698575 TI - Repair of gluteus medius muscle avulsion following transgluteal hip replacement. AB - During a transgluteal approach to the hip joint the anterior part of the gluteus medius and minimus muscles are detached and subsequently reattached to the greater trochanter. Avulsion or rupture of these muscles may result in weak abduction, pain and/or instability. 15 patients with these symptoms were treated, of whom 13 had muscle avulsion at surgery. Reinsertion of these muscles resulted in improvement of pain in 6 (55%) patients and improvement of walking ability in 9 (82%) patients. Reinsertion of avulsed gluteal muscles after transgluteal approaches to the hip may relieve pain and improve walking ability. PMID- 21698576 TI - Gluteal tendon reconstruction in association with hip arthroplasty. AB - We studied a prospective cohort of patients in whom gluteal tendon reconstruction was undertaken in association with hip arthroplasty. Over the course of 10 years, 24 patients had gluteal tendon reconstruction performed either at the time of hip arthroplasty or post-operatively, using the Ligament Augment and Reconstruction System (LARS), suture anchors, direct suture to bone, or a combination of these techniques. All patients were assessed clinically and by patient-centred outcome measures, including the hip disability and osteoarthritis score (HOOS). The mean post-operative HOOS was significantly better than pre-operative score (p < 0.05). The mean post operative score in the domains of symptoms, pain, activities of daily living (ADL), sports and quality of life (QoL) was 72 (SD 12.8), 73 (SD 15.9), 71 (SD 11.8), 54 (SD 22.6) and 57 (SD 21.76) respectively. There were two failures of gluteal tendon reconstruction which required revision using LARS. One patient died of an unrelated cause. Surgical intervention should be considered in gluteal tendinopathy at the time of hip arthroplasty or when symptoms occur following arthroplasty. PMID- 21698577 TI - Results following repair of gluteus medius defects following total hip arthroplasty. AB - 13 patients with tears in the gluteus medius tendon following total hip arthroplasty were studied. The diagnosis of a gluteal tear was made on the basis of clinical signs and a positive arthrogram of the hip in all cases. 11 patients underwent gluteus medius repair and two patients declined surgery. 10 patients attended a review clinic (eight gluteal repair patients and two conservatively managed patients) and three were reviewed by telephone and medical notes. The mean follow up was 61 months (range 12-116 months). The mean age at follow up was 71.42 years (69-79 years) and the male to female ratio was 5:8. The mean duration of symptoms prior to repair was 16 months. An anterolateral transgluteal approach had been used for primary surgery in nine cases and in four cases the original surgical approach was unknown. The mean Harris Hip score prior to repair was 77.4 (range 55-87), which improved to a mean post operative Harris hip score of 86.97 (range 79-96) following repair. The Oxford hip score prior to repair was 20 (range 16-25) which improved to a mean of 14.2 after repair (range 4-29). 9 out of 11 patients who had the repair were satisfied and would recommend the procedure. We believe an accurate and timely diagnosis together with repair can reduce the morbidity associated with this post-operative complication following THA. PMID- 21698578 TI - The short rotators do not influence capsular compliance or pain in severe hip osteoarthritis. A randomised controlled trial. AB - A randomised controlled trial was performed to investigate if the short rotators affected the compliance of the capsule in osteoarthritis (OA). 68 OA patients admitted for total hip arthroplasty (THA) were randomised to have their compliance estimated during surgery with either their short rotators intact or released. Radiographic severity of OA, range of motion and pain were assessed in the affected hip before surgery. There was no significant difference in the compliance of the capsule whether the short rotators were intact or released (p= 0.5). Furthermore, there was no significant correlation between pain and capsular compliance (p=0.4 and p=0.5). We found no significant effect of the short rotators on compliance of the hip joint capsule, and no significant correlation between pain and capsular compliance. PMID- 21698579 TI - Periacetabular osteotomy: validation of intraoperative fluoroscopic monitoring of acetabular orientation. AB - During periacetabular osteotomy (PAO) the acetabulum is reorientated and the correction monitored by one or more anteroposterior pelvic radiographs. Obtaining these images is time consuming and requires additional technical and personal resources. Such disadvantages could be overcome with the use of fluoroscopy. However, information obtained from fluoroscopy should have the same quality when compared to standard pelvic radiography. Our purpose was to define a suitable fluoroscopy setup and compare the information obtained from the fluoroscopic images to that obtained from a traditional anteroposterior pelvic radiograph. In a consecutive series of 22 patients the acetabular fragment was monitored by a defined intraoperative fluoroscopy setup in addition to a pelvic radiograph. The images were analyzed in random order utilizing common parameters to judge the quality of acetabular orientation. Agreement between the two images was assessed using kappa statistics and compared to the intra-observer reliability obtained from an independent experienced hip surgeon reading the same set of pelvic radiographs on two occasions. In 5 patients the radiation exposure during both fluoroscopy and standard AP pelvic radiography was measured and compared. Agreement of angular measurements of acetabular coverage and version as well as qualitative parameters of acetabular orientation and position between fluoroscopy and pelvic radiographs was at least equal to the intra-observer agreement of an independent experienced hip surgeon reviewing the pelvic radiographs alone. Significantly less radiation exposure was recorded with the use of fluoroscopy when compared to traditional pelvic radiography. We conclude that the use of intraoperative pelvic radiographs during PAO procedures can be replaced by fluoroscopy without quality impairment. PMID- 21698580 TI - A radiological study of the true anatomical position of the acetabulum in Japanese women. AB - There is sometimes uncertainty concerning the correct socket position prior to total hip arthroplasty (THA). We conducted a study to determine the hip centre in Japanese women in order to define the true anatomical position of the acetabulum. The study involved 200 consecutive female patients in whom the contralateral hip joint was normal or was prearthritic and who underwent unilateral THA. The 'normal' group comprised 100 hip joints with no acetabular hip dysplasia, and the prearthritis group comprised 100 hip joints with Crowe type I dysplasia. The length of a perpendicular line drawn under the teardrop (interteardrop line) connecting both inferior edges of the teardrop with the centre of the femoral head was recorded as the vertical distance, and the distance from the intersection of the perpendicular line and interteardrop line up to the teardrop was recorded as the horizontal distance. We measured these distances on the femoral head of the side that did not undergo THA. The mean vertical distances in the 'normal' and prearthritis groups were 14.6 +/- 2.8 mm and 16.8 +/- 2.7 mm, respectively, and the mean horizontal distances were 30.2 +/- 2.8 mm and 32.5 +/- 2.7 mm, respectively. We therefore determined the mean centre of the hips to lie at a vertical distance of 11 to 22 mm and a horizontal distance of 27 to 38 mm. These values can serve as a useful index for socket positioning in THA. PMID- 21698581 TI - Changes of periprosthetic bone density after implantation of an anatomical femoral stem with cemented and cementless fixation. AB - This prospective 12 months dual energy x-ray absorptiometry study evaluated differences in periprosthetic bone mineral density (BMD) in 25 patients undergoing cementless and in 18 patients undergoing cemented unilateral total hip arthroplasty (THA) using the Optan stem, which has the same geometric design for both fixation options. The clinical outcome scores after one year were excellent in both groups. Periprosthetic BMD measurement demonstrated bone loss medially and laterally in the proximal femoral regions following cementless fixation, whereas cemented fixation resulted in predominantly lateral bone resorption. The fixation technique appeared to have a major influence on the femoral BMD changes after THA. PMID- 21698582 TI - Subsidence of the Corail femoral component in the elderly. A retrospective radiological review. AB - 206 patients age 70 years or older who underwent uncemented total hip arthroplasty (THA) using the Corail stem were studied. Radiographs taken post operatively and at one year were measured for subsidence of the stem. 13 patients had subsidence of the femoral stem of more than 2 mm. 5 of these were associated with fractures (mean age 78.06 years--average subsidence 14.52 mm), while 8 did not have associated fractures (mean age 77.43 years--average subsidence 4.99 mm). These 13 patients were then followed up for an average of 25 months (with fractures) and 26.88 months (without fractures). Radiographs were taken and measured for further subsidence using a VIDAR scanner. There was no evidence of further subsidence in any of the 13 patients, and all the stems had stabilised at one year with good evidence of osteointegration. None of the patients required revision. Uncemented THA using the Corail stem can be employed in this age group and poor bone quality is not a contraindication. PMID- 21698583 TI - Hammering force during cementless total hip arthroplasty and risk of microfracture. AB - During cementless stem fixation, impaction of the stem is occasionally complicated by bony injuries. Small fractures not visible to the eye during surgery or on post-operative radiographs may remain undetected, and the incidence of such injuries may be underestimated. Employing the same techniques as those employed during total hip arthroplasty, we implanted cementless stems into artificial femora, with equivalent mechanical characteristics to living femora. The hammering force applied to the femur and the displacement of the stem and femur were measured using a load sensor and imaging, respectively. The von Mises stress generated in the femur during cementless stem press-fixation was also measured using finite element analysis. Average hammering force under these conditions (9.25 kN) was sufficient to cause damage to the artificial femur. The first two of eight hammer strikes caused most displacement of the stem. The von Mises stresses generated by the first and second hammer strikes were 31 and 68 MPa, respectively. Applying a high average hammering force to the stem after displacement has ceased probably contributes to the generation of intraoperative fractures during cementless stem fixation. Given that two strikes appeared to be sufficient, we believe that hammering force should be reduced to a micro adjustment level after the second hit. PMID- 21698584 TI - Bilateral simultaneous total hip arthroplasty in a fast track setting. AB - Simultaneous bilateral hip arthroplasty has been reported to have varying results in the literature when performed using conventional postoperative care. Unilateral hip and knee arthroplasty as well as bilateral simultaneous knee arthroplasty may be associated with reduced length of stay and low complication rates when performed in a fast-track setting. We believed it would be useful to assess hip arthroplasty in this context, and we report 50 consecutive fast-track simultaneous bilateral hip arthroplasty procedures. The median length of stay was 4 days. Mortality within 90 days was 4% and 8% required a further operative procedure. The overall complication rate was 22%. 55% of the complications were considered to be caused by failures in surgical technique and 45% by other factors. Bilateral simultaneous hip arthroplasty may have a high complication rate in a fast-track setting and further evaluation may be warranted. PMID- 21698585 TI - Effect of body weight on the outcome of displaced intracapsular fracture neck of femur treated by internal fixation; a clinical study of 198 patients. AB - The aim of this study was to assess any possible correlation between body weight and fracture union following displaced intracapsular fractures of the neck of femur treated by a closed reduction and internal fixation. A total of 198 patients with such injuries treated by closed reduction and internal fixation, were recruited retrospectively. Patients were followed up until fracture endpoint (union or non-union) with a minimum follow up of 100 days. The mean body weight for the 118 patients without fracture healing complications was 64.6 kg versus 61.8 kg for the 80 patients with complications, a difference that was not statistically significant (p=0.17). Analysis of data related to sex and age also found no relationship between weight and fracture healing complications. Our results indicate there is no relationship between body weight and fracture healing complications following displaced intracapsular fractures treated by internal fixation. PMID- 21698586 TI - Total hip arthroplasty for acute displaced femoral neck fractures via the posterior approach: a protocol to minimise hip dislocation risk. AB - Total hip arthroplasty (THA) is considered superior to hip hemiarthroplasty (HHA) in long term pain relief and functional outcome after femoral neck fracture; high early dislocation rates may however negate these advantages. This study elucidates whether a protocol of careful patient selection, surgical technique algorithm and use of modern implants could yield low dislocation rates in hip fracture patients treated with THA via the posterior approach. Over a seven year period all patients admitted to our institution that were cognitively lucid, independent ambulators and without Parkinson's disease underwent THA for acute displaced femoral neck fractures using a posterior approach, large femoral heads, elevated acetabular liners and a surgical technique algorithm. Twenty-nine THAs were performed in 26 patients (mean age of 71 years, range 50-87 years) and were followed for a mean of 32 months (range 13-48 months). There was one dislocation 7 weeks postoperatively in a non-compliant patient resulting in reoperation. There were no other reoperations or major complications. Our results indicate that low dislocation rates can be accomplished for displaced femoral neck fractures treated with THA via the posterior approach using a protocol that includes careful patient selection, surgical technique focused on intraoperative stability, and the use of modern implants. PMID- 21698587 TI - Prevalence of Parkinsonism in older patients with hip fracture. AB - Parkinsonism in hip fracture (HF) patients is a potential source for complications during surgery, postoperative period and rehabilitation and a risk factor of second HF. We investigated whether parkinsonism was more prevalent in older subjects with HF than in other older patient groups undergoing surgery. We prospectively assessed patients who had suffered HF and controls. We assigned all patients aged 68 and older admitted in our hospital for HF surgery during last year and compared them with age- and gender matched patients attending other surgical departments. 80 HF patients and 80 controls were assessed for parkinsonism. Parkinsonism was common in both groups, presumably reflecting the mean ages of approximately 80 years, plus hospitalization-status. However, parkinsonism was much higher in the hip fracture group (76.25%) compared to the control hospitalised subjects (37.5%; p<0.001). The majority of HF patients with parkinsonism were undiagnosed for their parkinsonism symptoms prior to HF and the same was observed in the control group (91.8% and 86.7% respectively, p= 0.471). Among those with parkinsonism, pre-hospitalization drug therapy may have been contributory in 24.5% of HF patients and 30% of controls (p=0.589). Parkinsonism is very common in older patients admitted for surgery to a general hospital and extremely common in those with HF. It seems that parkinsonism, is heavily under recognised in the elderly. Our data seem to confirm that parkinsonism is a major risk factor of HF in the elderly. PMID- 21698588 TI - The Birmingham mid-head resection arthroplasty--minimum two year clinical and radiological follow-up: an independent single surgeon series. AB - We report the results of the Birmingham Mid-Head Resection Arthroplasty (BMHR) for patients with poor femoral head bone quality where standard hip resurfacing is contraindicated. This is a clinical and radiological follow-up of the first 35 consecutive procedures (34 patients, 16 male, 18 female) performed by an independent surgeon. The mean follow-up was 2.8 years (2.1 to 4.1) and no patients were lost to follow-up. The mean age at the time of surgery was 50.4 years (23.8 to 69.4). There were no failures. The mean HHS improved from 46.6 (25 to 70) pre-operatively to 96.1 (72 to 100) post-operatively. The mean OHS was 36.4 (19 to 53) pre-operatively and 14.2 (12 to 34) post-operatively. The mean WOMAC score was 45.6 (7 to 92) pre-operatively and 4.3 (0 to 28) post operatively. The mean UCLA activity score was 4.5 (1 to 9) pre-operatively and 7.6 (5 to 10) post-operatively. Radiographic analysis did not show any adverse features such as stress shielding, loosening or femoral neck narrowing. The BMHR provides an excellent alternative to conventional total hip arthroplasty in patients with poor femoral head bone quality who are not suitable for standard resurfacing. PMID- 21698589 TI - SUSHI: the Super Simple Hip score for younger patients. AB - We describe the development of a simple patient-based score for young patients with hip problems which concentrates on activities that are difficult for someone with a hip problem and includes an activity rating scale that measures the highest level of physical activity reached during the past year. We compared the super simple hip score (SUSHI) with the more extensive hip osteoarthritis outcome score (HOOS) and evaluated the validity, sensitivity to change and floor and ceiling effects of the SUSHI score. We found that the SUSHI score is an adequate score to measure hip problems and that this score was preferred to the HOOS score by patients. PMID- 21698590 TI - The ligamentum capitis femoris: anatomic, magnetic resonance and computed tomography study. AB - The objective of the study was to describe the normal anatomy of the ligamentum capitis femoris and to determine the neurovascular structures potentially at risk during its reconstruction. Ten cadaveric specimens of the ligamentum capitis femoris (LCF) were dissected and photographed. Magnetic resonance (MR) and Computed tomography (CT) arthrography evaluation of the anatomy of the LCF in 30 hips were performed to measure length of the ligament and to study the proximity of neurovascular structures. The anatomical study showed that the LCF has a pyramidal structure and a banded appearance. The thickness of the medial wall of the acetabulum 3 mm superior to the inferior acetabular boundary was found to be 6.7 mm (4-9 mm) at point 1 (anterior), 4.1 mm (3-7 mm) at point 2 (central), and 6.5 mm (4-9 mm) at point 3 (posterior). Central anchors or screws were found to lie within 1.7 cm (1.6-1.9 cm) of the external iliac vein and artery. Angulation of anchors in the anterior and posterior columns in the axial plane with respect to acetabular fossa floor (the Optimal Angulation Angle or OAA), is safer (0 to 45o the safest optimal angles). The sagittal angulation created by the safe pathway in the anterior and posterior columns with respect to the plane of the facies lunata in this area was also measured and termed the Optimal Angle of Penetration (OAP) with normal values being: 110o (102-123o) for the posterior column and 90o (85-94o) for the anterior column. Our results suggest that reconstruction of the LCF can be safely performed if these guidelines are followed. PMID- 21698591 TI - Analgesic control after hip arthroscopy: a randomised, double-blinded trial comparing portal with intra-articular infiltration of bupivacaine. AB - The optimum anaesthetic and analgesic management following hip arthroscopy is yet to be determined. There is, in addition, some concern over the use of intraarticular local anaesthetic. We compared the analgesic efficacy of intra articular infiltration compared with portal infiltration of bupivacaine following hip arthroscopy. Patients were randomised to receive either 10 ml of 0.25% bupivacaine either into the joint or around the portal sites following completion of surgery. 73 patients were recruited (40 intra-articular). The portal infiltration group required significantly more rescue analgesia immediately after surgery (2.33 mg vs.0.57 mg, p=0.036). Visual Analogue Scale pain scores were not significantly different at 1 and 2 hours following surgery, but at 6 hours the portal group had significantly lower VAS scores (p=0.0036). We believe that the initial pain following surgery results from capsular injury and this explains the need for more rescue analgesia in the portal infiltration group. Further work is needed to establish the ideal regimen. A combination of portal and intra articular infiltration may be the most efficacious. PMID- 21698592 TI - Chylous hip joint effusion and bone absorption after total hip arthroplasty in a patient with chylocolporrhoea: a case of Gorham's disease. AB - Chyle is a sterile, milky fluid consisting of lymph and emulsified fats that is formed in the small intestines and taken up by lymph vessels. Chylous effusions usually occur after destruction or obstruction of lymphatic channels, and chylous joint effusions have been reported in association with rheumatoid and/or septic arthritis, and as the result of penetrating trauma to subsynovial fatty tissue and the intra-articular fat pad. We report a case of bone absorption and lytic change in the femur associated with a chylous hip joint effusion after a total hip arthroplasty (THA) in a patient with chylocolporrhoea and a history of chylous ascites. PMID- 21698593 TI - Coxa recta (cam-type) proximal femoral morphology: what causes it. PMID- 21698594 TI - Application of a water jet system to the pretreatment of cellulose. AB - Plant cellulose is the most abundant organic compound on earth. Technologies for producing cellulose fiber or improving the enzymatic saccharification of cellulose hold the key to biomass applications. A technology for atomizing biomass without strong acid catalysis remains to be developed. The water jet is a well-known device used in machines (e.g., washing machines, cutters, and mills) that use high-pressure water. In this study, we examined whether a water jet system could be used to atomize crystalline cellulose, which comprises approximately 50% of plant biomass. The Star Burst System manufactured by Sugino Machine Limited (Sugino Machine; Toyama, Japan) is a unique atomization machine that uses a water jet to atomize materials and thereby places lower stress on the environment. After treatment with this system, the crystalline cellulose was converted into a gel-like form. High-angular annular dark-field scanning transmission electron microscopy showed that the cellulose fibers had been converted from a solid crystalline into a matrix of cellulose nanofibers. In addition, our results show that this system can improve the saccharification efficiency of cellulases by more than three-fold. Hence, the Star Burst System provides a new and mild pretreatment system for processing biomass materials. PMID- 21698595 TI - Diverse role of conformational dynamics in carboxypeptidase A-driven peptide and ester hydrolyses: disclosing the "perfect induced fit" and "protein local unfolding" pathways by altering protein stability. AB - Catalytic mechanisms of carboxypeptidase A (CPA) are well known for their diversity and the relative inaccessibility for a decisive comprehension. Recent encouraging attempts through modern computational techniques promoted new challenges for the complementary experimental endeavors. In this work, we have applied the stopped-flow technique and the method of reaction progress curve fitting to extract kinetic parameters for the CPA-catalyzed hydrolyses of smaller (typical) peptide and ester substrates, known for their strong activating/inhibiting impact, thus to which the traditional method of "initial rates" is not applicable. Our approach that innately implies the overall constancy of the affecter (substrate plus "active" product) concentration, made it possible to rigorously determine the physically meaningful "effective" values for the catalytic and Michaelis constants under diverse experimental conditions including variable temperature and urea or trimethylamine N-oxide concentrations. Analysis of the obtained results allowed for: (i) the further substantiation of diverse mechanistic patterns for archetypal specific peptide and ester substrates, (ii) testing and disclosure of intrinsic links between the stabilizing/destabilizing and activating/inhibiting effects for the important model enzyme, CPA, and (iii) tentative explanation of a distinct activating/inhibiting impact of these substrates through the strong specific interaction of their benzyl (Bz) moiety with the substrate binding S(3) subsite of CPA. We have demonstrated that stabilization of CPA either through the interaction with an extra Bz moiety (belonging to another substrate or to the product) leads to the increase of its catalytic power with respect to the specific peptide substrate and to its decrease with respect to the counterpart ester substrate. We conjecture that the catalytic mechanisms operating in these two cases include: (a) the "promoted water" mechanism for the peptide substrate that, seemingly, provides the almost "perfect induced fit" (low-barrier conformational adaptation), and (b) presumably, the "anhydride intermediate" mechanism for the ester substrate that, anyway, requires substantial conformational rearrangement (in fact, "partial or local unfolding") of the protein environment in the course of the rate-determining step. PMID- 21698596 TI - Mutually reinforced multicomponent polysaccharide networks. AB - Networks made from chitosan and alginate have been utilized as prospective tissue engineering scaffolds due to material biocompatibility and degradability. Calcium (Ca(2+) ) is often added to these networks as a modifier for mechanical strength enhancement. In this work, we examined changes in the bulk material properties of different concentrations of chitosan/alginate mixtures (2, 3, or 5% w/w) upon adding another modifier, chondroitin. We further examined how material properties depend on the order the modifiers, Ca(2+) and chondroitin, were added. It was found that the addition of chondroitin significantly increased the mechanical strength of chitosan/alginate networks. Highest elastic moduli were obtained from samples made with mass fractions of 5% chitosan and alginate, modified by chondroitin first and then Ca(2+) . The elastic moduli in dry and hydrated states were (4.41 +/- 0.52) MPa and (0.11 +/- 0.01) MPa, respectively. Network porosity and density were slightly dependent on total polysaccharide concentration. Average pore size was slightly larger in samples modified by Ca(2+) first and then chondroitin and in samples made with 3% starting mass fractions. Here, small angle neutron scattering (SANS) was utilized to examine mesh size of the fibrous networks, mass-fractal parameters and average dimensions of the fiber cross sections prior to freeze-drying. These studies revealed that addition of Ca(2+) and chondroitin modifiers increased fiber compactness and thickness, respectively. Together these findings are consistent with improved network mechanical properties of the freeze-dried materials. PMID- 21698599 TI - Dimorphism of the prodrug L-tyrosine ethyl ester: pressure-temperature state diagram and crystal structure of phase II. AB - Polymorphism is important in the field of solid-state behavior of drug molecules because of the continuous drive for complete control over drug properties. By comparing different structures of a series of L-tyrosine alkyl esters, it became apparent that the ethyl ester possesses dimorphism. Its structure was determined by powder diffraction and verified by density functional theory calculations; it is orthorhombic, P2(1) 2(1) 2(1) with a = 12.8679(8) A, b = 14.7345(7) A, c = 5.8333 (4) A, V = 1106.01(11) A, and Z = 4. The density of phase II is in line with other tyrosine alkyl esters and its conformation is similar to that of l tyrosine methyl ester. The hydrogen bonds exhibit similar geometries for phase I and phase II, but the H-bonds in phase I are stronger. The solid II-solid I transition temperature is heating-rate dependent; it levels off at heating rates below 0.5 K min(-1), leading to a transition temperature of 306 +/- 4 K. Application of the Clapeyron equation in combination with calorimetric and X-ray data has led to a topological diagram providing the relative stabilities of the two solid phases as a function of pressure and temperature; phase II is stable under ambient conditions. PMID- 21698601 TI - Characterization of subvisible particle formation during the filling pump operation of a monoclonal antibody solution. AB - Characterization and control of aggregate and subvisible particle formation during fill-finish process steps are important for biopharmaceutical products. The filling step is of key importance as there is no further filtration of the drug product beyond sterile filtration. Filling processes can impact product quality by introducing physical stresses such as shear, friction, and cavitation. Other detrimental factors include temperature generated in the process of filling, foaming, and contact with filling system materials, including processing aids such as silicone oil. Certain pumps may shed extrinsic particles that may lead to heterogeneous nucleation-induced aggregation. In this work, microflow imaging, size-exclusion chromatography (SEC), and turbidimetry were utilized to quantify subvisible particles, aggregation, and opalescence, respectively. The filling process was performed using several commonly used filling systems, including rotary piston pump, rolling diaphragm pump, peristaltic pump, and time pressure filler. The rolling diaphragm pump, peristaltic pump, and time-pressure filler generated notably less protein subvisible particles than the rotary piston pump, although no change in aggregate content by SEC was observed by any pump. An extreme increase in subvisible particles was also reflected in an increase in turbidity. PMID- 21698600 TI - Effect of hyperlipidemia on ketoconazole-midazolam drug-drug interaction in rat. AB - Hyperlipidemia (HL) was previously shown to lower liver uptake of the more potent (-) enantiomer of ketoconazole (KTZ) in rat. The current study examined the possible modifying influence of experimental HL on a KTZ pharmacokinetic interaction with midazolam (MDZ). Normolipidemic and hyperlipidemic rats were administered a single intravenous dose of MDZ (5 mg/kg) with or without a single oral dose of racemic KTZ (40 mg/kg). Serial blood samples were collected over 8 h following MDZ injections via jugular vein cannulas. Plasma was jointly assayed for MDZ and KTZ concentrations using a validated assay. MDZ mean clearance (CL) was unchanged by KTZ coadministration. HL caused a significantly 61% lower MDZ unbound fraction and decreases in volume of distribution (VD) but by itself had no effect on MDZ CL. This suggested that MDZ could bind to lipoproteins. With KTZ coadministered to hyperlipidemic rats, there were significant decreases in MDZ CL and VD. HL caused a decrease in unbound plasma fraction of oral KTZ but no significant difference in its pharmacokinetics. HL caused a more pronounced KTZ associated inhibition of MDZ CL. This may be related to the decrease of MDZ's unbound fraction and perhaps to attenuation of CYP3A by HL in the rat. PMID- 21698602 TI - Profoundly improving flow properties of a cohesive cellulose powder by surface coating with nano-silica through comilling. AB - Poor flow properties hinder the easy handling of powders during industrial-scale processing. In this work, we show that powder flow can be substantially improved by reducing the cohesion of powders by coating them with nanosized guest particles. We further show that comilling is an efficient process for nanocoating. We have systematically investigated the effects of total number of comilling cycles (10-70 cycles) and silica loading (0-1.0 wt %) on the flow behavior of a highly cohesive and poorly flowing grade of microcrystalline cellulose powder (Avicel PH105). Optimum flow enhancement has been achieved with 1.0 wt % silica loading at 40 comilling cycles. The flow properties of nanocoated Avicel PH105 are comparable to those of Avicel PH102, which exhibits adequate flowability for processing on a high-speed tablet press. Comilling is fast and suitable for continuous processing. It shows potential for addressing industrial powder handling problems caused by poor powder flow properties. PMID- 21698598 TI - Influence of drug transport proteins on the pharmacokinetics and drug interactions of HIV protease inhibitors. AB - Protease inhibitors, a class of antiretroviral agents frequently used in the treatment of HIV infection, interact with numerous transport proteins resulting in clinically significant drug-drug interactions (DDIs). This review focuses on the proteins that transport protease inhibitors and directly influence the pharmacokinetics of these drugs, as well as the transport proteins that are inhibited or induced by protease inhibitors. Clinically relevant DDIs involving drug transporters and protease inhibitors, either as "victim" drugs or as "perpetrator" drugs, and the pharmacokinetic consequences of such interactions are highlighted. A summary of transporter-mediated processes underlying the toxicity of protease inhibitors is provided. Finally, the effect of HIV infection or co-infection on drug transport proteins, and the implications for protease inhibitor pharmacokinetics is discussed. Transport proteins significantly influence the pharmacokinetics, efficacy and toxicity profiles of this important class of drugs. PMID- 21698603 TI - Synthesis and characterization of surface-modified PBLG nanoparticles for bone targeting: in vitro and in vivo evaluations. AB - In this study, poly(gamma-benzyl-l-glutamate) (PBLG) polypeptide derivatives were synthesized by ring-opening polymerization of amino acid N-carboxyanhydride using selected amine-terminated initiators. Alendronate, a targeting moiety that has a strong affinity for bone, was conjugated to PBLG. Monomethoxy polyethylene glycol (PEG) was used for a hydrophilic layer on the surface of the nanoparticles (NPs) to avoid reticuloendothelial system uptake. NPs were prepared by nanoprecipitation technique not only for PBLG or PBLG-PEG but also for composite polymers with different ratios. Fluorescein isothiocyanate would be attached to the NPs as a labeling agent. The size and morphology of NPs were evaluated by dynamic laser light scattering and transmission electron microscopy, and were found to be in a useful range (less than 80 nm) for bone-targeted drug delivery. In addition, the PEGylation of NPs was supported by isothermal titration calorimetry analysis. The bone-targeting potential of NPs was evaluated in vitro by calcium binding and hydroxyapatite affinity assays, and in vivo by fluorescent imaging experiments on rats. The targeted NPs showed bright fluorescent labeling in femur tissue. These results demonstrated the possibility of optimized NPs prepared with new PBLG derivatives to accumulate in bone successfully. PMID- 21698604 TI - The global counterfeit drug trade: patient safety and public health risks. AB - Counterfeit drugs are a global problem with significant and well-documented consequences for global health and patient safety, including drug resistance and patient deaths. This multibillion-dollar industry does not respect geopolitical borders, and threatens public health in both rich and resource-poor nations alike. The epidemiology of counterfeits is also wide in breadth and scope, including thousands of counterfeit incidents per year, encompassing all types of therapeutic classes, and employing a complex global supply chain network enabling this illegal activity. In addition, information technologies available through the Internet and sales via online pharmacies have allowed the criminal element to thrive in an unregulated environment of anonymity, deception, and lack of adequate enforcement. Though recent global enforcement efforts have led to arrests of online counterfeit sellers, such actions have not stemmed supplies from illegal online sellers or kept up with their creativity in illegally selling their products. To address this issue, we propose a global policy framework utilizing public-private partnership models with centralized surveillance reporting that would enable cooperation and coordination to combat this global health crisis. PMID- 21698606 TI - [New malaria drugs: screening against the entire parasite or target-based - which is the right path?]. PMID- 21698608 TI - [Gene Therapy - What is it? "Healing" with genes]. PMID- 21698605 TI - [Personalized therapy for HIV infection]. PMID- 21698609 TI - [Viral gene transfer medicinal products. Therapy with "disarmed" human pathogens]. PMID- 21698610 TI - [Non-viral gene transfer medicinal products. Therapy with synthetic vectors]. PMID- 21698611 TI - [Mini Circle - The next generation of non-viral gene therapy vectors. Circular, supercoiled plasmid DNA expression cassettes]. PMID- 21698612 TI - [When gene vectors are equipped with the correct key, the cell surface can be targeted]. PMID- 21698613 TI - [Lifelong healing via gene transfer - reality or utopia? Stable versus transient gene transfer]. PMID- 21698614 TI - [Prevention of insertional mutagenesis. Inevitable or manageable?]. PMID- 21698615 TI - [Clinical application of gene therapy. Previous experience and the future]. PMID- 21698616 TI - [Gene therapy for septic granulomatosis: risks and opportunities. The road to successful treatment of congenital immunodeficiency]. PMID- 21698617 TI - [Regulatory aspects of gene therapy. The new infrastructure for "Advanced Therapies"]. PMID- 21698625 TI - [Programmed cell death in bacteria]. PMID- 21698626 TI - [Dysregulation of histone acetylation as a molecular basis for the development of dementia]. PMID- 21698627 TI - [What rules apply here and who is responsible? How drugs are distinguished from other health care products?]. PMID- 21698629 TI - [A consideration from the scientific perspective. Health products: which is food, which is medicine?]. PMID- 21698630 TI - [Toxicological evaluation and delineation. Food - nutritional supplements - pharmaceuticals]. PMID- 21698631 TI - [A question of distribution options. Demarcation of plant products]. PMID- 21698632 TI - [Demarcation problem. Clinical trials of dietary supplements]. PMID- 21698633 TI - [Botanicals, medicinal plants in food. Substance lists of the federation and the states]. PMID- 21698634 TI - [Europeanisation of law. Demarcation issues in court]. PMID- 21698635 TI - [Classification by individual case decisions. Demarcation of cosmetics versus drug]. PMID- 21698637 TI - [Paul Martini Prize 2011: award for effective gene therapy]. PMID- 21698638 TI - [What is HUSEC041 MLST ST678?]. PMID- 21698646 TI - Clarifying variability of corticomotoneuronal function in kennedy disease. AB - INTRODUCTION: Although Kennedy disease (KD) is regarded as a pure lower motor neuron disorder, recent transcranial magnetic stimulation (TMS) studies have reported subclinical corticomotoneuronal dysfunction in KD. To clarify these findings, this study applied novel triple stimulation (TST) and threshold tracking TMS techniques to gain further insights into corticomotoneuronal function in KD. METHODS: TMS studies were undertaken in 12 KD patients and 38 age matched controls. Motor evoked potentials were recorded over the abductor pollicis brevis (threshold tracking TMS) and abductor digiti minimi (TST). RESULTS: The mean TSTtest:TSTcontrol amplitude (99 +/- 0.7%, normal >93%) and area (98.4 +/- 1.6%, normal >92%) ratios were normal in Kennedy disease. In addition, short-interval intracortical inhibition (SICI) was similar in KD and controls (KD: 8.1 +/- 1.3%; controls: 10.1 +/- 0.7%; P = 0.11), as were the motor evoked potential amplitude, resting motor threshold, intracortical facilitation, and cortical silent period duration. CONCLUSIONS: Triple stimulation and threshold tracking TMS techniques have reiterated normal corticomotoneuronal function in KD. PMID- 21698647 TI - Reliability of the Modified Hammersmith Functional Motor Scale in young children with spinal muscular atrophy. AB - INTRODUCTION: The test-retest reliability of the Modified Hammersmith Functional Motor Scale (MHFMS) in children with spinal muscular atrophy (SMA) <=30 months of age was assessed. The age at which typically developing children (TD) achieve maximum MHFMS scores was also studied. METHODS: Twenty-two children with SMA type II [mean age (SD) = 20 (5) months, range 9-30 months) were tested twice using the MHFMS. Twenty-five TD children [mean age (SD) = 18 (7) months, range 9-30 months) were tested once. RESULTS: The average difference between MHFMS scores for SMA children was 0.18 [first assessment: mean (SD) = 12.8 (9.8); second assessment: mean (SD) = 13.0 (8.8)]. Reliability was excellent (ICC(1,3) = 0.96, SEM 1.86). TD participants had MHFMS scores ranging from 36 to 40 [mean (SD) = 39.2 (1.2)] and achieved maximum test scores at 12 months of age. DISCUSSION: MHFMS scores in young children with SMA type II showed excellent test-retest stability. This suggests that the MHFMS can be used reliably in this younger population for clinical trials and follow-up. PMID- 21698648 TI - Multiple cranial neuropathy variant of Guillain-Barre syndrome: a case series. AB - INTRODUCTION: Prompt identification of the rare cranial variant of Guillain-Barre syndrome (GBS) is crucial, but the clinical characteristics remain poorly defined. METHODS: We conducted a retrospective review of 12 GBS patients hospitalized from 1995 to 2009 with multiple cranial nerve (CN) impairment at disease onset. RESULTS: Eight patients had impairment of CN IX and X; 3 of CN VII; and 1 of CN VII, IX, and X. All patients had areflexia or hyporeflexia, 6 had Lasegue sign, and 5 required tracheostomy and mechanical ventilation. All patients had cerebrospinal fluid (CSF) albuminocytologic dissociation within 2-3 weeks after onset. Electrophysiological studies showed motor conduction velocity and F-wave abnormalities in 10 of 12 and 10 of 11 patients, respectively. Treatment with intravenous immunoglobulin was effective. CONCLUSIONS: Bilateral CN IX, X, and/or VII impairment with areflexia or hyporeflexia, early abnormal F wave response, nerve conduction abnormalities, and CSF albuminocytologic dissociation support a diagnosis of this GBS cranial variant. PMID- 21698649 TI - CINRG pilot trial of coenzyme Q10 in steroid-treated Duchenne muscular dystrophy. AB - INTRODUCTION: Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin-deficient muscle. METHODS: We performed an open-label, "add-on" pilot study of CoQ10 in thirteen 5 10-year-old DMD patients on steroids. The primary outcome measure was the total quantitative muscle testing (QMT) score. RESULTS: Twelve of 16 children (mean age 8.03 +/- 1.64 years) completed the trial. Target serum levels of CoQ10 (>=2.5 MUg/ml) were shown to be subject- and administration-dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in an 8.5% increase in muscle strength (P = 0.03). CONCLUSIONS: Addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD. PMID- 21698650 TI - Effect of gender and obesity on electrical current thresholds. AB - INTRODUCTION: In this study we investigated the influence of gender and obesity on electrical current thresholds in an attempt to optimize the application of skeletal muscle electrical stimulation (ES) in clinical practice. METHODS: Thirty two obese and 35 age-matched, non-obese men and women received graded ES to the quadriceps muscle for sensory (detection) and motor (contraction) threshold assessment. Concomitant pain and tolerance to ES were recorded. RESULTS: Sensory threshold was lower in women than in men (P < 0.001), both obese and non-obese. Sensory and motor thresholds were higher in obese than in non-obese subjects (P < 0.05), and body mass index was a strong predictor of motor excitability (r(2) = 0.56-0.61). Current tolerance to motor stimulation was reduced in obese individuals, particularly in women, whereas pain was not influenced by gender or obesity. CONCLUSIONS: We suggest that both gender and obesity factors should be carefully considered in the design of rational ES treatments. PMID- 21698651 TI - Lower limb electromygraphy and kinematics of neuropathic diabetic patients during real-life activities: stair negotiation. AB - INTRODUCTION: In this study we investigate the influence of diabetic neuropathy (DN) on lower limb electromyography (EMG) and kinematics during stair negotiation. METHODS: Forty-six adults (healthy and DN) performed stair ascent and descent tasks. Kinematic and EMG data were assessed unilaterally. RESULTS: DN patients had lower ankle dorsiflexion while ascending and plantarflexion while descending. This reduced dorsiflexion compromises proper ankle and knee positions necessary for an efficient lifting action by the vastus lateralis (VL). The mechanical disadvantage of VL at the beginning of the stance triggered prolonged VL activation at the end of stair ascent. In stair descent, DN patients showed lower tibialis anterior activity in the early phase that can potentially impair the mechanism of impact absorption when the forefoot contacts the step. CONCLUSIONS: Our results reveal an adaptive motor strategy in DN patients to overcome the challenge of stair ascent, which promoted more biomechanical deficits. PMID- 21698654 TI - Response to 'Role of age, sex, and race on cardiac and total mortality associated with Super Bowl wins and losses'. PMID- 21698652 TI - Sodium and chloride channelopathies with myositis: coincidence or connection? AB - INTRODUCTION: A proximal myopathy develops in some patients with muscle channelopathies, but the causative molecular mechanisms are unknown. METHODS: We reviewed retrospectively all clinical and muscle biopsy findings of 3 patients with channelopathy and additional myositis. Direct DNA sequencing was performed. RESULTS: Pathogenic mutations were identified in each case. Biopsies demonstrated inflammatory infiltrates. CONCLUSIONS: Clinicians should consider muscle biopsy in channelopathy patients with severe myalgia and/or subacute weakness and accompanying elevated creatine kinase. Chance association of myositis and channelopathy is statistically unlikely. An alternative hypothesis suggests that inflammatory insults could contribute to myopathy in some patients. PMID- 21698655 TI - Peptide and protein drugs: the study of their metabolism and catabolism by mass spectrometry. AB - Peptide and protein drugs have evolved in recent years into mainstream therapeutics, representing a significant portion of the pharmaceutical market. Peptides and proteins exhibit highly diverse structures, broad biological activities as hormones, neurotransmitters, structural proteins, metabolic modulators and therefore have a significant role as both therapeutics and biomarkers. Understanding the metabolism of synthetic or biotechnologically derived peptide and protein drugs is critical for pharmaceutical development as metabolism has a significant impact on drug efficacy and safety. Although the same principles of pharmacokinetics and metabolism of small molecule drugs apply to peptide and protein drugs, there are few notable differences. Moreover, the study of peptide and protein drug metabolism is a rather complicated process which requires sophisticated analytical techniques, and mass spectrometry based approaches have provided the capabilities for efficient and reliable quantification, characterization, and metabolite identification. This review article will focus on the current use of mass spectrometry for the study of the metabolism of peptide and protein drugs. PMID- 21698656 TI - Social network modeling: a powerful tool for the study of group scale phenomena in primates. AB - Social Network Analysis is now a valuable tool to study social complexity in many animal species, including primates. However, this framework has rarely been used to implement quantitative data on the social structure of a group within computer models. Such approaches allow the investigation of how social organization constrains other traits and also how these traits can impact the social organization in return. In this commentary, we discuss the powerful potential of social network modeling as a way to study group scale phenomena in primates. We describe the advantages of using such a method and we focus on the specificity of this approach in primates, given the particularities of their social networks compared with those of other taxa. We also give practical considerations and a list of examples as for the choice of parameters that can be used to implement the social layer within the models. PMID- 21698657 TI - Space to choose: network analysis of social preferences in a captive chimpanzee community, and implications for management. AB - Social network analysis (SNA) is rapidly gaining popularity in primatology, but its application to the management of zoo-housed primates has been largely overlooked. Here I use SNA techniques to explore the social structure of chimpanzees (Pan troglodytes) housed in the new "Budongo Trail" exhibit at Edinburgh Zoo, UK. Given that individuals have extensive space (2332 m(2)), and access to several interconnected exhibit sections, I test the hypothesis that individuals are able to choose to interact with specific social partners. Spatial association and social interaction data were recorded from 400 focal watches on 11 individuals, and association, affiliative, and agonistic networks were constructed. Matrix correlations showed that individuals who spent time in close proximity were likely to affiliate with one another, but spatial association did not predict the frequency of agonistic encounters. Cluster analysis revealed significantly distinct sub-groups in the affiliative network (but not association or agonistic networks) in line with maternal kinship. Overall my findings support the hypothesis that the Budongo Trail exhibit facilitates the expression of social preferences, and suggests that SNA can be a useful tool to study zoo primates when proximity between individuals is not forced (i.e. in large, modern exhibits). Now that I have validated a set of SNA methods for this community, they can be used to trace changes in social dynamics over a longer time period, and ultimately assist zoo staff in their management decisions. PMID- 21698658 TI - Grooming network cohesion and the role of individuals in a captive chimpanzee group. AB - Social network analysis offers new tools to study the social structure of primate groups. We used social network analysis to investigate the cohesiveness of a grooming network in a captive chimpanzee group (N = 17) and the role that individuals may play in it. Using data from a year-long observation, we constructed an unweighted social network of preferred grooming interactions by retaining only those dyads that groomed above the group mean. This choice of criterion was validated by the finding that the properties of the unweighted network correlated with the properties of a weighted network (i.e. a network representing the frequency of grooming interactions) constructed from the same data. To investigate group cohesion, we tested the resilience of the unweighted grooming network to the removal of central individuals (i.e. individuals with high betweenness centrality). The network fragmented more after the removal of individuals with high betweenness centrality than after the removal of random individuals. Central individuals played a pivotal role in maintaining the network's cohesiveness, and we suggest that this may be a typical property of affiliative networks like grooming networks. We found that the grooming network correlated with kinship and age, and that individuals with higher social status occupied more central positions in the network. Overall, the grooming network showed a heterogeneous structure, yet did not exhibit scale-free properties similar to many other primate networks. We discuss our results in light of recent findings on animal social networks and chimpanzee grooming. PMID- 21698659 TI - Effects of natal male alliances on aggression and power dynamics in rhesus macaques. AB - In the wild, male rhesus macaques disperse at sexual maturity. In captivity, however, males cannot disperse from their natal groups. Thus, the presence of natal males in captive rhesus social groups is unnatural and has the potential to negatively influence group dynamics and stability. A primary difference between natal males and non-natal (immigrant) males is that natal males have the opportunity to form long-term alliances with their maternal kin as well as nonkin. We investigated the factors associated with natal males' kin alliances and the impact of these alliances on measures of natal male behavior, group dynamics, and group stability. We found that natal males more frequently formed alliances with maternal kin when they were from high-ranking matrilines, had more siblings, and were younger. More frequent kin alliances were associated with more frequent use of intense aggression, higher individual rank, and higher degree of integration within the male displacement network. Thus, it seems that natal males use their alliances to be more active and influential in the social group, which may affect group stability. It appears that juvenile natal males from high ranking matrilines, in particular, have the largest impact on group stability. Younger natal males from high-ranking matrilines formed alliances with kin more frequently and used intense aggression more frequently than older or lower ranking males. Furthermore, groups with a higher proportion of juvenile males from high-ranking matrilines also had higher rates of wounding. We suggest that the presence of natal males in rhesus groups may act in opposition to group stability. PMID- 21698660 TI - Social relationships between adult females and the alpha male in wild tufted capuchin monkeys. AB - Primates are notable for the widespread presence of long-term female-male associations which go beyond the mating context. However, little attention has been given to the factors that affect within-species variation in female-male relationships, especially among New World primates. Although detailed accounts of heterosexual relationships in Cebus species are scarce, a few studies have suggested the occurrence of strong associations between adult females and high ranking males. This study explores affiliative relationships between females and the alpha male during the nonbreeding season in wild tufted capuchin monkeys (Cebus apella nigritus). Affiliative relationships were explored through female male patterns of spatial proximity and grooming. By adopting a social network approach, we analyzed: (1) whether the alpha male is the preferred male partner for females and, (2) whether variation (if any) in female-alpha male affiliation can be explained through both female individual characteristics and social network metrics. Our results showed that alpha males were the favorite male partner for adult females in the proximity networks, but this did not hold true in the grooming networks. In addition, female-alpha male interaction patterns showed considerable variation, with only some females being strongly associated with the alpha male. Our results suggest that such a variation can be explained by female dominance rank, level of centrality (the quantity and intensity of spatial connection with other females) and prestige (the quantity of grooming received by other females) in female-female social networks. Taken together, these findings highlight two aspects of female-alpha male relationships in tufted capuchin monkeys: the alpha male represents the most socially integrated male in the group, and females with high dominance ranks and high centrality in both proximity and grooming networks show stronger relationships with the alpha male. PMID- 21698661 TI - Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy. AB - OBJECTIVE: Small nerve fiber neuropathy (SFN) often occurs without apparent cause, but no systematic genetic studies have been performed in patients with idiopathic SFN (I-SFN). We sought to identify a genetic basis for I-SFN by screening patients with biopsy-confirmed idiopathic SFN for mutations in the SCN9A gene, encoding voltage-gated sodium channel Na(V)1.7, which is preferentially expressed in small diameter peripheral axons. METHODS: Patients referred with possible I-SFN, who met the criteria of >=2 SFN-related symptoms, normal strength, tendon reflexes, vibration sense, and nerve conduction studies, and reduced intraepidermal nerve fiber density (IENFD) plus abnormal quantitative sensory testing (QST) and no underlying etiology for SFN, were assessed clinically and by screening of SCN9A for mutations and functional analyses. RESULTS: Twenty-eight patients who met stringent criteria for I-SFN including abnormal IENFD and QST underwent SCN9A gene analyses. Of these 28 patients with biopsy-confirmed I-SFN, 8 were found to carry novel mutations in SCN9A. Functional analysis revealed multiple gain of function changes in the mutant channels; each of the mutations rendered dorsal root ganglion neurons hyperexcitable. INTERPRETATION: We show for the first time that gain of function mutations in sodium channel Na(V)1.7, which render dorsal root ganglion neurons hyperexcitable, are present in a substantial proportion (28.6%; 8 of 28) of patients meeting strict criteria for I-SFN. These results point to a broader role of Na(V)1.7 mutations in neurological disease than previously considered from studies on rare genetic syndromes, and suggest an etiological basis for I-SFN, whereby expression of gain of function mutant sodium channels in small diameter peripheral axons may cause these fibers to degenerate. PMID- 21698662 TI - The relationships among spatiotemporal collagen gene expression, histology, and biomechanics following full-length injury in the murine patellar tendon. AB - Tendon injuries are major orthopedic problems that worsen as the population ages. Type-I (Col1) and type-II (Col2) collagens play important roles in tendon midsubstance and tendon-to-bone insertion healing, respectively. Using double transgenic mice, this study aims to spatiotemporally monitor Col1 and Col2 gene expression, histology, and biomechanics up to 8 weeks following a full-length patellar tendon injury. Gene expression and histology were analyzed weekly for up to 5 weeks while mechanical properties were measured at 1, 2, 5, and 8 weeks. At week 1, the healing region displayed loose granulation tissue with little Col1 expression. Col1 expression peaked at 2 weeks, but the ECM was highly disorganized and hypercellular. By 3 weeks, Col1 expression had reduced and by 5 weeks, the ECM was generally aligned along the tendon axis. Col2 expression was not seen in the healing midsubstance or insertion at any time point. The biomechanics of the healing tissue was inadequate at all time points, achieving ultimate loads and stiffnesses of 48% and 63% of normal values by 8 weeks. Future studies will further characterize the cells within the healing midsubstance and insertion using tenogenic markers and compare these results to those of tendon cells during normal development. PMID- 21698663 TI - Three-dimensional high frequency power Doppler ultrasonography for the assessment of microvasculature during fracture healing in a rat model. AB - We aimed to establish a novel approach with 3D high frequency power Doppler ultrasonography (3D-HF-PDU) to assess microvasculature at the fracture site in rat femurs by comparing with microCT-based microangiography. Twenty-four 9-month old ovariectomized (OVX) osteoporotic rats and age-matched sham-ovariectomized (Sham) rats were used for establishing closed fracture models on right femora. At 2, 4, and 8 weeks post-operatively, four rats in each group underwent in vivo 3D HF-PDU scanning for evaluation of vascularization and blood flow at the fracture site. Then the fractured femora were harvested for ex vivo microangiography, and neovasculatures within the callus were reconstructed for vascular volume analysis. Correlation between the vascular volumes of the two methodologies was examined. Both 3D-HF-PDU and microangiography showed a decline of vascular volume at the fracture site from 2 to 8 weeks and a significantly larger volume in the Sham group than the OVX group. A significant linear positive correlation (r = 0.87, p < 0.001) was detected between the volumes measured by the two methodologies. Osteoporotic rats had a diminished angiogenic response and lower blood perfusion than Shams. We believe 3D-HF-PDU is feasible and reproducible for in vivo assessment of microvasculature during femoral fracture healing in rats. PMID- 21698664 TI - Leptin's balancing act between bone and fat. PMID- 21698665 TI - Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa. AB - Anorexia nervosa (AN) is prevalent in adolescents and is associated with decreased bone mineral accrual at a time critical for optimizing bone mass. Low BMD in AN is a consequence of nutritional and hormonal alterations, including hypogonadism and low estradiol levels. Effective therapeutic strategies to improve BMD in adolescents with AN have not been identified. Specifically, high estrogen doses given as an oral contraceptive do not improve BMD. The impact of physiologic estrogen doses that mimic puberty on BMD has not been examined. We enrolled 110 girls with AN and 40 normal-weight controls 12 to 18 years of age of similar maturity. Subjects were studied for 18 months. Mature girls with AN (bone age [BA] >=15 years, n = 96) were randomized to 100 ug of 17beta-estradiol (with cyclic progesterone) or placebo transdermally for 18 months. Immature girls with AN (BA < 15 years, n = 14) were randomized to incremental low-dose oral ethinyl estradiol (3.75 ug daily from 0 to 6 months, 7.5 ug from 6 to 12 months, 11.25 ug from 12 to 18 months) to mimic pubertal estrogen increases or placebo for 18 months. All BMD measures assessed by dual-energy X-ray absorptiometry (DXA) were lower in girls with AN than in control girls. At baseline, girls with AN randomized to estrogen (AN E + ) did not differ from those randomized to placebo (AN E-) for age, maturity, height, BMI, amenorrhea duration, and BMD parameters. Spine and hip BMD Z-scores increased over time in the AN E+ compared with the AN E- group, even after controlling for baseline age and weight. It is concluded that physiologic estradiol replacement increases spine and hip BMD in girls with AN. PMID- 21698667 TI - High serum 25-hydroxyvitamin D is associated with a low incidence of stress fractures. AB - Low serum 25-hydroxyvitamin D [25(OH)D] concentrations are associated with hip fractures, but the dose-response relationship of serum 25(OH)D with risk of stress fractures in young women is unknown. This nested case-control study in a cohort of female Navy recruits was designed to determine whether those with low prediagnostic serum 25(OH)D concentrations had greater risk of stress fracture. Sera were drawn in 2002-2009 from 600 women who were diagnosed subsequently with stress fracture of the tibia or fibula and 600 matched controls who did not experience a stress fracture. The 25(OH)D concentration was measured using the DiaSorin radioimmunoassay method. Controls were individually matched to cases on race (white, black, or other), length of service (+/-30 days), and day blood was drawn (+/-2 days). There was approximately half the risk of stress fracture in the top compared with the bottom quintile of serum 25(OH)D concentration (odds ratio [OR] = 0.51, 95% CI 0.34-0.76, p <= 0.01). The range of serum 25(OH)D in the lowest quintile was 1.5 to 19.7 (mean 13.9) ng/mL, whereas in the highest it was 39.9 to 112 (mean 49.7) ng/mL. It is concluded that there was a monotonic inverse dose-response gradient between serum 25(OH)D and risk of stress fracture. There was double the risk of stress fractures of the tibia and fibula in women with serum 25(OH)D concentrations of less than 20 ng/mL compared to those with concentrations of 40 ng/mL or greater. A target for prevention of stress fractures would be a serum 25(OH)D concentration of 40 ng/mL or greater, achievable with 4000 IU/d of vitamin D(3) supplementation. PMID- 21698666 TI - Regulation of postnatal trabecular bone formation by the osteoblast endothelin A receptor. AB - Endothelin-1 (ET-1) is a potent vasoconstrictor that also stimulates cells in the osteoblast lineage by binding to the endothelin A receptor (ETAR). ET-1 ligand is widely secreted, particularly by the vasculature. However, the contributions of ETAR signaling to adult bone homeostasis have not been defined. ETAR was inactivated in osteoblasts by crossing ETAR-floxed and osteocalcin-Cre mice. Histomorphometric analyses were performed on 4-, 8-, and 12-week-old osteoblast targeted ETAR knockout (KO) and wild-type (WT) male and female mice. Tibial trabecular bone volume was significantly lower from 12 weeks in KO versus WT mice in both males and females. Bone-formation rate, osteoblast density, and in vitro osteoblast differentiation were reduced by targeted inactivation of ETAR. A separate longitudinal analysis was performed between 8 and 64 weeks to examine the effect of aging and castration on bone metabolism in ETAR KO mice. Hypogonadism did not change the rate of bone accrual in WT or KO females. However, eugonadal KO males had a significantly larger increase in tibial and femoral bone acquisition than WT mice. Male mice castrated at 8 weeks of age showed the reverse: KO mice had reduced rates of tibial and femoral BMD acquisition compared with WT mice. In vitro, ET-1 increased osteoblast proliferation, survival, and differentiation. Dihydrotestosterone also increased osteoblast differentiation using a mechanism distinct from the actions of ET-1. These results demonstrate that endothelin signaling in osteoblasts is an important regulator of postnatal trabecular bone remodeling and a modulator of androgen effects on bone. PMID- 21698669 TI - Modulating Bcl-2 family proteins and caspase-3 in induction of apoptosis by paeoniflorin in human cervical cancer cells. AB - Paeoniflorin (PF), the principal bioactive component in the paeony root, has been used alone or combined with other herbs for many years in traditional Chinese medicine. New studies have shown that PF possesses an antitumor effect. However, the effect of PF on human cervical cancer cells has not been reported previously. This study determined the effect of PF on human cervical cancer cell line (HeLa) cells by the methyl thiazolyl tetrazolium (MTT) assay, flow cytometry with annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) technology, the transmission electron microscope (TEM) and immunocytochemical technique. After treatment with PF, the proliferation of HeLa cells was inhibited in a dose and time-dependent manner (p < 0.05). The apoptosis rate of HeLa cells increased with ascending concentrations of PF (p < 0.05) and the proportion of HeLa cells in S phase showed an increasing trend also. Typical apoptotic changes of HeLa cells exposed to PF were seen under the TEM. Meanwhile, there was a decrease in the expression of Bcl-2 and an enhancement in the expression of Bax and caspase-3 genes compared with the control group (p < 0.05). In conclusion, PF can induce significantly the apoptosis of HeLa cells, which may be demonstrated by the down regulation of anti-apoptosis gene Bcl-2 and the up-regulation of pro-apoptosis genes Bax and caspase-3. PMID- 21698671 TI - Effect of Ganoderma lucidum on pollen-induced biphasic nasal blockage in a guinea pig model of allergic rhinitis. AB - Ganoderma lucidum (GL), an oriental medical mushroom, has been used in Asia for the prevention and treatment of a variety of diseases. However, the effect of GL on allergic rhinitis has not been well defined. The current study describes the inhibitory effect of GL on the biphasic nasal blockage and nasal hyperresponsiveness induced by repeated antigen challenge in a guinea pig model of allergic rhinitis. Intranasally sensitized guinea pigs were repeatedly challenged by inhalation of Japanese cedar pollen once every week. Ganoderma lucidum was orally administered once daily for 8 weeks from the time before the first challenge. The treatment with GL dose-dependently inhibited the early and late phase nasal blockage at the fifth to ninth antigen challenges. Furthermore, nasal hyperresponsiveness to intranasally applied leukotriene D4 on 2 days after the eighth antigen challenge was also inhibited by the treatment with GL. However, Cry j 1-specific IgE antibody production was not affected by the treatment. In conclusion, we demonstrated that the pollen-induced biphasic nasal blockage and nasal hyperresponsiveness were suppressed by the daily treatment with GL in the guinea pig model of allergic rhinitis. These results suggest that GL may be a useful therapeutic drug for treating patients with allergic rhinitis. PMID- 21698670 TI - Antiproliferative action of Xylopia aethiopica fruit extract on human cervical cancer cells. AB - The anticancer potential of Xylopia aethiopica fruit extract (XAFE), and the mechanism of cell death it elicits, was investigated in various cell lines. Treatment with XAFE led to a dose-dependent growth inhibition in most cell lines, with selective cytotoxicity towards cancer cells and particularly the human cervical cancer cell line C-33A. In this study, apoptosis was confirmed by nuclear fragmentation and sub-G(0)/G(1) phase accumulation. The cell cycle was arrested at the G(2)/M phase with a decreased G(0)/G(1) population. A semi quantitative gene expression study revealed dose-dependent up-regulation of p53 and p21 genes, and an increase in the Bax/Bcl-2 ratio. These results indicate that XAFE could be a potential therapeutic agent against cancer since it inhibits cell proliferation, and induces apoptosis and cell cycle arrest in C-33A cells. PMID- 21698673 TI - Mass spectrometric identification of an intramolecular disulfide bond in thermally inactivated triosephosphate isomerase from a thermophilic organism Methanocaldococcus jannaschii. AB - The triosephosphate isomerase from the hyperthermophilic organism Methanocaldococcus jannaschii (MjTIM) is a tetrameric enzyme, with a monomer molecular mass of 23245 Da. The kinetic parameters, the k(cat) and the K(m) values, of the enzyme, examined at 25 degrees C and 50 degrees C, are 4.18 * 10(4) min(-1) and 3.26 * 10(5) min(-1) , and 0.33 and 0.86 mM(-1) min(-1) , respectively. Although the circular dichroism and fluorescence emission spectra of the protein remain unchanged up to 95 degrees C, suggesting that the secondary and tertiary structures are not lost even at this extreme temperature, surprisingly, incubation of this thermophilic enzyme at elevated temperature (65 85 degrees C) results in time-dependent inactivation, with almost complete loss of activity after 3 h at 75 degrees C. High-resolution electrospray ionization mass spectrometry (ESI-MS) reveals the monomeric mass of the heated sample to be 23243 Da. The 2 Da difference between native and heated samples suggests a probable formation of a disulfide bridge between proximal cysteine thiol groups. Liquid chromatography (LC)/ESI-MS/MS analysis of tryptic digests in the heated samples permits identification of a pentapeptide (DCGCK, residues 80-84) in which a disulfide bond formation between Cys81 and Cys83 was established through the collision-induced dissociation (CID) fragmentation of the intact disulfide-bonded molecule, yielding characteristic fragmentation patterns with key neutral losses. Neither residue is directly involved in the catalytic activity. Inspection of the three-dimensional structure suggests that subtle conformation effects transmitted through a network of hydrogen bonds to the active site residue Lys8 may be responsible for the loss of catalytic activity. PMID- 21698672 TI - Antiinflammatory effects of ginger and some of its components in human bronchial epithelial (BEAS-2B) cells. AB - The proinflammatory chemokine interleukin-8 is increased in asthmatic patients. Traditionally, ginger is used as an antiinflammatory drug. An extract and several compounds of Zingiber officinale (ginger) were tested in human bronchial epithelial cells (BEAS-2B cells) with respect to their effect on lipopolysaccharide (LPS)-induced secretion of the proinflammatory chemokine interleukin 8 (IL-8) and RANTES (regulated upon activation, normal T-cell expressed and secreted). An oily extract of ginger rhizome with > 25% total pungent compounds, ginger volatile oil, ar-curcumene and alpha-pinene reduced the LPS-induced IL-8 secretion (measured by a specific enzyme-linked immunosorbent assay), whereas a spissum extract, the pungents [6]-gingerol and its metabolite [6]-shogaol, and the terpenoids citral and beta-phellandrene showed no effect. The LPS-induced slight increase of RANTES was reduced by volatile oil, ar curcumene and alpha-pinene. There was no effect of LPS on TNF-alpha. Our results suggest that distinct ginger compounds could be used as antiinflammatory drugs in respiratory infections. PMID- 21698674 TI - Carbon disulfide reagent allows the characterization of nonpolar analytes by atmospheric pressure chemical ionization mass spectrometry. AB - While atmospheric pressure ionization methodologies have revolutionized the mass spectrometric analysis of nonvolatile analytes, limitations native to the chemistry of these methodologies hinder or entirely inhibit the analysis of certain analytes, specifically, many nonpolar compounds. Examination of various analytes, including asphaltene and lignin model compounds as well as saturated hydrocarbons, demonstrates that atmospheric pressure chemical ionization (APCI) using CS(2) as the reagent produces an abundant and stable molecular ion (M(+*)) for all model compounds studied, with the exception of completely saturated aliphatic hydrocarbons and the two amino acids tested, arginine and phenylalanine. This reagent substantially broadens the applicability of mass spectrometry to nonvolatile nonpolar analytes and also facilitates the examination of radical cation chemistry by mass spectrometry. PMID- 21698675 TI - Stable isotope ratio measurements of royal jelly samples for controlling production procedures: impact of sugar feeding. AB - The carbon and nitrogen stable ratios of royal jelly (RJ) samples from various origins are determined using an elemental analyser linked online to an isotope ratio mass spectrometer to evaluate authenticity and adulteration. The (13)C/(12)C and (15)N/(14)N stable isotope ratios are measured in more than 500 RJs (domestic, imported and derived from feeding experiments) in order to obtain isotopic measurements that take into account seasonal, botanical and geographical effects. Authenticity intervals are established for traditional beekeeping practices, without feeding, in the range -22.48 to -27.900/00 for delta(13)C. For these samples, the delta(15)N values range from -1.58 to 7.980/00, depending on the plant sources of pollen and nectar. The delta(13)C values of the commercial samples vary from -18.54 to -26.580/00. High delta(13)C values are typical of sugar cane or corn syrups which have distinctive isotopic (13)C signatures because both plants use the C4 photosynthetic cycle, in contrast to most RJs which are derived from C3 plants. These differences in the (13)C-isotopic composition allow the detection of the addition of such sugars. RJs from traditional sources and from industrial production by sugar feeding are thus successfully distinguished. PMID- 21698676 TI - Acetonitrile covalent adduct chemical ionization tandem mass spectrometry of non methylene-interrupted pentaene fatty acid methyl esters. AB - Acetonitrile covalent adduct chemical ionization tandem mass spectrometry (CACIMS/MS) has shown to be an efficient method for the identification of double bond position in homoallylic, conjugated and several polyene non-methylene interrupted (NMI) fatty acid methyl esters. However, it has not been thoroughly evaluated for NMI highly unsaturated fatty acids (HUFA) with more than four double bonds. Docosahexaenoic acid (DHA)-rich single cell oil (DHASCO((r)); Martek Biosciences, Corp.) was partially hydrogenated (partially hydrogenated DHASCO; PHDO) producing ten novel 22:5 and 22:6 HUFA isomers. In single-stage MS, the ratio of [M+54](+)/[M+54-32](+) for the 22:5 and 22:6 isomers indicated the presence of homoallylic or partially conjugated double-bond systems. The CACIMS/MS spectra revealed six 22:5 isomers with diagnostic ions corresponding to the homoallylic 22:5n-6 and 22:5n-3 isomers, and four distinct NMI 22:5 isomers. Diagnostic ions for four 22:6 isomers were identical to the native DHA illustrating that CACIMS/MS is sensitive to double-bond position but not geometry. Three gas chromatography (GC) peaks for partially conjugated 22:6 isomers were also detected and clearly distinguishable from homoallylic 22:6 isomers, but their CACIMS/MS spectra did not yield prominent ions indicative of double-bond position, possibly due to co-elution. Overall, CACIMS/MS was effective for determining double-bond position in NMI 22:5 isomers. Further investigations are warranted to evaluate and determine fragmentation patterns for partially conjugated and NMI 22:6 HUFA. PMID- 21698677 TI - Determination of vitamins A, D and E in a small volume of human plasma by a high throughput method based on liquid chromatography/tandem mass spectrometry. AB - We have developed an automated high-throughput assay for the determination of vitamin A (retinol), ergocalciferol (25-OH D2), cholecalciferol (25-OH D3) and vitamin E (alpha-tocopherol) in a small volume of human plasma. Sample preparation involved mixing 50 MUL of plasma with 100 MUL of ethanol containing isotope-labelled internal standards, followed by mixing with isooctane/chloroform (3:1, 300 MUL). The organic phase was evaporated, and the sample reconstituted in 50 MUL methanol. The analysis was performed using reversed-phase liquid chromatography with a gradient mobile phase containing water, methanol and ammonium formate. Chromatographic run-time was 5 min, and positive mode electrospray tandem mass spectrometry (MS/MS) was used for detection. The limits of detection were 0.10 MUM for all-trans retinol and 3.3 nM for 25-OH D2 and 25 OH D3. Recoveries were 91.9-105.0%, and within- and between-day coefficients of variance (CVs) 2.4-5.3 and 3.1-8.2, respectively. The assay is presently being used in large-scale studies. PMID- 21698678 TI - Characterization of Nalpha-Fmoc-protected dipeptide isomers by electrospray ionization tandem mass spectrometry (ESI-MS(n)): effect of protecting group on fragmentation of dipeptides. AB - A series of positional isomeric pairs of Fmoc-protected dipeptides, Fmoc-Gly-Xxx OY/Fmoc-Xxx-Gly-OY (Xxx=Ala, Val, Leu, Phe) and Fmoc-Ala-Xxx-OY/Fmoc-Xxx-Ala-OY (Xxx=Leu, Phe) (Fmoc=[(9-fluorenylmethyl)oxy]carbonyl) and Y=CH(3)/H), have been characterized and differentiated by both positive and negative ion electrospray ionization ion-trap tandem mass spectrometry (ESI-IT-MS(n)). In contrast to the behavior of reported unprotected dipeptide isomers which mainly produce y(1)(+) and/or a(1)(+) ions, the protonated Fmoc-Xxx-Gly-OY, Fmoc-Ala-Xxx-OY and Fmoc-Xxx Ala-OY yield significant b(1)(+) ions. These ions are formed, presumably with stable protonated aziridinone structures. However, the peptides with Gly- at the N-terminus do not form b(1)(+) ions. The [M+H](+) ions of all the peptides undergo a McLafferty-type rearrangement followed by loss of CO(2) to form [M+H Fmoc+H](+). The MS(3) collision-induced dissociation (CID) of these ions helps distinguish the pairs of isomeric dipeptides studied in this work. Further, negative ion MS(3) CID has also been found to be useful for differentiating these isomeric peptide acids. The MS(3) of [M-H-Fmoc+H](-) of isomeric peptide acids produce c(1)(-), z(1)(-) and y(1)(-) ions. Thus the present study of Fmoc protected peptides provides additional information on mass spectral characterization of the dipeptides and distinguishes the positional isomers. PMID- 21698679 TI - Elimination of the helium requirement in high-field asymmetric waveform ion mobility spectrometry (FAIMS): beneficial effects of decreasing the analyzer gap width on peptide analysis. AB - Cylindrical geometry high-field asymmetric waveform ion mobility spectrometry (FAIMS) focuses and separates gas-phase ions at atmospheric pressure and room (or elevated) temperature. Addition of helium to a nitrogen-based separation medium offers significant advantages for FAIMS including improved resolution, selectivity and sensitivity. Aside from gas composition, ion transmission through FAIMS is governed by electric field strength (E/N) that is determined by the applied voltage, the analyzer gap width, atmospheric pressure and electrode temperature. In this study, the analyzer width of a cylindrical FAIMS device is varied from 2.5 to 1.25 mm to achieve average electric field strengths as high as 187.5 Townsend (Td). At these electric fields, the performance of FAIMS in an N(2) environment is dramatically improved over a commercial system that uses an analyzer width of 2.5 mm in 1:1 N(2) /He. At fields of 162 Td using electrodes at room temperature, the average effective temperature for the [M+2H](2+) ion of angiotensin II reaches 365 K. This has a dramatic impact on the curtain gas flow rate, resulting in lower optimum flows and reduced turbulence in the ion inlet. The use of narrow analyzer widths in a N(2) carrier gas offers previously unattainable baseline resolution of the [M+2H](2+) and [M+3H](3+) ions of angiotensin II. Comparisons of absolute ion current with FAIMS to conventional electrospray ionization (ESI) are as high as 77% with FAIMS versus standard ESI MS. PMID- 21698680 TI - High-performance liquid chromatography-diode array detection-electrospray ionization multi-stage mass spectrometric screening of an insect/plant system: the case of Spodoptera littoralis/Lycopersicon esculentum phenolics and alkaloids. AB - High-performance liquid chromatography-diode array detection-electrospray ionization multi-stage mass spectrometry (HPLC-DAD-ESI-MS(n)) is considered to be a very valuable tool for the characterization of compounds found in trace amounts in natural matrices, as their previous isolation and clean-up steps can be avoided. Micro-scale separation increases the potential of this analytical technique, allowing the determination of compounds in reduced samples. Spodoptera littoralis represents a major challenge to Solanaceae plants, as it is one of the most deleterious pests. The S. littoralis/Lycopersicon esculentum system was studied for the first time concerning glycoalkaloids and phenolics. Using HPLC DAD-ESI-MS(n) we were able to characterize 15 phenolic compounds in L. esculentum leaves. Nine of them are reported for the first time. Some differences were found between leaves of cerasiforme and 'Bull's heart' varieties. However, in the materials of S. littoralis (larvae, adults, exuviae and excrements) reared in both L. esculentum leaves no phenolics were identified. alpha-Tomatine was the main glycoalkaloid in the host plant. The glycoalkaloid composition of the different S. littoralis materials was distinct, with alpha-tomatine and dehydrotomatine being the main detected compounds in larvae and excrements. These results add knowledge to the ecological interaction in this insect/plant duo, for which it is hard to obtain considerable sample amounts. PMID- 21698681 TI - Dissociation of deprotonated microcystin variants by collision-induced dissociation following electrospray ionization. AB - Microcystins (MC) are a family of hepatotoxic cyclic heptapeptides produced by a number of different cyanobacterial species. Considering the recent advances in the characterization of deprotonated peptides by mass spectrometry, the fragmentation behavior of four structurally related microcystin compounds was investigated using collision-induced dissociation (CID) experiments on an orbitrap mass spectrometer. It is demonstrated in this study that significant structural information can be obtained from the CID spectra of deprotonated microcystins. A predominant ring-opening reaction at the isoMeAsp residue, as well as two major complementary fragmentation pathways, was observed, reducing the complexity of the product ion spectra in comparison with spectra observed from protonated species. This proposed fragmentation behavior was applied to characterize [Leu(1)]MC-LR from a cyanobacterial cell extract. In conclusion, CID spectra of microcystins in the negative ion mode provide rich structurally informative mass spectra which greatly enhance confidence in structural assignments, in particular when combined with complementary positive ion CID spectra. PMID- 21698682 TI - Online measurement of denitrification rates in aquifer samples by an approach coupling an automated sampling and calibration unit to a membrane inlet mass spectrometry system. AB - Aquifers within agricultural catchments are characterised by high spatial heterogeneity of their denitrification potential. Therefore, simple but sophisticated methods for measuring denitrification rates within the groundwater are crucial for predicting and managing N-fluxes within these anthropogenic ecosystems. Here, a newly developed automated online (15)N-tracer system is presented for measuring (N(2)+N(2)O) production due to denitrification in aquifer samples. The system consists of a self-developed sampler which automatically supplies sample aliquots to a membrane-inlet mass spectrometer. The developed system has been evaluated by a (15)N-nitrate tracer incubation experiment using samples (sulphidic and non-sulphidic) from the aquifer of the Fuhrberger Feld in northern Germany. It is shown that the membrane-inlet mass spectrometry (MIMS) system successfully enabled nearly unattended measurement of (N(2)+N(2)O) production within a range of 10 to 3300 ug N L(-1) over 7 days of incubation. The automated online approach provided results in good agreement with simultaneous measurements obtained with the well-established offline approach using isotope ratio mass spectrometry (IRMS). In addition, three different (15)N-aided mathematical approaches have been evaluated for their suitability to analyse the MIMS raw data under the given experimental conditions. Two approaches, which rely on the measurement of (28)N(2), (29)N(2) and (30)N(2), exhibit the best reliability in the case of a clear (15) N enrichment of evolved denitrification gases. The third approach, which uses only the ratio of (29)N(2)/(28)N(2), overestimates the concentration of labelled denitrification products under these conditions. By contrast, at low (15)N enrichments and low fractions of denitrified gas, the latter approach is on a par with the other two approaches. Finally, it can be concluded that the newly developed system represents a comprehensive and simply applicable tool for the determination of denitrification in aquifers. PMID- 21698683 TI - Improving confidence in detection and characterization of protein N-glycosylation sites and microheterogeneity. AB - Protein glycosylation is one of the most common post-translational modifications, estimated to occur in over 50% of human proteins. Mass spectrometry (MS)-based approaches involving different fragmentation mechanisms have been frequently used to detect and characterize protein N-linked glycosylations. In addition to the popular Collision-Induced Dissociation (CID), high-energy C-trap dissociation (HCD) fragmentation, which is a feature of a linear ion trap orbitrap hybrid mass spectrometer (LTQ Orbitrap), has been recently used for the fragmentation of tryptic N-linked glycopeptides in glycoprotein analysis. The oxonium ions observed with high mass accuracy in the HCD spectrum of glycopeptides can be combined with characteristic fragmentation patterns in the CID spectrum resulting from consecutive glycosidic bond cleavages, to improve the detection and characterization of N-linked glycopeptides. As a means of automating this process, we describe here GlypID 2.0, a software tool that implements several algorithmic approaches to utilize MS information including accurate precursor mass and spectral patterns from both HCD and CID spectra, thus allowing for an unequivocal and accurate characterization of N-linked glycosylation sites of proteins. PMID- 21698684 TI - Re-examination of the anion derivatives of isoflavones by radical fragmentation in negative electrospray ionization tandem mass spectrometry: experimental and computational studies. AB - This paper reports theoretical and experimental studies of gas-phase fragmentation reactions of four naturally occurring isoflavones. The samples were analyzed in negative ion mode by direct infusion in ESI-QqQ, ESI-QqTOF and ESI Orbitrap systems. The MS/MS and MS(n) spectra are in agreement with the fragmentation proposals and high-resolution analyses have confirmed the formulae for each ion observed. As expected, compounds with methoxyl aromatic substitution have showed a radical elimination of *CH(3) as the main fragmentation pathway. A second radical loss (*H) occurs as previously observed for compounds which exhibit a previous homolytic *CH(3) cleavage (radical anion) and involves radical resonance to stabilize the anion formed. However, in this study we suggest another mechanism for the formation of the main ions, on the basis of the enthalpies for each species. Compounds without methoxy substituent dissociate at the highest energies and exhibit the deprotonated molecule as the most intense ion. Finally, energy-resolved experiments were carried out to give more details about the gas-phase dissociation reaction of the isoflavones and the results are in agreement with the theoretical approaches. PMID- 21698685 TI - Quantification of meCCNU-induced dG-dC crosslinks in oligonucleotide duplexes by liquid chromatography/electrospray ionization tandem mass spectrometry. AB - Chloroethynitrosoureas (CENUs) are important alkylating agents widely used in the treatment of cancers. Decomposition of CENUs generates active electrophilic ions that damage DNA, including the formation of dG-dC crosslinks which represents the most important cytotoxic mechanism of CENUs. In this work, a high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ESI MS/MS) method was employed to analyze the dG-dC crosslinks induced by 1-(2 chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (meCCNU, Semustine). The direct quantitation of dG-dC crosslinks in oligonucleotide duplexes was achieved by the selected reaction monitoring (SRM) mode using synthesized (15) N(3) -labeled dG dC as an internal standard. Methods of enzymatic digestion and HPLC separation were developed for obtaining separation and reproducibility of the dG-dC peak in chromatograms. The limit-of-detection (LOD) was determined to be 0.08 nM and the limit-of-quantification (LOQ) was determined to be 0.16 nM. The linearity of the calibration curve was 0.9997 over the range of 0.08 to 32 nM. The precision and accuracy of the method ranged from 1.1 to 6.6% and 96 to 109%, respectively. The recovery of the dG-dC crosslink in the enzymatic hydrolysates from the oligonucleotide duplex was determined to be from 91 to 106%. The results of the validation study indicate that the method is suitable for quantifying dG-dC crosslinks in DNA. Consequently, this method was used to determine meCCNU-induced dG-dC crosslinks in four duplexes with different GC contents. The results showed that the crosslinking fraction (CF) increased as the GC content in the duplex increased, and a relatively low CF was observed in the early period of the reaction. PMID- 21698686 TI - The protein profile of Theobroma cacao L. seeds as obtained by matrix-assisted laser desorption/ionization mass spectrometry. AB - The water-soluble protein profile of the seeds of green, red, and yellow Theobroma cacao L. fruits has been determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF-MS). The seeds were powdered under liquid nitrogen and defatted. The residues were dialyzed and lyophilized. The obtained samples were suspended in the matrix solution of sinapinic acid. The obtained MALDI mass spectra showed the presence of a wide number of proteins with molecular weight ranging from 8000 to 13,000 Da and a cluster of peaks centered at 21,000 Da that were attributed to albumin. The abundance of this peak was found to depend on the different portion of the seed (husk, apical and cortical parts); however, the MALDI mass spectra obtained from the different varieties of cocoa were practically superimposable. Changes in the protein profiles were also observed after the cocoa seeds were treated by fermentation and roasting, which are processes usually employed for the commercial production of cocoa. PMID- 21698687 TI - A new rapid and micro-scale hydrolysis, using triethylamine citrate, for lipopolysaccharide characterization by mass spectrometry. AB - Endotoxin (lipopolysaccharide, LPS) is, in general, composed of two moieties: a hydrophilic polysaccharide linked to a hydrophobic lipid A terminal unit and forms a major surface component of gram-negative bacteria. The structural features of LPS moieties play a role in pathogenesis and also involve immunogenicity and diagnostic serology. The major toxic factor of LPS resides in the lipid A moiety, anchored in the outer layer of the bacterium, and its relative biological activity is critically related to fine structural features within the molecule. In establishing relationships between structural features and biological activities of LPS it is of the utmost importance to develop new analytical methods that can be applied to the complete unambiguous characterization of a specific LPS molecule. Herein is presented a practical rapid and sensitive analytical procedure for the mass spectral screening of LPS using triethylamine citrate as an agent for both disaggregation and mild hydrolysis of LPS. It provides improved matrix-assisted laser desorption/ionization (MALDI) mass spectra and, in particular, affords the identification of fragments retaining labile substituents present in the native macromolecular LPS structures. The methods were developed and applied using purified LPS of Escherichia coli and Salmonella enterica, as well as more complex LPS of Actnobacillus pleuropneumoniae. PMID- 21698688 TI - Improved online delta18O measurements of nitrogen- and sulfur-bearing organic materials and a proposed analytical protocol. AB - It is well known that N(2) in the ion source of a mass spectrometer interferes with the CO background during the delta(18)O measurement of carbon monoxide. A similar problem arises with the high-temperature conversion (HTC) analysis of nitrogenous O-bearing samples (e.g. nitrates and keratins) to CO for delta(18)O measurement, where the sample introduces a significant N(2) peak before the CO peak, making determination of accurate oxygen isotope ratios difficult. Although using a gas chromatography (GC) column longer than that commonly provided by manufacturers (0.6 m) can improve the efficiency of separation of CO and N(2) and using a valve to divert nitrogen and prevent it from entering the ion source of a mass spectrometer improved measurement results, biased delta(18)O values could still be obtained. A careful evaluation of the performance of the GC separation column was carried out. With optimal GC columns, the delta(18)O reproducibility of human hair keratins and other keratin materials was better than +/- 0.15 0/00 (n=5; for the internal analytical reproducibility), and better than +/- 0.10 0/00 (n=4; for the external analytical reproducibility). PMID- 21698689 TI - Performance evaluation on a wide set of matrix-assisted laser desorption ionization matrices for the detection of oligosaccharides in a high-throughput mass spectrometric screening of carbohydrate depolymerizing enzymes. AB - Compared to other analytical methods, matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) presents several unique advantages for the structural characterization of degradation products of carbohydrates. Our final goal is to implement this technique as a high-throughput platform, with the aim of exploring natural bio-diversity to discover new carbohydrate depolymerizing enzymes. In this approach, a variety of carbohydrates will be used as enzymes substrates and MALDI-MS will be employed to monitor the oligosaccharides produced. One drawback of MALDI, however, is that the choice of the matrix is largely dependent on the chemical properties of the analyte. In this context, our objective in the present work was to find the smallest set of MALDI matrices able to detect chemically heterogeneous oligosaccharides. This was done through the performance evaluation of more than 40 MALDI matrices preparations. Homogeneity of analyte-matrix deposits was considered as a critical feature, especially since the final objective is to fully automate the analyses. Evaluation of the matrices was done by means of a rigorous statistical approach. Amongst all tested compounds, our work proposes the use of the DHB/DMA ionic matrix as the most generic matrix, for rapid detection of a variety of polysaccharides including neutral, anionic, methylated, sulfated, and acetylated compounds. The selected matrices were then used to screen crude bacterial incubation media for the detection of enzymatic degradation products. PMID- 21698690 TI - Evaluation of urinary ribonucleoside profiling for clinical biomarker discovery using constant neutral loss scanning liquid chromatography/tandem mass spectrometry. AB - The patterns and levels of urinary excreted ribonucleosides which reflect RNA turnover and metabolism in humans offer the potential for early detection of disease and monitoring of therapeutic intervention. A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method employing constant neutral loss (CNL) scanning for the loss of the ribose moiety (132 u) was used to detect ribonucleosides in human urine and to evaluate this analytical platform for biomarker research in clinical trials. Ribonucleosides were stable and not influenced by the time spent at room temperature prior to freezing or long-term storage at -80 degrees C. Matrix effects caused variation in the mass spectrometer response which was dependent on the concentration of the analysed urine sample. For the use of urinary ribonucleoside profiling in clinical biomarker studies, adjustment of the urine samples to a common concentration prior to sample preparation is therefore advocated. Changes in the mass spectrometer response should be accounted for by the use of an internal standard added after sample preparation. Diurnal variation exceeded inter-day variation of an individual's ribonucleoside profile, but inter-person differences were predominant and allowed the separation of individuals against each other in a multivariate space. Due to considerable diurnal variation the use of spot urine samples would introduce unnecessary variation and should be replaced by the collection of multiple spot urine samples across the day, where possible. Should such a protocol not be feasible, biological intra-day and inter-day variation must be considered and accounted for in the data interpretation. PMID- 21698691 TI - Nitrogen adduction by three coordinate group 10 organometallic cations: platinum is favoured over nickel and palladium. AB - Previous studies have shown that highly reactive product ions formed by collision induced dissociation (CID) of precursor ions generated via electrospray can readily react with residual solvent or drying gases, especially in ion trap mass spectrometers. Here we report on the rapid addition of nitrogen to the coordinatively unsaturated organoplatinum cation, [(phen)Pt(CH(3))](+) (phen=1,10 phenanthroline) formed via decarboxylation of the acetate complex [(phen)Pt(O(2) CCH(3))](+). This contrasts with the related coordinatively unsaturated group 10 cations: addition of nitrogen to [(phen)Pd(CH(3))](+) occurs at longer reaction times, whereas addition of nitrogen to [(phen)Ni(CH(3))](+) is virtually non existent. To better understand these reactions, density functional theory (DFT) calculations were carried out at the B3LYP/SDD6-31+G(d) level of theory to determine the N(2)-binding energies of [(phen)M(CH(3))](+). [(phen)Pt(CH(3))](+) has a higher binding energy to N(2) (1.06 eV) than either [(phen)Ni(CH(3))](+) (0.61 eV) or [(phen)Pd(CH(3))](+) (0.66 eV), consistent with the experimental ease of addition of nitrogen to the coordinatively unsaturated organometallic complexes, [(phen)M(CH(3))](+). Finally, [(phen)M(CH(3))](+) are reactive to other background gases, forming [(phen)M(O(2))](.+) (for M=Ni) in reactions with oxygen and undergoing water addition (for M=Ni, Pd and Pt) and water addition/CH(4) elimination reactions to yield [(phen)M(OH)](+) (for M=Ni and Pt). PMID- 21698692 TI - Depth-specific and spatiotemporal variation of delta13C and delta15N in Charophytes of Lake Constance: implications for food web studies. AB - Macrophytes are at the base of many lake food webs providing essential food resources for animals at higher trophic level, such as invertebrates, fish and waterbirds. However, data regarding the spatiotemporal variation in isotopic composition of macrophytes are generally missing. We measured the carbon and nitrogen stable isotope ratios of Charophytes at Lake Constance, where they constitute a major food source for waterbirds. Our data reveal seasonal and site specific differences as well as depth-specific variations in isotopic carbon values within the littoral zone. Charophytes were enriched in (13)C at sites of higher productivity: the delta(13)C values were high in summer, at shallow and at relatively nutrient-rich sites, and comparatively low in winter, and in deeper and nutrient-poorer sites. In contrast, no temporal or spatial trend was found to explain the variability in the isotopic nitrogen values. These results imply that the seasonal timing of food intake (relative to turnover rates of consumers tissue) and the potential depth of foraging need to be taken into account when calculating the relative contribution of energy sources to diets of consumers such as waterbirds. PMID- 21698693 TI - G-Quadruplex formation of deoxyguanosine in the presence of alkaline earth metal ions studied by electrospray ionization mass spectrometry. PMID- 21698694 TI - Mass spectrometry studies of iridoid aglycone derivatives. PMID- 21698695 TI - Investigation of in-source decay of oxime-linked peptide by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. PMID- 21698696 TI - Calcium signaling in cognition and aging-dependent cognitive decline. AB - Calcium-dependent signals are key triggers of the molecular mechanisms underlying learning and memory and dysregulation of calcium homeostasis in the aging brain has been proposed to underlie aging-dependent cognitive decline. Mechanisms triggered by calcium in neurons include activity-dependent activation of transcription responsible for the synthesis of molecules underlying the long-term changes of neuronal function. Effectors of calcium signaling with a primordial role in transcription regulation are calcium signal-regulated transcription factors. In this review, we summarize the current knowledge of the contribution of key calcium signal-regulated transcription factors, namely CREB, NFAT, and DREAM, to memory formation. We further describe evidence for dysregulation of the activity of these factors during aging. PMID- 21698697 TI - Ca2+ homeostasis defects and hereditary hearing loss. AB - Ca(2+) acts as a fundamental signal transduction element in inner ear, delivering information about sound, acceleration and gravity through a small number of mechanotransduction channels in the hair cell stereocilia and voltage activated Ca(2+) channels at the ribbon synapse, where it drives neurotransmission. The mechanotransduction process relies on the endocochlear potential, an electrical potential difference between endolymph and perilymph, the two fluids bathing respectively the apical and basolateral membrane of the cells in the organ of Corti. In mouse models, deafness and lack or reduction of the endocochlear potential correlate with ablation of connexin (Cx) 26 or 30. These Cxs form heteromeric channels assembled in a network of gap junction plaques connecting the supporting and epithelial cells of the organ of Corti presumably for K(+) recycle and transfer of key metabolites, for example, the Ca(2+) -mobilizing second messenger IP(3) . Ca(2+) signaling in these cells could play a crucial role in regulating Cx expression and function. Another district where Ca(2+) signaling alterations link to hearing loss is hair cell apex, where ablation or missense mutations of the PMCA2 Ca(2+) -pump of the stereocilia cause deafness and loss of balance. If less Ca(2+) is exported from the stereocilia, as in the PMCA2 mouse mutants, Ca(2+) concentration in endolymph is expected to fall causing an alteration of the mechanotransduction process. This may provide a clue as to why, in some cases, PMCA2 mutations potentiated the deafness phenotype induced by coexisting mutations of cadherin-23 (Usher syndrome type 1D), a single pass membrane Ca(2+) binding protein that is abundantly expressed in the stereocilia. PMID- 21698699 TI - Voltage-gated calcium channels and disease. AB - Voltage-gated calcium channels are a family of integral membrane calcium selective proteins found in all excitable and many nonexcitable cells. Calcium influx affects membrane electrical properties by depolarizing cells and generally increasing excitability. Calcium entry further regulates multiple intracellular signaling pathways as well as the biochemical factors that mediate physiological functions such as neurotransmitter release and muscle contraction. Small changes in the biophysical properties or expression of calcium channels can result in pathophysiological changes leading to serious chronic disorders. In humans, mutations in calcium channel genes have been linked to a number of serious neurological, retinal, cardiac, and muscular disorders. PMID- 21698698 TI - Ca2+ dysfunction in neurodegenerative disorders: Alzheimer's disease. AB - More than one century ago "a peculiar disorder of the cerebral cortex" was noticed in a middle-aged patient who had been affected by dementia in the last years of his life. The postmortem hallmarks of his brain were protein plaques, neurofibrillary tangles, and atherosclerotic changes: the neuropathologist who found these alterations and gave his name to the disease that underlied them was Alois Alzheimer (Alzheimer et al., Clin Anat 1995;8:429-431). Following its discovery, the disease has been studied with a vigor that went parallel to the increase of its social importance. The amount of information amassed in the literature is impressive, but knowledge on the mechanism underlying its onset and its progression is still very limited. Numerous hypotheses on the molecular pathogenesis of the Alzheimer's disease (AD) have been proposed and two have gradually gained wide consensus: (i) the amyloid cascade hypothesis, first proposed on the basis of the toxicity evoked by the deposition of amyloid beta (Abeta) aggregates; (ii) the Ca(2+) hypothesis, which focuses on the correlation between the dysfunction of Ca(2+) homeostasis and the neurodegeneration process. This succinct review will discuss the essential aspects of the role of Ca(2+) homeostasis dysregulation in the onset and development of AD. PMID- 21698700 TI - Possible role for Ca2+ in the pathophysiology of the prion protein? AB - Transmissible spongiform encephalopathies, or prion diseases, are lethal neurodegenerative disorders caused by the infectious agent named prion, whose main constituent is an aberrant conformational isoform of the cellular prion protein, PrP(C) . The mechanisms of prion-associated neurodegeneration and the physiologic function of PrP(C) are still unclear, although it is now increasingly acknowledged that PrP(C) plays a role in cell differentiation and survival. PrP(C) thus exhibits dichotomic attributes, as it can switch from a benign function under normal conditions to the triggering of neuronal death during disease. By reviewing data from models of prion infection and PrP-knockout paradigms, here we discuss the possibility that Ca(2+) is the hidden factor behind the multifaceted behavior of PrP(C) . By featuring in almost all processes of cell signaling, Ca(2+) might explain diverse aspects of PrP(C) pathophysiology, including the recently proposed one in which PrP(C) acts as a mediator of synaptic degeneration in Alzheimer's disease. PMID- 21698703 TI - MRI assessment of iron deposition in multiple sclerosis. AB - Iron deposition in the human brain tissue occurs in the process of normal aging and in many neurodegenerative diseases. Elevated iron levels in certain brain regions are also an increasingly recognized finding in multiple sclerosis (MS). The exact mechanism(s) for this phenomenon and its implication in terms of pathophysiology and clinical significance are still largely unknown and debated. Reliable methods to exactly quantify brain iron are a first step to clarify these issues. Therefore, the aim of this review is to present currently available magnetic resonance imaging (MRI) techniques for the assessment of brain iron. These include relaxation time mapping, phase imaging, susceptibility-weighted imaging, susceptibility mapping, magnetic field correlation imaging, and direct saturation imaging. After discussing their advantages and disadvantages, existing MRI clinical correlations with brain iron concentration in MS are summarized and future research directions are shown. PMID- 21698702 TI - High temporal and spatial resolution 3D time-resolved contrast-enhanced magnetic resonance angiography of the hands and feet. AB - Methods are described for generating 3D time-resolved contrast-enhanced magnetic resonance (MR) angiograms of the hands and feet. Given targeted spatial resolution and frame times, it is shown that acceleration of about one order of magnitude or more is necessary. This is obtained by a combination of 2D sensitivity encoding (SENSE) and homodyne (HD) acceleration methods. Image update times from 3.4-6.8 seconds are provided in conjunction with view sharing. Modular receiver coil arrays are described which can be designed to the targeted vascular region. Images representative of the technique are generated in the vasculature of the hands and feet in volunteers and in patient studies. PMID- 21698704 TI - Intracranial arterial wall imaging using three-dimensional high isotropic resolution black blood MRI at 3.0 Tesla. AB - PURPOSE: To develop a high isotropic-resolution sequence to evaluate intracranial vessels at 3.0 Tesla (T). MATERIALS AND METHODS: Thirteen healthy volunteers and 4 patients with intracranial stenosis were imaged at 3.0T using 0.5-mm isotropic resolution three-dimensional (3D) Volumetric ISotropic TSE Acquisition (VISTA; TSE, turbo spin echo), with conventional 2D-TSE for comparison. VISTA was repeated for 6 volunteers and 4 patients at 0.4-mm isotropic-resolution to explore the trade-off between SNR and voxel volume. Wall signal-to-noise-ratio (SNR(wall) ), wall-lumen contrast-to-noise-ratio (CNR(wall-lumen) ), lumen area (LA), wall area (WA), mean wall thickness (MWT), and maximum wall thickness (maxWT) were compared between 3D-VISTA and 2D-TSE sequences, as well as 3D images acquired at both resolutions. Reliability was assessed by intraclass correlations (ICC). RESULTS: Compared with 2D-TSE measurements, 3D-VISTA provided 58% and 74% improvement in SNR(wall) and CNR(wall-lumen) , respectively. LA, WA, MWT and maxWT from 3D and 2D techniques highly correlated (ICCs of 0.96, 0.95, 0.96, and 0.91, respectively). CNR(wall-lumen) using 0.4-mm resolution VISTA decreased by 27%, compared with 0.5-mm VISTA but with reduced partial-volume-based overestimation of wall thickness. Reliability for 3D measurements was good to excellent. CONCLUSION: The 3D-VISTA provides SNR-efficient, highly reliable measurements of intracranial vessels at high isotropic-resolution, enabling broad coverage in a clinically acceptable time. PMID- 21698705 TI - Investigation of acupoint specificity by multivariate granger causality analysis from functional MRI data. AB - PURPOSE: To investigate the acupoint specificity by exploring the effective connectivity patterns of the poststimulus resting brain networks modulated by acupuncture at the PC6, with the same meridian acupoint PC7 and different meridian acupoint GB37. MATERIALS AND METHODS: The functional MRI (fMRI) study was performed in 36 healthy right-handed subjects receiving acupuncture at three acupoints, respectively. Due to the sustained effects of acupuncture, a novel experimental paradigm using the nonrepeated event-related (NRER) design was adopted. Psychophysical responses (deqi sensations) were also assessed. Finally, a newly multivariate Granger causality analysis (mGCA) was used to analyze effective connectivity patterns of the resting fMRI data taken following acupuncture at three acupoints. RESULTS: Following acupuncture at PC6, the red nucleus and substantia nigra emerged as central hubs, in comparison with the fusiform gyrus following acupuncture at GB37. Red nucleus was also a target following acupuncture at PC7, but with fewer inputs than those of PC6. In addition, the most important target following acupuncture at PC7 was located at the parahippocampus. CONCLUSION: Our findings demonstrated that acupuncture at different acupoints may exert heterogeneous modulatory effects on the causal interactions of brain areas during the poststimulus resting state. These preliminary findings provided a clue to elucidate the relatively function oriented specificity of acupuncture effects. PMID- 21698706 TI - Dynamic late gadolinium enhancement simply quantified using myocardium to lumen signal ratio: normal range of ratio and diffuse abnormal enhancement of cardiac amyloidosis. AB - PURPOSE: To detect abnormal myocardial tissue in patients with diffuse myocardial disease, we propose a simple technique of late gadolinium enhancement (LGE) using routine myocardial imaging modalities. MATERIALS AND METHODS: We retrospectively reviewed LGE images from 51 patients with normal myocardium and 10 patients with pathologically proven cardiac amyloidosis (CA). We obtained sequential LGE images from patients at 2, 5, 10, and 20 minutes after injection of Gd-DTPA (0.15 mmol/kg) with a fixed inversion time of 300 msec. We evaluated the signal intensity ratio of the myocardium to the left ventricular lumen (M/L) in one long and two short axial sections within 463 and 120 segments of normal myocardium and CA, respectively. Visually unenhanced and enhanced regions of myocardium were evaluated in each segment of patients with CA. RESULTS: Among normal myocardium, M/L (means +/- standard deviation; SD) was stable with time (2, 5, 10, and 20 min: 0.34 +/- 0.03, 0.31 +/- 0.05, 0.34 +/- 0.07, and 0.42 +/- 0.11, respectively). The calculated M/L of unenhanced (0.60 +/- 0.20, 0.68 +/- 0.19, 0.76 +/- 0.20, and 1.09 +/- 0.25, respectively) and enhanced myocardium (0.77 +/- 0.27, 0.99 +/- 0.29, 1.20 +/- 0.40, and 1.45 +/- 0.54, respectively) in patients with CA was significantly greater than that seen for the normal myocardium at each time and increased over time. CONCLUSION: In patients with CA, diffuse myocardial abnormalities can be demonstrated using M/L, and this technique may be useful for the characterization of other myocardial diseases. PMID- 21698707 TI - Prostate cancer: utility of fusion of T2-weighted and high b-value diffusion weighted images for peripheral zone tumor detection and localization. AB - PURPOSE: To retrospectively assess the utility of fusion of T2-weighted images (T2WI) and high b-value diffusion-weighted images (DWI) for prostate cancer detection and localization. MATERIALS AND METHODS: In this IRB-approved HIPAA compliant study, 42 patients with prostate cancer underwent MRI including multiplanar T2WI and axial DWI before prostatectomy. Two independent radiologists first assessed multiplanar T2WI and axial DWI(b-1000) images and recorded whether tumor was present in each sextant. Axial T2WI was then fused with axial DWI(b 1000) images, and the radiologists re-evaluated each sextant for tumor. Accuracy was compared using generalized estimating equations based on a binary logistic regression model. RESULTS: The accuracy, sensitivity, specificity, PPV, and NPV for tumor detection on a sextant-basis using separate and fused image sets was 65.1%, 50.8%, 78.0%, 67.8%, and 63.6% and 71.0%, 60.8%, 80.3%, 73.7%, and 69.3%, respectively, for reader 1, and 54.0%, 42.5%, 64.4%, 52.0%, and 55.2%, and 61.1%, 56.7%, 65.2%, 59.6%, and 62.3%, respectively, for reader 2. The improvements in accuracy, sensitivity, and NPV using fused images were statistically significant for both readers, as was the improvement in PPV for reader 2 (P ranging from <0.0001 to 0.041). With either separate or fused images, there was greater sensitivity for tumors of higher grade or larger size (P ranging from <0.001 to 0.099). CONCLUSION: Fusion of T2WI and high b-value DWI resulted in significant improvements in sensitivity and accuracy for tumor detection on a sextant-basis, with similar specificity. PMID- 21698708 TI - dGEMRIC and subsequent T1 mapping of the hip at 1.5 Tesla: normative data on zonal and radial distribution in asymptomatic volunteers. AB - PURPOSE: To characterize the zonal distribution of three-dimensional (3D) T1 mapping in the hip joint of asymptomatic adult volunteers. MATERIALS AND METHODS: This study included 10 volunteers (3 males and 7 females with a mean age of 26.5 years; range, 24-31 years). MRI protocol included standard sequences for hip imaging and a dual-flip-angle 3D gradient-echo (GRE) sequence with volumetric interpolated breathhold examination (VIBE) postcontrast administration. Seven radial cuts were created clockwise around the femoral neck by using multi-planar reconstruction. RESULTS: Analysis of the radial distribution revealed an increase of T1-values toward the superior regions. T1-values differed between the peripheral and central portions. The standard deviation (SD) ranged from 76.2 ms to 124.1 ms in the peripheral zone, and from 69.1 ms to 112.9 ms in the central zone. In both zones, SD was low in the superior regions compared with the anterior and posterior regions of the joint. Based on the high intra- (0.95) and interobserver (0.87) agreement, normative data from this study will prepare the foundation for further studies of dGEMRIC and T1 in the hip. CONCLUSION: We noted a radial T1 mapping pattern with higher values in the superior zone that was not statistically significant and a notable trend in zonal distribution between peripheral and central zones. These findings are critical while outlining future studies for detailed objective evaluation of zonal cartilage lesions due to varying pathologies. PMID- 21698709 TI - Unenhanced ECG-gated fast spin-echo MR digital subtraction angiography (MRDSA) using short echo-spacing three-dimensional sequence of femoral arteries: initial experience. AB - PURPOSE: To compare the image qualities of unenhanced electrocardiographically (ECG)-gated fast spin-echo magnetic resonance digital subtraction angiography (MRDSA) using a short echo-spacing three-dimensional (3D) sequence, known as sampling perfection with application-optimized contrasts using different flip angle evolutions (SPACE), and the conventional half-Fourier single-shot turbo spin-echo (HASTE) sequence. MATERIALS AND METHODS: Unenhanced ECG-gated MRDSA using SPACE and HASTE of the femoral arteries were prospectively acquired in 13 healthy volunteers at 1.5 Tesla (T) MRI. Sequential frontal maximum-intensity projection images produced by subtracting each of 10 systolic images from a diastolic image were evaluated quantitatively using paired t-test and qualitatively by two blinded radiologists using the Mann-Whitney U-test. RESULTS: Quantitatively, relative contrast against the background, contour sharpness index, and slope of the sequential signal changes of the superficial femoral artery of MRDSA using SPACE were significantly better than those of HASTE (P = 0.005, P = 0.001, and P < 0.0001, respectively). Qualitatively, the overall subjective image quality and sequential appearance changes of MRDSA using SPACE were significantly better than those of HASTE (P < 0.0001 and P < 0.0001, respectively). CONCLUSION: Unenhanced ECG-gated fast spin-echo MRDSA using SPACE produces increments in signal intensity, which reflect arterial pulse wave transmission, more clearly than the conventional HASTE sequence. PMID- 21698710 TI - Subperitoneal adenomucinosis following proctocolectomy for ulcerative colitis. AB - Adenomucinosis is a rare condition characterized by accumulation of large volumes of mucin, typically related to mucinous neoplasms of the appendix within the peritoneal space. Extraperitoneal adenomucinosis is an uncommon variant where mucin accumulates outside the peritoneal space and usually arises following surgery for mucinous appendiceal neoplasms. This is a case of subperitoneal adenomucinosis resulting from retention of a small fragment of rectal mucosa following proctocolectomy for ulcerative colitis 16 years prior. The patient presented with a slow-growing boggy perineal mass. Contrast-enhanced magnetic resonance imaging (MRI) showed the mass to be localized to the pelvis, without solid enhancing components, and correctly facilitated local surgical excision without the risk of peritoneal dissemination and accurately predicted benignity. PMID- 21698711 TI - Measuring lung water: ex vivo validation of multi-image gradient echo MRI. AB - PURPOSE: To validate a fast gradient echo sequence for rapid (9 s) quantitative imaging of lung water. MATERIALS AND METHODS: Eleven excised pig lungs were imaged with a fast GRE sequence in triplicate, in the sagittal plane at 2 levels of inflation pressure (5 and 15 cm H(2) O), an intervention that alters T(2) *, but not total lung water. Images were acquired alternating between two closely spaced echoes and data were fit (voxel-by-voxel) to a single exponential to determine T(2) * and water content, and compared with gravimetric measurements of total water. RESULTS: T(2) * averaged 1.08 +/- 0.02 ms at 5 cm H(2) O and 1.02 +/ 0.02 ms at 15 cm H(2) O (P < 0.05). The measure was reliable (R(2) = 0.99), with an average mean error of 1.8%. There was a significant linear relationship between the two measures of water content: The regression equations for the relationship were y = 0.92x + 19 (R(2) = 0.94), and y = 1.04x + 4 (R(2) = 0.96), for 5 and 15 cm H(2) O inflation pressure respectively. Y-intercepts were not statistically different from zero (P = 0.86). CONCLUSION: The multi-echo GRE sequence is a reliable and valid technique to assess water content in the lung. This technique enables rapid assessment of lung water, which is advantageous for in vivo studies. PMID- 21698712 TI - Effects of respiratory cycle and body position on quantitative pulmonary perfusion by MRI. AB - PURPOSE: To evaluate the performance of lung perfusion imaging using two dimensional (2D) first pass perfusion MRI and a quantitation program based on model-independent deconvolution algorithm. MATERIALS AND METHODS: In eight healthy volunteers 2D first pass lung perfusion was imaged in coronal planes using a partial Fourier saturation recovery stead state free precession (SSFP) technique with a temporal resolution of 160 ms per slice acquisition. The dynamic signal in the lung was measured over time and absolute perfusion calculated based on a model-independent deconvolution program. RESULTS: In the supine position mean pulmonary perfusion was 287 +/- 106 mL/min/100 mL during held expiration. It was significantly reduced to 129 +/- 68 mL/min/100 mL during held inspiration. Similar differences due to respiration were observed in prone position with lung perfusion much greater during expiration than during inspiration (271 +/- 101 versus 99 +/- 38 mL/min/100 mL (P < 0.01)). There was a linear increase in pulmonary perfusion from anterior to posterior lung fields in supine position. The perfusion gradient reversed in the prone position with the highest perfusion in anterior lung and the lowest in posterior lung fields. CONCLUSION: Lung perfusion imaging using a 2D saturation recovery SSFP perfusion MRI coupled with a model-independent deconvolution algorithm demonstrated physiologically consistent dynamic heterogeneity of lung perfusion distribution. PMID- 21698713 TI - In vivo single scan detection of both iron-labeled cells and breast cancer metastases in the mouse brain using balanced steady-state free precession imaging at 1.5 T. AB - PURPOSE: To simultaneously detect iron-labeled cancer cells and brain tumors in vivo in one scan, the balanced steady-state free precession (b-SSFP) imaging sequence was optimized at 1.5 T on mice developing brain metastases subsequent to the injection of micron-sized iron oxide particle-labeled human breast cancer cells. MATERIALS AND METHODS: b-SSFP sequence parameters (repetition time, flip angle, and receiver bandwidth) were varied and the signal-to-noise ratio, contrast between the brain and tumors, and the number of detected iron-labeled cells were evaluated. RESULTS: Optimal b-SSFP images were acquired with a 26 msec repetition time, 35 degrees flip angle, and bandwidth of +/-21 kHz. b-SSFP images were compared with T(2) -weighted 2D fast spin echo (FSE) and 3D spoiled gradient recalled echo (SPGR) images. The mean tumor-brain contrast-to-noise ratio and the ability to detect iron-labeled cells were the highest in the b-SSFP images. CONCLUSION: A single b-SSFP scan can be used to visualize both iron labeled cells and brain metastases. PMID- 21698714 TI - A generalized strategy for designing (19)F/(1)H dual-frequency MRI coil for small animal imaging at 4.7 Tesla. AB - PURPOSE: To propose and test a universal strategy for building (19) F/(1) H dual frequency RF coil that permits multiple coil geometries. MATERIALS AND METHODS: The feasibility to design (19) F/(1) H dual-frequency RF coil based on coupled resonator model was investigated. A series capacitive matching network enables robust impedance matching for both harmonic oscillating modes of the coupled resonator. Two typical designs of (19) F/(1) H volume coils (birdcage and saddle) at 4.7T were implemented and evaluated with electrical bench test and in vivo (19) F/(1) H dual-nuclei imaging. RESULTS: For various combinations of internal resistances of the sample coil and secondary resonator, numerical solutions for the tunable capacitors to optimize impedance matching were obtained using a root seeking program. Identical and homogeneous B1 field distribution at (19) F and (1) H frequencies were observed in bench test and phantom image. Finally, in vivo mouse imaging confirmed the sensitivity and homogeneity of the (19) F/(1) H dual frequency coil design. CONCLUSION: A generalized strategy for designing (19) F/(1) H dual-frequency coils based on the coupled resonator approach was developed and validated. A unique feature of this design is that it preserves the B1 field homogeneity of the RF coil at both resonant frequencies. Thus it minimizes the susceptibility effect on image co-registration. PMID- 21698715 TI - Introduction: Bio and nano imaging and analysis. PMID- 21698716 TI - Visualization of bionanostructures using transmission electron microscopical techniques. AB - In the recent years, nanotechnology has rapidly evolved as promising toolbox for many applications, including sensing and drug delivery. Nanotechnology aims at forming man-designed two-dimensional and three-dimensional structures in the nanometer scale using e.g., the self-assembly properties of smaller building blocks such as DNA and RNA. The visualization and structural characterization of these nanostructures do not only provide evidence for the correct formation of the desired shapes, but can also contribute to a better understanding of their formation and functionality. Transmission electron microscopy offers the possibility to directly visualize the individual nanostructures. The vitrification of the sample by using the plunge-freezing method and subsequent electron cryomicroscopy (cryo-EM) provides in-solution snapshots of the nanostructures under cryogenic conditions and thus preserves the close-to-native structure of the particles. Here, we describe the plunge-freezing and other sample preparation protocols such as negative staining and cryo-negative staining as well as the various imaging and image processing methods, including electron crystallography, electron tomography, and single-particle EM. Typical example applications are provided together with a discussion of benefits and shortcomings of these approaches. We also discuss how deviations from an ideal symmetry and structural heterogeneity, in general, can limit the resolution. Finally, we suggest that nanotechnological approaches may not only offer new applications in the field of nanomaterial science and nanomedicine, but may also emerge as tools for structural biology and structure-related biomedical research. PMID- 21698717 TI - Single molecule microscopy methods for the study of DNA origami structures. AB - Single molecule microscopy techniques play an important role in the investigation of advanced DNA structures such as those created by the DNA origami method. Three single molecule microscopy techniques are particularly interesting for the investigation of complex self-assembled three-dimensional (3D) DNA nanostructures, namely single molecule fluorescence microscopy, atomic force microscopy (AFM), and cryogenic transmission electron microscopy (cryo-EM). Here we discuss the strengths of these three techniques and demonstrate how their interplay can yield very important and unique new insights into the structure and conformation of advanced biological nanostructures. The applications of the three single molecule microscopy techniques are illustrated by focusing on a self assembled DNA origami 3D box nanostructure. Its size and structure were studied by AFM and cryo-EM, while the lid opening, which can be controlled by the addition of oligonucleotide keys, was recorded by Forster/fluorescence resonance energy transfer (FRET) spectroscopy. PMID- 21698718 TI - Studies of the growth, evolution, and self-aggregation of beta-amyloid fibrils using tapping-mode atomic force microscopy. AB - Amyloid peptide (Abeta) is the major protein component of plaques found in Alzheimer's disease, and the aggregation of Abeta into oligomeric and fibrillic assemblies has been shown to be an early event of the disease pathway. Visualization of the progressive evolution of nanoscale changes in the morphology of Abeta oligomeric assemblies and amyloid fibrils has been accomplished ex situ using atomic force microscopy (AFM) in ambient conditions. In this report, the size and the shape of amyloid beta(1-40) fibrils, as well as the secondary organization into aggregate structures were monitored at different intervals over a period of 5 months. Characterizations with tapping-mode AFM serve to minimize the strong adhesive forces between the probe and the sample to prevent damage or displacement of fragile fibrils. The early stages of Abeta growth showed a predominance of spherical seed structures, oligomeric assemblies, and protofibrils; however the size and density of fibrils progressively increased with time. Within a few days of incubation, linear assemblies and fibrils became apparent. Over extended time scales of up to 5 months, the fibrils formed dense ensembles spanning lengths of several microns, which exhibit interesting changes due to self-organization of the fibrils into bundles or tangles. Detailed characterization of the Abeta assembly process at the nanoscale will help elucidate the role of Abeta in the pathology of Alzheimer's disease. PMID- 21698719 TI - Blushing propensity and psychological distress in people with rosacea. AB - Rosacea is a chronic skin disorder, characterized by persistent painful facial flushing and often accompanied by papules and pustules. To evaluate the psychological and social impacts of rosacea, 31 individuals with rosacea filled in the Blushing Propensity Scale, the Fear of Negative Evaluation Questionnaire, the Depression Anxiety and Stress Scale, the Social Interaction Anxiety Scale and the Social Phobia Scale. The questionnaires were also completed by 86 controls. Participants with extensive facial papules and pustules had higher blushing propensity, stress and social phobia scores than controls or others without papules or pustules. Childhood blushing was also reported more frequently by participants with rosacea than controls. Cognitive-behavioural therapy appeared to be helpful for managing social anxiety in three individuals with rosacea with a fear of blushing. These findings suggest that people with severe rosacea are anxious about the social consequences of blushing and generally prefer to avoid situations that might involve scrutiny by others. Persistent facial flushing could prime interoceptive cues of blushing or increase anxiety about facial coloration in provocative situations. Treatments that target fear of blushing may help to reduce social anxiety in people with severe rosacea. KEY PRACTITIONER MESSAGE: Blushing propensity scores are elevated in people with severe rosacea. Fear of blushing may contribute to social anxiety and avoidance in such cases. Cognitive-behavioural therapy for fear of blushing may help to reduce social anxiety in people with severe rosacea. PMID- 21698721 TI - Cantilever-free scanning probe molecular printing. PMID- 21698720 TI - Host-microbe relationships in inflammatory bowel disease detected by bacterial and metaproteomic analysis of the mucosal-luminal interface. AB - BACKGROUND: Host-microbe interactions at the intestinal mucosal-luminal interface (MLI) are critical factors in the biology of inflammatory bowel disease (IBD). METHODS: To address this issue, we performed a series of investigations integrating analysis of the bacteria and metaproteome at the MLI of Crohn's disease, ulcerative colitis, and healthy human subjects. After quantifying these variables in mucosal specimens from a first sample set, we searched for bacteria exhibiting strong correlations with host proteins. This assessment identified a small subset of bacterial phylotypes possessing this host interaction property. Using a second and independent sample set, we tested the association of disease state with levels of these 14 "host interaction" bacterial phylotypes. RESULTS: A high frequency of these bacteria (35%) significantly differentiated human subjects by disease type. Analysis of the MLI metaproteomes also yielded disease classification with exceptional confidence levels. Examination of the relationships between the bacteria and proteins, using regularized canonical correlation analysis (RCCA), sorted most subjects by disease type, supporting the concept that host-microbe interactions are involved in the biology underlying IBD. Moreover, this correlation analysis identified bacteria and proteins that were undetected by standard means-based methods such as analysis of variance, and identified associations of specific bacterial phylotypes with particular protein features of the innate immune response, some of which have been documented in model systems. CONCLUSIONS: These findings suggest that computational mining of mucosa-associated bacteria for host interaction provides an unsupervised strategy to uncover networks of bacterial taxa and host processes relevant to normal and disease states. (Inflamm Bowel Dis 2012;). PMID- 21698722 TI - Dimerization of a metal complex through thermally induced single-crystal-to single-crystal transformation or mechanochemical reaction. PMID- 21698723 TI - Use of labile precursors for the generation of hyperpolarized molecules from hydrogenation with parahydrogen and aqueous-phase extraction. PMID- 21698724 TI - Differentially charged hollow core/shell lipid-polymer-lipid hybrid nanoparticles for small interfering RNA delivery. PMID- 21698725 TI - Simple, stable, and easily accessible well-defined CuCF3 aromatic trifluoromethylating agents. PMID- 21698727 TI - Rhodium-catalyzed domino enantioselective synthesis of bicyclo[2.2.2]lactones. PMID- 21698726 TI - Supramolecular control of ligand coordination and implications in hydroformylation reactions. PMID- 21698728 TI - A simple and highly efficient iron catalyst for a [2+2+2] cycloaddition to form pyridines. PMID- 21698729 TI - Mesoporous ferrihydrite-based iron oxide nanoparticles as highly promising materials for ozone removal. PMID- 21698730 TI - Split personality of lithium chloride: recent salt effects in organometallic recipes. PMID- 21698731 TI - Assembly of substituted 2-alkylquinolines by a sequential palladium-catalyzed C-N and C-C bond formation. PMID- 21698733 TI - Visible-light-induced oxidation/[3+2] cycloaddition/oxidative aromatization sequence: a photocatalytic strategy to construct pyrrolo[2,1-a]isoquinolines. PMID- 21698732 TI - Caprolactam from renewable resources: catalytic conversion of 5 hydroxymethylfurfural into caprolactone. PMID- 21698734 TI - Formation of cyclo-E4(2-) units (E4 =P4, As4, AsP3) by a complex with a Cr-Cr quintuple bond. PMID- 21698735 TI - [Sn4Si{Si(SiMe3)3}4{SiMe3}2]: a model compound for the unexpected first-order transition from a singlet biradicaloid to a classical bonded molecule. PMID- 21698736 TI - Fusion of phosphole and 1,1'-biacenaphthene: phosphorus(V)-containing extended pi systems with high electron affinity and electron mobility. AB - A profusion of phospholes: Diacenaphtho[1,2-b:1',2'-d]phospholes, a new class of arene-fused phosphole pi-systems, were synthesized and their structural and electrochemical properties studied. The P-sulfide derivative has a high electron transporting ability (MU(E) =2.4*10(-3) cm(2) V(-1) s(-1)) in a vacuum-deposited film. PMID- 21698737 TI - Two induced fungal polyketide pathways converge into antiproliferative spiroanthrones. PMID- 21698738 TI - Bis-azobenzene crosslinkers for photocontrol of peptide structure. AB - Crosslinkers that undergo large changes in length upon photoisomerization can produce large conformational changes, and thereby functional changes, in biomolecules. We have designed and synthesized extended and rigid bis-azobenzene crosslinkers: 4,4'-bis(4-(2-chloroacetamido)phenyl)diazenylbiphenyl (BPDB) and the water-soluble sulfonated analogue 4,4'-bis(4-(2 chloroacetamido)phenyl)diazenylbiphenyl-2,2'-disulfonate (BPDBS). These photoswitches can produce end-to-end distance changes of a minimum of ~5 A and a maximum of ~23 A upon trans/cis isomerization. They have high absorption coefficients (45-60 000 M(-1) cm(-1) ) and can produce up to ~80 % cis isomers under favorable conditions. The photoswitching behavior of BPDBS-crosslinked peptides was found to be highly dependent on the crosslinker attachment site. Upon UV irradiation (365 nm), significant decreases in alpha-helix content were observed for peptides that were crosslinked with BPDBS through Cys residues at i,i+19, and i,i+21 positions. In contrast, large increases in alpha-helix content were exhibited by i,i+11 crosslinked peptides. BPDBS thus constitutes a particularly bright and effective photoswitch for biomolecule photocontrol. PMID- 21698739 TI - Glycine peptide bond formation catalyzed by faujasite. AB - The catalysis of peptide bond formation between two glycine molecules on H-FAU zeolite was computationally studied by the M08-HX density functional. Two reaction pathways, the concerted and the stepwise mechanism, starting from three differently adsorbed reactants, amino-bound, carboxyl-bound, and hydroxyl-bound, are studied. Adsorption energies, activation energies, and reaction energies, as well as the corresponding intrinsic rate constants were calculated. A comparison of the computed energetics of the various reaction paths for glycine indicates that the catalyzed reaction proceeds preferentially via the concerted reaction mechanism of the hydroxyl-bound configuration. This involves an eight-membered ring of the transition structure instead of the four-membered ring of the others. The step from the amino-bound configuration to glycylglycine is the rate determining step of the concerted mechanism. It has an estimated activation energy of 51.2 kcal mol(-1). Although the catalytic reaction can also occur via the stepwise reaction mechanism, this path is not favored. PMID- 21698740 TI - Conformational equilibria in adducts of alcohols with ethers: the rotational spectrum of ethylalcohol-dimethylether. AB - The rotational spectra of two conformers of the molecular complex ethylalcohol dimethylether were measured with pulsed-jet Fourier transform microwave spectroscopy. Both trans and gauche conformations of ethylalcohol are preserved in the complex, originating two conformations with dimethylether as the proton accepting unit. A switch of the conformational stability of ethyl alcohol is observed upon complexation with dimethyl ether, with the gauche form becoming the global minimum. The investigation of the O-D deuterated species allowed observing quantitatively the Ubbelohde effect, which is the shrinkage of the O???O distance of about 6 mA upon H->D isotopic substitution of the hydroxylic hydrogen participating in the O-H???O hydrogen bond. PMID- 21698741 TI - Synergistic role of B and F dopants in promoting the photocatalytic activity of rutile TiO2. PMID- 21698742 TI - Structural and size effects on the spectroscopic and redox properties of CdSe nanocrystals in solution: the role of defect states. AB - Two series of CdSe quantum dots (QDs) with different diameters are prepared, according to frequently used protocols of the same synthetic procedure. For each sample the photophysical properties and the potentials for the first reduction and oxidation processes in organic solution are determined. The band gap obtained from electrochemical experiments is compared with that determined from the absorption and luminescence spectra. While the optical band gap decreases upon increasing the nanocrystal diameter, as expected on the basis of quantum confinement, the redox potentials and the electrochemical band gap are not monotonously related to the QD size. For both series, the smallest and largest QDs are both easier to oxidize and reduce than mid-sized QDs. In fact, the latter samples exhibit very broad voltammetric profiles, which suggests that the heterogeneous electron-transfer processes from/to the electrode are kinetically hindered. Conversely, the electrochemical band gap for the smallest and largest particles of each series is somewhat smaller than the optical band gap. These results indicate that, while the optical band gap depends on the actual electron hole recombination within the nanocrystal, and therefore follows the size dependence expected from the particle-in-a-box model, the electrochemical processes of these QDs are strongly affected by other factors, such as the presence of surface defects. The investigations suggest that the influence of these defects on the potential values is more important for the smallest and largest QDs of each series, as confirmed by the respective luminescence bands and quantum yields. An interpretation for the size-dependent evolution of the surface defects in these nanocrystals is proposed based on the mechanism of their formation and growth. PMID- 21698743 TI - Multisensing emissive pyrimidine. AB - Fluorescent nucleoside analogs, commonly used to explore nucleic acid dynamics, recognition and damage, frequently respond to a single environmental parameter. Herein we address the development of chromophores that can simultaneously probe more than one environmental factor while having each associated with a unique spectroscopic signature. We demonstrate that an isomorphic emissive pyridine modified 2-deoxy-uridine 1, containing multiple sensory elements, responds to changes in acidity, viscosity, and polarity. Protonation of the pyridine moiety (pK(a) 4.4) leads to enhanced emission (lambda(em) =388 nm) and red-shifted absorption spectra (lambda(abs) =319 nm), suggesting the formation of an intramolecular hydrogen bond with the neighboring pyrimidine carbonyl. This "locked" conformation can also be mimicked by increasing solvent viscosity, resulting in a stark enhancement of emission quantum yield. Finally, increasing solvent polarity substantially impacts the chromophore's Stokes shift [from 5.8*10(3) cm(-1) at E(T) (30)=36.4 kcal mol(-1) to 9.3 *10(3) cm(-1) at E(T) (30)=63.1 kcal mol(-1)]. The opposite effect is seen for the impact of solvent polarity of the protonated form. The characteristic photophysical signature induced by each parameter facilitates the exploration of these environmental factors both individually and simultaneously. PMID- 21698744 TI - Laser analysis and control of complex molecular systems. PMID- 21698746 TI - Structural basis of thrombin-protease-activated receptor interactions. AB - Aggregation of platelets is an essential step in the formation of a stable blood clot during vascular injury. The trypsin-like protease thrombin acts as the dominant agonist of platelet activation on engagement of protease-activated receptors (PARs). Important details on the molecular aspects of thrombin-PAR interactions have been revealed recently by structural biology. In the case of human platelets, PAR1 engages thrombin via an extended surface of recognition encompassing the active site and exosite I. In the case of murine platelets, PAR4 binds to the active site in a conformation that leaves exosite I free for interaction with cofactors like PAR3. Human PAR4 mimics the murine receptor binding mechanism for residues upstream of the scissile bond. This information is consistent with existing functional data and provides a solid background for future structural and mutagenesis studies of PAR interaction with thrombin and related proteases. PMID- 21698747 TI - Muscle-type 6-phosphofructo-1-kinase and aldolase associate conferring catalytic advantages for both enzymes. AB - 6-Phosphofructo-1-kinase (PFK) and aldolase are two sequential glycolytic enzymes that associate forming heterotetramers containing a dimer of each enzyme. Although free PFK dimers present a negligible activity, once associated to aldolase these dimers are as active as the fully active tetrameric conformation of the enzyme. Here we show that aldolase-associated PFK dimers are not inhibited by clotrimazole, an antifungal azole derivative proposed as an antineoplastic drug due to its inhibitory effects on PFK. In the presence of aldolase, PFK is not modulated by its allosteric activators, ADP and fructose-2,6-bisphosphate, but is still inhibited by citrate and lactate. The association between the two enzymes also results on the twofold stimulation of aldolase maximal velocity and affinity for its substrate. These results suggest that the association between PFK and aldolase confers catalytic advantage for both enzymes and may contribute to the channeling of the glycolytic metabolism. PMID- 21698748 TI - Moonlighting proteins in neurological disorders. PMID- 21698749 TI - Moonlighting characteristics of G protein-coupled receptors: focus on receptor heteromers and relevance for neurodegeneration. AB - It is proposed that the moonlighting concept can be applied to G protein coupled receptors (GPCRs) as, obviously, they can carry out different types of functions. The same motifs in, for example, the third intracellular loop, can moonlight by switching between receptor-receptor interactions and interactions with signaling proteins such as G proteins or calmodulin. A "guide-and-clasp" manner of receptor receptor interactions has been proposed where the "adhesive guides" may be the triplet homologies. As an example, the triplets AAR (or RAA) and AAE (or EAA) homologies in A(2A) R-D2 R heteromers may guide-and-clasp binding not only of the two protomers but also of calmodulin and G(i) . A beautiful moonlighting phenomenon in the A(2A) R-D2 R heteromer is that the positively charged D2 R N terminal third intracellular loop epitope (VLRRRRKRVN) may switch between bindings to the negatively charged A(2A) R epitope (SAQEpSQGNT), localized in the medium segment of the C terminus of the A2A receptor to several negative epitopes of calmodulin. Furthermore, overlapping motifs may favor moonlighting to G(i/o) via inter alia electrostatic interaction between triplets AAR(in D2 R third intracellular loop) and AAE (G(i/alpha1) ) (and/or their symmetric variants) contributing to guide-and-clasp D2 R-G(i) interactions Thus, moonlighting in GPCR heteromers can take place via allosteric receptor-receptor interactions and is also described in D1 R-D2 R, D2 R-5-HT2 R,and A1 R-P2Y1 heteromers. Allosteric receptor-receptor interactions in GPCR-receptor tyrosine kinases (RTKs) heteromers and postulated ion channel receptor-RTK heteromers-like, for example, AMPA-NMDA-TrkB heteromers may lead to moonlighting of the participating GPCR and RTK protomers altering, for example, the pattern of the five major signaling pathways of the RTKs favoring MAPK and/or mTOR signaling with high relevance for neurodegenerative processes and depression induced atrophy of neurons. Moonlighting may also develop in the intracellular loops and C-terminal of the GPCRs as a result of dynamic allosteric interactions between different types of G proteins and other receptor interacting proteins in these domains of the receptor. PMID- 21698750 TI - Moonlighting cytochrome P450 monooxygenases. AB - Recently, cytochrome P450 170A1 (CYP170A1) has been found to be a bifunctional protein, which catalyzes both monooxygenase activity and terpene synthase activity by two distinct active sites in the well-established P450 protein structure. Therefore, CYP170A1 is identified clearly as a moonlighting protein. The known activities of a small number of the 13,000 members of the P450 superfamily fall into two general classes: promiscuous enzymes that are not considered as moonlighting and forms that participate in biosynthesis of endogenous compounds, such as steroids, vitamins and play different roles in different tissues, sometimes being moonlighting enzymes. Here, we review examples of moonlighting P450, which add to our understanding of the large CYP superfamily. PMID- 21698751 TI - Intrinsically unstructured proteins and neurodegenerative diseases: conformational promiscuity at its best. AB - Neurodegenerative diseases are complex, multifactorial disorders where misfolding of proteins cause aberrant protein-protein interactions. They are not usually characterized by specific mutations especially for nonfamilial disease types. Most of the causative proteins, however, are intrinsically unstructured (IUP), loss of whose fine balance could play pivotal role in these processes. Very fast conformational switch of these IUPs between different functional forms, so as to choose different interaction partners and different functional niches within the cell, is the basic premise on which these proteins maintain their interaction network. We are working on the hypothesis that even small perturbations in conformation leads to disruption of the network and to the disease phenotype. Based on a comprehensive data search, the evidence was obtained for the role of IUPs in neurodegenerative disorders, and their mode of action through conformational promiscuity is elaborated through three case studies. PMID- 21698752 TI - Proteins with neomorphic moonlighting functions in disease. AB - One gene can encode multiple protein functions because of RNA splice variants, gene fusions during evolution, promiscuous enzyme activities, and moonlighting protein functions. In addition to these types of multifunctional proteins, in which both functions are considered "normal" functions of a protein, some proteins have been described in which a mutation or conformational change imparts a second function on a protein that is not a "normal" function of the protein. We propose to call these new functions "neomorphic moonlighting functions". The most common examples of neomorphic moonlighting functions are due to conformational changes that impart novel protein-protein interactions resulting in the formation of protein aggregates in Alzheimers, Parkinsons disease, and the systemic amyloidoses. Other changes that can result in a neomorphic moonlighting function include a mutation in SMAD4 that causes the protein to bind to new promoters and thereby alter gene transcription patterns, mutations in two isocitrate dehydrogenase isoforms that impart a new catalytic activity, and mutations in dihydrolipoamide dehydrogenase that activate a hidden protease activity. These neomorphic moonlighting functions were identified because of their connection to disease. In the cases described herein, the new functions cause cancers or severe neurological impairment, although in most cases the mechanism by which the new function leads to disease is unknown. PMID- 21698753 TI - Brief update on different roles of tau in neurodegeneration. AB - Both Alzheimer's disease (AD) and almost every second case of frontotemporal lobar degeneration (FTLD) are characterized by the deposition of hyperphosphorylated forms of the microtubule-associated protein tau in neurons and/or glia. This unifying pathology led to coining the umbrella term "tauopathies" for these conditions. While the deposition of tau ultimately results in the formation of typical histopathological lesions, such as the neurofibrillary tangles (NFTs) in AD, it is now well accepted that tau interferes with normal functions in neurons already before its deposition. Together with the identification of pathogenic mutations in the tau-encoding gene MAPT in FTLD and evidence from a rising number of in vivo animal models a central role of tau in neurodegeneration has emerged. Here, we review the role of pathological tau in axonal transport, mitochondrial respiration, and in mediating amyloid-beta toxicity in AD. Furthermore, we review recent findings regarding the spreading of tau pathology throughout the brain as disease progresses. PMID- 21698754 TI - Cancer predisposing mutations in BRCT domains. AB - Members of the breast cancer 1 (BRCA1) carboxy-terminal (BRCT) superfamily are involved in the cellular response to the DNA damage sensing and repair, as well as in the cell cycle control. All proteins are characterized by one or more BRCT domain(s), which provides a flexible framework representing scaffolding element(s) in multi-protein complexes. In particular, BRCA1, nibrin (NBN), and microcephalin (MCPH1), generally considered as molecular models for cancer-prone syndromes, contain BRCT domains able to bind phosphorylated proteins. Mutations within the BRCT domains of BRCA1, NBN, and MCPH1 are responsible for cancer susceptibility, both at the homozygous and heterozygous status. Here, we report a critical analysis of: (i) the BRCT domain structure, (ii) the role of BRCA1, NBN, and MCPH1 in DNA damage sensing and repair as well as in cell cycle control, and (iii) the pathological effects of mutations within the BRCT domains of BRCA1, NBN, and MCPH1. PMID- 21698755 TI - Metabolic pathways and intracellular trafficking of gangliosides. AB - Gangliosides constitute a large and heterogeneous family of acidic glycosphingolipids that contain one or more sialic acid residues and are expressed in nearly all vertebrate cells. Their de novo synthesis starts at the endoplasmic reticulum and is continued by a combination of glycosyltransferase activities at the Golgi complex, followed by vesicular delivery to the plasma membrane. At the cell surface, gangliosides participate in a variety of physiological as well as pathological processes. The cloning of genes for most of the glycosyltransferases responsible for ganglioside biosynthesis has produced a better understanding of the cellular and molecular basis of the ganglioside metabolism. In addition, the ability to delete groups of glycosphingolipid structures in mice has been enormously important in determining their physiological roles. Recently, a number of enzymes for ganglioside anabolism and catabolism have been shown to be associated with the plasma membrane, which might contribute to modulate local glycolipid composition, and consequently, the cell function. PMID- 21698756 TI - Identification of galectins as novel regulators of platelet signaling and function. AB - Platelet activation at sites of vascular injury leads to the formation of a hemostatic plug. Activation of platelets is therefore crucial for normal hemostasis. However, uncontrolled platelet activation may also lead to the formation of occlusive thrombi that can cause ischemic events. Platelets can be activated by soluble molecules including thrombin, TXA2 , adenosine diphosphate (ADP), and serotonin or by adhesive extracellular matrix (ECM) proteins such as von Willebrand factor and collagen. In this article, we review recent advances on the role of galectins in platelet physiology. By acting in either soluble or immobilized form, these glycan-binding proteins trigger platelet activation through modulation of discrete signaling pathways. We also offer new hypotheses and some speculations about the role of platelet-galectin interactions not only in hemostasis and thrombosis but also in inflammation and related diseases such as atherosclerosis and cancer. PMID- 21698757 TI - How a neutral evolutionary ratchet can build cellular complexity. AB - Complex cellular machines and processes are commonly believed to be products of selection, and it is typically understood to be the job of evolutionary biologists to show how selective advantage can account for each step in their origin and subsequent growth in complexity. Here, we describe how complex machines might instead evolve in the absence of positive selection through a process of "presuppression," first termed constructive neutral evolution (CNE) more than a decade ago. If an autonomously functioning cellular component acquires mutations that make it dependent for function on another, pre-existing component or process, and if there are multiple ways in which such dependence may arise, then dependence inevitably will arise and reversal to independence is unlikely. Thus, CNE is a unidirectional evolutionary ratchet leading to complexity, if complexity is equated with the number of components or steps necessary to carry out a cellular process. CNE can explain "functions" that seem to make little sense in terms of cellular economy, like RNA editing or splicing, but it may also contribute to the complexity of machines with clear benefit to the cell, like the ribosome, and to organismal complexity overall. We suggest that CNE-based evolutionary scenarios are in these and other cases less forced than the selectionist or adaptationist narratives that are generally told. PMID- 21698758 TI - Fibronectin splice variants: understanding their multiple roles in health and disease using engineered mouse models. AB - The extracellular matrix (ECM) is a highly dynamic network of proteins, glycoproteins, and proteoglycans. Numerous diseases result from mutation in genes coding for ECM proteins, but only recently it has been reported that mutations in the fibronectin (FN) gene were associated with a human disorder. FN is one of the main components of the ECM. It generates protein diversity through alternative splicing of a single pre-mRNA, having at least 20 different isoforms in humans. The precise function of these protein isoforms has remained obscure in most cases. Only in the recent few years, it was possible to shed light on the multiple roles of the alternatively spliced FN isoforms. This substantial progress was achieved basically with the knowledge derived from engineered mouse models bearing subtle mutations in specific FN domains. These data, together with a recent report associating mutations in the FN gene to a form of glomerulopathy, clearly show that mutations in constitutive exons or misregulation of alternatively spliced domains of the FN gene may have nonlethal pathological consequences. In this review, we focus on the pathological consequences of mutations in the FN gene, by connecting the function of alternatively spliced isoforms of fibronectin to human diseases. PMID- 21698759 TI - Identification of a novel human Acyl-CoA binding protein isoform with a unique C terminal domain. AB - Seven isoforms of the multifunctional human Acyl-coenzyme A binding protein (ACBP) have been characterized so far. Through ab initio analysis of expressed sequence tag (ESTs), we identified a novel high-abundant ACBP splice variant ACBP1e encoding an ACBP isoform with a unique C-terminus of 81 amino acid residues. Bioinformatic analysis shows that this domain is evolutionary conserved and shares no significant homology with other known proteins, and its function is not known. Quantitative RT-polymerase chain reaction (PCR) revealed that ACBP1e is predominantly expressed in adipose tissue and hippocampus. Protein expression studies showed perinuclear clustering of ACBP1e. These clusters were not seen in ACBP1e mutants with an altered putative subtilisin/kexin isozyme-1 cleavage site within the C-terminus, indicating that this domain is required for proper localization of ACBP1e. Conclusively, we identified a novel ACBP isoforms with an unique C-terminal domain encoded by a high-abundant splice variant. PMID- 21698760 TI - miR-200a modulate HUVECs viability and migration. AB - The posttranscriptional regulation of miRNAs is important for organism development. To investigate the role of miRNAs in angiogenesis, we performed a loss-of-function screening assay in human umbilical vein endothelial cells (HUVECs) and found that knockdown of 7 miRNAs (miR-95a, miR-126, miR-129, miR 137, miR-139, miR-200a, and miR-335) significantly suppressed cell viability. As miR-200a was highly expressed in HUVECs, blocking endogenous miR-200a using 2' OMe antisense oligonucleotide (ASOs) resulted in a decrease of cell viability and migration. Bioinformatics analysis indicates the 3' untranslated region (UTR) of thrombospondin-1 (THBS1) has a putative binding site for miR-200a. MiR-200a can directly bind to THBS1 3'UTR and negatively regulate THBS1 expression. The identification of endothelial cells (ECs) related miRNA and its target gene may gain new insight into the mechanism of angiogenesis. PMID- 21698761 TI - Red blood cell extrudes nucleus and mitochondria against oxidative stress. AB - Mammal red blood cells (erythrocytes) contain neither nucleus nor mitochondria. Traditional theory suggests that the presence of a nucleus would prevent big nucleated erythrocytes to squeeze through these small capillaries. However, nucleus is too small to hinder erythrocyte deformation. And, there is no sound reason to abandon mitochondria for the living cells. Here, we found that mammal erythrocyte reactive oxygen species (ROS) levels kept stable under diabetes, ischemia reperfusion, and malaria conditions or in vitro sugar/heme treatments, whereas bird erythrocyte ROS levels increased dramatically in these circumstances. Nuclear and mitochondrial extrusion may help mammal erythrocytes to better adapt to high-sugar and high-heme conditions by limiting ROS generation. PMID- 21698762 TI - Ligand- and proton-linked conformational changes of the ferrous 2/2 hemoglobin of Pseudoalteromonas haloplanktis TAC125. AB - The spectroscopic and ligand-binding properties of a 2/2 globin from the Antarctic bacterium Pseudoalteromonas haloplanktis TAC125 have been studied in the ferrous state. It displays two major conformations characterized by CO association rates that differ by a factor of 20, with relative fractions that depend on pH. A dynamic equilibrium is found between the two conformations, as indicated by an enhanced slower phase when lower CO levels were used to allow a longer time to facilitate the transition. The deoxy form, in the absence of external ligands, is a mixture of a predominant six-coordinate low spin form and a five-coordinate high-spin state; the proportion of low spin increasing at alkaline pH. In addition, at temperatures above the physiological temperature of 1 degrees C, an enhanced tendency of the protein to oxidize is observed. PMID- 21698763 TI - Tyr306 near the C-terminus of protein phosphatase-1 affects enzyme stability and inhibitor binding. AB - Previous deletion studies have suggested that Tyr306 has an important influence on the properties of protein phosphatase-1 (PP1). To test this inference, we constructed three site-directed mutants, PP1Y306A, PP1Y306K, and PP1Y306E. The specific activity of PP1Y306A was 3.5-fold higher than that of PP1wt, especially with K-R-Tp-I-R-R as substrate, and it also had a 13-fold higher Kcat and a 43 fold higher Kcat /Km . PP1Y306K and PP1Y306E, in that order, and were next in terms of increased activity. Use of the denaturant guanidine hydrochloride (GdnHCl) demonstrated that mutation of this site decreased enzyme stability. PP1Y306A and PP1Y306E lost all activity when incubated for 24 h in 0.6 M GdnHCl, and their fluorescence spectra confirmed the loss of stability. Because all three substitutions had a similar effect, we infer that the aromatic group of Tyr plays a crucial role in maintaining enzyme stability. Our results show that Tyr306 does affect the spatial conformation of the catalytic subunit of PP1 molecule. The IC50 of PP1Y306A for the inhibitor microcystin-LR was threefold higher than that of PP1wt, whereas those of PP1Y306E for tautomycin and norcantharidin were 15 fold and 10-fold higher, respectively. We conclude that Tyr306 plays an important role in enzyme stability and inhibitor binding. PMID- 21698766 TI - Cystic fibrosis screening recommended for all women. PMID- 21698767 TI - A next generation sequencing test. PMID- 21698770 TI - Can we accurately quantify nanoparticle associated proteins when constructing high-affinity MRI molecular imaging probes? AB - Targeted magnetic resonance contrast agents (e.g. iron oxide nanoparticles) have the potential to become highly selective imaging tools. In this context, quantification of the coupled amount of protein is essential for the design of antibody- or antibody fragment-conjugated nanoparticles. Nevertheless, the presence of magnetic iron oxide nanoparticles is still an unsolved problem for this task. The aim of the present work was to clarify whether proteins can be reliably quantified directly in the presence of magnetic iron oxide nanoparticles without the use of fluorescence or radioactivity. Protein quantification via Bradford was not influenced by the presence of magnetic iron oxide nanoparticles (0-17.2 mmol Fe l(-1) ). Instead, bicinchoninic acid based assay was, indeed, distinctly affected by the presence of nanoparticle-iron in suspension (0.1-17.2 mmol Fe l(-1) ), although the influence was linear. This observation allowed for adequate mathematical corrections with known iron content of a given nanoparticle. The applicability of our approach was demonstrated by the determination of bovine serum albumin (BSA) content coupled to dextrane-coated magnetic nanoparticles, which was found with the QuantiPro Bicinchoninic acid assay to be of 1.5 +/- 0.2 ug BSA per 1 mg nanoparticle. Both Bradford and bicinchoninic acid assay protein assays allow for direct quantification of proteins in the presence of iron oxide containing magnetic nanoparticles, without the need for the introduction of radioactivity or fluorescence modules. Thus in future it should be possible to make more precise estimations about the coupled protein amount in high-affinity targeted MRI probes for the identification of specific molecules in living organisms, an aspect which is lacking in corresponding works published so far. Additionally, the present protein coupling procedures can be drastically improved by our proposed protein quantification method. PMID- 21698771 TI - Properties and suspension stability of dendronized iron oxide nanoparticles for MRI applications. AB - Functionalized iron oxide nanoparticles have attracted an increasing interest in the last 10 years as contrast agents for MRI. One challenge is to obtain homogeneous and stable aqueous suspensions of iron oxide nanoparticles without aggregates. Iron oxide nanoparticles with sizes around 10 nm were synthesized by two methods: the particle size distribution in water suspension of iron oxide nanoparticles synthesized by the co-precipitation method was improved by a process involving two steps of ligand exchange and phase transfer and was compared with that of iron oxide nanoparticles synthesized by thermal decomposition and functionalized by the same dendritic molecule. The saturation magnetization of dendronized nanoparticles synthesized by thermal decomposition was lower than that of nanoparticles synthesized by co-precipitation. The r(2) relaxivity values were shown to decrease with the agglomeration state in suspension and high r(2) values and r(2) /r(1) ratios were obtained with nanoparticles synthesized by co-precipitation by comparison with those of commercial products. Dendronized iron oxide nanoparticles thus have potential properties as contrast agent. PMID- 21698772 TI - A hyperpolarized choline molecular probe for monitoring acetylcholine synthesis. AB - Choline as a reporter molecule has been investigated by in vivo magnetic resonance for almost three decades. Accumulation of choline metabolites (mainly the phosphorylated forms) had been observed in malignancy in preclinical models, ex-vivo, in vivo and in patients. The combined choline metabolite signal appears in (1) H-MRS of the brain and its relative intensity had been used as a diagnostic factor in various conditions. The advent of spin hyperpolarization methods for in vivo use has raised interest in the ability to follow the physiological metabolism of choline into acetylcholine in the brain. Here we present a stable-isotope labeled choline analog, [1,1,2,2-D(4) ,2-(13) C]choline chloride, that is suitable for this purpose. In this analog, the (13) C position showed 24% polarization in the liquid state, following DNP hyperpolarization. This nucleus also showed a long T(1) (35 s) at 11.8 T and 25 degrees C, which is a prerequisite for hyperpolarized studies. The chemical shift of this (13) C position differentiates choline and acetylcholine from each other and from the other water-soluble choline metabolites, namely phosphocholine and betaine. Enzymatic studies using an acetyltransferase enzyme showed the synthesis of the deuterated-acetylcholine form at thermal equilibrium conditions and in a hyperpolarized state. Analysis using a comprehensive model showed that the T(1) of the formed hyperpolarized [1,1,2,2-D(4) ,2-(13) C]acetylcholine was 34 s at 14.1 T and 37 degrees C. We conclude that [1,1,2,2-D(4) ,2-(13) C]choline chloride is a promising new molecular probe for hyperpolarized metabolic studies and discuss the factors related to its possible use in vivo. PMID- 21698773 TI - How to assess cytotoxicity of (iron oxide-based) nanoparticles: a technical note using cationic magnetoliposomes. AB - The range of different types of nanoparticles and their biomedical applications is rapidly growing, creating a need to thoroughly examine the effects these particles have on biological entities. One of the most commonly used nanoparticle types is iron oxide nanoparticles, which can be used as MRI contrast agents. The main research topic is the in vitro labeling of cells with iron oxide nanoparticles to render the cells detectable for MRI upon in vivo transplantation. For the correct evaluation of cell function and behavior in vivo, any effects of the nanoparticles on the cells must be completely ruled out. The present work provides a technical note where a detailed overview is given of several assays that could be useful to determine nanoparticle toxicity. The assays described focus on (i) nanoparticle internalization, (ii) immediate cell toxicity, (iii) cell proliferation, (iv) cell morphology, (v) cell functionality and (vi) cell physiology. Potential pitfalls, appropriate controls and advantages/disadvantages of the different assays are given. The main focus of this work is to provide a detailed guide to help other researchers in the field interested in setting up nanoparticle-toxicity studies. PMID- 21698774 TI - NMR determination of free gallium(III) ions in aqueous solutions of Ga complexes, "cold" analogs of PET/SPECT tracers. AB - Ga complexes are widely used as radiopharmaceuticals for PET or SPECT imaging and as therapeutic agents. At physiological pH, free gallium(III) ions can stably exist as soluble gallate [Ga(OH)(4) ](-) , a nephrotoxic compound whose presence should be avoided. Any Ga complex, therefore, should be carefully checked for the absence of gallate before use. Here we show that (71) Ga NMR is a useful tool to rapidly detect the presence of gallate in aqueous solutions of Ga complexes and to follow the purification steps of the Ga complex solutions. PMID- 21698775 TI - Toward the discovery of novel anti-HIV drugs. Second-generation inhibitors of the cellular ATPase DDX3 with improved anti-HIV activity: synthesis, structure activity relationship analysis, cytotoxicity studies, and target validation. AB - A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD-box RNA helicase DDX3 led to the design and synthesis of second-generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV-1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure-activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti-HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV-1 host cofactors. PMID- 21698776 TI - Camptothecin and thiocamptothecin: the role of sulfur in shifting the hydrolysis equilibrium towards the closed lactone form. AB - Adverse effects have limited the clinical potential of 20-(S)-camptothecin (CPT) and led to a growing interest in the development of CPT analogues that exhibit less severe drawbacks, while maintaining their therapeutic activity. Recently, a thiopyridone isostere of CPT, 20-(S)-thiocamptothecin (TCPT), was developed that resulted more potent than the parent compound in H460, HT29 and IGROV-1 cell lines. The improved activity of TCPT over CPT might be due to the greater stability of the lactone ring. Here, reversible hydrolysis to the ring-open carboxylate forms of CPT and TCPT was studied by HPLC, both in the presence and absence of human serum albumin (HSA). The amount of TCPT that exists in the lactone form at equilibrium in buffer solution (24 h) was found to be significantly higher than CPT, and the same trend was observed in the presence of HSA. Specifically, HSA caused a shift in the hydrolysis equilibrium of TCPT towards the carboxylate form, but the proportion of lactone form remained higher than that observed for CPT under the same conditions, and also in the presence of a higher excess of the protein. The role of the sulfur atom in the stability of the open and closed lactone derivatives was investigated by theoretical calculations using stabilization energies and comparison between experimental and calculated absorption spectra. Our results suggest that, in aqueous solution, more ionic species (anionic and enolic forms) are present for TCPT. This study provides further insights into the effects of oxygen/sulfur replacement in the CPT pyridone ring. PMID- 21698777 TI - Efficient total synthesis of dysidenin, dysidin, and barbamide. PMID- 21698778 TI - Early drug discovery and the rise of pharmaceutical chemistry. AB - Studies in the field of forensic pharmacology and toxicology would not be complete without some knowledge of the history of drug discovery, the various personalities involved, and the events leading to the development and introduction of new therapeutic agents. The first medicinal drugs came from natural sources and existed in the form of herbs, plants, roots, vines and fungi. Until the mid-nineteenth century nature's pharmaceuticals were all that were available to relieve man's pain and suffering. The first synthetic drug, chloral hydrate, was discovered in 1869 and introduced as a sedative-hypnotic; it is still available today in some countries. The first pharmaceutical companies were spin-offs from the textiles and synthetic dye industry and owe much to the rich source of organic chemicals derived from the distillation of coal (coal-tar). The first analgesics and antipyretics, exemplified by phenacetin and acetanilide, were simple chemical derivatives of aniline and p-nitrophenol, both of which were byproducts from coal-tar. An extract from the bark of the white willow tree had been used for centuries to treat various fevers and inflammation. The active principle in white willow, salicin or salicylic acid, had a bitter taste and irritated the gastric mucosa, but a simple chemical modification was much more palatable. This was acetylsalicylic acid, better known as Aspirin(r), the first blockbuster drug. At the start of the twentieth century, the first of the barbiturate family of drugs entered the pharmacopoeia and the rest, as they say, is history. PMID- 21698779 TI - Characterization, thermal stability studies, and analytical method development of Paromomycin for formulation development. AB - Paromomycin (PM) is an aminoglycoside antibiotic, first isolated in the 1950s, and approved in 2006 for treatment of visceral leishmaniasis. Although isolated six decades back, sufficient information essential for development of pharmaceutical formulation is not available for PM. The purpose of this paper was to determine thermal stability and development of new analytical method for formulation development of PM. PM was characterized by thermoanalytical (DSC, TGA, and HSM) and by spectroscopic (FTIR) techniques and these techniques were used to establish thermal stability of PM after heating PM at 100, 110, 120, and 130 degrees C for 24 h. Biological activity of these heated samples was also determined by microbiological assay. Subsequently, a simple, rapid and sensitive RP-HPLC method for quantitative determination of PM was developed using pre column derivatization with 9-fluorenylmethyl chloroformate. The developed method was applied to estimate PM quantitatively in two parenteral dosage forms. PM was successfully characterized by various stated techniques. These techniques indicated stability of PM for heating up to 120 degrees C for 24 h, but when heated at 130 degrees C, PM is liable to degradation. This degradation is also observed in microbiological assay where PM lost ~30% of its biological activity when heated at 130 degrees C for 24 h. New analytical method was developed for PM in the concentration range of 25-200 ng/ml with intra-day and inter-day variability of < 2%RSD. Characterization techniques were established and stability of PM was determined successfully. Developed analytical method was found sensitive, accurate, and precise for quantification of PM. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 21698780 TI - PVC membrane sensor for potentiometric determination of iron (II) in some pharmaceutical formulations based on a new neutral ionophore. AB - A novel poly (vinyl chloride) PVC membrane sensor for Fe(2+) ions is described. The sensor is based on the use of newly synthesized chiral 2,6-bis-(carboxamide methyl ester)pyridine derivative as neutral ionophore in plasticized PVC membrane. The sensor display a fast, stable and near-Nernstian response over a relative wide ferrous concentration range (1 * 10(-3) to 6 * 10(-6) M), with cationic slope of 31.5 +/- 0.5, mV per concentration decade over a pH range of 5.0-9.0. The direct determination of 0.25-56.0 ug/ml of ferrous in aqueous solution shows an average recovery of 98.5% and a mean relative standard deviation of 1.5% at 20.0 ug/ml. The sensor displays long life-span, long-term stability, high reproducibility, and short response time. Selectivity coefficients for Fe(II) relative to a number of interfering substances were investigated. The sensor shows high significantly for Fe(2+) over Fe,(3+) Cu,(2+) Zn,(2+) Cd,(2+) Hg,(2+) Pb,(2+) Ni,(2+) Co,(2+) Mn,(2+) Al,(3+) alkaline earth and alkali metal ions. The sensor is successfully applied for measurement of ferrous in drug formulations. The results obtained for the determination of ferrous using the proposed sensor are comparable favourably with those obtained using the spectrophotometric method. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 21698781 TI - Spectral data analyses and structure elucidation of metoprolol tartrate. AB - The infrared spectrum, ultraviolet spectrum, mass spectra, and nuclear magnetic resonance spectra of metoprolol tartrate, an antiarrhythmic medicine, were reported and interpreted comprehensively. The vibrations of functional groups in infrared spectrum, electron transitions in ultraviolet spectrum, and main characteristic fragmentations in mass spectra of metoprolol tartrate were discussed. All the (1) H and (13) C NMR chemical shifts were assigned by means of distoritionless enhancement by polarization transfer-135 and -90, (1) H-(1) H correlation spectroscopy, and (13) C-(1) H correlation spectroscopy via short- and long-range coupling. PMID- 21698782 TI - The role of cytopathology in diagnosing HPV induced oropharyngeal lesions. AB - HPV detection in fine needle aspirates from suspected head and neck metastasis may be useful in clinching the diagnosis of HPV related oral squamous cell carcinoma. Ascertaining the HPV status of a particular tumor on cytological specimens could be useful for prognostication as HPV-related tumors appear to have a better prognosis and clinical outcome. The various techniques of detection are reviewed. PMID- 21698783 TI - Plasmablastic myeloma in ascitic fluid. PMID- 21698784 TI - Epithelioid angiosarcoma of the kidney: a diagnostic dilemma in fine-needle aspiration cytology. AB - Epithelioid angiosarcomas (EAS) of kidney are rare and aggressive tumors with noncharacteristic imaging features that overlap with those of inflammatory conditions and renal cell carcinoma (RCC). We report the fine-needle aspiration (FNA) cytology findings of a case of EAS that involved the left kidney of an 83 year-old male. The smears and cell block sections showed pleomorphic epithelioid cells with ample cytoplasm, eccentric nuclei, occasional cytoplasmic hyaline globules, and rare intracytoplasmic lumina. Immunohistochemical stains performed on cellblock sections showed that the tumor cells were positive for vimentin, CD31, CD34, Factor VIII, and CD10, but showed no staining for cytokeratins AE1/AE3 and 8/18, HMB45, CD45, smooth muscle actin, and S100. The morphological and immunohistochemical distinction between EAS, primary tumors of the kidney, and other epithelioid and rhabdoid neoplasms is discussed. PMID- 21698785 TI - Non-Hodgkin's lymphoma presenting as breast masses: a series of 10 cases diagnosed on FNAC. AB - Primary breast lymphoma (PBL) is a rare disease, which comprises 0.04-0.53% of all primary malignant tumors of the breast. The most frequent histological subtype is diffuse large B-cell type (DLBCL) (40-70%). Differentiation of PBLs from other breast tumors such as poorly differentiated carcinomas and lobular carcinoma may at times be difficult on cytomorphology alone. An audit of breast lymphomas diagnosed on fine needle aspiration cytology (FNAC) over a period of 9 years (2001-2009) was performed. Ten cases were retrieved and the cytomorphology was reviewed along with immunochemistry (IHC), flow cytometry as well as histopathology, wherever available. The age of patients ranged from 17 to 83 years. Eight cases were diagnosed as non-Hodgkin's lymphoma, high-grade on FNAC. Histopathology was available in four of these cases and cell block was available in one case. Lymphoid cells were positive for leukocyte-common antigen (LCA) and CD20 and negative for CD3 in these cases. The same was confirmed by flow cytometry on aspirated material in one case. A diagnosis of DLBCL was offered in these five cases. One case was a low-grade NHL and another case was a young male, a known case of acute leukemia and had leukemic infiltration in the breast lump. We wish to emphasize the potential importance of FNAC in breast lymphoma and the same can be helpful to avoid unnecessary surgery in these cases. The differential diagnostic entities have been discussed. IHC and flow cytometry can be performed on the aspirated material and provide valuable information. PMID- 21698786 TI - Giant cell tumor of bone mimicking metastatic renal cell carcinoma: a case report. PMID- 21698788 TI - [Preliminary discussion on the phylogenetic and taxonomic relationship of Pomatorhinus ruficollis]. AB - The phylogenetic relationships among subspecies of Pomatorhinus ruficollis are not clear. In this paper we sequenced two mitochondrial genes (Cyt b and ND2, in total 2 184 bp) and examined twenty individuals representing ten of the eleven subspecies of P. ruficollis in China. Molecular phylogenetic trees were reconstructed using maximum parsimony, maximum likelihood and Bayesian inference methods, with P. ruficollis and P. schisticeps as in-groups, P. montanus, P. ochraceiceps, P. ferruginosus and Xiphirhynchus superciliaris as out-groups. Results indicated that P. ruficollis was paraphyletic, in which P. schisticeps was embedded, and was divided into three phylogeographic groups: southwestern China group, southeastern China group and central China group. Our results also suggested discordances between phylogenetic relationships and morphological characteristics, and clarified some intraspecific taxonomic debates. PMID- 21698787 TI - Combined treatment for child refractory Mycoplasma pneumoniae pneumonia with ciprofloxacin and glucocorticoid. AB - OBJECTS: To evaluate the efficacy of combined treatment of ciprofloxacin and glucocorticoid for child refractory Mycoplasma pneumoniae (M. pneumoniae) pneumonia. METHODS: Clinical and laboratory characteristics of six pediatric refractory M. pneumoniae pneumonia cases treated with ciprofloxacin and glucocorticoids were reported. RESULTS: Five cases complicated with pleural effusion. The average febrile period prior to admission was 8.5 +/- 2.0 days, the average total febrile period was 14.6 +/- 7.6 days, and the average febrile period after treatment was 3.3 +/- 3.0 days. The average time in hospital for patients was 23.6 +/- 4.8 days. The initial mean WBC count was 10,100 +/- 2,400/mm(3) . The erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and C-reactive protein (CRP) in all cases were elevated during the course of illness. After combined therapy, all children clinically improved, with resolution of radiographic findings and normal laboratory items. We analyzed the 23S rRNA gene in four nasopharyngeal secretions, and found mutations in A2063G of domain V in three cases, and mutation in A2064G in the other case. CONCLUSION: Combined treatment of ciprofloxacin and glucocorticoids can significantly ameliorate child refractory M. pneumoniae pneumonia further comparative study is needed to well evaluate the treatment efficacy. PMID- 21698790 TI - Genetic differentiations between randomly and selectively bred pig populations in Yunnan, China. AB - To assess the genetic diversity between randomly and selectively bred populations, we sequenced 438 bp of the mitochondrial DNA control region from 102 pigs. These samples represented four native pig breeds, one nucleus and one conservation herd from Yunnan, China. Twenty haplotypes with sixteen polymorphic sites were identified. The number of haplotypes in the nucleus herd of Saba pig and the conservation herd of Banna miniature pig were restricted to three and one, respectively, while the randomly bred pig populations exhibited over six haplotypes. Notably, haplotype diversity in randomly bred populations was significantly greater than the selectively bred populations (h=0.732 vs. 0.425 and 0, exact test, P<=0.0036). These findings demonstrate that selective breeding generated low genetic diversity compared to randomly bred pig breeds. A timely intervention and well programmed breeding approach would stop further genetic diversity reduction in the nucleus and conservation herds of native pig breeds. Otherwise, selective breeding would dramatically reduce genetic diversity in only several years, indicating that sharp contradictions exist between breeding, conservation and genetic diversity. Genetic relationships are discussed based on net genetic distances among pig populations. PMID- 21698789 TI - Phylogenetic evaluation of the taxonomic status of Papilio maackii and P. syfanius (Lepidoptera: Papilionidae). AB - The taxonomic status of Papilio maackii and P. syfanius has long been disputed. We conducted a molecular phylogenetic study to evaluate the taxonomic status of P. maackii and P. syfanius. A total of twenty-four P. maackii individuals from six localities and sixteen P. syfanius individuals from two localities were analyzed. We sequenced the partial region of the CO-I gene (about 579 bp) and partial CO-II gene sequence (about 655bp) of the two species. The Kimura-2 Parameter distances among P. maackii and P. syfanius ranged from 0 to 0.6%. Fifteen haplotypes were obtained based on the combined data set. The results strongly supported that all P. maackii individuals and all P. syfanius individuals formed a large clade, and could not be divided into separated clades. This research indicated that the two species have only very recently undergone speciation. PMID- 21698791 TI - [An extension strategy of Discovery Studio 2.0 for non-bonded interaction energy automatic calculation at the residue level]. AB - Non-bonded interaction forces play crucial roles in molecular recognition and binding in biological systems. However, it is difficult for traditional methods to automatically calculate and batch the non-bonded energy at the residue level. In recent years, many studies have focused on non-bonded interactions and developed tools to calculate and analyze such interactions. In this study, we present a highly automated approach for the calculation of non-bonded energy. Our strategy invoked protocols relevant to non-bonded interactions within Discovery Studio 2.0 (DS2.0, Accelrys Inc.) bottom module using Perl script, and determined the direct command line operation of calculating non-bonded interaction energy batches without accessing the graphical interface of DS. This approach extended the DS2.0 module and was applied to a recent study of complex structure analysis. PMID- 21698792 TI - [Expression analysis of 5 hsp70 genes in Tetrahymena thermophila]. AB - Thirteen hsp70 genes with complete conserved domains were identified in Tetrahymena thermophila, and expression of five similar and non-intron hsp70 genes were analyzed. Under heat shock conditions of 37, 39 and 41oC, hsp70-2 mRNA had the highest relative expression level, suggesting it is closely related to heat shock. The basal level of constitutive T. thermophila hsp70-4 gene was high during 20 physiological/developmental stages of growth, starvation and conjugation, and it changed little upon exposure to heat shock: evidence that hsp70-4 is an hsc70 gene. The hsp70-4 cDNA is 2 208 bp long, and contains an open reading frame of 1 959 bp encoding 635 amino acids. Microarray data indicated that T. thermophila hsp70-3 gene probably participated in early starvation (0-12 h) stress and late conjugation (6-10 h) events, such as new macronuclear and micronuclear anlagen formation and old macronuclear elimination. However, hsp70-5 gene possibly participates in late starvation (12-15 h) stress and early conjugation (0-6 h) events such as micronuclear meiosis, micronuclear exchange and pronuclear fusion. Blast2GO indicated that they participated in dissimilar biological processes, suggesting hsp70-3 and hsp70-5 perform different functions. PMID- 21698793 TI - [Effects of salinity and betaine on BHMT mRNA expression in Lateolabrax japonicus]. AB - Betaine homocysteine methyltransferase (BHMT, EC 2.1.1.5) catalyzes the transfer of a methyl group from betaine to homocysteines (Hcy) to form dimethylglycine and Met, respectively. A full-length cDNA of the BHMT in Lateolabrax japonicus was amplified using RT-PCR and SMART RACE methods. The cDNA of the BHMT in L. japonicus is 1 461 bp in size, with 72 bp 5'-UTR, 183 bp 3'-UTR and 1206 bp ORF, encoding a protein of 401 amino acids with a molecular weight of 44.32 kD and pI 7.21. The sequence analysis indicated that the deduced amino acid sequence of BHMT shared high identity (77%-93%) with nine other species; the highest was 93% with Perca flavescens. Semi-quantitative RT-PCR was used to characterize the expression of BHMT in ten tissues including muscle, heart, eye, brain, gill, liver, intestine, kidney, adipose tissue and spleen. The results showed that BHMT is only expressed in the liver, intestines and kidney. BHMT mRNA in these three tissues declined after the fish were transferred from sea water to a higher salinity environment and induced when transferred to a lower salinity environment. BHMT gene in liver, intestine and kidney can also be induced after intraperitoneal injection of betaine. Our results show that betaine can induce the transcription of BHMT in fish, and BHMT play pivotal roles in adaptation to osmotic change. PMID- 21698794 TI - [Molecular cloning, tissue distribution and the expression in the regulation of food intake of prepro-orexin in Nile tilapia (Oreochromis niloticus)]. AB - We cloned the full length of tilapia prepro-orexin cDNA using RT-PCR and rapid amplification of cDNA ends (RACE). The full-length of prepro-orexin cDNA was 648 bp containing an open reading frame of 423 bp. The 140 amino acid prepro-orexin protein included a 37 AA signal peptide, a 43 AA Orexin-A and, and 28 AA Orexin-B and the end of the 32 AA peptide of unknown function. The expression of prepro orexin on tissue distribution, peri-prandial changes, starvation and re-feeding were quantified by real-time PCR. We found that prepro-orexin mRNA was present in all tissues tested and that the highest level was observed in hypothalamus. Expression levels were significantly higher at mealtime (0 h) than before (-2 h, 1 h) and after (+1 h, +2 h) mealtime. Fasting for 2, 4, 6 and 8 d caused significant increases in prepro-orexin mRNA expression in the hypothalamus, and after re-feeding, expression levels of prepro-o rexin mRNA returned to the same level compared to that in the fed group. PMID- 21698795 TI - [Correlation between cardiovascular risk factors and the expression of cardiovascular disease related genes in cynomolgus monkeys]. AB - The correlation between cardiovascular risk factors and cardiovascular disease related genes plays an important role in early-warning risk and early diagnosis. Thirty middle-aged male crab-eating macaques were fed a moderately atherogenic diet (0.053 mg cholesterol/kJ and 40% of calories as saturated fat) for twelve months. According to cardiovascular risk factors, we selected low-risk and high risk crab-eating macaques, then analyzed the expression of 113 cardiovascular related genes by real-time PCR. A total of 65 genes were detected in peripheral blood leukocytes by real-time PCR. Sixteen up-regulated genes and nineteen down regulated genes were detected in low-risk and high-risk crab-eating macaques compared to normal crab-eating macaques (P<0.05), in addition to fifteen genes that showed unique expression patterns (P<0.05). We also detected 42 genes in human peripheral blood leukocytes. The expression patterns of 22 genes were consistent between human and crab-eating macaques. These results narrowed the scope of genes for further research. PMID- 21698796 TI - [Expression status of diabetes-associated genes in middle and aged cynomolgus monkeys]. AB - A total of 138 middle and aged cynomolgus monkeys (Macaca fascicularis) (above 10 years) were classified into three groups based on fasting plasma glucose (FPG) values, specifically low FPG, normal FPG, and high FPG group. Total cholesterol (TCHO), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) were detected in blood by automatic biochemical analyzer. The mRNA expressions of 37 diabetes-associated genes were analyzed with Real-time PCR in monocytes isolated from monkey peripheral blood. No significant correlation between the four serum lipid indictors HDL-C, LDL-C, TCHO, TG and FPG (P>0.05) were found. However, the expressions of ACE, ACLY, PRKCB1, SLC2A4, SNAP23, VAPA, IGF2BP2, and IFNG were significantly enhanced when FPG increased (P<0.05). PMID- 21698797 TI - [Screening of spontaneous diabetes mellitus in middle-and old-aged cynomolgus monkey]. AB - To screen spontaneous diabetic mellitus and explore methods for its rapid identification, the basal and inferred levels of blood glucose of 440 overweight, middle- and old-aged cynomolgus monkeys were analyzed. Diagnostic diabetes was further validated by the oral glucose tolerance test (OGTT) and urine glucose. The average level of blood glucose of these cynomolgus monkeys was (3.88+/-0.98) mmol/L, which was lower than the level for suspected diabetes (5.0 mmol/L). Of them, 56 (12.72%) monkeys were identified with levels of blood glucose greater than 5.0 mmol/L and diagnosed as the diabetic subjects. This population showed impaired glucose tolerance using the OGTT and 39 of the 56 (69.23%) had glucose positive urine. The methods for screening diabetic mellitus used in this study were simple, quick, and limited the harm to animals. However, the incidence of diabetes was higher in these tested monkeys than in the regular human population in China (9.7%), suggesting that these methods are useful for screening diabetic disease in a large population but not suitable for all cynomolgus monkeys. PMID- 21698798 TI - [Inhibitory effect of ferulic acid on inflammatory response in microglia induced by lipopolysaccharides]. AB - Ferulic acid (FA) is a natural compound that expresses antioxidant and anti inflammatory activities. Microglial cells are innate immune cells that reside within the central nervous system (CNS). Activated microglia mediated neuronal immunity contributes to the neurodegeneration associated with Alzheimer's disease. In this study, we investigated the inhibitory effect of FA on neuroinflammation in BV-2 microglial cells induced by lipopolysaccharides (LPS). Our study showed that FA significantly suppressed the production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-1beta (IL-1beta), and decreased induced type II nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein in LPS-stimulated BV-2 microglia cells in a dose dependent manner. We hypothesized that this was achieved by suppressing the protein level of Toll-like receptor 4 (TLR4). PMID- 21698800 TI - [Acute effects of IL-1beta on sodium current in cortical neurons of rats]. AB - Interleukin-1beta (IL-1beta) is an important proinflammatory cytokine that plays a key role in injuries and diseases of the central nervous system (CNS). The voltage-gated Na(+) channel is the most important ion channel of neurons, and is essential for regenerative action potential (AP). The Na(+) channel also contributes to many diseases of the brain. However, relations between IL-1beta and central Na(+) channels remain unreported. In this study, whole cell patch clamp recording was used to investigate the acute effects of IL-1beta (10 ng/mL) on voltage-dependent Na(+) currents and AP of cultured cortical neurons from rats. Results showed that the half-activation voltage of Na(+) channels and the threshold of AP, but not the amplitude, slope factor of activation, and inactivation properties, were affected by IL-1beta. These data suggest that increased IL-1beta in injury and disease may upregulate the excitability of neurons, and thereby exacerbate neurotoxicity. PMID- 21698799 TI - [Estrogen receptor expression and vitellogenin synthesis induced in hepatocytes of male frogs Rana chensinensis exposed to bisphenol A]. AB - The effects of bisphenol A (BPA) on estrogen receptor (ER) and vitellogenin (VTG) in hepatocytes of male amphibians have attracted significant attention in recent years. Adult male frogs Rana chensinensis were exposed to different concentrations of 10(-7), 10(-6) and 10(-5) mol/L BPA consecutively for 10, 20, and 30 d, respectively. We used 10(-9), 10(-8) mol/L 17beta-esradiol (E(2)) as positive controls. The expressions of ER mRNA in the hepatocytes were detected by in situ hybridization, and ER and VTG protein were detected by immunohistochemistry. The results showed that positive effects of ER mRNA were detected in all BPA and E(2) treatment groups. Compared with the control group, the expression level of ER and VTG protein increased significantly in the hepatocytes of R. chensinensis. Both ER and VTG expression exhibited BPA dose dependence for the same exposure time. For the same concentration of BPA treatment, VTG synthesis markedly increased with prolonged treatment, whereas the expression of ER did not significantly fluctuate. It is suggested that BPA caused the synthesis of VTG by inducing ER up-regulation in the hepatocytes of male R. chensinensis, but its estrogenic activity was much lower than E(2). PMID- 21698801 TI - [Rat orbital frontal (orbital frontal cortex, OFC) GABA B receptor mechanisms in stress and depression]. AB - Stress-induced depression is a kind of functional and structural disability of the brain and involves many neurotransmitters and regions of the brain. A number of studies suggest involvement of gamma-Aminobutyric acid (GABA) in the orbital frontal cortex (OFC) in the mechanism of stress-associated depression-like behavior in rodents. However, little work has been done on the relationship between GABA and neural plasticity of the OFC under stress. Here we examine the effect of the GABA in the OFC during acute forced swim stress (FSS). We found remarkable depression-like behavior in FSS and an open field test (OFT), and we observed a marked decrease in Kalirin-7 expression and the basal dendritic spine density of layer V pyramidal neurons in OFC after FSS. GABA administration reversed these changes, which were inhibited by CGP35348, an antagonist of GABA-B receptors. These results suggest an anti-depression effect of GABA in the OFC, which may be mediated by GABA-B receptor. The anti-depression effect of GABA is related to the plasticity of the dendritic spine density. This discovery may be helpful in the development of new therapies to treat depression. PMID- 21698803 TI - [Morphologic differentiation analysis for rounded caudal fin group of Oreonectes (Balitoridae) from China]. AB - Morphological characteristics were compared between three recorded species of rounded caudal fin Oreonectes and specimens collected from Guan'an of Guangxi. The results showed the Oreonectes sp. from Guan'an was distinguished from O. anphthalmus. Although some morphologic differentiations existed among Oreonectes sp., O. polystigmus, and O. platycephalus, their differentiations were not enough to distinguish between them. Consequently, we used multivariate morphometrics to determine their morphologic differentiation. Twenty-six frame characteristics and 20 general characteristics of 63 specimens were measured. The results of the Principal Component Analysis showed that Oreonectes sp. and O. polystigmus, and Oreonectes sp. and O. platycephalus occupied obviously different areas in the scatter plot. It is suggested that the specimens collected from Guan'an may be a cryptic new species of Oreonectes. However, its taxonomic status should be decided by evidence from anatomical and molecular biological studies. PMID- 21698802 TI - Effects of urethane on the response properties of visual cortical neurons in young adult and old cats. AB - Previous studies have shown that visual cortical neurons in old mammals exhibit higher spontaneous activity, higher responsiveness to visual stimuli, and lower selectivity for stimulus orientations and motion directions than did neurons in young adult counterparts. However, whether the responsive difference in cortical neurons between young and old animals resulted from different effects induced by anesthetics has remained unclear. To clarify this issue, we recorded the response properties of individual neurons in the primary visual cortex of old and young adult cats while systematically varying the anesthesia level of urethane, a widely used anesthetic in physiology experiments. Our results showed that cumulatively administrating 50 mg and 100 mg of urethane upon the minimal level of urethane required to anesthetize an old or young adult cat did not significantly alter the degree of neuronal response selectivity for stimulus orientations and motion directions nor significantly change the visually-driven response and spontaneous activity of neurons in old and young adult cats. Cumulatively administrating 150 mg of urethane decreased neuronal responsiveness similarly in both age groups. Therefore, urethane appears to exert similar effects on neuronal response properties of old and young adult animals. PMID- 21698804 TI - [A new record species, Heniochus diphreutes, Chaetodontidae from China]. AB - A new record species of Chaetodontidae, Heniochus diphreutes, was found by comparative analysis of the morphological characteristics in a taxonomic revision of the family Chaetodontidae in China. It was distinguished from its relative species H. acuminatus by a combination of the following: Dorsal fin usually with 12 spines (vs. 11); 2-3 rows of teeth on both jaws (vs. 5-7); ventral profile of head convex (vs. almost straight); anal fin more angular, and black area on posterior part of anal fin usually extending anteriorly to longest soft ray (vs. more round, and usually not extending anteriorly to longest soft ray); and snout shorter than eye (vs. longer). PMID- 21698805 TI - Ask the doctor. I have a bad case of seborrheic keratoses on my back and chest. What can you tell me about this skin problem? PMID- 21698806 TI - Ask the doctor. What causes bags and puffiness around the eyes and dark circles underneath them? PMID- 21698807 TI - Mediterranean-type diet can fix multiple problems. PMID- 21698809 TI - Ask the doctor. I am 92 years old. I have atrial fibrillation and high blood pressure, both controlled by medication. Every so often when I am relaxed in my chair after dinner, my heart feels like it stops and then starts up again with a jerk. Is this something I should worry about? PMID- 21698808 TI - Ask the doctor. I am a 72-year-old with diabetes, and I need to have a hip replaced. Does my diabetes make this surgery too dangerous for my heart? PMID- 21698810 TI - [The way to reduce the prevalence of colorectal cancer in Moscow: from the pilot study to screening]. AB - Were made calculations of the Moscow population that needs screening for colorectal cancer (CRC). In screening will be needed about 2.7 million people- with high risk of colorectal cancer--300 thousand, and at average risk--2.4 million. It is expected that during screening for colorectal cancer would be detected at 1%, i.e. approximately 26 700 people, and 10% (267 000)--adenomatous polyps that can be removed. Since the organization and conduct screening of the adult population of Moscow to the CRC requires large additional economic costs, endoscopic equipment and expertise, this program can be divided into different stages. The first stage should be to conduct a population-based study of MUSE (see, L.B. Lazebnik, et al. in this issue) in all administrative districts of Moscow. The next stage should be planned implementation of annual preventive endoscopic examinations of the population in accordance with formed risk groups. This program will significantly reduce the incidence of and mortality from colorectal cancer in Moscow. PMID- 21698811 TI - [Efficacy of alverina citrate and simethicone combination in abdominal pain and discomfort of irritable bowel syndrome]. AB - The alverina citrate and simethicone combination (ACS-Meteospazmil) is used for irritable bowel syndrome (IBS) for almost 20 years, but the supporting scientific evidence for efficacy is limited. OBJECTIVE: to evaluate the effectiveness of ACS in patients with abdominal pain and discomfort at IBS. METHODS: In a double blind, randomized, placebo-controlled study enrolled 412 patients with IBS conform to Rome criteria III. Selection criterion in the study was to evaluate the intensity of abdominal pain or discomfort during the 2-week run-in period without medication, which according to analog scale (VAS) was to be 60-100 mm. With the help of an interactive voice communication system (IVCS), patients were randomized to treatment with either alverin citrate 60 mg with Simethicone 300 mg three times daily or corresponding placebo for 4 weeks. RESULTS: For analyze of the results of the study were selected 409 patients. After 4 weeks, patients treated with ACS, was observed lower scores in the VAS assessment of abdominal pain or discomfort compared to placebo (mean--40 and 50 mm, p = 0.047) and a higher level of response to treatment (46.8% and 34.3%, respectively). Recorded side effects were similar in both groups. CONCLUSION: The combination of ACS was significantly more effective in patients with IBS compared to placebo in reducing abdominal pain or discomfort. PMID- 21698812 TI - [Characteristics of the intestinal dysbiosis and endotoxemia after hemicolectomy]. AB - The normal intestinal microflora important for maintaining the optimum level of metabolic processes in the human body, the immune system, as well as to create a high colonization resistance against the pathogenic microbes. With aging, changes microbiocaenosis intestine, resulting in an increase in the total number of microbes in the gut and profound changes in the functional properties of microorganisms. Under physiological conditions, the main reservoir of endotoxin in the human body is the intestine. Endotoxins, penetrating through the intestinal mucosa, arrive first at the local (intestinal), and then through the portal system in the liver, are able to initiate it various lesions, including fatty degeneration of the parenchyma. OBJECTIVE: Based on clinical and laboratory studies to determine changes in gut microbiota and the level of endotoxemia in elderly patients in the remote period after undergoing surgery--hemicolectomy. RESULTS OF THE STUDY: Metabolic activity of microflora in the colon according to the concentrations of short chain fatty acids in the feces of elderly patients in distant periods after hemicolectomy revealed in various degrees of violation of the microbiota of the colon. Violation of gut microbiota leads to endotoxaemia, which has a toxic effect on liver function, level of endotoxin and protein that binds to endotoxin was significantly higher in patients who underwent left-sided hemicolectomy. PMID- 21698813 TI - [Correction of protein-energy metabolism in elderly patients with acute intestinal obstruction and hepatorenal dysfunction]. AB - Infringements of a protein-energetic metabolism in hepatorenal complications are an actual problem in urgent surgery. MATERIAL: 358 patients with a acute surgical pathology of intestines were analysed, in 27.4% of patients infringements of functions of a liver and kidneys were revealed, necessity for normalization of the protein-energetic metabolism was noted in 47-70% of cases. RESULTS: As a result the scheme for protein-energetic metabolism correction was specified in depending of a kind of intestinal impassability and a degree of severity of surgical disease. The early correction of a protein-energetic metabolism in complex with the extracorporeal support methods of a detoxication has provided the expressed positive clinical effect. PMID- 21698814 TI - [Clinical aspects of intestinal dysbacteriosis]. AB - The article presents data of domestic and foreign literature on intestinal dysbacteriosis. It is evident that intestinal dysbiosis always secondary and its correction should take into account the reasons that caused the violation of the microbial composition of the intestinal flora and the clinical manifestations of this syndrome. The characteristic of the normal intestinal microflora and its significance for the human body. It was emphasized that the resident microflora influences the development of the immune response of the intestinal mucosa, epithelial differentiation and proliferation, motility, is actively involved in the digestion and absorption, and synthesis of vitamins and bioactive substances. It was described factors leading to violation of the microbial composition of intestine, as well as methods of diagnosis and treatment of dysbiosis. Therapeutic measures for dysbiosis conducted according to the nature and severity of underlying disease and were in compliance with dietary recommendations and the use of drugs, normalizing the intestinal microflora. In order to remove from the intestinal lumen conditionally pathogenic microorganisms and toxins using different chelators. One of the members of this group of drugs is Laktofiltrum. Laktofiltrum drug effective in treating patients with bowel diseases, accompanied by dysbiosis, as a monotherapy and in combination with other drugs. PMID- 21698815 TI - [About expediency of terminology and classification modification for lymphadenectomy in the surgery for pancreatic cancer]. AB - While doing pancreatic gland resection for cancer the lymphadenectomy is performed in volume, recommended on a congress of pancreatologists in Castelfranco-Venetto (standard, radical, extended radical) or in manuals of Japanese investigators (D1, D2). These classifications have got several shortages: terminological inaccuracies, lack of information, concerning the borders of the vegetative neural plexuses dissection etc. The authors have proposed a modified terminology and classification of lymphadenectomy, in accordance to which four types of lymphadenectomy are delineated: D1p, D2p, D3p, corresponding to lymphatic collectors N1, N2, N3, as well as D4p--complete excision of lymphatic nodes in all three regions while total pancreatectomy performance. The symbols 9n-dex/sin and 14n-dex/sin were recommended to name the lymph nodes of the ninth and fourteenth groups, indicating availability of the nervous plexuses dissection performance of right/left hemicircumference of vessels only. The retroperitoneal dissection borders and criterions for the lymphadenectomy volume choice were proposed. PMID- 21698816 TI - [Treatment-diagnostic possibilities of interventional ultrasound investigation of hepatic pathology in conditions of a specialized surgical center]. AB - Possibilities of the intervention ultrasonographic investigation application in a work of a specialized Department of the liver, biliary ducts and pancreatic gland pathology both for diagnosis (in diffuse and focal hepatic affection) and treatment of the hepatobiliary zone diseases, were analyzed. In 1324 patients overall 1413 treatment-diagnostic interventions were performed. Morphological, cytological, virusological investigations of material, obtained in a trepan biopsy (in 796 patients), had permitted to verify a diffuse hepatic diseases, benign and malignant processes. First experience of radiofrequency thermoablation application for the hepatic hilus tumors under ultrasonographic control simultaneously with external cholangiostomy formation in a patient, suffering obturation jaundice, was obtained. PMID- 21698817 TI - [Partial denervation in complex treatment of occlusive diseases of the lower extremity arteries]. AB - The interventions efficacy, conducted on a nervous structures in 198 patients for occlusive diseases of the lower extremities arteries, in 68 of whom a femoral and sciatic nerves blockade were performed together with epidural anesthesia and open alcoholizing of sciatic nerve, was estimated. Efficacy of partial denervation in complex treatment of patients, suffering chronic ischemia of the lower extremities stages II - IlIA, was established, when performance of a direct revascularization is impossible because of a secured functional reserve present. PMID- 21698818 TI - [Analysis of the quality of lifetime diagnosis of renal cancer]. AB - The quality of the clinical and postmortem diagnosis of renal cancer was studied, by examining 510 cases of nephrectomies and resections of the kidney for its masses over 10 years. The clinical diagnosis of the stage of renal cell carcinoma (RCC) from the data available in the inpatients records cannot be considered qualitative in 76% of cases. Joint material cutting by a surgeon and a pathologist is the most important predictor that significantly affects the quality of lifetime clinical diagnosis of the TNM stage of renal cancer. The postmortem diagnosis of RCC can be recognized qualitative since the technique has been found to be highly sensitive and specific. However, the unavailability of data on tumor malignancy grade in two thirds of postmortem conclusions makes it impossible to tell about the impeccable quality of a study of renal carcinomas. The mean time needed to prepare a conclusion of the morphological study of surgical specimens was 5.8 days, which corresponded to the established standards, including for biopsy specimens. PMID- 21698819 TI - Proceedings of the 15th meeting of the International Society for Prenatal Diagnosis and Fetal Therapy. July 11-14, 2010. Amsterdam, The Netherlands. PMID- 21698820 TI - Proceedings of the 31st International Symposium of Research Group on the Central Nervous System. Montreal, Canada. May 4-5, 2009. Dedicated to the memory of James P. Lund. PMID- 21698821 TI - Proceedings of the 11th National Congress of the Italian Society of Internal Medicine. Rome, Italy. October 16-19, 2010. PMID- 21698822 TI - Silver or lead: the drug cartel La Familia gives local officials a choice: take a bribe or a bullet. PMID- 21698823 TI - Changing lanes: can Danica Patrick bridge the chasm between IndyCar and NASCAR? PMID- 21698824 TI - BLOCker-Sequencing: the next step from Sanger. PMID- 21698825 TI - Comment to the article: Magnetic resonance spectroscopic imaging for visualization of the infiltration zone of glioma. PMID- 21698826 TI - Face-blind: why are some of us terrible at recognizing faces? PMID- 21698827 TI - Mind game: when a murderous shrink moved to a trusting coastal town, both had a surprise in store. PMID- 21698828 TI - The covenant: Francis Collins, a fervent Christian, thought he had resolved the stem-cell debate. A federal judge disagreed. PMID- 21698829 TI - No daily specials: customs of a New Orleans roadhouse. PMID- 21698831 TI - Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. AB - With the constant advent of new developments and modifications in immunosuppressive regimens, clinicians are responsible for providing pregnancy counseling to all pre and posttransplant recipients of childbearing age. As individual physicians and centers accrue experience with these major therapeutic decisions, it is critical that both positive and negative outcomes be reported in appropriate settings-symposia, meetings, publications, and registries. The NTPR has acquired experience with 2000 pregnancy outcomes in female transplant recipients. For the NTPR's largest group, female kidney recipients, 71-76% of the pregnancies produce a livebirth. For the other organs combined, the livebirth likelihood ranges from 50-86%. The incidence of birth defects in the liveborn appears similar to the general population, except for pregnancies with MPA exposure that have a 23% incidence of birth defects. Long-term follow-up of the offspring of transplant recipients has provided reassurance after 20 years of observation. The continued recording of data in registries such as the NTPR is essential for assessing the safety of pregnancy in solid organ transplant recipients. Key benefits of the NTPR are the personal contact between registry staff and participants, the wide range of pregnancy-related variables that are analyzed, and the opportunity for health-care providers to obtain information that helps them care for transplant recipients on a case-by-case basis. PMID- 21698830 TI - Evolution of graft survival in kidney transplantation: an analysis of the OPTN/UNOS Renal Transplant Registry. AB - In summary, the analysis of more than 270,000 kidney transplants recipients who were transplanted between January 1988 and August 2010 showed the following important points: Despite enormous progress in short-term graft survival in the last decades, long-term graft survival remained largely unchanged over the period from 1988 to 2010. The marked decline in acute rejection episodes in the early transplantation period mainly contributed to the improvement of shortterm graft survival. The immunosuppressive agents that were introduced in the past 3 decades have not improved long-term graft survival. Therefore, new treatment approaches are strongly required to prevent and treat chronic allograft injury especially caused by immunologic factors. Avoiding and controlling risk factors that are responsible for cardiovascular diseases are the sine qua non for increased long term graft survival. PMID- 21698832 TI - Columbia University/New York-Presbyterian Hospital: improving access to renal transplantation. AB - There continues to be an increasing disparity between organ supply and demand in kidney transplantation with over 87,000 patients currently on the waiting list. Prolonged waiting times on dialysis is associated with significant morbidity and mortality rates. At Columbia University Medical Center/New York-Presbyterian Hospital we have implemented several strategies to improve access to transplantation. Here we present these key steps that have resulted in a significant reduction in our median waiting times and successfully increased the rate of transplantation at our center. PMID- 21698833 TI - Lung and heart lung transplantation at the University of Alberta 1986-2010. AB - The lung transplantation program at the University of Alberta has been in existence for 25 years. The current volume is 35-40 new lung transplants per year. We offer single-lung, bilateral lung, heart/lung and bilateral living lobar transplantation as options. Experience has allowed for widening of the indications and acceptance of patients with more risk. Donor evaluation and management has allowed for extended donors to be included in the donor pool. Results will likely continue to improve with increased understanding of the mechanisms and management of bronchiolitis obliterans syndrome. Our research interests have been in the areas of risk analysis, outcome assessment, and quality of life changes from transplantation. PMID- 21698834 TI - Clinical islet transplantation at the University of California, San Francisco. AB - The UCSF clinical islet transplant program has evolved to utilize immunosuppressive strategies that do not rely on CNIs or other nephro- and beta cell-toxic immunosuppressive agents. These novel strategies depend on lymphocyte depleting induction immunotherapy and maintenance immunosuppression with novel agents that focus on co-stimulation and/or lymphocyte migration blockade. These drugs are well tolerated, frequently allow establishment of insulin independence after single islet infusions, and minimize allosensitization. Our early results suggest these regimens will be attractive immunosuppressive agents for future protocols in allogeneic islet transplantation as well as protocols utilizing stem cell-derived beta cells. PMID- 21698835 TI - A "new" road to tolerance: clonal deletion and drugs added when needed (DAWN). AB - We propose clonal deletion--immunization followed by deletion--as a "new" way to achieve tolerance. Immunization of a donor results in specific stimulation of a clone of cells, which can then be killed by various agents, leaving the patient otherwise immunologically normal. The theory of clonal deletion is supported by experimental evidence as well as earlier experiences with kidney transplants and donor-specific transfusions. To date, 22 patients who underwent clonal deletion have been surviving for 1.5 to 2.5 years with only low-dose prednisone. In addition, those patients who required conventional immunosuppressive drugs were treated with the new Drugs Added When Needed (DAWN) protocol. With DAWN as a tactic ready for intervention, and by using antibodies to monitor the completeness of clonal deletion, we assure that patients are subjected to the minimal amount of drugs on a personalized basis. We suggest that risks involved in testing this new procedure are small and the benefits immeasurable. PMID- 21698836 TI - Options for successful renal transplantation in recipients with incompatible living donors: Severance Hospital experience. AB - Exchange donor programs and desensitization protocols are available options for ABO-incompatible and positive cross-match living donor kidney transplantations. Patient and donor blood types, the degree of sensitization, and DSA titers should be considered to achieve successful kidney transplantation in recipients with incompatible living donors. Highly sensitized blood type O patients with ABO incompatible living donors, or highly sensitized patients with a positive cross match (with low DSA titer) to their AB donors should be considered for a desensitization protocol as a first priority. Narrowly sensitized patients with a positive cross-match (and high DSA titer) should be considered for an exchange donor program if possible. Patients with positive cross-match O donors can be easily matched and benefit from an exchange program. Exchange donor programs and desensitization protocols are complementary strategies to overcome HLA and ABO antibody barriers. PMID- 21698837 TI - Bortezomib for acute humoral rejection treatment at the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran in Mexico City: an update. AB - The use of bortezomib as a treatment modality of AHR improved and stabilized graft function (clinical response) in the majority of patients. Its use in single dose, even combined with rituximab, does not seem to be useful to obtain a sustained clinical response, or to reduce HLAabs level. The use of 4 doses of bortezomib in days 1, 4, 7, and 10 (1.3 mg/m2 BSA each) plus plasmapheresis produced both a good clinical response and a reduction in DSA. Moving forward, it will be necessary to define the long-term effectiveness of bortezomib and whether rituximab administration is indispensable to achieve this goal. Until now, it is evident that many patients needed retreatment and they were well tolerated. PMID- 21698838 TI - Bortezomib use in chronic antibody-mediated allograft dysfunction: updates and additional cases. PMID- 21698840 TI - Proceedings of the European Congress on Obesity (ECO). Geneva, Switzerland. May 2008. PMID- 21698839 TI - Rescue therapy for acute antibody mediated rejection with a proteosome inhibitor after kidney transplantation. PMID- 21698841 TI - Mrt, a gene unique to fungi, encodes an oligosaccharide transporter and facilitates rhizosphere competency in Metarhizium robertsii. PMID- 21698842 TI - A meta-analysis of anxiety symptom prevention with cognitive-behavioral interventions. AB - This meta-analysis assessed efficacy of cognitive-behavioral interventions in preventing anxiety symptoms. A systematic review identified 15 independent pretest-posttest randomized or quasi-randomized efficacy trials for analysis. At posttest, intervention groups demonstrated significantly greater symptom reduction compared to control groups resulting in weighted mean effect sizes (Hedges' g) of 0.25 for general anxiety, 0.24 for disorder-specific symptoms, and 0.22 for depression after the removal of outliers. These effects appeared to diminish over 6- and 12-month follow-up. Exploratory moderator analyses indicated that individually administered media interventions were more effective than human administered group interventions at preventing general anxiety and depression symptoms. Implications of current findings are discussed with attention to existing gaps in the literature. PMID- 21698843 TI - The musical substance of Charles R. Schuster, Ph.D. (1930-2011). PMID- 21698851 TI - [Pediatric cardiac anesthesia]. PMID- 21698852 TI - [Recent advances in pediatric anesthesia]. PMID- 21698853 TI - [Postoperative cognitive dysfunction]. PMID- 21698854 TI - [Interpretation of ECG - The transient analysis of abnormal electrocardiogram -]. PMID- 21698855 TI - [Impact of fluid therapy based on fluid volume dynamics]. PMID- 21698856 TI - [Clinically oriented respiratory physiology]. PMID- 21698857 TI - [Diagnosis and surgical management in gastrointestinal neuroendocrine tumors]. AB - Neuroendocrine tumors, known as carcinoid tumors constitute a heterogeneous group of neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause specific clinical syndromes. Assessment of specific or general tumors markers offers high sensitivity in establishing the diagnosis and they also have prognostic significance. Management strategies include curative surgery, whenever possible-that can be rarely achieved, palliative surgery, chemotherapy, radiologic therapy, such as radiofrequency ablation and chemoembolisations and somatostatin analogues therapy in order to control the symptoms. The aim of this paper is to review recent publications in this field and to give recommendations that take into account current advances in order to facilitate improvement in management and outcome. PMID- 21698858 TI - [Current problems in surgical oncology 2. A lesson from Japan. D2 lymphadenectomy in gastric cancer]. AB - At present there is accumulating evidence supporting the D2 lymphadenectomy in gastric cancer performed according the rules of the Japanese school of surgery. The D2 lymphadenectomy by open surgery seems to gain a wide acceptance and to become a standard therapy. The minimally invasive D2 lymphadenectomy (by laparoscopic or robotic surgery) in advanced gastric cancer showed promising results. However, these advanced minimally invasive techniques have still to be performed only in highly specialized surgical centers, with a large experience in oncological surgery. Further clinical trials are needed in order to verify the encouraging data of the few studies published until now in this field. PMID- 21698859 TI - [The management of acute pancreatitis according to the modern guidelines]. AB - Severe acute pancreatitis is a critical illness as the organism that produces a significant mortality despite diagnostic and therapeutic acquisitions. While new mechanisms have been identified for production and were crystallized management principles, a number of controversies remain awaiting resolution in the near future. Aim is to establish, based on their experience and literature data, place the current means of diagnosis and treatment in close correlation with the pathophysiological events of acute pancreatitis. PMID- 21698860 TI - [The problem of iatrogenic common bile duct injury, or the picture of an iceberg peak]. AB - The goal of this study was to increase the awareness of the problem of iatrogenic common bile duct injury. METHODS: A retrospective review of the biliary primary or redo reconstructions performed at our clinic, for iatrogenic injuries, was done. A total of 34 cases were followed for 2 to 16 (mean 8.5 +/- 4.5) years in order to asses their long-term outcomes. RESULTS: There were 8 Strasberg D lesions and 26 Strasberg E lesions. The mortality rate was 6% (2 patients). The mid and long term outcomes were good in 82% cases (28 patients). Over all there were 108 surgical, radiological or endoscopic interventions (mean 3.2 +/- 1.8). Only 2 patients didn't have a complicate course after the initial surgery. We have counted 87 (mean 2.5 +/- 2.9) complications, 107 (mean 3.1 +/- 2.2) hospital admissions, and 1182 (mean 37 +/- 25) hospitalization days. General and local sepses were the main risk factors for the failure of the biliary reconstruction. CONCLUSIONS: As a rule, iatrogenic common bile duct injuries have a complicated postoperative course, with many hospital admissions and surgical, endoscopic or radiological interventions. Before biliary reconstruction, every attempt must be done to prevent or control general and local sepsis. Biliary injuries are more easy to prevent than to treat. PMID- 21698861 TI - [Sentinel lymph node mapping in colorectal cancer]. AB - Colorectal cancer is the most common malignant tumor of digestive tract with high mortality due to local reccurences and metastases. These are due to micrometastases undetected by classical microscopic examination of regional lymph nodes. Sentinel lymph node SLN technique in colorectal cancer may lead to identification of micrometastases using immunohistochemistry. METHODS: We present our experience in SLN mapping in colorectal cancer using a limphofil dye, on 52 patients. We present the patients selection criteria in the study, the technique of SLN detection. RESULTS: Identification of SLN was performed in 48 cases, it failed in 4 cases. In 27 cases, 1 SLN was identified, in 21 cases 2 SLN were found. In 4 cases the SLN were false negative. In 30 cases SLN were negative on histopathology and immunohistochemistry. In 14 cases, SLN were positive, 4 cases presented micrometastases confirmed only by immunohistochemical methods. CONCLUSION: SLN technique in colorectal cancer: - doesn't change the surgical approach regarding the regional lymphadenectomy; - can modify the tumor stadialization by detecting lymph nodes micrometastases; - increase the number of patients who can benefit from the adjuvant chemotherapy and therefore, it may improve the prognosis. PMID- 21698862 TI - [Neurogenic tumors of the posterior mediastinum]. AB - The posterior mediastinum is the potential space along each side of the vertebral column and adjacent proximal portions of the ribs--the paravertebral sulci. From the posterior mediastinal tumors, the most commonly encountered are the neurogenic tumors (75%), the remaining 25% are represented by a heterogenous group of rare tumors including teratoma, lymphoma, sarcoma and other lesions arising outside the mediastinum and projecting into the posterior compartment. Surgical excision, by thoracotomy or miniinvasive techniques, is the first line of treatment in the posterior mediastinal tumors. Tumors with extension into the spinal canal (dumbbell tumors), accounting for nearly 10% of the posterior mediastinal tumors, require a multidisciplinary approach: thoracic surgeon and neurosurgeon. We present the experience of the "Carol Davila" University of Medicine and Pharmacy Thoracic Surgery Clinic in the surgery of neurogenic posterior mediastinal tumors throughout a 9 year period (2001 - 2010). 42 cases admitted and operated in this period are being analysed. PMID- 21698863 TI - [Hepatoprotective effects of orally administered melatonin and tinospora cordifolia in experimental jaundice]. AB - Posthepatic cholestasis is figured by the onset of an intense oxidative stress, followed by important cellular morphological and functional abnormalities. The aim of this experimental study is to assess the hepatoprotective effects of Melatonin and extract of Tinospora cordifolia in bile duct ligation induced jaundice in rats. We choosed to administrate both pharmacological products per os, in order to compare the results with those already published, in which melatonin was administrated injectable. The assessment of microscopy, lab tests and the measurement of oxidative stress products indicates a marked hepatoprotective effect of those two compounds. The results allowed us to recomand the use of melatonin and Tinospora cordifolia to reduce the cholestasis's oxidative stress in human. PMID- 21698864 TI - [Temporary loop-ileostomy for distal anastomosis protection in colorectal resections]. AB - Temporary loop-ileostomy (TLI) is an efficient modality to protect distal anastomosis in colorectal resections. TLI reduces the consequences of distal anastomosis leakage. We present the technique of construction and closure of TLI, the indications, postoperative complications and personal experience in early closure. PMID- 21698865 TI - [Heurteaux phlegmons. 1934]. PMID- 21698866 TI - [Jejunal ischemic ulcer with perforation: a case report]. AB - Ulcerative ischemic lesions of the small bowel represents a rare abdominal pathology. We present the case of a 68-year-old male who was admitted to our hospital for abdominal pain, nausea and vomiting. Ultrasound examination followed by upper endoscopy raised up the suspicion of a jejunal ulcerative perforated lesion. Surgery confirmed the diagnosis, revealing the jejunal ulcer, perforated and blocked by the adjacent enteral loops. Ischemic etiology of the ulceration was indicated by the mesenteric thrombus. The anatomopathologic finding together with the clinical and imagistic examinations lead us to the diagnosis of thromboangiitis obliterans, cause of the mesenteric ischemia; the future problems regarding this case are the long term follow up, in order to be able to recognise the visceral ischemic recurency that might occur. PMID- 21698867 TI - [Endoscopic treatment of vesicoureteral reflux in children]. AB - INTRODUCTION: Although vesicoureteral reflux (VUR) is a relatively common disease, in present there are different opinions regarding its approach by paediatric urologist, nephrologist and paediatrician. European Society for Paediatric Urology, European Association of Perinatal Medicine in collaboration with paediatric nephrologists developed--based on multicentric studies--a consensus approach for this disease. An efficient alternative is represented by endoscopic treatment. MATERIALS AND METHODS: From January 2002 to December 2008 a number of 58 children, confirmed after mictional cistography with the diagnosis of VUR grade II - V, went endoscopic subureteral injection of dextranomer/ hyaluronic acid (Deflux). The reflux was unilateral in 21 cases and bilateral for the rest of 37. From 95 ureters, VUR was considered grade II - V in 15(15,79%), 45(47,37%), 28(29,47%) and 7(7,37%) cases. Follow-up and evaluation were based on mictional cistography and ultrasound examination. RESULTS AND CONCLUSIONS: Reflux remitted after the first, the second or the third injection in 63(66,31%), 13(13,68%) and 1(1,05%) of the ureters. These results confirm the fact that endoscopic subureteral injection of an adequate material confers semnificative advantages. High rate of success, absence of postoperative complications, reduced period of hospitalization sustain this kind of treatment that is indicated in all grades of reflux. PMID- 21698868 TI - [Difficult case of thoraco-abdominal injuries due to a motor vehicle accident]. AB - Recently, in our country we experience an increase incidence of motor vehicle accidents, which often leads to some severe cases brought to the A&E's departments, requiring prompt complex surgical treatment, with the surgeon facing out of ordinary situations. This is the case for the combined trauma of the chest and abdomen. The authors present the case of a 32 years old female patient, victim of a MVA, who had suffered a deep penetrating wound of her right chest and right upper quadrant, caused by a woden pole which penetrated the anterior V and VI intercostal spaces, went through the right inferior pulmonar lobe, the diaphragm and the 7th segment of the liver, resting on the posterior wall of the ribcage. This patient required emergency surgery, making un uneventful postoperative course. PMID- 21698869 TI - [Iliac venous aneurysm: a case report and review of literature]. AB - Primary iliac vein aneurisms are extremely rare being described as anomaly, without any history of trauma, cardiovascular pathology or arteriovenous fistula. This clinical condition has a high rate of potentially fatal complications: pulmonary embolism; ruptured aneurism; deep vein thrombosis. There are only 7 cases of iliac vein aneurism described in the literature. We describe an additional case of a 59-year old patient presented with abdominal pain, right lower limb edema and palpable mass in the right iliac area. Ultrasound (US) revealed a liquid formation, confirmed by computed tomography (CT). Surgical removal of the aneurism with lateral venorrhaphy was performed. Postoperative evolution was uneventful. The patient is asymptomatic during 36 month follow-up. PMID- 21698870 TI - [Evaluation of vibration exposure long-term effects in people with diagnosed vibration syndrome]. AB - BACKGROUND: Long-term exposure to hand-transmitted vibration can increase the occurrence of symptoms and signs of vascular neurological and musculoskeletal disorders of the upper extremities. The most common is the angioneurotic type of the vibration syndrome. Very little is known about possibility of withdrawal of symptoms after exposure cessation. OBJECTIVES: The aim of the study was to evaluate the long-term effects of vibration exposure in people with diagnosed vibration syndrome. The particular aim of the study was to gain the information on possible withdrawal of symptoms in the peripheral vascular and nervous system after exposure cessation. MATERIALS AND METHODS: The medical documentation of patients with vibration syndrome symptoms, examined in the years 1999-2004 in the Outpatient Clinic of the Nofer Institute of Occupational Medicine and in three Voivodeship Centers of Occupational Medicine has been analyzed. RESULTS: A group of 45 people who had been suffering from diagnosed angioneurotic vibration syndrome for at least 5 years was chosen. The mean age of the examined group at the time of occupational disease certification was 48.2 and the mean period of exposure to hand-transmitted vibration was nearly 20 years. The major group comprised persons with vibration syndrome diagnosed at an 'early symptoms' stage, an advanced stage of the disease was described in only 5 cases. From the time of occupational disease certification only 7 persons have been performing any job, and more than a half of the group has been granted disability pension. CONCLUSIONS: The results of the study show a bad prognosis of angioneurotic vibration syndrome despite cessation of the exposure to vibration. The total withdrawal of symptoms is possible only in people with vibration syndrome diagnosed at an 'early symptoms' stage, at young age and after short period of exposure. PMID- 21698871 TI - [Dust concentration analysis in non-coal mining. Exposure evaluation based on measurements performed by occupational hygiene laboratories in the years 2001 2005 in Poland]. AB - BACKGROUND: Non-coal mining includes the extraction of materials for construction (stone, gravel, sand and clay), chemical industry (salt and sulfur), metallurgy (metal ores, uranium and thorium) and other mining and quarrying. Regardless of the type of mining company one of the most common health hazards in this sector is exposure to high concentrations of dust occurring during the extraction of materials. Such activities as drilling, use of blasting agents, processing of raw material, its transportation and loading are the source of large amounts of dust containing crystalline silica. MATERIALS AND METHODS: Data on exposure to dust, collected by industrial hygiene laboratories on the basis of dust concentration measurements in the work environment, were obtained from the sanitary inspection service. The analysis of dust concentrations at workplaces in non-coal mining covered the years 2001-2005. The average concentration of inhalable and respirable dust and the degree of results dispersion at workposts in different branches of non-coal mining (according to NACE rev1.1) were evaluated. Also there was estimated the percentage of surveys indicating dust concentrations above hygiene standards. RESULTS: Almost 5000 measurements of dust concentrations were performed in the years under study. The highest concentration of inhalable dust was noted for the production of salt (5.51 mg/m3), other mining and quarrying (4.30 mg/m3) and quarrying of slate (3.77 mg/m3). For respirable dust the highest concentrations were noted in other mining and quarrying (1.10 mg/m3), quarrying of slate (1.09 mg/m3) and quarrying of stone (0.81 mg/m3). CONCLUSIONS: Exposure to high concentrations of dust during the extraction of non-carbon is still an important hazard to human health. Almost for all workposts under study the excess of hygiene standards were observed. PMID- 21698872 TI - [Assessment workaholism as a behavioral tendency: the Polish adaptation of the Mudrack and Naughton questionnaire]. AB - INTRODUCTION: There are many approaches to workaholism presented in the scientific literature. The behavioral developed by Mudrack and Naughton is one of them. The authors understand workaholism as a tendency towards unnecessary activity that is not expected by an employer and intrusive strive for control over co-workers. Mudrack and Naughton developed the diagnostic tool for workaholism measurement. This is an 8-item questionnaire consisted of two subscales named: non-required work and control of others. The operationalisation of the workaholism phenomenon proposed by the authors seems to be the subject of interest to both scientists and practitioners. It allows for quick and easy diagnosis of the problem and also offers tools for behavioral change of unhealthy activities. That is why, the Polish adaptation of this questionnaire has been decided. METHODS: The following analyses were applied: item analysis, explanatory and confirmatory factor analyses and the reliability of scales were calculated. RESULTS: This paper presents stages of the adaptation study which has resulted in the construction of a 12-item questionnaire. CONCLUSION: The Polish version of Mudrack and Naughton's tool, like the original, has a two-factor structure, and preliminary psychometric properties seem to be satisfactory (Cronbach alfa = 0.87). PMID- 21698873 TI - [Professional burnout among university and high school teachers--comparative study]. AB - BACKGROUND: Professional burnout is a set of negative emotional and behavioral symptoms, observed in workers of widely understood human service occupations, including teachers. In spite of the considerable number of studies of burnout in teachers, a few of them concern university teachers. The aim of the article was to estimate the degree of burning threat in this professional group and to analyze individual determinants and dynamics of burning out in academic teachers. Gender, age, personality traits and temperament traits were given the status of main factors in the study. The role of the perceived social support was also analyzed. MATERIALS AND METHODS: 97 academic workers of three state universities (University, Medical University and Technical University) in Lodz took part in the study; 100 teachers of high schools formed a comparative group. MBI General Survey was applied to measure dependent variables (burnout and its three components: Emotional Exhaustion, Cinicism and Professional Efficacy). The level of factors was measured with standard psychological tests: NEO-FFI and FCZ-KT. The Scale of Perceived Social Support was also applied. RESULTS: The results show considerably lower threat of the burning out syndrome in university than in high school teachers. Among individual factors only two temperament traits (emotional reactivity and perseveration) and one personality trait (extroversion) seem to be important determinants of professional burnout. The perceived social support does not prevent the progress of burnout syndrome. CONCLUSIONS: Based on the obtained results several practical conclusions were formulated. They refer mainly to preventive training for beginners in teaching and changes in the organization of academic teachers' work. PMID- 21698874 TI - [Exposure to biological agents used in Polish enterprises: analysis of data derived from the National Register of Biological Agent]. AB - INTRODUCTION: The National Register of Biological Agents at Work and the National Information Centre for Biological Agents Present at Workplaces were established in the Nofer Institute of Occupational Medicine in 2005. The National Information Centre carries out consultation and education activities concerning occupational exposure and risk assessment, development and implementation of preventive programs and accurate registration of reliable information about the use of biological agents. Educational materials on biological exposure are published on the website. MATERIAL AND METHODS: The National Register of Biological Agents (database) collects and periodically analyzes the information obtained from employers about the use of biological agents for research, diagnostic or industrial purposes. RESULTS AND CONCLUSION: As of 10 December 2010 there were 240 notifications from companies, which use biological agents for the following purposes: research--69, industrial--30 and diagnostic--321. Near 75% of all notifications were obtained from different diagnostic laboratories (public and private). In total, 3226 workers, including 2967 (92%) women and 256 (8%) men were exposed to biological agents. In general, occupational exposure to 209 biological agents (186 of risk group 2 and 23 of risk group 3, of which 16 are additionally marked by 3**) were registered in the data base. PMID- 21698875 TI - [Acquired musculoskeletal dysfunction syndromes in workers in the light of epidemiological studies]. AB - Acquired musculoskeletal dysfunction syndromes (overload syndromes) that cause limitation of the system efficiency belong nowadays to the most serious problems in the medical care of workers. The etiology of overload syndromes is multifactorial, which means that occupational factors constitute only one of many causes fostering the development of those disorders. Occupational factors which increase the risk of musculoskeletal disorders include physical factors related to the work environment or the way the work is performed, such as body posture, value of exerted forces, movement repetitiveness, load handling, mechanical vibration or microclimate as well as psychosocial factors, such as quantitative and qualitative overload, lack of control, lack of social support or work insecurity. The consequence of musculoskeletal overload syndromes is the progressing reduction of its efficiency causing limitation or even loss of work ability, which results in premature exclusion from social and occupational activities. This article presents etiological factors of musculoskeletal complains and overload syndromes and their prevalence in workers. PMID- 21698876 TI - [Cleaners'asthma--etiology, diagnostics, prophylaxis and medical certification]. AB - Asthma is the most common occupational allergic respiratory disease. The results of several current studies reveal also high risk of work-related asthma among cleaners. This kind of work may increase the risk of allergic as well as non allergic asthma. However, the mechanism by which inflammation in respiratory airways is induced by cleaning chemicals is still unknown. This paper shows the results of numerous studies regarding exposure and respiratory symptoms among cleaning personnel. The increased risk of respiratory diseases among cleaners suggests the need to educate workers and to devise safety methods during multiuse cleaning both in occupational settings and in private households. PMID- 21698877 TI - [Prophylactic care of workers with disabilities--the problem of contemporary occupational health service?]. AB - According to the 2002 data there are in Poland 14.3% of people with disabilities. On the other hand, an employment level of people with disabilities in Poland is one of the lowest in Europe with its percentage rate of 13% in the year 2004. Therefore, the improvement in certification system and its efficacy is needed. Occupational health service (OHS) plays an important role in the process of occupational elicitation of this group of people. Barriers at the level of OHS mainly result from the lack of guidelines in this field, so now it is essential to implement those that have been proposed. The improvement in occupational medicine physicians training is also essential. Difficulties in certification of ability to work is also the result of unavailable data on patient's health. Psychiatric problems, epilepsy and diabetes cause the major problems in the certification of capacity to work. PMID- 21698878 TI - [Low back pain among farmers exposed to whole body vibration: a literature review]. AB - A literature review was performed for the years 1990-2007. It covered reports addressing the problems associated with the prevalence of low back pain and musculoskeletal disorders among farmers. In addition, the anticipated relationship between low back pain and whole body vibration in farmers was evaluated based on 12 reports for the years 1987-2009. The review confirmed that the prevalence of back pain is significantly higher in farmers exposed to whole body vibration than in the control group (not exposed to vibration). The frequency of back pain is related with whole body vibration, as well as with prolonged sitting position, wrong body posture and physical work load (especially lifting and carrying loads). The prevalence of these symptoms increases with the increased vibration dose and duration of exposure. Disorders in the lower section of the spine were associated with age, accidents (concerning the back), cumulative dose of whole body vibration, and overload due to wrong body posture. Long-term exposure affecting the whole body is harmful to the skeletal system (degeneration of the spine). The results of the study suggest that the repeated or constant exposure to mechanical shocks may increase the risk of low back pain. The investigations confirmed that there is a dose-response type of relationship between exposure to whole body vibration and pain in the lumbar section of the spine. PMID- 21698879 TI - [Toxic liver injuries--a current view on pathogenesis. Part II]. AB - Liver plays an important role in biological detoxication of xenobiotics. During this process, one can observe the inactivation and successful elimination of metabolites and toxic substances. The metabolic reactions responsible for detoxications include phases I and II. The phase I reactions increase polarity of xenobiotics through inserting new functional groups to xenobiotic molecules, while during phase II conjugation to endogenous hydrophilic molecules results in potent increase in polarity and water solubility. Phase III involves the transport process mediated by transmembranous transporter proteins, which remove a large number of xenobiotics from blood into liver. Oxidative stress and oxidation of lipids may lead to liver injury. Functional impairment of mitochondrial metabolism is associated with intensive production of reactive oxygen species. The underlying mechanisms during mitochondrial dysfunction may lead to cellular necrosis and apoptosis. PMID- 21698881 TI - [Fatal semantic]. PMID- 21698880 TI - [Hospitality workers' exposure to environmental tobacco smoke before and after implementation of smoking ban in public places: a review of epidemiological studies]. AB - Environmental tobacco smoke (ETS) exposure induces serious negative health consequences, of which the increased risk of cardiovascular diseases, cancer, respiratory symptoms and poor pregnancy outcomes appear to be most important. Taking into account those health consequences of ETS exposure most countries have introduced legislation to ban or restrict smoking in public places. In this paper the effectiveness of the introduced legislation was analyzed with regard to the protection of hospitality workers from ETS exposure in the workplace. The analysis of 12 papers published after 2000 covered the year of publication, type of legislation, study population, hospitality venue (pub, bar, restaurant, disco) and type of markers or self-reported perception of exposure to ETS. The analysis indicates that the legislation to ban smoking in hospitality venues protects workers from ETS exposure when the venues are 100% tobacco smoke free. The reduction of the cotinine level in biological samples after the implementation of smoke free law was 57-89%, comparing to the biomarker level in the samples taken before the new law was introduced. About 90% of reduction in nicotine and PM levels was also noted. In addition, the positive self perception reported by workers proved the effectiveness of new legislation protecting them from ETS exposure. PMID- 21698882 TI - [Does the concept of lung age help the smokers to quit smoking?]. PMID- 21698883 TI - [Pulmonary hypertension and migrated ventriculoatrial shunt]. PMID- 21698884 TI - [Adult acute lymphoblastic leukemia]. AB - The diagnosis of adult acute lymphoblastic leukemia (ALL) and the recognition of immuno-genetic entities according to the WHO classification require a comprehensive clinical and biological work-up. The diagnosis of Burkitt mature B cell ALL is an emergency, since intensive chemotherapy and tumour lysis syndrome prevention lead to an 80% cure rate. Within one week, distinction must be established between B-cell Philadelphia chromosome-positive (Ph+) ALL on one side, Philadelphia-negative B-cell ALL and T cell ALL on the other. The once severe Ph+ ALL now displays a 70% long-term survival rate when treated by associations of chemotherapy and targeted therapy by tyrosine-kinase inhibitors. In Ph-negative ALL, identification of new relapse risk factors, mostly minimal residual disease, justifies to revisit the indications for allogeneic hematopoietic stem cell transplantation, in comparison to pediatric-inspired chemotherapy regimens, with the goal of curing 60% of the patients. However, the outcome of patients above the age of 60 remains dismal. PMID- 21698885 TI - [Inflammatory pseudotumour of the gallbladder]. PMID- 21698886 TI - [Acute abdominal pain in children. Emergencies and conducting diagnostic]. PMID- 21698887 TI - [Diagnosis of acute abdominal pain in infants]. AB - In front of infant and toddler presenting with unexplained cries, unusual behavior, and tachycardia, pain should be recognized, and signs and symptoms of shock and intestinal occlusion should be sought without any delay. Meningitis, pyelonephritis, and pneumonia must be taken into consideration in a young child with fever and irritability. In the presence of any paroxystic pain with refusal of feeding, one should consider acute intestinal occlusion, volvulus due to intestinal malrotation if associated with signs of shock, and volvulus related to postsurgical adhesions if history of abdominal surgery. Abdominal ultrasonography is the exam of choice in these cases. Examination of inguino-scrotal region is essential in order to rule-out inguinal hernia, ovarian hernia, and testicular torsion. Infant colic and peptic esophagitis are common causes of recurrent pain. PMID- 21698888 TI - [Surgical abdominal pain in children]. AB - Abdominal pain in child could be related to surgical pathologies in 10 to 20 % of cases. The more frequent etiology remains appendicitis. Regarding to clinical presentation, age and medical history, intestinal intussusception, incarcerated hernia, adhesive occlusion and Meckel's diverticulum could be evocated. But the most dreadful diagnosis is malrotation with volvulus, because of mortality and morbidities induced by bowel necrosis. Usually, medical history and clinical exam allowed diagnosis. Ultrasound remains the more helpful exam in children with surgical pathologies and in some selected cases, CT scan and others biological and/or radiological exams could be performed. PMID- 21698889 TI - [Which imaging in front of abdominal pain in children?]. AB - Imaging plays an important role in the diagnosis of abdominal pain. Plain abdomen radiography is of very limited value, but is still too often requested. Ultrasound is the first-line procedure. However, it does not always provide answers to all the questions. It is thus essential to know its limitations and flaws. Ultrasound should complement the physical examination. PMID- 21698890 TI - [Girls' abdominal pains and gynaecological emergencies]. AB - Among many causes of abdominal pain in children, gynaecological ones have to be systematically considered in even no pubescent girls. Diagnosis leans on physical and US examinations and has to screen first urgent causes before frequent ones. Rare but urgent are ovarian torsions either on a normal ovary or an underlying ovarian tumor, an earlier surgery may avoid oophorectomy. Hematocolpos linked to imperforate hymen is the most common obstructive congenital abnormality of the female genital tract and the diagnosis is easy with inspection of external genitalia. Ovarian tumors are infrequent and most often begnin but torsion, rupture or bleeding complications causes acute abdominal pains. Dysmenorrhea is the most common cause of abdominal pain in pubescent girls. In adolescents, genital tract infections and rare ectopic pregnancy have also to be mentioned. PMID- 21698891 TI - [Abdominal pain and gastritis in children]. AB - Gastritis, as gastric and duodenal ulcer, is associated with epigastric abdominal pain, influenced by meals, associated with nausea and vomiting and weight loss. Diagnosis s based upon upper gastrointestinal fibre endoscopy that allows direct visualisation of gastric lesions and realization of antral and fundic biopsies for anatomopathology and culture. Main etiologies are drug induced, stress and H. pylori infection. Looking for H. pylori is only justified in those children presenting with digestive symptoms requiring upper gastrointestinal endoscopy. Therefore non invasive test are only indicated for control of eradication. Treatment of H. pylori infection associates proton pump inhibitors and two antibiotics for 7 to 10 days. PMID- 21698892 TI - [When to think about Crohn's disease when facing with chronic abdominal pain in children and adolescents?]. AB - Crohn's disease (CD) together with ulcerative colitis (UC) and indeterminate colitis (IC) are the so called inflammatory bowel diseases (IBD). Epidemiological data show an increased incidence of both UC and CD and, especially in North America and in Europe, an increased prevalence of CD. European data show that northern countries present higher rates of IBD than southern ones. It is estimated that 15%-20% of CD patients experience onset of their symptoms under 20 years of age. An increasing number of children enter disease before 8 years of age. The pathogenesis of CD has became more documented involving both the immune system and changes in intestinal microbiota. Chronic abdominal pain associated with failure to thrive and inflammatory syndrome with or without intestinal transit disorders suggest CD. Onset of a anoperineal disease is also suggestive of CD and is a severity sign. The diagnosis is based on clinical history, physical examination, radiological studies, endoscopy, and histology. CD is defined by evidence of a discontinuous chronic inflammation of the gastrointestinal tract with or without granulomas and supported by clinical, biochemical, and radiological evidence. Treatment aims to reducing inflammation and restauring growth. Enteral feeding has become a key issue in allowing to avoid steroids. Immunosuppressive treatment based on azathioprine is increasingly used for maintaining remission. Anti-TNF treatment is a rescue therapy in case of refractory, frequently relapsing disease especially those with ano-perineal disease. PMID- 21698893 TI - [When to evoke an Henoch-Schonlein disease in a child with acute abdominal pain?]. PMID- 21698894 TI - [Chronic abdominal pains in children]. PMID- 21698895 TI - [Early childhood abuse: an underestimated phenomenon that doctors must learn to recognize]. PMID- 21698896 TI - [Recognizing clinical signs suggesting child abuse in young children]. AB - It is difficult to diagnose child abuse. Any injury to a child should raise the essential question as to its plausibility. Any incompatibility between the nature of the lesion and the child's age, or the explanations given, should suggest intentional injury. The presence of a bruise on an infant too young to move about is a serious warning sign. Any fractures before the infant is able to walk should raise the suspicion of intentional injury. Regardless of the type of abuse noted for an infant, it must be hospitalized. Supplementary examinations, in association with a psychosocial evaluation, will enable exploration for other lesions and the elimination of differential diagnoses. This allows the child to be protected, while including the family in the treatment process. PMID- 21698897 TI - [Shaken baby syndrome]. PMID- 21698898 TI - [What signs are suggestive of sexual assault in child?]. PMID- 21698899 TI - [Risk factors of child abuse and neglect in childhood]. AB - Among factors identified as being statistically associated with child abuse, we can broadly distinguish those related to characteristics of the child itself and those related to family characteristics, bearing in mind that parents are the perpetrators of child abuse in the vast majority of cases. Observed among children are: young age (abuse begins very early in life); male sex, as concerns shaken baby syndrome and lethal violence; the presence of mental disability and/or behavioural disorders; and particularly frequently, prematurity, especially if it requires neonatal hospitalisation. In fact, any circumstance that makes early attachment between the newborn and its parents difficult or impossible, such as prematurity or postpartum depression, constitutes a situation of risk for subsequent child abuse. Among parents, psycho-affective factors take precedence over socio-economic factors, which play no role. Child abuse is found in all social classes, as is the transgenerational transmission of violence, with those parents having suffered from abuse as children being more at risk than others of becoming abusive themselves. PMID- 21698900 TI - [What position should the practitioner adopt when confronted with a suspicion of abuse to an infant?]. AB - The role of physicians in the identification of child abuse is essential. The changes introduced by the Act of March 2007 created new procedures that practitioners must be aware of and be able to implement. Thus, in addition to reporting to judicial authorities, the law establishes the concept of "information that is cause for concern" and its evaluation by the CRIP (Departmental Unit for Gathering and Evaluating Reports Citing Concern). The relative isolation of independent physicians in these situations adds to their difficulties. Comprehensive knowledge of available tools should help them in their practice. PMID- 21698901 TI - [Long-term consequences of child abuse and neglect]. AB - In the international scientific literature, data from birth cohorts clearly show the statistical relationships existing between abuse experienced in childhood and disorders in adulthood, in particular somatic, psychological (depression, suicide, anti-social behaviour, addiction, etc.), and cognitive problems, as well as difficulties in social integration. When abused children are cared for by Child Protective Services, the success or failure of placements is conditioned by a web of factors in which the severity of the initial trauma becomes intertwined with characteristics of the care given. Autonomy in adulthood is more likely to be achieved when placement is continuous and long-term, includes siblings and allows the creation of new bonds of attachment and identification with adult role models. Only these characteristics can attenuate the deleterious effects of the violence suffered in the past, one of the most disturbing consequences of which is the trans-generational transmission of violence. It is therefore important that physicians (general practitioners and paediatricians) who see foster children for vaccinations or childhood diseases are aware of their situation, enquire about the quality of care and know how to establish partnerships with those responsible for the education of these children (foster families, special educators). PMID- 21698902 TI - [Maltreatment of young children: 12 golden rules to help identify it and take action]. PMID- 21698903 TI - [Conflict of interest: the impact on readers]. PMID- 21698904 TI - [GP, primary care physician ... to serve the patient and public health]. PMID- 21698905 TI - [Challenges of medical psychology]. PMID- 21698906 TI - [Diagnosis and treatment of congenital hemochromatosis. Misconduct, abuses and excesses!]. PMID- 21698907 TI - [Arthrosis]. PMID- 21698908 TI - [Jaundice]. PMID- 21698909 TI - [Asthma in children]. PMID- 21698910 TI - [Cirrhosis and complications]. PMID- 21698911 TI - [Vaccinations]. PMID- 21698912 TI - [Acute urinary retention]. PMID- 21698913 TI - [Medical recollections. Leonardo da Vinci: brilliant anatomist who wanted to understand the movement]. PMID- 21698914 TI - [The hand project: more hugs, no shakings]. AB - The purpose of the study was to determine if an educational program for parents of newborns can be useful to prevent Shaken Baby Syndrome in Puerto Rican families. Staff training was performed, parents observed an educational video & infant crying management strategies were discussed. Pre-post tests, follow up phone calls and medical chart reviews (53%) were conducted. A total of 65 newborns participated (62 mothers, 11 fathers). Parents reported that 50% had college studies, 78.7% lived together and 83.1% had government insurance. Pre post tests demonstrated increase in knowledge (p < 0.05). Over 75% were contacted; 94% recalled learned strategies & 98% reported the infants had been well. Two infants were removed from home; no incidents of head trauma were reported. Almost half (44.5%) indicated taking care of the baby was difficult; managing the baby's crying was most difficult. All reported the program helped them. The program should be offered in other hospitals. PMID- 21698915 TI - [Early referrals of patients with bile duct lesion improve reconstructive surgery outcome]. AB - Damage to the bile ducts caused during open cholecystectomy or laparoscopic cholecystectomy remains a major problem in the practice of surgery today. This is associated with a poor quality of life and increased morbidity. The incidence of bile duct damage varies with the type of damage and the type of surgery performed. Currently the incidence of bile duct damage in Puerto Rico, as a result of the removal of the gallbladder is unknown. Without doubt the seriousness of complications, high costs due to handling and suffering of both patient and family make it necessary to further research on the subject. It is for this reason that we made the following research on population, with the aim of improving the quality of care offered in the island, and in turn reduce the time of referral of patients with bile duct damage. It has been shown to decrease the time of referral improved patient outcomes. PMID- 21698916 TI - [History notes of Dr. Raul Marcial Rojas on the development of regional academic medical centers in Puerto Rico]. AB - Since 1976, with the foundation of the first private school of medicine in Puerto Rico, it was realized that governmental help was of the essence in order to maintain its accreditation from the official federal accrediting agency, the Liaison Committee on Medical Education. This special article summarizes the history of such endeavor, which progressively resulted in the invaluable cooperation, validated through administrative regulations and legislative proceedings, of the Universidad Central del Caribe School of Medicine and its other paramedical programs. At present law number 126 of 2006, signed by then the past governor authorized the creation of four regional academic medical centers, one in each of the four medical schools operating independently as non-profit corporations. As of today, January 7, 2011 a budget has not been assigned. The rresent Governor in his April 2010 speech to the Legislative Assembly, stated that the development of the regulations has been finished and the Academic Medical Centers will finally become a reality. PMID- 21698917 TI - [Surgical approaches to thalamic tumors]. AB - The paper summarizes the results of surgical treatment of patients with thalamic tumors of different topographic variants. Since 1985 till 2010 127 patients were operated, 147 direct surgical interventions were performed. Repeated surgeries were required due to partial resection of a tumor or recurrence. In most cases resection of tumors was performed via transcallosal (48%) and occipital interhemispheric (29%) approaches. Less common approaches included transcortical (frontal, temporal, parietal) (14%), pterional through lateral and basal parts of Sylvian fissure (6%) and subtentorial supracerebellar (3%). Selection of approach is based on topographic features of tumor within thalamus, direction of its growth and relations with adjacent structures (internal capsule, brainstem, hypothalamus, ventricular system). Each approach has its own advantages and drawbacks which are highlighted in the paper. PMID- 21698918 TI - [Surgical treatment of cranioorbital injuries combined with brain trauma]. AB - Cranioorbital injuries (COI) are combined with brain trauma in 45-53% of patients and in 21--24% of cases require surgical treatment. Aim of this study was to evaluate the results of surgical treatment of patients with COI in acute period of traumatic brain injury (TBI). Among 4078 patients with TBI admitted to neurosurgical department of Sklifosovsky Institute of Emergency Medicine, 428 (10,5%) had COI. In acute period of TBI reconstructive procedures were performed in 158 (36,9%) cases. In 78 (49,4%) patients reconstructive surgical procedures were done within 48 hours after injury, in 35 (22,2%) of them simultaneously with neurosurgical operation. In 53 (33,5%) patients underwent surgical treatment in 1 week after trauma or later. Majority of procedures were reconstructive operations with reposition and rigid fixation of fractured bones using different implants. Overall mortality in patients with COIl was 5,3%, postoperative mortality--4,6%. Postoperatively position of the eyeball was restored totally or partially in 127 (97,7%), oculomotor disorders regressed in 132 (98,5%) patients. Obtained results of surgical treatment of COI in acute period of TBI demonstrate high effectiveness and safety of active surgical tactics. Application of modern diagnostic methods and interdisciplinary approach in management of COI in early period after trauma provide good functional and cosmetic results. PMID- 21698919 TI - [Experimental anatomical study of transpedicular stabilization of the spine]. AB - Currently transpedicular fixators (TPF) are widely used for stabilization in treatment of degenerative spine disease. Despite indisputable advantages of transpedicular stabilization (durability and comfort in use) there are certain drawbacks of their application: 1) degeneration of adjacent segments (development of protrusions, herniations, instability); 2) absence of cyclic load in tissues of stabilized segment which may lead to their degeneration and osteolysis. We studied effects of loading on mobility of lumbar spine using cadaver specimens with preserved bony, ligamentous and articular structures. Mechanical features of initial specimen was compared to its properties after surgical intervention (laminectomy, diskectomy etc.). Effects of altered tissue properties and different kinds of injuries on mechanical features of injured and intact segments and on strain in bony structures and elements of transpedicular system were evaluated using finite-element method. Performed studies demonstrated the following: 1) after removal of posterior column (according to Dennis) by decompressive laminectomy, TPF with stiffness below 20 N/mm (e.g., using nitinol bars) is ideal for stabilization of lumbar spine. It provides close to normal stability of lumbar region and its certain segments as well. 2) in simultaneous injury of posterior and anterior columns of lumbar spine (in decompressive laminectomy like in case of using transpedicular constructions for treatment of spondylolisthesis, spinal canal stenosis, disk herniations etc.) its stabilization should be performed using TPF with stiffness 30-45 N/mm (nitinol of titanium alloy bars). Application of more rigid TPF (steel bars) increases difference in stiffness between segments which leads to hypermobility of adjacent segments in certain functional loads (flexion and extension). PMID- 21698920 TI - [Specific features of technique and long-term results of portal endoscopic procedures in lumbosacral disk herniations]. AB - Aim of the study was to investigate technique, long-term results and complications of portal endoscopic procedures in lumbosacral disk herniations. We analyzed results of surgical treatment of 112 patients with lumbosacral disk herniations operated in Burdenko Moscow Neurosurgical Institute during 2008 and 2009 years. To compare our data we used foreign publications and standard MacNab scale. Analysis of long-term outcomes 6 months after surgery revealed excellent results in 83,9% (using MacNab scale), good - in 8,9%, satisfactory--in 2,7% of patients. Poor results was observed in 1,8%, dissatisfactory--in 2,7%. Frequency of postoperative complications comprised 10,7%, recurrent disk herniation in 2,7% and neuropathy in 1,8% of cases. Our experience demonstrated that of portal endoscopic procedures are advanced highly-effective and minimally traumatic alternative to existing methods of microsurgical treatment of lumbosacral disk herniations. Portal endoscopic procedures, like any high-technology manipulations, require special education, development of skills of endoscopic surgery, update of devices and surgical techniques. PMID- 21698921 TI - [Clinical-epidemiological analysis of a group of patients with surgically verified lumbar herniated discs]. AB - Results of surgical treatment of 1085 patients with lumbar disc herniation operated from 1999 to 2009 were analyzed. It was shown, that frequency of LIII-IV and LIV-V herniated discs increases and that of LV-SI, decreases with ageing. PMID- 21698922 TI - [Investigation of epidemiology of neurotrauma in the Republic of Guinea]. AB - The paper focuses on analysis of incidence of neurotrauma in economically underdeveloped country such as Republic of Guinea. It is found that leading etiology of central nervous system injuries are road accidents and indoor traumatism. Investigation of system of medical care revealed its poor condition and severe defects which prevent practical application of evidence-based recommendations for management of traumatic brain injury in underdeveloped countries including Republic of Guinea. Development of multiplanar strategy of control of neurotrauma is required which can be achieved only in case of massive governmental and international aid. PMID- 21698923 TI - [Monosymptomatic clinical course of posttraumatic normal pressure hydrocephalus]. AB - Triad of Hakim--Adams is well known for normal pressure hydrocephalus (NPH): dementia, gait disturbances and urinary incontinence. Variability of intensity of these symptoms is obvious. However in clinical practice all classic signs are present. We describe a case of posttraumatic NPH producing only gait impairment with intact intellect and memory and bladder function. Such reports were not found in literature. PMID- 21698924 TI - [Practical problems of contemporary neuroanesthesiology]. AB - The paper written in the format of lecture, focuses on practical problems of neuroanesthesiology, current tendencies in technologies and medicaments, prevention and management of complications. PMID- 21698925 TI - [Multiple echinococcosis of brain, heart and kidneys]. AB - The authors report a rare case of multiple echinococcosis (brain, heart and kidneys). Neuronavigation, intraoperative ultrasound scanning have allowed to plan exact and non-traumatic access to the cysts. Microsurgical technique and intraoperative neurophysiological monitoring provided removal of seven cysts without their rupture from the left parietooccipital and right parietal area with good postoperative functional result. Serologic analysis of antibodies with antigens of echinococci and histological research confirmed the diagnosis of cystic echinococcosis. PMID- 21698926 TI - [Intraabdominal hypertension and secondary abdominal compartment-syndrome in the patient with craniopharyngioma in postoperative period]. AB - Currently problem of intraabdominal hypertension in patients with brain tumors is practically uninvestigated. Authors describe a case of complicated course of early postoperative period in the patient with craniopharyngioma due to secondary abdominal compartment-syndrome. Causes of intraabdominal hypertension in patients with CNS lesions requiring intensive care are analyzed. Risk factors of intraabdominal hypertension deserving attention in management of patients in neurolCU are determined. PMID- 21698927 TI - [Proton "radiosurgery" of cerebral arteriovenous malformations]. AB - Arteriovenous malformations (AVM) are vascular lesions arising from impaired angiogenesis at the stage of transformation of primary embryonic arteriovenous anastomoses into capillaries. Commonly AVMs manifest with spontaneous hemorrhage. Stereotactic radiosurgery is method of choice for treatment of surgically inaccessible AVMs, which are characterized by high risk of damage of adjacent critical structures. In addition, stereotactic radiosurgery is used either as a component of complex management of large AVMs or pre-planned procedure combined with endovascular intervention, or as a second line therapeutic option in residual AVM after subtotal surgical resection. Comparing with photons protons due to their unique physical properties have advantages in spatial spread of dose thus allowing to significantly decrease integral dose to the surrounding brain tissue when treating large AVMs with complex shape proximal to critical structures. PMID- 21698928 TI - [Surgical tactics in acute paraproctitis]. AB - Individualized tactics of radical surgical treatment, applied in 100 patients, suffering an acute paraproctitis, was presented. Performing comparative estimation of the treatment results in 110 patients, in whom the conventional surgical approaches were applied, there was established, that an active surgical tactics secures essential reduction of the patients stationary treatment duration, the rate of the disease recurrence occurrence and transformation into the chronic illness. PMID- 21698929 TI - [Application of antiseptic decasan in purulent infections of pararectal region]. AB - The results of studying of antiseptic preparation Decasan for the treatment of patients, suffering purulent infections of pararectal region, are adduced. Efficacy of Decasan was analyzed in 102 patients. The results of investigation obtained are trusting hig antiseptic efficacy of preparation, witnessing possibility of its application as a preparation of choice for the treatment of patients, suffering purulent infections of pararectal region. PMID- 21698930 TI - [The role of connective tissue nonspecific dysplasia in postoperative and recurrent abdominal hernias formation]. AB - There were studied the rate of clinical indices diagnosis concerning nondifferentiated form of connective tissue dysplasia (NFCTD) as well as their significance in postoperative and recurrent abdominal hernias formation in 61 patients, ageing 20 - 78 years. It was established, that in 77% of patients the hernia have had formated on a NFCTD background, including in 16.4%--with a mild degree, in 27.8%--moderate degree and in 32.8%--a severe one. The authors recommend while abdominal hernia is present to study a characteristic phenotypical signs of a connective tissue dysplasia and, if more than 4 signs are diagnosed, to prefer the application of alloplastic methods. PMID- 21698931 TI - [Predictive value of test with procalcitonin in diagnostics of endogenous intoxication severity in extended purulent peritonitis]. AB - Diagnostic significance of the test with procalcitonin (PCT) for estimation of the patients state severity in extended purulent peritonitis (EPP) and prognostication of hospital lethality were studied up. For the comparison making the state severity was estimated in the patients in accordance to SOFA scale, basing on the clinical and laboratory data analysis, the leukocyte index of intoxication (LII) and hematological index of intoxication (HII) on the second postoperative day. In all the patients the symptoms, corresponding to criteria of endogenous abdominal intoxication, were revealed. The EPP course severity was estimated in accordance with the hospital lethality index. There was established, that specific test with PCT owes high prognostic validity in diagnosis of endogenous intoxication severity, it may be applied as a secure diagnostic marker for the state severity estimation and hospital lethality prognostication in patients, suffering EPP. Otherwise, nonspecific markers of endotoxicosis, including LII and HII, lack informativity, owes low prognostic validity and do not permit to estimate of such a patients state severity. PMID- 21698932 TI - [Drainage in surgery: history, theory, drainage procedures]. AB - Brief historical review of drainage procedures of the wounds and abdominal cavity was adduced. The main mechanisms of the drainage process, from the hydrodynamics laws point, were discussed. There was shown, that drainage occurs due to hydrostatic tissue of liquid and the capillarity laws. The main modern draining gears were analyzed and a comparative characteristics of their efficacy was adduced, depending on the drain construction and clinical situation present. PMID- 21698933 TI - [Possibilities of bilateral transsternal pulmonary resection]. AB - Possibilities of modern antibacterial therapy of pulmonary tuberculosis do not satisfy specialists. To apply a standard resection methods is not always possible because of the extended process present. The authors had summarized the experience of performance of simultaneous bilateral transsternal pulmonary resection for different forms of tuberculosis in 23 patients, proposing it as an alternative to present resectional methods. PMID- 21698934 TI - [Clinical application of the plasma substitutes in patients with postoperative complications after surgeries for brain meningioma]. AB - The issues on optimization of the restoration treatment of patients, suffering the brain meningioma, were discussed, basing on analysis of 498 observations. Tactics of the patients management in noncomplicated, complicated and severe course of postoperative period is adduced. The indices of survival and lethality, peculiarities of the infusion therapy were analyzed. The role of plasm restituting preparations was demonstrated in complicated course of postoperative period. Rational complex approach to the restoration measures and intensive therapy conduction promotes the treatment efficacy raising, the patients fair quality of life securing in the brain meningioma in postoperative period. PMID- 21698935 TI - [First experience of supraclavicular flap application for the closure of defects localized in the lower third of the face and neck]. AB - First experience of the supraclavicular flap transposition for closure of superficial, but extended, defects of the soft tissues in the lower third of face and neck region in 6 patients is presented. In all the patients good functional and cosmetic result was achieved. PMID- 21698936 TI - [Organization-methodical aspects of health care delivery to the patients with acute gastro-intestinal hemorrhage]. AB - The analysis of organization-methodic work, done with an active participation of academician M. P. Pavlovskiy, for establishment of a Lviv City Center for the treatment of patients, suffering an acute gastro-intestinal hemorrhage, was conducted. During 25 years of the Center activity the organization, diagnostic and treatment and rehabilitation approaches for an acute gastro-intestinal hemorrhage treatment have changed essentially. PMID- 21698937 TI - [Application of standardized systems for assessment of prognosis of the traumatic process in patients with penetrating abdominal wounds and hepatic injuries]. AB - There were examined 131 injured persons, suffering penetrating abdominal wounding and hepatic injury. Correlation analysis was done, basing on studying of the results of the injured persons state estimation, using prognostic scales, aiming to prognosticate the traumatic process course. PMID- 21698938 TI - [Robotic-assisted mini-invasive surgery: history, modern state, perspectives]. PMID- 21698939 TI - [Resistance to antibiotics of the pathogens of abdominal infections]. PMID- 21698940 TI - [Application of endobronchial rubber valve "Medlung" in a patient with chronic pleural empyema and bronchopleural fistulas]. PMID- 21698941 TI - [Expert assessment of psychiatric illnesses in work disability]. PMID- 21698942 TI - [Assessment of the capability of performance of patients with psychic and psychosomatic diseases--a diagnostic model]. AB - The limited availability of appropriate methods and criteria makes the assessment of capability by psychic and psychosomatic disorders difficult. This article displays and discusses the standards relating to content and method in capability assessments. The underlying diagnostic model of assessment capability has been conceptualised and tested empirically by a multicentric and interdisciplinary work-group. Different diagnostic levels of the manual are outlined as well as the procedures of operationalisation of the diagnostic categories. Furthermore, first results of empirical analysis are described and important conditions of the application of the diagnostic model are discussed. PMID- 21698943 TI - [Integration of psychological tests into clinical expert reports on mental disorders]. AB - Norm-referenced psychological tests may provide crucial information that cannot be derived from non-standardised assessment techniques. However, little is known about the use of psychological tests in medical expert reports. Based on 90 medical expert reports from private invalidity insurances, the use of psychological tests and the appropriateness of test-score interpretation was analysed. About 60% of the reports included test-related data. Two-third of these reports revealed deficits of either test description or interpretation or utilisation of test results. It was recommended how to interpret test results appropriately. Psychological tests should be used to validate diagnostic findings. Tests should be integrated into a multi-method assessment strategy. PMID- 21698944 TI - [Assessment of malingering and dissimulation in the examination of subjects with mental and psychosomatic disorders]. AB - The consideration of response bias is essential in the assessment of mental and psychosomatic disorders. In forensic contexts, as compared to clinical evaluations, an elevated rate of response distortions must be expected. Assessment methods should be selected with respect to the risk of either malingering or defensiveness. The choice of assessment strategies and instruments depends on the legal context of the examination. It is recommended that the consistency and plausibility of data from different levels and sources should be systematically analysed. Psychological test results should be integrated in this analysis. If the purpose of a test is obvious to the patient, the test result should be interpreted with respect to results from additional validity scales or symptom validity tests. In civil forensic evaluations of mental and psychosomatic disorders, the use of criterion-based content analysis is expected to be of limited benefit for the validation of symptoms and disability. PMID- 21698945 TI - [Relation of external biometric parameters to health risk and mortality--analysis and evaluation of different measurement methods and study results]. AB - In clinical practice diagnoses can be found which are partially based on body measurements. By measuring body height and body weight the patient is categorised, for example by Body-Mass Index (BMI), in different adipose grades. Different diseases are associated with specific biometric parameters. Abdominal adiposity measured by waist circumference correlates with the risk of colon carcinoma and is one diagnostic criteria of the metabolic syndrome. An unhealthy waist-hip ratio (WHR) can cause a higher risk of a cardiovascular disease and dementia. By combining body measurement with cause of death found during the medicolegal autopsy, clinical relevant correlations can be uncovered. Research in medical databases (e.g. PubMed) was carried out to find studies showing possible associations between body measurements, their indices and morbidity or causes of death. This article is a selective survey of these published studies, current guidelines and the German Institute for Standardisation - Norm (DIN-Norm). We give a wide thematic overview and select relevant parameters, which should be taken during medico-legal autopsies in future. The ascertainment of those parameters and their adjustment with the findings of the medico-legal autopsies can be a key to finding predictors of history of disease and relevant morbidity risks in the institutes of forensic medicine. Such findings are very important in the assessment of risk for living patients and necessary preventive actions. Beside the measurement of waist and hip circumference mentioned in specific clinical guidelines in Germany, we suggest, after analysing the parameters, to measure the thickness of the subcutaneous fat on the anterior chest and the thigh circumference as well. PMID- 21698946 TI - [Vocational interventions integrated in inpatient rehabilitation]. AB - Orientation on work place associated problems is a typical assignment of medical rehabilitation in Germany. The implementation of special vocational programmes, however, may be associated with several challenges concerning staff and space required, which could be difficult to overcome. PMID- 21698947 TI - [Breach of secrecy by handing out psychiatric certificates]. AB - The article reports about a medical malpractice case against the director of a psychiatric University Hospital, who was convicted for breach of secrecy by the Oberlandesgericht in Munich. The court found him guilty of issuing and giving to the plaintiff's wife an unauthorised psychiatric certificate, stating that the plaintiff, a carpet dealer for oriental rugs, who was caught in a war of roses with his wife at this time and was never a patient of the psychiatrist, let alone properly examined by him or his staff, suffered from an acute and severe psychosis with immediate need for compulsory admission. This all happened behind his back and enabled the wife to spread rumors of the alleged mental illness of her husband. Banks and trading partners therefore shunned him, which nearly caused his bankruptcy. This is why this unusual case led to the decision that the psychiatrist had to reimburse Euro 15000 for pain and suffering and additionally cover all material damages resulting from the tort. PMID- 21698948 TI - [Reflections on the the future cultural development of humanity in relation to advancing globalization]. PMID- 21698949 TI - [No work disability in supposed post-borreliosis syndrome. On the decision of the OLG Saarbrucken of 19 May 2010]. PMID- 21698950 TI - [Female Genital Cosmetic Surgery (FGCS) - a considerable increase in intimate surgery interventions]. PMID- 21698951 TI - [New health requirements for driving qualification in street traffic. Implementation of the EU guidelines of the regulation updates of the driving permit regulation of 17 December 2010]. PMID- 21698952 TI - [Treatment of muscle fiber rupture with high frequency therapy]. PMID- 21698953 TI - [S. Homola: Real orthopaedic sublubluxations versus imaginary chiropractic subluxations (Focus on Alternative and Complementary Therapies 15, 2010, 284)]. PMID- 21698954 TI - [Could nurses be difficult patients?]. PMID- 21698955 TI - [National debate on dependency, a progress report]. PMID- 21698956 TI - [Toward improved reporting of nosocomial infections]. PMID- 21698957 TI - [Management of complications with antivitamin K in elderly people]. AB - latrogenic complications with antivitamin K (AVK) largely entail haemorrhages, apparently more frequent in the elderly. Recent French and North American recommendations are available and must be widely circulated, in community practices as well as hospitals, in order to improve the treatment of overdoses and/or haemorrhagic accidents under AVK. PMID- 21698958 TI - [The frailty process, risk factors and prevention]. AB - The frailty process, risk factors and prevention. Frailty syndrome is a clinical condition which manifests itself by a gradual loss of functional capacities. It testifies to a state of exhaustion of the organism's reserves and is associated with high morbidity/mortality. Its prevention is based on functional and psycho cognitive stimulation as well as on the maintaining of a good nutritional status. PMID- 21698959 TI - [Supporting caregivers in the palliative care unit (interview by Severine Coste)]. PMID- 21698960 TI - [The elderly person is not asexual]. PMID- 21698961 TI - [Eating, it is much more than nourishing oneself]. PMID- 21698962 TI - [Should caregivers be concerned with the nutritional state of elderly patients?]. AB - A geriatric syndrome in its own right, malnutrition must be systematically looked for whenever an elderly patient is being treated. A marker of vulnerability, once identified it requires repeated assessment and adapted treatment. Undernutrition is often the consequence of various aetiologies justifying a full assessment and an assertive, multi-professional treatment. PMID- 21698963 TI - [Malnutrition risk assessment]. AB - Protein-energy malnutrition is most frequent in extremely frail elderly people. The malnutrition risk can be assessed through Mini nutritional assessment as well as clinical or biological parameters. PMID- 21698964 TI - [Finger foods, old-age and autonomy]. AB - The finger foods project, based on the natural tendency to use the fingers to eat, was initiated by caregivers in response to the problems encountered by some elderly people when eating. It is part of an approach to help people suffering from dementia to feed themselves. PMID- 21698965 TI - [Dementia and the gestures surrounding meals]. AB - The nursing research project "Praxalim" was initiated by a nursing team. Confronted with Alzheimer's disease and related illnesses, the nursing staff wanted to work on help with daily living tasks and in particular meals. PMID- 21698966 TI - [A look inside people's refrigerators, the Clic Reliage initiative]. AB - A person's diet can be revealed through an examination of the contents of his/her refrigerator and a simple questionnaire. To present the risk of malnutrition and dehydration in the elderly, Reliage, a community information and coordination centre in Lagny-sur-Marne, carried out a survey into volunteer elderly peoples' diets. PMID- 21698968 TI - [Preventing malnutrition. Bibliography]. PMID- 21698967 TI - [The Val d'Oise inter-institution and service gerontology network]. AB - The widespread problems surrounding nutrition in care homes for dependent elderly people requires a multidisciplinary and cross-functional approach. Professionals have tackled this issue in the framework of a gerontology network covering the whole of the Val d'Oise department. PMID- 21698969 TI - [8/12. Housing quarters]. PMID- 21698970 TI - [1/5. The foot of the elderly patient, a clue to overall health status]. PMID- 21698971 TI - [On collaboration with psychiatrists through support of young patients with dementia]. PMID- 21698972 TI - [On diagnosis of schizophrenia--from the viewpoints of molecular biology and psychiatric pathology]. PMID- 21698973 TI - Museum of TMH multimodality imaging center. PMID- 21698974 TI - Dr. Michael E. DeBakey was a loyal friend of China. PMID- 21698976 TI - [Abstracts of the 54th Annual Meeting of the Japanese Society for Medical Mycology, Tokyo, Japan, October 16-17, 2010]. PMID- 21698975 TI - The compassionate care of Dr. DeBakey. PMID- 21698977 TI - Surveillance of antibiotic resistance in Neisseria gonorrhoeae in the WHO Western Pacific and South East Asian Regions, 2009. AB - Long-term surveillance of antimicrobial resistance in Neisseria gonorrhoeae has been conducted in the World Health Organization (WHO) Western Pacific Region (WPR) to optimise antibiotic treatment of gonococcal disease since 1992. From 2007, the Gonococcal Antimicrobial Surveillance Programme (GASP) has been enhanced by the inclusion of data from the South East Asian Region (SEAR) and recruitment of additional centres in the WPR. Approximately 8,704 isolates of N. gonorrhoeae were examined for their susceptibility to one or more antibiotics used for the treatment of gonorrhoea, incorporating External Quality Assurance controlled methods, from reporting centres in 21 countries and/or jurisdictions. A high proportion of penicillin and/or quinolone resistance was again detected amongst isolates tested in North Asia and the WHO SEAR. In contrast, from the Pacific Island states Fiji reported low penicillin and quinolone resistance, New Caledonia again reported no penicillin resistance and little quinolone resistance, Tonga reported no penicillin resistance and there was a continued absence of quinolone resistance reported in Papua New Guinea in 2009. The proportion of gonococci reported as 'decreased susceptibility' and 'resistant' to the third-generation cephalosporin antibiotic ceftriaxone varied widely but no major changes were evident in cephalosporin minimum inhibitory concentrations (MIC) patterns in 2009. Altered cephalosporin susceptibility has been associated with treatment failures following therapy with oral third-generation cephalosporins. There is a need for revision and clarification of some of the in vitro criteria that are currently used to categorise the clinical importance of gonococci with different ceftriaxone and oral cephalosporin MIC levels. The number of instances of spectinomycin resistance remained low. A high proportion of strains tested continued to exhibit high-level plasmid mediated resistance to tetracyclines. The continuing emergence and spread of antibiotic resistant gonococci in and from the WHO WPR and SEAR suggests that surveillance programs such as GASP be maintained and expanded. PMID- 21698978 TI - An influenza outbreak among pilgrims sleeping at a school without purpose built overnight accommodation facilities. AB - This report describes a respiratory illness outbreak amongst a group of over 700 World Youth Day 2008 pilgrims staying at a basic accommodation venue for 1 week in July 2008. At this venue, 1 group of pilgrims was accommodated as a large group in a gymnasium and another group was sub-divided into smaller groups and accommodated in classrooms. Following confirmation of an influenza B outbreak by influenza point of care testing, control measures were promptly implemented. Isolation of cases, improved hand, respiratory and general hygiene, establishment of a mobile tent health facility at the accommodation venue, and the use of oseltamivir for the treatment of cases and prophylaxis of high risk contacts were implemented and the outbreak was brought under control within the week. Overall, 20% of pilgrims met the case definition for an influenza-like illness and 36% had an onset prior to arrival at the venue. The attack rate for those with onset while at the venue was significantly higher amongst pilgrims accommodated in the gymnasium than those staying in the classrooms. Findings from this study highlight the importance of early detection, the rapid implementation of control measures and appropriate prescribing of antivirals to manage influenza outbreaks. The findings also highlight the benefits of accommodating individuals in smaller groups within basic accommodation venues in the context of mass gatherings. PMID- 21698979 TI - Improving surveillance for acute hepatitis C. AB - Understanding patterns of newly acquired hepatitis C virus (HCV) infection is fundamental to assessing the impact of prevention and treatment interventions. However, identifying newly acquired cases is difficult, usually requiring documented testing before and after exposure. As the proportion of cases identified as newly acquired by current New South Wales surveillance methodologies is significantly lower than that identified nationally, the impact on the identification of newly acquired cases of systematic reporting of past negative HCV test results from notifying laboratories was assessed. HCV notifications data for 2007 from two New South Wales laboratories were analysed. Cases with a negative HCV antibody test within the past 24 months were classified as newly acquired. These were linked to the NSW Department of Health (NSW Health) identified cases to assess the effectiveness of accessing laboratory data. The laboratories accounted for approximately half of all new HCV notifications in 2007. Of the 2,206 newly diagnosed cases, 21 (1.0%) were newly acquired, 18 of which had not been identified under the current surveillance system, increasing the total number of newly acquired cases to 83 from 65. This increased the yield by 28% and increased the proportion of newly acquired cases from 65/4,192 (1.6%) to 83/4,196 (2.0%). Laboratory-identified cases were significantly more likely than NSW Health-identified cases to be aged 30 years or over. Combined with current reporting mechanisms, laboratory data on previous HCV test results have the potential to increase the number of newly acquired cases identified through the New South Wales surveillance system and to enhance the identification of cases among those aged 30 years or more. PMID- 21698980 TI - Supplementary report: surveillance of adverse events following immunisation among children aged less than 7 years in Australia, 1 January to 30 June 2010. PMID- 21698982 TI - Communicable diseases surveillance. PMID- 21698983 TI - Surveillance systems reported in CDI, 2011. PMID- 21698981 TI - OzFoodNet quarterly report, 1 October to 31 December 2010. PMID- 21698984 TI - Wear of resin composites and primary enamel and their applicability to full crown restoration of primary molars. AB - PURPOSE: To determine whether resin composites are appropriate for full crown restoration of primary molars by evaluating their wear characteristics. Specifically, the wear properties of resin composite specimens and the opposing enamel surfaces were characterized by means of impacting-sliding wear testing. METHODS: Three types of light-cured resin composites (Estelite Sigma quick, Litefill IIP, and Metafil C), one type of chemical-cured resin composite (Clearfil FII), and a hybrid composite (Estenia C&B) were tested in this study. The enamel sample was used as the control. The hemispherically prepared specimens were subjected to impacting-sliding wear testing against the flattened enamel of primary molars. The worn surfaces were examined by laser scanning microscopy and scanning electron microscopy. The volumetric loss was estimated by using micro-CT images. The areas of worn enamel surfaces were measured by 3D color laser microscopy. On most of the worn enamel surfaces, cracks appeared. Scatter plot analyses between their width and depth were carried out. Data for each specimen were statistically analyzed by multiple comparisons among the means of treatment by Bonferroni's method (P< 0.01). RESULTS: Clearfil showed significantly higher surface area wear, volumetric loss, and worn enamel surface area than did the other resin composites and the control enamel (P< 0.01). There was no significant difference among the worn surface areas ofEstelite, Litefill, Metafil, and Estenia (P< 0.01). The control enamel showed significantly lower worn surface area than did the resin composites (P< 0.01). There was no significant difference in volumetric loss and worn enamel surface areas among Estelite, Litefill, Metafil, Estenia, and the control enamel (P< 0.01). Cracks larger than that on the control enamel were seen on the worn enamel surface opposing Estenia. PMID- 21698985 TI - Detection of cavitated or non-cavitated approximal enamel caries lesions using CMOS and CCD digital X-ray sensors and conventional D and F-speed films at different exposure conditions. AB - PURPOSE: To determine the ability of digital sensors (CMOS and CCD sensors) and D and F-speed films to detect cavitated and non-cavitated enamel caries lesions at different exposure conditions compared to a gold standard. METHODS: 100 extracted human molars and premolars were selected and mounted in a block between two neighboring teeth. Sensors or films were exposed with voltages of 60 or 70 kVp at varying times. Three observers assessed each approximal site independently. Lesion depth was rated according to an anatomical five-point scale (0 = no lesion to 4 = lesion reaching inner half of dentin). Serial sections of resin-embedded teeth were prepared. Gold-standard scores were established by consensus based on histological sectioning. A carious lesion was present at scores of 1 and higher. Statistical evaluation (sensitivity, specificity and receiver-operating curves) was based on caries-free surfaces and those presenting enamel caries (n=116). RESULTS: The ROC curves had "area under the curve" values (Az) from 0.50 (F speed, 70 kVp, 0.20 seconds) to 0.58 (CCD 60 kVp, 0.08 seconds). The detection percentage of cavitated lesions was generally higher (0-52%, depending on technique and observer) than that of non-cavitated lesions (3-32%). The CMOS sensor showed Az values comparable to the CCD sensors but required higher exposure times. There was no significant difference between 60 and 70 kVp. PMID- 21698986 TI - Evaluation of silica-coating techniques for zirconia bonding. AB - PURPOSE: To evaluate silica-coating/silane treatment techniques for zirconia bonding. METHODS: 19 groups of zirconia disks were subjected to different surface treatments: polished or sandblasted by CoJet or alumina, and treatment with silane or zirconia primers (containing phosphate- or phosphonate-monomer). After surface treatments, the zirconia disks were cemented with resin cements and stored in deionized water for 2 hours at 370 degrees C prior to shear bond strength testing. Zirconia surface (polished and unpolished), CoJet sand, Cojet treated zirconia surface (before and after water rinsing) and representative debonded surfaces were examined by scanning electron microscopy (SEM). The zirconia surface after silica-coating was examined by Fourier Transform Infrared Attenuated Total Reflectance (FTIR-ATR) spectroscopy. RESULTS: A non-phosphate containing resin cement (Choice 2) had almost no bond strength on polished zirconia, while MDP-containing cements (Panavia F2.0) had mild bond strength. After zirconia was sandblasted with CoJet or alumina, bond strengths were slightly increased. Silane treatment did not increase bond strength, while phosphate/carboxylate-based primer (i.e. Exp Z-Prime) doubled the bond strengths. Silica nanoparticles identified by FTIR-ATR spectra, were observed by SEM on the zirconia surface after CoJet treatment. However, these nanoparticles were removed by forceful water stream. PMID- 21698987 TI - Clinical effectiveness of a desensitizing system on dentin hypersensitivity in periodontitis patients. AB - PURPOSE: To evaluate the efficacy of the DenShield desensitizing system, based on calcium sodium phosphosilicate, in the hypersensitivity reduction for a 6-month period in periodontitis patients previously subjected to periodontal treatment and to compare the combination of the in-office paste and at-home dentifrice use to the at-home dentifrice use alone. METHODS: A total of 248 teeth (eight teeth in each subject) in 31 periodontitis patients (mean age 48 +/- 8 years) previously subjected to periodontal treatment were studied. 193 (77.8%) teeth had been treated with phase I periodontal treatment alone (non-surgical treatment) and 55 (22.2%) had been additionally subjected to periodontal surgery. Periodontal clinical parameters were recorded for each subject. Hypersensitivity was assessed by tactile and air-blast stimuli. The hypersensitive teeth of each of two quadrants in each subject were randomly assigned with split-mouth design to in-office application of DenShield Starter paste (four teeth) or placebo (distilled water) (four teeth). After the in-office application each patient used the DenShield dentifrices (Builder and Saver) for 6 months. The final evaluation was at 6 months. RESULTS: The prevalence and the degree of baseline hypersensitivity was significantly higher for the surgically than the non surgically-treated teeth (83.6% versus 68.4%) and it was greater in teeth with attachment loss. The dentin hypersensitivity observed after periodontal treatment was significantly reduced in periodontitis patients who used the DenShield system for 6 months. There was no difference in hypersensitivity reduction between the additional in-office application of the DenShield and the at-home use of the DenShield dentifrices alone. PMID- 21698988 TI - Bond strengths of a silorane composite to various substrates. AB - PURPOSE: To evaluate the shear bond strength (SBS) of a novel low-shrink posterior resin composite (Filtek LS) to various substrates. METHODS: The dedicated LS System Adhesive was used to bond Filtek LS to bovine dentin, ground bovine enamel, resin-modified glass-ionomer liner (Vitrebond Plus), conventional glass-ionomer restorative material (Fuji IX GP Extra), and bovine dentin previously exposed to zinc oxide-eugenol (IRM) (n=10 for each group). Vitrebond Plus and Fuji IX GP Extra substrates were fabricated by filling standardized preparations that had been made in epoxy resin. Adper Scotchbond SE/Filtek Z250 was used as a control. Composites were applied using the Ultradent specimen former. The bonded specimens were stored in water at 37 degrees C for 24 hours, and SBS testing was done using an Instron universal testing machine. The data were analyzed using ANOVA and Tukey-Kramer HSD test at a significance level of 0.05. RESULTS: The mean SBS values of the Filtek LS system were generally somewhat lower than the values of Adper Scotchbond SE/Filtek Z250 to the various substrates, but the differences were not statistically significant. Exposure of dentin to IRM resulted in a statistically significant reduction in the mean SBS values of Adper Scotchbond SE/Z250 and a slight but statistically insignificant reduction for the Filtek LS system. PMID- 21698989 TI - Polymerization characteristics, flexural modulus and microleakage evaluation of silorane-based and methacrylate-based composites. AB - PURPOSE: To compare the behavior of a new low-shrinkage silorane-based composite (P90) with two conventional methacrylate-based composites, in terms of polymerization shrinkage, polymerization stress, gel point, flexural modulus and microleakage. METHODS: The materials tested were P90 (3M ESPE), AP-X (Kuraray), Quixfil (Dentsply). Polymerization shrinkage was measured using the Accuvol method. Polymerization stress was assessed using a stress-strain analyzer. Polymerization shrinkage (%) and force (N) were continuously recorded for 300 seconds. Polymerization shrinkage and stress after 300 seconds and gel point were recorded. Flexural modulus was obtained by three-point bending. A laboratory microleakage test was performed. Class V cavities prepared on labial surfaces of 70 freshly extracted human teeth were randomly assigned to the seven groups (N=10): P90/PSA (P90 System Adhesive), AP-X/CBA (Clearfil SE Bond Adhesive), Quixfil/XBA (XP Bond Adhesive), P90/CBA, P90/XBA, AP-X/PSA, Quixfil/PSA. The teeth were immersed in 1% basic fuchsin dye for 24 hours at room temperature. All teeth were cut in a labial-lingual direction and the penetration of dye along the wall of cavities was observed under a stereoscopic light microscope. Statistical analysis was performed with one-way ANOVA, Kruskal-Wallis ANOVA test and post hoc tests (P< 0.05). RESULTS: The low-shrinkage silorane-based composite (P90) exhibited significantly lower polymerization shrinkage, polymerization stress, flexural modulus and a later gel point than the conventional methacrylate-based composites. In the microleakage test, P90/PSA, AP-X/CBA, AP-X/PSA demonstrated the lowest microleakage scores without a significant difference among them (P> 0.05). Quixfil/XPA exhibited the highest microleakage scores. PMID- 21698991 TI - Occlusal caries prevention in high and low risk schoolchildren. A clinical trial. AB - PURPOSE: To evaluate the caries-preventive effect of a resin-modified glass ionomer cement used as occlusal sealant (Vitremer) compared with fluoride varnish (Duraphat) application on occlusal surfaces of permanent first molars (OSPFM) in 6-8 year-old schoolchildren (n=268) at high (HR) and low (LR) caries risk. METHODS: The children were followed-up for 24 months after being systematically allocated into six groups as follows: Control Groups HRC and LRC: children receiving oral health education (OHE) every 3 months; Groups HRV and LRV: children receiving OHE plus varnish application biannually; and Groups HRS and LRS: children receiving OHE plus a single sealant application . The baseline and follow-up examinations were performed by the same calibrated dentist under natural light, using CPI probes and mirrors, after toothbrushing and air-drying. The DMFS was used to record dental caries, in addition to the detection of initial lesions (IL). Data analysis was performed with two primary outcome measures: DMF and DMF+ IL on the OSPFM. RESULTS: After 24 months, only the HRS group showed statistically lower DMF and DMF+IL increments on OSPFM compared with HRC group. HRV group did not differ from HRC and HRS groups. For LR groups, no statistical difference (P> 0.05) was observed among the treatments. PMID- 21698990 TI - Influence of laboratory degradation methods and bonding application parameters on microTBS of self-etch adhesives to dentin. AB - PURPOSE: To evaluate the laboratory resistance to degradation and the use of different bonding treatments on resin-dentin bonds formed with three self-etching adhesive systems. METHODS: Flat, mid-coronal dentin surfaces from extracted human molars were bonded according to manufacturer's directions and submitted to two challenging regimens: (A) chemical degradation with 10% NaOC1 immersion for 5 hours; and (B) fatigue loading at 90 N using 50,000 cycles at 3.0 Hz. Additional dentin surfaces were bonded following four different bonding application protocols: (1) according to manufacturer's directions; (2) acid-etched with 36% phosphoric acid (H3PO4) for 15 seconds; (3) 10% sodium hypochlorite (NaOClaq) treated for 2 minutes, after H3PO4-etching; and (4) doubling the application time of the adhesives. Two one-step self-etch adhesives (an acetone-based: Futurabond/FUT and an ethanol-based: Futurabond NR/FNR) and a two-step self-etch primer system (Clearfil SE Bond/CSE) were examined. Specimens were sectioned into beams and tested for microtensile bond strength (microTBS). Selected debonded specimens were observed under scanning electron microscopy (SEM). Data (MPa) were analyzed by ANOVA and multiple comparisons tests (alpha= 0.05). RESULTS: microTBS significantly decreased after chemical and mechanical challenges (P< 0.05). CSE showed higher microTBS than the other adhesive systems, regardless the bonding protocol. FUT attained the highest microTBS after doubling the application time. H3PO4 and H3PO4 + NaOCl pretreatments significantly decreased bonding efficacy of the adhesives. PMID- 21698992 TI - Influence of curing rate on softening in ethanol, degree of conversion, and wear of resin composite. AB - PURPOSE: To investigate the effect of curing rate on softening in ethanol, degree of conversion, and wear of resin composites. METHOD: With a given energy density and for each of two different light-curing units (QTH or LED), the curing rate was reduced by modulating the curing mode. Thus, the irradiation of resin composite specimens (Filtek Z250, Tetric Ceram, Esthet-X) was performed in a continuous curing mode and in a pulse-delay curing mode. Wallace hardness was used to determine the softening of resin composite after storage in ethanol. Degree of conversion was determined by infrared spectroscopy (FTIR). Wear was assessed by a three-body test. Data were submitted to Levene's test, one and three-way ANOVA, and Tukey HSD test (alpha = 0.05). RESULTS: Immersion in ethanol, curing mode, and material all had significant effects on Wallace hardness. After ethanol storage, resin composites exposed to the pulse-delay curing mode were softer than resin composites exposed to continuous cure (P< 0.0001). Tetric Ceram was the softest material followed by Esthet-X and Filtek Z250 (P< 0.001). Only the restorative material had a significant effect on degree of conversion (P< 0.001): Esthet-X had the lowest degree of conversion followed by Filtek Z250 and Tetric Ceram. Curing mode (P= 0.007) and material (P< 0.001) had significant effect on wear. Higher wear resulted from the pulse-delay curing mode when compared to continuous curing, and Filtek Z250 showed the lowest wear followed by Esthet-X and Tetric Ceram. PMID- 21698993 TI - Effect of CPP-ACP and APF on Streptococcus mutans biofilm: A laboratory study. AB - PURPOSES: (1) To determine the effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and acidulated phosphate fluoride (APF) on S. mutans viability, (2) to observe their effects on biofilm structure, and (3) to examine the element content of the hydroxyapatite (HA) surfaces after exposure to CPP-ACP and APF. METHODS: HA discs were coated with: CPP-ACP (GC Tooth-Mousse), APF, CPP ACP+APF (1/1). Uncoated HA discs were used as control. Following application of the materials, the discs were immersed in human saliva and incubated with S. mutans ATCC (27315) for 24 hours. Growth of bacteria on the discs was evaluated by microbial culturing methods. The structure of the biofilm was examined with confocal laser scanning microscope (CLSM). The change in element content of HA surfaces (without biofilm) was evaluated with energy-dispersive x-ray spectroscopy (EDS). The values were statistically analyzed using Kruskal-Wallis and Dunn's test. RESULTS: The total number of bacteria of APF and CPP-ACP+APF applied groups were found significantly lower than the control group (P< 0.05). All specimens showed similar microbial colonization structure. No statistically significant differences were observed in O, F, Na, P, Ca content on HA surfaces after exposure to the tested agents, although fluoride concentration of the APF treated HA surfaces were increased compared to CPP-ACP, CPP-ACP +APF. PMID- 21698994 TI - Strength and wear resistance of a dental glass-ionomer cement with a novel nanofilled resin coating. AB - PURPOSE: To evaluate the influence of different resin coating protocols on the fracture strength and wear resistance of a commercial glass-ionomer cement (GIC). METHODS: A new restorative concept [Equia (GC Europe)] has been introduced as a system application consisting of a condensable GIC (Fuji IX GP Extra) and a novel nanofilled resin coating material (G-Coat Plus). Four-point fracture strength (FS, 2 x 2 x 25 mm, 14-day storage, distilled water, 37 degrees C) were produced and measured from three experimental protocols: no coating GIC (Group 1), GIC coating before water contamination (Group 2), GIC coating after water contamination (Group 3). The strength data were analyzed using Weibull statistics. Three-body wear resistance (Group 1 vs. Group 2) was measured after each 10,000 wear cycles up to a total of 200,000 cycles using the ACTA method. GIC microstructure and interfaces between GIC and coating materials were investigated under SEM and CLSM. RESULTS: The highest FS of 26.1 MPa and the most homogenous behavior (m = 7.7) has been observed in Group 2. The coated and uncoated GIC showed similar wear resistance until 90,000 cycles. After 200,000 wear cycles, the coated version showed significantly higher wear rate (ANOVA, P< 0.05). The coating protocol has been shown to determine the GIC fracture strength. Coating after water contamination and air drying is leading to surface crack formation thus significantly reducing the FS. The resin coating showed a proper sealing of GIC surface porosities and cracks. In terms of wear, the coating did not improve the wear resistance of the underlying cement as similar or higher wear rates have been measured for Group 1 versus Group 2. PMID- 21698995 TI - Who's in charge of the healthcare home? PMID- 21698996 TI - From practitioner to practice manager. PMID- 21698997 TI - Collaborative practice: understanding is the key. PMID- 21698998 TI - Prostate cancer: overview of screening, diagnosis and treatment. PMID- 21698999 TI - Necrotizing pancreatitis: halting a harmful progression. PMID- 21699000 TI - Take cover: shielding patients from skin cancer. PMID- 21699001 TI - A dangerous one-two punch: sleep apnea and arrhythmia. PMID- 21699002 TI - 8 do's & don'ts of mental health: integrating behavioral health treatment into primary care practice. PMID- 21699003 TI - Anterior knee pain: the pitfalls of plica and chondromalacia patellae. PMID- 21699004 TI - Statistical 'coverage' of NPs & PAs. PMID- 21699005 TI - Perioperative innate immunity and its modulation. AB - Innate immunity plays a pivotal role in host defense. The trauma of major surgery induces a variety of immunologic alterations in patients, which can lead to subsequent increased susceptibility to postoperative infections. Surgical stress inhibits innate immunity from the time of incision until about the first postoperative day. This is an alert period with susceptibility to bacterial infections. Normal patients regain innate immunity in the first postoperative day. The absence of recovery of innate immunity may cause susceptibility to infection and eventually lead to postoperative complications. Surgical stress causes catabolism, pain, ileus, nausea and vomiting, immunosuppression, increase of cardiac demands and coagulation cascade, and pulmonary dysfunction. Perioperative treatment or remedy will affect these surgical responses. Prevention of surgical site infections (SSI) is very important for clinicians. In the past, we worked with sterilization techniques, prophylactic antibiotics and environmental support such as maintaining body temperature and supplying a high concentration of oxygen. The goal of further clinical studies must be to establish the immunomodulating property of the individual, which is very important for controlling innate immunity and inflammation in each patient. The strategy for minimizing post-surgical infections is to optimize the immune response by maintaining homeostasis through nutritional support, and to reduce the surgical trauma by using minimal invasive surgery, which consequently reduces the stress response and immunesupression. PMID- 21699006 TI - Non-Hodgkin's lymphoma of the vaginal wall in a hemodialysis patient with hepatocellular carcinoma. AB - A 66 year old woman with end-stage renal disease and liver cirrhosis due to chronic hepatitis C virus infection was introduced to hemodialysis therapy in 2003. In 2007, hepatocellular carcinoma was identified and the patient underwent radio frequency ablation (RFA) and ethanol injection therapy (EIT) under laparotomy. A large vaginal tumor was incidentally found at gynecological examination. Histological diagnosis was diffuse large B-cell lymphoma (Stage IE). During the first course of chemotherapy, the vaginal tumor began to prolapse from the vaginal wall due to an excellent response to the chemotherapy and finally was resected. The patient received another course of chemotherapy followed by radiotherapy. The vaginal tumor was undetectable in the follow-up imaging studies. Although patients with end-stage renal disease are at increased risk for several cancers, the occurrence of malignant lymphoma following hepatocellular carcinoma is rare. Furthermore, lymphomas arising from the female genital tract are very uncommon. PMID- 21699007 TI - Parting observations and potential directions for future scholarship. PMID- 21699008 TI - An agenda for occupational therapy's contribution to collaborative chronic disease research. AB - BACKGROUND: To meet the needs of adults with chronic diseases, Canadian health care is moving toward more interdisciplinary, collaborative practice. There is limited high-quality evidence to support practice in this area. Occupational therapists can play a significant role in this area of practice and research. PURPOSE: To develop an agenda of priority areas within collaborative chronic disease research to which occupational therapy can make a contribution. METHODS: The project involved literature and Internet review, a consensus meeting with a range of stakeholders, a survey of occupational therapists, and synthesis of findings to create a research agenda. FINDINGS: An interdisciplinary and intersectoral group of stakeholders identified seven main priority areas. One priority is specific to occupational therapy while the remaining six cross disciplines. IMPLICATIONS: The research agenda can support funding applications and encourage interdisciplinary research collaboration to ultimately produce research evidence that can benefit people with chronic diseases. PMID- 21699009 TI - Talking about life after early psychosis: the impact on occupational performance. AB - BACKGROUND: In early psychosis, the phase of illness and developmental stage pose unique challenges to recovery and provision of services. Insight into subjective experience is needed to achieve optimal outcomes. PURPOSE: To understand the complex ways that early psychosis affects occupational performance. METHODS: Phenomenology and occupational life history were used to explore lived experience of occupational performance with five participants. Three interviews with each person focused on life before, during, and following illness onset. FINDINGS: Qualitative analysis identified eight themes describing how psychosis is experienced as a lifelong phenomenon, how changes in occupational performance occur as life unfolds around the acute episode, and how participants move ahead with their lives. IMPLICATIONS: Integration of developmental frameworks, focus on productive roles, and thoughtful application of client-centred practice emerge as issues with important practice implications as individuals develop awareness of disability and strive to maintain control over occupational choices and, ultimately, their lives. PMID- 21699010 TI - Constructions of disability: a call for critical reflexivity in occupational therapy. AB - BACKGROUND: Within professional and practice knowledge there are many assumptions about disability that underpin occupational therapy philosophy. PURPOSE: The objectives of this paper are to (a) critically examine how disability has been constructed in mainstream society by introducing perspectives from contemporary disability studies theories, and (b) apply a critically reflexive lens informed by disability studies perspectives to occupational therapy practice. KEY ISSUES: Drawing upon critical disability perspectives, notions of "nondisabled" versus "disabled"; metanarratives of disability; built environments and social structures; and social and attitudinal constructions of disability and identity are examined. Key issues pertaining to rehabilitation, norms, client-centred practice, language, and education within occupational therapy are discussed. IMPLICATIONS: This critically reflexive examination has revealed the ways in which occupational therapy and society at large are embedded in discourses that may reinforce negative connotations around disability. A renewed understanding of disability may challenge current practices. PMID- 21699011 TI - Research lessons learned: occupational therapy with culturally diverse mothers of premature infants. AB - BACKGROUND: Evaluation studies of the effectiveness of home-based occupational therapy are scarce but are needed to justify the impact of occupational therapy intervention. When the intervention is for persons from diverse cultural backgrounds, additional research challenges arise. PURPOSE: To share lessons learned in conducting home-based occupational therapy research with Canadian, and immigrant South Asian and Chinese mothers of premature infants in a large Canadian city. KEY ISSUES: Lessons learned were to implement a culturally sensitive recruitment process, change the research design to include more interviews and focus groups, and be aware of the need for culturally appropriate instruments. IMPLICATIONS: Researchers need to be sensitized to the Western cultural values upon which most research designs and instrumentation are constructed. Involvement of a culturally diverse research team, openness to feedback, adaptability, and critical reflection on what is important to the cultural groups are among the suggestions for researchers planning home-based occupational therapy research with culturally diverse populations. PMID- 21699012 TI - Cultural competence in occupational therapists working in early intervention therapy programs. AB - BACKGROUND: Cultural competence promotes equity in health care outcomes and ensures that occupational therapists support clients in culturally relevant daily activities. However, it is unclear to what extent occupational therapists in early intervention therapy (EIT) settings practise cultural competence. PURPOSE: To explore how occupational therapists working in EITsettings work towards cultural competence in practice. METHODS: Qualitative methods in the ethnographic tradition were used to explore five occupational therapists' experiences of working with culturally diverse clients. FINDINGS: Four major themes emerged from the data: (1) learning about culture; (2) applying cultural knowledge; (3) reflecting on culture; (4) family-centred partnerships. The first three themes occurred as a dynamic learning process within the context of family-centred partnerships. The findings corresponded with existing models; however, discussions lacked critical examination of power relationships. Implications. Occupational therapists could develop cultural competence further by engaging in reflexive practice and taking actions to promote equity in healthcare outcomes. PMID- 21699013 TI - Cross-cultural adaptation and reliability of child-initiated pretend play assessment (chlPPA). AB - BACKGROUND: Play is an indication of a children's development. Purpose. Organize a culturally adapt the Child-Initiated Pretend Play Assessment to Brazilian population. METHOD: Translation and cultural adaptation procedures consisted of translation, synthesis, back translation, author's approval, and pretest of the assessment. For the pretest, 14 typically developing children were assessed. Was evaluated the use of play materials, duration of the assessment, and reliability. FINDINGS: Play materials and duration of the assessment were appropriate for Brazilian children. Analysis of intra-rater reliability showed good agreement ranging from 0.90 to 1.00. Inter-rater reliability showed good to moderate agreement for five items ranging from 0.76 to 0.59. Four items showed chance to poor agreement (rho = -0.13 to 0.50). IMPLICATIONS: Results of the pretest indicate the Brazilian version of the ChlPPA is potentially useful for Brazilian children. ChlPPA training in Portuguese in Brazil with play observation feedback is recommended to improve inter-rater reliability. PMID- 21699014 TI - Floor time play with a child with autism: a single-subject study. AB - BACKGROUND: Children with autism exhibit difficulties with social interaction and communication skills, and they present with restricted interests and stereotyped patterns of behaviour that affect their daily lives. Floor time play (FTP) is an intervention approach that addresses these issues; however, there are few published studies on its effectiveness. PURPOSE: This study determines the effectiveness of FTP intervention with a child diagnosed with autism. METHODS: A single subject AB design was used with circles of communication as the behaviour indicator for improvement. Visual and statistical analyses were completed. The child's mother kept a daily journal describing FTP intervention sessions at home. FINDINGS: Despite variability in the data, statistical analyses indicate a significant difference between the numbers of circles of communication during the intervention phase as compared with the observation phase. Implications. This study provides preliminary evidence for the use of the FTP approach with a child with autism. PMID- 21699015 TI - Valproic acid inhibits human hepatocellular cancer cells growth in vitro and in vivo. AB - BACKGROUND: Valproic acid (VPA) a histone deacetylase inhibitor has been shown to inhibit the growth of a variety of cancer cells. We examined the effect of VPA in human hepatocellular cancer cells (HuH7) in vitro and in vivo. We hypothesized that VPA may be able to modulate Notch-1 signaling in hepatic carcinoma cells, with antitumor effects. METHODS: HuH7 cells were used in this study. The inhibition of cell proliferation was determined by MTT assay. A caspase assay was used to determine the enzymatic activity of caspase-3. The impact of the activation or inhibition on HuH7 cell cycling was examined by FACS. analysis. HuH7 cells were injected subcutaneously in athymic male BALB/c mice. Animals were divided into two groups of 14 animals each (Group I non-treated and Group II treated). Group II received 16 mg daily of VPA orally for 30 days. Tumor size and volumes were measured and calculated until the end of the experiment. Notch-1 mRNA levels in HuH7 cells and tumor samples were assessed by qRT-PCR. RESULTS: VPA suppressed tumor cell proliferation in a dose-dependent manner. A significant statistical difference regarding DNA degradation and an increased activity of caspase-3 were observed in treated cells in comparison to non-treated cells. We observed a significant reduction of tumor xenografted growth and a significant down-regulation of Notch-1 mRNA levels in Group II. CONCLUSION: VPA inhibits the growth of HOC in vitro and in vivo, suggesting that it could be used in the treatment of HCC alone or in combination with other drugs. PMID- 21699016 TI - Myeloperoxidase: the yin and yang in tumour progression. AB - Myeloperoxidase (MPO) is a heme- containing enzyme abundantly expressed in neutrophils. It catalyzes the reaction between chloride and hydrogen peroxide to generate a potent oxidant, hypochlorous acid (HOCl). It plays an important role in innate immune defense mechanism. However, excessive generation of MPO-derived oxidants has been linked to tissue damage and in the initiation and progression of diseases such as cancer which arise from chronic inflammation. The oxidant activity of MPO is believed to promote the metabolism of chemical carcinogens, cause DNA damage and compromise the repair process. It is also considered as important mediators of gastric ulcers caused by Helicobacter pylori (H. pylori) through its ability to catalyze the generation of reactive oxidants. A G-463 a polymorphism located in the promoter of the MPO gene plays an important role in its transcription. Moreover the reactive oxidants produced by neutrophilic enzyme have the potential to interact with tumour cells and contribute to their metastasis. There has been a considerable interest in the screening of plant extracts and compounds isolated from them for their potential use as HOCl scavengers. This review will discuss the role of MPO in tumour progression and provide an overview of its part in tumour metastasis and ulcer. PMID- 21699017 TI - Effect of myricetin on 1,2 dimethylhydrazine induced rat colon carcinogenesis. AB - Colorectal cancer (CRC) is a leading cause of cancer mortality especially in the western world. The incidence of CRC in Asia is now increasing at an alarming rate from the previously negligible levels. The pathogenesis of CRC is a multistep process wherein pre cancer lesions accumulate in the mucosal cells finally resulting in cancer. Diet plays an important role in its aetio-pathogenesis--the high levels of dietary fat correlates to the increased incidence of CRC. This along with hereditary, environmental factors and singular lack of physical exercise provides a potent combination in its pathogenesis. Besides CRC isfrequently associated with persistent oxidative stress which results not only in DNA damage but also in mutation of cancer related genes besides the epigenetic silencing of the tumor suppressor gene. An important approach in the prevention of cancer is chemoprevention. Variety of plant products have been found to be highly effective in retarding the pathogenesis of the colorectal cancer. Myricetin is a well known bioflavonoid that is claimed to have anti cancer action particularly in colorectal cancer. Myricetin not only brought about significant decrease in the incidence of number of tumor bearing rats but also the tumor incidence. Myricetin supplementation significantly reduced liver TBARS. Further the anti oxidant enzymes like Catalase, Glutathione peroxidase and GSH were significantly rejuvenated following myricetin supplementation in a dose dependent manner. The fecal and colonic bacterial enzyme activity was also significantly decreased with the supplementation of myricetin 50 and 100 mg/kg. There was no additional benefit with the supplementation of 200 mg/kg of myricetin. PMID- 21699018 TI - Expression of death decoy receptor-3 (DcR3) in human breast cancer and its functional effects on breast cancer cells in vitro. AB - BACKGROUND: Death Decoy Receptor-3 (DcR3), otherwise known as tumour necrosis factor receptor superfamily member 6b, is suggested to be involved in the progression and immune evasion of malignant tumours. Its ligands include FASL and LIGHT (Tumour necrosis factor ligand superfamily member 14). DcR3 has been found to be amplified in certain solid tumours. However, its role in breast tumours remains unclear. In the present study, we examined the role played by DcR3 in MCF7 and MDA-MB-231 cell lines. MATERIALS AND METHODS: The expression of DcR3 was examined in MCF7 and MDA-MB-231 cell lines using immunocytochemical staining and RT-PCR. Anti-DcR3 hammerhead ribozyme transgenes were constructed and transfected into cells to create DcR3 knock-down cell sublines. The biological impact of modifying DcR3 expression in breast cancer cells was evaluated using a variety of in vitro assays, including growth, adhesion, migration and invasion models. RESULTS: MCF7 and MDA-MB-231 cells, usually expressing DcR3, were transfected with the anti-DcR3 ribozyme transgene. Stable transfectants containing the DcR3 ribozyme transgene (MCF7DcR3KO, MDA-MB-231DcR3KO) displayed a reduction of DcR3 expression at mRNA and protein levels. DcR3 knockdown in MCF7 cells was found to significantly reduce invasive capacity compared to pEF6 control cell lines (30.78 +/- 6.40 vs.151.67 +/- 17.67 P < 0.001). The rate of migration in MCF7DcR3KO was significantly lower than MCF7pEF6 (P < 0.001). In contrast, no such significant differences was seen between MDA-MB-231DcR3KO and MDA-MB-231pEF6. CONCLUSION: Suppressing DcR3 expression was found to have an inhibitory effect on cellular invasion and migration in MCF7 breast cancer cells. This suggests that the invasion and migration capacity of this breast cancer cell line may, at least partly, depend on DcR3. DcR3 may be regarded as a negative regulator for aggressiveness during the development and progression of certain types of breast cancer. PMID- 21699019 TI - Role of reactive oxygen species (ROS) in CDDO-Me-mediated growth inhibition and apoptosis in colorectal cancer cells. AB - CDDO-Me, an oleanane synthetic triterpenoid has shown strong antitumorigeic activity towards diverse cancer cell types including colorectal cancer cells. In the present study, we investigated the role of free radicals in the growth inhibitory and apoptosis-inducing activity of CDDO-Me in colorectal cancer cells lines. Results demonstrated that CDDO-Me potently inhibited the growth of colorectal cancer cells and pretreatment of cancer cells with small-molecule antioxidant N-acetylcysteine (NAC) completely blocked the growth inhibitory activity of CDDO-Me. CDDO-Me caused the generation of reactive oxygen species, which was inhibited by NAC and mitochondrial chain 1 complex inhibitors DPI and rotenone. CDDO-Me induced apoptosis as demonstrated by the cleavage of PARP-1, activation of procaspases -3, -8, and -9 and mitochondrial depolarization and NAC blocked the activation of these apoptosis related processes. Furthermore, induction of apoptosis by CDDO-Me was associated with the inhibition of antiapoptotic/ prosurvival Akt, mTOR and NF-kappaB signaling proteins and the inhibition of these signaling molecules was blocked by NAG. Together these studies provided evidence that CDDO-Me is a potent anticancer agent, which imparts growth inhibition and apoptosis in colorectal cancer cells through the generation of free radicals. PMID- 21699021 TI - Inhibition of invasion and experimental metastasis of murine melanoma cells by Ipomoea obscura (L.) is mediated through the down-regulation of inflammatory mediators and matrix-metalloproteinases. AB - In this study, we tested the anti-metastatic activity of Ipomoea obscura extract and elucidated its underlying mechanisms by in vitro system using B16F-10 melanoma cells and in vivo experimental lung metastasis model. I. obscura suppressed proliferation, invasion and migration of highly metastatic B16F-10 melanoma cells in vitro. I. obscura could also decrease transcription factors such as nuclear factor kappaB (NF-kappaB) and activator protein (AP-1) in B16F-10 melanoma cells. Administration of I. obscura resulted significant suppression of B16F-10 melanoma induced tumor nodule formation and enhanced the survival of tumor-bearing mice. The level of various biochemical parameters associated with lung metastasis were also found to be decreased by the I. obscura treatment. A significant down regulation in the expression of inflammatory mediators such inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), pro-inflammatory cytokines related to tumor metastasis was observed by the treatment with I. obscura. Higher expression levels of pro-metastatic genes such as matrix metalloproteinase (MMP-2 and 9), was observed in the metastatic group, but these were down-regulated by the treatment with I. obscura. The endogenous MMP inhibitor tissue inhibitor of metalloproteinases (TIMP) was found to be up regulated by I. obscura treatment. Our results indicate that the anti- invasive and antimetastatic effect of I. obscura is mediated at least in part by reduced expression of inflammatory mediators by inhibiting NF-kappaB signaling with their downstream targets iNOS, COX-2 and pro-inflammatory cytokine and also by inhibiting MMP-9 and MMP-2. PMID- 21699020 TI - The small-molecule TNF-alpha modulator, UTL-5g, reduces side effects induced by cisplatin and enhances the therapeutic effect of cisplatin in vivo. AB - We investigated a small-molecule modulator of tumor necrosis factor alpha (TNF alpha), UTL-5g (also referred to as GBL-5g), as a potential chemoprotective agent against cisplatin-induced side effects including nephrotoxicity, hepatotoxicity and hematotoxicity. Pretreatment of UTL-5g i.p. in BDF1 mice reduced the levels of blood urea nitrogen (BUN) and creatinine induced by cisplatin treatment. The levels of both aspartate transaminase (AST) and alanine transaminase (ALT) in these animals were also reduced by UTL-5g. Pretreatment of UTL-5g did not significantly affect the number of white blood cells (WBC) under current experimental conditions, yet it markedly increased blood platelet counts by more than threefold. Therapeutic assessment in SCID mice inoculated with human HCT-15 tumor cells showed that UTL-5g did not attenuate the anti-tumor effect of cisplatin but increased the therapeutic efficacy of cisplatin. The LD50 of UTL-5g was determined to be > 2,000 mg/kg by an acute toxicity study. In summary, our studies showed that 1) UTL-5g significantly reduces nephrotoxicity and hepatotoxicity induced by cisplatin in mice, presumably by lowering the levels of TNF-alpha, 2) UTL-5g markedly increased blood platelet counts in mice and 3) UTL 5g treatment increased the therapeutic efficacy of cisplatin against HCT-15 cells inoculated in SCID mice. PMID- 21699022 TI - A case control study on the lung cancer risk factors in north of Iran. AB - In this case control study, the risk factors of lung cancer was assessed in the north of Iran. Two groups were matched for gender and age (+/- 5 years). Data were collected from 40 cases and 40 controls attending to hospitals. A public information questionnaire was used for data collection. Incidence odds ratios (OR) and corresponding 95% confidence intervals calculated using logistic regression analyses. Results showed that in adjusted odd ratio positive family history of cancer (OR = 0/19, 95% CI: 0/04-0/8) was associated with a reduction, and consumption of baked bread in traditional oven (OR = 22/6, 95% CI: 1/9-270), was associated with increase in lung cancer risk. Based on the results, smoking was not correlated with lung cancer. In conclusion, the data offers consumption of traditional oven-baked bread may enhance the risk of lung cancer but positive family history of cancer may reduce it. PMID- 21699023 TI - Potential cross-reactivity between HPV16 L1 protein and sudden death-associated antigens. AB - In exploring the primary sequence of the human papilloma virus (HPV) 16 major capsid L1 protein for peptide sharing with human proteins, we find that 34 pentamers from the viral capsid protein are shared with human proteins that, when altered, have been linked to short QT syndrome, arrhythmogenic cardiac disorders, cardiovascular diseases and sudden death. In particular, nine out of the 34 viral pentamers are present in a human protein, titin, alterations of which have been linked to cardiac failure and sudden cardiac death. The present data may help evaluate the potential crossreactivity risks in anti-tumor vaccination protocols based on HPV16 L1 protein. PMID- 21699024 TI - Adnexal masses in postmenopausal and reproductive age women. AB - We aimed to evaluate and compare the management and clinical characteristics of adnexal masses in postmenopausal and reproductive age women. This prospective study was performed at Dicle University, School of Medicine, Department of Obstetrics and Gynecology, from January 2007 to June 2009.The data were collected from hospital records and patients files, descriptively. The cases were divided into two groups as cases with adnexal masses in postmenopausal age women (Group 1, n = 40), and reproductive age (Group 2, n = 40). All of the cases operated for benign adnexal masses. Statistical analyses were carried out by using the statistical packages for SPSS 15.0 for Windows (SPSS Inc., Chicago, IL, USA). The demographic characteristics of the cases that were enrolled in our study are depicted in Table 1.The initial compliant of the cases were abdominal pain in 62 (77.5%) of the cases and 8 (20%) vaginal bleeding and 10 (12.5%) were asymptomatic. The initial diagnose of the cases were; pelvic mass in 34 (75%) of the cases, ovarian cyst 26 (32.5%), dermoid cyst 10 (12.5%), endometrioma 7 (8.75%) and postmenopausal bleeding 4 (5%). The tumor markers were evaluated. All of the cases were subjected to laparotomy or laparoscopy. The frozen section diagnose were made by the pathology department. The postoperative characteristics of the masses were also evaluated. The adnexal masses in postmenopausal woman with benign characteristics can be followed conservatively, without surgery. Surgery may be indicated to women with family history of cancer, a mass that appears enlarging and symptomatic. PMID- 21699025 TI - Alphabet soup of auditors creates new world for CMs. AB - Multiple auditors are scrutinizing hospital records looking for improper payments and fraud and abuse, which makes medical necessity, documentation, and coding more important than ever. Case managers are likely to be key players in the audit process. Dealing with the auditing process requires a tremendous amount of time and resources. Hospitals need to develop a process to track the audit requests and responses and to identify areas where improvements can be made. PMID- 21699026 TI - Multiple hospitals experience RAC activity. PMID- 21699027 TI - ZPICs audit records looking for fraud. PMID- 21699028 TI - Medicaid audit programs rolled out by CMS. PMID- 21699029 TI - Interdisciplinary meetings play critical role in inpatient setting. PMID- 21699030 TI - Steps for establishing effective meetings. PMID- 21699031 TI - 'Get it right the first time' should be the mantra. PMID- 21699032 TI - Systemwide approach tracks audits. PMID- 21699033 TI - Proactive approach for appropriate admissions. PMID- 21699034 TI - Left ventricular diverticulum: incidental finding on dual source cardiac CT. AB - The purpose of this retrospective study is to describe the prevalence, size and location of left ventricular (LV) diverticulum-diverticuli on cardiac dual source CT. Dual source computed tomography cardiac angiography (DS CTCA) was performed in 482 patients. Where literature states their rare occurrence, this retrospective study demonstrates the fairly common finding of incidental LV diverticulum on DS CTCA examinations. LV diverticuli were found incidentally in 20 out of 482 patients (4.1%), a substantially higher incidence than previously reported. Although diverticuli were most common along the inferoseptal wall (45%) they also occurred in all parts of the left ventricular wall. Multiple diverticuli were found in 30% of patients. Dimensions of the LV diverticuli varied enormously. LV diverticuli are reported to be frequently associated with other congenital anomalies. Complications ranging from sudden death and heart failure to embolic events have been described in literature. No relevant associated anomaly or complication was present in the studied 20 patients. Our data support the hypothesis that LV diverticuli, incidentally found in adulthood, follow a benign course and can be managed conservatively. More knowledge is however required to understand history and prognosis about this condition. PMID- 21699036 TI - Extensive neurosarcoidosis and optic nerve complications. AB - We present the case of a 35-year-old patient suffering from nasal obstruction and headache for 3 years. The patient was hospitalized for a recent and progressive decline of vision of the right eye associated with afferent pupillary deficit and inferior altitudinal hemianopsia. He was diagnosed with systemic sarcoidosis involving the central nervous system as illustrated by magnetic resonance imaging (MRI) scans showing different type diffuse lesions of meningo-encephalitis. Our case is characterized by severe cerebral pachyleptomeningeal lesions complicated by optic nerve compression and cervical spinal cord damage. MRI value of diagnosis for systemic neurosarcoidosis was supported by histological examination of a biopsy of the sphenoid sinus lesions that showed epithelioid granulomas presence without caseous necrosis. Thus, MRI of the brain and spinal cord is a powerful tool method in monitoring and diagnosing asymptomatic and symptomatic neurosarcoiodosis. MRI is also a powerful tool in monitoring the neurosarcoidosis during therapeutic treatments. PMID- 21699035 TI - Primary appendicealtumors: clinical imaging and pathological findings. Report of four cases. AB - Primary appendiceal tumors are rare clinical and radiological entities. We report 4cases including muscinous cystadenoma associated with pseudomyxoma peritonei, muscinous cystadenoma associated with mucocele, low-grade muscinous neoplasia associated with appendicitis in elderly patients, and carcinoid tumor associated with appendicitis in a young adult. PMID- 21699038 TI - Exceptional, potentially fatal combination of emphysematous pancreatitis and gas forming cholecystitis: successful multidisciplinary conservative treatment supported by repeated CT-staging. AB - Usually considered as a life-threatening disease, emphysematous pancreatitis requires early diagnosis and aggressive multidisciplinary treatment including the Departments of Gastroenterology, Intensive Care Medicine, Interventional Radiology and even Surgery. The prognosis for emphysematous cholecystitis is also quite poor. It requires surgery even if a percutaneous cholecystostomy can contribute to a temporary stabilization of the patient. Computed tomography is the imaging modality of choice to detect emphysematous pancreatitis and gas forming cholecystitis. It enables their grading and helps identify their complications. Moreover, it proves essential in the follow-up of the lesions. PMID- 21699037 TI - Ruptured hepatocellular carcinoma following transcatheter arterial chemoembolization. AB - Transcatheter arterial chemoembolization (TACE) is known to be an effective palliative treatment in unresectable hepatocellular carcinoma (HCC). Although TACE can control tumour growth and palliate the patients, complications of TACE with significant morbidity are well known and adversely affect the outcome of patients. Necrotic tumor rupture is a serious complication of TACE and has a high mortality rate. We report a case of ruptured HCC followingTACE in a 78-year-old male patient who subsequently developed peritonitis and pneumoperitoneum. This case gives us the opportunity to underline the importance of such complications and demonstrates the utility of CT imaging for diagnosis and management of patients with ruptured HCC. PMID- 21699039 TI - A rare presentation of breast cancer. AB - The case of a 67-year-old woman with a large lump in the left axillary region and the left breast is presented. Pathologic investigation of these masses in 2 hospitals was inconclusive. Further work-up in our radiologic department showed beside the presence of the two tumoral masses, abnormalities with the radiologic characteristics of granulomatous mastitis. Final pathologic analysis showed the presence of an invasive ductal carcinoma in the two masses in combination with a granulomatous stromal reaction. PMID- 21699040 TI - Malignant transformation of an abdominal inflammatory myofibroblastic tumor with distant metastases in a child. AB - Inflammatory myofibroblastic tumors (IMT) are lesions that mostly affect young adults and children. The tumor is made up of myofibroblasts and a mixed inflammatory infiltrate and rarely undergoes malignant transformation. We present a case of a 13-year-old boy with a pelvic mass diagnosed as IMT which underwent malignant transformation and metastasised to the liver. We report the ultrasound, computed tomography (CT) and magnetic resonance (MR) findings of this rare disorder. PMID- 21699041 TI - Ultrasonography and mri findings of cutaneous B-cell lymphoma, leg type. PMID- 21699042 TI - Posttraumatic priapism in child. PMID- 21699043 TI - Complicated pulmonary interstitial emphysema. PMID- 21699044 TI - Tympanic plate fracture following mandibular trauma with emphasis on 3D imaging. PMID- 21699045 TI - Spinal abnormalities in vitamin B12 deficiency. PMID- 21699046 TI - Duodenal varices. PMID- 21699047 TI - Renal fornix rupture following diagnostic coronarography. PMID- 21699048 TI - Adrenal gland fusion. PMID- 21699049 TI - Pulmonary arteriovenous malformation. PMID- 21699050 TI - Ileo-colic hernia through the foramen of Winslow. PMID- 21699051 TI - Round ligament varicocele. PMID- 21699052 TI - Bilateral globus pallidus infarcts in ecstasy use. PMID- 21699053 TI - Focal eosinophilic hepatitis simulating a solitary metastatic lesion on FDG PET/CT in a patient with history of head and neck cancer. PMID- 21699054 TI - Lipedematous scalp: a rare dermatological entity. PMID- 21699055 TI - Schwannoma of the seminal vesicle. PMID- 21699056 TI - Agenesis of the pubic symphysis detected with SPECT-CT. PMID- 21699057 TI - Primary breast tuberculosis. PMID- 21699058 TI - Grynfelt hernia. PMID- 21699059 TI - Computed tomography (CT) is the main source of radiation from diagnostic procedures. PMID- 21699060 TI - Neuroradiology plays a crucial role in the management of stroke patients. PMID- 21699061 TI - WHO Expert Committee on Specifications for Pharmaceutical Preparations. AB - The Expert Committee on Specifications for Pharmaceutical Preparations works towards clear, independent and practical standards and guidelines for the quality assurance of medicines. Standards are developed by the Committee through worldwide consultation and an international consensus-building process. The following new guidelines were adopted and recommended for use: procedure for adoption of International Chemical Reference Substances; WHO good practices for pharmaceutical microbiology laboratories; good manufacturing practices: main principles for pharmaceutical products; good manufacturing practices for blood establishments (jointly with the Expert Committee on Biological Standardization); guidelines on good manufacturing practices for heating, ventilation and air conditioning systems for non-sterile pharmaceutical dosage forms; good manufacturing practices for sterile pharmaceutical products; guidelines on transfer of technology in pharmaceutical manufacturing; good pharmacy practice: standards for quality of pharmacy services (joint FIP/WHO); model guidance for the storage and transport of time- and temperature-sensitive pharmaceutical products (jointly with the Expert Committee on Biological Standardization); procedure for prequalification of pharmaceutical products; guide on submission of documentation for prequalification of innovator finished pharmaceutical products approved by stringent regulatory authorities; prequalification of quality control laboratories: procedure for assessing the acceptability, in principle, of quality control laboratories for use by United Nations agencies; guidelines for preparing a laboratory information file; guidelines for drafting a site master file; guidelines on submission of documentation for a multisource (generic) finished product: general format: preparation of product dossiers in common technical document format. PMID- 21699062 TI - Evaluation of certain contaminants in food. AB - This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of various food contaminants, with the aim to advise on risk management options for the purpose of public health protection. The first part of the report contains a general discussion of the principles governing the toxicological evaluation of contaminants and assessments of dietary exposure. A summary follows of the Committee's evaluations of technical, toxicological and dietary exposure data for certain food contaminants: acrylamide, arsenic, deoxynivalenol, furan, mercury and perchlorate. Annexed to the report are tables summarizing the Committee's recommendations for dietary exposures and toxicological evaluations of the food contaminants considered. PMID- 21699063 TI - SiRNA delivery: challenges and role of carrier systems. AB - Gene silencing by RNA interference is a rapidly growing therapeutic area for managing diseases. Despite research advances in this direction, the poor cellular uptake of synthetic small interfering RNAs is a major impediment to their clinical applications. Polymer and lipid-based systems are attractive carrier systems for delivery of siRNA and provide options for desirable engineering of carrier particles. In this review, there is a detailed discussion of RNAi delivery systems and recent advances in the field. PMID- 21699064 TI - Use of prebiotics in oral delivery of bioactive compounds: a nanotechnology perspective. AB - The oral route is considered the most patient-convenient means of drug administration. In recent years there has been a tendency to employ smart carrier systems that enable controlled or timed release of a bioactive material, thereby providing a better dosing pattern and minimizing side effects. Nano-encapsulation systems (nanocarriers) offer important advantages over conventional drug delivery techniques. Nanocarriers can protect the drug from chemical/enzymatic degradation and enhance bioavailability. Prebiotics are ideal ingredients for the nano encapsulation and oral drug delivery due to their natural ability to protect the encapsulated compound in the upper gasterointestinal (GI) tract. Here the potential of prebiotics for oral delivery of drugs and other bioactives is reviewed. PMID- 21699065 TI - Evaluation of physicochemical properties and aggregation of the photosensitizers TPCS2a and TPPS2a in aqueous media. AB - Physicochemical properties of the novel photosensitizer meso-tetraphenyl chlorin disulphonate (TPCS2a) and the chemically related meso-tetraphenyl porphyrin disulphonate (TPPS2a) were investigated in aqueous solutions as part of pharmaceutical preformulation. Inflection points were calculated to be 3.9 for both compounds based on spectral shifts of aqueous solutions in the pH range 2 12, which likely correlate with indistinguishable pKa values of the imino nitrogens of the molecular cores. Accordingly, the fluorescence emission spectra showed pH dependent spectral shifts. Porphyrin-like compounds are known for aggregation in aqueous environments, and a small percentage of Tween 80 (0.006 % v/v = 4 x cmc) seemed to stabilize the aqueous samples of the two photosensitizers through hindrance of aggregation. The distribution coeffient of TPCS2a determined spectrophotometrically in 1-octanol/water is 0.4 (- 0.4 SD) and 1.5 (- 0.5 SD) for the reference TPPS2a. This confirms amphiphilicity which indicates preferred distribution and further restrain of diffusion in membranes, which is relevant for the use of TPCS2a as a photosensitizer in the process of photochemical internalization in vivo. PMID- 21699066 TI - Positively charged polymeric nanoparticles: application in improving therapeutic efficacy of meloxicam after oral administration. AB - The potential of positively charged polymeric nanoparticles in improving therapeutic efficacy of meloxicam (MLX), a poorly water-soluble anti-inflammatory agent was evaluated. MLX loaded positively charged nanoparticles were prepared by using poly-epsilon-caprolactone (PCL) as a biodegradable polymer and didodecyldimethylammonium bromide (DDAB) as a cationic surfactant. The MLX nanoparticles were characterized for particle size and encapsulation efficiency. MLX loaded PCL nanoparticles and MLX suspension were evaluated for their in vivo anti-inflammatory activity and ulcerogenic potential. MLX loaded PCL nanoparticles had particle sizes of approximately 300 nm and the encapsulation efficiency of MLX was approximately 90%. The polymeric nanoparticles significantly improved the anti-inflammatory activity of MLX (P< 0.01) as compared to that of MLX suspension. The higher anti-inflammatory effect was maintained for a longer duration (6 h). The polymeric nanoparticles also resulted in less ulcerogenicity as compared to that of MLX suspension. PMID- 21699067 TI - Box-Behnken optimization design and enhanced oral bioavailability of thymopentin loaded poly (butyl cyanoacrylate) nanoparticles. AB - This study was done to prepare thymopentin (TP5)-loaded poly (butyl cyanoacrylate) nanoparticles (TP5-PBCA-NPs) and evaluate thier efficacy for oral delivery. TP5-PBCA-NPs were prepared by emulsion polymerization, and the formulation was optimized based on Box-Behnken experimental design. The physico chemical characteristics of TP5-PBCA-NPs were evaluated using transmission electron microscopy (TEM), malvern zetasizer, Fourier transform infra-red spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The encapsulation efficiency, enzymatic degradation and release behavior of TP5-PBCA NPs in various media were evaluated using a high-performance liquid chromatography (HPLC) method. The pharmacodynamic studies on oral administration of TP5-PBCA-NPs were performed in FACScan flow cytometry. An optimum formulation consisted of 0.7% poloxamer 188 (Pol), 0.6% dextran-70 (Dex), 0.1% sodium metabisulfite (Sm), 0.1% TP5 and 1% (v/v) n-butyl cyanoacrylate. The particle size and zeta potential of optimized TP5-PBCA-NPs was 212 nm and -22.6 mV respectively with 82.45% encapsulation efficiency. TP5 was entrapped inside the nanoparticles in molecular dispersion form. The release of TP5 from PBCA-NPs was pH dependent; the cumulative release percentage in 0.1 M HCI for 4 hours was less than 16% while it was more than 80% in pH6.8 PBS. The PBCA-NPs could efficiently protect TP5 from enzymatic degradation; the remained percentage of TP5 encapsulated in PBCA-NPs was 58.40% after incubated with trypsin in pH6.8 PBS for 4 h while it was only 32.29% for free drug. In the oral administration study in vivo, the lowered T-lymphocyte subsets values were significantly increased and the raised CD4+/CD8+ ratio was evidently reduced compared with that of TP5 solution (p < 0.05), and the improvement of bioavailability was dose-dependent. These results indicated that the PBCA nanoparticles may be a promising carrier for oral delivery of TP5. PMID- 21699068 TI - Physical and chemical stability of nanostructured lipid drug carriers (NLC) based on natural lipids from Baikal region (Siberia, Russia). AB - At the turn of the millennium, a new generation of lipid nanoparticles for pharmacology was developed, nanostructured lipid carriers (NLC). The features of NLC structure which allow the inclusion of natural biologically active lipids in the NLC matrix open a wide prospect for the creation of high performance drug carriers. In this study NLC formulations were developed based on natural lipids from the Siberia region (Russia): fish oil from Lake Baikal fish; polyunsaturated fatty acid fractions and monounsaturated and saturated fatty acid fractions from fish oil and Siberian pine seed oil. Formulation parameters of NLC such as as type of surfactant and storage conditions were evaluated. The data obtained indicated high physical stability of NLC formulated on the basis of pure fish oil stabilized by Tween 80 and NLC formulated on the basis of free fatty acids stabilized by Poloxamer 188. The good chemical stability of the lipid matrix and the high concentrations of the biologically active polyunsaturated fatty acids in the NLC developed open wide prospects for their use in pharmaceutics and cosmetics. PMID- 21699069 TI - Nanostructured lipid carriers as delivery system for the phopholipase A2 inhibitors PX-18 and PX-13 for dermal application. AB - PX-18 and PX-13 are secretory phospholipase A2-IIA (sPLA2-IIA) inhibitors. An increased expression of sPLA2 in psoriatic skin has been reported. The selective inhibition of this enzyme is a new therapeutic approach. For dermal application PX-18 and PX-13 have been loaded to Nanostructured lipid carriers (NLC). The PX 18-loaded and PX-13-loaded NLC possessed an average particles size of about 250 nm, a narrow particle size distribution (PI < 0.2), a high entrapment efficiency as well as a good physical stability, as already indicated by their high zeta potential. Both NLC formulations have been incorporated into a hydroxyethyl cellulose gel and an o/w cream. In the gel and in the o/w cream PX-18-loaded and PX-13-loaded NLC showed a good physical stability. Neither aggregation nor dissolution of NLC took place. PMID- 21699070 TI - Melittin liposomes surface modified with poloxamer 188: in vitro characterization and in vivo evaluation. AB - Melittin liposomes surface modified with poloxamer 188 were developed, and the effect of poloxamer 188 was investigated with regard to anti-cancer effect and vascular stimulation. Melittin liposomes surface modified with poloxamer 188 at different concentrations (0%, 2%, and 5%) were prepared using the adsorption method, followed by in vitro characterization, including entrapment efficiency, zeta potential, particle size, and morphology. Subsequently, the influence of repeated freeze-thawing on the liposomes was investigated, and the effect of poloxamer 188 on the repeated freeze-thawing process was explored. Vascular stimulation effects of MLT, and MLT liposome that surface coated with or without poloxamer were all studied. Pharmacokinetics of the different MLT preparations were determined and the anticancer activity of the MLT formulations was investigated. The particle size of the liposomes gradually increased with increasing poloxamer 188 content, while the entrapment efficiency did not change significantly. After the first freeze-thaw cycle, size and PDI were both markedly reduced, entrapment efficiency rose, and there was no significant change of zeta potential. The vascular irritation caused by MLT could be reduced to an extent by encapsulation in liposome, but not completely eliminated, while liposomes coated with poloxamer 188 can effectively abolish the phenomenon. Melittin liposomes with surface modified by poloxamer exhibit enhanced bioavailability, effective anticancer activity, and reduced side effects compared with melittin solution. Poloxamer plays an important role in melittin liposomes. PMID- 21699072 TI - Pharmacokinetics of baicalin-phospholipid complex in rat plasma and brain tissues after intranasal and intravenous administration. AB - The aim of this study is to determine whether baicalin can be transferred along the olfactory pathway to the brain after nasal administration of baicalin phospholipid (BP) complex to rats, thereby circumventing the blood brain barrier. The concentration of baicalin in plasma and different brain tissues (olfactory bulb, cerebral cortex, striatum and cerebellum) were measured by high-performance liquid chromatography (HPLC). The ratios of the area under the concentration-time curve (AUC) values of intranasal to intravenous administrations were 54.21%, 240.59%, 374.71%, and 114.54% in plasma, cerebral cortex, striatum, and cerebellum, respectively. In the olfactory bulb, the AUC values of intranasal to intravenous administrations were 3355.4 +/- 378.8 microg/g-min versus 0 microg/g x min following intravenous administration. The ratios of AUC values of intranasal to intravenous administrations were72.75 %, 240.59 %, 374.71%, 114.54% in plasma, cortex, striatum, cerebellum respetively. The proportion of baicalin in the brain tissues from the olfactory transfer was also calculated, and the result shows that, following intranasal administration, approximately 52.36%-100% baicalin content at 8 h was transported to the brain via the olfactory pathway. In conclusion, the BP complex is transferred into the olfactory bulb via the olfactory pathway in rats, and the BP complex intranasal delivery is a promising approach to protect against cerebral ischemic injury. PMID- 21699071 TI - Double liposomes mediated dual drug targeting for treatment of Helicobacter pylori infections. AB - In the present study the potential of phosphatidylethanolamine (PE) lipid anchored double liposomes (DL) to incorporate two drugs in a single system is exploited as a tool to augment the H. pylori eradication rate. Preparation of DL involves two steps, first formation of primary (inner) liposomes by thin film hydration method containing one drug, then addition of suspension of inner liposomes on thin film of lipid containing the other drug. The success of formation of DL was characterized by optical and transmission electron microscopy. Quantitation of DL-bacterial interaction was evaluated in terms of percent growth inhibition (%GI) on reference strain of H. pylori ATCC 26695. To confirm specific binding efficacy of DL to H. pylori PE surface receptor we performed an agglutination assay. Agglutination in DL treated H. pylori suspension suggested selectivity of DL towards the PE surface receptor of H. pylori. Monotherapy is generally not recommended for treatment of a H. pylori infection due to the danger of development of resistance and unacceptably low eradication rates. Therefore combination therapy with amoxicillin trihydrate (AMOX) as anti-H. pylori agent and ranitidine bismuth citrate (RBC) as antisecretory agent were selected for the study with an expectation that this dual-drug delivery approach will exert acceptable anti-H. pylori activity. PMID- 21699073 TI - Role of oxidative/nitrative stress in hepatic encephalopathy induced by thioacetamide. AB - The study was designed to reveal the pathogenic mechanism of peroxynitrite in hepatic encephalopathy (HE), assess oxidative/nitrative stress in relation to HE induced by thiacetamide (TAA) and provide new ideas and scientific basis for the etiology and treatment of HE. Male Wistar rats were divided into four groups randomly: A (control), B (model), C (ebselen) and D (solvent). All the groups were treated with TAA by intraperitoneal (i.p.) except group A (treated with saline i.p.) to manufacture the model of HE. When rats treated with TAA came to the second stage of HE the four groups were administered intragastrically (i.g.) with saline (A, B), ebselen (C) and dimethyl sulfoxide (DMSO) (D), respectively. Plasma was collected to detect the levels of 3-nitrotyrosine (3-NT), NO, T-SOD and MDA. The results showed that the levels of 3-NT, NO, MDA significantly increased and T-SOD decreased obviously in rats suffering from HE. With the development and progression of HE the extent of oxidative/nitrative stress increased. When treated with ebselen the symptoms of HE mitigated and the levels of biochemical indicators ameliorated significantly. This indicates that oxidative/nitrative stress is involved in the mechanisms of hepatic encephalopathy. PMID- 21699074 TI - Isothiocyanates from Broccolini seeds induce apoptosis in human colon cancer cells: proteomic and bioinformatic analyses. AB - Isothiocyanates (ITCs) have been shown to possess antitumor activity in colon cancer, however, the detailed mechanism is still unclear. The objective of this study was to investigate apoptosis-inducing activity of ITCs from Broccolini seeds and proteomic changes in SW480 cells, and to identify the molecular pathways responsible for the anticancer action of ITCs. We found that ITCs induces SW480 cells apoptosis in a dose-dependent manner by using MTT assay, phase contrast microscope and flow cytometry, and the IC50 was calculated to be 77.72 microg/ml, superior to the chemotherapeutical drug 5-flurouracil. Subsequently, 15 altered proteins in ITCs treated SW480 cells were identified. Further bioinformatics analysis predicted the potential pathways for ITCs to induce apoptosis of SW480 cells. In conclusion, this is the first report to investigate anticancer activity of ITCs from Broccolini seeds and its mechanism of action by proteomics analysis. Our observations provide potential therapeutic targets for colon cancer inhibitor intervention and implicate the development of novel anti-cancer therapeutic strategies. PMID- 21699075 TI - Metronidazole and the immune system. AB - Metronidazole (MTZ) is a nitroimidazole antibiotic used mainly for the treatment of infections caused by susceptible organisms, particularly anaerobic bacteria and protozoa. Distinct from its antibiotic, amoebicidal, and antiprotozoal effects, MTZ displays immunopharmacological behaviour. This review outlines multiple effects of MTZ on different aspects of immunity, including innate and acquired immunity, and also highlights the immunopharmacological behaviour of MTZ in terms of its relevance to inflammation, delayed type hypersensitivity (DTH) and graft versus host disease (GVHD). PMID- 21699076 TI - Design, synthesis and biological evaluation of new 2-benzoxazolinone derivatives as potential cholinesterase inhibitors for therapy of alzheimer's disease. AB - Currently acetylcholinesterase inhibitor (AChEI) therapy is one of the most frequently used methods in the treatment of Alzheimer's disease; tacrine, donepezil, rivastygmine and galantamine are applied in different stages of AD. In the present study, we propose a new series of 2-benzoxazolinone derivatives as potential cholinesterase inhibitors. These compounds were synthesized by condensation of 6-chloro acetyl-2-benzoxa zolinone with the corresponding amine and evaluated as acetylcholinesterase inhibitors using the colorimetric Ellman's method. Selectivity and the IC50 values were determined for the received derivatives. All tested compounds exhibited the inhibitory activity towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compound 3e showed stronger activity than the standard tacrine, and compound 3a showed activity similar to that of tacrine for AChE. Compounds 3a, 3b, 3c, and 3e showed stronger activity than the standard donepezil towards the inhibition of BChE, and the compound 3e showed stronger activity than donepezil towards AChE. PMID- 21699077 TI - Preparation, characterization and in vivo distribution of solid lipid nanoparticles loaded with syringopicroside. AB - A solvent emulsification evaporation method was employed to prepare solid lipid nanoparticles (SLN) loaded with syringopicroside. The conventional broad-spectrum antibacterial and antiviral drug syringopicroside was incorporated into SLN to improve drug targeting. The SYR-SLNs were spherical and uniform in transmission electron microscopy (TEM). The mean particle size and potential were 180.31 +/- 10 nm, and -41.9 +/- 10.3 mV, respectively. Also, a sephadex column chromatography was adopted to investigate the encapsulation efficiency (EE %) of the SLN. This method is based on the principle of molecular sieve effect, and the EE% of the optimal formulation was 42.35 %. Drug-loading capacity was 5.33 %. The in vitro release profile revealed that syringopicroside was released from SLN efficiently and completely in normal saline (NS) compared with other release media. A HPLC method was established for in vivo assay of syringopicroside. A tissue distribution study was conducted in rats after iv administration of 15 mg/kg SYR-SLN and syringopicroside NS, and it was found that SYR-SLN has improved delivery to the liver compared with any other organizations. These results indicated that solvent emulsification evaporation is a simple, easy, available and effective method for preparing SYR-SLN. PMID- 21699079 TI - Preparation, characterization and dissolution enhancement of mefloquine hydrochloride-betaCD inclusion complex. AB - The solid state properties and dissolution behaviour of binary systems of mefloquine hydrochloride (MH) with betaCD were investigated. MH-betaCD interaction in the solution state was studied by phase solubility analysis and demonstrates the ability of 3CD to complex with MH giving AL type profile with 120.34 M-1 stability constant. The kneading method was adopted to prepare binary sytems of MH with betaCD in 1:1 molar ratio. The solid inclusion was characterized by differential scanning calorimetry, fourier transformation infrared spectroscopy and X-ray powder diffractometry. Experimental results confirmed the existence of 1:1 inclusion complex of MH with ICD. Aqueous solubility of MH was found to be enhanced by 118% for inclusion complex. The dissolution properties of binary systems were studied in simulated gastric fluid without enzyme and compared with MH alone. The inclusion complex of MH prepared with 3CD showed a dissolution rate several times faster than that of physical mixture and pure drug. PMID- 21699078 TI - Nevirapine nanosuspensions for HIV reservoir targeting. AB - In this paper we discuss, production, characterization and in-vivo evaluation of nevirapine nanosuspensions. Laser diffraction showed that the average particles size was 457 nm. Following single-dose administration, the plasma gamma concentration profiles showed fast release. Macrophage uptake studies confirmed enhanced cellular uptake for nanonized nevirapine with no added cytotoxicity. Gamma scintigraphy showed that the nanosuspension prepared can be used to target spleen, thymus and lungs, which represent anatomical viral reservoirs. Thus nevirapine nanosuspensions with targeting potential have been prepared successfully. PMID- 21699080 TI - Antimicrobial activity of liposome encapsulated cyclo(L-tyrosyl-L-prolyl). AB - Various studies have shown the potentially beneficial biological activities of cyclic dipeptides and in particular, cyclo(L-tyrosyl-L-prolyl) (cyclo(Tyr-Pro)) has shown fair antibacterial activity in vitro. This study aimed to determine if liposome encapsulation would have any significant effects on the antibacterial activity of this compound. The thin-film hydration method with extrusion was used to produce small unilamellar vesicles containing cyclo(Tyr-Pro) that were shown to have an average encapsulation of 9.4% with a mean particle size of 160.4 nm. Minimum inhibitory concentrations tested against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Bacillus subtillis were shown to be lower in liposome encapsulated cyclo(Tyr-Pro) than for the free form, while no antimicrobial activity was noted for either encapsulated nor non-encapsulated drug against the fungus Candida albicans or two methicillin-resistant strains of Staphylococcus aureus (MRSA). A positive control of liposome encapsulated amoxicillin was shown to be extremely active against both MRSA strains. The results confirm that liposome encapsulation has the potential to enhance activity as well as to overcome bacterial resistance towards current antibacterial agents. PMID- 21699081 TI - Minor effects of the citrus flavonoids naringin, naringenin and quercetin, on the pharmacokinetics of doxorubicin in rats. AB - We investigated the effects of naringin, naringenin and quercetin on the pharmacokinetics of doxorubicin in rats. These Citrus flavonoids are known as P glycoprotein (P-gp) inhibitors and thus suspected to interact with doxorubicin, as shown by in vitro cell studies. Plasma concentrations, tissue distribution, and the urinary and biliary excretion of doxorubicin after intravenous infusion were investigated in rats followed by oral administration of Citrus flavonoids. To evaluate the impact of the biotransformation of Citrus flavonoids on the P-gp inhibition, the inhibitory effects of quercetin and its metabolite on P-gp were compared using ex vivo analysis. Contrary to previous in vitro results, the plasma concentration, biliary and urinary clearance, and tissue distribution of doxorubicin were not altered by pre-treatment with naringin and naringenin. Biliary clearance and urinary clearance were slightly decreased by quercetin, but there was no statistical difference. The minor effects of these flavonoids may relate to their low systemic concentration, due to the biotransformation in vivo situation. S9 stability assay and calcein accumulation assay showed that quercetin was a metabolically unstable compound, and the inhibitory effect of its metabolites on P-gp was negligible. In conclusion, naringin, naringenin and quercetin did not affect the in vivo pharmacokinetics of intravenously administered doxorubicin. PMID- 21699082 TI - Topical application of liposomal cobalamin hydrogel for atopic dermatitis therapy. AB - Topical vitamin B12 was shown to be effective for atopic dermatitis. However, vitamin B12 itself is light sensitive and has low skin permeability, thus reducing its therapeutic effectiveness. In the present study, we prepared a liposomal hydrogel of adenosylcobalamin (AdCbl), a vitamin B12 derivative, and investigated possible beneficial effects of AdCbl on atopic dermatitis using an NC/Nga murine atopic dermatitis model. AdCbl was loaded into liposomes prepared by a thin film hydration method using a pH gradient method that employed citric acid buffer solution. This resulted in AdCbl-loaded liposomes that were 106.4 +/- 2.2 nm in size. The loading efficiency was 40% (of the initial AdCbl amount). Lipo-AdCbl had enhanced skin permeability, being about 17-fold compared with AdCbl-gel. Topical administration of Lipo-AdCbl-gel to 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis-like skin lesions in NC/Nga mice ameliorated lesion intensity scores, dorsal skin thickness, and total serum IgE in a concentration-dependent manner. Other preparations, including AdCbl solution, AdCbl cream, liposomes alone, and a mixture of AdCbl solution and liposomes had little effect. Taken together, our findings indicate that Lipo-AdCbl-gel has protective effects against atopic dermatitis symptoms, and suggest that it may be of benefit in the treatment of human inflammatory skin diseases. PMID- 21699083 TI - Regulation of AMH and SCF expression in human granulosa cells by GnRH agonist and antagonist. AB - With the progress of cancer treatment, fertility preservation has become an urgent requisition. Gonadotropin-releasing hormone agonist (GnRH-a) and antagonist (GnRH-ant) have been used to protect fertility for these patients. However, studies showed that although GnRH-a and GnRH-ant had a comparable down regulating effect on the pituitary, GnRH-ant could not preserve ovarian function. Moreover, GnRH-ant alone could deplete primordial follicles. It might be speculated that an additional intraovarian system existed except the pituitary system. Anti-Muerian hormone (AMH) and Stem cell factor (SCF) proved to be the key factors in follicle recruitment and development. The balance between AMH and SCF was tightly related to ovarian reserve. To investigate the intraovarian effect of GnRH-a or GnRH-ant on ovarian reserve, we examined AMH and SCF expression in human granulosa cells (hGCs). GCs were isolated from follicular aspirates after oocyte removal from the patients undergoing assisted reproduction techniques. After pretreated with GnRH-a (triptorelin) or GnRH-ant (cetrorelix) for 48 h, mRNA and protein of AMH and SCF were analyzed by Real-time PCR and Immunoblot assay respectively. The results indicated that AMH mRNA and protein expressions were down-regulated in the GnRH-ant groups, SCF mRNA and protein expressions were up-regulated in the high-dose GnRH-ant group. There was no difference of AMH and SCF expression in the GnRH-a group or GnRH-a + GnRH-ant group compared with control. These results suggested the effects of GnRH-a and GnRH-ant on the regulation of AMH and SCF were different, which may provide insight into the mechanism of GnRH-a and GnRH-ant interventions on ovarian reserve. PMID- 21699084 TI - Inhibition of thioredoxin reductase by auranofin induces apoptosis in adriamycin resistant human K562 chronic myeloid leukemia cells. AB - Mammalian thioredoxin reductase (TrxR) catalyzes the NADPH-dependent reduction of oxidized thioredoxin (Trx) and plays a central role in regulating cellular redox homeostasis, cell growth and apoptosis. Increasing evidence shows that TrxR is over-expressed or constitutively active in many tumor cells. Moreover, TrxR appears to contribute to increased tumor cell growth and a resistance to chemotherapy. In this study, we evaluated the activity of TrxR in adriamycin resistant leukemic cells (K562/ADM) and adriamycin-sensitive parental lines (K562), and found that TrxR activity was higher in the drug resistant cell sublines K562/ADM than in K562 drug sensitive parental cells. Auranofin, a gold(I) compound clinically used as an antirheumatic agent, reduced TrxR activity and was more effective than adriamycin in decreasing cell viability in K562/ADM cells. In addition, auranofin induced apoptosis in dose-dependent manners, accompanied by caspase-3 activation in K562/ADM cells. Our results demonstrate that inhibition of TrxR and induction of apoptosis by auranofin provides its ability in overcoming adriamycin resistance in K562/ADM cells. PMID- 21699085 TI - Hepatotoxicity of kaurene glycosides from Xanthium strumarium L. fruits in mice. AB - The fruit of Xanthium strumarium L. (Cang-Er-Zi) is a traditional Chinese medicine that is used in curing nasal diseases and headache according to the Chinese Pharmacopoeia. However, clinical utilization of Xanthium strumarium is relatively limited because of its toxicity. The present investigation was carried out to evaluate the toxic effects on acute liver injury in mice of the two kaurene glycosides (atractyloside and carbxyatractyloside), which are main toxic constituents isolated from Fructus Xanthii on acute liver injury in mice. Histopathological examinations revealed that there were not obviously visible injury in lungs, heart, spleen, and the central nervous system in the mice by intraperitoneal injection of atractyloside (ATR, at the doses 50,125 and 200 mg/kg) and carbxyatractyloside (CATR, at the doses 50,100 and 150 mg/kg) for 5 days. However, it revealed extensive liver injuries compared with the normal group. In the determination of enzyme levels in serum, intraperitoneal injection of ATR and CATR resulted in significantly elevated serum alanine aminotransferase (ALT), asparate aminotransferase (AST), alkaline phosphatase (ALP) activities compared to controls. In the hepatic oxidative stress level, antioxidant-related enzyme activity assays showed that ATR and CATR administration significantly increased hepatic malondialdehyde (MDA) concentration, as well as decreased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) concentration, and this was in good agreement with the results of serum aminotransferase activity and histopathological examinations. Taken together, our results demonstrate that kaurene glycosides induce hepatotoxicity in mice by way of its induction of oxidative stress as lipid peroxidation in liver, which merited further studies. Therefore, these toxic constituents explain, at least in part, the hepatotoxicity of X. strumarium L. in traditional medicine. PMID- 21699086 TI - Improved lipid profile in ovariectomized rats by red ginseng extract. AB - The effects of red ginseng extract on lipid metabolism were examined in ovariectomized rats. Twenty-four female Sprague-Dawley rats (210 +/- 20 g) were studied for 10 weeks. The rats were divided into four groups: (I) "sham" non ovariectomized rats treated with olive oil, (II) control ovariectomized rats treated with olive oil, (III) ovariectomized rats treated with 0.5 mg/kg 17beta estradiol in olive oil, and (IV) ovariectomized rats treated with 5mg/kg red ginseng extract in olive oil. Red ginseng extract induced significant reductions in total cholesterol, low density lipoprotein cholesterol/total cholesterol, high density lipoprotein cholesterol/total cholesterol, and low density lipoprotein cholesterol/high density lipoprotein cholesterol, implying the effectiveness of ginseng in targeting postmenopausal symptoms. PMID- 21699087 TI - Isolation of two new bioactive proanthocyanidins from Cistus salvifolius herb extract. AB - Two new proanthocyanidins, epigallocatechin-3-O-p-hydroxybenzoate-(4beta-->8) epigallocatechin (1) and epigallocatechin-3-O-p-hydroxybenzoate-(4beta-->8) epigallocatechin-3-O-gallate (2) in addition to the known compound epigallocatechin-(4beta-->6)-epigallocatechin-3-O-gallate (3), were isolated from the air-dried herb of Cistus salvifolius. The chemical structures were determined on the basis of 1D-and 2D-NMR-spectra (HSQC, HMBC) of their peracetylated derivatives, MALDI-TOF-mass spectra, and by acid-catalysed degradation with phloroglucinol. The isolated compounds 1-3 and the water extract of C. salvifolius herb were tested for their inhibitory activities against COX-1 and COX-2. Compound 2 showed the strongest inhibitory effect on COX-2 followed by compound 3, compound 1 and the water extract, while compounds 1-3 exhibited moderate in vitro inhibition against COX-1. PMID- 21699088 TI - Biotransformation of extracted digitoxin from Digitalis lanata by Streptomyces. AB - The biotransformation of digitoxin and some of its derivatives extracted from Digitalis lanata by Streptomyces isolated species was investigated. Cultures of a Streptomyces strain designated EUSA2003B, isolated from an Egyptian soil sample, efficiently induced selective 12beta-hydroxylation of the steroid aglycone of digitoxin (DT) and its alpha-acetyl and beta-methyl derivatives. The transformation reaction was performed within a 5-day fermentation process, products were isolated and their aglycone moiety was obtained by acid hydrolysis and their structures were elucidated by 13C and 1H NMR. The biotransformation resulted mainly digoxin (DG, approximately 87%), meanwhile, digoxigenone (DGON, approximately 7.0%) was also afforded as a side product. The present study revealed that: 1-Streptomyces isolate EUSA2003B harbors its specific 12beta hydroxlase and has the capability to transform DT and it's alpha-acetyl and beta methyl derivatives into their corresponding digoxins at reasonable yields. 2-The minor structural differences in the trisaccharide side chain seemed ineffective on the transformational capability of this organism. 3-The Streptomyces might also possess a specific glycosidase that splits the saccharidic side chain beside another dehydrogenase that oxidizes C3 at the steroid nucleus into its ketone form (DGON). PMID- 21699089 TI - Skin penetration of silica microparticles. AB - Knowledge about skin penetration of nano- and microparticles is essential for the development of particle-core drug delivery systems and toxicology. A large number of studies have been devoted to metallic particle penetration. However, little work has been published about the importance of chemical material properties of the particles and the skin penetration effect of the applied formulation. Here, we investigated the penetration of 3 microm silica particles in water and in a 65% ethanolic plant extract on ex vivo human skin using scanning electron microscopy. Contrary to most other microsphere skin studies, we observed for the first time that 3 microm silica particles can penetrate the living epidermis. Moreover, when formulated in the ethanolic medium, particles even reach the dermis. The deviating chemical properties of silica compared to previously investigated microparticles (titanium dioxide, zinc oxide) and confounding effect of the formulation in which the silica microparticles are presented, is thus demonstrated. PMID- 21699090 TI - Design of a drug delivery system with bimodal pH dependent release of a poorly soluble drug. AB - A delivery system which provides bimodal pH dependent release of poorly water soluble carvedilol in gastric and intestinal environment was designed. Preparation of solid dispersion with porous silica ensured a significantly higher dissolution rate of carvedilol in acidic and alkaline media in comparison to pure drug, while granulation of that solid dispersion with enteric polymer dispersion resulted in diminished immediate release in acidic media and fast release of the remaining drug in alkaline media. The ratio in quantities of first vs. second release was controlled with amount of enteric polymer dispersion used for granulation process. Desired 25 mg release of carvedilol at pH values 1.2 and 6.8 was achieved when 1.80 g of polymer per 1.0 g of solid dispersion (drug to silica ratio= 0.25 g : 2.0 g) was used. PMID- 21699091 TI - Drug safety and efficacy impaired by quality failure. AB - The three main pillars of drug evaluation are quality, safety and efficacy. Each marketing authorization dossier has to demonstrate conformity with quality, safety and efficacy requirements separately. While this is justifiable, it may nevertheless lead to some important problems being overlooked. The relationship between these three aspects of a medicinal product can be of great importance. Little is said about how quality can affect safety or even efficacy. It is worth discussing these connections in order to assess side-effects appropriately and to distinguish between quality failures and real pharmacovigilance problems. Not every side-effect is a result of the drug's pharmacodynamic or pharmacokinetic properties or other therapy-related issues such as interactions. Sometimes a patient complaint is caused by substandard quality of the drug. This possibility should never be ignored in any assessment of side-effects. This paper presents a useful check-list of quality failures that can endanger drug safety. PMID- 21699092 TI - Assessment of the antihistomonal effect of paromomycin and tiamulin. AB - Histomonosis, a parasitic disease of galliformes and sporadically of other birds caused by Histomonas meleagridis, can result in very high mortality, especially in turkeys. The ban on the last antihistomonal drug prompted an urgent search for alternative prevention and treatment strategies. As both paromomycin and tiamulin have been reported to have antihistomonal activity, these antibiotics were investigated in vitro by adding two-fold serial dilutions ranging from 12.5 to 400 microg/mL to cultures of H. meleagridis. Controls (no antibiotics, or 12.5 microg or 400 microg/mL dimetridazole) were included. Parasites were counted after 3, 20, 28, 44, 51, and 71 hours of incubation. Tiamulin did not have a clear antihistomonal effect, but paromomycin had an inhibitory effect at all concentrations tested. The latter antibiotic was subsequently examined in an in vivo study. Five groups of 20 1-day-old poults, matched by weight and sex, were either not treated (infected and uninfected control groups) or treated with paromomycin (100, 200, or 400 ppm) added to their feed. After 2 weeks all groups, except for the uninfected control group, were intracloacally inoculated with 200,000 histomonads per bird. A clear dose-response effect was found for paromomycin. In the 100-ppm paromomycin group, mortality was similar to that in the untreated control group, whereas about half of the birds died in the 200-ppm paromomycin group; almost complete protection against histomonosis was seen in the 400-ppm paromomycin group. This study shows that paromomycin supplied in feed at 400 ppm is a potentially preventive strategy against H. meleagridis. PMID- 21699093 TI - Multiple small-intestine intussusceptions: a complication of purpura haemorrhagica in a horse. AB - A Belgian draft horse stallion presented with classical signs of purpura haemorrhagica: oedema of the distal limbs, ventral abdomen and head, ecchymotic haemorrhage of mucous membranes, epistaxis, fever, lethargy, reluctance to move, and anorexia. Serum chemistry revealed a highly elevated gamma-globulin fraction. Streptococcal lymphadenitis (strangles) had been present on a neighbouring farm in the past few months. After an initial positive response to therapy with benzylpenicillin, flunixin and dexamethasone, the horse's condition deteriorated suddenly on day 4 of hospitalization, with signs of severe endotoxaemia and small intestine obstruction. The horse was euthanized because of its poor prognosis and because of economic considerations. On necropsy, large serosal haemorrhages in the small and large intestine and multiple jejunojejunal intussusceptions were found. Intussusception is a well-known complication in children with Henoch Schonlein purpura, a human autoimmune disease resembling purpura haemorrhagica in horses. To the author's knowledge, this is the first report to describe intussusception as a complication of purpura haemorrhagica in a horse. PMID- 21699094 TI - Movement variability in the golf swing: theoretical, methodological, and practical issues. PMID- 21699095 TI - BMI-referenced cut-points for recommended daily pedometer-determined steps in Australian children and adolescents. AB - The purpose of this study was to establish sex-specific criterion-referenced standards for pedometer-determined physical activity related to body mass index (BMI)-defined weight status among youth. We analyzed data from 7-16-year-old boys (n = 338) and girls (n = 337) and used pedometer-assessed physical activity and anthropometric data to derive average steps/day and BMI. Sex-specific criterion referenced standards for steps/day relating to healthy weight and overweight/obese were determined using the contrasting groups method. Healthy weight children took more steps/day than overweight or obese (boys: 14,413 vs. 12,088, and girls: 12,562 vs. 10,114, respectively; p < .001). The optimal BMI referenced cut-point emerging flom our sample was 16,000 steps/day for both boys and girls. Our results and those reported elsewhere suggest that youth take insufficient pedometer-determined steps/day to avoid becoming overweight. PMID- 21699096 TI - Developmental and contextual risks of social physique anxiety among female athletes. AB - In the present study, we examined developmental and contextual factors that may increase the odds of reporting higher social physique anxiety (SPA) among 404 adolescent athletes 11 to 16 years old. Findings showed older, later maturing athletes past peak height velocity and with greater body mass index (BMI) reported higher SPA. Individual aesthetic sport athletes were older at menarche, had lower BMI, and reported higher SPA. The odds of reporting higher SPA were 4.5 times higher (odds ratio = 4.61) for individual aesthetic sport athletes than for nonaesthetic sport athletes. Team aesthetic sport contexts were not implicated in SPA risk. Results are discussed in terms of self-selection away from individual aesthetic sports and the relevance of physical size and puberty in the SPA construct. PMID- 21699097 TI - Learning from the experts: gaining insights into best practice during the acquisition of three novel motor skills. AB - The amount and quality of practice predicts expertise, yet optimal conditions of practice have primarily been explored with novice learners. Ten expert musicians and ten novices practiced disc-throwing skills under self-regulated conditions. A third novice group practiced with the same schedule as the music experts (yoked). The groups did not differ in terms of the amount of contextual interference, only in terms of when in-practice interference was introduced. The music experts progressed from a more blocked to random schedule which was opposite to the novices. This resulted in more accurate performance in retention for the experts in comparison to both novice groups (self-scheduled and yoked). The music expert and yoked groups showed higher form scores than the novice self-scheduled group, which might be related to the greater frequency of augmented information for these groups. There was no evidence that non-task-domain experts choose a more random practice schedule than novices, but in accord with good practice principles, they gradually introduced high amounts of interference into their practice. This strategy was associated with less error in retention for the experts. Because the yoked group showed more error than the music experts, the advantage of this schedule was also performance dependent. PMID- 21699098 TI - Acquisition of a complex basketball-dribbling task in school children as a function of bilateral practice order. AB - The purpose of this study was to investigate order-of-practice effects for the acquisition of a complex basketball skill in a bilateral transfer paradigm. The task required participants to dribble as fast as possible in slalom-like movements across six javelins and return to the initial position. Fifty-two right handed school children (M age = 11.7years) practiced this skill in eight sessions over 4 weeks under one of two training schedules: (a) with the dominant hand, before changing to their nondominant hand (D-ND group), or (b) with the nondominant hand, before changing to the dominant hand (ND-D group). All tests were conducted with the right hand or the left hand only, and a transfer test was given with both hands alternating. The results of a retention test yielded significantly larger learning gains for the ND-D group as compared to the D-ND group. It is interesting that this performance advantage was independent of the respective hand tested. The same pattern of result was found in the transfer test, with significantly shorter movement times for the ND-D group with both hands alternating. Such order-of-practice effects for the acquisition of complex skills can be explained with hemispheric brain asymmetries for the processing of specific task requirements. PMID- 21699099 TI - Effects of strategy use on children's motor performance in a continuous timing task. AB - The purposes of this study were to associate age-related performance deficits in children with the use of recall strategies and to determine whether children who performed poorly in cycling would benefit from learning a recall strategy. In Experiment 1, 18 younger children (ages 5-7years) and 18 older children (ages 8 10 years) were asked to recall selected pedaling cadences. The majority of the older children used strategies and performed with less error than the younger children. In Experiment 2, children with a high number of errors in Experiment 1 were assigned to an experimental or a control group. The children in the experimental group were taught to use a specific recall strategy. The results showed that children who received the instruction in strategy use improved their performance. PMID- 21699100 TI - New walkers with Down syndrome use cautious but effective strategies for crossing obstacles. AB - Perception of affordances research in children with developmental disabilities has only examined well practiced skills. Ten toddlers with Down syndrome and 10 with typical development walked across a GAITRite mat, with and without an obstacle. We coded the toddlers' behaviors after 1 and 3 months of walking experience when they encountered the obstacle (avoid, crawl, error and walk successfully) and calculated gait parameters (step length, width, and velocity). Both groups actively explored their affordances. Despite similar decreases in step length and velocity when approaching the obstacle, toddlers with Down syndrome were more likely to select successful but conservative crawling strategies that minimized balance requirements and reduced risk of falling. Group differences were due to risk management rather than difficulty perceiving affordances. PMID- 21699101 TI - The overarm-throwing pattern among U-14 ASA female softball players: a comparative study of gender, culture, and experience. AB - A developmental description of overarm-throwing characteristics of U-14female ASA softballplayers is presented here. Comparisons were made between these athletes and teens of similar age in the United States (Runion, Roberton, & Langendorfe 2003) and in Germany (Ehl, Roberton, & Langendorfer, 2005). A majority of the softball players demonstrated the most advanced developmental levels for the backswing foot, humerus, and forearm components. Seventy percent (n = 26) demonstrated a Level 2 trunk, while 30% (n = 11) demonstrated a differentiated trunk, Level 3. The average throwing velocity was 62.58 ft/s (19.07 m/s). Comparisons were made to girls with less throwing experience in the United States (Runion et al.) and Germany (Ehl et al.); the softball players threw with greater velocity (9.12ft/s [2.77 m/s]and 15.89 ft/s [4.84 m/s], respectively) and demonstrated superior trunk, humerus, and forearm actions. The boys from both countries threw the ball faster than the softball players. Significant chi-square analyses found the softball players had superior humeral actions (Level 3) compared to the German boys and superior forearm actions (Level 3) compared to both groups of bays. Experience seems to have an impact when comparisons among girls are made; yet, explanations for differences seen between boys and girls still remain unclear and warrant further research. PMID- 21699102 TI - Excellence in coaching: the art and skill of elite practitioners. AB - During this study, 10 expert coaches were interviewed to examine their views on aspects of their individual coaching practice. Four themes emerged from the interviews: (a) the long-term approach, (b) the authentic coaching environment, (c) creating a learning environment, and (d) the quality and quantity of training sessions. These coaches were consistent in their attempts to facilitate learning experiences for the athletes, while setting high standards in both training and competition. The study's findings show that expert coaches have to orchestrate a large number of variables when planning and executing a training session, and their success depends on their coaching knowledge and their skill at contextualizing the necessary components for specific situations. PMID- 21699103 TI - Physical education teachers' beliefs and intentions toward teaching students with disabilities. AB - The Theory of Planned Behavior (TpB) measures the effect that individuals' behavioral belief normative belief and control beliefs have on their intentions to perform a specific behavior The purpose of this study was to examine: (a) whether the TpB could predict physical educators' intentions and (b) whether physical educators' intentions and control beliefs could predict their self reported teaching behavior. A sample of 220 physical educators completed the questionnaire. Stepwise multiple regression analysis revealed that the TpB significantly predicted physical educators' intentions, F(3, 216) = 57.21, p < .01. However, only intention was a significant predictor of physical educators'self-reported behavior in teaching students with disabilities, F(2, 123) = 34.04, p < .01. PMID- 21699104 TI - Using social cognitive theory to predict physical activity and fitness in underserved middle school children. AB - Few researchers have used social cognitive theory and environment-based constructs to predict physical activity (PA) and fitness in underserved middle school children. Hence, we evaluated social cognitive variables and perceptions of the school environment to predict PA and fitness in middle school children (N = 506, ages 10-14 years). Using multiple regression analyses we accounted for 12% of the variance in PA and 13-21% of the variance in fitness. The best predictors of PA were barrier self-efficacy, classmate social support, and gender; whereas, only gender predicted fitness. The results affirmed the importance of barrier self-efficacy and gender differences. Our findings regarding classmate social support are some of the first to illuminate the importance of school-specific peers in promoting PA. PMID- 21699105 TI - Heart rates of elementary physical education students during the dancing classrooms program. AB - We examined how different types of dance activities, along with their duration, influenced heart rate responses among fifth-grade physical education students (N = 96) who participated in the Dancing Classrooms program. Results indicated that the overall Dancing Classrooms program elicits a moderate cardiovascular heart rate response (M = 124.4 bpm), in which 47% of class time was spent above a 60% maximal heart rate threshold. The swing dance in particular (M = 143.4 bpm) stimulated a much higher heart rate level than all other dances in the program, with a mean heart rate change of 52.6 bpm. Girls (127.3 bpm) achieved marginally higher heart rates (p = .059) than boys (121.1 bpm). PMID- 21699106 TI - VO2 prediction and cardiorespiratory responses during underwater treadmill exercise. AB - We compared cardiorespiratory responses to exercise on an underwater treadmill (UTM) and land treadmill (LTM) and derived an equation to estimate oxygen consumption (VO2) during UTM exercise. Fifty-five men and women completed one LTM and five UTM exercise sessions on separate days. The UTM sessions consisted of chest-deep immersion, with 0, 25, 50, 75, and 100% water-jet resistance. All session treadmill velocities increased every 3 min from 53.6 to 187.8 m x min( 1). Cardiorespiratory responses were similar between LTM and UTM when jet resistance for UTM was 50%. Using multiple regression analysis, weight-relative VO2 could be estimated as: VO2 (mLO2 c kg(-1) x min(-1)) = 0.19248 x height (cm) + 0.17422 x jet resistance (% max) + 0.14092 x velocity (m x min(-1)) -0.12794 x weight (kg)-27.82849, R2 = .82. Our data indicate that similar LTM and UTM cardiorespiratory responses are achievable, and we provide a reasonable estimate of UTM VO2. PMID- 21699108 TI - There is an "I" in TEAM: narcissism and social loafing. AB - We investigated narcissism as a moderator of social loafing on a physical performance task. High and low narcissistic individuals twice performed a cycling task in same-sex teams of three: once when identifiability was low; and once when identifiability was high. A significant interaction between narcissism and identifiability was revealed, F(1, 40) = 4.09, p < .05, eta2 = .09 for performance. Follow-up tests indicated that high narcissists' performance significantly increased with greater identifiability, whereas low narcissists displayed no such performance differences. Results suggested that this effect was due to an increase in narcissists' on-task effort (ratings of perceived exertion and heart rate) when they knew that their performance was to be identified. PMID- 21699107 TI - Revisiting the relationship between exercise heart rate and music tempo preference. AB - In the present study, we investigated a hypothesized quartic relationship (meaning three inflection points) between exercise heart rate (HR) and preferred music tempo. Initial theoretical predictions suggested a positive linear relationship (Iwanaga, 1995a, 1995b); however, recent experimental work has shown that as exercise HR increases, step changes and plateaus that punctuate the profile of music tempo preference may occur (Karageorghis, Jones, & Stuart, 2008). Tempi bands consisted of slow (95-100 bpm), medium (115-120 bpm), fast (135-140 bpm), and very fast (155-160 bpm) music. Twenty-eight active undergraduate students cycled at exercise intensities representing 40, 50, 60, 70, 80, and 90% of their maximal HR reserve while their music preference was assessed using a 10-point scale. The Exercise Intensity x Music Tempo interaction was significant, F(6.16, 160.05) = 7.08, p < .001, 7,2 = .21, as was the test for both cubic and quartic trajectories in the exercise HR-preferred-music-tempo relationship (p < .001). Whereas slow tempo music was not preferred at any exercise intensity, preference for fast tempo increased, relative to medium and very fast tempo music, as exercise intensity increased. The implications for the prescription of music in exercise and physical activity contexts are discussed. PMID- 21699110 TI - Attentional bias for exercise-related images. AB - This research examined attentional bias toward exercise-related images using a visual probe task. It was hypothesized that more-active participants would display attentional bias toward the exercise-related images. The results showed that men displayed attentional bias for the exercise images. There was a significant interaction of activity level by gender, and simple slopes analysis showed that active women displayed attentional bias toward the exercise-related images and inactive women displayed attentional bias toward the control images. A similar analysis with explicit attention to the pictures as the outcome variable was not significant. These findings confirm that attention for exercise-related images can be captured automatically regardless of whether people report they are attending to them. PMID- 21699109 TI - Effects of a 12-week resistance exercise program on physical self-perceptions in college students. AB - There is an increase in literature suggesting exercise can promote positive changes in physical self-perceptions that can manifest as an increase in global self-esteem. In the present study, we assessed self-esteem using the hierarchical framework of the Exercise and Self-Esteem Model (EXSEM) along with cognitive facets at the subdomain level (e.g., competence, certainty, importance, and ideal self-discrepancy). This allowed for an analysis of cognitive facets as possible contributors to changes in physical self-perceptions. We addressed these aims with a sample of 120 college-age adults who completed a 12-week resistance exercise program. Results indicated significant improvements in self-perception constructs at all levels of the EXSEM. The hierarchical structure of the EXSEM was partially supported, as we observed successively smaller improvements at each level of the model (e.g., self-esteem showed lesser improvements than physical self-worth). In addition, a path model developed to explain the impact of strength changes on self-esteem proved a good fit for the data. Results are discussed in terms of contemporary models of self-perception, potential mediators of exercise on self-esteem, and the need to consider cognitive facets of self perception. PMID- 21699111 TI - Muscle dysmorphia, gender role stress, and sociocultural influences: an exploratory study. AB - Our study explored the contribution of gender role stress (GRS) and sociocultural appearance demands to symptoms of muscle dysmorphia (MD) in a college sample of 219 women and 154 men. For women, five GRS subscales, sociocultural appearance demands, age, and frequency of aerobic exercise predicted MD symptoms (model R2 = .33; F(8,210) = 12.81, p < . 001); for men, only one GRS subscale, age, and sociocultural appearance demands predicted MD symptoms (model R2 = .40; F(3,150) = 9.52, p < .001). Post hoc analyses revealed that a small number of items explained a substantial portion of the variation, suggesting that MD may be more related to specific perceptions of pressure to attain an attractive body than to global gender role stress. PMID- 21699112 TI - Striving to be in the profession and of It: the African American experience in physical education and kinesiology. AB - This study analyzes the experiences of African Americans in the physical education and kinesiology profession since the late 1850s. Using a variety of primary and secondary source material, we place special emphasis on the experiences of African American physical educators in higher education and in the American Alliance for Health, Physical Education, Recreation and Dance and its southern, regional, and state chapters. Apparent from this examination is that African Americans have experienced various forms of racially discriminatory practices in physical education and kinesiology and have found it extraordinarily difficult to assume leader ship positions in the profession and be acknowledged for their scholarly and academic accomplishments. PMID- 21699113 TI - Positive functions of emotions in achievement sports. AB - This article presents the results of two research projects on the emotions of men engaged in achievement outdoor sports. The conditions were analyzed under which emotions carry out positive functions. The question strikes us as a fundamental one, because it is of crucial importance when it comes to increasing sportspeople's success. The theoretical framework applied was that of microfunctionalism. The method, of a qualitative nature, was based on in-depth interviews, each lasting between 1.5 and 2 hr with a total of 14 sportspersons. The results show that in order for emotions to fulfill positive functions, three conditions must be met: (a) existence of passion, which, with its dialectical character of pleasure and suffering underlies all the other emotions and acts as a motor that pushes the sportsperson forward, despite all the contretemps he might meet on the way; (b) intense emotion work, which may be conducted only if accompanied by knowledge and experience of the natural environment acquired over the years; and (c) conciliation between emotion work and the feeling rules characteristic of each sport subculture. For those individuals who pursue achievement in outdoor sports, these results will provide more concrete indications regarding how to carry out the emotional preparation required for these sports. PMID- 21699114 TI - Body mass index and skinfold thickness measurements as body composition screening tools in Caucasian and African American youth. PMID- 21699115 TI - The effect of climbing wall use on the grip strength of fourth-grade students. PMID- 21699116 TI - Effect of a mastery climate motor program on object control skills and perceived physical competence in preschoolers. PMID- 21699117 TI - Feedback after good versus poor trials affects intrinsic motivation. PMID- 21699118 TI - How much walking is needed to improve cardiorespiratory fitness? An examination of the 2008 Physical Activity Guidelines for Americans. PMID- 21699119 TI - The field effect. PMID- 21699120 TI - Botanical briefs: kiwifruit (Actinidia chinensis). PMID- 21699121 TI - Symptomatic dermatographism: current concepts in clinical practice with an emphasis on the pediatric population. AB - Symptomatic dermatographism reflects an exaggerated cutaneous response to the physical stimulus of pressure. Some consider it a common type of childhood physical urticaria. Its etiology can vary widely from drug reactions and infectious agents to systemic diseases and genetic inheritance. The mechanism is thought to be related to histamine degranulation due to a mechano-immunologic trigger, leading to the common symptoms of pruritus and burning in areas exposed to increased pressure, such as tight clothing, belts, and waistbands. The diagnosis typically is made with a blunt object such as a tongue blade or unopened ball-point pen pressed along the back and/or forearm, which elicits urtication. The mainstay of treatment is H1- and H2-receptor antagonists but also can include immunosuppressive agents, steroids, and phototherapy for refractory or severe cases. PMID- 21699122 TI - Simple onycholysis. AB - Onycholysis may be defined as separation of the nail plate from the underlying nail bed due to disruption of the onychocorneal band. Simple onycholysis is a common condition seen in the dermatologist's office. It is not associated with inheritance, systemic diseases or drugs, dermatophyte infections, warts or neoplasms, or primary dermatologic disease such as psoriasis or lichen planus. It is generally assumed that the longer the disorder has been present, the less likely it is to resolve. As a result, we provide directions that should be given to patients presenting with simple onycholysis. PMID- 21699123 TI - What is your diagnosis? Tinea nigra. PMID- 21699124 TI - Quick saturation of a cotton tip applicator using a handheld cryosurgical spray device. PMID- 21699125 TI - Subcutaneous sarcoidosis in a melanoma scar. AB - Cutaneous sarcoidosis often has been referred to. as the great imitator because skin lesions can present with various morphologies. Skin lesions may be the only site of involvement or may accompany systemic disease. Occasionally, sarcoidosis also may infiltrate scars from prior trauma, tattoos, or surgery. We report a case of subcutaneous sarcoidosis limited to a melanoma scar without any other cutaneous or systemic involvement. Familiarity with and proper diagnosis of cutaneous sarcoidosis can allow for appropriate systemic screening and timely management of the disease. PMID- 21699126 TI - Primary adenoid cystic carcinoma of the skin. AB - We report a case of primary adenoid cystic carcinoma of the skin in a 44-year-old Brazilian man that was present for 6 years with no metastasis. It is a rare malignant neoplasm of the eccrine gland. Metastases have been found in a few cases, usually to the lungs or lymph nodes. This neoplasm microscopically presents with large nests of cells with adenoid or cribriform features and many epithelial small solid islands. Histopathologic analysis is necessary for diagnosis. PMID- 21699127 TI - Granuloma annulare in a zoster scar of a patient with multiple myeloma. AB - Granuloma annulare (GA) is a common benign inflammatory skin disorder with an unknown pathogenesis. Granuloma annulare occurring in prior sites of herpes zoster (HZ) infection is rarely reported; however, it is the most common granulomatous reaction described at these sites. We report a case of localized GA on scars of prior HZ infection in a patient with multiple myeloma who had received an autologous peripheral stem cell transplant (PSCT). This patient's GA was successfully treated with intralesional corticosteroid injections. PMID- 21699128 TI - Recurrent and metastatic primary cutaneous mucinous carcinoma after excision and Mohs micrographic surgery. AB - Primary cutaneous mucinous carcinoma is a neoplasm of sweat gland origin. Optimal management guidelines have not been established for this rare tumor. It is treated most commonly by traditional excision and more recently by Mohs micrographic surgery in an effort to decrease its recurrence rate. We report a case of primary cutaneous mucinous carcinoma with multiple recurrences and metastases following 3 excisions and 2 Mohs procedures, highlighting the potential difficulty in treating this cancer and suggesting the need for a more effective treatment approach. PMID- 21699129 TI - Interaction between adalimumab with concurrent pregabalin and duloxetine administration in a psoriasis patient with diabetic peripheral neuropathy. PMID- 21699130 TI - The appearance of facial foundation cosmetics applied after metronidazole gel 1%. AB - The purpose of this study was to assess the cosmetic appearance of commonly marketed facial cosmetics when used after the application of metronidazole gel 1%. An observational. open-label, single-site study was conducted with women (N=30) aged 20 to 75 years and diagnosed with moderate papulopustular rosacea (investigator global severity score of 3). After cleansing the face with a gentle skin cleanser, participants applied metronidazole gel 1% once daily before applying their usual facial foundation. Two surveys were conducted: (1) investigator assessment of cosmetic appearance; and (2) participant assessment of cosmetic appearance. The investigator also evaluated erythema, disease severity, and tolerability at baseline and week 2. Adverse events were collected. The 28 per-protocol (PP) participants had a mean age (standard deviation [SD]) of 54.0 (10.3) years and a mean duration (SD) of rosacea of 15.4 (13.2) years. The median response score for both the investigator and participant assessments of cosmetic appearance was 10 (best) for each survey question. Signs and symptoms of rosacea did not increase with use of metronidazole gel 1% and the participants' selected cosmetic regimen. At baseline all 28 participants were classified as having moderate erythema. At week 2, 18 (64%) participants were classified as having moderate erythema and 10 (36%) mild. At baseline all 28 (100%) participants were classified as having moderate rosacea according to the investigator global severity score. At week 2, 10 (36%) participants were classified as mild and 18 (64%) moderate. In addition, few participants reported cutaneous irritation during the study. At week 2, 10 participants had dryness, 2 had itching, 8 had scaling, and 2 had stinging/burning. According to surveys completed by the investigator and the participants themselves, most participants had a good cosmetic appearance with their facial foundation cosmetics that were applied after metronidazole gel 1%. The use of various cosmetic regimens after application of metronidazole gel 1% did not cause rosacea symptoms to worsen and treatment was well-tolerated. PMID- 21699131 TI - Comparative susceptibility of Deschutes River, Oregon, Tubifex tubifex populations to Myxobolus cerebralis. AB - Dams along the Deschutes River (DR) in central Oregon have blocked fish migration for over 40 years. Reestablishment of anadromous fish runs above the dams as part of a fish passage plan may introduce fish pathogens, such as Myxobolus cerebralis, the myxozoan parasite that causes salmonid whirling disease. This parasite is carried by adult salmon that stray into the DR system during their return to enzootic areas of the upper Columbia River basin, and it is now known to be established in at least one lower DR tributary. The life cycle of M. cerebralis involves two obligate hosts: a salmonid and the oligochaete worm Tubifex tubifex. To determine the likelihood of parasite establishment above the DR dams, we conducted benthic sediment surveys between 1999 and 2007 and found that T. tubifex had a patchy distribution and low relative abundance. Mitochondrial 16S ribosomal DNA gene analysis indicated that two lineages of T. tubifex (III and VI) were present both above and below the dams. Laboratory susceptibility studies to characterize differences in infection prevalence and parasite production between nine T. tubifex populations revealed that production varied considerably among exposed groups and was proportional to the number of lineage III worms present. Our results suggest that M. cerebralis could become established above the dams if infected fish are allowed passage into the upper DR system, but not all areas of the DR basin can be classified as having the same likelihood for parasite establishment, and the potential impact will be location dependent. PMID- 21699132 TI - Iridovirus infections among Missouri River sturgeon: initial characterization, transmission, and evidence for establishment of a carrier state. AB - Iridovirus infections of the integument were associated with disease and mortality among hatchery-reared populations of juvenile pallid sturgeon Scaphirhynchus albus and shovelnose sturgeon S. platorynchus from the Missouri River. Virus-infected cells in the integument of fins and body were greatly enlarged, possessed pleomorphic and eccentric nuclei, and exhibited an amphophilic to eosinophilic staining of the cytoplasm in hematoxylin-and-eosin stained sections. Virus particles found in the host cell cytoplasm were composed of an outer hexagonal capsid measuring 254 nm in diameter and surrounding a dense nucleoid. Despite numerous attempts, the virus could not be propagated on routine cell lines used in fish viral diagnostics or from established cell lines from white sturgeon Acipenser transmontanus, pallid sturgeon, or shovelnose sturgeon. Bath exposures of healthy juvenile pallid sturgeon to a crude extract or a 0.45 microm-filtered extract from the fins of infected fish resulted in transmission of the virus and mortality. At water temperatures of 15 degrees C, the first deaths occurred at approximately 1 month; mortality peaked between 50 and 60 d postexposure, after which surviving fish recovered. Presence of the virus was confirmed among dead and moribund pallid sturgeon by both histology and detection of viral DNA by polymerase chain reaction methods. Feeding of infected tissues and cohabitation with virus-infected shovelnose sturgeon also resulted in successful virus transmission to juvenile pallid sturgeon. Virus infections among experimentally exposed pallid sturgeon that recovered from clinical episodes persisted for at least 8.5 months, and these apparently healthy fish transmitted the virus and disease to juvenile pallid sturgeon by cohabitation. The newly described Missouri River sturgeon iridovirus (MRSIV) as found in pallid sturgeon and shovelnose sturgeon shares many properties with a group of iridoviruses associated with serious skin and gill infections in several species of sturgeon. PMID- 21699133 TI - Comparative evaluation of molecular diagnostic tests for Nucleospora salmonis and prevalence in migrating juvenile salmonids from the Snake River, USA. AB - Nucleospora salmonis is an intranuclear microsporidian that primarily infects lymphoblast cells and contributes to chronic lymphoblastosis and a leukemia-like condition in a range of salmonid species. The primary goal of this study was to evaluate the prevalence of N. salmonis in out-migrating juvenile hatchery and wild Chinook salmon Oncorhynchus tshawytscha and steelhead O. mykiss from the Snake River in the U.S. Pacific Northwest. To achieve this goal, we first addressed the following concerns about current molecular diagnostic tests for N. salmonis: (1) nonspecific amplification patterns by the published nested polymerase chain reaction (nPCR) test, (2) incomplete validation of the published quantitative PCR (qPCR) test, and (3) whether N. salmonis can be detected reliably from nonlethal samples. Here, we present an optimized nPCR protocol that eliminates nonspecific amplification. During validation of the published qPCR test, our laboratory developed a second qPCR test that targeted a different gene sequence and used different probe chemistry for comparison purposes. We simultaneously evaluated the two different qPCR tests for N. salmonis and foundthat both assays were highly specific, sensitive, and repeatable. The nPCR and qPCR tests had good overall concordance when DNA samples derived from both apparently healthy and clinically diseased hatchery rainbow trout were tested. Finally, we demonstrated that gill snips were a suitable tissue for nonlethal detection of N. salmonis DNA in juvenile salmonids. Monitoring of juvenile salmonid fish in the Snake River over a 3-year period revealed low prevalence of N. salmonis in hatchery and wild Chinook salmon and wild steelhead but significantly higher prevalence in hatchery-derived steelhead. Routine monitoring of N. salmonis is not performed for all hatchery steelhead populations. At present, the possible contribution of this pathogen to delayed mortality of steelhead has not been determined. PMID- 21699134 TI - Evaluation of emamectin benzoate for the control of experimentally induced infestations of Argulus sp. in goldfish and koi carp. AB - The effect of 0.2% emamectin benzoate (SLICE; Intervet/ Schering-Plough Animal Health, Roseland, New Jersey) administered in top-dressed, pelleted commercial fish feed was evaluated for control of freshwater Argulus sp. in goldfish Carassius auratus and koi carp, a variant of common carp Cyprinus carpio, in freshwater aquaria at 24-25 degrees C. Sixteen individually housed goldfish were each exposed to 37 Argulus. The number of fish lice attached to each fish at the start of the experiment was not determined; however, the total number of motile fish lice in each aquarium (on fish and in the water) was determined at the start and end of each experiment. Eight goldfish were fed the control diet (0 microg x kg fish biomass(-1) x d(-1)) and eight were fed the medicated diet (50 microg x kg fish biomass(-1) x d(-1)) for seven consecutive days. After treatment, fish louse infestation in controls was 20.5 +/- 1.5 (mean +/- SE) lice per fish. No Argulus were found on fish in the treated group. In a separate experiment, 10 individually housed koi were each exposed to 128 Argulus. Five koi were fed the control diet and five were fed a low-dose medicated diet (5 microg x kg fish biomass(-1) x d(-1)) for 7 d. After treatment, fish louse infestation among the controls was 14.6 +/- 3.8 lice per koi. No Argulus were found on koi in the treated group. Hence, a 7-d regimen of oral emamectin benzoate controlled experimental infestation of Argulus when administered to goldfish at 50 microg x kg fish biomass(-1) x d(-1) and to koi at 5 microg x kg fish biomass(-1) x d(-1). PMID- 21699135 TI - An evaluation of the influence of stock origin and out-migration history on the disease susceptibility and survival of juvenile Chinook salmon. AB - Various methods have been developed to mitigate the adverse effects of the Federal Columbia River Power System on juvenile Pacific salmon out-migrating through the Columbia River basin. In this study, we found that hatchery-reared spring Chinook salmon Oncorhynchus tshawytscha in the river are in varying degrees of health, which may affect delayed mortality and the assessment of the effectiveness of management actions to recover listed stocks (e.g., barging fish downstream versus leaving fish in the river). A laboratory disease challenge with Listonella anguillarum was completed on fish from Rapid River Hatchery and Dworshak National Fish Hatchery (NFH) with different out-migration histories: (1) transported by barge, (2) removed from the river before barging, or (3) left to travel in-river. Barged fish from Rapid River Hatchery experienced less mortality than fish from Dworshak NFH. No statistical differences were found between the hatcheries with fish that had in-river out-migration histories. We suggest that the stressors and low survival associated with out-migration through the hydropower system eliminated any differences that could have been present. However, 18-25% of the fish that were barged or collected before barging died in the laboratory before the disease challenge, compared with less than 2% of those that traveled in-river. Owing to disproportionate prechallenge mortality, the disease-challenged populations may have been biased; thus, they were also considered together with the prechallenge mortalities. The synthesis of prechallenge and disease-challenged mortalities and health characteristics evaluated during out-migration indicated that the benefit of barging was not consistent between the hatcheries. This finding agrees with adult survival and delayed mortality estimates for the individual hatcheries determined from adult returns. The results suggest that the health status of fish and their history before entering the hydropower system (hatchery of origin and out-migration path) are critical variables affecting the conclusions drawn from studies that evaluate mitigation strategies. PMID- 21699136 TI - Selectivity of kinase inhibitor fragments. AB - A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases. PMID- 21699137 TI - Effect of alcohols on aggregation behaviors of branched block polyether Tetronic 1107 at an air/liquid surface. AB - The aggregation behaviors of branched block polyether Tetronic 1107 (T1107) at an air/liquid surface was investigated in mixed solvents consisting of water and one of the following polar cosolvents: ethanol, n-propanol, ethylene glycol (EG), or glycerol (GLY). Surface tension measurements provide information about the effects of cosolvents on the critical micellization concentration (cmc), the standard Gibbs energy (DeltaG degrees (mic)), the maximum surface excess concentration (Gamma(max)), the minimum area per polyether molecule at the air/liquid surface (A(min)), and the standard free energy of adsorption (DeltaG degrees (ads)). The addition of ethanol and n-propanol to water disfavors the micellization and progressively increases the cmc of T1107, whereas the cmc decreases with the addition of EG and GLY. The values of DeltaG degrees (mic) of T1107 are all negative in mixed solvents, and their absolute values become smaller as the ethanol or n-propanol content increases but become larger as the EG or GLY content increases. The cosolvents have a significant effect on the surface adsorption and cmc, and the order is as follows: n-propanol-water > ethanol-water > water > EG-water > GLY-water. The octanol/water partition coefficient (log P) of the cosolvent is used to correlate the effects, and it could capture the effect of cosolvents on the cmc qualitatively. The surface dilational rheological properties of T1107 in water and water-alcohol mixtures were also studied by surface dilational viscoelasticity and surface tension relaxation measurements. The dilational elasticity decreases monotonously in the presence of ethanol or n-propanol. With the increasing concentration of EG and GLY, the dilational elasticity of T1107 passes through a maximum that coincides with the change in Gamma(max). PMID- 21699140 TI - Organocatalytic tail-to-tail dimerization of olefin: umpolung of methyl methacrylate mediated by N-heterocyclic carbene. AB - Highly selective tail-to-tail dimerization of methyl methacrylate has been realized by an N-heterocyclic carbene catalyst, giving dimethyl 2,5-dimethyl-2 hexenedioate with an E/Z ratio of 95:5 in 86% isolated yield. The umpolung mechanism is proposed on the basis of interception of the intermediates using ESI MS analyses and deuterium-labeling experiments. PMID- 21699139 TI - New synthetic methodology for the construction of 7-substituted farnesyl diphosphate analogs. AB - Through the use of a 1,2-metalate rearrangement, six 7-substituted farnesol analogs were generated in a concise manner. This new synthetic route allowed us to quickly prepare several diverse farnesyl diphosphate analogs with interesting biological activities against mammalian protein-farnesyl transferase. PMID- 21699141 TI - Synthesis of multiresponsive and dynamic chitosan-based hydrogels for controlled release of bioactive molecules. AB - An inexpensive, facile, and environmentally benign method has been developed for the preparation of multiresponsive, dynamic, and self-healing chitosan-based hydrogels. A dibenzaldehyde-terminated telechelic poly(ethylene glycol) (PEG) was synthesized and was allowed to form Schiff base linkages between the aldehyde groups and the amino groups in chitosan. Upon mixing the telechelic PEG with chitosan at 20 degrees C, hydrogels with solid content of 4-8% by mass were generated rapidly in <60 s. Because of the dynamic equilibrium between the Schiff base linkage and the aldehyde and amine reactants, the hydrogels were found to be self-healable and sensitive to many biochemical-stimuli, such as pH, amino acids, and vitamin B6 derivatives. In addition, chitosan could be digested by enzymes such as papain, leading to the decomposition of the hydrogels. Encapsulation and controlled release of small molecules such as rhodamine B and proteins such as lysozyme have been successfully carried out, demonstrating the potential biomedical applications of these chitosan-based dynamic hydrogels. PMID- 21699142 TI - Ab initio design of chelating ligands relevant to Alzheimer's disease: influence of metalloaromaticity. AB - Evidence supporting the role of metal ions in Alzheimer's disease (AD) has rendered metal ion chelation as a promising therapeutic treatment. The rational design of efficient chelating ligands requires, however, a good knowledge of the electronic and molecular structure of the complexes formed. In the present work, the coordinative properties of a set of chelating ligands toward Cu(II) have been analyzed by means of DFT(B3LYP) calculations. Special attention has been paid to the aromatic behavior of the metalated rings of the complex and its influence on the chelating ability of the ligand. Ligands considered have identical metal binding sites (through N/O coordination) and only differ on the kind and size of the aromatic moieties. Results indicate that there is a good correlation between the stability constants (log beta(2)) and the degree of metalloaromaticity determined through the I(NG) and HOMA indices; that is, the higher the metalloaromaticity, the larger the log beta(2) value. MOs and aromaticity descriptors confirm that present complexes exhibit Mobius metalloaromaticity. Detailed analysis of the nature of the Cu(II)-ligand bonding, performed through an energy decomposition analysis, indicates that ligands with less aromatic moieties have the negative charge more localized in the metalated ring, thus increasing their sigma-donor character and the metalloaromaticity of the complexes they form. PMID- 21699143 TI - Micropatterned arrays of porous silicon: toward sensory biointerfaces. AB - We describe the fabrication of arrays of porous silicon spots by means of photolithography where a positive photoresist serves as a mask during the anodization process. In particular, photoluminescent arrays and porous silicon spots suitable for further chemical modification and the attachment of human cells were created. The produced arrays of porous silicon were chemically modified by means of a thermal hydrosilylation reaction that facilitated immobilization of the fluorescent dye lissamine, and alternatively, the cell adhesion peptide arginine-glycine-aspartic acid-serine. The latter modification enabled the selective attachment of human lens epithelial cells on the peptide functionalized regions of the patterns. This type of surface patterning, using etched porous silicon arrays functionalized with biological recognition elements, presents a new format of interfacing porous silicon with mammalian cells. Porous silicon arrays with photoluminescent properties produced by this patterning strategy also have potential applications as platforms for in situ monitoring of cell behavior. PMID- 21699144 TI - Lithiation and delithiation of silicon oxycarbide single particles with a unique microstructure. AB - Single particles (11 and 13 MUm diameter) of a silicon oxycarbide (Si-O-C) glass were electrochemically analyzed using a microelectrode technique. A micromanipulator-guided nickel-plated rhodium-platinum microfilament (25 MUm diameter, 13 wt % rhodium) was used to maintain electrical contact to a single Si O-C glass particle in an organic solution containing 1 mol dm(-3) LiClO(4). The cyclic voltammograms of a single Si-O-C glass particle (11 MUm diameter) featured a characteristic sharp peak at ca. 0.1 V vs Li/Li(+), along with a broad peak and a shoulder, in the anodic reaction. This result indicates that there are several electrochemically active sites for lithium storage in the single Si-O-C glass particle. The first lithiation and delithiation capacities of a single Si-O-C glass particle (13 MUm diameter) were 1.67 nA h and 1.12 nA h, respectively, at 5 nA (4C rate) in the potential range 0.01-2.5 V vs Li/Li(+), leading to a Coulombic efficiency of 67%. These results are in good agreement with those observed in typical porous composite electrodes. The 13 MUm diameter particle gives 75% of the full-delithiation capacity even at 100 nA (80C rate), demonstrating that its intrinsic delithiation rate capability is suitable for practical purposes. Assuming that the Tafel equation is applicable to the delithiation of the single Si-O-C glass particle, the charge-transfer resistance tended to increase as lithium was released. PMID- 21699145 TI - Oxidation state analysis of a four-component redox series [Os(pap)2(Q)]n involving two different non-innocent ligands on a redox-active transition metal. AB - Complexes [Os(pap)(2)(Q)] (1-4) have been obtained and structurally characterized for pap = 2-phenylazopyridine and Q = 4,6-di-tert-butyl-N-aryl-o iminobenzoquinone (aryl = phenyl (1), 3,5-dichlorophenyl (2), 3,5-dimethoxyphenyl (3), or 3,5-di-tert-butylphenyl (4)). The oxidized form (3)(ClO(4))(2) was also crystallographically characterized while the odd-electron intermediates [Os(pap)(2)(Q)](+) (1(+)-4(+)) and [Os(pap)(2)(Q)](-) (2(-)) were investigated by electron paramagnetic resonance (EPR) and UV-vis-NIR spectroelectrochemistry in conjunction with density functional theory (DFT) spin density and time-dependent DFT (TD-DFT) calculations. The results from the structural, spectroscopic, and electrochemical experiments and from the computational studies allow for the assignments [Os(II)(pap(0))(2)(Q(0))](2+), [Os(II)(pap(0))(2)(Q(*-))](+), [Os(IV)(pap(*-))(2)(Q(2-))], and [Os(II)(pap(*-))(pap(0))(Q(2-))](-), with comproportionation constants K(c) ~ 10(3.5), 10(10), 10(18), and 10(5), respectively. The redox potentials and the comproportionation constants exhibit similarities and differences between Ru and Os analogues. While the Q-based redox reactions show identical potentials, the more metal-involving processes exhibit cathodic shifts for the osmium systems, leading to distinctly different comproportionation constants for some intermediates, especially to a stabilization of the neutral osmium compounds described in this article. The example [Os(pap)(2)(Q)](n) illustrates especially the power of combined structural and EPR analysis with support from DFT towards the valence state description of transition metal complexes incorporating redox non-innocent ligands. PMID- 21699146 TI - Structure and bonding energy analysis of cationic metal-ylyne complexes of molybdenum and tungsten, [(MeCN)(PMe3)4M=EMes]+ (M = Mo, W; E = Si, Ge, Sn, Pb): a theoretical study. AB - The molecular and electronic structures and bonding analysis of terminal cationic metal-ylyne complexes (MeCN)(PMe(3))(4)M=EMes](+) (M = Mo, W; E = Si, Ge, Sn, Pb) were investigated using DFT/BP86/TZ2P/ZORA level of theory. The calculated geometrical parameters for the model complexes are in good agreement with the reported experimental values. The M-E sigma-bonding orbitals are slightly polarized toward E except in the complex [(MeCN)(PMe(3))(4)W(SnMes)](+), where the M-E sigma-bonding orbital is slightly polarized toward the W atom. The M-E pi bonding orbitals are highly polarized toward the metal atom. In all complexes, the pi-bonding contribution to the total M=EMes bond is greater than that of the sigma-bonding contribution and increases upon going from M = Mo to W. The values of orbital interaction DeltaE(orb) are significantly larger in all studied complexes I-VIII than the electrostatic interaction DeltaE(elstat). The absolute values of the interaction energy, as well as the bond dissociation energy, decrease in the order Si > Ge > Sn > Pb, and the tungsten complexes have stronger bonding than the molybdenum complexes. PMID- 21699147 TI - Magnetic exchange interactions and magneto-structural correlations in heterobridged MU-phenoxo-MU(1,1)-azide dinickel(II) compounds: a combined experimental and theoretical exploration. AB - This investigation presents the syntheses, crystal structures, magnetic properties, and density functional theoretical modeling of magnetic behavior of two heterobridged MU-phenoxo-MU(1,1)-azido dinickel(II) compounds [Ni(II)(2)(L(1))(2)(MU(1,1)-N(3))(N(3))(H(2)O)].CH(3)CH(2)OH (1) and [Ni(II)(2)(L(2))(2)(MU(1,1)-N(3))(CH(3)CN)(H(2)O)](ClO(4)).H(2)O.CH(3)CN (2), where HL(1) and HL(2) are the [1+1] condensation products of 3 methoxysalicylaldehyde and 1-(2-aminoethyl)-piperidine (for HL(1))/4-(2 aminoethyl)-morpholine (for HL(2)), along with density functional theoretical magneto-structural correlations of MU-phenoxo-MU(1,1)-azido dinickel(II) systems. Compounds 1 and 2 crystallize in orthorhombic (space group Pbca) and monoclinic (space group P2(1)/c) systems, respectively. The coordination environments of both metal centers are distorted octahedral. The variable-temperature (2-300 K) magnetic susceptibilities at 0.7 T of both compounds have been measured. The interaction between the metal centers is moderately ferromagnetic; J = 16.6 cm( 1), g = 2.2, and D = -7.3 cm(-1) for 1 and J = 16.92 cm(-1), g = 2.2, and D(Ni1) = D(Ni2) = -6.41 cm(-1) for 2. Broken symmetry density functional calculations of exchange interaction have been performed on complexes 1 and 2 and provide a good numerical estimate of J values (15.8 cm(-1) for 1 and 15.35 cm(-1) for 2) compared to experiments. The role of Ni-N bond length asymmetry on the magnetic coupling has been noted by comparing the structures and J values of complexes 1 and 2 together with previously published dimers 3 (Eur. J. Inorg. Chem. 2009, 4982), 4 (Inorg. Chem. 2004, 43, 2427), and 5 (Dalton Trans. 2008, 6539). Our extensive DFT calculations reveal an important clue to the mechanism of coupling where the orientation of the magnetic orbitals seems to differ with asymmetry in the Ni-N bond lengths. This difference in orientation leads to a large change in the overlap integral between the magnetic orbitals and thus the magnetic coupling. DFT calculations have also been extended to develop several magneto structural correlations in this type of complexes and the correlation aim to focus on the asymmetry of the Ni-N bond lengths reveal that the asymmetry plays a proactive role in governing the magnitude of the coupling. From a completely symmetric Ni-N bond length, two behaviors have been noted: with a decrease in bond length there is an increase in the ferromagnetic coupling, while an increase in the bond lengths leads to a decrease in ferromagnetic interaction. The later correlation is supported by experiments. The magnetic properties of 1, 2, and three previously reported related compounds have been discussed in light of the structural parameters and also in light of the theoretical correlations determined here. PMID- 21699148 TI - Minutissamides A-D, antiproliferative cyclic decapeptides from the cultured cyanobacterium Anabaena minutissima. AB - Four cyclic decapeptides, minutissamides A-D (1-4), were isolated from the cultured cyanobacterium Anabaena minutissima (UTEX 1613). The planar structures were determined using various spectroscopic techniques including HRESIMS and 1D and 2D NMR experiments. The absolute configurations of the alpha-amino acid residues were assigned using Marfey's method after acid hydrolysis. The absolute configuration of a beta-amino acid residue was assigned by a combination of the advanced Marfey's method, J-based configurational analysis, and ROE spectroscopic analysis. The structures of minutissamides A-D (1-4) were characterized by the presence of three nonstandard alpha-amino acid residues (two alpha,beta-dehydro alpha-aminobutyric acids and one N-methylated Asn) and one beta-amino acid residue (2-hydroxy-3-amino-4-methyldodecanoic acid or 2-hydroxy-3-amino-4 methylhexadecanoic acid). Minutissamides A-D (1-4) exhibited antiproliferative activity against the HT-29 human colon cancer cell line with IC50 values of 2.0, 20.0, 11.8, and 22.7 MUM, respectively. PMID- 21699149 TI - Ieodomycins A-D, antimicrobial fatty acids from a marine Bacillus sp. AB - Bioassay-guided isolation of the EtOAc extract of a marine Bacillus sp., cultured in modified Bennett's broth medium, yielded four new antimicrobial fatty acids, named ieodomycins A-D. The planar structures of these new compounds were determined by extensive 1D and 2D NMR and HRESIMS spectroscopic data analysis. Their absolute configurations were elucidated by modified Mosher's method and literature data review. All four new compounds demonstrated antimicrobial activities in vitro. PMID- 21699154 TI - Metallohosts with a heart of carbon. AB - Single-crystal X-ray diffraction studies have confirmed that Ni(3)S(3)-based molecular bowls prepared in one-pot reactions capture either CH(2)Cl(2) or C(60). The nature of the pendant substituents (naphthalen-2-ylmethyl, benzyl, or ethyl) around the rim of the bowl dictates the formation of a 1:1 (bowl host-C(60) guest) or 2:1 (capsule host-C(60) guest) architecture. In CDCl(3), the trimeric complexes were found to be in equilibrium with dimeric analogues. For the naphthalen-2-ylmethyl-substituted host, NMR spectroscopic titration data confirmed a 1:1 host-C(60) guest complex in 1,2-Cl(2)C(6)D(4) solution. PMID- 21699150 TI - Facile diversity-oriented synthesis and antitubercular evaluation of novel aryl and heteroaryl tethered pyridines and dihydro-6H-quinolin-5-ones derived via variants of the Bohlmann-Rahtz Reaction. AB - The diversity oriented synthesis of substituted pyridines and dihydro-6H-quinolin 5-ones tethered with aryls and heteroaryls was achieved in very good yields through CeCl(3).7H(2)O-NaI catalyst via variants of the Bohlmann-Rahtz reaction. beta-Enaminones derived from various aryl and heteroaryl methyl ketones were regioselectively reacted with ethyl acetoacetate or 5,5-dimethylcyclohexane-1,3 dione or 4,4-dimethylcyclohexane-1,3-dione and ammonium acetate refluxing in 2 propanol. Applicability of nontoxic cerium catalyst, high reactivity with wide range of aryl and heteroaryl beta-enaminones leading to diverse analogues, operational simplicity, and shorter reaction time at comparatively low temperatures are prominent features of the developed protocol. These synthesized substituted pyridines and dihydro-6H-quinolin-5-one analogues have been evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) by agar dilution method. Among the 48 compounds screened, six compounds 2-(5-chlorothiophen-2-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 4{13,2}, 2-(5-bromothiophen-2-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 4{14,2}, 2-(5-chloro thiophen-2-yl)-6,6-dimethyl-7,8-dihydroquinolin-5(6H)-one 4{13,3}, and 2-(5-bromothiophen-2-yl)-6,6-dimethyl-7,8-dihydroquinolin-5(6H)-one 4{14,3}, 7,7-dimethyl-2-(naphthalen-2-yl)-7,8-dihydroquinoline-5(6H)-one 4{6,2}, 6,6-dimethyl-2-(naphthalen-2-yl)-7,8-di hydroquinolin-5(6H)-one 4{6,3} resulted as the most promising antitubercular agents. PMID- 21699155 TI - Plasmonic vesicles of amphiphilic gold nanocrystals: self-assembly and external stimuli-triggered destruction. AB - We have developed a new class of plasmonic vesicular nanostructures assembled from amphiphilic gold nanocrystals with mixed polymer brush coatings. One major finding is that the integration of gold nanocrystals (nanoparticles and nanorods) with two types of chemically distinct polymer grafts, which are analogous to block copolymers as a whole, creates a new type of hybrid building block inheriting the amphiphilicity-driven self-assembly of block copolymers to form vesicular structures and the plasmonic properties of the nanocrystals. In contrast to other vesicular structures, the disruption of the plasmonic vesicles can be triggered by stimulus mechanisms inherent to either the polymer or the nanocrystal. Recent advances in nanocrystal synthesis and controlled surface initiated polymerization have opened a wealth of possibilities for expanding this concept to other types of nanocrystals and integrating different types of nanocrystals into multifunctional vesicles. The development of multifunctional vesicles containing stimuli-responsive polymers could enable their broader applications in biosensing, multimodality imaging, and theragnostic nanomedicine. PMID- 21699156 TI - Preparation and characterization of pore-wall modification gradients generated on porous silicon photonic crystals using diazonium salts. AB - One-dimensional photonic crystals (rugate filters) constructed from porous silicon were modified by the chemical hydrosilylation of terminal alkenes (decyl, 10-carboxydecyl, and 10-hydroxydecyl) in the presence of a concentration gradient of diazonium salt initiators. The concentration gradient was generated by vertically orienting the Si wafer containing the porous Si layer in an alkene solution and then introducing the diazonium salt at the bottom edge of the wafer. Slow diffusion of the salt led to a varying density of grafted alkene across the surface of the porous layer. The modified surfaces were end-capped with methyl groups by electrochemical grafting to impart improved stability and greater hydrophobicity. The surface modified with 10-carboxydecyl species was ionized by deprotonation of the carboxy groups to increase the hydrophilicity of this porous silicon surface. The pore-wall modification gradients were characterized using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and scanning electron microscopy (SEM) with energy-dispersive spectroscopy (EDS). The more hydrophilic portion of the gradient changes color when water infiltrates the porous nanostructure because of a shift in the stop band of the photonic crystal. The more hydrophobic portion of the gradient excludes water, although mixtures of water and ethanol will infiltrate this region, depending on the concentration of ethanol in the mixture. A simple visual sensor for small quantities of ethanol in water, capable of detecting ethanol concentrations of between 0 and 8% with a resolution of 1% is demonstrated. PMID- 21699157 TI - Lipid bilayer templated gold nanoparticles nanoring formation using zirconium ion coordination chemistry. AB - We used positively charged lipids to prepare lipid bilayer assemblies (LBAs) upon which we assembled negatively charged gold nanoparticles (AuNPs). Treatment of the assembly with zirconium chloride resulted in the formation of nanorings of the diameters inversely related to the zirconium ion concentration. The nanorings were attributed to the zirconium ion coordinated AuNPs formed during the lipid bilayer budding process promoted by the acid effect of zirconium chloride. Nanoring organization was also dependent on the fluidity of lipid bilayers, an indication of LBA-assisted nanomaterials organization. We suggest that such bioorganic-inorganic hybrid assemblies coupled to unique topological and morphological variations might be useful as stimuli-responsive sensors or storage compartments for proteins or drugs. PMID- 21699159 TI - A mild liquid reduction route toward uniform blue-emitting EuCl2 nanoprisms and nanorods. AB - In this work, for the first time, uniform blue-emitting EuCl(2) nanoprisms and nanorods were synthesized from Eu(CCl(3)COO)(3).2H(2)O [or Eu(CH(3)COO)(3).H(2)O] by a novel mild liquid reduction route, using acetamidine hydrochloride (or picolinamidine hydrochloride) as the reductant in oleylamine. The synthetic reaction even can take place under an atmosphere in the absence of inert gas at around 300 degrees C. The EuCl(2) nanoprism dispersion in n-hexane showed an intense blue emission when excited by UV light. PMID- 21699160 TI - Strengthening the stability of a tunnel-shaped homotetramer protein with nanogels. AB - Urate oxidase (UOX, EC 1.7.3.3) is effective for the treatment of gout and hyperuricaemia associated with tumor lysis syndrome. The inherent poor stability of UOX to temperature, proteolysis, and acidic environments is known to limit its efficacy. Herein, we encapsulated UOX into spherical and porous nanogels with diameters of 20-40 nm via a two-step in situ polymerization in the presence of oxonic acid potassium salt, an inhibitor of UOX. The UOX nanogel retained 70% of the initial activity but showed an expanded pH spectrum from pH 6-10 to 3-10 and an extended half-life at 37 degrees C from 5 min to 3 h. The enhanced pH stability, thermal stability, and enzyme resistance of the UOX nanogels were also confirmed by using fluorescence spectroscopy and enzymatic digestion. A molecular dynamics simulation was performed as a way to probe the mechanism underlying the formation of UOX nanogels as well as the strengthened stability against harsh conditions. It was shown that the encapsulation into the polyacrylamide network reinforced the intersubunit hydrogen bonding, shielded the hydrolytic reaction site, and thus protected the tertiary and quaternary structure of UOX. The UOX nanogel with enhanced stability provided a stable enzyme model that enables the exploration of UOX in the diagnosis and therapy of disorders associated with altered purine metabolism. PMID- 21699161 TI - Direct Michael addition of alkenes via a cobalt-dinitrosyl mediated vinylic C-H functionalization reaction. AB - We report a one-pot, direct C-H functionalization reaction of alkenes mediated by [CpCo(NO)(2)]. All intermediates in the proposed reaction sequence have been characterized. A variety of Michael acceptors can be utilized with the one-pot procedure to give the desired cyclic tetra-alkyl-substituted, gamma,delta unsaturated compounds in good yields. We also provide a preliminary result for catalytic turnover in both base and [CpCo(NO)(2)]. PMID- 21699162 TI - Capillary electrophoresis with lamp-based wavelength-resolved fluorescence detection for the probing of protein conformational changes. AB - Native protein fluorescence spectra encompass information on protein conformation. In this study, capillary electrophoresis (CE) combined with lamp based wavelength-resolved fluorescence detection (wrFlu) is presented as a novel tool for the analysis of protein mixtures and the monitoring of protein unfolding. The CE-wrFlu system provides three-dimensional data (time, emission wavelength, intensity) from which electropherograms and accurate emission spectra of separated proteins can be extracted. For model proteins, linear detector responses (peak height vs concentration) were obtained (R(2) > 0.96) with detection limits (LODs) in the 6-32 nM range. The minimum protein concentration required for precise determination of the maximum emission wavelength by CE-wrFlu was about 15 times the LOD. Unfolding of various model proteins was induced by protein incubation and analysis in background electrolyte (BGE) containing 7.0 M urea. CE-wrFlu of the unfolded species revealed peaks with clear red-shifted spectra, which adequately corresponded to reference spectra obtained on a standard spectrophotometer. Moreover, unfolded proteins showed a significant decrease in effective electrophoretic mobility (after correction for BGE viscosity) due to the increase of their molecular hydrodynamic radii. It is concluded that the CE-wrFlu system provides two independent indicators for changes in protein folding and will allow the simultaneous assessment of protein purity and conformation. PMID- 21699163 TI - Disentangling intrinsic ultrafast excited-state dynamics of cytosine tautomers. AB - Gas-phase ultrafast excited-state dynamics of cytosine, 1-methylcytosine, and 5 fluorocytosine were investigated in molecular beams using femtosecond pump-probe photoionization spectroscopy to identify the intrinsic dynamics of the major cytosine tautomers. The results indicate that, upon photoexcitation in the first absorption band, the cytosine enol tautomer exhibits a significantly longer excited-state lifetime than its keto and imino counterparts. The initially excited states of the cytosine keto and imino tautomers decay with sub-picosecond dynamics for excitation wavelengths shorter than 300 nm, whereas that of the cytosine enol tautomer decays with time constants ranging from 3 to 45 ps for excitation between 260 and 285 nm. PMID- 21699164 TI - On the causes of altered photophysics of luminescent metal complexes embedded in polymer hosts. AB - A suite of luminescent Re(I) complexes has been prepared whose emissive properties are responsive to the probe's local environment. These complexes were embedded in a series of chemically similar polymers whose room temperature rigidity varied over a significant range. It is shown that the degree of local rigidity experienced by the embedded complexes significantly alters the observed emission in terms of both spectra and lifetime. Time resolved emission measurements show that the spectral shifts and lifetime complexity are correlated and track well the polymers' T(g) within the series. Fluorescence confocal microscopy did not show the presence of discrete domains, and thus, the environmental features responsible for the altered photophysics must be submicrometer in size. PMID- 21699165 TI - Mechanisms of the thermal cyclotrimerizations of fluoro- and chloroacetylenes: density functional theory investigation and intermediate trapping experiments. AB - Theoretical studies of the mechanisms of the thermal cyclotrimerization of fluoro and chloroacetylenes, which were reported by Viehe and Ballester, respectively, were conducted with the aid of density functional theory calculations of the (U)B3LYP functional, indicating that the thermal cyclotrimerizations of fluoro- and chloroacetylenes involve tandem processes of regioselectively stepwise [2+2] and stepwise [4+2] cycloadditions. These tandem processes generate 1,2,6-trihalo Dewar benzenes and 1,2,4-trihalo-Dewar benzenes, which then isomerize to the corresponding benzenes when heated. The rate-determining step of the cyclotrimerizations of haloacetylenes is the dimerization step involving open shell singlet diradical transition states and intermediates. The substituent effects in the thermal cyclotrimerization of haloacetylenes have been rationalized using frontier molecular orbital theory. The higher reactivity of fluoroacetylenes compared to that of chloroacetylenes is due to the fact that fluoroacetylenes have lower singlet-triplet gaps than chloroacetylenes and more easily undergo dimerization and cyclotrimerization. In this report, additional experiments were performed to verify the theoretical prediction about the cyclotrimerization of chloroacetylene and to trap the proposed 1,4 dichlorocyclobutadiene intermediate. Experiments revealed that the thermal reaction of phenylchloroacetylene at 110 degrees C gave 1,2,3 triphenyltrichlorobenzene and 1,2,4-triphenyltrichlorobenzene together with a tetramer, cis-1,2,5,6-tetrachloro-3,4,7,8-tetraphenyltricyclo[4.2.0.0(2,5)]octa 3,7-diene. The proposed 1,4-diphenyldichlorocyclobutadiene intermediate in the thermal cyclotrimerization of phenylchloroacetylene was successfully trapped using dienophiles of maleic anhydride and dimethyl acetylenedicarboxylate. PMID- 21699167 TI - Role of the meniscus shape in large-area convective particle assembly. AB - Dense and uniform particle films are deposited using a robust version of the convective particle assembly process. We analyze how the shape of the gas-liquid interface and the three-phase contact line govern the stability of convective deposition and, thus, the achievable quality of films. Interference microscopy indicates that a highly curved meniscus cannot compensate for the ubiquitous perturbation during deposition. A moderately curved meniscus provides flexibility to compensate and localize perturbation and enables reliable homogeneous deposition. We analyze which setup geometry and meniscus velocity yield appropriate meniscus shapes. The quality of the resulting films is analyzed and compared to the deposition conditions. Uniform films over areas beyond the centimeter range are accessible using the optimized process, which is suitable for functional particle coatings and templates for microstructured materials. PMID- 21699168 TI - Perylene anhydride fused porphyrins as near-infrared sensitizers for dye sensitized solar cells. AB - Two perylene anhydride fused porphyrins 1 and 2 have been synthesized and employed successfully in dye-sensitized solar cells (DSCs). Both compounds showed broad incident monochromatic photon-to-current conversion efficiency spectra covering the entire visible spectral region and even extending into the near infrared (NIR) region up to 1000 nm, which is impressive for ruthenium-free dyes in DSCs. PMID- 21699169 TI - Modulation of GABAA-receptors by honokiol and derivatives: subtype selectivity and structure-activity relationship. AB - A series of 31 analogues of the neolignan honokiol (a major constituent of Magnolia officinalis) was synthesized, and their effects on GABA(A) receptors expressed in Xenopus oocytes were investigated. Honokiol enhanced chloride currents (I(GABA)) through GABA(A) receptors of seven different subunit compositions with EC(50) values ranging from 23.4 MUM (alpha(5)beta(2)) to 59.6 MUM (alpha(1)beta(3)). Honokiol was most efficient on alpha(3)beta(2) (maximal I(GABA) enhancement 2386%) > alpha(2)beta(2) (1130%) > alpha(1)beta(2) (1034%) > alpha(1)beta(1) (260%)). On alpha(1)beta(2)-receptors, N-substituted compounds were most active with 3-acetylamino-4'-O-methylhonokiol (31), enhancing I(GABA) by 2601% (EC(50) (alpha(1)beta(2)) = 3.8 MUM). Pharmacophore modeling gave a model with an overall classification accuracy of 91% showing three hydrophobic regions, one acceptor and one donor region. Unlike honokiol, 31 was most efficient on alpha(2)beta(2)- (5204%) > alpha(3)beta(2)- (3671%) > alpha(1)beta(2)-receptors (2601%), suggesting a role of the acetamido group in subunit-dependent receptor modulation. PMID- 21699170 TI - Quantitative assessment of the enzymatic degradation of amorphous cellulose by using a quartz crystal microbalance with dissipation monitoring. AB - The systematic evaluation of the degradation of an amorphous cellulose film by a monocomponent endoglucanase (EG I) by using a quartz crystal microbalance with dissipation monitoring (QCM-D) identified several important aspects relevant to the study the kinetics of cellulose degradation by enzymes. It was demonstrated that, to properly evaluate the mechanism of action, steady state conditions in the experimental set up need to be reached. Rinsing or diluting the enzyme, as well as concentration of the enzyme, can have a pronounced effect on the hydrolysis. Quantification of the actual hydrolysis was carried out by measuring the film thickness reduction by atomic force microscopy after the enzymatic treatment. The values correlated well with the frequency data obtained by QCM-D measurement for corresponding films. This demonstrated that the evaluation of hydrolysis by QCM-D can be done quantitatively. Tuning of the initial thickness of films enabled variation of the volume of substrate available for hydrolysis which was then utilized in establishing a correlation between substrate volume and hydrolytic activity of EG I as measured by QCM-D. It was shown that, although the amount of substrate affects the absolute rate of hydrolysis, the relative rate of hydrolysis does not depend on the initial amount of substrate in steady state system. With this experimental setup it was also possible to demonstrate the impact of concentration on crowding of enzyme and subsequent hydrolysis efficiency. This effort also shows the action of EG I on a fully amorphous substrate as observed by QCM-D. The enzyme was shown to work uniformly within the whole volume of swollen film, however being unable to fully degrade the amorphous film. PMID- 21699171 TI - Total synthesis of isofregenedadiol. AB - The first total synthesis of isofregenedadiol, a bicyclic diterpene isolated from H. Viscosum, is reported starting from a D-(-)-pantolactone chiral pool. A one pot quadruple reaction sequence comprising an enyne ring-closing metathesis/cross metathesis/Diels-Alder/aromatization for the construction of a target skeleton is the highlight of the present synthesis. PMID- 21699172 TI - Homologous Mukaiyama reactions via trapping of the Nazarov intermediate with silyloxyalkenes. AB - Treatment of 1,4-pentadien-3-ones and silyloxyalkenes with BF(3).OEt(2) at room temperature or lower initiates a domino process consisting of sequential 4pi electrocyclization and capture of the resulting cyclopentenyl cation by the electron-rich trap. The overall process furnishes 1,4-dicarbonyl products containing highly substituted cyclopentanones in good yields and with the establishment of up to five new stereocenters. PMID- 21699173 TI - A 3D Cu(II) coordination framework with MU4-/MU2-oxalato anions and a bent dipyridyl coligand: unique zeolite-type NiP2 topological network and magnetic properties. AB - The reaction of copper(II) nitrate, oxamide, and an angular bridging ligand 2,5 bis(4-pyridyl)-1,3,4-oxadiazole (4-bpo) under hydrothermal conditions affords a 3D pillared-layer coordination framework {[Cu(2)(4-bpo)(ox)(2)](H(2)O)(4)}(n) (1) (ox = oxalate), featuring the unique zeolite-type NiP(2) network and interesting properties. PMID- 21699174 TI - Analysis of patulin in pear- and apple-based foodstuffs by liquid chromatography electrospray ionization tandem mass spectrometry. AB - A liquid chromatography electrospray ionization tandem mass spectrometry method for the determination of patulin in apple- and pear-based foodstuffs was developed. The sample preparation is based on the QuEChERS procedure involving an initial extraction step with water and acetonitrile, followed by a partitioning step after the addition of magnesium sulfate and sodium chloride. The cleanup was performed by using dispersive solid-phase extraction with a mixture of magnesium sulfate, primary secondary amine sorbent, and n-octadecylsiloxane sorbent added together to the extract. The cleaned extract was finally evaporated and reconstituted in water prior to injection. Quantitation was performed by isotope dilution using ((13)C(7))-patulin as internal standard. The method was first fully validated in three different baby food products including apple-pear juice, apple-pear puree, and infant cereals. Then the scope of application of the method was extended to pear concentrate, raw apples, apple flakes (naturally contaminated), dried apples, and yogurt. The sensitivity achieved by the method in all matrices gave limits of detection (LOD) and quantitation (LOQ) of <=0.5 and <=10 MUg/kg, respectively, which was compliant with maximum levels settled in Commission Regulation (EC) No. 1881/2006. Method performances for all matrices also fulfilled the criteria established in the CEN/TR 16059:2010 document. Indeed, recoveries were within the 94-104% range; relative standard deviations of repeatability (RSD(r)) and intermediate reproducibility (RSD(IR)) were <=7.5 and <=13.0%, respectively, and trueness in an infant apple drink (FAPAS 1642) was measured at 99%. PMID- 21699175 TI - Synthesis of Pd3Tl and Pd6Tl2 complexes based on a trinuclear aryl-palladium(II) complex acting as a metallaligand toward thallium(I) through Tl-arene and Tl-I bonds. AB - The metallaligand [(PdIL(2))(3)(C(6)Me(3)-1,3,5)] (L(2) = 4,4'-di-tert-butyl-2-2' bipyridine = tbbpy) reacts with TlOTf to afford the complex [{(PdIL(2))(3)C(6)Me(3)-1,3,5}Tl]OTf, which exists in the solid state as a 2:1 mixture of monomer and dimer, both showing Tl(I)-I and Tl(I)-eta(6)-mesitylene bonds. In solution, only the monomer is observed. Heating of toluene solutions of [(PdIL(2))(3)(C(6)Me(3)-1,3,5)] affords the dinuclear complex [(PdIL(2))(2)(C(6)HMe(3)-1,3,5)]. PMID- 21699176 TI - Layer-by-layer electrostatic assembly with a control over orientation of molecules: anisotropy of electrical conductivity and dielectric properties. AB - While forming layer-by-layer (LbL) electrostatic assembly of a magnetic organic molecule, namely, nickel phthalocyanine (NiPc), we apply a magnetic field. The field orients the magnetic moment of the molecules on a monolayer along the direction of magnetic field. Such an orientation of the molecules is then electrostatically immobilized with a monolayer of a polycation. By repeating the dipping cycle, we form LbL films with planar NiPc molecules facing a particular direction. With NiPc's moment perpendicular to the molecular plane, two types of LbL films were formed: (a) NiPc's molecular plane parallel to the substrate (moment is perpendicular) and (b) molecules perpendicular to the substrate and facing one particular direction, the direction of magnetic field. Such films, with the molecules lying either (a) parallel or (b) perpendicular to the substrate, provide unique systems to study anisotropy of optical, dielectric, and electrical characteristics in these planar organic molecules. The latter film responds to the polarization of incident beam in electronic absorption spectroscopy. Here we show methods to obtain an orientation of molecules in LbL films and study anisotropy of dielectric constant and conductivity of the molecules in ultrathin films. PMID- 21699178 TI - Roughness and ordering at the interface of oxidized polystyrene and water. AB - For the first time, atomistically detailed molecular dynamics calculations revealed molecular ordering of the water-oxidized atactic polystyrene (aPS) interface. Both ordering of the water molecules and the phenyl rings occur. In addition, the natural roughness of the surface has been simulated and compared to experimental values. The composition of the simulated aPS films is based on spin coated aPS films that have been oxidized and characterized experimentally. The aPS surfaces are oxidized with ultraviolet-ozone radiation and have been characterized by XPS, AFM, and water contact angle measurements. XPS measurements show that the oxygen content in the sample increases rapidly with exposure and reaches saturation near 24 at. % of oxygen. The molecular dynamics simulations show smoothening of an hydrophobic aPS surface upon transition from vacuum to water. The smoothening decreases with increasing hydrophilicity. The calculations reveal ordering of oxidized phenyl rings for aPS surfaces in water. The order increases with increasing hydrophilicity. Additionally, we investigated the water structure near the aPS-water interface as a function of the surface hydrophilicity. With increasing hydrophilicity, the density of water at the aPS water interface increases. The water density profile is steeper in the presence of hydrophobic aPS. The water shows an ordered layer near both the hydrophobic and hydrophilic surfaces; the position of this layer shifts toward the interface with increasing hydrophilicity. PMID- 21699177 TI - Defining the substrate specificity determinants recognized by the active site of C-terminal Src kinase-homologous kinase (CHK) and identification of beta synuclein as a potential CHK physiological substrate. AB - C-Terminal Src kinase-homologous kinase (CHK) exerts its tumor suppressor function by phosphorylating the C-terminal regulatory tyrosine of the Src-family kinases (SFKs). The phosphorylation suppresses their activity and oncogenic action. In addition to phosphorylating SFKs, CHK also performs non-SFK-related functions by phosphorylating other cellular protein substrates. To define these non-SFK-related functions of CHK, we used the "kinase substrate tracking and elucidation" method to search for its potential physiological substrates in rat brain cytosol. Our search revealed beta-synuclein as a potential CHK substrate, and Y127 in beta-synuclein as the preferential phosphorylation site. Using peptides derived from beta-synuclein and positional scanning combinatorial peptide library screening, we defined the optimal substrate phosphorylation sequence recognized by the CHK active site to be E-x-[Phi/E/D]-Y-Phi-x-Phi, where Phi and x represent hydrophobic residues and any residue, respectively. Besides beta-synuclein, cellular proteins containing motifs resembling this sequence are potential CHK substrates. Intriguingly, the CHK-optimal substrate phosphorylation sequence bears little resemblance to the C-terminal tail sequence of SFKs, indicating that interactions between the CHK active site and the local determinants near the C-terminal regulatory tyrosine of SFKs play only a minor role in governing specific phosphorylation of SFKs by CHK. Our results imply that recognition of SFKs by CHK is mainly governed by interactions between motifs located distally from the active site of CHK and determinants spatially separate from the C-terminal regulatory tyrosine in SFKs. Thus, besides assisting in the identification of potential CHK physiological substrates, our findings shed new light on how CHK recognizes SFKs and other protein substrates. PMID- 21699179 TI - Discovery of naturally occurring aurones that are potent allosteric inhibitors of hepatitis C virus RNA-dependent RNA polymerase. AB - We have identified naturally occurring 2-benzylidenebenzofuran-3-ones (aurones) as new templates for non-nucleoside hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) inhibitors. The aurone target site, identified by site-directed mutagenesis, is located in thumb pocket I of HCV RdRp. The RdRp inhibitory activity of 42 aurones was rationally explored in an enzyme assay. Molecular docking studies were used to determine how aurones bind to HCV RdRp and to predict their range of inhibitory activity. Seven aurone derivatives were found to have potent inhibitory effects on HCV RdRp, with IC(50) below 5 MUM and excellent selectivity index (inhibition activity versus cellular cytotoxicity). The most active aurone analogue was (Z)-2-((1-butyl-1H-indol-3-yl)methylene)-4,6 dihydroxybenzofuran-3(2H)-one (compound 51), with an IC(50) of 2.2 MUM. Their potent RdRp inhibitory activity and their low toxicity make these molecules attractive candidates as direct-acting anti-HCV agents. PMID- 21699180 TI - Ruling out any electrophilicity equalization principle. AB - Two gas-phase electrophilicity indices, omega(1) and omega(2), introduced by Parr, von Szentpaly, and Liu are tested with respect to the recently proposed "principle of electrophilicity equalization." Although electronegativity is equalized in many cases, there is no functioning "hardness equalization principle" nor are the electrophilicity indices principally equalized during molecule formation: they cannot be generally expressed as the mean of the corresponding atomic indices. For large metal clusters and [n]fullerenes, both electrophilicity indices increase proportional to n(1/3) and n(1/2), respectively, as the hardness values converge to zero. Two "principles" are shown to be obsolete: the "geometric mean principle for hardness equalization" and the "principle of electrophilicity equalization", with the latter somewhat relying on the former. An appeal is made to exercise careful judgment before proposing and publishing new structural principles. PMID- 21699182 TI - In situ infrared spectroscopic study of forsterite carbonation in wet supercritical CO2. AB - Carbonation reactions are central to the prospect of CO(2) trapping by mineralization in geologic reservoirs. In contrast to the relevant aqueous mediated reactions, little is known about the propensity for carbonation in the key partner fluid: supercritical carbon dioxide containing dissolved water ("wet" scCO(2)). We employed in situ mid-infrared spectroscopy to follow the reaction of a model silicate mineral (forsterite, Mg(2)SiO(4)) for 24 h with wet scCO(2) at 50 degrees C and 180 atm. The results show a dramatic dependence of reactivity on water concentration and the presence of liquid water on the forsterite particles. Exposure to neat scCO(2) showed no detectable carbonation reaction. At 47% and 81% water saturation, an Angstrom-thick liquid-like water film was detected on the forsterite particles and less than 1% of the forsterite transformed. Most of the reaction occurred within the first 3 h of exposure to the fluid. In experiments at 95% saturation and with an excess of water (36% above water saturation), a nanometer-thick water film was detected, and the carbonation reaction proceeded continuously with approximately 2% and 10% conversion, respectively. Our collective results suggest constitutive links between water concentration, water film formation, reaction rate and extent, and reaction products in wet scCO(2). PMID- 21699181 TI - Kinetic mechanisms in morpholino-DNA surface hybridization. AB - Morpholinos (MOs) are DNA analogues whose uncharged nature can bring fundamental advantages to surface hybridization technologies such as DNA microarrays, by using MOs as the immobilized, or "probe", species. Advancement of MO-based diagnostics, however, is challenged by limited understanding of the surface organization of MO molecules and of how this organization impacts hybridization kinetics and thermodynamics. The present study focuses on hybridization kinetics between monolayers of MO probes and DNA targets as a function of the instantaneous extent of hybridization (i.e., duplex coverage), total probe coverage, and ionic strength. Intriguingly, these experiments reveal distinct kinetic stages, none of which are consistent with Langmuir kinetics. The initial stage, in which duplex coverage remains relatively sparse, indicates confluence of two effects: blockage of target access to unhybridized probes by previously formed duplexes and deactivation of the solid support due to consumption of probe molecules. This interpretation is consistent with a surface organization in which unhybridized MO probes localize near the solid support, underneath a layer of MO DNA duplexes. As duplex coverage builds, provided saturation is not reached first, the initial stage can transition to an unusual regime characterized by near independence of hybridization rate on duplex coverage, followed by a prolonged approach to equilibrium. The possible origins of these more complex latter behaviors are discussed. Comparison with published data for DNA and peptide nucleic acid (PNA) probes is carried out to look for universal trends in kinetics. This comparison reveals qualitative similarities when comparable surface organization of probes is expected. In addition, MO monolayers are found capable of a broad range of reactivities that span reported values for PNA and DNA probes. PMID- 21699184 TI - Recognition of drug degradation products by target proteins: isotetracycline binding to Tet repressor. AB - Tetracycline antibiotics and their degradation products appear in medically treated tissues, food, soil, and manure sludge in the environment. In the context of protein interactions with various tetracyclines we performed crystal structure analyses of the tetracycline repressor in complex with weak or noninducing tetracycline derivatives. Isotetracyclines are degradation products of tetracyclines, which occur under physiological conditions. The typical framework of the antibiotic is irreversibly broken at the BC-ring connection, leading to a modified orientation of the AB to the new C*D ring fragments. The shape of the zwitterionic AB-ring fragment is unchanged and still binds to the TetR recognition site in a manner comparable to the intact antibiotic but without typical Mg(2+) chelation. This work is an example that drug degradation products can still bind to specific targets and should be discussed in light of potential and critical side effects. PMID- 21699183 TI - Rapid and selective nitroxyl (HNO) trapping by phosphines: kinetics and new aqueous ligations for HNO detection and quantitation. AB - Recent studies distinguish the biological and pharmacological effects of nitroxyl (HNO) from its oxidized/deprotonated product nitric oxide (.NO), but the lack of HNO detection methods limits the understanding its in vivo mechanisms and the identification of endogenous sources. We previously demonstrated that reaction of HNO with triarylphosphines provides aza-ylides and HNO-derived amides, which may serve as stable HNO biomarkers. We now report a kinetic analysis for the trapping of HNO by phosphines, ligations of enzyme-generated HNO, and compatibility studies illustrating the selectivity of phosphines for HNO over other physiologically relevant nitrogen oxides. Quantification of HNO using phosphines is demonstrated using an HPLC-based assay and ligations of phosphine carbamates generate HNO-derived ureas. These results further demonstrate the potential of phosphine probes for reliable biological detection and quantification of HNO. PMID- 21699185 TI - Derivation by infrared spectroscopy with multivariate analysis of bimodal contaminant-induced dose-response effects in MCF-7 cells. AB - Toxic responses to contaminants following exposure concentrations typically used in laboratory tests may not reflect how biological systems respond to lower environmental levels from which hormetic effect mechanisms have been suggested. We investigated the pattern of dose-response in mammalian cells to various environmental contaminants using a range of concentrations that span those that are environmentally relevant (10(-12)M to 10(-3)M). MCF-7 cell cultures were treated for 24 h with benzo[a]pyrene (B[a]P), lindane (gamma hexachlorocyclohexane), or polybrominated diphenyl ethers (PBDEs) congeners (47, 153, 183, and 209), then fixed in ethanol and interrogated using attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy. Mode of action was further studied by examining if test agents stimulated cell growth or altered CYP1A1 expression. Bimodal dose response curves were observed when MCF-7 cells were treated with PBDEs or lindane. The first peak distribution was associated with lower doses (10(-12)M to 10(-9)M), while the second occurred only after MCF 7 cells were exposed to concentrations >10(-9)M. Cellular alterations associated with low-dose PBDEs were mainly due to lipid and secondary protein structural changes, whereas lindane induced DNA/RNA effects as well. In contrast, DNA reactive B[a]P gave rise to a monotonic linear dose-response relationship and induced mainly DNA/RNA cellular changes. This study shows that environmentally realistic exposures to chemical contaminants can induce nonmonotonic dose responses in cellular systems. PMID- 21699186 TI - An efficient fluorescence sensor for superoxide with an acridinium ion-linked porphyrin triad. AB - Addition of potassium superoxide with 18-crown-6 ether (KO(2)(*-)-18-crown-6) to a toluene solution of an acridinium ion-linked porphyrin triad (Acr(+)-H(2)P Acr(+)) resulted in a remarkable enhancement of the fluorescence intensity. Thus, Acr(+)-H(2)P-Acr(+) acts as an efficient fluorescence sensor for superoxide. Electron transfer from KO(2)(*-)-18-crown-6 to the Acr(+) moiety to produce the two-electron-reduced species (Acr(*)-H(2)P-Acr(*)) results in inhibition of the fluorescence quenching via photoinduced electron transfer, as revealed by laser flash photolysis measurements. PMID- 21699187 TI - Complexation of beta-lactoglobulin fibrils and sulfated polysaccharides. AB - Fibrils of beta-lactoglobulin, formed by heating at pH 2, were titrated with a sulfated polysaccharide (kappa-carrageenan) to determine the morphology and mechanism of complex formation at low pH. Structural information on the resultant complexes was gathered using transmission electron microscopy, atomic force microscopy, Doppler electrophoresis, and small-angle neutron scattering. Electrophoresis demonstrated that the carrageenan complexed with protein fibrils until reaching a maximum complexation efficiency at a protein/polysaccharide (r) weight ratio of 5:3. Neutron scattering and microscopy indicated an increasing formation of spherical aggregates attached along the protein fibrils with increases in the carrageenan concentration. These globular particles had an average diameter of 30 nm. Small-angle neutron scattering of these complexes could be accurately described by a form factor corresponding to multistranded twisted ribbons with spherical aggregates along their contour length, arranged in a necklace configuration. PMID- 21699188 TI - Segregated donor-acceptor columns in liquid crystals that exhibit highly efficient ambipolar charge transport. AB - Liquid crystalline donor (i.e., phthalocyanine) was covalently linked to acceptor (i.e, fullerene) to achieve efficient charge-transport properties in a liquid crystalline phase. The columnar structure exhibited highly efficient ambipolar charge-transport character, demonstrating the potential utility of the strategy in organic electronics. PMID- 21699189 TI - Role of Zr4+ cations in NO2 adsorption on Ce(1-x)Zr(x)O2 mixed oxides at ambient conditions. AB - Mixed oxides Ce(1-x)Zr(x)O(2) prepared by slow coprecipitation in NaOH were tested for NO(2) adsorption in dynamic conditions at room temperature. The samples were characterized before and after exposure to NO(2) by XRD, N(2) adsorption, thermal analysis, potentiometric titration, and FT-IR. Mixed oxides show a better NO(2) adsorption capacity than the parent materials (CeO(2) and Zr(OH)(4)). This effect is linked to the presence of reduced cerium and oxygen vacancies induced by the addition of Zr(4+) cations to the structure. The results indicate that NO(2) reacts with Ce(3+) to form nitrite and nitrate species on the surface. The NO retention increases with an increase in the Zr(OH)(4) content. A decrease in the density of -OH groups on the surface after the exposure to NO(2), suggests their involvement in reactive adsorption of NO and/or NO(2). From the structural point of view, no real difference was observed on the Ce(1-x)Zr(x)O(2) materials before and after exposure to NO(2). PMID- 21699190 TI - Systematic study of protein detection mechanism of self-assembling 19F NMR/MRI nanoprobes toward rational design and improved sensitivity. AB - (19)F NMR/MRI probe is expected to be a powerful tool for selective sensing of biologically active agents owing to its high sensitivity and no background signals in live bodies. We have recently reported a unique supramolecular strategy for specific protein detection using a protein ligand-tethered self assembling (19)F probe. This method is based on a recognition-driven disassembly of the nanoprobes, which induced a clear turn-on signal of (19)F NMR/MRI. In the present study, we conducted a systematic investigation of the relationship between structure and properties of the probe to elucidate the mechanism of this turn-on (19)F NMR sensing in detail. Newly synthesized (19)F probes showed three distinct behaviors in response to the target protein: off/on, always-on, and always-off modes. We clearly demonstrated that these differences in protein response could be explained by differences in the stability of the probe aggregates and that "moderate stability" of the aggregates produced an ideal turn on response in protein detection. We also successfully controlled the aggregate stability by changing the hydrophobicity/hydrophilicity balance of the probes. The detailed understanding of the detection mechanism allowed us to rationally design a turn-on (19)F NMR probe with improved sensitivity, giving a higher image intensity for the target protein in (19)F MRI. PMID- 21699191 TI - Ratchetlike slip angle anisotropy on printed superhydrophobic surfaces. AB - The fabrication and properties of superhydrophobic surfaces that exhibit ratchet like anisotropic slip angle behavior is described. The surface is composed of arrays of poly(dimethylsiloxane) (PDMS) posts fabricated by a type of 3D printing. By controlling the dispense parameters, regular arrays of asymmetric posts were deposited such that the slope of the posts was varied from 0 to 50 relative to the surface normal. Advancing and receding contact angles as well as slip angles were measured as a function of the post slope and droplet volume. Ratchetlike slip angle anisotropy was observed on surfaces composed of sloped features. The maximum slip angle difference (for a 180 degrees tilt angle variation) was 32 degrees for 20 MUL droplets on surfaces with posts fabricated with a slope of 50 degrees . This slip angle anisotropy is attributed to an increase in the triple contact line (TCL) length as the droplet is tilted in a direction against the post slope whereas the TCL decreases continuously when the drop travels in a direction parallel to the post slope. The increasing length of the TCL creates an increased energy barrier that accounts for the higher slip angles in this direction. PMID- 21699192 TI - Monoanionic molybdenum and tungsten tris(dithiolene) complexes: a multifrequency EPR study. AB - Numerous Mo and W tris(dithiolene) complexes in varying redox states have been prepared and representative examples characterized crystallographically: [M(S(2)C(2)R(2))(3)](z) [M = Mo, R = Ph, z = 0 (1) or 1- (2); M = W, R = Ph, z = 0 (4) or 1- (5); R = CN, z = 2-, M = Mo (3) or W (6)]. Changes in dithiolene C-S and C-C bond lengths for 1 versus 2 and 4 versus 5 are indicative of ligand reduction. Trigonal twist angles (Theta) and dithiolene fold angles (alpha) increase and decrease, respectively, for 2 versus 1, 5 versus 4. Cyclic voltammetry reveals generally two reversible couples corresponding to 0/1- and 1 /2- reductions. The electronic structures of monoanionic molybdenum tris(dithiolene) complexes have been analyzed by multifrequency (S-, X-, Q-band) EPR spectroscopy. Spin-Hamiltonian parameters afforded by spectral simulation for each complex demonstrate the existence of two distinctive electronic structure types. The first is [Mo(IV)((A)L(3)(5-*))](1-) ((A)L = olefinic dithiolene, type A), which has the unpaired electron restricted to the tris(dithiolene) unit and is characterized by isotropic g-values and small molybdenum superhyperfine coupling. The second is formulated as [Mo(V)((B)L(3)(6-))](1-) ((B)L = aromatic dithiolene, type B) with spectra distinguished by a prominent g-anisotropy and hyperfine coupling consistent with the (d(z(2)))(1) paramagnet. The electronic structure disparity is also manifested in their electronic absorption spectra. The compound [W(bdt)(3)](1-) exhibits spin-Hamiltonian parameters similar to those of [Mo(bdt)(3)](1-) and thus is formulated as [W(V)((B)L(3)(6-))](1-). The EPR spectra of [W((A)L(3))](1-) display spin-Hamiltonian parameters that suggest their electronic structure is best represented by two resonance forms {[W(IV)((A)L(3)(5-*))](1-) <-> [W(V)((A)L(3)(6-))](1-)}. The contrast with the corresponding [Mo(IV)((A)L(3)(5-*))](1-) complexes highlights tungsten's preference for higher oxidation states. PMID- 21699193 TI - Catching the first oligomerization event in the catalytic formation of polyaminoboranes: H3B.NMeHBH2.NMeH2 bound to iridium. AB - We report the first insertion step at a metal center for the catalytic dehydropolymerization of H(3)B.NMeH(2) to form the simplest oligomeric species, H(3)B.NMeHBH(2).NMeH(2), by the addition of 1 equiv of H(3)B.NMeH(2) to [Ir(PCy(3))(2)(H)(2)(eta(2)-H(3)B.NMeH(2))][BAr(F)(4)] to give [Ir(PCy(3))(2)(H)(2)(eta(2)-H(3)B.NMeHBH(2).NMeH(2))][BAr(F)(4)]. This reaction is also catalytic for the formation of the free linear diborazane, but this is best obtained by an alternative stoichiometric synthesis. PMID- 21699194 TI - Correlation between the structure and wettability of photoswitchable hydrophilic azobenzene monolayers on silicon. AB - Photoresponsive monolayers of hydrophilically substituted azobenzenes have been prepared by reaction on aminosilane monolayers on silicon surfaces. Grafting densities in the 0.2-1.0 molecule/nm(2) range were determined by X-ray reflectometry. The monolayers exhibit reversible photoisomerization, switching from a more hydrophilic trans state to a less hydrophilic cis state upon UV irradiation, in contrast with the usual behavior of most azobenzene monolayers that switch from a less to a more hydrophilic state. This indicates that the wettability is not dominated by the change in the dipole moment of the azobenzene moiety but originates from variations in the composition of the outer surface of the monolayers resulting from the reorientation of the substituent groups. The light-driven change in the water contact angle correlates linearly with the grafting density but remains small. However, the wettability contrast can be increased by forcing the molecules to stand in an improved vertical orientation, either by densifying the underlying aminosilane monolayer or by filling the voids left at the bottom of the layer of grafted azobenzene molecules. PMID- 21699196 TI - Probing the electronic structure and property of neutral and charged arsenic clusters (As(n)(+1,0,-1), n<=8) using Gaussian-3 theory. AB - The structures and energies of As(n) (n = 2-8) neutrals, anions, and cations have been systematically investigated by means of the G3 schemes. The electron affinities, ionization potentials, binding energies, and several dissociation energies have been calculated and compared with limited experimental values. The results revealed that the potential surfaces of neutral As(n) clusters are very shallow, and two types of structural patterns compete with each other for the ground-state structure of As(n) with n >= 6. One type is derived from the benzvalene form of As(6), and another is derived from the trigonal prism of As(6). The previous photoelectron spectrum (taken from J. Chem. Phys. 1998 , 109 , 10727 ) for As(3) has been reassigned in light of the G3 results. The experimental electron affinities of As(3) were measured to be 1.81 eV, not 1.45 eV. We inferred from the conclusion of G3 and density functional theory that the experimental electron affinities of 1.7 and 3.51 eV for As(5) are unreliable. The reliable electron affinities were predicted to be 0.83 eV for As(2), 1.80 eV for As(3), 0.54 eV for As(4), 3.01 eV for As(5), 2.08 eV for As(6), 2.93 eV for As(7), and 2.02 eV for As(8). The G3 ionization potentials were calculated to be 9.87 eV for As(2), 7.33 eV for As(3), 8.65 eV for As(4), 6.68 eV for As(5), 7.97 eV for As(6), 6.58 eV for As(7), and 7.65 eV for As(8). The binding energies per atom were evaluated to be 1.99 eV for As(2), 2.01 eV for As(3), 2.61 eV for As(4), 2.39 eV for As(5), 2.51 eV for As(6), 2.55 eV for As(7), and 2.67 eV for As(8). These theoretical values of As(2), As(3), and As(4) are in excellent agreement with those of experimental results. Several dissociation energies were carried out to examine relative stabilities. This characterized the even-numbered clusters as more stable than the odd-numbered species. PMID- 21699197 TI - Oxide-confined formation of germanium nanowire heterostructures for high performance transistors. AB - Over the past several years, the formation of nanowire heterostructures via a solid-state reaction between a semiconductor nanowire and metal contact pads has attracted great interest. This is owing to its ready application in nanowire field-effect transistors (FETs) with a well-controlled channel length using a facile rapid thermal annealing process. We report the effect of oxide confinement on the formation of Ge nanowire heterostructures via a controlled reaction between a vapor-liquid-solid-grown, single-crystalline Ge nanowire and Ni pads. In contrast to the previous formation of Ni(2)Ge/Ge/Ni(2)Ge nanowire heterostructures, a segment of high-quality epitaxial NiGe was formed between Ni(2)Ge and Ge with the confinement of Al(2)O(3) during annealing. Significantly, back-gate FETs based on this Ni(2)Ge/NiGe/Ge/NiGe/Ni(2)Ge heterostructure demonstrated a high-performance p-type transistor behavior, showing a large on/off ratio of more than 10(5) and a high normalized transconductance of 2.4 MUS/MUm. The field-effect hole mobility was extracted to be 210 cm(2)/(V s). Temperature-dependent I-V measurements further confirmed that NiGe has an ideal ohmic contact to p-type Ge with a small Schottky barrier height of 0.11 eV. Moreover, the hysteresis during gate bias sweeping was significantly reduced after Al(2)O(3) passivation, and our Omega-gate Ge nanowire FETs using Al(2)O(3) as the top-gate dielectric showed an enhanced subthreshold swing and transconductance. Therefore, we conclude that the Al(2)O(3) layer can effectively passivate the Ge surface and also serve as a good gate dielectric in Ge top-gate FETs. Our innovative approach provides another freedom to control the growth of nanowire heterostructure and to further achieve high-performance nanowire transistors. PMID- 21699198 TI - Interactions between magnetic nanowires and living cells: uptake, toxicity, and degradation. AB - We report on the uptake, toxicity, and degradation of magnetic nanowires by NIH/3T3 mouse fibroblasts. Magnetic nanowires of diameters 200 nm and lengths between 1 and 40 MUm are fabricated by controlled assembly of iron oxide (gamma Fe(2)O(3)) nanoparticles. Using optical and electron microscopy, we show that after 24 h incubation the wires are internalized by the cells and located either in membrane-bound compartments or dispersed in the cytosol. Using fluorescence microscopy, the membrane-bound compartments were identified as late endosomal/lysosomal endosomes labeled with lysosomal associated membrane protein (Lamp1). Toxicity assays evaluating the mitochondrial activity, cell proliferation, and production of reactive oxygen species show that the wires do not display acute short-term (<100 h) toxicity toward the cells. Interestingly, the cells are able to degrade the wires and to transform them into smaller aggregates, even in short time periods (days). This degradation is likely to occur as a consequence of the internal structure of the wires, which is that of a noncovalently bound aggregate. We anticipate that this degradation should prevent long-term asbestos-like toxicity effects related to high aspect ratio morphologies and that these wires represent a promising class of nanomaterials for cell manipulation and microrheology. PMID- 21699199 TI - Self-association and stability of the ApoE isoforms at low pH: implications for ApoE-lipid interactions. AB - Apolipoprotein E (apoE) isoforms are known to differentially accumulate in the lysosomes of neuronal cells, and the deleterious effects of the apoE4 isoform in Alzheimer's disease may relate to its properties at the low lysosomal pH. However, the effect of pH on the molecular properties of full-length apoE is unclear. Here we examine the pH dependence of the monomer-dimer-tetramer reaction, of lipid binding, and of the stability of the three major apoE isoforms. Using FRET measurements, we find that the association-dissociation behavior of apoE proteins changes dramatically with changes in pH. At pH 4.5, approximating the pH of the lysosome, rate constants for association and dissociation are 2-10 times faster than those at pH 7.4. Aggregation beyond the tetrameric form is also more evident at lower pH values. Stability, as measured by urea denaturation at pH 4.5, is found to be considerably greater than that at neutral pH and to be isoform dependent. Lipid binding, as measured by turbidity clearance of unilamellar vesicles of DMPC, is faster at acidic pH values and consistent with our previous hypothesis that it is only the monomeric form of apoE that binds lipid tightly. Since apoE is more stable at pH 4.5 than at neutral pH, the more rapid apoE-lipid interactions at low pH are not correlated with the stability of the apoE isoforms, but rather to the faster association dissociation behavior. Our results indicate that pathological behavior of apoE4 may arise from altered molecular properties of this protein at the acidic pH of the lysosome. PMID- 21699200 TI - Suspended, straightened carbon nanotube arrays by gel chapping. AB - We report large-scale self-assembly of suspended, straightened, single-walled carbon nanotubes (SWNTs) across regular TiO(2) gel islands. By coating a SWNT network on top of a pool of the TiO(2) colloid and inducing a rapid drying and chapping process, initially curled, random SWNTs can be straightened into aligned arrays and suspended across the island gaps. The suspended SWNT arrays were grafted by semiconducting or metallic nanoparticles, resulting in hybrid structures with tailored and neat morphology, and enhanced photoresponse. We further demonstrate these suspended SWNTs can sustain high speed gas blowing (up to 20 m per second) reversibly for hundreds of cycles, and detect gas velocity by the resistance change. PMID- 21699202 TI - (99m)technetium-HYNIC(tricine/TPPTS)-Aca-bombesin(7-14) as a targeted imaging agent with microSPECT in a PC-3 prostate cancer xenograft model. AB - The peptide bombesin (BN) and derivates thereof show high binding affinity for the gastrin-releasing peptide receptor (GRPR), which is highly expressed in primary and metastasized prostate cancer. We have synthesized a new BN-based radiopharmaceutical (99m)technetium-HYNIC(tricine/TPPTS)-Aca-BN(7-14) ((99m)Tc HABN) and evaluated its GRPR targeting properties in vitro and in a xenograft tumor model for human prostate cancer in athymic mice. (99m)Tc-HABN was synthesized, and its lipophilicity and stability were investigated. The IC(50), internalization and efflux properties were determined in vitro using the GRPR expressing human prostate cancer cell line PC-3. (99m)Tc-HABN biodistribution and microSPECT imaging were performed in PC-3 tumor-bearing athymic mice. (99m)Tc HABN was prepared with high labeling yield (>90%), high radiochemical purity (>95%) and a specific activity of ~19.8 MBq/nmol. The partition coefficient log D value was -1.60 +/- 0.06. (99m)Tc-HABN proved to be stable in human serum for 6 h. The IC50 of HYNIC-Aca-BN(7-14) was 12.81 +/- 0.14 nM. Incubation of PC-3 cells with (99m)Tc-HABN demonstrated rapid cellular internalization and a long intracellular retention time. When mice were injected with (99m)Tc-HABN, the activity was predominantly cleared via the kidneys. Uptake in the tumor was 2.24 +/- 0.64% ID/g after 30 min, with a steady decrease during the 4 h study period. In vivo experiments with a blocking agent showed GRPR mediated uptake. (99m)Tc HABN microSPECT imaging resulted in clear delineation of the tumor. (99m)Tc-HABN is a novel BN-based radiopharmaceutical that proved to be suitable for targeted imaging of prostate cancer with microSPECT using the human prostate cancer cell line PC-3 in a xenograft mouse model. PMID- 21699201 TI - Interaction of poly(ethylenimine)-DNA polyplexes with mitochondria: implications for a mechanism of cytotoxicity. AB - Poly(ethylenimine) (PEI) and PEI-based systems have been widely studied for use as nucleic acid delivery vehicles. However, many of these vehicles display high cytotoxicity, rendering them unfit for therapeutic use. By exploring the mechanisms that cause cytotoxicity, and through understanding structure-function relationships between polymers and intracellular interactions, nucleic acid delivery vehicles with precise intracellular properties can be tailored for specific function. Previous research has shown that PEI is able to depolarize mitochondria, but the exact mechanism as to how depolarization is induced remains elusive and therefore is the focus of the current study. Potential mechanisms for mitochondrial depolarization include direct mitochondrial membrane permeabilization by PEI or PEI polyplexes, activation of the mitochondrial permeability transition pore, and interference with mitochondrial membrane proton pumps, specifically Complex I of the electron transport chain and F(0)F(1) ATPase. Herein, confocal microscopy and live cell imaging showed that PEI polyplexes do colocalize to some degree with mitochondria early in transfection, and the degree of colocalization increases over time. Cyclosporin a was used to prevent activation of the mitochondrial membrane permeability transition pore, and it was found that early in transfection cyclosporin a was unable to prevent the loss of mitochondrial membrane potential. Further studies done using rotenone and oligomycin to inhibit Complex I of the electron transport chain and F(0)F(1) ATPase, respectively, indicate that both of these mitochondrial proton pumps are functioning during PEI transfection. Overall, we conclude that direct interaction between polyplexes and mitochondria may be the reason why mitochondrial function is impaired during PEI transfection. PMID- 21699204 TI - An easy entry into 2-halo-3-aryl-4(3H)-quinazoliniminium halides from heteroenyne allenes. AB - An efficient three-step synthesis of 2-halo-3-aryl-4(3H)-quinazoliniminium halides from commercially available materials is described. Upon reaction with hydrogen halides, generated in situ from a Lewis acid (MX) and trace water, a variety of easily accessible heteroenyne-allenes underwent facile intramolecular cyclization to afford the title compounds in good yields. The method is highly versatile and provides a general way to construct quinazoliniminium ring systems with a variety of different substitutions. PMID- 21699205 TI - Quartz crystal microbalance with dissipation monitoring and surface plasmon resonance studies of carboxymethyl cellulose adsorption onto regenerated cellulose surfaces. AB - Adsorption of anionic polyelectrolytes, sodium salts of carboxymethyl celluloses (CMCs) with different degrees of substitution (DS = 0.9 and 1.2), from aqueous electrolyte solutions onto regenerated cellulose surfaces was studied using quartz crystal microbalance with dissipation monitoring (QCM-D) and surface plasmon resonance (SPR) experiments. The influence of both calcium chloride (CaCl(2)) and sodium chloride (NaCl) on CMC adsorption was examined. The QCM-D results demonstrated that CaCl(2) (divalent cation) caused significantly greater CMC adsorption onto regenerated cellulose surfaces than NaCl (monovalent cation) at the same ionic strength. The CMC layers adsorbed onto regenerated cellulose surfaces from CaCl(2) solutions exhibited greater stability upon exposure to flowing water than layers adsorbed from NaCl solutions. Both QCM-D and SPR results showed that CMC adsorption onto regenerated cellulose surfaces from CaCl(2) solutions increased with increasing CaCl(2) concentration up to the solubility limit (10 mM). Voigt-based viscoelastic modeling of the QCM-D data indicated that the CMC layers adsorbed onto regenerated cellulose surfaces had shear viscosities of eta(f) ~ 10(-3) N.s.m(-2) and elastic shear moduli of MU(f) ~ 10(5) N.m(-2). Furthermore, the combination of SPR spectroscopy and QCM-D showed that the CMC layers contained 90-95% water. Adsorption isotherms for CMCs in CaCl(2) solutions were also obtained from QCM-D and were fit by Freundlich isotherms. This study demonstrated that CMC adsorption from CaCl(2) solutions is useful for the modification of cellulose surfaces. PMID- 21699206 TI - Probing stepwise reaction of NNP-ligand copper(I) complex with elemental sulfur by using N-heterocyclic carbene as a trapper. AB - The dinuclear NNP-ligand copper(I) complex [o-N?CH(C(4)H(3)N) PPh(2)C(6)H(4)](2)Cu(2) (1) has been synthesized by the reaction of (CuMes)(4) (Mes = 2,4,6-Me(3)C(6)H(2)) with N-((1H-pyrrol-2-yl)-methylene)-2 (diphenylphosphino)benzenamine under an elimination of MesH. Further reaction of 1 with an excess of S(8) produced a mononuclear Cu(II) complex [o-N?CH(C(4)H(3)N) P(S)Ph(2)C(6)H(4)](2)Cu (5) and CuS. CuS was identified by Raman spectroscopy and 1 and 5 were clearly confirmed by X-ray crystallography. The N-heterocyclic carbene was employed to react with 1 to give a mononuclear [o-N?CH(C(4)H(3)N) PPh(2)C(6)H(4)]Cu{C[N(iPr)CMe](2)} (2). The reactions of 2 were carried out with (1)/(8), (2)/(8), and (5)/(8) equiv of S(8), leading to compounds [o N?CH(C(4)H(3)N)-P(S)Ph(2)C(6)H(4)]Cu{C[N(iPr)CMe](2)} (3), [o-N?CH(C(4)H(3)N) P(S)Ph(2)C(6)H(4)]Cu (4), and 5 respectively, in which CuS was generated in the third reaction and S?C[N(iPr)CMe](2) in the latter two reactions. The clean confirmation of 2-4 demonstrates a stepwise reaction process of 1 with S(8) to 5 and CuS and the N-heterocyclic carbene acts well as a trapping agent. PMID- 21699207 TI - The first and second static electronic hyperpolarizabilities of zigzag boron nitride nanotubes. An ab initio approach through the coupled perturbed Kohn-Sham scheme. AB - The coupled perturbed Kohn-Sham (CPKS) computational scheme for the evaluation of electric susceptibility tensors in periodic systems, recently implemented in the CRYSTAL code, has been extended to third-order. It is, then, used to obtain static electronic hyperpolarizabilities of zigzag BN nanotubes for the first time. This procedure, which is fully analytic in all key steps, requires a double self-consistent treatment for taking into account the first- and second-order response of the system to the applied field. The performance of different functionals is compared and the B3LYP hybrid is ultimately chosen for calculations on nanotubes having radii as large as R = 20 A (6-200 atoms in the unit cell). Such large radii are sufficient to give the pure longitudinal component of the (hyper)polarizability tensors to within 1% of the "exact" hexagonal BN monolayer limit. Other tensor components involving the transverse direction converge more slowly. They can, however, be extrapolated to the monolayer limit to within 4% accuracy except for the pure transverse second hyperpolarizability, which has an error of 13% in that limit. PMID- 21699208 TI - Rational catalysis design on the basis of mechanistic understanding: highly efficient Pd-catalyzed cyanation of aryl bromides with NaCN in recyclable solvents. AB - Rational catalysis design on the basis of a detailed mechanistic understanding has been used to successfully develop the first efficient general Pd-catalyzed aromatic cyanation reaction under the highly sought after practicable conditions: (i) MCN (M = Na or K) as a cyanide source; (ii) low-boiling recyclable solvents; and (iii) minimal quantities of inexpensive, nontoxic promoters. The developed catalytic reaction converts aromatic bromides to the corresponding nitriles in 88 99% isolated yield with NaCN and 0.5-1.0 mol % of a t-Bu(3)P-monoligated Pd catalyst in MeCN-THF within 2 h at 70 degrees C. The process exhibits high functional group tolerance. PMID- 21699210 TI - Direct arylation of polycyclic aromatic hydrocarbons through palladium catalysis. AB - We have discovered that the combination of Pd(OAc)(2)/o-chloranil can catalyze the direct C-H bond arylation of polycyclic aromatic hydrocarbons (PAHs) with arylboroxins that occurs selectively at the K-region. The sequential integration of Pd-catalyzed direct arylation of PAHs and FeCl(3)-mediated cyclodehydrogenation is effective in rapidly extending a parent PAH pi-system with high directionality. PMID- 21699209 TI - Design, synthesis, and biological evaluation of 3,4-dihydroquinolin-2(1H)-one and 1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors. AB - Neuronal nitric oxide synthase (nNOS) inhibitors are effective in preclinical models of many neurological disorders. In this study, two related series of compounds, 3,4-dihydroquinolin-2(1H)-one and 1,2,3,4-tetrahydroquinoline, containing a 6-substituted thiophene amidine group were synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). A structure-activity relationship (SAR) study led to the identification of a number of potent and selective nNOS inhibitors. Furthermore, a few representative compounds were shown to possess druglike properties, features that are often difficult to achieve when designing nNOS inhibitors. Compound (S)-35, with excellent potency and selectivity for nNOS, was shown to fully reverse thermal hyperalgesia when given to rats at a dose of 30 mg/kg intraperitonieally (ip) in the L5/L6 spinal nerve ligation model of neuropathic pain (Chung model). In addition, this compound reduced tactile hyperesthesia (allodynia) after oral administration (30 mg/kg) in a rat model of dural inflammation relevant to migraine pain. PMID- 21699211 TI - Are there atomic orbitals in a molecule? AB - Effective atomic orbitals (AOs) have been calculated by the method of the "fuzzy atoms" analysis by using the numerical molecular orbitals (MOs) obtained from plane-wave DFT calculation, i.e., without introducing any atom-centered functions. The results show that in the case of nonhypervalent atoms there are as many effective AOs with non-negligible occupation numbers, as many orbitals are in the classical minimal basis set of the given atom. This means that, for nonhypervalent systems, it is possible to present the MOs as sums of effective atomic orbitals that resemble very much the atomic minimal basis orbitals of the individual atoms (or their hybrids). For hypervalent atoms some additional orbitals basically of d-type are also of some importance; they are necessary to describe the back-donation to these positive atoms. It appears that the d-type orbitals play a similar role also for strongly positive carbon atoms. The method employed here is also useful to decide whether the use of polarization functions of a given type is a matter of conceptual importance or has only a numerical effect. PMID- 21699213 TI - Colorimetric assay of lead ions in biological samples using a nanogold-based membrane. AB - We have developed a simple paper-based colorimetric membrane for sensing lead ions (Pb(2+)) in aqueous solutions. The nitrocellulose membrane (NCM) was used to trap bovine serum albumin (BSA) modified 13.3-nm Au nanoparticles (BSA-Au NPs), leading to the preparation of a nanocomposite film of a BSA-Au NP-decorated membrane (BSA-Au NPs/NCM). The BSA-Au NPs/NCM operates on the principle that Pb(2+) ions accelerate the rate of leaching of Au NPs induced by thiosulfate (S(2)O(3)(2-)) and 2-mercaptoethanol (2-ME). The BSA-Au NPs/NCM allowed for the detection of Pb(2+) by the naked eye in nanomolar aqueous solutions in the presence of leaching agents such as S(2)O(3)(2-) and 2-ME. We employed the assistance of microwave irradiation to shorten the reaction time (<10 min) for leaching the Au NPs. Under optimal solution conditions (5 mM glycine-NaOH (pH 10), S(2)O(3)(2-) (100 mM), and 2-ME (250 mM), microwaves (450 W)), the BSA-Au NPs/NCM allowed the detection of Pb(2+) at concentrations as low as 50 pM with high selectivity (at least 100-fold over other metal ions). This cost-effective sensing system allowed for the rapid and simple determination of the concentrations of Pb(2+) ions in real samples (in this case, sea water, urine, and blood samples). PMID- 21699212 TI - Oil biodegradation and bioremediation: a tale of the two worst spills in U.S. history. AB - The devastating environmental impacts of the Exxon Valdez spill in 1989 and its media notoriety made it a frequent comparison to the BP Deepwater Horizon spill in the popular press in 2010, even though the nature of the two spills and the environments impacted were vastly different. Fortunately, unlike higher organisms that are adversely impacted by oil spills, microorganisms are able to consume petroleum hydrocarbons. These oil degrading indigenous microorganisms played a significant role in reducing the overall environmental impact of both the Exxon Valdez and BP Deepwater Horizon oil spills. PMID- 21699214 TI - Efficient immobilization and patterning of biomolecules on poly(ethylene terephthalate) films functionalized by ion irradiation for biosensor applications. AB - The surface of a poly(ethylene terephthalate) (PET) film was selectively irradiated with proton beams at various fluences to generate carboxylic acid groups on the surface; the resulting functionalized PET surface was then characterized in terms of its wettability, chemical structure, and chemical composition. The results revealed that (i) carboxylic acid groups were successfully generated in the irradiated regions of the PET surface, and (ii) their relative amounts were dependent on the fluence. A capture biomolecule, anthrax toxin probe DNA, was selectively immobilized on the irradiated regions on the PET surface. Cy3-labeled DNA as a target biomolecule was then hybridized with the probe DNA immobilized on the PET surface. Liver-cancer-specific alpha fetoprotein (AFP) antigen, as a target biomolecule, was also selectively immobilized on the irradiated regions on the PET surface. Texas Red-labeled secondary antibody was then reacted with an AFP-specific primary antibody prebound to the AFP antigen on the PET surface for the detection of the target antigen, using an indirect immunoassay method. The results revealed that (i) well defined micropatterns of biomolecules were successfully formed on the functionalized PET surfaces and (ii) the fluorescence intensity of the micropatterns was dependent mainly on the concentrations of the target DNA hybridized to the probe DNA and the target AFP antigen immobilized on the PET films. The lowest detectable concentrations of the target DNA and target AFP antigen in this study were determined to be 4 and 16 ng/mL, respectively, with the PET film prepared at a fluence of 5 * 10(14) ions/cm(2). PMID- 21699215 TI - Carbon microspheres as ball bearings in aqueous-based lubrication. AB - We present an exploratory study on a suspension of uniform carbon microspheres as a new class of aqueous-based lubricants. The surfactant-functionalized carbon microspheres (~0.1 wt %) employ a rolling mechanism similar to ball bearings to provide low friction coefficients (MU ~ 0.03) and minimize surface wear in shear experiments between various surfaces, even at high loads and high contact pressures. The size range, high monodispersity, and large yield stress of the C(MUsphere), as well as the minimal environmental impact, are all desirable characteristics for the use of a C(MUsphere)-SDS suspension as an alternative to oil-based lubricants in compatible devices and machinery. PMID- 21699216 TI - Solvothermal preparation of Pd nanostructures under nitrogen and air atmospheres and electrocatalytic activities for the oxidation of methanol. AB - Monodispersed Pd nanoparticles and their porous spherelike aggregates with different lattice parameters were solvothermally prepared under nitrogen and air atmospheres. Here PdCl(2) acted as Pd precursor and hexadecylamine played the roles of solvent, reductant, and surface capping agent. Oxygen existing in air resulted in the change of surface capping agent, which then induced the aggregation of Pd nanoparticles, and the incorporation of oxygen led to the expansion of its lattice parameter to 0.398 nm, whereas the standard lattice parameter in metallic Pd is 0.389 nm. The monodispersed nanoparticles presented better catalytic activity and stability for the oxidation of methanol than the sphere-like Pd aggregates. PMID- 21699218 TI - Flavanols and methylxanthines in commercially available dark chocolate: a study of the correlation with nonfat cocoa solids. AB - Intake of flavanols, a subgroup of dietary polyphenols present in many fruits and vegetables, may be associated with health benefits, particularly with reducing the risk of coronary diseases. Cocoa and chocolate products are rich in flavanol monomers, oligomers, and polymers (procyanidins). This study used normal phase HPLC to detect, identify, and quantify epicatechin, catechin, total monomers, procyanidin oligomers and polymers in 14 commercially available chocolate bars. In addition, methylxanthines (theobromine and caffeine) were also quantified. Nonfat cocoa solids (NFCS) were determined both gravimetrically and by calculation from theobromine contents. The flavanol levels of 12 commonly consumed brands of dark chocolate have been quantified and correlated with % theobromine and % NFCS. Epicatechin comprised the largest fraction of total chocolate flavonoids, with the remainder being catechin and procyanidins. Calculated NFCS did not reflect epicatechin (R(2) = 0.41) or total flavanol contents (R(2) = 0.49). Epicatechin (R(2) = 0.96) was a reliable marker of total flavanols, catechin (R(2) = 0.67) to a lesser extent. All dark chocolate tested contained higher levels of total flavanols (93.5-651.1 mg of epicatechin equiv/100 g of product) than a milk or a white "chocolate" (40.6 and 0.0 mg of epicatechin equiv/100 g, respectively). The amount and integrity of procyanidins often suffer in the manufacturing of chocolate, chiefly due to oxidation and alkalinization. In this study, the labeled cocoa content of the chocolate did not always reflect analyzed levels of flavonoids. Increasingly, high % NFCS is being used commercially to reflect chocolate quality. If the flavanol content of chocolate is accepted to be a key determinant of health benefits, then continued monitoring of flavanol levels in commercially available chocolate products may be essential for consumer assurance. PMID- 21699217 TI - Predicting drug-induced hepatotoxicity using QSAR and toxicogenomics approaches. AB - Quantitative structure-activity relationship (QSAR) modeling and toxicogenomics are typically used independently as predictive tools in toxicology. In this study, we evaluated the power of several statistical models for predicting drug hepatotoxicity in rats using different descriptors of drug molecules, namely, their chemical descriptors and toxicogenomics profiles. The records were taken from the Toxicogenomics Project rat liver microarray database containing information on 127 drugs ( http://toxico.nibio.go.jp/datalist.html ). The model end point was hepatotoxicity in the rat following 28 days of continuous exposure, established by liver histopathology and serum chemistry. First, we developed multiple conventional QSAR classification models using a comprehensive set of chemical descriptors and several classification methods (k nearest neighbor, support vector machines, random forests, and distance weighted discrimination). With chemical descriptors alone, external predictivity (correct classification rate, CCR) from 5-fold external cross-validation was 61%. Next, the same classification methods were employed to build models using only toxicogenomics data (24 h after a single exposure) treated as biological descriptors. The optimized models used only 85 selected toxicogenomics descriptors and had CCR as high as 76%. Finally, hybrid models combining both chemical descriptors and transcripts were developed; their CCRs were between 68 and 77%. Although the accuracy of hybrid models did not exceed that of the models based on toxicogenomics data alone, the use of both chemical and biological descriptors enriched the interpretation of the models. In addition to finding 85 transcripts that were predictive and highly relevant to the mechanisms of drug-induced liver injury, chemical structural alerts for hepatotoxicity were identified. These results suggest that concurrent exploration of the chemical features and acute treatment-induced changes in transcript levels will both enrich the mechanistic understanding of subchronic liver injury and afford models capable of accurate prediction of hepatotoxicity from chemical structure and short-term assay results. PMID- 21699220 TI - A gold nanoparticle platform for protein-protein interactions and drug discovery. AB - Gold nanoparticles hold great promise for studying protein-protein interactions because of their intrinsic optical properties. Pink when in a homogeneous suspension, the solution turns blue-gray when particles are drawn close together, for example, when immobilized proteins specifically interact with each other. However, the nanoparticle stability, size, and method of protein attachment contribute to the unreliable outcome of current assays. To overcome these hurdles, we developed novel and reliable methods first to synthesize homogenous particles of optimal diameter and second to apply a heterologous NTA-Ni-SAM coating for controlled orientation and optimal presentation of histidine-tagged proteins. Both methods were proven to greatly enhance assay sensitivity and specificity by increasing the signal and minimizing the nonspecific binding. Our assay reproducibly detected known protein-protein interactions and unambiguously identified small molecules that inhibited them. We believe our gold nanoparticle bioassay is a versatile and trustworthy new platform for analyzing protein protein interactions and high-throughput screening of small-molecule inhibitors. PMID- 21699219 TI - Structure and biosynthesis of amychelin, an unusual mixed-ligand siderophore from Amycolatopsis sp. AA4. AB - Actinobacteria generate a large number of structurally diverse small molecules with potential therapeutic value. Genomic analyses of this productive group of bacteria show that their genetic potential to manufacture small molecules exceeds their observed ability by roughly an order of magnitude, and this revelation has prompted a number of studies to identify members of the unknown majority. As a potential window into this cryptic secondary metabolome, pairwise assays for developmental interactions within a set of 20 sequenced actinomycetes were carried out. These assays revealed that Amycolatopsis sp. AA4, a so-called "rare" actinomycete, produces a novel siderophore, amychelin, which alters the developmental processes of several neighboring streptomycetes. Using this phenotype as an assay, we isolated amychelin and solved its structure by NMR and MS methods coupled with an X-ray crystallographic analysis of its Fe-complex. The iron binding affinity of amychelin was determined using EDTA competition assays, and a biosynthetic cluster was identified and annotated to provide a tentative biosynthetic scheme for amychelin. PMID- 21699221 TI - Printing of sub-100-nm metal nanodot arrays by carbon nanopost stamps. AB - This work reports an efficient method to fabricate hexagonally patterned metal nanodot arrays at the sub-100-nm scale, which is based on contact printing via novel nanometer-scaled stamps. Vertically aligned carbon nanoposts, supported by hexagonally ordered nanochannels of anodic aluminum oxide templates, are employed as the stamping platform to directly transfer controlled metal nanodot arrays. Using the fabrication platform, a number of patterned metal nanodot arrays made of Au, Cu, Ni, Ag, Pt, Al, and Ti can be contact-printed over large substrate areas in ambient conditions. The size, density, and interdistance of the printed nanodots are controllable with a tight correspondence to the mother stamp geometries, which can be precisely tuned by modifying the pore dimensions of the alumina matrixes. An advanced example of contact printing of metal nanoparticles is successfully demonstrated by the controlled formation of nanodot arrays in a specific area. PMID- 21699223 TI - Self-assembled hollow nanospheres strongly enhance photoluminescence. AB - We report that two molecular building blocks differ only by two protons, yet they form totally different nanostructures. The protonated one self-organized into hollow nanospheres (~200 nm), whereas the one without the protons self-assembled into rectangular plates. Consequently, the geometrically defined nanoassemblies exhibit radically different properties. As self-assembly directing units, protons impart ion-pairing and hydrogen-bonding probabilities. The plate-forming nanosystem fluoresces weakly, probably due to energy transfer among chromophores (Phi < 0.2), but the nanospheres emit strong yellow fluorescence (Phi ~ 0.58 0.85). PMID- 21699222 TI - Polymer-based photocoupling agent for the efficient immobilization of nanomaterials and small molecules. AB - A highly efficient photocoupling agent, based on perfluorophenylazide (PFPA) conjugated polyallylamine (PAAm), was developed for the efficient immobilization of polymers, nanoparticles, graphene, and small molecules. The conjugate, PAAm PFPA, was synthesized, and the percentage of the photoactive moiety, PFPA, can be controlled by the ratio of the two components in the synthesis. By treating epoxy functionalized wafers with PAAm-PFPA, photoactive surfaces were generated. Compared with the PFPA surface, these polymer-based photocoupling matrix resulted in significantly enhanced immobilization efficiencies, especially for nanomaterials and small molecules. Thus, polystyrene nanoparticles (PS NPs) and alkyl-functionalized silica nanoparticles (SNPs) were successfully immobilized on the PAAm-PFPA surface, resulting in a high material density. Graphene flakes patterned on the PAAm-PFPA surface showed improved feature resolution in addition to a higher material density compared to that of flakes immobilized on the PFPA surface. Furthermore, 2-O-alpha-D-mannopyranosyl-D-mannopyranose (Man2) immobilized on the PAAm-PFPA surface exhibited significantly enhanced signals when treated with lectin concanavalin A (Con A). PMID- 21699224 TI - Extended frequency range depolarized light scattering study of N-acetyl-leucine methylamide-water solutions. AB - We have studied the influence of the amphiphilic model peptide N-acetyl-leucine methylamide (NALMA) on the dynamics of water using extended frequency range depolarized light scattering (EDLS), between 0.3 GHz and 36 THz. This technique allowed us to separate solute from solvent dynamics and bulk from hydration water, providing both characteristic times and relative fractions. In the temperature range 5-65 degrees C, a retardation factor from 9 to 7 is found for water hydrating NALMA. Moreover, in the same range, a hydration number from 62 to 50 is observed, corresponding to more than two hydration layers. This strong perturbation suggests the existence of a collective effect of amphiphilic molecules on surrounding water molecules. PMID- 21699225 TI - Structural percolation in the PbM(1-x)M(x)'O(3) (M, M' =Ti, Cr, and V) perovskites. AB - Structural properties and the influence of d electrons' insertion in PbTiO(3) have been determined in the study of PbM(1-x)M(x)'O(3) (M, M' = Ti, Cr, and V) solid solutions by means of X-ray diffraction, high-resolution transmission electron microscopy, magnetization measurements, and strain mapping analysis. PbTi(1-x)V(x)O(3) is the only system that preserves the same space group (P4mm) for all x, whereas PbTi(1-x)Cr(x)O(3) and PbV(1-x)Cr(x)O(3) change to cubic (Pm 3m) at x = 0.30 and 0.4, respectively. These values have been related with the percolation threshold for a cubic net (P(c) = 0.31). The microscopy study coincides with the X-ray diffraction determination, and neither supercell nor short-range order maxima are observed. However, for x >= 0.7 in PbTi(1 x)Cr(x)O(3) the presence of modulated zones is observed in both the electron diffraction pattern as well as high-resolution transmission electron micrographs, as is typical for PbCrO(3). (1) Furthermore, the tetragonal region in PbV(1 x)Cr(x)O(3) suffers a great stress because of the contrast of [Cr-O(6)] octahedra and [V-O(5)] square-based pyramids end members basic units. PMID- 21699226 TI - Trifluoroethanol and 19F magic angle spinning nuclear magnetic resonance as a basic surface hydroxyl reactivity probe for zirconium(IV) hydroxide structures. AB - A novel technique for determining the relative accessibility and reactivity of basic surface hydroxyl sites by reacting various zirconium(IV) hydroxide materials with 2,2,2-trifluoroethanol (TFE) and characterizing the resulting material using (19)F magic angle spinning (MAS) nuclear magnetic resonance (NMR) is presented here. Studied here are three zirconium hydroxide samples, two unperturbed commercial materials, and one commercial material that is crushed by a pellet press. Factors, such as the ratio of bridging/terminal hydroxyls, surface area, and pore size distribution, are examined and found to affect the ability of the zirconium(IV) hydroxide to react with TFE. X-ray diffraction, nitrogen isotherms, and (1)H MAS NMR were used to characterize the unperturbed materials, while thermogravitric analysis with gas chromatography and mass spectrometry along with the (19)F MAS NMR were used to characterize the materials that were reacted with TFE. Zirconium hydroxide materials with a high surface area and a low bridging/terminal hydroxyl ratio were found to react TFE in the greatest amounts. PMID- 21699229 TI - Conducting polyaniline nanoparticles and their dispersion for waterborne corrosion protection coatings. AB - A novel approach for preparing waterborne corrosion protection polyaniline (PANI) containing coatings was developed. First, conducting polyaniline/partially phosphorylated poly(vinyl alcohol) (PANI/P-PVA) spherical nanoparticles with significant dispersibility in aqueous media were prepared by the chemical oxidative dispersion polymerization in presence of partially phosphorylated poly(vinyl alcohol) (P-PVA). The PANI/P-PVA-containing coatings with different PANI/P-PVA contents were then prepared, employing waterborne epoxy resin as the matrix. The corrosion protection property of PANI/P-PVA-containing coatings on mild steel was investigated by salt spray test and electrochemical impedance spectroscopy (EIS) technique in 3.0 wt % NaCl aqueous solution. The results indicated that the waterborne PANI/P-PVA-containing coatings (PANI/P-PVA content, 2.5 wt %) could offer high protection because the impedance values remained at higher than 1 * 10(7) Omega cm(2) after 30 days of salt spray tests. All the results were compared with these of the waterborne coatings containing PANI nanoparticles in the emeraldine salt form (PANI ES), and the protection mechanism was also proposed with the evidence of scanning electron microscope (SEM) and X ray photoelectron spectrometry (XPS). PMID- 21699228 TI - Quantitative analysis of cohesin complex stoichiometry and SMC3 modification dependent protein interactions. AB - Cohesin is a protein complex that plays an essential role in pairing replicated sister chromatids during cell division. The vertebrate cohesin complex consists of four core components including structure maintenance of chromosomes proteins SMC1 and SMC3, RAD21, and SA2/SA1. Extensive research suggests that cohesin traps the sister chromatids by a V-shaped SMC1/SMC3 heterodimer bound to the RAD21 protein that closes the ring. Accordingly, the single "ring" model proposes that two sister chromatids are trapped in a single ring that is composed of one molecule each of the 4 subunits. However, evidence also exists for alternative models. The hand-cuff model suggests that each sister chromatid is trapped individually by two rings that are joined through the shared SA1/SA2 subunit. We report here the determination of cohesin subunit stoichiometry of endogenous cohesin complex by quantitative mass spectrometry. Using qConCAT-based isotope labeling, we show that the cohesin core complex contains equimolar of the 4 core components, suggesting that each cohesin ring is closed by one SA1/SA2 molecule. Furthermore, we applied this strategy to quantify post-translational modification dependent cohesin interactions. We demonstrate that quantitative mass spectrometry is a powerful tool for measuring stoichiometry of endogenous protein core complex. PMID- 21699230 TI - Electrochemically triggered Au nanoparticles "sponges" for the controlled uptake and release of a photoisomerizable dithienylethene guest substrate. AB - 1,2-Di(2-methyl-5-(N-methylpyridinium)-thien-3-yl)-cyclopentene undergoes a reversible photoisomerization between open and closed states. The closed isomer state exhibits electron acceptor properties, whereas its irradiation using visible light (lambda > 530 nm) yields the open state that lacks electron acceptor features. The electropolymerization of thioaniline-functionalized Au nanoparticles (NPs) in the presence of the closed photoisomer state yields a molecularly imprinted Au NPs matrix, cross-linked by redox-active bis-aniline pi donor bridges. The closed isomer is stabilized in the imprinted sites of the bis aniline-bridged Au NPs composite by donor-acceptor interactions. The electrochemical oxidation of the bis-aniline bridging units to the quinoid acceptor state leads to imprinted sites that lack affinity interactions for the binding of the closed state to the matrix, leading to the release of the closed photoisomer to the electrolyte solution. By the cyclic reduction and oxidation of the bridging units to the bis-aniline and quinoid states, the reversible electrochemically controlled uptake and release of the closed photoisomer is demonstrated. The quantitative uptake and release of the closed isomer to and from the imprinted Au NPs composites is followed by application of CdSe/ZnS quantum dots as auxiliary probes. Similarly, by the reversible photochemical isomerization of the closed substrate to the open substrate (lambda > 530 nm) and the reversible photoizomerization of the open substrate to the closed state (lambda = 302 nm), the cyclic photonic uptake and release of the closed substrate to and from the imprinted Au NPs matrix are demonstrated. Finally, we demonstrate that the electrochemically stimulated uptake and release of the closed substrate to and from the imprinted Au NPs composite controls the wettability of the resulting surface. PMID- 21699231 TI - Honeycomb-structured films by multifunctional amphiphilic biodegradable copolymers: surface morphology control and biomedical application as scaffolds for cell growth. AB - Recently, fabrication of functional porous polymer films with patterned surface structures at the scale from nanometer to micrometer has been attracting increasing interests in material science and nanobiotechnology. In this work, we present new preparation of two series of multifunctional amphiphilic copolymers and preparation of their microporous thin films on solid substrates. First, diblock dendritic poly(l-lysine)-b-poly(l-lactide)s and triblock dendritic poly(l lysine)-b-poly(l-lactide)-b-dendritic poly(l-lysine)s (C1-C6) were synthesized through 4-dimethylaminopyridine (DMAP)-catalyzed living ring-opening polymerization of (l-)-lactide with (l-)-lysine dendron initiators, and their structures were characterized by nuclear magnetic resonance spectrometer (NMR), gel permeation chromatography (GPC) and matrix-assisted laser desorption/ionization Fourier-transformed mass spectra (MALDI-FTMS). Employing the breath-figure (BF) fabrication strategy, thin films of the synthesized amphiphiles (C1-C6) were drop-cast, and their surface topologies were examined by scanning electron microscopy (SEM) and atomic force microscopy (AFM), and the effects of new amphiphile structure and drop-casting parameters of amphiphile concentration, humidity and temperature on self-assembly of ordered porous surface were studied. Furthermore, the influence of surface energy of drop casting substrates was additionally investigated. With a human cervical epithelial carcinoma cell line (HeLa), cytotoxicity of the prepared honeycomb structured films by new amphiphile C6 was evaluated by thiazoyl-blue-tetrazolium bromide (MTT) assay, and HeLa cell growth behavior with microporous amphiphile films as the scaffolds was also examined. It was found that tunable micropore diameter sizes and well ordered surface topologies of BF films could be achieved for the new prepared amphiphiles, and utilization of the honeycomb-like microporous films as scaffolds indicated favorable enhancement in cell proliferation. Therefore, the honeycomb-structured films by these biocompatible multifunctional amphiphiles may provide new materials as 3D-scaffold materials for potential application in tissue engineering and regeneration. PMID- 21699232 TI - Patterned removal of molecular organic films by diffusion. AB - We demonstrate that "contact patterning" subtractively patterns a wide range of molecular organic films of nanoscale thickness with nanometer-scale accuracy. In "contact patterning", an elastomeric stamp with raised features is brought into contact with the organic film and subsequently removed, generating patterns by the diffusion of the film molecules into the stamp. The mechanism of material removal via diffusion is documented over spans of minutes, hours, and days and is shown to be consistently repeatable. Contact patterning provides a photolithography-free, potentially scalable approach to subtractive patterning of a wide range of molecular organic films. PMID- 21699233 TI - Hybrid bilayer membrane: a platform to study the role of proton flux on the efficiency of oxygen reduction by a molecular electrocatalyst. AB - In this report, we present a novel platform to study proton-coupled electron transfer (PCET) by controlling the proton flux using an electrode-supported hybrid bilayer membrane (HBM). Oxygen reduction by an iron porphyrin was used as a model PCET reaction. The proton flux was controlled by incorporating an aliphatic proton carrier, decanoic acid, into the lipid layer of the HBM. Using this system, we observed a different catalytic behavior than obtained by simply changing the pH of the solution in the absence of an HBM. PMID- 21699234 TI - Temperature-induced aggregation kinetics in aqueous solutions of a temperature sensitive amphiphilic block copolymer. AB - Time effects for the temperature-induced association complexes in solutions of the thermoresponsive poly(N-isopropylacrylamide)-block-poly(ethylene glycol) block-poly(N-isopropylacrylamide) (PNIPAAM(69)-b-PEG(23)-b-PNIPAAM(69)) copolymer that exhibit a lower critical solution temperature were studied by means of turbidimetry and dynamic light scattering (DLS). The DLS results clearly show that at temperatures below the cloud point (CP) unimers coexist with intermicellar structures, which contract as the CP is approached. At this stage, no time effect was detected. At temperatures above the CP, large association structures are formed, and these aggregates dominate the decay of the correlation functions. A novel time-dependent growth of the aggregates was observed over several hours. The growth of the clusters is strengthened as the temperature rises, and this feature is supported by the turbidity results and the reduced scattered intensity experiments. For a low polymer concentration, an initial growth of the clusters is observed, whereas at longer times the apparent hydrodynamic radius from DLS is virtually constant. The results from this work stress the importance to check possible time effects in solutions of thermosensitive copolymers as the cloud point is approached. PMID- 21699235 TI - Laser-induced chemical reaction characterization in photosensitive aqueous solutions. AB - A dual-wavelength on/off-excitation thermal lens technique was used to identify and quantify a laser-induced chemical reaction in ionic aqueous solutions of Fe(II)-TPTZ. On/off modeling was used to fit the TL experimental data, which provided the primary effect generated during laser-excitation. The addition of HCl in the solutions reduced the activation barrier; this behavior followed the Arrhenius correlation. The nature of the photo-oxidation of Fe(II)-TPTZ complex is discussed. The results suggest that this technique may contribute to the understanding of the dynamics of complex reactions, which may lead to a more precise determination of the physicochemical properties involved in a photochemical reaction. PMID- 21699236 TI - PbSe/CdSe and PbSe/CdSe/ZnSe hierarchical nanocrystals and their photoluminescence. AB - Multiple CdSe and ZnSe semiconductor shells were grown on PbSe semiconductor spherical cores with monolayer control. For CdSe shell coating, we found that there was little room to further increase the quantum yields of freshly-made high quality PbSe nanocrystals that already owned very high initial values because of their good surface status; but there was great improvement for the PbSe nanocrystals with low initial quantum yields because of the poor surface status. Nonetheless, the quantum yield for the latter case could not reach the former's value. Additional ZnSe shells on PbSe/CdSe could further increase the quantum yield and protect the nanocrystals from air oxidation. The observed phenomena in the synthesis of the PbSe/CdSe and PbSe/CdSe/ZnSe core/shell structures were explained through the carrier wave function expansion and the surface polarization. PMID- 21699237 TI - Multiplexed analytical glycomics: rapid and confident IgG N-glycan structural elucidation. AB - N-glycans attached to the C(H)2 domains of the Fc or the antigen binding regions of IgG play an important role in stabilizing and modulating antibody activity. Exhaustive elucidation of 32 IgG N-glycans using a combination of weak anion exchange enrichment and exoglycosidase array digestion with subsequent profiling exceeded 48 h. Pursuing increased throughput and associated structural annotation confidence, we compared the 1.7 MUm hydrophilic interaction phase for UPLC with CE-LIF for the rapid and comprehensive characterization of N-glycans released from healthy human serum polyclonal IgG. Combination of the data individually generated using each technique demonstrated that complete structural annotation was possible within a total analysis time of 20 min due to the advantageous orthogonality of the separation mechanisms. The parallel use of both analytical techniques provides a powerful platform for rapid and comprehensive analysis of IgG N-glycosylation present on therapeutic antibodies or on antibodies of biomedical or pathological significance. PMID- 21699238 TI - Functional proteomics of neuropeptidome dynamics during the feeding process of Rhodnius prolixus. AB - In hematophagous insects, blood intake triggers a prompt response mediated by neuropeptides, which regulates a variety of physiological processes. Here we report a quantitative proteomic analysis of the postfeeding response in the central nervous system of Rhodnius prolixus, a vector of Chagas disease. The concentration of neuropeptides NVP-like, ITG-like, kinin-precursor peptide, and neuropeptide-like precursor 1 (NPLP1) significantly changes in response to blood intake. We also performed a neuropeptidomic analysis of other feeding-related organs, namely salivary glands and gut. We identified NPLP1 in salivary glands and myosuppressin in midgut. This is the first report suggesting a role for NPLP1, involving the peptides processed from this precursor in the hormonal control of the production and/or release of saliva. Our results contribute to the understanding of the postprandial neuroendocrine response in hematophagous and provide important information for physiological and pharmacological studies aimed to the design of next-generation insecticides such as peptidomimetics. PMID- 21699239 TI - Interactive configuration through force analysis of GM1 pentasaccharide-Vibrio cholera toxin interaction. AB - Understanding of the molecular relationships in carbohydrate-protein interactions provides useful information on biological processes in living organisms and is also helpful for development of potent biomedical agents. Herein, the interaction unbinding force between GM1 pentasaccharide and Vibrio cholera toxin (ctx) proteins was measured using atomic force microscopy (AFM), which enabled us to determine the interaction of ctx holotoxin (ctxAB) with GM1 and the interactive formation. First, the interaction force measured between A and B subunits (ctxA ctxB) was 184.2 +/- 4.5 pN, and the unbinding forces were evaluated to confirm the role of ctxA in ctxAB complex formation and were determined to be 443.7 +/- 7.5 and 535.7 +/- 25.9 pN for GM1-ctxB and GM1-ctxAB complexes, respectively. The force difference of ~90 pN between GM1-ctxB and GM1-ctxAB might be due to the formation of the cholera toxin complex. Importantly, from the analogue analyses, we understand how structural and binding positional differences in complex carbohydrates affect the interaction with protein and surmise that the GM1-ctxAB complex makes a "two-finger grip" formation through the conformational change of a flexible carbohydrate. In conclusion, using AFM force analysis, we successfully quantified and characterized the interactive configuration of carbohydrate protein molecules. PMID- 21699240 TI - Pressure-induced phase transitions in ammonium squarate: a supramolecular structure based on hydrogen-bonding and pi-stacking interactions. AB - We report the results of high-pressure Raman and X-ray diffraction measurements performed on ammonium squarate ((NH(4))(2)C(4)O(4), AS), a representative supramolecular architecture based on hydrogen bonding and pi-stacking interactions, at various pressures up to 19 GPa. Two phase transitions at ~2.7 GPa and in the pressure range of 11.1-13.6 GPa were observed. Both Raman and XRD results provide convincing evidence for these two phase transitions. The first phase transition is attributed to the rearrangements of hydrogen-bonding networks, resulting in the symmetry transformation from P2(1)/c to P1. The second one, which is identified as an order-disorder phase transition, arises from significant modifications of squarate rings and random orientations of NH(4)(+) cations. The cooperative effects between hydrogen-bonding and pi-stacking interactions, as well as mechanisms for the phase transitions, are discussed by virtue of the local structure of AS. PMID- 21699241 TI - Polychlorodibenzodioxin and -furan (PCDD and PCDF) and dioxin-like polychlorobiphenyl (DL-PCB) congener levels in milk of grazing sheep as indicators of the environmental quality of rural areas. AB - An observational study was set up to evaluate how the quality of the environment may influence the levels of of PCDDs, PCDFs, and DL-PCBs in sheep's milk. Seven farms under natural and anthropogenic pressures were considered, along with an inventory of the surrounding regular and natural sources of emissions. Analysis by HRGC-HRMS revealed the highest cumulative levels (2.1 pg of WHO(1998)-TE/g fat) in one organic and one conventional farm, each close to a relevant bushfire. Their pattern was characterized by a noticeable contribution (24%) from mono ortho-PCB congeners to the cumulative WHO-TE. For the other farms, close to potential anthropogenic sources, the levels recorded in milk ranged from 0.7 to 1.3 pg of WHO-TE/g fat. The health and reproductive indicators were in all herds within the physiological range. Results suggest the environmental quality in extensive farming system should be eligible as a food safety factor, also for organic productions. PMID- 21699243 TI - Genetic and marine cyclonic eddy analyses on the largest macroalgal bloom in the world. AB - In 2008, a massive Ulva prolifera bloom, with a 3-million-ton biomass covering an area of 1.29 * 10(4) km(2) at its largest, suddenly appeared from May to July in South Yellow Sea. The mechanism behind the rapid growth of these seaweeds was investigated. Molecular phylogenetic analysis of free-floating algal samples from the Yellow Sea suggested that U. prolifera belong to one population, and that temporary cyclonic eddies in the Yellow Sea in late spring and early summer may help promote the proliferation of this bloom by providing seaweeds with sufficient growth time, abundant nutrition, and favorable habitats. The initial investigation on the relationship between marine cyclonic eddies and the route of free-floating algae extends our knowledge on how the emergence of free-floating macroalgal blooms in coastal areas could yield a large biomass. PMID- 21699244 TI - Bioactive phytochemicals of leaf essential oils of Cinnamomum osmophloeum prevent lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced acute hepatitis in mice. AB - The purpose of this study was to investigate the bioactive phytochemicals of leaf essential oils of Cinnamomum osmophloeum on lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced acute hepatitis. The results revealed that post-treatment with 100 MUmol/kg trans-cinnamaldehyde, (-)-aromadendrene, T-cadinol, or alpha cadinol significantly decreased the aspartate aminotransferase (AST), alanine aminotransferase (ALT), tumor necrosis factor-alpha (TNF-alpha), and interleukin 6 (IL-6) levels in serum. Moreover, both T-cadinol and alpha-cadinol treatments decreased the expressions of cleaved caspase-3 and cleaved poly-ADP ribose polymerase (PARP) in the liver tissues when compared with the LPS/D-GalN group. Liver histopathology also showed that silymarin, trans-cinnamaldehyde, (-) aromadendrene, T-cadinol, or alpha-cadinol significantly reduced the incidence of liver lesions induced by LPS/D-GalN. These results suggest that the above phytochemicals exhibit potent hepatoprotection against LPS/D-GalN-induced liver damage in mice, and their hepatoprotective effects may be due to the modulation of anti-inflammatory activities. PMID- 21699245 TI - Ultraviolet-induced oxidation of ascorbic acid in a model juice system: identification of degradation products. AB - Degradation products of ultraviolet (UV-C, 254 nm) treated ascorbic acid (AA) are reported. Analysis by high-performance liquid chromatography-mass spectroscopy (HPLC-MS) conducted in a 0.5% malic acid model juice system (pH 3.3) demonstrated increased degradation of AA above untreated controls with concomitant increases in dehydroascorbic acid (DHA) and 2,3-diketogulonic acid (DKGA) levels. Electron spin resonance (ESR) spectroscopy studies, conducted in phosphate buffer (pH 7.0) to increase detection sensitivity, demonstrated that ascorbyl radical (AA*) formation occurs simultaneously with AA degradation. Consistent with a previous study in which UV treatments were shown to accelerate dark storage degradation, AA* radicals continued to form for up to 200 min after an initial UV treatment. Results from this study suggest that the mechanism for UV-induced degradation is the same as the general mechanism for metal-catalyzed oxidation of AA in juice. PMID- 21699246 TI - Normalizing molecular docking rankings using virtually generated decoys. AB - Drug discovery research often relies on the use of virtual screening via molecular docking to identify active hits in compound libraries. An area for improvement among many state-of-the-art docking methods is the accuracy of the scoring functions used to differentiate active from nonactive ligands. Many contemporary scoring functions are influenced by the physical properties of the docked molecule. This bias can cause molecules with certain physical properties to incorrectly score better than others. Since variation in physical properties is inevitable in large screening libraries, it is desirable to account for this bias. In this paper, we present a method of normalizing docking scores using virtually generated decoy sets with matched physical properties. First, our method generates a set of property-matched decoys for every molecule in the screening library. Each library molecule and its decoy set are docked using a state-of-the-art method, producing a set of raw docking scores. Next, the raw docking score of each library molecule is normalized against the scores of its decoys. The normalized score represents the probability that the raw docking score was drawn from the background distribution of nonactive property-matched decoys. Assuming that the distribution of scores of active molecules differs from the nonactive score distribution, we expect that the score of an active compound will have a low probability of having been drawn from the nonactive score distribution. In addition to the use of decoys in normalizing docking scores, we suggest that decoy sets may be a useful tool to evaluate, improve, or develop scoring functions. We show that by analyzing docking scores of library molecules with respect to the docking scores of their virtually generated property-matched decoys, one can gain insight into the advantages, limitations, and reliability of scoring functions. PMID- 21699247 TI - Ring-opening copolymerization of maleic anhydride with epoxides: a chain-growth approach to unsaturated polyesters. AB - We report the ring-opening copolymerization of maleic anhydride with a variety of epoxides catalyzed by a chromium(III) salen complex. Quantitative isomerization of the cis-maleate form of all polymers affords the trans-fumarate analogues. Addition of chain transfer reagents yields low M(n), narrow PDI polymer samples. This method provides access to a range of new unsaturated polyesters with versatile functionality, as well as the first synthesis of high molecular weight poly(propylene fumarate). PMID- 21699249 TI - Interplay of olefin metathesis and multiple hydrogen bonding interactions: covalently cross-linked zippers. AB - Hydrogen-bonded zippers bearing terminal alkene groups were treated with Grubbs' catalyst, leading to covalently cross-linked zippers without violating H-bonding sequence specificity. The yield of a cross-linked zipper depended on the stability of its H-bonded precursor, with a weakly associating pair giving reasonable yields only at high concentrations while strongly associating pairs showed nearly quantitative yields. The integration of thermodynamic (H-bonding) and kinetic (irreversible C?C bond formation) processes suggests the possibility of developing many different covalent association units for constructing molecular structures based on a self-assembling way. PMID- 21699248 TI - Stereodifferentiation in the compartmentalized photooxidation of a protein-bound anthracene. AB - Encapsulation within transport proteins strongly reduces the photooxidation rate of (S)- and (R)-2-(9-anthracenyl)propanoic acid (1) and results in a significant stereodifferentiation. The most remarkable effects are observed within human serum albumin (HSA). PMID- 21699251 TI - Rhodium-catalyzed anti-Markovnikov addition of secondary amines to arylacetylenes at room temperature. AB - An efficient method for synthesis of E-enamines by the anti-Markovnikov addition of secondary amines to terminal alkynes is described. The reaction of a variety of aryl- and heteroarylacetylenes proceeded at room temperature using a combination of a 8-quinolinolato rhodium complex and P(p-MeOC(6)H(4))(3) as a catalyst. The products were obtained as enamines by simple bulb-to-bulb distillation. PMID- 21699250 TI - A remarkable multicomponent cascade sequence for the formation of a spirocyclic polyether. AB - A reaction of 2-hydroxy-2-methylbutan-3-one with sodium hydride in the presence or absence of ethyl formate after acid workup gave the spirocyclic ether 3. PMID- 21699252 TI - New Dirac fermions in periodically modulated bilayer graphene. AB - We investigate the effect of periodic potentials on the electronic structure of bilayer graphene and show that there is a critical value of the external potential below which new Dirac fermions are generated in the low-energy band structure, and above which a band gap is opened in the system. Our results, obtained from a self-consistent tight-binding calculation, can be simply explained by a two-band continuum model as a consequence of the pseudospin physics in graphene. The findings are robust against changes in the form of the potential, as well as bias voltages between the layers. PMID- 21699253 TI - Online comprehensive two-dimensional characterization of puff-by-puff resolved cigarette smoke by hyphenation of fast gas chromatography to single-photon ionization time-of-flight mass spectrometry: quantification of hazardous volatile organic compounds. AB - This work presents the direct coupling of a custom-made smoking machine (SM) to fast gas chromatography combined with single-photon ionization mass spectrometry (GC * SPI-MS) utilizing a six-port, two-position valve for online puff-resolved comprehensive two-dimensional investigation of cigarette smoke. The innovative electron-beam pumped rare gas excimer light source (EBEL) filled with argon provided vacuum ultraviolet (VUV) photons of 9.8 +/- 0.4 eV (126 +/- 9 nm) for SPI. Puff-by-puff quantification of 14 hazardous volatile organic smoke constituents from the 2R4F Kentucky research cigarette was enabled for two smoking regimes, i.e., ISO and Canadian Intense, after determination of photoionization cross sections. The investigated analytes comprised NO, acetaldehyde, butadiene, acrolein, propanal, acetone, isoprene, furan, crotonaldehyde, isobutanal, butanal, 2-butanone, benzene, and toluene. The determined amounts of these compounds in cigarette smoke agreed excellently with the literature values. Furthermore, the two well-known patterns of puff-by-puff behaviors for these different smoke constituents were obtained for both whole smoke and gas-phase measurements. PMID- 21699255 TI - CuO nanostructures as quartz crystal microbalance sensing layers for detection of trace hydrogen cyanide gas. AB - In this work, quartz crystal microbalance (QCM) sensors for detection of trace hydrogen cyanide (HCN) gas were developed based on nanostructural (flower-like, boat-like, ellipsoid-like, plate-like) CuO. Responses of all the sensors to HCN were found to be in an opposite direction as compared with other common volatile substances, offering excellent selectivity for HCN detection. The sensitivity of these sensors is dependent on the morphology of CuO nanostructures, among which the plate-like CuO has the highest sensitivity (2.26 Hz/MUg). Comparison of the specific surface areas of CuO nanostructures shows that CuO of higher surface area (9.3 m(2)/g) is more sensitive than that of lower surface area (1.5 m(2)/g), indicating that the specific surface area of these CuO nanostructures plays an important role in the sensitivity of related sensors. On the basis of experimental results, a sensing mechanism was proposed in which a surface redox reaction occurs between CuO and Cu(2)O on the CuO nanostructures reversibly upon contact with HCN and air, respectively. The CuO-functionalized QCM sensors are considered to be a promising candidate for trace HCN gas detection in practical applications. PMID- 21699254 TI - DFT study on the radical anions formed by primaquine and its derivatives. AB - The electron affinities (EA) of the 8-aminoquinoline antimalarial drug primaquine and several of its metabolites were studied using the density functional theory method. We first considered six substituents at the 5-position, -CH(3), -OH, OCH(3), -Ph, -OPh, and -CHO. We found that in the gas phase the adiabatic EAs are similar to that of the parent primaquine for the -CH(3), -OH, and -OCH(3) substituents. In contrast, the -Ph, -OPh, and -CHO substituents all markedly increase the adiabatic EA. However, only the -CHO substituted compound is predicted to form a stable covalently bound radical anion in the gas phase due to its significant positive vertical EA relative to that of the parent primaquine. In addition, when the 8-position is substituted by the N-hydroxyl group or a quinone-imine structure is formed, the electron capture ability is significantly increased. In aqueous solution, all these molecules have significantly larger adiabatic EAs than in the gas phase. In addition, all of the vertical EAs are positive in aqueous solution. The implications of these findings for contributing to our mechanistic understanding of the red cell toxicity of 8-aminoquinoline compounds are further discussed. PMID- 21699256 TI - Improved photocatalytic activity of WO3 through clustered Fe2O3 for organic degradation in the presence of H2O2. AB - Photocatalytic degradation of organic substrates over WO(3) in an aerated aqueous suspension is very slow due to the difficulty of O(2) reduction by the conduction band electron on WO(3). In this work, we report on H(2)O(2) as an electron scavenger significantly accelerating the photodegradation of phenol and azo-dye X3B in water under UV or visible light. More importantly, an iron-containing WO(3) (FeW) synthesized through thermal decomposition of a ferrotungstenic acid displayed a much higher activity than pure WO(3) (HW) prepared in parallel. As the sintering temperature increased, both FeW and HW showed an exponential increase in activity. The maximum rate constant of phenol degradation obtained with FeW at 400 degrees C was about 2 times larger than that with HW at 600 degrees C. Sample characterization with electron paramagnetic resonance (EPR) spectroscopy and other techniques revealed that ferric species (0.3 wt % Fe(2)O(3)) were mainly present as clusters on the oxide surface at 120 degrees C and then they diffused toward the lattice sites of WO(3) at high temperature, which was detrimental to the photocatalytic reaction. 5,5-Dimethyl-1-pyrroline N oxide spin-trapping EPR showed that the production of hydroxyl radicals was greatly enhanced upon the addition of H(2)O(2), the trend of which among different catalysts was the same as that of the rate of phenol degradation. The catalysts after excitation at 350 nm displayed a blue emission centered at 469 nm, the intensity of which varied with the catalyst activity nearly as expected. A possible mechanism for the improved photoactivity of WO(3) is proposed involving the electron transfer from WO(3) to Fe(2)O(3) and the reaction of the reduced oxide with H(2)O(2) to generate hydroxyl radicals. PMID- 21699257 TI - Monitoring the glycosylation status of proteins using Raman spectroscopy. AB - Protein-based biopharmaceuticals are becoming increasingly widely used as therapeutic agents, and the characterization of these biopharmaceuticals poses a significant analytical challenge. In particular, monitoring posttranslational modifications (PTMs), such as glycosylation, is an important aspect of this characterization because these glycans can strongly affect the stability, immunogenicity, and pharmacokinetics of these biotherapeutic drugs. Raman spectroscopy is a powerful tool, with many emerging applications in the bioprocessing arena. Although the technique has a relatively rich history in protein science, only recently has Raman spectroscopy been investigated for assessing posttranslational modifications, including phosphorylation, acetylation, trimethylation, and ubiquitination. In this investigation, we develop for the first time Raman spectroscopy combined with multivariate data analyses, including principal components analysis and partial least-squares regression, for the determination of the glycosylation status of proteins and quantifying the relative concentrations of the native ribonuclease (RNase) A protein and RNase B glycoprotein within mixtures. PMID- 21699258 TI - Self-assembly of dendronized perylene bisimides into complex helical columns. AB - The synthesis of perylene 3,4:9,10-tetracarboxylic acid bisimides (PBIs) dendronized with first-generation dendrons containing 0 to 4 methylenic units (m) between the imide group and the dendron, (3,4,5)12G1-m-PBI, is reported. Structural analysis of their self-organized arrays by DSC, X-ray diffraction, molecular modeling, and solid-state (1)H NMR was carried out on oriented samples with heating and cooling rates of 20 to 0.2 degrees C/min. At high temperature, (3,4,5)12G1-m-PBI self-assemble into 2D-hexagonal columnar phases with intracolumnar order. At low temperature, they form orthorhombic (m = 0, 2, 3, 4) and monoclinic (m = 1) columnar arrays with 3D periodicity. The orthorhombic phase has symmetry close to hexagonal. For m = 0, 2, 3, 4 ,they consist of tetramers as basic units. The tetramers contain a pair of two molecules arranged side by side and another pair in the next stratum of the column, turned upside down and rotated around the column axis at different angles for different m. In contrast, for m = 1, there is only one molecule in each stratum, with a four strata 2(1) helical repeat. All molecules face up in one column, and down in the second column, of the monoclinic cell. This allows close and extended pi stacking, unlike in the disruptive up-down alteration from the case of m = 0, 2, 3, 4. Most of the 3D structures were observed only by cooling at rates of 1 degrees C/min or less. This complex helical self-assembly is representative for other classes of dendronized PBIs investigated for organic electronics and solar cells. PMID- 21699259 TI - Graphene-wrapped sulfur particles as a rechargeable lithium-sulfur battery cathode material with high capacity and cycling stability. AB - We report the synthesis of a graphene-sulfur composite material by wrapping poly(ethylene glycol) (PEG) coated submicrometer sulfur particles with mildly oxidized graphene oxide sheets decorated by carbon black nanoparticles. The PEG and graphene coating layers are important to accommodating volume expansion of the coated sulfur particles during discharge, trapping soluble polysulfide intermediates, and rendering the sulfur particles electrically conducting. The resulting graphene-sulfur composite showed high and stable specific capacities up to ~600 mAh/g over more than 100 cycles, representing a promising cathode material for rechargeable lithium batteries with high energy density. PMID- 21699261 TI - Growth suppression of HER2-overexpressing breast cancer cells by berberine via modulation of the HER2/PI3K/Akt signaling pathway. AB - Berberine (BBR) is a natural alkaloid with significant antitumor activities against many types of cancer cells. This study investigated the molecular mechanisms by which BBR suppresses the growth of HER2-overexpressing breast cancer cells. The results show that BBR induces G1-phase cell cycle arrest by interfering with the expression of cyclins D1 and E and that it induces cellular apoptosis through the induction of a mitochondria/caspase pathway. The data also indicate that BBR inhibits cellular growth and promotes apoptosis by down regulating the HER2/PI3K/Akt signaling pathway. Furthermore, it is also shown that a combination of taxol and BBR significantly slows the growth rate of HER2 overexpressing breast cancer cells. In conclusion, this study suggests that BBR could be a useful adjuvant therapeutic agent in the treatment of HER2 overexpressing breast cancer. PMID- 21699262 TI - Regioselective radical bromoallylation of allenes leading to 2-bromo-substituted 1,5-dienes. AB - The regioselective radical bromoallylation of allenes proceeded efficiently in the presence of AIBN as a radical initiator to give 2-bromo-substituted 1,5 dienes in excellent yields. The addition of a bromine radical took place regioselectively onto the central carbon of allenes generating a stable allyl radical, which underwent addition/beta-fragmentation reactions with allylbromides. The products could be further functionalized by Pd-catalyzed coupling reactions. PMID- 21699263 TI - Versatile method for the detection of covalently bound substrates on solid supports by DART mass spectrometry. AB - Analysis of substrates directly on solid phase resins without the need for separate cleavage conditions remains an outstanding challenge in the field of solid phase synthesis. We now present the first example of simultaneous cleavage and mass spectrometric analysis of peptides from solid supports using direct analysis in real time (DART) mass spectrometry. We have shown that this method is compatible with a diverse array of solid phase resins and is suitable for analysis of both peptides and organic substrates. PMID- 21699264 TI - Ruthenium-catalyzed reductive amination of allylic alcohols. AB - Straighforward access to various saturated amines from allylic alcohols and isostructural mixture can now be achieved in the presence of arene ruthenium catalyst featuring phosphinesulfonate ligand and a hydrogen donor. PMID- 21699265 TI - Organocatalyzed regio- and enantioselective allylic trifluoromethylation of Morita-Baylis-Hillman adducts using Ruppert-Prakash reagent. AB - The organocatalyzed regioselective allylic trifluoromethylation of Morita-Baylis Hillman adducts using Ruppert-Prakash reagent was achieved in high to excellent yields via a successive S(N)2'/S(N)2' mode for the first time. The reaction was extended to the asymmetric allylic trifluoromethylation by the use of a bis cinchona alkaloid catalyst with high enantioselectivities up to 94% ee. PMID- 21699266 TI - Chrysin protects epidermal keratinocytes from UVA- and UVB-induced damage. AB - Chrysin (5,7-dihydroxyflavone), a natural flavonoid occurring in various plants and foods such as propolis and honey, reportedly opposes inflammation and carcinogenesis, but has rarely been applied in skin care. This study, therefore, aimed to explore the roles of chrysin in protection against UV-induced damage in HaCaT keratinocytes. Results showed that chrysin can attenuate apoptosis, reactive oxygen species (ROS) production, and cyclooxygenase 2 (COX-2) expression induced by UVB and UVA. Chrysin predominantly reversed the down-regulation of aquaporin 3 (AQP-3) by UVB. It predominantly reversed JNK activation and also mildly inhibited p38 activation triggered by UVA and UVB. Animal studies revealed that chrysin's topical application demonstrated efficient percutaneous absorption and no skin irritation. Overall, results demonstrated significant benefits of chrysin on the protection of keratinocytes against UVA- and UVB-induced injuries and suggested its potential use in skin photoprotection. PMID- 21699267 TI - Widom line for the liquid-gas transition in Lennard-Jones system. AB - The locus of extrema (ridges) for heat capacity, thermal expansion coefficient, compressibility, and density fluctuations for model particle systems with Lennard Jones (LJ) potential in the supercritical region have been obtained. It was found that the ridges for different thermodynamic values virtually merge into a single Widom line at T < 1.1T(c) and P < 1.5P(c) and become practically completely smeared at T < 2.5T(c) and P < 10P(c), where T(c) and P(c) are the critical temperature and pressure. The ridge for heat capacity approaches close to critical isochore, whereas the lines of extrema for other values correspond to density decrease. The lines corresponding to the supercritical maxima for argon and neon are in good agreement with the computer simulation data for LJ fluid. The behavior of the ridges for LJ fluid, in turn, is close to that for the supercritical van der Waals fluid, which is indicative of a fairly universal behavior of the Widom line for a liquid-gas transition. PMID- 21699268 TI - Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge. AB - Attention-deficit hyperactivity disorder (ADHD), a common neurobehavioural disorder characterized by inattention, hyperactivity and impulsivity, is a chronic disorder and often persists into adulthood. CNS stimulants have been the most well known treatment for ADHD for several decades due to their high effectiveness, good safety profiles and relatively minor adverse effects. Non stimulant agents, including atomoxetine, extended-release guanfacine and extended release clonidine (US FDA approved), and several non-FDA-approved agents, such as bupropion and tricyclic antidepressants (TCAs), were recently proven to be effective alternatives to the stimulants in several open-label and placebo controlled trials. However, most medication trials for ADHD have been short term and thus have not provided information on the long-term outcomes of ADHD treatment. Since the medical treatment of many children with ADHD, especially those with more severe symptoms or co-morbid disorders, has to be continued for several years, recent studies have shifted their focus from the acute effectiveness of stimulants or non-stimulant drugs to the long-term outcomes of medications for ADHD. Evidence has shown that stimulants, along with the non stimulants atomoxetine and extended-release guanfacine, are continuously effective for 24-month treatment periods with few and tolerable adverse effects. PMID- 21699269 TI - Enhancing CNS repair in neurological disease: challenges arising from neurodegeneration and rewiring of the network. AB - Repair of the central nervous system (CNS) constitutes an integral part of treating neurological disease and plays a crucial role in restoring CNS architecture and function. Distinct strategies have been developed to reconstruct the damaged neural tissue, with many tested preclinically in animal models. We review cell replacement-based repair strategies. By taking spinal cord injury, cerebral ischaemia and degenerative CNS disorders as examples for CNS repair, we discuss progress and potential problems in utilizing embryonic stem cells and adult neural/non-neural stem cells to repair cell loss in the CNS. Nevertheless, CNS repair is not simply a matter of cell transplantation. The major challenge is to induce regenerating neural cells to integrate into the neural network and compensate for damaged neural function. The neural cells confront an environment very different from that of the developmental stage in which these cells differentiate to form interwoven networks. During the repair process, one of the challenges is neurodegeneration, which can develop from interrupted innervations to/from the targets, chronic inflammation, ischaemia, aging or idiopathic neural toxicity. Neurodegeneration, which occurs on the basis of a characteristic vascular and neural web, usually presents as a chronically progressive process with unknown aetiology. Currently, there is no effective treatment to stop or slow down neurodegeneration. Pathological changes from patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis indicate a broken homeostasis in the CNS. We discuss how the blood-brain barrier and neural networks are formed to maintain CNS homeostasis and their contribution to neurodegeneration in diseased conditions. Another challenge is that some inhibitors produced by CNS injury do not facilitate the regenerating neural cells to incorporate into a pre-existing network. We review glial responses to CNS injury. Of note, the reactive astrocytes not only encompass the lesions/pathogens but may also form glial scars to impede regenerating axons from traversing the lesions. In addition, myelin debris can prevent axon growth. Myelination enables saltatory transduction of electrical impulses along axonal calibers and actually provides trophic support to stabilize the axons. Therefore, repair strategies should be designed to promote axonal growth, myelination and modulate astrocytic responses. Finally, we discuss recent progress in developing human monoclonal IgMs that regulate CNS homeostasis and promote neural regeneration. PMID- 21699270 TI - Pharmacological management of treatment-resistant obsessive-compulsive disorder. AB - Once considered rare and resistant to treatment, obsessive-compulsive disorder (OCD) has now emerged as a common, yet often unrecognized, psychiatric condition. Treatment with selective serotonin reuptake inhibitors (SSRIs) is effective in 40 60% of patients with OCD. Management of the remaining 40-60% of patients with treatment-resistant OCD is challenging. We review up-to-date evidence focusing on strategies for treatment-resistant OCD, including increasing the dose of SSRI, switching to another SSRI, augmentation with antipsychotics, and the use of serotonin noradrenaline (norepinephrine) reuptake inhibitors (SNRIs) and monoamine oxidase inhibitors (MAOIs). Finally, we provide a flow chart, which includes nonpharmacological interventions such as cognitive-behavioural therapy, family interventions and physical interventions such as neurosurgery and deep brain stimulation, alongside the pharmacological strategies. PMID- 21699271 TI - Issues in the management of challenging behaviours of adults with autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a particularly important risk factor for challenging behaviours such as aggression, tantrums, self-injury and pica. Adults with ASD have rarely been studied with respect to these problems. This is particularly disconcerting since there are far more adults than children with ASD. In addition, because of adults' increased physical size and longer history of these problems, treating these behaviours effectively is important. Psychological methods, particularly applied behaviour analysis, and pharmacotherapy have been the most frequently addressed treatments for challenging behaviours associated with ASD in the research literature. In many cases, challenging behaviours have clear environmental antecedents. In these cases, behavioural interventions, such as applied behaviour analysis, should be used to reduce the behaviours. When environmental factors cannot be identified or when challenging behaviours are very severe, pharmacological treatments may be necessary in combination with behavioural interventions. Newer antipsychotics are the most researched medications for use with this population. Currently, risperidone and aripiprazole are the only medications that have US FDA approval for the treatment of behaviours associated with ASD, specifically irritability; however, they are indicated for use in children not adults. It is important not to use medications unnecessarily, due to possible side effects associated with their use. Based on available research, some recommendations for the treatment of challenging behaviours of adults (and children) with ASD include the use of functional assessment, side-effect monitoring of medications and behavioural methods whenever possible. Additionally, future research in this area needs to focus more on adults, as most current research has used child samples. PMID- 21699272 TI - Rituximab for secondary progressive multiple sclerosis: a case series. AB - BACKGROUND: While numerous substances have been developed for the treatment of relapsing-remitting multiple sclerosis over recent years, options are still limited for patients with secondary progressive multiple sclerosis (SPMS). OBJECTIVES AND METHODS: In this observational study we present clinical and CSF findings in three patients with SPMS who were treated with rituximab for at least 15 months. RESULTS: During the observation period, no severe adverse effects occurred and the Expanded Disability Status Scale (EDSS) score stabilized in all patients after a dramatic increase over the previous years. In contrast to other publications, we showed that the time to reoccurrence of B cells was very variable and that serial CSF examinations in the course of treatment revealed a decline in intrathecal IgG synthesis. CONCLUSION: Rituximab seems to be effective in active SPMS. Restitution of the pathogenic immune response after administration of rituximab is variable. Further studies are needed to determine the optimal dosage and timing for rituximab therapy in multiple sclerosis. PMID- 21699273 TI - Vilazodone: in major depressive disorder. AB - Vilazodone, a novel antidepressant agent that combines selective serotonin reuptake inhibitor (SSRI) activity and serotonin 5-HT(1A) receptor partial agonist activity in a single molecule, is indicated for the treatment of major depressive disorder (MDD) in the US. It is administered orally, once daily, with food. At the recommended dosage of 40 mg/day, vilazodone was effective in the short-term treatment of MDD in adults, as evidenced by significant improvements versus placebo on multiple measures of depression, including the Montgomery Asberg Depression Rating Scale (MADRS) and the 17-item Hamilton Rating Scale for Depression (HAM-D-17), in two pivotal, 8-week, randomized, double-blind, phase III studies. Significant differences between vilazodone and placebo on the MADRS and HAM-D-17 were seen after 1 week of treatment (first efficacy timepoint) in one of the two studies. Long-term treatment with vilazodone 40 mg/day was associated with an improvement from baseline in depressive symptoms in a 52-week, noncompar-ative, phase III study. Vilazodone was generally well tolerated in the short- and long-term treatment of MDD, with diarrhoea and nausea being the most frequently occurring treatment-emergent adverse events. Vilazodone had a minimal impact on sexual functioning in the three phase III studies. PMID- 21699274 TI - Blood pressure-lowering response to amlodipine as a determinant of the antioxidative activity of small, dense HDL3. AB - BACKGROUND AND OBJECTIVE: High-density lipoproteins (HDLs) exert multiple antiatherogenic activities including protection of low-density lipoproteins (LDLs) from oxidative stress. Beneficial effects of calcium channel blockers on cardiovascular disease may in part be related to the reduction of oxidative stress, potentially enhancing the antioxidative activity (AOX) of HDLs. This study aimed to assess the effect of 1 month's treatment with amlodipine on HDL AOX in hypertensive subjects. METHODS: This was a prospective trial of amlodipine 10 mg/day administered for 1 month in primary-care patients with hypertension (n = 28), 46% of whom were obese and 57% of whom displayed the metabolic syndrome. The main outcome measure was HDL AOX, assessed as the capacity of small, dense HDL3c particles to attenuate LDL oxidation induced in vitro by an azo initiator (AAPH). RESULTS: Mean (+/- SD) systolic (SBP) and diastolic (DBP) BP were reduced by amlodipine by 22.1 mmHg (+/- 13.2) and 10.4 mmHg (+/- 7.5), respectively (p < 0.001). Body mass index, waist circumference, and plasma levels of triglycerides, cholesterol, and fasting blood glucose did not change significantly. Amlodipine treatment did not modify HDL3c AOX in the whole study population; changes in AOX were, however, positively correlated with SBP (r = 0.37, p = 0.05 for maximal diene concentration; r = 0.34, p = 0.08 for LDL oxidation rate). When the population was divided into two subgroups according to the BP response to amlodipine (change in SBP below or above the median), HDL3c AOX was significantly improved in hyper-responders (BP-lowering response >22/10 mmHg) as compared with hypo-responders (BP-lowering response <22/10 mmHg: mean [+/- SD] change in the LDL oxidation rate in the presence of HDL3c, -6.8% [+/- 11.2] vs +1.9% [+/- 5.2], respectively, p = 0.04; maximal diene concentration, -8.6% [+/- 13.0] vs +1.9% [+/- 8.2], respectively, p < 0.05). By contrast, neither plasma concentrations of oxidized LDL, a marker of systemic oxidative stress, nor the chemical composition of HDL3c were modified between the subgroups. CONCLUSIONS: In hypertensive patients, amlodipine treatment enhanced HDL AOX in subjects who had a BP reduction that exceeded the median response. This effect appears to be secondary to the hypotensive effect, rather than to the direct antioxidant properties, of the drug. PMID- 21699275 TI - Observation of collective atomic recoil motion in a degenerate fermion gas. AB - We demonstrate collective atomic recoil motion with a dilute, ultracold, degenerate fermion gas in a single spin state. By utilizing an adiabatically decompressed magnetic trap with an aspect ratio different from that of the initial trap, a momentum-squeezed fermion cloud is achieved. With a single pump pulse of the proper polarization, we observe, for the first time, multiple wave mixing processes that result in distinct collective atomic recoil motion modes in a degenerate fermion cloud. Contrary to the case with Bose condensates, no pump laser detuning asymmetry is present. PMID- 21699276 TI - More nonlocality with less purity. AB - Quantum information is nonlocal in the sense that local measurements on a composite quantum system, prepared in one of many mutually orthogonal states, may not reveal in which state the system was prepared. It is shown that in the many copy limit this kind of nonlocality is fundamentally different for pure and mixed quantum states. In particular, orthogonal mixed states may not be distinguishable by local operations and classical communication, no matter how many copies are supplied, whereas any set of N orthogonal pure states can be perfectly discriminated with m copies, where mK(S)(0)P(0). AB - We have searched for CP violation in the decays D(0)->K(S)(0)P(0) where P(0) denotes a neutral pseudoscalar meson that is either a pi(0), eta, or eta' using KEKB asymmetric-energy e(+)e(-) collision data corresponding to an integrated luminosity of 791 fb(-1) collected with the Belle detector. No evidence of significant CP violation is observed. We report the most precise CP asymmetry measurement in the decay D(0)->K(S)(0)pi(0) to date: A(CP)(D(0)->K(S)(0)pi(0))=( 0.28+/-0.19+/-0.10)%. We also report the first measurements of CP asymmetries in the decays D(0)->K(S)(0)eta and D(0)->K(S)(0)eta': A(CP)(D(0) >K(S)(0)eta)=(+0.54+/-0.51+/-0.16)% and A(CP)(D(0)->K(S)(0)eta')=(+0.98+/-0.67+/ 0.14)%, respectively. PMID- 21699289 TI - Baryonic Z' explanation for the CDF Wjj excess. AB - The latest CDF anomaly, the excess of dijet events in the invariant-mass window 120-160 GeV in associated production with a W boson, can be explained by a baryonic Z' model in which the Z' boson has negligible couplings to leptons. Although this Z' model is hardly subject to the Drell-Yan constraint from Tevatron, it is constrained by the dijet data from UA2 (?s=630 GeV), and the precision measurements at LEP through the mixing with the SM Z boson. We show that under these constraints this model can still explain the excess in the M(jj)~120-160 GeV window, as well as the claimed cross section sigma(WZ')~4 pb. Implications at the Tevatron would be the associated production of gammaZ', ZZ', and Z'Z' with the Z'->jj. We show that with tightened jet cuts and improved systematic uncertainties both gammaZ'->gammajj and ZZ'->l(+)l(-) jj channels could be useful to probe this model at the Tevatron. PMID- 21699290 TI - Identifying multiquark hadrons from heavy ion collisions. AB - Identifying hadronic molecular states and/or hadrons with multiquark components either with or without exotic quantum numbers is a long-standing challenge in hadronic physics. We suggest that studying the production of these hadrons in relativistic heavy ion collisions offers a promising resolution to this problem as yields of exotic hadrons are expected to be strongly affected by their structures. Using the coalescence model for hadron production, we find that, compared to the case of a nonexotic hadron with normal quark numbers, the yield of an exotic hadron is typically an order of magnitude smaller when it is a compact multiquark state and a factor of 2 or more larger when it is a loosely bound hadronic molecule. We further find that some of the newly proposed heavy exotic states could be produced and realistically measured in these experiments. PMID- 21699293 TI - Pulsed Sisyphus scheme for laser cooling of atomic (anti)hydrogen. AB - We propose a laser cooling technique in which atoms are selectively excited to a dressed metastable state whose light shift and decay rate are spatially correlated for Sisyphus cooling. The case of cooling magnetically trapped (anti)hydrogen with the 1S-2S-3P transitions by using pulsed ultraviolet and continuous-wave visible lasers is numerically simulated. We find a number of appealing features including rapid three-dimensional cooling from ~1 K to recoil limited, millikelvin temperatures, as well as suppressed spin-flip loss and manageable photoionization loss. PMID- 21699292 TI - Influence of shear viscosity of quark-gluon plasma on elliptic flow in ultrarelativistic heavy-ion collisions. AB - We investigate the influence of a temperature-dependent shear viscosity over entropy density ratio eta/s on the transverse momentum spectra and elliptic flow of hadrons in ultrarelativistic heavy-ion collisions. We find that the elliptic flow in ?S(NN)=200 GeV Au+Au collisions at RHIC is dominated by the viscosity in the hadronic phase and in the phase transition region, but largely insensitive to the viscosity of the quark-gluon plasma (QGP). At the highest LHC energy, the elliptic flow becomes sensitive to the QGP viscosity and insensitive to the hadronic viscosity. PMID- 21699294 TI - Laser controlled tunneling in a vertical optical lattice. AB - Raman laser pulses are used to induce coherent tunneling between neighboring sites of a vertical 1D optical lattice. Such tunneling occurs when the detuning of a probe laser from the atomic transition frequency matches multiples of the Bloch frequency, allowing for a spectroscopic control of the coupling between Wannier-Stark (WS) states. In particular, we prepare coherent superpositions of WS states of adjacent sites, and investigate the coherence time of these superpositions by realizing a spatial interferometer. This scheme provides a powerful tool for coherent manipulation of external degrees of freedom of cold atoms, which is a key issue for quantum information processing. PMID- 21699295 TI - Method for high-resolution frequency measurements in the extreme ultraviolet regime: random-sampling Ramsey spectroscopy. AB - Ramsey-like schemes have been recently introduced in combination with high-order laser harmonic sources for high-resolution spectroscopic studies in the extreme ultraviolet (XUV). Here we demonstrate a novel method, combining measurements only in a limited subset of randomly chosen time-sampling intervals, which lead us to perform the first high-resolution XUV spectroscopy of atomic argon with a simple split-pulse setup. Providing an experimentally simple and convenient solution to the problem of performing high-resolution absolute frequency measurements in the XUV, our approach will help paving new roads into this challenging spectral territory. PMID- 21699296 TI - Stimulated light emission and inelastic scattering by a classical linear system of rotating particles. AB - The rotational dynamics of particles subject to external illumination is found to produce light amplification and inelastic scattering at high rotation velocities. Light emission at frequencies shifted with respect to the incident light by twice the rotation frequency dominates over elastic scattering within a wide range of light and rotation frequencies. Remarkably, net amplification of the incident light is produced in this classical linear system via stimulated emission. Large optically induced acceleration rates are predicted in vacuum accompanied by moderate heating of the particle, thus supporting the possibility of observing these effects under extreme rotation conditions. PMID- 21699297 TI - Unidirectional invisibility induced by PT-symmetric periodic structures. AB - Parity-time (PT) symmetric periodic structures, near the spontaneous PT-symmetry breaking point, can act as unidirectional invisible media. In this regime, the reflection from one end is diminished while it is enhanced from the other. Furthermore, the transmission coefficient and phase are indistinguishable from those expected in the absence of a grating. The phenomenon is robust even in the presence of Kerr nonlinearities, and it can also effectively suppress optical bistabilities. PMID- 21699298 TI - Accelerating light beams along arbitrary convex trajectories. AB - We demonstrate, theoretically and experimentally, nonbroadening optical beams propagating along any arbitrarily chosen convex trajectory in space. We present a general method to construct such beams, and demonstrate it by generating beams following polynomial and exponential trajectories. We find that all such beams, accelerating along any convex trajectory, display the same universal intensity cross section, irrespective of their acceleration. The universal features of these beams are explored using catastrophe theory. PMID- 21699299 TI - Self-accelerating self-trapped optical beams. AB - We present self-accelerating self-trapped beams in nonlinear optical media, exhibiting self-focusing and self-defocusing Kerr and saturable nonlinearities, as well as a quadratic response. In Kerr and saturable media such beams are stable under self-defocusing and weak self-focusing, whereas for strong self focusing the beams off-shoot solitons while their main lobe continues to accelerate. Self-accelerating self-trapped wave packets are universal, and can also be found in matter waves, plasma, etc. PMID- 21699300 TI - Dynamics of Boolean networks: an exact solution. AB - The dynamics of Boolean networks (BN) with quenched disorder and thermal noise is studied via the generating functional method. A general formulation, suitable for BN with any distribution of Boolean functions, is developed. It provides exact solutions and insight into the evolution of order parameters and properties of the stationary states, which are inaccessible via existing methodology. We identify cases where the commonly used annealed approximation is valid and others where it breaks down. Broader links between BN and general Boolean formulas are highlighted. PMID- 21699302 TI - Drag reduction by Leidenfrost vapor layers. AB - We demonstrate and quantify a highly effective drag reduction technique that exploits the Leidenfrost effect to create a continuous and robust lubricating vapor layer on the surface of a heated solid sphere moving in a liquid. Using high-speed video, we show that such vapor layers can reduce the hydrodynamic drag by over 85%. These results appear to approach the ultimate limit of drag reduction possible by different methods based on gas-layer lubrication and can stimulate the development of related energy saving technologies. PMID- 21699301 TI - Packing of elastic wires in spherical cavities. AB - We investigate the morphologies and maximum packing density of thin wires packed into spherical cavities. Using simulations and experiments, we find that ordered as well as disordered structures emerge, depending on the amount of internal torsion. We find that the highest packing densities are achieved in low torsion packings for large systems, but in high torsion packings for small systems. An analysis of both situations is given in terms of energetics and comparison is made to analytical models of DNA packing in viral capsids. PMID- 21699303 TI - Propagation of drop coalescence in a two-dimensional emulsion: a route towards phase inversion. AB - The phase inversion that undergoes an emulsion while being sheared is a sudden phenomenon that is still puzzling. In this Letter, we report an experimental investigation on propagative coalescence by using a microfluidic device where a calibrated two-dimensional emulsion is created and destabilized. The velocity of propagation and the probability of the coalescence are reported as a function of the size and the spatial distribution of the drops, respectively. We then discuss the efficiency of this novel scenario of phase inversion and suggest that inversion can be favored by the existence of a drop size distribution. PMID- 21699304 TI - Direct visualization of laser-driven focusing shock waves. AB - Direct real-time visualization and measurement of laser-driven shock generation, propagation, and 2D focusing in a sample are demonstrated. A substantial increase of the pressure at the convergence of the cylindrical acoustic shock front is observed experimentally and simulated numerically. Single-shot acquisitions using a streak camera reveal that at the convergence of the shock wave in water the supersonic speed reaches Mach 6, corresponding to the multiple gigapascal pressure range ~30 GPa. PMID- 21699305 TI - Edge temperature gradient as intrinsic rotation drive in Alcator C-Mod tokamak plasmas. AB - Intrinsic rotation has been observed in I-mode plasmas from the C-Mod tokamak, and is found to be similar to that in H mode, both in its edge origin and in the scaling with global pressure. Since both plasmas have similar edge ?T, but completely different edge ?n, it may be concluded that the drive of the intrinsic rotation is the edge ?T rather than ?P. Evidence suggests that the connection between gradients and rotation is the residual stress, and a scaling for the rotation from conversion of free energy to macroscopic flow is calculated. PMID- 21699306 TI - Evidence for the importance of trapped particle resonances for resistive wall mode stability in high beta tokamak plasmas. AB - Active measurements of the plasma stability in tokamak plasmas reveal the importance of kinetic resonances for resistive wall mode stability. The rotation dependence of the magnetic plasma response to externally applied quasistatic n=1 magnetic fields clearly shows the signatures of an interaction between the resistive wall mode and the precession and bounce motions of trapped thermal ions, as predicted by a perturbative model of plasma stability including kinetic effects. The identification of the stabilization mechanism is an essential step towards quantitative predictions for the prospects of "passive" resistive wall mode stabilization, i.e., without the use of an "active" feedback system, in fusion-alpha heated plasmas. PMID- 21699307 TI - Fast magnetic reconnection in laser-produced plasma bubbles. AB - Recent experiments have observed magnetic reconnection in high-energy-density, laser-produced plasma bubbles, with reconnection rates observed to be much higher than can be explained by classical theory. Based on fully kinetic particle simulations we find that fast reconnection in these strongly driven systems can be explained by magnetic flux pileup at the shoulder of the current sheet and subsequent fast reconnection via two-fluid, collisionless mechanisms. In the strong drive regime with two-fluid effects, we find that the ultimate reconnection time is insensitive to the nominal system Alfven time. PMID- 21699308 TI - Pattern formation in a complex plasma in high magnetic fields. AB - Low-pressure room-temperature neon, argon, krypton, and air plasmas were studied in magnetic fields up to flux densities of 2.3 T. Filaments appeared parallel to the magnetic field lines, and patterns such as spirals and concentric circles formed in the perpendicular direction. We link these effects to the magnetization of the ions. We also used a layer of embedded microparticles as probes in the plasma. Their motion changed dramatically from a collective rotation of the whole ensemble in moderate magnetic fields to a rotation in several small vortices centered at the filaments. PMID- 21699309 TI - Coherent light scattering from a two-dimensional Mott insulator. AB - We experimentally demonstrate coherent light scattering from an atomic Mott insulator in a two-dimensional lattice. The far-field diffraction pattern of small clouds of a few hundred atoms was imaged while simultaneously laser cooling the atoms with the probe beams. We describe the position of the diffraction peaks and the scaling of the peak parameters by a simple analytic model. In contrast to Bragg scattering, scattering from a single plane yields diffraction peaks for any incidence angle. We demonstrate the feasibility of detecting spin correlations via light scattering by artificially creating a one-dimensional antiferromagnetic order as a density wave and observing the appearance of additional diffraction peaks. PMID- 21699310 TI - Interaction-dependent temperature effects in Bose-Fermi mixtures in optical lattices. AB - We present a quantitative finite temperature analysis of a recent experiment with Bose-Fermi mixtures in optical lattices, in which the dependence of the coherence of bosons on the interspecies interaction was analyzed. Our theory reproduces the characteristics of this dependence and suggests that intrinsic temperature effects play an important role in these systems. Namely, under the assumption that the ramping up of the optical lattice is an isentropic process, adiabatic temperature changes of the mixture occur that depend on the interaction between bosons and fermions. Matching the entropy of two regimes-no lattice on the one hand and deep lattices on the other-allows us to compute the temperature in the lattice and the visibility of the quasimomentum distribution of the bosonic atoms, which we compare to the experiment. PMID- 21699311 TI - Fermi-liquid behavior of the normal phase of a strongly interacting gas of cold atoms. AB - We measure the magnetic susceptibility of a Fermi gas with tunable interactions in the low-temperature limit and compare it to quantum Monte Carlo calculations. Experiment and theory are in excellent agreement and fully compatible with the Landau theory of Fermi liquids. We show that these measurements shed new light on the nature of the excitations of the normal phase of a strongly interacting Fermi gas. PMID- 21699312 TI - Dynamics and statics of DNA-programmable nanoparticle self-assembly and crystallization. AB - DNA linker mediated self-assembly is emerging as a very general strategy for designing new materials. In this Letter, we characterize both the dynamics and thermodynamics of nanoparticle-DNA self-assembly by molecular dynamics simulations from a new coarse-grained model. We establish the general phase diagram and discuss the stability of a previously overlooked crystalline phase (D bcc). We also characterize universal properties about the dynamics of crystallization. We point out the connection to f-star polymer systems and discuss the implications for ongoing experiments as well as for the general field of DNA mediated self-assembly. PMID- 21699313 TI - Electron-deficient and polycenter bonds in the high-pressure gamma-B28 phase of boron. AB - The peculiar bonding situation in gamma boron is characterized on the basis of an experimental electron-density distribution which is obtained by multipole refinement against low-temperature single-crystal x-ray diffraction data. A topological analysis of the electron-density distribution reveals one-electron two-center bonds connecting neighboring icosahedral B(12) clusters. A unique polar-covalent two-electron-three-center bond between a pair of atoms of an icosahedral cluster and one atom of the interstitial B(12) dumbbell explains the observed charge separation in this high-pressure high-temperature polymorph of boron. PMID- 21699314 TI - Universality and diversity in a phonon-transmission histogram of isotope disordered carbon nanotubes. AB - Universal fluctuations in phonon transmission and other features of phonon transmission histograms are investigated by performing numerical simulations of coherent-phonon transport in isotope-disordered carbon nanotubes. Interestingly, the phonon-transmission fluctuation in the diffusive regime is universal, irrespective of the average phonon transmission, the tube chirality, and the concentrations, and masses of isotopes. We also find that the histogram, which has a Gaussian distribution in the diffusive regime, has a log-normal distribution in the localization regime. PMID- 21699315 TI - Shape change of nanocontainers via a reversible ionic buckling. AB - We demonstrate that small charged nanocages can undergo reversible changes of shapes by modifying the ionic conditions including salt concentration, pH, and dielectric permittivity of the medium. Using numerical simulations, we analyze structures with various charge stoichiometric ratios. At zero or low charge densities, the shape of the cage is determined by its elastic properties, and the surface charge pattern is dictated by the globally fixed geometry. As the charge density per molecule increases, the shape is strongly affected by the electrostatic forces. In this regime, the shape of the nanocage is controlled by the charge distribution. PMID- 21699316 TI - Atomic-scale structural evolution and stability of supercooled liquid of a Zr based bulk metallic glass. AB - In this Letter, direct experimental evidence is provided for understanding the thermal stability with respect to crystallization in the Zr(41.2)Ti(13.8)Cu(12.5)Ni(10)Be(22.5) glass-forming liquid. Through high resolution transmission electron microscopy, the atomic-structure evolution in the glass-forming liquid during the isothermal annealing process is clearly revealed. In contrast with the existing theoretical models, our results reveal that, prior to nanocrystallization, there exists a metastable state prone to forming icosahedralike atomic clusters, which impede the subsequent crystallization and hence stabilize the supercooled liquid. The outcome of the current research underpins the topological origin for the excellent thermal stability displayed by the Zr-based bulk metallic glass. PMID- 21699317 TI - Crystallization mechanism of hard sphere glasses. AB - In supercooled liquids, vitrification generally suppresses crystallization. Yet some glasses can still crystallize despite the arrest of diffusive motion. This ill-understood process may limit the stability of glasses, but its microscopic mechanism is not yet known. Here we present extensive computer simulations addressing the crystallization of monodisperse hard-sphere glasses at constant volume (as in a colloid experiment). Multiple crystalline patches appear without particles having to diffuse more than one diameter. As these patches grow, the mobility in neighboring areas is enhanced, creating dynamic heterogeneity with positive feedback. The future crystallization pattern cannot be predicted from the coordinates alone: Crystallization proceeds by a sequence of stochastic micronucleation events, correlated in space by emergent dynamic heterogeneity. PMID- 21699318 TI - Thermal stability of corrugated epitaxial graphene grown on Re(0001). AB - We report on a novel approach to determine the relationship between the corrugation and the thermal stability of epitaxial graphene grown on a strongly interacting substrate. According to our density functional theory calculations, the C single layer grown on Re(0001) is strongly corrugated, with a buckling of 1.6 A, yielding a simulated C 1s core level spectrum which is in excellent agreement with the experimental one. We found that corrugation is closely knit with the thermal stability of the C network: C-C bond breaking is favored in the strongly buckled regions of the moire cell, though it requires the presence of diffusing graphene layer vacancies. PMID- 21699319 TI - Chemical resolution at ionic crystal surfaces using dynamic atomic force microscopy with metallic tips. AB - We demonstrate that well prepared and characterized Cr tips can provide atomic resolution on the bulk NaCl(001) surface with dynamic atomic force microscopy in the noncontact regime at relatively large tip-sample separations. At these conditions, the surface chemical structure can be resolved yet tip-surface instabilities are absent. Our calculations demonstrate that chemical identification is unambiguous, because the interaction is always largest above the anions. This conclusion is generally valid for other polar surfaces, and can thus provide a new practical route for straightforward interpretation of atomically resolved images. PMID- 21699320 TI - Controlling the charge state of a single redox molecular switch. AB - Scanning tunneling microscopy and dynamic force microscopy in the noncontact mode are used in combination to investigate the reversible switching between two stable states of a copper complex adsorbed on a NaCl bilayer grown on Cu(111). The molecular conformation in these two states is deduced from scanning tunneling microscopy imaging, while their charge is characterized by the direct measurement of the tip-molecule electrostatic force. These measurements demonstrate that the molecular bistability is achieved through a charge-induced rearrangement of the coordination sphere of the metal complex, qualifying this system as a new electromechanical single-molecular switch. PMID- 21699321 TI - Space charge induced surface stresses: implications in ceria and other ionic solids. AB - Volume changes associated with point defects in space charge layers can produce strains that substantially alter thermodynamic equilibrium near surfaces in ionic solids. For example, near-surface compressive stresses exceeding -10 GPa are predicted for ceria. The magnitude of this effect is consistent with anomalous lattice parameter increases that occur in ceria nanoparticles. These stresses should significantly alter defect concentrations and key transport properties in a wide range of materials (e.g., ceria electrolytes in fuel cells). PMID- 21699322 TI - Theory of carrier concentration-dependent electronic behavior in layered cobaltates. AB - A natural explanation for the carrier concentration-dependent electronic behavior in the layered cobaltates emerges within correlated-electron Hamiltonians with finite on-site and significant nearest neighbor hole-hole Coulomb repulsions. The nearest neighbor repulsion decreases hole double occupancy below hole density 1/3, but increases the same at higher hole densities. Our conclusion is valid for both single-band and three-band extended Hubbard Hamiltonians, and sheds light on concentration dependent e'(g) hole occupancy within the latter. PMID- 21699323 TI - Band bending in conjugated polymer layers. AB - We use the Kelvin probe method to study the energy-level alignment of four conjugated polymers deposited on various electrodes. Band bending is observed in all polymers when the substrate work function exceeds critical values. Through modeling, we show that the band bending is explained by charge transfer from the electrodes into a small density of states that extends several hundred meV into the band gap. The energetic spread of these states is correlated with charge carrier mobilities, suggesting that the same states also govern charge transport in the bulk of these polymers. PMID- 21699324 TI - Spin pumping by parametrically excited exchange magnons. AB - We experimentally show that exchange magnons can be detected by using a combination of spin pumping and the inverse spin-Hall effect proving its wavelength integrating capability down to the submicrometer scale. The magnons were injected in a ferrite yttrium iron garnet film by parametric pumping and the inverse spin-Hall effect voltage was detected in an attached Pt layer. The role of the density, wavelength, and spatial localization of the magnons for the spin pumping efficiency is revealed. PMID- 21699325 TI - Acoustically induced spin-orbit interactions revealed by two-dimensional imaging of spin transport in GaAs. AB - Magneto-optic Kerr microscopy was employed to investigate the spin-orbit interactions of electrons traveling in semiconductor quantum wells using surface acoustic waves (SAWs). Two-dimensional images of the spin flow induced by SAWs exhibit anisotropic spin precession behaviors caused by the coexistence of different types of spin-orbit interactions. The dependence of spin-orbit effective magnetic fields on SAW intensity indicates the existence of acoustically controllable spin-orbit interactions resulting from the strain and Rashba contributions induced by the SAWs. PMID- 21699326 TI - Quantum criticality in a Mott pn junction in an armchair carbon nanotube. AB - In an armchair carbon nanotube pn junction the p and n regions are separated by a region of a Mott insulator, which can backscatter electrons only in pairs. We predict a quantum-critical behavior in such a pn junction. Depending on the junction's built-in electric field E, its conductance G scales either to zero or to 4e(2)/h as the temperature T is lowered. The two types of the G(T) dependence indicate the existence, at some special value of E, of an intermediate quantum critical point with a finite conductance G<4e(2)/h. This makes the pn junction drastically different from a simple potential barrier in a Luttinger liquid. PMID- 21699327 TI - Exciton-spin memory with a semiconductor quantum dot molecule. AB - We report on a single photon and spin storage device based on a semiconductor quantum dot molecule. Optically excited single electron-hole pairs are trapped within the molecule, and their recombination rate is electrically controlled over 3 orders of magnitude. Single photons are stored up to 1 MUs and read out on a subnanosecond time scale. By using resonant excitation, the circular polarization of individual photons is transferred into the spin state of electron-hole pairs with a fidelity above 80%, which does not degrade for storage times up to the 12.5 ns repetition period of the experiment. PMID- 21699328 TI - Direct measurement of the out-of-plane spin texture in the Dirac-cone surface state of a topological insulator. AB - We have performed spin- and angle-resolved photoemission spectroscopy of Bi(2)Te(3) and present the first direct evidence for the existence of the out-of plane spin component on the surface state of a topological insulator. We found that the magnitude of the out-of-plane spin polarization on a hexagonally deformed Fermi surface of Bi(2)Te(3) reaches maximally 25% of the in-plane counterpart, while such a sizable out-of-plane spin component does not exist in the more circular Fermi surface of TlBiSe(2), indicating that the hexagonal deformation of the Fermi surface is responsible for the deviation from the ideal helical spin texture. The observed out-of-plane polarization is much smaller than that expected from the existing theory, suggesting that an additional ingredient is necessary for correctly understanding the surface spin polarization in Bi(2)Te(3). PMID- 21699329 TI - Incoherent c-axis interplane response of the iron chalcogenide FeTe(0.55)Se(0.45) superconductor from infrared spectroscopy. AB - We report on the interplane c-axis electronic response of FeTe(0.55)Se(0.45) investigated by infrared spectroscopy. We find that the normal-state c-axis electronic response of FeTe(0.55)Se(0.45) is incoherent and bears significant similarities to those of mildly underdoped cuprates. The c-axis optical conductivity sigma(c)(omega) of FeTe(0.55)Se(0.45) does not display well-defined Drude response at all temperatures. As temperature decreases, sigma(c)(omega) is continuously suppressed. The incoherent c-axis response is found to be related to the strong dissipation in the ab-plane transport: a pattern that holds true for various correlated materials as well as FeTe(0.55)Se(0.45). PMID- 21699330 TI - Competing pairing symmetries in a generalized two-orbital model for the pnictide superconductors. AB - We introduce and study an extended "t-U-J" two-orbital model for the pnictides that includes Heisenberg terms deduced from the strong coupling expansion. Including these J terms explicitly allows us to enhance the strength of the (pi,0)-(0,pi) spin order which favors the presence of tightly bound pairing states even in the small clusters that are here exactly diagonalized. The A(1g) and B(2g) pairing symmetries are found to compete in the realistic spin-ordered and metallic regime. The dynamical pairing susceptibility additionally unveils low-lying B(1g) states, suggesting that small changes in parameters may render any of the three channels stable. PMID- 21699331 TI - Real-time observation of discrete Andreev tunneling events. AB - We provide a direct proof of two-electron Andreev transitions in a superconductor normal-metal tunnel junction by detecting them in a real-time electron counting experiment. Our results are consistent with ballistic Andreev transport with an order of magnitude higher rate than expected for a uniform barrier, suggesting that only part of the interface is effectively contributing to the transport. These findings are quantitatively supported by our direct current measurements in single-electron transistors with similar tunnel barriers. PMID- 21699332 TI - Both electron and hole Dirac cone states in Ba(FeAs)2 confirmed by magnetoresistance. AB - Quantum transport of Dirac cone states in the iron pnictide Ba(FeAs)(2) with a d multiband system is studied by using single crystal samples. Transverse magnetoresistance develops linearly against the magnetic field at low temperatures. The transport phenomena are interpreted in terms of the zeroth Landau level by applying the theory predicted by Abrikosov. The results of the semiclassical analyses of a two carrier system in a low magnetic field limit show that both the electron and hole reside as the high mobility states. Our results show that pairs of electron and hole Dirac cone states must be taken into account for an accurate interpretation in iron pnictides, which is in contrast with previous studies. PMID- 21699333 TI - Bright side of the Coulomb blockade. AB - We explore the photonic (bright) side of the dynamical Coulomb blockade (DCB) by measuring the radiation emitted by a dc voltage-biased Josephson junction embedded in a microwave resonator. In this regime Cooper pair tunneling is inelastic and associated with the transfer of an energy 2eV into the resonator modes. We have measured simultaneously the Cooper pair current and the photon emission rate at the resonance frequency of the resonator. Our results show two regimes, in which each tunneling Cooper pair emits either one or two photons into the resonator. The spectral properties of the emitted radiation are accounted for by an extension to DCB theory. PMID- 21699334 TI - Multistep approach to microscopic models for frustrated quantum magnets: the case of the natural mineral azurite. AB - The natural mineral azurite Cu(3)(CO(3))(2)(OH)(2) is a frustrated magnet displaying unusual and controversially discussed magnetic behavior. Motivated by the lack of a unified description for this system, we perform a theoretical study based on density functional theory as well as state-of-the-art numerical many body calculations. We propose an effective generalized spin-1/2 diamond chain model which provides a consistent description of experiments: low-temperature magnetization, inelastic neutron scattering, nuclear magnetic resonance measurements, magnetic susceptibility as well as new specific heat measurements. With this study we demonstrate that the balanced combination of first principles with powerful many-body methods successfully describes the behavior of this frustrated material. PMID- 21699335 TI - Spin-polarized transient electron trapping in phosphorus-doped silicon. AB - Experimental evidence of electron spin precession during travel through the phosphorus-doped Si channel of an all-electrical device simultaneously indicates two distinct processes: (i) short time scales (~50 ps) due to purely conduction band transport from injector to detector and (ii) long time scales (~1 ns) originating from delays associated with capture or reemission in shallow impurity traps. The origin of this phenomenon, examined via temperature, voltage, and electron density dependence measurements, is established by means of a comparison to a numerical model and is shown to reveal the participation of metastable excited states in the phosphorus-impurity spectrum. This work therefore demonstrates the potential to make the study of macroscopic spin transport relevant to the quantum regime of individual spin interactions with impurities as envisioned for quantum information applications. PMID- 21699336 TI - Tracking the effects of interactions on spinons in gapless Heisenberg chains. AB - We consider the effects of interactions on spinon excitations in Heisenberg spin 1/2 chains. We compute the exact two-spinon part of the longitudinal structure factor of the infinite chain in zero field for all values of anisotropy in the gapless antiferromagnetic regime, via an exact algebraic approach. Our results allow us to quantitatively describe the behavior of these fundamental excitations throughout the observable continuum, for cases ranging from free to fully coupled chains, thereby explicitly mapping the effects of "turning on the interactions" in a strongly correlated system. PMID- 21699337 TI - Anisotropic hysteretic Hall effect and magnetic control of chiral domains in the chiral spin states of Pr2Ir2O7. AB - We uncover a strong anisotropy in both the anomalous Hall effect (AHE) and the magnetoresistance of the chiral spin states of Pr(2)Ir(2)O(7). The AHE appearing below 1.5 K at a zero magnetic field shows hysteresis which is most pronounced for fields cycled along the [111] direction. This hysteresis is compatible with the field-induced growth of domains composed by the 3-in 1-out spin states which remain coexisting with the 2-in 2-out spin ice manifold once the field is removed. Only for fields applied along the [111] direction, we observe a large positive magnetoresistance and Shubnikov-de Haas oscillations above a metamagnetic critical field. These observations suggest the reconstruction of the electronic structure of the conduction electrons by the field-induced spin texture. PMID- 21699338 TI - Anomalous decoherence effect in a quantum bath. AB - Decoherence of quantum objects in noisy environments is important in quantum sciences and technologies. It is generally believed that different processes coupled to the same noise source have similar decoherence behaviors and stronger noises cause faster decoherence. Here we show that in a quantum bath, the case can be the opposite. We predict that the multitransition of a nitrogen-vacancy center spin-1 in diamond can have longer coherence time than the single transitions, even though the former suffers twice stronger noises from the nuclear spin bath than the latter. This anomalous decoherence effect is due to manipulation of the bath evolution via flips of the center spin. PMID- 21699339 TI - Open XXZ spin chain: nonequilibrium steady state and a strict bound on ballistic transport. AB - An explicit matrix product ansatz is presented, in the first two orders in the (weak) coupling parameter, for the nonequilibrium steady state of the homogeneous, nearest neighbor Heisenberg XXZ spin 1/2 chain driven by Lindblad operators which act only at the edges of the chain. The first order of the density operator becomes, in the thermodynamic limit, an exact pseudolocal conservation law and yields-via the Mazur inequality-a rigorous lower bound on the high-temperature spin Drude weight. Such a Mazur bound is a nonvanishing fractal function of the anisotropy parameter Delta for |Delta|<1. PMID- 21699340 TI - Anisotropic interface magnetoresistance in Pt/Co/Pt sandwiches. AB - We report on an effect of reduced dimensionality on the magnetotransport in cobalt layers sandwiched by platinum. In a current in-plane geometry it is found that the resistivity depends on the magnetization orientation within the plane perpendicular to the current direction. The resistivity shows a symmetry adapted cos(2) dependence on the angle to the surface normal, with the maximum along the surface normal. The Co thickness dependence of the effect in Pt/Co/Pt sandwiches clearly points out that the mechanism behind this effect originates at the Co/Pt interfaces and is disparate to the texture induced geometrical size effect. PMID- 21699342 TI - Spin resonance in EuTiO3 probed by time-domain gigahertz ellipsometry. AB - We show an example of a purely magnetic spin resonance in EuTiO(3) and the resulting new record high Faraday rotation of 590 degrees /mm at 1.6 T for 1 cm wavelengths probed by a novel technique of magneto-optical gigahertz time-domain ellipsometry. From our transmission measurements of linear polarized light, we map out the complex index of refraction n=?epsilonMU in the gigahertz to terahertz range. We observe a strong resonant absorption by magnetic dipole transitions involving the Zeeman split S=7/2 magnetic energy levels of the Eu(2+) ions, which causes a very large dichroism for circular polarized radiation. PMID- 21699341 TI - Photoinduced melting of antiferromagnetic order in La(0.5)Sr(1.5)MnO4 measured using ultrafast resonant soft x-ray diffraction. AB - We used ultrafast resonant soft x-ray diffraction to probe the picosecond dynamics of spin and orbital order in La(0.5)Sr(1.5)MnO(4) after photoexcitation with a femtosecond pulse of 1.5 eV radiation. Complete melting of antiferromagnetic spin order is evidenced by the disappearance of a (1/4,1/4,1/2) diffraction peak. On the other hand, the (1/4,1/4,0) diffraction peak, reflecting orbital order, is only partially reduced. We interpret the results as evidence of destabilization in the short-range exchange pattern with no significant relaxation of the long-range Jahn-Teller distortions. Cluster calculations are used to analyze different possible magnetically ordered states in the long-lived metastable phase. Nonthermal coupling between light and magnetism emerges as a primary aspect of photoinduced phase transitions in manganites. PMID- 21699343 TI - Infinite penetration of a projectile into a granular medium. AB - An object falling in a fluid reaches a terminal velocity when the drag force and its weight are balanced. Contrastingly, an object impacting into a granular medium rapidly dissipates all its energy and comes to rest always at a shallow depth. Here we study, experimentally and theoretically, the penetration dynamics of a projectile in a very long silo filled with expanded polystyrene particles. We discovered that, above a critical mass, the projectile reaches a terminal velocity and, therefore, an endless penetration. PMID- 21699344 TI - Excitable patterns in active nematics. AB - We analyze a model of mutually propelled filaments suspended in a two-dimensional solvent. The system undergoes a mean-field isotropic-nematic transition for large enough filament concentrations, and the nematic order parameter is allowed to vary in space and time. We show that the interplay between nonuniform nematic order, activity, and flow results in spatially modulated relaxation oscillations, similar to those seen in excitable media. In this regime the dynamics consists of nearly stationary periods separated by "bursts" of activity in which the system is elastically distorted and solvent is pumped throughout. At even higher activity, the dynamics becomes chaotic. PMID- 21699345 TI - Phase transitions in shear-induced segregation of granular materials. AB - We computationally study shear-induced segregation of different-sized particles in vertical chute flow. We find that, for low solid fractions, large particles segregate toward regions of low shear rates where the granular temperature (velocity variance) is low. As the solid fraction increases, this trend reverses, and large particles segregate toward regions of high shear rates and temperatures. We find that this is a global phenomenon: local segregation trends reverse at high system solid fractions even where local solid fractions are small. The reversal corresponds to the growth of a single enduring cluster of 30% 60% of the particles that we propose changes the segregation dynamics. PMID- 21699346 TI - Synergy in spreading processes: from exploitative to explorative foraging strategies. AB - An epidemiological model which incorporates synergistic effects that allow the infectivity and/or susceptibility of hosts to be dependent on the number of infected neighbors is proposed. Constructive synergy induces an exploitative behavior which results in a rapid invasion that infects a large number of hosts. Interfering synergy leads to a slower and sparser explorative foraging strategy that traverses larger distances by infecting fewer hosts. The model can be mapped to a dynamical bond percolation with spatial correlations that affect the mechanism of spread but do not influence the critical behavior of epidemics. PMID- 21699347 TI - Comment on "Two-spinon and four-spinon continuum in a frustrated ferromagnetic spin-1/2 chain". PMID- 21699349 TI - Usefulness of methadone plasma concentration measurement in patients receiving nevirapine or efavirenz. AB - OBJECTIVE: To determine methadone plasma trough and peak concentrations in patients presenting opiate withdrawal symptoms after introduction of nevirapine or efavirenz. To describe the disappearance of these symptoms after methadone titration based on plasma concentrations rather than on the symptoms. METHODS: Nine patients undergoing highly active antiretroviral therapy (HAART) and either nevirapine or efavirenz treatment were monitored daily for opiate withdrawal in a specialized drug addiction center. Methadone dose was titrated daily, and plasma concentrations were measured. The data are retrospective (case series). RESULTS: Several patients complained of symptoms such as nausea, vomiting, accelerated intestinal transit, or insomnia. Even after methadone titration based on clinical symptoms, patients and health-care providers trained in infectious disease did not classify these as withdrawal symptoms and considered them as the side effects of HAART or anxiety. Methadone plasma trough concentration showed low levels of (R)- and (R,S)-methadone. Further methadone dose adjustment according to plasma level resulted in the disappearance of these withdrawal symptoms. The daily methadone dose was split when the peak/trough (R)-methadone ratio was more than 2. CONCLUSIONS: When introducing efavirenz or nevirapine to patients undergoing methadone treatment, withdrawal symptoms should be monitored, especially those such as insomnia, vomiting, or nausea. Methadone plasma trough and peak measurements can be of value in preventing unnecessary side effects of HAART. PMID- 21699350 TI - FRONTLINE: teaching affect recognition to medical students: evaluation and reflections. AB - Techniques developed for teaching more empathic affect recognition and reflection to medical students during their introduction to psychiatric interviewing begin with a concrete grounding in facial muscular movements and facial affect recognition, and proceed to the use of countertransferential affective experience to aid in ascertaining personality types. Observations about the temper of today's medical students by psychoanalysts may be of help in avoiding increasing their already substantial characterological resistance to affective learning and empathy that has recently been reported in the medical education literature. PMID- 21699351 TI - A neural network model for schemas based on pattern completion. AB - Abstract Recent developments in neuroscience have provided us with a wealth of the basic knowledge and tools which are required for neurobiological understanding of the psychological concepts. This advantage enables contemporary scientists to suggest and test brain models for psychological concepts, theories, and methods. Considering the current dominance of biological ideas in psychiatry and psychology, such models are essential in confirmation of the psychological theories of mind. In this article a brain model for schemas as essential to cognitive theory is proposed. Schemas are seen as patterns which are recognized and memorized through the training phase of an autoassociative neural network. Then, these patterns are used to complete ambiguous aspects of future experiences through thalamo and hippocampal-cortical pathways. In relation to the self or the outside world when a pattern with unknown, noisy, or vague aspects is encountered, those aspects are completed by the principal components of previously learned patterns (schema). This process is to help the observer acquire a better understanding of the environment or the self. However, the patterns which are used to complete the uncertainties about the self or the environment are sometimes not good estimates of the reality and lead the person/patient to an illusionary perception of the self/environment. In this article, the role of the mirror neuron system in pattern recognition is also explained. Psychological and biological therapeutic implications of this model are discussed and the importance of a link between dynamic and cognitive therapies is rationalized. PMID- 21699353 TI - Aspects of psychodynamic neuropsychiatry II: psychical locality and biology: toward the neurobiology of psychotherapy. AB - Throughout his career, Freud believed that psychiatry in general and psychoanalysis in particular would one day be rooted in anatomical/biological ground. He felt confidant that such ground would replace the psychological understanding on which he had been forced to base most of his clinical theory and practice. He felt confidant that one day psychotherapy would be more "scientific." This article seeks to demonstrate that this day is arriving. A clinical case is presented where assessment and formulation are largely based on neurobiology, where treatment was conducted less in accord with psychodynamic theory than neurodynamic data of anatomy and biology. PMID- 21699354 TI - The turn of the screw: the James family's encounters with the terrors lurking in the unconscious mind. AB - Abstract The dynamics of the family of psychologist and philosopher William James and his brother, the novelist Henry James, are explored. The need for love, the hate and rage, the guilt, and the terror arising from their father's four-year confinement in bed as an adolescent due to an accident in which he lost his right leg, haunted him and his children and yet were the source of his and, indirectly, his sons' fierce determination to lead meaningful lives and to share with the world their extraordinary insights into the complicated functioning of the mind. PMID- 21699352 TI - The clinical and predictive value of the initial dream of treatment. AB - The authors collected the initial dreams of treatment from 63 patients and independently evaluated the manifest dream report (MDR). Variables included: Affect and Valence of Affect; Associations; Psychodynamic Theme; Psychodynamic Theme as Predictor of Core Psychodynamic Issues; Transference; Gender; Psychodynamic Theme Categories; Clinical Progress in relation to Psychodynamic Theme Categories and Transference. The initial MDR invariably contains Affect that is frequently Negative. The Psychodynamic Themes of MDRs are dependable predictors of Core Psychodynamic Issues that emerge during treatment. Transference is evident in a significant number of MDRs and is often Negative. Gender of the majority of MDRs is predictable. The most frequent Psychodynamic Themes of initial MDRs fall into Relational and Injury Categories. Relational and Injury Themes, as well as Positive and Negative Transference, are associated with clinical progress. This study confirms that the initial MDR of treatment provides a significant amount of clinical and predictive information. PMID- 21699355 TI - Commentary on "The turn of the screw: the James family's encounters with the terrors lurking in the unconscious mind" by Barbara Young. PMID- 21699358 TI - Commentary on "The rise and fall of the autochthonous self..." The self is alive and well and living at MoMA. PMID- 21699357 TI - Introduction: commentaries and author's response to "The rise and fall of the autochthonous self: from Italian Renaissance Art and Shakespeare to Hediegger, Lacan, and Intersubjectivism" by Richard D. Chessick. AB - This article addresses the unresolved question of the existence of a private core autochthonous self, as it has been described by Winnicott, Modell, and others. The postmodern version of the self has eliminated this concept entirely, relegating the self to a changing and unstable display, or regarding it as totally chaotic, or even an illusion. The question is raised whether by returning to the origins of this notion of a private self and then tracing its apparent dissolution it might be possible to discover some evidence that it still exists. The methodology used is that of obtaining knowledge directly through the arts and the claim is made that because empirical science has clamored to be the only source of knowledge, we have lost what could be obtained by direct intuitive seeing and experiencing the works of creative geniuses. To explore the rise of the autochthonous self this article provides an examination of the shift from Gothic art to Italian Renaissance art, a time which engendered the origin of "man" with his or her elusive private individual self that then became expressed in changing works of art. As this spread north, Shakespeare appeared and similarly invented and illustrated in his characters the private individual self, a concept not appreciated or recognized before the Renaissance. But as science arose and Western civilization began to decline, a corresponding disillusionment with "man" took place. The self began to be viewed as solely a social construction with no core except perhaps a genetic endowment. This was accompanied by a reduction in the concept of the human as a valuable and precious living being and was replaced by regarding the human as an object of control and exploitation. After the Second World War a movement in contemporary United States psychoanalysis gradually replaced the ideas of Freud and his emphasis on the "I" in the psychoanalytic process, with forms of relational therapy, assuming that the self was ab initio intersubjectively formed and could be altered fundamentally by focus on intersubjective processes. The author contends that this attitude makes it less likely for the psychoanalyst to focus on the regressive transferences from which derivatives of the private self arise and to grasp the phenomenological whole of the patient (p. 625). PMID- 21699359 TI - Commentary on "the rise and fall of the autochthonous self..." did art really start in Italy? PMID- 21699360 TI - Richard d. Chessick responds to commentaries by Mark Leffert and Scott C. Schwartz: harmonics in a disharmonious era, the era of Techne. PMID- 21699362 TI - Improving health and social outcomes with targeted services in comprehensive substance abuse treatment. AB - BACKGROUND: Improved life functioning along with substance use reduction is increasingly recognized as the definition of effective addiction treatment. OBJECTIVES: To assess whether targeted health and social services contribute to improved physical/mental health and employment. METHODS: This study used data from the National Treatment Improvement Evaluation Study (N = 3027) and modeled the improvement in physical/mental health and employment at discharge or 12 months after discharge compared with intake measures as a function of receipts of matched services. RESULTS: Receiving matched medical service improves physical health only at treatment discharge; receiving matched mental health services improves mental health at discharge and 12 months after discharge; receiving matched vocational services improves employment only 12 months after discharge. CONCLUSIONS: Need-service matching contributes to improved health and social outcomes when longitudinal assessments of treatment outcomes are used to evaluate treatment effectiveness. SCIENTIFIC SIGNIFICANCE: Study findings document the value of targeted services for achieving success in health and social functioning in comprehensive substance abuse treatment. PMID- 21699363 TI - Neck skin rejuvenation: histological and clinical changes after combined therapy with a fractional non-ablative laser and stabilized hyaluronic acid-based gel of non-animal origin. AB - BACKGROUND: The laser AffirmTM (LA) is a microthermal, non-ablative fractional laser used for skin rejuvenation. Restylane VitalTM Light (RVL) in the Restylane(r) Injector, a formulation of stabilized hyaluronic acid-based gel of non-animal origin, is indicated for rejuvenation of delicate skin. OBJECTIVES: To assess the interaction between the LA and RVL in aging skin of the neck using clinical and histological parameters, and to determine whether combined therapy is effective. METHODS: Nine female patients aged 42-62 years received four treatments, each comprising RVL followed immediately by LA treatment. Photographs and skin biopsies were taken before treatment, after the fourth session and 1 month later. RESULTS: Improvements in fine wrinkles, tightness and skin texture were observed. Histologic evaluations showed favourable changes in cellularity, collagen and elastic fibres. Laser-induced effects (400 MUm) and an inflammatory reaction (1000 MUm) were seen. RVL was present at the mid-deep dermis (1000-1500 MUm). CONCLUSIONS: Combined treatment with the LA and RVL improved skin appearance and structure as assessed, for the first time, with histology. The LA produced epidermal and superficial dermal changes whereas RVL acted deeper, together treating the full skin thickness. PMID- 21699364 TI - The effects of a high glycerin content hydrogel premolded mask dressing on post laser resurfacing wounds. AB - BACKGROUND: Laser resurfacing for the rejuvenation of facial skin remains a popular cosmetic procedure. Postoperative care for laser resurfacing is important to optimize healing, reduce pain and minimize complications. OBJECTIVE: To compare the efficacy of the new dressing against placebo (Vaseline(r) cream) after Er:YAG laser resurfacing. METHODS: Fifteen patients between 45 and 72 years of age with facial wrinkles were enrolled in the study. Patients underwent full face Er:YAG procedures. The wounds were then dressed: one side of the face was treated with Vaseline and the other with a hydrogel dressing. Erythema, edema, pigmentation, average time of re-epithelization, pain score, itching, clinical evaluation of infection, crust formation and acidity were documented. RESULTS: The hydrogel dressing decreased postoperative morbidity. The site treated by hydrogel showed a shorter epithelial healing time than the Vaseline site. The dressing relieved the immediate pain of facial resurfacing as well as preventing crust formation and itching. CONCLUSION: A hydrogel dressing is a better and suitable alternative to the open technique to manage post-laser wound healing. PMID- 21699365 TI - A review of tinnitus symptoms beyond 'ringing in the ears': a call to action. AB - BACKGROUND: Tinnitus, often referred to as 'ringing in the ears', is highly prevalent. However, patients may also present with a number of other symptoms. SCOPE: To review the broad range of symptoms of tinnitus, to evaluate their impact on patient quality of life and to explore methods of diagnosis and assessment. An electronic literature search was performed in PubMed between September and December 2010. FINDINGS: Accumulating evidence suggests that the symptoms of tinnitus are not confined to the characteristic 'ringing in the ears', but instead encompass wide-ranging symptoms that include emotional components such as sleep disturbance, anxiety, depression, irritation, and concentration difficulties. CONCLUSION: Patients with tinnitus experience a spectrum of distressing symptoms that impact their quality of life and there is a clear need for action. Clinicians need to recognize and diagnose tinnitus that occurs with other wide-ranging symptoms to ensure that these symptoms are identified and patients receive effective treatment. PMID- 21699366 TI - Systematic literature review of economics analysis on treatment of mild-to moderate bleeds with aPCC versus rFVIIa. AB - OBJECTIVE: Two bypassing agents, activated prothrombin complex concentrates (aPCC) and recombinant factor VIIa (rFVIIa), have shown similar efficacy and safety in the treatment of bleeding episodes in patients with hemophilia and inhibitors as demonstrated through the only two head-to-head clinical trials. Given the economic burden of bypassing treatment, it is crucial to have a valid estimate of cost effectiveness of alternative treatments. The aims of this study were to conduct a systematic review of published pharmacoeconomic literature on the cost-effectiveness of aPCC versus rFVIIa to treat mild-to-moderate bleeds in patients with hemophilia and inhibitors, with a focus on the model assumptions and their impact on results. METHODS: An English language search was conducted for original economic studies comparing aPCC and rFVIIa published between 1995 and July 2010. Detailed information on sponsorship, study design, assumptions and their impact on results was collected for each study. RESULTS: A total of 11 economic studies were included in the review. Nine studies assessed cost per bleeding episode (eight cost-minimization analysis (CMA) and one cost effectiveness analysis (CEA)). Two studies were from longitudinal perspective. Studies on cost per bleeding episode were evaluated and systematically compared. All studies were from a third-party payer perspective. Most analyses, except one study, used a similar decision-tree model. The assumptions for all CMA studies were obtained from non-comparable single-armed trials or observational data. All studies were sponsored by the two competing manufacturers of rFVIIa (seven studies) and aPCC (two studies). The crucial parameter assumptions on treatment efficacy and dosing drove their reported findings. Eight of these nine studies favored their sponsor's product. CONCLUSION: With one exception, published economic studies tend to favor their sponsor's product primarily by assuming a higher efficacy and lower dosing for the sponsored agent, even though the two existing head-to-head clinical studies do not support superior efficacy for either product. PMID- 21699367 TI - Archwire depth is a significant parameter in the frictional resistance of active and interactive, but not passive, self-ligating brackets. AB - OBJECTIVE: To elucidate some of the parameters determining the frictional behavior of passive, active, and interactive self-ligating brackets during sliding mechanics. MATERIALS AND METHODS: A custom jig mimicking the three dimensional tooth movements that occur during sliding mechanics and an Instron testing machine were used to determine the resistance to sliding of six different self-ligating brackets (SPEED, In-Ovation C, CarriereSLB, ClaritySL, SmartClip, VisionLP). Each bracket was tested on three rectangular stainless steel wires: 0.017 * 0.022 inch, 0.017 * 0.025 inch, and 0.019 * 0.025 inch. A two-way balanced analysis of variance was used for statistical analysis. RESULTS: The four passive self-ligating brackets (CarriereSLB, ClaritySL, SmartClip, VisionLP) displayed significantly lower frictional resistance (P < .001) than the remaining brackets, which featured an active (SPEED) or interactive (In-Ovation C) clip. The SPEED bracket consistently demonstrated the highest resistance to sliding. CONCLUSIONS: The mode of self-ligation appears to be the primary variable in determining the frictional behavior of orthodontic brackets undergoing sliding mechanics. Passive self-ligating brackets demonstrated significantly lower frictional resistance to sliding. With regard to the resistance of active self ligating brackets, the depth (buccolingual thickness) of the wire had a more significant influence than its height. PMID- 21699369 TI - Begin with the real-world patients of non-goal-achieved hypercholesterolemia in taiwan through the ezetimibe/simvastatin tablet - The BRAVO Study. AB - OBJECTIVE: To assess the efficacy, safety, and tolerability of a combination of 10 mg ezetimibe and 20 mg simvastatin in Taiwanese patients with hypercholesterolemia. RESEARCH DESIGN AND METHODS: A prospective, open-label, multi-center, hospital-based cohort study was conducted to evaluate the efficacy, safety, and tolerability of a single tablet combination of ezetimibe/simvastatin for the treatment of hypercholesterolemia. Taiwanese adults without low-density lipoprotein cholesterol (LDL-C) goal achievement, based on the National Cholesterol Education Program Adult Treatment Panel III guidelines, were treated with ezetimibe/simvastatin once daily for 6 weeks. The primary endpoint was the percentage of patients achieving LDL-C treatment goals after 6 weeks of treatment. Secondary endpoints included percentage change from baseline of LDL-C, total cholesterol, high-density lipoprotein cholesterol, and triglyceride. Safety and tolerability were assessed via clinical and laboratory examinations. The clinicaltrial.gov identifier of this study was NCT00654628. RESULTS: In total, 173 patients with a mean age of 57.9 +/- 10.4 years were included. Of these, 57.8% were female and the average body mass index was 25.5 +/- 3.4 kg/m(2). After 6 weeks of treatment, the great majority of the patients had reached their treatment goals (90.4% for LDL-C; 87% for TC; and 59% for TG). LDL-C levels were significantly reduced from 156.8 +/- 30.8 mg/dL at baseline to 75.9 +/- 25.4 mg/dL (51.4%, P < 0.0001) after only 6 weeks of therapy. Forty-nine adverse events (AEs), including one non-drug related serious AE, were reported. For non serious AEs, the most common reported AEs during the entire study period were myalgia and upper respiratory infection (both n = 7). Nine patients dropped out of the study, reportedly due to AEs. CONCLUSIONS: A single tablet combination of 10 mg ezetimibe and 20 mg simvastatin in Taiwanese patients with hypercholesterolemia provided high LDL-C goal attainment rates and resulted in significant reductions in LDL-C. PMID- 21699370 TI - Mitochondrial DNA sequence variation and phylogeography of the scarlet kingsnake (Lampropeltis elapsoides). AB - BACKGROUND AND AIMS. With the goal of assessing population structure and geographic distribution of haplotype lineages among Lampropeltis elapsoides, we sequenced the ND4 mitochondrial DNA locus from 96 specimens of this snake across its area of distribution. MATERIALS AND METHODS. We relied heavily on formalin fixed museum specimens to accomplish this analysis. RESULTS. The sequence alignment consisted of 491 bp of the selected gene, with 28% missing data. A simulation used to assess the effect of missing data on population genetic and phylogenetic resolution indicated increased character conflict, but with minimal loss of phylogenetic structure. CONCLUSION. This limited dataset suggests that L. elapsoides constitutes a largely unstructured population, with both widespread haplotypes and large number of private haplotypes, a moderate level of nucleotide diversity, and a low, but significant, degree of north-south population differentiation. Haplotype structure and frequency, nucleotide frequency, and values for Tajima's D and Fu's F(S) indicate a recent range or population expansion following a historic bottleneck. PMID- 21699368 TI - Identification of Mre11 as a target for heat radiosensitization. AB - Thermal radiosensitization is believed to be mediated by an inhibition of double strand break (DSB) repair, but the exact mechanism of radiosensitization remains to be elucidated. Previously, we demonstrated that proteins of the Mre11/Rad50/Nbs1 complex (MRN) translocate from the nucleus to the cytoplasm in cells have that been heated or heated and then irradiated; this finding led us to propose that heat radiosensitization was due at least in part to translocation of MRN. In the current study, we used leptomycin B to inhibit MRN translocation in heated, irradiated cells, but we found that heat radiosensitization was not altered. Thus enhanced radiosensitivity was not attributed to translocation of MRN proteins. To determine which of the MRN subunits contributed to heat radiosensitization, we compared the extent of heat radiosensitization in wild type cells with that of cells hypomorphic for Mre11 or Nbs1 or cells in which the level of Rad50 was suppressed. We found that neither Nbs1 nor Rad50 is involved in heat radiosensitization, because a similar amount of heat radiosensitization was observed in cells deficient in those proteins compared to cells expressing normal levels. However, heat radiosensitization was not observed in A-TLD1 cells deficient in Mre11. Measurement of exonuclease activity of purified Mre11 heated at 42.5 degrees C or 45.5 degrees C indicated that the protein is very heat labile. Immunoprecipitation of Mre11 from heated HeLa cells also revealed that hsp70 associates with Mre11 and that this association is maintained long after heating. Taken together, these findings implicate Mre11 as a target for heat radiosensitization and suggest that heat radiosensitization and inhibition of DSB repair may be mediated by heat-induced conformational changes in Mre11. PMID- 21699371 TI - Development of a multiplex amplification refractory mutation system for simultaneous authentication of Korean ginseng cultivars "Gumpoong" and "Chungsun". AB - BACKGROUND AND AIMS. Molecular authentication of Korean ginseng cultivars was investigated using the mitochondrial nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 7 (nad7) intron 3 region. MATERIALS AND METHODS. A mutation site specific to Panax ginseng "Gumpoong" and "Chungsun" cultivars was detected within the sequence data. Based on this mutation site and the "Gumpoong"-specific single nucleotide polymorphism site reported in 26S rDNA, two modified allele specific primer pairs were designed and a multiplex amplification refractory mutation system (MARMS) was applied to identify "Gumpoong" and "Chungsun." RESULTS. The results showed that "Gumpoong" and "Chungsun" can be clearly discriminated from the other Korean ginseng cultivars by simultaneously identifying the haplotype of "Gumpoong" and the specific allele of "Chungsun" by applying the MARMS. CONCLUSION. This study, therefore, provides a simple and reliable method for simultaneous authentication of "Gumpoong" and "Chungsun" cultivars. PMID- 21699372 TI - Divergence at Cyt-b and Co-1 mtDNA genes on different taxonomic levels and genetics of speciation in animals. AB - Genetic divergence estimates using p-distances and similar measures were generated for 20,731 vertebrate and invertebrate animal species. The results of this analysis demonstrate that the data series are realistic and interpretable when the p-distance and its various derivates are used. The focus is on vertebrates and fish species in particular and the newest data set. Distance data reveal increasing levels of genetic divergence of the sequences of the two genes, cytochrome b (Cyt-b) and cytochrome c oxidase subunit 1 (Co-1), in the five groups compared: populations within species; subspecies, semi-species, or/and sibling species; species within a genus; species from different genera within a family; and species from separate families within an order. Mean unweighted scores of p-distances (%) for these five groups are Cyt-b-1.38 +/- 0.30, 5.10 +/- 0.91, 10.31 +/- 0.93, 17.86 +/- 1.36, and 26.36 +/- 3.88, respectively; and Co-1 0.89 +/- 0.16, 3.78 +/- 1.18, 11.06 +/- 0.53, 16.60 +/- 0.69, and 20.57 +/- 0.40, respectively. The estimates show good correspondence with other analyses. These results testify to the applicability of p-distance for most intra-species and inter-species comparisons of genetic divergence up to the order level in animals for the two genes compared. Data reviewed provide empirical and theoretical background on the geographic speciation mode prevalence in species origin and give a framework why per-individual species identification (DNA barcoding) is usually successful. PMID- 21699373 TI - Deep barcode divergence in Brazilian freshwater fishes: the case of the Sao Francisco River basin. AB - BACKGROUND AND AIMS: The application of DNA barcoding as a global standard for fish identification is probing diverse worldwide realms (Nearctic, Australian and the Neotropics) and environments (e.g. marine and freshwater). Comparing the patterns of sequence divergence among conspecific and congeneric taxa between realms can provide valuable information on recent evolutionary histories of lineages as barcode data accumulates. MATERIALS AND METHODS: Herein, we have analyzed over 100 species (around 50%) of the Neotropical fish fauna from the Sao Francisco River, in southeast Brazil. Our aims were to test the performance of DNA barcoding in this biodiversity-rich region, and to compare patterns of genetic divergence with previous studies. RESULTS: The mean Kimura two-parameter distances within species, genera, families, orders, and classes were 0.5, 10.6, 21.0, 22.7, and 24.4%, respectively, with 100% of the species examined successfully differentiated by barcoding. With the exception of Astyanax bimaculatus lacustris, Piabina argentea, and Bryconamericus stramineus, all other species yield a single, cohesive cluster of barcode sequences. The average 'nearest-neighbor distance' was 11.12%, 21-fold higher than the mean within species distance of around 0.54%. In a few instances, deep lineage divergences among conspecifics (up to 10%) and congenerics (up to 22.9%) taxa were revealed. CONCLUSIONS: Reflecting possible cases of cryptic speciation and the deeper phylogeographic history of Sao Francisco fish fauna, with some higher clades extending back into the late Cretaceous and Cenozoic (90 mya), when much of the diversification of the Neotropical region apparently took place. In addition, barcodes also highlighted misidentifications and helped to document range extensions for known species. PMID- 21699374 TI - Effects of dopaminergic compounds on carbonic anhydrase isozymes I, II, and VI. AB - Studies on carbonic anhydrase (CA, EC 4.2.1.1) inhibitors have increased due to several therapeutic applications while there are few investigations on activators. Here we investigated CA inhibitory and activatory capacities of a series of dopaminergic compounds on human carbonic anhydrase (hCA) isozymes I, II, and VI. 2-Amino-1,2,3,4-tetrahydronaphthalene-6,7-diol hydrobromide and 2 amino-1,2,3,4-tetrahydronaphthalene-5,6-diol hydrobromide were found to show effective inhibitory action on hCA I and II whereas 2-amino-5,6-dibromoindan hydrobromide and 2-amino-5-bromoindan hydrobromide exhibited only moderate inhibition against both isoforms, being more effective inhibitors of hCA VI. K(i) values of the molecules 3-6 were in the range of 41.12-363 MUM against hCA I, of 0.381-470 MUM against hCA II and of 0.578-1.152 MUM against hCA VI, respectively. Compound 7 behaved as a CA activator with K(A) values of 27.3 MUM against hCA I, of 18.4 MUM against hCA II and of 8.73 MUM against hCA VI, respectively. PMID- 21699375 TI - Synthesis and exploration of QSAR model of 2-methyl-3-[2-(2-methylprop-1-en-1-yl) 1H-benzimidazol-1-yl]pyrimido[1,2-a]benzimidazol-4(3H)-one as potential antibacterial agents. AB - Present communication deals with the synthesis of novel 2-methyl-3-[2-(2 methylprop-1-en-1-yl)-1H-benzimidazol-1-yl]pyrimido[1,2-a]benzimidazol-4(3H)-one derivatives under phase transfer catalysis (PTC) conditions using benzyl triethyl ammonium chloride (BTEAC) as PTC. It also elicits the studies on in vitro antimicrobial evaluation of synthesized compounds against a representative genera of gram-negative and gram-positive bacteria i.e., Bacillus subtilis, Staphylococcus aureus, Pseudomonas diminuta and Escherichia coli. All the compounds have been found to manifest profound antimicrobial activity. Moreover, extensive quantitative structure-activity relationship (QSAR) studies have been performed to deduce a correlation between molecular descriptors under consideration and the elicited biological activity. A tri-parametric QSAR model has been generated upon rigorous statistical treatment. PMID- 21699376 TI - Advancing through maintenance in mantle cell lymphoma. PMID- 21699377 TI - Pre-transplant positron emission tomography in patients with relapsed Hodgkin lymphoma. AB - This retrospective study evaluated the secondary clinical risk score at relapse, the prognostic significance of pre-transplant positron emission tomography (PET), and complete remission (CR) assessed by computed tomography (CT) after salvage chemotherapy before autologous stem cell transplant (ASCT) in 76 patients with relapsed/refractory Hodgkin lymphoma (HL). Median follow-up after ASCT was 23 months. Overall 11/20 PET-positive and 14/56 PET-negative patients relapsed after ASCT. In univariate analysis, only PET negativity before ASCT was significantly associated with better 2-year progression-free survival (PFS) (72.7 +/- 6.3% vs. 36.1 +/- 11.6%, p = 0.01) and 2-year overall survival (OS) (90.3 +/- 4.1% vs. 61.4 +/- 11.6%, p = 0.009). Other factors were not significant. In multivariate analysis, none of the evaluated factors were significant for PFS and OS. However, positive pre-transplant PET identified a population with worse PFS and OS at least in univariate analysis. PMID- 21699379 TI - Endogenous interferon alpha therapy in follicular lymphoma? PMID- 21699378 TI - Tubacin suppresses proliferation and induces apoptosis of acute lymphoblastic leukemia cells. AB - Over the past decade, histone deacetylase inhibitors have increasingly been used to treat various malignancies. Tubacin (tubulin acetylation inducer) is a small molecule that inhibits histone deacetylase 6 (HDAC6) and induces acetylation of alpha-tubulin. We observed a higher antiproliferative effect of tubacin in acute lymphoblastic leukemia (ALL) cells than in normal hematopoietic cells. Treatment with tubacin led to the induction of apoptotic pathways in both pre-B and T cell ALL cells at a 50% inhibitory concentration (IC(50)) of low micromolar concentrations. Acetylation of alpha-tubulin increases within the first 30 min following treatment of ALL cells with tubacin. We also observed an accumulation of polyubiquitinated proteins and poly(ADP-ribose) polymerase (PARP) cleavage. Furthermore, the signaling pathways activated by tubacin appear to be distinct from those observed in multiple myeloma. In this article, we demonstrate that tubacin enhances the effects of chemotherapy to treat primary ALL cells in vitro and in vivo. These results suggest that targeting HDAC6 alone or in combination with chemotherapy could provide a novel approach to treat ALL. PMID- 21699291 TI - Study of Z Boson Production in PbPb Collisions at ?S(NN)=2.76 TeV. AB - A search for Z bosons in the MU(+)MU(-) decay channel has been performed in PbPb collisions at ?S(NN)=2.76 TeV with the CMS detector at the LHC, in a 7.2 MUb(-1) data sample. The number of opposite-sign muon pairs observed in the 60-120 GeV/c(2) invariant mass range is 39, corresponding to a yield per unit of rapidity (y) and per minimum bias event of [33.8+/-5.5(stat)+/-4.4(syst)]*10(-8), in the |y|<2.0 range. Rapidity, transverse momentum, and centrality dependencies are also measured. The results agree with next-to-leading order QCD calculations, scaled by the number of incoherent nucleon-nucleon collisions. PMID- 21699380 TI - Predicting outcomes in multiple myeloma: do we really need another model? PMID- 21699381 TI - Angiogenesis and multiple myeloma: is there a role for angiogenic biomarkers in the context of autologous stem cell transplant? PMID- 21699383 TI - Death receptor 4 is preferentially recruited to lipid rafts in chronic lymphocytic leukemia cells contributing to tumor necrosis related apoptosis inducing ligand-induced synergistic apoptotic responses. AB - Tumor necrosis related apoptosis inducing ligand receptor 1 (TRAIL-R1, death receptor 4 [DR4]) and TRAIL-R2 (DR5) have been proposed as targets for cancer therapy, but which death receptor to target for chemotherapy in chronic lymphocytic leukemia (CLL) is uncertain. Herein, we discovered that Burkitt lymphoma B cell line, BJAB, CLL-like cell line, I-83, and pre-acute lymphocytic leukemia B cell line, NALM-6, underwent apoptosis following TRAIL, whereas a CLL like cell line, JMV-3, and primary CLL cells failed to undergo apoptosis. In TRAIL resistant CLL cells, only activation of DR4 provided an increase in fludarabine induced apoptosis. This was mediated in part by the localization of DR4 but not DR5 in lipid rafts following TRAIL and fludarabine treatment. This preference for DR4 activation leading to increased fludarabine induced apoptosis was also observed following SAHA, PS-341, and chlorambucil treatment in primary CLL cells. Thus, CLL cells selectively activate DR4 partially mediated through its localization to lipid rafts leading to apoptosis when combined with chemotherapeutic drugs. PMID- 21699382 TI - Superior overall survival of patients with myeloma achieving very good partial response or better to initial treatment with bortezomib, pegylated liposomal doxorubicin, and dexamethasone, predicted after two cycles by a free light chain- and M-protein-based model: extended follow-up of a phase II trial. AB - In myeloma, achievement of very good partial response (VGPR) post-transplant is associated with prolonged overall (OS) and progression-free survival (PFS). In this study of bortezomib, pegylated liposomal doxorubicin, and dexamethasone (VDD) in 40 patients with newly diagnosed myeloma (median follow-up 45.1 months), 2-/4-year OS estimates were 95.7%/86.5% versus 82.4%/58.2% for patients achieving >=VGPR versus =VGPR to VDD. Achievement of >=VGPR was predicted by a novel model based on occurrence after two cycles of >=90% involved free light chain reduction, free light kappa/lambda ratio normalization, and/or >=90% M-protein reduction. Prediction of >=VGPR was associated with superior PFS and OS in patients with transplant. These findings emphasize the importance of achieving >=VGPR to initial therapy, associated with prolonged OS. The predictive model provides a potential basis for developing individualized therapy, which requires further study. PMID- 21699384 TI - Highlights of the 5th Young Investigators' Meeting on chronic lymphocytic leukemia. PMID- 21699386 TI - Immunoglobulin class switch recombination in chronic lymphocytic leukemia. AB - During B lymphocyte maturation, a subset of B cells undergo class switch recombination (CSR), a process wherein the heavy chain constant region is changed to a different immunoglobulin isotype without introduction of variable region mutations. CSR thus allows for the production of various antibody isotypes with different effector functions. Similar to naive B cells, chronic lymphocytic leukemia (CLL) cells co-express surface immunoglobulin (Ig) M and D (IgM+IgD+), though a minority of cases express terminally differentiated isotypes. In this brief report, we discuss the capacity of CLL to undergo CSR and the relevance of CSR to the clinical behavior of CLL. PMID- 21699385 TI - Patients with early stage chronic lymphocytic leukemia: new risk stratification based on molecular profiling. AB - We investigated molecular and biological parameters reflecting the biology of chronic lymphocytic leukemia (CLL) that may help us to predict the time to first treatment (TTT). A group of 33 patients with newly diagnosed CLL (Binet stage A) were analyzed. We developed a new scoring system based on the serum levels of beta(2)-microglobulin (beta(2)M) and vascular endothelial growth factor (VEGF) and the expression of lipoprotein lipase (LPL). Patients with a score of 0 had a TTT of 58.4 months, while patients with a score of 3 (increased levels of beta(2)M, LPL, and VEGF) had a significantly shorter TTT of only 10.6 months (p < 0.0001). PMID- 21699387 TI - Rituximab-cyclophosphamide-dexamethasone combination in management of autoimmune cytopenias associated with chronic lymphocytic leukemia. AB - We report our experience on rituximab-cyclophosphamide-dexamethasone (RCD) combination therapy for the treatment of autoimmune disorders in 48 patients with chronic lymphocytic leukemia (CLL). The diagnosis of autoimmune disease (AID) was autoimmune hemolytic anemia (AIHA) in 26 (54%), autoimmune thrombocytopenic purpura (AITP) in nine (18.8%), Evans syndrome in eight (16.7%), and pure red cell anemia (PRCA) in five patients (10.5%). CLL was considered progressive in 40% of subjects upon AID diagnosis. Overall, an 89.5% response rate was obtained with this combination, irrespective of the AID type. Relapse occurred in 19 patients (39.6%). The median duration of autoimmunity was 24 months, but the duration of response of autoimmunity (DR-AI) was higher for patients presenting with: (1) AID early during the CLL course (<3 years), or (2) both and pure red cell aplasia (PRCA) in five patients (10.5%) and AIHA. PMID- 21699388 TI - Genomic and phenotypic characterization of nurse-like cells that promote drug resistance in chronic lymphocytic leukemia. AB - Here, we examined both genetic and phenotypic determinants of nurse-like cells (NLCs) to better predict their putative functions in chronic lymphocytic leukemia (CLL). We showed that NLCs belong to the wound-healing macrophage subset (so called 'M2 subset'), but most of all, unsupervised clustering analysis positions NLCs as CLL-specific tumor associated macrophages (TAMs). Chemokinome assays confirmed that NLCs secrete prototypical M2 cytokines and chemokines. Extending previous reports of fludarabine resistance, NLCs are able to promote multidrug resistance. Altogether, we propose that NLCs are not just nursing, but actively participate in the setting of an environment-mediated drug resistance (EM-DR) and immune escape for CLL cells. PMID- 21699288 TI - Search for supersymmetry in pp collisions at ?7 TeV in events with two photons and missing transverse energy. AB - A search for supersymmetry in the context of general gauge-mediated breaking with the lightest neutralino as the next-to-lightest supersymmetric particle and the gravitino as the lightest is presented. The data sample corresponds to an integrated luminosity of 36 pb(-1) recorded by the CMS experiment at the LHC. The search is performed by using events containing two or more isolated photons, at least one hadronic jet, and significant missing transverse energy. No excess of events at high missing transverse energy is observed. Upper limits on the signal cross section for general gauge-mediated supersymmetry between 0.3 and 1.1 pb at the 95% confidence level are determined for a range of squark, gluino, and neutralino masses, excluding supersymmetry parameter space that was inaccessible to previous experiments. PMID- 21699389 TI - Inclusion complex of colchicine in hydroxypropyl-beta-cyclodextrin tenders better solubility and improved pharmacokinetics. AB - CONTEXT: Colchicine (CLC) causes cell death by destabilizing the tubulin unit. However, it ionizes at physiological pH resultant low bioavailability and therapeutic efficacy. OBJECTIVES: We have attempted to augment the bioavailability of CLC by fabricating the inclusion complex with hydroxypropyl beta-cyclodextrin (HP-beta-CD). MATERIALS AND METHODS: CLC-HP-beta-CD inclusion complex was prepared and evaluated with Fourier-transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy, (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy and rotating frame overhauser enhancement spectroscopy (ROESY). Oral bioavailability of CLC-HP beta-CD inclusion complex was analyzed using high performance liquid chromatography method. RESULTS AND DISCUSSION: Our phase-solubility data indicated the formation of a stable complex with K(c) ~0.31 mM(-1) at pH 7.4. (1)H NMR ascertains that NHCOCH(3) moiety of CLC enters in the HP-beta-CD cavity and deshielded the H-3 and H-5 protons. ROESY also correlates the H(f) and H(g) of CLC with H-3 and H-5 protons of HP-beta-CD and indicates that H(f) and H(g) protons of CLC are present either as cis and/or trans form in CLC-HP-beta-CD inclusion complex. Pharmacokinetic studies showed a 1.82-fold increase in absolute bioavailability of CLC upon complexation. CONCLUSION: CLC-HP-beta-CD inclusion complex may potentially be used as a viable formulation of CLC. PMID- 21699392 TI - Classifying personality disorders: an evolution-based alternative to an evidence based approach. AB - The study of personality disorders, no less psychology as a wole, remains divorced from broader spheres of scientific knowledge. Development of a conceptual schema for classifying personality disorders should include the examination of research limitations and inductive inconsistences that undermine the likely achievements of the evidential approach. An alternative course of action is outlined here, one that looks to evolutionary theory rather than evidence-based methods for classification guidance. PMID- 21699391 TI - The current state of personality disorder classification: introduction to the special feature on the classification. PMID- 21699390 TI - In vitro characterization of nebulizer delivery of liposomal amphotericin B aerosols. AB - Pharmaceutical aerosols have the potential to prevent pulmonary infectious diseases. Liposomal amphotericin B (LAMB, Ambisome, Astellas Pharma US, Deerfield, IL, USA) is approved as an intravenous infusion for empiric treatment of presumed fungal infections in neutropenic, febrile patients, as well as patients infected with Aspergillus, Cryptococcus, and other fungal pathogens. In this study, four different nebulizers were tested for their ability to deliver LAMB in aerodynamic droplet-size ranges relevant to lung deposition by an inertial sampling technique Mass median aerodynamic diameter (MMAD) and fine particle fraction percent <3.3 MUm (FPF(3.3)) and <5.8 MUm (FPF(5.8)) were determined by cascade impaction during a 2 min sampling period for each of three trials of all nebulizers. The MMADs for all nebulizers ranged from 1.72 +/- 0.11 MUm to 2.89 +/- 0.12 MUm; FPF(3.3) and FPF(5.8) were approximately 80% and 90%, respectively. Although all nebulizers appear acceptable for delivery of LAMB, the Pari LC Star and the Aeroeclipse II were considered the best in terms of delivery of aerosol efficiently and the proportion suitable for lung deposition. Additional research on pulmonary delivery and clinical tolerability is warranted. PMID- 21699393 TI - Personality assessment in DSM-5: empirical support for rating severity, style, and traits. AB - Despite a general consensus that dimensional models are superior to the categorical representations of personality disorders in DSM-IV, proposals for how to depict personality pathology dimensions vary substantially. One important question involves how to separate clinical severity from the style of expression through which personality pathology manifests. This study empirically distinguished stylistic elements of personality pathology symptoms from the overall severity of personality disorder in a large, longitudinally assessed clinical sample (N = 605). Data suggest that generalized severity is the most important single predictor of current and prospective dysfunction, but that stylistic elements also indicate specific areas of difficulty. Normative personality traits tend to relate to the general propensity for personality pathology, but not stylistic elements of personality disorders. Overall, findings support a three-stage diagnostic strategy involving a global rating of personality disorder severity, ratings of parsimonious and discriminant valid stylistic elements of personality disorder, and ratings of normative personality traits. PMID- 21699394 TI - Classifying personality disorder according to severity. AB - Current systems for classifying personality disorder according to specific categories are unsatisfactory because they do not take account of wide variations in levels of personality disturbance and associated impairment. We review previous attempts to classify personality disorder according to severity and place these findings in the context of work exploring the severity of other mental disorders. On the basis of these findings, we propose a new system for classifying personality-related problems based on severity defined by the extent of personality disturbance, the level of social dysfunctioning, and the impact of the disorder for individuals and society. We recognize that studies using these definitions will need piloting and testing in field trials, but believe that this simplified approach to classifying personality disorder would encourage greater use by clinicians and assist those involved in planning services for people with personality disorder. PMID- 21699395 TI - Beyond dysfunction and threshold-based classification: a multidimensional model of personality disorder diagnosis. AB - An alternative dimensional model of personality disorder (PD) diagnosis that addresses several difficulties inherent in the current DSM conceptualization of PDs (excessive PD overlap and comorbidity, use of arbitrary thresholds to distinguish normal from pathological personality functioning, failure to capture variations in the adaptative value of PD symptoms, and inattention to the impact of situational influences on PD-related behaviors) is outlined. The model uses a set of diagnostician-friendly strategies to render PD diagnosis in three steps: (1) the diagnostician assigns every patient a single dimensional rating of overall level of personality dysfunction on a 50-point continuum; (2) the diagnostician assigns separate intensity and impairment ratings for each PD dimension (e.g., narcissism, avoidance, dependency); and (3) the diagnostician lists any personality traits-including PD-related traits-that enhance adaptation and functioning (e.g., histrionic theatricality, obsessive attention to detail). Advantages of the proposed model for clinicians and clinical researchers are discussed. PMID- 21699396 TI - Integrating normal and abnormal personality structure: a proposal for DSM-V. AB - The personality disorders section of the American Psychiatric Association's fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) is currently being developed. The purpose of the current paper is to encourage the authors of DSM-V to integrate normal and abnormal personality structure within a common, integrative model, and to suggest that the optimal choice for such an integration would be the five-factor model (FFM) of general personality structure. A proposal for the classification of personality disorder from the perspective of the FFM is provided. Discussed as well are implications and issues associated with an FFM of personality disorder, including validity, coverage, feasibility, clinical utility, and treatment implications. PMID- 21699397 TI - The central domains of personality pathology in psychiatric patients. AB - There is general agreement that the classification of personality disorders in DSM-IV is unsatisfactory. We systematically reviewed all studies that have analyzed patterns of personality disorder symptoms and signs in psychiatric patients; twenty-two papers were included in the final synthesis. There is reasonable consistency over the number and type of personality pathology traits reported despite differing samples, varying assessment methods, and different statistical manipulations. There are three or four high order traits; an externalizing factor incorporating borderline, narcissistic, histrionic, and antisocial traits (the latter is sometimes recorded as a separate trait); an internalizing factor incorporating avoidant and dependent traits; a schizoid factor; and often a compulsive factor. Using these domains of personality pathology would simplify classification, have higher clinical utility, and allow relatively easy translation of current research. PMID- 21699398 TI - The structure of personality disorders: comparing the DSM-IV-TR Axis II classification with the five-factor model framework using structural equation modeling. AB - Earlier factor analytical studies on the empirical validity of the DSM-IV-TR (American Psychological Association, 2000) Axis II classification have offered little support for the current three-cluster structure. In his large-scale meta analysis of previously published personality disorder correlation matrices, O'Connor (2005) found four factors, corresponding to the neuroticism, extraversion, agreeableness, and conscientiousness domains of the five-factor model of personality. In the present study, this dimensional four-factor model and the categorical DSM three-cluster structure were fitted to the Assessment of DSM-IV Personality Disorders questionnaire (ADP-IV; Schotte & De Doncker, 1994) scale scores using structural equation modelling. The results strongly favored the dimensional model, which also resembled other well-founded four-factor proposals (Livesley, Jang, & Vernon, 1998; Widiger & Simonsen, 2005). Moreover, a multigroup confirmatory factor analysis showed that this model was highly invariant and thus generalizable across two large clinical (n = 1,029) and general population (n = 659) samples. PMID- 21699399 TI - An empirically-based classification of personality disorder. AB - An empirically-based classification is proposed based on studies of the phenotypic structure and genetic architecture of personality disorder. The proposed system has two parts: (1) a definition of general personality disorder, and (2) a system for diagnosing different forms of disorder. General personality disorder is conceptualized as a pervasive disturbance in the overall structure and organization of the personality system that is manifested as the failure to establish a coherent self-system and the capacity for adaptive interpersonal and social behavior. Different forms of disorder are represented by a dimensional system consisting of 30 primary traits organized into four higher-order domains. The system is intended to offer a systematic and comprehensive diagnosis of personality disorder for clinical and research purposes. It is also intended to be used in a flexible but prescribed way to provide a diagnostic assessment tailored to different assessment needs. PMID- 21699400 TI - Electro-acupuncture can alleviate the cerebral oedema of rat after ischemia. AB - PRIMARY OBJECTIVE: This study was designed to determine whether electro acupuncture (EA) could alleviate cerebral oedema after cerebral ischemia. RESEARCH DESIGN: EA has been widely used for cerebrovascular disease in East Asian countries. However, whether EA might reduce cerebral oedema after stroke remains unclear. In the current study, diffusion-weighted MRI, which is a reliable method for detecting cerebral oedema, was used to determine whether EA could ameliorate cerebral oedema. METHODS AND PROCEDURES: Twelve rats with induced strokes were divided into two groups: one group with EA treatment (EA group) and one group without EA treatment (non-EA group). Both groups of rats underwent MRI scanning at the same time point following ischemia. MAIN OUTCOMES AND RESULTS: Diffusion-weighted imaging showed that the relative apparent diffusion coefficient increased significantly in the cortical and sub-cortical areas of the EA group relative to the non-EA group, indicating that EA can alleviate cerebral oedema after ischemic stroke. CONCLUSIONS: Electro-acupuncture can alleviate cerebral oedema in rats following ischemia. PMID- 21699401 TI - A topology-preserving selection and clustering approach to multidimensional biological data. AB - Multidimensional genome-wide data (e.g., gene expression microarray data) provide rich information and widespread applications in integrative biology. However, little attention has been paid to the inherent relationships within these natural data. By simply viewing multidimensional microarray data scattered over hyperspace, the spatial properties (topological structure) of the data clouds may reveal the underlying relationships. Based on this idea, we herein make analytical improvements by introducing a topology-preserving selection and clustering (TPSC) approach to complex large-scale microarray data. Specifically, the integration of self-organizing map (SOM) and singular value decomposition allows genome-wide selection on sound foundations of statistical inference. Moreover, this approach is complemented with an SOM-based two-phase gene clustering procedure, allowing the topology-preserving identification of gene clusters. These gene clusters with highly similar expression patterns can facilitate many aspects of biological interpretations in terms of functional and regulatory relevance. As demonstrated by processing large and complex datasets of the human cell cycle, stress responses, and host cell responses to pathogen infection, our proposed method can yield better characteristic features from the whole datasets compared to conventional routines. We hence conclude that the topology-preserving selection and clustering without a priori assumption on data structure allow the in-depth mining of biological information in a more accurate and unbiased manner. A Web server ( http://www.cs.bris.ac.uk/~hfang/TPSC ) hosting a MATLAB package that implements the methodology is freely available to both academic and nonacademic users. These advances will expand the scope of omics applications. PMID- 21699402 TI - Where in the genome are significant single nucleotide polymorphisms from genome wide association studies located? AB - Recent technological progress has permitted the efficient performance of genome wide association studies (GWAS) to map genetic variants associated with common diseases. Here, we analyzed 2,893 single nucleotide polymorphisms (SNPs) that have been identified in 593 published GWAS as associated with a disease phenotype with respect to their genomic location. In absolute numbers, most significant SNPs are located in intergenic regions and introns. When compared to their representation on the chips, there is essentially overrepresentation of nonsynonymous coding SNPs (nsSNPs), synonymous coding SNPs, and SNPs in untranscribed regions upstream of genes among the disease associated SNPs. A Gene Ontology term analysis showed that genes putatively causing a phenotype often code for membrane associated proteins or signal transduction genes. PMID- 21699403 TI - Genome diversity of the TetR family of transcriptional regulators in a metal reducing bacterial family Geobacteraceae and other microbial species. AB - Members of the TetR family of bacterial transcriptional regulators affect expression of genes whose products are involved in a variety of important functions, including osmotic stress, catabolic pathways, homeostasis, biosynthesis of antibiotics, expression of efflux pumps, multidrug resistance, and virulence of pathogenic bacteria. We used genome sequence information to carry out phylogenetic classification of 864 TetR family members with a special focus on TetR regulators in Geobacteraceae, an environmentally important family of delta-Proteobacteria. The genome of Geobacter sulfurreducens, a model representative of Geobacteraceae, contains nine genes from the tetR family. Several of these genes are located immediately upstream of operons encoding functionally important c-type cytochromes. Computational analyses identified the presence of conserved promoters and other regulatory binding sites upstream of several G. sulfurreducens tetR genes. This suggests the possibility of an intermediary role of TetR family proteins in Geobacteraceae in regulatory cascades involving a variety of sigma factors. In order to understand the role of the TetR regulatory family in Geobacteraceae, we have inferred phylogenetic relationships among the Geobacteraceae TetR proteins and their homologs in other microbial species. PMID- 21699404 TI - Bacterial proteome of streptococcus pneumoniae through multidimensional separations coupled with LC-MS/MS. AB - Streptococcus pneumoniae is a major human respiratory pathogen causing considerable morbidity and mortality worldwide. In order to better understand the pathogenesis of S. pneumoniae, we employed SDS-PAGE combined with LC-MS/MS analysis and in-solution digestion coupled with 2D-LC-MS/MS to obtain the whole cell proteome of the bacterium. Among the identified 1,210 proteins, 345 proteins were annotated for cellular components, 613 for biological processes, and 421 for molecular functions. Important virulence-associated surface proteins such as Eno, ZmpB, and PrtA were identified. Classification analysis and protein-protein interaction map revealed that these identified proteins are involved in many biological processes including protein biosynthesis, protein folding and proteolysis, cell cycle, or regulation and carbohydrate metabolism. These data represent a comprehensive reference map of S. pneumoniae proteome, providing a useful source for further analysis of the virulence factors and the regulatory network involved in the pathogenesis of the bacterium. PMID- 21699405 TI - G2019S mutation of the leucine-rich repeat kinase 2 gene in a cohort of Egyptian patients with Parkinson's disease. AB - AIM: This work investigates the prevalence of G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) gene in a cohort of Egyptian patients with sporadic Parkinson's disease (PD) and its relation to various features of the disease. MATERIALS AND METHODS: The study included 113 patients with sporadic PD and 87 healthy individuals as a control group. Clinical assessment was done using the Unified PD Rating Scale (UPDRS) and staging of PD was done according to Hoehn Yahr score. The G2019S mutation was detected by polymerase chain reaction (PCR) followed by restriction digestion; results were confirmed using a 5' nuclease allelic discrimination real-time PCR method. RESULTS: The G2019S mutation was detected in 11 patients (9.7%) with PD, all of whom were heterozygous, but it was not present in any of the controls. Among PD patients, carriers of the G2019S mutation had significantly higher UPDRS motor score and a higher score for resting tremor than noncarriers (p=0.019 and p=0.004, respectively). CONCLUSIONS: The G2019S mutation in the LRRK2 gene is quite common in Egyptian patients with sporadic PD. The mutation is associated with a higher degree of motor effect but does not seem to affect mentation or behavioral aspects of the disease. PMID- 21699406 TI - Angiotensin-converting enzyme gene polymorphism in patients with multiple sclerosis from Bosnia and Herzegovina. AB - BACKGROUND: Increased activity of angiotensin-converting enzyme (ACE) in the blood and cerebrospinal fluid of patients with multiple sclerosis (MS), and the inhibition of ACE in experimental autoimmune encephalomyelitis, suggested that ACE may play a role in the pathogenesis and progression of MS. We recently published the first report on the potential association of MS and ACE I/D polymorphism in Slovenian and Croatian patients with MS, in which it was shown that the DD genotype might contribute to a higher risk of developing MS in men. To confirm these findings in a similar ethnic population, we analyzed ACE I/D gene polymorphism in patients with MS from Bosnia and Herzegovina. SUBJECTS AND METHODS: One hundred and seventy patients with MS and 170 healthy controls were genotyped by the polymerase chain reaction method. RESULTS: There was no significant difference in the distribution of ACE I/D genotypes (p=0.783) or in the allelic frequencies (p=0.538) between patients with MS and control subjects. When patients with MS were stratified by sex, no statistically significant differences in allele or genotype distributions were observed. Finally, there was no indication of an impact of the ACE I/D genotype on disease course or severity. CONCLUSION: The ACE I/D polymorphism is not a risk factor for development of MS, nor does it contribute to disease severity in this Bosnia and Herzegovina population. PMID- 21699407 TI - Lack of association between polymorphism -592A/C in the promoter region of the IL10 gene and Tourette's syndrome in a family-based association study in the Chinese Han population. AB - We evaluated the genetic contribution of the IL10-592A/C polymorphism in 108 trios with Tourette's syndrome (TS) including all their parents in a Chinese Han population by using the transmission disequilibrium test and haplotype relative risk design; no evidence for association or linkage disequilibrium was found between IL10-592A/C polymorphism and TS. These results suggested that IL10 may not play a major role in the development of TS in the Chinese Han population. PMID- 21699408 TI - The reliability of maternal serum triple test in prenatal diagnosis of fetal chromosomal abnormalities of pregnant Turkish women. AB - AIM: The purpose of this article was to evaluate the reliability of maternal serum triple marker screening of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol for the prenatal diagnosis of fetal chromosomal abnormalities in Turkish pregnant women. METHOD: Medical records were used to analyze indications of amniocentesis and quantitative fluorescent-polymerase chain reaction. Anomaly screening was performed for all patients between 13 and 22 weeks of pregnancy. A total of 1725 pregnancies with chromosomal abnormality risk according to triple test screening were accepted for fetal chromosome analysis and quantitative fluorescent-polymerase chain reaction. RESULTS: Chromosomal aberrations were observed in 56 (3.2%) cases. About 44.6% of the abnormalities detected were numerical aberrations; however, 55.3% of the abnormalities were structural aberrations. Abnormalities detected were inversion of chromosome 9 in 20 cases, trisomy 21 in 14 cases, 46,XX/47,XX, +21 in 1 case, trisomy 18 in 2 cases, trisomy 13 in 1 case, 47,XXY, in 1 case, 45,X, in 1 case, structural abnormalities in 12 cases, and mosaic or tetraploidy in 6 cases. CONCLUSION: Second trimester triple test is an effective screening tool for detecting fetal Down syndrome in Turkish women. PMID- 21699409 TI - Combined effect of Factor V Leiden, MTHFR, and angiotensin-converting enzyme (insertion/deletion) gene mutations in hypertensive adult individuals: a population-based study from Sivas and Canakkale, Turkey. AB - BACKGROUND: Hypertension is one of the leading causes of mortality and morbidity in the world, which is influenced by environmental and genetic factors. The methylenetetrahydrofolate reductase (MTHFR) and angiotensin-converting enzymes (ACE) are possible candidate genes that may influence both body fatness and blood pressure (BP). The purpose of this study was to examine the carriage of gene combinations of the ACE (insertion/deletion [I/D]), MTHFR 677T and 1298C, and lipid profiles in patients with essential hypertension (EH) in Turkey. METHODS: A total of 150 adult individuals (50 hypertensive, 50 first-degree relatives, and 50 healthy controls) from Sivas/Turkey with the same age and gender were assessed for body composition, lipid profiles, resting BP, and gene profiles. Additionally, 149 individuals (99 hypertensive, 50 controls) from Canakkale/Turkey had been investigated for ACE I/D polymorphism. Peripheral blood samples were genotyped using strip assay reverse-hybridization multiplex polymerase chain reaction tests for target genes. RESULTS: Heterozygous mutation in FV Leiden was found to be higher in the hypertensive and first-degree relatives when compared with the control group (p<0.05). Homozygous DD alleles of the ACE gene were also higher than the ACE I/D and control groups (p<0.05). The high rates of cholesterol and low-density lipoprotein and low rates of high density lipoprotein were found in patients with EH when compared with the control. CONCLUSION: Results show that ACE with DD alleles and mutated alleles of FV Leiden and MTHFR genes were significantly different between genotypes and have a combined effect on EH in Turkish population. Further studies are needed to investigate the genetics of obesity, EH, and BP phenotypes in the current adult population. PMID- 21699410 TI - Comparison of KRAS mutation tests in colorectal cancer patients. AB - The KRAS pathway and studies evaluating KRAS as a prognostic marker in colorectal cancer are discussed along with advances in KRAS gene mutation testing. Highly sensitive real-time polymerase chain reaction (PCR) methods were developed for this purpose. We examined the applicability of direct sequencing and two real time PCR methods in the diagnosis of KRAS mutations. We used real-time PCR and direct sequencing-based methods to determine applicability of these KRAS mutation tests in 64 colorectal cancers. The two DNA samples found to be mutation positive by real-time PCR were analyzed again after diluting 100-fold. The results were the same. When we applied the same strategy for the direct sequencing, even a 10 fold dilution did not show the mutations. Therefore, we found that sequencing may not be informative when there are only a few mutant cells in the tumor. KRAS mutation screening on formalin-fixed, paraffin-embedded DNA is very efficient with real-time PCR methods in comparison to direct sequencing. The development and adoption of guidelines for KRAS mutation testing are crucial for success. PMID- 21699411 TI - Control of reactive oxygen species production in contracting skeletal muscle. AB - SIGNIFICANCE: The increased activities of free radicals or reactive oxygen species in tissues of exercising humans and animals were first reported ~30 years ago. A great deal has been learned about the processes that can generate these molecules, but there is little agreement on which are important, how they are controlled, and there are virtually no quantitative data. Superoxide and nitric oxide are generated by skeletal muscle and their reactions lead to formation of secondary species. A considerable amount is known about control of superoxide generation by xanthine oxidase activity, but similar information for other generation systems is lacking. RECENT ADVANCES: Re-evaluation of published data indicates potential approaches to quantification of the hydrogen peroxide concentration in resting and contracting muscle cells. Such calculations reveal that, during contractions, intracellular hydrogen peroxide concentrations in skeletal muscle may only increase by ~100 nM. The primary effects of this modest increase appear to be in "redox" signaling processes that mediate some of the responses and adaptations of muscle to exercise. These act, in part, to increase the expression of cytoprotective proteins (e.g., heat shock proteins and antioxidant enzymes) that help maintain cell viability. During aging, these redox mediated adaptations fail and this contributes to age-related loss of skeletal muscle. CRITICAL ISSUES AND FUTURE DIRECTIONS: Understanding the control of ROS generation in muscle and the effect of aging and some disease states will aid design of interventions to maintain muscle mass and function, but is dependent upon development of new analytical approaches. The final part of this review indicates areas where such developments are occurring. PMID- 21699413 TI - Rat embryonic fibroblasts improve reprogramming of human keratinocytes into induced pluripotent stem cells. AB - Patient-specific human induced pluripotent stem (hiPS) cells not only provide a promising tool for cellular disease models in general, but also open up the opportunity to establish cell-type-specific systems for personalized medicine. One of the crucial prerequisites for these strategies, however, is a fast and efficient reprogramming strategy from easy accessible somatic cell populations. Keratinocytes from plucked human hair had been introduced as a superior cell source for reprogramming purposes compared with the widely used skin fibroblasts. The starting cell population is, however, limited and thereby further optimization in terms of time, efficiency, and quality is inevitable. Here we show that rat embryonic fibroblasts (REFs) should replace mouse embryonic fibroblasts as feeder cells in the reprogramming process. REFs enable a significantly more efficient reprogramming procedure as shown by colony number and total amount of SSEA4-positive cells. We successfully produced keratinocyte derived hiPS (k-hiPS) cells from various donors. The arising k-hiPS cells display the hallmarks of pluripotency such as expression of stem cell markers and differentiation into all 3 germ layers. The increased reprogramming efficiency using REFs as a feeder layer occurred independent of the proliferation rate in the parental keratinocytes and acts, at least in part, in a non-cell autonomous way by secreting factors known to facilitate pluripotency such as Tgfb1, Inhba and Grem1. Hence, we provide an easy to use and highly efficient reprogramming system that could be very useful for a broad application to generate human iPS cells. PMID- 21699412 TI - Chromatin insulator elements block transgene silencing in engineered human embryonic stem cell lines at a defined chromosome 13 locus. AB - Lineage reporters of human embryonic stem cell (hESC) lines are useful for differentiation studies and drug screening. Previously, we created reporter lines driven by an elongation factor 1 alpha (EF1alpha) promoter at a chromosome 13q32.3 locus in the hESC line WA09 and an abnormal hESC line BG01V in a site specific manner. Expression of reporters in these lines was maintained in long term culture at undifferentiated state. However, when these cells were differentiated into specific lineages, reduction in reporter expression was observed, indicating transgene silencing. To develop an efficient and reliable genetic engineering strategy in hESCs, we used chromatin insulator elements to flank single-copy transgenes and integrated the combined expression constructs via PhiC31/R4 integrase-mediated recombination technology to the chromosome 13 locus precisely. Two copies of cHS4 double-insulator sequences were placed adjacent to both 5' and 3' of the promoter reporter constructs. The green fluorescent protein (GFP) gene was driven by EF1alpha or CMV early enhancer/chicken beta actin (CAG) promoter. In the engineered hESC lines, for both insulated CAG-GFP and EF1alpha-GFP, constitutive expression at the chromosome 13 locus was maintained during prolonged culture and in directed differentiation assays toward diverse types of neurons, pancreatic endoderm, and mesodermal progeny. In particular, described here is the first normal hESC fluorescent reporter line that robustly expresses GFP in both the undifferentiated state and throughout dopaminergic lineage differentiation. The dual strategy of utilizing insulator sequences and integration at the constitutive chromosome 13 locus ensures appropriate transgene expression. This is a valuable tool for lineage development study, gain- and loss-of-function experiments, and human disease modeling using hESCs. PMID- 21699414 TI - Restoration of skeletal muscle defects with adult human cells delivered on fibrin microthreads. AB - Large-scale musculoskeletal wounds, such as those seen in trauma injuries, present poor functional healing prognoses. In severe trauma, when the native tissue architecture is destroyed or lost, the regenerative capacity of skeletal muscle is diminished by scar formation. Here we demonstrate that a scaffold system composed of fibrin microthreads can provide an efficient delivery system for cell-based therapies and improve regeneration of a large defect in the tibialis anterior of the mouse. Cell-loaded fibrin microthread bundles implanted into a skeletal muscle resection reduced the overall fibroplasia-associated deposition of collagen in the wound bed and promoted in-growth of new muscle tissue. When fibrin microthreads were seeded with adult human cells, implanted cells contributed to the nascent host tissue architecture by forming skeletal muscle fibers, connective tissue, and PAX7-positive cells. Stable engraftment was observed at 10 weeks postimplant and was accompanied by reduced levels of collagen deposition. Taken together, these data support the design and development of a platform for microthread-based delivery of autologous cells that, when coupled to an in vitro cellular reprogramming process, has the potential to improve healing outcomes in large skeletal muscle wounds. PMID- 21699417 TI - Accuracy and precision of glucose monitoring are relevant to treatment decision making and clinical outcome in hospitalized patients with diabetes. AB - BACKGROUND AND METHODS: The accuracy and precision of three blood glucose meters (BGMs) were evaluated in 600 hospitalized patients with type 1 (n = 200) or type 2 (n = 400) diabetes. Capillary blood glucose values were analyzed with Accu Chek((r)) Aviva [Roche (Hellas) S.A., Maroussi, Greece], Precision-Xceed((r)) [Abbott Laboratories (Hellas) S.A., Alimos, Greece], and Glucocard X-Sensor((r)) (Menarini Diagnostics S.A., Argyroupolis, Greece). At the same time plasma glucose was analyzed using the World Health Organization's glucose oxidase method. RESULTS: Median plasma glucose values (141.2 [range, 13-553] mg/dL) were significantly different from that produced by the BGMs (P < 0.001). The Accu-Chek Aviva underestimated hypoglycemia (plasma glucose <=55 mg/dL) by a mean difference of 4.1 mg/dL (95% confidence interval [CI] 0-28 mg/dL), and the Precision-Xceed did so by a mean difference of 6.2 mg/dL (95% CI 0-29 mg/dL); the same was true for the Glucocard X-Sensor by a mean difference of 9.1 mg/dL (CI 0 57 mg/dL) (P < 0.001 for all BGMs). Hyperglycemia (plasma glucose >=250 mg/dL) was overestimated with the Accu-Chek Aviva and the Precision-Xceed by a mean difference of 4.8 mg/dL (95% CI 0-41 mg/dL) and 10.4 mg/dL (CI 0-92 mg/dL), respectively; the same was true for the Glucocard X-Sensor by a mean difference of 20.3 mg/dL (95% CI 0-100 mg/dL) (P < 0.001 for all BGMs). Asymptomatic hypoglycemia was detected in 28% of type 1 and in 18% of type 2 diabetes patients. In all cases, the BGMs were unreliable in sensing hypoglycemia. Multivariate linear regression analysis demonstrated that low blood pressure and hematocrit significantly affected glucose measurements obtained with all three BGMs (P < 0.05). CONCLUSIONS: In hospitalized diabetes patients, all three frequently used BGMs undersensed hypoglycemia and oversensed hyperglycemia to some extent. Patients and caregivers should be aware of these restrictions of the BGMs. PMID- 21699422 TI - A national rollout of an insufficiently evaluated practice: how evidence based are our end-of-life care policies? PMID- 21699421 TI - Terminal extubation of the alert patient. PMID- 21699424 TI - Should our hospice patients be driving? PMID- 21699425 TI - Levorphanol #240. PMID- 21699426 TI - Improving communication when hearing loss is present #241. PMID- 21699427 TI - A brief experiment in time travel. PMID- 21699428 TI - "Dios bendiga usted!" "God bless you!". PMID- 21699429 TI - The lilies in my white coat pocket. PMID- 21699431 TI - Submillimeter-resolution fluorescence laparoscopy of pancreatic cancer in a carcinomatosis mouse model visualizes metastases not seen with standard laparoscopy. AB - BACKGROUND: Staging laparoscopy can visualize peritoneal and liver metastases in pancreatic cancer otherwise undetectable by preoperative imaging. However, false negative rates may be as high as 18%-26%. The aim of the present study was to improve detection of metastatic pancreatic cancer with the use of fluorescence laparoscopy (FL) in a nude-mouse model with the tumors expressing green fluorescent protein (GFP). METHODS: The carcinomatosis mouse model of human pancreatic cancer was established by intraperitoneal injections of green fluorescent protein-expressing MiaPaca-2 human pancreatic cancer cells into 6 week-old female athymic mice. Two weeks later, mice underwent diagnostic laparoscopy. Laparoscopy was performed first under standard brightfield lighting, followed by fluorescent lighting. The number of metastatic foci identified within the four quadrants of the peritoneal cavity was recorded. After laparoscopy, the animals were sacrificed, opened, and imaged with the OV-100 Small Animal Imaging system as a positive control to identify metastasis. Tumors were collected and processed for histologic review. RESULTS: FL enabled visualization of pancreatic cancer metastatic foci not visualized with standard brightfield laparoscopy (BL). Under FL, in 1 representative mouse, 26 separate micrometastatic lesions were identified. In contrast, only very large tumors were seen using BL. Use of the OV 100 images, as positive controls, confirmed the presence of tumor foci. FL thus allowed identification and exact localization of submillimeter tumor foci. Such small-sized tumor foci were not distinguished from surrounding tissue under BL. All malignant lesions were histologically confirmed. CONCLUSIONS: The use of FL enables the identification of tumor foci that cannot be seen with standard laparoscopy. The technology described in this report has important potential for the clinical development of FL. PMID- 21699432 TI - Effect of pressure- versus volume-controlled ventilation on the ventilatory and hemodynamic parameters during laparoscopic appendectomy in children: a prospective, randomized study. AB - BACKGROUND: Several ventilatory strategies have been introduced to minimize the respiratory and hemodynamic effects of carbon dioxide pneumoperitoneum during laparoscopic surgery. The purpose of this study was to compare the effects of pressure-controlled ventilation (PCV) with that of volume-controlled ventilation (VCV) on the ventilatory and hemodynamic parameters in children undergoing laparoscopic appendectomy. METHODS: Thirty-four children undergoing laparoscopic appendectomy were randomly allocated to receive mechanical ventilation using either VCV (n=17) or PCV (n=17) mode. Positive end-expiratory pressure (PEEP) 5 cm H(2)O was applied to all patients. Hemodynamic and ventilatory parameters were measured 10 minutes before pneumoperitoneum (T1) and 30 minutes after pneumoperitoneum (T2). RESULTS: Peak and mean airway pressures were significantly increased at T2 from T1 in both groups. Mean airway pressure was significantly higher in the PCV group compared with that in the VCV group. Dynamic compliance was significantly higher in the PCV group than in the VCV group at T2, although it was decreased at T2 from T1 in both groups. Mean blood pressure was significantly increased at T2 from T1 in both groups without intergroup difference. During the study period, SpO(2) remained constant without intergroup or within-group differences. CONCLUSION: During laparoscopy, mean airway pressure and dynamic compliance were significantly higher during PCV with 5 cm H(2)O PEEP compared with that in VCV with 5 cm H(2)O PEEP. And, as there were no differences in other ventilatory parameters and oxygen saturation, both VCV and PCV can be used safely in children undergoing laparoscopic surgery. PMID- 21699433 TI - Biomaterial selection for tooth regeneration. AB - Biomaterials are native or synthetic polymers that act as carriers for drug delivery or scaffolds for tissue regeneration. When implanted in vivo, biomaterials should be nontoxic and exert intended functions. For tooth regeneration, biomaterials have primarily served as a scaffold for (1) transplanted stem cells and/or (2) recruitment of endogenous stem cells. This article critically synthesizes our knowledge of biomaterial use in tooth regeneration, including the selection of native and/or synthetic polymers, three dimensional scaffold fabrication, stem cell transplantation, and stem cell homing. A tooth is a complex biological organ. Tooth loss represents the most common organ failure. Tooth regeneration encompasses not only regrowth of an entire tooth as an organ, but also biological restoration of individual components of the tooth including enamel, dentin, cementum, or dental pulp. Regeneration of tooth root represents perhaps more near-term opportunities than the regeneration of the whole tooth. In the adult, a tooth owes its biological vitality, arguably more, to the root than the crown. Biomaterials are indispensible for the regeneration of tooth root, tooth crown, dental pulp, or an entire tooth. PMID- 21699434 TI - Polymeric nanofibers in tissue engineering. AB - Polymeric nanofibers can be produced using methods such as electrospinning, phase separation, and self-assembly, and the fiber composition, diameter, alignment, degradation, and mechanical properties can be tailored to the intended application. Nanofibers possess unique advantages for tissue engineering. The small diameter closely matches that of extracellular matrix fibers, and the relatively large surface area is beneficial for cell attachment and bioactive factor loading. This review will update the reader on the aspects of nanofiber fabrication and characterization important to tissue engineering, including control of porous structure, cell infiltration, and fiber degradation. Bioactive factor loading will be discussed with specific relevance to tissue engineering. Finally, applications of polymeric nanofibers in the fields of bone, cartilage, ligament and tendon, cardiovascular, and neural tissue engineering will be reviewed. PMID- 21699436 TI - Manufacture of liposomes by isopropanol injection: characterization of the method. AB - Unilamellar liposomes are conventionally prepared by rapid injection of an ethanolic solution of lipids into an aqueous medium. The aim of the present study was to control, more efficiently, vesicle diameter by using an alternative solvent. The results show that isopropanol injection is a good alternative to ethanol injection for the manufacture of liposomes. Particle size can be controlled by the variation of process parameters, such as stirring speed of the aqueous phase and injection flow rate of lipid-isopropanol solution. Diameter of vesicles obtained by this method is less affected by the nature of phospholipid, as well as lipid concentration, than in the ethanol-injection process. In addition, the vesicles are generally smaller (approximately 40-210 nm). Accurate characterization of the particles, by fluorescence, (31)P-NMR, and cryo transmission electron microscopy, showed that particles are formed of a single lipid bilayer around an aqueous cavity. We thus provide the scientific community with a fully characterized alternative method to produce unilamellar vesicles. PMID- 21699437 TI - A critical review on the improvement of photosynthetic carbon assimilation in C3 plants using genetic engineering. AB - Global warming is one of the most serious challenges facing us today. It may be linked to the increase in atmospheric CO2 and other greenhouse gases (GHGs), leading to a rise in sea level, notable shifts in ecosystems, and in the frequency and intensity of wild fires. There is a strong interest in stabilizing the atmospheric concentration of CO2 and other GHGs by decreasing carbon emission and/or increasing carbon sequestration. Biotic sequestration is an important and effective strategy to mitigate the effects of rising atmospheric CO2 concentrations by increasing carbon sequestration and storage capacity of ecosystems using plant photosynthesis and by decreasing carbon emission using biofuel rather than fossil fuel. Improvement of photosynthetic carbon assimilation, using transgenic engineering, potentially provides a set of available and effective tools for enhancing plant carbon sequestration. In this review, firstly different biological methods of CO2 assimilation in C3, C4 and CAM plants are introduced and three types of C4 pathways which have high photosynthetic performance and have evolved as CO2 pumps are briefly summarized. Then (i) the improvement of photosynthetic carbon assimilation of C3 plants by transgenic engineering using non-C4 genes, and (ii) the overexpression of individual or multiple C4 cycle photosynthetic genes (PEPC, PPDK, PCK, NADP-ME and NADP-MDH) in transgenic C3 plants (e.g. tobacco, potato, rice and Arabidopsis) are highlighted. Some transgenic C3 plants (e.g. tobacco, rice and Arabidopsis) overexpressing the FBP/SBPase, ictB and cytochrome c6 genes showed positive effects on photosynthetic efficiency and growth characteristics. However, over the last 28 years, efforts to overexpress individual, double or multiple C4 enzymes in C3 plants like tobacco, potato, rice, and Arabidopsis have produced mixed results that do not confirm or eliminate the possibility of improving photosynthesis of C3 plants by this approach. Finally, a prospect is provided on the challenges of enhancing carbon assimilation of C3 plants using transgenic engineering in the face of global warming, and the trends of the most promising approaches to improving the photosynthetic performance of C3 plants. PMID- 21699438 TI - Detailed fetal anatomy assessment in the first trimester at 11, 12 and 13 weeks of gestation. AB - OBJECTIVE: The aim of the present observational study was to evaluate the feasibility of a morphological scan and determine the detection rate of fetal organs, structures and systems in the first trimester of pregnancy. METHODS: 977 single pregnant women attending our Fetal Medicine Section to undergo first trimester screening for aneuploidies were enrolled and divided into three groups depending on gestational age and crown-rump-length measurement. Scans targeted on a total of 26 fetal anatomical structures were performed by a single operator. RESULTS: The overall detection rate was 96% at 11 weeks and reached 100% at 12 and 13 weeks, with a significant statistical difference between 11 and 12/13 weeks for the majority of the investigated fetal anatomical structures. CONCLUSIONS: Evaluation of most part of the fetal anatomical structures is feasible with high accuracy in the first trimester. Visualization of the majority of the targeted fetal organs improves from 11 to 13 weeks. PMID- 21699439 TI - Impact of prenatal diagnosis on outcome of pulmonary atresia and intact ventricular septum. AB - OBJECTIVES: To determine the impact of fetal echocardiography on the management of pregnancy and of newborns affected by pulmonary atresia and intact ventricular septum (PAIVS) and to evaluate the outcome of infants with and without prenatal diagnosis of PAIVS. METHODS: We searched our database for cases of PAIVS prenatally and postnatally diagnosed during the period January 1993-December 2009. Postnatal follow-up was available in all cases included in the study. Karyotyping and fluorescent in situ hybridization analysis for the DiGeorge critical region (22q11.2) were performed in all but one case. RESULTS: The study comprised 60 cases of PAIVS: 36 with (Group A) and 24 without (Group B) prenatal diagnosis. In Group A, there were two intrauterine deaths, six postnatal deaths (five early after birth) and one termination of pregnancy. In this group, radiofrequency (RF) perforation was successfully performed in 25 cases; 20/25 infants had a biventricular (BV) repair, without further operation in 13 of them. No patient of Group B died. In this group, RF perforation was successfully performed in 22 cases; 20/22 had a BV repair without further procedure in 15 of them. CONCLUSIONS: Prenatal diagnosis of PAIVS allows a reliable prognosis of severity and planning of proper surgical repair strategies. Fetuses that are prenatally diagnosed present a more severe spectrum of the disease; for the cases capable of getting through the neonatal period, the mortality rate and the need for further intervention were not significantly different when compared with babies with only postnatal diagnosis. PMID- 21699435 TI - Proteolysis in illness-associated skeletal muscle atrophy: from pathways to networks. AB - Improvements in health in the past decades have resulted in increased numbers of the elderly in both developed and developing regions of the world. Advances in therapy have also increased the prevalence of patients with chronic and degenerative diseases. Muscle wasting, a feature of most chronic diseases, is prominent in the elderly and contributes to both morbidity and mortality. A major research goal has been to identify the proteolytic system(s) that is responsible for the degradation of proteins that occurs in muscle atrophy. Findings over the past 20 years have clearly confirmed an important role of the ubiquitin proteasome system in mediating muscle proteolysis, particularly that of myofibrillar proteins. However, recent observations have provided evidence that autophagy, calpains and caspases also contribute to the turnover of muscle proteins in catabolic states, and furthermore, that these diverse proteolytic systems interact with each other at various levels. Importantly, a number of intracellular signaling pathways such as the IGF1/AKT, myostatin/Smad, PGC1, cytokine/NFkappaB, and AMPK pathways are now known to interact and can regulate some of these proteolytic systems in a coordinated manner. A number of loss of function studies have identified promising therapeutic approaches to the prevention and treatment of wasting. However, additional biomarkers and other approaches to improve early identification of patients who would benefit from such treatment need to be developed. The current data suggests a network of interacting proteolytic and signaling pathways in muscle. Future studies are needed to improve understanding of the nature and control of these interactions and how they work to preserve muscle function under various states of growth and atrophy. PMID- 21699440 TI - WNT/beta-catenin pathway is modulated in asthma patients and LPS-stimulated RAW264.7 macrophage cell line. AB - In the present study, we investigated the possibility that the WNT/beta-catenin pathway plays a role in inflammatory responses both in an human inflammatory condition and in an in vitro inflammation model. First, we analyzed gene expression patterns of the peripheral blood cells from asthma patients compared with those from normal subjects using microarray analyses. We found that intracellular signaling molecules of the WNT/beta-catenin pathway were significantly changed in asthma patients compared with the levels in the controls. Next, we determined whether major components of the WNT/beta-catenin pathway were involved in the lipopolysaccharide (LPS)-induced inflammatory response of the RAW264.7 macrophage cell line. Among the members of WNT/beta catenin pathway, the protein levels of low-density lipoprotein receptor-related protein (LRP) 6, dishevelled (DVL) 2, and AXIN1, which were measured using western blotting, did not significantly change in the presence of LPS. In contrast, the LPS induced a rapid phosphorylation of glycogen synthase kinase (GSK) 3beta and accumulation of beta-catenin protein. It was found that beta catenin plays a significant role in the LPS-induced inflammatory response through the performance of small interfering RNA (siRNA) transfection experiments. The mRNA level of IL-6 was significantly elevated in beta-catenin siRNA-transfected cells compared with that in control siRNA-transfected cells after LPS treatment. Furthermore, nuclear factor-kappaB (NF-kappaB) activity was also significantly increased in beta-catenin siRNA-transfected cells compared with the level seen in control siRNA-transfected cells. Taken together, these results suggest that beta catenin plays a role as a negative regulator, preventing the overproduction of inflammatory cytokines such as IL-6 in LPS-induced inflammatory responses. PMID- 21699441 TI - Emerging drugs for varicella-zoster virus infections. AB - INTRODUCTION: Varicella-zoster virus (VZV) is the etiological agent of two distinct diseases, varicella (chickenpox) and shingles (herpes zoster). Chickenpox occurs following primary infection, while herpes zoster (usually associated with ageing and immunosuppression) is the consequence of reactivation of the latent virus. Post-herpetic neuralgia is the major complication of shingles. AREAS COVERED: This review will discuss vaccination strategies and the current status of antivirals against VZV. A live attenuated vaccine, Varivax, is available for pediatric varicella while Zostavax was developed to boost VZV specific cell-mediated immunity in adults older than 60 years and, via this mechanism, to decrease the burden of herpes zoster and pain associated with post herpetic neuralgia. Despite the availability of a vaccine, there is a need for new antiviral agents. Current drugs approved for the treatment of VZV infections include nucleoside analogs that target the viral DNA polymerase and depend on the viral thymidine kinase. Novel anti-VZV drugs have recently been evaluated in clinical trials, including the bicyclic nucleoside analog FV-100, the helicase primase inhibitor ASP2151 and valomaciclovir (prodrug of the acyclic guanosine derivative H2G). EXPERT OPINION: New anti-VZV drugs should be as safe as and more effective than acyclovir and its prodrug valacyclovir (current gold standard for the treatment of VZV). PMID- 21699442 TI - Establishing bioequivalence for inhaled drugs; weighing the evidence. AB - INTRODUCTION: During drug development and product life-cycle management, it may be necessary to establish bioequivalence between two pharmaceutical products. Methodologies to determine bioequivalence are well established for oral, systemically acting formulations. However, for inhaled drugs, there is currently no universally adopted methodology, and regulatory guidance in this area has been subject to debate. AREAS COVERED: This paper covers the current status of regulatory guidance on establishing the bioequivalence of topically acting, orally inhaled drugs, the value and limitations of in vitro and in vivo bioequivalence testing, and the practical issues associated with various approaches. The reader will gain an understanding of the issues pertaining to bioequivalence testing of orally inhaled drugs, and the current status of regulatory approaches to establishing bioequivalence in different regions. EXPERT OPINION: Establishing bioequivalence of inhaled drug products involves a multistep process; however, methodologies for each step have yet to be fully validated. Our lack of understanding about the relationship between in vitro, in vivo and clinical data suggests that in most cases, unless there is a high degree of pharmaceutical equivalence between the test and reference products, consideration of a combination of preclinical and clinical data may be preferable to abridged approaches relying on in vitro data alone. PMID- 21699443 TI - Emerging data on the efficacy and safety of fulvestrant, a unique antiestrogen therapy for advanced breast cancer. AB - INTRODUCTION: Fulvestrant is an antiestrogen therapy with a unique mechanism of action. Unlike the selective estrogen receptor modulator tamoxifen, fulvestrant has no known estrogen agonist activity and is considered a pure antiestrogen. Its primary mechanism of action is thought to result from downregulation of the estrogen receptor (ER). Considerable data have demonstrated the efficacy of fulvestrant in postmenopausal women with ER-positive advanced breast cancer, both in the first-line setting and following disease progression on tamoxifen or aromatase inhibitors. Recent studies report improved benefit with alternative dosing strategies. At all administration schedules, fulvestrant has an excellent safety profile with no significant adverse effects. AREAS COVERED: This article provides a review of the mechanism of action of fulvestrant and the preclinical and clinical data evaluating its use as a form of endocrine therapy. The reader will gain insight into the pharmacologic properties of the drug and its role in the treatment of advanced hormone receptor-positive breast cancer in postmenopausal women. EXPERT OPINION: Based on data demonstrating the efficacy of fulvestrant, including prolonged clinical benefit in many patients, this well tolerated antiestrogen is an important therapy for breast cancer. The optimal position of fulvestrant in the sequence of endocrine therapies for postmenopausal women and its role in combination regimens are not yet resolved. PMID- 21699444 TI - Romidepsin: a novel histone deacetylase inhibitor for cancer. AB - INTRODUCTION: Romidepsin is a novel histone deacetylase (HDAC) inhibitor, with a recent approval for treatment of cutaneous T-cell lymphoma (CTCL). HDAC inhibitors represent a novel approach to anti-tumor therapy. In contrast to traditional cytotoxic chemotherapy, HDAC inhibitors target underlying epigenetic changes leading to malignant transformation. Further study of romidepsin and similar agents in solid and hematologic malignancies is ongoing. AREAS COVERED: This review discusses the development of romidepsin, its mechanism of action, pivotal clinical trials, drug toxicity and its recent approval for CTCL treatment. Key clinical trials covered include Phase I/II testing of romidepsin in solid and hematologic malignancies. In addition, the Phase II trial in CTCL leading to FDA approval of romidepsin is reviewed in detail. Literature search was performed using PubMed; keywords and concepts used included romidepsin, T cell lymphoma and HDAC inhibitors. EXPERT OPINION: Romidepsin is a potent HDAC inhibitor with demonstrable activity in T-cell lymphoma. In contrast to vorinostat, romidepsin is approved as second-line therapy. Current approval only includes CTCL; promising results have been demonstrated in Phase II testing of peripheral T-cell lymphoma subtypes. Future directions include expanded indications in T-cell lymphomas as well as novel combinations with other HDAC inhibitors and other therapeutic agents. PMID- 21699445 TI - Preface - 12th Japanese Annual Conference on Chronocardiology and Hypertension. PMID- 21699446 TI - Amlodipine and loop diuretics as the second anti-hypertensive medication for the treatment of hypertension with chronic kidney diseases. AB - Renoprotective effects of renin-angiotensin system inhibitors are well known. However, hypertension with chronic kidney diseases (CKDs) is usually hard to manage with a single agent, and requires the addition of either a calcium antagonist or diuretics to achieve the goal of blood pressure (BP) lowering. Retrospective study was performed among the patients who regularly visited our office, and whose BP had not reached the goal of BP despite of treatment with an angiotensin receptor blocker. Clinical parameters were observed for 6 months. Comparisons of home BP and proteinuria were made between 16 patients prescribed additional calcium antagonists and 15 patients with diuretics. Patient background including age, sex BP, augmentation index, and renal function were similar between the two groups. Both calcium antagonists and diuretics considerably decreased BP. An addition of either agent resulted in similar control of home BP. While both agents reduced augmentation index (AI), calcium antagonist exerted greater improvements in AI (-7 +/- 5 vs. -4 +/- 3%, p < 0.01). Although urinary protein excretion in both groups was decreased, the degree of these decreases was greater among the patients treated with a calcium antagonist (-28 +/- 15 vs. -11 +/- 15%, p < 0.01). During observation periods, eGFR in both groups did not show any significant changes from the base line. Under the inhibition of a renin angiotensin system, calcium antagonists elicited a greater decrease in urinary protein excretion than diuretics when BP similarly controlled. Calcium antagonists also improved AI more strongly than diuretics. Calcium antagonists appear suited for adding on renin angiotensin system inhibitors to treat hypertension with CKDs. PMID- 21699447 TI - Effect of salt reduction intervention program using an electronic salt sensor and cellular phone on blood pressure among hypertensive workers. AB - We investigated the effectiveness of a workplace intervention program that utilized self-monitoring of daily salt excretion by an electronic salt sensor and sent personalized e-mail advice via cellular phone. Forty-one hypertensive male workers were assigned to intervention and control groups, then counseled together. Intervention group members were asked to measure daily salt excretion and received e-mail advice. After 4 weeks, a greater decrease of blood pressure (BP) was observed in the intervention group, with significant reductions to daily salt excretion and home BP. The new intervention program is considered useful for BP control among hypertensive workers. PMID- 21699448 TI - Role of angiotensin-(1-7) in rostral ventrolateral medulla in blood pressure regulation via sympathetic nerve activity in Wistar-Kyoto and spontaneous hypertensive rats. AB - Angiotensin (Ang)-(1-7) Ang-(1-7) is formed from angiotensin II by angiotensin converting enzyme 2 (ACE2) and modulates the renin-angiotensin system. We evaluated whether the Ang-(1-7)-Mas axis in the rostral ventrolateral medulla (RVLM) contributes to neural mechanisms of blood pressure (BP) regulation. We microinjected Ang-(1-7), Ang-(1-7)-Mas receptor antagonist A-779, and ACE2 inhibitor DX600 into the RVLM of anesthetized Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHRs). Unilateral Ang-(1-7) microinjection induced a significantly greater increase in AP (arterial blood pressure) in SHR than in WKY. Bilateral A-779 microinjection induced a significantly greater decrease in AP and renal sympathetic nerve activity in SHR than in WKY. Bilateral DX600 microinjection induced a significantly greater decrease in AP in SHR than in WKY. Our results suggest that endogenous Ang-(1-7) in the RVLM contributes to maintain AP and renal sympathetic nerve activity both in SHR and WKY and that its activity might be enhanced in SHR. PMID- 21699449 TI - Comparison of daily anti-hypertensive effects of amlodipine and nifedipine coat core using ambulatory blood pressure monitoring - utility of "hypobaric curve" and "hypobaric area". AB - When selecting anti-hypertensives, most physicians do not consider daily blood pressure (BP) variation. To evaluate the effectiveness of anti-hypertensives on the temporal profile of BP, we proposed three new parameters obtained by ambulatory BP monitoring and evaluated these parameters by comparing 5 mg of amlodipine and 40 mg of nifedipine coat-core. Hypobaric values were determined by subtracting BP data collected before administration of the drug from those collected after drug treatment at the corresponding time of day. The hypobaric curve was drawn by plotting the hypobaric values in chronological order, with the time at which the drug was taken set as the starting point. The hypobaric area was the area encircled between the 0 mmHg level line and the hypobaric curve. For amlodipine, the hypobaric areas of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were -19,110 mmHg/min and -10,695 mmHg/min, respectively. Systolic BP decreased -13.3 mmHg, and DBP BP -7.4 mmHg as daily averages. For nifedipine coat-core, the hypobaric areas of SBP and DBP were -32,235 mmHg/min and -18,150 mmHg/min, respectively. Systolic BP decreased -22.3 mmHg and DBP 12.6 mmHg as daily averages. From the hypobaric curves, the trough-to-peak ratios of amlodipine and nifedipine coat-core were measured as 0.67 and 0.60, respectively. The total anti-hypertensive power of nifedipine coat-core, measured by the hypobaric area, was 1.69 times more potent than that of amlodipine. These parameters seem to be useful for evaluating the daily temporal profile of the BP lowering effects of anti-hypertensive drugs. PMID- 21699450 TI - Calorie restriction inhibits sympathetic nerve activity via anti-oxidant effect in the rostral ventrolateral medulla of obesity-induced hypertensive rats. AB - In the patients and animals with metabolic syndrome (MetS), sympathetic nerve activity (SNA) is increased. We have demonstrated that oxidative stress in the rostral ventrolateral medulla (RVLM), a vasomotor center in the brainstem, increases SNA. The aim of the present study was to determine whether calorie restriction inhibits SNA via anti-oxidant effect in the RVLM of obesity-induced obesity rats. Male Sprague-Dawley rats were fed on a high-fat diet and segregated into obesity-prone (OP) showing a MetS profile and obesity-resistant (OR) after 13 weeks. Obesity-prone was divided into OP treated with calorie restriction (CR OP) for 8 weeks and control (CTR-OP). Systolic blood pressure (SBP), heart rate (HR), SNA, and thiobarbituric acid-reactive substances (TBARS) levels as a marker of oxidative stress in the RVLM were significantly higher and the depressor effects due to the microinjection of tempol, a superoxide dismutase mimetic into the RVLM, were significantly greater in OP than in OR. Body weight was significantly lower in CR-OP than in CTR-OP. SBP, HR, SNA, TBARS, and the depressor effects due to the microinjection of tempol into the RVLM were significantly lower in CR-OP than in CTR-OP. These results suggest that calorie restriction inhibits SNA via anti-oxidant effect in the RVLM of obesity-induced obesity rats. PMID- 21699451 TI - Administration of an angiotensin-converting enzyme inhibitor improves vascular function and urinary albumin excretion in low-risk essential hypertensive patients receiving anti-hypertensive treatment with calcium channel blockers. Organ-protecting effects independent of anti-hypertensive effect. AB - Concomitant administration of calcium channel blockers (CCBs) and angiotensin converting enzyme inhibitors (ACEIs) to hypertensive patients at high risk for cardiovascular disease can prevent cardiovascular disease occurrence, but the effects of this treatment on renal and vascular function in low-risk hypertensive patients are unknown. The current study was an open-label prospective study. Hypertensive patients with no history of cardiovascular disease who had not met their blood pressure (BP) goals with CCB treatment were administered perindopril and followed for 6 months. Both home and office BP were significantly lowered by perindopril administration. The morning/evening (M/E) ratios calculated from home BP were 1.31 and 1.05 for systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively. When the patients were divided into two groups based on the presence or absence of an anti-hypertensive response, urinary albumin excretion, and cardio ankle vascular index were significantly reduced by perindopril administration in all the subjects, irrespective of the presence or absence of anti-hypertensive reaction. In low-risk hypertensive patients, perindopril improves renal and vascular function probably via its persistent anti hypertensive effects and the concomitant effects of CCB. PMID- 21699452 TI - Effects of multiple factorial intervention on ambulatory BP profile and renal function in hypertensive type 2 diabetic patients with overt nephropathy - a pilot study. AB - Accumulating evidence has shown that diabetic patients are increasing in number, and renal and cardiovascular complications are the most common cause of death in diabetic patients. Thus, it would be of considerable value to identify the mechanisms involved in the progression of renal impairment and cardiovascular injury associated with diabetes. Recent evidence also indicated that multifactorial intervention is able to reduce the risk of cardiovascular disease and death among patients with diabetes and microalbuninuria. In this pilot study, we examined the effects of intensified multifactorial intervention, with tight glucose regulation and the use of valsartan and fluvastatin on ambulatory blood pressure (BP) profile, estimated glomerular filtration rate (eGFR), and urinary albumin to creatinine ratio (UACR), in 20 hypertensive patients (16 male and 4 female) with type 2 diabetes mellitus and overt nephropathy. After 12 months of intensified treatment, office BP, fasting plasma glucose (FPG), and low-density lipoprotein cholesterol (LDLC) were significantly decreased compared to baseline (systolic blood pressure (SBP), 130 +/- 2 vs. 150 +/- 1 mmHg; diastolic blood pressure (DBP), 76 +/- 1 vs. 86 +/- 1 mmHg; FPG, 117 +/- 5 vs. 153 +/- 7 mg/dl; LDLC, 116 +/- 8 vs. 162 +/- 5 mg/dl, P < 0.0001). Also, compared to the baseline values, the daytime and nighttime ambulatory BP and short-term BP variability were significantly decreased after 12 months. Furthermore, while eGFR was not altered (44.3 +/- 5.1 vs. 44.3 +/- 6.5 ml/min/1.73 m(2), not significant (NS)), UACR showed a significant reduction after 12 months of intensified treatment (1228 +/- 355 vs. 2340 +/- 381 mg/g-cr, P < 0.05). These results suggest that the intensified multifactorial intervention is able to improve ambulatory BP profile, preserve renal function, and reduce urinary albumin excretion in type 2 diabetic hypertensive patients with overt nephropathy. PMID- 21699453 TI - Allogeneic hematopoietic cell transplant for peripheral T-cell non-Hodgkin lymphoma results in long-term disease control. AB - The study analyzed outcomes of a consecutive case series of 37 patients with peripheral T-cell non-Hodgkin lymphoma, from related and unrelated donors, using allogeneic hematopoietic cell transplant (allo-HCT), between the years 2000 and 2007. All patients were pretreated; the majority had either relapsed or progressive disease (n = 25, 68%), 13 had cutaneous histologies (CTCL), and all were ineligible for autologous transplant. Fully ablative conditioning regimens were used in 13 patients while 24 patients underwent reduced intensity conditioning (RIC). At 5 years the overall survival (OS) and progression-free survival (PFS) probabilities were 52.2% and 46.5%, respectively. At the time of analysis, nine (24.3%) patients had either relapsed (n = 6) or progressed (n = 3) post allo-HCT. The cumulative incidences of relapse/progression and non-relapse mortality at 5 years were 24.3% and 28.9%. No statistically significant variables for survival or relapse were discovered by univariate Cox regression analysis of disease and patient characteristics; differences between CTCL and other histologies were not significant. The median follow-up of 64.0 months (range: 16.4-100.4) indicates a mature data-set with probable cure in the survivors. The relapse/progression curves reached and maintained plateaus after 1 year post transplant, demonstrating that long-term disease control is possible after allo HCT in patients with peripheral T-cell lymphoma with advanced disease. PMID- 21699454 TI - Primary anaplastic large-cell lymphoma associated with breast implants. AB - Primary T-cell anaplastic large-cell lymphoma (ALCL) of the breast is a rare entity, which has been reported in association with breast implants. In a retrospective analysis of the City of Hope pathology database, we uncovered nine such patients, eight of whom had breast implants proximal to primary ALCL. The diagnosis of ALCL in the implant capsule occurred at a median of 7 years (range 5 30) following implant surgery, and median patient age was 45.5 years (range 32 62). Malignancy was effusion-associated in two cases and tissue-associated in six. Seven patients were negative for anaplastic large-cell kinase (ALK) and one patient was positive. Treatment and follow-up data were available for four patients, all tissue-associated cases: two patients were lost to follow-up after failing to mobilize stem cells and two patients were in remission, 6 years and 7.5 years post-autologous transplant. These cases represent 24% of reported primary ALCL cases associated with breast implants. Our review of these cases and the literature suggest that (1) there is a strong skew in primary breast lymphomas associated with implant capsules toward T-cell, ALCL ALK-, and (2) the disease course for tissue-associated cases is not always indolent, with four patients requiring multiple treatment regimens. PMID- 21699456 TI - Methotrexate area under the curve as a prognostic factor in primary central nervous system lymphoma treated with immunochemoradiotherapy. AB - A higher methotrexate area under the curve (MTX AUC) observed during the first chemotherapy cycle has been associated with improved tumor control in patients with primary central nervous system lymphoma. To confirm these findings, we conducted a post hoc analysis of data from a prospective phase II trial of rituximab, methotrexate, procarbazine, vincristine, cytarabine, and low-dose radiotherapy. Thirty-nine patients were included (24 men; 15 women). The median age was 60 years (range 30-76) and median Karnofsky performance status (KPS) score was 70 (range 50-100). There was substantial inter-individual variability in MTX AUC (median: 795.5 uM*h/L, range 44.8-8326.44). However, there were no differences in progression-free survival (PFS) in patients below and above the median MTX AUC (2-year PFS 78% vs. 85% respectively; p = 0.51). Similarly, there were no differences in response rates or overall survival according to MTX AUC, suggesting that intra-patient dose escalation to increase MTX exposure is unnecessary when our regimen is utilized. PMID- 21699457 TI - Composite primary cutaneous peripheral T-cell lymphoma and Epstein-Barr virus positive large B-cell lymphoma. PMID- 21699455 TI - Curcumin nanodisk-induced apoptosis in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is a pre-germinal center neoplasm characterized by cyclin D1 overexpression resulting from t(11;14)(q13;q32). Since MCL is incurable with standard lymphoma therapies, new treatment approaches are needed that target specific biologic pathways. In the present study, we investigated a novel drug delivery nanovehicle enriched with the bioactive polyphenol, curcumin (curcumin nanodisks; curcumin-ND). Cells treated with curcumin-ND showed a dose-dependent increase in apoptosis. This was accompanied by enhanced generation of reactive oxygen species (ROS). The antioxidant, N-acetylcysteine, inhibited curcumin-ND induced apoptosis, suggesting that ROS generation plays a role in curcumin action on MCL cells. Curcumin-ND decreased cyclin D1, pAkt, pIkappaBalpha, and Bcl(2) protein. In addition, enhanced FoxO3a and p27 expression as well as caspase-9, 3, and poly(ADP-ribose) polymerase (PARP) cleavage were observed. Curcumin-ND treatment led to enhanced G(1) arrest in two cultured cell models of MCL. PMID- 21699458 TI - Potential clinical application of imatinib mesylate in patients with leukemic large granular lymphocytes. PMID- 21699459 TI - Pharmacophore modelling and atom-based 3D-QSAR studies on N-methyl pyrimidones as HIV-1 integrase inhibitors. AB - Pharmacophore modelling and atom-based 3D-QSAR studies were carried out for a series of compounds belonging to N-methyl pyrimidones as HIV-1 integrase inhibitors. Based on the ligand-based pharmacophore model, we got 5-point pharmacophore model AADDR, with two hydrogen bond acceptors (A), two hydrogen bond donors (D) and one aromatic ring (R). The generated pharmacophore-based alignment was used to derive a predictive atom-based 3D-QSAR model for the training set (r(2) = 0.92, SD = 0.16, F = 84.8, N = 40) and for test set (Q(2) = 0.71, RMSE = 0.06, Pearson R = 0.90, N = 10). From these results, AADDR pharmacophore feature was selected as best common pharmacophore hypothesis, and atom-based 3D-QSAR results also support the outcome by means of favourable and unfavourable regions of hydrophobic and electron-withdrawing groups for the most potent compound 30. These results can be useful for further design of new and potent HIV-1 IN inhibitors. PMID- 21699460 TI - Antiproliferative effects of metal complexes of new isatin hydrazones against HCT116, MCF7 and HELA tumour cell lines. AB - New hydrazone ligands (HL) derived from 5-substituted isatins and 1-(4-(2 methoxybenzyl)-6-arylpyridazin-3-yl)hydrazines and its complexes with Co(II) and Cu(II) were synthesized. The new hydrazones and their complexes were characterized by means of elemental, spectral analyses and magnetic studies. Primary cytotoxicity evaluation of HL 5a and the new complexes showed that these complexes could act as anticancer agents since they reduced the growth of samples of human tumour cell lines (HCT116((Colon)), MCF7((Breast)) and HELA((Cervix))) to <=18.5 MUg/mL for the new complexes. PMID- 21699461 TI - Association of beta-amyloid peptide fragments with neuronal nitric oxide synthase: Implications in the etiology of Alzheimers disease. AB - Neuronal nitric oxide synthase (nNOS) was purified on DEAE-Sepharose anion exchange in a 38% yield, with 3-fold recovery and specific activity of 5 umol.min(-1).mg(-1). The enzyme was a heterogeneous dimer of molecular mass 225 kDa having a temperature and pH optima of 40 degrees C and 6.5, K(m) and V(max) of 2.6 MUM and 996 nmol.min(-1).ml(-1), respectively and was relatively stable at the optimum conditions (t(1/2) = 3 h). beta-Amyloid peptide fragments Abeta(17 28) was the better inhibitor for nNOS (K(i) = 0.81 uM). After extended incubation of nNOS (96 h) with each of the peptide fragments, Congo Red, turbidity and thioflavin-T assays detected the presence of soluble and insoluble fibrils that had formed at a rate of 5 nM.min(-1). A hydrophobic fragment Abeta(17-21) [Leu(17) - Val(18) - Phe(19) - Phe(20) - Ala(21)] and glycine zipper motifs within the peptide fragment Abeta(17-35) were critical in binding and in fibrillogenesis confirming that nNOS was amyloidogenic catalyst. PMID- 21699462 TI - Oxidases and oxygenases in regulation of neutrophil redox pathways in Behcet's disease patients. AB - This study aimed to determine plasma and neutrophil oxidase activities that may contribute to vascular inflammation in Behcet's disease (BD) patients. Cyclooxygenase (COX), NADPH oxidase and myeloperoxidase (MPO) activity was determined in neutrophils isolated from BD patients and healthy controls. Functional assay of NADPH oxidase was significantly increased in BD patients, both at basal conditions and in response to fMLP stimulation. There was a significant increase in plasma MPO activity in the disease group as compared to controls. Total COX activity was significantly increased in BD neutrophils. The increase in total COX activity was accompanied with enhanced activity of COX-2, differentiated by using the COX-1 isoform-specific inhibitor SC-560. Neutrophil nitrate/nitrite levels showed no significant difference in BD; however, plasma nitrate/nitrite contents in BD patients were significantly greater compared to controls. In conclusion, increased plasma MPO, neutrophil NADPH and COX activities may contribute to intravascular inflammation documented in BD patients. PMID- 21699463 TI - Antibacterial dimeric copper(II) complexes with chromone-derived compounds. AB - A new series of six chromone-derived compounds and their Cu(II) complexes have been synthesized and characterized by their physical, spectral and analytical data. The ligands and their Cu(II) complexes were screened for their in vitro antibacterial activity against four Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Shigella flexneri) and two Gram-positive (Bacillus subtilis, Staphylococcus aureus) bacterial strains by agar-well diffusion method. The ligands were found to exhibit either no or low-to-moderate activities against one or more bacterial species whereas, the Cu(II) complexes exhibited moderate-to high activity. The ligands which were inactive before complexation became active upon complexation with the Cu(II) metal ion and less active became more active. PMID- 21699464 TI - Attempt of quantitative analysis of visual evaluation for (123)I-BMIPP myocardial scintigraphy images. AB - We developed a new technique to quantitatively analyze visual evaluation single photon emission computed tomography (SPECT). Short axis tomograms and color scales were computer scanned. The scales were divided into 25 parts; numbers of each hue pixel were scored 0-100%. Short-axis images were divided into eight equal partitions, numbers of hue pixels distributed in each partition were scored, and total scores were obtained. Each partition's radio-isotope (RI) accumulation index was calculated as partition score/highest score. For method validation, scintigrams from each left ventricular phantom part were divided into eight partitions and filled with (123)I-BMPP (10-100%). The error between theoretical and calculated concentrations was within 20% in the concentration range of >=50%, suggesting a good correlation and indicating the method's validity. PMID- 21699465 TI - Consequence of masked hypertension in treated hypertensive outpatients: 1-year follow-up study. AB - Since masked hypertension (MHT) is high risk for cardiovascular disease, the importance of home blood pressure (HBP) control is emphasized. The aim of this study was to investigate the prevalence of MHT in the treated hypertensives and the consequence of their BP control status after a 1-year follow up period. Subjects are 262 treated hypertensive outpatients. We assessed BP control status, background characteristics, and antihypertensive drugs in both 2008 and 2009. Clinic BP (CBP) and morning HBP in 2008 were 133 +/- 12/73 +/- 9 mmHg and 132 +/- 11/77 +/- 8 mmHg, which significantly decreased to 129 +/- 11/70 +/- 10 mmHg and 130 +/- 10/76 +/- 8 mmHg in 2009, respectively (p < 0.01). The patients with sustained hypertension (SHT) decreased from 17.9% in 2008 to 6.9% in 2009. Thirty four percent of SHT patients in 2008 turned out to be MHT and another 34.0% belonged to normotension (NT) in 2009. Among 79 MHT patients in 2008, 62.0% remained as MHT, while 32.9% turned out to be NT in 2009. The sustained MHT patients were more male and showed a higher prevalence of habitual alcohol intake. Nighttime dosing of antihypertensive drugs and the addition of diuretics were major causes of improving morning HBP. Results suggest that one-third of MHT patients showed the improvement of HBP after the 1-year follow-up period. Not only intensive antihypertensive treatment with the appropriate use of diuretics, but also the encouragement of lifestyle modification including alcohol restriction, seems to be important to the management of MHT. PMID- 21699466 TI - Potential role for valproate in the treatment of high--risk brain tumors of childhood-results from a retrospective observational cohort study. AB - Although substantial progress has been made in pediatric brain tumor management, patients with brainstem tumors and high-grade gliomas, as well as patients less than 3 years of age with high-risk malignant tumors, have a poorer prognosis. The authors have been treating these patients with radiotherapy and standard carboplatin and vincristine chemotherapy. Since January 2007 the authors have been using valproate as anticonvulsant for prophylaxis. The authors performed a retrospective cohort analysis of pediatric patients with high-risk brain tumors treated with chemotherapy, radiotherapy, and valproate prophylaxis, comparing this group with a historical control. The 2007-2008 group was comprised of 22 patients, 15 with brainstem tumors (7 diffuse intrinsic pontine glioma [DIPG], 3 focal, the remaining infiltrating with a solid portion), 4 with diencephalic tumors (2 thalamic), and 3 with supratentorial high-grade tumors (1 glioblastoma, 1 recurrent grade III ependymoma, 1 with gliomatosis). There were 15 patients alive (68%) after a mean follow-up time of 19 months. Survival function comparison by log rank test was highly significant (P = .004) with a hazard ratio of 0.31 (0.14-0.70). Radiological response showed 3 complete responses (14%), 8 partial responses (36%), 5 stable diseases (23%), and 5 progresssive diseases (23%). The authors hypothesize that valproate may have potentiated the antiangiogenic effect of vincristine, diminished expression of resistance to carboplatin, and sensitized tumor cells to radiotherapy. The authors suggest that clinical trials of carboplatin and vincristine associated with oral continuous low-dose valproate are indicated for pediatric patients with high-risk brain tumor. PMID- 21699467 TI - The value of echocardiography versus cardiac troponin I levels in the early detection of anthracycline cardiotoxicity in childhood acute leukemia: prospective evaluation of a 7-year-long clinical follow-up. AB - The present study was designed to evaluate the significance of echocardiography versus cardiac troponin I levels in early detection of anthracycline dependent cardiotoxicity in acute lymphoblastic leukemia (ALL) patients. A total of 276 pediatric ALL patients were included in the study prospectively along 3 phases of data collection lasted from 2002 to 2009; including phase I (March 2002 to February 2003; n = 25; 53.3% females), phase II (September 2003 to April 2004; n = 35; 57.1% females), and phase III (January 2005 to June 2009; n = 216; 52.7% females) with respect to cumulative anthracycline doses applied. Anthracycline was administered in accordance with berlin-Franfurt-Munich (BFM)-2000 protocol in doses of 30 to 350 mg/m(2) (in the first phase) and 30 to 240 mg/m(2) (in the following phases). Evaluation of cardiotoxicity was performed via echocardiography and measurement of cardiac troponin I levels. Patients in each phase were homogenous in terms of gender and age. Diastolic dysfunction determined via reduction E/A ratio below the cutoff value was demonstrated to deteriorate earlier than systolic functions and alteration in cardiac enzymes. Being similar between dose groups, cTnI levels were shown to rise in the presence of congestive heart failure. In conclusion, anthracycline cardiotoxicity appears to be detected in an earlier stage by using diastolic parameters compared to systolic parameters and cardiac enzymes. PMID- 21699468 TI - A rare complication of intrathecal methotrexate in a child with acute lymphoblastic leukemia. AB - Methotrexate (MTX) is an essential component of chemotherapy for childhood acute lymphoblastic leukemia (ALL). Both intravenous and most commonly intrathecal routes of MTX have been implicated in acute, subacute, and chronic neurotoxicity syndromes. Subacute MTX neurotoxicity occurs within days to weeks after the intravenous or intrathecal therapy and characterized by a distinct presentation with remarkable clinical resemblance to stroke, including hemiparesis, hemisensory deficits, aphasia, dysarthria, dysphagia, and diplopia. Herein the authors describe the clinical and typical neuroimaging features of a female patient with ALL who presented with subacute MTX neurotoxicity that rapidly progressed to a severe clinical condition in a few hours but eventually resolved completely with dexamethasone and folinic acid. Subacute MTX neurotoxicity is a transient neurological dysfunction that should be considered in patients presenting with stroke-like and various neurological symptoms 10 to 14 days after intrathecal therapy and diffusion-weighted magnetic resonance imaging should be undertaken for the correct diagnosis and exclusion of possible ischemic infarct. Discontinuation of subsequent intrathecal MTX therapies should be considered in severe cases and treatment with dexamethasone and folinic acid may help to resolve the symptoms. PMID- 21699469 TI - Nitric oxide: a new biomarker of Doxorubicin toxicity in children? AB - Doxorubicin (DOX) has been used in the treatment of childhood cancers, but its usage is limited because of cardiotoxicity. There are many studies on the role of nitric oxide (NO) in several cardiac diseases. However, to the authors' knowledge, no studies have investigated the plasma levels of total nitrite, a stable product of NO, in children that received DOX. The authors determined plasma total nitrite levels in 29 children who received DOX and investigated the correlations between these and other clinical and laboratory findings. All patients were in remission during the study period. Plasma total nitrite levels and cardiac functions were determined prospectively. The mean cumulative DOX dose was 310.0 +/- 90.9 mg/m(2). In echocardiographic evaluation, 3 patients (10.3%) had a pathological value for ejection fraction (EF) and/or fractional shortening (FS), whereas 11 patients (37.9%) had a threshold value. Total nitrite levels were higher in patients than in matched controls (75.24 +/- 39.4 vs 43.14 +/- 10.58 MUmol/L, respectively, P < .001). It was also found to be higher in patients who had a pathological/threshold value of EF and FS than in patients who had a physiological value of EF and FS (92.35 +/- 50.36 vs 59.26 +/- 13.56 MUmol/L, respectively, P = .038). A negative correlation was found between FS and plasma total nitrite level (r = -.42, P = .023). The authors speculate that increased NO may be a sign of subclinical cardiotoxicity of DOX. PMID- 21699470 TI - The use of bioabsorbable screws to fix Type II odontoid fractures: a biomechanical study. AB - OBJECT: Anterior screw fixation of the Type II odontoid fracture stabilizes the odontoid without restricting the motion of the cervical spine. The metal screw may limit bone remodeling because of stress shielding (if not placed properly) and limit imaging of the fracture. The use of bioabsorbable screws can overcome such shortcomings of the metal screws. The purpose of this study was to compare the strength of a 5-mm bioabsorbable screw with single 4-mm metal and double 3.5 mm lag screw fixation for Type II fractures of the odontoid process. METHODS: Three different modalities of anterior screw fixation were used in 19 C-2 vertebrae. These fixation methods consisted of a single 5-mm cannulated bioabsorbable lag screw (Group A), a single 4-mm cannulated titanium lag screw (Group B), and two 3.5-mm cannulated titanium lag screws (Group C). Anteroposterior (AP) stiffness and rotational stiffness were evaluated in all constructs. RESULTS: There was no statistical difference among the ages of the cadavers in each group (p = 0.52). The AP bending stiffness in Groups A, B, and C was 117 +/- 86, 66 +/- 43, and 305 +/- 130 Nm/mm, respectively. The AP bending stiffness in Group C was significantly higher than that in Groups A and B (p = 0.01 and p = 0.001, respectively). The difference in AP bending stiffness values of bioabsorbable and 4-mm metal screws was not statistically significant (p = 0.23). The rotational stiffness of the double 3.5-mm metal screws was significantly greater than that of the 5-mm bioabsorbable and the 4-mm titanium screws. CONCLUSIONS: Double screw fixation with 3.5-mm screws provides the stiffest construct in Type II odontoid fractures. Bioabsorbable lag screws (5 mm) have the same AP bending and rotational stiffness as the single titanium lag screw (4 mm) in odontoid fractures. PMID- 21699471 TI - Prospective, randomized, multicenter study of cervical arthroplasty: 269 patients from the Kineflex|C artificial disc investigational device exemption study with a minimum 2-year follow-up: clinical article. AB - OBJECT: Cervical total disc replacement (CTDR) represents a relatively novel procedure intended to address some of the shortcomings associated with anterior cervical discectomy and fusion (ACDF) by preserving motion at the treated level. This prospective, randomized, multicenter study evaluates the safety and efficacy of a new metal-on-metal CTDR implant (Kineflex|C) by comparing it with ACDF in the treatment of single-level spondylosis with radiculopathy. METHODS: The study was a prospective, randomized US FDA Investigational Device Exemption (IDE) pivotal trial conducted at 21 centers across the US. The primary clinical outcome measures included the Neck Disability Index (NDI), visual analog scale (VAS) scores, and a composite measure of clinical success. Patients were randomized to CTDR using the Kineflex|C (SpinalMotion, Inc.) cervical artificial disc or ACDF using structural allograft and an anterior plate. RESULTS: A total of 269 patients were enrolled and randomly assigned to either CTDR (136 patients) or to ACDF (133 patients). There were no significant differences between the CTDR and ACDF groups when comparing operative time, blood loss, length of hospital stay, or the reoperation rate at the index level. The overall success rate was significantly greater in the CTDR group (85%) compared with the ACDF group (71%) (p = 0.05). In both groups, the mean NDI scores improved significantly by 6 weeks after surgery and remained significantly improved throughout the 24-month follow up (p < 0.0001). Similarly, the VAS pain scores improved significantly by 6 weeks and remained significantly improved through the 24-month follow-up (p < 0.0001). The range of motion (ROM) in the CTDR group decreased at 3 months but was significantly greater than the preoperative mean at 12- and 24-month follow-up. The ROM in the ACDF group was significantly reduced by 3 months and remained so throughout the follow-up. Adjacent-level degeneration was also evaluated in both groups from preoperatively to 2-year follow-up and was classified as none, mild, moderate, or severe. Preoperatively, there were no significant differences between groups when evaluating the different levels of adjacent-level degeneration. At the 2-year follow-up, there were significantly more patients in the ACDF group with severe adjacent-level radiographic changes (p < 0.0001). However, there were no significant differences between groups in adjacent-level reoperation rate (7.6% for the Kineflex|C group and 6.1% for the ACDF group). CONCLUSIONS: Cervical total disc replacement allows for neural decompression and clinical results comparable to ACDF. Kineflex|C was associated with a significantly greater overall success rate than fusion while maintaining motion at the index level. Furthermore, there were significantly fewer Kineflex|C patients showing severe adjacent-level radiographic changes at the 2-year follow up. These results from a prospective, randomized study support that Kineflex|C CTDR is a viable alternative to ACDF in select patients with cervical radiculopathy. PMID- 21699472 TI - The real value of cervical arthroplasty? PMID- 21699473 TI - Long-term outcomes of revision fusion for lumbar pseudarthrosis: clinical article. AB - OBJECT: The number of low-back fusion procedures for the treatment of spine disorders has increased steadily over the past 10 years. Lumbar pseudarthrosis is a potential complication of lumbar arthrodesis and can be associated with significant pain and disability. The aim of this study was to assess, using validated patient-reported outcomes measures, the long-term effectiveness of revision arthrodesis in the treatment of symptomatic pseudarthrosis. METHODS: This is a retrospective study of 47 patients who underwent revision lumbar arthrodesis for pseudarthrosis-associated back pain. Baseline 2-year outcomes were assessed using the following: visual analog scale (VAS) for back pain, Oswestry Disability Index (ODI), Zung Self-Rating Depression Scale, time to narcotic independence, time to return to work, EuroQol health-state utility, and physical and mental quality of life (Short Form [SF]-12 Physical and Mental Component Summary scores). RESULTS: The mean duration of time between prior fusion and development of symptomatic pseudarthrosis was 2.69 years. Bone morphogenetic protein was used in 4 cases (8.5%) of revision arthrodesis. A significant improvement in VAS back pain (7.31 +/- 0.81 vs 5.06 +/- 2.64, p = 0.001), ODI (29.74 +/- 5.35 vs 25.42 +/- 6.0, p = 0.001), and physical health SF 12 (23.83 +/- 6.89 vs 27.85 +/- 8.90, p = 0.001) scores was observed when comparing baseline and 2-year post-revision arthrodesis scores, respectively, with a mean cumulative 2-year gain of 0.35 quality-adjusted life years. The median time to narcotics independence was 12.16 (interquartile range 1.5-24.0) months and the median time to return to work was 4 months (interquartile range 3 5 months). By 2 years after revision surgery, no patients had experienced pseudarthrosis. The SF-12 Mental Component Summary (44.72 +/- 7.90 vs 43.46 +/- 7.51, p = 0.43) and Zung Self-Rating Depression Scale scores (39.36 +/- 7.48 vs 41.39 +/- 10.72, p = 0.37) were not significantly improved by 2 years. CONCLUSIONS: The authors' study suggests that revision lumbar arthrodesis for symptomatic pseudarthrosis provides improvement in low-back pain, disability, and quality of life. Revision lumbar arthrodesis should be considered a viable treatment option for patients with pseudarthrosis-related back pain. Mental health symptoms from pseudarthrosis-associated back pain may be more refractory to revision surgery. PMID- 21699474 TI - Percutaneous screw placement. PMID- 21699475 TI - Bioabsorbable screws. PMID- 21699477 TI - Two-level motor nerve transfer for the treatment of long thoracic nerve palsy. AB - The authors report a case of long thoracic nerve (LTN) palsy treated with two level motor nerve transfers of a pectoral fascicle of the middle trunk, and a branch of the thoracodorsal nerve. This procedure resulted in near-total improvement of the winged scapula deformity, and a return of excellent shoulder function. A detailed account of the postoperative physical therapy regimen is included, as this critical component of the favorable result cannot be overlooked. This case establishes the two-level motor nerve transfer as a new option for treating LTN palsy, and demonstrates that nerve transfers should be considered in the therapeutic algorithm of an idiopathic mononeuritis. PMID- 21699476 TI - Spinal duraplasty materials and hydrostasis: a biomechanical study: laboratory investigation. AB - OBJECT: Dural tears are a frequent complication of spinal surgery and contribute to significant morbidity. Occasionally, dural tears cannot be closed primarily and dural patch grafts must be utilized. No data exist on the comparative immediate hydrostatic strength of various patch materials used alone or with a biological adhesive in a spinal dural tear model. Thus, the authors conducted this study to determine the comparative effectiveness of various patch materials used with and without biological adhesive. METHODS: Twenty-four thoracic spines from calves were prepared with laminectomies and spinal cord evacuation, leaving the dura intact. Foley catheters were inflated on either side of a planned dural defect, and baseline hydrostasis was measured using a fluid column at 30, 60, and 90 cm of H(2)O. A standard dural defect (1 * 2 cm) was created, and 8 patches of each material (human fascia lata, Duragen, and Preclude) were sutured in place using 5-0 Prolene hemo-seal running sutures. Hydrostasis was again tested at the same pressures. Finally, a hydrogel sealant (Duraseal) was placed over the defect and hydrostasis was again tested. Results were analyzed with repeated measures ANOVA. RESULTS: The leakage rate increased significantly at each pressure tested for all conditions. There was no difference in leakage among the 3 patch materials at any of the pressures or for either condition (with or without sealant). All patch materials allowed significantly greater leakage than the intact condition at all pressures. The use of sealant reduced leakage significantly at the 30 and 60 mm Hg pressures to levels similar to the intact condition. At 90 mm Hg, leakage of the sealed construct was greater than at the intact condition but significantly less than without the use of sealant. CONCLUSIONS: All 3 dural patch materials were of similar hydrostatic strength and allowed greater leakage than at the intact condition. The use of sealant reduced the amount of leakage at all pressures compared with patching alone but allowed more leakage than the intact state at a high hydrostatic pressure (90 mm Hg). PMID- 21699478 TI - Superciliary keyhole surgery for unruptured posterior communicating artery aneurysms with oculomotor nerve palsy: maximizing symptomatic resolution and minimizing surgical invasiveness. AB - OBJECT: For oculomotor nerve palsy (ONP) induced by unruptured posterior communicating artery (PCoA) aneurysms, the authors performed surgical clipping via a superciliary keyhole approach as an optimal treatment modality with high efficiency and low invasiveness. In this study, they then evaluated the technical feasibility, safety, clinical outcomes, including recovery from ONP as well as cosmetic results, and durability of the procedure. METHODS: Thirteen patients presenting with complete (7 patients) or incomplete (6 patients) ONP underwent surgery via a superciliary approach. The operative video record was used to evaluate the technical feasibility, neurological examinations and CT were performed to analyze the safety of the treatment, and neuroophthalmological examinations and 3D CT angiography were undertaken to determine the effectiveness and durability of the treatment. RESULTS: In all cases, the aneurysms were successfully clipped using a 3.5-cm eyebrow incision and supraorbital minicraniotomy. The mean operative time was 108 +/- 24 minutes. Twelve (92.3%) of the 13 patients showed complete resolution of the ONP. All 6 patients (100%) with incomplete ONP recovered completely within 1-2 months after surgery, whereas 6 (85.7%) of the 7 patients with complete ONP recovered completely within 1-6 months after surgery. Cosmetic results for the operative wounds were excellent without frontalis palsy. The durability of the treatment was ascertained based on 3D CT angiograms obtained 1 year after surgery. CONCLUSIONS: Surgical clipping via a superciliary keyhole approach can be an optimal treatment modality for PCoA aneurysms inducing ONP because it is effective, safe, and durable. PMID- 21699479 TI - Generation of chordoma cell line JHC7 and the identification of Brachyury as a novel molecular target. AB - OBJECT: Chordoma is a malignant bone neoplasm hypothesized to arise from notochordal remnants along the length of the neuraxis. Recent genomic investigation of chordomas has identified T (Brachyury) gene duplication as a major susceptibility mutation in familial chordomas. Brachyury plays a vital role during embryonic development of the notochord and has recently been shown to regulate epithelial-to-mesenchymal transition in epithelial-derived cancers. However, current understanding of the role of this transcription factor in chordoma is limited due to the lack of availability of a fully characterized chordoma cell line expressing Brachyury. Thus, the objective of this study was to establish the first fully characterized primary chordoma cell line expressing gain of the T gene locus that readily recapitulates the original parental tumor phenotype in vitro and in vivo. METHODS: Using an intraoperatively obtained tumor sample from a 61-year-old woman with primary sacral chordoma, a chordoma cell line (JHC7, or Johns Hopkins Chordoma Line 7) was established. Molecular characterization of the primary tumor and cell line was conducted using standard immunostaining and Western blotting. Chromosomal aberrations and genomic amplification of the T gene in this cell line were determined. Using this cell line, a xenograft model was established and the histopathological analysis of the tumor was performed. Silencing of Brachyury and changes in gene expression were assessed. RESULTS: The authors report, for the first time, the successful establishment of a chordoma cell line (JHC7) from a patient with pathologically confirmed sacral chordoma. This cell line readily forms tumors in immunodeficient mice that recapitulate the parental tumor phenotype with conserved histological features consistent with the parental tumor. Furthermore, it is demonstrated for the first time that silencing of Brachyury using short hairpin RNA renders the morphology of chordoma cells to a more differentiated-like state and leads to complete growth arrest and senescence with an inability to be passaged serially in vitro. CONCLUSIONS: This report represents the first xenograft model of a sacral chordoma line described in the literature and the first cell line established with stable Brachyury expression. The authors propose that Brachyury is an attractive therapeutic target in chordoma and that JHC7 will serve as a clinically relevant model for the study of this disease. PMID- 21699480 TI - Radiotherapy for atypical meningiomas. AB - OBJECT: The role of postoperative radiotherapy in patients undergoing first-time resection of WHO Grade II meningioma remains unclear as reflected by varied practices in published clinical studies and national professional surveys. Much of the relevant literature is based on pre-2000 WHO grading criteria for atypical meningiomas. Authors in this study set out to explore the role of postoperative radiotherapy in patients undergoing first-time surgery for WHO Grade II meningiomas diagnosed using revised WHO 2000 criteria, against a background of otherwise limited published literature on this issue. METHODS: The authors retrospectively collected data on 114 consecutive patients who underwent first time resection of WHO Grade II atypical meningiomas diagnosed using 2000 WHO criteria, and who variably underwent postoperative radiotherapy according to individual surgeon practices. Outcomes, including radiological recurrence, were submitted to Kaplan-Meier and Cox regression analyses. RESULTS: Postoperative radiotherapy demonstrated a significant benefit only when patients who had undergone gross-total tumor resection and those who had undergone subtotal resection along with postoperative radiosurgery to the tumor remnant were excluded from analysis. CONCLUSIONS: The authors have performed the largest study in the literature to examine the use of radiotherapy for WHO Grade II, atypical, meningiomas following a first-time resection. They suggest that radiotherapy is not appropriate after first-time resection of those lesions in which a gross total resection (Simpson Grade 1 or 2) has been achieved. They also advise that any tumor remnant radiologically demonstrated on postoperative imaging should be treated with radiosurgery and that postoperative radiotherapy after a first-time resection should be reserved for tumor remnants too large for radiosurgery and for which a second staged operation is not planned. PMID- 21699481 TI - Surgery for gliomas involving the left inferior parietal lobule: new insights into the functional anatomy provided by stimulation mapping in awake patients. AB - OBJECT: Surgery in the left dominant inferior parietal lobule (IPL) is challenging because of a high density of somatosensory and language structures, both in the cortex and white matter. In the present study, on the basis of the results provided by direct cerebral stimulation in awake patients, the authors revisit the anatomofunctional aspects of surgery within the left IPL. METHODS: Fourteen consecutive patients underwent awake craniotomy for a glioma involving the left IPL. Intraoperative motor, sensory, and language mapping was performed before and during the tumor removal, at both the cortical and subcortical levels, to optimize the extent of resection, which was determined based on functional boundaries. Anatomofunctional correlations were performed by combining the results of intraoperative mapping and those provided by pre- and postoperative MR imaging. RESULTS: At the cortical level, the primary somatosensory area (retrocentral gyrus) limited the resection anteriorly in all cases, at least partially. Less frequently, speech arrest or articulatory problems were observed within the parietal operculum (4 cases). The lateral limit was determined by language sites that were variably distributed. Anomia was the most frequent response (9 cases) at the posterior third of the superior (and/or middle) temporal gyrus. Posteriorly, less reproducible reorganized language sites were seldom observed in the posterior portion of the angular gyrus (2 cases). At the subcortical level, in addition to somatosensory responses due to stimulation of the thalamocortical pathways, articulatory disturbances were induced by stimulation of white matter in the anterior and lateral part of the surgical cavity (11 cases). This tract anatomically corresponds to the horizontal portion of the lateral segment of the superior longitudinal fascicle (SLF III). Deeper and superiorly, phonemic paraphasia was the main language disturbance (12 cases), elicited by stimulation of the posterosuperior portion of the arcuate fascicle. All these eloquent structures were surgically preserved. Despite slight cognitive disorders (working memory, writing, or calculation) in 6 cases, no patient retained a severe or a moderate postoperative deficit (except one with right hemianopia [mean follow-up 41.8 months]). Resection was total or near total in 9 patients and partial in 3 cases. CONCLUSIONS: To the authors' knowledge, this is the first series dedicated to the surgery of gliomas involving the left IPL. Interestingly, a certain degree of interindividual variability was observed in the distribution of the cortical maps, especially for language. Therefore, it is suggested that no rigid pattern of resection can be considered within the left IPL, and that surgery in this region should be performed in awake patients to adapt the tumor removal to individual functional limits. Nonetheless, several landmarks have been regularly identified, especially at the subcortical levels (SLF III and arcuate fascicle); a better knowledge of these functional tracts could be helpful to optimize functional outcomes. PMID- 21699482 TI - Intraoperative magnetic resonance imaging findings during deep brain stimulation surgery. AB - OBJECT: Deep brain stimulation (DBS) is an established neurosurgical technique used to treat a variety of neurological disorders, including Parkinson disease, essential tremor, dystonia, epilepsy, depression, and obsessive-compulsive disorder. This study reports on the use of intraoperative MR imaging during DBS surgery to evaluate acute hemorrhage, intracranial air, brain shift, and accuracy of lead placement. METHODS: During a 46-month period, 143 patients underwent 152 DBS surgeries including 289 lead placements utilizing intraoperative 1.5-T MR imaging. Imaging was supervised by an MR imaging physicist to maintain the specific absorption rate below the required level of 0.1 W/kg and always included T1 magnetization-prepared rapid gradient echo and T2* gradient echo sequences with selected use of T2 fluid attenuated inversion recovery (FLAIR) and T2 fast spin echo (FSE). Retrospective review of the intraoperative MR imaging examinations was performed to quantify the amount of hemorrhage and the amount of air introduced during the DBS surgery. RESULTS: Intraoperative MR imaging revealed 5 subdural hematomas, 3 subarachnoid hemorrhages, and 1 intraparenchymal hemorrhage in 9 of the 143 patients. Only 1 patient experiencing a subarachnoid hemorrhage developed clinically apparent symptoms, which included transient severe headache and mild confusion. Brain shift due to intracranial air was identified in 144 separate instances. CONCLUSIONS: Intraoperative MR imaging can be safely performed and may assist in demonstrating acute changes involving intracranial hemorrhage and air during DBS surgery. These findings are rarely clinically significant and typically resolve prior to follow-up imaging. Selective use of T2 FLAIR and T2 FSE imaging can confirm the presence of hemorrhage or air and preclude the need for CT examinations. PMID- 21699483 TI - Magnetic resonance imaging and deep brain stimulation. PMID- 21699485 TI - Anti-neuroinflammatory effects of psychopharmaceuticals: further than monoamine modulators. PMID- 21699484 TI - Bardoxolone methyl and kidney function in CKD with type 2 diabetes. AB - BACKGROUND: Chronic kidney disease (CKD) associated with type 2 diabetes is the leading cause of kidney failure, with both inflammation and oxidative stress contributing to disease progression. Bardoxolone methyl, an oral antioxidant inflammation modulator, has shown efficacy in patients with CKD and type 2 diabetes in short-term studies, but longer-term effects and dose response have not been determined. METHODS: In this phase 2, double-blind, randomized, placebo controlled trial, we assigned 227 adults with CKD (defined as an estimated glomerular filtration rate [GFR] of 20 to 45 ml per minute per 1.73 m(2) of body surface area) in a 1:1:1:1 ratio to receive placebo or bardoxolone methyl at a target dose of 25, 75, or 150 mg once daily. The primary outcome was the change from baseline in the estimated GFR with bardoxolone methyl, as compared with placebo, at 24 weeks; a secondary outcome was the change at 52 weeks. RESULTS: Patients receiving bardoxolone methyl had significant increases in the mean (+/ SD) estimated GFR, as compared with placebo, at 24 weeks (with between-group differences per minute per 1.73 m(2) of 8.2+/-1.5 ml in the 25-mg group, 11.4+/ 1.5 ml in the 75-mg group, and 10.4+/-1.5 ml in the 150-mg group; P<0.001). The increases were maintained through week 52, with significant differences per minute per 1.73 m(2) of 5.8+/-1.8 ml, 10.5+/-1.8 ml, and 9.3+/-1.9 ml, respectively. Muscle spasms, the most frequent adverse event in the bardoxolone methyl groups, were generally mild and dose-related. Hypomagnesemia, mild increases in alanine aminotransferase levels, and gastrointestinal effects were more common among patients receiving bardoxolone methyl. CONCLUSIONS: Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks. The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD. (Funded by Reata Pharmaceuticals; BEAM ClinicalTrials.gov number, NCT00811889.). PMID- 21699486 TI - Antidepressants and neuroinflammation: Can antidepressants calm glial rage down? AB - Neuroinflammation is traditionally defined as the brain's innate immune response and is also considered to be a glial-cell propagated inflammation. Increasing evidence indicates that neuroinflammation plays an important role in some cases of major depression and also that antidepressants possess anti-neuroinflammatory properties. Inhibition of neuroinflammation may represent a novel mechanism of action of antidepressant treatment. In vivo studies with animal models of neurological conditions have shown that various types of antidepressants exert inhibitory effects on the expression of inflammatory mediators, including cytokines, as well as on both microgliosis and astrogliosis in the inflamed CNS. In vitro studies using pathologically activated rodent microglia or mixed glial cells have demonstrated that various types of antidepressants diminish glial generation of inflammatory molecules. One of the most plausible mechanisms of such anti-neuroinflammatory efficacy of the drugs, as well as their antidepressant actions, seems to involve elevated intracellular cAMP levels. But the exact mechanism has still to be elucidated. PMID- 21699487 TI - Anti-Inflammatory properties of antipsychotics via microglia modulations: are antipsychotics a 'fire extinguisher' in the brain of schizophrenia? AB - Schizophrenia is one of the most severe psychiatric diseases noted for its chronic and often debilitating processes; affecting approximately 1% of the world's population, while its etiology and therapeutic strategies still remain elusive. In the 1950s, the discovery of antipsychotic effects of haloperidol and chlorpromazine shifted the paradigm of schizophrenia. These drugs proved to be antagonists of dopamine D2 receptor (D2R), thus dopamine system dysfunction came to be hypothesized in the pathophysiology of schizophrenia, and D2R antagonism against dopamine neurons has been considered as the primary therapeutic target for schizophrenia. In addition, abnormalities of glutamatergic neurons have been indicated in the pathophysiology of schizophrenia. On the other hand, recent neuroimaging studies have shown that not only dementia but also schizophrenic patients have a significant volume reduction of some specific regions in the brain, which indicates that schizophrenia may involve some neurodegenerative process. Microglia, major sources of various inflammatory cytokines and free radicals such as superoxide and nitric oxide (NO) in the CNS, play a crucial role in a variety of neurodegenerative diseases such as dementia. Recent postmortem and positron emission computed tomography (PET) studies have indicated that activated microglia may be present in schizophrenic patients. Recent in vitro studies have suggested the anti-inflammatory effects of antipsychotics on microglial activation. In this article, we review the anti-inflammatory effects of antipsychotics on microglia, and propose a novel therapeutic hypothesis of schizophrenia from the perspective of microglial modulation. PMID- 21699488 TI - Possible role of BDNF-induced microglial intracellular Ca(2+) elevation in the pathophysiology of neuropsychiatric disorders. AB - Microglia are intrinsic immune cells that release factors, including proinflammatory cytokines, nitric oxide (NO) and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca(2+) concentration ([Ca(2+)]i) is important for microglial functions, such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. We have recently reported that BDNF induces a sustained increase in [Ca(2+)]i through binding with the truncated TrkB receptor, resulting in activation of the PLC pathway and store-operated calcium entry (SOCE) in rodent microglial cells. Sustained activation of SOCE, possibly mediated by TRP channels, occurred after brief BDNF application and contributed to the maintenance of sustained [Ca(2+)]i elevation. Pretreatment with BDNF significantly suppressed the release of NO from activated microglia. Additionally, selective serotonin reuptake inhibitors (SSRIs), including paroxetine or sertraline, potentiated the BDNF-induced increase in [Ca(2+)]i in rodent microglial cells This article provides a review of recent findings on the role of BDNF in the pathophysiology of neuropsychiatric disorders, especially by focusing on its effect on intracellular Ca(2+) signaling in microglial cells. PMID- 21699489 TI - Therapeutic potential of cannabinoids in the treatment of neuroinflammation associated with Parkinson's disease. AB - The cannabinoid system is represented by two principal receptor subtypes, termed CB1 and CB2, along with several endogenous ligands. In the central nervous system it is involved in several processes. CB1 receptors are mainly expressed by neurons and their activation is primarily implicated in psychotropic and motor effects of cannabinoids. CB2 receptors are expressed by glial cells and are thought to participate in regulation of neuroimmune reactions. This review aims to highlight several reported properties of cannabinoids that could be used to inhibit the adverse neuroinflammatory processes contributing to Parkinson's disease and possibly other neurodegenerative disorders. These include anti oxidant properties of phytocannabinoids and synthetic cannabinoids as well as hypothermic and antipyretic effects. However, cannabinoids may also trigger signaling cascades leading to impaired mitochondrial enzyme activity, reduced mitochondrial biogenesis, and increased oxidative stress, all of which could contribute to neurotoxicity. Therefore, further pharmacological studies are needed to allow rational design of new cannabinoid-based drugs lacking detrimental in vivo effects. PMID- 21699490 TI - Stem cell-mediated delivery of therapies in the treatment of glioma. AB - High grade gliomas can be seldom controlled, due to the infiltrative nature of these tumors and the presence of cell populations resistant to radio- and chemotherapy. Current research aims to develop novel therapeutic approaches to track and eliminate the disseminated glioma-driving cells. Selected delivery of therapeutic agents taking advantage of the tropism of normal stem cells for glioma cells might be one. PMID- 21699491 TI - Has selenium a chemopreventive effect on hepatocellular carcinoma? AB - Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Its etiology includes chronic liver disease, viral hepatitis, alcoholism, and hepatic cirrhosis. Both oxidative stress and inflammatory mechanisms have been implicated in HCC pathophysiology. Surgical resection and liver transplants are currently used to treat HCC. Consequently, there exists a decisive requirement to explore possible alternative chemopreventive and therapeutic strategies for HCC. The use of dietary antioxidants and micronutrients has been proposed as a useful means for the HCC management. Trace elements such as selenium are involved in several major metabolic pathways as well as antioxidant defense systems. In particular, selenium is an important oligo-element that plays a central role in cellular redox processes even if the amount necessary for the cell functions is in a very narrow range. However, selenium is involved in the prevention of numerous chronic diseases and cancers. This review will examine the potential role of selenium in HCC prevention and treatment and, in detail, focus on: i) description of selenium in biological systems and in mammalian proteins, ii) involvement of selenium in HCC, iii) in vivo and in vitro effects of selenium in preclinical models of HCC and iv) potential challenges involved in the selenium use in the prevention and treatment of HCC. PMID- 21699492 TI - Strategies on the development of small molecule anticancer drugs for targeted therapy. AB - The main challenges currently encountered in chemotherapy are the lack of tumor selectivity and drug resistance. The design of novel cytostatic drugs has become the state-of-the-art technology in terms of targeted tumor therapy. This review illustrates the mechanisms and the advantages of representative chemotherapeutic agents, and presents an updated summary of the various drug design strategies developed by modern medicinal chemists during the most recent tumor targeting research which include rational design for overcoming drug resistance, the combi targeting strategy, the prodrug approach, and tumor specific transporter based drug design. The concept of transporter related tumor targeting strategies for small molecule anticancer drug design discussed in this review may be amenable to predictable drug discovery for targeted therapy. PMID- 21699493 TI - Importance of oxidative damage on the electron transport chain for the rational use of mitochondria-targeted antioxidants. AB - The electron transport chain (ETC) has become a promising pharmacological target as ETC impairment by reactive oxygen species (ROS) has been detected in several diseases. Therefore, for a better understanding of the actions of mitochondria targeted antioxidants, it must be considered the interplay between the sources of ROS during disease, the chemical interconversions of ROS and their differential reactivity with ETC components. This review contrasts these aspects with available data about mitochondrial damage in specific diseases to give an insight into the importance of ROS chemistry in the rational use of mitochondria-targeted antioxidants, putting emphasis on the case of MitoQ. PMID- 21699494 TI - Overlooked issues of snakebite management: time for strategic approach. AB - Snakebite is a medical emergency in many parts of the world, particularly in the temperate regions. According to 2007 World Health Organization (WHO) report, there are about 5 million snakebite incidences resulting in 2.5 million envenoming, and 125,000 deaths occur annually. Most affected are the healthy individuals like children and farming populations with resource poor settings and away from health care centers in low-income countries of Africa, Asia and Latin America. In view of this, the WHO has declared snakebite as an ignored health crisis and a tropical disease. Although the death rate has reduced markedly due to anti-venom regiment, several limitations of it offer scope for better understanding of various ignored issues. Currently, snakebite therapeutics facing plethora of scientific, technological and public health challenges, including secondary/long term complications that have not been given importance so far. Because of dearth of knowledge, venom researchers and medical practitioners from affected countries worldwide should join together to accomplish this scenario. In view of this, the present review provides a broader perspective on the possible production and application of highly effective therapeutic master anti-venom, designing master diagnostic kit and also to deal with the inefficacy of anti venom therapy against local manifestations and secondary complications of snakebite. The review demands thorough understanding of venom pharmacology, inculcating new strategies to handle and to enhance the efficacy of snakebite management and urge the governing systems of affected countries to take steps to curtail accidental debilitation and death rate of healthy individuals due to snakebite. PMID- 21699495 TI - Requirement for store-operated calcium entry in sodium butyrate-induced apoptosis in human colon cancer cells. AB - The SOCE (store-operated Ca2+ entry) pathway plays a key role in both normal cells and cancerous cells. However, its molecular mechanism remains a long lasting puzzle of Ca2+ signalling. In this paper, we provide evidence that butyric acid, a dietary fibre-derived short-chain fatty acid, induces apoptosis of colon cancer cells via SOCE signalling networks. We found that sodium butyrate (NaB) induces Ca2+ release from endoplasmic reticulum, which in turn causes extracellular Ca2+ influx in HCT-116 cells. The Ca2+ release and influx are important, because the addition of chelators, EGTA or BAPTA/AM [1,2-bis-(o aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetrakis(acetoxymethyl ester)] respectively blocked NaB-induced apoptosis. Furthermore, down-regulation of STIM1 (stromal interaction molecule 1) by RNA interference or pharmacological blockade of the SOCC (store-operated Ca2+ channel) by 2-APB (2-aminoethoxydiphenyl borate) or SKF-96365 inhibited NaB-induced extracellular Ca2+ influx and apoptosis in HCT 116 cells. Thus we conclude that NaB triggers colon cancer cell apoptosis in an SOCE-dependent manner. This finding provides new insights into how butyric acid suppresses colon carcinogenesis. PMID- 21699496 TI - Helicase dissociation and annealing of RNA-DNA hybrids by Escherichia coli Cas3 protein. AB - CRISPR (clustered regularly interspaced short palindromic repeat)/Cas (CRISPR associated) is a nucleic acid processing system in bacteria and archaea that interacts with mobile genetic elements. CRISPR DNA and RNA sequences are processed by Cas proteins: in Escherichia coli K-12, one CRISPR locus links to eight cas genes (cas1, 2, 3 and casABCDE), whose protein products promote protection against phage. In the present paper, we report that purified E. coli Cas3 catalyses ATP-independent annealing of RNA with DNA forming R-loops, hybrids of RNA base-paired into duplex DNA. ATP abolishes Cas3 R-loop formation and instead powers Cas3 helicase unwinding of the invading RNA strand of a model R loop substrate. R-loop formation by Cas3 requires magnesium as a co-factor and is inactivated by mutagenesis of a conserved amino acid motif. Cells expressing the mutant Cas3 protein are more sensitive to plaque formation by the phage lambdavir. A complex of CasABCDE ('Cascade') also promotes R-loop formation and we discuss possible overlapping roles of Cas3 and Cascade in E. coli, and the apparently antagonistic roles of Cas3 catalysing RNA-DNA annealing and ATP dependent helicase unwinding. PMID- 21699497 TI - Enhancement of mDia2 activity by Rho-kinase-dependent phosphorylation of the diaphanous autoregulatory domain. AB - It is clear that RhoA activates the DRF (diaphanous-related formin) mDia2 by disrupting the molecular interaction between the DAD (diaphanous autoregulatory domain) and the DID (diaphanous inhibitory domain). Previous studies indicate that a basic motif within the DAD contributes to mDia2 auto-inhibition, and results shown in the present study suggest these residues bind a conserved acidic region within the DID. Furthermore, we demonstrate that mDia2 is phosphorylated by ROCK (Rho-kinase) at two conserved residues (Thr(1061) and Ser(1070)) just C terminal to the DAD basic region. Phosphomimetic mutations to these residues in the context of the full-length molecule enhanced mDia2 activity as measured by increased actin polymerization, SRF (serum response factor)-dependent smooth muscle-specific gene transcription, and nuclear localization of myocardin-related transcription factor B. Biochemical and functional data indicate that the T1061E/S1070E mutation significantly inhibited the ability of DAD to interact with DID and enhanced mDia2 activation by RhoA. Taken together, the results of the present study indicate that ROCK-dependent phosphorylation of the mDia2 DAD is an important determinant of mDia2 activity and that this signalling mechanism affects actin polymerization and smooth muscle cell-specific gene expression. PMID- 21699499 TI - Abdominal palpation to determine fetal position at labor onset: a test accuracy study. AB - OBJECTIVE: To examine the accuracy of abdominal palpation for identifying left occipito-anterior (LOA) fetal position using abdominal ultrasound as the reference standard. DESIGN: Classical test accuracy study undertaken in 2005 2007. SETTING: Birmingham Women's Foundation NHS Trust serving a large, socio economically and ethnically varied population. SAMPLE: All nulliparous women with spontaneous or induced labor before established labor (cervix <4cm dilated), with a singleton live pregnancy of over 37 completed gestational weeks without known fetal abnormalities. METHODS. Accuracy of abdominal palpation (index test) in identifying LOA fetal position, with abdominal ultrasound as reference. Trained observers blind to the index test results performed the ultrasound independently. MAIN OUTCOME MEASURES: Accuracy of palpation in determining LOA position. RESULTS: Midwives' abdominal palpation and ultrasound data were obtained from 629 women. There were 61 (9%) fetuses in LOA position that were verified by ultrasound. The sensitivity and specificity of palpation to detect LOA position were 34% (95%CI 23-46) and 71% (67-74), respectively. Midwives with experience >5 years achieved higher sensitivity compared to those with <=5 years (odds ratio 4.02; 1.26-12.9; p=0.019). Sensitivity was higher for community compared with hospital midwives (OR 6.59; 1.11-39.11; p=0.038). CONCLUSIONS: Abdominal palpation to determine LOA position at the onset of labor had poor accuracy in nulliparous women on arrival at the maternity unit with a cervix dilation of <4cm. If future research demonstrates that an optimal fetal position at labor onset exists, ultrasound scan to confirm fetal position on arrival for birth may improve midwives' ability to prognosticate. PMID- 21699500 TI - Evaluating the use and limitations of the Danish National Patient Register in register-based research using an example of multiple sclerosis. AB - BACKGROUND: The Danish National Patient Register, Landspatientregistret (LPR), is a register of all hospital discharges and outpatient treatments in Denmark. AIMS: It is increasingly used in research so it is important to understand to what extent this can be used as an accurate source of information. Virtually all patients in Denmark with multiple sclerosis (MS) are reported to the Combined MS Registry (DMSR), so this was used as the standard which the LPR was compared against. METHODS: All residents of Denmark are assigned a unique Civil Register (CPR) number; this was used to compare data between registers. The LPR completeness was estimated by the proportion of cases from the DMSR that could be retrieved from the LPR. The LPR validity was estimated by the proportion of cases, listed in the LPR and DMSR, in whom the MS diagnosis could be confirmed as definite/probable/possible by the DMSR. RESULTS: We found that 86.9% of those who were DMSR listed with an approved MS diagnosis were also listed in the LPR with a MS diagnosis. The diagnosis was valid in 96.3% of patients listed in the LPR when compared against the DMSR. CONCLUSIONS: The low completeness reduces the usefulness of the LPR in epidemiological MS research, in particular incidence studies. The study also found that the completeness of the LPR could be increased to 92.8% by including LPR records from other departments in addition, but this reduced the validity of the LPR to 95.1%. However, these results cannot uncritically be applied to registration of other diseases in the LPR. PMID- 21699498 TI - Molecular mechanisms of cardiomyocyte aging. AB - Western societies are rapidly aging, and cardiovascular diseases are the leading cause of death. In fact, age and cardiovascular diseases are positively correlated, and disease syndromes affecting the heart reach epidemic proportions in the very old. Genetic variations and molecular adaptations are the primary contributors to the onset of cardiovascular disease; however, molecular links between age and heart syndromes are complex and involve much more than the passage of time. Changes in CM (cardiomyocyte) structure and function occur with age and precede anatomical and functional changes in the heart. Concomitant with or preceding some of these cellular changes are alterations in gene expression often linked to signalling cascades that may lead to a loss of CMs or reduced function. An understanding of the intrinsic molecular mechanisms underlying these cascading events has been instrumental in forming our current understanding of how CMs adapt with age. In the present review, we describe the molecular mechanisms underlying CM aging and how these changes may contribute to the development of cardiovascular diseases. PMID- 21699503 TI - Indolinones and anilinophthalazines differentially target VEGF-A- and basic fibroblast growth factor-mediated responses in primary human endothelial cells. AB - BACKGROUND AND PURPOSE: The potent pro-angiogenic growth factors VEGF-A and basic fibroblast growth factor (bFGF) exert their effects by binding VEGF receptor 2 and FGF receptor tyrosine kinases, respectively. Indolinones (e.g. SU5416 and Sutent) and anilinophthalazines (e.g. PTK787) are potent small molecule inhibitors of VEGFR2 and other tyrosine kinases, but their effects on VEGF-A- and bFGF-stimulated endothelial responses are unclear. Here we assess the ability of these compounds to inhibit pro-angiogenic responses through perturbation of receptor activity and endothelial function(s). EXPERIMENTAL APPROACH: We used in silico modelling, in vitro tyrosine kinase assays, biochemistry and microscopy to evaluate the effects of small molecules on receptor tyrosine kinase activation and intracellular signalling. Primary human endothelial cells were used to assess intracellular signalling, cell migration, proliferation and tubulogenesis. KEY RESULTS: We predicted that the anilinophthalazine PTK787 binds the tyrosine kinase activation loop whereas indolinones are predicted to bind within the hinge region of the split kinase domain. Sutent is a potent inhibitor of both VEGFR2 and FGFR1 tyrosine kinase activity in vitro. The compounds inhibit both ligand dependent and -independent VEGFR2 trafficking events, are not selective for endothelial cell responses and inhibit both VEGF-A- and bFGF-mediated migration, wound healing and tubulogenesis at low concentrations. CONCLUSIONS AND IMPLICATIONS; We propose that these compounds have novel properties including inhibition of bFGF-mediated endothelial responses and perturbation of VEGFR2 trafficking. Differential inhibitor binding to receptor tyrosine kinases translates into more potent inhibition of bFGF- and VEGF-A-mediated intracellular signalling, cell migration and tubulogenesis. Indolinones and anilinophthalazines thus belong to a class of multi-kinase inhibitors that show clinical efficacy in disease therapy. PMID- 21699504 TI - Pharmacological activation of KCa3.1/KCa2.3 channels produces endothelial hyperpolarization and lowers blood pressure in conscious dogs. AB - BACKGROUND AND PURPOSE: In rodents, the endothelial KCa channels, KCa3.1 and KCa2.3, have been shown to play a crucial role in initiating endothelium-derived hyperpolarizing factor (EDHF) vasodilator responses. However, it is not known to what extent these channels are involved in blood pressure regulation in large mammals, which would also allow us to address safety issues. We therefore characterized canine endothelial KCa3.1 and KCa2.3 functions and evaluated the effect of the KCa3.1/KCa2.3 activator SKA-31 on blood pressure and heart rate in dogs. EXPERIMENTAL APPROACH: Canine endothelial KCa3.1/KCa2.3 functions were studied by patch-clamp electrophysiology and wire myography in mesenteric arteries. Systemic cardiovascular actions of acute SKA-31 administration were monitored in conscious, unstressed beagle dogs. KEY RESULTS: Mesenteric endothelial cells expressed functional KCa3.1 and KCa2.3 channels that were strongly activated by SKA-31. SKA-31 hyperpolarized the endothelial membrane and doubled endothelial hyperpolarization-dependent vasodilator responses in mesenteric arteries. SKA-31 (2 mg.kg(-1), i.v.) rapidly decreased the MAP by 28 +/- 6 mmHg; this response was transient (8 +/- 1 s), and the initial drop was followed by a fast and pronounced increase in HR (+109 +/- 7 beats min(-1)) reflecting baroreceptor activation. SKA-31 significantly augmented similar transient depressor responses elicited by ACh (20 ng.kg(-1)) and doubled the magnitude of the response over time. CONCLUSIONS AND IMPLICATIONS: Activation of endothelial KCa3.1 and KCa2.3 lowers arterial blood pressure in dogs by an immediate electrical vasodilator mechanism. The results support the concept that pharmacological activation of these channels may represent a potential unique endothelium-specific antihypertensive therapy. PMID- 21699505 TI - Induction of prolonged, continuous slow-wave sleep by blocking cerebral H1 histamine receptors in rats. AB - BACKGROUND AND PURPOSE: Classic H(1) histamine receptor (H(1)R) antagonists are non-selective for H(1)R and known to produce drowsiness. Modern antihistamines are more selective for H(1)R, and are 'non-drowsy' presumably due to reduced permeability through the blood-brain barrier. To characterize both histaminergic sleep regulation and the central actions of antihistamines, in the present study we analysed the effect of classic and modern antihistamines on rats' sleep using continuous i.c.v. infusions. EXPERIMENTAL APPROACH: Effects of classic (d chlorpheniramine; d-CPA) and second-generation (cetirizine) antihistamines on sleep were compared after i.p. injections or continuous i.c.v. infusions into rats. Fluorescent cetirizine/DBD-pz was synthesized to trace the approximate distribution of cerebral cetirizine. Furthermore, the effects of H(1) R antagonists on cultured preoptic neurons were examined using calcium imaging. KEY RESULTS: d-CPA 4 mg.kg(-1) i.p. increased non-rapid eye movement (REM) sleep whereas 10-40 mg.kg(-1) d-CPA decreased non-REM sleep at dark onset time. Nocturnal i.c.v. infusions of d-CPA (10 umol.100 uL(-1).10 h(-1)) increased drowsiness but not non-REM sleep, whereas the same i.c.v. infusions of cetirizine significantly increased non-REM sleep, abolished REM sleep, and decreased wakefulness for more than 10 h. The medial preoptic area contained the greatest fluorescent labelling after i.c.v. cetirizine/DBD-pz infusions. Histamine-induced Ca(2+) increases in medial preoptic neurons were blocked by d-CPA or cetirizine, whereas d-CPA, but not cetirizine, increased Ca(2+) irrespective of antihistaminergic activity at >= 100 uM. CONCLUSION AND IMPLICATIONS: The excitatory action of d-CPA may explain the seemingly inconsistent actions of d CPA on sleep. Cerebral H(1)R inhibition by cetirizine induces synchronization of cerebral activity and prolonged, continuous slow-wave sleep. PMID- 21699507 TI - Effects of NMDA receptor antagonists with different subtype selectivities on retinal spreading depression. AB - BACKGROUND AND PURPOSE: Spreading depression (SD) is a local, temporary disruption of cellular ionic homeostasis that propagates slowly across the cerebral cortex and other neural tissues such as the retina. Spreading depolarization associated with SD occurs in different types of stroke, and this phenomenon correlates also with the initiation of classical migraine aura. The aim of this study was to investigate how NMDA receptor antagonists with different subtype selectivity alter SD. EXPERIMENTAL APPROACH: Immunoblotting was applied to the chick retina for NMDA receptor subunit protein analysis, and an efficient in vitro chick retinal model used with SD imaging for NMDA receptor pharmacology. KEY RESULTS: The prominent NMDA receptor subtypes GluN1, GluN2A and GluN2B were found highly expressed in the chick retina. Nanomolar concentrations of NVP AAM077 (GluN2A-preferring receptor antagonist) markedly suppressed high K(+) induced SD; that is, ~30 times more effectively than MK801. At sub-micromolar concentrations, Ro 25-6981 (GluN2B-preferring receptor antagonist) produced a moderate SD inhibition, whereas CP-101,606 (also GluN2B-preferring receptor antagonist) and UBP141 (GluN2C/2D-preferring receptor antagonist) had no effect. CONCLUSIONS AND IMPLICATIONS: The expression of major NMDA receptor subtypes, GluN1, GluN2A and GluN2B in the chick retina makes them pertinent targets for pharmacological inhibition of SD. The high efficacy of NVP-AAM077 on SD inhibition suggests a critical role of GluN2A-containing receptors in SD genesis. Such high anti-SD potency suggests that NVP-AAM077, and other GluN2A-selective drug-like candidates, could be potential anti-migraine agents. PMID- 21699510 TI - Physiologic changes and dermatoses of pregnancy. AB - Like all organ systems, the skin undergoes significant changes during pregnancy. The majority of physiologic skin conditions related to gestation resolve after childbirth. However, they may cause significant concern or cosmetic distress or be mistaken for one of the specific dermatoses of pregnancy. Dermatoses unique to pregnancy are rare but important to recognize because they may be intensely pruritic or painful to the mother, and they may pose significant risks to the patient, her fetus, or both. Clinicians familiar with the cutaneous manifestations of pregnancy can most effectively treat and counsel patients, guide expectations, and avoid unnecessary diagnostic tests and therapies. This review summarizes physiologic skin changes in the gravid patient and the specific dermatoses of pregnancy. PMID- 21699509 TI - Combined effects of THC and caffeine on working memory in rats. AB - BACKGROUND AND PURPOSE: Cannabis and caffeine are two of the most widely used psychoactive substances. Delta(9) -Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, induces deficits in short-term memory. Caffeine, a non-selective adenosine receptor antagonist, attenuates some memory deficits, but there have been few studies addressing the effects of caffeine and THC in combination. Here, we evaluate the effects of these drugs using a rodent model of working memory. EXPERIMENTAL APPROACH: Rats were given THC (0, 1 and 3 mg.kg(-1) , i.p.) along with caffeine (0, 1, 3 and 10 mg.kg(-1) , i.p.), the selective adenosine A(1) -receptor antagonist CPT (0, 3 and 10 mg.kg(-1) ) or the selective adenosine A(2A) -receptor antagonist SCH58261 (0 and 5 mg.kg(-1) ) and were tested with a delayed non-matching-to-position procedure in which behaviour during the delay was automatically recorded as a model of memory rehearsal. KEY RESULTS: THC alone produced memory deficits at 3 mg.kg(-1) . The initial exposure to caffeine (10 mg.kg(-1) ) disrupted the established pattern of rehearsal-like behaviour, but tolerance developed rapidly to this effect. CPT and SCH58261 alone had no significant effects on rehearsal or memory. When a subthreshold dose of THC (1 mg.kg(-1) ) was combined with caffeine (10 mg.kg(-1) ) or CPT (10 mg.kg( 1) ), memory performance was significantly impaired, even though performance of the rehearsal-like pattern was not significantly altered. CONCLUSION AND IMPLICATIONS: Caffeine did not counteract memory deficits induced by THC but actually exacerbated them. These results are consistent with recent findings that adenosine A(1) receptors modulate cannabinoid signalling in the hippocampus. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7. PMID- 21699506 TI - Pharmacological modulation of chemokine receptor function. AB - G protein-coupled chemokine receptors and their peptidergic ligands are interesting therapeutic targets due to their involvement in various immune related diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease, HIV-1 infection and cancer. To tackle these diseases, a lot of effort has been focused on discovery and development of small-molecule chemokine receptor antagonists. This has been rewarded by the market approval of two novel chemokine receptor inhibitors, AMD3100 (CXCR4) and Maraviroc (CCR5) for stem cell mobilization and treatment of HIV-1 infection respectively. The recent GPCR crystal structures together with mutagenesis and pharmacological studies have aided in understanding how small-molecule ligands interact with chemokine receptors. Many of these ligands display behaviour deviating from simple competition and do not interact with the chemokine binding site, providing evidence for an allosteric mode of action. This review aims to give an overview of the evidence supporting modulation of this intriguing receptor family by a range of ligands, including small molecules, peptides and antibodies. Moreover, the computer-assisted modelling of chemokine receptor-ligand interactions is discussed in view of GPCR crystal structures. Finally, the implications of concepts such as functional selectivity and chemokine receptor dimerization are considered. PMID- 21699511 TI - Stress and quality of life in psoriasis: an update. AB - Psoriasis is a chronic, relapsing, cutaneous condition with 1-2% prevalence in the general population. There are many factors involved in the induction and/or exacerbation of psoriasis of which stress is a well-known trigger factor in the appearance or exacerbation of psoriasis. Stress reaction in patients with psoriasis is probably mediated by the hypothalamic-pituitary-adrenal relationship with immunologic effects. Stress response involves increased levels of neuroendocrine hormones and autonomic neurotransmitters. Psychological stress or an abnormal response to stressors has been found to modify the evolution of skin disorders such as psoriasis. It can also have substantial psychological, and psychosocial impact on a patient's quality of life. Treatment regimens include stress-reduction strategies, such as biofeedback, meditation, yoga, and self-help approaches. This review focuses the relationship between psoriasis and stress, especially relating to psychosocial, psychological, and emotional stress aspects. PMID- 21699512 TI - Pink verrucous plaque over the right foot. PMID- 21699508 TI - Regulation of GPCR activity, trafficking and localization by GPCR-interacting proteins. AB - GPCRs represent the largest family of integral membrane proteins and were first identified as receptor proteins that couple via heterotrimeric G-proteins to regulate a vast variety of effector proteins to modulate cellular function. It is now recognized that GPCRs interact with a myriad of proteins that not only function to attenuate their signalling but also function to couple these receptors to heterotrimeric G-protein-independent signalling pathways. In addition, intracellular and transmembrane proteins associate with GPCRs and regulate their processing in the endoplasmic reticulum, trafficking to the cell surface, compartmentalization to plasma membrane microdomains, endocytosis and trafficking between intracellular membrane compartments. The present review will overview the functional consequence of beta-arrestin, receptor activity-modifying proteins (RAMPS), regulators of G-protein signalling (RGS), GPCR-associated sorting proteins (GASPs), Homer, small GTPases, PSD95/Disc Large/Zona Occludens (PDZ), spinophilin, protein phosphatases, calmodulin, optineurin and Src homology 3 (SH3) containing protein interactions with GPCRs. PMID- 21699513 TI - Hyperpigmented spots within and partly around a hypopigmented macule. PMID- 21699514 TI - Clinical features of idiopathic guttate hypomelanosis in 646 subjects and association with other aspects of photoaging. AB - BACKGROUND: The lesions of idiopathic guttate hypomelanosis (IGH) are commonly seen in elderly persons, although this is an often unrecognized skin disease with an obscure etiopathogenesis. The prevalence and clinical features of IGH have not yet been well studied. OBJECTIVES: The purposes of this study were to evaluate the prevalence of IGH in different age groups and to determine the association of IGH with other dermatoses related to photoaging. METHODS: A total of 1174 subjects were examined for IGH. A detailed history was taken and general, systemic, and cutaneous examinations were carried out on the basis of clinical features. Woods lamp examination, KOH wet mounting, and/or histopathologic examination were conducted as required. RESULTS: Of 1174 subjects, 646 showed signs of IGH. The prevalence of IGH in the group of patients aged >=40 years was 87%. This prevalence increased with advancing age. The prevalence of IGH was 54% (n = 307) among males and 56% (n = 339) among females. Sites of frequent involvement included the distal part of the lower extremity in 93% (n = 598) of cases, the distal part of the upper extremity in 91% (n = 585), the proximal part of the upper extremity in 73% (n = 474), and the proximal part of the lower extremity in 58% (n = 376). Thirty-nine (6%) subjects also developed IGH on the face. Frequency of dermatoses related to aging was found to be significantly associated with IGH, including numerous solar lentigo [odds ratio (OR) = 5.95] and xerosis (OR = 2.40). In addition, the subjects who used "body scrubbers" were significantly more likely to have IGH lesions (OR = 1.64). CONCLUSIONS: It is very likely that IGH is a phenomenon associated with the skin's normal aging process and repeated microtrauma to skin. PMID- 21699516 TI - Egg allergy in patients over 14 years old suffering from atopic eczema. AB - OBJECTIVE: The aim of this study was to evaluate the occurrence of egg allergy in patients over 14 years old suffering from atopic eczema and especially to evaluate if egg allergy can deteriorate the course of atopic eczema in this group of patients. MATERIALS AND METHODS: Altogether 179 patients suffering from atopic eczema were included in the study: 51 men and 128 women, with an average age of 26.2 years (SD 9.5 years), with median SCORAD 31.6 (SD 13.3) points. A complete allergological and dermatological examination was performed on all patients, including diagnostic work-up of food allergy to egg [skin prick tests, atopy patch tests (APTs), measurement of specific IgE level to egg yolks or whites]. Open exposure test (OET) with egg was performed in patients with positive results in some of these diagnostic methods. Food allergy to egg was determined according to positive results in the OET or according to sufficient anamnestical data about the severe allergic reaction after the ingestion of an egg. RESULTS: An allergy to egg was confirmed in 11 patients out of 179 (6%). Of these patients, only six (3.3%) had a clear improvement in the SCORAD after the elimination of egg. Other triggering factors may cause exacerbation of the atopic eczema in the patients enrolled in the study. Twenty-eight percent of patients were only sensitized to egg without clinical symptoms. ATPs were a useful tool in the diagnosis of food allergy to egg in patients without IgE reactivity. CONCLUSION: Egg allergy may play an important role in the worsening of atopic eczema acting as a triggering exacerbating factor in a minority of patients. The diagnostic work-up may comprise the challenge tests to confirm the food allergy to egg. PMID- 21699515 TI - Contact sensitization pattern in 172 atopic subjects. AB - BACKGROUND: Some authors have claimed a decreased cell-mediated immunity among atopic individuals, which would lead to observations of decreased rates of allergic contact dermatitis (ACD). OBJECTIVES: The purpose of our study was to investigate contact sensitization patterns in atopic subjects compared with non atopic subjects. METHODS: Patch test data for 1247 patients undergoing patch testing at Massachusetts General Hospital between 1990 and 2006 were reviewed. Using accepted criteria, 172 subjects were classified as atopic individuals (AIs), and 1075 were classified as non-atopic individuals (NAIs). Sensitization rates were compared between these two groups. RESULTS: Sensitization rates (65.0% and 57.4% in the AI and NAI groups, respectively) and average numbers of positive responses (1.5 and 1.2 in the AI and NAI groups, respectively) were higher in AIs. Leading allergens observed were similar for both groups. Sensitization to potassium dichromate and phenylmercuric acetate was significantly greater in the AI group. The most frequent diagnosis in both groups was ACD (41.9% and 45.5% in the AI and NAI groups, respectively). In addition, more NAIs who were employed in occupations with exposure to wet and/or irritant conditions had hand eczema (P < 0.005). CONCLUSIONS: Atopic individuals were shown to be at least as likely to have ACD as NAIs. The most common sensitizers were similar in both groups, suggesting common sources of sensitization. PMID- 21699517 TI - Investigation of pajama properties on skin under mild cold conditions: the interaction between skin and clothing. AB - BACKGROUND: Clothing is considered the second skin of the human body. The aim of this study was to determine clothing-wearer interaction on skin physiology under mild cold conditions. METHODS: Skin physiological parameters, subjective sensory response, stress level, and physical properties of clothing fabric from two longitude parallel-designed wear trials were studied. The wear trials involved four kinds of pajamas made from cotton or polyester material that had hydrophilic or hydrophobic treatment, conducted for three weeks under mild cold conditions. Statistical tools, factor analysis, hierarchical linear regression, and logistic regression were applied to analyze the strong predictors of skin physiological parameters, stress level, and sensory response. RESULTS: A framework was established to illustrate clothing-wearer interactions with clothing fabric properties, skin physiology, stress level, and sensory response under mild cold conditions. DISCUSSION: Fabric has various effects on the human body under mild cold conditions. A fabric's properties influence skin physiology, sensation, and psychological response. PMID- 21699518 TI - Autoimmune diseases in patients with pemphigus and their first-degree relatives. AB - BACKGROUND: Pemphigus is an autoimmune blistering disease affecting the skin and mucosa, which mostly in anecdotal reports has been associated with several autoimmune diseases. OBJECTIVE: The aim of this study was to assess the frequency of autoimmune diseases in a large group of patients with pemphigus and their first-degree relatives. METHODS: One hundred and ten patients with pemphigus were interviewed for the existence of various autoimmune diseases. Patients' sera were examined for the presence of several autoantibodies. The existence of autoimmune diseases in 969 first-degree relatives of the patients was assessed via questionnaires. RESULTS: Seven of 110 (6.3%) patients with pemphigus had concurrent autoimmune diseases, including four (3.6%) with autoimmune thyroid disease and three (2.7%) with rheumatoid arthritis. Ten of 969 (1.03%) first degree relatives of patients with pemphigus had autoimmune thyroid disease, three (0.31%) had rheumatoid arthritis, and three (0.31%) had type 1 diabetes mellitus. The patient's group had a statistically significant higher prevalence of thyroid disease and rheumatoid arthritis than their first-degree relatives (P = 0.046 and 0.016 respectively). CONCLUSIONS: Patients with pemphigus seem to have a higher rate of autoimmune thyroid disease and rheumatoid arthritis than both the general population and their own first-degree relatives. Further studies comparing patients with pemphigus with healthy controls are needed to stratify their risk factors for developing other autoimmune diseases and to define guidelines regarding diagnosis and treatment of coexistent autoimmune disorders. PMID- 21699519 TI - Altered epidermal lipid layers induced by long-term exposure to suberythemal-dose ultraviolet. AB - BACKGROUND: Although several studies have reported on the biological effects of ultraviolet (UV) radiation, there have been only a few reports on the changes in epidermal lipids following long-term UV irradiation at suberythemal dose (SED), to which people are usually exposed during their lifetime. OBJECTIVES: To investigate the changes of epidermal lipid properties after long-term UV radiation with SED. MATERIALS AND METHODS: Hairless mice were irradiated three times weekly for 15 weeks at an SED of UV (UVB: 20 mJ/cm(2) ; UVA: 14 J/cm(2) ). Every three weeks, transepidermal water loss (TEWL) was measured by a Tewameter. The morphological alterations of stratum corneum (SC) lipid lamellae were examined by electron microscopy (EM). Activities of three key enzymes for mRNA of serine palmitoyl transferase, fatty acid synthase, and HMG CoA reductase were analyzed with real time reverse transcriptase-polymerase chain reaction. We also measured the amount of ceramide, cholesterol sulfate, and free fatty acid in the SC by high-performance thin-layer chromatography with exposed times. RESULTS: The SED UV-irradiated group showed increased TEWL after 12 weeks. Following the irradiation period, EM revealed incomplete and separated lamellae at SC intercellular space. mRNA of three key enzymes was increased until six weeks of UV irradiation and decreased thereafter. However, three major lipid amounts gradually decreased throughout the exposed period, with a notable decrease in ceramide. CONCLUSIONS: Long-term UV irradiation even with SED influences skin barrier function and structure with prominent ceramide decrease in SC intercellular lipid. PMID- 21699520 TI - PTCH1 gene mutations in exon 17 and loss of heterozygosity on D9S180 microsatellite in sporadic and inherited human basal cell carcinomas. AB - BACKGROUND: Basal cell carcinomas (BCCs) are the most frequent human cancer that results from malignant transformation of basal cells in the epidermis. Gorlin syndrome is a rare inherited autosomal dominant disease that predisposes with multiple BCCs and other birth defects. Both sporadic and inherited BCCs are associated with mutations in the tumor suppressor gene PTCH1, but there is still uncertainty on the role of its homolog PTCH2. OBJECTIVES: To search for mutations and genomic instability in sporadic and inherited BCCs. METHODS: DNA obtained from leukocytes and tumor cells was amplified by polymerase chain reaction regarding five exons of PTCH1 and PTCH2 and neighboring microsatellites. Exons were sequenced and compared with the GenBank database. RESULTS: Only D9S180, of six microsatellites, showed loss of heterozygosity in three BCCs (two sporadic and one inherited). One sporadic BCC presented the mutation g.2885G>C in exon 17 of PTCH1, which predicts the substitution p.R962T in an external domain of the protein. In addition, the leukocytes and tumor cells of one patient with Gorlin syndrome showed the mutation g.2839T>G in the same exon and gene, which predicts a p.E947stop and truncated protein. All control and tumor samples presented IVS9 + 217T in intron 9 of PTCH1. CONCLUSION: Mutations found in the PTCH1 gene and neighboring repetitive sequences may have contributed to the development of the studied BCCs. PMID- 21699521 TI - Pattern of skin diseases in Cairo, Egypt. AB - BACKGROUND: Information on patterns of skin diseases in Egypt is scanty. METHODS: The medical records of patients attending dermatology outpatient clinics at Ain Shams University Hospitals from January 2001 to December 2001 were retrieved. Valid data of 7528 patients were included in the study. Demographic data (age and sex) and diagnoses of skin disease were extracted, coded, and analyzed. RESULTS: Patients' attendance revealed mean age of 23.5 +/- 15.6 years and female predominance in a female to male ratio of 1.6:1. Most patients presented in summer (40.7%). Infections constituted most of the dermatoses (45.4%), and scabies was the most common disease (9.26%). Hypersensitivity diseases came after (22%) and, interestingly, the dermatitis subgroup (12.94%) followed fungal infections (15.83%) immediately, preceding other infection subgroups. Females predominated in most dermatoses. Urticaria predominated in infants, bacterial infections in preschool stage, fungal infections in school and young adult stages, and dermatitis in old adult and geriatric stages. Fungal infections predominated in all seasons. The peak presentation of all diseases was in summer except urticaria that was represented more in spring. CONCLUSION: Dermatitis preceded many infectious diseases as an index of the development and urbanization of a community. However, infections still represent the most common dermatoses. Fortunately, they are potentially controllable and, therefore, healthcare strategies that target infections may represent the key for an efficient national healthcare program. PMID- 21699522 TI - Actinomycetoma of the scalp after a car accident. AB - BACKGROUND: Actinomycetoma is the most frequent type of mycetoma in Mexico. Localization on the scalp is very rare. Because of this topography and potential spread to the brain, the present case became a diagnostic and therapeutic challenge. MATERIALS AND METHODS: We report the case of a 44-year-old woman with a 6 * 5 cm red, friable, granulomatous, vascular neoformation on the scalp and eye diagnosed as Nocardia brasiliensis actinomycetoma. RESULTS: A combination of amikacin and oral trimethoprim-sulfamethoxazole (SXT) was successfully administered with an excellent outcome and no side effects. CONCLUSIONS: This is a rare presentation of mycetoma of the scalp that was cured in 12 weeks with a combination of amikacin and SXT. PMID- 21699523 TI - Leukocytoclastic vasculitis presenting as acute hemorrhagic edema in a 21-year old patient. PMID- 21699524 TI - Coexistence of pigmentary demarcation lines types C and E in one subject. PMID- 21699526 TI - Fatal systemic nonuremic calciphylaxis in a patient with primary autoimmune myelofibrosis. PMID- 21699525 TI - Erythema nodosum and Sweet's syndrome in patients with glandular tularemia. PMID- 21699527 TI - Longitudinal lift biopsy technique with flat fixation for the diagnosis of mycosis fungoides. PMID- 21699528 TI - Severe adverse cutaneous drug eruptions: epidemiological and clinical features. AB - INTRODUCTION: Adverse cutaneous drug reactions (ACDR) are common, and some can be lethal. The aim of our study was to discuss the epidemiological and clinical features of severe ACDR. MATERIALS AND METHODS: We retrospectively analyzed 100 cases of ACDR from 1981 to 2007, collected in the Department of Dermatology of the La Rabta Hospital in Tunis, which is located in the north of Tunisia. Severity was defined on three criteria: hospitalization; visceral involvement; and severity markers. RESULTS: Characteristics of the 54 included cases were: women (70%); mean age: 44.8 years; responsible drugs: anticonvulsants (28%), antibiotics (28%), and nonsteroidal anti-inflammatory drugs (15%). The most common dermatoses were maculopapular rash (50%). We observed fever (76%), lymphadenopathy (31.5%), eosinophilia (35%), and visceral involvement (50%). Twelve patients died directly related to the ACDR. CONCLUSION: This study underlines the polymorphous clinical presentation of ACDR and the importance of researching some severity markers, which have important practical implications. PMID- 21699529 TI - Barrier function of intact and impaired skin: percutaneous penetration of caffeine and salicylic acid. AB - BACKGROUND: Normally, percutaneous absorption tests are carried out using skin biopsies for an apparent and acceptable physiological condition. However, under different pathological conditions, the stratum corneum (SC) barrier function is impaired. METHODS: The barrier function of the SC was assessed by correlation between the number of repeated applications of tape strips on the skin and its transepidermal water loss (TEWL), as well as by in vitro percutaneous absorption studies of different compounds, using Franz diffusion cells and porcine skin previously stripped. RESULTS: A progressive diminution of the skin barrier function has been detected by TEWL both in vitro and in vivo as the number of skin tape strips increases. On the other hand, the percutaneous absorption of the compounds tested increases in a different way as the number of strips increases. Salicylic acid increases linearly depending on the barrier disturbance. However, percutaneous absorption of caffeine exponentially increased with barrier disturbance. Our results indicate that the barrier impairment of skin always increases the penetration behavior of a given compound; however, the hydrophilic lipophilic balance of the compounds or formulations used could greatly modify its penetration profile, especially when a modified skin is used. CONCLUSIONS: This in vitro protocol may be useful to simulate the percutaneous absorption profile of some drugs applied onto skin with an impaired SC barrier function and could be used to avoid, to some extent, the use of in vivo experimental animal models in the dermopharmaceutical field. PMID- 21699530 TI - Hiroshima, an experience that can never be forgotten: long-term follow-up of Hiroshima survivors. PMID- 21699531 TI - Lichenoid red tatoo reaction and alopecia areata. PMID- 21699532 TI - Mycophenolate sodium in the treatment of mucocutaneous Behcet's diseases. PMID- 21699533 TI - Plaque-type cutaneous focal mucinosis. PMID- 21699534 TI - Annular erythemas diagnosed as cutaneous metastasis of breast carcinoma: spontaneous resolution of the lesions. PMID- 21699535 TI - Marshall Blankenship Travel Scholarship awarded at the 2nd Tropical Dermatology Seminar. PMID- 21699536 TI - ISD International Mentorship: a lesson in humanistic medicine. PMID- 21699539 TI - Nesting songbirds assess spatial heterogeneity of predatory chipmunks by eavesdropping on their vocalizations. AB - 1. Information benefits organisms living in a heterogeneous world by reducing uncertainty associated with decision making. For breeding passerines, information reliably associated with nest failure, such as predator activity, can be used to adjust breeding decisions leading to higher reproductive success. 2. Predator vocalizations may provide a source of current information for songbirds to assess spatial heterogeneity in risk that enables them to make appropriate nest-site and territory placement decisions. 3. To determine whether ground-nesting passerines eavesdrop on a common nest predator, the eastern chipmunk (Tamias striatus), we conducted a playback experiment to create spatial heterogeneity in perceived predation risk. We established three types of playback plots broadcasting: (i) chipmunk vocalizations (increased risk), (ii) frog calls (procedural control) and (iii) no playback (silent control). We conducted point counts from plot centres to compare bird activity among treatments and measured the distance of two ground nesting species' nests, ovenbird (Seiurus aurocapilla) and veery (Catharus fuscescens), from playback stations. 4. Ground-nesting birds significantly reduced their activities up to 30 m from plot centres in response to playbacks of chipmunk calls suggesting an adjustment of territory placement or a reduction of overt behaviours (e.g. singing frequency). In contrast, less vulnerable canopy nesting species showed no effect across experimental plots. Correspondingly, veeries and ovenbirds nested significantly further from chipmunk playback stations relative to control stations. Interestingly, the magnitude of this response was more than twice as high in ovenbirds than in veeries. 5. Our findings indicate that some breeding passerines may eavesdrop on predator communication, providing an explanation for how some birds assess spatial heterogeneity in predation risk to make breeding site decisions. Thus, heterospecific eavesdropping may be a common feature of predator-prey interactions that allows birds to avoid nest predators in space and provide greater stability to predator-prey dynamics. PMID- 21699540 TI - The cyclooxygenase-2 pathway via the PGE2 EP2 receptor contributes to oligodendrocytes apoptosis in cuprizone-induced demyelination. AB - Cyclooxygenases (COX)-1 and -2 are key enzymes required for the conversion of arachidonic acid to eicosanoids, potent mediators of inflammation. In patients with multiple sclerosis, COX-2 derived prostaglandins (PGs) are elevated in the CSF and COX-2 is up-regulated in demyelinating plaques. However, it is not known whether COX-2 activity contributes to oligodendrocyte death. In cuprizone-induced demyelination, oligodendrocyte apoptosis and a concomitant increase in the gene expression of COX-2 and PGE2-EP2 receptor precede histological demyelination. COX 2 and EP2 receptor were expressed by oligodendrocytes, suggesting a causative role for the COX-2/EP2 pathway in the initiation of oligodendrocyte death and demyelination. COX-2 gene deletion, chronic treatment with the COX-2 selective inhibitor celecoxib, or with the EP2 receptor antagonist AH6809 reduced cuprizone induced oligodendrocyte apoptosis, the degree of demyelination and motor dysfunction. These data indicate that the PGE2 EP2 receptor contributes to oligodendrocyte apoptosis and open possible new therapeutic approaches for multiple sclerosis. PMID- 21699541 TI - N-cadherin enhances APP dimerization at the extracellular domain and modulates Abeta production. AB - Sequential processing of amyloid precursor protein (APP) by beta- and gamma secretase leads to the generation of amyloid-beta (Abeta) peptides, which plays a central role in Alzheimer's disease pathogenesis. APP is capable of forming a homodimer through its extracellular domain as well as transmembrane GXXXG motifs. A number of reports have shown that dimerization of APP modulates Abeta production. On the other hand, we have previously reported that N-cadherin-based synaptic contact is tightly linked to Abeta production. In the present report, we investigated the effect of N-cadherin expression on APP dimerization and metabolism. Here, we demonstrate that N-cadherin expression facilitates cis dimerization of APP. Moreover, N-cadherin expression led to increased production of Abeta as well as soluble APPbeta, indicating that beta-secretase-mediated cleavage of APP is enhanced. Interestingly, N-cadherin expression affected neither dimerization of C99 nor Abeta production from C99, suggesting that the effect of N-cadherin on APP metabolism is mediated through APP extracellular domain. We confirmed that N-cadherin enhances APP dimerization by a novel luciferase-complementation assay, which could be a platform for drug screening on a high-throughput basis. Taken together, our results suggest that modulation of APP dimerization state could be one of mechanisms, which links synaptic contact and Abeta production. PMID- 21699543 TI - Peptide release upon photoconversion of 2-nitrobenzyl compounds into nitroso derivatives. AB - The photoinduced conversion via the aci-nitro into the nitroso form was studied for 4,5-dimethoxy-2-nitrobenzyl alcohols attached to various leaving groups: amino acids histidine (NHis) and aspartate (NAsp) as well as their fluorenylmethoxycarbonyl derivatives (FHis) and (FAsp). In addition, two peptides containing either of the two amino acids were studied, carrying the photoreactive group attached to a histidine (PHis), or to an aspartate (PAsp). The aci-nitro forms with maximum at lambda(aci) = 420 nm were observed for FHis and FAsp after the decay of a triplet-triplet absorption, analogous to those of other 2 nitrobenzyl type compounds. For both FHis and FAsp the quantum yield of photoconversion Phi(p) is 0.03 and for the peptides PHis and PAsp ca 0.01 and 0.005, respectively. PMID- 21699542 TI - Homeostatic NMDA receptor down-regulation via brain derived neurotrophic factor and nitric oxide-dependent signalling in cortical but not in hippocampal neurons. AB - Nitric oxide (NO) has been proposed to down-regulate NMDA receptors (NMDA-Rs) in a homeostatic manner. However, NMDA-R-dependent NO synthesis also can cause excitotoxic cell death. Using bicuculline-stimulated hippocampal and cortical cell cultures, we have addressed the role of the brain-derived neurotrophic factor-NO pathway in NMDA-R down-regulation. This pathway protected cortical cells from NMDA-induced death and led to NMDA-R inhibition. In contrast, no evidence was gained for the presence of this protective pathway in hippocampal neurons, in which NMDA-induced NO synthesis was confirmed to be toxic. Therefore, opposing effects of NO depended on the activation of different signalling pathways. The pathophysiological relevance of this observation was investigated in synaptosomes and post-synaptic densities isolated from rat hippocampi and cerebral cortices following kainic acid-induced status epilepticus. In cortical, but not in hippocampal synaptosomes, brain-derived neurotrophic factor induced NO synthesis and inhibited NMDA-R currents present in isolated post-synaptic densities. In conclusion, we identified a NO-dependent homeostatic response in the rat cerebral cortex induced by elevated activity. A low performance of this pathway in brain areas including the hippocampus may be related to their selective vulnerability in pathologies such as temporal lobe epilepsy. PMID- 21699544 TI - Photodynamic treatment of Chaoborus crystallinus larvae with chlorophyllin induces necrosis and apoptosis. AB - Chlorophyllin kills mosquito larvae (Culex, Aedes) in the aquatic habitat at low concentrations via photodynamic reactions under irradiation. The effects of chlorophyllin were investigated at the cellular level using the transparent larvae of Chaoborus crystallinus as a model system. Their transparency enabled in situ fluorescence investigation, showing that chlorophyllin accumulates in the intestine of the larvae. Uptake of chlorophyllin at room temperature took about 2 h. The fluorescence signal peaked after 5 h of incubation. Chlorophyllin accumulates up to about 15 ng per larvae. The intestine of treated larvae was dissected and stained with several dyes (acridine orange, Hoechst 33342 and propidium iodide). Apoptosis and necrosis increased with higher concentrations of chlorophyllin (to a smaller extent in dark controls) and were elevated in irradiated samples. Single cells from treated larvae were isolated and subjected to Annexin V flow cytometry. The fraction of apoptotic and necrotic cells increased significantly at a high chlorophyllin concentration (21.4 mg L(-1)) and under intensive irradiation. The activity of caspases-3, -8 and -9 as well as Bcl 2 and cytochrome c was investigated by means of western blot analysis. The data suggest a possible chlorophyllin concentration-dependent shift of the apoptotic pathway. PMID- 21699545 TI - Ultraviolet-B irradiation induces differential regulations of hyaluronidase expression and activity in normal human keratinocytes. AB - Skin aging is a complex process determined by genetic factors (intrinsic aging) and environmental factors (extrinsic aging). One of the most influential environmental factor is UV-B irradiation. Hyaluronic acid (HA) is an abundant component of skin extracellular matrix where it plays many roles such as hydration and architectural support. Downregulation of HA during photoaging was reported previously. Changes in expression and function of its degrading enzymes, the hyaluronidases (Hyals) might be involved in this decrease. In the present study, normal human keratinocytes were submitted to increasing doses of UV-B. The mRNA expression of HYAL1, HYAL2 and HYAL3 and the hyaluronidase enzymatic activity were quantified using real-time PCR and a microtiter-based assay, respectively. After UV-B irradiation, HYAL1 mRNA expression was upregulated whereas HYAL2 and HYAL3 mRNAs were downregulated and hyaluronidase enzymatic activity was increased in both cell layer and culture medium. In parallel, immunohistochemical studies performed on UV-B irradiated reconstructed epidermis confirmed that Hyal-1, Hyal-2 and Hyal-3 protein expression were differently regulated by UV-B. Taken together, our results demonstrate that UV-B irradiation induces differential regulations of hyaluronidase expression and enzymatic activity in human keratinocytes. These differential modulations of hyaluronidase expression and activity by UV-B could contribute to cutaneous photoaging. PMID- 21699546 TI - Detection of altered extracellular matrix in surface layers of unstable carotid plaque: an optical spectroscopy, birefringence and microarray genetic analysis. AB - Erosion and rupture of surface layers in atherosclerotic plaque can cause heart attack and stroke; however, changes in luminal surface composition are incompletely defined. Laser-induced fluorescence spectroscopy (LIFS), with limited tissue penetration, was used to investigate the surface of unstable carotid plaque and correlated with microscopy, birefringence and gene expression. Arterial matrix collagens I, III and elastin were assessed in unstable plaques (n = 25) and reference left internal mammary arteries (LIMA, n = 10). LIFS in addition to selective histological staining with picrosirius red, Movat pentachrome and immunostaining revealed decreased elastin and increased collagen I and III (P < 0.05) in carotid plaque when compared with LIMA. Within plaque, collagen I was elevated in the internal carotid region versus the common carotid region. Polarized light microscopy detected layers of aligned collagen and associated mechanical rigidity of the fibrous cap. Microarray analysis of three carotid and three LIMA specimens confirmed up-regulation of collagen I, III and IV, lysyl oxidase and MMP-12. In conclusion, LIFS analysis coupled with microscopy revealed marked regional differences in collagen I, III and elastin in surface layers of carotid plaque; indicative of plaque instability. Birefringence measurements demonstrated mechanical rigidity and weakening of the fibrous cap with complementary changes in ECM gene expression. PMID- 21699547 TI - Structural reorganizations control intermolecular conductance and charge trapping in paraquat-tetraphenylborate inverse photochemical cell. AB - Miniaturization of electronic devices to the level of single molecules requires detailed understanding of the mechanisms of their operation. One of the questions here is the identification of the role of structural alterations in charge separation and stabilization in photoactive complexes. To address this question, we calculate optimized molecular and electronic structures, and optical and vibrational spectra of l,l'-dimethyl 4,4'-bipyridinium-bis tetraphenylborate PQ(BPh(4))(2) complex ab initio using density functional theory approach and compare them with the experimentally observed UV-Vis and Raman spectra of the molecules in solid-state films. The results indicate that the association of PQ and BPh(4) leads to the formation of an internally ionized structure that is accompanied by the structural reorganization of both PQ (the twisting of pyridinium rings) and BPh(4) (phenyl rings rotation) moieties. The quanta of light do not seem to be directly involved in the formation of this ionized structure, but provide energy for fast recombination of the separated charges between BPh(4)(-) and PQ(2+). The high efficiency of the dark charge separation and the stabilization of separated charges in the complex permit the using of PQ(BPh(4))(2) in various charge-transfer devices like molecular probes, photovoltaic devices or chemical memory units. PMID- 21699548 TI - A UVC device for intra-luminal disinfection of catheters: in vitro tests on soft polymer tubes contaminated with Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli and Candida albicans. AB - Bacterial colonization of central venous catheters (CVCs) causes severe complications in patients. As a result, developing methods to remove and prevent bacterial and fungal colonization of CVCs is imperative. Recently, we have demonstrated that disinfection by radiation of polymer tubes with UVC light is possible. In this paper we present dose-response results using a newly developed UVC disinfection device, which can be connected to a Luer catheter hub. The device was tested on soft polymer tubes contaminated with a pallet of microorganisms, including Candida albicans, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa (ca 10(3) CFU mL(-1)). The tubes were equipped with a modified catheter hub and interfaced to the disinfection device via a middle piece separating the disinfection device from the hub. The contamination lasted for 3 h prior to treatment to simulate an aseptic breach. Our results show UVC killing in a dose and time dependent manner, with no viable counts after 2 min of radiation for bacteria. Killing of C. albicans was obtained at >20 min in an UVC absorbing suspension. We believe our results to be transferable directly to the clinic, and we are currently working on a setup for clinical trial. PMID- 21699549 TI - Increased mass levels of certain serine proteases in the stratum corneum in acute eczematous atopic skin. AB - Acute eczematous atopic dermatitis (AD) is associated with increases in stratum corneum (SC) serine protease activity. The purpose of this study was to examine whether the increased SC protease activities in acute eczematous atopic dermatitis were associated with increased mass levels of SC proteases. Six subjects with healthy skin and six patients with AD each with non-lesional skin or lesional acute eczematous skin had the mass levels of their extractable SC kallikreins (KLK), plasmin and urokinase quantified using Luminex multiplex bead based assays from SC tape strippings. The mass levels of KLK5 and KLK14 together with urokinase were not elevated in the SC in atopic skin. However, the mass levels of KLK7 and KLK11 together with plasmin were greatly elevated compared with the extracts from the non-lesional and the healthy skin and correlated with the corresponding enzymatic activities. PMID- 21699550 TI - Combination tibial plateau leveling osteotomy and transverse corrective osteotomy of the proximal tibia for the treatment of complex tibial deformities in 12 dogs. AB - OBJECTIVE: To describe a surgical technique, and outcome, for treatment of proximal tibial deformity (varus, valgus, excessive tibial plateau angle [eTPA], tibial torsion and patellar luxation) by combined tibial plateau leveling osteotomy (TPLO) and transverse corrective osteotomy. STUDY DESIGN: Cases series. ANIMALS: Dogs (n=12; 19 stifle joints). METHODS: Medical records of dogs that had combination TPLO and transverse corrective osteotomy, were reviewed. Pre- and postoperative tibial angulation, tibial torsion, tibial plateau angle (TPA), corrective osteotomy technique, method of fixation, and complications were recorded. In hospital re-evaluation of limb function and alignment and length of time to radiographic healing were reviewed. Long-term outcome was assessed by visual analog scale (VAS) questionnaire and owner telephone interview. RESULTS: Proximal tibial varus or valgus was present in 68.4%; 73.7% had eTPA; and 47.4% had both. Medial patellar luxation (MPL) was present in 57.9%, of which 47.4% had tibial tuberosity displacement. Severe tibial torsion was present in 68.4%. Mean pre- and postoperative TPA was 37.5 degrees and 5.7 degrees , respectively. The mean postoperative mechanical medial proximal tibial angle (mMPTA) and mechanical medial distal tibial angle (mMDTA) were 92.2 degrees (range, 88-96 degrees ) and 96.1 degrees (range, 94-101 degrees ), respectively. Postoperative surgical complications were documented in 21.0%, which included implant loosening or breakage (5.3%), seroma (5.3%), septic arthritis (5.3%), and infection of the proximal tibia (5.3%). All complications were considered major because they required additional surgery. Mean time to document radiographic healing was 10.4 weeks. In-hospital re-evaluation of lameness was obtained at the same time; 82.4% were not lame or had a mild lameness, 17.6% had severe lameness (2/3 with infection). The VAS evaluation revealed excellent results and owner satisfaction in all ten dogs in which long-term follow-up was obtained. CONCLUSIONS: Long-term clinical outcome of combination TPLO and transverse corrective osteotomy was excellent, and had a high owner satisfaction. Healing times were comparable to standard TPLO with a similar complication rate. PMID- 21699551 TI - Risk factors for fibular fracture after TPLO. AB - OBJECTIVE: To determine (1) risk factors for fibular fracture after tibial plateau leveling osteotomy (TPLO) and (2) if a single postoperative radiographic measurement or measurement ratio of the proximal tibial fragment can be used as a predictor for fibular fracture. STUDY DESIGN: Multivariate retrospective clinical study. ANIMALS: Dogs (n=326) with cranial cruciate ligament rupture that had TPLO (n=355). METHODS: Medical records (January 2004-November 2007) and radiographs of dogs that had TPLO were reviewed. TPLO plate type, distance between tibial plateau and proximal screw, proximodistal tibial plateau fragment length, tibial plateau width, the presence of a fibular drill hole filled with a screw or not, and fibular fractures were recorded. RESULTS: The odds of having a fibular fracture were 10 times greater in dogs with a fibular drill hole than in dogs without a drill hole. The odds of having a fibular fracture were 1.46 times greater for every 4.5 g increase in body weight. Tibial plateau angle (TPA) at the time of reevaluation was larger than the postoperative TPA and TPA increase was larger in dogs with fibular drill holes than without (P<.01) and in dogs with fibular fractures than without (P<.01). CONCLUSION: An unfilled fibular drill hole and increased body weight are risk factors for fibular fracture. PMID- 21699552 TI - Postoperative complications after surgical management of incomplete ossification of the humeral condyle in dogs. AB - OBJECTIVE: To describe incidence and type of postoperative complications in the surgical management of incomplete ossification of the humeral condyle (IOHC) and identify any risk factors associated with development of these complications. STUDY DESIGN: Case series. METHODS: Clinical records of dogs (n=57) that had prophylactic transcondylar screw insertion for treatment of IOHC (79 elbows) at 6 UK referral centers were reviewed. Signalment, presentation, surgical management, postoperative care, and complications were recorded. Postoperative complications were divided into seroma, surgical site infections (SSI) and implant complications. RESULTS: Spaniel breeds and entire males were overrepresented. The overall complication rate was 59.5%. Seroma (n=25) and SSI (24) were the most commonly encountered complications. Implant failure occurred in 2 dogs. Labrador retrievers were at greater risk of developing a postoperative complication than other breeds (P=.03). Increasing bodyweight was a significant risk factor for development of a SSI (P=.03). Placement of the transcondylar screw in lag fashion rather than as a positional screw reduced the incidence of postoperative SSI (P=.007). CONCLUSIONS: Surgical management of IOHC is associated with a high rate of postoperative complications. Placement of the transcondylar screw in lag fashion may limit postoperative complications and warrants further consideration. PMID- 21699553 TI - Investigation of the faecal microbiota of geriatric cats. AB - AIMS: Aim of the study was to investigate the faecal microbiota of geriatric cats, as aging affects the nutrient digestibility and metabolic function of the feline intestine. METHODS AND RESULTS: Twenty geriatric cats were randomly assigned to two groups that were fed different foods. Coriobacteriaceae, Clostridium cluster XIV, bifidobacteria and lactic acid bacteria were the dominant faecal bacterial groups, accounting for c. 40% of total bacteria. Clostridium cluster IX was less predominant (0.5% of total bacteria), while the remaining bacterial populations enumerated only accounted for 0.2% of total bacteria. Highly diverse microbial profiles were demonstrated for geriatric cats with denaturing gradient gel electrophoresis, although a few common bands were evident. Some differences were seen in the feline faecal microbiota between animal groups at the same time or over time for individual animals. However, no obvious clustering based on animal group or sample time was indicated. CONCLUSIONS: Geriatric cats harboured a complex faecal microbiota and c. 41% of total bacteria have been detected with the probes employed. SIGNIFICANCE AND IMPACT OF THE STUDY: First molecular-based study examining faecal microbiota of geriatric felines. Knowledge of the microbiota associated with ageing in cats may allow improved development of foods specific for the needs of senior cats. PMID- 21699554 TI - Case report of clinical salmonellosis by Salmonella Typhimurium that occurred in Portuguese children. AB - AIMS: Aim of this study is to characterize clinical isolates of Salmonella Typhimurium that occurred in Portuguese children on the basis of their virulence and antimicrobial resistance profiles and pulsed-field gel electrophoresis typing and to analyse possible strain relatedness. METHODS AND RESULTS: Different Salmonella serotypes were isolated from clinical cases of salmonellosis that had occurred in two Portuguese hospitals (a total of 259 isolates). All Salm. Typhimurium strains, with the age of the patients known, (total of 26 isolates) were selected for this study. These isolates were characterized for their virulence gene profiles (agfA, iroB, slyA, hin/H2, spv), antimicrobial resistance profiles and investigated for the occurrence of multidrug-resistant Salm. Typhimurium DT 104 by PCR. Salmonella isolates showed high rates of resistance to four or more antibiotics, 100% resistance to sulfadiazine and a high percentage of strains with the resistance profile of Salm. Typhimurium DT 104, two of them with this phage type (determined by PCR). A relationship between some clusters and their resistance and virulence profiles was detected, each cluster having the same profile. CONCLUSIONS: This study showed high-antibiotic resistance of the Salmonella strains investigated, and the presence of multidrug-resistant Salm. Typhimurium DT104 in infections of Portuguese children. SIGNIFICANCE AND IMPACT OF THE STUDY: Study is based on regarding the increase in antibiotic resistance by Salmonella strains isolated from infections in Portuguese children and on the presence of Salm. Typhimurium DT 104 circulating in Portugal. PMID- 21699555 TI - Mineralocorticoid antagonism: a novel way to treat sarcopenia and physical impairment in older people? AB - Dysregulation of the renin-angiotensin-aldosterone system has been associated with a number of age-related pathologies including hypertension, heart failure and chronic kidney disease. More recently, it has been suggested that alterations within the RAAS may contribute to the development of sarcopenia and subsequent decline in physical function. There is growing interest in developing interventions to prevent age-associated decline in muscle function. We postulate that inhibition of the RAAS with the mineralocorticoid antagonist spironolactone may have a role in countering the effects of physical impairment in older people by improving skeletal muscle function. Spironolactone may prevent skeletal myocyte apoptosis, improve vascular endothelial function and enhance muscle contractility by increasing muscle magnesium and sodium-potassium pumps. This article will review the literature underpinning the hypothesis that spironolactone may have a role in maintaining muscle function in older people. PMID- 21699556 TI - An H5N1 highly pathogenic avian influenza virus isolated from a local tree sparrow in Indonesia. AB - The isolation of an H5N1 influenza A virus from a tree sparrow (Passer montanus) captured in East Java, Indonesia in 2010 is reported here. Its hemagglutinin and neuraminidase were genetically similar to those of human isolates from 2006-2007 in Indonesia. The finding of a tree sparrow H5N1 virus that possesses genetically similar surface molecules to those of human viruses highlights the importance of monitoring resident wild birds, as well as migratory birds, for pandemic preparedness. PMID- 21699557 TI - Innate memory phenotype CD4+ T cells play a role in early protection against infection by Listeria monocytogenes in a CD30L-dependent manner. AB - CD30 ligand (CD30L, CD153) is a type II membrane-associated glycoprotein belonging to the tumor necrosis factor family. It is shown here that CD30L knock out (KO) mice are highly susceptible to primary infection with Listeria monocytogenes as assessed by the survival rate. There were significantly more bacteria on day 3 after infection in the peritoneal cavity, spleen and liver of CD30LKO mice than in wild type (WT) mice. The innate function of memory phenotype (MP) CD44+ CD4+ T cells for interferon-gamma production was significantly lower in CD30LKO mice than in WT mice in response to interleukin (IL)-12 and IL-15 in vitro. Depletion of CD4+ T cells by in vivo administration of anti-CD4 mAb at an early stage after infection hampered protection against Listeria. Furthermore, in vivo administration of agonistic anti-CD30 mAb restored protection against Listeria in CD30LKO mice, whereas treatment with soluble mCD30-Ig hampered protection in WT mice. Taken together, it appears that CD30L/CD30 signaling plays an important role in innate MPCD4+ T cell-mediated protection against infection with L. monocytogenes. PMID- 21699558 TI - Detection by using monoclonal antibodies of Yersinia enterocolitica in artificially-contaminated pork. AB - Monoclonal antibodies against Yersinia enterocolitica were produced by fusion of NS-1 mouse myeloma cells with spleen cells of ICR mice immunized with heat-killed and heat-killed plus SDS-mercaptoethanol treated forms of Y. enterocolitica ATCC 27729 alone or mixed with Y. enterocolitica MU. The twenty-five MAbs obtained from five fusions were divided into nine groups according to their specificities to different bacterial strains and species, as determined by dot blotting. The first five groups of MAbs were specific only to Y. enterocolitica, but did not recognize all of the isolates tested. MAbs in groups 6 and 7 reacted with all isolates of Y. enterocolitica tested but showed cross-reaction with some Yersinia spp. and Edwardsiella tarda, especially in the case of group 7. MAbs in groups 8 and 9 reacted with all isolates of Y. enterocolitica and Yersinia spp., as well as other Gram-negative bacteria that belong to the family Enterobacteriaceae. These MAbs recognized Y. enterocolitica antigens with apparent molecular weights ranging from 10-43 kDa by Western blotting, and could detect Y. enterocolitica from ~103-105 colony forming units (CFUs) by dot blotting. The hybridoma clone YE38 was selected for detection of Y. enterocolitica in pork samples which had been artificially-contaminated by inoculation with Y. enterocolitica ATCC 27729 at concentrations of ~104-106 CFUs/g and incubation in peptone sorbitol bile broth at 4 degrees C. Samples were collected and applied on a nitrocellulose membrane for dot blotting with trypticase soy and cefsulodin-Irgasan-novobiocin agars. After 48 hr of incubation, the detection limit was ~102-103 CFU/g by dot blotting. PMID- 21699559 TI - Characterization of the skin fungal microbiota in patients with atopic dermatitis and in healthy subjects. AB - Patients with atopic dermatitis (AD) are highly susceptible to viral, bacterial, and fungal skin infections because their skin is dry and this compromises the barrier function of the skin. Therefore, the skin microbiota of patients with AD is believed to be different from that of healthy individuals. In the present study, the skin fungal microbiota of nine patients with mild, moderate, or severe AD and ten healthy subjects were compared using an rRNA clone library. Fungal D1/D2 large subunit analysis of 3647 clones identified 58 species and seven unknown phylotypes in face scale samples from patients with AD and healthy subjects. Malassezia species were predominant, accounting for 63%-86% of the clones identified from each subject. Overall, the non-Malassezia yeast microbiota of the patients was more diverse than that of the healthy individuals. In the AD samples 13.0 +/- 3.0 species per case were detected, as compared to 8.0 +/- 1.9 species per case in the samples taken from healthy individuals. Notably, Candida albicans, Cryptococcus diffluens, and Cryptococcus liquefaciens were detected in the samples from the patients with AD. Of the filamentous fungal microbiota, Cladosporium spp. and Toxicocladosporium irritans were the predominant species in these patients. Many pathogenic fungi, including Meyerozyma guilliermondii (anamorphic name, Candida guilliermondii), and Trichosporon asahii, and allergenic microorganisms such as Alternaria alternata and Aureobasidium pullulans were found on the skin of the healthy subjects. When the fungal microbiota of the samples from patients with mild/moderate to severe AD and healthy individuals were clustered together by principal coordinates analysis they were found to be clustered according to health status. PMID- 21699560 TI - Diabetes UK evidence-based nutrition guidelines for the prevention and management of diabetes. AB - This article summarizes the Diabetes UK evidence-based guidelines for the prevention of Type 2 diabetes and nutritional management of diabetes. It describes the development of the recommendations and highlights the key changes from previous guidelines. The nutrition guidelines include a series of recommendations for the prevention of Type 2 diabetes, nutritional management of Type 1 and Type 2 diabetes, weight management, management of microvascular and macrovascular disease, hypoglycaemia management, and additional considerations such as nutrition support, end-of-life care, disorders of the pancreas, care of the older person with diabetes, nutrition provided by external agencies and fasting. The evidence-based recommendations were graded using the Scottish Intercollegiate Guidelines Network methodology and, in a small number of topic areas, where strong evidence was lacking, the recommendations were reached by consensus. The Diabetes UK 2011 guidelines place an emphasis on carbohydrate management and a more flexible approach to weight loss, unlike previous guidelines which were expressed in terms of recommendations for individual nutrient intakes. Additionally, the guidelines for alcohol have been aligned to national recommendations. The full evidence-based nutrition guidelines for the prevention and management of diabetes are available from: http://www.diabetes.org.uk/nutrition-guidelines. PMID- 21699562 TI - Messenger RNA processing and its role in diabetes. AB - The past few years have seen huge advances in our understanding of the genetics of diabetes. However, definition of the mechanisms that underpin these observations is less clear. It is now becoming apparent that the processes that mediate these effects are complex and interlinked, and will require consideration of other factors in addition to the DNA sequence. The information in our genes is conveyed to the cellular machinery via an intermediate molecule, RNA. However, we now understand that RNA is not merely a messenger, as RNA-based mechanisms are responsible for a large proportion of the fine-tuning of gene expression and gene regulation. The initial RNA transcript produced undergoes a series of modifications known as RNA processing to generate a mature messenger RNA (mRNA). This includes addition of the 5' cap sequences and the poly-A tail of the mRNA molecule, and removal of its intronic sequences. The exact pattern of mRNA processing may vary from cell type to cell type and differ in response to internal and external stimuli. In this review, using examples from my own work, I will outline how mRNA processing mechanisms can sometimes provide a mode of action for mutations causing monogenic diabetes, and also suggest potential explanations for phenotypic variation in this condition. The potential for mRNA processing to impact on more complex causes of diabetes as well will also be considered. PMID- 21699561 TI - Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy. AB - AIM: We have assessed whether corneal confocal microscopy can be used to detect alterations in nerve morphology following an improvement in risk factors associated with diabetic neuropathy. METHODS: Twenty-five patients with diabetes with mild to moderate neuropathy and 18 control subjects underwent corneal confocal microscopy to quantify corneal nerve fibre (density, branch density, length and tortuosity) at baseline and after 24 months from first visit. This was not planned as an intervention trial and was simply an observational follow-up. RESULTS: At baseline, nerve fibre density (18.8 +/- 2.1 vs. 46.0 +/- 3.8 number/mm(2), P = 0.001), nerve branch density (6.9 +/- 1.5 vs. 35.6 +/- 6.7 number/mm(2), P < 0.0001), nerve fibre length (8.3 +/- 0.9 vs. 13.5 +/- 0.8 mm/mm(2), P < 0.0001) and nerve fibre tortuosity (19.8 +/- 1.6 vs. 22.7 +/- 2.2, P < 0.05) were significantly lower in patients with diabetes than in control subjects. At follow-up, glycaemic control (HbA(1c) 64 +/- 3 to 58 +/- 2 mmol/mol, P = 0.08), total cholesterol (4.9 +/- 0.2 to 4.2 +/- 0.2 mmol/l, P = 0.01), systolic blood pressure (145.8 +/- 4.9 to 135.9 +/- 3.7 mmHg, P = 0.09) and diastolic blood pressure (77.8 +/- 2.7 to 70.8 +/- 2.5, P = 0.03) improved. Nerve fibre density (24.1 +/- 2.0, P = 0.05), nerve branch density (11.1 +/- 1.3, P < 0.01) and nerve fibre tortuosity (22.6 +/- 1.5, P = 0.05) increased significantly, with no change in nerve fibre length (8.4 +/- 0.5). Improvement in nerve fibre density correlated significantly with the improvement in HbA(1c) (r = -0.51, P = 0.008). Via four multifactorial regressions, this confirms the negative association between HbA(1c) and nerve fibre density (P = 0.02). CONCLUSIONS: This study shows that corneal confocal microscopy may be employed in longitudinal studies to assess progression of human diabetic neuropathy and also supports the hypothesis that improvements in risk factors for diabetic neuropathy, in particular HbA(1c) , may lead to morphological repair of nerve fibres. PMID- 21699563 TI - Airborne particulate matter and gaseous air pollutants in residential structures in Lodi province, Italy. AB - The province of Lodi is located in northern Italy on the Po River plain, where high background levels of air pollutants are prevalent. Lodi province is characterized by intensive agriculture, notably animal husbandry. This paper assesses indoor levels of selected airborne pollutants in 60 homes in the province, with special attention to size-fractionated particulate matter (PM). Indoor PM2.5 concentrations are frequently higher than current guidelines. PM10 and nitrogen dioxide also exceed the respective guideline recommendations in some cases, noting that 24-h nitrogen dioxide levels were compared with an annual limit value. All other studied pollutant levels are below current international guidelines. Among indoor PM size fractions, PM0.5 is predominant in terms of mass concentrations corresponding to 57% of PM10 in summer and 71% in winter. A strong seasonal trend is observed for all studied pollutants, with higher levels in winter corresponding to changes in ambient concentrations. The seasonal variation in PM10 is largely due to PM0.5 increase from summer to winter. Summer indoor PM levels are mainly from indoor-generated particles, while particles of outdoor origin represent the main contribution to winter indoor PM levels. On average, indoor concentrations of coarse PM are mostly constituted by indoor-generated particles. PRACTICAL IMPLICATIONS: This study presents a comparison between measured indoor concentrations in the study area and indoor air quality guideline criteria. Accordingly, particulate matter (PM) and NO2 are identified as key pollutants that may pose health concerns. It is also found that indoor PM in residential units is mainly constituted by particles with aerodynamic diameters <0.5 MUm, especially in winter. Risk mitigation strategies should be focused on the reduction in indoor levels of NO2 and ultrafine and fine particles, both infiltrated from outdoors and generated by indoor sources. PMID- 21699565 TI - Mediastinal emphysema after esophageal endoscopic submucosal dissection: its prevalence and clinical significance. AB - AIMS: To assess the prevalence and clinical significance of mediastinal emphysema (ME) after esophageal endoscopic submucosal dissection (ESD). METHODS: A total of 105 patients in whom assessment of ME was prospectively carried out with multi detector row computed tomography (MDCT) after esophageal ESD were included in this study. ME was graded as follows: Grade-0, no ME; Grade-I, bubbles around the esophagus; Grade-II, ME around the thoracic aorta; Grade-III, ME extending around the heart or beyond the mediastinum into the neck; and Grade-IV, ME with pneumothorax or subcutaneous emphysema. MDCT grading was compared with the finding of conventional chest X-ray images (CXR) and clinical symptoms. RESULTS: CXR revealed the presence of ME in 6.6% of the subjects. On MDCT, ME was recognized in 62.9% (Grade-0, 37.1%; I, 46.7%; II, 10.5%; III, 5.7%; and IV, 0%), most (83.8%) being Grade-I or 0. CXR was able to visualize ME of Grade-II or greater. Exposure of the muscularis propria layer and location of the lesion were significant risk factors for development of ME of Grade-II or greater (P = 0.008 and P = 0.03, respectively). The duration of a fever of 37 degrees C or higher was longer and the serum C-reactive protein level was higher in patients with a higher grade of ME. CONCLUSIONS: MDCT revealed the occurrence of ME in 62.9% of the patients who had undergone esophageal ESD, most of which, however, was clinically silent. Exposure of the muscular layer during ESD and location of the lesion were independent risk factors for the development of ME. PMID- 21699566 TI - Factors related to lateral margin positivity for cancer in gastric specimens of endoscopic submucosal dissection. AB - BACKGROUND: With the widespread use of endoscopic submucosal dissection (ESD), more large early gastric cancers (EGC) have become candidates for endoscopic resection. A precise diagnosis of the extent of cancer is indispensable to obtain R0 resection. The aim of the present study was to clarify the factors related to lateral margin positivity for cancer in specimens resected by ESD for EGC. METHODS: Among 1549 EGC treated by ESD during September 2002 to December 2008, lesions that were resected in an en-bloc fashion and resulted in a pathological diagnosis of lateral margin positive (LM+) for cancer, were extracted. The reason for LM+ and pathological characteristics of the lesions were studied and compared to lesions successfully resected with margins negative for cancer. RESULTS: There were three types of lesion that resulted in LM+ resection: lesions with a flat spreading area, lesions with an unexpected nearby lesion, and lesions with lateral extension beneath a non-cancerous mucosa. Compared to lesions resected with margins negative for cancer, diameter of the tumor, recurrent-type cancer, submucosal cancer, and undifferentiated-type cancer were factors significantly related to LM+ resection. CONCLUSION: Other than misdiagnosing a small portion of cancer extension, lateral margin positivity for cancer by ESD could result from a neighboring lesion and an unexpected lateral submucosal cancer extension. To avoid LM+ resection of EGC by ESD, one should be careful of unexpected lateral extension and simultaneous multi-lesions. PMID- 21699567 TI - Morphometry for microvessels in early gastric cancer by narrow band imaging equipped magnifying endoscopy. AB - BACKGROUND AND AIM: Microvascular architecture is a variable characterizing early gastric cancer (EGC) against the background. The aims of the present study were to measure morphological variables of the microvessels and to compare the variables between EGC and the background. METHODS: Narrow band imaging (NBI) equipped magnifying endoscopic pictures from 32 patients with EGC were used. The endoscopic pictures were taken under maximal magnification and processed for the microvessels in an in-focus area after correction of image distortion. The segmented microvessels were numbered for microvessel density (counts/mm(2)) and vascular bed area (% ratio of vascular bed against the region of interest). The microvessels were further processed for a set of skeletonized pixels to count the characteristic points, including end-points, crossing points, branching points and connecting points. RESULTS: Microvessels in cancer were found to have a significantly larger connected point number (20.5 +/- 6.1, P = 0.0002) than those in the background (17.4 +/- 3.9). Numbers of the end-points and branching points were found to be significantly larger in cancer than in the background (end points 3.6 +/- 0.7 for cancer vs 3.3 +/- 0.4 for background, P = 0.0005; branching points 0.8 +/- 0.4 for cancer vs 0.7 +/- 0.2 for background, P = 0.0014). However, microvessel density, vascular bed area and mean diameter did not significantly differ between cancer and the background. CONCLUSION: This finding can be considered to reflect the reported observation of an irregular vascular pattern in gastric cancer. This method may provide a means for microvessel morphometry, regardless of the organ studied. PMID- 21699568 TI - Endoscopic sphincterotomy plus endoprostheses in the treatment of large or multiple common bile duct stones. AB - BACKGROUND AND AIM: Little information is available on the outcomes of endoscopic sphincterotomy plus biliary stent placement without stone extraction as primary therapy at initial endoscopic retrograde cholangiopancreatography (ERCP) in the treatment of large or multiple common bile duct (CBD) stones. The aim of the present study was to study the effect of biliary stents and sphincterotomy as primary therapy for patients with choledocholithiasis. METHODS: Patients with large (>=20 mm) or multiple (>=3) CBD stones were retrospectively studied. The patients underwent endoscopic sphincterotomy and placement of plastic stents in the bile duct without stone extraction at the initial ERCP. Three or more months later, a second ERCP was carried out and stone removal was attempted. Differences in stone size and the largest CBD diameter before and after stenting were compared. Stone clearance and complications were also evaluated. RESULTS: 52 patients were enrolled. After a median of 124 days of biliary plastic stent placement the mean maximal stone diameter decreased from 16.6 mm to 10.0 mm (P < 0.01). The mean CBD diameter also decreased from 15.3 mm to 11.5 mm (P < 0.01). The total stone clearance at second ERCP was 94.2%, only 5.7% of which needed mechanical lithotripsy. COMPLICATIONS: pancreatitis in one (1.9%) at initial ERCP, cholangitis in two (3.8%) after 52 days and 84 days of placement of stent. No complications were recorded at second ERCP. CONCLUSIONS: Biliary plastic stents plus endoscopic sphincterotomy without stone extraction as primary therapy at initial ERCP is a safe and effective method in the management of large or multiple CBD stones. PMID- 21699569 TI - Gastric adenocarcinoma of fundic gland type (chief cell predominant type) treated with endoscopic aspiration mucosectomy. AB - Upper endoscopy screening in an asymptomatic 56-year-old man showed a small, yellowish elevated lesion with a central depression on the posterior wall in the gastric cardia. Biopsy specimens from this lesion were suspicious of carcinoid tumor. We suspected this lesion to be a sporadic gastric carcinoid tumor with a diameter of 5 mm, limited to the mucosal layer. We then performed an endoscopic aspiration mucosectomy with a cap-fitted endoscope. Microscopically, the lesion obtained from the resected specimen was minimally invasive to the submucosa and showed highly differentiated columnar cells in irregularly anastomosing glands. Immunohistology was positive for pepsinogen-I, and MUC6, partially positive for H(+)/K(+)-ATPase, and negative for MUC5AC. In addition, it was positive for synaptophysin and CD56, and negative for chromogranin A. We finally diagnosed the patient as having gastric adenocarcinoma of fundic gland type (chief cell predominant type) with minimal invasion (100 um) to the submucosa. Surveillance endoscopy with biopsy specimens and abdominal computed tomography at 1 year revealed no evidence of tumor recurrence. We herein report this rare case of gastric adenocarcinoma of fundic gland type (chief cell predominant type). PMID- 21699570 TI - Direct peroral cholangioscopy and pancreatoscopy for diagnosis of a pancreatobiliary fistula caused by an intraductal papillary mucinous neoplasm of the pancreas: a case report. AB - Here, we report a case of a pancreatobiliary (PB) fistula caused by an intraductal papillary mucinous neoplasm (IPMN) of the pancreas. The PB fistula was suspected after endoscopic retrograde cholangiopancreatography (ERCP) and diagnosed after direct visualization with a direct peroral cholangioscopy and pancreatoscopy by using an ultra-slim endoscope. No previous reports exist on the precise diagnosis of a PB fistula with direct peroral cholangioscopy and pancreatoscopy. In our case report, a 69-year-old man underwent an ERCP because of a pancreatic head mass and biliary tract obstruction. During ERCP, a fistula between the common bile duct (CBD) and main pancreatic duct (MPD) was suspected. After endoscopic sphincterotomy, we examined both the CBD and MPD with an ultra slim videoendoscope (GIF-N260; Olympus Optical Co, Tokyo, Japan) under direct visualization and biopsy of the mass. The analysis of the biopsy specimen confirmed this mass to be an IPMN of the pancreas. When we examined the CBD, one fistula with copious mucin secretion was identified at the distal CBD. In conclusion, direct peroral cholangioscopy and pancreatoscopy using the ultra-slim endoscope is an efficient tool for diagnosis of PB fistula and pancreatic IPMN. PMID- 21699571 TI - Proceedings of a preliminary workshop at Gastro 2009--narrow banding imaging in digestive endoscopy: clinical outcome of classification (Omed-Jges Educational Meeting held on 22 November, 2009). AB - This publication reports the proceedings of the preliminary meeting of the working party that met at Gastro 2009 during the World Congress in London. The purpose of the preliminary meeting was to consider the areas that require attention, to discuss some of the findings that have already been published and to agree on the way forward. Our reason for publishing these proceedings is to stimulate interest in this venture and to provide the opportunity for input from the endoscopy community worldwide. The next meeting of the working party will be at the JGES Society meeting in Aomori in April 2011 when we hope to prepare a preliminary classification. This will be presented for general discussion and debate at the International Congress of Endoscopy (ICE) in Los Angeles in September 2011. PMID- 21699572 TI - Endoscopic band ligation with double-balloon enteroscopy for treatment of jejunal diverticular bleeding. PMID- 21699573 TI - Antiplatelet agents and bleeding time after endoscopic biopsy of the gastric antrum in Japanese patients. PMID- 21699574 TI - Endoscopic ultrasound-guided transmural drainage of inflammatory peripancreatic fluid collections with a wire-guided triple-lumen needle knife. PMID- 21699575 TI - Endoscopic ultrasound fine-needle aspiration in the diagnosis of intrapancreatic accessory spleen. PMID- 21699576 TI - Mycobacterium lentiflavum ileitis using aspirated intestinal fluid during endoscopy in HIV-infected patient. PMID- 21699579 TI - Report of the international journal of urology editorial board meeting 2011 in Nagoya. PMID- 21699580 TI - Urology in Asia--Bangladesh. PMID- 21699581 TI - Editorial comment to effect of hyaluronic acid on urine nerve growth factor in cyclophosphamide-induced cystitis. PMID- 21699582 TI - Older patients suffer from adverse histopathological features after radical cystectomy. AB - OBJECTIVES: Radical cystectomy (RC) remains a complex procedure in older patients. Perioperative morbidity can be significant and it can represent a limitation for its indication in this population. The aim of the present study was to evaluate the outcomes of RC in elderly patients from a large single-center cohort. METHODS: A total of 447 patients who underwent RC between 1996 and 2009 at our institution were considered. Patients were stratified by age (<=70 vs >70 years). Logistic regression analyses were carried out comparing both groups regarding clinical, perioperative and histopathological findings, as well as complications according to the modified Clavien system and survival. RESULTS: Data of 390 patients were available for the analysis. Of these, 265 (67.9%) versus 125 (32.1%) patients were <70 versus >=70 years-of-age. The median age was 61 and 75 years, respectively. In the elderly, ASA score (P < 0.001), delay between transurethral resection of the bladder (TURBT) and RC (P = 0.004), and number of perioperative blood transfusions (P = 0.002) were significantly higher. Additionally, a clear trend towards higher stages (pT3-4) was observed (P = 0.04). However, complications, and overall and cancer-specific mortality were not increased in older patients. Finally, age was identified as a significant risk factor for upstaging (P = 0.04). Upstaging between TURBT and final histopathology in patients <70 versus >=70 years occurred in 45% versus 58%, respectively (P = 0.03). CONCLUSIONS: RC is equally feasible in older patients without increasing morbidity or mortality. On the contrary, older patients have a higher risk of significant upstaging and advanced stages at final histopathology. These findings suggest that RC should neither be delayed in nor withheld from elderly patients. PMID- 21699583 TI - Editorial comment to single site with multichannel transumbilical laparoscopic implantation of long-term peritoneal dialysis catheters: initial clinical experience of two cases. PMID- 21699584 TI - Maintenance nitrogen requirements of adult female ostriches (Struthio camelus). AB - Successful ostrich farming requires knowledge of the nutritional needs of the birds. While much information is available on the nutritional value of various feed ingredients fed to ostriches, there is little known about their specific nutrient requirements. In this study, we measured the maintenance nitrogen requirements (MNR) of ostriches by nitrogen balance. We predict, based on the previous analysis of nitrogen requirements of various species of birds, that ostriches would have a MNR of 13.6-19.1 g N/day and a total endogenous nitrogen loss (TENL) of 2.8-5.1 g N/day. Three adult female ostriches were fed five pelleted diets containing 0.6-2.3% N [4-14.6% crude protein (CP)], 17.5 kJ/g gross energy (11.4 kJ/g ME) and 30% neutral detergent fibre. Each dietary trial consisted of a 10-day adaptation period, followed by a 5-day total excreta collection period. Body mass (109 +/- 3 kg) and metabolizable energy intake (20.5 +/- 0.7 MJ/day) were unaffected by dietary nitrogen levels. After correcting for excreta nitrogen losses during drying, MNR was calculated to be 481 mg N/kg(0.75) /day or 16.2 g N/day (100 g CP/day), and TENL as 310 mg N/kg(0.75) /day or 10.5 g N/day. Failure to correct for the 10.9 +/- 4.1% average N losses during drying would underpredict the 'true' MNR by 35% and TENL by 46%. Our estimate for MNR of ostriches predicts a dietary requirement of 6.7% protein. Our estimate of TENL was nearly twice that predicted, possibly reflecting the high fibre content of their diet. PMID- 21699585 TI - Effect of supplementation of multi-microbe probiotic product on growth performance, apparent digestibility, cecal microbiota and small intestinal morphology of broilers. AB - The present study investigated the effect of inclusion of multi-microbe probiotic product on growth performance, apparent digestibility of nutrients, cecal microbiota and small intestinal morphology in broilers. Four hundred days-old Ross chicks were randomly allotted to five treatments on the basis of body weight (BW). Each treatment had four replicates of 20 chicks in each. Experimental diets were fed in two phases, starter (day 0-21) and finisher (day 22-35). Dietary treatments were; basal diet without any antimicrobial (NC), basal diet added with 20 mg Avilamycin/kg of diet (PC), 10(7) cfu multi-microbe probiotic/kg of diet (P1), 10(8) cfu multi-microbe probiotic/kg of diet (P2), and 10(9) cfu multi microbe probiotic/kg of diet (P3). Overall BW gain and feed conversion ratio were better (p < 0.05) for treatments PC, P2 and P3 compared with NC and P1, with P1 being better (p < 0.05) than NC. Overall feed intake in treatments PC, P1, P2 and P3 were greater (p < 0.05) than NC. Apparent digestibility of dry matter and crude protein were greater (p < 0.05) in treatments PC, P2 and P3 compared with NC, with P1 being intermediate and not different form NC, PC, P2 and P3. At d 21 and 35, treatments PC, P1, P2 and P3 showed lower (p < 0.05) cecal Clostridium and Coliforms count in relation to NC. Moreover, cecal Clostridium (d 21) and Coliforms (d 21 and 35) count were lower (p < 0.05) in treatment PC in relation to P1; with P2 and P3 being intermediate and not different from PC. However, there was no effect of dietary treatments on cecal total anaerobic bacteria and Bifidobacterium spp. count. The villus height of duodenum in treatment PC was greater (p < 0.05) than NC, with P1, P2 and P3 being intermediate. Villus height of ileum in treatment PC was greater (p < 0.05) than in treatments P1 and NC, whereas it remained comparable among treatments PC, P2 and P3. Villus height to crypt depth ratio of ileum was greater (p < 0.05) for treatment PC, P2 and P3 compared with that in P1 and NC. It is concluded that multi-microbe probiotic inclusion at 10(8) and 10(9) cfu/kg diet had beneficial effects on broilers growth performance, apparent digestibility of nutrients and intestinal morphology and can be used as replacement to antibiotics growth promoter in broiler nutrition. PMID- 21699586 TI - Effect of supplementing Rhodes grass hay (Chloris gayana) with Berchemia discolor or Zizyphus mucronata on the performance of growing goats in Kenya. AB - Twenty growing Small East African goats were used to determine the effects of feeding sun-dried leaves of the browse forages Berchemia discolor and Zizyphus mucronata as supplements to low-quality basal diet, Rhodes grass (Chloris gayana) hay, on voluntary feed intake (VFI), digestibility and growth performance. The grass hay and maize bran were used as a control. The dried leaves were then included at the rates of 15% and 30% of the dry matter intake (DMI). Berchemia discolor had the highest crude protein (CP) content of 195.5 g/kg DM, while Z. mucronata had CP content of 169.5 g/kg DM. The grass hay had the lowest CP content of 50.9 g/kg DM. The browse forages had low fibre content [Neutral detergent fibre (NDF); 257.9-369.5 g/kg DM], while the grass hay had high fibre content (NDF; 713.1 g/kg DM). Goats in the groups supplemented with either of the browse forages had higher total DMI, nitrogen (N) intake and retention and live weight gains than those in the control diet group. The digestibility of DM and organic matter (OM) was not affected by supplementation, but the CP digestibility increased with supplementation. The use of the browse forages as supplements for goats fed on poor-quality basal diets would enhance the performance of the animals. PMID- 21699587 TI - An unblinded randomised controlled trial of preoperative oral supplements in colorectal cancer patients. AB - BACKGROUND: Perioperative oral supplementation has been shown to reduce post operative complications. However, the use of preoperative standard oral supplements in a cohort of colorectal cancer patients has not been evaluated. The present study examined whether preoperative supplements are beneficial in this group. METHODS: In a randomised controlled trial, patients were assigned to receive 400 mL of oral supplement and dietary advice or dietary advice alone. Primary outcome was the number of post-operative complications. One hundred and twenty-five patients were recruited (59 randomised to the intervention group and 66 to the control group) and nine were excluded. RESULTS: In the intervention group, 24 (44%) patients had a complication compared to 26 (42%) in the control group (P = 0.780). In the intervention and control groups, there were eight (15%) and 16 (25%) surgical site infections, respectively (P = 0.140) and seven (13%) and 11 (17%) chest infections, respectively (P = 0.470). Subgroup analysis for hypothesis generation included 83 (71%) weight-losing patients, where there was a significant reduction in surgical site infections using the Buzby definition (P = 0.034), although this was not the case for the Centre for Disease Control definition (P = 0.052). CONCLUSIONS: There was no evidence that preoperative supplements were beneficial in reducing the number of complications, although there may be some benefit for surgical site infections in selected weight-losing preoperative patients. PMID- 21699588 TI - Elemental formula annotation of polar and lipophilic metabolites using (13) C, (15) N and (34) S isotope labelling, in combination with high-resolution mass spectrometry. AB - The unbiased and comprehensive analysis of metabolites in any organism presents a major challenge if proper peak annotation and unambiguous assignment of the biological origin of the peaks are required. Here we provide a comprehensive multi-isotope labelling-based strategy using fully labelled (13) C, (15) N and (34) S plant tissues, in combination with a fractionated metabolite extraction protocol. The extraction procedure allows for the simultaneous extraction of polar, semi-polar and hydrophobic metabolites, as well as for the extraction of proteins and starch. After labelling and extraction, the metabolites and lipids were analysed using a high-resolution mass spectrometer providing accurate MS and all-ion fragmentation data, providing an unambiguous readout for every detectable isotope-labelled peak. The isotope labelling assisted peak annotation process employed can be applied in either an automated database-dependent or a database independent analysis of the plant polar metabolome and lipidome. As a proof of concept, the developed methods and technologies were applied and validated using Arabidopsis thaliana leaf and root extracts. Along with a large repository of assigned elemental compositions, which is provided, we show, using selected examples, the accuracy and reliability of the developed workflow. PMID- 21699589 TI - Cytokinin antagonizes ABA suppression to seed germination of Arabidopsis by downregulating ABI5 expression. AB - Abscisic acid (ABA) and cytokinin are key hormones controlling plant development. How ABA and cytokinin interplay to control the transition from a dry seed into a young seedling remains elusive. Here we undertook a gain-of-function genetic screen to identify ABA-insensitive mutants during seed germination in Arabidopsis using an estradiol-inducible approach. In the presence of estradiol, one of these mutants gim1 (germination insensitive to ABA mutant 1) exhibited an elevated level of cytokinin that was attributed to the estradiol-induced expression of AtIPT8 that encodes an isopentenyltransferase for the biosynthesis of cytokinins. Our data on OE-2 and Com-1 transgenic plants carrying the ectopically expressing AtIPT8 gene indicated that the elevation of cytokinin level was responsible for the ABA-insensitivity of gim1 seed germination. Further analyses on alterations of gene transcriptomes in the gim1 mutant demonstrated that the expression of some ABA-inducible genes, including ABI5, was reduced, and could not be restored by exogenous ABA treatment. Moreover, we also failed to observe the ABA-mediated repression of a family of cytokinin signal transducers and transcription repressors called type-A ARR4, ARR5 and ARR6 in the gim1 seedlings. Further analysis demonstrated that type-A ARR4, ARR5 and ARR6 could negatively regulate ABI5 expression, and the physical interaction of ABI5 and type-A ARR4, ARR5 and ARR6 proteins was detected. In summary, our study suggests that the interaction of ABA and cytokinin during seed germination and seedling growth can be mediated by the interplay of transcriptional regulators in Arabidopsis. PMID- 21699590 TI - A horizontally transferred tRNA(Cys) gene in the sugar beet mitochondrial genome: evidence that the gene is present in diverse angiosperms and its transcript is aminoacylated. AB - Of the two tRNA(Cys) (GCA) genes, trnC1-GCA and trnC2-GCA, previously identified in mitochondrial genome of sugar beet, the former is a native gene and probably a pseudo-copy, whereas the latter, of unknown origin, is transcribed into a tRNA [tRNA(Cys2) (GCA)]. In this study, the trnC2-GCA sequence was mined from various public databases. To evaluate whether or not the trnC2-GCA sequence is located in the mitochondrial genome, the relative copy number of its sequence to nuclear gene was assessed in a number of angiosperm species, using a quantitative real time PCR assay. The trnC2-GCA sequence was found to exist sporadically in the mitochondrial genomes of a wide range of angiosperms. The mitochondrial tRNA(Cys2) (GCA) species from sugar beet (Beta vulgaris), spinach (Spinacea oleracea) and cucumber (Cucumis sativus) were found to be aminoacylated, indicating that they may participate in translation. We also identified a sugar beet nuclear gene that encodes cysteinyl-tRNA synthetase, which is dual-targeted to mitochondria and plastids, and may aminoacylate tRNA(Cys2) (GCA). What is of particular interest is that trnC1-GCA and trnC2-GCA co-exist in the mitochondrial genomes of eight diverse angiosperms, including spinach, and that the spinach tRNA(Cys1) (GCA) is also aminoacylated. Taken together, our observations lead us to surmise that trnC2-GCA may have been horizontally transferred to a common ancestor of eudicots, followed by co-existence and dual expression of trnC1-GCA and trnC2-GCA in mitochondria with occasional loss or inactivation of either trnC GCA gene during evolution. PMID- 21699591 TI - An analysis of pattern of dental injuries after fall accidents in 0- to 2-year old children - does the use of pacifier at the time of injury make a difference? AB - AIM: To assess the relation between type of traumatic injury and use of pacifier at the time of a fall accident in 0- to 2-year olds. MATERIAL AND METHODS: The study draws on data from the database on traumatic dental injuries at the Department of Oral and Maxillofacial Surgery, Copenhagen University Hospital. RESULTS: The study includes 1125 patients <= 2 years of age, representing a total of 1886 injuries. A total of 176 patients had fallen while using a pacifier, whereas 949 children suffered a fall without using a pacifier. In the pacifier group, 11.9% had crown fractures compared with 20.0% of children who had fallen without a pacifier (P = 0.012). Tooth displacement (lateral luxation, extrusion or avulsion) was relatively more frequent in children falling with a pacifier compared to children falling without a pacifier (64.8%vs 54.8%; P = 0.014). Furthermore, soft tissue injury was less frequent among the former (28.4%vs 38.3%; P = 0.013). CONCLUSIONS: Injuries occurring while using a pacifier tend to be tooth displacement rather than fractures. This is in accordance with the theoretical consideration that a blunt impact tends to favour displacement, whereas a sharp impact tends to favour fractures of the hard dental tissues. PMID- 21699594 TI - Optimization of the Gal4-UAS system in an Anopheles gambiae cell line. AB - The development of the bipartite Gal4-UAS system in Anopheles gambiae would improve the functional characterization of genes in this important malaria vector. Towards this aim, we used Gal4 driver plasmids to successfully activate expression of the reporter gene, luciferase, from UAS responder plasmids when cotransfected into an An. gambiae cell line. To optimize Gal4-regulated gene expression in mosquitoes, we compared the efficiency of a series of alternative Gal4 transactivators to drive reporter gene expression from responder plasmids incorporating different numbers of tandemly arrayed Gal4 binding sites or upstream activation sequences (UAS). The results indicated that the native Gal4 is only weakly active in these cells. Modified forms of Gal4, including those carrying minimal VP16 activation domains, as well as a deleted form of Gal4, give up to 20-fold greater activity than the native protein, when used in conjunction with a responder plasmid having 14 UAS repeats. The identification of Gal4-UAS vectors that are efficiently expressed in a mosquito cell line should facilitate the transfer of this versatile expression system to An. gambiae, and potentially to other insects of medical importance. PMID- 21699593 TI - Comparison of transgene expression in Aedes aegypti generated by mariner Mos1 transposition and PhiC31 site-directed recombination. AB - Transgenic mosquitoes generated by transposable elements (TEs) often poorly express transgenes owing to position effects. To avoid these effects, the PhiC31 site-directed recombination system was used to insert transgenes into a locus favourable for gene expression in Aedes aegypti. We describe phenotypes of mariner Mos1 TE and PhiC31 transgenic mosquitoes expressing the enhanced green fluorescent protein (EGFP) reporter in midguts of blood-fed females. Mosquitoes of nine TE-generated lines [estimated transformation frequency (TF): 9.3%] clearly expressed the eye-specific selection marker but only 2/9 lines robustly expressed the EGFP reporter. The piggyBac TE-generated PhiC31 docking strain, attP26, supported recombination with attB site containing donors at an estimated TF of 1.7-4.9%. Using a codon-optimized PhiC31 integrase mutant instead of the 'wild-type' enzyme did not affect TF. Site-directed recombination of line attP26 with an attB-containing donor expressing EGFP from the Ae. aegypti carboxypeptidase promoter produced one transgenic line with blood-fed females expressing the reporter in midgut tissue. Docking strain attP26 also supported robust expression of Flock House virus B2 from the Ae. aegypti polyubiquitin promoter. Our data confirm that eye-specific selection marker expression alone is not a reliable indicator for robust gene-of-interest expression in Ae. aegypti and that the PhiC31 system can ensure predictable transgene expression in this mosquito species. PMID- 21699592 TI - Characterization of the oxysterol-binding protein gene family in the yellow fever mosquito, Aedes aegypti. AB - The oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) are sterol binding proteins that may be involved in cellular sterol transportation, sterol metabolism and signal transduction pathways. Four ORP genes were cloned from Aedes aegypti. Based on amino acid sequence homology to human proteins, they are AeOSBP, AeORP1, AeORP8 and AeORP9. Splicing variants of AeOSBP and AeORP8 were identified. The temporal and spatial transcription patterns of members of the AeOSBP gene family through developmental stages and the gonotrophic cycle were profiled. AeORP1 transcription seemed to be head tissue-specific, whereas AeOSBP and AeORP9 expression was induced by a bloodmeal. Furthermore, over-expression of AeORPs facilitated [(3)H]-cholesterol uptake in Ae. aegypti cultured Aag -2 cells. PMID- 21699595 TI - Host translational control of a polydnavirus, Cotesia plutellae bracovirus, by sequestering host eIF4A to prevent formation of a translation initiation complex. AB - Host translational control is a viral strategy to exploit host cellular resources. Parasitization by some endoparasitoids containing polydnaviruses inhibits the synthesis of specific host proteins at post-transcriptional level. Two host translation inhibitory factors (HTIFs) have been proposed in Cotesia plutellae bracovirus (CpBV). Parasitization by C. plutellae inhibited storage protein 1 (SP1) synthesis of Plutella xylostella at post-transcriptional level. One HTIF, CpBV15beta, inhibited the translation of SP1 mRNA in an in vitro translation assay using rabbit reticulocyte lysate, but did not inhibit its own mRNA. To further analyse the discrimination of target and nontarget mRNAs of the inhibitory effect of HTIF, 5' untranslated regions (UTRs) of SP1 and CpBV15beta mRNA were reciprocally exchanged. In the presence of HTIFs, the chimeric CpBV15beta mRNA that contained SP1 5' UTR was not translated, whereas the chimeric SP1 mRNA that contained CpBV15beta 5' UTR was translated. There was a difference in the 5' UTR secondary structures between target (SP1) and nontarget (CpBV15alpha and CpBV15beta) mRNAs in terms of thermal stability. Different mutant 5' UTRs of SP1 mRNA were prepared by point mutations to modify their secondary structures. The constructs containing 5' UTRs of high thermal stability in their secondary structures were inhibited by HTIF, but those of low thermal stability were not. Immunoprecipitation with CpBV15beta antibody coprecipitated eIF4A, which would be required for unwinding the secondary structure of the 5' UTR. These results indicate that the viral HTIF discriminates between host mRNAs according to their dependency on eIF4A to form a functional initiation complex for translation. PMID- 21699596 TI - DNA methylation in insects: on the brink of the epigenomic era. AB - DNA methylation plays an important role in gene regulation in animals. However, the evolution and function of DNA methylation has only recently emerged as the subject of widespread study in insects. In this review we profile the known distribution of DNA methylation systems across insect taxa and synthesize functional inferences from studies of DNA methylation in insects and vertebrates. Unlike vertebrate genomes, which tend to be globally methylated, DNA methylation is primarily targeted to genes in insects. Nevertheless, mounting evidence suggests that a specialized role exists for genic methylation in the regulation of transcription, and possibly mRNA splicing, in both insects and mammals. Investigations in several insect taxa further reveal that DNA methylation is preferentially targeted to ubiquitously expressed genes and may play a key role in the regulation of phenotypic plasticity. We suggest that insects are particularly amenable to advancing our understanding of the biological functions of DNA methylation, because insects are evolutionarily diverse, display several lineage-specific losses of DNA methylation and possess tractable patterns of DNA methylation in moderately sized genomes. PMID- 21699597 TI - Identification and expression analysis of the genes involved in serotonin biosynthesis and transduction in the field cricket Gryllus bimaculatus. AB - Serotonin (5-HT) modulates various aspects of behaviours such as aggressive behaviour and circadian behaviour in the cricket. To elucidate the molecular basis of the cricket 5-HT system, we identified 5-HT-related genes in the field cricket Gryllus bimaculatus DeGeer. Complementary DNA of tryptophan hydroxylase and phenylalanine-tryptophan hydroxylase, which convert tryptophan into 5-hydroxy L-tryptophan (5-HTP), and that of aromatic L-amino acid decarboxylase, which converts 5-HTP into 5-HT, were isolated from a cricket brain cDNA library. In addition, four 5-HT receptor genes (5-HT(1A) , 5-HT(1B) , 5-HT(2alpha) , and 5 HT(7) ) were identified. Expression analysis of the tryptophan hydroxylase gene TRH and phenylalanine-tryptophan hydroxylase gene TPH, which are selectively involved in neuronal and peripheral 5-HT synthesis in Drosophila, suggested that two 5-HT synthesis pathways co-exist in the cricket neuronal tissues. The four 5 HT receptor genes were expressed in various tissues at differential expression levels, suggesting that the 5-HT system is widely distributed in the cricket. PMID- 21699598 TI - Do photobionts influence the ecology of lichens? A case study of environmental preferences in symbiotic green alga Asterochloris (Trebouxiophyceae). AB - The distribution patterns of symbiotic algae are thought to be conferred mainly by their hosts, however, they may originate in algal environmental requirements as well. In lichens, predominantly terrestrial associations of fungi with algae or cyanobacteria, the ecological preferences of photobionts have not been directly studied so far. Here, we examine the putative environmental requirements in lichenized alga Asterochloris, and search for the existence of ecological guilds in Asterochloris-associating lichens. Therefore, the presence of phylogenetic signal in several environmental traits was tested. Phylogenetic analysis based on the concatenated set of internal transcribed spacer rDNA and actin type I intron sequences from photobionts associated with lichens of the genera Lepraria and Stereocaulon (Stereocaulaceae, Ascomycota) revealed 13 moderately to well-resolved clades. Photobionts from particular algal clades were found to be associated with taxonomically different, but ecologically similar lichens. The rain and sun exposure were the most significant environmental factor, clearly distinguishing the Asterochloris lineages. The photobionts from ombrophobic and ombrophilic lichens were clustered in completely distinct clades. Moreover, two photobiont taxa were obviously differentiated based on their substrate and climatic preferences. Our study, thus reveals that the photobiont, generally the subsidiary member of the symbiotic lichen association, could exhibit clear preferences for environmental factors. These algal preferences may limit the ecological niches available to lichens and lead to the existence of specific lichen guilds. PMID- 21699599 TI - DWI findings of optic nerve ischemia in the setting of central retinal artery occlusion. AB - A 67-year-old African-American male with untreated hypertension, hyperlipidemia, and diabetes mellitus presented with sudden, staggering, progressive loss of vision in his left eye over the course of 8 days. Ophthalmologic and fluorescein angiography exams confirmed central retinal artery conclusion, but revealed no embolus. Magnetic resonance imaging of the brain serendipitously revealed restricted diffusion within the distal left optic nerve, illustrating a more proximal occlusion, which matched the fluorescein angiographic findings. Extensive workup revealed no embolic source, postulating primary hypertension as the underlying etiology. PMID- 21699600 TI - Juvenile psammomatoid ossifying fibroma with visual disturbance: a case report with imaging features. AB - Juvenile psammomatoid ossifying fibroma (JPOF) of the sphenoid sinus is a rare subtype of ossifying fibroma of the sinonasal cavity and facial bone in young adults. Computed tomographic (CT) and magnetic resonance (MR) imaging features of JPOF have been reported, but to our knowledge, positron emission tomography (PET) findings have not been described. We present a 19-year-old woman with right visual disturbance whom we diagnosed with JPOF and describe imaging findings in her case. CT revealed a well-circumscribed fibro-osseous mass surrounding the right optic canal, with expansile, mixed soft tissue and thick bone density. MR imaging showed low signal intensity in the mass on both T(1)- and T(2)-weighted images. [(18)F]fluorodeoxyglucose ([(18)F]FDG) and [(11)C]methyl-L-methionine ([(11)C]Met) PET/CT showed abnormal uptake in the lesion, with standardized uptake values (SUV) of 6.2 ([(18)F]FDG) and 4.6 ([(11)C]Met). Familiarity with the imaging features of this rare disease aids its differentiation from other more familiar lesions to permit appropriately aggressive therapy and improve prognosis. PMID- 21699601 TI - Three-dimensional perfused blood volume computed tomography: attention to technical principles is crucial. PMID- 21699602 TI - Ultrasound characteristics of a glomus jugulare tumor. AB - A 33-year-old woman presented a chronic headache and sore throat on the right side of her body, continuous pulsatile tinnitus with decreasing hearing in the right ear, and recurrent bleeding from the right ear. Computer tomography and magnetic resonance imaging scan depicted a mass in the external ear canal and an enlarged right jugular bulb, which was revealed on duplex ultrasound in the upper portion of the right internal jugular vein. Surgical dissection of the tumor was performed. Pathological study revealed the mass was glomus jugulare tumor. PMID- 21699603 TI - Expansion of corticomedullary junction high-susceptibility region (CMJ-HSR) with aging: a clue in the pathogenesis of Alzheimer's disease? AB - BACKGROUND: Susceptibility-weighted imaging (SWI) microscopy on a 7.0T system demonstrated the corticomedullary junction (CMJ) to be a high-susceptibility region (HSR) in young normal subjects, suggesting that functional alteration of cortical microcirculation could be assessed with this imaging method. METHODS: Focused microscopic studies were performed on the parietal association cortex in 74 normal volunteers (ages 20-79 years; 35 female, 39 male) using a SWI algorithm on a system constructed based on General Electric Signa LX (Waukesha, WI, USA), equipped with a 900-mm clear bore superconducting magnet operating at 7.0T. RESULTS: There was a clear-cut reduction in the thickness of the normal-appearing cortex (cortex, R2 = .5290, P < .001) and expansion of CMJ-HSR (R(2) = .6919, P < .001). The sum of cortex thickness and CMJ-HSR thickness was essentially constant, suggesting that the observed expansion of CMR-HSR with aging likely occurred within the cortical mantle. CONCLUSION: CMJ-HSR expands significantly as a function of aging. Since CMJ-HSR represents a functionally distinct area with relatively slow venous flow, the observed expansion is believed to reflect alteration in cerebral microcirculation with increased age, providing another clue for pathogenesis of Alzheimer's disease. PMID- 21699604 TI - Epidermoid cyst with a metabolite pattern mimicking a brain abscess. A magnetic resonance spectroscopy study. AB - BACKGROUND AND PURPOSE: Intracranial epidermal cysts are benign uncommon lesions. Such lesions arise from an inclusion of an ectodermal element during neural tube closure, in which dermal elements become trapped in the suture line, diploe, meninges, or scalp. Reports have extensively demonstrated the typical magnetic resonance (MR) spectra with the presence of large lactate signals with a virtual absence of healthy brain metabolites. METHODS: A 20-year-old male patient with a parietal lobe brain lesion was studied by magnetic resonance imaging and magnetic resonance spectroscopy in a 1.5-T Philips scanner. RESULTS: The lesion presented atypical MR spectra with presence of alanine (1.46 ppm), lactate (1.31 ppm), and amino acids such as valine, isoleucine (0.97 ppm), and glicine (3.52 ppm). No evidence of normal parenchyma tissue metabolites (N-acetylaspartate, creatine, and choline) or succinate and acetate signals was observed. This spectral pattern was unexpected being proposed the differential diagnosis of brain abscess versus epidermoid cyst. Finally, surgical total excision biopsy confirmed the diagnosis of epidermal cyst. CONCLUSIONS: In this report, we describe a case of an epidermal cyst with an unusual metabolic pattern observed by magnetic resonance spectroscopy mimicking a brain abscess. PMID- 21699605 TI - Brachium pontis stroke revealing neurofibromatosis type-2. AB - NF2 is an autosomal dominant disorder with neuroectodermal dysplasia. Most patients present with characteristic clinical tumors during or beyond the adolescent age group. The diagnosis is mainly clinical. Vasculopathy is rarely associated with NF2. Vascular complication as the presenting symptom in NF-2 is unknown. We report a case of a 2-year-old child with no prior family history of neurofibromatosis presenting with ataxia and brain-stem stroke. PMID- 21699606 TI - Hippocampus: a "forgotten" border zone of brain ischemia. AB - BACKGROUND: Hippocampus is selectively susceptible to ischemic damage and it could be, in some conditions, considered as a border zone of brain ischemia. RESULTS: We illustrate this concept with three cases of hippocampal diffusion weighted imaging (DWI) restrictions secondary to a carotid artery dissection with an ipsilateral fetal posterior cerebral artery (PCA) in two cases and to global brain hypoperfusion consequent to a cardiac arrest in the last case. CONCLUSION: The hypoperfusion induced by a cardiac arrest or an internal carotid dissection with an incomplete circle of Willis promotes hippocampal ischemia in the territories of the anterior choroidal artery and the longitudinal terminal segments of the hippocampal arteries. PMID- 21699607 TI - Evaluation of the regional cerebral blood flow changes during long-term donepezil therapy in patients with Alzheimer's disease using 3DSRT. AB - BACKGROUND: We attempt to evaluate objectively the regional cerebral blood flow (rCBF) changes during long-term donepezil therapy and the relationship between the clinical response and rCBF change in patients with Alzheimer's disease (AD). PATIENTS AND METHODS: Thirty-one patients with mild-to-moderate AD (11 men, 20 female; mean age, 76.2 +/- 6.7 years) were treated with donepezil and underwent brain perfusion single-photon emission computed tomography (SPECT) twice with an interval of 24.5 +/- 4.2 months. The rCBF was calculated using 3-dimensional stereotaxic region of interest template, a fully automated each region of interest technique. We compared the differences in rCBF between baseline and follow-up SPECT studies. Moreover, all patients were divided into stabilized (n = 14) and nonstabilized subgroups (n = 17) based on Mini-Mental State Examination (MMSE) score changes and the changes in rCBF were compared between two subgroups. RESULTS: The mean MMSE score significantly decreased from 20.7 +/- 4.6 at baseline to 16.5 +/- 6.5 after 2 years. The mean rCBF significantly decreased in the widespread brain regions between the baseline and follow-up SPECT studies. The nonstabilized subgroup showed a significant decrease in rCBF of the parietal and temporal segments compared to the stabilized subgroup. CONCLUSION: The progression of cognitive deterioration may be related to rCBF affected by the neuropathologic changes of AD. PMID- 21699608 TI - Congenital external carotid-internal carotid artery anastomosis diagnosed by MR angiography. AB - We present what we believe is the first report of external carotid-internal carotid artery anastomosis, which forms a large arterial ring at the proximal cervical internal carotid artery (ICA). If the small channel of the proximal cervical ICA is occluded, the remaining large channel of the external carotid artery may be diagnosed as a nonbifurcating cervical carotid artery. PMID- 21699609 TI - Neocortical atrophy in Machado-Joseph disease: a longitudinal neuroimaging study. AB - BACKGROUND/PURPOSE: Previous imaging studies in the Machado-Joseph disease (MJD/SCA3) have mostly concentrated on the cerebellum and brainstem. Our goal was to perform a whole brain longitudinal evaluation. METHODS: We included 45 patients and 51 controls, who underwent two brain magnetic resonance imaging and magnetic resonance spectroscopy (mean interval of 12.5 +/- 1.5 months). We used voxel-based morphometry (VBM) and the MarsBar analysis toolbox to extract grey matter density (GMD) values from regions of interest. We used a linear regression model and a general linear model to correlate GMD with clinical markers, and paired t-test for the longitudinal evaluation. RESULTS: We observed decreased GMD (P < .01) at frontal, parietal, temporal and occipital lobes, subcortical grey matter, cerebellum, and brainstem. White matter atrophy was restricted to the cerebellum. Age, CAG, and disease duration predicted GMD in different areas, but age and CAG were the most important predictors. The longitudinal analysis failed to demonstrate changes. Changes in regions other than the cerebellum appeared to contribute significantly to the final International Cooperative Ataxia Rating Scale score. CONCLUSION: We confirmed cortical involvement in MJD/SCA3. The most important factors in predicting GMD were age and CAG. The lack of progression of atrophy may indicate floor effect and/or short duration of follow-up. PMID- 21699610 TI - Stroke following epidural injections--case report and review of literature. AB - BACKGROUND AND PURPOSE: To describe a growing number of cases associated with spinal cord and posterior circulation ischemia as a complication of cervical epidural steroid injection (CESI). METHODS: Case report and review of literature. RESULTS: Sixteen cases of spinal cord and posterior circulation ischemia were analyzed. Two cases had transient symptoms and 10 had long-term sequelae. Four resulted in death. CONCLUSION: Infarction is a rare but potentially devastating complication of CESI. It may occur despite the use of fluoroscopic guidance. PMID- 21699611 TI - MRS findings in cerebral coenurosis due to Taenia multiceps. AB - Cerebral coenurosis due to Taenia multiceps is a rare infection with no case reports from India. A 55-year-old male patient had presented with progressive symptoms of hemiparesis of 1-year duration. Magnetic resonance imaging (MRI) with magnetic resonance spectroscopy (MRS) of the lesion was performed that showed a septated cystic lesion in left parieto-occipital lobe. Multivoxel MRS through the lesion was performed using repetition time of 1500 ms and time to echo of 144 ms at 3T MRI. MRS showed mildly elevated choline (Cho), depressed creatine (Cr), and N-acetyl aspartate (NAA), a large peak of lactate, pyruvate, and acetate peaks. To best of our knowledge, there has been no reported case of in vivo proton MRS finding ever reported. We present MRS findings in this operatively proven case of T. multiceps cyst of the brain. PMID- 21699612 TI - Correlation analysis of quantitative diffusion parameters in ipsilateral cerebral peduncle during Wallerian degeneration with motor function outcome after cerebral ischemic stroke. AB - BACKGROUND AND PURPOSE: To evaluate the time periods of Wallerian degeneration (WD) in which the diffusion parameters of ipsilateral corticalspinal tract (CST) can be used to predict the motor function outcome after brain infarction. METHODS: This retrospective study classified 48 diffusion tensor imaging patients with WD along CST into four groups based on the following time points after stroke onset, Group 1: within the first 2 weeks; Group 2: from 3 to 4 weeks; Group 3: from 5 to 14 weeks; Group 4: after 14 weeks. The apparent diffusion coefficient (ADC), fractional anisotropy (FA), and their ratios (=ipsilateral diffusion value/contralateral value) of cerebral peduncle were evaluated. The correlation between imaging parameters in each group and the motor function scores appraised at 8 months after stroke onset were assessed. RESULTS: There was no evident correlation of FA ratio (rFA) in Group 1 with motor function score (P = .05). The rFA and FA correlated with motor function score in other groups (P < .001 in each group). The ADC ratio and ipsilateral ADC value only showed significant correlation of with motor function score in Group 4 (P= .016 and .029, respectively). CONCLUSIONS: The rFA and ipsilateral FA values after 2 weeks of stroke onset correlate with the motor function outcome. PMID- 21699613 TI - Effect of illiteracy on neuropsychological tests and glucose metabolism of brain in later life. AB - BACKGROUND AND PURPOSE: The acquisition of literacy during childhood may affect the functional organization of the brain. We studied the effects of illiteracy on neuropsychological tests and brain glucose metabolism in later life. METHODS: We recruited 12 illiterate elderly farmers who never attended school and acquired no knowledge of reading or writing. These illiterate subjects were compared with literate subjects in terms of neuropsychological performance and brain glucose metabolism. All subjects were over 65 years and had same socioeconomic environment and normal activities of daily living. RESULTS: Neuropsychological tests indicated that the performance of illiterate subjects was worse than that of literate subjects in all cognitive domains with the exception of forward digit span, tool-use and tool-free gestures, and verbal generation of grocery items. The SPM analysis showed that illiterate subjects had reduced FDG-uptake relative to literate subjects, predominantly in the rostral part of the left superior frontal gyrus and less strikingly in the left rectal gyrus, right cerebellar declive, and right cerebellar tonsil. In contrast, hypermetabolism was found only in the left precuneus. CONCLUSION: These results suggest that reading and writing during childhood is associated with activation of the frontal pole that may play a critical role in complex aspects of human cognition. PMID- 21699614 TI - Ectopic pituitary adenoma associated with an empty sella: a case report and review of the literature. AB - A case of ectopic pituitary adenoma in the sphenoid sinus associated with an empty sella is reported. The coexistence of an ectopic pituitary adenoma and an empty sella is quite rare. The diagnosis was made with an intraoperative finding of the intact dura mater of the sellar floor. In the present case, the hypointense line that coated the pituitary gland was clearly demonstrated on 3 tesla T2-weighted magnetic resonance imaging. The hypointense line is considered to be the pituitary capsule and was critical in diagnosing this rare entity. PMID- 21699615 TI - Portable head computed tomography scanner--technology and applications: experience with 3421 scans. AB - OBJECTIVE: The use of head computed tomography (CT) is standard in the management of acute brain injury; however, there are inherent risks of transport of critically ill patients. Portable CT can be brought to the patient at any location. METHODS: We describe the clinical use of a portable head CT scanner (CereTom: NeuroLogica: Danvers, MA) that can be brought to the patient's bedside or to other locations such as the operating room or angiography suite. RESULTS: Between June of 2006 and December of 2009, a total of 3421 portable CTs were performed. A total of 3278 (95.8%) were performed in the neuroscience intensive care unit (ICU) for an average of 2.6 neuroscience ICU CT scans per day. Other locations where CTs were performed included other ICUs (n = 97), the operating room (n = 53), the emergency department (n = 1), and the angiography suite (n = 2). Most studies were non-contrasted head CT, though other modalities including xenon/CT, contrasted CT, and CT angiography were performed. CONCLUSION: Portable head CT can reliably and consistently be performed at the patient's bedside. This should lead to decreased transportation-related morbidity and improved rapid decision making in the ICU, OR, and other locations. Further studies to confirm this clinical advantage are needed. PMID- 21699616 TI - Use of cone-beam computed tomography to characterize daily urinary bladder variations during fractionated radiotherapy for canine bladder cancer. AB - Urinary bladder cancer is difficult to treat accurately with fractionated radiation therapy (RT) due to daily positional changes of the bladder and surrounding soft-tissue structures. We quantified the daily motion experienced by the canine bladder with patients in dorsal vs. sternal vs. lateral recumbency. We also described the dose distribution for three different planning target volume expansions (5, 10, and 15 mm) for each of the three positions to ensure adequate bladder dose and minimize irradiation of nearby healthy tissues. Analysis was based on data from retrospective daily cone-beam computed tomography (CT) (CBCT) images obtained for positioning of canine patients undergoing routine RT. Organs of interest were contoured on each CBCT data set and the images, along with the contours, were registered to the original planning CT. All measurements were made relative to the planning CT and dosimetric data for the organs of interest was determined using a dose volume histogram generated from sample parallel-opposed beam configuration. There was a wide range in bladder position throughout treatment. The least amount of bladder variation and the lowest rectal dose was with dogs in lateral recumbency. It was also determined that a margin of 10 mm would allow for sufficient dose to be delivered to the bladder while minimizing rectal dose. PMID- 21699617 TI - The use of computed tomographic three-dimensional reconstructions to develop instructional models for equine pelvic ultrasonography. AB - Ultrasonography has gained increased utility to diagnose pelvic fractures in horses; however, internal pelvic contours can be difficult to appreciate from external palpable landmarks. We developed three-dimensional (3D) simulations of the pelvic ultrasonographic examination to assist with translation of pelvic contours into two-dimensional (2D) images. Contiguous 1mm transverse computed tomography (CT) images were acquired through an equine femur and hemipelvis using a single slice helical scanner. 3D surface models were created using a DICOM reader and imported into a 3D modeling and animation program. The bone models were combined with a purchased 3D horse model and the skin made translucent to visualize pelvic surface contours. 3D models of ultrasound transducers were made from reference photos, and a thin sector shape was created to depict the ultrasound beam. Ultrasonographic examinations were simulated by moving transducers on the skin surface and rectally to produce images of pelvic structures. Camera angles were manipulated to best illustrate the transducer-beam bone interface. Fractures were created in multiple configurations. Animations were exported as QuickTime movie files for use in presentations coupled with corresponding ultrasound videoclips. 3D models provide a link between ultrasonographic technique and image generation by depicting the interaction of the transducer, ultrasound beam, and structure of interest. The horse model was important to facilitate understanding of the location of pelvic structures relative to the skin surface. While CT acquisition time was brief, manipulation within the 3D software program was time intensive. Results were worthwhile from an instructional standpoint based on user feedback. PMID- 21699618 TI - Contrast harmonic ultrasound appearance of consecutive percutaneous renal biopsies in dogs. AB - Ultrasound-guided percutaneous renal biopsy may be associated with complications, especially when using larger needles. Contrast harmonic ultrasound increases blood pool echo intensity, enhancing parenchymal lesions. Therefore, contrast harmonic ultrasound is a potential alternative screening method for postbiopsy renal lesions. Renal biopsies were performed using 14 G needles in 11 healthy Beagles, at three occasions: 0 ("Baseline Biopsy"; BB), 4 ("Biopsy 2"; B2), and 6 months ("Biopsy 3"; B3). Ultrasound and contrast harmonic ultrasound of biopsied kidneys were performed approximately 30 min after biopsy (week 0) at BB and B2, and repeated once every week (weeks 1-3) until normal appearance. At B3, only contrast harmonic ultrasound was performed, both immediately and 30-min postbiopsy. Contrast harmonic ultrasound images were reviewed using subjective and semiquantitative methods to describe lesions including number, shape, size, sharpness, echogenicity, and evolution. More renal lesions were detected with contrast harmonic ultrasound (22/22) compared with conventional ultrasound (14/22). The majority appeared at week 0 as hypoechoic tract(s) (27/33), the other (6/ 33) as ill-defined areas or area/tract combination, all having variable size, shape, and echogenicity. Seven tracts had a small subcapsular hematoma. In most kidneys, similar or gradual decrease of size and sharpness, and increased echogenicity was observed until normal appearance occurred at week 1 (1/22), week 2 (18/22), or week 3 (22/22). Two Beagles developed complications. At B3, immediately postbiopsy, tracts were hyperechoic in 9/11 kidneys, becoming hypoechoic again 30 min later. Contrast harmonic ultrasound is a valuable method to evaluate postbiopsy renal lesions in dogs. PMID- 21699619 TI - Magnetic resonance imaging in foals with infectious arthritis. AB - The magnetic resonance (MR) imaging findings of foals with infectious and noninfectious arthritis are described. Six foals with infectious arthritis and three foals with noninfectious arthritis were grouped based on synovial fluid analysis results and examined with radiography and MR imaging. Four out of six foals with infectious arthritis had osseous lesions in MR images indicative of osteomyelitis and only 4/19 lesions were detected on digital radiographs. The three foals with noninfectious arthritis had no osseous lesions in MR images or radiographically. Of the six joints that had osseous lesions detected with MR imaging, three had at least one lytic lesion detected radiographically. Osseous lesions in the epiphysis, metaphysis, and physis appeared in MR images as T2W, short tau inversion recovery, and proton density hyperintense foci with a hypointense halo. The same lesions appeared hyperintense in the 3D RSSG water excitation pulse sequence but lacked a surrounding hypointense halo. Most joints of foals with infectious arthritis had heterogenous signals within the synovial fluid whereas all of the nonseptic joints had homogenous synovial fluid signals. MR imaging appears to be better than radiography in the detection of osseous lesions in foals diagnosed with infectious arthritis and may be a valuable screening test for the presence of osteomyelitis. PMID- 21699620 TI - Comparison of radiographic and scintigraphic findings of the spinous processes in the equine thoracolumbar region. AB - Back pain is common in horses, but there has been no large-scale in-depth study describing radiographic changes of the spinous processes, the relationship between radiographic and scintigraphic findings, and the effect of size, age, breed, or discipline. The objectives were to investigate the frequency of occurrence in horses with perceived back pain of: (1) radiographic alteration of the spinous process structure; (2) increased radiopharmaceutical uptake (IRU) in the spinous processes; and (3) to compare radiographic and scintigraphic findings; and to determine if there was breed, gender, age, bodyweight, height, or work discipline predisposition for close, impinging, or overriding spinous processes. Radiographic and scintigraphic images of the thoracolumbar spine of 604 horses were graded. A radiographic grade for each spinous process (T8-L6) was assigned (0-7). The maximum radiographic grade for each horse was defined as the highest grade assigned to any spinous process; the total radiographic grade was the sum of all grades for each horse. A scintigraphic grade for each spinous process was determined (0-3). The maximum scintigraphic grade for each horse was defined as the highest grade assigned to any spinous process; the total scintigraphic grade was the sum of all grades for each horse. Associations between radiology and scintigraphy and age, gender, breed, height, weight, and discipline were analyzed statistically. The severity of radiographic lesions of the spinous processes was associated with the severity of scintigraphic abnormalities. The caudal thoracic spine (T14-T17) was most frequently affected. There was a significant breed and age effect, with Thoroughbreds and older horses having higher total and maximum radiographic grades. The severity of the lesions of the spinous processes was significantly associated with the presence of osteoarthritis of the articular process joints. It was concluded that there is a wide range of radiographic abnormalities of the spinous processes seen in horses with or without back pain. There is an association between radiographic and scintigraphic grades of the spinous processes. PMID- 21699621 TI - Discrimination of viable Acanthamoeba castellani trophozoites and cysts by propidium monoazide real-time polymerase chain reaction. AB - Even though the advent of quantitative polymerase chain reaction (PCR) has improved the detection of pathogen microorganisms in most of areas of microbiology, a serious limitation of this method may arise from the inability to discriminate between viable and nonviable pathogens. To overcome it, the use of real-time PCR and selective nucleic acid intercalating dyes like propidium monoazide (PMA) have been effectively evaluated for different microorganisms. To assess whether PMA pretreatment can inhibit PCR amplification of nonviable amoeba DNA, Acanthamoeba castellani survival was measured using cell culture and real time PCR with and without PMA pretreatment. Autoclave and contact lens disinfecting solutions were used to inactivate amoebae. After these inactivation treatments, the results indicated that the PMA pretreatment approach is appropriate for differentiating viable A. castellani, both trophozoites and cysts. Therefore, the PMA-PCR approach could be useful as a rapid and sensitive analytical tool for monitoring treatment and disease control, assessing effective disinfection treatments, and for a more reliable understanding of the factors that contribute to the interaction amoeba-pathogenic bacteria. PMID- 21699622 TI - In memoriam: David Marshall Prescott (1926-2011). PMID- 21699623 TI - In vitro dual culture of Polymyxa betae in Agrobacterium rhizogenes transformed sugar beet hairy roots in liquid media. AB - Polymyxa betae is a soil-borne protist and an obligate parasite of sugar beet that transmits the beet necrotic yellow vein virus. Sugar beet hairy roots, transformed by Agrobacterium rhizogenes, were inoculated with surface-sterilized root fragments infected by P. betae. After 10 wk in a liquid medium, typical structures of P. betae were observed in this in vitro system. This first in vitro culture of P. betae in liquid medium will contribute to a better understanding of this protist's biology through providing a way to conserve and produce purified isolates of the protist. PMID- 21699624 TI - Symbiosis, morphology, and phylogeny of Hoplonymphidae (Parabasalia) of the wood feeding roach Cryptocercus punctulatus. AB - Anaerobic cellulolytic flagellate protists of the hindguts of lower termites and the wood-feeding cockroach Cryptocercus are essential to their host's ability to digest lignocellulose. Many have bacteria associated with their surfaces and within cytoplasmic vesicles-likely important symbioses as suggested by molecular and other data. Some of the most striking examples of these symbioses are in the parabasalid family Hoplonymphidae, but little or no data exist on the structural aspects of their symbioses, their relationships with bacteria through different life-cycle stages, or their diversity and phylogenetic relationships in Cryptocercus. We investigated these areas in the hoplonymphid genera Barbulanympha and Urinympha from Cryptocercus punctulatus using light and electron microscopy, and analysis of small subunit rRNA. Microscopy reveals variation in density of bacterial surface symbionts related to life-cycle stage, a glyococalyx possibly important in bacterial adhesion and/or metabolite exchange, and putative viruses associated with bacterial surface symbionts. Patterning of surface bacteria suggests protists emerging from the resistant (dormant) stage are colonized by a small population of bacterial cells, which then divide to cover their surface. Additionally, cytoplasmic protrusions from the protist are covered by bacteria. Phylogenetic analysis rejects the monophyly of Hoplonymphidae, suggesting multiple origins or losses of these bacterial symbioses. PMID- 21699626 TI - Exaggerated neutrophil-mediated reperfusion injury after ischemic stroke in a rodent model of type 2 diabetes. AB - OBJECTIVE: We tested the hypothesis that both chronic and acute inflammatory processes contribute to worse reperfusion injury and stroke outcome in an experimental model of T2DM. MATERIALS AND METHODS: Twelve- to thirteen-week-old male Zucker Diabetic Fatty (ZDF) rats vs. Zucker Lean Controls (ZLC) rats were tested at baseline and after middle cerebral artery occlusion (ischemia) and reperfusion (I-R). Neutrophil adhesion to the cerebral microcirculation, neutrophil expression of CD11b, infarction size, edema, neurologic function, sICAM, and cerebral expression of neutrophil-endothelial inflammatory genes were measured. RESULTS: At baseline, CD11b and sICAM were significantly increased in ZDF vs. ZLC animals (p < 0.05). After I-R, significantly more neutrophil adhesion and cell aggregates were observed in ZDF vs. ZLC (p < 0.05); infarction size, edema, and neurologic function were significantly worse in ZDF vs. ZLC (p < 0.05). CD11b and sICAM-1 remained significantly increased in ZDFs (p < 0.05), and cerebral expression of IL-1beta, GRO/KC, E-selectin, and sICAM were significantly induced in ZDF, but not ZLC groups (p < 0.05) after 2.5 hours of reperfusion. CONCLUSION: Both sides of the neutrophil-endothelial interface appear to be primed prior to I-R, and remain significantly more activated during I-R in an experimental model of T2DM. Consequently, reperfusion injury appears to play a significant role in poor stroke outcome in T2DM. PMID- 21699625 TI - Volutin granules of Eimeria parasites are acidic compartments and have physiological and structural characteristics similar to acidocalcisomes. AB - The structural organization of parasites has been the subject of investigation by many groups and has lead to the identification of structures and metabolic pathways that may represent targets for anti-parasitic drugs. A specific group of organelles named acidocalcisomes has been identified in a number of organisms, including the apicomplexan parasites such as Toxoplasma and Plasmodium, where they have been shown to be involved in cation homeostasis, polyphosphate metabolism, and osmoregulation. Their structural counterparts in the apicomplexan parasite Eimeria have not been fully characterized. In this work, the ultrastructural and chemical properties of acidocalcisomes in Eimeria were characterized. Electron microscopy analysis of Eimeria parasites showed the dense organelles called volutin granules similar to acidocalcisomes. Immunolocalization of the vacuolar proton pyrophosphatase, considered as a marker for acidocalcisomes, showed labeling in vesicles of size and distribution similar to the dense organelles seen by electron microscopy. Spectrophotometric measurements of the kinetics of proton uptake showed a vacuolar proton pyrophosphatase activity. X-ray mapping revealed significant amounts of Na, Mg, P, K, Ca, and Zn in their matrix. The results suggest that volutin granules of Eimeria parasites are acidic, dense organelles, and possess structural and chemical properties analogous to those of other acidocalcisomes, suggesting a similar functional role in these parasites. PMID- 21699628 TI - Successful hip arthroplasty in an adult male with severe factor XI deficiency using Hemoleven(r), a factor XI concentrate. AB - Severe factor XI (sFXI) deficiency is a rare bleeding disorder (RBD). FXI replacement is most often required for surgical hemostasis. Plasma, the sole US treatment option, is often complicated by life-threatening allergic reactions. In such circumstances, the FDA offers a mechanism for institution-industry collaboration to facilitate limited use of replacement products licensed abroad. A 58 years old man with sFXI deficiency, required hip replacement. In the past, he received prophylactic plasma for thyroidectomy and experienced a severe allergic reaction. A single use institutional IND FDA application was initiated in collaboration with LFB (Les Ulis, France) to access Hemoleven(r), a plasma derived FXI concentrate. The application required an investigator-initiated IRB approved protocol for treatment and safety/efficacy monitoring that included: preoperative thrombophilia, FXI inhibitor and pharmacokinetic (PK) evaluations; peri- postoperative administration of <= 4 doses of 10-15 U/kg Hemoleven(r) ; DIC monitoring; postoperative thromboprophylaxis; observation for product efficacy and potential complications. PK study demonstrated the expected 1.8% FXI recovery per U/kg with half-life of 62 hours. Mild D-Dimer elevation was noted 6-9 hours post-infusion. The initial dose (15 U/kg) was administered 15 hours before surgery; subsequently, 3 doses (10 U/kg) were infused every 72 hours. Hemostasis was excellent. No complications were observed. Collaboration allowed for successful patient access to Hemoleven(r) with excellent PK, safety, and efficacy. This case underscores the need for additional efforts to ensure safe and effective licensed replacement therapies for RBD patients. PMID- 21699627 TI - Improvements in nocturnal symptoms with ropinirole prolonged release in patients with advanced Parkinson's disease. AB - BACKGROUND: The 24-week, double-blind Efficacy and Safety Evaluation in PD Adjunct (EASE-PD Adjunct) study randomized patients with advanced Parkinson's disease (PD) suboptimally controlled with levodopa to once-daily placebo or adjunctive ropinirole prolonged release (2-24 mg/day). We investigated the effect of ropinirole prolonged release on nocturnal symptoms in these patients. METHODS: Total and grouped item PD Sleep Scale (PDSS) scores were analyzed post hoc in patients with baseline PDSS total scores <= 100 (troublesome nocturnal symptoms) and >100. RESULTS: Baseline PDSS total score was <= 100 in 93 of 198 (47%) and 89 of 189 (47%) patients receiving ropinirole prolonged release and placebo, respectively; this subgroup displayed evidence at baseline of greater daily awake 'off' time, reduced night-time sleep and worse quality of life, than the PDSS >100 subgroup. Significant improvements with ropinirole prolonged release versus placebo in PDSS score from baseline to Week 24 last observation carried forward were observed for those with baseline PDSS <= 100 [adjusted mean treatment difference 9.0 (95% CI: 2.76, 15.33; P = 0.0051)], but not >100. The PDSS <= 100 subgroup demonstrated treatment benefits for PDSS groupings of motor symptoms on waking and global quality of sleep. Changes in daytime sleepiness were similar between treatment groups. The PDSS >100 subgroup demonstrated significant treatment benefit for global quality of sleep. The unadjusted odds ratio for a positive response with ropinirole prolonged release relative to placebo, for the PDSS <= 100 subgroup, was 2.90 (95% CI: 1.42, 5.95, P = 0.004). CONCLUSIONS: Once daily ropinirole prolonged release improves nocturnal symptoms in patients with advanced PD not optimally controlled with levodopa who suffer troublesome nocturnal disturbance. PMID- 21699629 TI - Clinical experience with Optivate(r), high-purity factor VIII (FVIII) product with von Willebrand factor (VWF) in young children with haemophilia A. AB - Optivate(r) is a high-purity FVIII/VWF product. Its safety, tolerability and efficacy in subjects >= 12 years have been demonstrated. This study was undertaken to assess Optivate(r) in children with haemophilia A. Twenty-five children, including one PUP (previously untreated patient), aged 1-6 years (mean 4.67 years) were treated with Optivate(r) for 26 weeks. Inhibitors were assessed every 3 months and viral status at the study start and end. Prophylaxis was used by five boys and on demand by twenty. The mean number of bleeds in the study was lower compared to the same period pre-study (12.0/child vs. 16.2/child), with fewer bleeds (P < 0.05) in the prophylactic subgroup (8.0/child) compared with the on-demand sub-group (13.4/child). Fourteen major bleeds were reported, all by the on-demand sub-group. Children on prophylaxis were administered a mean of 59.4 infusions; on-demand group 35.1 infusions. A total of 998 infusions were used with a mean dose of 29.1 IU kg-1, and a mean of 38.6 exposure days (ED). Children < 4 years used higher doses, and reported fewer bleeds than older children. Children's Parents/Guardians rated Optivate(r) as helpful or very helpful in controlling 97.5% of bleeds by the prophylactic group, and in 98.5% of the bleeds in the on-demand group. Only 5 of 101 ADRs were treatment-related events (5%), all were mild and non-serious. There were no clinically significant changes in vital signs, viral transmissions or inhibitors. In young children Optivate(r) was well tolerated, safe and efficacious. PMID- 21699630 TI - Hepatitis C virus persistence after sustained virological response to antiviral therapy in patients with or without past exposure to hepatitis B virus. AB - Hepatitis C virus (HCV) and hepatitis B virus (HBV) frequently coinfect and persist long after clinical resolution. We assessed the incidence of low-level (occult) HCV infection (OCI) after sustained virological response (SVR) to standard anti-HCV therapy in individuals with or without past exposure to HBV to recognize whether HBV could influence the prevalence of OCI, HCV level and hepatic histology. Plasma and peripheral blood mononuclear cells (PBMC) were collected from 24 individuals at 6- to 12-month intervals for up to 72 months after SVR. Liver histology was available for nine patients. HCV and HBV genomes were detected with sensitivity <10 genome copies/mL. In individuals without HBV exposure (n = 15), comprehensive analyses of sequential plasma and PBMC samples revealed HCV RNA in all 15 cases (75% plasma and 61% PBMC). In the group with HBV exposure (n = 9), evidenced by circulating anti-HBc and/or HBV DNA detection by a highly sensitive assay, HCV RNA was identified in all cases (83% plasma and 59% PBMC), at levels similar to those in HBV nonexposed individuals. In both groups of patients, most liver biopsies included those reactive for viral genomes displayed low-grade inflammation (8 of 9) and fibrosis (7 of 9). Sequence polymorphisms at the 5'-UTR between PBMC and liver or plasma, as well as circulating HCV virion-like particles, were observed in patients with or without HBV exposure. In conclusion, the prevalence of OCI after SVR is comparable in individuals with or without past exposure to HBV. HCV loads and liver alterations in OCI appear to be unaffected by low-level HBV DNA carriage. PMID- 21699631 TI - Effect of a low concentration of a cationic steroid antibiotic (CSA-13) on the formation of a biofilm by Pseudomonas aeruginosa. AB - AIMS: Cationic steroids like CSA-13 have been designed by analogy with antimicrobial cationic peptides and have bactericidal properties. The purpose of this work was to evaluate the effect of a low concentration (1 mg l(-1)) of CSA 13 on the formation of a biofilm by eight strains of Pseudomonas aeruginosa (four mucoid and four nonmucoid strains) on an inert surface. METHOD AND RESULTS: The biofilm formation was measured with the Crystal Violet method. CSA-13 inhibited the formation of a biofilm by three strains. The zeta potential varied among the strains. The inhibition by the cationic steroid analogue affected the populations of bacteria with the lowest zeta potential. P. aeruginosa bound a fluorescent, more hydrophobic analogue of CSA-13 but there was no correlation between this binding and the inhibition by CSA-13 of biofilm formation. The interaction of CSA 13 with bacteria did not modify their ability to produce rhamnolipids. CONCLUSIONS: A low concentration of CSA-13 inhibits the formation of a biofilm by P. aeruginosa through electrostatic interactions and without affecting the production of rhamnolipids. SIGNIFICANCE AND IMPACT OF THE STUDY: A low, nontoxic concentration of CSA-13 might be beneficial for the prevention of biofilm formation. PMID- 21699632 TI - Global transcriptional responses of Bacillus subtilis to xenocoumacin 1. AB - AIMS: To determine the global transcriptional response of Bacillus subtilis to an antimicrobial agent, xenocoumacin 1 (Xcn1). METHODS AND RESULTS: Subinhibitory concentration of Xcn1 applied to B. subtilis was measured according to Hutter's method for determining optimal concentrations. cDNA microarray technology was used to study the global transcriptional response of B. subtilis to Xcn1. Real time RT-PCR was employed to verify alterations in the transcript levels of six genes. The subinhibitory concentration was determined to be 1 MUg ml(-1). The microarray data demonstrated that Xcn1 treatment of B. subtilis led to more than a 2.0-fold up-regulation of 480 genes and more than a 2.0-fold down-regulation of 479 genes (q <= 0.05). CONCLUSIONS: The transcriptional responses of B. subtilis to Xcn1 were determined, and several processes were affected by Xcn1. Additionally, cluster analysis of gene expression profiles after treatment with Xcn1 or 37 previously studied antibiotics indicated that Xcn1 has similar mechanisms of action to protein synthesis inhibitors. SIGNIFICANCE AND IMPACT OF THE STUDY: These microarray data showed alterations of gene expression in B. subtilis after exposure to Xcn1. From the results, we identified various processes affected by Xcn1. This study provides a whole-genome perspective to elucidate the action of Xcn1 as a potential antimicrobial agent. PMID- 21699633 TI - Linoleate isomerase activity occurs in lactic acid bacteria strains and is affected by pH and temperature. AB - AIMS: To investigate the ability of lactic acid bacteria (LAB) to convert linoleic acid (LA) and alpha-linolenic acid (alpha-LNA) to conjugated linoleic acid (CLA) and conjugated linolenic acid (CLNA), respectively. To assess pH and temperature influences on CLA and CLNA production by Lactobacillus sakei LMG 13558. METHODS AND RESULTS: A screening of 48 LAB yielded one Lactobacillus curvatus, five Lactobacillus plantarum and four Lact. sakei strains displaying linoleate isomerase (LAI) activity. CLNA conversion percentages varied largely (1 60%). CLA conversion, occurring in three strains, was lower (2-5%). The LAI gene sequences of the ten LAI-positive strains shared 75-99% identity with the LAI gene sequence of a Lact. plantarum AS1.555. At pH 6.2, CLA and CLNA production by Lact. sakei LMG 13558 was higher at 30 degrees C than at 20 and 25 degrees C. At pH 5.5 (30 degrees C) or 37 degrees C (pH 6.2), LA was not converted and alpha LNA only slightly converted. CONCLUSIONS: LAB show strain-dependent LAI activity. Production of CLA and CLNA is affected by pH and temperature, as shown for Lact. sakei LMG 13558. SIGNIFICANCE AND IMPACT OF THE STUDY: Several LAB produce CLA and/or CLNA, as shown for Lact. sakei and Lact. curvatus for the first time. These findings offer potential for the manufacturing of fermented functional foods. PMID- 21699634 TI - Liver regeneration is promoted by increasing serotonin content in rat liver with secondary biliary cirrhosis. AB - AIM: Liver cirrhosis clinically shows thrombocytopenia and hypersplenism. Although splenectomy is performed to achieve higher platelet count and better hemostasis, the effect of splenectomy for liver cirrhosis remains unclear. The aim of the present study that was focused on serotonin was to investigate the relationship between splenectomy and liver regeneration in rats with secondary biliary cirrhosis. METHODS: Liver cirrhosis was induced in Sprague-Dawley rats by bile duct ligation (BDL). In addition, splenectomy and administration of ketanserin, which selectively antagonizes 5-HT2A and 2B serotonin receptors, were performed. Three weeks after the interventions, whole blood, plasma, serum, and liver specimens were obtained for the following studies: peripheral platelet counts, hemodynamics of serotonin, histopathological examination, immunostaining, and quantification of mRNA expression. RESULTS: Splenectomy induced thrombocytosis, and increased serotonin content in cirrhotic liver. Stimulation of liver regeneration was indicated by the following parameters: hepatocyte ratio to the entire liver area, Ki67-positive hepatocyte count, and expression of phosphorylated extracellular signal-regulated kinases. This enhancement of liver regeneration was negated by ketanserin. CONCLUSION: Our results showed that splenectomy promoted liver regeneration by increasing serotonin content in liver even under cirrhotic conditions. PMID- 21699635 TI - Effect of prednisone on transforming growth factor-beta1, connective tissue growth factor, nuclear factor-kappaBp65 and tumor necrosis factor-alpha expression in a murine model of hepatic sinusoidal obstruction syndrome induced by Gynura segetum. AB - AIM: One major cause of hepatic sinusoidal obstruction syndrome (HSOS) is the consumption of products containing pyrrolizidine alkaloids (PA). As the use of herbal preparations has increased in China, so has the number of reports of HSOS induced by ingesting PA-containing herbs. The aim of the present study was to investigate the mechanisms by which prednisone and the related factors, transforming growth factor (TGF)-beta1 and connective tissue growth factor (CTGF), prevent liver fibrosis and the pathogenesis of HSOS. METHODS: A murine model of HSOS was created by oral gavage with Gynura segetum with or without prednisone for 30 days. Histological changes in liver tissue were evaluated by a scoring system in tissue slices subjected to hematoxylin-eosin and Masson trichrome staining. Hepatic expression of TGF-beta1 and CTGF mRNA and protein was detected by immunohistochemistry, reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. RT-PCR was also used to detect tumor necrosis factor (TNF)-alpha and nuclear factor (NF)-kappaBp65 mRNA expression. Activation of NF-kappaBp65 was detected by immunohistochemistry. RESULTS: Intervention with prednisone diminished the symptoms of HSOS in mice treated with G. segetum. Prednisone treatment significantly inhibited expression of TGF-beta1 and CTGF mRNA and protein (P < 0.05), and inhibited expression of TNF-alpha and NF kappaBp65 mRNA (P < 0.05) in the liver tissue of HSOS mice. CONCLUSION: Prednisone suppresses the development of liver fibrosis in HSOS mice by inhibiting TGF-beta1, CTGF, TNF-alpha and NF-kappaBp65 expression. PMID- 21699636 TI - Portal blood supply to locally progressed hepatocellular carcinoma after transcatheter arterial chemoembolization: Observation on CT during arterial portography. AB - AIM: To analyze the clinical features of locally progressed hepatocellular carcinoma (HCC) supplied by portal blood (PB) after transcatheter arterial chemoembolization (TACE). METHODS: This cohort included 12 tumors (mean diameter +/- SD, 1.8 +/- 0.8 cm) in 10 patients. PB supply to tumors was judged by CT during arterial portography (CTAP). Imaging data and the clinical course were retrospectively evaluated. RESULTS: Six tumors initially had a small tumor portion supplied by PB. In four tumors, TACE was incomplete because of technical problems. PB supply to recurrent tumors was demonstrated 7.3 +/- 3.7 months after TACE. On follow-up arteriography, all embolized branches were occluded or severely attenuated. Four tumors showing a partial stain were treated by additional TACE (n = 3) or TACE plus radiofrequency (RF) ablation (n = 1), one without staining was treated by RF ablation, and seven were followed-up. All tumors progressed except for one treated by RF ablation. On serial CTAP images, relatively large-diameter portal veins directly entered 11 tumors (91.7%) and connected with intratumoral vessels in nine (75%). During follow-up, partial arterial supply was demonstrated in two tumors and additional TACE was performed. Nine patients died after 31.4 +/- 16.2 months due to tumor progression (n = 8), or hepatic failure (n = 1). One patient has survived for 53 months despite multiple tumors. CONCLUSIONS: PB supply to locally progressed tumor after TACE became apparent on CTAP. Arterial damage by TACE, incomplete TACE, and preexisting tumor tissues supplied by PB may be the main causes. PMID- 21699637 TI - Clinical features and risk factors of extrahepatic seeding after percutaneous radiofrequency ablation for hepatocellular carcinoma. AB - AIM: To clarify the clinical features of and risk factors for extrahepatic seeding, a major complication following radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODS: Our prospective database of 351 nodules in 257 patients with HCC who had undergone RFA between April 2001 and April 2008 was reviewed. The following variables were assessed to identify the risk factors for extrahepatic seeding: age, sex, viral markers, Child-Pugh class, tumor size, number of tumors, RFA indication (tumor size <=3 cm, number of tumors <=3), tumor biopsy prior to RFA, degree of histological differentiation, tumor markers, tumor location, number of sessions, and combined transcatheter arterial chemoembolization. RESULTS: The median follow-up period was 36.5 months, during which the rate of seeding after was 5.1% and the 5-year cumulative seeding rate was 8.4%. The survival rate after neoplastic seeding was 21% at 5 years. Univariate analysis of the risk factors for neoplastic seeding showed significant differences in tumor size, RFA indication, subcapsular lesion, number of sessions, tumor biopsy prior to RFA, and des-gamma-carboxy prothrombin value. However, multivariate analysis showed that the only independent risk factor was RFA indication. CONCLUSIONS: The prognosis of patients with neoplastic seeding was poor. In particular, RFA performed for HCC not satisfying the RFA indication showed a high risk of seeding, and careful consideration should be given to the optimal treatment method and avoiding direct puncture of subcapsular tumors. PMID- 21699638 TI - Clarification of interspousal hepatitis C virus infection in acute hepatitis C patients by molecular evolutionary analyses: Consideration on sexual and non sexual transmission between spouses. AB - AIM: Previous studies evaluating the possibilities of interspousal sexual transmission of hepatitis C virus (HCV) have yielded many conflicting results. The aim of this study was to clarify the source of HCV infection in acute hepatitis C patients using phylogenetic analyses of nucleotide sequences of HCV E1 region. METHODS: Four acute hepatitis C patients were hospitalized in 2002 2007. The diagnosis was based on medical records, laboratory tests including HCV markers, and ultrasonographic examination of the liver. In each spouse of four patients, serum HCV antibody was assayed. In the subjects whose serum HCV antibody was positive, additional tests on HCV viral load and genotype were carried out. Then phylogenetic analyses of nucleotide sequences of partial HCV E1 region (440 nucleotides) of the patients and their spouses were performed. RESULTS: Hepatitis C virus antibody changed from negative to positive in the course of hospitalization and HCV RNA could be detected in every patient. Therefore they were diagnosed as acute hepatitis caused by HCV infection. In every spouse of four patients, HCV antibody and HCV RNA were positive. Three of four couples had the identical genotype and homogeneity of nucleotide sequences of HCV E1 region in three couples ranged from 97.9% to 100%. The results of phylogenic analyses suggested that interspousal HCV infection occurred in the three couples. CONCLUSION: In conclusion, interspousal infection might be one of the important sources of acute HCV infection in Japan. The usefulness of phylogenetic analysis of nucleotide sequences of HCV E1 region for clarifying interspousal HCV infection was validated. PMID- 21699639 TI - Evaluation of a combined blood glucose monitoring and gaming system (Didget(r)) for motivation in children, adolescents, and young adults with type 1 diabetes. AB - The purpose of this study was to assess the performance and acceptability of a blood glucose meter coupled with a gaming system for children, adolescents, and young adults with type 1 diabetes. During an in-clinic visit, duplicate blood samples were tested by subjects (N = 147; aged 5-24 yr) and health care providers (HCPs) to evaluate the accuracy and precision of the Didget(r) system. Subjects' meter results were compared against Yellow Springs Instruments (YSI) reference results and HCP results using least squares regression and error grid analyses. Precision was measured by average within-subject and within-HCP coefficient of variation (CV). During the home-use component of this study, subjects (n = 58) tested their blood glucose at least two to three times daily for 3-5 d to evaluate routine use of the system. Subjects' meter results showed significant correlations with both YSI (r(2) = 0.94; p < 0.001 for regression slope) and HCP results (r(2) = 0.96; p < 0.001). Average within-subject and within-HCP CVs were 5.9 and 7.2%, respectively. Overall satisfaction was assessed by subjects, their parents or guardians, and HCP surveys. Subject satisfaction with the Didget(r) system was good to excellent; most subjects found the system easy to use, motivating, and helpful for building good blood glucose monitoring habits. Most HCPs agreed that the system fulfilled a need in diabetes management. In conclusion, the Didget(r) system was precise and clinically accurate in the hands of children, adolescents, and young adults with type 1 diabetes. PMID- 21699640 TI - Analysis of a hyper-diverse seed dispersal network: modularity and underlying mechanisms. AB - Mutualistic interactions involving pollination and ant-plant mutualistic networks typically feature tightly linked species grouped in modules. However, such modularity is infrequent in seed dispersal networks, presumably because research on those networks predominantly includes a single taxonomic animal group (e.g. birds). Herein, for the first time, we examine the pattern of interaction in a network that includes multiple taxonomic groups of seed dispersers, and the mechanisms underlying modularity. We found that the network was nested and modular, with five distinguishable modules. Our examination of the mechanisms underlying such modularity showed that plant and animal trait values were associated with specific modules but phylogenetic effect was limited. Thus, the pattern of interaction in this network is only partially explained by shared evolutionary history. We conclude that the observed modularity emerged by a combination of phylogenetic history and trait convergence of phylogenetically unrelated species, shaped by interactions with particular types of dispersal agents. PMID- 21699641 TI - A conceptual framework for the evolution of ecological specialisation. AB - Ecology Letters (2011) 14: 841-851 ABSTRACT: Ecological specialisation concerns all species and underlies many major ecological and evolutionary patterns. Yet its status as a unifying concept is not always appreciated because of its similarity to concepts of the niche, the many levels of biological phenomena to which it applies, and the complexity of the mechanisms influencing it. The evolution of specialisation requires the coupling of constraints on adaptive evolution with covariation of genotype and environmental performance. This covariation itself depends upon organismal properties such as dispersal behaviour and life history and complexity in the environment stemming from factors such as species interactions and spatio-temporal heterogeneity in resources. Here, we develop a view on specialisation that integrates across the range of biological phenomena with the goal of developing a more predictive conceptual framework that specifically accounts for the importance of biotic complexity and coevolutionary events. PMID- 21699642 TI - Plasmodium falciparum soluble extracts potentiate the suppressive function of polyclonal T regulatory cells through activation of TGFbeta-mediated signals. AB - Increased numbers of T regulatory cells (Tregs), key mediators of immune homeostasis, were reported in human and murine malaria and it is current opinion that these cells play a role in balancing protective immunity and pathogenesis during infection. However, the mechanisms governing their expansion during malaria infection are not completely defined. In this article we show that soluble extracts of Plasmodium falciparum (PfSEs), but not equivalent preparation of uninfected erythrocytes, induce the differentiation of polyclonally activated CD4(+) cells in Tregs endowed with strong suppressive activity. PfSEs activate latent TGFbeta bound on the membrane of Treg cells, thus allowing the cytokine interaction with TGFbeta receptor, and inducing Foxp3 gene expression and TGFbeta production. The activation of membrane-bound latent TGFbeta by PfSEs is significantly reduced by a broad-spectrum metalloproteinases inhibitor with Zn(++) -chelating activity, and completely inhibited by the combined action of such inhibitor and antibodies to a P. falciparum thrombospondin-related adhesive protein (PfTRAP). We conclude that Pf-Zn(++) -dependent proteinases and, to a lesser extent, PfTRAP molecules are involved in the activation of latent TGFbeta bound on the membrane of activated Treg cells and suggest that, in malaria infection, this mechanism could contribute to the expansion of Tregs with different antigen specificity. PMID- 21699644 TI - Multicenter evaluation of the prognostic value of pT0 stage after radical cystectomy due to urothelial carcinoma of the bladder. AB - OBJECTIVE: *To evaluate the characteristics and long-term outcome of patients with pT0 stage after radical cystectomy (RC) for urothelial carcinoma of the urinary bladder (UCB). PATIENTS AND METHODS: *Clinical and pathological records of 2403 patients treated with RC for UCB were collected in a multi-institutional database. *The patients met the following criteria: clinical tumour stage cTa cT2, cN0, cM0, no neoadjuvant chemotherapy or radiotherapy. *Overall (OS) and cancer-specific survival rates (CSS) were calculated for the various clinical tumour stages in relation to their corresponding pathological tumour stage in the RC sample. *Further to this, a multivariable prediction model was developed based on the available clinical data to estimate the probability of tumour stage pT0. RESULTS: *The mean follow-up was 53 months and 132 patients (5.5%) were stage pT0. *Patients with stage cT2-pT0 had a 5-year CSS of 87% vs 69% for cT2-pT2 (P= 0.012) and 57% for cT2-pT+ (P < 0.001). *In a multivariable Cox-model, stage pT0 led to a significant reduction of cancer-specific mortality (hazard ratio0.27; 95% confidence interval 0.12-0.61). *A logistical regression model identified clinical tumour stage (advantage for non-invasive stages) and transurethral resection of the urinary bladder (TURB) time frame (advantage for more recent surgery) as independent predictors for stage pT0. CONCLUSIONS: *In muscle invasive clinical tumour stages, patients with pathological tumour stage pT0 form a subgroup showing a significantly better CSS. *A radical TURB is, assumedly, not causative of this improved survival rate, but rather it is that individual tumour characteristics allow for complete tumour eradication through the TURB procedure. *A TURB with R0 resection is, as such, only a sign of a better tumour prognosis. PMID- 21699645 TI - Usefulness of prostate-specific antigen (PSA) rise as a marker of prostate cancer in men treated with dutasteride: lessons from the REDUCE study. AB - OBJECTIVES: To determine if dutasteride-treated men can be monitored safely and adequately for prostate cancer based on data from the Reduction by Dutasteride in Prostate Cancer Events (REDUCE) study. To analyse whether the use of treatment specific criteria for repeat biopsy maintains the usefulness of prostate-specific antigen (PSA) level for detecting high grade cancers. PATIENTS AND METHODS: The REDUCE study was a randomized, double-blind, placebo-controlled investigation of whether dutasteride (0.5 mg/day) reduced the risk of biopsy-detectable prostate cancer in men with a previous negative biopsy. The usefulness of PSA was evaluated using biopsy thresholds defined by National Comprehensive Cancer Network guidelines in the placebo group and any rise in PSA from nadir (the lowest PSA level achieved while in the study) in the dutasteride group. The number of cancers detected on biopsy in the absence of increased/suspicious PSA level as well as sensitivity, specificity, positive predictive value and negative predictive value for high grade prostate cancer detection were analysed by treatment group. Prostate cancer pathological characteristics were compared between men who did and did not meet biopsy thresholds. RESULTS: Of 8231 men randomized, 3305 (dutasteride) and 3424 (placebo) underwent at least one prostate biopsy during the study and were included in the analysis. If only men meeting biopsy thresholds underwent biopsy, 25% (47/191) of Gleason 7 and 24% (7/29) of Gleason 8-10 cancers would have been missed in the dutasteride group, and 37% (78/209) of Gleason 7 and 22% (4/18) Gleason 8-10 cancers would have been missed in the placebo group. In both groups, the incidence of Gleason 7 and Gleason 8-10 cancers generally increased with greater rises in PSA. Sensitivity of PSA kinetics was higher and specificity was lower for the detection of Gleason 7-10 cancers in men treated with dutasteride vs placebo. Men with Gleason 7 and Gleason 8-10 cancer meeting biopsy thresholds had greater numbers of positive cores, percent core involvement, and biopsy cancer volume vs men not meeting thresholds. CONCLUSION: Using treatment-specific biopsy thresholds, the present study shows that the ability of PSA kinetics to detect high grade prostate cancer is maintained with dutasteride compared with placebo in men with a previous negative biopsy. The sensitivity of PSA kinetics with dutasteride was similar to (Gleason 8-10) or higher than (Gleason 7-10) the placebo group; however, biopsy decisions based on a single increased PSA measurement from nadir in the dutasteride group resulted in a lower specificity compared with using a comparable biopsy threshold in the placebo group, indicating the importance of confirmation of PSA measurements. PMID- 21699646 TI - A dangerous entanglement. AB - Entrapment of guidewires by inferior vena cava filters can occur during the blind insertion of a jugular or a subclavian central venous catheter. Recently, few case reports have been published in the radiology literature. In addition, others have described endovascular techniques aimed at removing entrapped guidewires, avoiding the possibility of vena cava rupture. Given that a temporary hemodialysis venous catheter is frequently used as a first access, the possibility of entrapping the dialysis catheter guidewire should not be neglected. PMID- 21699648 TI - Maldynia as a moral judgment? PMID- 21699650 TI - The business of pain medicine: the present mirrors antiquity. AB - The practice of pain medicine is often considered a fledgling field, as are the economic, business, and related ethical issues associated with providing these services. This article first traces the history of pain care and its relationships to industry and business, as well as the impact of government regulations over the ages. The authors challenge the view that the commonly discussed health care issues facing pain medicine are new by tracing the business and regulatory-related antecedents of pain care practice from the first through 21st century. The controversies associated with the practice of delivering pain related health care services in an ethical manner are discussed with specific reference to the early work of clinicians, health care activists, and policy makers. The early activities of noteworthy individuals such as Pliny the Great, Hua T'o, John Locke, Benjamin Franklin, Oliver Wendell Holmes Sr., William Morton, Henry and William James, Heinrick Dresser, and other recent health care activists are reviewed. Issues of practitioner liability and regulatory restrictions on practice are also discussed in a historical context. The authors conclude that familiar ethical dilemmas commonly arose in past centuries, and history may be repeating itself with respect to the concerns now being discussed within our field. These arguments are reflected against the pain medicine Ethics Charters of the American Academy of Pain Medicine throughout the document. Finally, we outline the challenges for the present and future. With an understanding of these eight historical events as a backdrop, we may be at an opportune time to better address these issues in a manner that could provide the most effective pain care in our society. PMID- 21699651 TI - Brachial plexus entrapment of interscalene nerve catheter after uncomplicated ultrasound-guided placement. AB - We report on the case of an entrapped interscalene nerve catheter in a 46-year old male undergoing left shoulder arthroscopic lysis of adhesions for a frozen shoulder. The catheter was placed under ultrasound guidance without any apparent complications. The continuous interscalene nerve block was successfully used as the primary anesthetic and for postoperative pain management. Upon attempted catheter removal, the patient experienced severe pain and paresthesias. Fluoroscopy revealed possible brachial plexus involvement, and surgery was performed to extract the catheter, which had become hooked and entrapped around the C5 nerve root and sheath. PMID- 21699652 TI - Molecular basis of Bernard-Soulier syndrome in 27 patients from India. AB - BACKGROUND: Bernard-Soulier syndrome (BSS) is an extremely rare (1:1 million) bleeding disorder of platelet adhesion, caused by defects in the glycoprotein (GP)Ib/IX/V complex. PATIENTS AND METHODS: The diagnosis in 27 patients was based on low platelet count, presence of giant platelets and aggregometry studies. Flow cytometry to assess the surface GPIb/IX/V complex showed reduced (7.7-57%) expression. gDNA was screened for mutations in the GPIBA, GPIBB, GP9 genes using PCR-conformation sensitive gel electrophoresis (CSGE). RESULTS: Thirteen different disease-causing mutations, including missense (54%), frameshifts (38%) and nonsense (8%) mutations, were identified in 27 patients. Eleven of them were novel including five novel frameshifts (GPIbalpha: p.Gln97_98fsX113, p.Pro402_403fsX52; GPIbbeta: p.Arg17fsX14; GPIX: p.Gly24fsX43, p. Pro130fs, a nonsense mutation (GPIX, p.94, Gln>X) and five novel missense mutations (GPIbalpha: p.492, Tyr>His; GPIbbeta: p.65, Pro>Arg, p.129, Gln>His, p.132, Leu>Pro; GPIX: p.55, Phe>Cys). Interestingly, four common mutations, Cys8Arg (n = 6) and Phe55Ser (n = 2), Phe55Cys (n = 2) in GPIX and a novel 22-bp deletion in the GPIBB gene predicting p.Arg17fsX 14 (n = 10) were seen in 20 patients. CONCLUSION: The molecular data presented here is the largest series of BSS patients to be reported so far, adding significantly to the mutation database of this condition and also useful for its genetic diagnosis in India. PMID- 21699653 TI - Acceptance of oral health promotion programmes by dental hygienists and dental nurses in public dental service. AB - OBJECTIVES: The aim of this study was to analyse how dental hygienists and in service trained dental nurses accepted new health promotion programmes, how did they experience them in practice, and how did these programmes affect their attitudes to work. METHODS: The subjects were all the dental hygienists and in service trained dental nurses (n = 28) involved in health promotion of small children. Education and written instructions on two new programmes had been given to the professionals in two areas of Vantaa and those in the third area used the routine programme. The transtheoretical model (TTM) was selected as the theoretical framework for counselling. A structured questionnaire of 31-35 items was sent to all subjects. Independent samples Mann-Whitney U and Fisher's exact tests were used as statistical methods. RESULTS: The response rate was 89%. All respondents felt that the work they had carried out had always been important during their working career. Twenty-one of 25 respondents reported that the instructions and education were suitable for oral health promotion. The respondents within the new programmes felt they had advanced more as health professionals (P = 0.020) and acquired more confidence from the education (P = 0.018) compared with the routine programme. CONCLUSIONS: The new programmes for small children were well accepted by the dental hygienists and the in-service trained dental nurses, and the majority of them gained some new practices for their work. PMID- 21699654 TI - Abstracts of the 10th Congress of the European Association for Clinical Pharmacology and Therapeutics. June 26-29, 2011. Budapest, Hungary. PMID- 21699655 TI - Effects of levosimendan on cardiac gene expression profile and post-infarct cardiac remodelling in diabetic Goto-Kakizaki rats. AB - The calcium sensitizer levosimendan has shown beneficial effects on cardiac remodelling in spontaneously diabetic Goto-Kakizaki (GK) rats 12 weeks after experimental myocardial infarction (MI). However, the short-term effects and the cellular mechanisms remain partially unresolved. The aim was to study the effects of oral levosimendan treatment on the myocardial gene expression profile in diabetic GK rats 4 weeks after MI/sham operation. MI was induced to diabetic GK rats. Twenty-four hours after surgery, rats were randomized into four groups: MI, MI +levosimendan (1 mg/kg/day), sham-operated and sham-operated +levosimendan. Cardiac function and histology were examined 1, 4 and 12 weeks after MI. The effects of levosimendan on cardiac gene expression profile were investigated by microarray analysis. Levosimendan ameliorated post-infarct heart failure and cardiac remodelling. Levosimendan altered the expression of 264 of MI and sham rats, respectively; these changes were associated with alterations in two Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Levosimendan up-regulated 3 genes in the renin-angiotensin system pathway [angiotensin receptor 1 (Agtr1), chymase 1 (Cma1) and thimet oligopeptidase 1 (Thop1)] and down-regulated 3 genes in the glycerolipid metabolism pathway [diacylglycerol kinase gamma (Dgkg), carboxyl ester lipase (Cel) and Diacylglycerol kinase iota]. Levosimendan induced opposite effects on the gene expression of pleckstrin homology (PH) domain containing family f (Plekhf1), carboxymethylenebutenolidase homologue (Cmbl) (up regulation) and hydroxyprostaglandin dehydrogenase 15 (Hpgd) (down-regulation) as compared with MI. MI versus sham affected 420 genes and was associated with alterations in 12 KEGG pathways. The beneficial effects of levosimendan on cardiac hypertrophy in sham-operated GK rats was associated with altered expression in 522 genes and associated with three KEGG pathways including purine metabolism, cell cycle pathway and pathways in cancer. Levosimendan protects against post-infarct heart failure and cardiac remodelling. Analysis of the cardiac transcriptome revealed several genes that are regulated by levosimendan. These genes may represent novel drug targets for heart failure and diabetic cardiomyopathy. PMID- 21699656 TI - Effects of memantine, a non-competitive N-methyl-D-aspartate receptor antagonist, on genomic stability. AB - Memantine is an aminoadamantane drug useful in neurodegenerative diseases, with beneficial effects on cognitive functions. Some studies have shown that memantine protects brain cells, thereby decreasing glutamate excitotoxicity. This study evaluated the genotoxic/antigenotoxic and mutagenic effects of memantine in CF-1 mice, following standardized protocols. Memantine was administered i.p. at 7.5, 15 or 30 mg/kg for three consecutive days. Blood and brain samples were collected to assess DNA damage using the alkaline comet assay. The mutagenic effect was assessed using the bone marrow micronucleus test. In addition, possible antioxidant effects were evaluated measuring the survival of Saccharomyces cerevisiae yeast strains [wild-type (WT) and isogenic mutants lacking superoxide dismutase] to cotreatment of memantine plus hydrogen peroxide. Memantine decreased DNA oxidative damage mainly in brain tissue. This antigenotoxic effect corroborated an increase observed in the survival of S. cerevisiae WT strain against hydrogen peroxide-induced damage. Furthermore, memantine did not increase the micronucleus frequency. The overall results indicate that memantine showed no mutagenic activity, did not cause DNA damage in the blood and brain tissues and showed antigenotoxic effects in brain tissue. PMID- 21699657 TI - Prenatal exposure to carbon black (printex 90): effects on sexual development and neurofunction. AB - Maternal pulmonary exposure to ultrafine particles during pregnancy may affect the health of the child. Developmental toxicity of carbon black (Printex 90) nanoparticles was evaluated in a mouse model. Time-mated mice were intratracheally instilled with Printex 90 dispersed in Millipore water on gestation days (GD) 7, 10, 15 and 18, with total doses of 11, 54 and 268 MUg Printex 90/animal. The female offspring prenatally exposed to 268 MUg Printex 90/animal displayed altered habituation pattern during the Open field test. PMID- 21699658 TI - Antinociception and anti-inflammation induced by simvastatin in algesiometric assays in mice. AB - Statins, belonging to a well-known drug class used for lowering cholesterol through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, also have other pleiotropic properties, such as anti-inflammatory action. The purpose of this study was to evaluate the antinociceptive and anti inflammatory effects of simvastatin in five models of nociceptive behaviour. Oral gavage administration of simvastatin induced a dose-dependent inhibition of nociception for 1 day in the acetic acid writhing (ED(50) = 5.59 +/- 0.07), tail flick (ED(50) = 112.96 +/- 8.00), hot-plate (ED(50) = 134.87 +/- 2.20), formalin hind paw (ED(50) = 19.86 +/- 1.12 in phase I and 23.30 +/- 2.05 in phase II) and orofacial formalin (ED(50) = 5.54 +/- 2.74 in phase I and 11.48 +/- 1.88 in phase II) tests. However, after 3 days, the values were in the acetic acid writhing (ED(50) = 6.14 +/- 0.51), tail-flick (ED(50) = 154 +/- 8.88), hot-plate (ED(50) = 136.14 +/- 2.94), formalin hind paw (ED(50) = 15.93 +/- 0.42 in phase I and 17.10 +/- 1.80 in phase II) and orofacial formalin (ED(50) = 6.79 +/- 0.66 in phase I and 5.80 +/- 1.49 in phase II) tests. This study demonstrated the antinociceptive and anti-inflammatory activities of simvastatin in five models of tonic or phasic pain. These actions seem to be related to the inhibition of cytokine and prostanoid release and stimulation of nitric oxide synthesis. A possible clinical role of simvastatin could be related to the potentially beneficial effects in the neuropathic pain, and by their pleiotropic properties, they could play a clinical role in anti-inflammatory disease. PMID- 21699659 TI - Priapism and sickle-cell anemia: diagnosis and nonsurgical therapy. AB - INTRODUCTION: Priapism describes a persistent erection lasting longer than 4 hours. Ischemic priapism and stuttering priapism are phenotypic manifestations of sickle-cell disease (SCD). AIMS: To define the types of priapism associated with SCD, to address pathogenesis, and to recommend best practices. SOURCES: Literature review and published clinical guidelines. SUMMARY OF FINDINGS: Priapism is a full or partial erection that persists more than 4 hours. There are three kinds of priapism: ischemic priapism (veno-occlusive, low flow), stuttering priapism (recurrent ischemic priapism), and nonischemic priapism (arterial, high flow). Ischemic priapism is a pathologic phenotype of SCD. Ischemic priapism is a urologic emergency when untreated priapism results in corporal fibrosis and erectile dysfunction. The recommended treatment for ischemic priapism is decompression of the penis by needle aspiration and if needed, injection (or irrigation) with dilute sympathomimetic drugs. Stuttering priapism describes a pattern of recurring unwanted painful erections in men with SCD. Patients typically awaken with an erection that persists for several hours and becomes painful. The goals of managing stuttering ischemic priapism are: prevention of future episodes, preservation of erectile function, and balancing the risks vs. benefits of various treatment options. The current molecular hypothesis for stuttering priapism in SCD proposes that insufficient basal levels of phosphodiesterase type-5 are available in the corpora to degrade cyclic guanosine monophosphate (cGMP). Nocturnal erections result from normal neuronal production and surges of cGMP. In the context of SCD stuttering priapism, these nocturnal surges in cGMP go unchecked, resulting in stuttering priapism. CONCLUSIONS: Considering the embarrassing nature of the problem and the dire consequences to erectile function, it is important to inform patients, parents, and providers about the relationship of SCD to prolonged painful erections. Prompt diagnosis and appropriate medical management of priapism are necessary to spare patients surgical interventions and preserve erectile function. PMID- 21699660 TI - Orgasm-associated urinary incontinence and sexual life after radical prostatectomy. AB - INTRODUCTION: Involuntary release of urine during sexual climax, orgasm associated urinary incontinence, occurs frequently after radical prostatectomy. We know little about its prevalence and its effect on sexual satisfaction. AIM: To determine the prevalence of orgasm-associated incontinence after radical prostatectomy and its effect on sexual satisfaction. METHODS: Consecutive series, follow-up at one point in calendar time of men having undergone radical prostatectomy (open surgery or robot-assisted laparoscopic surgery) at Karolinska University Hospital, Stockholm, Sweden, 2002-2006. Of the 1,411 eligible men, 1,288 (91%) men completed a study-specific questionnaire. MAIN OUTCOME MEASURE: Prevalence rate of orgasm-associated incontinence. RESULTS: Of the 1,288 men providing information, 691 were sexually active. Altogether, 268 men reported orgasm-associated urinary incontinence, of whom 230 (86%) were otherwise continent. When comparing them with the 422 not reporting the symptom but being sexually active, we found a prevalence ratio (with 95% confidence interval) of 1.5 (1.2-1.8) for not being able to satisfy the partner, 2.1 (1.1-3.5) for avoiding sexual activity because of fear of failing, 1.5 (1.1-2.1) for low orgasmic satisfaction, and 1.4 (1.2-1.7) for having sexual intercourse infrequently. Prevalence ratios increase in prostate-cancer survivors with a higher frequency of orgasm-associated urinary incontinence. CONCLUSION: We found orgasm-associated urinary incontinence to occur among a fifth of prostate cancer survivors having undergone radical prostatectomy, most of whom are continent when not engaged in sexual activity. The symptom was associated with several aspects of sexual life. PMID- 21699661 TI - Quality of life and sexual health after sex reassignment surgery in transsexual men. AB - INTRODUCTION: Although sexual health after genital surgery is an important outcome factor for many transsexual persons, little attention has been attributed to this subject. AIMS: To provide data on quality of life and sexual health after sex reassignment surgery (SRS) in transsexual men. METHODS: A single-center, cross-sectional study in 49 transsexual men (mean age 37 years) after long-term testosterone therapy and on average 8 years after SRS. Ninety-four percent of the participants had phalloplasty. MAIN OUTCOME MEASURES: Self-reported physical and mental health using the Dutch version of the Short Form-36 Health Survey; sexual functioning before and after SRS using a newly constructed specific questionnaire. RESULTS: Compared with a Dutch reference population of community dwelling men, transsexual men scored well on self-perceived physical and mental health. The majority reported having been sexually active before hormone treatment, with more than a quarter having been vaginally penetrated frequently before starting hormone therapy. There was a tendency toward less vaginal involvement during hormone therapy and before SRS. Most participants reported an increase in frequency of masturbation, sexual arousal, and ability to achieve orgasm after testosterone treatment and SRS. Almost all participants were able to achieve orgasm during masturbation and sexual intercourse, and the majority reported a change in orgasmic feelings toward a more powerful and shorter orgasm. Surgical satisfaction was high, despite a relatively high complication rate. CONCLUSION: Results of the current study indicate transsexual men generally have a good quality of life and experience satisfactory sexual function after SRS. PMID- 21699662 TI - Latent structures of male sexual functioning. AB - INTRODUCTION: Strong debate has been brought out around the upcoming editions of the International Classification of Diseases, the World Health Organization, and the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association) regarding new criteria for sexual dysfunction. Although criteria for male sexual dysfunction have been supported by traditional models of sexual response, recent data suggest that male sexual functioning could be conceptualized differently, offering new directions for diagnostic and assessment tools. AIM: The aim of this study was to test, through structural equation modeling, four conceptual alternative models of male sexual response. MAIN OUTCOME MEASURES: A modified version of the International Index of Erectile Function was used, assessing sexual desire, erectile function, orgasmic function, and premature ejaculation. METHODS: A total of 1,558 Portuguese men participated in the study. Participants were divided into two groups according to the presence or absence of sexual difficulties. RESULTS: Findings suggested different factor solutions for men with and without sexual difficulties. Male sexual response of men with sexual difficulties was best characterized by a two-factor structure: (i) a general sexual function factor (including sexual desire, erectile function, and orgasmic function); and (ii) premature ejaculation; while a three-factor solution was the model that best fitted the data regarding men without sexual difficulties: (i) sexual desire; (ii) erectile and orgasmic function (which merged into a single dimension); and (iii) premature ejaculation. Discriminant validity between factors was strongly supported, suggesting that these dimensions measure distinct phenomena in both samples. CONCLUSIONS: Results regarding sexually healthy men suggest that erectile function is structurally independent from sexual desire, and that ejaculatory control could be conceptualized as a different phenomenon in relation to the current orgasmic disorders. Additionally, findings related to sexually dysfunctional men suggest the existence of a general sexual distress disorder. PMID- 21699663 TI - Sexual function in female patients with obstructive sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea is defined as repetitive (>=5/hour) partial or complete cessation of breathing during sleep. Whereas obstructive sleep apnea is often considered to be associated with sexual problems in men, studies concerning effects of obstructive sleep apnea on female sexual function and distress are sparse. AIM: To investigate sexual dysfunction and sexual distress in female patients with obstructive sleep apnea and to determine which factors are of importance for their sexual function. METHODS: We investigated 80 female patients (ages 28-64) admitted to a sleep laboratory and who after investigation received a diagnosis of obstructive sleep apnea. All subjects answered questions drawn from three self-administered questionnaires on sexuality. The results were compared with a population sample (N=240). MAIN OUTCOME MEASURE: Data from nocturnal respiratory recordings. Female Sexual Function Index, Female Sexual Distress Scale and four questions from Life Satisfaction-11 (Lisat-11). RESULTS: Female Sexual Function Index indicated that obstructive sleep apnea patients were at a higher risk for having sexual difficulties. Female Sexual Distress Scale showed significantly more sexual distress in the obstructive sleep apnea group. Manifest Female Sexual Dysfunction (combined data from Female Sexual Function Index and Female Sexual Distress Scale) showed that female patients with obstructive sleep apnea also had more sexual dysfunction. Severity of sleep apnea was, however, not related to any of these indices but consumption of psychopharmaca was. In Lisat-11, we found that obstructive sleep apnea females scored lower than women in the population sample regarding life as a whole but not regarding domains of closeness. CONCLUSIONS: This study indicates that sexuality of women with untreated obstructive sleep apnea is negatively affected compared with a female population sample. This was not related to severity of obstructive sleep apnea, whereas psychopharmaca may act as an important confounder. PMID- 21699665 TI - Risk of stroke among men with erectile dysfunction in Taiwan--patient-based or population-based? PMID- 21699664 TI - Treatment with a uroselective alpha1-blocker improves voiding and sexual function: a study in Thai men with lower urinary tract symptoms. AB - INTRODUCTION: Lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) negatively affect quality of life. The alpha1-blockers are effective for LUTS suggestive of benign prostatic hypertrophy. AIM: To analyze the effect of a uroselective alpha1-blocker on both voiding and sexual dysfunction in Thai men with LUTS. METHODS: Of 488 men with LUTS who received 10 mg alfuzosin monotherapy once daily (OD) at a men's health clinic, 313 men (64%) completed 8 months of alfuzosin treatment and filled the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF)-5 questionnaires. MAIN OUTCOME MEASURE: The relationships among the IPSS, IIEF-5 score, and select clinical characteristics were analyzed using multiple regression analysis. To identify changes from the baseline, the chi-square or Fisher's exact test was used for categorical or dichotomous variables and a paired Student's t-test was used for continuous variables. RESULTS: The 313 men were followed up for a mean (standard deviation [SD]) of 35.6 (2.2) weeks. LUTS were categorized by IPSS as moderate in 100 patients (31.9%) and severe in 213 patients (68.1%). ED was graded according to the IIEF-5 as normal in 46 patients (14.7%), mild in 29 patients (9.3%), mild to moderate in 81 patients (25.9%), moderate in 47 patients (15.0%), and severe in 110 patients (35.1%). ED is associated with LUTS (P=0.008). After 8 months of alfuzosin treatment, the mean (SD) IPSS and IIEF-5 score significantly improved from 19.95 (6.4) to 11.13 (4.6) (P<0.001) and from 11.5 (6.9) to 14.9 (5.7) (P<0.001), respectively. However, the IIEF-5 score did not improve significantly in patients with severe LUTS as determined using the IPSS. The most common adverse event with alfuzosin treatment was mild (dizziness, 2.2%). CONCLUSION: Treatment with 10 mg alfuzosin OD is safe and effective in improving voiding and sexual function in Thai men with LUTS and ED. PMID- 21699666 TI - Effect of periodontitis on erectile function and its possible mechanism. AB - INTRODUCTION: Periodontitis is one of the important risk factors resulting in cardiovascular diseases. Erectile dysfunction (ED) is strongly correlated with cardiovascular diseases. The expression of endothelial nitric oxide synthase (eNOS) in penile tissue has an important role in the mechanism of erection. AIM: To investigate the effect of periodontitis on erectile function and the possible mechanism. METHODS: After induction of periodontitis in rat, the ratio of maximum intracavernosal pressure/mean arterial pressure (ICPmax /MAP)*100, the expression of eNOS in penile tissue, the level of serum C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-alpha), and the ultrastructural changes of the cavernous tissue were examined and compared between periodontitis rats (group A) and control rats (group B). MAIN OUTCOME MEASURE: Periodontitis significantly decrease not only the ICPmax/MAP*100 and the expression of eNOS but also the activity of NOS and the level of cyclic guanosine monophosphate (cGMP) in cavernous tissue of rat. RESULTS: After electrostimulation by 3 and 5 voltage, the ratio of ICPmax /MAP*100 in group A was significantly less than that in group B (19.54+/-6.16 vs. 30.45+/-3.12; 30.91+/-5.61 vs. 50.52+/-9.52, respectively; P<0.05).The level of serum CRP and TNF-alpha in group A is significantly higher in group B (P<0.05).The quantitative real-time reverse transcription polymerase chain reaction study demonstrated no statistically significant difference in the expression of mRNA of eNOS in cavernous tissue between the two groups (P>0.05). But there was significant decrease in eNOS protein of the cavernous tissue in group A than in group B (P<0.05). Total NOS activity and cGMP level in cavernosal tissue were significantly lower in group A than in group B (P<0.05). There was no significant alternation occurred in the ultrastructures of penile cavernous tissue. CONCLUSIONS: The function of penile erection is impaired by periodontitis. The decreased in the expression of eNOS and NOS activity in penile cavernous tissue caused by mild systemic inflammatory status in periodontitis may be one of the important risk factors of ED. PMID- 21699667 TI - Racial differences in sexuality profiles among American, Japanese, and Japanese American men with localized prostate cancer. AB - INTRODUCTION: Although there were marked racial differences in the clinical outcomes among Japanese men (JP), Caucasian men (CA), and Japanese American (JA) men with localized prostate cancer, the effect of race/ethnicity on sexual profiles remains unclear. AIM: To determine differences of sexual profiles in JP, CA, and JA with localized prostate cancer. METHODS: A total of 412 JP, 352 CA, and 54 JA with clinically localized prostate cancer were enrolled in separate studies of health-related quality of life outcomes. We developed a collaborative study in each database. MAIN OUTCOME MEASURE: Sexual function and bother were estimated before treatment with validated English and Japanese versions of the University of California in Los Angeles Prostate Cancer Index (UCLA PCI). RESULTS: The CA reported the highest sexual function score of all. Even after controlling for age, prostate specific antigen, clinical T stage, Gleason score and comorbidity, the JP were more likely than the CA to report poor sexual desire, poor erection ability, poor overall ability to function sexually, and poor ability to attain orgasm. With regard to sexual bother, however, no differences were reported between CA and JP. The JA reported sexual function closely approximate that of the JP, and they were less likely than the CA to report erection ability and intercourse. The JA were more likely to feel distress from their sexual function than the CA. When the JA were divided into two groups according to the ethnicity of their partners, UCLA PCI sexual function scores were equivalent between JA-partnered men and men partnered with other races. On the other hand, JA-partnered men were significantly less likely to report sexual bother scores than men partnered with other races. CONCLUSION: We found significant interethnic variations among CA, JP, and JA with prostate cancer in terms of their sexual profiles. Ethnicity and/or country appear to modify some of these variables. PMID- 21699668 TI - Anti-infection dip suggestions for the Coloplast Titan Inflatable Penile Prosthesis in the era of the infection retardant coated implant. AB - INTRODUCTION: Infection is the worst complication seen with inflatable penile prosthesis (IPP). Both the American Medical Systems (AMS) and Coloplast IPP have infection retardant coatings. AMS is coated at the factory with rifampicin and minocycline (InhibiZone). The Coloplast IPP has a hydrophilic coating covalently bonded to its components that will absorb any aqueous solution before implantation and provides increased surface lubricity to decrease bacterial adherence. AIM: We tested several antibiotic dips comparing zones of inhibition (ZOI) against five commonly infecting bacteria with coated Coloplast implants. Results were compared with those ZOI created with strips of an AMS IPP precoated with InhibiZone. METHODS: Pieces of sterile Coloplast Titan IPP were dipped in (i) trimethoprim/polymixin B ophthalmic solution; (ii) trimethoprim/sulfamethoxazole infusion solution; (iii) bacitracin; (iv) rifampicin/minocycline; and (v) rifampin/trimehtoprim/sulfamethoxazole. ZOI for the Titan strips and for AMS InhibiZone coated strips were tested against Staphylococcus epidermidis, Staphylococcus lugdunensis, Staphylococcus aureus, Pseudomonas, and Enterococcus. MAIN OUTCOME MEASURE: ZOIs of the Coloplast Titan for each of the medicated solutions were compared with ZOI created by undipped strips of a sterile InhibiZone coated IPP placed on plates of the identical bacteria. RESULTS: All dips except bacitracin showed ZOI>=InhibiZone (P>=0.005) for most organisms. Because of broad-spectrum effectiveness, ease of handling, and cost, infusion vial of trimehtoprim/sulfamethoxazole seemed optimal at this time. If trimehtoprim/sulfamethoxazole is unavailable; the ZOI with Polytrim ophthalmic solution zones were almost as good. CONCLUSIONS: The Coloplast strips when dipped in several solutions showed equal or significantly larger ZOI against commonly infecting organisms than the InhibiZone coated strips. At the present time using off the shelf trimethoprim sulfamethoxazole infusion solution seems optimum. The flexibility of choosing the drug eluting from the Coloplast device seems promising in the changing bacterial environment. PMID- 21699669 TI - The effects of long-term androgen deprivation therapy on penile length in patients with prostate cancer: a single-center, prospective, open-label, observational study. AB - INTRODUCTION: The adverse effects of long-term drug therapy for prostate cancer (PCa) can dramatically impact patient quality of life and are considered to be important factors when selecting treatment. AIM: To assess stretched penile length before and after long-term androgen deprivation therapy (ADT) for treatment of PCa. METHODS: From January 2008 to June 2010 at a single institution, 39 consecutive patients without distant metastases who were elected to receive ADT as initial therapy for PCa were prospectively enrolled. Exclusion criteria were history of penile anomalies and/or trauma, and prior radical prostate surgery or radiation therapy. Erectile functions were evaluated at baseline according to the International Index of Erectile Function (IIEF). Vertically stretched penile length was measured every 3 months from the pubopenile junction to the meatus with a spring scale. MAIN OUTCOME MEASURE: After ADT, significant 3-month interval changes in stretched penile length were noted for up to 15 months (P < 0.001). The relationship between potency and penile shortening was not significant (P = 0.45). RESULTS: The mean patient age was 67.1 years. Before therapy, the mean stretched penile length was 10.76 cm. After 24 months of ADT, mean penile length had decreased to 8.05 cm. However, these changes plateaued after 15 months. Normal erectile function (EF) was reported by 41% of patients before therapy, while 10.5% reported normal EF at the 24-month follow-up. The relationship between potency and penile shortening was not significant. However, patients who preserved their potency tended to experience less penile shortening. CONCLUSIONS: The administration of luteinizing hormone-releasing hormone (LHRH) agonists induced significant decreases in penile length for only up to 15 months in the absence of the confounding effects of surgery and radiation. PMID- 21699670 TI - Relationship between erectile dysfunction and silent myocardial ischemia in type 2 diabetic patients with no known macrovascular complications. AB - INTRODUCTION: Erectile dysfunction (ED) is associated with cardiovascular disease (CVD) because it is highly prevalent among those with cardiovascular risk factors (CVRFs). Moreover, it precedes the development of CVD and is considered a subrogate marker of subclinical CVD. AIM: The aim of this study was to evaluate the presence of ED among patients with type 2 diabetes (DM2) without macroangiopathy, and to assess the association between ED and other CVRFs, chronic diabetes complications, silent myocardial ischemia (SMI), and peripheral arterial disease (PAD). METHODS: One hundred fifty-four male patients with DM2 and without clinical evidence of CVD were included in the study. The presence of ED, PAD, SMI, chronic diabetic complications, and other CVRFs was evaluated in these patients. MAIN OUTCOME MEASURES: PAD; SMI; ED; 24-hour blood pressure Holter; lipid profile; insulin resistance; testosterone; chronic inflammation; nephropathy; retinopathy; neuropathy. RESULTS: Prevalence of ED was 68.2%. Patients with ED were older and characterized by DM2, systolic blood pressure (BP), retinopathy, and insulin treatment of longer duration than patients without ED, even when adjusting for age was performed. Adjusting for duration of diabetic condition revealed significant differences in age and systolic BP. Independent factors for ED were age (57.7+/-7.5 years, relative risks [RR 1.1], P=0.003) and duration of diabetes (9[3-15] years, RR 1.1, P=0.006). SMI was detected in 13.6% of patients (18.1% in patients with ED vs. 4.1% in patients without ED). Asymptomatic PAD was detected in 13.2% of subjects (14.4% in patients with ED vs. 10.4% in patients without). CONCLUSIONS: ED is highly prevalent in DM2, and is associated with the presence of SMI, higher systolic BP and chronic microvascular diabetic complications. PMID- 21699671 TI - Impact of incontinence surgery on sexual function: a systematic review and meta analysis. AB - INTRODUCTION: Urinary incontinence has an adverse impact on sexual function. The reports on sexual function following the treatment of urinary incontinence are confusing. AIM: To investigate the impact of surgery for stress incontinence on coital incontinence and overall sexual function. METHODS: Cochrane Incontinence Group Specialized Register of Controlled Trials, The Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE were searched for trials of incontinence surgery assessing sexual function and coital incontinence before and after surgery. Observational studies and randomized controlled trials investigating the impact of surgical correction of stress urinary incontinence on sexual function were included. Surgical interventions included tension-free vaginal tape (TVT), Tension Free Vaginal Tape-Obturator (TVT-O), transobturator tape (TOT), Burch, and autologous fascial sling (AFS). Studies that included patients undergoing concurrent prolapse surgery were excluded from the analysis. Data extraction and analysis was performed independently by two authors. Coital incontinence was analyzed separately and odds ratios (ORs) with 95% confidence intervals (CI ) calculated. The data were analyzed in Review Manager 5 software. MAIN OUTCOME MEASURE: Changes in sexual function and coital incontinence following surgery for urinary incontinence. RESULTS: Twenty-one articles were identified, which assessed sexual function and/or coital incontinence following continence surgery in the absence of prolapse. Results suggest evidence for a significant reduction in coital incontinence post surgery (OR 0.11; 95% CI 0.07, 0.17). CONCLUSIONS: Coital incontinence is significantly reduced following continence surgery. There were several methodological problems with the quality of the primary research particularly related to heterogeneity of studies, use of different outcome measures, and the absence of well-designed randomized controlled trials. PMID- 21699672 TI - Practical tips for sexual counseling and psychotherapy in premature ejaculation. AB - INTRODUCTION: A number of milestones in the treatment of premature ejaculation (PE) have occurred over the past five decades, including the development of various behavioral and cognitive techniques as well as pharmacotherapies that modify neurophysiological processes involved in ejaculation. Nevertheless, the notion that sexual responses such as PE are influenced by physiological, psychobehavioral, cultural, and relationship factors is as valid now as it was 50 years ago, and therefore, interventions should consider all such domains in the development of effective treatment strategies. AIM: Provide an overview of which patients with PE are suitable to receive psychosexual treatment and the psychological approaches for managing this disorder. METHODS: Review of the literature. MAIN OUTCOME MEASURE: Psychosexual treatments that integrate behavioral, psychological, and relationship functioning. RESULTS: PE is typically a couple's problem and, therefore, psychotherapy is best when the partner is involved. Before embarking on psychotherapy, the clinician should obtain a medical history pertaining to sexual-, psychological-, and relationship-related factors, so that the treatment strategy can be tailored to the needs of the individual. General strategies underpinning integrative, "process-oriented" elements of psychotherapy most relevant to PE are: developing the therapist patient relationship; expressing empathy, genuineness, and positive regard; motivational interviewing, i.e., developing motivation to change; developing discrepancy; working through resistance; identifying PE-related affect, cognitions, and behaviors (including interaction with partners); and supporting self-efficacy. The four main domains that encompass psychotherapy techniques specific to the treatment of PE are: behavioral; cognitive; affective; and relational. Sustained positive outcomes in PE may be obtained using a combination treatment strategy that addresses all elements of PE, including psychological and biological factors. CONCLUSIONS: Psychosexual treatments may help the patient with PE and his partner to address their sexual problems and improve their overall relationship. The effects of psychosexual therapy may be augmented by combining this intervention with pharmacotherapy. PMID- 21699673 TI - Detection of lumpy skin disease virus antigen and genomic DNA in formalin-fixed paraffin-embedded tissues from an Egyptian outbreak in 2006. AB - An outbreak of lumpy skin disease (LSD) was reported in 2006 in Egypt affecting 16 provinces. Biopsies and post-mortem tissue samples were collected from calves that showed typical clinical signs of LSD and fixed in formalin. These samples were collected from a private dairy farm in the Damietta province of Egypt. Formalin-fixed paraffin-embedded tissue samples were assessed using histology, and skin lesions were classified as either acute or subacute/chronic. Both lumpy skin disease virus (LSDV) DNA detected by polymerase chain reaction and LSDV antigen detected by immunohistochemistry using a capripoxvirus-specific monoclonal antibody were observed in the acute skin lesions and in some subacute/chronic skin lesions. PMID- 21699674 TI - Nocardia cyriacigeorgica bacteraemia presenting with cytomegalovirus disease and rapidly fatal pneumonia in a renal transplant patient: a case report. AB - INTRODUCTION: Nocardia cyriacigeorgica bacteraemia has been described in the setting of profound immunodeficiency in only two previous case reports. In both instances, diagnosis was rapidly facilitated by 16S rRNA gene sequencing of blood culture isolates. To the best of our knowledge, we believe that our case is the first presentation of N. cyriacigeorgica bacteraemia associated with acute cytomegalovirus disease in a kidney transplant recipient, which was then followed by severe and fatal pneumonia only seven days later. CASE PRESENTATION: We present the case of a 73-year-old Caucasian woman, a renal transplant recipient, with peripheral vascular disease, hypertension, osteoporosis and vascular dementia who was diagnosed with septicemia and pneumonia. In spite of appropriate anti-microbial therapy for nocardial sepsis, she developed severe pneumonia and acute renal failure. CONCLUSION: This case illustrates a potential for disseminated nocardial infection to produce clinical syndromes that may be indistinguishable from acute cytomegalovirus disease. An atypical presentation (pneumonia and renal failure) of a rare disease (nocardial septicemia) in the setting of renal transplantation is discussed. This case illustrates that the possibility of severe cytomegalovirus disease should be considered in renal transplanted patients diagnosed with nocardial septicemia who subsequently develop severe sepsis, pneumonia, and renal failure. Molecular diagnosis should readily be available to assist with the prompt diagnosis and treatment of these infections in renal transplant patients. PMID- 21699675 TI - Decomposing cross-country differences in quality adjusted life expectancy: the impact of value sets. AB - BACKGROUND: The validity, reliability and cross-country comparability of summary measures of population health (SMPH) have been persistently debated. In this debate, the measurement and valuation of nonfatal health outcomes have been defined as key issues. Our goal was to quantify and decompose international differences in health expectancy based on health-related quality of life (HRQoL). We focused on the impact of value set choice on cross-country variation. METHODS: We calculated Quality Adjusted Life Expectancy (QALE) at age 20 for 15 countries in which EQ-5D population surveys had been conducted. We applied the Sullivan approach to combine the EQ-5D based HRQoL data with life tables from the Human Mortality Database. Mean HRQoL by country-gender-age was estimated using a parametric model. We used nonparametric bootstrap techniques to compute confidence intervals. QALE was then compared across the six country-specific time trade-off value sets that were available. Finally, three counterfactual estimates were generated in order to assess the contribution of mortality, health states and health-state values to cross-country differences in QALE. RESULTS: QALE at age 20 ranged from 33 years in Armenia to almost 61 years in Japan, using the UK value set. The value sets of the other five countries generated different estimates, up to seven years higher. The relative impact of choosing a different value set differed across country-gender strata between 2% and 20%. In 50% of the country-gender strata the ranking changed by two or more positions across value sets. The decomposition demonstrated a varying impact of health states, health state values, and mortality on QALE differences across countries. CONCLUSIONS: The choice of the value set in SMPH may seriously affect cross-country comparisons of health expectancy, even across populations of similar levels of wealth and education. In our opinion, it is essential to get more insight into the drivers of differences in health-state values across populations. This will enhance the usefulness of health-expectancy measures. PMID- 21699676 TI - Colonoscopic perforation leading to a diagnosis of Ehlers Danlos syndrome type IV: a case report and review of the literature. AB - INTRODUCTION: Colonoscopic perforation is a rare but serious complication of colonoscopy. Factors known to increase the risk of perforation include colonic strictures, extensive diverticulosis, and friable tissues. We describe the case of a man who was found to have perforation of the sigmoid colon secondary to an undiagnosed connective tissue disorder (Ehlers-Danlos syndrome type IV) while undergoing surveillance for hereditary non-polyposis colorectal cancer. CASE PRESENTATION: A 33-year-old Caucasian man presented to our hospital with an acute abdomen following a colonoscopy five days earlier as part of hereditary non polyposis colorectal cancer screening. His medical history included bilateral clubfoot. His physical examination findings suggested left iliac fossa peritonitis. A computed tomographic scan revealed perforation of the sigmoid colon and incidentally a right common iliac artery aneurysm as well. Hartmann's procedure was performed during laparotomy. The patient recovered well post operatively and was discharged. Reversal of the Hartmann's procedure was performed six months later. This procedure was challenging because of dense adhesions and friable bowel. The histology of bowel specimens from this surgery revealed thinning and fibrosis of the muscularis externa. The patient was subsequently noted to have transparency of truncal skin with easily visible vessels. An underlying collagen vascular disorder was suspected, and genetic testing revealed a mutation in the collagen type III, alpha1 (COL3A1) gene, which is consistent with a diagnosis of Ehlers-Danlos syndrome type IV. CONCLUSIONS: Ehlers-Danlos syndrome type IV, the vascular type, is a rare disorder caused by mutations in the COL3A1 gene on chromosome 2q31. It is characterized by translucent skin, clubfoot, and the potentially fatal complications of spontaneous large vessel rupture, although spontaneous uterine and colonic perforations have also been reported in the literature. The present case presentation describes the identification of Ehlers-Danlos syndrome type IV in a patient with a non-spontaneous colonic perforation secondary to an invasive investigation for another hereditary disorder pre-disposing him to colorectal cancer. Invasive procedures such as arteriograms and endoscopies are relatively contra-indicated in Ehlers-Danlos syndrome type IV. Alternatives with a lower risk of perforation, such as computed tomographic colonography, need to be considered for patients requiring ongoing colorectal cancer surveillance. Furthermore, management of vascular aneurysms in patients with Ehlers-Danlos syndrome type IV requires consideration of the risks of endovascular stenting, as opposed to open surgical intervention, because of tissue friability. Genetic and reproductive counseling should be offered to affected individuals and their families. PMID- 21699677 TI - Aspects of bovine herpesvirus-1 infection in dairy and beef herds in the Republic of Ireland. AB - BACKGROUND: Infection with bovine herpesvirus-1 (BHV-1) causes a wide range of disease manifestations, including respiratory disease and abortion, with world wide distribution. The primary objective of the present study was to describe aspects of BHV-1 infection and control on Irish farms, including herd-level seroprevalence (based on pooled sera) and vaccine usage. METHODS: The characteristics of a diagnostic indirect BHV-1 antibody ELISA test when used on serum pools were evaluated using laboratory replicates for use in the seroprevalence study. The output from this indirect ELISA was expressed as a percentage positivity (PP) value. A proposed cut off (PCO) PP was applied in a cross-sectional study of a stratified random sample of 1,175 Irish dairy and beef cattle herds in 2009, using serum pools, to estimate herd seroprevalence. The study was observational, based primarily on the analysis of existing samples, and only aggregated results were reported. For these reasons, ethical approval was not required. Bulk milk samples from a subset of 111 dairy herds were analysed using the same ELISA. Information regarding vaccine usage was determined in a telephone survey. RESULTS: A PCO PP of 7.88% was determined to give 97.1% sensitivity and 100% specificity relative to the use of the ELISA on individual sera giving maximization of the prevalence independent Youden's index, on receiver operating characteristics analysis of replicate results. The herd-level BHV-1 seroprevalence was 74.9% (95% CI - 69.9%-79.8%), with no significant difference between dairy and beef herds. 95.5% agreement in herd classification was found between bulk milk and serum pools. Only 1.8 percent of farmers used BHV 1 marker vaccine, 80% of which was live while 75% of vaccinated herds were dairy.A significant association was found between herd size (quartiles) and seroprevalence (quartiles). CONCLUSIONS: The results from this study indicate BHV 1 infection is endemic, although BHV-1 vaccines are rarely used, in the cattle population in Ireland. PMID- 21699678 TI - A dentigerous cyst associated with bilaterally impacted mandibular canines in a girl: a case report. AB - INTRODUCTION: A dentigerous cyst is the most common developmental odontogenic cyst and is frequently noted as an incidental finding on radiographs. The most common teeth affected are impacted mandibular third molars and permanent maxillary canines. This case involves a dentigerous cyst encompassing the right and left impacted mandibular canines and crossing the midline. This is, to the best of our knowledge, the first reported case of a dentigerous cyst encompassing non-adjacent teeth and crossing the midline. CASE PRESENTATION: The patient presented to our orthodontic clinic for treatment of malocclusion. The patient was a 10-year, one-month-old Caucasian girl with a dentigerous cyst encompassing the right and left impacted mandibular canines and crossing the midline. CONCLUSION: This case involves an unusual clinical and radiographic presentation of a dentigerous cyst. It shows a new variant of presentation that medical professionals, specifically dentists and radiologists, should be aware of, since a dentigerous cyst crossing the midline has not been previously reported as far as we are aware. This additional knowledge is important for inclusion on differential diagnosis lists and aids in the development of a proper treatment plan. PMID- 21699679 TI - Extra-corporeal life support for near-fatal multi-drug intoxication: a case report. AB - INTRODUCTION: Severe mixed beta-blocker and calcium channel blocker intoxication presents a significant risk for patient mortality. Although treatment is well established, it sporadically fails to support the patient through massive overdoses, thus requiring non-conventional treatments. We report the use of extra corporeal life support in a patient with refractory hemodynamic impairment due to multi-drug intoxication. Although sometimes used in clinical practice, extra corporeal membrane oxygenation for intoxications has rarely been reported. CASE PRESENTATION: A 36-year-old Caucasian man presented to our hospital with refractory hypotension, severe cardiac insufficiency and multi-organ failure due to mixed intoxication with atenolol, nifedipine, Lacidipine and sertraline. Together with standard treatment, we performed extra-corporeal membrane oxygenation to overcome refractory cardiogenic shock and lead the patient to achieve a full recovery. CONCLUSION: Standard of care for beta-blocker and calcium channel blocker intoxication is well-defined and condensed into protocols of treatment. Although aimed at clearing the noxious agents from the patient's system, standard measures may fail to provide adequate hemodynamic support to allow recovery. In selected cases, extra-corporeal membrane oxygenation could be considered a bridge to drug clearance while preventing multi-organ failure due to profound shock. PMID- 21699680 TI - Unresolved orthology and peculiar coding sequence properties of lamprey genes: the KCNA gene family as test case. AB - BACKGROUND: In understanding the evolutionary process of vertebrates, cyclostomes (hagfishes and lamprey) occupy crucial positions. Resolving molecular phylogenetic relationships of cyclostome genes with gnathostomes (jawed vertebrates) genes is indispensable in deciphering both the species tree and gene trees. However, molecular phylogenetic analyses, especially those including lamprey genes, have produced highly discordant results between gene families. To efficiently scrutinize this problem using partial genome assemblies of early vertebrates, we focused on the potassium voltage-gated channel, shaker-related (KCNA) family, whose members are mostly single-exon. RESULTS: Seven sea lamprey KCNA genes as well as six elephant shark genes were identified, and their orthologies to bony vertebrate subgroups were assessed. In contrast to robustly supported orthology of the elephant shark genes to gnathostome subgroups, clear orthology of any sea lamprey gene could not be established. Notably, sea lamprey KCNA sequences displayed unique codon usage pattern and amino acid composition, probably associated with exceptionally high GC-content in their coding regions. This lamprey-specific property of coding sequences was also observed generally for genes outside this gene family. CONCLUSIONS: Our results suggest that secondary modifications of sequence properties unique to the lamprey lineage may be one of the factors preventing robust orthology assessments of lamprey genes, which deserves further genome-wide validation. The lamprey lineage-specific alteration of protein-coding sequence properties needs to be taken into consideration in tackling the key questions about early vertebrate evolution. PMID- 21699681 TI - Resveratrol retards progression of diabetic nephropathy through modulations of oxidative stress, proinflammatory cytokines, and AMP-activated protein kinase. AB - BACKGROUND: Diabetic nephropathy (DN) has been recognized as the leading cause of end-stage renal disease. Resveratrol (RSV), a polyphenolic compound, has been indicated to possess an insulin-like property in diabetes. In the present study, we aimed to investigate the renoprotective effects of RSV and delineate its underlying mechanism in early-stage DN. METHODS: The protective effects of RSV on DN were evaluated in streptozotocin (STZ)-induced diabetic rats. RESULTS: The plasma glucose, creatinine, and blood urea nitrogen were significantly elevated in STZ-induced diabetic rats. RSV treatment markedly ameliorated hyperglycemia and renal dysfunction in STZ-induced diabetic rats. The diabetes-induced superoxide anion and protein carbonyl levels were also significantly attenuated in RSV-treated diabetic kidney. The AMPK protein phosphorylation and expression levels were remarkably reduced in diabetic renal tissues. In contrast, RSV treatment significantly rescued the AMPK protein expression and phosphorylation compared to non-treated diabetic group. Additionally, hyperglycemia markedly enhanced renal production of proinflammatory cytokine IL-1beta. RSV reduced IL 1beta but increased TNF-alpha and IL-6 levels in the diabetic kidneys. CONCLUSIONS: Our findings suggest that RSV protects against oxidative stress, exhibits concurrent proinflammation and anti-inflammation, and up-regulates AMPK expression and activation, which may contribute to its beneficial effects on the early stage of DN. PMID- 21699682 TI - Symptom interpretation and health care seeking in ovarian cancer. AB - BACKGROUND: Ovarian cancer is the leading cause of death among women suffering from gynaecological malignancies in the Western world. Worldwide, approximately 200,000 women are diagnosed with the disease each year. This article deals with the health care seeking and symptom interpretation process among Danish women, who have a very high mortality rate. METHODS: The health seeking and symptom interpretation process was analysed via combining study methods. The material consisted of registry data dealing with the use of public health care and hospital services of Danish women, newly diagnosed with ovarian cancer. These results were combined with findings from semi-structured qualitative research interviews on women's bodily experiences with symptom development. RESULTS: A number of 663 Danish women with ovarian cancer attended 27 different kinds of primary health care providers in a total of 14,009 visits during 2007. The women also had 6,214 contacts with various hospitals, and obtained 562 different diagnoses.From the main theme "Women's experiences with the onset of symptoms" three sub-themes were identified: "Bodily sensations", "From bodily sensation to symptom", and "Health seeking and treatment start". In all cases the General Practitioner represented the first contact to public health care, acting as gate keeper to specialist and hospital referral.The women were major users of public health care throughout the diagnostic process and subsequent treatment. All women held personal knowledge concerning the onset of their symptoms. The early symptoms of ovarian cancer might be uncharacteristic and non-disease-specific when interpreted as personal experiences, but they had similarities when analysed together. CONCLUSIONS: Diagnostic delay in ovarian cancer seems far from being exclusively a medical problem, as the delay proved to be influenced by organisational, cultural, and social factors, too. Initiatives facilitating the diagnostic process and research concerning the selection of individuals for further investigation are indicated. The way in which the women interpreted their symptoms was influenced by their personal experiences, their cultural, and their social background. This became crucial to the diagnostic process. These issues need to be explored through further research on women's experiences during the diagnostic process. PMID- 21699683 TI - Bovine spongiform encephalopathy infection alters endogenous retrovirus expression in distinct brain regions of cynomolgus macaques (Macaca fascicularis). AB - BACKGROUND: Prion diseases such as bovine spongiform encephalopathies (BSE) are transmissible neurodegenerative diseases which are presumably caused by an infectious conformational isoform of the cellular prion protein. Previous work has provided evidence that in murine prion disease the endogenous retrovirus (ERV) expression is altered in the brain. To determine if prion-induced changes in ERV expression are a general phenomenon we used a non-human primate model for prion disease. RESULTS: Cynomolgus macaques (Macaca fasicularis) were infected intracerebrally with BSE-positive brain stem material from cattle and allowed to develop prion disease. Brain tissue from the basis pontis and vermis cerebelli of the six animals and the same regions from four healthy controls were subjected to ERV expression profiling using a retrovirus-specific microarray and quantitative real-time PCR. We could show that Class I gammaretroviruses HERV-E4-1, ERV-9, and MacERV-4 increase expression in BSE-infected macaques. In a second approach, we analysed ERV-K-(HML-2) RNA and protein expression in extracts from the same cynomolgus macaques. Here we found a significant downregulation of both, the macaque ERV-K-(HML-2) Gag protein and RNA in the frontal/parietal cortex of BSE infected macaques. CONCLUSIONS: We provide evidence that dysregulation of ERVs in response to BSE-infection can be detected on both, the RNA and the protein level. To our knowledge, this is the first report on the differential expression of ERV derived structural proteins in prion disorders. Our findings suggest that endogenous retroviruses may induce or exacerbate the pathological consequences of prion-associated neurodegeneration. PMID- 21699684 TI - Study of large and highly stratified population datasets by combining iterative pruning principal component analysis and structure. AB - BACKGROUND: The ever increasing sizes of population genetic datasets pose great challenges for population structure analysis. The Tracy-Widom (TW) statistical test is widely used for detecting structure. However, it has not been adequately investigated whether the TW statistic is susceptible to type I error, especially in large, complex datasets. Non-parametric, Principal Component Analysis (PCA) based methods for resolving structure have been developed which rely on the TW test. Although PCA-based methods can resolve structure, they cannot infer ancestry. Model-based methods are still needed for ancestry analysis, but they are not suitable for large datasets. We propose a new structure analysis framework for large datasets. This includes a new heuristic for detecting structure and incorporation of the structure patterns inferred by a PCA method to complement STRUCTURE analysis. RESULTS: A new heuristic called EigenDev for detecting population structure is presented. When tested on simulated data, this heuristic is robust to sample size. In contrast, the TW statistic was found to be susceptible to type I error, especially for large population samples. EigenDev is thus better-suited for analysis of large datasets containing many individuals, in which spurious patterns are likely to exist and could be incorrectly interpreted as population stratification. EigenDev was applied to the iterative pruning PCA (ipPCA) method, which resolves the underlying subpopulations. This subpopulation information was used to supervise STRUCTURE analysis to infer patterns of ancestry at an unprecedented level of resolution. To validate the new approach, a bovine and a large human genetic dataset (3945 individuals) were analyzed. We found new ancestry patterns consistent with the subpopulations resolved by ipPCA. CONCLUSIONS: The EigenDev heuristic is robust to sampling and is thus superior for detecting structure in large datasets. The application of EigenDev to the ipPCA algorithm improves the estimation of the number of subpopulations and the individual assignment accuracy, especially for very large and complex datasets. Furthermore, we have demonstrated that the structure resolved by this approach complements parametric analysis, allowing a much more comprehensive account of population structure. The new version of the ipPCA software with EigenDev incorporated can be downloaded from http://www4a.biotec.or.th/GI/tools/ippca. PMID- 21699685 TI - Iron deposition is independent of cellular inflammation in a cerebral model of multiple sclerosis. AB - BACKGROUND: Perivenular inflammation is a common early pathological feature in multiple sclerosis (MS). A recent hypothesis stated that CNS inflammation is induced by perivenular iron deposits that occur in response to altered blood flow in MS subjects. In order to evaluate this hypothesis, an animal model was developed, called cerebral experimental autoimmune encephalomyelitis (cEAE), which presents with CNS perivascular iron deposits. This model was used to investigate the relationship of iron deposition to inflammation. METHODS: In order to generate cEAE, mice were given an encephalitogen injection followed by a stereotactic intracerebral injection of TNF-alpha and IFN-gamma. Control animals received encephalitogen followed by an intracerebral injection of saline, or no encephalitogen plus an intracerebral injection of saline or cytokines. Laser Doppler was used to measure cerebral blood flow. MRI and iron histochemistry were used to localize iron deposits. Additional histological procedures were used to localize inflammatory cell infiltrates, microgliosis and astrogliosis. RESULTS: Doppler analysis revealed that cEAE mice had a reduction in cerebral blood flow compared to controls. MRI revealed T2 hypointense areas in cEAE animals that spatially correlated with iron deposition around vessels and at some sites of inflammation as detected by iron histochemistry. Vessels with associated iron deposits were distributed across both hemispheres. Mice with cEAE had more iron labeled vessels compared to controls, but these vessels were not commonly associated with inflammatory cell infiltrates. Some iron-laden vessels had associated microgliosis that was above the background microglial response, and iron deposits were observed within reactive microglia. Vessels with associated astrogliosis were more commonly observed without colocalization of iron deposits. CONCLUSION: The findings indicate that iron deposition around vessels can occur independently of inflammation providing evidence against the hypothesis that iron deposits account for inflammatory cell infiltrates observed in MS. PMID- 21699686 TI - Iron deposition and inflammation in multiple sclerosis. Which one comes first? AB - Whether iron deposition is an epiphenomenon of the multiple sclerosis (MS) disease process or may play a primary role in triggering inflammation and disease development remains unclear at this time, and should be studied at the early stages of disease pathogenesis. However, it is difficult to study the relationship between iron deposition and inflammation in early MS due to the delay between the onset of symptoms and diagnosis, and the poor availability of tissue specimens. In a recent article published in BMC Neuroscience, Williams et al. investigated the relationship between inflammation and iron deposition using an original animal model labeled as "cerebral experimental autoimmune encephalomyelitis", which develops CNS perivascular iron deposits. However, the relative contribution of iron deposition vs. inflammation in the pathogenesis and progression of MS remains unknown. Further studies should establish the association between inflammation, reduced blood flow, iron deposition, microglia activation and neurodegeneration. Creating a representative animal model that can study independently such relationship will be the key factor in this endeavor. PMID- 21699687 TI - Current smoking behaviour among rural South African children: Ellisras Longitudinal Study. AB - BACKGROUND: The use of tobacco products is the major cause of chronic diseases morbidity and mortality. Most smokers start the smoking habits from childhood and adolescent stages. METHOD: This was a cross-sectional study. A total of 1654 subjects (854 boys and 800 girls), aged 11 to 18 years, who were part of the Ellisras Longitudinal Study completed the questionnaire. Association between tobacco products use and habits, attitudes and beliefs were explored in this study. Logistic regression was used to estimate the association. RESULTS: The prevalence of tobacco product use increases with increasing (4.9 to 17.1%) age among boys whereas girls do not smoke cigarette but only considerable number (1.0 to 4.1%) use home made tobacco products (pipe and snuff) among the Ellisras rural children. Parents and grand parents play a significant (about 50%) role in influencing smoking behaviour among the Ellisras rural children. Seeing actors smoking on TV shows was positively associated (p < 0.05) with smoking (OR = 2.3 95%CI (1.3-4.1 and OR = 2.3 95%CI 1.3-4.1 after adjusting for age and gender). However, women who smoke cigarette were significantly (p < 0.001) associated with success and success and wealth (OR = 2.8, 95% CI 1.5-5.2) even after adjusting for age and gender (OR = 2.9 95% CI 1.5-5.4). CONCLUSION: The usage of tobacco products was high among older boys. Girls did not smoke cigarette. This tobacco use behaviour mirrors the cultural norms and adult behaviour. The association of this tobacco used products with biological parameters will shed more light on the health of these children over time. PMID- 21699688 TI - Chemical analysis of Greek pollen - Antioxidant, antimicrobial and proteasome activation properties. AB - BACKGROUND: Pollen is a bee-product known for its medical properties from ancient times. In our days is increasingly used as health food supplement and especially as a tonic primarily with appeal to the elderly to ameliorate the effects of ageing. In order to evaluate the chemical composition and the biological activity of Greek pollen which has never been studied before, one sample with identified botanical origin from sixteen different common plant taxa of Greece has been evaluated. RESULTS: Three different extracts of the studied sample of Greek pollen, have been tested, in whether could induce proteasome activities in human fibroblasts. The water extract was found to induce a highly proteasome activity, showing interesting antioxidant properties. Due to this activity the aqueous extract was further subjected to chemical analysis and seven flavonoids have been isolated and identified by modern spectral means. From the methanolic extract, sugars, lipid acids, phenolic acids and their esters have been also identified, which mainly participate to the biosynthetic pathway of pollen phenolics. The total phenolics were estimated with the Folin-Ciocalteau reagent and the total antioxidant activity was determined by the DPPH method while the extracts and the isolated compounds were also tested for their antimicrobial activity by the dilution technique. CONCLUSIONS: The Greek pollen is rich in flavonoids and phenolic acids which indicate the observed free radical scavenging activity, the effects of pollen on human fibroblasts and the interesting antimicrobial profile. PMID- 21699689 TI - The evaluation of Pat-Pat related injuries in the Western Black Sea region of Turkey. AB - BACKGROUND: Accidents caused by motorized vehicle in the agricultural sector are frequently observed. In Turkey; accidents arising from motorized vehicles, named Pat-Pat, which are used by farmers in the Western Black Sea region is not unusual. METHODS: One hundred five patients who were brought into the Emergency Department of Duzce University, Medical Faculty Hospital between September 2009 and August 2010 due to Pat-Pat related accidents were evaluated. RESULTS: The cases consisted of 73 (69.5%) males and 32 (30.5%) females, ranging from 2 to 73 years of age. In the 10-39 age group, a total of 63 (60.0%) cases were determined. The months when the greatest rate of cases applied to the hospital consisted of July, August, September and the season is summer. The cases were exposed to trauma in roads in 54 (51.4%), and 51 (48.6%) occurred in agricultural area without roads. Eighty seven (82.9%) cases were injured due to the overturning of vehicle. The patients were brought to the hospital using a private vehicle in 54 (51.4%) of the cases and in 51 (48.6%) cases, 112 ambulance system was used. The cases were determined to apply to the hospital most frequently between 6 pm-12 am. The injuries frequently consisted of head-neck and spine traumas, thorax traumas and upper extremity traumas. In 55 (52.4%) cases, open wound-laceration was determined. Seventy five (71.4%) cases were treated in the Emergency Department, and 28 (26.7%) were hospitalized. Three (2.9%) cases were deceased. CONCLUSIONS: Serious injuries can occur in Pat-Pat related accidents, and careful systematic physical examination should be conducted. In order to prevent these accidents, education of farm operators and engineering studies on the mechanics and safety of these vehicles should be taken and legal regulations should be created. PMID- 21699690 TI - Robotic image-guided reirradiation of lateral pelvic recurrences: preliminary results. AB - BACKGROUND: The first-line treatment of a pelvic recurrence in a previously irradiated area is surgery. Unfortunately, few patients are deemed operable, often due to the location of the recurrence, usually too close to the iliac vessels, or the associated surgical morbidity. The objective of this study is to test the viability of robotic image-guided radiotherapy as an alternative treatment in inoperable cases. METHODS: Sixteen patients previously treated with radiotherapy were reirradiated with CyberKnife(r) for lateral pelvic lesions. Recurrences of primary rectal cancer (4 patients), anal canal (6), uterine cervix cancer (4), endometrial cancer (1), and bladder carcinoma (1) were treated. The median dose of the previous treatment was 45 Gy (EqD2 range: 20 to 96 Gy). A total dose of 36 Gy in six fractions was delivered with the CyberKnife over three weeks. The responses were evaluated according to RECIST criteria. RESULTS: Median follow-up was 10.6 months (1.9 to 20.5 months). The actuarial local control rate was 51.4% at one year. Median disease-free survival was 8.3 months after CyberKnife treatment. The actuarial one-year survival rate was 46%. Acute tolerance was limited to digestive grade 1 and 2 toxicities. CONCLUSIONS: Robotic stereotactic radiotherapy can offer a short and well-tolerated treatment for lateral pelvic recurrences in previously irradiated areas in patients otherwise not treatable. Efficacy and toxicity need to be evaluated over the long term, but initial results are encouraging. PMID- 21699691 TI - DeBi: Discovering Differentially Expressed Biclusters using a Frequent Itemset Approach. AB - BACKGROUND: The analysis of massive high throughput data via clustering algorithms is very important for elucidating gene functions in biological systems. However, traditional clustering methods have several drawbacks. Biclustering overcomes these limitations by grouping genes and samples simultaneously. It discovers subsets of genes that are co-expressed in certain samples. Recent studies showed that biclustering has a great potential in detecting marker genes that are associated with certain tissues or diseases. Several biclustering algorithms have been proposed. However, it is still a challenge to find biclusters that are significant based on biological validation measures. Besides that, there is a need for a biclustering algorithm that is capable of analyzing very large datasets in reasonable time. RESULTS: Here we present a fast biclustering algorithm called DeBi (Differentially Expressed BIclusters). The algorithm is based on a well known data mining approach called frequent itemset. It discovers maximum size homogeneous biclusters in which each gene is strongly associated with a subset of samples. We evaluate the performance of DeBi on a yeast dataset, on synthetic datasets and on human datasets. CONCLUSIONS: We demonstrate that the DeBi algorithm provides functionally more coherent gene sets compared to standard clustering or biclustering algorithms using biological validation measures such as Gene Ontology term and Transcription Factor Binding Site enrichment. We show that DeBi is a computationally efficient and powerful tool in analyzing large datasets. The method is also applicable on multiple gene expression datasets coming from different labs or platforms. PMID- 21699692 TI - In vivo imaging of the airway wall in asthma: fibered confocal fluorescence microscopy in relation to histology and lung function. AB - BACKGROUND: Airway remodelling is a feature of asthma including fragmentation of elastic fibres observed in the superficial elastin network of the airway wall. Fibered confocal fluorescence microscopy (FCFM) is a new and non-invasive imaging technique performed during bronchoscopy that may visualize elastic fibres, as shown by in vitro spectral analysis of elastin powder. We hypothesized that FCFM images capture in vivo elastic fibre patterns within the airway wall and that such patterns correspond with airway histology. We aimed to establish the concordance between the bronchial elastic fibre pattern in histology and FCFM. Second, we examined whether elastic fibre patterns in histology and FCFM were different between asthmatic subjects and healthy controls. Finally, the association between these patterns and lung function parameters was investigated. METHODS: In a cross-sectional study comprising 16 subjects (8 atopic asthmatic patients with controlled disease and 8 healthy controls) spirometry and bronchoscopy were performed, with recording of FCFM images followed by endobronchial biopsy at the airway main carina. Elastic fibre patterns in histological sections and FCFM images were scored semi-quantitatively. Agreement between histology and FCFM was analysed using linearly weighted kappa kappaw. RESULTS: The patterns observed in histological sections and FCFM images could be divided into 3 distinct groups. There was good agreement between elastic fibre patterns in histology and FCFM patterns (kappaw 0.744). The semi-quantitative pattern scores were not different between asthmatic patients and controls. Notably, there was a significant difference in post-bronchodilator FEV1 %predicted between the different patterns by histology (p = 0.001) and FCFM (p = 0.048), regardless of asthma or atopy. CONCLUSION: FCFM captures the elastic fibre pattern within the airway wall in humans in vivo. The association between post-bronchodilator FEV1 %predicted and both histological and FCFM elastic fibre patterns points towards a structure-function relationship between extracellular matrix in the airway wall and lung function. TRIAL REGISTRATION: Netherlands Trial Register NTR1306. PMID- 21699693 TI - Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation. AB - BACKGROUND: The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) (OMIM 225400) is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC 1.14.11.4) due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP) and hydroxylysyl pyridinoline (HP) crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal. METHODS: We describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome. RESULTS: Age at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial), independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients. CONCLUSION: In view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity. PMID- 21699694 TI - Assessment of anti-inflammatory tumor treatment efficacy by longitudinal monitoring employing sonographic micro morphology in a preclinical mouse model. AB - BACKGROUND: With the development of increasingly sophisticated three-dimensional volumetric imaging methods, tumor volume can serve as a robust and reproducible measurement of drug efficacy. Since the use of molecularly targeted agents in the clinic will almost certainly involve combinations with other therapeutic modalities, the use of volumetric determination can help to identify a dosing schedule of sequential combinations of cytostatic drugs resulting in long term control of tumor growth with minimal toxicity. The aim of this study is to assess high resolution sonography imaging for the in vivo monitoring of efficacy of Infliximab in pancreatic tumor. METHODS: In the first experiment, primary orthotopic pancreatic tumor growth was measured with Infliximab treatment. In the second experiment, orthotopic tumors were resected ten days after inoculation of tumor cells and tumor recurrence was measured following Infliximab treatment. Tumor progression was evaluated using 3D high resolution sonography. RESULTS: Sonography measurement of tumor volume in vivo showed inhibitory effect of Infliximab on primary tumor growth in both non-resected and resected models. Measurement of the dynamics of tumor growth by sonography revealed that in the primary tumor Infliximab is effective against established tumors while in the resection model, Infliximab is more effective at an early stage following tumor resection. Infliximab treatment is also effective in inhibiting tumor growth growth as a result of tumor cell contamination of the surgical field. CONCLUSIONS: Clinical application of Infliximab is feasible in both the neoadjuvant and adjuvant setting. Infliximab is also effective in slowing the growth of tumor growth under the peritoneum and may have application in treating peritoneal carcinomatosis. Finally the study demonstrates that high resolution sonography is a sensitive imaging modality for the measurement of pancreatic tumor growth. PMID- 21699695 TI - Admission hypo- or hyperthermia and survival after trauma in civilian and military environments. AB - BACKGROUND: In the care of patients with traumatic injuries, focus is placed on hypothermia secondary to its deleterious impact on the coagulation cascade. However, there is scant information on the mortality effect of hyperthermia. STUDY OBJECTIVES: We hypothesized that both hypothermia and hyperthermia are associated with decreased survival in patients with traumatic injuries. Furthermore, we hypothesized that in the military setting, the incidence of hyperthermia would be greater compared to the civilian environment and thus contributing to an increase in mortality. METHODS: Registries compared were the National Trauma Data Bank (NTDB), three civilian Level I trauma centers, and military combat support hospitals. The NTDB was used as a reference to define hypothermia and hyperthermia based upon survival. Admission temperature and outcome were known for 4,093 civilian and 4,394 military records. RESULTS: Hypothermia was defined as < 36 degrees C and hyperthermia > 38 degrees C as mortality increased outside this range. The overall mortality rates were 3.5% for civilians and 2.5% for military (p < 0.05). Of civilians, 9.3% (382) were hypothermic and 2.2% (92) hyperthermic. The incidence of hypothermia in the military patients was 6.0% (263) and for hyperthermia the incidence was 7.4% (327). Irrespective of group, patients with hypothermia or hyperthermia had an increased mortality compared to those with normal temperatures, ([for civilian:military ] hypothermia 12%:11%; normal 2%:2%; hyperthermia 14%:4%). CONCLUSION: Care of the victim with traumatic injuries emphasizes avoidance of hypothermia; however, hyperthermia is also detrimental. The presence of hypothermia or hyperthermia should be considered in the initial treatment of the patient with traumatic injuries. PMID- 21699696 TI - Totally biological composite aortic stentless valved conduit for aortic root replacement: 10-year experience. AB - OBJECTIVES: To retrospectively analyze the clinical outcome of a totally biological composite stentless aortic valved conduit (No-React(r) BioConduit) implanted using the Bentall procedure over ten years in a single centre. METHODS: Between 27/10/99 and 19/01/08, the No-React(r) BioConduit composite graft was implanted in 67 patients. Data on these patients were collected from the in hospital database, from patient notes and from questionnaires. A cohort of patients had 2D-echocardiogram with an average of 4.3 +/- 0.45 years post operatively to evaluate valve function, calcification, and the diameter of the conduit. RESULTS: Implantation in 67 patients represented a follow-up of 371.3 patient-year. Males were 60% of the operated population, with a mean age of 67.9 +/- 1.3 years (range 34.1-83.8 years), 21 of them below the age of 65. After a mean follow-up of 7.1 +/- 0.3 years (range of 2.2-10.5 years), more than 50% of the survivors were in NYHA I/II and more than 60% of the survivors were angina free (CCS 0). The overall 10-year survival following replacement of the aortic valve and root was 51%. During this period, 88% of patients were free from valved conduit related complications leading to mortality. Post-operative echocardiography studies showed no evidence of stenosis, dilatation, calcification or thrombosis. Importantly, during the 10-year follow-up period no failures of the valved conduit were reported, suggesting that the tissue of the conduit does not structurally change (histology of one explant showed normal cusp and conduit). CONCLUSIONS: The No-React(r) BioConduit composite stentless aortic valved conduit provides excellent long-term clinical results for aortic root replacement with few prosthesis-related complications in the first post-operative decade. PMID- 21699697 TI - Clinical trial of extended-dose chloroquine for treatment of resistant falciparum malaria among Afghan refugees in Pakistan. AB - BACKGROUND: Falciparum malaria is a significant problem for Afghan refugees in Pakistan. Refugee treatment guidelines recommended standard three-day chloroquine treatment (25 mg/kg) for first episodes and extended five-day treatment (40 mg/kg) for recrudescent infections, based on the assumption that a five-day course would more likely achieve a cure. An in-vivo randomized controlled trial was conducted among refugees with uncomplicated falciparum malaria to determine whether five-day treatment (CQ40) was more effective than standard treatment (CQ25). METHODS: 142 falciparum patients were recruited into CQ25 or CQ40 treatment arms and followed up to 60 days with regular blood smears. The primary outcome was parasitological cure without recrudescence. Treatment failures were retreated with CQ40. PCR genotyping of 270 samples, from the same and nearby sites, was used to support interpretation of outcomes. RESULTS: 84% of CQ25 versus 51% of CQ40 patients experienced parasite recrudescence during follow-up (adjusted odds ratio 0.17, 95%CI 0.08-0.38). Cure rates were significantly improved with CQ40, particularly among adults. Fever clearance time, parasite clearance time, and proportions gametocytaemic post-treatment were similar between treatment groups. Second-line CQ40 treatment resulted in higher failure rates than first-line CQ40 treatment. CQ-resistance marker pfcrt 76T was found in all isolates analysed, while pfmdr1 86Y and 184Y were found in 18% and 37% of isolates respectively. CONCLUSIONS: CQ is not suitable for first-line falciparum treatment in Afghan refugee communities. The extended-dose CQ regimen can overcome 39% of resistant infections that would recrudesce under the standard regimen, but the high failure rate after directly observed treatment demonstrates its use is inappropriate. PMID- 21699698 TI - Preventing childhood obesity during infancy in UK primary care: a mixed-methods study of HCPs' knowledge, beliefs and practice. AB - BACKGROUND: There is a strong rationale for intervening in early childhood to prevent obesity. Over a quarter of infants gain weight more rapidly than desirable during the first six months of life putting them at greater risk of obesity in childhood. However, little is known about UK healthcare professionals' (HCPs) approach to primary prevention. This study explored obesity-related knowledge of UK HCPs and the beliefs and current practice of general practitioners (GPs) and practice nurses in relation to identifying infants at risk of developing childhood obesity. METHOD: Survey of UK HCPs (GPs, practice nurses, health visitors, nursery, community and children's nurses). HCPs (n = 116) rated their confidence in providing infant feeding advice and completed the Obesity Risk Knowledge Scale (ORK-10).Semi-structured interviews with a sub-set of 12 GPs and 6 practice nurses were audio recorded, taped and transcribed verbatim. Thematic analysis was applied using an interpretative, inductive approach. RESULTS: GPs were less confident about giving advice about infant feeding than health visitors (p = 0.001) and nursery nurses (p = 0.009) but more knowledgeable about the health risks of obesity (p < 0.001) than nurses (p = 0.009). HCPs who were consulted more often about feeding were less knowledgeable about the risks associated with obesity (r = -0.34, n = 114, p < 0.001). There was no relationship between HCPs' ratings of confidence in their advice and their knowledge of the obesity risk.Six main themes emerged from the interviews: 1) Attribution of childhood obesity to family environment, 2) Infant feeding advice as the health visitor's role, 3) Professional reliance on anecdotal or experiential knowledge about infant feeding, 4) Difficulties with recognition of, or lack of concern for, infants "at risk" of becoming obese, 5) Prioritising relationship with parent over best practice in infant feeding and 6) Lack of shared understanding for dealing with early years' obesity. CONCLUSIONS: Intervention is needed to improve health visitors and nursery nurses' knowledge of obesity risk and GPs and practice nurses' capacity to identify and manage infants' at risk of developing childhood obesity. GPs value strategies that maintain relationships with vulnerable families and interventions to improve their advice-giving around infant feeding need to take account of this. Further research is needed to determine optimal ways of intervening with infants at risk of obesity in primary care. PMID- 21699699 TI - Antiviral drugs against hepatitis C virus. AB - Hepatitis C virus (HCV) infection is a major worldwide problem causes acute and chronic HCV infection. Current treatment of HCV includes pegylated interferon alpha (PEG IFN- alpha) plus ribavirin (RBV) which has significant side effects depending upon the type of genotype. Currently, there is a need to develop antiviral agents, both from synthetic chemistry and Herbal sources. In the last decade, various novel HCV replication, helicase and entry inhibitors have been synthesized and some of which have been entered in different phases of clinical trials. Successful results have been acquired by executing combinational therapy of compounds with standard regime in different HCV replicons. Even though, diverse groups of compounds have been described as antiviral targets against HCV via Specifically Targeted Antiviral Therapy for hepatitis C (STAT-C) approach (in which compounds are designed to directly block HCV or host proteins concerned in HCV replication), still there is a need to improve the properties of existing antiviral compounds. In this review, we sum up potent antiviral compounds against entry, unwinding and replication of HCV and discussed their activity in combination with standard therapy. Conclusively, further innovative research on chemical compounds will lead to consistent standard therapy with fewer side effects. PMID- 21699701 TI - Attitude toward contraception and abortion among Curacao women. Ineffective contraception due to limited sexual education? AB - BACKGROUND: In Curacao is a high incidence of unintended pregnancies and induced abortions. Most of the induced abortions in Curacao are on request of the woman and performed by general practitioners. In Curacao, induced abortion is strictly prohibited, but since 1999 there has been a policy of connivance. We present data on the relevance of economic and socio-cultural factors for the high abortion rates and the ineffective use of contraception. METHODS: Structured interviews to investigate knowledge and attitudes toward sexuality, contraception and abortion and reasons for ineffective use of contraceptives among women, visiting general practitioners. RESULTS: Of 158 women, 146 (92%) participated and 82% reported that their education on sexuality and about contraception was of good quality. However 'knowledge of reliable contraceptive methods' appeared to be--in almost 50% of the cases--false information, misjudgements or erroneous views on the chance of getting pregnant using coitus interruptus and about the reliability and health effects of oral contraceptive pills. Almost half of the interviewed women had incorrect or no knowledge about reliability of condom use and IUD. 42% of the respondents risked by their behavior an unplanned pregnancy. Most respondents considered abortion as an emergency procedure, not as contraception. Almost two third experienced emotional, physical or social problems after the abortion. CONCLUSIONS: Respondents had a negative attitude toward reliable contraceptives due to socio-cultural determined ideas about health consequences and limited sexual education. Main economic factors were costs of contraceptive methods, because most health insurances in Curacao do not cover contraceptives. To improve the effective use of reliable contraceptives, more adequate information should be given, targeting the wrong beliefs and false information. The government should encourage health insurance companies to reimburse contraceptives. Furthermore, improvement of counseling during the abortion procedure is important. PMID- 21699700 TI - Multiple platform assessment of the EGF dependent transcriptome by microarray and deep tag sequencing analysis. AB - BACKGROUND: Epidermal Growth Factor (EGF) is a key regulatory growth factor activating many processes relevant to normal development and disease, affecting cell proliferation and survival. Here we use a combined approach to study the EGF dependent transcriptome of HeLa cells by using multiple long oligonucleotide based microarray platforms (from Agilent, Operon, and Illumina) in combination with digital gene expression profiling (DGE) with the Illumina Genome Analyzer. RESULTS: By applying a procedure for cross-platform data meta-analysis based on RankProd and GlobalAncova tests, we establish a well validated gene set with transcript levels altered after EGF treatment. We use this robust gene list to build higher order networks of gene interaction by interconnecting associated networks, supporting and extending the important role of the EGF signaling pathway in cancer. In addition, we find an entirely new set of genes previously unrelated to the currently accepted EGF associated cellular functions. CONCLUSIONS: We propose that the use of global genomic cross-validation derived from high content technologies (microarrays or deep sequencing) can be used to generate more reliable datasets. This approach should help to improve the confidence of downstream in silico functional inference analyses based on high content data. PMID- 21699702 TI - Expression analysis of asthma candidate genes during human and murine lung development. AB - BACKGROUND: Little is known about the role of most asthma susceptibility genes during human lung development. Genetic determinants for normal lung development are not only important early in life, but also for later lung function. OBJECTIVE: To investigate the role of expression patterns of well-defined asthma susceptibility genes during human and murine lung development. We hypothesized that genes influencing normal airways development would be over-represented by genes associated with asthma. METHODS: Asthma genes were first identified via comprehensive search of the current literature. Next, we analyzed their expression patterns in the developing human lung during the pseudoglandular (gestational age, 7-16 weeks) and canalicular (17-26 weeks) stages of development, and in the complete developing lung time series of 3 mouse strains: A/J, SW, C57BL6. RESULTS: In total, 96 genes with association to asthma in at least two human populations were identified in the literature. Overall, there was no significant over-representation of the asthma genes among genes differentially expressed during lung development, although trends were seen in the human (Odds ratio, OR 1.22, confidence interval, CI 0.90-1.62) and C57BL6 mouse (OR 1.41, CI 0.92-2.11) data. However, differential expression of some asthma genes was consistent in both developing human and murine lung, e.g. NOD1, EDN1, CCL5, RORA and HLA-G. Among the asthma genes identified in genome wide association studies, ROBO1, RORA, HLA-DQB1, IL2RB and PDE10A were differentially expressed during human lung development. CONCLUSIONS: Our data provide insight about the role of asthma susceptibility genes during lung development and suggest common mechanisms underlying lung morphogenesis and pathogenesis of respiratory diseases. PMID- 21699703 TI - Efficacy of PermaNet(r) 2.0 and PermaNet(r) 3.0 against insecticide-resistant Anopheles gambiae in experimental huts in Cote d'Ivoire. AB - BACKGROUND: Pyrethroid resistance in vectors could limit the efficacy of long lasting insecticidal nets (LLINs) because all LLINs are currently treated with pyrethroids. The goal of this study was to evaluate the efficacy and wash resistance of PermaNet(r) 3.0 compared to PermaNet(r) 2.0 in an area of high pyrethroid in Cote d'Ivoire. PermaNet(r) 3.0 is impregnated with deltamethrin at 85 mg/m2 on the sides of the net and with deltamethrin and piperonyl butoxide on the roof. PermaNet(r) 2.0 is impregnated with deltamethrin at 55 mg/m2 across the entire net. METHODS: The study was conducted in the station of Yaokoffikro, in central Cote d'Ivoire. The efficacy of intact unwashed and washed LLINs was compared over a 12-week period with a conventionally-treated net (CTN) washed to just before exhaustion. WHO cone bioassays were performed on sub-sections of the nets, using wild-resistant An. gambiae and Kisumu strains. Mosquitoes were collected five days per week and were identified to genus and species level and classified as dead or alive, then unfed or blood-fed. RESULTS: Mortality rates of over 80% from cone bioassays with wild-caught pyrethroid-resistant An. gambiae s.s were recorded only with unwashed PermaNet(r) 3.0. Over 12 weeks, a total of 7,291 mosquitoes were collected. There were significantly more An. gambiae s.s. and Culex spp. caught in control huts than with other treatments (P < 0.001). The proportion of mosquitoes exiting the huts was significantly lower with the control than for the treatment arms (P < 0.001). Mortality rates with resistant An. gambiae s.s and Culex spp, were lower for the control than for other treatments (P < 0.001), which did not differ (P > 0.05) except for unwashed PermaNet(r) 3.0 (P < 0.001), which gave significantly higher mortality (P < 0.001). CONCLUSIONS: This study showed that unwashed PermaNet(r) 3.0 caused significantly higher mortality against pyrethroid resistant An. gambiae s.s and Culex spp than PermaNet(r) 2.0 and the CTN. The increased efficacy with unwashed PermaNet(r) 3.0 over PermaNet(r) 2.0 and the CTN was also demonstrated by higher KD and mortality rates (KD > 95% and mortality rate > 80%) in cone bioassays performed with wild pyrethroid-resistant An. gambiae s.s from Yaokoffikro. PMID- 21699705 TI - Regulating duty free sales and tobacco advertising in airports: a call for action. PMID- 21699706 TI - On the path to translation: Highlights from the 2010 Canadian Conference on Ovarian Cancer Research. AB - Ovarian cancer continues to be the most lethal of the gynaecologic malignancies due to the lack of early detection, screening strategies and ineffective therapeutics for late-stage metastatic disease, particularly in the recurrent setting. The gathering of researchers investigating fundamental pathobiology of ovarian cancer and the clinicians who treat patients with this insidious disease is paramount to meeting the challenges we face. Since 2002, the Canadian Conference on Ovarian Cancer Research, held every two years, has served this essential purpose. The objectives of this conference have been to disseminate new information arising from the most recent ovarian cancer research and identify the most pressing challenges we still face as scientists and clinicians. This is best accomplished through direct encounters and exchanges of innovative ideas among colleagues and trainees from the realms of basic science and clinical disciplines. This meeting has and continues to successfully facilitate rapid networking and establish new collaborations from across Canada. This year, more guest speakers and participants from other countries have extended the breadth of the research on ovarian cancer that was discussed at the meeting. This report summarizes the key findings presented at the fifth biennial Canadian Conference on Ovarian Cancer Research held in Toronto, Ontario, and includes the important issues and challenges we still face in the years ahead to make a significant impact on this devastating disease. PMID- 21699704 TI - Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits. AB - Atypical bovine spongiform encephalopathy (BSE) has recently been identified in Europe, North America, and Japan. It is classified as H-type and L-type BSE according to the molecular mass of the disease-associated prion protein (Pr(PSc)). To investigate the topographical distribution and deposition patterns of immunolabeled Pr(PSc), H-type BSE isolate was inoculated intracerebrally into cattle. H-type BSE was successfully transmitted to 3 calves, with incubation periods between 500 and 600 days. Moderate to severe spongiform changes were detected in the cerebral and cerebellar cortices, basal ganglia, thalamus, and brainstem. H-type BSE was characterized by the presence of PrP-immunopositive amyloid plaques in the white matter of the cerebrum, basal ganglia, and thalamus. Moreover, intraglial-type immunolabeled Pr(PSc) was prominent throughout the brain. Stellate-type immunolabeled Pr(PSc) was conspicuous in the gray matter of the cerebral cortex, basal ganglia, and thalamus, but not in the brainstem. In addition, Pr(PSc) accumulation was detected in the peripheral nervous tissues, such as trigeminal ganglia, dorsal root ganglia, optic nerve, retina, and neurohypophysis. Cattle are susceptible to H-type BSE with a shorter incubation period, showing distinct and distinguishable phenotypes of Pr(PSc) accumulation. PMID- 21699707 TI - A genome-wide DNA methylation study in colorectal carcinoma. AB - BACKGROUND: We performed a genome-wide scan of 27,578 CpG loci covering 14,475 genes to identify differentially methylated loci (DML) in colorectal carcinoma (CRC). METHODS: We used Illumina's Infinium methylation assay in paired DNA samples extracted from 24 fresh frozen CRC tissues and their corresponding normal colon tissues from 24 consecutive diagnosed patients at a tertiary medical center. RESULTS: We found a total of 627 DML in CRC covering 513 genes, of which 535 are novel DML covering 465 genes. We also validated the Illumina Infinium methylation data for top-ranking genes by non-bisulfite conversion q-PCR-based methyl profiler assay in a subset of the same samples. We also carried out integration of genome-wide copy number and expression microarray along with methylation profiling to see the functional effect of methylation. Gene Set Enrichment Analysis (GSEA) showed that among the major "gene sets" that are hypermethylated in CRC are the sets: "inhibition of adenylate cyclase activity by G-protein signaling", "Rac guanyl-nucleotide exchange factor activity", "regulation of retinoic acid receptor signaling pathway" and "estrogen receptor activity". Two-level nested cross validation showed that DML-based predictive models may offer reasonable sensitivity (around 89%), specificity (around 95%), positive predictive value (around 95%) and negative predictive value (around 89%), suggesting that these markers may have potential clinical application. CONCLUSION: Our genome-wide methylation study in CRC clearly supports most of the previous findings; additionally we found a large number of novel DML in CRC tissue. If confirmed in future studies, these findings may lead to identification of genomic markers for potential clinical application. PMID- 21699708 TI - T-bet controls severity of hypersensitivity pneumonitis. AB - Hypersensitivity Pneumonitis (HP) is an interstitial lung disease that develops following repeated exposure to inhaled environmental antigens. The disease is characterized by alveolitis, granuloma formation and in some patients' fibrosis. IFNgamma plays a critical role in HP; in the absence of IFNgamma granuloma formation does not occur. However, recent studies using animal models of HP have suggested that HP is a Th17 disease calling into question the role of IFNgamma. In this study, we report that initially IFNgamma production is dependent on IL-18 and the transcription factor T-bet, however as the disease continues IFNgamma production is IL-18-independent and partially T-bet dependent. Although IFNgamma production is required for granuloma formation its role is distinct from that of T-bet. Mice that are deficient in T-bet and exposed to S. rectivirgula develop more severe disease characterized by an exacerbated Th17 cell response, decreased Th1 cell response, and increased collagen production in the lung. T-bet-mediated protection does not appear to be due to the development of a protective Th1 response; shifting the balance from a Th17 predominant response to a Th1 response by inhibition of IL-6 also results in lung pathology. The results from this study suggest that both Th1 and Th17 cells can be pathogenic in this model and that IFNgamma and T-bet play divergent roles in the disease process. PMID- 21699709 TI - Dynamics of mitochondrial heteroplasmy in three families investigated via a repeatable re-sequencing study. AB - BACKGROUND: Originally believed to be a rare phenomenon, heteroplasmy - the presence of more than one mitochondrial DNA (mtDNA) variant within a cell, tissue, or individual - is emerging as an important component of eukaryotic genetic diversity. Heteroplasmies can be used as genetic markers in applications ranging from forensics to cancer diagnostics. Yet the frequency of heteroplasmic alleles may vary from generation to generation due to the bottleneck occurring during oogenesis. Therefore, to understand the alterations in allele frequencies at heteroplasmic sites, it is of critical importance to investigate the dynamics of maternal mtDNA transmission. RESULTS: Here we sequenced, at high coverage, mtDNA from blood and buccal tissues of nine individuals from three families with a total of six maternal transmission events. Using simulations and re-sequencing of clonal DNA, we devised a set of criteria for detecting polymorphic sites in heterogeneous genetic samples that is resistant to the noise originating from massively parallel sequencing technologies. Application of these criteria to nine human mtDNA samples revealed four heteroplasmic sites. CONCLUSIONS: Our results suggest that the incidence of heteroplasmy may be lower than estimated in some other recent re-sequencing studies, and that mtDNA allelic frequencies differ significantly both between tissues of the same individual and between a mother and her offspring. We designed our study in such a way that the complete analysis described here can be repeated by anyone either at our site or directly on the Amazon Cloud. Our computational pipeline can be easily modified to accommodate other applications, such as viral re-sequencing. PMID- 21699710 TI - Unusual finding of endocervical-like mucinous epithelium in continuity with urothelium in endocervicosis of the urinary bladder. AB - Endocervicosis in the urinary bladder is a rare benign condition. We present a case in a 37-year-old woman with classical clinical and pathological features of endocervicosis. The unusual observation of endocervical-like mucinous epithelium in continuity with the urothelium in addition to fully developed endocervicosis prompted immunohistochemical profiling of the case using antibodies to cytokeratins (AE1/AE3, CK19, CK7, CK5/6, CK20), HBME-1, estrogen receptor (ER) and progesterone receptor (PR) to assess the relationship of the surface mucinous and endocervicosis glandular epithelia. The surface mucinous epithelium, urothelium and endocervicosis glands were immunopositive for AE1/AE3, CK7 and CK19 while CK20 was only expressed by few urothelial umbrella cells. The surface mucinous epithelium was CK5/6 and HBME-1 immunonegative but showed presence of ER and PR. This was in contrast to the urothelium's expression of CK5/6 but not ER and PR. In comparison, endocervicosis glands expressed HBME-1, unlike the surface mucinous epithelium. The endocervicosis epithelium also demonstrated the expected presence of ER and PR and CK5/6 immunonegativity. The slightly differing immunohistochemical phenotypes of the surface mucinous and morphologically similar endocervicosis glandular epithelium is interesting and requires further clarification to its actual nature. The patient has remained well and without evidence of disease 18-months following transurethral resection of the lesion. PMID- 21699712 TI - Collaborations for leadership in applied health research and care: lessons from the theory of communities of practice. AB - BACKGROUND: The paper combines the analytical and instrumental perspectives on communities of practice (CoPs) to reflect on potential challenges that may arise in the process of interprofessional and inter-organisational joint working within the Collaborations for Leaderships in Applied Health Research and Care (CLAHRCs)- partnerships between the universities and National Health Service (NHS) Trusts aimed at conducting applied health research and translating its findings into day to-day clinical practice. DISCUSSION: The paper discusses seminal theoretical literature on CoPs as well as previous empirical research on the role of these communities in healthcare collaboration, which is organised around the following three themes: knowledge sharing within and across CoPs, CoP formation and manageability, and identity building in CoPs. It argues that the multiprofessional and multi-agency nature of the CLAHRCs operating in the traditionally demarcated organisational landscape of the NHS may present formidable obstacles to knowledge sharing between various professional groupings, formation of a shared 'collaborative' identity, and the development of new communities within the CLAHRCs. To cross multiple boundaries between various professional and organisational communities and hence enable the flow of knowledge, the CLAHRCs will have to create an effective system of 'bridges' involving knowledge brokers, boundary objects, and cross-disciplinary interactions as well as address a number of issues related to professional and organisational identification. SUMMARY: The CoP approach can complement traditional 'stage-of-change' theories used in the field of implementation research and provide a basis for designing theory-informed interventions and evaluations. It can help to illuminate multiple boundaries that exist between professional and organisational groups within the CLAHRCs and suggest ways of crossing those boundaries to enable knowledge transfer and organisational learning. Achieving the aims of the CLAHRCs and producing a sustainable change in the ways applied health research is conducted and implemented may be influenced by how effectively these organisations can navigate through the multiple CoPs involved and promote the development of new multiprofessional and multi organisational communities united by shared practice and a shared sense of belonging--an assumption that needs to be explored by further empirical research. PMID- 21699711 TI - Neuroregeneration in neurodegenerative disorders. AB - BACKGROUND: Neuroregeneration is a relatively recent concept that includes neurogenesis, neuroplasticity, and neurorestoration--implantation of viable cells as a therapeutical approach. DISCUSSION: Neurogenesis and neuroplasticity are impaired in brains of patients suffering from Alzheimer's Disease or Parkinson's Disease and correlate with low endogenous protection, as a result of a diminished growth factors expression. However, we hypothesize that the brain possesses, at least in early and medium stages of disease, a "neuroregenerative reserve", that could be exploited by growth factors or stem cells-neurorestoration therapies. SUMMARY: In this paper we review the current data regarding all three aspects of neuroregeneration in Alzheimer's Disease and Parkinson's Disease. PMID- 21699713 TI - Variations on a theme: diversification of cuticular hydrocarbons in a clade of cactophilic Drosophila. AB - BACKGROUND: We characterized variation and chemical composition of epicuticular hydrocarbons (CHCs) in the seven species of the Drosophila buzzatii cluster with gas chromatography/mass spectrometry. Despite the critical role of CHCs in providing resistance to desiccation and involvement in communication, such as courtship behavior, mating, and aggregation, few studies have investigated how CHC profiles evolve within and between species in a phylogenetic context. We analyzed quantitative differences in CHC profiles in populations of the D. buzzatii species cluster in order to assess the concordance of CHC differentiation with species divergence. RESULTS: Thirty-six CHC components were scored in single fly extracts with carbon chain lengths ranging from C29 to C39, including methyl-branched alkanes, n-alkenes, and alkadienes. Multivariate analysis of variance revealed that CHC amounts were significantly different among all species and canonical discriminant function (CDF) analysis resolved all species into distinct, non-overlapping groups. Significant intraspecific variation was found in different populations of D. serido suggesting that this taxon is comprised of at least two species. We summarized CHC variation using CDF analysis and mapped the first five CHC canonical variates (CVs) onto an independently derived period (per) gene + chromosome inversion + mtDNA COI gene for each sex. We found that the COI sequences were not phylogenetically informative due to introgression between some species, so only per + inversion data were used. Positive phylogenetic signal was observed mainly for CV1 when parsimony methods and the test for serial independence (TFSI) were used. These results changed when no outgroup species were included in the analysis and phylogenetic signal was then observed for female CV3 and/or CV4 and male CV4 and CV5. Finally, removal of divergent populations of D. serido significantly increased the amount of phylogenetic signal as up to four out of five CVs then displayed positive phylogenetic signal. CONCLUSIONS: CHCs were conserved among species while quantitative differences in CHC profiles between populations and species were statistically significant. Most CHCs were species-, population-, and sex-specific. Mapping CHCs onto an independently derived phylogeny revealed that a significant portion of CHC variation was explained by species' systematic affinities indicating phylogenetic conservatism in the evolution of these hydrocarbon arrays, presumptive waterproofing compounds and courtship signals as in many other drosophilid species. PMID- 21699714 TI - Maternal feeding behaviour and young children's dietary quality: a cross sectional study of socially disadvantaged mothers of two-year old children using the Theory of Planned Behaviour. AB - BACKGROUND: Having breakfast, eating food 'cooked from scratch' and eating together as a family have health and psychosocial benefits for young children. This study investigates how these parentally determined behaviours relate to children's dietary quality and uses a psychological model, the Theory of Planned Behaviour (TPB), to investigate socio-cognitive predictors of these behaviours in socially disadvantaged mothers of young children in Scotland. METHOD: Three hundred mothers of children aged 2 years (from 372 invited to participate, 81% response rate), recruited via General Practitioners, took part in home-based semi structured interviews in a cross-sectional survey of maternal psychological factors related to their children's dietary quality. Regression analyses examined statistical predictors of maternal intentions and feeding behaviours. RESULTS: Mothers of children with poorer quality diets were less likely than others to provide breakfast every day, cook from 'scratch' and provide 'proper sit-down meals'. TPB socio-cognitive factors (intentions, perceived behavioural control) significantly predicted these three behaviours, and attitudes, norms, and perceived behavioural control significantly predicted mothers' intentions, with medium to large effect sizes. CONCLUSIONS: Interventions to improve young children's dietary health could benefit from a focus on modifying maternal motivations and attitudes in attempts to improve feeding behaviours. PMID- 21699715 TI - EST mining identifies proteins putatively secreted by the anthracnose pathogen Colletotrichum truncatum. AB - BACKGROUND: Colletotrichum truncatum is a haploid, hemibiotrophic, ascomycete fungal pathogen that causes anthracnose disease on many economically important leguminous crops. This pathogen exploits sequential biotrophic- and necrotrophic- infection strategies to colonize the host. Transition from biotrophy to a destructive necrotrophic phase called the biotrophy-necrotrophy switch is critical in symptom development. C. truncatum likely secretes an arsenal of proteins that are implicated in maintaining a compatible interaction with its host. Some of them might be transition specific. RESULTS: A directional cDNA library was constructed from mRNA isolated from infected Lens culinaris leaflet tissues displaying the biotrophy-necrotrophy switch of C. truncatum and 5000 expressed sequence tags (ESTs) with an average read of > 600 bp from the 5-prime end were generated. Nearly 39% of the ESTs were predicted to encode proteins of fungal origin and among these, 162 ESTs were predicted to contain N-terminal signal peptides (SPs) in their deduced open reading frames (ORFs). The 162 sequences could be assembled into 122 tentative unigenes comprising 32 contigs and 90 singletons. Sequence analyses of unigenes revealed four potential groups: hydrolases, cell envelope associated proteins (CEAPs), candidate effectors and other proteins. Eleven candidate effector genes were identified based on features common to characterized fungal effectors, i.e. they encode small, soluble (lack of transmembrane domain), cysteine-rich proteins with a putative SP. For a selected subset of CEAPs and candidate effectors, semiquantitative RT-PCR showed that these transcripts were either expressed constitutively in both in vitro and in planta or induced during plant infection. Using potato virus X (PVX) based transient expression assays, we showed that one of the candidate effectors, i. e. contig 8 that encodes a cerato-platanin (CP) domain containing protein, unlike CP proteins from other fungal pathogens was unable to elicit a hypersensitive response (HR). CONCLUSIONS: The current study catalogues proteins putatively secreted at the in planta biotrophy-necrotrophy transition of C. truncatum. Some of these proteins may have a role in establishing compatible interaction with the host plant. PMID- 21699716 TI - A prospective controlled study: minimally invasive stereotactic puncture therapy versus conventional craniotomy in the treatment of acute intracerebral hemorrhage. AB - BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke with the high mortality twofold to sixfold higher than that for ischemic stroke. But the treatment of haematomas within the basal ganglia continues to be a matter of debate among neurologists and neurosurgeons. The purpose of this study is to judge the clinical value of minimally invasive stereotactic puncture therapy (MISPT) on acute ICH. METHODS: A prospective controlled study was undertaken. The clinical trial was in compliance with the WMA Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects. According to the enrollment criterion, there were 168 acute ICH cases analyzed, of which 90 cases were performed by MISPT (MISPT group, MG) and 78 cases by Conventional craniotomy (CC group, CG), by means of compare of Glasgow Coma Scale (GCS) score, postoperative complications (PC) and rebleeding incidence (RI), moreover, long-term outcome of 1 year postoperation judged by Glasgow Outcome Scale (GOS), Barthel Index (BI), modified Rankin Scale (mRS) and case fatality(CF). RESULTS: MG patients showed obvious amelioration in GCS score compared with that of CG. The total incidence of PC in MG decreased obviously compared with that of CG. The incidences of rebleeding in MG and CG were 10.0% and 15.4% respectively. There was no obvious difference between CFs of MG and CG. For three parameters representing long-term outcome, the GOS, BI and mRS in MG were ameliorated significantly than that of CG. CONCLUSION: These data suggested that the advantage of MISPT was displayed in minute trauma and safety, and seemed to be feasible and to had a trend towards improved long-term outcome. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR), the registration number: ACTRN12610000945022. PMID- 21699717 TI - A cluster randomised controlled trial of the efficacy of a brief walking intervention delivered in primary care: study protocol. AB - BACKGROUND: The aim of the present research is to conduct a fully powered explanatory trial to evaluate the efficacy of a brief self-regulation intervention to increase walking. The intervention will be delivered in primary care by practice nurses (PNs) and Healthcare Assistants (HCAs) to patients for whom increasing physical activity is a particular priority. The intervention has previously demonstrated efficacy with a volunteer population, and subsequently went through an iterative process of refinement in primary care, to maximise acceptability to both providers and recipients. METHODS/DESIGN: This two arm cluster randomised controlled trial set in UK general practices will compare two strategies for increasing walking, assessed by pedometer, over six months. Patients attending practices randomised to the self-regulation intervention arm will receive an intervention consisting of behaviour change techniques designed to increase walking self-efficacy (confidence in ability to perform the behaviour), and to help people translate their "good" intentions into behaviour change by making plans. Patients attending practices randomised to the information provision arm will receive written materials promoting walking, and a short unstructured discussion about increasing their walking.The trial will recruit 20 PN/HCAs (10 per arm), who will be trained by the research team to deliver the self-regulation intervention or information provision control intervention, to 400 patients registered at their practices (20 patients per PN/HCA). This will provide 85% power to detect a mean difference of five minutes/day walking between the self-regulation intervention group and the information provision control group. Secondary outcomes include health services costs, and intervention effects in sub-groups defined by age, ethnicity, gender, socio-economic status, and clinical condition. A mediation analysis will investigate the extent to which changes in constructs specified by the Theory of Planned Behaviour lead to changes in objectively assessed walking behaviour. DISCUSSION: This trial addresses the current lack of evidence for interventions that are effective at increasing walking and that can be offered to patients in primary care. The intervention being evaluated has demonstrated efficacy, and has been through an extensive process of adaptation to ensure acceptability to both provider and recipient, thus optimising fidelity of intervention delivery and treatment receipt. It therefore provides a strong test of the hypothesis that a self-regulation intervention can help primary care patients increase their walking. TRIAL REGISTRATION: Current Controlled Trials ISRCTN95932902. PMID- 21699718 TI - Semantic inference using chemogenomics data for drug discovery. AB - BACKGROUND: Semantic Web Technology (SWT) makes it possible to integrate and search the large volume of life science datasets in the public domain, as demonstrated by well-known linked data projects such as LODD, Bio2RDF, and Chem2Bio2RDF. Integration of these sets creates large networks of information. We have previously described a tool called WENDI for aggregating information pertaining to new chemical compounds, effectively creating evidence paths relating the compounds to genes, diseases and so on. In this paper we examine the utility of automatically inferring new compound-disease associations (and thus new links in the network) based on semantically marked-up versions of these evidence paths, rule-sets and inference engines. RESULTS: Through the implementation of a semantic inference algorithm, rule set, Semantic Web methods (RDF, OWL and SPARQL) and new interfaces, we have created a new tool called Chemogenomic Explorer that uses networks of ontologically annotated RDF statements along with deductive reasoning tools to infer new associations between the query structure and genes and diseases from WENDI results. The tool then permits interactive clustering and filtering of these evidence paths. CONCLUSIONS: We present a new aggregate approach to inferring links between chemical compounds and diseases using semantic inference. This approach allows multiple evidence paths between compounds and diseases to be identified using a rule-set and semantically annotated data, and for these evidence paths to be clustered to show overall evidence linking the compound to a disease. We believe this is a powerful approach, because it allows compound-disease relationships to be ranked by the amount of evidence supporting them. PMID- 21699719 TI - Transport of Babesia venatorum-infected Ixodes ricinus to Norway by northward migrating passerine birds. AB - BACKGROUND: Bovine babesiosis is regarded as a limited health problem for Norwegian cows, and the incidence has decreased markedly since the 1930s. Rare cases of babesiosis in splenectomised humans from infection with Babesia divergens and B.venatorum have been described. The objective of this study was to determine whether birds can introduce Babesia-infected ticks. There are between 30 and 85 million passerine birds that migrate to Norway every spring. METHODS: Passerine birds were examined for ticks at four bird observatories along the southern Norwegian coast during the spring migrations of 2003, 2004 and 2005. The presence of Babesia was detected in the nymphs of Ixodes ricinus by real-time PCR. Positive samples were confirmed using PCR, cloning and phylogenetic analyses. RESULTS: Of 512 ticks examined, real-time PCR revealed five to be positive (1.0%). Of these, four generated products that indicated the presence of Babesia spp.; each of these were confirmed to be from Babesia venatorum (EU1). Two of the four B. venatorum-positive ticks were caught from birds having an eastern migratory route (P< 0.001). CONCLUSIONS: Birds transport millions of ticks across the North Sea, the Skagerrak and the Kattegat every year. Thus, even with the low prevalence of Babesia-infected ticks, a substantial number of infected ticks will be transported into Norway each year. Therefore, there is a continuous risk for introduction of new Babesia spp. into areas where I. ricinus can survive. PMID- 21699720 TI - Comparison of three different prehospital wrapping methods for preventing hypothermia--a crossover study in humans. AB - BACKGROUND: Accidental hypothermia increases mortality and morbidity in trauma patients. Various methods for insulating and wrapping hypothermic patients are used worldwide. The aim of this study was to compare the thermal insulating effects and comfort of bubble wrap, ambulance blankets / quilts, and Hibler's method, a low-cost method combining a plastic outer layer with an insulating layer. METHODS: Eight volunteers were dressed in moistened clothing, exposed to a cold and windy environment then wrapped using one of the three different insulation methods in random order on three different days. They were rested quietly on their back for 60 minutes in a cold climatic chamber. Skin temperature, rectal temperature, oxygen consumption were measured, and metabolic heat production was calculated. A questionnaire was used for a subjective evaluation of comfort, thermal sensation, and shivering. RESULTS: Skin temperature was significantly higher 15 minutes after wrapping using Hibler's method compared with wrapping with ambulance blankets / quilts or bubble wrap. There were no differences in core temperature between the three insulating methods. The subjects reported more shivering, they felt colder, were more uncomfortable, and had an increased heat production when using bubble wrap compared with the other two methods. Hibler's method was the volunteers preferred method for preventing hypothermia. Bubble wrap was the least effective insulating method, and seemed to require significantly higher heat production to compensate for increased heat loss. CONCLUSIONS: This study demonstrated that a combination of vapour tight layer and an additional dry insulating layer (Hibler's method) is the most efficient wrapping method to prevent heat loss, as shown by increased skin temperatures, lower metabolic rate and better thermal comfort. This should then be the method of choice when wrapping a wet patient at risk of developing hypothermia in prehospital environments. PMID- 21699721 TI - Human papillomavirus and Epstein-Barr virus infections in breast cancer from chile. AB - BACKGROUND: Human papillomavirus (HPV) and Epstein Barr virus (EBV) have been found in breast carcinomas (BCs) around the world. In this study, fifty-five BCs from Chile were analyzed for HPV and EBV presence. In addition, HPV-16 viral load/physical status and E6/E7 expressions were determined. RESULTS: The amplification of a housekeeping gene showed that 46/55 samples (84%) had amplifiable DNA. HPV-16 was detected in 4/46 BCs (8.7%) and EBV was detected in 3/46 (6.5%) BCs. The analysis of HPV-16 physical status showed that this virus was integrated in all of the tumors with a relatively low viral load (range: 0.14 to 33.8 copies/cell). E6 and E7 transcripts, however, were not detected in any HPV-16 positive specimens. Using a Cox-regression model, we found a statistically significant association between EBV presence and poor survival (p = 0.013). CONCLUSIONS: The findings in this study suggest that it is unlikely that HPV and/or EBV play a direct role in the etiology of BC. PMID- 21699722 TI - Perceptions of the role of general practice and practical support measures for carers of stroke survivors: a qualitative study. AB - BACKGROUND: Informal carers frequently suffer adverse consequences from caring. General practice teams are well positioned to support them. However, what carers of stroke survivors want and expect from general practice, and the practical support measures they might like, remain largely unexplored.The aims of this study are twofold. Firstly it explores both the support stroke carers would like from general practice and their reactions to the community based support proposed in the New Deal. Secondly, perceptions of a general practice team are investigated covering similar topics to carer interviews but from their perspective. METHODS: Semi-structured interviews were conducted with 13 stroke carers and 10 members of a general practice team. Carers' experiences and expectations of general practice and opinions of support measures from recent government policy were explored. General practice professionals were asked about their perceived role and their perceptions of carers' support needs. Interviews were content analysed. RESULTS: Carers' expectations of support from general practice were low and they neither received nor expected much support for themselves. General practice was seen as reactive primarily because of time constraints. Some carers would appreciate emotional support but others did not want additional services. Responses to recent policy initiatives were mixed with carers saying these might benefit other carers but not themselves.General practice professionals' opinions were broadly similar. They recognise carers' support needs but see their role as reactive, focussed on stroke survivors, rather than carers. Caring was recognised as challenging. Providing emotional support and referral were seen as important but identification of carers was considered difficult. Time constraints limit their support. Responses to recent policy initiatives were positive. CONCLUSIONS: Carers' expectations of support from general practice for themselves are low and teams are seen as reactive and time constrained. Both the carers and the general practice team participants emphasised the valuable role of general practice team in supporting stroke survivors. Research is needed to determine general practice teams' awareness and identification of carers and of the difficulties they encounter supporting stroke carers. Carer policy initiatives need greater specificity with greater attention to diversity in carer needs. PMID- 21699723 TI - Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment. AB - INTRODUCTION: Circulating tumor cells (CTCs) represent an independent predictor of outcome in patients with metastatic breast cancer (MBC). We assessed the prognostic impact of CTCs according to different first-line systemic treatments, and explored their potential predictive value in MBC patients. METHODS: We retrospectively evaluated 235 newly diagnosed MBC patients, treated at the University of Texas MD Anderson Cancer Center. All patients had a baseline CTC assessment performed with CellSearch((r)). Progression-free survival and overall survival were compared with the log-rank test between groups, according to CTC count (< 5 vs. >= 5) and type of systemic therapy. We further explored the predictive value of baseline CTCs in patients receiving different treatments. RESULTS: At a median follow-up of 18 months, the CTC count was confirmed to be a robust prognostic marker in the overall population (median progression-free survival 12.0 and 7.0 months for patients with CTC < 5 and >= 5, respectively; P < 0.001). Conversely, in patients with human epidermal growth factor receptor-2 overexpressed/amplified tumors receiving trastuzumab or lapatinib, the baseline CTC count was not prognostic (median progression-free survival 14.5 months for patients with CTC < 5 and 16.1 months for those with CTC >= 5; P = 0.947). Furthermore, in patients with human epidermal growth factor receptor-2 normal tumors, a baseline CTC count >= 5 identified subjects who derived benefit from more aggressive treatments, including combination chemotherapy and chemotherapy plus bevacizumab. CONCLUSIONS: This analysis suggests that the prognostic information provided by CTC count may be useful in patient stratifications and therapeutic selection, particularly in the group with positive CTCs, in which various therapeutic choices may procure differential palliative benefit. PMID- 21699725 TI - How local IRBs view central IRBs in the US. AB - BACKGROUND: Centralization of IRB reviews have been increasing in the US and elsewhere, but many questions about it remain. In the US, a few centralized IRBs (CIRBs) have been established, but how they do and could operate remain unclear. METHODS: I contacted 60 IRBs (every fourth one in the list of the top 240 institutions by NIH funding), and interviewed leaders from 34 (response rate = 55%) and an additional 12 members and administrators. RESULTS: These interviewees had often interacted with CIRBs, but supported local reviews, and offered advantages and disadvantages of each. Interviewees argued that local IRBs can provide "local knowledge" of subjects and PIs, and "curbside consults" with PIs, facilitating mutual trust. PIs may interact more fully and informally, and hence effectively with local IRBs. IRBs also felt additional responsibility to protect "their own" subjects. Respondents mentioned a few advantages of CIRBs (e.g., CIRBs may streamline reviews), though far more rarely and cursorily. Overall, interviewees were wary of CIRBs, which they saw as varying widely in quality, depending on who happened to be members. Both local and centralized IRBs appear to have unintended consequences. For instance, discrepancies arose between IRBs that appeared to reflect differences in institutional culture and history, and personalities of chairs and/or vocal members, more than in local community values per se, and thus do not seem to be the intent of the regulations. While some critics see CIRBs as solutions to many IRB problems, critical tradeoffs and uncertainties emerge. CONCLUSIONS: These data have critical implications for future policy and research. Debates need to evolve beyond simply a binary discussion of whether CIRBs should replace local IRBs, to examine how and to what degree different models might operate, and what the relative advantages and disadvantages of each are. While some critics see CIRBs as panaceas, certain problems appear likely to continue. Careful consideration needs to be given to whether the advantages of local IRBs outweigh the problems that result, and whether a system can be developed that provides these benefits, while avoiding the disadvantages of local IRBs. PMID- 21699724 TI - Circulating angiopoietin-2 and soluble Tie-2 in type 2 diabetes mellitus: a cross sectional study. AB - BACKGROUND: Type 2 diabetes is associated with increased levels of Angiopoietin-2 (Ang-2) and soluble Tie-2 (sTie-2), but its impact on vascular disease is still unknown. This study aimed to further explore the associations of Ang-2 and sTie-2 with metabolic control and diabetic complications. METHODS: In a cross-sectional designed study, levels of Ang-2 and sTie-2 as well as their relationships to cardiometabolic parameters were determined in 80 type 2 diabetic subjects (age 65 +/- 7 years, female 47.4%). RESULTS: After controlling for age and BMI, Ang-2 levels were associated with levels of sTie-2, diastolic blood pressure, plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR), creatinine, glomerular filtration rate (GFR), and gamma-glutamyl transferase (GGT) (all p < 0.02). Presence of diabetic macrovascular complications, polyneuropathy and insulin therapy were associated with higher Ang-2 levels (p < 0.05). Conversely, sTie-2 levels were associated with glycated hemoglobin (HbA1c), fasting plasma glucose and insulin, HOMA-IR, triglyceride, and liver function parameters (all p < 0.03). Multiple linear regression analysis showed that Ang-2 remained significantly associated only with levels of GGT (p < 0.04), whereas sTie-2 remained significantly associated with HbA(1c), insulin levels, and HOMA-IR (p < 0.03). No differences in Ang-2 and sTie-2 levels were observed with regard to gender of participants. CONCLUSIONS: Ang-2 is independently associated with levels of GGT while sTie-2 is independently associated with levels of HbA(1c), plasma insulin and HOMA-IR in type 2 diabetic subjects. Therefore we suggest that the associations of Ang-2 and sTie-2 with type 2 diabetes are based on different patho-physiological mechanisms. PMID- 21699726 TI - Prevention of the beta-amyloid peptide-induced inflammatory process by inhibition of double-stranded RNA-dependent protein kinase in primary murine mixed co cultures. AB - BACKGROUND: Inflammation may be involved in the pathogenesis of Alzheimer's disease (AD). There has been little success with anti-inflammatory drugs in AD, while the promise of anti-inflammatory treatment is more evident in experimental models. A new anti-inflammatory strategy requires a better understanding of molecular mechanisms. Among the plethora of signaling pathways activated by beta amyloid (Abeta) peptides, the nuclear factor-kappa B (NF-kappaB) pathway could be an interesting target. In virus-infected cells, double-stranded RNA-dependent protein kinase (PKR) controls the NF-kappaB signaling pathway. It is well-known that PKR is activated in AD. This led us to study the effect of a specific inhibitor of PKR on the Abeta42-induced inflammatory response in primary mixed murine co-cultures, allowing interactions between neurons, astrocytes and microglia. METHODS: Primary mixed murine co-cultures were prepared in three steps: a primary culture of astrocytes and microglia for 14 days, then a primary culture of neurons and astrocytes which were cultured with microglia purified from the first culture. Before exposure to Abeta neurotoxicity (72 h), co cultures were treated with compound C16, a specific inhibitor of PKR. Levels of tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, and IL-6 were assessed by ELISA. Levels of PT451-PKR and activation of IkappaB, NF-kappaB and caspase-3 were assessed by western blotting. Apoptosis was also followed using annexin V-FITC immunostaining kit. Subcellular distribution of PT451-PKR was assessed by confocal immunofluorescence and morphological structure of cells by scanning electron microscopy. Data were analysed using one-way ANOVA followed by a Newman-Keuls' post hoc test RESULTS: In these co-cultures, PKR inhibition prevented Abeta42-induced activation of IkappaB and NF-kappaB, strongly decreased production and release of tumor necrosis factor (TNFalpha) and interleukin (IL) 1beta, and limited apoptosis. CONCLUSION: In spite of the complexity of the innate immune response, PKR inhibition could be an interesting anti-inflammatory strategy in AD. PMID- 21699727 TI - Cognition after malignant media infarction and decompressive hemicraniectomy--a retrospective observational study. AB - BACKGROUND: Decompressive hemicraniectomy is a life-saving procedure for patients with malignant middle cerebral artery infarctions. However, the neuropsychological sequelae in such patients have up to now received little attention. In this study we not only describe neuropsychological deficits but also the quality of life and the extent of depression and other psychiatric symptoms in patients after complete media infarction of the non-speech dominant hemisphere. METHODS: 20 patients from two different university hospitals (mean +/ standard deviation: 52 +/- 14 years of age) who had undergone hemicraniectomy with duraplasty above the non-speech dominant hemisphere at least one year previously were examined using a thorough neurological and neuropsychological work-up. The quality of life and the extent of psychiatric problems were determined on the basis of self-estimation questionnaires. The patients were asked whether they would again opt for the surgical treatment when considering their own outcome. 20 healthy persons matched for age, gender and education served as a control group. RESULTS: All patients but one were neurologically handicapped, half of them severely. Age was significantly correlated with poorer values on the Rankin scale and Barthel index. All cognitive domain z values were significantly lower than in the control group. Upon re-examination, 18 of 20 patients were found to be cognitively impaired to a degree that fulfilled the formal DSM IV criteria for dementia. CONCLUSIONS: Patients with non-speech dominant hemispheric infarctions and decompressive hemicraniectomy are at high risk of depression and severe cognitive impairment. PMID- 21699728 TI - Severe morbidity and mortality in untreated HIV-infected children in a paediatric care programme in Abidjan, Cote d'Ivoire, 2004-2009. AB - BACKGROUND: Clinical evolution of HIV-infected children who have not yet initiated antiretroviral treatment (ART) is poorly understood in Africa. We describe severe morbidity and mortality of untreated HIV-infected children. METHODS: All HIV-infected children enrolled from 2004-2009 in a prospective HIV programme in two health facilities in Abidjan, Cote d'Ivoire, were eligible from their time of inclusion. Risks of severe morbidity (the first clinical event leading to death or hospitalisation) and mortality were documented retrospectively and estimated using cumulative incidence functions. Associations with baseline characteristics were assessed by competing risk regression models between outcomes and antiretroviral initiation. RESULTS: 405 children were included at a median age of 4.5 years; at baseline, 66.9% were receiving cotrimoxazole prophylaxis, and 27.7% met the 2006 WHO criteria for immunodeficiency by age. The risk of developing a severe morbid event was 14% (95%CI: 10.7 - 17.8) at 18 months; this risk was lower in children previously exposed to any prevention of mother-to-child-transmission (PMTCT) intervention (adjusted subdistribution hazard ratio [sHR]: 0.16, 95% CI: 0.04 - 0.71) versus those without known exposure. Cumulative mortality reached 5.5% (95%CI: 3.5 - 8.1) at 18 months. Mortality was associated with immunodeficiency (sHR: 6.02, 95% CI: 1.28-28.42). CONCLUSIONS: Having benefited from early access to care minimizes the severe morbidity risk for children who acquire HIV. Despite the receipt of cotrimoxazole prophylaxis, the risk of severe morbidity and mortality remains high in untreated HIV-infected children. Such evidence adds arguments to promote earlier access to ART in HIV-infected children in Africa and improve care interventions in a context where treatment is still not available to all. PMID- 21699729 TI - Therapeutic efficacy of TBC3711 in monocrotaline-induced pulmonary hypertension. AB - BACKGROUND: Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats. METHODS: Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed. RESULTS: The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling. CONCLUSION: The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension. PMID- 21699730 TI - Developing cessation interventions for the social and community service setting: a qualitative study of barriers to quitting among disadvantaged Australian smokers. AB - BACKGROUND: Smoking rates remain unacceptably high among individuals who are socially disadvantaged. Social and community service organisations (SCSO) are increasingly interested in providing smoking cessation support to clients, however little is known about the best way to assist disadvantaged smokers to quit in this setting. This study aimed to explore barriers and facilitators to quitting within the conceptual framework of the PRECEDE model to identify possible interventions appropriate to the social and community service setting. METHODS: Semi-structured focus groups were conducted with clients attending five community welfare organisations located in New South Wales, Australia. Thirty-two clients participated in six focus groups. A discussion guide was used to explore the barriers and facilitators to smoking and smoking cessation including: current smoking behaviour, motivation to quit, past quit attempts, barriers to quitting and preferences for cessation support. Focus groups were audio-taped, transcribed and analysed using thematic analysis techniques. RESULTS: Participants were current smokers and most expressed a desire to quit. Factors predisposing continued smoking included perceived benefits of smoking for stress relief, doubting of ability to quit, fear of gaining weight, and poor knowledge and scepticism about available quit support. The high cost of nicotine replacement therapy was a barrier to its use. Continual exposure to smoking in personal relationships and in the community reinforced smoking. Participants expressed a strong preference for personalised quit support. CONCLUSIONS: Disadvantaged smokers in Australia express a desire to quit smoking, but find quitting difficult for a number of reasons. SCSOs may have a role in providing information about the availability of quit support, engaging disadvantaged smokers with available quit support, and providing personalised, ongoing support. PMID- 21699731 TI - Stimulation of neoplastic mouse lung cell proliferation by alveolar macrophage derived, insulin-like growth factor-1 can be blocked by inhibiting MEK and PI3K activation. AB - BACKGROUND: Worldwide, lung cancer kills more people than breast, colon and prostate cancer combined. Alterations in macrophage number and function during lung tumorigenesis suggest that these immune effector cells stimulate lung cancer growth. Evidence from cancer models in other tissues suggests that cancer cells actively recruit growth factor-producing macrophages through a reciprocal signaling pathway. While the levels of lung macrophages increase during tumor progression in mouse models of lung cancer, and high pulmonary macrophage content correlates with a poor prognosis in human non-small cell lung cancer, the specific role of alveolar macrophages in lung tumorigenesis is not clear. METHODS: After culturing either an immortalized lung macrophage cell line or primary murine alveolar macrophages from naive and lung-tumor bearing mice with primary tumor isolates and immortalized cell lines, the effects on epithelial proliferation and cellular kinase activation were determined. Insulin-like growth factor-1 (IGF-1) was quantified by ELISA, and macrophage conditioned media IGF-1 levels manipulated by IL-4 treatment, immuno-depletion and siRNA transfection. RESULTS: Primary macrophages from both naive and lung-tumor bearing mice stimulated epithelial cell proliferation. The lungs of tumor-bearing mice contained 3.5-times more IGF-1 than naive littermates, and media conditioned by freshly isolated tumor-educated macrophages contained more IGF-1 than media conditioned by naive macrophages; IL-4 stimulated IGF-1 production by both macrophage subsets. The ability of macrophage conditioned media to stimulate neoplastic proliferation correlated with media IGF-1 levels, and recombinant IGF 1 alone was sufficient to induce epithelial proliferation in all cell lines evaluated. Macrophage-conditioned media and IGF-1 stimulated lung tumor cell growth in an additive manner, while EGF had no effect. Macrophage-derived factors increased p-Erk1/2, p-Akt and cyclin D1 levels in neoplastic cells, and the combined inhibition of both MEK and PI3K ablated macrophage-mediated increases in epithelial growth. CONCLUSIONS: Macrophages produce IGF-1 which directly stimulates neoplastic proliferation through Erk and Akt activation. This observation suggests that combining macrophage ablation therapy with IGF-1R, MEK and/or PI3K inhibition could improve therapeutic response in human lung cancer. Exploring macrophage-based intervention could be a fruitful avenue for future research. PMID- 21699732 TI - A nucleotide binding rectification Brownian ratchet model for translocation of Y family DNA polymerases. AB - Y-family DNA polymerases are characterized by low-fidelity synthesis on undamaged DNA and ability to catalyze translesion synthesis over the damaged DNA. Their translocation along the DNA template is an important event during processive DNA synthesis. In this work we present a Brownian ratchet model for this translocation, where the directed translocation is rectified by the nucleotide binding to the polymerase. Using the model, different features of the available structures for Dpo4, Dbh and polymerase iota in binary and ternary forms can be easily explained. Other dynamic properties of the Y-family polymerases such as the fast translocation event upon dNTP binding for Dpo4 and the considerable variations of the processivity among the polymerases can also be well explained by using the model. In addition, some predicted results of the DNA synthesis rate versus the external force acting on Dpo4 and Dbh polymerases are presented. Moreover, we compare the effect of the external force on the DNA synthesis rate of the Y-family polymerase with that of the replicative DNA polymerase. PMID- 21699733 TI - Glutamate acts as a neurotransmitter for gastrin releasing peptide-sensitive and insensitive itch-related synaptic transmission in mammalian spinal cord. AB - Itch sensation is one of the major sensory experiences of human and animals. Recent studies have proposed that gastrin releasing peptide (GRP) is a key neurotransmitter for itch in spinal cord. However, no direct evidence is available to indicate that GRP actually mediate responses between primary afferent fibers and dorsal horn neurons. Here we performed integrative neurobiological experiments to test this question. We found that a small population of rat dorsal horn neurons responded to GRP application with increases in calcium signaling. Whole-cell patch-clamp recordings revealed that a part of superficial dorsal horn neurons responded to GRP application with the increase of action potential firing in adult rats and mice, and these dorsal horn neurons received exclusively primary afferent C-fiber inputs. On the other hands, few A(delta) inputs receiving cells were found to be GRP positive. Finally, we found that evoked sensory responses between primary afferent C fibers and GRP positive superficial dorsal horn neurons are mediated by glutamate but not GRP. CNQX, a blocker of AMPA and kainate (KA) receptors, completely inhibited evoked EPSCs, including in those Fos-GFP positive dorsal horn cells activated by itching. Our findings provide the direct evidence that glutamate is the principal excitatory transmitter between C fibers and GRP positive dorsal horn neurons. Our results will help to understand the neuronal mechanism of itch and aid future treatment for patients with pruritic disease. PMID- 21699736 TI - Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome. AB - The insulin/insulin-like growth factor-1 (IGF-1) pathway drives an evolutionarily conserved network that regulates lifespan and longevity. Individuals with Laron syndrome who carry mutations in the growth hormone receptor (GHR) gene that lead to severe congenital IGF-1 deficiency with decreased insulin/IGF-1 signaling (IIS) exhibit reduced prevalence rates of acne, diabetes and cancer. Western diet with high intake of hyperglycemic carbohydrates and insulinotropic dairy over-stimulates IIS. The reduction of IIS in Laron subjects unmasks the potential role of persistent hyperactive IIS mediated by Western diet in the development of diseases of civilization and offers a rational perspective for dietary adjustments with less insulinotropic diets like the Paleolithic diet. PMID- 21699735 TI - Granulocyte colony-stimulating factor increases the therapeutic efficacy of bone marrow mononuclear cell transplantation in cerebral ischemia in mice. AB - BACKGROUND: Bone marrow mononuclear cell (BMMC) transplantation is a promising therapy for cerebral ischemia; however, little is known if its therapeutic efficacy may be improved by co-administration of potential modulatory factors in vivo. To explore this possibility, the present study examined the effect of BMMCs and G-CSF on cell proliferation, early neuronal development and neurological function recovery in experimental cerebral ischemia relative to controls that received neither treatment. RESULT: Ischemia/infarct area was significantly reduced in BMMCs+G-CSF group relative to animal groups treated with BMMCs only, G CSF only or saline. Transplanted BMMCs were found to colocalize with the proliferative cell nuclear antigen (PCNA) and the immature neuronal marker doublecortin (DCX). The BMMCs+G-CSF group showed increased numerical density of cells expressing PCNA and DCX, improved performance in adhesive sticker removal test and reduced neurological function severity scores relative to other groups in a time-dependent manner. CONCLUSION: BMMCs and G-CSF co-administration exhibits synergistic beneficial effect over time. This effect could be at least partially related to increased proliferation and differentiation of bone marrow stem cells and enhanced host brain regeneration and functional recovery. The results suggest that G-CSF can increase the therapeutic efficacy of BMMCs transplantation in an experimental mouse model of cerebral ischemia. PMID- 21699734 TI - Evolutionary conserved microRNAs are ubiquitously expressed compared to tick specific miRNAs in the cattle tick Rhipicephalus (Boophilus) microplus. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs that act as regulators of gene expression in eukaryotes modulating a large diversity of biological processes. The discovery of miRNAs has provided new opportunities to understand the biology of a number of species. The cattle tick, Rhipicephalus (Boophilus) microplus, causes significant economic losses in cattle production worldwide and this drives us to further understand their biology so that effective control measures can be developed. To be able to provide new insights into the biology of cattle ticks and to expand the repertoire of tick miRNAs we utilized Illumina technology to sequence the small RNA transcriptomes derived from various life stages and selected organs of R. microplus. RESULTS: To discover and profile cattle tick miRNAs we employed two complementary approaches, one aiming to find evolutionary conserved miRNAs and another focused on the discovery of novel cattle-tick specific miRNAs. We found 51 evolutionary conserved R. microplus miRNA loci, with 36 of these previously found in the tick Ixodes scapularis. The majority of the R. microplus miRNAs are perfectly conserved throughout evolution with 11, 5 and 15 of these conserved since the Nephrozoan (640 MYA), Protostomian (620MYA) and Arthropoda (540 MYA) ancestor, respectively. We then employed a de novo computational screening for novel tick miRNAs using the draft genome of I. scapularis and genomic contigs of R. microplus as templates. This identified 36 novel R. microplus miRNA loci of which 12 were conserved in I. scapularis. Overall we found 87 R. microplus miRNA loci, of these 15 showed the expression of both miRNA and miRNA* sequences. R. microplus miRNAs showed a variety of expression profiles, with the evolutionary-conserved miRNAs mainly expressed in all life stages at various levels, while the expression of novel tick-specific miRNAs was mostly limited to particular life stages and/or tick organs. CONCLUSIONS: Anciently acquired miRNAs in the R. microplus lineage not only tend to accumulate the least amount of nucleotide substitutions as compared to those recently acquired miRNAs, but also show ubiquitous expression profiles through out tick life stages and organs contrasting with the restricted expression profiles of novel tick-specific miRNAs. PMID- 21699737 TI - A proof of the DBRF-MEGN method, an algorithm for deducing minimum equivalent gene networks. AB - BACKGROUND: We previously developed the DBRF-MEGN (difference-based regulation finding-minimum equivalent gene network) method, which deduces the most parsimonious signed directed graphs (SDGs) consistent with expression profiles of single-gene deletion mutants. However, until the present study, we have not presented the details of the method's algorithm or a proof of the algorithm. RESULTS: We describe in detail the algorithm of the DBRF-MEGN method and prove that the algorithm deduces all of the exact solutions of the most parsimonious SDGs consistent with expression profiles of gene deletion mutants. CONCLUSIONS: The DBRF-MEGN method provides all of the exact solutions of the most parsimonious SDGs consistent with expression profiles of gene deletion mutants. PMID- 21699738 TI - DADA: Degree-Aware Algorithms for Network-Based Disease Gene Prioritization. AB - BACKGROUND: High-throughput molecular interaction data have been used effectively to prioritize candidate genes that are linked to a disease, based on the observation that the products of genes associated with similar diseases are likely to interact with each other heavily in a network of protein-protein interactions (PPIs). An important challenge for these applications, however, is the incomplete and noisy nature of PPI data. Information flow based methods alleviate these problems to a certain extent, by considering indirect interactions and multiplicity of paths. RESULTS: We demonstrate that existing methods are likely to favor highly connected genes, making prioritization sensitive to the skewed degree distribution of PPI networks, as well as ascertainment bias in available interaction and disease association data. Motivated by this observation, we propose several statistical adjustment methods to account for the degree distribution of known disease and candidate genes, using a PPI network with associated confidence scores for interactions. We show that the proposed methods can detect loosely connected disease genes that are missed by existing approaches, however, this improvement might come at the price of more false negatives for highly connected genes. Consequently, we develop a suite called DADA, which includes different uniform prioritization methods that effectively integrate existing approaches with the proposed statistical adjustment strategies. Comprehensive experimental results on the Online Mendelian Inheritance in Man (OMIM) database show that DADA outperforms existing methods in prioritizing candidate disease genes. CONCLUSIONS: These results demonstrate the importance of employing accurate statistical models and associated adjustment methods in network-based disease gene prioritization, as well as other network based functional inference applications. DADA is implemented in Matlab and is freely available at http://compbio.case.edu/dada/. PMID- 21699739 TI - Impact of established prognostic factors and molecular subtype in very young breast cancer patients: pooled analysis of four EORTC randomized controlled trials. AB - INTRODUCTION: Young age at the time of diagnosis of breast cancer is an independent factor of poor prognosis. In many treatment guidelines, the recommendation is to treat young patients with adjuvant chemotherapy regardless of tumor characteristics. However, limited data on prognostic factors are available for young breast cancer patients. The purpose of this study was to determine the prognostic value of established clinical and pathological prognostic factors in young breast cancer patients. METHODS: Data from four European Organisation for Research and Treatment of Cancer (EORTC) clinical trials were pooled, resulting in a dataset consisting of 9,938 early breast cancer patients with a median follow-up of 11 years. For 549 patients aged less than 40 years at the time of diagnosis, including 341 node negative patients who did not receive chemotherapy, paraffin tumor blocks were processed for immunohistochemistry using a tissue microarray. Cox proportional hazard analysis was applied to assess the association of clinical and pathological factors with overall and distant metastasis free survival. RESULTS: For young patients, tumor size (P = 0.01), nodal status (P = 0.006) and molecular subtype (P = 0.02) were independent prognostic factors for overall survival. In the node negative subgroup, only molecular subtype was a prognostic factor for overall survival (P = 0.02). Young node negative patients bearing luminal A tumors had an overall survival rate of 94% at 10 years' follow-up compared to 72% for patients with basal-type tumors. CONCLUSIONS: Molecular subtype is a strong independent prognostic factor in breast cancer patients younger than 40 years of age. These data support the use of established prognostic factors as a diagnostic tool to assess disease outcome and to plan systemic treatment strategies in young breast cancer patients. PMID- 21699740 TI - Collaborative Care for patients with severe borderline and NOS personality disorders: a comparative multiple case study on processes and outcomes. AB - BACKGROUND: Structured psychotherapy is recommended as the preferred treatment of personality disorders. A substantial group of patients, however, has no access to these therapies or does not benefit. For those patients who have no (longer) access to psychotherapy a Collaborative Care Program (CCP) is developed. Collaborative Care originated in somatic health care to increase shared decision making and to enhance self management skills of chronic patients. Nurses have a prominent position in CCP's as they are responsible for optimal continuity and coordination of care. The aim of the CCP is to improve quality of life and self management skills, and reduce destructive behaviour and other manifestations of the personality disorder. METHODS/DESIGN: Quantitative and qualitative data are combined in a comparative multiple case study. This makes it possible to test the feasibility of the CCP, and also provides insight into the preliminary outcomes of CCP. Two treatment conditions will be compared, one in which the CCP is provided, the other in which Care as Usual is offered. In both conditions 16 patients will be included. The perspectives of patients, their informal carers and nurses are integrated in this study. Data (questionnaires, documents, and interviews) will be collected among these three groups of participants. The process of treatment and care within both research conditions is described with qualitative research methods. Additional quantitative data provide insight in the preliminary results of the CCP compared to CAU. With a stepped analysis plan the 'black box' of the application of the program will be revealed in order to understand which characteristics and influencing factors are indicative for positive or negative outcomes. DISCUSSION: The present study is, as to the best of our knowledge, the first to examine Collaborative Care for patients with severe personality disorders receiving outpatient mental health care. With the chosen design we want to examine how and which elements of the CC Program could contribute to a better quality of life for the patients. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR2763. PMID- 21699741 TI - Urban malaria and associated risk factors in Jimma town, south-west Ethiopia. AB - BACKGROUND: Malaria kills millions around the world. Until recently it was believed to be a disease of rural areas, since the Anopheles mosquito, which transmits Plasmodium species breeds in rural areas. Urban malaria is emerging as a potential, but "avertable" crisis, in Africa. In view of the rapidly growing number of small and medium-sized towns in Ethiopia there is a pressing need to improve the understanding of the epidemiology of malaria. Therefore, the aim of this study was to determine malaria prevalence and associated risk factors in Jimma town. METHODS: A cross-sectional study was carried out in Jimma town from April 1 to May 28, 2010. 804 study participants were included from 291 households for microscopic examination of malaria parasites. Socio-demography data and risk factors were collected using structured questionnaires. Logistic regression analysis was done using SPSS 15.0 statistical software. RESULTS: From a total of 804 study participants in current survey only 42 (5.2%) were positive for malaria parasites. Plasmodium vivax, Plasmodium falciparum and mixed infection accounted 71.4%, 26.2% and 2.4%, respectively. Higher malaria prevalence rate was observed among under-five children (11%). Those who do not use insecticide-treated bed nets (ITN) were more likely to be infected with malaria (OR = 13.6; 95% CI 4.9 37.2, p < 0.001) compared with those who use the ITN. Living in areas where stagnant water existed (OR = 2.1; 95% CI 1.00-4.2, p = 0.047) and its distance of existence <1 km from the house(OR = 2.1; 95% CI 2.0-15.8, p = 0.001) were more likely to be infected with malaria parasite compared with those who live away from stagnant at a distance greater than 1 km. CONCLUSION: Malaria is a major health problem with P. vivax becoming a predominant species in the town. The prevalence was strongly associated with proximity of residence to potential mosquito breeding sites. Malaria is affecting significant proportions of the urban settlers and human activities nevertheless play an important role in bringing the mosquito breeding sites closer to residences. PMID- 21699744 TI - microRNAs become macro players in somatic cell reprogramming. AB - Embryonic stem cell specific microRNAs (miRNAs) have previously been shown to enhance the efficiency of transcription-factor-based reprogramming. However, whether reprogramming could be achieved entirely by miRNAs remained unclear. A recent report shows that the expression of the miR-302/367 cluster of miRNAs can directly reprogram somatic cells without the use of any transcription factors. This new method raises interesting questions about the mechanisms of reprogramming and is likely to facilitate the generation of induced pluripotent stem cells for potential future clinical use. PMID- 21699745 TI - Exploring the ELSI universe: critical issues in the evolution of human genomic research. AB - A report on the National Human Genome Research Institute's Ethical, Legal, and Social Implications Research Program 2011 Congress, 'Exploring the ELSI Universe', Chapel Hill, North Carolina, USA, 12-14 April 2011. PMID- 21699742 TI - Hepatoprotective effects of methanol extract of Carissa opaca leaves on CCl4 induced damage in rat. AB - BACKGROUND: Carissa opaca (Apocynaceae) leaves possess antioxidant activity and hepatoprotective effects, and so may provide a possible therapeutic alternative in hepatic disorders. The effect produced by methanolic extract of Carissa opaca leaves (MCL) was investigated on CCl4-induced liver damages in rat. METHODS: 30 rats were divided into five groups of six animals of each, having free access to food and water ad libitum. Group I (control) was given olive oil and DMSO, while group II, III and IV were injected intraperitoneally with CCl4 (0.5 ml/kg) as a 20% (v/v) solution in olive oil twice a week for 8 weeks. Animals of group II received only CCl4. Rats of group III were given MCL intragastrically at a dose of 200 mg/kg bw while that of group IV received silymarin at a dose of 50 mg/kg bw twice a week for 8 weeks. However, animals of group V received MCL only at a dose of 200 mg/kg bw twice a week for 8 weeks. The activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma-glutamyltransferase (gamma-GT) were determined in serum. Catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px), glutathione reductase (GSR) and quinone reductase (QR) activity was measured in liver homogenates. Lipid peroxidation (thiobarbituric acid reactive substances; TBARS), glutathione (GSH) and hydrogen peroxide (H2O2) concentration was also assessed in liver homogenates. Phytochemicals in MCL were determined through qualitative and high performance liquid chromatography (HPLC) analysis. RESULTS: Hepatotoxicity induced with CCl4 was evidenced by significant increase in lipid peroxidation (TBARS) and H2O2 level, serum activities of AST, ALT, ALP, LDH and gamma-GT. Level of GSH determined in liver was significantly reduced, as were the activities of antioxidant enzymes; CAT, POD, SOD, GSH-Px, GSR, GST and QR. On cirrhotic animals treated with CCl4, histological studies showed centrilobular necrosis and infiltration of lymphocytes. MCL (200 mg/kg bw) and silymarin (50 mg/kg bw) co-treatment prevented all the changes observed with CCl4-treated rats. The phytochemical analysis of MCL indicated the presence of flavonoids, tannins, alkaloids, phlobatannins, terpenoids, coumarins, anthraquinones, and cardiac glycosides. Isoquercetin, hyperoside, vitexin, myricetin and kaempherol was determined in MCL. CONCLUSION: These results indicate that MCL has a significant protective effect against CCl4 induced hepatotoxicity in rat, which may be due to its antioxidant and membrane stabilizing properties. PMID- 21699743 TI - Clinical review: gene-based therapies for ALI/ARDS: where are we now? AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) confer substantial morbidity and mortality, and have no specific therapy. The accessibility of the distal lung epithelium via the airway route, and the relatively transient nature of ALI/ARDS, suggest that the disease may be amenable to gene-based therapies. Ongoing advances in our understanding of the pathophysiology of ALI/ARDS have revealed multiple therapeutic targets for gene based approaches. Strategies to enhance or restore lung epithelial and/or endothelial cell function, to strengthen lung defense mechanisms against injury, to speed clearance of infection and to enhance the repair process following ALI/ARDS have all demonstrated promise in preclinical models. Despite three decades of gene therapy research, however, the clinical potential for gene-based approaches to lung diseases including ALI/ARDS remains to be realized. Multiple barriers to effective pulmonary gene therapy exist, including the pulmonary architecture, pulmonary defense mechanisms against inhaled particles, the immunogenicity of viral vectors and the poor transfection efficiency of nonviral delivery methods. Deficits remain in our knowledge regarding the optimal molecular targets for gene-based approaches. Encouragingly, recent progress in overcoming these barriers offers hope for the successful translation of gene based approaches for ALI/ARDS to the clinical setting. PMID- 21699746 TI - Systemic sclerosis-associated pulmonary hypertension: why disease-specific composite endpoints are needed. AB - Pulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc). In clinical trials PAH-SSc has been grouped with other forms, including idiopathic PAH. The primary endpoint for most pivotal studies was improvement in exercise capacity. However, composite clinical endpoints that better reflect long-term outcome may be more meaningful. We discuss potential endpoints and consider why the same measures may not be appropriate for both idiopathic PAH and PAH-SSc due to inherent differences in clinical outcome and management strategies of these two forms of PAH. Failure to take this into account may compromise progress in managing PAH in SSc. PMID- 21699747 TI - Polycystic kidney disease and therapeutic approaches. AB - Polycystic kidney disease (PKD) is a common genetic disorder in which extensive epithelial-lined cysts develop in the kidneys. In previous studies, abnormalities of polycystin protein and its interacting proteins, as well as primary cilia, have been suggested to play critical roles in the development of renal cysts. However, although several therapeutic targets for PKD have been suggested, no early diagnosis or effective treatments are currently available. Current developments are active for treatment of PKD including inhibitors or antagonists of PPAR-gamma, TNF-alpha, CDK and VEGF. These drugs are potential therapeutic targets in PKD, and need to be determined about pathological functions in human PKD. It has recently been reported that the alteration of epigenetic regulation, as well as gene mutations, may affect the pathogenesis of PKD. In this review, we will discuss recent approaches to PKD therapy. It provides important information regarding potential targets for PKD. PMID- 21699748 TI - Tmp21, a novel MHC-I interacting protein, preferentially binds to Beta2 microglobulin-free MHC-I heavy chains. AB - MHC-I molecules play a critical role in immune surveillance against viruses by presenting peptides to cytotoxic T lymphocytes. Although the mechanisms by which MHC-I molecules assemble and acquire peptides in the ER are well characterized, how MHC-I molecules traffic to the cell surface remains poorly understood. To identify novel proteins that regulate the intracellular transport of MHC-I molecules, MHC-I-interacting proteins were isolated by affinity purification, and their identity was determined by mass spectrometry. Among the identified MHC-I associated proteins was Tmp21, the human ortholog of yeast Emp24p, which mediates the ER-Golgi trafficking of a subset of proteins. Here, we show that Tmp21 binds to human classical and non-classical MHC-I molecules. The Tmp21-MHC-I complex lacks Beta(2)-microglobulin, and the number of the complexes is increased when free MHC-I heavy chains are more abundant. Taken together, these results suggest that Tmp21 is a novel protein that preferentially binds to Beta(2)-microglobulin free MHC-I heavy chains. PMID- 21699749 TI - Carboxy-terminus truncations of Bacillus licheniformis SK-1 CHI72 with distinct substrate specificity. AB - Bacillus licheniformis SK-1 naturally produces chitinase 72 (CHI72) with two truncation derivatives at the C-terminus, one with deletion of the chitin binding domain (ChBD), and the other with deletions of both fibronectin type III domain (FnIIID) and ChBD. We constructed deletions mutants of CHI72 with deletion of ChBD (CHI72DeltaChBD) and deletions of both FnIIID and ChBD (CHI72DeltaFnIIIDDeltaChBD), and studied their activity on soluble, amorphous and crystalline substrates. Interestingly, when equivalent amount of specific activity of each enzyme on soluble substrate was used, the product yield from CHI72- DeltaChBD and CHI72DeltaFnIIIDDeltaChBD on colloidal chitin was 2.5 and 1.6 fold higher than CHI72, respectively. In contrast, the product yield from CHI72DeltaChBD and CHI72DeltaFnIIID- DeltaChBD on Beta-chitin reduced to 0.7 and 0.5 fold of CHI72, respectively. These results suggest that CHI72 can modulate its substrate specificities through truncations of the functional domains at the C-terminus, producing a mixture of enzymes with elevated efficiency of hydrolysis. PMID- 21699750 TI - Human HS1BP3 induces cell apoptosis and activates AP-1. AB - In the present study, we characterized the function of HS1-binding protein 3 (HS1BP3), which is mutated in essential tremor and may be involved in lymphocyte activation. We found that HS1BP3 localized to the mitochondria and endoplasmic reticulum partially. Overexpression of HS1BP3 induced apoptosis in HEK293T and HeLa cell lines. When these cell lines were transfected with HS1BP3, they exhibited nuclear DNA condensation, externalization of phosphatidylserine (PS), and cleavage of poly ADP ribose polymerase (PARP). Furthermore, suppression of HS1BP3 or HS1 expression attenuates HS1BP3 induced apoptosis. In addition, HS1BP3 enhanced activator protein 1 (AP-1)-mediated transcription in a dose-dependent manner. Therefore, we conclude that HS1BP3 regulates apoptosis via HS1 and stimulates AP-1-mediated transcription. PMID- 21699751 TI - Characterization of the molecular features and expression patterns of two serine proteases in Hermetia illucens (Diptera: Stratiomyidae) larvae. AB - To investigate the molecular scavenging capabilities of the larvae of Hermetia illucens, two serine proteases (SPs) were cloned and characterized. Multiple sequence alignments and phylogenetic tree analysis of the deduced amino acid sequences of Hi-SP1 and Hi-SP2 were suggested that Hi-SP1 may be a chymotrypsin- and Hi-SP2 may be a trypsin-like protease. Hi-SP1 and Hi-SP2 3-D homology models revealed that a catalytic triad, three disulfide bonds, and a substrate-binding pocket were highly conserved, as would be expected of a SP. E. coli expressed Hi SP1 and Hi-SP2 showed chymotrypsin or trypsin activities, respectively. Hi-SP2 mRNAs were consistently expressed during larval development. In contrast, the expression of Hi-SP1 mRNA fluctuated between feeding and molting stages and disappeared at the pupal stages. These expression pattern differences suggest that Hi-SP1 may be a larval specific chymotrypsin-like protease involved with food digestion, while Hi-SP2 may be a trypsin-like protease with diverse functions at different stages. PMID- 21699752 TI - Exogenous JH and ecdysteroid applications alter initiation of polydnaviral replication in an endoparasitoid wasp, Cotesia plutellae (Braconidae: Hymenoptera). AB - Polydnaviruses are a group of double-stranded DNA viruses and are symbiotically associated with some ichneumonoid wasps. As proviruses, the replication of polydnaviruses occurs in the female reproductive organ at the pupal stage. This study analyzed the effects of two developmental hormones, juvenile hormone (JH) and ecdysteroid, on the viral replication of Cotesia plutellae bracovirus (CpBV). All 23 CpBV segments identified contained a conserved excision/rejoining site ('AGCTTT') from their proviral segments. Using quantitative real-time PCR based on this excision/rejoining site marker, initiation of CpBV replication was determined to have occurred on day 4 on the pupal stage. Pyriproxyfen, a JH agonist, significantly inhibited adult emergence of C. plutellae, whereas RH5992, an ecdysteroid agonist, had no inhibitory effect. Although RH5992 had no effect dose on adult development, it significantly accelerated viral replication. The results of immunoblotting assays against viral coat proteins support the effects of the hormone agonists on viral replication. PMID- 21699753 TI - Anti-inflammatory effects of ethanol extract from Orostachys japonicus on modulation of signal pathways in LPS-stimulated RAW 264.7 cells. AB - In this study, powder of Orostachys japonicus A. Berger (O. japonicus) was extracted with 95% ethyl alcohol and fractionated using a series of organic solvents, including n-hexane (hexane), dichloromethane (DCM), ethylacetate (EtOAc), n-butanol (BuOH), and water (H(2)O). We investigated the anti inflammatory effects of these O. japonicus extracts on lipopolysaccharide (LPS) stimulated RAW 264.7 cells. Their effects on the expression of inflammatory mediators and transcription factors were analyzed by Western blotting. DCM fraction significantly inhibited formation of reactive oxygen species (ROS) as well as nitric oxide (NO) in LPS-stimulated RAW 264.7 cells. Phosphorylation of the pro-inflammatory transcription factor complex nuclear factor-kappa B (NF kappaB) p65 and expression of inducible nitric oxide synthase (iNOS), one of its downstream proteins, were also suppressed by DCM fraction. These effects were regulated by upsteam proteins in the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/Akt (PI3K/Akt) signaling pathways. Taken together, our data suggest that O. japonicus could be used as a potential source for anti inflammatory agents. PMID- 21699754 TI - Transcriptional activation of human GM3 synthase (hST3Gal V) gene by valproic acid in ARPE-19 human retinal pigment epithelial cells. AB - The present study demonstrated that valproic acid (VPA) transcriptionally regulates human GM3 synthase (hST3Gal V), which catalyzes ganglioside GM3 biosynthesis in ARPE-19 human retinal pigment epithelial cells. For this, we characterized the promoter region of the hST3Gal V gene. Functional analysis of the 5'-flanking region of the hST3Gal V gene revealed that the -177 to -83 region functions as the VPA-inducible promoter and that the CREB/ATF binding site at 143 is crucial for VPA-induced expression of hST3Gal V in ARPE-19 cells. In addition, the transcriptional activity of hST3Gal V induced by VPA in ARPE-19 cells was inhibited by SP600125, a c-Jun N-terminal kinase (JNK) inhibitor. In summary, our results identified the core promoter region in the hST3Gal V promoter and for the first time demonstrated that ATF2 binding to the CREB/ATF binding site at -143 is essential for transcriptional activation of hST3Gal V in VPA-induced ARPE-19 cells. PMID- 21699755 TI - Effects of novel chalcone derivatives on alpha-glucosidase, dipeptidyl peptidase 4, and adipocyte differentiation in vitro. AB - Chana series are new chalcone derivatives. To evaluate the possibility of Chana series as therapeutic agents of type 2 diabetes, the inhibitory effects of Chana series on the activities of alpha-glucosidase and DPP-4 were investigated using in vitro enzyme assays, and their effects on adipocyte differentiation were investigated in C3H10T1/2 cells. Chana 1 and Chana 7 among the Chana series showed significant inhibition of alpha-glucosidase activity. In DPP-4 enzyme assay, Chana 1 exhibited the highest inhibitory activity while Chana 7 did not. In MTT assay, Chana 1 did not show significant cytotoxicity up to a concentration of 250 MUM, whereas cytotoxicity was observed with Chana 7 at a concentration of 300 MUM. In addition, Chana 1 induced adipocyte differentiation. Therefore, Chana 1 showed inhibitory effects on alpha-glucosidase and DPP-4 as well as a stimulatory effect on adipocyte differentiation, suggesting that Chana 1 may be a potential beneficial agent for the treatment of type 2 diabetes. PMID- 21699756 TI - Glucosamine increases vascular contraction through activation of RhoA/Rho kinase pathway in isolated rat aorta. AB - Diabetes is a well-known independent risk factor for vascular disease. However, its underlying mechanism remains unclear. It has been reported that increased influx of the hexosamine biosynthesis pathway (HBP) induces O-GlcNAcylation of proteins, leading to insulin resistance. In this study, we determined whether or not O-GlcNAc modification of proteins could increase vessel contraction. Using an endothelium-denuded aortic ring, we observed that glucosamine induced OGlcNAcylation of proteins and augmented vessel contraction stimulated by U46619, a thromboxane A(2) agonist, via augmentation of the phosphorylation of MLC(20), MYPT1(Thr855), and CPI17, but not phenylephrine. Pretreatment with OGT inhibitor significantly ameliorated glucosamine-induced vessel constriction. Glucosamine treatment also increased RhoA activity, which was also attenuated by OGT inhibitor. In conclusion, glucosamine, a product of glucose influx via the HBP in a diabetic state, increases vascular contraction, at least in part, through activation of the RhoA/Rho kinase pathway, which may be due to O-GlcNAcylation. PMID- 21699757 TI - Developmentally dependent and different roles of fatty acids OMEGA-6 and OMEGA-3. AB - The developmentally-dependent differences in the biological significances and effects of PUFA-OMEGA-6 (namely of arachidonic acid) and PUFA-OMEGA-3 (namely of docosahexaenoic acid) are discussed. The clinical results as well as developmental experiences are indicating a hypothesis of the evolution that created mutual relationship between those two substances (with immunological basis and following recuperation). The anti-inflammatory actions of PUFA-OMEGA-3 are the most visible (and significant) contrasts as compared with the large affects of namely arachidonic acid and its metabolites. PMID- 21699758 TI - Placental tissue as model for pilot study focused on RNA analysis from human foetal tissue. AB - Early neonatal adaptation to extrauterine life is i.a. dependent on effective mitochondrial biogenesis during foetal development. Understanding of mitochondrial biogenesis is limited, because only scarce data are available from prenatal studies including RNA analyses in human foetal tissues. Aims of the study were focused on the factors affecting RNA quality in human placental tissue (HPT) including temperature, time period before HPT freezing and the Apgar score. In addition, optimal reference genes for mRNA quantification by real-time PCR in HPT were studied. Samples of HPT were obtained after the birth of 20 term neonates. Seven HPT were used for the time-course study of RNA degradation in two different temperatures (0 degrees C and 24 degrees C). Various instruments NanoDrop (NanoDrop Technologies), Experion (Bio-Rad Laboratories), Agilent 2100 Bioanalyzer (Agilent Technologies) were used for analysis of RNA integrity, purity and yield. Identification of suitable reference genes was achieved by analysing six candidate genes (ATP5O, SDHA, TBP, HPRT, PMBS, ATP6) for their expression stability (GeNorm application). The results showed that the HPT samples for RNA analyses must be frozen immediately after birth in -80 degrees C or stored at 0 degrees C maximally for 1 hour. The reference genes ATP50 and SDHA were the most stable for mRNA quantification in HPT. Human placenta represents easily obtainable source of foetal tissue for studies concerning mitochondrial biogenesis. We demonstrated that the critical limit for optimal storage and handling of HPT are the temperature and the time period before freezing of the samples. PMID- 21699760 TI - Endoscopic versus mini-invasive radial artery graft harvesting for purposes of aortocoronary bypass. AB - The aim of the study was to compare three different methods of radial artery harvesting with regard to postoperative complications and perioperative stress of the patient. A total of 60 patients admitted for coronary artery bypass surgery were randomized into three groups. Each patient underwent extraction of radial artery, all performed by a single surgeon. The radial artery was harvested by one of the following three techniques: classical technique (20 patients), mini invasive technique (20), and endoscopic technique (20). The time required for the graft harvest was greater in the group where the endoscopic technique was used (52.6 +/- 11.3 min) than with the mini-invasive (41.5 +/- 7.3 min) or the classical (27.8 +/- 4.6 min) technique. Postoperative blood loss into drains was higher where the classical technique was used (35.5 +/- 9.4 ml) as compared to the mini-invasive (20 +/- 5 ml) or the endoscopic (10 +/- 7.3 ml) technique. There was no significant difference among the groups in the rate of local neurological complications, contusion of wound edge, edema of the extremity, or wound infection rate. We observed no case of ischemia of the extremity, and a single case of postoperative myocardial ischemia in the group where the classical technique was used. From a clinical point of view, the mini-invasive and the endoscopic approach are comparable, but the latter is more expensive. Both mini invasive and endoscopic techniques prolong the operation, reduce perioperative blood loss, and require additional training time. PMID- 21699759 TI - Impact of prenatal methamphetamine exposure on the sensitivity to the same drug in adult male rats. AB - There are only few studies that examine the effect of prenatal methamphetamine (MA) exposure on the sensitivity to the same drug and the drug-seeking behavior in adulthood. The aim of the present study was to examine the effect of prenatal MA exposure on exploratory behavior and nociception with respect to challenge dose of the same drug. Mothers of the tested offspring received a daily injection of MA (5 mg/kg) or saline throughout the gestation period. Adult male offspring (prenatally MA- or saline-exposed) were divided to groups with challenge dose of MA (1 mg/kg) or saline. A modified Open field test (Laboras) was used to examine behavior in unknown environment. Plantar test was used to measure nociception on forelimbs, hind limbs, and the tail. Conditioned place preference (CPP) test was used to examine drug-seeking behavior. Our results in Laboras demonstrated that prenatal MA exposure sensitized the animals to the challenge dose of MA. Specifically prenatally MA-exposed animals that received the challenge MA in adulthood displayed higher locomotion and rearing activity relative to all the other groups. The Plantar test data suggest analgesic effect of MA (1 mg/kg), which however, did not differ based on the prenatal drug exposure. The results of CPP test showed that MA (5 mg/kg) conditioning resulted in increased drug-seeking behavior, but this effect was not affected by prenatal drug exposure. Thus, our data demonstrate that the effects of prenatal MA exposure and the challenge dose of the same drug in adulthood depend on behavioral model used. PMID- 21699761 TI - Idiopathic infantile hypercalcaemia in 5-month old girl. AB - Idiopathic infantile hypercalcaemia (IIH) is a mineral metabolism disorder of unknown origin. It is characterized by high levels of serum calcium resulting in parathyroid hormone (PTH) suppression, muscle hypotonia, thirst, anorexia, failure to thrive, psychomotor retardation, constipation, nephrocalcinosis. Treatment consists of low calcium diet, glucocorticoids, furosemide. We present a case of 5-month old girl with IIH, where total calcaemia peaked to 4.25 mmol/l. The leading symptoms were failure to thrive, constipation, muscle hypotonia, dehydration. Rehydration, low calcium diet, and application of glucocorticoids and furosemide resulted in a drop in calcaemia to normal values and an overall clinical improvement within two weeks. Williams-Beuren syndrome (WBS), benign familial hypocalciuric hypercalcaemia (FHH), neonatal severe primary hyperparathyroidism (NSHPT), Jansen's metaphyseal dysplasia, primary hyperparathyroidism, vitamin D intoxication, granulomatous diseases, thyroid disease, malignancy were all ruled out. In conclusion, infants with failure to thrive should have their serum levels of minerals, especially, calcium, checked. In case of hypercalcaemia, treatment with corticosteroids and furosemide should be initiated, together with further diagnostic steps in order to elucidate its origin. PMID- 21699762 TI - Hemobilia and occult cystic artery stump bleeding after a laparoscopic cholecystectomy: endovascular treatment with N-butyl cyanoacrylate. AB - Hemobilia is a rare phenomenon. In this case report we present an emergent transcatheter glue embolization (in which N-butyl cyanoacrylate is used as an embolizing agent) due to arteriobilary fistula occurred following the laparoscopic cholecystectomy in a 41-year-old woman. PMID- 21699763 TI - Schwannoma of the kidney with magnetic resonance images of non-homogenous renal mass--a case presentation. AB - Schwannomas are rare tumours that originate from the neural sheath and are usually located in the head and neck, extremities, and posterior mediastinum. Although 3% of schwannomas occur in the retroperitoneum, involvement of visceral organs is extremely uncommon. Schwannomas of the kidney are rare, with only a few reported cases. A 55-year-old woman was referred to our hospital with an abdominal sonography showing a spherical lesion in the upper pole of the left kidney that did not have the characteristics of a cortical cyst. The ultrasound had been recommended from her family doctor, due to a non specific pain in the hypogastrium in the previous 10 days. The final pathologic diagnosis was intrarenal benign schwannoma. Schwannomas are rare renal tumours with usually benign behaviour. Due to nonspecific symptoms and limited radiologic features for the diagnosis and assessment of the benign or malignant character of the tumour, the therapeutic approach is similar to other renal tumours. The definitive diagnosis is achieved with the help of immunohistochemistry. PMID- 21699764 TI - Severe tentorial haemorrhage of the term newborn with a favourable outcome--case report. AB - The traumatic intracranial haemorrhage still remains a serious complication of instrumental deliveries with an uncertain prognosis. Regarding tentorial haemorrhage, surprisingly few clinical neurological data are available. Most of the references in literature are older case reports, associated frequently with an unfavourable outcome. We report a newborn after a serious tentorial haemorrhage with an excellent neurodevelopmental outcome. Computed tomography (CT) scan of our patient demonstrated an extensive bilateral tentorial haemorrhage extending to the foramen magnum. The newborn showed a good respiratory effort, but a neurological impairment including anisocoria, apathy, hypotonia, incomplete grasp and Moro reflex. Despite these signs, the development at 9 and 18 months of age was appropriate. The aim of this report is to accentuate that the prognosis of infants with tentorial haemorrhage should be always evaluated carefully with main respect to clinical signs. The outcome of the newborn even after a large tentorial haemorrhage can be surprisingly without a serious neurological deficit. Spontaneous breathing without support, normal blood pressure and absence of seizures are clinical indicators that may be associated with a good outcome despite an extensive tentorial haemorrhage. PMID- 21699765 TI - Transgene insertion affects transcription and epigenetic modification of flanking host sequence in transgenic pigs. AB - Transgenic technology has been used for years to study gene function, produce important proteins, and generate models for the study of human diseases. However, the efficiency of producing transgenic animal lines that retain normal function is extremely low. The low efficiency can be mainly attributed to the integrated transgene. A further understanding of the effects of transgene integration on transcription and epigenetic modification of the host genome would improve the transgenic efficiency. Therefore, we utilized three transgenic pigs produced by SCNT expressing GFP, to identify alterations of transcription, DNA methylation and histone acetylation resulting from integration of the GFP gene. Multiple copies of the transgene integrated into a single site of the three transgenic pigs were verified by TAIL—PCR and the integration sites were different in each pig. We observed that the integrated transgene frequently resulted in significantly low transcription of flanking sequences in various tissues of transgenic pigs in comparison with wild—type pigs. Corresponding with the low transcription, DNA hypermethylation and loss of acetylation of histone H3 and H4 were detected. Our results demonstrate that the abnormal transcription and epigenetic modification of sequences flanking the transgene were not correlated with the expression of the transgene. However, the disturbance caused by the insertion of the transgene, was dependent upon the integration site. This suggests that some sequences in the host genome could permit integration and expression of transgene without causing defects in the host. PMID- 21699766 TI - Effects of lipopolysaccharides on TLR4 expression in INS-1 rat insulinoma cells. AB - The aim of the study was to obtain insight into the mechanism of sepsis-induced hyperglycemia, to explore the expression of Toll-like receptor 4 (TLR4) on INS-1 cells, the effects of lipopolysaccharide (LPS) on TLR4 expression and cell viability. The expression of TLR4 on INS-1 was detected by both RT-PCR and Western blot assays. After being intervened by LPS of various concentrations (0.01, 0.1, 1, 5, 10mg/L) for a certain time, the effects of LPS on TLR4 expression and cell viability were detected by quantitative real-time reverse transcriptase polymerase chain reaction, western blotting and CCK-8 assay. Then INS-1 cells were stimulated by LPS (0.1, 1mg/L) together with anti-TLR4 antibody, cell viability and TLR4 expression were detected again. TLR4 expressed in INS-1 cell line. Its expression was up-regulated by the stimulation of LPS higher than 0.1mg/L for 12h (P<0.05). However, there was a little down-regulation of TLR4 between the LPS treated groups and controls with further LPS treatment for 24 and 48 h (P>0.05). In certain concentrations(0.1~10mg/L), viability of INS-1 cells was inhibited by LPS in a dose dependent manner (P<0.05) These effects could be blocked by anti-TLR4 antibody partially. These results suggest that LPS may act directly on the pancreatic beta cells via TLR4 on the beta-cell membrane. LPS increased TLR4 expression in the early short period of time and caused injury to INS-1 cells after a certain time. It could be one of the mechanisms that hyperglycemia occurs in the early stage of sepsis. PMID- 21699767 TI - Intestinal parasites isolated in a large teaching hospital, Italy, 1 May 2006 to 31 December 2008. AB - Intestinal parasites account for the majority of parasitic diseases, particularly in endemic areas. Most are transmitted via contaminated food. Because of increased immigration and travel, enteric parasitoses are now distributed worldwide. Between May 2006 and December 2008, we examined stool specimens from 5,351 patients (4,695 Italians, 656 non-Italians) for ova and parasites using microscopy, culture techniques, and molecular methods. Stools from 594 patients (11.1%) were contaminated and for all patients samples combined, a total of 700 intestinal parasites were counted. Ninety of the 594 infected patients had more than one parasite in their stools. Parasites causing intestinal disease occurred in 8.8% of patients. The prevalence was over twice as high among non-Italians (26.8% vs 8.9% in Italians, p<0.001) and higher in males (13.0% vs 9.5% in females, p=0.003). Most isolates were pathogenic protozoa, including in decreasing order of frequency: Blastocystis hominis, Giardia intestinalis, Entamoeba histolytica, and Cyclospora cayetanensis. The latter two species tended to be more common in Italians, although not at significant level (3.6% (15/418) vs 1.7% (3/176) in non-Italians, OR: 2.15; 95%CI: 0.60-11.70, p=0.22). Helminthes were found in 28 patients, mainly non-Italians (5.7% (10/176) vs 4.3% (18/418), OR: 1.34; 95%CI: 0.54-3.13, p=0.47). Ascaris lumbricoides and Hymenolepis nana were the most common. Strongyloides stercoralis, Enterobius vermicularis, Taenia spp. and Trichuris trichiura were also found. Intestinal parasites are a serious problem in developing countries, but should not be underestimated in industrialised countries. PMID- 21699768 TI - Rapidly controlled outbreak of Serratia marcescens infection/colonisations in a neonatal intensive care unit, Pescara General Hospital, Pescara, Italy, April 2011. AB - In April 2011, an outbreak of Serratia marcescens infection/ colonisations occurred in the neonatal intensive care unit of Pescara General Hospital. Rapid microbiological investigations lead to identification of five cases of likely cross-transmission from a neonate hospitalised for S. marcescens sepsis: four infections and one neonate colonised post-mortem. Two low birth weight neonates died. The environmental investigation detected S. marcescens from two soap dispensers. Strict hygiene measures lead to early interruption of the outbreak, without recurrences to date. PMID- 21699770 TI - Characteristics of the enteroaggregative Shiga toxin/verotoxin-producing Escherichia coli O104:H4 strain causing the outbreak of haemolytic uraemic syndrome in Germany, May to June 2011. AB - The Escherichia coli strain causing a large outbreak of haemolytic uraemic syndrome and bloody diarrhoea in Germany in May and June 2011 possesses an unusual combination of pathogenic features typical of enteroaggregative E. coli together with the capacity to produce Shiga toxin. Through rapid national and international exchange of information and strains the known occurrence in humans was quickly assessed.We describe simple diagnostic screening tools to detect the outbreak strain in clinical specimens and a novel real-time PCR for its detection in foods. PMID- 21699769 TI - Enhanced surveillance during a large outbreak of bloody diarrhoea and haemolytic uraemic syndrome caused by Shiga toxin/verotoxin-producing Escherichia coli in Germany, May to June 2011. AB - Germany has a well established broad statutory surveillance system for infectious diseases. In the context of the current outbreak of bloody diarrhoea and haemolytic uraemic syndrome caused by Shiga toxin/ verotoxin-producing Escherichia coli in Germany it became clear that the provisions of the routine surveillance system were not sufficient for an adequate response. This article describes the timeline and concepts of the enhanced surveillance implemented during this public health emergency. PMID- 21699771 TI - Enteroaggregative, Shiga toxin-producing Escherichia coli O104:H4 outbreak: new microbiological findings boost coordinated investigations by European public health laboratories. PMID- 21699772 TI - Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool. AB - BACKGROUND & AIMS: Adenomatous polyps are precursors to colorectal cancer (CRC), whereas hyperplastic polyps (HPPs) have low risk of progression to CRC. Mutations in KRAS are found in ~40% of CRCs and large adenomas and a subset of HPPs. We investigated the reasons why HPPs with KRAS mutations lack malignant potential and compared the effects of Kras/KRAS activation with those of Apc/APC inactivation, which promotes adenoma formation. METHODS: We activated a KrasG12D mutant allele or inactivated Apc alleles in mouse colon epithelium and analyzed phenotypes and expression of selected genes and proteins. The mouse data were validated using samples of human HPPs and adenomas. Signaling pathways and factors contributing to Kras/KRAS-induced phenotypes were studied in intestinal epithelial cells. RESULTS: Activation of Kras led to hyperplasia and serrated crypt architecture akin to that observed in human HPPs. We also observed loss of Paneth cells and increases in goblet cell numbers. Abnormalities in Kras-mediated differentiation and proliferation required mitogen-activated protein kinase signaling and were linked to activation of the Hes1 transcription factor. Human HPPs also had activation of HES1. In contrast to Apc/APC inactivation, Kras/KRAS activation did not increase expression of crypt stem cell markers in colon epithelium or colony formation in vitro. Kras/KRAS activation was not associated with substantial induction of p16(INK4a) protein expression in mouse colon epithelium or human HPPs. CONCLUSIONS: Although Kras/KRAS mutation promotes serrated and hyperplastic morphologic features in colon epithelium, it is not able to initiate adenoma development, perhaps in part because activated Kras/KRAS signaling does not increase the number of presumptive stem cells in affected crypts. PMID- 21699773 TI - Sleeve gastrectomy in rats improves postprandial lipid clearance by reducing intestinal triglyceride secretion. AB - BACKGROUND & AIMS: Postprandial hyperlipidemia is a risk factor for atherosclerotic heart disease and is associated with the consumption of high-fat diets and obesity. Bariatric surgeries result in superior and more durable weight loss than dieting. These surgeries are also associated with multiple metabolic improvements, including reduced plasma lipid levels. We investigated whether the beneficial effects of vertical sleeve gastrectomy (VSG) on plasma lipid levels are weight independent. METHODS: VSG was performed on Long-Evans rats with diet induced obesity. Controls were sham-operated animals who were either pair-fed or ad libitum-fed. We measured fasting and postprandial levels of plasma lipid. To determine hepatic and intestinal triglyceride secretion, we injected the lipase inhibitor poloxamer 407 alone or before oral lipid gavage. (13)C-Triolein was used to estimate postprandial uptake of lipid in the intestine. RESULTS: Rats that received VSG and high-fat diets had markedly lower fasting levels of plasma triglyceride, cholesterol, and phospholipid than obese and lean (pair-fed) controls that were fed high-fat diets. Rats that received VSG had a marked, weight-independent reduction in secretion of intestinal triglycerides. VSG did not alter total intestinal triglyceride levels or size of the cholesterol storage pool nor did it affect the expression of genes in the intestine that control triglyceride metabolism and synthesis. VSG did not affect fasting secretion of triglyceride, liver weight, hepatic lipid storage, or transcription of genes that regulate hepatic lipid processing. CONCLUSIONS: VSG reduced postprandial levels of plasma lipid, independently of body weight. This resulted from reduced intestinal secretion of triglycerides following ingestion of a lipid meal and indicates that VSG has important effects on metabolism. PMID- 21699774 TI - The complement regulator CD46 is bactericidal to Helicobacter pylori and blocks urease activity. AB - BACKGROUND & AIMS: CD46 is a C3b/C4b binding complement regulator and a receptor for several human pathogens. We examined the interaction between CD46 and Helicobacter pylori (a bacterium that colonizes the human gastric mucosa and causes gastritis), peptic ulcers, and cancer. METHODS: Using gastric epithelial cells, we analyzed a set of H pylori strains and mutants for their ability to interact with CD46 and/or influence CD46 expression. Bacterial interaction with full-length CD46 and small CD46 peptides was evaluated by flow cytometry, fluorescence microscopy, enzyme-linked immunosorbent assay, and bacterial survival analyses. RESULTS: H pylori infection caused shedding of CD46 into the extracellular environment. A soluble form of CD46 bound to H pylori and inhibited growth, in a dose- and time-dependent manner, by interacting with urease and alkyl hydroperoxide reductase, which are essential bacterial pathogenicity associated factors. Binding of CD46 or CD46-derived synthetic peptides blocked the urease activity and ability of bacteria to survive in acidic environments. Oral administration of one CD46 peptide eradicated H pylori from infected mice. CONCLUSIONS: CD46 is an antimicrobial agent that can eradicate H pylori. CD46 peptides might be developed to treat H pylori infection. PMID- 21699775 TI - p53 and PUMA independently regulate apoptosis of intestinal epithelial cells in patients and mice with colitis. AB - BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is associated with increased apoptosis of intestinal epithelial cells (IECs). Mutations in the tumor suppressor p53 appear during early stages of progression from colitis to cancer. We investigated the role of p53 and its target, p53-upregulated modulator of apoptosis (PUMA), in inflammation-induced apoptosis of IECs. METHODS: Apoptosis was induced in mouse models of mucosal inflammation. Responses of IECs to acute, T-cell activation were assessed in wild-type, p53-/-, Bid-/-, Bim-/-, Bax3-/-, Bak-/-, PUMA-/-, and Noxa-/- mice. Responses of IECs to acute and chronic colitis were measured in mice following 1 or 3 cycles of dextran sulfate sodium (DSS), respectively. Apoptosis was assessed by TUNEL staining and measuring activity of caspases 3 and 9; levels of p53 and PUMA were assessed in colon tissue from patients with and without ulcerative colitis. RESULTS: Apoptosis of IECs occurred in the lower crypts of colitic tissue from humans and mice. Colitis induction with anti-CD3 or 3 cycles of DSS increased apoptosis and protein levels of p53 and PUMA in colonic crypt IECs. In p53-/- and PUMA-/- mice, apoptosis of IECs was significantly reduced but inflammation was not. Levels of p53 and PUMA were increased in inflamed mucosal tissues of mice with colitis and in patients with UC, compared with controls. Induction of PUMA in IECs of p53-/- mice indicated that PUMA-mediated apoptosis was independent of p53. CONCLUSIONS: In mice and humans, colon inflammation induces apoptosis of IECs via p53-dependent and - independent mechanisms; PUMA also activates an intrinsic apoptosis pathway associated with colitis. PMID- 21699776 TI - Altered endoplasmic reticulum stress affects translation in inactive colon tissue from patients with ulcerative colitis. AB - BACKGROUND & AIMS: Ulcerative colitis (UC) is a chronic inflammatory disorder that affects the colonic epithelium. Epidemiology studies indicate an environmental component is involved in pathogenesis, although the primary changes in the digestive epithelium that cause an uncontrolled inflammatory response are not known. Animal studies have shown that altered endoplasmic reticulum (ER) stress response initiates intestinal inflammation in epithelial tissues, but abnormalities associated with ER stress have not been identified in patients with UC. METHODS: Using immunoblotting, real-time polymerase chain reaction, immunohistochemistry, and immunofluorescence analyses, we assessed ER stress signaling in uninflammed colonic mucosa from patients with UC and controls. Genome-wide microarray analysis of actively translated polysome-bound messenger RNA was performed using samples of unaffected mucosa from patients with UC, and data were compared with those from controls. RESULTS: Inositol-requiring kinase and activating transcription factor signaling pathways were activated in inactive colonic epithelium from patients with UC; these mediate proinflammatory and regenerative responses. Blocking phosphorylation of the translation initiation factor 2 (eIF2alpha), which mediates the integrated stress response, deregulated initiation of translation and reduced the numbers of stress granules in colonic epithelial cells from patients with UC. Genome-wide microarray analysis of actively translated, polysome-bound messenger RNA from patients revealed changes in protein translation that altered colonic epithelial barrier function (levels of detoxification and antioxidant enzymes and proteins that regulate the cell cycle, cell-cell adhesion, and secretion), compared with controls. CONCLUSIONS: Colonic mucosa samples from patients with UC have defects in the eIF2alpha pathway that controls protein translation and the cell stress response. This pathway might be investigated to identify new therapeutic targets for patients with UC. PMID- 21699777 TI - Faster recovery of gastrointestinal transit after laparoscopy and fast-track care in patients undergoing colonic surgery. AB - BACKGROUND & AIMS: Postoperative ileus is characterized by delayed gastrointestinal (GI) transit and is a major determinant of recovery after colorectal surgery. Both laparoscopic surgery and fast-track multimodal perioperative care have been reported to improve clinical recovery. However, objective measures supporting faster GI recovery are lacking. Therefore, GI transit was measured following open and laparoscopic colorectal surgery with or without fast-track care. METHODS: Patients (n = 93) requiring elective colonic surgery were randomized to laparoscopic or conventional surgery with fast-track multimodal management or standard care, resulting in 4 treatment arms. Gastric emptying and colonic transit were scintigraphically assessed from days 1 to 3 in 78 patients and compared with clinical parameters such as time to tolerance of solid food and/or bowel movement and time until (ready for) discharge. RESULTS: A total of 71 patients without mechanical bowel obstructions or surgical complications requiring intervention were available for analysis. No differences in gastric emptying 24 hours after surgery between the different groups were observed (P = .61). However, the median colonic transit of patients undergoing laparoscopic/fast-track care was significantly faster compared with the laparoscopic/standard, open/fast-track, and open/standard care groups. Multiple linear regression analysis showed that both laparoscopic surgery and fast-track care were significant independent predictive factors of improved colonic transit. Both were associated with significantly faster clinical recovery and shorter time until tolerance of solid food and first bowel movement. CONCLUSIONS: Colonic transit recovers significantly faster after laparoscopic surgery and the fast track program; laparoscopy and fast-track care lead to faster recovery of GI motility and improve clinical recovery. PMID- 21699778 TI - Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation. AB - BACKGROUND & AIMS: Matrix metalloproteases (MMPs) mediate pathogenesis of chronic intestinal inflammation. We characterized the role of the gelatinase (GelE), a metalloprotease from Enterococcus faecalis, in the development of colitis in mice. METHODS: Germ-free, interleukin-10-deficient (IL-10(-/-)) mice were monoassociated with the colitogenic E faecalis strain OG1RF and isogenic, GelE mutant strains. Barrier function was determined by measuring E-cadherin expression, transepithelial electrical resistance (TER), and translocation of permeability markers in colonic epithelial cells and colon segments from IL-10(-/ ) and TNF(DeltaARE/Wt) mice. GelE specificity was shown with the MMP inhibitor marimastat. RESULTS: Histologic analysis (score 0-4) of E faecalis monoassociated IL-10(-/-) mice revealed a significant reduction in colonic tissue inflammation in the absence of bacteria-derived GelE. We identified cleavage sites for GelE in the sequence of recombinant mouse E-cadherin, indicating that it might be degraded by GelE. Experiments with Ussing chambers and purified GelE revealed the loss of barrier function and extracellular E-cadherin in mice susceptible to intestinal inflammation (IL-10(-/-) and TNF(DeltaARE/Wt) mice) before inflammation developed. Colonic epithelial cells had reduced TER and increased translocation of permeability markers after stimulation with GelE from OG1RF or strains of E faecalis isolated from patients with Crohn's disease and ulcerative colitis. CONCLUSIONS: The metalloprotease GelE, produced by commensal strains of E faecalis, contributes to development of chronic intestinal inflammation in mice that are susceptible to intestinal inflammation (IL-10(-/-) and TNF(DeltaARE/Wt) mice) by impairing epithelial barrier integrity. PMID- 21699779 TI - Cross beta-sheet conformation of keratin 8 is a specific feature of Mallory-Denk bodies compared with other hepatocyte inclusions. AB - BACKGROUND & AIMS: Mallory-Denk bodies (MDBs) are cytoplasmic protein aggregates in hepatocytes in steatohepatitis and other liver diseases. We investigated the molecular structure of keratin 8 (K8) and 18 (K18), sequestosome 1/p62, and ubiquitin, which are the major constituents of MDBs, to investigate their formation and role in disease pathogenesis. METHODS: Luminescent conjugated oligothiophenes (LCOs), h-HTAA, and p-FTAA are fluorescent amyloid ligands that specifically bind proteins with cross beta-sheet conformation. We used LCOs to investigate conformational changes in MDBs in situ in human and murine livers as well as in transfection studies. RESULTS: LCO analysis showed cross beta-sheet conformation in human MDBs from patients with alcoholic and nonalcoholic steatohepatitis or hepatocellular carcinoma, but not in intracellular hyaline bodies, alpha1-antitrypsin deficiency, or ground-glass inclusions. LCOs bound to MDBs induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine feeding of mice at all developmental stages. CHO-K1 cells transfected with various combinations of SQSTM1/p62, ubi, and Krt8/Krt18 showed that K8 was more likely to have cross beta sheet conformation than K18, whereas p62 never had cross beta-sheet conformation. The different conformational properties of K8 and K18 were also shown by circular dichroism analysis. CONCLUSIONS: K8 can undergo conformational changes from predominantly alpha-helical to cross beta-sheet, which would allow it to form MDBs. These findings might account for the observation that krt8-/- mice do not form MDBs, whereas its excess facilitates MDB formation. LCOs might be used in diagnosis of liver disorders; they can be applied to formalin-fixed, paraffin embedded tissues to characterize protein aggregates in liver cells. PMID- 21699780 TI - Tests for serum levels of trefoil factor family proteins can improve gastric cancer screening. AB - BACKGROUND & AIMS: Improving methods for early detection of gastric cancer could reduce mortality. Measurements of serum pepsinogen levels have been used for screening in Japan without satisfactory levels of sensitivity or specificity. Trefoil factor family (TFF) proteins (TFF1, TFF2, and TFF3) are small and stable molecules secreted by the mammalian gastrointestinal tract. Foveolar hyperplasia, spasmolytic polypeptide (TFF2)-expressing metaplasia, and intestinal metaplasia are histologic changes observed in patients with atrophic gastritis; they express TFF1, TFF2, and TFF3, respectively. We investigated whether serum levels of TFF can be used as markers for gastric cancer screening. METHODS: Serum was collected from 183 patients with gastric cancer and 280 healthy individuals without cancer. Serum levels of anti-Helicobacter pylori immunoglobulin G, pepsinogen I, pepsinogen II, TFF1, TFF2, and TFF3 were measured by enzyme-linked immunosorbent assay and associated with gastric cancer. RESULTS: Using a cutoff of 3.6 ng/mL, the level of TFF3 was significantly increased in serum samples from patients with cancer (odds ratio, 18.1; 95% confidence interval, 11.2-29.2); using this test, patients with cancer were identified with 80.9% sensitivity and 81.0% specificity. The test for TFF3 had a significantly higher odds ratio than that for pepsinogen. A test for the combination of TFF3 and pepsinogen had better results than the test for only pepsinogen. CONCLUSIONS: Serum levels of TFF3 are a better marker of gastric cancer than pepsinogen; a test for the combined levels of serum pepsinogen and TFF3 could improve gastric cancer screening. PMID- 21699781 TI - Deletion of Rb accelerates pancreatic carcinogenesis by oncogenic Kras and impairs senescence in premalignant lesions. AB - BACKGROUND & AIMS: Rb1 encodes a cell-cycle regulator that is functionally disrupted in most human cancers. Pancreatic ductal adenocarcinomas (PDACs) have a high frequency of mutations in KRAS and INK4A/CDKN2A that might allow cells to bypass the regulatory actions of retinoblastoma (RB). To determine the role of loss of RB function in PDAC progression, we investigated the effects of Rb disruption during pancreatic malignant transformation initiated by oncogenic Kras. METHODS: We generated mice with pancreas-specific disruption of Rb, in the absence or presence of oncogenic Kras, to examine the role of RB in pancreatic carcinogenesis. RESULTS: In the presence of oncogenic Kras, loss of Rb from the pancreatic epithelium accelerated formation of pancreatic intraepithelial neoplasia (PanIN), increased the frequency of cystic neoplasms, and promoted rapid progression toward PDAC. Early stage cancers were characterized by acute pancreatic inflammation, associated with up-regulation of proinflammatory cytokines within the pancreas. Despite the presence of markers associated with oncogene-induced senescence, low-grade PanIN were highly proliferative and expressed high levels of p53. Pancreatic cancer cell lines derived from these mice expressed high levels of cytokines, and transcriptional activity of p53 was impaired. CONCLUSIONS: Rb encodes a tumor suppressor that attenuates progression of oncogenic Kras-induced carcinogenesis in the pancreas by mediating the senescence response and promoting activity of the tumor suppressor p53. PMID- 21699783 TI - TLE1 modifies the effects of NOD2 in the pathogenesis of Crohn's disease. AB - BACKGROUND & AIMS: The mechanisms by which specific mutations in NOD2/CARD15 increase the risk for Crohn's disease (CD) are unclear. We identified proteins that interact with NOD2 and investigated them by expression, genetic, and functional analyses. METHODS: By using a yeast 2-hybrid screen of an intestinal epithelial library, we identified proteins that interact with NOD2 and confirmed the interactions in mammalian cells using co-immunoprecipitation. We used microarray analysis to analyze gene expression patterns in 302 intestinal biopsy samples (129 from patients with ulcerative colitis [UC], 106 with CD, and 67 controls). Eighty single-nucleotide polymorphisms within the genes that encoded 6 interacting proteins were genotyped in a discovery cohort (869 cases of inflammatory bowel disease [IBD], 885 controls) and a replication cohort (504 patients with IBD, 713 controls). We investigated interaction between transducin like enhancer of split 1 (TLE1) and NOD2 in HEK293 cells. RESULTS: We identified 6 NOD2-interacting proteins (TLE1, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2 [GALNT2], HIV-1 Tat interactive protein [HTATIP], Vimentin, fission 1 (mitochondrial outer membrane) homolog [FIS1], and protein phosphatase 2, regulatory subunit B', epsilon isoform [PPP2R5E]). Of these, expression of GALNT2 (CD, P = .004) and vimentin (CD, P = .006; UC, P = .0025) was altered in patients with IBD compared with controls. Single-nucleotide polymorphisms within TLE1 were associated with susceptibility to CD, specifically with ileal disease (rs6559629, P = 3.1 * 10-5; odds ratio, 1.45). The TLE1 risk allele is required for susceptibility to CD in carriers of NOD2 mutations. In cells, TLE1 and NOD2 co-localized around the nuclear membrane and TLE1 inhibited activation of nuclear factor-kappaB by NOD2. CONCLUSIONS: Epistatic and biological interactions between TLE1 and NOD2 are involved in IBD pathogenesis. NOD2 might be involved in a series of pathways such as epigenetic regulation of expression (via TLE1 and HTATIP), biosynthesis of mucin (via GALNT2), apoptosis (via PPP2R5E and FIS1), and integrity of the intracellular cytoskeleton (vimentin). PMID- 21699782 TI - Localization and regulation of fluorescently labeled delta opioid receptor, expressed in enteric neurons of mice. AB - BACKGROUND & AIMS: Opioids and opiates inhibit gastrointestinal functions via MU, delta, and kappa receptors. Although agonists of the delta opioid receptor (DOR) suppress motility and secretion, little is known about the localization and regulation of DOR in the gastrointestinal tract. METHODS: We studied mice in which the gene that encodes the enhanced green fluorescent protein (eGFP) was inserted into Oprd1, which encodes DOR, to express an approximately 80-kilodalton product (DOReGFP). We used these mice to localize DOR and to determine how agonists regulate the subcellular distribution of DOR. RESULTS: DOReGFP was expressed in all regions but was confined to enteric neurons and fibers within the muscularis externa. In the submucosal plexus, DOReGFP was detected in neuropeptide Y-positive secretomotor and vasodilator neurons of the small intestine, but rarely was observed in the large bowel. In the myenteric plexus of the small intestine, DOReGFP was present in similar proportions of excitatory motoneurons and interneurons that expressed choline acetyltransferase and substance P, and in inhibitory motoneurons and interneurons that contained nitric oxide synthase. DOReGFP was present mostly in nitrergic myenteric neurons of colon. DOReGFP and MU opioid receptors often were co-expressed. DOReGFP expressing neurons were associated with enkephalin-containing varicosities, and enkephalin-induced clathrin- and dynamin-mediated endocytosis and lysosomal trafficking of DOReGFP. DOReGFP replenishment at the plasma membrane was slow, requiring de novo synthesis, rather than recycling. CONCLUSIONS: DOR localizes specifically to submucosal and myenteric neurons, which might account for the ability of DOR agonists to inhibit gastrointestinal secretion and motility. Sustained down-regulation of DOReGFP at the plasma membrane of activated neurons could induce long-lasting tolerance to DOR agonists. PMID- 21699785 TI - Mesenchymal stem cells promote formation of colorectal tumors in mice. AB - BACKGROUND & AIMS: Tumor-initiating cells are a subset of tumor cells with the ability to form new tumors; however, they account for less than 0.001% of the cells in colorectal or other types of tumors. Mesenchymal stem cells (MSCs) integrate into the colorectal tumor stroma; we investigated their involvement in tumor initiation. METHODS: Human colorectal cancer cells, MSCs, and a mixture of both cell types were injected subcutaneously into immunodeficient mice. We compared the ability of each injection to form tumors and investigated the signaling pathway involved in tumor initiation. RESULTS: A small number (<= 10) of unsorted, CD133-, CD166-, epithelial cell adhesion molecule-(EpCAM-), or CD133 /CD166-/EpCAM- colorectal cancer cells, when mixed with otherwise nontumorigenic MSCs, formed tumors in mice. Secretion of interleukin (IL)-6 by MSCs increased the expression of CD133 and activation of Janus kinase 2-signal transducer and activator of transcription 3 (STAT3) in the cancer cells, and promoted sphere and tumor formation. An antibody against IL-6 or lentiviral-mediated transduction of an interfering RNA against IL-6 in MSCs or STAT3 in cancer cells prevented the ability of MSCs to promote sphere formation and tumor initiation. CONCLUSIONS: IL 6, secreted by MSCs, signals through STAT3 to increase the numbers of colorectal tumor-initiating cells and promote tumor formation. Reagents developed to disrupt this process might be developed to treat patients with colorectal cancer. PMID- 21699784 TI - Estrogen regulation of duodenal bicarbonate secretion and sex-specific protection of human duodenum. AB - BACKGROUND & AIMS: The reason that women have a lower prevalence of duodenal ulcer is not clear. We investigated whether estrogen regulates human duodenal bicarbonate secretion (DBS) and whether this process accounts for sex differences in the prevalence of duodenal ulcer. METHODS: We performed an epidemiologic study to correlate duodenal ulcer prevalence with sex and age. Proximal DBS was measured from healthy subjects. Estrogen-receptor expression was examined in human duodenal mucosa by immunoblot and immunohistochemical analyses. RESULTS: Among women, the prevalence of duodenal ulcer was significantly lower than among men. The reduced prevalence was greatest among premenopausal women (20-49 y), who were 3.91- to 5.09-fold less likely to develop duodenal ulcers than age-matched men; the difference was reduced to 1.32-fold or less among subjects aged 60 years or older. Premenopausal (20-29 y), but not postmenopausal (60-69 y), women had significantly higher basal and acid-stimulated DBS than the age-matched men. Basal and acid-stimulated DBS in premenopausal women (20-29 y) were significantly higher than in postmenopausal women (60-69 y), whereas there were no significant differences in basal or acid-stimulated DBS between men who were aged 20-29 years or 60-69 years. Serum levels of estradiol changed in parallel with basal and acid stimulated DBS during the physiological menstrual cycle in premenopausal women. 17beta-estradiol-stimulated DBS was independent of age or sex. Estrogen receptors alpha and beta were detected on plasma membranes and in the cytosol of human duodenal epithelial cells. CONCLUSIONS: Estrogen regulates human DBS, which could reduce the risk for duodenal ulcer in women and contribute to sex differences in the prevalence of duodenal ulcer. PMID- 21699786 TI - Telaprevir alone or with peginterferon and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not genotype 3 infections. AB - BACKGROUND & AIMS: We evaluated antiviral activity of 2 weeks therapy with telaprevir alone, peginterferon alfa-2a and ribavirin (PR), or all 3 drugs (TPR) in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 2 or 3 infections. METHODS: We performed a randomized, multicenter, partially blinded study of patients (23 with HCV genotype 2, 26 with genotype 3) who received telaprevir (750 mg every 8 h), placebo plus PR (peginterferon, 180 MUg, once weekly and ribavirin, 400 mg, twice daily), or TPR for 15 days, followed by PR for 22 or 24 weeks. Plasma levels of HCV RNA were quantified. RESULTS: Levels of HCV RNA decreased in all patients with HCV genotype 2, including those who received telaprevir monotherapy. The decrease was more rapid among patients who received telaprevir. By day 15, 0% (telaprevir), 40% (TPR), and 22% (PR) of patients with HCV genotype 2 had undetectable levels of HCV RNA; rates of sustained virologic response were 56%, 100%, and 89%, respectively. Overall, 6 of 9 HCV genotype 2 patients that received only telaprevir had viral breakthrough within 15 days after an initial response. HCV RNA levels decreased slightly among patients with HCV genotype 3 who received telaprevir and decreased rapidly among patients given PR or TPR (telaprevir had no synergistic effects with PR). Sustained virologic response rates were 50%, 67%, and 44% among patients given telaprevir, TPR, or PR respectively; 7 patients with HCV genotype 3 relapsed after therapy (2 given telaprevir, 3 given TPR, and 2 given PR) and 3 patients with HCV genotype 3 had viral breakthrough during telaprevir monotherapy. The incidence of adverse events was similar among groups. CONCLUSIONS: Telaprevir monotherapy for 2 weeks reduces levels of HCV RNA in patients with chronic HCV genotype 2 infections, but has limited activity in patients with HCV genotype 3. PMID- 21699787 TI - Val66Met in brain-derived neurotrophic factor affects stimulus-induced plasticity in the human pharyngeal motor cortex. AB - BACKGROUND & AIMS: Polymorphisms in brain-derived neurotrophic factor (BDNF) can affect brain and behavioral responses. However, little is known about the effects of a single nucleotide polymorphism (SNP) in BDNF, at codon 66 (the Val-Met substitution, detected in approximately 33% of the Caucasian population) on stimulation-induced plasticity in the cortico-bulbar system. We examined whether this SNP influenced outcomes of different forms of neurostimulation applied to the pharyngeal motor cortex. METHODS: Thirty-eight healthy volunteers were assessed for corticobulbar excitability after single-pulse, transcranial magnetic stimulation of induced pharyngeal electromyographic responses, recorded from a swallowed intraluminal catheter. Thereafter, volunteers were conditioned with pharyngeal electrical stimulation, or 2 forms of repetitive (1 and 5 Hz) transcranial magnetic stimulation (rTMS). Repeated measurements of pharyngeal motor-evoked potentials were assessed with transcranial magnetic stimulation for as long as 1 hour after the 3 forms of neurostimulation and correlated with SNPs at codon 66 of BDNF (encoding Val or Met). RESULTS: Pharyngeal electrical stimulation significantly increased the amplitude of motor-evoked potentials in individuals with the SNP that encoded Val66, compared to those that encoded Met66, with a strong GENOTYPE*TIME interaction (F8,112 = 2.4; P = .018). By contrast, there was a significant reduction in latencies of subjects with the SNP that encoded Met66 after 5-Hz rTMS (F3,60 = 4.9; P = .04). In addition, the expected inhibitory effect of 1-Hz rTMS on amplitude was not observed in subjects with the SNP that encoded Met66 in BDNF (F7,140 = 2.23; P = .035). CONCLUSIONS: An SNP in human BDNF at codon 66 affects plasticity of the pharyngeal cortex to different forms of neurostimulation. Genetic analysis might help select specific forms of neurostimulation as therapeutics for patients with disorders such as dysphagic stroke. PMID- 21699788 TI - HLA-Cw*1202-B*5201-DRB1*1502 haplotype increases risk for ulcerative colitis but reduces risk for Crohn's disease. AB - BACKGROUND & AIMS: There are many genetic factors that are associated with both ulcerative colitis (UC) and Crohn's disease (CD). However, genetic factors that have distinct effects on UC and CD have not been examined. METHODS: We performed a comparative genome-wide association study (GWAS) and a replication study using data from 748 patients with UC and 979 with CD, selected from a Japanese population. We conducted high-resolution (4-digit) genotyping of human leukocyte antigen (HLA) alleles in patients with UC and CD and additional 905 healthy individuals (controls). We performed haplotype-based analysis using data from the GWAS and HLA alleles to associate them with UC or CD. RESULTS: The comparative GWAS and the replication study identified significant associations in the major histocompatibility complex region at 6p21 with UC and CD (rs9271366, P = 1.6 * 10 70; odds ratio [OR] = 4.44). Haplotype-based analysis in the major histocompatibility complex region showed that HLA-Cw*1202-B*5201-DRB1*1502 haplotype was significantly associated with increased risk of UC compared with CD (P = 1.1 * 10-33; OR = 6.58), accounting for most of the associations observed in the GWAS. Compared with the controls, this HLA haplotype significantly increases susceptibility to UC (P = 4.0 * 10-21; OR = 2.65), but reduces risk for CD (P = 1.1 * 10-7; OR = 0.40). Distinct effects of this HLA haplotype on UC and CD were independent of other HLA alleles and haplotypes (P = 2.0 * 10-19 and P = 7.2 * 10 5, respectively). CONCLUSIONS: The HLA-Cw*1202-B*5201-DRB1*1502 haplotype increases susceptibility to UC but reduces risk for CD, based on a GWAS of a Japanese population. PMID- 21699789 TI - Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats. AB - BACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) reduce weight and improve glucose metabolism in obese patients, although it is not clear if metabolic changes are independent of weight loss. We investigated alterations in glucose metabolism in rats following RYGB or VSG. METHODS: Rats underwent RYGB or VSG and were compared to sham-operated rats fed ad lib or pair-fed to animals that received RYGB. Intraperitoneal glucose tolerance and insulin sensitivity tests were performed to assess glycemic function independent of incretin response. A hyperinsulinemic euglycemic clamp was used to compare tissue-specific changes in insulin sensitivity following each procedure. A mixed-meal tolerance test was used to assess the effect of each surgery on postprandial release of glucagon-like peptide 1 (GLP-1)(7-36) and glucose tolerance, and was also performed in rats given GLP-1 receptor antagonist exendin(9-39). RESULTS: Following RYGB or VSG, glucose tolerance and insulin sensitivity improved in proportion to weight loss. Hepatic insulin sensitivity was significantly better in rats that received RYGB or VSG compared with rats fed ad lib or pair-fed, whereas glucose clearance was similar in all groups. During the mixed-meal tolerance test, plasma levels of GLP-1(7-36) and insulin were greatly and comparably increased in rats that received RYGB and VSG compared with those that were pair-fed or fed ad lib. Administration of a GLP-1 receptor antagonist prevented improvements in glucose and insulin responses after a meal among rats that received RYGB or VSG. CONCLUSIONS: In obese rats, VSG is as effective as RYGB for increasing secretion of GLP-1 and insulin and improving hepatic sensitivity to insulin; these effects are independent of weight loss. PMID- 21699790 TI - Interferon regulatory factor-2 regulates exocytosis mechanisms mediated by SNAREs in pancreatic acinar cells. AB - BACKGROUND & AIMS: Pancreatic acinar cells are used to study regulated exocytosis. We investigated the role of interferon regulatory factor-2 (IRF2) in exocytosis in pancreatic acinar cells. METHODS: Pancreas tissues from Irf2+/+, Irf2+/-), and Irf2-/- mice were examined by microscopy, immunohistochemical, and immunoblot analyses; amylase secretion was quantified. We also compared salivary glands and pancreatic islets of Irf2-/- mice with those of Irf2+/- mice. To examine the effects of increased signaling by type I interferons, we studied pancreatic acini from Irf2-/-Ifnar1-/- mice. The effect of IRF2 on amylase secretion was studied using an acinar cell line and a retroviral system. We studied expression of IRF2 in wild-type mice with cerulein-induced pancreatitis and changes in pancreatic tissue of Irf2-/- mice, compared with those of Irf2+/- mice. RESULTS: Irf2-/- pancreas was white and opaque; numerous and wide-spread zymogen granules were observed throughout the cytoplasm, along with lack of fusion between zymogen granules and the apical membrane, lack of secretagogue stimulated amylase secretion, and low serum levels of amylase and elastase-1, indicating altered regulation of exocytosis. The expression pattern of soluble N ethylmaleimide-sensitive factor attachment protein receptors changed significantly, specifically in pancreatic acini, and was not rescued by disruption of type I interferon signaling. Down-regulation of IRF2 decreased amylase secretion in an acinar cell line. In mice with pancreatitis, levels of IRF2 were reduced. Irf2-/- acini were partially resistant to induction of pancreatitis. CONCLUSIONS: IRF2 regulates exocytosis in pancreatic acinar cells; defects in this process might be involved in the early phases of acute pancreatitis. PMID- 21699791 TI - Regulatory T cells suppress development of colitis, blocking differentiation of T helper 17 into alternative T-helper 1 cells. AB - BACKGROUND & AIMS: Although T-helper (Th) 17 and Th1 cells are involved in pathogenesis of intestinal inflammation, their developmental pathways and sufficiency to promote disease are not known; nor are the roles of CD4+CD25+ regulatory T (T(R)) cells in their development. METHODS: We performed adoptive transfer experiments to investigate the induction and suppression of colitis using naive CD4+CD45RB(high) T cells and/or CD4+CD25+ T(R) cells that were obtained from retinoid-related orphan receptor gamma t (RORgammat) gfp/+ or Ly5.1/Ly5.2 congenic mice. RESULTS: We observed 3 types of colitogenic CD4+ Th1 cells (interleukin [IL]-17A-interferon [IFN]-gamma+): RORgammat- classical Th1 cells that differentiated directly from naive T cells; RORgammat+ Th1-like cells; and RORgammat- alternative Th1 cells that were terminally differentiated from RORgammat+ cells via Th17 (IL-17A+IFN-gamma-), Th17/Th1 (IL-17A+IFN-gamma+), or Th1-like (IL-17A-IFN-gamma+) cells. In this pathway, CD4+CD25+ T(R) cells suppress the development of not only classical Th1 cells, but also alternative Th1 cells at the transition of Th17/Th1 into alternative Th1 cells, resulting in accumulation of Th17 and Th17/Th1 cells in mice in which the development of colitis was suppressed. Furthermore, T(R) cells regulated the established balance of Th17 and Th1 cells under colitic conditions to yield a high ratio of Th17 and Th17/Th1 cells to Th1 cells in noncolitic conditions. CONCLUSIONS: Th17 and Th17/Th1 cells become colitogenic alternative Th1 cells via Th17, Th17/Th1, and Th1-like cells, independently of classical Th1 cells. T(R) cells suppress this pathway, resulting in accumulation of Th17 and Th17/Th1 cells. PMID- 21699792 TI - Analysis of the sacral neural crest cell contribution to the hindgut enteric nervous system in the mouse embryo. AB - BACKGROUND & AIMS: The majority of the enteric nervous system is derived from the vagal neural crest, with a second contribution, which is restricted to the post umbilical gut, originating from the sacral neural crest. In mammals, although sacral neural crest cells (NCCs) have been shown to enter the hindgut, information on their development and role remains scant. Our aim was to determine the migratory routes of sacral NCCs to the hindgut, their timing and site of entry into the gut, and their migratory behaviors and differentiation within the hindgut. METHODS: We used in situ cell labeling, whole embryo culture, immunofluorescence, organotypic culture, and time-lapse live-cell imaging in mouse embryos. RESULTS: Sacral NCCs emigrated from the neural tube at embryonic day 9.5, accumulated bilateral to the hindgut to form prospective pelvic ganglia at embryonic day 11.5, and from there entered the distal hindgut through its ventrolateral side at embryonic day 13.5. They then migrated along nerve fibers extending from the pelvic ganglia toward the proximal hindgut, intermingling with rostrocaudally migrating vagal NCCs to differentiate into neurons and glia. In organotypic culture, genetically labeled sacral and vagal NCCs displayed different capabilities of entering the hindgut, implying differences in their intrinsic migratory properties. Time-lapse live-cell imaging on explants ex vivo showed that sacral NCCs migrated along nerve fibers and exhibited different migratory behaviors from vagal NCCs. CONCLUSIONS: Murine sacral NCCs are a distinct group of cells that migrate along defined pathways from neural tube to hindgut. They exhibit discrete migratory behaviors within the gut mesenchyme and contribute neurons and glial cells to the hindgut enteric nervous system. PMID- 21699793 TI - Differential efficacy of protease inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant viruses. AB - BACKGROUND & AIMS: The hepatitis C virus (HCV) genotype influences efficacy of interferon (IFN)-based therapy. HCV protease inhibitors are being licensed for treatment of genotype 1 infection. Because there are limited or no data on efficacy against HCV genotypes 2-7, we aimed at developing recombinant infectious cell culture systems expressing genotype-specific nonstructural (NS) protein 3 protease (NS3P). METHODS: Viability of J6/JFH1-based recombinants with genotypes 1-7 NS3P/NS4A was evaluated in Huh7.5 human hepatoma cells. Adaptive mutations were identified in reverse genetic studies. Efficacy of lead compound linear protease inhibitors VX-950 (telaprevir) and SCH503034 (boceprevir) and macrocyclic inhibitors TMC435350, ITMN-191 (danoprevir), and MK-7009 (vaniprevir) was determined in high-throughput infection assays. RESULTS: For genotype(isolate) 2a(J6), 3a(S52), 5a(SA13), and 6a(HK6a), we developed culture systems producing supernatant infectivity titers of 3.5-4.0 log10 focus forming units/mL. Against 2a(J6), 5a(SA13), and 6a(HK6a), all inhibitors showed similar efficacy; macrocyclic inhibitors had ~10-fold greater potency than linear inhibitors. However, compared with 2a recombinant J6/JFH1, efficacy against 3a(S52) was 16- to 70-fold lower for macrocyclic inhibitors and 2- to 7-fold lower for linear inhibitors. Testing of additional genotype 2a and 3a isolates showed that these differences were genotype specific. The resistance of 3a isolates was similar to J6/JFH1 with engineered resistance mutations originally observed for genotype 1 patients. In contrast, we found similar efficacy of NS5A inhibitor BMS-790052 and interferon-alfa2. CONCLUSIONS: Novel HCV culture systems with genotype specific NS3P/NS4A revealed similar efficacy of protease inhibitors against genotypes 2a, 5a, and 6a and comparatively low but varying efficacy against genotype 3a isolates. These systems will facilitate genotype-specific studies of HCV protease inhibitors and of viral resistance. PMID- 21699794 TI - FERGIcor, a randomized controlled trial on ferric carboxymaltose for iron deficiency anemia in inflammatory bowel disease. AB - BACKGROUND & AIMS: Iron deficiency anemia (IDA) is common in chronic diseases and intravenous iron is an effective and recommended treatment. However, dose calculations and inconvenient administration may affect compliance and efficacy. We compared the efficacy and safety of a novel fixed-dose ferric carboxymaltose regimen (FCM) with individually calculated iron sucrose (IS) doses in patients with inflammatory bowel disease (IBD) and IDA. METHODS: This randomized, controlled, open-label, multicenter study included 485 patients with IDA (ferritin <100 MUg/L, hemoglobin [Hb] 7-12 g/dL [female] or 7-13 g/dL [male]) and mild-to-moderate or quiescent IBD at 88 hospitals and clinics in 14 countries. Patients received either FCM in a maximum of 3 infusions of 1000 or 500 mg iron, or Ganzoni-calculated IS dosages in up to 11 infusions of 200 mg iron. Primary end point was Hb response (Hb increase >= 2 g/dL); secondary end points included anemia resolution and iron status normalization by week 12. RESULTS: The results of 240 FCM-treated and 235 IS-treated patients were analyzed. More patients with FCM than IS achieved Hb response (150 [65.8%] vs 118 [53.6%]; 12.2% difference, P = .004) or Hb normalization (166 [72.8%] vs 136 [61.8%]; 11.0% difference, P = .015). Both treatments improved quality of life scores by week 12. Study drugs were well tolerated and drug-related adverse events were in line with drug specific clinical experience. Deviations from scheduled total iron dosages were more frequent in the IS group. CONCLUSIONS: The simpler FCM-based dosing regimen showed better efficacy and compliance, as well as a good safety profile, compared with the Ganzoni-calculated IS dose regimen. PMID- 21699795 TI - Stromal regulation of human gastric dendritic cells restricts the Th1 response to Helicobacter pylori. AB - BACKGROUND & AIMS: Mucosal dendritic cells (DCs) play a key role in initiating the T-helper (Th)1 response to Helicobacter pylori. To further elucidate the mucosal response to H pylori, we examined whether gastric stromal factors condition DCs to support tolerance to H pylori, analogous to intestinal stromal factor-driven macrophage tolerance to commensal bacteria. METHODS: To model mucosal DC development, we isolated and cultured cell-depleted human stroma/extracellular matrix from fresh gastric and intestinal mucosa to generate stroma-conditioned media. We then analyzed the capacity of stroma-conditioned media-treated monocyte-derived DCs and primary human gastric and intestinal DCs pulsed in vitro with H pylori to induce T-cell proliferation and interferon gamma secretion. RESULTS: Stromal factors in gastric mucosa suppressed H pylori stimulated DC activation and the ability of DCs to drive a Th1 proliferative and cytokine response to H pylori. The ability of gastric stromal factors to down regulate DC function was similar to that of intestinal stromal factors and was independent of transforming growth factor beta, prostaglandin E2, interleukin (IL)-10, and thymic stromal lymphopoietin. Stroma-conditioned media-induced reduction in DC-stimulated Th1 responses was associated with reduced DC release of IL-12. CONCLUSIONS: Gastric stromal factors down-regulate DC responsiveness to H pylori, resulting in a dampened gastric Th1 response. We speculate that stroma induced down-regulation of DC function contributes to the permissiveness of both gastric and intestinal mucosa to colonization by persistent residential microbes. PMID- 21699796 TI - Rate of progression of hepatic fibrosis in patients with chronic hepatitis C: results from the HALT-C Trial. AB - BACKGROUND & AIMS: The gradual accumulation of hepatic fibrosis in chronic liver disease results in clinical complications. The rate of hepatic fibrosis score progression (RFSP) in predicting clinical outcomes was assessed by extending the 4-year Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial to include preenrollment liver biopsies. METHODS: The RFSP was calculated from the linear regression slope of Ishak fibrosis score vs time in 457 patients with liver biopsies (>=10-mm length) prior to the HALT-C Trial (575 biopsies) plus 1101 on-study biopsies (total 1676 biopsies). Individual slopes were calculated if duration from first to last biopsy was > 4 years. RESULTS: The RFSP as average fibrosis score vs average time in intervals (0-3 and >3 years prestudy, screening, month 24 and 48 on-study) in 455 patients in cohorts of baseline Ishak score ranged from 0.005 with Ishak score 2 to 0.124 with Ishak 6. The RFSP in individual patients (-0.35 to +0.97 Ishak units/year) had a mean of 0.12 +/- 0.23 in 344 patients with prestudy and on-study biopsies (group A) and only 0.17 +/- 0.22 in 169 with prestudy and screening biopsies (group B). Group A patients with RFSP slope >= 0.2 (95 patients, 27.6%) had higher 7-year cumulative rates of non hepatocellular carcinoma outcomes (46% vs 8%, respectively) and with a hepatocellular carcinoma (10% vs 3%, respectively) than RFSP slope < 02 (249 patients, 72.4%) (P < .0001). RFSP and screening Ishak score correlated independently (P <.0001) with clinical outcomes in multivariate analysis. CONCLUSIONS: Rapid RFSP (>0.2), which occurred in 26.7% of HALT-C Trial patients, correlated strongly with clinical outcomes. PMID- 21699797 TI - Neuroticism influences brain activity during the experience of visceral pain. AB - BACKGROUND & AIMS: One particularly important individual dynamic known to influence the experience of pain is neuroticism, of which little is known about in visceral pain research. Our aim was to study the relationship between neuroticism, psychophysiologic response, and brain processing of visceral pain. METHODS: Thirty-one healthy volunteers (15 male; age range, 22-38 years) participated in the study. The Eysenck Personality Questionnaire was used to assess neuroticism. Skin conductance level, pain ratings, and functional magnetic resonance imaging data were acquired during anticipation of pain and painful esophageal distention. The effect of neuroticism was assessed using correlation analysis. RESULTS: There was a wide spread of neuroticism scores (range, 0-22) but no influence of neuroticism on skin conductance level and pain tolerance or pain ratings. However, a positive correlation between brain activity and neuroticism during anticipation was found in regions associated with emotional and cognitive pain processing, including the parahippocampus, insula, thalamus, and anterior cingulate cortex. These regions showed a negative correlation with neuroticism during pain (P < .001). CONCLUSIONS: This study provides novel data suggesting higher neuroticism is associated with engagement of brain regions responsible for emotional and cognitive appraisal during anticipation of pain but reduced activity in these regions during pain. This may reflect a maladaptive mechanism in those with higher neuroticism that promotes overarousal during anticipation and avoidance coping during pain. PMID- 21699798 TI - A poxvirus vaccine is safe, induces T-cell responses, and decreases viral load in patients with chronic hepatitis C. AB - BACKGROUND & AIMS: Therapy for chronic hepatitis C (CHC) has limited efficacy, adverse effects, and high costs. Cohort and vaccine-based preclinical studies have indicated the importance of T-cell-based immunity in controlling viral infection. TG4040 is a recombinant poxvirus vaccine that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase I clinical trial to assess the safety, immunogenicity, and early antiviral efficacy of TG4040 in patients with CHC. METHODS: In an open-label, dose-escalating study, patients with mild CHC (genotype 1) were assigned to 3 groups of 3 patients each; they received subcutaneous injections of 106, 107, or 108 plaque-forming units of TG4040 on study days 1, 8, and 15. Six additional patients were given the highest dose of vaccine (108 plaque-forming units). Patients were followed for 6 months after the last injection. T-cell-based and antibody responses and levels of HCV RNA were measured. RESULTS: All 3 doses of TG4040 were well tolerated, without serious adverse events. Vaccine-induced HCV-specific cellular immune responses were observed in 5 of the 15 patients (33%). A transient decrease in circulating levels of HCV RNA, from -0.52 log10 to -1.24 log10, was observed in 8 patients; in 5 patients, the lowest level of HCV RNA was observed on day 37, after the first injection. The most pronounced decrease in viral load occurred in 2 patients, who also had marked vaccine-induced T-cell responses. CONCLUSIONS: In patients with CHC, the viral-vector-based vaccine TG4040 had a good safety profile, induced HCV-specific cellular immune responses, and reduced viral load. This vaccine should be investigated in further clinical studies, in combination with standard of care. PMID- 21699799 TI - Mouse hepatic cells support assembly of infectious hepatitis C virus particles. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) has a high propensity to establish persistence; better understanding of this process requires the development of a fully permissive and immunocompetent small animal model. Mouse cells can be engineered to express the human orthologs of the entry molecules CD81 and occludin to allow entry of HCV. However, RNA replication is poor in mouse cells, and it is not clear whether they support assembly and release of infectious HCV particles. We used a trans-complementation-based system to demonstrate HCV assembly competence of mouse liver cell lines. METHODS: A panel of 3 mouse hepatoma cell lines that contain a stable subgenomic HCV replicon was used for ectopic expression of the HCV structural proteins, p7, nonstructural protein 2, and/or apolipoprotein E (apoE). Assembly and release of infectious HCV particles was determined by measuring viral RNA, proteins, and infectivity of virus released into the culture supernatant. RESULTS: Mouse replicon cells released low amounts of HCV particles, but ectopic expression of apoE increased release of infectious HCV to levels observed in the human hepatoma cell line Huh7.5. Thus, apoE is the limiting factor for assembly of HCV in mouse hepatoma cells but probably not in primary mouse hepatocytes. Products of all 3 human alleles of apoE and mouse apoE support HCV assembly with comparable efficiency. Mouse and human cell-derived HCV particles have similar biophysical properties, dependency on entry factors, and levels of association with apoE. CONCLUSIONS: Mouse hepatic cells permit HCV assembly and might be developed to create an immunocompetent and fully permissive mouse model of HCV infection. PMID- 21699800 TI - The importance of the gastrointestinal tract in the control of bone mass accrual. AB - One of the least anticipated and less heralded outcomes of mouse genetics has been to rediscover whole organism physiology. Among the many unexpected findings that it has brought to our attention has been the realization that gut-derived serotonin is a hormone-inhibiting bone formation. The importance of this discovery presented in this review is 2-fold. First, it provides a molecular explanation for 2 human genetic diseases-osteoporosis, pseudoglioma, and high bone mass syndrome; second, it suggests a novel and anabolic way to treat osteoporosis. These findings illustrate the importance of the gastrointestinal tract in the regulation of organ physiology at yet another extraluminal site. PMID- 21699801 TI - Bilateral foot necrosis caused by hepatitis C virus-induced mixed type II cryoglobulinemia. PMID- 21699802 TI - Colchicine or methotrexate, with ursodiol, are effective after 20 years in a subset of patients with primary biliary cirrhosis. AB - BACKGROUND & AIMS: The combination of ursodeoxycholic acid (UDCA), colchicine, and methotrexate (MTX) is effective therapy for a subset of patients with primary biliary cirrhosis (PBC) who do not respond to UDCA. However, the durability of the response is unclear. We investigated whether the response to combination therapy was durable. METHODS: We followed, for 10 additional years (range 9-13 years), 29 patients with PBC who had been treated with the combination of UDCA and MTX or UDCA and colchicine in a randomized controlled trial that began in 1988 and lasted 10 years. RESULTS: Of the 11 patients given MTX plus UDCA, 9 were still alive and well, whereas 2 died from causes unrelated to liver disease at the ages of 79 and 70. Of the 18 patients given the combination of colchicine and UDCA, 12 were alive and well 20 years after the trial ended. Three had progressive liver disease; 2 of these had liver transplantation and 1 died of pneumonia. Three died of unrelated causes at the ages of 73, 76, and 76 years, respectively. CONCLUSIONS: Treatment with the combination of UDCA and MTX or UDCA and colchicine led to sustained clinical remission in a subset of patients with PBC. The response to the combination of UDCA and MTX appeared to be more durable than to UDCA and colchicine. PMID- 21699803 TI - No impact of hepatitis C virus infection on mortality among drug users during the first decade after seroconversion. AB - BACKGROUND & AIMS: Most studies of progression of chronic hepatitis C virus (cHCV) infection were conducted in hospital settings and were therefore biased for patients with severe disease. We evaluated the long-term outcomes of hepatitis C virus (HCV) infection among injecting drug users, recruited from outside the hospital setting, and examined the effect of cHCV on mortality after seroconversion. METHODS: We studied data from 106 seroconverters with a documented or estimated date of HCV seroconversion. Cox proportional hazards analysis was used to determine the effect of HCV persistence, compared with HCV clearance, on survival after HCV seroconversion. The median follow-up time was 14.8 years (interquartile range, 7.8-19.6). RESULTS: cHCV infection developed in 71 of the subjects (67%; 95% confidence interval [CI], 57%-76%); 33 subjects died. One HCV-related death was observed 23 years after HCV seroconversion. Most causes of death were non-natural (n = 12) or acquired immune deficiency syndrome related (n = 8). The effect of cHCV on mortality was nonproportional over time. When survival time was analyzed separately for 0-5 years, >5-10 years, and >10 years after HCV seroconversion, the age-adjusted hazard ratios for cHCV were 0.59 (95% CI, 0.16-2.20), 1.76 (95% CI, 0.36-8.53), and 8.28 (95% CI, 1.10-64.55), respectively, compared with resolved HCV infection. CONCLUSIONS: cHCV infection does not affect overall mortality in the first decade after seroconversion, compared with individuals who resolve HCV infection; however, during the second decade after infection, individuals with cHCV have an increased risk for all cause mortality. Mortality from liver-related causes was low but might have been masked by competing mortality. PMID- 21699804 TI - Toothpick perforation of the small bowel. PMID- 21699805 TI - Factors that predict relief from upper abdominal pain after cholecystectomy. AB - BACKGROUND & AIMS: Upper abdominal pain (UAP) in patients with gallstones is often treated by cholecystectomy but it frequently persists. We aimed to identify symptoms associated with relief. METHODS: We followed 1008 patients who received cholecystectomy for gallstones and UAP at the Mayo Clinic (Rochester, Minnesota) or Kaiser Permanente (San Diego, California) for 12 months. A validated, self completed biliary symptoms questionnaire identified features of UAP, gastroesophageal reflux disease (GERD), and irritable bowel syndrome (IBS); the questionnaire was given initially and 3 and 12 months after cholecystectomy, to identify features that predicted sustained relief of UAP. RESULTS: Five hundred ninety-four patients (59%) reported relief from UAP. Factors associated univariately (P < .05) with relief included frequency of UAP <=1 per month, onset <=1 year preoperatively, usual duration (30 minutes to 24 hours, most often in the evening or night), and severity >5/10. Compared to no features, multiple predictive features of UAP (frequency, onset, duration, or timing) were associated with increasing odds ratios (95% confidence interval) for relief: 1, 2, or 3 features (4.2 [1.1-16]; P = .03) and 4 features (6.3 [1.6-25]; P = .008). Negative univariate associations included lower abdominal pain (LAP), usual bowel pattern, nausea >=1 per week, often feeling bloated or burpy, GERD, and/or IBS. There was an inverse association between relief and somatization; relief was not associated with postprandial UAP. Multivariable logistic regression analysis revealed independent associations (P < .05) with UAP frequency, onset, and nocturnal awakening, but inverse associations with lower abdominal pain, abnormal bowel pattern, and frequent bloated or burpy feelings. CONCLUSIONS: UAP features and concomitant GERD, IBS, and somatization determine the odds for relief from UAP after cholecystectomy. PMID- 21699806 TI - Insights into gastroesophageal reflux disease-associated dyspeptic symptoms. AB - BACKGROUND & AIMS: Patients with GERD frequently report dyspeptic-like symptoms, including nausea, vomiting, early satiety, bloating, and belching. The purpose of this review was to define the epidemiology and underlying mechanisms for dyspeptic symptoms in GERD patients. METHODS: We performed a systematic literature review to identify the prevalence of dyspeptic symptoms in GERD patients. We identified 2057 studies, and 37 studies (2%) met the entry criteria, including 17 articles describing the prevalence of dyspeptic symptoms in GERD subjects, 7 studies describing mechanistic evaluation of dyspeptic symptoms in GERD, 7 studies describing questionnaires used to measure dyspeptic symptoms, and 6 studies assessing the role of proton pump inhibitor therapy for dyspeptic symptoms associated with GERD. We used an evidence-based approach to assess the literature. RESULTS: The median (+/- standard deviation) prevalence of GERD in 30,384 subjects from 8 studies conducted in Western countries was 30% +/- 8% (range, 20%-40%). Dyspeptic symptoms were present in 38% +/- 14% (range, 21%-63%) and were more frequent in patients with frequent GERD symptoms, compared with patients with intermittent or no GERD symptoms [Evidence B]. Patients with nonerosive disease had a higher prevalence of dyspeptic symptoms [Evidence B] in addition to a lower response to proton pump inhibitor therapy [Evidence A], compared with patients with erosive esophagitis. Epigastic pain, belching, bloating, and early satiety demonstrated improvement on PPI therapy [Evidence A], compared with symptoms of nausea and vomiting that did not improve [Evidence A]. Patients with dyspepsia were at risk for a subsequent new diagnosis of GERD [Evidence B]. Dyspeptic symptoms contributed significantly to the decrement in health-related quality of life associated with GERD. CONCLUSIONS: Dyspeptic symptoms are common in GERD patients and impact health-related quality of life. PMID- 21699808 TI - Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. AB - BACKGROUND & AIMS: We performed a meta-analysis of data from randomized trials to estimate the risk of all-cause mortality and bleeding (and especially gastrointestinal [GI] bleeding) in patients treated with low doses of acetylsalicylic acid (ASA) (75-325 mg/d), alone or in combination with other medications. METHODS: We searched 10 electronic databases (until October 2010) and collected data on adverse events in randomized controlled studies that evaluated low doses of ASA, alone (35 trials) or in combination with anticoagulants (18 trials), clopidogrel (5 trials), or proton pump inhibitors (PPIs; 3 trials). We analyzed data using random-effects meta-analysis and meta regression, applying Peto's odds ratio (OR) for adverse events. RESULTS: Low doses of ASA alone decreased the risk for all-cause mortality (relative risk, 0.93, 95% confidence interval [CI], 0.87-0.99), largely because of effects in secondary prevention populations. The risk of major GI bleeding increased with low doses of ASA alone (OR, 1.55; 95% CI, 1.27-1.90), compared with inert control reagents. The risk increased when ASA was combined with clopidogrel, compared with aspirin alone (OR, 1.86; 95% CI, 1.49-2.31), anticoagulants vs low doses of ASA alone (OR, 1.93; 95% CI, 1.42-2.61), or in studies that included patients with a history of GI bleeding or of longer duration. Importantly, PPI use reduced the risk for major GI bleeding in patients given low doses of ASA (OR, 0.34; 95% CI, 0.21-0.57). CONCLUSIONS: In a meta-analysis, low doses of ASA increased the risk for GI bleeding; risk increased with accompanying use of clopidogrel and anticoagulant therapies, but decreased in patients who took PPIs. PMID- 21699807 TI - Endoscopic retrograde cholangiography does not reliably distinguish IgG4 associated cholangitis from primary sclerosing cholangitis or cholangiocarcinoma. AB - BACKGROUND & AIMS: Distinction of immunoglobulin G4-associated cholangitis (IAC) from primary sclerosing cholangitis (PSC) or cholangiocarcinoma is challenging. We aimed to assess the performance characteristics of endoscopic retrograde cholangiography (ERC) for the diagnosis of IAC. METHODS: Seventeen physicians from centers in the United States, Japan, and the United Kingdom, unaware of clinical data, reviewed 40 preselected ERCs of patients with IAC (n = 20), PSC (n = 10), and cholangiocarcinoma (n = 10). The performance characteristics of ERC for IAC diagnosis as well as the kappa statistic for intraobserver and interobserver agreement were calculated. RESULTS: The overall specificity, sensitivity, and interobserver agreement for the diagnosis of IAC were 88%, 45%, and 0.18, respectively. Reviewer origin, specialty, or years of experience had no statistically significant effect on reporting success. The overall intraobserver agreement was fair (0.74). The operating characteristics of different ERC features for the diagnosis of IAC were poor. CONCLUSIONS: Despite high specificity of ERC for diagnosing IAC, sensitivity is poor, suggesting that many patients with IAC may be misdiagnosed with PSC or cholangiocarcinoma. Additional diagnostic strategies are likely to be vital in distinguishing these diseases. PMID- 21699809 TI - Differentiating small polyp histologies using real-time screening colonoscopy with Fuji Intelligent Color Enhancement. AB - BACKGROUND & AIMS: There are limited data describing the performance of Fuji Intelligent Color Enhancement (FICE, EC 590 ZW; Fujinon Inc, Saitama, Japan) for differentiating polyp histologies during screening colonoscopy. We evaluated the ability of an endoscopist to diagnose small polyp histology during a screening colonoscopy using FICE. METHODS: A prospective study was performed on 763 consecutive, asymptomatic subjects who were undergoing screening colonoscopy. Pit patterns and vascular patterns were used to predict the histology of 525 polyps (mean size, 4.5 +/- 2.2 mm, 315 adenomas) of less than 10 mm using FICE with high magnification and without. The performances of the FICE analyses were calculated and compared with the results from the histopathology. RESULTS: The overall accuracy achieved by FICE with high magnification in the diagnosis of adenomas of less than 10 mm (87.0%) was significantly greater than that achieved without high magnification (80.4%; P < .05). Moreover, the improvement of accuracy attained when using high-magnification FICE was most pronounced and significant compared without using high-magnification FICE in the diagnosis for diminutive polyps (<=5 mm; 85.4% vs 79.1%; P < .05). Among all types of adenomas, the sensitivity of FICE was lowest for sessile serrated adenomas (38.5% vs 89.4%; P < .01), even when FICE was used with high magnification. CONCLUSIONS: FICE with high magnification is better for differentiating the histology of small polyps during screening colonoscopy than FICE without high magnification, especially for diminutive polyps. Large-scale studies are needed to improve the identification of serrated adenomas and small diminutive polyps using FICE. PMID- 21699810 TI - Reproducibility and agreement of pharyngeal automated impedance manometry with videofluoroscopy. AB - BACKGROUND & AIMS: Automated impedance manometry analysis (AIM) measures swallow function variables that define bolus timing, intrabolus pressure, contractile vigor, and bolus presence; these are combined to derive a swallow risk index (SRI) that is correlated with pharyngeal dysfunction and aspiration. We assessed intra-rater and inter-rater reproducibility of AIM analysis-derived variables; the diagnostic accuracy of AIM-based criteria for detecting aspiration was determined by using expertly scored videofluoroscopy as the standard. METHODS: Data on 50 bolus swallows of 10 mL each were randomly selected from a database of swallows that were simultaneously recorded with impedance, manometry, and videofluoroscopy. Data were divided into 5 subgroups of 10 swallows for analysis: 10 dysphagic liquid, 10 dysphagic liquid with aspiration, 10 dysphagic semisolid, 10 control liquid, and 10 control semisolid. Repeat analyses were performed by 10 observers with varying levels of expertise in manometry by using purpose-designed software (AIMplot). Swallow videos were scored by 4 experts by using the penetration-aspiration scale (PAS) score. Reproducibility of calculation of swallow function variables and the SRI and PAS was assessed by using intraclass correlation coefficient (ICC). The majority consensus of expert PAS scores was used to dichotomously define aspiration (consensus PAS >3). Observer analyses were compared by Cohen kappa statistical analysis. RESULTS: The intra-rater and inter-rater reproducibility of swallow function variables was high (SRI mean intra-rater ICC, 0.97 and mean inter-rater ICC, 0.91). SRI >15-20 was optimal for detecting the presence of aspiration during liquid bolus swallows with an almost perfect agreement with expert scoring of videofluoroscopy (kappa > 0.8). CONCLUSIONS: AIM analysis has high intra-rater and inter-rater reproducibility, and among observers of varying expertise, SRI predicts the presence of aspiration. PMID- 21699811 TI - A Crohn's disease patient who does not respond to infliximab: what is next? PMID- 21699812 TI - Early multiple intrahepatic artery pseudoaneurysm formation after liver trauma. PMID- 21699813 TI - Full-dose peginterferon Alfa-2a and low-dose ribavirin treatment of genotypes 1 and 4 chronic hepatitis C patients with end-stage renal disease. PMID- 21699814 TI - Cronkhite-Canada syndrome associated with sigmoid colon cancer. PMID- 21699815 TI - Effects of a sustained virologic response on outcomes of patients with chronic hepatitis C. AB - For patients with chronic hepatitis C virus infection, the goal of antiviral therapy is to achieve a sustained virologic response (SVR). We review the durability of the SVR and its effects on liver-related mortality, hepatic decompensation, and the development of hepatocellular carcinoma. We performed a systematic review of the effects of the SVR on liver-related hepatic outcomes and found the SVR to be durable (range, 98.4%-100%). An SVR reduced liver-related mortality among patients with chronic hepatitis C (3.3- to 25-fold), the incidence of hepatocellular carcinoma (1.7- to 4.2-fold), and hepatic decompensation (2.7- to 17.4-fold). An SVR can lead to regression of fibrosis and cirrhosis, and has been associated with a reduced rate of hepatic decompensation, a reduced risk for hepatocellular carcinoma, and reduced liver-related mortality. PMID- 21699816 TI - Surveillance for hepatocellular carcinoma in patients with cirrhosis. PMID- 21699817 TI - Prednisolone and budesonide for short- and long-term treatment of microscopic colitis: systematic review and meta-analysis. AB - BACKGROUND & AIMS: The incidence of microscopic colitis and its disease burden are increasing, yet there is limited systematic information addressing the use of conventional corticosteroids and budesonide in microscopic colitis. We performed a systematic review and meta-analysis on the short- and long-term efficacy of corticosteroids in treatment of microscopic colitis. METHODS: Randomized controlled trials that met predetermined selection criteria were included. Articles were identified through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, proceedings of major gastroenterology meetings, and reference lists of trials and review articles. RESULTS: Eight randomized trials were identified. A total of 248 patients were randomized to corticosteroid versus placebo. The intervention was budesonide in 7 trials and prednisolone in 1 trial. Budesonide was significantly more effective than placebo for short-term clinical response (risk ratio [RR], 3.07; 95% confidence interval [CI], 2.06-4.57) and long-term clinical response (RR, 3.22; 95% CI, 1.05-9.89). Prednisolone was not superior to placebo for short-term clinical response (RR, 2.00; 95% CI, 0.38 10.58). Histologic improvement was seen with both short- and long-term budesonide (RR, 3.76; 95% CI, 2.00-7.06, and RR, 2.50; 95% CI, 1.25-4.98, respectively). Symptom relapse occurred in 46%-80% of patients within 6 months of treatment cessation. Withdrawal because of adverse effects occurred in 4.4% of patients, with no difference between study groups (P = .55). CONCLUSIONS: Both short- and long-term treatment with budesonide is effective and well-tolerated for microscopic colitis. However, the rate of symptom relapse once budesonide is discontinued is high. Further studies are needed to determine optimal treatment duration, dose, and withdrawal procedure. PMID- 21699818 TI - The appendix may protect against Clostridium difficile recurrence. AB - BACKGROUND & AIMS: Several risk factors have been identified for the development of recurrent Clostridium difficile infection (CDI) that alter host immunity and disrupt colonic flora. Although the function of the appendix has been debated, its active, gut-associated lymphoid tissue and biofilm production indicate potential roles in recovery from initial CDI and protection against recurrent CDI. We investigated whether the presence or absence of an appendix is associated with CDI recurrence. METHODS: We reviewed the medical records of adult inpatients with CDI who were admitted to a tertiary-care teaching hospital from 2005 to 2007 to identify those with and without an appendix. The primary dependent variable for statistical analysis was CDI recurrence. RESULTS: In a multivariate analysis of 11 clinical variables, the presence of an appendix was associated inversely with CDI recurrence (P < .0001; adjusted relative risk, .398). Age older than 60 years also was associated with CDI recurrence (P = .0280; adjusted relative risk, 2.44). CONCLUSIONS: The presence of an appendix has a significant and independent, inverse association with CDI recurrence, but this finding requires validation in a prospective study. Assessing the presence or absence of an appendix might be useful in predicting CDI recurrence. PMID- 21699819 TI - The diagnosis and misdiagnosis of Achalasia: it does not have to be so difficult. PMID- 21699822 TI - Death during acute myocardial infarction: dodging the first bullet. PMID- 21699821 TI - Patient-reported outcomes for irritable bowel syndrome are associated with patients' severity ratings of gastrointestinal symptoms and psychological factors. AB - BACKGROUND & AIMS: Patient-reported outcomes (PROs) are used to gauge the benefit of treatments for functional gastrointestinal disorders, including irritable bowel syndrome (IBS). Commonly used end points derived from scales of symptom severity differ in their structure, format, and the extent to which they are based on established psychometric fundamentals. We evaluated the overlap between 2 measures of IBS symptom severity, documented their association with different symptoms (pain, bloating, altered defecation), and identified psychological factors that might bias PRO ratings, by affecting how patients interpret IBS symptom severity. METHODS: Ninety-eight patients diagnosed with IBS, based on Rome III criteria, completed the multicomponent IBS Symptom Severity Scale and the single-item, UCLA Symptom Severity Scale. Data were collected on pain, bloating, and bowel habits, as well as somatization, sensitivity to arousal symptoms (anxiety sensitivity), and a negative thinking style called pain catastrophizing. RESULTS: The 2 global scales were correlated with one another (r = 0.56); each scale was associated most strongly with variation in abdominal pain. Data were consistent with a model in which pain catastrophizing and somatization influenced 1 or more of patients' judgments of pain, bloating, and/or bowel habits, which then affected the PROs. CONCLUSIONS: Depending on their structure and format, PROs can have different levels of sensitivity to core IBS symptoms and be influenced by psychological and somatic complaints that are beyond the aim of therapy and labeling claim. PROs that rely on patients' perspectives to index symptom severity can be improved by consideration of psychometric principles that influence self-report. PMID- 21699820 TI - Using transjugular intrahepatic portosystemic shunts for complications of cirrhosis. AB - Transjugular intrahepatic portosystemic shunt (TIPS) decompresses the portal venous system. TIPS has been used to manage the complications of portal hypertension in cirrhosis, including variceal hemorrhage and refractory ascites. The uncoated TIPS stents are limited by stent stenosis; however, the introduction of coated stents has decreased this. With the introduction of coated stents, we must reevaluate the utility of TIPS in the management of complications of portal hypertension. PMID- 21699823 TI - Predicting the degree of drug-induced QT prolongation and the risk for torsades de pointes. PMID- 21699824 TI - Differential effectiveness of pharmacological strategies to reveal dormant pulmonary vein conduction: a clinical-experimental correlation. AB - BACKGROUND: Atrial fibrillation recurs in ~30%-40% of patients after pulmonary vein (PV) isolation (PVI) procedures, often because of restored PV-left atrial (LA) conduction. Adenosine or isoproterenol are used clinically to reveal dormant PV conduction and guide additional ablation. OBJECTIVE: The purpose of this study was to assess the differential efficacy of adenosine and/or isoproterenol in revealing dormant PV conduction. METHODS: In 25 patients undergoing PVI, dormant conduction was assessed sequentially in response to intravenous adenosine, isoproterenol, and adenosine plus isoproterenol in 100 PVs. To study mechanisms, PVs were isolated by radiofrequency ablation in coronary-perfused canine LA-PV preparations. After PVI, resting membrane potential from PV cells was recorded before and after 1 mM adenosine, 1 MUM isoproterenol, 1 MUM isoproterenol plus 1 mM adenosine, or no drug (controls). RESULTS: Clinical PVI was successful in all 100 PVs, with dormant conduction in 31. Sensitivity for dormant conduction was isoproterenol 10%; adenosine 87% (P <.001 vs. isoproterenol); and isoproterenol + adenosine 100% (P = .13 vs. adenosine). Dormant PV conduction in vitro was revealed with adenosine (53%) and adenosine + isoproterenol (60%) but not with isoproterenol alone or in controls (P <.01). Radiofrequency lesions producing PVI depolarized resting membrane potential, causing inexcitability. Postablation, resting membrane potential hyperpolarized after both adenosine and isoproterenol, but adenosine-induced changes were greater (9.1 +/- 0.6 mV, vs. 3.8 +/- 0.6 mV; P <0.001), with no significant additional effect when isoproterenol was added to adenosine. CONCLUSION: Adenosine is superior to isoproterenol in revealing dormant PVs clinically and experimentally because of more effective adenosine induced hyperpolarization. Adding isoproterenol to adenosine had no significant additional value. PMID- 21699825 TI - Long-term single- and multiple-procedure outcome and predictors of success after catheter ablation for persistent atrial fibrillation. AB - BACKGROUND: Stepwise ablation is an effective treatment for persistent atrial fibrillation (AF), although it often requires multiple procedures to eliminate recurrent arrhythmias. OBJECTIVE: This study evaluated single- and multiple procedure long-term success rates and potential predictors of a favorable single procedure outcome of stepwise ablation for persistent AF. METHODS: This study comprised 395 patients with persistent AF (duration 16 months) undergoing de novo catheter ablation using the stepwise approach. Procedural success was defined as the absence of any arrhythmia recurrence. Patient characteristics and electrophysiological parameters were analyzed with respect to single- and multiple-procedure outcomes. RESULTS: After a follow-up of 27 +/- 7 months, 108 (27%) patients were free of arrhythmia recurrences with a single procedure. After 2.3 +/- 0.6 procedures, 312 (79%) patients were free of arrhythmia with concomitant antiarrhythmic treatment in 38% (23% on beta-blocker). Female gender, duration of persistent AF, and congestive heart failure were predictive for the outcome after first ablation. However, the strongest predictors for single procedure success were longer baseline AF cycle length (CL) and procedural AF termination. Moreover, procedural AF termination during the index procedure also predicted a favorable outcome after the last procedure, while the existence of congestive heart failure was associated with an increased risk for eventual arrhythmia recurrences. CONCLUSIONS: Single-procedure long-term success is anticipated in approximately a quarter of patients undergoing de novo ablation of persistent AF. Baseline AFCL emerged as the strongest predictor of single procedure success, while AF termination during index ablation predicts the overall outcome. However, an overall success rate of 79% is achievable with multiple procedures. PMID- 21699826 TI - Shift in the pattern of autonomic atrial innervation in subjects with persistent atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is a multifactorial disease of the atria. OBJECTIVE: We studied the differences in the atrial autonomic innervation pattern in subjects with AF compared with sinus rhythm (SR). METHODS: Preparation of postmortem isolated hearts of subjects with documented persistent AF (group A) and SR (group B) included: (1) histological sectioning of predefined areas and quantification of nerve density, and (2) differentiation using immunohistochemistry in adrenergic (sympathetic, tyrosine-hydroxylase antibody), cholinergic (parasympathetic, choline-acetyltransferase antibody) and mixed (adrenergic and cholinergic staining) nerves. RESULTS: Characteristics of subjects in group A (N = 15) and group B (N = 24) did not differ. The mean overall nerve density was similar between groups (A: 0.31 +/- 0.25/mm(2); B: 0.35 +/- 0.25/mm(2); P = .87). Nerve density appeared higher in the region of the pulmonary vein ostia and antrum (group A: 0.38 +/- 0.21/mm(2); group B: 0.32 +/- 0.19/mm(2),) compared with other locations of the right and left atrium. A total of 2,224 (group A: 685; group B: 1539) nerves were differentiated using immunohistochemistry. There was a high degree of colocalization of adrenergic and cholinergic nerves (group A: 80% mixed staining, group B: 69% mixed staining). In group A hearts there was a significantly lower density of predominantly cholinergic nerves (0.025 +/- 0.052/mm(2) vs. 0.058 +/- 0.099/mm(2); P = .008) and a higher density of nerves containing adrenergic components (0.24 +/- 0.18/mm(2) vs. 0.18 +/- 0.17/mm(2), P = .046). CONCLUSION: Overall autonomic nerve density did not differ between atria with persistent AF compared with SR. On a morphological level, we detected a shift toward a lower density of cholinergic nerves and a higher density of nerves containing adrenergic components in AF subjects. PMID- 21699827 TI - Risk factors for lead complications in cardiac pacing: a population-based cohort study of 28,860 Danish patients. AB - BACKGROUND: Lead complications are the main reason for reoperation after implantation of pacemakers (PM) or cardiac resynchronization therapy (CRT-P) devices. OBJECTIVE: This study sought to describe the incidence of lead complications causing reoperation after device implantation and to identify risk factors for lead complications. METHODS: A nationwide, population-based, historic cohort study was performed based on data from the Danish Pacemaker Register, which includes all Danish patients who received their first PM or CRT-P device from 1997 to 2008. Follow-up occurred 3 months after implantation. RESULTS: The study population consisted of 28,860 patients. The incidence of any lead complication was 3.6%, encompassing right atrial (RA; 2.3%), right ventricular (2.2%), and left ventricular (4.3%) lead complications. The lead complication risk declined during the first part of the study period and remained stable after 2002. Multivariate analysis identified the following significant risk factors: chronic heart failure as indication (adjusted odds ratio (aOR) 3.0; 95% confidence interval [CI] 2.1 to 4.3), implantation in a nonuniversity center (aOR 1.4; 95% CI 1.2 to 1.6), inexperienced operator with <25 implantations (aOR 1.6; 95% CI 1.3 to 2.0), single-lead RA device (aOR 1.4; 95% CI 1.1 to 1.8), dual chamber pacing device (aOR 1.6; 95% CI 1.4 to 1.9), CRT-P device (aOR 3.3; 95% CI 2.4 to 4.4) and passive-fixation RA lead (aOR 2.2; 95% CI 1.7 to 2.9). CONCLUSION: Lead complications causing reoperation remain a clinically important problem in device therapy. Mainly procedure-related factors were identified as independent risk factors for lead complications. PMID- 21699828 TI - Cardiac resynchronization therapy and the relationship of percent biventricular pacing to symptoms and survival. AB - BACKGROUND: With the advent of cardiac resynchronization therapy, it was unclear what percentage of biventricular pacing would be required to obtain maximal symptomatic and mortality benefit from the therapy. The optimal percentage of biventricular pacing and the association between the amount of continuous pacing and survival is unknown. OBJECTIVE: The purpose of this study was to assess the optimal percentage of biventricular pacing and any association with survival in a large cohort of networked patients. METHODS: A large cohort of 36,935 patients followed up in a remote-monitoring network, the LATITUDE Patient Management system (Boston Scientific Corp., Natick, Massachusetts), was assessed to determine the association between the percentage of biventricular pacing and mortality. RESULTS: The greatest magnitude of reduction in mortality was observed with a biventricular pacing achieved in excess of 98% of all ventricular beats. Atrial fibrillation and native atrial ventricular condition can limit a high degree of biventricular pacing. Incremental increases in mortality benefit are observed with an increasing percentage of biventricular pacing. CONCLUSION: Every effort should be made to reduce native atrioventricular conduction with cardiac resynchronization therapy systems in an attempt to achieve biventricular pacing as close to 100% as possible. PMID- 21699829 TI - Sudden cardiac death won't go away: what are we to do? PMID- 21699831 TI - How can we stabilize QT variability? PMID- 21699830 TI - Ablation: search and destroy dormant gaps awakened by adenosine. PMID- 21699832 TI - Direct visualization of radiofrequency lesion formation and gap in humans. PMID- 21699833 TI - Temporal relationship of atrial tachyarrhythmias, cerebrovascular events, and systemic emboli based on stored device data: a subgroup analysis of TRENDS. AB - BACKGROUND: The temporal relationship between atrial tachyarrhythmias (atrial tachycardia [AT] and atrial fibrillation [AF]) and cerebrovascular events/systemic emboli (CVE/SE) is unknown. OBJECTIVE: The purpose of this study was to evaluate this relationship using stored AT/AF diagnostic data from implanted devices in patients with and those without AF. METHODS: The TRENDS study enrolled 2,486 patients with an indication for an implantable device, at least one stroke risk factor, and available device data. The current study includes the subgroup of 40 (1.6%) patients enrolled in TRENDS who experienced CVE/SE. RESULTS: AT/AF was detected prior to CVE/SE in 20 (50%) of 40 patients. Other than average and maximum daily AT/AF burden and duration of device monitoring prior to CVE/SE, no statistically significant differences were found between patients with and those without AT/AF prior to CVE/SE. For the 20 patients with AT/AF detected prior to CVE/SE, 9 (45%) did not have any AT/AF in the 30 days prior to CVE/SE. Therefore, 29 (73%) of 40 patients with CVE/SE had zero AT/AF burden within 30 days prior to CVE/SE. Fourteen (70%) of the 20 patients with AT/AF detected prior to CVE/SE were not in AT/AF at diagnosis of CVE/SE. The last episode of AT/AF in these 14 patients was 168 +/- 199 days (range 3-642 days) before CVE/SE. CONCLUSION: The majority of CVE/SE in this population did not occur proximal to recent AT/AF episodes. These data imply that the mechanisms of CVE/SE in patients with implantable devices may importantly involve mechanisms other than cardioembolism due to atrial tachyarrhythmias. PMID- 21699834 TI - Noninvasive vectorcardiographic evaluation of pulmonary vein-atrial reconnection after pulmonary vein isolation for atrial fibrillation. AB - BACKGROUND: Although pulmonary vein (PV)-left atrium (LA) reconnection is associated with recurrence of atrial fibrillation (AF) in patients who undergo pulmonary vein isolation (PVI), no noninvasive method for evaluating PV reconnection has yet been established. OBJECTIVE: The purpose of this study was to examine whether PV-LA reconnection could be detected noninvasively by analyzing the change of P-loop configuration by vectorcardiography (VCG). METHODS: The study included 80 patients with paroxysmal AF (8 female; mean age 58 +/- 10 years) who underwent PVI. VCG was prospectively analyzed by recording during the procedure (before and after PVI) and 1 year after the procedure to noninvasively evaluate PV-LA reconnection. RESULTS: All patients showed a significant antero-leftward shift in the middle portion of the P loop on the horizontal plane of VCG, with an increase of the area within the P loop after the initial PVI (2.4 +/- 1.7 vs 4.6 +/- 2.7 * 10(3) mV(2), P <.001). Sixty-three (78.8%) patients without AF recurrence demonstrated no remarkable change in the P loop area after 16 +/- 11 months of follow-up (4.4 +/- 2.7 vs 4.1 +/- 2.5 * 10(3) mV(2), P = .51), whereas 17 (21.2%) patients with AF recurrence demonstrated P loop reversion to the preprocedural P-loop morphology, with a decrease of P-loop area (5.6 +/- 2.7 vs 3.2 +/- 1.7 * 10(3) mV(2), P <.001). CONCLUSION: Change of the P loop on VCG was associated with subsequent PV-LA reconnection. VCG is helpful as a noninvasive method for detecting PV-LA reconnection after PVI for paroxysmal AF. PMID- 21699835 TI - Feasibility and findings of large-scale electrocardiographic screening in young adults: data from 32,561 subjects. AB - BACKGROUND: Large-scale electrocardiographic (ECG) screening of young athletes has been shown to reduce the incidence of sudden cardiac death in Italy. Debate exists regarding the feasibility and benefits of such a program in the United States. OBJECTIVE: The purpose of this study was to describe implementation and results of a large-scale high school ECG screening program (Young Hearts for Life [YH4L]) developed in the Chicago area. METHODS: A retrospective cohort study of 32,561 high school students from 38 ECG screenings was performed between September 2006 and May 2009. Screenings were performed by the YH4L program, which consisted of a core group of administrators, cardiologists, and community volunteers who underwent specialized training and quality review. The rates of abnormal ECGs requiring further evaluation and unacceptable ECGs due to poor quality were determined. RESULTS: Of the 32,561 students screened, 817 (2.5%) had abnormal ECGs requiring further evaluation. The majority of abnormal ECGs occurred in males (66%). Only 0.81% of ECGs were determined to be technically inadequate, requiring repeat ECGs on the same day of the screening. The prevalence of left ventricular hypertrophy and abnormal ST-T wave changes was lower in our study than in the rates reported in an Italian registry, possibly due to the lower frequency of men and highly trained athletes in our study. CONCLUSION: Large-scale ECG screening of U.S. high school students is feasible and identifies ECGs requiring further evaluation in 2.5% of individuals. These findings have implications for implementing screening and preventing sudden cardiac death in U.S. youth. PMID- 21699836 TI - Percent biventricular pacing in cardiac resynchronization therapy: is more always better? PMID- 21699838 TI - Pathways for CaMKII activation in disease. PMID- 21699837 TI - Reversal of outflow tract ventricular premature depolarization-induced cardiomyopathy with ablation: effect of residual arrhythmia burden and preexisting cardiomyopathy on outcome. AB - BACKGROUND: Outflow tract ventricular premature depolarizations (VPDs) can be associated with reversible left ventricular cardiomyopathy (LVCM). Limited data exist regarding the outcome after ablation of outflow tract VPDs from the LV and the impact of residual VPDs or preexisting LVCM prior to the diagnosis of VPDs on recovery of LV function. OBJECTIVE: To examine the safety, efficacy, and long term effect of radiofrequency ablation on LV function in patients with LVCM and frequent outflow tract VPDs and examine the effect of ablation in patients with LVCM known to precede the onset of VPDs and the impact of residual VPD frequency on recovery of LV function. METHODS: Sixty-nine patients (43 men; age 51 +/- 16 years) with nonischemic LVCM (left ventricular ejection fraction [LVEF] 35% +/- 9%, left ventricular diastolic diameter [LVDD] 5.8 +/- 0.7 cm) were referred for ablation of frequent outflow tract VPDs (29% +/- 13%). RESULTS: VPDs originated in the right ventricular outflow tract in 27 (39%) patients and the left ventricular outflow tract in 42 (61%) patients. After follow-up of 11 +/- 6 months, 44 (66%) patients had rare (<2%) VPDs, 15 (22%) had decreased VPD burden (>80% reduction and always <5000 VPDs), and 8 (12%) had no clinical improvement with persistent (5 patients) or recurrent (3 patients) VPDs. Only patients with either rare or decreased VPD burden had a significant improvement in LVEF (DeltaLVEF 14% +/- 9% vs 13% +/- 7% vs -3% +/- 6%, respectively, P <.001) and LVDD (DeltaLVDD -4 +/- 5 vs -2 +/- 4 vs 0 +/- 4, respectively, P = .038), regardless of chamber of origin. The magnitude of LVEF improvement correlated with the decline in residual VPD burden (r = 0.475, P = .007). Patients with preexisting LVCM had a more modest but still significant improvement in LV function compared to patients without preexisting LVCM (DeltaLVEF 8% vs 13%, P = .046). Multivariate analysis revealed ablation outcome, higher LVEF, and absence of preexisting LVCM were independently associated with LVEF improvement. CONCLUSION: Frequent outflow tract VPDs are associated with LVCM regardless of ventricle of origin. Significant (>80%) reduction in VPD burden has comparable improvement in LV function to complete VPD elimination. Successful VPD ablation may be beneficial even in patients with preexisting LVCM. PMID- 21699839 TI - Impact of mitral isthmus anatomy on the likelihood of achieving linear block in patients undergoing catheter ablation of persistent atrial fibrillation. AB - BACKGROUND: Although prior studies have described the anatomy of the mitral isthmus in patients undergoing left atrial (LA) ablation of atrial fibrillation (AF), none has examined the impact of isthmus anatomy on the likelihood of achieving conduction block. OBJECTIVE: The purpose of this study was to identify morphologic characteristics of the mitral isthmus that may influence the acute efficacy of linear ablation at the mitral isthmus. METHODS: Fifty-five patients (age 61 +/- 10 years, 41 [75%] men, LA 46 +/- 6 mm, ejection fraction 0.55 +/- 0.11, AF duration 4 +/- 3 years) underwent linear ablation at the mitral isthmus during an ablation procedure for persistent AF. Computed tomographic scan was performed before the procedure. The morphology of the mitral isthmus and its anatomic relationship to the adjacent vasculature were analyzed. RESULTS: Complete block along the mitral isthmus was achieved in 35 (64%) of 55 patients, 23 (66%) of whom required radiofrequency ablation in the coronary sinus (CS). Patients with incomplete block were more likely to have a pouch at the isthmus (40% vs 9%; P = .01), a greater isthmus depth (8.1 +/- 4.2 mm vs 5.7 +/- 3.4 mm; P = .04), and a higher prevalence of an interposed circumflex artery between the CS and the mitral isthmus (60% vs 20%; P = .003) compared to patients with isthmus block. An interposed circumflex artery was the only independent predictor of incomplete conduction block at the mitral isthmus (odds ratio 4.9, 95% confidence interval 1.3-18.2; P = .02). CONCLUSION: Preprocedural computed tomographic imaging identifies patients in whom linear ablation at the mitral isthmus is unlikely to be successful. Interposition of the circumflex artery between the mitral isthmus and the CS is associated with a lower probability of achieving complete mitral isthmus block. PMID- 21699840 TI - Respiratory cycle-dependent atrial tachycardia: prevalence, electrocardiographic and electrophysiologic characteristics, and outcome after catheter ablation. AB - BACKGROUND: Little is known about the tachyarrhythmias relating to respiration. Case reports presented patients with respiratory cycle-dependent atrial tachycardias (RCATs), which cyclically emerge after starting inspiration and cease during expiration. OBJECTIVE: The aim of the present study was to elucidate the prevalence, characteristics, and long-term outcome after radiofrequency catheter ablation (RFCA) of RCATs. METHODS: The electrocardiographic and electrophysiologic properties and results of RFCA were analyzed in 60 patients with a total of 71 focal atrial tachycardias (ATs). RESULTS: Nine RCATs (13%) were observed in 7 patients (12%). RCATs were irregular, with a mean cycle length ranging from 220 to 650 ms, and developed incessantly accounting for 32% +/- 14% of the 24-hour heartbeats. The P-wave morphology was positive or biphasic (positive to negative) in V1, and positive in I and II. The electroanatomical mapping demonstrated a centrifugal activation pattern, with the earliest site located at the antrum of the right superior pulmonary vein (RSPV), inside the RSPV, and inside the superior vena cava (SVC) in 4, 2, and 3 RCATs, respectively. Radiofrequency energy delivery at the earliest site or the electrical isolation of the RSPV and SVC suppressed all RCATs. During a follow-up of 25 +/- 15 months, 1 RCAT recurred and was eliminated in a second procedure. CONCLUSION: RCATs were observed in 13% of the focal ATs. As presumed from the P-wave morphologies, their foci converged around the RSPV or inside the SVC. RFCA was effective to eliminate RCATs. PMID- 21699841 TI - The use of a radiofrequency needle improves the safety and efficacy of transseptal puncture for atrial fibrillation ablation. AB - BACKGROUND: Atrial fibrillation (AF) ablation requires transseptal puncture to gain entry to the left atrium (LA). On rare occasions, LA entry cannot be achieved or cardiac perforation results in pericardial tamponade. OBJECTIVE: This study sought to compare a new radiofrequency (RF) transseptal needle with the standard needle. METHODS: We evaluated 1,550 AF ablations in 1,167 patients. We compared 975 transseptal punctures done using a standard needle to 575 done using a new electrode-tipped needle attached to an RF perforation generator. RESULTS: The rate of failure to cross the atrial septum was lower for the RF needle (1 of 575 [0.17%] vs. 12 of 975 [1.23%], P = .039) and there were fewer pericardial tamponades with the RF needle (0 of 575 [0.00%] vs. 9 of 975 [0.92%], P = .031). Multivariate analysis showed the RF needle use was the only variable associated with a lower incidence of tamponade (P = .04). Becasuse the RF needle was used later in our series, we examined our 975 standard needle punctures over time for evidence of improved operator experience that might explain the superior RF results. For the standard needle, there was no trend for improved septal crossing rates (P = .794) or fewer tamponades (P = .456) with more operator experience. Instrumentation time was shorter for the RF needle (27.1 +/- 10.9 vs. 36.4 +/- 17.7 minutes, P < .0001). CONCLUSION: Our data suggest that the RF needle is superior to the standard transseptal needle. It results in shorter instrumentation times, a greater efficacy in transseptal crossing, and fewer episodes of pericardial tamponade. PMID- 21699842 TI - Short-term variability of repolarization predicts ventricular tachycardia and sudden cardiac death in patients with structural heart disease: a comparison with QT variability index. AB - BACKGROUND: Monitoring arrhythmic risk may improve management of patients with implantable cardioverter-defibrillators (ICD) and prevent ICD shocks. Changes in repolarization duration between subsequent beats quantified as short-term variability (STV) is associated with ventricular arrhythmias in several animal models. OBJECTIVE: We evaluated STV of QT from right ventricular intracardiac ICD electrograms in patients with structural heart disease and compared its predictive value with the QT variability index (QTVI). METHODS: In 233 patients, STV over 60 beats for QT and RR intervals and their ratio was calculated (STV(QT), STV(RR), STV(Ratio), respectively). QTVI was derived from mean and SD of QT and heart rate. Follow-up duration was 26 +/- 15 months. Predictive value was determined for sudden arrhythmic death (SAD) defined as sudden cardiac death or fast ventricular tachycardia/fibrillation [CL < 240 ms]. RESULTS: In univariate analysis, STV(Ratio), but not STV(QT) or STV(RR), was predictive of SAD. Hazard ratios for highest quartile STV(Ratio) and QTVI were comparable (STV(Ratio): 1.9, 95% confidence interval [CI] 1.1 to 3.3, P = .038, QTVI: 2.2, 95% CI 1.2 to 3.8, P = .010). In a multivariate model, highest quartile STV(Ratio) was predictive of SAD after adjustment for New York Heart Association class, history of ischemia, ICD indication, and use of class I antiarrhythmics (hazard ratio 1.8, 95% CI 1.0 to 3.4, P < .050). A combined criterion of highest quartile for both STV(Ratio) and QTVI identified patients at highest risk (hazard ratio 2.4, 95% CI 1.3 to 4.3, P = .005, positive predictive value 38%, negative predictive value 82%). CONCLUSION: STV(Ratio) from ICD electrograms is predictive of SAD. Predictive value is similar for order-based STV(Ratio) and distribution based QTVI, but the combination of both parameters can further improve results. PMID- 21699844 TI - Left ventricular pacing with long pulse duration can avoid phrenic nerve stimulation. AB - BACKGROUND: One of the major limitations of left ventricular pacing is phrenic nerve stimulation. OBJECTIVE: We evaluated the characteristics of the strength duration curves of the left phrenic nerve (PN) and epicardium of the left ventricle (LV). METHODS: A total of 12 mongrel dogs were studied. Capture threshold was assessed during pacing with 180 beats/min and various pulse durations (0.25 to 2.0 ms) in an open chest model. A commercially available LV lead was inserted through a small hole created in the pericardium. The tip electrode position was maintained at the course of the left PN with gentle manual pressure under visual inspection. The LV threshold was evaluated at the epicardium just below the PN. The LV threshold was defined as the highest amplitude that showed loss of 1:1 capture. The PN threshold was defined as the highest amplitude that could not induce any diaphragmatic contraction. RESULTS: The strength-duration curve of the PN had a higher rheobase and shorter chronaxie than that of the LV. The LV threshold was higher than that of the PN at pulse duration <1.0 ms in bipolar pacing, but significantly lower than that of the PN at a pulse duration of 2.0 ms, especially during unipolar pacing (1.3 +/- 0.21 V vs. 2.0 +/- 0.56 V, LV vs. PN, P =.012). CONCLUSION: LV pacing without PN stimulation could be achieved in pacing with long pulse duration. The longer pulse duration option can be considered in the development of devices for LV pacing such as cardiac resynchronization therapy. PMID- 21699843 TI - Protein kinase C downregulates I(Ks) by stimulating KCNQ1-KCNE1 potassium channel endocytosis. AB - BACKGROUND: The slow-activating cardiac repolarization K(+) current (I(Ks)), generated by the KCNQ1-KCNE1 potassium channel complex, is controlled via sympathetic and parasympathetic regulation in vivo. Inherited KCNQ1 and KCNE1 mutations predispose to ventricular fibrillation and sudden death, often triggered by exercise or emotional stress. Protein kinase C (PKC), which is activated by alpha1 adrenergic receptor stimulation, is known to downregulate I(Ks) via phosphorylation of KCNE1 serine 102, but the underlying mechanism has remained enigmatic. We previously showed that KCNE1 mediates dynamin-dependent endocytosis of KCNQ1-KCNE1 complexes. OBJECTIVE: This study sought to determine the potential role of endocytosis in I(Ks) downregulation by PKC. METHODS: We utilized patch clamping and fluorescence microscopy to study Chinese hamster ovary (CHO) cells coexpressing KCNQ1, KCNE1, and wild-type or dominant-negative mutant (K44A) dynamin 2, and neonatal mouse ventricular myocytes. RESULTS: The PKC activator phorbol 12-myristate 13-acetate (PMA) decreased I(Ks) density by >60% (P < .05) when coexpressed with wild-type dynamin 2 in CHO cells, but had no effect when coexpressed with K44A-dynamin 2. Thus, functional dynamin was required for downregulation of I(Ks) by PKC activation. PMA increased KCNQ1-KCNE1 endocytosis in CHO cells expressing wild-type dynamin 2, but had no effect on KCNQ1-KCNE1 endocytosis in CHO cells expressing K44A-dynamin 2, determined using the Pearson correlation coefficient to quantify endosomal colocalization of KCNQ1 and KCNE1 with internalized fluorescent transferrin. KCNE1-S102A abolished the effect of PMA on I(Ks) currents and endocytosis. Importantly, PMA similarly stimulated endocytosis of endogenous KCNQ1 and KCNE1 in neonatal mouse myocytes. CONCLUSION: PKC activation downregulates I(Ks) by stimulating KCNQ1-KCNE1 channel endocytosis. PMID- 21699845 TI - Computed tomography of a coronary sinus diverticulum associated with Wolff Parkinson-White syndrome. PMID- 21699846 TI - Myocardial edema underlies dynamic T-wave inversion (Wellens' ECG pattern) in patients with reversible left ventricular dysfunction. AB - BACKGROUND: The Wellens' electrocardiogram (ECG) pattern of dynamic T-wave inversion in the anterior leads is observed in clinical conditions characterized by reversible left ventricular (LV) dysfunction (stunned myocardium), either ischemic or nonischemic. The pathophysiologic basis of this ECG pattern remains to be elucidated. OBJECTIVE: The purpose of this study was to report the contrast enhanced cardiac magnetic resonance (CE-CMR) findings in 4 cases of Wellens' ECG pattern associated with transient LV dysfunction from a variety of clinical conditions such as myocardial bridge, coronary artery dissection, cholecystitis, and takotsubo syndrome. METHODS: All patients underwent CE-CMR at the time of acute clinical manifestations and after 6 to 8 weeks of follow-up to assess the presence and dynamics of LV myocardial changes. RESULTS: In all patients, the Wellens' ECG abnormalities were associated with increased signal intensity of the LV myocardium on T2-weighted sequences suggesting myocardial edema, in the absence of late enhancement on postcontrast sequences. Repolarization abnormalities and myocardial edema had a parallel time course with persistence beyond recovery of mechanical abnormalities. T-wave inversion was associated with transient prolongation of the QTc interval in all cases. CONCLUSION: The study results suggest that myocardial edema rather than systolic dysfunction underlies the Wellens' ECG pattern, regardless of the causative mechanism. PMID- 21699847 TI - Atrial fibrillation and stroke: it's not necessarily all about the rhythm. PMID- 21699848 TI - Deciphering the pecking order of HCN4 expression in the developing heart: lessons from chicken. PMID- 21699849 TI - Time- and frequency-domain analyses of atrial fibrillation activation rate: the optical mapping reference. AB - BACKGROUND: Time- and frequency-domain estimates of activation rate have been proposed to guide atrial fibrillation (AF) ablation in patients, but their electrophysiological correlates are unclear. OBJECTIVE: This study sought to examine the relative correlation of average electrical cycle length (CL) and dominant frequency (DF) during AF with reference optical mapping measures. METHODS: Eight sheep hearts were Langendorff-perfused and superfused with oxygenated Tyrode solution inside a tank representing the human thorax. Optical mapping (DI-4-ANEPPS) of 4 * 4 cm2 in the left atrium was performed at 0.5 mm/pixel and 600 fps. A 20-pole catheter was placed in the optical field of view to acquire 1.2-kHz unipolar recordings by the EnSite NavX System (ENS; St. Jude Medical, St. Paul, MN) optimized for CL and DF calculation. During AF, 5-second long simultaneous optical and electrical signals were analyzed for CL and DF. RESULTS: During pacing, DF measurements had fewer false results than CL (6.6% to 2.5% vs. 21.5% to 4.4% depending on filtering, P <.001). During AF in regions showing periodic waves on both sides of the catheter optical 1,000/CL versus DF correlation showed 95% confidence identity and was better than unipolar measurements in the ENS (adjusted R(2): 0.58879 vs. 0.12902; P < 10(-6)). DFs of unipolar signals correlated better than CLs with DFs of optical signals. Similarly, bipolar DF correlation with optical DF was not different from identity (P >.157), but the bipolar CL showed smaller identity with the optical CL (P <.0004). CONCLUSION: DF values of unipolar and bipolar signals correlate with those of optical signals better than CL values for the respective signals. PMID- 21699850 TI - Early temporal and spatial regularization of persistent atrial fibrillation predicts termination and arrhythmia-free outcome. AB - BACKGROUND: Termination of persistent atrial fibrillation (AF) is a valuable ablation endpoint but is difficult to anticipate. We evaluated whether temporal and spatial indices of AF regularization predict intraprocedural AF termination and outcome. OBJECTIVE: The purpose of this study was to test whether temporospatial organization of AF after pulmonary vein isolation (PVI) predicts whether subsequent stepwise ablation will terminate persistent AF or predict outcome. METHODS: In 75 patients with persistent AF, we measured AF cycle length (AFCL), temporal regularity index (TRI, a spectral measure of timing regularity), and spatial regularity index (SRI, cycle-to-cycle variations in spatial vector) between right atrial appendage and proximal and distal coronary sinus before and during stepwise ablation to the endpoint of AF termination. RESULTS: AF termination was achieved in 59 patients (79%) by ablation. AF terminated during PVI in 11 patients, who were excluded from analysis. In the remaining 48 patients, TRI and SRI increased during stepwise ablation, as compared with 16 patients without termination (P<.05). AFCL was prolonged in both groups. From receiver operating characteristics analysis of the first 22 patients (training set), a post-PVI TRI increase predicted AF termination in the latter 42 patients (test set) with a positive predictive value of 96%, negative predictive value of 53%, sensitivity of 71%, and specificity of 91%. Results were similar for SRI. After 36 months, higher arrhythmia-free outcome was observed in patients in whom PVI caused temporospatial regularization in AF. CONCLUSIONS: Temporal and spatial regularization of persistent AF after PVI identifies patients in whom stepwise ablation subsequently terminates AF and prevents recurrence. PMID- 21699851 TI - Reduced diameter spheres increases the risk of chest blow-induced ventricular fibrillation (commotio cordis). AB - BACKGROUND: Sudden death due to low-energy blunt trauma to the precordium (commotio cordis) has been described with a variety of sporting objects. However, the risk of ventricular fibrillation (VF) relative to the shape of the impact object is not known. OBJECTIVE: The objective of the current experiment is to test whether the impact object shape is a clinical variable that affects the risk for commotio cordis. METHODS: In a juvenile swine model, impacts were given in random order with two different spherical shapes (72 mm diameter, equivalent to a baseball; 42 mm diameter, equivalent to a golf ball) and a flat round object 72 mm in diameter. Objects were equal in weight (150 g), thrown at 30 mph, and gated to the vulnerable portion of the cardiac cycle. RESULTS: Sixteen swine received 144 impacts. The flat object did not cause VF (P = .01 compared with the two spherical objects), nonsustained VF, ST elevation, or bundle branch block. The smaller diameter sphere caused VF in nine of 48 impacts (19%), and the larger diameter sphere caused VF in five of 48 impacts (10%; P = .25). The smaller diameter sphere was associated with a greater increase in left ventricular pressure (P <.0001 and P = .001 compared with larger sphere only) and a higher likelihood of ST segment elevations (P <.001 and P = .08 compared with larger sphere only) and bundle branch block (Fisher's exact P = .008, and Fisher's exact P = .18 compared with larger sphere only). CONCLUSION: The shape of the projectile markedly influences the risk of VF from chest wall impact. This effect is likely mediated via a greater increase in left ventricular pressure with smaller diameter objects. Spreading the impact force over a larger area may decrease the risk of sudden death and has implications for the design of protective athletic equipment. PMID- 21699852 TI - ECG screening in athletes: time to develop infrastructure. PMID- 21699853 TI - Unraveling the riddle of transient T-wave inversion (Wellens' ECG pattern): T2 weighted magnetic resonance imaging identifies myocardial edema. PMID- 21699854 TI - Antitachycardia pacing as both therapy and diagnostic tool: what is the diagnosis? PMID- 21699855 TI - Impact of timing of device removal on mortality in patients with cardiovascular implantable electronic device infections. AB - BACKGROUND: Cardiovascular implantable electronic device (CIED) infections are associated with increased mortality. However, detailed analyses of the impact of device removal on mortality have been limited. OBJECTIVE: This study sought to evaluate the impact of timing device removal on mortality in patients with CIED infections. METHODS: We retrospectively reviewed all cases of CIED infections seen at Mayo Clinic Rochester between 1991 and 2008. The impact of device removal on 30-day and 1-year mortality was evaluated using Cox proportional hazards models. RESULTS: Of 416 patients with CIED infection, 23 (5.5%) died by 30 days and 61 (14.6%) died by 1 year. Forty-four (12.0%) developed complications related to device removal, and 3 (0.8%) died. Complete procedural success was achieved in 341 (81.9%) and clinical success in 391 (93.9%) cases. In multivariate analysis, antimicrobial therapy without device removal was associated with a 7-fold increase in 30-day mortality (hazard ratio [HR] 6.97, 95% confidence interval [CI] 1.36 to 35.60). Although device removal complications were associated with increased mortality at 30 days (HR 4.33, 95% CI 1.47 to 12.70) and at 1 year (HR 3.77, 95% CI 1.88 to 7.55), immediate device removal, when compared to delay in device removal in favor of initial conservative therapy with antimicrobials alone, and no device removal, was associated with a 3-fold decrease in 1-year mortality (HR 0.35, 95% CI 0.16 to 0.75). CONCLUSION: Although device removal resulted in fatal complications in a few patients, the mortality associated with a delay in device removal was significantly higher. Therefore, early and complete device removal was associated with improved outcomes. PMID- 21699857 TI - Incidence and predictors of major complications from contemporary catheter ablation to treat cardiac arrhythmias. AB - BACKGROUND: Updated understanding of the risks of catheter ablation is important because techniques have evolved for procedures treating non-life-threatening as well as potentially lethal arrhythmias. OBJECTIVE: This prospective study sought to assess the incidence and predictors of major complications from contemporary catheter ablation procedures at a high-volume center. METHODS: Over a 2-year period, 1,676 consecutive ablation procedures were prospectively evaluated for major complications throughout 30 days postprocedure. Predictors of major complications were determined in a multivariate analysis adjusted for demographics, clinical variables, ablation type, and procedural factors. RESULTS: Rates of major complications differed between procedure types, ranging from 0.8% for supraventricular tachycardia, 3.4% for idiopathic ventricular tachycardia (VT), 5.2% for atrial fibrillation (AF), and 6.0% for VT associated with structural heart disease (SHD). Ablation type (ablation for AF [odds ratio (OR) 5.53, 95% confidence interval (CI) 1.81 to 16.83], for VT with SHD [OR 8.61, 95% CI 2.37 to 31.31], or for idiopathic VT [OR 5.93, 95% CI 1.40 to 25.05] all referenced to supraventricular tachycardia ablation), and serum creatinine level >1.5 mg/dl (OR 2.48, 95% CI 1.07 to 5.76) were associated with increased adjusted risk of major complications, whereas age, gender, body mass index, international normalized ratio level, hypertension, coronary artery disease, diabetes, and prior cerebrovascular accident were not associated with increased risk. CONCLUSION: In a large cohort of contemporary catheter ablation, major complication rates ranged between 0.8% and 6.0% depending on the ablation procedure performed. Aside from ablation type, renal insufficiency was the only independent predictor of a major complication. PMID- 21699858 TI - The diagnostic utility of recovery phase QTc during treadmill exercise stress testing in the evaluation of long QT syndrome. AB - BACKGROUND: Nearly 40% of patients with long QT syndrome (LQTS) can have a nondiagnostic QTc at rest. Treadmill and cycle exercise stress testing are used in the diagnostic evaluation of LQTS. OBJECTIVE: The purpose of this study was to determine the diagnostic significance of peak exercise and recovery phase QTc values during treadmill stress testing in LQTS. METHODS: An Institutional Review Board-approved, retrospective analysis was performed on the treadmill stress tests in 243 patients including 82 LQT1, 55 LQT2, 18 LQT3, and 88 genotype negative patients dismissed as normal. Blinded to genotype, QTc was calculated at rest, peak exercise, and 1, 2, 3, 4, and 5 minutes of recovery. RESULTS: Compared with those dismissed as normal, the average QTc was greater at all scored stages in LQT1 and LQT3 patients and at all stages in LQT2 patients except peak exercise and 1 minute of recovery (P < .01). Either an absolute QTc >= 460 ms during the recovery phase or a maladaptive, paradoxical increase in QTc, defined as QTc recovery--QTc baseline >= 30 ms (DeltaQTc), distinguished patients with either manifest or concealed LQT1 from all other subsets (P < .0001). The presence of beta-blockers did not blunt these abnormal repolarization profiles. CONCLUSION: Treadmill stress testing can unmask patients with concealed LQTS, particularly LQT1, with good diagnostic accuracy. PMID- 21699856 TI - Postpacing abnormal repolarization in catecholaminergic polymorphic ventricular tachycardia associated with a mutation in the cardiac ryanodine receptor gene. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disease for which electrophysiological studies (EPS) have shown to be of limited value. OBJECTIVE: This study presents a CPVT family in which marked postpacing repolarization abnormalities during EPS were the only consistent phenotypic manifestation of ryanodine receptor (RyR2) mutation carriers. METHODS: The study was prompted by the observation of transient marked QT prolongation preceding initiation of ventricular fibrillation during atrial fibrillation in a boy with a family history of sudden cardiac death (SCD). Family members underwent exercise and pharmacologic electrocardiographic testing with epinephrine, adenosine, and flecainide. Noninvasive clinical test results were normal in 10 patients evaluated, except for both epinephrine- and exercise-induced ventricular arrhythmias in 1. EPS included bursts of ventricular pacing and programmed ventricular extrastimulation reproducing short-long sequences. Genetic screening involved direct sequencing of genes involved in long QT syndrome as well as RyR2. RESULTS: Six patients demonstrated a marked increase in QT interval only in the first beat after cessation of ventricular pacing and/or extrastimulation. All 6 patients were found to have a heterozygous missense mutation (M4109R) in RyR2. Two of them, presenting with aborted SCD, also had a second missense mutation (I406T- RyR2). Four family members without RyR2 mutations did not display prominent postpacing QT changes. CONCLUSION: M4109R- RyR2 is associated with a high incidence of SCD. The contribution of I406T to the clinical phenotype is unclear. In contrast to exercise testing, marked postpacing repolarization changes in a single beat accurately predicted carriers of M4109R- RyR2 in this family. PMID- 21699859 TI - The left coronary cusp as an unusual location for accessory pathway ablation. PMID- 21699860 TI - Relationship among complex signals, short cycle length activity, and dominant frequency in patients with long-lasting persistent AF: a high-density epicardial mapping study in humans. AB - BACKGROUND: Complex fractionated atrial electrograms (CFAEs) and regions of high dominant frequency (DF) both may identify sites critical to the maintenance of atrial fibrillation (AF). CFAEs may be defined by either (1) complex multicomponent electrograms (EGMs) and/or continuous electrical activity (multicomponent/continuous EGM) or (2) discrete high-frequency EGMs. OBJECTIVE: The purpose of this study was to test if the 2 definitions of CFAE identify the same arrhythmia substrate and determine the relationship of CFAE to areas of high DF. METHODS: High-density epicardial mapping of the posterior left atrium was performed in 10 patients with long-lasting persistent AF. Point-by-point analysis was performed to determine the spatial distribution and correlation of CFAE defined as either (1) multicomponent/continuous-EGMs or (2) AF cycle length <120 ms. Additionally, spatial analysis was performed to determine the relationship of high DF sites to CFAE sites defined by each of the 2 definitions. RESULTS: The percentage of sites deemed CFAE varied markedly between patients and was different depending on the definition of CFAE adopted. There was a poor correlation between CFAE defined by multicomponent/continuous EGMs and AF cycle length <120 ms (r = 0.18). High DF sites were arranged in clusters evenly distributed throughout the posterior left atrium, with 4.2 +/- 1.0 high DF clusters per patient. Although there was poor point-by-point correlation between multicomponent/continuous EGMs and high DF sites (r = 0.107), spatial analysis revealed that 96% of multicomponent/continuous EGMs were found adjacent to and partially surrounding (<=5 mm) high DF sites. CONCLUSION: There is poor anatomic overlap between CFAE defined by multicomponent/continuous EGMs and CFAE defined by AF cycle length <120 ms. Multicomponent/continuous EGMs are found adjacent to and surrounding sites of high DF. Further studies are needed to determine the mechanisms responsible for these different signals. PMID- 21699861 TI - Understanding arrhythmogenesis by looking inside the cell. PMID- 21699862 TI - Commotio cordis: size matters, so does shape. PMID- 21699865 TI - To the editor--on the safety and efficacy of high-frequency jet ventilation during posterior left atrial ablation. PMID- 21699863 TI - Quantification of repolarization reserve to understand interpatient variability in the response to proarrhythmic drugs: a computational analysis. AB - BACKGROUND: "Repolarization reserve" is frequently invoked to explain why potentially proarrhythmic drugs cause, across a population, a range of changes to cardiac action potentials (APs). However, the mechanisms underlying this interindividual variability are not understood quantitatively. OBJECTIVE: The purpose of this study was to perform a novel analysis of mathematical models of ventricular myocytes to quantify repolarization reserve and gain insight into the factors responsible for variability in the response to proarrhythmic drugs. METHODS/RESULTS: In several models of human or canine ventricular myocytes, variability was simulated by randomizing model parameters and running repeated simulations. With each randomly generated set of parameters, APs before and after simulated 75% block of the rapid delayed rectifier current (I(Kr)) were calculated. Multivariable regression was performed to determine how much each model parameter attenuated or exacerbated the AP prolongation caused by the I(Kr) blocking drug. Simulations with a human ventricular myocyte model suggest that drug response is influenced most strongly by (1) the density of I(Kr), (2) the density of slow delayed rectifier current I(Ks), (3) the voltage dependence of I(Kr) inactivation, (4) the density of L-type Ca2+ current, and (5) the kinetics of I(Ks) activation. The analysis also identified mechanisms underlying nonintuitive behavior, such as ionic currents that prolong baseline APs but decrease drug-induced AP prolongation. Finally, the simulations provided quantitative insight into conditions that aggravate the drug response, such as silent ion channel mutations and heart failure. CONCLUSION: These modeling results provide the first thorough quantification of repolarization reserve and improve our understanding of interindividual variability in adverse drug reactions. PMID- 21699866 TI - Time- and frequency-domain analysis of AF electrograms: simple approaches to a complex arrhythmia? PMID- 21699867 TI - Ranolazine: Deja vu of the amiodarone story. PMID- 21699869 TI - Prolonged QRS duration on the resting ECG is associated with sudden death risk in coronary disease, independent of prolonged ventricular repolarization. AB - BACKGROUND: Abnormalities of ventricular repolarization as well as depolarization have been associated with increased risk of ventricular arrhythmias. OBJECTIVE: To evaluate the relative contribution of these predictors to risk of sudden cardiac death (SCD) in patients with coronary artery disease (CAD). METHODS: In the ongoing Oregon Sudden Unexpected Death Study, adult residents from the Portland, Oregon, metropolitan area (population ~1 million) who suffered SCD were identified prospectively (2002-2007). Of these, we analyzed the subgroup of SCDs that had a resting 12-lead ECG prior to SCD and also had associated CAD. Comparisons were conducted with a control group of subjects with known CAD but no history of SCD from the same geographic region. Corrected QT interval (QTc), JT interval (JTc), QRS duration (QRSd), and other parameters were measured from ECG prior and unrelated to SCD. Analysis of left ventricular function was limited to those subjects who had undergone echocardiography prior to and remote from SCD. RESULTS: A total of 642 SCD cases (71 +/- 13 years, 62% male) were compared to 450 controls (66 +/- 12 years, 64% male). SCD cases had significantly longer QRSd (102 +/- 25 ms vs 97 +/- 20 ms, P = .0008) as well as JTc (348 +/- 44 ms vs 339 +/- 34 ms, P = .0006) vs controls. In cases with prolonged QRSd, 38% had severe left ventricular systolic dysfunction and 62% had normal, mild, or moderately decreased left ventricular systolic function. In a multivariable model, QRSd, JTc, age, and severe left ventricular systolic dysfunction were independent predictors. There was minimal overlap between prolonged QRSd and JTc in both case and control groups (3% and 4%, respectively). CONCLUSION: Prolonged QRSd, JTc, and severe left ventricular systolic dysfunction had independent contributions to risk of SCD in coronary disease, in this community-based setting. PMID- 21699870 TI - Arrhythmia triggers in heart failure: the smoking gun of [Ca2+]i dysregulation. AB - Among the most serious problems associated with heart failure is the increased likelihood of life-threatening arrhythmias. Both triggered and reentrant arrhythmias in heart failure may arise as a result of aberrant intracellular Ca cycling. This article presents some new ideas, based on recent studies, about how altered Ca cycling in heart failure might serve as the cellular basis for arrhythmogenesis. PMID- 21699871 TI - A farewell to arms: are complex fractionated atrial electrograms doomed as a target for AF ablation? PMID- 21699872 TI - Successes and failures in modeling heart cell electrophysiology. AB - Mathematical models of the electrical activity of the heart using equations for protein ion channels and other transporters began with the Noble 1962 model. These models then developed over a period of about 50 years. Cell types in all regions have been modeled and now are available for download from the CellML website (www.cellml.org). Simulation is a necessary tool of analysis in attempting to understand biological complexity. We often learn as much from the failures as from the successes of mathematical models. It is the iterative interaction between experiment and simulation that is important. PMID- 21699868 TI - HRS policy statement: clinical cardiac electrophysiology fellowship curriculum: update 2011. PMID- 21699873 TI - Complex problems require complex solutions...but may result in other complex problems. PMID- 21699874 TI - Assessing electrocardiographic data quality and possible replacement of pharmacologic positive control in thorough QT/QTc studies by investigations of drug-free QTc stability. PMID- 21699875 TI - How to perform antral pulmonary venous isolation using the cryoballoon. PMID- 21699876 TI - The influence of perceived control and self-efficacy on the sensory evaluation of experimentally induced pain. AB - BACKGROUND AND AIMS: Prior research has demonstrated the role of perceived control and self-efficacy beliefs over pain in reducing pain and pain-related disability. The present study aimed to examine the independent influence of perceived control and self-efficacy beliefs on the subjective evaluation of pain. METHODS: Healthy participants (N = 79) were randomly assigned to one of four conditions that were formed by manipulations of perceived control and self efficacy. At two occasions in the experimental procedure pain was induced by means of electrical stimulation (16 s) to the lower forearm. Prior to and following upon each pain stimulus, participants completed ratings of pain intensity and pain unpleasantness. RESULTS: High self-efficacy regarding the ability to exert control over pain resulted in a significant reduction in anticipated pain intensity, anticipated pain unpleasantness, and experienced pain intensity ratings. Furthermore, anticipated pain intensity was found to mediate the relation between self-efficacy and experienced pain intensity. CONCLUSIONS: It is concluded that in order to observe beneficial effects of offering control over pain, it is important that individuals are convinced (i.e. have high self efficacy) that they are able to exert this control successfully. PMID- 21699877 TI - Estimating the growth of internal evidence guiding perceptual decisions. AB - Perceptual decision-making is thought to involve a gradual accrual of noisy evidence. Temporal integration of the evidence reduces the relative contribution of dynamic internal noise to the decision variable, thereby boosting its signal to-noise ratio. We aimed to estimate the internal evidence guiding perceptual decisions over time, using a novel combination of external noise and the response signal methods. Observers performed orientation discrimination of patterns presented in external noise. We varied the contrast of the patterns and the delay at which observers were forced to signal their decision. Each test stimulus (patterns and noise sample) was presented twice. Across two experiments we varied the availability of the visual stimulus for processing. Observer model analyses of discrimination accuracy and response consistency to two passes of the same stimulus, suggested that there was very little growth in the internal evidence. The improvement in accuracy over time characterised by the speed-accuracy trade off function predominantly reflected a decreasing proportion of non-visual decisions, or pure guesses. There was no advantage to having the visual patterns visible for longer than 80 ms, indicating that only the visual information in a short window after display onset was used to drive the decisions. The remarkable constancy of the internal evidence over time suggests that temporal integration of the sensory information was very limited. Alternatively, more extended integration of the evidence from memory could have taken place, provided that the dominant source of internal noise limiting performance occurs between-trials, which cannot be reduced by prolonged evidence integration. PMID- 21699878 TI - Outcomes of patients treated and one human leukocyte antigen-mismatched related compared with matched unrelated donors. PMID- 21699879 TI - Comparison of reduced-intensity hematopoietic cell transplantation with chemotherapy in patients age 60-70 years with acute myelogenous leukemia in first remission. AB - We compared the outcomes of patients age 60-70 years with acute myelogenous leukemia receiving reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in first remission (CR1) reported to the Center for International Blood and Marrow Research (n = 94) with the outcomes in patients treated with induction and postremission chemotherapy on Cancer and Leukemia Group B protocols (n = 96). All patients included had been in CR1 for at least 4 months. The HCT recipients were slightly younger than the chemotherapy patients (median age, 63 years vs 65 years; P < .001), but there were no significant between-group differences in the proportion with therapy-related leukemia or in different cytogenetic risk groups. Time from diagnosis to CR1 was longer for the HCT recipients (median, 44 days vs 38 days; P = .031). Allogeneic HCT was associated with significantly lower risk of relapse (32% vs 81% at 3 years; P < .001), higher nonrelapse mortality (36% vs 4% at 3 years; P < .001), and longer leukemia-free survival (32% vs 15% at 3 years; P = .001). Although overall survival was longer for HCT recipients, the difference was not statistically significant (37% vs 25% at 3 years; P = .08). Our findings suggest that reduced intensity conditioning allogeneic HCT in patients age 60-70 with acute myelogenous leukemia in CR1 reduces relapse and improves leukemia-free survival. Strategies that reduce nonrelapse mortality may yield significant improvements in overall survival. PMID- 21699880 TI - Altered mitochondrial function in type 2 granular corneal dystrophy. AB - Type 2 granular corneal dystrophy (GCD2) is caused by point mutation R124H in the transforming growth factor-beta-induced gene (TGFBI) and is characterized by age dependent progression of corneal deposits. Mitochondrial features in heterozygous GCD2 and normal corneal tissues was evaluated using electron microscopy. Primary corneal fibroblasts of homozygous and normal corneas were cultured to passage 4 or 8. Keratocytes of normal corneal tissue are narrow, and details of their intracellular organelles are difficult to distinguish. Keratocytes of heterozygous GCD2 tissues exhibited many degenerative mitochondria. MitoTracker and cytochrome c staining demonstrated increased mitochondrial activity in mutated cells at early passages. Decreases in depolarized mitochondria, cellular proliferation, and expression of complexes I to V and increases in apoptotic change were observed in late-passage mutant fibroblasts. PGC-1alpha, ANT-1, p Akt, and p-mTOR but not NF-kappaB expression demonstrated a passage-dependent decrease in all cells. Increased passage- or mutation-related intracellular reactive oxygen species and delayed proliferation of methanethiosulfonate (MTS) were recovered using application of antioxidant butylated hydroxyanisole. Mitochondrial features and function were altered in mutated GCD2 keratocytes, in particular in older cells. Alteration of mitochondrial function is critical for understanding the pathogenesis of GCD2. PMID- 21699882 TI - Modulation of sulfide oxidation and toxicity in rat mitochondria by dehydroascorbic acid. AB - Hydrogen sulfide is enzymatically produced in mammalian tissues and functions as a gaseous transmitter. However, H(2)S is also highly toxic as it inhibits mitochondrial respiration at the level of cytochrome c oxidase, which additionally is involved in sulfide oxidation. The accumulation of toxic sulfide levels contributes to the pathology of some diseases. This paper demonstrates that sulfide toxicity can be modified, and dehydroascorbic acid functions as an effector in this process. It significantly reduces the inhibitory effect of sulfide on cytochrome c oxidase, resulting in higher rates of respiration and sulfide oxidation in rat mitochondria. After the addition of dehydroascorbic acid mitochondria maintained more than 50% of the oxygen consumption and ATP production rates with different substrates in the presence of high concentrations of sulfide that would normally lead to complete inhibition. Dehydroascorbic acid significantly increased the sulfide concentration necessary to cause half maximal inhibition of mitochondrial respiration and thus completely prevented inhibition at low, physiological sulfide concentrations. In addition, sulfide oxidation was stimulated and led to ATP production even at high concentrations. The decrease in sulfide toxicity was more pronounced when analyzing supermolecular functional units of the respiratory chain than in isolated cytochrome c oxidase activity. Furthermore, the protective effect of dehydroascorbic acid at high sulfide concentrations was completely abolished by quantitative solubilization of mitochondrial membrane proteins with dodeclymaltoside. These results suggest that binding of cytochrome c oxidase to other proteins probably within respiratory chain supercomplexes is involved in the modulation of sulfide oxidation and toxicity by dehydroascorbic acid. PMID- 21699883 TI - Influence of the lipid composition of biomimetic monolayers on the structure and orientation of the gp41 tryptophan-rich peptide from HIV-1. AB - The tryptophan-rich peptide of gp41 (so-called gp41W), one of the two envelope glycoproteins of HIV-1, is known to play a crucial role in the fusion between this virus and the host cell membranes. The influence of lipids on this role was investigated using different lipid monolayers at the air-water interface. Gp41W affinity for the lipid monolayer was measured by following the peptide-induced variation in the lateral surface pressure and we demonstrated that gp41W binds to monolayers containing the saturated zwitterionic dipalmitoylphosphatidylcholine (DPPC) as well as to the anionic dipalmitoylphosphatidylglycerol (DPPG) and to mixed monolayers containing DPPC and cholesterol (Chol). The secondary structure of gp41W in the presence of these lipid monolayers was determined by polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS). The data showed that gp41W was an oriented alpha-helix in the presence of DPPG. However this spectroscopic method was unable to detect the gp41W structure in the presence of DPPC and DPPC/Chol monolayer. The peptide-induced modifications of the DPPC/Chol, DPPC and DPPG monolayer morphology were analyzed by Brewster angle microscopy (BAM). The peptide-induced changes in the DPPG monolayer morphology suggest that gp41W disturbed the lipid intermolecular interactions. Furthermore the peptide delayed the condensed state of DPPC and DPPC/Chol, indicating that, although gp41W was not detected by PM-IRRAS, it was present in these lipid monolayers. PMID- 21699881 TI - Eosinophils contribute to IL-4 production and shape the T-helper cytokine profile and inflammatory response in pulmonary cryptococcosis. AB - Susceptibility to infection with Cryptococcus neoformans is tightly determined by production of IL-4. In this study, we investigated the time course of IL-4 production and its innate cellular source in mice infected intranasally with C. neoformans. We show that pulmonary IL-4 production starts surprisingly late after 6 weeks of infection. Interestingly, in the lungs of infected mice, pulmonary T helper (Th) cells and eosinophils produce significant amounts of IL-4. In eosinophil-deficient DeltadblGATA mice, IL-33 receptor-expressing Th2s are significantly reduced, albeit not absent, whereas protective Th1 and Th17 responses are enhanced. In addition, recruitment of pulmonary inflammatory cells during infection with C. neoformans is reduced in the absence of eosinophils. These data expand previous findings emphasizing an exclusively destructive effector function by eosinophilic granulocytes. Moreover, in DeltadblGATA mice, fungal control is slightly enhanced in the lung; however, dissemination of Cryptococcus is not prevented. Therefore, eosinophils play an immunoregulatory role that contributes to Th2-dependent susceptibility in allergic inflammation during bronchopulmonary mycosis. PMID- 21699884 TI - Directed evolution of efficient secretion in the SRP-dependent export of TolB. AB - Signal sequence non-optimal codons have been shown to be important for the folding and efficient export of maltose binding protein (MBP), a SecB dependent protein. In this study, we analysed the importance of signal sequence non-optimal codons of TolB, a signal recognition particle (SRP) dependent exported protein. The protein production levels of wild type TolB (TolB-wt) and a mutant allele of TolB in which all signal sequence non-optimal codons were changed to a synonymous optimal codon (TolB-opt), revealed that TolB-opt production was 12-fold lower than TolB-wt. This difference could not be explained by changes in mRNA levels, or plasmid copy number, which was the same in both strains. A directed evolution genetic screen was used to select for mutants in the TolB-opt signal sequence that resulted in higher levels of TolB production. Analysis of the 46 independent TolB mutants that reverted to wild type levels of expression revealed that at least four signal sequence non-optimal codons were required. These results suggest that non-optimal codons may be required for the folding and efficient export of all proteins exported via the Sec system, regardless of whether they are dependent on SecB or SRP for delivery to the inner membrane. PMID- 21699885 TI - In vitro and in vivo activity of 4-thio-uridylate against JY cells, a model for human acute lymphoid leukemia. AB - We have previously reported the in vitro anti-proliferative effect of 4-thio uridylate (s(4)UMP) on OCM-1 uveal melanoma cells. Here, we assessed the efficacy of s(4)UMP on JY cells. Treatment of JY cells with s(4)UMP suppressed their colony forming activity and induced apoptosis; healthy human bone marrow granulocyte-macrophage progenitor cells were 14-fold less sensitive to the nucleotide. In vivo effectiveness of s(4)UMP was determined using xenograft SCID mouse model. s(4)UMP decreased the cell number and colony forming activity of the total cell content of the femur of SCID mice transplanted with JY cells without affecting the bone marrow of healthy mice. These results suggest that s(4)UMP alone or in combination with other clinically approved anti-leukemic remedies should be further explored as a potential novel therapeutic agent. PMID- 21699886 TI - Current and new insights on phytosterol oxides in plant sterol-enriched food. AB - Over the past 15 years, plant sterol-enriched foods have faced a great increase in the market, due to the asserted cholesterol-lowering effect of plant sterols. However, owing to their chemical structures, plant sterols can oxidize and produce a wide variety of oxidation products with controversial biological effects. Although oxyphytosterols can derive from dietary sources and endogenous formation, their single contribution should be better defined. The following review provides an overall and critical picture on the current knowledge and future perspectives of plant sterols-enriched food, particularly focused on occurrence of plant sterol oxidation products and their biological effects. The final objective of this overview is to evince the different aspects of plant sterols-enriched food that require further research, for a better understanding of the influence of plant sterols and their oxides on consumers' health. PMID- 21699887 TI - Improved prolidase activity assay allowed enzyme kinetic characterization and faster prolidase deficiency diagnosis. AB - BACKGROUND: Prolidase is a metallo-exopeptidase hydrolyzing X-Pro and X-Hyp dipeptides. Its absence or reduced level is typical in prolidase deficiency (PD) patients, and altered prolidase activity was reported in various diseases. Therefore, standardized and accurate measurement of prolidase activity is essential for PD diagnosis, as well as to elucidate the pathophysiology of other disorders. METHODS: Human recombinant prolidase was used to optimize a spectrophotometric enzyme activity assay. Kinetic parameters and Mn(2+) affinity were evaluated. The method was validated on blood and fibroblasts from PD patients. RESULTS: An activation step consisting in prolidase incubation with 1 mmol/l MnCl(2) and 0.75 mmol/l reduced glutathione at 50 degrees C for 20 min was necessary to obtain the maximum activity and to accurately determine, for the recombinant enzyme, V(max) (489 U/mg), K(m) (5.4 mM) and Mn(2+) affinity (54 mM( 1)). The method applied to PD diagnosis revealed an intra-assay CV=8% for blood and 9% for fibroblasts lysates. The inter-assay CV was 21% for blood and 20% for cell lysates. CONCLUSION: We optimized a faster spectrophotometric method to measure the activity when the enzyme is fully activated, this is crucial to allow a reliable evaluation of prolidase activity from different sources. PMID- 21699888 TI - CRP in term and preterm newborns. PMID- 21699889 TI - Adipocytokines, gut hormones and growth factors in anorexia nervosa. AB - Anorexia nervosa is a complex eating disorder of unknown etiology which affects adolescent girls and young women and leads to chronic malnutrition. Clinical manifestations of prolonged semistarvation include a variety of physical features and psychiatric disorders. The study of different biological factors involved in the pathophysiology of anorexia nervosa is an area of active interest. In this review we have described the role of adipocytokines, neurotrophins, peptides of the gastrointestinal system and growth factors in appetite regulation, energy balance and insulin sensitivity in anorexia nervosa patients. PMID- 21699890 TI - Cell differentiation and morphogenesis in the colony-forming choanoflagellate Salpingoeca rosetta. AB - It has been posited that animal development evolved from pre-existing mechanisms for regulating cell differentiation in the single celled and colonial ancestors of animals. Although the progenitors of animals cannot be studied directly, insights into their cell biology may be gleaned from comparisons between animals and their closest living relatives, the choanoflagellates. We report here on the life history, cell differentiation and intercellular interactions in the colony forming choanoflagellate Salpingoeca rosetta. In response to diverse environmental cues, S. rosetta differentiates into at least five distinct cell types, including three solitary cell types (slow swimmers, fast swimmers, and thecate cells) and two colonial forms (rosettes and chains). Electron microscopy reveals that cells within colonies are held together by a combination of fine intercellular bridges, a shared extracellular matrix, and filopodia. In addition, we have discovered that the carbohydrate-binding protein wheat germ agglutinin specifically stains colonies and the slow swimmers from which they form, showing that molecular differentiation precedes multicellular development. Together, these results help establish S. rosetta as a model system for studying simple multicellularity in choanoflagellates and provide an experimental framework for investigating the origin of animal multicellularity and development. PMID- 21699891 TI - Intrathecal propranolol displays long-acting spinal anesthesia with a more sensory-selective action over motor blockade in rats. AB - To prevent cardiovascular effects of peripherally administered propranolol, the aim of this study was to evaluate the spinal anesthetic effect of propranolol, a Na(+/-) channel blocker. After rats were injected with drugs intrathecally, the spinal anesthetic effect of propranolol was compared with that of lidocaine, which is known to produce local anesthesia. We also evaluated the effect of the addition of clonidine with propranolol on spinal anesthesia. Our results showed that propranolol produced a dose-dependent spinal blockade in motor, proprioception, and nociception. On a 50% effective dose (ED(50)) basis, the spinal anesthetic effect of propranolol in motor, proprioception, and nociception [1.16 (1.01-1.34), 1.10 (0.92-1.31), 1.05 (0.89-1.24)] was equal to lidocaine [1.03 (0.94-1.13), 0.95 (0.84-1.07), 0.87 (0.79-0.96)], respectively. On an equipotent basis (0.5, 1.0, 2.5 MUmol), the sensory/nociceptive block duration caused by propranolol was longer than that caused by lidocaine (P<=0.01). Co administration of propranolol (1.1 MUmol) and clonidine (0.5 MUmol) produced greater spinal anesthesia than propranolol (1.1 MUmol) or clonidine (0.5 MUmol) alone. These preclinical findings demonstrated that propranolol produces similar spinal anesthesia to lidocaine and that alpha(2)-adrenergic receptors also contribute to improve the quality and duration of the spinal anesthetic effect of propranolol. Propranolol with a more sensory-selective action over motor blockade elicited longer spinal blockade than did lidocaine. PMID- 21699892 TI - Synaptic plasticity and pain aversion. AB - Negative affective emotions are defined as the conceptual feature of pain. A number of clinical and animal studies have indicated that the limbic system including the anterior cingulate cortex (ACC) and amygdala plays a critical role in the processing of affective components of pain. Glutamatergic transmission plays an important role in the processing of affective aspects of pain. Long-term changes on glutamatergic synapses contribute to the expression of aversion behavior induced by pain. In this article, the neurocircuits involved in the processing of affective aspects of pain, the glutamatergic synaptic plasticity in these brain regions, and the epigenetic mechanisms underlying pain-related synaptic plasticity will be reviewed and discussed. New discoveries regarding the interaction between the synaptic plasticity and affective components of pain may advance our understanding on the pain mechanism, and lead to new strategies for pain treatment. PMID- 21699893 TI - Cytotoxic effect and apoptotic mechanism of tanshinone A, a novel tanshinone derivative, on human erythroleukemic K562 cells. AB - Tanshinone A is a novel derivative of phenanthrene-quinone extracted from Salvia miltiorrhiza BUNGE, a traditional herbal medicine. Cytotoxic effect of tanshinone A was observed in this study. Additionally its mechanism of promoting apoptosis was also investigated. MTT and SRB assays were applied to measure the effects of tanshinone A on the cell viability, the cell cycle distribution and cell apoptosis were measured by flow cytometry using PI staining and Annexin V/PI double staining method respectively. The changes of mitochondrial membrane potential were also detected by flow cytometry. Spectrophotometric method was used to detect the changes of caspase-3 activity. Western blotting assay was used to evaluate the expression of bcl-2, bax and c-Myc proteins. Results indicated that tanshinone A displayed a significant inhibitory effect on the growth of K562 cells in a dose- and time-dependent manner, and showed obvious minor damage to LO2 cells. Tanshinone A could arrest K562 cells in the G(0)/G(1) phase and induce apoptosis, decrease the mitochondrial transmembrane potential, decrease the expressions of bcl-2 and c-Myc proteins, increase the expression of bax protein and the activity of caspase-3. Accordingly, it was presumed that the apoptosis induction may be through the endogenous pathway. Subsequently, tanshinone A could be a promising candidate in the development of a novel antitumor agent. PMID- 21699894 TI - Is there a trigger role of peroxynitrite in the anti-arrhythmic effect of ischaemic preconditioning and peroxynitrite infusion? AB - This study has examined whether peroxynitrite (PN), generated during the preconditioning (PC) procedure or administered by brief intracoronary infusions, plays a trigger role in the anti-arrhythmic effects of preconditioning and peroxynitrite in anaesthetized dogs. To achieve this we infused the peroxynitrite scavenger uric acid (UA; 0.2 mg/kg/min, i.v.) over a 30 min period, just prior to a 25 min occlusion of the left anterior descending coronary artery, in preconditioned (UA+PC, n=8), peroxynitrite-treated (UA+PN, n=8) and in control (UAC; n=9) dogs. The effects were compared to those obtained from groups (PC, n=10; PN, n=10; C1, n=14) without uric acid administration. Severities of ischaemia (ST-segment elevation, inhomogeneity of electrical activation) and ventricular arrhythmias (VPBs, VT, VF), plasma nitrate/nitrite levels, as well as myocardial superoxide and nitrotyrosine productions were determined. Both preconditioning and the infusion of peroxynitrite increased nitrotyrosine formation which was abolished by the simultaneous administration of urate. Despite this, the protective effects of preconditioning (i.e. reductions in arrhythmias, superoxide and nitrotyrosine productions, as well as the increase in nitric oxide availability), occurring during the prolonged period of occlusion and reperfusion were still present. In contrast, urate completely abolished the protection resulted from peroxynitrite administration. This effect is most probably due to the fact that urate has already scavenged peroxynitrite during the infusion. Interestingly, urate itself, given prior to ischaemia and reperfusion, was also protective. We conclude that peroxynitrite in nanomolar concentrations can induce an anti-arrhythmic effect but peroxynitrite, generated during the preconditioning stimulus, is not necessary for the preconditioning induced anti-arrhythmic protection. PMID- 21699895 TI - Carboxymethylated chitosan stimulates proliferation of Schwann cells in vitro via the activation of the ERK and Akt signaling pathways. AB - Proliferation of Schwann cell in the injured peripheral nerve supports axonal regeneration and also is critical for the regeneration of injured nerves. In this publication, carboxymethylated chitosan (CMCS) was studied to determine its capacity (i) to induce proliferation and synthesis of proliferating cell nuclear antigen (PCNA) and (ii) to activate mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) and phosphatidylinositil-3 kinase (PI3K)/Akt signaling pathways in rat Schwann cells. CMCS was found to induce proliferation and PCNA synthesis in Schwann cells in a dose and time dependent manner. CMCS was shown to phosphorylate ERK1/2 and Akt in Schwann cell proliferation. The phosphorylation of ERK1/2 and Akt in Schwann cells was blocked by the MEK inhibitor PD98059 and the PI3K inhibitor wortmannin. In addition, inhibition of the MEK/ERK or the PI3K/Akt signaling pathways significantly decreased the proliferative effects of CMCS in Schwann cells. Overall, the above results indicate that CMCS stimulates proliferation of Schwann cells by activating the intracellular signaling cascades of ERK1/2 and PI3K/Akt. PMID- 21699896 TI - Myelin associated inhibitors: a link between injury-induced and experience dependent plasticity. AB - In the adult, both neurologic recovery and anatomical growth after a CNS injury are limited. Two classes of growth inhibitors, myelin associated inhibitors (MAIs) and extracellular matrix associated inhibitors, limit both functional recovery and anatomical rearrangements in animal models of spinal cord injury. Here we focus on how MAIs limit a wide spectrum of growth that includes regeneration, sprouting, and plasticity in both the intact and lesioned CNS. Three classic myelin associated inhibitors, Nogo-A, MAG, and OMgp, signal through their common receptors, Nogo-66 Receptor-1 (NgR1) and Paired-Immunoglobulin-like Receptor-B (PirB), to regulate cytoskeletal dynamics and inhibit growth. Initially described as inhibitors of axonal regeneration, subsequent work has demonstrated that MAIs also limit activity and experience-dependent plasticity in the intact, adult CNS. MAIs therefore represent a point of convergence for plasticity that limits anatomical rearrangements regardless of the inciting stimulus, blurring the distinction between injury studies and more "basic" plasticity studies. PMID- 21699897 TI - Delayed induction, not impaired recruitment, of specific CD8+ T cells causes the late onset of acute hepatitis C. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is characterized by lack of immune-mediated liver injury despite a high level of HCV replication during the incubation phase, which lasts about 8 weeks. We investigated whether this results from delayed recruitment of HCV-specific T cells and whether it facilitates HCV persistence. METHODS: Six chimpanzees were infected with HCV; blood and liver samples were collected for 28 weeks and analyzed for immune cells and chemokines. RESULTS: Two chimpanzees developed self-limited infections, whereas the remaining 4 developed chronic infections. Levels of the chemokines CXCL10, CXCL11, CCL4, and CCL5 increased in blood and liver samples from all chimpanzees within 1 month of HCV infection. Chemokine induction correlated with intrahepatic type I interferon (IFN) responses in vivo and was blocked by neutralizing antibodies against IFN-beta in vitro. Despite the early-stage induction of chemokines, the intrahepatic lymphocytic infiltrate started to increase no earlier than 8 weeks after HCV infection, when HCV-specific, tetramer-positive CD8(+) T cells appeared in the circulation. The HCV-specific CD8(+) T cells expressed chemokine receptors when they were initially detected in blood samples, so they could be recruited to the liver as soon as they entered the circulation. CONCLUSIONS: Chemokines are induced during early stages of HCV infection, which requires a type I IFN mediated response. The delayed onset of acute hepatitis does not result from delayed recruitment of HCV-specific T cells, but could instead be related to a primary delay in the induction of HCV-specific T cells. Divergent outcomes occur without evident differences in chemokine induction and T-cell recruitment. PMID- 21699898 TI - Oxaliplatin uses JNK to restore TRAIL sensitivity in cancer cells through Bcl-xL inactivation. PMID- 21699899 TI - Irradiated Mesenchymal Stem Cells improve the ex vivo expansion of Hematopoietic Progenitors by partly mimicking the bone marrow endosteal environment. AB - Mesenchymal Stem Cells (MSCs) regulate the growth and differentiation of Hematopoietic Progenitor cells (HPCs) through the release of soluble factors or through their differentiation into osteoblasts. We recently demonstrated that expansion of megakaryocyte (MK) progenitors ex vivo had reached a plateau when CD34(+) cells were grown with two optimized cytokine cocktails developed for the growth of MK. Hence, we sought to determine whether co-culture of CD34(+) cells with Bone Marrow (BM) MSCs could further increase the expansion of myeloid and MK progenitors. First, we tested the impact of cell-cell contact and pre-irradiation treatment of the MSCs to identify the condition that best supports HPC expansion. This screen revealed that HPC expansions were generally greater in the non contact conditions, and that pre-irradiation of the MSCs appeared to be of added benefits. Improved expansion of both myeloid and MK progenitors in co-culture with irradiated MSCs without contact was subsequently confirmed. Next, cytokine array profiling was carried out to investigate why irradiation promoted progenitor expansion. This revealed that the levels of as many as 33 factors were potentially altered. ELISA confirmed the significant up regulation of NT-3 and IGFBP-2. Since, these factors are known to be released by and important for osteogenic and endothelial cells, we investigated and confirmed that irradiation of MSCs induced their rapid differentiation into osteogenic-like cells, but not into endothelial-like cells. Supporting this finding, expansions of myeloid and MK progenitors were increased when CD34(+) cells were co-culture with MSCs derived osteoblasts. Altogether, these results indicate that the improved expansion of HPCs obtained with irradiated MSCs is due in part to their differentiation into osteoblast-like cells, thereby recreating an endosteal-like environment that provides improved support for HPCs expansion. PMID- 21699901 TI - p38alpha MAP kinase dimers with swapped activation segments and a novel catalytic loop conformation. AB - Many protein kinase functions, including autophosphorylation in trans, require dimerization, possibly by activation segment exchange. Such dimers have been reported for a few autophosphorylating protein kinases, but not for mitogen activated protein kinases (MAPKs). Activation of MAPKs proceeds not only via the well-characterized action of dual T/Y specificity MAPK kinases, phosphorylating both residues of the MAPK TxY activation loop motif, but also via a noncanonical activation pathway triggered by phosphorylation at Tyr323 and homodimerization. Here, we report the 2. 7-A-resolution structure of p38alpha MAPK from Salmo salar in a novel domain-swapped homodimeric form. The tyrosines of the conserved sequence YxAPE anchor the swapped activation segments in a configuration suitable for autophosphorylation in trans and provide a model for the noncanonical pathway. In the dimer, a structural unit containing Tyr323 is formed at a dimerization contact region that stabilizes the HRD catalytic loop in a unique inactive geometry. This feature is consistent with the requirement of Tyr323 phosphorylation for the initiation of the noncanonical pathway. Despite the interacting surface of more than 2600 A(2), the dimer is not obligate, as gel filtration shows the dimerization to occur only at relatively high concentrations. The transition from monomer to dimer involves a relatively simple hinged displacement of helix EF and adjacent residues. Thus, dimer formation is likely to be transient, compatible with functional requirements for autophosphorylation, allowing further modulation, for example, by scaffolding mechanisms. PMID- 21699903 TI - FAD-binding site and NADP reactivity in human renalase: a new enzyme involved in blood pressure regulation. AB - Renalase is a recently discovered flavoprotein that regulates blood pressure, regulates sodium and phosphate excretion, and displays cardioprotectant action through a mechanism that is barely understood to date. It has been proposed to act as a catecholamine-degrading enzyme, via either O(2)-dependent or NADH dependent mechanisms. Here we report the renalase crystal structure at 2.5 A resolution together with new data on its interaction with nicotinamide dinucleotides. Renalase adopts the p-hydroxybenzoate hydroxylase fold topology, comprising a Rossmann-fold-based flavin adenine dinucleotide (FAD)-binding domain and a putative substrate-binding domain, the latter of which contains a five stranded anti-parallel beta-sheet. A large cavity (228 A(3)), facing the flavin ring, presumably represents the active site. Compared to monoamine oxidase or polyamine oxidase, the renalase active site is fully solvent exposed and lacks an 'aromatic cage' for binding the substrate amino group. Renalase has an extremely low diaphorase activity, displaying lower k(cat) but higher k(cat)/K(m) for NADH compared to NADPH. Moreover, its FAD prosthetic group becomes slowly reduced when it is incubated with NADPH under anaerobiosis, and binds NAD(+) or NADP(+) with K(d) values of ca 2 mM. The absence of a recognizable NADP-binding site in the protein structure and its poor affinity for, and poor reactivity towards, NADH and NADPH suggest that these are not physiological ligands of renalase. Although our study does not answer the question on the catalytic activity of renalase, it provides a firm framework for testing hypotheses on the molecular mechanism of its action. PMID- 21699902 TI - Roadblock repression of transcription by Bacillus subtilis CodY. AB - CodY is a global transcriptional regulator that is known to control, directly or indirectly, expression of more than 100 genes and operons in Bacillus subtilis. Using a combination of mutational analysis and DNase I footprinting experiments, we identified two high-affinity CodY-binding sites that contribute to repression of the ybgE gene and appear to act independently. One of these sites, located 80 bp downstream of the transcription start site, accounted for the bulk of ybgE repression. Using in vitro transcription experiments, we demonstrated that in the presence of CodY, a shorter-than-expected ybgE transcript that terminates at the downstream CodY-binding site was synthesized. Thus, CodY binding to the downstream site represses transcription by a roadblock mechanism. Similar premature termination of transcription was observed for bcaP and yufN, two other CodY-regulated genes with binding sites downstream of the promoter. In accord with the roadblock mechanism, CodY-mediated repression at downstream sites was partly relieved if the transcription-repair coupling factor Mfd was inactivated. PMID- 21699900 TI - Facioscapulohumeral muscular dystrophy region gene 1 is a dynamic RNA-associated and actin-bundling protein. AB - FSHD region gene 1 (FRG1) is a dynamic nuclear and cytoplasmic protein that, in skeletal muscle, shows additional localization to the sarcomere. Maintaining appropriate levels of FRG1 protein is critical for muscular and vascular development in vertebrates; however, its precise molecular function is unknown. This study investigates the molecular functions of human FRG1, along with mouse FRG1 and Xenopus frg1, using molecular, biochemical, and cellular-biological approaches, to provide further insight into its roles in vertebrate development. The nuclear fraction of the endogenous FRG1 is localized in nucleoli, Cajal bodies, and actively transcribed chromatin; however, contrary to overexpressed FRG1, the endogenous FRG1 is not associated with nuclear speckles. We characterize the nuclear and nucleolar import of FRG1, the potential effect of phosphorylation, and its interaction with the importin karyopherin alpha2. Consistent with a role in RNA biogenesis, human FRG1 is associated with mRNA in vivo and invitro, interacts directly with TAP (Tip-associated protein; the major mRNA export receptor), and is a dynamic nuclear-cytoplasmic shuttling protein supporting a function for FRG1 in mRNA transport. Biochemically, we characterize FRG1 actin binding activity and show that the cytoplasmic pool of FRG1 is dependent on an intact actin cytoskeleton for its localization. These data provide the first biochemical activities (actin binding and RNA binding) for human FRG1 and the characterization of the endogenous human FRG1, together indicating that FRG1 is involved in multiple aspects of RNA biogenesis, including mRNA transport and, potentially, cytoplasmic mRNA localization. PMID- 21699905 TI - Comparison of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockade for the prevention of premalignant changes in the liver. AB - AIM: We investigate and compare the possible antitumor activity of clinically used angiotensin converting enzyme (ACE) inhibitors; captopril, perindopril and angiotensin II type 1 receptor (AT1R) blocker, losartan against hepatocarcinogenesis initiated by diethylnitrosoamines (DENA) and promoted by carbon tetrachloride (CCl(4)). MAIN METHODS: Diethylnitrosamine (DENA) (200mg/kgi.p.) initiated and carbon tetrachloride (CCl(4)) (2ml/kgi.p.) promoted hepatocarcinogenesis in male Wistar rats after 8weeks. RESULTS: Hepatocarcinogenesis was manifested biochemically by elevation of serum hepatic tumor markers tested; alpha-feto protein (AFP) and carcinoembryonic antigen (CEA). In addition, hepatic carcinogenesis was further confirmed by a significant increase in hepatic tissue growth factors; vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF). Moreover a marked increase in matrix metalloproteinase-2 and hydroxyproline content were also observed. Hepatocarcinogenesis was further confirmed by a significant decrease in hepatic endostatin and metallothonein level. KEY FINDINGS: Long-term administration of the selected drugs for 2weeks before and throughout the experimental period produced a significant protection against hepatic carcinogenesis. The present results claimed that different doses of the selected drugs succeeded in normalization of serum tumor markers. Furthermore, the drugs reduced the elevated level in the hepatic growth factors, matrix metalloproteinase-2 and hydroxyproline induced by the hepatocarcinogen. Moreover, the amelioration was also accompanied by augmentation of hepatic content of metallothionein and endostatin. Histopathological examination of liver tissues of rats treated with DENA-CCl(4) correlated with the biochemical observations. SIGNIFICANCE: These findings suggest a similar protective effect of ACE inhibitors; captopril; perindopril and AT1R blocker, losartan against premalignant stages of liver cancer in the DENA initiated and CCl(4) promoted hepatocarcinogenesis model in rats. Therefore, RAS especially angiotensin II (Ang II) and AT1R interaction plays a pivotal role hepatocarcinogenesis development. PMID- 21699904 TI - Varying modulation of HIV-1 LTR activity by Baf complexes. AB - The human immunodeficiency virus type 1 (HIV-1) long terminal repeat is present on both ends of the integrated viral genome and contains regulatory elements needed for transcriptional initiation and elongation. Post-integration, a highly ordered chromatin structure consisting of at least five nucleosomes, is found at the 5' long terminal repeat, the location and modification state of which control the state of active viral replication as well as silencing of the latent HIV-1 provirus. In this context, the chromatin remodeling field rapidly emerges as having a critical role in the control of viral gene expression. In the current study, we focused on unique Baf subunits that are common to the most highly recognized of chromatin remodeling proteins, the SWI/SNF (switching-defective sucrose non-fermenting) complexes. We find that at least two Baf proteins, Baf53 and Baf170, are highly regulated in HIV-1-infected cells. Previously, studies have shown that the depletion of Baf53 in uninfected cells leads to the expansion of chromosomal territories and the decompaction of the chromatin. Baf53, in the presence of HIV-1 infection, co-elutes off of a chromatographic column as a different-sized complex when compared to uninfected cells and appears to be predominantly phosphorylated. The innate function of Baf53-containing complexes appears to be transcriptionally suppressive, in that knocking down Baf53 increases viral gene expression from cells both transiently and chronically infected with HIV-1. Additionally, cdk9/cyclin T in the presence of Tat is able to phosphorylate Baf53 in vitro, implying that this posttranslationally modified form relieves the suppressive effect and allows for viral transcription to proceed. PMID- 21699906 TI - Liver preconditioning induced by iron in a rat model of ischemia/reperfusion. AB - AIMS: Liver preconditioning against ischemia-reperfusion (IR) injury is a major area of experimental research, in which regulation of gene expression with cytoprotective responses due to transient oxidative stress development has been reported. Considering that significant cytoprotection occurs after exposure to low levels of iron (Fe), we tested the hypothesis that sub-chronic administration of Fe to rats underlying transient oxidative stress preconditions the liver against IR injury. MAIN METHODS: Animals received six doses (50 mg Fe-dextran/kg ip) every second day during 10 days, before partial IR (vascular clamping) or sham laparotomy (control). Transient oxidative stress was defined by liver glutathione and protein carbonyl contents (24, 48, and 72 h after Fe treatment). Plasma and liver Fe status and ferritin content (western blot) were assessed in animals not subjected to IR. Liver injury and inflammatory response were evaluated by serum transaminases, liver morphology and serum TNF-alpha. Fe preconditioning against IR injury was correlated with liver glutathione content and the redox-sensitive NF-kappaB signaling pathway (EMSA) and western blot analysis of haptoglobin. KEY FINDINGS: Significant hepatoprotection against IR injury, underlying transient oxidative stress and enhancement in the total and labile Fe pools, was achieved by Fe administration. Abrogation of IR injury is related to reduced TNF-alpha response (91%), abolishment of the IR-induced liver glutathione depletion and recovery of the NF-kappaB signaling pathway (75%), lost during IR. SIGNIFICANCE: Sub-chronic Fe administration protects the liver against IR injury through antioxidant and anti-inflammatory responses, with recovery of NF-kappaB activation and related acute-phase response signaling. PMID- 21699907 TI - Lack of eyeblink entrainments in autism spectrum disorders. AB - Interpersonal synchrony is the temporal coordination of movements between individuals during social interactions. For example, it has been shown that listeners synchronize their eyeblinks to a speaker's eyeblinks, especially at breakpoints of speech, when viewing a close-up video clip of the speaker's face. We hypothesized that this interpersonal synchronous behavior would not be observed in individuals with autism spectrum disorders (ASD), which are characterized by impaired social communication. To test this hypothesis, we examined eyeblink entrainments in adults with ASD. As we reported previously, the eyeblinks of adults without ASD were significantly synchronized with the speaker's eyeblinks at pauses in his speech when they viewed the speaker's entire face. However, the significant eyeblink synchronization disappeared when adults without ASD viewed only the speaker's eyes or mouth, suggesting that information from the whole face, including information from both the eyes and the mouth, was necessary for eyeblink entrainment. By contrast, the ASD participants did not show any eyeblink synchronization with the speaker, even when viewing the speaker's eyes and mouth simultaneously. The lack of eyeblink entrainment to the speaker in individuals with ASD suggests that they are not able to temporally attune themselves to others' behaviors. The deficits in temporal coordination may impair effective social communication with others. PMID- 21699908 TI - Zinc supplementation provides behavioral resiliency in a rat model of traumatic brain injury. AB - Depression, anxiety, and impairments in learning and memory are all associated with traumatic brain injury (TBI). Because of the strong link between zinc deficiency, depression, and anxiety, in both humans and rodent models, we hypothesized that dietary zinc supplementation prior to injury could provide behavioral resiliency to lessen the severity of these outcomes after TBI. Rats were fed a marginal zinc deficient (5 ppm), zinc adequate (30 ppm), or zinc supplemented (180 ppm) diet for 4 weeks followed by a moderately-severe TBI using the well-established model of controlled cortical impact (CCI). Following CCI, rats displayed depression-like behaviors as measured by the 2-bottle saccharin preference test for anhedonia. Injury also resulted in evidence of stress and impairments in Morris water maze (MWM) performance compared to sham-injured controls. While moderate zinc deficiency did not worsen outcomes following TBI, rats that were fed the zinc supplemented diet for 4 weeks showed significantly attenuated increases in adrenal weight (p<0.05) as well as reduced depression like behaviors (p<0.001). Supplementation prior to injury improved resilience such that there was not only significant improvements in cognitive behavior compared to injured rats fed an adequate diet (p<0.01), there were no significant differences between supplemented and sham-operated rats in MWM performance at any point in the 10-day trial. These data suggest a role for supplemental zinc in preventing cognitive and behavioral deficits associated with TBI. PMID- 21699909 TI - Pontine and thalamic influences on fluid rewards: II. Sucrose and corn oil conditioned aversions. AB - In this study conditioned aversions were produced in sham feeding rats to limit postingestive feedback from the oral stimulus. All control rats learned an aversion to either 100% corn oil or 0.3 M sucrose when ingestion of these stimuli was followed by an injection of lithium chloride (LiCl). Rats with lesions of the ventroposteromedial thalamus also learned to avoid either corn oil or sucrose. After 3 trials, rats with damage to the parabrachial nuclei (PBN) learned to avoid 100% corn oil, but failed to do so when the stimulus was 0.3 M sucrose. These results support our hypothesis that the PBN is necessary to appropriately respond to a taste, but not an oil cue as a function of experience (i.e., pairings with LiCl). The results also are consistent with our results from operant tasks demonstrating that the trigeminal thalamus, the ventroposteromedial nucleus, is not required for responding to the rewarding properties of sucrose, oil, or for modifying the response to these stimuli as a function of experience. PMID- 21699910 TI - Simultaneous detection of nine cyanotoxins in drinking water using dual solid phase extraction and liquid chromatography-mass spectrometry. AB - A solid-phase extraction (SPE)-liquid chromatography (LC)-mass spectrometry (MS) method was developed to concentrate and detect nine cyanotoxins simultaneously, including six microcystins (MCs) congeners, nodularin (NOD), anatoxin-a (ATX) and cylindrospermopsin (CYN), in pure and natural waters. A dual cartridge SPE assembly was tested for the operating parameters of cyanotoxin extraction. A surrogate standard (SS), 1,9-diaminononane, was spiked in all the samples before the SPE extraction, and an internal standard (IS), 2,3,5-trimethylphenyl methyl carbamate, was spiked before LC/MS analysis. The method detection limit (MDL) was 2-100 ng/L for nine cyanotoxins in pure water and was increased by a factor of three to ten in a more complicated water matrix. The recoveries based on SS were between 83 and 104%, while those based on IS were 80-120%. The developed method was successfully employed in analyzing 33 water samples collected from eutrophic lakes, water treatment plants and distribution taps. MCs, NOD, and CYN were detected in the reservoir water, with concentrations as high as 36 MUg/L. In addition, for the first time in Taiwan's tap water, CYN was detected at concentrations as high as 8.6 MUg/L. Quality control data for the field samples shows that the analytical scheme developed is appropriate for monitoring cyanotoxins. PMID- 21699911 TI - Age-related changes in the renal dopaminergic system and expression of renal amino acid transporters in WKY and SHR rats. AB - This study examined age-related changes in renal dopaminergic activity and expression of amino acid transporters potentially involved in renal tubular uptake of l-DOPA in Wistar Kyoto (WKY) and spontaneously hypertensive rats. Aging (from 13 to 91 weeks) was accompanied by increases in systolic blood pressure (SBP) in both WKY and SHR. The sum of urinary dopamine and DOPAC and the urinary dopamine/l-DOPA ratio were increased in aged SHR but not in aged WKY. The urinary dopamine/renal delivery of l-DOPA ratio was increased in both rat strains with aging. LAT2 abundance was increased in aged WKY and SHR. The expression of 4F2hc was markedly elevated in aged SHR but not in aged WKY. ASCT2 was upregulated in both aged WKY and SHR. Plasma aldosterone levels and urinary noradrenaline levels were increased in aged WKY and SHR though levels of both entities were more elevated in aged SHR. Activation of the renal dopaminergic system is more pronounced in aged SHR than in aged WKY and is associated with an upregulation of renal cortical ASCT2 in WKY and of LAT2/4F2hc and ASCT2 in SHR. This activation may be the consequence of a counter-regulatory mechanism for stimuli leading to sodium reabsorption. PMID- 21699912 TI - Contribution of mechanical factors to arrhythmogenesis in calcium overloaded cardiomyocytes: model predictions and experiments. AB - It is well-known that Ca2+ overload in cardiomyocytes may underlie arrhythmias. However, the possible contribution of mechanical factors to rhythm disturbances in Ca2+ overloaded myocytes has not been sufficiently investigated. We used a mathematical model of the electrical and mechanical activity of cardiomyocytes to reveal an essential role of the mechanisms of cardiac mechano-electric feedback in arrhythmogenesis in Ca2+ overloaded myocardium. In the model, the following mechanical factors increased Ca2+ overload in contracting cardiomyocytes and promoted rhythm disturbances: i) a decrease in the mechanical load for afterloaded contractions; and ii) a decrease in the initial length of sarcomeres for isometric twitches. In exact accordance with the model predictions, in experiments on papillary muscles from the right ventricle of guinea pigs with Ca2+ overloaded cardiomyocytes (using 0.5-1 MUM of ouabain), we found that emergence of rhythm disturbances and extrasystoles depends on the mechanical conditions of muscle contraction. PMID- 21699913 TI - Carbamazepine inhibits distinct chemoconvulsant-induced seizure-like activity in Dugesia tigrina. AB - Planaria, non-parasitic flatworms, were recently shown to be a simple yet sensitive model for investigating the pharmacology of convulsants and anticonvulsants. The present findings show that three distinct chemoconvulsants, (-)-nicotine, picrotoxin, and N-methyl-D-aspartate (NMDA), induce dose-dependent seizure-like paroxysms in the planarian Dugesia tigrina. Carbamazepine and oxcarbazepine, iminodibenzyl derivatives, exhibit anticonvulsive effects mediated mainly through the inactivation of voltage-gated sodium channels. Apart from these primary molecular targets, both carbamazepine and oxcarbazepine are known to activate gamma-aminobutyric acid type A (GABA(A)) receptors and inhibit NMDA activated glutamate receptors and neuronal nicotinic acetylcholine receptors (nAChRs). The present study shows that in D. tigrina both carbamazepine and oxcarbazepine inhibit chemoconvulsant-induced seizure behaviors in a dose dependent manner. Carbamazepine (100 MUM) decreased by ~65% the cumulative mean planarian seizure-like activity (pSLA) observed in the presence of (-)-nicotine (10 MUM), picrotoxin (5mM), or NMDA (3mM), whereas oxcarbazepine (1 MUM) decreased by 45% the cumulative mean pSLA induced by (-)-nicotine (10MUM). The results demonstrate, for the first time, the anti-seizure pharmacology of carbamazepine and oxcarbazepine in an invertebrate seizure model. PMID- 21699914 TI - Eszopiclone facilitation of the antidepressant efficacy of fluoxetine using a social defeat stress model. AB - This study analyzed the interaction of the sleep aid eszopiclone (ESZ) and antidepressant fluoxetine (FLX) on social defeat stress (SDS) in the mouse. Beta adrenoreceptors, brain-derived neurotrophic factor (BDNF) and cAMP response element binding protein (CREB) expression in the hippocampus and frontal cortex were also analyzed. Subjects were adult male 'intruder' C57/B6 mice that were exposed to a retired 'resident' male breeder ICR mouse in this animal's home cage for a 5 min period for each of 10 consecutive days, and the resident established physical dominance. The following day, all animals were assigned to one of four drug treatment groups, and treatment was given for up to 18 days: vehicle, ESZ only (3mg/kg), FLX (10mg/kg) only, or ESZ+FLX. A social interaction test was given on days 1, 5, 10, and 15 of drug treatment to assess SDS. Results showed that the ESZ+FLX group spent less time in avoidance zones during the interaction test at days 1 and 5, and more time in the interaction zone at day 5 compared to defeated mice given vehicle. All drug treatment groups spent more time in the interaction zone compared to defeated mice given vehicle on day 1 as well as day 10. SDS completely dissipated by the fourth interaction test according to both behavioral measures. Neurochemically, SDS did not produce changes in any marker analyzed. This study shows the combination of ESZ and FLX alleviated SDS, but a neurochemical correlate remains elusive. PMID- 21699915 TI - Peripheral 5-HT1B and 5-HT2A receptors mediate the nociceptive response induced by 5-hydroxytryptamine in mice. AB - While the role of 5-hydroxytryptamine (5-HT, serotonin) in the nociceptive processing has been widely investigated in the central nervous system, information regarding its role in peripheral tissues is still lacking. Noteworthy, 5-HT induces phenotypic changes of nociceptors and peripheral injection induces pain in humans and nociceptive response in rodents. However, local receptors involved in 5-HT effects are not well characterized. Thus, we aimed to investigate the role of 5-HT and some of its receptors in the peripheral nociceptive processing in mice. Intraplantar injection of 5-HT (10, 20 or 40 MUg) into the hind-paw of mice induced paw licking behavior, which was inhibited by previous intraplantar treatment with cyproheptadine (5-HT(1) and 5-HT(2) antagonist; 0.5 or 5 MUg), mianserin (5-HT(2) and 5-HT(6) antagonist; 0.1 MUg), isamoltane (5-HT(1B) antagonist; 0.5 or 5 MUg) and ketanserin (5-HT(2A) antagonist; 0.1 or 1 MUg), but not by BRL 15572 (5-HT(1D) antagonist; 1 or 10 MUg), ondansetron (5-HT(3) antagonist; 1, 5, 10 or 20 MUg) and SB 269970 (5-HT(7) antagonist; 2.5 and 25 MUg). Altogether, these results indicate the local involvement of 5-HT(1), 5-HT(2) and 5-HT(6), especially 5-HT(1B) and 5-HT(2A), in the nociceptive response induced by 5-HT in mice, thus contributing to a better understanding of 5-HT role in the peripheral nociceptive processing. In addition, they also point to important species differences and the need of a wide evaluation of the peripheral nociceptive processing in mice as these animals have been increasingly used in studies investigating the cellular and molecular mechanisms mediating the nociceptive response. PMID- 21699916 TI - Emotion recognition in Huntington's disease: a systematic review. AB - There is increasing interest in the nature of the emotion recognition deficit in Huntington's disease (HD). There are conflicting reports of disproportionate impairments for some emotions in some modalities in HD. A systematic review and narrative synthesis was conducted for studies investigating emotion recognition in HD. Embase, MEDLINE, PsychINFO and Pubmed were searched from 1993 to 2010, and citations and reference lists were searched. 1724 citations were identified. Sixteen studies were included. In manifest HD evidence of impaired recognition of facial expressions of anger was found consistently, although recognition of all negative emotions (facial and vocal) tended to be impaired. In premanifest HD impairments were inconsistent, but are seen in all facial expressions of negative emotion. Inconsistency may represent the variability inherent in HD although may also be due to between-study differences in methodology. Current evidence supports the conclusion that recognition of all negative emotions tends to be impaired in HD, particularly in the facial domain. Future work should focus on using more ecologically-valid tests, and testing inter-modality differences. PMID- 21699917 TI - IgG avidity in differential serodiagnosis of human strongyloidiasis active infection. AB - IgG avidity assays have been developed for several parasitic diseases although there are no researches focused in strongyloidiasis diagnosis. Definitive diagnosis of strongyloidiasis is based on the presence of Strongyloides larvae in stool, but majority of cases involve low and irregular larval output. While limitations of serological assays for strongyloidiasis are well known, characteristics of persons who are misdiagnosed based on negative coproparasitological tests have been little explored. The aim of the present study was to evaluate the use of IgG avidity to detect patients with active strongyloidiasis and to characterize sources of disagreement between serology and coproparasitology. A total of 80 serum samples was analyzed, 40 from patients with Strongyloides larvae in stool (G1) and 40 from individuals with negative coproparasitology, but positive serology (G2). Serum samples were analyzed in an indirect IgG avidity ELISA using urea 6M in serial double dilutions from 1:80 to 1:2560. Avidity index (AI) was calculated to each serum dilution and analyzed as screening AI (serum dilution of 1:160) or mean AI of different serum dilutions that had a positive result. Statistical analyzes were performed by Mann-Whitney's (U) and Fisher's exact tests. At screening dilution, median of AI was 68% in G1 and 88% in G2 (P<0.0001), whereas median of mean AI in G1 was 72% and in G2 94% (P<0.0001), but there was no significant differences between both AI in each patient group. A cut off value established at AI of 75% demonstrated a significant difference between groups, with G1 sera showing AI<75% and G2 sera with AI>75% (P<0.0001). In conclusion, IgG avidity assays may distinguish active infection with Strongyloides stercoralis from suspect or serologically false positive cases. PMID- 21699918 TI - Identification of epitopes in Indian human papilloma virus 16 E6: a bioinformatics approach. AB - HPV-16 is reported as the cause of cervical and other related carcinomas. The early expressed protein E6 in cancer cells is found to be the target for immune therapeutic methods. The sequence of HPV-16 E6 (Accession No: ABK32509) from NCBI databank has been taken for this study. Hydrophilicity, flexibility, accessibility, turns, exposed surface, polarity and antigenic propensity scales were used for the B cell epitope prediction. MHC Class I and Class II alleles for the accession were predicted by the MHCPred 2.0 Program. The epitope sequences were also found out. Computer-based prediction program results show, A0203 and DRB0101 lower IC50 than other alleles. The best peptide binding affinity was 21HLCTELQTT30 of A0203 allele. In DRB0101 allele the peptide found was 39YCKQQLLRR48. Different structural features of the protein have also been predicted including glycosylation, kinase C phosphorylation, casein kinase II phosphorylation and N-myristylation sites. These computational prediction programs show four glycosylation, five kinase C phosphorylation, two casein kinase II phosphorylation, zero N-myristylation sites and seven disulphide sites. Development and approval of new vaccines are the keys for control of cancer. Epitopes and other structural features of protein prediction could be the best source of information and can help in molecular and medical studies of viral infection and development of HPV associated cancer drugs. PMID- 21699919 TI - In vitro inhibition of CSFV replication by multiple siRNA expression. AB - Classical swine fever (CSF) is a highly contagious viral disease of pigs which causes major economic losses worldwide. No specific drug is currently available for the effective treatment of CSFV infection; however, RNA interference (RNAi) has been applied successfully to inhibit the replication of human and other animal viruses. In this study, three effective siRNAs targeting NS3 of CSFV were selected. siNS3-2 targeting NS3 gene was chosen for further experimentation, while siN1 and siN2 targeting N(pro) gene, and siNS5B targeting NS5B gene describe previously. Single, double and quadruple anti-CSFV siRNA expression plasmids, with loxp sites at each end of the selectable marker genes, were constructed and analyzed using the same promoters or four different promoters, targeting N(pro), NS3 and NS5B genes of CSFV. Results indicate that single or multiple siRNA expression plasmids can efficiently inhibit CSFV replication and that inhibition was markedly stronger when multiple siRNAs were expressed targeting different genes of CSFV. Since RNAi applied to anti-CSFV research, this study provides anti-CSFV methods by single and multiple siRNA expression which can target most viral isolates of different subtypes and prevent viral escape. It also provides a basis for development of CSFV-resistant transgenic pigs. PMID- 21699920 TI - Prospects of control and eradication of capripox from the Indian subcontinent: a perspective. AB - Sheeppox and goatpox, two endemic capripox infections in India, pose a significant economic threat to small ruminant productivity in the subcontinent. Vaccination of all susceptible sheep and goats is the feasible and sustainable means of control. Availability of effective live attenuated vaccines that are inherently thermostable and development of improved diagnostics provide the opportunities to initiate effective control measures for capripox. All animals older than 4 months can be vaccinated with the current homologous vaccines using a single vaccination by intradermal or subcutaneous routes. The success of the control program needs to be monitored by active surveillance particularly for the presence of virus, as sero-monitoring does not enable the differentiation of infection and vaccination. And also the sero-conversion following capripox vaccination is not detectable enough by the available tools. Sustained control efforts call for socio-economic and political stability, adequate infrastructure and logistic support to store and transport vaccines for reaching out vaccines to the remote end users. Availability of veterinary services, improved extension services for increased awareness among farmers, contribute significantly to the control campaigns. Poor vaccination coverage and in-adequate infrastructure in major parts of the country are some of the major elements that come in the way of effective implementation of building herd immunity through immunization. PMID- 21699922 TI - Neural networks associated with the speed-accuracy tradeoff: evidence from the response signal method. AB - This functional neuroimaging (fMRI) study examined the neural networks (spatial patterns of covarying neural activity) associated with the speed-accuracy tradeoff (SAT) in younger adults. The response signal method was used to systematically increase probe duration (125, 250, 500, 1000 and 2000 ms) in a nonverbal delayed-item recognition task. A covariance-based multivariate approach identified three networks that varied with probe duration--indicating that the SAT is driven by three distributed neural networks. PMID- 21699924 TI - An optimized method for suicide vector-based allelic exchange in Klebsiella pneumoniae. AB - Klebsiella pneumoniae is an important and versatile bacterium that can be found in diverse environments and is also a frequent cause of human infections. Limited data exists on the mechanisms of interaction between K. pneumoniae and the human host and of adaptations to other environments. Coupled with the high genetic diversity of this species, these factors highlight the necessity for substantial further K. pneumoniae-focused molecular genetics studies. In this report we describe a simple and efficient experimental protocol for suicide vector-based allelic exchange in K. pneumoniae. The protocol has been validated by mutating multiple loci in four distinct K. pneumoniae strains, including highly capsulated and/or multi-antibiotic resistant clinical isolates. Three key enhancements are reported:(1) Use of pDS132-derived conjugative plasmids carrying improved cloning sites, (2) Performance of sacB counterselection at 25 degrees C as opposed to higher temperatures, and (3) Exploitation of Flp-recombinase-mediated deletion of FRT (Flp recombinase target) flanked resistance cassettes to allow for reiterative manipulations with a single selectable marker. This study also highlights a problem that may be encountered when the aacC1 gentamicin resistance marker is used in K. pneumoniae and suggests alternative markers. The protocol developed in this study will help investigate the plethora of uncharacterized genes present in the K. pneumoniae pan-genome and shed further light upon clinically and industrially important phenotypes observed in this ubiquitous species. PMID- 21699921 TI - Minigenomes, transcription and replication competent virus-like particles and beyond: reverse genetics systems for filoviruses and other negative stranded hemorrhagic fever viruses. AB - Reverse-genetics systems are powerful tools enabling researchers to study the replication cycle of RNA viruses, including filoviruses and other hemorrhagic fever viruses, as well as to discover new antivirals. They include full-length clone systems as well as a number of life cycle modeling systems. Full-length clone systems allow for the generation of infectious, recombinant viruses, and thus are an important tool for studying the virus replication cycle in its entirety. In contrast, life cycle modeling systems such as minigenome and transcription and replication competent virus-like particle systems can be used to simulate and dissect parts of the virus life cycle outside of containment facilities. Minigenome systems are used to model viral genome replication and transcription, whereas transcription and replication competent virus-like particle systems also model morphogenesis and budding as well as infection of target cells. As such, these modeling systems have tremendous potential to further the discovery and screening of new antivirals targeting hemorrhagic fever viruses. This review provides an overview of currently established reverse genetics systems for hemorrhagic fever-causing negative-sense RNA viruses, with a particular emphasis on filoviruses, and the potential application of these systems for antiviral research. PMID- 21699923 TI - Chronic epigallocatechin-3-gallate ameliorates learning and memory deficits in diabetic rats via modulation of nitric oxide and oxidative stress. AB - Due to anti-diabetic and antioxidant activity of green tea epigallocatechin gallate (EGCG) and the existence of evidence for its beneficial effect on cognition and memory, this research study was conducted to evaluate, for the first time, the efficacy of chronic EGCG on alleviation of learning and memory deficits in streptozotocin (STZ)-diabetic rats. Male Wistar rats were divided into control, diabetic, EGCG-treated-control and -diabetic groups. EGCG was administered at a dose of 20 and 40 mg/kg/day for 7 weeks. Learning and memory was evaluated using Y maze, passive avoidance, and radial 8-arm maze (RAM) tests. Oxidative stress markers and involvement of nitric oxide system were also evaluated. Alternation score of the diabetic rats in Y maze was lower than that of control and a significant impairment was observed in retention and recall in passive avoidance test (p<0.01) and EGCG treatment (40 mg/kg) of diabetic rats significantly improved these parameters (p<0.05). Also, diabetic animals exhibited fewer correct choices (p<0.01) and more errors (p<0.005) in the RAM task and EGCG (40 mg/kg) significantly ameliorated these changes (p<0.05). Further, pretreatment with l-arginine as a substrate for nitric oxide synthase (NOS) and/or 7-nitroindazole as a neuronal NOS inhibitor attenuated and potentiated the beneficial effect of EGCG regarding learning and memory respectively. Meanwhile, increased levels of malondialdehyde (MDA) and nitrite in diabetic rats significantly reduced due to EGCG treatment (p<0.05). In summary, chronic green tea EGCG dose-dependently could ameliorate learning and memory deficits in STZ-diabetic rats through attenuation of oxidative stress and modulation of NO. PMID- 21699925 TI - Evaluation of MALDI-TOF MS as a tool for high-throughput dereplication. AB - The present study examined the suitability of matrix assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) for the rapid grouping of bacterial isolates, i.e. dereplication. Dereplication is important in large-scale isolation campaigns and screening programs since it can significantly reduce labor intensity, time and costs in further downstream analyses. Still, current dereplication techniques are time consuming and costly. MALDI-TOF MS is an attractive tool since it performs fast and cheap analyses with the potential of automation. However, its taxonomic resolution for a broad diversity of bacteria remains largely unknown. To verify the suitability of MALDI TOF MS for dereplication, a total of 249 unidentified bacterial isolates retrieved from the rhizosphere of potato plants, were analyzed with both MALDI TOF MS and repetitive element sequence based polymerase chain reaction (rep-PCR). The latter technique was used as a benchmark. Cluster analysis and inspection of the profiles showed that for 204 isolates (82%) the taxonomic resolution of both techniques was comparable, while for 45 isolates (18%) one of both techniques had a higher taxonomic resolution. Additionally, 16S rRNA gene sequence analysis was performed on all members of each delineated cluster to gain insight in the identity and sequence similarity between members in each cluster. MALDI-TOF MS proved to have higher reproducibility than rep-PCR and seemed to be more promising with respect to high-throughput analyses, automation, and time and cost efficiency. Its taxonomic resolution was situated at the species to strain level. The present study demonstrated that MALDI-TOF MS is a powerful tool for dereplication. PMID- 21699926 TI - GDNF-pretreatment enhances the survival of neural stem cells following transplantation in a rat model of Parkinson's disease. AB - Cell transplantation has been shown to be an effective therapy for central nervous system disorders in animal models. Improving the efficacy of cell transplantation depends critically on improving grafted cell survival. We investigated whether glial cell line-derived neurotrophic factor (GDNF) pretreatment of neural stem cells (NSCs) enhanced grafted cell survival in a rat model of Parkinson's disease (PD). We first examined the neuroprotective effects of GDNF on oxygen-glucose deprivation (OGD) in NSCs. Cells were pretreated with GDNF for 3 days before subjecting them to OGD. After 12h of OGD, GDNF-pretreated NSCs showed significant increases in survival rates compared with PBS-pretreated NSCs. An apoptosis assay showed that the number of apoptotic cells was significantly decreased in GDNF-pretreated NSCs at 1h and 6h after OGD. A PD rat model was then established by unilateral injection of 6-hydroxydopamine (6-OHDA, 9MUg) into the medial forebrain bundle. Two weeks after 6-OHDA injection, GDNF pretreated NSCs, PBS-pretreated NSCs, or PBS were injected into PD rat striatum. The survival of grafted cells in the striatum was significantly increased in the GDNF-pretreated NSC group compared with the control groups. GDNF pretreatment increased survival of NSCs following transplantation, at least partly through suppression of cell apoptosis. PMID- 21699927 TI - Effects of NADH-preferring xylose reductase expression on ethanol production from xylose in xylose-metabolizing recombinant Saccharomyces cerevisiae. AB - Efficient conversion of xylose to ethanol is an essential factor for commercialization of lignocellulosic ethanol. To minimize production of xylitol, a major by-product in xylose metabolism and concomitantly improve ethanol production, Saccharomyces cerevisiae D452-2 was engineered to overexpress NADH preferable xylose reductase mutant (XR(MUT)) and NAD+-dependent xylitol dehydrogenase (XDH) from Pichia stipitis and endogenous xylulokinase (XK). In vitro enzyme assay confirmed the functional expression of XR(MUT), XDH and XK in recombinant S. cerevisiae strains. The change of wild type XR to XR(MUT) along with XK overexpression led to reduction of xylitol accumulation in microaerobic culture. More modulation of the xylose metabolism including overexpression of XR(MUT) and transaldolase, and disruption of the chromosomal ALD6 gene encoding aldehyde dehydrogenase (SX6(MUT)) improved the performance of ethanol production from xylose remarkably. Finally, oxygen-limited fermentation of S. cerevisiae SX6(MUT) resulted in 0.64 g l-1 h-1 xylose consumption rate, 0.25 g l-1 h-1 ethanol productivity and 39% ethanol yield based on the xylose consumed, which were 1.8, 4.2 and 2.2 times higher than the corresponding values of recombinant S. cerevisiae expressing XR(MUT), XDH and XK only. PMID- 21699928 TI - Poly(beta-amino ester)-DNA complexes: time-resolved fluorescence and cellular transfection studies. AB - A large number of different polymers have been developed and studied for application as DNA carriers for non-viral gene delivery, but the DNA binding properties are not understood. This study describes the efficiency of nanoparticle formation by time-resolved fluorescence measurements for poly(beta amino esters), cationic biodegradable polymers with DNA complexation and transfection capability. From the large library of poly(beta-amino esters) ten polymers with different transfection efficacies were chosen for this study. The binding constants for nanoparticle formation were determined and compared to with the same method. Although the DNA binding efficiency of the amine groups are similar for both types of polymers, the overall binding constants are an order of magnitude smaller for poly(beta-amino esters) than for 25 kDa polyethylenimines, yet poly(beta-amino esters) show comparable DNA transfection efficacy with polyethylenimines. Within this series of polymers the transfection efficacy showed increasing trend in association with relative efficiency of nanoparticle formation. PMID- 21699929 TI - Viral genome DNA/lipoplexes elicit in situ oncolytic viral replication and potent antitumor efficacy via systemic delivery. AB - Modifying the viral genome to express potent and cancer-selective therapeutic genes has enhanced the role of adenoviruses (Ads) in cancer molecular therapeutics. However, the efficacy of Ad systemic delivery in vivo is limited by neutralizing antibodies, short blood circulation time, and high levels of nonspecific liver uptake resulting in hepatotoxicity. We therefore investigated the systemic delivery of tumor necrosis factor-related apoptosis-inducing ligand expressing oncolytic Ad genome DNA (pmT-d19/stTR) via lipid envelopment as an alternative approach for cancer virotherapy in an orthotopic lung cancer model. Cationic liposomes (DOTAP/DOPE) were complexed with pmT-d19/stTR to generate pmT d19/stTR+DOTAP/DOPE with the average diameter of which was 143.3 +/- 5.7 nm at the optimal DNA:lipid ratio (1:6). Systemic administration of pmT d19/stTR+DOTAP/DOPE elicited highly effective antitumor responses in vivo, with tumor volumes decreasing 94.5%, 90.5%, and 92.4% compared to phosphate buffered saline-, naked Ad (mT-d19/stTR)-, or pmT-d19/stTR-treated groups, respectively. Additionally, innate immune responses and Ad-specific neutralizing antibodies were significantly decreased in pmT-d19/stTR+DOTAP/DOPE-treated mice compared to those in the mT-d19/stTR-treated group. The biodistribution profile analyzed by quantitative-PCR and immunohistochemical analysis demonstrated that viral replication occurred preferentially in tumor tissues. Moreover, the viral genome tumor-to-liver ratio was significantly elevated in pmT-d19/stTR+DOTAP/DOPE treated mice, which was 934- and 27-fold greater than the mT-d19/stTR- and pmT d19/stTR-treated mice, respectively. These results demonstrate that systemic delivery of oncolytic viral genome DNA with liposomes is a powerful alternative to naked Ad, overcoming the limited clinical applicability of conventional Ads and enabling effective treatment of disseminated metastatic tumors. PMID- 21699930 TI - Design and cellular internalization of genetically engineered polypeptide nanoparticles displaying adenovirus knob domain. AB - Hepatocytes and acinar cells exhibit high-efficiency, fiber-dependent internalization of adenovirus; however, viral capsids have unpredictable immunological effects and are challenging to develop into targeted drug carriers. To exploit this internalization pathway and minimize the use of viral proteins, we developed a simple gene product that self assembles nanoparticles decorated with the knob domain of adenovirus serotype 5 fiber protein. The most significant advantages of this platform include: (i) compatibility with genetic engineering; (ii) no bioconjugate chemistry is required to link fusion proteins to the nanoparticle surface; and (iii) it can direct the reversible assembly of large nanoparticles, which are monodisperse, multivalent, and biodegradable. These particles are predominantly composed from diblock copolymers of elastin-like polypeptide (ELP). ELPs have unique phase transition behavior, whereby they self assemble above a transition temperature that is simple to control. The diblock ELP described contains two motifs with distinct transition temperatures, which assemble nanoparticles at physiological temperatures. Analysis by non-denaturing PAGE demonstrated that the purified knob-ELP formed trimers or dimers, which is a property of the native knob/fiber protein. Dynamic light scattering indicated that the diblock copolymer, with or without knob, is able to self assemble into nanoparticles ~40 nm in diameter. To examine the functionality of knob-ELP, their uptake was assessed in a hepatocyte cell-line that expresses the receptor for adenovirus serotype 5 fiber and knob, the coxsackievirus and adenovirus receptor (CAR). Both plain ELP and knob-ELP were bound to the outside of hepatocytes; however, the knob-ELP fusion protein exhibits more internalization and localization to lysosomes of hepatocytes. These findings suggest that functional fusion proteins may only minimally influence the assembly temperature and diameter of ELP nanoparticles. These results are a proof-of-principal that large fusion proteins (>10 kDa) can be assembled by diblock ELPs without the need for bioconjugate chemistry, which greatly simplifies the design and evaluation of targeted drug carriers. PMID- 21699931 TI - RAFT-synthesized graft copolymers that enhance pH-dependent membrane destabilization and protein circulation times. AB - Here we describe a new graft copolymer architecture of poly(propylacrylic acid) (polyPAA) that displays potent pH-dependent, membrane-destabilizing activity and in addition is shown to enhance protein blood circulation kinetics. PolyPAA containing a single telechelic alkyne functionality was prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization with an alkyne functional chain transfer agent (CTA) and coupled to RAFT polymerized poly(azidopropyl methacrylate) (polyAPMA) through azide-alkyne [3 + 2] Huisgen cycloaddition. The graft copolymers become membrane destabilizing at endosomal pH values and are active at significantly lower concentrations than the linear polyPAA. A biotin terminated polyPAA graft copolymer was prepared by grafting PAA onto polyAPMA polymerized with a biotin functional RAFT CTA. The blood circulation time and biodistribution of tritium labeled avidin conjugated to the polyPAA graft copolymer was characterized along with a clinically utilized 40kDa branched polyethylene glycol (PEG) also possessing biotin functionalization. The linear and graft polyPAA increase the area under the curve (AUC) over avidin alone by 9 and 12 times, respectively. Furthermore, polyPAA graft copolymer conjugates accumulated in tumor tissue significantly more than the linear polyPAA and the branched PEG conjugates. The collective data presented in this report indicate that the polyPAA graft copolymers exhibit robust pH-dependent membrane destabilizing activity, low cytotoxicity, significantly enhanced blood circulation time, and increased tumor accumulation. PMID- 21699932 TI - Design of multi-drug release coatings targeting infection and inflammation. AB - Although infection and inflammation commonly coexist, there is a paucity of appropriate methods for concurrent localized delivery of antibiotics and non steroidal anti-inflammatory drugs (NSAIDs) at appropriate concentrations and timescales. The commonly used therapeutic approach of systemic delivery of antibiotics and NSAIDs is associated with many complications, including rises in antibiotic resistant bacteria and severe gastrointestinal problems. As a potential solution, in this work we have assembled polymer multilayers to concurrently release therapeutic concentrations of an antibiotic, vancomycin, and an NSAID, diclofenac. Prior to film assembly, interactions between film components were thoroughly examined. Taking advantage of novel interactions found to exist between film components, several optimal film architectures were engineered using both dip and spray layer-by-layer assembly. A wide range of drug release profiles were obtained, with vancomycin delivery lasting from 4 hours to 2.3 days at final loadings of 13 to 30 MUg/cm(2), while diclofenac released over 1.7 to 14 days at final loadings of 10 to 36 MUg/cm(2). These drug release profiles have the potential to address a range of infection and inflammation requirements, from short term infection and inflammation eradication for trauma relief to infection prevention and long term inflammation mitigation from biomedical implants. Film-released vancomycin and diclofenac were found to be highly active against their respective targets in vitro, Staphylococcus aureus and cyclooxygenase. These films were also successfully applied to several medically relevant substrates, including intraocular lenses, bandages, and sutures, demonstrating potential for use as medical device coatings. PMID- 21699933 TI - Biodegradable star HPMA polymer-drug conjugates: Biodegradability, distribution and anti-tumor efficacy. AB - Herein, new biodegradable star polymer-doxorubicin conjugates designed for passive tumor targeting were investigated, and their synthesis, physico-chemical characterization, drug release, biodegradation, biodistribution and in vivo anti tumor efficacy are described. In the conjugates, the core formed by poly(amidoamine) (PAMAM) dendrimers was grafted with semitelechelic N-(2 hydroxypropyl)methacrylamide (HPMA) copolymers bearing doxorubicin (Dox) attached by hydrazone bonds, which enabled intracellular pH-controlled drug release. The described synthesis facilitated the preparation of biodegradable polymer conjugates in a broad range of molecular weights (200-1000g/mol) while still maintaining low polydispersity (~1.7). The polymer grafts were attached to the dendrimers through either stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high-molecular weight polymer carrier to excretable products. Biodegradability tests in suspensions of EL4 T-cell lymphoma cells showed that the rate of degradation was much faster for reductively degradable conjugates (close to completion within 24h of incubation) than for conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (slow degradation taking several days). This finding was likely due to the differences in steric hindrance in terms of the accessibility of the small molecule glutathione and the bulky enzyme cathepsin B to the polymer substrate. Regarding drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin under mild acidic conditions that model the tumor cell microenvironment. The star polymer-Dox conjugates exhibited significantly prolonged blood circulation and enhanced tumor accumulation in tumor-bearing mice, indicating the important role of the EPR effect in its anti-cancer activity. The star polymer conjugates showed prominently higher in vivo anti-tumor activities than the free drug or linear polymer conjugate when tested in mice bearing EL4 T-cell lymphoma, with a significant number of long-term surviving (LTS). Based on the results, we conclude that a M(w) of HPMA copolymers of 200,000 to 600,000g/mol is optimal for polymer carriers designed for the efficient passive targeting to solid tumors. In addition, an expressive therapy-dependent stimulation of the immune system was observed. PMID- 21699935 TI - Efficient topical delivery of plasmid DNA to lung in vivo mediated by putative triggered, PEGylated pDNA nanoparticles. AB - Non-viral vectors are considered safer than viral vectors and show clinical potential, but remain less efficient in terms of DNA delivery. Here we report how cationic liposomes, prepared from new cationic lipid, N',N',-dioctadecyl-N-4,8 diaza-10-aminodecanoylglycine amide (DODAG) and neutral lipid dioleoyl-L-alpha phos-phatidylethanolamine (DOPE), can be formulated with plasmid DNA (pDNA) in the presence of stabilizer cholesteryl-oxycarbonylpolyethlylene glycol(4600) (PEG(4600)-Chol) giving PEGylated pDNA nanoparticles (pDNA-ABC nanoparticles) that are proposed to be half-life triggered nanoparticles. In particular, the PEGylated pDNA nanoparticle formulation DODAG/DOPE/PEG(4600)-Chol (43:43:14, m/m/m)-pDNA (total lipid/pDNA ratio 4:1 w/w) (pTRANSplus nanoparticles) is shown to mediate efficient transfection of murine lung tissue in vivo. Levels of transfection compare well with the results of polyethylenimine (PEI) mediated pDNA transfection in vivo and even of adenovirus mediated transduction. Cryo-EM imaging indicates that pTRANSplus formulations are somewhat heterogeneous but do consist primarily of bilammellar lipoplex nanoparticles with a few multilammellar nanoparticle aggregates. Lung histology confirms that pTRANSplus mediated transfection in vivo targets substantially the epithelial cells of bronchii and bronchioli airway passages. The pTRANSplus nanoparticle system is a useful new starting point for nucleic acid therapeutic strategies to counter lung disorders such as viral infection and possibly cystic fibrosis. PMID- 21699934 TI - Advanced molecular design of biopolymers for transmucosal and intracellular delivery of chemotherapeutic agents and biological therapeutics. AB - Hydrogels have been instrumental in the development of polymeric systems for controlled release of therapeutic agents. These materials are attractive for transmucosal and intracellular drug delivery because of their facile synthesis, inherent biocompatibility, tunable physicochemical properties, and capacity to respond to various physiological stimuli. In this contribution, we outline a multifaceted hydrogel-based approach for expanding the range of therapeutics in oral formulations from classical small-molecule drugs to include proteins, chemotherapeutics, and nucleic acids. Through judicious material selection and careful design of copolymer composition and molecular architecture, we can engineer systems capable of responding to distinct physiological cues, with tunable physicochemical properties that are optimized to load, protect, and deliver valuable macromolecular payloads to their intended site of action. These hydrogel carriers, including complexation hydrogels, tethered hydrogels, interpenetrating networks, nanoscale hydrogels, and hydrogels with decorated structures are investigated for their ability to respond to changes in pH, to load and release insulin and fluorescein, and remain non-toxic to Caco-2 cells. Our results suggest these novel hydrogel networks have great potential for controlled delivery of proteins, chemotherapeutics, and nucleic acids. PMID- 21699936 TI - Introduction to nanocoatings produced by layer-by-layer (LbL) self-assembly. AB - Studies on the adsorption of oppositely charged colloidal particles ultimately resulted in multilayered polyelectrolyte self-assembly. The inception of layer-by layer constructed particles facilitated the production of multifunctional, stimuli-responsive carrier systems. An array of synthetic and natural polyelectrolytes, metal oxides and clay nanoparticles is available for the construction of multilayered nanocoats on a multitude of substrates or removable cores. Numerous substrates can be encapsulated utilizing this technique including dyes, enzymes, drugs and cells. Furthermore, the outer surface of the particles presents and ideal platform that can be functionalized with targeting molecules or catalysts. Some processing parameters determining the properties of these successive self-assembly constructs are the surface charge density, coating material concentration, rinsing and drying steps, temperature and ionic strength of the medium. Additionally, the simplicity of the layer-by-layer assembly technique and the availability of established characterization methods, render these constructs extremely versatile in applications of sensing, encapsulation and target- and trigger-responsive drug delivery. PMID- 21699937 TI - Role of the lymphatics in cancer metastasis and chemotherapy applications. AB - The lymphatic system was first described centuries ago. The recent discovery of various molecular markers has allowed for more in-depth research of the lymphatic system and its role in health and disease. The lymphatic system has recently been elucidated as playing an active role in cancer metastasis. The knowledge of the active processes involved in lymphatic metastasis provides novel treatment targets for various malignancies. PMID- 21699938 TI - Protein ultrastructure and the nanoscience of complement activation. AB - The complement system constitutes an important barrier to infection of the human body. Over more than four decades structural properties of the proteins of the complement system have been investigated with X-ray crystallography, electron microscopy, small-angle scattering, and atomic force microscopy. Here, we review the accumulated evidence that the nm-scaled dimensions and conformational changes of these proteins support functions of the complement system with regard to tissue distribution, molecular crowding effects, avidity binding, and conformational regulation of complement activation. In the targeting of complement activation to the surfaces of nanoparticulate material, such as engineered nanoparticles or fragments of the microbial cell wall, these processes play intimately together. This way the complement system is an excellent example where nanoscience may serve to unravel the molecular biology of the immune response. PMID- 21699939 TI - Neuropeptide Y modulates functions of inflammatory cells in the rat: distinct role for Y1, Y2 and Y5 receptors. AB - Neuropeptide Y (NPY) has been reported to be a potent anti-inflammatory peptide with ability to directly modulate activity of granulocytes and macrophages. The present study aimed to correlate the effects of NPY in vivo on lipopolysaccharide induced air-pouch exudates cells and in vitro on peripheral blood leukocytes functions. The role of different Y receptors was examined using NPY-related peptides and antagonists with diverse subtype specificity and selectivity for Y receptors. Y1, Y2 and Y5 receptors were detected on air-pouch exudates cells (flow cytometry) and peripheral blood granulocytes (immunocytochemistry). NPY in vivo reduced inflammatory cells accumulation into the air pouch, and decreased their adherence and phagocytic capacity via Y2/Y5 and Y1/Y2 receptors, respectively. Quite the opposite, NPY in vitro potentiated adhesiveness and phagocytosis of peripheral blood granulocytes and monocytes by activating Y1 receptor. The differences between in vivo and in vitro effects of NPY on rat inflammatory cells functions are mostly due to dipeptidyl peptidase 4 activity. In addition, suppressive effect of NPY in vivo is highly dependent on the local microenvironment, peptide truncation and specific Y receptors interplay. PMID- 21699941 TI - Activation of neural precursors in the adult neurogenic niches. AB - The generation of new neurons within the dentate gyrus of the mature hippocampus is critical for spatial learning, object recognition and memory, whereas new neurons born in the subventricular zone (SVZ) contribute to olfactory function. Adult neurogenesis is a multistep process that begins with the activation and proliferation of a pool of stem/precursor cells. Although the presence of self renewing and multipotent neural precursors is well established in the SVZ, it is only recently that the existence of such a precursor population has been demonstrated in the hippocampus, the region of the brain involved in learning and memory. Determining how this normally latent pool can be activated therefore offers considerable potential for the development of targeted neurogenic-based therapeutics to ameliorate the cognitive decline associated with hippocampal dysfunction in several neurodegenerative diseases. In this review, we summarize the effects of neural activity, various molecular factors and pharmaceutical agents, as well as voluntary exercise, in activating endogenous neural precursors in the two neurogenic niches of the adult brain, and highlight the role of activation-driven enhancement of neurogenesis for the treatment of psychiatric illness and aging dementia. PMID- 21699943 TI - Autoimmune and inflammatory responses in Kashin-Beck disease compared with rheumatoid arthritis and osteoarthritis. AB - To examine plasma levels of arthritis-related autoantibodies and inflammatory factors in Kashin-Beck disease (KBD) patients compared with rheumatoid arthritis (RA) patients, osteoarthritis (OA) patients, and healthy controls, the plasma levels of autoantibodies to types II, IX, and XI collagen and cyclic citrullinated peptide (CCP) and immunoglobulin (Ig)-G and IgM rheumatoid factors (IgG-RF and IgM-RF) from 45 KBD patients, 39 RA patients, 46 OA patients, and 30 healthy controls were determined by enzyme-linked immunosorbent assay. The plasma concentrations of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) were measured using the Griess method and bioassay, respectively. Statistical analysis was performed using one-way analysis of variance followed by the least significant difference t test for differences among groups. Results indicated that the plasma levels of collagen IX antibodies, IgG-RF, and NO significantly increased in KBD patients compared with patients with RA and OA and the control group. The levels of collagen XI antibodies, CCP antibodies, and IgM-RF but not collagen II antibodies and TNF-alpha were significantly increased in the plasma of the KBD group compared with that of the control group. We conclude that autoimmunity and inflammation may be involved in the pathogenesis of KBD, in particular in the advanced stage. PMID- 21699942 TI - Human myeloid dendritic cells are refractory to tryptophan metabolites. AB - The enzyme indoleamine 2,3-dioxygenase (IDO) degrades the essential amino acid tryptophan and is expressed, among other cell types, in immune cells such as dendritic cells (DCs), monocytes, and macrophages. It has been shown that the activity of IDO has a broad regulatory function in the immune system by inhibiting effector T-cell responses, inducing regulatory T cells and facilitating the development of regulatory DCs. The degradation of tryptophan has 2 consequences, both of which have been postulated to be physiologically relevant, namely the reduction of tryptophan levels and the accumulation of tryptophan catabolites. Recently, we have shown that DCs that had differentiated under low-tryptophan conditions acquire a tolerogenic phenotype with increased expression of the inhibitory receptors immunoglobulin-like transcript 2 (ILT2), ILT3, and ILT4. In the present study, we investigated the effect of distinct tryptophan catabolites on the function of human DCs and the expression of ILT2, ILT3, and ILT4 on these cells. We show that, in contrast to low tryptophan levels alone, the combination of several metabolites along the tryptophan-kynurenine degradation pathway during DC differentiation does not induce ILT2, ILT3, or ILT4 on these DCs and does not reduce the T-cell stimulatory capacity of these DCs. PMID- 21699944 TI - Development of a novobiocin-resistant Edwardsiella ictaluri as a novel vaccine in channel catfish (Ictalurus punctatus). AB - The efficacy of a novel attenuated Edwardsiella ictaluri vaccine (B-50348) was determined in channel catfish (Ictalurus punctatus) by bath immersion and intraperitoneal (IP) injection. The vaccine was developed from a virulent strain of E. ictaluri (AL93-58) through selection for novobiocin resistance. When channel catfish (average weight 10 g) were IP injected with 4.2 * 106 colony forming units (CFU) of the attenuated vaccine B-50348, no fish died. However, when the same age and size matched group of the catfish were IP injected with a lesser amount (2.4 * 106 CFU/fish) of modified live RE-33 vaccine or the AL93-58 virulent strain (2.5 * 106 CFU/fish) of E. ictaluri, 65% and 95% fish died, respectively. When channel catfish were challenged with AL93-58, relative percent survival values of vaccinated fish were all greater than 90% at 22, 32, and 63 days post B-50348 vaccination through intraperitoneal injection. By bath immersion, at 37 and 57 days post vaccination of B-50348, relative percent survival values were both 100% when fish were challenged by virulent E. ictaluri AL93-58. Our results suggest that B-50348 could be used as a novel safe and efficacious vaccine against ESC in channel catfish. PMID- 21699945 TI - Coalition against Typhoid (CaT): a new, global initiative to advance typhoid vaccination. PMID- 21699946 TI - Assessing the potency of oral polio vaccine kept outside of the cold chain during a national immunization campaign in Chad. AB - This study is the first systematic documentation of the potency of monovalent oral polio vaccine type 3 (mOPV3) kept at ambient temperatures during a polio immunization campaign in Chad. During the study test vials were exposed to temperatures of up to 47.1 degrees C, and kept outside of the 2-8 degrees C range for a maximum of 86.9 hours. Post-campaign laboratory testing confirmed that the test vials were still potent, and in conformity with the defined release specifications. Further, the Vaccine Vial Monitors performed as expected, giving an early warning indication of when cumulative exposure to heat reached levels that may have negatively affected the vaccine's potency. This study provides proof-of-concept evidence that certain types of OPV remain potent and thus can be kept, for limited periods of time, as well as administered at ambient temperatures. PMID- 21699940 TI - New insights and perspectives on intrarenal renin-angiotensin system: focus on intracrine/intracellular angiotensin II. AB - Although renin, the rate-limiting enzyme of the renin-angiotensin system (RAS), was first discovered by Robert Tigerstedt and Bergman more than a century ago, the research on the RAS still remains stronger than ever. The RAS, once considered to be an endocrine system, is now widely recognized as dual (circulating and local/tissue) or multiple hormonal systems (endocrine, paracrine and intracrine). In addition to the classical renin/angiotensin I-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II receptor (AT1/AT2) axis, the prorenin/(Pro)renin receptor (PRR)/MAP kinase axis, the ACE2/Ang (1-7)/Mas receptor axis, and the Ang IV/AT4/insulin-regulated aminopeptidase (IRAP) axis have recently been discovered. Furthermore, the roles of the evolving RAS have been extended far beyond blood pressure control, aldosterone synthesis, and body fluid and electrolyte homeostasis. Indeed, novel actions and underlying signaling mechanisms for each member of the RAS in physiology and diseases are continuously uncovered. However, many challenges still remain in the RAS research field despite of more than one century's research effort. It is expected that the research on the expanded RAS will continue to play a prominent role in cardiovascular, renal and hypertension research. The purpose of this article is to review the progress recently being made in the RAS research, with special emphasis on the local RAS in the kidney and the newly discovered prorenin/PRR/MAP kinase axis, the ACE2/Ang (1-7)/Mas receptor axis, the Ang IV/AT4/IRAP axis, and intracrine/intracellular Ang II. The improved knowledge of the expanded RAS will help us better understand how the classical renin/ACE/Ang II/AT1 receptor axis, extracellular and/or intracellular origin, interacts with other novel RAS axes to regulate blood pressure and cardiovascular and kidney function in both physiological and diseased states. PMID- 21699947 TI - A collaborative approach to investigating the risk of thrombocytopenic purpura after measles-mumps-rubella vaccination in England and Denmark. AB - The assessment of rare adverse events following vaccination may not be possible within a single country due to an insufficiently large denominator population. In 2008 a European consortium (VAESCO) was funded to perform collaborative vaccine safety studies. To help assess the feasibility of multi-country collaboration England and Denmark, who have established vaccine safety research infrastructures, undertook to work to a common protocol and share results and data to estimate the risk of a known true adverse event, thrombocytopenic purpura (TP) following measles-mumps-rubella (MMR) vaccination. TP is a known rare reaction to MMR and therefore provided an opportunity to assess whether two countries would produce similar results when working collaboratively. Despite some initial problems with ensuring data were comparable, the two countries gave very similar estimates of the relative incidence in the 6 weeks after vaccination and a pooled relative incidence estimate of 2.13 (95% confidence interval 1.55 2.94) and attributable risk of 1 in 50,000 doses. Both countries used hospital admissions for TP and the analysis was performed using the self controlled case series method which is particularly suited to collaborative studies because of its implicit control for individual level confounding. The study therefore shows the potential for vaccine safety collaborations across Europe to detect true associations through use of common protocols and sharing of results or data. PMID- 21699948 TI - Factors associated with pandemic influenza A/H1N1 vaccine coverage in a French cohort of HIV-infected patients. AB - BACKGROUND: A mass influenza A/H1N1 vaccination campaign took place in France during the 2009 winter. Overall, 7.9% of the general population was vaccinated. However, vaccine coverage data are missing for at-risk groups. METHODS: A vaccination centre was implemented for HIV-infected patients followed-up in a French University Hospital. Demographical, clinical and biological characteristics were collected. Adjusted odds ratios (aOR) were calculated to identify factors associated with being vaccinated against A/H1N1 influenza. RESULTS: A/H1N1 vaccine coverage was 44.4% (635/1430) in HIV-infected patients. In univariate analysis, uptake of vaccination was significantly associated with male gender, men who have sex with men, age >= 50 years, >= 1 seasonal influenza risk factor, longer HIV disease, longer duration of antiretroviral therapy, greater number of lines of antiretroviral treatments, lower nadir CD4, recent HIV RNA<50 copies/ml, previous pneumococcal vaccination, > 2 visits to the unit during the study period and follow-up by a physician who assessed >= 100 patients/year (senior physician). CDC stage, recent CD4 count, diabetes, BMI>30 and pregnancy were not associated with vaccination. After multivariate analysis, vaccination remained significantly associated with age >= 50 years (aOR 1.56, CI 1.16-2.09), time since HIV diagnosis (aOR per 1 year 1.02, CI 1.00-1.04), previous pneumococcal vaccination (aOR 2.56, CI 1.96-3.34), >2 visits to the unit (aOR 5.09, CI 3.87-6.68) and follow-up by a senior physician (aOR 1.73, CI 1.20 2.48). CONCLUSION: A/H1N1 vaccination was more successful in HIV-infected patients than in the French general population. Organization of the vaccination in a convenient location and implication of the physicians seem to be determining factors for A/H1N1 acceptability in this population. PMID- 21699950 TI - Motivating factors for high rates of influenza vaccination among healthcare workers. AB - BACKGROUND: Recent guidance from related regulatory agencies and medical societies supports mandatory vaccination of healthcare workers (HCW) against influenza. At St. Jude Children's Research Hospital, a pediatric oncology referral center, more than 90% of HCWs receive vaccine each year without a policy mandating immunization. Factors associated with HCW uptake of influenza vaccines have not previously been evaluated in a high compliance rate setting. METHODS: A structured, anonymous, electronic questionnaire was distributed in August 2010 to employees (HCW and non-HCW). Demographics, prior receipt of influenza vaccines, reasons for acceptance or refusal of seasonal and 2009 H1N1 pandemic vaccine, and attitudes on mandatory vaccination were assessed. RESULTS: 95.0% of 925 HCWs and 63.1% of all 3227 qualifying employees responded to the survey. 93.8% and 75.2% of HCW reported receiving seasonal and 2009 H1N1 influenza vaccines, respectively, in the 2009-2010 season. Benefits to self and/or patients were cited as the most frequent reasons for accepting seasonal (83.5% and 78.3%, respectively) and 2009 H1N1 (85.9% and 81.1%, respectively) vaccination. 36.6% of HCWs opposed mandating influenza vaccination; 88.2% and 59.9% of whom reported receiving the seasonal and 2009 H1N1 influenza vaccines, respectively. Violation of freedom of choice and personal autonomy were the most frequently reported reasons for opposition. CONCLUSION: In this cohort of HCWs with a high influenza vaccination rate, realistic assessments of the potential benefits of vaccination appear to have driven the choice to accept immunization. Despite this, mandating vaccination was viewed unfavorably by a significant minority of vaccinated individuals. Employee concerns over autonomy should be addressed as institutions transition to mandatory vaccination policies. PMID- 21699949 TI - Models of the impact of dengue vaccines: a review of current research and potential approaches. AB - Vaccination reduces transmission of pathogens directly, by preventing individual infections, and indirectly, by reducing the probability of contact between infected individuals and susceptible ones. The potential combined impact of future dengue vaccines can be estimated using mathematical models of transmission. However, there is considerable uncertainty in the structure of models that accurately represent dengue transmission dynamics. Here, we review models that could be used to assess the impact of future dengue immunization programmes. We also review approaches that have been used to validate and parameterize models. A key parameter of all approaches is the basic reproduction number, R(0), which can be used to determine the critical vaccination fraction to eliminate transmission. We review several methods that have been used to estimate this quantity. Finally, we discuss the characteristics of dengue vaccines that must be estimated to accurately assess their potential impact on dengue virus transmission. PMID- 21699952 TI - The hormesis database: the occurrence of hormetic dose responses in the toxicological literature. AB - In 2005 we published an assessment of dose responses that satisfied a priori evaluative criteria for inclusion within the relational retrieval hormesis database (Calabrese and Blain, 2005). The database included information on study characteristics (e.g., biological model, gender, age and other relevant aspects, number of doses, dose distribution/range, quantitative features of the dose response, temporal features/repeat measures, and physical/chemical properties of the agents). The 2005 article covered information for about 5000 dose responses; the present article has been expanded to cover approximately 9000 dose responses. This assessment extends and strengthens the conclusion of the 2005 paper that the hormesis concept is broadly generalizable, being independent of biological model, endpoint measured and chemical class/physical agent. It also confirmed the definable quantitative features of hormetic dose responses in which the strong majority of dose responses display maximum stimulation less than twice that of the control group and a stimulatory width that is within approximately 10-20-fold of the estimated toxicological or pharmacological threshold. The remarkable consistency of the quantitative features of the hormetic dose response suggests that hormesis may provide an estimate of biological plasticity that is broadly generalized across plant, microbial and animal (invertebrate and vertebrate) models. PMID- 21699951 TI - Comparison of the immunogenicity and safety of a split-virion, inactivated, trivalent influenza vaccine (Fluzone(r)) administered by intradermal and intramuscular route in healthy adults. AB - The aim of the study was to determine whether reduced doses of trivalent inactivated influenza vaccine (TIV) administered by the intradermal (ID) route generated similar immune responses to standard TIV given intramuscularly (IM) with comparable safety profiles. Recent changes in immunization recommendations have increased the number of people for whom influenza vaccination is recommended. Thus, given this increased need and intermittent vaccine shortages, means to rapidly expand the vaccine supply are needed. Previously healthy subjects 18-64 years of age were randomly assigned to one of four TIV vaccine groups: standard 15 MUg HA/strain TIV IM, either 9 MUg or 6 MUg HA/strain of TIV ID given using a new microinjection system (BD SoluviaTM Microinjection System), or 3 MUg HA/strain of TIV ID given by Mantoux technique. All vaccines contained A/New Caledonia (H1N1), A/Wyoming (H3N2) and B/Jiangsu strains of influenza. Sera were obtained 21 days after vaccination and hemagglutination inhibition (HAI) assays were performed and geometric mean titers (GMT) were compared among the groups. Participants were queried immediately following vaccination regarding injection pain and quality of the experience. Local and systemic reactions were collected for 7 days following vaccination and compared. Ten study sites enrolled 1592 subjects stratified by age; 18-49 years [N=814] and 50-64 years [N=778]. Among all subjects, for each of the three vaccine strains, the GMTs at 21 days post-vaccination for both the 9 MUg and the 6 MUg doses of each strain given ID were non inferior to GMTs generated after standard 15 MUg doses/strain IM. However, for the 3 MUg ID dose, only the A/Wyoming antigen produced a GMT that was non-inferior to the standard IM dose. Additionally, in the subgroup of subjects 50-64 years of age, the 6MUg dose given ID induced GMTs that were inferior to the standard IM TIV for the A/H1N1 and B strains. No ID dose produced a GMT superior to that seen after standard IM TIV. Local erythema and swelling were significantly more common in the ID groups but the reactions were mild to moderate and short-lived. No significant safety issues related to intradermal administration were identified. Participants given TIV ID provided favorable responses to questions about their experiences with ID administration. In conclusion, for the aggregated cohorts of adults 18-64 years of age, reduced doses (6 MUg and 9 MUg) of TIV delivered ID using a novel microinjection system stimulated comparable HAI antibody responses to standard TIV given IM. The reduced 3 MUg dose administered ID by needle and syringe, as well as the 6 MUg ID for subjects aged 50-64 years of age generated poorer immune responses as compared to the 15 MUg IM dose. PMID- 21699953 TI - Antioxidant effects of Panax ginseng C.A. Meyer in healthy subjects: a randomized, placebo-controlled clinical trial. AB - We investigated the antioxidant effects of Panax ginseng C.A. Meyer on healthy volunteers. In a double-blind randomized controlled design, 82 participants (21 men and 61 women) who were considered healthy by both objective and subjective health standard were divided into three groups, the control group and the groups received P. ginseng extract (1 or 2g/day) for 4 weeks. Serum level of reactive oxygen species (ROS), malondialdehyde (MDA), total antioxidant capacity (TAC), the activities of catalase, superoxide dismutase (SOD), glutathione reductase (GSH-Rd), and peroxidase (GSH-Px), and total glutathione content were determined before and after the trial. Administration of P. ginseng led to significant decreases in the levels of serum ROS and MDA. Notably, the total glutathione content and GSH-Rd activity considerably improved in the groups that received 2g of P. ginseng. No significant alterations were observed in TAC, catalase, SOD, and GSH-Px activities. In conclusion, our findings indicate that P. ginseng was shown to have antioxidant property. It enhanced the antioxidant defense mechanism in healthy populations and the results may reinforce the use of P. ginseng as a potential antioxidant supplement. PMID- 21699954 TI - Conformational studies and solvent-accessible surface area analysis of known selective DNA G-Quadruplex binders. AB - Human telomeres are comprised of d(TTAGGG) repeats involved in the formation of G quadruplex DNA structures. Ligands that stabilize these G-quadruplex DNA structures are potential inhibitors of the cancer cell-associated enzyme telomerase. In human cells, telomerase adds multiple copies of the 5'-GGTTAG-3' motif to the end of the G-strand of the telomere and in the majority of tumor cells it results over-expressed. Several structural studies have revealed a diversity of topologies for telomeric quadruplexes, as confirmed by the different conformations deposited in the Protein Data Bank. In recent years an increasing number of chemically diverse telomerase inhibitors have been identified, including both natural and synthetic compounds. Thus telomerase has been regarded as one of the most attractive targets in cancer treatment. In this manuscript, with the aim to rationalize the different experimental activities of known telomerase inhibitors, a computational study was carried out to investigate their conformational properties and the relationships between the target affinity and the ligands solvent-accessible surface area. Among the analyzed different scaffolds of G-quadruplex binders, such a descriptor provided helpful preliminary information to discriminate end-stacking ligand binding affinities, revealing itself as a useful predictive tool in drug design and lead optimization processes. PMID- 21699955 TI - Naphthalene diimide scaffolds with dual reversible and covalent interaction properties towards G-quadruplex. AB - Selective recognition and alkylation of G-quadruplex oligonucleotides has been achieved by substituted naphathalene diimides (NDIs) conjugated to engineered phenol moieties by alkyl-amido spacers with tunable length and conformational mobility. FRET-melting assays, circular dichroism titrations and gel electrophoresis analysis have been carried out to evaluate both reversible stabilization and alkylation of the G-quadruplex. The NDIs conjugated to a quinone methide precursor (NDI-QMP) and a phenol moiety by the shortest alkyl amido spacer exhibited a planar and fairly rigid geometry (modelled by DFT computation). They were the best irreversible and reversible G-quadruplex binders, respectively. The above NDI-QMP was able to alkylate the telomeric G quadruplex DNA in the nanomolar range and resulted 100-1000 times more selective on G-quadruplex versus single- and double-stranded oligonucleotides. This compound was also the most cytotoxic against a lung carcinoma cell line. PMID- 21699957 TI - Antimanic-like effect of tamoxifen is not reproduced by acute or chronic administration of medroxyprogesterone or clomiphene. AB - Tamoxifen, a protein kinase C (PKC) inhibitor and antiestrogenic drug, has clinical antimanic effects and blocks psychostimulant-induced hyperlocomotion. Medroxyprogesterone (MPA), which has antiestrogenic effects, also exerts some clinical benefits in female manic patients and partially blocks amphetamine induced hyperlocomotion, indicating that the antiestrogenic effect of tamoxifen could contribute to its antimanic effect. The present study evaluated the effect of acute and chronic (21 day) treatment of two antiestrogenic drugs, MPA and clomiphene (an estrogenic receptor antagonist), on methylphenidate (MPH, 5.0mg/kg)-induced hyperlocomotion in mice, an animal model of mania. Acute and chronic tamoxifen administration was used as a positive control. Acute and chronic tamoxifen (1.0mg/kg) administration blocked MPH-induced hyperlocomotion. Acute and chronic MPA (acute: 3.0 or 6.0mg/kg; chronic: 3.0mg/kg) and clomiphene (acute: 1.5 or 3.0mg/kg; chronic: 1.5mg/kg) treatment did not alter MPH-induced hyperlocomotion. These results indicate that tamoxifen exerts antimanic-like effects, and reduced estrogenic activity does not have antimanic-like effects in this psychostimulant-induced hyperlocomotion model. Therefore, the antiestrogenic effect of tamoxifen likely does not contribute to its antimanic effect, which may instead be related to its effect on PKC activity. Therefore, PKC inhibition may be associated with the antimanic effect of mood stabilizers. PMID- 21699956 TI - Effect of paliperidone and risperidone on extracellular glutamate in the prefrontal cortex of rats exposed to prenatal immune activation or MK-801. AB - The NMDA glutamate hypofunction model of schizophrenia is based in part upon acute effects of NMDA receptor blockade in humans and rodents. Several laboratories have reported glutamate system abnormalities following prenatal exposure to immune challenge, a known environmental risk factor for schizophrenia. Here we report indices of NMDA glutamate receptor hypofunction following prenatal immune activation, as well as the effects of treatment during periadolescence with the atypical antipsychotic medications risperidone and paliperidone. Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or saline on gestational day 14. Male offspring were treated orally via drinking water with vehicle, risperidone (0.01mg/kg/day), or paliperidone (0.01mg/kg/day) between postnatal days 35 and 56 (periadolescence) and extracellular glutamate levels in the prefrontal cortex were determined by microdialysis at PD 56. Consistent with decreased NMDA receptor function, MK-801-induced increases in extracellular glutamate concentration were markedly blunted following prenatal immune activation. Further suggesting NMDA receptor hypofunction, prefrontal cortex basal extracellular glutamate was significantly elevated (p<0.05) in offspring of poly I:C treated dams. Pretreatment with low dose paliperidone or risperidone (0.01mg/kg/day postnatal days 35-56) normalized prefrontal cortical basal extracellular glutamate (p<0.05 vs. poly I:C vehicle-treatment). Pretreatment with paliperidone and risperidone also prevented the acute MK-801-induced increase in extracellular glutamate. These observations demonstrate decreased NMDA receptor function and elevated extracellular glutamate, two key features of the NMDA glutamate receptor hypofunction model of schizophrenia, during periadolescence following prenatal immune activation. Treatment with the atypical antipsychotic medications paliperidone and risperidone normalized basal extracellular glutamate. Demonstration of glutamatergic abnormalities consistent with the NMDA glutamate receptor hypofunction model of schizophrenia as an early developmental consequence of prenatal immune action provides a model to identify novel early interventions targeting glutamatergic systems which play an important role in both positive and negative symptoms of schizophrenia. PMID- 21699958 TI - Rat hippocampal proteomic alterations following intrahippocampal injection of amyloid beta peptide (1-40). AB - Amyloid beta peptide 1-40 (Abeta(1-40)) is closely associated with the progressive neuronal loss and cognitive decline observed in Alzheimer's disease (AD). This study aimed to establish a proteomic strategy for the profiling of AD tissues for disease-specific changes in protein abundance. Intrahippocampal injection of Abeta(1-40) induced spatial memory and learning decline in rats. Proteomic analysis revealed the changes in protein expression in the rat hippocampus treated with Abeta(1-40). Four proteins of interest which was in abundance was significantly altered in Abeta(1-40)-treated rats were identified by peptide mass fingerprint (PMF). These proteins corresponded to synapsin Ib, protein disulfide-isomerase A3 precursor, tubulin beta chain and ATP synthase beta subunit. Our results provide new insights into the relationship between Abeta and the pathogenesis of AD, and suggest potential targets for the therapy of AD. PMID- 21699960 TI - Double-blind, vehicle-controlled randomized twelve-month neurodevelopmental toxicity study of common aluminum salts in the rat. AB - This good laboratory practice (GLP) study of aluminum salts in Sprague-Dawley rats was conducted according to double-blind, vehicle-controlled randomized design by exposing offspring to aluminum citrate in-utero, through lactation, and then in drinking water post-weaning. Three dose levels were used: 30, 100, 300 mg Al/kg bw/day, in addition to control groups that received either water or a sodium citrate solution (27.2 g/L). Endpoints were assessed in both female and male pups: behavioral (motor activity, T-maze, auditory startle, the Functional Observational Battery (FOB) with domains targeting autonomic function, activity, neuromuscular function, sensimotor function, and physiological function), cognitive function (Morris swim maze), brain weight, clinical chemistry, hematology, tissue/blood levels of aluminum and neuropathology. The most notable treatment-related effect observed in the offspring was renal pathology, most prominently in the male pups. Higher mortality and significant morbidity were observed in the male pups in the high Al-citrate dose group; leading to euthanization of this group at day 89. There was evidence for dose-response relationships between neuromuscular measurements-hind-limb and fore-limb grip strength-and Al-treatment in both males and females, although some of the effects may be secondary to body weight changes. No consistent treatment-related effects were observed in ambulatory counts (motor activity) in the different cohorts. No significant effects were observed for the auditory startle response, T-maze tests (pre-weaning day 23 cohort) or the Morris water maze test (day 120 cohort). None of the lesions seen on histopathological examination of brain tissues of the day 364 group was reported as treatment-related and, as these were also seen in the control group, were likely due to aging. In conclusion, these results indicate that concentrations of aluminum in the drinking water that are required to produce minimally detectable neurobiological effects in the rat are about 10,000 times higher than what is typically found in potable drinking water. PMID- 21699959 TI - Kinetics of iron release from transferrin bound to the transferrin receptor at endosomal pH. AB - BACKGROUND: Human serum transferrin (hTF) is a bilobal glycoprotein that reversibly binds Fe(3+) and delivers it to cells by the process of receptor mediated endocytosis. Despite decades of research, the precise events resulting in iron release from each lobe of hTF within the endosome have not been fully delineated. SCOPE OF REVIEW: We provide an overview of the kinetics of iron release from hTF+/-the transferrin receptor (TFR) at endosomal pH (5.6). A critical evaluation of the array of biophysical techniques used to determine accurate rate constants is provided. GENERAL SIGNIFICANCE: Delivery of Fe(3+)to actively dividing cells by hTF is essential; too much or too little Fe(3+) directly impacts the well-being of an individual. Because the interaction of hTF with the TFR controls iron distribution in the body, an understanding of this process at the molecular level is essential. MAJOR CONCLUSIONS: Not only does TFR direct the delivery of iron to the cell through the binding of hTF, kinetic data demonstrate that it also modulates iron release from the N- and C-lobes of hTF. Specifically, the TFR balances the rate of iron release from each lobe, resulting in efficient Fe(3+) release within a physiologically relevant time frame. This article is part of a Special Issue entitled Molecular Mechanisms of Iron Transport and Disorders. PMID- 21699961 TI - Reduced locomotor responses to cocaine in ghrelin-deficient mice. AB - Ghrelin, an orexigenic hormone produced by the stomach, increases food intake and enhances the locomotor and rewarding effects of cocaine. Consistent with these behavioral effects, ghrelin increases dopamine cell activity in the mesolimbic system resulting in elevated levels of dopamine release and turnover in target regions such as the ventral striatum. In the current study, we examined the psychostimulant effects of acute and daily cocaine in mice with targeted deletion of the ghrelin gene (ghrelin knockout; KO) and that of their wild-type (WT) littermates. We hypothesized that ghrelin-KO mice would be hyporesponsive to the effects of cocaine as reflected in attenuated locomotor activity following both acute and chronic injections, and that this would be correlated with striatal dopamine and dopamine metabolite concentrations. Results show that the locomotor stimulating effect of cocaine (10 mg/kg) was decreased in ghrelin-KO mice as compared with their WT littermates. In addition, repeated daily injection of cocaine resulted in gradual increases in locomotor activity in WT mice, an effect that was attenuated in ghrelin-KO mice. These behavioral effects were correlated with changes in dopamine utilization in the striatum of WT mice that were not seen in ghrelin-KO mice unless these were pretreated with ghrelin. These data suggest that ghrelin is important for normal function of the mesolimbic dopaminergic system, potentially modulating both dopamine release and reuptake. PMID- 21699962 TI - Peripheral orthopaedic surgery down-regulates hippocampal brain-derived neurotrophic factor and impairs remote memory in mouse. AB - Peripheral orthopaedic surgery induces a profound inflammatory response. This includes a substantial increase in cytokines and, especially, in the level of interleukin (IL)-1beta in the hippocampus, which has been shown to impair hippocampal-dependent memory in mice. We have employed two tests of contextual remote memory to demonstrate that the inflammatory response to surgical insult in mice also results in impairment of remote memory associated with prefrontal cortex (PFC). We have also found that, under the conditions presented in the social interaction test, peripheral orthopaedic surgery does not increase anxiety like behaviour in our animal model. Although such surgery induces an increase in the level of IL-1beta in the hippocampus, it fails to do so in the PFC. Peripheral orthopaedic surgery also results in a reduction in the level of hippocampal brain-derived neurotrophic factor (BDNF) and this may contribute, in part, to the memory impairment found after such surgery. Our data suggest that a reduction in the level of hippocampal BDNF and an increase in the level of hippocampal IL-1beta following surgery may affect the transference of fear memory in the mouse brain. PMID- 21699963 TI - Anti-inflammatory activities of Taxusabietane A isolated from Taxus wallichiana Zucc. AB - Current study was conducted to identify constituents of Taxus wallichiana Zucc. that might be responsible for its folk use in anti-inflammatory conditions. Taxusabietane A was isolated from the bark extract of Taxus wallichiana Zucc. Taxusabietane A was analyzed for in-vitro and in-vivo anti-inflammatory activities using Lipoxygenase (LOX) inhibition assay and carrageenan-induced paw edema model. Taxusabietane A revealed considerable LOX inhibitory activity with the IC(50) value being 57 +/- 0.31. Standard compound Baicalein showed the IC(50) value being 22.1 +/- 0.03 MUM. Taxusabietane A also showed significant (5 and 10 mg/kg) anti-inflammatory activity induced by carrageenan. However, this study highlighted the potential of Taxusabietane A to be further explored as a new lead compound for management of conditions associated with inflammation. PMID- 21699965 TI - Anaesthetic potency of diazepam is resistant to cholinergic overstimulation. AB - Patients suffering from organophosphorus intoxication are compromised by generalised seizures and respiratory insufficiency, either being potentially lethal. In these patients induction of general anaesthesia to allow artificial ventilation is an important therapeutic option. Previously, it has been demonstrated that cholinergic overstimulation impaired network depressing effects of etomidate and sevoflurane. In this study we tested the impact of cholinergic overstimulation on inhibitory effects of diazepam in organotypic slice cultures of cerebrocortical neurons. Effects of clinically relevant concentrations of diazepam on spontaneous action potential activity were assessed by extracellular action potential recordings under basal cholinergic tone as well as in the presence of acetylcholine (1 MUM). Diazepam at anaesthetic concentrations (25-500 MUM) impeded spontaneous network activity in a concentration dependent manner (EC50 80.5+/-8.0 MUM). In the presence of 1 MUM acetylcholine the potency of diazepam was not significantly altered (EC50 83.6+/-8.4 MUM). The results demonstrate that the potency of diazepam to depress neocortical network excitability is not significantly impaired by cholinergic overstimulation. Diazepam thereby differs from other anaesthetics like etomidate or sevoflurane whose potencies and efficacies were severely attenuated. Hence diazepam might be preferable for induction and maintenance of general anaesthesia in patients suffering from nerve agent intoxication. PMID- 21699964 TI - The Alzheimer's amyloid beta-peptide (Abeta) binds a specific DNA Abeta interacting domain (AbetaID) in the APP, BACE1, and APOE promoters in a sequence specific manner: characterizing a new regulatory motif. AB - Deposition of extracellular plaques, primarily consisting of amyloid beta peptide (Abeta), in the brain is the confirmatory diagnostic of Alzheimer's disease (AD); however, the physiological and pathological role of Abeta is not fully understood. Herein, we demonstrate novel Abeta activity as a putative transcription factor upon AD-associated genes. We used oligomers from 5'-flanking regions of the apolipoprotein E (APOE), Abeta-precursor protein (APP) and beta amyloid site cleaving enzyme-1 (BACE1) genes for electrophoretic mobility shift assay (EMSA) with different fragments of the Abeta peptide. Our results suggest that Abeta bound to an Abeta-interacting domain (AbetaID) with a consensus of "KGGRKTGGGG". This peptide-DNA interaction was sequence specific, and mutation of the first "G" of the decamer's terminal "GGGG" eliminated peptide-DNA interaction. Furthermore, the cytotoxic Abeta25-35 fragment had greatest DNA affinity. Such specificity of binding suggests that the AbetaID is worth of further investigation as a site wherein the Abeta peptide may act as a transcription factor. PMID- 21699966 TI - Biological monitoring of indoor-exposure to dioxin-like and non-dioxin-like polychlorinated biphenyls (PCB) in a public building. AB - The release of PCBs from sealant material in public buildings and the resulting indoor air levels have raised growing concerns about possible human health effects connected with this exposure. Ambient monitoring of PCBs in a public building has revealed a contamination with the more volatile lower chlorinated PCB 28, PCB 52 and PCB 101. This gave reason for a large biological monitoring study in order to examine the internal exposure to PCBs in persons working in that building. Blood samples from 209 persons employed in the PCB-contaminated building were drawn. 98 persons matched for age and gender working in non contaminated buildings served as control group. Plasma samples were analysed for the six indicator PCBs (PCB 28, 52, 101, 138, 153, 180) and 12 dioxin-like PCBs using GC/MS (LOD: 0.01 MUg/L). Significant differences between both collectives were only found for the plasma levels of the lower chlorinated PCB 28, PCB 52 and PCB 101 and for the dioxin-like congeners PCB 105 and PCB 118, which are due to inhalative exposure to these congeners via indoor air. Median plasma levels of PCB 28, PCB 52 and PCB 101 in the employees of the contaminated building were 0.087 MUg/L, 0.024 MUg/L and 0.012 MUg/L, respectively. The concentrations of the higher chlorinated PCBs and all other dioxin-like congeners investigated were within the normal range of the general population. There was no relationship between indoor air measurements and internal exposure of the employees in the corresponding office, but estimated lifetime exposure of the employees turned out to be a significant factor for plasma levels of PCB 28. Our biomonitoring results served as a basis for individual risk communication and successful risk management. PMID- 21699967 TI - Dihydrolipoamide dehydrogenase and cAMP are associated with cadmium-mediated Leydig cell damage. AB - Cadmium (Cd) directly inhibits testosterone production in Leydig cells, but its mechanism is still unclear. To further explore the signaling pathway of Cd mediated toxicity to Leydig cells, various concentrations of Cd were cultured with R2C cells for 24h, and two-dimensional gel electrophoresis (2DE)-based proteomics profiling was used to analyze the change of protein expressions. Cd caused a concentration-dependent inhibition of cell viability with IC(25), IC(50) and IC(75) of 2.42*10(-5)M, 4.83*10(-5)M and 7.39*10(-5)M, respectively. Cd significantly reduced progesterone production and mitochondrial membrane potential (DeltaPsi(m)) in a concentration-dependent manner. 2DE-based proteomics showed 34 protein spots with altered expression by 2-folds or more, and dihydrolipoamide dehydrogenase (DLD) was the hub in the network of these altered proteins. Real-time polymerase chain reaction (PCR) and Western blotting showed that Cd downregulated the expression of DLD. Cd also decreased intracellular levels of cyclic adenosine monophosphate (cAMP). The results suggest that DLD and cAMP may be key elements related to Cd toxicity to Leydig cells. PMID- 21699968 TI - Layer-by-layer microcapsules templated on erythrocyte ghost carriers. AB - This work reports the fabrication of layer-by-layer (LbL) microcapsules that provide a simple mean for controlling the burst and subsequent release of bioactive agents. Red blood cell (RBC) ghosts were loaded with fluorescently labeled dextran and lysozyme as model compounds via hypotonic dialysis with an encapsulation efficiency of 27-31%. It is demonstrated that these vesicles maintain their shape and integrity and that a uniform distribution of the encapsulated agents within these carriers is achieved. The loaded vesicles were then successfully coated with the biocompatible polyelectrolytes, poly-L-arginine hydrochloride and dextran sulfate. It is demonstrated that the release profiles of the encapsulated molecules can be regulated over a wide range by adjusting the number of polyelectrolyte layers. In addition, the LbL shell also protects the RBC ghost from decomposition thereby potentially preserving the bioactivity of encapsulated drugs or proteins. These microcapsules, consisting of an RBC ghost coated with a polyelectrolyte multilayer, provide a simple mean for the preparation of loaded LbL microcapsules eliminating the core dissolution and post loading of bioactive agents, which are required for conventional LbL microcapsules. PMID- 21699969 TI - Stabilization and encapsulation of recombinant human erythropoietin into PLGA microspheres using human serum albumin as a stabilizer. AB - The aim of this study was to prepare recombinant human erythropoietin (rhEPO) loaded poly(lactic-co-glycolic acid) (PLGA) microspheres using human serum albumin (HSA) as a stabilizer. Prior to encapsulation, the rhEPO-HSA mixture microparticles were fabricated using a modified freezing-induced phase separation method. The microparticles were subsequently encapsulated into PLGA microspheres. Process optimization revealed that the polymer concentration in the organic phase and the sodium chloride (NaCl) concentration in the outer water phase of the s/o/w emulsion played critical roles in determining the properties of the resultant microspheres. An in vitro release test showed that rhEPO was released from PLGA microspheres in a sustained manner up to 30 days. A single injection of rhEPO-loaded PLGA microspheres in Sprague-Dawley rats resulted in elevated hemoglobin and red blood cell concentrations for about 33 days. The stability of the rhEPO within the PLGA microspheres was systematically investigated by size exclusion high-performance liquid chromatography (SEC-HPLC), SDS-PAGE, western blot and in vivo biological activity assay. The stability of rhEPO released from rhEPO-loaded microspheres was also examined by western blot. The results suggested that the integrity of rhEPO was successfully protected during the encapsulation process and the release period from polymeric matrices. PMID- 21699970 TI - Auditory brainstem responses predict auditory nerve fiber thresholds and frequency selectivity in hearing impaired chinchillas. AB - Noninvasive auditory brainstem responses (ABRs) are commonly used to assess cochlear pathology in both clinical and research environments. In the current study, we evaluated the relationship between ABR characteristics and more direct measures of cochlear function. We recorded ABRs and auditory nerve (AN) single unit responses in seven chinchillas with noise-induced hearing loss. ABRs were recorded for 1-8 kHz tone burst stimuli both before and several weeks after 4 h of exposure to a 115 dB SPL, 50 Hz band of noise with a center frequency of 2 kHz. Shifts in ABR characteristics (threshold, wave I amplitude, and wave I latency) following hearing loss were compared to AN-fiber tuning curve properties (threshold and frequency selectivity) in the same animals. As expected, noise exposure generally resulted in an increase in ABR threshold and decrease in wave I amplitude at equal SPL. Wave I amplitude at equal sensation level (SL), however, was similar before and after noise exposure. In addition, noise exposure resulted in decreases in ABR wave I latency at equal SL and, to a lesser extent, at equal SPL. The shifts in ABR characteristics were significantly related to AN fiber tuning curve properties in the same animal at the same frequency. Larger shifts in ABR thresholds and ABR wave I amplitude at equal SPL were associated with greater AN threshold elevation. Larger reductions in ABR wave I latency at equal SL, on the other hand, were associated with greater loss of AN frequency selectivity. This result is consistent with linear systems theory, which predicts shorter time delays for broader peripheral frequency tuning. Taken together with other studies, our results affirm that ABR thresholds and wave I amplitude provide useful estimates of cochlear sensitivity. Furthermore, comparisons of ABR wave I latency to normative data at the same SL may prove useful for detecting and characterizing loss of cochlear frequency selectivity. PMID- 21699971 TI - Evaluation of the anti-neuraminidase activity of the traditional Chinese medicines and determination of the anti-influenza A virus effects of the neuraminidase inhibitory TCMs in vitro and in vivo. AB - ETNOPHARMACOLOGICAL RELEVANCE: Neuraminidase (NA) inhibitors are currently the most effective drugs to treat influenza A viruses infection. Many traditional Chinese medicines (TCMs) have been used in the clinics to treat influenza. The anti-viral mechanisms of these TCMs and their inhibitory effects towards NA need to be systematically tested. AIM OF THE STUDY: To evaluate the anti-NA activity of the TCMs and the anti-influenza A virus effects of the NA inhibitory TCMs in vitro and in vivo. MATERIAL AND METHODS: We tested the inhibitory activity of water extracts from 439 TCMs towards NA. The in vitro anti-influenza virus activities of the 5 TCMs were evaluated using the strain A/California/7/2009 (H1N1) NYMC X-179A of influenza A virus. A randomly selected TCM with NA inhibitory activity, Melia toosendan extract, was further evaluated using a mouse model infected with influenza A virus. RESULTS: Five TCMs, Duchesnea indica (Andr.) Focke [Fragaria indica Andr.], Liquidambar formosana Hance., Lithospermum erythrorhizon Sieb. et Zucc., Melia toosendan Sieb. et Zucc., and Prunella vulgaris L., exerted potent inhibitory activity towards NA. These TCMs in the range of 25-250 MUg/mL had the ability to reduce virus-induced cytopathic effect (CPE) and the virus yield in MDCK cells. Melia toosendan significantly reduced death rate and prolonged mean day to death (MDD) of the viral infected mice. CONCLUSIONS: This study describes five TCMs exerted strong inhibitory activities towards NA, and exhibited antiviral effect against influenza A virus by reducing viral reproduction and reduced CPE of the viral infected cells. Melia toosendan, significantly reduced death rate and prolonged survival of the H1N1 viral infected mice. PMID- 21699972 TI - Autolytic Mycobacterium leprae Hsp65 fragments may act as biological markers for autoimmune diseases. AB - Investigating the proteolytic activity of the recombinant Mycobacterium leprae Heat Shock Protein of 65 kDa (rHsp65), chaperonin 2 (cpn2), we observed that it displays high instability. The fragmentation process starts at the C-terminus followed by progressive degradation of the N-terminus, which leads to a stable fragment comprising the middle region of the molecule. Urea was able to prevent autolysis, probably due to its denaturing action, while EDTA increased degradation levels indicating the need for metal ions. Peptides originated from autolysis were purified and analyzed by mass spectrometry, generating a continuous map. Since the bacteria and mammalian Hsp60 are known to be targets of the immune response and have been implicated in autoimmune diseases and chronic inflammation, the in vivo effect of rHsp65 peptides was evaluated in the spontaneous Systemic Lupus Erythematosus (SLE) model developed by the (NZB/NZW)F(1) mouse hybrids, and their individual anti-rHsp65 IgG2a/IgG1 antibody titer ratio was determined. The results showed orientation toward a T(H)1 responsiveness, and the treatment with the rHsp65 peptides diminished the environmental variance of the survival time of treated animals. These results outline the fact that environmental factors may also act through the modified stability expression of Heat Shock Proteins intervening during autoimmune processes. PMID- 21699973 TI - Mechanism of hydrogen peroxide-induced keratinocyte migration in a scratch-wound model. AB - Recent studies have shown that low concentrations of H(2)O(2) are produced endogenously by nonphagocytes after wounding. We observed that H(2)O(2) at such concentrations can stimulate proliferation as well as migration of keratinocytes in a scratch-wound assay. Both wounding and H(2)O(2) can induce phosphorylation of ERK1/2 via EGFR, but the activation of ERK1/2 by H(2)O(2) is more sustained and can last more than 8h. Sustained ERK1/2 activation is required for the increased proliferation and migration induced by H(2)O(2). The p38 MAPK was also found to be phosphorylated upon treatment with H(2)O(2) but it was not required for H(2)O(2)-induced migration or proliferation. Furthermore, it was observed that there is a cross talk between the ERK1/2 and the p38 pathways whereby inhibition of either pathway can lead to activation of the other. As a result, the motogenic effects of H(2)O(2) were further enhanced when p38 was inhibited. Our data are consistent with the view that H(2)O(2) may play an important signaling role in wound healing. PMID- 21699974 TI - Dietary flavonoids: Role of (-)-epicatechin and related procyanidins in cell signaling. AB - Plant polyphenols are among the most abundant phytochemicals present in human diets. Increasing evidence supports the health-promoting effects of certain polyphenols, including flavonoids. This review discusses current knowledge of the capacity of monomeric flavanols, i.e., (-)-epicatechin and (+)-catechin, and their derived procyanidins to modulate cell signaling and the associations of these actions with better health. Flavanols and procyanidins can regulate cell signaling through different mechanisms of action. Monomers and dimeric procyanidins can be transported inside cells and directly interact and modulate the activity of signaling proteins and/or prevent oxidation. Larger and nonabsorbable procyanidins can regulate cell signaling by interacting with cell membrane proteins and lipids, inducing changes in membrane biophysics, and by modulating oxidant production. All these actions would be limited by the bioavailability of flavanols at the target tissue. The protection from cardiac and vascular disease and from cancer that is associated with a high consumption of fruit and vegetables could be in part explained by the capacity of flavanols and related procyanidins to modulate proinflammatory and oncogenic signals. PMID- 21699976 TI - Particle size dependence of polymorphism in spray-dried mannitol. AB - The purpose of this project was to investigate the polymorphic variation of spray dried mannitol model formulations as a function of particle size. Spray-dried powders with varying mannitol polymorphs were produced by adjusting process parameters, using co-solvent and adding a model protein (lysozyme). The obtained dry powders were dispersed into different size fractions using a Next Generation Pharmaceutical Impactor. The mannitol polymorphs in the different size fractions were analyzed using X-ray powder diffraction (XRPD), Fourier transform near infrared (FT-NIR) and Raman spectroscopy. Chemometrics was applied to interpret the FT-NIR and Raman spectra. Different spray-dried mannitol systems were established in this study, which contain mixtures of alpha- and beta-mannitol. The XRPD, FT-NIR and Raman studies showed that the use of ethanol as a co-solvent increased the amount of alpha-mannitol in the smaller particles. The addition of low levels of lysozyme resulted in more alpha-mannitol in the smaller particles, while an increased content of lysozyme in spray-dried mannitol system resulted in more beta-mannitol in the smaller particle size fraction. In conclusion spray drying of mannitol based formulations can result in variation in the solid state composition of mannitol as a function of particle size. This finding may be clinically relevant and underlines the need for proper process control of inhalable dry powder produced by spray-drying. PMID- 21699975 TI - Central and C-terminal domains of heterotrimeric G protein gamma subunits differentially influence the signaling necessary for primordial germ cell migration. AB - Heterotrimeric G protein signaling is involved in many pathways essential to development including those controlling cell migration, proliferation, differentiation and apoptosis. One key developmental event known to rely on proper heterotrimeric G protein signaling is primordial germ cell (PGC) migration. We previously developed an in vivo PGC migration assay that identified differences in the signaling capacity of G protein gamma subunits. In this study we developed Ggamma subunit chimeras to determine the regions of Ggamma isoforms that are responsible for these differences. The central section of the Ggamma subunit was found to be necessary for the ability of a Ggamma subunit to mediate signaling involved in PGC migration. Residues found in the carboxy-terminal segment of Ggamma transducin (gngt1) were found to be responsible for the ability of this subunit to disrupt PGC migration. The type of prenylation did not affect the ability of a Ggamma subunit to reverse prenylation-deficient-Ggamma-induced PGC migration defects. However, a version of gng2, engineered to be farnesylated instead of geranylgeranylated, still lacks the ability to reverse PGC migration defects known to result from treatment of zebrafish with geranylgeranyl transferase inhibitors (GGTI), supporting the notion that Ggamma subunits are one of several protein targets that need to be geranylgeranylated to orchestrate the proper long-range migration of PGCs. PMID- 21699977 TI - Enhancing immunogenicity to PLGA microparticulate systems by incorporation of alginate and RGD-modified alginate. AB - Poly-lactide-co-glycolide acid (PLGA) and alginate represent two different families of polymers widely used for microencapsulation application, even more, for vaccination purposes as particulate delivery/adjuvant systems. Combination of these polymers has been previously considered for tissue engineering and drug delivery, however there is currently no report regarding their combination for vaccine application. In the present work, a w/o/w solvent extraction technique was developed to prepare novel 1MUm microparticles (MP) composed of PLGA and a small percentage of alginate (PLGA-alg MP). In addition, RGD-modified alginate was also employed as biofunctionalized material favoring MP-cell interaction (PLGA-alg-RGD MP). Two malaria synthetic peptides, SPf66 and S3, were microencapsulated into PLGA, PLGA-alg and PLGA-alg-RGD MP. The diverse MP formulations resulted very similar in terms of size and morphology, although the addition of alginate improved encapsulation efficiency and reduced the amount of surface adsorbed peptide. Immunization studies in Balb/c mice by intradermal route demonstrated that incorporation of alginate elicited higher humoral and cellular immune responses leading to more balanced Th1/Th2 responses. Furthermore, administration of MP containing RGD-modified alginate showed evidence of cell targeting by enhancing immunogenicity of microparticles, in particular with regard to cellular responses such as IFN-gamma secretion and lymphoproliferation. PMID- 21699978 TI - Isolation and functional characterization of an allatotropin receptor from Manduca sexta. AB - Manduca sexta allatotropin (Manse-AT) is a multifunctional neuropeptide whose actions include the stimulation of juvenile hormone biosynthesis, myotropic stimulation, cardioacceleratory functions, and inhibition of active ion transport. Manse-AT is a member of a structurally related peptide family that is widely found in insects and also in other invertebrates. Its precise role depends on the insect species and developmental stage. In some lepidopteran insects including M. sexta, structurally-related AT-like (ATL) peptides can be derived from alternatively spliced mRNAs transcribed from the AT gene. We have isolated a cDNA for an AT receptor (ATR) from M. sexta by a PCR-based approach using the sequence of the ATR from Bombyx mori. The sequence of the M. sexta ATR is similar to several G protein-coupled receptors from other insect species and to the mammalian orexin receptor. We demonstrate that the M. sexta ATR expressed in vertebrate cell lines is activated in a dose-responsive manner by Manse-AT and each Manse-ATL peptide in the rank order ATL-I > ATL-II > ATL-III > AT, and functional analysis in multiple cell lines suggest that the receptor is coupled through elevated levels of Ca(2+) and cAMP. In feeding larvae, Manse-ATR mRNA is present at highest levels in the Malpighian tubules, followed by the midgut, hindgut, testes, and corpora allata, consistent with its action on multiple target tissues. In the adult corpora cardiaca--corpora allata complex, Manse-ATR mRNA is present at relatively low levels in both sexes. PMID- 21699979 TI - Evidence that nitric oxide mediates the blood pressure lowering effect of a polyphenol-rich cocoa powder in spontaneously hypertensive rats. AB - The involvement of endothelial-relaxing factors on the antihypertensive effect of a polyphenol-rich cocoa powder named CocoanOX (CCX) was studied. Thirty 17-20 week-old male spontaneously hypertensive rats (SHR), weighing 314 +/- 3g were used. They were divided into two groups of 15 animals, that were respectively administered by gastric intubation distilled water or 300 mg/kg CCX dissolved in distilled water, between 9 am and 10 am. 2h after the oral administration, 5 of the animals in each group were intraperitoneally administered 1 ml saline. The remaining rats in both groups were divided into another two groups of 5 animals that were respectively administered 30 mg/kg Nw-nitro-L-arginine methyl ester (L NAME) dissolved in 1 ml of saline or 5 mg/kg indomethacin also dissolved in 1 ml of saline by the same procedure. Systolic blood pressure (SBP) was recorded in the rats by the tail cuff method before the initial oral administration and also 4h after this administration. CCX caused a significant decrease in SBP (-49.5 +/- 4.9 mmHg; p<0.05). L-NAME caused a clear increase in SBP in the rats (+16.2 +/- 4.3 mmHg; p<0.05), and the effect of CCX was not observed in the SHR that were treated with L-NAME (+4.1 +/- 1.7 mmHg; p<0.05). Nevertheless, indomethacin treatment did not modify SBP in the SHR and this compound failed to modify the antihypertensive effect of CCX in these animals. In conclusion, this study proves the participation of NO in the antihypertensive effect of CCX in the SHR strain. When CCX is administered, the synthesis, or the bioavailability, of this endothelial factor could increase, but other mechanisms may also participate in the antihypertensive effect of this cocoa powder. In any case, further investigation should be carried out to characterize the signalling pathways involved in the antihypertensive effect of CCX. PMID- 21699981 TI - Nonparametric population modeling and Bayesian analysis. PMID- 21699980 TI - A neurochemical basis for an epigenetic vision of psychiatric disorders (1994 2009). AB - In 1996, Dr. Costa was invited by Prof. Boris Astrachan, Chairman of the Department of Psychiatry at the University of Illinois at Chicago, to direct the research of the "Psychiatric Institute, Department of Psychiatry, School of Medicine, at the University of Illinois at Chicago." He was asked to develop a seminal research program on psychiatric disorders. Viewed in retrospect, Dr. Costa met and surpassed the challenge, as was usual for him. To elucidate the molecular mechanisms whereby nurture (epigenetic factors) and nature (genetic factors) interact to cause major psychiatric disorders was at the center of Dr. Costa's mission for the last 15 years of his research at the Psychiatric Institute. The challenge for Dr. Costa and his colleagues (Auta, Caruncho, Davis, Grayson, Guidotti, Impagnatiello, Kiedrowski, Larson, Manev, Pappas, Pesold, Pinna, Sharma, Smalheiser, Sugaya, Tueting, Veldic [1-111]) had always been to find new ways to prevent and treat psychiatric disorders with pharmacological agents that failed to have major unwanted side effects. In this list, we have quoted the first authors of the papers pertaining to the field of research highlighted in the title. As you know, Dr. Costa was an eclectic scientist and in his 15 years of studies at UIC, he touched many other aspects of neuroscience research that are not discussed in this overview. PMID- 21699983 TI - The carbohydrate CT1 is expressed in topographically fixed glomeruli in the mouse olfactory bulb. AB - Cell surface carbohydrates define subpopulations of primary olfactory neurons whose axons terminate in select glomeruli in the olfactory bulb. The combination of carbohydrates present on axon subpopulations has been proposed to confer a unique identity that contributes to the establishment of the olfactory topographic map. We have identified a novel subpopulation of primary olfactory neurons in mice that express blood group carbohydrates with GalNAc beta1,4[NeuAcalpha 2,3]Galbeta1 residues recognised by the CT1 antibody. The CT1 carbohydrate has been shown to modulate adhesion of nerve terminals to the extracellular matrix and to synaptic proteins. The axons of the CT1-positive primary olfactory neurons terminate in a subpopulation of glomeruli in the olfactory bulb. Four lines of evidence support the view that CT1 glomeruli are topographically fixed. First, CT1 glomeruli were restricted predominantly to the dorsomedial olfactory bulb and were absent from large patches of the ventrolateral bulb. Second, similar distributions were observed for CT1 glomeruli on both the left and right olfactory bulbs of each animal, and between animals. Third, CT1 glomeruli were typically present as small clusters of 2-4 glomeruli. Fourth, a single CT1 glomerulus was always apposed to the glomeruli innervated by axons expressing the M72 odorant receptor. We also show that the CT1 carbohydrate is lost in gain-of-function transgenic mice over-expressing the blood group A glycosyltransferase in which there is aberrant targeting of M72 axons. Taken together, these results suggest that the CT1 carbohydrate, together with other carbohydrates, contributes to axon guidance during the establishment of the olfactory topographic map. PMID- 21699982 TI - Rho GTPase regulation of alpha-synuclein and VMAT2: implications for pathogenesis of Parkinson's disease. AB - Accumulation of alpha-synuclein (Asyn) in neuronal perikarya and dystrophic neurites is characteristic of idiopathic and familial Parkinson's disease. In this study, we investigated the relationship between alpha-synuclein expression and neurite outgrowth-maturation using MN9D dopaminergic cells and demonstrated key features of Asyn regulation in hippocampal neurons. Neurite elongation elicited by inhibition of Rho GTPase activity with C3 transferase or by db-cAMP treatment was associated with marked reduction of alpha-synuclein mRNA and protein expression. Rho inhibition resulted in reduction of transcription factor SRF in the nuclear fraction and retention of MKL-1 - the SRF co-transactivator of SRE - in cytosol, indicating that these effects of Rho inhibition may be mediated though reduction of SRF-SRE transcription. Inhibition of Rho GTPase activity led to decreased nuclear localization of GATA2, a key regulator of alpha-synuclein promoter activity. Rho inhibition-induced neurite extension was associated with increased VMAT2 and SNARE proteins synaptophysin and synapsin I. These results indicate that in the MN9D dopaminergic cell line, alpha-synuclein transcription and levels of synaptic vesicle associated proteins are inversely correlated with neurite growth. We confirm that in mature hippocampal neurons inhibition of RhoA and knock down of SRF by siRNA also lead to decrease GATA2 and Asyn. The results suggest that RhoA signaling may be potential therapeutic target for the treatment of synucleinopathies. PMID- 21699984 TI - Three-dimensional reconstruction using an adaptive simultaneous algebraic reconstruction technique in electron tomography. AB - Three-dimensional (3D) reconstruction of electron tomography (ET) has emerged as an important technique in analyzing structures of complex biological samples. However most of existing reconstruction methods are not suitable for extremely noisy and incomplete data conditions. We present an adaptive simultaneous algebraic reconstruction technique (ASART) in which a modified multilevel access scheme and an adaptive relaxation parameter adjustment method are developed to improve the quality of the reconstructed 3D structure. The reconstruction process is facilitated by using a column-sum substitution approach. This modified multilevel access scheme is adopted to arrange the order of projections so as to minimize the correlations between consecutive views within a limited angle range. In the adaptive relaxation parameter adjustment method, not only the weight matrix (as in the existing methods) but the gray levels of the pixels are employed to adjust the relaxation parameters so that the quality of the reconstruction is improved while the convergence process of the reconstruction is accelerated. In the column-sum substitution approach, the computation to obtain the reciprocal of the sum for the columns in each view is avoided so that the needed computations for each iteration can be reduced. Experimental results show that the proposed technique ASART is better based on objective quality measures than other methods, especially when data is noisy and limited in tilt angles. At the same time, the reconstruction by ASART outperforms that of simultaneous algebraic reconstruction technique (SART) in speed. PMID- 21699985 TI - Anti-baculovirus activity in a protein extracted from the exoskeleton of Pleuroncodes planipes [Decapoda: Galatheidae]. AB - Antiviral activity (99.5% inhibition) against the Autographa californica polyhedrosis nuclear virus AcNPV+GFP was shown by a polypeptide of approximately 10 kDa, isolated from the exoskeleton of Pleuroncodes planipes, the pelagic red crab. This thermo-stable polypeptide retained its anti-viral properties after being exposed to 76 degrees C for 30 min and showed no apparent cytotoxic effect. Its anti-viral activity was observed when incubated with the virus, previous to the inoculation of cells. Using Tandem Mass Spectrometry (LC/ESI MS/MS), this polypeptide showed sequence identity to a fragment of a myohemeritrin-like metalloprotein found in the Scoloplos armiger sea worm (VFYANLDEEHK). PMID- 21699986 TI - Stimulating the immune response of Litopenaeus vannamei using the phagocytosis activating protein (PAP) gene. AB - High mortality in the shrimp farming industry is caused by several pathogens such as white spot syndrome virus (WSSV), yellow head virus (YHV) and Vibrio harveyi (V. harveyi). A PAP (Phagocytosis activating protein) gene able to activate phagocytosis of shrimp hemocytes was cloned into the eukaryotic expression vector phMGFP. In vitro expression was confirmed by transfection of PAP-phMGFP into CHO (Chinese Hamster Ovary) cells and the expression of the Green Fluorescent Protein (GFP) was observed. In order to activate the phagocytic activity of shrimp, 20, 40 and 80 MUg/shrimp of this PAP-phMGFP vector were injected into Litopenaeus vannamei muscle. After challenged with WSSV, 40 MUg/shrimp produced the highest relative percent survival (77.78 RPS). Analysis for the expression of the GFP gene in various tissues showed the expression mostly in the hemolymph of the immunized shrimp. The expression level of PAP and proPO (Prophenoloxidase) gene were highest at 7 days after immunization. This agreed with the efficiency of protection against WSSV that also occurred 7 days after immunization with the highest RPS of 86.61%. However there was no protection 30 days after immunization. Hemocytes of shrimp injected with PAP-phMGFP had 1.9 folds and 3 folds higher percentage phagocytosis and phagocytic index than the shrimp injected with PBS. Accordingly, copies of WSSV reduced in the PAP-phMGFP injected shrimp. In addition, PAP-phMGFP also protected shrimp against several pathogens: WSSV, YHV and V. harveyi, with RPS values of 86.61%, 63.34% and 50% respectively. This finding shows that the immune cellular defense mechanisms in shrimp against pathogens can be activated by injection of PAP-phMGFP and could indicate possible useful ways to begin to control this process. PMID- 21699987 TI - Naturalizing aesthetics: brain areas for aesthetic appraisal across sensory modalities. AB - We present here the most comprehensive analysis to date of neuroaesthetic processing by reporting the results of voxel-based meta-analyses of 93 neuroimaging studies of positive-valence aesthetic appraisal across four sensory modalities. The results demonstrate that the most concordant area of activation across all four modalities is the right anterior insula, an area typically associated with visceral perception, especially of negative valence (disgust, pain, etc.). We argue that aesthetic processing is, at its core, the appraisal of the valence of perceived objects. This appraisal is in no way limited to artworks but is instead applicable to all types of perceived objects. Therefore, one way to naturalize aesthetics is to argue that such a system evolved first for the appraisal of objects of survival advantage, such as food sources, and was later co-opted in humans for the experience of artworks for the satisfaction of social needs. PMID- 21699988 TI - Graphical models, potential outcomes and causal inference: comment on Linquist and Sobel. PMID- 21699991 TI - Energy budget during four successive bouts of lactation in striped hamsters exposed to decreases in ambient temperature. AB - A prediction of the seasonal investment hypothesis is that overall energy investment needs to be greater for young being produced at colder temperatures. Then, that energy cost is lower as temperature becomes warmer. To evaluate this assumption, I performed a series of measures of food intake and reproductive output throughout four successive bouts of lactation in striped hamsters (Cricetulus barabensis) exposed to a constant warm temperature (Warm, 21 degrees C) or exposed to consecutive decreases in ambient temperatures from warm to cold (Warm-Cold, 30-0 degrees C). Warm hamsters showed similar asymptotic food intake, litter size and mass over the course of four successive bouts of lactation. Warm Cold females consumed more food, but raised lighter litters during the third bout than first bout of lactation. Ambient temperatures had significant effects on energy budget and reproductive output, by which resting metabolic rate, nonshivering thermogenesis and activity of cytochrome c oxidase (EC 1.9.3.1) of brown adipose tissue were increased, but reproductive output was decreased with declines of temperatures. These findings suggest that a trade-off occurs between different components of energy expenditure during the successive course of four bouts of lactation. Seasonal hamsters decrease their reproductive output, but increase the energy spent on thermogenesis as the ambient temperature becomes colder. It may also indicate that temperature has a direct effect on metabolism, leading to an increase in overall energy expenditure at lower temperatures. PMID- 21699990 TI - Anaerobes: a piece in the puzzle for alternative biofuels. AB - Although much newsprint is devoted to the subject of reducing the United States and other major developed countries dependence on their respective foreign energy sources; the most challenging issues for society is to provide long-term, sustainable energy sources to accommodate the global population as a whole. The projected population of planet Earth for the year 2050 is estimated to be in excess of 9 billion. With hydrocarbon-based energy becoming limiting it is unlikely that one type of energy will alone replace our dependence on this source. So-called "green" technologies that include solar, wind and wave powers are now being explored to reduce on traditional hydrocarbon-based fuel sources. The diverse and functional properties of microbes, and in particular anaerobes, are now being utilized in the production of biofuels and may provide one piece of the jigsaw for future energy requirements. Here we present some results of a screening program to identify and characterize a number of carbon monoxide oxidizing, ethanol-producing acetogenic anaerobes phylogenetically located within the Clostridiales. PMID- 21699989 TI - White matter characterization with diffusional kurtosis imaging. AB - Diffusional kurtosis imaging (DKI) is a clinically feasible extension of diffusion tensor imaging that probes restricted water diffusion in biological tissues using magnetic resonance imaging. Here we provide a physically meaningful interpretation of DKI metrics in white matter regions consisting of more or less parallel aligned fiber bundles by modeling the tissue as two non-exchanging compartments, the intra-axonal space and extra-axonal space. For the b-values typically used in DKI, the diffusion in each compartment is assumed to be anisotropic Gaussian and characterized by a diffusion tensor. The principal parameters of interest for the model include the intra- and extra-axonal diffusion tensors, the axonal water fraction and the tortuosity of the extra axonal space. A key feature is that these can be determined directly from the diffusion metrics conventionally obtained with DKI. For three healthy young adults, the model parameters are estimated from the DKI metrics and shown to be consistent with literature values. In addition, as a partial validation of this DKI-based approach, we demonstrate good agreement between the DKI-derived axonal water fraction and the slow diffusion water fraction obtained from standard biexponential fitting to high b-value diffusion data. Combining the proposed WM model with DKI provides a convenient method for the clinical assessment of white matter in health and disease and could potentially provide important information on neurodegenerative disorders. PMID- 21699992 TI - 15-Deoxy-Delta(12,14)-prostaglandin J(2) interferes inducible synthesis of prostaglandins E(2) and F(2alpha) that suppress subsequent adipogenesis program in cultured preadipocytes. AB - Cultured preadipocytes enhance the synthesis of prostaglandin (PG) E(2) and PGF(2alpha) involving the induction of cyclooxygenase (COX)-2 during the growth phase upon stimulation with a mixture of phorbol 12-myristate 13-acetate, a mitogenic factor, and calcium ionophore A23187. Here, we studied the interactive effect of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) on the inducible synthesis of the endogenous PGs in cultured preadipocytes and its implication in adipogenesis program. 15d-PGJ(2) interfered significantly the endogenous synthesis of those PGs in response to cell stimuli by suppressing the induction of COX-2 following the attenuation of NF-kappaB activation. In contrast, Delta(12)-PGJ(2) and troglitazone had almost no inhibitory effects, indicating a mechanism independent of the activation of peroxisome proliferator-activated receptor gamma for the action of 15-PGJ(2). Pyrrolidinedithiocarbamate (PDTC), an NF-kappaB inhibitor, effectively inhibited on the inducible synthesis of those PGs in preadipocytes. Endogenous PGs generated by preadipocytes only during the growth phase in response to the cell stimuli autonomously attenuated the subsequent adipogenesis program leading to the differentiation and maturation of adipocytes. These effects were prevented by additional co-incubation of preadipocytes with either 15d-PGJ(2) or PDTC although 15d-PGJ(2) alone has no stimulatory effect. Moreover, 15d-PGJ(2) did not block the inhibitory effects of exogenous PGE(2) and PGF(2alpha) on the adipogenesis program in preadipocytes. Taken together, 15d-PGJ(2) can interfere the COX pathway leading to the induced synthesis of endogenous PGs that contribute to negative regulation of adipogenesis program in preadipocytes. PMID- 21699994 TI - Protection against genotoxic damages following whole body gamma radiation exposure in mice by lipoic acid. AB - Alpha-lipoic acid (LA) protected plasmid pBR 322 DNA, under in vitro conditions from gamma radiation induced strand breaks as evidenced by the prevention of the loss of supercoiled covalently closed circular form upon irradiation. It also protected the membrane lipids of liver homogenates from the oxidative damages. Whole body exposure of mice to gamma-radiation resulted in damage to cellular DNA in various tissues and administration of LA prior to the radiation exposure prevented the radiation induced DNA damage as assessed by alkaline comet assay. Administration of LA to mice prior to the radiation exposure also prevented induction of chromosomal damages in bone marrow cells and formation of micronuclei in blood reticulocytes. Thus taken together, LA a normal cellular constituent could be used as a radioprotector against whole body radiation exposure scenarios. PMID- 21699993 TI - Characterization of clinical isolates of the Cryptococcus neoformans-Cryptococcus gattii species complex from the Amazonas State in Brazil. AB - BACKGROUND: The differentiation and classification of pathogenic Cryptococcus species provides useful data for epidemiological studies and for the clinical diagnosis and treatment of patients. AIMS: The aim of this study was to characterise 40 clinical Cryptococcus isolates obtained from patients at the Tropical Medicine Foundation of Amazonas (FMTAM) from 2006 to 2008. METHODS: It was used phenotypic (i.e., enzyme production and antifungal resistance) and molecular biological (URA5-RFLP) experiments. RESULTS: Patients with HIV/AIDS were most affected with cryptococcosis. Thirty-one (75.5%) of the clinical isolates were classified as Cryptococcus neoformans and 9 (22.5%) as Cryptococcus gattii. High amounts of protease and phospholipase enzymes were produced by most of the isolates. Using the disk diffusion test (CLSI M44-A), 81, 35 and 100% of the C. neoformans isolates were characterized as susceptible to fluconazole, itraconazole and amphotericin B, respectively, whereas 78, 56 and 100% of the C. gattii isolates were susceptible to these antimicrobial agents. The average of Minimal Inhibitory Concentration (MIC) for C. neoformans and C. gattii isolates was 0.26 and 0.58 MUg/mL, respectively. The 9 isolates of C. gattii had a fingerprint pattern comparable with the VGII molecular type, while all 31 isolates of C. neoformans presented with a pattern consistent with the VNI type. CONCLUSIONS: This study confirms the importance of HIV/AIDS for the cryptococcosis epidemiology, the susceptibility of the isolates to amphotericin B and the high prevalence of the molecular genotypes VNI and VGII in the north of Brazil. PMID- 21699995 TI - Isolation and functional characterization of proinflammatory acidic phospholipase A2 from Bothrops leucurus snake venom. AB - In the present study, an acidic PLA(2), designated Bl-PLA(2), was isolated from Bothrops leucurus snake venom through two chromatographic steps: ion-exchange on CM-Sepharose and hydrophobic chromatography on Phenyl-Sepharose. Bl-PLA(2) was homogeneous on SDS-PAGE and when submitted to 2D electrophoresis the molecular mass was 15,000Da and pI was 5.4. Its N-terminal sequence revealed a high homology with other Asp49 acidic PLA(2)s from snake venoms. Its specific activity was 159.9U/mg and the indirect hemolytic activity was also higher than that of the crude venom. Bl-PLA(2) induced low myotoxic and edema activities as compared to those of the crude venom. Moreover, the enzyme was able to induce increments in IL-12p40, TNF-alpha, IL-1beta and IL-6 levels and no variation of IL-8 and IL 10 in human PBMC stimulated in vitro, suggesting that Bl-PLA(2) induces proinflammatory cytokine production by human mononuclear cells. Bothrops leucurus venom is still not extensively explored and knowledge of its components will contribute for a better understanding of its action mechanism. PMID- 21699997 TI - Studying the altered timing of physiological events during development: it's about time...or is it? AB - The investigation of the altered timing of developmental events is key to understanding evolution. Most empirical investigations of event timing are biased towards studying morphological variation. Recent reviews, however, have attempted to marshal the evidence for the importance of altered timing of physiological events, focusing on such timing shifts between species (physiological heterochrony) and within species (physiological heterokairy). Here we update these reviews. We firstly take a comparative developmental physiology approach to explore how recent studies have furthered our understanding of the links between physiological event timing shifts at different levels of biological organisation (i.e. individual, population and species). The alternative strategy of concentrating effort on one model system is then considered, in particular focussing on substantial recent advances in our understanding of fetal haemoglobin expression in humans. We conclude that, while the fetal haemoglobin model may be appropriate as a model for some questions, it can never be the model study system. We also discuss the different quantitative analyses available for investigating event timing alterations. We consider the efficacy of the terms heterochrony and heterokairy. PMID- 21699996 TI - Various responses to copper and manganese exposure of Carassius auratus gibelio from two populations. AB - The aim of this study was to compare the effect of pro-oxidants copper (Cu(2+), 0.005 and 0.050mg L(-1)) or manganese (Mn(2+), 0.17 and 1.7mg L(-1)) on Carassius auratus gibelio from polluted (B) and unpolluted (Z) sites after exposure for fourteen days. Fish from site B showed high levels of lipid peroxidation (TBARS concentration), lower levels of metallothionein (MT)-related metal, total glutathione (GSH), its redox index, superoxide dismutase (Cu,Zn- and Mn-SOD), glutathione-S-transferase (GST) and cholinesterase (ChE) activities and also higher MT-related thiol concentration in the liver and gills. A common effect of exposure was related to genotoxicity, a decrease in GSH and an increase in microsomal ethoxyresorufin O-deethylase activity in the liver. However, the systems of oxidative stress and biotransformation were more efficient in fish from the polluted site, while the responsivity of MTs in this fish was impaired. Principle Component Analysis separated the subgroups from the unpolluted site and fish loaded by lesser concentrations of metals on the one side, and fish from the polluted site jointly with fish exposed to higher concentrations of metals on the other side. The main distinguishing indices of sites and exposures selected by classification and regression tree (CART) analysis were MT characteristics and genotoxicity. PMID- 21699998 TI - Surface EMG to assess and quantify upper airway dilators activity during non invasive ventilation. AB - This study tests the hypothesis that the surface electromyographic (EMG) activity of upper airway dilators would respond to inspiratory loading in a healthy humans model of ventilator trigger asynchrony. EMG activity was measured in levator alae nasi, genioglossus, parasternal, scalene and diaphragm muscles in eight subjects. They breathed quietly through a face mask and then were connected to a mechanical ventilator. Recordings were performed during nasal breathing against negative pressure triggers (-2.5%, -5% and -10% of maximal inspiratory pressure) and during oro-nasal breathing with a "-10% trigger". Scalene, alae-nasi and genioglossus EMG activity level increased with the "-10% trigger". While no breathing route dependence was found in scalene, the significant increase was only found for nasal breathing in alae-nasi and for oro-nasal breathing in genioglossus. The dyspnea intensity was significantly correlated with the EMG activity level of these three muscles. Surface EMG of airway dilator muscles could be used as a complementary tool to assess inspiratory drive during mechanical ventilation. PMID- 21700000 TI - Morphological analysis of the trachea and pattern of breathing in betaENaC-Tg mice. AB - Cystic fibrosis (CF) is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene which is a Cl- channel and a regulator of the epithelial Na+ channel (ENaC). We have recently shown that newborn CFTR deficient mice exhibit abnormalities of the tracheal cartilage leading to altered ventilation (Bonvin et al., 2008). However, the mechanism by which a lack of CFTR causes tracheal cartilage defects remains unknown. The main goal of the present study was to determine whether the development of airway cartilage defects is related to ENac channel dysfunction. We thus performed macroscopic analysis of the trachea and explored ventilatory function in adult betaENaC-overexpressing (betaENaC-Tg) mice with airway Na+ hyperabsorption and "CF-lung" lung disease, at 2 and 5 month of age. Only minor cartilaginous abnormalities were observed in 8 out of 16 betaENaC-Tg mice and in 2 out of 20 littermate controls. Breathing pattern was progressively altered in betaENaC-Tg mice as evidenced by a significant decrease in respiratory frequency. Our results suggest that Na+ hyperabsorption alone is not a major contributor to the development of tracheal malformation observed in CF mice and that breathing pattern changes in betaENaC Tg mice likely reflect airflow limitation due to airway mucus obstruction. PMID- 21699999 TI - A neonatal mouse model of intermittent hypoxia associated with features of apnea in premature infants. AB - A neonatal mouse model of intermittent hypoxia (IH) simulating the recurring hypoxia/reoxygenation episodes of apnea of prematurity (AOP) was developed. C57BL/6 P2 pups were culled for exposure to either intermittent hypoxia or intermittent air as control. The IH paradigms consisted of alternation cycles of 20.9% O2 and either 8.0% or 5.7% O2 every 120 or 140s for 6h a day during daylight hours from day 2 to day 10 postnatally, i.e., roughly equivalent to human brain development in the perinatal period. IH exposures elicited modest to severe decrease in oxygen saturation along with bradycardia in neonatal mice, which were severity-dependent. Hypomyelination in both central and peripheral nervous systems was observed despite the absence of visible growth retardation. The neonatal mouse model of IH in this study partially fulfills the current diagnostic criteria with features of AOP, and provides opportunities to reproduce in rodents some of the pathophysiological changes associated with this disorder, such as alterations in myelination. PMID- 21700001 TI - A novel dominant mutation in SIX1, affecting a highly conserved residue, result in only auditory defects in humans. AB - Branchio-oto-renal (BOR) and Branchio-otic (BO) syndromes are dominant disorders characterized by variable hearing impairment (HI) and branchial defects. BOR includes additional kidney malformations. BO/BOR syndromes are genetically heterogeneous and caused by mutations in EYA1 and SIX1 genes. Mutation in SIX1 is responsible also for DFNA23, a locus for non-syndromic HI. Strikingly, the severity of the phenotype did not seem to correlate with the type of SIX1 mutation. Herein, we identified a novel mutation in SIX1 (p.E125K) in a Tunisian family with variable HI and preauricular pits. This mutation is located at the same position as the mutation identified in the Catwhesel (Cwe) mouse. No renal and branchial defects were observed in our family nor in Cwe/+ mice. A homology model revealed that the replacement of the Glutamate by a Lysine alters the electrostatic potential surface propriety which may affect the DNA-binding activity. PMID- 21700002 TI - A de novo 1.1Mb microdeletion of chromosome 19p13.11 provides indirect evidence for EPS15L1 to be a strong candidate for split hand split foot malformation. AB - We describe a 3.5 year old girl presenting with short stature, developmental delay, marked muscular hypotonia with ataxia, premature pubarche, and dysmorphic features. A 1.07-1.12Mb-sized de novo microdeletion of chromosome 19p13.11 is most likely the cause for the clinical phenotype. The patient did not show any abnormalities of the extremities which contrasts with the finding of one previously reported patient with an overlapping deletion presenting with split hand and foot malformation (SHFM). The remarkable difference is that in the previously described patient but not in the patient reported herein the genes EPS15L1 and CALR3 were deleted. As EPS15L1 has been associated with limb development previously, the presented case provides indirect evidence that this may be a new candidate gene for SHFM. A possible genotype-phenotype correlation is provided based on literature review and comparison of our patient to the previously reported patients with overlapping or partly overlapping copy number variations in 19p13.11. PMID- 21700003 TI - Influence of age and gender on associations of body mass index with bone mineral density, bone turnover markers and circulating calcium-regulating and bone-active sex hormones. AB - Although it is well known that body mass index (BMI) and bone mineral density (BMD) are positively correlated, the mechanisms by which adiposity reduces the risk of osteoporotic fractures are not fully understood. The present study was initiated to gain deeper insight into the mechanisms underlying the osteoprotective effect of adiposity, and to assess particularly the relevance that BMI-associated changes in circulating hormone levels could have for the build-up of additional bone mineral density. Using data from a previous study on a large cohort of healthy adult Austrians, we analyzed correlations of BMI with (i) BMD at sites in the lumbar spine and hip region, (ii) bone resorption and formation markers, (iii) circulating levels of vitamin D, parathyroid hormone, testosterone and estrogen, and (iv) rates of daily vitamin D and calcium intake. After adjustment for age, positive correlations between BMI and BMD were highly significant (P<0.0001) at all skeletal sites across the entire study cohort. Associations were stronger in post-menopausal women than in pre-menopausal women and in men. In absolute values, the gain in BMD at the lumbar spine from an incremental rise of BMI in post-menopausal women was 1.5-fold higher than in pre menopausal women, and three times of that observed in men (P<0.05). Inverse relations between BMI and beta-crosslaps were consistently found in men (P<0.01) and in women before and after menopause (P<0.01 and P<0.05, respectively), suggesting that inhibition of osteoclastic bone resorption is responsible at least in part for the positive effect of high BMI on BMD. Sub-group analysis revealed that increasing BMI was associated with a significant fall of testosterone in men (P<0.05), and of 25-(OH)D in pre- and post-menopausal women (P<0.001 and P<0.05, respectively), but with a significant rise in PTH (P<0.01) in women before menopause. Since all these hormonal changes would cause bone loss, this excludes their playing any role in the osteoprotective effect of adiposity. PMID- 21700004 TI - Epigenetic regulation of alkaline phosphatase in human cells of the osteoblastic lineage. AB - Epigenetic mechanisms play an important role in the tissue-specific regulation of gene expression. This study analyzed the relationship between tissue non-specific alkaline phosphatase (ALPL) gene expression and the methylation of a CpG island located in its proximal region. Gene expression was analyzed by real time RT-qPCR in primary human osteoblasts (hOBs), the osteoblastic cell line MG-63, the mammary cell line MCF-7, and bone tissue. DNA methylation was analyzed by qMSP in those cells and also in lining osteoblasts and in osteocytes obtained from human bone samples by laser-assisted capture. hOBs expressed much more ALPL mRNA than MG-63 cells (7.3+/-3.2 vs. 0.2+/-0.1 arbitrary units, respectively). hOBs showed a very weak DNA methylation (<10%), whereas MG-63 had a higher degree of methylation (58+/-6%). Likewise, MCF-7 cells, which scarcely expressed ALPL, had a hypermethylated CpG island. Thus, the degree of methylation in the CpG island was inversely associated with the transcriptional levels of ALPL in the studied cells. Furthermore, treatment with the DNA demethylating agent AzadC induced a 30 fold increase in ALPL expression, in MG-63 cells, accompanied by a parallel increase in alkaline phosphatase activity. However, AzadC did not affect ALPL levels in the already hypomethylated hOBs. In addition, in microdissected osteocytes, which do not express alkaline phosphatase, the CpG island was highly methylated (>90%), whereas lining osteoblasts showed an intermediate degree of methylation (58+/-13%). These results suggest an important role of DNA methylation in the regulation of ALPL expression through the osteoblast-osteocyte transition. PMID- 21700005 TI - Strontium ranelate inhibits key factors affecting bone remodeling in human osteoarthritic subchondral bone osteoblasts. AB - INTRODUCTION: In osteoarthritis (OA) the progression of cartilage degeneration has been associated with remodeling of the subchondral bone. Human OA subchondral bone osteoblasts were shown to have an abnormal phenotype and altered metabolism leading to an abnormal resorptive process. Bone resorption is suggested to occur, at least in part, through the increased levels of two proteolytic enzymes, MMP-2 and MMP-9, and RANKL, which are mainly produced by osteoblasts. In this study, we investigated in human OA subchondral bone osteoblasts the modulatory effect of strontium ranelate on the above key factors. METHODS: Human subchondral bone osteoblasts were cultured in a medium containing 0.1, 1 and 2 mM of strontium ranelate for 18 h for mRNA and 72 h for protein determination. The effect of strontium ranelate was evaluated on the expression (qPCR) of MMP-2, MMP-9, OPG, RANKL (total), RANKL-1, and RANKL-3, on the production of OPG (ELISA), membranous RANKL (flow cytometry), and MT1-MMP, ADAM17, and ADAM19 (Western blot). After incubation of osteoblasts with pre-osteoclasts (i.e., differentiated human peripheral blood mononuclear cells), the resorbed surface was measured using a sub-micron synthetic calcium phosphate thin film. RESULTS: Firstly, the expression levels of MMP-2, MMP-9, OPG, and RANKL were determined in normal and OA subchondral bone osteoblasts. As expected, the gene expression of MMP-9 and RANKL were not detectable in normal cells, whereas MMP-2 was very low but detectable and OPG demonstrated high gene expression. Further experiments looking at the effect of strontium ranelate on expression levels, except for OPG, were performed only on the OA subchondral bone osteoblasts. In OA cells, the expression levels of MMP-2 and MMP-9 were significantly decreased by strontium ranelate at 1mM (p<=0.005, p<=0.02, respectively) and 2 mM (p<=0.003, p<=0.007), and for MMP-9 only at 0.1 mM (p<=0.05). In normal cells, the expression of OPG was increased with strontium ranelate at 2 mM, and in OA both the expression (p<=0.02) and synthesis (p<=0.002) of OPG were significantly increased with strontium ranelate at 1 and 2 mM. RANKL (total) as well as the isoforms RANKL-1 and RANKL-3 were significantly increased by strontium ranelate at 1 and 2 mM. Of note, it is known that the different RANKL isoforms differentially regulate RANKL membranous localization: RANKL-3, in contrast to RANKL-1, prevents such membranous localization. This is reflected by the significant (p<=0.02) reduction in the level of membranous RANKL by strontium ranelate at 2 mM. This latter finding was not likely to be related to a proteolytic cleavage of membranous RANKL, as the enzymes known to cleave it, MT1-MMP, ADAM17 and ADAM19, were unaffected by strontium ranelate. In addition, OA osteoblasts treated with strontium ranelate induced a significant (p<=0.002) decrease in resorbed surface at the three tested concentrations. CONCLUSION: This study provides new insights into the mode of action of strontium ranelate on the metabolism of human OA subchondral bone osteoblasts. These data suggest that strontium ranelate may exert a positive effect on OA pathophysiology by inhibiting, in these cells, the synthesis of key factors leading to bone resorption, a feature associated with the OA process. PMID- 21700006 TI - Invited review: associations between variables of routine herd data and dairy cattle welfare indicators. AB - As farm animal welfare is high on the political and societal agendas of many countries, considerable pressure exists to establish audit programs in which farm animal welfare is routinely monitored. On-farm assessment of animal welfare, however, is time-consuming and costly. A promising strategy to monitor animal welfare more efficiently is to first estimate the level of animal welfare on a farm based on routine herd data that are available in national databases. It is not currently known which variables of routine herd data (VRHD) are associated with dairy cattle welfare indicators (WI). Our aim was to identify VRHD that are associated with WI in a literature review. The 27 VRHD used in this review included the main types of data that are currently collected in national herd databases of developed countries, and related to identification and registration, management, milk production, and reproduction of dairy herds. The 34 WI used in this review were based on the Welfare Quality Assessment Protocol for Cattle. The search yielded associations in 146 studies. Twenty-three VRHD were associated with 16 WI. The VRHD that related to milk yield, culling, and reproduction were associated with the largest number of WI. Few associations were found for WI that referred to behavioral aspects of animal welfare, nonspecific disease symptoms, or resources-based indicators. For 18 WI, associations with VRHD were not significant (n=5 WI) or no studies were found that investigated associations with VRHD (n=13 WI). It was concluded that many VRHD have potential to estimate the level of animal welfare on dairy farms. As strengths of associations were not considered in this review, however, the true value of these VRHD should be further explored. Moreover, associations found at the animal level and in an experimental setting might not appear at the farm level and in common practice and should be investigated. Cross-sectional studies using integrated welfare scores at the farm level are needed to more accurately determine the potential of VRHD to estimate levels of animal welfare on dairy farms. PMID- 21700008 TI - beta-Galactosidase activity of commercial lactase samples in raw and pasteurized milk at refrigerated temperatures. AB - Many consumers are unable to enjoy the benefits of milk due to lactose intolerance. Lactose-free milk is available but at about 2 times the cost of regular milk or greater, it may be difficult for consumers to afford. The high cost of lactose-free milk is due in part to the added cost of the lactose hydrolysis process. Hydrolysis at refrigerated temperatures, possibly in the bulk tank or package, could increase the flexibility of the process and potentially reduce the cost. A rapid beta-galactosidase assay was used to determine the relative activity of commercially available lactase samples at different temperatures. Four enzymes exhibited low-temperature activity and were added to refrigerated raw and pasteurized milk at various concentrations and allowed to react for various lengths of time. The degree of lactose hydrolysis by each of the enzymes as a function of time and enzyme concentration was determined by HPLC. The 2 most active enzymes, as determined by the beta-galactosidase assay, hydrolyzed over 98% of the lactose in 24h at 2 degrees C using the supplier's recommended dosage. The other 2 enzymes hydrolyzed over 95% of the lactose in 24h at twice the supplier's recommended dosage at 2 degrees C. Results were consistent in all milk types tested. The results show that it is feasible to hydrolyze lactose during refrigerated storage of milk using currently available enzymes. PMID- 21700007 TI - Diversity of lactic acid bacteria associated with traditional fermented dairy products in Mongolia. AB - Spontaneous milk fermentation has a long history in Mongolia, and beneficial microorganisms have been handed down from one generation to the next for use in fermented dairy products. The objective of this study was to investigate the diversity of lactic acid bacteria (LAB) communities in fermented yak, mare, goat, and cow milk products by analyzing 189 samples collected from 13 different regions in Mongolia. The LAB counts in these samples varied from 3.41 to 9.03 log cfu/mL. Fermented yak and mare milks had almost identical mean numbers of LAB, which were significantly higher than those in fermented goat milk but slightly lower than those in fermented cow milk. In total, 668 isolates were obtained from these samples using de Man, Rogosa, and Sharpe agar and M17 agar. Each isolate was considered to be presumptive LAB based on gram-positive and catalase-negative properties, and was identified at the species level by 16S rRNA gene sequencing, multiplex PCR assay, and restriction fragment length polymorphism analysis. All isolates from Mongolian dairy products were accurately identified as Enterococcus faecalis (1 strain), Enterococcus durans (3 strains), Lactobacillus brevis (3 strains), Lactobacillus buchneri (2 strains), Lactobacillus casei (16 strains), Lactobacillus delbrueckii ssp. bulgaricus (142 strains), Lactobacillus diolivorans (17 strains), Lactobacillus fermentum (42 strains), Lactobacillus helveticus (183 strains), Lactobacillus kefiri (6 strains), Lactobacillus plantarum ssp. plantarum (7 strains), Lactococcus lactis ssp. lactis (7 strains), Leuconostoc lactis (22 strains), Leuconostoc mesenteroides (21 strains), Streptococcus thermophilus (195 strains), and Weissella cibaria (1 strain). The predominant LAB were Strep. thermophilus and Lb. helveticus, which were isolated from all sampling sites. The results demonstrate that traditional fermented dairy products from different regions of Mongolia have complex compositions of LAB species. Such diversity of LAB provides useful information for further studies of probiotic strain selection and starter culture design, with regard to the industrial production of traditional fermented milk. PMID- 21700009 TI - Determination of molecular weight of a purified fraction of colloidal calcium phosphate derived from the casein micelles of bovine milk. AB - Colloidal calcium phosphate (CCP) plays a key role in the formation and integrity of casein (CN) micelles. However, limited information is available on the molecular weight (M(w)) of CCP. Recently, we theoretically derived the M(w) of CCP and the objectives of this study were to experimentally determine the M(w) of CCP. We used 2 methods to prepare CCP fractions: skim milk was enzymatically digested with either trypsin or a combination of papain and proteinase enzymes to remove most CN. The CN phosphopeptides are resistant to trypsin hydrolysis. Digestion was carried out in a membrane tube that was dialyzed against the same bulk milk used in sample preparation to remove small peptides and to minimize perturbation of CCP. After digestion, the protein contents of the enzyme-treated milks were 0.92 and 0.36% for the trypsin and papain-proteinase treatments, respectively. Size-exclusion chromatography, coupled with multi-angle laser light scattering, was used to separate the CCP-phosphopeptide fraction from the digested mixture. Simulated milk ultrafiltrate was used as a mobile phase during size-exclusion chromatography separation to try to preserve the integrity of CCP. Size-exclusion chromatography peaks, which had higher Ca and P contents than the baseline, were identified as the likely fractions containing the phosphopeptide stabilized CCP; this peak eluted with retention times of 100 to approximately 110 min for trypsinated samples. The papain-proteinase treatment caused excessive loss of CN that were needed to stabilize CCP, which resulted in no obvious peak that had elevated Ca and P contents. Debye plots at these retention times indicated that the weight-average M(w) for the fraction prepared by trypsin was 17,450 g/mol. Attempts to estimate the M(w) of the phosphopeptides associated with CCP using sodium dodecyl sulfate-PAGE were not successful, as we did not observe any peptide bands in these gels, presumably because of their low concentration in the isolated, unconcentrated fraction. Assuming that 4 CN phosphopeptides stabilized each CCP and if the M(w) of each of these phosphopeptides was about 2,500 g/mol, then the M(w) of CCP would be around 7,450 g/mol. This experimental value was close to the theoretically-derived M(w) of 4,897 and 9,757 g/mol for tetrahedron and bi-pyramid shaped objects, respectively, when using the brushite form of calcium phosphate. PMID- 21700010 TI - Lactococcus strains treated with heat and hen-egg-white lysozyme induce abundant interleukin-12 production by J774.1 macrophages and murine spleen cells. AB - The IL-12-inducing ability of lactic acid bacteria could be a critical index of immunomodulatory activity, especially in promoting T-helper-1 responses and in suppressing T-helper-2-mediated allergic responses. We aimed to develop a simple method for enhancing the IL-12-inducing ability of bacteria. We examined the in vitro effects of strains of lysozyme-modified Lactococcus (ML-LYS), prepared by heat treatment of the Lactococcus strain in the presence of lysozyme, on the ability of mouse macrophage-like J774.1 cells and spleen cells to produce IL-12. An IL-12-inducing ability greater than that of heat-killed bacteria was shown by 41 of 46 ML-LYS strains in J774.1 cells and by all 46 ML-LYS strains in mouse spleen cells. In contrast, bacteria modified by alpha-lactalbumin, beta lactoglobulin, or ovalbumin did not enhance IL-12 production in J774.1 cells. Microscopically, ML-LYS showed stronger resistance to lysozyme and macrophage digestion than did heat-killed bacteria or the other modified bacteria. Addition of chitotriose, a lysozyme inhibitor, enhanced IL-12 production by J774.1 cells stimulated with heat-killed bacteria. Therefore, enhancement of resistance to lysozyme may be a key factor in the strong IL-12-inducing ability of ML-LYS. These findings have important implications for the design of dairy products that have an immunomodulatory effect using the modified bacteria. PMID- 21700011 TI - Evaluation of yogurt and various beverages as carriers of lactic acid bacteria producing 2-branched (1,3)-beta-D-glucan. AB - Probiotic cultures are increasingly being incorporated into a wide variety of food products. Although lactobacilli and bifidobacteria are the most frequently used, other lactic acid bacteria (LAB) have been reported to be potential probiotics. Of these, the cider isolates Pediococccus parvulus (strains 2.6 and CUPV22) and Lactobacillus suebicus CUPV221 produce a 2-branched (1,3)-beta-d glucan exopolysaccharide that decreases serum cholesterol levels and affects the activation of human macrophages. For this reason, these 3 strains were incorporated into yogurt, orange juice, and 2 juice-milk beverages to evaluate the effect of the food matrix on the resistance of these strains to simulated gastrointestinal tract conditions. Our results showed that incorporation of the LAB did not significantly affect the physical and rheological properties of the food matrices tested. When incorporated in yogurt, LAB strains population decreased by 2 to 3 log orders of magnitude during the shelf life of the product (28 d). However, no significant decrease was observed in the juice and juice-milk beverages during the same storage period, except for Lb. suebicus, whose viability decreased by 3 log orders of magnitude. When strains were subjected to gastrointestinal tract conditions, a decrease in the survival was observed at the lower pH (1.8). However, incorporation of these LAB strains into orange juice increases their resistance to lower pH conditions, thus improving survival to gastrointestinal stress. Moreover, a protective effect was observed for P. parvulus CUPV22 and 2.6 to gastric stress in juice-milk beverages and to gastrointestinal stress in yogurt. Lactobacillus suebicus CUPV221 did not survive when incorporated into yogurt and juice-milk beverage. PMID- 21700012 TI - Assessment of the application of an automated electronic milk analyzer for the enumeration of total bacteria in raw goat milk. AB - Automated electronic milk analyzers for rapid enumeration of total bacteria counts (TBC) are widely used for raw milk testing by many analytical laboratories worldwide. In Ontario, Canada, Bactoscan flow cytometry (BsnFC; Foss Electric, Hillerod, Denmark) is the official anchor method for TBC in raw cow milk. Penalties are levied at the BsnFC equivalent level of 50,000 cfu/mL, the standard plate count (SPC) regulatory limit. This study was conducted to assess the BsnFC for TBC in raw goat milk, to determine the mathematical relationship between the SPC and BsnFC methods, and to identify probable reasons for the difference in the SPC:BsnFC equivalents for goat and cow milks. Test procedures were conducted according to International Dairy Federation Bulletin guidelines. Approximately 115 farm bulk tank milk samples per month were tested for inhibitor residues, SPC, BsnFC, psychrotrophic bacteria count, composition (fat, protein, lactose, lactose and other solids, and freezing point), and somatic cell count from March 2009 to February 2010. Data analysis of the results for the samples tested indicated that the BsnFC method would be a good alternative to the SPC method, providing accurate and more precise results with a faster turnaround time. Although a linear regression model showed good correlation and prediction, tests for linearity indicated that the relationship was linear only beyond log 4.1 SPC. The logistic growth curve best modeled the relationship between the SPC and BsnFC for the entire sample population. The BsnFC equivalent to the SPC 50,000 cfu/mL regulatory limit was estimated to be 321,000 individual bacteria count (ibc)/mL. This estimate differs considerably from the BsnFC equivalent for cow milk (121,000 ibc/mL). Because of the low frequency of bulk tank milk pickups at goat farms, 78.5% of the samples had their oldest milking in the tank to be 6.5 to 9.0 d old when tested, compared with the cow milk samples, which had their oldest milking at 4 d old when tested. This may be one of the major factors contributing to the larger goat milk BsnFC equivalence. Correlations and interactions between various test results were also discussed to further understand differences between the 2 methods for goat and cow milks. PMID- 21700013 TI - Effect of probiotic yogurt containing Lactobacillus acidophilus and Bifidobacterium lactis on lipid profile in individuals with type 2 diabetes mellitus. AB - The purpose of this study was to investigate the effects of probiotic and conventional yogurt on the lipid profile in type 2 diabetic people. In a randomized double-blind controlled trial, 60 people (23 males and 37 females) with type 2 diabetes and low-density lipoprotein cholesterol (LDL-C) greater than 2.6 mmol/L were assigned to 2 groups. Participants consumed daily 300 g of probiotic yogurt containing Lactobacillus acidophilus La5 and Bifidobacterium lactis Bb12 or 300 g of conventional yogurt for 6 wk. Fasting blood samples, anthropometric measurements and 3-d, 24-h dietary recalls were collected at the baseline and at the end of the trial. Probiotic yogurt consumption caused a 4.54% decrease in total cholesterol and a 7.45% decrease in LDL-C compared with the control group. No significant changes from baseline were shown in triglyceride and high-density lipoprotein cholesterol (HDL-C) in the probiotic group. The total cholesterol:HDL-C ratio and LDL-C:HDL-C ratio as atherogenic indices significantly decreased in the probiotic group compared with the control group. Probiotic yogurt improved total cholesterol and LDL-C concentrations in type 2 diabetic people and may contribute to the improvement of cardiovascular disease risk factors. PMID- 21700014 TI - Effect of polymorphisms in the leptin, leptin receptor, and acyl-coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) genes and genetic polymorphism of milk proteins on cheese characteristics. AB - Cheese production has increased worldwide during the last decade and is expected to increase within the coming decade as well. Despite this, the relations between cow genetics and cheese characteristics are not fully known. The aim of this study was to determine if polymorphisms in the leptin (LEP), leptin receptor (LEPR), and acyl-coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) genes as well as genetic variants of beta-casein (beta-CN), kappa-CN, and beta lactoglobulin (beta-LG) affect technological properties important for cheese production and, hence, could act as genetic makers for cheese quality. Individual milk samples from the Swedish Red and the Swedish Holstein breeds were analyzed for sizes of CN micelles and fat globules as well as rennet-induced gel strength, gelation time, and yield stress. Model cheeses were produced to study yield, hardness, and pH of the cheeses. The A1457G, A252T, A59V, and C963T single nucleotide polymorphisms (SNP) were analyzed on the LEP gene, the T945M SNP on the LEPR gene, and the Nt984+8(A-G) SNP on the DGAT1 gene. In addition, genetic variants of beta-CN, kappa-CN, and beta-LG were determined. The results indicate that technological properties were influenced by the LEPR(T945M) polymorphism, which had an association with gel strength, yield stress, and cheese hardness (T > C). However, also LEP(A252T) was shown to affect gel strength (T > A), whereas the LEP(A59V) had an effect on fat globule size (T > C). For the milk protein genes, favorable effects were found for the A and B variants of beta-LG and kappa CN, respectively, on gel strength, gelation time, and yield stress. In addition, the B variant of kappa-CN was shown to be associated with smaller CN micelles than the A variant. Thus, the results demonstrate potential genetic markers for cheese characteristics. However, milk composition traits also affected the obtained results, thus making it necessary to thoroughly assess the different aspects regarding the influence of gene effects on cheese characteristics before directly selecting for certain alleles or genetic variants to improve the processing and quality of cheese. PMID- 21700015 TI - Short communication: profile of virulence factors of Staphylococcus aureus isolated from subclinical bovine mastitis in the state of Rio de Janeiro, Brazil. AB - Staphylococcus aureus produces exoproteins that contribute to its ability to colonize the mammary gland such as hemolysins, coagulase, slime, and protein A. This study characterized phenotypically and genotypically these virulence factors in 50 Staph. aureus isolates. These isolates were obtained from milk samples from subclinical mastitis cases identified in 15 dairy cattle farms located in the state of Rio de Janeiro, Brazil. All of the confirmed Staph. aureus samples were PCR positive for the coa gene, which displayed 3 different size polymorphisms. The amplification of the spaA X region yielded a single amplicon for each isolate with the prevalent amplicon sized 315 bp. The Staph. aureus isolates were 24 and 16% positive for the hla and hlb genes, respectively, and 22 and 20% positive for the icaA and icaD genes, respectively. Amplification of the agr gene RNAIII was positive in 74% of the strains. Twenty-seven different profiles were identified among the samples, indicating a great diversity of Staph. aureus involved in the etiology of mastitis cases in the analyzed region. These findings are valuable to the comprehension of the distribution of the profiles of Staph. aureus strains isolated from subclinical mastitis cases in the state of Rio de Janeiro. PMID- 21700016 TI - Short communication: characterization of microflora in Mexican Chihuahua cheese. AB - This work was performed to identify the bacterial species present in 10 Chihuahua cheeses obtained from commercial producers in Mexico using 16S rRNA gene analysis. As expected, some of the agar media initially used for isolation were not very selective, supporting the growth of several unrelated bacterial species. Sequence analysis identified potential pathogens, including Escherichia coli and Staphylococcus aureus, in all raw milk samples and 2 pasteurized milk samples. Streptococcus thermophilus and Lactococcus lactis ssp. lactis were identified in 9 and 6 samples, respectively, and would serve as acidifying agents during cheese production. Lactobacilli were identified in all cheeses, with the most prevalent being Lactobacillus plantarum identified in 7 raw milk and 1 pasteurized milk cheeses. Leuconostoc mesenteroides and Streptococcus macedonicus were identified in 4 raw milk cheeses and both were present in all pasteurized milk samples, suggesting that they may play a role in the development of traditional Chihuahua cheese attributes. PMID- 21700017 TI - Short communication: determination of inulin in milk using high-performance liquid chromatography with evaporative light scattering detection. AB - The objective of this study was to develop an HPLC method for the determination of inulin in a dairy matrix. Inulin is often added to dairy products to act as a source of dietary fiber as well as to provide technological functionality (e.g., water-holding or fat-replacing functions). The method includes hydrolysis of inulin with inulinase enzyme and determination of released fructose and glucose by HPLC coupled with evaporative light scattering detection, using water as the mobile phase. The effect of the milk background was investigated, preparing standards in milk, whey, or permeate and subjecting them to inulinase treatment. The developed method showed satisfactory linearity (R(2)=0.98 for glucose and 0.99 for fructose), good repeatability (relative standard deviation, RSD, ranging from 2.2 to 7.3% for glucose and from 0.6 to 2.3% for fructose), satisfactory reproducibility (RSD from 8.1 to 12.9% for glucose and from 3.1 to 4.9% for fructose), and good recovery (98.4 to 103.6%). PMID- 21700018 TI - Incidence of metabolic disorders and reproductive performance following a short (35-d) or conventional (60-d) dry period management in commercial Holstein herds. AB - A total of 850 Holstein cows from 13 commercial dairy herds were involved in the present study to compare the effects of 2 different dry period (DP) management strategies on health and reproductive parameters. Cows were assigned to either a short (SDP; 35-d) or a conventional (CDP; 60-d) DP management within each herd, based on previous 305-d milk yield, parity (414 primiparous and 436 multiparous), and estimated calving interval. Cows assigned to CDP were fed a dry cow ration from dry-off until 21 d prepartum, and were then switched to a precalving ration. Cows assigned to SDP were fed the precalving ration throughout their DP. Rations were specific to each herd. A significant treatment * parity interaction was found for culling rate. Dry period management did not affect culling rate for second-lactation cows but a significantly higher culling rate occurred in multiparous CDP cows compared with SDP (42.6 vs. 31.6% +/- 3.7 for CDP and SDP, respectively). Management used in the DP did not affect incidence of severe ketosis, displaced abomasum, milk fever, and mastitis, although incidence of these metabolic disorders were lower in second-lactation than third- or greater lactation cows. The incidence of mild ketosis (evaluated by milk ketone concentration) was lower following SDP, probably as a result of better energy balance. On the other hand, the incidence of retained placenta was higher in multiparous cows assigned to SDP, but the reason for this increase remains unclear. Nevertheless, this did not lead to increased incidence of metritis. Moreover, DP management did not influence reproductive measures, including days in milk at first breeding, number of breedings per conception, as well as conception rates at first and second services. Regarding days open, overall, all 13 herds were not significantly affected by treatment, but 1 herd clearly showed opposite results to the 12 others. Our results indicate that a short DP management strategy could facilitate transition from one lactation to the next by decreasing the incidence of mild ketosis, with no major negative effects on other health parameters and reproduction. The variation in results observed among herds suggests that other management practices influence the response observed following a short or conventional DP, emphasizing the need for other field studies. PMID- 21700019 TI - Bovine neuronal vesicular glutamate transporter activity is inhibited by ergovaline and other ergopeptines. AB - l-Glutamate (Glu) is a major excitatory neurotransmitter responsible for neurotransmission in the vertebrate central nervous system. Vesicular Glu transporters VGLUT1 and VGLUT2 concentrate (50mM) Glu [Michaelis constant (measuring affinity), or K(m),=1 to 4mM] into synaptic vesicles (SV) for subsequent release into the synaptic cleft of glutamatergic neurons. Vesicular Glu transporter activity is dependent on vacuolar H(+)-ATPase function. Previous research has shown that ergopeptines contained in endophyte-infected tall fescue interact with dopaminergic and serotoninergic receptors, thereby affecting physiology regulated by these neuron types. To test the hypothesis that ergopeptine alkaloids inhibit VGLUT activity of bovine cerebral SV, SV were isolated from cerebral tissue of Angus-cross steers that were naive to ergot alkaloids. Immunoblot analysis validated the enrichment of VGLUT1, VGLUT2, synaptophysin 1, and vacuolar H(+)-ATPase in purified SV. Glutamate uptake assays demonstrated the dependence of SV VGLUT-like activity on the presence of ATP, H(+)-gradients, and H(+)-ATPase function. The effect of ergopeptines on VGLUT activity was evaluated by ANOVA. Inhibitory competition (IC(50)) experiments revealed that VGLUT-mediated Glu uptake (n=9) was inhibited by ergopeptine alkaloids: bromocriptine (2.83+/-0.59MUM)97%) for most organisms. Factors such as lactation number and stage of lactation were evaluated for their influence on the Se and Sp of composite sampling, but were only found to be significant for coagulase-negative staphylococci. Predictive values using the herd prevalences found across Canada were calculated and can be useful in field scenarios when composite sampling is employed to assist mastitis management. When used to detect newly occurring IMI in pairs of samples taken before dry-off, post-calving, and also prior to and subsequent to the dry period, composite samples were shown to have lower Se but similar Sp for all pathogens investigated. Composite samples can be used to detect IMI and new IMI in dairy cows, but the Se and Sp of the procedure should be taken into account. PMID- 21700025 TI - Risk factors associated with short-term post-treatment outcomes of clinical mastitis. AB - The objectives of this study were to characterize 60-d outcomes after treatment of mild (abnormal milk) and moderate (abnormal milk and abnormal udder) cases of clinical mastitis (CM) occurring in a single quarter of cows on Wisconsin farms (n=4) and to determine risk factors associated with those outcomes. Duplicate milk samples were collected from the affected quarter of each cow for microbiological analysis at the onset of CM (PRE) and 21 d later (POST). Cows were treated only in the affected quarter using an intramammary product containing 125 mg of ceftiofur. Bacteriological cure was defined as absence of pathogens in the POST sample obtained from the enrolled quarter. Recurrence was defined for the cow when CM occurred after the milk-withholding period for the enrolled case of CM. Retention in the herd was defined when a cow was retained within the herd for the 60-d follow-up period. Somatic cell count reduction (SCCR) was defined at the cow level as somatic cell count (SCC) below 200,000 cells/mL at the Dairy Herd Improvement Association test day occurring between 21 to 55 d post-treatment. The effects of farm, days in milk, parity, severity, microbiological diagnosis at PRE, previous milk yield, previous SCC, previous occurrence of CM and treatment duration on selected post-treatment outcomes were assessed using Chi-squared analysis and logistic regression. Microbiological results at PRE were distributed as: Escherichia coli (n=14), Klebsiella spp. (n=11), Enterobacter spp. (n=8), Serratia spp. (n=7), other gram-negative species (n=3), Streptococcus spp. (n=25), coagulase-negative staphylococci (n=4); Staphylococcus aureus (n=1); Streptococcus agalactiae (n=1), other gram-positive species (n=9), and culture negative (n=60). Treated quarters were more likely to experience bacteriological cure when the cow experienced CM for the first time in the lactation and when no pathogen was recovered from PRE milk samples obtained from the enrolled quarter. Parity and bacteriological cure were associated with the probability of recurrence. Greater milk yield at previous Dairy Herd Improvement test was the most important predictor for retention within the herd. When SCC before CM was >200,000 cells/mL the probability of having SCCR after treatment was decreased. When the case experienced bacteriological cure, the cow was less likely to experience recurrent cases and was more likely to have SCCR below 200,000 cells/mL. Post-treatment outcomes, such as recurrence and SCCR, are strongly associated with bacteriological cure and, when monitored, can be used to help determine if a treatment has been successful. Information about the etiology of CM, history of clinical and subclinical mastitis, and parity are useful to review when making strategic treatment decisions. PMID- 21700026 TI - Detection of multiple Mycoplasma species in bulk tank milk samples using real time PCR and conventional culture and comparison of test sensitivities. AB - The objective of this study was to further validate a SYBR PCR protocol for Mycoplasma spp. by comparing it with standard microbial culture in the detection of Mycoplasma spp. in bulk tank milk samples. Additionally, we identified Mycoplasma spp. present by analysis of PCR-generated amplicons [dissociation (melt) temperature (T(m)), length, and DNA sequence]. The research presented herein tests the hypothesis that the SYBR PCR protocol is as sensitive as conventional culture for the detection of Mycoplasma spp. in bulk tank milk samples. Mycoplasmas cause several important disease syndromes in cattle, including mastitis in dairy cows. The standard diagnostic method at the herd level has been microbial isolation of mycoplasmas on 1 of several specialized media and speciation through biochemical or immunological techniques; repeated sampling schemes are recommended. The development of a real-time SYBR PCR protocol offers advantages in decrease of time to detection, cost, and complexity. The T(m) of the double-stranded DNA generated from the PCR reaction was used to detect the presence of and tentatively identify the species of mycoplasmas other than Mycoplasma bovis. In the SYBR PCR protocol, the presence of multiple species of mycoplasmas is indicated by an atypical dissociation curve. Gel electrophoresis and sequencing of the amplicons was used to confirm the mycoplasma species present when a non-M. bovis organism was detected (T(m) not equal to M. bovis) and used to identify all the mycoplasma species present for the samples with atypical dissociation curves. Mycoplasma bovis was identified in 83% of SYBR PCR mycoplasma-positive bulk tank samples. Another mycoplasma was identified either alone or in addition to M. bovis in 25% of SYBR PCR mycoplasma-positive bulk tank milk samples. Four species of mycoplasma other than M. bovis (Mycoplasma alkalescens, Mycoplasma arginini, Mycoplasma bovigenitalium, and Mycoplasma gateae) were identified in bulk tank milk samples tested with this method. Five farms had 2 mycoplasma species occurring at different times in their bulk tanks. Two mycoplasma species were identified in the same bulk tank sample in 7 instances on 2 farms. The finding of multiple Mycoplasma spp. coexisting on a farm and even in the same bulk tank milk sample indicates that the clinical significance of multiple mycoplasma species in the pathology of intramammary infections should be investigated further. In comparison with conventional culture, the SYBR PCR protocol was slightly (but not statistically significantly) more sensitive in the detection of mycoplasmas in bulk tank milk. PMID- 21700027 TI - Ranking experts' preferences regarding measures and methods of assessment of welfare in dairy herds using Adaptive Conjoint Analysis. AB - Welfare in dairy herds can be addressed using different concepts. The difficulty is to extract which measures are the most important to practically address welfare at the herd level and the methods to assess traits considered most important. Therefore, the preferences of 24 acknowledged European welfare experts were ranked regarding 70 measures suitable to assess dairy cattle welfare at herd level using the Adaptive Conjoint Analysis (ACA; Sawtooth Software, Inc., Sequim, WA) technique. The experts were selected on the basis of 3 criteria: at least 5 yr experience in animal welfare research; recent scientific publications in the field of animal welfare; and, at the most, 3 animal species including dairy cattle as their field of expertise. The 70 traits were ranked by using the median ACA questionnaire utility scores and the range between the answers of the 24 experts. A high utility score with a low range between the answers of the experts was considered as suitable to assess welfare at farm level. Measures meeting these criteria were prevalence of lameness cases (107.3+/-11.7), competition for feed and water (96.4+/-13.9), and number of freestalls per 10 cows (84.8+/-13.3). Based on the utility score alone, these former measures were replaced by stereotypic behavior (111.7+/-17.1), prevalence of lameness cases (107.3+/-11.7), body condition score (108.0+/-18.9), and hock lesions (104.7+/-16.1). Subsequently, to demonstrate that the ACA technique can be used to rank either well-known or inconclusive methods of assessment, the methods for the traits lameness cases and the hygiene of the calving pen were ranked using another 2 ACA questionnaires. The results are based on the opinions of selected, internationally acknowledged dairy cattle welfare experts within the European Union. In the future, other parties like dairy farmers and farmers' organization should be included to achieve consensus about the most suitable traits applicable in practice. The currently investigated traits do not always apply to all dairy husbandry systems across the world, but are based on a system that includes indoor housing during winter. It is concluded that ACA is a useful technique to rank the different scientific opinions of experts regarding suitable traits and methods of assessment of dairy cattle at the herd level. PMID- 21700028 TI - Differential regulation of bovine pyruvate carboxylase promoters by fatty acids and peroxisome proliferator-activated receptor-alpha agonist. AB - Pyruvate carboxylase (PC) is a critical enzyme in supplying carbon for gluconeogenesis and oxaloacetate for the tricarboxylic acid cycle. The bovine PC (EC 6.4.1.1) gene contains 3 promoter sequences (P3, P2, and P1 from 5' to 3'). Physiological stressors, including the onset of calving and feed restriction, lead to elevated nonesterified fatty acids and glucocorticoid levels that coincide with an increase in PC mRNA expression. The effects of elevated fatty acids on bovine PC mRNA expression and promoter function have not been determined. The objective of this experiment was to determine the direct effects of stearic, oleic, and linoleic acids, dexamethasone, and Wy14643 (a peroxisome proliferator-activated receptor-alpha agonist) on bovine PC promoter activity. Promoter-luciferase constructs, containing 1,005 bp of P1, 1,079 bp of P2, or 1,010 bp of P3, were transiently transfected into rat hepatoma (H4IIE) cells. Cells were then treated with 1mM stearic, oleic, or linoleic acids, 1 MUM dexamethasone, or 10 MUM Wy14643 for 23 h. Activity of P1 was suppressed with exposure to stearic acid (1.58 vs. 6.19+/-0.81 arbitrary units for stearic vs. control, respectively) and enhanced with exposure to Wy14643 (9.26 vs. 6.19+/ 0.81 arbitrary units for Wy14643 vs. control, respectively). Conversely, stearic acid enhanced P3 activity (2.55 vs. 0.40+/-0.33 arbitrary units for stearic vs. control, respectively). Dexamethasone, linoleic acid, and oleic acid failed to elicit a response from any of the promoters tested. These data demonstrate the direct role of fatty acids in regulating PC expression and indicate that fatty acids provide promoter-specific regulation of PC promoters. PMID- 21700029 TI - Efficacy of embryo transfer in lactating dairy cows during summer using fresh or vitrified embryos produced in vitro with sex-sorted semen. AB - The objective was to determine whether transfer of fresh or vitrified embryos produced in vitro with sex-sorted semen improves pregnancy and calving rates during summer in lactating dairy cows compared with artificial insemination (AI). Lactating dairy cows (n=722) were enrolled during summer months at 2 commercial dairies in Central Texas and randomly assigned to 1 of 3 treatments: AI with conventional semen (n=227), embryo transfer-vitrified (ET-V; n=279) or embryo transfer-fresh (ET-F; n=216). Embryos were produced in vitro using sex-sorted semen and with Block-Bonilla-Hansen-7 culture medium. For vitrification, grade 1 expanded blastocysts were harvested on d 7 after fertilization and vitrified using the open-pulled straw method. Fresh embryos were grade 1 blastocysts and expanded blastocysts harvested on d 7 after fertilization. Cows were submitted to the Ovsynch56 protocol: d -10 GnRH, d -3 PGF(2alpha), d -1 GnRH and d 0 timed AI; or Select Synch protocol: d -9 GnRH, d -2 PGF(2alpha), and AI following detected estrus (day of AI=d 0). On d 7, all cows were examined for presence of a corpus luteum (CL). A vitrified or fresh embryo was transferred to cows with CL in ET-V and ET-F groups. Cows were considered synchronized if progesterone was <1ng/mL on d 0 and a CL was present on d 7. At d 40+/-7 of gestation, the percentage of cows pregnant was greater for the ET-F compared with the ET-V and AI groups among all cows (42.1 vs. 29.3 and 18.3%, respectively) and synchronized cows (45.5 vs. 31.6 and 24.8%, respectively). Also, the percentage of cows pregnant was greater for the ET-V than the AI group among all cows and tended to be greater among synchronized cows. At d 97+/-7 of gestation, the percentage of cows pregnant among all cows was greater for ET-F and ET-V groups than for the AI group (36.4 and 25.7 vs. 17.0%, respectively) and the percentage for the ET-F group was greater than for the ET-V group. Among synchronized cows, the percentage of cows pregnant was significantly increased for the ET-F group than for ET-V and AI groups (39.4 vs. 27.8 and 23.1%, respectively) and no difference was found between ET-V and AI groups. No effect of treatment on embryo loss was observed. The percentage of cows with live births was significantly increased for the ET-F than for ET-V and AI groups among all cows (27.5 vs. 17.1 and 14.6%, respectively) and synchronized cows (29.9 vs. 18.5 and 20.0%, respectively). The percentage of cows giving birth to a live heifer was significantly increased for the ET-F and ET-V groups compared with the AI group among all cows (79.1 and 72.5 vs. 50.0%, respectively) and synchronized cows (79.1 and 72.5 vs. 50.0%, respectively). No difference existed between ET-F and ET-V groups for percent live heifer births but both were greater than for the AI group. The transfer of fresh embryos produced in vitro using sex-sorted semen to lactating dairy cows during summer can effectively increase the percentage of cows that establish pregnancy and also the percentage of cows that give birth to a live heifer compared with percentages from AI with conventional semen. PMID- 21700030 TI - Lactose in blood plasma and the ability of dairy cows to tolerate once-daily milking in terms of milk loss and milk recovery. AB - This experiment described the variability among cows with the aim of studying the ability of dairy cows to tolerate once-daily milking (ODM) in terms of milk losses and milk recoveries observed when cows are switched from twice- to once daily milking and then back to twice-daily milking (TDM). It also aimed to investigate whether or not lactose in blood plasma, which indicates the mammary epithelium permeability, is correlated with milk losses and recoveries and, consequently, a potential candidate assessor of dairy cow tolerance to ODM. The study used 86 crossbred dairy cows (Holstein * Normande) split into 5 groups over 2 yr. The trial consisted of 3 successive periods: a 1-wk control period of TDM, then 3 wk of ODM, followed by 2 wk of TDM. Blood samples were collected 1 to 1.5h before the morning milking and 5 to 6h after milking on d -3, 0, 1, 3, 7, 21, 23, and 28, where d 0 is the last d of the control period. Milk losses measured as kilograms per day were higher in cows with highest control-period milk yields (r= 0.66). When expressed in relative terms (%), milk losses were weakly correlated with the control-period milk yield (r=-0.22). When switched back to TDM, cows recovered only 47% of the milk lost. Milk recovery (kg/d) was weakly correlated with control milk yield (r=0.34) and not correlated with ODM milk yield. Milk recovery was correlated with milk yield losses: the higher the milk yield losses (kg/d or %), the higher the milk recovery (kg/d; r=-0.59 and -0.52, respectively). Rate of milk recovery expressed as the quantity of milk recovered per kilogram of milk lost, was not correlated with milk loss expressed as a percentage. This means that to be considered well-adapted to ODM scheduling, a cow must be well adapted to milk loss, and be well adapted to milk recovery. Blood plasma lactose concentration (log(10)-transformed data) was not correlated with milk production levels in either control, ODM, or back-to-TDM periods. It was poorly correlated with milk loss but was positively correlated with milk recovery (kg/d) and rate of milk recovery. We conclude that blood plasma lactose needs to be coupled with other indicators for evaluating dairy cow tolerance to ODM. PMID- 21700031 TI - Cefquinome sulfate behavior after intramammary administration in healthy and infected cows. AB - Maintenance of adequate drug concentration at the site of infection is an important problem in mastitis antibiotic therapy, and the efficacy of intramammary beta-lactams can be optimized by maintaining the drug concentration at the site of infection above the minimum inhibitory concentration (MIC) as long as possible. The most important pharmacokinetic and pharmacodynamic parameter for efficacy evaluation is time during which drug concentrations exceed the MIC (t>MIC). In this study, we assessed the pharmacokinetic profile of cefquinome (CFQ) after repeated intramammary administration in healthy cows and cows subclinically infected with Staphylococcus aureus as well as the MIC of Staph. aureus field strains. In addition, the degree of drug passage was investigated from udder to bloodstream by measuring systemic drug absorption in healthy and infected animals. Cefquinome concentrations were quantified by HPLC (UV-visible detection) in milk samples collected from quarters and from blood serum samples. The systemic drug absorption was negligible in healthy and subclinically infected animals (maximum concentration 0.09+/-0.02 and 0.1+/-0.01 MUg/mL in healthy and subclinically infected animals, respectively). The MIC(90) value for CFQ in Staph. aureus field strains (n=20) was 0.24 MUg/mL. The pharmacokinetic and pharmacodynamic evaluation, determined by t>MIC, showed an equal persistence of CFQ in all quarters, indicating an equivalent activity of the drug regardless of the pathological status of the udder. Moreover, with literature data regarding CFQ MIC, the t>MIC has been calculated for other bacterial species. PMID- 21700032 TI - Vitamin D2 impairs utilization of vitamin D3 in high-yielding dairy cows in a cross-over supplementation regimen. AB - Vitamin D exists in 2 forms that are important regarding vitamin D status and supply in cattle: vitamin D(2) (D(2)) and vitamin D(3) (D(3)). To become physiologically active, both D(2) and D(3) must undergo 25-hydroxylation in the liver. The resulting 25-hydroxyvitamin D(2) [25(OH)D(2)] and 25-hydroxyvitamin D(3) [25(OH)D(3)] are measured as indicators of the physiological vitamin D status of cattle. The study used 14 Danish Holstein cows housed without access to sunlight. The cows were orally administered 250 mg (1.0 * 10(7)IU) of D(2) and D(3) in a cross-over design with 2 treatment groups and 2 study periods, rendering 4 treatments when carryover effects were taken into account: D(2) given first, D(2) given last after D(3), D(3) given first, and D(3) given last after D(2). Two weeks elapsed between the treatment in the first study period and the treatment in the second study period. Blood samples were collected 0, 3, 6, 14, 17, 20, 23, 26, 40, 48, 70, 94, 166, and 214 h after providing the oral bolus of vitamin to the cows. Comparisons between plasma levels of the metabolites D(2), D(3), 25(OH)D(2), and 25(OH)D(3) over time were made by comparing areas under the plasma concentration curves. Oral administration of D(3) increased plasma D(3) (182.6+/-17.1 ng/mL; mean +/- SEM) and 25(OH)D(3) (103.5+/-10.0 ng/mL) more efficiently than oral administration of D(2) increased plasma D(2) (49.1+/-32.6 ng/mL) and 25(OH)D(2) (27.9+/-2.1 ng/mL). The D(3) given after an oral dose of D(2) was less efficient for increasing plasma concentrations of 25(OH)D(3) (61.2+/-12.0 ng/mL) compared with D(3) given without previous D(2) administration (103.5+/-10.0 ng/mL), whereas the plasma concentrations of D(3) itself were the same when given first (182.6+/-17.1 ng/mL) as when given after D(2) (200.0+/ 123.9 ng/mL). The same occurred for plasma concentrations of D(2) metabolites both if D(2) was given first (49.1+/-32.6 ng/mL) and after D(3) (54.7+/-7.7 ng/mL). In conclusion, D(3) given after D(2) is less efficient at increasing the plasma status of 25(OH)D(3) than D(3) given without previous D(2) administration. PMID- 21700033 TI - Transcript abundance of amino acid transporters, beta-casein, and alpha lactalbumin in mammary tissue of periparturient, lactating, and postweaned sows. AB - The objective of these experiments was to test the hypothesis that transcript abundance of cationic AA transporter- and milk protein-encoding genes increase in the porcine mammary gland in response to higher lactation demand. Genes of interest included those encoding for the milk proteins alpha-lactalbumin (alpha LA) and beta-casein (beta-CN; LALBA and CSN2, respectively), and AA transporter b(0,+)AT, y(+)LAT1, y(+)LAT2, ATB(0,+), CAT-1, and CAT-2b (SLC7A9, SLC7A7, SLC7A6, SLC6A14, SLC7A1, and SLC7A2, respectively). Mammary tissue was biopsied from 4 sows on d 110 of gestation (prepartum), on d 2 (early postpartum), on d 5 (early), and d 17 (peak) of lactation, and on d 5 after weaning (postweaning), and mRNA of target genes quantified by reverse transcription quantitative PCR. Compared with prepartum, CAT-1, ATB(0,+), y(+)LAT2, beta-CN, and alpha-LA mRNA abundance was higher at early lactation, whereas compared with early lactation, only CAT-1 and alpha-LA mRNA abundance was higher at peak lactation. The CAT-2b, y(+)LAT1, and b(0,+)AT mRNA abundance did not differ when comparing either prepartum or peak lactation to early lactation. Compared with peak lactation, postweaning mRNA abundance of CAT-1, ATB(0,+), alpha-LA, and beta-CN decreased, y(+)LAT2, CAT-2b, and b(0,+)AT remained unchanged, and y(+)LAT1 increased. The mRNA abundance of y(+)LAT2 increased from early postpartum to early lactation, and remained unchanged for CAT-1, ATB(0,+), alpha-LA, and beta-CN. From prepartum to peak lactation, the mRNA abundance of CAT-1, y(+)LAT2, and ATB(0,+) was positively correlated with that of beta-CN and alpha-LA. In conclusion, the expression of genes encoding for y(+)LAT1, CAT-2b, and b(0,+)AT remained unchanged in porcine mammary glands over prepartum to peak lactation period, whereas expression of genes encoding for CAT-1, ATB(0,+), and y(+)LAT2 was upregulated and positively correlated to expression of genes encoding for the mammary synthesized milk proteins beta-CN and alpha-LA. PMID- 21700034 TI - Effects of sex-sorting and sperm dosage on conception rates of Holstein heifers: is comparable fertility of sex-sorted and conventional semen plausible? AB - The conception rates of Holstein heifers after AI with 2.1 or 10 * 10(6) sperm dosages of sex-sorted or conventionally processed sperm were compared. Ejaculates collected by artificial vagina from 8 Holstein sires were cryopreserved at either 2.1 or 10 * 10(6) sperm per dose with or without sorting to 90% purity for X chromosome-bearing spermatozoa using flow cytometry. All treatments were processed in an egg-yolk (20%), TRIS, glycerol (7%) extender and packaged in color-coded 0.25-mL French straws. Straws (n=350 straws/treatment per sire) were packaged and distributed in aliquots of 12 (3 straws of each treatment) to 51 herds of Holstein heifers. Straw color was recorded in the on-farm record keeping system at the time of AI and retrieved by electronic download. In total, 9,172 services were recovered, providing a mean sample size of 287+/-3.5 services/sperm dose per semen type within sire (range: 248 to 318). Conception rates were influenced by the main effects of herd, sire, semen type, sperm dosage, and service number. The herd by sperm dosage interaction was the only interaction determined to be significant and implies that some herds (technicians) are more proficient than others at maintaining high levels of conception with decreased sperm dosages. Across herds and sires, the conception rates of each semen type by sperm dosage combination were as follows: 2.1 * 10(6) sex-sorted, 38%, n=2,319; 10 * 10(6) sex-sorted, 44%, n=2,279; 2.1 * 10(6) conventional, 55%, n=2,282; and 10 * 10(6) conventional, 60%, n=2,292. The observation that conception rates of sex-sorted semen were improved by the 10 * 10(6) sperm dosage is encouraging toward the prospectus of development of a commercially available sex-sorted product with improved conception potential over existing technology. However, the failure of the 10 * 10(6) sex-sorted sperm dosage to achieve conception rates comparable to either dosage of conventional semen is somewhat discouraging toward the plausibility of comparable conception rates to conventional semen in the absence of major technological advances in efficiency of sperm sorting or cryopreservation. PMID- 21700035 TI - Endocrine changes and liver mRNA abundance of somatotropic axis and insulin system constituents during negative energy balance at different stages of lactation in dairy cows. AB - The liver has an important role in metabolic regulation and control of the somatotropic axis to adapt successfully to physiological and environmental changes in dairy cows. The aim of this study was to investigate the adaptation to negative energy balance (NEB) at parturition and to a deliberately induced NEB by feed restriction at 100 days in milk. The hepatic gene expression and the endocrine system of the somatotropic axis and related parameters were compared between the early and late NEB period. Fifty multiparous cows were subjected to 3 periods (1=early lactation up to 12 wk postpartum, 2=feed restriction for 3 wk beginning at around 100 days in milk with a feed-restricted and a control group, and 3=subsequent realimentation period for the feed-restricted group for 8 wk). In period 1, plasma growth hormone reached a maximum in early lactation, whereas insulin-like growth factor-I (IGF-I), leptin, the thyroid hormones, insulin, and the revised quantitative insulin sensitivity check index increased gradually after a nadir in early lactation. Three days after parturition, hepatic mRNA abundance of growth hormone receptor 1A, IGF-I, IGF-I receptor and IGF-binding protein-3 (IGFBP-3) were decreased, whereas mRNA of IGFBP-1 and -2 and insulin receptor were upregulated as compared with wk 3 antepartum. During period 2, feed restricted cows showed decreased plasma concentrations of IGF-I and leptin compared with those of control cows. The revised quantitative insulin sensitivity check index was lower for feed-restricted cows (period 2) than for control cows. Compared with the NEB in period 1, the changes due to the deliberately induced NEB (period 2) in hormones were less pronounced. At the end of the 3-wk feed restriction, the mRNA abundance of IGF-I, IGFBP-1, -2, -3, and insulin receptor was increased as compared with the control group. The different effects of energy deficiency at the 2 stages in lactation show that the endocrine regulation changes qualitatively and quantitatively during the course of lactation. PMID- 21700036 TI - Short communication: effect of vitamins E and C on cortisol production by bovine adrenocortical cells in vitro. AB - The aim was to determine if vitamins E and C inhibit the release of cortisol from bovine adrenocortical cells when stimulated with ACTH in vitro. A factorial arrangement of treatments was used to culture bovine adrenocortical cells with different concentrations of vitamins E and C [(+)-alpha-tocopherol at 0, 2.3, and 16 MUM and l-ascorbic acid at 0, 15, and 50 MUM]. After 3 and 7 d of vitamin treatments, cell cultures were stimulated with ACTH (1 nM) for 24h and the culture medium extracted to measure cortisol released by the cells using HPLC with UV detection. Vitamin E, vitamin C, or their combination did not affect the amount of cortisol released by the adrenal cultures to the media. Cortisol released by the adrenal cultures ranged from 33.6+/-6.85 to 49.7+/-8.01 nmol per 10(7) cells. The modulation effect of vitamins E and C on the stress response does not take place at the cortex of the adrenal gland. PMID- 21700037 TI - Technical note: the use of a physical activity monitor to estimate the eating time of cows in pasture. AB - Accurate eating time can be used as an index of forage dry matter intake in grazing cows. To develop a method for easily estimating the eating time of dairy cows in a pasture, 8 lactating Holstein cows were fitted with collars equipped with commercial uniaxial accelerometers; namely, the Kenz Lifecorder EX (LCEX; Suzuken Co. Ltd., Nagoya, Japan), and were allowed to graze in a pasture for 4, 8, or 20 h daily for 7 d. The LCEX device recorded the intensity of the physical activity categorized into 1 of 11 activity levels ranging among 0 (no movement), 0.5 (subtle) and from 1 to 9 (1, light; 9, vigorous intensity) every 4s during the experimental period. The activities of the animals were also video-recorded for 11h and were manually classified into 7 categories (eating, searching, ruminating, standing resting, lying resting, drinking, and walking) at 4-s intervals. According to the count distribution of the activity levels for the categorized activities, 94.4% of the counts involving eating activity ranged from activity level 1 to 7. On the other hand, most of the counts were activity level 0 or 0.5 when ruminating and resting activities were observed. No records of activity level 8 or 9 were found in any activities. When activity level 1 was used as a threshold for discriminating eating from the other activities, the lowest misclassification rate of 5.5% was observed. With a threshold of activity level 1, the eating times in pasture for cows grazing for 4, 8, and 20 h/d were 142.8, 290.6, and 438.4 min/d, respectively, and the proportions of the time spent in pasture that were made up of eating time were 0.66, 0.67, and 0.38, respectively [the proportion during daytime (8h of the 20-h grazing treatment) was 0.63 and that at nighttime (12h of the 20-h grazing treatment) was 0.23]. The use of the LCEX device allows for easy measurement of eating time and facilitates the determination of the pattern of eating activity in pasture for grazing cows. PMID- 21700038 TI - Technical note: validation of an ELISA for measurement of tumor necrosis factor alpha in bovine plasma. AB - Tumor necrosis factor alpha (TNFalpha) is an inflammatory cytokine that is involved in immune function and is proposed to play a role in metabolic disorders. Although some bovine-specific methods have been published recently, assays used for determining plasma TNFalpha concentration in bovine disease models often do not offer acceptable precision for measurement of basal concentrations in healthy animals. The objective of this work was to develop an effective, low-cost sandwich ELISA procedure with improved sensitivity. A protocol developed for use with cell culture supernatant was modified for use with bovine plasma and serum by optimizing antibody concentrations, incubation times and temperatures, and standard diluents. The coating antibody concentration was decreased from 10 to 6.8 MUg/mL, whereas the detection antibody concentration remained 2.5 MUg/mL. Sample incubation was increased from 1h at room temperature to an overnight incubation at 4 degrees C, which increased the sensitivity of the assay. Multiple matrices were tested for dilution of standards and were assessed by determining recovery of bovine TNFalpha spiked into bovine serum and plasma. Recoveries were acceptable in both bovine serum and plasma (71-103%) when quantified with standards diluted in human serum or phosphate-buffered saline. The modified bovine TNFalpha ELISA offers a detection range of 2 to 250 pg/mL. This detection limit is at least an order of magnitude lower than previously reported, and will allow for greater precision in determining basal TNFalpha concentrations in bovine plasma. The improved sensitivity of this ELISA will be critical to assessing current hypotheses concerning the metabolic effects of moderately elevated TNFalpha concentrations. PMID- 21700039 TI - An evaluation of the effect of altering nutrition and nutritional strategies in early lactation on reproductive performance and estrous behavior of high-yielding Holstein-Friesian dairy cows. AB - Reproductive performance in the high-yielding dairy cow has severely decreased in the last 40 yr. The aim of this study was to compare the effectiveness of 4 nutritional strategies in improving the reproductive performance of high-yielding dairy cows. It was hypothesized that offering cows a high-starch ration in early lactation would enhance the onset of luteal activity, and that decreasing the severity of negative energy balance in the early postcalving period would improve reproductive parameters. Nutritional regimens aimed at improving fertility were applied to 96 Holstein-Friesian dairy animals. Upon calving, animals were allocated in a balanced manner to one of 4 dietary treatments. Primiparous animals were balanced according to live weight, body condition score and calving date. Multiparous animals were balanced according to parity, previous lactation milk yield, liveweight, body condition score and calving date. Treatment 1 was based on an industry best practice diet (control) to contain 170 g of crude protein/kg of dry matter. Treatment 2 was an individual cow feeding strategy, whereby the energy balance (EB) of individual animals was managed so as to achieve a predetermined target daily EB profile (+/-10 MJ/d). Treatment 3 was a high-starch/high-fat combination treatment, whereby an insulinogenic (high starch) diet was offered in early lactation to encourage cyclicity and followed by a lipogenic (low-starch, high-fat) diet to promote embryo development. Treatment 4 was a low-protein diet, containing 140 g of crude protein/kg of dry matter, supplemented with protected methionine at an inclusion level of 40 g per animal per day. The nutritional strategies implemented in this study had no statistically significant effects on cow fertility measures, which included the onset of luteal activity, conception rate, in-calf rate, and the incidence of atypical cycles. The individual cow feeding strategy improved EB in early lactation but had no benefit on conception rate to first insemination. However, conception rate to second insemination, 100-d pregnancy rate (from the commencement of breeding), and overall pregnancy rate tended to be higher in this group. The high-starch/high-fat treatment tended to decrease the proportion of delayed ovulations and increase the proportion of animals cycling by d 50 postcalving. Animals that failed to conceive to first insemination had a significantly longer luteal phase in the first cycle postpartum and a longer inter-ovulatory interval in the second cycle postpartum. With regards to estrous behavior, results indicate that as the size of the sexually active group increased, the intensity of estrus and the expression of mounting or attempting to mount another cow also increased. Furthermore, cows that became pregnant displayed more intense estrous behavior than cows that failed to become pregnant. PMID- 21700040 TI - Effect of varying total mixed ration particle size on rumen digesta and fecal particle size and digestibility in lactating dairy cows. AB - The objective of this experiment was to evaluate the effects of feeding rations of different particle sizes on rumen digesta and fecal matter particle size. Four rumen-cannulated, multiparous, Holstein cows (104+/-15 d in milk) were randomly assigned to treatments in a 4*4 Latin square design. The diets consisted of 29.4% corn silage, 22.9% ground corn, 17.6% alfalfa haylage, and 11.8% dry grass hay [20% of forage dry matter (DM)] on a DM basis. Dry grass hay was chopped to 4 different lengths to vary the total mixed ration (TMR) particle size. Geometric mean particle sizes of the rations were 4.46, 5.10, 5.32, and 5.84 mm for short, medium, long, and extra long diets, respectively. The ration affected rumen digesta particle size for particles >=3.35 mm, and had no effect on distribution of particles <3.35 mm. All rumen digesta particle size fractions varied by time after feeding, with soluble particle fractions increasing immediately after feeding and 0.15, 0.6, and 1.18-mm particle size fractions decreasing slightly after feeding. Particle fractions >1.18 mm had ration by time interactions. Fecal neutral detergent fiber (NDF) and indigestible NDF concentrations decreased with increasing TMR particle size. Fecal particle size expressed as total geometric mean particle length followed this same tendency. Fecal particle size, expressed as retained geometric mean particle length, averaged 1.13 mm with more than 36% of particles being larger than 1.18 mm. All fecal nutrient concentrations measured were significantly affected by time after feeding, with NDF and indigestible NDF increasing after feeding and peaking at about 12h later and then decreasing to preprandial levels. Starch concentrations were determined to have the opposite effect. Additionally, apparent digestibility of diet nutrients was analyzed and DM digestibility tended to decrease with increasing TMR particle size, whereas other nutrient digestibilities were not different among rations. These results show that the critical size for increased resistance to rumen escape is larger than 1.18 mm and this critical size is constant throughout the day. This study also concludes that, when using average quality grass hay to provide the range of particle sizes fed, DM digestibility tends to decrease with increasing ration particle size. PMID- 21700041 TI - Effect of biotin on milk performance of dairy cattle: a meta-analysis. AB - A meta-analysis of the effect of biotin on production outcomes of dairy cattle was conducted following a literature review. A total of 11 studies from 9 papers, with information on the milk production and composition data from a total number of 238 cows were extracted and analyzed using meta-analysis software in Stata. Estimated size of effect of biotin was calculated for dry matter intake (DMI), milk production, and composition. Heterogeneity was not significant for all of the parameters (the highest I(2)=12%). Therefore, fixed effects models were used for analysis. With the addition of biotin to lactating dairy cattle, DMI and milk production increased by 0.87 and 1.66 kg/d. No significant effect on percentage of milk fat and milk protein was observed. Additionally, Begg's test indicated no evidence of substantial publication bias for all variables. The influence analysis shows that the removal of any study did not change the direction or significance of the point estimates. It can be concluded that the use of biotin supplements increases DMI and milk yield in lactating dairy cows. PMID- 21700042 TI - Hay intake improves performance and rumen development of calves fed higher quantities of milk. AB - Research to date has suggested that access to forage before weaning can limit rumen development in calves, but no research has yet addressed the role of forage for calves fed higher quantities of milk. This study compared performance and rumen development of calves provided high volumes (equivalent to approximately 20% of calf birth weight) of milk with and without access to hay. At d 3 of age, individually housed calves were randomly assigned to treatment (either ad libitum access to chopped grass hay or no forage; n=15 calves per treatment, 10 heifers, and 5 bulls). All calves were provided ad libitum access to water and starter throughout the study. All calves were offered 8L of milk/d from a nipple bottle from d 3 to 35, 4 L/d from d 36 to 53, and 2L/d until weaning at d 56. Solid feed intake and growth parameters were monitored from d 3 to 70. At d 70, males from both treatments were slaughtered to measure rumen development parameters. Overall dry matter (DM) intake from solid feed did not differ between treatments before wk 5. However, during wk 6 to 10, calves fed forage consumed more total DM (starter plus hay) than did calves fed no forage. Hip and wither height, heart girth, and body barrel at d 3, 56, and 70 did not differ between treatments. Reticulorumen weight was heavier in calves fed hay versus those fed only starter (12.77+/-1.29 vs. 7.99+/-0.69 kg with digesta; 1.89+/-0.05 vs.1.60+/-0.09 kg without digesta). Body weight without digesta was similar in calves fed forage or no forage. Mean rumen pH was higher in calves fed hay compared with those fed no forage (5.49+/-0.08 vs. 5.06+/-0.04). In conclusion, provision of chopped hay to calves fed high volumes of milk can promote solid feed DM intake and rumen development without affecting BW gain. PMID- 21700043 TI - Effect of intensified feeding of heifer calves on growth, pubertal age, calving age, milk yield, and economics. AB - The objective of this study was to determine if increasing the energy and protein intake of heifer calves would affect growth rates, age at puberty, age at calving, and first lactation milk yield. A second objective was to perform an economic analysis of this feeding program using feed costs, number of nonproductive days, and milk yield data. Holstein heifer calves born at the Michigan State Dairy Cattle Teaching and Research Center were randomly assigned to 1 of 2 dietary treatments (n=40/treatment) that continued from 2 d of age until weaning at 42 d of age. The conventional diet consisted of a standard milk replacer [21.5% crude protein (CP), 21.5% fat] fed at 1.2% of body weight (BW) on a dry matter basis and starter grain (19.9% CP) to attain 0.45 kg of daily gain. The intensive diet consisted of a high-protein milk replacer (30.6% CP, 16.1% fat) fed at 2.1% of BW on a dry matter basis and starter grain (24.3% CP) to achieve 0.68 kg of daily gain. Calves were gradually weaned from milk replacer by decreasing the amount offered for 5 and 12 d before weaning for the conventional and intensive diets, respectively. All calves were completely weaned at 42 d of age and kept in hutches to monitor individual starter consumption in the early postweaning period. Starting from 8 wk of age, heifers on both treatments were fed and managed similarly for the duration of the study. Body weight and skeletal measurements were taken weekly until 8 wk of age, and once every 4 wk thereafter until calving. Calves consuming the intensive diet were heavier, taller, and wider at weaning. The difference in withers height and hip width was carried over into the early post-weaning period, but a BW difference was no longer evident by 12 wk of age. Calves fed the intensive diet were younger and lighter at the onset of puberty. Heifers fed the high-energy and protein diet were 15 d younger at conception and 14 d younger at calving than heifers fed the conventional diet. Body weight after calving, daily gain during gestation, withers height at calving, body condition score at calving, calving difficulty score, and calf BW were not different. Energy-corrected, age-uncorrected 305-d milk yield was not different, averaging 9,778 kg and 10,069 kg for heifers fed the conventional and intensive diets, respectively. However, removing genetic variation in milk using parent average values as a covariate resulted in a tendency for greater milk from heifers fed the intensive diet. Preweaning costs were higher for heifers fed the intensive diet. However, total costs measured through first lactation were not different. Intensified feeding of calves can be used to decrease age at first calving without negatively affecting milk yield or economics. PMID- 21700044 TI - The use of a radiotelemetric ruminal bolus to detect body temperature changes in lactating dairy cattle. AB - The objective of this study was to validate the efficacy of a radiotelemetric bolus (RTB) to detect changes in ruminal temperature resulting from (1) systemic illnesses that are associated with febrile responses and (2) subacute ruminal acidosis (SARA). Eight rumen-fistulated, lactating Holstein cows (586+/-37 kg of body weight, 106+/-18 d in milk) were used in a replicated 4 * 4 Latin square design with a 2 * 2 factorial arrangement. Each period consisted of 21 d. The factors were 2 diets, a moderate forage:concentrate [MFC; 52:48; % of dry matter (DM)] or a high forage:concentrate (HFC; 65:35, % of DM) total mixed ration, and a challenge with a single intramammary injection of lipopolysaccharide (LPS; 100 MUg derived from Escherichia coli 0111:B4) or no LPS (sterile saline). Thus, the 4 resulting treatments were (1) MFC with LPS challenge, (2) MFC with saline, (3) HFC with LPS challenge, and (4) HFC with saline. Cows were fed at 0800 and 1400 h daily. Cows received the intramammary injections at 0900 h of d 21. Ruminal pH and ruminal temperature were also measured on d 21 every minute via an indwelling logging system that resided in the ventral sac of the rumen and via a radiotelemetric bolus that resided in the reticulum. Vaginal temperature was also recorded every minute via temperature loggers. Prior to LPS injection, the duration of rumen pH below 5.6 (indicative of SARA) was higher in cows receiving MFC than cows receiving HFC (148+/-24 and 62+/-24 min/d, respectively). The temperature measured at the same time via RTB was higher for MFC than HFC cows (167+/-21 vs. 104 vs. 21 min/d above 38.8 degrees C, respectively). The following day, cows challenged with LPS showed signs of mastitis within the injected quarters, depressed DM intake, decreased milk yield, and a peak vaginal temperature of 41.3+/-0.1 degrees C 5.5h after the LPS injection. The RTB system successfully detected a fever response parallel to that measured by the vaginal loggers but temperature peak detected by RTB was, on average, 0.5 degrees C lower than that detected by the vaginal logger. Although the RTB system was able to detect a temperature response to the diet effect before LPS challenge, it was unable to detect this effect during the LPS challenge, likely because cows receiving the LPS challenge had decreased feed consumption. In conclusion, radiotelemetry has the potential to improve the detection of SARA and fever on farm. PMID- 21700045 TI - Residues of melamine and cyanuric acid in milk and tissues of dairy cows fed different doses of melamine. AB - Melamine (1,3,5-triazine-2,4,6-triamine) may be degraded into cyanuric acid and some other compounds by rumen microorganisms. This study was conducted to assess the transfer of melamine and cyanuric acid in to milk and tissues by dairy cows fed different doses of melamine. Forty mid-lactation dairy cows (157+/-43 d in milk, 20.8+/-1.4 kg of milk/d) were divided into 4 groups (n=10/group) using a completely randomized design. The groups were fed the following amounts of melamine (purity >=99.5%) at 0 (control), 300 [treatment (Trt) 1], 500 (Trt 2), and 1,000 (Trt 3) mg/d per cow, respectively. The trial lasted for 18 d (12-d feeding period, followed by a 6-d clearance period). Milk samples were collected from the 4 groups on d 1, 2, 3, 4, 8, 12, 13, 14, 15, and 18, and analyzed for melamine and cyanuric acid. On d 13, 3 cows from Trt 2 and Trt 3 were randomly selected and slaughtered; tissue samples including kidney, liver, mammary, bladder, gluteus medius, and longissimus dorsi were collected for melamine and cyanuric acid analyses. Milk and tissue samples were analyzed for melamine and cyanuric acid using a simultaneous liquid chromatography tandem mass spectrometry procedure. Neither melamine nor cyanuric acid was detected in concentrated feed that was being fed to the cows. In melamine-treated groups, milk melamine concentration increased quickly and reached a stable level by d 4 and was at similar levels on d 8 and 12 after the first administration of melamine. Milk melamine levels in treated groups were 0.18, 0.27, and 0.50mg/L for Trt 1, Trt 2, and Trt 3, respectively, and were highly correlated (R(2)=0.91) with melamine dosing levels. No cyanuric acid was detected in any of the milk collected from the various groups. Melamine residue levels in tissues of Trt 3 were about 2-fold higher than that in Trt 2, with the highest concentration being found in kidney. No differences in cyanuric acid levels in tissues were found between Trt 3 and Trt 2. Liver, kidney, and bladder tissues were found to contain the highest cyanuric acid levels. This study shows a relationship between dietary melamine levels and cyanuric acid levels found in tissues, which might be the result of melamine being converted to cyanuric acid by microorganisms in the rumen. PMID- 21700046 TI - Genetic strain and diet effects on grazing behavior, pasture intake, and milk production. AB - Understanding how dairy cows adjust their grazing behavior in response to feed supplements is important for the development of management strategies that optimize profit from supplementation. New Zealand Holstein-Friesian (HF) cows have been selected for milk production on a predominantly pasture-based diet; in comparison, HF cows of North American (NA) ancestry have been selected almost exclusively for milk yield and fed diets high in nonfiber carbohydrates (NFC). We hypothesized, therefore, that supplementation would have differing effects on grazing behavior, pasture dry matter intake (DMI), and milk production in these genetic strains at peak, mid, and late lactation. A study was conducted over 2 consecutive lactations, with NA and NZ cows randomly allocated at calving to 0, 3, or 6 kg of dry matter/day concentrate plus unrestricted access to pasture. Pasture DMI, milk production, and grazing behavior were recorded at peak, mid, and late lactation. Concentrates were fed in equal amounts at morning and afternoon milking. The NA cows produced more milk and milk components, and had a greater pasture DMI, despite spending less time grazing. Declines in time spent grazing and pasture DMI were associated with increasing concentrate DMI. Grazing behavior following morning supplementation was different from that recorded following afternoon supplementation. Grazing ceased following morning supplementation before rumen fill could be a limiting factor, and the length of the grazing interval was inversely proportional to the amount of concentrate offered; these results suggest that physiological rather than physical stimuli were responsible for grazing cessation. The decrease in time spent grazing with increasing concentrate DMI is consistent with changes in neuroendocrine factors secreted in response to the presence of food in the digestive tract or with circulating products of digestion. After afternoon supplementation, sunset signaled the end of grazing irrespective of stage of lactation, timing of sunset, or supplementation status, suggesting that photoperiod influenced grazing behavior. Results confirmed changes in grazing behavior, an associated reduction in pasture DMI, and an increase in milk production when cows consume increasing amounts of concentrates. However, as the effect of supplement on grazing behavior differed between morning and afternoon supplementation, further research is required to better understand the factors controlling grazing behavior, to allow improved milk production responses to supplementary feeding. PMID- 21700047 TI - Substitution rate and milk yield response to corn silage supplementation of late lactation dairy cows grazing low-mass pastures at 2 daily allowances in autumn. AB - Feed costs in dairy production systems may be decreased by extending the grazing season to periods such as autumn when grazing low-mass pastures is highly probable. The aim of this autumn study was to determine the effect of corn silage supplementation [0 vs. 8 kg of dry matter (DM) of a mixture 7:1 of corn silage and soybean meal] on pasture intake (PI), milk production, and grazing behavior of dairy cows grazing low-mass ryegrass pastures at 2 daily pasture allowances (PA; low PA=18 vs. high PA=30 kg of DM/cow above 2.5 cm). Twelve multiparous Holstein cows were used in a 4 * 4 Latin square design with 14-d periods. Pre grazing pasture mass and pre-grazing plate meter pasture height averaged 1.8 t of DM/ha (above 2.5 cm) and 6.3 cm, respectively. The quality of the offered pasture (above 2.5 cm) was low because of dry conditions before and during the experiment (crude protein=11.5% of DM; net energy for lactation=5.15 MJ/kg of DM; organic matter digestibility=61.9%). The interaction between PA and supplementation level was significant for PI but not for milk production. Supplementation decreased PI from 11.6 to 7.6 kg of DM/d at low PA and from 13.1 to 7.3 kg of DM/d at high PA. The substitution rate was, therefore, lower at low than at high PA (0.51 vs. 0.75). Pasture intake increased with increasing PA in unsupplemented treatments, and was not affected by PA in supplemented treatments. Milk production averaged 13.5 kg/d and was greater at high than at low PA (+1.4 kg/d) and in supplemented than unsupplemented treatments (+5.2 kg/d). Milk fat concentration averaged 4.39% and was similar between treatments. Milk protein concentration increased from 3.37 to 3.51% from unsupplemented to supplemented treatments, and did not vary according to PA. Grazing behavior parameters were only affected by supplementation. On average, daily grazing time decreased (539 vs. 436 min) and daily ruminating time increased (388 vs. 486 min) from 0 to 8 kg of supplement DM. The PI rate was 6g of DM/min lower in supplemented than in unsupplemented treatments (17 vs. 23 g of DM/min). The high milk yield response to supplementation may be related to a cumulative effect of the low-mass pasture (low PI) and the low quality of the pasture, which strongly limited energy supply in unsupplemented cows. PMID- 21700048 TI - Short communication: effects of replacing part of corn silage and alfalfa hay with Leymus chinensis hay on milk production and composition. AB - The objective of this research was to investigate the effects of replacing part of corn silage (CS) and alfalfa hay (AH) with Leymus chinensis hay on milk production and composition. Twenty multiparous Holstein dairy cows were used in a randomized block design for a 14-week period and 2 treatments. Treatments were (dry matter basis): (1) Non-Leymus chinensis hay diet (NLC; 35% CS, 15% AH) and (2) added Leymus chinensis hay diet (ALC; 30% CS, 10% AH, 10% Leymus chinensis hay). Adding Leymus chinensis hay increased neutral detergent fiber content and in vitro digestibility of the diet. Cows receiving the ALC diet had higher dry matter intake, milk yield, milk protein yield, lactose yield, solids-not-fat yield, and milk fat content compared with those fed the NLC diet. Somatic cell counts of cows decreased in the ALC compared with the NLC treatment. Cis-11 18:1 and 18:2 contents in milk increased, whereas trans-9 and cis-9 18:1 fatty acid contents decreased. Trans-9, cis-11 conjugated linoleic acid content was not influenced by adding Leymus chinensis hay to the diet. Leymus chinensis hay can be used to replace part of CS and AH in diets of dairy cows to get higher milk yield and good milk quality. PMID- 21700049 TI - Short communication: serum immunoglobulin G and total protein concentrations in dairy calves fed a colostrum-replacement product. AB - Neonatal calf health is largely dependent on the ingestion and absorption of maternally derived antibodies via colostrum administration. The objective of this study was to evaluate the efficacy of a commercially available plasma-derived colostrum-replacement (CR) product as compared with bovine colostrum. Holstein calves were removed from the dam immediately after birth and randomly allocated to 1 of 3 groups. Group 1 calves (n=22) were fed 1 package of the CR product; group 2 calves (n=22) were fed 2 packages of the CR product; and group 3 calves (n=22) were fed 3 L of bovine colostrum. Blood samples were collected from all calves 24h after colostrum or CR feeding and analyzed for serum IgG and total protein concentrations. Calves fed bovine colostrum had significantly higher serum IgG and total protein concentration than calves in either group fed the CR product. Group 1 calves (1 package of CR product) had a significantly higher incidence of failure of transfer of passive immunity than calves in groups 2 or 3. The results of this study indicated that 2 packages of this CR product achieved adequate IgG concentrations in calves. However, calves fed 1 package of this CR product consistently had failure of transfer of passive immunity. PMID- 21700050 TI - Technical note: improved methodology for analyses of acid detergent fiber and acid detergent lignin. AB - The objective of this study was to evaluate the methodology of the acid detergent lignin (ADL) assay in an effort to evaluate particle loss, improve repeatability, and decrease variation within and among samples. The original ADL method relied on asbestos as a filtering aid, but that was removed in 1989 with the mandate from the Environmental Protection Agency to eliminate asbestos in the environment. Furthermore, recent work on fiber methodology indicated that pore size in the Gooch sintered glass crucible (40-60 MUm) was too large to trap all of the small particles associated with neutral detergent fiber (NDF) and acid detergent fiber (ADF). Thus, any loss of ADF could potentially result in a loss of ADL. Sixty forages including conventional and brown midrib corn silages, alfalfa silages and hays, mature grasses, early vegetative grasses, and 9 feces samples, were analyzed sequentially for ADF and ADL as outlined in the 1973 procedure of Van Soest except for the use of the asbestos fiber. A glass microfiber filter with a 1.5-MUm pore size was chosen as a filtering aid because it met the criteria required by the assay: glass, heat resistant, acid resistant, chemically inert, and hydrophobic. To compare with the current ADF and ADL assays, the assays were conducted with either no filter or the glass filter inserted into crucibles, rinsed with acetone, and then according to the 1973 procedure of Van Soest. The samples analyzed covered a range from 18.11 to 55.79% ADF and from 0.96 to 9.94% ADL on a dry matter (DM) basis. With the use of the filter, the mean ADF values increased 4.2% and mean ADL values increased 18.9%. Overall, both ADF and ADL values were greater with the use of the glass microfiber filter than without, indicating that as the type of sample analyzed changed, use of the Gooch crucible without the filtering aid results in particle loss. The adoption of the use of a small pore size (1.5 MUm) glass microfiber filter to improve filtration and recovery of ADF and ADL and to reduce variation in the ADL assay is recommended, especially when sintered glass bottom crucibles are used. These differences in recovery and repeatability have implications for other fiber and lignin methods, as well as for estimating the potential changes in digestibility of fibrous feeds and feed quality. PMID- 21700051 TI - Evidence that leptin genotype is associated with fertility, growth, and milk production in Holstein cows. AB - This study investigated associations between single nucleotide polymorphisms (SNP) in the leptin, leptin receptor, and neuropeptide Y (NPY) genes with growth, milk production, and fertility traits. Holstein Friesian heifers from 19 UK dairy farms were recruited at birth, providing an initial population of 509. Animals were monitored until they either reached the end of their second lactation or were culled. Size (weight, height, length, girth) was measured at 1, 6, and 15 mo to assess growth traits. Heifer fertility was assessed by recording age at service, age at conception, age at first calving, and number of services. Cow fertility was assessed by recording days from calving to service and conception, services per conception, percentage of animals in calf at 100 d after calving and the calving interval in each lactation. Milk production was recorded as days in milk, total milk per lactation, 305-d yield, milk per day, and peak yield. Mixed model analyses revealed that leptin SNP were associated with early skeletal growth (height, A1457G; length, A59V), fertility (UASMS1, UASMS2, A1457G, A59V) and milk production (A59V). The leptin receptor SNP (T945M) was only weakly associated with milk per day and days to first service. The NPY SNP (NPY1) was associated with the prevalence of the animal being in calf 100 d after calving and 305-d milk yield in the first lactation. The association of leptin SNP with fertility traits in heifers, in addition to lactating cows, suggests that some effects on fertility are direct and not necessarily mediated via altered tissue mobilization. In accord with this, other work has shown that leptin can affect oocyte quality and early embryo development. These results support the use of leptin SNP to inform marker-assisted selection in dairy cows. PMID- 21700052 TI - Genetic parameters for milk somatic cell score and relationship with production and udder type traits in dairy Alpine and Saanen primiparous goats. AB - Goat milk somatic cell counts have been collected for several years in France by the national milk recording organization. Information is used for health management, because repeatedly elevated somatic cell counts are a good indirect predictor of intramammary infection. Genetic parameters were estimated for 67,882 and 49,709 primiparous goats of the dairy Alpine and Saanen breeds, respectively, with complete information for milk somatic cell counts and milk production traits. About 40% of the goats had additional information for 11 udder type traits scored by official classifiers of the breeders' association CAPGENES. Estimates were obtained by REML with an animal model. The studied trait was lactation somatic cell score (LSCS), the weighted mean of somatic cell score (log transformed SCC) adjusted for lactation stage. Heritability of LSCS was 0.20 and 0.24 in the Alpine and Saanen breeds, respectively. Relationships with milk production and udder type traits were additionally estimated by using multitrait analyses. Heritability estimates in first lactation ranged from 0.30 to 0.35 for lactation milk, fat, and protein yields; from 0.60 to 0.67 for fat and protein contents; and from 0.22 to 0.50 for udder type traits. Genetic correlations of somatic cell score with milk production traits were generally low, ranging from 0.13 to 0.12. Slightly more negative correlations were estimated for fat content: -0.18 and -0.20 in Saanen and Alpine breeds, respectively. Lactation somatic cell score was genetically correlated with udder floor position (r(g)=-0.24 and -0.19 in the Alpine and Saanen breeds, respectively), and, in Saanen, teat length, teat width, and teat form (r(g)=0.29, 0.34 and -0.27, respectively). These results suggest that a reduction in somatic cell count can be achieved by selection while still improving milk production and udder type and teat traits. PMID- 21700053 TI - Genetic variation of toll-like receptor genes and infection by Mycobacterium avium ssp. paratuberculosis in Holstein-Friesian cattle. AB - Toll-like receptors (TLR) are membrane proteins that play a key role in innate immunity, by recognizing pathogens and subsequently activating appropriate responses. Mutations in TLR genes are associated with susceptibility to inflammatory and infectious diseases in humans. In cattle, 3 members of the TLR family, TLR1, TLR2, and TLR4, are associated with Mycobacterium avium ssp. paratuberculosis infection, although the extent of this association for the TLR1 and TLR4 receptors has not yet been determined. Moreover, the causal variant in the TLR2 gene has not yet been unequivocally established. In this study, 24 single nucleotide polymorphisms (SNP) in the bovine TLR1, TLR2, and TLR4 genes were selected from the literature, databases, and in silico searches, for a population-based genetic association study of a Spanish Holstein-Friesian sample. Whereas previous results regarding the TLR1 gene were not corroborated, a risk haplotype was detected in TLR2; however, its low frequency indicates that this detected association should be interpreted with caution. In the case of the TLR4 gene, 3 tightly linked SNP were found to be associated with susceptibility to M. avium ssp. paratuberculosis infection. Moreover, one of these SNP, the SNP c. 226G>C, which is localized in the 5'UTR region of the TLR4 gene, has been reported to be able to alter TLR4 expression, raising the possibility that this mutation may contribute to the response of the individual to infection. PMID- 21700054 TI - Accuracy of genomic prediction using low-density marker panels. AB - Genomic selection has been widely implemented in national and international genetic evaluation in the dairy cattle industry, because of its potential advantages over traditional selection methods and the availability of commercial high-density (HD) single nucleotide polymorphism (SNP) panels. However, this method may not be cost-effective for cow selection and for other livestock species, because the cost of HD SNP panels is still relatively high. One possible solution that can enable other species to benefit from this promising method is genomic selection with low-density (LD) SNP panels. In this simulation study, LD SNP panels designed with different strategies and different SNP densities were compared. The effects of number of quantitative trait loci, heritability, and effective population size were evaluated in the framework of genomic selection with LD SNP panels. Methodologies of Bayesian variable selection; BLUP with a trait-specific, marker-derived relationship matrix; and BLUP with a realized relationship matrix were employed to predict genomic estimated breeding values with both HD and LD SNP panels. Up to 95% of accuracy obtained by using an HD panel can be obtained by using only a small proportion of markers. The LD panel with markers selected on the basis of their effects always performs better than the LD panel with evenly spaced markers. Both the genetic architecture of the trait and the effective population size have a significant effect on the performance of the LD panels. We concluded that, to implement genomic selection with LD panels, a training population of sufficient size and genotyped with an HD panel is necessary. The trade-off between the LD panels with evenly spaced markers and selected markers must be considered, which depends on the number of target traits in a breeding program and the genetic architecture of these traits. Genomic selection with LD panels could be feasible and cost-effective, though before implementation, a further detailed genetic and economic analysis is recommended. PMID- 21700055 TI - The use of mid-infrared spectrometry to predict body energy status of Holstein cows. AB - Energy balance, especially in early lactation, is known to be associated with subsequent health and fertility in dairy cows. However, its inclusion in routine management decisions or breeding programs is hindered by the lack of quick, easy, and inexpensive measures of energy balance. The objective of this study was to evaluate the potential of mid-infrared (MIR) analysis of milk, routinely available from all milk samples taken as part of large-scale milk recording and milk payment operations, to predict body energy status and related traits in lactating dairy cows. The body energy status traits investigated included energy balance and body energy content. The related traits of body condition score and energy intake were also considered. Measurements on these traits along with milk MIR spectral data were available on 17 different test days from 268 cows (418 lactations) and were used to develop the prediction equations using partial least squares regression. Predictions were externally validated on different independent subsets of the data and the results averaged. The average accuracy of predicting body energy status from MIR spectral data was as high as 75% when energy balance was measured across lactation. These predictions of body energy status were considerably more accurate than predictions obtained from the sometimes proposed fat-to-protein ratio in milk. It is not known whether the prediction generated from MIR data are a better reflection of the true (unknown) energy status than the actual energy status measures used in this study. However, results indicate that the approach described may be a viable method of predicting individual cow energy status for a large scale of application. PMID- 21700056 TI - The effect of improving cow productivity, fertility, and longevity on the global warming potential of dairy systems. AB - This study compared the environmental impact of a range of dairy production systems in terms of their global warming potential (GWP, expressed as carbon dioxide equivalents, CO(2)-eq.) and associated land use, and explored the efficacy of reducing said impact. Models were developed using the unique data generated from a long-term genetic line * feeding system experiment. Holstein Friesian cows were selected to represent the UK average for milk fat plus protein production (control line) or were selected for increased milk fat plus protein production (select line). In addition, cows received a low forage diet (50% forage) with no grazing or were on a high forage (75% forage) diet with summer grazing. A Markov chain approach was used to describe the herd structure and help estimate the GWP per year and land required per cow for the 4 alternative systems and the herd average using a partial life cycle assessment. The CO(2)-eq. emissions were expressed per kilogram of energy-corrected milk (ECM) and per hectare of land use, as well as land required per kilogram of ECM. The effects of a phenotypic and genetic standard deviation unit improvement on herd feed utilization efficiency, ECM yield, calving interval length, and incidence of involuntary culling were assessed. The low forage (nongrazing) feeding system with select cows produced the lowest CO(2)-eq. emissions of 1.1 kg/kg of ECM and land use of 0.65 m(2)/kg of ECM but the highest CO(2)-eq. emissions of 16.1t/ha of the production systems studied. Within the herd, an improvement of 1 standard deviation in feed utilization efficiency was the only trait of those studied that would significantly reduce the reliance of the farming system on bought-in synthetic fertilizer and concentrate feed, as well as reduce the average CO(2) eq. emissions and land use of the herd (both by about 6.5%, of which about 4% would be achievable through selective breeding). Within production systems, reductions in CO(2)-eq. emissions per kilogram of ECM and CO(2)-eq. emissions per hectare were also achievable by an improvement in feed utilization. This study allowed development of models that harness the biological trait variation in the animal to improve the environmental impact of the farming system. Genetic selection for efficient feed use for milk production according to feeding system can bring about reductions in system nutrient requirements, CO(2)-eq. emissions, and land use per unit product. PMID- 21700057 TI - Effect of imputing markers from a low-density chip on the reliability of genomic breeding values in Holstein populations. AB - The purpose of this study was to investigate the imputation error and loss of reliability of direct genomic values (DGV) or genomically enhanced breeding values (GEBV) when using genotypes imputed from a 3,000-marker single nucleotide polymorphism (SNP) panel to a 50,000-marker SNP panel. Data consisted of genotypes of 15,966 European Holstein bulls from the combined EuroGenomics reference population. Genotypes with the low-density chip were created by erasing markers from 50,000-marker data. The studies were performed in the Nordic countries (Denmark, Finland, and Sweden) using a BLUP model for prediction of DGV and in France using a genomic marker-assisted selection approach for prediction of GEBV. Imputation in both studies was done using a combination of the DAGPHASE 1.1 and Beagle 2.1.3 software. Traits considered were protein yield, fertility, somatic cell count, and udder depth. Imputation of missing markers and prediction of breeding values were performed using 2 different reference populations in each country: either a national reference population or a combined EuroGenomics reference population. Validation for accuracy of imputation and genomic prediction was done based on national test data. Mean imputation error rates when using national reference animals was 5.5 and 3.9% in the Nordic countries and France, respectively, whereas imputation based on the EuroGenomics reference data set gave mean error rates of 4.0 and 2.1%, respectively. Prediction of GEBV based on genotypes imputed with a national reference data set gave an absolute loss of 0.05 in mean reliability of GEBV in the French study, whereas a loss of 0.03 was obtained for reliability of DGV in the Nordic study. When genotypes were imputed using the EuroGenomics reference, a loss of 0.02 in mean reliability of GEBV was detected in the French study, and a loss of 0.06 was observed for the mean reliability of DGV in the Nordic study. Consequently, the reliability of DGV using the imputed SNP data was 0.38 based on national reference data, and 0.48 based on EuroGenomics reference data in the Nordic validation, and the reliability of GEBV using the imputed SNP data was 0.41 based on national reference data, and 0.44 based on EuroGenomics reference data in the French validation. PMID- 21700058 TI - Short communication: influence of the muscle hypertrophy mutation of the myostatin gene on milk production traits and milk fatty acid composition in dual purpose Belgian Blue dairy cattle. AB - The objective of this study was to estimate genetic effects for the muscle hypertrophy mutation (mh) of the myostatin gene for conventional milk production traits and for milk fatty acid composition in dual-purpose Belgian Blue dairy cows. For the present study, only cows from a single herd, in which genotype frequencies were as balanced as possible (0.266 for +/+, 0.523 for mh/+, and 0.211 for mh/mh), were chosen to avoid confounding between herd and genotype effects. A total of 109 cows with 3,190 test-day records for fat, protein, and milk yields and 1,064 test-day records for saturated and monounsaturated fatty acids were used for the calculations. Variance component and gene effect estimations were performed via expectation-maximization REML and BLUP methods, respectively, using a multi-trait mixed test-day model with an additional fixed regression on the muscle hypertrophy genotype. Results showed that one copy of the wild-type "+" allele led to a significant additive effect of 26.35 g/d for fat yield. Significant dominance effects of 23.22 g/d for protein yield and 30.28 g/d for fat yield were also observed. In contrast, a nonsignificant trend was observed in favor of lower saturated fatty acid contents in milk for one copy of the mutant "mh" allele. Concerning milk, fat, and protein yields, our results confirmed literature results indicating a superior effect of the "+" allele compared with the mutant allele. Therefore, the selection of the "+" allele has the potential to increase conventional milk production traits in the dual-purpose Belgian Blue breed. However, when focus is given to milk fatty acid profile, a possible antagonistic effect between the benefit of the "+" allele for higher milk production and the "mh" allele for reduced saturated fatty acid content in milk should be confirmed in further studies. PMID- 21700059 TI - Short communication: estimates of genetic parameters of body condition score in the first 3 lactations using a random regression animal model. AB - The objective of this research was to estimate the genetic parameters of body condition score (BCS) in the first 3 lactations in Canadian Holstein dairy cattle using a multiple-lactation random regression animal model. Field staff from Valacta milk recording agency (Sainte-Anne-de-Bellevue, QC, Canada) collected BCS from Quebec herds several times throughout each lactation. Approximately 32,000, 20,000, and 11,000 first-, second-, and third-parity BCS were analyzed, respectively, from a total of 75 herds. Body condition score was a moderately heritable trait over the lactation for parity 1, 2, and 3, with average daily heritabilities of 0.22, 0.26, and 0.30, respectively. Daily heritability ranged between 0.14 and 0.26, 0.19 and 0.28, and 0.24 and 0.33 for parity 1, 2, and 3, respectively. Genetic variance of BCS increased with days in milk within lactations. The low genetic variance in early lactation suggests that the evolution of the ability to mobilize tissue reserves in early lactation provided cattle with a major advantage, and is, therefore, somewhat conserved. The increasing genetic variance suggests that more genetic differences were related to how well cows recovered from the negative energy balance state. More specifically, increasing genetic variation as lactation progressed could be a reflection of genetic differences in the ability of cows to efficiently control the rate of mobilization of tissue reserves, which would not be crucial in early lactation. The shape of BCS curves was similar across parities. From first to third parity, differences included the progressively deeper nadir and faster rate of recovery of condition. Daily genetic correlations between parities were calculated from 5 to 305 DIM, and were summed and divided by 301 to obtain average daily genetic correlations. The average daily genetic correlations were 0.84 between parity 1 and 2, 0.83 between parity 1 and 3, and 0.86 between parity 2 and 3. Although not 1, these genetic correlations are still strong, so much of the variation observed in BCS was controlled by the same genes for each of the first 3 lactations. If a genetic evaluation for BCS is developed, regular collection of first-lactation BCS records should be sufficient for genetic evaluation. PMID- 21700060 TI - Factors affecting the incidence of first-quality wheels of Trentingrana cheese. AB - Trentingrana (or Grana Trentino) is a Protected Designation of Origin hard cheese produced in the eastern Italian Alps by small cooperative dairy factories. To obtain the certification of quality, wheels are evaluated at 9+/-1 mo of ripening and those classified as first quality are revaluated at 18+/-1 mo. Traditionally, the assessment is based on 2 sensory features: namely, the external aspect of the wheel and the internal texture; the latter is evaluated through the sound produced by beating the wheel with a special hammer. Traits considered in the study were the percentage of first-quality wheels of total wheels examined at 9+/ 1 (QW(9 mo)) and 18+/-1 (QW(18 mo)) mo of ripening, and their combination [i.e., the percentage of first-quality wheels at 18+/-1 mo of ripening of the number of wheels evaluated at 9+/-1 mo (QW(tot))]. The experimental unit was the batch of 2 mo of production of each of 10 cooperative dairy factories from 2002 to 2008. Data were analyzed with a model that included fixed effects of dairy factory, year and season of production, and interactions between dairy factory and year, and dairy factory and season. The coefficients of determination of the models were 0.57, 0.68, and 0.67 for QW(9mo), QW(18 mo), and QW(tot), respectively. All factors significantly influenced the traits, with dairy factory being the most important source of variation, followed by season and year of production. Remarkable differences were found between the best and the worst dairy factory for QW(9 mo) (11.5%), QW(18 mo) (21.1%), and QW(tot) (25.6%). The first 4 yr of production had a negative effect on the percentage of wheels labeled as first quality and QW(tot) decreased from 74 to 64%; nevertheless, a complete recovery was detected in the following years. The season of production strongly influenced the studied traits with the best results in spring and summer, and the worst in autumn and winter. Compared with average, the 3 best dairy factories were smaller, with smaller associated farms, and showed lower variation across years and seasons of production. Results support the relevance of routinely assessing and monitoring the quality of Trentingrana cheese. PMID- 21700061 TI - Fortification of Cheddar cheese with vitamin D does not alter cheese flavor perception. AB - Currently, dietary guidelines for vitamin D consumption are under review, considering new information that >50% of the US population is vitamin D deficient, and may lead to a recommendation of a higher dietary intake of this vitamin. Vitamin D fortification of cheese aims to improve the current availability of fortified dairy foods beyond liquid milk. However, cheese is susceptible to undesirable flavor changes during long-term cheese ripening, and cheese bacteria and enzymes may degrade added vitamins. To test the retention of vitamin D(3) in Cheddar cheese curd, cheese milk was fortified initially during manufacture at a level of 150 IU/serving, using commercial sources that contained vitamin D(3) in powder, oil, or emulsion form, with and without homogenization of the fortified milk. When fortification was done directly to the cheese milk, we found that more than 80% vitamin D(3) was retained in cheese curd, irrespective of homogenization or form of fortification. Further, Cheddar cheese was fortified with the emulsion form of vitamin D(3) directly in cheese milk at 200 and 400 IU/serving to test stability and flavor changes. Vitamin D(3) fortified in this manner was stable for up to 9 mo in Cheddar cheese. Consumer acceptance and descriptive analysis of flavor profiles of cheese were also conducted and showed that vitamin D(3) fortified cheeses were equally liked by consumers, and cheese taste and flavor remained unaltered with vitamin D(3) addition even after aging for 9 mo. PMID- 21700062 TI - Assessing economic and demographic factors that influence United States dairy demand. AB - Low-fat dairy products are key components of a healthy diet for all Americans. As the USDA increases its focus on nutrition and healthy eating, it is important to understand the underlying demands for dairy products, both the healthy and the less healthy ones. The consumption of fluid milk products has decreased over the last decade, whereas milk used for manufactured dairy products such as cheese, ice cream, yogurt, and butter, and for use as an ingredient in other food products, has risen. The objective of this study is to determine the effects of changes in demographic variables, retail prices, and total dairy expenditure on at-home consumption of dairy products, using purchase data from Nielsen 2007 Homescan (ACNielsen, New York, NY) data. To derive the demand elasticities for 16 products, a censored Almost Ideal Demand System model is used. Results reveal that demographic variables do have effects on the purchase of the 16 products, and own-price elasticities are 1 or greater for all 16 products for both uncompensated and compensated elasticities except 4: ice cream, refrigerated yogurt, processed cheese, and margarine. A substitution relationship exists among all fluid milk categories, natural and processed cheese, low-fat ice cream, and refrigerated yogurt, butter, and margarine. PMID- 21700063 TI - [Solution to case 29. Congenital Subglottic hemangioma]. PMID- 21700064 TI - [Solution to case 30. Choroid plexus papilloma with meningeal enhancement]. PMID- 21700065 TI - [Guidelines for clinical practice: why and how?]. PMID- 21700066 TI - [Is proliferation of guidelines improving patient care?]. PMID- 21700067 TI - [Expert consensus on the management of Merkel cell carcinoma]. AB - INTRODUCTION: Merkel cell carcinoma (MCC) is a rare form of tumour that develops from neuroendocrine skin cells. There is no consensus concerning diagnosis and therapy for this disease. To establish recommendations, the Skin Oncology Group of the French Dermatology Society drew on existing recommendations in the US and Germany. Concordance between the two sets of recommendations was validated by the group, who, in view of the large number of discrepancies, decided to use the formalised expert consensus method. METHODS: Twelve practitioners known for their experience in the management of Merkel cell carcinoma completed a standardised questionnaire. This group consisted of seven dermatologists, three radiotherapists and two plastic surgeons. They answered a total of 82 questions concerning the diagnosis, treatment and follow-up of MCC. A strong consensus was declared where all answers were in the same third of the table; a weak or relative consensus was declared where answers overlapped for adjacent scores, and an absence of consensus was declared in the event of dispersal of values. RESULTS: On completion of this process, the method revealed strong concordance on the following points: value of CK7 and CK20 immunolabelling; lack of value of chest radiography in the initial work-up, but value of lymph node ultrasound; inadequacy of an excision margin of 1cm but lack of any need for a margin greater than 3cm; absence of any value of chemotherapy for inoperable tumours; value of seeking sentinel nodes in tumours measuring less than 2cm outside the head and neck and more than 2cm for head and neck tumours; value of additional radiotherapy at the initial tumour site. Relative agreement was reached concerning the value of thoracic-abdominal-pelvic computed tomography (CT) scans in all cases, together with a head CT scan for cervical-facial tumour sites. CONCLUSION: The creation of a formalised expert consensus helps complete the existing recommendations, particularly on those points where no consensus exists between the American and German recommendations and where no strong evidence is to be found in the literature. PMID- 21700068 TI - [Guidelines for the diagnosis and treatment of Merkel cell carcinoma]. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma that originates in the skin. Epidemiological factors strongly associated with MCC are: age over 65 years, fair skin, history of extensive sun exposure and chronic immune suppression. The literature is sparse and many questions currently remain unanswered regarding optimal treatment of MCC. OBJECTIVE: To provide clinical practice guidelines for the diagnosis and treatment of MCC. METHODS: Literature data were analysed and the existing German and American practice guidelines were compared. Where German and US guidelines were identical, the recommendations in question were adopted. Regarding discordant points, a formalized consensus process was devised. The guidelines were then written by an editorial group and validated by the cutaneous oncology group of the French Society of Dermatology. RESULTS: The guidelines were drawn up according to three levels of scientific evidence: a: complete agreement between the German and American guidelines; b: results of the formalized consensus process; c: expert opinion of the steering group based on available evidence. Our guidelines present up-to-date recommendations on clinical and pathological procedures for diagnosis, staging, surgical treatment, sentinel lymph node biopsy, radiotherapy and follow-up. CONCLUSION: We created a set of diagnostic and treatment guidelines in order to standardize management of MCC, which may be not optimal throughout France. PMID- 21700069 TI - [Neuro-cardio-facial-cutaneous syndrome]. AB - The concept of neuro-cardio-facio-cutaneous (NCFC) syndrome has recently been formulated in order to bring together a number of hereditary diseases that include a number of shared phenotypic features to differing degrees: (i) craniofacial dysmorphia; (ii) delayed growth; (iii) mental retardation or learning difficulties; (iv) cardiac malformations (most commonly pulmonary valve stenosis and hypertrophic cardiomyopathy); (v) cutaneous anomalies, and in some cases, predisposition to certain forms of malignant solid tumors and blood diseases, associated at the physiopathological level with deregulation of the Ras MAP kinase cellular signaling pathways 1. NCFC subsumes neurofibromatosis type1, Legius syndrome, LEOPARD syndrome, Noonan syndrome, Costello syndrome and cardiofaciocutaneous (CFC) syndrome. While the majority of these diseases are readily distinguishable in clinical terms, with or without diagnostic criteria, none of them have any pathognomonic signs. Many cases attest to the strong clinical homologies and forms of overlapping between these different diseases. In recent years, the discovery of germinal mutations of these different diseases has in fact reinforced the unifying clinical and biochemical concept of NCFC syndrome. PMID- 21700070 TI - [Functional impairment and radiologic fasciitis under erlotinib therapy]. AB - BACKGROUND: Targeted molecules are recent and valuable weapons in the management of certain cancers. Among them, erlotinib is an inhibitor of epidermal growth factor receptor approved in non-small lung cancer and pancreatic cancer after failure of first line treatment. Erlotinib is responsible for many cutaneous side effects. We report a case of acute symptomatic fasciitis that has occurred during erlotinib therapy. To our knowledge it is the first case described. CASE REPORT: A 56-year-old man was treated with erlotinib for a metastatic non-small lung adenocarcinoma. Shortly after the treatment by erlotinib was introduced, he had a severe acneiform rash resistant to doxycycline treatment. After a year of treatment, he presented intense pain in the legs with functional impairment. Medical imaging confirmed fasciitis. It regressed along with the rash after using strong topical corticosteroids during ten days. DISCUSSION: Besides bacterial fasciitis, inflammatory and oedematous fasciitis have varied aetiologies. The occurrence of a documented fasciitis during anti EGFR-therapy is original and raises the question of underlying mechanism. We suggest three pathophysiological mechanisms: spreading by contiguity; paraneoplastic fasciitis, or specific lesion of the fascia due to anti-EGFR. PMID- 21700072 TI - [Cutaneous phaeohyphomycosis due to Cladophialophora bantiana]. AB - BACKGROUND: Among dematiaceous fungi responsible for phaeohyphomycosis, Cladophialophora bantiana is an opportunistic pathogen that causes central nervous system infections, chiefly in immunocompromised patients. Only a few reports on skin involvements have been reported in the recent dermatological literature. Herein we report the case of an immunocompetent patient with cutaneous phaeohyphomycosis. CASE REPORT: A 48-year-old male presented a nodular, painless and non-suppurative lesion with a diameter of 1cm on the right buttock that had developed since his return from a trip to Vietnam. A diagnosis of phaeohyphomycosis due to C. bantiana was made based on the histopathology and mycology examinations, which allowed the identification of C. bantiana, a dematiaceous (black) fungus from hyphomycete species. DISCUSSION: C. bantiana is a neurotropic fungus that causes central nervous system infections in particular. Extracerebral involvement is rare and only a few cases of cutaneous phaeohyphomycosis have been reported. Furthermore, since immunocompromised hosts are more vulnerable, this mycosis is more commonly seen in immunocompromised patients. However in this particular case, an intramuscular injection of corticosteroids could have caused local immunosuppression. The prognosis depends on both localization and site. There are no guidelines for optimal treatment. PMID- 21700071 TI - [Interstitial pneumonia after infliximab therapy for psoriasis]. AB - BACKGROUND: Tumour necrosis factor (TNF)-alpha inhibitors are increasingly used for treatment of severe psoriasis. Hypersensitivity pneumonia is a rare but frequently fatal side-effect of such therapy that is unknown to most dermatologists. PATIENTS AND METHODS: A 68-year-old woman was hospitalized for subacute dyspnoea, fever, dry cough and basal chest pain 3 months after beginning infliximab therapy for severe psoriasis. Blood tests revealed an inflammatory syndrome and hypoxaemia. Thoracic computed tomography showed bilateral basal interstitial infiltrates with pleural effusion. The results of bronchoalveolar lavage and of the other microbiology testing were negative. Probabilistic treatment with amoxicillin/clavulanic acid and spiramycin was ineffective. We suspected drug-induced alveolitis and began corticosteroid therapy which improved dyspnoea, gas exchange and X-ray images. DISCUSSION: Hypersensitivity pneumonia is a potential pulmonary complication of anti-TNF alpha therapy and is frequently fatal. We report the first case of interstitial pneumonia secondary to infliximab given for severe psoriasis without any other pneumotoxic agents. Clinical features include dry cough, dyspnoea, and fever of acute or subacute onset. A diagnosis of allergic alveolitis was retained after elimination of other possible causes of the patient's interstitial pneumonia. CONCLUSION: The indications for anti-TNF agents are increasing in dermatology, and it is thus vital to consider their very rare but serious complications such as hypersensitivity pneumonia. PMID- 21700073 TI - [Recurrent breast cellulitis associated with lymphangiectasia after tumorectomy for breast cancer]. AB - BACKGROUND: Recurrent breast cellulitis has been described as a complication following breast conservation therapy. OBSERVATION: A 50-year-old woman undergoing tumour excision, postoperative radiotherapy and chemotherapy presented recurrent breast cellulitis in the same region. The presence of lymphangiectasia suggested a complication subsequent to lymph stasis. DISCUSSION: Conservative therapy for breast cancer, allowing the development of subclinical or patent lymphoedema, constitutes a prominent risk factor for recurrent cellulitis. This complication has also been considered in patients with lower extremity cellulitis following saphenous venectomy for coronary bypass surgery. The unusual presence of lymphangiectasia observed in our patient provides clear evidence that lymphoedema is the most prominent risk factor for the development of cellulitis after breast conservation therapy. PMID- 21700074 TI - [Annular lipoatrophy of the ankles]. AB - BACKGROUND: Annular lipoatrophy of the ankles (ALA) is an extremely rare form of localized lipoatrophy characterized by atrophy of subcutaneous fat. We report a case of annular atrophy of the ankles associated with a history of diabetes and Graves' disease. PATIENTS AND METHODS: A 22-year-old woman with a history of Graves' disease and diabetes consulted for annular lesions of ankles which had appeared three years earlier. She had suddenly developed erythematous annular plaques on the right ankle. One week later, the plaques had evolved towards progressive atrophic bands involving the lower third of the legs. The overlying skin was normal and muscle involvement was absent. Laboratory studies revealed an antinuclear antibody (ANA) titre of 1/640 while a skin biopsy specimen showed diffuse lobular lymphohistiocytic panniculitis rich in lymphocytes and lipophages foam cells without any evidence of vasculitis. A direct immunofluorescence microscopy study was negative. Lipoatrophy was still present after six months of chloroquine treatment (300mg per day). DISCUSSION: ALA is a rare and poorly understood condition. Based on the ten or so case reports in the literature, we attempted to define the clinical and histological profile of the disease as well as its course and its relationship with other forms of atrophic panniculitis. In particular, the onset of LAC in our patient presenting several autoimmune diseases underlines its close relationship to the condition described as "connective tissue panniculitis". PMID- 21700075 TI - [Iatrogenic psychiatric disorders to corticosteroids in patients treated for chronic dermatoses]. PMID- 21700076 TI - [Multiple molluscum contagiosum under etanercept]. PMID- 21700077 TI - [Nodular papular lesions of the eyelids]. PMID- 21700078 TI - [Management of pain in dermatology: opioid therapy]. PMID- 21700079 TI - [Subungual exostosis]. PMID- 21700080 TI - [Incontinentia pigmenti]. PMID- 21700081 TI - [Hairpin vessels]. PMID- 21700082 TI - [Who, when and how to send a patient to the "shrink": proposition of a progress in six questions]. PMID- 21700083 TI - [Vitiligo on a tattoo]. PMID- 21700084 TI - Apical ballooning syndrome (Takotsubo cardiomyopathy) presenting with typical left ventricular morphology at initial presentation and mid-ventricular variant during a recurrence. PMID- 21700086 TI - Impact of insulin receptor substrate-1 genotypes on platelet reactivity and cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. AB - OBJECTIVES: The aim of this study was to assess the association between genetic variants of the insulin receptor substrate (IRS)-1 gene, platelet function, and long-term outcomes in patients with type 2 diabetes mellitus (DM) and stable coronary artery disease while on aspirin and clopidogrel therapy. BACKGROUND: The effects of pharmacogenetic determinants on platelet function and cardiovascular outcomes in type DM patients are unknown. METHODS: The association between IRS-1 genetic variants, platelet function, and the risk of major adverse cardiac events (MACE) at 2 years was assessed in 187 patients with type 2 DM and stable coronary artery disease on maintenance aspirin and clopidogrel therapy. RESULTS: Seven tag single nucleotide polymorphisms were selected. Individuals with high platelet reactivity were more frequent among carriers of the C allele (GC and CC genotypes; approximately 20% of population) of the rs956115 marker (44.4% vs. 20.5%; odds ratio: 3.1, 95% confidence interval [CI]: 1.44 to 6.67; p = 0.006). These patients were at higher risk of MACE (28.0% vs. 10.9%; hazard ratio: 2.90, 95% CI: 1.38 to 6.11; p = 0.005). The C allele carriers of the rs956115 marker were more commonly associated with a hyperreactive platelet phenotype. This was confirmed in an external validation cohort of patients with type 2 DM but not in an external validation cohort of patients without DM. Carriers of the C allele of the rs956115 marker also had a significantly higher risk of MACE compared with noncarriers (30.6% vs. 11.4%; hazard ratio: 2.88, 95% CI: 1.35 to 6.14; p = 0.006). CONCLUSIONS: Type 2 DM patients who are carriers of the C allele of the rs956115 marker of the IRS-1 gene have a hyperreactive platelet phenotype and increased risk of MACE. PMID- 21700085 TI - Bleeding avoidance strategies. Consensus and controversy. AB - Bleeding complications after coronary intervention are associated with prolonged hospitalization, increased hospital costs, patient dissatisfaction, morbidity, and 1-year mortality. Bleeding avoidance strategies is a term incorporating multiple modalities that aim to reduce bleeding and vascular complications after cardiovascular catheterization. Recent improvements in the rates of bleeding complications after invasive cardiovascular procedures suggest that the clinical community has successfully embraced specific strategies and improved patient care in this area. There remains controversy regarding the efficacy, safety, and/or practicality of 3 key bleeding avoidance strategies for cardiac catheterization and coronary intervention: procedural (radial artery approach, safezone arteriotomy), pharmacological (multiple agents), and technological (vascular closure devices) approaches to improved access. In this paper, we address areas of consensus with respect to selected modalities in order to define the role of each strategy in current practice. Furthermore, we focus on areas of controversy for selected modalities in order to define key areas warranting cautious clinical approaches and the need for future randomized clinical trials in this area. PMID- 21700087 TI - Reconstituted high-density lipoprotein shortens cardiac repolarization. AB - OBJECTIVES: We hypothesize that increasing high-density lipoprotein cholesterol (HDL-C) shortens cardiac repolarization. BACKGROUND: HDL-C is inversely associated with sudden death. The relation between HDL-C and repolarization of the heart is unexplored. METHODS: HDL-C was elevated with reconstituted high density lipoprotein (rHDL). Cardiac repolarization was studied by recording cardiac transmembrane potentials with the patch clamp technique from isolated rabbit cardiomyocytes that were superfused with rHDL. Infusions with rHDL (40 mg/kg body weight) were performed in dyslipidemic patients and healthy volunteers. Electrocardiograms were recorded to assess cardiac repolarization before and 24 h after infusion with rHDL. RESULTS: rHDL as well as purified human apolipoprotein AI shortened repolarization of isolated rabbit cardiomyocytes by ~25% (p < 0.05). rHDL infusion shortened the heart rate-corrected QT interval on surface electrocardiograms in all participants (p < 0.001). CONCLUSIONS: rHDL shortens cardiac repolarization. These data provide evidence for a novel mechanism of HDL infusion that may contribute to reduction of sudden cardiac death. PMID- 21700088 TI - High-density lipoprotein shortens the ventricular action potential. A novel explanation for how statins prevent sudden arrhythmic death? PMID- 21700089 TI - Monomorphic ventricular tachycardia and mediastinal adenopathy due to granulomatous infiltration in patients with preserved ventricular function. AB - OBJECTIVES: This report characterizes a syndrome of granulomatous infiltration presenting as sustained monomorphic ventricular tachycardia (SMVT) with mediastinal adenopathy in patients with preserved ventricular function. BACKGROUND: Unlike truly idiopathic ventricular tachycardia, SMVT due to granulomatous infiltration responds poorly to radiofrequency ablation and has a poor prognosis. METHODS: Patients without obstructive coronary artery disease and with normal ventricular function presenting with SMVT other than posterior fascicular morphology were evaluated. Computed chest tomograms, cardiac magnetic resonance imaging, and 18-fluorodeoxyglucose positron emission tomographic scans ((18)FDG PET-CT) were performed. Significant lymph nodes were evaluated for tuberculosis and sarcoidosis. Initial treatment included antiarrhythmic drugs +/- radiofrequency ablation. Additionally, patients with evidence of tuberculosis received anti-tuberculosis therapy; the rest were treated as sarcoidosis. RESULTS: Mediastinal adenopathy with mid-myocardial scar and/or focal myocardial inflammation was observed in 14 patients; lymph nodes revealed noncaseating granulomas in all. Evidence of tuberculosis was present in 79%. During follow-up (median duration 25 months), SMVT recurred despite initial treatment in 92%. Addition of disease-specific therapy abolished further recurrences in 64% of them. Decrease in SMVT correlated with resolution of myocardial inflammation on serial (18)FDG PET-CTs. Appropriate therapies occurred in 67% of patients receiving implantable cardioverter-defibrillators. CONCLUSIONS: A subset of patients with SMVT with preserved ventricular function has a syndrome of arrhythmogenic myocarditis with granulomatous mediastinal adenopathy due to myocardial tuberculosis or cardiac sarcoidosis. This entity is optimally managed with a combination of disease-specific therapy and antiarrhythmic measures. PMID- 21700090 TI - N-terminal pro-brain natriuretic Peptide is a more useful predictor of cardiovascular disease risk than C-reactive protein in older men with and without pre-existing cardiovascular disease. AB - OBJECTIVES: We aimed to compare the predictive capabilities of N-terminal pro brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) for risk of cardiovascular disease (CVD) in older men with and without pre-existing CVD. BACKGROUND: The clinical utility of NT-proBNP in CVD risk stratification in the general population remains unclear. METHODS: A prospective study of 3,649 men age 60 to 79 years were followed for a mean of 9 years during which there were 608 major CVD events (major fatal and nonfatal coronary heart disease, stroke, and CVD death). RESULTS: NT-proBNP was significantly associated with risk of all major CVD outcomes after adjustment for CV risk factors in both men with and without CVD. The adjusted standardized hazard ratios for CVD events in those without pre-existing CVD and those with pre-existing CVD were 1.49 (95% confidence interval [CI]: 1.33 to 1.65) and 1.52 (95% CI: 1.33 to 1.75), respectively. CRP was associated with CVD outcomes only in men without pre existing CVD (adjusted standardized hazard ratios: 1.22 [95% CI: 1.10 to 1.34] and 1.00 [95% CI: 0.86 to 1.38], respectively). NT-proBNP was more strongly associated with CVD outcome than CRP, particularly among those with pre-existing CVD. Inclusion of NT-proBNP in a Framingham-based model yielded significant improvement in C-statistics in both men with and without CVD and resulted in a net reclassification improvement of 8.8% (p = 0.0009) and 8.2% (p < 0.05), respectively, for major CVD events. Inclusion of CRP in the Framingham-based model did not improve prediction in either group (net reclassification improvement 3.8% and 0.6%, respectively). CONCLUSIONS: NT-proBNP, but not CRP, improved prediction of major CVD events in older men with and without pre existing CVD. PMID- 21700091 TI - Real-time assessment of myocardial contractility using shear wave imaging. AB - OBJECTIVES: The goal of this study was to assess whether myocardial stiffness could be measured by shear wave imaging (SWI) and whether myocardial stiffness accurately quantified myocardial function. BACKGROUND: SWI is a novel ultrasound based technique for quantitative, local, and noninvasive mapping of soft tissue elastic properties. METHODS: SWI was performed in Langendorff perfused isolated rat hearts (n = 6). Shear wave was generated and imaged in the left ventricular myocardium using a conventional ultrasonic probe connected to an ultrafast scanner (12,000 frames/s). The local myocardial stiffness was derived from shear wave velocity every 7.5 ms during 1 single cardiac cycle. RESULTS: The average myocardial stiffness was 8.6 +/- 0.7 kPa in systole and 1.7 +/- 0.8 kPa in diastole. Myocardial stiffness was compared with isovolumic systolic pressure at rest and during administration of isoproterenol (10(-9), 10(-8), and 10(-7) mol/l, 5 min each). Systolic myocardial stiffness increased strongly up to 23.4 +/- 3.4 kPa. Myocardial stiffness correlated strongly with isovolumic systolic pressure (r(2) = [0.94; 0.98], p < 0.0001). CONCLUSIONS: Myocardial stiffness can be measured in real time over the cardiac cycle using SWI, which allows quantification of stiffness variation between systole and diastole. Systolic myocardial stiffness provides a noninvasive index of myocardial contractility. PMID- 21700092 TI - Bilateral left-sidedness heterotaxy syndrome. PMID- 21700093 TI - Exercise-induced left ventricular outflow tract obstruction in symptomatic patients with Anderson-Fabry disease. PMID- 21700095 TI - Reports of heart failure trials and the dissociation with the prevailing clinical practice. PMID- 21700096 TI - Femtosecond laser: the future of cataract surgery? PMID- 21700097 TI - Phaco windmill: nondividing, nonchopping phacoemulsification technique. AB - We describe a nondividing, nonchopping phacoemulsification technique for nucleus removal with minimal zonular stress. It can be applied in any type of cataract surgery, regardless of nuclear color or density, as long as the anterior chamber is stabilized and properly maintained and there is sufficient followability using torsional modality. This technique uses less phacoemulsification energy, thereby avoiding zonular stress, and does not require an initial division of the nucleus, which is another advantage for beginners. The procedure is safe and easy to learn and is most advisable for beginners as it can prevent complications. PMID- 21700098 TI - Oval capsulorhexis for phacoemulsification in posterior polar cataract with preexisting posterior capsule rupture. AB - We describe use of an oval capsulorhexis rather than the conventional circular capsulorhexis for phacoemulsification in posterior polar cataract with preexisting posterior capsule rupture. An oval capsulorhexis minimizes the turbulence in the capsular bag by increasing the area available for efflux of fluid. It also enables end-to-end nuclear sculpting, removal of the nuclear fragment from the bag, intraocular lens (IOL) implantation, and vitrectomy without stretching the capsular bag. The smaller axis of the oval capsulorhexis facilitates optic capture of a sulcus-fixated IOL. The oval capsulorhexis can be used safely for phacoemulsification of all grades of nuclear sclerosis in posterior polar cataract with preexisting posterior capsule rupture. PMID- 21700099 TI - Femtosecond laser capsulotomy. AB - PURPOSE: To evaluate a femtosecond laser system to create the capsulotomy. SETTING: Porcine and cadaver eye studies were performed at OptiMedica Corp., Santa Clara, California, USA; the human trial was performed at the Centro Laser, Santo Domingo, Dominican Republic. DESIGN: Experimental and clinical study. METHODS: Capsulotomies performed by an optical coherence tomography-guided femtosecond laser were evaluated in porcine and human cadaver eyes. Subsequently, the procedure was performed in 39 patients as part of a prospective randomized study of femtosecond laser-assisted cataract surgery. The accuracy of the capsulotomy size, shape, and centration were quantified and capsulotomy strength was assessed in the porcine eyes. RESULTS: Laser-created capsulotomies were significantly more precise in size and shape than manually created capsulorhexes. In the patient eyes, the deviation from the intended diameter of the resected capsule disk was 29 MUm +/- 26 (SD) for the laser technique and 337 +/- 258 MUm for the manual technique. The mean deviation from circularity was 6% and 20%, respectively. The center of the laser capsulotomies was within 77 +/- 47 MUm of the intended position. All capsulotomies were complete, with no radial nicks or tears. The strength of laser capsulotomies (porcine subgroup) decreased with increasing pulse energy: 152 +/- 21 mN for 3 MUJ, 121 +/- 16 mN for 6 MUJ, and 113 +/- 23 mN for 10 MUJ. The strength of the manual capsulorhexes was 65 +/- 21 mN. CONCLUSION: The femtosecond laser produced capsulotomies that were more precise, accurate, reproducible, and stronger than those created with the conventional manual technique. PMID- 21700100 TI - Pseudophakic negative dysphotopsia: Surgical management and new theory of etiology. AB - PURPOSE: To evaluate the benefit of various surgical methods to address pseudophakic negative dysphotopsia. SETTING: Private practice, Los Angeles, California, USA. DESIGN: Interventional case series. METHODS: The following 4 surgical methods were used to treat negative dysphotopsia: secondary piggyback intraocular lens (IOL) implantation, reverse optic capture, in-the-bag IOL exchange, and iris suture fixation. Ultrasound biomicroscopy (UBM) was used to analyze posterior chamber anatomy. The primary outcome was partial or complete resolution of the negative dysphotopsia symptoms 3 months postoperatively. RESULTS: Twelve eyes of 11 patients with negative dysphotopsia had surgical treatment. All 10 patients who had piggyback IOL implantation or reverse optic capture had partial or complete resolution of symptoms by 3 months. No patient who had in-the-bag IOL exchange (n = 3) or iris suture fixation of the capsular bag-IOL complex (n = 1) improved despite alteration of IOL material or edge design in the case of IOL exchange or UBM confirmation of posterior chamber collapse in the case of iris suture fixation of the capsular bag-IOL complex. CONCLUSIONS: Consistent with a new hypothesis, resolution of negative dysphotopsia symptoms depended on IOL coverage of the anterior capsule edge rather than on collapse of the posterior chamber alone. Furthermore, negative dysphotopsia was not attributed to a particular IOL material or edge design. . PMID- 21700101 TI - Improvements in visual ability with first-eye, second-eye, and bilateral cataract surgery measured with the visual symptoms and quality of life questionnaire. AB - PURPOSE: To determine whether the Visual Symptoms and Quality of Life Questionnaire (VSQ), which was developed to be sensitive to second-eye cataract surgery, has satisfactory psychometric properties and, if so, to examine first eye, second-eye, and bilateral cataract surgery outcomes. SETTING: Ophthalmology Clinic, Flinders Medical Centre, Adelaide, Australia. DESIGN: Cohort study. METHODS: The 26-item VSQ was self-administered by cataract patients before and after cataract surgery and by those on the cataract surgery waiting list. The VSQ was revised by Rasch analysis using preoperative questionnaire data. The surgical outcome measures were logMAR visual acuities and the Rasch-refined VSQ. RESULTS: The VSQ was self-administered by 92 patients before and after surgery (25 first eye, 38 second eye, and 29 bilateral) and by 147 on the waiting list. The preoperative visual acuity (surgical eye) was similar across groups. Cataract surgery improved visual acuities in all groups; the mean better-seeing eye visual acuity was significantly better (by 2 lines) in second and bilateral surgery patients than in first-eye surgery patients. Preoperative visual disability was significantly higher in patients awaiting cataract surgery in both eyes than in those awaiting second-eye surgery. Postoperatively, visual disability decreased significantly in all groups (first eye, 1.66 logits; second eye, 1.52 logits; bilateral, 2.58 logits). However, a floor effect limited the measurement of visual disability after cataract surgery. CONCLUSIONS: The revised visual disability scale of the VSQ measured a reduction in visual disability after first, second, and bilateral cataract surgery. However, the VSQ could not measure lower levels of visual disability, suggesting better questionnaires are required. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21700102 TI - Vector analysis of astigmatic changes after cataract surgery with implantation of a new toric multifocal intraocular lens. AB - PURPOSE: To analyze the astigmatic changes after cataract surgery with the implantation of a new toric multifocal intraocular lens (IOL) using the Alpins vector method. SETTING: Vissum-Instituto de Oftalmologico de Alicante, Alicante, Spain. DESIGN: Prospective case series. METHODS: After cataract surgery with implantation of an AT Lisa 909M toric multifocal IOL, the visual, refractive, corneal topographic, internal astigmatism, defocus curves, and contrast sensitivity outcomes were evaluated over 6 months. Refractive astigmatic changes (target astigmatism [TIA]; surgically induced astigmatism [SIA]; difference vector; magnitude of error; flattening effect; torque) were analyzed using the Alpins vectorial method. RESULTS: The study enrolled 23 eyes (12 patients). Postoperatively, there was a significant reduction in refractive cylinder (P < .01) with an associated visual improvement for near (P = .03) and distance (P=.01). The magnitude of SIA vector was significantly larger than the TIA 3 months postoperatively (P = .03). The mean magnitude of the difference vector was 0.67 diopter (D) +/- 0.51 (SD) at 6 months. The mean magnitude of error remained positive and close to zero over the entire follow-up (P >= .19). The mean magnitude of torque vector was 0.49 +/- 0.54 D at 6 months. Significant positive correlation was found between the magnitude of torque and the difference vector (r >= 0.70, P<.01). CONCLUSION: The new toric IOL restored distance and near visual function with excellent predictability in eyes with moderate to high corneal astigmatism having cataract surgery. PMID- 21700103 TI - Visual outcomes and complications of scleral-fixated posterior chamber intraocular lenses. AB - PURPOSE: To report the long-term visual outcomes and complications after implantation of scleral-fixated posterior chamber intraocular lenses (PC IOLs). SETTING: Princess Alexandra Hospital, Mater Hospital, and Queensland Eye Institute, Brisbane, Australia. DESIGN: Case series. METHODS: This study reviewed the records of patients who had anterior vitrectomy and scleral-fixated PC IOL implantation between 1993 and 2008 and had a minimum follow-up of 6 months. RESULTS: The study comprised 82 eyes of 72 patients (47 men). The mean follow-up was 83.3 months (range 6.7 to 166.5 months) and the mean age at surgery, 62 years (range 15 to 97 years). The mean improvement in corrected distance visual acuity (CDVA) was 1.6 Snellen chart lines of vision, which was statistically significant; 59 eyes (72%) had an improved or unchanged CDVA, and 23 eyes (28%) had a reduced CDVA. The most common postoperative complication was ocular hypertension (25 eyes [30.5%]). Suture breakage occurred in 5 eyes (6%) after a mean of 4.9 years; 4 of these patients were younger than 40 years. Overall, 44 eyes (53.7%) had at least 1 complication, 36.4% within 1 week postoperatively and 63.6% after 1 week. Thirteen eyes (15.8%) required at least 1 further operation. CONCLUSIONS: Scleral-fixated PC IOL insertion provided favorable visual outcomes in many cases. Complications were common, and suture rupture is an important long term complication, particularly in young patients. These issues affect IOL choice for the surgical treatment of aphakia and should be discussed with patients during the consent process. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 21700104 TI - Severity of lens opacity, age, and correlation of the level of silent information regulator T1 expression in age-related cataract. AB - PURPOSE: To evaluate the correlation between the severity of lens opacity, patient age, and the level of silent information regulator T1 (SirT1) expression in the lens epithelium of age-related cataracts. SETTING: Department of Ophthalmology, Zuoying Armed Forces General Hospital, Kaohsiung, Taiwan. DESIGN: Case control study. METHODS: Patient age at the time of cataract surgery and lens opacity severity, classified using the modified version of the Lens Opacities Classification System III (LOCS III), were recorded. Lens epithelium samples were obtained, and the expression level of SirT1 mRNA was evaluated. RESULTS: The study evaluated 233 eyes with cataract. Older patients had higher nuclear (N), cortical (C), and posterior subcapsular (P) cataract LOCS III scores. The expression of SirT1 in lens opacity was significantly less in patients 51 years and older than in those younger than 51 years. The level of SirT1 expression was significantly negatively associated with patient age (r = -0. 746, P < .001). A significant correlation was also found between a higher N, C, and P cataract score and lower expression of SirT1 in patients with age-related cataract (P < .001). CONCLUSIONS: The decreased expression of SirT1 in the lens epithelium was associated with higher cataract scores and patient age. The results suggest that a local SirT1 decrease in cataractous lens could be a risk factor for the initiation of age-related cataract formation. PMID- 21700105 TI - Corneal topography indices after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. AB - PURPOSE: To evaluate changes in corneal topography indices after corneal collagen crosslinking (CXL) in patients with keratoconus and corneal ectasia and analyze associations of these changes with visual acuity. SETTING: Cornea and refractive surgery subspecialty practice. DESIGN: Prospective randomized controlled clinical trial. METHODS: Corneal collagen crosslinking was performed in eyes with keratoconus or ectasia. Quantitative descriptors of corneal topography were measured with the Pentacam topographer and included 7 indices: index of surface variance, index of vertical asymmetry, keratoconus index, central keratoconus index, minimum radius of curvature, index of height asymmetry, and index of height decentration. Follow-up was 1 year. RESULTS: The study comprised 71 eyes, 49 with keratoconus and 22 with post-LASIK ectasia. In the entire patient cohort, there were significant improvements in the index of surface variance, index of vertical asymmetry, keratoconus index, and minimum radius of curvature at 1 year compared with baseline (all P < .001). There were no significant differences between the keratoconus and ectasia subgroups. Improvements in postoperative indices were not correlated with changes in corrected or uncorrected distance visual acuity. CONCLUSIONS: There were improvements in 4 of 7 topography indices 1 year after CXL, suggesting an overall improvement in corneal shape. However, no significant correlation was found between the changes in individual topography indices and changes in visual acuity after CXL. PMID- 21700106 TI - Clinical characterization of corneal ectasia after myopic laser in situ keratomileusis based on anterior corneal aberrations and internal astigmatism. AB - PURPOSE: To evaluate and characterize the clinical features of corneal ectasia after myopic laser in situ keratomileusis (LASIK) considering internal astigmatism and corneal aberrations and their correlation with other clinical data. SETTING: Vissum-Instituto de Oftalmologico de Alicante, Alicante, Spain. DESIGN: Retrospective comparative case series. METHODS: In this multicenter study, eyes were divided into 2 groups. The study group comprised eyes that had corneal ectasia after myopic LASIK. The control group comprised eyes that had successful LASIK to correct high myopia. The clinical outcomes were analyzed and compared. Internal astigmatism was calculated using vectorial analysis. RESULTS: The study enrolled 91 eyes (48 study group; 40 control group) of 81 patients (age 18 to 67 years). Uncorrected and corrected (CDVA) distance visual acuities and the refractive status were significantly worse in the study group (P <= .01). Corneas in the study group had a significantly higher steepest keratometry (K) reading and a more negative central asphericity (P < .01). Internal astigmatism and corneal aberrations were also significantly higher in the study group (P < .01). The CDVA was significantly correlated with primary spherical aberration (r = -0.561, P =.01) and primary coma root mean square (r = 0.451, P =.04). Age was significantly correlated with mean K (r = -0.44, P =.01) and internal astigmatism (r = -0.34, P =.04). CONCLUSION: Larger levels of internal astigmatism and anterior corneal aberrations leading to a visual deterioration were present in eyes with corneal ectasia after myopic LASIK. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21700107 TI - Objective evaluation of through-focus optical performance of presbyopia correcting intraocular lenses using an optical bench system. AB - PURPOSE: TO evaluate spherical aberration and through-focus optical performances of 5 presbyopia-correcting and 2 monofocal intraocular lenses (IOLs). SETTING: Flaum Eye Institute, University of Rochester, Rochester, New York, USA. DESIGN: Experimental study. METHODS: Five presbyopia-correcting IOLs (Restor +4D SN6AD3, Restor +3D SN6AD1, Rezoom NXG1, Tecnis multifocal ZM900, Crystalens HD500) were tested using an optical bench system consisting of a model eye, a high-resolution Hartmann-Shack wavefront sensor, and an image-capturing device. Two monofocal IOLs (Sofport AO LI60AOV, Acrysof SN60AT) were measured for comparison. No accommodation was simulated. The spherical aberration profiles of each IOL were measured using the wavefront sensor. Through-focus performance was evaluated by calculating cross-correlation coefficients and comparing the likenesses of captured images of a resolution target and a perfect reference image. RESULTS: With a 5.0 mm entrance pupil, the SN6AD3, SN6AD1, ZM900, NXG1, and HD500 IOLs had spherical aberration of -0.18 MUm, -0.14 MUm, -0.15 MUm, -0.07 MUm, and -0.01 MUm, respectively. Distance image quality was poorer with multifocal and accommodating IOLs than with monofocal IOLs. All multifocal IOLs had effective distance and near image quality but had a loss in intermediate image quality. The HD 500 accommodating IOL had decreased distance image quality and slightly increased depth of focus compared with the monofocal IOLs because of the bispheric design. CONCLUSIONS: The presbyopia-correcting IOLs had different optical characteristics, including spherical aberration profile and through-focus performance. An accurate understanding of the optical characteristics of individual IOLs is essential to selecting the best presbyopia-correcting IOL and thus improving cataract surgery outcomes. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21700108 TI - Predicting crystalline lens fall caused by accommodation from changes in wavefront error. AB - PURPOSE: To illustrate and develop a method for estimating crystalline lens decentration as a function of accommodative response using changes in wavefront error and show the method and limitations using previously published data (2004) from 2 iridectomized monkey eyes so that clinicians understand how spherical aberration can induce coma, in particular in intraocular lens surgery. SETTINGS: College of Optometry, University of Houston, Houston, USA. DESIGN: Evaluation of diagnostic test or technology. METHODS: Lens decentration was estimated by displacing downward the wavefront error of the lens with respect to the limiting aperture (7.0 mm) and ocular first surface wavefront error for each accommodative response (0.00 to 11.00 diopters) until measured values of vertical coma matched previously published experimental data (2007). Lens decentration was also calculated using an approximation formula that only included spherical aberration and vertical coma. RESULTS: The change in calculated vertical coma was consistent with downward lens decentration. Calculated downward lens decentration peaked at approximately 0.48 mm of vertical decentration in the right eye and approximately 0.31 mm of decentration in the left eye using all Zernike modes through the 7th radial order. Calculated lens decentration using only coma and spherical aberration formulas was peaked at approximately 0.45 mm in the right eye and approximately 0.23 mm in the left eye. CONCLUSIONS: Lens fall as a function of accommodation was quantified noninvasively using changes in vertical coma driven principally by the accommodation-induced changes in spherical aberration. The newly developed method was valid for a large pupil only. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 21700109 TI - Safety assessment of a new single-use small-incision injector for intraocular lens implantation. AB - PURPOSE: To evaluate the safety of a new injector, the Raysert R-INJ-04/18, for implantation of the C-flex intraocular lens (IOL). SETTING: Ophthalmology Department, Kaplan Medical Center, Rehovot, Israel. DESIGN: Experimental study. METHODS: Sixty IOLs were subdivided into 2 equally sized groups. Group A IOLs were injected using the established R-INJ-04 injector, and those in Group B were injected with the new injector. The IOLs were injected into a Petri dish. Subsequently, all IOLs and injectors were evaluated macroscopically and microscopically and then photographed under light microscopy (LM). Two IOLs in each group were randomly chosen and sent for evaluation by scanning electron microscopy (SEM) and energy dispersive analysis of x-ray. All remaining IOLs were sent for power and modulation transfer function (MTF) analysis. RESULTS: All Group B IOLs were successfully injected without evident signs of scratching, cracks, or deposits on LM and SEM examination. In Group A, findings were confined to a singular incidence of a small deposit detected on the periphery of the posterior optical surface of the IOL, with corresponding findings detected on the injector nozzle. No signs of scratching, cracks, or deposits were found in the rest of the IOLs or injectors. The power and MTF analyses were within the normal range for all IOLs. CONCLUSION: The new 1.8 mm external diameter soft-tipped injector for 2.4 to 2.2 mm incisions was shown to be safe for the implantation of the C-flex 21.0 diopter IOL. PMID- 21700110 TI - Cell adhesion on explanted intraocular lenses: part 1: analysis of explanted IOLs. AB - PURPOSE: To determine whether cell adhesion on an intraocular lens (IOL) in Japanese patients is affected by the optic material. SETTING: Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan. DESIGN: Experimental study. METHODS: Intraocular lenses of various materials explanted from Japanese patients were histologically examined under light microscopy. Specimens included 271 poly(methyl methacrylate) (PMMA) IOLs, 117 hydrophobic soft acrylic IOLs, and 48 silicone IOLs. The mean cell adhesion on the central area of the anterior surface of each IOL material (referred to as cell number) was evaluated. RESULTS: The cell number in the PMMA group was significantly higher than that in the silicone group in the periods of 1 to 5, 6 to 11, and more than 24 months. Although the cell number in the silicone group was less than one-third and one twentieth the cell number in the hydrophobic soft acrylic group in the periods 1 to 5 months and 6 to 11 months, respectively, the difference was not statistically significant. CONCLUSION: In Japanese patients, the cell adhesion on silicone IOLs was less than that on PMMA IOLs. PMID- 21700111 TI - Cell adhesion on explanted intraocular lenses part 2: experimental study of a surface-modified IOL in rabbits. AB - PURPOSE: To develop a hydrophobic acrylic IOL with a hydrophilic, anti-cell adhesive surface characteristic. SETTING: Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan. DESIGN: Experimental study. METHODS: Hydrophobic acrylic IOLs were coated with hydrophilic 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer and implanted in rabbit eyes following lens extraction. Cell adhesion on the IOL surface was histologically compared with that on an uncoated IOL under light microscopy. Specimens were also observed under scanning electron microscopy to examine the effects of MPC coating on cell morphology. RESULTS: Hydrophilic MPC coating reduced cell adhesion on acrylic IOLs at 1 month postoperatively. CONCLUSION: Coating an acrylic IOL with a hydrophilic polymer inhibited cell adhesion on the IOL surface. PMID- 21700112 TI - Microbial keratitis trends following refractive surgery: results of the ASCRS infectious keratitis survey and comparisons with prior ASCRS surveys of infectious keratitis following keratorefractive procedures. AB - In 2008, the American Society of Cataract and Refractive Surgery (ASCRS) surveyed its 9121 United States and international members to evaluate the changing trends and incidence, culture results, treatment, and visual outcomes of infectious keratitis following keratorefractive procedures worldwide. This paper presents and analyzes the results with comparisons to the data in surveys conducted in 2001 and 2004. Nineteen infections were reported by 14 surgeons who had performed an estimated 20,941 keratorefractive procedures, an incidence of 1 infection in every 1102 procedures. Sixteen cases presented in the first postoperative week, 1 case during the second week, 1 case between the second and fourth weeks, and 1 case at 1 month or later. The 16 cases that presented in the first week were diagnosed at initial presentation. The most common organism cultured was methicillin-resistant Staphylococcus aureus (MRSA). Microbial keratitis following refractive surgery is an increasingly recognized sight-threatening complication. PMID- 21700114 TI - Traumatic cataract associated with mini glaucoma shunt. AB - We report a case of a 30-year-old woman with aniridia who developed a traumatic cataract related to placement of an Ex-PRESS mini glaucoma shunt. To our knowledge, this potential complication of the device has not been reported. PMID- 21700115 TI - Quiescent posterior capsule trauma after intravitreal injection: implications for the cataract surgeon. PMID- 21700113 TI - Recurrent enterococcal endophthalmitis seeded by an intraocular lens biofilm. AB - A case of endophthalmitis following uneventful phacoemulsification and posterior chamber intraocular lens (IOL) implantation in a 77-year-old diabetic man was culture-positive for Enterococcus faecalis. After successful treatment with intravitreal, topical, and systemic antibiotic agents, the infection seemed to clear and the patient achieved a corrected visual acuity of 20/25. Four months after the initial presentation, the patient again developed signs and symptoms of endophthalmitis, with regrowth of E faecalis. The antibiotic therapy was repeated. One month later, the IOL was removed surgically and found to harbor a biofilm of the strain demonstrated by DNA analysis. The microbiologic and DNA analyses support that a biofilm on an IOL could be a vector for a cause of recurrent endophthalmitis. Intraocular lens exchange in cases of postoperative endophthalmitis caused by E faecalis may be considered to decrease the risk for recurrent infection. PMID- 21700117 TI - Consultation section. Refractive surgical problem. PMID- 21700122 TI - Refractive surprise after piggyback intraocular lens implantation. PMID- 21700123 TI - Air-assisted donor preparation for DMEK. PMID- 21700125 TI - Keratoconus correction using intrastromal corneal ring segments and posterior chamber phakic intraocular lens implantation. PMID- 21700128 TI - Optical coherence tomography studies of clear corneal incision wound architecture. PMID- 21700130 TI - Preventing posterior capsule opacification. PMID- 21700131 TI - The digital age: top breastfeeding resources. PMID- 21700132 TI - Readers' survey results. PMID- 21700133 TI - A limited study on which to base national guidelines: the national survey of the primary and acute care pediatric nurse practitioner educational preparation. PMID- 21700135 TI - Health-related quality of life in children and adolescents with sickle cell disease. AB - OBJECTIVE: To assess health-related quality of life (HRQOL) in children and adolescents with sickle cell disease (SCD). DESIGN, SETTING, AND PARTICIPANTS: The PedsQL 4.0 Generic Scales, a multidimensional self-report instrument that has been shown to be valid and reliable for use in children and adolescents with chronic illness, consists of 23 items that assess physical, emotional, social, and school functioning. Questionnaires were administered to 124 children and adolescents (ages 8 to 18 years, child self-report) with SCD (100 sickle cell anemia, 24 sickle beta zero thalassemia) and their parents (parent-proxy report). Summary scores for children's and parents' ratings of overall HRQOL and psychosocial health and subscale scores for physical, emotional, social, and school functioning were compared with published data for healthy children. Both summary and subscale scores for children with SCD also were compared with those of their parents. RESULTS: Children with SCD and their parents rated overall HRQOL and all subdomains of HRQOL lower than did healthy children and their parents (P < .001). Children with SCD rated their own HRQOL significantly better than their parents did for overall HRQOL and all subdomains (P < .001) except emotional functioning (P = .06). CONCLUSIONS: Children with SCD and their parents perceived overall HRQOL and all HRQOL subdomains to be lower than scores reported in healthy children. Therefore, successful therapeutic efforts to improve HRQOL could represent important advances in the health of children with SCD. PMID- 21700136 TI - Correlates among healthy lifestyle cognitive beliefs, healthy lifestyle choices, social support, and healthy behaviors in adolescents: implications for behavioral change strategies and future research. AB - INTRODUCTION: The foundation for healthy lifestyle behaviors begins in childhood. As such, the relationships among cognitive beliefs, healthy lifestyle choices, and healthy lifestyle behaviors in adolescents have been explored. The purpose of this study was to assess the relationships among cognitive variables, social support, and healthy lifestyle behaviors in adolescents. METHOD: A descriptive correlational design was used for this study. Students from two high schools in the Southwest United States were recruited to participate (N = 404). RESULTS: Significant correlations existed among cognitive variables, social support, behavioral skills, and health lifestyle behaviors. DISCUSSION: This study demonstrated that cognitive beliefs about leading a healthy lifestyle, including attitudes and intended choices, are related to physical activity as well as the intake of fruits and vegetables. In working with adolescents on healthy lifestyle behavior change, it is important to implement strategies to strengthen their cognitive beliefs about their ability to make healthy choices and engage in healthy lifestyle behaviors. Strengthening these beliefs should lessen their perception that these behaviors are difficult to perform, which ultimately should result in healthy behaviors. PMID- 21700137 TI - Adolescent early death perception: links to behavioral and life outcomes in young adulthood. AB - INTRODUCTION: The purpose of this study was to examine the relationship between changes in adolescent perception of risk for early death over time and behavioral and life outcomes in young adulthood. METHODS: This is a secondary data analysis of 7202 respondents participating in waves 1 (1995), 2 (1996), and 3 (2001-2002) of the in-home interviews from the National Longitudinal Study of Adolescent Health. Linear and logistic regression models were used to determine the predictive ability of adolescent early death perception at waves 1 and 2 on young adult outcomes of health risk, human capital, and prosocial development, and fitness at wave 3. RESULTS: Nearly one in four youth (23%) expressed perceived risk of premature death at some point in time; 6% of youth persisted in this outlook. Perceived risk of premature death during adolescence was linked to poor health and productivity on multiple levels in young adulthood. DISCUSSION: Adolescent perceived risk for premature death portends poor outcomes in young adulthood. Findings support incorporating screening questions on adolescents' mortality beliefs into psychosocial assessments and interviews. PMID- 21700138 TI - Improving asthma care for African American children by increasing national asthma guideline adherence. AB - INTRODUCTION: Children, particularly African American children, bear a disproportionate burden of asthma and are at highest risk for associated morbidity and mortality. The under-utilization of the National Asthma Education and Prevention Program (NAEPP) guidelines across all demographics and the under use of inhaled corticosteroids (ICS) as controller therapy in these children are well-documented. The primary aim of this study was to increase health care provider (HCP) adherence to the NAEPP guidelines by means of a guideline reminder tool, the Multi-colored Simplified Asthma Guideline Reminder, consequently increasing the prescription of ICS in this population. METHOD: This study had a pre-experimental design with descriptive analysis. RESULTS: The Multi-colored Simplified Asthma Guideline Reminder was effective in increasing HCP adherence to the NAEPP guidelines as evidenced by increased use of ICS as controller therapy. DISCUSSION: Despite the increasing prevalence and burden of asthma in African American children, the associated prescriptive use of ICS has not increased substantially in the past decade. The greatest obstacle in the scope of improving asthma outcomes is the underuse of ICS by HCPs. PMID- 21700139 TI - Medical evaluation for child sexual abuse: what the PNP needs to know. AB - Sexual abuse is a problem of epidemic proportions. Pediatric nurse practitioners (PNPs) will most likely encounter sexually abused children in their practice, both those who have been previously diagnosed and others who are undiagnosed and require identification by the PNP. This continuing education article will discuss the medical evaluation of children with concerns of suspected sexual abuse. Acute and non-acute sexual abuse/assault examinations will be discussed. Physical findings and sexually transmitted infections concerning for sexual abuse/assault will also be discussed. PMID- 21700140 TI - Hair loss in an adolescent. PMID- 21700141 TI - Solving a neurologic mystery: recognizing rheumatic fever in the pediatric patient. PMID- 21700142 TI - The accidental echocardiographer. PMID- 21700143 TI - Always at a crossroads. PMID- 21700144 TI - TEE and Interventional Cardiology. PMID- 21700145 TI - Echocardiography: a requisite friend of the cardiac geneticist. PMID- 21700146 TI - Echo and stem cell therapy: more than just an ejection fraction. PMID- 21700147 TI - Perspectives of adolescents with attention-deficit hyperactivity disorder do matter. PMID- 21700148 TI - Toward a new agenda for rehabilitation and reintegration processes for child soldiers. PMID- 21700149 TI - Parents: an under-realized resource for protecting working adolescents. PMID- 21700150 TI - Receiving treatment for attention-deficit hyperactivity disorder: do the perspectives of adolescents matter? AB - PURPOSE: This study describes the perspectives of parents and adolescents regarding clinical need for and attitudes toward care for attention-deficit hyperactivity disorder (ADHD). In addition, it explores as to how these views relate to past year usage of mental health services. METHODS: Parents and adolescents were interviewed 6 years after the school district was screened for ADHD. Using standardized measures, mental health service usage, adolescent and parent perceived clinical needs (ADHD symptoms, disruptive behavior disorders, anxiety and/or depression, functioning), and enabling attitudes (treatment receptivity, ADHD stigma), as well as parent factors (caregiver strain, distress, instrumental social support) were assessed. Nested logistic regression modeling was used to determine the hierarchical contribution of parent and adolescent perspectives on past year service usage, after adjusting for previous usage of mental health services. Stepwise regression was conducted to identify the variables that were most predictive of service usage. RESULTS: Among the adolescents who were at a high risk for ADHD, 79% had a history of lifetime mental health service usage, but only 42% had received any kind of mental health services in the past year. In hierarchical modeling, only parent inattention ratings and medication receptivity and adolescent ADHD stigma perceptions contributed significantly toward improved model fit. Stepwise regression confirmed these three variables to be predictors (OR: 1.2, 3.8, and .2, respectively) and identified adolescents-reported functioning as an additional predictor of service usage (OR: 1.1). CONCLUSION: Perceptions of adolescents regarding the stigma related to ADHD are influential in treatment receipt. Quality improvement interventions for adolescents with ADHD should include psychoeducational interventions for adolescents and their parents that target medication receptivity and the stigma related to ADHD. PMID- 21700151 TI - Beliefs about attention-deficit/hyperactivity disorder and response to stereotypes: youth postings in Facebook groups. AB - PURPOSE: Attention-deficit/hyperactivity disorder (ADHD) is a common childhood psychiatric disorder characterized by abnormal levels of hyperactivity and distractibility. However, very few studies have been conducted to examine how youth with ADHD view themselves in the context of their disorder. The aim of this project was to examine what youth think about having ADHD by collecting data in a naturalistic setting - a popular social networking site. METHODS: Using ethnographic content analysis, we examined text from 25 public, English-language Facebook groups with "ADHD" in the title. The groups chosen were those that were either created or administered by someone with a current high school or university affiliation and had at least 100 members. To capture narratives from youth, postings between September 1, 2006, and April 30, 2007 were examined; postings from individuals who self-identified as high school or university students were included. RESULTS: The dominant theme that was identified (202 of 479 coded items) concerned the collective construction of a positive group identity. The Facebook groups functioned like electronic support groups, with members providing support to one another and sharing experiences and information, including advice about medication. Many jokes referencing ADHD stereotypes were posted. CONCLUSION: Youth used the supportive environment of an electronic group to develop a positive group identity and to reject negative aspects of common stereotypes related to young people with ADHD. PMID- 21700152 TI - Sierra Leone's child soldiers: war exposures and mental health problems by gender. AB - PURPOSE: To examine associations between war experiences, mental health, and gender in a sample of male and female Sierra Leonean former child soldiers. METHODS: A total of 273 former child soldiers (29% females) were assessed for depression and anxiety by using the Hopkins Symptoms Checklist, and for hostility, confidence, and prosocial attitudes by using an instrument developed for use with Sierra Leonean child soldiers. RESULTS: The former child soldiers had witnessed and perpetrated violence at largely comparable rates, although females experienced higher rates of rape (p < .0001). More females scored within clinical ranges for depression (p = .008) and anxiety (p < .0001). In multiple regression analyses, female gender was a significant predictor of lower levels of confidence but not of mental health problems. Children who perpetrated injury or killing reported greater levels of depression (p < .0001), anxiety (p < .0001), and hostility (p < .0001). Surviving rape was associated with increased anxiety (p < .05) and hostility (p < .05), in males. Surviving rape was also related to higher confidence levels (p < .05) and prosocial attitudes (p < .05). Male former child soldiers who lost caregivers were also more vulnerable to depression (p < .05) and anxiety (p < .05), strong and significant effects noted among male child soldiers. CONCLUSIONS: In our sample, female and male child soldiers experienced comparable levels of most war exposures. Female soldiers reported higher rates of rape and lower levels of adaptive outcomes. Toxic forms of violence (killing or injuring; rape) were associated with particularly poor outcomes. Although all boys and girls who experience rape and loss of caregivers are generally at risk for mental health problems, boys in our sample demonstrated increased vulnerability; these findings indicate a need for more inclusive mental health services. PMID- 21700153 TI - Development of a researcher codebook for use in evaluating social networking site profiles. AB - INTRODUCTION: Social networking sites (SNSs) are immensely popular and allow for the display of personal information, including references to health behaviors. Evaluating displayed content on an SNS for research purposes requires a systematic approach and a precise data collection instrument. The purpose of this article is to describe one approach to the development of a research codebook so that others may develop and test their own codebooks for use in SNS research. METHODS: Our SNS research codebook began on the basis of health behavior theory and clinical criteria. Key elements in the codebook developmental process included an iterative team approach and an emphasis on confidentiality. RESULTS: Codebook successes include consistently high inter-rater reliability. Challenges include time investment in coder training and SNS server changes. CONCLUSION: We hope that this article will provide detailed information about one systematic approach to codebook development so that other researchers may use this structure to develop and test their own codebooks for use in SNS research. PMID- 21700154 TI - Individual and structural vulnerability among female youth who exchange sex for survival. AB - PURPOSE: Because of growing concerns regarding the heightened vulnerabilities and risk of human immunodeficiency virus infection among youth who exchange sex for survival, we investigated individual risk patterns and structural barriers among young (<=24 years) female sex workers (FSWs) in Vancouver, Canada. METHODS: Between 2005 and 2008, a total of 255 street-based FSWs (>=14 years) were enrolled into a community-based prospective cohort, and were asked to participate in baseline and biannual questionnaires administered through interviews and human immunodeficiency virus screening. We used contingency table analysis to compare individual and structural barrier results obtained at baseline for younger (<=24 years) FSWs with those of the older (>25 years) FSWs. For longitudinal data, we used generalized estimating equations throughout the follow-up period to determine factors associated with being a young FSW in the past 6 months. RESULTS: In comparison with older FSWs (n = 199), youth (n = 56) were more likely to spend fewer years engaging in sex exchange (median: 6.4 [interquartile range: 4.6-9.1] vs. 19.9 [interquartile range: 10.0-26.8]; p <= .001), belong to an aboriginal ancestry (59% vs. 44%; p = .052), and be homeless (68% vs. 36%; p <= .001). In the multivariate generalized estimating equations analysis, youth reported a significantly elevated proportional odds of being homeless (odds ratio [OR]: 1.26 [confidence interval {CI}: 1.08-1.48]), servicing clients in public places (OR: 1.28 [CI: 1.04-1.57]), injecting heroin on a daily basis (OR: 1.35 [CI: 1.06-1.74]), and a significantly reduced odds of accessing methadone maintenance therapy (OR: .76 [CI: .62-.93]). CONCLUSIONS: This study demonstrates significant displacement of youth who engage in sex exchange to marginalized working and living spaces. The findings of this study bring to attention the critical need for targeted structural interventions including access to youth and gender-specific social housing, safe working spaces, reduction in the amount of harm caused to them, and addiction treatment services for youth engaged in survival sex work. PMID- 21700155 TI - Sexual health, HIV risk, and retention in an adolescent HIV-prevention trial preparatory cohort. AB - PURPOSE: Although adolescents are at high risk for human immunodeficiency virus (HIV) infection, they have not been, included in HIV vaccine trials. METHODS: In preparation for enrollment in HIV vaccine trials, 100 HIV-negative adolescents aged 14-17 years from Cape Town were recruited into a cohort. HIV, syphilis, pregnancy testing, and sexual risk questionnaires were conducted at varying intervals for a year. RESULTS: The mean age of the participants was 15 years, and 70% of them were female. Recruitment was completed within 3 months. Retention was found to be 82% at 1-year follow-up. The main reasons for dropout were as follows: relocation to other communities, phlebotomy, and visit frequency. In a Cox proportional hazards model, only female gender was significantly associated with retention. No change in reported sexual risk occurred, but the proportion of individuals who were aware of their partner's HIV status was significantly higher (17% at baseline, 83% at 1-year follow-up; p < .001). Five pregnancies were reported during follow-up. CONCLUSIONS: To our knowledge, this is the first prospective adolescent HIV-prevention cohort in Southern Africa. Despite reports of risky sexual behaviors and high pregnancy rates, HIV seroconversions did not occur in the retained cohort. HIV-prevention trials with high-risk adolescents will require rigorous efforts to prevent future pregnancies, and may require risk eligibility criteria. Retention may improve with transport provision, visits with incentives, and efforts to retain males. PMID- 21700157 TI - Partnerships between parents and health care professionals to improve adolescent health. AB - INTRODUCTION: Research on partnerships between parents and health care professionals (HCPs) to improve adolescent health is limited. In this study, we have developed an empirically derived framework to guide research in this particular area. METHODS: We conducted a qualitative study using focus groups and in-depth semi-structured interviews. A total of 85 participants (51 HCPs, 17 mothers of patients of ages 12-18 years, and 17 adolescents) were recruited from three free-standing adolescent health clinics and five school-based health centers across North Carolina. We independently explored the perceptions of HCPs and mothers regarding the roles of parents, HCPs, and parent-HCP partnerships in preventing and addressing adolescent health problems. We then elicited feedback of adolescents on mother and HCP perceptions. We identified common and informative themes during content analysis using ATLAS.ti, and triangulated perspectives of HCPs, mothers, and adolescents to develop a framework for building parent-HCP partnerships to improve adolescent health. RESULTS: A general framework emerged that conceptualizes both direct and indirect strategies for building parent-HCP partnerships. Direct strategies involve strengthening relationships and/or communication between parents and HCPs in both practice and community settings. Indirect strategies involve opportunities for HCPs to influence parent-adolescent relationships and/or communication within the context of adolescent visits. For example, HCPs can discuss the importance of parental involvement and monitoring with adolescents, encourage and facilitate parent adolescent communication, and deliver tailored parental guidance while also respecting adolescents' desires for confidential health care when appropriate. CONCLUSIONS: Interventions that directly strengthen parent-HCP relationships and/or communication, and those that indirectly support parent-HCP partnerships within the context of adolescent health care, should be designed targeting health outcomes. PMID- 21700156 TI - Annual physical examination reports vary by gender once teenagers become sexually active. AB - INTRODUCTION: Few sexually active male adolescents receive sexual and reproductive health (SRH) services. To understand this, we examined the association between sexual behavior status and physical examination of the adolescents over time. METHODS: We conducted longitudinal cohort analysis of the National Longitudinal Study of Adolescent Health with 9,239 adolescents who completed the baseline school (1994/1995) and wave 2 (1996) follow-up surveys approximately 1.5 years later (retention rate = 71%). The logistic regression models were fitted with random effects to estimate individual odds of reporting a physical examination in the past 12 months at follow-up, compared with baseline, stratified by sexual behavior status and gender, and adjusting for sociodemographic and healthcare access factors. RESULTS: In all, 34.5% of male and 38.2% of female adolescents reported experiencing vaginal intercourse by follow-up, and 22.4% of male and 24.7% of female adolescents reported first experiencing intercourse during the study period. Among sexually active adolescents, about half reported having annual physical examinations and one fifth reported not having any physical examinations. Among female adolescents, baseline to follow-up examination reports significantly increased in the following: sex initiators (adjusted odds ratio [OR] = 2.09, 95% confidence interval [CI] = 1.66-2.64); those reporting sex at both times (OR = 2.16, CI = 1.51-3.09); and those reporting no sex either time (OR = 2.47, CI = 2.00-3.04). Among male adolescents, baseline to follow-up examination reports significantly increased in those reporting no sex either time (OR = 1.57, CI = 1.26-1.96) and showed increasing trends in sex initiators (OR = 1.27, CI = .92-1.76). DISCUSSION: A majority of sexually active adolescents report annual physical examinations over time. Providers should not miss opportunities to deliver evidence-based SRH to sexually active adolescents. Future efforts are needed to increase access of all adolescents to SRH services. MESH TERMS: Health Services Accessibility, Male, Female. PMID- 21700158 TI - Examining the link between neighborhood context and parental messages to their adolescent children about violence. AB - PURPOSE: Living in violent neighborhoods has been shown to alter adolescent's social cognitions and increase aggressive behavior. A similar process may also occur for parents and result in parental support of aggressive behavior. This research examines the influence of perceived neighborhood violence and neighborhood collective efficacy on parental attitudes toward violence and the messages they give their adolescent children about how to resolve interpersonal conflict. METHOD: Data were collected from 143 African American parents and their adolescent children recruited from three inner-city middle schools to participate in a parenting intervention. Models were fit using structural equation modeling in Mplus. RESULTS: Contrary to expectations, exposure to neighborhood violence was not predictive of either aggressive attitudes or conflict solutions for parents or adolescents. Rather, a mixed effect was found for neighborhood collective efficacy, with higher perceived neighborhood collective efficacy related to less violent attitudes for adolescents but not for parents. Collective efficacy also predicted the messages that parents gave their adolescents about interpersonal conflict, with higher collective efficacy related to messages that were less supportive of violence. CONCLUSION: Parent and adolescent perception of neighborhood collective efficacy influences the messages that adolescents receive about interpersonal conflict resolution. This suggests that for parents living in violent neighborhoods, their appraisal of the neighborhood is more important in shaping conflict resolution messages than their own experiences with violence. Parent- and family-based programs to prevent youth violence need to address neighborhood factors that influence the messages adolescents receive about how to resolve conflict. PMID- 21700160 TI - Adolescents' support for smoke-free public settings: the roles of social norms and beliefs about exposure to secondhand smoke. AB - PURPOSE: To assess support for smoke-free policies in public settings among adolescent smokers and nonsmokers in a pro-smoking culture. METHODS: A total of 1,924 Greek secondary school students (mean age = 14 years, standard deviation = 1.00, 50% female) from nine schools in the urban area of Thessaloniki, Greece, participated in the study. The main outcome measures were supportiveness of smoke free policies in public settings. RESULTS: Smoker adolescents were less supportive of smoke-free policies, compared with nonsmokers. Regression analysis showed that policy support was predicted by smoking status and motivation to smoke, social norms, and beliefs about the effects of smoking and exposure to secondhand smoke. A significant interaction between smoking status and social norms was also observed, as smoker adolescents who often encountered others smoking in public places reported less support for smoke-free public settings. CONCLUSIONS: Three important processes underlying adolescents' support for smoke free policies not mentioned in previous research were identified. First, social norms of the immediate social environment play a pivotal role in shaping policy support of young people. Second, the effects of smoking status on policy support are significantly moderated by exposure to public smoking. Finally, beliefs about the effects of exposure to secondhand smoke significantly predict young people's support for smoke-free public settings. PMID- 21700159 TI - Depressive symptoms in severely obese compared with normal weight adolescents: results from a community-based longitudinal study. AB - PURPOSE: Little is known about the relationship between severe obesity and depressive symptoms, particularly in community as opposed to clinic-based samples. This study determined the relationship of severe obesity and depressive symptoms over 3 years in a community-based sample of non-Hispanic black and white adolescents in grades 7-12 at baseline. METHODS: The nested matched cohort study using data from a longitudinal school-based study of youth followed up for 3 years. A total of 51 severely obese participants (body mass index-for-age >=99% and a body mass index >=40 at one or more study visit) were identified and paired with an age-, gender-, and race-matched normal weight subject. Depressive symptoms (Center for Epidemiological Studies Depression [CES-D] scale) were assessed at baseline, 2 and 3 years later. High-depressive symptoms were defined by CES-D score above cut points predictive of major depressive disorder or use of antidepressant medication. RESULTS: Pairs were 73% non-Hispanic black, 67% females. There was no relationship between weight status and high-depressive symptoms at any assessment point. However, a positive association between weight status and CES-D scores, while not present at baseline or at 2 years, emerged at 3 years (p = .02). This relationship was present only among non-Hispanic whites (p = .006 whites, p = .25 blacks) and did not differ by gender. CONCLUSION: Severely obese youth in this community sample did not have increased likelihood of high levels of depressive symptoms. However, significantly increased depressive symptoms among non-Hispanic white youth at the end of the follow-up period suggests that this racial/ethnic group may be particularly vulnerable to the psychological effects of obesity in late adolescence and/or early adulthood. PMID- 21700161 TI - Tongue piercing: the effect of material on microbiological findings. AB - PURPOSE: Biofilms on oral piercings may serve as a bacterial reservoir and lead to systemic bacteremia or local transmission of pathogenic microbiota. The use of piercing materials which are less susceptible to biofilm accumulation could contribute to prevention of problems. The present study investigated whether there are microbiological differences in bacterial samples collected from tongue piercings made of different materials. METHODS: A total of 85 subjects with tongue piercings participated in this study. After a baseline dental examination, sterile piercings of four different materials were randomly allocated to the study subjects. After 2 weeks, microbiologic samples were collected and processed by checkerboard deoxyribonucleic acid- deoxyribonucleic acid hybridization methods. RESULTS: About 28.8% of subjects reported 61 lingual recessions (1.91 +/ .96 mm), whereas 5% reported tooth chipping on one tooth each. With the exception of Aggregatibacter actinomycetemcomitans (Y4), Fusobacterium nucleatum species, and Parvimonas micra, bacteria associated with periodontitis were not commonly found in the samples from studs or piercing channels. Of the 80 bacterial species, 67 were found at significantly higher levels (p < .001) in samples from stainless steel than from polytetrafluoroethylene or polypropylene piercings. CONCLUSION: The low bacterial counts from piercing channels suggest that having a tongue pierced would not contribute to an increased risk for oral infection. The present study demonstrated that studs made of steel might promote the development of a biofilm, whereas those made of polytetrafluoroethylene or polypropylene may be rather inert to bacterial colonization. The finding of Staphylococci on steel and titanium studs may suggest an elevated risk for complication if the piercing channel is infected. PMID- 21700162 TI - Parental involvement with their working teens. AB - Adolescents work in varied environments and are exposed to hazards. Parents of these working adolescents have an opportunity to help them select jobs and address worker safety issues with employers. The present study conducted telephonic interviews among a national sample of 922 working adolescents along with one parent of each to examine the involvement of parents in their children's employment and safety issues. Over 70% of parents were found who helped their children identify job opportunities, consider questions about work hours or tasks, fill out job applications, prepare for interviews, or handle difficult safety issues. Parents suggested stronger actions in response to hypothetical situations than when confronted with real problems. Mean level of parental involvement did not vary by the number of hazards reported by teen workers. Parents were involved in helping their teens with work. Further research should explore how to enhance parental effectiveness by making work safe for teens. PMID- 21700163 TI - Parental perspectives on sources of sex information for young people. AB - PURPOSE: To examine parental perspectives toward sources of sex information. METHODS: Interviews were conducted with 1605 parents. RESULTS: Most parents indicated that youth should receive information from their parents; however, in reality, believe they obtain most of their information from friends and the media. CONCLUSION: Nearly all parents want young people to receive information about sex from their parents. PMID- 21700164 TI - Health-related quality of life in adolescents with comorbidities related to obesity. AB - INTRODUCTION: Psychosocial correlates of medically complex obesity are poorly understood in adolescents. METHODS: Health-related quality of life was examined among 111 obese adolescents with medical comorbidities. RESULTS AND CONCLUSION: A higher body mass index and greater number of comorbidities were associated with diminished health-related quality of life, thus underscoring the relevance of psychosocial functioning in obese youth. PMID- 21700165 TI - Impact of maternal communication about skin, cervical, and lung cancer prevention on adolescent prevention behaviors. AB - PURPOSE: To explore whether maternal communication about behaviors that prevent skin, cervical, and lung cancer is associated with adolescent cancer prevention behaviors. METHODS: The study sample consisted of 10,409 girls and boys (14-21 years) who participated in a longitudinal survey study of U.S. adolescents. The independent variables were adolescent report of how often mothers had spoken with them (never, once, occasionally, sometimes, often) about sunscreen use, Pap screening, and quitting smoking. Outcome variables included adolescent self report of sunscreen use, Pap screening, and quitting smoking (among past-year smokers). We used multivariate logistic regression models to determine whether maternal communication in 2001 was associated independently with the three adolescent cancer prevention behaviors in 2001 and 2003. RESULTS: In adjusted logistic regression models, maternal communication about sunscreen use and Pap screening was positively associated with adolescent behaviors in 2001 and 2003, and maternal communication about quitting smoking was positively associated with adolescent behavior in 2001. CONCLUSIONS: In a national sample, maternal communication encouraging sunscreen use, Pap screening, and quitting smoking was associated with the corresponding behaviors in their adolescent children. The findings suggest that intergenerational interventions could enhance adolescent practice of cancer prevention behaviors. PMID- 21700166 TI - Effects of a national information campaign on compliance with age restrictions for alcohol sales. AB - PURPOSE: To investigate the effect of a national information campaign, introduced by the Dutch Food Retail Organization, named "Under 20? Show Your ID!," on compliance with age restrictions on alcohol sales. The compliance level after the campaign was compared with a baseline compliance, that we calculated based on 458 preintervention compliance measurements. METHODS: Data were collected using the method of mystery shopping. Three teams, each consisting of two 15-year-old mystery shoppers, conducted 105 alcohol purchase attempts in supermarkets in three regions in the Netherlands. RESULTS: A compliance rate of 24.8% was found, which is a significant improvement compared with Dutch basement compliance rate from the past (14.9%), but is nominally still very low. CONCLUSIONS: This mass media intervention campaign failed to increase compliance to an acceptable level. Also the specific goal of the campaign (ask everybody under <20 years old for identification [ID]) failed because fewer than half of the 15-year-old mystery shoppers in the study were asked to show their ID when purchasing alcoholic beverages. PMID- 21700168 TI - Bidi and hookah use among Canadian youth: an examination of data from the 2006 Canadian Youth Smoking Survey. AB - PURPOSE: To examine the prevalence and associated factors of bidi and hookah use among Canadian youth. METHODS: Data from 41,886 grade 7 to 12 youth were used to examine factors associated with bidi and hookah use. RESULTS: Youth who are current or former cigarette smokers, have tried marijuana or alcohol, were more likely to use bidi or hookah. CONCLUSIONS: Results suggest bidi and hookah use may be an emerging issue in tobacco control among youth. Findings also support an integrated approach where future prevention efforts should address multiple risk behaviors. PMID- 21700167 TI - Restrictive anorexia nervosa and set-shifting in adolescents: a biobehavioral interface. AB - PURPOSE: Set-shifting is a neurocognitive concept defined as the ability to switch tasks flexibly. Set-shifting scores are worse in adults with restrictive anorexia nervosa (AN-R) than in controls. Adolescence is a developmental period when young people must respond flexibly to new situations. The purpose of this study was to compare the set-shifting scores of 24 adolescent females with AN-R with 37 matched normal adolescent controls (ages, 14-20). METHODS: Methods used for the study included sociodemographic, psychological, and biological data, and neurocognitive testing using the Behavior Rating of Executive Function - Self- and Parent-Reports, the Cambridge Neuropsychological Automated Battery, and the Wisconsin Card-Sorting Test. Statistical analyses included t-tests, multiple analysis of variance, and correlations. RESULTS: Sociodemographic data and intelligence quotient of study and control subjects were similar. There were differences in body mass index and the Eating Disorder Inventory-3 evaluation. Significant differences in the composite score of set-shifting between the study and control groups were found using multiple analysis of variance. CONCLUSION: Adolescent females with AN-R had significantly worse set-shifting scores than the control subjects. Future studies of adolescent AN-R subjects should include biological (functional magnetic resonance imaging) and neurocognitive measures to determine the mechanisms at the brain-behavioral interface so that treatment can be directed specifically to set-shifting deficits. PMID- 21700169 TI - Alcohol expectancies among adolescent nondrinkers: they may not be drinking now, but they're "thinkin bout it". AB - PURPOSE: To examine the associations of alcohol expectancy outcomes and valuations with intention to use. METHOD: A total of 157 adolescent nonusers completed anonymous self-report surveys. RESULTS: Adolescents who perceived more access to alcohol, expected less negative and more positive drinking outcomes, and evaluated positive outcomes favorably reported greater intentions to drink in adulthood. CONCLUSION: Findings may be useful for efforts to further delay the initiation of alcohol use. PMID- 21700171 TI - Nondrinking adolescents' intentions to drink as adults: this might be an indication of following rules. PMID- 21700172 TI - Surgery 2010: Finding the silver lining on a cloud of regulation. PMID- 21700179 TI - Improved survival after resection of liver and lung colorectal metastases compared with liver-only metastases: a study of 112 patients with limited lung metastatic disease. AB - BACKGROUND: Lung metastases are considered a poor prognostic factor in patients with resectable colorectal liver metastases. STUDY DESIGN: We reviewed records of 1,260 consecutive patients with liver-only or liver-plus-lung (L+L) metastases from colorectal cancer who underwent resection with curative intent (1995 to 2009). Survival and prognostic factors were analyzed. RESULTS: There were 112 patients who underwent resection of L+L (mean 2 liver, 2 lung metastases). Mean tumor sizes were 3 cm and 1 cm, respectively. Thirty-four (31%) had bilateral lung metastases. Ten (9%) had synchronous L+L metastases, 60 (54%) had diagnosis of lung metastases within 1 year of liver resection. Most (108 of 112, 96%) had resection of liver before or at the same time as lung. Preoperative chemotherapy was used in 77 (69%) before liver resection and 56 (50%) before lung resection. Among L+L patients, no postoperative deaths occurred; postoperative morbidity rates were 26% after liver resection and 4% after lung resection. After a median of 49 months follow-up, L+L patients (n = 112) had better survival than liver only (n = 1,148) (5-year overall survival, L+L, 50% vs liver only, 40%; p = 0.01). CEA level > 5 ng/dL (hazard ratio [HR] 2.1, 95% CI 1.1 to 4.4, p = 0.04) and rectal primary (HR 2.9, 95% CI 1.4 to 6, p = 0.004) were associated with worse survival in L+L patients. CONCLUSIONS: The survival rate for patients who undergo resection of L+L metastases from colorectal cancer is greater than the survival rate of the general population of patients who undergo resection of liver metastases only. The presence of resectable lung metastases is neither a poor prognostic factor nor a contraindication to resection of liver metastases. PMID- 21700195 TI - Use of NSQIP to study the influence of resident involvement on surgical outcomes. PMID- 21700198 TI - The distinction between the use of a control group in a study and the use of a case-control design. PMID- 21700199 TI - Determination of the optimal perioperative blood glucose level to reduce surgical site infection in diabetic patients. PMID- 21700202 TI - Motor-dependent and -independent roles of CENP-E at kinetochores: the cautionary tale of UA62784. PMID- 21700203 TI - GenomeWeb: information for the genomics community. PMID- 21700204 TI - "Going KiNativ": probing the Native Kinome. AB - In this issue, Patricelli et al. (2011) describe an in situ chemoproteomics approach (KiNativTM) for profiling the kinome and kinome response to specific kinase inhibitors that enables characterization of inhibitor interactions with endogenously expressed kinases in native conditions. PMID- 21700205 TI - Traffic jam at the bacterial sec translocase: targeting the SecA nanomotor by small-molecule inhibitors. AB - The rapid rise of drug-resistant bacteria is one of the most serious unmet medical needs facing the world. Despite this increasing problem of antibiotic resistance, the number of different antibiotics available for the treatment of serious infections is dwindling. Therefore, there is an urgent need for new antibacterial drugs, preferably with novel modes of action to potentially avoid cross-resistance with existing antibacterial agents. In recent years, increasing attention has been paid to bacterial protein secretion as a potential antibacterial target. Among the different protein secretion pathways that are present in bacterial pathogens, the general protein secretory (Sec) pathway is widely considered as an attractive target for antibacterial therapy. One of the key components of the Sec pathway is the peripheral membrane ATPase SecA, which provides the energy for the translocation of preproteins across the bacterial cytoplasmic membrane. In this review, we will provide an overview of research efforts on the discovery and development of small-molecule SecA inhibitors. Furthermore, recent advances on the structure and function of SecA and their potential impact on antibacterial drug discovery will be discussed. PMID- 21700206 TI - In situ kinase profiling reveals functionally relevant properties of native kinases. AB - Protein kinases are intensely studied mediators of cellular signaling, yet important questions remain regarding their regulation and in vivo properties. Here, we use a probe-based chemoprotemics platform to profile several well studied kinase inhibitors against >200 kinases in native cell proteomes and reveal biological targets for some of these inhibitors. Several striking differences were identified between native and recombinant kinase inhibitory profiles, in particular, for the Raf kinases. The native kinase binding profiles presented here closely mirror the cellular activity of these inhibitors, even when the inhibition profiles differ dramatically from recombinant assay results. Additionally, Raf activation events could be detected on live cell treatment with inhibitors. These studies highlight the complexities of protein kinase behavior in the cellular context and demonstrate that profiling with only recombinant/purified enzymes can be misleading. PMID- 21700207 TI - Functional characterization of a SUMO deconjugating protease of Plasmodium falciparum using newly identified small molecule inhibitors. AB - Small ubiquitin-related modifier (SUMO) is implicated in the regulation of numerous biological processes including transcription, protein localization, and cell cycle control. Protein modification by SUMO is found in Plasmodium falciparum; however, its role in the regulation of the parasite life cycle is poorly understood. Here we describe functional studies of a SUMO-specific protease (SENP) of P. falciparum, PfSENP1 (PFL1635w). Expression of the catalytic domain of PfSENP1 and biochemical profiling using a positional scanning substrate library demonstrated that this protease has unique cleavage sequence preference relative to the human SENPs. In addition, we describe a class of small molecule inhibitors of this protease. The most potent lead compound inhibited both recombinant PfSENP1 activity and P. falciparum replication in infected human blood. These studies provide valuable new tools for the study of SUMOylation in P. falciparum. PMID- 21700208 TI - Development of small molecule inhibitors and probes of human SUMO deconjugating proteases. AB - Sentrin specific proteases (SENPs) are responsible for activating and deconjugating SUMO (Small Ubiquitin like MOdifier) from target proteins. It remains difficult to study this posttranslational modification due to the lack of reagents that can be used to block the removal of SUMO from substrates. Here, we describe the identification of small molecule SENP inhibitors and active site probes containing aza-epoxide and acyloxymethyl ketone (AOMK) reactive groups. Both classes of compounds are effective inhibitors of hSENPs 1, 2, 5, and 7 while only the AOMKs efficiently inhibit hSENP6. Unlike previous reported peptide vinyl sulfones, these compounds covalently labeled the active site cysteine of multiple recombinantly expressed SENP proteases and the AOMK probe showed selective labeling of these SENPs when added to complex protein mixtures. The AOMK compound therefore represents promising new reagents to study the process of SUMO deconjugation. PMID- 21700210 TI - Identification of a small-molecule inhibitor of DNA topoisomerase II by proteomic profiling. AB - BNS-22, a chemically synthesized derivative of the natural plant product GUT-70, has antiproliferative activity against human cancer cells, the mechanism of which is unknown. Here, we identify a target of BNS-22 by proteomic profiling analysis, which suggests that BNS-22 belongs to the same cluster as ICRF-193, a DNA topoisomerase II (TOP2) catalytic inhibitor. BNS-22 inhibits kinetoplast DNA decatenation that is mediated by human TOP2alpha and TOP2beta in vitro at an IC(50) of 2.8 and 0.42 MUM, respectively. BNS-22 does not affect DNA damage and antagonizes TOP2 poison-mediated DNA damage. Like ICRF-193, BNS-22 induces mitotic abnormalities, characterized by impairments in chromosome alignment and segregation, thereby causing polyploidy in HeLa cells. These results indicate that BNS-22 targets TOP2 and acts as its catalytic inhibitor. PMID- 21700209 TI - Evidence from Chlamydomonas on the photoactivation of rhodopsins without isomerization of their chromophore. AB - Attachment of retinal to opsin forms the chromophore N-retinylidene, which isomerizes during photoactivation of rhodopsins. To test whether isomerization is crucial, custom-tailored chromophores lacking the beta-ionone ring and any isomerizable bonds were incorporated in vivo into the opsin of a blind mutant of the eukaryote Chlamydomonas reinhardtii. The analogs restored phototaxis with the anticipated action spectra, ruling out the need for isomerization in photoactivation. To further elucidate photoactivation, responses to chromophores formed from naphthalene aldehydes were studied. The resulting action spectral shifts suggest that charge separation within the excited chromophore leads to electric field-induced polarization of nearby amino acid residues and altered hydrogen bonding. This redistribution of charge facilitates the reported multiple bond rotations and protein rearrangements of rhodopsin activation. These results provide insight into the activation of rhodopsins and related GPCRs. PMID- 21700212 TI - Lacidipine remodels protein folding and Ca 2+ homeostasis in Gaucher's disease fibroblasts: a mechanism to rescue mutant glucocerebrosidase. AB - The hallmark of Gaucher's disease cellular pathogenesis is the lysosomal accumulation of glucosylceramide, which is caused by misfolding of mutated glucocerebrosidase (GC) and loss of lysosomal GC activity, and leads to depletion of [Ca(2+)](ER). We demonstrate that modulation of Ca(2+) homeostasis and enhancement of the cellular folding capacity synergize to rescue the folding of mutated GC variants. Lacidipine, an L-type Ca(2+) channel blocker that also inhibits [Ca(2+)](ER) efflux, enhances folding, trafficking, and activity of degradation-prone GC variants. Lacidipine remodels mutated GC proteostasis by simultaneously activating a series of distinct molecular mechanisms, namely modulation of Ca(2+) homeostasis, upregulation of the ER chaperone BiP, and moderate induction of the unfolded protein response. However, unlike previously reported proteostasis regulators, lacidipine treatment is not cytotoxic but prevents apoptosis induction typically associated with sustained activation of the unfolded protein response. PMID- 21700211 TI - Development of Neh2-luciferase reporter and its application for high throughput screening and real-time monitoring of Nrf2 activators. AB - The NF-E2-related factor 2 (Nrf2) is a key transcriptional regulator of antioxidant defense and detoxification. To directly monitor stabilization of Nrf2, we fused its Neh2 domain, responsible for the interaction with its nucleocytoplasmic regulator, Keap1, to firefly luciferase (Neh2-luciferase). We show that Neh2 domain is sufficient for recognition, ubiquitination, and proteasomal degradation of Neh2-luciferase fusion protein. The Neh2-luc reporter system allows direct monitoring of the adaptive response to redox stress and classification of drugs based on the time course of reporter activation. The reporter was used to screen the Spectrum library of 2000 biologically active compounds to identify activators of Nrf2. The most robust and yet nontoxic Nrf2 activators found--nordihydroguaiaretic acid, fisetin, and gedunin--induced astrocyte-dependent neuroprotection from oxidative stress via an Nrf2-dependent mechanism. PMID- 21700213 TI - Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment. AB - Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion within Huntingtin (Htt) protein. In the phenotypic screen we identified a class of quinazoline-derived compounds that delayed a progression of a motor phenotype in transgenic Drosophila HD flies. We found that the store operated calcium (Ca(2+)) entry (SOC) pathway activity is enhanced in neuronal cells expressing mutant Htt and that the identified compounds inhibit SOC pathway in HD neurons. The same compounds exerted neuroprotective effects in glutamate toxicity assays with YAC128 medium spiny neurons primary cultures. We demonstrated a key role of TRPC1 channels in supporting SOC pathway in HD neurons. We concluded that the TRPC1-mediated neuronal SOC pathway constitutes a novel target for HD treatment and that the identified compounds represent a novel class of therapeutic agents for treatment of HD and possibly other neurodegenerative disorders. PMID- 21700214 TI - Anamorsin is a [2Fe-2S] cluster-containing substrate of the Mia40-dependent mitochondrial protein trapping machinery. AB - Human anamorsin was implicated in cytosolic iron-sulfur (Fe/S) protein biogenesis. Here, the structural and metal-binding properties of anamorsin and its interaction with Mia40, a well-known oxidoreductase involved in protein trapping in the mitochondrial intermembrane space (IMS), were characterized. We show that (1), anamorsin contains two structurally independent domains connected by an unfolded linker; (2), the C-terminal domain binds a [2Fe-2S] cluster through a previously unknown cysteine binding motif in Fe/S proteins; (3), Mia40 specifically introduces two disulfide bonds in a twin CX(2)C motif of the C terminal domain; (4), anamorsin and Mia40 interact through an intermolecular disulfide-bonded intermediate; and (5), anamorsin is imported into mitochondria. Hence, anamorsin is the first identified Fe/S protein imported into the IMS, raising the possibility that it plays a role in cytosolic Fe/S cluster biogenesis also once trapped in the IMS. PMID- 21700215 TI - Measuring in vivo protein half-life. AB - Protein turnover critically influences many biological functions, yet methods have been lacking to assess this parameter in vivo. Here, we demonstrate how chemical labeling of SNAP-tag fusion proteins can be exploited to measure the half-life of resident intracellular and extracellular proteins in living mice. First, we demonstrate that SNAP-tag substrates have wide bioavailability in mice and can be used for the specific in vivo labeling of SNAP-tag fusion proteins. We then apply near-infrared probes to perform noninvasive imaging of in vivo-labeled tumors. Finally, we use SNAP-mediated chemical pulse-chase labeling to perform measurement of the in vivo half-life of different extra- and intracellular proteins. These results open broad perspectives for studying protein function in living animals. PMID- 21700216 TI - PKM2 and the tricky balance of growth and energy in cancer. AB - In this issue of Molecular Cell, Lv et al. (2011) identify a novel feedback mechanism in which increased glycolysis induces the acetylation and chaperone mediated autophagic degradation of the glycolytic regulator PKM2, revealing a novel metabolic feedback loop that drives tumor growth. PMID- 21700217 TI - No country for old misfolded glycoproteins. AB - Gauss et al. (2011) present evidence that an endoplasmic reticulum (ER) sugar removing enzyme with a folding sensor subunit enables a stochastic quality control mechanism, which marks with increasing probability misfolded glycoproteins for destruction the longer they reside in the ER. PMID- 21700218 TI - Sen-sing RNA terminators. AB - In this issue of Molecular Cell,Skourti-Stathaki et al. (2011) report that human Senataxin, like its yeast homolog Sen1, promotes termination by RNA polymerase II and resolves RNA/DNA duplexes formed during transcription. Their results may help uncover a cause of motor neuron degeneration. PMID- 21700219 TI - Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. AB - Most tumor cells take up more glucose than normal cells but metabolize glucose via glycolysis even in the presence of normal levels of oxygen, a phenomenon known as the Warburg effect. Tumor cells commonly express the embryonic M2 isoform of pyruvate kinase (PKM2) that may contribute to the metabolism shift from oxidative phosphorylation to aerobic glycolysis and tumorigenesis. Here we show that PKM2 is acetylated on lysine 305 and that this acetylation is stimulated by high glucose concentration. PKM2 K305 acetylation decreases PKM2 enzyme activity and promotes its lysosomal-dependent degradation via chaperone mediated autophagy (CMA). Acetylation increases PKM2 interaction with HSC70, a chaperone for CMA, and association with lysosomes. Ectopic expression of an acetylation mimetic K305Q mutant accumulates glycolytic intermediates and promotes cell proliferation and tumor growth. These results reveal an acetylation regulation of pyruvate kinase and the link between lysine acetylation and CMA. PMID- 21700220 TI - Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin induced autophagy arrest. AB - Autophagy, a catabolic pathway that delivers cellular components to lysosomes for degradation, can be activated by stressful conditions such as nutrient starvation and endoplasmic reticulum (ER) stress. We report that thapsigargin, an ER stressor widely used to induce autophagy, in fact blocks autophagy. Thapsigargin does not affect autophagosome formation but leads to accumulation of mature autophagosomes by blocking autophagosome fusion with the endocytic system. Strikingly, thapsigargin has no effect on endocytosis-mediated degradation of epidermal growth factor receptor. Molecularly, while both Rab7 and Vps16 are essential regulatory components for endocytic fusion with lysosomes, we found that Rab7 but not Vps16 is required for complete autophagy flux, and that thapsigargin blocks recruitment of Rab7 to autophagosomes. Therefore, autophagosomal-lysosomal fusion must be governed by a distinct molecular mechanism compared to general endocytic fusion. PMID- 21700221 TI - Regulation of ubiquitin chain initiation to control the timing of substrate degradation. AB - Processive reactions, such as transcription or translation, often proceed through distinct initiation and elongation phases. The processive formation of polymeric ubiquitin chains can accordingly be catalyzed by specialized initiating and elongating E2 enzymes, but the functional significance for this division of labor has remained unclear. Here, we have identified sequence motifs in several substrates of the anaphase-promoting complex (APC/C) that are required for efficient chain initiation by its E2 Ube2C. Differences in the quality and accessibility of these chain initiation motifs can determine the rate of a substrate's degradation without affecting its affinity for the APC/C, a mechanism used by the APC/C to control the timing of substrate proteolysis during the cell cycle. Based on our results, we propose that initiation motifs and their cognate E2s allow E3 enzymes to exert precise temporal control over substrate degradation. PMID- 21700222 TI - Client-loading conformation of the Hsp90 molecular chaperone revealed in the cryo EM structure of the human Hsp90:Hop complex. AB - Hsp90 is an essential molecular chaperone required for the folding and activation of many hundreds of cellular "client" proteins. The ATP-dependent chaperone cycle involves significant conformational rearrangements of the Hsp90 dimer and interaction with a network of cochaperone proteins. Little is known about the mechanism of client protein binding or how cochaperone interactions modulate Hsp90 conformational states. We have determined the cryo-EM structure of the human Hsp90:Hop complex that receives client proteins from the Hsp70 chaperone. Hop stabilizes an alternate Hsp90 open state, where hydrophobic client-binding surfaces have converged and the N-terminal domains have rotated and match the closed, ATP conformation. Hsp90 is thus simultaneously poised for client loading by Hsp70 and subsequent N-terminal dimerization and ATP hydrolysis. Upon binding of a single Hsp70, the Hsp90:Hop conformation remains essentially unchanged. These results identify distinct functions for the Hop cochaperone, revealing an asymmetric mechanism for Hsp90 regulation and client loading. PMID- 21700223 TI - A complex of Pdi1p and the mannosidase Htm1p initiates clearance of unfolded glycoproteins from the endoplasmic reticulum. AB - Endoplasmic reticulum (ER)-resident mannosidases generate asparagine-linked oligosaccharide signals that trigger ER-associated protein degradation (ERAD) of unfolded glycoproteins. In this study, we provide in vitro evidence that a complex of the yeast protein disulfide isomerase Pdi1p and the mannosidase Htm1p processes Man(8)GlcNAc(2) carbohydrates bound to unfolded proteins, yielding Man(7)GlcNAc(2). This glycan serves as a signal for HRD ligase-mediated glycoprotein disposal. We identified a point mutation in PDI1 that prevents complex formation of the oxidoreductase with Htm1p, diminishes mannosidase activity, and delays degradation of unfolded glycoproteins in vivo. Our results show that Pdi1p is engaged in both recognition and glycan signal processing of ERAD substrates and suggest that protein folding and breakdown are not separated but interconnected processes. We propose a stochastic model for how a given glycoprotein is partitioned into folding or degradation pathways and how the flux through these pathways is adjusted to stress conditions. PMID- 21700224 TI - Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. AB - We present a molecular dissection of pause site-dependent transcriptional termination for mammalian RNA polymerase II (Pol II)-transcribed genes. We show that nascent transcripts form RNA/DNA hybrid structures (R-loops) behind elongating Pol II and are especially prevalent over G-rich pause sites positioned downstream of gene poly(A) signals. Senataxin, a helicase protein associated with AOA2/ALS4 neurodegenerative disorders, acts to resolve these R-loop structures and by so doing allows access of the 5'-3' exonuclease Xrn2 at 3' cleavage poly(A) sites. This affords 3' transcript degradation and consequent Pol II termination. In effect, R-loops formed over G-rich pause sites, followed by their resolution by senataxin, are key steps in the termination process. PMID- 21700225 TI - Recombination hotspots and single-stranded DNA binding proteins couple DNA translocation to DNA unwinding by the AddAB helicase-nuclease. AB - AddAB is a helicase-nuclease that processes double-stranded DNA breaks for repair by homologous recombination. This process is modulated by Chi recombination hotspots: specific DNA sequences that attenuate the nuclease activity of the translocating AddAB complex to promote downstream recombination. Using a combination of kinetic and imaging techniques, we show that AddAB translocation is not coupled to DNA unwinding in the absence of single-stranded DNA binding proteins because nascent single-stranded DNA immediately re-anneals behind the moving enzyme. However, recognition of recombination hotspot sequences during translocation activates unwinding by coupling these activities, thereby ensuring the downstream formation of single-stranded DNA that is required for RecA mediated recombinational repair. In addition to their implications for the mechanism of double-stranded DNA break repair, these observations may affect our implementation and interpretation of helicase assays and our understanding of helicase mechanisms in general. PMID- 21700226 TI - NanoRNAs prime transcription initiation in vivo. AB - It is often presumed that, in vivo, the initiation of RNA synthesis by DNA dependent RNA polymerases occurs using NTPs alone. Here, using the model Gram negative bacterium Pseudomonas aeruginosa, we demonstrate that depletion of the small-RNA-specific exonuclease, Oligoribonuclease, causes the accumulation of oligoribonucleotides 2 to ~4 nt in length, "nanoRNAs," which serve as primers for transcription initiation at a significant fraction of promoters. Widespread use of nanoRNAs to prime transcription initiation is coupled with global alterations in gene expression. Our results, obtained under conditions in which the concentration of nanoRNAs is artificially elevated, establish that small RNAs can be used to initiate transcription in vivo, challenging the idea that all cellular transcription occurs using only NTPs. Our findings further suggest that nanoRNAs could represent a distinct class of functional small RNAs that can affect gene expression through direct incorporation into a target RNA transcript rather than through a traditional antisense-based mechanism. PMID- 21700227 TI - Integrated approaches reveal determinants of genome-wide binding and function of the transcription factor Pho4. AB - DNA sequences with high affinity for transcription factors occur more frequently in the genome than instances of genes bound or regulated by these factors. It is not clear what factors determine the genome-wide pattern of binding or regulation for a given transcription factor. We used an integrated approach to study how trans influences shape the binding and regulatory landscape of Pho4, a budding yeast transcription factor activated in response to phosphate limitation. We find that nucleosomes significantly restrict Pho4 binding. At nucleosome-depleted sites, competition from another transcription factor, Cbf1, determines Pho4 occupancy, raising the threshold for transcriptional activation in phosphate replete conditions and preventing Pho4 activation of genes outside the phosphate regulon during phosphate starvation. Pho4 binding is not sufficient for transcriptional activation-a cooperative interaction between Pho2 and Pho4 specifies genes that are activated. Combining these experimental observations, we are able to globally predict Pho4 binding and its functionality. PMID- 21700229 TI - [Invasive fungal diseases in solid organ transplant recipients]. PMID- 21700228 TI - The polycomb group mutant esc leads to augmented levels of paused Pol II in the Drosophila embryo. AB - Many developmental control genes contain paused RNA polymerase II (Pol II) and are thereby "poised" for rapid and synchronous activation in the early Drosophila embryo. Evidence is presented that Polycomb group (PcG) repressors can influence paused Pol II. ChIP-Seq and GRO-Seq assays were used to determine the genome-wide distributions of Pol II, H3K27me3, and H3K4me3 in extra sex combs (esc) mutant embryos. ESC is a key component of the Polycomb repressive complex 2 (PRC2), which mediates H3K27me3 modification. Enhanced Pol II occupancy is observed for thousands of genes in esc mutant embryos, including genes not directly regulated by PRC2. Thus, it would appear that silent genes lacking promoter-associated paused Pol II in wild-type embryos are converted into "poised" genes with paused Pol II in esc mutants. We suggest that this conversion of silent genes into poised genes might render differentiated cell types susceptible to switches in identity in PcG mutants. PMID- 21700231 TI - [Epidemiology of invasive fungal infection in solid organ transplant]. AB - Despite advances made in the last decades, invasive fungal infections (IFI) continue to be a major cause of morbidity and mortality in solid organ transplant recipients. The most common pathogens causing IFI are Candida species, followed by Aspergillus and Cryptococcus. A shift in the epidemiology of IFI has been reported in the last few years. Non-Candida albicans Candida species and non Aspergillus filamentous moulds have been increasingly observed in transplant patients. A change in the IFI onset time has also been described recently. In the RESITRA (Spanish Network of Infection in Transplantation) study, at least 50% of invasive aspergillosis (IA) infections and 40% of invasive Candida infections had been observed after 180 days of transplant. Some cases of cryptococcal infection, traditionally considered as a late onset infection, have been observed in the early post transplant period. Mortality due to IFI is still high, particularly in patients with IA. However, the progressive improvement achieved in diagnosis and prevention of IFI has led to a lower mortality rate. PMID- 21700230 TI - [Candidiasis, aspergillosis and other invasive mycoses in recipients of solid organ transplants]. AB - Invasive fungal diseases (IFD) are important causes of solid organ transplant related morbidity and mortality. Modifications and improvements in the transplant surgical procedures, supportive care, and advances in the diagnosis and treatment of these IFD have produced notable changes in their epidemiology and outcome. Candida and other yeast genera continue to play an important etiological role, but Aspergillus and other filamentous fungi are the cause of most IFD in lung transplant recipients. This review is an update of the relevant findings in the literature related to the epidemiology, diagnosis and treatment of IFD in solid organ transplant recipients, with a main focus on invasive aspergillosis and candidiasis. PMID- 21700232 TI - [Invasive candidiasis in liver transplant recipient: early rescue antifungal treatment]. AB - BACKGROUND: Some liver transplant recipients could be at risk for candidemia or invasive candidiasis during the immediate postoperative period after transplantation. Prophylaxis is the best strategy to reduce the incidence of invasive fungal infection caused by Candida species in high-risk liver transplant recipients (HR-LTR), but in cases of suspected breakthrough invasive fungal infection due to Candida, both a rapid diagnosis process and early antifungal treatment are the most important factors impacting on the prognosis. CLINICAL CASE: We report a case of early rescue treatment with anidulafungin in a HR-LTR with complicated postoperative course. We discuss risk factors, prophylaxis, sensitivity of biomarkers, and characteristics of antifungal management. CONCLUSIONS: Early rescue antifungal treatment using candins improves the prognosis in HR-LTR suffering from invasive candidiasis. PMID- 21700233 TI - [Aspergillus tracheobronchitis in a lung transplant recipient]. AB - BACKGROUND: Aspergillus tracheobronchitis is an uncommon cause of pulmonary aspergillosis and almost exclusively affects lung transplant recipients. There is no lung tissue involvement, thus the tracheobron-chial tree is only affected. Patients are asymptomatic, so it is important to make an early diagnosis to prevent progression of the infection and airway complications. Several prophylaxis and treatment strategies have proven to improve the prognosis. CLINICAL CASE: This is the case of a 56 year-old man who underwent bilateral lung transplant for chronic obstructive pulmonary disease (COPD) and developed Aspergillus tracheobronchitis. He received the usual prophylaxis with nebulized liposomal amphotericin B every 48 h. Routine bronchoscopy performed 2 weeks after transplantation showed inflammation with the presence of pseudomembranes that produced a 50% stenosis of the right bronchial anastomosis. Biopsy of the pseudomembranes and bronchial aspirate yielded Aspergillus fumigatus. The patient started treatment with voriconazole twice a day, bronchial debridement through bronchoscopy was carried out, and the treatment with nebulized liposomal amphotericin B was continued every other day. Ten weeks later, there were no endobronchial lesions and the bronchial aspirate cultures were negative. CONCLUSIONS: Aspergillus tracheobronchitis is a complication of the lung transplant recipient. Early diagnosis and prompt antifungal therapy, including new antifungal agents and local debridement, may significantly improve the outcome. PMID- 21700234 TI - [Cardiac invasive aspergillosis in a heart transplant recipient]. AB - BACKGROUND: Solid organ transplant recipients are a population at risk of invasive aspergillosis. The lung and the central nervous system are usually affected. OBJECTIVES: We report the case of a patient with proven cardiac invasive aspergillosis two years after heart transplantation, and perform a review of cardiac aspergillosis in solid organ transplant recipients. CASE REPORT: A 52-year old woman received a heart transplant. Several complications appeared in the post-operative period, including the development of invasive aspergillosis in the surgical wound. She was readmitted two years later with dyspnea. A thoracic CT-scan revealed multiple lung embolisms and a mass in the retroxiphoid, invading the right atrium and the tricuspid valve. Septated hyphae invading this tissue were observed and Aspergillus fumigatus was subsequently isolated. Serum galactomannan determinations were negative. Antifungal therapy with voriconazole was started. Two months later, the patient visited the hospital for a routine check-up control in good clinical condition, but with undetectable voriconazole serum levels. These levels were associated to the concomitant use of omeprazole. One year later, the patient was still receiving voriconazole and remained asymptomatic. CONCLUSIONS: Invasive aspergillosis affecting the mediastinum can progress and affect the heart tissues. The use of omeprazole may be associated with the undetectable voriconazole serum levels. PMID- 21700236 TI - Measles once again. PMID- 21700235 TI - [Scedosporium apiospermum disseminated infection in a single lung transplant recipient]. AB - BACKGROUND: Scedosporium spp. are filamentous fungi, and the 2 most important species are Scedosporium prolificans and Scedosporium apiospermum. S. apiospermum accounts for approximately 25% of non-Aspergillus filamentous fungi infections in organ transplant recipients. Scedosporium can colonize the sinuses and airways of lung recipients with underlying pulmonary diseases, such as bronchiectasis or cystic fibrosis before transplant, and develop invasive disease after lung transplantation. In fact, invasive diseases caused by S. apiospermum have been reported only rarely, in single lung transplant recipients and cystic fibrosis transplant patients. The treatment of scedosporiasis is complicated due to the difficulty in early diagnosis together with inherent resistance to amphotericin B. CASE REPORT: A case of disseminated S. apiospermum infection after single lung transplant in a patient with pulmonary fibrosis is reported. Leg mycetoma was the initial sign of this disseminated infection. In this case report, current treatment options are discussed, and a review of the literature of previously published cases of lung transplants is made. CONCLUSIONS: One conclusion based on this case is the risk of emergent molds related to antifungal prophylaxis. In addition, colonization by Scedosporium in transplant recipients should not be ignored, and target prophylaxis or suppressive therapy should be considered in all those cases with residual lesions in native lung or chronic rejection in transplanted lungs. PMID- 21700237 TI - Adjuvanted or whole-virion vaccine for 2009 influenza A (H1N1). PMID- 21700239 TI - ACTs for the treatment of schistosomiasis. PMID- 21700240 TI - Effectiveness of ACTs in cases of resistance to partner drugs. PMID- 21700241 TI - Consequences of HIV infection on malaria and therapeutic implications: a systematic review. AB - Despite recent changes in the epidemiology of HIV infection and malaria and major improvements in their control, these diseases remain two of the most important infectious diseases and global health priorities. As they have overlapping distribution in tropical areas, particularly sub-Saharan Africa, any of their clinical, diagnostic, and therapeutic interactions might have important effects on patient care and public health policy. The biological basis of these interactions is well established. HIV infection induces cellular depletion and early abnormalities of CD4+ T cells, decreases CD8+ T-cell counts and function (cellular immunity), causes deterioration of specific antigen responses (humoral immunity), and leads to alteration of innate immunity through impairment of cytolytic activity and cytokine production by natural killer cells. Therefore, HIV infection affects the immune response to malaria, particularly premunition in adolescents and adults, and pregnancy-specific immunity, leading to different patterns of disease in HIV-infected patients compared with HIV-uninfected patients. In this systematic review, we collate data on the effects of HIV on malaria and discuss their therapeutic consequences. HIV infection is associated with increased prevalence and severity of clinical malaria and impaired response to antimalarial treatment, depending on age, immunodepression, and previous immunity to malaria. HIV also affects pregnancy-specific immunity to malaria and response to intermittent preventive treatment. Co-trimoxazole (trimethoprim sulfamethoxazole) prophylaxis and antiretroviral treatment reduce occurrence of clinical malaria; however, these therapies interact with antimalarial drugs, and new therapeutic guidelines are needed for concomitant use. PMID- 21700242 TI - Disseminated Mycobacterium haemophilum infection. AB - Mycobacterium haemophilum is a slow-growing organism first identified in 1978. Since that time, it has emerged as an unusual pathogen, but one that is identified increasingly, mainly affecting immunocompromised patients and healthy children. The range of disease caused by this organism includes skin and soft tissue infections, pulmonary infections, lymphadenitis, and frequently, bone and joint infections. Laboratory identification of M haemophilum needs special culture techniques and media and can be difficult in a setting at which these methods are not routinely used. We describe a case of chronic, disseminated M haemophilum infection in a patient with AIDS, and we review published work. PMID- 21700243 TI - Gastroenterology in a new era of accountability: Part 1. An overview of performance measurement. PMID- 21700244 TI - Total ischemic time: the correct focus of attention for optimal ST-segment elevation myocardial infarction care. AB - Currently accepted standards for gauging quality of care in the treatment of ST segment elevation myocardial infarction (STEMI) mainly focus on shortening the time to treatment after the patient arrives at the hospital. But this narrow focus fails to consider the substantial duration of myocardial ischemia that exists prior to hospital arrival, and the large number of deaths that occur during the pre-hospital period. The time from symptom onset until reperfusion occurs is one estimate of total ischemic time. Several experimental studies and now human clinical studies have confirmed that infarct size and mortality are strongly correlated with the total ischemic time, and much less so with its subintervals like door-to-balloon time. This review will discuss the importance of total ischemic time in STEMI. PMID- 21700246 TI - Facilitated percutaneous coronary intervention still searching for the right patients. PMID- 21700245 TI - Randomized comparison of pre-hospital-initiated facilitated percutaneous coronary intervention versus primary percutaneous coronary intervention in acute myocardial infarction very early after symptom onset: the LIPSIA-STEMI trial (Leipzig immediate prehospital facilitated angioplasty in ST-segment myocardial infarction). AB - OBJECTIVES: This multicenter trial sought to assess the merits of facilitated percutaneous coronary intervention (PCI) versus primary PCI in an ST-segment elevation myocardial infarction (STEMI) network with long transfer distances in patients presenting early after symptom onset. BACKGROUND: Facilitated PCI with fibrinolysis might be beneficial in specific high-risk STEMI situations to prevent myocardial necrosis expansion. METHODS: Patients with STEMI (<3 h after symptom onset) were randomized to either pre-hospital-initiated facilitated PCI using tenecteplase (Group A; n = 81) or primary PCI (Group B; n = 81) plus optimal antithrombotic comedication. The primary endpoint was infarct size assessed by delayed-enhancement magnetic resonance imaging. Secondary endpoints were microvascular obstruction and myocardial salvage, early ST-segment resolution, and a composite of death, repeated myocardial infarctions, and congestive heart failure within 30 days. RESULTS: The median time from symptom onset to randomization was 64 min (interquartile range [IQR]: 42 to 103 min) in Group A versus 55 min in Group B (IQR: 27 to 91 min; p = 0.26). Despite better pre-interventional TIMI (Thrombolysis In Myocardial Infarction) flow in Group A (71% vs. 35% TIMI flow grade 2 or 3; p < 0.001), the infarct size tended to be worse in Group A versus Group B (17.9% of left ventricle [IQR: 8.4% to 35.0%] vs. 13.7% [IQR: 7.5% to 24.0%]; p = 0.10). There was also a strong trend toward more early and late microvascular obstruction, (p = 0.06 and 0.09) and no difference in ST-segment resolution (p = 0.26). The combined clinical endpoint showed a trend toward higher event rates in Group A (19.8% vs. 13.6%; p = 0.13, relative risk: 0.52, 95% confidence interval: 0.23 to 1.18). CONCLUSIONS: In STEMI patients presenting early after symptom onset with relatively long transfer times, a fibrinolytic-based facilitated PCI approach with optimal antiplatelet comedication does not offer a benefit over primary PCI with respect to infarct size and tissue perfusion. ([LIPSIA-STEMI] The Leipzig Immediate Prehospital Facilitated Angioplasty in ST-Segment Myocardial Infarction; NCT00359918). PMID- 21700247 TI - Percutaneous coronary intervention of unprotected left main coronary artery disease as culprit lesion in patients with acute myocardial infarction. AB - OBJECTIVES: This study sought to evaluate short- and long-term outcomes of patients undergoing emergency percutaneous coronary intervention (PCI) for acute myocardial infarction due to a culprit lesion in an unprotected left main coronary artery. METHODS: In this retrospective, 2-center, international observational study, 5,261 patients were admitted between February 2005 and December 2008 with acute myocardial infarction and treated with PCI; of these, 1,277 were ST-segment elevation myocardial infarction and 3,984 non-ST-segment elevation myocardial infarction. We identified 48 patients among this cohort who underwent emergency PCI to an unprotected left main coronary artery culprit lesion. RESULTS: Mean age was 70 +/- 12.5 years, and 45% of the patients presented with ST-segment elevation myocardial infarction or new left bundle branch block. Cardiogenic shock was present in 45%, and distal left main coronary artery disease was present in 71% of patients. Angiographic procedural success was achieved in 92% of patients. Overall in-hospital mortality was 21%, due in all cases to refractory, multiorgan failure. Twenty-five percent experienced major adverse cardiac events, defined as death, myocardial infarction, stent thrombosis, and target vessel revascularization. In patients presenting in cardiogenic shock, in-hospital mortality was 32%. At 1-year follow-up, in hospital survivors had a mortality rate of 10.5%, whereas 18.4% experienced subsequent major adverse cardiac events. Long-term prognosis was excellent in hospital survivors with a 1-year survival rate of 89.5%. CONCLUSIONS: Patients with acute myocardial infarction and thrombosis of the unprotected left main coronary artery are a high-risk subgroup with a substantial mortality, particularly if they present in cardiogenic shock. We demonstrate that in these patients, PCI is a feasible treatment option associated with reasonably good outcomes. Long-term prognosis is excellent in hospital survivors with an 89.5% survival rate at 1 year. PMID- 21700248 TI - Primary percutaneous coronary intervention for unprotected left main disease in patients with acute ST-segment elevation myocardial infarction the AMIS (Acute Myocardial Infarction in Switzerland) plus registry experience. AB - OBJECTIVES: This study sought to assess outcomes in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (PCI) for unprotected left main (LM) disease. BACKGROUND: Limited data are available on outcomes in patients with ST-segment elevation myocardial infarction undergoing LM PCI. METHODS: Of 9,075 patients with ST-segment elevation myocardial infarction enrolled in the AMIS (Acute Myocardial Infarction in Switzerland) Plus registry between 2005 and June 30, 2010, 6,666 underwent primary PCI. Of them, 348 (5.2%; mean age: 63.5 +/- 12.6 years) underwent LM PCI, either isolated (n = 208) or concomitant to PCI for other vessel segments (n = 140). They were compared with 6,318 patients (94.8%; mean age: 61.9 +/- 12.5 years) undergoing PCI of non-LM vessel segments only. RESULTS: The LM patients had higher rates of cardiogenic shock (12.2% vs. 3.5%; p < 0.001), cardiac arrest (10.6% vs. 6.3%; p < 0.01), in-hospital mortality (10.9% vs. 3.8%; p < 0.001), and major adverse cardiac and cerebrovascular events (12.4% vs. 5.0%; p < 0.001) than non-LM PCI. Rates of mortality and major adverse cardiac and cerebrovascular events were highest for concurrent LM and non-LM PCI (17.9% and 18.6%, respectively), intermediate for isolated LM PCI (6.3% and 8.3%, respectively), and lowest for non-LM PCI (3.8% and 5.0%, respectively). Rates of mortality and major adverse cardiac and cerebrovascular events for LM PCI were higher than for non-LM multivessel PCI (10.9% vs. 4.9%, p < 0.001, and 12.4% vs. 6.4%, p < 0.001, respectively). LM disease independently predicted in-hospital death (odds ratio: 2.36; 95% confidence interval: 1.34 to 4.17; p = 0.003). CONCLUSIONS: Emergent LM PCI in the context of acute myocardial infarction, even including 12% cardiogenic shock, appears to have a remarkably high (89%) in-hospital survival. Concurrent LM and non-LM PCI has worse outcomes than isolated LM PCI. PMID- 21700249 TI - Clinical and angiographic predictors and prognostic value of failed thrombus aspiration in primary percutaneous coronary intervention. AB - OBJECTIVES: This study sought to investigate which factors are associated with failure of thrombus aspiration (TA) and if this has prognostic implications. BACKGROUND: The pathophysiological mechanism and clinical benefit of TA during primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction is still in debate. METHODS: Between August 2001 and October 2007, TA was attempted in 1,399 patients. Failure of TA was defined as the inability to reach and/or cross the occlusion with the aspiration catheter for effective thrombus removal. In addition, we analyzed patients in which no material could be obtained. We examined baseline clinical and angiographic variables related to failure of TA or to the lack of aspirate. Follow-up on vital status was obtained at 1 year. RESULTS: In 144 (10.3%) patients, the aspiration catheter failed to cross the lesion. After multivariable adjustment, marked proximal tortuosity (odds ratio [OR]: 2.88, 95% confidence interval [CI]: 1.92 to 4.31, p < 0.001), the presence of a calcified lesion (OR: 2.70, 95% CI: 1.77 to 4.13, p < 0.001), and a bifurcation lesion (OR: 1.97, 95% CI: 1.15 to 3.37, p = 0.013) were independent predictors of failed TA. Age over 60 years and the circumflex as infarct-related artery were associated with the lack of aspirate. Mortality rates at 1 year were 6.2% in patients with failed TA and 6.4% with successful TA (hazard ratio: 0.98, 95% CI: 0.49 to 1.95, p = 0.95). CONCLUSIONS: The presence of marked proximal tortuosity of the infarct-related artery, a calcified lesion, and a bifurcation lesion are independent predictors of failure of thrombus aspiration. We found that unsuccessful TA did not affect 1-year mortality. PMID- 21700250 TI - Thrombus aspiration in primary percutaneous coronary intervention how to manage failure. PMID- 21700251 TI - A patient-level pooled analysis assessing the impact of the SYNTAX (synergy between percutaneous coronary intervention with taxus and cardiac surgery) score on 1-year clinical outcomes in 6,508 patients enrolled in contemporary coronary stent trials. AB - OBJECTIVES: This study sought to assess the impact of the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score (SXscore) on clinical outcomes in patients undergoing percutaneous coronary intervention. BACKGROUND: The SXscore has been demonstrated to have an ability to predict clinical outcomes in patients undergoing percutaneous revascularization. Current studies are limited by the relatively small number of patients in each SXscore group. METHODS: Patient-level data from 7 contemporary coronary stent trials were pooled by an independent academic research organization (Cardialysis, Rotterdam, the Netherlands). Analysis was performed on a cohort of 6,508 patients treated with drug-eluting stents and who had calculated SXscores. Clinical outcomes in terms of death, myocardial infarction (MI), repeat revascularization, and major adverse cardiac events (MACE, a composite of death, MI, and repeat revascularization) were subsequently stratified according to SXscore quartiles: SXscore(Q1) <= 8 (n = 1,702); 8 < SXscore(Q2) < 15 (n = 1,528); 15 <= SXscore(Q3) < 23 (n = 1,620); and SXscore(Q4) >= 23 (n = 1,658). RESULTS: One-year outcomes were available in 6,496 patients (99.8%). At 1-year follow-up, all clinical outcomes including mortality, MI, repeat revascularization, MACE, and definite and any stent thrombosis were all significantly higher in patients in the highest SXscore quartile. Similar trends were observed in a subgroup of 2,093 patients (32.2%) who presented with an ST- or non-ST-segment elevation MI. The rate of MACE among patients with an SXscore > 32 and <= 32 was 24.9% and 14.0%, respectively (p < 0.001). The SXscore was identified as an independent predictor of all clinical outcomes including mortality, MACE, and stent thrombosis (p < 0.001 for all). CONCLUSIONS: This study confirms the consistent ability of the SXscore to identify patients who are at highest risk of adverse events. PMID- 21700252 TI - Impact of bleeding on mortality after percutaneous coronary intervention results from a patient-level pooled analysis of the REPLACE-2 (randomized evaluation of PCI linking angiomax to reduced clinical events), ACUITY (acute catheterization and urgent intervention triage strategy), and HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trials. AB - OBJECTIVES: This study sought to develop a risk score predictive of bleeding in patients undergoing percutaneous coronary intervention (PCI) and to investigate the impact of bleeding on subsequent mortality. BACKGROUND: Bleeding complications after PCI have been independently associated with early and late mortality. METHODS: This study represents a patient-level pooled analysis including 17,034 patients undergoing PCI from 3 large, randomized trials of bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitors, including the REPLACE-2 (Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events), ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy), and HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trials. We developed a risk score to predict noncoronary artery bypass graft (CABG)-related TIMI (Thrombolysis In Myocardial Infarction) major bleeding and evaluated the impact of various types of bleeding on 1-year mortality. RESULTS: A non-CABG-related TIMI major bleed occurred within 30 days in 267 patients (1.6%), and death occurred in 497 patients (2.9%) within 1 year. A risk score was developed to predict the bleeding risk of patients undergoing PCI, consisting of 7 variables (serum creatinine, age, sex, presentation, white blood cell count, cigarette smoking, and randomized treatment). The TIMI major bleeding rates increased by bleeding risk score groups: from 0.4% for those in the lowest to 5.8% for those in the highest risk group. Non-CABG-related TIMI major bleeding and the occurrence of myocardial infarction within 30 days were independent predictors of subsequent mortality, with respective hazard ratios of 4.2 and 2.9, each p < 0.001. Ranked in order of severity, TIMI major bleeding, blood transfusion without TIMI bleed, TIMI minor bleeding requiring blood transfusion, and TIMI minor bleeding not requiring blood transfusion were independent predictors of subsequent mortality with hazard ratios of 4.89, 2.91, 2.73, and 1.66, respectively. Isolated hematomas were not predictive of subsequent mortality. CONCLUSIONS: Non-CABG-related bleeding within 30 days is strongly associated with an increased risk of subsequent mortality at 1 year in patients undergoing PCI for all indications. A risk score was established to calculate the bleeding risk for patients undergoing PCI, allowing therapeutic decision making to minimize the incidence of bleeding. PMID- 21700253 TI - Validation of minimal luminal area measured by intravascular ultrasound for assessment of functionally significant coronary stenosis comparison with myocardial perfusion imaging. AB - OBJECTIVES: This study sought to evaluate the ability of minimal luminal area (MLA) measured by intravascular ultrasound (IVUS) to assess the functional significance of coronary artery disease. BACKGROUND: The use of IVUS to determine the functional significance of coronary artery lesions remains a matter for debate. METHODS: From our prospective IVUS imaging database, between July 2009 and April 2010, 170 coronary lesions in 150 patients who underwent stress myocardial single-photon emission computed tomography (SPECT) performed within 1 month of IVUS evaluation were identified and analyzed. MLA and other parameters were measured by IVUS and compared with the results of myocardial SPECT. RESULTS: Overall, 45 lesions had positive SPECT, and 125 lesions had negative SPECT. The MLA of lesions with positive SPECT was smaller than the MLA of those with negative SPECT (1.7 +/- 0.5 mm2 vs. 2.3 +/- 1.1 mm2, p < 0.001). By logistic regression analysis, MLA (odds ratio: 3.1 by decrease of 1 mm2, 95% confidence interval [CI]: 1.75 to 5.5, p < 0.01) was an independent predictor of the positive SPECT. Using receiver-operator characteristic curve analysis, the best cutoff value of MLA was <= 2.1 mm2 with an 86.7% sensitivity, a 50.4% specificity, a 38.6% positive predictive value, and a 91.3% negative predictive value versus lesions with a positive SPECT (area under the curve: 0.690, 95% CI: 0.615 to 0.759, p < 0.01). CONCLUSIONS: The best cutoff value of MLA measured by IVUS to predict myocardial ischemia was 2.1 mm2. The IVUS-measured MLA appeared to play a limited role in detecting functionally significant lesions assessed by myocardial SPECT. PMID- 21700254 TI - Comparison of titanium-nitride-oxide-coated stents with zotarolimus-eluting stents for coronary revascularization a randomized controlled trial. AB - OBJECTIVES: This study sought to compare the efficacy of passive stent coating with titanium-nitride-oxide (TiNO) with drug-eluting stents releasing zotarolimus (ZES) (Endeavor, Medtronic, Minneapolis, Minnesota). BACKGROUND: Stent coating with TiNO has been shown to reduce restenosis compared with bare-metal stents in experimental and clinical studies. METHODS: In an assessor-blind noninferiority study, 302 patients undergoing percutaneous coronary intervention were randomized to treatment with TiNO or ZES. The primary endpoint was in-stent late loss at 6 to 8 months, and analysis was by intention to treat. RESULTS: Both groups were well balanced with respect to baseline clinical and angiographic characteristics. The TiNO group failed to reach the pre-specified noninferiority margin for the primary endpoint (in-stent late loss: 0.64 +/- 0.61 mm vs. 0.47 +/- 0.48 mm, difference: 0.16, upper 1-sided 95% confidence interval [CI]: 0.26; p(noninferiority) = 0.54), and subsequent superiority testing was in favor of ZES (p(superiority) = 0.02). In-segment binary restenosis was lower with ZES (11.1%) than with TiNO (20.5%; p(superiority) = 0.04). A stratified analysis of the primary endpoint found particularly pronounced differences between stents among diabetic versus nondiabetic patients (0.90 +/- 0.69 mm vs. 0.39 +/- 0.38 mm; p(interaction) = 0.04). Clinical outcomes showed a similar rate of death (0.7% vs. 0.7%; p = 1.00), myocardial infarction (5.3% vs. 6.7%; p = 0.60), and major adverse cardiac events (21.1% vs. 18.0%, hazard ratio: 1.19, 95% CI: 0.71 to 2.00; p = 0.50) at 1 year. There were no differences in rates of definite or probable stent thrombosis (0.7% vs. 0%; p = 0.51) at 1 year. CONCLUSIONS: Compared with TiNO, ZES was superior with regard to late loss and binary restenosis. The concept of passive stent coating with TiNO remains inferior to drug-eluting stent technology in reducing restenosis. ([TIDE] Randomized Trial Comparing Titan Stent With Zotarolimus-Eluting Stent: NCT00492908). PMID- 21700255 TI - Evaluation of culprit saphenous vein graft lesions with optical coherence tomography in patients with acute coronary syndromes. AB - OBJECTIVES: This study sought to assess, with optical coherence tomography (OCT), presumably culprit atherosclerotic lesions of saphenous vein grafts (SVGs) in patients with acute coronary syndromes (ACS). BACKGROUND: Atherosclerotic lesions of SVGs have been studied in vivo with angioscopy and intravascular ultrasound. However, imaging with OCT, which has a higher resolution than intravascular ultrasound and better penetration than angioscopy, has not been conducted systematically. METHODS: Using a nonocclusive OCT technique, we performed angiography and OCT of culprit SVG lesions in patients with unstable angina (UA), ST-segment elevation myocardial infarction (STEMI), and non-STEMI. Fibrous and fatty tissue, calcification, thrombus, and plaque rupture were defined according to OCT objective criteria. RESULTS: Twenty-eight SVGs (average age 14.6 years) in 26 patients were imaged. Lesions on angiography were complex (96.4%), with ulceration in 32.1% and thrombus in 21.4%. OCT disclosed a fibrofatty composition in all lesions, calcification in 32.1%, plaque rupture in 60.7%, and thrombus in 46.4%. Thrombus was progressively more frequent across groups (UA to STEMI, p = 0.003; UA vs. myocardial infarction, p = 0.006). A thin fibrous cap was marginally more frequent in myocardial infarction patients (UA vs. myocardial infarction, p = 0.06; STEMI 100% vs. non-STEMI 53.3% vs. UA 20%, p = 0.03). OCT features of friability were present in 67.9% of SVGs not correlating with clinical presentation. CONCLUSIONS: OCT of culprit lesions of old SVGs in patients with ACS demonstrates fibrofatty composition, relatively thin fibrous cap, plaque rupture, and thrombus, which correlate with the clinical spectrum of ACS. This suggests that similar mechanisms with native vessels' atherosclerosis may be involved in SVG-related ACS. PMID- 21700256 TI - Safety of contemporary percutaneous peripheral arterial interventions in the elderly insights from the BMC2 PVI (Blue Cross Blue Shield of Michigan Cardiovascular Consortium Peripheral Vascular Intervention) registry. AB - OBJECTIVES: This study sought to evaluate the effect of age on procedure type, periprocedural management, and in-hospital outcomes of patients undergoing lower extremity (LE) peripheral vascular intervention (PVI). BACKGROUND: Surgical therapy of peripheral arterial disease is associated with significant morbidity and mortality in the elderly. There are limited data related to the influence of advanced age on the outcome of patients undergoing percutaneous LE PVI. METHODS: Clinical presentation, comorbidities, and in-hospital outcomes of patients undergoing LE PVI in a multicenter, multidisciplinary registry were compared between 3 age groups: < 70 years, between 70 and 80 years, and >= 80 years (elderly group). RESULTS: In our cohort, 7,769 patients underwent LE PVI. The elderly patients were more likely to be female and to have a greater burden of comorbidities. Procedural success was lower in the elderly group (74.2% for age >= 80 years vs. 78% for age 70 to < 80 years and 81.4% in patients age < 70 years, respectively; p < 0.0001). Unadjusted rates of procedure-related vascular access complications, post-procedure transfusion, contrast-induced nephropathy, amputation, and major adverse cardiac events were higher in elderly patients. After adjustment for baseline covariates, the elderly patients were more likely to experience vascular access complications; however, advanced age was not found to be associated with major adverse cardiac events, transfusion, contrast-induced nephropathy, or amputation. CONCLUSIONS: Contemporary PVI can be performed in elderly patients with high procedural and technical success with low rates of periprocedural complications including mortality. These findings may support the notion of using PVI as a preferred revascularization strategy in the treatment of severe peripheral arterial disease in the elderly population. PMID- 21700257 TI - A "win-win" for peripheral vascular intervention. PMID- 21700258 TI - Variability of left ventricular outflow tract gradient during cardiac catheterization in patients with hypertrophic cardiomyopathy. AB - OBJECTIVES: This study characterizes left ventricular outflow tract (LVOT) gradient variability in patients with hypertrophic cardiomyopathy (HCM) during cardiac catheterization. BACKGROUND: Management of HCM is directed by the presence and magnitude of LVOT obstruction. The magnitude and clinical impact of spontaneous variability during a single cardiac catheterization has not been described. METHODS: Fifty symptomatic patients with HCM (mean age 55 +/- 15 years; 48% men) underwent cardiac catheterization with high-fidelity, micromanometer-tip catheters and transseptal measurement of left ventricular pressures. Obstruction was defined as resting LVOT gradient >= 30 mm Hg and severe obstruction as >= 50 mm Hg. Variability in LVOT gradient was calculated as the difference of the largest and smallest LVOT gradients in the absence of provocative maneuvers or interventions. RESULTS: The largest LVOT gradient was 54.6 +/- 56.4 mm Hg. The spontaneous variability in LVOT gradient was 49.0 +/- 53.1 mm Hg (range 0 to 210.8 mm Hg, median 15 mm Hg). Discrepant classification of resting LVOT gradient severity was possible in 25 patients (50%). Twenty patients (40%) with severe obstruction could have been misclassified with regard to obstruction severity. CONCLUSIONS: In patients with HCM, the LVOT gradient fluctuates significantly during a single hemodynamic assessment. Spontaneous variability could lead to misclassification of obstruction severity in one-half of studied patients. The dynamic nature of LVOT obstruction must be considered when assessing resting hemodynamics or the success of a given intervention during cardiac catheterization. PMID- 21700259 TI - Left-to-Right Interventricular Shunt as a Late Complication of Transapical Aortic Valve Implantation. PMID- 21700261 TI - Paclitaxel-eluting balloons for sirolimus-eluting stent restenosis. PMID- 21700260 TI - Percutaneous intervention of an acute left main coronary occlusion due to dissection of the aortic root. PMID- 21700263 TI - Harmonizing for health. PMID- 21700264 TI - [Role of genomic medicine in middle and inner ear diseases]. AB - INTRODUCTION AND OBJECTIVES: Genomic medicine investigates groups of genetic markers that determine susceptibility for complex diseases. The aim of this review was to introduce genomics to the clinical otorhinolaryngologist. Technological advances in genotyping and sequencing that have facilitated genome wide association studies in common causes of hearing loss during the last years are summarised. METHODS: A search strategy in PubMed was designed using the following keywords: (gene OR genomics OR GWAS OR high throughput) AND (hearing loss OR chronic otitis media OR age-related hearing loss OR otosclerosis OR Meniere's disease) during the last 5 years. A total of 1,846 references were obtained. After filtering by human studies and English as the language of publication, 1,295 summaries were evaluated, selecting 58 papers. RESULTS: The impact of sequencing the human genome in the knowledge of genome architecture, DNA variability and the significance of structural variations in the sequence to cause diseases is presented. The evolution of sequencing technology has determined the design and performance of genetic association studies. Finally, we present genetic association studies performed in common causes of ear diseases. PMID- 21700265 TI - Complement receptor 1 gene variants are associated with erythrocyte sedimentation rate. AB - The erythrocyte sedimentation rate (ESR), a commonly performed test of the acute phase response, is the rate at which erythrocytes sediment in vitro in 1 hr. The molecular basis of erythrocyte sedimentation is unknown. To identify genetic variants associated with ESR, we carried out a genome-wide association study of 7607 patients in the Electronic Medical Records and Genomics (eMERGE) network. The discovery cohort consisted of 1979 individuals from the Mayo Clinic, and the replication cohort consisted of 5628 individuals from the remaining four eMERGE sites. A nonsynonymous SNP, rs6691117 (Val->IIe), in the complement receptor 1 gene (CR1) was associated with ESR (discovery cohort p = 7 * 10(-12), replication cohort p = 3 * 10(-14), combined cohort p = 9 * 10(-24)). We imputed 61 SNPs in CR1, and a "possibly damaging" SNP (rs2274567, His->Arg) in linkage disequilibrium (r(2) = 0.74) with rs6691117 was also associated with ESR (discovery p = 5 * 10(-11), replication p = 7 * 10(-17), and combined cohort p = 2 * 10(-25)). The two nonsynonymous SNPs in CR1 are near the C3b/C4b binding site, suggesting a possible mechanism by which the variants may influence ESR. In conclusion, genetic variation in CR1, which encodes a protein that clears complement-tagged inflammatory particles from the circulation, influences interindividual variation in ESR, highlighting an association between the innate immunity pathway and erythrocyte interactions. PMID- 21700267 TI - Depression, stress, and heart disease in earthquakes and Takotsubo cardiomyopathy. AB - The preponderance of evidence links depressive disorder and coronary heart disease (CHD). Despite this evidence, multiple clinical trials have failed to show that effective treatment of depression favorably modifies the development, clinical course, or outcome of comorbid CHD. Possible reasons for these failures include the heterogeneity of depression, limitations of assessment instruments, limited understanding of the biology of depressive disorders, lack of biological markers, and the observation that depression may be more a product of CHD than a true risk factor for it. In this commentary, to better address the effects of externally provoked stress on physical health, we examine evidence about 2 specific examples of stress and subsequent heart disease: earthquake-induced adverse cardiac events among individuals with coronary artery disease, and stress induced Takotsubo cardiomyopathy. In the former case, existing studies suggest that the stress and distress of earthquakes accelerate the development of poor cardiac outcomes for individuals with established coronary artery disease. In the latter example, existing case studies indicate that the profound left ventricular dysfunction of Takotsubo cardiomyopathy tends to quickly normalize once the acute stress is relieved. Together, these examples indicate that the presence or absence of prestress medical illness and its severity may better determine the outcome of the medical illness than the nature and severity of the stress, including depression. That is, any effort to look at depression among individuals with medical illness must look carefully at the medical illness itself and consider depression a possible nonspecific stress. In patients with comorbid depression and CHD, we propose using the more firmly established CHD outcome measurements to better understand how depression or other stressors and their associated treatments influence the prognosis and outcome of this medical illness. PMID- 21700266 TI - Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency. AB - We have identified two families with a previously undescribed lethal X-linked disorder of infancy; the disorder comprises a distinct combination of an aged appearance, craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, and cardiac arrhythmias. Using X chromosome exon sequencing and a recently developed probabilistic algorithm aimed at discovering disease-causing variants, we identified in one family a c.109T>C (p.Ser37Pro) variant in NAA10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase (NAT). A parallel effort on a second unrelated family converged on the same variant. The absence of this variant in controls, the amino acid conservation of this region of the protein, the predicted disruptive change, and the co-occurrence in two unrelated families with the same rare disorder suggest that this is the pathogenic mutation. We confirmed this by demonstrating a significantly impaired biochemical activity of the mutant hNaa10p, and from this we conclude that a reduction in acetylation by hNaa10p causes this disease. Here we provide evidence of a human genetic disorder resulting from direct impairment of N-terminal acetylation, one of the most common protein modifications in humans. PMID- 21700268 TI - Placental expression of endothelial and inducible nitric oxide synthase and nitric oxide levels in patients with HELLP syndrome. AB - OBJECTIVE: To determine placental gene expression of endothelial and inducible nitric oxide synthases and measure nitric oxide levels in patients with hemolysis, elevated liver enzyme levels, and low platelet count syndrome. STUDY DESIGN: Preterm placentas were obtained from 15 patients with hemolysis, elevated liver enzyme levels, and low platelet count syndrome and 30 controls matched for age, parity, and gestational age. mRNA levels were evaluated by real-time polymerase chain reaction, whereas nitric oxide and peroxynitrite production was measured by a commercially available kit. RESULTS: Placental gene expression of inducible nitric oxide and endothelial nitric oxide synthases were significantly lower in the hemolysis, elevated liver enzyme levels, and low platelet count syndrome group than in controls, whereas nitric oxide and peroxynitrite production were significantly higher in hemolysis, elevated liver enzyme levels, and low platelet count syndrome compared with controls. CONCLUSION: The reduced endothelial nitric oxide and inducible nitric oxide synthases gene expression in women with hemolysis, elevated liver enzyme levels, and low platelet count syndrome may indicate extreme placental dysfunction that is unable to compensate the endothelial derangement and the related hypertension. The higher nitric oxide formation found in hemolysis, elevated liver enzyme levels, and low platelet count syndrome placentas could be explained as a counteraction to the impaired fetoplacental perfusion, typical of the syndrome. PMID- 21700269 TI - Effect of PGE2 induced by compressive and tensile stresses on cementoblast differentiation in vitro. AB - OBJECTIVE: The aim of the study was to clarify the mechanisms underlying orthodontically induced root resorption by characterizing the role of PGE(2) induced by compressive stress (CS) and tensile stress (TS) on cementoblast metabolism in vitro. DESIGN: Mouse cementoblast cell line OCCM-30 was continuously stimulated with 0.2 KPa CS or 5.0 KPa TS. COX-2 mRNA expression and PGE(2) production were thus quantified. In addition, cells were treated with COX 2 inhibitor and the role of PGE(2) induced by CS or TS on the expression of genes related to cementoblast differentiation was examined. PGE(2) receptors mRNA expression induced by CS or TS was also evaluated. Moreover, cells were treated with exogenous PGE(2) and the role of PGE(2) concentration on matrix mineralization was verified. RESULTS: CS and TS enhanced COX-2 mRNA expression and PGE(2) production. PGE(2) synthesis, however, was markedly induced by CS. Gene expression of bone morphogenetic protein 2 (BMP-2), osteocalcin (OCN) and receptor activator for nuclear factor kappaB ligand (RANKL) was enhanced by CS on an endogenous PGE(2)-mediated manner. Osteoprotegerin (OPG) expression was not affected by CS. Meanwhile, TS up-regulated the expression of BMP-2 and alkaline phosphatase (ALP) on an endogenous PGE(2)-mediated manner. TS down-regulated RANKL mRNA expression, whilst OPG expression was not affected. Moreover, EP4 mRNA expression was considerably enhanced by TS. Regarding PGE(2) concentration, only cells treated with low concentration presented anabolic response. CONCLUSIONS: Gene expression was differentially regulated according to the type of mechanical stimulation applied to cementoblasts. In addition, it is shown that PGE(2) plays an important role on mediating cementoblast mechanosensitivity. PMID- 21700270 TI - AT1 receptor blockade in the lateral parabrachial nucleus reduces the effects of muscimol on sodium intake. AB - The blockade of the lateral parabrachial nucleus (LPBN) with GABA(A) receptor agonist muscimol induces robust hypertonic NaCl and water intake by rats. In the present study we investigated the effects of previous injections of losartan (AT(1) angiotensin receptor antagonist) into the LPBN on 0.3M NaCl and water intake induced by muscimol injected bilaterally in the same area in fluid replete rats and in rats treated with the diuretic furosemide combined with a low dose of the angiotensin-converting enzyme inhibitor captopril injected subcutaneously. Male Wistar rats with stainless steel cannulas implanted bilaterally into the LPBN were used. Bilateral injections of muscimol (0.5 nmol/0.2 MUl, n=8) into the LPBN in fluid replete rats induced 0.3M NaCl intake (23.4+/-4.1 vs. saline: 0.4+/ 0.4 ml/3h) and water intake (9.3+/-1.9 vs. saline: 0.7+/-0.4 ml/3h) and pre treatment of the LPBN with losartan (50 MUg/0.2 MUl) reduced 0.3M NaCl intake (3.3+/-2.5 ml/3h) and water intake (4.0+/-2.9 ml/3h) induced by muscimol. In rats treated with furosemide+captopril, pre-treatment with losartan into the LPBN attenuated the increase of 0.3M NaCl intake produced by muscimol (12.8+/-5.3, vs. saline+muscimol: 36.7+/-6.7 ml/3h) without changing water intake. Therefore, the results suggest that deactivation of LPBN inhibitory mechanisms by muscimol injections into the LPBN is facilitated by endogenous angiotensin II acting on AT(1) receptors in the LPBN, which drives rats to ingest large amounts of hypertonic NaCl. PMID- 21700271 TI - Characteristics of deacetylation and depolymerization of beta-chitin from jumbo squid (Dosidicus gigas) pens. AB - This study evaluated the deacetylation characteristics of beta-chitin from jumbo squid (Dosidicus gigas) pens by using strongly alkaline solutions of NaOH or KOH. Taguchi design was employed to investigate the effect of reagent concentration, temperature, time, and treatment step on molecular mass (MM) and degree of deacetylation (DDA) of the chitosan obtained. The optimal treatment conditions for achieving high MM and DDA of chitosan were identified as: 40% NaOH at 90 degrees C for 6h with three separate steps (2h+2h+2h) or 50% NaOH at 90 degrees C for 6h with one step, or 50% KOH at 90 degrees C for 4h with three steps (1h+1h+2h) or 6h with one step. The most important factor affecting DDA and MM was temperature and time, respectively. The chitosan obtained was then further depolymerized by cellulase or lysozyme with cellulase giving a higher degradation ratio, lower relative viscosity, and a larger amount of reducing-end formations than that of lysozyme due to its higher susceptibility. This study demonstrated that jumbo squid pens are a good source of materials to produce beta-chitosan with high DDA and a wide range of MM for various potential applications. PMID- 21700272 TI - Polymer-mediated cyclodehydration of alditols and ketohexoses. AB - The polymer PEDOT(+) (1 or 2) mediates a cyclodehydration reaction with alditols 3, 5, 7, 9, in hydrocarbon solvents, to give cyclic ethers 4, 6, 8, or 10, respectively, in high yield with a trivial isolation protocol. Polymers 1 or 2 also mediate the cyclodehydration of ketohexoses such as d-fructose, but not aldohexoses, to the important industrial intermediate 5-hydroxymethylfurfural (17), under milder conditions when compared to reactions mediated by mineral acids. A cascade reaction with ketohexoses is observed in toluene via cyclodehydration followed by Friedel-Crafts alkylation of the initially formed benzylic alcohol to give 16. PMID- 21700273 TI - Synthesis of mimetic peptides containing glucosamine. AB - A convenient synthesis of 2-amino-3,4,6-tri-O-benzyl-2-deoxy-beta-d glucopyranoside was described from the readily available starting material 2 acetamido-2-deoxy-d-glucose (N-acetyl-d-glucosamine). Herein, the coupling of different lipophilic amino acids with 2-amino-3,4,6-tri-O-benzyl-2-deoxy-beta-d glucose was reported via an amide linkage as useful building blocks for the synthesis of glycopeptides. Of particular interest, bioactive peptide Arg-Gly-Asp (RGD) was incorporated into the building block containing valine was also reported. The 15 examples of corresponding di-, tri- and tetra-peptides were obtained as single alphaanomers. PMID- 21700274 TI - A homogalacturonan from the radix of Platycodon grandiflorum and the anti angiogenesis activity of poly-/oligogalacturonic acids derived therefrom. AB - A polysaccharide, PGA4-3b, with an average molecular weight of 8.9kDa estimated by high-performance gel-permeation chromatography (HPGPC), was isolated from radix of Platycodon grandiflorum (Jacq.) A. DC. Using monosaccharide analysis, methylation analysis and NMR spectroscopy, PGA4-3b was elucidated to be a linear poly-(1->4)-alpha-d-galactopyranosyluronic acid that contains no methyl ester groups. Partial acid hydrolysis of PGA4-3b yielded a series of poly- or oligogalacturonic acids with different degrees of polymerization (DP), that is, 4 3bde, 4-3bde-O-1, 4-3bde-O-2, 4-3bde-O-3, and 4-3bde-O-4. Cell tube formation inhibition tests with human microvascular endothelial cells (HMEC) for antiangiogenesis analysis showed that 4-3bde-O-1 and 4-3bde-O-2, the fractions with higher molecular weights, could inhibit tube formation, while the native PGA4-3b and low molecular weight fraction 4-3bde-O-3 and 4-3bde-O4 are ineffective. Moreover, 4-3bde-O-2 with DP 5-10 impaired cell tube formation in a dose-dependent way, suggesting its potential to be developed as an anti angiogenesis drug. This is the first time oligogalacturonic acids are reported to show an anti-angiogenesis effect. PMID- 21700275 TI - The source of human mesenchymal stromal cells influences their TLR profile as well as their functional properties. AB - Mesenchymal stromal cells (MSC) can be expanded from different sources. We compared the influence of inflammation and TLR ligation on the phenotype and function of MSC derived from bone marrow (BM), adipose tissue (AT), and Wharton's jelly (WJ). WJ-MSC were featured by a lack of TLR4 expression. While inflammation upregulated TLR3 in all three MSC types, TLR4 upregulation was observed only on BM-MSC. TLR ligation increased the production of inflammatory cytokines in BM- and AT-MSC but not in WJ-MSC and augmented anti-inflammatory cytokines in AT-MSC. Although inflammation increased in all MSC types the secretion of inflammatory cytokines, additional TLR triggering did not have further effect on WJ-MSC. The immunosuppressive potential of WJ-MSC on MLR was affected neither by inflammation nor by TLR triggering. This resistance was related to an overproduction of HGF. These data indicate that MSC source could be of importance while designing immunomodulating cell therapy in transplantation. PMID- 21700277 TI - Assessing risk of mercury exposure and nutritional benefits of consumption of caribou (Rangifer tarandus) in the Vuntut Gwitchin First Nation community of Old Crow, Yukon, Canada. AB - The contamination of traditional foods with chemical pollutants is a challenge to the food security of Aboriginal Peoples. Mercury levels are generally low in terrestrial animals; however renal mercury levels have been shown to change over time in the Porcupine Caribou Herd, the principal food source for the Vuntut Gwitchin First Nation of Old Crow in Yukon, Canada. Seventy-five Porcupine Caribou muscle, sixty-three kidney and three liver samples were analyzed for total mercury. Average concentrations were 0.003, 0.360 and 0.120mg/kg wet weight total mercury for muscle, kidney and liver, respectively. Consumption data of caribou muscle, kidney and liver were collected from twenty-six adults in Vuntut Gwitchin households. Women of child-bearing age (n=5) consumed a median of 71.5g/person/day of caribou muscle and 0.0g/person/day kidney but consumed no liver; median consumptions for all other adults (women aged 40+ and all men, n=21) were 75.8, 3.2 and 2.5g/person/day for meat, kidney and liver, respectively. Median dietary exposures to total mercury from caribou tissues were estimated to be 0.138MUg/kg body weight for women of child-bearing age and 0.223MUg/kg body weight for other adults. Caribou tissues were found to contribute high levels of important nutrients to the diet and pose minimal health risk from mercury exposure. PMID- 21700276 TI - Childhood attention deficit hyperactivity disorder features in adult mood disorders. AB - A significant overlap between childhood mood disorders and many aspects of attention deficit hyperactivity disorder (ADHD) has been established. High rates of co-occurrence, familial aggregation, and more severe clinical manifestations of the illnesses when they are comorbid suggest that common genetic and environmental factors may contribute to the development of both disorders. Research on the co-occurrence of childhood ADHD and mood disorders in childhood has been conducted. We retrospectively investigated childhood ADHD features in adults with mood disorders. Childhood ADHD features were measured with the Korean version of the Wender Utah Rating Scale (WURS). The sample consisted of 1305 subjects: 108 subjects were diagnosed with bipolar disorder type I, 41 with bipolar disorder type II, 101 with major depressive disorder, and 1055 served as normal controls. We compared total WURS scores as well as scores on 3 factors (impulsivity, inattention, and mood instability and anxiety) among the 4 different diagnostic groups. The 4 groups differed significantly from one another on all scores. The group with bipolar disorder type II obtained the highest total scores on the WURS. The impulsivity and inattention associated with childhood ADHD were more significantly related to bipolar disorder type II than with bipolar disorder type I. The mood instability and anxiety associated with childhood ADHD seem to be significantly related to major depressive disorder in adulthood. In conclusion, multifactorial childhood ADHD features were associated with mood disorders of adulthood. PMID- 21700278 TI - [Hyper-IgE recurrent infection syndrome: pathogenesis, diagnosis and therapeutic management]. AB - Hyper-IgE recurrent infection syndrome is an uncommon primary immunodeficiency characterized by high serum levels of total IgE, eczema-like dermatitis, recurrent skin abscesses and staphylococci pneumonias, which can produce abscesses with mild inflammatory signs. It also causes dental, musculoskeletal and connective tissue abnormalities. The classical (type 1) variation is caused by autosomal-dominant mutations in signal transducer and activator of transcription 3. An incomplete form (type 2) has been described with only the immunological manifestations, but without the mesenchymal manifestations, has been described. This incomplete form is caused by recessive mutations in the tyrosine kinase 2 gene. Both kinds of mutations produce deficient formation of Th17-cells. These advances in the genetic and immunologic knowledge of hyper-IgE recurrent infection syndrome have allowed a better clinical comprehension of the clinical phenomena of the disease. PMID- 21700279 TI - New treatment option for early spontaneous rupture of a postmyomectomy gravid uterus. AB - OBJECTIVE: To report the successful treatment of a postmyomectomy, early uterine rupture with the use of a Bakri balloon. DESIGN: Case report. SETTING: University hospital, department of obstetrics and gynecology. PATIENT(S): A 32-year-old patient, gravida 1, at 19 weeks' gestation, with postmyomectomy spontaneous uterine rupture and concurrent uterine atony. INTERVENTION(S): Laparotomy was done because of massive hemoperitoneum. A Bakri balloon was inserted, and a two layer suture of the uterine defect was performed. MAIN OUTCOME MEASURE(S): Possibility of controlling hemorrhage and avoiding hysterectomy. RESULT(S): Contemporary surgical sutures and insertion of a Bakri balloon were effective at controlling hemorrhage. The uterus was preserved. CONCLUSION(S): The use of a Bakri balloon, combined with traditional surgical techniques, is described as a new method to successfully treat hemorrhage in the case of early spontaneous uterine rupture. In this case, hysterectomy was also avoided. PMID- 21700281 TI - Diagnostic value of progesterone level and progesterone/estradiol ratio on the day of human chorionic gonadotropin administration. PMID- 21700282 TI - A simple way to determine appropriate implant size when fixing fractures. PMID- 21700284 TI - What should be the characteristics of the ideal bone graft substitute? PMID- 21700285 TI - Re: letter to the editor, injury of 15/02/2011. PMID- 21700286 TI - Emergency obstetric surgery by non-physician clinicians in Tanzania. AB - OBJECTIVE: To calculate the met need for comprehensive emergency obstetric care (CEmOC) in 2 Tanzanian regions (Mwanza and Kigoma) and to document the contribution of non-physician clinicians (assistant medical officers [AMOs]) and medical officers (MOs) with regard to meeting the need for CEmOC. METHODS: All hospitals in the 2 regions were visited to determine the proportion of major obstetric interventions performed by AMOs and MOs. All deliveries (n = 38 758) in these hospitals in 2003 were reviewed. The estimated met need for emergency obstetric care (EmOC) was calculated using UN process indicators, as was the contribution to that attainment by AMOs. Hospital case fatality rates were also determined. RESULTS: Estimated met need was 35% in Mwanza and 23% in Kigoma. AMOs operating independently performed most major obstetric surgery. Outside of the single university hospital, AMOs performed 85% of cesareans and high proportions of other obstetric surgeries. The case fatality rate was 2.0% in Mwanza and 1.2% in Kigoma. CONCLUSION: AMOs carried most of the burden of life-saving EmOC particularly cesarean deliveries-in the regions investigated. Case fatality was close to the 1% target set by the UN process indicators, but met need was far below the goal of 100%. PMID- 21700288 TI - A structurally optimal control model for predicting and analyzing human postural coordination. AB - This paper proposes a closed-loop optimal control model predicting changes between in-phase and anti-phase postural coordination during standing and related supra-postural activities. The model allows the evaluation of the influence of body dynamics and balance constraints onto the adoption of postural coordination. This model minimizes the instantaneous norm of the joint torques with a controller in the head space, in contrast with classical linear optimal models used in the postural literature and defined in joint space. The balance constraint is addressed with an adaptive ankle torque saturation. Numerical simulations showed that the model was able to predict changes between in-phase and anti-phase postural coordination modes and other non-linear transient dynamics phenomena. PMID- 21700287 TI - Contractile and non-contractile tissue volume and distribution in ankle muscles of young and older adults. AB - Magnetic resonance imaging (MRI) enables accurate in vivo quantification of human muscle volumes, which can be used to estimate subject-specific muscle force capabilities. An important consideration is the amount of contractile and non contractile tissue in the muscle compartment, which will influence force capability. We quantified age-related differences in the proportion and distribution of contractile and non-contractile tissue in the dorsiflexor and plantar flexor (soleus, and medial and lateral heads of gastrocnemius) muscles, and examined how well these volumes can be estimated from single MRI cross sections. Axial MRIs of the left leg for 12 young (mean age 27 years) and 12 older (72 years) healthy, active adults were used to compute muscle volumes. Contractile tissue distribution along the leg was characterized by mathematical functions to allow volume prediction from single-slice cross-sectional area (CSA) measurements. Compared to young, older adults had less contractile volume and a greater proportion of non-contractile tissue. In both age groups the proportion of non-contractile tissue increased distally, with the smallest proportion near the maximum compartment CSA. A single CSA measurement predicted contractile volume with 8-11% error, with older adults in the higher end of this range. Using multiple slices improved volume estimates by roughly 50%, with average errors of about 3-4%. These results demonstrate significant age-related differences in non contractile tissue for the dorsi- and plantar-flexor muscles. Although estimates of contractile volume can be obtained from single CSA measurements, multiple slices are needed for increased accuracy due to inter-individual variations in muscle volume and composition. PMID- 21700289 TI - Large eddy simulation of the pharyngeal airflow associated with obstructive sleep apnea syndrome at pre and post-surgical treatment. AB - Obstructive Sleep Apnea Syndrome (OSAS) is the most common sleep-disordered breathing medical condition and a potentially life-threatening affliction. Not all the surgical or non-surgical OSAS therapies are successful for each patient, also in part because the primary factors involved in the etiology of this disorder are not completely understood. Thus, there is a need for improving both diagnostic and treatment modalities associated with OSAS. A verified and validated (in terms of mean velocity and pressure fields) Large Eddy Simulation approach is used to characterize the abnormal pharyngeal airflow associated with severe OSAS and its interaction with the airway wall in a subject who underwent surgical treatment. The analysis of the unsteady flow at pre- and post-treatment is used to illustrate the airflow dynamics in the airway associated with OSAS and to reveal as well, the changes in the flow variables after the treatment. At pre treatment, large airflow velocity and wall shear stress values were found at the obstruction site in all cases. Downstream of obstruction, flow separation generated flow recirculation regions and enhanced the turbulence production in the jet-like shear layers. The interaction between the generated vortical structures and the pharyngeal airway wall induced large fluctuations in the pressure forces acting on the pharyngeal wall. After the surgery, the flow field instabilities vanished and both airway resistance and wall shear stress values were significantly reduced. PMID- 21700290 TI - Isolation and characterization of therapeutic antibody charge variants using cation exchange displacement chromatography. AB - In this report, we have demonstrated the isolation and enrichment of charge variants of a monoclonal antibody IgG1 using cation exchange displacement chromatography. We successfully achieved the separation of acidic, main and basic charge variants with high recovery (>70%) and purity (>90%) by using a commercially available stationary phase in conjunction with a commercially available displacer. In addition, we have isolated and enriched a trace methionine-oxidized variant of the monoclonal antibody allowing a secondary means of identification of this variant while providing sufficient enrichment for further analysis, stability tests and potency determination. Further characterization of the displacement trains by SEC indicate the possibility of enrichment of high and low molecular weight species. Glycan analysis of the displacement fractions indicates minimal variation in glycan distribution patterns among a wide spectrum of charge variants. These results provide a case study demonstrating the utility of cation exchange displacement chromatography as a viable approach to isolate and enrich antibody charge variants for enhanced molecular characterization. PMID- 21700291 TI - Modelling oligomer formation in chromatographic separations. AB - Oligomer forms of proteins are formed by self and cross association or complex formation with ligands. Modelling studies using an ion-exchange adsorbent have demonstrated that the formation of an oligomer form of a target protein can improve a chromatographic separation because the oligomer form displaces the impurities. The results of the investigation show that the process is very robust, that the purity, the yield, and the productivity increase with increasing load and increasing salt concentration in the eluant. An impurity level less than 1 ppm is easy to achieve having a yield of 98%. A universal model for the adsorption equilibria of mono and oligomer forms of proteins on ion-exchange, hydrophobic, and bimodal adsorbents has been developed. PMID- 21700292 TI - Electrophoresis of concentrated colloidal dispersions in low-polar solvents. AB - We present a method to accurately measure the electrophoretic mobility of spherical colloids at high volume fractions in real space using confocal laser scanning microscopy (CLSM) and particle tracking. We show that for polymethylmethacrylate (PMMA) particles in a low-polar, density- and refractive index-matched mixture of cyclohexylbromide and cis-decahydronaphthalene, the electrophoretic mobility decreases nonlinearly with increasing volume fraction. From the electrophoretic mobilities, we calculate the zeta-potential and the particle charge with and without correcting for volume fraction effects. For both cases, we find a decreasing particle charge as a function of volume fraction. This is in accordance with the fact that the charges originate from chemical equilibria that represent so-called weak association and/or dissociation reactions. Finally, as our methodology also provides data on particle self diffusion in the presence of an electric field, we also analyze the diffusion at different volume fractions and identify a nonlinear decreasing trend for increasing volume fraction. PMID- 21700293 TI - Adsorption of pyridine onto the metal organic framework MIL-101. AB - The adsorption of pyridine onto the metal organic framework MIL-101 was investigated by experimental and theoretical methods. The amount of pyridine adsorbed on MIL-101 was extraordinarily large at 20 degrees C, corresponding to about 950 mg/g of dried MIL-101 and approximately half of the voids being filled. Most of the pyridine that had filled the voids was rapidly removed by evacuation at room temperature, but some of the pyridine was so strongly adsorbed that it was retained even under evacuation at 150 degrees C. Although IR spectra of the adsorbed pyridine indicated the adsorption of pyridine as pyridinium ions and coordinated pyridine at low temperatures, increasing the adsorption temperature induced partial cleavage of the pyridine rings. The high stabilization energy of pyridine on the coordinative unsaturated sites (CUS) of MIL-101, obtained by theoretical calculation, -103 kJ/mol, supported the strong adsorption of pyridine on the CUS. PMID- 21700294 TI - Charged polystyrene nanoparticles: role of ionic comonomers structures. AB - Emulsion copolymerizations of styrene were carried out with four structurally different ionic comonomers namely acrylic acid (AAc), methacrylic acid (MAA), 2 hydroxyethyl methacrylate (HEMA), and sodium styrene sulfonate (NaSS) to study the effect of monomer structure on the copolymerization kinetics and size, morphology, charge density, and the self-assembly of the particles. The copolymerization kinetics was found to be highly dependent upon the ionic comonomer structure, and the nature of this dependence altered from homogeneous to micellar nucleation regime. The decrease in particle size (D) with increasing surfactant concentration (S) was observed in all the cases; however, the exponents of D vs. S were not similar for all the cases. In the homogeneous nucleation regime, exponents followed the order as AAc (0.446) > MAA (0.396) > NaSS (0.252) > HEMA (0.241), whereas the order was almost reversed in the micellar nucleation regime as NaSS (0.406) > HEMA (0.228) > AAc (0.206) > MAA (0.172). The hydrophobic/hydrophilic character and the steric factors were found to be the driving force for the variation in D vs. S exponents with ionic comonomer structure. The presence of charges on the particle surface contributed by the ionic comonomers triggered the self-assembly of the particles upon sedimentation and diffracted visible light obeying Bragg's law. PMID- 21700295 TI - Association of plasma IL-6 and soluble IL-6 receptor levels with the Asp358Ala polymorphism of the IL-6 receptor gene in schizophrenic patients. AB - Recent studies indicate a role of excessive interleukin-6 (IL-6) signaling in the pathogenesis of schizophrenia. A previous study reported a significant association of schizophrenia with the IL-6 receptor (IL-6R) gene Asp358Ala polymorphism, which is known to regulate circulating IL-6 and soluble IL-6R (sIL 6R) levels in healthy subjects. To further examine the influence of the polymorphism in schizophrenic patients, we compared the plasma levels of IL-6 and sIL-6R between schizophrenic patients and healthy controls for each genotype of the Asp358Ala polymorphism. Asp358Ala genotyping and plasma IL-6 level measurements were performed in 104 patients with schizophrenia and 112 healthy controls. Of these participants, 53 schizophrenic patients and 49 controls were selected for the measurement of plasma sIL-6R levels. A two-way factorial analysis of covariance was performed with the transformed plasma levels as the dependent variable, diagnosis and genotype as independent variables, and sex and age as covariates. No significant diagnosis * genotype interaction was observed for IL-6 and sIL-6R levels. The Ala allele of Asp358Ala was significantly associated with higher levels of both IL-6 and sIL-6R. IL-6 levels were significantly elevated in schizophrenic patients compared to those in controls, whereas no significant difference in sIL-6R levels was observed between schizophrenic patients and controls. Our findings suggest that the presence of schizophrenia is associated with elevated IL-6 levels, whereas sIL-6R levels are mainly predetermined by the Asp358Ala genotype and are not associated with the disease status. Increased IL-6 levels without alterations in sIL-6R levels may result in excessive IL-6 signaling in schizophrenia. PMID- 21700296 TI - Radiotherapy for node positive penile cancer: experience of the Leeds teaching hospitals. AB - PURPOSE: We studied the outcomes in patients with node positive penile cancer who received radiotherapy to inguinal and pelvic nodes. Although half of node positive cases are cured by lymphadenectomy, little data are available on the potential further benefits and toxicities of postoperative radiotherapy. MATERIALS AND METHODS: We retrospectively audited the clinical notes and electronic records of 23 patients referred to a specialist center from 2002 to 2008 who received radiotherapy to the inguinal/pelvic nodes as adjuvant treatment after lymphadenectomy (14), or as high grade palliation for extensive/fixed nodes (8) or extensive local tumor (1). The primary outcome measure was overall survival. Secondary end points were locoregional recurrence-free survival and toxicity. RESULTS: All 13 deaths were due to penile cancer. Patients with adjuvant therapy had better overall survival (66% vs 11%, p<0.001) and locoregional relapse-free survival (56% vs 22%, p=0.03) than those with high grade palliation. Six of 14 adjuvant cases and 7 of 9 with high grade palliation relapsed locoregionally. Of patients with adjuvant therapy and extracapsular spread 1 of 6 with N1, 1 of 4 with N2 and 3 of 4 with N3 disease relapsed (p=0.31). No life threatening toxicity was observed. It was difficult to determine the relative contributions of radiotherapy and surgery to leg/scrotal lymphedema. The study was limited by its small size, which reflects the rarity of this tumor. CONCLUSIONS: Adjuvant radiotherapy appears to have a role after inguinal lymphadenectomy, particularly in patients with extracapsular nodal spread, in whom historically survival rates have been poor. Our findings warrant further investigation in larger series of patients. PMID- 21700297 TI - Editorial comment. PMID- 21700298 TI - Small plastic debris changes water movement and heat transfer through beach sediments. AB - We investigated the physical properties of beaches contaminated with plastic fragments. We compared sediment cores from Hawai'i Island's Kamilo Beach, notable for plastic accumulation, to cores from a nearby beach. Compared to the nearby beach, Kamilo sediments contained more plastics (up to 30.2% by weight), were coarser-grained, and were more permeable (t-test, p<0.0001). 85% of the fragments were polyethylene, and 95% were concentrated in the top 15 cm of the cores. We constructed artificial cores of standardized grain size and varying plastic-to sediment ratios. Adding plastic significantly increased the permeability (ANOVA, p=0.002), which was partially attributed to the fragments increasing the mean grain size. Sediments with plastic warmed more slowly (16% maximum decrease in thermal diffusivity), and reached lower maximum temperatures (21% maximum increase in heat capacity). These changes have a variety of potential effects on beach organisms, including those with temperature-dependent sex-determination such as sea turtle eggs. PMID- 21700299 TI - The occurrence of chemical elements and POPs in loggerhead turtles (Caretta caretta): an overview. AB - Chemical elements and persistent organic pollutants (POPs) are globally present in aquatic systems and their potential transfer to loggerhead marine turtles (Caretta caretta) has become a serious threat for their health status. The environmental fate of these xenobiotics may be traced by the analysis of turtles' tissues and blood. Generally, loggerhead turtles exhibited a higher metal load than other turtle species, this could be explained by differences in diet habits being food the main source of exposure. Literature shows that muscle, liver and kidney are most considered for the quantification of chemical elements, while, organic compounds are typically investigated in liver and fat. This paper is an overview of the international studies carried out on the quantification of chemical elements, polychlorinated biphenyls (PCBs), organochlorines (OCs) and perfluorinated compounds (PFCs), in tissues, organs and fluids of C. caretta from the Mediterranean Sea, the Atlantic and the Pacific Oceans. PMID- 21700300 TI - Nutrient inputs from submarine groundwater discharge on the Santiago reef flat, Bolinao, Northwestern Philippines. AB - Submarine groundwater discharge (SGD) on the reef flat of Bolinao, Pangasinan (Philippines) was mapped using electrical resistivity, 222Rn, and nutrient concentration measurements. Nitrate levels as high as 126 MUM, or 1-2 orders of magnitude higher than ambient concentrations, were measured in some areas of the reef flat. Nutrient fluxes were higher during the wet season (May-October) than the dry season (November-April). Dissolved inorganic nitrogen (DIN=NO3+NO2+NH4) and soluble reactive phosphorus (SRP) fluxes during the wet season were 4.4 and 0.2 mmoles m(-2) d(-1), respectively. With the increase population size and anthropogenic activities in Bolinao, an enhancement of SGD-derived nitrogen levels is likely. This could lead to eutrophic conditions in the otherwise oligotrophic waters surrounding the Santiago reef flat. PMID- 21700301 TI - Cardiorespiratory fitness predicts insulin action and secretion in healthy individuals. AB - Long-term cardiorespiratory fitness (CRF) and the development of type 2 diabetes mellitus are inversely correlated. Here, we examined the relationships between peak oxygen uptake (VO(2)peak), on the one hand, and glucose infusion rate at rest (GIR(rest)) and during exercise (GIR(exercise)), as well as insulin secretion (both the early and late phases of response [area under the curve {AUC}(insulin)]), on the other. Eight male and 4 female healthy, lean, nonsmoking volunteers were recruited. The VO(2)peak was measured during graded exercise on a cycle ergometer until exhaustion was reached. The GIR(rest) and GIR(exercise) were determined using a euglycemic-hyperinsulinemic clamp, and insulin secretion at rest was evaluated with an intravenous glucose tolerance test. The VO(2)peak correlated positively to GIR(rest) (r = 0.81, P = .001) and GIR(exercise) (r = 0.87, P < .001) and negatively to AUC(insulin) (r = -0.64, P = .03). The respiratory exchange ratio (RER) during insulin infusion was positively correlated to GIR(rest) (r = 0.83, P < .001) and GIR(exercise) (r = 0.86, P < .01) and negatively correlated to both the early insulin response (r = -0.86, P < .0001) and AUC(insulin) (r = -0.87, P = .001). The VO(2)peak accounted for 45% of the variability in RER (R(2) = 0.45, P = .035). In this healthy population, CRF and RER were highly correlated to insulin sensitivity and secretion, as well as to the ability to alter the substrate being oxidized during exercise. These findings highlight the importance of good CRF to maintaining normal insulin action. PMID- 21700302 TI - Intensive practical lifestyle intervention improves endothelial function in metabolic syndrome independent of weight loss: a randomized controlled trial. AB - The objective was to evaluate the metabolic and vascular effects of lifestyle interventions involving a healthy diet and either a moderate- or a high-intensity exercise regimen in nondiabetic subjects with metabolic syndrome. The effects of these interventions on flow-mediated vasodilation (FMD) and risk profiles were compared with a standard low-fat diet and engaging in daily walking (standard of care). Seventy-five healthy adults with metabolic syndrome (30-55 years old) were randomized to a 10,000-steps-a-day exercise program, a 3-times-a-week fitness (>75% peak VO(2)) program, or a 1-hour-walking-a-day program for 12 weeks. The first 2 interventions were combined with an accessible healthy, no-sugar diet; and the third was combined with a tailored low-fat diet. The outcomes, including FMD and risk factors, were examined at 12 weeks and at 1-year reassessment. Significant increase in FMD (mean difference = 1.51%, 95% confidence interval = 1.05%-3.017%, P = .0007) and decrease in arterial pressure (mean difference = 19.3 +/- 2.3/-12.6 +/- 1.8 mm Hg, P = .0001) were observed in all groups. However, the FMD changed most favorably in the high-intensity, low-sugar group (mean difference = 1.56%, 95% confidence interval = 0.1%-3.02%, P = .036). Significant improvements in body mass index, waist, insulin-like growth factor-1, homeostasis model assessment of insulin resistance, insulin, glucose, urinary albumin excretion, and lipid profiles occurred in all groups. Metabolic syndrome was resolved in 64%. One year later, weight loss (-9.1 +/- 2.3 kg, P = .0001) and arterial pressure decrease (-18.5 +/- 2.3/-12.3 +/- 2.1 mm Hg, P = .0001) were maintained. Practical, health-centered diet combined with high-intensity exercise is associated with enhanced vascular protection. These data suggest that more intense exercise combined with a low-sugar diet modulates endothelium-dependent vasodilation. PMID- 21700303 TI - Lower survival rate, longevity and fecundity of Aedes aegypti (Diptera: Culicidae) females orally challenged with dengue virus serotype 2. AB - As the pathogenic effects of a parasite on its hosts can strongly influence its epidemiology, we compared the life-histories of dengue virus serotype 2 (DENV-2) infected and uninfected Aedes aegypti females. Unexposed mosquitoes lived longer than exposed ones, but those infected lived longer than exposed but negative (as assayed by Real-Time quantitative Reverse Transcription PCR [qRT-PCR]) mosquitoes. Infected mosquitoes from a long-established laboratory colony presented more viral RNA copies at death than those from the F1-generation of a field population from Rio de Janeiro. The mortality of infected colony-mosquitoes was independent of the number of viral RNA copies at death, whereas in the field population, longevity decreased with the number of viral RNA copies, suggesting that F1 of field mosquitoes are less tolerant to infection than the laboratory colony. Infected females had a lower fecundity than controls. F1 of field mosquitoes were more likely to lay eggs than the colony; egg-laying success was strongly affected by mosquito age for both mosquito populations: from 49.28 in the first clutch to 20.7 in the fifth. Overall, DENV-2 reduced Aedes aegypti survival and fecundity, clearly affecting vectorial capacity and consequently transmission intensity. PMID- 21700304 TI - A preliminary investigation of microsatellite-based genotyping in Trichomonas vaginalis. AB - The genetic epidemiology of Trichomonas vaginalis is poorly understood at present. The recent release of the organism's genome sequence opens the way to investigation of polymorphic markers allowing strain identification. We here report a preliminary analysis of microsatellite loci in T. vaginalis and show that this approach holds promise for future studies of infection transmission and organism diversity. PMID- 21700305 TI - Implanted bone marrow-derived mesenchymal stem cells fail to metabolically stabilize or recover electromechanical function in infarcted hearts. AB - Mesenchymal stem cells (MSCs) have been used with success in several clinical applications for clinical treatment of ischemic hearts. However, the reported effects of MSC-based therapy on myocardial infarction (MI) are inconsistent. In particular, the preventive effects of MSC-based therapy on arrhythmic sudden death and metabolic disorders after infarction remain controversial. Here, we investigated the effects of MSCs on reverse remodeling in an infarcted myocardium, and found that MSC-therapy failed to achieve the complete regeneration of infarcted myocardium. Histological analyses showed that although infarct size and interstitial fibrosis induced by MI recovered significantly after MSC treatment, these improvements were marginal, indicating that a significant amount of damaged tissue was still present. Furthermore, transplanted MSCs had slight anti-apoptotic and anti-inflammatory effects in MSC-implanted regions and no significant improvements in cardiac function were observed, suggesting that naive MSCs might not be the right cell type to treat myocardial infarction. Furthermore, small ion profiling using ToF-SIMS revealed that the metabolic stabilization provided by the MSCs implantation was not significant compared to the sham group. Together, these results indicate that pretreatment of MSCs is needed to enhance the benefits of MSCs, particularly when MSCs are used to treat arrhythmogenicity and metabolically stabilize infarcted myocardium. PMID- 21700306 TI - Use of a tandem affinity purification assay to detect interactions between West Nile and dengue viral proteins and proteins of the mosquito vector. AB - West Nile and dengue viruses are (re)emerging mosquito-borne flaviviruses that cause significant morbidity and mortality in man. The identification of mosquito proteins that associate with flaviviruses may provide novel targets to inhibit infection of the vector or block transmission to humans. Here, a tandem affinity purification (TAP) assay was used to identify 18 mosquito proteins that interact with dengue and West Nile capsid, envelope, NS2A or NS2B proteins. We further analyzed the interaction of mosquito cadherin with dengue and West Nile virus envelope protein using co-immunoprecipitation and immunofluorescence. Blocking the function of select mosquito factors, including actin, myosin, PI3-kinase and myosin light chain kinase, reduced both dengue and West Nile virus infection in mosquito cells. We show that the TAP method may be used in insect cells to accurately identify flaviviral-host protein interactions. Our data also provides several targets for interrupting flavivirus infection in mosquito vectors. PMID- 21700308 TI - Soil aquifer treatment of artificial wastewater under saturated conditions. AB - A 2000 mm long saturated laboratory soil column was used to simulate soil aquifer treatment under saturated conditions to assess the removal of chemical and biochemical oxygen demand (COD and BOD), dissolved organic carbon (DOC), nitrogen and phosphate, using high strength artificial wastewater. The removal rates were determined under a combination of constant hydraulic loading rates (HLR) and variable COD concentrations as well as variable HLR under a constant COD. Within the range of COD concentrations considered (42 mg L-1-135 mg L-1) it was found that at fixed hydraulic loading rate, a decrease in the influent concentrations of dissolved organic carbon (DOC), biochemical oxygen demand (BOD), total nitrogen and phosphate improved their removal efficiencies. At the high COD concentrations applied residence times influenced the redox conditions in the soil column. Long residence times were detrimental to the removal process for COD, BOD and DOC as anoxic processes and sulphate reduction played an important role as electron acceptors. It was found that total COD mass loading within the range of 911 mg d-1-1780 mg d-1 applied as low COD wastewater infiltrated coupled with short residence times would provide better effluent quality than the same mass applied as a COD with higher concentration at long residence times. The opposite was true for organic nitrogen where relatively high concentrations coupled with long residence time gave better removal efficiency. PMID- 21700307 TI - The adenovirus E4 11 k protein binds and relocalizes the cytoplasmic P-body component Ddx6 to aggresomes. AB - The adenovirus E4 11 k protein, product of E4 ORF3, is required in infection for processes including normal accumulation of viral late mRNAs. 11 k restructures both the nucleus and cytoplasm of infected cells by relocalizing specific host cell target proteins, most strikingly components of nuclear PML oncogenic domains. It is likely that in many cases relocalization inactivates target proteins to produce 11 k's effects, although the mechanism and targets for stimulation of late mRNA accumulation is unknown. We have identified a new set of proteins relocalized by 11 k: at least five protein components of cytoplasmic mRNA processing bodies (p-bodies) are found in 11 k-induced cytoplasmic aggresomes, sites where proteins are inactivated or destroyed. One of these p body proteins, RNA helicase Ddx6, binds 11 k, suggesting a mechanism for relocalization. Because p-bodies are sites for mRNA degradation, their modification by 11 k may provide an explanation for the role of 11 in viral late mRNA accumulation. PMID- 21700309 TI - Toxic metals in commercial marine fish in Oman with reference to national and international standards. AB - Commercially important fresh (581) and frozen (292) marine fish samples of 10 species were collected from seafood factories and evaluated using AAS and ICP OES. Metal levels significantly (p<0.05) varied within and between species. However, there were no significant correlations among metals. There were significant interspecific differences for all metals, and yellowfin tuna had the highest level of cadmium and mercury however, red seabream had maximum numbers above the standards. The metal accumulation significantly varied between bottom feeders of intermediately size locally caught fish. The mean cadmium level ranged from 0.0049 to 0.036 mg kg(-1) and 1.37% of the total samples exceeded the EU and FAO standards. Mean lead content varied between 0.029 and 0.196 mg kg(-1), few samples crossed the EU (2.63%) and FAO (1.6%) limits. Mean mercury level ranged from 0.015 to 0.101 mg kg(-1) and none of the samples exceeded the EU limit. Of the total samples analyzed red seabream (2.06%), yellowfin tuna (1.14%), emperor (0.34%), santer bream (0.22%), king fish (0.11%) and skipjack tuna (0.11%) samples crossed the EU limits. In general, fish from these regions are within the safety levels recommended by various organizations and do not pose a health risk in terms of human diet. PMID- 21700310 TI - Removal of Rhodamine B under visible irradiation in the presence of Fe0, H2O2, citrate and aeration at circumneutral pH. AB - A new Vis-Fe(0)-H(2)O(2)-citrate-O(2) system comprising zero-valent iron, hydrogen peroxide, citrate anion and aeration at circumneutral pH under visible irradiation was studied. 21 MUmol L(-1) of Rhodamine B (RhB) was chosen as the substrate to be tested. Experiments were conducted under conditions of 2.9 mmol L(-1) of H(2)O(2), 12.6g of Fe(0) and 1.0 mmol L(-1) of citrate at pH 7.5. Results showed that, in 1h reaction, 54% of RhB was removed with corresponding 26% of COD reduced. Meanwhile, the amount of released dissolved irons from Fe(0) surface was found to be at a very low level as <5.4 MUmol L(-1). Extinguishing tests with isopropanol suggested that RhB oxidation by hydroxyl radicals was the main process taken place in Vis-Fe(0)-H(2)O(2)-citrate-O(2) system, which accounted for 75% of substrate removal in 3h reaction. Control and factor influencing experiments showed that the prohibitive extents of individual factor importance on RhB removal followed a decreasing order of Fe(0)>H(2)O(2)>citrate>Vis>O(2). This study showed an excellent system that could remove refractory organic compounds from water in laboratory researches, and also provided a good idea to reduce secondary contamination by dissolved irons in future investigations. PMID- 21700311 TI - Assessment of risk to humans of bisphenol A in marine and freshwater fish from Pearl River Delta, China. AB - Bisphenol A (BPA) is a high production-volume chemical used in the manufacture of a wide variety of consumer products. However it is also a ubiquitous contaminant that can interfere with endocrine systems of wildlife and humans. China is the "world factory" and the Pearl River Delta is the major manufacturing center and is consequently polluted. Concentrations of BPA in meats of marketable fish had not been previously reported for this region. In the study upon which we report here concentrations of BPA were determined in 20 common species of freshwater and marine fish, collected from markets in Hong Kong, SAR, China. A comprehensive analytical method based on SPE extraction and liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) was developed, validated and applied. The method limit of detection (LOD) and limit of quantification (LOQ) were 0.5 and 1.25 ng g(-1) dw, respectively. BPA was detected in 19 species of fish at concentrations, ranging from 0.5 to 2.0 ng g(-1) ww. Average daily BPA intake per person ranged from 1.1*10(2) ng d(-1) for marine fish and 2.2*10(2) ng d(-1) for freshwater fish. Concentrations of BPA in fish from Hong Kong markets unlikely would be causing adverse population-level effects in humans. PMID- 21700312 TI - Thermodynamic and kinetic study of phenol degradation by a non-catalytic wet air oxidation process. AB - This work is dedicated to an accurate evaluation of thermodynamic and kinetics aspects of phenol degradation using wet air oxidation process. Phenol is a well known polluting molecule and therefore it is important having data of its behaviour during this process. A view cell is used for the experimental study, with an internal volume of 150 mL, able to reach pressures up to 30 MPa and temperatures up to 350 degrees C. Concerning the thermodynamic phase equilibria, experimental and modelling results are obtained for different binary systems (water/nitrogen, water/air) and ternary system (water/nitrogen/phenol). The best model is the Predictive Soave Redlich Kwong one. This information is necessary to predict the composition of the gas phase during the process. It is also important for an implementation in a process simulation. The second part is dedicated to kinetics evaluation of the degradation of phenol. Different compounds have been detected using GC coupled with a MS. A kinetic scheme is deduced, taking into account the evolution of phenol, hydroquinones, catechol, resorcinol and acetic acid. The kinetic parameters are calculated for this scheme. These data are important to evaluate the evolution of the concentration of the different polluting molecules during the process. A simplified kinetic scheme, which can be easily implemented in a process simulation, is also determined for the direct degradation of phenol into H(2)O and CO(2). The Arrhenius law data obtained for the phenol disappearance are the following: k=1.8*10(6)+/-3.9*10(5)M(-1)s(-1) (pre-exponential factor) and E(a)=77+/-8 kJ mol(-1) (activation energy). PMID- 21700314 TI - The spectroscopic studies of humic acid extracted from sediment collected at different seasons. AB - Goczalkowice Reservoir is the biggest water reservoir in the south of Poland. For our studies bottom sediments were collected from eight different places of the reservoir at various seasons of the year. EPR spectroscopy was applied to analyse both quantitatively and qualitatively the humic acids (HA) present in the samples. EPR spectra of the extracted HA exhibited broad lines from the paramagnetic metal ions and narrow lines from free radicals. The values of the free radical concentration obtained for HA amounted to 1.14-13.6 * 1016 spin g( 1) depending on the season and the place of sample collection. The values of the g factor obtained for HA were of the range 2.0027-2.0035. The EPR studies show that HA extracted from bottom sediment collected at various points of the Goczalkowice Reservoir exhibit similar physical-chemical properties. It was also observed that the depth of the reservoir affects the content of the oxygen functional groups as well as the free radical concentration in HA. The identification of the functional groups was done by means of IR. UV/VIS spectroscopy was used to estimate the maturity of the HA. PMID- 21700313 TI - Photocatalytic inactivation of Escherichia coli by natural sphalerite suspension: effect of spectrum, wavelength and intensity of visible light. AB - The photocatalytic disinfection of Escherichia coli K-12 is investigated by the natural sphalerite (NS) under different spectra, wavelengths and intensities of visible light (VL) emitted by light-emitting-diode lamp (LED). The spectrum effect of VL on disinfection efficiency is studied by using white LED, fluorescent tube (FT) and xenon lamp (XE), which indicates that the "discreted peak spectrum" of FT is more effective to inactivate bacteria than "continuous spectrum" of LED and XE. Besides, the photocatalytic disinfection of bacteria is compared under different single spectrum (blue, green, yellow and red color) LEDs. The results show that the most effective wavelength ranges of VL for photocatalytic disinfection with the NS are 440-490 and 570-620 nm. Furthermore, a positive relationship is obtained between the disinfection efficiency and the VL intensity. The experiment shows that NS can completely inactivate 10(7)cfu mL( 1)E. coli K-12 within 8h irradiation by white LED with the intensity of 200 mW cm(-2) at pH 8. Moreover, the destruction process of the cell wall and the cell membrane are directly observed by TEM. Finally, no bacterial colony can be detected within a 96 h regrowth test of inactivated bacteria, which reveals that the VL-photocatalytic disinfection leads to an irreversible damage to the bacterial cells. PMID- 21700315 TI - Can we remove iodine-131 from tap water in Japan by boiling? - Experimental testing in response to the Fukushima Daiichi Nuclear Power Plant accident. AB - Iodine-131 concentrations in tap water higher than 100 BqL(-1) were reported by several local governments in Japan following the Fukushima Daiichi Nuclear Power Plant accident. Some individuals in the emergency-response community recommended the boiling of tap water to remove iodine-131. However, the tap water boiling tests in this study showed no iodine-131 loss from the tap water with either short-term boiling (1-10 min) or prolonged boiling (up to 30 min) resulting in up to 3-fold volume reductions. In this situation, boiling was shown to be not effective in removing iodine-131 from tap water; indeed even higher concentrations may result from the liquid-volume reduction accompanying this process. PMID- 21700316 TI - Wild fire impact on copper, zinc, lead and cadmium distribution in soil and relation with abundance in selected plants of Lamiaceae family from Vidlic Mountain (Serbia). AB - Fire has been considered as an improving factor in soil quality, but only if it is controlled. Severe wild fire occurred in the summer 2007 on the Vidlic Mountain (Serbia) overspreading a huge area of meadows and forests. Main soil characteristics and content of heavy metals (Cu, Pb, Cd, Zn) in different fractions obtained after sequential extraction of soil from post-fire areas and from fire non disturbed areas were studied. In four plant species of Lamiaceae family (Ajuga genevensis L., Lamium galeobdolon (L.) L., Teucrium chamaedrys L., Acinos alpinus (L.) Moench.), that grow in typical habitats of the mountain, distribution of heavy metals in aerial parts and roots was investigated too. For all samples from post-fire area cation exchange capacity and soil organic matter content are increased while rH is decreased. Fire caused slightly increased bioavailability of the observed metals but more significant rise happened in metal amounts bound to oxides and organics. The plants showed variable behavior. T. chamaedrys collected on the post-fire area contained elevated concentrations of all analyzed metals. A. alpinus showed higher phytoaccumulation for Zn and Cd, while the other two plant species for Pb and Cd in the post-fire areas. PMID- 21700317 TI - Polarity effect of pulsed corona discharge for the oxidation of gaseous elemental mercury. AB - The effect of polarity on the oxidation of Hg(0) was examined in the presence of O(2) via a pulsed corona discharge (PCD). The experimental result showed no difference in the energy yield of Hg(0) oxidation at both positive and negative PCDs (~8 MUg Hg Wh(-1) at following conditions: total flow rate=2 L min(-1) (Hg(0)=50 MUg Nm(-3), O(2)=10%, and N(2) balance), temperature=150 degrees C, and specific energy density=5-15 Wh Nm(-3)). This suggests that the positive PCD process used to control gaseous air pollutants may play an essential key role in Hg(0) oxidation because it consumes enough energy (~15 Wh Nm(-3)) but an electrical precipitator could not because it consumes less energy (~0.3 Wh Nm( 3)) to oxidize Hg(0). PMID- 21700318 TI - Identification of new ozonation disinfection byproducts of 17beta-estradiol and estrone in water. AB - Estrogens are a class of micro-pollutants found in water at low concentrations (in the ng L(-1) range), but often sufficient to exert estrogenic effects due to their high estrogenic potency. Disinfection of waters containing estrogens through oxidative processes has been shown to lead to the formation of disinfection byproducts, which may also be estrogenic. The present work investigates the formation of disinfection byproducts of 17beta-estradiol (E2) and estrone (E1) in the treatment of water with ozone. Experiments have been carried out at two different concentrations of the estrogens in ground water (100 ng L(-1) and 100 MUg L(-1)) and at varying ozone dosages (0-30 mg L(-1)). Detection of the estrogens and their disinfection byproducts in the water samples has been performed by means of ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) with a triple quadrupole (QqQ) and a quadrupole time of flight (QqTOF) instrument. Both E2 and E1 have been found to form two main byproducts, with molecular mass (MM) 288 and 278 in the case of E2, and 286 and 276 in the case of E1, following presumably the same reaction pathways. The E2 byproduct with MM 288 has been identified as 10 epsilon-17beta-dihydroxy-1,4 estradieno-3-one (DEO), in agreement with previously published results. The molecular structures and the formation pathways of the other three newly identified byproducts have been suggested. These byproducts have been found to be formed at both high and low concentrations of the estrogens and to be persistent even after application of high ozone dosages. PMID- 21700319 TI - Climatic conditions, settlement patterns and cultures in the Paleolithic: the example of the Garonne Valley (southwest France). AB - In this paper, we present a critical analysis of the distribution of Paleolithic sites between the Massif Central and the Pyrenees (southwestern France) to understand the settlement patterns during the last climatic deterioration of the Quaternary period. This analysis used recent stratigraphic and archaeological data from thousands of systematic test pits conducted for rescue archaeology in different geomorphological contexts. Our analysis addresses crucial questions about the role of the Garonne alluvial plain in this territory during the Upper Paleolithic. The implications are discussed in the context of this region of Europe, which was considered to be a favorable zone for human occupation during glacial periods. The conclusions reveal a division of this territory into two parts separated by a large unoccupied or rarely occupied zone. We discuss perspectives not only concerning the territoriality of the prehistoric groups who lived on the margins of this no man's land, but also the cultural endemism that could have led to this geography, influenced by climatic conditions clearly more rigorous than previously recognized in this region. PMID- 21700320 TI - Assessing the ability of mechanistic volatilization models to simulate soil surface conditions: a study with the Volt'Air model. AB - Ammonia and pesticide volatilization in the field is a surface phenomenon involving physical and chemical processes that depend on the soil surface temperature and water content. The water transfer, heat transfer and energy budget sub models of volatilization models are adapted from the most commonly accepted formalisms and parameterizations. They are less detailed than the dedicated models describing water and heat transfers and surface status. The aim of this work was to assess the ability of one of the available mechanistic volatilization models, Volt'Air, to accurately describe the pedo-climatic conditions of a soil surface at the required time and space resolution. The assessment involves: (i) a sensitivity analysis, (ii) an evaluation of Volt'Air outputs in the light of outputs from a reference Soil-Vegetation-Atmosphere Transfer model (SiSPAT) and three experimental datasets, and (iii) the study of three tests based on modifications of SiSPAT to establish the potential impact of the simplifying assumptions used in Volt'Air. The analysis confirmed that a 5 mm surface layer was well suited, and that Volt'Air surface temperature correlated well with the experimental measurements as well as with SiSPAT outputs. In terms of liquid water transfers, Volt'Air was overall consistent with SiSPAT, with discrepancies only during major rainfall events and dry weather conditions. The tests enabled us to identify the main source of the discrepancies between Volt'Air and SiSPAT: the lack of gaseous water transfer description in Volt'Air. They also helped to explain why neither Volt'Air nor SiSPAT was able to represent lower values of surface water content: current classical water retention and hydraulic conductivity models are not yet adapted to cases of very dry conditions. Given the outcomes of this study, we discuss to what extent the volatilization models can be improved and the questions they pose for current research in water transfer modeling and parameterization. PMID- 21700321 TI - A model approach to assess the long-term trends of indirect photochemistry in lake water. The case of Lake Maggiore (NW Italy). AB - A model-based approach is here developed and applied to predict the long-term trends of indirect photochemical processes in the surface layer (5m water depth) of Lake Maggiore, NW Italy. For this lake, time series of the main parameters of photochemical importance that cover almost two decades are available. As a way to assess the relevant photochemical reactions, the modelled steady-state concentrations of important photogenerated transients ((*)OH, 3CDOM* and CO3(-*)) were taken into account. A multivariate analysis approach was adopted to have an overview of the system, to emphasise relationships among chemical, photochemical and seasonal variables, and to highlight annual and long-term trends. Over the considered time period, because of the decrease of the dissolved organic carbon (DOC) content of water and of the increase of alkalinity, a significant increase is predicted for the steady-state concentrations of the radicals (*)OH and CO3( *). Therefore, the photochemical degradation processes that involve the two radical species would be enhanced. Another issue of potential photochemical importance is related to the winter maxima of nitrate (a photochemical (*)OH source) and the summer maxima of DOC ((*)OH sink and 3CDOM* source) in the lake water under consideration. From the combination of sunlight irradiance and chemical composition data, one predicts that the processes involving (*)OH and CO3(-*) would be most important in spring, while the reactions involving 3CDOM* would be most important in summer. PMID- 21700322 TI - Preoperative assessment of myometrial and cervical invasion in endometrial carcinoma by transvaginal ultrasound. AB - OBJECTIVE: To evaluate the diagnostic accuracy of transvaginal ultrasound (TVS) in preoperative assessment of the depth of myometrial infiltration and the presence of cervical invasion in endometrial carcinoma. METHODS: 298 consecutive patients with a diagnosis of endometrial cancer were evaluated by TVS within 3 days of surgical intervention. The depth of myometrial invasion was classified into two groups: no or <50% invasion and >=50% invasion. Invasion of cervix was diagnosed when the neoplastic tissue distended the cervix and showed ill-defined borders with the cervical stroma. RESULTS: The sensitivity, specifity, positive predictive value (PPV), negative predictive value (NPV) and overall diagnostic accuracy of TVS in evaluation of the depth of myometrial infiltration were 68.4%, 82%, 65.1%, 84.1% and 77.5%, respectively. While the sensitivity and PPV were significantly higher among grade 3 tumors, the specifity, NPV and accuracy were significantly higher among grade 1 tumors. The sensitivity, specifity, PPV, NPV, and overall diagnostic accuracy of TVS in assessment of the presence or absence of neoplastic tissue in cervix were 76.5%, 99.3%, 86.7%, 98.2% and 98%, respectively. While the sensitivity and PPV were significantly higher among grade 1 tumors, the NPV and accuracy were significantly lower among grade 3 tumors. CONCLUSION: TVS can be considered as a feasible, economical and simple imaging modality with a high diagnostic accuracy for the prediction of cervical involvement. However, it is not a reliable method in estimating the depth of myometrial infiltration. PMID- 21700324 TI - Hypersensitivity to systemic corticosteroids in aspirin-sensitive patients with asthma. PMID- 21700325 TI - Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. AB - Parkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we show that functional loss of GD linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of alpha-synuclein (alpha-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified alpha-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that alpha-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of alpha-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies. PMID- 21700326 TI - Fatigue life prediction of dentin-adhesive interface using micromechanical stress analysis. AB - OBJECTIVES: The objective of this work was to develop a methodology for the prediction of fatigue life of the dentin-adhesive (d-a) interface. METHODS: At the micro-scale, the d-a interface is composed of dissimilar material components. Under global loading, these components experience different local stress amplitudes. The overall fatigue life of the d-a interface is, therefore, determined by the material component that has the shortest fatigue life under local stresses. Multiple 3d finite element (FE) models were developed to determine the stress distribution within the d-a interface by considering variations in micro-scale geometry, material composition and boundary conditions. The results from these models were analyzed to obtain the local stress concentrations within each d-a interface component. By combining the local stress concentrations and experimentally determined stress versus number of cycle to failure (S-N) curves for the different material components, the overall fatigue life of the d-a interface was predicted. RESULTS: The fatigue life was found to be a function of the applied loading amplitude, boundary conditions, microstructure and the mechanical properties of the material components of the d a interface. In addition, it was found that the overall fatigue life of the d-a interface is not determined by the weakest material component. In many cases, the overall fatigue life was determined by the adhesive although exposed collagen was the weakest material component. Comparison of the predicted results with experimental data from the literature showed both qualitative and quantitative agreement. SIGNIFICANCE: The methodology developed for fatigue life prediction can provide insight into the mechanisms that control degradation of the bond formed at the d-a interface. PMID- 21700327 TI - An acoustic emission study on interfacial debonding in composite restorations. AB - OBJECTIVE: This paper studied in vitro the effect of the C-factor on interfacial debonding during curing of composite restorations using the acoustic emission (AE) technique. Finite element (FE) analyzes were also carried out to evaluate the interfacial stresses caused by shrinkage of the composite resin in restorations with different C-factors. MATERIALS AND METHODS: Twenty extracted third molars were divided into 4 groups of 5. They were cut to form Class-I (Groups 1 and 2) and Class-II (Groups 3 and 4) cavities with different C-factors. The average C-factors of the four groups were 3.37, 2.88, 2.00, and 1.79, respectively. The cavities were then applied with an adhesive and restored with a composite, which was cured by a halogen light for 40 s. A 2-channel AE system was used to monitor the interfacial debonding, caused by shrinkage stress, between the tooth and restoration through an AE sensor attached to the surface of the specimen. Recording of the AE started at the same time as curing of the composite and lasted 10 min. Simplified FE models were used to evaluate the interfacial stresses in restorations with different C-factors, with a thermal load (temperature decrease) being applied to the composite resin to simulate its shrinkage. RESULTS: The mean and standard deviation of the total number of AE events for the four groups were 29.6+/-15.7, 10.0+/-5.8, 2.6+/-1.5, and 2.2+/ 1.3, i.e. the number of AE events increased with an increase in the C-factor. The FE results also showed that, the higher the C-factor of the restoration, the higher the interfacial tensile stress between the tooth and restoration. SIGNIFICANCE: From the results of the AE tests and FE simulations, it can be concluded that, the higher the C-factor, the higher the shrinkage stress and the more likely is interfacial debonding. PMID- 21700328 TI - Organic matter features, degradation and remineralisation at two coastal sites in the Ligurian Sea (NW Mediterranean) differently influenced by anthropogenic forcing. AB - Organic matter (OM) features, degradation and remineralisation were studied in the seawater of a natural coastal site (Marine Protected Area of Portofino) and at an urbanised coastal site (Quarto, Genoa city) of the Ligurian Sea. The accumulation of low trophic value OM and the persistence of phytoplanktonic biomass throughout the year were observed only at the urbanised site. Efficient OM degradation and remineralisation via high-activity (two times higher than at the Portofino site) hydrolytic enzymatic activities (alkaline phosphatase and leucine aminopeptidase) were recorded. This active degradation indicated a generally good resistance of the Quarto system to environmental pressures (coastal inputs and anthropogenic influence). However, the high potential release of recycled inorganic nutrients and the favourable environmental conditions (i.e. higher seawater temperature at the Quarto site and allochthonous inputs), could encourage unpredictable development of the autotrophic fraction, including an already observed dystrophic blooming of toxic microalgae. PMID- 21700330 TI - The balance between adipogenesis and osteogenesis in bone regeneration by platelet-rich plasma for age-related osteoporosis. AB - The aim of this study was to develop a new diagnostic and therapeutic approach for the treatment of osteoporosis. Previously, we demonstrated that intraosseous transplantation of platelet-rich plasma (PRP) treated-osteoblast-like cells into ovariectomized senescence-accelerated mice (OVX-SAMP8) prevented the development of osteoporosis. In continuation, we aimed to explore the complex etiology of osteoporosis using this platform. An inverse relationship between bone marrow adipogenesis and osteogenesis has been suggested in the development of osteoporosis but the underlying mechanisms remain poorly described. To address these issues, we used PRP to inhibit adipocyte differentiation by promoting osteoblastic differentiation in adipocytes. In addition, a positive correlation between an increase in bone marrow adipocytes and bone loss was established. We assessed this relationship using an osteoporotic animal disease model which consisted of young (for prevention) and old (for treatment) OVX-SAMP8 mice. This animal model demonstrated that PRP treatment mainly exerted its action via promoting bone regeneration but also appeared to suppress adipogenesis within the marrow. The findings and methodology of this study could potentially be applied in the prevention and treatment of osteoporosis. PMID- 21700329 TI - Prediction of spatio-temporal bone formation in scaffold by diffusion equation. AB - Developing a successful bone tissue engineering strategy entails translation of experimental findings to clinical needs. A major leap forward toward this goal is developing a quantitative tool to predict spatial and temporal bone formation in scaffold. We hypothesized that bone formation in scaffold follows diffusion phenomenon. Subsequently, we developed an analytical formulation for bone formation, which had only three unknown parameters: C, the final bone volume fraction, alpha, the so-called scaffold osteoconduction coefficient, and h, the so-called peri-scaffold osteoinduction coefficient. The three parameters were estimated by identifying the model within vivo data of polymeric scaffolds implanted in the femoral condyle of rats. In vivo data were obtained by longitudinal micro-CT scanning of the animals. Having identified the three parameters, we used the model to predict the course of bone formation in two previously published in vivo studies. We found the predicted values to be consistent with the experimental ones. Bone formation into a scaffold can then adequately be described through diffusion phenomenon. This model allowed us to spatially and temporally predict the outcome of tissue engineering scaffolds with only 3 physically relevant parameters. PMID- 21700331 TI - Polyamidoamine dendrimer-conjugated quantum dots for efficient labeling of primary cultured mesenchymal stem cells. AB - Monitoring of cells in vivo after transplantation could supply important information for determining the efficacy of stem cell therapy. The use of quantum dots (QDs) has several advantages for in vivo imaging, such as remarkable resistance to photo bleaching, high fluorescence efficiency, and size-tunable emission. After they are taken up by cells via endocytosis, QDs lose their fluorescence intensity in endosomes/lysosomes at low pH because the intensity cannot survive under acidic conditions. Moreover, the amount of QD uptake by mesenchymal stem cells (MSCs) is extremely small. Therefore, for effective labeling of MSCs and long observation of MSCs labeled by QDs in vivo, it is essential both to increase cellular uptake of QDs and to promote endosomal escape into the cytosol. The polyamidoamine (PAMAM) dendrimer had plenty of cationic charge, which promoted cellular uptake though electrostatic interactions, and a "buffering capacity," which enhanced endosomal escape into the cytosol. In this study, QDs were modified with PAMAM dendrimer for the efficient labeling of MSCs by QDs. The uptake efficiency and cytosolic distribution of QDs in primary cultured MSCs were increased by the modification of the PAMAM dendrimer. The fluorescence intensity in MSCs labeled by PAMAM dendrimer-conjugated QDs lasted for a longer time in harvested culture plates or in cell-transplanted mice than that in MSCs labeled by non-conjugated QDs. PMID- 21700332 TI - Cellular trafficking of low molecular weight heparin incorporated in layered double hydroxide nanoparticles in rat vascular smooth muscle cells. AB - This paper reports a clear elucidation of the pathway for the cellular delivery of layered double hydroxide (LDH) nanoparticles intercalated with anti-restenotic low molecular weight heparin (LMWH). Cellular uptake of LMWH-LDH conjugates into cultured rat vascular smooth muscle cells (SMCs) measured via flow cytometry was more than ten times greater than that of LMWH alone. Confocal and transmission electron microscopy showed LMWH-LDH conjugates taken up by endosomes, then released into the cytoplasm. We propose that LMWH-LDH is taken up via a unique 'modified endocytic' pathway, whereby the conjugate is internalized by SMCs in early endosomes, sorted in late endosomes, and quickly released from late endosomes/lysosomes, avoiding degradation. Treatment of cells with LMWH-LDH conjugates suppressed the activation of ERK1/2 in response to foetal calf serum (FCS) for up to 24h, unlike unconjugated LMWH which had no significant effect at 24h. Improved understanding of the intracellular pathway of LMWH-LDH nanohybrids in SMC will allow for refinement of design for LDH nanomedicine applications. PMID- 21700333 TI - Dual targeting effect of Angiopep-2-modified, DNA-loaded nanoparticles for glioma. AB - Gene therapy offers a promising cure of brain glioma and tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is able to induce cell apoptosis of glioma selectively without affecting the normal cells. In this study, the nanoscopic high-branching dendrimer, polyamidoamine (PAMAM), was selected as the principal vector. Angiopep-2, which can target to the low-density lipoprotein receptor-related protein-1 (LRP1) expressed on BCECs and glial cells, was exploited as the targeting ligand to conjugate PAMAM via bifunctional polyethyleneglycol (PEG) and then complexed with the DNA, designated as PAMAM-PEG Angiopep/DNA nanoparticles (NPs). The cellular uptake mechanism explored in glial cells showed that the DNA of PAMAM-PEG-Angiopep/DNA NPs entered into the nuclei through the endosome/lysosome pathway. The in vivo biodistribution of PAMAM-PEG Angiopep/DNA NPs in the brain especially the tumor site was higher than that of PAMAM-PEG/DNA NPs and PAMAM/DNA NPs. Furthermore, the TUNEL analysis showed a more wide-extended apoptosis in the PAMAM-PEG-Angiopep/pORF-TRAIL NPs treated group, compared to other groups including commercial Temozolomide-treated one. The median survival time of PAMAM-PEG-Angiopep/pORF-TRAIL NPs and Temozolomide treated on brain tumor-bearing mice was 61 and 49 days respectively, significantly longer than that of other groups. Besides, the NPs suggested low cytotoxicity after in vitro transfection. Thus, the results showed that Angiopep 2 could be exploited as a specific ligand to cross the BBB and targeted to glial cells, and PAMAM-PEG-Angiopep/DNA NPs can be a potential non-viral delivery system for gene therapy of glial tumor. PMID- 21700334 TI - How endometrial secretomics can help in predicting implantation. AB - The receptive endometrium represents a physiologic state of the uterus when embryo implantation is possible. It occurs at a discreet stage of the menstrual cycle referred to as window of implantation, outside of which the uterus is refractory to the initiation of pregnancy. In modern society, assisted reproductive technologies (ART) are an ever-growing demand to counter infertility; however, pregnancy rates remain below expectations, not least because current diagnostic tools fail to provide accurate assessment of endometrial receptivity. In the last decade, widespread arrival of large-scale analytical techniques has brought a stream of studies seeking to identify specific biomarkers of endometrial receptivity by extracting global molecular information from endometrial biopsies. The latter are an undesired requirement for dating the endometrium, which has prompted development of alternative strategies whereby large-scale analyses and non-invasive methods can converge. In this context, secretomics represents an attractive possibility to assess endometrial maturation and receptivity. Endometrial-cell secretions poured into the uterine cavity are suitable for collection and analysis without the need of biopsying, and might provide important additional molecular information reflective of endometrial physiology and day of cycle. If properly validated, the outgoing results would represent a step forward in the development of diagnostic tools to assess endometrial receptivity. PMID- 21700336 TI - The expression of IgM is helpful in the differentiation of primary cutaneous diffuse large B cell lymphoma and follicle center lymphoma. AB - Diffuse large B-cell infiltration of the skin includes mainly primary cutaneous follicle center lymphoma (PCFCL) with diffuse architecture and diffuse large B cell lymphoma (PCDLBCL), leg type. Differentiation of these lymphomas on morphology may be troublesome. Immunohistochemistry panel, including CD20, CD79a, bcl-6, bcl-2, MUM-1, FOX-P1 is mandatory. However, in minority of cases, these markers would not suffice. In order to search the value of another marker, IgM, 30 cases of PCFCL and 10 cases of PCDLBCL, leg type were included in the study. As suggested in a recent literature, our study denoted that expression of IgM was useful as an additional tool for differentiation. PMID- 21700335 TI - Expression of inhibitor of apoptosis protein (IAP) livin/BIRC7 in acute leukemia in adults: correlation with prognostic factors and outcome. AB - The clinical relevance of livin/BIRC7 expression is still controversial in different types of malignancies, therefore this study was designed to evaluate the gene expression of livin in Egyptian adult AML and ALL. Livin expression level was higher in patients with unfavorable prognostic factors at diagnosis in both ALL (p=0.002) and AML (p=0.042) and its level was negatively correlated with event free survival (EFS) and overall survival (OS) in both ALL (p<0.001for both) and AML (p=0.001 and 0.023 respectively). This study suggests that livin expression is a novel prognostic marker in adult acute leukemia and thus needs to be incorporated into the patient stratification and treatment protocols. PMID- 21700337 TI - High-grade solitary extramedullary plasmacytoma arising in skeletal muscle of a kidney transplant recipient. PMID- 21700338 TI - Clinical parameters and biomarkers of oxidative stress in agricultural workers who applied copper-based pesticides. AB - Copper based-pesticides are widely used in agricultural practice throughout the world. We studied the (i) concentration of Cu and proteins involved in Cu homeostasis, (ii) plasma redox status, and (iii) biomarkers of exposure in Cu based pesticide applicators in order to compare them with clinical biochemical tests. Thirty-one professional applicators and 32 control subjects were recruited. Oxidative stress biomarkers, ceruloplasmin (CRP), metallothioneins (MTs), copper, hematological parameters, and biochemical markers for pancreatic, hepatic and renal function were measured in plasma. Copper was increased in the exposed group compared to the control group concomitantly with TBARS, protein carbonyls, and nitrate+nitrite levels. In the exposed group, alpha-tocopherol and the FRAP assay were lower and LDH, transaminases, GGT, ALP, urea, creatinine, CRP and MTs were higher than in the control group. The relative leukocyte subclasses were also different between the two groups. Clinical chemistry tests did not surpass the upper reference limit. Our results suggest that the incorporation of oxidative stress biomarkers to biochemical/clinical tests should be considered for validation and included in the human health surveillance protocols. PMID- 21700339 TI - Degradation of diesel-originated pollutants in wetlands by Scirpus triqueter and microorganisms. AB - The wetland ecological environment near Huangpu-Yangtze River Estuary (HYRE) is deteriorating more and more seriously due to oil spills. In this paper, the simulation experiment of degradation was conducted to restore the diesel pollution in soils where the decontaminating potential of indigenous hydrocarbon degrading microorganisms (HDMs) was evaluated with pot experiments and the co activation between HDMs and native plant, Scirpus triqueter L.(STL), was investigated. The experimental results indicated that HDMs isolated from HYRE wetland had a degradation effect on diesel pollutants. Within 60 days, the removal ratio of diesel compared with initial amount could be up to 57.27 +/- 8.18% in the HDMs inoculated soils at different concentrations of diesel. It was also found that the growth of Scirpus triqueter could enhance the degradation and remediation of diesel pollutants by increasing the populations of microorganisms. A community of STL and HDMs showed a remarkable capability of degrading hydrocarbon components in diesels. Under the combined effects of HDMs and STL (STL-Ms), the removal ratio of diesel pollutants could reach 67.42 +/- 8.92%. For example, at 15,000 mg kg(-1) diesel concentration the removal ratios in the HDMs and STL-Ms soils were 67.41% and 72.62%, respectively. Moreover, the saturated hydrocarbons were more readily degraded than the aromatic hydrocarbons in treated soils showing a good degradation effect on the range of C(16)-C(24)n-alkanes, especially C(19). Positive correlations between microbial populations and diesel removal ratios were observed during the experiment. Microbial populations were found significantly higher in the HDMs soils and rhizosphere soils than in the control ones. The results confirmed that the HDMs and plant improved the biodegradation ability for diesel pollutants and they could be reasonably matched to cure and restore the ecological environment of oil-contaminated wetlands. PMID- 21700340 TI - Early life-stage and multigeneration toxicity study with bisphenol A and fathead minnows (Pimephales promelas). AB - Regulatory guidelines for long term testing to assess the toxicity of xenobiotic compounds such as bisphenol A (BPA) with fish have focused on survival, growth, and development in early life stages. Early life stages are critical windows of exposure, but do not address later phases in the life cycle, such as reproduction, that are equally important for the continued survival of the organisms. Residual amounts of BPA are released to surface water. BPA has, therefore, been the subject of considerable toxicity testing with fish and other aquatic organisms. A long term multigeneration test with fish has been conducted to better interpret the environmental relevance of detectable levels of BPA. Fathead minnow (Pimephales promelas) were exposed for 444 days over the course of three generations that included F0 reproducing adults, F1 eggs grown to be reproducing adults, and F2 eggs. Endpoints included survival, growth, reproduction, and vitellogenin concentrations. Concentrations tested ranged from 1 to 1,280 MUg/L. No observed effect concentrations (NOEC) of 640 MUg/L and higher for growth parameters show few differences between age or generation. Reproductive NOEC in F0 and F1 breeding pairs were 640 and 160 MUg/L, respectively. The lowest NOEC related to survival, growth and development or reproduction was 16 MUg/L for F2 hatching success. This long term study covered both early life and adult reproduction stages that allowed examination of all critical windows of exposure. Overall, NOEC ranging from 16 to 1,280 MUg/L were found, which are well above median and upper 95th percentile concentrations of BPA in fresh waters in North America and Europe (0.081 and 0.47 MUg/L and 0.01 and 0.035 MUg/L, respectively). The likelihood is low that measured concentrations of BPA in surface water would affect fish, even if exposed over more than one generation. PMID- 21700341 TI - Membrane-bound proteinase 3 and PAR2 mediate phagocytosis of non-opsonized bacteria in human neutrophils. AB - The molecular mechanisms underlying the non-opsonic phagocytosis of bacteria by neutrophils are poorly understood. We previously reported the efficient uptake of Streptococcus sanguinis by human neutrophils in the absence of opsonins. To characterize the phagocytosis receptor, protein lysates from neutrophils and HL 60 cells were subjected to affinity chromatography using epoxy beads coated with S. sanguinis. Denaturing electrophoresis of the eluted proteins and subsequent mass spectrometry revealed that one of the proteins eluted from neutrophils was proteinase 3 (PR3). Enzymatic cleavage of the glycosylphosphatidylinositol linker of NB1, a co-receptor for membrane-bound PR3 (mPR3), significantly reduced the phagocytosis of S. sanguinis. In addition, the neutralization of mPR3 with antibody reduced both binding and phagocytosis of S. sanguinis. Treatment of neutrophils with a serine proteinase inhibitor indicated that protease activity is required for phagocytosis. Thus, we studied whether protease-activated receptor 2 (PAR2) is involved in signal transmission from mPR3 during this process. Indeed, neutralizing antibodies against PAR2 inhibited phagocytosis and S. sanguinis-induced calcium mobilization desensitized PAR2. Furthermore, the phagocytosis of S. sanguinis and the concomitant activation of Rho family GTPases were inhibited by the intracellular calcium chelator, BAPTA-AM. Collectively, mPR3 acts as a non-opsonic phagocytosis receptor for bacteria probably by activating PAR2 in neutrophils. PMID- 21700342 TI - MRI exploration of pineal volume in bipolar disorder. AB - BACKGROUND: Circadian rhythm instability and abnormalities of melatonin secretion are considered as trait markers of bipolar disorder. Melatonin is secreted by the pineal gland. We investigated pineal volume in patients with bipolar disorder, and expected to observe smaller than normal pineal glands in cases of bipolar disorder. METHODS: The primary outcome was the total pineal volume measured for each pineal gland with T1 MRI sequence. Twenty patients with bipolar I and II disorder and twenty controls were recruited. Pineal glands with large cysts (type 3) were excluded. RESULTS: After exclusion of individuals with type 3 cysts, 32 subjects were analyzed for total pineal volume (16 patients with bipolar disorder and 16 controls). Total pineal volume did not differ significantly between patients (total pineal volume=115+/-54.3mm(3)) and controls (total pineal volume=110+/-40.5mm(3)). CONCLUSIONS: Contrary to our hypothesis, no difference in total pineal volume between patients with bipolar disorder and healthy subjects was observed. These results indicate that the putative dysfunction of the pineal gland in bipolar disorder could be not directly related to an abnormal volume of the pineal gland. PMID- 21700343 TI - Update on the role of innate immune receptors during Brucella abortus infection. AB - The innate immune system constitutes an efficient defense mechanism against invading microbial pathogens. Recent studies have revealed the intracellular signaling cascades involved in the TLR-initiated immune response to Brucella spp. infection. However, there is a piece of the puzzle missing that is the role of non-TLR receptors in innate immunity. The involvement of TLR receptors in brucellosis has been investigated by different research groups. It was demonstrated that TLR2 clearly does not play any role in controlling Brucella abortus infection in vivo, whereas TLR9 has been shown to be required for clearance of this bacterium in infected mice. The participation of adaptor molecules, such as MyD88 and TRIF has also been discussed. Recently, we and others have reported the critical role of MyD88- and not TRIF-mediated signaling in dendritic cell maturation and in vivo resistance during B. abortus infection. However, the relationship between specific Brucella molecules and non-TLR receptors and signal transduction pathways needs to be better understood. It is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Finally, this review discusses the mechanisms used by Brucella to escape detection by the host innate immune system. PMID- 21700344 TI - CD4+CD25+ T cells expressing FoxP3 in Icelandic horses affected with insect bite hypersensitivity. AB - Insect bite hypersensitivity (IBH) is an IgE-mediated dermatitis caused by bites of midges from the genus Culicoides. We have shown previously that peripheral blood mononuclear cells (PBMC) from IBH-affected horses produce higher levels of IL-4 and lower levels of IL-10 and TGF-beta1 than those from healthy horses, suggesting that IBH is associated with a reduced regulatory immune response. FoxP3 is a crucial marker of regulatory T cells (Tregs). Here we have determined the proportion of CD4(+)CD25(+)FoxP3(+) T cells by flow cytometry in PBMC directly after isolation or after stimulation with Culicoides extract or a control antigen (Tetanus Toxoid). There were no differences between healthy and IBH horses either in the proportion of FoxP3(+)CD4(+)CD25(+) cells in freshly isolated PBMC or in the following stimulation with Tetanus Toxoid. However, upon stimulation of PBMC with the allergen, expression of FoxP3 by CD4(+)CD25(+high) and CD4(+)CD25(+dim) cells was significantly higher in healthy than in IBH horses. Addition of recombinant IL-4 to PBMC from healthy horses stimulated with the allergen significantly decreased the proportion of FoxP3 expressing cells within CD4(+)CD25(+high). These results suggest that IBH is associated with a decreased number of allergen-induced Tregs. This could be a consequence of the increased IL-4 production by PBMC of IBH-affected horses. PMID- 21700345 TI - TLR9 agonists: immune mechanisms and therapeutic potential in domestic animals. AB - Toll like receptors (TLRs) are transmembrane glycoproteins that recognize conserved microbial molecules. Engagement of TLRs activates innate and adaptive immunity. TLR-mediated activation of immune cells results in upregulation of cytokines, chemokines and costimulatory molecules. These early innate responses control pathogen spread and initiates adaptive immune responses. Synthetic CpG oligodeoxynucleotides (ODN), agonists for TLR9, had shown great promise as immunotherapeutic agents and vaccine adjuvants in laboratory animal models of infectious disease, allergy and cancer. However, it has become apparent that CpG ODN are less potent immune activators in domestic animals and humans. The disparity in immune responses between rodents and mammals has been mainly attributed to differences in cellular expression of TLR9 in the various species. In this article, our current understanding of the immune mechanisms, as well as the potential applications of CpG ODN will be reviewed, with particular emphasis on domestic animals. PMID- 21700347 TI - TDP-43 and FUS: a nuclear affair. AB - Misfolded TAR DNA binding protein 43 (TDP-43) and Fused-In-Sarcoma (FUS) protein have recently been identified as pathological hallmarks of the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) characterized by the presence of ubiquitin-positive inclusions (FTLD-U). Although TDP-43 and FUS are normally located predominantly in the nucleus, pathological TDP-43 and FUS inclusions are mostly found in the cytosol. Cytosolic deposition is paralleled by a striking nuclear depletion of either protein. Based on a number of recent findings, we postulate that defects in nuclear import are an important step towards TDP-43 and FUS dysfunction. Failure of nuclear transport can arise from mutations within a nuclear localization signal or from age-related decline of nuclear import mechanisms. We propose that nuclear import defects in combination with additional hits, for example cellular stress and genetic risk factors, may be a central underlying cause of ALS and FTLD-U pathology. PMID- 21700346 TI - Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. AB - Substantial evidence suggests that psychosis in schizophrenia is associated with dysregulation of subcortical dopamine system function. Here we examine evidence that this dysregulation is secondary to hyperactivity within hippocampal subfields. Enhanced hippocampal activity has been reported in preclinical models and in schizophrenia patients. Moreover, this hippocampal hyperactivity is correlated with enhanced dopamine neuron activity and positive symptoms, respectively. Thus, restoration of hippocampal function could provide a more effective therapeutic approach than current therapeutics based on blockade of dopamine D2 receptors. Indeed, initial studies demonstrate that allosteric modulation of the alpha5GABA(A) receptor can decrease aberrant dopamine signaling and associated behaviors in a verified rodent model of psychosis. PMID- 21700348 TI - Eosinophilic responses to stent implantation and the risk of Kounis hypersensitivity associated coronary syndrome. AB - The use of drug eluting stents constitutes a major breakthrough in current interventional cardiology because it is more than halves the need of repeat interventions. It is incontrovertible that coronary stents, in general, have been beneficial for the vast majority of patients. A small increase in thrombosis, following DES implantation, is offset by a diminished risk of complications associated with repeat vascularization. However, late and, especially, very late stent thrombosis is a much feared complication because it is associated with myocardial infarction with increased mortality. Despite that stent thrombosis is thought to be multifactorial, so far clinical reports and reported pathology findings in patients died from coronary stent thrombosis as well as animal studies and experiments, point toward a hypersensitivity inflammation. The stented and thrombotic areas are infiltrated by interacting, via bidirectional stimuli inflammatory cells including eosinophils, macrophages, T-cells and mast cells. Stented regions constitute an ideal surrounding for endothelial damage and dysfunction, together with hemorheologic changes and turbulence as well as platelet dysfunction, coagulation and fibrinolytic disturbances. Drug eluting stent components include the metal strut which contains nickel, chromium, manganese, titanium, molybdenum, the polymer coating and the impregnated drugs which for the first generation stents are: the antimicrotubule antineoplastic agent paclitaxel and the anti-inflammatory, immunosuppressive and antiproliferative agent sirolimus. The newer stents which are called cobalt chromiun stents and elute the sirolimus analogs everolimus and zotarolimus both contain nickel and other metals. All these components constitute an antigenic complex inside the coronary arteries which apply chronic, continuous, repetitive and persistent inflammatory action capable to induced Kounis syndrome and stent thrombosis. Allergic inflammation goes through three phases, the early phase, the late phase and the chronic phase and these three phases correspond temporally with early (acute and sub acute), late and very late stent thrombosis. Bioabsorbable allergy free poly lactic acid self expanding stents, nickel free stainless steel materials, stent coverage with nitric oxide donors and antibodies with endothelial progenitor cell capturing abilities as well as stents eluting anti-inflammatory and anti-allergic agents might be the solution of this so feared and devastating stent complication. PMID- 21700349 TI - Benefit of adding lifestyle-related risk factors for prediction of cardiovascular death among cardiac patients. AB - OBJECTIVE: The aim of our study was to evaluate the efficacy of the addition of lifestyle related variables to the existing Framingham risk score (FRS) for predicting cardiovascular death in patients with pre-existing cardiovascular disease (CVD). DESIGN: Survey analysis. METHODS: Participants were recruited from the Health Survey for England and Scottish Health Survey, both representative population-based studies sampling adults in each country. 1372 patients with CVD (age 66.4 +/- 10.9 yrs, 54.7% male) were included. Parameter estimates from Cox proportional hazards models were used to derive a new global risk score (termed the Health Survey Risk Score; HSRS) to predict CVD death. Receiver operating characteristic curves were compared to the FRS algorithm. The addition of each risk factor to the conventional FRS model examined the discriminative power of alternative lifestyle-related variables. RESULTS: Cholesterol/HDL ratio, diabetes, smoking, C-reactive protein and moderate-vigorous physical activity (MVPA) were all independently associated with CVD death in males. In females, only age, diabetes, smoking, and BMI were significant independent predictors. The FRS risk factor model was predictive of CVD death (AUC=0.659; 95% CI 0.609-0.708 in males; AUC=0.689; 95% CI 0.621-0.756 in females). However, there was an additional benefit of including other lifestyle-related variables for the prediction of CVD death in CVD patients (AUC=0.751, 95% CI 0.710-0.792 in males; AUC=0.748, 95% CI 0.687-0.810 in females). CONCLUSIONS: The additional inclusion of lifestyle-related risk factors (body mass index, MVPA and psychological distress) and inflammatory marker (CRP) improved risk prediction of cardiovascular death in patients with pre-existing CVD, especially in males. PMID- 21700350 TI - Varying virulence: epigenetic control of expression noise and disease processes. AB - Gene expression noise is a significant source of phenotypic heterogeneity in otherwise identical populations of cells. Phenotypic heterogeneity can cause reversible drug resistance in diseased cells, and thus a better understanding of its origins might improve treatment strategies. In eukaryotes, data strongly suggest that intrinsic noise arises from transcriptional bursts caused by slow, random transitions between inactive and active gene states that are mediated by chromatin remodeling. In this review, we consider how chromatin modifications might modulate gene expression noise and lead to phenotypic diversity in diseases as varied as viral infection and cancer. Additionally, we argue that this fundamental information can be applied to develop innovative therapies that counteract 'pathogenic noise' and sensitize all diseased cells to therapeutic intervention. PMID- 21700351 TI - Radioresistant head and neck squamous cell carcinoma cells: intracellular signaling, putative biomarkers for tumor recurrences and possible therapeutic targets. AB - PURPOSE: Treatment of local and distant head and neck cancer recurrences after radiotherapy remains an unsolved problem. In order to identify potential targets for use in effective therapy of recurrent tumors, we have investigated protein patterns in radioresistant (FaDu-IRR and SCC25-IRR, "IRR cells") as compared to parental (FaDu and SCC25) head and neck carcinoma cells. METHODS AND MATERIALS: Radiation resistant IRR cells were derived from parental cells after repeated exposure to ionizing radiation 10 times every two weeks at a single dose of 10 Gy, resulting in a total dose of 100 Gy. Protein profiling in parental and IRR cells was carried out using two-dimensional differential gel electrophoresis (2D DIGE) followed by MALDI-TOF/TOF mass spectrometry. Cell viability, cell migration assays and Western blot analysis were used to confirm results obtained using the proteome approach. RESULTS: Forty-five proteins that were similarly modulated in FaDu-IRR and SCC25-IRR cells compared to parental cells were selected to analyze their common targets. It was found that these either up- or down-regulated proteins are closely related to the enhancement of cell migration which is regulated by Rac1 protein. Further investigations confirmed that Rac1 is up regulated in IRR cells, and inhibiting its action reduces the migratory abilities of these cells. Additionally, the Rac1 inhibitor exerts cytostatic effects in HNSCC cells, mostly in migratory cells. CONCLUSIONS: Based on these results, we conclude that radioresistant HNSCC cells possess enhanced metastatic abilities that are regulated by a network of migration-related proteins. Rac1 protein may be considered as a putative biomarker of HNSCC radiation resistance, and as a potential therapeutic target for treating local and distant HNSCC recurrences. PMID- 21700352 TI - Locomotor strategies in response to altered lower limb segmental mechanical properties. AB - The present study sought to use stilt walking as a model to uncover modifications to gait dynamics caused by changes in lower limb anthropometrics. We examined 10 novice and 10 expert stilt walkers, each walking with and without stilts, to determine the specific adaptations brought about by experience. Three-dimensional kinematics and force platform data were used to calculate the intersegmental forces, net joint moments and moment powers at the ankle, knee and hip. Spatio temporal data were computed to aid the interpretation of these data. Non dimensional scaling was used to facilitate comparison between stilt- and normal walking. In general, the stilts induced largely the same alterations in the locomotor patterns of both novices and experts, which did not allow for the conclusion that the experts employed locomotor dynamics that were better suited to the challenges imposed by alterations to limb length, mass and mass moment of inertia induced by the stilts. Nevertheless, the experts exhibited a lesser reduction in dimensionless stride length and velocity and generated larger concentric knee flexor and hip extensor powers, relative to the novices, which may be indicative of enhanced dynamic stability control. PMID- 21700353 TI - Antibiotic resistance in bacteria isolated from vegetables with regards to the marketing stage (farm vs. supermarket). AB - The aim of this study was to elucidate whether and to what extent fresh produce from Germany plays a role as a carrier and reservoir of antibiotic resistant bacteria. For this purpose, 1001 vegetables (fruit, root, bulbous vegetables, salads and cereals) were collected from 13 farms and 11 supermarkets in Germany and examined bacteriologically. Phenotypic resistance of Enterobacter cloacae (n=172); Enterobacter gergoviae (n=92); Pantoea agglomerans (n=96); Pseudomonas aeruginosa (n=295); Pseudomonas putida (n=106) and Enterococcus faecalis (n=100) against up to 30 antibiotics was determined by using the microdilution method. Resistance to beta-lactams was most frequently expressed by P. agglomerans and E. gergoviae against cefaclor (41% and 29%). Relatively high resistance rates were also observed for doxycycline (23%), erythromycin (21%) and rifampicin (65%) in E. faecalis, for spectinomycin (28%) and mezlocillin (12%) in E. cloacae, as well as for streptomycin (19%) in P. putida. In P. aeruginosa, relatively low resistance rates were observed for the aminoglycosides amikacin, apramicin, gentamicin, neomycin, netilmicin and tobramycin (<4%); 11% was resistant to streptomycin. No glycopeptide-resistant enterococci were observed. Resistance rates of bacteria isolated from farm samples were higher than those of the retail markets whenever significant differences were observed. This suggests that expressing resistance is at the expense of bacterial viability, since vegetables purchased directly at the farm are probably fresher than at the supermarket, and they have not been exposed to stress factors. However, this should not keep the customer from buying directly at the farm, since the overall resistance rates were not higher than observed in bacteria from human or animal origin. Instead, peeling or washing vegetables before eating them raw is highly recommended, since it reduces not only the risk of contact with pathogens, but also that of ingesting and spreading antibiotic resistant bacteria. PMID- 21700354 TI - Galactooligosaccharides derived from lactose and lactulose: influence of structure on Lactobacillus, Streptococcus and Bifidobacterium growth. AB - The effect of structure on the fermentative properties of potential prebiotic trisaccharides derived from lactulose like 6'-galactosyl-lactulose (beta-d galactopyranosyl-(1->6)-beta-d-galactopyranosyl-(1->4)-beta-d-fructopyranose), 4' galactosyl-lactulose (beta-d-galactopyranosyl-(1->4)-beta-d-galactopyranosyl-(1 >4)-beta-d-fructopyranose), and 1-galactosyl-lactulose (beta-d-galactopyranosyl (1->4)-beta-d-fructopyranosyl-(1->1)-beta-d-galactopyranose); and from lactose like 4'-galactosyl-lactose (beta-d-galactopyranosyl-(1->4)-beta-d galactopyranosyl-(1->4)-beta-d-glucopyranose) and 6'-galactosyl-lactose (beta-d galactopyranosyl-(1->6)-beta-d-galactopyranosyl-(1->4)-beta-d-glucopyranose), has been assessed in vitro. Fermentations with twelve pure strains of Lactobacillus, Streptococcus and Bifidobacterium were carried out using the purified trisaccharides as the sole carbon source, and bacteria growth was evaluated at 600nm by means of a microplate reader during 48h. Maximum growth rates (MU(max)) and lag phase were calculated. In general, all the strains tested were able to utilize lactulose and pure trisaccharides derived from lactulose and lactose when they were used as sole carbon source. Nonetheless, glycosidic linkage and/or the monosaccharide composition of the trisaccharides affected the individual strains lag phase, cell densities and growth rates. A general preference towards beta galactosyl residues beta(1-6) and beta(1-1) linked over those beta(1-4) linked was observed, and some strains showed higher cell densities and speed of growth on 6'-galactosyl-lactulose than on 6'-galactosyl-lactose. This is the first study of the effect of lactulose-derived oligosaccharides on pure culture growth which shows that transglycosylation of lactulose allows for obtaining galactooligosaccharides with new glycosidic structures and would open new routes to the synthesis of compounds with potential prebiotic effects. PMID- 21700355 TI - Design and implementation of a distributed teleradiaography system: DIPACS. AB - Medical imaging informatics has origins spanning back over two or more decades. Currently, sharing of radiological images for diagnosis, collaborative and administrative purposes is one of the challenging issues in both medicine and computer science. In this study, we designed and implemented a distributed PACS system, namely DIPACS, for small and medium scale medical networks. DIPACS forms a virtual organization by combining the storage of health centers and providing transparent access to images. In this study, we introduce the DIPACS architecture together with the implementation details. PMID- 21700356 TI - Hydrogen peroxide stabilization in one-dimensional flow columns. AB - Rapid hydrogen peroxide decomposition is the primary limitation of catalyzed H(2)O(2) propagations in situ chemical oxidation (CHP ISCO) remediation of the subsurface. Two stabilizers of hydrogen peroxide, citrate and phytate, were investigated for their effectiveness in one-dimensional columns of iron oxide coated and manganese oxide-coated sand. Hydrogen peroxide (5%) with and without 25 mM citrate or phytate was applied to the columns and samples were collected at 8 ports spaced 13 cm apart. Citrate was not an effective stabilizer for hydrogen peroxide in iron-coated sand; however, phytate was highly effective, increasing hydrogen peroxide residuals two orders of magnitude over unstabilized hydrogen peroxide. Both citrate and phytate were effective stabilizers for manganese coated sand, increasing hydrogen peroxide residuals by four-fold over unstabilized hydrogen peroxide. Phytate and citrate did not degrade and were not retarded in the sand columns; furthermore, the addition of the stabilizers increased column flow rates relative to unstabilized columns. These results demonstrate that citrate and phytate are effective stabilizers of hydrogen peroxide under the dynamic conditions of one-dimensional columns, and suggest that citrate and phytate can be added to hydrogen peroxide before injection to the subsurface as an effective means for increasing the radius of influence of CHP ISCO. PMID- 21700357 TI - The cellular basis of chitin synthesis in fungi and insects: common principles and differences. AB - Chitin is a polymer of N-acetylglucosamine, which assembles into microfibrils of about 20 sugar chains. These microfibrils serve as a structural component of natural biocomposites found in cell walls and specialized extracellular matrices such as cuticles and peritrophic membranes. Chitin synthesis is performed by a wide range of organisms including fungi and insects. The underlying biosynthetic machinery is highly conserved and involves several enzymes, of which the chitin synthase is the key enzyme. This membrane integral glycosyltransferase catalyzes the polymerization reaction. Most of what we know about chitin synthesis derives from studies of fungal and insect systems. In this review, common principles and differences will be worked out at the levels of gene organization, enzymatic properties, cellular localization and regulation. PMID- 21700359 TI - [Thomson anterior capsular dots]. PMID- 21700360 TI - A randomized, single-blind trial of 5% minoxidil foam once daily versus 2% minoxidil solution twice daily in the treatment of androgenetic alopecia in women. AB - BACKGROUND: Although twice-daily application of propylene glycol-containing 2% minoxidil topical solution (MTS) stimulates new hair growth, higher concentrations of minoxidil in a once-daily, propylene glycol-free formulation may improve efficacy and reduce unpleasant side effects. OBJECTIVE: We sought to compare the efficacy, safety, and acceptability and to show noninferiority of once-daily 5% minoxidil topical foam (MTF) with twice-daily 2% MTS in women with androgenetic alopecia. METHODS: A total of 113 women with androgenetic alopecia were randomized to 24 weeks of treatment with 5% MTF or 2% MTS. The primary efficacy parameter was change from baseline in nonvellus target area hair count at week 24. Secondary end points included change in nonvellus target area hair width, overall efficacy by global photographic review as assessed by treatment blinded evaluators and the subject herself, adverse events, and participants' assessment of product aesthetics. RESULTS: After 24 weeks, women randomized to 5% MTF once daily showed noninferior target area hair count and target area hair width and experienced greater, but nonsignificant, improvements in target area hair count, target area hair width, and overall efficacy by global photographic review than those randomized to 2% MTS used twice daily. 5% MTF was significantly superior to 2% MTS in participants' agreement with "the treatment does not interfere with styling my hair" (P = .002). Women randomized to 5% MTF experienced significantly lower rates of local intolerance (P = .046) especially in pruritus and dandruff compared with 2% MTS. LIMITATION: Because of differences in the formulations tested, study participants were not blinded to treatment. CONCLUSIONS: Once-daily 5% MTF is noninferior and as effective for stimulating hair growth as twice-daily 2% MTS in women with androgenetic alopecia and is associated with several aesthetic and practical advantages. PMID- 21700358 TI - A role for Tctex-1 (DYNLT1) in controlling primary cilium length. AB - The microtubule motor complex cytoplasmic dynein is known to be involved in multiple processes including endomembrane organization and trafficking, mitosis, and microtubule organization. The majority of studies of cytoplasmic dynein have focused on the form of the motor that is built around the dynein-1 heavy chain. A second isoform, dynein heavy chain-2, and its specifically associated light intermediate chain, LIC3 (D2LIC), are known to be involved in the formation and function of primary cilia. We have used RNAi in human epithelial cells to define the cytoplasmic dynein subunits that function with dynein heavy chain 2 in primary cilia. We identify the dynein light chain Tctex-1 as a key modulator of cilia length control; depletion of Tctex-1 results in longer cilia as defined by both acetylated tubulin labeling of the axoneme and Rab8a labeling of the cilia membrane. Suppression of dynein heavy chain-2 causes concomitant loss of Tctex-1 and this correlates with an increase in cilia length. Compared to individual depletions, double siRNA depletion of DHC2 and Tctex-1 causes an even greater increase in cilia length. Our data show that Tctex-1 is a key regulator of cilia length and most likely functions as part of dynein-2. PMID- 21700361 TI - Hazard rates for recurrent and secondary cutaneous melanoma: an analysis of 33,384 patients in the German Central Malignant Melanoma Registry. AB - BACKGROUND: Knowledge about the risk for recurrence and secondary cutaneous melanoma (CM) is an important basis for patient counseling and planning of follow up examinations. OBJECTIVES: This study aimed to analyze stage- and time dependent hazard rates (HR) and discusses current surveillance recommendations. METHODS: Follow-up data of 33,384 patients with incident CM in stages I to III (American Joint Committee on Cancer 2002) were recorded by the German Central Malignant Melanoma Registry in 1976 through 2007. Survival was based on Kaplan Meier estimates and HRs were calculated. RESULTS: Recurrences were recorded in 4999 patients (stage I, 7.1%; stage II, 32.8%; and stage III, 51.0%). Ten-year recurrence-free survival was 78.9% (95% confidence interval 73.1-90.5); in stage I, 89.0%; stage II, 56.9%; and stage III, 36.0%. Whereas HR for recurrent CM showed a constantly low level less than or equal to 1:125 per year for stage IA, clearly higher HRs of greater than or equal to 1:40 were recorded in stage IB for the first 3 years and generally in stages II to III. Of all patients 2.3% developed secondary melanomas, with a consistently low HR of less than 1:220 per year. LIMITATIONS: As German recommendations discontinued regular follow-up examinations after 10 years, no information can be given beyond this time point. Follow-up data of longer than 5 years were available in 41.4% of patients. CONCLUSION: For patients at stage IA with thin melanoma and low HR for recurrent CM the need for surveillance remains questionable. For patients with higher HR greater than 1:40 per year, intensified surveillance strategies should be taken into account. PMID- 21700362 TI - Expression of CD10 predicts tumor progression and unfavorable prognosis in malignant melanoma. AB - BACKGROUND: CD10 expression in malignant melanoma (MM) has been reported to increase according to tumor progression and metastasis; however, its association with patient outcome has not been clarified. OBJECTIVE: We examined the immunohistochemical expression of CD10 in MM to determine whether or not it could serve as a marker for tumor progression and prognosis. METHODS: A total of 64 formalin-fixed, paraffin-embedded samples of primary MM were immunostained for CD10. Similarly, 40 samples of melanocytic nevus and 20 of metastatic MM were analyzed for comparison. The following clinicopathologic variables were evaluated: age, gender, histologic type, tumor site, Breslow thickness, Clark level, the presence or absence of ulceration and tumor-infiltrating lymphocytes, and survival. Statistical analyses were performed to assess for associations. Several parameters were analyzed for survival using the Kaplan-Meier method and Cox proportional hazards model. RESULTS: Immunohistochemical analysis revealed that 34 of 64 cases (53%) of primary MM expressed CD10, compared with 15 of 20 cases (75%) of metastatic MM and only 4 of 40 cases (10%) of nevus. There was a significant positive relationship between CD10 expression and Breslow thickness, Clark level, and ulceration. Univariate analysis revealed 4 significant factors for shorter survival periods: CD10 expression, high Breslow thickness, high Clark level, and the presence of ulceration (P < .01 each). In multivariate analysis, CD10 expression was revealed to be a statistically significant and independent prognostic factor. LIMITATIONS: The major limitation was the small sample size. CONCLUSION: CD10 expression may serve as a progression marker and can predict unfavorable prognosis in patients with MM. PMID- 21700363 TI - High Horn's index score predicts poor outcomes in patients with Clostridium difficile infection. AB - Several variables have been proposed to predict the prognosis of patients with Clostridium difficile infection (CDI), but a clinically useful tool to stratify resource utilization has not been determined. Horn's index, a severity score based on underlying clinical illness, reliably predicts patients at high risk of CDI. The purpose of this study was to assess the use of Horn's index to stratify patients with CDI at high risk of poor clinical and economic outcomes. Hospitalized patients diagnosed with CDI were followed prospectively for three months. Horn's index scores were calculated for each patient on the day of the positive toxin test for C. difficile, and used to stratify differences in outcome variables (length of hospital stay, mortality and hospital costs). Eighty-five CDI patients (50% male, 64% Caucasian) were recruited. Discharge mortality was 0% for patients with Horn's index scores of 1 or 2, 5% for those with a score of 3, and 50% for those with a score of 4 (P < 0.001). Three-month mortality was 0%, 5%, 17% and 60% for patients with Horn's index scores of 1, 2, 3 and 4, respectively (P = 0.0004). Median three-month hospital costs were $8,585, $12,670, $29,077 and $68,708 for patients with Horn's index scores of 1, 2, 3 and 4, respectively (P < 0.001). Patients with Horn's index scores of 3 or 4 had a significantly longer hospital stay [mean 33.4 (standard deviation, SD 33.3) days] than patients with scores of 1 or 2 [mean 15.1 (SD 16.2) days, P = 0.001]. This study found Horn's index to be a simple and useful method for identifying CDI patients at high risk of poor clinical and economic outcomes. PMID- 21700364 TI - Glucose meters and opportunities for in-hospital transmission of infection: Quantitative assessment and management with and without patient assignment. AB - BACKGROUND: Increasing use of glucose meters in hospitals has increased opportunities for infection transmission that have not been quantitatively assessed or managed. METHODS: Before-and-after study of the effects of augmentation of glucose meter inventory and of assignment of glucose meters to individual patients on the sequential use of glucose meters on different patients in a 214-bed hospital. RESULTS: During October 2008, 11,665 measurements were performed using 38 glucose meters on 803 patients. A total of 9,302 tests (79.7%) was performed sequentially within 24 hours on different patients. From October 28 through November 27, 2009, the glucose meter inventory on 3 high-use units glucose meters was increased (from 22 to 87) with meters assigned to individual patients; on 4 low-use units, glucose meter inventory was increased (from 16 to 28) without assignment to individual patients. Sequential glucose meter use on different patients within 24 hours decreased by 95.1% on high-use units and increased by 17% on low-use units. CONCLUSION: Use of glucose meters was associated with a high number of opportunities to transmit infections, and those opportunities were reduced only when glucose meters were assigned to individual patients. Recent guidance from the Centers for Disease Control and Prevention and the US Food and Drug Administration to assign glucose meters to individual persons whenever possible is relevant to inpatient care. PMID- 21700365 TI - [Outcomes of expanded use of PCA3 testing in a Spanish population with clinical suspicion of prostate cancer]. AB - OBJECTIVES: DD3(PCA3) (PCA3) gene expression is prostate cancer-specific. Routine use of this biomarker has resulted in a 35-67% reduction in the number of required biopsies. The aim of this study is to evaluate our outcomes in its routine use and to establish in which group of patients this is the most efficient, depending on the number of previous PCA3 biopsies. MATERIAL AND METHODS: A total of 474 consecutive patients who had previously undergone a biopsy (group A, n=337) or not (group B, n=134) for whom a PCA3 was requested were analyzed. We subdivided group A into A(1) (a previous biopsy, n=182) and A(2) (<1 previous biopsy, n=155). The recommendation of whether to perform a biopsy or not was made independently by each of the 11 clinicians and guided by prostatic specific antigen (PSA) levels and digital rectal examination. RESULTS: Median age was 65 years (range 38 to 84). PCA3 score had an informative ratio of 99.6%, with a median of 29 (range 1-3245). The percentage of biopsy sparing was 49% of the cases. ROC analysis demonstrated an AUC for PSA and PCA3 of 0.532 (P=.417) and 0.672 (P<.0001), respectively. Sensitivities of PSA>= 4 and PCA3>= 35 were 87% vs. 85%, with specificities of 12% vs. 33%, PPV 34% vs. 39% and NPV 63% vs. 81%, respectively. The PCA3 score showed direct correlation with the percentage of positive biopsies (P<.0001). CONCLUSIONS: Routine use of PCA3, due to its high NPV, results in a significant reduction in the number of biopsies. PCA3 appears to be more efficient in biopsy-naive patients. Among patients already biopsied, the results are superior in those biopsied only once. PMID- 21700366 TI - [Transperitoneal laparoscopic adrenalectomy]. AB - OBJECTIVES: To present our results with transperitoneal laparoscopic adrenalectomy after completion of 70 procedures. MATERIAL AND METHODS: Between July 2002 and December 2010, transperitoneal laparoscopic adrenalectomy was performed in 70 patients with the following diagnoses: Conn syndrome (22 cases), nonfunctioning adenomas (18), Cushing syndrome (10), pheochromocytomas (7), myelolipomas (4), metastasis after treatment of primary nonadrenal tumors (6), ganglioneuroma (1), adrenal gland hematoma (1) and adrenal carcinoma (1). We describe the size, surgical and hospitalization times, blood loss, need for transfusion, surgical complications and rate of conversion to open surgery. RESULTS: Of 70 patients, 35 were men and 35 women (1:1) with a mean age of 58.2 years (range, 82.2- 29.1). The most common site was left (58%) compared to right (42%). The mean size of the surgical specimen was 5.11 cm, mean surgical time was 119.2 minutes (50-240) and mean operative bleeding was 140.6 (30-800) cc. Only 3 patients required blood transfusion. The mean time until oral feeding was 17 hours, and the mean hospital stay was 4.3 (2-15) days. Complications included 2 cases of surgical infections, 1 of prolonged paralytic ileus, and 1 of splenic laceration and 1 of intestinal perforation which both which required reconversion to open surgery (4.28%). CONCLUSIONS: Laparoscopic adrenalectomy is a safe procedure, with a low percentage of complications and a short hospital stay. The choice of this approach will depend on the surgeon's experience with the lesion etiology and size in each case. PMID- 21700369 TI - New insights into the structural requirements for pro-apoptotic agents based on 2,4-diaminoquinazoline, 2,4-diaminopyrido[2,3-d]pyrimidine and 2,4 diaminopyrimidine derivatives. AB - As a continuation of our work on new anti-tumoral derivatives with selective pro apoptotic activity in cancer cells, we describe the synthesis and the preliminary evaluation of the cytotoxic and pro-apoptotic activities of a series of pyrimidin 2,4-diamine derivatives that are structurally related to quinazolin-2,4-diamine and pyrido[2,3-d]pyrimidin-2,4-diamine derivatives. We also describe the structure-activity relationship studies carried out on four series' of quinazolin 2,4-diamine, 2-(alkylsulfanyl)-N-alkyl- and 2-(alkylsulfanyl)-N alkylarylpyrido[2,3-d]pyrimidine and pyrimidin-2,4-diamine derivatives. The proposed preliminary pharmacophore consists of a flat heterocyclic ring, preferably a pyrido[2,3-d]pyrimidine, with two equivalent alkylarylamine chains, preferably N-benzyl- or N-ethylphenylamine, located in positions 2 and 4 of the ring, and with a preferred ALogP in the range 4.5-5.5. The nitrogen present in the central ring can act as hydrogen bond acceptors (HBA) whereas the amino group in the 4-position can act as a donor (HBD) or an HBA and the amino group in the 2 position can act as an HBD. On the basis of the analyzed structural profiles, different mechanisms of action can be suggested for the quinazolin-2,4-diamine, the 2-(alkylsulfanyl)-N-alkylpyrido[2,3-d]pyrimidin-4-amine and the pyrido[2,3 d]pyrimidin-2,4-diamine derivatives. PMID- 21700368 TI - Synthesis, antiviral activity, cytotoxicity and cellular pharmacology of l-3' azido-2',3'-dideoxypurine nucleosides. AB - Microwave-assisted optimized transglycosylation reactions were used to prepare eleven modified l-3'-azido-2',3'-dideoxypurine nucleosides. These l-nucleoside analogs were evaluated against HIV and hepatitis B virus. The l-3'-azido-2',3' dideoxypurines nucleosides were metabolized to nucleoside 5'-triphosphates in primary human lymphocytes, but exhibited weak or no antiviral activity against HIV-1. The nucleosides were also inactive against HBV in HepG2 cells. Pre-steady state kinetic experiments demonstrated that the l-3'-azido-2',3'-dideoxypurine triphosphates could be incorporated by purified HIV-1 reverse transcriptase, although their catalytic efficiency (k(pol)/K(d)) of incorporation was low. Interestingly, a phosphoramidate prodrug of l-3'-azido-2',3'-dideoxyadenosine exhibited anti-HIV-1 activity without significant toxicity. PMID- 21700370 TI - Oleate-enriched diet improves insulin sensitivity and restores muscle protein synthesis in old rats. AB - BACKGROUND & AIMS: Age-related inflammation and insulin resistance (IR) have been implicated in the inability of old muscles to properly respond to anabolic stimuli such as amino acids (AA) or insulin. Since fatty acids can modulate inflammation and IR in muscle cells, we investigated the effect of palmitate enriched diet and oleate-enriched diet on inflammation, IR and muscle protein synthesis (MPS) rate in old rats. METHODS: Twenty-four 25-month-old rats were fed either a control diet (OC), an oleate-enriched diet (HFO) or a palmitate-enriched diet (HFP) for 16 weeks. MPS using labeled amino acids and mTOR activation were assessed after AA and insulin anabolic stimulation to mimic postprandial state. RESULTS: IR and systemic and adipose tissue inflammation (TNFalpha and IL1beta) were improved in the HFO group. Muscle genes controlling mitochondrial beta oxidation (PPARs, MCAD and CPT-1b) were up-regulated in the HFO group. AA and insulin-stimulated MPS in the HFO group only, and this stimulation was related to activation of the Akt/mTOR pathway. CONCLUSIONS: The age-related MPS response to anabolic signals was improved in rats fed an oleate-enriched diet. This effect was related to activation of muscle oxidative pathways, lower IR, and a decrease in inflammation. PMID- 21700371 TI - Use of two-piece polyetheretherketone (PEEK) implants in orbitozygomatic reconstruction. PMID- 21700372 TI - Arsenic distribution in soils and plants of an arsenic impacted former mining area. AB - A mining area affected by the abandoned exploitation of an arsenical tungsten deposit was studied in order to assess its arsenic pollution level and the feasibility of native plants for being used in phytoremediation approaches. Soil and plant samples were collected at different distances from the polluting sources and analysed for their As content and distribution. Critical soil total concentrations of As were found, with values in the range 70-5330 mg kg(-1) in the uppermost layer. The plant community develops As tolerance by exclusion strategies. Of the plant species growing in the most polluted site, the shrubs Salix atrocinerea Brot. and Genista scorpius (L.) DC. exhibit the lowest bioaccumulation factor (BF) values for their aerial parts, suggesting their suitability to be used with revegetation purposes. The species Scirpus holoschoenus L. highlights for its important potential to stabilise As at root level, accumulating As contents up to 3164 mg kg(-1). PMID- 21700373 TI - Hydrocarbon degradation, plant colonization and gene expression of alkane degradation genes by endophytic Enterobacter ludwigii strains. AB - The genus Enterobacter comprises a range of beneficial plant-associated bacteria showing plant growth promotion. Enterobacter ludwigii belongs to the Enterobacter cloacae complex and has been reported to include human pathogens but also plant associated strains with plant beneficial capacities. To assess the role of Enterobacter endophytes in hydrocarbon degradation, plant colonization, abundance and expression of CYP153 genes in different plant compartments, three plant species (Italian ryegrass, birdsfoot trefoil and alfalfa) were grown in sterile soil spiked with 1% diesel and inoculated with three endophytic E. ludwigii strains. Results showed that all strains were capable of hydrocarbon degradation and efficiently colonized the rhizosphere and plant interior. Two strains, ISI10 3 and BRI10-9, showed highest degradation rates of diesel fuel up to 68% and performed best in combination with Italian ryegrass and alfalfa. All strains expressed the CYP153 gene in all plant compartments, indicating an active role in degradation of diesel in association with plants. PMID- 21700374 TI - [Instent restenosis related to vessel injury score degree. Are current experimental models valid for drug-eluting stents analysis?]. AB - INTRODUCTION AND OBJECTIVES: Drug-eluting stents are useful for preventing restenosis, but the patho-physiological processes involved in the proliferative response after implantation are still not known in detail. The aim of this study is to compare the coronary vascular histomorphometry after implanting drug eluting stents and bare metal stents in a swine model. METHODS: Sixty stents were randomly implanted in 20 Large White female pigs with a ratio of baremetal/drug eluting stents of 1:2. After 28 days, euthanasia and histomorphometry were performed. We defined the vessel injury score in accordance to whether the internal elastic lamina was intact or ruptured. RESULTS: There were no differences between drug-eluting stents and bare metal stents in the intact internal elastic lamina group regarding neointimal area or % restenosis (1.3 [1.1 2.2]) vs 2.0 [1.3-2.5] mm2; P=.6; and 14.0 [12.1-20.8] vs 22.2 [14.1-23.3] %; P=.5). We assessed statistically significant differences for the ruptured internal elastic lamina group, (neointimal area 1.2 [0.8-2.0] vs 2.9 [2.3-3.7] mm2; P=.001 and % restenosis 16.63 [11.2-23.5] vs 30.4 [26.4-45.7] %; P=.001). CONCLUSIONS: In our swine model, we did not find any differences between proliferative response of drug-eluting stents and bare metal stents when the internal elastic lamina is intact; differences are only found when vascular injury is deeper. PMID- 21700375 TI - [Comparison of the management of non-ST segment elevation myocardial infarction during emergency care according to sex of the patient]. AB - The atypical characteristics of acute coronary syndrome in women lead to differences in management and treatment. We investigated these differences in the urgent management of non-ST-segment acute myocardial infarction (NSTEMI). Data on 39 variables were collected from 539 patients with NSTEMI treated at 97 Spanish emergency departments. After adjustment for 10 baseline differences, the only significant differences were that time-to-arrival at the emergency department was longer for women (odds ratio [OR]=0.52; 95% confidence interval [CI], 0.28-0.95) and that they received more clopidogrel (OR=1.65; 95% CI, 1.06-2.56). The trend to fewer admissions to coronary or intensive care units (42.9% vs 55.6%) and fewer catheterization procedures (29.7% vs 40.7%) disappeared after adjustment. We conclude that there are virtually no differences in treatment in women with N STEMI in prehospital and emergency care. PMID- 21700376 TI - Methods for the measurement of the terminal 40-millisecond (T40-ms) frontal plane axis in tricyclic antidepressant poisoning. PMID- 21700377 TI - Hypocapnia induced cerebral ischaemia during therapeutic hypothermia-Potential for harm? PMID- 21700378 TI - Surgical skills training: does it improve clinical outcome? PMID- 21700379 TI - Did the 2005 AHA Guidelines bundle improve outcome following out-of-hospital cardiac arrest? PMID- 21700380 TI - Nutrient intake, anthropometric data and correlations with the systemic antioxidant capacity of women with pelvic endometriosis. AB - OBJECTIVE: Endometriosis is a multifactorial disease of uncertain etiology. There is currently insufficient evidence to assess the participation of nutritional and anthropometric aspects and their association with systemic oxidative stress. STUDY DESIGN: Twenty-five women with endometriosis and twenty controls were selected and evaluated to determine calorie and nutrient intake, to obtain data on body composition and analyze antioxidant capacity by measuring total serum thiol levels using DTNB (5,5'-dithiobis-(2-nitrobenzoic acid). RESULTS: Mean total daily calorie intake in the women in the endometriosis group was significantly higher than that of the women in the control group (p=0.005). With respect to nutrient intake, the only statistically significant difference found referred to a higher intake of fiber in the endometriosis group and of polyunsaturated fatty acids in the control group (p<0.05). CONCLUSIONS: Nutrient intake by the women in the endometriosis group was similar to that of women in the control group, the only differences being a higher intake of fiber in the endometriosis group and of polyunsaturated fatty acids in the control group. Antioxidant capacity was lower in the women with endometriosis but there was no correlation with nutrient intake or overweight. PMID- 21700381 TI - Predicting deer-vehicle collisions in an urban area. AB - Collisions with deer and other large animals are increasing, and the resulting economic costs and risks to public safety have made mitigation measures a priority for both city and wildlife managers. We created landscape models to describe and predict deer-vehicle collision (DVCs) within the City of Edmonton, Alberta. Models based on roadside characteristics revealed that DVCs occurred frequently where roadside vegetation was both denser and more diverse, and that DVCs were more likely to occur when the groomed width of roadside right-of-ways was smaller. No DVCs occurred where the width of the vegetation-free or manicured roadside buffer was greater than 40 m. Landscape-based models showed that DVCs were more likely in more heterogeneous landscapes where road densities were lower and speed limits were higher, and where non-forested vegetation such as farmland was in closer proximity to larger tracts of forest. These models can help wildlife and transportation managers to identify locations of high collision frequency for mitigation. Modifying certain landscape and roadside habitats can be an effective way to reduce deer-vehicle collisions. PMID- 21700382 TI - A conjoint analysis of landholder preferences for reward-based land-management contracts in Kapingazi watershed, Eastern Mount Kenya. AB - Unsustainable land-use decisions and agricultural practices have become the key drivers of deteriorating watershed services in developing countries. However, landholders may have little or no incentives to take these impacts into account in their decision-making process. In recent years, reward-based provision of environmental services has emerged as an important market-based incentive for motivating landholders to adopt environmentally friendly land-use changes and agricultural practices. In this regard, for instance, the Pro-Poor Rewards for Environmental Services in Africa (PRESA) project has emerged as a large network to support and facilitate reward mechanisms in Africa. However, in many African rural settings, little is known about landholder attitudes and preferences related to the alternative land-management schemes. Using locally identified sets of six key land-management attributes, this paper applies conjoint methods to evaluate landholder preferences towards alternative land-management schemes aimed at enhancing the provision of watershed services in the River Kapingazi catchment in central Kenya. Data were collected from primary sources through focus groups and a questionnaire based conjoint survey. Three conjoint models were used; a traditional conjoint ratings model, a binary logit model, and an ordered logit model. Results from the focus groups indicated that shortage of water for both domestic use and irrigation was perceived as the most acute environmental problem in the area. Deforestation, poor river bank management and agricultural practices were identified as the major causes of the problem. Results from conjoint models show that the three principal attributes influencing landholder's ratings and probability of adopting the proposed land management options were 'size of land area to be committed', 'length of contract period', and 'granting or prohibiting rights to harvest environmental products from the committed land'. Thus, these attributes should be the focal points in designing land-management contract for watershed services in the study area. PMID- 21700383 TI - Screening of factors influencing Cu(II) extraction by soybean oil-based organic solvents using fractional factorial design. AB - This study aimed to identify the significant factors that give large effects on the efficiency of Cu(II) extraction from aqueous solutions by soybean oil-based organic solvents using fractional factorial design. Six factors (mixing time (t), di-2-ethylhexylphosphoric acid concentration ([D2EHPA]), organic to aqueous phase ratio (O:A), sodium sulfate concentration ([Na(2)SO(4)]), equilibrium pH (pH(eq)) and tributylphosphate concentration ([TBP])) affecting the percentage extraction (%E) of Cu(II) were investigated. A 2(6-1) fractional factorial design was applied and the results were analyzed statistically. The results show that only [D2EHPA], pH(eq) and their second-order interaction ([D2EHPA] * pH(eq)) influenced the %E significantly. Regression models for %E were developed and the adequacy of the reduced model was examined. The results of this study indicate that fractional factorial design is a useful tool for screening a large number of variables and reducing the number of experiments. PMID- 21700384 TI - OCT assessment of morphological changes of the optic nerve head and macula in idiopathic intracranial hypertension. AB - OBJECTIVE: To assess the morphologic changes of the optic nerve head and macula in patients with idiopathic intracranial hypertension (IIH) with optical coherence tomography (OCT). METHODS: Data was extracted from the medical records and Stratus OCT images of IIH patients. RESULTS: Ninety-one eyes of 48 IIH patients were divided into 3 groups according to their clinical optic disc appearance. Average retinal nerve fiber layer (RNFL) thickness was statistically different between the groups: normal optic disc/mild elevation group (N=20) - 89 MUm (95% CI, 80-98 MUm), mild elevation group (N=51) - 109 MUm (95% CI, 101-117 MUm), and papilledema group (N=20) 124 MUm (95% CI, 100-153 MUm) (P=0.004). Fast macular thickness map did not demonstrate a significant difference between the groups for most measured macular areas (N=49 eyes). CONCLUSIONS: Peripapillary RNFL measurements correlated with the clinical appearance of the optic discs, suggesting that OCT may assist in the follow up of IIH patients. PMID- 21700385 TI - Discrimination of organic solid materials by LIBS using methods of correlation and normalized coordinates. AB - The methods of linear and rank correlation and normalized coordinates (MNC) have been applied to the identification of organic solid materials with a very similar chemical composition by laser-induced breakdown spectroscopy (LIBS). The present study evaluated these three statistical methods using an Echelle spectrometer coupled with an intensified charge-coupled device (ICCD). Moreover, three instrumental parameters (laser pulse energy, delay time and integration time) were evaluated in terms of their influence on the signal-to-noise ratio of carbon and hydrogen emission lines. The probability of a right identification can be estimated by means the described methods in this paper. Methods of correlation provide better identification and discrimination than normalized coordinates at a 95% confidence level. PMID- 21700386 TI - Enhanced sorption and photodegradation of chlorophenol over fluoride-loaded TiO2. AB - The presence of NaF in the aqueous suspension of TiO(2) can accelerate the photocatalytic degradation of organic pollutants. However, disposal of such a fluoride-containing wastewater is not allowed by environmental regulation. In the present work, we report on surface modification of TiO(2) with a hardly water soluble salt, fluorite and fluorapatite. The modified catalysts at low loading displayed a higher activity than bare TiO(2) for the sorption and photocatalytic degradation of phenol and 2,4-dichlorophenol in water. A kinetic study using butanol as hydroxyl radical scavenger revealed that the fluoride-modified catalysts produced more hydroxyl radicals than bare TiO(2). Five repeated experiments showed that the fluorapatite-modified TiO(2) was very stable, and could be re-used without significant loss in activity. PMID- 21700387 TI - Detoxification of PAX-21 ammunitions wastewater by zero-valent iron for microbial reduction of perchlorate. AB - US Army and the Department of Defense (DoD) facilities generate perchlorate (ClO(4)(-)) from munitions manufacturing and demilitarization processes. Ammonium perchlorate is one of the main constituents in Army's new main charge melt-pour energetic, PAX-21. In addition to ammonium perchlorate, hexahydro-1,3,5-trinitro 1,3,5-triazine (RDX) and 2,4-dinitroanisole (DNAN) are the major constituents of PAX-21. In order to evaluate microbial perchlorate reduction as a practical option for the treatment of perchlorate in PAX-21 wastewater, we conducted biodegradation experiments using glucose as the primary sources of electrons and carbon. Batch experiments showed that negligible perchlorate was removed in microbial reactors containing PAX-21 wastewater while control bottles containing seed bacteria and glucose rapidly and completely removed perchlorate. These results suggested that the constituents in PAX-21 wastewater may be toxic to perchlorate reducing bacteria. A series of batch toxicity test was conducted to identify the toxic constituents in PAX-21 and DNAN was identified as the primary toxicant responsible for inhibiting the activity of perchlorate reducing bacteria. It was hypothesized that pretreatment of PAX-21 by zero-valent iron granules will transform toxic constituents in PAX-21 wastewater to non-toxic products. We observed complete reduction of DNAN to 2,4-diaminoanisole (DAAN) and RDX to formaldehyde in abiotic iron reduction study. After a 3-day acclimation period, perchlorate in iron-treated PAX-21 wastewater was rapidly decreased to an undetectable level in 2 days. This result demonstrated that iron treatment not only removed energetic compounds but also eliminated the toxic constituents that inhibited the subsequent microbial process. PMID- 21700388 TI - Probing metabolic stability of CdSe nanoparticles: alkaline extraction of free cadmium from liver and kidney samples of rats exposed to CdSe nanoparticles. AB - Cadmium selenide nanoparticles (CdSe NPs) exhibit novel optoelectronic properties for potential biomedical applications. However, their metabolic stability is not fully understood because of the difficulties in measurement of free Cd from biological tissues of exposed individuals. In this study, alkaline dissolution with tetramethylammonium hydroxide (TMAH) is demonstrated for selective determination of free Cd and intact NPs from liver and kidney samples of animals that were exposed to thiol-capped CdSe NPs. Aqueous suspensions of CdSe NPs (3.2 nm) were used to optimize the conditions for extracting free Cd without affecting NPs. Nanoparticles were found to aggregate when heated in TMAH without releasing any significant Cd to solution. Performance of the method in discriminating free Cd and intact NPs were verified by Dogfish Liver (DOLT-4) certified reference material. The samples from the animals were digested in 4 mL TMAH at 70 degrees C to extract free Cd followed by analysis of aqueous phase by ICP-MS. Both liver and kidney contained significant levels of free Cd. Total Cd was higher in the liver, while kidney accumulated mostly free Cd such that up to 47.9% of total Cd in the kidney was free Cd when NPs were exposed to UV-light before injection. PMID- 21700389 TI - Detection of reactive oxygen species (ROS) generated by TiO2(R), TiO2(R/A) and TiO2(A) under ultrasonic and solar light irradiation and application in degradation of organic dyes. AB - In the present work, the rutile, anatase and mixed (rutile and anatase) crystal phase TiO(2) powders were irradiated by ultrasound and solar light, respectively, and the generation of reactive oxygen species (ROS) were detected through the oxidation reaction from 1,5-diphenyl carbazide (DPCI) to 1,5-diphenyl carbazone (DPCO). The DPCO can be extracted by the mixed solvent of benzene and carbon tetrachloride and the extract liquors display an obvious absorption peak around 563nm. In addition, the influences of (ultrasonic or solar light) irradiation time, TiO(2) addition amount and DPCI concentration on the quantities of generated ROS were also reviewed. The kinds of generated ROS were determined by using several radical scavengers. At last, the researches on the sonocatalytic and photocatalytic degradation of several organic dyes were also performed. It is wished that this paper might offer some important subjects for broadening the applications of sonocatalytic and photocatalytic technologies. PMID- 21700390 TI - Choi WJ et al. Radiofrequency treatment relieves chronic knee osteoarthritis pain: a double-blind randomized controlled trial. Pain 2011; 152: 481-7. PMID- 21700391 TI - Montanide IMS 1313 N VG PR nanoparticle adjuvant enhances antigen-specific immune responses to profilin following mucosal vaccination against Eimeria acervulina. AB - This study investigated protection against Eimeria acervulina (E. acervulina) following vaccination of chickens with an Eimeria recombinant profilin in conjunction with different adjuvants, or by changing the route of administration of the adjuvants. Day-old broilers were immunized twice with profilin emulsified in Montanide IMS 1313 N VG PR adjuvant (oral, nasal, or ocular routes), Montanide ISA 71 VG adjuvant (subcutaneous route), or Freund's adjuvant (subcutaneous route) and orally challenged with virulent E. acervulina parasites. Birds orally immunized with profilin plus IMS 1313 N VG PR, or subcutaneously immunized with profilin plus ISA 71 VG, had increased body weight gains compared with animals nasally or ocularly immunized with profilin plus IMS 1313 N VG PR, or subcutaneously immunized with profilin plus Freund's adjuvant. All adjuvant formulations, except for IMS 1313 N VG PR given by the nasal or ocular routes, decreased fecal parasite excretion and/or reduced intestinal lesions, compared with non-vaccinated and infected controls. Compared with animals vaccinated with profilin plus Freund's adjuvant, chickens immunized with profilin plus IMS 1313 N VG PR or ISA 71 VG showed higher post-infection intestinal levels of profilin reactive IgY and secretary IgA antibodies. Finally, immunization with profilin in combination with ISA 71 VG was consistently better than profilin plus IMS 1313 N VG PR or Freund's adjuvant for increasing the percentages of CD4(+), CD8(+), BU1(+), TCR1(+), and TCR2(+) intestinal lymphocytes. These results indicate that experimental immunization of chickens with the recombinant profilin subunit vaccine in conjunction with IMS 1313 or ISA 71 VG adjuvants increases protective mucosal immunity against E. acervulina infection. PMID- 21700392 TI - Molecular diagnosis of infections and resistance in veterinary and human parasites. AB - Since 1977, >2000 research papers described attempts to detect, identify and/or quantify parasites, or disease organisms carried by ecto-parasites, using DNA based tests and 148 reviews of the topic were published. Despite this, only a few DNA-based tests for parasitic diseases are routinely available, and most of these are optional tests used occasionally in disease diagnosis. Malaria, trypanosomiasis, toxoplasmosis, leishmaniasis and cryptosporidiosis diagnosis may be assisted by DNA-based testing in some countries, but there are very few cases where the detection of veterinary parasites is assisted by DNA-based tests. The diagnoses of some bacterial (e.g. lyme disease) and viral diseases (e.g. tick borne encephalitis) which are transmitted by ecto-parasites more commonly use DNA based tests, and research developing tests for these species makes up almost 20% of the literature. Other important uses of DNA-based tests are for epidemiological and risk assessment, quality control for food and water, forensic diagnosis and in parasite biology research. Some DNA-based tests for water-borne parasites, including Cryptosporidium and Giardia, are used in routine checks of water treatment, but forensic and food-testing applications have not been adopted in routine practice. Biological research, including epidemiological research, makes the widest use of DNA-based diagnostics, delivering enhanced understanding of parasites and guidelines for managing parasitic diseases. Despite the limited uptake of DNA-based tests to date, there is little doubt that they offer great potential to not only detect, identify and quantify parasites, but also to provide further information important for the implementation of parasite control strategies. For example, variant sequences within species of parasites and other organisms can be differentiated by tests in a manner similar to genetic testing in medicine or livestock breeding. If an association between DNA sequence and phenotype has been demonstrated, then qualities such as drug resistance, strain divergence, virulence, and origin of isolates could be inferred by DNA-based tests. No such tests are in clinical or commercial use in parasitology and few tests are available for other organisms. Why have DNA-based tests not had a bigger impact in veterinary and human medicine? To explore this question, technological, biological, economic and sociological factors must be considered. Additionally, a realistic expectation of research progress is needed. DNA-based tests could enhance parasite management in many ways, but patience, persistence and dedication will be needed to achieve this goal. PMID- 21700393 TI - Serological survey of Babesia bovis and Babesia bigemina in cattle in South Africa. AB - A total of 719 serum samples collected from clinically healthy cattle from eight provinces located in different districts of South Africa were examined by the indirect enzyme-linked immunosorbent assay (ELISA) and the standard indirect fluorescent antibody test (IFAT) to determine the serological prevalence of Babesia bovis and Babesia bigemina. The results showed that 35.3% and 39.7% of cattle were positive for B. bovis and 30% and 36.5% were positive for B. bigemina antibodies on ELISA and IFAT, respectively. Mixed infections were detected in 18.2% and 26.3% of the samples using ELISA and IFAT, respectively. Consequently, the ELISAs with recombinant B. bovis spherical body protein-4 (BbSBP-4) and B. bigemina C-terminal rhoptry-associated protein-1 (BbigRAP-1/CT) were proven to be highly reliable in the serological diagnoses of bovine babesiosis in South African cattle, as evidenced by the significant concordance rates when the results were compared to those of IFAT. Moreover, the serological prevalence was significantly different among the tested provinces, in which the ranges exhibited between 15% and 73% for B. bovis infection and between 13% and 54% for B. bigemina infection. High sero-positive rates were present in Mpumalanga and KwaZulu-Natal provinces, while the lowest rate was in the North West province. Our data provide important information regarding the current seroprevalence of bovine babesiosis in South Africa, which might be beneficial in developing rational strategies for disease control and management. PMID- 21700394 TI - Identification of Theileria parva and Theileria sp. (buffalo) 18S rRNA gene sequence variants in the African Buffalo (Syncerus caffer) in southern Africa. AB - Theileria parva is the causative agent of Corridor disease in cattle in South Africa. The African buffalo (Syncerus caffer) is the reservoir host, and, as these animals are important for eco-tourism in South Africa, it is compulsory to test and certify them disease free prior to translocation. A T. parva-specific real-time polymerase chain reaction (PCR) test based on the small subunit ribosomal RNA (18S rRNA) gene is one of the tests used for the diagnosis of the parasite in buffalo and cattle in South Africa. However, because of the high similarity between the 18S rRNA gene sequences of T. parva and Theileria sp. (buffalo), the latter is also amplified by the real-time PCR primers, although it is not detected by the T. parva-specific hybridization probes. Preliminary sequencing studies have revealed a small number of sequence differences within the 18S rRNA gene in both species but the extent of this sequence variation is unknown. The aim of the current study was to sequence the 18S rRNA genes of T. parva and Theileria sp. (buffalo), and to determine whether all identified genotypes can be correctly detected by the real-time PCR assay. The reverse line blot (RLB) hybridization assay was used to identify T. parva and Theileria sp. (buffalo) positive samples from buffalo blood samples originating from the Kruger National Park, Hluhluwe-iMfolozi Park, the Greater Limpopo Transfrontier Park, and a private game ranch in the Hoedspruit area. T. parva and Theileria sp. (buffalo) were identified in 42% and 28%, respectively, of 252 samples, mainly as mixed infections. The full-length 18S rRNA gene of selected samples was amplified, cloned and sequenced. From a total of 20 sequences obtained, 10 grouped with previously published T. parva sequences from GenBank while 10 sequences grouped with a previously published Theileria sp. (buffalo) sequence. All these formed a monophyletic group with known pathogenic Theileria species. Our phylogenetic analyses confirm the distinction between Theileria sp. (buffalo) and T. parva and indicate the existence of a single group of T. parva and two Theileria sp. (buffalo) 18S rRNA gene variants in the African buffalo. Despite the observed variation in the full-length parasite 18S rRNA gene sequences, the area in the V4 hypervariable region where the RLB and real-time PCR hybridization probes were developed was relatively conserved. The T. parva specific real-time PCR assay was able to successfully detect all T. parva variants and, although amplicons were obtained from Theileria sp. (buffalo) DNA, none of the Theileria sp. (buffalo) 18S rRNA sequence variants were detected by the T. parva-specific hybridization probes. PMID- 21700395 TI - Molecular genetic approaches for identifying the basis of variation in resistance to tick infestation in cattle. AB - In recent years there has been renewed interest in the adaptation of cattle to challenging environments, largely driven by advances in genomic methods. The current interest in tick resistance is understandable given the major production and welfare implications of tick infestation in tropical and subtropical zones where around 70% of beef cattle are located. Heritability for tick burden in cattle has been shown to range about 0.30, which is sufficient to result in the success of some programs of selection for tick resistance in cattle. Gene expression studies strongly indicate that both immune and non-immune mechanisms are associated with tick resistance in cattle. Recent quantitative-trait mapping studies have identified chromosome segments and single nucleotide polymorphisms associated with tick burden, but no causal variant has been identified so far. Most of the genetic markers identified for tick burden explain a relatively small proportion of the variance, which is typical of markers for quantitative traits. This leads to the conclusion that panels of multiple markers for tick resistance rather than a single marker will most likely be developed, possibly involving specific panels for zebu or taurine breeds, which could be used for future selection and breeding programs in cattle. PMID- 21700396 TI - Predicting relapse among young adults: psychometric validation of the Advanced WArning of RElapse (AWARE) scale. AB - OBJECTIVE: Failure to maintain abstinence despite incurring severe harm is perhaps the key defining feature of addiction. Relapse prevention strategies have been developed to attenuate this propensity to relapse, but predicting who will, and who will not, relapse has stymied attempts to more efficiently tailor treatments according to relapse risk profile. Here we examine the psychometric properties of a promising relapse risk measure-the Advance WArning of RElapse (AWARE) scale (Miller & Harris, 2000) in an understudied but clinically important sample of young adults. METHOD: Inpatient youth (N=303; Ages 18-24; 26% female) completed the AWARE scale and the Brief Symptom Inventory-18 (BSI) at the end of residential treatment, and at 1-, 3-, and 6-months following discharge. Internal and convergent validity was tested for each of these four timepoints using confirmatory factor analysis and correlations (with BSI scores). Predictive validity was tested for relapse 1, 3, and 6 months following discharge, as was incremental utility, where AWARE scores were used as predictors of any substance use while controlling for treatment entry substance use severity and having spent time in a controlled environment following treatment. RESULTS: Confirmatory factor analysis revealed a single, internally consistent, 25-item factor that demonstrated convergent validity and predicted subsequent relapse alone and when controlling for other important relapse risk predictors. CONCLUSIONS: The AWARE scale may be a useful and efficient clinical tool for assessing short-term relapse risk among young people and, thus, could serve to enhance the effectiveness of relapse prevention efforts. PMID- 21700397 TI - 'Spontaneous molecular reactivation' of herpes simplex virus type 1 in the brain as a pathogenic mechanism of Alzheimer's disease. PMID- 21700398 TI - The mammalian fetus, a naturally occurring graft. PMID- 21700399 TI - Effect of morning vs. afternoon grazing on intramuscular fatty acid composition in lamb. AB - The aim of this study was to assess whether different grazing management affect animal performance and meat fatty acid composition. Thirty-five lambs were divided into three groups: 12 lambs grazed from 9 am to 5 pm (8 h group); 11 lambs grazed from 9 am to 1 pm (4hAM group) and 12 lambs grazed from 1 pm to 5 pm (4hPM group). The trial was conducted over 72 days. The 8 h lambs had greater DMI (P<0.0005) and final body weight (P<0.05) than the 4hPM and 4hAM lambs while carcass weight was not different between the three groups. The meat of the 4hPM lambs contained greater (P<0.05) percentages of polyunsaturated fatty acids, C18:2 cis-9 trans-11 and lower saturated fatty acids and C18:0 than the meat of the 8 h and 4hAM lambs. It is concluded that allowing lambs to graze during the afternoon rather than during 8 h does not compromise the carcass yield and results in a healthier meat fatty acid profile. PMID- 21700400 TI - Stereotactic radiosurgery for acoustic neuromas: what happens long term? AB - PURPOSE: To determine the clinical outcomes for acoustic neuroma treated with low dose linear accelerator stereotactic radiosurgery (SRS) >10 years earlier at the Royal Adelaide Hospital using data collected prospectively at a dedicated SRS clinic. METHODS AND MATERIALS: Between November 1993 and December 2000, 51 patients underwent SRS for acoustic neuroma. For the 44 patients with primary SRS for sporadic (unilateral) lesions, the median age was 63 years, the median of the maximal tumor diameter was 21 mm (range, 11-34), and the marginal dose was 14 Gy for the first 4 patients and 12 Gy for the other 40. RESULTS: The crude tumor control rate was 97.7% (1 patient required salvage surgery for progression at 9.75 years). Only 8 (29%) of 28 patients ultimately retained useful hearing (interaural pure tone average <=50 dB). Also, although the Kaplan-Meier estimated rate of hearing preservation at 5 years was 57% (95% confidence interval, 38 74%), this decreased to 24% (95% confidence interval, 11-44%) at 10 years. New or worsened V and VII cranial neuropathy occurred in 11% and 2% of patients, respectively; all cases were transient. No case of radiation oncogenesis developed. CONCLUSIONS: The long-term follow-up data of low-dose (12-14 Gy) linear accelerator SRS for acoustic neuroma have confirmed excellent tumor control and acceptable cranial neuropathy rates but a continual decrease in hearing preservation out to >=10 years. PMID- 21700401 TI - Targeting the neurovascular unit: development of a new model and consideration for novel strategy for Alzheimer's disease. AB - Alzheimer's disease involves the complex and interconnected cascade of cellular and molecular events. Only a few treatments are available to slow the course of the disease at present. Recent studies suggest that neurovascular unit serves to maintain cerebral homeostasis, and pathological interactions between components of neurovascular unit lead to cerebral dysfunction. In present study, we established a functional unit trying to target major components of the neurovascular unit by the co-culture of rat cortical parenchymal culture and cerebral microvascular endothelial cells. This entity allowed the application of techniques such as immunofluorescent imaging and biological assays under defined conditions. The morphology of cell types, blood-brain barrier function and neuronal activation were investigated. The insight revealed that targeting components of the neurovascular unit, rather than just the neuron, might be a priority in Alzheimer's disease and more likely to provide cerebroprotection. PMID- 21700403 TI - The Pho regulon and the pathogenesis of Escherichia coli. AB - During the course of infection, bacteria must coordinately regulate gene expression in response to environmental stimuli. The phosphate (Pho) regulon is controlled by the two component-regulatory system PhoBR. PhoBR is activated during starvation and regulates genes involved in phosphate homeostasis. Several studies have highlighted the importance of the Pho regulon in bacterial pathogenesis, showing how induction of PhoBR, in addition to regulating genes participating in phosphate metabolism, leads to modulation of many cellular processes. The pleiotropic effects of Pho regulon activation include attenuated virulence and alteration of many virulence traits, including adhesion to host cells and resistance to cationic antimicrobial peptides, acidity and oxidative stresses. This review provides an overview of the relationship between the Pho regulon and virulence in Escherichia coli and illustrates that, in addition to regulating phosphate homeostasis, the Pho regulon plays a key role in regulating stress responses and virulence. PMID- 21700402 TI - Evidence of high-risk sexual behaviors among injection drug users in the Kenya PLACE study. AB - BACKGROUND: Injection drug users (IDUs) in resource poor settings are at high risk for HIV transmission through unsafe needle-sharing and sexual practices. We report on the injecting and sexual behavior of a sample of IDUs from Malindi, Kenya. METHODS: A Priority for Local AIDS Control Efforts (PLACE) study was conducted from April to May 2010 to identify areas where HIV transmission is most likely to occur and specific venues where people meet new sexual partners. Community informants (n=202) listed 157 unique venues from which 29 were randomly selected using a systematic fixed interval sampling strategy with probability of selection proportional to venue size. Twenty patrons and four workers were interviewed at each venue. Drug use practices were elicited in a staff administered interview. RESULTS: Between 40% and 50% of IDUs reported needle sharing, taking drugs from a common reservoir, using a ready-made solution without boiling, and not exchanging a used for a new syringe in the past month. Most could inconsistently or never get new syringes. In multivariate logistic regression models controlling for age, education, residence, and poverty status, IDUs were twice as likely as non-IDUs to report multiple partners in the past year (OR 1.94, 95% CI 1.26-3.00, p<.01) and multiple new partners in the past year (OR 2.11, 95% CI 1.30-3.42, p<.01). CONCLUSIONS: High prevalence of multiple sexual partnerships and risky injecting behaviors among IDUs and unavailability of new injecting needles are likely facilitating HIV transmission in Malindi, Kenya. PMID- 21700404 TI - Mediators involved in retinopathy of prematurity and emerging therapeutic targets. AB - Retinopathy of prematurity (ROP) is a potentially blinding disease of premature infants and despite timely treatment some infants develop retinal detachment and sight loss. Current treatment utilises laser therapy which causes destruction of treated retinal tissue resulting in field loss. There is considerable research work ongoing on neovascular eye disease which is likely to result in antiangiogenic approaches that will arrest the development of ROP by specifically targeting the involved molecular mediators. Some of these new therapeutic interventions have entered clinical trials. This article reviews new information available on the molecular pathogenesis of ROP which may result in novel treatments for ROP; it does not discuss the well-known role of oxygen in the development of ROP. PMID- 21700405 TI - Nuclear transfer procedures in the ovine can induce early embryo fragmentation and compromise cloned embryo development. AB - Cytoplasmic fragmentations are frequently observed in early mammalian embryos, and especially in the human. In our research we have observed subtle clues that the occurrence of fragmentation was most likely a result of somatic cell nuclear transfer (NT) protocols, and in particular, the in vitro culture system. In this study we examined various putative factors that might induce early embryo fragmentation in the ovine. The results indicate that nuclear transfer protocols such as the fusion parameter, activation treatment, and especially the choice of culture medium affected embryo cleavage rates and resulted in a higher incidence of fragmented embryos. Upon using the same fusion parameter, activation parameters that were based upon amino acids containing synthetic oviduct fluids (SOFaa) culture system resulted in significantly lower fragmentation rates than when utilizing a Charles Rosenkrans 1 (CR1aa) culture system. Fragmented embryos typically exhibited irregular numbers of blastomeres with the majority of blastomeres devoid of chromatin. Factors such as fusion DC pulse, activation treatment and culture system led to higher fragmentation and also affected in vitro and in vivo embryo development. The SOFaa based culture system produced a higher number of quality NT embryos resulting in higher pregnancy rates and the birth of live lambs as compared to the CR1aa based system (P<0.05). We conclude that early embryo fragmentation in the ovine is caused by suboptimal cloning protocols, and NT embryo development is especially affected by the culture system used. PMID- 21700406 TI - How the 1932 and 1947 mental surveys of Aberdeen schoolchildren provide a framework to explore the childhood origins of late onset disease and disability. AB - OBJECTIVES: To describe the discovery and development of the Aberdeen 1921 and 1936 birth cohort studies. STUDY DESIGN: The Aberdeen birth cohort studies were started in 1998 when the Scottish Mental Survey archives of the Scottish Council for Research in Education were re-discovered and permissions granted to follow-up survivors born in 1921 or 1936 and then aged about 77 or 64 years and who had entered (or were about to enter) the age of greatest risk for Alzheimer's disease (AD). MAIN OUTCOME MEASURES: Sources of attrition from the study, exposures to childhood adversity, nutritional, genetic and life style factors of possible relevance to extent of age-related cognitive decline and the timing of onset of dementia. RESULTS: By 2010, the feasibility of following up more than 75% of Scottish Mental Survey survivors living in the Aberdeen area without dementia was well-established, dementia ascertainment to age about 88 years was completed in the 1921 birth cohort and was underway in the 1936 born cohort. CONCLUSION: These databases are available to other bone fide research groups wishing to test specific hypotheses that may either replicate their own findings or make best use of the data collected in the Aberdeen studies. PMID- 21700407 TI - [Hepatitis B reactivation with rituximab in an HIV-infected anti-HBs antibody carrier]. PMID- 21700408 TI - Comparative survival analysis in patients with pulmonary metastases from nasopharyngeal carcinoma treated with radiofrequency ablation. AB - PURPOSE: The aim of this retrospective study was to evaluate technical efficacy and the impact of CT-guided pulmonary radiofrequency ablation (RFA) on survival in patients with pulmonary metastases from nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Between 2000 and 2009, 480 patients were pathologically or clinically confirmed pulmonary metastases from NPC. And ten included patients of them had a total of 23 pulmonary metastases treated with percutaneous RFA under the real-time CT fluoroscopy. Safety, local tumor progression, and survival were evaluated in our institutions. Matched-pair survival was compared using Kaplan Meier analysis. RESULTS: A total of 25 ablations were performed to 23 pulmonary metastases in 13 RFA sessions. Pneumothorax requiring chest tube placement developed in 3 of 13 (23.1%) RFA sessions. The median metastatic overall survival was 36.1 months for all the 480 NPC patients with pulmonary metastases. Furthermore, matched-pair analysis demonstrated patients with RFA treatment had a greater metastatic overall survival than patients without RFA treatment (77.1 months vs 32.4 months, log-rank test, p=0.009). There were no statistically significant differences in the survival probability of patients with RFA treatment (n=10) and surgical resection of pulmonary metastases (n=27) (log-rank test, p=0.75). CONCLUSION: CT-guided pulmonary RFA is safe and offers a treatment alternative for local tumor control, providing promising survival in selected patients with pulmonary metastases from NPC. PMID- 21700409 TI - Clinical usefulness of free-breathing navigator-triggered 3D MRCP in non cooperative patients: comparison with conventional breath-hold 2D MRCP. AB - PURPOSE: To assess the clinical usefulness of free-breathing 3D MRCP in non cooperative patients compared conventional breath-hold 2D MRCP. MATERIALS AND METHODS: We performed FB navigator-triggered 3D MRCP using prospective acquisition correction and BH 2D MRCP in 48 consecutive, non-cooperative patients among 772 patients. Thirteen patients had malignant obstruction. Two radiologists independently graded the likelihood of a malignant obstruction, the overall image quality, and the visibility of ten, individual anatomic segments of both the biliary and pancreatic duct in each sequence. The area under the ROC curve and the repeated measures analyses of variance with multiple comparisons were used for the comparison. The kappa statistics were used for interobserver agreement. RESULT: The diagnostic performance for detecting malignancy was significantly higher on FB MRCP (A(z)=0.962) than on either BH SS-RARE (A(z)=0.820, P<0.0185) or MS-HASTE MRCP (A(z)=0.816, P<0.0067). Interobserver agreement was excellent for FB MRCP (kappa=0.889) and fair for both BH SS-RARE (kappa=0.578) and MS-HASTE MRCP (kappa=0.49). FB MRCP had a significantly higher technical quality than BH MRCP (P<0.001). FB MRCP was seen to have statistically better visibility of peripheral IHD, right main IHD, CHD, cystic duct, and CBD than BH MRCP (P<0.001). FB MRCP and BH SS-RARE MRCP had statistically better visibility of both the left main IHD and pancreatic duct than did BH MS-HASTE MRCP (P<0.001). CONCLUSION: FB 3D MRCP is useful for non-cooperative patients in whom conventional BH 2D methods cannot be used successfully. PMID- 21700410 TI - Transfer of analytical procedures: a panel of strategies selected for risk management, with emphasis on an integrated equivalence-based comparative testing approach. AB - In 2001, a multidisciplinary team made of analytical scientists and statisticians at Sanofi-aventis has published a methodology which has governed, from that time, the transfers from R&D sites to Manufacturing sites of the release monographs. This article provides an overview of the recent adaptations brought to this original methodology taking advantage of our experience and the new regulatory framework, and, in particular, the risk management perspective introduced by ICH Q9. Although some alternate strategies have been introduced in our practices, the comparative testing one, based equivalence testing as statistical approach, remains the standard for assays lying on very critical quality attributes. This is conducted with the concern to control the most important consumer's risk involved at two levels in analytical decisions in the frame of transfer studies: risk, for the receiving laboratory, to take poor release decisions with the analytical method and risk, for the sending laboratory, to accredit such a receiving laboratory on account of its insufficient performances with the method. Among the enhancements to the comparative studies, the manuscript presents the process settled within our company for a better integration of the transfer study into the method life-cycle, just as proposals of generic acceptance criteria and designs for assay and related substances methods. While maintaining rigor and selectivity of the original approach, these improvements tend towards an increased efficiency in the transfer operations. PMID- 21700411 TI - Comparative utility of a single-item versus multiple-item measure of self efficacy in predicting relapse among young adults. AB - Single-item measures of psychological experiences are often viewed as psychometrically suspect. The purpose of this study was to evaluate the validity and utility of a single-item measure of self-efficacy in a clinical sample of treatment-seeking young adults. Inpatient young adults (N = 303, age = 18-24, 26% female) were assessed at intake to residential treatment, end of treatment, and at 1, 3, and 6 months following discharge. The single-item measure of self efficacy consistently correlated positively with a well-established 20-item measure of self-efficacy and negatively with temptation scores from the same scale, demonstrating convergent and discriminant validity. It also consistently predicted relapse to substance use at 1-, 3-, and 6-month assessments postdischarge, even after controlling for other predictors of relapse (e.g., controlled environment), whereas global or subscale scores of the 20-item scale did not. Based on these findings, we encourage the use of this single-item measure of self-efficacy in research and clinical practice. PMID- 21700412 TI - Substance abuse treatment utilization among adults living with HIV/AIDS and alcohol or drug problems. AB - This is a prospective cohort study to identify factors associated with receipt of substance abuse treatment (SAT) among adults with alcohol problems and HIV/AIDS. Data from the HIV Longitudinal Interrelationships of Viruses and Ethanol study were analyzed. Generalized estimating equation logistic regression models were fit to identify factors associated with any service utilization. An alcohol dependence diagnosis had a negative association with SAT (adjusted odds ratio [AOR] = 0.36, 95% confidence interval [95% CI] = 0.19-0.67), as did identifying sexual orientation other than heterosexual (AOR = 0.46, CI = 0.29-0.72) and having social supports that use alcohol/drugs (AOR = 0.62, CI = 0.45-0.83). Positive associations with SAT include presence of hepatitis C antibody (AOR = 3.37, CI = 2.24-5.06), physical or sexual abuse (AOR = 2.12, CI = 1.22-3.69), social supports that help with sobriety (AOR = 1.92, CI = 1.28-2.87), homelessness (AOR = 2.40, CI = 1.60-3.62), drug dependence diagnosis (AOR = 2.64, CI = 1.88-3.70), and clinically important depressive symptoms (AOR = 1.52, CI = 1.08-2.15). While reassuring that factors indicating need for SAT among people with HIV and alcohol problems (e.g., drug dependence) are associated with receipt, nonneed factors (e.g., sexual orientation, age) that should not decrease likelihood of receipt of treatment were identified. PMID- 21700413 TI - Cognitive changes after surgery vs stenting for carotid artery stenosis. AB - OBJECTIVES: Cognitive function has not been evaluated systematically in the context of carotid endarterectomy (CEA) versus carotid artery stenting (CAS). Cognitive decline can occur from microembolization or hypoperfusion during CEA or CAS. Carotid revascularization may, however, also improve cognitive dysfunction resulting from chronic hypoperfusion. We compared cognitive outcomes in consecutive asymptomatic patients undergoing CAS or CEA. METHODS: This is a prospective nonrandomized single-center study of patients with asymptomatic carotid stenosis >= 70% undergoing CAS or CEA using standard techniques. Neurologic symptoms were evaluated by history, physical examination, and the National Institutes of Health Stroke Scale. A 50-minute cognitive battery was performed 1 to 3 days before and 4 to 6 months after CEA/CAS. The tests (Trail Making Tests A/B, Processing Speed Index (PSI) of the Wechsler Adult Intelligence Scale - Third Edition (WAIS-III), Boston Naming Test, Working Memory Index (WMI) of the Wechsler Memory Scale - Third Edition (WMS-III), Controlled Oral Word Association, and Hopkins Verbal Learning Test) for six cognitive domains (motor speed/coordination and executive function, psychomotor speed, language (naming), working memory/concentration, verbal fluency, and learning/memory) were conducted by a neuropsychologist. The primary analysis of impact of treatment modality was a normalized cognitive change score. RESULTS: Forty-six patients underwent prepost testing (CEA = 25, CAS = 21). Women comprised 36% of the cohort, mean preprocedural stenosis was 84%, and 54% were right-sided lesions. All patients were successfully revascularized without periprocedural complications. The scores for each test improved after CEA except WMI, which decreased in 20 of 25 patients. Improvement occurred in all tests after CAS except PSI, which decreased in 18 of 21 patients. In addition to comparing the changes in individual test scores, overall cognitive change was measured by calculating the change in composite cognitive score (CCS) postprocedure versus baseline. To compute the CCS, the raw scores from each test were transformed into z scores and then averaged to calculate each patient's composite score. The composite score at baseline was then compared with that from the postprocedure testing. The CCS improved after both CEA and CAS, and the changes were not significantly different between the groups (.51 vs .47; P = NS). CONCLUSIONS: Carotid revascularization results in an overall improvement in cognitive function. There are no differences in the composite scores of five major cognitive domains between CEA and CAS. When individual tests are compared, CEA results in a reduction in memory, while CAS patients show reduced psychomotor speed. Larger studies will help confirm these findings. PMID- 21700414 TI - Association of death receptor 4, Caspase 3 and 5 gene polymorphism with increased risk to bladder cancer in North Indians. AB - PURPOSE: Perturbed apoptosis due to missense alterations in candidate tumor suppressor gene Death receptor 4 (DR4) and in caspases (Casp) lead to deregulated cell proliferation and cancer predisposition. Some data indicate that normal variations within the sequence of apoptotic genes may lead to suboptimal apoptotic capacity and therefore increased cancer risk. To test our proposal we examined whether six single nucleotide polymorphisms (SNPs) of the DR4 and Casp3, 5 genes contrive the risk of bladder cancer (BC) in a North Indian population. MATERIALS AND METHODS: Genotyping was performed in 200 BC patients and 225 controls by Allele-specific PCR and by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: In DR4 Arg141His, BC patients having AA genotype (p = 0.036; OR = 2.51. In Casp5Leu13Phe G > C, significant association was observed with GC (p = 0.025; OR = 1.78) and also in GC + CC (p = 0.026; OR = 1.68). C allele carriers in Casp5Ala90Thr T > C showed low risk of BC (p = 0.036; OR = 0.83). While in Casp3 G > A, AG (p = 0.003; OR = 2.11), GG (p = 0.050; OR = 2.18), G allele (p < 0.001; OR = 1.85) and its carrier AG + GG (p = 0.001; OR = 2.12) have shown significant BC risk. Significant association between DR4 Ala228Glu polymorphism and smoking was observed in BC risk. Haplotype analysis demonstrated that DR4 (Thr209Arg-Arg141His-Ala228Glu) C-G-C is associated with 1.8 folds (OR = 1.85; p = 0.033) risk. GG genotype of Casp3 G > A polymorphism showed increased risk of recurrence (p = 0.009; HR = 5.20). CONCLUSION: This study provided new support for the association of DR4 and Casp3, 5 in BC development, the tumorigenic effect of which was observed to be more enhanced in case of smoking exposure. PMID- 21700415 TI - Spontaneous rupture of the left common iliac vein. AB - A 63-year-old woman was admitted because she presented with acute lower abdominal pain and left leg pain without any history of trauma. Lower extremity venous duplex ultrasound demonstrated deep vein thrombosis in the left lower extremity. Computed tomography scan revealed high-density, irregular clumps in the pelvic region and a soft-tissue mass shadow in the right lower abdomen. Emergency laparotomy revealed a 1.5-cm longitudinal tear in the left common iliac vein. The vein was repaired primarily and the postoperative course was uneventful. PMID- 21700416 TI - An ecological approach of Constraint Induced Movement Therapy for 2-3-year-old children: a randomized control trial. AB - The aim was to evaluate the effect of Eco-CIMT in young children with unilateral cerebral palsy in a randomized controlled crossover design. The training was implemented within the regular pediatric services, provided by the child's parents and/or preschool teacher and supervised by the child's regular therapist. METHODS: Twenty-five children (mean age 28.8 months [SD 11.2], 72% male) participated. Assisting Hand Assessment (AHA) was used as the outcome measure. The Eco-CIMT was provided for 2h a day over a period of two months. Children were randomized into two groups and started either with Eco-CIMT or as controls with a four-month washout period before crossing over. RESULT: A significant effect of Eco-CIMT was found when compared to the control period, and the estimated treatment effect was 5.47 (95% C.I. 2.93-8.02) (including both Group 1 and Group 2) (p < 0.001). The non-significant estimated carryover effect allowed us to collapse the two groups based on estimates from the ANOVA model. No clear relationship to hours of training, age or general attitudes of mastery was found. CONCLUSION: Eco-CIMT influenced development more than ordinary treatment at this age when Eco-CIMT was performed by parents and preschool teachers supervised by the child's ordinary therapist. PMID- 21700417 TI - Sleep, anxiety and challenging behaviour in children with intellectual disability and/or autism spectrum disorder. AB - Children with an intellectual disability (ID) and/or autism spectrum disorder (ASD) are known to suffer from significantly more sleep problems, anxiety and challenging behaviour (CB) than typically developing children (TD), yet little is known about the relationship between these factors in the child ID/ASD population. The study aim was to examine these relationships. We hypothesised that there would be significant positive correlations between the three factors and that sleep problems and anxiety would predict a significant amount of the variance in levels of CB. Parental measures of sleep problems, anxiety and CB were completed by 187 parents of children with ID and/or ASD. Significant positive associations were found between the three factors. A hierarchical multiple regression showed that medication, sleep problems and anxiety accounted for 42% of the variance in CB, with a large effect size. These findings suggest that these relationships should be considered during clinical practice, particularly in the case of CB interventions where sleep problems and/or anxiety are also present. PMID- 21700418 TI - Staff behavior toward children and adolescents in a residential facility: a self report questionnaire. AB - The purpose of the present study was to examine psychometric properties of the Staff Behavior toward Clients questionnaire (SBC), a self-report measure for care staff working with children and adolescents with mild to borderline intellectual disabilities in residential care. Ninetynine care staff completed the SBC and the Strengths and Difficulties Questionnaire (SDQ) for 99 of their clients. Factor analysis revealed four factors (i.e. behavior regulation, client-directed care, teaching and empowerment). Results indicated excellent internal consistency of all factors and ability of the SBC to detect differences in client populations with respect to behavior problems. These data suggest that the SBC could provide a reliable and valid measure of staff behavior toward clients in residential facilities. PMID- 21700419 TI - An examination of the effects of stimulant medication on response inhibition: a comparison between children with and without attention deficit hyperactivity disorder. AB - This study investigated whether methylphenidate is effective in improving response inhibition in children with Attention Deficit Hyperactivity Disorder (ADHD). Children with ADHD were compared with normally developing children on measures of response inhibition. Participants with ADHD were compared across two conditions--medicated and unmedicated. There was no significant difference between the inhibitory control of children with and without ADHD. Children with ADHD showed significant improvements in inhibitory control following methylphenidate. The findings of the present study contrast with previous studies which document reduced inhibitory control in ADHD, compared with normally developing children. Reports of methylphenidate improving functioning in children with ADHD are supported. Limitation and implications of the study are discussed. PMID- 21700420 TI - Aggression as positive reinforcement in people with intellectual disabilities. AB - From an applied behavior-analytic perspective, aggression in people with intellectual disabilities is mostly maintained by social reinforcement consequences. However, nonsocial consequences have also been identified in functional assessments on aggression. Behaviors producing their own reinforcement have been labeled "automatic" or "nonsocial" in the behavior-analytic literature, a label that bares a striking resemblance to biobehavioral explanations of reward seeking behaviors. Biobehavioral studies have revealed that aggression activates the same endogenous brain mechanisms as primary reinforcers like food. Therefore, integrating brain-environment explanations would result in a better understanding of the functional mechanisms associated with nonsocial aggression. The purpose of this paper was to explore aggression as a reinforcing consequence for reinforcement-seeking behaviors in people with intellectual disabilities. First, the literature establishing aggression as reinforcement for arbitrary responding will be reviewed. Next, the reward-related biological process associated with aggression was described. Finally, the paper discusses what might be done to assess and treat aggression maintained by nonsocial reinforcement. PMID- 21700421 TI - The relationship between gross motor skills and academic achievement in children with learning disabilities. AB - The present study compared the gross motor skills of 7- to 12-year-old children with learning disabilities (n = 104) with those of age-matched typically developing children (n = 104) using the Test of Gross Motor Development-2. Additionally, the specific relationships between subsets of gross motor skills and academic performance in reading, spelling, and mathematics were examined in children with learning disabilities. As expected, the children with learning disabilities scored poorer on both the locomotor and object-control subtests than their typically developing peers. Furthermore, in children with learning disabilities a specific relationship was observed between reading and locomotor skills and a trend was found for a relationship between mathematics and object control skills: the larger children's learning lag, the poorer their motor skill scores. This study stresses the importance of specific interventions facilitating both motor and academic abilities. PMID- 21700423 TI - Psychometric testing of the Depressive Cognition Scale in Korean adults. AB - This study translated the Depressive Cognition Scale (DCS) from English into Korean and tested the reliability and validity of the scale. Data were from a convenient sample of 795 community-dwelling Korean adults with a self administered questionnaire. With regard to the reliability estimate, the internal consistency of the Korean version of the DCS (K-DCS) was acceptable, where the Chronbach's alpha is .93 and the average item-to-total correlation r = .760. With regard to the validity estimate, the mean scores of the K-DCS were significantly different according to gender, age, and marital status. A single factor was extracted that accounted for 67.37% of the total variance. The average score of the K-DCS also correlated significantly with the subscales of the Korean version of the Profile of the Mood States Brief Form. These findings suggest that the K DCS can be used as a reliable and valid measure of depressive cognition among Korean adults. PMID- 21700422 TI - Coronin 1A is an essential regulator of the TGFbeta receptor/SMAD3 signaling pathway in Th17 CD4(+) T cells. AB - Transforming growth factor beta (TGFbeta) plays a central role in maintaining immune homeostasis by regulating the initiation and termination of immune responses and thus preventing the development of autoimmune diseases. In this study, we describe an essential mechanism by which the actin regulatory protein Coronin 1A (Coro1A) ensures the proper response of Th17 CD4(+) T cells to TGFbeta. Coro1A has been established as a key player in T cell survival, migration, activation, and Ca(2+) regulation in naive T cells. We show that mice lacking Coro1a developed less severe experimental autoimmune encephalomyelitis (EAE). Unexpectedly, upon the re-induction of EAE, Coro1a(-/-) mice exhibited enhanced EAE signs that correlated with increased numbers of IL-17 producing CD4(+) cells in the central nervous system (CNS) compared to wild-type mice. In vitro differentiated Coro1a(-/-) Th17 CD4(+) T cells consistently produced more IL-17 than wild-type cells and displayed a Th17/Th1-like phenotype in regard to the expression of the Th1 markers T-bet and IFNgamma. Mechanistically, the Coro1a(-/-) Th17 cell phenotype correlated with a severe defect in TGFbetaR mediated SMAD3 activation. Taken together, these data provide experimental evidence of a non-redundant role of Coro1A in the regulation of Th17 CD4(+) cell effector functions and, subsequently, in the development of autoimmunity. PMID- 21700424 TI - Conducting research with end-of-life populations: overcoming recruitment challenges when working with clinical agencies. AB - Conducting end-of-life (EOL) research can present numerous challenges associated with recruitment and retention of research subjects. Such issues may result from working with a variety of clinical settings or the uniqueness of the patient population. The purposes of this article were to describe recruitment challenges in EOL research when collaborating with different types of clinical agencies and to discuss strategies that are being used to overcome these recruitment issues. PMID- 21700425 TI - 26th Hohenheim Consensus Conference, September 11, 2010 Scientific substantiation of health claims: evidence-based nutrition. AB - OBJECTIVE: The objective was to define the term evidence based nutrition on the basis of expert discussions and scientific evidence. METHODS AND PROCEDURES: The method used is the established Hohenheim Consensus Conference. The term "Hohenheim Consensus Conference" defines conferences dealing with nutrition related topics. The major aim of the conference is to review the state of the art of a given topic with experts from different areas (basic science, clinicians, epidemiologists, etc.). Based on eight to 12 questions, the experts discuss short answers and try to come to a consensus. A scientifically based text is formulated that justifies the consensus answer. To discuss the requirements for the scientific substantiation of claims, the 26th Hohenheim Consensus Conference gathered the views of many academic experts in the field of nutritional research and asked these experts to address the various aspects of a claims substantiation process and the possibilities and limitations of the different approaches. RESULTS: The experts spent a day presenting and discussing their views and arrived at several consensus statements that can serve as guidance for bodies performing claims assessments in the framework of regulatory systems. CONCLUSION: The 26th Hohenheim Consensus Conference addresses some general aspects and describes the current scientific status from the point of view of six case studies to illustrate specific areas of scientific interest: carotenoids and vitamin A in relation to age-related macular degeneration, the quality of carbohydrates (as expressed by the glycemic index) in relation to health and well being, probiotics in relation to intestinal and immune functions, micronutrient intake and maintenance of normal body functions, and food components with antioxidative properties and health benefits. PMID- 21700426 TI - Increased risk for radiation-related caries in cancer patients using topical honey for the prevention of oral mucositis. PMID- 21700427 TI - Hoist the mainsail! The use of standardised colour-coded sloops to aid vascular control in head and neck surgery. AB - The authors have adopted a set pattern of colour coded vascular sloops that they use to identify and isolate vital structures in the head and neck. This simple and cost-effective technique aids vascular control and has applications in elective head and neck surgery, as well as in controlling haemorrhage secondary to trauma. PMID- 21700428 TI - Oral cleft volumetric assessment by 3D multislice computed tomographic images. AB - The aim of this study was to determine the quantitative assessment of bone volume defects using multislice computed tomography (CT), and to establish an image processing protocol that enables this analysis. Bone defects were created in nine dry skulls, to mimic oral clefts. All the defects were modelled with wax, following the contralateral shape of the alveolo-palatal region. The wax was used to obtain the real volume of the cleft (gold standard). The skulls (with and without wax) were submitted to multislice CT examination, and the images were processed in an independent workstation using volumetric software. All the images were analysed twice, by two examiners at different times, performing intra- and inter-examiner analyses. The results show that the protocol for image processing has high efficiency (P=0.995). Multislice CT showed excellent results, with high reliability in the study of bone defect volume (P=0.997). The intra- and inter observer analysis showed no statistically significant differences. It was demonstrated that multislice CT is a reliable technique in the volumetric assessment of bone defects in the alveolar and palatal regions, and that this method was efficient for calculating the volume of the clefts. PMID- 21700429 TI - The relationship of ketosis and growth to the efficacy of the ketogenic diet in infantile spasms. AB - The ketogenic diet (KD) is a treatment of infantile spasms (IS). Here, we examine the efficacy of KD in medically refractory IS, examine its impact on growth in infants, and explore its mechanism of action. At 1-3 months after the initiation of the KD, 46% of twenty-six patients had a greater than 90% reduction in IS. No significant relationships between reduction in IS and serum beta-hydroxybutyrate, or glucose levels were identified. Also, the KD had not significantly altered patient's growth parameters. Thus, in corroborating with prior studies, we demonstrate the KD is a well-tolerated and efficacious treatment of IS. PMID- 21700430 TI - Efficacy of iloperidone in schizophrenia: a PANSS five-factor analysis. AB - BACKGROUND: The Positive and Negative Syndrome Scale (PANSS) total score is widely used to assess antipsychotic efficacy, however schizophrenia is a multi dimensional disorder. We conducted a 5-factor analysis for evaluating the efficacy of iloperidone vs. placebo across these different domains in the treatment of schizophrenia. METHOD: The 5-factor model was determined from pooled data from 7 clinical trials (4 placebo- and active-controlled and 3 non inferiority active-comparator trials of iloperidone) in schizophrenia (N=3580).Five factors were derived (excitement/hostility [P4,P7,G8,G14], depression/anxiety [G1,G2,G3,G4,G6], cognition [P2,N5,N7,G5,G10,G11,G12,G13,G15], positive [P1,P3,P5,P6,G9], and negative [N1,N2,N3,N4,N6,G7,G16]) from a factor analysis on the covariance matrix of 30 baseline PANSS items using a varimax rotation; factors retained had eigenvalues of >= 0.5. These newly derived 5 factors differ only slightly from other 5-factor analyses published by others using different datasets. The analysis of covariance model was then applied to assess these efficacy outcomes from the 4-6 week double-blind placebo and active controlled clinical trials of iloperidone. RESULTS: Based on the placebo controlled trials, iloperidone improvements from baseline (least squared mean change +/- standard error) were as follows: excitement/hostility, 0.4 +/- 0.21 for 10-16 mg, 0.6 +/- 0.43 for 20-24 mg vs. -1.0 +/- 0.23 for placebo; P<0.001 for both iloperidone doses vs. placebo; depression/anxiety, 1.9 +/- 0.21 for 10 16 mg, 1.9 +/- 0.41 for 20-24 mg vs. 1.1 +/- 0.22 for placebo; P<0.05 for 10-16 mg dose vs. placebo; cognition, 2.8 +/- 0.35 for 10-16 mg, 3.9 +/- 0.69 for 20-24 mg vs. 1.6 +/- 0.38 for placebo; P<0.05 for both iloperidone doses vs. placebo; positive, 3.7 +/- 0.26 for 10-16 mg, 4.1 +/- 0.53 for 20-24 mg vs. 2.7 +/- 0.29 for placebo; P<0.05 for both iloperidone doses vs. placebo; and negative, 2.2 +/- 0.29 for 10-16 mg, 2.5 +/- 0.58 for 20-24 mg vs. 1.3 +/- 0.32 for placebo; P<0.05 for 10-16 mg vs. placebo. Active controls validated iloperidone efficacy. CONCLUSIONS: Iloperidone demonstrated positive treatment effects on these newly derived PANSS factors. The 10-16 mg and 20-24 mg dose groups had similar efficacy on the PANSS factors, with the exception of the depression/anxiety and negative factors, on which the 10-16 mg dose group showed statistical separation from placebo and the 20-24 mg dose group did not. At 6 weeks, the lack of separation from placebo for the higher dose group may have been due to the much smaller sample size in that group. PMID- 21700431 TI - Neutralization of endogenous digitalis-like compounds alters catecholamines metabolism in the brain and elicits anti-depressive behavior. AB - Depressive disorders are among the world's greatest public health problems. Na(+), K(+)-ATPase is the established receptor for the steroidal digitalis-like compounds (DLC). Alteration in brain Na(+), K(+)-ATPase and DLC have been detected in depressive disorders raising the hypothesis of their involvement in these pathology. The present study was designed to further elaborate this hypothesis by investigating the behavioral and biochemical consequences of neutralization in brain DLC activity attained by anti-ouabain antibodies administrations, in normal Sprague-Dawley (SD) and in the Flinders Sensitive Line (FSL) of genetically depressed rats. Chronic i.c.v. administration of anti ouabain antibodies to FSL rats elicited anti-depressive behavior. Administration of anti-ouabain antibodies intracerebroventriculary (i.c.v.) to SD rats significantly changed the levels of catecholamines and their metabolites in the hippocampus, ventral tegmentum and nucleus accumbence. These results are in accordance with the notion that endogenous DLC may be involved in the manifestation of depressive disorders and suggests that alteration in their levels may be of significant therapeutic value. PMID- 21700432 TI - Method for detection of Hg2+ based on the specific thymine-Hg2+-thymine interaction in the DNA hybridization on the surface of quartz crystal microbalance. AB - A simple and sensitive method was developed for the detection of mercury ions with quartz crystal microbalance (QCM), based on the specific thymine-Hg(2+) thymine (T-Hg(2+)-T) interaction and gold nanoparticle-mediated signal amplification. To enhance the sensitivity of detection a sandwich hybridization approach was adopted in this work. The QCM gold surface was modified with the probe SH-oligonucleotides (Oligo-1) and 6-Mercapto-1-hexanol to form an active surface for the hybridization of a longer ss-DNA (Oligo-2), and then Oligo-3 hybridazated with an excess and matching part of Oligo-2. In all oligonucleotides, there existed T bases. In the presence of Hg(2+) ions, special T-Hg(2+)-T reaction greatly enhanced the hybridization of oligonucleotides and detection sensitivity. The gold nanoparticle (Au NPs) amplifier method further increased the sensitivity of detection. A detection sensitivity of 5nM Hg(2+) was obtained in the QCM system, whereas other coexisting metal ions (such as Ni(2+), Mg(2+), Co(2+), Cr(3+), Pb(2+), Cd(2+), Mn(2+), Ba(2+)) had no significant interference. This method reveals a new approach for the manufacture of a kind of simple and low cost sensors for the Hg(2+) detection. PMID- 21700433 TI - Synthesis of hydrogels based on poly(NIPAM) inserted into collagen sponge. AB - The study presents the preparation of a semi-synthetic hydrogel based on poly(N isopropyl acrylamide-co-diethylene glycol diacrylate) inserted onto the collagen porous membrane. The synthesis of the hydrogels was performed through radical copolymerization of N-isopropyl acrylamide (NIPAM) with diethylene glycol diacrylate (DEGDA) also as crosslinking agent, using ammonium persulfate as initiator and N,N,N',N'-tetramethylethylene diamine as activator, and it was achieved in the presence of the collagen matrix. The prepared hydrogels were characterized by Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy and Scanning Electron Microscopy. The swelling behaviour of the semi interpenetrated polymer network related on the hydrogel composition, it was also evaluated. The pore sizes of the synthesized hydrogels, much larger than the typical mesh size of a conventional hydrogel, allow to consider the hybrid hydrogel based on the inserted poly(NIPAM-co-DEGDA) onto collagen fibrils as a super-porous hydrogel. PMID- 21700434 TI - Phagostimulatory effect of uptake of PLGA microspheres loaded with rifampicin on alveolar macrophages. AB - Our previous results on the phagocytic activity of alveolar macrophages (Mphis) toward poly(lactic-co-glycolic) acid microspheres (PLGA MS) loaded with the anti tuberculosis agent rifampicin (R-PLGA MS) suggest that the phagocytosis of R-PLGA MS enhances the phagocytic activity of Mphi cells. To confirm this possibility, we examined the effect of phagocytosis of R-PLGA MS and polystyrene latex (PSL) MS on the phagocytic uptake of fluorescent PSL (F-PSL) MS by cells of the rat alveolar macrophage cell line NR8383 at 37 degrees C. Phagocytic activity was examined in terms of the population of Mphi cells that had phagocytosed MS (N(total)) and the total number of MS phagocytosed (n(total)) by counting the phagocytic Mphi cells and the MS ingested in optical microscopic fields. Phagocytosis of R-PLGA MS enhanced about 1.5 times the values of N(total) and n(total) of the phagocytosis of F-PSL MS under the conditions where the phagocytosis of F-PSL MS did not attain the saturated level. In contrast, the phagocytosis of PSL MS did not enhance the phagocytic activity of Mphi cells toward F-PSL MS. In conclusion, R-PLGA MS are favorable for drug delivery of anti tuberculosis agents into alveolar Mphis due to their ability to up-regulate the phagocytosis of MS. PMID- 21700435 TI - Crystalline titania nanoparticles synthesized in nonpolar Lalpha lecithin liquid crystalline media in one stage at ambient conditions. AB - High-temperature modification of titania in the form of nanoplatelets is synthesized fast in one step at ambient conditions without any additional treatment like aging or calcination. Lecithin, which is the main component of lipid matrix of biological membranes, is first used as a structure-driven template. It is demonstrated that this natural surfactant can self-organize into lamellar L(alpha) mesophase when small amounts of water are admixed in its solution in nonpolar solvent. The water locating mainly in lecithin polar region as hydration shell at this concentration triggers the hydrolysis-condensation reactions after the precursor addition that results in instantaneous titania formation in the form of crystalline nanoparticles. Planar lamellar sheets serve as the template specifying its crystallinity. PMID- 21700436 TI - Association of Paramecium bursaria Chlorella viruses with Paramecium bursaria cells: ultrastructural studies. AB - Paramecium bursaria Chlorella viruses were observed by applying transmission electron microscopy in the native symbiotic system Paramecium bursaria (Ciliophora, Oligohymenophorea) and the green algae Chlorella (Chlorellaceae, Trebouxiophyceae). Virus particles were abundant and localized in the ciliary pits of the cortex and in the buccal cavity of P. bursaria. This was shown for two types of the symbiotic systems associated with two types of Chlorella viruses - Pbi or NC64A. A novel quantitative stereological approach was applied to test whether virus particles were distributed randomly on the Paramecium surface or preferentially occupied certain zones. The ability of the virus to form an association with the ciliate was investigated experimentally; virus particles were mixed with P. bursaria or with symbiont-free species P. caudatum. Our results confirmed that in the freshwater ecosystems two types of P. bursaria Chlorella symbiotic systems exist, those without Chlorella viruses and those associated with a large amount of the viruses. The fate of Chlorella virus particles at the Paramecium surface was determined based on obtained statistical data and taking into account ciliate feeding currents and cortical reorganization during cell division. A life cycle of the viruses in the complete symbiotic system is proposed. PMID- 21700437 TI - The influence of fundamental design parameters on ciliates community structure in Irish activated sludge systems. AB - The protozoan community in eleven activated sludge wastewater treatment plants (WWTPs) in the greater Dublin area has been investigated and correlated with key physio-chemical operational and effluent quality parameters. The plants represented various designs, including conventional and biological nutrient removal (BNR) systems. The aim of the study was to identify differences in ciliate community due to key design parameters including anoxic/anaerobic stages and to identify suitable bioindicator species for performance evaluation. BNR systems supported significantly different protozoan communities compared to conventional systems. Total protozoan abundance was reduced in plants with incorporated anoxic and anaerobic stages, whereas species diversity was either unaffected or increased. Plagiocampa rouxi and Holophrya discolor were tolerant to anoxic/anaerobic conditions and associated with high denitrification. Apart from process design, influent wastewater characteristics affect protozoan community structure. Aspidisca cicada was associated with low dissolved oxygen and low nitrate concentrations, while Trochilia minuta was indicative of good nitrifying conditions and good sludge settleability. Trithigmostoma cucullulus was sensitive to ammonia and phosphate and could be useful as an indicator of high effluent quality. The association rating assessment procedure of Curds and Cockburn failed to predict final effluent biological oxygen demand (BOD5) indicating the method might not be applicable to treatment systems of different designs. PMID- 21700438 TI - WITHDRAWN: Efficacy and safety of Flutiform compared with individual fluticasone and formoterol reference products. PMID- 21700439 TI - Pregnancy related treatment disparities of acute asthma exacerbations in the emergency department. AB - OBJECTIVE: Asthma is one of the most common medical conditions complicating pregnancy. Despite the presence of published guidelines outlining the care of the pregnant patient with asthma, disparities in the treatment of acute asthma exacerbations in the emergency department related to pregnancy status are known to exist. We sought to determine if pregnancy status affected the treatment of women presenting to a tertiary emergency department for care of acute asthma exacerbations. METHODS: We retrospectively compared the emergency department treatment of acute asthma exacerbations in 123 pregnant women to 123 non-pregnant controls. Asthma exacerbations were classified by severity according to pre determined criteria. RESULTS: In the emergency department (ED), pregnant women were significantly less likely to be treated with systemic corticosteroids than non-pregnant controls (50.8% versus 72.4%, p = 0.001). Similarly, 41% of pregnant women received prescriptions for prednisone at the time of discharge from the ED compared to 69.2% of non-pregnant women (p < 0.001). CONCLUSIONS: In this population of asthmatics presenting to a tertiary emergency department with acute asthma exacerbations, pregnant women were less likely to receive appropriate therapy with systemic corticosteroids. PMID- 21700440 TI - Minimal (clinically) important differences for the Fatigue Assessment Scale in sarcoidosis. AB - OBJECTIVE: The usefulness of any questionnaire in clinical management and research trials depends on its ability to indicate a likelihood of treatment success during follow-up. The Minimal Clinically Important Difference (MCID) reflects a clinically relevant change score. The aim of this study was to estimate the MCID for the Fatigue Assessment Scale (FAS) in patients with sarcoidosis. METHODS: Outpatients (n = 321) of the ild care team of the Department of Respiratory Medicine of the Maastricht University Medical Centre, The Netherlands, participated in this prospective follow-up study. Anchor-based and distribution-based methods were used to estimate the MCID. Based on the anchor Physical Quality of Life, a Receiver Operating Characteristic (ROC) was obtained. The distribution-based methods consisted of the Effect Size and Standard Error Measurement (SEM). RESULTS: The anchor-based MCID found with ROC was 3.5. The distribution-based methods showed that the corresponding change scores in the FAS for a small effect was 4.2. The SEM criterion was 3.6 points change in the FAS. CONCLUSIONS: Based on the anchor-based and distribution-based methods, the MCID is a 4-point difference on the FAS. This MCID can be used in the follow-up of fatigue (FAS) in clinical trials and in the management of individual sarcoidosis cases. PMID- 21700441 TI - How do Australian news media depict illicit drug issues? An analysis of print media reporting across and between illicit drugs, 2003-2008. AB - BACKGROUND: Media reporting on illicit issues has been frequently criticised for being sensationalised, biased and narrow. Yet, there have been few broad and systematic analyses of the nature of reporting. Using a large sample and methods commonly adopted in media communications analysis this paper sought to identify the dominant media portrayals used to denote illicit drugs in Australian newspapers and to compare and contrast portrayals across drug types. METHODS: A retrospective content analysis of Australian print media was carried out over the period 2003-2008 from a sample comprised of 11 newspapers. Articles that contained one or more mention of five different drugs (or derivatives) were identified: cannabis, amphetamines, ecstasy, cocaine and heroin. A sub-sample of 4397 articles was selected for media content analysis (with 2045 selected for full content analysis) and a large number of text elements coded for each. Key elements included topic, explicit or implicit messages about the consequences of drugs/use and three value dimensions: overall tone, whether drugs were portrayed as a crisis issue and moral evaluations of drugs/use. RESULTS: The dominant media portrayals depicted law enforcement or criminal justice action (55%), but most articles were reported in a neutral manner, in the absence of crisis framings. Portrayals differed between drugs, with some containing more narrow frames and more explicit moral evaluations than others. For example, heroin was disproportionately framed as a drug that will lead to legal problems. In contrast, ecstasy and cocaine were much more likely to emphasise health and social problems. CONCLUSION: Media reporting on illicit drugs is heavily distorted towards crime and deviance framings, but may be less overtly sensationalised, biased and narrowly framed than previously suggested. This is not to suggest there is no sensationalism or imbalance, but this appears more associated with particular drug types and episodes of heightened public concern. PMID- 21700442 TI - High HIV and hepatitis C prevalence amongst injecting drug users in Mauritius: findings from a population size estimation and respondent driven sampling survey. AB - BACKGROUND: Mauritius, an Indian Ocean Island nation of approximately 1,000,000 people, has a large number of injecting drug users (IDUs), many of whom are infected with HIV and HCV. Mauritius has been expanding harm reduction and HIV services based in the belief that HIV prevalence amongst IDUs is somewhere between 30 and 60% and the IDU population size is around 20,000. In 2009, the government of Mauritius conducted a survey to estimate the infection prevalence and risk factors and to estimate the population size of IDUs in order to more effectively expand programmes. METHODS: Men and women aged >15 years living in Mauritius and injecting illicit drugs in the past three months were recruited using respondent driven sampling (RDS). Consenting participants were interviewed about HIV-risk behaviours and tested for HIV, syphilis, HCV and HBV. Six multipliers were collected from service data and by the 'unique identifier' method in conjunction with the RDS survey. Proportions were calculated using the RDS analysis tool. RESULTS: 511 IDUs enrolled in the survey; 61.2% reported injecting 2-3 times/day and 29.3% reported past month injection with a previously used needle. Amongst the 60% of IDUs who reported having sexual intercourse in the past three months, 39.5% did so with >=2 partners. Almost all IDUs (98.1%) reported inconsistent condom use in the past 12 months. HIV prevalence was 47.4%, HCV 97.3%, HBV 9.0%, and syphilis 2.7%; 99.7% of those infected with HIV were also infected with HCV. Our population size estimates put the number of IDUs in Mauritius at around 9500, lower than previous estimates. CONCLUSIONS: We observed high rates of HCV and HIV infection amongst IDUs in Mauritius. The scale-up of targeted HCV and HIV prevention, care and treatment services for IDUs should be a high priority. PMID- 21700443 TI - Uptake, benefits of and barriers to safer crack use kit (SCUK) distribution programmes in Victoria, Canada--a qualitative exploration. AB - BACKGROUND: Crack use is prevalent amongst street drug users in Canadian cities, and associated with severe drug use, health and social problems. Whilst few targeted interventions are available for crack use, the common use and sharing of hazardous makeshift paraphernalia are a key concern, as these risks may be associated with oral injury and blood-borne virus (BBV)--e.g., hepatitis C virus (HCV)--transmission amongst users. Recently, distribution programmes of so-called 'safer crack use kits' (SCUKs) have been initiated in select Canadian cities, primarily to reduce the use of unsafe materials and paraphernalia sharing amongst crack users. This study explored uptake and benefits of, barriers to, and possible improvements to two recently implemented SCUK distribution programme in Victoria, Canada. METHODS: N=31 regular crack smokers were recruited through community-based efforts between June and August 2010, and assessed via an interviewer-administered protocol involving quantitative and qualitative data items. Descriptive analyses were completed with the quantitative data, and thematic content analyses were conducted with the qualitative data in order to identify and extract prominent themes and issues. RESULTS: The sample indicated high levels of socio-economic marginalization, poly-substance use, health problems, lengthy crack use histories and common crack paraphernalia sharing. Most participants exclusively utilized the SCUK programme including glass-stems in addition to other paraphernalia materials. Participants described: lesser need to share--or to commit property crimes to obtain resources for--crack to paraphernalia, increased health awareness, and increased personal and community safety as benefits experienced from SCUK use. Limitations in SCUK resources and distribution, shortcomings in materials, and police interference were cited as barriers to current SCUK program delivery. CONCLUSIONS: SCUK distribution in Victoria appears to result in a variety of individual and community health benefits. These benefits could be solidified by addressing current programme limitations, including better resourcing, expanding geographic distributions and eliminating police interference. PMID- 21700444 TI - Bi-cell surface plasmon resonance detection of aptamer mediated thrombin capture in serum. AB - The serine protease coagulation factor thrombin functions primarily in hemostasis, but is also involved in atherosclerosis, thromboembolic disease, cancer and inflammatory disease. Direct measurement of coagulation proteins including thrombin in plasma samples poses a significant challenge because of lack of specific probes and low thrombin concentrations. In addition, high plasma protein concentrations in samples can result in high backgrounds. These challenges were overcome using a bi-cell surface plasmon resonance (SPR) spectrometer with an immobilized thrombin aptamer to measure thrombin in samples passed through a low volume flow cell. For thrombin in Tris-EDTA buffer, the limit of detection (LOD) was 25 nM. Coefficient of variation (CV) for detection of 50 nM was 12.2% and 12.4% for intra and inter-day measurements respectively. This detection was specific for both thrombin aptamer and for thrombin. Using serum samples spiked with thrombin, the LOD was 50 nM with a linear range of detection from 50 nM to 200 nM. However use of serum samples was associated with consistent, low-level background drift. The contributions of nonspecific protein absorption onto the sensor surface and sample flow speed were assessed, and strategies to reduce this background drift were explored. We conclude that the bi cell SPR platform with an aptamer capture probe can be employed as a highly sensitive real-time, label-free biosensor for the detection of coagulation factors in plasma samples. PMID- 21700445 TI - Development of a quantum dot-based fluorescent immunoassay for progesterone determination in bovine milk. AB - The use of semiconductor quantum dots (QDs) as fluorescent labels to develop a competitive immunoassay for sensitive detection and quantification of progesterone in cow's milk is described. Colloidal water-soluble CdSe/ZnS QDs are conjugated to an antigen derivative (progesterone-BSA conjugate) and a simple methodology is optimised to determine the antigen concentration in the final bioconjugate. The obtained QD-linked antigens were then employed together with unlabelled anti-progesterone monoclonal antibodies, as the biological recognition elements, in the development of the quantitative QDs-based fluorescent immunoassay for progesterone in bovine milk. After optimization, the developed immunoassay proved to cover a progesterone concentration range from 0.3 to 14.5 ng/mL in cow milk. Milk samples were just diluted 10-fold with deionised water and directly analysed with the proposed immunoassay, without additional sample pre-treatment or analyte extraction. The minimum detectable level (IC(10)) of the developed immunoassay turned out to be 0.1 ng/mL of progesterone in bovine milk. The sensitivity (IC(50)) achieved was 2.2 ng/mL with a reproducibility of 3.5% RSD as obtained from the results of the analysis of the triplicate of same samples but in three different days. Applicability of the proposed methodology was evaluated by analyzing cow's milk samples enriched with known concentrations of progesterone and recoveries better than 90% were achieved. PMID- 21700446 TI - Conducting polymer nanowires-based label-free biosensors. AB - Label-free sensing technologies have recently attracted a great deal of interest for sensitive, rapid and facile analysis for applications in health care, environmental monitoring, food safety and homeland security. One-dimensional (1 D) nanostructures such as nanowires, configured as field-effect transistors (FETs)/chemiresistors that change conductance upon binding of charged macromolecules to receptors linked to the device surfaces are extremely attractive for label-free biosensors. Herein, we review recent advances in label free biosensors based on conducting polymer nanowires based FET/chemiresistor. Specifically, we address the fabrication, functionalization, assembly/alignment and sensing applications of FET/chemiresistor based on these nanomaterials. The advantages and disadvantages of various fabrication, functionalization, and assembling procedures of these nanosensors are reviewed and discussed. PMID- 21700447 TI - Malignant peripheral nerve sheath tumours in NF1: improved survival in women and in recent years. AB - BACKGROUND: Malignant peripheral nerve sheath tumours (MPNST) are the main soft tissue malignancy associated with neurofibromatosis 1. These uncommon tumours are known to occur at high frequency and lead to poor survival. Our aim was to determine risk of MPNST in NF1 patients, and survival rates. METHODS: The incidence of MPNST in NF1 was identified through the NF1 genetic register and The North West Cancer Intelligence Service (NWCIS). Data were used to generate incidence and survival curves. Strict regional boundaries were adhered to avoid ascertainment bias. Kaplan-Meier curves were used to determine five and ten-year survival. RESULTS: Of the 1059 NF1 patients 52 developed MPNST (30 cases in females and 22 in males), 43 cases were resident within the strict regional boundary. The risk of MPNST was 10.2% in males and 12.7% in females by age 70 years (p=0.9), with a statistically better survival in females than males (5 and 10 year survival 46% and 41.5% versus 22% and 8.2%; p=0.05). Survival was also significantly improved for patients diagnosed in the last 14 years compared to the previous 13-year period (p=0.03). CONCLUSION: With fifteen strict regional MPNSTs in the fourteen years since our previous population study an annual incidence of above 1 per 1000 NF1 patients has now been maintained over a 27-year period. No significant increase in risk of MPNST in females compared to males was found, though the difference in survival is intriguing. Male survival is particularly poor with <10% alive at 10 years. PMID- 21700448 TI - Effects of microwave and alkali induced pretreatment on sludge solubilization and subsequent aerobic digestion. AB - Individual and combined effects of microwave (MW) and alkali pretreatments on sludge disintegration and subsequent aerobic digestion of waste activated sludge (WAS) were studied. Pretreatments with MW (600W-85 degrees C-2 min), conventional heating (520 W-80 degrees C-12 min) and alkali (1.5 g NaOH/L - pH 12-30 min) achieved 8.5%, 7% and 18% COD solubilization, respectively. However, combined MW alkali pretreatment synergistically enhanced sludge solubilization and achieved 46% COD solubilization, 20% greater than the additive value of MW alone and alkali alone (8.5+18%=26.5%). Moreover, the results of the batch aerobic digestion study on MW-alkali pretreated sludge showed 93% and 63% reductions in SCOD and VSS concentrations, respectively, at 16 days of SRT. The VSS reduction was 20% higher than that of WAS without pretreatment. PMID- 21700449 TI - Enhanced biological removal of NOchi from flue gas in a biofilter by Fe(II)Cit/Fe(II)EDTA absorption. AB - A mixed absorbent had been proposed to enhance the chemical absorption-biological reduction process for NO(x) removal from flue gas. The mole ratio of the absorbent of Fe(II)Cit to Fe(II)EDTA was selected to be 3. After the biofilm was formed adequately, some influential factors, such as the concentration of NO, O(2), SO(2) and EBRT were investigated. During the long-term running, the system could keep on a steady NO removal efficiency (up to 90%) and had a flexibility in the sudden changes of operating conditions when the simulated flue gas contained 100-500 ppm NO, 100-800 ppm SO(2), 1-5% (v/v) O(2), and 15% (v/v) CO(2). However, high NO concentration (>800 ppm) and relative short EBRT (<100s) had significant negative effect on NO removal. The results indicate that the new system by using mixed-absorbent can reduce operating costs in comparison with the single Fe(II)EDTA system and possesses great potential for scale-up to industrial applications. PMID- 21700450 TI - Effect of starch addition on the biological conversion and microbial community in a methanol-fed UASB reactor during long-term continuous operation. AB - The effect of starch addition on the microbial composition and the biological conversion was investigated using two upflow anaerobic sludge bracket (UASB) reactors treating methanolic wastewater: one reactor was operated with starch addition, and another reactor was operated without starch addition. Approximately 300 days of operation were performed at 30 kg COD/m(3)/d, and then, the organic load of the reactors was gradually increased to 120 kg COD/m(3)/d. Successful operation was achieved at 30 kg COD/m(3)/d in both reactors; however, the methanol-fed reactor did not perform well at 120 kg COD/m(3)/d while the methanol starch-fed reactor did. The granule analysis revealed the granule developed further only in the methanol-starch-fed reactor. The results of the microbial community analysis revealed more Methanosaeta cells were present in the methanol starch-fed reactor, suggesting the degradation of starch produced acetate as an intermediate, which stimulated the growth of Methanosaeta cells responsible for the extension of granules. PMID- 21700451 TI - Oxalate production at different initial Pb2+ concentrations and the influence of oxalate during solid-state fermentation of straw with Phanerochaete chrysosporium. AB - The production of oxalate at different initial Pb(2+) concentrations during solid state fermentation of straw with Phanerochaete chrysosporium was investigated. It was found that the maximal peak value of oxalate concentration (22.84 mM) was detected at the initial Pb(2+) concentration of 200 mg kg(-1) dry straw, while the minimum (15.89 mM) at the concentration of 600 mg Pb(2+)kg(-1) dry straw, and at moderate concentration of Pb(2+) the capability of oxalic acid secretion was enhanced. In addition, it was also found that more oxalic acid accumulation went together with better Pb(2+) passivation effect and higher manganese peroxidase (MnP) activity. The present findings will improve the understandings of the interactions of heavy metals with white-rot fungi and the role of oxalate in lignin degradation system, which could provide useful references for more efficient treatment of Pb-contaminated lignocellulosic waste. PMID- 21700452 TI - Effect of temperature on gas composition and char structural features of pyrolyzed agricultural residues. AB - The gases and chars produced during fast pyrolysis of maize stalk, rice straw, cotton straw and rice husk at temperatures ranging from 600 to 1000 degrees C were studied by Fourier transform infrared spectroscopy, non-dispersive infrared technique, thermal conductivity detection method, ultimate analysis, X-ray diffraction, helium density measurement and N(2) adsorption method. The gas yield increased by more than 80% from 600 to 1000 degrees C, while the char and liquid yield decreased. The content of CO(2), CO and CH(4) accounted for more than 86%. The CO and CH(4) content increased with temperature, while the CO(2) content decreased. The hydroxyl, aliphatic CH, carbonyl, olefinic CC and ether groups were lost above 800 degrees C. Carbon skeleton shrinkage increased by more than 23% when the temperature increased from 600 to 1000 degrees C. Maximum porosity appeared at 900 degrees C. This study revealed the relationships between gas composition/char properties and pyrolysis temperature under high heating rate conditions. PMID- 21700453 TI - Optimisation of pharmacokinetic properties to afford an orally bioavailable and selective V1A receptor antagonist. AB - The previously described lead compound 5 is a potent and selective V(1A) antagonist with affinity at both the rat and human receptor, but displays poor oral bioavailability and moderate clearance. We report herein the successful optimisation of the pharmacokinetic (PK) properties to afford the potent, selective, orally bioavailable and CNS penetrant compound 15f. A custom optimisation approach was required which demonstrated the value of using early, rapid in vivo PK studies to show improvements in oral exposure. Such assays may be of particular value where low oral bioavailability is anticipated to be multifactorial (e.g., permeability, gut wall metabolism and/or transport) where satisfactory modelling of in vitro data is likely to be difficult within a drug discovery context. PMID- 21700454 TI - Synthesis of d-labeled and unlabeled benzoyloxysuccinimides and application to quantitative analysis of peptides and a protein by isotope differential mass spectrometry. AB - Benzoyloxysuccinimide and its d(5)-labeled version, which react with amino groups in the N-termini and lysine side chains in proteins, were synthesized and applied to quantitative analysis of peptides and a commercially available protein in combination with a MALDI mass spectrometer. PMID- 21700455 TI - Intrathecal administration of trastuzumab with cytarabine and methotrexate in breast cancer patients with leptomeningeal carcinomatosis. AB - HER2-positive status is associated with increased risk of central nervous system (CNS) metastases in breast cancer patients. Leptomeningeal carcinomatosis (LMC) represents a rare but disastrous manifestation of metastatic breast cancer (MBC) with limited treatment options and poor prognosis. Several case reports of intrathecal (i.t.) trastuzumab in the treatment of LCM were published so far. Usually, i.t. trastuzumab was administered in monotherapy or in combination with metothrexate. Herein, we report for the first time two patients with metastatic breast cancer and leptomeningeal carcinomatosis treated by intrathecal methotrexate (15 mg total dose) and cytarabine (24 mg total dose) with escalating dose of trastuzumab. We observed that up to 100 mg of trastuzumab can be safely administered intratecally with i.t. metothrexate and cytarabine. Both patients achieved good control of leptomeningeal disease for 13.5 and 6 months without significant toxicity. We suggest that i.t. trastuzumab with cytarabine and metothrexate is associated with promising benefit and warrant further investigation. PMID- 21700456 TI - Estrogen receptor positive operable breast cancer: does menopausal status impact on HER2 and progesterone receptor status? AB - PURPOSE: The objective of the present study was to determine whether progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) status differs by menopausal status in estrogen receptor (ER)-positive breast cancers. PATIENTS AND METHODS: We retrospectively analyzed the clinicopathological data of 588 with operable ER(+) breast cancers patients. ER, HER2 and PgR expression in the tumor specimens were examined by immunohistochemistry. The relationship between different variables was assessed by Pearson's chi(2) and Fisher's exact probability tests in univariate analyses. Logistic regression was used for multivariate analyses of relationship between HER2 expression and selected clinicopathological characteristics. Maximum likelihood estimates of the odds ratio (OR) were obtained and 95% confidence intervals (CI) were calculated. RESULTS: In the postmenopausal women with ER(+) tumors, HER2 was independently inversely associated with PgR expression (P = 0.017; OR 3.02; 95% CI 1.22-7.49). An ER(+)/PgR(-) tumor was 3.02 times more likely to express HER2 than an ER(+)/PgR(+) tumor in the postmenopausal women. However, an ER(+) tumor in the premenopausal patients failed to show an independent relationship between HER2 and PgR. CONCLUSION: Menopausal status played a very important role in determining HER2 and PgR status in ER(+) breast cancer patients. HER2 was independently inversely associated with PgR only in the postmenopausal women with ER(+) breast cancers but not in the premenopausal ones. PMID- 21700457 TI - Arabidopsis PLETHORA transcription factors control phyllotaxis. AB - The pattern of plant organ initiation at the shoot apical meristem (SAM), termed phyllotaxis, displays regularities that have long intrigued botanists and mathematicians alike. In the SAM, the central zone (CZ) contains a population of stem cells that replenish the surrounding peripheral zone (PZ), where organs are generated in regular patterns. These patterns differ between species and may change in response to developmental or environmental cues [1]. Expression analysis of auxin efflux facilitators of the PIN-FORMED (PIN) family combined with modeling of auxin transport has indicated that organ initiation is associated with intracellular polarization of PIN proteins and auxin accumulation [2-10]. However, regulators that modulate PIN activity to determine phyllotactic patterns have hitherto been unknown. Here we reveal that three redundantly acting PLETHORA (PLT)-like AP2 domain transcription factors control shoot organ positioning in the model plant Arabidopsis thaliana. Loss of PLT3, PLT5, and PLT7 function leads to nonrandom, metastable changes in phyllotaxis. Phyllotactic changes in plt3plt5plt7 mutants are largely attributable to misregulation of PIN1 and can be recapitulated by reducing PIN1 dosage, revealing that PLT proteins are key regulators of PIN1 activity in control of phyllotaxis. PMID- 21700458 TI - Cleaner wrasses Labroides dimidiatus are more cooperative in the presence of an audience. AB - Humans may help others even in situations where the recipient will not reciprocate [1-5]. In some cases, such behavior can be explained by the helpers increasing their image score, which will increase the probability that bystanders will help them in the future [5-7]. For other animals, the notion that many interactions take place in an environment containing an audience of eavesdropping bystanders has also been proposed to have important consequences for social behavior, including levels of cooperation [8]. However, experimental evidence is currently restricted to the demonstration that cleaner fish Labroides dimidiatus can learn to solve a foraging task [9]. The cleaners learned to feed against their preference on artificial clients if that allowed them to access additional artificial clients, which would translate into cooperatively eating ectoparasites rather than cheating by eating client mucus under natural conditions [10]. Here we show that cleaners immediately increase current levels of cooperation in the presence of bystander client reef fish. Furthermore, we find that bystanders respond to any occurrence of cleaners cheating their current client with avoidance. In conclusion, the results demonstrate, for the first time, that image scoring by an audience indeed leads to increased levels of cooperation in a nonhuman animal. PMID- 21700459 TI - Regulation of DNA replication through Sld3-Dpb11 interaction is conserved from yeast to humans. AB - Cyclin-dependent kinases (CDKs) play crucial roles in promoting DNA replication and preventing rereplication in eukaryotic cells [1-4]. In budding yeast, CDKs promote DNA replication by phosphorylating two proteins, Sld2 and Sld3, which generates binding sites for pairs of BRCT repeats (breast cancer gene 1 [BRCA1] C terminal repeats) in the Dpb11 protein [5, 6]. The Sld3-Dpb11-Sld2 complex generated by CDK phosphorylation is required for the assembly and activation of the Cdc45-Mcm2-7-GINS (CMG) replicative helicase. In response to DNA replication stress, the interaction between Sld3 and Dpb11 is blocked by the checkpoint kinase Rad53 [7], which prevents late origin firing [7, 8]. Here we show that the two key CDK sites in Sld3 are conserved in the human Sld3-related protein Treslin/ticrr and are essential for DNA replication. Moreover, phosphorylation of these two sites mediates interaction with the orthologous pair of BRCT repeats in the human Dpb11 ortholog, TopBP1. Finally, we show that DNA replication stress prevents the interaction between Treslin/ticrr and TopBP1 via the Chk1 checkpoint kinase. Our results indicate that Treslin/ticrr is a genuine ortholog of Sld3 and that the Sld3-Dpb11 interaction has remained a critical nexus of S phase regulation through eukaryotic evolution. PMID- 21700460 TI - Evolutionary conservation of the basal ganglia as a common vertebrate mechanism for action selection. AB - BACKGROUND: Although the basal ganglia are thought to play a key role in action selection in mammals, it is unknown whether this mammalian circuitry is present in lower vertebrates as a conserved selection mechanism. We aim here, using lamprey, to elucidate the basal ganglia circuitry in the phylogenetically oldest group of vertebrates (cyclostomes) and determine how this selection architecture evolved to accommodate the increased behavioral repertoires of advanced vertebrates. RESULTS: We show, using immunohistochemistry, tract tracing, and whole-cell recordings, that all parts of the mammalian basal ganglia (striatum, globus pallidus interna [GPi] and externa [GPe], and subthalamic nucleus [STN]) are present in the lamprey forebrain. In addition, the circuit features, molecular markers, and physiological activity patterns are conserved. Thus, GABAergic striatal neurons expressing substance P project directly to the pallidal output layer, whereas enkephalin-expressing striatal neurons project indirectly via nuclei homologous to the GPe and STN. Moreover, pallidal output neurons tonically inhibit tectum, mesencephalic, and diencephalic motor regions. CONCLUSIONS: These results show that the detailed basal ganglia circuitry is present in the phylogenetically oldest vertebrates and has been conserved, most likely as a mechanism for action selection used by all vertebrates, for over 560 million years. Our data also suggest that the mammalian basal ganglia evolved through a process of exaptation, where the ancestral core unit has been co-opted for multiple functions, allowing them to process cognitive, emotional, and motor information in parallel and control a broader range of behaviors. PMID- 21700461 TI - Retromer controls epithelial cell polarity by trafficking the apical determinant Crumbs. AB - The evolutionarily conserved apical determinant Crumbs (Crb) is essential for maintaining apicobasal polarity and integrity of many epithelial tissues [1]. Crb levels are crucial for cell polarity and homeostasis, yet strikingly little is known about its trafficking or the mechanism of its apical localization. Using a newly established, liposome-based system described here, we determined Crb to be an interaction partner and cargo of the retromer complex. Retromer is essential for the retrograde transport of numerous transmembrane proteins from endosomes to the trans-Golgi network (TGN) and is conserved between plants, fungi, and animals [2]. We show that loss of retromer function results in a substantial reduction of Crb in Drosophila larvae, wing discs, and the follicle epithelium. Moreover, loss of retromer phenocopies loss of crb by preventing apical localization of key polarity molecules, such as atypical protein kinase C (aPKC) and Par6 in the follicular epithelium, an effect that can be rescued by overexpression of Crb. Additionally, loss of retromer results in multilayering of the follicular epithelium, indicating that epithelial integrity is severely compromised. Our data reveal a mechanism for Crb trafficking by retromer that is vital for maintaining Crb levels and localization. We also show a novel function for retromer in maintaining epithelial cell polarity. PMID- 21700462 TI - The reproducibility of signals from skin-mounted accelerometers following removal and replacement. AB - Signals from skin-mounted accelerometers may contain measurement error when compared to those obtained from bone-mounted sensors. While this error may be minimized through various techniques, additional error may arise as a result of accelerometer removal from the skin and subsequent replacement. The purpose of this experiment was to determine if skin-mounted accelerometer signals remain similar before and after sensor replacement when sensors are stimulated within a consistent vibration environment. The spines of five porcine and five human cadavers were vibrated non-invasively and the resulting response measured using accelerometers glued to the skin overlying the vertebrae of interest (T-9 in porcine cadavers, L2-L4 in human cadavers). Accelerometers were removed, then replaced, to their perceived original positions. Accelerometer signals showed high repeatability within an original placement, however, once replaced, pre- and post-replacement signals were statistically dissimilar in all cadavers tested. Specifically, the similarity of pre- and post-replacement signals was poor for different skin types (porcine and human) and did not improve with accelerometer proximity to the vibration source. From these data, we conclude that accelerometers adhered to the skin overtop spinous processes are able to obtain highly repeatable signals for a given placement, however, signals change significantly after sensor replacement. When skin-mounted accelerometers are used in gait and other studies, investigators should consider performing test/re-test analyses to ensure that sensor data are not affected if sensor replacement is required by design or by accident. PMID- 21700463 TI - The influence of stride-length on plantar foot-pressures and joint moments. AB - PURPOSE: Joint moments have been acknowledged as key factors in understanding gait abnormalities. Gait velocity is further known to affect joint moments and foot pressures. Keeping gait velocity constant is thus a strategy to cancel out the influence of different preferred gait speed between groups. But even if gait velocity is controlled, individuals can choose different stride length-stride frequency combinations to cope with an imposed gait velocity. SCOPE: To understand the influence of stride frequency-stride length on joint moments and plantar pressures. METHODS: Twenty healthy young adults had to cross an 8m walkway with a walking speed of 1.3ms(-1). The wooden walkway was equipped with a force and a pressure platform. While walking speed was kept constant each participant walked with five different imposed stride lengths (SL): preferred (SL0); with a decrease of 10% (SL-10); with a decrease of 20% (SL-20); with an increase of 10% (SL+10) and with an increase of 20% (SF+20). RESULTS: Ankle and knee joint moments significantly decreased with a decrease in SL. A significant (p<.05) lower peak pressure was achieved with a decreased SL under the heel, toes and midfoot. DISCUSSION/CONCLUSION: The results showed that a change in stride lengths alters both, joint moments and foot pressures with clinically interesting indications. Redistribution of joint moments in the elderly for example might rather result from decreased SL than from age. PMID- 21700464 TI - Gait, balance and plantar pressures in older people with toe deformities. AB - Older people with toe deformities have been identified as having an increased risk of falling. Little is known, however, about the biomechanical changes that might contribute to this increased risk. Therefore, the purpose of this study was to determine whether older people with hallux valgus and lesser toe deformities displayed different gait, balance and plantar pressure characteristics compared to individuals without toe deformities. The presence of hallux valgus and lesser toe deformities were assessed for 312 community-dwelling older men and women. Spatiotemporal gait parameters were measured using the GAITrite((r)) system, postural sway was assessed on two surfaces using a sway-meter and dynamic plantar pressure distribution was measured using an Emed-AT4 pressure plate. The results indicated that, although there were no effects of toe deformities on spatiotemporal gait characteristics or postural sway, older people with hallux valgus (n=36) and lesser toe deformities (n=71) were found to display altered forefoot plantar pressure patterns. These findings suggest that toe deformities alter weight distribution under the foot when walking, but that the relationship between toe deformities and falls may be mediated by factors other than changes in spatiotemporal gait parameters or impaired postural sway. PMID- 21700465 TI - Hypermetabolism in the left thalamus and right inferior temporal area on positron emission tomography-statistical parametric mapping (PET-SPM) in a patient with Charles Bonnet syndrome resolving after treatment with valproic acid. AB - Charles Bonnet syndrome (CBS) is characterized by the occurrence of complex visual hallucinations in visually impaired patients who understand that what they see is unreal. The pathophysiologic mechanism of CBS is poorly understood. However, hypermetabolism of the thalamocortical pathway as a result of deafferentation was recently proposed as a possible mechanism. A 69-year-old patient with CBS presented with a 5-year history of visual hallucinations after bilateral visual impairment, which had progressed to troublesome images of many unreal people and animals. Positron emission tomography-statistical parametric mapping (PET-SPM) imaging studies initially revealed hypermetabolism in the right inferior temporal area and left thalamus, which disappeared after treatment with valproic acid. This case, using PET-SPM analysis, supports the thalamic hypermetabolism theory of CBS. PMID- 21700466 TI - Imidazo[1,2-a]pyridin-3-amines as potential HIV-1 non-nucleoside reverse transcriptase inhibitors. AB - During random screening of a small in-house library of compounds, certain substituted imidazo[1,2-a]pyridines were found to be weak allosteric inhibitors of HIV-1 reverse transcriptase (RT). A library of these compounds was prepared using the Groebke reaction and a subset of compounds prepared from 2 chlorobenzaldehyde, cyclohexyl isocyanide and a 6-substituted 2-aminopyridine showed good inhibitory activity in enzymatic (RT) and HIV anti-infectivity MAGI whole cell assays. The compound showing the best anti-HIV-1 IIIB whole cell activity (MAGI IC(50)=0.18 MUM, IC(90)=1.06 MUM), along with a good selectivity index (>800), was 2-(2-chlorophenyl)-3-(cyclohexylamino)imidazo[1,2-a]pyridine-5 carbonitrile 38. PMID- 21700467 TI - Synthesis of new series of alpha-cyclodextrin esters as dopamine carrier molecule. AB - A new series of amphiphilic alpha-cyclodextrins were synthesized by grafting N acylated amino acids [valine, leucine, phenylalanine, methionine, and tryptophan (3a-e)] to the primary hydroxyl groups via ester bond formation. The synthetic pathway involves selective hexa-bromination of the primary hydroxyls followed by per-substitution with the carboxylate moiety of the N-acetyl residues in the presence of DBU (1,8-diazabicyclo[5,4,0]undec-7-ene). The ability of the synthetic compounds for the extraction of dopamine was studied. The results showed a considerable ability of some of the amphiphilic compounds for the extraction of dopamine into octanol phase from water. To complete the study, the binding affinity of dopamine toward the synthetic host molecules was calculated by using of the molecular docking technique. PMID- 21700468 TI - Bamboo-shaped carbon nanotubes generated by methane thermal decomposition using Ni nanoparticles synthesized in water-oil emulsions. AB - Ni nanoparticles were synthesized using two water-in-oil emulsions formulated with different surfactants and using n-heptane as the organic phase and aqueous nickel acetate as the catalytic metallic precursor. Characterization by transmission electron microscopy showed that the Ni nanoparticles have diameters ranging from 3 to 12 nm, and that the surface is lightly oxidized. The decomposition of diluted methane catalyzed by the as-prepared Ni nanoparticles was studied in a thermogravimetric analyzer (TGA), operated in the 25-930 degrees C range. The weight gains measured during the analysis showed that the Ni nanoparticles decomposed methane above 480 degrees C, producing similar g.C/g.cat ratios (6-7) at the end of the tests. High resolution transmission electron microscopy (HRTEM) confirmed that the carbons collected at 930 degrees C were bamboo-shaped carbon nanotubes (BSCNTs) with well defined conical compartments. The average outside diameter of the tubes was between 30 and 60 nm. PMID- 21700469 TI - Chlorogenic acid participates in the regulation of shoot, root and root hair development in Hypericum perforatum. AB - Chlorogenic acid (CGA), a product of the phenylpropanoid pathway, is one of the most widespread soluble phenolic compounds in the plant kingdom. Although CGA is known to have important roles in plant function, its relevance in plant de novo organogenesis is not yet understood. With a series of experiments, here we show that CGA has a potential role in shoot, root and root hair development. In the first phase of our investigation, we developed an efficient and novel thin cell layer (TCL) regeneration protocol for Hypericum perforatum which could bridge all the in vitro morphogenetic stages between single cell and complete plant. Tissues at different morphogenetic states were analysed for their phenolic profile which revealed that shoot differentiation from callus tissues of H. perforatum is accompanied by the onset of CGA production. Further, the relevance of CGA in de novo organogenesis was deciphered by culturing highly organogenic root explants on media augmented with various concentrations of CGA. Results of this experiment showed that CGA concentrations lower than 10.0 mg l-1 did not affect shoot organogenesis, whereas, higher concentrations significantly reduced this process in a concentration-dependent manner. In spite of the differential concentration dependent effects of CGA on shoot regeneration, supplementation of CGA did not have any effect on the production of lateral roots and root hairs. Interestingly, CGA showed a concentration-dependent positive correlation with lateral roots and root hairs production in the presence of alpha-naphthaleneacetic acid (NAA). When the culture medium was augmented with 2-aminoindane-2-phosphonic acid (AIP), an inhibitor of phenylalanine ammonia lyase (PAL), induction of shoots, lateral roots and root hairs from the explants was significantly affected. Addition of an optimum concentration of CGA in these cultures partially restored all these organogenic processes. PMID- 21700470 TI - Squamous cell carcinoma and piercing of the tongue - a case report. AB - Tongue piercings can be associated with local and systemic complications. Local complications occur frequently immediately after the surgery but also long-term local effects can cause problems such as speech and swallowing difficulties. Aspiration, transmission of infectious diseases, hypersensitivity reaction belong to the systemic complications. In the presented paper an unusual case of cancer development in a 26-year-old man who had a metal piercing inserted for 5 years in the right anterior third of the tongue. Despite of intense concommitant chemoradiotherapy the patient died 18 months from the first symptoms. In prevention of various complications it would be the best solution spread information about the risks of the tongue piercing especially within teenage population. PMID- 21700471 TI - An unusual cause of hemo-pneumothorax. PMID- 21700473 TI - Support time-dependent outcome analysis for veno-venous extracorporeal membrane oxygenation. AB - OBJECTIVE: The majority of patients suffering from pulmonary failure refractory to mechanical ventilation require extracorporeal membrane oxygenation (ECMO) support between 1 and 2 weeks. This study was designed to evaluate differences in outcome depending on ECMO duration. METHODS: A retrospective analysis on n = 127 patients requiring veno-venous (VV) ECMO support at our institution between April 2006 and March 2010 was applied. The patient population was divided into three groups according to the support duration (A: 0-10 days), 75 patients; B: 11-20 days, 32 patients; C: >21 days, (max. 67 days), 19 patients). Statistical comparisons between groups were calculated. RESULTS: Mean age of all patients (? = 42 patients ?=85 patients) was 48 +/- 16 years (range 15-78 years). Bilateral pneumonia due to bacterial infection (n = 45 patients) or due to aspiration (n = 19 patients) was the main cause for pulmonary failure, other causes were extrapulmonary sepsis (n = 27 patients), major surgery (n = 17 patients), and severe trauma (n = 12 patients). Mean lung injury score (LIS) according to Murray was 3.4 +/- 0.4, and mean sequential organ failure assessment (SOFA) score was 12.6 +/- 3.7. Statistical comparisons revealed no significant difference in demographic parameters between groups. VV ECMO support immediately improved oxygenation, within 2h the PaO(2)/FiO(2) ratio rose from 80 +/- 42 mm Hg to 129 +/- 72 mm Hg (p = 0.001). Overall survival to discharge was 51.2%. There was a statistical difference in survival between groups (A = 59%, B = 31%, C = 52%; p = 0.029). Multivariate logistic regression analysis revealed renal failure (odds ratio (OR) 12.1; confidence interval (CI) 3.9-30.0; p < 0.001) and the use of NO (OR=5.8; CI=1.9-24.9; p=0.002) as risk factors for mortality. Complications consisted of cannula-related complications (14%), bleeding issues (13%), partial vein thrombosis of the cannulated vessels (9.5%), and pumphead failure (1.5%). CONCLUSION: VV ECMO in patients suffering from severe lung failure is effective in improving gas exchange with an overall survival of higher than 50%. Prolonged need of ECMO support does not have an impact on survival. PMID- 21700474 TI - PPARgamma agonist rosiglitazone ameliorates LPS-induced inflammation in vascular smooth muscle cells via the TLR4/TRIF/IRF3/IP-10 signaling pathway. AB - The activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) can induce inflammation that are one of key etiological conditions for the development of many chronic inflammatory diseases including atherosclerosis and diabetes. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists play a crucial role in improving glucose and lipid homeostasis in the development of cardiovascular diseases. Evidence is growing that benefits of PPARgamma agonists may also be derived from the anti-inflammatory and anti-atherosclerotic properties of these agents. However, the role of rosiglitazone in regulating LPS induced vascular inflammation has yet to be fully elucidated. The current study demonstrated that rosiglitazone exerted a potent anti-inflammatory action via decreasing interleukin-18 (IL-18), tissue inhibitor of metalloproteinase-1 (TIMP 1), TLR4 and increasing PPARgamma in LPS-induced VSMCs. Furthermore, treatment of VSMCs with the TLR4 blocker or TLR4 small-interfering RNA presented that the regulatory effects of rosiglitazone on LPS-mediated inflammation in VSMCs were dependent on TLR4. Interestingly, the results indicated that beneficial effects of rosiglitazone on LPS-induced inflammation in VSMCs were mediated via interference of TLR4 and its downstream signaling components including Toll interleukin-1 (IL-1) receptor domain-containing adaptor inducing interferon-beta (TRIF), interferon regulatory factor 3 (IRF3) and interferon-gamma inducible protein 10 (IP-10). In summary, PPARgamma agonist rosiglitazone exerts anti inflammatory property by antagonizing LPS-mediated inflammation in VSMCs. More importantly, the regulation of the TRIF-dependent TLR4 signaling pathway (TLR4/TRIF/ IRF3/IP-10) provides new insight to understand the mode of action of rosiglitazone for its anti-inflammatory effects. PMID- 21700475 TI - Growth promotion of genetically modified hematopoietic progenitors using an antibody/c-Mpl chimera. AB - Thrombopoietin is a potent cytokine that exerts proliferation of hematopoietic stem cells (HSCs) through its cognate receptor, c-Mpl. Therefore, mimicry of c Mpl signaling by a receptor recognizing an artificial ligand would be attractive to attain specific expansion of genetically modified HSCs. Here we propose a system enabling selective expansion of genetically modified cells using an antibody/receptor chimera that can be activated by a specific antigen. We constructed an antibody/c-Mpl chimera, in which single-chain Fv (ScFv) of an anti fluorescein antibody was tethered to the extracellular D2 domain of the erythropoietin receptor and transmembrane/cytoplasmic domains of c-Mpl. When the chimera was expressed in interleukin (IL)-3-dependent pro-B cell line Ba/F3, genetically modified cells were selectively expanded in the presence of fluorescein-conjugated BSA (BSA-FL) as a specific antigen. Furthermore, highly purified mouse HSCs transduced with the retrovirus carrying antibody/c-Mpl chimera gene proliferated in vitro in response to BSA-FL, and the cells retained in vivo long-term repopulating abilities. These results demonstrate that the antibody/c-Mpl chimera is capable of signal transduction that mimics wild-type c Mpl signaling. PMID- 21700476 TI - Unified immune modulation by 4-1BB triggering leads to diverse effects on disease progression in vivo. AB - 4-1BB (CD137) is a powerful T-cell costimulatory molecule in the treatment of virus infections and tumors, but recent studies have also uncovered regulatory functions of 4-1BB signaling. Since 4-1BB triggering suppresses autoimmunity by accumulating indoleamine 2,3-dioxygenase (IDO) in dendritic cells (DCs) in an interferon (IFN)-gamma-dependent manner, we asked whether similar molecular and cellular changes were induced by 4-1BB triggering in virus-infected mice. 4-1BB triggering increased IFN-gamma and IDO, and suppressed CD4(+) T cells, in C57BL/6 mice infected with the type 1 KOS strain of Herpes simplex virus (HSV-1), as it does in an autoimmune disease model. Detailed analysis of the CD4(+) T suppression showed that freshly activated CD62L(high) T cells underwent apoptosis in the early phase of suppression, and CD62L(low) effector/memory T cells in the later phase. Although 4-1BB triggering resulted in similar cellular changes - increased CD8(+) T and decreased CD4(+) T cells, it had different effects on mortality in mice infected with HSV-1 RE, influenza, and Japanese encephalitis virus (JEV); it increased mortality in influenza-infected mice but decreased it in JEV-infected mice. Since the dominant type of immune cell generated to protect the host was different for each virus - CD4(+) T cells and neutrophils in HSV-1 RE infection, both CD4(+) T and CD8(+) T cells in influenza infection, and a crucial role for B cells in JEV infection, 4-1BB triggering resulted in different therapeutic outcomes. We conclude that the therapeutic outcome of 4-1BB triggering is determined by whether the protective immunity generated against the virus was beneficially altered by the 4-1BB triggering. PMID- 21700477 TI - Intraprocedural cortisol levels in the evaluation of proper catheter placement in adrenal venous sampling. AB - PURPOSE: Adrenal venous sampling (AVS) is limited by technical failures that result from incorrect catheter placement or failure to catheterize the right adrenal vein. The existence of an inadequate sample may not be recognized at the time of the procedure, which can lead to nondiagnostic results. Rapid assay of serum cortisol levels allows for intraprocedural evaluation of the ratio of adrenal and peripheral cortisol concentrations and confirmation of adequate sampling. MATERIALS AND METHODS: Retrospective review was performed of 64 AVS procedures, 36 performed with digital subtraction venography (DSV) guidance alone and 28 performed with DSV guidance plus intraprocedural quantitative determinations of plasma cortisol levels. RESULTS: Technical success was achieved in 26 of 28 procedures (93%) that included intraprocedural cortisol measurements in addition to DSV. Analysis of cortisol ratios (adrenal vein cortisol level divided by inferior vena cava cortisol level) revealed technical success in 29 of 36 procedures (81%) that used DSV alone (P = .16). Procedure note indication of successful/unsuccessful sampling coincided with cortisol ratios in 28 of 28 cases (100%) that included cortisol measurement and 29 of 36 cases (81%) that did not (P = .01).The feedback provided by the measurement of cortisol levels allowed the operator to salvage three of five inadequate AVS procedures (60%), increasing the overall technical success rate from 82% to 93%. CONCLUSIONS: Intraprocedural measurement of cortisol with rapid results allows for prediction of successful adrenal vein catheterization, which may increase the technical success rate of AVS. PMID- 21700478 TI - Accuracy and performance of the state-based Phi and liveliness measures of information integration. AB - A number of people have suggested that there is a link between information integration and consciousness, and a number of algorithms for calculating information integration have been put forward. The most recent of these is Balduzzi and Tononi's state-based Phi algorithm, which has factorial dependencies that severely limit the number of neurons that can be analyzed. To address this issue an alternative state-based measure known as liveliness has been developed, which uses the causal relationships between neurons to identify the areas of maximum information integration. This paper outlines the state-based Phi and liveliness algorithms and sets out a number of test networks that were used to compare their accuracy and performance. The results show that liveliness is a reasonable approximation to state-based Phi for some network topologies, and it has a much more scalable performance than state-based Phi. PMID- 21700479 TI - The long term effect of an intra-articular injection of corticosteroids in the acromioclavicular joint. AB - BACKGROUND: A prospective study was established to assess the effect of an intra articular injection of corticosteroid and local anaesthetic into the acromioclavicular (AC) joint. METHODS: Fifty-eight patients with isolated AC joint symptoms were included. Clinical tests were repeated immediately following the injection, as well as at 1-month follow-up. If symptoms failed to improve at this time, arthroscopic surgery was offered. All other patients were dismissed from standard care and contacted for this study. Both American Shoulder and Elbow Surgeons (ASES) and University of California at Los Angeles (UCLA) scores were obtained at final follow-up. RESULTS: Sixteen patients had improved sufficiently. Between the 1 month and average final follow-up of 42 months, 1 patient had arthroscopic resection of the distal clavicle. Four of the 15 patients reported occasional mild pain. Average visual analogue scale (VAS) score for pain was 0.5 (0-3). Average ASES score was 94.1 (70-100) and average UCLA score was 33.9 (28 35). DISCUSSION: Pain relief achieved with an injection into the AC joint has both a diagnostic and therapeutic value. The decrease of pain with clinical testing affirms the correct position of the injection. Only a minority of patients has sufficient pain relief from the injection at 1 month follow-up; however, this is sustained at the longer-term follow-up in the patients that have a positive reaction. CONCLUSION: The diagnostic value of the injection of a local anaesthetic in the AC joint is immediate. Only 28% have a clear positive result at 1 month; but, this result is sustained at long-term follow-up. There were no complications. PMID- 21700481 TI - Comments regarding 'Prevalence and predictors of persistent health status impairment in patients referred to a vascular clinic with intermittent claudication'. PMID- 21700480 TI - Missing data and interpretation of cancer surgery outcomes at the American College of Surgeons National Surgical Quality Improvement Program. AB - BACKGROUND: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) has become an important surgical quality program in the United States, yet few studies describe their methods for handling missing data. Our study examines the impact of missing data on predictive models for short-term operative outcomes after cancer surgery in the ACS NSQIP database. STUDY DESIGN: We identified 97,230 patients who underwent oncologic resections for neoplasms in the 2005-2009 ACS NSQIP. We used multivariable logistic regression to assess the impact of pre-, intra-, and postoperative factors on short-term operative outcomes by type of procedure where missing values were included as a variable category, excluded, and imputed. RESULTS: A large proportion (72.8%) of patients had one or more missing pre-, intra-, or postoperative characteristics, particularly preoperative laboratory values. Missing data were more frequent in healthier patients and those undergoing lower risk procedures. Although data were not missing at random, the impact of preoperative risk factors on adverse operative outcomes after cancer surgery was similar across methods for handling missing data. However, analytic approaches using only patients with complete or imputed information risk basing the analysis on a potentially nonrepresentative sample. CONCLUSIONS: Missing data present challenges to interpreting predictors of short-term operative outcomes after cancer surgery at ACS NSQIP hospitals. Similar to best practices for other data sets, this study highlights the importance of using missing values carefully when using ACS NSQIP. Given its potential to introduce bias, the approach to handling missing values should be detailed in future ACS NSQIP studies. PMID- 21700482 TI - Non-cryogenic anatomical imaging in ultra-low field regime: hand MRI demonstration. AB - Ultra-low field (ULF) MRI with a pulsed prepolarization is a promising method with potential for applications where conventional high-, mid-, and low-field medical MRI cannot be used due to cost, weight, or other restrictions. Previously, successful ULF demonstrations of anatomical imaging were made using liquid helium-cooled SQUIDs and conducted inside a magnetically shielded room. The Larmor frequency for these demonstrations was ~3 kHz. In order to make ULF MRI more accessible, portable, and inexpensive, we have recently developed a non cryogenic system. To eliminate the requirement for a magnetically shielded room and improve the detection sensitivity, we increased the frequency to 83.6 kHz. While the background noise at these frequencies is greatly reduced, this is still within the ULF regime and most of its advantages such as simplicity in magnetic field generation hardware, and less stringent requirements for uniform fields, remaining. In this paper we demonstrate use of this system to image a human hand with up to 1.5mm resolution. The signal-to-noise ratio was sufficient to reveal anatomical features within a scan time of less than 7 min. This prototype can be scaled up for constructing head and full body scanners, and work is in progress toward demonstration of head imaging. PMID- 21700483 TI - X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism. AB - X-linked adrenoleukodystrophy (X-ALD) is a progressive peroxisomal disorder affecting adrenal glands, testes and myelin stability that is caused by mutations in the ABCD1 (NM_000033) gene. Males with X-ALD may be diagnosed by the demonstration of elevated very long chain fatty acid (VLCFA) levels in plasma. In contrast, only 80% of female carriers have elevated plasma VLCFA; therefore targeted mutation analysis is the most effective means for carrier detection. Amongst 489 X-ALD families tested at Kennedy Krieger Institute, we identified 20 cases in which the ABCD1 mutation was de novo in the index case, indicating that the mutation arose in the maternal germ line and supporting a new mutation rate of at least 4.1% for this group. In addition, we identified 10 cases in which a de novo mutation arose in the mother or the grandmother of the index case. In two of these cases studies indicated that the mothers were low level gonosomal mosaics. In a third case biochemical, molecular and pedigree analysis indicated the mother was a gonadal mosaic. To the best of our knowledge mosaicism has not been previously reported in X-ALD. In addition, we identified one pedigree in which the maternal grandfather was mosaic for the familial ABCD1 mutation. Less than 1% of our patient population had evidence of gonadal or gonosomal mosaicism, suggesting it is a rare occurrence for this gene and its associated disorders. However, the residual maternal risk for having additional ovum carrying the mutant allele identified in an index case that appears to have a de novo mutation is at least 13%. PMID- 21700484 TI - Differences in neutral foot positions when measured barefoot compared to in shoes with varying stiffnesses. AB - BACKGROUND: This study examined the absolute differences in neutral positions of the joints of the foot with different footwear. This addresses the question of whether separate static trials should be collected for each footwear condition to establish neutral positions. METHODS: A multi-segment kinematic foot model and optical motion analysis system measured four inter-segmental joints of the foot: (1) hindfoot-to-midfoot in the frontal plane, (2) forefoot-to-midfoot in the frontal plane, (3) hallux-to-forefoot in the sagittal plane, and (4) the height to-length ratio of the medial longitudinal arch. Barefoot was compared to three shoe condition using Nike Free trainers of varying longitudinal torsional stiffness in ten male volunteers. FINDINGS: There was high variability both within subjects and shoe conditions. Shoes in general tended to raise the medial longitudinal arch and dorsiflex the hallux compared to barefoot condition. For the hallux, a minimum important difference of 5 degrees or more was found between shoe conditions and the barefoot condition for majority of the subjects in all three shoe conditions (90% for control, 60% for least stiff, 50% for most stiff). This was less for the frontal plane inter-segmental joints of the foot where 50% of the subjects experience a change above 5 degrees for at least one of the conditions. INTERPRETATION: The choice of using condition-specific neutral trials versus a single common neutral trials should be considered carefully. A single common trial allows for differences in absolute joint angles to be compared between footwear conditions. This can be important clinically to determine whether a joint is approaching its end-of-range and therefore at risk of injury. Several condition-specific neutral trials allows for subtleties in kinematic waveforms to be better compared between conditions, since absolute shifts in joint angles due to changing neutral position are removed and the waveforms are better aligned. PMID- 21700485 TI - Recent development in pleiotropic effects of statins on cardiovascular disease through regulation of transforming growth factor-beta superfamily. AB - BACKGROUND: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are a drug class that reduce the level of cholesterol in the blood. As a result, statins are used to suppress the progression of cardiovascular disease. Evidence points to another component of statins involving the non-lipid effects of the drug class in preventing cardiovascular disease. One specific mediator of this action is the transforming growth factor beta (TGF beta) superfamily. The TGF-beta superfamily consists of proteins that include TGF beta and bone morphogenetic proteins (BMPs). These proteins regulate cellular pathways to mediate effects including immunomodulation, cell cycling, and angiogenesis. One pathway that mediates these effects is Ras. Moreover, within this pathway, different functions are possible depending on the activation of the specific receptor subtype. This review discusses the recent development of the non-lipid effects of statins in preventing cardiovascular disease progression by regulating Ras pathway of the TGF-beta superfamily, especially RhoA/ROCK pathway. METHODS: A systematic PubMed database search of all English-language articles up to 2011 was conducted using the following terms: statin, TGF-beta, Ras, ROCK, GGPP, inducible nitric oxide synthase, endothelial nitric oxide synthase, actin filament formation, PPARgamma, MMP-2, and human trials. CONCLUSION: With better understanding of the pathway, various mediators were identified; some of these mediators are important biomarkers producing more specific and accurate assessment of the pleiotropic effects of statins. The review of human trials also highlights that more specific biomarkers are employed in recent studies, and the non-lipid effects on human subjects are more accurately documented. Confirmation of the accuracy of these biomarkers by further large-scale studies and further development of new biomarkers may prove an important path leading to better patient selection for treatment, and thus better cost-effectiveness may be achieved. PMID- 21700486 TI - Expression level polymorphisms: heritable traits shaping natural variation. AB - Natural accessions of many species harbor a wealth of genetic variation visible in a large array of phenotypes. Although expression level polymorphisms (ELPs) in several genes have been shown to contribute to variation in diverse traits, their general impact on adaptive variation has likely been underestimated. At present, ELPs have predominantly been correlated to quantitative trait loci (eQTLs) that occupy central hubs in signaling networks, which pleiotropically affect numerous traits. To increase the sensitivity of detecting minor effect eQTLs or those that act in a trait-specific manner, we emphasize the need for more systematic approaches. This requires, but is not limited to, refining experimental designs such as reduction of tissue complexity and combinatorial methods including a priori defined networks. PMID- 21700487 TI - Towards food, feed and energy crops mitigating climate change. AB - Agriculture is an important source of anthropogenic emissions of the greenhouse gases (GHG), methane (CH(4)) and nitrous oxide (N(2)O), and crops can affect the microbial processes controlling these emissions in many ways. Here, we summarize the current knowledge of plant-microbe interactions in relation to the CH(4) and N(2)O budgets and show how this is promoting new generations of crop cultivars that have the potential to mitigate GHG emissions for future agricultural use. The possibility of breeding low GHG-emitting cultivars is a paradigm shift towards sustainable agriculture that balances climate change and food and bioenergy security. PMID- 21700488 TI - Effects of methyl substituent on the charge-transfer complexations of dicarbazolylalkanes with p-chloranil, tetracyanoethylene and tetracyanoquinodimethane. AB - Series of 1,n-dicarbazolylalkanes and 1,n-di(3-methylcarbazolyl)alkanes (where n=1-5) were synthesized and the molar extinction coefficients, equilibrium constants, enthalpies, and entropies of their charge-transfer (CT) complexes with the pi-acceptors p-chloranil, tetracyanoethylene, and tetracyanoquinodimethane were investigated. 1,n-Di(3-methylcarbazolyl)alkanes formed CT complexes with higher equilibrium constants, more negative enthalpies and entropies than 1,n dicarbazolylalkanes. Vibrational spectra of CT complexes of one of the donor molecules (1,4-dicarbazolylbutane) with all three acceptors were compared. PMID- 21700489 TI - Electrospinning preparation and photoluminescence properties of erbium complex doped composite fibers. AB - In this paper, an Er(III) complex of Er(DBM)3IPD, where DBM=1,3-diphenyl-propane 1,3-dione and IPD=4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-N,N diphenylaniline, is synthesized and doped into poly(vinylpyrrolidone) submicron fibers through electrospinning technique. The crystal structure and morphology are investigated in detail. The composite fibers exhibit smooth and uniform morphology on the substrate, with an average diameter of ~1.4 MUm. Photophysical data suggest that DBM ligand sensitizes Er(III) center efficiently and provides an optimal condition for radiative decay, and low temperature can enhance the emission intensity by suppressing the quenching effect. It is found that the photostability of Er(III) complex doped composite fibers is largely improved compared with that of pure complex. PMID- 21700490 TI - The synthesis of (N2O2S2)-Schiff base ligands and investigation of their ion extraction capability from aqueous media. AB - Two new Schiff bases (I) and (II) containing nitrogen-sulfur-oxygen donor atoms were designed and synthesized in a multi-step reaction sequence. The Schiff base (I) was used in solvent extraction of metal chlorides such as Cu2+ and Cr3+ as well as metal picrates such as Hg2+ and UO2(2+) from aqueous phase to the organic phase. The influences of the parameter functions, such as pH, solvent, ionic strength of aqueous phase, aqueous to organic phase and concentration of the extractant were investigated to shed light on their chemical extracting properties upon the extractability of metal ions. The effect of chloroform, dichloromethane and nitrobenzene as organic solvents over the metal chlorides extraction was investigated at 25+/-0.1 degrees C by using flame atomic absorption and the result is that the ability of extraction in solvents as follows: C6H5NO2>CHCl3>CH2Cl2 and the compositions of the extracted species have been determined. The metal picrate extraction was investigated at 25+/-0.1 degrees C by using UV-visible spectrometry. As well that the extraction of picrates metal such as UO2(2+) and Hg2+ with Schiff base(I) in absence and presence of 2-(2-aminoethyl) pyridine was investigated in chloroform. The extraction results revealed the presence of neutral donors 2-(2-aminoethyl) pyridine shifts the extraction percentage curves towards higher pH region, indicating a synergistic effect of this donors on extraction of UO2(2+) and Hg2+ by the studied Schiff base (I). PMID- 21700491 TI - Adsorption kinetics of a fluorescent dye in a long chain fatty acid matrix. AB - This work reports the adsorption kinetics of a highly fluorescent laser dye rhodamine B (RhB) in a preformed stearic acid (SA) Langmuir monolayer. The reaction kinetics was studied by surface pressure-time (pi-t) curve at constant area and in situ fluorescence imaging microscopy (FIM). Increase in surface pressure (at constant area) with time as well as increase in surface coverage of monolayer film at air-water interface provide direct evidence for the interaction. ATR-FTIR spectra also supported the interaction and consequent complexation in the complex films. UV-vis absorption and Fluorescence spectra of the complex Langmuir-Blodgett (LB) films confirm the presence of RhB molecules in the complex films transferred onto solid substrates. The outcome of this work clearly shows successful incorporation of RhB molecules into SA matrix without changing the photophysical characteristics of the dye, thus making the dye material as LB compatible. PMID- 21700492 TI - Synthesis, crystal structure, EPR spectra of Cu2+ doped [Zn(methylisonicotinate)2(H2O)4].(sac)2 single crystal. AB - The tetraaquabis(methylisonicotinate)zinc(II) disaccharinate [hereafter, [Zn(mein)2(H2O)4].(sac)2], complex has been synthesized and characterized by spectroscopic IR, EPR and X-ray diffraction technique. The octahedral Zn(II) ion, which rides on a crystallographic centre of symmetry, is coordinated by two monodentate mein ligands through the ring nitrogen and four aqua ligands to form discrete [Zn(mein)2(H2O)4] unit, which captures two saccharinate ions in up and down positions, each through intermolecular hydrogen bonds. The magnetic environments of Cu2+ doped [Zn(mein)2(H2O)4].(sac)2 complex have been identified by electron paramagnetic resonance (EPR) technique. EPR spectra of Cu2+ doped [Zn(mein)2(H2O)4].(sac)2 single crystals have been studied between 113 and 300 K in three mutually perpendicular planes. The calculated results of the Cu2+ doped [Zn(mein)2(H2O)4].(sac)2 indicate that Cu2+ ion contains two different complexes and each complexes are located in different chemical environments and each environment contains two magnetically inequivalent Cu2+ sites in distinct orientations occupying substitutional positions in the lattice. The vibrational spectra of this compound were discussed in relation to other compounds containing methyl isonicotinate and saccharinate complexes. The assignments of the observed bands were discussed. PMID- 21700493 TI - Growth, structural, vibrational, optical, laser and dielectric aspects of L alanine alaninium nitrate single crystal. AB - Bulk single crystals of l-alanine alaninium nitrate [abbreviated as LAAN], an intriguing material for frequency conversion has been grown from its aqueous solution by both slow solvent evaporation and by slow cooling techniques. The optimized pH value to grow good quality LAAN single crystal was found to be 2.5. The grown crystals were subjected to single crystal X-ray diffraction studies to determine the unit cell dimensions and morphology. Vibrational frequencies of the grown crystals by Fourier transform infrared spectroscopic technique were investigated. Also, the presence of hydrogen and carbon atoms in the grown sample was confirmed using proton and carbon NMR analyses. The dielectric constant and dielectric loss measurements of the as grown crystal at different temperatures and frequencies of the applied field are measured and reported. LAAN has good optical transmission in the entire visible region with cutoff wavelength within the UV region confirms its suitability for device fabrications. The existence of second harmonic generation signals was observed using Nd:YAG laser with fundamental wavelength of 1064 nm. Its Laser Damage Threshold (LDT) was measured and also tested by using a Q-switched Nd:YAG laser and the value of LDT of LAAN is 17.76GW/cm2 respectively, is found to be better than certain organic and semiorganic materials. PMID- 21700494 TI - Current hypopnea scoring criteria underscore pediatric sleep disordered breathing. AB - OBJECTIVE: This is a retrospective study comparing 2007 American Academy of Sleep Medicine (AASM) pediatric scoring criteria and Stanford scoring criteria of pediatric polysomnograms to characterize the impact different scoring systems have upon the diagnosis of sleep disordered breathing in children. METHODS: The diagnostic and post-treatment nocturnal polysomnograms (PSGs) of children (age 2 18 years) consecutively referred to an academic sleep clinic for evaluation of suspected sleep disordered breathing (SDB) for 1 year were independently analyzed by a single researcher using AASM and Stanford scoring criteria in a blinded fashion. RESULTS: A total of 209 (83 girls) children with suspected SDB underwent clinical evaluation and diagnostic PSG. Analysis of the diagnostic PSGs using the Stanford and AASM criteria classified 207 and 39 studies as abnormal, respectively. The AASM scoring criteria classified 19% of subjects as having obstructive sleep apnea (OSA) while the Stanford criteria diagnosed 99% of the subjects with OSA who were referred for evaluation of suspected sleep disordered breathing. There was a positive correlation between SDB-related clinical symptoms and anatomic risk factors for SDB. Scatter-plot analyses showed that the AASM apnea hypopnea index (AHI) was not only significantly lower compared to the Stanford AHI but also skewed in distribution. Ninety-nine children were restudied with PSG (9 were initially diagnosed with SDB with AASM criteria, whereas all 99 were diagnosed with SDB with Stanford criteria). All 99 children had been treated and had a post-treatment clinical evaluation and post-treatment PSG during the study period. All 99 children evaluated after treatment showed improvement in clinical presentation, Stanford AHI, and oxygen saturation during sleep. CONCLUSION: The AASM scoring criteria classified 19% of subjects as having OSA while the Stanford criteria diagnosed 99% of the subjects with OSA who were referred for evaluation of suspected sleep disordered breathing. The primary factor differentiating the AASM and Stanford criteria was the scoring of hypopneas. The AASM definition of hypopnea may be detrimental to the recognition of SDB in children. PMID- 21700495 TI - Utility of the REM sleep behavior disorder screening questionnaire (RBDSQ) in Parkinson's disease patients. AB - OBJECTIVE: We evaluated the usefulness of the REM sleep behavior disorder (RBD) screening questionnaire (RBDSQ) among patients with Parkinson's disease (PD). METHODS: Forty-five patients with PD were evaluated (22 male and 23 female, 72.9+/-9.1 years old). After patients completed the RBDSQ, we conducted interviews regarding RBD symptoms and performed polysomnographic examinations on the subjects. We then compared RBDSQ scores among the following groups: PD with RBD (n=19), PD without RBD (n=26), and idiopathic RBD (n=31, 22 male and 9 female, 67.8+/-6.5 years old), and estimated the cut-off score for an RBD diagnosis. RESULTS: RBDSQ scores in PD with RBD and idiopathic RBD groups were similar and higher than those in the PD without RBD group (PD with RBD: 7.2+/ 1.9, idiopathic RBD: 7.9+/-2.8, PD without RBD: 2.9+/-1.6). Cronbach's alpha for RBDSQ sub-scores was 0.73, suggesting a fair internal consistency. A receiver operator characteristics curve revealed that a total score of 6 points on the RBDSQ represented the best cut-off value for detecting RBD (sensitivity=0.842, specificity=0.962). CONCLUSION: RBDSQ could be a useful tool for the screening of RBD in PD patients. PMID- 21700496 TI - Electrical and mechanical cardiac resynchronisation by novel direct his-bundle pacing in a heart failure patient. AB - Efficacy of standard cardiac resynchronisation therapy (CRT) by biventricular pacing via coronary sinus depends on the target site for left ventricular (LV) pacing, which in a not insignificant number of patients is limited by anatomical constraints. Direct His-bundle pacing (DHBP) is considered an alternative method of pacing for patients requiring cardiac stimulation in order to obviate detrimental effects of right ventricular pacing on LV function. However, its role in CRT has not been investigated, with scarce number of cases recently reported. We present a case of a heart failure patient in whom CRT was considered and treated by DHBP. In addition to electrical resynchronisation and optimal clinical response, echocardiography showed successful ventricular mechanical synchrony. To our knowledge, these latter findings are for the first time described in the setting of CRT by DHBP. PMID- 21700497 TI - MicroRNA-offset RNAs (moRNAs): by-product spectators or functional players? PMID- 21700498 TI - Acute pain crisis as a presentation of primary megaureter in children. AB - PURPOSE: Congenital ureteropelvic junction obstruction may present with flank pain, commonly referred to as a Dietl's crisis. We report on a similar presentation of primary megaureter. METHODS AND MATERIALS: We identified all patients with any diagnosis of megaureter treated at our institution between 1993 and 2009 (n = 465). We included 103 patients with primary megaureter and, of these, identified patients presenting with pain. All patients with secondary megaureter were excluded. RESULTS: Seventeen patients (20 megaureters) presented with pain and 10 (13 megaureters) presented with an acute pain crisis. Median age at presentation was 77 months. Seven children initially presented to the emergency department for evaluation and two of them required urgent stent placement for intractable pain. Obstruction was diagnosed in 8 patients. Six patients underwent ureteral reimplantation. Four patients were initially observed: one failed observation at 12 months due to worsening hydronephrosis and required surgery, one was lost to follow up, and two are still successfully being followed. All patients who underwent surgery had pain resolution. CONCLUSION: In this contemporary cohort, approximately 17% of patients with primary megaureter presented with pain and 10% presented with an acute pain crisis. Most presenting in acute pain required surgery, which resolved presenting symptoms. PMID- 21700499 TI - Structural abnormalities of the thalamus in juvenile myoclonic epilepsy. AB - Studies have suggested that the thalamus is a key structure in the pathophysiology of juvenile myoclonic epilepsy. The objective of the present investigation was to examine the thalami of patients with juvenile myoclonic epilepsy using a combination of multiple structural neuroimaging modalities. The association between these techniques may reveal the mechanisms underlying juvenile myoclonic epilepsy and help to identify the neuroanatomical structures involved. Twenty-one patients with juvenile myoclonic epilepsy (13 women, mean age=30+/-9 years) and a control group of 20 healthy individuals (10 women, mean age=31+/-8 years) underwent MRI in a 2-T scanner. The volumetric three dimensional sequence was used for structural investigation. Evaluation of the thalamus comprised voxel-based morphometry, automatic volumetry, and shape analysis. Comparisons were performed between patient and control groups. Voxel based morphometry analysis identified areas of atrophy located in the anterior portion of the thalamus. Post hoc analysis of automatic volumetry did not reveal significant differences between the groups. Shape analysis disclosed differences between patients and controls in the anterior and inferior portions of the right thalamus and in the anterior portion of the left thalamus. The present investigation confirms that thalami of patients with juvenile myoclonic epilepsy are structurally abnormal with impairments located mainly in the anterior and inferior sections. PMID- 21700500 TI - Sudden unexpected death in epilepsy: uncovering the magic in hippocampal deep brain stimulation. PMID- 21700501 TI - Hyperammonemic encephalopathy related to valproate, phenobarbital, and topiramate synergism. AB - We present a woman with epilepsy secondary to a lesion in the left frontal lobe. She developed episodes of disorientation and behavioral changes. She was taking valproic acid (1500 mg/day), topiramate (200 mg/day), and phenobarbital (100 mg/day). During an episode, the EEG revealed moderate encephalopathy and ammonia levels were increased (195 MUg/dL, reference range: 11-60 MUg/dL). Episodes ceased after withdrawal of valproic acid. PMID- 21700502 TI - Collaboration and the physician/advanced practice nurse team. PMID- 21700503 TI - Screening older people at risk of malnutrition or malnourished using the Simplified Nutritional Appetite Questionnaire (SNAQ): a comparison with the Mini Nutritional Assessment (MNA) tool. AB - OBJECTIVES: The Mini-Nutritional Assessment (MNA) is recommended to assess malnutrition in older people. However, its implementation is challenging in large elderly population, nursing home, or community or large clinical research programs. The Simplified Nutritional Appetite Questionnaire (SNAQ), a self assessment nutritional screening tool that predicts weight loss, could be used to screen older people at risk of malnutrition or malnourishment. Our objective was to assess whether the SNAQ is related to the MNA and can screen older people at risk of malnutrition or malnourishment. DESIGN/SETTING/PARTICIPANTS: Cross sectional study conducted of 175 persons aged 65 or older who were community dwelling, hospitalized, and nursing home residents. MEASUREMENTS: The SNAQ and the MNA score were performed. Correlation between the scores was studied. The most discriminating SNAQ value, which separated the participant at risk of malnutrition or malnourishment from the participant with a normal nutrition status (defined by MNA), was calculated. RESULTS: The SNAQ and the MNA score were significantly correlated (Spearman test r = 0.48, P < .001). The distribution of the population using the SNAQ or the MNA was significantly different (MacNemar P < .01). The area under the receiver operator characteristic curve, which assesses the ability of the SNAQ score to predict an abnormal MNA score, was 0.767 (95% confidence interval, 0.69-0.85). An SNAQ score under 14 was the best clinical indicator of older people at risk of malnutrition or malnourishment (sensitivity = 71%, specificity = 74%). Using this cut-off, 26.8% of the population (n = 47) were misclassified. Most of them (n = 33; 18.8%) had an abnormal SNAQ with a normal MNA. CONCLUSION: The SNAQ is a poor screening tool to predict older people with an abnormal MNA score. However, an abnormal SNAQ might identify those who will lose weight earlier than will the MNA. PMID- 21700504 TI - A rare anomaly of the course of the vertebral artery. PMID- 21700505 TI - Bearing surfaces for total disc arthroplasty: metal-on-metal versus metal-on polyethylene and other biomaterials. AB - BACKGROUND CONTEXT: Concerns about the effect of metallic wear debris from metal on-metal bearing surfaces in total hip arthroplasty have increased. Some spinal arthroplasty devices include metal-on-metal bearing surfaces. PURPOSE: To review the literature for clinical reports of complications because of wear debris from metal-on-metal spinal arthroplasty devices. To review the biology of wear debris from metal-on-metal bearing surfaces drawn from the hip arthroplasty literature and place it in the context of global regulatory actions and clinical and laboratory studies. STUDY DESIGN: Literature review. METHODS: To identify clinical reports, the PubMed database from the United States National Library of Medicine was queried using Medical Subject Headings terms and additional keyword terms. In addition, experts from academia and regulatory agencies were questioned regarding their knowledge of reports, including experts who attended the US Food and Drug Administration roundtable in September 2010. RESULTS: Three case reports and one case series including seven total cases were identified in which abnormal inflammatory reactions and soft-tissue masses after metal-on-metal disc replacements were consistent with pseudotumor and metal hypersensitivity. Spinal cases are present as pain and neurologic symptoms. On plain radiography, there is no clear periprosthetic osteolysis or loosening. On magnetic resonance imaging, there is increased magnetic susceptibility artifact because of metallic debris that renders images inadequate. Computed tomography myelography demonstrates a soft-tissue mass, which exhibits epidural extension surgically. Histologically, large areas of necrotic debris and exudates are interspersed with chronic inflammatory cells. Lymphocyte or macrophage predominance is determined by the rate of wear and the presence of gross, microscopic, or submicron metallic wear debris. The metallurgy of the involved devices is cobalt-chromium-molybdenum (CoCrMo) alloy, and the bearing surface is CoCrMo-on-CoCrMo. CONCLUSIONS: Metal on-metal spinal arthroplasty devices are subject to postoperative complications because of metallic wear debris with similar clinical, radiographic, histologic, gross anatomic, and device-related features to those found in metal-on-metal bearing surfaces in total hip arthroplasty. PMID- 21700506 TI - Comparison of efficacy and safety of low-dose-rate vs. high-dose-rate intraluminal brachytherapy boost in patients with superficial esophageal cancer. AB - PURPOSE: To compare the efficacy and the incidence of complications of high-dose rate (HDR) and low-dose-rate (LDR) intraluminal brachytherapy (IBT) boost after external beam radiation therapy in patients with superficial esophageal cancer. METHODS AND MATERIALS: Fifty-four consecutive patients with Stage I thoracic esophageal squamous cell carcinoma who were treated with definitive radiotherapy using IBT between 1991 and 2007 were studied retrospectively. LDR-IBT and HDR-IBT were performed for 19 and 35 patients, respectively. After external beam radiation therapy of 56-60 Gy with a conventional fractionation, LDR-IBT (5 Gy * 2) or HDR-IBT (3 Gy * 3) was given within 2 weeks. The median follow-up was 47 months (7-151 months). RESULTS: Overall, the 5-year overall survival, cause specific survival (CSS), and locoregional control (LRC) rates were 61%, 86%, and 79%, respectively. The 5-year overall survival, CCS, and LRC rates did not differ significantly between the LDR-IBT and HDR-IBT groups (68% vs. 58% (p=0.50), 83% vs. 85% (p=0.63), and 84% vs. 75% (p=0.42), respectively). Salvage treatment was given in 8 locally recurrent patients, and 6 patients were rescued. The Grade >=2 late morbidities of esophagus and heart/lung were observed in 5 patients (4 in the LDR-IBT group and 1 in the HDR-IBT group) and 2 patients (one from each group), respectively. CONCLUSIONS: In view of the safety profile and effectiveness, our results encourage the continued adoption of HDR-IBT as radiation boost in medically inoperable or elderly superficial esophageal cancer patients undergoing definitive radiotherapy. PMID- 21700507 TI - Relationship between prostate-specific antigen bounce body fat distribution and body mass index in permanent seed brachytherapy for prostate cancer. AB - PURPOSE: To analyze the influence of body mass index (BMI) and adipose tissue distribution on prostate-specific antigen (PSA) bounce after iodine-125 prostate brachytherapy. METHODS AND MATERIALS: We studied 20 patients who had PSA bounce (>=0.50ng/mL) after exclusive prostate brachytherapy. These patients were compared with 48 patients without a bounce (<0.50ng/mL). All patients in the comparison group had a followup of >=24 months and a last PSA <=0.5ng/mL. Within these 48 patients, there was a group matched for age (n=20). Univariate and multivariate logistic models were estimated to assess the association between age, baseline PSA, prostate volume, D(90), visceral fat (VF) volume, and BMI on PSA-bouncing status. RESULTS: When comparing the patients with a bounce to those without, only BMI showed a significantly different distribution (mean, 25.18 vs. 27.47kg/m(2); p=0.0342). On a multivariate analysis, BMI had an odds ratio of 0.85 (95% confidence interval, 0.71-0.99, p=0.049), indicating that an increase of 1kg/m(2) in BMI is associated with a 15% reduction in the odds of having a bounce. In the univariate analysis with the matching patients, BMI was a significant predictor of a bounce (p=0.0147). In the multivariate conditional logistic model, BMI showed a trend toward an influence on a bounce (p=0.0615). All other factors, including VF, did not have any influence on a PSA bounce. CONCLUSIONS: Patients with a lower BMI are more likely to experience a PSA bounce >=0.50ng/mL. VF did not have an influence on a PSA bounce. PMID- 21700508 TI - Association of rs6983561 polymorphism at 8q24 with prostate cancer mortality in a Japanese population. AB - We conducted present study to address whether the rs6983561 polymorphism, an established genetic marker for prostate cancer susceptibility, was a prognostic indicator. We genotyped 518 Japanese patients with prostate cancer and analysed their survival retrospectively. As a result, patients with the CA/CC genotype of rs6983561 survived significantly longer than those with the AA genotype (P = .033). BACKGROUND: Genome-wide association studies have revealed several genetic variants at 8q24 that are associated with prostate cancer susceptibility. Rs6983561 (A/C) is a single-nucleotide polymorphism located at 8q24 that has been established as a genetic risk marker for prostate cancer susceptibility. The present study investigated the association between the rs6983561 polymorphism and prostate cancer mortality in a Japanese population. PATIENTS AND METHODS: The study examined 518 native Japanese male patients with sporadic prostate cancer. Germline DNA samples were obtained from all participants and genotyping of rs6983561 was performed using a TaqMan assay. Observation periods were from the date of diagnosis of prostate cancer to May 21, 2010. The Cox proportional hazards model was used to estimate the cause-specific survival (CSS) and the overall survival (OS). RESULTS: Patients with the CA/CC genotype of rs6983561 survived significantly longer than those with the AA genotype. In a multivariate model, the hazard ratios (HRs) and 95% confidence intervals (CIs) of the CSS and the OS for the rs6983561 polymorphism were 2.438 (1.262 - 5.046, P = .007) and 1.957 (1.142 - 3.485, P = .014), respectively. When the analysis was restricted to subjects with metastatic disease, the HRs of the CSS and the OS were 3.353 (95% CI, 1.689 - 7.446; P = 3.76 x 10(-4)) and 3.361 (95% CI, 1.741 - 7.136; P = 1.70 x 10(-4)), respectively. CONCLUSION: In the Japanese population examined in this study, the rs6983561 polymorphism at 8q24 was significantly associated with prostate cancer mortality, especially among patients with metastatic disease. PMID- 21700509 TI - Retrospective analysis of satraplatin in patients with metastatic urothelial cancer refractory to standard platinum-based chemotherapy. AB - Satraplatin is a novel platinum agent with favorable clinical attributes including oral bioavailability and lack of significant treatment-associated neuropathy and nephropathy. Furthermore, preclinical studies have shown that satraplatin is active is cisplatin-resistant tumors. We retrospectively evaluated the activity of satraplatin in patients with cisplatin or carboplatin-refractory urothelial carcinoma and demonstrated lack of significant antitumor activity in this population. BACKGROUND: Satraplatin is an oral platinum analogue with antitumor activity in cisplatin-resistant cells lines. The activity of satraplatin in patients with metastatic cancers of the urothelial tract refractory to standard platinum agents has not previously been reported. METHODS: We previously reported a phase I study of the safety and pharmacokinetics of satraplatin in patients with refractory solid tumors and varying degrees of renal impairment. Given that the majority of patients enrolled in the study had metastatic cancers of the urothelial tract, and all patients were treated with a uniform dose and schedule, we performed a retrospective analysis to describe the activity of satraplatin in this cohort. RESULTS: A total of 12 patients with metastatic cancers of the urothelial tract were enrolled. The majority (83%) had transitional cell carcinomas, whereas 2 patients (17%) had adenocarcinomas. All patients were treated previously with platinum agents; 6 patients (50%) had previously received cisplatin and 8 patients (67%) had previously received carboplatin. Patients were treated with a median of 1.5 cycles of satraplatin (range, 1-4). There were no objective responses; 1/12 (8%) patients experienced transient stable disease and 11/12 (92%) experienced disease progression as best response. CONCLUSIONS: Treatment with satraplatin in patients with metastatic cancers of the urothelial tract who had progressed on standard platinum-based chemotherapy resulted in negligible antitumor activity. These conclusions are limited by the retrospective nature of the analysis and the phase I population from which the data were derived. The activity of satraplatin in patients with metastatic cancers of the urothelial tract who have been less heavily pretreated is unknown. PMID- 21700510 TI - Factors affecting the electrochemical regeneration of NADH by (2,2'-bipyridyl) (pentamethylcyclopentadienyl)-rhodium complexes: impact on their immobilization onto electrode surfaces. AB - Complexes of the (2,2'-bipyridyl) (pentamethylcyclopentadienyl)-rhodium family ([Cp*Rh(bpy)Cl](+), which is actually hydrolyzed in the form of [Cp*Rh(bpy)H(2)O](2+) in aqueous medium) are suitable solution-phase mediators likely to regenerate nicotinamide cofactors associated to dehydrogenases involved in many biocatalytic applications. Their practical application as bioelectrocatalysts, e.g., in fine chemicals synthesis or biosensors, remains however restricted to their durable immobilization in an active form onto solid electrode surfaces. This paper reports some new observations on the electrocatalytic properties of this mediator towards NAD(+) reduction, notably the critical effect of pH and cofactor-to-mediator concentration ratio, and investigates the behavior of a series of ([Cp*Rh(bpy)Cl](+)) derivatives bearing various substituents on the bipyridine ligand in view of their subsequent integration in electrochemical bioreactors. It will be shown that such compounds containing S- or N- moieties (i.e., often used as precursors to functionalize electrode surfaces) lead to inactivation of the electrocatalyst because their interaction with the Rh center prevents the formation of the active rhodium hydride complex. It was thus necessary to find another strategy of immobilization, and we found that adsorption of [Cp*Rh(bpy)Cl](+) by pi-stacking on single-walled carbon nanotubes is an effective mean to reach this goal, leading to efficient and stable catalytic responses for NAD(+) reduction. Preliminary electroenzymatic experiments in the presence of d-sorbitol dehydrogenase further point out the interest of this approach for bioelectrocatalysis purposes and provide the proof-of-concept for this immobilization strategy. PMID- 21700511 TI - Glycerophosphocholine molecular species profiling in the biological tissue using UPLC/MS/MS. AB - A strategy consisting of a two-phase analytical procedure was used to obtain detailed molecular species composition for glycerophosphocholines (GPCs) profiling in biological tissue using ultra performance liquid chromatography coupled with a triple quadrupole mass spectrometer operating under electrospray mode. In phase one of the analytical procedure, the precursor ion scan was first conducted to obtain the preliminary lipid profile that revealed the composition of the molecular species possessing phosphocholine structure in the biological tissue. In phase two of the analytical procedure, each product ion spectrum obtained for the GPC components in the profile was sequentially acquired for the determination of the molecular structure. A simple guide with high differentiability was proposed for the diacyl-, alkyl-acyl- and alk-1-enyl-acyl GPC, and related lyso-GPCs molecular structure decision. Total 93 GPCs molecular species were identified in the fetal mouse lung with the relative amounts from 14.39% to less than 0.01% (normalizing by the total GPCs signal). The optimized chromatographic conditions were also proposed in the analytical procedure based on the compromise between the separation efficiency and electrospray signal response. The plate number of the probing GPCs was obviously improved to above 30,000 and the detection limits of the probing GPCs were between 0.002 and 0.016 ng/MUL. The practical usability of the analytical procedure has been validated using a study of chemically induced early lung maturation. The metabolic difference between chemically treated and untreated fetal mouse lung was clearly distinguished by the composition of GPCs with several characteristics of molecular structure. The overall results showed that this two-phase analytical procedure was reliable for comprehensive GPC profiling. PMID- 21700512 TI - An optimized method for the determination of perfluorooctanoic acid, perfluorooctane sulfonate and other perfluorochemicals in different matrices using liquid chromatography/ion-trap mass spectrometry. AB - Perfluorochemicals (PFC's) are widely spread in the environment and have been detected in blood of wildlife and humans world-wide. Recently, various toxic effects of PFC's in laboratory rats have been demonstrated, resulting in increased government concerns regarding the presence of PFC's in the environment and the implications they have on human health. In the last decade, various analytical methods have been developed for the analysis of PFC's in different matrices whereby the majority of methods have utilised liquid chromatography coupled with mass spectrometry (LC-MS). Here we describe an optimized method for the quantitation of PFC's, including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), in food packaging, polytetrafluoroethylene (PTFE) sealant tape and drinking water. The method involved PFC's extraction via off-line SPE followed by separation using reversed-phase liquid chromatography on a Phenyl-Hexyl column coupled with ion-trap (IT) mass spectrometric detection. The optimized approach minimized ion-suppression effects commonly seen with conventional elution buffers, improving detection limits down to 25 pg/mL and allowed effective quantitation down to 50 pg/mL for PFOA and PFOS. The optimized LC-MS method detected PFOA and other PFC's in microwave popcorn packaging and PFOA in PTFE sealant tape in the low MUg/kg. In all samples, PFOS was not detected. PMID- 21700513 TI - Determination of octreotide and assessment of matrix effects in human plasma using ultra high performance liquid chromatography-tandem mass spectrometry. AB - A selective UHPLC-MS/MS method for determination of the therapeutic peptide octreotide in human plasma was developed and validated. This assay used a UHPLC C(18) column with 1.7 MUm particle size for efficient separation and an ion exchange SPE for selective extraction. Octreotide and its labeled internal standard, [(13)C(6)Phe(3)] octreotide, were extracted from human plasma using a simple Oasis(r) WCX MUElution SPE method and analyzed with a total chromatographic run time of 7.5 min. Matrix effects were studied during method development by direct monitoring of representative phospholipids. On-line removal of phospholipids using column switching and pre-column back-flushing was carried out to trap and remove any residual phospholipid matrix interferences. The UHPLC column provided baseline separation between the analyte and matrix peaks. The chromatographic conditions yielded optimal retention and excellent peak shape for both the analyte and internal standard. The assay was linear in the concentration range of 0.025-25.0 ng/ml, inter- and intra-assay precision and accuracy were within 6.1% and +/-1.93%, respectively. Recovery was ~73%. Post-extraction addition experiments showed that matrix effects were less than 4%. This method for octreotide in human plasma has been validated and utilized to support of clinical pharmacokinetic studies. PMID- 21700514 TI - Hepato-gastroenterologists and oncologists are complementary in the management of digestive cancers. PMID- 21700515 TI - Immune-mediated diseases in primary sclerosing cholangitis. AB - BACKGROUND: Primary sclerosing cholangitis is a chronic cholestatic liver disease. An immune aetiology is suggested by associations between PSC and inflammatory bowel disease. Data on concomitant prevalence of other immune mediated diseases is limited. AIM: To assess the prevalence of concomitant immune mediated diseases and the impact on disease outcome in PSC. METHODS: We included 241 patients and retrospectively reviewed medical charts. RESULTS: Altogether 172 (71.4%) patients had concomitant immune-mediated disease, including IBD (149, 61.8%), autoimmune hepatitis (15, 6.2%) and other immune-mediated diseases (47, 19.5%). Thirty nine patients (22.7%) had more than one immune-mediated disease other than PSC. Most frequent extrahepatic non-IBD immune-mediated diseases were sarcoidosis, thyroid disease, and type I diabetes mellitus. Age at PSC diagnosis was lower in patients with IBD. In patients with other immune-mediated diseases than autoimmune hepatitis or IBD, age at PSC diagnosis was higher. Younger age at diagnosis and concomitant IBD related to longer survival till death or liver transplantation. CONCLUSIONS: In a large PSC population, a high prevalence of concomitant immune-mediated diseases was found. IBD occurred more often in early acquired PSC, and the other immune-mediated diseases more often in later-acquired PSC. No effect on outcome was found for non-IBD immune mediated disease. PMID- 21700517 TI - Bacterial infection in association with snakebite: a 10-year experience in a northern Taiwan medical center. AB - BACKGROUND: Microbiological data of secondary wound infections following snakebites is rarely reported in Taiwan. The objective of this study was to assess the secondary wound infection after venomous snakebites. METHODS: We conducted a 10-year retrospective survey on patients admitted for venomous snakebites and microbiological data of wound cultures at a medical center in northern Taiwan. RESULTS: Between April 2001 and April 2010, 231 patients who experienced snakebites were included. Male predominated, accounting for 62.3% (144). The age range of patients was 4-95 years. Ninety-five (41.1%) people were bitten by Trimeresurus mucrosquamatus, followed by Tstejnegeri, and cobra. A total of 61 pathogens were obtained from 21 patients. Thirty-nine (63.9%) isolates were gram-negative bacteria, 14 (23%) gram-positive pathogens, and 8 (13.1%) anaerobic pathogens. There were 17 patients bitten by cobra in these 21 patients. Morganella morganii and Enterococcus species were the most common pathogens identified in the wound cultures. CONCLUSION: Cobra bite causes more severe bacterial infection than other kinds of snakebites. Oral amoxicillin/clavulanate plus ciprofloxacin or parenteral piperacillin/tazobactam alone can be the choices for empirical or definitive treatment, and surgical intervention should be considered for established invasive soft tissue infections. PMID- 21700519 TI - Patient education on effective skin self-examination: which patient groups require special attention? PMID- 21700518 TI - An exploration of body dissatisfaction and perceptions of Black and White girls enrolled in an intervention for overweight children. AB - Silhouette measures are one approach to assessing body dissatisfaction in children, although little is known about their use among racially diverse, overweight girls seeking weight-loss treatment. This study assessed racial differences in body dissatisfaction and body size perceptions of 58 girls (ages 6 11, 66% Black, 34% White) participating in a randomized trial for pediatric overweight. Body dissatisfaction did not differ between races; 99% of girls reported an ideal figure smaller than their current one. Black girls selected a larger silhouette to represent their ideal body size, and most girls in both racial groups underestimated their actual size. Outcomes strengthen the argument that, despite an overall preference for a larger body size, obesity might mitigate cultural factors that protect Black girls from body dissatisfaction. Additional research is needed to enhance understanding of children's body size perceptions and dissatisfaction to inform assessment and treatment of pediatric obesity and associated disordered eating symptoms. PMID- 21700520 TI - The versatility of the temporoparietal fascia flap in head and neck reconstruction. AB - OBJECTIVES: The temporoparietal fascia flap (TPFF) is a versatile tool in head and neck reconstruction. This article aims to describe the spectrum of TPFF applications through a series of case studies and related review of the literature. METHODS: Medical records were reviewed to identify cases that represent major TPFF application categories. A literature review was performed to support the presentation and discussion of each case category. RESULTS: Seven cases were identified each representing a distinct application category. These included auricular reconstruction, hair-bearing tissue transfer, facial soft tissue augmentation, cutaneous and mucosal oncologic defect repair, reconstruction after salvage laryngectomy, skull base reconstruction, and orbital reconstruction. CONCLUSION: The TPFF is a uniquely versatile tool in head and neck reconstructive surgery. Outstanding in its pliable, ultra-thin yet hardy and highly vascular form, the temporoparietal fascia flap is a workhorse for the creative head and neck reconstructive surgeon. PMID- 21700521 TI - Arthroscopic treatment of calcaneonavicular coalition in children. AB - Calcaneonavicular coalition is a common source of pain and more or less severe flat and stiff foot in children. Classically, treatment consists in resecting the coalition using a dorsolateral approach. Good quality resection and interposition can prevent recurrence. The most common complications are infection, hematoma and neuroma. Arthroscopy offers a minimally invasive alternative, but the optimal approach remains undetermined. We describe a surgical technique with an approach based on the anterolateral process of the calcaneus, in three cases with 12 months' follow-up. Arthroscopic resection has certain advantages: recovery is quicker, and the esthetic result is better. For the instrumental portal, skin incision should be superficial, followed by blunt dissection of subcutaneous tissue to avoid superficial peroneal nerve injury. Although longer term follow-up is needed, arthroscopy seems to be an attractive minimally invasive technique in this kind of pathology. PMID- 21700522 TI - Previous gastric banding increases morbidity and gastric leaks after laparoscopic sleeve gastrectomy for obesity. AB - GOAL: Laparoscopic sleeve gastrectomy (LSG) is performed in certain circumstances after failure of gastric banding. The goal of this study was to evaluate the impact of first-line gastric banding on the morbidity associated with secondary LSG for obesity. PATIENTS AND METHODS: The case records of 102 consecutive patients undergoing LSG were studied retrospectively. The technique of LSG was standardized. Two groups were compared: one with patients having undergone LSG after first-line gastric banding (n = 31) and the second, with patients having undergone first-line LSG (n = 71). Endpoints were overall morbidity and intra/postoperative complications including gastric leaks consecutive to staple line disruption as well as other septic or hemorrhagic complications. Multivariable analysis was performed to detect independent risk factors for morbidity. RESULTS: Overall morbidity was significantly higher in patients having undergone LSG after first-line gastric banding compared with those undergoing first-line LSG (32.2% vs. 7%, P = 0.002). Gastric leaks secondary to staple line disruption also occurred statistically significantly more often in patients with first-line gastric banding (16.1% vs. 2.8%, P = 0.043). Waiting 6 months between gastric band removal and performing LSG did not prevent the increased morbidity compared with first-line LSG. Multivariable analysis revealed that among the factors analyzed (age, gender, comorbidity, body mass index, surgeon, first-line gastric banding), the only independent risk factor for staple line disruption was first-line gastric banding with an odds ratio = 6.6 (95% confidence interval = [1.2-36.3]). CONCLUSION: Undergoing first-line gastric banding increases the risk of complications after secondary LSG. We recommend that patients who undergo LSG after a first-line gastric banding should be warned of the increased risks of morbidity or, alternatively, that LSG be performed preferentially as the initial procedure. PMID- 21700523 TI - Totally robotic gastric bypass. PMID- 21700524 TI - Imagery of a nasal obstruction. Respiratory epithelial adenomatoid hamartoma. PMID- 21700525 TI - Acinic cell carcinoma of the parotid gland with skull base invasion: case study, managed by exclusive external 3D radiation therapy. AB - OBJECTIVE: To review treatment options in a rare type of parotid tumor, in a clinical case study. CASE STUDY: A 62-year-old woman presenting with recurrence of acinic cell carcinoma of the parotid gland with invasion of the skull base was treated by external 3D conformational radiation, having refused large-scale exeresis. Sixty-six Gy (70Gy equivalent) were delivered in 2007. Clinical and paraclinical follow-up found regular tumor volume regression over a 2.5-year period without side-effects of radiation. DISCUSSION: There are no specific data on the efficacy of external radiation therapy in acinic cell carcinoma; reports on exclusive radiation treatment of salivary gland cancer include different histological types. Exclusive radiation treatment should be at least 66-70Gy, preferably by neutron- or hadrontherapy. CONCLUSION: Management of acinic cell carcinoma of the parotid is surgical with possible secondary radiation therapy; exclusive external radiation therapy is, however, an option in case of contra indication for surgery or patient refusal. PMID- 21700526 TI - Biological characterization of nodal versus extranodal presentation of diffuse large B-Cell lymphoma using immunohistochemistry. AB - INTRODUCTION: Diffuse large B cell lymphoma (DLBCL) of primary nodal (PN) or primary extranodal (PEN) origin may differ immunophenotypically, in that PEN lymphoma cells may originate from activated rather than germinal center B (GCB) cells. We evaluated the relationship between DLBCL clinicopathological features, including expression of B-cell differentiation markers, and primary tumor site. PATIENTS AND METHODS: Expression of CD10, Bcl-6, Bcl-2, and MUM1 was determined in paraffin-embedded tissues from 123 patients with DLBCL. RESULTS: Of the 123 patients with DLBCL, 40 (32.5%) had the GCB and 83 (67.5%) had the non-GCB phenotype. Fifty-one patients (42%) showed disease involvement at PEN sites, including 29 with disease in the gastrointestinal (GI) tract (14 in the stomach, 15 in the intestine). Of these 51 patients, 16 (31.4%) were classified with the GCB and 35 (68.5%) with the non-GCB subtype. There were no differences in the frequencies of GCB and non-GCB subtypes among primary sites. Of the 72 patients with PN DLBCL, 22 (31%) had the GCB and 50 (69%) had the non-GCB subtype. There were no differences in the frequencies of GCB and non-GCB subtypes between patients with PN and PEN DLBCL. Although lactate dehydrogenase (LDH) concentration > normal, stage >II, and rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) treatment were independent predictors of overall survival (OS), GCB subtype, and presence of PEN disease failed to predict survival upon multivariate analysis. CONCLUSION: There was no difference in GCB and non-GCB phenotypes between patients with PN and PEN DLBCLs. Additional studies are needed to further assess molecular differences between the two groups. PMID- 21700527 TI - Safety and efficacy of combination therapy with fludarabine, mitoxantrone, and rituximab followed by yttrium-90 ibritumomab tiuxetan and maintenance rituximab as front-line therapy for patients with follicular or marginal zone lymphoma. AB - BACKGROUND: We conducted a single-institution phase II clinical trial evaluating the safety and efficacy of combination chemoimmunotherapy followed by radioimmunotherapy consolidation and rituximab maintenance as front-line treatment in indolent lymphomas. PATIENTS AND METHODS: We enrolled 20 patients with intermediate- to high-risk follicular lymphoma and 2 patients with marginal zone lymphoma. Treatment consisted of 4-6 cycles of FM (fludarabine 25 mg/m(2) on days 1-3, mitoxantrone 12 mg/m(2) on day 1 of each 28-day cycle). The protocol was amended after enrolling the first 4 patients to include rituximab 375 mg/m(2) on day 1. After 6-8 weeks, responders received (90)Y-ibritumomab tiuxetan (Zevalin) followed by maintenance rituximab (375 mg/m(2) weekly * 4 doses, repeated every 6 months for 2 years). RESULTS: After R-FM, the overall response rate was 95% with a complete response rate (CR) of 45% (n = 10), a partial response (PR) rate of 50% (n = 11), and stable disease in 1 patient. Nineteen patients received (90)Y-ibritumomab tiuxetan with a 60% conversion rate of PR to CR, resulting in an improved CR of 79% (n = 15) and a PR of 21% (n = 4). Fifteen patients proceeded to rituximab maintenance resulting in 3 patients with PR converting to CR. At median follow-up of 49.6 months, median progression-free survival (PFS) was 47.2 months and median overall survival (OS) was not reached in an intent-to-treat analysis. The most common adverse effects were hematologic, with 2 patients experiencing treatment-related myelodysplastic syndrome (MDS), evolving to acute myelogenous leukemia (AML) in 1 patient. CONCLUSION: R-FM with (90)Y-ibritumomab tiuxetan consolidation and rituximab maintenance is well tolerated, improving CR rates and maintaining durable responses in patients with untreated indolent lymphomas. PMID- 21700528 TI - Comparison of skeletal complications and treatment patterns associated with early vs. delayed zoledronic acid therapy in multiple myeloma. AB - BACKGROUND: This study retrospectively compared the risks of skeletal-related events (SREs) and zoledronic acid (ZOL) treatment discontinuation associated with early vs. delayed ZOL therapy for patients with symptomatic multiple myeloma (MM). PATIENTS AND METHODS: Data were collected from a physician-administered medical chart review among US patients with a confirmed diagnosis of symptomatic MM treated after 01/01/2002. Early and delayed ZOL therapy were defined, respectively, as initiating ZOL <= 60 days (N = 126) vs. > 60 days (N = 186) after the first symptomatic MM diagnosis. Kaplan-Meier analysis with a log-rank test was performed to compare the risk of SREs between the cohorts. Cox proportional hazard modeling compared the risk of SREs associated with early vs. delayed ZOL treatment, controlling for demographic factors, stage of MM, bone health status, and presence of major comorbidities at diagnosis. Time to ZOL discontinuation was evaluated using the Kaplan-Meier method, following patients from the date of ZOL initiation. RESULTS: Time to the first SRE was significantly longer for patients who received early treatment with ZOL (P = .005). At 2 years after diagnosis, the SRE-free rate was 74.6% vs. 56.5% in the early vs. delayed treatment group, respectively. Early ZOL therapy was associated with a significantly lower risk of any SRE (hazard rate [HR] = .625 vs. delayed ZOL therapy; P = .029). At 2 years from ZOL therapy initiation, rates of ZOL discontinuation were 9.6% vs. 16.4% among patients with early vs. delayed therapy, respectively (P < .05). CONCLUSION: Early treatment with ZOL was associated with significantly reduced risks of SREs and with better treatment persistence compared with delayed treatment. PMID- 21700529 TI - Liver magnetic resonance diffusion weighted imaging: 2011 update. AB - Diffusion-Weighted-Imaging (DWI) assesses proton motion on a cellular scale. Owing to recent instrumentation developments, diffusion sequences are now routinely used for liver imaging. This review will go through the physical principles that underlie this technique, and then highlight up-to-date liver applications including quantification of liver fibrosis, focal lesions detection and characterization, and therapy response monitoring. PMID- 21700530 TI - Cutaneous phaeohyphomycosis on the auricle due to Veronaea botryosa. PMID- 21700531 TI - Congenital Langerhans cell histiocytosis involving only one of non-identical twins. PMID- 21700532 TI - Adverse cutaneous drug reactions to ibandronate. AB - Bisphosphonates are frequently used to treat bone diseases characterized by increased osteoclastic bone resorption. Adverse skin reactions to bisphosphonates are rare and range from benign to severe. Different cutaneous skin reactions have been reported with ibandronate in clinical and pharmacovigilance studies, from macula-papular rashes to toxic epidermal necrolysis. We report two new cases of erythematous and oedematous skin lesions to oral monthly ibandronate, appearing after multiple intakes of the drug. Prick tests were positive in both cases at 48 or 96 hours, and one could be confirmed histologically. Lesions did not relapse after substituting the culprit bisphosphonate with another one. A wide range of rare-to-very-rare adverse skin reactions exist with bisphosphonates, and especially ibandronate. We review the reported cases of adverse cutaneous drug reactions to bisphosphonates and illustrate the polymorphism and variety of the skin lesions. These reactions are not well known and may be misdiagnosed as they do not always suggest drug-induced eruptions. Furthermore, delays between drug intake and the first lesions can be misleading. The absence of cross-reactions among bisphosphonates allows substitution. PMID- 21700533 TI - Eosinophilic pyoderma gangrenosum with pulmonary and oral lesions preceded by eosinophilic pneumonia: Unrecognized syndromic manifestations? PMID- 21700534 TI - Nestin expression in Bowen's disease and Bowen's carcinoma associated with human papillomavirus. AB - Human papillomaviruses (HPVs) have been detected in lesions of Bowen's disease (BD) and Bowen's carcinoma (BC); the invasive tumor retains the cytological characteristics of BD. Previous reports suggest that nestin-expressing hair follicle stem cells are undifferentiated and pluripotent, and nestin expression in some tumors indicates poor differentiation and high grade of malignancy. We identified HPV-DNA in BD (n=25) and BC (n=23) by in situ hybridization (ISH) analysis with INFORM((r)) HPV III (Ventana Medical Systems. AZ, USA) and determined nestin expression by indirect immunohistochemical staining with anti nestin polyclonal antibody (IBL, Gunma, Japan). We detected HPV-DNA in 68% of BD and in 87% of BC. In BD, 13 cases demonstrated the punctuate pattern, and four showed nestin expression. In BC, 19 cases showed the punctuate pattern and 16 showed nestin expression. HPV-DNA integrates into the host genome, and this is observed as the punctuate pattern on ISH. The nestin expression was statistically high in group of BC than BD (P<0.01). These results therefore suggest that HPV DNA integrated in the genome of tumor cells of these diseases and contributed to malignant alteration. From the standpoint of tumorigenesis, BC might represent one type of poorly differentiated, high-grade squamous cell carcinoma. PMID- 21700535 TI - High social phobia frequency and related disability in patients with acne vulgaris. AB - Acne is an easily recognizable abnormality which may cause some adverse psychosocial consequences. We aimed to determine the social phobia frequency, social anxiety level, and disease related disability in a group of acne vulgaris patients. One-hundred and forty acne vulgaris patients and 98 healthy control subjects were included in the study. Acne severity was determined by the Global Acne Grading System (GAGS). A psychiatrist interviewed each participant and the Liebowitz Social Anxiety Scale (LSAS) was administered to all participants, who also completed the Hospital Anxiety and Depression Scale (HADS) and Sheehan Disability Scale (SDS). Social phobia was diagnosed in 45.7% of acne vulgaris patients and in 18.4% of control subjects. Acne vulgaris patients demonstrated higher performance avoidance and total avoidance scores in LSAS than controls. Acne vulgaris patients without social phobia had higher scores in HADS and LSAS than the acne vulgaris patients with social phobia. They were more disabled in their occupational, social, and familial lives. Social phobia diagnosis predicted disability at work, whereas education level predicted the disability in family life of acne vulgaris patients. Social phobia seems to be a common psychiatric comorbidity which may give rise to some additional disability among acne vulgaris patients. PMID- 21700536 TI - Warning: some genetic resource crises we may encounter in the near future: a thought from an EPPK kindred research. PMID- 21700537 TI - N-terminal pro-brain natriuretic peptide in systemic sclerosis: new insights. AB - OBJECTIVE: To identify the relation between serum levels of N-terminal pro-brain natriuretic peptide (NT-pro BNP) and severity of systemic sclerosis (SSc). SUBJECT AND METHODS: 25 SSc patients and 25 age- and sex-matched healthy controls were included. Assay of serum NT-pro BNP was done for all patients and controls. Patients were subjected to modified Rodnan skin score (mRss), echocardiography, pulmonary function tests and skin biopsies for histopathological skin thickness score assessment. There was a significant increase in the mean values of serum levels of NT- pro BNP in SSc patients compared to controls (t=11, p<0.001). RESULTS: There was a significant positive correlation between serum levels of NT pro BNP in SSc patients and mRss, systolic pulmonary artery pressure (sPAP) and histopathological skin thickness score (r=0.93, r=0.92, r=0.92, p<0.001 respectively). There was a significant increase in the mean value of serum levels of NT-pro BNP and sPAP in SSc patients with restrictive pulmonary affection compared to those with normal respiratory function tests (p<0.001). CONCLUSION: NT-pro BNP may be a useful biological marker for assessing the severity of SSc as it has a role in detecting the extent of skin fibrosis, the severity of PAH and the degree of restricted pulmonary involvement in SSc patients. PMID- 21700538 TI - Bone involvement in two cases of thoracic primary cutaneous diffuse large B-cell lymphoma, leg type. AB - Primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT), is defined by a predominance of confluent sheets of centroblasts and immunoblasts, which strongly express Bcl-2 protein. This cutaneous lymphoma is mainly characterized by the development of skin lesions on the lower leg. Other localizations are possible (namely non-leg PCLBCL-LT) and usually affect younger patients. PCLBCL LT is distinguished from the two other subtypes of primary cutaneous B-cell lymphomas by its immunohistopathological features, its aggressive clinical behaviour with a worse prognosis linked to skin recurrences, but also secondary extracutaneous spread. Bone involvement underlying skin lesions has been reported in few series and cases reports during PCLBCL-LT. We describe here two aggressive cases of PCLBCL-LT with high burden and infiltrative thoracic tumours, with localized bone involvement. PMID- 21700539 TI - Type A and B pigmentary demarcation lines in a white, pregnant woman- a rare observation? PMID- 21700540 TI - Angiosarcoma of the forearm arising in an arteriovenous fistula in a renal transplant recipient. PMID- 21700541 TI - Heavy metal in hair samples of 109 non-industrial (miners) population in Katanga. AB - INTRODUCTION: This survey aims at proposing reference values of metals in the hair, in the copper-belt (Province of Katanga). MATERIALS AND METHODS: We ran a descriptive study, in an etiologic perspective, on a sample of non-industrial population, constituted by students of the University of Lubumbashi, healthy and without medical treatment (n = 109). Hair samples were analyzed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). RESULTS: Twenty metals were identified and quantified: aluminium, antimony, silver, barium, cadmium, calcium, cerium, chromium, cobalt, copper, tin, iron, magnesium, manganese, mercury, molybdenum, nickel, lead, vanadium, and zinc. DISCUSSION: Regarding similar surveys ran upon european no-industrial populations, our results are ranging in the same percentiles. They spread out those percentiles only when our results were too close to quantification limits (silver, tin, mercury, nickel and vanadium). For certain metals, in particular aluminium, cadmium, chromium, cobalt, copper, manganese, molybdenum and lead, we have obtained higher contents. Several reasons can explain this specificity: ICP-MS sensitivity, analysis and preparation technique difference, diet difference or simply public health issues... CONCLUSION: Our results are close to others surveys' values. They can be validated as reference values for Katanga general population and used to highlight occupational exposure. PMID- 21700542 TI - Protracted herpes zoster and severe postherpetic neuralgia after inadvertant infliximab administration. PMID- 21700543 TI - Primary cutaneous peripheral primitive neuroectodermal tumor with multiple papules and nodules. PMID- 21700545 TI - Seborrheic keratosis in a young patient with non-bullous congenital ichthyosiform erythroderma. PMID- 21700544 TI - Dramatic response of recalcitrant warts as a side effect of colorectal cancer treatment with oral capecitabine. PMID- 21700546 TI - Ulcerative necrobiosis lipoidica successfully treated by vacuum-assisted closure therapy. PMID- 21700547 TI - [Molecules involved in apoptosis regulation as therapeutic targets in oncology]. AB - Apoptosis is a programmed cellular death, a fast process (between four and six hours) in answer to a cellular stress. It involves a sequence of genetically determined intracellular events, allowing the inhibition of the main functions of the cell and its elimination by phagocytosis. The apoptosis inactivation is implied in tumours carcinogenesis. Although the tumour physiopathology implies a defect in activation-induced cell death, the treatment is designed to kill the transformed cells. The aim of this review is to describe the apoptotic mechanisms and to explain the interest of new therapeutic tools targeting apoptosis. Apoptosis is an orderly and synchronized process, regulated by two different pathways, the intrinsic way (mitochondrial) and extrinsic one (the death receptor). The targeting of apoptosis, a pathway intrinsically deficient in the tumor cells, is a potentially interesting strategy when the mechanism of its inhibition is well-identified. Small molecules targeting B-cell leukemia/lymphoma 2 (Bcl-2), inhibitor of apoptosis protein (IAPs) and tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors are currently under phase I/II studies, which show preliminary efficacy and safety. Their association with standard treatments seems an interesting therapeutic way in order to obtain a synergistic effect on tumor cell death. PMID- 21700548 TI - [HPV-Hr detection by home self sampling in women not compliant with pap test for cervical cancer screening. Results of a pilot programme in Bouches-du-Rhone]. AB - The non-participation to cervical screening is the major determinant in the risk of mortality due to cervical cancer. In France, around 40% of women do not participate to regular screening. The cultural or economic barriers for performing screening by Pap test are numerous; one of the most frequent is the refusal of gynaecological examination. A persistent HPV(HR) infection is a necessary factor for developing cervical cancer. The HPV(HR) testing has a high sensibility to detect high grade cervical intra-epithelial neoplasia (CIN 2-3) and a satisfactory specificity after 30-35 years old. The principal objective of this study was to compare the participation rates in women 35-69 years old who did not perform a Pap test after a first individual invitation, either when an HPV(HR) auto-test was offered to be performed at home or a second invitation to Pap test was sent. We also evaluated the quality of the two tests, the positive results obtained by age groups and the following histological type of lesions diagnosed in the women with positive results. The study included 9,334 women, 35 69 years old, who did not realized a Pap-test during the 2 previous years and who did not respond at a first individual invitation. These non-responders were randomized into two groups: one group (n=4,934) received a second individual invitation and the other (n=4,400) an offer of receiving and performing an HPV auto-test at home. In women 35-69 years the participation to the second invitation to Pap test was significantly lower (7.2%) than the participation to auto-test (26.4%) with P<0.001. The quality of the two tests was satisfactory; the auto-test was not altered by the postage to laboratory (non interpretable rate=1.4% [CI at 95%=0.65%; 2.15%]. From the 311 Pap tests done, 5.5% (17) were classified "abnormal" (nine ASCUS, one high grade and seven low grades). The follow up of 13 women out of 17 confirmed the diagnosis for 1 case of CIN2 and 2 cases of CIN3, 4 women are lost of follow up after 6 months. From the 939 HPV(HR) tests done, 6.2% (58) were positive. Such positivity rate was not influenced by age. Out of the 58 positive HPV(HR) cases, 27 only were of the 16 genotype (46.5% [CI 95%=33.7%; 59.3%]). This law rate is a consequence of an inversion of the ratio HPV 16 versus other types in women 60 years old and over. In this group, the follow-up of 36 women diagnosed five cases of CIN1, one of CIN2 and four of CIN3; 22 patients are lost of follow up at 6 months. Globally, in the studied population, an individual recall for pap test allowed to diagnose and treat 3 high grade lesions (70/00) and the dispatching of an auto test allowed the diagnosis and treatment of five high grade lesions (1,40/00), this difference is significant (P=0.02; OR=0.25 [0.05; 0.97]). The HPV(HR) auto-test seems to be better accepted than the Pap test in the 35-69 years old women previously non responders to individual invitation, and the quality of the test is satisfactory. Such a test can be proposed to the 35-69 years old non-participant to Pap test to increase the coverage for cervical screening, if the rates of diagnostic examinations performed in case of an HPV(HR) positive is sufficiently high. PMID- 21700549 TI - [Breast cancer in Sub-Saharan African women: review]. AB - Breast cancer is the second most frequent cancer in Sub-Saharan African women with an incidence of 15-53 per 100,000 women. Using PubMed, we reviewed all the articles published on this topic between 1989 and 2009. Breast cancer is usually diagnosed in women younger than in developed countries (mean age: 42-53 years), with later stages (III or IV, i.e. with axillary nodes and distant metastases). Reported tumors are mostly invasive ductal carcinomas with aggressive characteristics: grade III histoprognosis, absence of hormonal receptors or HER2 expression. According to the new breast cancer classification, nearly half of these tumors should be classified as triple negative. However, studies are rare and require confirmation. In conclusion, data on epidemiology and biology of breast cancer in Sub-Saharan African women are still scarce and need more extensive studies. In these countries, the pattern of breast cancer will likely change in the future, according to the evolution of lifestyle namely urbanisation. There is a great need for commitment of research and clinical resources in Sub-Saharan Africa in order to develop specific strategies. PMID- 21700550 TI - [Is AP24534 (Ponatinib) the next treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia?]. AB - Distinct clinicopathologic acute lymphoblastic leukemia (ALL) entities have been identified, resulting in the adoption of risk-oriented treatment approaches. In Philadelphia chromosome-positive (Ph(+)) ALL, the optimal treatment requires the addition of BCR-ABL tyrosine kinase inhibitors, as imatinib. However, the outcome remains poor in absence of allogeneic stem cell transplantation, and novel agents are desperately required. Resistance attributable to kinase domain mutations can lead to relapse despite the development of second-generation compounds, including dasatinib and nilotinib. Despite these therapeutic options, the cross-resistant BCR-ABL (T315I) mutation remains a major clinical challenge. The first evaluations of AP24534 present this drug as a potent multi-targeted kinase inhibitor active against T315I and all other BCR-ABL mutants. AP24534 could be the next treatment of choice in hematological malignancies with Philadelphia positive chromosome, particularly Ph(+) ALL known for its frequent occurrence of T315I mutation. PMID- 21700551 TI - [The role of RANK/RANKL/osteoprotegerin (OPG) triad in cancer-induced bone diseases: physiopathology and clinical implications]. AB - Bone homeostasis is maintained by the remodelling of bone which depends on a balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Malignant bone lesions are very common in patients with cancer; whether they result from a tumor in bone (giant cell tumour of bone, osteosarcoma, multiple myeloma...) or they are bony metastases from advanced cancers of which the most osteotropic are breast and prostate cancer. Malignant cells within the bone disrupt the normal bone remodelling process, leading to increased bone destruction and occurence of pathological fractures. Receptor activator of NF-kB (RANK) and its ligand (RANKL) play a pivotal role in the regulation of bone remodelling; by binding to RANK, RANKL stimulates osteoclastogenesis and bone resorption, whereas its cognate decoy receptor osteoprotegerin (OPG) blocks this process by interacting with RANKL. Tumour cells produce different factors that manipulate the RANK/RANKL/OPG pathway in order to stimulate bone destruction. Furthermore, pending on the tumour type, RANKL plays a role in the migration, invasion and proliferation of malignant cells within the bone, while OPG increases survival of tumour cells. Inhibition of RANK/RANKL system may therefore offer new therapeutic perspectives for the treatment of primitive and secondary bone cancers. PMID- 21700552 TI - [Adjuvant chemotherapy for breast cancer and fertility: estimation of the impact, options of preservation and role of the oncologist]. AB - Fifty-two thousand new breast cancers occur each year in France, 7% in patients less than 40 years. The standard regimens of adjuvant chemotherapy for breast cancer now include anthracyclines and taxanes. These therapeutics advances have significantly improved the prognosis of these young women who may later wish to become mother and have biological offspring. The impact of chemotherapy on reproductive function should be accurately assessed and the ovarian reserve has to be taken into account. The estimated risk of chemo-induced amenorrhea and infertility has to be balanced with the expected results and risks of methods of fertility preservation. The place of different options for fertility preservation depends on patient age, presence or not of a partner and the time available before the initiation of treatment. For these breast cancer patients who will receive chemotherapy, new techniques of in vitro oocyte maturation seem promising. Even if some ethical and technical issues are unresolved, fertility preservation must now be part of the management of these young patients receiving adjuvant chemotherapy for breast cancer. This new approach must be multidisciplinary and complex. PMID- 21700553 TI - [Pancreatic tuberculosis as a pseudotumor: a case report]. AB - Tuberculosis is a major public health problem in our country. Abdominal tuberculosis ranks third among the extrapulmonary localisations and account for 3% of the various topographic forms in Morocco. The pancreas and peripancreatic locations are much rarer than peritoneal and intestinal lesions. They present a pseudotumoral appearance that creates a diagnostic emergency. We report a case of pancreatic tuberculosis observed in the general surgery department of the 5th Military Hospital. PMID- 21700554 TI - [Prevalence of maternal and placental malaria and of neonatal low birth weight in a semi-urban area of Bamako (Mali)]. AB - In 2006, the Malian government established a program for free insecticide-treated net (ITNs) distribution during antenatal care visit (ANC) and intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) for pregnant women. In March to November of 2009, we conducted a cross-sectional study in peri-urban areas of Bamako, Mali to determine the malaria prevalence among pregnant women and their newborn children in the context of this policy. We included 379 pregnant women aged 15 to 45 years. At delivery, malaria was diagnosed using peripheral thick smears in mothers and newborns, as well as umbilical cord blood and placental blood. The prevalence of Plasmodium falciparum malaria was 2.4, 1.6 and 0.5% respectively in mother, placenta and cord samples; we observed a low birth weight rate of 12.1%. Approximately 77% of our parturient were housewives. The illiteracy rate among this group was 72.3%. Of the 379 women, 73% had at least three prenatal visits, 83% had received at least one free ITNs and 72% had received IPTp-SP during antenatal visit. Among them, 81% claimed to have complied with IPTp-SP. No congenital malaria was found. The prevalence of malaria in both mother and newborn has show a significant decrease in Bamako, compared with previous studies before the implementation of IPTp-SP policy in Mali. A high rate of coverage and use of IPTp-SP and ITNs correlate with lower malaria prevalence in pregnant women. PMID- 21700555 TI - [Lipid profile of patients on chronic hemodialysis (Morocco)]. AB - INTRODUCTION: Patients with end-stage renal disease (ESRD) receiving chronic hemodialysis show a high incidence and prevalence of cardiovascular disease of multifactorial etiology and an association between dyslipidemia and accelerated atherosclerosis. OBJECTIVE: Our aim was to study lipid profiles in ESRD patients receiving dialysis regularly at our hospital (Morocco).Subjects and methods : The patient population consisted of 30 ESRD patients on maintenance haemodialysis. Matched control subjects were recruited among healthy normolipidemic patients. Concentrations of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density-lipoprotein cholesterol (LDL-C) were measured. The atherogenic index (AI = TC/HDL-C ratio) was calculated. RESULTS: The TG, the HDL-C levels and atherogenic index were significantly higher in groups of hemodialysis patients. We saw no increase in the levels of TC and LDL-C. The prevalence of dyslipidemia in hemodialysis group was high (80%). The most frequent lipid alterations were decreased HDL-C (70%), increased TG (33,3%) and increased LDL-C (23,3%); 50% of ESRD patients have more than two different dyslipidemic findings. AI was higher (>= 5) in 33,3% of cases. CONCLUSION: The prevalence of dyslipidemia is higher than normal in ESRD patients on maintenance hemodialysis. Classically, these patients have had low levels of HDL-C and elevated TG levels. Strict control of dyslipidemia should be part of the cardiovascular risk prevention strategy in this population. PMID- 21700556 TI - [Tuberculosis of the breast in a man]. AB - Tuberculosis is a major public health problem in Morocco. A mammary localisation is very rare. The incidence of tuberculosis remains very low, even in developing countries where it is considered endemic, but the spread of the human immunodeficiency virus has led to an increased number of cases of extrapulmonary tuberculosis, even in the most developed countries. This disease presents essentially diagnostic problems, resolved only by histological and bacteriological study. The treatment is essentially medical, based on antibacterial chemotherapy associated with surgery in some advanced cases. PMID- 21700557 TI - [Factors associated with the quality of well water and the prevalence of waterborne diseases in the municipality of Abomey-Calavi in Benin]. AB - The objective of this work is to assess the factors associated with the water quality of household wells, suggest solutions to improve it, and study the prevalence of water-borne diseases in this community. The quality of well water and the prevalence of waterborne diseases in the municipality were studied by analysis of the microbiological indicators currently used to assess drinking water quality and the retrospective study of waterborne diseases treated in the local health centres. The wells surveyed were contaminated by Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus, Salmonella spp, Clostridium perfringens and fecal streptococci, at prevalences of 12.5, 12.2, 12.2, 12.1, 12 and 11.1%, respectively. The high rates of diarrhea, urinary infections, typhoid fever and abdominal pain found in the retrospective study were consistent with the results of the well-water quality assessment. These results showed that human activity has strongly influenced water quality, especially the lack of sanitation in the different districts and neighbourhoods. Other factors affecting the vulnerability of well water include poor waste management by households, the low depth of the water table, the nature of the soil, and the permeability of the aquifer used. Improvement in water quality, sanitation, and personal hygiene will make it possible to reduce considerably the propagation of these diseases and several others. It is therefore important to provide these populations with the necessary equipment for an adequate drinking water supply, but also to promote health education to avoid water pollution. The search for solutions to these problems will lead to a plan for future action. PMID- 21700558 TI - Glucocorticoid- and androgen-secreting black adrenocortical adenomas: unique cause of corticotropin-independent Cushing syndrome. AB - OBJECTIVE: To describe the unique association of corticotropin-independent Cushing syndrome caused by cortisol- and androgen-secreting black adrenal cortical adenomas with myelolipomatous change. METHODS: We report the clinical, laboratory, radiologic, and pathologic findings from 2 patients who presented with androgen excess and typical signs and symptoms of Cushing syndrome. RESULTS: Endocrine investigations showed high serum cortisol concentrations that lacked diurnal rhythm, undetectable plasma corticotropin concentrations, and absence of serum cortisol suppression after overnight dexamethasone suppression tests. Serum levels of adrenal androgens were elevated. Computed tomography of the abdomen revealed unilateral adrenal masses (largest lesional diameters 4.0 and 3.1 cm). On the basis of the plurihormonal hypersecretion and the imaging characteristics, adrenocortical carcinoma was considered as a possible diagnosis. However, histopathologic analysis in both patients revealed black adrenal cortical adenomas with myelolipomatous change. After surgery, adrenal androgens normalized, and the signs and symptoms of Cushing syndrome and androgen excess resolved. There was no evidence of recurrent disease at last follow-up. CONCLUSIONS: A unique form of corticotropin-independent Cushing syndrome is described: cortisol- and androgen-secreting black adrenal cortical adenomas with myelolipomatous change. Although most patients with corticotropin-independent Cushing syndrome associated with androgen excess prove to have adrenocortical carcinoma, the clinician should be aware of the possibility of benign, black adrenal adenomas in this clinical setting. PMID- 21700559 TI - The American Thyroid Association and American Association of Clinical Endocrinologists guidelines for hyperthyroidism and other causes of thyrotoxicosis: an appraisal. PMID- 21700560 TI - Incretin-based therapy and pancreatitis-what is the risk? PMID- 21700561 TI - Mild renal impairment and the efficacy and safety of liraglutide. AB - OBJECTIVE: To determine the effect of mild renal impairment (RI) on the efficacy and safety of liraglutide in patients with type 2 diabetes mellitus. METHODS: In this meta-analysis, we examined the 6 LEAD (Liraglutide Effect and Action in Diabetes) studies. Data from patients with type 2 diabetes who had normal renal function, mild RI, or moderate or severe RI were pooled for analysis. Renal function was measured by creatinine clearance as determined by the Cockcroft Gault equation: normal renal function = creatinine clearance >89 mL/min; mild RI = 60 mL/min <= creatinine clearance <= 89 mL/min; and moderate or severe RI = creatinine clearance <60 mL/min. The meta-analysis included patients administered once-daily liraglutide (1.2 or 1.8 mg) or placebo as either monotherapy or in combination with oral antidiabetic drugs for 26 weeks. In addition, a pooled analysis of all phase 2 and 3 liraglutide trials was done to examine rates of altered renal function. RESULTS: Mild RI did not affect the estimated treatment differences in hemoglobin A1c. Patients with normal renal function demonstrated decreases in body weight and systolic blood pressure with either dosage of liraglutide, whereas patients in either RI group also demonstrated a decrease in body weight and systolic blood pressure, but these differences were not significant compared with differences observed in the placebo group. Liraglutide treatment vs placebo was safe and well tolerated in patients with mild RI, as there were no significant differences in rates of renal injury, minor hypoglycemia, or nausea. A trend towards increased nausea was observed in patients with moderate or severe RI receiving liraglutide, although the number of patients in this treatment group was too low to determine significance. CONCLUSION: Mild RI, as determined by the Cockcroft-Gault equation, had no effect on the efficacy and safety of liraglutide in this meta-analysis. PMID- 21700562 TI - Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. AB - OBJECTIVE: Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This article describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspeciality physicians and others providing care for patients with this condition. METHODS: The development of these guidelines was commissioned by the American Thyroid Association in association with the American Association of Clinical Endocrinologists. The American Thyroid Association and American Association of Clinical Endocrinologists assembled a task force of expert clinicians who authored this report. The task force examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to develop the text and a series of specific recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. RESULTS: Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' ophthalmopathy; and management of other miscellaneous causes of thyrotoxicosis. CONCLUSIONS: One hundred evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice. PMID- 21700563 TI - Policy implementation for inpatient management of U-500 insulin resulting in lower incidence of hypoglycemia. PMID- 21700565 TI - The magnitude of center-surround facilitation in the discrimination of amplitude spectrum is dependent on the amplitude of the surround. AB - Recent studies explored the sensitivity of human perception to natural images, in particular the sensitivity of the visual system to discriminate changes in the amplitude spectrum slope. Previous slope discrimination experiments were carried out with stimuli presented either in the fovea or the parafovea/periphery and show that both yield poor discrimination at very steep or relatively shallow slopes. We verified if the well-known center-surround spatial interactions that operate early on in the visual processing stream influence the perception of real world images. The results show that amplitude slope discrimination is greatly reduced (i.e., flat) when the stimulus is viewed in isolation. However, when a 2 degrees target is placed within a surround containing an amplitude spectrum slope of 1 or 1.3, we see significant facilitation in detecting variations in the slope of the amplitude spectrum, particularly when the target contains an amplitude spectrum slope of 1 and 1.3. The results suggest that our visual system is sensitive to contextual interactions for stimuli that have the characteristics of natural images. PMID- 21700566 TI - Mathematical modelling the age dependence of Epstein-Barr virus associated infectious mononucleosis. AB - Most people get Epstein-Barr virus (EBV) infection at young age and are asymptomatic. Primary EBV infection in adolescents and young adults, however, often leads to infectious mononucleosis (IM) with symptoms including fever, fatigue and sore throat that can persist for months. Expansion in the number of CD8(+) T cells, especially against EBV lytic proteins, are the main cause of these symptoms. We propose a mathematical model for the regulation of EBV infection within a host to address the dependence of IM on age. This model tracks the number of virus, infected B cell and epithelial cell and CD8(+) T-cell responses to the infection. We use this model to investigate three hypotheses for the high incidence of IM in teenagers and young adults: saliva and antibody effects that increase with age, high cross-reactive T-cell responses and a high initial viral load. The model supports the first two of these hypotheses and suggests that variation in host antibody responses and the complexity of the pre existing cross-reactive T-cell repertoire, both of which depend on age, may play important roles in the etiology of IM. PMID- 21700567 TI - Masticatory motor programs in Australian herbivorous mammals: diprotodontia. AB - Movement of the jaw during molar occlusion is determined by the sequence of activity in the adductor muscles and this sequence is one way to define a masticatory motor program. Based on the similarity of molar structure, it is probable that the American opossum and the early Tertiary mammals that gave rise to all Australian marsupials probably shared a common "primitive" masticatory motor program. The distinct and various patterns of movement of the jaw in the major groups of Australian marsupial herbivores (diprotodontids) are achieved by both subtle and substantial shifts in the timing of the primitive sequence. All diprotodonts divide jaw movements during occlusion into a vertical Phase Im and horizontal Phase IIm, but the number of muscles involved and the level of activity associated with each phase varies considerably. In macropodids (potoroos and kangaroos) Phase Im dominates; in wombats Phase IIm dominates and in koalas the two phases are more evenly divided, with a more equal distribution of muscles between them. The motor program of koalas parallels that of some placental ungulates, while both macropodids and wombats have motor programs unique among mammals. PMID- 21700568 TI - Partly shared spinal cord networks for locomotion and scratching. AB - Animals produce a variety of behaviors using a limited number of muscles and motor neurons. Rhythmic behaviors are often generated in basic form by networks of neurons within the central nervous system, or central pattern generators (CPGs). It is known from several invertebrates that different rhythmic behaviors involving the same muscles and motor neurons can be generated by a single CPG, multiple separate CPGs, or partly overlapping CPGs. Much less is known about how vertebrates generate multiple, rhythmic behaviors involving the same muscles. The spinal cord of limbed vertebrates contains CPGs for locomotion and multiple forms of scratching. We investigated the extent of sharing of CPGs for hind limb locomotion and for scratching. We used the spinal cord of adult red-eared turtles. Animals were immobilized to remove movement-related sensory feedback and were spinally transected to remove input from the brain. We took two approaches. First, we monitored individual spinal cord interneurons (i.e., neurons that are in between sensory neurons and motor neurons) during generation of each kind of rhythmic output of motor neurons (i.e., each motor pattern). Many spinal cord interneurons were rhythmically activated during the motor patterns for forward swimming and all three forms of scratching. Some of these scratch/swim interneurons had physiological and morphological properties consistent with their playing a role in the generation of motor patterns for all of these rhythmic behaviors. Other spinal cord interneurons, however, were rhythmically activated during scratching motor patterns but inhibited during swimming motor patterns. Thus, locomotion and scratching may be generated by partly shared spinal cord CPGs. Second, we delivered swim-evoking and scratch-evoking stimuli simultaneously and monitored the resulting motor patterns. Simultaneous stimulation could cause interactions of scratch inputs with subthreshold swim inputs to produce normal swimming, acceleration of the swimming rhythm, scratch swim hybrid cycles, or complete cessation of the rhythm. The type of effect obtained depended on the level of swim-evoking stimulation. These effects suggest that swim-evoking and scratch-evoking inputs can interact strongly in the spinal cord to modify the rhythm and pattern of motor output. Collectively, the single neuron recordings and the results of simultaneous stimulation suggest that important elements of the generation of rhythms and patterns are shared between locomotion and scratching in limbed vertebrates. PMID- 21700569 TI - Heat for nothing or activity for free? Evidence and implications of activity thermoregulatory heat substitution. AB - If heat generated through activity can substitute for heat required for thermoregulation, then activity in cold environments may be energetically free for endotherms. Although the possibility of activity-thermoregulatory heat substitution has been long recognized, its empirical generality and ecological implications remain unclear. We combine a review of the literature and a model of heat exchange to explore the generality of activity-thermoregulatory heat substitution, to assess the extent to which substitution is likely to vary with body size and ambient temperature, and to examine some potential macroecological implications. A majority of the 51 studies we located showed evidence of activity thermoregulatory heat substitution (35 of 51 studies), with 28 of 32 species examined characterized by substitution in one or more study. Among studies that did detect substitution, the average magnitude of substitution was 57%, but its occurrence and extent varied taxonomically, allometrically, and with ambient temperature. Modeling of heat production and dissipation suggests that large birds and mammals, engaged in intense activity and exposed to relatively warm conditions, have more scope for substitution than do smaller endotherms engaged in less intense activity and experiencing cooler conditions. However, ambient temperature has to be less than the lower critical temperature (the lower bound of the thermal neutral zone) for activity-thermoregulatory heat substitution to occur and this threshold is lower in large endotherms than in small endotherms. Thus, in nature, substitution is most likely to be observed in intermediate-sized birds and mammals experiencing intermediate ambient temperatures. Activity thermoregulatory heat substitution may be an important determinant of the activity patterns and metabolic ecology of endotherms. For example, a pattern of widely varying field metabolic rates (FMR) at low latitudes that converges to higher and less variable FMR at high latitudes has been interpreted as suggesting that warm environments at low latitudes allow a greater variety of feasible metabolic niches than do cool, high-latitude environments. However, activity thermoregulatory heat substitution will generate this pattern of latitudinal FMR variation even if endotherms from cold and warm climates are metabolically and behaviorally identical, because the metabolic rates of resting and active animals are more similar in cold than in warm environments. Activity-thermoregulatory heat substitution is an understudied aspect of endotherm thermal biology that is apt to be a major influence on the physiological, behavioral and ecological responses of free-ranging endotherms to variation in temperature. PMID- 21700570 TI - Introduction to the symposium: environment, energetics, and fitness: a symposium honoring Donald W. Thomas. PMID- 21700571 TI - Speciation genes in free-spawning marine invertebrates. AB - Research on speciation of marine organisms has lagged behind that of terrestrial ones, but the study of the evolution of molecules involved in the adhesion of gametes in free-spawning invertebrates is an exception. Here I review the function, species-specificity, and molecular variation of loci coding for bindin in sea urchins, lysin in abalone and their egg receptors, in an effort to assess the degree to which they contribute to the emergence of reproductive isolation during the speciation process. Bindin is a protein that mediates binding of the sperm to the vitelline envelope (VE) of the egg and the fusion of the gametes' membranes, whereas lysin is a protein involved only in binding to the VE. Both of these molecules are important in species recognition by the gametes, but they rarely constitute absolute blocks to interspecific hybridization. Intraspecific polymorphism is high in bindin, but low in lysin. Polymorphism in bindin is maintained by frequency-dependent selection due to sexual conflict arising from the danger of polyspermy under high densities of sperm. Monomorphism in lysin is the result of purifying selection arising from the need for species recognition. Interspecific divergence in lysin is due to strong positive selection, and the same is true for bindin of four out of seven genera of sea urchins studied to date. The differences between the sea urchin genera in the strength of selection can only partially be explained by the hypothesis of reinforcement. The egg receptor for lysin (VERL) is a glycoprotein with 22 repeats, 20 of which have evolved neutrally and homogenized by concerted evolution, whereas the first two repeats are under positive selection. Selection on lysin has been generated by the need to track changes in VERL, permitted by the redundant structure of this molecule. Both lysin and bindin are important in reproductive isolation, probably had a role in speciation, but it is hard to determine whether they meet the strictest criteria of "speciation loci," defined as genes whose differentiation has caused speciation. PMID- 21700572 TI - The neuroecology of competitor recognition. AB - Territorial animals can be expected to distinguish among the types of competitors and noncompetitors that they encounter on a regular basis, including prospective mates and rivals of their own species, but they may not correctly classify individuals of other species. Closely related species often have similar phenotypes and this can cause confusion when formerly allopatric populations first come into contact. Errors in recognizing competitors can have important ecological and evolutionary effects. I review what is known about the mechanisms of competitor recognition in animals generally, focusing on cases in which the targets of recognition include other species. Case studies include damselflies, ants, skinks, salamanders, reef fishes, and birds. In general, recognition systems consist of a phenotypic cue (e.g., chemical, color, song), a neural template against which cues are compared, a motor response (e.g., aggression), and sensory integration circuits for context dependency of the response (if any). Little is known about how competitor recognition systems work at the neural level, but inferences about specificity of cues and about sensory integration can be drawn from the responses of territory residents to simulated intruders. Competitor recognition often involves multiple cues in the same, or different, sensory modalities. The same cues and templates are often, but not always, used for intraspecific and interspecific recognition. Experiments have shown that imprinting on local cues is common, which may enable templates to track evolved changes in cues automatically. The dependence of aggression and tolerance on context is important even in the simplest systems. Species in which mechanisms of competitor recognition are best known offer untapped opportunities to examine how competitor-recognition systems evolve (e.g., by comparing allopatric and sympatric populations). Cues that are gene products (peptides, proteins) may provide insights into rates of evolution. There are many avenues for further research on the important but understudied question of how animals recognize competitors. PMID- 21700573 TI - Shorebirds' seasonal adjustments in thermogenic capacity are reflected by changes in body mass: how preprogrammed and instantaneous acclimation work together. AB - Phenotypic flexibility in shorebirds has been studied mainly in the context of adjustments to migration and to quality of food; little is known on how birds adjust their phenotype to harsh winter conditions. We showed earlier that red knot (Calidris canutus islandica) can acclimate to cold by elevating body mass. This goes together with larger pectoral muscles, i.e., greater shivering machinery, and thus, better thermogenic capacity. Here, we present results of a yearlong experiment with indoor captive knots to determine whether this strategy is part of their natural seasonal phenotypic cycle. We maintained birds under three thermal regimes: constant cold (5 degrees C), constant thermoneutrality (25 degrees C) and natural seasonal variation between these extremes (9-22 degrees C). Each month we measured variables related to the birds' endurance to cold and physiological maintenance [body mass, thickness of pectoral muscles, summit metabolic rate (M(sum)), food intake, gizzard size, basal metabolic rate (BMR)]. Birds from all treatments expressed synchronized and comparable variation in body mass in spite of thermal treatments, with a 17-18% increase between the warmest and coldest months of the year; which appeared regulated by an endogenous driver. In addition, birds living in the cold exhibited a 10% higher average body mass than did those maintained at thermoneutrality. Thickness of the pectoral muscle tracked changes in body mass in all treatments and likely contributed to greater capacity for shivering in heavier birds. Consequently, M(sum) was 13% higher in cold-acclimated birds compared to those experiencing no thermoregulation costs. However, our data also suggest that part of maximal heat production comes from nonshivering processes. Birds facing cold conditions ate up to 25% more food than did birds under thermoneutral conditions, yet did not develop larger gizzards. Seasonal variation in BMR followed changes in body mass, probably reflecting changes in mass of metabolically active tissues. Just as cold exposed birds, red knots in the variable treatment increased body mass in winter, thereby improving cold endurance. During summer, however, they maintained a lower body mass and thermogenic capacity compared to cold-exposed birds, similar to individuals kept at thermoneutrality. We conclude that red knots acclimate to seasonal variations in ambient temperature by modulating body mass, combining a preprogrammed increase in mass during winter with a capacity for fine-tuning body mass and thermogenic capacity to temperature variations. PMID- 21700575 TI - Hibernation and torpor in tropical and subtropical bats in relation to energetics, extinctions, and the evolution of endothermy. AB - Torpor, the most effective means of energy conservation available to endotherms, is still widely viewed as a specific adaptation in a few high-latitude, cold climate endotherms with no adaptive function in warm regions. Nevertheless, a growing number of diverse terrestrial mammals and birds from low latitudes (0-30 degrees ), including species from tropical and subtropical regions, are heterothermic and employ torpor. Use of torpor is especially important for bats because they are small, expend large amounts of energy when active, rely on a fluctuating food supply, and have only a limited capacity for storage of fat. Patterns of torpor in tropical/subtropical bats are highly variable, but short bouts of torpor with relatively high body temperatures (T(b)) are most common. Hibernation (a sequence of multiday bouts of torpor) has been reported for free ranging subtropical tree-dwelling vespertilionids, cave-dwelling hipposiderids, and house-dwelling molossids. The observed range of minimum T(b) is ~6-30 degrees C, and the reduction of energy expenditure through the use of torpor, in comparison to normothermic values, ranges from 50 to 99%. Overall, torpor in the tropics/subtropics has been reported for 10 out of the currently recognized 18 bat families, which contain 1079 species, or 96.7% of all bats. Although it is unlikely that all of these are heterothermic, the large majority probably will be. Frequent use of torpor, including hibernation in diverse groups of tropical/subtropical bats, suggests that heterothermy is an ancestral chiropteran trait. Although data especially from the field are still scarce, it is likely that torpor, highly effective in reducing requirements for energy and water even under warm conditions, plays a crucial role in the long-term survival of the majority of small tropical and subtropical bats. Discovering how bats achieve this provides numerous opportunities for exiting new research. PMID- 21700574 TI - Overview of FEED, the feeding experiments end-user database. AB - The Feeding Experiments End-user Database (FEED) is a research tool developed by the Mammalian Feeding Working Group at the National Evolutionary Synthesis Center that permits synthetic, evolutionary analyses of the physiology of mammalian feeding. The tasks of the Working Group are to compile physiologic data sets into a uniform digital format stored at a central source, develop a standardized terminology for describing and organizing the data, and carry out a set of novel analyses using FEED. FEED contains raw physiologic data linked to extensive metadata. It serves as an archive for a large number of existing data sets and a repository for future data sets. The metadata are stored as text and images that describe experimental protocols, research subjects, and anatomical information. The metadata incorporate controlled vocabularies to allow consistent use of the terms used to describe and organize the physiologic data. The planned analyses address long-standing questions concerning the phylogenetic distribution of phenotypes involving muscle anatomy and feeding physiology among mammals, the presence and nature of motor pattern conservation in the mammalian feeding muscles, and the extent to which suckling constrains the evolution of feeding behavior in adult mammals. We expect FEED to be a growing digital archive that will facilitate new research into understanding the evolution of feeding anatomy. PMID- 21700576 TI - Morphological and behavioral evidence for adaptive diversification of sympatric Hawaiian limpets (Cellana spp.). AB - The endemic Hawaiian limpets (Cellana exarata, Cellana sandwicensis, and Cellana talcosa), reside at different elevations on wave-exposed rocky shores and comprise a monophyletic lineage that diversified within Hawai'i. Here, I report phenotypic differences in shell, soft tissue, and behavioral characters among these limpets and discuss their potential utility in exploiting their respective niches. The high-shore limpet, C. exarata, is characterized by a tall round shell, short mantle tentacles, and long evasion distance when confronted by a predatory gastropod. The mid-shore limpet, C. sandwicensis, is characterized by a shorter oblong shell, long mantle tentacles, and a short evasion distance when confronted by a predatory snail. The low-shore, shallow-subtidal limpet, C. talcosa, is characterized by a flat shell that is thin in juveniles and disproportionately massive in large adults (relative to the other two species), and mantle tentacles of varying lengths (some individuals exhibit short tentacles, some long). These species-specific suites of characters are likely to confer specific fitness advantages on the high shore (C. exarata) where thermal and desiccation stress is severe, on the mid shore (C. sandwicensis) where hydrodynamic forces are severe, and on the low-shallow subtidal shore (C. talcosa) where pelagic predators have free access to the limpets. These data add to the growing body of evidence for adaptive diversification and speciation in the Hawaiian Cellana, and in marine species in general. PMID- 21700577 TI - Does animal behavior underlie covariation between hosts' exposure to infectious agents and susceptibility to infection? Implications for disease dynamics. AB - Animal behavior is unique in influencing both components of the process of transmission of disease: exposure to infectious agents, and susceptibility to infection once exposed. To date, the influence of behavior on exposure versus susceptibility has largely been considered separately. Here, we ask whether these two key mechanisms act in concert in natural populations, whereby individuals who are most exposed to infectious agents or have the most contact with conspecifics are also the most susceptible or infectious. We propose three mechanisms that can generate covariation between these two key elements of the transmission of disease within and among hosts, and we provide empirical examples of each. We then use a mathematical model to examine the effect of this covariation on the dynamics of disease at the population level. First, we show that the empirical mechanisms generating covariation between behavioral and physiological components of disease transmission are widespread and include endocrine mediators of behavior, mate choice, group size, sickness behaviors, and behavioral avoidance of infectious conspecifics. The diversity of these empirical mechanisms underscores the potential importance and breadth of covariation in the disease process. Second, we show mathematically that the variability in hosts' exposure to infectious agents and susceptibility or infectiousness, and how tightly they are coupled, strongly influences the ability of a disease to invade a host population. Overall, we propose that covariation between behavioral and physiological components of transmission is likely widespread in natural populations, and can have important consequences for the dynamics of disease at the population level as well as for our understanding of sexual selection, social behavior, and animal communication. PMID- 21700578 TI - Shake rattle and roll: the bony labyrinth and aerial descent in squamates. AB - Controlled aerial descent has evolved many times independently in vertebrates. Squamates (lizards and snakes) are unusual in that respect due to the large number of independent origins of the evolution of this behavior. Although some squamates such as flying geckos of the genus Ptychozoon and the flying dragons of the genus Draco show obvious adaptations including skin flaps or enlarged ribs allowing them to increase their surface area and slow down their descent, many others appear unspecialized. Yet, specializations can be expected at the level of the sensory and neural systems allowing animals to maintain stability during controlled aerial descent. The vestibular system is a likely candidate given that it is an acceleration detector and is well-suited to detect changes in pitch, roll and yaw. Here we use conventional and synchrotron MUCT scans to quantify the morphology of the vestibular system in squamates able to perform controlled aerial descent compared to species characterized by a terrestrial or climbing life style. Our results show the presence of a strong phylogenetic signal in the data with the vestibular system in species from the same family being morphologically similar. However, both our shape analysis and an analysis of the dimensions of the vestibular system showed clear differences among animals with different life-styles. Species able to perform a controlled aerial descent differed in the position and shape of the inner ear, especially of the posterior ampulla. Given the limited stability of squamates against roll and the fact that the posterior ampulla is tuned to changes in roll this suggests an adaptive evolution of the vestibular system in squamates using controlled aerial descent. Future studies testing for similar differences in other groups of vertebrates known to use controlled aerial descent are needed to test the generality of this observation. PMID- 21700579 TI - CSF soluble amyloid precursor proteins in the diagnosis of incipient Alzheimer disease. AB - OBJECTIVE: To explore if soluble amyloid precursor proteins (sAPP) in CSF improve the identification of patients with incipient Alzheimer disease (AD) in a group of patients with mild cognitive impairment (MCI). METHODS: A cohort study with follow-up assessments of 58 patients with MCI with baseline CSF sampling was conducted: 21 patients had progressed to probable AD (MCI-AD), 27 still had MCI, 8 had reverted to normal (MCI-NAD), and 2 patients with frontotemporal dementia (FTD) were excluded. Sixteen additional patients with FTD were included to explore the specificity of the CSF markers. CSF concentrations of sAPPalpha, sAPPbeta, tau, and Abeta(1-42) were measured with sensitive and specific ELISAs. Associations between diagnostic status, CSF protein concentrations, and other patient characteristics were explored using multiple logistic regression analyses with stepwise variable selection. The optimal sensitivity and specificity of the best models were derived from receiver operating characteristic curves. RESULTS: The MCI-AD group had significantly higher sAPPbeta concentrations than the MCI NAD and the FTD groups. A combination of sAPPbeta, tau, and age differentiated the MCI-AD and the MCI-NAD groups with a sensitivity of 80.00% and a specificity of 81.00%. The best model for the differentiation of the MCI-AD and the FTD groups included sAPPbeta and tau, and showed a sensitivity of 95.20% and a specificity of 81.20%. Abeta(1-42) and sAPPalpha did not significantly contribute to the models. CONCLUSION: These findings suggest that sAPPbeta may be clinically useful, and superior to Abeta(1-42), in the early and differential diagnosis of incipient AD. PMID- 21700581 TI - Early detection of Alzheimer disease: 11C-PiB PET in twins discordant for cognitive impairment. AB - OBJECTIVE: The aim of this study was to investigate whether cognitively preserved monozygotic or dizygotic cotwins of persons with Alzheimer disease (AD) exhibit increased brain amyloid accumulation. METHODS: We performed a cross-sectional carbon-11 labeled 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ((11)C) Pittsburgh compound B (PiB) PET study on 9 monozygotic and 8 dizygotic twin pairs discordant for cognitive impairment as well as on 9 healthy elderly control subjects. (11)C-PiB uptake was analyzed with Statistical Parametric Mapping and with region of interest analysis with the region-to-cerebellum ratio as a measure of tracer uptake. RESULTS: Cognitively preserved monozygotic cotwins of cognitively impaired probands had increased cortical (11)C-PiB uptake (117%-121% of control mean) in their temporal and parietal cortices and the posterior cingulate. Cognitively preserved dizygotic subjects did not differ from the controls. Further, the cognitively preserved monozygotic subjects showed similar (11)C-PiB uptake patterns as their cognitively impaired cotwins. The cognitively impaired subjects (monozygotic and dizygotic individuals combined) showed typical Alzheimer-like patterns of (11)C-PiB uptake. CONCLUSIONS: Genetic factors appear to influence the development of Alzheimer-like beta-amyloid plaque pathology. The dissociation between cognitive impairment and brain beta-amyloidosis in monozygotic twins implies that there may be important environmental/acquired factors that modulate the relationship between brain amyloidosis and neurodegeneration. AD may be detectable in high-risk individuals in its presymptomatic stage with (11)C-PiB PET, but clinical follow-up will be needed to confirm this. PMID- 21700580 TI - Severity of leukoaraiosis determines clinical phenotype after brain infarction. AB - OBJECTIVE: To determine whether the extent of leukoaraiosis, a composite marker of baseline brain integrity, differed between patients with TIA with diffusion weighted imaging (DWI) evidence of infarction (transient symptoms with infarction [TSI]) and patients with ischemic stroke. METHODS: Leukoaraiosis volume on MRI was quantified in a consecutive series of 153 TSI and 354 ischemic stroke patients with comparable infarct volumes on DWI. We explored the relationship between leukoaraiosis volume and clinical phenotype (TIA or ischemic stroke) using a logistic regression model. RESULTS: Patients with TSI tended to be younger (median age 66 vs 69 years, p = 0.062) and had smaller median normalized leukoaraiosis volume (1.2 mL, interquartile range [IQR] 0.2-4.7 mL vs 3.5 mL, IQR 1.2-8.6 mL, p < 0.001). In multivariable analysis controlling for age, stroke risk factors, etiologic stroke mechanism, infarct volume, and infarct location, increasing leukoaraiosis volume remained associated with ischemic stroke (odds ratio 1.05 per mL, 95%confidence interval 1.02-1.09, p = 0.004), along with infarct volume and infarct location. CONCLUSION: The probability of ischemic stroke rather than TSI increases with increasing leukoaraiosis volume, independent of infarct size and location. Our findings support the concept that the integrity of white matter tracts connecting different parts of the brain could contribute to whether or not patients develop TSI or ischemic stroke in an event of brain infarction. PMID- 21700582 TI - Comment: Affective symptoms associated with subthalamic nucleus dysfunction. PMID- 21700583 TI - Precuneus amyloid burden is associated with reduced cholinergic activity in Alzheimer disease. AB - OBJECTIVE: This study examined the relationship between postmortem precuneus cholinergic enzyme activity, Pittsburgh compound B (PiB) binding, and soluble amyloid-beta concentration in mild cognitive impairment (MCI) and Alzheimer disease (AD). METHODS: Choline acetyltransferase (ChAT) activity, [(3)H]PiB binding, and soluble amyloid-beta(1-42) (Abeta42) concentration were quantified in precuneus tissue samples harvested postmortem from subjects with no cognitive impairment (NCI), MCI, and mild AD and correlated with their last antemortem Mini Mental State Examination (MMSE) score and postmortem pathologic evaluation according to the National Institute on Aging-Reagan criteria, recommendations of the Consortium to Establish a Registry for Alzheimer's Disease, and Braak stage. RESULTS: Precuneus ChAT activity was lower in AD than in NCI and was comparable between MCI and NCI. Precuneus [(3)H]PiB binding and soluble Abeta42 levels were elevated in MCI and significantly higher in AD than in NCI. Across all case subjects, reduced ChAT activity was associated with increased [(3)H]PiB binding, increased soluble Abeta42, lower MMSE score, presence of the APOE*4 allele, and more advanced AD pathology. CONCLUSIONS: Despite accumulating amyloid burden, cholinergic enzyme activity is stable in the precuneus during prodromal AD. A decline in precuneus ChAT activity occurs only in clinical AD, when PiB binding and soluble Abeta42 levels are substantially elevated compared with those in MCI. Anti-amyloid interventions in MCI case subjects with a positive PiB PET scan may aid in reducing cholinergic deficits and cognitive decline later in the disease process. PMID- 21700584 TI - From Jekyll to Hyde after limbic subthalamic nucleus infarction. PMID- 21700586 TI - PLA2G6 gene mutation in autosomal recessive early-onset parkinsonism in a Chinese cohort. AB - OBJECTIVE: Mutations in the PLA2G6 gene at the PARK14 locus have been reported in complicated parkinsonism. To assess the prevalence of and phenotypes associated with PLA2G6 gene mutations, we screened PLA2G6 mutations in a cohort of patients with autosomal recessive early-onset parkinsonism (AREP). METHODS: We selected 12 families with AREP in which the Parkin, PINK1, DJ-1, ATP13A2, and FBXO7 gene mutations had been previously excluded. All patients came from the mainland of China. The entire PLA2G6 coding region and exon-intron boundaries were sequenced from genomic DNA templates. We then performed PET studies on individuals in the pedigree with a homozygous PLA2G6 mutation, and investigated the enzyme activity level of the mutation. RESULTS: A homozygous missense mutation, c.G991T (p.D331Y), was identified in an autosomal recessive case. A younger sister of the p.D331Y-carrying patient was also homozygous for the mutation, but with no extrapyramidal symptoms. A PET study showed a substantial reduction in dopamine transporter (DAT) binding in the p.D331Y patient, and a slight reduction in DAT binding in his sister. In vitro, we experimentally demonstrate that the D331Y mutation caused an approximately 70%reduction in enzyme activity. CONCLUSIONS: We have confirmed that the PLA2G6 gene allocated PARK14 locus and is associated with AREP. PMID- 21700585 TI - Cerebral microhemorrhage and brain beta-amyloid in aging and Alzheimer disease. AB - OBJECTIVES: Incidental cerebral microhemorrhage (MH) is frequently found in older individuals scanned with susceptibility-weighted MRI (SWI) or gradient-recalled echo MRI. MH have been linked with beta-amyloid (Abeta) deposition using (11)C Pittsburgh compound B (PiB) PET in Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). We hypothesized that Abeta deposition in asymptomatic elderly individuals is associated with lobar MH (LMH). METHODS: This was a cross sectional study of 84 elderly healthy controls (HC), 28 subjects with mild cognitive impairment (MCI), and 26 subjects with probable AD who underwent 3-T SWI and (11)C-PiB PET. (11)C-PiB cortical binding was quantified normalized to cerebellar cortex (standardized uptake value ratio [SUVR]) and scans classified as positive (PiB+) or negative (PiB-) by visual inspection. MH were manually counted and categorized by region and as lobar or nonlobar. RESULTS: LMH were present in 30.8% of AD, 35.7% of MCI, and 19.1% of HC. The prevalence of LMH among PiB+ subjects was similar, regardless of clinical classification (AD 30.8%, MCI 38.9%, HC 41.4%, p > 0.7). HC with LMH had significantly higher mean neocortical SUVR (1.7 +/- 0.5) than HC without LMH (1.3 +/- 0.3, p +/- 0.01). In HC, there was a positive correlation between number of LMH and SUVR, and between LMH and age. In HC, PiB+ (odds ratio [OR] 7.3, 95% confidence interval [CI] 1.6 33.7, p = 0.01) and age (OR 1.2, 95% CI 1.03-1.3, p = 0.02) both independently predicted the occurrence of LMH using logistic regression. CONCLUSION: Asymptomatic Abeta deposition in older adults is strongly associated with LMH. PMID- 21700587 TI - Cardiac abnormalities in a follow-up study on carriers of Duchenne and Becker muscular dystrophy. AB - OBJECTIVES: Cardiac involvement has been reported in carriers of dystrophin mutations giving rise to Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). The progress of these abnormalities during long-term follow-up is unknown. We describe the long-term follow-up of dilated cardiomyopathy (DCM) in DMD/BMD carriers. METHODS: A long-term follow-up study was performed among Dutch DMD/BMD carriers first analyzed in 1995. A cardiac history was taken, and all carriers were assigned a functional score to assess skeletal muscle involvement. Electrocardiography and M-mode and 2-D echocardiography were performed. DCM was defined as an enlarged left ventricle with a global left ventricle dysfunction or fractional shortening less than 28%. Slow vital capacity of the lung was measured by a hand-held spirometer. RESULTS: Ninety-nine carriers were monitored with a median follow-up of 9 years (range 7.0-10.6 years). Eleven carriers with DCM (10 DMD, 1 BMD) were identified. Nine of them developed DCM in the follow-up period. One of the patients with DCM reported in the 1995 study died of cardiac failure at age 57 years. DCM was more frequently found in carriers who were functionally symptomatic. CONCLUSION: Cardiac abnormalities in DMD/BMD carriers are progressive, as in patients with DMD/BMD. PMID- 21700588 TI - Vision science and schizophrenia research: toward a re-view of the disorder. Editors' introduction to special section. AB - This theme section on vision science and schizophrenia research demonstrates that our understanding of the disorder could be significantly accelerated by a greater adoption of the methods of vision science. In this introduction, we briefly describe what vision science is, how it has advanced our understanding of schizophrenia, and what challenges and opportunities lay ahead regarding schizophrenia research. We then summarize the articles that follow. These include reviews of abnormal form perception (perceptual organization and backward masking) and motion processing, and an article on reduced size contrast illusions experienced by hearing but not deaf persons with schizophrenia. These articles reveal that the methods of basic vision research can provide insights into a number of aspects of the disorder, including pathophysiology, development, cognition, social cognition, and phenomenology. Importantly, studies of visual processing in schizophrenia make it clear that there are impairments in the functioning of basic neural mechanisms (e.g., center-surround modulation, contextual modulation of feedforward processing, reentrant processing) that are found throughout the cortex and that are operative in multiple forms of cognitive dysfunction in the illness. Such evidence allows for an updated view of schizophrenia as a condition involving generalized failures in neural network formation and maintenance, as opposed to a primary failure in a higher level factor (e.g., cognitive control) that accounts for all other types of perceptual and cognitive dysfunction. Finally, studies of vision in schizophrenia can identify sensitive probes of neural functioning that can be used as biomarkers of treatment response. PMID- 21700589 TI - Perceptual organization impairment in schizophrenia and associated brain mechanisms: review of research from 2005 to 2010. AB - Perceptual organization (PO) refers to the processes by which visual information is structured into coherent patterns such as groups, contours, perceptual wholes, and object representations. Impairments in PO have been demonstrated in schizophrenia since the 1960s and have been linked to several illness-related factors including poor premorbid functioning, poor prognosis, and disorganized symptoms. This literature was last reviewed in 2005. Since then, electrophysiological (electroencephalographic, event-related potential, and magnetoencephalographic) and fMRI studies in both patient and nonpatient samples have clarified brain mechanisms involved in the impairment, and additional behavioral studies in patients and nonpatients have clarified the computational mechanisms. In addition, data now exist on the functional consequences of PO impairments, in terms of secondary difficulties in face processing, selective attention, working memory, and social cognition. Preliminary data on drug effects on PO and on changes in response to treatment suggest that anomalies in PO may furnish a biomarker for the integrity of its associated biological mechanisms. All of this recent evidence allows for a clearer picture of the nature of the impairment and how it relates to broader aspects of brain and behavioral functioning in schizophrenia. PMID- 21700591 TI - Reverse subclavian flap and aorto-pulmonary window technique for repair of interrupted aortic arch and truncus arteriosus. AB - We report a surgical strategy for repairing an interrupted aortic arch (IAA) with truncus arteriosus (TA) by using a reverse subclavian flap and an aorto-pulmonary (A-P) window technique for preserving the pulmonary artery architecture. A 10-day old neonate with type B IAA and type I TA with echocardiographic evidence of a significant distance between the ascending and descending aorta underwent surgical repair at the Bristol Royal Hospital for Children. The superior part of the arch was reconstructed using a reverse subclavian flap and the undersurface with a pulmonary homograft patch. The ascending aorta was separated from the pulmonary arteries using a Gore-Tex patch (A-P window type of repair) without disconnecting the branch pulmonary arteries, in order to preserve their architecture. The continuity between the right ventricle and the pulmonary artery bifurcation was established using a 12 mm Contegra conduit. The postoperative course was uneventful, and the neonate was discharged after 12 days. At follow up, the patient remains well, gaining weight, with no echocardiographic evidences of obstruction. Reverse subclavian flap with homograft patch combined with and 'A P window' technique for preservation of the pulmonary artery architecture is a useful and effective surgical strategy for neonates presenting with IAA associated with TA. PMID- 21700590 TI - Visual context processing deficits in schizophrenia: effects of deafness and disorganization. AB - Visual illusions allow for strong tests of perceptual functioning. Perceptual impairments can produce superior task performance on certain tasks (i.e., more veridical perception), thereby avoiding generalized deficit confounds while tapping mechanisms that are largely outside of conscious control. Using a task based on the Ebbinghaus illusion, a perceptual phenomenon where the perceived size of a central target object is affected by the size of surrounding inducers, we tested hypotheses related to visual integration in deaf (n = 31) and hearing (n = 34) patients with schizophrenia. In past studies, psychiatrically healthy samples displayed increased visual integration relative to schizophrenia samples and thus were less able to correctly judge target sizes. Deafness, and especially the use of sign language, leads to heightened sensitivity to peripheral visual cues and increased sensitivity to visual context. Therefore, relative to hearing subjects, deaf subjects were expected to display increased context sensitivity (ie, a more normal illusion effect as evidenced by a decreased ability to correctly judge central target sizes). Confirming the hypothesis, deaf signers were significantly more sensitive to the illusion than nonsigning hearing patients. Moreover, an earlier age of sign language acquisition, higher levels of linguistic ability, and shorter illness duration were significantly related to increased context sensitivity. As predicted, disorganization was associated with reduced context sensitivity for all subjects. The primary implications of these data are that perceptual organization impairment in schizophrenia is plastic and that it is related to a broader failure in coordinating cognitive activity. PMID- 21700592 TI - Pneumothorax associated with treatment for pulmonary malignancy. AB - Pneumothorax associated with treatment for pulmonary malignancy (PATPM) is a rare complication. Its clinicopathological features have not yet been clearly defined. Forty-one patients with PATPM from September 2002 to March 2009 were included. We evaluated the clinicopathological findings and treatment outcome of these patients. Of the 41 patients, 21 had primary lung cancer and 20 had metastatic lung tumours. Twenty-four patients (58.5%) required chest tube drainage for more than six days. Ten patients (24%) finally, received surgical treatment. Regarding the surgical procedure, conversion to open thoracotomy was required in seven (70%) of these 10 patients because of dense adhesions or anatomical changes in the thoracic cavity caused by treatment or the progression of the tumours. Two patients had severe complications after surgery. One of these two patients and another patient died of primary disease within 30 days after surgery. The median survival time in the 10 patients with surgery was 223 days (range 22-1059 days). PATPM tends to require chest tube drainage for a long period, and sometimes needs surgical treatment, which may be difficult. We should carefully identify patients who would derive considerable benefit from surgical treatment. PMID- 21700593 TI - Pericardial fat pad tissue produces angiogenic factors for healing the bronchial stump. AB - Maintaining blood flow in and supplying various anti-inflammatory or angiogenic cytokines to the bronchial stump are very important factors involved in its healing. Pericardial fat pad tissue samples surgically obtained from 20 patients were assessed, and their angiogenic ability was investigated. The messenger RNA level of all angiogenic cytokines, including vascular endothelial growth factor, fibroblast growth factor-2 (FGF-2), platelet-derived growth factor-A (PDGF-A), angiopoietin-1 (Ang-1), Ang-2 and hepatocyte growth factor (HGF) were detected in the pericardial fat pad tissue. The protein levels of all cytokines except PDGF-A increased with time from day one to day seven after primary culture of the pericardial fat pad tissue. In particular, both HGF and Ang-2 protein levels on day seven were significantly higher than those on day one (P=0.0475 and P=0.0417, respectively). On the other hand, the protein level of FGF-2 decreased in time and was significantly lower on day seven than on day one (P=0.0296). The present study demonstrated the angiogenic ability of the pericardial fat pad. These results suggest that reinforcement of the bronchial stump by the pericardial fat pad is a worthwhile and justified procedure, and may prevent bronchopleural fistula after pulmonary resections. PMID- 21700594 TI - Total cricoidectomy and laryngotracheal reconstruction for subglottic stenosis with glottic involvement. AB - We present a case of subglottic stenosis involving the glottis with inflammatory destruction of the cricoid cartilage after prolonged endotracheal intubation. Total cricoidectomy and laryngotracheal anastomosis were performed with T-tube placement that was retained for five months postoperatively. After decannulation of the T-tube, the airway was well restored, with good vocal cord opening. Good respiratory and phonatory results were obtained during normal daily activity, although a slightly hoarse voice was present, but no aspiration was observed. Total cricoidectomy and laryngotracheal reconstruction may be considered suitable for subglottic stenosis with glottic involvement, if accompanied by inflammatory destruction of the cricoid cartilage. PMID- 21700595 TI - Is there a place for video-associated thoracoscopy for dissecting intramural haematoma of the oesophagus? AB - Spontaneous haematoma of the oesophagus is a rare cause of chest pain. We report the case of a 63-year-old female in whom spontaneous rupture of the oesophagus was suspected, but who was subsequently, found to have a dissecting intramural haematoma of the oesophagus. She successfully underwent mediastinal and thoracic drainage by right video-assisted thoracoscopy. Although conservative treatment is widely described in the literature, surgical treatment by right video-associated thoracoscopy may be a suitable alternative if there is a diagnostic doubt. PMID- 21700596 TI - Comparing the outcome of on-pump versus off-pump coronary artery bypass grafting in patients with preoperative atrial fibrillation. AB - OBJECTIVES: Around 5-15% of patients undergoing coronary artery bypass grafting (CABG) suffer from preoperative/pre-existing atrial fibrillation (PAF). This is a benign arrhythmia but can affect the outcome of the surgery. The aim of this study was to assess the effect of PAF on the immediate postoperative course of patients undergoing on-pump (ONCAB) vs. off-pump (OPCAB) CABG. METHODS: Over a 10 year period, data were prospectively entered into the database of our institution. A total of 10,461 patients underwent CABG, of whom 477 (4.6%) were in PAF. We analyzed these patients in two separate groups: group A (n=310) who underwent ONCAB and group B (n=167) who underwent OPCAB. After 4:1 propensity matching and adjusting for the preoperative and operative characteristics of these two groups with patients in SR (sinus rhythm), early, mid- and long-term outcomes of PAF patients were analyzed. RESULTS: After adjusting for preoperative characteristics, postoperative complications were significantly higher in patients who had ONCAB when there was PAF compared to those in SR (P<0.001). In the OPCAB patients, on the other hand, there was no statistically significant difference in the postoperative complications between the patients with preoperative SR or PAF. In-hospital and short-term mortality were no different in the PAF group undergoing OPCAB compared to those in SR; however, the mid- and long-term survival rates in PAF patients who underwent OPCAB/ONCAB were worse compared than was seen in SR. CONCLUSIONS: PAF is associated with a higher incidence of postoperative complications. Our results have demonstrated that patients in PAF undergoing ONCAB are more susceptible to the postoperative complications compared to those in SR. However, there were no differences in mid- and long-term outcomes. PMID- 21700597 TI - Dangerous mediastinal basal pulmonary artery during left upper lobectomy. AB - Anatomical variations in the pulmonary vessels present a potential risk for intraoperative bleeding and damage to the pulmonary circulation during pulmonary resection. Here, we present a patient who underwent left upper lobectomy for lung cancer. The patient had a dangerous mediastinal basal pulmonary artery variation that could be mistaken for the mediastinal lingular pulmonary artery and be divided during left upper lobectomy. PMID- 21700598 TI - Percutaneous endoscopic transapical aortic valve implantation: three experimental transcatheter models. AB - We sought to demonstrate the feasibility of an endoscopic approach to transapical aortic valve implantation (AVI), avoiding the morbidity of a thoracotomy incision. Using an experimental pig model, we performed three different approaches to transapical AVI, using a standard minithoracotomy (n=4), a robotic approach using the da Vinci telemanipulator (n=4) and an endoscopic approach using a port and camera access (n=4). The feasibility of the different techniques, exposure of the left ventricular apex, postoperative blood loss and total operative time were evaluated. Left ventricular apical exposure, 'purse string' suture control and 33-F introducer access were successfully performed and confirmed videoscopically, fluoroscopically and at a post mortem in all 12 animals. The haemodynamics were stable in all animals. Mean intraoperative and postoperative (two-hour) blood losses were 88 and 65 ml with minithoracotomy, and 228 and 138 ml with the robotic and 130 and 43 ml with the endoscopic technique (P=0.26, P=0.14, respectively). There was no significant change in perioperative haematocrit (P=0.53). The mean total operative times were 1.4, 3.9 and 1.1 h (P=0.06), respectively. Percutaneous endoscopic and robotic transapical AVI are both feasible and can be performed in a timely manner with reasonable perioperative blood loss. Future research will focus on identifying optimal candidates for surgery based upon preoperative thoracic imaging. PMID- 21700599 TI - New cardiac surgery programs established from 1993 to 2004 led to little increased access, substantial duplication of services. AB - Despite decreasing demand for bypass surgery, 301 new cardiac surgery programs opened between 1993 and 2004. We used Medicare data to identify where the new programs opened and to assess their impact on access and efficiency. Forty-two percent of the new programs opened in communities that already had access to cardiac surgery, which suggests that their creation has led to a fight for shares of a shrinking market. New programs were much more likely to open in states that did not require them to show a certificate-of-need. Overall, travel time to the nearest cardiac surgery program changed little, which suggests that these programs have done little to improve geographic access. The duplication of services that resulted in many areas may have engendered competition based on quality, price, or both, but it may also have increased surgical rates, with unknown results. We observe that certificate-of-need requirements may help avoid unnecessary duplication of services by preventing new programs from opening in close proximity to existing ones. PMID- 21700600 TI - New forecasting methodology indicates more disease and earlier mortality ahead for today's younger Americans. AB - Traditional methods of projecting population health statistics, such as estimating future death rates, can give inaccurate results and lead to inferior or even poor policy decisions. A new "three-dimensional" method of forecasting vital health statistics is more accurate because it takes into account the delayed effects of the health risks being accumulated by today's younger generations. Applying this forecasting technique to the US obesity epidemic suggests that future death rates and health care expenditures could be far worse than currently anticipated. We suggest that public policy makers adopt this more robust forecasting tool and redouble efforts to develop and implement effective obesity-related prevention programs and interventions. PMID- 21700601 TI - Diagnosing tuberculosis with urine lipoarabinomannan: systematic review and meta analysis. AB - Lipoarabinomannan (LAM) is a potential marker of active tuberculosis (TB). We performed a systematic review and meta-analysis regarding use of urinary LAM assays for diagnosing active TB. We systematically searched for published and unpublished studies that evaluated urinary LAM for active TB diagnosis. Extracted data were pooled using bivariate random effects models and hierarchical summary receiver operating characteristic curves. Heterogeneity was explored through subgroup analysis and meta-regression. Quality was assessed according to standardised QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. In seven studies that assessed test accuracy in microbiologically confirmed cases only, estimates of sensitivity ranged from 13% to 93%, while specificity ranged from 87% to 99%. In five studies that assessed accuracy in clinical and confirmed TB cases, sensitivity ranged from 8% to 80%, while specificity ranged from 88% to 99%. In five studies with results stratified by HIV status, sensitivity was 3-53% higher in HIV-positive than HIV-negative subgroups; sensitivity was highest with advanced immunosuppression. The LAM urinary assay has several characteristics that make it attractive for diagnosing active TB, but has suboptimal sensitivity for routine clinical use. Further studies are needed to evaluate the potential value of the LAM assay in individuals with advanced HIV or for diagnosis of paediatric TB. PMID- 21700602 TI - Tiotropium improves walking endurance in COPD. AB - The primary objective of this study was to evaluate the effects of a 3-week treatment with tiotropium on walking capacity in chronic obstructive pulmonary disease (COPD). After familiarisation with study procedures, 36 patients were randomised to receive tiotropium 18 MUg once daily or a matching placebo in a double-blind, parallel-group study. Pre- (trough) and 2-h post-dose pulmonary function was measured. An endurance shuttle walk was then completed. The same procedures were repeated after 3 weeks of treatment. Ventilatory parameters were monitored during exercise. At 3 weeks, tiotropium significantly improved walking endurance time in comparison with placebo, with a mean+/-sd between-group difference of 128+/-141 s (p=0.017). At 3 weeks, trough values for forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC) were significantly improved with tiotropium in comparison with placebo. The post-dose response to tiotropium was statistically superior to placebo after the first dose and after 3 weeks of treatment for FEV(1), FVC and inspiratory capacity. Ventilation and tidal volume at the end of walking were significantly improved with tiotropium. 3 weeks of tiotropium resulted in a greater walking endurance in patients with COPD. Improvements in FEV(1), maximal ventilation and tidal volume may contribute to this enhanced exercise capacity. PMID- 21700603 TI - Aerobic exercise attenuates pulmonary injury induced by exposure to cigarette smoke. AB - It has recently been suggested that regular exercise reduces lung function decline and risk of chronic obstructive pulmonary disease (COPD) among active smokers; however, the mechanisms involved in this effect remain poorly understood. The present study evaluated the effects of regular exercise training in an experimental mouse model of chronic cigarette smoke exposure. Male C57BL/6 mice were divided into four groups (control, exercise, smoke and smoke+exercise). For 24 weeks, we measured respiratory mechanics, mean linear intercept, inflammatory cells and reactive oxygen species (ROS) in bronchoalveolar lavage (BAL) fluid, collagen deposition in alveolar walls, and the expression of antioxidant enzymes, matrix metalloproteinase 9, tissue inhibitor of metalloproteinase (TIMP)1, interleukin (IL)-10 and 8-isoprostane in alveolar walls. Exercise attenuated the decrease in pulmonary elastance (p<0.01) and the increase in mean linear intercept (p=0.003) induced by cigarette smoke exposure. Exercise substantially inhibited the increase in ROS in BAL fluid and 8 isoprostane expression in lung tissue induced by cigarette smoke. In addition, exercise significantly inhibited the decreases in IL-10, TIMP1 and CuZn superoxide dismutase induced by exposure to cigarette smoke. Exercise also increased the number of cells expressing glutathione peroxidase. Our results suggest that regular aerobic physical training of moderate intensity attenuates the development of pulmonary disease induced by cigarette smoke exposure. PMID- 21700604 TI - Preschool asthma after bronchiolitis in infancy. AB - Asthma risk is lower after wheezing associated with respiratory syncytial virus (RSV) than with non-RSV infection in infancy. RSV is the main wheezing-associated virus in infants aged <6 months. We evaluated the outcome of children hospitalised for bronchiolitis at <6 months of age, with special focus on viral aetiology and early risk factors. Out of 205 infants hospitalised for bronchiolitis at <6 months of age, 127 (62%) attended a control visit at a mean age of 6.5 yrs and the parents of an additional 39 children were interviewed by telephone. Thus, follow-up data collected by identical structured questionnaires were available from 166 (81%) children. Viral aetiology of bronchiolitis, studied on admission by antigen detection or PCR, was demonstrable in 97% of cases. Current asthma was present in 21 (12.7%) children: 8.2% in the 110 former RSV patients versus 24% in non-RSV patients (p=0.01). 45 (27%) children had ever had asthma. In adjusted analyses, atopic dermatitis, non-RSV bronchiolitis and maternal asthma were independently significant early-life risk factors for asthma. The risk of asthma was lower after RSV bronchiolitis than after bronchiolitis caused by other viruses in children hospitalised at <6 months of age. PMID- 21700605 TI - Circulating fibrocytes are increased in children and young adults with pulmonary hypertension. AB - Chronic inflammation is an important component of the fibroproliferative changes that characterise pulmonary hypertensive vasculopathy. Fibrocytes contribute to tissue remodelling in settings of chronic inflammation, including animal models of pulmonary hypertension (PH). We sought to determine whether circulating fibrocytes were increased in children and young adults with PH. 26 individuals with PH and 10 with normal cardiac anatomy were studied. Fresh blood was analysed by flow cytometry for fibrocytes expressing CD45 and procollagen. Fibrocyte numbers were correlated to clinical and haemodynamic parameters, and circulating CC chemokine ligand (CCL)2 and CXC chemokine ligand (CXCL)12 levels. We found an enrichment of circulating fibrocytes among those with PH. No differences in fibrocytes were observed among those with idiopathic versus secondary PH. Higher fibrocytes correlated to increasing mean pulmonary artery pressure and age, but not to length or type of treatment. Immunofluorescence analysis confirmed flow sorting specificity. Differences in plasma levels of CCL2 or CXCL12, which could mobilise fibrocytes from the bone marrow, were not found. We conclude that circulating fibrocytes are significantly increased in individuals with PH compared with controls. We speculate that these cells might play important roles in vascular remodelling in children and young adults with pulmonary hypertension. PMID- 21700606 TI - Unrecognised ventricular dysfunction in COPD. AB - While both chronic congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD) impose a substantial disease burden and share aetiological and epidemiological associations, they have largely been studied separately. The aim of our study was to assess the prevalence and the prognostic implications of the coexistence of left ventricular dysfunction in COPD patients and airway obstruction in CHF patients. We used a prospective cohort study including stable >= 60-yr-old patients with echocardiographically confirmed CHF (n=201) and stable >= 60-yr-old patients with clinically and spirometry-confirmed COPD (n=218). All CHF patients underwent routine spirometry, and all COPD patients underwent routine echocardiographic assessment and B-type natriuretic peptide (BNP) measurement. Patients were followed for 2 yrs. The prevalence of airway obstruction among CHF patients was 37.3% and the prevalence of ventricular dysfunction among COPD patients was 17%. The presence of ventricular dysfunction in patients with COPD tended to increase the risk of mortality during follow-up (hazard ratio 2.34, 95% CI 0.99-5.54; p=0.053). The presence of airway obstruction in patients with CHF did not influence survival. CHF and COPD frequently coexist, and ventricular dysfunction worsens survival in patients with COPD. Considering the high prevalence and the prognostic implications of ventricular dysfunction, routine assessment with either BNP or echocardiogram should be considered in COPD patients. PMID- 21700607 TI - Parent misperception of control in childhood/adolescent asthma: the Room to Breathe survey. AB - The aim of our study was to determine how often asthma control is achieved in children and adolescents, and how asthma affects parents' and children's daily lives. Interviews, including the childhood asthma control test (C-ACT), were conducted with 1,284 parents of asthmatic children (aged 4-15 yrs), as well as with the children themselves (aged 8-15 yrs; n=943), in Canada, Greece, Hungary, the Netherlands, South Africa and the UK. Parents reported mild asthma attacks at least weekly in 11% of children, and serious attacks (requiring oral corticosteroids or hospitalisation) at least annually in 35%. Although 73% of parents described their child's asthma as mild or intermittent, 40% of children/adolescents had C-ACT scores <= 19, indicating inadequate control, and only 14.7% achieved complete Global Initiative for Asthma (GINA)-defined control and just 9.2% achieved Scottish Intercollegiate Guidelines Network (SIGN)/British Thoracic Society (BTS)-defined control. Guideline-defined asthma control was significantly less common than well-controlled asthma using the C-ACT (p<0.001). Asthma restricted the child's activities in 39% of families and caused lifestyle changes in 70%. Complete asthma control is uncommon in children worldwide. Guideline-defined control measures appear to be more stringent than those defined by C-ACT or families. Overall, parents underestimate their child's asthma severity and overestimate asthma control. This is a major potential barrier to successful asthma treatment in children. PMID- 21700608 TI - Metalloproteinases in idiopathic pulmonary fibrosis. AB - In this article, we outline the current state of knowledge about the balance between collagen production and degradation in idiopathic pulmonary fibrosis (IPF). The dysregulated action of metalloproteinases implicated in IPF may play a central role in IPF pathogenesis. Inhibiting metalloproteinases in IPF may, therefore, have therapeutic potential, but our knowledge of their pathophysiological role is held back by limited animal models and the lack of specific inhibitors. PMID- 21700609 TI - Endobronchial ultrasound-guided lymph node biopsy with transbronchial needle forceps: a pilot study. AB - One limitation of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the size of the available needles, frequently yielding only cells for cytological examination. The aim of this pilot study was to evaluate the efficacy and safety of newly developed needle forceps to obtain tissue for the histological diagnosis of enlarged mediastinal lymph nodes. Patients with enlarged, positron emission tomography (PET)-positive lymph nodes were included. The transbronchial needle forceps (TBNF), a sampling instrument combining the characteristics of a needle (bevelled tip for penetrating through the bronchial wall) with forceps (two serrated jaws for grasping tissue) was used through the working channel of the EBUS-TBNA scope. Efficacy and safety was assessed. 50 patients (36 males and 14 females; mean age 51 yrs) with enlarged or PET-positive lymph nodes were included in this pilot study. In 48 (96%) patients penetration of the bronchial wall was possible and in 45 patients tissue for histological diagnosis was obtained. In three patients TBNF provided inadequate material. For patients in whom the material was adequate for a histological examination, a specific diagnosis was established in 43 (86%) out of 50 patients (nonsmall cell lung cancer: n=24; small cell lung cancer: n=7; sarcoidosis: n=4; Hodgkin's lymphoma: n=4; tuberculosis: n=2; and non-Hodgkin's lymphoma: n=2).No clinically significant procedure-related complications were encountered. This study demonstrated that EBUS-TBNF is a safe procedure and provides diagnostic histological specimens of mediastinal lymph nodes. PMID- 21700610 TI - Exhaled air molecular profiling in relation to inflammatory subtype and activity in COPD. AB - Eosinophilic inflammation in chronic obstructive pulmonary disease (COPD) is predictive for responses to inhaled steroids. We hypothesised that the inflammatory subtype in mild and moderate COPD can be assessed by exhaled breath metabolomics. Exhaled compounds were analysed using gas chromatography and mass spectrometry (GC-MS) and electronic nose (eNose) in 28 COPD patients (12/16 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I/II, respectively). Differential cell counts, eosinophil cationic protein (ECP) and myeloperoxidase (MPO) were measured in induced sputum. Relationships between exhaled compounds, eNose breathprints and sputum inflammatory markers were analysed and receiver operating characteristic (ROC) curves were constructed. Exhaled compounds were highly associated with sputum cell counts (eight compounds with eosinophils, 17 with neutrophils; p < 0.01). Only one compound (alkylated benzene) overlapped between eosinophilic and neutrophilic profiles. GC-MS and eNose breathprints were associated with markers of inflammatory activity in GOLD stage I (ECP: 19 compounds, p < 0.01; eNose breathprint r = 0.84, p = 0.002) (MPO: four compounds, p < 0.01; eNose r = 0.72, p = 0.008). ROC analysis for eNose showed high sensitivity and specificity for inflammatory activity in mild COPD (ECP: area under the curve (AUC) 1.00; MPO: AUC 0.96) but not for moderate COPD. Exhaled molecular profiles are closely associated with the type of inflammatory cell and their activation status in mild and moderate COPD. This suggests that breath analysis may be used for assessment and monitoring of airway inflammation in COPD. PMID- 21700611 TI - Supplementation with vitamin A early in life and subsequent risk of asthma. AB - Animal models suggest that vitamin A deficiency affects lung development adversely and promotes airway hyperresponsiveness, and may predispose to an increased risk of asthma. We examined the long-term effects of vitamin A supplementation early in life on later asthma risk. In 2006-2008, we revisited participants from two cohorts in rural Nepal who were enrolled in randomised trials of vitamin A supplementation. The first cohort received vitamin A or placebo for <16 months during their pre-school years (1989-1991). The second cohort was born to mothers who received vitamin A, beta-carotene or placebo before, during and after pregnancy (1994-1997). At follow-up, we asked about asthma symptoms and performed spirometry. Out of 6,421 subjects eligible to participate, 5,430 (85%) responded to our respiratory survey. Wheezing prevalence during the previous year was 4.8% in participants aged 9-13 yrs and 6.6% in participants aged 14-23 yrs. We found no differences between the vitamin A supplemented and placebo groups from either trial in the prevalence of lifetime or current asthma and wheeze or in spirometric indices of obstruction (p >= 0.12 for all comparisons). Vitamin A supplementation early in life was not associated with a decreased risk of asthma in an area with chronic vitamin A deficiency. PMID- 21700612 TI - Non-invasive measurement of pulse pressure variation and systolic pressure variation using a finger cuff corresponds with intra-arterial measurement. AB - BACKGROUND: Pulse pressure variation (PPV) and systolic pressure variation (SPV) are reliable predictors of fluid responsiveness in patients undergoing controlled mechanical ventilation. Currently, PPV and SPV are measured invasively and it is unknown if an arterial pressure (AP) signal obtained with a finger cuff can be used as an alternative. The aim of this study was to validate PPV and SPV measured using a finger cuff. METHODS: Patients receiving mechanical ventilation under sedation after cardiac artery bypass graft (CABG) surgery were included after arrival on the intensive care unit. AP was measured invasively in the radial artery and non-invasively using the finger cuff of the NexfinTM monitor. I.V. fluid challenges were administered according to clinical need. The mean value of PPV and SVV was calculated before and after administration of a fluid challenge. Agreement of the calculated PPV and SPV from both methods was assessed using the Bland-Altman analysis. RESULTS: Nineteen patients were included and 28 volume challenges were analysed. Correlation between the two methods for PPV and SPV [mean (sd)=6.9 (4.3)% and 5.3 (2.6)%, respectively] was r=0.96 (P<0.0001) and r=0.95 (P<0.0001), respectively. The mean bias was -0.95% for PPV and -0.22% for SPV. Limits of agreement were -4.3% and 2.4% for PPV and -2.2% and 1.7% for SPV. The correlation between changes in PPV and SPV as a result of volume expansion measured by the two different methods was r=0.88 (P<0.0001) and r=0.87 (P<0.0001), respectively. CONCLUSIONS: In patients receiving controlled mechanical ventilation after CABG, PPV and SPV can be measured reliably non invasively using the inflatable finger cuff of the NexfinTM monitor. PMID- 21700613 TI - Dependence of the gradient between arterial and end-tidal P(CO(2)) on the fraction of inspired oxygen. AB - BACKGROUND: End-tidal P(CO(2)) (Pe'(CO(2))) is routinely used in the clinical assessment of the adequacy of ventilation because it provides an estimate of Pa(CO(2)). How well Pe'(CO(2)) reflects Pa(CO(2)) depends on the gradient between them, expressed as DeltaPa-e'(CO(2)). The major determinant of DeltaPa-e'(CO(2)) is alveolar dead space (Vd(alv)). The fraction of inspired O(2) (Fi(O(2))) is not thought to substantially affect DeltaPa-e'(CO(2)) in anaesthetized patients. We hypothesized that a high Fi(O(2)) may indeed increase DeltaPa-e'(CO(2)) by preferentially vasodilating well-perfused alveoli, resulting in the redistribution of blood flow to these alveoli from poorly perfused alveoli and an increase in Vd(alv). We therefore investigated the effects of changes in Fi(O(2)) on DeltaPa-e'(CO(2)) and Vd(alv). METHODS: With Institutional Review Board approval and informed consent, we studied 20 ASA I-II supine patients undergoing elective lower abdominal surgery under combined general and epidural anaesthesia. At constant levels of ventilation, Fi(O(2)) levels of 0.21, 0.33, 0.5, 0.75, and 0.97 were applied in a random order and DeltaPa-e'(CO(2)) and Vd(alv) were calculated. RESULTS: The DeltaPa-e'(CO(2)) values were, in order of ascending Fi(O(2)), {mean [standard error of the mean (SEM)]} 0.13 (0.04), 0.28 (0.08), 0.29 (0.09), 0.44 (0.11), and 0.53 (0.09) kPa. The corresponding values of Vd(alv) were 25.5, 33.8, 35.8, 48.9, and 47.4 ml. Each successive hyperoxic level showed a significant increase in DeltaPa-e'(CO(2)) except between the 0.33-0.5 and 0.75-0.97 Fi(O(2)) levels. CONCLUSIONS: These data demonstrate that DeltaPa e'(CO(2)), in anaesthetized patients depends on Fi(O(2)). PMID- 21700614 TI - Bibliometric analysis of anaesthesia journal editorial board members: correlation between journal impact factor and the median h-index of its board members. AB - BACKGROUND: h-index is useful for quantifying scholarly activity in medicine, but this statistic has not been extensively applied as a measure of productivity in anaesthesia. We conducted a bibliometric analysis of h-index in editorial board members and tested the hypothesis that editorial board members of anaesthesia journals with higher impact factors (IFs) have higher h-indices. METHODS: Ten of 19 journals with 2009 IF>1 were randomly chosen from Journal Citation Reports((r)). Board members were identified using each journal's website. Publications, citations, citations per publication, and h-index for each member were obtained using Scopus((r)). RESULTS: Four hundred and twenty-three individuals filled 481 anaesthesia editorial board positions. The median h-index of all editorial board members was 14. Board members published 75 papers (median) with 1006 citations and 13 citations per publication. Members serving on journals with IF greater than median had significantly (P<0.05; Wilcoxon's rank-sum test) greater median h-index, citations, and citations per publication than those at journals with IF less than median. A significant correlation between the median h index of a journal's editorial board members and its IF (h-index=3.01*IF+6.85; r( 2)=0.452; P=0.033) was observed for the 10 journals examined. Board members of subspeciality-specific journals had bibliometric indices that were less than those at general journals. The h-index was greater in individuals serving more than one journal. European editorial board members had higher h-index values than their American colleagues. CONCLUSIONS: The results suggest that editorial board members of anaesthesia journals with higher IFs have higher h-indices. PMID- 21700618 TI - Genome-wide association study identifies novel alleles associated with risk of cutaneous basal cell carcinoma and squamous cell carcinoma. AB - We conducted a genome-wide association study on cutaneous basal cell carcinoma (BCC) among 2045 cases and 6013 controls of European ancestry, with follow-up replication in 1426 cases and 4845 controls. A non-synonymous SNP in the MC1R gene (rs1805007 encoding Arg151Cys substitution), a previously well-documented pigmentation gene, showed the strongest association with BCC risk in the discovery set (rs1805007[T]: OR (95% CI) for combined discovery set and replication set [1.55 (1.45-1.66); P= 4.3 * 10(-17)]. We identified that an SNP rs12210050 at 6p25 near the EXOC2 gene was associated with an increased risk of BCC [rs12210050[T]: combined OR (95% CI), 1.24 (1.17-1.31); P= 9.9 * 10(-10)]. In the locus on 13q32 near the UBAC2 gene encoding ubiquitin-associated domain containing protein 2, we also identified a variant conferring susceptibility to BCC [rs7335046 [G]; combined OR (95% CI), 1.26 (1.18-1.34); P= 2.9 * 10(-8)]. We further evaluated the associations of these two novel SNPs (rs12210050 and rs7335046) with squamous cell carcinoma (SCC) risk as well as melanoma risk. We found that both variants, rs12210050[T] [OR (95% CI), 1.35 (1.16-1.57); P= 7.6 * 10(-5)] and rs7335046 [G] [OR (95% CI), 1.21 (1.02-1.44); P= 0.03], were associated with an increased risk of SCC. These two variants were not associated with melanoma risk. We conclude that 6p25 and 13q32 are novel loci conferring susceptibility to non-melanoma skin cancer. PMID- 21700619 TI - Prolonged impairment in inhibition and semantic fluency in a follow-up study of recurrent major depression. AB - Several studies have demonstrated impaired performance in inhibition and semantic fluency in the acute phase of illness in patients with recurrent major depression. However, few studies have investigated these functions longitudinally, focusing on how these impairments relate to symptoms over time. The present longitudinal study investigated whether the specific impairment in inhibition and semantic fluency seen in the acute phase of Major Depressive Disorder (MDD) was prolonged or normalized with symptom reduction in a 9-month follow-up. Twenty recurrent major depressive patients and 19 control subjects were included in the study. Inhibition and semantic fluency were investigated using tests from the Delis-Kaplan Executive Function System. The results show that the patient group still had significantly lower scores in inhibition and semantic fluency compared with the control group despite significant symptom reduction. Further, the results show that impaired inhibition in the acute phase was strongly correlated with impaired inhibition in the follow-up, suggesting that the inability to inhibit may represent a trait marker in recurrent MDD. PMID- 21700621 TI - Complex sample data recommendations and troubleshooting. AB - Complex survey data, as highlighted in this issue of Evaluation Review, provide a wealth of opportunities for answering methodological and/or applied research questions. However, the analytic issues of nonindependence and unequal selection probability must be addressed when analyzing this type of data. Thus, to ensure that research questions are accurately answered when using complex survey data, researchers must take extra precautions to ensure complex survey data are correctly analyzed. The purpose of this article is to provide software recommendations for analysis of and tips on troubleshooting when analyzing complex sample data. PMID- 21700620 TI - Autoimmune alternating hypo- and hyperthyroidism in children. AB - Two children presented with autoimmune alternating hypo- and hyperthyroidism related to the presence of blocking and stimulating thyroid antibodies. It was difficult to control their thyroid function adequately with an appropriate single drug regimen, and both children underwent total thyroidectomy with subsequent stable management with levothyroxine replacement therapy postsurgically. Although this phenomenon is well described in adults, this report is the first of such occurrence in children. The possible mechanism for the variation in the type of clinical presentation and options for management are discussed. PMID- 21700622 TI - Evaluation of antifungal therapy in patients with candidaemia based on susceptibility testing results: implications for antimicrobial stewardship programmes. AB - BACKGROUND: Definitive antifungal therapy is typically based on Candida species and clinical status, rather than susceptibility reports. Antifungal susceptibility testing is available, but the impact on treatment decisions is unknown. The purpose of this study was to assess antifungal therapy in hospitalized patients with candidaemia during the time period between the start of empirical therapy and after antifungal susceptibility testing reports are available. METHODS: A retrospective study of 161 hospitalized patients with candidaemia was conducted. Patients who received fluconazole or an echinocandin were evaluated for changes in empirical antifungal therapy prior to and after susceptibility reporting. RESULTS: One hundred and sixty-one patients aged 59 +/- 16 years (male, 54%; Caucasian, 52%; APACHE II score >= 15, 48%; and intensive care unit, 50%) were identified, of whom 130 (81%) had fluconazole-susceptible candidaemia. Fifty-eight patients (36%) were initiated on fluconazole and 103 (64%) on an echinocandin. The mean time from culture to the susceptibility report was 5 +/- 2 days. Prior to availability of the susceptibility report, 20 fluconazole-initiated patients (34%) were switched to an echinocandin, while 14 echinocandin-initiated patients (14%) were switched to fluconazole. Once a susceptibility report was available, 35 of 89 (39%) patients with fluconazole susceptible candidaemia on an echinocandin were de-escalated to fluconazole. Eleven patients on fluconazole just prior to a susceptibility report were identified with a fluconazole-resistant Candida species. CONCLUSIONS: Using antifungal susceptibility testing, patients given fluconazole with fluconazole resistant Candida species were identified. Less than 40% of echinocandin-treated patients with fluconazole-susceptible organisms were de-escalated to fluconazole. Antifungal susceptibility testing may help to identify patients in need of clinical intervention. PMID- 21700623 TI - Oseltamivir pharmacokinetics in morbid obesity (OPTIMO trial). AB - BACKGROUND: Detailed pharmacokinetics to guide oseltamivir (Tamiflu(r)) dosing in morbidly obese patients is lacking. METHODS: The OPTIMO trial was a single centre, non-randomized, open-label pharmacokinetic study of single-dose and steady-state oral oseltamivir phosphate and its carboxylate metabolite in healthy, morbidly obese [body mass index (BMI) > 40)] and healthy, non-obese (BMI < 30) subjects. RESULTS: In the morbidly obese versus control subjects, respectively, the single-dose median oseltamivir oral clearance (CL/F) [840 (range 720-1640) L/h versus 580 (470-1800) L/h] was higher, the area under the curve from time zero to infinity (AUC(0-infinity)) [89 (46-104) ng.h/mL versus 132 (42-160) ng.h/mL] was lower and the volume of distribution (V/F) [2320 (900 8210) L versus 1670 (700-7290) L] was unchanged. In the morbidly obese versus control subjects, respectively, the single-dose median oseltamivir carboxylate CL/F [22 (17-40) L/h versus 23 (12-33) L/h], AUC(0-infinity) [3100 (1700-4100) ng.h/mL versus 3000 (2100-5900) ng.h/mL] and V/F [200 (130-370) L versus 260 (150 430) L] were similar. Similar results for oseltamivir and oseltamivir carboxylate CL/F, AUC0-12 and V/F values were observed in the multiple-dose study. CONCLUSIONS: With single and multiple dosing, the systemic exposure to oseltamivir is decreased but that of oseltamivir carboxylate is largely unchanged. Based on these pharmacokinetic data, an oseltamivir dose adjustment for body weight would not be needed in morbidly obese individuals. PMID- 21700624 TI - Ciprofloxacin use and susceptibility of Gram-negative organisms to quinolone and non-quinolone antibiotics. AB - OBJECTIVES: A Trust strategy to reduce ciprofloxacin use was implemented at a University hospital. This study aimed to investigate whether the susceptibility of Gram-negative organisms (GNO) to alternative antimicrobials (co-amoxiclav, doxycycline, aztreonam, piperacillin/tazobactam, meropenem and gentamicin) changed, and whether there was any relationship between GNO susceptibility to these antimicrobials and ciprofloxacin usage. METHODS: The first isolate of each GNO from blood cultures, sputum and urine of hospitalized adults, between January 2008 and August 2009, was included. Antibiotic usage and GNO susceptibility were investigated using linear regression. The association between defined daily dose/1000 occupied bed days (DDD/1000 OBD) and susceptibility was assessed using Pearson correlation and linear regression. RESULTS: Ciprofloxacin use decreased significantly by 4.37 DDD/1000 OBD per month [95% confidence interval (CI) 2.99, 5.75; P < 0.001], while aztreonam and gentamicin use increased significantly (aztreonam: 0.22 DDD/1000 OBD increase per month; 95% CI 0.10, 0.34; P = 0.001; gentamicin: 0.46 DDD/1000 OBD increase per month; 95% CI 0.12, 0.79; P = 0.01). There was no change in meropenem, co-amoxiclav, doxycycline or piperacillin/tazobactam use. When DDD/1000 OBD for all non-quinolone antimicrobials were pooled, use increased significantly by 3.33 DDD/1000 OBD per month (95% CI 0.79, 5.87; P = 0.013). There were 5410 GNO isolates. A significant increase was recorded in the proportion of GNO susceptible to ciprofloxacin (0.55% increase in susceptibility per month; 95% CI 0.38, 0.72; P < 0.001), aztreonam (1.87% susceptibility increase per month; 95% CI 1.18, 2.55; P < 0.001), piperacillin/tazobactam (0.18% susceptibility increase per month; 95% CI 0.03, 0.33; P = 0.021), meropenem (0.27% susceptibility increase per month; 95% CI 0.08, 0.47; P = 0.009) and gentamicin (0.17% susceptibility increase per month; 95% CI 0.04, 0.29; P = 0.011). An inverse association between ciprofloxacin use and susceptibility to ciprofloxacin (P < 0.001), piperacillin/tazobactam (P = 0.12), aztreonam (P= 0.002), meropenem (P = 0.015) and gentamicin (P = 0.034) is suggested. CONCLUSIONS: These data demonstrate reduced ciprofloxacin usage and concomitant increasing GNO susceptibility to beta lactams. While definitive evidence of a causal relationship is beyond the capability of a single-centre study, the results suggest that reducing quinolone exposure may exert a favourable effect on the quinolone, beta-lactam and gentamicin susceptibility of GNO. PMID- 21700625 TI - Effective antibacterials: at what cost? The economics of antibacterial resistance and its control. AB - The original and successful business model of return on investment being sufficiently attractive to the pharmaceutical industry to encourage development of new antibacterial molecules and related diagnostics has been compromised by increasing development costs and regulatory hurdles, resulting in a decreasing chance of success and financial return. The supply of new effective agents is diminishing along with the number of companies engaged in antibacterial research and development. The BSAC Working Party on The Urgent Need:Regenerating Antibacterial Drug Discovery and Development identified the need to establish, communicate and apply the true health and economic value of antibacterials, along with the adoption of meaningful incentives, as part of the future model for antibacterial development. Robust data are needed on the cost of resistance and ineffective treatment of bacterial infection, along with national and local holistic analyses of the cost-benefit of antibacterials. An understanding of the true health and economic value of antibacterials and the cost of resistance across healthcare systems needs to be generated, communicated and used in order to set a pricing and reimbursement structure that is commensurate with value. The development and economic model of antibacterial use needs to be rebuilt based on this value through dialogue with the various stakeholders, including the pharmaceutical industry, and alternative incentives from 'push' to 'pull' and funding models, such as public/private partnerships, agreed. A research and development model that succeeds in developing and delivering new antibacterial agents that address the health needs of society from start to finish, 'from cradle to grave', must be established. PMID- 21700627 TI - The urgent need for new antibacterial agents. PMID- 21700626 TI - Discovery research: the scientific challenge of finding new antibiotics. AB - The dwindling supply of new antibiotics largely reflects regulatory and commercial challenges, but also a failure of discovery. In the 1990s the pharmaceutical industry abandoned its classical ways of seeking antibiotics and instead adopted a strategy that combined genomics with high-throughput screening of existing compound libraries. Too much emphasis was placed on identifying targets and molecules that bound to them, and too little emphasis was placed on the ability of these molecules to permeate bacteria, evade efflux and avoid mutational resistance; moreover, the compound libraries were systematically biased against antibiotics. The sorry result is that no antibiotic found by this strategy has yet entered clinical use and many major pharmaceutical companies have abandoned antibiotic discovery. Although a raft of start-up companies variously financed by venture capital, charity or public money--are now finding new antibiotic compounds (some of them very promising in vitro or in early trials), their development through Phase III depends on financial commitments from large pharmaceutical companies, where the discouraging regulatory environment and the poor likely return on investment remain paramount issues. PMID- 21700628 TI - Efflux inhibition by selective serotonin reuptake inhibitors in Escherichia coli. AB - OBJECTIVES: To evaluate the antimicrobial and synergistic (hypothetically due to the inhibition of efflux pumps) effects of selective serotonin reuptake inhibitors (SSRIs) in Escherichia coli strains overproducing various resistance nodulation-division (RND) efflux pumps. METHODS: MICs of various SSRIs and of clinically relevant antibiotics in the presence and absence of sertraline were determined for E. coli strains overproducing the RND efflux pumps AcrAB, AcrEF, MdtEF and MexAB. The effect of sertraline on Nile red efflux was evaluated in a real-time efflux assay. Expression of marA and acrB was monitored using quantitative RT-PCR. RESULTS: In MIC assays there was limited synergy of sertraline with tetracycline, oxacillin, linezolid and clarithromycin, depending on the individual pump overexpressed and on whether rich or minimal medium was used. Sertraline, as the most potent SSRI with regard to bacterial growth inhibition, led to rapid dose-dependent Nile red efflux inhibition, and was also found to increase the expression of marA and acrB. CONCLUSIONS: A possible explanation for the discrepancy between the MIC and real-time efflux assays was that sertraline is a weak inducer of marA and acrB, thereby reducing its initial antibacterial and sensitizing effects over time. The results indicate that sertraline may be useful as a model efflux pump inhibitor for in vitro short-term experiments in E. coli, but is unlikely to be clinically useful as a co-drug against Gram-negative bacteria. PMID- 21700629 TI - Regulatory opportunities to encourage technology solutions to antibacterial drug resistance. AB - Regulatory agencies play a critical role in the licensing of new antimicrobial agents. To address the pivotal role played by regulatory agencies, particularly in the context of a paucity of new drugs active against bacteria resistant to currently available drugs, the BSAC formed the 'Urgent Need' Working Party to address the regeneration of antibacterial drug discovery and development. The Working Party identified a number of issues, including: increased application of pharmacokinetic/pharmacodynamic principles to expedite drug development; the need to prioritize licensing of drugs (including 'orphan' drugs) active in life threatening infections; and expansion of the use of surrogate markers and rapid point of care diagnostics to facilitate drug development. PMID- 21700630 TI - Single and dual mutations at positions 2058, 2503 and 2504 of 23S rRNA and their relationship to resistance to antibiotics that target the large ribosomal subunit. AB - OBJECTIVES: To study mutations at positions A2058, A2503 and U2504 (Escherichia coli numbering) of 23S rRNA and their relationship to resistance to antibiotics that target the large ribosomal subunit. METHODS: Single and dual mutations at positions 2058, 2503 and 2504 of 23S rRNA were introduced into a Mycobacterium smegmatis strain with a single functional rRNA operon. MICs of macrolide, pleuromutilin, phenicol, lincosamide and oxazolidinone antibiotics were determined for the engineered mutants. The doubling times of the mutant strains were measured to investigate how the introduced mutations affected growth rate. RESULTS: Single mutations A2058G, A2503U and U2504G and double mutations A2058G A2503U and A2058G-U2504G were successfully introduced. The A2058G mutation resulted in various levels of resistance to macrolides and clindamycin. The A2503U and U2504G mutations conferred resistance to valnemulin, chloramphenicol, florfenicol and linezolid. In addition, the A2503U mutant showed reduced susceptibility to the 16-membered macrolides tylosin, spiramycin and josamycin, and the U2504G mutant exhibited decreased susceptibility to spiramycin and josamycin. Moreover, the dual mutations A2058G-A2503U and A2058G-U2504G had co effects on resistance to 16-membered macrolides. CONCLUSIONS: 23S rRNA mutations A2058G, A2503U and U2504G play key roles in resistance to clinically useful antibiotics that target the large ribosomal subunit. Furthermore, the double mutations A2058G-A2503U and A2058G-U2504G have combined effects on resistance to 16-membered macrolides. PMID- 21700631 TI - Expression of MUC1 and MUC2 in ampullary cancer. AB - BACKGROUND: Mucins are high-molecular-weight glycoproteins that play important roles in carcinogenesis or tumor invasion. The authors investigated the expression of mucins in ampullary cancer. METHODS: MUC1 and MUC2 expressions were examined using immunohistochemistry. Tissue samples were obtained from 32 patients with ampullary cancer who underwent resection at Yamagata University Hospital, Japan. The authors classified the cases with ampullary cancer into 2 subtypes--pancreatobiliary type (PB type) and intestinal type (I type)--using H&E, MUC1, and MUC2 staining. Then, the authors made a comparison of the clinicopathologic data of the 2 subtypes. RESULTS: Fourteen patients (44%) were classified as PB type and 18 patients (56%) as I type. The PB-type group had significantly worse histopathologic characteristics than the I-type group in nodal involvement (PB type 57% vs I type 22%; P = .04), perineural invasion (PB type 50% vs I type 17%; P = .04), duodenal invasion (PB type 100% vs I type 33%; P = .01), and pancreatic invasion (PB type 71% vs I type 33%; P = .03). The PB type group had significantly worse outcome than the I-type group (5-year survival: PB type 40% vs I type 72%; P = .03). CONCLUSION: PB-type ampullary cancers were more aggressive than I-type carcinomas. MUC1 and MUC2 expression was useful for classification as PB or I type. PMID- 21700632 TI - Freshwater ascomycetes: two new species of Lindgomyces (Lindgomycetaceae, Pleosporales, Dothideomycetes) from Japan and USA. AB - During independent surveys of freshwater ascomycetes in Japan and USA two new species of Lindgomyces were collected from submerged wood in freshwater. These species are described and illustrated based on morphological data and phylogenetic relationships based on analyses of nuclear ribosomal sequence data (partial SSU and LSU, and ITS). Lindgomyces apiculatus, collected in Japan, is characterized by immersed to erumpent, globose to subglobose ascomata; fissitunicate, cylindrical to clavate asci; and fusiform, one-septate ascospores with acute ends and short terminal appendages. Lindgomyces lemonweirensis, collected in Wisconsin, USA, differs from L. apiculatus in having clavate to cymbiform asci and oblong to fusiform ascospores that are distinctively multiguttulate and surrounded by an oval, ephemeral gelatinous sheath. The new species formed a strongly supported clade within the family Lindgomycetaceae (Pleosporales, Dothideomycetes) based on analyses of combined SSU and LSU sequence data. In addition phylogenetic analyses with ITS sequence data support the establishment of the new taxa as separate species within Lindgomyces because they were separated from each other and other Lindgomyces species based on maximum likelihood bootstrap and Bayesian analyses. PMID- 21700633 TI - ITS-1 versus ITS-2 pyrosequencing: a comparison of fungal populations in truffle grounds. AB - In a recent study pyrosequencing of the ribosomal internal transcribed spacer-1 (ITS-1) has validated the effectiveness of such technology in the survey of soil fungal diversity. Here we compare the two ITS regions, ITS-1 and ITS-2, of the fungal populations occurring in Tuber melanosporum/Quercus pubescens truffle grounds and sampled in two areas, one devoid of vegetation ("burned", brule in French) where T. melanosporum fruiting bodies are usually collected, and outside the brule. TS1F/ITS2 and ITS3/ITS4 were used respectively for the amplification of the ITS-1 and ITS-2 regions. Two amplicon libraries were built, one for inside and the other for outside. A set of 15.788 reads was obtained. After the removal of low quality sequences, 3568 and 3156 sequences were obtained from inside the brule with the ITS-1 and ITS-2 primers respectively. The sequences obtained from outside the brule were 4490 with the ITS-1 primers and 2432 with the ITS-2 primers. Most of the sequences obtained for both ITS fragments could be attributed to fungal organisms. The pair of primers, ITS1-F/ITS2, was more selective, producing fewer non-fungal sequences (1% inside, 3% outside), in addition to a higher number of sequences, than the pair ITS3/ITS4 (6% inside, 11% outside). Although differences are present in the taxa percentages between ITS-1 and ITS-2, both reveal that Ascomycota were the dominant fungal phylum and that their number decreased moving from inside the brule to outside, while the number of Basidiomycota increased. Taken together, both the short ITS-1 and ITS-2 reads obtained by the high throughput 454 sequencing provide adequate information for taxon assignment and are suitable to correlate the dynamics of the fungal populations to specific environments. PMID- 21700634 TI - Agaricales of the Hawaiian Islands 9. Five new white-spored species from native montane wet forests. AB - Five new species of white-spored agarics are described from native montane wet forests in the Hawaiian Islands as follows: Callistosporium vinosobrunneum, Marasmiellus hapuuarum, Marasmius koae, Mycena marasmielloides, Pleurocybella ohiae. Comprehensive descriptions, illustrations and comparisons with phenetically similar species are provided. An itemization of the 24 known putatively endemic agarics described from this unique habitat is provided. PMID- 21700635 TI - Linking mycorrhizas to sporocarps: a new species, Geopora cercocarpi, on Cercocarpus ledifolius (Rosaceae). AB - Mycorrhizal assemblages characterized by molecular data frequently differ from collections of mycorrhizal sporocarps at the same site. Geopora species are frequent mycobionts of ectomycorrhizal roots, but except for G. cooperi they are rarely identified to species by molecular methods. Among the mycobionts of ectomycorrhizas with Cercocarpus ledifolius (Rosaceae) was a fungal species with a 91% BLAST match to G. arenicola. To determine the species of Geopora we surveyed for hypogeous sporocarps under C. ledifolius at sites in southern Oregon where the Geopora mycorrhizas had been collected and identified by DNA sequences of the ITS region. We found sporocarps of a Geopora species with 100% BLAST match to the mycorrhizas. Morphological characters of a white hymenium, inrolled entire margin and large spores, along with a hypogeous habit and a mycorrhizal host of C. ledifolius, distinguished these specimens from previously described species. Here we describe a new species, Geopora cercocarpi. PMID- 21700636 TI - New species from the Fusarium solani species complex derived from perithecia and soil in the old World tropics. AB - A large collection of strains belonging to the Fusarium solani species complex (FSSC) was isolated from soil and perithecia in primary forests in Sri Lanka (from fallen tree bark) and tropical Australia (Queensland, from fallen tree fruits and nuts). Portions of the translation elongation factor 1-alpha (tef1) gene, the nuclear large subunit (NLSU) and internal transcribed spacer regions (ITS) of the nuclear ribosomal RNA genes were sequenced in 52 isolates from soil and perithecia. The FSSC was divided previously into three clades with some biogeographic structure, termed Clades 1, 2 and 3. All Sri Lankan and Australian soil isolates were found to be members of Clade 3, most grouping with the cosmopolitan soil-associated species F. falciforme. All but two Sri Lankan perithecial isolates were associated with a set of five divergent phylogenetic lineages that were associated with Clade 2. Australian perithecial isolates resided in a subclade of Clade 3 where most of the previously defined mating populations of the FSSC reside. Isolates from perithecia and those cultured from soil were always members of different species lineages, even when derived from proximal locations. The previous biogeographic assignment of Clade 2 to South America is now expanded to the worldwide tropics. Sri Lanka appears to be an important center of diversity for the FSSC. Nectria haematococca is epitypified with a collection from the type locality in Sri Lanka; its anamorph is described as a new species, Fusarium haematococcum. Neocosmospora E.F. Smith is adopted as the correct genus for Nectria haematococca. These new species are described: F. kurunegalense/Neo. kurunegalensis, F. rectiphorus/Neo. rectiphora/, F. mahasenii/Neo. mahasenii/, F. kelerajum/Neo. keleraja. PMID- 21700637 TI - 95% of basidiospores fall within 1 m of the cap: a field-and modeling-based study. AB - Plant establishment patterns suggest that ectomycorrhizal fungal (EMF) inoculant is not found ubiquitously. The role of animal vectors dispersing viable EMF spores is well documented. Here we investigate the role of wind in basidiospore dispersal for six EMF species, Inocybe lacera, Laccaria laccata, Lactarius rufus, Suillus brevipes, Suillus tomentosus and Thelephora americana. Basidiospores adhered to microscope slides placed on three 60 cm transects radiating from sporocarps. Morphological characteristics of species as well as average basidiospore volume were recorded. Number of basidiospores was quantified at specific distances to produce actual dispersal gradients. We found a negative exponential decay model using characteristics for each species fit the field data well. The 95% modeled downwind dispersal distance of basidiospores was calculated for each species. The 95% modeled downwind dispersal distance increased with increasing cap height and decreasing basidiospore volume for the species sampled, with 95% of basidiospores predicted to fall within 58 cm of the cap. Differences in anatomical characteristics of EMF species influence how far basidiospores are dispersed by wind. We discuss the role of wind dispersal leading to patterns of EMF establishment during primary succession. PMID- 21700638 TI - Neonothopanus gardneri: a new combination for a bioluminescent agaric from Brazil. AB - The bioluminescent agaric, Agaricus gardneri Berk., was rediscovered recently in central Brazil. The new combination, Neonothopanus gardneri, is proposed for this long-forgotten taxon supported by morphological and molecular data. PMID- 21700639 TI - Unusual fungal niches. AB - Fungi are found in all aerobic ecosystems, colonizing a diversity of substrates and performing a wide diversity of functions, some of which are not well understood. Many spices of fungi are cosmopolitan and generalists or habitats. Unusual fungal niches are habitats where extreme conditions would be expected to prevent the development of a mycobiota. In this review we describe five unusual fungal habitats in which fungi occupy poorly understood niches: Antarctic dry valleys, high Arctic glaciers, salt flats and salterns, hypersaline microbial mats and plant trichomes. Yeasts, black yeast-like fungi, melanized filamentous species as well as representatives of Aspergillus and Penicillium seem to be dominant among the mycobiota adapted to cold and saline niches. Plant trichomes appear to be a taxa. The advent of new sequencing technologies is helping to elucidate the microbial diversity in many ecosystems, but more studies are needed to document the functional role of fungi in the microbial communities thriving in these unusual environments. PMID- 21700640 TI - A new species and new records of Cercophora from Argentina. AB - Three species of Cercophora were found during a survey of the biodiversity of microfungi in northwest Argentina. Cercophora argentina possesses a unique combination of morphological characters and is described as a new species, while C. costaricensis and C. solaris are reported as new records for Argentina. Other species of Cercophora known from this region include C. natalita and C. coprogena, which is fully illustrated for the first time and determined herein to be a synonym of C. californica. All other species are described and illustrated. PMID- 21700641 TI - Novel species of Celoporthe from Eucalyptus and Syzygium trees in China and Indonesia. AB - Many species in the Cryphonectriaceae cause diseases of trees, including those in the genera Eucalyptus and Syzygium. During disease surveys on these trees in southern China, fruiting structures typical of fungi in the Cryphonectriaceae and associated with dying branches and stems were observed. Morphological comparisons suggested that these fungi were distinct from the well known Chrysoporthe deuterocubensis, also found on these trees in China. The aim of this study was to identify these fungi and evaluate their pathogenicity to Eucalyptus clones/species as well as Syzygium cumini. Three morphologically similar fungal isolates collected previously from Indonesia also were included in the study. Isolates were characterized based on comparisons of morphology and DNA sequence data for the partial LSU and ITS nuclear ribosomal DNA, beta-tubulin and TEF 1alpha gene regions. After glasshouse trials to select virulent isolates field inoculations were undertaken to screen different commercial Eucalyptus clones/species and S. cumini trees for susceptibility to infection. Phylogenetic analyses showed that the Chinese isolates and those from Indonesia reside in a clade close to previously identified South African Celoporthe isolates. Based on morphology and DNA sequence comparisons, four new Celoporthe spp. were identified and they are described as C. syzygii, C. eucalypti, C. guangdongensis and C. indonesiensis. Field inoculations indicated that the three Chinese Celoporthe spp., C. syzygii, C. eucalypti and C. guangdongensis, are pathogenic to all tested Eucalyptus and S. cumini trees. Significant differences in the susceptibility of the inoculated Eucalyptus clones/species suggest that it will be possible to select disease-tolerant planting stock for forestry operations in the future. PMID- 21700642 TI - High cervical spinal cord stimulation for chronic cluster headache. AB - BACKGROUND: Cluster headache (CH) is the most painful and debilitating primary headache syndrome. Conventional treatment combines acute and prophylactic drugs. Also with maximal therapy a substantial proportion of patients do not experience a meaningful prevention or pain relief. Recent case series and early trials have suggested that occipital nerve stimulation can be very effective in the management of intractable CH. METHODS: Seven patients with medically intractable chronic cluster headache were implanted with high cervical epidural electrodes. After a median test phase of 10 days (range 4-19 days) an impulse generator was implanted subcutaneously. Mean follow up was 23 months (median 12 months, range 3 78 months). RESULTS: All patients showed significant treatment effects. In all patients, improvement occurred immediately after electrode implantation. The mean attack frequency decreased, as well as the mean duration and intensity of attacks. Also, depression, anxiety, and pain-related impairment scores decreased and medication intake was markedly reduced. CONCLUSIONS: In this prospective series, high cervical spinal cord stimulation shows an effect size equal or larger than occipital nerve stimulation with immediate onset after surgery and may serve as a valuable additional treatment option of intractable cluster headache in the future. PMID- 21700643 TI - Evaluation of cutaneous allodynia following induction of cortical spreading depression in freely moving rats. AB - BACKGROUND: Cortical spreading depression (CSD) is a wave of depolarization followed by depression of bioelectrical activity that slowly propagates through the cortex. CSD is believed to be the underlying mechanism of aura in migraine; however, whether CSD can elicit pain associated with migraine headache is unclear. METHODS: Awake, freely moving rats were monitored for both CSD events and behavioral responses resulting from dural-cortical pinprick and/or KCl injection to the occipital cortex. RESULTS: We observed tactile allodynia of the face and hindpaws, as well as enhanced Fos expression within the trigeminal nucleus caudalis (TNC) following CSD induced by KCl injection into the cortex, but not by pinprick. Application of KCl onto the dura elicited cutaneous allodynia and increased Fos staining in the TNC but did not elicit CSD events. CONCLUSIONS: These data suggest that sustained activation of trigeminal afferents that may be required to establish cutaneous allodynia may not occur following CSD events in normal animals. PMID- 21700644 TI - Rebound following oxygen therapy in cluster headache. AB - BACKGROUND: Rapid recurrence of a new cluster headache attack following oxygen treatment was named the 'rebound effect' by Kudrow (1981). It has never been studied properly. To study this effect, we defined it as a more rapid than usual (for the individual patient) recurrent cluster headache attack after complete relief following oxygen therapy, or an increase in the number of attacks per 24 hours while using oxygen therapy as acute attack treatment. We reviewed the literature and searched our cluster headache study databases. CASE SERIES: In our eight patients with rebound cluster headache, the effect was experienced following 87.5% of oxygen treated attacks. Duration until the next cluster headache attack was on average 894 minutes shorter and frequency was on average 1.6 cluster headache attacks per day higher than without oxygen therapy. CONCLUSION: Although the 1981 trial reported a prevalence of 25%, rebound cluster headache following oxygen therapy is rarely reported nowadays. This may be due to better techniques in oxygen application, the use of higher oxygen flow rates or underreporting. The few literature data and data on our eight patients did not provide clues about the mechanism of the rebound effect. Further study, applying the proposed definition, seems useful. PMID- 21700645 TI - Changes in headache frequency in premenopausal obese women with migraine after bariatric surgery: a case series. AB - BACKGROUND: The association between migraine and obesity gives the clinician with an exciting possibility to alleviate migraine suffering through weight-reduction gastric-restrictive operations. We hypothesized that bariatric weight-reduction intervention (gastric banding) will be associated with reduction of migraine burden in this population. METHODS: A total of 105 women between 18 and 50 years of age, admitted for bariatric surgery between April 2006 and February 2007, were screened for migraine. Twenty-nine with diagnosis of migraine were enrolled into the prospective phase. We followed the migraine pattern of these patients for 6 months post bariatric surgery. RESULTS: Baseline median migraine frequency was six headache days a month. Post bariatric surgery, the migraine-suffering women reported of a lower frequency of migraine attacks (p < 0.001), shorter duration of the attacks (p = 0.02), lower medication use during the attack (p = 0.005), less non-migraine pain (44.8 vs. 33%, p = 0.05), and post-bariatric surgery reduction in headache-related disability assessed by the MIDAS and HIT-6 scores. There was a reduction in migraine frequency among both episodic (from four to one episodes a month) and chronic (from 16.8 to 8.5 episodes per month) migraine patient cohorts separately and combined. CONCLUSIONS: Among migraine-suffering premenopausal obese women, we found a reduced frequency of migraine attacks and improvement of headache-related disability post bariatric surgery. Our findings should be interpreted cautiously. The absence of a control group and the non blinded nature of our small study make it difficult to draw firm conclusions about the causal nature of the headache changes observed in this population. Further study is needed to evaluate the possible specific effects of surgical weight loss on migraine in obese women. PMID- 21700646 TI - In-patient versus out-patient withdrawal programmes for medication overuse headache: a 2-year randomized trial. AB - BACKGROUND: Medication-overuse headache (MOH) management usually includes a medication withdrawal. The choice of withdrawal modalities remains a matter of debate. METHODS: We compared the efficacy of in-patient versus out-patient withdrawal programmes in 82 consecutive patients with MOH in an open-label prospective randomized trial. The main outcome measure was the reduction in number of headache days after 2 months and after 2 years. The responders were defined as patients who had reverted to episodic headaches and to an intake of acute treatments for headache less than 10 days per month. RESULTS: Seventy-one patients had a complete drug withdrawal (n = 36 in the out-patient group; n = 35 in the in-patient group). The reduction of headache frequency and subjective improvement did not differ between groups. The long-term responder rate was similar in the out- and in- patient groups (44% and 44%; p = 0.810). The only predictive factor of a bad outcome 2 years after withdrawal was an initial consumption of more than 150 units of acute treatments for headache per month (OR = 3.1; 95% confidence interval 1.1-9.3; p = 0.044). CONCLUSION: Given that we did not observe any difference in efficacy between the in- and out-patient withdrawals, we would recommend out-patient withdrawal in the first instance for patients with uncomplicated MOH. PMID- 21700647 TI - Inquiry "busts the myth" that combat trauma is linked to criminal behaviour. PMID- 21700648 TI - A lactoferrin-derived peptide (PXL01) for the reduction of adhesion formation in flexor tendon surgery: an experimental study in rabbits. AB - Injuries to flexor tendons can lead to loss of finger function after healing due to adhesion formation. The aim of this study was to assess the efficacy and safety of the new peptide, PXL01, in the prevention of peritendinous adhesions. The effect of a single intraoperative administration of PXL01 in sodium hyaluronate on mobility of the affected digit after surgery was assessed in a rabbit model by measuring total active motion, metatarsophalangeal-claw distance and resistance to bending the digits. Load-to-failure testing was done in the same specimens to assess tendon healing. The results demonstrated that a single application of PXL01 in sodium hyaluronate significantly improved mobility of the treated digits compared with the digits in which the same surgery was carried out but no treatment was provided. No negative effects on tendon healing were observed in connection with the treatment. PMID- 21700649 TI - A systematic review of the treatment of acute fractures of the scaphoid. AB - A systematic review of the literature identified eight trials comparing surgery with cast treatment and found no significant difference in pain, tenderness, cost, functional outcome or patient satisfaction. In the group treated surgically, the rate of non-union was three times less, there was a quicker return to function and grip strength and range of movement was also transiently better. There were, however, more complications among those treated surgically. No significant differences were reported in the two trials that compared above and below elbow casts or the trial that compared scaphoid and Colles' casts. PMID- 21700650 TI - The use of screws in the treatment of scapholunate instability. AB - Seven patients with chronic scapholunate instability (Geissler grade 2-4) were treated by percutaneous placement of screws across the scapholunate joint after arthroscopic debridement of the remnants of the scapholunate ligament. In all seven cases, the screw caused partial destruction of the lunate and/or scaphoid requiring screw removal within 6 months. We no longer perform this procedure. PMID- 21700652 TI - Why system inertia makes health reform so difficult. PMID- 21700651 TI - Performance of stroke risk scores in older people with atrial fibrillation not taking warfarin: comparative cohort study from BAFTA trial. AB - OBJECTIVE: To compare the predictive power of the main existing and recently proposed schemes for stratification of risk of stroke in older patients with atrial fibrillation. DESIGN: Comparative cohort study of eight risk stratification scores. SETTING: Trial of thromboprophylaxis in stroke, the Birmingham Atrial Fibrillation in the Aged (BAFTA) trial. PARTICIPANTS: 665 patients aged 75 or over with atrial fibrillation based in the community who were randomised to the BAFTA trial and were not taking warfarin throughout or for part of the study period. MAIN OUTCOME MEASURES: Events rates of stroke and thromboembolism. RESULTS: 54 (8%) patients had an ischaemic stroke, four (0.6%) had a systemic embolism, and 13 (2%) had a transient ischaemic attack. The distribution of patients classified into the three risk categories (low, moderate, high) was similar across three of the risk stratification scores (revised CHADS(2), NICE, ACC/AHA/ESC), with most patients categorised as high risk (65-69%, n = 460-457) and the remaining classified as moderate risk. The original CHADS(2) (Congestive heart failure, Hypertension, Age >= 75 years, Diabetes, previous Stroke) score identified the lowest number as high risk (27%, n = 180). The incremental risk scores of CHADS(2), Rietbrock modified CHADS(2), and CHA(2)DS(2)-VASc (CHA(2)DS(2)-Vascular disease, Age 65-74 years, Sex) failed to show an increase in risk at the upper range of scores. The predictive accuracy was similar across the tested schemes with C statistic ranging from 0.55 (original CHADS(2)) to 0.62 (Rietbrock modified CHADS(2)), with all except the original CHADS(2) predicting better than chance. Bootstrapped paired comparisons provided no evidence of significant differences between the discriminatory ability of the schemes. CONCLUSIONS: Based on this single trial population, current risk stratification schemes in older people with atrial fibrillation have only limited ability to predict the risk of stroke. Given the systematic undertreatment of older people with anticoagulation, and the relative safety of warfarin versus aspirin in those aged over 70, there could be a pragmatic rationale for classifying all patients over 75 as "high risk" until better tools are available. PMID- 21700653 TI - Why do some ex-armed forces personnel end up in prison? PMID- 21700654 TI - Clinicians' offer to help monitor public health responsibility deal is ignored by government. PMID- 21700655 TI - The causes of death in Korean patients with systemic lupus erythematosus over 11 years. AB - We investigated the causes of death and analyzed the prognostic factors in Korean systemic lupus erythematosus (SLE) patients. We evaluated 1010 patients with SLE who visited Seoul Saint Mary's Hospital from 1997-2007. Changing patterns in the causes of death were analyzed. Survival rate was calculated by the Kaplan-Meier method and the log-rank test. The risk factors for death were analyzed by multivariate logistic regression analysis. The 5-year survival rate was 97.8%. Over the period of the study, 59 deaths were observed. Among 44 patients who died in our hospital, the most common cause of death was infection (37.3%), with SLE related death as the next most frequent cause (22.0%). In comparison with earlier data, the proportion of SLE-related deaths has fallen and the proportion of infections has risen. SLE-related death was the most frequent cause of early death, while infection was the most common cause of death in the overall population. In univariate analysis, damage related to SLE, cumulative glucocorticoid dose, mean glucocorticoid dose for 1 month before death, intravenous methylprednisolone therapy and cyclophosphamide treatment were associated with death (p < 0.001 each). The late onset of SLE and renal involvement were predictive factors of poor outcome (p = 0.03 and p < 0.001). In multivariate analysis, the risk factors for death were irreversible damage related to SLE, cyclophosphamide therapy and mean glucocorticoid dose for 1 month before death. The most common cause of death in Korean SLE patients was infection. The judicious use of immunosuppressive agents may be important to decrease infection and to improve survival in SLE patients. PMID- 21700657 TI - Association between variable number tandem repeats within the 3' flanking region of the interleukin-6 gene and systemic lupus erythematosus in Korean patients. AB - Variable number tandem repeat (VNTR) polymorphism located in the 3' flanking region of the interleukin-6 (IL-6) gene was examined in Koreans with systemic lupus erythematosus (SLE). We identified 15 VNTR alleles (K1 to K15) in the 3' flanking region by Genescan analysis. The VNTR K8 allele, a 648-base pair (bp) allele, was most commonly found in Koreans, being present in 74.8% of the SLE patients and 70.3% of the normal controls. The VNTR K9 (642 bp) allele was associated with susceptibility to SLE. In addition, the VNTR K9 was significantly associated with leukopenia (p = 0.048), thrombocytopenia (p = 0.020), and elevated C-reactive protein (p = 0.019). These data suggest that the VNTR K9 in the 3' flanking region of the IL-6 gene may be associated with disease susceptibility and the clinical phenotypes of SLE. PMID- 21700656 TI - Using Wii Fit to reduce fatigue among African American women with systemic lupus erythematosus: a pilot study. AB - Fatigue and physical deconditioning are common, difficult to treat conditions among patients with systemic lupus erythematosus (SLE). The aim of this pilot study was to evaluate the effectiveness of a home-based exercise program using the Wii Fit system in patients with SLE. Fifteen sedentary African American women with SLE experiencing moderate to severe fatigue participated in a home exercise program using the Wii Fit 3 days a week for 30 minutes each for 10 weeks. A one group pretest-post test design was used to evaluate the effectiveness of this program. Primary outcome measure was severity of fatigue. Secondary outcome measures were body weight, waist circumference, fatigue-related symptoms of distress, activity level, and physical fitness. At the completion of the 10-week Wii Fit exercise program, participants perceived fatigue severity as measured by the Fatigue Severity Scale to be significantly decreased (p = 0.002), and body weight and waist circumference were significantly reduced (p = 0.01). In addition, anxiety level, as measured by Hospital Anxiety and Depression Scale, and overall intensity of total pain experience, as measured by Short-form of the McGill Pain Questionnaire, were also significantly reduced (p < 0.05). Findings provide preliminary evidence that the Wii Fit motivates this population to exercise, which leads to alleviation of fatigue and reduced body weight, waist circumference, anxiety level, and overall intensity of total pain experience. PMID- 21700658 TI - Clinical expression and morbidity of systemic lupus erythematosus during a post diagnostic 5-year follow-up: a male:female comparison. AB - The aim of this study was to analyse the prevalence of the most relevant clinical features of the diagnosis of systemic lupus erythematosus (SLE) in a sample of male patients with lupus as well as the incidence of the main causes of morbidity in a 5-year period after the diagnosis. A further aim of this study was to investigate the impact of gender on expression and morbidity of SLE. Data were collected from the medical records of 59 male and 535 female patients with SLE who were diagnosed at the hospitals in the region of Thessaloniki. Several differences in the expression and morbidity of the disease were found in relation to the gender of the patient. Male patients had a higher prevalence of thromboses, nephropathy, strokes, gastrointestinal tract symptoms and antiphospholipid syndrome when compared with female patients, but tended to present less often with arthralgia, hair loss, Raynaud's phenomenon and photosensitivity as the initial clinical manifestations. During the 5-year follow up, positive associations have been found between male gender and the incidence of tendonitis, myositis, nephropathy and infections, particularly of the respiratory tract. In conclusion, this study has provided information regarding the features of clinical expression and morbidity in male patients, and has shown that gender is a possible factor that can influence the clinical expression of SLE. PMID- 21700659 TI - A primary defect in glucose production alone cannot induce glucose intolerance without defects in insulin secretion. AB - Increased glucose production is associated with fasting hyperglycaemia in type 2 diabetes but whether or not it causes glucose intolerance is unclear. This study sought to determine whether a primary defect in gluconeogenesis (GNG) resulting in elevated glucose production is sufficient to induce glucose intolerance in the absence of insulin resistance and impaired insulin secretion. Progression of glucose intolerance was assessed in phosphoenolpyruvate carboxykinase (PEPCK) transgenic rats, a genetic model with a primary increase in GNG. Young (4-5 weeks of age) and adult (12-14 weeks of age) PEPCK transgenic and Piebald Virol Glaxo (PVG/c) control rats were studied. GNG, insulin sensitivity, insulin secretion and glucose tolerance were assessed by intraperitoneal and intravascular substrate tolerance tests and hyperinsulinaemic/euglycaemic clamps. Despite elevated GNG and increased glucose appearance, PEPCK transgenic rats displayed normal glucose tolerance due to adequate glucose disposal and robust glucose mediated insulin secretion. Glucose intolerance only became apparent in the PEPCK transgenic rats following the development of insulin resistance (both hepatic and peripheral) and defective glucose-mediated insulin secretion. Taken together, a single genetic defect in GNG leading to increased glucose production does not adversely affect glucose tolerance. Insulin resistance and impaired glucose mediated insulin secretion are required to precipitate glucose intolerance in a setting of chronic glucose oversupply. PMID- 21700660 TI - Identification of estradiol/ERalpha-regulated genes in the mouse pituitary. AB - Estrogen acts to prime the pituitary prior to the GnRH-induced LH surge by undiscovered mechanisms. This study aimed to identify the key components that mediate estrogen action in priming the pituitary. RNA extracted from the pituitaries of metestrous (low estrogen) and proestrus (high estrogen) stage mice, as well as from ovariectomized wild-type and estrogen receptor alpha (ERalpha) knockout mice treated with 17beta-estradiol (E(2)) or vehicle, was used for gene expression microarray. Microarray data were then aggregated, built into a functional electronic database, and used for further characterization of E(2)/ERalpha-regulated genes. These data were used to compile a list of genes representing diverse biological pathways that are regulated by E(2) via an ERalpha-mediated pathway in the pituitary. This approach substantiates ERalpha regulation of membrane potential regulators and intracellular vesicle transporters, among others, but not the basic components of secretory machinery. Subsequent characterization of six selected genes (Cacna1a, Cacna1g, Cited1, Abep1, Opn3, and Kcne2) confirmed not only ERalpha dependency for their pituitary expression but also the significance of their expression in regulating GnRH induced LH secretion. In conclusion, findings from this study suggest that estrogen primes the pituitary via ERalpha by equipping pituitary cells with critical cellular components that potentiate LH release on subsequent GnRH stimulations. PMID- 21700661 TI - Stock culture heterogeneity rather than new mutational variation complicates short-term cell physiology studies of Escherichia coli K-12 MG1655 in continuous culture. AB - Nutrient-limited continuous cultures in chemostats have been used to study microbial cell physiology for over 60 years. Genome instability and genetic heterogeneity are possible uncontrolled factors in continuous cultivation experiments. We investigated these issues by using high-throughput (HT) DNA sequencing to characterize samples from different phases of a glucose-limited accelerostat (A-stat) experiment with Escherichia coli K-12 MG1655 and a duration regularly used in cell physiology studies (20 generations of continuous cultivation). Seven consensus mutations from the reference sequence and five subpopulations characterized by different mutations were detected in the HT sequenced samples. This genetic heterogeneity was confirmed to result from the stock culture by Sanger sequencing. All the subpopulations in which allele frequencies increased (betA, cspG/cspH, glyA) during the experiment were also present at the end of replicate A-stats, indicating that no new subpopulations emerged during our experiments. The fact that ~31 % of the cells in our initial cultures obtained directly from a culture stock centre were mutants raises concerns that even if cultivations are started from single colonies, there is a significant chance of picking a mutant clone with an altered phenotype. Our results show that current HT DNA sequencing technology allows accurate subpopulation analysis and demonstrates that a glucose-limited E. coli K-12 MG1655 A-stat experiment with a duration of tens of generations is suitable for studying cell physiology and collecting quantitative data for metabolic modelling without interference from new mutations. PMID- 21700663 TI - The LysR-type PcaQ protein regulates expression of a protocatechuate-inducible ABC-type transport system in Sinorhizobium meliloti. AB - The LysR protein PcaQ regulates the expression of genes encoding products relevant to the degradation of the aromatic acid protocatechuate (3,4 dihydroxybenzoate), and we have previously defined a PcaQ DNA-binding site located upstream of the target pcaDCHGB operon in Sinorhizobium meliloti. In this work, we show that PcaQ also regulates the expression of the S. meliloti smb20568 smb20787-smb20786-smb20785-smb20784 gene cluster, which is predicted to encode an ABC transport system. ABC transport systems have not been shown before to transport protocatechuate, and we have designated this gene cluster pcaMNVWX. The transcriptional start site of pcaM was mapped, and the predicted PcaQ DNA-binding site was located at -73 to -58 relative to this site. Results from electrophoretic mobility shift assays with purified PcaQ and from expression assays indicated that PcaQ activates expression of the transport system in the presence of protocatechuate. To investigate this transport system further, we generated a pcaM deletion mutant (predicted to encode the substrate-binding protein) and introduced a polar insertion mutation into pcaN, a gene that is predicted to encode a permease. These mutants grew poorly on protocatechuate, presumably because they fail to transport protocatechuate. Genome analyses revealed PcaQ-like DNA-binding sites encoded upstream of ABC transport systems in other members of the alpha-proteobacteria, and thus it appears likely that these systems are involved in the uptake of protocatechuate. PMID- 21700662 TI - Genetic analysis of surface motility in Acinetobacter baumannii. AB - The Gram-negative pathogen Acinetobacter baumannii strain M2 was found to exhibit a robust surface motility on low-percentage (0.2-0.4 %) agar plates. These patterns of motility were dramatically different depending on whether Difco or Eiken agar was used. Motility was observed in many, but not all, clinical and environmental isolates. The use of drop collapse assays to demonstrate surfactant production was unsuccessful, and the role of surfactants in A. baumannii M2 motility remains unclear. Surface motility was impaired by an insertion in pilT, encoding a gene product that is often required for retraction of the type IV pilus. Motility was also dependent on quorum sensing, as a null allele in the abaI autoinducer synthase decreased motility, and the addition of exogenous N-(3 hydroxy)-dodecanoylhomoserine lactone (3-OH C12-HSL) restored motility to the abaI mutant. Transposon mutagenesis was used to identify additional genes required for motility and revealed loci encoding various functions: non-ribosomal synthesis of a putative lipopeptide, a sensor kinase (BfmS), a lytic transglycosylase, O-antigen biosynthesis (RmlB), an outer membrane porin (OmpA) and de novo purine biosynthesis (PurK). Two of the above genes required for motility were highly activated by quorum sensing, and may explain, in part, the requirement for quorum sensing in motility. PMID- 21700664 TI - Lactobacillus S-layer protein inhibition of Salmonella-induced reorganization of the cytoskeleton and activation of MAPK signalling pathways in Caco-2 cells. AB - Surface layer (S-layer) proteins are crystalline arrays of proteinaceous subunits that are present as the outermost component of the cell wall in several Lactobacillus species. The S-layer proteins have been shown to play a role in the antimicrobial activity of certain lactobacilli. However, it is not fully understood how the S-layer proteins exert this biological function. The aim of this study was to test the hypothesis that Lactobacillus acidophilus S-layer proteins antagonize Salmonella Typhimurium (S. Typhimurium) infection by protecting against F-actin cytoskeleton rearrangements and the activation of mitogen-activated protein kinase (MAPK) signalling pathways. Monolayer transepithelial electrical resistance (TER) was measured after S. Typhimurium infection in Caco-2 cultured human intestinal cells with L. acidophilus S-layer proteins. F-actin rearrangement and MAPK activation were also assessed by immunofluorescence staining or Western blotting. The results showed that when S. Typhimurium was co-incubated with S-layer proteins, the S. Typhimurium-induced Caco-2 cell F-actin rearrangement was reduced, and the S. Typhimurium-induced TER decrease and interleukin 8 (IL-8) secretion were attenuated. Additionally, L. acidophilus S-layer proteins could inhibit S. Typhimurium-induced phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinase (JNK) and p38. This study indicates that L. acidophilus S-layer proteins are able to inhibit S. Typhimurium infection through blocking S. Typhimurium induced F-actin rearrangements and S. Typhimurium-induced ERK1/2, JNK and p38 activation in Caco-2 cells. These data provide a rationale for the use of lactobacillus S-layer proteins as therapeutic and preventative agents, at least in infectious diarrhoea. PMID- 21700665 TI - purL gene expression affects biofilm formation and symbiotic persistence of Photorhabdus temperata in the nematode Heterorhabditis bacteriophora. AB - Extensive studies of the well-known legume and rhizobium symbiosis model system suggest that the purine metabolic pathway plays a key role in microbe-plant interactions, although the exact mechanism is unknown. Here, we report the impact of a key purine metabolic gene, purL, on the symbiotic interaction between the bacterium Photorhabdus temperata and its nematode partner Heterorhabditis bacteriophora. Real-time PCR assays showed that the purL gene was upregulated in P. temperata in the nematode infective juvenile compared with artificial media. Mutation of the purL gene by in-frame deletion dramatically decreased the capacity of the bacterium to persist in infective juveniles and its ability to form biofilm in vitro. It was further demonstrated that purL gene expression was positively related to bacterial biofilm formation and the symbiotic persistence of the bacterium in nematode infective juveniles. A DeltapurL mutant lost the ability to support infective juvenile formation in the media which weakly supported biofilm formation, suggesting that a critical level of biofilm formation is required by the bacteria to support infective juvenile formation and thus establish their partnership. In addition, the defects in both biofilm formation and symbiotic ability due to the disruption of the purL gene could be partially restored by the addition of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an intermediate of the purine biosynthesis pathway. Overall, these data indicate that the purine metabolic pathway is important in microbe-animal symbioses, and that it may influence symbiotic interactions at the level of biofilm formation. PMID- 21700666 TI - A Mig-14-like protein (PA5003) affects antimicrobial peptide recognition in Pseudomonas aeruginosa. AB - The evolution of antibiotic resistance in pathogenic bacteria is a growing global health problem which is gradually making the treatment of infectious diseases less efficient. Antimicrobial peptides are small charged molecules found in organisms from the complete phylogenetic spectrum. The peptides are attractive candidates for novel drug development due to their activity against bacteria that are resistant to conventional antibiotics, and reports of peptide resistance are rare in the clinical setting. Paradoxically, many clinically relevant bacteria have mechanisms that can recognize and respond to the presence of cationic antimicrobial peptides (CAMPs) in the environment by changing the properties of the microbial surface thereby increasing the tolerance of the microbes towards the peptides. In Pseudomonas aeruginosa an essential component of this inducible tolerance mechanism is the lipopolysaccharide modification operon arnBCADTEF PA3559 which encodes enzymes required for LPS alterations leading to increased antimicrobial peptide tolerance. The expression of the operon is induced by the presence of CAMPs in the environment but the molecular mechanisms underlying the cellular recognition of the peptides are poorly elucidated. In this work, we investigate the factors influencing arnB expression by transposon mutagenesis and arnB promoter green fluorescent protein reporters. We have identified a novel gene encoding a Mig-14-like protein that is required for recognition of the CAMPs colistin and Novispirin G10 by P. aeruginosa. Moreover, we show that this gene is also required for the formation of CAMP-tolerant subpopulations in P. aeruginosa hydrodynamic flow chamber biofilms. PMID- 21700667 TI - Is anyone promoting the health of men? PMID- 21700668 TI - Correlates of receiving reproductive health care services among U.S. men aged 15 to 44 years. AB - Men have a significant role in reproductive health decision making and behavior, including family planning and prevention of sexually transmitted diseases (STDs).Yet studies on reproductive health care of men are scarce. The National Survey of Family Growth 2006-2008 provided data that allowed assessment of the predisposing, enabling, and need factors associated with men's receipt of reproductive health services in the United States. Although more than half (54%) of U.S. men received at least one health care service in the 12 months prior to the survey, far fewer had received birth control counseling/methods, including condoms (12%) and STD/HIV testing/STD treatment (12%). Men with publicly funded health insurance and men who received physical exam were more likely to receive reproductive health services when compared with men with private health insurance and men who did not receive a physical exam. Men who reported religion was somewhat important were significantly more likely to receive birth control counseling/ methods than men who stated religion was very important. The pseudo-R (2) (54%), a measure of model fit improvement, suggested that enabling factors accounted for the strongest association with receiving either birth control counseling/ methods or STD/HIV testing/STD treatment. PMID- 21700669 TI - Malaria diagnostics: a comparative study of blood microscopy, a rapid diagnostic test and polymerase chain reaction in the diagnosis of malaria. PMID- 21700670 TI - 3D-Image analysis platform monitoring relocation of pluripotency genes during reprogramming. AB - Nuclear organization of chromatin is an important level of genome regulation with positional changes of genes occurring during reprogramming. Inherent variability of biological specimens, wide variety of sample preparation and imaging conditions, though pose significant challenges to data analysis and comparison. Here, we describe the development of a computational image analysis toolbox overcoming biological variability hurdles by a novel single cell randomizing normalization. We performed a comparative analysis of the relationship between spatial positioning of pluripotency genes with their genomic activity and determined the degree of similarity between fibroblasts, induced pluripotent stem cells and embryonic stem cells. Our analysis revealed a preferred positioning of actively transcribed Sox2, Oct4 and Nanog away from the nuclear periphery, but not from pericentric heterochromatin. Moreover, in the silent state, we found no common nuclear localization for any of the genes. Our results suggest that the surrounding gene density hinders relocation from an internal nuclear position. Altogether, our data do not support the hypothesis that the nuclear periphery acts as a general transcriptional silencer, rather suggesting that internal nuclear localization is compatible with expression in pluripotent cells but not sufficient for expression in mouse embryonic fibroblasts. Thus, our computational approach enables comparative analysis of topological relationships in spite of stark morphological variability typical of biological data sets. PMID- 21700671 TI - eResponseNet: a package prioritizing candidate disease genes through cellular pathways. AB - MOTIVATION: Although genome-wide association studies (GWAS) have found many common genetic variants associated with human diseases, it remains a challenge to elucidate the functional links between associated variants and complex traits. RESULTS: We developed a package called eResponseNet by implementing and extending the existing ResponseNet algorithm for prioritizing candidate disease genes through cellular pathways. Using type II diabetes (T2D) as a study case, we demonstrate that eResponseNet outperforms currently available approaches in prioritizing candidate disease genes. More importantly, the package is instrumental in revealing cellular pathways underlying disease-associated genetic variations. AVAILABILITY: The eResponseNet package is freely downloadable at http://hanlab.genetics.ac.cn/eResponseNet. CONTACT: jdhan@picb.ac.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21700672 TI - Gaia: automated quality assessment of protein structure models. AB - MOTIVATION: Increasing use of structural modeling for understanding structure function relationships in proteins has led to the need to ensure that the protein models being used are of acceptable quality. Quality of a given protein structure can be assessed by comparing various intrinsic structural properties of the protein to those observed in high-resolution protein structures. RESULTS: In this study, we present tools to compare a given structure to high-resolution crystal structures. We assess packing by calculating the total void volume, the percentage of unsatisfied hydrogen bonds, the number of steric clashes and the scaling of the accessible surface area. We assess covalent geometry by determining bond lengths, angles, dihedrals and rotamers. The statistical parameters for the above measures, obtained from high-resolution crystal structures enable us to provide a quality-score that points to specific areas where a given protein structural model needs improvement. AVAILABILITY AND IMPLEMENTATION: We provide these tools that appraise protein structures in the form of a web server Gaia (http://chiron.dokhlab.org). Gaia evaluates the packing and covalent geometry of a given protein structure and provides quantitative comparison of the given structure to high-resolution crystal structures. CONTACT: dokh@unc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21700673 TI - A rank-based statistical test for measuring synergistic effects between two gene sets. AB - MOTIVATION: Due to recent advances in high-throughput technologies, data on various types of genomic annotation have accumulated. These data will be crucially helpful for elucidating the combinatorial logic of transcription. Although several approaches have been proposed for inferring cooperativity among multiple factors, most approaches are haunted by the issues of normalization and threshold values. RESULTS: In this article, we propose a rank-based non parametric statistical test for measuring the effects between two gene sets. This method is free from the issues of normalization and threshold value determination for gene expression values. Furthermore, we have proposed an efficient Markov chain Monte Carlo method for calculating an approximate significance value of synergy. We have applied this approach for detecting synergistic combinations of transcription factor binding motifs and histone modifications. AVAILABILITY: C implementation of the method is available from http://www.hgc.jp/~yshira/software/rankSynergy.zip. CONTACT: yshira@hgc.jp SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21700675 TI - KEGGtranslator: visualizing and converting the KEGG PATHWAY database to various formats. AB - SUMMARY: The KEGG PATHWAY database provides a widely used service for metabolic and nonmetabolic pathways. It contains manually drawn pathway maps with information about the genes, reactions and relations contained therein. To store these pathways, KEGG uses KGML, a proprietary XML-format. Parsers and translators are needed to process the pathway maps for usage in other applications and algorithms. We have developed KEGGtranslator, an easy-to-use stand-alone application that can visualize and convert KGML formatted XML-files into multiple output formats. Unlike other translators, KEGGtranslator supports a plethora of output formats, is able to augment the information in translated documents (e.g. MIRIAM annotations) beyond the scope of the KGML document, and amends missing components to fragmentary reactions within the pathway to allow simulations on those. AVAILABILITY: KEGGtranslator is freely available as a Java(TM) Web Start application and for download at http://www.cogsys.cs.uni tuebingen.de/software/KEGGtranslator/. KGML files can be downloaded from within the application. CONTACT: clemens.wrzodek@uni-tuebingen.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21700674 TI - UCHIME improves sensitivity and speed of chimera detection. AB - MOTIVATION: Chimeric DNA sequences often form during polymerase chain reaction amplification, especially when sequencing single regions (e.g. 16S rRNA or fungal Internal Transcribed Spacer) to assess diversity or compare populations. Undetected chimeras may be misinterpreted as novel species, causing inflated estimates of diversity and spurious inferences of differences between populations. Detection and removal of chimeras is therefore of critical importance in such experiments. RESULTS: We describe UCHIME, a new program that detects chimeric sequences with two or more segments. UCHIME either uses a database of chimera-free sequences or detects chimeras de novo by exploiting abundance data. UCHIME has better sensitivity than ChimeraSlayer (previously the most sensitive database method), especially with short, noisy sequences. In testing on artificial bacterial communities with known composition, UCHIME de novo sensitivity is shown to be comparable to Perseus. UCHIME is >100* faster than Perseus and >1000* faster than ChimeraSlayer. CONTACT: robert@drive5.com AVAILABILITY: Source, binaries and data: http://drive5.com/uchime. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21700676 TI - ODORactor: a web server for deciphering olfactory coding. AB - SUMMARY: ODORactor is an open access web server aimed at providing a platform for identifying odorant receptors (ORs) for small molecules and for browsing existing OR-ligand pairs. It enables the prediction of ORs from the molecular structures of arbitrary chemicals by integrating two individual functionalities: odorant verification and OR recognition. The prediction of the ORs for several odorants was experimentally validated in the study. In addition, ODORactor features a comprehensive repertoire of olfactory information that has been manually curated from literature. Therefore, ODORactor may provide an effective way to decipher olfactory coding and could be a useful server tool for both basic olfaction research in academia and for odorant discovery in industry. AVAILABILITY: Freely available at http://mdl.shsmu.edu.cn/ODORactor CONTACT: jian.zhang@sjtu.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21700677 TI - Enriching targeted sequencing experiments for rare disease alleles. AB - MOTIVATION: Next-generation targeted resequencing of genome-wide association study (GWAS)-associated genomic regions is a common approach for follow-up of indirect association of common alleles. However, it is prohibitively expensive to sequence all the samples from a well-powered GWAS study with sufficient depth of coverage to accurately call rare genotypes. As a result, many studies may use next-generation sequencing for single nucleotide polymorphism (SNP) discovery in a smaller number of samples, with the intent to genotype candidate SNPs with rare alleles captured by resequencing. This approach is reasonable, but may be inefficient for rare alleles if samples are not carefully selected for the resequencing experiment. RESULTS: We have developed a probability-based approach, SampleSeq, to select samples for a targeted resequencing experiment that increases the yield of rare disease alleles substantially over random sampling of cases or controls or sampling based on genotypes at associated SNPs from GWAS data. This technique allows for smaller sample sizes for resequencing experiments, or allows the capture of rarer risk alleles. When following up multiple regions, SampleSeq selects subjects with an even representation of all the regions. SampleSeq also can be used to calculate the sample size needed for the resequencing to increase the chance of successful capture of rare alleles of desired frequencies. SOFTWARE: http://biostat.mc.vanderbilt.edu/SampleSeq PMID- 21700679 TI - Commentary: Increasing cultural diversity in pediatric psychology family assessment research. PMID- 21700678 TI - Commentary: Birthweight and childhood cognition: the use of twin studies. PMID- 21700680 TI - BRCA1 loss induces GADD153-mediated doxorubicin resistance in prostate cancer. AB - BRCA1 plays numerous roles in the regulation of genome integrity and chemoresistance. Although BRCA1 interaction with key proteins involved in DNA repair is well known, its role as a coregulator in the transcriptional response to DNA damage remains poorly understood. In this study, we show that BRCA1 plays a central role in the transcriptional response to genotoxic stress in prostate cancer. BRCA1 expression mediates apoptosis, cell-cycle arrest, and decreased viability in response to doxorubicin treatment. Xenograft studies using human prostate carcinoma PC3 cells show that BRCA1 depletion results in increased tumor growth. A focused survey of BRCA1-regulated genes in prostate carcinoma reveals that multiple regulators of genome stability and cell-cycle control, including BLM, FEN1, DDB2, H3F3B, BRCA2, CCNB2, MAD2L1, and GADD153, are direct transcriptional targets of BRCA1. Furthermore, we show that BRCA1 targets GADD153 promoter to increase its transcription in response to DNA damage. Finally, GADD153 depletion significantly abrogates BRCA1 influence on cell-cycle progression and cell death in response to doxorubicin treatment. These findings define a novel transcriptional pathway through which BRCA1 orchestrates cell fate decisions in response to genotoxic insults, and suggest that BRCA1 status should be considered for new chemotherapeutic treatment strategies in prostate cancer. PMID- 21700682 TI - High prevalence of ultrasonographic synovitis and enthesopathy in patients with psoriasis without psoriatic arthritis: a prospective case-control study. AB - OBJECTIVE: To investigate the presence of synovitis, tenosynovitis and enthesitis with power Doppler (PD) ultrasonography (US) in patients with psoriasis without musculoskeletal diseases as compared with controls with other skin diseases without musculoskeletal disorders. METHODS: A total of 162 patients with plaque psoriasis and 60 age-matched controls with other skin diseases, all without musculoskeletal diseases, were prospectively recruited at 14 centres. They underwent dermatological and rheumatological assessment and a blinded PDUS evaluation. Clinical assessment included demographics, comorbidities, severity of psoriasis, work and sport activities and musculoskeletal clinical examination. PDUS evaluation consisted of the detection of grey scale (GS) synovitis and synovial PD signal in 36 joints, GS tenosynovitis and tenosynovial PD signal at 22 sites, and GS enthesopathy and entheseal PD signal in 18 entheses. RESULTS: US synovitis and enthesopathy were significantly more frequent in psoriatic patients than in controls (P = 0.024 and 0.005, respectively). The percentage of joints with US synovitis was 3.2% in the psoriasis group and 1.3% in the control group (P < 0.0005). US enthesopathy was present in 11.6% of entheses in the psoriasis group and 5.3% of entheses in the control group (P < 0.0005). Entheseal PD signal was found in 10 (7.4%) psoriatic patients, whereas no controls showed this finding (P = 0.05). Among demographic and clinical data, having psoriasis was the only significant predictive variable of the presence of US synovitis [odds ratio (OR) 2.1; P = 0.007] and enthesopathy (OR 2.6; P = 0.027). CONCLUSION: Psoriatic patients showed a significant prevalence of asymptomatic US synovitis and enthesopathy, which may indicate a subclinical musculoskeletal involvement. PMID- 21700681 TI - TAK1-TAB2 signaling contributes to bone destruction by breast carcinoma cells. AB - Advanced-stage breast cancers frequently metastasize to the bones and cause bone destruction, but the underlying mechanism is not fully understood. This study presents evidence that TGF-beta-activated protein kinase 1 (TAK1) signaling in tumor cells promotes bone destruction by metastatic breast carcinoma cells, controlling expression of prometastatic factors including matrix metalloproteinase (MMP) 9 and COX2. Suppression of TAK1 signaling by dominant negative TAK1 (dn-TAK1) in breast carcinoma MDA-MB-231 cells impairs bone colonization by carcinoma cells and bone osteolysis in the intracardiac injection model. Mechanistic studies showed that inhibition of TAK1 by dn-TAK1 or siRNA blocked expression of factors implicated in bone metastasis, such as MMP-9, COX2/PTGS2, parathyroid hormone-related protein (PTHrP) and interleukin 8 (IL-8), but did not affect activation of p38MAPK by TGF-beta. TAK1 signaling is mediated by TAK1-binding partners TAB1, TAB2, and TAB3. Carcinoma cells express elevated mRNA levels of TAB2 and TAB3, whereas the TAB1 expression is noticeably low. Accordingly, depletion of TAB2 by siRNA reduced expression of MMP-9 and COX2. Together, these studies show that the TAK1-TAB2-TAB3 signaling axis is critical for carcinoma-induced bone lesions, mediating expression of proinvasive and osteolytic factors. These findings identify the TAK1-TAB2 axis as a potential therapeutic target in bone metastasis. PMID- 21700683 TI - High-dose etanercept in ankylosing spondylitis: results of a 12-week randomized, double blind, controlled multicentre study (LOADET study). AB - OBJECTIVES: Etanercept 50 mg a week is approved in the treatment of AS. Increasing the etanercept dose to 100 mg/week improves efficacy in cutaneous psoriasis, a clinical manifestation related to the spondylarthritis family, while maintaining its safety profile. The purpose of this study was to evaluate the efficacy and safety of etanercept 100 vs 50 mg/week in patients with AS. METHODS: Adult patients with AS were randomized to receive etanercept 50 mg twice a week (biw), or etanercept 50 mg once a week (qw) for 12 weeks. The primary efficacy endpoint was Ankylosing Spondylitis Assessment Study (ASAS20) response at Week 12; secondary endpoints included ASAS40, ASAS50, ASAS70 and ASAS5/6 responses, partial remission and quality of life. Safety was assessed until 15 days after the last visit. RESULTS: A total of 108 patients were randomly selected and treated, 54 in each arm. At 12 weeks, ASAS20 response was achieved by 34 (71%) out of 48 patients of the etanercept 50 mg biw group and by 37 (76%) out of 49 patients of the etanercept 50 mg qw group (not statistically significant differences). Other efficacy variables improved significantly over time, but not between treatment groups. Fifty-six patients experienced at least one adverse event (generally, infections and infestations, gastrointestinal disorders and injection site reactions), most of them mild or moderate. CONCLUSIONS: High-dose (100 mg/week) etanercept in the treatment of AS for 12 weeks is as safe as the standard dose (50 mg/week). However, it does not significantly increase its efficacy. Trial Registration. Clinicaltrials.gov, http://clinicaltrials.gov/, NCT00873730. PMID- 21700684 TI - Cryptococcal meningitis in an HIV-negative patient with rheumatoid arthritis treated with rituximab. PMID- 21700685 TI - The impact of sleep consultation prior to a diagnostic polysomnogram on continuous positive airway pressure adherence. AB - BACKGROUND: Polysomnograms (PSGs) are routinely ordered by nonsleep specialists. However, it is unknown whether a sleep specialist consultation prior to a diagnostic PSG influences adherence to continuous positive airway pressure (CPAP) therapy. METHODS: This study was done at the University of Chicago Sleep Disorders Center and included 403 patients with obstructive sleep apnea who had CPAP adherence data available. CPAP was set up at home, and objective adherence was remotely monitored during the first 30 days of therapy. Physicians who ordered PSGs were divided into two groups: sleep specialists and nonsleep specialists. RESULTS: Patients were aged 52.5 +/- 14 years, 47% were men, and 54% were African American. Mean daily CPAP use was greater in patients who were referred by sleep specialists (n = 105, 279 +/- 179 min/d) than in patients referred by nonsleep specialists (n = 298, 219 +/- 152 min/d, P = .005). In the linear regression model adjusting for several covariates, only two predictors were significantly associated with CPAP adherence. A sleep specialist consultation prior to the diagnostic PSG was associated with 58.2 min more per day (P = .002), and African American race was associated with 56.0 min less per day (P = .002) of CPAP use. CONCLUSIONS: In this cohort study, CPAP adherence was significantly higher with a sleep specialist consultation prior to the diagnostic PSG. In addition, African American race was associated with worse adherence to therapy. A better understanding of predictors of CPAP adherence may be useful in identifying patients who may benefit from a sleep specialist consultation prior to ordering a diagnostic PSG. PMID- 21700686 TI - Combining tricuspid valve repair with double lung transplantation in patients with severe pulmonary hypertension, tricuspid regurgitation, and right ventricular dysfunction. AB - BACKGROUND: Concomitant tricuspid valve repair (TVR) and double lung transplantation (DLTx) has been a surgical option at our institution since 2004 in an attempt to improve the outcome of DLTx for end-stage pulmonary hypertension, severe tricuspid regurgitation, and right ventricle (RV) dysfunction. This study is a review of that single institutional experience. METHODS: Consecutive cases of concomitant TVR and DLTx performed between 2004 and 2009 (TVR group, n = 20) were retrospectively compared with cases of DLTx alone for severe pulmonary hypertension without TVR (non-TVR group, n = 58). RESULTS: There was one in-hospital death in the TVR group. The 90-day and 1- and 3-year survival rates for the TVR group were 90%, 75%, and 65%, respectively, which were not significantly different from those for the non-TVR group. The TVR group required less inotropic support and less prolonged mechanical ventilation in the ICU. Follow-up echocardiography demonstrated immediate elimination of both volume and pressure overload in the RV and tricuspid regurgitation in the TVR group. Notably, there was a significantly lower incidence of primary graft dysfunction following transplantation in the TVR group (P < .05). Pulmonary functional improvement shown by an FEV(1) increase after 6 months was also significantly better in the TVR group (40% vs 20%, P < .05). CONCLUSIONS: Combined TVR and DLTx procedures were successfully performed without an increase in morbidity or mortality and contributed to decreased primary graft dysfunction. In our experience, this combined operative approach achieves clinical outcomes equal or superior to the outcomes seen in DLTx patients without RV dysfunction and severe tricuspid regurgitation. PMID- 21700687 TI - Diagnosing peripheral lung cancer: the additional value of the Ras-association domain family 1A gene methylation and Kirsten rat sarcoma 2 viral oncogene homolog mutation analyses in washings in nondiagnostic bronchoscopy. AB - BACKGROUND: The diagnostic yield of bronchoscopy in patients with endoscopically nonvisible (peripheral) tumors varies from 40% to 56%. Increasingly, molecular markers in bronchial washings are being investigated to improve the diagnostic yield. The aim of this study was to analyze the diagnostic value of the Ras association domain family 1A gene (RASSF1A) methylation analysis in washings in nondiagnostic bronchoscopy in the analysis of patients with suspected lung cancer who had peripheral tumors. Furthermore, the additional diagnostic value of Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutations with RASSF1 methylation was analyzed. METHODS: From a prospectively collected series, 129 patients with lung cancer and 28 control subjects were analyzed retrospectively regarding the methylation status of the promoter region of the RASSF1A gene by quantitative methylation-specific polymerase chain reaction and KRAS point mutations by using the sensitive Point-EXACCT method. RESULTS: A total of 40% of the lung cancer patients had peripheral tumors, and 17 patients had a nondiagnostic bronchoscopy. In these patients, RASSF1A methylation was detected in the washings of four patients (24%), and KRAS mutations were detected in the washings of two patients (12%). In total, 29% of the false-negative or doubtful cytology results were accompanied by RASSF1A methylation or KRAS mutation results that were highly suggestive of malignancy. The proportion of RASSF1A methylation was significantly higher in central and larger tumors. No relevant RASSF1A methylation was detected in control samples. CONCLUSIONS: Our data suggest that the molecular analysis of two biomarkers in nondiagnostic bronchial washings may better guide diagnostic procedures in patients with suspected lung cancer. PMID- 21700688 TI - Systemic vascular dysfunction in patients with chronic mountain sickness. AB - BACKGROUND: Chronic mountain sickness (CMS) is a major public health problem characterized by exaggerated hypoxemia and erythrocytosis. In more advanced stages, patients with CMS often present with functional and structural changes of the pulmonary circulation, but there is little information on the systemic circulation. In patients with diseases associated with chronic hypoxemia at low altitude, systemic vascular function is altered. We hypothesized that patients with CMS have systemic vascular dysfunction that may predispose them to increased systemic cardiovascular morbidity. METHODS: To test this hypothesis, we assessed systemic endothelial function (by flow-mediated dilation [FMD]), arterial stiffness, and carotid intima-media thickness and arterial oxygen saturation (Sao(2)) in 23 patients with CMS without additional classic cardiovascular risk factors and 27 age-matched healthy mountain dwellers born and permanently living at 3,600 m. For some analyses, subjects were classified according to baseline Sao(2) quartiles; FMD of the highest quartile subgroup (Sao(2) >= 90%) was used as a reference value for post hoc comparisons. RESULTS: Patients with CMS had marked systemic vascular dysfunction as evidenced by impaired FMD (CMS, 4.6% +/- 1.2%; control subjects, 7.6% +/- 1.9%; P < .0001), greater pulse wave velocity (10.6 +/- 2.1 m/s vs 8.4 +/- 1.0 m/s, P < .001), and greater carotid intima-media thickness (690 +/- 120 MUm vs 570 +/- 110 MUm, P = .001). A positive relationship existed between Sao(2) and FMD (r = 0.62, P < .0001). Oxygen inhalation improved (P < .001) but did not normalize FMD in patients with CMS, although it normalized FMD in hypoxemic control subjects (Sao(2) < 90%) and had no detectable effect in normoxemic control subjects (Sao(2) >= 90%). CONCLUSIONS: Patients with CMS show marked systemic vascular dysfunction. Structural and functional alterations contribute to this problem that may predispose these patients to premature cardiovascular disease. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01182792; URL: www.clinicaltrials.gov. PMID- 21700689 TI - Changes in mortality among US adults with COPD in two national cohorts recruited from 1971-1975 and 1988-1994. AB - BACKGROUND: COPD is a major contributor to the global burden of disease. Our objective was to examine changes in the mortality rate among persons with COPD in the United States. METHODS: We conducted prospective studies using data from 5,185 participants in the National Health and Nutrition Examination Survey (NHANES) I Epidemiologic Follow-up Study (baseline examination from 1971-1975; follow-up from 1992-1993) and 10,954 participants of the NHANES III Linked Mortality Study (baseline examination from 1988-1994; follow-up through 2006). RESULTS: The age-adjusted rate (per 1,000 person-years) among participants with moderate or severe COPD (23.9 and 20.2) was about 2.5 to 3 times higher than the rate among participants with normal lung function (10.4 and 6.2) in NHANES I and NHANES III, respectively. Compared with NHANES I, the mortality rate among participants in NHANES III decreased by 15.8% for those with moderate or severe COPD, 25.2% for those with mild COPD, 35.9% for those with respiratory symptoms with normal lung function, 16.6% for those with restrictive impairment, and 40.1% for those with normal lung function. However, the decrease did not reach statistical significance among participants with moderate or severe COPD. The decreases in the mortality rate among men with moderate or severe COPD (-17.8%) or with restrictive impairment (-35.1%) exceeded the changes among women (+3% and -6.1%, respectively). CONCLUSIONS: The secular decline in the mortality rate in the United States benefited people with COPD less than those with normal lung function. PMID- 21700690 TI - Anesthetizing the obese. PMID- 21700691 TI - The effect of obesity and anesthetic maintenance regimen on postoperative pulmonary complications. PMID- 21700692 TI - Do let the blood pressure fall: but maybe not so much or so often. PMID- 21700693 TI - Echo didactics: a new venue for basic and advanced echo education in Anesthesia & Analgesia. PMID- 21700694 TI - Let the patient drive the informed consent process: ignore legal requirements. PMID- 21700695 TI - Is hand contamination of anesthesiologists really an "important" risk factor for intraoperative bacterial transmission? PMID- 21700696 TI - Rational design of end-points to evaluate performance of the C-MAC D-blade videolaryngoscope during routine and difficult intubation. PMID- 21700697 TI - Successful tracheal intubation using the Airtraq in thoraco-omphalopagus twins. PMID- 21700698 TI - Exchange catheter-assisted fiberoptic nasal intubation: a modified technique. PMID- 21700699 TI - Dermabond decreases pericatheter local anesthetic leakage after continuous perineural infusions. PMID- 21700700 TI - Acid ceramidase expression modulates the sensitivity of A375 melanoma cells to dacarbazine. AB - Dacarbazine (DTIC) is the treatment of choice for metastatic melanoma, but its response in patients remains very poor. Ceramide has been shown to be a death effector and to play an important role in regulating cancer cell growth upon chemotherapy. Among ceramidases, the enzymes that catabolize ceramide, acid ceramidase (aCDase) has been implicated in cancer progression. Here we show that DTIC elicits a time- and dose-dependent decrease of aCDase activity and an increase of intracellular ceramide levels in human A375 melanoma cells. The loss of enzyme activity occurred as a consequence of reactive oxygen species-dependent activation of cathepsin B-mediated degradation of aCDase. These events preceded autophagic features and loss of cell viability. Down-regulation of acid but not neutral or alkaline ceramidase 2 resulted in elevated levels of ceramide and sensitization to the toxic effects of DTIC. Conversely, inducible overexpression of acid but not neutral ceramidase reduced ceramide levels and conferred resistance to DTIC. In conclusion, we report that increased levels of ceramide, due to enhanced degradation of aCDase, are in part responsible for the cell death effects of DTIC. These results suggest that down-regulation of aCDase alone or in combination with DTIC may represent a useful tool in the treatment of metastatic melanoma. PMID- 21700701 TI - Phospholipid synthesis participates in the regulation of diacylglycerol required for membrane trafficking at the Golgi complex. AB - The lipid metabolite diacylglycerol (DAG) is required for transport carrier biogenesis at the Golgi, although how cells regulate its levels is not well understood. Phospholipid synthesis involves highly regulated pathways that consume DAG and can contribute to its regulation. Here we altered phosphatidylcholine (PC) and phosphatidylinositol synthesis for a short period of time in CHO cells to evaluate the changes in DAG and its effects in membrane trafficking at the Golgi. We found that cellular DAG rapidly increased when PC synthesis was inhibited at the non-permissive temperature for the rate-limiting step of PC synthesis in CHO-MT58 cells. DAG also increased when choline and inositol were not supplied. The major phospholipid classes and triacylglycerol remained unaltered for both experimental approaches. The analysis of Golgi ultrastructure and membrane trafficking showed that 1) the accumulation of the budding vesicular profiles induced by propanolol was prevented by inhibition of PC synthesis, 2) the density of KDEL receptor-containing punctated structures at the endoplasmic reticulum-Golgi interface correlated with the amount of DAG, and 3) the post-Golgi transport of the yellow fluorescent temperature-sensitive G protein of stomatitis virus and the secretion of a secretory form of HRP were both reduced when DAG was lowered. We confirmed that DAG-consuming reactions of lipid synthesis were present in Golgi-enriched fractions. We conclude that phospholipid synthesis pathways play a significant role to regulate the DAG required in Golgi-dependent membrane trafficking. PMID- 21700702 TI - N-acetylglucosamine (GlcNAc) induction of hyphal morphogenesis and transcriptional responses in Candida albicans are not dependent on its metabolism. AB - N-acetylglucosamine (GlcNAc) stimulates important signaling pathways in a wide range of organisms. In the human fungal pathogen Candida albicans, GlcNAc stimulates hyphal cell morphogenesis, virulence genes, and the genes needed to catabolize GlcNAc. Previous studies on the GlcNAc transporter (NGT1) indicated that GlcNAc has to be internalized to induce signaling. Therefore, the role of GlcNAc catabolism was examined by deleting the genes required to phosphorylate, deacetylate, and deaminate GlcNAc to convert it to fructose-6-PO(4) (HXK1, NAG1, and DAC1). As expected, the mutants failed to utilize GlcNAc. Surprisingly, GlcNAc inhibited the growth of the nag1Delta and dac1Delta mutants in the presence of other sugars, suggesting that excess GlcNAc-6-PO(4) is deleterious. Interestingly, both hxk1Delta and an hxk1Delta nag1Delta dac1Delta triple mutant could be efficiently stimulated by GlcNAc to form hyphae. These mutants could also be stimulated to express GlcNAc-regulated genes. Because GlcNAc must be phosphorylated by Hxk1 to be catabolized, and also for it to enter the anabolic pathways that form chitin, N-linked glycosylation, and glycosylphosphatidylinositol anchors, the mutant phenotypes indicate that GlcNAc metabolism is not needed to induce signaling in C. albicans. Thus, these studies in C. albicans reveal a novel role for GlcNAc in cell signaling that may also regulate critical pathways in other organisms. PMID- 21700703 TI - D-amino acid oxidase activity is inhibited by an interaction with bassoon protein at the presynaptic active zone. AB - Schizophrenia is a highly heritable neuropsychiatric disorder affecting ~1% of the world's population. Linkage and association studies have identified multiple candidate schizophrenia susceptibility genes whose functions converge on the glutamatergic neurotransmitter system. One such susceptibility gene encoding D amino acid oxidase (DAO), an enzyme that metabolizes the NMDA receptor (NMDAR) co agonist D-serine, has the potential to modulate NMDAR function in the context of schizophrenia. To further investigate its cellular regulation, we sought to identify DAO-interacting proteins that participate in its functional regulation in rat cerebellum, where DAO expression is especially high. Immunoprecipitation with DAO-specific antibodies and subsequent mass spectrometric analysis of co precipitated proteins yielded 24 putative DAO-interacting proteins. The most robust interactions occurred with known components of the presynaptic active zone, such as bassoon (BSN) and piccolo (PCLO). The interaction of DAO with BSN was confirmed through co-immunoprecipitation assays using DAO- and BSN-specific antibodies. Moreover, DAO and BSN colocalized with one another in cultured cerebellar granule cells and in synaptic junction membrane protein fractions derived from rat cerebellum. The functional consequences of this interaction were studied through enzyme assay experiments, where DAO enzymatic activity was significantly inhibited as a result of its interaction with BSN. Taking these results together, we hypothesize that synaptic D-serine concentrations may be under tight regulation by a BSN-DAO complex. We therefore predict that this mechanism plays a role in the modulation of glutamatergic signaling through NMDARs. It also furthers our understanding of the biology underlying this potential therapeutic entry point for schizophrenia and other psychiatric disorders. PMID- 21700704 TI - Purkinje cell degeneration in pcd mice reveals large scale chromatin reorganization and gene silencing linked to defective DNA repair. AB - DNA repair protects neurons against spontaneous or disease-associated DNA damage. Dysfunctions of this mechanism underlie a growing list of neurodegenerative disorders. The Purkinje cell (PC) degeneration mutation causes the loss of nna1 expression and is associated with the postnatal degeneration of PCs. This PC degeneration dramatically affects nuclear architecture and provides an excellent model to elucidate the nuclear mechanisms involved in a whole array of neurodegenerative disorders. We used immunocytochemistry for histone variants and components of the DNA damage response, an in situ transcription assay, and in situ hybridization for telomeres to analyze changes in chromatin architecture and function. We demonstrate that the phosphorylation of H2AX, a DNA damage signal, and the trimethylation of the histone H4K20, a repressive mark, in extensive domains of genome are epigenetic hallmarks of chromatin in degenerating PCs. These histone modifications are associated with a large scale reorganization of chromatin, telomere clustering, and heterochromatin-induced gene silencing, all of them key factors in PC degeneration. Furthermore, ataxia telangiectasia mutated and 53BP1, two components of the DNA repair pathway, fail to be concentrated in the damaged chromatin compartments, even though the expression levels of their coding genes were slightly up-regulated. Although the mechanism by which Nna1 loss of function leads to PC neurodegeneration is undefined, the progressive accumulation of DNA damage in chromosome territories irreversibly compromises global gene transcription and seems to trigger PC degeneration and death. PMID- 21700705 TI - FtsH-dependent processing of RNase colicins D and E3 means that only the cytotoxic domains are imported into the cytoplasm. AB - It has long been suggested that the import of nuclease colicins requires protein processing; however it had never been formally demonstrated. Here we show that two RNase colicins, E3 and D, which appropriate two different translocation machineries to cross the outer membrane (BtuB/Tol and FepA/TonB, respectively), undergo a processing step inside the cell that is essential to their killing action. We have detected the presence of the C-terminal catalytic domains of these colicins in the cytoplasm of target bacteria. The same processed forms were identified in both colicin-sensitive cells and in cells immune to colicin because of the expression of the cognate immunity protein. We demonstrate that the inner membrane protease FtsH is necessary for the processing of colicins D and E3 during their import. We also show that the signal peptidase LepB interacts directly with the central domain of colicin D in vitro and that it is a specific but not a catalytic requirement for in vivo processing of colicin D. The interaction of colicin D with LepB may ensure a stable association with the inner membrane that in turn allows the colicin recognition by FtsH. We have also shown that the outer membrane protease OmpT is responsible for alternative and distinct endoproteolytic cleavages of colicins D and E3 in vitro, presumably reflecting its known role in the bacterial defense against antimicrobial peptides. Even though the OmpT-catalyzed in vitro cleavage also liberates the catalytic domain from colicins D and E3, it is not involved in the processing of nuclease colicins during their import into the cytoplasm. PMID- 21700706 TI - Building blocks of the nexin-dynein regulatory complex in Chlamydomonas flagella. AB - The directional flow generated by motile cilia and flagella is critical for many processes, including human development and organ function. Normal beating requires the control and coordination of thousands of dynein motors, and the nexin-dynein regulatory complex (N-DRC) has been identified as an important regulatory node for orchestrating dynein activity. The nexin link appears to be critical for the transformation of dynein-driven, linear microtubule sliding to flagellar bending, yet the molecular composition and mechanism of the N-DRC remain largely unknown. Here, we used proteomics with special attention to protein phosphorylation to analyze the composition of the N-DRC and to determine which subunits may be important for signal transduction. Two-dimensional electrophoresis and MALDI-TOF mass spectrometry of WT and mutant flagellar axonemes from Chlamydomonas identified 12 N-DRC-associated proteins, including all seven previously observed N-DRC components. Sequence and PCR analyses identified the mutation responsible for the phenotype of the sup-pf-4 strain, and biochemical comparison with a radial spoke mutant revealed two components that may link the N-DRC and the radial spokes. Phosphoproteomics revealed eight proteins with phosphorylated isoforms for which the isoform patterns changed with the genotype as well as two components that may play pivotal roles in N-DRC function through their phosphorylation status. These data were assembled into a model of the N-DRC that explains aspects of its regulatory function. PMID- 21700707 TI - Cutting off functional loops from homodimeric enzyme superoxide dismutase 1 (SOD1) leaves monomeric beta-barrels. AB - Demetallation of the homodimeric enzyme Cu/Zn-superoxide dismutase (SOD1) is known to unleash pronounced dynamic motions in the long active-site loops that comprise almost a third of the folded structure. The resulting apo species, which shows increased propensity to aggregate, stands out as the prime disease precursor in amyotrophic lateral sclerosis (ALS). Even so, the detailed structural properties of the apoSOD1 framework have remained elusive and controversial. In this study, we examine the structural interplay between the central apoSOD1 barrel and the active-site loops by simply cutting them off; loops IV and VII were substituted with short Gly-Ala-Gly linkers. The results show that loop removal breaks the dimer interface and leads to soluble, monomeric beta-barrels with high structural integrity. NMR-detected nuclear Overhauser effects are found between all of the constituent beta-strands, confirming ordered interactions across the whole barrel. Moreover, the breathing motions of the SOD1 barrel are overall insensitive to loop removal and yield hydrogen/deuterium protection factors typical for cooperatively folded proteins (i.e. the active site loops act as a "bolt-on" domain with little dynamic influence on its structural foundation). The sole exceptions are the relatively low protection factors in beta-strand 5 and the turn around Gly-93, a hot spot for ALS-provoking mutations, which decrease even further upon loop removal. Taken together, these data suggest that the cytotoxic function of apoSOD1 does not emerge from its folded ground state but from a high energy intermediate or even from the denatured ensemble. PMID- 21700709 TI - Beta-arrestin-1 protein represses adipogenesis and inflammatory responses through its interaction with peroxisome proliferator-activated receptor-gamma (PPARgamma). AB - One of the master regulators of adipogenesis and macrophage function is peroxisome proliferator-activated receptor-gamma (PPARgamma). Here, we report that a deficiency of beta-arrestin-1 expression affects PPARgamma-mediated expression of lipid metabolic genes and inflammatory genes. Further mechanistic studies revealed that beta-arrestin-1 interacts with PPARgamma. beta-Arrestin-1 suppressed the formation of a complex between PPARgamma and 9-cis-retinoic acid receptor-alpha through its direct interaction with PPARgamma. The interaction of beta-arrestin-1 with PPARgamma repressed PPARgamma/9-cis-retinoic acid receptor alpha function but promoted PPARgamma/nuclear receptor corepressor function in PPARgamma-mediated adipogenesis and inflammatory gene expression. Consistent with these results, a deficiency of beta-arrestin-1 binding to PPARgamma abolished its suppression of PPARgamma-dependent adipogenesis and inflammatory responses. These results indicate that the regulation of PPARgamma by beta-arrestin-1 is critical. Furthermore, in vivo expression of beta-arrestin-1 (but not the binding-deficient mutant) significantly repressed adipogenesis, macrophage infiltration, and diet induced obesity and improved glucose tolerance and systemic insulin sensitivity. Therefore, our findings not only reveal a molecular mechanism for the modulation of obesity by beta-arrestin-1 but also suggest a potential tactical approach against obesity and its associated metabolic disorders. PMID- 21700708 TI - Inducible nitric-oxide synthase and nitric oxide donor decrease insulin receptor substrate-2 protein expression by promoting proteasome-dependent degradation in pancreatic beta-cells: involvement of glycogen synthase kinase-3beta. AB - Insulin receptor substrate-2 (IRS-2) plays a critical role in the survival and function of pancreatic beta-cells. Gene disruption of IRS-2 results in failure of the beta-cell compensatory mechanism and diabetes. Nonetheless, the regulation of IRS-2 protein expression in beta-cells remains largely unknown. Inducible nitric oxide synthase (iNOS), a major mediator of inflammation, has been implicated in beta-cell damage in type 1 and type 2 diabetes. The effects of iNOS on IRS-2 expression have not yet been investigated in beta-cells. Here, we show that iNOS and NO donor decreased IRS-2 protein expression in INS-1/832 insulinoma cells and mouse islets, whereas IRS-2 mRNA levels were not altered. Interleukin-1beta (IL 1beta), alone or in combination with interferon-gamma (IFN-gamma), reduced IRS-2 protein expression in an iNOS-dependent manner without altering IRS-2 mRNA levels. Proteasome inhibitors, MG132 and lactacystin, blocked the NO donor induced reduction in IRS-2 protein expression. Treatment with NO donor led to activation of glycogen synthase kinase-3beta (GSK-3beta) and c-Jun N-terminal kinase (JNK/SAPK) in beta-cells. Inhibition of GSK-3beta by pharmacological inhibitors or siRNA-mediated knockdown significantly prevented NO donor-induced reduction in IRS-2 expression in beta-cells. In contrast, a JNK inhibitor, SP600125, did not effectively block reduced IRS-2 expression in NO donor-treated beta-cells. These data indicate that iNOS-derived NO reduces IRS-2 expression by promoting protein degradation, at least in part, through a GSK-3beta-dependent mechanism. Our findings suggest that iNOS-mediated decreased IRS-2 expression may contribute to the progression and/or exacerbation of beta-cell failure in diabetes. PMID- 21700711 TI - Latent transforming growth factor beta-binding proteins-2 and -3 inhibit the proprotein convertase 5/6A. AB - The basic amino acid-specific proprotein convertase 5/6 (PC5/6) is an essential secretory protease, as knock-out mice die at birth and exhibit multiple homeotic transformation defects, including impaired bone morphogenesis and lung structure. Some of the observed defects were attributed to impaired processing of the TGFbeta-like growth differentiating factor 11 precursor (proGdf11). In this work we present evidence that the latent TGFbeta-binding proteins 2 and 3 (LTBP-2 and 3) inhibit the extracellular processing of proGdf11 by PC5/6A. This is partly due to the binding of LTBPs in the endoplasmic reticulum to the zymogen proPC5/6A, thus allowing the complex to exit the endoplasmic reticulum and be sequestered as an inactive zymogen in the extracellular matrix but not at the cell surface. This results in lower levels of PC5/6A in the media, without affecting those of PACE4, Furin, or a soluble form of PC7. The secreted soluble protease-specific activity of PC5/6A or a variant lacking the C-terminal Cys-rich domain (PC5/6-DeltaCRD) is significantly decreased when co-expressed with LTBPs in cells. A similar enzymatic inhibition seems to apply to PACE4 and Furin. In situ hybridization analyses revealed extensive co-localization of PC5/6 and LTBP-3 mRNAs in mice at embryonic day 15.5 and post partum day 1. In conclusion, this is the first time that a zymogen of the proprotein convertases was shown to exit the endoplasmic reticulum in the presence of LTBPs, representing a potential novel mechanism for the regulation of PC5/6A activity, e.g. in tissues such as bone and lung where LTBP-3 and PC5/6 co-localize. PMID- 21700710 TI - Peroxisome proliferator-activated receptor gamma induces apoptosis and inhibits autophagy of human monocyte-derived macrophages via induction of cathepsin L: potential role in atherosclerosis. AB - Macrophages play a pivotal role in the pathophysiology of atherosclerosis. These cells express cathepsin L (CatL), a cysteine protease that has been implicated in atherogenesis and the associated arterial remodeling. In addition, macrophages highly express peroxisome proliferator-activated receptor (PPAR) gamma, a transcription factor that regulates numerous genes important for lipid and lipoprotein metabolism, for glucose homeostasis, and inflammation. Hence, PPARgamma might affect macrophage function in the context of chronic inflammation such as atherogenesis. In the present study, we examined the effect of PPARgamma activation on the expression of CatL in human monocyte-derived macrophages (HMDM). Activation of PPARgamma by the specific agonist GW929 concentration dependently increased the levels of CatL mRNA and protein in HMDM. By promoter analysis, we identified a functional PPAR response element-like sequence that positively regulates CatL expression. In addition, we found that PPARgamma induced CatL promotes the degradation of Bcl2 without affecting Bax protein levels. Consistently, degradation of Bcl2 could be prevented by a specific CatL inhibitor, confirming the causative role of CatL. PPARgamma-induced CatL was found to decrease autophagy through reduction of beclin 1 and LC3 protein levels. The reduction of these proteins involved in autophagic cell death was antagonized either by the CatL inhibitor or by CatL knockdown. In conclusion, our data show that PPARgamma can specifically induce CatL, a proatherogenic protease, in HMDM. In turn, CatL inhibits autophagy and induces apoptosis. Thus, the proatherogenic effect of CatL could be neutralized by apoptosis, a beneficial phenomenon, at least in the early stages of atherosclerosis. PMID- 21700712 TI - Perceived rewards at work and cardiovascular health. PMID- 21700714 TI - Ecological momentary assessment of maternal cortisol profiles over a multiple-day period predicts the length of human gestation. AB - OBJECTIVE: Biobehavioral models of prenatal stress highlight the importance of the stress-related hormone cortisol. However, the association between maternal cortisol levels and the length of human gestation requires further investigation because most previous studies have relied on one-time cortisol measures assessed at varying gestational ages. This study assessed whether ecological momentary assessment (EMA) of cortisol sampling improves the ability to predict the length of human gestation. In addition, associations between EMA-based measures of psychological state (negative affect) with cortisol levels during pregnancy were assessed. METHODS: For a 4-day period, 25 healthy pregnant women (mean gestational age at assessment = 23.4 [standard deviation = 9.1] weeks) collected seven salivary samples per day for the assessment of cortisol and provided a rating of negative affect every waking hour using an electronic diary. RESULTS: Higher salivary cortisol concentrations at awakening and throughout the day (p = .001), as well as a flatter cortisol response to awakening (p = .005), were associated with shorter length of gestation. Women who delivered an infant at 36 weeks of gestations had 13% higher salivary cortisol levels at awakening than women who delivered an infant at 41 weeks of gestation. The EMA-based measure of negative affect was associated with higher cortisol throughout the day (p = .006) but not to gestational length (p = .641). The one-time measure of cortisol was not associated with length of gestation, and traditional retrospective recall measures of negative affect were not associated with cortisol. CONCLUSIONS: Our findings support the ecological validity of repeated ambulatory assessments of cortisol in pregnancy and their ability to improve the prediction of adverse birth outcomes. PMID- 21700713 TI - The interplay between physical activity and anxiety sensitivity in fearful responding to carbon dioxide challenge. AB - OBJECTIVE: Physical activity may confer protective effects in the development of anxiety and its disorders. These effects may be particularly strong among individuals who have elevated levels of anxiety sensitivity (AS; i.e., the fear of somatic arousal), an established cognitive-based risk factor for anxiety and its disorders. The present study performed a laboratory test of the interplay between physical activity and AS. METHODS: The participants were adults free of Axis I psychopathology (n = 145) who completed measures of physical activity and AS before undergoing a recurrent 20% carbon dioxide-enriched air (CO(2)) challenge. RESULTS: Consistent with the hypothesis, physical activity was significantly related to CO(2) challenge reactivity among persons with elevated levels of AS, at high levels of physical activity (p < .001) but not at low levels of physical activity (p = .90). Also consistent with hypothesis, irrespective of the level of physical activity, physical activity did not relate significantly to CO(2) challenge reactivity among persons with normative levels of AS (p = .28). CONCLUSIONS: These findings provide novel empirical insight into the role that physical activity may play in terms of resiliency for the development of anxiety disorders. Specifically, the protective effects of physical activity may only be evident at higher doses and among persons who are at increased risk of developing anxiety disorders because they have elevated AS. PMID- 21700715 TI - Contributions of area Te2 to rat recognition memory. AB - Ablations and local intracerebral infusions were used to determine the role of rat temporal association cortex (area Te2) in object recognition memory, so that this role might be compared with that of the adjacent perirhinal cortex (PRH). Bilateral lesions of Te2 impaired recognition memory measured by preferential exploration of a novel rather than a familiar object at delays >=20 min but not after a 5-min delay. Local infusion bilaterally into Te2 of (1) CNQX to block AMPA/kainate receptors or (2) lidocaine to block axonal transmission or (3) AP5, an NMDA receptor antagonist, impaired recognition memory after a 24-h but not a 20-min delay. In PRH all these manipulations impair recognition memory after a 20 min as well as a 24-h delay. UBP302, a GluK1 kainate receptor antagonist, impaired recognition memory after a 24-h but not a 20-min delay, contrasting with its action in PRH where it impairs only shorter-term (20 min) recognition memory. Also in contrast to PRH, infusion of the muscarinic receptor antagonist scopolamine was without effect. The Te2 impairments could not readily be ascribed to perceptual deficits. Hence, Te2 is essential for object recognition memory at delays >5 or 20 min. Thus, at long delays both area Te2 and PRH are necessary for object recognition memory. PMID- 21700717 TI - Can the hair follicle become a model for studying selected aspects of human ocular immune privilege? AB - Immune privilege (IP) is important in maintaining ocular health. Understanding the mechanism underlying this dynamic state would assist in treating inflammatory eye diseases. Despite substantial progress in defining eye IP mechanisms, because of the scarcity of human ocular tissue for research purposes, most of what we know about ocular IP is based on rodent models (of unclear relevance to human eye immunology) and on cultured human eye-derived cells that cannot faithfully mirror the complex cell-tissue interactions that underlie normal human ocular IP in situ. Therefore, accessible, instructive, and clinically relevant human in vitro models are needed for exploring the general principles of why and how IP collapses under clinically relevant experimental conditions and how it can be protected or even restored therapeutically. Among the few human IP sites, the easily accessible and abundantly available hair follicle (HF) may offer one such surrogate model. There are excellent human HF organ culture systems for the study of HF IP in situ that instructively complement in vivo autoimmunity research in the human system. In this article, we delineate that the human eye and HF, despite their obvious differences, share key molecular and cellular mechanisms for maintaining IP. We argue that, therefore, human scalp HFs can provide an unconventional, but highly instructive, accessible, easily manipulated, and clinically relevant preclinical model for selected aspects of ocular IP. This essay is an attempt to encourage professional eye researchers to turn their attention, with appropriate caveats, to this candidate surrogate model for ocular IP in the human system. PMID- 21700716 TI - Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4. AB - Programmed cell death 4 (PDCD4) has been described as a tumor suppressor, with high expression correlating with better outcomes in a number of cancer types. Yet a substantial number of cancer patients with high PDCD4 in tumors have poor survival, suggesting that oncogenic pathways may inhibit or change PDCD4 function. Here, we explore the significance of PDCD4 in breast cancer and identify protein arginine methyltransferase 5 (PRMT5) as a cofactor that radically alters PDCD4 function. Specifically, we find that coexpression of PDCD4 and PRMT5 in an orthotopic model of breast cancer causes accelerated tumor growth and that this growth phenotype is dependent on both the catalytic activity of PRMT5 and a site of methylation within the N-terminal region of PDCD4. In agreement with the xenograft model, elevated PDCD4 expression was found to correlate with worse outcome within the cohort of breast cancer patients whose tumors contain higher levels of PRMT5. These results reveal a new cofactor for PDCD4 that alters its tumor suppressor functions and point to the utility of PDCD4/PRMT5 status as both a prognostic biomarker and a potential target for chemotherapy. PMID- 21700718 TI - Blink efficiency: a neglected area of ocular surface disease management? PMID- 21700719 TI - CrkL is a co-activator of estrogen receptor alpha that enhances tumorigenic potential in cancer. AB - Signaling via estrogen receptor (ER) occurs by interacting with many proteins. Nuclear interactome analysis of ERalpha in an embryo implantation model revealed the association of chicken tumor virus no. 10 regulator of kinase like (CrkL) with ERalpha, which was further validated by mammalian two-hybrid assay as well as coimmunoprecipitation and colocalization. Mutation in LPALL motif of CrkL disrupts the ERalpha-CrkL interaction and its transactivation potential, thereby suggesting that the interaction is mediated via its single ER binding motif, Leu Pro-Ala-Leu-Leu (LXXLL) motif in the sarcoma homology (SH)2 domain. CrkL deletion constructs of SH2 domain target to the nucleus due to presence of nuclear localization signal. Interestingly, the SH2-SH3 (N terminal) construct shows an increased transactivation potential like CrkI. Weak interaction capability of mutated ERalpha-Y538F with CrkL validates that CrkL interacts with ERalpha via its YDLL motif at Tyr 541. In an attempt to understand the physiological relevance of this association, we investigated the impact on cell proliferation using a cancer model, because events associated in the process of pregnancy and cancer are analogous. Also, overexpression of CrkL is frequently associated with tumorigenesis. However, its significance in hormone-regulated cancers still remains obscure. Here, we demonstrate that association of ERalpha and CrkL directly enhances the tumorigenic potential of CrkL, thus pointing to its role in cell proliferation. In human endometrial cancers, we observed a strong association between ERalpha and CrkL levels. Thus, the molecular signaling set off by ERalpha and CrkL association may have a central role in pregnancy and cancer, two events which share parallels in growth, invasion, and immune tolerance. PMID- 21700720 TI - Impaired FSHbeta expression in the pituitaries of Foxl2 mutant animals. AB - Forkhead box L2 (FoxL2) is required for ovarian development and differentiation. FoxL2 is also expressed in the pituitary where it has been implicated in the development and regulation of gonadotropes, which secrete LH and FSH, the endocrine signals that regulate folliculogenesis in the ovary and spermatogenesis in the testis. Here, we show that FoxL2 is not required for the specification of gonadotropes; the pituitaries of Foxl2 mutant mice contain normal numbers of gonadotropes that express glycoprotein alpha subunit and LHbeta. Whereas the specification of gonadotropes and all other hormonal cell types is normal in the pituitaries of Foxl2 mutant animals, FSHbeta levels are severely impaired in both male and female animals, suggesting that FoxL2 is required for normal Fshb expression. The size of the pituitary is reduced in proportion to the smaller body size of Foxl2 mutants, with a concomitant increase in the pituitary cellular density. In primary pituitary cultures, activin induces FSH secretion and Fshb mRNA expression in cells from wild-type mice. In cells from Foxl2 mutant mice, however, FSH secretion is not detected, and activin is unable to drive Fshb expression, suggesting that the mechanism of activin-dependent activation of Fshb transcription is impaired. However, a small number of gonadotropes in the ventromedial region of the pituitaries from Foxl2 mutant mice maintain FSHbeta expression, suggesting that a FoxL2- and activin-independent mechanism can drive Fshb transcription. These data indicate that, in addition to its role in the ovary, FoxL2 function in the pituitary is required for normal expression of FSH. PMID- 21700721 TI - Asymmetric leaves2 and Elongator, a histone acetyltransferase complex, mediate the establishment of polarity in leaves of Arabidopsis thaliana. AB - Leaf primordia are generated around the shoot apical meristem. Mutation of the ASYMMETRIC LEAVES2 (AS2) gene of Arabidopsis thaliana results in defects in repression of the meristematic and indeterminate state, establishment of adaxial abaxial polarity and left-right symmetry in leaves. AS2 represses transcription of meristem-specific class 1 KNOX homeobox genes and of the abaxial-determinant genes ETTIN/ARF3, KANADI2 and YABBY5. To clarify the role of AS2 in the establishment of leaf polarity, we isolated mutations that enhanced the polarity defects associated with as2. We describe here the enhancer-of-asymmetric-leaves two1 (east1) mutation, which caused the formation of filamentous leaves with abaxialized epidermis on the as2-1 background. Levels of transcripts of class 1 KNOX and abaxial-determinant genes were markedly higher in as2-1 east1-1 mutant plants than in the wild-type and corresponding single-mutant plants. EAST1 encodes the histone acetyltransferase ELONGATA3 (ELO3), a component of the Elongator complex. Genetic analysis, using mutations in genes involved in the biogenesis of a trans-acting small interfering RNA (ta-siRNA), revealed that ELO3 mediated establishment of leaf polarity independently of AS2 and the ta-siRNA related pathway. Treatment with an inhibitor of histone deacetylases (HDACs) caused additive polarity defects in as2-1 east1-1 mutant plants, suggesting the operation of an ELO3 pathway, independent of the HDAC pathway, in the determination of polarity. We propose that multiple pathways play important roles in repression of the expression of class 1 KNOX and abaxial-determinant genes in the development of the adaxial domain of leaves and, thus, in the establishment of leaf polarity. PMID- 21700722 TI - EMF1 interacts with EIP1, EIP6 or EIP9 involved in the regulation of flowering time in Arabidopsis. AB - The EMBRYONIC FLOWER (EMF) 1 gene has been shown to be necessary for maintenance of vegetative development. To investigate the molecular mechanism of EMF1 mediated plant development, we screened EMF1-interacting proteins and identified 11 candidate proteins using the yeast two-hybrid system. Among the candidate genes, three EMF1-Interacting Protein (EIP) genes, EIP1, EIP6 and EIP9, are predicted to encode a WNK (with-no-lysine) kinase, a B-box zinc-finger protein and a DnaJ-domain protein, respectively. The expression patterns of EIP1, EIP6 and EIP9 were similar to that of EMF1, and EMF1-EIP1, EMF1-EIP6 and EMF1-EIP9 heterodimers were localized in the nucleus. In addition, eip1, eip6 and eip9 mutants flowered early and showed increased expression of flowering-time and floral organ identity genes, while EIP1-, EIP6- and EIP9-overexpressing transgenic plants showed late flowering phenotypes. Our results suggest that EMF1 interacts with EIP1, EIP6 and EIP9 during vegetative development to regulate flowering time in Arabidopsis. PMID- 21700723 TI - Beyond the hormone: insulin as an autoimmune target in type 1 diabetes. AB - Insulin is not only the hormone produced by pancreatic beta-cells but also a key target antigen of the autoimmune islet destruction leading to type 1 diabetes. Despite cultural biases between the fields of endocrinology and immunology, these two facets should not be regarded separately, but rather harmonized in a unifying picture of diabetes pathogenesis. There is increasing evidence suggesting that metabolic factors (beta-cell dysfunction, insulin resistance) and immunological components (inflammation and beta-cell-directed adaptive immune responses) may synergize toward islet destruction, with insulin standing at the crossroad of these pathways. This concept further calls for a revision of the classical dichotomy between type 1 and type 2 diabetes because metabolic and immune mechanisms may both contribute to different extents to the development of different forms of diabetes. After providing a background on the mechanisms of beta-cell autoimmunity, we will explain the role of insulin and its precursors as target antigens expressed not only by beta-cells but also in the thymus. Available knowledge on the autoimmune antibody and T-cell responses against insulin will be summarized. A unifying scheme will be proposed to show how different aspects of insulin biology may lead to beta-cell destruction and may be therapeutically exploited. We will argue about possible reasons why insulin remains the mainstay of metabolic control in type 1 diabetes but has so far failed to prevent or halt beta-cell autoimmunity as an immune modulatory reagent. PMID- 21700724 TI - Post-trial period surveillance for randomised controlled cardiovascular studies: submitted protocols, consent forms and the role of the ethics board. AB - BACKGROUND: The post-trial period is the time period after the end of study drug administration. It is unclear whether post-trial arrangements for patient surveillance are routinely included in study protocols and consents, and whether research ethics boards (REB) consider the post-trial period. OBJECTIVES: The objective was to determine whether trial protocols and consent forms reviewed by the REB describe procedures for post-trial period surveillance. METHODS: An observational study of protocols of randomised trials of chronic therapies for cardiac conditions, approved by the REB of two academic institutions affiliated with the University of Toronto in Canada (University Health Network and Mount Sinai Hospital) from 1995 to 2007. Plans for patient surveillance in the post trial period described in the protocol or in the consent form before and after REB approval were recorded. RESULTS: 42 studies were identified including 18 heart failure and 15 coronary artery disease trials. Only four studies planned a clinical visit after trial termination, and an additional three planned a telephone contact after trial completion. Five trials submitted consent forms to the REB with a discussion of the post-trial period. CONCLUSIONS: The majority of protocols and consent forms did not discuss plans for post-trial period surveillance. The post-trial period and the REB approval process could be improved by systematic follow-up being described in the protocol and consent form. The small number of trial protocols evaluated in the study may impair the degree to which the results can be generalised. PMID- 21700726 TI - Double-stranded RNA binding proteins DRB2 and DRB4 have an antagonistic impact on polymerase IV-dependent siRNA levels in Arabidopsis. AB - Biogenesis of the vast majority of plant siRNAs depends on the activity of the plant-specific RNA polymerase IV (PolIV) enzyme. As part of the RNA-dependent DNA methylation (RdDM) process, PolIV-dependent siRNAs (p4-siRNAs) are loaded onto an ARGONAUTE4-containing complex and guide de novo DNA methyltransferases to target loci. Here we show that the double-stranded RNA binding proteins DRB2 and DRB4 are required for proper accumulation of p4-siRNAs. In flowers, loss of DRB2 results in increased accumulation of p4-siRNAs but not ta-siRNAs, inverted repeat (IR)-derived siRNAs, or miRNA. Loss of DRB2 does not impair uniparental expression of p4-dependent siRNAs in developing endosperm, indicating that p4 siRNA increased accumulation is not the result of the activation of the polIV pathway in the male gametophyte. In contrast to drb2, drb4 mutants exhibit reduced p4-siRNA levels, but the extent of this reduction is variable, according to the nature and size of the p4-siRNAs. Loss of DRB4 also leads to a spectacular increase of p4-independent IR-derived 24-nt siRNAs, suggesting a reallocation of factors from p4-dependent to p4-independent siRNA pathways in drb4. Opposite effects of drb2 and drb4 mutations on the accumulation of p4-siRNAs were also observed in vegetative tissues. Moreover, transgenic plants overexpressing DRB2 mimicked drb4 mutants at the morphological and molecular levels, confirming the antagonistic roles of DRB2 and DRB4. PMID- 21700725 TI - Structural aspects of translation termination on the ribosome. AB - Translation of genetic information encoded in messenger RNAs into polypeptide sequences is carried out by ribosomes in all organisms. When a full protein is synthesized, a stop codon positioned in the ribosomal A site signals termination of translation and protein release. Translation termination depends on class I release factors. Recently, atomic-resolution crystal structures were determined for bacterial 70S ribosome termination complexes bound with release factors RF1 or RF2. In combination with recent biochemical studies, the structures resolve long-standing questions about translation termination. They bring insights into the mechanisms of recognition of all three stop codons, peptidyl-tRNA hydrolysis, and coordination of stop-codon recognition with peptidyl-tRNA hydrolysis. In this review, the structural aspects of these mechanisms are discussed. PMID- 21700727 TI - Team situation awareness and the anticipation of patient progress during ICU rounds. AB - BACKGROUND: The ability of medical teams to develop and maintain team situation awareness (team SA) is crucial for patient safety. Limited research has investigated team SA within clinical environments. This study reports the development of a method for investigating team SA during the intensive care unit (ICU) round and describes the results. METHODS: In one ICU, a sample of doctors and nurses (n = 44, who combined to form 37 different teams) were observed during 34 morning ward rounds. Following the clinical review of each patient (n = 105), team members individually recorded their anticipations for expected patient developments over 48 h. Patient-outcome data were collected to determine the accuracy of anticipations. Anticipations were compared among ICU team members, and the degree of consensus was used as a proxy measure of team SA. Self-report and observational data measured team-member involvement and communication during patient reviews. RESULTS: For over half of 105 patients, ICU team members formed conflicting anticipations as to whether patients would deteriorate within 48 h. Senior doctors were most accurate in their predictions. Exploratory analysis found that team processes did not predict team SA. However, the involvement of junior and senior trainee doctors in the patient decision-making process predicted the extent to which those team members formed team SA with senior doctors. CONCLUSIONS: A new method for measuring team SA during the ICU round was successfully employed. A number of areas for future research were identified, including refinement of the situation awareness and teamwork measures. PMID- 21700728 TI - ALS patients with SOD1 mutations in Switzerland show very diverse phenotypes and extremely long survival. PMID- 21700729 TI - Movement related potentials and oscillatory activities in the human internal globus pallidus during voluntary movements. AB - OBJECTIVE: To study internal globus pallidus (GPi) activities and the interactions among the bilateral GPi and motor cortical areas during voluntary movements. METHODS: Five patients with cervical dystonia who underwent bilateral GPi deep brain stimulation (DBS) were studied. Local field potentials from the GPi DBS electrodes and EEG were recorded while the patients performed externally triggered and self-initiated right wrist movements. RESULTS: Movement related potentials were recorded at the GPi bilaterally before the onset of self initiated but not externally triggered movements. In all movements studied, frequency analysis revealed a ~ 10-24 Hz beta event related desynchronisation at bilateral GPi and with EEG recorded over the mid-frontal (Cz-Fz) and the bilateral sensorimotor cortical regions (C3/C4-Cz). A ~ 64-68 Hz, gamma event related synchronisation was found with EEG recorded over the mid-frontal (Cz-Fz), the sensorimotor cortices (C3-Cz) and the GPi contralateral to movements. Both beta event related desynchronisation and gamma event related synchronisation occurred before the onset of self-initiated movements and at the onset of externally triggered movements. There was a resting ~ 5-18 Hz coherence between the bilateral GPi, which attenuated for ~ 1 s during movements. Gamma coherences were observed between EEG recorded over the mid-frontal (Cz-Fz), contralateral sensorimotor cortices (C3-Cz) and the GPi from 0 to 0.5 s after movement onset for externally triggered movements and from 0.5 s before to 0.5 s after movement onset for self-initiated movements. CONCLUSIONS: The beta and gamma frequency bands in the GPi are modulated by the preparation of self-initiated movements and the execution of self-initiated and externally triggered movements. The 5-18 Hz coherence at the bilateral GPi may be related to dystonia and its attenuation may facilitate voluntary movements. PMID- 21700730 TI - Acute disseminated encephalomyelitis following filarial infection. PMID- 21700732 TI - Metaplastic carcinoma with extensive dendritic cell differentiation: a previously unrecognised type of triple-negative breast cancer. PMID- 21700731 TI - Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy. AB - BACKGROUND: This phase II study evaluated single-agent bosutinib in pretreated patients with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Patients received oral bosutinib 400 mg/day. The primary end point was the progression-free survival (PFS) rate at 16 weeks. Secondary end points included objective response rate, clinical benefit rate, 2-year overall survival rate, safety, and changes in levels of bone resorption/formation biomarkers. RESULTS: Seventy-three patients were enrolled and treated. Median time from diagnosis of metastatic disease to initiation of bosutinib treatment was 24.5 months. For the intent-to-treat population, the PFS rate at 16 weeks was 39.6%. Unexpectedly, all responding patients (n = 4) were hormone receptor positive. The clinical benefit rate was 27.4%. The 2-year overall survival rate was 26.4%. The main toxic effects were diarrhea (66%), nausea (55%), and vomiting (47%). Grade 3-4 laboratory aminotransferase elevations occurred in 14 (19%) patients. Myelosuppression was minimal. No consistent changes in the levels of bone resorption/formation biomarkers were seen. CONCLUSIONS: Bosutinib showed promising efficacy in prolonging time to progression in chemotherapy-pretreated patients with locally advanced or metastatic breast cancer. Bosutinib was generally well tolerated, with a safety profile different from that of the Src/Abl tyrosine kinase inhibitor dasatinib in a similar patient population. PMID- 21700733 TI - Is adjuvant chemotherapy useful in lobular breast cancer patients? PMID- 21700734 TI - Evaluating the risk-benefit ratio of adjuvant trastuzumab-based therapy for T1a,bN0M0 HER2-positive breast carcinomas. PMID- 21700737 TI - In vitro assessment of the antifungal and paradoxical activity of different echinocandins against Candida tropicalis biofilms. PMID- 21700735 TI - Sam68 expression and cytoplasmic localization is correlated with lymph node metastasis as well as prognosis in patients with early-stage cervical cancer. AB - BACKGROUND: This study was aimed at investigating the role and molecular mechanism of Sam68 in cervical cancer lymph node metastasis. MATERIALS AND METHODS: Sam68 expression profile was detected by quantitative polymerase chain reaction, western blotting and immunohistochemical staining. Short hairpin RNA interfering approach was employed to suppress endogenous Sam68 expression in cervical cancer cells to determine its role in metastasis and the possible mechanism. RESULTS: Sam68 expression in cervical cancer was significantly up regulated at both messenger RNA and protein levels compared with that in normal cervical tissues. The high expression level of Sam68 and its cytoplasmic localization were significantly associated with risk factors including pelvic lymph node metastasis (P < 0.001), and served as independent prognostic factors for predicting shortening of the overall survival time and disease-free survival time in patients with early-stage cervical cancer. Moreover, down-regulation of Sam68 in cervical cancer cells remarkably inhibited cellular motility and invasion. In addition, down-regulation of Sam68 reversed epithelial-mesenchymal transition through inhibiting the Akt/ GSK-3beta/Snail pathway. CONCLUSION: This study demonstrated that Sam68 could induce cervical cancer lymph node metastasis through regulating epithelial-mesenchymal transition, and Sam68 expression profile possessed the potential to serve as predictors of pelvic lymph node metastasis in cervical cancer patients. PMID- 21700739 TI - Emergence of pandemic B2-O25b-ST131 Escherichia coli harbouring blaCTX-M-3, blaCTX-M-27 and qnrS1 genes. PMID- 21700738 TI - Inhibition of the cytotoxic effect of Clostridium difficile in vitro by Clostridium butyricum MIYAIRI 588 strain. AB - In contrast to most modern pharmaceuticals, probiotics are used in many parts of the world with little or no research data on the complex system of interactions that each strain may elicit in the human body. Research on probiotics has recently become more significant, as probiotics have begun to be prescribed by clinicians as an alternative for some gut infections, especially when antibiotics are contraindicated. This study attempted to elucidate the inhibitory interaction between the Japanese probiotic strain Clostridium butyricum MIYAIRI 588 (CBM588) and the hospital pathogen Clostridium difficile, which is responsible for a large proportion of antibiotic-associated diarrhoea and colitis. CBM588 has previously shown effectiveness against C. difficile in vivo, and here it was found that the toxicity of C. difficile in in vitro co-culture with CBM588 was greatly decreased or absent. This was dependent on the inoculation ratio and was not accounted for by the small degree of growth and mRNA inhibition observed. CBM588 and its cell free supernatant also had no effect on toxin already secreted into the culture medium, and culture of the two strains separated by a semi-permeable membrane resulted in loss of the inhibition. Therefore, it was concluded that the detoxification probably occurred by the inhibition of toxin protein production and that this required close proximity or contact between the two species. The low-pH conditions caused by organic acid secretion were also observed to have inhibitory effects on C. difficile growth, metabolism and toxicity. PMID- 21700740 TI - Administration of a nitric oxide donor inhibits mglA expression by intracellular Francisella tularensis and counteracts phagosomal escape and subversion of TNF alpha secretion. AB - Francisella tularensis is a highly virulent intracellular bacterium capable of rapid multiplication in phagocytic cells. Previous studies have revealed that activation of F. tularensis-infected macrophages leads to control of infection and reactive nitrogen and oxygen species make important contributions to the bacterial killing. We investigated the effects of adding S-nitroso-acetyl penicillamine (SNAP), which generates nitric oxide, or 3-morpholinosydnonimine hydrochloride, which indirectly leads to formation of peroxynitrite, to J774 murine macrophage-like cell cultures infected with F. tularensis LVS. Addition of SNAP led to significantly increased colocalization between LAMP-1 and bacteria, indicating containment of F. tularensis in the phagosome within 2 h, although no killing occurred within 4 h. A specific inhibitory effect on bacterial transcription was observed since the gene encoding the global regulator MglA was inhibited 50-100-fold. F. tularensis-infected J774 cells were incapable of secreting TNF-alpha in response to Escherichia coli LPS but addition of SNAP almost completely reversed the suppression. Similarly, infection with an MglA mutant did not inhibit LPS-induced TNF-alpha secretion of J774 cells. Strong staining of nitrotyrosine was observed in SNAP-treated bacteria, and MS identified nitration of two ribosomal 50S proteins, a CBS domain pair protein and bacterioferritin. The results demonstrated that addition of SNAP initially did not affect the viability of intracellular F. tularensis LVS but led to containment of the bacteria in the phagosome. Moreover, the treatment resulted in modification by nitration of several F. tularensis proteins. PMID- 21700741 TI - Phenotypic and genotypic characterization of two closely related subgroups of Candida rugosa in clinical specimens. AB - In this study, six clinical isolates (two from blood, two from urine and one each from a bronchoalveolar lavage and a vaginal swab) were identified as Candida rugosa based on carbohydrate assimilation profiles using API 20C AUX and ID32 C kits (bioMerieux). Sequence analysis of the D1/D2 domain of the yeasts differentiated the isolates into two subgroups, A and B (three isolates per subgroup), which were closely related (99.1-99.6 % nucleotide similarity) to C. rugosa strain ATCC 10571. Compared with the C. rugosa type strain, the intergenic transcribed spacer (ITS) nucleotide similarity for subgroup A was only 89.2 % (29 mismatches and one deletion) and for subgroup B was 93.7 % (20 mismatches). All isolates grew green colonies on Oxoid Chromogenic Candida Agar, with darker pigmentation observed for subgroup A. All isolates were able to grow at 25-42 degrees C but not at 45 degrees C. The isolates had identical enzymic profiles, as determined by API ZYM (bioMerieux) analysis, and produced proteinase. High amphotericin MICs (>=1 ug ml(-1)) were noted for two isolates from each subgroup. Dose-dependent susceptibility to fluconazole (MIC 32 ug ml(-1)) was noted in a blood isolate. The biofilms of the isolates demonstrated increased resistance to amphotericin and fluconazole. The greater ITS sequence variability of subgroup A isolates is in support of this yeast being recognized as a distinct species; however, further verification using more sophisticated molecular approaches is required. A sequence comparison study suggested the association of subgroup A with environmental sources and subgroup B with clinical sources. Accurate identification and antifungal susceptibility testing of C. rugosa are important in view of its decreased susceptibility to amphotericin and fluconazole. The ITS region has been shown to be a valuable region for differentiation of closely related subgroups of C. rugosa. PMID- 21700742 TI - Differences in Chlamydia trachomatis growth rates in human keratinocytes among lymphogranuloma venereum reference strains and clinical isolates. AB - The pathogenesis of the primary stage of lymphogranuloma venereum (LGV) is poorly understood. There is no skin cell model and LGV pathogenesis studies are therefore carried out on cells of different origin. Moreover, such studies usually use reference strains, which may have evolved over the years in culture. In this study, a model was developed in which Chlamydia trachomatis enters and grows in human keratinocytes at 37 and 33 degrees C. Keratinocytes were infected with fresh clinical isolates and the three LGV reference strains L1, L2 and L3. Growth was monitored for 5 days post-infection using fluorescence microscopy and image analysis software. Chlamydial replication was quicker at 37 than at 33 degrees C, despite 33 degrees C being the temperature of human skin. The serovar L2 reference strain grew significantly faster than the other strains, although the fresh clinical isolates were also serovar L2. When grown in keratinocytes at 33 degrees C, the L2 and L3 reference strains produced much larger inclusions than the other strains tested. This model, which utilizes keratinocytes, better simulates the conditions present at the initial site of infection in LGV than previously published literature, making it a useful tool for future LGV pathogenesis studies. In addition, the results indicate that fresh clinical isolates should be included in LGV pathogenesis studies. PMID- 21700743 TI - Is Lansley for turning? PMID- 21700745 TI - Dying spell caused by vascular ring. PMID- 21700746 TI - Two days with a broken knife blade in the neck--an interesting case of Horner's syndrome. AB - A 25-year-old man presented to the Emergency department in a rural South African hospital after a left, submental neck stab with a knife. Examination was deemed unremarkable, and the patient was discharged, but re-attended 2 days later complaining of a painful, swollen neck. Further examination identified Horner's syndrome, and further investigation revealed that the blade of the knife had remained in the patient's neck. This was successfully removed in theatre. This case illustrates the importance of careful history, examination and diagnostic imaging in the management of penetrating neck injuries. Horner's syndrome can be easily missed in a busy Emergency department and may indicate life-threatening pathology in the context of neck trauma. The difficulties in assessing and managing this type of injury are discussed. PMID- 21700747 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: Use of non-sedating antihistamines in the common cold. AB - A short cut review was carried out to establish whether non-sedating antihistamines reduced symptom severity or duration in the common cold. 156 papers were found using the reported searches, of which 4 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that there is no good evidence for the use of non-sedating antihistamines in the common cold. PMID- 21700749 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: Routine coagulation testing in adult patients with epistaxis. AB - A short cut review was carried out to establish whether routine testing of coagulation status was necessary in adult patients who present with epistaxis. 156 papers were found using the reported searches, of which 4 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that coagulation studies are only indicated in adults with epistaxis if the history suggests a potential cause for coagulopathy. PMID- 21700750 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 4: Hydrotherapy following rotator cuff repair. AB - A short cut review was carried out to establish whether hydrotherapy is beneficial in rehabilitation after rotator cuff repair. 27 papers were found using the reported searches, of which one presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of that best paper are tabulated. It is concluded that while there may be some short term benefit to passive range of movement, further research is needed. PMID- 21700751 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: Fucidic acid or chloramphenicol for neonates with sticky eyes. AB - A short cut review was carried out to establish whether fucidic acid was as good as chloramphenicol in curing neonatal sticky eyes. 53 papers were found using the reported searches, of which one presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of this best paper are tabulated. It is concluded that fucidic acid drops have an equivalent cure rate to chloramphenicol drops in neonates with sticky eyes. PMID- 21700752 TI - Response to the recent best evidence topic on the use of thrombolysis in stroke. PMID- 21700754 TI - Telmisartan reduces neointima volume and pulse wave velocity 8 months after zotarolimus-eluting stent implantation in hypertensive type 2 diabetic patients. AB - OBJECTIVE: Telmisartan is a peroxisome proliferator-activated receptor-gamma activator with potent anti-inflammatory and antiatherogenic effects. The authors compared the effects of telmisartan and valsartan on neointima volume, atherosclerosis progression and brachial-ankle pulse wave velocity (baPWV) after stenting in hypertensive type 2 diabetes. DESIGN: This was a prospective, randomised, 8-month follow-up study that included patients with significant coronary stenosis who received telmisartan (n=36) or valsartan (n=37). SETTING: University hospital. MAIN OUTCOME MEASURES: Neointima volume and atherosclerosis progression 10 mm proximal and distal to the stented segment were analysed using repeat intravascular ultrasonography. baPWV and inflammatory markers such as interleukin 6, tumour necrosis factor alpha, C-reactive protein and adiponectin were compared. RESULTS: Neointima volume at 8 months was significantly lower in the telmisartan group than the valsartan group (1.9+/-1.0 vs 2.6+/-1.4 mm(3)/1 mm, p=0.007, respectively). Total plaque volumes 10 mm proximal (7.1+/-1.5 vs 7.8+/-1.6 mm(3)/1 mm, p=0.032, respectively) and distal (3.5+/-1.4 vs 4.1+/-1.3 mm(3)/1 mm, p=0.028, respectively) to the stent were significantly lower in the telmisartan group than the valsartan group at 8 months. The decrease from baseline in baPWV was significantly greater in the telmisartan group than the valsartan group (-52+/-104 vs 30+/-113 cm/s, p=0.002, respectively). The increase from baseline in adiponectin levels and the decreases from baseline in interleukin 6 and tumour necrosis factor alpha levels were significantly greater in the telmisartan group at 8 months. Retinol-binding protein-4, homeostasis model of assessment index, hemoglobin A(1c) and low-density lipoprotein cholesterol levels decreased significantly in both groups without differences in changes from baseline between the two groups. CONCLUSIONS: Telmisartan reduced neointima volume; atherosclerosis progression 10 mm proximal and distal to the stented segment and baPWV independent of blood pressure, glucose and lipid control in hypertensive type 2 diabetes. Clinical trial no NCT00599885 (clinicaltrials.gov.). PMID- 21700755 TI - Effect of partial inhibition of fatty acid oxidation by trimetazidine on whole body energy metabolism in patients with chronic heart failure. AB - OBJECTIVE: Trimetazidine may have beneficial effects on left ventricular (LV) function in patients with systolic heart failure. The authors assessed whether long-term addition of trimetazidine to conventional treatment could improve, along with LV function, resting whole body energy metabolism in patients with chronic systolic heart failure. DESIGN: Single blind randomised study. SETTING: University Hospital. PATIENTS: 44 patients with systolic heart failure receiving full medical treatment. INTERVENTIONS: Indirect calorimetry and two-dimensional echocardiography at baseline and after 3 months. MAIN OUTCOME MEASURES: Whole body resting energy expenditure (REE), percentage of predicted REE, LV ejection fraction (EF), NYHA class, quality of life. RESULTS: Trimetazidine increased EF compared with conventional therapy alone (from 35+/-8% to 42+/-11% vs from 35+/ 7% to 36+/-6%; p=0.02, analysis of variance for repeated measures). NYHA class and quality of life also improved compared with conventional therapy (p<0.0001). REE (from 1677+/-264 to 1580+/-263 kcal/day) and percentage of predicted REE (based on the Harris-Benedict equation: from 114+/-10% to 108+/-9%) decreased in the trimetazidine group, but not in the control group (REE from 1679+/-304 to 1690+/-337 kcal/day and percentage of predicted REE from 113+/-12% to 115+/-14%). The variation was different between groups (p=0.03 and 0.023, respectively). CONCLUSIONS: In patients with systolic heart failure, improvement in functional class and LV function induced by middle-term trimetazidine therapy is paralleled by a reduction in whole body REE. The beneficial cardiac effects of trimetazidine may be also mediated by a peripheral metabolic effect. PMID- 21700756 TI - Comparison of two-dimensional and three-dimensional imaging techniques for measurement of aortic annulus diameters before transcatheter aortic valve implantation. AB - AIMS: Different two-dimensional (2D) and three-dimensional (3D) imaging techniques are used for procedure planning and selection of prosthesis size before transcatheter aortic valve implantation. This study sought to compare different 2D and 3D imaging techniques and determine the accuracy of 3D transoesophageal echocardiography (TEE) for accurate analysis of aortic annulus dimensions. METHODS: In 49 consecutive patients with severe aortic stenosis undergoing transcatheter aortic valve implantation angiography, 2D transthoracic echocardiography (TTE), 2D and 3D TEE, and dual-source CT (DSCT) were performed to determine aortic annulus diameters. TTE and 2D TEE provided only one diameter of the aortic annulus. Angiography, DSCT and 3D TEE allowed measurement of diameters in sagittal and coronal views. The distance between aortic annulus and left main coronary artery ostium was measured by angiography, DSCT and 3D TEE. RESULTS: Sagittal diameters determined by angiography, TTE, 2D TEE, 3D TEE and DSCT were smaller than coronal diameters determined by angiography, 3D TEE and DSCT. Coronal and sagittal diameters determined by 3D TEE were in high agreement with corresponding measurements by DSCT (23.60+/-1.89 vs 23.46+/-2.07 mm and 22.19+/-1.96 vs 22.27+/-2.01 mm, respectively; mean+/-SD). There was a high correlation between DSCT and 3D TEE for the definition of coronal and sagittal aortic annulus diameters (r=0.88, SEE=0.89 mm and r=0.77, SEE=1.26 mm, respectively). Correlation of 3D TEE (13.47+/-1.67 mm) and DSCT (13.64+/-1.82 mm) in the analysis of the distance between aortic annulus and left main coronary artery ostium was better (r=0.54, SEE=1.55 mm) than between angiography (14.85+/ 3.84 mm) and DSCT (r=0.35, SEE=1.77 mm). CONCLUSIONS: 3D imaging techniques should be used to evaluate aortic annulus diameters, as 2D imaging techniques, providing only a sagittal view, underestimate them. 3D TEE provides measurements of aortic annulus diameters similar to those obtained by DSCT. PMID- 21700757 TI - Does ventricular dyssynchrony on echocardiography predict response to cardiac resynchronisation therapy? A randomised controlled study. AB - OBJECTIVE: To determine the value of echocardiography in predicting response to cardiac resynchronisation therapy (CRT). METHODS: This is a prospective randomised study that recruited patients with (group 1) and without (group 2) echocardiographic evidence of mechanical dyssynchrony. 73 heart failure patients (NYHA III-IV) with a requirement for an implantable cardioverter defibrillator, QRS >=120 ms and LV ejection fraction (EF) <35% were studied. Group 1 patients received CRT-D (26 patients). Group 2 patients were randomised to CRT-D (group 2a: 23 patients) or implantable cardioverter defibrillator (group 2b: 21 patients). MAIN OUTCOME MEASURES: were peak oxygen consumption (VO(2)max), NYHA class, and echocardiography at baseline and at 6 months. RESULTS: 62% of group 1 patients achieved >=1 ml/kg/min increase in VO(2)max at 6 months versus 50% in group 2a and 21% in group 2b (p=0.04). Group 1 patients showed significant improvements in VO(2)max (15.8+/-2 to 18.0+/-4 ml/kg/min, p=0.01), NYHA class (3.1+/-0.3 to 1.9+/-0.7, p<0.001) and EF (22+/-7% to 26+/-9%, p=0.02). Group 2a showed significant improvement in NYHA class (3.1+/-0.3 to 2.2+/-0.7, p<0.001) but no change in EF or VO(2)max. Group 2b showed no change in NYHA class or EF with a decline in VO(2)max (16.4+/-4 to 14.1+/-4, p=0.03). A significantly higher proportion of patients in group 2b showed >=1 ml/kg/min deterioration in VO(2)max compared to group 2a (68% vs 23%, HR for group 2b: 2.4, 95% CI 1.2 to 4.8, p=0.005). CONCLUSIONS: The presence of echocardiographic dyssynchrony identifies patients who derive the most improvement from CRT. Patients without dyssynchrony also show more benefit and less deterioration with CRT than without and should not be denied CRT. PMID- 21700759 TI - Use of non-invasive haemodynamic measurements to detect treatment response in precapillary pulmonary hypertension. AB - BACKGROUND: Haemodynamic measurements may be superior to the 6-min walk distance (6MWD) as outcome measures in pulmonary hypertension (PH) as they are directly linked to the mechanisms of disease and are not subject to a ceiling effect. The aim of this study was to determine if treatment response in precapillary PH could be detected by pulmonary blood flow (PBF) and stroke volume (SV) measured non invasively by the inert gas rebreathing (IGR) method at rest and during submaximal constant-load cycle exercise. METHODS: Twenty-four patients with precapillary PH receiving de novo or modified disease-targeted therapy were studied. Isotime metabolic variables, PBF and SV were measured at rest and during constant-load cycle exercise at 40% maximal work rate alongside conventional outcome variables, at baseline and after 3 months of new therapy. RESULTS: At follow-up there was a significant increase in PBF (supine rest: mean 0.7+/-SD 0.9 l/min, erect rest: 0.7+/-0.8 l/min, exercise: 0.8+/-1.0 l/min, p<0.005) and SV (supine rest: 7+/-10 ml, erect rest: 10+/-11 ml, exercise: median 6 (IQR 3-11) ml, p<0.005). There was a trend for 6MWD to increase by 17+/-42 or 29 (13-47) m (p=0.061), whereas WHO functional class, N-terminal pro-brain natriuretic peptide or Cambridge Pulmonary Hypertension Outcome Review score were unchanged. In patients with higher baseline 6MWD, IGR measurements were more sensitive than 6MWD in detecting treatment response. CONCLUSIONS: Non-invasive IGR haemodynamic measurements could be used to detect treatment response in patients with precapillary PH and may be more responsive to change than 6MWD in fitter patients. PMID- 21700758 TI - Association of cytochrome P450 2C19*2 polymorphism with clopidogrel response variability and cardiovascular events in Koreans treated with drug-eluting stents. AB - BACKGROUND: Although East Asians carry the cytochrome P450 (CYP) 2C19*2 allele more frequently than do Caucasians, the impact of the CYP2C19*2 allele on clopidogrel pharmacodynamics and clinical outcomes is unknown. OBJECTIVE: To evaluate the effect of CYP2C19 variants on clopidogrel pharmacodynamics and long term prognosis in East Asian patients with drug-eluting stents (DES). METHODS: DES-treated patients taking dual antiplatelet therapy were enrolled from a Korean multicentre genetic registry. The CYP2C19*2 allele was genotyped using the Taqman method (n=2146), and on-treatment platelet reactivity was measured with the VerifyNow P2Y12 assay (n=1415). RESULTS: 1011 patients (47%) carried at least one CYP2C19*2 allele. The mean on-treatment platelet reactivity was significantly higher in carriers than in non-carriers (250+/-76 vs 231+/-83 P2Y12 reaction unit, p<0.001). For up to 12 months' follow-up, the composite of cardiovascular death, non-fatal myocardial infarction and stent thrombosis was significantly higher in carriers of the CYP2C19*2 allele than non-carriers (2.0% vs 0.8%, p=0.02). On landmark analysis, there was no difference in clinical outcome after 12 months between the groups. CONCLUSION: The CYP2C19*2 genetic variant may be associated with worse outcome in Korean patients treated exclusively with DES and dual-antiplatelet therapy due to a significant increase in cardiac death, myocardial infarction or stent thrombosis. PMID- 21700761 TI - Longitudinal changes in psychosocial factors and their association with knee pain and function after anterior cruciate ligament reconstruction. AB - BACKGROUND: Evidence in the musculoskeletal rehabilitation literature suggests that psychosocial factors can influence pain levels and functional outcome. OBJECTIVE: The purpose of this study was to examine changes in select psychosocial factors and their association with knee pain and function over 12 weeks after anterior cruciate ligament (ACL) reconstruction. DESIGN: This was a prospective, longitudinal, observational study. METHODS: Patients with ACL reconstruction completed self-report questionnaires for average knee pain intensity (numeric rating scale [NRS]), knee function (International Knee Documentation Committee Subjective Knee Form [IKDC-SKF]), and psychosocial factors (pain catastrophizing [Pain Catastrophizing Scale], fear of movement or reinjury [shortened version of the Tampa Scale for Kinesiophobia (TSK-11)], and self-efficacy for rehabilitation tasks [modified Self-Efficacy for Rehabilitation Outcome Scale (SER)]). Data were collected at 4 time points after surgery (baseline and 4, 8, and 12 weeks). Repeated-measures analyses of variance determined changes in questionnaire scores across time. Hierarchical linear regression models were used to examine the association of psychosocial factors with knee pain and function. RESULTS: Seventy-seven participants completed the study. All questionnaire scores changed across 12 weeks. Baseline psychosocial factors did not predict the 12-week NRS or IKDC-SKF score. The 12-week change in modified SER score predicted the 12-week change in NRS score (r(2)=.061), and the 12-week change in modified SER and TSK-11 scores predicted the 12-week change in IKDC-SKF score (r(2)=.120). LIMITATIONS: The psychometric properties of the psychosocial factor questionnaires are unknown in people with ACL reconstruction. The study focused on short-term outcomes using only self-report measures. CONCLUSIONS: Psychosocial factors are potentially modifiable early after ACL reconstruction. Baseline psychosocial factor levels did not predict knee pain or function 12 weeks postoperatively. Interventions that increase self-efficacy for rehabilitation tasks or decrease fear of movement or reinjury may have potential to improve short-term outcomes for knee pain and function. PMID- 21700762 TI - A patient with internal carotid artery dissection. AB - BACKGROUND AND PURPOSE: The purpose of this case report is to raise physical therapist awareness of Horner syndrome as a "red flag" for immediate medical referral. CASE DESCRIPTION: A 45-year-old man sought physical therapy for examination and treatment of neck pain and headache symptoms 5 days after experiencing a whiplash-type injury while waterskiing. His complaints were similar to a prior condition diagnosed as occipital neuralgia that had successfully responded to education, cervical and thoracic joint mobilization, and exercise provided by a physical therapist. The initial examination findings also were similar to those of the previous episode. However, signs consistent with Horner syndrome were noted on the second visit. This finding raised immediate concern on the part of the treating clinician and resulted in prompt physician referral, medical diagnosis, and intervention. OUTCOMES: A magnetic resonance imaging angiogram revealed an internal carotid artery dissection. A successful outcome was achieved over the course of 6 months through medical intervention, which consisted of anticoagulant therapy and modification of activity levels. DISCUSSION: In this case, the patient's sudden onset of signs of Horner syndrome was indicative of a medical emergency-internal carotid artery dissection. PMID- 21700760 TI - Multimodal nutritional rehabilitation improves clinical outcomes of malnourished patients with chronic respiratory failure: a randomised controlled trial. AB - BACKGROUND: In chronic respiratory failure (CRF), body composition strongly predicts survival. METHODS: A prospective randomised controlled trial was undertaken in malnourished patients with CRF to evaluate the effects of 3 months of home rehabilitation on body functioning and composition. 122 patients with CRF on long-term oxygen therapy and/or non-invasive ventilation (mean (SD) age 66 (10) years, 91 men) were included from eight respiratory units; 62 were assigned to home health education (controls) and 60 to multimodal nutritional rehabilitation combining health education, oral nutritional supplements, exercise and oral testosterone for 90 days. The primary endpoint was exercise tolerance assessed by the 6-min walking test (6MWT). Secondary endpoints were body composition, quality of life after 3 months and 15-month survival. RESULTS: Mean (SD) baseline arterial oxygen tension was 7.7 (1.2) kPa, forced expiratory volume in 1 s 31 (13)% predicted, body mass index (BMI) 21.5 (3.9) kg/m2 and fat-free mass index (FFMI) 15.5 (2.4) kg/m2. The intervention had no significant effect on 6MWT. Improvements (treatment effect) were seen in BMI (+0.56 kg/m2, 95% CI 0.18 to 0.95, p=0.004), FFMI (+0.60 kg/m2, 95% CI 0.15 to 1.05, p=0.01), haemoglobin (+9.1 g/l, 95% CI 2.5 to 15.7, p=0.008), peak workload (+7.2 W, 95% CI 3.7 to 10.6, p<0.001), quadriceps isometric force (+28.3 N, 95% CI 7.2 to 49.3, p=0.009), endurance time (+5.9 min, 95% CI 3.1 to 8.8, p<0.001) and, in women, Chronic Respiratory Questionnaire (+16.5 units, 95% CI 5.3 to 27.7, p=0.006). In a multivariate Cox analysis, only rehabilitation in a per-protocol analysis predicted survival (HR 0.27, 95% CI 0.07 to 0.95, p=0.042). CONCLUSIONS: Multimodal nutritional rehabilitation aimed at improving body composition increased exercise tolerance, quality of life in women and survival in compliant patients, supporting its incorporation in the treatment of malnourished patients with CRF. Clinical Trial number NCT00230984. PMID- 21700763 TI - Development of a scale to assess avoidance behavior due to a fear of falling: the Fear of Falling Avoidance Behavior Questionnaire. AB - BACKGROUND: A history of falls or imbalance may lead to a fear of falling, which may lead to self-imposed avoidance of activity; this avoidance may stimulate a vicious cycle of deconditioning and subsequent falls. OBJECTIVE: The purpose of this study was to develop a questionnaire that would quantify avoidance behavior due to a fear of falling. DESIGN: This study consisted of 2 parts: questionnaire development and psychometric testing. Questionnaire development involved an expert panel and 39 residents of an assisted living facility. Sixty-three community-dwelling individuals with various health conditions participated in psychometric testing. METHOD: Questionnaire development included the evaluation of face and content validity and factor analysis of the initial questionnaire. The final result of questionnaire development was the Fear of Falling Avoidance Behavior Questionnaire (FFABQ). In order to determine its psychometric properties, reliability and construct validity were assessed through administration of the FFABQ to participants twice, 1 week apart, and comparison of the FFABQ with other questionnaires related to fear of falling, functional measures of balance and mobility, and daily activity levels using an activity monitor. RESULTS: The FFABQ had good overall test-retest reliability (intraclass correlation coefficient=.812) and was found to differentiate between participants who were considered "fallers" (ie, at least one fall in the previous year) and those who were considered "nonfallers." The FFABQ predicted time spent sitting or lying and endurance. LIMITATIONS: A relatively small number of people with a fear of falling were willing to participate. CONCLUSION: Results from this study offer evidence for the reliability and validity of the FFABQ and support the notion that the FFABQ measures avoidance behavior rather than balance confidence, self efficacy, or fear. PMID- 21700764 TI - Prostate cancer immunotherapy. AB - The interaction between the immune system and prostate cancer has been an area of research interest for several decades. The recent U.S. Food and Drug Administration approval of 2 first-in-class proof-of-concept immunotherapies (sipuleucel-T and ipilimumab) has stimulated broader interest in manipulating immunity to fight cancer. In the context of prostate cancer, the immunotherapy strategies that have garnered the most interest are the therapeutic vaccination strategies, exemplified by sipuleucel-T and PROSTVAC-VF, and immune checkpoint blockade of CTLA-4 and PD-1. Improved understanding of the immune responses generated by these strategies and development of predictive biomarkers for patient selection will guide rational combinations of these treatments and provide building blocks for future immunotherapies. PMID- 21700765 TI - Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. AB - PURPOSE: We investigated the antitumor activity of the combination of two different humanized monoclonal human epidermal growth factor receptor (HER) 2 antibodies, pertuzumab and trastuzumab, for gastric cancer. EXPERIMENTAL DESIGN: Tumor mouse xenograft models were used to examine antitumor activity. Cell proliferation was examined using crystal violet staining. HER family proteins' expression was analyzed by ELISA and immunohistochemistry. Phosphorylated proteins and heterodimers were detected by Western blotting and in situ proximity ligation assay (PLA), respectively. Apoptosis activity was examined by caspase 3/7 activity. Antibody-dependent cellular cytotoxicity (ADCC) activity was detected by xCELLigence. Microvessel density was examined by CD31 staining. RESULTS: Pertuzumab in combination with trastuzumab showed significant antitumor activity compared with each monotherapy in NCI-N87, an HER2-positive human gastric cancer xenograft model. The efficacy was stronger than that of the maximum effective dose with each monotherapy. Similar antitumor activity was shown in 4-1ST, another HER2-positive gastric cancer model, but not in MKN-28, an HER2-negative model. Combining pertuzumab with trastuzumab enhanced cell growth inhibition and apoptosis activity by inhibiting EGFR-HER2 heterodimerization and the phosphorylation of these receptors and their downstream factors. This effect was also seen in HER2-HER3 signaling. Furthermore, pertuzumab in combination with trastuzumab potentiated the ADCC activity of those antibodies and reduced tumor microvessel density. CONCLUSIONS: We showed the significantly enhanced efficacy of pertuzumab combining with trastuzumab for HER2 overexpressing gastric cancer through the potentiation of cell growth inhibition, apoptosis activity, cell killing activity by ADCC, and antiangiogenic activity. This study suggests the clinical benefit of combination therapy with pertuzumab and trastuzumab for patients with HER2-positive gastric cancers. PMID- 21700766 TI - A probabilistic disease-gene finder for personal genomes. AB - VAAST (the Variant Annotation, Analysis & Search Tool) is a probabilistic search tool for identifying damaged genes and their disease-causing variants in personal genome sequences. VAAST builds on existing amino acid substitution (AAS) and aggregative approaches to variant prioritization, combining elements of both into a single unified likelihood framework that allows users to identify damaged genes and deleterious variants with greater accuracy, and in an easy-to-use fashion. VAAST can score both coding and noncoding variants, evaluating the cumulative impact of both types of variants simultaneously. VAAST can identify rare variants causing rare genetic diseases, and it can also use both rare and common variants to identify genes responsible for common diseases. VAAST thus has a much greater scope of use than any existing methodology. Here we demonstrate its ability to identify damaged genes using small cohorts (n = 3) of unrelated individuals, wherein no two share the same deleterious variants, and for common, multigenic diseases using as few as 150 cases. PMID- 21700767 TI - What makes migrant live-in home care workers in elder care be satisfied with their job? AB - PURPOSE: The study aims to examine job satisfaction of migrant live-in home care workers who provide care to frail older adults and to examine the extent to which quality of relationships between the care provider and care recipient and workplace characteristics is associated with job satisfaction. DESIGN AND METHODS: A convenience sample that included 335 dyads of Philippine workers and their frail care recipients were recruited through 2 national home care agencies and snowballing. Multiple regression analyses examined the extent to which workplace characteristics, quality of relationships, care recipient characteristics, and care worker characteristics explain job satisfaction. RESULTS: Scores for job satisfaction, quality of relationships, and workplace characteristics were strongly positive. Overall and intrinsic job satisfactions were explained by workers' qualifications, workplace characteristics, and quality of relationships from the perspective of care recipients, whereas satisfaction with benefits was affected by workplace characteristics and quality of relationships from the perspective of the care workers. IMPLICATIONS: Findings suggest that workers who were better qualified in terms of more years of formal education and more years as care workers and who reported improved workplace characteristics, in particular more job decision authority and variety, reported increased job satisfaction. Therefore, enabling migrant live-in care workers more job decision authority and variety may increase their job satisfaction. More research is needed to deepen our understanding of additional job-related characteristics that explain job satisfaction among this group of care workers. PMID- 21700768 TI - Seizing interdisciplinary opportunities in the changing landscape of health and aging: a social work perspective. AB - PURPOSE OF THE STUDY: This paper is a revision of the Kent Award Lecture given at the Annual Meeting of the Gerontological Society of America held in New Orleans, Louisiana, in November, 2010. DESIGN AND METHODS: This paper looks at the evolution in geriatric social work assessment and outcomes research and concludes with observations of the changing landscape in health and aging. RESULTS: Since the 1960s, the policies and the context of health care delivery have changed many times as have geriatric health screening and assessment of patients in need of social health care services. Research on social-behavioral and environmental factors critical in measurement of outcomes of health care has progressed significantly as theories of care and the research technologies that allow us to study these factors have become more sophisticated. IMPLICATIONS: Researchers from multiple disciplines need to study the questions which can build the evidence necessary for empirically supported social policy direction. Opportunities in interdisciplinary geriatric assessment and measurement of outcomes, which are presented to researchers today, are highlighted. PMID- 21700769 TI - Understanding nonresponse to the 2007 Medicare CAHPS survey. AB - PURPOSE: The Medicare Consumer Assessments of Healthcare Providers and Systems (MCAHPS) survey, a primarily English-language mail survey with English and Spanish telephone follow-up, is the primary means of assessing the health care experiences of American seniors. We examine unit (whole survey) and item nonresponse for this survey to explore issues regarding surveying seniors about their health care. DESIGN AND METHODS: We describe overall rates and analyze predictors of unit and item nonresponse for the 695,197 Medicare beneficiaries selected for the 2007 MCAHPS survey (335,249 unit respondents, 49% overall response rate). RESULTS: Asians, African Americans, and Hispanics responded at adjusted response rates 7-17 percentage points lower than non-Hispanic Whites (p < .001 for each). Among seniors, response rates dropped beyond age 75. Asians and older beneficiaries were especially likely to respond by mail, and African Americans and Hispanics by phone. Breakoff from telephone surveys was most common among African Americans and older respondents. Among respondents, older age was the strongest predictor of item missingness (e.g., those 85 years and older failed to answer items at twice the rate of those aged 65-74 years, p < .001). Non-Hispanic Whites had lower rates of item missingness than other racial/ethnic groups (p < .001 for each; one-third lower than African Americans). IMPLICATIONS: Survey research on older adults, especially regarding racial/ethnic disparities in health care, could benefit from improved response rates. These results suggest that targeted prenotification materials and campaigns, tailored follow-up, targeted Spanish mailings, Chinese translations/calls, and adjustments to telephone protocols may improve representation and response. PMID- 21700770 TI - The molecular pathogenesis of primary mediastinal large B-cell lymphoma. AB - Primary mediastinal large B-cell lymphoma (PMBCL) is a recognized non-Hodgkin lymphoma entity with unique pathologic, clinical, and molecular characteristics distinct from those of other diffuse large B-cell lymphomas. Immunohistochemical characterization and molecular studies strongly suggest that PMBCL is of germinal center or postgerminal center origin. Pivotal gene expression profiling work defined major deregulated pathway activities that overlap with Hodgkin lymphoma and prompted a more detailed analysis of candidate genes. In particular, the nuclear factor-kappaB and the Janus Kinase-Signal Transducer and Activator of Transcription signaling pathways are targeted by multiple genomic hits, and constitutive activity of both pathways can be considered molecular hallmark alterations of PMBCL. Moreover, data are emerging giving unique insight into remodeling of the epigenome that affects transcriptional regulation of a multitude of genes. More recently, the tumor microenvironment of PMBCL has shifted into focus based on a number of gene perturbations altering expression of surface molecules that contribute to immune escape. These findings highlight the importance of immune privilege in the pathogenesis of PMBCL and suggest that disrupting crosstalk between the tumor cells and the microenvironment might be a rational new therapeutic target in conjunction with traditional treatment strategies. PMID- 21700771 TI - Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide. AB - Current management of hemophilia B entails multiple weekly infusions of factor IX (FIX) to prevent bleeding episodes. In an attempt to make a longer acting recombinant FIX (rFIX), we have explored a new releasable protraction concept using the native N-glycans in the activation peptide as sites for attachment of polyethylene glycol (PEG). Release of the activation peptide by physiologic activators converted glycoPEGylated rFIX (N9-GP) to native rFIXa and proceeded with normal kinetics for FXIa, while the K(m) for activation by FVIIa-tissue factor (TF) was increased by 2-fold. Consistent with minimal perturbation of rFIX by the attached PEG, N9-GP retained 73%-100% specific activity in plasma and whole-blood-based assays and showed efficacy comparable with rFIX in stopping acute bleeds in hemophilia B mice. In animal models N9-GP exhibited up to 2-fold increased in vivo recovery and a markedly prolonged half-life in mini-pig (76 hours) and hemophilia B dog (113 hours) compared with rFIX (16 hours). The extended circulation time of N9-GP was reflected in prolonged correction of coagulation parameters in hemophilia B dog and duration of effect in hemophilia B mice. Collectively, these results suggest that N9-GP has the potential to offer efficacious prophylactic and acute treatment of hemophilia B patients at a reduced dosing frequency. PMID- 21700772 TI - Monocytic microparticles activate endothelial cells in an IL-1beta-dependent manner. AB - Microparticles (MPs) are shed from activated and dying cells. They can transmit signals from cell to cell, locally or at a distance through the circulation. Monocytic MPs are elevated in different diseases, including bacterial infections. Here, we investigated how monocytic MPs activate endothelial cells. We found that MPs from lipopolysaccharide (LPS)-treated THP-1 monocytic cells bind to and are internalized by human endothelial cells. MPs from LPS-treated THP-1 cells, but not untreated cells, induced phosphorylation of ERK1/2, activation of the nuclear factor-kappaB pathway and expression of cell adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. Similar results were observed using MPs from LPS-treated peripheral blood mononuclear cells. We next investigated the mechanism by which monocytic MPs activated endothelial cells and found that they contain IL-1beta and components of the inflammasome, including apoptosis-associated speck-like protein containing a CARD, caspase-1, and NLRP3. Importantly, knockdown of NLRP3 in THP-1 cells reduced the activity of the MPs and blockade of the IL-1 receptor on endothelial cells decreased MP-dependent induction of cell adhesion molecules. Therefore, monocytic MPs contain IL-1beta and may amplify inflammation by enhancing the activation of the endothelium. PMID- 21700773 TI - Hepcidin regulates ferroportin expression and intracellular iron homeostasis of erythroblasts. AB - The iron-regulatory hormone, hepcidin, regulates systemic iron homeostasis by interacting with the iron export protein ferroportin (FPN1) to adjust iron absorption in enterocytes, iron recycling through reticuloendothelial macrophages, and iron release from storage in hepatocytes. We previously demonstrated that FPN1 was highly expressed in erythroblasts, a cell type that consumes most of the serum iron for use in hemoglobin synthesis. Herein, we have demonstrated that FPN1 localizes to the plasma membrane of erythroblasts, and hepcidin treatment leads to decreased expression of FPN1 and a subsequent increase in intracellular iron concentrations in both erythroblast cell lines and primary erythroblasts. Moreover, injection of exogenous hepcidin decreased FPN1 expression in BM erythroblasts in vivo, whereas iron depletion and associated hepcidin reduction led to increased FPN1 expression in erythroblasts. Taken together, hepcidin decreased FPN1 expression and increased intracellular iron availability of erythroblasts. We hypothesize that FPN1 expression in erythroblasts allows fine-tuning of systemic iron utilization to ensure that erythropoiesis is partially suppressed when nonerythropoietic tissues risk developing iron deficiency. Our results may explain why iron deficiency anemia is the most pronounced early manifestation of mammalian iron deficiency. PMID- 21700774 TI - The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development. AB - The Notch signaling pathway plays a fundamental role during blood vessel development. Notch signaling regulates blood vessel morphogenesis by promoting arterial endothelial differentiation and providing spatial and temporal control over "tip cell" phenotype during angiogenic sprouting. Components of the Notch signaling pathway have emerged as potential regulators of lymphatic development, joining the increasing examples of blood vessel regulators that are also involved in lymphatic development. However, in mammals a role for the Notch signaling pathway during lymphatic development remains to be demonstrated. In this report, we show that blockade of Notch1 and Dll4, with specific function-blocking antibodies, results in defective postnatal lymphatic development in mice. Mechanistically, Notch1-Dll4 blockade is associated with down-regulation of EphrinB2 expression, been shown to be critically involved in VEGFR3/VEGFC signaling, resulting in reduced lymphangiogenic sprouting. In addition, Notch1 Dll4 blockade leads to compromised expression of distinct lymphatic markers and to dilation of collecting lymphatic vessels with reduced and disorganized mural cell coverage. Finally, Dll4-blockade impairs wound closure and severely affects lymphangiogenesis during the wound healing in adult mouse skin. Thus, our study demonstrates for the first time in a mammalian system that Notch1-Dll4 signaling pathway regulates postnatal lymphatic development and pathologic lymphangiogenesis. PMID- 21700775 TI - Histones induce rapid and profound thrombocytopenia in mice. AB - Histones are released from dying cells and contribute to antimicrobial defense during infection. However, extracellular histones are a double-edged sword because they also damage host tissue and may cause death. We studied the interactions of histones with platelets. Histones bound to platelets, induced calcium influx, and recruited plasma adhesion proteins such as fibrinogen to induce platelet aggregation. Hereby fibrinogen cross-linked histone-bearing platelets and triggered microaggregation. Fibrinogen interactions with alphaIIbbeta3 integrins were not required for this process but were necessary for the formation of large platelet aggregates. Infused histones associated with platelets in vivo and caused a profound thrombocytopenia within minutes after administration. Mice lacking platelets or alphaIIbbeta3 integrins were protected from histone-induced death but not from histone-induced tissue damage. Heparin, at high concentrations, prevented histone interactions with platelets and protected mice from histone-induced thrombocytopenia, tissue damage, and death. Heparin and histones are evolutionary maintained. Histones may combine microbicidal with prothrombotic properties to fight invading microbes and maintain hemostasis after injury. Heparin may provide an innate counter mechanism to neutralize histones and diminish collateral tissue damage. PMID- 21700776 TI - A pilot study of subcutaneous decitabine in beta-thalassemia intermedia. AB - Ineffective erythropoiesis, the hallmark of beta-thalassemia, is a result of alpha/non-alpha globin chain imbalance. One strategy to redress globin-chain imbalance is to induce gamma-globin gene (HBG) expression. Repression of HBG in adult erythroid cells involves DNA methylation and other epigenetic changes. Therefore, the cytosine analog decitabine, which can deplete DNA methyltransferase 1 (DNMT1), can potentially activate HBG. In 5 patients with beta-thalassemia intermedia, a dose and schedule of decitabine intended to deplete DNMT1 without causing significant cytotoxicity (0.2 mg/kg subcutaneous 2 times per week for 12 weeks) increased total hemoglobin from 7.88 +/- 0.88 g/dL to 9.04 +/- 0.77 g/dL (P = .004) and absolute fetal hemoglobin from 3.64 +/- 1.13 g/dL to 4.29 +/- 1.13 g/dL (P = .003). Significant favorable changes also occurred in indices of hemolysis and red blood cell densitometry. Consistent with a noncytotoxic, differentiation altering mechanism of action, the major side effect was an asymptomatic increase in platelet counts without erythrocyte micronucleus or VDJ recombination assay evidence of genotoxicity. This study was registered at www.clinicaltrials.gov as #NCT00661726. PMID- 21700778 TI - Ph: not bad at all. PMID- 21700779 TI - Self-enabling T cells. PMID- 21700777 TI - Genetic polymorphisms of multiple DNA repair pathways impact age at diagnosis and TP53 mutations in breast cancer. AB - Defective DNA repair may contribute to early age and late stage at time of diagnosis and mutations in critical tumor suppressor genes, such as TP53 in breast cancer. Using DNA samples from 436 breast cancer cases (374 Caucasians and 62 African-Americans), we tested these associations with 18 non-synonymous single nucleotide polymorphisms (nsSNPs) in four DNA repair pathways: (i) base excision repair: ADPRT V762A, APE1 D148E, XRCC1 R194W/R280H/R399Q and POLD1 R119H; (ii) double-strand break repair: NBS1 E185Q and XRCC3 T241M; (iii) mismatch repair: MLH1 I219V, MSH3 R940Q/T1036A and MSH6 G39E and (iv) nucleotide excision repair: ERCC2 D312N/K751Q, ERCC4 R415Q, ERCC5 D1104H and XPC A499V/K939Q. Younger age at diagnosis (<50) was associated with ERCC2 312 DN/NN genotypes [odds ratio (OR) = 1.76; 95% confidence interval (CI) = 1.10, 2.81] and NBS1 185 QQ genotype (OR = 3.09; 95% CI = 1.47, 6.49). The XPC 939 QQ genotype was associated with TP53 mutations (OR = 5.80; 95% CI = 2.23, 15.09). There was a significant trend associating younger age at diagnosis (<50) with increasing numbers of risk genotypes for ERCC2 312 DN/NN, MSH6 39 EE and NBS1 185 QQ (P(trend) < 0.001). A similar significant trend was also observed associating TP53 mutations with increasing numbers of risk genotypes for XRCC1 399 QQ, XPC 939 QQ, ERCC4 415 QQ and XPC 499 AA (P(trend) < 0.001). Our pilot data suggest that nsSNPs of multiple DNA repair pathways are associated with younger age at diagnosis and TP53 mutations in breast cancer and larger studies are warranted to further evaluate these associations. PMID- 21700780 TI - A new fish for the beta2GPI hook: LPS! PMID- 21700781 TI - ATG and RIC: not such a good match? PMID- 21700783 TI - Gender-based differences in outcome after anatomic double-bundle anterior cruciate ligament reconstruction with hamstring tendon autografts. AB - BACKGROUND: Although previous studies suggested that female patients are predisposed to increase graft laxity compared with male patients after single bundle anterior cruciate ligament reconstruction using autogenous hamstring tendons, there have been no studies specifically examining gender-based differences in outcome after anatomic double-bundle anterior cruciate ligament reconstruction with hamstring tendon autografts. HYPOTHESES: (1) Female patients have significantly smaller hamstring graft diameters than do men for anatomic double-bundle anterior cruciate ligament reconstruction surgery; (2) female patients will have increased graft laxity compared with male patients after anatomic double-bundle anterior cruciate ligament reconstruction using autogenous hamstring tendons. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: The consecutive 174 patients who underwent anatomic double-bundle anterior cruciate ligament reconstruction using autogenous hamstring tendons were enrolled. Of these patients, 49 women and 73 men were prospectively evaluated 2 years after surgery. RESULTS: The diameters for anteromedial and posterolateral grafts in the female group were significantly smaller than those in the male group. On Lachman testing, 98% of the female group and 97% of the male group were rated as negative. Regarding the pivot-shift test, 80% of the female group and 85% of the male group were rated as negative. No significant differences were found between the female and male groups in these tests. The average side-to-side differences in the KT-2000 knee ligament arthrometer values were 1.3 mm in the female group and 1.4 mm in the male group; this difference between females and males was not statistically significant. The average Lysholm scores were 96.7 points in the female group and 97.2 points in the male group. Thirty-five cases (73%) in the female group and 54 cases (74%) in the male group were graded as normal on the International Knee Documentation Committee (IKDC) evaluation. There were no significant differences in Lysholm score or IKDC evaluation between the female and male groups. CONCLUSION: The results of assessment for ligament laxity at the 2-year postoperative evaluation in the female group were approximately identical to those of the male group after anatomic double-bundle anterior cruciate ligament reconstruction using autogenous hamstring tendons. Therefore, the present study suggests that anatomic double-bundle anterior cruciate ligament reconstruction using autogenous hamstring tendons provides satisfactory knee stability to female patients as well as male patients. PMID- 21700784 TI - Results of isolated lateral meniscus allograft transplantation: focus on objective evaluations with magnetic resonance imaging. AB - BACKGROUND: Although numerous studies have reported outcomes of meniscus allograft transplantation, only a few dealt with isolated procedures or employed objective evaluation methods. HYPOTHESIS: Isolated lateral meniscus allograft transplantation (LMAT) provides clinical improvements and favorable objective results in symptomatic lateral meniscus-deficient knees. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The authors collected and analyzed the results of 29 consecutive isolated LMATs with a minimum of 24 months' follow-up. The mean age of the patients was 29.6 years (range, 18-48 years). The modified Lysholm scoring system and the Hospital for Special Surgery score were used to evaluate subjective improvements. Every patient underwent postoperative magnetic resonance imaging (MRI) or second-look arthroscopy or both as objective evaluation. The allograft extrusion and relative percentage of extrusion (RPE) was measured on final MRI. Status of the allograft was classified according to the above 3 categories into 3 grades; satisfactory, fair, or poor. RESULTS: The average length of follow-up was 53.6 months. Symptoms and functions of the involved knee improved in 28 knees (96.6%) at the last follow-up. The average preoperative modified Lysholm score was 69.5, which increased to 89.9 postoperatively (P < .001). The average preoperative Hospital for Special Surgery pain score was 15.3, which increased to 26.7 postoperatively (P < .001). Postoperative MRI alone was performed in 22 knees (75.9%), second-look arthroscopy alone in 1 knee (3.4%), and both examinations in 6 knees (20.7%). The MRI scans revealed 4 gross and 5 small tears in the allograft and also provided valuable information despite magnetic susceptibility artifacts. Mean allograft extrusion was 4.0 mm and mean RPE was 45.4%. At second-look arthroscopy, 3 gross tears and a small flap tear were identified in 4 cases. According to the clinical and the objective criteria, the allografts were graded as satisfactory in 20 cases (69.0%), fair in 5 cases (17.2%), and poor in 4 cases (13.8%). CONCLUSION: The results of the present study showed remarkable symptomatic improvements and acceptable objective findings in short- to intermediate-term follow-up. Even in cases with favorable clinical results, MRI or second-look arthroscopy was necessary to identify the actual status of the allograft. Isolated LMAT could be an effective treatment for symptomatic, lateral meniscus-deficient knees. PMID- 21700785 TI - Sickle cell disease: reference values and interhemispheric differences of nonimaging transcranial Doppler blood flow parameters. AB - BACKGROUND AND PURPOSE: TCD screening is widely used to identify children with SCD at high risk of stroke. Those with high mean flow velocities in major brain arteries have increased risk of stroke. Thus, our aim was to establish reference values of interhemispheric differences and ratios of blood flow Doppler parameters in the tICA, MCA, and ACA as determined by conventional TCD in children with sickle cell anemia. MATERIALS AND METHODS: Reference limits of blood flow parameters were established on the basis of a consecutive cohort of 56 children (mean age, 100 +/- 40 months; range, 29-180 months; 30 females) free of neurologic deficits and intracranial stenosis detectable by MRA, with blood flow velocities <170 cm/s by conventional TCD. Reference limits were estimated by using tolerance intervals, within which are included with a probability of .90 of all possible data values from 95% of a population. RESULTS: Average peak systolic velocities were significantly higher in the right hemisphere in the MCA and ACA (185 +/- 28 cm/s versus 179 +/- 27 and 152 +/- 30 cm/s versus 143 +/- 34 cm/s respectively). Reference limits for left-to-right differences in the mean flow velocities were the following: -43 to 33 cm/s for the MCA; -49 to 38 cm/s for the ACA, and -38 to 34 cm/s for the tICA, respectively. Respective reference limits for left-to-right velocity ratios were the following: 0.72 to 1.25 cm/s for the MCA; 0.62 to 1.39 cm/s for the ACA, and 0.69 to 1.27 cm/s for the tICA. Flow velocities in major arteries were inversely related to age and Hct or Hgb. CONCLUSIONS: The study provides reference intervals of TCD flow velocities and their interhemispheric differences and ratios that may be helpful in identification of intracranial arterial stenosis in children with SCD undergoing sonographic screening for stroke prevention. PMID- 21700786 TI - Biexponential analysis of diffusion-tensor imaging of the brain in patients with cirrhosis before and after liver transplantation. AB - BACKGROUND AND PURPOSE: DTI has shown increased MD of water molecules in the brain of patients with cirrhosis, consistent with low-grade edema. This study further characterizes this edema by using biexponential analysis of DTI data, a technique that may differentiate cytotoxic and vasogenic edema. MATERIALS AND METHODS: A total of 41 patients with cirrhosis awaiting liver transplantation and 16 healthy controls were studied by DTI by using a single-shot echo-planar technique with 11 b-values (range, 0-7500 s/mm(2)) and 6 noncollinear directions. Measurements were fitted to biexponential function to determine MD and FA for the fast and slow diffusion components. Regions of interest were selected in the parietal white matter and corticospinal tract. The assessment was repeated 1 year after liver transplantation in 24 of these patients. RESULTS: In parietal white matter, patients with cirrhosis showed an increase in fast MD and a decrease in fast FA that normalized after liver transplantation. In the corticospinal tract, there was an increase in fast and slow MD that normalized after transplantation, and a decrease in FA that persisted posttransplantation. There was no association of DTI parameters with minimal HE (n =12). CONCLUSIONS: Biexponential analysis of DTI supports the presence of edema in the brain of patients with cirrhosis that reverts after transplantation. In parietal white matter, the increase in brain water was mainly located in the interstitial compartment, while the corticospinal tract showed a mixed pattern (intra- and extracellular). In addition, the findings on posttransplantation were consistent with microstructural damage along the corticospinal tract. PMID- 21700788 TI - Detecting misery perfusion in unilateral steno-occlusive disease of the internal carotid artery or middle cerebral artery by MR imaging. AB - BACKGROUND AND PURPOSE: Elevated OEF is a surrogate for misery perfusion. Our aim was to detect misery perfusion in patients with unilateral steno-occlusive disease of the ICA or MCA by using T2*-based MR imaging and to determine the relationship between brain ischemia and OEF. MATERIALS AND METHODS: Twenty-three patients with unilateral steno-occlusive disease of the ICA or MCA and 8 healthy volunteers were included in this study. Hemodynamic information was obtained in all subjects by MR imaging. Three regions of interest were placed in the anterior, middle, and posterior parts of the brain bilaterally to measure the OEF and CBF values. The OEFs of the regions of interest in the hemispheres ipsilateral and contralateral to the vascular lesions were compared. Brain regions with OEF greater than that in controls were determined as misery perfusion in patients. The association of vascular lesions, rCBF, and the presence of territory infarction with elevated OEF was investigated. RESULTS: There was a statistically significant difference in OEF between the ipsilateral and contralateral hemispheres in the patients (t = 3.632, P = .001). Fourteen regions of interest with misery perfusion were determined in the ipsilateral hemispheres, while 3 regions with elevated OEFs were found in the contralateral hemispheres. In the ipsilateral hemispheres, decreased rCBF was associated with elevated OEF (r = -0.451, P < .001). Patients with territory infarction had more regions of interest with misery perfusion than patients without territory infarction (chi(2) = 3.889, P = .049). CONCLUSIONS: By using the MR imaging technique, misery perfusion demonstrated as elevated OEF was detected in patients with severe atherosclerotic ICA or MCA disease. Identification of misery perfusion with MR imaging may be helpful in the evaluation of brain ischemia. PMID- 21700787 TI - Xenon-enhanced cerebral blood flow at 28% xenon provides uniquely safe access to quantitative, clinically useful cerebral blood flow information: a multicenter study. AB - BACKGROUND AND PURPOSE: Xe-CT measures CBF and can be used to make clinical treatment decisions. Availability has been limited, in part due to safety concerns. Due to improvements in CT technology, the concentration of inhaled xenon gas has been decreased from 32% to 28%. To our knowledge, no data exist regarding the safety profile of this concentration. We sought to better determine the safety profile of this lower concentration through a multicenter evaluation of adverse events reported by all centers currently performing xenon/CT studies in the US. MATERIALS AND METHODS: Patients were prospectively recruited at 7 centers to obtain safety and efficacy information. All studies were performed to answer a clinical question. All centers used the same xenon delivery system. CT imaging was used during a 4.3-minute inhalation of 28% xenon gas. Vital signs were monitored on all patients throughout each procedure. Occurrence and severity of adverse events were recorded by the principal investigator at each site. RESULTS: At 7 centers, 2003 studies were performed, 1486 (74.2%) in nonventilated patients. The most common indications were occlusive vascular disease and ischemic stroke; 93% of studies were considered clinically useful. Thirty-nine studies (1.9%) caused respiratory suppression of >20 seconds, all of which resolved spontaneously. Shorter respiratory pauses occurred in 119 (5.9%), and hyperventilation, in 34 (1.7%). There were 53 additional adverse events (2.9%), 7 of which were classified as severe. No adverse event resulted in any persistent neurologic change or other sequelae. CONCLUSIONS: Xe-CT CBF can be performed safely, with a very low risk of adverse events and, to date, no risk of permanent morbidity or sequelae. On the basis of the importance of the clinical information gained, Xe-CT should be made widely available. PMID- 21700789 TI - Diffusion tensor imaging of the optic nerve in subacute anterior ischemic optic neuropathy at 3T. AB - BACKGROUND AND PURPOSE: DTI can provide in vivo information about the pathology of optic nerve disease, but there is no study of DTI in the setting of ION, the most frequent acute optic neuropathies in patients over 50 years of age. Our aim was to investigate the potential of DTI in the diagnosis of subacute AION at 3T. MATERIALS AND METHODS: Twenty-six patients with unilateral AION and 15 healthy controls were enrolled in this study. DTI and pattern VEP were performed on the ONs of all subjects. The mean ADC, FA, and eigenvalue maps were obtained for quantitative analysis. Quantitative electrophysiology was also performed on all subjects. RESULTS: The mean ADC and orthogonal eigenvalue lambda(?) in affected nerves increased, and the mean FA was reduced compared with clinically unaffected contralateral nerves (P < .001) and control nerves (P < .001). However, no significant changes of the mean principal eigenvalue lambda(||) in affected nerves compared with unaffected contralateral nerves (P = .13) and control nerves (P = .14) were seen. There was a significant correlation of whole-field VEP amplitude with ADC (r = -0.63, P = .001) and lambda(?) (r = -0.47, P = .015) but no correlation with FA (P = .06) and lambda(||) (P = .06). CONCLUSIONS: DTI measurement of ischemic ONs provides in vivo information about pathology and may serve as a biomarker of axonal and myelin damage in AION. PMID- 21700790 TI - Differential diagnosis of idiopathic normal pressure hydrocephalus from other dementias using diffusion tensor imaging. AB - BACKGROUND AND PURPOSE: Because DTI can provide good markers of white matter pathology, it could be useful in differentiating white matter changes of INPH from those of other dementias. The aim of this study was, by using DTI, to compare the characteristic white matter changes in INPH with those in AD, subcortical vascular dementia, and healthy control subjects. MATERIALS AND METHODS: Sixteen patients with presurgical INPH, 10 with AD, 10 with subcortical vascular dementia, and 20 healthy control subjects underwent DTI. All patients with INPH showed clinical improvement after shunt surgery, and 9 of them also underwent postshunting DTI. Regions of interest were selected at the periventricular white matter, the anterior limb of the internal capsule, the posterior limb of the internal capsule, the genu and the splenium of the corpus callosum, the superior longitudinal fasciculus, and the inferior longitudinal fasciculus. FA and MD were obtained from each region of interest and were compared among the groups. RESULTS: Presurgical INPH showed significantly higher FA than all the other groups in the posterior limb of the internal capsule, which was decreased after shunt surgery. Presurgical MD of the INPH group was higher than that in the AD and healthy control groups but lower than that in the subcortical vascular dementia group in the anterior periventricular white matter, the anterior limb of the internal capsule, and the superior longitudinal fasciculus. In differentiating INPH, the sensitivity and specificity of FA in the posterior limb of the internal capsule was 87.5% and 95.0%, respectively. CONCLUSIONS: Patients with shunt-responsive INPH showed higher FA in the posterior limb of the internal capsule compared with healthy controls and those in other groups of dementia that was reversible with shunt surgery. With this parameter, shunt-responsive INPH could be distinguished from AD, subcortical vascular dementia, and healthy conditions with high diagnostic accuracy. PMID- 21700791 TI - Aneurysm ostium angle: a predictor of the need for stent as assistance for endovascular aneurysm coiling in internal carotid artery sidewall aneurysms. AB - BACKGROUND AND PURPOSE: There is no satisfactory parameter that can predict the need for assistant devices for endovascular aneurysm coiling. Our aim was to evaluate the utility of MOA as a predictor of the need for stent-assisted coiling in ICA sidewall aneurysms. MATERIALS AND METHODS: From a retrospective review of an internal data base, 55 consecutive ICA sidewall aneurysms were identified. Thirty-two of the aneurysms were treated by using endovascular techniques. Because 23 of the 55 aneurysms were either untreated or clipped, 3 experienced interventionalists reviewed the 3D images of these aneurysms and then made a decision as to whether stent-assisted coiling would have been required. Thirty one of the 55 aneurysms would have required stent-assisted coiling, while 24 would not. Neck width, DNR, AR, and MOA were obtained from each aneurysm by using prototype software. These parameters were then correlated with the requirement of stent-assisted coiling. RESULTS: MOA and neck width of aneurysms requiring stent assisted coiling were significantly larger than those not requiring stent assisted coiling (P < .001 and <0.001, respectively). Although the DNR and AR of aneurysms requiring stent-assisted coiling were smaller than those not requiring it, the difference was not significant (P = .22 and 0.12, respectively). ROC analysis revealed that MOA was the parameter that best correlated with the need for stent-assisted coiling. Inclusion of MOA with the rest of the parameters significantly increased the predictive performance regarding the need for stent assisted coiling (P = .005). CONCLUSIONS: In this small study, MOA was a useful parameter to predict the need for stent-assisted coiling in ICA sidewall aneurysms. Further prospective study of this parameter for aneurysms at multiple locations is required to determine its ultimate value. PMID- 21700792 TI - Basal forebrain involvement in low-functioning autistic children: a voxel-based morphometry study. AB - BACKGROUND AND PURPOSE: Imaging studies have revealed brain abnormalities in the regions involved in functions impaired in ASD (social relations, verbal and nonverbal communication, and adaptive behavior). We performed a VBM whole-brain analysis to assess the areas involved in autistic children with DD. MATERIALS AND METHODS: Twenty-one developmentally delayed children with ASD (aged 3-10 years) were compared with 21 controls matched for age, sex, and sociocultural background. All ASD cases had been diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, with the Autism Diagnostic Observation Schedule-Generic, and the Autism Diagnostic Interview Revised. The VBM data, covaried with intelligence quotient, age, and brain volume, were analyzed. RESULTS: ASD patients showed a pattern of regional GM reduction symmetrically affecting the basal forebrain, accumbens nucleus, cerebellar hemispheres, and perisylvian regions, including insula and putamen. Asymmetric involvement of GM was observed in other brain regions functionally connected to the basal forebrain, ie, an area located close to the medial and ventral surface of the frontal lobe. No regional WM differences were observed between the 2 groups. No significant differences between patients and controls were found regarding total brain volume, GM, and WM. CONCLUSIONS: In children with ASD and DD, the novel finding of our VBM study was the demonstration of reduced GM volume in the basal forebrain and the areas connected with it. This system is involved in social behavior, communication, and cognitive skills. Whether the involvement of the basal forebrain is characteristic of ASD or is related to the DD present in our patients needs further investigation. PMID- 21700793 TI - Volumetric measurement for comparison of the accuracy between intraoperative CT and postoperative MR imaging in pituitary adenoma surgery. AB - BACKGROUND AND PURPOSE: To improve the resection rate of unexpected residual pituitary tumor under image guidance, iCT provides a less time-consuming and more convenient approach of promising the safety of the trans-sphenoidal surgery. However, iCT was thought to have worse image quality than MR imaging. This study was designed to determine the predictive concordance of iCT with standard postoperative high-strength MR imaging for the detection of residual tumors. MATERIALS AND METHODS: From February to December 2009, 33 patients with pituitary macroadenomas were enrolled in this prospective study. All patients received endoscopic trans-sphenoidal surgery for tumor removal and underwent iCT before the surgery finished. If an accessible tumor remnant was suspected and resectable, the surgery was continued. To assess the accuracy of intraoperative evaluation of tumor resection, the intraoperative findings were compared with MR imaging findings obtained 2 to 3 months after surgery by individually calculating the residual tumor volume. RESULTS: There were no statistically significant differences in the comparison between iCT and postoperative MR imaging findings (P > .05), and the predictive rates were also high (R(2) value >0.9). The GTR rate in the case of the noninvasive and fresh cases was 89% (17/19). The overall GTR rate was 58% (19/33), the second-look rate was 21% (7/33), and only one fourth of the recurrent cases reached GTR. CONCLUSIONS: The extent of resection in trans-sphenoidal surgery can be reliably assessed by iCT. Compared with postoperative MR imaging findings, the findings in this study provided quantitative evidence that iCT not only holds significant promise for maximizing the extent of tumor resection but also eliminates the unnecessary blind surgical manipulation, thus increasing the safety of the procedure. PMID- 21700795 TI - Are cultures becoming individualistic? A cross-temporal comparison of individualism-collectivism in the United States and Japan. AB - Individualism-collectivism is one of the best researched dimensions of culture in psychology. One frequently asked but underexamined question regards its cross temporal changes: Are cultures becoming individualistic? One influential theory of cultural change, modernization theory, predicts the rise of individualism as a consequence of economic growth. Findings from past research are generally consistent with this theory, but there is also a body of evidence suggesting its limitations. To examine these issues, cross-temporal analyses of individualism collectivism in the United States and Japan were conducted. Diverging patterns of cultural changes were found across indices: In both countries, some of the obtained indices showed rising individualism over the past several decades, supporting the modernization theory. However, other indices showed patterns that are best understood within the frameworks of a shifting focus of social relationships and a persisting cultural heritage. A comprehensive theory of cultural change requires considerations of these factors in addition to the modernization effect. PMID- 21700794 TI - Self-determination theory and diminished functioning: the role of interpersonal control and psychological need thwarting. AB - Drawing from self-determination theory, three studies explored the social environmental conditions that satisfy versus thwart psychological needs and, in turn, affect psychological functioning and well-being or ill-being. In cross sectional Studies 1 and 2, structural equation modeling analyses supported latent factor models in which need satisfaction was predicted by athletes' perceptions of autonomy support, and need thwarting was better predicted by coach control. Athletes' perceptions of need satisfaction predicted positive outcomes associated with sport participation (vitality and positive affect), whereas need thwarting more consistently predicted maladaptive outcomes (disordered eating, burnout, depression, negative affect, and physical symptoms). In addition, athletes' perceptions of psychological need thwarting were significantly associated with perturbed physiological arousal (elevated levels of secretory immunoglobulin A) prior to training. The final study involved the completion of a diary and supported the relations observed in the cross-sectional studies at a daily level. These findings have important implications for the operationalization and measurement of interpersonal styles and psychological needs. PMID- 21700796 TI - Development and characterization of 20 novel polymorphic STS markers in Vicia faba (fava bean). AB - PREMISE OF THE STUDY: Sequence tagged site (STS) primers were developed for Vicia faba, based on amplified bands by ISSR primers. The usefulness of these STS markers was validated for size polymorphism among fava bean accessions. METHODS AND RESULTS: Based on the sequences derived from intersimple sequence repeat (ISSR) amplification, 66 sequence tagged site (STS) primer pairs were developed and screened, and 20 of them were polymorphic. The polymorphism of these markers was identified in 32 fava bean germplasm from different global geographical locations. Alleles (N(a)) per locus numbered 2 to 4, and expected heterozygosity (H(E)) per locus ranged from 0.000 to 0.714. There was significant variation in H(E) among germplasm from different regions for individual primers. CONCLUSIONS: These novel polymorphic STS markers may be useful and convenient for further studies of population genetics, cultivar identification, and evolution in fava bean. PMID- 21700797 TI - Development of microsatellite markers in Capsella rubella and Capsella bursa pastoris (Brassicaceae). AB - PREMISE OF THE STUDY: We developed microsatellite markers to investigate genetic diversity within and among populations of Capsella rubella and Capsella bursa pastoris and between these two species. METHODS AND RESULTS: Fourteen polymorphic microsatellite loci were identified in the two species and one more polymorphic microsatellite locus only in C. rubella. Samples from different European localities were genotyped. Up to six alleles per locus were observed in C. rubella, and up to 22 alleles per locus in C. bursa-pastoris. Observed heterozygosities were low, indicating high selfing rates, especially in C. rubella. CONCLUSIONS: The results provide valuable information on genetic diversity for future studies of population genetics in C. rubella and C. bursa pastoris. PMID- 21700798 TI - Root suckering in a Triassic conifer from Antarctica: paleoecological and evolutionary implications. AB - PREMISE OF THE STUDY: Although root suckering and other types of sprouting are well studied in extant woody plants, little is known about the distribution of these traits at a macroevolutionary scale. Anatomically preserved fossil plants represent an excellent but understudied source of information of the distribution of sprouting behavior through time and across taxa. METHODS: A block of silicified peat collected in the Middle Triassic Fremouw Formation at the Fremouw Peak locality, Central Transantarctic Mountains, Antarctica, contains a group of anatomically preserved roots of the fossil conifer Notophytum krauselii that bear young shoots. The specimen was prepared using the standard acetate peel technique and studied in reflected and transmitted light. KEY RESULTS: Young sucker shoots bearing well-preserved leaves are produced in groups in some areas of the Notophytum roots. CONCLUSIONS: The production of root suckers in Notophytum indicates that some of the trees growing in polar forests during the Triassic could respond to environmental stresses by regenerating their vegetative structures and had the potential to reproduce vegetatively. The specimens also represent the first anatomical evidence of root suckering in any fossil seed plant, and its occurrence in an early putative podocarp supports the idea that this trait might be ancestral in at least some extant conifer families. PMID- 21700799 TI - Pollination and protection against herbivory of Nepalese Coelogyninae (Orchidaceae). AB - PREMISE OF THE STUDY: Although many species in the orchid genus Coelogyne are horticulturally popular, hardly anything is known about their pollination. Pollinators of three species were observed in the field in Nepal. This information is urgently needed because many orchid species in Nepal are endangered. Whether the exudates produced by extrafloral nectaries played a role in protection against herbivory was also investigated. METHODS: Pollinators of C. flaccida, C. nitida, and Otochilus albus were filmed, captured, and identified. Ant surveys and exclusion experiments were carried out. To investigate whether pollinators are needed for fruit set, plants were wrapped in mesh wire bags. Inflorescence stems were examined with microscopy. Fehling's reagent was used to detect sugars in extrafloral exudates. KEY RESULTS: Coelogyne flaccida and C. nitida need pollinators to set fruit and are pollinated by wild bees identified as Apis cerana. Otochilus albus was found to be pollinated by Bombus kashmirensis. Extrafloral nectar was found to be exuded by nectary-modified stomata and contained high amounts of sugars. Different species of ants were observed collecting these exudates. A significant difference was found in damage inflicted by flower and leaf-eating beetles between C. nitida plants living in trees with ant nests and those in ant-free trees. CONCLUSIONS: Floral syndromes include scented and colored trap flowers without reward to their pollinators. All orchids investigated exude extrafloral nectar by nectary-modified stomata. This nectar was found to flow from the phloem to the stomata through intercellular spaces in the outer parenchymatous layer of the inflorescence. PMID- 21700800 TI - Development of microsatellite markers for Miscanthus sinensis (Poaceae) and cross amplification in other related species. AB - PREMISE OF THE STUDY: We developed microsatellite loci for the biomass crop Miscanthus sinensis to investigate genetic diversity and population structure of M. sinensis and its closely related species. METHODS AND RESULTS: Fourteen microsatellite loci were identified from an enriched genomic library of M. sinensis and tested in one M. sinensis population. The number of alleles per locus ranged from 1 to 15, with a mean of 7.0. The observed and expected heterozygosities varied from 0.318 to 0.864 and from 0.424 to 0.901, respectively. Of them, 12 primers could be applied to three other species in Miscanthus (M. sacchariflorus, M. floridulus, and M. lutarioriparius). CONCLUSIONS: These markers will be important for further analyzing population genetics and evolutionary history, as well as facilitating molecular breeding of Miscanthus sinensis and its related species. PMID- 21700801 TI - Anomalous capitulum structure and monoecy may confer flexibility in sex allocation and life history evolution in the Ifloga lineage of paper daisies (Compositae: Gnaphalieae). AB - PREMISE OF THE STUDY: Evolutionary significance of the Compositae capitulum and variation in its structure is poorly understood, although it may permit flexibility in sexual expression. Optimal sex ratio differs with life-history and reproductive strategy. We explore how the genus Ifloga and related members of southern African Gnaphalieae achieved different sex ratios, and the associations of these ratios with annual and perennial life history. METHODS: Sex allocation was measured using the male to female ratio (M/F), a novel approximator of the pollen to ovule ratio (P/O). Life-history (annuality/perenniality), capitulum structure, capitular sexual system, and M/F were reconstructed on time proportional phylogenies. Trait associations were examined using phylogenetically independent contrasts (PICs). KEY RESULTS: Annual taxa have strongly female biased capitula, as measured by M/F, and either gynomonoecious or monoecious sexual systems, while perennials have equal or male-biased capitula that are hermaphroditic or monoecious. These results are largely supported by PIC analysis. Different sexual systems afford differing flexibility in sex allocation, with hermaphrodites having the least, and monoecious taxa the greatest, range in M/F. Within Ifloga, the anomalous capitulum evolved in an annual, gynomonoecious ancestor, followed by two independent gains of monoecy. Two subsequent gains of perenniality occurred within a monoecious sublineage. CONCLUSIONS: Different life histories have divergent sex allocation optima and are strongly associated with different sexual systems in gnaphalioid daisies. An anomalous capitulum structure in Ifloga may have facilitated the evolution of monoecy, which in turn may be linked to the evolution of life-history diversity in the genus. PMID- 21700802 TI - Isolation and characterization of microsatellite markers in distylous Palicourea padifolia (Rubiaceae). AB - PREMISE OF THE STUDY: Eighteen microsatellite loci of distylous Palicourea padifolia were isolated and characterized for population genetics studies. METHODS AND RESULTS: Following a microsatellite enrichment protocol, 18 primer pairs amplified successfully, and the polymorphism of the loci was initially evaluated in 15 individuals from three populations in Mexico. Seven loci were polymorphic, and their variability was further assessed in 60 individuals from three populations. The total number of alleles per locus, combining samples from all populations, ranged from 7 to 12. Nei's genetic diversity average across loci was 0.681, 0.714, and 0.703 for El Riscal, Montebello, and Ruiz Cortinez, respectively. Palicourea padifolia individuals had one to four alleles, confirming the polyploidy of this species. CONCLUSIONS: These markers will facilitate genetic diversity studies of P. padifolia across its distribution range and facilitate investigations on the evolution of its breeding system. PMID- 21700803 TI - Isolation and characterization of microsatellite markers for Bothriochloa ischaemum (Poaceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed for Bothriochloa ischaemum to investigate the structure of invasive populations within Texas and determine the origin of introduction from within the native range. METHODS AND RESULTS: We adapted the biotinylated nucleotide method of developing an enriched genomic library to isolate and characterize 10 polymorphic microsatellite markers. The number of alleles per locus (A) ranged from five to 18 (mean A = 10.45), expected heterozygosity (H(E)) ranged from 0.620 to 0.895 (mean H(E) = 0.785), and expected heterozygosity corrected for sample size (H(EC)) ranged from 0.635 to 0.909 (mean H(EC) = 0.799). The primers were also tested for amplification in Schizachyrium scoparium var. scoparium, Andropogon gerardii, Bothriochloa saccharoides, and Dichanthium annulatum. CONCLUSIONS: The use of microsatellite markers may assist in understanding the pattern of spread, determining the source of invasive populations, and developing biological control agents for invasive populations of Bothriochloa ischaemum. PMID- 21700804 TI - Development and characterization of microsatellite markers for Polygonum cespitosum (Polygonaceae). AB - PREMISE OF THE STUDY: We isolated and characterized microsatellite markers in Polygonum cespitosum Blume, an herbaceous annual plant species introduced into North America from Asia that has recently become invasive. METHODS AND RESULTS: A total of 12 polymorphic and 3 monomorphic loci were screened in 1-2 individuals from each of 20 populations from the introduced and native range, for a total of 24 samples. The number of alleles per locus in the polymorphic loci ranged from 3 to 9, and expected heterozygosity ranged from 0.156 to 0.838. CONCLUSIONS: These new loci will provide tools for examining genetic relatedness among introduced and native populations of this and other related species. PMID- 21700805 TI - Leaf fossils of the ancient Tasmanian relict Microcachrys (Podocarpaceae) from New Zealand. AB - PREMISE OF THE STUDY: Microcachrys tetragona (Podocarpaceae), endemic to the mountains of Tasmania, represents the only remaining taxon of one of the world's most ancient and widely distributed conifer lineages. Remarkably, however, despite its ~150 Myr heritage, our understanding of the fossil history of this lineage is based almost entirely on the pollen record. Fossils of Microcachrys are especially important in light of recent molecular phylogenetic and dating evidence. This evidence dates the Microcachrys lineage to the Mesozoic and does not support the traditional placement of Microcachrys as sister to the southeastern Australian genus Pherosphaera. METHODS: We undertook comparative studies of the foliage architecture, cuticle, and paleoecology of newly discovered fossils from the Oligo-Miocene of New Zealand and M. tetragona and discussed the importance of Microcachrys in the context of Podocarpaceae phylogeny. KEY RESULTS: The fossils represent the oldest and first extra Australian macrofossils of Microcachrys and are described as the new foliage species M. novae-zelandiae. These fossils confirm that the distinctive opposite decussate phyllotaxy of the genus is at least as old as the Oligo-Miocene and contribute to evidence that Microcachrys plants were sometimes important components of oligotrophic swampy habitats. CONCLUSIONS: Leaf fossils of Microcachrys closely comparable with the only extant species confirm that this lineage had a much wider past distribution. The fossil record and recent molecular phylogenetic studies, including that of Microcachrys, also serve to emphasize the important status of Tasmania as a refugium for seed plant lineages. PMID- 21700806 TI - Development and polymorphism of microsatellite primers in Ficus pumila L. (Moraceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed in the functionally dioecious Ficus pumila L. to provide polymorphic markers for further population genetic studies and parentage analysis. METHODS AND RESULTS: Eleven polymorphic microsatellite loci were developed in F. pumila. These loci were successfully amplified in four F. pumila populations from eastern China (Fodu, Xiangshan, Xianju, and Hexi). These loci had 3-11 alleles across all 80 F. pumila individuals. At the population level, the number of alleles per locus varied from 1 to 8, and the observed (H(O)) and expected (H(E)) heterozygosities ranged from 0.000 to 0.900 and from 0.000 to 0.830, respectively. Linkage disequilibrium between loci FP213 and FP435 was found in three of the four tested populations. CONCLUSIONS: These loci showed high levels of polymorphism, indicating the utility of these primers in population genetic studies as well as parentage analysis of F. pumila. PMID- 21700807 TI - Microsatellite markers for Butia eriospatha (Arecaceae), a vulnerable palm species from the Atlantic Rainforest of Brazil. AB - PREMISE OF THE STUDY: Microsatellite markers were developed for the vulnerable palm species Butia eriospatha (Mart. ex Drude) Becc. to investigate genetic diversity, spatial genetic structure, mating system, and population dynamics. METHODS AND RESULTS: From a genomic library enriched for GA/CA repeats, 14 sets of primers were isolated and characterized for 50 B. eriospatha samples from two populations. The number of alleles per locus ranged from 2 to 6 (with amplified dinucleotide repeat-based primers); the observed and expected heterozygosities ranged from 0.000 to 1.000 and from 0.120 to 0.690, respectively. At least 86% of primers were also amplified for Butia catarinensis Noblick & Lorenzi, another threatened palm species from the Atlantic Rainforest in Brazil. CONCLUSIONS: The new marker set described here will be useful for studies of population genetics of B. eriospatha, and they have been shown to be applicable for other species from the Butia genus. PMID- 21700808 TI - Increased genetic differentiation but no reduced genetic diversity in peripheral vs. central populations of a steppe grass. AB - PREMISE OF THE STUDY: Intraspecific genetic variation is essential for the performance and evolution of species. Populations at a species' geographic range periphery receive considerable attention in biogeography and conservation because they are smaller and spatially more isolated than central populations, a pattern expected to lead to higher genetic differentiation and lower within-population genetic diversity. We tested these predictions in central and peripheral populations of the Eurasian steppe grass Stipa capillata. METHODS: We analyzed AFLP fingerprint patterns in 319 individuals from 20 large and abundant populations in the core, in Kazakhstan, and 23 small and isolated populations at the periphery, in Central Europe. We calculated different genetic diversity estimates and assessed genetic differentiation among populations by examining F(ST) values, a neighbor-net network, and an AMOVA. KEY RESULTS: As expected, genetic differentiation among populations was significantly larger at the range periphery (F(ST) = 0.415) than in the range core (F(ST) = 0.164). In contrast to predictions, however, we found similarly low genetic diversity within central (proportion of polymorphic bands = 21.9%) and peripheral (20%) populations. CONCLUSIONS: Higher genetic differentiation in the small and spatially isolated peripheral populations is likely driven by genetic drift and reduced gene flow due to a complex landscape structure and the abandonment of traditional management regimes. With regard to unchanged genetic diversity, it appears that life-history traits like longevity or sufficiently large population sizes could allow S. capillata to escape deleterious effects at the range edge. PMID- 21700809 TI - Salivary detection of H1N1 virus: a clinical feasibility investigation. AB - The fast and efficient transportation among continents will continue to play a role in the spread of airborne pandemics. The objective of this study was to detect H1N1 virus in the saliva of individuals who visited the emergency department and were diagnosed as having H1N1 influenza. Nasopharyngeal swabs and saliva samples from those who presented to the emergency department with flu-like symptoms were sent to the laboratory. RNA was extracted from both samples. Real time RT-PCR tests were performed, and the saliva and nasopharyngeal swab tests were compared. Samples were drawn from 26 individuals. A positive nasopharyngeal swab test and salivary test was found in 14 persons, and negative tests were found in 12 persons. Saliva sampling for H1N1 has excellent predictive value, is highly accurate and reliable, and is more convenient than the nasopharyngeal swab. Clinical trial with the Helsinki Committee at Rambam Health Care Campus, registration number 036309-RMB. PMID- 21700810 TI - The "real" big question. PMID- 21700811 TI - "If not us, who? If not now, when?". PMID- 21700812 TI - Tissue injury and pulp regeneration. PMID- 21700814 TI - Parents of children newly diagnosed with type 1 diabetes: experiences with social support and family management. AB - PURPOSE: The purpose of this mixed-methods descriptive study with parents of children newly diagnosed with type 1 diabetes was to explore their experiences with peer social support following the Social Support to Empower Parents (STEP) intervention and the usefulness of the Family Management Measure (FaMM) in this population. METHODS: Parents who were in the experimental arm of STEP were recruited. Qualitative interviews were conducted (n = 21), and 11 parents completed the FaMM, a quantitative family-functioning measure. Qualitative content data analysis was conducted and compared to the descriptive measure analysis. Findings Three themes were identified: availability, practical tips, and common ground. Five FaMM subscales were reliable (alpha > .80) in this small sample. CONCLUSIONS: The findings illustrate that the STEP intervention is helpful, providing the participants with emotional, affirmational, and informational social support. The use of the FaMM is a first step in assessing family management in families with children with type 1 diabetes. PMID- 21700815 TI - Restaurant challenge offers healthful meal options and builds diabetes awareness. AB - PURPOSE: The Frederick Restaurant Challenge is an innovative project based on a collaborative effort among community organizations and partners designed to offer delicious healthful meal options at local restaurants during the month of November for American Diabetes Month. Local restaurants were challenged to participate and submitted recipes for healthful meals to the Frederick County Diabetes Coalition for review by registered dietitians. Diners voted on meals to determine the challenge winner(s), and were eligible to win prizes as well. Publicity prior to and during the month was effective in creating positive news about healthful meals when eating out, raised awareness about diabetes, and provided restaurants with desirable advertising opportunities. Feedback from restaurants and diners was overwhelmingly positive. The purpose of this article is to describe this successful low-budget project to encourage its replication in local communities. CONCLUSIONS: The Frederick Restaurant Challenge proved to be a very successful, innovative, low-budget project that met its intended goals: to develop healthful meal options for people with diabetes (or for anyone wishing to eat healthier); to demonstrate that healthful food can taste delicious; and to encourage restaurants to continue offering healthful options on their menus beyond the challenge month. Community interventions such as the Frederick Restaurant Challenge offer unique and important strategies for affecting change and raising awareness not only for people with diabetes but also for the entire community. PMID- 21700816 TI - Positron-emission computed tomography in cyst infection diagnosis in patients with autosomal dominant polycystic kidney disease. AB - BACKGROUND: Cyst infection remains a challenging issue in patients with autosomal dominant polycystic kidney disease (ADPKD). In most patients, conventional imaging techniques are inconclusive. Isolated observations suggest that (18)fluorodeoxyglucose (18FDG) positron-emission computed tomography (PET/CT) might help detect cyst infection in ADPKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Comparative assessment of administrative databases from January 2005 to December 2009 identified 27 PET/CT scans performed in 24 ADPKD patients for suspicion of abdominal infection. Cyst infection was definite if confirmed by cyst fluid analysis. Cyst infection was probable if all four of the following criteria were met: temperature of >38 degrees C for >3 days, loin or liver tenderness, C-reactive protein plasma level of >5 mg/dl, and no CT evidence for intracystic bleeding. Episodes with only two or three criteria were grouped as "fever of unknown origin". RESULTS: Thirteen infectious events in 11 patients met all criteria for kidney (n = 3) or liver (n = 10) cyst infection. CT was contributive in only one patient, whereas PET/CT proved cyst infection in 11 patients (84.6%). In addition, 14 episodes of "fever of unknown origin" in 13 patients were recorded. PET/CT identified the source of infection in nine patients (64.3%), including 2 renal cyst infections. Conversely, PET/CT showed no abnormal 18FDG uptake in 5 patients, including 2 intracystic bleeding. The median delay between the onset of symptoms and PET/CT procedure was 9 days. CONCLUSIONS: This retrospective series underscores the usefulness of PET/CT to confirm and locate cyst infection and identify alternative sources of abdominal infection in ADPKD patients. PMID- 21700817 TI - Estimated net endogenous acid production and serum bicarbonate in African Americans with chronic kidney disease. AB - BACKGROUND AND OBJECTIVES: Metabolic acidosis may contribute to morbidity and disease progression in patients with chronic kidney disease (CKD). The ratio of dietary protein, the major source of nonvolatile acid, to dietary potassium, which is naturally bound to alkali precursors, can be used to estimate net endogenous acid production (NEAP). We tested the association between estimated NEAP and serum bicarbonate in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: NEAP was estimated among 462 African American adults with hypertensive CKD using published equations: NEAP (mEq/d) = -10.2 + 54.5 (protein [g/d]/potassium [mEq/d]). Dietary protein and potassium intake were estimated from 24-hour urinary excretion of urea nitrogen and potassium, respectively. All of the eligible measurements during follow-up were modeled using generalized linear regression clustered by participant and adjusted for demographics, 24-hour urinary sodium, kidney function, and selected medications. RESULTS: Higher NEAP was associated with lower serum bicarbonate in a graded fashion (P trend < 0.001). Serum bicarbonate was 1.27 mEq/L lower among those in the highest compared with the lowest quartile of NEAP (P < 0.001). There was a greater difference in serum bicarbonate between the highest and lowest quartiles of NEAP among patients with stage 4/5 CKD (-2.43 mEq/L, P < 0.001) compared with those with stage 2/3 disease (-0.77 mEq/L, P = 0.01; P-interaction = 0.02). CONCLUSIONS: Reducing NEAP, through reduction of dietary protein and increased intake of fruits and vegetables, may prevent metabolic acidosis in patients with CKD. PMID- 21700818 TI - Predicting renal risk in the general population: do we have the right formula? PMID- 21700819 TI - Circulating miR-210 predicts survival in critically ill patients with acute kidney injury. AB - BACKGROUND AND OBJECTIVES: MicroRNAs (miRNAs) are small ribonucleotides regulating gene expression. MicroRNAs are present in the blood in a remarkably stable form. We tested whether circulating miRNAs in the plasma of critically ill patients with acute kidney injury (AKI) at the inception of renal replacement therapy are deregulated and may predict survival. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We profiled miRNAs using RNA isolated from the plasma of patients with AKI and healthy controls. The results were validated in 77 patients with acute kidney injury, 30 age-matched healthy controls, and 18 critically ill patients with acute myocardial infarction by quantitative real-time PCR. RESULTS: Circulating levels of miR-16 and miR-320 were downregulated in the plasma of kidney injury AKI patients, whereas miR-210 was upregulated compared with healthy controls (all P < 0.0001) and disease controls (miR-210 and miR-16: P < 0.0001; miR-320: P = 0.03). Cox regression (P < 0.05) and Kaplan-Meier curve analysis (P = 0.03) revealed miR-210 as an independent and powerful predictor of 28-day survival. CONCLUSIONS: Circulating miRNAs are altered in patients with kidney injury AKI. MiR-210 predicts mortality in this patient cohort and may serve as a novel biomarker AKI reflecting pathophysiological changes on a cellular level. PMID- 21700820 TI - Family income and survival in Brazilian Peritoneal Dialysis Multicenter Study Patients (BRAZPD): time to revisit a myth? AB - BACKGROUND AND OBJECTIVES: Although low socioeconomic status has been considered a contraindication to peritoneal dialysis (PD), no published data clearly link it to poor outcomes. The goal of this study was assessing the effect of income on survival in the Brazilian Peritoneal Dialysis Multicenter STUDY. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Incident PD patients enrolled in this prospective cohort from December 2004 to October 2007 were divided according to monthly family income. The median age was 59 years, 54% were women, 60% Caucasians, 41% diabetics, and 24% had cardiovascular disease. Most of them were in continuous ambulatory PD, had not received predialysis care, had <4 school years, and had a family income of <5 minimum wage (80%). Survival analysis was performed using the Kaplan-Meier method and the Cox proportional hazards model adjusting the results for age, gender, educational status, predialysis care, first therapy, PD modality, calendar year, and comorbidities. RESULTS: There were no differences in technique (log rank test chi2 = 4.36) and patient (log rank test chi2 = 2.92) survival between the groups. In the multivariate analysis, low family income remained not associated either to worse technique survival (hazard ratio [HR] = 1.29; 95% confidence interval [CI] = 0.91 to 1.84) or to patient survival (HR = 1.40; 95% CI = 0.99 to 1.99). CONCLUSIONS: According to these results, economic status is not independently associated with outcomes in this large cohort and should not be considered a barrier for PD indication. PMID- 21700821 TI - Diagnostic accuracy of cystatin C-based eGFR equations at different GFR levels in children. AB - BACKGROUND AND OBJECTIVES: The diagnostic accuracy of cystatin C estimated GFR (eGFR) by various cystatin C equations have varied in different studies. We hypothesized that the GFR level of enrolled patients affects the diagnostic accuracy of a cystatin C equation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed 240 consecutively enrolled children at a single Canadian center in a prospective and cross-sectional study. Cystatin C was analyzed with nephelometry, and cystatin C eGFR was estimated by the equations validated in children. GFR was measured by technetium-99m-diethylene-triamine penta-acetic acid (99m)Tc DTPA). RESULTS: We compared various cystatin C equations across GFR strata < 60, < 90, >= 135, and >= 150 ml/min per 1.73 m2 for an accurate prediction and appropriate classification of the measured GFR. The CKiD, Zappitelli-CysEq, and Zappitelli CysCrEq equations had a higher accuracy, estimated by eGFR values within 10% and 30% of the respective (99m)Tc DTPA, in the GFR categories < 60 and < 90 ml/min per 1.73 m2, whereas the Bokenkamp, Bouvet, and Filler equations had a greater accuracy in the GFR categories >= 135 and >= 150 ml/min per 1.73 m2. The Bouvet, CKiD, Filler, Zappitelli-CysEq, and Zappitelli-CysCrEq equations had a greater sensitivity to classify GFR < 60 and < 90 ml/min per 1.73 m2, whereas the Bokenkamp equation had a higher sensitivity for GFR >= 135 and >= 150 ml/min per 1.73 m2. CONCLUSIONS: The diagnostic accuracy of various cystatin C equations varies with GFR. This issue needs consideration while applying these equations in clinical practice and for further research on eGFR equations. PMID- 21700823 TI - Patterns of noncryoglobulinemic glomerulonephritis with monoclonal Ig deposits: correlation with IgG subclass and response to rituximab. AB - BACKGROUND AND OBJECTIVES: Several different entities have recently been described among glomerular diseases associated with monoclonal IgG deposits. The aim of this study was to describe the distribution of the different pathologic subtypes of IgG-associated glomerulopathy and to evaluate the IgG isotype involved in these diseases. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective study including all patients with glomerular deposits of monoclonal IgG referred to three nephrology departments between 1980 and 2008. RESULTS: Twenty-six patients were included. Nephrotic syndrome was almost constantly associated with a renal dysfunction in 14 of 26 patients. The presence of M-spike was detected in only 30% of the patients, and an overt hematologic malignancy (myeloma, lymphoma) was identified in 9 of 26 patients. Patients were almost equally divided into two distinct histologic patterns: membranous nephropathy (MN) or membranoproliferative glomerulonephritis (MPGN). IgG3 deposits were identified in 80% of patients with MPGN, whereas IgG1 deposits were present in 64% of patients with MN. Ultrastructural study showed that immune deposits were nonorganized in most patients. Seven patients were treated with rituximab with excellent results: five of seven had a complete remission of the nephrotic syndrome and two of seven had a partial response. After a mean 24-month follow-up, only one patient experienced relapse of the nephropathy. CONCLUSIONS: GN with monoclonal Ig deposits can be associated with MPGN or MN, which are correlated with IgG3 and IgG1 isotypes, respectively. Rituximab appears to have a very favorable benefit-to-risk ratio for patients with no overt hematologic malignancy. PMID- 21700824 TI - All-cause mortality in hemodialysis patients with heart valve calcification. AB - BACKGROUND AND OBJECTIVES: Calcification of the mitral and aortic valves is common in dialysis patients (CKD-5D). However, the prognostic significance of valvular calcification (VC) in CKD is not well established. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 144 adult CKD-5D patients underwent bidimensional echocardiography for qualitative assessment of VC and cardiac computed tomography (CT) for quantification of coronary artery calcium (CAC) and VC. The patients were followed for a median of 5.6 years for mortality from all causes. RESULTS: Overall, 38.2% of patients had mitral VC and 44.4% had aortic VC on echocardiography. Patients with VC were older and less likely to be African American; all other characteristics were similar between groups. The mortality rate of patients with calcification of either valve was higher than for patients without VC. After adjustment for age, gender, race, diabetes mellitus, and history of atherosclerotic disease, only mitral VC remained independently associated with all-cause mortality (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.03 to 2.91). Patients with calcification of both valves had a two-fold increased risk of death during follow-up compared with patients without VC (HR, 2.16; 95% CI, 1.14 to 4.08). A combined CT score of VC and CAC was strongly associated with all-cause mortality during follow-up (HR for highest versus lowest tertile, 2.21; 95% CI, 1.08 to 4.54). CONCLUSIONS: VC is associated with a significantly increased risk for all-cause mortality in CKD-5D patients. These findings support the use of echocardiography for risk stratification in CKD 5D as recently suggested in the Kidney Disease Improving Global Outcomes guidelines. PMID- 21700825 TI - A critically swift response: insulin-stimulated potassium and glucose transport in skeletal muscle. PMID- 21700826 TI - Endogenous testosterone, endothelial dysfunction, and cardiovascular events in men with nondialysis chronic kidney disease. AB - BACKGROUND AND OBJECTIVES: Deterioration of kidney function impairs testosterone production, with hypogonadism being common in men with chronic kidney disease (CKD). In nonrenal populations, testosterone is suggested to participate in the atherosclerotic process. In male dialysis patients, we showed that low testosterone increases the risk of mortality. We here studied plausible links among testosterone levels, vascular derangements, and cardiovascular events in nondialysis CKD men. DESIGN, SETTING, PARTICIPANTS, & METHODS: This was a cross sectional analysis in which flow-mediated dilation (FMD) was assessed in 239 CKD male patients (stages 1 to 5; mean age 52 +/- 12 years), together with routine measurements, serum total and free testosterone, and follow-up for cardiovascular outcomes. RESULTS: Total and free testosterone levels decreased in parallel with the reduction of kidney function. Multiple regression analyses showed that total and free testosterone significantly and independently contributed to explain the variance of FMD. After a median follow-up of 31 months (range 8 to 35 months), 22 fatal and 50 nonfatal cardiovascular events occurred. In Cox analysis, the risk of cardiovascular events was reduced by 22% for each nanomole-per-liter increment of total testosterone. This reduced risk persisted after adjustment for age, renal function, diabetes mellitus, previous cardiovascular history, C-reactive protein, albumin, and FMD. The same was true for free testosterone concentrations. CONCLUSIONS: The reduction in endogenous testosterone levels observed with progressive CKD was inversely associated with endothelial dysfunction and exacerbated the risk of future cardiovascular events in nondialysis male CKD patients. PMID- 21700828 TI - Hospital-acquired acute kidney injury: an analysis of nadir-to-peak serum creatinine increments stratified by baseline estimated GFR. AB - BACKGROUND AND OBJECTIVES: Serum creatinine (sCr) increments currently used to define acute kidney injury (AKI) do not take into consideration the baseline level of kidney function. The objective of this study was to establish whether baseline estimated GFR (eGFR) provides additional risk stratification to sCr based increments for defining AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 29,645 adults hospitalized at an acute care facility were analyzed. Hospital acquired AKI was defined by calculating the difference between the nadir and subsequent peak sCr. RESULTS: Different thresholds of nadir-to-peak sCr were found to be independently associated with increased in-hospital mortality according to baseline eGFR strata. A nadir-to-peak sCr minimum threshold of >=0.2, >=0.3, and >=0.5 mg/dl was required to be independently associated with increased in-hospital mortality among patients with baseline eGFR >=60 ml/min per 1.73 m2 (odds ratio [OR] 1.67; 95% confidence interval [CI] 1.13 to 2.47), 30 to 59 ml/min per 1.73 m2 (OR 2.69; 95% CI, 1.82 to 3.97), and <30 ml/min per 1.73 m2 (OR 2.15; 95% CI 1.02 to 4.51), respectively. There was a significant interaction between the nadir-to-peak sCr and baseline eGFR for in-hospital mortality (P < 0.001). Using these thresholds, survivors of AKI episodes had an increased hospital length of stay and were more likely to be discharged to a facility rather than home. Sensitivity analyses showed a significant interaction between baseline eGFR strata and relative increases in sCr, as well as absolute and relative decreases in eGFR for in-hospital mortality (P < 0.001). Conclusions This study suggests that future sCr-based definitions of AKI should take into consideration baseline eGFR. PMID- 21700827 TI - Long-term outcome of renal transplantation patients with Henoch-Schonlein purpura. AB - BACKGROUND AND OBJECTIVES: Although Henoch-Schonlein purpura (HSP) is the most common form of renal vasculitis in childhood, progression to ESRD is rare, and there are few data on outcomes of renal transplantation in patients with HSP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a matched retrospective cohort study of renal allografts using the United Network of Organ Sharing database (1987 to 2005). Of the 189,211 primary renal allografts, there were 339 with a diagnosis of HSP. The primary end point was allograft survival. RESULTS: Compared with the remainder of the database, the HSP population was younger (25 years versus 46 years), and had a higher proportion of women (47% versus 40%), live donors (50% versus 35%), and Caucasians (77% versus 60%). Controlling for age, gender, donor source, ethnicity, and year of transplantation, death-censored graft survival for patients with HSP was 80.0% at 5 years and 58.8% at 10 years compared with 79.0% at 5 years and 55.4% at 10 years in the non-HSP population. Among patients with reported causes of graft loss, failure from recurrent disease occurred in 13.6% of patients with HSP, compared with 6.6% in the non-HSP population. When analyzing allograft survival in recipients with HSP compared with those with IgA nephropathy, there was no difference in 10-year allograft survival (58.4% and 59.3%, respectively). CONCLUSIONS: These data indicate that although there is an increased risk of graft failure attributable to recurrent disease in patients with HSP, a diagnosis of HSP has little effect on overall renal allograft survival. PMID- 21700829 TI - Casual blood pressure and neurocognitive function in children with chronic kidney disease: a report of the children with chronic kidney disease cohort study. AB - BACKGROUND AND OBJECTIVES: Children with chronic kidney disease (CKD) are at risk for cognitive dysfunction, and over half have hypertension. Data on the potential contribution of hypertension to CKD-associated neurocognitive deficits in children are limited. Our objective was to determine whether children with CKD and elevated BP (EBP) had decreased performance on neurocognitive testing compared with children with CKD and normal BP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a cross-sectional analysis of the relation between auscultatory BP and neurocognitive test performance in children 6 to 17 years enrolled in the Chronic Kidney Disease in Children (CKiD) project. RESULTS: Of 383 subjects, 132 (34%) had EBP (systolic BP and/or diastolic BP >=90(th) percentile). Subjects with EBP had lower mean (SD) scores on Wechsler Abbreviated Scales of Intelligence (WASI) Performance IQ than those with normal BP (normal BP versus EBP, 96.1 (16.7) versus 92.4 (14.9), P = 0.03) and WASI Full Scale IQ (97.0 (16.2) versus 93.4 (16.5), P = 0.04). BP index (subject's BP/95(th) percentile BP) correlated inversely with Performance IQ score (systolic, r = 0.13, P = 0.01; diastolic, r = -0.19, P < 0.001). On multivariate analysis, the association between lower Performance IQ score and increased BP remained significant after controlling for demographic and disease-related variables (EBP, beta = -3.7, 95% confidence interval [CI]: -7.3 to -0.06; systolic BP index, beta = -1.16 to 95% CI: -2.1, -0.21; diastolic BP index, beta = -1.17, 95% CI: -1.8 to -0.55). CONCLUSIONS: Higher BP was independently associated with decreased WASI Performance IQ scores in children with mild-to-moderate CKD. PMID- 21700830 TI - Chromatin-based mechanisms of renal epithelial differentiation. AB - Successful regenerative renal medicine depends on understanding the molecular mechanisms by which diverse phenotypes of epithelial cells differentiate from metanephric mesenchyme to populate nephrons. Whereas many genes are maintained in a poised state within the population of pluripotent progenitors, specialized epithelial functions reflect the selective expression of a subset of genes and the repression of all others. Here we highlight some common mechanisms of cell differentiation and epigenetic regulation to discuss their implications for renal epithelial development, repair, and disease. PMID- 21700831 TI - Racial and ethnic differences in kidney function decline among persons without chronic kidney disease. AB - Whether the rate of kidney function decline before the onset of CKD differs among racial and ethnic groups remains unclear. Here, we evaluated kidney function decline and incident CKD among white, black, Hispanic, and Chinese participants in the Multi-Ethnic Study of Atherosclerosis (MESA) during 5 years of follow-up. We estimated GFR using both cystatin C (eGFRcys) and creatinine (eGFRcreat). The definition of incident CKD required eGFRcys <60 ml/min per 1.73 m(2) and a decline in eGFRcys >=1 ml/min per year. Among participants with eGFRcreat >60 ml/min per 1.73 m(2) at baseline, blacks had a significantly higher rate of kidney function decline than whites (0.31 ml/min per 1.73 m(2)/yr faster on average, P=0.001), even after adjusting for multiple potential confounders. Among Hispanics, Dominicans and Puerto Ricans had faster rates of decline than whites (0.55 and 0.47 ml/min per 1.73 m(2)/yr faster, respectively). Mexicans, South Americans, or other Hispanics had similar rates of decline compared to whites. We did not detect significant differences in the rates of kidney function decline among Chinese and white participants. Among those with normal or near-normal kidney function at baseline, blacks and Hispanics had the highest rates of incident CKD during follow-up. Adjustment for comorbidities attenuated some of these differences. In conclusion, the average rate of kidney function decline before the onset of CKD differs among racial and ethnic groups. Traditional risk factors do not explain these differences fully, highlighting the need to explore these disparities. PMID- 21700832 TI - Impact of APE1/Ref-1 redox inhibition on pancreatic tumor growth. AB - Pancreatic cancer is especially a deadly form of cancer with a survival rate less than 2%. Pancreatic cancers respond poorly to existing chemotherapeutic agents and radiation, and progress for the treatment of pancreatic cancer remains elusive. To address this unmet medical need, a better understanding of critical pathways and molecular mechanisms involved in pancreatic tumor development, progression, and resistance to traditional therapy is therefore critical. Reduction-oxidation (redox) signaling systems are emerging as important targets in pancreatic cancer. AP endonuclease1/Redox effector factor 1 (APE1/Ref-1) is upregulated in human pancreatic cancer cells and modulation of its redox activity blocks the proliferation and migration of pancreatic cancer cells and pancreatic cancer-associated endothelial cells in vitro. Modulation of APE1/Ref-1 using a specific inhibitor of APE1/Ref-1's redox function, E3330, leads to a decrease in transcription factor activity for NFkappaB, AP-1, and HIF1alpha in vitro. This study aims to further establish the redox signaling protein APE1/Ref-1 as a molecular target in pancreatic cancer. Here, we show that inhibition of APE1/Ref 1 via E3330 results in tumor growth inhibition in cell lines and pancreatic cancer xenograft models in mice. Pharmacokinetic studies also show that E3330 attains more than10 MUmol/L blood concentrations and is detectable in tumor xenografts. Through inhibition of APE1/Ref-1, the activity of NFkappaB, AP-1, and HIF1alpha that are key transcriptional regulators involved in survival, invasion, and metastasis is blocked. These data indicate that E3330, inhibitor of APE1/Ref 1, has potential in pancreatic cancer and clinical investigation of APE1/Ref-1 molecular target is warranted. PMID- 21700833 TI - Serum bilirubin levels in familial hypercholesterolemia: a new risk marker for cardiovascular disease? AB - Low concentrations of bilirubin are associated with an increased risk for cardiovascular disease (CVD). Possibly, bilirubin exerts its effect through the protection of LDL from oxidation. Therefore, we examined whether low bilirubin might also be a risk marker for CVD in patients with familial hypercholesterolemia (FH) and whether statins influence serum bilirubin levels. Patients with FH were recruited from 37 lipid clinics. After a washout period of 6 weeks, all patients were started on monotherapy with simvastatin 80 mg for a period of two years. A total of 514 patients were enrolled. Bilirubin at baseline was inversely associated with the presence of CVD, also after adjustment for age, gender, presence of hypertension, and HDL cholesterol levels. Moreover, bilirubin levels were significantly raised, by 7%, from 10.0 to 10.8 MUmol/L after treatment with simvastatin 80 mg. We hypothesize first that high bilirubin levels might protect patients with FH from CVD. Furthermore, bilirubin levels were significantly increased after treatment with simvastatin 80 mg, independent of changes in liver enzymes, which might confer additional protection against CVD. Whether this is also true for lower doses of simvastatin or for other statins remains to be investigated. PMID- 21700834 TI - Circulating insulin stimulates fatty acid retention in white adipose tissue via KATP channel activation in the central nervous system only in insulin-sensitive mice. AB - Insulin signaling in the central nervous system (CNS) is required for the inhibitory effect of insulin on glucose production. Our aim was to determine whether the CNS is also involved in the stimulatory effect of circulating insulin on the tissue-specific retention of fatty acid (FA) from plasma. In wild-type mice, hyperinsulinemic-euglycemic clamp conditions stimulated the retention of both plasma triglyceride-derived FA and plasma albumin-bound FA in the various white adipose tissues (WAT) but not in other tissues, including brown adipose tissue (BAT). Intracerebroventricular (ICV) administration of insulin induced a similar pattern of tissue-specific FA partitioning. This effect of ICV insulin administration was not associated with activation of the insulin signaling pathway in adipose tissue. ICV administration of tolbutamide, a K(ATP) channel blocker, considerably reduced (during hyperinsulinemic-euglycemic clamp conditions) and even completely blocked (during ICV administration of insulin) WAT-specific retention of FA from plasma. This central effect of insulin was absent in CD36-deficient mice, indicating that CD36 is the predominant FA transporter in insulin-stimulated FA retention by WAT. In diet-induced insulin resistant mice, these stimulating effects of insulin (circulating or ICV administered) on FA retention in WAT were lost. In conclusion, in insulin sensitive mice, circulating insulin stimulates tissue-specific partitioning of plasma-derived FA in WAT in part through activation of K(ATP) channels in the CNS. Apparently, circulating insulin stimulates fatty acid uptake in WAT but not in BAT, directly and indirectly through the CNS. PMID- 21700836 TI - Targeted genome editing across species using ZFNs and TALENs. AB - Evolutionary studies necessary to dissect diverse biological processes have been limited by the lack of reverse genetic approaches in most organisms with sequenced genomes. We established a broadly applicable strategy using zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) for targeted disruption of endogenous genes and cis-acting regulatory elements in diverged nematode species. PMID- 21700822 TI - An assessment of the Acute Kidney Injury Network creatinine-based criteria in patients submitted to mechanical ventilation. AB - BACKGROUND AND OBJECTIVES: The aim of our study was to assess the new diagnostic criteria of acute kidney injury (AKI) proposed by the Acute Kidney Injury Network (AKIN) in a large cohort of mechanically ventilated patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a prospective observational cohort study enrolling 2783 adult intensive care unit patients under mechanical ventilation (MV) with data on serum creatinine concentration (SCr) in the first 48 hours. The absolute and the relative AKIN diagnostic criteria (changes in SCr >= 0.3 mg/dl or >= 50% over the first 48 hours of MV, respectively) were analyzed separately. In addition, patients were classified into three groups according to their change in SCr (DeltaSCr) over the first day on MV (DeltaSCr): group 1, DeltaSCr <= -0.3 mg/dl; group 2, DeltaSCr between -0.3 and +0.29 mg/dl; and group 3, DeltaSCr >= +0.3 mg/dl). The primary end point was in-hospital mortality, and secondary end points were intensive care unit and hospital length of stay, and duration of MV. RESULTS: Of 2783 patients, 803 (28.8%) had AKI according to both criteria: 431 only absolute (AKI(A)), 362 both relative and absolute (AKI(R+A)), and 10 only relative. The relative criterion identified more patients when baseline SCr (SCr0) was <0.9 mg/dl and the absolute when SCr0 was >1.5 mg/dl. The diagnosis of AKI was associated with mortality. CONCLUSIONS: Our study confirms the validity of the AKIN criteria in a population of mechanically patients and the criteria's relationship with the baseline SCr. PMID- 21700835 TI - Self-recognition in social amoebae is mediated by allelic pairs of tiger genes. AB - Free-living cells of the social amoebae Dictyostelium discoideum can aggregate and develop into multicellular fruiting bodies in which many die altruistically as they become stalk cells that support the surviving spores. Dictyostelium cells exhibit kin discrimination--a potential defense against cheaters, which sporulate without contributing to the stalk. Kin discrimination depends on strain relatedness, and the polymorphic genes tgrB1 and tgrC1 are potential components of that mechanism. Here, we demonstrate a direct role for these genes in kin discrimination. We show that a matching pair of tgrB1 and tgrC1 alleles is necessary and sufficient for attractive self-recognition, which is mediated by differential cell-cell adhesion. We propose that TgrB1 and TgrC1 proteins mediate this adhesion through direct binding. This system is a genetically tractable ancient model of eukaryotic self-recognition. PMID- 21700837 TI - Dinosaur body temperatures determined from isotopic (13C-18O) ordering in fossil biominerals. AB - The nature of the physiology and thermal regulation of the nonavian dinosaurs is the subject of debate. Previously, arguments have been made for both endothermic and ectothermic metabolisms on the basis of differing methodologies. We used clumped isotope thermometry to determine body temperatures from the fossilized teeth of large Jurassic sauropods. Our data indicate body temperatures of 36 degrees to 38 degrees C, which are similar to those of most modern mammals. This temperature range is 4 degrees to 7 degrees C lower than predicted by a model that showed scaling of dinosaur body temperature with mass, which could indicate that sauropods had mechanisms to prevent excessively high body temperatures being reached because of their gigantic size. PMID- 21700838 TI - The mosaic of surface charge in contact electrification. AB - When dielectric materials are brought into contact and then separated, they develop static electricity. For centuries, it has been assumed that such contact charging derives from the spatially homogeneous material properties (along the material's surface) and that within a given pair of materials, one charges uniformly positively and the other negatively. We demonstrate that this picture of contact charging is incorrect. Whereas each contact-electrified piece develops a net charge of either positive or negative polarity, each surface supports a random "mosaic" of oppositely charged regions of nanoscopic dimensions. These mosaics of surface charge have the same topological characteristics for different types of electrified dielectrics and accommodate significantly more charge per unit area than previously thought. PMID- 21700839 TI - Organization of intracellular reactions with rationally designed RNA assemblies. AB - The rules of nucleic acid base-pairing have been used to construct nanoscale architectures and organize biomolecules, but little has been done to apply this technology in vivo. We designed and assembled multidimensional RNA structures and used them as scaffolds for the spatial organization of bacterial metabolism. Engineered RNA modules were assembled into discrete, one-dimensional, and two dimensional scaffolds with distinct protein-docking sites and used to control the spatial organization of a hydrogen-producing pathway. We increased hydrogen output as a function of scaffold architecture. Rationally designed RNA assemblies can thus be used to construct functional architectures in vivo. PMID- 21700840 TI - Education is not a race. PMID- 21700845 TI - Biosecurity. Panel selects most dangerous select agents. PMID- 21700847 TI - Lunar science. Apollo physicist launches noisy dustup over old moon data. PMID- 21700846 TI - Biomedicine. NIH's secondhand shop for tried-and-tested drugs. PMID- 21700848 TI - Technology. Getting there. PMID- 21700849 TI - Technology. Battery FAQs. PMID- 21700850 TI - Biotechnology. Lab-on-a-chip maker looks to put Hong Kong on biotech map. PMID- 21700851 TI - Profile: Ogobara Doumbo. Mali researcher shows how to reverse brain drain. PMID- 21700852 TI - Effects of creating order from chaos. PMID- 21700853 TI - Dolphin research: educating the public. PMID- 21700854 TI - Dolphin research: continue captivity. PMID- 21700856 TI - Science festivals open doors. PMID- 21700857 TI - Education. Mathematics teachers' subtle, complex disciplinary knowledge. PMID- 21700858 TI - Physiology. Synthetic physiology. PMID- 21700859 TI - Planetary Science. The Earth and the Sun. PMID- 21700860 TI - Molecular biology. A new twist for topoisomerase. PMID- 21700861 TI - Neuroscience. Attention--voluntary control of brain cells. PMID- 21700862 TI - Physics. The limits of ordinary matter. PMID- 21700863 TI - Ecology. Why did you Levy? PMID- 21700864 TI - SPORE series winner. Computational experiments for science education. PMID- 21700865 TI - Human fatty liver disease: old questions and new insights. AB - Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects one-third of adults and an increasing number of children in developed countries. The disease begins with the aberrant accumulation of triglyceride in the liver, which in some individuals elicits an inflammatory response that can progress to cirrhosis and liver cancer. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood, and therapeutic options are limited. Here, we discuss recent mechanistic insights into NAFLD, focusing primarily on those that have emerged from human genetic and metabolic studies. PMID- 21700866 TI - 16-month-olds rationally infer causes of failed actions. AB - Sixteen-month-old infants (N = 83) rationally used sparse data about the distribution of outcomes among agents and objects to solve a fundamental inference problem: deciding whether event outcomes are due to themselves or the world. When infants experienced failed outcomes, their causal attributions affected whether they sought help or explored. PMID- 21700867 TI - Scale for the phase diagram of quantum chromodynamics. AB - Matter described by quantum chromodynamics (QCD), the theory of strong interactions, may undergo phase transitions when its temperature and the chemical potentials are varied. QCD at finite temperature is studied in the laboratory by colliding heavy ions at varying beam energies. We present a test of QCD in the nonperturbative domain through a comparison of thermodynamic fluctuations predicted in lattice computations with the experimental data of baryon number distributions in high-energy heavy ion collisions. This study provides evidence for thermalization in these collisions and allows us to find the crossover temperature between normal nuclear matter and a deconfined phase called the quark gluon plasma. This value allows us to set a scale for the phase diagram of QCD. PMID- 21700868 TI - The oxygen isotopic composition of the Sun inferred from captured solar wind. AB - All planetary materials sampled thus far vary in their relative abundance of the major isotope of oxygen, (16)O, such that it has not been possible to define a primordial solar system composition. We measured the oxygen isotopic composition of solar wind captured and returned to Earth by NASA's Genesis mission. Our results demonstrate that the Sun is highly enriched in (16)O relative to the Earth, Moon, Mars, and bulk meteorites. Because the solar photosphere preserves the average isotopic composition of the solar system for elements heavier than lithium, we conclude that essentially all rocky materials in the inner solar system were enriched in (17)O and (18)O, relative to (16)O, by ~7%, probably via non-mass-dependent chemistry before accretion of the first planetesimals. PMID- 21700869 TI - A 15N-poor isotopic composition for the solar system as shown by Genesis solar wind samples. AB - The Genesis mission sampled solar wind ions to document the elemental and isotopic compositions of the Sun and, by inference, of the protosolar nebula. Nitrogen was a key target element because the extent and origin of its isotopic variations in solar system materials remain unknown. Isotopic analysis of a Genesis Solar Wind Concentrator target material shows that implanted solar wind nitrogen has a (15)N/(14)N ratio of 2.18 +/- 0.02 * 10(-3) (that is, ~40% poorer in (15)N relative to terrestrial atmosphere). The (15)N/(14)N ratio of the protosolar nebula was 2.27 +/- 0.03 * 10(-3), which is the lowest (15)N/(14)N ratio known for solar system objects. This result demonstrates the extreme nitrogen isotopic heterogeneity of the nascent solar system and accounts for the (15)N-depleted components observed in solar system reservoirs. PMID- 21700870 TI - Net oxidative addition of C(sp3)-F bonds to iridium via initial C-H bond activation. AB - Carbon-fluorine bonds are the strongest known single bonds to carbon and as a consequence can prove very hard to cleave. Alhough vinyl and aryl C-F bonds can undergo oxidative addition to transition metal complexes, this reaction has appeared inoperable with aliphatic substrates. We report the addition of C(sp(3)) F bonds (including alkyl-F) to an iridium center via the initial, reversible cleavage of a C-H bond. These results suggest a distinct strategy for the development of catalysts and promoters to make and break C-F bonds, which are of strong interest in the context of both pharmaceutical and environmental chemistry. PMID- 21700871 TI - Abiotic pyrite formation produces a large Fe isotope fractionation. AB - The iron isotope composition of sedimentary pyrite has been proposed as a potential proxy to trace microbial metabolism and the redox evolution of the oceans. We demonstrate that Fe isotope fractionation accompanies abiotic pyrite formation in the absence of Fe(II) redox change. Combined fractionation factors between Fe(II)(aq), mackinawite, and pyrite permit the generation of pyrite with Fe isotope signatures that nearly encapsulate the full range of sedimentary delta(56)Fe(pyrite) recorded in Archean to modern sediments. We propose that Archean negative Fe isotope excursions reflect partial Fe(II)(aq) utilization during abiotic pyrite formation rather than microbial dissimilatory Fe(III) reduction. Late Proterozoic to modern sediments may reflect greater Fe(II)(aq) utilization and variations in source composition. PMID- 21700872 TI - Levy walks evolve through interaction between movement and environmental complexity. AB - Ecological theory predicts that animal movement is shaped by its efficiency of resource acquisition. Focusing solely on efficiency, however, ignores the fact that animal activity can affect resource availability and distribution. Here, we show that feedback between individual behavior and environmental complexity can explain movement strategies in mussels. Specifically, experiments show that mussels use a Levy walk during the formation of spatially patterned beds, and models reveal that this Levy movement accelerates pattern formation. The emergent patterning in mussel beds, in turn, improves individual fitness. These results suggest that Levy walks evolved as a result of the selective advantage conferred by autonomously generated, emergent spatial patterns in mussel beds. Our results emphasize that an interaction between individual selection and habitat complexity shapes animal movement in natural systems. PMID- 21700873 TI - Gametogenesis eliminates age-induced cellular damage and resets life span in yeast. AB - Eukaryotic organisms age, yet detrimental age-associated traits are not passed on to progeny. How life span is reset from one generation to the next is not known. We show that in budding yeast resetting of life span occurs during gametogenesis. Gametes (spores) generated by aged cells show the same replicative potential as gametes generated by young cells. Age-associated damage is no longer detectable in mature gametes. Furthermore, transient induction of a transcription factor essential for later stages of gametogenesis extends the replicative life span of aged cells. Our results indicate that gamete formation brings about rejuvenation by eliminating age-induced cellular damage. PMID- 21700874 TI - A cell cycle phosphoproteome of the yeast centrosome. AB - Centrosomes organize the bipolar mitotic spindle, and centrosomal defects cause chromosome instability. Protein phosphorylation modulates centrosome function, and we provide a comprehensive map of phosphorylation on intact yeast centrosomes (18 proteins). Mass spectrometry was used to identify 297 phosphorylation sites on centrosomes from different cell cycle stages. We observed different modes of phosphoregulation via specific protein kinases, phosphorylation site clustering, and conserved phosphorylated residues. Mutating all eight cyclin-dependent kinase (Cdk)-directed sites within the core component, Spc42, resulted in lethality and reduced centrosomal assembly. Alternatively, mutation of one conserved Cdk site within gamma-tubulin (Tub4-S360D) caused mitotic delay and aberrant anaphase spindle elongation. Our work establishes the extent and complexity of this prominent posttranslational modification in centrosome biology and provides specific examples of phosphorylation control in centrosome function. PMID- 21700875 TI - Mutagenic processing of ribonucleotides in DNA by yeast topoisomerase I. AB - The ribonuclease (RNase) H class of enzymes degrades the RNA component of RNA:DNA hybrids and is important in nucleic acid metabolism. RNase H2 is specialized to remove single ribonucleotides [ribonucleoside monophosphates (rNMPs)] from duplex DNA, and its absence in budding yeast has been associated with the accumulation of deletions within short tandem repeats. Here, we demonstrate that rNMP associated deletion formation requires the activity of Top1, a topoisomerase that relaxes supercoils by reversibly nicking duplex DNA. The reported studies extend the role of Top1 to include the processing of rNMPs in genomic DNA into irreversible single-strand breaks, an activity that can have distinct mutagenic consequences and may be relevant to human disease. PMID- 21700876 TI - A synthetic optogenetic transcription device enhances blood-glucose homeostasis in mice. AB - Synthetic biology has advanced the design of genetic devices that can be used to reprogram metabolic activities in mammalian cells. By functionally linking the signal transduction of melanopsin to the control circuit of the nuclear factor of activated T cells, we have designed a synthetic signaling cascade enabling light inducible transgene expression in different cell lines grown in culture or bioreactors or implanted into mice. In animals harboring intraperitoneal hollow fiber or subcutaneous implants containing light-inducible transgenic cells, the serum levels of the human glycoprotein secreted alkaline phosphatase could be remote-controlled with fiber optics or transdermally regulated through direct illumination. Light-controlled expression of the glucagon-like peptide 1 was able to attenuate glycemic excursions in type II diabetic mice. Synthetic light-pulse transcription converters may have applications in therapeutics and protein expression technology. PMID- 21700877 TI - Inducing sleep by remote control facilitates memory consolidation in Drosophila. AB - Sleep is believed to play an important role in memory consolidation. We induced sleep on demand by expressing the temperature-gated nonspecific cation channel Transient receptor potential cation channel (UAS-TrpA1) in neurons, including those with projections to the dorsal fan-shaped body (FB). When the temperature was raised to 31 degrees C, flies entered a quiescent state that meets the criteria for identifying sleep. When sleep was induced for 4 hours after a massed training protocol for courtship conditioning that is not capable of inducing long term memory (LTM) by itself, flies develop an LTM. Activating the dorsal FB in the absence of sleep did not result in the formation of LTM after massed training. PMID- 21700878 TI - Sleep and synaptic homeostasis: structural evidence in Drosophila. AB - The functions of sleep remain elusive, but a strong link exists between sleep need and neuronal plasticity. We tested the hypothesis that plastic processes during wake lead to a net increase in synaptic strength and sleep is necessary for synaptic renormalization. We found that, in three Drosophila neuronal circuits, synapse size or number increases after a few hours of wake and decreases only if flies are allowed to sleep. A richer wake experience resulted in both larger synaptic growth and greater sleep need. Finally, we demonstrate that the gene Fmr1 (fragile X mental retardation 1) plays an important role in sleep-dependent synaptic renormalization. PMID- 21700879 TI - Novel locus FER is associated with serum HMW adiponectin levels. AB - OBJECTIVE: High molecular weight (HMW) adiponectin is a predominant isoform of circulating adiponectin and has been related to type 2 diabetes. Previous linkage studies suggest that different genetic components might be involved in determining HMW and total adiponectin levels. RESEARCH DESIGN AND METHODS: We performed a genome-wide association study (GWAS) of serum HMW adiponectin levels in individuals of European ancestry drawn from the Nurses' Health Study (NHS) (N = 1,591). The single nucleotide polymorphisms (SNPs) identified in the GWAS analysis were replicated in an independent cohort of Europeans (N = 626). We examined the associations of the identified variations with diabetes risk and metabolic syndrome. RESULTS: We identified a novel locus near the FER gene (5q21) at a genome-wide significance level, best represented by SNP rs10447248 (P = 4.69 * 10(-8)). We also confirmed that variations near the adiponectin-encoding ADIPOQ locus (3q27) were related to serum HMW adiponectin levels. In addition, we found that FER SNP rs10447248 was related to HDL cholesterol levels (P = 0.009); ADIPOQ variation was associated with fasting glucose (P = 0.04), HDL cholesterol (P = 0.04), and a metabolic syndrome score (P = 0.002). CONCLUSIONS: Our results suggest that different loci may be involved in regulation of circulating HMW adiponectin levels and provide novel insight into the mechanisms that affect HMW adiponectin homeostasis. PMID- 21700880 TI - Higher cord C-peptide concentrations are associated with slower growth rate in the 1st year of life in girls but not in boys. AB - OBJECTIVE: To understand the relationships between maternal glycemia during pregnancy and prenatal and early postnatal growth by evaluating cord C-peptide and IGF-I as mediating biomarkers in boys and girls separately. RESEARCH DESIGN AND METHODS: We evaluated 342 neonates within the EDEN mother-child cohort study born to mothers without diabetes diagnosis before pregnancy. We measured maternal glycemia at 24-28 weeks of gestation and neonates' cord blood C-peptide (used as a proxy for fetal insulin) and IGF-I at birth. Reported maternal prepregnancy BMI and all measured infant weights and lengths in the 1st year were recorded. Growth modeling was used to obtain an individual growth curve for each infant in the 1st year. Path models, a type of structural equation modeling, were used for statistical analysis. Path analysis is a multivariate method associated with a graphical display that allows evaluation of mediating factors and distinguishes direct, indirect, and total effects. RESULTS: Cord C-peptide at birth was positively correlated with maternal prepregnancy BMI and maternal glycemia and was higher in girls. In a path model that represented prenatal growth, there was no significant direct effect of maternal glycemia on birth weight, but the effect of maternal glycemia on birth weight was mediated by fetal insulin and IGF-I in both girls and boys. However, in girls only, higher concentrations of cord C peptide (but not cord IGF-I or maternal glucose) were associated with slower weight growth in the first 3 months of life. CONCLUSIONS: Our study underlines the role of the fetal insulin-IGF-I axis in the relationship between maternal glycemia during pregnancy and birth weight. We also show for the first time that high insulin concentration in female fetuses is associated with slower early postnatal growth. This slow, early growth pattern may be programmed by fetal hyperinsulinemia, and girls may be more susceptible than boys to its consequences. PMID- 21700881 TI - CD14 modulates inflammation-driven insulin resistance. AB - OBJECTIVE: The study objective was to evaluate the possible role of the macrophage molecule CD14 in insulin resistance. RESEARCH DESIGN AND METHODS: The effects of recombinant human soluble CD14 (rh-sCD14) on insulin sensitivity (clamp procedure) and adipose tissue gene expression were evaluated in wild-type (WT) mice, high fat-fed mice, ob/ob mice, and CD14 knockout (KO) mice. We also studied WT mice grafted with bone marrow stem cells from WT donor mice and CD14 KO mice. Finally, CD14 was evaluated in human adipose tissue and during differentiation of human preadipocytes. RESULTS: rh-sCD14 led to increased insulin action in WT mice, high-fat-fed mice, and ob/ob mice, but not in CD14 KO mice, in parallel to a marked change in the expression of 3,479 genes in adipose tissue. The changes in gene families related to lipid metabolism were most remarkable. WT mice grafted with bone marrow stem cells from WT donor mice became insulin resistant after a high-fat diet. Conversely, WT mice grafted with cells from CD14 KO mice resisted the occurrence of insulin resistance in parallel to decreased mesenteric adipose tissue inflammatory gene expression. Glucose intolerance did not worsen in CD14 KO mice grafted with bone marrow stem cells from high fat-fed WT mice when compared with recipient KO mice grafted with cells from CD14 KO donor mice. CD14 gene expression was increased in whole adipose tissue and adipocytes from obese humans and further increased after tumor necrosis factor-alpha. CONCLUSIONS: CD14 modulates adipose tissue inflammatory activity and insulin resistance. PMID- 21700882 TI - Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. AB - Neuronal development is the result of a multitude of neural migrations, which require extensive cell-cell communication. These processes are modulated by extracellular matrix components, such as heparan sulfate (HS) polysaccharides. HS is molecularly complex as a result of nonrandom modifications of the sugar moieties, including sulfations in specific positions. We report here mutations in HS 6-O-sulfotransferase 1 (HS6ST1) in families with idiopathic hypogonadotropic hypogonadism (IHH). IHH manifests as incomplete or absent puberty and infertility as a result of defects in gonadotropin-releasing hormone neuron development or function. IHH-associated HS6ST1 mutations display reduced activity in vitro and in vivo, suggesting that HS6ST1 and the complex modifications of extracellular sugars are critical for normal development in humans. Genetic experiments in Caenorhabditis elegans reveal that HS cell-specifically regulates neural branching in vivo in concert with other IHH-associated genes, including kal-1, the FGF receptor, and FGF. These findings are consistent with a model in which KAL1 can act as a modulatory coligand with FGF to activate the FGF receptor in an HS-dependent manner. PMID- 21700883 TI - Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans. AB - Impaired immune functions leading to primary immunodeficiencies often correlate with paradoxical autoimmune complications; patients with hyper-IgM syndromes who are deficient in activation-induced cytidine deaminase (AID), which is required for class-switch recombination and somatic hypermutation, are prone to develop autoimmune diseases. To investigate the impact of AID-deficiency on early B-cell tolerance checkpoints in humans, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from AID-deficient patients. New emigrant/transitional and mature naive B cells from AID-deficient patients express an abnormal Ig repertoire and high frequencies of autoreactive antibodies, demonstrating that AID is required for the establishment of both central and peripheral B-cell tolerance. In addition, B-cell tolerance was further breached in AID-deficient patients as illustrated by the detection of anti-nuclear IgM antibodies in the serum of all patients. Thus, we identified a major and previously unsuspected role for AID in the removal of developing autoreactive B cells in humans. PMID- 21700884 TI - RNA structure probing dash seq. PMID- 21700886 TI - Natural time analysis of critical phenomena. AB - A quantity exists by which one can identify the approach of a dynamical system to the state of criticality, which is hard to identify otherwise. This quantity is the variance kappa(1)(= - (2)) of natural time chi, where = Sigmap(k)f(chi(k)) and p(k) is the normalized energy released during the kth event of which the natural time is defined as chi(k) = k/N and N stands for the total number of events. Then we show that kappa(1) becomes equal to 0.070 at the critical state for a variety of dynamical systems. This holds for criticality models such as 2D Ising and the Bak-Tang-Wiesenfeld sandpile, which is the standard example of self-organized criticality. This condition of kappa(1) = 0.070 holds for experimental results of critical phenomena such as growth of rice piles, seismic electric signals, and the subsequent seismicity before the associated main shock. PMID- 21700885 TI - Activation-induced cytidine deaminase mediates central tolerance in B cells. AB - The Aicda gene product, activation-induced cytidine deaminase (AID), initiates somatic hypermutation, class-switch recombination, and gene conversion of Ig genes by the deamination of deoxycytidine, followed by error-prone mismatch- or base-excision DNA repair. These processes are crucial for the generation of genetically diverse, high affinity antibody and robust humoral immunity, but exact significant genetic damage and promote cell death. In mice, physiologically significant AID expression was thought to be restricted to antigen-activated, mature B cells in germinal centers. We now demonstrate that low levels of AID in bone marrow immature and transitional B cells suppress the development of autoreactivity. Aicda(-/-) mice exhibit significantly increased serum autoantibody and reduced capacity to purge autoreactive immature and transitional B cells. In vitro, AID deficient immature/transitional B cells are significantly more resistant to anti-IgM-induced apoptosis than their normal counterparts. Thus, early AID expression plays a fundamental and unanticipated role in purging self-reactive immature and transitional B cells during their maturation in the bone marrow. PMID- 21700887 TI - Stomatal numbers, leaf and canopy conductance, and the control of transpiration. PMID- 21700888 TI - Impaired response to deep inspiration in obesity. AB - Deep inspirations modulate airway caliber and airway closure and their effects are impaired in asthma. The association between asthma and obesity raises the question whether the deep inspiration (DI) effect is also impaired in the latter condition. We assessed the DI effects in obese and nonobese nonasthmatics. Thirty six subjects (17 obese, 19 nonobese) underwent routine methacholine (Mch) challenge and 30 of them also had a modified bronchoprovocation in the absence of DIs. Lung function was monitored with spirometry and forced oscillation (FO) [resistance (R) at 5 Hz (R5), at 20 Hz (R20), R5-R20 and the integrated area of low-frequency reactance (AX)]. The response to Mch, assessed with area under the dose-response curves (AUC), was consistently greater in the routine challenge in the obese (mean +/- SE, obese vs. nonobese AUC: R5: 15.7 +/- 2.3 vs. 2.4 +/- 2.0, P < 0.0005; R20: 5.6 +/- 1.4 vs. 1.4 +/- 1.2, P = 0.027; R5-R20: 10.2 +/- 1.6 vs. 0.9 +/- 0.1.4, P < 0.0005; AX: 115.6 +/- 22.0 vs. 1.5 +/- 18.9, P < 0.0005), but differences between groups in the modified challenge were smaller, indicating reduced DI effects in obesity. Given that DI has bronchodilatory and bronchoprotective effects, we further assessed these components separately. In the obese subjects, DI prior to Mch enhanced Mch-induced bronchoconstriction, but DI after Mch resulted in bronchodilation that was of similar magnitude as in the nonobese. We conclude that obesity is characterized by increased Mch responsiveness, predominantly of the small airways, due to a DI effect that renders the airways more sensitive to the stimulus. PMID- 21700889 TI - Bronchoconstriction in nonhuman primates: a species comparison. AB - Bronchoconstriction is a characteristic symptom of various chronic obstructive respiratory diseases such as chronic obstructive pulmonary disease and asthma. Precision-cut lung slices (PCLS) are a suitable ex vivo model to study physiological mechanisms of bronchoconstriction in different species. In the present study, we established an ex vivo model of bronchoconstriction in nonhuman primates (NHPs). PCLS prepared from common marmosets, cynomolgus macaques, rhesus macaques, and anubis baboons were stimulated with increasing concentrations of representative bronchoconstrictors: methacholine, histamine, serotonin, leukotriene D4 (LTD4), U46619, and endothelin-1. Alterations in the airway caliber were measured and compared with previously published data from rodents, guinea pigs, and humans. Methacholine induced maximal airway constriction, varying between 74 and 88% in all NHP species, whereas serotonin was ineffective. Histamine induced maximal bronchoconstriction of 77 to 90% in rhesus macaques, cynomolgus macaques, and baboons and a lesser constriction of 53% in marmosets. LTD4 was ineffective in marmosets and rhesus macaques but induced a maximum constriction of 44 to 49% in cynomolgus macaques and baboons. U46619 and endothelin-1 caused airway constriction in all NHP species, with maximum constrictions of 65 to 91% and 70 to 81%, respectively. In conclusion, PCLS from NHPs represent a valuable ex vivo model for studying bronchoconstriction. All NHPs respond to mediators relevant to human airway disorders such as methacholine, histamine, U46619, and endothelin-1 and are insensitive to the rodent mast cell product serotonin. Only PCLS from cynomolgus macaques and baboons, however, responded also to leukotrienes, suggesting that among all compared species, these two NHPs resemble the human airway mechanisms best. PMID- 21700890 TI - Peripheral vascular decoupling in porcine endotoxic shock. AB - Cardiac output measurement from arterial pressure waveforms presumes a defined relationship between the arterial pulse pressure (PP), vascular compliance (C), and resistance (R). Cardiac output estimates degrade if these assumptions are incorrect. We hypothesized that sepsis would differentially alter central and peripheral vasomotor tone, decoupling the usual pressure wave propagation from central to peripheral sites. We assessed arterial input impedance (Z), C, and R from central and peripheral arterial pressures, and aortic blood flow in an anesthetized porcine model (n = 19) of fluid resuscitated endotoxic shock induced by endotoxin infusion (7 MUg.kg-1.h-1 increased to 14 and 20 MUg.kg-1.h-1 every 10 min and stopped when mean arterial pressure <40 mmHg or Sv(O2) < 45%). Aortic, femoral, and radial artery pressures and aortic and radial artery flows were measured. Z was calculated by FFT of flow and pressure data. R and C were derived using a two-element Windkessel model. Arterial PP increased from aortic to femoral and radial sites. During stable endotoxemia with fluid resuscitation, aortic and radial blood flows returned to or exceeded baseline while mean arterial pressure remained similarly decreased at all three sites. However, aortic PP exceeded both femoral and radial arterial PP. Although Z, R, and C derived from aortic and radial pressure and aortic flow were similar during baseline, Z increases and C decreases when derived from aortic pressure whereas Z decreases and C increases when derived from radial pressure, while R decreased similarly with both pressure signals. This central-to-peripheral vascular tone decoupling, as quantified by the difference in calculated Z and C from aortic and radial artery pressure, may explain the decreasing precision of peripheral arterial pressure profile algorithms in assessing cardiac output in septic shock patients and suggests that different algorithms taking this vascular decoupling into account may be necessary to improve their precision in this patient population. PMID- 21700891 TI - Mesenteric lymph from rats with trauma-hemorrhagic shock causes abnormal cardiac myocyte function and induces myocardial contractile dysfunction. AB - Myocardial contractile dysfunction develops following trauma-hemorrhagic shock (T/HS). We have previously shown that, in a rat fixed pressure model of T/HS (mean arterial pressure of 30-35 mmHg for 90 min), mesenteric lymph duct ligation before T/HS prevented T/HS-induced myocardial contractile depression. To determine whether T/HS lymph directly alters myocardial contractility, we examined the functional effects of physiologically relevant concentrations of mesenteric lymph collected from rats undergoing trauma-sham shock (T/SS) or T/HS on both isolated cardiac myocytes and Langendorff-perfused whole hearts. Acute application of T/HS lymph (0.1-2%), but not T/SS lymph, induced dual inotropic effects on myocytes with an immediate increase in the amplitude of cell shortening (1.4 +/- 0.1-fold) followed by a complete block of contraction. Similarly, T/HS lymph caused dual, positive and negative effects on cellular Ca2+ transients. These effects were associated with changes in the electrophysiological properties of cardiac myocytes; T/HS lymph initially prolonged the action potential duration (action potential duration at 90% repolarization, 3.3 +/- 0.4-fold), and this was followed by a decrease in the plateau potential and membrane depolarization. Furthermore, intravenous infusion of T/HS lymph, but not T/SS lymph, caused myocardial contractile dysfunction at 24 h after injection, which mimicked actual T/HS-induced changes; left ventricular developed pressure (LVDP) and the maximal rate of LVDP rise and fall (+/-dP/dt(max)) were decreased and inotropic response to Ca2+ was blunted. However, the contractile responsiveness to beta-adrenergic receptor stimulation in the T/HS lymph-infused hearts remained unchanged. These results suggest that T/HS lymph directly causes negative inotropic effects on the myocardium and that T/HS lymph-induced changes in myocyte function are likely to contribute to the development of T/HS-induced myocardial dysfunction. PMID- 21700893 TI - Dehydration reduces left ventricular filling at rest and during exercise independent of twist mechanics. AB - The purpose of this study was to determine whether the reduction in stroke volume (SV), previously shown to occur with dehydration and increases in internal body temperatures during prolonged exercise, is caused by a reduction in left ventricular (LV) function, as indicated by LV volumes, strain, and twist ("LV mechanics"). Eight healthy men [age: 20 +/- 2, maximal oxygen uptake (VO2max): 58 +/- 7 ml.kg-1.min-1] completed two, 1-h bouts of cycling in the heat (35 degrees C, 50% peak power) without fluid replacement, resulting in 2% and 3.5% dehydration, respectively. Conventional and two-dimensional speckle-tracking echocardiography was used to determine LV volumes, strain, and twist at rest and during one-legged knee-extensor exercise at baseline, both levels of dehydration, and following rehydration. Progressive dehydration caused a significant reduction in end-diastolic volume (EDV) and SV at rest and during one-legged knee-extensor exercise (rest: Delta-33 +/- 14 and Delta-21 +/- 14 ml, respectively; exercise: Delta-30 +/- 10 and Delta-22 +/- 9 ml, respectively, during 3.5% dehydration). In contrast to the marked decline in EDV and SV, systolic and diastolic LV mechanics were either maintained or even enhanced with dehydration at rest and during knee extensor exercise. We conclude that dehydration-induced reductions in SV at rest and during exercise are the result of reduced LV filling, as reflected by the decline in EDV. The concomitant maintenance of LV mechanics suggests that the decrease in LV filling, and consequently ejection, is likely caused by the reduction in blood volume and/or diminished filling time rather than impaired LV function. PMID- 21700892 TI - Pulmonary function, bronchial reactivity, and epithelial permeability are response phenotypes to ozone and develop differentially in healthy humans. AB - Effect of laboratory exposure to O3 (220 ppb) and filtered air (FA) on respiratory physiology were evaluated at two time points (acute and 1 day postexposure) in healthy cohort (n = 138, 18-35 yr, 40% women) comprised mainly of Caucasian (60%) and African American (33.3%) subjects. Randomized exposures had a crossover design and durations of 2.25 h that included rest and treadmill walking. Airway responsiveness (AHR) to methacholine (Mch) and permeability of respiratory epithelium (EI) to hydrophilic radiomarker ((99m)Tc-DTPA, MW = 492), were measured at 1-day postexposure. O3 significantly affected FEV1 and FVC indices acutely with mean decrements from pre-exposure values on the order of 7.7 to 8.8% and 1.8 to 2.3% at 1-day post. Acute FEV1 and FVC decreases were most robust in African American male subjects. At 1-day post, O3 induced significant changes in AHR (slope of Mch dose response curve) and EI (Tc(99m)-DTPA clearance half-time). Based on conventional thresholds of response and dichotomous classification of subjects as responders and nonresponders, sensitivity to O3 was shown to be nonuniform. Acute decrements >= 15% in FEV1, a doubling of Mch slope, or >= 15% increase in EI developed in 20.3%, 23.1%, and 25.9%, respectively, of subjects evaluated. Results demonstrate a diffuse sensitivity to O3 and physiological responses, either acutely (decreases in FEV1) or 1 day post (development of AHR or change in EI) occur differentially in healthy young adults. Random overlap among subjects classified as responsive for respective FEV1, AHR, and EI endpoints suggests these are separate and independent phenotypes of O3 exposure. PMID- 21700894 TI - A physiological systems approach to modeling and resetting of mouse thermoregulation under heat stress. AB - Heat stroke (HS) is a serious civilian and military health issue. Due to the limited amount of experimental data available in humans, this study was conducted on a mouse mathematical model fitted on experimental data collected from mice under HS conditions, with the assumption there is good agreement among mammals. Core temperature (T(c)) recovery responses in a mouse model consist of hypothermia and delayed fever during 24 h of recovery that represent potential biomarkers of HS severity. The objective of this study was to develop a simulation model of mouse T(c) responses and identify optimal treatment windows for HS recovery using a three-dimensional predictive heat transfer simulation model. Several bioenergetic simulation variables, including nonlinear metabolic heat production (W/m3), temperature-dependent convective heat transfer through blood mass perfusion (W/m3), and activity-related changes in circadian T(c) were used for model simulation. The simulation results predicted the experimental data with few disparities. Using this simulation model, we tested a series of ambient temperature treatment strategies to minimize hypothermia and delayed fever to accelerate HS recovery. Using a genetic algorithm, we identified eight time segments (ambient temperature = 27, 30, 31, 29, 28, 28, 27, 26 degrees C) of 110 min total duration that optimized HS recovery in our model simulation. PMID- 21700895 TI - Effects of acute and chronic endurance exercise on intracellular nitric oxide and superoxide in circulating CD34+ and CD34- cells. AB - We investigated the influence of acute and chronic endurance exercise on levels of intracellular nitric oxide (NO), superoxide (O2.-), and expression of genes regulating the balance between these free radicals in CD34+ and CD34- peripheral blood mononuclear cells (PBMCs; isolated by immunomagnetic cell separation). Blood samples were obtained from age- and body mass index (BMI)-matched endurance trained (n = 10) and sedentary (n = 10) men before and after 30 min of exercise at 75% maximal oxygen uptake (.VO(2max)). Baseline levels of intracellular NO (measured by DAF-FM diacetate) and O2.- (measured by dihydroethidium) were 26% (P < 0.05) and 10% (P < 0.05) higher, respectively, in CD34+ PBMCs from the sedentary group compared with the endurance-trained group. CD34+ PBMCs from the sedentary group at baseline had twofold greater inducible nitric oxide synthase (iNOS) mRNA and 50% lower endothelial NOS (eNOS) mRNA levels compared with the trained group (P < 0.05). The baseline group difference in O2.- was eliminated by acute exercise. Experiments with apocynin indicated that the training-related difference in O2.- levels was explained by increased NADPH oxidase activity in the sedentary state. mRNA levels of additional angiogenic and antioxidant genes were consistent with a more angiogenic profile in CD34+ cells of trained subjects. CD34- PBMCs, examined for exploratory purposes, also displayed a more angiogenic mRNA profile in trained subjects, with vascular endothelial growth factor (VEGF) and eNOS being more highly expressed in trained subjects. Overall, our data suggest an association between the sedentary state and increased nitro oxidative stress in CD34+ cells. PMID- 21700896 TI - Reductions in RIP140 are not required for exercise- and AICAR-mediated increases in skeletal muscle mitochondrial content. AB - Receptor interacting protein 1 (RIP140) has recently been demonstrated to be a key player in the regulation of skeletal muscle mitochondrial content. We have shown that beta-guanadinopropionic acid (beta-GPA) feeding reduces RIP140 protein content and mRNA levels concomitant with increases in mitochondrial content (Williams DB, Sutherland LN, Bomhof MR, Basaraba SA, Thrush AB, Dyck DJ, Field CJ, Wright DC. Am J Physiol Endocrinol Metab 296: E1400-E1408, 2009). Since beta GPA feeding reduces high-energy phosphate levels and activates AMPK, alterations reminiscent of exercise, we hypothesized that exercise training would reduce RIP140 protein content. We further postulated that an acute bout of exercise, or interventions known to induce the expression of mitochondrial enzymes or genes involved in mitochondrial biogenesis, would result in decreases in nuclear RIP140 content. Two weeks of daily swim training increased markers of mitochondrial content in rat skeletal muscle independent of reductions in RIP140 protein. Similarly, high-intensity exercise training in humans failed to reduce RIP140 content despite increasing skeletal muscle mitochondrial enzymes. We found that 6 wk of daily 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) injections had no effect on RIP140 protein content in rat skeletal muscle while RIP140 content from LKB1 knockout mice was unaltered despite reductions in mitochondria. An acute bout of exercise, AICAR treatment, and epinephrine injections increased the mRNA levels of PGC-1alpha, COXIV, and lipin1 independent of decreases in nuclear RIP140 protein. Surprisingly these interventions increased RIP140 mRNA expression. In conclusion our results demonstrate that decreases in RIP140 protein content are not required for exercise and AMPK dependent increases in skeletal muscle mitochondrial content, nor do acute perturbations alter the cellular localization of RIP140 in parallel with the induction of genes involved in mitochondrial biogenesis. PMID- 21700897 TI - Reactive oxygen species formation during tetanic contractions in single isolated Xenopus myofibers. AB - Contracting skeletal muscle produces reactive oxygen species (ROS) that have been shown to affect muscle function and adaptation. However, real-time measurement of ROS in contracting myofibers has proven to be difficult. We used amphibian (Xenopus laevis) muscle to test the hypothesis that ROS are formed during contractile activity in isolated single skeletal muscle fibers and that this contraction-induced ROS formation affects fatigue development. Single myofibers were loaded with 5 MUM dihydrofluorescein-DA (Hfluor-DA), a fluorescent probe that reacts with ROS and results in the formation of fluorescein (Fluor) to precisely monitor ROS generation within single myofibers in real time using confocal miscroscopy. Three identical periods of maximal tetanic contractions (1 contraction/3 s for 2 min, separated by 60 min of rest) were conducted by each myofiber (n = 6) at 20 degrees C. Ebselen (an antioxidant) was present in the perfusate (10 MUM) during the second contractile period. Force was reduced by ~30% during each of the three contraction periods, with no significant difference in fatigue development among the three periods. The Fluor signal, indicative of ROS generation, increased significantly above baseline in both the first (42 +/- 14%) and third periods (39 +/- 10%), with no significant difference in the increase in fluorescence between the first and third periods. There was no increase of Fluor in the presence of ebselen during the second contractile period. These results demonstrated that, in isolated intact Xenopus myofibers, 1) ROS can be measured in real time during tetanic contractions, 2) contractile activity induced a significant increase above resting levels of ROS production, and 3) ebselen treatment reduced ROS generation to baseline levels but had no effect on myofiber contractility and fatigue development. PMID- 21700898 TI - Vitamin D-dependent rickets type 1: a rare, but treatable, cause of severe hypotonia in infancy. AB - Vitamin D-dependent rickets type 1 is an autosomal recessive disorder caused by an inactivating mutation of the 25-hydroxyvitamin-D-1alpha-hydroxylase (CYP27B1) gene. Clinical presentation is characterized by early onset of severe rickets and can include severe hypotonia. Here, we report a 16-month-old white male who presented with severe muscle weakness, failure to thrive, renal tubular dysfunction, and skeletal deformities, including osteopenia and multiple fractures. At presentation, he had severe hypocalcemia, hypophosphatemia, hypomagnesemia, and elevated alkaline phosphatase and parathyroid hormone levels, although normal 25-hydroxyvitamin D levels. DNA sequencing of the CYP27B1 gene revealed a novel mutation in exon 2 (c286_300de115) and a previously reported mutation in exon 7 (c.1166G>A). Once calcitriol therapy was initiated, the patient showed significant improvement in muscle strength and linear growth. Serum calcium, phosphorous, and alkaline phosphatase returned to normal range. Organic aciduria resolved and aminoaciduria significantly improved 2 months after parathyroid hormone levels normalized. PMID- 21700899 TI - Hypothermia is correlated with seizure absence in perinatal stroke. AB - Within a single-center prospective cohort study of neonatal encephalopathy involving 315 subjects, 15 neonates were found to have a focal stroke on magnetic resonance imaging. These 15 patients were matched on the basis of gender and degree of encephalopathy to 30 neonates without stroke from the same cohort. On Bayley Scales of Infant Development, the stroke group had Mental Development Index scores that were 1.7 standard deviations lower compared with controls (P = .007). This association was no longer seen after adjustment for the presence of neonatal seizures (P = .11). Of the 15 patients with stroke, 5 had been treated with hypothermia. None of these 5 had seizures in the neonatal period, compared with 7 of the untreated 10. This is the first human study to demonstrate a potential treatment effect of therapeutic hypothermia on perinatal stroke. It was also shown that seizures are associated with worse cognitive outcomes for stroke that presents with encephalopathy. PMID- 21700900 TI - Specific effects of BCL10 Serine mutations on phosphorylations in canonical and noncanonical pathways of NF-kappaB activation following carrageenan. AB - To determine the impact of B cell leukemia/lymphoma (BCL) 10 on the phosphorylation of crucial mediators in NF-kappaB-mediated inflammatory pathways, human colonic epithelial cells were exposed to carrageenan (CGN), a sulfated polysaccharide commonly used as a food additive and known to induce NF-kappaB nuclear translocation by both canonical and noncanonical pathways. Phosphorylations of intermediates in inflammatory cascades, including NF-kappaB inducing kinase (NIK) at Thr(559), transforming growth factor-beta-activating kinase (TAK) 1 at Thr(184), Thr(187), and Ser(192), and inhibitory factor kappaBalpha (IkappaBalpha) at Ser(32), were examined following mutation of BCL10 at Ser(138) and at Ser(218). Specific phosphoantibodies were used for detection by enzyme-linked immunosorbent assay, immunoblot, and confocal microscopy of differences in phosphorylation following transfection by mutated BCL10. Both mutations demonstrated dominant-negative effects, with inhibition of phospho(Ser(32))-IkappaBalpha to less than control levels. Both of the BCL10 mutations reduced the CGN-induced increases in nuclear RelA and p50, but only the Ser(138) mutation inhibited the CGN-induced increases in nuclear RelB and p52 and in NIK Thr(559) phosphorylation. Hence, the phosphorylation of BCL10 Ser(138), but not Ser(218), emerged as a critical event in activation of the noncanonical pathway of NF-kappaB activation. Either BCL10 Ser(138) or Ser(218) mutation inhibited the phosphorylation of TAK1 at Thr(184) and at Thr(187), but not at Ser(192). These findings indicate that BCL10 phosphorylations act upstream of phosphorylations of NIK, TAK1, and IkappaBalpha and differentially affect the canonical and noncanonical pathways of NF-kappaB activation. PMID- 21700903 TI - Transition from parenteral to enteral nutrition induces immediate diet-dependent gut histological and immunological responses in preterm neonates. AB - Necrotizing enterocolitis (NEC) in preterm infants develops very rapidly from a mild intolerance to enteral feeding into intestinal mucosal hemorrhage, inflammation, and necrosis. We hypothesized that immediate feeding-induced gut responses precede later clinical NEC symptoms in preterm pigs. Fifty-six preterm pigs were fed total parenteral nutrition (TPN) for 48 h followed by enteral feeding for 0, 8, 17, or 34 h with either colostrum (Colos, n = 20) or formula (Form, n = 31). Macroscopic NEC lesions were detected in Form pigs throughout the enteral feeding period (20/31, 65%), whereas most Colos pigs remained protected (1/20, 5%). Just 8 h of formula feeding induced histopathological lesions, as evidenced by capillary stasis and necrosis, epithelial degeneration, edema, and mucosal hemorrhage. These immediate formula-induced changes were paralleled by decreased digestive enzyme activities (lactase and dipeptidylpeptidase IV), increased nutrient fermentation, and altered expression of innate immune defense genes such as interleukins (IL-1alpha, IL-6, IL-18), nitric oxide synthetase, tight junction proteins (claudins), Toll-like receptors (TLR-4), and TNF-alpha. In contrast, the first hours of colostrum feeding induced no histopathological lesions, increased maltase activity, and induced changes in gene expressions related to tissue development. Total bacterial density was high after 2 days of parenteral feeding and was not significantly affected by diet (colostrum, formula) or length of enteral feeding (8-34 h), except that a few bacterial groups (Clostridium, Enterococcus, Streptococcus species) increased with time. We conclude that a switch from parenteral to enteral nutrition rapidly induces diet dependent histopathological, functional, and proinflammatory insults to the immature intestine. Great care is required when introducing enteral feeds to TPN fed preterm infants, particularly when using formula, because early feeding induced insults may predispose to NEC lesions that are difficult to revert by later dietary or medical interventions. PMID- 21700902 TI - Colitis development during the suckling-weaning transition in mucin Muc2 deficient mice. AB - The mucin Muc2 is the structural component of the colonic mucus layer. Adult Muc2 knockout (Muc2(-/-)) mice suffer from severe colitis. We hypothesized that Muc2 deficiency induces inflammation before weaning of mother's milk [postnatal day (P) 14] with aggravation of colitis after weaning (P28). Muc2(-/-) and wild-type mice were killed at embryonic day 18.5 and P1.5, P7.5, P14, P21, and P28. Colonic morphology, influx of T cells, and goblet cell-specific protein expression was investigated by (immuno)histochemistry. Cytokine and Toll-like receptor (TLR) profiles in the colon were analyzed by quantitative RT-PCR. Muc2(-/-) mice showed an increased and persistent influx of Cd3epsilon-positive T cells in the colonic mucosa as of P1.5. This was accompanied by mucosal damage at P28 in the distal colon but not in the proximal colon. At P14, the proinflammatory immune response [i.e., increased interleukin (IL)-12 p35, IL-12 p40, and tumor necrosis factor alpha, expression] in the distal colon of Muc2(-/-) mice presented with an immune suppressive response [i.e., increased Foxp3, transforming growth factor (TGF) beta1, IL-10, and Ebi3 expression]. In contrast, at P28, a proinflammatory response remained in the distal colon, whereas the immune suppressive response (i.e., Foxp3 and TGF-beta1 expression) declined. The proximal colon of Muc2(-/-) mice did not show morphological damage and was dominated by an immune suppressive response at P14 and P28. Interestingly, changes in expression of TLRs and TLR related molecules were observed in the distal colon at P14 and P28 and in the proximal colon only at P28. Colitis in Muc2(-/-) mice is limited before weaning by immune suppressive responses and exacerbates in the distal colon after weaning because of the decline in the immune suppressive response. PMID- 21700904 TI - Mechanisms underlying distension-evoked peristalsis in guinea pig distal colon: is there a role for enterochromaffin cells? AB - The mechanisms underlying distension-evoked peristalsis in the colon are incompletely understood. It is well known that, following colonic distension, 5 hydroxytryptamine (5-HT) is released from enterochromaffin (EC) cells in the intestinal mucosa. It is also known that exogenous 5-HT can stimulate peristalsis. These observations have led some investigators to propose that endogenous 5-HT release from EC cells might be involved in the initiation of colonic peristalsis, following distension. However, because no direct evidence exists to support this hypothesis, the aim of this study was to determine directly whether release of 5-HT from EC cells was required for distension-evoked colonic peristalsis. Real-time amperometric recordings of 5-HT release and video imaging of colonic wall movements were performed on isolated segments of guinea pig distal colon, during distension-evoked peristalsis. Amperometric recordings revealed basal and transient release of 5-HT from EC cells before and during the initiation of peristalsis, respectively. However, removal of mucosa (and submucosal plexus) abolished 5-HT release but did not inhibit the initiation of peristalsis nor prevent the propagation of fecal pellets or intraluminal fluid. Maintained colonic distension by fecal pellets induced repetitive peristaltic waves, whose intrinsic frequency was also unaffected by removal of the submucosal plexus and mucosa, although their propagation velocities were slower. In conclusion, the mechanoreceptors and sensory neurons activated by radial distension to initiate peristalsis lie in the myenteric plexus and/or muscularis externa, and their activation does not require the submucosal plexus, release of 5-HT from EC cells, nor the presence of the mucosa. The propagation of peristalsis and propulsion of liquid or solid content along the colon is entrained by activity within the myenteric plexus and/or muscularis externa and does not require sensory feedback from the mucosa, nor neural inputs arising from submucosal ganglia. PMID- 21700905 TI - Activated AMPK inhibits PPAR-{alpha} and PPAR-{gamma} transcriptional activity in hepatoma cells. AB - AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) are critical regulators of short-term and long-term fatty acid oxidation, respectively. We examined whether the activities of these molecules were coordinately regulated. H4IIEC3 cells were transfected with PPAR alpha and PPAR-gamma expression plasmids and a peroxisome-proliferator-response element (PPRE) luciferase reporter plasmid. The cells were treated with PPAR agonists (WY-14,643 and rosiglitazone), AMPK activators 5-aminoimidazole-4 carboxamide riboside (AICAR) and metformin, and the AMPK inhibitor compound C. Both AICAR and metformin decreased basal and WY-14,643-stimulated PPAR-alpha activity; compound C increased agonist-stimulated reporter activity and partially reversed the effect of the AMPK activators. Similar effects on PPAR-gamma were seen, with both AICAR and metformin inhibiting PPRE reporter activity. Compound C increased basal PPAR-gamma activity and rosiglitazone-stimulated activity. In contrast, retinoic acid receptor-alpha (RAR-alpha), another nuclear receptor that dimerizes with retinoid X receptor (RXR), was largely unaffected by the AMPK activators. Compound C modestly increased AM580 (an RAR agonist)-stimulated activity. The AMPK activators did not affect PPAR-alpha binding to DNA, and there was no consistent correlation between effects of the AMPK activators and inhibitor on PPAR and the nuclear localization of AMPK-alpha subunits. Expression of either a constitutively active or dominant negative AMPK-alpha inhibited basal and WY-14,643-stimulated PPAR-alpha activity and basal and rosiglitazone stimulated PPAR-gamma activity. We concluded that the AMPK activators AICAR and metformin inhibited transcriptional activities of PPAR-alpha and PPAR-gamma, whereas inhibition of AMPK with compound C activated both PPARs. The effects of AMPK do not appear to be mediated through effects on RXR or on PPAR/RXR binding to DNA. These effects are independent of kinase activity and instead appear to rely on the activated conformation of AMPK. AMPK inhibition of PPAR-alpha and gamma may allow for short-term processes to increase energy generation before the cells devote resources to increasing their capacity for fatty acid oxidation. PMID- 21700901 TI - The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer? AB - Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States, and, even though 5-15% of the total CRC cases can be attributed to individual genetic predisposition, environmental factors could be considered major factors in susceptibility to CRC. Lifestyle factors increasing the risks of CRC include elevated body mass index, obesity, and reduced physical activity. Additionally, a number of dietary elements have been associated with higher or lower incidence of CRC. In this context, it has been suggested that diets high in fruit and low in meat might have a protective effect, reducing the incidence of colorectal adenomas by modulating the composition of the normal nonpathogenic commensal microbiota. In addition, it has been demonstrated that changes in abundance of taxonomic groups have a profound impact on the gastrointestinal physiology, and an increasing number of studies are proposing that the microbiota mediates the generation of dietary factors triggering colon cancer. High throughput sequencing and molecular taxonomic technologies are rapidly filling the knowledge gaps left by conventional microbiology techniques to obtain a comprehensive catalog of the human intestinal microbiota and their associated metabolic repertoire. The information provided by these studies will be essential to identify agents capable of modulating the massive amount of gut bacteria in safe noninvasive manners to prevent CRC. Probiotics, defined as "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host" (219), are capable of transient modulation of the microbiota, and their beneficial effects include reinforcement of the natural defense mechanisms and protection against gastrointestinal disorders. Probiotics have been successfully used to manage infant diarrhea, food allergies, and inflammatory bowel disease; hence, the purpose of this review was to examine probiotic metabolic activities that may have an effect on the prevention of CRC by scavenging toxic compounds or preventing their generation in situ. Additionally, a brief consideration is given to safety evaluation and production methods in the context of probiotics efficacy. PMID- 21700906 TI - Intensive care unit management of patients with severe pulmonary hypertension and right heart failure. AB - Despite advances in medical therapies, pulmonary arterial hypertension (PAH) continues to cause significant morbidity and mortality. Although the right ventricle (RV) can adapt to an increase in afterload, progression of the pulmonary vasculopathy that characterizes PAH causes many patients to develop progressive right ventricular failure. Furthermore, acute right ventricular decompensation may develop from disorders that lead to either an acute increase in cardiac demand, such as sepsis, or to an increase in ventricular afterload, including interruptions in medical therapy, arrhythmia, or pulmonary embolism. The poor reserve of the right ventricle, RV ischemia, and adverse right ventricular influence on left ventricular filling may lead to a global reduction in oxygen delivery and multiorgan failure. There is a paucity of data to guide clinicians caring for acute right heart failure in PAH. Treatment recommendations are frequently based on animal models of acute right heart failure or case series in humans with other causes of pulmonary hypertension. Successful treatment often requires that invasive hemodynamics be used to monitor the effect of strategies that are based primarily on biological plausibility. Herein we have developed an approach based on the current understanding of RV failure in PAH and have attempted to develop a treatment paradigm based on physiological principles and available evidence. PMID- 21700908 TI - Dynamic hyperinflation and auto-positive end-expiratory pressure: lessons learned over 30 years. AB - Auto-positive end-expiratory pressure (auto-PEEP; AP) and dynamic hyperinflation (DH) may affect hemodynamics, predispose to barotrauma, increase work of breathing, cause dyspnea, disrupt patient-ventilator synchrony, confuse monitoring of hemodynamics and respiratory system mechanics, and interfere with the effectiveness of pressure-regulated ventilation. Although basic knowledge regarding the clinical physiology and management of AP during mechanical ventilation has evolved impressively over the 30 years since DH and AP were first brought to clinical attention, novel and clinically relevant characteristics of this complex phenomenon continue to be described. This discussion reviews some of the more important aspects of AP that bear on the care of the ventilated patient with critical illness. PMID- 21700909 TI - Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. AB - RATIONALE: Gastroesophageal reflux (GER) is highly prevalent in patients with idiopathic pulmonary fibrosis (IPF). Chronic microaspiration secondary to GER may play a role in the pathogenesis and natural history of IPF. OBJECTIVES: To investigate the relationship between GER-related variables and survival time in patients with IPF. METHODS: Regression analysis was used to investigate the relationship between GER-related variables and survival time in a retrospectively identified cohort of patients with well-characterized IPF from two academic medical centers. MEASUREMENTS AND MAIN RESULTS: Two hundred four patients were identified for inclusion. GER-related variables were common in this cohort: reported symptoms of GER (34%), a history of GER disease (45%), reported use of GER medications (47%), and Nissen fundoplication (5%). These GER-related variables were significantly associated with longer survival time on unadjusted analysis. After adjustment, the use of GER medications was an independent predictor of longer survival time. In addition, the use of gastroesophageal reflux medications was associated with a lower radiologic fibrosis score. These findings were present regardless of center. CONCLUSIONS: The reported use of GER medications is associated with decreased radiologic fibrosis and is an independent predictor of longer survival time in patients with IPF. These findings further support the hypothesis that GER and chronic microaspiration may play important roles in the pathobiology of IPF. PMID- 21700910 TI - The effect of insurance status on mortality and procedural use in critically ill patients. AB - RATIONALE: Lack of health insurance maybe an independent risk factor for mortality and differential treatment in critical illness. OBJECTIVES: To determine whether uninsured critically ill patients had differences in 30-day mortality and critical care service use compared with those with private insurance and to determine if outcome variability could be attributed to patient level or hospital-level effects. METHODS: Retrospective cohort study using Pennsylvania hospital discharge data with detailed clinical risk adjustment, from fiscal years 2005 and 2006, consisting of 167 general acute care hospitals, with 138,720 critically ill adult patients 64 years of age or younger. MEASUREMENTS AND MAIN RESULTS: Measurements were 30-day mortality and receipt of five critical care procedures. Uninsured patients had an absolute 30-day mortality of 5.7%, compared with 4.6% for those with private insurance and 6.4% for those with Medicaid. Increased 30-day mortality among uninsured patients persisted after adjustment for patient characteristics (odds ratio [OR], 1.25 for uninsured vs. insured; 95% confidence interval [CI], 1.04-1.50) and hospital-level effects (OR, 1.26; 95% CI, 1.05-1.51). Compared with insured patients, uninsured patients had decreased risk-adjusted odds of receiving a central venous catheter (OR, 0.84; 95% CI,0.72-0.97), acute hemodialysis (OR, 0.59; 95% CI, 0.39-0.91), and tracheostomy (OR, 0.43; 95% CI, 0.29-0.64). CONCLUSIONS: Lack of health insurance is associated with increased 30-day mortality and decreased use of common procedures for the critically ill in Pennsylvania. Differences were not attributable to hospital-level effects, suggesting that the uninsured have a higher mortality and receive fewer procedures when compared with privately insured patients treated at the same hospitals. PMID- 21700911 TI - Estrogen rescues preexisting severe pulmonary hypertension in rats. AB - RATIONALE: Pulmonary hypertension (PH) is characterized by progressive increase in pulmonary artery pressure leading to right ventricular (RV) hypertrophy, RV failure, and death. Current treatments only temporarily reduce severity of the disease, and an ideal therapy is still lacking. OBJECTIVES: Estrogen pretreatment has been shown to attenuate development of PH. Because PH is not often diagnosed early, we examined if estrogen can rescue preexisting advanced PH. METHODS: PH was induced in male rats with monocrotaline (60 mg/kg). At Day 21, rats were either treated with 17-beta estradiol or estrogen (E2, 42.5 MUg/kg/d), estrogen receptor-beta agonist (diarylpropionitrile, 850 MUg/kg/d), or estrogen receptor alpha-agonist (4,4',4"-[4-Propyl-(1H)-pyrazole-1,3,5-triyl] trisphenol, 850 MUg/kg/d) for 10 days or left untreated to develop RV failure. Serial echocardiography, cardiac catheterization, immunohistochemistry, Western blot, and real-time polymerase chain reaction were performed. MEASUREMENTS AND MAIN RESULTS: Estrogen therapy prevented progression of PH to RV failure and restored lung and RV structure and function. This restoration was maintained even after removal of estrogen at Day 30, resulting in 100% survival at Day 42. Estradiol treatment restored the loss of blood vessels in the lungs and RV. In the presence of angiogenesis inhibitor TNP-470 (30 mg/kg) or estrogen receptor-beta antagonist (PHTPP, 850 MUg/kg/d), estrogen failed to rescue PH. Estrogen receptor-beta selective agonist was as effective as estrogen in rescuing PH. CONCLUSIONS: Estrogen rescues preexisting severe PH in rats by restoring lung and RV structure and function that are maintained even after removal of estrogen. Estrogen-induced rescue of PH is associated with stimulation of cardiopulmonary neoangiogenesis, suppression of inflammation, fibrosis, and RV hypertrophy. Furthermore, estrogen rescue is likely mediated through estrogen receptor-beta. PMID- 21700912 TI - Transglutaminase 2 and its role in pulmonary fibrosis. AB - RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a deadly progressive disease with few treatment options. Transglutaminase 2 (TG2) is a multifunctional protein, but its function in pulmonary fibrosis is unknown. OBJECTIVES: To determine the role of TG2 in pulmonary fibrosis. METHODS: The fibrotic response to bleomycin was compared between wild-type and TG2 knockout mice. Transglutaminase and transglutaminase-catalyzed isopeptide bond expression was examined in formalin-fixed human lung biopsy sections by immunohistochemistry from patients with IPF. In addition, primary human lung fibroblasts were used to study TG2 function in vitro. MEASUREMENTS AND MAIN RESULTS: TG2 knockout mice developed significantly reduced fibrosis compared with wild-type mice as determined by hydroxyproline content and histologic fibrosis score (P < 0.05). TG2 expression and activity are increased in lung biopsy sections in humans with IPF compared with normal control subjects. In vitro overexpression of TG2 led to increased fibronectin deposition, whereas transglutaminase knockdown led to defects in contraction and adhesion. The profibrotic cytokine transforming growth factor-beta causes an increase in membrane-localized TG2, increasing its enzymatic activity. CONCLUSIONS: TG2 is involved in pulmonary fibrosis in a mouse model and in human disease and is important in normal fibroblast function. With continued research on TG2, it may offer a new therapeutic target. PMID- 21700913 TI - Long-term exposure to air pollution and cardiorespiratory disease in the California teachers study cohort. AB - RATIONALE: Several studies have linked long-term exposure to particulate air pollution with increased cardiopulmonary mortality; only two have also examined incident circulatory disease. OBJECTIVES: To examine associations of individualized long-term exposures to particulate and gaseous air pollution with incident myocardial infarction and stroke, as well as all-cause and cause specific mortality. METHODS: We estimated long-term residential air pollution exposure for more than 100,000 participants in the California Teachers Study, a prospective cohort of female public school professionals.We linked geocoded residential addresses with inverse distance-weighted monthly pollutant surfaces for two measures of particulate matter and for several gaseous pollutants. We examined associations between exposure to these pollutants and risks of incident myocardial infarction and stroke, and of all-cause and cause-specific mortality, using Cox proportional hazards models. MEASUREMENTS AND MAIN RESULTS: We found elevated hazard ratios linking long-term exposure to particulate matter less than 2.5 MUm in aerodynamic diameter (PM2.5), scaled to an increment of 10 MUg/m3 with mortality from ischemic heart disease (IHD) (1.20; 95% confidence interval [CI], 1.02-1.41) and, particularly among postmenopausal women, incident stroke (1.19; 95% CI, 1.02-1.38). Long-term exposure to particulate matter less than 10 MUm in aerodynamic diameter (PM10) was associated with elevated risks for IHD mortality (1.06; 95% CI, 0.99-1.14) and incident stroke (1.06; 95% CI, 1.00-1.13), while exposure to nitrogen oxides was associated with elevated risks for IHD and all cardiovascular mortality. CONCLUSIONS: This study provides evidence linking long term exposure to PM2.5 and PM10 with increased risks of incident stroke as well as IHD mortality; exposure to nitrogen oxides was also related to death from cardiovascular diseases. PMID- 21700914 TI - Parental stress increases the detrimental effect of traffic exposure on children's lung function. AB - RATIONALE: Emerging evidence indicates that psychosocial stress enhances the effect of traffic exposure on the development of asthma. OBJECTIVES: We hypothesized that psychosocial stress would also modify the effect of traffic exposure on lung function deficits. METHODS: We studied 1,399 participants in the Southern California Children's Health Study undergoing lung function testing (mean age, 11.2 yr). We used hierarchical mixed models to assess the joint effect of traffic-related air pollution and stress on lung function. MEASUREMENTS AND MAIN RESULTS: Psychosocial stress in each child's household was assessed based on parental response to the perceived stress scale (range, 0-16) at study entry. Exposures to nitric oxide, nitrogen dioxide, and total oxides of nitrogen (NOx), surrogates of the traffic-related pollution mixture, were estimated at schools and residences based on a land-use regression model. Among children from high stress households (parental perceived stress scale > 4) deficits in FEV1 of 4.5 (95% confidence interval, -6.5 to -2.4) and of 2.8% (-5.7 to 0.3) were associated with each 21.8 ppb increase in NOx at homes and schools, respectively. These pollutant effects were significantly larger in the high-stress compared with lower-stress households (interaction P value 0.007 and 0.05 for residential and school NOx, respectively). No significant NOx effects were observed in children from low-stress households. A similar pattern of association was observed for FVC. The observed associations for FEV1 and FVC remained after adjusting for sociodemographic factors and after restricting the analysis to children who do not have asthma. CONCLUSIONS: A high-stress home environment is associated with increased susceptibility to lung function effects of air pollution both at home and at school. PMID- 21700916 TI - Ozone and survival in four cohorts with potentially predisposing diseases. AB - RATIONALE: Time series studies have reported associations between ozone and daily deaths. Only one cohort study has reported the effect of long-term exposures on deaths, and little is known about effects of chronic ozone exposure on survival in susceptible populations. OBJECTIVES: We investigated whether ozone was associated with survival in four cohorts of persons with specific diseases in 105 United States cities, treating ozone as a time varying exposure. METHODS: We used Medicare data (1985-2006), and constructed cohorts of persons hospitalized with chronic conditions that might predispose to ozone effects: chronic obstructive pulmonary disease, diabetes, congestive heart failure, and myocardial infarction. Yearly warm-season average ozone was merged to the individual follow-up in each city. We applied Cox proportional hazard model for each cohort within each city, adjusting for individual risk factors, temperature, and city-specific long-term trends. MEASUREMENTS AND MAIN RESULTS: We found significant associations with a hazard ratio for mortality of 1.06 (95% confidence interval [CI], 1.03-1.08) per 5-ppb increase in summer average ozone for persons with congestive heart failure; of 1.09 (95% CI, 1.06-1.12) with myocardial infarction; of 1.07 (95% CI, 1.04 1.09) with chronic obstructive pulmonary disease; and of 1.07 (95% CI, 1.05-1.10) for diabetics.We also found that the effect varied by region, but that this was mostly explained by mean temperature, which is likely a surrogate of air conditioning use, and hence exposure. CONCLUSIONS: This is the first study that follows persons with specific chronic conditions, and shows that long-term ozone exposure is associated with increased risk of death in these groups. PMID- 21700917 TI - High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes. AB - OBJECTIVE: Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-alpha (HNF1A) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes. RESEARCH DESIGN AND METHODS: hs-CRP levels were assessed in 750 patients (220 HNF1A, 245 GCK, 54 HNF4-alpha [HNF4A], 21 HNF1-beta (HNF1B), 53 type 1 diabetes, and 157 type 2 diabetes). RESULTS: hs CRP was lower in HNF1A-MODY (median [IQR] 0.3 [0.1-0.6] mg/L) than type 2 diabetes (1.40 [0.60-3.45] mg/L; P < 0.001) and type 1 diabetes (1.10 [0.50-1.85] mg/L; P < 0.001), HNF4A-MODY (1.45 [0.46-2.88] mg/L; P < 0.001), GCK-MODY (0.60 [0.30-1.80] mg/L; P < 0.001), and HNF1B-MODY (0.60 [0.10-2.8] mg/L; P = 0.07). hs CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP <0.75 mg/L showing 79% sensitivity and 70% specificity (receiver operating characteristic area under the curve = 0.84). CONCLUSIONS: hs-CRP levels are lower in HNF1A-MODY than other forms of diabetes and may be used as a biomarker to select patients for diagnostic HNF1A genetic testing. PMID- 21700918 TI - Polychlorinated biphenyls and organochlorine pesticides in plasma predict development of type 2 diabetes in the elderly: the prospective investigation of the vasculature in Uppsala Seniors (PIVUS) study. AB - OBJECTIVE: Persistent organic pollutants (POPs), lipophilic chemicals that accumulate mainly in adipose tissue, have recently been linked to type 2 diabetes. However, evidence from prospective studies is sparse. This study was performed to evaluate prospective associations of type 2 diabetes with selected POPs among the elderly. RESEARCH DESIGN AND METHODS: Nineteen POPs (14 polychlorinated biphenyl [PCB] congeners, 3 organochlorine pesticides, 1 brominated diphenyl ether, and 1 dioxin) were measured in plasma collected at baseline in 725 participants, aged 70 years, of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). RESULTS: After adjusting for known type 2 diabetes risk factors, including obesity, odds ratios (ORs) (95% CIs) for type 2 diabetes at age 75 years (n = 36) according to the quintiles of a summary measure of concentrations of PCBs (vs. the lowest quintile) were 4.5, 5.1, 8.8 (1.8-42.7), and 7.5 (1.4-38.8) (P(trend) <0.01). Among organochlorine pesticides, adjusted ORs across concentrations of trans-nonachlor showed that P(trend) = 0.03. Adjusted ORs (95% CIs) across quintiles of the sum of three organochlorine pesticides were 1.1, 1.6, 1.5, and 3.4 (1.0-11.7) (P(trend) = 0.03). Neither brominated diphenyl ether 47 nor dioxin was significantly associated with incident diabetes. The sum of PCBs improved reclassification significantly when added to traditional risk factors for diabetes. CONCLUSIONS: Despite the small number of incident cases, this study found that environmental exposure to some POPs substantially increased risk of future type 2 diabetes in an elderly population. PMID- 21700919 TI - Weight-based, insulin dose-related hypoglycemia in hospitalized patients with diabetes. AB - OBJECTIVE: To determine the association of weight-based insulin dose with hypoglycemia in noncritically ill inpatients with diabetes. RESEARCH DESIGN AND METHODS: We performed a retrospective, case-control study of 1,990 diabetic patients admitted to hospital wards. Patients with glucose levels <70 mg/dL (case subjects) were matched one to one with nonhypoglycemic control subjects on the basis of the hospital day of hypoglycemia, age, sex, and BMI. RESULTS: Relative to 24-h insulin doses <0.2 units/kg, the unadjusted odds of hypoglycemia increased with increasing insulin dose. Adjusted for insulin type, sliding-scale insulin use, and albumin, creatinine, and hematocrit levels, the higher odds of hypoglycemia with increasing insulin doses remained (0.6-0.8 units/kg: odds ratio 2.10 [95% CI 1.08-4.09], P = 0.028; >0.8 units/kg: 2.95 [1.54-5.65], P = 0.001). The adjusted odds of hypoglycemia were not greater in patients who received 0.2 0.4 units/kg (1.08 [0.64-1.81], P = 0.78) or 0.4-0.6 units/kg (1.60 [0.90-2.86], P = 0.11). Although the relationship between insulin dose and hypoglycemia did not vary by insulin type, patients who received NPH trended toward greater odds of hypoglycemia compared with those given other insulins. CONCLUSIONS: Higher weight-based insulin doses are associated with greater odds of hypoglycemia independent of insulin type. However, 0.6 units/kg seems to be a threshold below which the odds of hypoglycemia are relatively low. These findings may help clinicians use insulin more safely. PMID- 21700920 TI - Fear of injury with physical activity is greater in adults with diabetes than in adults without diabetes. AB - OBJECTIVE: Physical activity is a cornerstone of treatment for diabetes, yet people with diabetes perform less moderate and vigorous physical activity (MVPA) than people without diabetes. In contrast, whether differences in walking activity exist has been understudied. Diabetes-specific barriers to physical activity are one possible explanation for lower MVPA in diabetes. We hypothesized that people with diabetes would perform less walking and combined MVPA and would be less likely to anticipate increasing physical activity if barriers were theoretically absent, compared with people without diabetes. RESEARCH DESIGN AND METHODS: We surveyed 1,848 randomly selected rural Colorado adult residents by telephone from 2002 to 2004. Respondents reported weekly walking and MVPA duration and their likelihood of increasing physical activity if each of seven barriers was theoretically absent. RESULTS: People with diabetes (n = 129) had lower odds of walking and MVPA than people without diabetes (walking: adjusted odds ratio 0.62 [95% CI 0.40-0.95]; MVPA: adjusted odds ratio 0.60 [0.36-0.99]; >=10 vs. <10 min/week, adjusted for age, sex, BMI, and ethnicity). Respondents with diabetes reported fear of injury as a barrier to physical activity more often than respondents without diabetes (56 vs. 39%; P = 0.0002), although this relationship was attenuated after adjusting for age and BMI (adjusted odds ratio 1.36 [0.93-1.99]). CONCLUSIONS: Although walking is a preferred form of activity in diabetes, people with diabetes walk less than people without diabetes. Reducing fear of injury may potentially increase physical activity for people with diabetes, particularly in older and more overweight individuals. PMID- 21700921 TI - Does glucose variability influence the relationship between mean plasma glucose and HbA1c levels in type 1 and type 2 diabetic patients? AB - OBJECTIVE: The A1C-Derived Average Glucose (ADAG) study demonstrated a linear relationship between HbA(1c) and mean plasma glucose (MPG). As glucose variability (GV) may contribute to glycation, we examined the association of several glucose variability indices and the MPG-HbA(1c) relationship. RESEARCH DESIGN AND METHODS: Analyses included 268 patients with type 1 diabetes and 159 with type 2 diabetes. MPG during 3 months was calculated from 7-point self monitored plasma glucose and continuous glucose monitoring. We calculated three different measures of GV and used a multiple-step regression model to determine the contribution of the respective GV measures to the MPG-HbA(1c) relationship. RESULTS: GV, as reflected by SD and continuous overlapping net glycemic action, had a significant effect on the MPG-HbA(1c) relationship in type 1 diabetic patients so that high GV led to a higher HbA(1c) level for the same MPG. In type 1 diabetes, the impact of confounding and effect modification of a low versus high SD at an MPG level of 160 mg/dL on the HbA(1c) level is 7.02 vs. 7.43 and 6.96 vs. 7.41. All GV measures showed the same tendency. CONCLUSIONS: In only type 1 diabetic patients, GV shows a significant interaction with MPG in the association with HbA(1c). This effect is more pronounced at higher HbA(1c) levels. However, the impact of GV on the HbA(1c) level in type 1 diabetes is modest, particularly when HbA(1c) is close to the treatment target of 7%. PMID- 21700922 TI - Prism adaptation therapy enhances rehabilitation of stroke patients with unilateral spatial neglect: a randomized, controlled trial. AB - BACKGROUND: and objective. Unilateral spatial neglect (USN) can interfere with rehabilitation processes and lead to poor functional outcome. The purpose of this study was to determine whether prism adaptation (PA) therapy improves USN and functional outcomes in stroke patients in the subacute stage. METHODS: . A multicenter, double-masked, randomized, controlled trial was conducted to evaluate the effects of a 2-week PA therapy on USN assessed with the Behavioral Inattention Test (BIT), the Catherine Bergego Scale (CBS), and activities of daily living (ADL) as evaluated with the Functional Independence Measure (FIM). A total of 38 USN patients with right-brain damage were divided into prism (n = 20) and control (n = 18) groups. Patients were divided into mild and severe USN groups according to BIT behavioral test (mild >= 55 and severe<55). The prism group performed repetitive pointing with prism glasses that induce rightward optical shift twice daily, 5 days per week, for 2 weeks, whereas the control group performed similar pointing training with neutral glasses. RESULTS: . The FIM improved significantly more in the prism group. In mild USN patients, there was significantly greater improvement of BIT and FIM in the prism group. CONCLUSIONS: . PA therapy can significantly improve ADL in patients with subacute stroke. PMID- 21700923 TI - Poststroke conscious visual deficit: clinical course and changes in cerebral activations. AB - BACKGROUND AND PURPOSE: Little is known about the outcome and recovery mechanisms of visual perception after a focal lesion of the occipital lobe in humans, especially after stroke. In this study, the authors aimed to describe the clinical course and the neural substrates of conscious perceptive visual deficit after posterior cerebral artery infarct. METHODS: The authors prospectively included 8 patients (7 men and 1 woman; mean age, 64.6 +/- 18 years) with visual deficit induced by partial damage of the striate cortex related to acute posterior cerebral artery infarct. Conscious perception of color and motion was assessed from the acute phase to the third month. Functional magnetic resonance imaging was performed to investigate neural substrates of visual recovery. RESULTS: In the acute phase of stroke, visual deficiency was global (3/8 patients), selective to color (4/8 patients), or selective to motion (1/8 patients). During the follow-up, visual performance increased with respect to color (from 29% to 70%; P < .005) and with respect to motion (from 47% to 74%; P < .005). Despite a lack of ipsilesional V1 area activation in the acute phase, activations in this area and in the contralesional extrastriate cortex were obtained during follow-up. Both ipsilesional and contralesional V4 activations were correlated with better outcome. CONCLUSIONS: Extensive visual recovery occurs early after partial acute posterior cerebral artery infarct. Spared islands in ipsilesional V1 area and transcallosal pathways might be involved in poststroke visual recovery. PMID- 21700924 TI - Bimanual training and constraint-induced movement therapy in children with hemiplegic cerebral palsy: a randomized trial. AB - BACKGROUND: Constraint-induced movement therapy (CIMT) promotes hand function using intensive unimanual practice along with restraint of the less-affected hand. CIMT has not been compared with a treatment with equivalent dosing frequency and intensity in children with cerebral palsy (CP). OBJECTIVES: The authors report a randomized trial comparing CIMT and a bimanual intervention (hand-arm intensive bimanual therapy; HABIT) that maintains the intensity of practice associated with CIMT but where children are engaged in functional bimanual tasks. METHODS: A total of 42 participants with hemiplegic CP between the ages of 3.5 and 10 years (matched for age and hand function) were randomized to receive 90 hours of CIMT or an equivalent dosage of functional bimanual training (HABIT) conducted in day-camp environments. A physical therapist blinded to treatment allocation tested hand function before and after treatment. The primary outcomes were changes in Jebsen-Taylor Test of Hand Function (JTTHF) and Assisting Hand Assessment (AHA) scores. Secondary measures included the Goal Attainment Scale (GAS). RESULTS: Both the CIMT and HABIT groups demonstrated comparable improvement from the pretest to immediate posttest in the JTTHF and AHA (P < .0001), which were maintained at 6 months. GAS, however, revealed greater progress toward goals for the HABIT group (P < .0001), with continued improvement across test sessions for both groups (P < .0001). CONCLUSIONS: Both CIMT and bimanual training lead to similar improvements in hand function. A potential benefit of bimanual training is that participants may improve more on self-determined goals. PMID- 21700925 TI - Re: Breast cancer risk in relation to the interval between menopause and starting hormone therapy. PMID- 21700926 TI - The oral spleen tyrosine kinase inhibitor fostamatinib attenuates inflammation and atherogenesis in low-density lipoprotein receptor-deficient mice. AB - OBJECTIVE: Spleen tyrosine kinase (SYK) has come into focus as a potential therapeutic target in chronic inflammatory diseases, such as rheumatoid arthritis and asthma, as well as in B-cell lymphomas. SYK has also been involved in the signaling of immunoreceptors, cytokine receptors, and integrins. We therefore hypothesized that inhibition of SYK attenuates the inflammatory process underlying atherosclerosis and reduces plaque development. METHODS AND RESULTS: Low-density lipoprotein receptor-deficient mice consuming a high-cholesterol diet supplemented with 2 doses of the orally available SYK inhibitor fostamatinib for 16 weeks showed a dose-dependent reduction in atherosclerotic lesion size by up to 59+/-6% compared with the respective controls. Lesions of fostamatinib-treated animals contained fewer macrophages but more smooth muscle cells and collagen characteristics associated with more stable plaques in humans. Mechanistically, fostamatinib attenuated adhesion and migration of inflammatory cells and limited macrophage survival. Furthermore, fostamatinib normalized high-cholesterol diet induced monocytosis and inflammatory gene expression. CONCLUSIONS: We present the novel finding that the SYK inhibitor fostamatinib attenuates atherogenesis in mice. Our data identify SYK inhibition as a potentially fruitful antiinflammatory therapeutic strategy in atherosclerosis. PMID- 21700927 TI - Age as a modulator of inflammatory cardiovascular risk factors. AB - OBJECTIVE: Levels of acute phase reactants are affected by age. The extent to which cardiovascular risk associated with aging is due to an increase in the inflammatory burden is not known. We assessed the relationship with age of inflammatory markers, representing (1) systemic (C-reactive protein, fibrinogen, and serum amyloid-A) and (2) vascular (lipoprotein-associated phospholipase A(2) and pentraxin-3) inflammation. METHODS AND RESULTS: We determined lipoprotein associated phospholipase A(2) mass and activity, C-reactive protein, fibrinogen, serum amyloid-A, and pentraxin-3 levels and other cardiovascular disease risk factors in 336 whites and 224 African Americans. Levels of systemic inflammatory markers increased significantly with age in both ethnic groups (P<0.05 for all), whereas trend patterns of vascular inflammatory markers did not change significantly with age for either group. In multivariate regression models adjusting for confounding variables, age remained independently associated with a composite Z score for systemic but not vascular inflammation (beta=0.250, P<0.001, and beta=0.276, P<0.001, for whites and African Americans, respectively). CONCLUSIONS: We report an increase in the systemic but not vascular inflammatory burden with age. Levels of both categories of inflammatory markers with age were similar across ethnicity after adjustment for confounders. Our results underscore the importance of age in evaluating inflammatory markers to assess cardiovascular risk. PMID- 21700928 TI - Reversibility of adverse, calcineurin-dependent cardiac remodeling. AB - RATIONALE: Studies to dissect the role of calcineurin in pathological cardiac remodeling have relied heavily on murine models, in which genetic gain- and loss of-function manipulations are initiated at or before birth. However, the great majority of clinical cardiac pathology occurs in adults. Yet nothing is known about the effects of calcineurin when its activation commences in adulthood. Furthermore, despite the fact that ventricular hypertrophy is a well-established risk factor for heart failure, the relative pace and progression of these 2 major phenotypic features of heart disease are unknown. Finally, even though therapeutic interventions in adults are designed to slow, arrest, or reverse disease pathogenesis, little is known about the capacity for spontaneous reversibility of calcineurin-dependent pathological remodeling. OBJECTIVE: We set out to address these 3 questions by studying mice engineered to harbor in cardiomyocytes a constitutively active calcineurin transgene driven by a tetracycline-responsive promoter element. METHODS AND RESULTS: Expression of the mutant calcineurin transgene was initiated for variable lengths of time to determine the natural history of disease pathogenesis, and to determine when, if ever, these events are reversible. Activation of the calcineurin transgene in adult mice triggered rapid and robust cardiac growth with features characteristic of pathological hypertrophy. Concentric hypertrophy preceded the development of systolic dysfunction, fetal gene activation, fibrosis, and clinical heart failure. Furthermore, cardiac hypertrophy reversed spontaneously when calcineurin activity was turned off, and expression of fetal genes reverted to baseline. Fibrosis, a prominent feature of pathological cardiac remodeling, manifested partial reversibility. CONCLUSIONS: Together, these data establish and define the deleterious effects of calcineurin signaling in the adult heart and reveal that calcineurin-dependent hypertrophy with concentric geometry precedes systolic dysfunction and heart failure. Furthermore, these findings demonstrate that during much of the disease process, calcineurin-dependent remodeling remains reversible. PMID- 21700929 TI - Ets2 determines the inflammatory state of endothelial cells in advanced atherosclerotic lesions. AB - RATIONALE: Neovascularization is required for embryonic development and plays a central role in diseases in adults. In atherosclerosis, the role of neovascularization remains to be elucidated. In a genome-wide microarray-screen of Flk1+ angioblasts during murine embryogenesis, the v-ets erythroblastosis virus E26 oncogene homolog 2 (Ets2) transcription factor was identified as a potential angiogenic factor. OBJECTIVES: We assessed the role of Ets2 in endothelial cells during atherosclerotic lesion progression toward plaque instability. METHODS AND RESULTS: In 91 patients treated for carotid artery disease, Ets2 levels showed modest correlations with capillary growth, thrombogenicity, and rising levels of tumor necrosis factor-alpha (TNFalpha), monocyte chemoattractant protein 1, and interleukin-6 in the atherosclerotic lesions. Experiments in ApoE(-/-) mice, using a vulnerable plaque model, showed that Ets2 expression was increased under atherogenic conditions and was augmented specifically in the vulnerable versus stable lesions. In endothelial cell cultures, Ets2 expression and activation was responsive to the atherogenic cytokine TNFalpha. In the murine vulnerable plaque model, overexpression of Ets2 promoted lesion growth with neovessel formation, hemorrhaging, and plaque destabilization. In contrast, Ets2 silencing, using a lentiviral shRNA construct, promoted lesion stabilization. In vitro studies showed that Ets2 was crucial for TNFalpha-induced expression of monocyte chemoattractant protein 1, interleukin-6, and vascular cell adhesion molecule 1 in endothelial cells. In addition, Ets2 promoted tube formation and amplified TNFalpha-induced loss of vascular endothelial integrity. Evaluation in a murine retina model further validated the role of Ets2 in regulating vessel inflammation and endothelial leakage. CONCLUSIONS: We provide the first evidence for the plaque-destabilizing role of Ets2 in atherosclerosis development by induction of an intraplaque proinflammatory phenotype in endothelial cells. PMID- 21700930 TI - AIP1 prevents graft arteriosclerosis by inhibiting interferon-gamma-dependent smooth muscle cell proliferation and intimal expansion. AB - RATIONALE: ASK1-interacting protein-1 (AIP1), a Ras GTPase-activating protein family member, is highly expressed in endothelial cells and vascular smooth musccells (VSMCs). The role of AIP1 in VSMCs and VSMC proliferative disease is not known. OBJECTIVE: We used mouse graft arteriosclerosis models characterized by VSMC accumulation and intimal expansion to determine the function of AIP1. METHODS AND RESULTS: In a single minor histocompatibility antigen (male to female)-dependent aorta transplantation model, AIP1 deletion in the graft augmented neointima formation, an effect reversed in AIP1/interferon-gamma receptor (IFN-gammaR) doubly-deficient aorta donors. In a syngeneic aortic transplantation model in which wild-type or AIP1-knockout mouse aortas were transplanted into IFN-gammaR-deficient recipients and in which neointima formation was induced by intravenous administration of an adenovirus that encoded a mouse IFN-gamma transgene, donor grafts from AIP1-knockout mice enhanced IFN gamma-induced VSMC proliferation and neointima formation. Mechanistically, knockout or knockdown of AIP1 in VSMCs significantly enhanced IFN-gamma-induced JAK-STAT signaling and IFN-gamma-dependent VSMC migration and proliferation, 2 critical steps in neointima formation. Furthermore, AIP1 specifically bound to JAK2 and inhibited its activity. CONCLUSIONS: AIP1 functions as a negative regulator in IFN-gamma-induced intimal formation, in part by downregulating IFN gamma-JAK2-STAT1/3-dependent migratory and proliferative signaling in VSMCs. PMID- 21700931 TI - Caloric restriction primes mitochondria for ischemic stress by deacetylating specific mitochondrial proteins of the electron transport chain. AB - RATIONALE: Caloric restriction (CR) confers cardioprotection against ischemia/reperfusion injury. However, the exact mechanism(s) underlying CR induced cardioprotection remain(s) unknown. Recent evidence indicates that Sirtuins, NAD(+)-dependent deacetylases, regulate various favorable aspects of the CR response. Thus, we hypothesized that deacetylation of specific mitochondrial proteins during CR preserves mitochondrial function and attenuates production of reactive oxygen species during ischemia/reperfusion. OBJECTIVE: The objectives of the present study were (1) to investigate the effect of CR on mitochondrial function and mitochondrial proteome and (2) to investigate what molecular mechanisms mediate CR-induced cardioprotection. METHODS AND RESULTS: Male 26-week-old Fischer344 rats were randomly divided into ad libitum-fed and CR (40% reduction) groups for 6 months. No change was observed in basal mitochondrial function, but CR preserved postischemic mitochondrial respiration and attenuated postischemic mitochondrial H(2)O(2) production. CR decreased the level of acetylated mitochondrial proteins that were associated with enhanced Sirtuin activity in the mitochondrial fraction. We confirmed a significant decrease in the acetylated forms of NDUFS1 and cytochrome bc1 complex Rieske subunit in the CR heart. Low-dose resveratrol treatment mimicked the effect of CR on deacetylating them and attenuated reactive oxygen species production during anoxia/reoxygenation in cultured cardiomyocytes without changing the expression levels of manganese superoxide dismutase. Treatment with nicotinamide completely abrogated the effect of low-dose resveratrol. CONCLUSIONS: These results strongly suggest that CR primes mitochondria for stress resistance by deacetylating specific mitochondrial proteins of the electron transport chain. Targeted deacetylation of NDUFS1 and/or Rieske subunit might have potential as a novel therapeutic approach for cardioprotection against ischemia/reperfusion. PMID- 21700932 TI - Enzymatic single-chain antibody tagging: a universal approach to targeted molecular imaging and cell homing in cardiovascular disease. AB - RATIONALE: Antibody-targeted delivery of imaging agents can enhance the sensitivity and accuracy of current imaging techniques. Similarly, homing of effector cells to disease sites increases the efficacy of regenerative cell therapy while reducing the number of cells required. Currently, targeting can be achieved via chemical conjugation to specific antibodies, which typically results in the loss of antibody functionality and in severe cell damage. An ideal conjugation technique should ensure retention of antigen-binding activity and functionality of the targeted biological component. OBJECTIVE: To develop a biochemically robust, highly reproducible, and site-specific coupling method using the Staphylococcus aureus sortase A enzyme for the conjugation of a single chain antibody (scFv) to nanoparticles and cells for molecular imaging and cell homing in cardiovascular diseases. This scFv specifically binds to activated platelets, which play a pivotal role in thrombosis, atherosclerosis, and inflammation. METHODS AND RESULTS: The conjugation procedure involves chemical and enzyme-mediated coupling steps. The scFv was successfully conjugated to iron oxide particles (contrast agents for magnetic resonance imaging) and to model cells. Conjugation efficiency ranged between 50% and 70%, and bioactivity of the scFv after coupling was preserved. The targeting of scFv-coupled cells and nanoparticles to activated platelets was strong and specific as demonstrated in in vitro static adhesion assays, in a flow chamber system, in mouse intravital microscopy, and in in vivo magnetic resonance imaging of mouse carotid arteries. CONCLUSIONS: This unique biotechnological approach provides a versatile and broadly applicable tool for procuring targeted regenerative cell therapy and targeted molecular imaging in cardiovascular and inflammatory diseases and beyond. PMID- 21700933 TI - Restoration of normal L-type Ca2+ channel function during Timothy syndrome by ablation of an anchoring protein. AB - RATIONALE: L-type Ca(2+) (Ca(V)1.2) channels shape the cardiac action potential waveform and are essential for excitation-contraction coupling in heart. A gain of-function G406R mutation in a cytoplasmic loop of Ca(V)1.2 channels causes long QT syndrome 8 (LQT8), a disease also known as Timothy syndrome. However, the mechanisms by which this mutation enhances Ca(V)1.2-LQT8 currents and generates lethal arrhythmias are unclear. OBJECTIVE: To test the hypothesis that the anchoring protein AKAP150 modulates Ca(V)1.2-LQT8 channel gating in ventricular myocytes. METHODS AND RESULTS: Using a combination of molecular, imaging, and electrophysiological approaches, we discovered that Ca(V)1.2-LQT8 channels are abnormally coupled to AKAP150. A pathophysiological consequence of forming this aberrant ion channel-anchoring protein complex is enhanced Ca(V)1.2-LQT8 currents. This occurs through a mechanism whereby the anchoring protein functions like a subunit of Ca(V)1.2-LQT8 channels that stabilizes the open conformation and augments the probability of coordinated openings of these channels. Ablation of AKAP150 restores normal gating in Ca(V)1.2-LQT8 channels and protects the heart from arrhythmias. CONCLUSION: We propose that AKAP150-dependent changes in Ca(V)1.2-LQT8 channel gating may constitute a novel general mechanism for Ca(V)1.2-driven arrhythmias. PMID- 21700934 TI - The von Willebrand inhibitor ARC1779 reduces cerebral embolization after carotid endarterectomy: a randomized trial. AB - BACKGROUND AND PURPOSE: Inhibition of von Willebrand factor offers a novel approach to prevention of stroke and myocardial ischemia but has not yet been demonstrated to show efficacy on clinically relevant end points. ARC1779 is an aptamer that inhibits the prothrombotic function of von Willebrand factor by binding to the A1 domain of von Willebrand factor and thereby blocking its interaction with glycoprotein. Phase 1 studies suggest it inhibits platelet aggregation with less increase in bleeding than conventional antiplatelet agents. The effect of ARC 1779 on cerebral emboli immediately after carotid endarterectomy was investigated in a randomized clinical trial. METHODS: Patients undergoing carotid endarterectomy were randomized double-blind to ARC1779 or placebo administered intravenously. Transcranial Doppler recording, to detect cerebral embolic signals, was performed in the first 3 hours postoperatively. The primary end point was time to first embolic signals. RESULTS: Thirty-six patients were recruited, 18 in each arm. The Kaplan-Meier median time to first embolic signals was 83.6 minutes for ARC1779 compared with 5.5 minutes for placebo. Using Cox proportional hazards embolic signals occurred statistically significantly later on ARC1779 (P=0.007). Reduced embolic signals counts were correlated with inhibition of von Willebrand factor activity (P=0.03). Increased perioperative bleeding and anemia were seen with ARC1779. CONCLUSIONS: von Willebrand factor inhibition reduces thromboembolism in humans. It may play a role in treatment of stroke and myocardial ischemia. The extent to which bleeding complications occur in nonoperated patients needs to be assessed in further studies. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique identifier: NCT00742612. PMID- 21700935 TI - Adults with late stage 3 chronic kidney disease are at high risk for prevalent silent brain infarction: a population-based study. AB - BACKGROUND AND PURPOSE: The close relationship between stroke and chronic kidney disease (CKD) has been well-documented. However, few studies have focused on silent brain infarction (SBI) in CKD. We investigated the prevalence of SBI in different stages of CKD. METHODS: We included 1312 participants aged 30 to 93 years who came from either a random sample of residents or from a group of physically examined subjects in the same community. Basic information, clinical evaluations, laboratory tests, and MRI images were assessed. Subjects were divided into groups 1, 2, 3a, and 3b, corresponding to the estimated glomerular filtration rate (eGFR) levels of >= 90.0, 60.0 to 89.9, 45.0 to 59.9, and 30.0 to 44.9 mL/min/1.73 m2. RESULTS: The crude prevalence was 4.7%: 2.6% (20 of 759 subjects) in group 1; 6.3% (32 of 506) in group 2; 12.9% (4 of 31) in group 3a; and 37.5% (6 of 16) in group 3b (P<0.001). Additionally, SBI also correlated with age, male sex, hypertension, diabetes, moderate carotid plaque, higher blood pressures, obesity, and levels of triglyceride, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and uric acid (all P<0.05). The effects for SBI risk in each eGFR group versus group 1 did not increase except for group 3b (OR, 9.34; P<0.001). CONCLUSIONS: A close association exists between SBI and eGFR. We have found a significant increase in prevalence of SBI when eGFR is between 30.0 and 44.9 mL/min/1.73 m2. Adults with late stage 3 CKD are at high risk for prevalent SBI. PMID- 21700936 TI - A systematic review of stenting and angioplasty of symptomatic extracranial vertebral artery stenosis. AB - BACKGROUND AND PURPOSE: Extracranial vertebral artery stenosis (ECVAS) is common among patients with ischemic stroke. Despite the limited knowledge of the natural history of patients with symptomatic vertebral disease, endovascular revascularization techniques are now utilized in clinical practice. We sought to determine the risk of endovascular treatment for ECVAS with a systematic review of the literature. METHODS: A search strategy was used using the terms "stenting," "vertebral," "ostium," "origin," and "extracranial" through Medline. All articles were reviewed along with their references to determine the risk and durability of endovascular treatment. RESULTS: A total of 27 articles were identified that met inclusion criterion, with a total of 980 of 993 patients treated with stents. The majority of patients (56%) were noted to have contralateral vertebral artery stenosis or occlusion and 92% were symptomatic at the time of treatment. A total of 11 patients (1.1%) experienced a stroke and 8 (0.8%) experienced a transient ischemic attack within 30 days of the procedure. Drug-eluting stents were associated with lower restenosis rates (11%) compared to bare metal stents (30%) at a mean of 24 months of follow-up. CONCLUSIONS: Stenting and angioplasty of ECVAS appear to have a low rate of periprocedural stroke or transient ischemic attack and restenosis rates that may not be as high as suspected. Given the frequency of ECVAS as an etiology for ischemic stroke, future studies aimed at determining efficacy of this treatment modality relative to medical therapy would be of benefit to clinicians caring for these patients. PMID- 21700937 TI - Limited ability to activate protein C confers left atrial endocardium a thrombogenic phenotype: a role in cardioembolic stroke? AB - BACKGROUND AND PURPOSE: Atrial fibrillation is the most important risk factor for cardioembolic stroke. Thrombi form in the left atrial appendage rather than in the right. The causes of this different thrombogenicity are not well-understood. The goal herein was to compare the activation of the anticoagulant protein C and the thrombomodulin and endothelial protein C receptor/activated protein C receptor expression on the endocardium between right and left atria. METHODS: We harvested the atria of 6 monkeys (Macaca fascicularis) and quantified their ability to activate protein C ex vivo and we measured the thrombomodulin and endothelial protein C receptor expression by immunofluorescence. RESULTS: We found the ability to activate protein C decreased by half (P=0.028) and there was lower expression of thrombomodulin in the left atrial endocardium than the right (52.5+/-19.9 and 72.1+/-18.8 arbitrary intensity units, mean+/-standard deviation; P=0.028). No differences were detected in endothelial protein C receptor expression. CONCLUSIONS: Impaired protein C activation on the left atrial endocardium attributable to low thrombomodulin expression may explain its higher thrombogenicity and play a role in cardioembolic stroke. PMID- 21700938 TI - Osteopontin enhances endogenous repair after neonatal hypoxic-ischemic brain injury. AB - BACKGROUND AND PURPOSE: Hypoxic-ischemic (HI) brain injury is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. To identify molecules important for cerebral damage and repair, we investigated the growth factor-related gene expression profile after neonatal cerebral HI. We identified osteopontin (OPN) as the most highly upregulated factor early after HI. We therefore explored the role of endogenous OPN in brain damage and repair. METHODS: Nine-day-old wild-type mice were exposed to cerebral HI; growth factor related gene expression profiles were analyzed 1 to 7 days later by reverse transcriptase-polymerase chain reaction arrays. To determine the contribution of OPN to brain damage, we used p9 OPN(-/-) and wild-type mice. HI brain damage, sensorimotor function, and cell proliferation and differentiation were compared. RESULTS: Gene expression profiling of 150 genes related to growth factors and neurotrophins showed that expression of 52 genes changed during the first 7 days after HI. OPN was the gene with the strongest increase expression at all time points measured. We show here for the first time that in response to neonatal HI, OPN-deficient mice developed increased gray and white matter loss and more pronounced sensorimotor deficits as compared with wild-type littermates. Furthermore, OPN deficiency decreases HI-induced cell proliferation/survival and oligodendrogenesis without affecting neuronal differentiation. CONCLUSIONS: OPN plays an important role in repairing brain injury after neonatal HI by regulating cerebral cell proliferation/survival and oligodendrocyte differentiation after injury. The observed promyelinative effect of OPN may offer novel possibilities for a therapy targeting white matter injury. PMID- 21700939 TI - Insulin-like growth factor I serum levels influence ischemic stroke outcome. AB - BACKGROUND AND PURPOSE: Insulin-like growth factor I (IGF-I) is neuroprotective in animal models of stroke. We investigated whether serum IGF-I levels in patients with acute ischemic stroke influence stroke severity and outcome. METHODS: Concentrations of IGF-I and IGF binding protein 3 were measured in serum samples obtained within 6 hours after stroke onset from 255 patients who took part in the placebo arm of the United States and Canadian Lubeluzole in Acute Ischemic Stroke Study. Stroke severity was assessed with the National Institutes of Health Stroke Scale. Multivariate analysis was performed to assess the overall shift in modified Rankin Scale score and changes in the National Institutes of Health Stroke Scale score at 3 months. Survival curves were plotted using the Kaplan-Meier method, and the Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival. RESULTS: After controlling for statistically relevant risk factors, subjects with high IGF-I levels or IGF-I/IGF binding protein 3 ratios had a better neurological and functional outcome at 3 months. Baseline stroke severity was not different between high and low IGF-I groups. In contrast to the low IGF-I group, neurological symptoms gradually improved from Day 3 in the high IGF-I group. CONCLUSIONS: Our results suggest that high serum IGF-I levels just after ischemic stroke onset are associated with neurological recovery and a better functional outcome. PMID- 21700940 TI - Delayed paraplegia after spinal cord ischemic injury requires caspase-3 activation in mice. AB - BACKGROUND AND PURPOSE: Delayed paraplegia remains a devastating complication after ischemic spinal cord injury associated with aortic surgery and trauma. Although apoptosis has been implicated in the pathogenesis of delayed neurodegeneration, mechanisms responsible for the delayed paraplegia remain incompletely understood. The aim of this study was to elucidate the role of apoptosis in delayed motor neuron degeneration after spinal cord ischemia. METHODS: Mice were subjected to spinal cord ischemia induced by occlusion of the aortic arch and left subclavian artery for 5 or 9 minutes. Motor function in the hind limb was evaluated up to 72 hours after spinal cord ischemia. Histological studies were performed to detect caspase-3 activation, glial activation, and motor neuron survival in the serial spinal cord sections. To investigate the impact of caspase-3 activation on spinal cord ischemia, outcome of the spinal cord ischemia was examined in mice deficient for caspase-3. RESULTS: In wild-type mice, 9 minutes of spinal cord ischemia caused immediate paraplegia, whereas 5 minutes of ischemia caused delayed paraplegia. Delayed paraplegia after 5 minutes of spinal cord ischemia was associated with histological evidence of caspase-3 activation, reactive astrogliosis, microglial activation, and motor neuron loss starting at approximately 24 to 48 hours after spinal cord ischemia. Caspase-3 deficiency prevented delayed paraplegia and motor neuron loss after 5 minutes of spinal cord ischemia, but not immediate paraplegia after 9 minutes of ischemia. CONCLUSIONS: The present results suggest that caspase-3 activation is required for delayed paraplegia and motor neuron degeneration after spinal cord ischemia. PMID- 21700941 TI - Oxidative damage in ischemic stroke revealed using multiple biomarkers. AB - BACKGROUND AND PURPOSE: We investigated changes in oxidative damage after ischemic stroke using multiple biomarkers. METHODS: Serial blood and urine samples of ischemic stroke subjects and age-matched control subjects were assayed for F2-isoprostanes, hydroxyeicosatetraenoic acid products, F4-neuroprostanes, 24 hydroxycholesterol, allantoin, and urate. RESULTS: Sixty-six stroke subjects (mean age, 65 years; median National Institutes of Health Stroke Scale 17) and 132 control subjects were recruited. A bimodal pattern of change was observed in plasma and urinary F2-isoprostanes and plasma 24-hydroxycholesterol. The rise in plasma hydroxyeicosatetraenoic acid products, F4-neuroprostanes, and allantoin was highest 6 to 12 hours after stroke onset, whereas plasma urate was significantly lower than controls on Days 1 to 3. After adjusting for age and baseline National Institutes of Health Stroke Scale, baseline plasma esterified hydroxyeicosatetraenoic acid products (OR, 1.01; 95% CI, 1.01 to 1.02), plasma urate (1.01; 1.00 to 1.01), and plasma free F4-neuroprostanes (2.73; 1.76 to 3.93) were associated with 90-day good functional recovery (modified Rankin Scale <=1). CONCLUSIONS: Multiple markers of oxidative damage are increased immediately after stroke and remain elevated for several days. Recognition of these temporal changes may help design better antioxidant treatment trials for acute ischemic stroke. PMID- 21700943 TI - The decline in stroke mortality: exploration of future trends in 7 Western European countries. AB - BACKGROUND AND PURPOSE: This article aims to make projections of future trends in stroke mortality in the Year 2030 based on recent trends in stroke mortality in 7 Western European countries. METHODS: Mortality data were obtained from national cause of death registries. Annual rates of decline in stroke mortality of 1980 to 2005 were determined for men and women in the United Kingdom, France, the Netherlands, and 4 Nordic countries on the basis of regression analysis. Estimated rates of decline were extrapolated until 2030. Cause-elimination life tables were used to determine the effect of stroke in 2030 in terms of potential gain in life expectancy. The absolute numbers of stroke deaths in 2030 were estimated using national population projections of Eurostat. RESULTS: In all countries, stroke mortality rates declined incessantly until 2005 among both men and women. If these trends were to continue, age-adjusted mortality rates would decline by approximately half between 2005 and 2030 with larger declines in France (approximately two thirds) and smaller declines in the Netherlands, Denmark, and Sweden (approximately one fourth). Similar rates of decline would be observed in terms of potential gain in life expectancy. Because of population aging, the absolute number of stroke deaths would decline slowly in the United Kingdom and France and stabilize or even increase in other countries. CONCLUSIONS: In the near future, stroke may lose much of its effects on life expectancy but remain a frequent cause of death among elderly populations. The prevention of stroke-related disability instead of mortality may become increasingly more important. PMID- 21700942 TI - Successful microbubble sonothrombolysis without tissue-type plasminogen activator in a rabbit model of acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Microbubbles (MB) combined with ultrasound (US) have been shown to lyse clots without tissue-type plasminogen activator (tPA) both in vitro and in vivo. We evaluated sonothrombolysis with 3 types of MB using a rabbit embolic stroke model. METHODS: New Zealand White rabbits (n=74) received internal carotid angiographic embolization of single 3-day-old cylindrical clots (0.6 * 4.0 mm). Groups included: (1) control (n=11) embolized without treatment; (2) tPA (n=20); (3) tPA+US (n=10); (4) perflutren lipid MB+US (n=16); (5) albumin 3 MUm MB+US (n=8); and (6) tagged albumin 3 MUm MB+US (n=9). Treatment began 1 hour postembolization. Ultrasound was pulsed-wave (1 MHz; 0.8 W/cm2) for 1 hour; rabbits with tPA received intravenous tPA (0.9 mg/kg) over 1 hour. Lipid MB dose was intravenous (0.16 mg/kg) over 30 minutes. Dosage of 3 MUm MB was 5 * 109 MB intravenously alone or tagged with eptifibatide and fibrin antibody over 30 minutes. Rabbits were euthanized at 24 hours. Infarct volume was determined using vital stains on brain sections. Hemorrhage was evaluated on hematoxylin and eosin sections. RESULTS: Infarct volume percent was lower for rabbits treated with lipid MB+US (1.0%+/- 0.6%; P=0.013), 3 MUm MB+US (0.7% +/- 0.9%; P=0.018), and tagged 3 MUm MB+US (0.8% +/- 0.8%; P=0.019) compared with controls (3.5%+/- 0.8%). The 3 MB types collectively had lower infarct volumes (P=0.0043) than controls. Infarct volume averaged 2.2% +/- 0.6% and 1.7%+/- 0.8% for rabbits treated with tPA alone and tPA+US, respectively (P=nonsignificant). CONCLUSIONS: Sonothrombolysis without tPA using these MB is effective in decreasing infarct volumes. Study of human application and further MB technique development are justified. PMID- 21700945 TI - Effects of blood pressure lowering on major vascular events among patients with isolated diastolic hypertension: the perindopril protection against recurrent stroke study (PROGRESS) trial. AB - BACKGROUND AND PURPOSE: Despite clear evidence that blood pressure (BP) lowering is effective for prevention of cardiovascular events among patients with isolated systolic hypertension and systolic-diastolic hypertension, there is ongoing uncertainty about its effects in those with isolated diastolic hypertension. The objective of the present analysis is to determine whether BP lowering provides benefits to patients with isolated diastolic hypertension. METHODS: Patients with cerebrovascular disease and hypertension at baseline (n=4283) were randomly assigned to either active treatment (perindopril in all participants plus indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo(s). The primary outcome was total major vascular events. RESULTS: There were 1923 patients with isolated systolic hypertension (systolic BP >= 140 mm Hg and diastolic BP < 90 mm Hg), 315 with isolated diastolic hypertension (systolic BP <140 mm Hg and diastolic BP >= 90 mm Hg), and 2045 with systolic-diastolic hypertension (systolic BP >= 140 mm Hg and diastolic BP >= 90 mm Hg) at baseline. Active treatment reduced the relative risk of major vascular events by 27% (95% CI, 10% to 41%) among patients with isolated systolic hypertension, by 28% (-29% to 60%) among those with isolated diastolic hypertension, and by 32% (17% to 45%) among those with systolic-diastolic hypertension. There was no evidence of differences in the magnitude of the effects of treatment among different types of hypertension (P homogeneity=0.89). CONCLUSIONS: BP lowering is likely to provide a similar level of protection against major vascular events for patients with isolated diastolic hypertension as for those with isolated systolic hypertension and systolic-diastolic hypertension. Clinical Trial Registration Information- This trial was not registered because patients were enrolled before July 1, 2005. PMID- 21700944 TI - Comparison of plasmin with recombinant tissue-type plasminogen activator in lysis of cerebral thromboemboli retrieved from patients with acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Plasmin is a direct-acting thrombolytic with a better safety profile than recombinant tissue-type plasminogen activator (rtPA) in animal models. With the application of retrieval devices for managing acute ischemic stroke, extracted thromboemboli are available for ex vivo examination. We ask whether such thrombi are amenable to plasmin thrombolysis and whether such activity is different with rtPA. METHODS: Thromboembolic fragments (total 29) were retrieved from the intracranial carotid artery system of 15 patients with acute ischemic stroke and randomly assigned to ex vivo thrombolysis with plasmin or rtPA. After an initial 2-hour exposure, residual material was exposed to the other agent for an additional 2 hours. Thrombolysis was quantified by change in thrombus area and released d-dimer. RESULTS: Plasmin induced significant ex vivo thrombolysis of cerebral arterial thromboemboli, decreasing area by 45.9% +/- 29.4% and 69.2% +/- 52.5% and inducing median D-dimer release of 108,180 MUg/L (range, 16,780 to 668,050 MUg/L) and 16,905 MUg/L (range, 240 to 403 085 MUg/L) during the first and second 2-hour incubation periods, respectively. These changes were not different from those obtained with rtPA, which decreased area by 34.7% +/- 57.8% (P=0.63) and by 68.4% +/- 26.9% (P=0.97) and induced median D dimer release of 151,990 MUg/L (range, 9870 to 338,350 MUg/L; P=0.51) and 34,520 MUg/L (range 3794 to 325,400 MUg/L; P=0.19) during the first and second 2-hour incubations. CONCLUSIONS: Retrieved human cerebral thromboemboli were amenable to ex vivo lysis by plasmin, the rate and degree of which was not different than that achieved with rtPA. PMID- 21700946 TI - The 12-month effects of early motivational interviewing after acute stroke: a randomized controlled trial. AB - BACKGROUND AND PURPOSE: The purpose of this study was to determine whether motivational interviewing (MI), a patient-centered counseling technique, can benefit patients' mood and mortality poststroke. METHODS: This was a single center, open, randomized, controlled trial. The setting was a hospital with a stroke unit. Four hundred eleven consecutive patients on the stroke register were >18 years old, not known to be moving out-of-area postdischarge, not receiving psychiatric or clinical psychology intervention, and were without severe cognitive or communication problems preventing participation in interviews. All patients received usual stroke care. Patients in the intervention group also received 4 individual, weekly sessions of MI. The primary outcome was the proportion of patients with normal mood measured by the 28-item General Health Questionnaire (normal <5; low >=5) using a mailed questionnaire at 12 months poststroke. RESULTS: At 12-month follow-up (including imputed data), 37.7% patients in the control group and 48.0% patients in the intervention group had normal mood. Twenty-five (12.8%) of 195 patients in the control group and 13 (6.5%) of 199 patients in the intervention group had died. A significant benefit of motivational interviewing over usual stroke care was found for mood (P=0.020; OR, 1.66; 95% CI, 1.08 to 2.55) and mortality (P=0.035; OR, 2.14; 95% CI, 1.06 to 4.38). CONCLUSIONS: Results suggest that motivational interviewing improves patients' mood and reduces mortality 12 months poststroke. CLINICAL TRIAL REGISTRATION: URL: www.controlled-trials.com. Unique identifier: ISRCTN54465472. PMID- 21700947 TI - Oxfordshire community stroke project classification poorly differentiates small cortical and subcortical infarcts. AB - BACKGROUND AND PURPOSE: The Oxfordshire Community Stroke Project (OCSP) is a common clinical stroke classification tool. We evaluated the accuracy of OCSP classification with a prospective magnetic resonance imaging (MRI) study. METHODS: Stroke/transient ischemic attack patients presenting within 48 hours of onset were included in the study (n=130). Following computed tomography scan, OCSP classification, total anterior circulation infarcts (TACI), partial anterior circulation infarcts (PACI), lacunar circulation infarcts (LACI), and posterior circulation infarcts (POCI) were performed by 3 independent examiners. All patients underwent diffusion-weighted MRI with planimetric volume measurement and classification into OCSP categories, organized by lesion location. RESULTS: Patients were clinically classified as TACI (12 patients), PACI (62 patients), LACI (38 patients), and POCI (18 patients). In 101 patients with diffusion weighted MRI lesions, correct classification rates were: TACI (83.3%), PACI (83%), LACI (39%), and POCI (86%). OCSP had the following sensitivity (SE), specificity (SP), and positive predictive value (PPV): TACI (SE, 100%; SP, 98%; PPV, 83%), PACI (SE, 73%; SP, 78%; PPV, 83%), LACI (SE, 47%; SP, 83%; PPV, 39%), and POCI (SE, 92%; SP, 98%; PPV, 86%). Sixty-one percent of patients in the LACI group had radiographic appearances consistent with PACI, and 15% of those classified as PACI had lacunar infarcts. No differences in stroke severity existed between patients classified correctly (median National Institutes of Health Stroke Scale [NIHSS]=4; interquartile range [IQR]=7) or incorrectly (median NIHSS=3; IQR=3). Patients classified correctly had larger infarct volume (median=6.75 mL; IQR=33.2) than did those who were incorrectly classified (1.86 mL; IQR=5; P=0.008). CONCLUSIONS: OCSP classification does not permit accurate discrimination between lacunar and small-volume cortical infarcts. Differential patterns of investigation for stroke etiology should not be based solely on clinical criteria. PMID- 21700949 TI - At the source: treating heart failure by altering muscle motor function. PMID- 21700948 TI - The beat goes on: human heart muscle from pluripotent stem cells. PMID- 21700950 TI - Disease pathways and novel therapeutic targets in hypertrophic cardiomyopathy. AB - As described in earlier reviews in this series on the molecular basis of hypertrophic cardiomyopathy (HCM), HCM is one of the archetypal monogenic cardiovascular disorders to be understood at the molecular level. Twenty years after the discovery of the first HCM disease gene, genetic studies still confirm that HCM is principally a disease of the sarcomere. At the biophysical level, myofilament mutations generally enhance Ca(2+) sensitivity, maximal force production, and ATPase activity. These defects ultimately appear to converge on energy deficiency and altered Ca(2+) handling as major common paths leading to the anatomic (hypertrophy, myofiber disarray, and fibrosis) and functional features (pathological signaling and diastolic dysfunction) characteristic of HCM. In this review, we provide an account of the consequences of HCM mutations and describe how specifically targeting these molecular features has already yielded early promise for novel therapies for HCM. Although substantial efforts are still required to understand the molecular link between HCM mutations and their clinical consequences, HCM endures as an exemplar of how novel insights derived from molecular characterization of Mendelian disorders can inform the understanding of biological processes and translate into rational therapies. PMID- 21700951 TI - Phenotypic manifestations of mutations in genes encoding subunits of cardiac potassium channels. AB - Since 1995, when a potassium channel gene, hERG (human ether-a-go-go-related gene), now referred to as KCNH2, encoding the rapid component of cardiac delayed rectifier potassium channels was identified as being responsible for type 2 congenital long-QT syndrome, a number of potassium channel genes have been shown to cause different types of inherited cardiac arrhythmia syndromes. These include congenital long-QT syndrome, short-QT syndrome, Brugada syndrome, early repolarization syndrome, and familial atrial fibrillation. Genotype-phenotype correlations have been investigated in some inherited arrhythmia syndromes, and as a result, gene-specific risk stratification and gene-specific therapy and management have become available, particularly for patients with congenital long QT syndrome. In this review article, the molecular structure and function of potassium channels, the clinical phenotype due to potassium channel gene mutations, including genotype-phenotype correlations, and the diverse mechanisms underlying the potassium channel gene-related diseases will be discussed. PMID- 21700952 TI - Microparticles in angiogenesis: therapeutic potential. AB - Considered during the past decades as cell dust, microparticles are now deemed true biomarkers and vectors of biological information between cells. Depending on their origin, the composition of microparticles varies and the subsequent message transported by them, such as proteins, mRNA, or miRNA, can differ. Recent studies have described microparticles as "cargos" of deleterious information in blood vessel wall under pathological situations such as hypertension, myocardial infarction, and metabolic syndrome. In addition, it has been reported that depending on their origin, microparticles also possess a therapeutic potential regarding angiogenesis. Microparticles can act directly through the interaction ligand/receptor or indirectly on angiogenesis by modulating soluble factor production involved in endothelial cell differentiation, proliferation, migration, and adhesion; by reprogramming endothelial mature cells; and by inducing changes in levels, phenotype, and function of endothelial progenitor cells. This results in an increase in formation of in vitro capillary-like tubes and the generation of new vessels in vivo under ischemic conditions, for instance. Taking into consideration these properties of microparticles, recent evidence provides new basis to expand the possibility that microparticles might be used as therapeutic tools in pathologies associated with an alteration of angiogenesis. PMID- 21700953 TI - The spatial tuning of "motion streak" mechanisms revealed by masking and adaptation. AB - We previously reported that fast-moving dot arrays cause orientation-tuned masking of static gratings (D. Apthorp, J. Cass, & D. Alais, 2010), which we attribute to "motion streaks." Using similar "streaky" dot motion, we describe spatial frequency tuning of grating threshold elevations caused by masking (Experiment 1) and adaptation (Experiment 2) to motion. To compare the streaks with psychophysical tunings, we Fourier analyzed time-averaged translating dots, which were bandpass (peaking at ~2.3 c/deg). Masking, however, was strongest at lower test frequencies (<=1 c/deg) and largely isotropic over orientation, although a small orientation-tuned effect occurred at ~1.2 c/deg. Results were broadly similar across monoptic and dichoptic conditions. Adaptation to fast motion produced spatially bandpass threshold elevations for parallel test gratings, peaking slightly lower than the peak Fourier frequency, with little elevation below 1 c/deg (unlike the low-pass elevation resulting from masking). Slow adaptation produced little elevation for parallel gratings. For orthogonal test gratings, fast motion adaptation produced low-pass threshold elevations and slow motion produced bandpass elevations, suggesting that separable mechanisms process fast (streaky) and slow motion. The different threshold elevation patterns over spatial frequency for masking and adaptation suggest that the adaptation effects are mainly within-channel suppression, whereas the masking effects may be mainly due to between-channel suppression. PMID- 21700954 TI - Lipoprotein subclass abnormalities and incident hypertension in initially healthy women. AB - BACKGROUND: Abnormalities in traditional lipids, particularly decreased HDL cholesterol and increased triglycerides, can precede the onset of hypertension. Whether lipoprotein particle size or subclass concentrations play a role in the development of hypertension is unknown. METHODS: We followed 17 527 initially healthy women without baseline hypertension prospectively for 8 years. At baseline, information regarding traditional lipids and hypertension risk factors was obtained, and lipoprotein size and subclass concentrations were measured by nuclear magnetic resonance spectroscopy. RESULTS: Baseline lipoprotein size and subclass concentrations were significantly associated with incident hypertension. Although LDL cholesterol was not associated with hypertension [odds ratio (OR) for quintile 5 vs 1: 1.08 (95% CI 0.96-1.20)], increased concentrations of LDL particles were associated with greater risk [OR 1.73 (1.54-1.95)], especially small LDL particles [OR 1.62 (1.45-1.83)]. Increased HDL cholesterol was associated with lower risk of hypertension [OR for quintile 5 vs 1: 0.79 (0.70 0.89)]. By contrast, increased concentrations of HDL particles had greater risk [OR 1.48 (1.32-1.67)], especially small HDL particles [OR 1.36 (1.22-1.53)], whereas large HDL particles had lower risk [OR 0.80 (0.71-0.90)]. Triglycerides and triglyceride-rich VLDL particles were positively associated with hypertension, with large VLDL particles associated with greater risk [OR 1.68 (1.50-1.89)]. Adding particle subclasses improved discrimination over a model with traditional lipids and risk factors (c-statistic 0.671 compared to 0.676; P < 0.001). CONCLUSIONS: In this study of initially healthy women, lipoprotein particle size and subclass concentrations were associated with incident hypertension and provided additive information to traditional lipids and risk factors. PMID- 21700955 TI - DNA methylation of tumor suppressor and metastasis suppressor genes in circulating tumor cells. AB - BACKGROUND: Circulating tumor cells (CTCs) are associated with prognosis in a variety of human cancers and have been proposed as a liquid biopsy for follow-up examinations. We show that tumor suppressor and metastasis suppressor genes are epigenetically silenced in CTCs isolated from peripheral blood of breast cancer patients. METHODS: We obtained peripheral blood from 56 patients with operable breast cancer, 27 patients with verified metastasis, and 23 healthy individuals. We tested DNA extracted from the EpCAM-positive immunomagnetically selected CTC fraction for the presence of methylated and unmethylated CST6, BRMS1, and SOX17 promoter sequences by methylation-specific PCR (MSP). All samples were checked for KRT19 (keratin 19, formerly CK-19) expression by reverse-transcription quantitative PCR. RESULTS: In CTCs of patients with operable breast cancer, promoter methylation of CST6 was observed in 17.9%, BRMS1 in 32.1%, and SOX17 in 53.6% of patients. In CTCs of patients with verified metastasis, promoter methylation of CST6 was observed in 37.0%, BRMS1 in 44.4%, and SOX17 in 74.1%. In healthy individuals, promoter methylation of CST6 was observed in 4.3%, BRMS1 in 8.7%, and SOX17 in 4.3%. DNA methylation of these genes for both operable and metastatic breast cancer was significantly different from that of the control population. CONCLUSIONS: DNA methylation of tumor suppressor and metastasis suppressor genes is a hallmark of CTCs and confirms their heterogeneity. Our findings add a new dimension to the molecular characterization of CTCs and may underlie the acquisition of malignant properties, including their stem-like phenotype. PMID- 21700956 TI - High-sensitivity cardiac troponin I measurement for risk stratification in a stable high-risk population. AB - BACKGROUND: Past investigations regarding the utility of high-sensitivity cardiac troponin I (cTnI) assays have been focused primarily on the acute coronary syndrome setting. We assessed whether such assays can predict future ischemic cardiovascular events in a stable high-risk population. METHODS: We quantified serum cTnI using an investigational high-sensitivity assay (hs-cTnI IUO, Beckman Coulter) in 2572 participants from the Heart Outcomes Prevention Evaluation (HOPE) study. The derived ROC curve cutoff and the 99th percentile for the hs cTnI assay were assessed by Kaplan-Meier and Cox analyses for the primary outcome [composite of myocardial infarction (MI), stroke, and cardiovascular death] at 4.5 years of follow-up. We also assessed individual outcomes (MI, stroke, cardiovascular death) and the combined outcome (MI/cardiovascular death) by regression analyses to determine hazard ratios (HRs) and c statistics in models that included established risk factors, C-reactive protein, and N-terminal pro-B type natriuretic peptide (NT-proBNP). RESULTS: Participants with hs-cTnI >6 ng/L (ROC cutoff) were at higher risk for the primary outcome (HR 1.38, 95% CI 1.09 1.76; P = 0.008, adjusted models). For the individual outcomes, participants with hs-cTnI above the 99th percentile (>=10 ng/L) had higher risk for cardiovascular death (HR 2.15, 95% CI 1.32-3.52; P = 0.002) and MI (HR 1.49, 95% CI 1.05-2.10; P = 0.025) but not stroke (HR 1.38, 95% CI 0.76-2.47; P = 0.288, adjusted models). Addition of hs-cTnI to an established risk model with NT-proBNP also yielded a higher c statistic for the combined outcome of MI/cardiovascular death. CONCLUSIONS: The investigational Beckman Coulter hs-cTnI assay provides prognostic information for future MI and cardiovascular death in a stable high risk population. PMID- 21700957 TI - Published and perished? The influence of the searched protein database on the long-term storage of proteomics data. AB - In proteomics, protein identifications are reported and stored using an unstable reference system: protein identifiers. These proprietary identifiers are created individually by every protein database and can change or may even be deleted over time. To estimate the effect of the searched protein sequence database on the long-term storage of proteomics data we analyzed the changes of reported protein identifiers from all public experiments in the Proteomics Identifications (PRIDE) database by November 2010. To map the submitted protein identifier to a currently active entry, two distinct approaches were used. The first approach used the Protein Identifier Cross Referencing (PICR) service at the EBI, which maps protein identifiers based on 100% sequence identity. The second one (called logical mapping algorithm) accessed the source databases and retrieved the current status of the reported identifier. Our analysis showed the differences between the main protein databases (International Protein Index (IPI), UniProt Knowledgebase (UniProtKB), National Center for Biotechnological Information nr database (NCBI nr), and Ensembl) in respect to identifier stability. For example, whereas 20% of submitted IPI entries were deleted after two years, virtually all UniProtKB entries remained either active or replaced. Furthermore, the two mapping algorithms produced markedly different results. For example, the PICR service reported 10% more IPI entries deleted compared with the logical mapping algorithm. We found several cases where experiments contained more than 10% deleted identifiers already at the time of publication. We also assessed the proportion of peptide identifications in these data sets that still fitted the originally identified protein sequences. Finally, we performed the same overall analysis on all records from IPI, Ensembl, and UniProtKB: two releases per year were used, from 2005. This analysis showed for the first time the true effect of changing protein identifiers on proteomics data. Based on these findings, UniProtKB seems the best database for applications that rely on the long-term storage of proteomics data. PMID- 21700958 TI - Pharmacological characterization of adenosine receptors on isolated human bronchi. AB - Adenosine induces airways obstruction in subjects with asthma, but the receptor subtype responsible remains unknown. The objectives of this study were to determine the pharmacological profile of adenosine receptor subtypes mediating contraction and to investigate the mechanism in normal and passively sensitized human airway tissues. Contraction of bronchial rings isolated from resected lung tissue of patients with lung carcinoma was measured in response to nonselective adenosine receptor agonists, 5-AMP and 5'-(N-Ethylcarboxamido)adenosine, and A(1) receptor agonist, N(6)-cyclopentyladenosine, in the absence and presence of selective adenosine receptor antagonists. Pharmacological antagonists, chemical ablation of airway sensory nerves using capsaicin, and passive sensitization of tissue with serum from subjects with atopy and asthma was used to investigate the mechanism of contraction. Human bronchial tissue contracted in a concentration dependent manner to adenosine agonists that showed a rank order of activity of A(1) > A(2B) >> A2(A) = A3. The maximum contractile response to N(6) cyclopentyladenosine (231.0 +/- 23.8 mg) was significantly reduced in tissues chemically treated with capsaicin to desensitize sensory nerves (desensitized: 101.6 +/- 15.2 mg; P < 0.05). Passive sensitization significantly augmented the contraction induced by adenosine A(1) receptor activation (sensitized: 389.7 +/- 52.8 mg versus nonsensitized; P < 0.05), which was linked to the release of leukotrienes, and not histamine (MK571: 25.5 +/- 1.7 mg; epinastine 260.0 +/- 22.2 mg versus control; P < 0.05). This study provides evidence for a role for adenosine A(1) receptors in eliciting human airway smooth muscle constriction, which, in part, is mediated by the action of capsaicin sensitive sensory nerves. PMID- 21700960 TI - Trustworthy clinical guidelines--how do we measure up? PMID- 21700961 TI - Microbial contamination of parenteral nutrition--how could it happen? PMID- 21700959 TI - The milieu of damaged alveolar epithelial type 2 cells stimulates alveolar wound repair by endogenous and exogenous progenitors. AB - Alveolar epithelial integrity is dependent upon the alveolar milieu, yet the milieu of the damaged alveolar epithelial cell type 2 (AEC2) has been little studied. Characterization of its components may offer the potential for ex vivo manipulation of stem cells to optimize their therapeutic potential. We examined the cytokine profile of AEC2 damage milieu, hypothesizing that it would promote endogenous epithelial repair while recruiting cells from other locations and instructing their engraftment and differentiation. Bronchoalveolar lavage and lung extract from hyperoxic rats represented AEC2 in vivo damage milieu, and medium from a scratch-damaged AEC2 monolayer represented in vitro damage. CINC-2 and ICAM, the major cytokines detected by proteomic cytokine array in AEC2 damage milieu, were chemoattractive to normoxic AECs and expedited in vitro wound healing, which was blocked by their respective neutralizing antibodies. The AEC2 damage milieu was also chemotactic for exogenous uncommitted human amniotic fluid stem cells (hAFSCs), increasing migration greater than 20-fold. hAFSCs attached within an in vitro AEC2 wound and expedited wound repair by contributing cytokines migration inhibitory factor and plasminogen activator inhibitor 1 to the AEC2 damage milieu, which promoted wound healing. The AEC2 damage milieu also promoted differentiation of a subpopulation of hAFSCs to express SPC, TTF-1, and ABCA3, phenotypic markers of distal alveolar epithelium. Thus, the microenvironment created by AEC2 damage not only promotes autocrine repair but also can attract uncommitted stem cells, which further augment healing through cytokine secretion and differentiation. PMID- 21700962 TI - The drug shortage crisis. PMID- 21700963 TI - Parenteral nutrition electrolyte/mineral product shortage considerations. PMID- 21700964 TI - Comment on Monod et al: "Ethical issues in nutrition support of severely disabled elderly persons". PMID- 21700965 TI - Pure oats and the gluten-free diet: are they safe? PMID- 21700966 TI - omega-3 Fatty acids have no impact on serum lactate levels after major gastric cancer surgery. AB - BACKGROUND: Preoperative and intraoperative nutrition support in patients undergoing major surgery results in decreased incidence of morbidity and mortality. Studies investigating the role of omega-3 fatty acids in these patients are increasing. Some are focused on perfusion at the cellular level. This study was undertaken to address the effect of postoperative administration of omega-3 fatty acids on cellular hypoperfusion associated with major gastric surgery. METHODS: Twenty-six patients undergoing gastric cancer surgery were randomly assigned to receive parenteral nutrition (PN) supplemented with a combination of omega-6 and omega-3 fatty acids (Omegaven, 0.2 g/kg/d; Lipovenoes 10%, 0.6 g/kg/d) or with omega-6 fatty acid (Lipovenoes 10%, 0.8 g/kg/d) for 5 days. Blood samples were taken preoperatively, postoperative day 1, and on the last day of PN therapy (day 5). RESULTS: Patients receiving omega-3 and omega-6 fatty acids showed neither lower serum lactate levels nor lower rates of complications compared with patients receiving omega-6 only. There were no statistically significant differences between the groups in other biochemical parameters, complications, or length of hospital stay or mortality. CONCLUSION: PN with omega-3 fatty acid supplementation does not have a significant impact on cellular hypoperfusion and lactate clearance after major gastric surgery. PMID- 21700967 TI - A new enteral diet, MHN-02, which contains abundant antioxidants and whey peptide, protects against carbon tetrachloride-induced hepatitis. AB - BACKGROUND: Inflammatory or oxidative stress is related to various diseases, including not only inflammatory diseases, but also diabetes, cancer, and atherosclerosis. The aim of this study was to evaluate the anti-inflammatory effects of a new enteral diet, MHN-02, which contains abundant antioxidants and whey peptide. The study also investigated the ability of MHN-02 to attenuate lethality, liver injury, the production of inflammatory cytokines, and the production of oxidized products using a carbon tetrachloride-induced rat model of severe fulminant hepatitis. METHODS: Male Sprague-Dawley rats were fed either a control diet or the MHN-02 diet for 14 days and injected with 2 mL/kg of carbon tetrachloride. Survival of rats was monitored from day 0 to day 3. To evaluate liver injury, inflammation, and oxidative stress, blood and liver samples were collected, and aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, interleukin 6, tumor necrosis factor-alpha, and superoxide dismutase activity as a free radical scavenger were measured. A portion of the liver was evaluated histologically. RESULTS: The survival rates of rats receiving the MHN-02 diet and the control diet were 90% and 55%, respectively. In the MHN 02 diet group, levels of serum liver enzymes and serum cytokines were significantly lower than in the control group. Superoxide dismutase activity in the MHN-02 diet was significantly higher in the MHN-02 group. Pathological lesions were significantly larger in the control group. CONCLUSION: Supplementation of enteral diets containing whey peptide and antioxidants may protect against severe hepatitis. PMID- 21700969 TI - Patterns of fat stranding. PMID- 21700968 TI - Verification of an electromagnetic placement device compared with abdominal radiograph to predict accuracy of feeding tube placement. AB - BACKGROUND: Use of an electromagnetic placement device (EMPD) facilitates placement of feeding tubes at the bedside. Standard practice for verification of feeding tube placement is via radiographic confirmation. The purpose of this research study was to assess the accuracy of placement of small-bore feeding tubes (SBFTs) as determined by EMPD interpretation compared with that of abdominal radiograph verification by a radiologist. METHODS: This multicenter prospective study enrolled patients requiring bedside feeding tube placement. SBFTs were placed by an experienced investigator using the EMPD. Two abdominal radiographs were then obtained: one after initial SBFT placement and an additional radiograph after injection of contrast. Documentation of location based on clinician interpretation using the EMPD was then compared with radiologist interpretation. RESULTS: The final sample size was 194 patients, including 18 pediatric patients. Patient age ranged from 12 days to 102 years. Median time for tube placement was 12 minutes. Of the 194 patients, only 1 patient had data showing discrepancies between the original EMPD verification and the final abdominal radiograph interpretation, providing a 99.5% agreement. No patient experienced complications during SBFT placement, and 15 patients had inadvertent airway placement that was avoided with the use of the EMPD. CONCLUSIONS: There was a high percentage of agreement between EMPD and radiologic interpretation after contrast injection. The EMPD aided in avoiding inadvertent airway placement, with no patient complications. This device can be used safely at the bedside to facilitate placement of feeding tubes, leading to the delivery of early enteral nutrition. PMID- 21700970 TI - MDCT of variations and anomalies of the neural arch and its processes: part 1- pedicles, pars interarticularis, laminae, and spinous process. AB - OBJECTIVE: The purpose of this pictorial essay is to review the anatomic variations and congenital anomalies of the neural arch and its processes as seen on MDCT images of the spine. CONCLUSION: Variations and anomalies of the pedicles, pars interarticularis, laminae, and spinous processes may be readily identified on MDCT studies. Familiarity with their MDCT appearances is required for characterization and differential diagnosis and may help assess their potential clinical relevance. PMID- 21700971 TI - MDCT of variations and anomalies of the neural arch and its processes: part 2- articular processes, transverse processes, and high cervical spine. AB - OBJECTIVE: The purpose of this pictorial essay is to review the variations and anomalies of the neural arch and its processes with a focus on the articular and transverse processes. We also discuss variations and anomalies of the neural arch at the high cervical spine. CONCLUSION: Variations and anomalies of the neural arch and its processes may be identified on MDCT studies. Familiarity with their MDCT appearances is required for characterization and may help evaluate their potential clinical relevance. PMID- 21700972 TI - Ultrasound-guided intervention around the hip joint. AB - OBJECTIVE: The purpose of this article is to review some of the most common reasons for ultrasound intervention around the hip joint, and describe the techniques involved. CONCLUSION: Ultrasound alleviates the need for exposure to radiation and is already the modality of choice for aspiration of the hip joint, an intervention that may be helpful in guiding antimicrobial therapy and help avoid the need for surgical intervention. Ultrasound can also be used to access the hip for diagnostic or therapeutic injection. PMID- 21700973 TI - Radiographic and CT evaluation of recombinant human bone morphogenetic protein-2 assisted spinal interbody fusion. AB - OBJECTIVE: Bone morphogenetic proteins BMPs, when used in spinal fusion, hasten healing and initiate distinct imaging features. We undertook a study to record and analyze the radiographic and CT changes after the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion surgery. MATERIALS AND METHODS: This study included 95 patients who underwent spinal interbody fusion using rhBMP-2. The lumbar spine fusion cohort consisted of 23 patients who underwent anterior lumbar interbody fusion, 36 patients who underwent transforaminal lumbar interbody fusion, and two patients who underwent posterior lumbar interbody fusion. The remaining 34 patients underwent anterior cervical decompression and fusion. RESULTS: A polyetheretherketone cage was used as an interbody spacer in 59 patients (82 levels) and an allograft bone was the spacer in 36 patients (55 levels). Patients were evaluated 2 and 6 weeks after the procedure and then 3, 6, 12, and 24 months after the procedure. All patients underwent radiography at every follow-up visit, and CT evaluation was performed in 32 patients. CONCLUSION: Features observed on imaging that we attributed to the use of rhBMP-2 included an enhanced fusion rate and an increased incidence of prevertebral soft-tissue swelling in patients who underwent cervical fusion. Endplate resorption was observed in 100% of patients who underwent cervical fusion and in 82% of the lumbar levels. Subsidence of the cage resulting in narrowing of the disk space was seen in more than 50% of cases. Cage migration and heterotopic bone formation in the spinal canal and neural foramen occurred maximally in the lumbar spine of patients in whom a polyetheretherketone cage was placed using a transforaminal approach. PMID- 21700974 TI - New MRI grading system for the cervical canal stenosis. AB - OBJECTIVE: The purpose of this study was to propose a new MRI grading system for cervical canal stenosis and to evaluate the reproducibility of the system. MATERIALS AND METHODS: Cervical canal stenosis was classified according to the T2 weighted sagittal images into the following grades: grade 0, absence of canal stenosis; grade 1, subarachnoid space obliteration exceeding 50%; grade 2, spinal cord deformity; and grade 3, spinal cord signal change. The MRI scans of 82 patients (37 men and 45 women; mean age, 65.2 years; range, 60-86 years) were independently analyzed by six radiologists. Interobserver and intraobserver agreements were analyzed using intraclass correlation coefficient (ICC), along with the percentage agreement and kappa statistics. RESULTS: The ICC for interobserver agreement was 0.716-0.802, indicating good-to-excellent agreement. For the distinction among the four grades, the percentage of agreement was 63-64% (kappa = 0.60-0.62). The percentage of agreement for the presence of cervical canal stenosis (grade 0 vs grades 1, 2, and 3) was 79-85% (kappa = 0.51-0.59). The percentage of agreement for insignificant (grade 0-1) or significant (grade 2 3) stenosis was 81-85% (kappa = 0.57-0.66). The percentage of agreement for the presence of spinal cord signal change (grade 0-2 vs grade 3) was 92-95% (kappa = 0.70-0.73). The overall intraobserver agreement was excellent, as determined by an ICC of 0.768. CONCLUSION: The new grading system provides a reliable assessment of cervical canal stenosis. PMID- 21700975 TI - Vascular lesions presenting as musculoskeletal neoplasms. AB - OBJECTIVE: The purpose of this article is to describe how to distinguish between vascular lesions and other soft-tissue tumors such as sarcomas on various imaging modalities. CONCLUSION: Careful attention to imaging characteristics, patient history, and presentation is essential to differentiate vascular lesions from sarcomas and other tumors. PMID- 21700976 TI - Superficial siderosis of the CNS. AB - OBJECTIVE: The objective of this article is to illustrate and describe the cause, physiopathology, natural history, and clinical and imaging presentations of superficial siderosis as a cause of progressive cerebellar ataxia with sensorineural hearing loss and to discuss the therapeutic rationale. CONCLUSION: Superficial siderosis resulting in subpial deposition of hemosiderin along the surface of the cerebellum, brain, spinal cord, and cranial and peripheral nerves is a known cause of progressive cerebellar ataxia and sensorineural hearing loss. MRI evaluation of the entire neuraxis plays a key role in establishing the diagnosis and identifying the source of chronic bleeding. Treatment of the source of bleeding can halt the otherwise deteriorating clinical course of disease. PMID- 21700977 TI - MRI of the thymus. PMID- 21700978 TI - Juvenile dermatomyositis: correlation of MRI at presentation with clinical outcome. AB - OBJECTIVE: The clinical course of juvenile dermatomyositis (JDMS) is unpredictable. MRI is used to determine muscle biopsy site and to monitor disease activity. It is unknown whether soft-tissue features on MRI obtained at diagnosis correlate with clinical outcome. The purpose of our study is to determine whether initial MRI findings in the pelvis and thighs in children with JDMS can predict clinical disease course. MATERIALS AND METHODS: Forty-five children (31 girls and 14 boys; median age, 6 years; range, 1-18 years) with clinically diagnosed biopsy proven JDMS and at least 24 months of clinical follow-up were included. Clinical outcome was categorized as limited or chronic disease, according to the established Crowe clinical classification scheme. Pretreatment MRI examinations of the pelvis and thighs were evaluated for signal abnormalities of muscle and fascia and reticulated signal changes in subcutaneous fat; associations with clinical outcome were examined. RESULTS: Twenty-two patients had limited disease and 23 had chronic disease. Signal intensity ranged from normal (n = 3) to floridly increased in all muscle compartments (n = 17). Muscle and fascial involvement were not associated with clinical outcome. Controlling for duration of symptoms, the adjusted odds of progressing to chronic disease were higher for patients with abnormal subcutaneous fat signal than for those with normal fat signal (odds ratio, 9.0; 95% CI, 1.5-53.5; p < 0.02). CONCLUSION: MRI findings of muscle or fascia involvement do not predict clinical outcome in children with newly diagnosed JDMS. Abnormal subcutaneous fat signal appears to have a significant association with a more aggressive chronic disease course. PMID- 21700979 TI - The prevalence of uncommon fractures on skeletal surveys performed to evaluate for suspected abuse in 930 children: should practice guidelines change? AB - OBJECTIVE: The objective of our study was to evaluate the prevalence and site of fractures detected on skeletal surveys performed for suspected child abuse at a tertiary children's hospital and to determine whether any survey images may be eliminated without affecting clinical care or the ability to make a diagnosis. MATERIALS AND METHODS: We identified all skeletal surveys performed for suspected abuse from 2003 to 2009 of children younger than 2 years. Repeated studies were excluded, as were studies not performed to evaluate for suspected abuse. From the reports, we documented the sites of all the fractures. RESULTS. Nine hundred thirty children (515 boys and 415 girls) with a median age of 6 months met the entry criteria for the study. Fractures were detected in 317 children (34%), of whom 166 (18%) had multiple fractures. The most common sites for fractures were the long bones (21%), ribs (10%), skull (7%), and clavicle (2%). Ten children (1%) had fractures in the spine (n = 3), pelvis (n = 1), hands (n = 6), and feet (n = 2). All 10 children had other signs of physical abuse. CONCLUSION: In skeletal surveys performed for suspected child abuse, fractures limited to sites other than the long bones, ribs, skull, and clavicles are rare. The additional radiation exposure and cost of obtaining radiographs of the spine, pelvis, hands, and feet may outweigh their potential benefit. Given the rarity of fractures of the spine, pelvis, hands, and feet, consideration may be given to eliminating those views from routine skeletal surveys performed to evaluate for suspected child abuse. PMID- 21700980 TI - Abnormal preprocedural international normalized ratio and platelet counts are not associated with increased bleeding complications after ultrasound-guided thoracentesis. AB - OBJECTIVE: The objective of our study was to identify differences in hemorrhagic complications after ultrasound-guided thoracentesis on the basis of patient coagulation parameters. MATERIALS AND METHODS: The records of consecutive patients who underwent ultrasound-guided thoracentesis between January 1, 2008 and April 30, 2010 were reviewed to document the international normalized ratio (INR) and platelet count obtained within 72 hours before thoracentesis and to identify bleeding complications that occurred after the procedure. The observed complication rates and 95% CIs for differences in complication rates were calculated. RESULTS: There were 1076 procedures performed during the study period with no hemorrhagic complications identified (0% complication rate; 95% CI, 0.00 0.34%). INR values before thoracentesis were available for 822 procedures: INR exceeded 2.0 in 139 cases (17%), 2.5 in 59 cases (7%), and 3.0 in 32 cases (4%). The 95% CI for the 0% difference in complications observed between two groups of patients determined by specific INR values was -0.008 to 0.014 (INR, 1.5), -0.007 to 0.026 (INR, 2.0), -0.007 to 0.061 (INR, 2.5), and -0.009 to 0.11 (INR, 3.0). Platelet values before thoracentesis were available for 953 procedures; the platelet count was less than 100,000/MUL for 148 procedures (16%), less than 50,000/MUL for 58 procedures (6%), and less than 25,000/MUL for 12 procedures (1%). The 95% CI for the 0% difference in complications between two groups of patients determined by a platelet count threshold of 50,000/MUL was -0.007 to 0.062. CONCLUSION: The risk of bleeding after ultrasound-guided thoracentesis performed by radiologists is low even if the preprocedural INR and platelet count are abnormal. An approach in which no coagulation testing or correction is performed before thoracentesis may be justified. PMID- 21700981 TI - Side-branch embolization before 90Y radioembolization: rate of recanalization and new collateral development. AB - OBJECTIVE: The purpose of this study was to assess the rate of recanalization and collateral vessel formation after side-branch embolization during mapping angiography for planned (90)Y radioembolization. MATERIALS AND METHODS: Patients who underwent side-branch embolization at mapping angiography before (90)Y administration were included. Embolized vessels included the gastroduodenal artery, right gastric artery, and accessory arteries. Four interventional radiologists reviewed follow-up angiograms to assess recanalization and new collateral formation of embolized vessels. The time to recanalization or new collateral formation was tracked within 60 days and after the final arteriographic study. Differences in outcome among patients who had and those who had not undergone previous arterial directed therapy were reviewed. RESULTS: Fifty-six patients underwent side-branch embolization and follow-up arteriography; 124 treatments were performed after side-branch embolization (median, 2; range, 1-7), and the median follow-up period was 134 days (range, 7 684 days). Recanalization or new collateral vessel formation was found in 6 of 56 patients (10.7%) and in 8 of 56 patients (14.3%) 60 days after treatment or at final angiography, respectively. Embolization of 110 arteries was accomplished (42 gastroduodenal arteries, 46 right gastric arteries, and 22 accessory arteries). Two of 110 arteries (1.8%) recanalized, and four of 110 (3.6%) had new collateral vessels within 60 days. At final evaluation, 2 of 110 arteries (1.8%) had recanalized and 7 of 110 (6.4%) had new collaterals. Previous liver-directed therapy did not affect outcome (p > 0.05). No patient had symptomatic gastrointestinal ulceration. CONCLUSION: In more than 89% of patients, side branch embolization provides durable occlusion for (90)Y radioembolization without collateral development or recanalization for a bilobar cycle of therapy. Further recanalization and collateral development at longer-term follow-up are minimal. PMID- 21700982 TI - Dynamic Doppler evaluation of the hand arteries to distinguish between primary and secondary raynaud phenomenon. AB - OBJECTIVE: The objective of our study was to use Doppler sonography to detect the flow characteristics and parameters of the hand arteries that are needed to distinguish between primary Raynaud phenomenon (RP) and secondary RP. SUBJECTS AND METHODS: The diameter, resistive index (RI), and flow volume of the digital, ulnar, and radial arteries of patients with primary RP and those with secondary RP were measured at rest and after cold provocation. The flow starting time in the digital artery and the flow normalizing time of all three arteries were also recorded after cold provocation. RESULTS: At baseline and after cold provocation, the diameters of the radial and digital arteries and the flow volumes of the three arteries were less in patients with secondary RP than in primary RP patients. In primary RP and secondary RP, the flow normalizing times (mean +/- SD) were 9.8 +/- 3.88 and 25.88 +/- 7.14 minutes, respectively, in the radial artery; 11.3 +/- 7.43 and 32.15 +/- 12.57 minutes in the ulnar artery; and 12.22 +/- 6.82 and 32.67 +/- 10.76 minutes in the digital artery. A flow normalizing time cutoff in the radial artery of 17 minutes yielded a sensitivity of 90% and specificity of 100%. A flow normalizing time cutoff in the ulnar artery of 23 minutes yielded a sensitivity and specificity of 71% and 100%, respectively. A flow normalizing time cutoff in the digital artery of 23 minutes yielded a sensitivity and specificity of 82.6% and 98%, respectively. The flow starting time of the digital artery was 3.80 +/- 3.27 minutes in primary RP and 16.78 +/- 9.97 minutes in secondary RP (p < 0.0001). The flow starting time cutoff of the digital artery was 7 minutes (sensitivity, 82.6%; specificity, 95.7%). CONCLUSION: The diameter of the radial and distal arteries; flow volume; and flow volume normalizing time of the digital, ulnar, and radial arteries' flow starting time in the digital artery may be helpful in distinguishing between primary RP and secondary RP with high sensitivity and specificity values. These parameters may also facilitate objective follow-up of treatment. The noninvasive nature of Doppler sonography is an additional advantage, and there is no need for extra hardware or software. PMID- 21700983 TI - A double-wire technique for transjugular intrahepatic portosystemic shunt through a transabdominal-transjugular portosystemic approach. AB - OBJECTIVE: The purpose of this article is to describe a double-wire technique for transjugular intrahepatic portosystemic shunt (TIPS) procedures in which a transabdominal-transjugular portosystemic route is created that allows placement of a safety wire and a working wire. The safety wire provides a backup for the loss of the portosystemic tract and straightens the transjugular portosystemic route through a two-hand technique to facilitate shunt creation. CONCLUSION: Potential advantages of this technique include a precise and expeditious procedure for pediatric patients and those with small and hard liver or with focal lesions. PMID- 21700984 TI - Adenomyoepithelial tumors of the breast: imaging findings with histopathologic correlation. AB - OBJECTIVE: The purpose of this essay is to describe the imaging characteristics of adenomyoepithelial tumors of the breast. CONCLUSION: Adenomyoepithelial tumors of the breast are rare, and most are benign. The predominant mammographic and ultrasound feature is an irregular mass with suspicious imaging findings. This uncommon condition should be included in the differential diagnosis of noncalcified masses found on mammograms and of solid masses with associated hypervascularity on ultrasound images. Biopsy is necessary for histologic evaluation, and the management is surgical excision. PMID- 21700985 TI - Curbstone consultations. PMID- 21700986 TI - Critical findings. PMID- 21700987 TI - Systemic-to-pulmonary venous shunt in superior vena cava obstruction. PMID- 21700988 TI - Axillary lymph nodes in breast cancer: ultrasound appearance. PMID- 21700989 TI - Atypical proximal femoral fractures in patients with paget disease receiving bisphosphonate therapy. PMID- 21700990 TI - Private practice: what is expected of the new graduate? PMID- 21700991 TI - Early evaluation of cancer response by a new functional biomarker: apparent diffusion coefficient. AB - OBJECTIVE: The purpose of this article is to investigate whether apparent diffusion coefficient (ADC) might be used as a universal biomarker for response evaluation in different tumors. SUBJECTS AND METHODS: Twenty-one patients with lung cancer, 12 patients with esophageal cancer, 19 patients with liver metastases, 24 patients with gastric cancer, and 26 patients with rectal cancer were recruited to the study. Percentage changes in the ADC and changes in the size of responding and nonresponding lesions of different tumors after treatment were analyzed using repeated measures analysis of variance. RESULTS: There was no significant difference among the percentage ADC changes of different tumors (F = 1.57; p = 0.192). Clear differences were seen in the percentage ADC changes between responding and nonresponding tumors (F = 21.62; p < 0.001), which were significant at every time point after the start of treatment (early time point, F = 19.75 and p < 0.001; middle time point, F = 11.23 and p = 0.001; and later time point, F = 15.98 and p < 0.001). The percentage size changes after treatment between responding and nonresponding tumors were significantly different (F = 19.38; p < 0.001). However, at the early time point after treatment, the difference was not statistically significant (F = 0.02; p = 0.894). CONCLUSION: The ADC changes correlated with treatment response in five types of body tumor but were independent of the tumor's location. Early increases in ADC during treatment indicate good response to treatment. ADC change is a promising biomarker for detecting therapeutic responses at an early stage that could be widely used. PMID- 21700992 TI - Imaging of radiation-associated sarcoma. AB - OBJECTIVE: The objective of this article is to show the imaging features of radiation-associated sarcoma arising after radiation therapy using multiple imaging modalities. CONCLUSION: A multimodality imaging strategy and collaboration between multidisciplinary teams are important for the management of radiation-associated sarcoma. Because radiation-associated sarcoma often displays locally aggressive behavior and may metastasize, resulting in a poor prognosis, it is important to consider this diagnosis in any patient previously treated with radiation therapy and to recognize the imaging findings. PMID- 21700993 TI - Imaging of liposarcoma: classification, patterns of tumor recurrence, and response to treatment. AB - OBJECTIVE: The purpose of this study was to illustrate the subtypes of liposarcoma (LPS) and the significance of the nonlipomatous tumor components using multiple imaging modalities. CONCLUSION: The subtypes of LPS with greater nonlipomatous soft-tissue components on imaging studies tend to show less differentiation and are usually more aggressive both histologically and clinically. Imaging plays an important role in the diagnosis, surveillance, and response assessment of LPS. PMID- 21700995 TI - Prospective evaluation of reader performance on MDCT in characterization of cystic pancreatic lesions and prediction of cyst biologic aggressiveness. AB - OBJECTIVE: Our objective was to evaluate the accuracy of MDCT features of pancreatic cystic lesions in cyst characterization and in predicting cyst biologic aggressiveness. SUBJECTS AND METHODS: In this prospective study, 114 patients (40 men and 74 women; age range, 23-89 years) with 130 cystic lesions (size range, 31-160 mm) in the pancreas underwent contrast-enhanced dual-phase (n = 92) and portal phase (n = 22) examinations with 16- or 64-MDCT scanners. Using defined morphologic features of cystic lesions on MDCT, two readers performed blinded evaluations for cystic characterization and predicting biologic aggressiveness (invasive lesions, carcinoma in situ, and moderate grade dysplasias) before pancreatic surgery. Receiver operating characteristic analysis was performed to assess the accuracy of MDCT using pathologic evaluation of the surgical specimen as a reference standard. RESULTS: On the basis of MDCT features, the radiologic accuracy (reader 1 and reader 2) for stratifying lesions into mucinous and nonmucinous subtypes was 85% and 82% and for recognizing cysts with aggressive biology was 86% and 85%, respectively. Predictive values of MDCT were superior for lesions > 30 mm and nonmucinous lesions. Features favoring aggressive biology were main pancreatic duct dilation > 10 mm (p < 0.0001), biliary obstruction (p=0.01), mural nodule (p < 0.0001), main-duct intraductal papillary mucinous neoplasm (p < 0.0001), and advanced age (p = 0.0001). Sensitivity of detecting morphologic features was higher with the dual-phase pancreatic protocol CT. CONCLUSION: Morphologic features of pancreatic cystic lesions on MDCT allow reliable characterization into mucinous and nonmucinous subtypes and enable prediction of biologic aggressiveness. PMID- 21700994 TI - Differentiation of hepatic hyperintense lesions seen on gadoxetic acid-enhanced hepatobiliary phase MRI. AB - OBJECTIVE: The purpose of this study was to define imaging features that may help characterize hyperintense lesions seen in the hepatobiliary phase of gadoxetic acid-enhanced hepatic MRI examinations. MATERIALS AND METHODS: This retrospective study included 48 hyperintense nodules depicted on gadoxetic acid disodium enhanced hepatobiliary phase MR images: 16 hepatocellular carcinomas (HCCs), 14 lesions of focal nodular hyperplasia, and 18 benign nodules associated with cirrhosis. Two observers independently reviewed hepatobiliary phase images and recorded the shape, margin, focal defects in contrast uptake, nodule-in-nodule pattern of uptake, central scar, internal septation, and presence of a hypointense rim around the lesion. Interobserver agreement was assessed with kappa statistics, and consensus opinions were reached by conference. For quantitative analysis, one observer measured lesion-to-liver contrast ratio (signal intensity of tumor divided by signal intensity of liver) on hepatobiliary phase images. Logistic regression analysis was used to determine the value of individual clinical and MR findings in prediction of malignancy. RESULTS: Compared with benign lesions, hyperintense HCC more commonly had focal defects in uptake (68.8% vs 3.1%, respectively; p < 0.001), nodule-in-nodule appearance (75.0% vs 0%, p < 0.001), absence of a central scar (100% vs 46.9%, p < 0.001), internal septation (50.0% vs 3.1%, p < 0.001), and a hypointense rim (75.0% vs 15.6%, p < 0.001) on hepatobiliary phase MR images. The mean contrast ratios of HCC (1.31) and benign lesions (1.28) were not significantly different (p = 0.63). Multiple logistic regression analysis showed that a focal defect in contrast uptake (p = 0.025) and a hypointense rim (p = 0.019) were significant predictors of HCC, having odds ratios of 36.8 (95% CI, 1.56-870.0) and 17.5 (1.60-191.4). CONCLUSION: On gadoxetic acid-enhanced MR images, hyperintense nodules can be differentiated with several imaging characteristics, especially a focal defect in contrast uptake and a hypointense rim, that indicate the diagnosis of hyperintense HCC. PMID- 21700996 TI - AJR teaching file: intermittent chronic abdominal pain, fever, and fatigue in a middle-aged woman. PMID- 21700997 TI - Chronic epigastric pain in a middle-aged man. AB - OBJECTIVE: The objective of this article is to describe and show a number of imaging findings that are classical for an intussusception in an adult and discuss the clinical manifestations and associated findings. We also discuss the differential diagnosis of intussusception in an adult and the most likely causes. CONCLUSION: A malignant cause of intussusception is more likely when an intussusception involves the large bowel, in which case primary adenocarcinoma of the colon is the most prevalent. Therefore, surgical resection followed by careful pathologic analysis is typically indicated in nonresolving cases. Nevertheless, when intussusception is transiently diagnosed in an asymptomatic adult, follow-up is favored over surgery. PMID- 21700998 TI - The reversed halo sign on high-resolution CT in infectious and noninfectious pulmonary diseases. AB - OBJECTIVE: The purpose of this article is to describe diseases that may present with the reversed halo sign on high-resolution CT. We emphasize the tomographic features most frequently associated with this sign and correlate them with histologic findings. CONCLUSION: A wide spectrum of infectious and noninfectious diseases may present with the reversed halo sign on chest CT. The nonspecific nature of this sign should not cloud an otherwise fairly straightforward diagnosis, especially when associated background findings are typical. Although a rigorous analysis of associated CT findings may help with the differential diagnosis, histologic assessment is often needed for a definitive determination of the cause. PMID- 21700999 TI - In vivo evaluation of the chemical composition of urinary stones using dual energy CT. AB - OBJECTIVE: The purpose of this article is to evaluate in vivo the chemical composition of urinary stones using dual-source and dual-energy CT, with crystallography as the reference standard. MATERIALS AND METHODS: Forty patients (mean [+/- SD] age, 49 +/- 17 years) with known or suspected nephrolithiasis underwent unenhanced abdominal CT for urinary tract evaluation using a dual energy technique (tube voltages, 140 and 80 kVp). For each stone 5 mm or larger in diameter, we evaluated the site, diameter, CT density, surface (smooth vs rough), and stone composition. Patients were treated with extracorporeal shock wave lithotripsy (n = 34), percutaneous nephrolithotomy (n = 4), or therapeutic ureterorenoscopy (n = 2). Collected stones underwent crystallography, and the agreement with the results of dual-energy CT was calculated with the Cohen kappa coefficient. The correlation among stone composition, diameter, and CT density was estimated using the Kruskal-Wallis test. RESULTS: Thirty-one patients had a single stone and nine had multiple stones, for a total of 49 stones. Forty-five stones were in the kidneys, and four were in the ureters; 23 had a smooth surface and 26 had a rough surface. The mean stone diameter was 12 +/- 6 mm; mean CT density was 783 +/- 274 HU. According to crystallography, stone composition was as follows: 33 were calcium oxalate, seven were cystine, four were uric acid, and five were of mixed composition. Dual-energy CT failed to identify four stones with mixed composition, resulting in substantial agreement between dual-energy CT and crystallography (Cohen kappa = 0.684). Stone composition was not correlated with either stone diameter (p = 0.920) or stone CT density (p = 0.185). CONCLUSION: CT showed excellent accuracy in classifying urinary stone chemical composition, except for uric acid-hydroxyapatite mixed stones. PMID- 21701000 TI - Hematuria evaluation with MDCT urography: is a contrast-enhanced phase needed when calculi are detected in the unenhanced phase? AB - OBJECTIVE: The purpose of this study was to assess the added utility of the contrast-enhanced phase of MDCT urography (MDCTU) when urinary tract calculi are detected in the preliminary unenhanced phase. MATERIALS AND METHODS: A computer search of CT reports with the term "hematuria" yielded the records of 1209 patients who had undergone MDCTU. The reports of 286 MDCTU examinations in which urinary tract calculi were detected were identified, and two blinded abdominal radiologists reviewed the images to find a second source of hematuria. The unenhanced images were reviewed first, and the findings were compared with those on the subsequent contrast-enhanced images. The aggregate findings of the 286 examinations in which calculi were present were compared with those of the 923 examinations in which calculi were absent. The follow-up diagnosis was based on histopathologic findings, findings at urologic procedures, or the imaging diagnosis. RESULTS: In 119 of the 1209 patients (10%), 127 lesions other than urinary tract calculi were identified as possible sources of hematuria. Eighty two lesions were diagnosed in 77 patients (6%) at follow-up evaluation. A second source of hematuria was found in 19 of the 286 examinations (7%) with calculi compared with 58 of the 923 examinations (6%) without calculi (p = 0.828), and contrast was needed to make a specific diagnosis in 16 of the 19 examinations (84%). CONCLUSION: When urinary tract calculi are identified at MDCTU, the rate of detection of other potential causes of hematuria is not different from that in MDCTU examinations without calculi. The contrast-enhanced portion of the MDCTU examination is needed even if calculi are seen because important pathologic changes are diagnosed only after the contrast-enhanced phase. PMID- 21701001 TI - Role of MRI in minimally invasive focal ablative therapy for prostate cancer. AB - OBJECTIVE: The purpose of this article is to review the roles that MRI is expected to play in emerging minimally invasive focal ablative therapies for prostate cancer. CONCLUSION: MRI, in combination with biopsy, will impact patient selection for focal ablation by helping to localize clinically significant tumor foci. Also, some ablation procedures may be performed using real-time MRI guidance. In addition, MRI may be used for assessment of extent of necrosis shortly after therapy and for long-term surveillance for recurrent tumor. PMID- 21701002 TI - Radiation dose levels for interventional CT procedures. AB - OBJECTIVE: The purpose of this study was to determine typical radiation dose levels to patients undergoing CT-guided interventional procedures. MATERIALS AND METHODS: A total of 571 patients undergoing CT interventional procedures were included in this retrospective data analysis study. Enrolled patients underwent one of five procedures: cryoablation, aspiration, biopsy, drain, or injection. With each procedure, two scan modes were used, either intermittent (no table increment) or helical mode. Skin dose was estimated from the volumetric CT dose index (CTDI(vol)) and phantom measurements. Effective dose was calculated by multiplying dose-length product (DLP) and conversion factor (k factor) for helical mode, and using Monte Carlo organ dose coefficients for intermittent mode. RESULTS: The mean (+/- SD) skin doses were 728 +/- 382, 130 +/- 104, 128 +/ 81, 152 +/- 105, and 195 +/- 147 mGy, and the mean effective doses were 119.7 +/ 50.3, 20.1 +/- 11.0, 13.8 +/- 9.2, 25.3 +/- 15.4, and 9.1 +/- 5.5 mSv for each of the five procedures, respectively. The maximum skin dose was 1.95 Gy. The mean effective dose across all procedure types was 24.1 mSv, with 2.3 mSv from intermittent scans and 21.8 mSv from helical scans. CONCLUSION: Substantial dose differences were observed among the five procedures. The risk of deterministic effects appears to be very low, because the maximum observed skin dose did not exceed the threshold for transient skin erythema (2 Gy). The average risk of stochastic effects was comparable to that of 1-10 abdomen and pelvis CT examinations. Although the intermittent mode can contribute substantially to skin dose, it contributes minimally to the effective dose because of the much shorter scan range used. PMID- 21701003 TI - The digital media revolution: what it means for the AJR. AB - OBJECTIVE: The digital media revolution is in full swing, fueled by rapid growth of the Internet and proliferation of handheld devices capable of accessing electronically data from virtually anywhere. With this growth of digital media, the printing industry is seeing declines in circulation and advertising revenue. CONCLUSION: Scholarly journals, including the American Journal of Roentgenology, are not immune from this changing paradigm. The scholarly journal of the future should be a platform for the active exchange of new information and ideas. PMID- 21701004 TI - Classification of benign vascular lesions: history, current nomenclature, and suggestions for imagers. PMID- 21701005 TI - Response to treatment series: part 1 and introduction, measuring tumor response- challenges in the era of molecular medicine. PMID- 21701006 TI - Response to treatment series: part 2, tumor response assessment--using new and conventional criteria. AB - OBJECTIVE: Conventional anatomic imaging biomarkers, including World Health Organization (WHO) criteria and Response Evaluation Criteria in Solid Tumors (RECIST), although effective, have limitations. This article will discuss the conventional and newer morphologic imaging biomarkers for the assessment of tumor response to therapy. CONCLUSION: Applying established methods of assessing tumor response to therapy allows consistency in image interpretation and facilitates communication with oncologists. Because of the new methods of treatment, assessment of necrosis and volumetric information will need to be incorporated into size-based criteria. PMID- 21701007 TI - Luminal imaging in the 21st century. PMID- 21701008 TI - Body CT: technical advances for improving safety. AB - OBJECTIVE: In this review, we attempt to address many of the issues that are related to ensuring patient benefit in body CT, balancing the use of ionizing radiation and iodinated contrast media. We attempt to not only summarize the literature but also make recommendations relevant to CT protocols, including the technical parameters of both the scanner and the associated contrast media. CONCLUSION: Although CT is a powerful tool that has transformed the practice of medicine, the benefits are accompanied by important risks. Radiologists must understand these risks and the strategies available to minimize them as well as the risks associated with contrast medium delivery in abdominal CT. PMID- 21701009 TI - Gastroenterology review and perspective: the role of cross-sectional imaging in evaluating bowel damage in Crohn disease. AB - OBJECTIVE: This article will review the performance and limitations of cross sectional imaging methods to detect and display critical features of Crohn disease (CD)-related bowel damage, including stenosis and penetrating complications (i.e., fistula, abscess). International efforts to incorporate cross-sectional imaging findings along with endoscopic and surgical findings to create a global bowel damage score over the length of the gastrointestinal tract are summarized along with the rationale for these efforts. CONCLUSION: The first digestive damage score, the Lemann score, will incorporate surgical history, endoscopic findings, and imaging findings of stenosis and penetrating complications to provide a global assessment of CD-related destruction of the gastrointestinal tract. It is anticipated that the score will permit better understanding of the impact of modern therapeutics on the natural history of CD. Because CT is a technique that involves ionizing radiation and accuracy of ultrasound is highly related to CD location, MRI is proposed as first choice for nonemergent follow-up of CD patients. PMID- 21701010 TI - A prospective comparison of standard-dose CT enterography and 50% reduced-dose CT enterography with and without noise reduction for evaluating Crohn disease. AB - OBJECTIVE: The purpose of this study was to prospectively compare standard-dose CT enterography (CTE) and 50% reduced-dose CTE, obtained with and without an image noise reduction method, in the evaluation of Crohn disease. SUBJECTS AND METHODS: Ninety-two patients (69 men and 23 women; mean age [+/- SD], 31.2 +/- 9.5 years) with Crohn disease underwent CTE. Using a dual-source scanner equipped with a proprietary noise reduction method (iterative reconstruction in image space [IRIS]), three sets of CTE images were obtained: standard-dose filtered back projection (FBP) (i.e., weighted FBP), low-dose (i.e., 50% reduction) FBP, and low-dose IRIS CTE. Image noise was measured. Two independent radiologists evaluated subjective image quality (1 [worst] to 4 [best]) and findings of active Crohn disease in the terminal small-bowel segment, including mural hyperenhancement, thickening and stratification, comb sign, and increased perienteric fat attenuation (1 [definitely absent] to 5 [definitely present]). RESULTS: The mean (+/- SD) volume CT dose index (CTDI(vol)) was 7.0 +/- 0.9 mGy and 3.5 +/- 0.5 mGy for standard-dose and low-dose CTE examinations, respectively. The mean (+/- SD) image noise for standard-dose FBP, low-dose FBP, and low-dose IRIS CTE was 10.6 +/- 1.7 HU, 13.9 +/- 2.1 HU, and 9.7 +/- 1.7 HU, respectively (p < 0.001 for all comparisons). Both assessors found that image quality was poorer with low-dose (mean grade (+/- SD), 2.3 +/- 0.4-2.7 +/- 0.5) than in standard-dose (3 +/- 0) CTE (p < 0.01), and one found that image quality was poorer with low-dose IRIS (2.3 +/- 0.4) than with low-dose FBP (2.7 +/- 0.5) CTE (p < 0.01). Low-dose (with or without IRIS) and standard-dose CTE showed >= 85% agreement (one-sided 95% CI >= 77%) in interpretation of bowel findings. CONCLUSION: Low-dose CTE using 50% reduced-dose performed similarly to standard dose CTE in identifying findings of enteric inflammation of Crohn disease. Although a noise reduction method markedly reduced image noise in half-dose examinations, its effect on image quality was not as great and was reader dependent. PMID- 21701011 TI - Evolution of hypointense hepatocellular nodules observed only in the hepatobiliary phase of gadoxetate disodium-enhanced MRI. AB - OBJECTIVE: We sought to determine whether hypointense hepatocellular nodules observed in the hepatobiliary phase of MRI enhanced with gadolinium-ethoxybenzyl diethylenetriamine pentaacetic acid (gadoxetate disodium) progress to hypervascular hepatocellular carcinoma. MATERIALS AND METHODS: Gadoxetate disodium-enhanced MRI was repeated for 30 patients with 49 nodules determined to be hypointense in the hepatobiliary phase but nonenhancing in the arterial phase of dynamic MRI. The correlation between characteristics of hypointense nodules with slightly or markedly low signal intensity relative to surrounding liver parenchyma and their progression to hypervascular hepatocellular carcinoma was analyzed in cirrhotic livers. All patients underwent angiography-assisted CT before MRI. The rate of progression to classic hepatocellular carcinoma was calculated by the Kaplan-Meier method. RESULTS: The overall 6- and 12-month cumulative incidences of vascularization were 27.6% and 43.5%. The 6- and 12 month cumulative incidences of vascularized nodules with a maximum diameter 15 mm or greater were 43.3% and 77.3% and a maximum diameter less than 15 mm were 16.9% and 16.9%. The difference between these incidences was significant (p = 0.0147). CONCLUSION: Hypointense nodules with a maximum diameter of at least 15 mm often become hypervascular. Therefore, patients with hypointense nodules characterized by a maximum diameter of 15 mm or greater should be observed carefully because of the high incidence of vascularization. PMID- 21701013 TI - MR enterography of Crohn disease: part 1, rationale, technique, and pitfalls. AB - OBJECTIVE: The purpose of this article is to review the technique of performing MR enterography examinations and to review the imaging findings suggestive of Crohn disease. This article will also allow the reader to self-assess and improve his or her skills in the performance and interpretation of MR enterography examinations. CONCLUSION: MRI plays a valuable role in providing accurate information about the severity of and complications related to Crohn disease and can help in guiding surgical or medical treatment. PMID- 21701012 TI - Dynamic postprandial hepatic stiffness augmentation assessed with MR elastography in patients with chronic liver disease. AB - OBJECTIVE: MR elastography (MRE) is an MRI-based technique for quantitatively assessing tissue stiffness by studying shear wave propagation through tissue. The goal of this study was to test the hypothesis that hepatic MRE performed before and after a meal will result in a postprandial increase in hepatic stiffness among patients with hepatic fibrosis because of transiently increased portal pressure. SUBJECTS AND METHODS: Twenty healthy volunteers and 25 patients with biopsyproven hepatic fibrosis were evaluated. Preprandial MRE measurements were performed after overnight fasting. A liquid test meal was administered, and 30 minutes later a postprandial MRE acquisition was performed. Identical imaging parameters and analysis regions of interest were used for pre- and postprandial acquisitions. RESULTS: The results in the 20 subjects without liver disease showed a mean stiffness change of 0.16 +/- 0.20 kPa (range, -0.12 to 0.78 kPa) or 8.08% +/- 10.33% (range, -5.36% to 41.7%). The hepatic stiffness obtained in the 25 patients with hepatic fibrosis showed a statistically significant increase in postprandial liver stiffness, with mean augmentation of 0.89 +/- 0.96 kPa (range, 0.17-4.15 kPa) or 21.24% +/- 14.98% (range, 7.69%-63.3%). CONCLUSION: MRE assessed hepatic stiffness elevation in patients with chronic liver disease has two major components: a static component reflecting structural change or fibrosis and a dynamic component reflecting portal pressure that can increase after a meal. These findings will provide motivation for further studies to determine the potential value of assessing postprandial hepatic stiffness augmentation for predicting the progression of fibrotic disease and the development of portal hypertension. The technique may also provide new insights into the natural history and pathophysiology of chronic liver disease. PMID- 21701014 TI - MR enterography of Crohn disease: part 2, imaging and pathologic findings. AB - OBJECTIVE: The purpose of this article is to review MR enterography technique and imaging findings suggestive of Crohn disease on these examinations. This article will also allow the reader to self-assess and improve his or her skills in the performance and interpretation of MR enterography examinations. CONCLUSION: This article reviews the technique of performing MR enterography examinations. MRI plays a valuable role in providing accurate information about severity of and complications related to Crohn disease and can help in guiding surgical or medical treatment. PMID- 21701015 TI - Abdominal twists and turns: part I, gastrointestinal tract torsions with pathologic correlation. AB - OBJECTIVE: The gastrointestinal tract is secured in place by various suspensory ligaments. Laxity or incomplete development of these anchoring ligaments can lead to hypermobility and predispose the patient to torsion-related ischemic pathology. A prompt diagnosis is necessary to avoid life-threatening consequences of prolonged visceral ischemia. Abdominal torsions are rarely diagnosed clinically, and it is often the responsibility of the radiologist to recognize and make the diagnosis through radiography, fluoroscopy, or cross-sectional imaging. This article reviews the imaging spectrum (with radiologic-pathologic correlations) and therapeutic implications of gastrointestinal tract torsions. CONCLUSION: Torsion-related ischemic pathology may involve any portion of the gastrointestinal tract from the stomach to the colon. The clinical presentation of gastrointestinal tract torsion is nonspecific, and radiologists are relied on to make this diagnosis. Recognition of the predisposing factors and imaging spectrum of gastrointestinal tract torsions is essential to help direct timely intervention in these potentially life-threatening entities. PMID- 21701016 TI - Abdominal twists and turns: part 2, solid visceral torsions with pathologic correlation. AB - OBJECTIVE: The solid abdominal viscera are secured in place by various suspensory ligaments. Laxity or incomplete development of these anchoring ligaments can lead to hypermobility and predispose the patient to torsion-related ischemic pathology. The clinical symptoms of solid visceral intraabdominal torsions are nonspecific. A prompt diagnosis is critical to avoid life-threatening consequences of prolonged visceral ischemia. Abdominal torsions are rarely diagnosed clinically, and it is often the responsibility of the radiologist to recognize and make the diagnosis through cross-sectional imaging. This article reviews the imaging spectrum, radiologic-pathologic correlations, and therapeutic implications of solid visceral intraabdominal torsions, including some unusual solid organ and abdominal fat torsions. CONCLUSION: The clinical presentation of solid visceral intraabdominal torsion is nonspecific and radiologists are relied on to make this diagnosis on cross-sectional imaging studies. Recognition of the predisposing factors and imaging spectrum of intraabdominal torsions is essential to help direct timely intervention in these potentially life-threatening entities. PMID- 21701017 TI - Cardiovascular MRI for assessment of infectious and inflammatory conditions of the heart. AB - OBJECTIVE: This article reviews the role of cardiovascular MRI in the diagnosis and characterization of the spectrum of infectious and inflammatory disorders of the heart. An imaging protocol is described, and typical MRI findings are discussed and illustrated. CONCLUSION: Radiologists should be aware of the spectrum of infectious and inflammatory conditions that can affect the heart and the role of MRI in conjunction with other imaging techniques in their assessment. PMID- 21701018 TI - Reproducibility of perfusion parameters obtained from perfusion CT in lung tumors. AB - OBJECTIVE: The purpose of this article is to assess the variability of perfusion CT measurements in lung tumors and the effects of motion and duration of data acquisition on perfusion CT parameter values. SUBJECTS AND METHODS: Two perfusion CT scans were obtained in 11 patients with lung tumors, 2-7 days apart, using phase 1 scans (30-second breath-hold cine) followed by phase 2 scans (six intermittent helical breath-holds), spanning 125 seconds. Tumor blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability were calculated for phase 1 using all-cine and motion-corrected (rigidly registered) images, both with and without matching phase 2 images (manually or rigidly registered). Variability was assessed by the within-patient coefficient of variation (CV) and Bland-Altman analyses. RESULTS: BF, BV, MTT, and permeability values varied widely by method of analysis (median BF, 45.3-65.1 mL/min/100 g; median BV, 2.6 3.8 mL/100 g; median MTT, 3.6-4.1 seconds, and median permeability, 13.7-39.3 mL/min/100 g), as did within-patient CVs (10.9-114.4%, 25.3-117.6%, 22.3-51.5%, and 29.6-134.9%, respectively). Parameter values and variability were affected by motion and duration of data analyzed: permeability values doubled when phase 2 images were added to phase 1 data. Overall, the best reproducibility was obtained with registered phase 1 and 2 data, with within-patient CVs of 11.6%, 26.5%, 45.4%, and 30.2%, respectively. CONCLUSION: The absolute values and reproducibility of perfusion parameters in lung tumors are markedly influenced by motion and duration of data acquisition. Permeability, in particular, probably requires data acquisition beyond a single breath-hold. The smallest variability in parameter values was obtained with motion correction and extended acquisition durations. PMID- 21701019 TI - Are chest radiographs routinely indicated after chest tube removal following cardiac surgery? AB - OBJECTIVE: The purpose of this prospective study was to determine the incidence and clinical significance of pneumothoraces detected on routine radiography after chest tube removal following cardiac surgery and correlate those findings with an immediate postprocedure assessment of the likelihood of new pneumothorax. SUBJECTS AND METHODS: Routine portable chest radiographs obtained after chest tube removal in 400 consecutive cardiac surgery patients were assessed by a radiologist to determine the incidence and grade of pneumothoraces and were correlated with the clinical estimation of the likelihood of this complication, and whether the radiographic finding changed medical management or led to surgical intervention. RESULTS: Of 9.3% of cases (37/400) of new pneumothoraces after chest tube removal, 70.3% were tiny (barely perceptible), 27.0% were small (< 1 cm from the pleural line to the apex of the hemithorax), and 2.7% were medium (6-10 cm from the pleural line to the apex of the hemithorax). The incidences of small and medium pneumothoraces were substantially greater in patients with higher levels of clinical suspicion. All tiny pneumothoraces had no clinical importance. Not obtaining routine chest radiographs after chest tube removal in the 345 patients (86.3%) with the lowest level of clinical suspicion would have resulted in missing six small pneumothoraces (1.7%), none of which led to medical or surgical intervention or a delay in discharge. CONCLUSION: Chest radiography performed after chest tube removal following cardiac surgery is necessary only if the patient has respiratory or hemodynamic changes or if there are problems with the technical aspect of chest tube removal. Following this guideline in our patient population could have eliminated 86.3% of radiographs without missing any clinically significant pneumothoraces. PMID- 21701020 TI - Less common causes of disease involving the coronary arteries: MDCT findings. AB - OBJECTIVE: We aimed to illustrate and describe various imaging findings of nonatherosclerotic, nonanomalous coronary artery diseases (CADs) revealed by cardiac MDCT. CONCLUSION: Cardiac MDCT can show various causes of nonatherosclerotic CADs and of coronary atherosclerosis. Radiologists should be aware of the diverse imaging findings of nonatherosclerotic, nonanomalous CADs that can be identified with cardiac MDCT to facilitate accurate diagnosis and proper management. PMID- 21701021 TI - Characterization of adrenal masses with diffusion-weighted imaging. AB - OBJECTIVE: The purpose of this article is to assess the role of diffusion weighted MRI in characterizing adrenal masses. MATERIALS AND METHODS: A retrospective review of the MRI database from August 2007 to July 2009 was performed. The MRI examinations of 48 patients, with 49 lesions, were reviewed independently and blindly by two experienced abdominal radiologists who measured the signal intensities on in-phase and opposed-phase T1-weighted imaging and apparent diffusion coefficient (ADC). ADC measurements and quantitative parameters of chemical shift imaging (signal intensity index and adrenal-to spleen ratio) were assessed separately and in combination. Lesions with indeterminate signal intensity index (< 16.5%) were considered benign if ADC was greater than or equal to 1.0 * 10(-3) mm(2)/s and malignant if ADC was less than 1.0 * 10(-3) mm(2)/s. Stepwise logistic regression analysis and receiver operating characteristic curves analysis were performed. RESULTS: There were 12 malignant and 37 benign lesions. On multivariate analysis, the only significant predictors of lesion status were signal intensity index from reviewer 2 (p = 0.05) and lesion size (p = 0.04); ADC values were not found to be useful. On receiver operating characteristic curve analysis, there was no significant difference in area under the curve for ADC, signal intensity index, adrenal-to spleen ratio, or the combined signal intensity index and ADC assessment. For lesions that were indeterminate according to signal intensity index, ADC values greater than 1.50 * 10(-3) mm(2)/s were found only in benign lesions, and nine of 11 lesions with ADC less than 1.0 * 10(-3) mm(2)/s were malignant. CONCLUSION: In general, ADC values are not useful in differentiating adrenal lesions. However, when ADC values are applied to lesions that are indeterminate on signal intensity index, they may help in differentiating a subset of benign and malignant lesions. PMID- 21701022 TI - Incidental finding of renal masses at unenhanced CT: prevalence and analysis of features for guiding management. AB - OBJECTIVE: The purposes of this study were to investigate the frequency and clinical relevance of the incidental finding of renal masses at low-dose unenhanced CT and to analyze the results for features that can be used to guide evaluation. MATERIALS AND METHODS: Images from unenhanced CT colonographic examinations of 3001 consecutively registered adults without symptoms (1667 women, 1334 men; mean age, 57 years) were retrospectively reviewed for the presence of cystic and solid renal masses 1 cm in diameter or larger. An index mass, that is, the most complex or concerning, in each patient was assessed for size, mean attenuation, and morphologic features. Masses containing fat or with attenuation less than 20 HU or greater than 70 HU were considered benign if they did not contain thickened walls or septations, three or more septations, mural nodules, or thick calcifications. Masses with attenuation between 20 and 70 HU or any of these features were considered indeterminate. The performance of CT colonography in the detection of renal cell carcinoma was calculated for masses with 2 or more years of follow-up. RESULTS: At least one renal mass was identified in 433 (14.4%) patients. The mean size of the index masses was 25 +/- 16 mm; 376 (86.8%) masses were classified as benign and 57 (13.2%) as indeterminate. The 20- to 70-HU attenuation criterion alone was used for classification of 53 indeterminate lesions. Follow-up data (mean follow-up period, 4.4 years; range, 2-6.3 years) were available for 353 (81.5%) patients with masses (41 indeterminate, 312 benign). Four of the 41 indeterminate masses were diagnosed as renal cell carcinoma. The sensitivity and specificity for renal cell carcinoma on the basis of the indeterminate criteria were 100% and 89.4%. The positive and negative predictive values were 9.8% and 100%. CONCLUSION: The incidental finding of a renal mass is relatively common at unenhanced CT, but imaging criteria can be used for reliable identification of most of these lesions as benign without further workup. Mean attenuation alone appears reliable for determining which renal masses need further evaluation. PMID- 21701023 TI - Masters of radiology panel discussion: encouraging and fostering mentorship--how we can ensure that no faculty member is left behind and that leaders do not fail. PMID- 21701024 TI - Characteristics of falls in a large academic radiology department: occurrence, associated factors, outcomes, and quality improvement strategies. AB - OBJECTIVE: The objective of our study was to describe the characteristics of falls in a radiology department. MATERIALS AND METHODS: The departmental incident report database was retrospectively searched for fall incidents that occurred from March 2006 through October 2008. During that period, 1,801,275 radiologic examinations were performed in our department and there were 82 falls, yielding an incidence of 0.46 per 10,000 examinations. We collected patient information, associated factors, specific circumstances surrounding each incident, the location of each incident, and patient outcome. RESULTS: Eighty-two falls occurred involving 82 patients (35 males, 47 females; mean age, 58.2 years; range, 3-92 years): 66 falls (80%) involved outpatients; 11, inpatients; and five, visitors accompanying a patient. Radiography and CT-MRI units were the top two most common locations of falls (45/82, 55%). Thirty-six events (36/82, 44%) were directly related to a radiologic examination. Most falls were witnessed (61/82, 74%) and unassisted (50/82, 61%), and a majority occurred while the patient was standing or ambulating (59/82, 72%). Most patients (70/82, 85%) had at least one predisposing factor for falling. Sixteen patients (16/82, 20%) had fallen within the previous 3 months. Twenty-four falls (24/82, 29%) resulted in a documented injury (17 minor, seven moderate or severe) with one patient dying. Patients were more likely to be injured if they fell while ambulating (p = 0.0257, univariate analysis) or if they were taking antihypertensive medication (p = 0.02, multivariate analysis). CONCLUSION: Falls were uncommon in the radiology department studied; however, they can result in significant morbidity and mortality. PMID- 21701025 TI - A rational approach to the clinical use of cumulative effective dose estimates. AB - OBJECTIVE: This article will address ongoing efforts to track cumulative dose estimates of patient radiation exposure that have the potential to transform radiation protection research. CONCLUSION: There is no clear consensus on how to use this information clinically. A rational consideration of this question reveals that until the linear no-threshold model is supplanted, cumulative dose estimates are of little clinical relevance and never constitute a logical reason to avoid an imaging evaluation that is otherwise medically indicated. PMID- 21701026 TI - Comparison of radiation dose and image quality: 320-MDCT versus 64-MDCT coronary angiography. AB - OBJECTIVE: The purpose of this study was to compare radiation dose and image quality of 320- and 64-MDCT angiography using prospective gating. MATERIALS AND METHODS: One hundred seventy-four patients underwent 320-MDCT, and 95 patients underwent 64-MDCT. The scan parameters for 320-MDCT were 120 kVp, 400 mA, and gantry rotation of 350 milliseconds; the parameters for 64-MDCT were 120 kVp, 600 mA, and gantry rotation of 350 milliseconds. Effective dose (ED) was calculated from the dose-length product and a conversion factor (k = 0.014 mSv / mGy * cm). Two observers independently assessed image quality using a 3-point scale, where 3 denotes excellent quality and 1 denotes nondiagnostic quality, using a 16-segment model. Discrepancies were settled by consensus. RESULTS: The ED was significantly lower in patients undergoing 320-MDCT angiography, with a median ED of 4.4 mSv (interquartile range [IQR], 3.4-6.2 mSv), compared with 64-MDCT angiography, with a median ED of 6.2 mSv (IQR, 5.5-6.9 mSv) (p = 0.0001). In patients with a heart rate of 65 beats/min or less (92%), the median radiation dose using 320-MDCT was 4.1 mSv (IQR, 3.2-6.1 mSv), and that for 64-MDCT angiography was 6.2 mSv (IQR, 5.8-6.9 mSv) (p = 0.0001). In patients with heart rate greater than 65 beats/min (8%), the median dose was higher with 320-MDCT (8.7 mSv; IQR, 5.9-14.3 mSv) than with 64-MDCT (5.8 mSv; IQR, 5.3-6.7 mSv) (p = 0.02). Segmental image quality was significantly better for 320-MDCT (excellent or good quality, 96.66%; nondiagnostic quality, 0.1%) than for 64-MDCT angiography (excellent or good quality, 86%; nondiagnostic quality, 3.33%) (all p < 0.0001). CONCLUSION: Image quality was good for both 320- and 64-MDCT angiography. Overall radiation dose was significantly lower in 320-MDCT angiography when the heart rate was 65 beats/min or less. Every effort should be made to control heart rate to minimize radiation dose. PMID- 21701027 TI - MRI of the quadratus femoris muscle: anatomic considerations and pathologic lesions. AB - OBJECTIVE: The purpose of this review is to describe the gross anatomic and MRI appearance of the quadratus femoris muscle and the MRI appearance of common lesions of the quadratus femoris. CONCLUSION: Lesions of the quadratus femoris have been implicated as a cause of hip pain. It therefore is important to be familiar with the anatomy of the quadratus muscle and to be able to diagnose the causes of abnormal signal intensity in the quadratus femoris, which include tears and impingement. PMID- 21701028 TI - High-resolution MR neurography: evaluation before repeat tarsal tunnel surgery. AB - OBJECTIVE: The purpose of this study was to retrospectively determine the accuracy of high-resolution MR neurography (MRN) in presurgical evaluation before repeat tarsal tunnel surgery. MATERIALS AND METHODS: Ten MRN studies of nine patients (one man, eight women; mean age, 44.4 years; range, 23-67 years) who had been referred to a peripheral nerve specialist because of persistent symptoms after tarsal tunnel release were reviewed. The MRN findings studied included presence and location of focal fibrosis, presence or absence of nerve abnormality, location of nerve abnormality, and presence of neuroma formation and regional muscle denervation. The diagnostic accuracy of MRN in detection of posterior tibial nerve, medial plantar nerve, and lateral plantar nerve injury was calculated with clinical and intraoperative findings as the reference standards. RESULTS: Nine of 10 MRN studies (90%) had findings of nerve reentrapment related to focal fibrosis. Injured nerves were reliably visualized with MRN in all patients. MRN had a sensitivity of 77% for posterior tibial nerve, 100% for medial plantar nerve, and 100% for lateral plantar nerve injury, and the overall accuracy was 86%. The sensitivity of MRN was 91% for the presence of focal fibrosis affecting the three nerves and 67% for neuroma detection. Regional muscle denervation was better evaluated on MRN studies than at surgery. Smaller (1-3 mm) abnormal cutaneous nerve branches were better seen at surgery. CONCLUSION: MRN yields accurate morphologic information about the location and extent of nerve injury after failed tarsal tunnel release and facilitates preoperative diagnosis. PMID- 21701029 TI - Sacral fractures after lumbosacral fusion: a characteristic fracture pattern. AB - OBJECTIVE: The purpose of this study was to describe the radiologic pattern of sacral fractures after lumbosacral fusion and to identify clinical characteristics relevant to the radiologic diagnosis. MATERIALS AND METHODS: A search of CT, nuclear medicine, and MRI radiology reports over a 5-year period at our institution revealed a total of 23 patients with sacral fractures after lumbosacral fusion. Two radiologists reviewed all of the images to determine the sacral fracture pattern. The clinical records of these patients were reviewed for interval after surgery, fusion length, hardware, approach, preoperative diagnosis, symptoms, treatment, and risk factors. RESULTS: All 23 sacral fractures were horizontal through the sacral body, involved the screw holes, and exited through the posterosuperior sacral alae. The fractures occurred within 3 months of fusion in 19 of 23 patients. All 23 patients had symptoms at the time of fracture. Seventeen of 23 fusions were long (more than four vertebrae). Four of 23 patients had osteoporosis. Eleven of 23 fractures healed without surgery, and 12 were managed with transiliac fixation. CONCLUSION: Sacral fractures after lumbosacral fusion have a characteristic transverse pattern through the sacral screw holes that differs from the configuration of more common sacral insufficiency fractures. Most of these fractures occur within 3 months after surgery, and many of the patients need additional surgical fixation. Because few of the patients had osteoporosis and most underwent long fusion, the fractures might have been caused by hardware-related stress raisers in the sacrum. PMID- 21701030 TI - CT and MRI evaluation of nerve sheath tumors of the cervical vagus nerve. AB - OBJECTIVE: Nerve sheath tumors arising from the cervical vagus are rare. The purpose of this study was to evaluate the role of CT and MRI in the diagnosis of these uncommon neoplasms. MATERIALS AND METHODS: The CT and MR studies and clinical data of 11 patients with surgicopathologic evidence of a nerve sheath tumor of the cervical vagus (nine schwannomas [including two ancient schwannomas] and two neurofibromas) who had been referred to our institute from January 1999 through 2009 were retrospectively reviewed. The tumors were evaluated with respect to their location, number, morphology, attenuation and/or signal intensity, enhancement characteristics, and patterns of mass effect. RESULTS: The tumors were solitary and well circumscribed. On CT, eight tumors were hypodense with poor enhancement, two were predominantly isodense, and a single lesion had multiple cystic areas with enhancing solid components. On MRI, they were heterogeneously bright on T2-weighted images with intense, inhomogeneous postgadolinium enhancement. The "split fat" sign, "entering and exiting nerve" sign, "fascicular" sign, and "hyperintense rim" sign were seen in some patients. The internal or common carotid artery was displaced anteriorly in eight patients, maintained a neutral position in two patients, and was displaced posterolaterally in another patient. In all patients except two, the tumor separated the carotid artery from the internal jugular vein. Vagal schwannomas splayed the carotid bifurcation in three patients. CONCLUSION: In conclusion, we present the patterns of mass effect and a spectrum of CT and MRI characteristics of nerve sheath tumor of the cervical vagus including observations that are sparingly described in the published literature. PMID- 21701031 TI - Assessment of MRI issues for a 3-T "immune" programmable CSF shunt valve. AB - OBJECTIVE: A newly developed CSF shunt valve that incorporates a magnetically adjustable mechanism designed to resist unintended setting changes was evaluated for problems during 3-T MRI. MATERIALS AND METHODS: Standardized protocols were used to assess magnetic field interactions, MRI-related heating, artifacts, and functional changes related to multiple exposures and various MRI conditions in nine different samples at 3 T. RESULTS: The magnetic field interactions were not excessive. MRI-related heating, which was studied at a relatively high, MRI system-reported whole body-averaged specific absorption rate (2.9 W/kg), was at a level that should not pose a hazard to a patient. Although artifacts were large in relation to the dimensions of this programmable CSF shunt valve, the results were consistent with similar devices containing permanent magnets. Multiple exposures and various MRI conditions at 3 T did not damage or affect the functional aspects of the devices, and no unintentional changes to the valve setting were observed. CONCLUSION: In consideration of the test results, this new programmable CSF shunt valve is not adversely affected by the 3-T MRI environment and is acceptable for a patient undergoing MRI at 3 T or less when specific guidelines are followed, including verifying the valve setting according to manufacturer recommendations immediately after the MRI procedure. PMID- 21701032 TI - Adrenal masses in patients with cancer: PET/CT characterization with combined CT histogram and standardized uptake value PET analysis. AB - OBJECTIVE: Our purpose was to determine the diagnostic performance of 18F-FDG PET/CT for characterizing adrenal masses in patients with cancer, combining standardized uptake value (SUV) and CT histogram analysis. MATERIALS AND METHODS: A total of 117 adrenal masses in 93 patients with cancer (61 men and 32 women; mean [+/- SD] age, 67.2 +/- 10.3 years; range, 38-84 years) were evaluated with FDG PET/CT. Of the 117 lesions, 42 were malignant according to histopathologic analysis or size change, whereas 75 were benign on the basis of stability for 6 months. Size, mean attenuation value, percentage of negative pixels at CT histogram analysis, maximum SUV (SUV(max)), and average SUV were calculated for each adrenal lesion. Moreover, FDG adrenal uptake was compared with radioactivity of the aorta, liver, and spleen by calculating the SUV ratios of adrenal lesion to aorta, adrenal lesion to liver, and adrenal lesion to spleen. PET/CT value was assessed by using independent t tests and receiving operating characteristic (ROC) analysis. RESULTS: There was a statistically significant difference in size, attenuation value, percentage of negative pixels, and SUV between benign and malignant masses. All malignant lesions showed FDG activity higher than that in liver, spleen, and aorta, with SUV(max) greater than 2.8 in all cases, whereas with the CT histogram analysis, all lesions with a percentage of negative pixels higher than 10% were benign. Combined SUV and CT histogram analysis yielded 100% sensitivity, 97.3% specificity, 95.7% positive predictive value, and 100% negative predictive value. At ROC analysis, combined SUV and CT histogram analysis (area under the ROC curve [AUC], 0.996) was more accurate than simple SUV(max) analysis (AUC, 0.961) and the combination of SUV(max) and attenuation value (AUC, 0.987). CONCLUSION: The combination of SUV and CT histogram analysis allowed us to significantly improve the PET/CT diagnostic accuracy for characterizing adrenal lesions, leading to a significant reduction in the number of false-positive cases. PMID- 21701033 TI - Childhood cancer risk from conventional radiographic examinations for selected referral criteria: results from a large cohort study. AB - OBJECTIVE: Little is known about the long-term effects of exposure to diagnostic ionizing radiation in childhood. Current estimates are made with models derived mainly from studies of atomic bomb survivors, a population that differs from today's patients in many respects. MATERIALS AND METHODS: We analyzed the cancer incidence among children who underwent diagnostic x-ray exposures between 1976 and 2003 in a large German university hospital. We reconstructed individual radiation doses for each examination and sorted results by groups of referral criteria for all cancers combined, solid tumors, and leukemia and lymphoma combined. RESULTS: A total of 68 incidence cancer cases between 1980 and 2006 were identified in a 78,527-patient cohort in the German childhood cancer registry: 28 leukemia, nine lymphoma, six tumors of the CNS, and 25 other tumors. The standardized incidence ratio for all cancers was 0.97 (95% CI, 0.75-1.23). Dose-response relations were analyzed by multivariable Poisson regression. Although the cancer incidence risk differed by initial referral criterion for radiographic examination, a positive dose-response relation was observed in five patients with endocrine or metabolic disease. CONCLUSION: Overall, we observed no increase in cancer risk among children and youths with very low radiation doses from diagnostic radiation, which is compatible with model calculations. The growing use of CT warrants further studies to assess associated cancer risk. Our work is an early contribution of epidemiologic data for quantifying these risks among young patients. PMID- 21701035 TI - Evaluation of potential outcome predictors in type II Endoleak: a retrospective study with CT angiography feature analysis. AB - OBJECTIVE: The purpose of this study is to investigate which CT features of type II endoleaks following abdominal aortic aneurysm (AAA) endoluminal stent-graft repair can be used to predict clinical outcome. MATERIALS AND METHODS: We retrospectively identified 59 patients with type II endoleak after endovascular repair of an AAA with CT of the abdomen and pelvis. Patients were stratified into two groups: those who did (n = 23) and those who did not (n = 35) require reintervention. CT characteristics of type II endoleaks were recorded and correlated with the clinical outcome. RESULTS: The CT features showing the strongest association with the clinical outcome were the transverse diameter of the endoleak cavity (mean, 1.13 cm in the nonreintervention group vs 1.85 cm in the reintervention group; p = 0.007) and the maximum diameter of the vessel communicating with the endoleak (0.34 vs 0.40 cm; p = 0.046). The transverse diameter of the endoleak cavity on arterial phase imaging had the greatest predictive capability, with an area under the receiver operating characteristic curve of 0.74. A transverse diameter greater than 1.42 cm had a positive predictive value of 0.71 and a negative predictive value of 0.82. The anteroposterior diameter, location, and heterogeneity of the endoleak cavity and the number of patent communicating vessels did not correlate well with clinical outcome. The correlation between endoleak cavity measurements and clinical outcome was independent of the aneurysm size. CONCLUSION: There are identifiable CT features associated with the clinical outcome of patients with type II endoleak that have moderate predictive capabilities. PMID- 21701034 TI - Prospective evaluation of MR enterography as the primary imaging modality for pediatric Crohn disease assessment. AB - OBJECTIVE: The objectives of this study were prospective evaluation of MR enterographic accuracy for detecting Crohn disease imaging features in pediatric patients, compared with a CT reference standard, as well as determination of MR enterographic accuracy for detecting active bowel inflammation and fibrosis using a histologic reference standard. SUBJECTS AND METHODS: The study group for this blinded prospective study included 21 pediatric subjects with known Crohn disease scheduled for clinical CT and histologic bowel sampling for symptomatic exacerbation. All subjects and their parents gave informed consent to also undergo MR enterography. CT and MR enterography examinations were independently reviewed by two radiologists and were scored for Crohn disease features. All bowel histology specimens were reviewed by a single pathologist for the presence of active mucosal inflammation and mural fibrosis, followed by correlation of imaging and histologic findings. RESULTS: All 21 subjects underwent MR enterography and histologic sampling, 18 of whom also underwent CT. MR enterography had high sensitivity for detecting Crohn disease imaging features (e.g., bowel wall thickening, mesenteric inflammation, lymphadenopathy, fistula, and abscess) compared with CT, with individual sensitivity values ranging from 85.1% to 100%. Of a total of 53 abnormal bowel segments with correlation of MRI and histologic findings, MR enterography showed 86.7% accuracy (90.0% sensitivity and 82.6% specificity) for detecting active inflammation (p < 0.001). The accuracy of MR enterography for detecting mural fibrosis overall was 64.9%, compared with histology, but increased to 83.3% (p < 0.05) for detecting fibrosis without superimposed active inflammation. CONCLUSION: MR enterography can substitute for CT as the first-line imaging modality in pediatric patients with Crohn disease, on the basis of its ability to detect intestinal pathologic abnormalities in both small and large bowel as well as extraintestinal disease manifestations. Additionally, MR enterography provides an accurate noninvasive assessment of Crohn disease activity and mural fibrosis and can aid in formulating treatment strategies for symptomatic patients and assessing therapy response. PMID- 21701036 TI - Interventional radiology in the management of abdominal collections after distal pancreatectomy: a retrospective review. AB - OBJECTIVE: The purpose of this study was to assess the technical and clinical success and complications of imaging-guided percutaneous catheter drainage of peripancreatic fluid collections after distal pancreatectomy. MATERIALS AND METHODS: Between January 2001 and February 2009, the cases of patients who underwent distal pancreatectomy were selected from a surgical database, and the cases of those who underwent subsequent interventional radiologic percutaneous drainage were identified. Details of percutaneous catheter drainage were recorded, and technical and clinical success was determined. Technical success was defined as successful percutaneous imaging-guided placement of a drainage catheter. Primary clinical success was defined as resolution of peripancreatic fluid collection with percutaneous drainage only. Secondary clinical success was defined as resolution of peripancreatic fluid collection with percutaneous drainage and additional manipulations (i.e., tube repositioning, additional catheter drainage) and no surgical debridement. Multifactor logistic regression analysis was used to identify predictors of drain failure. RESULTS: Between January 2001 and February 2009, 365 patients underwent distal pancreatectomy. Of these, 51 patients (14%; 25 men, 26 women; mean age, 53.4 years; range, 18-81 years) underwent 57 CT-guided percutaneous procedures for drainage of postsurgical peripancreatic fluid collection. The mean interval between surgery and drainage was 23.5 days (median, 17 days; range, 2-120 days), and the mean collection size was 7.3 cm in transverse dimension (median, 6.9 cm; range, 2.3-16 cm). The mean duration of catheter drainage was 39.7 days (median, 24 days; range, 3-220 days). The technical success rate was 100%, primary clinical success rate was 60%, and primary and secondary clinical success rates together were 95%. Three of the 51 patients (6%) needed surgery for definitive management of the collection. One of 51 patients (2%) had a complication of the interventional radiologic procedure. Catheter size and the need for additional catheter manipulation were significantly associated with drainage failure (p < 0.05). CONCLUSION: Catheter drainage of peripancreatic fluid collections after distal pancreatectomy is a technically safe and clinically effective procedure. Although extra manipulations may be needed to achieve clinical success, the combined primary and secondary clinical success rates are high. PMID- 21701037 TI - Outcome of early first-trimester pregnancies (< 6.1 weeks) with slow embryonic heart rate. AB - OBJECTIVE: The purpose of this article is to assess prospectively the value of concordant versus discordant gestational age (GA) calculations in predicting subsequent embryonic demise in embryos with a slow heart rate, as determined on early first-trimester ultrasound. SUBJECTS AND METHODS: Thirty-six consecutive singleton pregnancies with slow embryonic heart rate (< 100 beats/min) measured on a 5.0- to 6.1-week ultrasound were prospectively identified. Pregnancies were defined as "discordant" if there was more than 5 days' difference between GA determined by biometrics compared with GA determined by last menstrual period and were defined as "concordant" if there was less than 5 days' difference between the GA measurements. RESULTS: Of the 36 embryos with heart rate less than 100 beats/min at 5.0-6.1 weeks' GA, 16 went on to demise and 20 survived. Of the 16 that went on to demise, 14 were discordant (88%) and two were concordant (12%). Of the 20 that survived, 16 were concordant (80%) and four were discordant (20%). The proportion of discordant pregnancies that went on to demise was 14 of 18 (negative predictive value, 78%). The proportion of concordant pregnancies that went on to survival was 16 of 18 (positive predictive value, 89%). The rate of demise in the discordant group was significantly higher than that in the concordant group (p < 0.001, Fisher's exact test). CONCLUSION: Embryonic heart rate less than 100 beats/min detected at 6.1 weeks or less is not necessarily a poor prognostic indicator. The likelihood of subsequent first-trimester survival is significantly higher if there is concordance between GA as calculated by biometrics and last menstrual period than if there is discordance. PMID- 21701038 TI - Endometrial cancer: correlation of apparent diffusion coefficient with tumor grade, depth of myometrial invasion, and presence of lymph node metastases. AB - OBJECTIVE: The objective of our study was to investigate whether apparent diffusion coefficient (ADC) values of endometrial cancer differ from those of normal endometrium and myometrium and whether they vary according to histologic tumor grade, the depth of myometrial invasion, or lymph node status. SUBJECTS AND METHODS: Seventy patients with histologically proved endometrial cancer and 36 control subjects with normal endometrium were enrolled in this prospective study. T2-weighted, dynamic T1-weighted, and diffusion-weighted images with b values of 0 and 1000 s/mm(2) were obtained of all patients. The ADC values of endometrial cancer, normal endometrium, and normal myometrium were recorded. Tumor grade, the depth of myometrial invasion, and lymph node status were assessed at postoperative histopathologic analysis. RESULTS: The mean (+/- SD) ADC value (10( 3) mm(2)/s) of endometrial cancer (0.77 +/- 0.12) was significantly lower than that of normal endometrium (1.31 +/- 0.11, p < 0.0001) and normal myometrium (1.52 +/- 0.21, p < 0.0001), with no overlap between the two former distributions. There was no significant difference between ADC values of endometrial cancer tissue in patients with tumor grade 1 (0.79 +/- 0.08, n = 14), grade 2 (0.76 +/- 0.14, n = 40), or grade 3 (0.75 +/- 0.12, n = 16) (p = 0.67); in patients with deep (0.77 +/- 0.13, n = 18) and those with superficial (0.76 +/ 0.12, n = 52) myometrial invasion (p = 0.87); and in patients with (0.78 +/- 0.10, n = 6) and those without (0.75 +/- 0.14, n = 39) lymph node metastases (p = 0.64). CONCLUSION: ADC values allow normal endometrium to be differentiated from endometrial carcinoma; however, they do not correlate with histologic tumor grade, the depth of myometrial invasion, or whether lymph node metastases are present. PMID- 21701039 TI - Breast imaging training and attitudes: update survey of senior radiology residents. AB - OBJECTIVE: The purpose of this study was to investigate the training and attitudes of senior residents regarding breast imaging. MATERIALS AND METHODS: In 2008 a follow-up survey was completed by a chief or senior resident at 201 radiology training programs in North America. Questions included organization of breast imaging rotation, resident responsibilities, clinical practice protocols at the institution, resident impressions regarding breast imaging, and resident interest in performing breast imaging after residency. Results were compared with those of a survey completed in 2000. RESULTS: Of 201 training programs, 200 (99.5%) had dedicated breast imaging rotations; 190 (95%), 12 weeks or longer; and 39 (19%), 16 weeks or longer. Residents regularly performed real-time ultrasound imaging in 138 programs (69%), needle localization in 159 (79%), ultrasound-guided biopsy in 154 (77%), and stereotactically guided biopsy in 145 programs (72%). One hundred sixty-two residents (81%) reported that interpreting mammograms was more stressful than interpretation of other imaging studies; 143 (71%) believed that only breast imaging subspecialists should interpret mammograms; and 104 (52%) would not consider pursuing a breast imaging fellowship. As in 2000, the most common reasons cited for not considering a fellowship were lack of interest in the field, fear of lawsuits, and the stressful nature of the job. CONCLUSION: Residency programs have devoted more time to breast imaging and made improvements in their curricula, but current residents report decreased opportunities to perform some studies and procedures. Although most residents would not consider a fellowship and did not want to interpret mammograms in future practice, the percentage of residents who would not consider breast imaging as a subspecialty has decreased since 2000. An accurate picture of current breast imaging curricula and variations among residency programs is necessary to identify and correct systemic problems and to improve the training of future breast imagers. PMID- 21701040 TI - Multiparity causes uncoordinated activity of pelvic- and perineal-striated muscles and urodynamic changes in rabbits. AB - Temporal and coordinated activation of pelvic- (pubococcygeous) and perineal- (bulbospongiosus and ischiocavernosus) striated muscles occurs during micturition in female rabbits. We have hypothesized that the coordinated activation of pelvic and perineal muscles is modified during the micturition of young multiparous rabbits. Young virgin and multiparous female chinchilla rabbits were used to simultaneously record cystometrograms and electromyograms of the pubococcygeous, ischocavernosus, and bulbospongiosus muscles. Bladder function was assessed using standard urodynamic variables. The temporal coordination of pelvic- and perineal striated muscle activity was changed in multiparous rabbits. The cystometrogram recordings were different than those obtained from virgin rabbits, as seen in alterations of the threshold volume, the residual volume, the voiding duration, and the maximum pressure. In rabbits, we find that multiparity causes uncoordinated activity of pubococcygeous, ischiocavernosus, and bulbospongiosus muscles and modifies the urodynamics. PMID- 21701041 TI - Dichloroacetate induces apoptosis of epithelial ovarian cancer cells through a mechanism involving modulation of oxidative stress. AB - Epithelial ovarian cancer (EOC) cells are under intrinsic oxidative stress, which alters metabolic activity and reduces apoptosis. Key oxidative stress enzymes, including myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS), are upregulated and colocalized in EOC cells. Oxidative stress is also regulated, in part, by superoxide dismutase (SOD) and hypoxia-inducible factor (HIF) 1a. Dichloroacetate (DCA) converts anaerobic to aerobic metabolism and thus was utilized to determine the effects on apoptosis, iNOS, MPO, extracellular SOD (SOD 3), and HIF-1a, in EOC cells. Protein and messenger RNA (mRNA) levels of iNOS, MPO, SOD-3, and HIF-1a were evaluated by immunoprecipitation/Western blot and real-time reverse transcriptase-polymerase chain reaction (RT-PCR), respectively, utilizing SKOV-3 and MDAH-2774 treated with DCA. Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and caspase 3 assays. Dichloroacetate induced apoptosis, reduced MPO, iNOS, and HIF 1a, whereas increased SOD, in both EOC cell lines. In conclusion, reduction of enhanced oxidative stress-induced apoptosis of EOC cells, which may serve as future therapeutic intervention for ovarian cancer. PMID- 21701042 TI - Increased nerve fibers in placental bed myometrium in women with preeclampsia. AB - Narrowing of the uterine spiral arterioles below the deciduomyometrial junction is 1 of the key pathophysiological changes in women with preeclampsia. The contribution of pelvic autonomic nerves to decidualization and impaired placentation in preeclampsia is not clear. Placental bed biopsies were obtained from 10 women with preeclampsia and 23 nornotensive women at caesarean section. We stained them with anti-S100 and CD34 antibodies to detect the presence of nerve fibers and blood vessels, respectively. We detected S100-immunoactive nerve fibers in the myometrium but not in the decidua in both groups of women. S100 immunoactive nerve fiber density in the placental bed myometrium was significantly increased in women with preeclampsia compared to normotensive women. There was no clear relationship between the densities of nerve fibers and CD34-positive blood vessels in these biopsies. These results suggest increased nerve fibers in the placental bed myometrium may play a role in the pathogenesis of the preeclampsia. PMID- 21701043 TI - Adaptation of a postoperative handoff communication process for children with heart disease: a quantitative study. AB - Handoff communication is a point of vulnerability when valuable patient information can be inaccurate or omitted. An institutional protocol was implemented in 2005 to improve the handoff from the operating room to the intensive care unit after pediatric cardiac surgery. A cross-sectional study of the present process was performed to understand how users adapt a communication intervention over time. Twenty-nine handoff events were observed. Individuals required for the handoff were present at 97% of the events. Content items averaged a 53% reporting rate. Some clinical information not specified in the protocol demonstrated a higher reporting rate, such as echocardiogram results (68%) and vascular access (79%). A mean of 2.3 environmental distractions per minute of communication were noted. Participant-directed adjustments in content reporting suggest that a facilitator in process improvement is user-centered innovation. Future handoff communication interventions should reduce nonessential distractions and incorporate a discussion of the anticipated patient course. PMID- 21701045 TI - Negative pressure wound therapy - a descriptive study. AB - To address a persistent lack of evidence regarding the clinical outcomes of negative pressure wound therapy (NPWT) and identify which patient groups are most likely to benefit from NPWT, a retrospective, descriptive study was conducted to describe outcomes of this treatment modality when used in clinical practice. Charts from a consecutive series of 87 patients (median age 68 years, range 16 - 92 years) who received NPWT during a period of 24 months were abstracted to a statistical software file. Patient demographics, history, and comorbidity variables as well as treatment outcomes were obtained from the computerized in- and outpatient record system. Treatment outcomes were grouped as successful (goal of care was met) or not successful (goal of care was not met). Successful treatment was noted for a total of 62 patients (71%) with a median treatment time of 17 days. The proportion of patients with a successful outcome was significantly higher in patients with infectious, postoperative, and traumatic wounds than in patients with wounds related to peripheral vascular disease or pressure ulcers (P = 0.001). Treatment complications were observed in 18 patients (21%); five were related to infection. Quality-of-life concerns were noted as a reason for stopping treatment in four patients and equipment problems were recorded for two patients receiving NPWT in the home. This study confirms previous re- search that NPWT may be an effective and safe treatment method for acute wounds but further studies are needed to evaluate treatment efficacy and effectiveness in patients with peripheral vascular disease or pressure-induced wounds. Results also suggest that research protocols should include patient quality-of-life outcomes. PMID- 21701044 TI - Bypass of a nick by the replisome of bacteriophage T7. AB - DNA polymerase and DNA helicase are essential components of DNA replication. The helicase unwinds duplex DNA to provide single-stranded templates for DNA synthesis by the DNA polymerase. In bacteriophage T7, movement of either the DNA helicase or the DNA polymerase alone terminates upon encountering a nick in duplex DNA. Using a minicircular DNA, we show that the helicase . polymerase complex can bypass a nick, albeit at reduced efficiency of 7%, on the non template strand to continue rolling circle DNA synthesis. A gap in the non template strand cannot be bypassed. The efficiency of bypass synthesis depends on the DNA sequence downstream of the nick. A nick on the template strand cannot be bypassed. Addition of T7 single-stranded DNA-binding protein to the complex stimulates nick bypass 2-fold. We propose that the association of helicase with the polymerase prevents dissociation of the helicase upon encountering a nick, allowing the helicase to continue unwinding of the duplex downstream of the nick. PMID- 21701046 TI - Blunt trauma as a cause of rib chondro-osteitis: a case study. AB - Rib chondro-osteitis is rare and usually caused by tuberculosis. A 63-year-old man presented with fever, painful swelling, and a burning sensation in the parasternal right submammary region. He had a history of cardiac interventions: percutaneous transcatheter angioplasty with stenting 1 year prior and coronary artery bypass graft surgery 16 years before; therefore, he was on dual antiplatelet therapy. He sustained blunt chest trauma 5 months before admission. A chest wall abscess was suspected and fine needle aspiration of the lesion revealed the presence of purulent fluid. Culture results were positive for Staphylococcus aureus and intravenous antibiotic therapy was started. Computed tomography showed a lesion involving the sternal, chondral, and proximal costal portions of the fourth, fifth, and sixth anterior costal arches. The patient was diagnosed with costal chondo-osteitis following blunt trauma. Following aggressive surgical debridement, the wound was managed with topical negative pressure therapy (constant -125 mm Hg setting with daily dressing changes). After 15 days, culture results were negative, the wound bed contained healthy granulation tissue, and the defect was surgically closed using a myocutaneous flap. No recurrence or complications have been observed during the 2-year follow up. This is the first reported case of pyogenic, posttraumatic, costal chondro osteitis secondary to a blunt trauma of the chest wall. PMID- 21701047 TI - SIRT1 and SIRT3 deacetylate homologous substrates: AceCS1,2 and HMGCS1,2. AB - SIRT1 and SIRT3 are NAD+-dependent protein deacetylases that are evolutionarily conserved across mammals. These proteins are located in the cytoplasm/nucleus and mitochondria, respectively. Previous reports demonstrated that human SIRT1 deacetylates Acetyl-CoA Synthase 1 (AceCS1) in the cytoplasm, whereas SIRT3 deacetylates the homologous Acetyl-CoA Synthase 2 (AceCS2) in the mitochondria. We recently showed that 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2) is deacetylated by SIRT3 in mitochondria, and we demonstrate here that SIRT1 deacetylates the homologous 3-hydroxy-3-methylglutaryl CoA synthase 1 (HMGCS1) in the cytoplasm. This novel pattern of substrate homology between cytoplasmic SIRT1 and mitochondrial SIRT3 suggests that considering evolutionary relationships between the sirtuins and their substrates may help to identify and understand the functions and interactions of this gene family. In this perspective, we take a first step by characterizing the evolutionary history of the sirtuins and these substrate families. PMID- 21701048 TI - Potential sources of 2-aminoacetophenone to confound the Pseudomonas aeruginosa breath test, including analysis of a food challenge study. AB - 2-Aminoacetophenone can be detected in the breath of Pseudomonas aeruginosa colonized cystic fibrosis patients; however, low levels were also detected in a small proportion of healthy subjects. It was hypothesized that food, beverages, cosmetics or medications could be a source of contamination of 2 aminoacetophenone in breath. To determine the potential confounding of these products on 2-aminoacetophenone breath analysis, screening for this volatile was performed in the laboratory by gas chromatography/mass spectrometry and a food challenge study carried out. 2-Aminoacetophenone was detected in four of the 78 samples tested in vitro: corn chips and canned tuna (high pmol mol(-1)) and egg white and one of the three beers (low pmol mol(-1)). No 2-aminoacetophenone was detected in the CF medication or cosmetics tested. Twenty-eight out of 30 environmental air samples were negative for 2-aminoacetophenone (below 50 pmol mol(-1)). A challenge study with ten healthy subjects was performed to determine if 2-aminoacetophenone from corn chips was detectable on the breath after consumption. Analysis of mixed breath samples reported that the levels of 2 aminoacetophenone were immediately elevated after corn chip consumption, but after 2 h the level of 2-aminoacetophenone had reduced back to the 'baseline' for each subject. PMID- 21701049 TI - Calculation of shear stiffness in noise dominated magnetic resonance elastography data based on principal frequency estimation. AB - Magnetic resonance elastography (MRE) is a non-invasive phase-contrast-based method for quantifying the shear stiffness of biological tissues. Synchronous application of a shear wave source and motion encoding gradient waveforms within the MRE pulse sequence enable visualization of the propagating shear wave throughout the medium under investigation. Encoded shear wave-induced displacements are then processed to calculate the local shear stiffness of each voxel. An important consideration in local shear stiffness estimates is that the algorithms employed typically calculate shear stiffness using relatively high signal-to-noise ratio (SNR) MRE images and have difficulties at an extremely low SNR. A new method of estimating shear stiffness based on the principal spatial frequency of the shear wave displacement map is presented. Finite element simulations were performed to assess the relative insensitivity of this approach to decreases in SNR. Additionally, ex vivo experiments were conducted on normal rat lungs to assess the robustness of this approach in low SNR biological tissue. Simulation and experimental results indicate that calculation of shear stiffness by the principal frequency method is less sensitive to extremely low SNR than previously reported MRE inversion methods but at the expense of loss of spatial information within the region of interest from which the principal frequency estimate is derived. PMID- 21701050 TI - Image quality assessment in digital mammography: part II. NPWE as a validated alternative for contrast detail analysis. AB - Assessment of image quality for digital x-ray mammography systems used in European screening programs relies mainly on contrast-detail CDMAM phantom scoring and requires the acquisition and analysis of many images in order to reduce variability in threshold detectability. Part II of this study proposes an alternative method based on the detectability index (d') calculated for a non prewhitened model observer with an eye filter (NPWE). The detectability index was calculated from the normalized noise power spectrum and image contrast, both measured from an image of a 5 cm poly(methyl methacrylate) phantom containing a 0.2 mm thick aluminium square, and the pre-sampling modulation transfer function. This was performed as a function of air kerma at the detector for 11 different digital mammography systems. These calculated d' values were compared against threshold gold thickness (T) results measured with the CDMAM test object and against derived theoretical relationships. A simple relationship was found between T and d', as a function of detector air kerma; a linear relationship was found between d' and contrast-to-noise ratio. The values of threshold thickness used to specify acceptable performance in the European Guidelines for 0.10 and 0.25 mm diameter discs were equivalent to threshold calculated detectability indices of 1.05 and 6.30, respectively. The NPWE method is a validated alternative to CDMAM scoring for use in the image quality specification, quality control and optimization of digital x-ray systems for screening mammography. PMID- 21701051 TI - Image quality assessment in digital mammography: part I. Technical characterization of the systems. AB - In many European countries, image quality for digital x-ray systems used in screening mammography is currently specified using a threshold-detail detectability method. This is a two-part study that proposes an alternative method based on calculated detectability for a model observer: the first part of the work presents a characterization of the systems. Eleven digital mammography systems were included in the study; four computed radiography (CR) systems, and a group of seven digital radiography (DR) detectors, composed of three amorphous selenium-based detectors, three caesium iodide scintillator systems and a silicon wafer-based photon counting system. The technical parameters assessed included the system response curve, detector uniformity error, pre-sampling modulation transfer function (MTF), normalized noise power spectrum (NNPS) and detective quantum efficiency (DQE). Approximate quantum noise limited exposure range was examined using a separation of noise sources based upon standard deviation. Noise separation showed that electronic noise was the dominant noise at low detector air kerma for three systems; the remaining systems showed quantum noise limited behaviour between 12.5 and 380 uGy. Greater variation in detector MTF was found for the DR group compared to the CR systems; MTF at 5 mm(-1) varied from 0.08 to 0.23 for the CR detectors against a range of 0.16-0.64 for the DR units. The needle CR detector had a higher MTF, lower NNPS and higher DQE at 5 mm(-1) than the powder CR phosphors. DQE at 5 mm(-1) ranged from 0.02 to 0.20 for the CR systems, while DQE at 5 mm(-1) for the DR group ranged from 0.04 to 0.41, indicating higher DQE for the DR detectors and needle CR system than for the powder CR phosphor systems. The technical evaluation section of the study showed that the digital mammography systems were well set up and exhibiting typical performance for the detector technology employed in the respective systems. PMID- 21701052 TI - An efficient algorithm for the inverse problem in elasticity imaging by means of variational r-adaption. AB - A novel finite element formulation suitable for computing efficiently the stiffness distribution in soft biological tissue is presented in this paper. For that purpose, the inverse problem of finite strain hyperelasticity is considered and solved iteratively. In line with Arnold et al (2010 Phys. Med. Biol. 55 2035), the computing time is effectively reduced by using adaptive finite element methods. In sharp contrast to previous approaches, the novel mesh adaption relies on an r-adaption (re-allocation of the nodes within the finite element triangulation). This method allows the detection of material interfaces between healthy and diseased tissue in a very effective manner. The evolution of the nodal positions is canonically driven by the same minimization principle characterizing the inverse problem of hyperelasticity. Consequently, the proposed mesh adaption is variationally consistent. Furthermore, it guarantees that the quality of the numerical solution is improved. Since the proposed r-adaption requires only a relatively coarse triangulation for detecting material interfaces, the underlying finite element spaces are usually not rich enough for predicting the deformation field sufficiently accurately (the forward problem). For this reason, the novel variational r-refinement is combined with the variational h-adaption (Arnold et al 2010) to obtain a variational hr-refinement algorithm. The resulting approach captures material interfaces well (by using r adaption) and predicts a deformation field in good agreement with that observed experimentally (by using h-adaption). PMID- 21701053 TI - Experimental determination of the effective point of measurement for various detectors used in photon and electron beam dosimetry. AB - The subject of this study is the 'shift of the effective point of measurement', Deltaz, well known as a method of correction compensating for the 'displacement effect' in photon and electron beam dosimetry. Radiochromic EBT 1 films have been used to measure the 'true' TPR curves of 6 and 15 MV photons and 6 and 9 MeV electrons in the solid water-equivalent material RW3. For the Roos and Markus chambers, the cylindrical 'PinPoint', 'Semiflex' and 'Rigid-Stem' chambers, the 2D-Array and the E-type silicon diode (all from PTW-Freiburg), the positions of the effective points of measurement have been determined by direct or indirect comparison between their TPR curves and those of the EBT 1 film. Both for the Roos and Markus chambers, we found Deltaz = (0.4 +/- 0.1) mm, which confirms earlier experimental and Monte Carlo results, but means a shortcoming of the 'water-equivalent window thickness' formula. For the cylindrical chambers, the ratio Deltaz/r was observed to increase with r, confirming a recent Monte Carlo prediction by Tessier (2010 E2-CN-182, Paper no 147, IDOS, Vienna) as well as the experimental observations by Johansson et al (1978 IAEA Symp. Proc. (Vienna) IAEA SM-222/35 pp 243-70). According to a theoretical consideration, the shift of the effective point of measurement from the reference point of the detector is caused by a gradient of the fluence of the ionizing particles. As the experiments have shown, the value of Deltaz depends on the construction of the detector, but remains invariant under changes of radiation quality and depth. Other disturbances, which do not belong to the class of 'gradient effects', are not corrected by shifting the effective point of measurement. PMID- 21701054 TI - Sophisticated test objects for the quality assurance of optical computed tomography scanners. AB - Optical computed tomography (CT), in conjunction with radiochromic gels and plastics, shows great potential for radiation therapy dose verification in 3D. However, an effective quality assurance (QA) regime for the various scanners currently available still remains to be developed. We show how the favourable properties of the PRESAGE(r) radiochromic polymer may be exploited to create highly sophisticated QA phantoms. Five 60 mm diameter cylindrical PRESAGE(r) samples were irradiated using the x-ray microbeam radiation therapy facility on the ID-17 biomedical beamline at the European Synchrotron Radiation Facility. Samples were then imaged on the University of Surrey parallel-beam optical CT scanner. The sample irradiations were designed to allow a variety of tests to be performed, including assessments of linearity, modulation transfer function (three independent measurements), geometric distortion and the effect of treatment fractionation. It is clear that, although the synchrotron method produces extremely high-quality test objects, it is not practical on a routine basis, because of its reliance on a highly specialized radiation source. Hence, we investigated a second possibility: three PRESAGE(r) samples were illuminated with ultraviolet light of wavelength 365 nm, using cheap masks created by laser printing patterns onto overhead projector acetate sheets. There was good correlation between optical densities measured by the CT scanner and the expected UV 'dose' delivered. The results are encouraging and a proposal is made for a scanner test regime based on calibrated and well-characterized PRESAGE(r) samples. PMID- 21701055 TI - Review and current status of SPECT scatter correction. AB - Detection of scattered gamma quanta degrades image contrast and quantitative accuracy of single-photon emission computed tomography (SPECT) imaging. This paper reviews methods to characterize and model scatter in SPECT and correct for its image degrading effects, both for clinical and small animal SPECT. Traditionally scatter correction methods were limited in accuracy, noise properties and/or generality and were not very widely applied. For small animal SPECT, these approximate methods of correction are often sufficient since the fraction of detected scattered photons is small. This contrasts with patient imaging where better accuracy can lead to significant improvement of image quality. As a result, over the last two decades, several new and improved scatter correction methods have been developed, although often at the cost of increased complexity and computation time. In concert with (i) the increasing number of energy windows on modern SPECT systems and (ii) excellent attenuation maps provided in SPECT/CT, some of these methods give new opportunities to remove degrading effects of scatter in both standard and complex situations and therefore are a gateway to highly quantitative single- and multi-tracer molecular imaging with improved noise properties. Widespread implementation of such scatter correction methods, however, still requires significant effort. PMID- 21701056 TI - Three-dimensional electrode arrays for retinal prostheses: modeling, geometry optimization and experimental validation. AB - Three-dimensional electrode geometries were proposed to increase the spatial resolution in retinal prostheses aiming at restoring vision in blind patients. We report here the results from a study in which finite-element modeling was used to design and optimize three-dimensional electrode geometries. Proposed implants exhibit an array of well-like shapes containing stimulating electrodes at their bottom, while the common return grid electrode surrounds each well on the implant top surface. Extending stimulating electrodes and/or the grid return electrode on the walls of the cavities was also considered. The goal of the optimization was to find model parameters that maximize the focalization of electrical stimulation, and therefore the spatial resolution of the electrode array. The results showed that electrode geometries with a well depth of 30 um yield a tenfold increase in selectivity compared to the planar structures of similar electrode dimensions. Electrode array prototypes were microfabricated and implanted in dystrophic rats to determine if the tissue would behave as hypothesized in the model. Histological examination showed that retinal bipolar cells integrate the electrode well, creating isolated cell clusters. The modeling analysis showed that the stimulation current is confounded within the electrode well, leading to selective electrical stimulation of the individual bipolar cell clusters and thereby to electrode arrays with higher spatial resolution. PMID- 21701057 TI - Neuro-fuzzy decoding of sensory information from ensembles of simultaneously recorded dorsal root ganglion neurons for functional electrical stimulation applications. AB - Functional electrical stimulation (FES) is used to improve motor function after injury to the central nervous system. Some FES systems use artificial sensors to switch between finite control states. To optimize FES control of the complex behavior of the musculo-skeletal system in activities of daily life, it is highly desirable to implement feedback control. In theory, sensory neural signals could provide the required control signals. Recent studies have demonstrated the feasibility of deriving limb-state estimates from the firing rates of primary afferent neurons recorded in dorsal root ganglia (DRG). These studies used multiple linear regression (MLR) methods to generate estimates of limb position and velocity based on a weighted sum of firing rates in an ensemble of simultaneously recorded DRG neurons. The aim of this study was to test whether the use of a neuro-fuzzy (NF) algorithm (the generalized dynamic fuzzy neural networks (GD-FNN)) could improve the performance, robustness and ability to generalize from training to test sets compared to the MLR technique. NF and MLR decoding methods were applied to ensemble DRG recordings obtained during passive and active limb movements in anesthetized and freely moving cats. The GD-FNN model provided more accurate estimates of limb state and generalized better to novel movement patterns. Future efforts will focus on implementing these neural recording and decoding methods in real time to provide closed-loop control of FES using the information extracted from sensory neurons. PMID- 21701058 TI - A wirelessly powered and controlled device for optical neural control of freely behaving animals. AB - Optogenetics, the ability to use light to activate and silence specific neuron types within neural networks in vivo and in vitro, is revolutionizing neuroscientists' capacity to understand how defined neural circuit elements contribute to normal and pathological brain functions. Typically, awake behaving experiments are conducted by inserting an optical fiber into the brain, tethered to a remote laser, or by utilizing an implanted light-emitting diode (LED), tethered to a remote power source. A fully wireless system would enable chronic or longitudinal experiments where long duration tethering is impractical, and would also support high-throughput experimentation. However, the high power requirements of light sources (LEDs, lasers), especially in the context of the extended illumination periods often desired in experiments, precludes battery powered approaches from being widely applicable. We have developed a headborne device weighing 2 g capable of wirelessly receiving power using a resonant RF power link and storing the energy in an adaptive supercapacitor circuit, which can algorithmically control one or more headborne LEDs via a microcontroller. The device can deliver approximately 2 W of power to the LEDs in steady state, and 4.3 W in bursts. We also present an optional radio transceiver module (1 g) which, when added to the base headborne device, enables real-time updating of light delivery protocols; dozens of devices can be controlled simultaneously from one computer. We demonstrate use of the technology to wirelessly drive cortical control of movement in mice. These devices may serve as prototypes for clinical ultra-precise neural prosthetics that use light as the modality of biological control. PMID- 21701059 TI - Common networks for selective auditory attention for sounds and words? An fMRI study with implications for attention rehabilitation. AB - PURPOSE: In an fMRI study the functional networks involved in auditory selective attention for sounds and words were investigated. METHODS: 24 healthy volunteers (12 male, 12 female) had to respond to a category of targets (animal sounds vs. musical instruments, spoken names of instruments vs. animals; 6 targets, 12 nontargets) presented via headphones. RESULTS: Under both the sound and word condition besides left superior and middle temporal lobe activation there was bilateral activity in the superior frontal (including the anterior cingulate cortex ACC), middle and inferior frontal and inferior parietal lobes. Under both conditions we also found cerebellar activity. In general there was a high overlap of the related attention networks for both conditions. CONCLUSIONS: The activation patterns revealed a high overlap across stimulus conditions with only slight modulation caused by the quality of the auditory material. For rehabilitation of attention deficits after brain damage this implicates that a single training procedure might address a common network for selective attention deficits under different stimulus conditions. PMID- 21701060 TI - Single-session tDCS-supported retraining does not improve fine motor control in musician's dystonia. AB - BACKGROUND: Focal dystonia in musicians (MD) is a task-specific movement disorder with a loss of voluntary motor control during instrumental playing. Defective inhibition on different levels of the central nervous system is involved in the pathophysiology. Sensorimotor retraining is a therapeutic approach to MD and aims to establish non-dystonic movements. Transcranial direct current stimulation (tDCS) modulates cortical excitability and alters motor performance. In this study, tDCS of the motor cortex was expected to assist retraining at the instrument. METHODS: Nine professional pianists suffering from MD were included in a placebo-controlled double-blinded study. Retraining consisted of slow, voluntarily controlled movements on the piano and was combined with tDCS. Patients were treated with three stimulation protocols: anodal tDCS, cathodal tDCS and placebo stimulation. RESULTS: No beneficial effects of single-session tDCS-supported sensorimotor retraining on fine motor control in pianists with MD were found in all three conditions. CONCLUSIONS: The main cause of the negative result of this study may be the short intervention time. One retraining session with a duration of 20 min seems not sufficient to improve symptoms of MD. Additionally, a single tDCS session might not be sufficient to modify sensorimotor learning of a highly skilled task in musicians with dystonia. PMID- 21701061 TI - Delayed rehabilitation with task-specific therapies improves forelimb function after a cervical spinal cord injury. AB - PURPOSE: The effect of activity based therapies on restoring forelimb function in rats was evaluated when initiated one month after a cervical spinal cord injury. METHODS: Adult rats received a unilateral over-hemisection of the spinal cord at C4/5, which interrupts the right side of the spinal cord and the dorsal columns bilaterally, resulting in severe impairments in forelimb function with greater impairment on the right side. One month after injury rats were housed in enriched housing and received daily training in reaching, gridwalk, and CatWalk. A subset of rats received rolipram for 10 days to promote axonal plasticity. Rats were tested weekly for six weeks for reaching, elevated gridwalk, CatWalk, and forelimb use during vertical exploration. RESULTS: Rats exposed to enriched housing and daily training significantly increased the number of left reaches and pellets grasped and eaten, reduced the number of right forelimb errors on the gridwalk, increased right forelimb use during vertical exploration, recovered more normal step cycles, and reduced their hindlimb base of support on the CatWalk compared to rats in standard cages without daily training. CONCLUSIONS: Delayed rehabilitation with enriched housing and daily forelimb training significantly improved skilled, sensorimotor, and automatic forelimb function together after cervical spinal cord injury. PMID- 21701062 TI - Goal-directed visuomotor skill learning: off-line enhancement and the importance of the primary motor cortex. AB - PURPOSE: The time course and neural substrates of motor skill learning are not well-understood in healthy or neurologic patient populations. Certain motor skills undergo off-line skill enhancement following training and the primary motor cortex (M1) may be involved. It is unknown if goal-directed visuomotor skill undergoes off-line enhancement or if M1 is associated with that enhancement. METHODS: 32 right-handed, healthy subjects were randomly assigned to two groups: real repetitive transcranial magnetic stimulation (rTMS) or sham rTMS applied to the contralateral M1 immediately following one 20-minute finger tracking training session. Tracking performance and cortical excitability were assessed before and after training, following rTMS and 24 hours post-training. RESULTS: Results demonstrate that skill performance continues to develop for at least 30 minutes after training completion, is maintained for 24 hours post training, and is not affected by inhibitory rTMS applied to M1. Level of skill improvement was associated with the degree of intracortical inhibition increase. CONCLUSIONS: These results suggest dispersed information processing for goal directed visuomotor skill learning following training and a relationship between cortical excitability and skill development in healthy individuals. These findings invite further investigation of the neural mechanisms underlying motor skill learning and may have rehabilitation implications for patients with neurologic injury. PMID- 21701063 TI - Longitudinal study of wind-up responses after graded spinal cord injuries in the adult rat. AB - PURPOSE: The main objectives of this work were to evaluate the development of neuropathic pain after spinal cord injuries of different severities, and to assess changes in central excitability and plasticity by means of wind-up responses and withdrawal reflexes. METHODS: Two groups of rats were subjected to spinal cord contusion with forces of 100 or 200 kdyn applied at T8. Measurements of thermal and mechanical pain thresholds as well as wind-up measurements were performed weekly during two months after injury. Withdrawal reflexes were also assessed electrophysiologically. RESULTS: We found that animals with contusion of different severities showed a similar reduction in nociceptive thresholds. All contused animals showed increased wind-up responses compared to intact animals during the first 2 to 6 weeks post injury. The mean increase of wind-up was higher in rats with stronger spinal cord contusion. Results from the withdrawal reflexes did not correlate with nociceptive behaviors nor wind-up responses, highlighting the plasticity of spinal circuits modulation after SCI. CONCLUSION: These results indicate that the graded-force spinal cord contusion model is suitable for studying central neuropathic pain, and for assessing changes in wind up responses. Wind-up measurements can be used as a non-invasive technique to detect changes in central excitability after SCI of different severities. PMID- 21701064 TI - Long-term morphometric stabilization of regenerating retinal ganglion cells in the adult rat. AB - PURPOSE: Adult retinal ganglion cells (RGCs) can regenerate their cut axons within peripheral nerve grafts used to replace the distal optic nerve stump. We examined the long-term stabilization of RGCs by guiding their regenerating axons into different termination areas. METHODS: The optic nerve (ON) of adult rats was completely cut intraorbitally and its ocular stump was connected with different visual target areas (cortex, midbrain) or with non-visual areas (e.g. muscle). Control groups consisted of blind ending graft and ON cut without graft. The function of the retina was regularly examined by electroretinography. At one, six and nine months postsurgery RGCs were retrogradely labelled with 4-(4 (didecylamino)styryl)-N-methylpyridinium iodide and examined morphometrically. Regenerating RGCs were categorized into three major classes representing the morphological types I, II and III. RESULTS: Our data show that regenerating RGCs remain stable up to nine months after grafting at the ON, although the numbers of axons are low, that is less than 1%, and this number is not significantly effected by reconnection with targets. However, there are significant quantitatively and morphometrically assessable differences between the experimental groups depending on the tissue the RGCs are connected with visual targets. Regenerating RGCs show the highest stability in morphology if reconnected with visual target tissue. CONCLUSIONS: Adult RGCs of the rat can be reconnected with visual centers using a peripheral nerve graft. This reconnection stabilizes the cells at morphological and the retina at functional levels for a long period of time, although it does not significantly increase cell survival. PMID- 21701065 TI - A ketogenic diet suppresses seizures in mice through adenosine A1 receptors. AB - A ketogenic diet (KD) is a high-fat, low-carbohydrate metabolic regimen; its effectiveness in the treatment of refractory epilepsy suggests that the mechanisms underlying its anticonvulsive effects differ from those targeted by conventional antiepileptic drugs. Recently, KD and analogous metabolic strategies have shown therapeutic promise in other neurologic disorders, such as reducing brain injury, pain, and inflammation. Here, we have shown that KD can reduce seizures in mice by increasing activation of adenosine A1 receptors (A1Rs). When transgenic mice with spontaneous seizures caused by deficiency in adenosine metabolism or signaling were fed KD, seizures were nearly abolished if mice had intact A1Rs, were reduced if mice expressed reduced A1Rs, and were unaltered if mice lacked A1Rs. Seizures were restored by injecting either glucose (metabolic reversal) or an A1R antagonist (pharmacologic reversal). Western blot analysis demonstrated that the KD reduced adenosine kinase, the major adenosine metabolizing enzyme. Importantly, hippocampal tissue resected from patients with medically intractable epilepsy demonstrated increased adenosine kinase. We therefore conclude that adenosine deficiency may be relevant to human epilepsy and that KD can reduce seizures by increasing A1R-mediated inhibition. PMID- 21701066 TI - Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice. AB - In addition to its role as an essential neurotransmitter, dopamine serves important physiologic functions in organs such as the kidney. Although the kidney synthesizes dopamine through the actions of aromatic amino acid decarboxylase (AADC) in the proximal tubule, previous studies have not discriminated between the roles of extrarenal and intrarenal dopamine in the overall regulation of renal function. To address this issue, we generated mice with selective deletion of AADC in the kidney proximal tubules (referred to herein as ptAadc-/- mice), which led to selective decreases in kidney and urinary dopamine. The ptAadc-/- mice exhibited increased expression of nephron sodium transporters, decreased natriuresis and diuresis in response to l-dihydroxyphenylalanine, and decreased medullary COX-2 expression and urinary prostaglandin E2 excretion and developed salt-sensitive hypertension. They had increased renin expression and altered renal Ang II receptor (AT) expression, with increased AT1b and decreased AT2 and Mas expression, associated with increased renal injury in response to Ang II. They also exhibited a substantially shorter life span compared with that of wild type mice. These results demonstrate the importance of the intrarenal dopaminergic system in salt and water homeostasis and blood pressure control. Decreasing intrarenal dopamine subjects the kidney to unbuffered responses to Ang II and results in the development of hypertension and a dramatic decrease in longevity. PMID- 21701067 TI - Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice. AB - Many cancers display increased NF-kappaB activity, and NF-kappaB inhibition is known to diminish tumor development in multiple mouse models, supporting an important role of NF-kappaB in carcinogenesis. NF-kappaB activation in premalignant or cancer cells is believed to promote tumor development mainly by protecting these cells from apoptosis. However, it remains unclear to what extent NF-kappaB activation exhibits additional protumorigenic functions in premalignant cells that could be sufficient to induce spontaneous tumor development. Here we show that expression of constitutively active IkappaB kinase 2 (IKK2ca) in mouse intestinal epithelial cells (IECs) induced spontaneous tumors in aged mice and also strongly enhanced chemical- and Apc mutation-mediated carcinogenesis. IECs expressing IKK2ca displayed altered Wnt signaling and increased proliferation and elevated expression of genes encoding intestinal stem cell-associated factors including Ascl2, Olfm4, DLK1, and Bmi-1, indicating that increased IKK2/NF-kappaB activation synergized with Wnt signaling to drive intestinal tumorigenesis. Moreover, IECs expressing IKK2ca produced cytokines and chemokines that induced the recruitment of myeloid cells and activated stromal fibroblasts to become myofibroblasts, thus creating a tumor-promoting microenvironment. Taken together, our results show that constitutively increased activation of IKK2/NF-kappaB signaling in the intestinal epithelium is sufficient to induce the full spectrum of cell-intrinsic and stromal alterations required for intestinal tumorigenesis. PMID- 21701068 TI - Ghrelin mediates stress-induced food-reward behavior in mice. AB - The popular media and personal anecdotes are rich with examples of stress-induced eating of calorically dense "comfort foods." Such behavioral reactions likely contribute to the increased prevalence of obesity in humans experiencing chronic stress or atypical depression. However, the molecular substrates and neurocircuits controlling the complex behaviors responsible for stress-based eating remain mostly unknown, and few animal models have been described for probing the mechanisms orchestrating this response. Here, we describe a system in which food-reward behavior, assessed using a conditioned place preference (CPP) task, is monitored in mice after exposure to chronic social defeat stress (CSDS), a model of prolonged psychosocial stress, featuring aspects of major depression and posttraumatic stress disorder. Under this regime, CSDS increased both CPP for and intake of high-fat diet, and stress-induced food-reward behavior was dependent on signaling by the peptide hormone ghrelin. Also, signaling specifically in catecholaminergic neurons mediated not only ghrelin's orexigenic, antidepressant-like, and food-reward behavioral effects, but also was sufficient to mediate stress-induced food-reward behavior. Thus, this mouse model has allowed us to ascribe a role for ghrelin-engaged catecholaminergic neurons in stress-induced eating. PMID- 21701069 TI - Integrin alpha6beta4 identifies an adult distal lung epithelial population with regenerative potential in mice. AB - Laminins and their integrin receptors are implicated in epithelial cell differentiation and progenitor cell maintenance. We report here that a previously unrecognized subpopulation of mouse alveolar epithelial cells (AECs) expressing the laminin receptor alpha6beta4, but little or no pro-surfactant C (pro-SPC), is endowed with regenerative potential. Ex vivo, this subpopulation expanded clonally as progenitors but also differentiated toward mature cell types. Integrin beta4 itself was not required for AEC proliferation or differentiation. An in vivo embryonic lung organoid assay, which we believe to be novel, was used to show that purified beta4+ adult AECs admixed with E14.5 lung single-cell suspensions and implanted under kidney capsules self-organized into distinct Clara cell 10-kDa secretory protein (CC10+) airway-like and SPC+ saccular structures within 6 days. Using a bleomycin model of lung injury and an SPC driven inducible cre to fate-map AECs, we found the majority of type II AECs in fibrotic areas were not derived from preexisting type II AECs, demonstrating that SPC- progenitor cells replenished type II AECs during repair. Our findings support the idea that there is a stable AEC progenitor population in the adult lung, provide in vivo evidence of AEC progenitor cell differentiation after parenchymal injury, and identify a strong candidate progenitor cell for maintenance of type II AECs during lung repair. PMID- 21701071 TI - Intestinal carcinogenesis: IKK can go all the way. AB - Chronic inflammation has long been suspected to support tumorigenesis in a variety of cancers. The IkappaB kinase (IKK)/NF-kappaB pathway is the critical signal transduction pathway regulating inflammation, and loss-of-function studies have demonstrated its involvement in tumorigenesis. In this issue of the JCI, Vlantis et al. present evidence that persistent genetic activation of IKK/NF kappaB signaling in intestinal epithelial cells not only accelerates tumorigenesis in models of both carcinogen- and mutation-induced colorectal cancer, but also is sufficient to induce intestinal tumors. PMID- 21701070 TI - Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. AB - Therapies that raise levels of HDL, which is thought to exert atheroprotective effects via effects on endothelium, are being examined for the treatment or prevention of coronary artery disease (CAD). However, the endothelial effects of HDL are highly heterogeneous, and the impact of HDL of patients with CAD on the activation of endothelial eNOS and eNOS-dependent pathways is unknown. Here we have demonstrated that, in contrast to HDL from healthy subjects, HDL from patients with stable CAD or an acute coronary syndrome (HDLCAD) does not have endothelial antiinflammatory effects and does not stimulate endothelial repair because it fails to induce endothelial NO production. Mechanistically, this was because HDLCAD activated endothelial lectin-like oxidized LDL receptor 1 (LOX-1), triggering endothelial PKCbetaII activation, which in turn inhibited eNOS activating pathways and eNOS-dependent NO production. We then identified reduced HDL-associated paraoxonase 1 (PON1) activity as one molecular mechanism leading to the generation of HDL with endothelial PKCbetaII-activating properties, at least in part due to increased formation of malondialdehyde in HDL. Taken together, our data indicate that in patients with CAD, HDL gains endothelial LOX 1- and thereby PKCbetaII-activating properties due to reduced HDL-associated PON1 activity, and that this leads to inhibition of eNOS-activation and the subsequent loss of the endothelial antiinflammatory and endothelial repair-stimulating effects of HDL. PMID- 21701072 TI - Integrin alpha6beta4 defines a novel lung epithelial progenitor cell: a step forward for cell-based therapies for pulmonary disease. AB - The many challenges associated with lung transplantation provide a strong rationale for the development of cell- and tissue-based therapies for patients with respiratory failure caused by the loss of lung tissue that is associated with chronic pulmonary disease, injury, or resection. In this issue of the JCI, Chapman et al. take an important step forward in the development of regenerative medicine for the treatment of lung disease by identifying a novel integrin alpha6beta4-expressing alveolar epithelial cell that serves as a multipotent progenitor during repair of the severely injured lung. PMID- 21701073 TI - Adenosine: front and center in linking nutrition and metabolism to neuronal activity. AB - Many individuals with epilepsy benefit from consuming a ketogenic diet, which is similar to the more commonly known Atkins diet. The underlying molecular reason for this has not been determined. However, in this issue of the JCI, Masino et al. have elucidated the mechanism responsible for the antiepileptic effects of the ketogenic diet in mice. The diet is shown to decrease expression of the enzyme adenosine kinase (Adk), which is responsible for clearing the endogenous antiepileptic agent adenosine (Ado) from the extracellular CNS space. Decreased expression of Adk results in increased extracellular Ado, activation of inhibitory Ado A1 receptors, and decreased seizure generation, the desired therapeutic effect. The authors' work serves to emphasize the importance of controlling Adk expression, not only as the mechanism of action of the ketogenic diet, but also as a potential target of future therapies. PMID- 21701074 TI - PON-dering differences in HDL function in coronary artery disease. AB - HDL cholesterol activates endothelial cell production of the atheroprotective signaling molecule NO, and it promotes endothelial repair. In this issue of the JCI, Besler et al. provide new data indicating that HDL from stable coronary artery disease (CAD) or acute coronary syndrome patients inhibits rather than stimulates endothelial NO synthesis and endothelial repair. This may be related to decreased HDL-associated paraoxonase 1 (PON1) activity. These observations support the concept that the cardiovascular impact of HDL is not simply related to its abundance, and the translation of the present findings to prospective studies of CAD risk and to evaluations of HDL-targeted therapeutics is a logical future goal. PMID- 21701075 TI - Glucose-incretin interaction revisited. AB - Pancreatic beta cell dysfunction is pivotal to the development of diabetes, and restoration of insulin action is of primary importance. Here, we present a review of the mechanism of insulin secretion by pancreatic beta cells and discuss the mutual interaction of signaling pathways in stimulus-secretion coupling to better understand the scientific basis of pharmacological treatment for insulin secretion deficiency. Glucose stimulates insulin secretion via membrane depolarization by closure of ATP-sensitive K(+) channels (K(ATP) channels) and opening of L-type voltage-dependent Ca(2+) channels. The resultant elevation of cytosolic free Ca(2+) triggers insulin exocytosis. This is termed the "K(ATP) dependent pathway" and is shared by sulfonylurea, which closes K(ATP) channels. Glucose also stimulates insulin release independent of its action on K(ATP) channels. This is referred to as the "K(ATP)-independent pathway," the molecular basis of which remains elusive. In the pancreatic beta cell, incretin hormones increase cAMP level, which enhances glucose-stimulated insulin release by protein kinase A-dependent and -independent mechanisms. Importantly, cAMP does not directly augment Ca(2+)-stimulated insulin release per se. The stimulatory level of ambient glucose is an absolute requirement for incretin to enhance insulin release. Therefore, incretin/cAMP enhances K(ATP)-independent insulinotropic action of glucose. The robust glucose-lowering effect of DPP4 inhibitor add-on in diabetic patients with sulfonylurea secondary failure is intriguing. With the clinical availability of DPP4 inhibitor and GLP-1 mimetics, the importance of the interactions between cAMP signaling and K(ATP) channel-independent actions of glucose is reappraised. PMID- 21701076 TI - cAMP response element-binding protein (CREB) is required for epidermal growth factor (EGF)-induced cell proliferation and serum response element activation in neural stem cells isolated from the forebrain subventricular zone of adult mice. AB - Neurogenesis, which occurs not only in the developing brain but also in restricted regions in the adult brain including the forebrain subventricular zone (SVZ), is regulated by a variety of environmental factors, extracellular signals, and intracellular signal transduction pathways. We investigated whether the transcription factor cAMP response element (CRE)-binding protein (CREB) is involved in the regulation of cell proliferation of neural stem cells (NSCs) isolated from the SVZ of adult mice. Treatment of NSCs with the protein kinase A (PKA) inhibitors H89 and KT5720 inhibited epidermal growth factor (EGF) stimulated NSC proliferation. Similar inhibition was observed when a dominant negative mutant of CREB (MCREB) was expressed. EGF treatment increased CRE mediated transcriptional activity, but this increase was much less than that caused by treatment with the adenylate cyclase activator forskolin, which changed neither basal nor EGF-stimulated proliferation of NSCs. Neither PKA inhibitors nor MCREB expression blocked EGF-induced phosphorylation of extracellular signal regulated kinase (ERK), a protein kinase mediating EGF's mitogenic action. However, MCREB suppressed EGF-induced expression of several immediately early genes including c-fos, c-jun, jun-B, and fra-1 and subsequent AP-1 transcriptional activation. MCREB expression also inhibited the ability of EGF to stimulate transcriptional activation mediated by the serum response element (SRE), a promoter sequence regulating c-fos gene expression. These results suggest that basal activity of CREB is required for the mitogenic signaling of EGF in NSCs at a level between ERK activation and SRE-mediated transcriptional activation. PMID- 21701078 TI - Effect of methotrexate on fracture healing. AB - Low doses of methotrexate (MTX) are safe and effective for treating adult and juvenile rheumatoid arthritis. However, because this powerful anti-inflammatory drug might negatively influence the healing of wounds and fractures, MTX administration is often stopped during surgical procedures. The present study assesses the effects of low- and high-dose MTX on early inflammatory processes and bone healing in an experimental model of fracture. Thirty male Sprague-Dawley rats were assigned to low- and high-dose MTX and control groups. A femur was cut using a reciprocating saw and a 2-mm fracture gap was made using a fixator. One or four weeks thereafter, macrophages were immunostained and new bone formation was histomorphometrically measured. Significantly less new bone was formed in the high-dose MTX, than in the control group (p< 0.01), whereas bone formation did not significantly differ between the low-dose MTX and control groups. These results suggested that a low dose of MTX does not affect the early process of endochondral bone formation during fracture healing, whereas a high dose might delay the progress of new periosteal bone formation. Although more macrophages were found in the groups treated with MTX, their impact on surrounding inflammatory processes remains unclear. PMID- 21701077 TI - Reinfection of cytomegalovirus in renal transplantation. AB - Cytomegalovirus (CMV) is the most important pathogen affecting the outcome of renal transplantation. Reinfection of CMV can occur in CMV-seropositive donors and CMV seropositive recipients (D+/R+) settings because the protection against CMV conferred by preexisting immunity is limited due to its strain-dependent immune responses. To analyze the influence of CMV reinfection in renal transplantation, ELISA using fusion proteins encompassing epitope of glycoprotein H(gH) from both AD169 and Towne strains was employed before transplantation. The CMV-gH seropositive rate increased with increases in age and the rate of samples which contained antibodies against both AD169 and Towne were significantly high in the age of 50 years or over. Antibodies from HLA-DR10 and DR11 were associated with a significantly lower response rate against CMV-gH. In renal transplantation, the high degrees of antigenemia and high incidences of CMV disease are more prevalent in the CMV gH antibody-mismatched group in D+/R+ setting. The nucleotide sequence of the region of the gH epitope in the CMV-DNA extracted from the transplant recipients who showed high degree of antigenemia revealed the CMV reinfection from the donors. As a CMV indirect effect, the incidence of acute rejection in the mismatched gH antibody group was higher than that observed in the matched and D+/R- groups. The adverse events were more likely to occur in cases of D+/R+ renal transplantation with mismatched strain specific antibodies which would indicates the risk of CMV reinfection after transplantation. PMID- 21701079 TI - Fluvastatin increases bone mineral density in postmenopausal women. AB - Although several studies have reported a lower risk of osteoporotic fracture in hypercholesterolemic patients (WHO IIa) treated with statin, longitudinal studies on the effects of statins on bone are lacking. The aim of the present study was to evaluate bone mineral density (BMD) and bone turnover changes induced by 3 year fluvastatin treatment in postmenopausal women. Twenty-eight consecutive postmenopausal non-diabetic, normotensive hypercholesterolemic women (64.0+/-3.6 years) were treated for 36 months with 30 mg/day fluvastatin and 28 non-diabetic, normotensive normocholesterolemic age- and body mass index-matched postmenopausal women served as the control subjects. The result revealed a significant increase of the BMD as compared with the level at the base line (p< 0.001) in the fluvastairn-treated group, from 6 months on ward after the start treatment. Significant differences of the BMD were found between the controls and fluvastatin-treated group (p< 0.001) were at 6, 12, 24 and 36 months after the start of the study. In conclusion our results, although obtained small sample of postmenopausal hypercholesterolemic women, suggest a probable favorable effect of fluvastatin on bone formation and BMD. PMID- 21701081 TI - Right atrium mass in a 28-year-old patient with pulmonary embolism taking contraceptives. AB - We report the case of a 28-year-old woman taking contraceptives diagnosed with pulmonary embolism with a mass in the right atrium demonstrated by trans-thoracic echocardiogram that was not recognized on a previous angio-CT. Initially, it was thought to be a thrombus, but trans-oesophageal echocardiography and cardiac MRI showed data suggestive of cardiac neoplasm. Pericardial effusion and adjacent myocardial wall thickening noted on trans-oesophageal echocardiography were reported as signs that supported the possibility of malignancy, although cardiac MRI did not show wall infiltration signs. On the contrary, it demonstrated enhancement, which excludes the thrombotic nature of the mass and supports the diagnosis of neoplasm. The patient underwent surgery and biopsy proved that the mass was a myxoma. While myxomas are the most common among primary cardiac tumors, its attachment to the atrium free wall, far from the inter-atrium septum, the bi-lobed shape and accompanying pericardial effusion were atypical. PMID- 21701080 TI - Prospective randomized comparative study of hemodynamic changes between ultrathin transnasal and conventional transoral esophagogastroduodenoscopy in percutaneous endoscopic gastrostomy placement with modified introducer method under sedation. AB - AIM: Percutaneous Endoscopic Gastrostomy (PEG) placement is a useful but invasive method. Recently, the hemodynamic change of ultrathin transnasal esophagogastroduodenoscopy (transnasal EGD) was reported as less than that of conventional transoral EGD (transoral EGD). This study compared hemodynamic changes between transnasal EGD and transoral EGD in the setting of PEG placement using a modified Introducer method under sedation. METHODS: All 25 patients who were performed PEG in our hospital during the period December 2007 to February 2009 were enrolled in this study. We assigned them randomly to one of two groups, Group A for transoral EGD and Group B transnasal EGD. For both groups, the modified Introducer method was used. Vital signs (systolic blood pressure; SBP, heart rate; HR and rate pressure product; RPP) were monitored before and after scope insertion. RESULTS: We assigned 13 patients to Group A and 12 patients to Group B. The mean age was 69.4 years old in Group A and 69.8 in Group B. After scope insertion, mean changes of vital signs in Group A and B were, respectively, 17.8 mmHg and 17.3 mmHg in SBP, 12.1 bpm and 5.08 bpm in HR, and 25.9 and 17.5 in RPP. CONCLUSION: No significant differences of hemodynamic changes were seen between transnasal EGD and transoral EGD for the PEG placement with modified Introducer method under sedation. Results show that both methods are tolerable and feasible for PEG placement. PMID- 21701082 TI - Comparison of the effect of cilostazol with aspirin on circulating endothelial progenitor cells and small-dense LDL cholesterol in diabetic patients with cerebral ischemia: a randomized controlled pilot trial. AB - AIM: A recent clinical trial showed the preventive effect of cilostazol on cerebrovascular diseases. We compared the effects of cilostazol with aspirin on circulating endothelial progenitor cells (EPCs), a surrogate marker for cardiovascular disease, and lipid metabolism in a randomized controlled trial (UMIN000000537). METHODS: Forty-nine diabetic outpatients with leukoaraiosis or asymptomatic old cerebral infarction were enrolled in the study with written informed consent. They were randomly assigned to a cilostazol (200 mg daily, n= 24) or aspirin group (100 mg daily, n= 25), and followed for 16 weeks. Changes in circulating CD34(+) CD45(low) CD133(+) VEGFR2(+) EPCs (DeltaEPC) were a primary endpoint. Changes in CD34(+) CD45(low) CD133(+) progenitor cells (DeltaPC), p selectin-positive platelet, platelet-monocyte binding measured by flow cytometry, LDL-, HDL-, small dense LDL (sdLDL)-cholesterol and triacylglycerol were the secondary endpoints. RESULTS: Twenty patients in each group completed the study. DeltaEPC were significantly higher in the cilostazol group than aspirin group at 16 weeks, while DeltaPC were already significantly higher at 4 weeks in the cilostazol group. Changes in p-selectin-positive platelets and platelet-monocyte binding were similar in both groups. The cilostazol group showed significantly less sdLDL- and higher HDL-cholesterol than the aspirin group at both 4 and 16 weeks. DeltaEPC were significantly and inversely correlated with changes of sdLDL, while positively with those of HDL. Analysis of covariance showed that a significant relation of DeltaEPCs with cilostazol treatment was confounded by changes in HDL- and sdLDL-cholesterol. CONCLUSION: Cilostazol increases circulating EPCs and decreases small-dense LDL in diabetic patients with cerebral ischemia. PMID- 21701083 TI - Add-on therapy of EPA reduces oxidative stress and inhibits the progression of aortic stiffness in patients with coronary artery disease and statin therapy: a randomized controlled study. AB - AIM: We examined the anti-oxidant mechanisms of combined therapy of eicosapentaenoic acid (EPA) plus statin on the progression of atherosclerosis. METHODS: Patients receiving statin therapy for dyslipidemia and with coronary artery disease (CAD) were assigned randomly in an open-label manner to the EPA (1,800 mg/day) -plus-statin group (n= 25; combined-therapy group) or to the statin-only group (n= 25), and followed for 48 weeks. At baseline and 48 weeks after enrollment, oxidative stress, brachial-ankle pulse wave velocity (baPWV) and stiffness parameter beta-index of the carotid were measured. RESULTS: The lipid profile remained unchanged throughout the study. Although the median value of baPWV increased more in the statin-only group than in the combined-therapy group, this difference was not significant (p= 0.29); however, a decrease in baPWV was associated with combined-therapy treatment by multiple regression analysis adjusted for age and mean blood pressure (p= 0.04). In addition, the beta-index of the carotid was lower in the combined-therapy group than in the statin-only group (p= 0.02). Furthermore, although the difference in the reduction of the urinary concentration of 8-isoprostane between the two groups did not reach statistical significance, this concentration was significantly lower in the combined-therapy group with higher baseline levels (>= 183 pg/mL . Cr) of urinary 8-isoprostane (p= 0.004). CONCLUSIONS: EPA may reduce oxidative stress and inhibit the progression of arterial stiffness more efficiently than statin-only therapy in patients with dyslipidemia and CAD. PMID- 21701084 TI - [Changes in neutrophil immune functions under different exercise stresses]. AB - The aim of this review is to provide a summary of the known effects of exercise on neutrophil immune functions of athletes. We measured three neutrophil immune functions (i.e., phagocytic activity (PA), reactive oxygen species (ROS) production, and serum opsonic activity (SOA)) in various types of exercise. The following is our recent findings. (1) A regular exercise increases ROS production and decreases PA. We call this change a normal pattern, and an abnormal pattern except this change. (2) A prolonged, strenuous activity (e.g., rugby match and marathon) decreases both ROS production and PA. This is one of the abnormal pattern. (3) The exercise loading performed after a camp training decreases ROS production whereas PA does not change. This is another abnormal pattern. (4) When judoists who had stopped judo training for 6 months restarted their training, the exercise loading at the beginning of their training decreases PA whereas ROS production does not change. This is another abnormal pattern. (5) A regular exercise 2 months after the beginning of their training increases ROS production and decreases PA. This change is a normal pattern. SOA showed a similar pattern of changes to ROS under all conditions. The changes in neutrophil immune functions after performing various exercises might result from the balance between external factors (intensity and style of exercise) and internal factors (e.g., fatigue and physical pain). Therefore, the changes in three neutrophil immune functions after exercise might be an index of athletes' condition. PMID- 21701085 TI - [Archives of "comprehensive approach on asbestos-related diseases" supported by the "special coordination funds for promoting science and technology (H18-1-3-3 1)"-- overview of group research project, care and specimen registration, cellular characteristics of mesothelioma and immunological effects of asbestos]. AB - The research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)" began in 2006 and was completed at the end of the Japanese fiscal year of 2010. This project included four parts; (1) malignant mesothelioma (MM) cases and specimen registration, (2) development of procedures for the early diagnosis of MM, (3) commencement of clinical investigations including multimodal approaches, and (4) basic research comprising three components; (i) cellular and molecular characterization of mesothelioma cells, (ii) immunological effects of asbestos, and (iii) elucidation of asbestos-induced carcinogenesis using animal models. In this special issue of the Japanese Journal of Hygiene, we briefly introduce the achievements of our project. The second and third parts and the third component of the fourth part are described in other manuscripts written by Professors Fukuoka, Hasegawa, and Toyokuni. In this manuscript, we introduce a brief summary of the first part "MM cases and specimen registration", the first component of the fourth part "Cellular and molecular characterization of mesothelioma cells" and the second component of the fourth part "Immunological effects of asbestos". In addition, a previous special issue presented by the Study Group of Fibrous and Particulate Substances (SGFPS) (chaired by Professor Otsuki, Kawasaki Medical School, Japan) for the Japanese Society of Hygiene and published in Environmental Health and Preventive Medicine Volume 13, 2008, included reviews of the aforementioned first component of the fourth part of the project. Taken together, our project led medical investigations regarding asbestos and MM progress and contributed towards the care and examination of patients with asbestos-related diseases during these five years. Further investigations are required to facilitate the development of preventive measures and the cure of asbestos-related diseases, particularly in Japan, where asbestos-related diseases are predicted to increase in the next 10 to 20 years. PMID- 21701086 TI - [Exploratory study on the detection of markers for diagnosing early-stage malignant mesothelioma]. AB - Malignant mesothelioma (MM) is a highly aggressive, incurable neoplasm associated with asbestos exposure. Early detection of MM is not easy and radiological surveillance is imperfect. The use of blood-based biomarkers might solve this difficulty and allow detection of MM at an early stage when combined treatment involving surgery, chemotherapy and radiotherapy might be effective. In the research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)", we conducted an exploratory study on the detection of markers for diagnosing early-stage MM. In this study, we have shown that serum soluble mesothelin-related peptide (SMRP) is a highly specific and moderately sensitive biomarker for diagnosing MM. SMRP levels in pleural effusion were elevated not only in advanced-stage malignant pleural mesothelioma (MPM), but also in early stage disease. SMRP in pleural effusion can be an MPM-specific biomarker with greater sensitivity than in serum, especially for the early stage of the disease. Circulating tumor cells (CTCs) and circulating endothelial cells (CECs) were considered to be useful surrogate markers of disease progression in MPM, although the lack of sensitivity for early-stage disease remains to be improved. Cytological analysis with gene expression profiling has been more effective in detecting early-stage MPM with pleural effusion. In conclusion, blood or effusion based biomarkers, possibly in combination with other new modalities, such as a thoracoscopy combined with the advanced imaging systems consisting of autofluorescence imaging (AFI) and narrow band imaging (NBI), will show some promise for curing MPM if the disease is detected at an early stage. PMID- 21701087 TI - [Current status and future direction of Japan's clinical trial for malignant pleural mesothelioma]. AB - The feasibility and efficacy of trimodality therapy for malignant pleural mesothelioma (MPM) are still controversial mainly due to the lack of clinical evidence. Although three major clinical trials on this therapy have been recently reported from North America and Europe, it remains unclear whether results in Caucasian populations may be directly applicable to Asian populations. In this context, as a project of the "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Fund for Promoting Science and Technology of MEXT, Japan", a prospective multi-institutional study has been planned to evaluate the feasibility of induction chemotherapy using pemetrexed plus cisplatin, followed by extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation in patients with resectable MPM. Primary endpoints are macroscopic complete resection rate by EPP and treatment-related mortality for trimodality therapy. The study was initiated in May 2008 and patient enrollment was finished in November 2010. PMID- 21701088 TI - [Mechanisms of asbestos-induced carcinogenesis]. AB - Several types of fibrous stone called asbestos have been an unexpected cause of human cancer in the history. This form of mineral is considered precious in that they are heat-, friction-, and acid-resistant, are obtained easily from mines, and can be modified to any form with many industrial merits. However, it became evident that the inspiration of asbestos causes a rare cancer called malignant mesothelioma. Because of the long incubation period, the peak year for malignant mesothelioma is expected to be 2025 in Japan. Thus, it is necessary to elucidate the mechanisms of asbestos-induced mesothelial carcinogenesis. In this review, we summarize the cutting edge results of our 5-year project funded by a MEXT grant, in which local iron deposition and the characteristics of mesothelial cells are the key issues. PMID- 21701089 TI - [Approach to elucidating the influences and factors affecting circulation system in humans in space environment]. AB - Many physiological changes associated with spaceflight, including decreases in orthostatic tolerance, exercise capacity, and blood volume have been reported. Orthostatic intolerance is a problem affecting many astronauts immediately postspaceflight. In particular, the relationship between orthostatic intolerance and cerebral autoregulation has been the focus of study in our research group. Although impairment of cerebral autoregulation was speculated to be one of the factors resulting in reduced post flight orthostatic tolerance, a 2-wk spaceflight study revealed that human cerebral autoregulation is preserved or even improved during and immediately after spaceflight in nonsymptomatic astronauts. To investigate the influences of the different kinds of reduction in central blood volume, we performed two ground-based studies. It is suggested that the mild intravascular dehydration partly explains the improved dynamic cerebral autoregulation observed during and immediately after a short-term spaceflight. Moreover, we also studied the relationship between orthostatic intolerance and cerebral autoregulation under hyperthermic conditions, because hyperthermia leads to orthostatic intolerance. Furthermore, we planned to conduct a study at the International Space Station (ISS) and ground-based studies to elucidate the influences and factors affecting the circulation system in humans in a space environment. PMID- 21701091 TI - [Age-, period-, and birth-cohort-specific effects on the male proportion in Japanese newborns and projections for male proportion for 20 periods (2008 2027)]. AB - OBJECTIVES: To determine the age-, period-, and cohort-specific effects on the male proportion in Japanese newborns, we performed an age-period-cohort (APC) analysis in this study. In addition, projections for the male proportion were analyzed. METHODS: We obtained data on live births of newborns for Japanese women in 1947-2007 from the National Vital Statistics. Cohort tables containing data on the male proportion were analyzed using a Bayesian APC model. Projections of the male proportion (2008-2027) were calculated. RESULTS: The age effect decreased when the mothers were 40-44 years old; however, the effect was relatively limited as compared with the period and cohort effects. The period effect increased from 1947 to 1969 and decreased thereafter. Analysis of the cohort effect on male proportion trends revealed a decreasing slope for birth cohorts born between 1905 and 1945 and a subsequent increase after 1958. The projections for male proportion indicated that the male proportion in 2027 would be similar to that in the 1970s. CONCLUSIONS: The age of the mother hardly affected the male proportion. The period effect started decreasing from the latter half of the 1960s. This may be attributable to the high economic growth since 1965 that promoted industrial development that led to environmental pollution, which in turn may have lead to the deterioration of the intrauterine environment. Cohort effects changed from 1958 and exhibited trends toward increase in male proportion; this may be due to improvements in obstetric care. Our results suggest that the male proportion in Japanese newborns will increase in the future. PMID- 21701090 TI - [Effect of lifestyle and health behavior on neutrophil function]. AB - OBJECTIVE: In this study, we investigated the relationships of neutrophil functions with lifestyle factors (namely, subjective stress, exercise habits, smoking habits, alcohol-drinking habits, and self-perceived status health) and health behavior in the Chinese urban elderly. METHODS: We performed a health survey of the elderly aged 65 years or older living in Tianjin. The subjects were 42 males (69.1 +/- 4.1 years old) and 41 females (69.1 +/- 4.1 years old). Investigations of subjective stress, exercise habits, smoking habits, alcohol drinking habits, and self-perceived health status were performed. The phagocytosis and superoxide productivity of neutrophils were measured by the nitroblue tetrazolium (NBT) reduction method. In addition, leukocyte count and serum total protein (TP) level were examined. RESULTS: The investigations revealed the associations of health behavior (p<0.05) and self-perceived health (p<0.10) with the balance between phagocytosis and subsequent superoxide production. CONCLUSIONS: The present study revealed that there were correlations of neutrophil functions with lifestyle factors (subjective stress, exercise habits, smoking habits, alcohol-drinking habits, and self-perceived status health) and health behavior in the Chinese urban elderly. PMID- 21701092 TI - [Variations of indoor environment and the prevalence of sick house syndrome over three-year period in detached houses in Sapporo]. AB - OBJECTIVES: The purpose of this study was to investigate annual variations in indoor environmental chemical, fungal and dust mite allergen levels, with regards to variations in sick house syndrome (SHS) symptoms over a three-year period. METHODS: Detached houses were randomly selected from a building plan approval application, and a questionnaire survey was conducted in 2003 in Sapporo, Japan. Indoor environmental measurements and a self-administered questionnaires survey were conducted on the selected houses in 2004, 2005 and 2006. The same protocol was used for the three-year period to measure the levels of chemicals, fungi and dust mite allergens. A personal questionnaire to assess SHS was distributed to all inhabitants of the dwellings along with one questionnaire to assess housing characteristics. RESULTS: In 2004, 2005 and 2006, the owners of 104, 64 and 41 houses, respectively, agreed to participate in this study. Forty-one houses and the 127 inhabitants who participated in this three-year survey period were included in the analysis to evaluate the associations between differences in environmental measurements and SHS. The levels of formaldehyde, acetone, toluene, Alternaria and Cladosporium tended to decrease, whereas those of limonene and Aspergillus tended to increase over the three-year period. Increasing levels of Cryptococcus and the dampness index in individual houses correlated with increasing SHS symptom scores in the inhabitants after mutual adjustment. CONCLUSIONS: Although the average levels of chemicals and fungi were relatively low, the results show the relationship between annual variations in indoor environmental measurements and variations in SHS symptom scores. PMID- 21701093 TI - [Fifteen trace elements in eluate from enameled cookware using inductively coupled plasma-mass spectrometry]. AB - OBJECTIVE: The purpose of this research is to clarify the effects of the following treatments on the elution of trace elements: water settling, 2 h boiling of water, acetic acid settling, and 2 h boiling of acetic acid in prebrushed enameled cookware, and the same four treatments after brushing the surface of enameled cookware. METHOD: The eluate samples from enameled cookware subjected to the above eight treatments ware obtained, and the concentrations of the fifteen trace elements (B, Al, Cr, Mn, Fe, Ni, Cu, Zn, As, Se, Mo, Cd, Sb, Pb, and U) were simultaneously analyzed by inductively coupled plasma-mass spectrometry (ICP-MS). RESULTS: The concentrations of the fifteen elements eluted from enameled cookware were low or very low after the treatments. Enameled cookware is made from iron covered with glass containing pigments. The concentrations of Al, Ni, and Sb were significantly higher (p<0.01) in almost all treatments. The concentrations of Fe, which is the base element of enameled cookware, showed almost no change. The safety level for enameled cookware are standardized at 70 ng/mL Cd and 400 ng/mL Pb. The Cd and Pb concentrations in all treatment samples were below these standard levels. CONCLUSION: The results of our study and other studies conducted so far suggest that the risk of acute or chronic toxicity associated with the use of enameled cookware under normal circumstances is extremely low and negligible. PMID- 21701094 TI - [An occupational physician-pharmacist cooperative management for hypertension by the use of educational letters and posters]. AB - OBJECTIVES: To provide an occupational physician-pharmacist cooperative management for hypertension, we aimed to improve blood pressure (BP) control for workers with high-normal BP or hypertension. METHOD: Health checkups were performed from May 2005 to May 2008 for male professional grooms and exercise riders aged 20-69 years working at Miho Training Center, the largest racing-horse training facility in Japan. An occupational physician-pharmacist cooperative hypertension management was performed from Jan 2007 to Mar 2008, including the use of posters at the work site and letters to employers and the subjects who were diagnosed as having high-normal BP (office systolic/diastolic BPs 130-139 and/or 85-89 mmHg) or hypertension (>= 140 and/or 90 mmHg) twice during 2005-2006 examinations. The observational study examined BP measurements before and after the hypertension management. RESULTS: We analyzed 232 participants in the 2008 Nov examination with had high-normal BP or hypertension in both of 2005 and 2006 Nov examinations. Office systolic and diastolic BP decreased after the hypertension management by the use of educational letters and posters (-3.1 mmHg; p<0.001, -1.5 mmHg; p=0.02). The prevalence of workers with high-normal BP and hypertension also decreased after those activities (-15% and -7%; p<0.001). The subjects who started or continued the antihypertensive medication were more likely to show reductions in office BP and body mass index than those who received no treatment. CONCLUSIONS: An occupational physician-pharmacist cooperated hypertension management by the use of educational letters and posters may improve BP control for subjects with high-normal BP or hypertension. PMID- 21701095 TI - Composition and thermal analysis of lard stearin and lard olein. AB - Lard being an edible fat could be used in different forms in food systems. In this study, composition and thermal analysis of lard stearin (LS) and lard olein (LO) were undertaken to determine some common parameters which would enable their detection in food. A sample of native lard was partitioned into LS and LO using acetone as solvent and the fractions were compared to the original sample with respect to basic physico-chemical parameters, fatty acid and triacylglycerol (TAG) composition, and thermal characteristics. Although LS and LO displayed wider variations in basic physico-chemical parameters, thermal properties and solidification behavior, they do possess some common characteristic features with regard to composition. In spite of the proportional differences in the major fatty acids, both LS and LO are found to possess extremely high amount of palmitic (C16:0) acid at the sn-2 positions of their TAG molecules. Similar to native lard, both LS and LO contained approximately equal proportions of TAG molecules namely, linoleoyl-palmitoyl-oleoyl glycerol (LPO) and dioleoyl palmitoyl glycerol (OPO). Hence, the calculated LPO/OPO ratio for LS and LO are comparably similar to that of native lard. PMID- 21701096 TI - Terahertz absorption spectra of Fatty acids and their analogues. AB - Absorption spectra in the terahertz (THz) region between 10 and 400 cm(-1) were measured for fatty acids and their analogues at room temperature. Saturated fatty acids such as palmitic and stearic acids had some sharp peaks, while unsaturated fatty acids such as oleic, linoleic and linolenic acids had two distinct peaks at 247 and 328 cm(-1). These peaks apparently derived from the carboxylic group because oleyl alcohol had no distinct peak. The THz absorption spectra of fatty acids may be affected by the crystalline as well as the chemical structure. The THz absorption spectra of oleic acid esters depended on ester types, although all oleic acid esters had some peaks due to the ester group. THz absorbance of fatty acids positively correlated with concentration. Based on these results, THz spectrometry may be a good analytical method for the non-destructive qualitative and quantitative evaluation of fatty acids and their analogues. PMID- 21701097 TI - Rapid separation of triacylglycerol positional isomers binding two saturated Fatty acids using octacocyl silylation column. AB - The rapid separation of a triacylglycerol positional isomer (TAG-PI) pair was examined via high-performance liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry using an octacocyl silylation (C28) column. A TAG-PI pair binding two palmitic acids and one fatty acid that structurally differs from palmitic acid was separated at 10 degrees C and 15 degrees C using acetone as the mobile phase. However, the TAG-PI pair binding two unsaturated fatty acids and one saturated fatty acid was not separated by the C28 column. The results indicate that the structures of the two palmitic acids (saturated fatty acids) and the other fatty acid at the alpha or beta position in TAG play an important role in the separation of the TAG-PI pair, and that the structure of the fatty acid needs to be considerably different from that of the palmitic acid, specifically in terms of the chain length or the location of the double bond. PMID- 21701098 TI - Pickering emulsions and capsules stabilized by wool powder particles. AB - We prepared emulsions and capsules that were stabilized by wool powder particles. These powder particles were adsorbed on oil-water interfaces, and they formed both oil-in-water and water-in-oil emulsions. These emulsions were observed in ternary systems containing silicone oil, n-dodecane, fluoric oil, oleic acid, or linoleic acid as the oil phase. PMID- 21701099 TI - Development of low-energy methods for preparing food Nano-emulsions. AB - The aim of this work was to investigate the effect of sucrose on the phase behavior of vegetable oil/polyoxyethylene sorbitan monooleate (MOPS, Tween 80) and decaglycerol monolaurilester (DGML)/aqueous solution systems to establish low energy emulsification methods for preparing nano-emulsions suitable for food uses. Phase diagrams were constructed to elucidate the optimal process for preparing the nano-emulsions. It was found that nano-emulsions were obtained when the composition was altered to either cross the sponge phase (L(3)) or lamellar phase (La) in the vegetable oil/MOPS/aqueous solution system or vegetable oil/DGML/aqueous solution system, respectively. The average droplet sizes in the former and latter emulsions were 0.203 um and 0.165 um, respectively. The addition of sucrose changed the hexagonal phase in the vegetable oil/MOPS/aqueous solution system into the sponge phase. As a result, the sponge region in the vegetable oil/MOPS/sucrose aqueous solution system occupied a larger area than that in the vegetable oil/MOPS/water system. In contrast, sucrose had no effect on the area of the La region in the vegetable oil/DGML/aqueous solution system. However, the addition of sucrose decreased the amount of emulsifier required to prepare nano-emulsions in both the vegetable oil/MOPS and DGML/aqueous solution systems. Sucrose was confirmed to facilitate the preparation of nano-emulsions in both systems. PMID- 21701100 TI - Adsorption mechanism of copper and cadmium onto defatted waste biomass. AB - In this study, the amount of copper or cadmium adsorbed using waste biomass (i.e., coffee grounds (CG) and rice bran (RB)) was investigated. The amount of crude protein in defatted CG (D-CG) or RB (D-RB) was greater than that in CG or RB, respectively. The amount of copper or cadmium adsorbed using CG was greater than that using RB. Additionally, the amount of copper or cadmium adsorbed was not affected by the presence of fat in CG. Adsorption data was fitted to the Freundlich equation, and the correlation coefficients were in the range of 0.794 0.991. The main adsorption mechanism was thought to be monolayer adsorption onto the surface of the waste biomass. The adsorption rate data was fitted to the pseudo-second-order model, and the correlation coefficient average was in the range of 0.891-0.945. This result showed that the rate-limiting step may be chemisorption. Moreover, the amount of copper or cadmium desorbed from CG or RB using 0.01 mol/L or 1.00 mol/L HNO(3) was investigated. Desorption with 0.01 mol/L HNO(3) resulted in the recovery of 86-97% of the copper and cadmium, indicating that copper or cadmium that was adsorbed using waste biomass was recoverable. PMID- 21701101 TI - Bioprocessing of glycerol into glyceric Acid for use in bioplastic monomer. AB - Utilization of excess glycerol supplies derived from the burgeoning biodiesel industry has recently become very important. Glyceric acid (GA) is one of the most promising glycerol derivatives, and it is abundantly obtained from glycerol by a bioprocess using acetic acid bacteria. In this study, a novel branched-type poly(lactic acid) (PLA) was synthesized by polycondensation of lactide in the presence of GA. The resulting branched PLA had lower crystallinity and glass transition temperatures than the conventional linear PLA, and the peak associated with the melting point of the branched PLA disappeared. Moreover, in a blend of the branched polymer, the crystallization of the linear PLA occurred at a lower temperature. Thus, the branched PLA containing GA synthesized in this study could potentially be used as a novel bio-based modifier for PLA. PMID- 21701102 TI - Influence of humidity and of the electric and magnetic microwave radiation fields on the remediation of TCE-contaminated natural sandy soils. AB - The influence of moisture content (15% w/w) on the remediation (vaporization) of trichloroethylene (TCE) present in natural sands, chosen as a TCE-polluted model system for soils, was investigated with regard to applied microwave power levels, the depth of the sand sample, and the dielectric factors. The heating process occurring in the sand samples arises through the microwave conduction loss heating and dielectric loss heating mechanisms. The characteristic relevance of the electric and magnetic microwave radiation fields to the heating mechanisms was also examined. Heating by the magnetic microwave radiation field was considerable when magnetite was added to the dry and wet sand samples as the microwave absorber. Optimal microwave conditions are reported for a single-mode microwave applicator. Near-quantitative elimination of the TCE contaminant was achieved for sandy soils within a very short time. PMID- 21701103 TI - Worldwide academic contributions of Japanese neurosurgeons. AB - Based on the data reported in the National Institute of Science and Technology Policy 2010, Japan is ranked in fourth place in the world in terms of the numbers of the articles in the fields of clinical medicine. However, there had not been any objective data regarding the numbers of publications by neurosurgeons. As it is important for neurosurgeons to realize the extent of academic contributions by the neurosurgeons in different countries, the numbers of publications in the major journals by the members of the Japan Neurosurgical Society and those from neurosurgical institutions around the world were analyzed using both the biomedical literature database PubMed and the publication database "ISI Web of Knowledge." Parts of the results were presented in the 69th Annual Meeting of the Japan Neurosurgical Society. As to the number of neurosurgical publications in English from the top 9 countries, the US has been consistently in first place and Japan in second. However, the number of publications from Japan has been decreasing since 2000. With regards to the "top 8 journals" such as the Lancet and the Journal of the American Medical Association, the number of first-author publications by Japanese neurosurgeons increased in the late 1980s and had been 2 9 articles per year until recently. In the "top 12 neuroscience journals" which include Stroke, Neuro-Oncology, Cancer Research, and others, Japan had been in the third next to the US and UK till 2004, but Germany surpassed Japan in 2005. In the "top 6 clinical journals" such as the Journal of Neurosurgery and Neurosurgery, the US has been consistently keeping first place and Japan second place since 1977. Searches using the key word elucidated that Japanese neurosurgeons are greatly contributing in the field of "aneurysm." Regarding the number of publications per neurosurgeon, Canada and UK are in the forefront and Japan is down to eighth place. Japanese neurosurgeons have been contributing greatly next to the Americans to the field of clinical neurosurgery and neuroscience by publishing in English. However, the number of publications by Japanese neurosurgeons has been declining since 2000. The Japan Neurosurgical Society must come up with countermeasures to address this problem. PMID- 21701105 TI - Clinical and radiographic characteristics of upper lumbar disc herniation: ten year microsurgical experience. AB - Upper and lower lumbar disc herniation apparently have different background, symptoms, and operative results. This retrospective study reviewed the clinical records of 403 patients (409 discs) who underwent lumbar microdiscectomy performed by different surgeons at our institute between 1999 and 2009. The 290 male (72.0%) and 113 female (28.0%) patients were aged from 19 to 77 years (mean 44 years). Demographics, symptoms, and static and dynamic radiographic and magnetic resonance images obtained at the L1-2, L2-3, L3-4, L4-5, and L5-S1 intervertebral levels were analyzed. Of the 409 herniations, 3 were at L1-2, 9 at L2-3, 21 at L3-4, 166 at L4-5, and 210 at L5-S1. The mean age at herniation at L1 2 and L2-3 levels was 55.7 years. Patients with herniation of discs at L3-4 or above were significantly older than patients who suffered herniation at L4-5 or below (p < 0.0001), and the incidence of urinary disturbance was significantly higher in patients with herniation at L1-2 and L2-3 levels (p = 0.0013). The incidence of degenerative scoliosis was significantly higher in patients with herniation at L1-2 and L2-3 than in those with herniated discs at L3-4 or below (p < 0.0001). Patients with upper lumbar disc herniation were older and manifested a higher incidence of urinary disturbance. A high incidence of degenerative scoliosis was noted in the course of prolonged degenerative processes. PMID- 21701104 TI - Radiological predictive factors for regrowth of residual benign meningiomas. AB - The pre- and postoperative radiological predictive factors for the regrowth of residual benign meningiomas were investigated in 80 of 327 patients who underwent first surgery for intracranial meningioma, who met the following conditions: residual tumor observed on postoperative imaging, follow up for more than 5 years or until regrowth of the residual tumor, histological diagnosis of World Health Organization grade I, and no additional therapy performed within 1 month after surgery. These 80 patients were divided into those with no regrowth during the follow-up period (Group A, n = 54) and those with regrowth (Group B, n = 26), and the clinical characteristics and pre- and postoperative imaging findings were compared. Univariate analysis of factors influencing regrowth showed 6 factors were significant: tumor size >=4 cm (p = 0.043), tumor volume >=30 cm(3) (p = 0.026), presence of edema (p = 0.036), unclear brain-tumor interface (p < 0.001), presence of a pial-cortical blood supply (p = 0.031), and residual tumor volume >=3.0 cm(3) (p < 0.001). Multivariate analysis showed only residual tumor volume >=3.0 cm(3) was significant (p = 0.001). Generally, the significant imaging findings on univariate analysis suggest malignant meningioma. Similar findings may be observed even in grade I cases, and residual tumors may regrow in such cases. The possibility is particularly high if the residual tumor volume exceeds 3.0 cm(3), so early radiotherapy should be performed to prevent regrowth. PMID- 21701106 TI - Delayed neurological insufficiency caused by transverse sacral fracture after minor trauma in elderly patients. AB - Sacral fractures in elderly patients with associated lumbosacral lesions can be overlooked easily because of vague symptoms and delayed neurological insufficiency. A 70-year-old female and a 73-year-old female presented with delayed neurological insufficiency caused by transverse sacral fracture after minor trauma. Both patients had suffered from lower extremity symptoms with dysuresia and dyschezia for more than a month. Coexisting lumbosacral pathological lesions may confuse the correct diagnosis for sacral fractures. Decompressive sacral laminectomy was performed, and the patients showed relatively favorable outcomes. PMID- 21701107 TI - Partially thrombosed vertebral artery aneurysm with wall enhancement treated by stent-assisted coil embolization. AB - A 50-year-old man presented with a 2-month history of dysarthria caused by a partially thrombosed vertebral artery (VA) aneurysm. Magnetic resonance imaging showed enhancement of the thickened wall and angiography detected staining. Stent assisted coil embolization with protection of the parent artery patency was performed. The patient's clinical course was unremarkable and shrinking of the aneurysm was obtained. The stent-assisted coil embolization promoted intra aneurysm flow disruption and stabilized the wall environment, suggesting another strategy for the treatment of partially thrombosed VA aneurysm. PMID- 21701108 TI - Contralateral hearing disturbance following posterior fossa surgery. AB - A 53-year-old man suffered contralateral hearing disturbance one day after acoustic neuroma surgery. Hearing function gradually recovered after steroid and hyperbaric therapy. Contralateral hearing disturbance after acoustic neuroma surgery is an extremely rare complication that can also occur after other posterior fossa surgery. The mechanism of this rare phenomenon remains unclear, but the patent cochlear aqueduct may be involved. PMID- 21701109 TI - Hydrocephalus due to diffuse villous hyperplasia of the choroid plexus. AB - An 8-month-old female presented with hydrocephalus caused by cerebrospinal fluid (CSF) overproduction due to bilateral choroid plexus enlargement, which was clinically diagnosed as diffuse villous hyperplasia of the choroid plexus, but differentiation from bilateral choroid plexus papilloma was difficult. She initially underwent ventriculoperitoneal shunt surgery, but developed marked retention of ascites. Therefore, the peritoneal end of the shunt was removed for external drainage, but excessive CSF (1,500 ml/day) was collected. Computed tomography and magnetic resonance imaging revealed marked symmetric enhancement of the choroid plexuses in the bilateral lateral ventricles. Thallium-201 chloride single-photon emission computed tomography showed pronounced uptake on both early and delayed images, and good washout. CSF examination revealed no abnormalities such as atypical cells, and a ventriculoatrial shunt was inserted, achieving good control of the hydrocephalus. PMID- 21701110 TI - Small supratentorial, extraaxial primitive neuroectodermal tumor causing large intracerebral hematoma. AB - A 16-year-old boy presented with an unusual case of a supratentorial, extraaxial small round blue cell tumor of the central nervous system, which was most likely a primitive neuroectodermal tumor (PNET). Preoperative computed tomography and magnetic resonance imaging showed a large multistage hematoma in the left central region. Intraoperatively, a small, superficial tumorous lesion was found between the sagittal sinus and a large cortical vein hidden by the hematoma. The histological diagnosis was PNET. This tumor is one of the most aggressive intracerebral tumors, not only in children, so treatment strategies must be early, profound, and interdisciplinary. This case represents an important example of atypical extraaxial appearance of this lesion, which should be considered in the differential diagnosis of cortical or subcortical hemorrhage, since complete resection of this lesion is critical for the successful treatment and outcome. PMID- 21701111 TI - Heparin-induced thrombocytopenia in a glioblastoma multiforme patient with inferior vena cava filter placement for deep venous thrombosis. AB - A 58-year-old woman presented with right supplementary motor area glioblastoma multiforme and deep venous thrombosis in her legs. The tumor was resected after temporary inferior vena cava filter placement, considering that increased thrombosis during and after the operation would cause fatal pulmonary embolism. After anticoagulation with unfractionated heparin, thrombocytopenia was aggravated, and computed tomography showed filter catheter-related thrombosis in the inferior vena cava. The diagnosis was heparin-induced thrombocytopenia, and argatroban and urokinase were administered. Thrombolysis with urokinase was completed and the temporary inferior vena cava filter catheter was removed without complication. The present case illustrates the possibility of heparin induced thrombocytopenia associated with catheter-related thrombosis in neurosurgery. PMID- 21701112 TI - Malignant brain tumor with rhabdoid features in an adult. AB - Rhabdoid tumor (RT) of the central nervous system is an uncommon and aggressive neoplasm that usually affects pediatric patients. Currently, these tumors are classified as malignant RT or atypical teratoid/RT. Another entity of intraparenchymal brain tumor with a rhabdoid component is the extremely rare rhabdoid glioblastoma. A 23-year-old woman presented with a malignant RT in the right thalamus. The tumor was adjacent to the right lateral ventricle and was partially resected. Histological examination revealed prominent proliferation of rhabdoid cells, which is consistent with a diagnosis of malignant RT; the typical features of glioblastoma were not observed. The tumor cells stained positively for integrase interactor-1 and glial fibrillary acidic protein. Therefore, the tumor may have originated from glial components. Genetic analysis using comparative genomic hybridization showed a deoxyribonucleic acid copy-number gain on chromosome 7 but not on chromosome 22. The tumor did not respond to chemotherapy or radiotherapy, and the patient survived for only 4 months after surgery. The present case of malignant RTs shows certain similarities with those of rhabdoid glioblastoma. Further accumulation and analysis of data, including data from genetic analyses, may lead to the identification of a new type of malignant RT. PMID- 21701113 TI - Pituitary abscess manifesting as meningitis and photophobia associated with Rathke's cleft cyst in a child. Case report. AB - A 12-year-old girl presented with complaints of headache, lethargy, photophobia, and fever. Cerebrospinal fluid examination revealed bacterial meningitis. Magnetic resonance (MR) imaging showed a cystic lesion with peripheral enhancement in the pituitary fossa. The patient underwent transnasal transsphenoidal surgery (TSS). The diagnosis was pituitary abscess associated with Rathke's cleft cyst. Postoperatively, the patient recovered rapidly. However, recurrence of the pituitary abscess causing meningitis occurred four times and required repeated TSS. She had diabetes insipidus and received hormone replacement. This case requiring repeated emergency surgeries shows that follow up examinations including MR imaging and pituitary endocrine evaluation are necessary because the rate of recurrence is high in patients with pituitary abscess associated with Rathke's cleft cyst. PMID- 21701114 TI - Lateral buttock congenital dermal sinus tract. AB - A 6-month-old female presented with purulent discharge from a dimple in the right lateral buttock. A subcutaneous abscess was palpated on the right paravertebral region at the L5-S1 level. She had low-grade fever with laboratory findings of leukocytosis and elevation of C-reactive protein levels. Klebsiella and Enterococcus species were cultured from the pus. Computed tomography (CT) clearly showed a tract traversing the subcutaneous tissue and connecting to the abscess. Magnetic resonance (MR) imaging showed no abnormality in the spinal canal. The diagnosis was infected congenital dermal sinus (CDS) in the right buttock. After normalization of body temperature and laboratory findings in response to antibiotic treatment, the dermal sinus tract was surgically removed. Intraoperative findings showed that the tract gradually tapered and ended at the subcutaneous abscess space over the lumbosacral fascia. Histological examination confirmed the lesion was dermal sinus. Although laterally placed CDS in the buttocks is extremely rare with only 5 previous cases reported, lateral CDS should be included in the differential diagnosis of a dimple in the buttocks. CT as well as MR imaging should be performed to evaluate suspected lateral CDS. PMID- 21701116 TI - Three-dimensional video presentation of microsurgery by the cross-eyed viewing method using a high-definition video system. AB - Three-dimensional (3-D) video recording of microsurgery is a more promising tool for presentation and education of microsurgery than conventional two-dimensional video systems, but has not been widely adopted partly because 3-D image processing of previous 3-D video systems is complicated and observers without optical devices cannot visualize the 3-D image. A new technical development for 3 D video presentation of microsurgery is described. Microsurgery is recorded with a microscope equipped with a single high-definition (HD) video camera. This 3-D video system records the right- and left-eye views of the microscope simultaneously as single HD data with the use of a 3-D camera adapter: the right- and left-eye views of the microscope are displayed separately on the right and left sides, respectively. The operation video is then edited with video editing software so that the right-eye view is displayed on the left side and left-eye view is displayed on the right side. Consequently, a 3-D video of microsurgery can be created by viewing the edited video by the cross-eyed stereogram viewing method without optical devices. The 3-D microsurgical video provides a more accurate view, especially with regard to depth, and a better understanding of microsurgical anatomy. Although several issues are yet to be addressed, this 3-D video system is a useful method of recording and presenting microsurgery for 3-D viewing with currently available equipment, without optical devices. PMID- 21701115 TI - Noonan syndrome with occipito-atlantal dislocation and upper cervical cord compression due to C1 dysplasia and basilar invagination. AB - A 11-year-old female with Noonan syndrome presented with occipito-atlantal dislocation and upper cervical cord compression due to C1 dysplasia and basilar invagination. Computed tomography (CT) of the cervical spine showed dysplasia of the C1 posterior arch and bilateral dislocation of the occipito-atlantal joints. Dynamic lateral radiography revealed no instability at the occipito-atlantal joints. CT also demonstrated basilar invagination. The tip of the odontoid process extended above the Chamberlain line by 9 mm and the McGregor line by 10 mm. Whole spinal radiography showed no scoliosis. C1 laminectomy was performed with instrumented occipito-C2 fixation. The postoperative course was uneventful, and magnetic resonance imaging revealed sufficient decompression of the upper cervical cord at 2 months after surgery. CT demonstrated solid bony fusion between the occipital bone and C2 at 8 months after surgery. Cervical neuraxial malformations are rare in patients with Noonan syndrome. PMID- 21701117 TI - Wireless modification of the intraoperative examination monitor for awake surgery. AB - The dedicated intraoperative examination monitor for awake surgery (IEMAS) was originally developed by us to facilitate the process of brain mapping during awake craniotomy and successfully used in 186 neurosurgical procedures. This information-sharing device provides the opportunity for all members of the surgical team to visualize a wide spectrum of the integrated intraoperative information related to the condition of the patient, nuances of the surgical procedure, and details of the cortical mapping, practically without interruption of the surgical manipulations. The wide set of both anatomical and functional parameters, such as view of the patient's mimic and face movements while answering the specific questions, type of the examination test, position of the surgical instruments, parameters of the bispectral index monitor, and general view of the surgical field through the operating microscope, is presented compactly in one screen with several displays. However, the initially designed IEMAS system was occasionally affected by interruption or detachment of the connecting cables, which sometimes interfered with its effective clinical use. Therefore, a new modification of the device was developed. The specific feature is installation of wireless information transmitting technology using audio visual transmitters and receivers for transfer of images and verbal information. The modified IEMAS system is very convenient to use in the narrow space of the operating room. PMID- 21701118 TI - Effect of connector design on fracture resistance of zirconia all-ceramic fixed partial dentures. AB - The purpose of the present study was to determine the relationship between cross sectional design and fracture load using a static load bearing test in yttria stabilized tetragonal zirconia polycrystal ceramic frameworks on a molar fixed partial denture. The test framework was designed as a 3-unit bridge with two abutment teeth at the second premolar and second molar of the mandible. The cross sectional area of the connector was 9.0, 7.0, or 5.0mm(2). In terms of shape, the cross-section was either circular or oval, with a height/width ratio of 1:1, 3:4, or 2:3. For each of the 9 combinations of cross-sectional area and shape, 5 frameworks were prepared (45 in total). Frameworks were cemented to a metallic test model with adhesive resin cement. After fracture load was measured, the percentage of fracture sites was determined and the fracture surfaces observed. In terms of cross-sectional area, there was a statistically significant difference in fracture load between 9.0, 7.0, and 5.0mm(2). No significant difference in fracture load was observed between any two shapes of connector (p>0.05). The fracture load of all frameworks with a cross-sectional area of 9.0 or 7.0mm(2) was over 880 N, which was recognized as parafunctional occlusal force. Fracture occurred at the distal connector in 82.2% of all frameworks on average. Fracture load decreased as cross-sectional area of the connector became smaller. The cross-sectional shape used in the present study was less influential on fracture load. It appears to be clinical possible to apply a connector with a cross-sectional area of 7.0mm(2). Fracture often occurred at the distal connector between the pontic and the abutment, corresponding to the second molar. PMID- 21701119 TI - Scanning and transmission electron microscopic observation of changes in cylindrical cytoplasmic processes of isolated single merkel cell. AB - The aim of the present study was to determine the reason isolated single Merkel cells do not respond to mechanical stimulation by fluorescent or histological techniques. Cells identified as Merkel cells by quinacrine fluorescence and measurement of intracellular calcium concentration were observed by transmission electron and scanning electron microscopy. Observations elucidated that the cylindrical cytoplasmic processes of single Merkel cells disappeared with time shortly after isolation. Transmission electron microscopy revealed the presence of numerous dense-cored granules, which may function as sensory receptors in the cytoplasm of the isolated single Merkel cell. Disappearance of the cylindrical cytoplasmic processes impeded reception of mechanical stimulation. The results suggest that an isolated single Merkel cell continues to function as a sensory receptor cell due to the presence of numerous dense-cored granules. Furthermore, the results show that an isolated single Merkel cell is not an appropriate specimen for investigation of mechanically-gated channels. PMID- 21701120 TI - Three-dimensional analysis of mesiobuccal root canal of Japanese maxillary first molar using Micro-CT. AB - The objective of this study was to three-dimensionally observe the morphological characteristics of mesiobuccal root canals of Japanese maxillary first molars using microcomputed tomography (Micro-CT) and classify root canal variations. This study used 90 maxillary first molars. Three-dimensional reconstruction was performed using data obtained by Micro-CT, and cross-sections of the root canals were observed. Moreover, the root canal morphology was classified by the configuration and root canal diameter, and was evaluated for occurrence using the classification by Weine et al. (1969) as a reference. Overall, single root canals were observed in 44.4%, incomplete separation root canals in 22.3%, and completely separate root canals (upper and lower separation root canals) in 33.3%. Mesiobuccal root canals often had intricate configurations, and accessory root canals (lateral canals and apical ramifications) were observed in most of the mesiobuccal root canals (76.7%), irrespective of whether there were ramifications of the main root canals. While there were no marked differences in the incidence of root canal ramifications between this study and earlier reports, the incidence of accessory root canals was higher in this study. This result may be explained by the far more superior visualization ability of Micro-CT than conventional methods, which allowed the detection of microscopic apical ramifications previously difficult to observe. PMID- 21701121 TI - Splenocyte cytokine profile in mouse with oral mucosa-sensitization and oral tolerization by NiSO(4). AB - Metals used in the oral cavity have been reported to cause various allergic diseases of the skin and mucosa. Skin manifestations due to dental restorations appear not only in the oral cavity, but also on the hands, feet or the whole body, as in the cases of pustulosis palmoplantaris and lichen planus. These phenomena implicate different pathogeneses from that of conventional skin sensitization and tolerance. Therefore, we compared skin and oral mucosa sensitization with nickel and oral tolerance for nickel in a mouse model. Female C57BL/6J mice were sensitized by injection of NiSO(4) into the skin or oral mucosa. Allergic reactions were evaluated by the mouse ear swelling test and splenocyte proliferation and cytokine profiles. Skin and oral mucosa sensitization succeeded in all mice. Ear swelling was significantly greater in the skin- than in the oral mucosa-sensitized mice at 48 hr after challenge. Ear swelling was also suppressed by single oral administration of NiSO(4) in both the skin- and oral mucosa-sensitized mice to the level of that in nonsensitized mice. Splenocytes from skin-sensitized mice proliferated similarly to those from oral mucosa-sensitized mice. Splenocytes from orally-tolerized mice also showed similar proliferation activity to those from skin and oral mucosa-sensitized mice. In the challenge phase, IL-2, IFN-gamma, and IL-10 production was induced in splenocytes from both skin- and oral mucosa-sensitized mice. However, IL-4 was induced only in those from skin-sensitized mice. In addition, IL-4 in splenocytes from oral mucosa-sensitized mice was up-regulated to the level in those from skin sensitized mice by oral tolerance. These results suggest that sensitization sites in mice influence not only the degree of excitation, but also Th-1 and Th-2 balance in the challenge phase and oral tolerance. PMID- 21701122 TI - Effect of diode laser on proliferation and differentiation of PC12 cells. AB - This study investigated the effects of diode (GaAlAs) laser irradiation at an effective energy density of 5 or 20 J/cm(2) on cell growth factor-induced differentiation and proliferation in pheochromocytoma cells (PC12 cells), and whether those effects were related to activation of the p38 pathway. Laser irradiation at 20 J/cm(2) significantly decreased the number of PC12 cells, while no difference was seen between the 5 J/cm(2) group and the control group (p<0.05). Western blotting revealed marked expression of neurofilament and beta tubulin, indicating greater neurite differentiation in the irradiation groups than in the control group at 48 hr. Irradiation also enhanced expression of phospho-p38. The decrease in number of cells after laser irradiation was accelerated by p38 inhibitor, while neurite differentiation was up-regulated by laser irradiation, even when the p38 pathway was blocked. This suggests that laser irradiation up-regulated neurite differentiation in PC12 cells involving p38 and another pathway. PMID- 21701123 TI - Application of interdental distraction osteogenesis to unilateral cleft lip and palate patients. AB - Distraction osteogenesis is widely used for the treatment of craniofacial deformities. In patients with cleft lip and palate, distraction osteogenesis can be employed to repair the alveolar cleft. In this report, we describe the management of three cases of unilateral cleft lip and palate by interdental distraction osteogenesis. Interdental distraction osteogenesis of the maxillary bone was performed to reduce the width of the alveolar cleft in these patients in conjunction with orthodontic treatment. Tooth-tooth type distraction devices were fabricated and delivered at the same time as osteotomy. Distraction was continued until the midline of the dentition coincided with the facial midline, and until the width of the alveolar cleft was reduced to the width of lateral incisor or had closed. One month after distraction was complete, orthodontic treatment with an edgewise appliance was initiated, and neighboring teeth were moved into the newly created bone. A favorable treatment outcome was achieved in all three cases. PMID- 21701124 TI - Risk factors for nausea and vomiting after day care general anesthesia in mentally challenged patients undergoing dental treatment. AB - Clinically, the incidence of postoperative nausea and vomiting (PONV) may be higher in mentally challenged patients than in normal healthy patients. The aim of this study was to investigate the risk factors for PONV after day care general anesthesia in mentally challenged patients undergoing dental treatment. We analyzed data on 231 day care general anesthesia cases involving mentally challenged patients undergoing dental treatment. Anesthetic records for the past 5 years were investigated retrospectively. Ten items (age, body weight, sex, duration of general anesthesia, use of propofol, use of sevoflurane, use of nitrous oxide, use of neostigmine, treatment accompanied with bleeding, and transfusion volume) were selected as risk factors for PONV. Postoperative nausea and vomiting was evaluated using the postoperative check sheet and linear discriminant analysis was performed to distinguish PONV incidence using the 10 items as independent variables. The reliability of the linear discriminant function was evaluated using a misjudgment rate and information criteria (AIC). Postoperative nausea and vomiting was observed in 13 cases out of 231 cases. The discriminant function with the smallest AIC (-25.0718) consisted of two independent variables: y=-0.077x(1)-0.001x(2)+0.0716(x(1)=use of propofol, x(2)=age). The misjudgment rate was 31.6%. This result suggests that PONV decreases when propofol is used and that the incidence of PONV decreases with age. To investigate other risk factors, an additional analysis was performed using 83 out of the 231 cases in which sevoflurane was used as an anesthetic agent. The results of the subgroup analysis suggest that the incidence of PONV decreases in male patients and higher weight patients, although the patient's body weight may be related to age, as the study cohort included many children. It is suggested that the major risks for PONV in mentally challenged patients after day care general anesthesia are no use of propofol, lower age, female sex and lower weight. PMID- 21701125 TI - Single nucleotide polymorphisms in the homologous recombination repair genes and breast cancer risk in Polish women. AB - Genetic polymorphisms in homologous recombination repair genes that can lead to protein haploinsufficiency are generally associated with increased cancer risk. The aim of the present study was to evaluate associations between the risk of breast cancer and single nucleotide polymorphisms in the genes, encoding three key proteins of the homologous recombination repair: RAD51 (the human homologue of the E. coli RecA protein), X-ray repair cross-complementing group (XRCC) 2 and XRCC3. The polymorphisms studied were G135C of the RAD51 gene (c. -98 G>C; rs1801320), Arg188His of the XRCC2 gene (c. 563 G>A; rs3218536), and Thr241Met of the XRCC3 gene (c. 722 C>T; rs861539). Each polymorphism was genotyped by the PCR RFLP (restriction fragment-length polymorphism) method in 700 Polish female patients with sporadic breast cancer and in 708 cancer-free women, who served as controls. In the present study, we showed the association between RAD51 G135C polymorphism and the incidence of breast cancer (p < 0.0001), but found no significant association with XRCC2 Arg188His or XRCC3 Thr241Met polymorphism. Instead, significant association was identified between XRCC2 Arg188His or XRCC3 Thr241Met polymorphism and breast cancer progression, assessed by the histological grading. However, each of these three polymorphisms was not associated with the tumor size or the lymph node metastases. This study provides evidence that links single nucleotide polymorphisms of RAD51 and XRCC2/3 genes with the risk of breast cancer in Polish women. In conclusion, RAD51 G135C, XRCC2 Arg188His and XRCC3 Thr241Met polymorphisms may be regarded as predictive factors of sporadic breast cancer in female population. PMID- 21701126 TI - Single dose administration of L-carnitine improves antioxidant activities in healthy subjects. AB - L-carnitine has been used as a supplement to treat cardiovascular or liver disease. However, there has been little information about the effect of L carnitine on anti-oxidation capability in healthy human subjects. This study was designed to investigate the correlation between plasma L-carnitine concentration and antioxidant activity. Liquid L-carnitine (2.0 g) was administered orally as a single dose in 12 healthy subjects. Plasma concentration of L-carnitine was detected by HPLC. The baseline concentration of L-carnitine was 39.14 +/- 5.65 umol/L. After single oral administration, the maximum plasma concentration (C(max)) and area under the curve (AUC(0-infinity)) were 84.7 +/- 25.2 umol/L and 2,676.4 +/- 708.3 umol/L.h, respectively. The half-life and the time required to reach the C(max) was 60.3 +/- 15.0 min and 3.4 +/- 0.46 h, respectively. There was a gradual increase in plasma concentrations of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase and total antioxidative capacity (T AOC) in the first 3.5 h following L-carnitine administration. The plasma concentrations of SOD, GSH-Px, catalase and T-AOC returned to baseline levels within 24 h. A positive correlation was found between L-carnitine concentration and the antioxidant index of SOD (r = 0.992, P < 0.01), GSH-Px (r = 0.932, P < 0.01), catalase (r = 0.972, P < 0.01) or T-AOC (r = 0.934, P < 0.01). In conclusion, L-carnitine increases activities of antioxidant enzymes and the total antioxidant capacity in healthy subjects. It may be useful as a supplementary therapy for chronic illnesses involving excessive oxidative stress. PMID- 21701127 TI - The nutritional index 'CONUT' is useful for predicting long-term prognosis of patients with end-stage liver diseases. AB - Organ allocation in Japan remains difficult due to the shortage of deceased-donor livers. The screening tool for controlling nutritional status (CONUT) has been considered to be an established assessment model for evaluating nutritional aspects in surgical patients. However, the application of this CONUT for evaluating the prognosis of patients with end-stage liver diseases has not been evaluated. We assessed the predictability of the prognoses of 58 patients with end-stage liver disease using various prognostic models. The patients registered at the transplantation center of Tohoku University Hospital for the waiting list of Japan Organ Transplant Network for liver transplantation were retrospectively analyzed. The prognoses of the patients were evaluated using the following 5 models: CONUT, the model for ELD with incorporation of sodium (MELD-Na), Child Turcotte-Pugh score (CTP), prognostic nutritional indices (Onodera: PNI-O), and the Japan Medical Urgency criteria of the liver (JMU). Cox's proportional hazard model, log-rank test and concordance(c)-static were used for the statistics. The indices were 17.74 +/- 5.80 for MELD-Na, 9.21 +/- 2.19 for CTP, 33.92 +/- 11.16 for PNI-O, and 7.57 +/- 3.09 for CONUT. Univariate analysis revealed the significance of CONUT (p = 0.017, Odds: 1.325) but not MELD-Na, CTP, JMU or PNI-O for prediction. The cumulative survival rate was clearly discriminated at CONUT point 7. The c-static was 0.081 for the 6-month (M) survival rate, 0.172 for 12M, 0.517 for 36M, 0.821 for 48M, and 0.938 for 60M for CONUT. In conclusion, CONUT shows best predictability for the distant prognoses of patients with ELD. PMID- 21701128 TI - Exercise improves recovery after ischemic brain injury by inducing the expression of angiopoietin-1 and Tie-2 in rats. AB - Post-ischemia angiogenesis plays a critical part in the recovery of neural networks. Angiopoietin (Ang) has received much attention recently due to its key role in neurovascular remodeling. Exercise is proved to contribute to angiogenesis in normal or injured human skeletal muscle. The therapeutic effect of exercise on central angiogenesis after cerebral ischemia, however, has not been studied. In the present study, we investigated the relationship between exercise and the expression of Ang-1, Ang-2, and Tie-2 receptor tyrosine kinase in the brain using a rat model of stroke, with right middle cerebral artery occluded (MCAO). Male Sprague-Dawley rats were randomly grouped (n = 12): stroke exercise (SE), stroke-no exercise (SNE) and sham-no exercise (SHAM). The SE group ran on a treadmill at a speed of 12 m/min, 30 min/day for 2 weeks. Functional recovery was assessed with neurological evaluation scores. Brain infarction was measured by Nissl staining. Expression of Ang-1, Ang-2, and Tie-2 were compared by immunohistochemical and real-time PCR analyses. The infarct volume in the SE group was significantly reduced compared with the SNE group (p < 0.05). Ang-1 (p < 0.05) and Tie-2 (p < 0.05) and their mRNA expression (p < 0.01 and p < 0.05, respectively) were increased in SE animals at 2 weeks, whereas Ang-2 expression remained unchanged. In conclusion, enhanced expression of Ang-1 and Tie-2 by exercise improves recovery of brain function in MCAO rats. Our results suggest the importance of angiogenesis in rehabilitation for post-ischemia brain injury and help to explain the underlying mechanism. PMID- 21701129 TI - Transplantation of adipose stromal cells promotes neovascularization of random skin flaps. AB - The delivery of bone marrow-derived mononulear cells (BM-MNCs) has been proved to be effective at promoting neovascularization of ischemic skin flaps. However, the limited source of BM-MNCs restricts their clinical application. Stromal vascular fraction (SVF) contains a group of heterogeneous cells in the adipose tissue, including adipose tissue-derived stem cells, and it has abundant reserve in human body. In this study, we evaluated the therapeutic potential of SVF to promote neovascularization of random skin flaps. Female Wistar rats were randomly devided into three groups with 8 in each group and received allogeneic SVF, BM-MNCs and phosphate-buffered saline (PBS), respectively, before surgery. Two days after cell administration, a 10 * 3 cm random skin flap was elevated. Flap survival, blood flow perfusion and capillary density were examined 7 days after surgery, and the relevant mechanism was also explored. Results showed that SVF group and BM-MNCs group had higher survival percentage (72.2 +/- 2.0% and 76.4 +/- 3.1%, respectively) as compared with the control group (56.8 +/- 4.6%, P < 0.05). Blood flow perfusion and capillary density of flap tissues in SVF and BM-MNCs groups were both improved. The expression levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were increased in flap tissues of SVF and BM-MNCs groups detected by ELISA. These results indicate that SVF could promote vascularization and increase flap survival probably by secreting VEGF and bFGF. The effect of transplantation of SVF on therapeutic angiogenesis of skin flaps is equivalent to that of BM-MNCs. PMID- 21701130 TI - A cyanobacterial toxin, microcystin-LR, induces apoptosis of sertoli cells by changing the expression levels of apoptosis-related proteins. AB - Toxic cyanobacterial blooms in freshwater have been considered as threats to human health. Microcystins are a family of cyclic polypeptides produced by cyanobacteria and are toxic to plants and animals. Microcystin-LR (MC-LR) is the most toxic variant among the microcystin family and could cause oxidative stress in various organs, including the reproduction system. The aim of this study was to investigate the effect of MC-LR on apoptosis of Sertoli cells that play an essential role in the development and maturation of sperm cells. Sertoli cells were isolated from healthy immature rats and cultured with MC-LR. The viability of Sertoli cells was decreased after treatment with MC-LR at 10 ug/ml for 24 h (P < 0.05). Moreover, the MC-LR-treated cells exhibited condensed chromatin and fragmented nuclei, features of apoptosis, as judged by Hoechst 33258 staining. We also analyzed the mRNA and protein levels of three apoptosis-related genes, p53, bax and bcl-2, using reverse transcription-polymerase chain reaction and Western blot analyses, respectively. Both p53 and bax function as promoters of apoptosis, while bcl-2 is an apoptotic suppressor. The mRNA and protein expression levels of p53 and bax were increased in Sertoli cells treated with MC-LR at 10 ug/ml compared with the control group (P < 0.05), while the bcl-2 protein levels were decreased in cells treated with MC-LR at 10 ug/ml (P < 0.05). Moreover, caspase-3 activity that is involved in the induction of apoptosis was significantly increased in Sertoli cells treated with MC-LR. These results indicate that MC-LR induces apoptosis of Sertoli cells. PMID- 21701131 TI - Frequent occurrence of the triphasic response (diabetes insipidus/hyponatremia/diabetes insipidus) after surgery for craniopharyngioma in childhood. AB - BACKGROUND/AIMS: It is not exactly known how many children develop the triphasic response (diabetes insipidus (DI)/hyponatremia/DI) immediately after surgery for childhood craniopharyngioma; neither is it known which factors predict this. We studied the occurrence of the triphasic response after primary surgery for craniopharyngioma in children, and aimed to identify possible predictors. METHODS: Patients <18 years old who had undergone a primary craniopharyngioma resection between January 1990 and February 2010 in either of the 2 academic centers in Amsterdam were studied retrospectively. RESULTS: Twenty-one patients (5 males) fulfilled the inclusion criteria. Median age at surgery was 9.1 (range: 4.0-15.1) years. Six patients developed a triphasic response (29%). Of all factors, only the duration of surgery was found to be a predictor of a triphasic response: 8.5 (6.0-11.0) versus 4.6 (3.5-11.5) h in patients who did not develop a triphasic response (p = 0.03). CONCLUSION: After primary surgery for a craniopharyngioma, a considerable number of patients develop a triphasic response in the regulation of the sodium and water balance. This is predicted by (factors associated with) a longer duration of surgery. Other predictors could not be identified, which may be due to the small sample size. PMID- 21701132 TI - Placental volume at 11-13 weeks' gestation in the prediction of birth weight percentile. AB - OBJECTIVE: To determine the value of placental volume measured by 3D ultrasound at 11-13 weeks' gestation in combination with maternal characteristics and serum pregnancy-associated plasma protein-A (PAPP-A) in the prediction of small and large for gestational age (SGA and LGA) neonates. METHODS: Maternal serum PAPP-A and placental volume were measured at 11-13 weeks in 3,104 singleton pregnancies. Regression analysis was used to examine the contribution of maternal characteristics, placental volume and PAPP-A in the prediction of SGA and LGA neonates. RESULTS: There was a significant association between placental volume and PAPP-A (r = 0.268, p < 0.0001). Median placental volume and PAPP-A, expressed as multiples of the median (MoM) in appropriate for gestational age (AGA) neonates, were reduced in the SGA group (placental volume 0.88 MoM, vs. 1.00 MoM in AGA, p < 0.0001; PAPP-A 0.92 MoM vs. 1.00 MoM in AGA, p = 0.019) and increased in the LGA group (placental volume 1.09 MoM vs. 1.00 MoM in AGA, p < 0.0001; PAPP A 1.15 MoM vs. 1.00 MoM in AGA, p = 0.015). Maternal characteristics with either placental volume or PAPP-A detected about 30% of the SGA or LGA neonates, at a false positive rate of 10%. CONCLUSION: Measurement of placental volume and serum PAPP-A can improve the prediction of SGA or LGA neonates provided by maternal characteristics alone. PMID- 21701133 TI - Optimal duration of androgen deprivation in combination with radiation therapy for Japanese men with high-risk prostate cancer. AB - OBJECTIVES: To evaluate the efficacy and toxicity of external beam radiation therapy (EBRT) combined with androgen deprivation therapy (ADT) for Japanese high risk prostate cancer (PCa) patients in a single institution. METHODS: Seventy five high-risk PCa patients were treated by three-dimensional conformal radiotherapy of 70 Gy combined with neoadjuvant, concurrent and adjuvant ADT. RESULTS: Median age was 72 (59-82) years. Median initial serum prostate-specific antigen (PSA) was 19.0 (4.7-200) ng/ml. Median duration of the entire ADT was 27 (8-63) months. Median follow-up after initiating ADT and after completing EBRT was 66 (41-105) and 59 (36-94) months, respectively. Five-year overall, clinical progression-free, and biochemical progression-free survival rates were 98.3, 97.2, and 87.4%; 2 (2.7%) cancer deaths, 3 (4.0%) clinical progressions, and 11 (14.7%) biochemical progressions. Multivariate analysis suggested a total duration of ADT shorter than 24 months as an independent risk factor of biochemical progression (p = 0.01). Grade 3 toxicities related to EBRT were observed: 1 patient with proctitis and rectal bleeding and 1 patient with rectal bleeding. CONCLUSIONS: It is suggested that 70 Gy EBRT combined with ADT confers disease-free survival benefit with tolerable adverse events for Japanese high risk PCa patients. ADT of 24 months or longer might be recommended to minimize biochemical progression. PMID- 21701134 TI - Prenatal diagnosis, management and outcome of fetal dysrhythmia: a tertiary fetal medicine centre experience over an eight-year period. AB - OBJECTIVE: To review the prenatal diagnosis, management and outcome of fetal dysrhythmia. SUBJECTS AND METHODS: Prenatal diagnosis, management and outcomes of fetuses with dysrhythmia were reviewed retrospectively (01/01/1997 to 31/12/2004). RESULTS: Over an 8-year period, 318 pregnant mothers were referred for assessment of suspected fetal dysrhythmias. Median gestation was 30 weeks (range 19-41). Fetal dysrhythmia was identified in 182 (57%) and classified as: (i) 126 atrial extrasystoles; (ii) 26 tachyarrhythmia, and (iii) 30 bradyarrhythmia. Of the fetuses with tachyarrhythmia, 23 had supraventricular tachycardia (SVT), 2 atrial flutter and 1 sinus tachycardia. One death associated with severe hydrops occurred in the tachyarrhythmia group. 19 cases of SVT were successfully treated in utero. Both cases of atrial flutter required direct current cardioversion in the neonatal period. In the bradyarrhythmia group, there were 15 isolated cases and 10 cases associated with congenital heart disease, with 73 and 20% survival, respectively. CONCLUSIONS: Benign atrial extrasystoles are the commonest cause for referral and assessment of fetal dysrhythmia. The overall prognosis for SVT is good with the majority responding to transplacental therapy. In cases with congenital atrioventricular block, the outcome was less favourable, especially when the atrioventricular block was associated with congenital heart disease. PMID- 21701135 TI - Long-term significance of the number of hours until surgical repair of penile fractures. AB - OBJECTIVES: We investigated whether a delay in time until surgery, in terms of hours, has any effect on the overall long-term results of surgical repair of penile fractures. METHODS: Between 2001 and 2009, we operated on 56 patients with penile fractures. We evaluated 43 patients sorted into 3 groups according to the time interval until surgery. We applied the validated Turkish version of the International Index of Erectile Function (IIEF) questionnaire 3 times: for the time period before the fracture, 1 year after the fracture, and at the time of the study. An erectile dysfunction score was calculated for every patient. RESULTS: Overall, the mean follow-up was 46.1 +/- 19.2 months. The mean number of hours from trauma to surgery was 11.3 +/- 8.5. There was no statistically significant difference between the 3 groups in terms of age and length of tears. The results of the IIEF questionnaires of each group for time periods and for individual patients in each separate group were statistically similar. CONCLUSIONS: Surgical repair has a good functional outcome and low complication rates in the long term. Neither serious deformities nor erectile dysfunction occur as a consequence of a delay in surgery in the long term in patients with no urethral involvement within a given period of time. PMID- 21701136 TI - Multi-parametric magnetic resonance imaging to rule-in and rule-out clinically important prostate cancer in men at risk: a cohort study. AB - OBJECTIVES: Overdiagnosis is arguably the greatest challenge in the management of men with prostate cancer. Multi-parametric (mp)-MRI prior to prostate biopsy may have a role in ruling-in and ruling-out clinically significant disease. PATIENTS AND METHODS: 114 consecutive men at risk of prostate cancer with previous biopsy underwent mp-MRI prior to transrectal ultrasound (TRUS)-guided biopsies. Standard systematic biopsies were carried out with targeting to suspicious areas. RESULTS: 59.6% had cancer detected by TRUS-guided biopsy. Mean age was 63.6 years (SD 9.0). If men had not been biopsied because of a negative mp-MRI, 21% (24/114) with no cancer and 5% (6/114) with clinically insignificant cancer could have avoided a biopsy. However, 4% (4/114) would have been advised to defer a biopsy that demonstrated the presence of clinically significant cancer. CONCLUSION: mp MRI may have a role in ruling-in and ruling-out clinically significant prostate cancer in men at risk prior to biopsy. PMID- 21701137 TI - Iatrogenic splenectomy during left nephrectomy: a single-institution experience of eight years. AB - INTRODUCTION: Iatrogenic injury to the spleen is not an uncommon complication. Left nephrectomy has been reported as the second commonest cause of iatrogenic splenectomy with a reported incidence between 1.3 and 24%. Iatrogenic splenectomy is associated with significant morbidity and mortality. AIMS: We reviewed the occurrence of iatrogenic splenectomy during left nephrectomy at our centre. Our aims were to determine the incidence of iatrogenic splenectomy within the Mid Yorkshire Hospitals NHS Trust in order to understand the nature of the splenic injury and the morbidity and mortality associated with it. METHODS: All splenectomy and nephrectomy histology reports from January 2000 to December 2007 were reviewed retrospectively. Indications for splenectomy and nephrectomy were identified. Patients' demographic data, tumour characteristics, operative details, length of hospital stay and any reported morbidity or mortality were collected. RESULTS: A total of 447 nephrectomies were identified which included 234 left nephrectomies. Within the same period 136 cases of splenectomy were performed. Thirty-four cases were iatrogenic splenectomies and 12 were caused by left nephrectomy. The incidence was 5.13%. The male to female ratio was 1:1 with an average age of 66 years. Grade 2 and stage pT2 renal cancer were the commonest tumour characteristics. All iatrogenic injuries occurred during mobilisation of the colon or division of adhesion. The average operative time was 4.7 h. Average length of hospital stay was 14 days. Five patients had postoperative complications and 1 died of respiratory failure and sepsis. CONCLUSION: Splenic injury during left nephrectomy is a morbid complication. A good understanding of anatomy and surgical approach may reduce the incidence, morbidity and mortality of iatrogenic splenectomy during left nephrectomy. PMID- 21701138 TI - Impact of the maternal age-related risk in first-trimester combined screening for trisomy 21. AB - OBJECTIVE: To examine the impact of the maternal age-related risk in first trimester combined screening for trisomy 21. METHODS: Prospective assessment of risk for trisomy 21 by a combination of maternal age, fetal NT thickness and maternal serum PAPP-A and free beta-hCG at 11+0 to 13+6 weeks of gestation between April 2002 and February 2007. Screening for trisomy 21 by patient specific risks based on the maternal and gestational age-related risk multiplied by a likelihood ratio for NT and for maternal serum biochemistry were compared with a screening policy that is only based on the combined likelihood ratio for fetal NT and maternal serum biochemistry. RESULTS: The study population consisted of 38,603 euploid pregnancies and 109 fetuses with trisomy 21. In screening for trisomy 21 by fetal NT and maternal serum biochemistry in combination with and without maternal age with a fixed false-positive rate of 3%, the detection rate was 82.6 and 79.8%, respectively. In the group of women with a maternal age of less than 30 years and between 30 and 35 years, there was no difference in the detection rate. For women with a maternal age of 35 years or older, the detection rate increased from 77.1% without maternal age to 94.3% with maternal age, respectively. CONCLUSION: The overall difference between first-trimester screening based on fetal NT and maternal serum biochemistry with and without maternal age is about 3%. In screening with a fixed cut-off, the maternal age related risk keeps the false-positive rate low in younger women and increases the detection rate in older women. PMID- 21701139 TI - Anatomic predictors of retropalatal mechanical loads in patients with obstructive sleep apnea. AB - BACKGROUND: The retropalatal airway is one of the most collapsible sites during sleep in patients with obstructive sleep apnea (OSA). The primary anatomical contributors to increased collapsibility in the retropalatal segment remain unclear. OBJECTIVES: This study seeks to investigate how the balance between pharyngeal soft tissues and the bony enclosure influences retropalatal mechanical loads in patients with OSA. METHODS: The segmental mechanical load of the retropalatal pharynx was determined by the region's critical closing pressure in 30 anesthetized, paralyzed and intubated subjects with OSA. The volumetric anatomical parameters of the retropalatal airway were evaluated using magnetic resonance imaging, and their associations with retropalatal closing pressures were analyzed. RESULTS: Increased retropalatal closing pressure was associated with the increased proportion of volumetric pharyngeal soft tissues to the surrounding cervicomandibular bony frame (r = 0.791, p < 0.001), enlarged soft tissues of the lateral wall (r = 0.752, p < 0.001) and soft palate (r = 0.726, p < 0.001). The decreased volume of the nasopharynx (r = -0.650, p < 0.001) and pharyngeal cavity (r = -0.653, p < 0.001) indicated a relatively higher retropalatal closing pressure. The multivariate linear regression model demonstrated that the proportion of retropalatal soft tissues to the bony frame and volume of the soft palate predicted 69.4% of the variability in closing pressure (F = 30.674, p < 0.001). CONCLUSIONS: The increased volumetric proportion of pharyngeal soft tissue to the bone enclosure may be an important contributor to increased retropalatal mechanical loads. PMID- 21701140 TI - Striatal neuroprotection from neonatal hypoxia-ischemia in piglets by antioxidant treatment with EUK-134 or edaravone. AB - Striatal neurons are highly vulnerable to hypoxia-ischemia (HI) in term newborns. In a piglet model of HI, striatal neurons develop oxidative stress and organelle disruption by 3-6 h of recovery and ischemic cytopathology over 6-24 h of recovery. We tested the hypothesis that early treatment with the antioxidants EUK 134 (a manganese-salen derivative that acts as a scavenger of superoxide, hydrogen peroxide, nitric oxide or NO and peroxynitrite) or edaravone (MCI-186, a scavenger of hydroxyl radical and NO) protects striatal neurons from HI. Anesthetized newborn piglets were subjected to 40 min of hypoxia and 7 min of airway occlusion. At 30 min after resuscitation, the piglets received vehicle, EUK-134 or edaravone. Drug treatment did not affect arterial blood pressure, blood gases, blood glucose or rectal temperature. At 4 days of recovery, the density of viable neurons in the putamen of vehicle-treated piglets was 12 +/- 6% (+/-SD) of sham-operated control density. Treatment with EUK-134 increased viability to 41 +/- 17%, and treatment with edaravone increased viability to 39 +/- 19%. In the caudate nucleus, neuronal viability was increased from 54 +/- 11% in the vehicle group to 78 +/- 15% in the EUK-134 group and to 73 +/- 13% in the edaravone group. Antioxidant drug treatment accelerated recovery from neurologic deficits and decreased oxidative and nitrative damage to nucleic acids. Treatment with EUK-134 reduced the HI-induced formation of protein carbonyl groups and tyrosine nitration at 3 h of recovery. We conclude that systemic administration of antioxidant agents by 30 min after resuscitation from HI can reduce oxidative stress and salvage neurons in the highly vulnerable striatum in a large-animal model of neonatal HI. Therefore, oxidative stress is an important mechanism for this injury, and antioxidant therapy is a rational, mechanism-based approach to neuroprotection in the newborn brain. PMID- 21701143 TI - Pallio-pallial tangential migrations and growth signaling: new scenario for cortical evolution? AB - Observations accruing in recent years imply that the areal patterning and size dimensioning of the mammalian neocortex are influenced by diverse sets of tangentially migrating glutamatergic neurons that invade the cortical plate and, in so doing, modify the properties of the neopallial proliferative compartments. This developmental scenario sheds new light upon the old issue of how the mammalian neocortex evolved its more complex structure from nonmammalian antecedent forms. In reviewing these novelties, I first point out the topological position of the neopallial island as a central component of the pallium in all gnathostomes, surrounded by a ring of prospective allocortical pallial regions and a more distant set of peripheral neighboring forebrain areas. Early patterning arises from the periphery via passive planar signaling. This process probably establishes the pallium field and its basic island plus allocortical ring organization, as well as a rough prepatterning of some regional subareas. Afterwards, patterning and modulated growth are also actively influenced by the convergence of separate streams of tangentially migrating subpial cells (partly peripheral and partly allocortical in origin) which collectively form the Cajal Retzius neuronal population in layer I. Effects of these cells include the inside out stratification of the cortical plate and they may also contribute to the evolutionary emergence of the 6-layered neocortical structure. The most recent addition to our knowledge of pallio-pallial migrations is the existence of a subsequent deep tangential migration of ventropallial cells into the neopallial primordium, whose signaling influence upon local progenitors magnifies the cortex population by 20%. These glutamatergic cells dispersedly invade the entire cortex but largely die postnatally. The crucial implications of these data for comparative thinking on mammalian neocortex evolution and interpretation of potential homologs in sauropsids are explored. Finally, a new conjecture regarding a possible role of the hitherto disregarded lateral pallium is advanced. PMID- 21701142 TI - Relationship between cardiovascular risk factors and adipokines in adolescents. AB - This study evaluated the associations of adipokines with cardiovascular risk factors. SUBJECTS/METHODS: 60 normal weight (BMI <=75th percentile) and 60 overweight (BMI >=95th percentile) adolescents aged 10-14 years. Resting systolic and diastolic blood pressures (SBP, DBP) and waist circumference were obtained in duplicate. Circulating adiponectin, resistin, tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6), total cholesterol (TC), high-density lipoprotein (HDL), and triglycerides (TG) were measured from fasting plasma samples. RESULTS: Simple correlations showed that SBP was significantly related (p < 0.05) to adiponectin (r = -0.185), resistin (r = 0.207), and IL-6 (r = 0.238); HDL was significantly related to adiponectin (r = 0.398) and TNF-alpha (r = -0.227). TG was only related to adiponectin (r = -0.292, p < 0.05). Multiple regression models controlling for puberty and ethnicity indicated that adiponectin (R(2) = 0.152, p < 0.05), resistin (R(2) = 0.152, p < 0.05), and IL-6 (R(2) = 0.170, p < 0.05) were associated with SBP. The association between adiponectin and HDL was stronger in normal weight versus overweight adolescents (R(2) = 0.336, p < 0.05). None of the other models showed differences in the associations by weight status. CONCLUSIONS: In adolescents, SBP but not DBP was associated with most adipokines. HDL, but not TC, was also associated with some adipokines. TG were only associated with adiponectin. Associations were mostly related to adiposity. PMID- 21701144 TI - Uselessness of percutaneous core needle renal biopsy in the management of small renal masses. PMID- 21701141 TI - All rodents are not the same: a modern synthesis of cortical organization. AB - Rodents are a major order of mammals that is highly diverse in distribution and lifestyle. Five suborders, 34 families, and 2,277 species within this order occupy a number of different niches and vary along several lifestyle dimensions such as diel pattern (diurnal vs. nocturnal), terrain niche, and diet. For example, the terrain niche of rodents includes arboreal, aerial, terrestrial, semi-aquatic, burrowing, and rock dwelling. Not surprisingly, the behaviors associated with particular lifestyles are also highly variable and thus the neocortex, which generates these behaviors, has undergone corresponding alterations across species. Studies of cortical organization in species that vary along several dimensions such as terrain niche, diel pattern, and rearing conditions demonstrate that the size and number of cortical fields can be highly variable within this order. The internal organization of a cortical field also reflects lifestyle differences between species and exaggerates behaviorally relevant effectors such as vibrissae, teeth, or lips. Finally, at a cellular level, neuronal number and density varies for the same cortical field in different species and is even different for the same species reared in different conditions (laboratory vs. wild-caught). These very large differences across and within rodent species indicate that there is no generic rodent model. Rather, there are rodent models suited for specific questions regarding the development, function, and evolution of the neocortex. PMID- 21701145 TI - Are wet-induced wrinkled fingers primate rain treads? AB - Wet fingers and toes eventually wrinkle, and this is commonly attributed by lay opinion to local osmotic reactions. However, nearly a century ago surgeons observed that no wrinkling occurs if a nerve to the finger has been cut. Here we provide evidence that, rather than being an accidental side effect of wetness, wet-induced wrinkles have been selected to enhance grip in wet conditions. We show that their morphology has the signature properties of drainage networks, enabling efficient removal of water from the gripped surface. PMID- 21701147 TI - Patients with psoriasis have a higher prevalence of parental cardiovascular disease. AB - BACKGROUND: Parental history of cardiovascular disease (CVD) is an independent risk factor for offspring CVD. Patients with chronic plaque psoriasis have an intermediate risk of developing CVD. OBJECTIVE: To investigate the prevalence of parental history of CVD in patients with psoriasis. METHOD: A cross-sectional study on 236 adult patients with chronic plaque psoriasis and 246 controls was performed. Parental history of myocardial infarction and/or stroke was investigated by using a structured questionnaire. The accuracy of the self reported information was confirmed by the hospital registry. RESULTS: A positive parental history of maternal myocardial infarction was observed in 28/236 cases compared to 16/246 controls (11.8 vs. 6.5%; p = 0.04). A positive parental history of premature maternal myocardial infarction (i.e. <65 years) was observed in 16/236 cases compared to 3/246 controls (6.8 vs. 1.2%; p = 0.01). Moreover, a positive parental history of paternal stroke was observed in 25/236 cases compared to 14/246 controls (10.5 vs. 5.6%; p = 0.04). A positive parental history of psoriasis was higher in cases than in controls (35 vs. 2%; p < 0.001). CONCLUSIONS: Parental history of CVD could also be investigated in patients with psoriasis for a more comprehensive estimation of their cardiovascular risk. PMID- 21701146 TI - Involvement of subtypes gamma and epsilon of protein kinase C in colon pain induced by formalin injection. AB - Protein kinase C (PKC) has been widely reported to participate in somatic pain; however, its role in visceral pain remains largely unclear. Using a colon inflammatory pain model by intracolonic injection of formalin in rats, the present study was to examine the role of PKC in visceral pain and determine which subtypes may be involved. The colon pain behavior induced by formalin injection could be enhanced by intrathecal pretreatment with a PKC activator (PMA), and alleviated by a PKC inhibitor (H-7). Wide dynamic range (WDR) neurons in the L6 S1 spinal dorsal horn that were responsive to colorectal distension were recorded extracellularly. It was found that neuronal activity was greatly increased following formalin injection. Microdialysis of PMA near the recorded neuron in the spinal dorsal horn facilitated the enhanced responsive activity induced by formalin injection, while H-7 inhibited significantly the enhanced response induced by formalin injection. Western blot analysis revealed that membrane translocation of PKC-gamma and PKC-epsilon, but not other subtypes, in the spinal cord was obviously increased following formalin injection. Therefore, our findings suggest that PKC is actively involved in the colon pain induced by intracolonic injection of formalin. PKC-gamma and PKC-epsilon subtypes seem to significantly contribute to this process. PMID- 21701148 TI - A prospective study of filaggrin null mutations in keratoconus patients with or without atopic disorders. AB - BACKGROUND: Atopic dermatitis (AD) is significantly associated with keratoconus (KC). An inherited component for KC has been suggested. Filaggrin (FLG) mutations are a strong genetic risk factor for AD. Since filaggrin is also expressed in the corneal epithelium, we hypothesized a common aetiology for ichthyosis vulgaris (IV), AD and KC. OBJECTIVES: We examined the prevalence of AD and IV in a KC population. We also studied the expression of filaggrin in normal and KC cornea and analysed 2 prevalent loss-of-function FLG alleles (R501X and 2282del4) in a KC population. Finally we examined whether the population with KC and FLG mutations had specific clinical characteristics. RESULTS: Of 89 KC patients, 38 had current or a history of AD and/or IV. Five patients were carriers of at least 1 FLG mutant allele and had a clinical diagnosis of AD and IV with a severer KC. CONCLUSION: The low frequency of FLG mutations is surprising since 42.7% of our KC population had AD associated or not with IV; the expected frequency would have been 12-15%, based on our previous studies. Further studies are required to look at other possible FLG mutations or other candidate genes. PMID- 21701149 TI - Levels of soluble triggering receptor expressed on myeloid cells 1 in infectious exacerbations of chronic obstructive pulmonary disease. AB - BACKGROUND: Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) is an activating receptor on inflammatory cells upregulated by microbial products. Elevated levels of sTREM-1 have been associated with the diagnosis and prognosis of patients with sepsis, severe pneumonia and chronic obstructive pulmonary disease (COPD). OBJECTIVES: The aim of this study was to define the role of sTREM 1 in acute exacerbations of COPD (AE-COPD) and to investigate the ability of sTREM-1 to differentiate between infectious triggers of AE-COPD. METHODS: Smokers without COPD (SM), patients with stable COPD (sCOPD) and patients with AE-COPD were prospectively recruited. sTREM-1 levels were determined by ELISA in serum. Potentially pathogenic bacteria were analyzed by sputum culture, and polymerase chain reaction was used to determine the presence of respiratory viruses. RESULTS: One hundred and ninety-five subjects were included: 64 sCOPD patients, 118 AE-COPD patients and 13 SM. In 62 (52.6%) AE-COPD patients, a respiratory pathogen was detected. Serum levels of sTREM-1 were barely detectable in SM but were significantly increased in patients with sCOPD [97.5 (interquartile value 76.6) pg/ml] and AE-COPD [110.9 (98.5) pg/ml; p<0.001]. There was no significant difference in sTREM-1 between sCOPD and AE-COPD (p=0.277). However, in AE-COPD, sTREM-1 was significantly lower in patients with virus detection [87.5 (97.3) pg/ml] compared to those without [120.3 (99.7) pg/ml; p=0.015]. No difference was found in AE-COPD patients with or without bacterial detection. CONCLUSIONS: The present study shows an increase in sTREM-1 in patients with COPD compared to SM but not in AE-COPD compared to sCOPD. Viral exacerbations showed significantly lower sTREM-1 levels than non-viral exacerbations. PMID- 21701151 TI - A giant encephalocele treated in Haiti. PMID- 21701150 TI - Chronic neurological deficits in mice after perinatal hypoxia and ischemia correlate with hemispheric tissue loss and white matter injury detected by MRI. AB - We investigated the effects of perinatal hypoxia-ischemia (HI) on brain injury and neurological functional outcome at postnatal day (P)30 through P90. HI was induced by exposing P9 mice to 8% O(2) for 55 min using the Vannucci HI model. Following HI, mice were treated with either vehicle control or Na(+)/H(+) exchanger isoform 1 (NHE1) inhibitor HOE 642. The animals were examined by the accelerating rotarod test at P30 and the Morris water maze (MWM) test at P60. T(2)-weighted MRI was conducted at P90. Diffusion tensor imaging (DTI) was subsequently performed in ex vivo brains, followed by immunohistochemical staining for changes in myelin basic protein (MBP) and neurofilament protein expression in the corpus callosum (CC). Animals at P30 after HI showed deficits in motor and spatial learning. T(2) MRI detected a wide spectrum of brain injury in these animals. A positive linear correlation was observed between learning deficits and the degree of tissue loss in the ipsilateral hemisphere and hippocampus. Additionally, CC DTI fractional anisotropy (FA) values correlated with MBP expression. Both FA and MBP values correlated with performance on the MWM test. HOE 642-treated mice exhibited improved spatial learning and memory, and less white matter injury in the CC. These findings suggest that HI-induced cerebral atrophy and CC injury contribute to the development of deficits in learning and memory, and that inhibition of NHE1 is neuroprotective in part by reducing white matter injury. T(2)-weighted MRI and DTI are useful indicators of functional outcome after perinatal HI. PMID- 21701153 TI - Dietary restriction studies in humans: focusing on obesity, forgetting longevity. AB - Dietary restriction (DR: food restriction without malnutrition) is often considered as a nearly universal means to extend longevity in animal species and we could make the hypothesis that DR could increase longevity in humans. Some authors support the opinion that DR has already increased longevity in Okinawa inhabitants, and thus that DR can increase longevity in humans. The purpose of this article is to stress that no data on humans with a normal body mass index (neither overweight nor obese) indicate that DR can increase life span and health span, particularly because the results observed in Okinawa inhabitants can probably be considered as showing mainly deleterious effects of malnutrition rather than positive effects of DR. Since DR does not appear to increase human life span, studies testing for the effect of DR in humans should focus on the health effects of a mild DR in overweight and obese people, rather than in normal weight people. PMID- 21701152 TI - Social status and sex effects on neural morphology in Damaraland mole-rats, Fukomys damarensis. AB - We previously reported that in a eusocial rodent, the naked mole-rat (Heterocephalus glaber), traditional neural sex differences were absent; instead, neural dimorphisms were associated with breeding status. Here we examined the same neural regions previously studied in naked mole-rats in a second eusocial species, the Damaraland mole-rat (Fukomys damarensis). Damaraland mole-rats live in social groups with breeding restricted to a small number of animals. However, colony sizes are much smaller in Damaraland mole-rats than in naked mole-rats and there is consequently less reproductive skew. In this sense, Damaraland mole-rats may be considered intermediate in social organization between naked mole-rats and more traditional laboratory rodents. We report that, as in naked mole-rats, breeding Damaraland mole-rats have larger volumes of the principal nucleus of the bed nucleus of the stria terminalis and paraventricular nucleus of the hypothalamus than do subordinates, with no effect of sex on these measures. Thus, these structures may play special roles in breeders of eusocial species. However, in contrast to what was seen in naked mole-rats, we also found sex differences in Damaraland mole-rats: volume of the medial amygdala and motoneuron number in Onuf's nucleus were both greater in males than in females, with no significant effect of breeding status. Thus, both sex and breeding status influence neural morphology in Damaraland mole-rats. These findings are in accord with the observed sex differences in body weight and genitalia in Damaraland but not naked mole-rats. We hypothesize that the increased sexual dimorphism in Damaraland mole rats relative to naked mole-rats is related to reduced reproductive skew. PMID- 21701154 TI - Comments on the article about the correlation between maternal serum concentrations of progesterone-induced blocking factor taken at 11-13 weeks' gestation and spontaneous preterm delivery before 34 weeks. PMID- 21701155 TI - Complication of Pneumocystis jiroveci pneumonia. PMID- 21701156 TI - Smoking abstinence rates and reasons for failure to quit smoking in cancer patients in Jordan. AB - BACKGROUND: Failure to quit smoking in cancer patients is associated with the development of a second primary tumor and a suboptimal response to chemotherapy. However, data characterizing cancer patients' ability to quit is scarce, particularly in developing countries. Such information is valuable in highlighting the potential of cessation interventions in countries where smoking rates are high and antismoking policies are not yet fully implemented. OBJECTIVES: To measure the abstinence rates and identify reasons for the failure to quit smoking in patients visiting a smoking cessation clinic in a comprehensive cancer center in Jordan. METHODS: Through retrospective medical chart review and prospective follow-up by phone, we studied long-term abstinence rates and reasons for the failure to quit smoking in 156 cancer patients referred to the smoking cessation clinic to receive counseling and pharmacological treatment. Patient demographics, clinical and smoking characteristics and long term abstinence at 12 months were recorded, as were reasons for the failure to quit smoking. RESULTS: The 12-month abstinence rate was 21.2%. The main reasons for failing to quit smoking included personal or professional stressful situations, not being able to handle withdrawal and the belief that quitting had no value. CONCLUSION: Abstinence rates in Jordanian cancer patients fall at the lower end of the range that has been reported in the literature for cancer patients. Efforts to improve these rates should focus on assisting patients in handling stress, and in adjusting medications to improve withdrawal symptoms. PMID- 21701157 TI - Blastic plasmacytoid dendritic cell neoplasm expressing the CD13 myeloid antigen. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN), currently considered to originate from immature plasmacytoid dendritic cells (DC), is a rare and aggressive CD4+CD56+ neoplasm that frequently involves the skin and bone marrow. We present a case of an 80-year-old man with a CD4+CD56+ BPDCN that affected the orbital cavity and bone marrow. Although BPDCN has not been reported to express any lineage-specific markers, the neoplastic cells strongly expressed the CD13 antigen. Therefore, in addition to pathological examination, we attempted to induce in vitro morphological and surface marker changes with IL-3 and CD40 ligand. After treatment with these cytokines, the tumor cells enlarged markedly, acquired many fine dendrites, similar to mature DC, and showed enhanced expression of antigens specific to DC or antigen-presenting cells, such as CD40, CD80, CD83 and CD86. To the best of our knowledge, this is the first report of BPDCN expressing a myeloid antigen, CD13, although CD33 expression has been described in some cases. The present patient received 2 courses of combination chemotherapy consisting of cytarabine and etoposide, which resulted in complete remission. Given that the cellular origin of plasmacytoid DC is still controversial, myeloid antigen expression involving CD13 may not exclude a diagnosis of BPDCN. PMID- 21701158 TI - Unusually long survival of a 67-year-old patient with near-tetraploid acute myeloid leukemia m0 without erythroblastic and megakaryocytic dysplasia. AB - Patients with near-tetraploid acute myeloid leukemia (NT-AML) typically have poor survival. We present the case of a 67-year-old Caucasian male with NT-AML M0 who had an unusually long first complete remission of 51 months and an overall survival of 80 months. The only characteristic distinguishing him from other previously described patients with NT-AML was the absence of erythroblastic and/or megakaryocytic dysplasia (EMD) at diagnosis. Molecular-genetic testing for AML fusion transcripts associated with a favorable prognosis (PML/RARalpha,AML1/ETO, and CBFbeta/MYH11) were negative, as were other prognostic markers like MLL-PTD,FLT3-ITD, or mutations of FLT3-D835,NPM1, or CEBPA. Expression studies of ERG,MN1, and EVI1 revealed overexpression of ERG only. The absence of EMD may be a useful prognostic/diagnostic feature of this new rare subtype of NT-AML. PMID- 21701159 TI - Successful treatment of amegakaryocytic thrombocytopenia with azathioprine. AB - Acquired amegakaryocytic thrombocytopenia (AAMT) is an entity characterized by severe thrombocytopenia with a significantly reduced number of megakaryocytes in the bone marrow. AAMT is rare and poorly defined. Therefore, standard treatment is not well established. In general, steroids are considered the frontline treatment while anti-thymocyte globulin and cyclosporine are reported to be effective in scattered reports. We report a case of AAMT which was successfully treated with azathioprine 3 mg/kg/day. The clinical bleeding tendency resolved after treatment for 4 weeks and complete remission was documented after 6 weeks. Azathioprine treatment for AAMT is low risk, convenient, and cost-effective. Our successful experience suggests that azathioprine is potentially the treatment of choice after steroid failure. PMID- 21701160 TI - Hemochromatosis, HFE C282Y homozygosity, and polycystic ovary syndrome: report of two cases and possible effects of androgens and hepcidin. PMID- 21701161 TI - Pathways responsible for apoptosis resulting from amadori-induced oxidative and nitrosative stress in human mesothelial cells. AB - BACKGROUND: Apoptosis and inflammatory/oxidative stress have been associated with hyperglycemia in human peritoneal mesothelial cells (HPMCs) and other cell types. We and others have highlighted the role of early products of non-enzymatic protein glycation in inducing proinflammatory conditions and increasing apoptotic rates in HPMCs. Loss of HPMCs seems to be a hallmark of complications associated with peritoneal membrane dysfunction. The aim of this work is to elucidate the mechanisms by which Amadori adducts may act upon HPMC apoptosis. METHODS: HPMCs isolated from different patients were exposed to different Amadori adducts, i.e. highly glycated hemoglobin (10 nM) and glycated bovine serum albumin (250 MUg/ml), to study cell death and several proapoptotic markers by different experimental approaches. RESULTS: Amadori adducts, but not their respective controls, impaired cell proliferation and cell viability by means of apoptosis in a time-dependent manner. They regulated the intrinsic mitochondrial cell death signaling pathway and modulated activation of caspases, Bax, iNOS, p53, NF kappaB, and mitogen-activated protein kinases (p38 and JNK) through different reactive oxygen and nitrosative species. CONCLUSIONS: Our data strongly support the idea that long-term hyperglycemia could act as an inducer of apoptosis in HPMCs through Amadori adducts, involving different oxidative and nitrosative reactive species. PMID- 21701162 TI - Nutrition of the low-birth-weight infant. Editorial. PMID- 21701163 TI - Meeting the nutritional needs of the low-birth-weight infant. AB - Delivering adequate amounts of nutrients to premature infants at all times is challenging because the infant's immature gastrointestinal tract is initially unable to accept feedings, necessitating the use of parenteral nutrition. In the past, inadequate amounts of nutrients have commonly been given to premature infants because the administration of nutrients was thought to be hazardous. Inadequate nutrient intakes have resulted in widespread postnatal growth restriction. Now that it is known that postnatal growth restriction is associated with poor neurocognitive development, efforts are made to increase nutrient intakes. In this review, nutrient requirements of premature infants that have been determined by the factorial and empirical methods are reviewed. Current good practices regarding parenteral nutrition are discussed, as are guidelines for the introduction and advancement of enteral feedings. Because of its trophic effects on the gastrointestinal tract and its anti-infectious effects, human milk is strongly preferred as the early feeding of choice for premature infants. Human milk also protects infants against necrotizing enterocolitis. Once full feeding is achieved, the challenge is to provide nutrients in amounts that support the infant's growth like that of the fetus. In the case of the infant fed his/her mother's milk or banked donor milk, nutrient fortification is necessary and is generally practiced. However, adequate intakes of protein are seldom achieved with routine fortification and methods of providing additional fortification are discussed. PMID- 21701164 TI - Feeding very-low-birth-weight infants: our aspirations versus the reality in practice. AB - Recently, new guidelines for enteral feedings in premature infants were issued by the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition Committee on Nutrition. Nevertheless, practice proves difficult to attain suggested intakes at all times, and occurrence of significant potential cumulative nutritional deficits 'lies in wait' in the neonatal intensive care unit. This review describes several aspects that are mandatory for optimizing nutritional intake in these vulnerable infants. These aspects range from optimal infrastructure to the initiation of parenteral nutrition with proper transition to enteral breast or formula feedings. Proper monitoring of nutritional tolerance includes serum biochemistry although proper specific markers are unknown and safety reference values are lacking. Although a lot of progress has been made through research during the last few decades, numerous questions still remain unanswered as to what would be the optimal quantity and quality of the various macronutrients. The inevitable suboptimal intake may, however, contribute significantly to the incidence of neonatal diseases, including impaired neurodevelopment. Therefore, it is pivotal that all hospital staff acknowledges that preterm birth is a nutritional emergency and that all must be done, both in clinical practice as well as in research, to reduce nutritional deficits. PMID- 21701165 TI - Nutrition of preterm infants after discharge. AB - The fundamental principle underlying nutritional support is that intake meets needs thereby ensuring the best outcome, which, in the case of the preterm infant, is optimal growth and development. Achieving this goal is problematic. Most, if not all, very-low-birth-weight infants (VLBWI) are undernourished and under-grown when they are first discharged from the hospital. This has important implications for the nutritional care of preterm, particularly the breast-fed, VLBWI after hospital discharge. PMID- 21701166 TI - Is early nutrition related to short-term health and long-term outcome? AB - This paper summarizes the literature concerning the effects of administering (1) long-chain polyunsaturated fatty acids (LCPUFA), (2) probiotics and/or (3) prebiotics to preterm infants. Clinically relevant, short- and long-term efficacy outcomes, such as those related to a reduced risk of disease, as well as outcomes related to safety, were sought. MEDLINE and the Cochrane Library literature searches performed in September 2010 were limited to randomized controlled trials, their systematic reviews or meta-analyses. LCPUFA supplementation, particularly docosahexaenoic acid (DHA), of infant formula for preterm infants has consistently demonstrated better visual development of preterm infants compared with unsupplemented formulas. There is increasing evidence to suggest that LCPUFA supplementation for preterm infants is also related to improvements in more global measures of development, without any adverse effects. It is, however, important to note that the DHA doses tested in the infant formula interventions for preterm infants have been rather conservative. Newer studies comparing dietary DHA concentrations that match in utero accumulation rates with dietary DHA concentrations typical in the milk of women consuming little fish or in supplemented infant formulas demonstrate that these higher DHA doses are related to improvements in domains of cognitive development. Although further work is needed to better understand the optimal DHA requirements of preterm infants, it is clear that a dietary source of DHA is important to support neurodevelopment. To date, the most promising application of probiotics in preterm infants is the prevention of necrotizing enterocolitis by the administration of certain probiotics. Many other benefits of administering probiotics and/or prebiotics to preterm infants are, however, largely unproven. Efficacy and safety should be established for each probiotic and/or prebiotic product. Further research should specify strain-specific outcomes and determine optimal dosing schedules. Safety and long-term follow-up studies are of particular interest. PMID- 21701167 TI - Early impact of prescription Omega-3 fatty acids on platelet biomarkers in patients with coronary artery disease and hypertriglyceridemia. AB - BACKGROUND: Prescription omega-3-acid ethyl esters (PO-3A) have been tested for outcome benefits in patients with coronary artery disease (CAD), arrhythmias and heart failure. Some evidence suggests that PO-3A may exert their benefit via inhibiting platelets. We tested the hypothesis that PO-3A may inhibit platelet activity in patients with documented stable CAD, beyond the antiplatelet properties of aspirin and statins. METHODS: Thirty patients with documented CAD and triglycerides over 250 mg/dl treated with aspirin (70-160 mg/daily) and statins (simvastatin equivalence dose: 5-40 mg/daily) were randomized 1:1:1 to OmacorTM 1 g/day (DHA/EPA ratio 1.25:1.0), Omacor 2 g/day, or a placebo for 2 weeks. Platelet tests including aggregometry and flow cytometry and cartridge analyzer readings were performed at baseline and at 1 and 2 weeks following PO-3A therapy. RESULTS: ADP-induced platelet aggregation (p = 0.037), GP IIb/IIIa antigen (p = 0.031) and activity (p = 0.024), and P-selectin (p = 0.041) were significantly reduced after PO-3A, while platelet/endothelial cell adhesion molecule (p = 0.09), vitronectin receptor (p = 0.16), formation of platelet monocyte microparticles (p = 0.19) and the VerifyNow IIb/IIIa test (p = 0.27) only exhibited nonsignificant trends suggestive of reduced platelet activity. Finally, collagen- and arachidonic acid-induced aggregation, closure time with the PFA-100 device and expression of thrombospondin (CD36), GP Ib (CD42b), LAMP-3 (CD63), LAMP-1 (CD107a), CD40-ligand (CD154), GP37 (CD165), and PAR-1 receptor intact (SPAN 12) and cleaved (WEDE-15) epitopes were not affected by 2 weeks of PO-3A. CONCLUSION: Independently of the dose and already at 1 week, short-term therapy with PO-3A provided a modest reduction of platelet activity biomarkers, despite concomitant aspirin and statin therapy, when compared to a placebo. The effect of PO-3A is unique, differs from other known antiplatelet agents and suggests potential pleiotropism. These preliminary randomized data call for confirmation in prospective studies. PMID- 21701168 TI - Collateral formation in the absence of obstructive coronary artery disease: potential new pathways in cardioprotection. PMID- 21701169 TI - Determinants of preformed collateral vessels in the human heart without coronary artery disease. AB - BACKGROUND: Coronary collaterals protect myocardium jeopardized by coronary artery disease (CAD). Promotion of collateral circulation is desirable before myocardial damage occurs. Therefore, determinants of collateral preformation in patients without CAD should be elucidated. METHODS: In 106 patients undergoing coronary angiography who were free of coronary stenoses, a total of 39 clinical test variables were collected. The coronary collateral flow index (CFI) was measured. Stepwise multiple linear regression analysis was performed after choosing a restricted number of candidates emerging from univariate testing. Separate multiple regression analyses were performed in patients with and without beta-blocker therapy. RESULTS: Nine parameters were found to be possible determinants of CFI by univariate analysis: arterial hypertension (aHT), dyslipidemia, statins, diuretics, age, height, heart rate (HR), pulse pressure amplitude, and left ventricular end-diastolic pressure (LVEDP). After multiple regression analysis, a low HR, absence of aHT, and elevated LVEDP were significantly related to CFI (F = 5.31, p = 0.002, adjusted r(2) = 0.12). In patients without beta-blockers, a low HR and absence of aHT were independent predictors of CFI (F = 8.03, p < 0.001, n = 50, adjusted r(2) = 0.30). CONCLUSIONS: A low HR and absence of aHT are both related to collateral preformation in humans. We suppose that bradycardia favors fluid shear stress in coronary arteries, thus triggering collateral growth. PMID- 21701170 TI - Associations between endothelin-1 and adiponectin in chronic heart failure. AB - OBJECTIVES: Endothelin-1 (ET-1) induces cardiac hypertrophy, whereas adiponectin may elicit protective effects in the vasculature and myocardium. We therefore evaluated the relationship between plasma ET-1 and adiponectin levels in heart failure (HF) patients, and the association between adiponectin expression and ET 1-induced hypertrophy of human cardiomyocytes (HCM) in vitro. METHODS: One hundred seventeen patients with chronic HF were enrolled into this study. A group of 7 patients with end-stage HF undergoing heart transplantation was included in the histopathological study. Baseline clinical evaluations and laboratory measurements were performed. HCM cultures were studied to investigate the effect of ET-1 on cell size and adiponectin expression. RESULTS: Plasma ET-1, adiponectin, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) increased with the severity of HF. Higher New York Heart Association functional class, plasma ET-1, adiponectin, and NT-proBNP levels were significant predictors of adverse outcomes in these patients. The myocardial expression of adiponectin was significantly higher in the recipient hearts of patients undergoing emergency or urgent heart transplantation. In cell culture, ET-1 significantly increased cell size and adiponectin expression in HCM. CONCLUSIONS: Adiponectin was significantly elevated in HF and was significantly associated with ET-1. The study provides a basis for further investigation of ET-1 and adiponectin modulation as a therapeutic strategy for ventricular remodeling in HF. PMID- 21701171 TI - Cardiospecific microRNA plasma levels correlate with troponin and cardiac function in patients with ST elevation myocardial infarction, are selectively dependent on renal elimination, and can be detected in urine samples. AB - OBJECTIVES: Circulating microRNAs (miRNAs) are promising as biomarkers for various diseases. We examined the release patterns of cardiospecific miRNAs in a closed-chest, large animal ischemia-reperfusion model and in patients with ST elevation myocardial infarction (STEMI). METHODS: Six anesthetized pigs were subjected to coronary occlusion-reperfusion. Plasma, urine, and clinical parameters were collected from 25 STEMI patients undergoing primary percutaneous coronary intervention. miRNA was extracted and measured with qPCR. RESULTS: In the pig reperfusion model miR-1, miR-133a, and miR-208b increased rapidly in plasma with a peak at 120 min, while miR-499-5p remained elevated longer. In patients with STEMI all 4 miRNAs increased abruptly from 70-fold to 3,000-fold in plasma, with a peak within 12 h (p < 0.01). miR-1 and miR-133a both correlated strongly with the glomerular filtration rate (GFR), indicating renal elimination. This was confirmed by detection of miR-1 and miR-133a, but not miR-208b or miR 499-5p, in urine. Peak values of miR-208b correlated with peak troponin and the ejection fraction. CONCLUSION: We demonstrate a distinct and rapid increase in levels of cardiospecific miRNA in the circulation after myocardial infarction. Release of miRNAs correlated with cardiomyocyte necrosis markers, the ejection fraction, and the GFR, indicating a possible role for these molecules as biomarkers for the diagnosis of STEMI as well as the prediction of long-term complications. PMID- 21701172 TI - Aortic regurgitation and coronary microfistulae: double jeopardy causing myonecrosis. AB - We describe a 3-case series of patients with a rare combination of mild-to moderate aortic regurgitation and coronary microfistulae but nonobstructed epicardial coronary arteries who presented with symptoms of unstable angina and had confirmed myonecrosis. A plausible pathophysiological mechanism for this phenomenon and its clinical implication are discussed. PMID- 21701173 TI - Effects of pregabalin on subjective sleep disturbance symptoms during withdrawal from long-term benzodiazepine use. AB - AIM: To evaluate the effectiveness of pregabalin as a tapering therapy on the subjective sleep quality of patients who underwent a benzodiazepine withdrawal program in routine medical practice. METHODS: Secondary analysis of a 12-week prospective, open noncontrolled study carried out in patients who met DSM-IV-TR criteria for benzodiazepine dependence. Sleep was evaluated with the Medical Outcomes Study Sleep Scale (MOS Sleep Scale). RESULTS: 282 patients were included in the analysis. Mean (+/-SD) pregabalin dose was 315 +/- 166 mg/day at the end of the trial. We observed a significant and clinically relevant improvement in sleep outcomes at the endpoint, with a total score reduction from 55.8 +/- 18.9 to 25.1 +/- 18.0 at week 12 (i.e. a 55% reduction). Similar findings were apparent using the six dimensions of the MOS Sleep Scale. Moderate correlations were observed between the MOS Sleep summary index and sleep domains, and there were improvements in anxiety symptoms and disease severity. CONCLUSIONS: These findings suggest that pregabalin may improve subjective sleep quality in patients who underwent a benzodiazepine withdrawal program. This effect appears to be partly independent of improvements in symptoms of anxiety or withdrawal. However, controlled studies are needed to establish the magnitude of the effect of pregabalin. PMID- 21701174 TI - Effect of methylphenidate and/or levodopa combined with physiotherapy on mood and cognition after stroke: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND/AIM: Stimulant medications can enhance mood and cognition in stroke rehabilitation, but human clinical trial results are inconclusive. We sought to prospectively study the effects of levodopa (LD) and/or methylphenidate (MPH) in combination with physiotherapy on mood and cognition following stroke in human subjects. METHODS: Ischemic stroke patients were enrolled in our study 15 to 180 days after stroke onset. The patients were randomized into four medication groups (MPH, LD, MPH + LD, or placebo) and received a 15-day course of medication therapy (1 dose daily) and 45-min standard physiotherapy treatment daily. Mood and cognitive function were assessed at the study onset and 15, 90 and 180 days after study enrollment. RESULTS: The strongest improvement of mood and cognition was found between baseline and the first follow-up immediately after the intervention. A significant improvement in mood was also found in the combined treatment group (MPH + LD) at 90 and 180 days, compared to the placebo group. CONCLUSIONS: A 15-day course of daily MPH + LD combined with physiotherapy over a 3-week period was safe and significantly improved mood status in ischemic stroke patients. Future studies are needed which determine the optimal therapeutic window for and dosage of psychostimulants as well as identify those stroke patients who might benefit the most from treatment. PMID- 21701175 TI - VladimirMikhailovic Bekhterev (1857-1927): strange circumstances surrounding the death of the great Russian neurologist. AB - The famous Russian neurologist Vladimir Mikhailovic Bekhterev (1857-1927) was ordered to examine Josef Stalin in December 1927 during the First All-Russian Neurological Congress in Moscow. Returning to the Congress after his consultation he told some colleagues that he had 'examined a paranoiac with a dry, small hand'. The next day, Bekhterev died and only his brain was examined postmortem, the body being cremated the same day. PMID- 21701176 TI - Direct effects of chemoradiotherapy following esophagectomy. AB - BACKGROUND: Esophageal cancer is a major cause of morbidity and mortality, but despite continuing research, few effective therapies have been identified. In recent years, surgical resection following chemoradiotherapy has been associated with improved survival in several clinical models. AIM: In a prospective, observational study, we evaluated the direct effects of chemoradiotherapy on postoperative mortality, morbidity, and inflammatory response in patients following esophagectomy. METHODS: The study cohort was divided into two groups: the first group received preoperative chemoradiotherapy, while the second group had surgical intervention without prior treatment. Nutritional status was evaluated for the members of both patient groups at various time points. RESULTS: Preoperative chemoradiotherapy did not influence morbidity or organ function, and the postoperative inflammatory response did not show immunosuppressive side effects directly after surgery. CONCLUSION: Preoperative chemoradiotherapy does not improve postoperative organ function, inflammatory response or nutritional status in the patients. These findings may help to improve outcome in patients with esophageal cancer in the future. PMID- 21701177 TI - Surgeon-performed ultrasound as preoperative localization study in patients with primary hyperparathyroidism. AB - BACKGROUND: Minimally invasive parathyroidectomy is the treatment of choice for single-gland primary hyperparathyroidism. However, the exact location of the abnormal gland has to be established. Sestamibi scintigraphy, computed tomography and ultrasound (US) are commonly used modalities. We describe our experience in a non-academic center with surgeon-performed US (S-US) of the neck as preoperative localization study in patients with primary hyperparathyroidism (PHPT). METHODS: Patients with a biochemically proven diagnosis of PHPT and preoperative S-US were included. Data were recorded prospectively. Perioperative gland location was compared to the preoperative S-US to determine sensitivity, specificity and accuracy rates. RESULTS: Two of the 50 patients who underwent S-US were not subjected to surgery. In 85% of the patients analyzed by S-US, the appropriate abnormal gland(s) were identified. In 11%, no gland was identified, but abnormal glands were found during surgery. Sensitivity of S-US in our hospital is 85%, with a positive predictive value of 97%. CONCLUSIONS: We achieved a satisfactory sensitivity rate. S-US provides anatomic information to the surgeon which enables a more detailed operation planning, and it is a valuable diagnostic modality for patients with PHPT in our opinion. We hope that our data encourage other centers to implement this technique as well. PMID- 21701178 TI - Effects of animal positioning on catecholamine and vasopressin levels in pigs undergoing laparoscopy. AB - BACKGROUND: The aim of this study was to determine the influence of different therapeutic interventions and positions on catecholamine and vasopressin levels in the pneumoperitoneum (PN) in a porcine model. METHODS: In 43 pigs, a 14-mm-Hg PN was established and plasma concentrations of epinephrine, norepinephrine and vasopressin were measured in head-up, supine and head-down positions. Additionally, the effects of the following changes were studied: (1) increase in intrathoracic blood volume (ITBV) by means of hydroxyethyl starch infusion; (2) vasodilatation induced by sodium nitroprusside, or (3) selective sympathicolysis induced by esmolol. Again, catecholamines (ELISA) and vasopressin (RIA) were determined. RESULTS: After PN, epinephrine levels did not significantly increase in the head-up position (p = 0.075) and remained also unchanged in the supine or head-down position. Plasma norepinephrine statistically significantly decreased in the head-up position (p = 0.046). Vasopressin concentrations remained unaltered. After increased ITBV, neither catecholamine nor vasopressin concentrations changed in any body position. Application of sodium nitroprusside or esmolol caused no changes. CONCLUSION: Changes in endogenous catecholamine levels safely prevent cardiocirculatory instability in small pigs. Volume substitution might reduce endocrine responses to PN in the head-up position. PMID- 21701179 TI - [Responsibility - the misunderstood resource]. PMID- 21701180 TI - Medicinal cupping therapy in 30 patients with fibromyalgia: a case series observation. AB - BACKGROUND: The aim of this study was to evaluate the therapeutic effect of traditional medicinal cupping for treatment of fibromyalgia. METHODS: A prospective case series was conducted in 30 consecutive patients with fibromyalgia at an outpatient department in a hospital in Beijing. Patients were diagnosed according to the criteria set by the American College of Rheumatology (1990). A bamboo cup, boiled in herbal decoction for 5 min, was applied to Ashi points for 10 min once daily for 15 days. Pain, assessed via a 10-point visual analogue scale (VAS), and the number of tender points were recorded at baseline, 5, 10, 15 days, and 2 weeks following the final treatment. RESULTS: At baseline, the average pain was 2.63 +/- 0.73 on the VAS, and patients had an average of 13.5 +/- 1.66 tender points. The pain scores decreased from baseline during treatment (2.22 +/- 0.77 at 5 days, 1.78 +/- 0.75 at 10 days, and 1.36 +/- 0.76 at 15 days) as did the number of tender points (12.57 +/- 2.25 at 5 days, 11.2 +/ 2.50 at 10 days, 9.33 +/- 2.89 at 15 days). A total of 29 patients completed follow-up 2 weeks after the final treatment, which suggested the reduction in pain and tender points was sustained (1.31 +/- 0.76 for VAS; 9.07 +/- 2.96 for pain points). There were no serious adverse effects as a result of cupping. CONCLUSIONS: Medicinal cupping therapy was associated with a reduction in fibromyalgia symptoms for both pain ratings and number of tender points. The findings from this case series should be tested in a controlled clinical trial. PMID- 21701181 TI - [The impact of an art therapy programme for cancer patients--an analysis from different points of view]. AB - BACKGROUND: Art therapy is used in the whole field of psycho-oncological maintenance to support coping mechanisms with creative techniques. Previous studies stated effects of art therapy just by referring to the participants' ratings. This study wants to extend the perspective by including the views of all involved parties--participating patients, dropouts, art therapist and supervisor. PATIENTS AND METHODS: We developed and tested an art therapy programme for cancer patients. The participants' and dropouts' ratings were documented by using a questionnaire with open and closed questions upon completion of the intervention. The art therapist and the supervisor described their personal point of view. RESULTS: 74 patients took part in the intervention whereof 18 dropped out. Of these, 8 could be interviewed regarding the reasons for not participating further in the study. The dropouts evaluated the intervention positively(4/8) or could not make a final statement (3/8). 55 questionnaires were available from the 56 participants. They described the importance of the programme in several ways. Most of all, they reported of: stimulation of imagination (50/55), emotional stabilisation(48/55), enlargement of means of expression (45/55) and contact with other patients (42/55). The dropouts named several reasons for their decision to cancel: too intense focus on the disease(N = 3), modern drawing (N = 1), too much talks (N = 1) and too much sketching (N = 1) were some points of criticism. The art therapist as well as the supervisor emphasized activation as a main outcome for the participants. CONCLUSIONS: Positive effects of the intervention programme highlight the importance of establishing an art therapy in ambulant care. It enlarges the range of psychosocial maintenance and enables oncological patients to cope with the disease and its consequences with artistic means. PMID- 21701182 TI - Topical herbal medicine for treatment of diabetic peripheral neuropathy: a systematic review of randomized controlled trials. AB - BACKGROUND: Topical Chinese herbal medicine (CHM) is generally used in China, separately or in combination with conventional medicine, to treat diabetic peripheral neuropathy (DPN). Clinical studies have shown beneficial effects of CHM compared with conventional medicine. MATERIALS AND METHODS: A systematic literature search of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, Chinese BioMedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI) and Chinese Scientific Journal Database (VIP) information was conducted till March 2010. Randomized controlled trials (RCTs) were included if they compared topical CHM to conventional medicine, placebo or no treatment for patients with DPN. Revman 5.0.17 was used as software for data analysis. The effect expectancy is depicted as relative risk and mean difference with a 95% confidence interval. RESULTS: 23 RCTs including 22 topical CHMs were included. The methodological quality of the included trials is generally poor in terms of sequence generation, concealment of allocations, blinding, incomplete data outcome and selective outcome reports. 17 trials showed beneficial effects of CHM on global symptom improvement, 6 beneficial effects of CHM on nerve velocity conduction, 4 beneficial effects of CHM on numbness improvement and 4 beneficial effects of CHM on pain relief. Adverse events with relation to CHM were reported in 3 trials including skin redness, a burning feeling, a prickling sensation and rash. CONCLUSIONS: Due to weak evidence, the claimed benefits of topical CHM for DPN are inconclusive; more stringent studies are needed to support clinical practice. PMID- 21701183 TI - Energy healing for cancer: a critical review. AB - BACKGROUND: This article explores the evidence base of efficacy and effectiveness of 'energy healing' for cancer patients. The term 'energy healing' refers to a wide variety of therapies which are based on the premise that the healer transfers energy to the patient. Among the most researched forms of energy healing are reiki, therapeutic touch and healing touch. MATERIAL AND METHODS: PubMed, AMED, JStor, Social Science Citation Index and PsycInfo databases were searched, and articles were rated according to the SIGN (Scottish Intercollegiate Guidelines Network) quality scale. Six quantitative and two qualitative studies on the efficacy and effectiveness of energy healing for cancer patients met the inclusion criteria. RESULTS: None of the studies are of a size or quality that allows to draw reliable conclusions. The results of the studies are, however, interesting and should be considered when developing new studies and hypotheses on working mechanisms. CONCLUSION: The existing research does not allow conclusions regarding the efficacy or effectiveness of energy healing. Future studies should adhere to existing standards of research on the efficacy and effectiveness of a treatment, and given the complex character of potential outcomes, cross-disciplinary methodologies may be relevant. To extend the scope of clinical trials, psychosocial processes should be taken into account and explored, rather than dismissed as placebo. PMID- 21701184 TI - Our systematic reviews are important and relevant--reply to Vickers. PMID- 21701186 TI - Expressive language skills in Finnish two-year-old extremely- and very-low-birth weight preterm children. AB - OBJECTIVE: Preterm children with low birth weight are at greater risk of experiencing speech and language difficulties than full-term children. The aim of the current study was to investigate expressive language skills of Finnish speaking preterm children with low birth weight [extremely-low-birth-weight (ELBW) children: n = 8; very-low-birth-weight (VLBW) children: n = 10] at 2 years of corrected age and to compare their language results with full-term controls (n = 18), using spontaneous speech samples. METHODS: The children were video recorded in semistructured free-play sessions with their mothers. From these video samples, expressive vocabulary size and maximum sentence length (MSL) were analyzed. In addition, the possible effect of children's gender on language measures as well as associations between different language measures were examined. RESULTS: The results showed that there was no statistically significant difference between the preterm and full-term groups in the size of expressive vocabulary. In contrast, the MSL, which measures morphosyntactic skills, was significantly shorter in preterm children. A positive correlation was found between MSL and expressive vocabulary. Children's gender was not associated with language skills measured. CONCLUSION: The findings indicate that Finnish-speaking preterm children, especially ELBW children, experience difficulties in morphosyntactic skills. PMID- 21701187 TI - Anti-infective properties of Lactobacillus fermentum against Staphylococcus aureus and Pseudomonas aeruginosa. AB - Surgical wounds and implant-associated Staphylococcus aureus and Pseudomonas aeruginosa infections are often difficult to treat because of limited susceptibility of several of these strains to conventional antibiotics. As a result, there is a constant need for new alternative drugs. The aim of this study was to investigate the antimicrobial properties of Lactobacillus fermentum, a probiotic bacterium, which we have isolated from colonic biopsies. The inhibition of S. aureus and P. aeruginosa growth was evaluated by coincubating with L. fermentum strains. Growth inhibition was tested for several of their clinical isolates using agar well diffusion assays. For biofilm assay S. aureus and P. aeruginosa were grown on the glass slides and in 96-well plates in presence of 2.5 MUg/ml culture filtrate of L. fermentum. Biofilms were photographed using confocal microscope or stained with 0.1% crystal violet. Reduction in the cytotoxicity of S. aureus and P. aeruginosa was observed in presence of 2.5 MUg/ml L. fermentum-spent media. Using in vitroexperiments, we showed that L. fermentum-secreted compound(s) inhibits the growth, cytotoxicity and biofilm formation of several S. aureus and P. aeruginosa strains. Compound(s) present in the culture supernatant of L. fermentum may have promising applications in treating hospital-acquired infections. PMID- 21701188 TI - Fluoride intake of children: considerations for dental caries and dental fluorosis. AB - Caries incidence and prevalence have decreased significantly over the last few decades due to the widespread use of fluoride. However, an increase in the prevalence of dental fluorosis has been reported simultaneously in both fluoridated and non-fluoridated communities. Dental fluorosis occurs due to excessive fluoride intake during the critical period of tooth development. For the permanent maxillary central incisors, the window of maximum susceptibility to the occurrence of fluorosis is the first 3 years of life. Thus, during this time, a close monitoring of fluoride intake must be accomplished in order to avoid dental fluorosis. This review describes the main sources of fluoride intake that have been identified: fluoridated drinking water, fluoride toothpaste, dietary fluoride supplements and infant formulas. Recommendations on how to avoid excessive fluoride intake from these sources are also given. PMID- 21701189 TI - Fluoride metabolism. AB - Knowledge of all aspects of fluoride metabolism is essential for comprehending the biological effects of this ion in humans as well as to drive the prevention (and treatment) of fluoride toxicity. Several aspects of fluoride metabolism - including gastric absorption, distribution and renal excretion - are pH-dependent because the coefficient of permeability of lipid bilayer membranes to hydrogen fluoride (HF) is 1 million times higher than that of F(-). This means that fluoride readily crosses cell membranes as HF, in response to a pH gradient between adjacent body fluid compartments. After ingestion, plasma fluoride levels increase rapidly due to the rapid absorption from the stomach, an event that is pH-dependent and distinguishes fluoride from other halogens and most other substances. The majority of fluoride not absorbed from the stomach will be absorbed from the small intestine. In this case, absorption is not pH-dependent. Fluoride not absorbed will be excreted in feces. Peak plasma fluoride concentrations are reached within 20-60 min following ingestion. The levels start declining thereafter due to two main reasons: uptake in calcified tissues and excretion in urine. Plasma fluoride levels are not homeostatically regulated and vary according to the levels of intake, deposition in hard tissues and excretion of fluoride. Many factors can modify the metabolism and effects of fluoride in the organism, such as chronic and acute acid-base disturbances, hematocrit, altitude, physical activity, circadian rhythm and hormones, nutritional status, diet, and genetic predisposition. These will be discussed in detail in this review. PMID- 21701190 TI - Contemporary biological markers of exposure to fluoride. AB - Contemporary biological markers assess present, or very recent, exposure to fluoride: fluoride concentrations in blood, bone surface, saliva, milk, sweat and urine have been considered. A number of studies relating fluoride concentration in plasma to fluoride dose have been published, but at present there are insufficient data on plasma fluoride concentrations across various age groups to determine the 'usual' concentrations. Although bone contains 99% of the body burden of fluoride, attention has focused on the bone surface as a potential marker of contemporary fluoride exposure. From rather limited data, the ratio surface-to-interior concentration of fluoride may be preferred to whole bone fluoride concentration. Fluoride concentrations in the parotid and submandibular/sublingual ductal saliva follow the plasma fluoride concentration, although at a lower concentration. At present, there are insufficient data to establish a normal range of fluoride concentrations in ductal saliva as a basis for recommending saliva as a marker of fluoride exposure. Sweat and human milk are unsuitable as markers of fluoride exposure. A proportion of ingested fluoride is excreted in urine. Plots of daily urinary fluoride excretion against total daily fluoride intake suggest that daily urinary fluoride excretion is suitable for predicting fluoride intake for groups of people, but not for individuals. While fluoride concentrations in plasma, saliva and urine have some ability to predict fluoride exposure, present data are insufficient to recommend utilizing fluoride concentrations in these body fluids as biomarkers of contemporary fluoride exposure for individuals. Daily fluoride excretion in urine can be considered a useful biomarker of contemporary fluoride exposure for groups of people, and normal values have been published. PMID- 21701191 TI - Historical and recent biological markers of exposure to fluoride. AB - Recent and historical biomarkers assess chronic or subchronic exposure to fluoride. The most studied recent biomarkers are nails and hair. Both can be non invasively obtained, although collection of nails is more accepted by the subjects. External contamination may be a problem for both biomarkers and still needs to be better evaluated. Nails have been more extensively studied. Although the available knowledge does not allow their use as predictors of dental fluorosis by individual subjects, since reference values of fluoride have not yet been established, they have a strong potential for use in epidemiological surveys. Toenails should be preferred instead of fingernails, and variables that are known to affect nail fluoride concentrations - such as age, gender and geographical area - should be considered. The main historical biomarkers that could indicate total fluoride body burden are bone and dentin. Of these, bone is more studied, but its fluoride concentrations vary according to the type of bone and subjects' age and gender. They are also influenced by genetic background, renal function and remodeling rate, variables that complicate the establishment of a normal range of fluoride levels in bone that could indicate 'desirable' exposure to fluoride. The main issue when attempting to use bone as biomarker of fluoride exposure is the difficulty and invasiveness of sample collection. In this aspect, collection of dentin, especially from 3rd molars that are commonly extracted, is advantageous. However, mean values also span a wide range and reference concentrations have not been published yet. PMID- 21701192 TI - Acute toxicity of ingested fluoride. AB - This chapter discusses the characteristics and treatment of acute fluoride toxicity as well as the most common sources of overexposure, the doses that cause acute toxicity, and factors that can influence the clinical outcome. Cases of serious systemic toxicity and fatalities due to acute exposures are now rare, but overexposures causing toxic signs and symptoms are not. The clinical course of systemic toxicity from ingested fluoride begins with gastric signs and symptoms, and can develop with alarming rapidity. Treatment involves minimizing absorption by administering a solution containing calcium, monitoring and managing plasma calcium and potassium concentrations, acid-base status, and supporting vital functions. Approximately 30,000 calls to US poison control centers concerning acute exposures in children are made each year, most of which involve temporary gastrointestinal effects, but others require medical treatment. The most common sources of acute overexposures today are dental products - particularly dentifrices because of their relatively high fluoride concentrations, pleasant flavors, and their presence in non-secure locations in most homes. For example, ingestion of only 1.8 ounces of a standard fluoridated dentifrice (900-1,100 mg/kg) by a 10-kg child delivers enough fluoride to reach the 'probably toxic dose' (5 mg/kg body weight). Factors that may influence the clinical course of an overexposure include the chemical compound (e.g. NaF, MFP, etc.), the age and acid-base status of the individual, and the elapsed time between exposure and the initiation of treatment. While fluoride has well-established beneficial dental effects and cases of serious toxicity are now rare, the potential for toxicity requires that fluoride-containing materials be handled and stored with the respect they deserve. PMID- 21701194 TI - Mechanisms of action of fluoride for caries control. AB - Fluoride was introduced into dentistry over 70 years ago, and it is now recognized as the main factor responsible for the dramatic decline in caries prevalence that has been observed worldwide. However, excessive fluoride intake during the period of tooth development can cause dental fluorosis. In order that the maximum benefits of fluoride for caries control can be achieved with the minimum risk of side effects, it is necessary to have a profound understanding of the mechanisms by which fluoride promotes caries control. In the 1980s, it was established that fluoride controls caries mainly through its topical effect. Fluoride present in low, sustained concentrations (sub-ppm range) in the oral fluids during an acidic challenge is able to absorb to the surface of the apatite crystals, inhibiting demineralization. When the pH is re-established, traces of fluoride in solution will make it highly supersaturated with respect to fluorhydroxyapatite, which will speed up the process of remineralization. The mineral formed under the nucleating action of the partially dissolved minerals will then preferentially include fluoride and exclude carbonate, rendering the enamel more resistant to future acidic challenges. Topical fluoride can also provide antimicrobial action. Fluoride concentrations as found in dental plaque have biological activity on critical virulence factors of S. mutans in vitro, such as acid production and glucan synthesis, but the in vivo implications of this are still not clear. Evidence also supports fluoride's systemic mechanism of caries inhibition in pit and fissure surfaces of permanent first molars when it is incorporated into these teeth pre-eruptively. PMID- 21701193 TI - Chronic fluoride toxicity: dental fluorosis. AB - Dental fluorosis occurs as a result of excess fluoride ingestion during tooth formation. Enamel fluorosis and primary dentin fluorosis can only occur when teeth are forming, and therefore fluoride exposure (as it relates to dental fluorosis) occurs during childhood. In the permanent dentition, this would begin with the lower incisors, which complete mineralization at approximately 2-3 years of age, and end after mineralization of the third molars. The white opaque appearance of fluorosed enamel is caused by a hypomineralized enamel subsurface. With more severe dental fluorosis, pitting and a loss of the enamel surface occurs, leading to secondary staining (appearing as a brown color). Many of the changes caused by fluoride are related to cell/matrix interactions as the teeth are forming. At the early maturation stage, the relative quantity of amelogenin protein is increased in fluorosed enamel in a dose-related manner. This appears to result from a delay in the removal of amelogenins as the enamel matures. In vitro, when fluoride is incorporated into the mineral, more protein binds to the forming mineral, and protein removal by proteinases is delayed. This suggests that altered protein/mineral interactions are in part responsible for retention of amelogenins and the resultant hypomineralization that occurs in fluorosed enamel. Fluoride also appears to enhance mineral precipitation in forming teeth, resulting in hypermineralized bands of enamel, which are then followed by hypomineralized bands. Enhanced mineral precipitation with local increases in matrix acidity may affect maturation stage ameloblast modulation, potentially explaining the dose-related decrease in cycles of ameloblast modulation from ruffle-ended to smooth-ended cells that occur with fluoride exposure in rodents. Specific cellular effects of fluoride have been implicated, but more research is needed to determine which of these changes are relevant to the formation of fluorosed teeth. As further studies are done, we will better understand the mechanisms responsible for dental fluorosis. PMID- 21701195 TI - Topical use of fluorides for caries control. AB - Since the early findings on the protective effects of fluoride present in drinking water upon caries incidence and prevalence, intensive research has been conducted in order to determine the benefits, safety, as well as the cost effectiveness of other modalities of fluoride delivery. The present chapter reviews the various forms of topical fluoride use - professionally and self applied - with special emphasis on clinical efficacy and possible side effects. The most widely used forms of fluoride delivery have been subject of several systematic reviews, providing strong evidence supporting the use of dentifrices, gels, varnishes and mouth rinses for the control of caries progression. Dentifrices with fluoride concentrations of 1,000 ppm and above have been shown to be clinically effective in caries prevention when compared to a placebo treatment, but the evidence regarding formulations with 450-550 ppm is still subject of debate. Therefore, the recommendation for low-fluoride dentifrice use must take into account both risks and benefits. The evidence for the combined use of two modalities of fluoride application in comparison to a single modality is still inconsistent, implying that more studies with adequate methodology are needed to determine the real benefits of each method. Considering the currently available evidence and risk-benefit aspects, it seems justifiable to recommend the use of fluoridated dentifrices to individuals of all ages, and additional fluoride therapy should also be targeted towards individuals at high caries risk. PMID- 21701196 TI - Systemic fluoride. AB - There is substantial evidence that fluoride, through different applications and formulas, works to control caries development. The first observations of fluoride's effects on dental caries were linked to fluoride naturally present in the drinking water, and then from controlled water fluoridation programs. Other systemic methods to deliver fluoride were later suggested, including dietary fluoride supplements such as salt and milk. These systemic methods are now being questioned due to the fact that many studies have indicated that fluoride's action relies mainly on its post-eruptive effect from topical contact with the tooth structure. It is known that even the methods of delivering fluoride known as 'systemic' act mainly through a topical effect when they are in contact with the teeth. The effectiveness of water fluoridation in many geographic areas is lower than in previous eras due to the widespread use of other fluoride modalities. Nevertheless, this evidence should not be interpreted as an indication that systemic methods are no longer relevant ways to deliver fluoride on an individual basis or for collective health programs. Caution must be taken to avoid excess ingestion of fluoride when prescribing dietary fluoride supplements for children in order to minimize the risk of dental fluorosis, particularly if there are other relevant sources of fluoride intake - such as drinking water, salt or milk and/or dentifrice. Safe and effective doses of fluoride can be achieved when combining topical and systemic methods. PMID- 21701197 TI - Oral fluoride reservoirs and the prevention of dental caries. AB - Current models for increasing the anti-caries effects of fluoride (F) agents emphasize the importance of maintaining a cariostatic concentration of F in oral fluids. The concentration of F in oral fluids is maintained by the release of this ion from bioavailable reservoirs on the teeth, oral mucosa and - most importantly, because of its association with the caries process - dental plaque. Oral F reservoirs appear to be of two types: (1) mineral reservoirs, in particular calcium fluoride or phosphate-contaminated 'calcium-fluoride-like' deposits; (2) biological reservoirs, in particular (with regard to dental plaque) F held to bacteria or bacterial fragments via calcium-fluoride bonds. The fact that all these reservoirs are mediated by calcium implies that their formation is limited by the low concentration of calcium in oral fluids. By using novel procedures which overcome this limitation, the formation of these F reservoirs after topical F application can be greatly increased. Although these increases are associated with substantive increases in salivary and plaque fluid F, and hence a potential increase in cariostatic effect, it is unclear if such changes are related to the increases in the amount of these reservoirs, or changes in the types of F deposits formed. New techniques have been developed for identifying and quantifying these deposits which should prove useful in developing agents that enhance formation of oral F reservoirs with optimum F release characteristics. Such research offers the prospect of decreasing the F content of topical agents while simultaneously increasing their cariostatic effect. PMID- 21701198 TI - Fluoride in dental erosion. AB - Dental erosion develops through chronic exposure to extrinsic/intrinsic acids with a low pH. Enamel erosion is characterized by a centripetal dissolution leaving a small demineralized zone behind. In contrast, erosive demineralization in dentin is more complex as the acid-induced mineral dissolution leads to the exposure of collagenous organic matrix, which hampers ion diffusion and, thus, reduces further progression of the lesion. Topical fluoridation inducing the formation of a protective layer on dental hard tissue, which is composed of CaF(2) (in case of conventional fluorides like amine fluoride or sodium fluoride) or of metal-rich surface precipitates (in case of titanium tetrafluoride or tin containing fluoride products), appears to be most effective on enamel. In dentin, the preventive effect of fluorides is highly dependent on the presence of the organic matrix. In situ studies have shown a higher protective potential of fluoride in enamel compared to dentin, probably as the organic matrix is affected by enzymatical and chemical degradation as well as by abrasive influences in the clinical situation. There is convincing evidence that fluoride, in general, can strengthen teeth against erosive acid damage, and high-concentration fluoride agents and/or frequent applications are considered potentially effective approaches in preventing dental erosion. The use of tin-containing fluoride products might provide the best approach for effective prevention of dental erosion. Further properly designed in situ or clinical studies are recommended in order to better understand the relative differences in performance of the various fluoride agents and formulations. PMID- 21701199 TI - Education level explains differences in stroke incidence among city districts in Joinville, Brazil: a three-year population-based study. AB - BACKGROUND: Current evidence suggests an inverse association between socioeconomic status and stroke incidence. Our aim was to measure the variation in incidence among different city districts (CD) and their association with socioeconomic variables. METHODS: We prospectively ascertained all possible stroke cases occurring in the city of Joinville during the period 2005-2007. We determined the incidence for each of the 38 CD, age-adjusted to the population of Joinville. By linear regression analysis, we correlated incidence data with mean years of education (MYE) and mean income per month (MIPM). RESULTS: Of the 1,734 stroke cases registered, 1,034 were first-ever strokes. In the study period, the crude incidence in Joinville was 69.5 per 100,000 (95% confidence interval, 65.3 73.9). The stroke incidence among CD ranged from 37.5 (22.2-64.6) to 151.0 per 100,000 (69.0-286.6). The stroke incidence was inversely correlated with years of education (r = -0.532; p < 0.001). MYE and MIPM were strongly related (R = 0.958), resulting in exclusion of MIPM by collinearity. CONCLUSIONS: Years of education can explain a wide incidence variation among CD. These results may be useful to guide the allocation of resources in primary prevention policies. PMID- 21701203 TI - Neonatal respiratory distress syndrome: an inflammatory disease? AB - Surfactant substitution has been a major breakthrough in the treatment of neonatal respiratory distress syndrome (RDS), primarily caused by a lack of pulmonary surfactant; it has significantly reduced mortality and acute pulmonary morbidity in preterm infants. Some very immature infants, however, have a poor response to surfactant replacement or an early relapse. This brief article is based on the hypothesis that neonatal RDS has a complex and multifactorial pathogenesis characterized by an injurious inflammatory sequence in the immature lung. Fetal exposure to chorioamnionitis has been shown to initiate an inflammatory reaction beginning in utero. A 'low-grade' inflammatory stimulus in utero may 'prime' the fetal lung for accelerated maturation of the surfactant system, especially in conjunction with prenatal steroids, and may protect the preterm infant from developing moderate to severe RDS. Depending on the severity of inflammatory injury to the alveolar-capillary unit, however, serum proteins will leak into the airways and induce surfactant inactivation. Following this intrauterine 'first hit', the immature infant may develop severe RDS and have a poor response to surfactant substitution. Secondary insults such as traumatic stabilization techniques, oxygen toxicity, initiation of mechanical ventilation and others injure the immature lung immediately after birth and perpetuate and may aggravate the inflammatory process. Observational studies in preterm infants and animal experiments support this concept. Whenever surfactant inactivation is suspected, higher or repetitive doses of natural surfactant may help to overcome surfactant inactivation and to restore lung function. PMID- 21701200 TI - Stroke awareness in urban and rural populations from northern Portugal: knowledge and action are independent. AB - BACKGROUND: Several studies conducted in hospital emergency departments have shown that most patients delay in responding to stroke symptoms. In the general population, recognition of stroke and the appropriate reactions are important for prevention and acute treatment, particularly in areas with a high stroke incidence. The objective of this study was to compare general knowledge about stroke/TIA and prompt action in urban and rural populations. METHODS: In the first half of 2007, a cross-sectional study on stroke knowledge was undertaken in rural and urban populations from the Viana do Castelo district. About 1% of people aged at least 18 years registered at three community health centers were asked to check a list of vascular risk factors (VRF), stroke/TIA warning signs, and other non-specific signs, as well as indicate how they would react in the presence of warning signs or stroke/TIA. RESULTS: The 347 urban participants were on average younger than the 316 rural participants (46 vs. 51 years) and fewer had a low educational level (44 vs. 62% had less than 5 years of full education). About 50% identified at least 8 out of 13 VRF and indicated the brain as the body location; 39.7% recognized simultaneously the three key warning signs of the FAST campaign - irrespective of gender, educational level, and residential area. Education and urban environment increased the odds of calling the emergency medical services (EMS), while age had the opposite effect. After adjustment, recognition of brain location and calling EMS in case of paralysis/weakness or dizziness/vertigo increased the odds of calling the EMS in case of stroke, while recognition of the warning signs was not associated with an EMS call. CONCLUSIONS: People's reaction to stroke depends mostly on their sociodemographic profile and their reaction to specific warning signs, independently of recognizing them as 'originating from stroke'. PMID- 21701204 TI - Chorioamnionitis - new ideas from experimental models. AB - Antenatal inflammation may be associated with adverse neonatal outcomes in several organ systems. Bacteria and a few viruses have been detected in cases of microbial invasion of the amniotic cavity which is referred to as chorioamnionitis. Many aspects of this disease remain unclear such as the causes, time of onset and the fetal responses. Chorioamnionitis was therefore induced in pregnant sheep by injections of lipopolysaccharide (LPS) or Ureaplasma species into the amniotic cavity under ultrasound guidance. LPS-induced chorioamnionitis caused a cascade of organ injury, inflammation, and remodeling. The organ specific changes were accompanied by systemic effects. The systemic effects after LPS-induced chorioamnionitis resulted in immune suppression against several Toll like receptor agonists (cross-tolerance). Ureaplasma induced chorioamnionitis made changes in the fetal lung structure depending on the time of infection during pregnancy. The mechanisms of inflammation, structural damage and decreased expression of growth factors need to be further studied to determine therapeutic targets in suitable animal models. PMID- 21701205 TI - Growth factors, stem cells and bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD) is the chronic lung disease of prematurity mainly affecting preterm infants that are born at 24-28 weeks of gestation. Surfactant therapy, antenatal steroids and incremental improvements in perinatal care have modified the pattern of injury and allowed survival of ever more immature infants, but there is still no specific treatment for BPD. As a consequence, this disorder remains the most common complication of extreme prematurity. Arrested alveolar growth and disrupted vasculogenesis, the histological hallmarks of BPD, may persist beyond childhood and lead to chronic lung diseases in adults. Recent advances in our understanding of stem cells and their potential to repair damaged organs offer the possibility for cell-based treatment for intractable diseases. This review summarizes basic concepts of stem cell biology and discusses the recent advances and challenges of stem cell-based therapies for lung diseases, with a particular focus on BPD. PMID- 21701206 TI - Lung-protective ventilation in neonatology. AB - Ventilator-induced lung injury (VILI) is considered an important risk factor in the development of bronchopulmonary dysplasia (BPD) and is primarily caused by overdistension (volutrauma) and repetitive opening and collapse (atelectrauma) of terminal lung units. Lung-protective ventilation should therefore aim to reduce tidal volumes, and recruit and stabilize atelectatic lung units (open lung ventilation strategy). This review will summarize the available evidence on lung protective ventilation in neonatology, discussing both high-frequency ventilation (HFV) and positive pressure ventilation (PPV). It shows that HFV does not appear to have a clear benefit over PPV, although most studies failed to apply a true open lung ventilation strategy during HFV. The evidence on the optimal tidal volume, positive end-expiratory pressure and the role for lung recruitment during lung-protective PPV is extremely limited. Volume-targeted ventilation seems to be a promising mode in terms of lung protection, but more studies are needed. Due to the lack of convincing evidence, lung-protective ventilation and modes seem to be implemented in daily clinical practice at a slow pace. PMID- 21701207 TI - Tailoring oxygen needs of extremely low birth weight infants in the delivery room. AB - Fetal to neonatal transition poses an extraordinary challenge for the extremely low birth weight (ELBW) neonate. Indeed a significant number of ELBW neonates will need proactive resuscitation to achieve postnatal stabilization. Positive pressure ventilation and oxygenation are the most relevant interventions in the delivery room (DR). Oxygen needs during resuscitation still represent a conundrum for neonatologists. While hyperoxemia favors oxidative stress and subsequent organ injury, hypoxemia is associated with long-term neurodevelopmental impairment. It has been shown that ELBW neonates can be successfully resuscitated with lower concentrations of oxygen as had been done traditionally. Moreover, reducing oxygen load has resulted in achievement of arterial partial pressures of oxygen at admission closer to the physiologic range, less oxidative stress and less inflammation. The availability of reference ranges for arterial oxygen saturation (SpO(2)) for ELBW neonates in the first 10 min after birth has been an extraordinary step forward in our ability to individually titrate oxygen needs thus avoiding the risks of both hypo- and hyperoxemia. The optimal fraction of inspired oxygen (FiO(2)) to initiate resuscitation and the safest SpO(2) percentiles for ELBW neonates during the first minutes of life are still unknown and will need further research in the future. Until then, optimal ventilation at birth and individually tailoring FiO(2) according to the nomogram seem to be the most reasonable and safe approach. PMID- 21701208 TI - Evidence-based delivery room care of the very low birth weight infant. AB - The first hour of a newborn's life is fraught with difficulty. Recommendations regarding the fundamental issues of resuscitation of these infants are developed and disseminated by the International Liaison Committee on Resuscitation and other organizations. However, these recommendations frequently do not address the needs of the very low birth weight infant and do not address some of the nuances that might lead to improved outcome. Improved organization and teamwork as well as improved monitoring and respiratory support can potentially improve the outcome of these infants. PMID- 21701209 TI - Surfactant replacement therapy in developing countries. AB - BACKGROUND: Since the first successful report of surfactant replacement therapy (SRT) in infants with respiratory distress syndrome (RDS), numerous randomized clinical trials have shown that SRT reduces mortality and morbidity in RDS. Surfactant is now a standard therapy for RDS. However, the use of SRT in the developing world has been extremely slow. OBJECTIVE: The objective of this paper is to review the published information regarding the usage and barriers encountered in the use of SRT in developing countries. METHODS: We reviewed the available literature and also gathered information from countries with a high burden of prematurity and high infant mortality rate regarding replacement therapy and the barriers to use of SRT. RESULTS: We reviewed the available literature and found that developing countries bear a high burden of prematurity and RDS that contribute to high neonatal and infant mortality rates. Based on the effectiveness of SRT in RDS, surfactant preparations were included in the Essential Drug List of WHO in 2008. However, the use of SRT in developing countries is still limited because of (1) high cost, (2) lack of skilled personnel to administer SRT, and (3) lack of support systems after the SRT. The cost of SRT may exceed the per-capita GNP (300-500 USD) in some countries. Data from India and South Africa suggests that SRT is limited to rescue therapy in babies with potential for better survival, usually >28 weeks' gestation. Recent studies show that infants with RDS respond well to initial continuous positive airway pressure (CPAP) followed by SRT for those who do not respond. CONCLUSIONS: In developing countries, CPAP may be used as the primary mode of management of RDS. SRT may be reserved for non-responders to CPAP. Alternate simpler methods of delivery of surfactant (aerosol technique) are also being explored. There is a need for further studies to develop and assess efficient and less expensive methods of application of CPAP and SRT in developing countries. PMID- 21701210 TI - Volume-targeted versus pressure-limited ventilation for preterm infants: a systematic review and meta-analysis. AB - BACKGROUND: The causes of bronchopulmonary dysplasia (BPD) are multifactorial. Overdistension of the lung (volutrauma) is considered an important contribution. As an alternative to traditional pressure-limited ventilation (PLV), modern neonatal ventilators offer modes which can target a set tidal volume. OBJECTIVES: To determine whether volume-targeted neonatal ventilation, compared with PLV, reduces death or BPD. METHODS: We performed a systematic review and meta-analysis using the methodology of the Neonatal Review Group of the Cochrane Collaboration. A comprehensive literature search was undertaken, and data for prespecified outcomes were combined where appropriate using the fixed effects model. RESULTS: Nine trials were eligible. Volume-targeted ventilation resulted in a reduction in: the combined outcome of death or BPD [typical relative risk, RR, 0.73 (95% confidence interval, 0.57-0.93), numbers needed to treat, NNT, 8 (95% CI 5-33)], the incidence of pneumothorax [typical RR 0.46 (95% CI 0.25-0.84), NNT 17 (95% CI 10-100)], days of ventilation [weighted mean difference 0.8 days (log-transformed data, p = 0.05)], hypocarbia (pCO(2) <35 mm Hg/4.7 kPa); [typical RR 0.56 (95% CI 0.33-0.96), NNT 4 (95% CI 2-25)], and the combined outcome of periventricular leukomalacia or grade 3-4 intraventricular hemorrhage [typical RR 0.48 (95% CI 0.28-0.84), NNT 11 (95% CI 7-50)]. CONCLUSIONS: Compared with PLV, infants ventilated using volume-targeted ventilation had reduced death/BPD, duration of ventilation, pneumothoraces, hypocarbia and periventricular leukomalacia/severe intraventricular hemorrhage. Further studies are needed to assess neurodevelopmental outcomes. PMID- 21701211 TI - Neurodevelopmental outcomes at 18 months' corrected age of infants born at 22 weeks of gestation. AB - BACKGROUND: Increased survival rates for extremely low birth weight infants have been reported. However, survival rates and prognoses of extremely preterm infants, such as infants born at 22 weeks of gestation, are still poor. OBJECTIVE: To investigate such infants' long-term outcomes, developmental assessments were performed. METHODS: Seven infants with gestational age of 22 weeks were delivered in our hospital from 2005 to 2008. One infant was a stillbirth despite resuscitation in the delivery room. Six infants, 4 boys and 2 girls, with a gestational age of 22 weeks (range 22(3/7)-22(6/7) weeks), were admitted to the neonatal intensive care unit (NICU). Birth weights ranged from 514 to 710 g. None of the infants suffered from sepsis, necrotizing enterocolitis, or severe intraventricular hemorrhage. RESULTS: The survival rate was 85.7% (6/7) as a percentage of deliveries and 100% (6/6) as a percentage of NICU admissions. None of the infants suffered from deafness, blindness, cerebral palsy, or epilepsy. Six infants were available for developmental assessments at 18 months' corrected age. Three infants showed normal developmental quotients, and 3 infants showed developmental delay. CONCLUSION: In our study, all infants admitted to the NICU at a gestational age of 22 weeks were discharged from the hospital alive. This might suggest that infants after 22 weeks' gestation be considered eligible for active treatment in Japan, though considering the size of the material, generalizibility of the results cannot be considered guaranteed. PMID- 21701212 TI - Cerebral oxygenation during different treatment strategies for a patent ductus arteriosus. AB - BACKGROUND: Preterm infants with a hemodynamically significant patent ductus arteriosus (hsPDA) are at risk for fluctuations in cerebral blood flow, but it is unclear how different hsPDA treatment strategies may affect cerebral oxygenation. OBJECTIVE: To compare regional cerebral oxygen saturation (rSO(2)) as measured by near-infrared spectroscopy (NIRS) in very low birth weight (VLBW) infants with a hsPDA treated with conservative management, indomethacin, or surgical ligation. METHODS: This prospective observational study enrolled 33 VLBW infants with a hsPDA diagnosed by echocardiogram and 12 control VLBW infants without a hsPDA. Infants had NIRS cerebral monitoring applied prior to conservative treatment, indomethacin, or surgical ligation. Cranial ultrasound and magnetic resonance imaging data were also collected. RESULTS: Infants undergoing surgical ligation had a greater time period with >20% change in rSO(2) from baseline (30%) compared to those receiving indomethacin (7.4%, p = 0.001) or control infants without a hsPDA (2.6%, p = 0.0004). NIRS measures were not associated with abnormal neuroimaging in this small cohort. CONCLUSION: These findings suggest that infants requiring surgical ligation for a hsPDA are at high risk for significant changes in cerebral oxygenation, whereas those receiving either indomethacin or conservative management maintain relatively stable cerebral oxygenation levels. Additional research is necessary to determine if NIRS monitoring identifies infants with a hsPDA at highest risk for brain injury. PMID- 21701213 TI - Increased postnatal inflammation in mechanically ventilated preterm infants born to mothers with early-onset preeclampsia. AB - BACKGROUND: Preeclampsia and preterm labor often underlie preterm birth, and are associated with maternal inflammation. In preterm infants, respiratory distress syndrome (RDS) and mechanical ventilation are associated with systemic inflammation. OBJECTIVE: We aimed to study whether early-onset preeclampsia or preterm labor modulate the systemic inflammation affecting preterm infants with RDS. METHODS: We recruited mechanically ventilated infants with gestational ages <32 weeks; 11 infants were born after early-onset preeclampsia and 25 after preterm labor. Blood was drawn during postnatal days 1-7, and the mean values of days 1-2, 3-4 and 5-6 were used. Phagocyte CD11b expression was analyzed with flow cytometry, and plasma C-reactive protein (CRP) concentrations with immunoturbidimetry. RESULTS: As compared with infants born after preterm labor, infants born after early-onset preeclampsia had higher CD11b expression on days 1 6 on both neutrophils and monocytes. In addition, infants born after early-onset preeclampsia had higher CRP concentrations on days 2-6 (all p < 0.05). CONCLUSIONS: As compared with infants born after preterm labor to mothers without preeclampsia, infants born after early-onset preeclampsia presented with a stronger postnatal systemic inflammatory reaction. Antenatal exposure to preeclampsia may induce fetal leukocyte priming and regulation of inflammation, and thereby modify postnatal inflammatory reactions and morbidity. PMID- 21701214 TI - Intestinal absorption of lipid emulsion in premature infants: a pilot study. AB - BACKGROUND: Adequate nutritional intake is essential in the very-low-birth-weight infant, but difficult to achieve in the first few postnatal days. Can lipids be given enterally in the first few days of life in sick preterm infants? OBJECTIVE: To determine tolerance and absorption of lipid emulsion when fed enterally to very-low-birth-weight infants. DESIGN/METHODS: Infants had a birth weight <1,500 g, an appropriate weight for gestational age, and were receiving parenteral nutrition. We performed a progressive series of studies, enrolling 5 infants in each group. Group 1 infants were fed enteral lipid emulsion at 1 g/kg/day for 4 days, starting when 60 ml/kg/day of breast milk was tolerated enterally. Simultaneously, a matched control group which received no oral lipid emulsion was enrolled. We then enrolled group 2 infants who were fed 3 g/kg/day with the same protocol as group 1. Group 3 infants were fed enteral lipid emulsion starting in the first 72 h of life. The infants were fed 1, 2 and 3 g/kg/day subsequently for 48 h each. Fat absorption was measured. RESULTS: Gestational age was 24.6-30.8 weeks and birth weight was 620-1,400 g. One infant (group 1) developed necrotizing enterocolitis 1 week after the study. There were no other adverse clinical findings. On average, enteral lipid emulsion was started on day 8 of life in groups 1 and 2, and on day 2 in group 3. The intestinal lipid absorption was 93.6% (min. = 76%). There was no difference in fat absorption between the 4 groups (p > 0.05). CONCLUSIONS: Lipid emulsions are an isotonic high-calorie source which can be given safely enterally instead of intravenously in the immediate neonatal period of very-low-birth-weight infants without clinical adverse effects and with almost complete absorption. There are potential advantages to oral administration of a lipid emulsion starting in early life which require further investigation. PMID- 21701215 TI - Tilting the head changes cerebral haemodynamics in neonates. AB - BACKGROUND: Tilting only the head influences cerebral haemodynamics in term and preterm neonates. OBJECTIVE: To evaluate near-infrared spectroscopy (NIRS) as a method to detect changes of cerebral oxygenated (HbO(2)) and deoxygenated haemoglobin (Hb) and 'cerebral tissue-oxygenation-index' (cTOI) while tilting. Furthermore to investigate whether the comparison of cTOI and 'cerebral mixed venous oxygen saturation' (tiltSvO(2)), calculated out of the increase of HbO(2) and Hb, improves reproducibility. METHODS: During five 'reapplication' periods of NIRS optodes on the left forehead of 40 neonates, five tilting manoeuvres of the head were performed. Changes of NIRS parameters during tilting were analysed. The first quality criterion was defined by a linear increase of total haemoglobin (HbT; r(2) > 0.95). The second quality criterion was: cTOI > tiltSvO(2) (= cTOI - tiltSvO(2)> 0). Analysis of variance components and comparison of mean of standard deviations were applied to data after introduction of each quality criterion. RESULTS: While HbO(2), Hb and HbT showed a linear increase in all neonates during tilting, cTOI did not change. With the introduction of the second criterion, mean cTOI increased from 73.7 +/- 6.9 to 75.1 +/- 6.9%, mean tiltSvO(2) decreased from 72.6 +/- 7.1 to 65.3 +/- 6.9% and mean of standard deviations of both parameters decreased. The analysis of variance components showed no significant change. CONCLUSION: A tilting-down manoeuvre of the head of term and preterm neonates can cause an increase of HbO(2), Hb and HbT. tiltSvO(2) can be calculated out of these changes. By introducing two quality criteria, reproducibility of cerebral NIRS measurements (cTOI and tiltSvO(2)) improved. PMID- 21701216 TI - Three-dimensional body scanning: a new method to estimate body surface area in neonates. AB - BACKGROUND: Body surface area (BSA) is usually estimated by calculation with mathematical formulae. Three-dimensional body scanning (3D scan) offers a suitable alternative. OBJECTIVES: We determined the BSA in healthy term and near term neonates by 3D scanning. This system should be useful in the setting of intensive care medicine. METHODS: The measuring system consisted of a projector, two cameras, mirrors and a computer, and used the fringe projection technique with visible light. The infants were examined in a supine position; the hidden parts of the bodies were corrected for using a mathematical factor developed with a baby doll model. Results of the 3D scans were compared with those from five mathematical formulae for each subject. RESULTS: A total of 209 infants were studied by 3D scanning, of whom 53 had acceptable images and were selected for further analysis. The mean BSA was 2,139 cm(2) (SD 223.72). The minimal BSA was 1,587 cm(2), the maximal 2,670 cm(2), with a good correlation to body weight and length. One mathematical formula (Du Bois and Du Bois) showed a distinct underestimation of BSA compared to 3D scanning, the others an overestimation. Mean percentage similarity was from 96.8 to 100.9%. CONCLUSIONS: 3D scanning is an accurate and practical method to estimate BSA in newborns. Individual and repeated measurements from day to day are possible. Further studies are warranted in preterm and sick neonates. PMID- 21701217 TI - Use of heliox in the management of neonates with meconium aspiration syndrome. AB - BACKGROUND: Helium-oxygen mixture (heliox) ventilation has been known as an alternative treatment in patients with airway obstruction. Because of the physical properties of heliox, mechanical ventilation with this gas mixture may offer advantages in the management of respiratory failure associated with meconium aspiration syndrome (MAS). OBJECTIVES: The purpose of this pilot study was to assess the effect of short-term mechanical ventilation with heliox in newborns with MAS on vital signs, oxygenation, acid-base balance and respiratory function parameters. METHODS: The study was carried out in newborns with respiratory failure requiring mechanical ventilation due to MAS. Eight patients were ventilated using pressure-controlled synchronized intermittent mandatory ventilation. Parameters of respiratory function, oxygenation, acid-base balance and vital signs were recorded at baseline, then twice during 1 h of heliox ventilation and finally twice during 1 h after switching back to air-oxygen ventilation. RESULTS: Mechanical ventilation with heliox did not affect vital signs and the infants' clinical condition remained stable during the study. Heliox ventilation was associated with a nonsignificant increase in tidal volume, minute ventilation and peak expiratory flow rate values. Mechanical ventilation with heliox allowed the use of significantly lower FiO(2), with a significant decrease in alveolar-arterial oxygen tension difference and a decrease in the oxygenation index which was not statistically significant. There was also a significant increase in the PaO(2)/FiO(2) ratio during heliox ventilation. CONCLUSIONS: Ventilation with a helium and oxygen mixture had a positive effect on the selected parameters of oxygenation, while its effects on other respiratory parameters were relatively small. PMID- 21701218 TI - Decorin and colchicine as potential treatments for post-haemorrhagic ventricular dilatation in a neonatal rat model. AB - BACKGROUND: Post-haemorrhagic ventricular dilatation (PHVD) after intraventricular haemorrhage (IVH) remains a significant problem in preterm infants. Due to serious disadvantages of ventriculoperitoneal shunt dependence, there is an urgent need for non-surgical interventions. Considerable experimental and clinical evidence implicates transforming growth factor beta (TGFbeta) in the pathogenesis of PHVD. Colchicine and decorin are both compounds with anti-TGFbeta properties. The former downregulates TGFbeta production and is in clinical use for another fibrotic disease, and the latter inactivates TGFbeta. OBJECTIVES: We hypothesized that administration of decorin or colchicine, which both have anti TGFbeta properties, would reduce ventricular dilatation in a model of PHVD. METHODS: 142 rat pups underwent intraventricular blood injection on postnatal days (PN) 7 and 8. Sixty-nine pups were randomized to colchicine 20 and 50 MUg/kg/day or water by gavage for 13 days. Seventy were randomized to decorin 4 mg/kg or saline by intraventricular injection on PN8 and PN13. At PN21, the ventricular area was measured on coronal brain sections. Negative geotaxis was tested at PN14 in controls and in the decorin study group. RESULTS: Ventricular size was not different between animals receiving either drug or water/saline. Intraventricular blood impaired neuromotor performance, but decorin had no effect. CONCLUSION: Two drugs that block TGFbeta by different mechanisms do not reduce ventricular dilatation in this model. Together with our previous work on losartan and pirfenidone, we conclude that blocking TGFbeta alone does not prevent the development of PHVD. PMID- 21701219 TI - A novel mutation in the MC2R gene causing familial glucocorticoid deficiency type 1. AB - Familial glucocorticoid deficiency (FGD) or hereditary unresponsiveness to adrenocorticotropin (ACTH) is an autosomal recessive disorder characterized by isolated glucocorticoid deficiency associated with normal mineralocorticoid secretion. Mutations in genes encoding either ACTH receptor or melanocortin 2 receptor accessory protein are responsible for the disease in about 50% of cases, named FGD type 1 and type 2, respectively. Patients may present with hyperpigmentation, recurrent infections, failure to thrive, hypoglycemic seizures, and coma in infancy or early childhood. Here we report the case of a 17 day-old newborn diagnosed with FGD type 1 who presented with hyperbilirubinemia and hyperpigmentation, a sign which was erroneously assumed to be due to prolonged phototherapy by the referring physician. Hormone analysis showed low cortisol and high ACTH levels with normal serum electrolytes and renin aldosterone axis. Genetic analysis revealed a novel homozygous melanocortin 2 receptor mutation p.Leu225Arg in the patient. The healthy parents were heterozygous for the mutation. PMID- 21701220 TI - Variability of influenza AH1N1 infections in a neonatal unit in Spain. AB - We describe three positive influenza AH1N1 cases in a neonatal unit during the influenza pandemic in Spain. One term baby presented with an upper respiratory tract infection, another preterm infant with an apnea episode following nosocomial infection, and thirdly, a term infant of a mother with influenza AH1N1 had severe respiratory distress and pneumothoraces needing high-frequency ventilation. PMID- 21701221 TI - Extremely low-dose dexamethasone to facilitate extubation in mechanically ventilated preterm babies. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is a major respiratory complication of extreme prematurity. Dexamethasone is effective in reducing ventilation requirements in babies with BPD, but follow-up studies have raised concerns about long-term neurological sequelae. Few studies have investigated the lowest dose effective for weaning from mechanical ventilation. OBJECTIVES: Between January 2004 and December 2008 the practice in a tertiary neonatal unit was to use extremely low doses of dexamethasone for severe BPD, commencing at 0.05 mg/kg/day and decreasing over 9 days, with a cumulative dose of 0.24 mg/kg. The objective of this observational study was to assess the effectiveness of the extremely low dose course in facilitating extubation. METHODS: The babies who had received extremely low-dose dexamethasone to facilitate weaning from mechanical ventilation were identified. Details of treatment and respiratory support were recorded. Serial oxygenation indices (OI) during the dexamethasone course were calculated, and these were analysed to assess the effect of treatment on ventilation requirements. RESULTS: One hundred and ninety extremely preterm babies were admitted during this 5-year period. Sixteen babies received extremely low-dose dexamethasone. The median gestation was 25 weeks and the median birth weight was 644 g. Before starting dexamethasone, the median OI was 10.6, but by day 7 of treatment it had fallen to 5.4. By the end of the course, 12 of the 16 babies had been successfully extubated. CONCLUSIONS: This short dexamethasone course appears effective in facilitating extubation. Randomised trials with long term follow-up are needed to determine the role of extremely low-dose dexamethasone in preterm babies with evolving BPD. PMID- 21701222 TI - Randomized controlled trial of a high dose of oral erythromycin for the treatment of feeding intolerance in preterm infants. AB - OBJECTIVES: To evaluate the effectiveness of high-dose erythromycin to treat feeding intolerance in preterm infants predominantly fed milk formula. DESIGN: This study is a prospective randomized controlled trial on 60 premature infants suffering from feeding intolerance. Thirty infants were given oral erythromycin ethylsuccinate at a dose of 50 mg/kg/day for 10 days or until they reached full enteral feeds. Randomization was stratified according to gestational age <32 weeks or >=32 weeks gestation. The primary end point was the time taken to establish full enteral feeding since enrollment. Potential adverse effects associated with erythromycin were also monitored. Student's t test was used for comparison of continuous variables and chi(2)for categorical data. RESULTS: In infants <32 weeks, the use of erythromycin was associated with more daily weight gain (12.8 +/- 2.6 g vs. 9.2 +/- 5.3 g, p = 0.04) compared to the control group. Time to reach full feed did not differ between the erythromycin (13.8 +/- 3.9 days) and the control (17.46 +/- 4.9 days) groups (p = 0.07). In infants >=32 weeks, there were no differences between the erythromycin and the control groups. CONCLUSION: High-dose erythromycin is associated with greater weight gain in preterm infants <32 weeks gestational age, who are predominantly fed cow's milk based protein formulas. PMID- 21701223 TI - The limit of viability: should we lower it. Commentary on T. Sugiura et al.: Neurodevelopmental outcomes at 18 months' corrected age of infants born at 22 weeks of gestation (Neonatology 2011;100:228-232). PMID- 21701224 TI - Erythromycin as a prokinetic agent in newborns--useful or doubtful. Commentary on Y. Mansi et al.: Randomized controlled trial of a high dose of oral erythromycin for the treatment of feeding intolerance in preterm infants (Neonatology 2011;100:290-294). PMID- 21701225 TI - Functional neuroimaging in obsessive-compulsive disorder. AB - BACKGROUND AND AIM: Obsessive-compulsive disorder (OCD) is a severe, highly prevalent and chronically disabling psychiatric disorder that usually emerges during childhood or adolescence. This paper aims to review the literature on functional neuroimaging in OCD, analysing the reported dysfunctional connectivity in the corticostriatothalamocortical circuitry. METHOD: This study included papers published in peer-reviewed journals dealing with functional imaging in OCD. RESULTS: Striatal dysfunction, mainly of the caudate nucleus, leads to inefficient thalamic gating, resulting in hyperactivity within the orbitofrontal cortex (intrusive thoughts) and the anterior cingulate cortex (non-specific anxiety). Compulsions consist of ritualistic behaviours performed to recruit the inefficient striatum and neutralise unwanted thoughts and anxiety. Functional neuroimaging findings are discussed against the background of specific cognitive impairments, mainly regarding visuospatial processing, executive functioning and motor speed. Cognitive deficits are partial and specific, matching imaging data. CONCLUSIONS: Several studies have targeted brain regions hypothesised to be involved in the pathogenesis of OCD, showing the existence of dysfunctional connectivity in the corticostriatothalamocortical circuitry. Improvements in spatial resolution of neuroimaging techniques may contribute to a better understanding of the neurocircuitry of OCD and other anxiety disorders. PMID- 21701226 TI - Reduced cortical inhibition in violent offenders: a study with transcranial magnetic stimulation. AB - BACKGROUND: Aggression and violent behaviour are often regarded as a threat to society. Therefore, understanding violent behaviour has high social relevance. We performed a study with transcranial magnetic stimulation on a sample of violent offenders in order to measure cortical inhibition in the motor neuron system that is part of the frontal cortex. METHODS: To investigate intracortical inhibition and intracortical facilitation, we conducted paired-pulse stimulation according to the technique of Kujirai and his group (see Method). The investigation sample comprised 62 right-handers: 32 prisoners who had committed severe violent crimes and 30 controls with no history of violence. All subjects were male and matched for age. RESULTS: Using the paired-pulse paradigm with interstimulus intervals (ISI) of 1-15 ms, a reduced cortical inhibition (ISI: 3 ms) was found in the left cortex of violent offenders compared with control subjects. CONCLUSIONS: These findings corroborate the hypothesis of inhibition deficits and frontal cortex dysfunction in violent offenders when compared with non-violent control subjects. PMID- 21701227 TI - Brain activity supporting working memory accuracy in patients with paranoid schizophrenia: a functional magnetic resonance imaging study. AB - BACKGROUND: Dysfunctional working memory (WM) has been recognized as one of the most consistent deficits in schizophrenia. Studies that investigated the neural correlates of WM-related pathology by comparing patients with schizophrenia and control participants have produced controversial results, reporting task-related hyper- or hypoactivity in frontoparietal networks. METHOD: We addressed this question by comparing BOLD signals for accurate responses during a WM task for emotional faces between a homogeneous group of high-performing patients and a control group. RESULTS: Our results confirm previous findings of left prefrontal hyperactivity contrasted with hypoactivity in right prefrontal cortex to support WM performance. We also extend previous work by reporting enhanced activity in higher visual areas of patients during encoding and maintenance. CONCLUSION: Our findings and those of the literature can be integrated into a model, where preserved visual cognition in high-functioning patients with hypofrontality is explained by activation of contralateral homologue areas combined with enhanced recruitment of sensory areas. PMID- 21701228 TI - Association between apolipoprotein E epsilon4 and longitudinal cognitive decline: nested case-control study among chinese community-dwelling elders. AB - BACKGROUND/AIMS: Cognitive decline in the elderly is an early predictor of dementia. The apolipoprotein E (APOE) epsilon4 allele is considered an important genetic determinant of Alzheimer's disease (AD), and strongly suspected to play a role in cognitive variation. However, its effects upon predicting the progression of cognitive decline more generally remain unclear. Our aim was to explore the role of APOE epsilon4 in longitudinal cognitive decline, considering sociodemographics, vascular disease, and lipid profile. METHODS: We chose a nested case-control design, and prospectively collected demographic and clinical data, determined APOE genotypes, and obtained follow-up information on cognitive variation (measured by a spectrum of cognitive tests) for 3 years. Cognitive decline was predefined as an increase in Clinical Dementia Rating Scale class, or at least a 4-point decrease (>1 SD) in MMSE, between baseline and follow-ups. RESULTS: Among 600 follow-up subjects with mild cognitive impairment and aged 65 years or older, 114 pairs of cognitive decline and stable subjects were identified and matched for sex, age, and educational level in a 1:1 ratio. The APOE epsilon4 frequency in the cognitive decline group was significantly higher than that in the stable group (p < 0.05), while the APOE epsilon2 and epsilon3 prevalence in the cognitive decline group did not differ significantly from that in controls (p > 0.05). At the first follow-up, modest but significant declines only in the memory domain were associated with APOE epsilon4. At the last follow up, significant associations were noted between APOE epsilon4 and cognitive decline from 5 of the 6 cognitive outcomes, which included story recall, memory, spatial recognition, naming, and sustained attention. Conditional logistic regression showed that the presence of APOE epsilon4 was significantly associated with the cognitive decline group, as compared to the stable group, adjusting for vascular diseases and lipid profile. CONCLUSIONS: APOE epsilon4 offered information on the risk of cognitive decline in this longitudinal study, and may exert detectable effects early in a long prodromal AD trajectory. PMID- 21701229 TI - Activating effects of chronic variable stress in rats with different exploratory activity: association with dopamine d(1) receptor function in nucleus accumbens. AB - BACKGROUND/AIMS: Rats display persistent behavioural phenotypes of low (LE) versus high (HE) exploratory activity in the exploration box paradigm. LE rats that prefer passive coping strategies show differential dopaminergic activity in the striatum. The main hypothesis of this study was that chronic variable stress (CVS) would have a higher impact on LE rats. METHODS: Animals were submitted to a CVS regimen lasting 32 days that was followed by a behavioural test battery. The functional states of their dopamine D(1) and D(2) receptors were measured in the striatum and nucleus accumbens (NAcc). Cerebral oxidative metabolism was assessed via cytochrome c oxidase histochemistry in 65 brain regions. RESULTS: CVS decreased weight gain, to a higher extent in LE rats, and lowered the sucrose preference after the first week, but habituation to the anhedonic effect had developed by the end of the experiment. CVS did not change the behavioural phenotypes initially assigned. No effect of stress on D(2) receptor function was found. Chronically stressed animals exhibited higher levels of social interaction and D(1) receptor-mediated cAMP accumulation in the NAcc, but not in the striatum. CVS was associated with higher oxidative metabolism levels in the anteroventral thalamus, median raphe nuclei and central periaqueductal grey matter. These changes after stress did not depend upon the exploratory phenotype. CONCLUSION: This study revealed changes in brain biochemistry after habituation to CVS that might be implicated in successful adaptation to chronic stress. PMID- 21701230 TI - Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib: a retrospective comparison with previously known prognostic models. AB - BACKGROUND: Sorafenib, a multitargeted tyrosine kinase inhibitor, is now the treatment of choice for systemic therapy of patients with advanced hepatocellular carcinoma (HCC). Herein, we present the clinical characteristics and outcomes of patients with advanced HCC who were treated with sorafenib. METHODS: Data of 201 sorafenib-treated, metastatic HCC patients were collected from a single institution tumor registry. The primary and secondary endpoints were overall survival (OS) and failure-free survival (FFS). RESULTS: Chronic hepatitis B was the predominant cause of HCC (84%). Of 162 evaluable patients, 4 partial responses were recorded. With a median follow-up of 15.7 months, the median FFS and OS were 2.5 months (95% CI 2.3-2.7) and 5.3 months (95% CI 4.4-6.3), respectively. In multivariate analysis, the prognostic factors associated with FFS were the presence of ascites, portal venous thrombosis, serum alpha fetoprotein >=400 ng/ml, albumin, bilirubin, tumor size and number, and performance status. Likewise, the presence of ascites, portal venous thrombosis, tumor size and number, performance status and baseline levels of alpha fetoprotein, albumin and bilirubin were significantly related with OS. After adjusting for performance status, the Cancer of the Liver Italian Program scoring system and Okuda stages can better predict the hazard of failure or death than the Child-Pugh classification. CONCLUSIONS: Our results suggest that Cancer of the Liver Italian Program scores or Okuda stages, along with performance status, can be useful in stratifying patients with advanced HCC treated with sorafenib. PMID- 21701231 TI - A prognostic model to predict clinical outcomes with first-line gemcitabine-based chemotherapy in advanced pancreatic cancer. AB - OBJECTIVE: Our aim was to devise a prognostic model for advanced pancreatic cancer based on clinical parameters. METHODS: We retrospectively analyzed the medical records of 298 patients who received gemcitabine-based chemotherapy from January 1999 to November 2008. RESULTS: The median survival of all patients was 7 months [95% confidence interval (CI) 6.2-7.8]. Multivariate analysis revealed poor prognostic factors for overall survival such as the presence of liver metastasis [p < 0.001, hazard ratio (HR) 2.628, 95% CI 1.620-4.264], the presence of ascites or peritoneal carcinomatosis (p = 0.005, HR 1.783, 95% CI 1.194 2.661), serum C-reactive protein levels >1.2 mg/dl (p = 0.021, HR 1.568, 95% CI 1.070-2.300), and serum albumin levels <3.5 g/dl (p = 0.021, HR 1.701, 95% CI 1.085-2.667). Of 298 patients, 168 patients (56.4%) were categorized as low-risk with 0 or 1 risk factor, 80 patients (26.8%) were categorized as intermediate risk with 2 risk factors, and 50 patients (16.8%) were categorized as high-risk with 3 or 4 risk factors. The median survival duration for the low-, intermediate , and high-risk groups was 10.0 months (95% CI 8.7-11.3), 6.7 months (95% CI 5.7 7.7), and 4.4 months (95% CI 3.2-5.6), respectively. CONCLUSIONS: This prognostic model could help to select treatment for patients in clinical practice, and these risk-adapted treatment strategies should be further investigated in prospective studies in such patient populations. PMID- 21701233 TI - Epigenetics lights up the obesity field. PMID- 21701232 TI - A high proliferative index of recurrent melanoma is associated with worse survival. AB - OBJECTIVE: Previous melanoma studies evaluating prognostic factors of survival at recurrence have focused on primary tumor characteristics and clinical variables at first recurrence. We examined the prognostic relevance of recurrent tumor proliferation. METHODS: 114 melanoma patients with available recurrent tissues who were prospectively enrolled at New York University Medical Center were studied. Standard of care prognostic variables (e.g. stage at initial diagnosis and lactate dehydrogenase level) and recurrent tissue expression of proliferative marker Ki-67 were evaluated for their association with overall survival. RESULTS: High Ki-67 expression was observed in 57 (50%) of the 114 recurrent melanomas. On univariate analysis, the median overall survival of patients whose recurrent tumors overexpressed Ki-67 was significantly shorter than that of patients whose recurrent tumors had low Ki-67 expression (3.6 vs. 9.5 years, p = 0.03). On multivariate analysis, a high proliferative index of the recurrent melanoma remained an independent predictor of worse overall survival, controlling for stage at initial diagnosis, disease-free survival, and stage at first recurrence [HR = 2.09 (95% CI 1.24-3.54), p = 0.006]. CONCLUSIONS: Our results demonstrate the prognostic relevance of tumor proliferation in recurrent melanoma patients. Data also support restratification of risk assessment upon recurrence that considers tumor biology in addition to clinical variables evaluated as part of the standard of care. PMID- 21701234 TI - Multi-factorial approach associated with a new 'on/off' Orlistat(r) use in a weight loss maintenance programme: 4 years follow-up. AB - AIM: To assess the efficacy of a specific long-term programme for weight loss maintenance using a new 'on/off' Orlistat approach in obese subjects who previously lost more than 10% of their body weight. METHODS: 50 patients were followed up during 4 years; 34 completed the study. Subjects were followed up by physicians trained in obesity management. Anthropometrical, biological and psychological parameters were measured. Insulin sensitivity was evaluated by euglycaemic insulin clamp. Orlistat was given in case of weight relapse more than 2.5%. Subjects could take Orlistat on a voluntary basis for special occasions. RESULTS: The BMI of completers remained stable (29.5 +/- 0.9 vs. 30.6 +/- 1.0 kg/m(2)). 73% of completers maintained 10% or more of their weight loss. Subjects from the no-regain group improved most of their parameters while the regain group did not. Insulin sensitivity was negatively linked to body weight during the follow up (p < 0.01, r(2) = 0.20). A negative relationship has been found between extent of the previous weight loss and the evolution of body weight during the 4 years follow-up (p < 0.01, r(2) = 0.26). Orlistat intake showed a body fat lowering effect (p < 0.05). CONCLUSION: 73% of subjects maintained more than 10% of their weight loss. Subject with a large weight loss amount are at high risk for weight regain. The Orlistat 'on/off' intake regarding his lowering body fat mass effect seems to be efficient. PMID- 21701235 TI - Association of the rs10830963 polymorphism in MTNR1B with fasting glucose levels in Chinese children and adolescents. AB - AIMS: We aimed to identify whether the risk G-allele was associated with fasting glucose level and other pre-diabetic and obesity-related phenotypes in Chinese children and adolescents. METHODS: The rs10830963 polymorphism in MTNR1B was genotyped in 2,030 Chinese children and adolescents of two independent studies. Association with fasting glucose levels and risk of impaired fasting glucose (IFG) were initially tested. Subsequently we analyzed the association with fasting insulin, homeostasis model assessment for insulin resistance (HOMA-IR) and for beta cell function (HOMA-B), the quantitative insulin sensitivity check index (QUICK) and obesity-related phenotypes (BMI standard deviation score, waist circumference etc.). RESULTS: The G-allele of rs10830963 was associated with increased fasting glucose level in Chinese children and adolescents (increase of 0.072 mmol/l per G-allele, 95% CI 0.034-0.111, p = 2.46 * 10(-4)). The G-allele was also associated with an increased risk of IFG (OR = 1.21, 95% CI 1.00-1.46, nominal p = 0.048). We found the glucose-raising G-allele was nominally associated with reduced HOMA-B. No association to other pre-diabetic or obesity related phenotypes was detected. CONCLUSIONS: The rs10830963 polymorphism in MTNR1B was associated with increased fasting glucose and risk of IFG in Chinese children and adolescents. The effect may result from reduced pancreatic beta cell function, but the mechanism awaits further studies. PMID- 21701236 TI - Association between obesity and adult attention-deficit/hyperactivity disorder in a German community-based sample. AB - OBJECTIVE: The goal of the present study was to examine the association between attention-deficit/hyperactivity disorder (ADHD) and obesity in a representative community based sample of the German population. METHOD: Participants were 1,633 German residents (53.6% female) aged 18-64 years. A retrospective assessment of childhood ADHD and a self-report assessment of adult ADHD were administered for diagnosis of adult ADHD. In addition, binge eating and purging behaviors as well as depression and anxiety were assessed using self-rating instruments. RESULTS: The estimated prevalence of ADHD in obese participants was 9.7% compared to 3.8% in overweight and 4.3% in under-/normal-weight participants. The prevalence of obesity was 22.1% among adults with ADHD and 10.2% among persons without ADHD. Adult ADHD was significantly associated with a greater likelihood of being obese but not overweight even after adjusting for sociodemographic characteristics. Results were similar when adjusting for depression and anxiety symptoms and for purging behaviors. Odds ratios decreased after adjusting for binge eating; however, the results were still significant which shows that the relationship between obesity and ADHD in adulthood is not fully explained by binge eating. CONCLUSION: Overall, the results indicate that adult ADHD is associated with obesity in a community-based sample of the adult German population. PMID- 21701237 TI - Influence of obesity and gender on the postural stability during upright stance. AB - OBJECTIVE: To assess the influence of BMI group (lean/overweight/obese) and gender on the postural sway of adults and adolescents during quiet upright stance. METHODS: 90 women and 90 men, aged 12 to 67 years old, accepted to participate. The center of pressure during quiet upright stance was recorded using a force platform, during 4 conditions (eyes open/closed on hard/soft surface). Statistical analysis was performed using multivariate analysis of covariance. RESULTS: During recordings on hard surface, closing the eyes produced a larger increase of sway on obese subjects than on lean and overweight subjects, with a larger increase on the length and the area of sway. Although gender differences were found during the four sensory conditions, no interaction was observed between the BMI group and the gender. These results were not related to the age of the subjects. CONCLUSION: Compared to non-obese subjects, the postural stability of obese subjects may be more vulnerable when vision is not available, with no influence of the gender. PMID- 21701238 TI - Do obese patients after weight loss become metabolically normal? AB - OBJECTIVE: To compare the metabolic cardiovascular risk factors of obese patients after weight loss and 4-year weight loss maintenance afterwards against a matched control group of subjects with a stable body weight and without history of weight loss. METHOD: 50 obese non-diabetic subjects in the study group who previously lost 10% or more of their weight and afterwards entered a 4-year weight loss maintenance programme were matched by age, BMI and sex and compared to 50 weight stable subjects without history of weight loss. The comparison between both groups was done in term of anthropometrical, metabolic and biological characteristics, early atherosclerosis and insulin sensitivity. RESULTS: Anthropometrical, metabolic and biological characteristics were similar between the weight loss group and the control matched group. However, insulin sensitivity was still significantly lower in the weight loss than in the matched control group (p = 0.02). Intima media thickness (IMT) also was similar in both groups. We found that lower atherosclerosis measured by IMT at the level of the carotid is associated with better insulin sensitivity (p < 0.05). After the 4-year weight loss maintenance programme, insulin sensitivity improved in the post-weight loss group from 7.9 +/- 3.2 to 8.4 +/- 3.6 mg/kg/min. CONCLUSION: All cardiometabolic parameters of obese subjects, except for insulin sensitivity, normalised completely after weight loss. The latter was improved by a weight loss maintenance programme if successfully completed. PMID- 21701239 TI - Comparison of education-only versus group-based intervention in promoting weight loss: a randomised controlled trial. AB - AIM: To compare the effectiveness of education-only versus group-based intervention in promoting weight loss. METHODS: Between April and October 2009, a 6-month randomised controlled trial was conducted at Mito Kyodo General Hospital in Japan (UMIN000001259). The participants were 188 overweight adults (145 women, 43 men) aged 40-65 years. They were randomly assigned to one of three groups: control, moderate or intensive intervention. A single motivational lecture was provided to all three groups, educational materials (textbooks, notebooks, and a pedometer) to the moderate and intensive intervention groups, and group-based support to the intensive intervention group. Amount of weight loss was the primary outcome measure. Secondary outcome measures were components of metabolic syndrome. RESULTS: Mean +/- SD weight loss of participants in the control, moderate and intensive intervention groups was 2.9 +/- 4.1, 4.7 +/- 4.0 and 7.7 +/- 4.1 kg, respectively. Bonferroni post-hoc comparisons revealed all between group differences to be significant (p < 0.05). Waist circumference decreased in the intensive intervention group more than in the other groups, whereas no significant differences were observed in the other secondary outcome measures. CONCLUSION: Education-only intervention is a cost-effective method to promote weight loss. Adding group-based intervention further promotes weight loss. PMID- 21701240 TI - The correlates and treatment of obesity in military populations: a systematic review. AB - OBJECTIVE: The emergence of obesity as a distinct disease could have far reaching consequences for an organisation where optimum health and physical fitness are required for personnel to perform their occupational roles effectively. The objectives of this paper are to systematically review the literature concerning correlates and treatment of obesity in military populations. METHODS: Through computerised searches of English language studies, 17 papers were identified (treatment (13), correlates (4)). RESULTS: Successful treatment interventions incorporated exercise, healthy eating information, behavioural modification, self monitoring, relapse prevention, and structured follow-up and were supported by trained personnel. Efficacy due to physical activity was underreported. Reduction in body fat rather than body weight was the most significant outcome. The major significant correlates of obesity were being enlisted personnel, male, >=35 years of age, African-American/Hispanic ethnicity, and married (with spouse present). CONCLUSION: This systematic review highlights the deficit in knowledge concerning treatment and the lack of engagement in relation to the specific correlates of obesity in military populations. PMID- 21701241 TI - Measurement of glomerular filtration rate in obese patients: pitfalls and potential consequences on drug therapy. AB - Epidemiological studies have shown that obesity is associated with chronic kidney disease and end stage renal disease. These studies have used creatinine derived equations to estimate glomerular filtration rate (GFR) and have indexed GFR to body surface area (BSA). However, the use of equations using creatinine as a surrogate marker of glomerular filtration and the indexation of GFR for BSA can be questioned in the obese population. First, these equations lack precision when they are compared to gold standard GFR measurements such as inulin clearances; secondly, the indexation of GFR for 1.73 m(2) of BSA leads to a systematic underestimation of GFR compared to absolute GFR in obese patients who have BSA that usually exceed 1.73 m(2). Obesity is also associated with pathophysiological changes that can affect the pharmacokinetics of drugs. The effect of obesity on both renal function and drug pharmacokinetics raises the issue of correct drug dosage in obese individuals. This may be particularly relevant for drugs known to have a narrow therapeutic range or excreted by the kidney. PMID- 21701242 TI - Endoscopic management of penetrated adjustable gastric band with its connecting tube: report of a case. AB - AIM: Laparoscopic adjustable gastric banding (LAGB) is a widely performed surgical procedure for the treatment of morbid obesity. Late complications mainly originate from either the injection port or the gastric band. Complications from the tube and band together are also described. CASE REPORT: We here report a case of adjustable gastric band migrated subserosally into the stomach with its whole connecting tube, which was removed endoscopically using a band cutter. CONCLUSION: In selected patients endoscopic techniques in combination with minimally invasive procedures can safely be used in the treatment of complete gastric band migration. PMID- 21701243 TI - A decrease in the density of HLA-DR-positive cells occurs faster in corneas stored in organ culture than under hypothermic conditions. AB - AIMS: To compare the number of antigen-presenting cells (APC) at various locations in fresh human corneoscleral disks and in those that are stored for grafting under hypothermic conditions or in organ culture (OC) with the aim of determining the conditions under which the decline in APC numbers is most substantial. METHODS: Cryosections obtained from fresh corneoscleral disks and disks stored under hypothermic (Optisol-GS) or OC conditions were used. The density of HLA-DR-positive cells was determined on cross sections using enzyme immunohistochemistry (alkaline phosphatase-antialkaline phosphatase technique). Longitudinal sections were used for detecting ATPase activity. RESULTS: The densities of HLA-DR-positive cells in both the epithelium and stroma increased from the central (3.79 and 0.61/mm(2)) to the peripheral cornea (5.56 and 1.35/mm(2)) as well as to the limbus and conjunctiva. A marked decrease in the number of HLA-DR-positive cells occurred after 7 days of storage in all corneal areas, the limbus and conjunctiva, compared to fresh tissue. No positive cells were found in the epithelium of corneas after 14 days in OC and after 21 days in hypothermic storage. Twenty-eight days of storage in OC led to the complete absence of HLA-DR-positive cells in the epithelium of the limbus and conjunctiva, and to a significant reduction in the stroma. CONCLUSION: Corneas stored in OC longer than 14 days are likely to be less immunogenic than corneas stored under hypothermic conditions, thus resulting in a possible positive effect on prolonging graft survival. PMID- 21701244 TI - A detailed meta-analysis shows no association between TNF-alpha -308G/A polymorphism and different forms of glaucoma. AB - OBJECTIVE: Glaucoma is the second leading cause of blindness worldwide. To date, several publications have evaluated the association between the tumor necrosis factor alpha (TNF-alpha) -308G/A polymorphism and glaucoma risk. However, the results remain inconclusive. The aim of our study was to clarify the effect of the TNF-alpha -308G/A polymorphism on glaucoma risk. METHOD: We conducted searches of the published literature in the PubMed database updated to May 2010. A meta-analysis was performed by critically reviewing 7 publications with a total of 1,199 glaucoma cases and 1,189 controls on the -308G/A polymorphism. Odds ratio (OR) and 95% confidence intervals (CIs) were used to assess the strength of this relationship. RESULTS: Overall, no association between the TNF-alpha -308G/A polymorphism and primary open-angle glaucoma or pseudoexfoliation glaucoma risk was found in the A allele versus G allele genetic model (OR = 1.68, 95% CI = 0.78 3.59 or OR = 2.44, 95% CI = 0.40-15.04, respectively), the same as genetic models in AG versus GG and AA + AG versus GG. In the stratified analysis by ethnicity and source of control subgroups, a significant association was still not observed in all genetic models. CONCLUSION: Our meta-analysis provides strong evidence that the TNF-alpha -308G/A polymorphism is not associated with different forms of glaucoma risk. PMID- 21701245 TI - Surgical technique for implantation of the MED-EL SONATATI. AB - AIMS: The objective of this study was to describe our surgical techniques following the general principles of cochlear implantation focusing on the small and thin design of the SONATATI(100) implant device. METHODS: From May 2007 to December 2010, 97 patients were implanted with the SONATATI(100) device. Due to the titanium housing, a bony bed and a muscle-periost pocket were created to host the biggest part of the device with its magnet. For device fixation, suture retaining holes were drilled at the end of the bed, and the electrode array was inserted deeply into the scala tympani via the round window or a cochleostomy. RESULTS: Up to now, no case of device failure, migration or intracranial complication has been reported. However, one minor wound healing complication has occurred. CONCLUSION: Following the principal rules of cochlear implantation using a 2-bed technique combined with sutures allows safe fixation of the SONATATI(100) device. PMID- 21701246 TI - Early-onset postirradiation sarcoma of the tongue after pseudotumor phase. AB - Radiation-induced sarcoma usually develops after an interval of more than 10 years from the completion of radiation therapy to the diagnosis of secondary sarcoma. However, the theory of radiation-induced transformation does not rule out postirradiation sarcomas with a short latency period. We experienced the case of a patient with postirradiation leiomyosarcoma of the tongue, which occurred 19 months after he had received chemoradiotherapy. Besides the short latency period, a pseudotumor stage developed between the time of radiation exposure and the development of leiomyosarcoma. In this article, we also describe an immunohistochemical approach to diagnose leiomyosarcoma and the efficacy of a gemcitabine and docetaxel regimen. PMID- 21701247 TI - Measuring the penetration of a skin sensitizer and its delivery vehicles simultaneously with confocal Raman spectroscopy. AB - Among the factors determining the propensity of a chemical to induce skin allergy are the penetration into skin and the kinetics of ingress. Confocal Raman spectroscopy can provide such information as it enables direct, spatially resolved measurement of the skin and of any chemical uptake. Several chemicals can be monitored at once, and the method is non-destructive (light in, light out) so that the skin can be kept intact for repeated and continuous measurement. Raman spectroscopy was used to follow the penetration of 2.5 weight percent trans cinnamaldehyde and its delivery vehicle into skin in vitro, up to 24 h after topical application. A custom-made Bronaugh-type diffusion cell that was suitable for the Raman experiment was used. Four different vehicles were tested: absolute ethanol, 50% aqueous ethanol, propylene glycol and acetone:olive oil (4:1); these gave different time scales for cinnamaldehyde penetration. The acetone:olive oil vehicle phase-separated on the skin surface and the cinnamaldehyde penetrated at different rates in the different phases, which may be of significance since this is the preferred solvent for the local lymph node assay (an in vivo animal test used to generate hazard information on skin sensitization). In conclusion, the Raman method gives valuable detailed information on chemical ingress, clearly differentiates between different delivery rates and allows solvent monitoring alongside the chemical of interest. PMID- 21701248 TI - Quantifying homicide trends in Australia: a methodological caution. PMID- 21701249 TI - Increased production of azadirachtin from an improved method of androgenic cultures of a medicinal tree Azadirachta indica A. Juss. AB - Present report is the first direct evidence of azadirachtin production in androgenic haploid cultures of Azadirachta indica, a woody medicinal tree. Anther cultures at early-late-uninucleate stage of microspores were established on MS medium with BAP (5 MUM), 2,4-D (1 MUM) and NAA (1 MUM) containing 12% sucrose. The calli, induced, were further multiplied on 2,4-D and Kinetin media. Shoots, differentiated on BAP (2.2 MUM) + NAA (0.05 MUM) medium, were elongated on MS + BAP (0.5 MUM) and multiplied on MS + BAP (1 MUM) + CH (250 mg/l). Thereafter, the shoots were rooted on 1/4 MS + IBA (0.5 MUM). Cytological analysis of the calli and regenerants have confirmed their haploid status with the chromosome number as 2n = x = 12. The haploid cell lines and leaves from in vitro grown plantlets were analyzed for azadirachtin by RP-HPLC and mass spectroscopy. Maximum azadirachtin (728.41 MUg/g DW) was detected in calli supporting best shoot proliferation while least (49 MUg/g DW) was observed in an undifferentiated line from maintenance medium. This study has brought us a step closer to develop genetically pure lines that could serve as new and attractive alternative ways of homogeneous controlled production of high value compounds, round the year, independent of geographical and climatic barrier. PMID- 21701250 TI - Leukocyte migratory responses to apoptosis: the attraction and the distraction. AB - An expanding body of evidence demonstrates that cells undergoing apoptosis send out a selection of molecular navigational signals including proteins, lipids and nucleotides that serve to recruit phagocytes to the dying targets which are subsequently engulfed and removed. This homeostatic process is essentially non phlogistic, contrasting markedly with the acute inflammatory responses elicited in phagocytes by damaging or infectious agents. The "professional" scavengers of apoptotic cells are mononuclear phagocytes-the macrophages-and sites of high-rate apoptosis are clearly characterized by macrophages associated with the apoptotic cells. By contrast, members of the other class of professional phagocytes-the granulocytes-are not recruited to sites of apoptosis as a direct consequence of the cell-death program. Indeed, recent work indicates that apoptotic cells release a mixture of migratory cues to leukocytes in order to selectively attract mononuclear phagocytes but not granulocytes through functional balancing of positive and negative signals. Here we discuss these molecular mechanisms which not only serve as migratory cues but also may activate responding phagocytes to engulf apoptotic cells effectively. Finally, we speculate upon new therapeutic opportunities these mechanisms offer for a range of pathological conditions, including inflammatory disorders and cancer. PMID- 21701251 TI - Spatio-temporal analysis of development of basal roots of common bean (Phaseolus vulgaris L.). AB - Temporal development of roots is key to the understanding of root system architecture of plants which influences nutrient uptake, anchorage and plant competition. Using time lapse imaging we analyzed developmental patterns of length, growth angle, depth and curvature of Phaseolus basal roots from emergence till 48 h in two genotypes, B98311 and TLP19 with contrasting growth angles. In both genotypes all basal roots appeared almost simultaneously, but their growth rates varied which accounted for differences in root length. The growth angles of the basal roots fluctuated rapidly during initial development due to oscillatory root growth causing local bends. Beyond 24 h, as the root curvature stabilized, so did the growth angle. Therefore growth angle of basal roots is not a very reliable quantity for characterizing root architecture, especially during early seedling development. Comparatively, tip depth is a more robust measure of vertical distribution of the basal roots even during early seedling development. PMID- 21701252 TI - Electrophysiological approach to examine a putative cold- and menthol- sensitive channel in the liverwort Conocephalum conicum. AB - The mechanism of cold perception by plants is still poorly understood. It was found that temperature drop evokes changes in the activity of ion pumps and channels, which leads to plasma membrane depolarization. The nature of the primary step of its action (alteration in membrane composition, transient influx of Ca2+ etc.,) has not been elicited yet. Our electrophysiological experiments conducted on the liverwort Conocephalum conicum showed that its cells respond not only to sudden cooling but also to menthol, generating depolarization of the plasma membrane and action potentials (APs). Similar results are well documented in mammals; cold or "cooling compounds" including menthol cause activation of thermosenstitive channel TRPM8 permeable to Ca2+ and generation of AP series. TRP receptors are detected, among others, in green and brown algae. Possible existence of TRPM8-like channel-receptor in Conocephalum conicum is discussed here. PMID- 21701253 TI - Dynamic protein trafficking to the cell wall. AB - Recently we have studied the secretion pattern of a pectin methylesterase inhibitor protein (PMEI1) and a polygalacturonase inhibitor protein (PGIP2) in tobacco protoplast using the protein fusions, secGFP-PMEI1 and PGIP2-GFP. Both chimeras reach the cell wall by passing through the endomembrane system but using distinct mechanisms and through a pathway distinguishable from the default sorting of a secreted GFP. After reaching the apoplast, sec-GFP-PMEI1 is stably accumulated in the cell wall, while PGIP2-GFP undergoes endocytic trafficking. Here we describe the final localization of PGIP2-GFP in the vacuole, evidenced by co-localization with the marker Aleu-RFP, and show a graphic elaboration of its sorting pattern. A working model taking into consideration the presence of a regulated apoplast-targeted secretion pathway is proposed. PMID- 21701254 TI - A 60-day probiotic protocol with Dietzia subsp. C79793-74 prevents development of Johne's disease parameters after in utero and/or neonatal MAP infection. AB - The research reported herein was designed to assess whether the bacterium, Dietzia subspecies C79793-74, used as a probiotic, could prevent development of parameters indicative of bovine paratuberculosis after potential in utero, birthing and neonatal (colostrum) exposure to Mycobacterium avium subspecies paratuberculosis (MAP). Such exposure avenues are especially relevant for dairy farms practicing good management procedures since calves on these farms could be infected via dams that have yet to be identified as MAP-positive. Indeed, of 18 calves in the present study that became paratuberculosis parameter-positive, five had dams that were negative for all parameters pre-calving. Parameters used herein to define paratuberculosis status were serum ELISA, serum agar gel immunodiffusion, cultureable fecal MAP, histopathology at necropsy and clinical disease. Thirty-four newborn calves, whose dams were paratuberculosis-positive, were assigned to four different treatment groups. Ten were treated daily for 60 days with viable Dietzia added to their antibiotic-free milk feedings; none became positive for any parameter with age. In contrast, seven of eight calves that were not treated became positive for one or more paratuberculosis-associated parameter. Sixteen calves were treated with viable Dietzia for the first two days of life; eight were then not treated further, whereas the other eight were treated an additional 58 days with Dietzia added to tetracycline-fortified milk (Dietzia is sensitive to tetracycline). In these two groups, positivity developed in five of eight and six of eight, respectively. These results indicated that (a) a daily, 60-day treatment with viable Dietzia effectively prevented development of parameters indicative of paratuberculosis and (b) this treatment, in combination with good management practices, has the potential to eradicate MAP from animals/herds, which should curtail the spread of MAP. Such results should significantly reduce human exposure to MAP, which in turn, could have relevance for the controversial role of MAP in Crohn's disease, type-1 diabetes mellitus, sarcoidosis, Blau syndrome, ulcerative colitis, irritable bowel syndrome and multiple sclerosis. PMID- 21701255 TI - Direct effects of non-antifungal agents used in cancer chemotherapy and organ transplantation on the development and virulence of Candida and Aspergillus species. AB - Conventional antineoplastic, novel immunosuppressive agents and antibiotics used in cancer treatment can directly affect the growth, development and virulence of Candida and Aspergillus species. Cytotoxic and cisplatin compounds have anti Candida activity and may be synergistic with antifungal drugs; they also inhibit Candida and Aspergillus filamentation/conidation and effect increased virulence in vitro. Glucocorticoids enhance Candida adherence to epithelial cells, germination in serum and in vitro secretion of phospholipases and proteases, as well as growth of A. fumigatus. Calcineurin and target of rapamycin inhibitors perturb Candida and Aspergillus morphogenesis, stress responses and survival in serum, reduce azole tolerance in Candida, but yield conflicting in vivo data. Inhibition of candidal heat shock protein 90 and candidal-specific histone deacetylase represent feasible therapeutic approaches for candidiasis. Tyrosine kinase inhibitors inhibit fungal cell entry into epithelial cells and phagocytosis. Quinolone and other antibiotics may augment activity of azole and polyene agents. The correlation of in vitro effects with clinically meaningful in vivo systems is warranted. PMID- 21701257 TI - NO way! Is nitric oxide level in tomato regulated by a mammalian IKK/NF-kappaB like signaling pathway? AB - Nitric oxide (NO) is an essential signaling molecule in plants. However little is known about signaling pathways regulating NO levels in plants. Recently we reported a NO overproducing mutant of tomato that had extremely short roots (shr) at seedling stage. The scavenging of NO restored root elongation in the shr mutant providing us with a convenient bioassay to analyze the signaling pathway upstream of NO production. The application of previously reported pharmacological inhibitors of ubiquitin-proteasome signaling caused a drastic reduction in NO levels and restored root elongation in the mutant. Since these pharmacological inhibitors specifically inhibit mammalian IKK/NF-kappaB signaling, we propose that a pathway functionally similar to IKK/NF-kappaB pathway regulates NO levels in tomato. PMID- 21701258 TI - Sucrose regulates plant responses to deficiencies in multiple nutrients. AB - Arabidopsis mutant hps1 that over-accumulates sucrose has enhanced sensitivity in almost all the aspects of plant responses to phosphate starvation. The detailed characterization of hps1 has led to the conclusion that sucrose is a global regulator of plant phosphate responses. Here, we show that hps1 is also hypersensitive to nitrogen and potassium deprivation, as well as to decreased levels of overall macronutrients. These results suggest that sucrose regulates plant deficiency responses to multiple nutrients and is part of a general response to nutrient deprivation. PMID- 21701256 TI - Animal models of external traumatic wound infections. AB - BACKGROUND: Despite advances in traumatic wound care and management, infections remain a leading cause of mortality,morbidity and economic disruption in millions of wound patients around the world. Animal models have become standard tools for studying a wide array of external traumatic wound infections and testing new antimicrobial strategies. RESULTS: Animal models of external traumatic wound infections reported by different investigators vary in animal species used, microorganism strains, the number of microorganisms applied, the size of the wounds and for burn infections, the length of time the heated object or liquid is in contact with the skin. METHODS: This review covers experimental infections in animal models of surgical wounds, skin abrasions, burns, lacerations,excisional wounds and open fractures. CONCLUSIONS: As antibiotic resistance continues to increase,more new antimicrobial approaches are urgently needed.These should be tested using standard protocols for infections in external traumatic wounds in animal models. PMID- 21701259 TI - Modulation of plant HMG-CoA reductase by protein phosphatase 2A: positive and negative control at a key node of metabolism. AB - The enzyme HMG-CoA reductase (HMGR) has a key regulatory role in the mevalonate pathway for isoprenoid biosynthesis, critical not only for normal plant development, but also for the adaptation to demanding environmental conditions. Consistent with this notion, plant HMGR is modulated by many diverse endogenous signals and external stimuli. Protein phosphatase 2A (PP2A) is involved in auxin, abscisic acid, ethylene and brassinosteroid signaling and now emerges as a positive and negative multilevel regulator of plant HMGR, both during normal growth and in response to a variety of stress conditions. The interaction with HMGR is mediated by B" regulatory subunits of PP2A, which are also calcium binding proteins. The new discoveries uncover the potential of PP2A to integrate developmental and calcium-mediated environmental signals in the control of plant HMGR. PMID- 21701260 TI - Gene profiling for assessment of cell-based therapies. PMID- 21701261 TI - The dynamic interplay between a PTK (Kit) and a PTP (Shp2) in hematopoietic stem and progenitor cells. PMID- 21701262 TI - Nucleotide excision repair and B lymphoma: somatic hypermutation is not the only culprit. AB - Different mechanisms account for the development of B lymphoma. Malignant transformation of B lymphocytes arises from progressive loss of genome integrity combined with uncontrolled cell proliferation, often triggered by foreign or self antigens. It is well established that somatic hypermutation, the pathway responsible for introducing high levels of mutations in immunoglobulin genes, also targets several other genes, contributing mainly to germinal center-derived B-cell lymphoma. We have recently discovered that a major DNA repair pathway, nucleotide excision repair (NER), is downregulated in quiescent B lymphocytes. Upon B-cell stimulation, unrepaired DNA damage results in the accumulation of mutations in a different and likely larger set of genes, including normally silent genes (e.g., oncogenes) as well as cell cycle and activation-induced genes. This mechanism potentially produces a transforming event relevant to a wider palette of B lymphomas. Here we discuss the relative contribution of both mechanisms to lymphomagenesis and possible implications of NER downregulation for other types of malignancies and for B cell-mediated immunity. Given that hematopoietic cancer stem cells remain quiescent for long periods of time, we propose that downregulation of NER during quiescence, in an environment that causes both genotoxic stress and proliferation, could be a general mechanism for carcinogenesis. PMID- 21701263 TI - The RNA surveillance protein SMG1 activates p53 in response to DNA double-strand breaks but not exogenously oxidized mRNA. AB - DNA damage, stalled replication forks, errors in mRNA splicing, and availability of nutrients activate specific phosphatidylinositiol-3 kinase-like kinases (PIKKs) that in turn phosphorylate downstream targets such as p53 on serine 15. While the PIKK proteins ATM and ATR respond to specific DNA lesions, SMG1 responds to errors in mRNA splicing and when cells are exposed to genotoxic stress. Yet, whether genotoxic stress activates SMG1 through specific types of DNA lesions or RNA damage remains poorly understood. Here, we demonstrate that siRNA oligonucleotides targeting the mRNA surveillance proteins SMG1, Upf1, Upf2, or the PIKK protein ATM attenuated p53 (ser15) phosphorylation in cells damaged by high oxygen (hyperoxia), a model of persistent oxidative stress that damages nucleotides. In contrast, loss of SMG1 or ATM, but not Upf1 or Upf2 reduced p53 (ser15) phosphorylation in response to DNA double strand breaks produced by expression of the endonuclease I-PpoI. To determine whether SMG1-dependent activation of p53 was in response to oxidative mRNA damage, mRNA encoding green fluorescence protein (GFP) transcribed in vitro was oxidized by Fenton chemistry and transfected into cells. Although oxidation of GFP mRNA resulted in dose dependent fragmentation of the mRNA and reduced expression of GFP, it did not stimulate p53 or the p53-target gene p21. These findings establish SMG1 activates p53 in response to DNA double-strand breaks independent of the RNA surveillance proteins Upf1 or Upf2; however, these proteins can stimulate p53 in response to oxidative stress but not necessarily oxidized RNA. PMID- 21701264 TI - A dual role for A-type lamins in DNA double-strand break repair. AB - A-type lamins are emerging as regulators of nuclear organization and function. Changes in their expression are associated with cancer and mutations are linked to degenerative diseases -laminopathies-. Although a correlation exists between alterations in lamins and genomic instability, the molecular mechanisms remain largely unknown. We previously found that loss of A-type lamins leads to degradation of 53BP1 protein and defective long-range non-homologous end-joining (NHEJ) of dysfunctional telomeres. Here, we determined how loss of A-type lamins affects the repair of short-range DNA double-strand breaks (DSBs) induced by ionizing radiation (IR). We find that lamins deficiency allows activation of the DNA damage response, but compromises the accumulation of 53BP1 at IR-induced foci (IRIF), hindering the fast phase of repair corresponding to classical-NHEJ. Importantly, reconstitution of 53BP1 is sufficient to rescue long-range and short range NHEJ. Moreover, we demonstrate an unprecedented role for A-type lamins in the maintenance of homologous recombination (HR). Depletion of lamins compromises HR by a mechanism involving transcriptional downregulation of BRCA1 and RAD51 by the repressor complex formed by the Rb family member p130 and E2F4. In line with the DNA repair defects, lamins-deficient cells exhibit increased radiosensitivity. This study demonstrates that A-type lamins promote genomic stability by maintaining the levels of proteins with key roles in DNA DSBs repair by NHEJ and HR. Our results suggest that silencing of A-type lamins by DNA methylation in some cancers could contribute to the genomic instability that drives malignancy. In addition, lamins-deficient tumor cells could represent a good target for radiation therapy. PMID- 21701265 TI - Spinal anesthesia failure after local anesthetic injection into cerebrospinal fluid: a multicenter prospective analysis of its incidence and related risk factors in 1214 patients. AB - BACKGROUND AND OBJECTIVES: Different mechanisms have been proposed to explain spinal anesthesia failure even after LA injection into the subarachnoid space. The aim of this prospective multicenter study was to assess the incidence of spinal anesthesia failure, excluding technical problems, and then to suggest independent factors leading to failure. METHODS: Consecutive spinal anesthetic procedures performed in 21 centers were included. Exclusion criteria were contraindications to spinal anesthesia and technical difficulties. Primary end point was the calculation of failure incidence. Factors leading to spinal anesthesia failure were investigated. RESULTS: One thousand two hundred fourteen spinals were included. Failure rate, reported by 17 of 21 centers, was 3.2% (95% confidence interval [CI], 2.2-4.2). A total failure (no sensory block) was noted in 41% of the 39 cases of failed block. Patients in the failure group were younger as compared with patients in the success group. Using backward logistic regression, factors associated with failure were the number of puncture attempts at 3 or more (odds ratio [OR], 2.86; 95% CI, 1.20-6.79) and the absence of the use of an adjuvant medication with the local anesthetic injected (OR, 2.32; 95% CI, 1.2-4.5). Age older than 70 years (OR, 0.3; 95% CI, 0.20-0.93) was associated with a decrease of failure. CONCLUSIONS: The results of this study showed that the incidence of spinal anesthesia failure was 3.2%. The number of puncture attempts at 3 or more and the absence of adjuvant medication associated with local anesthetic were independent factors associated with the increased risk of failure. The failure of spinal anesthesia was rare in patients older than 70 years. PMID- 21701266 TI - Patient perceptions of regional anesthesia: influence of gender, recent anesthesia experience, and perioperative concerns. AB - BACKGROUND AND OBJECTIVES: Anesthesiologists often find that patients would prefer a general anesthetic (GA) to a regional anesthetic (RA) for surgery. We surveyed patients' attitudes to RA in an Australian tertiary-care hospital, hoping to understand the reasons for acceptance or refusal. We explored how 3 main factors influence the patient's choice for subsequent RA: gender, type of anesthetic on the day of surgery, and perioperative concerns. METHODS: Consecutive patients at a single institution were interviewed on the first postoperative day by a research nurse, either as a face-to-face interview or by telephone after ambulatory surgery. A short description of RA and GA was given, and preferences for future anesthesia and concerns were recorded. RESULTS: Complete data were obtained from 1000 patients. More women preferred GA compared with men (76.3% vs 69.0%). Patients who received only RA during their surgery on the previous day were almost 3 times more likely to express a future preference for RA compared with those who received any GA, using hypothetical examples of arm or hip surgery (83.2% vs 21.1%, P = 0.00001). Patients expressed more concerns about hearing or seeing the surgery than experiencing a complication, and 84% preferred sedation. CONCLUSIONS: More patients, especially females, may accept RA if reassured appropriately about not hearing or seeing the surgery. Once patients have experienced RA, they are more likely to choose it in future. Modification of our discussion and consent process may increase the uptake of RA techniques. PMID- 21701267 TI - Midazolam activates the intrinsic pathway of apoptosis independent of benzodiazepine and death receptor signaling. AB - BACKGROUND AND OBJECTIVES: Midazolam has neurotoxic properties when administered neuraxially in vivo. Furthermore, midazolam induces neurodegeneration in neonatal animal models in combination with other general anesthetics. Therefore, this study focuses on the mechanism of neurotoxicity by midazolam in neuronal and nonneuronal cells. The study aims to evaluate the apoptotic pathway and to investigate the protective effects of the benzodiazepine antagonist flumazenil and the caspase inhibitor N-(2-quinolyl)valyl-aspartyl-(2,6-difluorophenoxy) methylketone. METHODS: The apoptosis-inducing effect of preservative-free midazolam on human lymphoma and neuroblastoma cell lines was evaluated using flow cytometric analysis of early apoptotic stages (annexin V/7AAD) and caspase 3 activation. B-cell lymphoma (Bcl2) protein overexpressing and caspase 9-deficient lymphoma cells were used to determine the role of the mitochondrial (intrinsic) pathway. Caspase 8-deficient and Fas-associated protein with death domain (FADD) deficient cells were used to evaluate the death receptor (extrinsic) pathway. The protective effects of flumazenil and the caspase inhibitor N-(2-quinolyl)valyl aspartyl-(2,6-difluorophenoxy)-methylketone were investigated in neuroblastoma cells and primary rat neurons using metabolic activity assays (2,3-bis(2-methoxy 4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) and immunofluorescence microscopy. RESULTS: Midazolam induced apoptosis in all investigated cell types in a concentration-dependent manner, indicated by flow cytometry. Bcl2 overexpression and caspase 9 deficiency protected against toxicity, whereas caspase 8 or FADD deficiency had no effect. Pancaspase inhibition had a strong protective effect, whereas flumazenil did not inhibit midazolam-induced apoptosis. CONCLUSIONS: Midazolam induces apoptosis via activation of the mitochondrial pathway in a concentration-dependent manner. The mechanism of midazolam toxicity switches from caspase-dependent apoptosis to necrosis with increasing concentrations. The induction of apoptosis and necrosis by midazolam is presumably unrelated to GABAA receptor pathway signaling. PMID- 21701268 TI - Short-term effects of hypertonic saline solution in acute heart failure and long term effects of a moderate sodium restriction in patients with compensated heart failure with New York Heart Association class III (Class C) (SMAC-HF Study). AB - INTRODUCTION: Hypertonic saline solution (HSS) and a moderate Na restriction plus high furosemide dose showed beneficial effects in compensated heart failure (HF), in short and long terms. The study was aimed to verify the effects of this combination on hospitalization time, readmissions and mortality in patients in New York Heart Association (NYHA) class III. METHOD: Chronic ischemic or nonischemic cardiomyopathy uncompensated patients with HF in NYHA III functional class with ejection fraction <40%, serum creatinine <2.5 mg/dL, blood urea nitrogen <60 mg/dL and reduced urinary volume were single-blind randomized in 2 groups: the first group received a 30-minute intravenous infusion of furosemide (250 mg) plus HSS (150 mL) twice daily and a moderate Na restriction (120 mmol); the second group received furosemide intravenous bolus (250 mg) twice a day, without HSS and a low Na diet (80 mmol); both groups received a fluid intake of 1000 mL/d. After discharge, the HSS group continued with 120 mmol Na/d; the second group continued with 80 mmol Na/d. RESULTS: A total of 1771 patients (881 HSS group and 890 without HSS group) met inclusion criteria: the first group (881 patients), compared with the second (890 patients), showed an increase in diuresis and serum Na levels, a reduction in hospitalization time (3.5 + 1 versus 5.5 + 1 days, P < 0.0001) and, during follow-up (57 + 15 months), a lower rate in readmissions (18.5% versus 34.2%, P < 0.0001) and mortality (12.9% versus 23.8%, P < 0.0001); the second group also showed a significant increase in blood urea nitrogen and serum creatinine. CONCLUSION: This study suggests that in-hospital HSS administration, combined with moderate Na restriction, reduces hospitalization time and that a moderate sodium diet restriction determines long term benefit in patients with NYHA class III HF. PMID- 21701269 TI - Hashimoto's ophthalmopathy. AB - The authors reported 2 cases of Hashimoto's ophthalmopathy. These cases presented with no preceding illness; euthyroid state; acute presentation of painful or painless ophthalmoplegia, preferentially affecting the lateral rectus muscles; positive antithyroglobulin/antithyroid peroxidase antibodies and good responses to steroid treatment. Awareness of this atypical form of ophthalmopathy is important, as glucocorticoid treatment results in a significant improvement of this disorder. PMID- 21701270 TI - Levitronix CentriMag third-generation magnetically levitated continuous flow pump as bridge to solution. AB - The Levitronix CentriMag (Levitronix LLC, Waltham, MA) ventricular assist device (VAD) is a magnetically levitated rotary pump designed for temporary extracorporeal support. Between February 2004 and May 2010, 42 consecutive adult patients were supported with Levitronix at our institution (32 men; age 62.3 +/- 10.5 years, range: 31-76 years). Indications for support were (group A, n = 37) failure to wean from the cardiopulmonary bypass in the setting of postcardiotomy (n = 23), primary donor graft failure (n = 4), or right ventricular failure after axial left VAD (LVAD) placement (n = 10) and (group B, n = 5) refractory heart failure after acute myocardial infarction. The mean support time was 11.2 +/- 6.8 days (range: 3-43 days) in group A and 8.6 +/- 4.3 days (range: 5-11 days) in group B. In the postcardiotomy cohort (group A), 11 (47.8%) patients were weaned from support as all were supported graft failure patients. Eight patients of axial LVAD cohort were weaned from right VAD (RVAD). One patient was bridged to heart transplantation (Htx). Thirteen (35.1%) patients died on support in group A. In group B, one patient was bridged to Htx and four died on support. In overall population, bleeding requiring reoperation occurred in 15 (35.7%) cases and cerebral major events in four (9.5%). There were no device failures. Of the 23 (54.7%) patients who recovered and were discharged home, 20 (47.6%) are presently alive, and additionally, two patients of both groups who were bridged to Htx (overall n = 22, 52.3%). The Levitronix proved to be useful in patients previously considered nonsuitable for transplantation or long-term assist device. The device was technically easy to manage, and the results were encouraging. PMID- 21701271 TI - Development of endovascular vibrating polymer actuator probe for mechanical thrombolysis: a phantom study. AB - In this study, we propose a new method for enhancement of intraarterial thrombolysis using an ionic polymer-metal composite (IPMC) actuator. The purpose of this study was to test the mechanical thrombolysis efficiency of IPMC actuators and evaluate the endovascular vibrating polymer actuator probe for mechanical thrombolysis in a phantom model; 2 * 1 * 15 mm (2 mm in width, 1 mm in thickness, and 15 mm in length) and 0.8 * 0.8 * 10 mm (0.8 mm in width, 0.8 mm in thickness, and 10 mm in length) IPMC actuators were fabricated by stacking five and four Nafion-117 films, respectively. We manufactured the endovascular vibrating polymer actuator probe, for which thrombolysis efficiency was tested in a vascular phantom. The phantom study using 2 * 1 * 15 mm IPMC actuators showed that 5 Hz actuation is the optimal frequency for thrombolysis under both 2 and 3 V, when blood clot was not treated with rtPA, and when exposed to rtPA, IPMC actuators under the optimized condition (3 V, 5 Hz, and 5 min) significantly increased the thrombolysis degree compared with control and other experimental groups (p < 0.05). In addition, 0.8 * 0.8 * 10 mm IPMC actuators also revealed a significantly higher thrombolysis degree under the optimized condition than the control and rtPA only groups (p < 0.05). Finally, the fabricated probe using 0.8 * 0.8 * 10 mm IPMC actuators also incurred higher thrombolysis degree under the optimized condition than the control and rtPA only groups (p < 0.05). A vibrating polymer actuator probe is a feasible device for intravascular thrombolysis, and further study in an animal model is warranted. PMID- 21701272 TI - Predicting three-year kidney graft survival in recipients with systemic lupus erythematosus. AB - Predicting the outcome of kidney transplantation is important in optimizing transplantation parameters and modifying factors related to the recipient, donor, and transplant procedure. As patients with end-stage renal disease (ESRD) secondary to lupus nephropathy are generally younger than the typical ESRD patients and also seem to have inferior transplant outcome, developing an outcome prediction model in this patient category has high clinical relevance. The goal of this study was to compare methods of building prediction models of kidney transplant outcome that potentially can be useful for clinical decision support. We applied three well-known data mining methods (classification trees, logistic regression, and artificial neural networks) to the data describing recipients with systemic lupus erythematosus (SLE) in the US Renal Data System (USRDS) database. The 95% confidence interval (CI) of the area under the receiver operator characteristic curves (AUC) was used to measure the discrimination ability of the prediction models. Two groups of predictors were selected to build the prediction models. Using input variables based on Weka (a open source machine learning software) supplemented with additional variables of known clinical relevance (38 total predictors), the logistic regression performed the best overall (AUC: 0.74, 95% CI: 0.72-0.77)-significantly better (p < 0.05) than the classification trees (AUC: 0.70, 95% CI: 0.67-0.72) but not significantly better (p = 0.218) than the artificial neural networks (AUC: 0.71, 95% CI: 0.69-0.73). The performance of the artificial neural networks was not significantly better than that of the classification trees (p = 0.693). Using the more parsimonious subset of variables (six variables), the logistic regression (AUC: 0.73, 95% CI: 0.71-0.75) did not perform significantly better than either the classification tree (AUC: 0.70, 95% CI: 0.68-0.73) or the artificial neural network (AUC: 0.73, 95% CI: 0.70-0.75) models. We generated several models predicting 3-year allograft survival in kidney transplant recipients with SLE that potentially can be used in practice. The performance of logistic regression and classification tree was not inferior to more complex artificial neural network. Prediction models may be used in clinical practice to identify patients at risk. PMID- 21701273 TI - Effectiveness of an audience response system in teaching pharmacology to baccalaureate nursing students. AB - It has been proposed that students' use of an audience response system, commonly called clickers, may promote comprehension and retention of didactic material. Whether this method actually improves students' grades, however, is still not determined. The purpose of this study was to evaluate whether a lecture format utilizing multiple-choice PowerPoint slides and an audience response system was more effective than a lecture format using only multiple-choice PowerPoint slides in the comprehension and retention of pharmacological knowledge in baccalaureate nursing students. The study also assessed whether the additional use of clickers positively affected students' satisfaction with their learning. Results from 78 students who attended lecture classes with multiple-choice PowerPoint slides plus clickers were compared with those of 55 students who utilized multiple-choice PowerPoint slides only. Test scores between these two groups were not significantly different. A satisfaction questionnaire showed that 72.2% of the control students did not desire the opportunity to use clickers. Of the group utilizing the clickers, 92.3% recommend the use of this system in future courses. The use of multiple-choice PowerPoint slides and an audience response system did not seem to improve the students' comprehension or retention of pharmacological knowledge as compared with those who used solely multiple-choice PowerPoint slides. PMID- 21701274 TI - Creating teaching objects: a case study of delivering recorded narrations in nursing education. AB - This article evaluates the use of PowerPoint presentations and recorded narrations (developed and saved as Flash content using software called Articulate Presenter) as a tool to help postgraduate nursing students taking a pharmacology course to learn key pharmacological and pharmacotherapeutic concepts. Students found that the teaching objects, provided as additional resources to assist students in learning about difficult concepts, supported them in their learning. Additionally, students reported that while they appreciated the provision of the teaching objects, the objects lacked an interactive component and did not replace interaction with the teacher. Articulate Presenter, as a tool to create a recorded narration, was easy for the teacher to use and promoted teacher independence in the creation of teaching objects. PMID- 21701275 TI - Nursing education enhanced by informatics. PMID- 21701276 TI - Notes from the net nomad... PMID- 21701277 TI - Comparing the teaching-learning process with and without the use of computerized technological resources. AB - Computerized technological resources have become essential in education, particularly for teaching topics that require the performance of specific tasks. These resources can effectively help the execution of such tasks and the teaching learning process itself. After the development of a Web site on the topic of nursing staff scheduling, this study aimed at comparing the development of students involved in the teaching-learning process of the previously mentioned topic, with and without the use of computer technology. Two random groups of undergraduate nursing students from a public university in Sao Paulo state, Brazil, were organized: a case group (used the Web site) and a control group (did not use the Web site). Data were collected from 2003 to 2005 after approval by the Research Ethics Committee. Results showed no significant difference in motivation or knowledge acquisition. A similar performance for the two groups was also verified. Other aspects observed were difficulty in doing the nursing staff scheduling exercise and the students' acknowledgment of the topic's importance for their training and professional lives; easy access was considered to be a positive aspect for maintaining the Web site. PMID- 21701278 TI - Using M-learning on nursing courses to improve learning. AB - Modern handheld devices and wireless communications foster new kinds of communication and interaction that can define new approaches to teaching and learning. Mobile learning (m-learning) seeks to use them extensively, exactly in the same way in which e-learning uses personal computers and wired communication technologies. In this new mobile environment, new applications and educational models need to be created and tested to confirm (or reject) their validity and usefulness. In this article, we present a mobile tool aimed at self-assessment, which allows students to test their knowledge at any place and at any time. The degree to which the students' achievement improved is also evaluated, and a survey on the students' opinion of the new tool was also conducted. An experimental group of 20- to 21-year-old nursing students was chosen to test the tool. Results show that this kind of tool improves students' achievement and does not make necessary to introduce substantial changes in current teaching activities and methodology. PMID- 21701279 TI - Exercise during pregnancy: developmental origins of disease prevention? PMID- 21701280 TI - Seeking the fountain of youth. PMID- 21701281 TI - Performance and fatigue during repeated sprints: what is the appropriate sprint dose? AB - When testing the ability of sportsmen to repeat maximal intensity efforts, or when designing specific training exercises to improve it, fatigue during repeated sprints is usually investigated through a number of sprints identical for all subjects, which induces a high intersubject variability in performance decrement in a typical heterogeneous group of athletes (e.g., team sport group, students, and research protocol volunteers). Our aim was to quantify the amplitude of the reduction in this variability when individualizing the sprint dose, that is, when requiring subjects to perform the number of sprints necessary to reach a target level of performance decrement. Fifteen healthy men performed 6-second sprints on a cycle ergometer with 24 seconds of rest until exhaustion or until 20 repetitions in case no failure occurred. Peak power output (PPO) was measured and a fatigue index (FI) computed. The variability in PPO decrement was compared between the 10th sprint and the sprint at which subject reached the target FI of 10%. Individual FI values after the 10th sprint were 14.6 +/- 6.9 vs. 11.1 +/- 1.2%, when individualizing the sprint dose, which corresponded to coefficients of interindividual variability of ~47.3 and ~10.8%, respectively. Individualizing the sprint dose substantially reduced intersubject variability in performance decrement, enabling a more standardized state of fatigue in repeated-sprints protocols designed to induce fatigue and test or train this specific repeated sprint ability in a heterogeneous group of athletes. A direct feedback on the values of performance parameters is necessary between each sprint for the experimenter to set this individualized sprint dose. PMID- 21701282 TI - The acute effects of a warm-up including static or dynamic stretching on countermovement jump height, reaction time, and flexibility. AB - The purpose of this research was to compare the effects of a warm-up with static vs. dynamic stretching on countermovement jump (CMJ) height, reaction time, and low-back and hamstring flexibility and to determine whether any observed performance deficits would persist throughout a series of CMJs. Twenty-one recreationally active men (24.4 +/- 4.5 years) completed 3 data collection sessions. Each session included a 5-minute treadmill jog followed by 1 of the stretch treatments: no stretching (NS), static stretching (SS), or dynamic stretching (DS). After the jog and stretch treatment, the participant performed a sit-and-reach test. Next, the participant completed a series of 10 maximal-effort CMJs, during which he was asked to jump as quickly as possible after seeing a visual stimulus (light). The CMJ height and reaction time were determined from measured ground reaction forces. A treatment * jump repeated-measures analysis of variance for CMJ height revealed a significant main effect of treatment (p = 0.004). The CMJ height was greater for DS (43.0 cm) than for NS (41.4 cm) and SS (41.9 cm) and was not less for SS than for NS. Analysis also revealed a significant main effect of jump (p = 0.005) on CMJ height: Jump height decreased from the early to the late jumps. The analysis of reaction time showed no significant effect of treatment. Treatment had a main effect (p < 0.001) on flexibility, however. Flexibility was greater after both SS and DS compared to after NS, with no difference in flexibility between SS and DS. Athletes in sports requiring lower-extremity power should use DS techniques in warm-up to enhance flexibility while improving performance. PMID- 21701283 TI - Smith machine counterbalance system affects measures of maximal bench press throw performance. AB - Equipment with counterbalance weight systems is commonly used for the assessment of performance in explosive resistance exercise movements, but it is not known if such systems affect performance measures. The purpose of this study was to determine the effect of using a counterbalance weight system on measures of smith machine bench press throw performance. Ten men and 14 women (mean +/- SD: age, 25 +/- 4 years; height, 173 +/- 10 cm; weight, 77.7 +/- 18.3 kg) completed maximal smith machine bench press throws under 4 different conditions (2 * 2; counterbalance * load): with or without a counterbalance weight system and using 'light' or 'moderate' net barbell loads. Performance variables (peak force, peak velocity, and peak power) were measured using a linear accelerometer attached to the barbell. The counterbalance weight system resulted in significant (p < 0.001) reductions in measures of peak force (mean difference +/- standard error: light: 112 +/- 20 N; moderate: -140 +/- 23 N), peak velocity (light: -0.49 +/- 0.10 m.s; moderate: -0.33 +/- 0.07 m.s), and peak power (light: -220 +/- 43 W; moderate: 143 +/- 28 W) compared with no counterbalance system for both load conditions. Load condition did not affect absolute or percentage reductions from the counterbalance weight system for any variable. In conclusion, the use of a counterbalance weight system reduces accelerometer-based performance measures for the bench press throw exercise at light and moderate loads. This reduction in measures is likely because of an increase in the external resistance during the movement, which results in a discrepancy between the manually input and the actual value for external load. A counterbalance weight system should not be used when measuring performance in explosive resistance exercises with an accelerometer. PMID- 21701284 TI - The ratio and allometric scaling of speed, power, and strength in elite male rugby union players. AB - This study compared the effectiveness of ratio and allometric scaling for normalizing speed, power, and strength in elite male rugby union players. Thirty rugby players (body mass [BM] 107.1 +/- 10.1 kg, body height [BH] 187.8 +/- 7.1 cm) were assessed for sprinting speed, peak power during countermovement jumps and squat jumps, and horizontal jumping distance. One-repetition maximum strength was assessed during a bench press, chin-up, and back squat. Performance was normalized using ratio and allometric scaling (Y/X), where Y is the performance, X, the body size variable (i.e., BM or BH), and b is the power exponent. An exponent of 1.0 was used during ratio scaling. Allometric scaling was applied using proposed exponents and derived exponents for each data set. The BM and BH variables were significantly related, or close to, performance during the speed, power and/or strength tests (p < 0.001-0.066). Ratio scaling and allometric scaling using proposed exponents were effective in normalizing performance (i.e., no significant correlations) for some of these tests. Allometric scaling with derived exponents normalized performance across all the tests undertaken, thereby removing the confounding effects of BM and BH. In terms of practical applications, allometric scaling with derived exponents may be used to normalize performance between larger rugby forwards and smaller rugby backs, and could provide additional information on rugby players of similar body size. Ratio scaling may provide the best predictive measure of performance (i.e., strongest correlations). PMID- 21701285 TI - Which measure of drop jump performance best predicts sprinting speed? AB - The purpose of this study was to evaluate which measure of a drop jump (DJ) has the highest correlation with sprinting speed over 60 m. For use of comparison, maximal leg strengths in a front squat, countermovement jump, and squat jump were also assessed. The subjects in the study were all high-caliber female university rugby players. Subjects did DJs from 0.12, 0.24, 0.36, 0.48, 0.60, 0.72, and 0.84 m. Jump height and reactive strength index (RSI) were calculated at each drop height. Pearson correlations were used to analyze the relationship between the strength and jumping measures with sprinting speed. The DJ height from 0.84 m had the highest negative correlation with 0- to 10-m split (r = -0.66), the 10- to 30 m split (r = -0.86) and 30- to 60-m split (r = -0.86). The use of RSI is questioned as a measurement of DJ performance. It is suggested that maximal height achieved in a DJ is the most important DJ measure. If it is desired to measure ground contact time, then it may be more useful to use a second test where the jump height for the athlete is set by having the athlete jump onto a box or touch a target overhead set at a standard height and measure the ground contact time with a switch mat or force plate. PMID- 21701286 TI - Rapid hamstring/quadriceps force capacity in male vs. female elite soccer players. AB - Knee joint injuries are a serious issue in soccer. The ability to protect the knee from injury depends largely on the strength of the hamstring relatively to the quadriceps, that is, a low hamstring/quadriceps (H/Q) strength ratio is suggested as a risk factor. Although maximal muscle strength (MVC) has often been used to evaluate the H/Q ratio, the ability to rapidly develop force (rate of force development [RFD]) is more relevant in relation to fast dynamic movements. The aim of this study was to introduce and investigate a rapid RFD H/Q strength ratio compared with the traditional MVC H/Q strength ratio in elite soccer players. Twenty-three elite soccer players (11 women, 12 men) performed maximal voluntary static contraction for the hamstring and quadriceps in an isokinetic dynamometer, from which the maximal muscles strength (MVC) and RFD were extracted. Test-retest reliability for the RFD H/Q ratio was high (intraclass correlation coefficient = 0.664-0.933). The initial contraction phase up to 50 milliseconds from the onset of contraction showed a low RFD H/Q ratio compared to the MVC H/Q ratio (p < 0.001). These results suggest a reduced potential for knee joint stabilization during the very initial phase of muscle contraction. Two female players-both with a markedly low RFD H/Q ratio, but a normal MVC H/Q ratio, compared with the group mean-sustained ACL rupture at a later occasion. The high reliability of the new RFD H/Q strength ratio indicates that the method is a relevant tool in standardized clinical evaluation of the knee joint agonist antagonist relationship. PMID- 21701287 TI - Time course of strength and power recovery after resistance training with different movement velocities. AB - The purpose of this study was to evaluate the time course of strength and power recovery after a single bout of strength training designed with fast and slow contraction velocities. Nineteen male subjects were randomly divided into 2 groups: the slow-velocity contraction (SV) group and the fast velocity contraction (FV) group. Resistance training protocols consisted of 5 sets of 12 repetition maximum (5 * 12RM) with 50 seconds of rest between sets and 2 minutes between exercises. Contraction velocity was controlled by the execution time for each repetition (SV-6 seconds to complete concentric and eccentric phases and for FV-1.5 seconds). Leg Press 45 degrees 1RM (LP 1RM), horizontal countermovement jump (HCMJ), and right thigh circumference (TC) were accessed in 6 distinct moments: base (1 week before exercise), 0 (immediately after exercises), 24, 48, 72, and 96 hours after exercise protocol. The SV and FV presented significant LP 1RM decrements at 0, and these were still evident 24-48 hours postexercise. The magnitude of decline was significantly (p < 0.05) higher for FV. The SV and FV presented significant HCMJ decrements at 0, but only for FV were these still evident 24-72 hours postexercise. The SV and FV presented significant TC increments at 0, and these were still evident 24-48 hours postexercise for SV but for FV it continued up to 96 hours. The magnitude of increase was significantly (p < 0.05) higher for FV. In conclusion, the fast contraction velocity protocol resulted in greater decreases in LP 1RM and HCMJ performance, when compared with slow velocity. The results lead us to interpret that this variable may exert direct influence on acute muscle strength and power generation capacity. PMID- 21701288 TI - Validity of two methods for estimation of vertical jump height. AB - The objectives of this study were (a) to determine the concurrent validity of the flight time (FT) and double integration of vertical reaction force (DIF) methods in the estimation of vertical jump height with the video method (VID) as reference; (b) to verify the degree of agreement among the 3 methods; (c) to propose regression equations to predict the jump height using the FT and DIF. Twenty healthy male and female nonathlete college students participated in this study. The experiment involved positioning a contact mat (CTM) on the force platform (FP), with a video camera 3 m from the FP and perpendicular to the sagittal plane of the subject being assessed. Each participant performed 15 countermovement jumps with 60-second intervals between the trials. Significant differences were found between the jump height obtained by VID and the results with FT (p <= 0.01) and DIF (p <= 0.01), showing that the methods are not valid. Additionally, the DIF showed a greater degree of agreement with the reference method than the FT did, and both presented a systematic error. From the linear regression test was determined the prediction equations with a high degree of linearity between the methods VID vs. DIF (R = 0.988) and VID vs. FT (R = 0.979). Therefore, the prediction equations suggested may allow coaches to measure the vertical jump performance of athletes by the FT and DIF, using a CTM or an FP, which represents more practical and viable approaches in the sports field; comparisons can then be made with the results of other athletes evaluated by VID. PMID- 21701289 TI - Myoelectric activation and kinetics of different plyometric push-up exercises. AB - The kinetic and myoelectric differences between 3 types of plyometric push-ups were investigated. Twenty-seven healthy, physically active men served as subjects and completed both familiarization and testing sessions. During these sessions, subjects performed 2 series of 3 plyometric push-up variations in a counterbalanced order according to the following techniques: Countermovement push ups (CPUs) were push-ups performed with the maximum speed of movement; jump push ups (JPUs) were similar to clapping push-ups; and fall push-ups (FPUs) required kneeling subjects to drop and then attempt to return to their initial position. Vertical ground reaction forces were determined by using a force plate. Myoelectric activity was recorded by means of electromyography. Impact force and impact rate of force development were significantly (p < 0.05) higher for FPUs than for JPUs. The maximum rate of force development was higher for CPUs (p < 0.05) than for JPUs, and the maximum force was higher for the CPUs than for the FPUs (p < 0.05). There were differences among exercises for the mean muscle activation of the pectoralis major (PM; p < 0.001), triceps brachii (p < 0.001), external oblique (p < 0.005) and anterior deltoid (p < 0.001), and in the maximum muscle activation of the PM (p < 0.001). Plyometric push-ups with countermovement achieved a higher maximum force and rate of force and did not cause impact forces. Thus, this type of push-up exercise may be regarded as the best for improving explosive force. The FPU exercise achieved higher levels of muscular activation in the agonist and synergist muscle groups, and greater impact forces and impact force development rates. PMID- 21701290 TI - Exercise intensity and pacing strategy of a 5-km indoor race walk during a World Record attempt: a case study. AB - The aim of this case study was to describe the physiological and regulatory processes, by means of heart rate (HR) monitoring and pacing strategy, in a top level race walker (age: 32 years; height: 1.76 m; body mass: 62 kg; training volume: 130-150 km.wk) who was focused on the attainment of the 5-km indoor race walk (RW) World Record. The HRmean was 185 +/- 14.9 b.min, with an HRmean/HRmax ratio of 0.96. Almost the whole race (91.8%) was performed to an intensity >=90% of the HRmax; lower intensity work was negligible (8.1%). The race profile was a reverse J-shaped pacing curve; in fact, the athlete completed the first 1,000 m in the fastest time, slowing during the middle 3,000 m, and increasing the speed during the final 1,000 m of the race. Despite the attempt failed (the athlete performed only the 2009 World leading performance, 18 minutes 23 seconds 47 tenths), these data suggest that a more linear strain distribution for the entire performance would be optimal instead of a fast-start strategy, which leads to a drastic decrement of the walking velocity. Moreover, this study supports the use of HR monitoring combined with the regulation of the effort to understand the physiological and regulatory processes during an indoor RW event. PMID- 21701291 TI - Tendon disorders of the hand. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Make decisions on flexor tendon repair based on current evidence. 2. Perform some important tendon transfers after viewing Dr. Kozin's videos. 3. Inject local anesthesia for wide-awake flexor tendon repair after viewing the appropriate videos in the article. 4. Use relative motion extension splints for the postoperative management of extensor tendon injuries. SUMMARY: This article provides a practical, clinically useful overview of some of the current best techniques and evidence available to the plastic surgeon in the treatment of flexor and extensor tendon injuries, tendon transfers, trigger fingers, mallet fingers, boutonniere deformities, and De Quervain tenosynovitis. Twelve short movies and drawings emphasize important points of diagnosis and treatment of tendon disorders. PMID- 21701292 TI - Discussion: Managing late periprosthetic fluid collections (seroma) in patients with breast implants: a consensus panel recommendation and review of the literature. PMID- 21701293 TI - Discussion: Managing late periprosthetic fluid collections (seroma) in patients with breast implants: a consensus panel recommendation and review of the literature. PMID- 21701295 TI - Brain plasticity after unilateral reconstruction in Mobius syndrome. PMID- 21701294 TI - Discussion: Managing late periprosthetic fluid collections (seroma) in patients with breast implants: a consensus panel recommendation and review of the literature. PMID- 21701296 TI - Reconstruction of cerebrospinal fluid leakage on the occipital region of the head with the pedicled pectoralis major myocutaneous flap. PMID- 21701297 TI - Sequential second free flap for head and neck reconstruction in a patient with fanconi anemia and metachronous squamous cell carcinoma. PMID- 21701298 TI - The Superficial Nasalis Aponeurotic System (SNAS) flap for nasal tip reconstruction. PMID- 21701299 TI - A biocompatible silicone framework for external ear reconstruction using a phosphorylcholine coating. PMID- 21701300 TI - Preoperative modeling of costal cartilage for the auricular reconstruction of microtia. PMID- 21701301 TI - Use of botulinum toxin (botox) in the management of masseter muscle hypertrophy: a simplified technique. PMID- 21701302 TI - Discussion: Diagnosis and management of seroma following breast augmentation: an update. PMID- 21701303 TI - Comparing clinical efficacy of botox and dysport in a small group of patients. PMID- 21701304 TI - Spectrum of imaging findings in the silicone-injected breast. PMID- 21701305 TI - Discussion: Diagnosis and management of seroma following breast augmentation: an update. PMID- 21701306 TI - The SGAP flap in breast reconstruction: backup or first choice? PMID- 21701307 TI - Novel use of acellularized dermis for breast reconstruction. PMID- 21701308 TI - A successful salvage protocol for breast implants. PMID- 21701309 TI - The role of postoperative antibiotics in reducing biofilm-related capsular contracture in augmentation mammaplasty. PMID- 21701310 TI - Accessory breast tissue in the axilla: classification and treatment. PMID- 21701311 TI - Lone star retractor for pediatric hand surgery. PMID- 21701312 TI - Francisella tularensis osteomyelitis of the hand following a cat bite: a case of clinical suspicion. PMID- 21701313 TI - German standardized translation of the michigan hand outcomes questionnaire for patient-related outcome measurement in Dupuytren disease. PMID- 21701314 TI - Comparison of meshed versus MEEK micrografted skin expansion rate: claimed, achieved, and polled results. PMID- 21701315 TI - The shield protection technique for microvascular anastomoses. PMID- 21701316 TI - Discussion: Immediate free flap reconstruction of advanced-stage breast cancer: is it safe? PMID- 21701317 TI - Micro-seed grant funding for residents: fostering academic productivity in plastic surgery. PMID- 21701318 TI - Ultrasound-guided bilateral transversus abdominis plane block for postoperative analgesia after breast reconstruction by DIEP flap. AB - BACKGROUND: Autologous breast reconstruction by deep inferior epigastric perforator (DIEP) flap provides higher postoperative pain at the abdominal donor site than at the thoracic one. The authors evaluated the analgesic efficacy of ultrasound-guided transverse abdominis plane block for postoperative analgesia after immediate breast reconstruction by DIEP flap. METHODS: The authors conducted an open prospective study of 30 consecutive women undergoing immediate DIEP flap breast reconstruction after modified radical mastectomy for cancer. The last 15 patients received a bilateral ultrasound-guided block with 1.5 mg/kg ropivacaine on each side after DIEP flap harvesting, under general anesthesia. All patients received postoperative acetaminophen and patient-controlled intravenous morphine and were assessed for morphine use, satisfaction with pain relief, and adverse effects. RESULTS: Morphine requirements were significantly lower in the block group than in the control group for the 0- to 12-hour (17.7 mg versus 22.7 mg, p = 0.0047) and 12- to 24-hour (14.2 mg versus 17.4 mg, p = 0.01) intervals but not for the 24- to 36-hour (11.3 mg versus 12.2 mg, p = 0.30) and 36- to 48-hour (8.6 mg versus 8.4 mg, p = 0.65) intervals. Cumulative morphine use was lower in the block group than in the control group for the first 24 hours (32.0 mg versus 40.2 mg, p = 0.0057) and the first 48 hours (51.7 mg versus 60.5 mg, p = 0.03). There was no complication attributable to the block, with an average follow-up of 9 months. CONCLUSIONS: Bilateral ultrasound-guided transversus abdominis plane block after breast reconstruction by DIEP flap reduces the interval and cumulative morphine requirements for the first 24 and 48 hours, respectively. CLINICAL QUESTION/LEVEL OF EVIDENCE: : Therapeutic, II.(Figure is included in full-text article.). PMID- 21701319 TI - Career steps in german academic plastic surgery. PMID- 21701320 TI - "Friending" Facebook? PMID- 21701321 TI - Contrast-enhanced magnetic resonance angiography for preoperative imaging in DIEP flap breast reconstruction. AB - BACKGROUND: Contrast-enhanced magnetic resonance angiography has been shown to be very accurate for identifying the perforator size, location, and intramuscular course, and the associated venous system, without exposing the patient to ionizing radiation. This study reports the authors' experience using this imaging modality in a large patient series. METHODS: A retrospective review of patients who had undergone preoperative contrast-enhanced magnetic resonance angiography followed by free abdominal flap breast reconstruction was conducted. The results of imaging were compared with intraoperative findings, and surgical outcomes were compared with scan data. The results were compared with control data in patients who did not undergo presurgical imaging. RESULTS: One hundred thirty-two patients underwent contrast-enhanced magnetic resonance angiography presurgical imaging, and the results were compared with 84 controls. The imaging was found to be accurate for evaluating the perforator anatomy for free abdominal flap planning, with a high concordance between imaging and intraoperative findings. Without presurgical angiography, the ratio of deep inferior epigastric perforator (DIEP) flap-to-free transverse rectus abdominis musculocutaneous flap harvest was 0.9:1; with presurgical imaging, the ratio was 1.6:1 (p < 0.05). With presurgical angiography, there was a mean reduction in operating time of 26 minutes for unilateral DIEP flap harvest and 40 minutes for bilateral harvest, although these values were not significant. There was a significant reduction in the partial flap failure rate with preoperative imaging. CONCLUSIONS: Presurgical imaging using contrast-enhanced magnetic resonance angiography demonstrates a high concordance with intraoperative findings. In this series, the percentage of flaps that were raised as DIEP flaps was significantly increased in patients who underwent preoperative imaging, and the partial flap failure rate was significantly reduced. CLINICAL QUESTION/LEVEL OF EVIDENCE: : Therapeutic, III.(Figure is included in full-text article.). PMID- 21701322 TI - An analysis of 277 consecutive latissimus dorsi breast reconstructions: a focus on capsular contracture. AB - BACKGROUND: Breast reconstruction by means of a latissimus dorsi myocutaneous flap in combination with a prosthesis is a well-established technique. Previous published series have highlighted significant rates of local complications, including capsular contracture. METHODS: A retrospective analysis of latissimus dorsi myocutaneous flap reconstructions performed between 2000 and 2010 was undertaken. A standardized preoperative, perioperative, and postoperative clinical protocol was applied to all cases, which included the use of textured, cohesive-gel silicone implants. RESULTS: Two hundred seventy-seven procedures were performed in 243 patients, with one-third being immediate reconstructions. The mean age at reconstruction was 50.4 years. Mean follow-up was 47 months, and 3.6 percent of patients developed Baker grade III capsular contracture requiring capsulotomy. Chemotherapy provided a protective effect (p = 0.0197) against capsular contracture formation. Previous radiotherapy had no significant influence on symptomatic capsule formation. The rate of infection requiring implant removal was 1.1 percent, and 0.7 percent of mastectomy scars showed evidence of recurrent disease. CONCLUSION: The use of textured, cohesive-gel silicone implants, combined with a standardized surgical approach, can reduce complications in the short- and long-term postoperative period, independent of radiotherapy. PMID- 21701323 TI - The scarless latissimus dorsi flap for full muscle coverage in device-based immediate breast reconstruction: an autologous alternative to acellular dermal matrix. AB - BACKGROUND: Thin patients have fewer autologous options in postmastectomy reconstruction and are frequently limited to device-based techniques. The latissimus dorsi flap remains a viable option with which to provide autologous coverage, although for certain patients the donor scar can be a point of contention. The scarless latissimus dorsi flap is a way of mitigating these concerns. The authors present their 6-year single-surgeon experience with scarless latissimus dorsi flap reconstruction. METHODS: A retrospective review of scarless latissimus dorsi flap reconstruction was performed. Charts from 2003 to 2009 were queried for demographic characteristics, nonoperative therapies, and short- and long-term complications. Results were compared with historical data. RESULTS: Thirty-one patients with 52 flaps were identified. Fifty-one flaps were immediate reconstructions, with an average age of 47 years and body mass index of 22.8 kg/m. Thirteen patients were treated with chemotherapy and four were irradiated, two preoperatively. The single drain was removed on average at 21 days. Complications included three hematomas (5.8 percent), two capsular contractures (3.8 percent), and two infections (3.8 percent). Average time to secondary reconstruction was 143 days. There were five unplanned revisions (9.6 percent). There were no flap failures or tissue expander losses. CONCLUSIONS: The scarless latissimus dorsi flap is an effective method for providing durable homogenous device coverage in the thinner patient (body mass index <24). With the advent of acellular dermal matrices, device coverage has been made simpler, but this comes at a cost. Coverage is thin, the matrix is not initially vascularized, and products are expensive. For these reasons, use of the scarless latissimus dorsi flap is an excellent alternative, particularly in the patient with a low body mass index. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.(Figure is included in full-text article.). PMID- 21701324 TI - Discussion: The scarless latissimus dorsi flap for full muscle coverage in device based immediate breast reconstruction: an autologous alternative to acellular dermal matrix. PMID- 21701325 TI - Molecular analysis of coronal perisutural tissues in a craniosynostotic rabbit model using polymerase chain reaction suppression subtractive hybridization. AB - BACKGROUND: In the United States, the incidence of craniosynostosis (premature fusion of the sutures of the cranial vault) is one in 2000 to 3000 live births. The condition can cause increased intracranial pressure, severely altered head shape, and mental retardation. The authors have previously described a colony of rabbits with heritable coronal suture synostosis. This model has been instrumental in describing the postsurgical craniofacial growth associated with craniosynostosis. The molecular analysis of this model has been limited by the lack of molecular tools for use in rabbits. To understand the pathogenesis of craniosynostosis, the authors compared gene expression in perisutural tissues between wild-type and craniosynostotic rabbits using polymerase chain reaction suppression subtractive hybridization. METHODS: Suppression subtractive hybridization polymerase chain reaction was performed on RNA derived from pooled samples of calvariae from 10-day-old wild-type (n = 3) and craniosynostotic (n = 3) rabbits to obtain cDNA clones enriched in either wild-type tissues (underexpressed in craniosynostotic tissue) or craniosynostotic tissues (overexpressed in craniosynostotic compared with wild-type). RESULTS: Differential expression was identified for approximately 140 recovered cDNA clones up-regulated in craniosynostotic tissues and 130 recovered clones for wild type tissues. Of these, four genes were confirmed by quantitative reverse transcriptase polymerase chain reaction as being overexpressed in craniosynostotic sutural tissue: beta-globin (HBB), osteopontin (SPP1), osteonectin (SPARC), and cathepsin K (CTSK). Two genes were confirmed to be underexpressed in the craniosynostotic samples: collagen 3, alpha 1 (COL3A1) and ring finger protein 12 (RNF12). CONCLUSION: The differential expression of these gene products in our naturally occurring craniosynostotic model appears to be the result of differences in the normal bone formation/resorption pathway. PMID- 21701326 TI - Comparative healing of human cutaneous surgical incisions created by the PEAK PlasmaBlade, conventional electrosurgery, and a standard scalpel. AB - BACKGROUND: The authors investigated thermal injury depth, inflammation, and scarring in human abdominal skin by comparing the histology of incisions made with a standard "cold" scalpel blade, conventional electrosurgery, and the PEAK PlasmaBlade, a novel, low-thermal-injury electrosurgical instrument. METHODS: Approximately 6 and 3 weeks before abdominoplasty, full-thickness incisions were created in the abdominal pannus skin of 20 women, using a scalpel (scalpel), the PlasmaBlade, and a conventional electrosurgical instrument. Fresh (0-week) incisions were made immediately before surgery. After abdominoplasty, harvested incisions were analyzed for scar width, thermal injury depth, burst strength, and inflammatory response. RESULTS: Acute thermal injury depth was reduced 74 percent in PlasmaBlade incisions compared with conventional electrosurgical instrument (p < 0.001). Significant differences in inflammatory response were observed at 3 weeks, with mean CD3 response (T-lymphocytes) 40 percent (p = 0.01) and 21 percent (p ~ 0.12) higher for the conventional electrosurgical instrument and PlasmaBlade, respectively, compared with the scalpel. CD68 response (monocytes/macrophages) was 52 percent (p = 0.05) and 16 percent (p ~ 0.35) greater for a conventional electrosurgical instrument and the PlasmaBlade, respectively. PlasmaBlade incisions demonstrated 65 percent (p < 0.001) and 42 percent (p < 0.001) stronger burst strength than a conventional electrosurgical instrument, with equivalence to the scalpel at the 3- and 6-week time points, respectively. Scar width was equivalent for the PlasmaBlade and the scalpel at both time points, and 25 percent (p = 0.01) and 12 percent (p = 0.15) less than for electrosurgery, respectively. CONCLUSIONS: PlasmaBlade incisions demonstrated reduced thermal injury depth, inflammatory response, and scar width in healing skin compared with electrosurgery. These results suggest that the PlasmaBlade may provide clinically meaningful advantages over conventional electrosurgery during human cutaneous wound healing. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.(Figure is included in full-text article.). PMID- 21701327 TI - Discussion: Comparative healing of human cutaneous surgical incisions created by the PEAK PlasmaBlade, conventional electrosurgery, and a standard scalpel. PMID- 21701328 TI - Dose-response effect of human equivalent radiation in the murine mandible: part I. A histomorphometric assessment. AB - BACKGROUND: The authors' laboratory previously demonstrated that radiation significantly alters new bone formation in the murine mandible, impeding the use of distraction osteogenesis as a viable reconstructive option after radiotherapy in head and neck cancer. The authors hypothesize that the deleterious effects of radiation on regenerate formation results from a dose-response depletion of essential osteogenic cells. The authors' specific aim was to use quantitative histomorphometry to objectively measure the human equivalent dose-response effects of radiation on the integrity of the mandible's cellular and tissue composition. METHODS: Twenty Sprague-Dawley rats were randomized into three radiation dosage groups: low (5.91 Gy), middle (7 Gy), and high (8.89 Gy), delivered in five daily fractions. These dosages approximated 75, 100, and 150 percent, respectively, of the biological equivalent dose the mandible experiences in the clinical regimen of head and neck cancer patients. Hemimandibles were harvested 56 days after radiation and stained with Gomori trichrome. Quantitative histomorphometry was performed using Bioquant software and analysis with a one way analysis of variance Kruskal-Wallis test. RESULTS: The authors' data revealed a statistically significant diminution in the mean number of osteocytes. The authors also demonstrated a corresponding significant increase in the mean values of empty lacunae. Both of these quantitative histomorphometric changes demonstrated a dose-response relationship. CONCLUSIONS: The authors' study supports their hypothesis that radiation induces a dose-response depletion in osteocytes and an increase in empty lacunae. These reliable and reproducible metrics can now be used to determine the efficacy of therapies aimed at safeguarding the cells essential for optimal bone regeneration and potentially enhance the use of distraction osteogenesis in head and neck cancer patients. PMID- 21701329 TI - Validation of the peripheral trigger point theory of migraine headaches: single surgeon experience using botulinum toxin and surgical decompression. AB - BACKGROUND: Migraine headache is a widespread neurovascular disorder that is often suboptimally or incompletely treated. This article confirms the efficacy of botulinum toxin treatment with surgical decompression as a deactivator of migraine headache trigger sites through the retrospective analysis of a single surgeon's experience. METHODS: A retrospective chart review was performed on 24 patients presenting with the diagnosis of migraine headache. Botulinum toxin type A injections were used to identify frontal, temporal, and/or occipital trigger points. The nasal trigger point was diagnosed with a decongestant trial, intranasal examination, and computed tomographic scan. Those patients with more than one trigger point underwent multiple surgical procedures, which were performed concomitantly during the same operation. All botulinum toxin injections, surgical procedures, and patient meetings were conducted by the principal investigator (J.E.J.), minimizing intrapatient treatment variability and multiprovider bias. RESULTS: Patient progress was tracked by consolidating migraine frequency, severity, and duration as a Migraine Headache Index. Nineteen patients (79.2 percent) benefited from surgery. Two patients (8.3 percent) reported migraine elimination and 17 patients (70.8 percent) reported significant improvement of their migraine symptoms. Among those patients who responded to surgery, average improvement from baseline levels was 96.9 percent. Among the entire patient population, average improvement was 78.2 percent from baseline. The mean postsurgical follow-up was 661 days. CONCLUSION: This study found botulinum toxin treatment with surgical decompression to be a potent deactivator of migraine headache trigger sites, corroborating the findings of the current literature in the field and underlining the reproducibility of the treatment. CLINICAL QUESTION/LEVEL OF EVIDENCE: : Therapeutic, IV.(Figure is included in full-text article.). PMID- 21701331 TI - Discussion: Qualitative and quantitative analyses of donor-site morbidity following suprafascial versus subfascial free fibula flap harvesting. PMID- 21701330 TI - Qualitative and quantitative analyses of donor-site morbidity following suprafascial versus subfascial free fibula flap harvesting. AB - BACKGROUND: The free fibular flap has become the workhorse flap for composite mandibular defect reconstruction. As advancements in microsurgery have improved flap survival, greater interest has shifted toward flap refinements to avert donor-site morbidities. METHODS: A total of 27 free fibular flaps used for mandible reconstruction were studied prospectively. Of the 27 flaps, 18 suprafascial and nine subfascial dissections were performed. A questionnaire was developed and completed by all patients to assess qualitative aspects of donor site morbidity and function. Quantitative studies focused on bilateral isokinetic testing of each patient's lower extremities by comparing and quantifying the ankle function. RESULTS: For the subfascial group, 42 percent of patients complained of pain and alteration in sensation. These donor-site morbidities within the suprafascial group were negligible. Using the Wilcoxon rank sum test, scores obtained from the questionnaires were analyzed, with significant differences seen in wound problems/cosmetic appearance between the two groups (p = 0.0114). For the subfascial group, the donor leg showed significantly less range of motion in plantar-flexion exercises (p = 0.03). Comparing the isokinetic examination results of the suprafascial and subfascial groups, a significant decrease in ankle dorsiflexion, plantar flexion, and foot eversion was evident in the subfascial group. CONCLUSIONS: The qualitative or subjective perception of donor-site morbidity, for the suprafascial method of fibular flap harvest, is relatively low. Quantitative analysis revealed that this method did not cause decreases in ankle function, and it had superior contour and aesthetic outcomes compared with the conventional, subfascial method. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.(Figure is included in full-text article.). PMID- 21701332 TI - Reconstruction of complex posterior cervical spine wounds using the paraspinous muscle flap. AB - BACKGROUND: The paraspinous muscle flap is often overlooked for use in cervical wounds, as surgeons cite the decreased size and mobility of the muscles in the cervical region. The purpose of this article is to introduce the paraspinous muscle flap technique for reconstruction of cervical spine wounds. METHODS: An 11 year, single-institution, retrospective chart review was performed on 14 consecutive patients from 1996 to 2007. All patients underwent paraspinous muscle flap surgery to provide soft-tissue coverage of the cervical spine following wound healing complications resulting in exposed hardware or bone. Variables of interest included demographics, comorbidities, and postreconstruction wound healing complications. RESULTS: The overall complication rate after paraspinous muscle flap surgery was low [two of 14 (14 percent)] and consisted of two minor wound infections. There was no postreconstruction seroma, a well-known complication of the trapezius muscle flap, which is often thought of as the first line option for posterior cervical soft-tissue reconstruction. CONCLUSION: The paraspinous muscle flap is an expeditious and reliable solution to complex cervical spine wounds. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.(Figure is included in full-text article.). PMID- 21701334 TI - Anatomical study of the medial gastrocnemius muscle flap: a quantitative assessment of the arc of rotation. AB - BACKGROUND: The authors compared the arc of rotation of medial gastrocnemius flaps according to three methods: standard harvesting, dissection of the "pes anserinus" muscle, and dissection of the medial condyle. METHODS: This study was performed using 20 fresh cadavers in two anatomy laboratories in Lyon, France; and Dallas, Texas. The area covered by each flap was calculated. The arc of rotation was calculated using distance from a fixed point, the anterior tibial tuberosity, to the distal flap (segment 1), to the lateral knee (segment 2), to the upper knee (segment 3), and to the medial thigh (segment 4). All measurements were done with leg stretched, applying a tensile strength of 1 daN on the muscle. RESULTS: The average surface of the flaps (32.5 +/- 8.55 cm) did not vary with the technique used; neither did the length of segment 1 (19.6 +/- 3.53 cm). Segment 2 (9.6 +/- 3.1 cm) and segment 3 (13.6 +/- 2.76 cm) were increased by 7.3 +/- 11.1 percent and 21.3 +/- 13.9 percent, respectively, when using pes anserinus dissection; and by 30.2 +/- 23 percent and 49.3 +/- 34 percent when combining with medial condyle dissection. Segment 4 (22.9 +/- 2.21 cm) increased by 15.3 +/- 12.8 percent with pes anserinus dissection alone and 36.2 +/- 13 percent when combining with medial condyle dissection. CONCLUSIONS: This study allowed precise measurement of the flaps and arcs of rotation according to the type of harvest. A marked length gain was achieved by pes anserinus dissection alone or the combination with medial condyle dissection. The authors' results support the importance of assessing the benefit/risk balance between different techniques according to the type and extent of soft-tissue loss requiring reconstruction. PMID- 21701333 TI - Avotermin for scar improvement following scar revision surgery: a randomized, double-blind, within-patient, placebo-controlled, phase II clinical trial. AB - BACKGROUND: Skin scarring is associated with psychosocial distress and has a negative effect on quality of life. The transforming growth factor (TGF)-beta family of cytokines plays a key role in scarring. TGF-beta3 improves scar appearance in a range of mammalian species. This study was performed to assess the efficacy of intradermal avotermin (TGF-beta3) for the improvement of scar appearance following scar revision surgery. METHODS: Sixty patients (35 men and 25 women; age, 19 to 78 years; 53 Caucasians; scar length, 5 to 21 cm) received intradermal avotermin (200 ng/100 MUl/linear cm wound margin) and placebo to outer wound segments immediately after, and again 24 hours after, complete (group 1) or staged (group 2) scar revision surgery. A within-patient design was chosen to control for interindividual factors that affect scarring. The primary efficacy variable was a total scar score derived from a visual analogue scale, scored by a lay panel from standardized photographs from months 1 through 7 following treatment. RESULTS: : Primary endpoint data from the combined surgical groups showed that avotermin significantly improved scar appearance compared with placebo (total scar score difference, 21.93 mm; p = 0.04). Profilometry showed a greater reduction in scar surface area from baseline with avotermin treatment compared with placebo, significant in group 2 at months 7 and 12 (difference, 41.99 mm and 25.85 mm, respectively; p = 0.03 for both comparisons). Histologic analysis from group 2 showed that, compared with placebo treatment, collagen organization in avotermin-treated scars more closely resembled normal skin in 14 of 19 cases. Avotermin was well tolerated. CONCLUSION: Avotermin administration following scar revision surgery is well tolerated and significantly improves scar appearance compared with placebo. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.(Figure is included in full-text article.). PMID- 21701335 TI - Vascular anatomy of the integument of the lateral lower leg: an anatomical study focused on cutaneous perforators and their clinical importance. AB - BACKGROUND: Certain studies have attempted to investigate the vascular anatomy of the integument of the lateral aspect of the lower leg. However, many issues remain controversial. The aim of this study was to investigate in detail the distribution and characteristics of cutaneous perforators of the lateral aspect of the lower leg. METHODS: Fifty-two fresh cadaver legs were dissected. The lateral lower leg was divided into five zones, and all cutaneous perforators were identified. Only perforators with a diameter greater than 0.5 mm were dissected further, and the type, location, course, length, and origin of those perforators were recorded. RESULTS: Three hundred two perforators were dissected. Two hundred twelve were septocutaneous (70.2 percent), 43 were septomusculocutaneous (14.2 percent), and 47 were musculocutaneous (15.6 percent). The majority of perforators (78.1 percent) originated from the peroneal artery. The peroneal artery was the dominant source vessel in all except for the proximal zone. The tibial-peroneal trunk predominated in the proximal zone. High contribution of the posterior tibial artery was noticed in the distal zone. Higher percentages of perforators were recorded in the middle and midproximal zones (26.8 percent and 25.2 percent, respectively). Septocutaneous perforators were present in all five zones, with higher percentages in the middle and middistal zones. Septomusculocutaneous and musculocutaneous perforators were identified in all except for the distal zone. CONCLUSION: The authors' findings provide information about the cutaneous perforators/perforasomes of the lateral aspect of the lower leg, useful for reliable planning and harvesting of perforator-based flaps in this area. PMID- 21701337 TI - Extensive percutaneous aponeurotomy and lipografting: a new treatment for Dupuytren disease. AB - BACKGROUND: Surgical resection of Dupuytren contracture is fraught with morbidity and prolonged recovery. This article introduces a novel minimally invasive alternative for Dupuytren disease and its outcome. METHODS: The procedure consists of an extensive percutaneous aponeurotomy that completely disintegrates the cord and separates it from the dermis. Subsequently, the resultant loosened structure is grafted with autologous lipoaspirate. After 1 week of postoperative extension splinting, patients are allowed normal hand use and are advised to use night splints for 3 to 6 months. The authors treated and report on their experience with 91 patients (99 hands) operated on in Miami and Rotterdam; from 50 patients, the authors report on goniometry (average follow-up, 44 weeks). RESULTS: The contracture from the proximal interphalangeal joint improved significantly from 61 degrees to 27 degrees, and contracture from the metacarpophalangeal joint improved from 37 degrees to -5 degrees. Ninety-four percent of patients returned to normal use of the hand within 2 to 4 weeks and 95 percent were very satisfied with the result. No new scars were added, and a supple palmar fat pad was mostly restored. Complications were digital nerve injury in one patient, postoperative wound infection in one patient, and complex regional pain syndrome in four patients. CONCLUSIONS: This new minimally invasive technique shortens recovery time, adds to the deficient subcutaneous fat, and leads to scarless supple skin. By its ability to treat multiple rays, it addresses the abnormality in the entire hand. The procedure is safe and effective, especially for primary cases. Currently, comparative prospective randomized studies are in process to fully determine its role in the treatment of Dupuytren contracture. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.(Figure is included in full-text article.). PMID- 21701336 TI - Development of a brief, 12-item version of the Michigan Hand Questionnaire. AB - BACKGROUND: The Michigan Hand Questionnaire is one of the most widely used hand specific surveys that measure health status relevant to patients with acute and chronic hand disorders. However, item redundancy exists in the original version, and an abbreviated survey could minimize responder burden and offer broader applicability. METHODS: Patients (n = 422) with four specific hand conditions- rheumatoid arthritis (n = 162), thumb carpometacarpal osteoarthritis (n = 31), carpal tunnel syndrome (n = 97), and distal radius fracture (n = 132)--completed the Michigan Hand Questionnaire at two time points. Correlation analysis identified two items from each of six domains (i.e., function, activities of daily living, work, pain, aesthetics, and satisfaction). The Brief Michigan Hand Questionnaire score was calculated as the sum of the responses to the 12 items. Psychometric analysis was performed to describe the reliability, validity, and responsiveness of the Brief Michigan Hand Questionnaire. RESULTS: The Brief Michigan Hand Questionnaire includes 12 items that were highly correlated with the summary Michigan Hand Questionnaire score (r = 0.99, p < 0.001). The Brief Michigan Hand Questionnaire scores were highly correlated between the two time periods (r = 0.78, p < 0.001) and by disease type. Responsiveness of the Brief Michigan Hand Questionnaire was high for all diseases and similar to that of the original Michigan Hand Questionnaire. CONCLUSIONS: The 12-item Brief Michigan Hand Questionnaire is an efficient and versatile outcomes instrument specific to hand disability that retains the psychometric properties of the original Michigan Hand Questionnaire. The Brief Michigan Hand Questionnaire is an important tool with which to measure patient outcomes and the quality of care in hand surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, I.(Figure is included in full text article.). PMID- 21701338 TI - Discussion: Extensive percutaneous aponeurotomy and lipografting: a new treatment for Dupuytren disease. PMID- 21701339 TI - Discussion: Temporal hollowing following surgical correction of unicoronal synostosis. PMID- 21701340 TI - The GILLS score: part I. Patient selection for tongue-lip adhesion in Robin sequence. AB - BACKGROUND: The compromised airway in Robin sequence demands prompt operative intervention. Tongue-lip adhesion is one alternative; however, the outcome of this technique is variable. The purpose of this study was to identify variables that preoperatively predict the success of adhesion in Robin sequence patients with life-threatening respiratory distress. METHODS: This is a retrospective review of infants with severe (Laberge grade II or III) Robin sequence managed by tongue-lip adhesion. Variables analyzed included diagnosis (syndromic versus nonsyndromic), age at operation, preoperative and postoperative airway management, duration of intubation, length of intensive care and hospital stay, serial weight, and postoperative complications. RESULTS: Fifty-three infants had tongue-lip adhesion for airway compromise: 47 (89 percent) were successfully managed and treatment failed in six. Preoperative intubation, days of intubation, intensive care unit days and hospitalization, and reintubation were more common in syndromic infants (p < 0.05). Those infants who had adhesion within 14 days of birth required shorter duration of postoperative ventilator support and intensive care unit/hospital stay (p < 0.05) than those who had a later procedure. Significant variables were gastroesophageal reflux (p = 0.002), intubation preoperatively (p = 0.002), late operation (older than 2 weeks) (p = 0.001), low birth weight (<2500 g) (p = 0.01), and syndromic diagnosis (p < 0.001). The acronym GILLS summarizes these predictive findings; one point was assigned for each variable present. Adhesion was successful in 100 percent of infants with a GILLS score of 2 or less (n = 39) but failed in 43 percent (six of 14 infants) with a score of 3 or more. CONCLUSION: The GILLS score may improve patient selection and predict outcome of tongue-lip adhesion in infants with Robin sequence. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.(Figure is included in full-text article.). PMID- 21701341 TI - Randomized sham-controlled trial to evaluate the safety and effectiveness of a high-intensity focused ultrasound device for noninvasive body sculpting. AB - BACKGROUND: High-intensity focused ultrasound presents a noninvasive approach to body sculpting for nonobese patients. The purpose of this study was to evaluate the safety and effectiveness of a high-intensity focused ultrasound device for sculpting of the abdomen and flanks. METHODS: Adults (aged 18 to 65 years) with subcutaneous abdominal fat greater than or equal to 2.5 cm thick who met screening criteria were randomized to receive high-intensity focused ultrasound treatment of the anterior abdomen and flanks at energy levels (a total of three passes each) of 47 J/cm (141 J/cm total), 59 J/cm (177 J/cm), or 0 J/cm (no energy applied, sham control). The primary endpoint was change from baseline waist circumference at the iliac crest level at posttreatment week 12. Subjective aesthetic assessments included the Global Aesthetic Improvement Scale and a patient satisfaction questionnaire. Safety assessments included adverse events, laboratory values, and physical examinations. RESULTS: For the primary endpoint, in the intent-to-treat population, statistical significance versus sham was achieved for the 59-J/cm (-2.44; p = 0.01) but not the 47-J/cm treatment group ( 2.06 cm; p = 0.13). In a per-protocol population, statistical significance versus sham was achieved for both the 59-J/cm (-2.52 cm; p = 0.002) and the 47-J/cm treatment groups (-2.10 cm; p = 0.04). Investigator subjective measures of global aesthetic improvement and patient satisfaction also favored each active treatment versus sham. Adverse events included mild to moderate discomfort, bruising, and edema. Laboratory values and physical examinations were unremarkable. CONCLUSIONS: Treatment with this high-intensity focused ultrasound device reduced waist circumference and was generally well tolerated for noninvasive body sculpting. Reduction in waist circumference was statistically significant with both active treatments (per protocol). CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.(Figure is included in full-text article.). PMID- 21701342 TI - Discussion: Randomized sham-controlled trial to evaluate the safety and effectiveness of a high-intensity focused ultrasound device for noninvasive body sculpting. PMID- 21701343 TI - Discussion: Traditional lower blepharoplasty: is additional support necessary? A 30-year review. PMID- 21701344 TI - Discussion: Traditional lower blepharoplasty: is additional support necessary? A 30-year review. PMID- 21701345 TI - Dorsal aesthetic lines in rhinoplasty: a quantitative outcome-based assessment of the component dorsal reduction technique. AB - BACKGROUND: Preservation or reconstruction of the middle nasal vault structure and internal nasal valve after dorsal reduction is challenging. The purpose of this study was to retrospectively analyze a series of 100 consecutive rhinoplasty cases with respect to preservation or restoration of the dorsal nasal lines following component dorsal reduction. A new quantitative mathematical application for subject digital images was performed. METHODS: Medical information and digital images were obtained from 100 consecutive primary rhinoplasty patients from one author (R.J.R.) with University of Texas Southwestern Medical Center Institutional Review Board consent. All postoperative subject digital images were taken at more than 1-year follow-up. Preoperative and postoperative digital images of the dorsal nasal aesthetic lines were analyzed using a software application that quantitated various facial anatomical features compared with landmark measurements unique for each subject (pupil-to-pupil distance). Dorsal line symmetry, nose width, and variation of deformities on each side of the face were determined. RESULTS: Mean subject dorsal line symmetry was 68 percent preoperatively and 94 percent postoperatively. Only 32.5 percent of dorsal lines were harmonious preoperatively, whereas 97 percent of dorsal lines were harmonious postoperatively. Identification of dorsal lines postoperatively versus preoperatively was similar in 74.6 percent, improved in 15.7 percent, and decreased in 9.7 percent. Nasal width lines were similar in 36 subjects, 21 subjects had wider nasal width lines, and 43 subjects had narrower width lines after surgery. CONCLUSIONS: Component dorsal hump reduction procedures result in reliable and reproducible clinical outcomes. Quantitative assessments provide evidence that improved and harmonious curves of dorsal aesthetic lines are achievable. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.(Figure is included in full-text article.). PMID- 21701346 TI - The use of standardized patients in the plastic surgery residency curriculum: teaching core competencies with objective structured clinical examinations. AB - BACKGROUND: As of 2006, the Accreditation Council for Graduate Medical Education had defined six "core competencies" of residency education: interpersonal communication skills, medical knowledge, patient care, professionalism, practice based learning and improvement, and systems-based practice. Objective structured clinical examinations using standardized patients are becoming effective educational tools, and the authors developed a novel use of the examinations in plastic surgery residency education that assesses all six competencies. METHODS: Six plastic surgery residents, two each from postgraduate years 4, 5, and 6, participated in the plastic surgery-specific objective structured clinical examination that focused on melanoma. The examination included a 30-minute videotaped encounter with a standardized patient actor and a postencounter written exercise. The residents were scored on their performance in all six core competencies by the standardized patients and faculty experts on a three-point scale (1 = novice, 2 = moderately skilled, and 3 = proficient). RESULTS: Resident performance was averaged for each postgraduate year, stratified according to core competency, and scored from a total of 100 percent. Residents overall scored well in interpersonal communications skills (84 percent), patient care (83 percent), professionalism (86 percent), and practice-based learning (84 percent). Scores in medical knowledge showed a positive correlation with level of training (86 percent). All residents scored comparatively lower in systems-based practice (65 percent). The residents reported unanimously that the objective structured clinical examination was realistic and educational. CONCLUSIONS: The objective structured clinical examination provided comprehensive and meaningful feedback and identified areas of strengths and weakness for the residents and for the teaching program. The examination is an effective assessment tool for the core competencies and a valuable adjunct to residency training. PMID- 21701347 TI - Survey says? A primer on web-based survey design and distribution. AB - The Internet has changed the way in which we gather and interpret information. Although books were once the exclusive bearers of data, knowledge is now only a keystroke away. The Internet has also facilitated the synthesis of new knowledge. Specifically, it has become a tool through which medical research is conducted. A review of the literature reveals that in the past year, over 100 medical publications have been based on Web-based survey data alone. Because of emerging Internet technologies, Web-based surveys can now be launched with little computer knowledge. They may also be self-administered, eliminating personnel requirements. Ultimately, an investigator may build, implement, and analyze survey results with speed and efficiency, obviating the need for mass mailings and data processing. All of these qualities have rendered telephone and mail based surveys virtually obsolete. Despite these capabilities, Web-based survey techniques are not without their limitations, namely, recall and response biases. When used properly, however, Web-based surveys can greatly simplify the research process. This article discusses the implications of Web-based surveys and provides guidelines for their effective design and distribution. PMID- 21701348 TI - The levels of evidence and their role in evidence-based medicine. PMID- 21701349 TI - The level of evidence pyramid: indicating levels of evidence in Plastic and Reconstructive Surgery articles. PMID- 21701350 TI - The second world congress for plastic surgeons of Chinese descent. PMID- 21701353 TI - Aesthetic and oncologic outcome after microsurgical reconstruction of complex scalp and forehead defects after malignant tumor resection: an algorithm for treatment. PMID- 21701355 TI - The anatomy of the greater occipital nerve: part II. Compression point topography. PMID- 21701356 TI - A four-type classification system for microvascular reconstruction of oncologic midface defects: but what about maxillofacial allotransplantation? PMID- 21701357 TI - A 5-year assessment of safety and aesthetic results after facial soft-tissue augmentation with polyacrylamide hydrogel (aquamid): a prospective multicenter study of 251 patients. PMID- 21701359 TI - Reconstruction after partial hypopharyngectomy with larynx preservation. PMID- 21701360 TI - Decolonization strategies to control Staphylococcus aureus infections in breast implant surgery. PMID- 21701362 TI - Retrocapsular pocket to correct symmastia. PMID- 21701364 TI - Should cosmetic augmentations of breasts by autologous fat injections no longer be performed because of mammographic confusion? PMID- 21701365 TI - Body contouring surgery with the V-loc suture. PMID- 21701366 TI - Arm position artifact in three-dimensional breast scanning technique. PMID- 21701367 TI - The nomenclature of perforator flaps. PMID- 21701370 TI - A prospective trial on the use of antibiotics in hand surgery. PMID- 21701371 TI - The solar system model for the reconstructive ladder. PMID- 21701373 TI - Comment on the safe management of sedation for plastic surgery. PMID- 21701377 TI - The prognostic importance of midline involvement in oral tongue cancer. AB - OBJECTIVES: To examine the importance of midline involvement and other clinicopathologic factors in predicting the rate of contralateral lymph node metastasis and survival in oral tongue squamous cell carcinoma. METHODS: We used Surveillance, Epidemiology, and End Results data to identify a cohort of 5430 patients with laterally rising tumors. Clinicopathologic factors examined as potentially predictive of contralateral lymph node metastasis included extension to midline, T classification, anatomic site, grade, histologic subtype, race, age, and sex. Survival analysis included the above factors plus lymph node status. RESULTS: T1 tumors and lateral T2 and T3 tumors had rates of contralateral lymph node metastasis ranging from 0.7% to 0.9% on presentation. T4 lesions and midline crossing T2 and T3 lesions had corresponding rates of 8.3% to 13.0%. Primary extension across the midline was associated with a mean survival about half that of strictly lateral tumors and its significance was maintained in multivariate analysis. CONCLUSIONS: Patients with T1 disease or T2-3 disease that does not cross midline are in a different prognostic class from patients with T2 3 disease that crosses midline or T4 tumors. These results give the strongest evidence to date that involvement of the midline is a powerful predictor for decreased survival in oral tongue squamous cell carcinoma. PMID- 21701378 TI - Effect of head elevation on passive upper airway collapsibility in normal subjects during propofol anesthesia. AB - BACKGROUND: Head elevation can restore airway patency during anesthesia, although its effect may be offset by concomitant bite opening or accidental neck flexion. The aim of this study is to examine the effect of head elevation on the passive upper airway collapsibility during propofol anesthesia. METHOD: Twenty male subjects were studied, randomized to one of two experimental groups: fixed-jaw or free-jaw. Propofol infusion was used for induction and to maintain blood at a constant target concentration between 1.5 and 2.0 MUg/ml. Nasal mask pressure (PN) was intermittently reduced to evaluate the upper airway collapsibility (passive PCRIT) and upstream resistance (RUS) at each level of head elevation (0, 3, 6, and 9 cm). The authors measured the Frankfort plane (head flexion) and the mandible plane (jaw opening) angles at each level of head elevation. Analysis of variance was used to determine the effect of head elevation on PCRIT, head flexion, and jaw opening within each group. RESULTS: In both groups the Frankfort plane and mandible plane angles increased with head elevation (P < 0.05), although the mandible plane angle was smaller in the free-jaw group (i.e., increased jaw opening). In the fixed-jaw group, head elevation decreased upper airway collapsibility (PCRIT ~ -7 cm H2O at greater than 6 cm elevation) compared with the baseline position (PCRIT ~ -3 cm H2O at 0 cm elevation; P < 0.05). CONCLUSION: : Elevating the head position by 6 cm while ensuring mouth closure (centric occlusion) produces substantial decreases in upper airway collapsibility and maintains upper airway patency during anesthesia. PMID- 21701379 TI - Developmental Stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. AB - BACKGROUND: Recent observations demonstrate that anesthetics rapidly impair synaptogenesis during neuronal circuitry development. Whether these effects are lasting and depend on the developmental stage at which these drugs are administered remains, however, to be explored. METHODS: Wistar rats received propofol anesthesia at defined developmental stages during early postnatal life. The acute and long-term effects of these treatments on neuronal cytoarchitecture were evaluated by Neurolucida and confocal microscopy analysis after iontophoretic injections of Lucifer Yellow into layer 5 pyramidal neurons in the medial prefrontal cortex. Quantitative electron microscopy was applied to investigate synapse density. RESULTS: Layer 5 pyramidal neurons of the medial prefrontal cortex displayed intense dendritic growth and spinogenesis during the first postnatal month. Exposure of rat pups to propofol at postnatal days 5 and 10 significantly decreased dendritic spine density, whereas this drug induced a significant increase in spine density when administered at postnatal days 15, 20, or 30. Quantitative electron microscopy revealed that the propofol-induced increase in spine density was accompanied by a significant increase in the number of synapses. Importantly, the propofol-induced modifications in dendritic spine densities persisted up to postnatal day 90. CONCLUSION: These new results demonstrate that propofol anesthesia can rapidly induce significant changes in dendritic spine density and that these effects are developmental stage-dependent, persist into adulthood, and are accompanied by alterations in synapse number. These data suggest that anesthesia in the early postnatal period might permanently impair circuit assembly in the developing brain. PMID- 21701380 TI - Human subthalamic neuron spiking exhibits subtle responses to sedatives. AB - BACKGROUND: During deep brain stimulation implant surgery, microelectrode recordings are used to map the location of targeted neurons. The effects produced by propofol or remifentanil on discharge activity of subthalamic neurons were studied intraoperatively to determine whether they alter neuronal activity. METHODS: Microelectrode recordings from 11 neurons, each from individual patients, were discriminated and analyzed before and after administration of either propofol or remifentanil. Subthalamic neurons in rat brain slices were recorded in patch-clamp to investigate cellular level effects. RESULTS: Neurons discharged at 42 +/- 9 spikes/s (mean +/- SD) and showed a common pattern of inhibition that lasted 4.3 ms. Unique discharge profiles were evident for each neuron, seen using joint-interval analysis. Propofol (intravenous bolus 0.3 mg/kg) produced sedation, with minor effects on discharge activity (less than 2.0% change in frequency). A prolongation of recurrent inhibition was evident from joint-interval analysis, and propofol's effect peaked within 2 min, with recovery evident at 10 min. Subthalamic neurons recorded in rat brain slices exhibited inhibitory synaptic currents that were prolonged by propofol (155%) but appeared to lack tonic inhibitory currents. Propofol did not alter membrane potential, membrane resistance, current-evoked discharge, or holding current during voltage clamp. Remifentanil (0.05 mg/kg) had little effect on overall subthalamic neuron discharge activity and did not prolong recurrent inhibition. CONCLUSIONS: These results help to characterize the circuit properties and feedback inhibition of subthalamic neurons and demonstrate that both propofol and remifentanil produce only minor alterations of subthalamic neuron discharge activity that should not interfere with deep brain stimulation implant surgery. PMID- 21701383 TI - Glucocorticoids: the devil is in the details. PMID- 21701384 TI - Validation of home blood pressure-monitoring devices, Omron HEM-1020 and Omron i Q132 (HEM-1010-E), according to the European Society of Hypertension International Protocol. AB - OBJECTIVE: Allowing patients to measure their blood pressure (BP) at home is recognized as being of clinical value. However, it is not known whether BP measurement is usually taken correctly outside of a clinical setting. Automated proper wrapping of the cuff and correction of wrong posture will help in taking BP measurement properly. This study aimed to evaluate the performance of the Omron HEM-1020 and the Omron i-Q132 devices, which are equipped with those functions. METHODS: A team of three trained doctors validated the performance of these devices by comparing data obtained from both devices with those from a standard mercury sphygmomanometer. Both devices passed the validation requirements of the European Society of Hypertension International Protocol. The magnitude of the difference in BP readings between the tested device and the standard mercury sphygmomanometer was within the range of +/- 3 mmHg, which is allowed by the European Society of Hypertension guidelines. CONCLUSION: Both the Omron HEM-1020 and the Omron i-Q132 devices were found to be useful for measuring BP at home because their performance fulfilled the requirement of the guidelines. PMID- 21701385 TI - Plasma B-type natriuretic peptide level can predict myocardial tissue perfusion in patients undergoing primary percutaneous coronary intervention for acute ST segment elevation myocardial infarction. AB - BACKGROUND: Inadequate myocardial tissue perfusion after successful revascularization in ST-segment elevation myocardial infarction (STEMI) is associated with worse clinical outcomes. We investigated whether the plasma B type natriuretic peptide (BNP) level on admission could predict the status of myocardial tissue perfusion in patients who underwent primary percutaneous coronary intervention (PCI). METHODS: The study prospectively enrolled 102 patients with STEMI who underwent primary PCI within 12 h of symptom onset. The grade of myocardial tissue perfusion was measured by ST-segment resolution, corrected thrombolysis in myocardial infarction frame count, and myocardial blush grade after primary PCI. All-cause mortality at 1 month after PCI was assessed. RESULTS: All patients were divided into two groups according to the BNP level; high-BNP group (>=80 pg/ml, n=43) and low-BNP group (<80 pg/ml, n=59). High-BNP group had significantly lower ST-segment resolution (42.69 +/- 24.85 vs. 71.15 +/ 19.37%, P<0.001), higher corrected thrombolysis in myocardial infarction frame count (53.7 +/- 19.7 vs. 44.5 +/- 15.5, P=0.04), lower myocardial blush grade (2.4 +/- 0.9 vs. 2.9 +/- 0.3, P=0.001), and higher short-term mortality (16.2 vs. 3.3%, P=0.023). In multivariate logistic regression analysis for prediction of good myocardial tissue perfusion after PCI, the odds ratio of low-BNP group was 4.12 (95% confidence interval 1.49-13.08, P<0.01). CONCLUSION: The patients with STEMI who had higher BNP level on admission showed inadequate myocardial tissue perfusion status after primary PCI. The plasma BNP level on admission may serve as a predictor of tissue perfusion after primary PCI in patients with STEMI. PMID- 21701387 TI - Nutrient-based dietary patterns, family history, and colorectal cancer. AB - The effect of dietary habits on colorectal cancer (CRC) risk may be modified by a family history of CRC. We analyzed data from an Italian case-control study, including 1953 CRC cases and 4154 controls. Odds ratios (OR) and 95% confidence intervals (CI) for combined categories of family history and tertiles of two a posteriori dietary patterns were derived using multiple logistic regression models. Compared with individuals without family history and in the lowest tertile category of the 'starch-rich' pattern, the ORs of CRC were 1.38 (95% CI: 1.19-1.61) for the group without family history and in the highest tertile, 2.89 (95% CI: 2.30-3.64) for the one with family history and in the lowest tertile, and 4.00 (95% CI: 3.03-5.27) for the one with family history and in the highest tertile. Compared with individuals without family history and in the highest tertile of the 'vitamins and fiber' pattern, the ORs were 1.29 (95% CI: 1.12 1.48) for the group without family history and in the lowest tertile, 2.89 (95% CI: 2.30-3.64) for the one with family history and in the highest tertile, and 3.74 (95% CI: 2.85-4.91) for the one with family history and in the lowest tertile. Family history of CRC and 'starch-rich' or 'vitamins and fiber' patterns has an independent effect on CRC risk in our population. However, as having a family history plausibly implies shared environmental and/or genetic risk factors, our results could not exclude that dietary habits can modify genetic susceptibility to CRC. PMID- 21701388 TI - Dietary transfatty acids and cancer risk. AB - This study assesses the association between dietary transfatty acid (TFA) intake and the risk of selected cancers. Mailed questionnaires were completed between 1994 and 1997 in eight Canadian provinces by 1182 incident, histologically confirmed cases of the stomach, 1727 of the colon, 1447 of the rectum, 628 of the pancreas, 3341 of the lung, 2362 of the breast, 442 of the ovary, 1799 of the prostate, 686 of the testis, 1345 of the kidney, 1029 of the bladder, 1009 of the brain, 1666 non-Hodgkin's lymphomas, 1069 leukemias, and 5039 population controls. Information on dietary habits and nutrition intake was obtained using a food frequency questionnaire, which provided data on eating habits 2 years before the study. Odds ratios (OR) and 95% confidenc530e intervals (CI) were derived by unconditional logistic regression to adjust for total energy intake and other potential confounding factors. Dietary TFA were positively associated with the risk of cancers of the colon (OR: 1.38 for the highest vs. the lowest quartile), breast in premenopause (OR: 1.60), and prostate (OR: 1.42). There were a borderline association for pancreas cancer (OR: 1.38; P=0.06). No significant association was observed for cancers of the stomach, rectum, lung, ovary, testis, kidney, bladder, brain, non-Hodgkin's lymphomas, and leukemia, although the ORs for the highest quartile were above unity for all neoplasms considered, except testis. Our findings add evidence that high TFA is associated with an increased risk of various cancers. Thus, a diet low in transfat may play a role in the prevention of several cancers. PMID- 21701389 TI - Proton pump inhibitors therapy and risk of hip fracture: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Previous studies have reported inconsistent findings that proton pump inhibitors (PPIs) therapy might increase the risk of hip fracture. We investigated the association between PPIs therapy and hip fracture by a systematic review and meta-analysis. METHODS: We systematically searched PubMed, EMBASE, and the Cochrane Library. We included studies assessing the effects of PPIs on hip fracture. Data from the studies about odds ratio and 95% confidence interval were gathered and summarized. RESULTS: Seven studies met the inclusion criteria. PPIs therapy was associated with a statistically significant increase of hip fracture risk (pooled odds ratio=1.24; 95% confidence interval: 1.15-1.34; P<0.00001) under a random model. Meanwhile, we found that the effect of PPIs on hip fracture differs in different duration groups. CONCLUSION: These results indicate that PPIs therapy might have the potential risk of hip fracture. Different effects on hip fracture in the subgroup analysis do not support a causal relationship between PPIs and hip fracture. Whether the risk exists warrants further investigation. PMID- 21701386 TI - The maternal womb: a novel target for cancer prevention in the era of the obesity pandemic? AB - The dramatic rise in worldwide prevalence of obesity has necessitated the search for more efficacious antiobesity strategies to counter the increased cancer risks in overweight and obese individuals. The mechanistic pathways linking obesity status with adult chronic diseases such as cancer remain incompletely understood. A growing body of evidence suggests that novel approaches and interventional agents to disrupt the feed-forward cycle of maternal to offspring obesity transfer that is initiated in utero will be important for stemming both the obesity pandemic and the associated increase in cancer incidence. The convergence of multiple research areas including those encompassing the insulin and insulin like growth factor systems, epigenetics, and stem cell biology is providing insights into the potential for cancer prevention in adult offspring previously exposed to the intrauterine environment of overweight/obese mothers. Here, we review the current state of this nascent research field, with a focus on three major cancers, namely breast, colorectal, and liver, and suggest some possible future directions to optimize its impact for the health of future generations. PMID- 21701390 TI - Perceptions of gastroenterologists and nurses regarding irritable bowel syndrome and inflammatory bowel disease. AB - OBJECTIVE: Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) have similar symptoms, and both adversely affect patients' quality of life. The objective of this study was to compare the perceptions of physicians and nurses regarding IBS and IBD. METHODS: The Illness Perception Questionnaire Revised, adapted for medical staff, was sent at random to 300 physicians and nurses of gastroenterology departments and outpatient clinics nationwide to assess perceptions of IBS or IBD. Responses were statistically analyzed by illness and professional group. RESULTS: Fifty-five physicians and 43 nurses returned the questionnaire (response rate, 32.6%). Fifty-two questionnaires pertained to IBS and 46 to IBD. More physicians than nurses stated that the course of both illnesses does not improve over time (P<0.05). Both groups showed that medical treatment is of greater benefit for IBD than IBS (P<0.05) and that patients with IBD better understand their illness than patients with IBS (P<0.05). CONCLUSION: Physicians and nurses hold different attitudes to and perceptions of IBD and IBS in terms of chronicity, severity of the consequences, treatment efficacy, personal control, and illness coherence. These differences may have important effects on the patient-health provider relationship and should be addressed. PMID- 21701392 TI - Radical vaginal trachelectomy (RVT) combined with laparoscopic lymphadenectomy: prospective study of 225 patients with early-stage cervical cancer. AB - OBJECTIVE: The aim of the study was to prove the surgical and oncological safety of radical vaginal trachelectomy (RVT) and laparoscopic lymphadenectomy for patients with early-stage cervical cancer who are seeking parenthood. METHODS: A database of 225 patients with early-stage cervical cancer and intention to treat by RVT after laparoscopic lymphadenectomy was prospectively maintained. A total of 212 patients were treated according to the protocol. The procedure was preformed in a standardized manner, and life table analysis was applied. RESULTS: In the cohort of patients treated according to protocol, 8 recurrences occurred and 4 patients died from recurrence. The median follow-up time was 37 months (range, 0-171 months). The 5-year recurrence-free and overall survival was 94.4% and 97.4%, respectively. Perioperative and short-term postoperative complications were rare (2.8% and 7.5%, respectively). No severe long-term complications occurred. CONCLUSIONS: Radical vaginal trachelectomy combined with laparoscopic lymphadenectomy is a safe method for treatment of patients with early-stage cervical cancer who are seeking parenthood. PMID- 21701391 TI - Barrett's, blood groups and progression to oesophageal cancer: is nitric oxide the link? AB - INTRODUCTION: Incidence of oesophageal adenocarcinoma (OAC) is increasing rapidly. OAC arises in columnar-lined oesophagus (CLO), a metaplastic change affecting some patients with gastro-oesophageal reflux disease (GORD). As yet there is no reliable method of identifying those at highest risk. Our earlier observation of an association between OAC and blood group O Rhesus negative, if confirmed, may help identify those at greatest risk. AIM AND METHODS: To assess the distribution of blood group and Rhesus D (RhD) factor in patients with GORD compared with the blood donating general population. GORD was categorized as nonerosive reflux (NER), erosive oesophagitis, CLO and OAC. The Rotherham Hospital database holds details of all GORD, CLO and OAC patients seen in the Gastroenterology Unit. Blood group information for patients with GORD was obtained from patients' records and the hospital's blood transfusion service. The blood group distribution in the general population was obtained from the National Blood Transfusion Service. The number of expected to observed patients in each blood group for each subtype was compared. RESULTS: Two thousand six hundred and ten NER, 2813 erosive oesophagitis, 568 CLO and 73 OAC patients had a recorded blood group. For RhD positive patients observed proportions in each blood group were similar to expected. The most striking difference was the marked excess of OAC in blood group O, Rhesus negative (P=0.002). CONCLUSION: CLO patients with blood group O, RhD negative carry a disproportionately higher risk of developing OAC. The mechanism is unknown but the finding has practical application in guiding risk stratification and intensity of surveillance. PMID- 21701393 TI - Clinical results of modified anterior chamber tube shunt to an encircling band surgery for uncontrolled intraocular pressure. AB - PURPOSE: To evaluate the clinical outcome of a modified anterior chamber tube shunt to an encircling band (ACTSEB) procedure in eyes with uncontrolled intraocular pressure (IOP) after scleral encircling band (EB) implantation for treatment of retinal detachment. METHODS: Eight eyes of 7 consecutive patients were analyzed. Silicone tube (external/internal diameter, 0.64/0.30 mm) with 3 to 4 side ports around the distal portion was prepared. Temporary partial ligation of the tube was performed. The fibrous capsule around the EB was incised and the distal portion of each tube was placed under the EB and anchored to the sclera. The proximal part of the tube was inserted into the anterior chamber. IOP, use of antiglaucoma medication, and complications were recorded for 1 year after surgery. Success was defined as an IOP of 8 to 21 mm Hg and no requirement for an additional procedure; complete success was defined as control of IOP without use of antiglaucoma medication; and qualified success as control of IOP with the use of medication. RESULTS: Mean preoperative IOP was 40.1 mm Hg under maximum tolerated medical therapy. Mean IOP was 10.6 mm Hg at 1 day and 16.9 mm Hg at 1 year after surgery. Antiglaucoma medication was used in 3 eyes during follow-up. Tube exposure was detected in 1 eye at 10 months after surgery. The complete success rate was 50% (4 eyes) and the qualified success rate 37.5% (3 eyes). CONCLUSION: Our modification of the ACTSEB procedure resulted in good clinical outcomes, with favorable control of IOP and a low rate of complications. PMID- 21701394 TI - Comparison of macular ganglion cell complex thickness by Fourier-domain OCT in normal tension glaucoma and primary open-angle glaucoma. AB - PURPOSE: To compare perimacular ganglion cell complex (GCC) parameters between patients with normal tension glaucoma (NTG) and primary open-angle glaucoma (POAG). METHODS: Participants, consecutively enrolled from January 2009 to June 2009, underwent optical coherence tomographic imaging with RTVue-100 (Optovue Inc, Fremont, CA). Optic nerve head (ONH) parameters, retinal nerve fiber layer (RNFL) parameters, and GCC parameters were acquired. Mean measurements of ONH, RNFL, and GCC parameters among the normal, NTG, and POAG groups were compared using analysis of variance. Area under the receiver operator characteristic curve was used to assess the ability of each parameter to detect glaucomatous changes. RESULTS: Fifty-eight normal controls, 51 patients with NTG, and 52 patients with POAG were included. Mean measurements of ONH parameters were similar between the NTG and POAG groups (all P>0.05). Average RNFL thickness did not differ between the NTG and POAG groups (P=0.053), whereas average GCC thickness significantly differed between the NTG and POAG groups (P=0.001). In terms of pattern-based parameters of GCC, focal loss volume did not differ between the NTG and POAG groups (P=0.165), whereas global loss volume was significantly higher in the POAG group (P<0.001). There were no statistically significant differences between RNFL and GCC measurements with respect to the ability to detect glaucomatous changes. CONCLUSIONS: GCC loss in the NTG group was more localized compared with diffuse GCC loss in the POAG group. Perimacular GCC parameters could be a good alternative or supplement to peripapillary RNFL measurements for diagnosis and research in patients with NTG. PMID- 21701395 TI - Repeatability and reproducibility of Goldmann applanation, dynamic contour, and ocular response analyzer tonometry. AB - PURPOSE: To evaluate the repeatability and interoperator reproducibility of the Pascal dynamic contour tonometry (DCT), ocular response analyzer (ORA), and Goldmann applanation tonometer (GAT) in a single population of normal individuals. METHODS: The study included 52 eyes from 26 normal individuals. One operator measured the intraocular pressure (IOP) with each tonometer 3 times while 2 additional operators each measured the IOP with each tonometer once. Repeatability and reproducibility were assessed by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Agreement among tonometers was also assessed using Bland-Altman plots. RESULTS: The mean age of included participants was 31.5+/-8.8 years and 15 (58%) were female individuals. In general, both intraoperator repeatability and interoperator reproducibility were significantly higher for DCT compared with the other tonometers. Intraoperator DCT (CV=3.7, ICC=0.89), GAT (CV=9.7, ICC=0.79), IOPg (CV=7.0, ICC=0.79), and IOPcc (CV=9.8, ICC=0.57). Interoperator DCT (CV=6.1, ICC=0.73), GAT (CV=9.0, ICC=0.82), and IOPg (CV=10.8, ICC=0.63), IOPcc (CV=11.7, ICC=0.49). CONCLUSION: Overall, DCT was significantly more repeatable and reproducible than GAT, IOPg and IOPcc. The better reproducibility of the DCT may result in more precise measurements for monitoring IOP changes over time compared to GAT and ORA. PMID- 21701396 TI - Risk factors for visual field progression in the groningen longitudinal glaucoma study: a comparison of different statistical approaches. AB - PURPOSE: To identify risk factors for visual field progression in glaucoma and to compare different statistical approaches with this risk factor analysis. PATIENTS AND METHODS: We included 221 eyes of 221 patients. Progression was analyzed using Nonparametric Progression Analysis applied to Humphrey Field Analyzer data. Risk factors were analyzed using the statistical approaches from the Advanced Glaucoma Intervention Study, the Early Manifest Glaucoma Trial, and the Canadian Glaucoma Study. Four intraocular pressure (IOP) variables (baseline IOP, mean IOP during follow-up, IOP fluctuation, and pretreatment IOP) and 8 other risk factors were investigated. RESULTS: On average, 7.1 reliable fields were available after a mean follow-up of 5.3 years; 89 eyes progressed. With the Advanced Glaucoma Intervention Study approach, age [odds ratio (OR) 1.03/y; 95% confidence interval (CI), 1.00-1.06; P = 0.044] predicted progression. With an additional stepwise selection procedure, mean IOP during follow-up (1.16 per mm Hg; 1.05-1.29; P=0.003),baseline HFA mean deviation (MD; 2.72 for worse versus better than --6 dB; 1.50-4.95; P=0.001) and age (1.03; 1.01-1.06;P=0.010) predicted progression [corrected]. With the Early Manifest Glaucoma Trial approach, baseline IOP [hazard ratio (HR) 1.07; 95% CI, 1.02-1.11; P = 0.010], baseline Frequency Doubling Perimeter MD (HR = 1.75; 95% CI, 1.14-2.70; P = 0.013), and age (HR = 1.03; 95% CI, 1.01-1.05; P = 0.006) predicted progression. Finally, with the Canadian Glaucoma Study approach, baseline IOP (HR = 1.07; 95% CI, 1.02-1.11; P = 0.010), baseline Frequency Doubling Perimeter MD (HR = 1.75; 95% CI, 1.14-2.70; P = 0.013), and age (HR = 1.03; 95% CI, 1.01-1.05; P = 0.006) predicted progression. CONCLUSIONS: IOP, disease stage, and age seemed to be robust independent risk factors for visual field progression in glaucoma. The IOP variable that was significant depended on the statistical approach applied. PMID- 21701397 TI - Comparison of optic disc parameters measured by RTVue-100 FDOCT versus HRT-II. AB - PURPOSE: To compare optic disc measurements between the new Fourier-domain optical coherence tomography (RTVue-100) and the confocal scanning laser ophthalmoscopy (Heidelberg retinal tomography, HRT-II) in clinical practice. METHODS: Patients seen from the glaucoma service of an academic department of ophthalmology between August 2008 to August 2009 with good-quality RTVue-100 and HRT-II images within 6 months of each other were included (363 patients were included, 1 eye from each patient). The rim of the optic disc was drawn automatically by RTVue-100 and manually by a single experienced observer for HRT II. Optic disc measurements from both imaging devices were compared using Bland Altman plots and the Student t test to assess agreement. The main outcome measure was the agreement in optic disc parameters between the two imaging devices. RESULTS: Bland-Altman plots indicate significant differences between the RTVue 100 and HRT-II for all optic nerve parameters. The mean HRT-II values were consistently larger than RTVue-100 values for optic disc area and rim area. The RTVue-100 values were larger for the cup area, cup-to-disc area ratio, and vertical and horizontal cup-to-disc ratio. The Student t test showed P<0.001 for averages of all measurements between the two devices. CONCLUSIONS: We conclude that the disc parameters from these two imaging devices are not interchangeable. PMID- 21701398 TI - Physical fitness and perceived psychological pressure at work: 30-year ischemic heart disease and all-cause mortality in the Copenhagen Male Study. AB - OBJECTIVE: Investigate if workers with low physical fitness have an increased risk of ischemic heart disease (IHD) mortality from regular psychological work pressure. METHODS: Thirty-year follow-up of 5249 middle-aged men without cardiovascular disease. RESULTS: Men perceiving regular psychological work pressure had no higher risk of IHD mortality than those who did not. Both among men perceiving regular and rare psychological work pressure, the physically fit had a reduced risk of IHD mortality referencing men with low physical fitness. For all-cause mortality, a stronger inverse association was found among men perceiving regular compared to rare psychological pressure at work. CONCLUSIONS: Physical fitness is equally important for the risk of IHD mortality among men experiencing regular and rare psychological pressure at work, but stronger associated to risk of all-cause mortality among men experiencing regular psychological pressure at work. PMID- 21701399 TI - Process evaluation of an occupational health guideline aimed at preventing weight gain among employees. AB - OBJECTIVE: To evuate the process of an occupational health guideline aimed at preventing weight gain. METHODS: Quantitative data on seven process items were assessed and linked to effects on employees' waist circumference and body weight at 6 months. RESULTS: Occupational physicians (n = 7) implemented the guideline partly with respect to the environmental level, but performed well at the individual level. Behavioral change counseling was performed "to some extent." Employees (n = 274) showed high reach (86%), satisfaction (7.1), and attendance rates (4.4 of 5 sessions). Significant effects were found on waist circumference (-1.5 cm to -2.1 cm) and body weight (-0.9 kg to -1.4 kg) among employees with higher attendance and satisfaction rates. CONCLUSIONS: Workplace health promotion via an occupational health guideline is feasible, but the environmental component and behavioral change counseling need revisions before practical application. PMID- 21701400 TI - Sleep habits, alertness, cortisol levels, and cardiac autonomic activity in short distance bus drivers: differences between morning and afternoon shifts. AB - OBJECTIVE: To evaluate sleep, alertness, salivary cortisol levels, and autonomic activity in the afternoon and morning shifts of a sample of short-distance bus drivers. METHODS: A sample of 47 bus drivers was evaluated. Data regarding subjects and working characteristics, alertness (psychomotor vigilance task), sleep habits (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Actigraphy), endocrine stress response (salivary cortisol), and autonomic activity (heart-rate variability) were collected. RESULTS: Sleep restriction was highly prevalent. Drivers in the morning shift slept 1 hour less than those in the afternoon shift, showed lower reaction time performance, a flattening of cortisol morning-evening difference, and higher overweight prevalence. CONCLUSIONS: The differences found between morning and afternoon shifts point out to the need of the implementation of educational strategies to compensate the sleep loss associated with an early work schedule. PMID- 21701401 TI - Firefighters, heart disease, and aspects of insulin resistance: the FEMA Firefighter Heart Disease Prevention study. AB - OBJECTIVE: To determine the association of cardiovascular risk markers with noninvasive imaging of atherosclerosis in firefighters. METHODS: Cross-sectional investigation of subclinical atherosclerosis with metabolic, work related, and life-style variables in 296 professional firefighters. RESULTS: Calcified coronary atherosclerosis (CAC), carotid arterial intimal thickness (CIMT), and electrocardiogram provided independent CVD assessments. Homeostatic Model Assessment (HOMA) concentrations were related to heart-rate-corrected QT (QTc) (slope +/- SE: 2.16 +/- 65, P = 0.001), average common CIMT (0.019 +/- 0.005 mm, P = 0.0005), and total CAC lesions (0.269 +/- 0.116, P = 0.02). Stepwise linear regression selected fasting insulin as the strongest predictor for QTc, HOMA as the strongest predictor of average CIMT, and fasting glucose as the strongest predictor of total coronary lesion number and score. CONCLUSION: Firemen's HOMA and fasting insulin and glucose concentrations were significantly associated with three measures of CVD. Aspects of insulin resistance are related to CVD risk among firefighters. PMID- 21701402 TI - Celiac disease in children with diarrhea in 4 cities in China. AB - OBJECTIVE: The aim of the study was to investigate whether celiac disease (CD) could be the cause of chronic diarrhea in Chinese patients. PATIENTS AND METHODS: During the period of January 2005 to December 2008, patients with chronic diarrhea in pediatric hospitals from 4 major cities (Shanghai, Wuhan, Jinan, and Chengdu) in China were included in the study. The clinical history, physical findings, and laboratory data were collected and analyzed. RESULTS: Among 199 patients with chronic diarrhea, 118 were enrolled in the study. Fourteen (11.9%) were diagnosed as being affected by CD. CONCLUSIONS: The 14 patients are the first reported cases of CD in Chinese patients with chronic diarrhea. PMID- 21701403 TI - Abandoning growth failure in neonatal intensive care units. PMID- 21701404 TI - Optimizing early nutritional support based on recent recommendations in VLBW infants and postnatal growth restriction. AB - OBJECTIVE: The aim of this study was to evaluate postnatal growth up to discharge in very low birth weight infants after optimizing nutritional support based on recent nutritional recommendations. PATIENTS AND METHODS: A prospective, nonrandomized, consecutive, and observational study in infants weighing <1250 g. RESULTS: One hundred two infants were included during a 2-year period (birth weight 1005 +/- 157 g, gestational age 28.5 +/- 1.9 weeks). First-day nutritional intake was 38 +/- 6 kcal/kg/day with 2.4 +/- 0.3 g/kg/day of protein. Mean intake during the first week of life was 80 +/- 14 kcal/kg/day with 3.2 +/- 0.5 g/kg/day of protein. On average from birth to discharge, 122 +/- 10 kcal/kg/day and 3.7 +/ 0.2 g/kg/day of protein were administered. Postnatal weight loss was limited to the first 3 days of life, and birth weight was regained after 7 days in average. Catch-up occurred after the second week in all groups of very low birth weight infants. Small-for-gestational age infants demonstrated an earlier and higher weight gain, allowing a rapid catch-up growth. The same proportion of infants was small-for-gestational age at birth and at discharge (20%, P = 0.74). CONCLUSIONS: This study confirmed that the first week of life is a critical period to promote growth and that early nutrition from the first day of life is essential. Postnatal weight loss may be limited and subsequent growth may be optimized with a dramatic reduction of postnatal growth restriction. PMID- 21701406 TI - Sequential therapy versus tailored triple therapies for Helicobacter pylori infection in children. AB - AIMS: The aim of the study was to compare sequential versus tailored triple therapy regimens on Helicobacter pylori (H pylori) eradication rates in children and to assess the effect of antimicrobial susceptibility. PATIENTS AND METHODS: Prospective, open-label, multicenter study. Children received randomly either a 10-day sequential treatment comprising omeprazole (OME) with amoxicillin for 5 days and OME, clarithromycin (CLA), and metronidazole (MET) for the remaining 5 days, or a 7-day triple therapy comprising OME with amoxicillin and CLA in cases of a CLA-susceptible strain or MET in cases of CLA-resistant strain. H pylori eradication was assessed by C-urea breath test. RESULTS: One hundred sixty-five children, 95 girls and 70 boys, of median age 10.4 years, were included. The intention-to-treat (ITT) eradication rate was 76.9% (sequential 68/83 = 81.9%, triple therapy 59/82 = 71.9%, ns), and the per-protocol (PP) eradication rate was 84.6% (sequential 68/77 = 88.3%, triple therapy 59/73 = 81.8%, ns). Eradication rates tended to be higher using the sequential treatment, but the difference was only statistically significant for ITT analysis in children harboring both CLA- and MET-susceptible strains (87.8% vs 68.5%, odds ratio [OR] 3.3, P = 0.03). Both ITT and PP eradication rates were significantly lower with sequential treatment in CLA-resistant compared with CLA-susceptible strains (ITT: 56.2% vs 72.7%, OR 5.5, P = 0.008; PP 64.3% vs 80.0%, OR 7.9, P = 0.009). Both treatments were well tolerated. CONCLUSIONS: Sequential treatment is greatly effective for eradicating H pylori in children except in CLA-resistant strains. Sequential treatment can be used as a first-line therapy, but only in areas with a low CLA resistance rate. PMID- 21701407 TI - Long-term follow-up of children with 6-thioguanine-related chronic hepatoxicity following treatment for acute lymphoblastic leukaemia. AB - 6-Thioguanine (6-TG) therapy in childhood acute lymphoblastic leukaemia results in chronic hepatotoxicity and portal hypertension. We report follow-up data in a cohort of 10 children with acute lymphoblastic leukaemia and 6-TG-related hepatotoxicity described initially in 2006. Clinically significant portal hypertension was present in the majority of patients several years after cessation of 6-TG treatment. These data reflect the natural history of noncirrhotic portal hypertension and emphasises the need to incorporate ongoing surveillance in the transition arrangement to adult services in this select group of patients. PMID- 21701408 TI - sTREM-1 and LBP in central venous catheter-associated bloodstream infections in pediatric intestinal failure. AB - OBJECTIVE: Central venous catheter-associated bloodstream infections (CVC-BSIs) are a major cause of morbidity and mortality in the pediatric intestinal failure (IF) population. We assessed plasma lipopolysaccharide-binding protein (LBP) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as biomarkers for CVC-BSI. We hypothesized that sTREM-1 and LBP rise with BSI and decline following treatment, and that baseline LBP is higher in the IF population than in controls. PATIENTS AND METHODS: Patients younger than 4 years were recruited from the IF registry at Cincinnati Children's Hospital. LBP and sTREM-1 levels were measured on 22 patients with IF at baseline, 17 patients with IF with BSIs, and 11 healthy controls. RESULTS: Mean sTREM-1 level (pg/mL) and LBP level (MUg/mL) rose with CVC-BSI over baseline (115.0 +/- 51.2 vs 85.9 +/- 27.6, P = 0.011 and 79.8 +/- 45.4 vs 20.5 +/- 11.3, P < 0.001, respectively) and declined following antibiotic therapy (115.0 +/- 51.2 vs 77.9 +/- 29.8, P = 0.003 and 79.8 +/- 45.4 vs 26.2 +/- 10.8, P < 0.001, respectively). Receiver operating characteristic curves showed that neither sTREM-1 nor LBP is sufficient to predict bacteremia versus fever without bacteremia (area under these curves = 0.57 and 0.82, respectively). Baseline LBP was higher in hospitalized patients than in outpatients (27.5 +/- 8.7 vs 13.5 +/- 9.2, P = 0.002), patients with previous BSIs versus those without (23.5 +/- 10.4 vs 10.1 +/- 8.3, P = 0.016), and those listed for transplantation versus those not listed (29.6 +/- 9.8 vs 16.2 +/- 9.5, P = 0.033). CONCLUSIONS: sTREM-1 and LBP rise with CVC-BSI in IF and decline after treatment; however, neither distinguishes infection from nonbacteremic febrile episodes. Baseline LBP may be a marker of disease severity in IF. PMID- 21701409 TI - Effects of wheel and hand-rim size on submaximal propulsion in wheelchair athletes. AB - PURPOSE: This study aimed to investigate the effects of fixed gear ratio wheel sizes on the physiological and biomechanical responses to submaximal wheelchair propulsion. METHODS: Highly trained wheelchair basketball players (N = 13) propelled an adjustable sports wheelchair in three different wheel sizes (24, 25, and 26 inches) on a motor-driven treadmill. Each wheel was equipped with force sensing hand-rims (SMARTWheel), which collected kinetic and temporal data. Oxygen uptake (VO2) and HR responses were measured with high-speed video footage collected to determine three-dimensional upper body joint kinematics. RESULTS: Mean power output and work per cycle decreased progressively with increasing wheel size (P < 0.0005). Increasing wheel size also reduced the physiological demand with reductions in VO2 for 25-inch (0.90 +/- 0.20 L . min(-1), P = 0.01) and 26-inch wheels (0.87 +/- 0.16 L . min(-1), P = 0.001) compared with 24-inch wheels (0.98 +/- 0.20 L . min(-1)). In addition, reductions in HR were observed for 26-inch wheels (99 +/- 6 beats . min(-1)) compared with 25-inch (103 +/- 8 beats . min(-1), P = 0.018) and 24-inch wheels (105 +/- 9 beats . min(-1), P = 0.004). Mean resultant forces also decreased progressively with increasing wheel size (P < 0.0005). However, no changes in temporal or upper body joint kinematics existed between wheel sizes. CONCLUSIONS: A greater power requirement owing to a greater rolling resistance in 24-inch wheels increased the physiological demand and magnitude of force application during submaximal wheelchair propulsion. PMID- 21701410 TI - Effect of fitness on reflex sympathetic neurovascular transduction in middle-age men. AB - PURPOSE: Muscle sympathetic nerve activity (MSNA) is increased in older endurance trained men, yet the reflex sympathetic forearm vasoconstrictor response to graded lower body negative pressure (LBNP) diminishes with age. The aim of this study was to assess the influence of aerobic exercise capacity on this altered neurovascular coupling. We hypothesized that during graded LBNP, the forearm vascular resistance (FVR)-MSNA relationship would be steeper in sedentary versus fit men. METHODS: We therefore studied 20 healthy middle-age men (age = 52 +/- 2 yr, mean +/- SE), 10 physically active (FIT) and 10 sedentary (SED) (129% +/- 4% vs 85% +/- 3% of predicted peak oxygen uptake) during 4 min each of LBNP at -5, 10, -20, and -40 mm Hg, applied in a random order. We determined HR, plasma norepinephrine, and MSNA (microneurography) and derived FVR from blood pressure and forearm blood flow (plethysmography). The FVR-MSNA relationship was determined by linear regression in each group separately, and groups were compared using multiple linear regression. RESULTS: MSNA burst frequency and FVR at rest and during LBNP (P < 0.003) were similar in the two groups, whereas HR was significantly lower (P < 0.002) both at rest and during LBNP in FIT men (P < 0.05). FVR during LBNP correlated positively with MSNA in the SED group (r = 0.44, P < 0.001) but not in the FIT group (r = 0.19, P = 0.10). Multiple linear regression confirmed that both MSNA (P < 0.001) and fitness level (P = 0.04) contribute to the forearm vascular response. CONCLUSIONS: Thus, during simulated orthostasis, middle-age SED men exhibit a significant FVR-MSNA relationship, which is not evident in age-matched FIT men. This alteration in neurovascular coupling may potentially affect cardiovascular risk in middle-age men. PMID- 21701412 TI - Role of nuclear medicine technologists: past, present and future. PMID- 21701413 TI - Intestinal ischemia-reperfusion injury leads to inflammatory changes in the brain. AB - Intestinal ischemia-reperfusion (I/R) injury is a well-established animal model of systemic inflammation and can lead to multiple organ failure as well as severe and lasting morbidity and even death. It can occur in humans as a result of vascular surgery or as secondary sequelae to many common conditions including low blood pressure, myocardial infarction, and necrotizing enterocolitis. Systemic inflammation induced through kidney I/R injury has been shown previously to lead to encephalopathic adverse effects, and it was theorized that intestinal injury would also cause secondary central nervous system effects. This study presents evidence that over a 6-h time frame, mouse intestinal I/R injury does not cause neuronal cell death in the brain in vivo. However, at the genetic level, certain inflammatory mediators such as endothelial nitric oxide synthase, intercellular adhesion molecule 1, P selectin, TNF-alpha, and IL-6 are significantly upregulated. There was a significant increase in brain edema observed in sham operated animals as well as in fasted and nonfasted I/R groups, but neurons were not apoptotic, in the 6-h time period. Conversely, Iba1-expressing activated microglia cells and glial fibrillary acidic protein-expressing astrocytes were found to be markedly increased in fasted and nonfasted I/R mice compared with controls and sham-operated animals. These data demonstrate that intestinal I/R injury induces inflammatory changes in the brain. PMID- 21701414 TI - The outcome of polymicrobial sepsis is independent of T and B cells. AB - The contribution of the adaptive and innate immune systems to the pathogenesis and outcome of sepsis remains a fundamental yet controversial question. Here, we use mice lacking the recombination activating gene 1 (Rag-1) to study the role of T and B cells in sepsis after cecal ligation and puncture (CLP). Spleens of Rag-1 mice were atrophic and completely devoid of CD3 T cells and CD19 B cells. Wild type mice and Rag-1 mice (both on a C57BL/6J background) underwent CLP or sham surgery. Both wild-type and Rag-1 mice developed clinical signs of sepsis within the first day after CLP. This included severe hypothermia as measured by a decrease in body surface temperature and organ dysfunction as detected by plasma increases in blood urea nitrogen and lactate dehydrogenase levels. Survival curves of wild-type and Rag-1 mice after CLP were superimposable, with 35% survival in the wild-type group and 27% survival in the Rag-1 group, respectively (not significant, P = 0.875). Using multiplex bead-based assays, the mediator concentrations for 23 cytokines and chemokines were measured in plasma of wild type and Rag-1 mice 8 h after CLP or sham surgery. Compared with sham surgery mice, the highest mediator levels were observed for granulocyte colony stimulating factor, keratinocyte chemoattractant, IL-6, monocyte chemotactic protein 1, and IL-10. Levels for most mediators were unaffected by the absence of T and B lymphocytes. Only the concentrations of IL-6 and IL-17 were found to be significantly lower in Rag-1 mice compared with wild-type mice. In conclusion, the absence of T and B cells in the CLP model used does not appear to affect the acute outcome of severe sepsis. PMID- 21701415 TI - The Angiotensin-converting enzyme inhibitor captopril inhibits poly(adp-ribose) polymerase activation and exerts beneficial effects in an ovine model of burn and smoke injury. AB - We investigated the effect of the angiotensin-converting enzyme (ACE) inhibitor captopril in a clinically relevant ovine model of smoke and burn injury, with special reference to oxidative stress and activation of poly(ADP-ribose) polymerase, in the lung and in circulating leukocytes. Female, adult sheep (28-40 kg) were divided into three groups. After tracheostomy and under deep anesthesia, both vehicle-control-treated (n = 5) and captopril-treated (20 mg/kg per day, i.v., starting 0.5 h before the injury) (n = 5) groups were subjected to 2 * 20%, third-degree burn injury and were insufflated with 48 breaths of cotton smoke. A sham group not receiving burn/smoke was also studied (n = 5). Animals were mechanically ventilated and fluid resuscitated for 24 h in the awake state. Burn and smoke injury resulted in an upregulation of ACE in the lung, evidenced by immunohistochemical determination and Western blotting. Burn and smoke injury resulted in pulmonary dysfunction, as well as systemic hemodynamic alterations. Captopril treatment of burn and smoke animals improved PaO2/FiO2 ratio and pulmonary shunt fraction and reduced the degree of lung edema. There was a marked increase in PAR levels in circulating leukocytes after burn/smoke injury, which was significantly decreased by captopril. The pulmonary level of ACE and the elevated pulmonary levels of transforming growth factor beta in response to burn and smoke injury were significantly decreased by captopril treatment. Our results suggest that the ACE inhibitor captopril exerts beneficial effects on the pulmonary function in burn/smoke injury. The effects of the ACE inhibitor may be related to the prevention of reactive oxygen species-induced poly(ADP ribose)polymerase overactivation. Angiotensin-converting enzyme inhibition may also exert additional beneficial effects by inhibiting the expression of the profibrotic mediator transforming growth factor beta. PMID- 21701416 TI - Prognostic significance of different subgroup classifications of critical illness related corticosteroid insufficiency in patients with septic shock. AB - The purpose of this study was to evaluate the prognostic significance of classification of patients with septic shock into different critical illness related corticosteroid insufficiency subgroups. A retrospective observational study was conducted in patients with septic shock who underwent a short corticotropin stimulation test within 72 h of the onset of shock. Patients were classified into normal adrenal function (NOM), low basal cortisol (LBC) (basal cortisol, <10 MUg/dL), or low Delta cortisol (LDC) (basal cortisol, >=10 MUg/dL; cortisol, <9 MUg/dL) groups. A total of 168 septic shock patients were recruited. Forty-two patients (25%) were assigned to the NOM group, 39 (23.2%) to the LBC group, and 87 (51.8%) to the LDC group. All of the patients received hydrocortisone therapy. Patients in the LDC group had significantly higher Simplified Acute Physiology Score 3 (P < 0.001) and Sequential Organ Failure Assessment score (P < 0.001) than did patients in the NOM group. The 28-day mortalities of the NOM, LBC, and LDC groups were 40.5%, 38.5%, and 63.2%, respectively (P = 0.007). Classification into the LDC group significantly increased the odds of 28-day mortality (odds ratio, 2.717; 95% confidence interval, 1.452-5.082; P = 0.002) and remained an independent risk factor for mortality even after controlling for all the other potential risk factors identified (odds ratio, 3.638; 95% confidence interval, 1.418-9.028; P = 0.006). Classification into the LDC group is an independent risk factor for mortality in hydrocortisone-treated septic shock patients. PMID- 21701417 TI - Novel hyperactive glucocorticoid receptor isoform identified within a human population. AB - Glucocorticoids serve as important therapeutic agents in diseases of inflammation, but clinical use, especially in advanced septic shock, remains controversial because of the unpredictable response. Prior studies correlate human glucocorticoid receptor (hGR) isoforms with a decreased response to steroid therapy. Further analysis of additional hGR isoforms may improve the understanding of the steroid response. Ninety-seven human volunteers' blood samples were surveyed for hGR isoforms. An isoform matching National Center for Biotechnology Informatics (NCBI) hGRalpha (hGR NCBI) served as a reference. Two isoforms were of particular interest-one isoform had three nonsynonymous single nucleotide polymorphisms (SNPs) (hGR NS-1), and the second had a single nucleotide deletion (hGR DL-1) resulting in a truncated protein. Transactivation potentials were measured using a luciferase reporter assay. Human glucocorticoid receptor NS-1 had activity more than twice of hGR NCBI, whereas hGR DL-1 demonstrated less than 10% of the activity of hGR NCBI. Cotransfection of two isoforms revealed that the presence of hGR NS-1 increased transactivation potential, whereas hGR DL-1 decreased activity. Synthetic constructs isolating individual and paired SNPs of hGR NS-1 were created to identify the SNP responsible for hyperactivity. Transactivation studies revealed a SNP within the ligand-binding domain exerted the greatest influence over hyperactivity. In evaluating the response to hydrocortisone, hGR NCBI and hGR NS-1 displayed an increased dose-dependent response, but hGR NS-1 had a response more than twice hGR NCBI. Characterization of the novel hyperactive hGR NS-1 provides insight into a possible mechanism underlying the unpredictable response to steroid treatment. PMID- 21701418 TI - Cecal ligation and puncture sepsis is associated with attenuated expression of adenylyl cyclase 9 and increased miR142-3p. AB - The host inflammatory response in sepsis may be resolved by endogenous anti inflammatory immune cell responses, avoiding fatal pathogenesis, organ injury, and death. The intracellular signaling mediator cyclic 3'5'-adenosine monophosphate is a potent modulator of inflammatory responses and initiates the polarization of immune cells in a direction that suppresses inflammatory activation. Cyclic 3'5'-adenosine monophosphate is enzymatically produced by adenylyl cyclases (ACs). The expression of ACs is previously shown to be reduced in rat organs after in vivo endotoxemia, concurrent with the progressing systemic inflammation. In the present study, tissue AC gene expression and regulation are explored in a rat model of cecal ligation and puncture (CLP) sepsis. Eighteen hours after CLP operation, expression of several AC isoforms in the liver, spleen, and kidney was reduced, significantly so for AC9 in all tissues. AC9 expression is regulated by the microRNA miR142-3p in T cells. When microRNA was extracted and amplified for miR142-3p expression, it was increasingly expressed 18 h after CLP. A correlation between increased miR142-3p and decreased AC9 expression was found in the liver, kidney, and spleen, and when hepatocytes, Kupffer cells (KCs), and liver sinusoidal endothelial cells were isolated after CLP, reduced AC expression and increased miR142-3p expression were found in KCs and liver sinusoidal endothelial cells. Transfecting a miR142-3p inhibitor probe in rat KCs abolished LPS-mediated AC9 inhibition in vitro. These results indicate that CLP leads to miR142-3p-mediated AC9 reduction in liver macrophages, which may further limit cyclic 3'5'-adenosine monophosphate signaling and the ability of macrophages to resolve the proinflammatory response. PMID- 21701419 TI - Lipoxin a4 increases survival by decreasing systemic inflammation and bacterial load in sepsis. AB - Sepsis is characterized by systemic inflammation with release of a large amount of inflammatory mediators. If sustained, this inflammatory response can lead to multiple organ failure and/or immunoparalysis. In the latter condition, the host may be susceptible to opportunistic infections or be unable to clear existing infections. Therefore, it is potentially beneficial to resolve inflammation by reducing inflammation without compromising host defense. We examined the effect of lipoxin A4 (LXA4), a compound with inflammatory resolution properties, in the cecal ligation and puncture (CLP) model of sepsis. Cecal ligation and puncture rats were given either saline or LXA4 (40 MUg/kg, i.p.) 5 h after surgery. Lipoxin A4 administration increased 8-day survival of CLP rats, which lived longer than 48 h, and attenuated tissue injury after 8 days. Therefore, we investigated the effects of LXA4 on systemic inflammation and bacterial load 48 h after CLP sepsis. Plasma IL-6, monocyte chemotactic protein 1, and IL-10 levels were reduced in LXA4-treated rats compared with CLP rats given saline vehicle. Lipoxin A4 reduced phosphorylation of the p65 subunit of nuclear factor kappaB (NF-kappaB) at serines 536 and 468 in peritoneal macrophages, suggesting that LXA4 reduced production of proinflammatory mediators through an NF-kappaB mediated mechanism. Lipoxin A4 reduced blood bacterial load and increased peritoneal macrophage number without affecting phagocytic ability, suggesting that LXA4 reduced blood bacterial load by enhancing macrophage recruitment. It also suggests that LXA4 reduced systemic inflammation and NF-kappaB activation without compromising host defense. Increased macrophage recruitment was in part due to a direct effect of LXA4 as LXA4 increased peritoneal macrophage recruitment in sham controls and partly due to reduced production of IL-10 as LXA4 decreased macrophage IL-10 release (a known inhibitor of macrophage migration) after CLP. The results suggest that LXA4 increased survival in sepsis by simultaneously reducing systemic inflammation as well as bacterial spread. PMID- 21701420 TI - Nonhematopoietic toll-like receptor 2 contributes to neutrophil and cardiac function impairment during polymicrobial sepsis. AB - Toll-like receptor 2 (TLR2) has been implicated in neutrophil and cardiac dysfunction during sepsis. Here we tested the hypothesis that nonhematopoietic (parenchymal) and hematopoietic TLR2 play distinct roles in sepsis pathogenesis. To achieve this, we generated two groups of chimeric mice with TLR2 deletions either in nonhematopoietic cells (knockout [KO] mice with wild-type [WT] bone marrow [BM]) or in BM cells (WT mice with KO-BM). Polymicrobial sepsis was created by cecal ligation and puncture (CLP). Neutrophil functions, cytokine production, and bacterial clearance were investigated following CLP or sham procedures. Cardiac contractile function was measured in a Langendorff apparatus. Intracellular reactive oxygen species (ROS) were measured using redox-sensitive dye and flow cytometry. Cecal ligation and puncture mice had markedly increased peritoneal neutrophil recruitment compared with the sham-operated mice. Toll-like receptor 2 KO mice, regardless their TLR2 phenotypes (WT vs. KO) in their BM derived hematopoietic cells, had markedly increased neutrophil migration as well as phagocytosis and reduced cytokine productions compared with TLR2 WT mice following polymicrobial peritonitis. These changes in the chimeric TLR2 KO mice were associated with enhanced blood bacterial clearance and markedly improved cardiac contractile function. Moreover, CLP induced a robust ROS production in the peritoneal leukocytes isolated from WT mice but not from TLR2 KO mice. Taken together, these data indicate that TLR2, particularly that of nonhematopoietic cells, plays a major role in sepsis pathogenesis by impairing neutrophil migratory and phagocytic function, promoting cytokine production, and mediating cardiac contractile dysfunction during polymicrobial sepsis. Toll-like receptor 2 also mediates critical ROS production during polymicrobial sepsis. PMID- 21701421 TI - Influence of severity of illness on the effects of eritoran tetrasodium (E5564) and on other therapies for severe sepsis. AB - Disease severity varies widely in patients with severe sepsis. Eritoran tetrasodium (E5564), a TLR4 antagonist, blocks the binding of endotoxin and is being evaluated as a novel therapy for severe sepsis. This analysis aimed to assess the efficacy of eritoran based on severity of illness and similar effects in other recent sepsis trials. Prospective covariates from a randomized, double blind, placebo-controlled, phase 2 trial were analyzed for treatment interaction measured by 28-day mortality. Five statistical interaction methodologies were used. The modified intent-to-treat population (n = 292), all-cause 28-day mortality was as follows: placebo, 33.3% (32/96); eritoran 45 mg/105 mg, 29.6% (58/196). Logistic regression analysis identified Acute Physiology and Chronic Health Evaluation II scores, predicted-risk-of-mortality scores, IL-6, age, sex, race, and eritoran use as associated with survival. Significant treatment interactions were observed (eritoran vs. placebo) for baseline covariates: Acute Physiology and Chronic Health Evaluation II (P = 0.035), predicted-risk-of mortality scores (P = 0.008), number of organ failures (P = 0.079), international normalized ratio (P = 0.05), and acute physiology score (P = 0.039). I analysis showed that 38% of the total eritoran treatment variance was explained by the severity-of-illness heterogeneity rather than by chance. No interactions observed with other variables. Consistent with the finding in this eritoran trial, other sepsis trials (IL-1 receptor antagonist, TNFsr-p55, antithrombin, drotrecogin alfa-activated) also demonstrated significant treatment by severity interaction. Potential survival benefits of eritoran in severe sepsis patients were associated with high severity of illness. These findings were used to design a phase 3 trial. Similar treatment by severity-of-illness interaction was found in most recent sepsis trials. PMID- 21701422 TI - Epidermal growth factor improves survival and prevents intestinal injury in a murine model of pseudomonas aeruginosa pneumonia. AB - Mortality from pneumonia is mediated, in part, through extrapulmonary causes. Epidermal growth factor (EGF) has broad cytoprotective effects, including potent restorative properties in the injured intestine. The purpose of this study was to determine the efficacy of EGF treatment following Pseudomonas aeruginosa pneumonia. FVB/N mice underwent intratracheal injection of either P. aeruginosa or saline and were then randomized to receive either systemic EGF or vehicle beginning immediately or 24 h after the onset of pneumonia. Systemic EGF decreased 7-day mortality from 65% to 10% when initiated immediately after the onset of pneumonia and to 27% when initiated 24 h after the onset of pneumonia. Even though injury in pneumonia is initiated in the lungs, the survival advantage conferred by EGF was not associated with improvements in pulmonary pathology. In contrast, EGF prevented intestinal injury by reversing pneumonia-induced increases in intestinal epithelial apoptosis and decreases in intestinal proliferation and villus length. Systemic cytokines and kidney and liver function were unaffected by EGF therapy, although EGF decreased pneumonia-induced splenocyte apoptosis. To determine whether the intestine was sufficient to account for extrapulmonary effects induced by EGF, a separate set of experiments was done using transgenic mice with enterocyte-specific overexpression of EGF (IFABP-EGF [intestinal fatty acid-binding protein linked to mouse EGF] mice), which were compared with wild-type mice subjected to pneumonia. IFABP-EGF mice had improved survival compared with wild-type mice following pneumonia (50% vs. 28%, respectively, P < 0.05) and were protected from pneumonia-induced intestinal injury. Thus, EGF may be a potential adjunctive therapy for pneumonia, mediated in part by its effects on the intestine. PMID- 21701423 TI - Endothelin-1 governs proliferation and migration of bronchoalveolar lavage derived lung mesenchymal stem cells in bronchiolitis obliterans syndrome. AB - BACKGROUND: Bronchiolitis obliterans syndrome (BOS) has an incidence of 57% at 5 years after lung transplantation, accounts for 30% of all deaths 3 years posttransplant and because treatment options are extremely limited, it constitutes a significant health care problem. Adult mesenchymal stem cells (MSCs) play a role in lung turnover; however, their role in BOS remains unknown. METHODS: MSCs were isolated from bronchoalveolar lavage (BAL) in 101 lung allograft recipients. BAL was screened by protein array and MSCs were analyzed by real-time polymerase chain reaction, proliferation, migration, and enzyme linked immunosorbent assays. RESULTS: Multipotent MSCs were isolated from BAL of lung recipients independent of BOS presence. However, MSCs from BOS patients proliferated at higher rates (P<0.001) and were associated with higher alpha smooth muscle actin (P = 0.03) but lower surfactant protein B (P = 0.02) compared with those from no-BOS patients. Histological analysis revealed that MSCs are abundant in lung tissue of BOS patients. MSCs from BOS patients produced higher endothelin-1 (ET-1) amounts (P<0.001) compared with those from no-BOS; and ET-1 stimulated whereas ET-1 blockade suppressed MSC proliferation, migration, and differentiation. CONCLUSIONS: These results indicate that MSCs are associated with BOS and are governed by ET-1. Targeting MSCs by ET-1 blockade might be useful in BOS treatment. PMID- 21701424 TI - Introduction to a special section on the causality, diagnosis, and management of abnormal uterine bleeding. PMID- 21701425 TI - Pathologic basis for abnormal uterine bleeding with organic uterine pathologies. AB - Research is ongoing into the mechanisms of abnormal uterine bleeding, including bleeding from organic etiologies, where there is an intrinsic uterine lesion. Most of the current studies are focused on abnormalities of angiogenesis. By elucidating these mechanisms, targeted therapies can be developed. This article reviews the literature on pathologic mechanisms involved in bleeding from organic etiologies. PMID- 21701426 TI - Endometrial bleeding in postmenopausal women: with and without hormone therapy. AB - The aim of this study was to present a review of the potential mechanisms involved in the occurrence of endometrial bleeding in postmenopausal women using hormone therapy. Selected literature on the incidence of bleeding in postmenopausal women using estrogen progestogen therapy was reviewed. The incidence of spotting and bleeding in women using continuous-combined hormone therapy was presented. Relevant articles related to the role of angiogenic factors and vasculogenesis in the endometrium, endometrial leukocytes, and endometrial metalloproteinases were used for the review. The cause or etiology of endometrial bleeding with hormone therapy is unknown. Several options are known to alter angiogenesis or be involved in tissue remodeling during normal menstruation. Vascular endothelial growth factor and thrombospondin-1 are proangiogenic and antiangiogenic factors that could cause dysfunction in vasculogenesis that could result in blood vessel fragility and bleeding. The role of pericytes in maintaining vessel morphology and integrity is discussed. Endometrial leukocytes and metalloproteinases are involved in normal menstruation, but their role in postmenopausal bleeding is not clear suggesting involvement of mechanisms in the bleeding. There is limited information on clinical investigation into the etiology of postmenopausal bleeding associated with hormone therapy. The major cause of hormone therapy-related bleeding is unknown. Alterations in angiogenic factors that could result in vascular dysfunction and vessel breakdown provide a working hypothesis as to the potential cause of vessel breakdown. PMID- 21701427 TI - Diagnosis of abnormal uterine bleeding with imaging. AB - The major role of ultrasound in the evaluation of abnormal uterine bleeding, other than that occurring during pregnancy, is in postmenopausal women. Because postmenopausal bleeding can be the presenting symptom of endometrial cancer, any woman with this symptom should be evaluated to diagnose or exclude carcinoma. Over the last two decades, the role of ultrasound in the evaluation of postmenopausal bleeding has changed markedly, from little or no role in 1990 to a major role today. In the intervening years, numerous studies have shown that ultrasound is at least as sensitive as endometrial biopsy for endometrial cancer and that ultrasound can reliably exclude cancer without the need for biopsy in some women with postmenopausal bleeding. In particular, numerous studies have shown that women with an endometrial thickness of 4 mm or less have an extremely low likelihood of endometrial cancer and thus do not need to undergo endometrial biopsy. Ultrasound can also help in the selection of an appropriate biopsy technique. In a woman with postmenopausal bleeding and a thick endometrium, a sonohysterogram can determine whether the endometrium is diffusely thick or has focal areas of thickening. With diffuse thickening, a blind endometrial biopsy is appropriate. When there are one or more focal areas of thickening, hysteroscopic biopsy is likely to be the better choice. We present two clinical algorithms, either of which is an acceptable approach to the use of ultrasound and/or endometrial biopsy in women with postmenopausal bleeding: the "ultrasound-first" approach and the "biopsy-first" approach. PMID- 21701428 TI - Diagnosis of abnormal uterine bleeding with biopsy or hysteroscopy. AB - Abnormal uterine bleeding in women is a common cause for gynecologic consultation. Physicians must maintain a low threshold for endometrial assessment in abnormal uterine bleeding. Accurately determining the etiology of the bleeding permits appropriate treatment, minimizes unnecessary delays in therapy, and prevents needless worry in women. There are few national consensus guidelines, best practice guidelines, or treatment algorithms that provide gynecologists with scrupulous data to make concise decisions for the utilization of technology such as endometrial biopsy, transvaginal ultrasound, saline infusion sonography, or hysteroscopy in the evaluation of menstrual aberrations. Using technology that has a high sensitivity to detect a disease allows a physician to make concise decisions for proceeding with minimally invasive procedures or reliance on medical therapies that will probably be effective. PMID- 21701429 TI - Significance of incidentally thick endometrial echo on transvaginal ultrasound in postmenopausal women. AB - Postmenopausal bleeding is "cancer until proven otherwise." A thin distinct endometrial echo on transvaginal ultrasound has a risk of malignancy of 1 in 917 and does not require an endometrial biopsy. If the endometrial echo is poorly visualized, then in such women, saline infusion sonohysterography is an appropriate next step. The prevalence of asymptomatic endometrial thickening (mostly due to inactive polyps) is high, approximately 10% to 17% of postmenopausal women. The risk of malignancy in such polyps is low (approximately 0.1%), and in structures that mimic polyps, it is also low (0.3%). The incidence of serious complications from an operative intervention in such postmenopausal women is not insignificant (1.3%-3.6%). Thus, automatic intervention in such women, without any high-risk status, is not warranted. PMID- 21701430 TI - Alternatives to hysterectomy: focus on global endometrial ablation, uterine fibroid embolization, and magnetic resonance-guided focused ultrasound. AB - The aim of this study was to inform the clinician of alternatives to hysterectomy through a critical evaluation of three treatment options: global endometrial ablation, uterine fibroid embolization, and magnetic resonance-guided focused ultrasound. Studies published in English-language, peer-reviewed journals were systematically searched using Cochrane and Medline. Keywords used included "alternatives to hysterectomy," "endometrial ablation," "uterine fibroid embolization," "uterine artery embolization," and "focused ultrasound." Articles meeting the inclusion criteria were reviewed and analyzed for themes and similarities. All three alternative methods of treatment reviewed are currently approved for use in the United States and abroad. In fact, five different global endometrial ablation devices are approved by the Food and Drug Administration for treatment of menorrhagia. Patient satisfaction scores after endometrial ablation are high (90%-95%), but amenorrhea rates are much lower (15%-60%). Data from randomized trials demonstrate that uterine fibroid embolization results in a shorter hospital stay and quicker return to work as compared with abdominal hysterectomy for leiomyomas, but after embolization, up to 20% of women need a second procedure. Ex-ablative therapy of leiomyomas with focused ultrasound is the newest of the three methods. It has a special set of patient selection criteria and is only available at less than 20 medical centers in the United States. Leiomyoma symptom relief after focused ultrasound therapy at 1 year post procedure is high (85%-95%). There are many effective alternatives to hysterectomy in women with menorrhagia and/or symptomatic leiomyomas. However, because these procedures are performed by individuals from different subspecialists, primarily gynecologists and interventional radiologists, clinicians must consider using a multidisciplinary approach to find the best procedure for a given patient. There are no randomized trials comparing uterine fibroid embolization to vaginal hysterectomy, laparoscopic hysterectomy, or laparoscopic myomectomy. PMID- 21701432 TI - Pharmacological therapy for abnormal uterine bleeding. AB - Pharmacological therapies for the treatment of abnormal uterine bleeding are effective and generally well tolerated. This review presents an evidence-based approach to medical therapy. Selection depends on the etiology and amount of bleeding, need for contraception or preservation of fertility, perimenopause status, and medication efficacy and adverse effects.Available nonhormonal agents include nonsteroidal anti-inflammatory agents, which reduce bleeding by 25% to 35% and improve dysmenorrhea through reduced prostaglandin levels; tranexamic acid, which inhibits plasminogen activator with a 40% to 60% reduction in menstrual blood loss; and intranasal desmopressin, which is an antifibrinolytic for women with an underlying bleeding disorder (eg, von Willebrand disease).Hormonal regimens cause the inhibition of endometrial growth. Cyclic progestogen therapy for 21 days results in a significant reduction in menstrual blood loss. Limited data suggest that oral contraceptives reduce menstrual blood loss by 40% to 50% with decreased breast tenderness and dysmenorrhea and a reduction in risk of uterine and ovarian cancer. The progestin-releasing intrauterine devices are effective up to 97% by 6 months and provide relief of dysmenorrhea and contraception. Long-acting progestogen injections produce amenorrhea and provide contraception but are associated with irregular spotting and reversible bone loss. Danazol leads to endometrial atrophy with a reduced menstrual loss; androgenic adverse effects may be lessened with lower doses or vaginal use. Gonadotrophin agonists lead to ovarian suppression and are used to shrink fibroids or the endometrium preoperatively but are limited by hypoestrogenic adverse events. Emergency use of parenteral conjugated estrogens has a 70% chance of stopping abnormal bleeding but an increased risk of thrombosis. PMID- 21701433 TI - Future developments in the medical treatment of abnormal uterine bleeding: what can we expect? AB - New therapies for abnormal uterine bleeding have been slow to reach the marketplace for a variety of reasons. These reasons include the availability of cost-effective therapies already available and the extraordinarily difficult and expensive regulatory barriers emphasizing long-term safety. Common comorbidities like bleeding diatheses, adenomyosis, and leiomyomata further complicate clinical development, necessitating large study samples and making it more expensive. Even the accurate measurement of menstrual blood loss adds an additional hindrance to novel drug development. These obstacles and the currently available therapies will be reviewed in the context of developing new methods for approaching this complicated and prevalent clinical problem. PMID- 21701434 TI - Checking the pulse of the menopausal hot flash: feeling the heat and saving the beat. PMID- 21701435 TI - New data on mindfulness-based stress reduction for hot flashes: how do alternative therapies compare with selective serotonin reuptake inhibitors? PMID- 21701437 TI - Acute oral toxicity of methanolic seed extract of Cassia fistula in mice. AB - BACKGROUND AND OBJECTIVE: Cassia fistula is widely used in traditional medicine to treat various types of ailments. The evaluation of toxic properties of C. fistula is crucial when considering public health protection because exposure to plant extracts can result in undesirable effects on consumers. Hence, in this study the acute oral toxicity of C. fistula seeds extract was investigated in mice. RESULTS: Oral administration of crude extract at the highest dose of 5000 mg/kg resulted in no mortalities or evidence of adverse effects, implying that C. fistula in nontoxic. Throughout 14 days of the treatment no changes in behavioural pattern, clinical sign and body weight of mice in both control and treatment groups. Also there were no any significant elevations observed in the biochemical analysis of the blood serum. Further, histopathological examination revealed normal architecture and no significant adverse effects observed on the kidney, heart, liver, lung and spleen. CONCLUSIONS: Overall, the results suggest that, the oral administration of C. fistula methanolic seeds extract did not produce any significant toxic effect in mice. Hence, the extract can be utilized for pharmaceutical formulations. PMID- 21701436 TI - Recent advances in the synthesis of N-containing heteroaromatics via heterogeneously transition metal catalysed cross-coupling reactions. AB - N-containing heteroaromatics are important substructures found in numerous natural or synthetic alkaloids. The diversity of the structures encountered, as well as their biological and pharmaceutical relevance, have motivated research aimed at the development of new economical, efficient and selective synthetic strategies to access these compounds. Over more than 100 years of research, this hot topic has resulted in numerous so-called "classical synthetic methods" that have really contributed to this important area. However, when the selective synthesis of highly functional heteroaromatics like indoles, quinolones, indoxyls, etc. is considered these methods remain limited. Recently transition metal-catalysed (TM-catalysed) procedures for the synthesis of such compounds and further transformations, have been developed providing increased tolerance toward functional groups and leading generally to higher reaction yields. Many of these methods have proven to be the most powerful and are currently applied in target- or diversity-oriented syntheses. This review article aims at reporting the recent developments devoted to this important area, focusing on the use of heterogeneous catalysed procedures that include either the formation of the heterocyclic ring towards the nuclei or their transformations to highly substituted compounds. PMID- 21701431 TI - The Surgical Treatments Outcomes Project for Dysfunctional Uterine Bleeding: summary of an Agency for Health Research and Quality-sponsored randomized trial of endometrial ablation versus hysterectomy for women with heavy menstrual bleeding. AB - Surgical Treatments Outcomes Project for Dysfunctional Uterine Bleeding is an agency for the Healthcare Research and Quality project built around a multicenter randomized clinical trial comparing hysterectomy and endometrial ablation (EA) for the treatment of heavy menstrual bleeding unrelated to structural causes. For inclusion, women self-defined their complaint, and the endometrial cavity was evaluated to exclude structural lesions. The primary outcomes were bleeding and major problem "solved" at 24 months, with length of institutional stay, surgical complications, quality of life, and reoperation included as secondary outcomes. Also measured was the baseline economic impact of heavy menstrual bleeding. The randomized controlled trial enrolled 237 women. Institutional stay was longer, and perioperative adverse events were more common and severe for those randomized to hysterectomy. At 24 months, 94.4% and 84.9% of women randomized to hysterectomy and EA, respectively, considered their major problem to be solved; at 48 months, the numbers were similar at 98.0% and 85.1%. Postprocedure quality of-life measures (SF-36, EuroQOL) improved similarly in both groups, but reoperation was more common for women undergoing EA (34, or 30.9%, at 60 mo), with most (32 of 34) selecting hysterectomy.At baseline, women reported missed work as well as activity and leisure limitations. Excess monetary costs were $306 per patient-year (95% CI, $30-$1,872). Excess work and home management loss costs were $2,152 (95% CI, $1,862-$2,479). It was estimated that successful treatment, regardless of the type of intervention, could result in a gain of 1.8 quality adjusted life years. Future studies will examine and compare the impact of the study interventions on economic outcomes. PMID- 21701439 TI - Enantio and diastereoselective addition of phenylacetylene to racemic alpha chloroketones. AB - In this report, we have presented the first diastereoselective addition of phenylacetylene to chiral racemic chloroketones. The addition is controlled by the reactivity of the chloroketones that allowed the stereoselective reaction to be performed at -20 degrees C. Chiral racemic chloroketones are used in the reaction. By carefully controlling the temperature and the reaction time we were able to isolate the corresponding products in moderate yields and with good, simple and predictable facial stereoselection. Our reaction is a rare example of the use of chiral ketones in an enantioselective alkynylation reaction and opens new perspectives for the formation of chiral quaternary stereocenters. PMID- 21701438 TI - The main anticancer bullets of the Chinese medicinal herb, thunder god vine. AB - The thunder god vine or Tripterygium wilfordii Hook. F. is a representative Chinese medicinal herb which has been used widely and successfully for centuries in treating inflammatory diseases. More than 100 components have been isolated from this plant, and most of them have potent therapeutic efficacy for a variety of autoimmune and inflammatory diseases. In the past four decades, the anticancer activities of the extracts from this medicinal herb have attracted intensive attention by researchers worldwide. The diterpenoid epoxide triptolide and the quinone triterpene celastrol are two important bioactive ingredients that show a divergent therapeutic profile and can perturb multiple signal pathways. Both compounds promise to turn traditional medicines into modern drugs. In this review, we will mainly address the anticancer activities and mechanisms of action of these two agents and briefly describe some other antitumor components of the thunder god vine. PMID- 21701441 TI - Spinosad (Natroba) topical suspension for head lice. AB - The FDA has approved spinosad 0.9% suspension(Natroba - ParaPro) for topical treatment of head liceinfestation in patients >4 years old. It is available only byprescription. PMID- 21701440 TI - Linagliptin (Tradjenta)--a new DPP-4 inhibitor for type 2 diabetes. PMID- 21701442 TI - Ipilimumab (Yervoy) for metastatic melanoma. PMID- 21701443 TI - Drugs for irritable bowel syndrome. PMID- 21701444 TI - Posterior reversible encephalopathy syndrome in the Intensive Care Unit after liver transplant: a comparison of our experience with the existing literature. AB - Posterior reversible encephalopathy syndrome (PRES) is a rare disease characterized by altered mental status, seizures, headache, vomiting and visual disturbances, most often described after transplantation and immunosuppressive therapy. PRES is commonly first diagnosed by the neuroradiologist, rather than the clinician, as it is characterized by very typical magnetic resonance imaging (MRI) features, i.e., hyperintense lesions in the territories of the posterior cerebral artery. Here we report our experience in the Intensive Care Unit (ICU) with a case of tacrolimus-related PRES after liver transplant, presenting with sudden neurological deterioration and diffuse and massive hyperintensities upon brain MRI. Discontinuation of tacrolimus, as prompted by the established literature, permitted the patient to eliminate tacrolimus-associated toxicity, whereas its substitution with everolimus and mycofenolic acid allowed the maintenance of immunosuppression while avoiding acute organ rejection and reducing the dosage of corticosteroids. The lowering of blood pressure with drugs reported in the literature for use in PRES proved to be effective but challenging, requiring the use of multiple drugs and only slowly leading to proper control of hypertensive peaks. Nonetheless, hypertension management and supportive therapy allowed for a complete neurological restitutio ad integrum of the patient. In conclusion, tacrolimus-related brain adverse events need to be promptly recognized, especially during the first months after transplantation. When tacrolimus-related PRES occurs, immunosuppressive therapy may be safely and efficiently switched to everolimus and mycofenolic acid. This strategy may help not only to avoid acute organ rejection but also to reduce the dosage of corticosteroids, which might interfere with proper control of hypertension. PMID- 21701445 TI - Possible counter effect in newborns of 1936A>G (I646V) polymorphism in the AKAP10 gene encoding A-kinase-anchoring protein 10. AB - OBJECTIVE: Cyclic adenosine monophosphate/protein kinase A (PKA) is important in embryonic development. The human AKAP10 gene is polymorphic: 1936A>G results in changes to a PKA-binding domain and increased targeting to mitochondria. Previous studies found G1936 as 'deleterious' in adults, and this study investigates whether this holds true in preterm birth. STUDY DESIGN: Study group consisted of 80 preterm newborns (PTNs) born before the 38th gestation week. Control group consisted of 123 full-term healthy newborns born after the 37th gestation week with uncomplicated pregnancies. Genomic DNA was extracted from umbilical blood and AKAP10 genotypes were identified by PCR/restriction enzyme. RESULT: Significant differences in frequencies of 1936A>G genotypes/alleles between both groups were found. PTNs had increased frequency (55%) of AA homozygotes (odds ratio, AA versus AG+GG: 2.63 (95% confidence interval: 1.33 to 5.20), P=0.006) after adjustments: mothers with previous PTNs, smoking, first pregnancy, first delivery and Cesarean section. CONCLUSION: Results suggest G1936 is preventative factor against preterm birth, in contrast with previously asserted negative effects in adults. PMID- 21701446 TI - Milk as a vehicle for oral medications: hidden osmoles. AB - OBJECTIVE: Once critically ill, preterm infants have transitioned to enteral or oral feedings, it is common to mix oral medications with milk feedings. The osmolality of oral and intravenous drugs were tested in the 1980s and many were found to exceed the American Academy of Pediatrics (AAP) recommended limit (400 mOsm kg(-1) H(2)O). Many new milks and medications have entered the neonatal intensive care unit (NICU) since then. The objective of this study was to measure the osmolality of common milk-medication combinations administered in the NICU. STUDY DESIGN: Common milk-medication mixtures were analyzed for osmolality by freezing point depression. RESULT: Only Elecare (30 kcal per oz) exceeded AAP recommendations for osmolality in its unadulterated state. The addition of multivitamins alone resulted in an osmolality that exceeded 400 mOsm kg(-1) H(2)O. The cumulative addition of other medications resulted in some osmolalities >1000 mOsm kg(-1) H(2)O. CONCLUSION: The coadministration of medications with milk products should be evaluated as a potential contributor to gastrointestinal intolerance of feedings in preterm infants. PMID- 21701447 TI - Microbiome: Human gut microbiota can be readily cultured, manipulated and archived. PMID- 21701448 TI - Periodontal disease--who cares? PMID- 21701449 TI - A substantial gap. PMID- 21701450 TI - An inappropriate challenge. PMID- 21701451 TI - Useful remedies. PMID- 21701452 TI - Restoration fragments. PMID- 21701453 TI - Impeccable article. PMID- 21701454 TI - Quackery risk. PMID- 21701455 TI - Ethically unacceptable. PMID- 21701456 TI - Mirror magic. PMID- 21701457 TI - BDA seeks urgent meeting over teeth whitening products. PMID- 21701458 TI - Thomas to target Welsh teeth. PMID- 21701460 TI - New resource will aid patient toothpaste choice. PMID- 21701461 TI - Dentists sought for rare judicial appointments. PMID- 21701462 TI - Eight hundred complete Diploma in Postgraduate Dental Studies. PMID- 21701464 TI - Dundee will spearhead cleft research. PMID- 21701465 TI - Sharp drop in referrals to National Clinical Assessment Service. PMID- 21701466 TI - King's is first centre of excellence. PMID- 21701471 TI - Effectiveness and acceptability of intravenous sedation in child and adolescent dental patients: report of a case series at King's College Hospital, London. AB - INTRODUCTION: Conscious sedation for young patients continues to be challenging. Few studies have shown positive results using intravenous midazolam when sedating young patients. This case series reports an investigation of conscious sedation using intravenous midazolam for young patients receiving dental treatment. OBJECTIVE: To determine acceptance, safety and efficacy of intravenous midazolam for conscious sedation in children and adolescent patients undergoing dental treatment.Patients and methods Patients from seven to 16 years of age, ASA I, II and III, opted to have extractions, minor oral surgery and/or conservative treatment with IV midazolam and local anaesthesia. A pulse oximeter was used to monitor vital signs and the Houpt scale to assess overall behaviour. RESULTS: A total of 552 patients, 234 boys and 318 girls with mean ages of 13.3 years and 13.5 years respectively, were included. Three hundred and sixty-five patients (66%) claimed to be anxious or very anxious before treatment. The average dose given was 5.7 mg and dosage ranged from 2 to 10 mg. Four hundred and fifty-seven patients (83%) scored 'very good' and 'excellent' for overall behaviour. Side effects included crying, drowsiness and amnesia. CONCLUSIONS: Intravenous midazolam is accepted by patients and is a safe and effective method of sedation for use in children and adolescents, producing some level of tearfulness. PMID- 21701472 TI - Patient anxiety and IV sedation in Northern Ireland. AB - BACKGROUND: In recent years there has been an increase in the provision of conscious sedation, which is said to be a safe and effective means of managing the anxious patient. However, there are no guidelines to aid the dental practitioner in assessing the patient's need for sedation based on their level of anxiety. AIMS AND METHODS: The present study investigated the importance of patient anxiety as an indicator for IV sedation, using focus groups to inform the development of narrative vignettes. Ninety-nine practitioners responded to a series of scenarios to determine whether the level of patient anxiety and the patient's demand for IV sedation influenced their decision making. RESULTS: Level of dental anxiety had a stronger influence on the clinician's decision making than patient demand, with increasing levels of dental anxiety being positively associated with the likelihood of clinicians indicating a need for IV patient sedation and also, the likelihood of clinicians providing IV sedation to these patients. Only 14% (n = 14) of respondents reported formally assessing dental anxiety. CONCLUSIONS: While dental anxiety is considered to be a key factor in determining the need for IV sedation, there is a lack of guidance regarding the assessment of anxiety among patients. PMID- 21701487 TI - Deregulated apoptosis signaling in core-binding factor leukemia differentiates clinically relevant, molecular marker-independent subgroups. AB - Core-binding factor (CBF) leukemias, characterized by translocations t(8;21) or inv(16)/t(16;16) targeting the CBF, constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, about 40% of patients relapse and the current classification system does not fully reflect this clinical heterogeneity. Previously, gene expression profiling (GEP) revealed two distinct CBF leukemia subgroups displaying significant outcome differences and identified apoptotic signaling, MAPKinase signaling and chemotherapy-resistance mechanisms among the most significant differentially regulated pathways. We now tested different inhibitors of the respective pathways in a cell line model (six cell lines reflecting the CBF subgroup-specific gene expression alterations), and found apoptotic signaling to be differentiating between the CBF subgroup models. In accordance, primary samples from newly diagnosed CBF AML patients (n=23) also showed differential sensitivity to in vitro treatment with a Smac mimetic such as BV6, an antagonist of inhibitor of apoptosis (IAP) proteins, and ABT-737, a BCL2 inhibitor. Furthermore, GEP revealed the BV6-resistant cases to resemble the previously identified unfavorable CBF subgroup. Thus, our current findings show deregulated IAP expression and apoptotic signaling to differentiate clinically relevant CBF subgroups, which were independent of known molecular markers, thereby providing a starting point for novel therapeutic approaches. PMID- 21701488 TI - MicroRNA signatures characterize multiple myeloma patients. PMID- 21701489 TI - MicroRNAs in acute leukemia: from biological players to clinical contributors. AB - MicroRNAs (miRNAs) are involved in the management of hematopoiesis. As a consequence, miRNA dysregulation causes disruption of the hematopoietic system and leukemia may arise. We here comprehensively discuss miRNAs found discriminative for cytogenetic and molecular subtypes of acute leukemia. These miRNAs are either known miRNAs involved in leukemogenesis with proven tumor suppressor or oncogenic activities or are newly identified by high-throughput sequencing with yet unknown function. Furthermore, forces are outlined that drive aberrant miRNA function, which include genetic abnormalities (for example, deletions, translocations and mutations) and epigenetic aberrations (for example, aberrant DNA methylation or histone modifications). Interestingly, leukemia silenced miRNAs can be re-expressed upon treatment with de-methylating agents. Targeting miRNA expression may serve a therapeutical role, albeit at present this way of targeted therapy is in its infancy. However, emerging knowledge about the biology of miRNAs in leukemia may result into a role for these miRNAs in the diagnosis and treatment of acute leukemia. PMID- 21701490 TI - Exposure to tungsten induces DNA damage and apoptosis in developing B lymphocytes. PMID- 21701491 TI - The different epidemiologic subtypes of Burkitt lymphoma share a homogenous micro RNA profile distinct from diffuse large B-cell lymphoma. AB - Sporadic Burkitt lymphoma (sBL) can be delineated from diffuse large B-cell lymphoma (DLBCL) by a very homogeneous mRNA expression signature. However, it remained unclear whether all three BL variants-sBL, endemic BL (eBL) and human immunodeficiency virus-associated BL (HIV-BL)-represent a uniform biological entity despite their differences in geographical occurrence, association with immunodeficiency and/or incidence of Epstein-Barr virus (EBV) infection. To address this issue, we generated micro RNA (miRNA) profiles from 18 eBL, 31 sBL and 15 HIV-BL cases. In addition, we analyzed the miRNA expression of 86 DLBCL to determine whether miRNA profiles recapitulate the molecular differences between BL and DLBCL evidenced by mRNA profiling. A signature of 38 miRNAs containing MYC regulated and nuclear factor-kB pathway-associated miRNAs was obtained that differentiated BL from DLBCL. The miRNA profiles of sBL and eBL displayed only six differentially expressed miRNAs, whereas HIV and EBV infection had no impact on the miRNA profile of BL. In conclusion, miRNA profiling confirms that BL and DLBCL represent distinct lymphoma categories and demonstrates that the three BL variants are representatives of the same biological entity with only marginal miRNA expression differences between eBL and sBL. PMID- 21701492 TI - Interleukin-27 inhibits pediatric B-acute lymphoblastic leukemia cell spreading in a preclinical model. AB - B-acute lymphoblastic leukemia (B-ALL) represents the most common pediatric hematological tumor that derives from the aberrant proliferation of early B lymphocytes in the bone marrow. Although most of the B-ALL children take advantage from current therapeutic protocols, some patients relapse and need alternative therapies. With this background, we investigated whether interleukin (IL)-27, an immunomodulatory cytokine with antitumor properties, may function as an antitumor agent against pediatric B-ALL cells. Here we show for the first time that pediatric B-ALL cells functional IL-27R and that IL-27 dampens directly tumor growth in vivo and in vitro through mechanisms elucidated in this study. The novelty of these results deals with the first demonstration that (1) B-ALL cells from pediatric patients injected intravenously (i.v.) into NOD/SCID/Il2rg( /-) (NSG) mice gave rise to leukemic spreading that was severely hampered by IL 27; (2) IL-27-treated mice, compared with controls, showed significant reduction of putative B-ALL-initiating cells and blasts in the peripheral blood (PB), bone marrow (BM) and spleen; and that (3) IL-27 reduced in vitro B-ALL cell proliferation and angiogenesis, induced apoptosis and downregulated miR-155. Our results strongly encourage the development of future clinical trials to evaluate the toxicity and efficacy of IL-27 in childhood B-ALL patients. PMID- 21701493 TI - Lyn-mediated SHP-1 recruitment to CD5 contributes to resistance to apoptosis of B cell chronic lymphocytic leukemia cells. AB - In B-cell chronic lymphocytic leukemia (B-CLL) cells, Lyn, a tyrosine kinase belonging to the Src family, is overexpressed and atypically localized in an aberrant cytosolic complex in an active conformation, contributing to the unbalance between cell survival and pro-apoptotic signals. In this study, we demonstrate that Lyn constitutively phosphorylates the immunoreceptor tyrosine inhibitory motifs of the inhibitory cell surface co-receptor CD5, a marker of B CLL. As a result, CD5 provides an anchoring site to Src homology 2 domain containing phosphatase 1 (SHP-1), a known negative regulator of hematopoietic cell function, thereby triggering the negative B-cell receptor (BCR) signaling. The subsequent segregation of SHP-1 into two pools, one bound to the inhibitory co-receptor CD5 in an active form, the other in the cytosol in an inhibited conformation, proves crucial for withstanding apoptosis, as shown by the use of phosphotyrosine phosphatase-I-I, a direct inhibitor of SHP-1, or SHP-1 knockdown. These results confirm that Lyn exhibits the unique ability to negatively regulate BCR signaling, in addition to positively regulating effectors downstream of the BCR, and identify SHP-1 as a novel player in the deranged signaling network and as a potential attractive target for new therapeutic strategies in B-CLL. PMID- 21701494 TI - Sequence analysis of 515 kinase genes in chronic lymphocytic leukemia. PMID- 21701495 TI - p53 independent epigenetic-differentiation treatment in xenotransplant models of acute myeloid leukemia. AB - Suppression of apoptosis by TP53 mutation contributes to resistance of acute myeloid leukemia (AML) to conventional cytotoxic treatment. Using differentiation to induce irreversible cell cycle exit in AML cells could be a p53-independent treatment alternative, however, this possibility requires evaluation. In vitro and in vivo regimens of the deoxycytidine analogue decitabine that deplete the chromatin-modifying enzyme DNA methyl-transferase 1 without phosphorylating p53 or inducing early apoptosis were determined. These decitabine regimens but not equimolar DNA-damaging cytarabine upregulated the key late differentiation factors CCAAT enhancer-binding protein E and p27/cyclin dependent kinase inhibitor 1B (CDKN1B), induced cellular differentiation and terminated AML cell cycle, even in cytarabine-resistant p53- and p16/CDKN2A-null AML cells. Leukemia initiation by xenotransplanted AML cells was abrogated but normal hematopoietic stem cell engraftment was preserved. In vivo, the low toxicity allowed frequent drug administration to increase exposure, an important consideration for S phase specific decitabine therapy. In xenotransplant models of p53-null and relapsed/refractory AML, the non-cytotoxic regimen significantly extended survival compared with conventional cytotoxic cytarabine. Modifying in vivo dose and schedule to emphasize this pathway of decitabine action can bypass a mechanism of resistance to standard therapy. PMID- 21701496 TI - Transcription factor TEAD4 regulates expression of myogenin and the unfolded protein response genes during C2C12 cell differentiation. AB - The TEAD (1-4) transcription factors comprise the conserved TEA/ATTS DNA-binding domain recognising the MCAT element in the promoters of muscle-specific genes. Despite extensive genetic analysis, the function of TEAD factors in muscle differentiation has proved elusive due to redundancy among the family members. Expression of the TEA/ATTS DNA-binding domain that acts as a dominant negative repressor of TEAD factors in C2C12 myoblasts inhibits their differentiation, whereas selective shRNA knockdown of TEAD4 results in abnormal differentiation characterised by the formation of shortened myotubes. Chromatin immunoprecipitation coupled to array hybridisation shows that TEAD4 occupies 867 promoters including those of myogenic miRNAs. We show that TEAD factors directly induce Myogenin, CDKN1A and Caveolin 3 expression to promote myoblast differentiation. RNA-seq identifies a set of genes whose expression is strongly reduced upon TEAD4 knockdown among which are structural and regulatory proteins and those required for the unfolded protein response. In contrast, TEAD4 represses expression of the growth factor CTGF (connective tissue growth factor) to promote differentiation. Together these results show that TEAD factor activity is essential for normal C2C12 cell differentiation and suggest a role for TEAD4 in regulating expression of the unfolded protein response genes. PMID- 21701497 TI - Autophagy promotes survival of retinal ganglion cells after optic nerve axotomy in mice. AB - Autophagy is an essential recycling pathway implicated in neurodegeneration either as a pro-survival or a pro-death mechanism. Its role after axonal injury is still uncertain. Axotomy of the optic nerve is a classical model of neurodegeneration. It induces retinal ganglion cell death, a process also occurring in glaucoma and other optic neuropathies. We analyzed autophagy induction and cell survival following optic nerve transection (ONT) in mice. Our results demonstrate activation of autophagy shortly after axotomy with autophagosome formation, upregulation of the autophagy regulator Atg5 and apoptotic death of 50% of the retinal ganglion cells (RGCs) after 5 days. Genetic downregulation of autophagy using knockout mice for Atg4B (another regulator of autophagy) or with specific deletion of Atg5 in retinal ganglion cells, using the Atg5(flox/flox) mice reduces cell survival after ONT, whereas pharmacological induction of autophagy in vivo increases the number of surviving cells. In conclusion, our data support that autophagy has a cytoprotective role in RGCs after traumatic injury and may provide a new therapeutic strategy to ameliorate retinal diseases. PMID- 21701498 TI - Phosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function. AB - The role of the serine protease HtrA2 in neuroprotection was initially identified by the demonstration of neurodegeneration in mice lacking HtrA2 expression or function, and the interesting finding that mutations adjacent to two putative phosphorylation sites (S142 and S400) have been found in Parkinson's disease patients. However, the mechanism of this neuroprotection and the signalling pathways associated with it remain mostly unknown. Here we report that cyclin dependent kinase-5 (Cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating HtrA2 at S400. HtrA2 and Cdk5 interact in human and mouse cell lines and brain, and Cdk5 phosphorylates S400 on HtrA2 in a p38-dependent manner. Phosphorylation of HtrA2 at S400 is involved in maintaining mitochondrial membrane potential under stress conditions and is important for mitochondrial function, conferring cells protection against cellular stress. PMID- 21701499 TI - Accelerating access to treatments for rare diseases. AB - Changes in regulatory policy and legislative incentives to promote the development of drugs for rare diseases - orphan drugs - have led to increases in the number of orphan drug designations, but the rate of such products reaching the market remains frustratingly flat. This article highlights areas in which novel approaches could facilitate regulatory approval and access to treatments for rare diseases. PMID- 21701503 TI - The media and food-risk perceptions. PMID- 21701501 TI - How were new medicines discovered? AB - Preclinical strategies that are used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. To investigate whether some strategies have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US Food and Drug Administration between 1999 and 2008. Out of the 259 agents that were approved, 75 were first-in-class drugs with new MMOAs, and out of these, 50 (67%) were small molecules and 25 (33%) were biologics. The results also show that the contribution of phenotypic screening to the discovery of first-in-class small molecule drugs exceeded that of target-based approaches - with 28 and 17 of these drugs coming from the two approaches, respectively - in an era in which the major focus was on target-based approaches. We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development. PMID- 21701504 TI - E-cadherin, a new mixer in the Yamanaka cocktail. PMID- 21701502 TI - Novel therapeutic targets for the treatment of heart failure. AB - Despite considerable therapeutic advances, heart failure remains a medical and socioeconomic problem. Thus, there is a compelling need for new drugs that could improve clinical outcomes. In recent years, new potential therapeutic targets that are involved in the pathogenesis of heart failure have been identified, and new drugs are currently under investigation. A repeated finding is that the positive results that have been observed in preclinical studies and Phase II trials are not always confirmed in Phase III studies. This Review analyses the new therapeutic targets (for example, ventricular remodelling, renin-angiotensin aldosterone system activation, defects in Ca(2+) cycling, and so on), the mechanism of action, efficacy and future perspectives of new drugs that are currently under development for the treatment of heart failure, and the possible explanations for the discrepancy between Phase II and Phase III trials. PMID- 21701505 TI - Memories in the snow: immune memory, persistent infection and chronic disease. AB - Under the cover of snow in February 2011, immunologists convened in Banff, Alberta, Canada, for the Keystone symposium 'Immunologic Memory, Persisting Microbes and Chronic Disease'. These are wide-ranging topics that are typically addressed in separate experimental settings. However, a theme that emerged was the way in which these subjects are inextricably linked, and the importance of addressing them together and deciphering their molecular determinants. PMID- 21701506 TI - Scribble-mediated membrane targeting of PHLPP1 is required for its negative regulation of Akt. AB - PHLPP1 (PH domain leucine-rich-repeats protein phosphatase) is a Ser/Thr protein phosphatase that acts as a tumour suppressor by negatively regulating Akt. Here, we show that PHLPP1 is recruited to the cell membrane by binding to a scaffolding protein: Scribble. Knockdown of Scribble (Scrib) results in redistribution of PHLPP1 from the membrane to the cytoplasm and an increase in Akt phosphorylation, whereas overexpression of Scrib has the opposite effect. Furthermore, PHLPP1 dependent inhibition of cell proliferation is facilitated by the formation of a Scrib, PHLPP1 and Akt trimeric complex. Thus, our findings identify a functional interaction between PHLPP1 and Scrib in negatively regulating Akt signalling. PMID- 21701507 TI - The law through the eye of a needle. How and when to apply the new European Directive on animals used in research. PMID- 21701511 TI - DNA interstrand crosslink repair and cancer. AB - Interstrand crosslinks (ICLs) are highly toxic DNA lesions that prevent transcription and replication by inhibiting DNA strand separation. Agents that induce ICLs were one of the earliest, and are still the most widely used, forms of chemotherapeutic drug. Only recently, however, have we begun to understand how cells repair these lesions. Important insights have come from studies of individuals with Fanconi anaemia (FA), a rare genetic disorder that leads to ICL sensitivity. Understanding how the FA pathway links nucleases, helicases and other DNA-processing enzymes should lead to more targeted uses of ICL-inducing agents in cancer treatment and could provide novel insights into drug resistance. PMID- 21701512 TI - Pro-senescence therapy for cancer treatment. AB - Abundant evidence points to a crucial physiological role for cellular senescence in combating tumorigenesis. Thus, the engagement of senescence may represent a key component for therapeutic intervention in the eradication of cancer. In this Opinion article, we focus on concepts that are relevant to a pro-senescence approach to therapy and we propose potential therapeutic strategies that aim to enhance the pro-senescence response in tumours. PMID- 21701514 TI - Is vasculogenesis crucial for the regrowth of irradiated tumours? PMID- 21701515 TI - Immune regulation: macrophages join the FOXP3 suppressor gang. PMID- 21701517 TI - Antiviral immunity: SAMHD1--stopping HIV in its tracks. PMID- 21701518 TI - Tumour immunology: MDSCs come at a cost. PMID- 21701513 TI - The physics of cancer: the role of physical interactions and mechanical forces in metastasis. AB - Metastasis is a complex, multistep process responsible for >90% of cancer-related deaths. In addition to genetic and external environmental factors, the physical interactions of cancer cells with their microenvironment, as well as their modulation by mechanical forces, are key determinants of the metastatic process. We reconstruct the metastatic process and describe the importance of key physical and mechanical processes at each step of the cascade. The emerging insight into these physical interactions may help to solve some long-standing questions in disease progression and may lead to new approaches to developing cancer diagnostics and therapies. PMID- 21701520 TI - Macrophages: support from the locals. PMID- 21701523 TI - Assessment of myocardial ischaemia using tissue Doppler imaging in pseudoexfoliation syndrome. AB - PURPOSE: Pseudoexfoliation (PEX) syndrome is characterized by the widespread deposition of abnormal extracellular fibrillary material on many ocular and extraocular tissues. We aimed to investigate the association between PEX syndrome and subclinical myocardial ischaemia, using tissue Doppler echocardiography. METHODS: Thirty-two patients with pseudoexfoliation syndrome (mean age: 66+/-9 years, 22 men) and 25 healthy individuals (mean age: 67+/-8 years, 13 men) were included in the study. Patients with overt coronary artery disease, congestive heart failure, valvular heart disease, cardiomyopathy, and left ventricular hypertrophy were excluded from the study. Tissue Doppler imaging was performed at the septal, lateral, anterior, and inferior mitral annuluses. Differences between the groups were evaluated by the unpaired t-test and the Mann-Whitney U-test, with a P-value of <0.05 considered significant. RESULTS: Baseline clinical characteristics, two-dimensional, and Doppler echocardiography parameters were similar in the PEX and control groups. Peak systolic velocities at the septal, lateral, anterior, and inferior annuluses were significantly lower in patients with PEX syndrome (P<0.001, 0.01, 0.02, and 0.02, respectively). The early diastolic velocity at the septal annulus, and the ratio of early/late diastolic velocity at the lateral annulus were significantly lower in the study group (P=0.03). CONCLUSION: PEX syndrome is a common disorder of extracellular matrix. Our data suggest that there may also be an association between PEX syndrome and subclinical myocardial ischaemia in patients who have no signs and symptoms of ischaemia. Thus, we think that ophthalmologists should consider informing their PEX syndrome patients' general practitioners about a possible cardiac risk. PMID- 21701522 TI - Signal integration and crosstalk during thymocyte migration and emigration. AB - The thymus produces self-tolerant functionally competent T cells. This process involves the import of multipotent haematopoietic progenitors that are then signalled to adopt the T cell fate. Expression of T cell-specific genes, including those encoding the T cell receptor (TCR), is followed by positive and negative selection and the eventual export of mature T cells. Significant progress has been made in elucidating the signals that direct progenitor cell trafficking to, within and out of the thymus. These advances are the subject of this Review, with a particular focus on the role of reciprocal cooperative and regulatory interactions between TCR- and chemokine receptor-mediated signalling. PMID- 21701524 TI - Awareness of blindness and other smoking-related diseases and its impact on motivation for smoking cessation in eye patients. AB - PURPOSE: Cigarette smoking is a major cause of morbidity and mortality. The association between smoking and eye diseases is less widely recognised relative to other better-known smoking-related conditions. This study aims to assess the awareness and fear of known smoking-related diseases among current smokers attending an ophthalmology outpatient clinic and to evaluate their relative impact on the likelihood of smoking cessation. PATIENTS AND METHODS: A cross sectional survey using a structured interview of randomly selected current smokers attending an eye clinic was conducted. The knowledge of six smoking related diseases (lung cancer, heart attack, stroke, blindness, other cancers, and other lung diseases) was assessed. The fear of smoking-related conditions and the relative impact of each smoking-related condition on the smoker's motivation to quit smoking were evaluated. RESULTS: Out of 200 current smokers aged from 14 to 83 years, only 42.5% (85 patients) were aware that smoking causes blindness. Smokers' perception of harm caused by smoking was 6.53+/-3.21 (mean+/-SD) on a visual analogue scale of 0 to 10. Patients placed blindness as the second most important motivating factor to quit smoking immediately, within 1 year and 5 years, after lung cancer. CONCLUSION: The awareness of the risk of blindness from smoking was lowest compared with five other smoking-related diseases among eye patients who smoke. However, blindness remains a key motivational factor in smoking cessation and hence should be emphasised as an important negative health consequence of smoking in public health education and anti-smoking campaigns. PMID- 21701525 TI - Long-term visual outcome of pigment epithelial tears in association with anti VEGF therapy of pigment epithelial detachment in AMD. AB - PURPOSE: Retinal pigment epithelium (RPE) tears may develop as a complication after anti-VEGF (vascular endothelial growth factor) treatment for pigment epithelial detachments (PEDs) in exudative age-related macular degeneration (AMD). This retrospective study analyses best-corrected visual acuity (BCVA) and foveal involvement after RPE tears that are associated with anti-VEGF therapy due to PED in exudative AMD. METHODS: A total of 37 patients with RPE tears during anti-VEGF therapy (bevacizumab 12, ranibizumab 21 and pegaptanib 4 eyes) for progressive PED in AMD (PED with occult choroidal neovascularization 25 eyes and PED with retinal angiomatous proliferation 12 eyes) were included in this study. We analyzed BCVA and different morphologic aspects by means of appearance on fluorescein angiography and optical coherence tomography. Mean follow-up was 88 weeks. RESULTS: RPE tears were diagnosed a mean of 56 days after the first injection. BCVA deteriorated after RPE tear and during follow-up significantly (P<0.001), with 53.2% of eyes being legally blind (WHO, world health organization) at 12 months. RPE-free foveal area, foveal wrinkling of the RPE, and fibrotic scar development were significantly associated with worse visual acuity. DISCUSSION: RPE tears can be observed in 12-15% of treated eyes during anti-VEGF therapy for PED in exudative AMD. Owing to the close time relationship with the therapy, this complication must be taken into consideration. Visual prognosis is associated with a decrease in vision in the long term, often resulting in a severe visual disability. Relevant factors for a negative visual prognosis were the potential foveal involvement of the central RPE and morphologic fibrovascular transformation of the RPE tear. PMID- 21701526 TI - Strabismus following retinal detachment repair: a comparison between scleral buckling and vitrectomy procedures. AB - PURPOSE: We conducted a study to investigate: (1) deviations caused by retinal detachment (RD) repair; (2) correlation between visual acuity and the number of surgeries to deviation size; and (3) differences between deviations following scleral buckling (SB) and pars plana vitrectomy (PPV). METHODS: A retrospective analysis of patients with persistent binocular diplopia following RD repair. Magnitude of manifest deviation (?dev?) in the primary position (PP) and position of greatest deviation (maxDev) was calculated. LogMAR acuity and number of previous vitreoretinal procedures were correlated to ?dev? in both PP and maxDev. Manifest ?dev? were compared between SB and PPV groups. RESULTS: Twenty-five patients were identified. The median ?dev? was 7 prism diopters (PD) in PP and 17 PD in maxDev. We found no association between number of surgeries or VA with ?dev? in either the PP (r=-0.18 and r=0.08) or maxDev (r=-0.26 and r=-0.05). Twelve patients underwent PPV: median ?dev? in PP 6 PD and maxDev 9 PD. In the SB group: median ?dev? in PP 8 PD and in maxDev 22 PD. ?dev? in PP showed no significant differences between PPV and SB (U=63, P=0.41); however, ?dev? in maxDev, showed that SB have significantly greater deviations (U=36.0, P=0.02). CONCLUSION: We report the largest cohort of patients with symptomatic ocular motility defects following PPV. We show no association between VA or number of procedures to strabismus magnitude. Ocular deviations in maxDev are significantly greater after SB procedures. PMID- 21701527 TI - Visual hallucinations after intravitreal injection of ranibizumab in neovascular age-related macular degeneration. PMID- 21701528 TI - Travoprost 0.004%/timolol 0.5%-fixed combination with and without benzalkonium chloride: a prospective, randomized, doubled-masked comparison of safety and efficacy. AB - PURPOSE: The purpose of this study is to compare the safety and intraocular pressure (IOP)-lowering efficacy of travoprost/timolol in a benzalkonium chloride (BAK)-free fixed combination preserved with polyquaternium-1 (TRA/TIM BAK-free), with travoprost/timolol-fixed combination preserved with BAK (TRA/TIM), in patients with open-angle glaucoma or ocular hypertension. METHODS: In this prospective randomized controlled trial, subjects with IOP of at least 22 mm Hg in one or both eyes at 0900 h, and IOP of at least 21 mm Hg in one or both eyes at 1100 h and 1600 h at two eligibility visits were randomly assigned to receive either TRA/TIM BAK-free (n=195) or TRA/TIM (n=193), dosed once daily in the morning (0900 h) for 6 weeks. IOP was assessed at 0900 h, 1100 h, and 1600 h at each scheduled visit (baseline, 2 and 6 weeks after randomization). RESULTS: Mean IOP reduction across all visits and time points was 8.0 mm Hg in the TRA/TIM BAK-free group and 8.4 mm Hg in the TRA/TIM group (P=0.0943). The difference in mean IOP between groups ranged from 0.2 to 0.7 mm Hg across visits and time points, with a mean pooled difference of 0.4 mm Hg (95% CI: -0.1 to 0.8), demonstrating equivalence of the two formulations. The most common drug related adverse event was hyperemia of the eye (ocular hyperemia and conjunctival hyperemia combined), occurring in 11.8% of the TRA/TIM BAK-free group and 13.0% of the TRA/TIM group. CONCLUSION: Travoprost/timolol BAK-free demonstrated equivalence to travoprost/timolol preserved with BAK in efficacy. No clinically relevant differences in the safety profiles of travoprost/timolol BAK-free and travoprost/timolol preserved with BAK were identified. PMID- 21701529 TI - Changes in tear protein profile in keratoconus disease. AB - PURPOSE: To analyze tear protein profile variations in patients with keratoconus (KC) and to compare them with those of control subjects. SUBJECTS AND METHODS: Tears from 12 normal subjects and 12 patients with KC were analyzed by two dimensional gel electrophoresis (2-DE) and liquid chromatography-mass spectrometry (LC-MS). Analysis of the 2-DE gels was performed using Progenesis SameSpots software (Nonlinear Dynamics). Proteins exhibiting high variation in expression levels (P-value <0.05) were identified using matrix-assisted laser desorption/ionization-TOF spectrometry. For LC-MS analysis, a label-free quantification approach was used. Tears were digested with trypsin, subjected to data-independent acquisition (MS(E)) analysis, and identified proteins were relatively quantified using ProteinLynx Global Server software (Waters). RESULTS: The 2-DE and LC-MS analyses revealed a significant decrease in the levels of members of the cystatin family and an increase in lipocalin-1 in KC patients. A 1.43-fold decrease was observed for cystatin-S by 2-DE, and 1.69- and 1.56-fold for cystatin-SN and cystatin-SA by LC-MS, respectively. The increase in lipocalin 1 was observed by both methods with fold changes of 1.26 in the 2-DE approach and 1.31 according to LC-MS. Significant protein upregulation was also observed for Ig-kappa chain C and Ig J chain proteins by 2-DE. Levels of lipophilin-C, lipophilin-A, and phospholipase A2 were decreased in tears from KC patients according to LC-MS. Serum albumin was found to be increased in KC patients according to LC-MS. CONCLUSION: The results show differences in the tear protein profile of KC and control subjects. These changes are indicative of alterations in tear film stability and in interactions with the corneal surface in KC patients. PMID- 21701531 TI - Baculovirus vectors for antiangiogenesis-based cancer gene therapy. AB - Baculovirus is an insect virus that is non-pathogenic to humans and has emerged as a promising gene therapy vector. Since solid tumor growth/metastasis critically relies on angiogenesis and hEA, a fusion protein comprising human endostatin and angiostatin, exhibits potent antiangiogenic and antitumor efficacy in mouse models; this study aimed to evaluate the feasibility of baculovirus for hEA expression and antiangiogenesis-based cancer gene therapy. Toward this end, we constructed Bac-hEA that mediated transient hEA expression and Bac-ITR-hEA that exploited the adeno-associated virus inverted terminal repeats (ITRs) for prolonged hEA expression. Western blot and ELISA analyses showed that both Bac hEA and Bac-ITR-hEA expressed hEA in transduced mammalian cells, yet Bac-ITR-hEA only marginally prolonged the hEA expression. In comparison with Bac-hEA, nonetheless, Bac-ITR-hEA significantly enhanced the hEA expression level that concurred with augmented antiangiogenic properties, as demonstrated by cell proliferation, migration and tubule network formation assays. Importantly, intratumoral injection of Bac-ITR-hEA into prostate cancer mouse models, when compared with Bac-hEA, exerted stronger antiangiogenic effects in vivo, more potently inhibited tumor growth and significantly prolonged mouse survival. This study collectively supported the notion that hEA is an effective antiangiogenic protein and proved the potential of baculovirus as a vector for antiangiogenesis based cancer therapy, which may be combined with chemotherapy, radiotherapy or gene therapies using other vectors. PMID- 21701532 TI - Armed and targeted measles virus for chemovirotherapy of pancreatic cancer. AB - No curative therapy is currently available for locally advanced or metastatic pancreatic cancer. Therefore, new therapeutic approaches must be considered. Measles virus (MV) vaccine strains have shown promising oncolytic activity against a variety of tumor entities. For specific therapy of pancreatic cancer, we generated a fully retargeted MV that enters cells exclusively through the prostate stem cell antigen (PSCA). Besides a high-membrane frequency on prostate cancer cells, this antigen is expressed on pancreatic adenocarcinoma, but not on non-neoplastic tissue. PSCA expression levels differ within heterogeneous tumor bulks and between human pancreatic cell lines, and we could show specific infection of pancreatic adenocarcinoma cell lines with both high- and low-level PSCA expression. Furthermore, we generated a fully retargeted and armed MV-PNP anti-PSCA to express the prodrug convertase purine nucleoside phosphorylase (PNP). PNP, which activates the prodrug fludarabine effectively, enhanced the oncolytic efficacy of the virus on infected and bystander cells. Beneficial therapeutic effects were shown in a pancreatic cancer xenograft model. Moreover, in the treatment of gemcitabine-resistant pancreatic adenocarcinoma cells, no cross-resistance to both MV oncolysis and activated prodrug was detected. PMID- 21701533 TI - Effect of a caspase inhibitor, zVADfmk, on the inhibition of breast cancer cells by herpes simplex virus type 1. AB - The oncolytic effects of herpes simplex virus-1 (HSV-1) are limited, possibly because of premature death of infected cells by apoptosis, which limits the amount of progeny virus that is produced. It has been proposed that inhibition of apoptosis in infected tumor cells would allow increased viral persistence, replication and therapeutic effect. To test this hypothesis, we infected monocyte chemoattractant factor-7 (MCF-7) and MDA-MB-231 breast cancer cells with HSV-1 strain 17(+) and 17Deltagamma34.5 in the presence or absence of N benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVADfmk), a pan-caspase inhibitor. At low doses of HSV-1 strain 17(+) and 17Deltagamma34.5, the growth of MCF-7 cells was reduced to 37% or 42%, respectively, of uninfected cells. However, when cells were infected in the presence of zVADfmk, cell growth was further reduced to 24 and 33%. Similar results were seen in MDA-MB-231 cells. Cells treated with zVADfmk contained roughly 10 times more infectious viral particles than cells infected without zVADfmk, as shown by both plaque-forming and quantitative polymerase chain reaction assays. To model the situation within an infected tumor, supernatant fluids were collected from infected and non infected cell cultures and then passed to non-infected cells. In the presence of zVADfmk, the cell growth inhibitory effect became stronger with repeated passages and was attributed to viral replication, because it could be prevented by anti HSV antibody. These results suggest that caspases represent a novel target for drugs that increase the therapeutic efficacy of oncolytic herpes viruses against breast cancer. PMID- 21701535 TI - The morphologic spectrum and clinical significance of light chain proximal tubulopathy with and without crystal formation. AB - The renal diseases most frequently associated with myeloma include amyloidosis, monoclonal immunoglobulin deposition disease, and cast nephropathy. Less frequently reported is light chain proximal tubulopathy, a disease characterized by kappa-restricted crystal deposits in the proximal tubule cytoplasm. Light chain proximal tubulopathy without crystal deposition is only loosely related to the typical light chain proximal tubulopathy, and little is known about this entity. A search was performed of the 10 081 native kidney biopsy samples processed by our laboratory over the past 2 years for cases that had light chain restriction limited to the proximal tubule cytoplasm. A total of 10 cases of light chain proximal tubulopathy without crystal deposition were found representing 3.1% of light chain-related diseases. Nine of these 10 showed lambda light chain restriction. Only three cases of light chain proximal tubulopathy with crystals were found accounting for 0.9% of light chain-related diseases. Two of these three were kappa subtype. Plasma cell dyscrasia was unsuspected in seven of the 10 patients with light chain proximal tubulopathy without crystals at the time of renal biopsy. After the biopsy was reported, follow-up was available on 9/10 patients with 9/9 showing a plasma cell dyscrasia including 8/9 with multiple myeloma. We found that light chain proximal tubulopathy without crystal formation, despite being rarely described in the literature, is over three times more common than light chain proximal tubulopathy with crystal formation in our series. And given that it is often associated with previously unrecognized myeloma, it is a critically important diagnosis. PMID- 21701534 TI - Extracapsular extension is a poor predictor of disease recurrence in surgically treated oropharyngeal squamous cell carcinoma. AB - Extracapsular extension in squamous cell carcinoma nodal metastases usually predicts worse outcome. However, there are no standard histologic grading criteria for extracapsular extension, and there have been few studies on oropharyngeal squamous cell carcinoma alone. We studied the extent of extracapsular extension utilizing a novel grading system and correlated grades with outcomes while controlling for p16 status. A cohort of surgically treated oropharyngeal squamous cell carcinoma cases were reviewed and metastases graded as 0 (within substance of node), 1 (filling subcapsular sinus with thickened capsule/pseudocapsule, but no irregular peripheral extension), 2 (<=1 mm beyond capsule), 3 (>1 mm beyond capsule), or 4 (no residual nodal tissue or architecture; 'soft tissue metastasis'). There were 101 cases, for which p16 was positive in 90 (89%). Extracapsular extension grades did not correlate with nodal size (P=0.28) or p16 status (P=0.8). In follow up, 10 patients (10%) had disease recurrence with only 3 of 64 (5%) grade 0-3 cases and 7 of 37 (19%) with grade 4 recurring (P=0.04). Grade 4 extracapsular extension was associated with poorer survival (P<0.01). However, grade 4 extracapsular extension correlated with higher T-stage (P=0.02), and in multivariate analysis, was not significantly associated with poorer overall (P=0.14) disease-free (P=0.2), or disease-specific survival (P=0.09). The impact of extracapsular extension in nodal metastases is limited in oropharyngeal squamous cell carcinoma. Only extracapsular extension grade 4 associates with poorer outcomes, but not independently of T-stage and other variables. PMID- 21701536 TI - An abundance of IgG4+ plasma cells is not specific for IgG4-related tubulointerstitial nephritis. AB - IgG4-related tubulointerstitial nephritis (IgG4-TIN), the renal parenchymal lesion of IgG4-related sclerosing disease, is characterized, among other things, by the presence of numerous IgG4-positive plasma cells (IgG4+PC) in the kidney infiltrate. The specificity of this finding for IgG4-TIN has not been addressed. To address this we examined 100 consecutive renal biopsy samples with active interstitial inflammation for the presence of IgG4+PC, and correlated the findings with principal diagnosis, the available clinical histories, and the findings in four biopsy samples of IgG4-TIN. Eleven of the survey biopsy samples contained an average of more than 10 IgG4+PC per * 200 field, including two with IgG4+PC in numbers comparable to those in two of the IgG4-related tubulointerstitial disease biopsy samples. The principal pathological diagnoses in the IgG4+PC-rich cases included anti-neutrophil cytoplasmic antibody-positive necrotizing glomerulonephritis (five cases), diabetic nephropathy (two cases), idiopathic interstitial nephritis (two cases), membranous glomerulonephritis (one case), and lupus nephritis (one case). There was no reason, based on histology or clinical history, to believe that any of these cases represented previously unsuspected IgG4-related tubulointerstitial disease. We conclude that the presence of numerous IgG4+PC is essential to, but not sufficient for, the diagnosis of IgG4-TIN. PMID- 21701537 TI - THBS4, a novel stromal molecule of diffuse-type gastric adenocarcinomas, identified by transcriptome-wide expression profiling. AB - Gastric adenocarcinomas can be divided into two major histological types, the diffuse and intestinal type (Lauren classification). Since they diverge in many clinical and molecular characteristics, it is widely accepted that they represent distinct disease entities that may benefit from different therapeutic approaches. Gene expression profiling studies have identified numerous genes that are differentially expressed between them. However, none of these studies covered the whole transcriptome and the published gene lists reveal little overlap, raising the need for further, more comprehensive analyses. Here, we present the first transcriptome-wide expression profiling study comparing the two types (diffuse n=19, intestinal n=24), which identified >1000 genes that are differentially expressed. Among them, thrombospondin 4 (THBS4) showed the strongest correlation to histological type, with vast overexpression in the diffuse type. Quantitative real-time PCR validated this strong overexpression and revealed that intestinal tumors generally lack THBS4 expression. Immunohistochemistry demonstrated THBS4 overexpression on the protein level (n=10) and localized THBS4 to the stromal aspect. Its expression was primarily observed within the extracellular matrix surrounding the tumor cells, with the highest intensities found in regions of high tumor cell density and invasion. Intestinal tumors and matched non neoplastic gastric epithelium and stroma did not feature any relevant THBS4 expression in a preliminary selection of analyzed cases (n=5). Immunohistochemical colocalization and in vitro studies revealed that THBS4 is expressed and secreted by cancer-associated fibroblasts. Furthermore, we show that THBS4 transcription in fibroblasts is stimulated by tumor cells. This study is the first to identify THBS4 as a powerful marker for diffuse-type gastric adenocarcinomas and to provide an initial characterization of its expression in the course of this disease. PMID- 21701538 TI - Tubal origin of 'ovarian' low-grade serous carcinoma. AB - Ovarian low-grade serous carcinomas are thought to evolve in a stepwise fashion from ovarian epithelial inclusions, cystadenomas, and borderline tumors. The current study was designed to gain insight into the origins of low-grade serous carcinomas (tubal versus ovarian) by comparatively evaluating the morphologic (secretory and ciliated cell distribution) and immunophenotypic (using antibodies to PAX8, tubulin, calretinin, and Ki67) attributes of its putative precursor lesions, the normal tubal epithelium, and the overt malignancy. A total of 226 adnexal tissues from 178 patients were studied, including 98 adnexae removed for non-neoplastic indications, 48 serous cystadenomas, 42 serous borderline tumors, and 38 low-grade serous carcinomas. Normal distal tubal epithelium comprised an admixture of PAX8+/tubulin- secretory cells and PAX8-/tubulin+ ciliated cells with a proliferative index of ~3%. The vast majority of ovarian surface epithelia displayed a mesothelial phenotype (calretinin+/PAX8-/tubulin-) and low proliferative index (0% (12 per 1000)), although 4% of cases also displayed foci with tubal phenotype (calretinin-/PAX8+/tubulin+). In contrast, most (78%) of the ovarian epithelial inclusions displayed a tubal phenotype and had a significantly higher proliferative index (1%) than ovarian surface epithelium, indicating that in most cases, the ovarian surface epithelium and ovarian epithelial inclusions are of different lineages. There was a progressive decrease in the population of ciliated cells, as evidenced by increasing secretory/ciliated cell ratio, from ovarian epithelial inclusions/cystadenomas to borderline tumors to low-grade serous carcinoma, indicating that the latter is a clonal expansion of secretory cells. Overall, the findings make a strong argument that the ovarian epithelial inclusions with a tubal phenotype is likely derived from fallopian tube through an intraovarian endosalpingiosis rather than through Mullerian metaplasia from ovarian surface epithelium. Genetic and molecular studies are needed to further confirm this finding as tubal origination of ovarian serous cancers will have a significant impact on ovarian cancer prevention and management. PMID- 21701539 TI - Time to up the research quality stakes. PMID- 21701540 TI - Diagnostic accuracy studies needed for cone beam computed tomography. AB - DATA SOURCES: Medline, Embase, CENTRAL and the reference lists of identified studies. STUDY SELECTION: Studies had to describe diagnostic accuracy efficacy, diagnostic thinking efficacy, therapeutic efficacy or any combination for CBCT in the diagnosis of impacted teeth or of important features associated with impactions. Criteria for the diagnosis had to be described in detail or referenced. For studies elucidating only observer performance, the analysis had to be based on a minimum of two observers. DATA EXTRACTION AND SYNTHESIS: Data were extracted with the aid of protocol based on critical appraisal of diagnostic studies. Two authors independently assessed the quality and internal validity of studies using the QUADAS tool,(1) with disagreements being resolved by discussion. The results were described narratively as meta-analyses could not be conducted. RESULTS: The search yielded 96 titles, of which seven were included. There was only limited evidence for diagnostic efficacy expressed as sensitivity, specificity and predictive values. Only two studies compared CBCT and panoramic radiographs with a valid reference method and presented the results in terms of percentage of correct diagnoses. CONCLUSIONS: There is a need for diagnostic accuracy studies on CBCT where accepted methodological criteria for diagnostic thinking, efficacy and therapeutic efficacy are incorporated. PMID- 21701541 TI - Cannabis use and oral diseases. AB - DATA SOURCES: Medline and the Cochrane Central register of controlled trails (CENTRAL). STUDY SELECTION: Randomised Controlled Trials, Controlled Clinical Trials and Cohort Studies conducted on humans investigating cannabis usage were included. Screening was performed independently by two reviewers. Only English language studies were included. Case reports, letters and historical reviews were excluded. DATA EXTRACTION AND SYNTHESIS: A narrative synthesis was conducted. RESULTS: Seven studies were included and a range of cannabis-associated oral side effects identified. CONCLUSIONS: Based on the limited data, it seems justified to conclude that with increasing prevalence of cannabis use, oral health care providers should be aware of cannabis-associated oral side effects such as xerostomia, leukoedema and an increased prevalence and density of Candida albicans. PMID- 21701542 TI - Limited evidence of the effect of chlorhexidine varnish (CHX-V) on root caries. AB - DATA SOURCES: Medline, CENTRAL and Embase and the reference lists of included articles. STUDY SELECTION: Randomised controlled clinical trials (RCTs) or controlled clinical trials (CCTs) conducted in adults over 18 that compared CHX-V against placebo or control that reported root caries incidence and/or root caries activity were included. Only papers written in English were included. DATA EXTRACTION AND SYNTHESIS: Study selection and data abstraction were carried out independently by two reviewers with disagreements resolved by discussion with third reviewer if required. Where appropriate, a meta-analysis was carried out using a 'random effect' model. As only a few studies could be included in the meta-analysis, data were also presented in a descriptive manner. RESULTS: Searches identified 32 papers with six meeting the inclusion criteria. Data extraction provided no conclusive evidence that the application of CHX-V is effective in patients when regular professional oral prophylaxis is performed. If effective, the 40% CHX-V was found to provide a benefit over a control or fluoride varnish. CHX-V at lower concentrations (1 and 10%) may provide protection against root caries in high-risk patients (such as geriatric and xerostomia patients) in the absence of regular professional oral prophylaxis. CONCLUSIONS: Within the limitations of this review, it may be concluded that in the absence of regular professional tooth cleaning and oral hygiene instructions, CHX-V may provide a beneficial effect in patients in need of special care. The strength of this recommendation is graded as 'weak'. PMID- 21701543 TI - Fluoride varnish may be effective in preschoolers. AB - DATA SOURCES: BBO, Lilacs, Medline and the Cochrane library were searched. STUDY SELECTION: Randomised or quasi-randomised controlled clinical trials (RCTs) or controlled clinical trials (CCTs) conducted in children up to six years of age undergoing any form of topical fluoride application reporting caries as an outcome were included. Articles in English, Spanish or Portuguese were included. DATA EXTRACTION AND SYNTHESIS: Data were extracted in duplicate and mean caries increment and prevented fraction was presented for each of the included studies. Meta-analysis was not performed owing to the heterogeneity of the data. RESULTS: Eight trials conducted in four countries China, the United States, Poland and Sweden were included. Most of the studies were of poor methodological quality. They were also heterogeneous in relation to participants' previous caries experience, type of intervention administered to the control group, children's exposure to other sources of fluoride and varnish application interval. The absolute differences between caries incidences in the control and test groups ranged from 0.30 to 1.64 and the preventive fractions varied from 5% to 63%. CONCLUSIONS: Fluoride varnish may be effective to decrease dental caries incidence in preschoolers, but more randomised clinical trials of better methodological quality are necessary to provide conclusive evidence in this respect. PMID- 21701544 TI - Little evidence that current interventions can benefit patients with OSMF. AB - DATA SOURCES: Pubmed was searched using the term 'oral submucous fibrosis' (OSF). Additional searches of the Indian and Chinese literature were conducted manually. STUDY SELECTION: Randomised controlled studies (RCTs), observational studies, or case series reports that included individuals of any age with confirmed diagnosis, by clinical examination and/or biopsy of OSF. Types of interventions included habit intervention, surgical procedures, medical treatments (i.e. systemic, submucosal injection or topical agents), or physical therapy. Primary outcomes were objective change or improvement in maximal jaw opening, subjective change in severity of oral/mucosal burning pain, subjective change in quality of life using any questionnaire, and reduction in the rate of malignant transformation. DATA EXTRACTION AND SYNTHESIS: Studies selected were evaluated independently by three reviewers using a data extraction form. Due to the heterogeneity of the studies synthesis was not conducted. The overall quality of evidence of RCTs for each outcome was assessed and reported using the GRADE approach. RESULTS: 50 studies were identified for inclusion. Only four of these were RCTs. The likely bias associated with these was thought to be high and therefore the authors urged caution in interpreting their conclusions. Interventions included oral pentoxifylline versus multivitamins; oral lycopene, oral lycopene with intralesional corticosteroids or an oral placebo; oral levamisole, an oral antioxidant, or oral levamisole; physiotherapy, injections with combination hyaluronidase/steroids, and a control group. Various objective and subjective outcomes improved with intervention. CONCLUSIONS: The current evidence for the benefit of current interventions to manage OSF is weak. PMID- 21701545 TI - Waterpipe smoking, oral cancer and other oral health effects. AB - DATA SOURCES: MEDLINE, EMBASE and ISI the Web of Science. STUDY SELECTION: Articles in any language that assessed the association between water pipe smoking and any health outcome. Included studies were cohort, case-control and cross sectional. Studies were excluded if they looked at physiological outcomes, non tobacco pipe use, or didn't differentiate between this and other smoking habits. DATA EXTRACTION AND SYNTHESIS: Data were abstracted independently by two reviewers using a standardised screening guide and GRADE used to evaluate study quality. The I(2) statistic was used to measure heterogeneity. Odds ratios for the effect of pipe smoking on lung, bladder, oesophageal and nasopharyngeal cancer, oral dysplasia, pregnancy outcomes, periodontal disease, hepatitis, respiratory illness and infertility were extracted. RESULTS: Twenty-three studies were included. Based on the available evidence, waterpipe tobacco smoking was significantly associated with lung cancer, respiratory illness, low birth-weight and periodontal disease. It was not significantly associated with bladder, nasopharyngeal and oesophageal cancers, neither with oral dysplasia or infertility, but the confidence Intervals (CIs) did not exclude important associations. Smoking a waterpipe in groups was not significantly associated with hepatitis C infection. The overall quality of evidence varied from very low to low. CONCLUSIONS: The evidence from very low to low quality studies is that waterpipe tobacco smoking is possibly associated with a number of deleterious health outcomes including lung cancer, respiratory illness, low birth-weight and periodontal disease. PMID- 21701546 TI - Insufficient evidence for photodynamic therapy use in periodontitis. AB - DATA SOURCES: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, Health and Psychosocial Instruments, HealthSTAR (OVID), Allied and Complementary Medicine and the International Pharmaceutical Abstracts. Abstracts from 2007 to 2009 of the annual meetings of the American Academy of Periodontology, International Association of Dental Research and the American Association of Dental Research. STUDY SELECTION: Randomised and quasi-randomised studies reported in any language comparing PDT as a primary or adjunctive therapy to no treatment, placebo or scaling and root planing (SRP). Eligible studies were those that included participants over 18 years of age and who had periodontitis, and where the primary outcome measurement was clinical attachment loss (CAL) and changes in probing depth. DATA EXTRACTION AND SYNTHESIS: Two reviewers reviewed, assessed and rated study quality and extracted relevant data. It is not reported how these data were collated. The quality of included studies was assessed according to Cochrane risk of bias domains. Mean difference (MD) and 95% confidence intervals (CI) were extracted. Data were combined in a meta-analysis where possible using the random-effects model. Homogeneity was assessed using the Cochrane test and heterogeneity assessed using I(2). RESULTS: Five studies at moderate to high risk of bias were included. The studies differed markedly in design and were clinically heterogenous. Studies that compared PDT to no treatment found no difference in CAL whereas those that compared PDT plus SRP (n=26) to those receiving just SRP (n=26) gave a MD of 0.34 mm with 95% CI 0.05 to 0.63 mm. Three studies that compared PDT alone to SRP alone showed a reduction in probing depth in favour of SRP (MD -0.21, 95% CI -0.40-0.02). In three studies that compared PDT plus SRP to SRP alone the MD was 0.25 mm (95% CI: 0.04 to 0.45 mm). CONCLUSIONS: There is insufficient evidence that photodynamic therapy as an independent treatment or as an adjunct to scaling and root planning is superior to SRP alone. PMID- 21701547 TI - Available evidence does not support use of oxalates for dentine hypersensitivity. AB - DATA SOURCES: Medline, CENTRAL, LILACS, TRIP Database, National Guideline Clearinghouse, OPENSigle and a number of other medical / dental databases and websites, as well as reference lists. STUDY SELECTION: Randomised controlled trials and controlled clinical trials in any language that compared oxalates with placebo or no treatment were eligible for inclusion. DATA EXTRACTION AND SYNTHESIS: Three reviewers extracted data with two people assessing quality independently using the Cochrane risk of bias domains. Standardized mean differences (SMD) were estimated by random-effects meta-analysis and heterogeneity between studies was quantified with the I2-statistic. RESULTS: 12 reports were included. Interventions were diverse and included: monohydrogen monopotassium oxalate, ferric oxalate, di-potassium oxalate, or oxalate containing pre-polymerized resin, and combinations of monohydrogen-monopotassium and di-potassium oxalate. Follow up intervals varied between immediate to 1 year. Hypersensitivity was elicited by tactile, evaporative or thermal stimuli, and a number of outcomes used to measure pain. Risk of bias was high in a number of studies and statistical heterogeneity high. Based on 187 and 179 units (patients or teeth) in the intervention and placebo groups from seven studies, the summary SMD for 3% monohydrogen-monopotassium oxalate was -0.71 (95% Confidence Interval (CI):-1.48, 0.06), which suggests it may not be beneficial. There was no improvement with the other interventions. CONCLUSIONS: The review identified no evidence to indicate benefit from treating dentine hypersensitivity with oxalates beyond a placebo effect. PMID- 21701548 TI - Hospitalisation associated with a deterioration in oral health. AB - DATA SOURCES: Ovid MEDLINE and Ovid OLDMEDLINE (January 1950 to January 2010), CINAHL (1982 to January 2010), Cochrane Library (up to 2010) and EMBASE (1981 to January 2010), bibliographies of potentially relevant reports and reviews, handsearching of Community Dentistry and Oral Epidemiology, Gerodontology, Journal of Disability and Oral Health and Special Care in Dentistry. STUDY SELECTION: Longitudinal prospective observational studies in individuals of all ages being hospitalised, that assessed changes of the following outcomes: tooth loss, any measures of periodontal health, dental caries and stomatological diseases. There were no language restrictions. DATA EXTRACTION AND SYNTHESIS: One reviewer scanned the titles and abstracts to select studies. Potentially eligible studies were screened by two reviewers who also data extracted using specially designed forms. Quality was assessed by both reviewers using the Newcastle-Ottawa scale for cohort studies. The authors assessed whether a power calculation was reported for each study and, if so, the magnitude of a change that the study was powered to detect. Heterogeneity between studies was anticipated so a narrative review was planned. RESULTS: Five studies were included and all were assessed to be adequately representative and had sufficient follow-up. Outcome assessments were adequate but validity of the outcome measures was found to be subjective. One investigation included children only, whilst the remainder included adults only. Four of the studies were in intensive care units. Duration of hospitalisation was 5-20 days. This was insufficient a period for caries to develop. A power calculation was reported in only one study. Three out of four studies that reported on plaque accumulation found increasing levels of plaque accumulation during hospitalisation, whilst one did not. Two of three studies assessing gingival inflammation found a statistically significant increase. Two studies found a statistically significant increased incidence of mucositis in intubated patients but not in non-intubated patients. CONCLUSIONS: Hospitalisation is associated with a deterioration in oral health, particularly in intubated patients. PMID- 21701549 TI - Corticosteroid administration in oral and orthognathic surgery. AB - DATA SOURCES: Medline and Cochrane Library. STUDY SELECTION: Clinical trials of oral and orthognathic surgery involving CS administration. DATA EXTRACTION AND SYNTHESIS: The administered doses of CS in the selected articles were recalculated to equivalent anti-inflammatory doses of methylprednisolone, to facilitate comparison; doses of orally administered dexamethasone were decreased by 20% to adjust the dose according to the bioavailability difference between oral and intravenous administration and local injection. Where possible meta analysis was performed using an inverse variance method, and results summarised using forest plots and relative risks, estimated based on fixed and random effects models. Heterogeneity was quantified. RESULTS: In oral surgery most clinical trials showed a significant decrease in oedema (p= <0.0001) after CS, and local injection of methylprednisolone >=25 mg was expected to result in a significant decrease in oedema. Regarding the analgesic effect, several clinical trials showed a decrease in pain after CS (P <0.0001). Furthermore, CS administration resulted in a slightly higher risk of infection (relative risk 1.0041 [95%CI 0.9451, 1.0669]), but with a p value of 0.89. In orthognathic surgery methylprednisolone >=85 mg administered intravenously seemed sufficient to produce a significant decrease in oedema, and several trials pointed toward a neuroregeneration effect, but no statistical analysis could be performed. Regarding the risk of other side effects, in oral surgery a minimal risk of chronic adrenal suppression was seen: in orthognathic surgery an elevated risk of avascular osteonecrosis, steroid-induced psychosis and adrenal suppression was seen. There were no reports of decreased healing. CONCLUSIONS: These findings suggest that the administration of CS in oral surgery decreases oedema and pain significantly, with no higher risk of infection and with a minimum risk of other side effects. PMID- 21701550 TI - Skill-mix and service transfer to primary care settings. AB - DATA SOURCES: British Nursing Index, CINAHL, Cochrane Database of Systematic Reviews, DARE (Database of Abstracts of Reviews of Effects), EMBASE, Medline, PsycINFO and the reference lists of eligible papers were searched. STUDY SELECTION: Studies that focused on practitioners with special interests (PwSIs) or roles clearly created/defined to be practising with special interests, detailing innovative ways of working with a special interest with evidence of formal evaluation of changing role of location of service from systematic reviews or interventions were included. Surveys of views on changing skill-mix or location of services, studies that did not concern dental or medical professionals, dental care or nursing professionals were excluded. Only studies in English and with a UK focus were included. DATA EXTRACTION AND SYNTHESIS: All titles and abstracts identified were screened for relevance. Two authors assessed quality and extracted data, queries were reviewed by a third author and a narrative synthesis was presented. RESULTS: Twenty-six papers met the criteria with a strong bias towards the medical literature. Five categories emerged:(i) specialist outreach; (ii) general practitioners with a special interest; (iii) nurse practitioners with a special interest; (iv) dental care professionals; (v) out-of-hospital services. Evidence showed specialist outreach clinics to be effective in relation to access and patient satisfaction with some having a higher quality of care but higher cost. However there may be cost-benefits associated with this care, particularly when part of a multifaceted intervention. There is controversy and a limited evidence as to whether the services provided by medical PwSIs are effective, and whether the benefits outweigh the risk and the cost. From the evidence obtained through early innovation, it appears that these services can increase access and are more satisfying for patients, and that these roles have the potential to bring more work satisfaction to the practitioners. Overall, the findings do support the view that moving specialist care into the primary care setting via appropriately trained nurse practitioners is an effective use of resources, but with the caveat that nurse practitioners in primary care are not necessarily cost-effective. There is evidence that professionals complementary to dentistry (PCDs) are able to diagnose a range of conditions and, with appropriate training, complete a wide range of dental procedures as well as dentists, but much of the evidence for other aspects of substitution was of lower quality, weak or insufficient. CONCLUSIONS: There was limited evidence of the cost-effectiveness and health outcomes associated with changes in setting and skill-mix. However, there was evidence of improved access, patient and professional satisfaction. There is an overwhelming need for well designed interventions with robust evaluation to examine cost-effectiveness and benefits to patients and the health workforce. PMID- 21701551 TI - Quality of reporting randomised controlled trials in major dental journals suboptimal. AB - DATA SOURCES: Hand searching of the most recent 24 issues of six high impact dental journals. STUDY SELECTION: RCTs involving only humans, from 24 issues of six leading specialty journals, covering a period up to July 2009 were included, including cluster randomised trials. DATA EXTRACTION AND SYNTHESIS: Each article included in the study was assessed and scored independently by two observers, with any discrepancies being resolved by a third observer. In this study the modified CONSORT checklist was used to score each applicable item of data. The sum of the scores was converted to a percentage value for each trial. The data were analysed using descriptive statistics. Data regarding the publishing journal, country of origin of the trial, number of authors, involvement of statistician/epidemiologist, number of centres involved, ethics committee approval were subject to quantitative analysis. RESULTS: Ninety-five RCTs were identified with, according to the authors, generally suboptimal scores on quality reporting on key CONSORT areas. Significant differences in scores were found among the journals covering the named specialties. Overall there was a positive association between the quality score in studies with more authors, multicentre studies and studies in which a statistician/epidemiologist was involved. CONCLUSIONS: The overall quality of reporting RCTs in major dental journals was considered suboptimal in key CONSORT areas. This is very important as the reported results of RCTs can have an impact on future patient care. PMID- 21701552 TI - Quality of reporting randomised controlled trials in dental public health. AB - DATA SOURCES: Electronic (PubMed and Medline) and hand searching of three dental public health journals, Community Dental Health, Community Dentistry and Oral Epidemiology and the Journal of Public Health Dentistry 1993 - 2008. STUDY SELECTION: Studies defined as controlled experiments using a random method to assign study units were included: papers reporting secondary analysis, pilot studies and those that provided brief methodological descriptions were excluded. DATA EXTRACTION AND SYNTHESIS: Each article included in the study was assessed and scored independently by two observers, with any discrepancies being resolved by discussion Articles were assessed using the CONSORT criteria. RESULTS: 119 RCTs were initially identified (85 electronically and 33 from hand searching) and of these 48 were assessed. Of the 56 CONSORT criteria there were on average 27 (SD 6.9) present. The average number of criteria increased over the period. CONCLUSIONS: There were inadequacies in the reporting of trials in dental public health journals. The quality of the reporting could be improved if the CONSORT statement were followed more closely. PMID- 21701554 TI - Understanding statistics 5. PMID- 21701553 TI - What is the best way to restore the worn dentition? PMID- 21701557 TI - A synthetic prestin reveals protein domains and molecular operation of outer hair cell piezoelectricity. AB - Prestin, a transporter-like protein of the SLC26A family, acts as a piezoelectric transducer that mediates the fast electromotility of outer hair cells required for cochlear amplification and auditory acuity in mammals. Non-mammalian prestin orthologues are anion transporters without piezoelectric activity. Here, we generated synthetic prestin (SynPres), a chimera of mammalian and non-mammalian prestin exhibiting both, piezoelectric properties and anion transport. SynPres delineates two distinct domains in the protein's transmembrane core that are necessary and sufficient for generating electromotility and associated non-linear charge movement (NLC). Functional analysis of SynPres showed that the amplitude of NLC and hence electromotility are determined by the transport of monovalent anions. Thus, prestin-mediated electromotility is a dual-step process: transport of anions by an alternate access cycle, followed by an anion-dependent transition generating electromotility. The findings define structural and functional determinants of prestin's piezoelectric activity and indicate that the electromechanical process evolved from the ancestral transport mechanism. PMID- 21701558 TI - Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1. AB - Breast cancer is a heterogeneous disease and several distinct subtypes exist based on differential gene expression patterns. Molecular apocrine tumours were recently identified as an additional subgroup, characterised as oestrogen receptor negative and androgen receptor positive (ER- AR+), but with an expression profile resembling ER+ luminal breast cancer. One possible explanation for the apparent incongruity is that ER gene expression programmes could be recapitulated by AR. Using a cell line model of ER- AR+ molecular apocrine tumours (termed MDA-MB-453 cells), we map global AR binding events and find a binding profile that is similar to ER binding in breast cancer cells. We find that AR binding is a near-perfect subset of FoxA1 binding regions, a level of concordance never previously seen with a nuclear receptor. AR functionality is dependent on FoxA1, since silencing of FoxA1 inhibits AR binding, expression of the majority of the molecular apocrine gene signature and growth cell growth. These findings show that AR binds and regulates ER cis-regulatory elements in molecular apocrine tumours, resulting in a transcriptional programme reminiscent of ER-mediated transcription in luminal breast cancers. PMID- 21701559 TI - Direct reprogramming of stem cell properties in colon cancer cells by CD44. AB - Cancer progression is commonly segregated into processes of primary tumour growth and secondary metastasis. Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumour growth in cancer. However, the role of CSCs in cancer metastasis is unclear. In this study, we found that the C terminus of CD44 contributes to sphere formation and survival in vitro via the CD44-SRC-integrin axis. In addition, nuclear CD44/acetylated-STAT3 is required for clonal formation in vitro and tumourigenicity in vivo. Nuclear CD44 binds to various promoters identified by chromatin immunoprecipitation-seq, including that of c-myc and Twist1, leading to cell fate change through transcriptional reprogramming. We propose that nuclear CD44/acetylated-STAT3 performs an unexpected tumour-progressing function by enhancing cell outgrowth into structures where cells with properties of CSCs can be generated from differentiated somatic cells in suspension culture, and then exhibit attributes of cells that have undergone an epithelial-mesenchymal transition, leading to tumour metastasis, and a resulting worse prognosis. PMID- 21701560 TI - Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fission. AB - Mitochondrial morphology is controlled by two opposing processes: fusion and fission. Drp1 (dynamin-related protein 1) and hFis1 are two key players of mitochondrial fission, but how Drp1 is recruited to mitochondria and how Drp1 mediated mitochondrial fission is regulated in mammals is poorly understood. Here, we identify the vertebrate-specific protein MIEF1 (mitochondrial elongation factor 1; independently identified as MiD51), which is anchored to the outer mitochondrial membrane. Elevated MIEF1 levels induce extensive mitochondrial fusion, whereas depletion of MIEF1 causes mitochondrial fragmentation. MIEF1 interacts with and recruits Drp1 to mitochondria in a manner independent of hFis1, Mff (mitochondrial fission factor) and Mfn2 (mitofusin 2), but inhibits Drp1 activity, thus executing a negative effect on mitochondrial fission. MIEF1 also interacts with hFis1 and elevated hFis1 levels partially reverse the MIEF1 induced fusion phenotype. In addition to inhibiting Drp1, MIEF1 also actively promotes fusion, but in a manner distinct from mitofusins. In conclusion, our findings uncover a novel mechanism which controls the mitochondrial fusion fission machinery in vertebrates. As MIEF1 is vertebrate-specific, these data also reveal important differences between yeast and vertebrates in the regulation of mitochondrial dynamics. PMID- 21701561 TI - The crystal structure of yeast CCT reveals intrinsic asymmetry of eukaryotic cytosolic chaperonins. AB - The cytosolic chaperonin CCT is a 1-MDa protein-folding machine essential for eukaryotic life. The CCT interactome shows involvement in folding and assembly of a small range of proteins linked to essential cellular processes such as cytoskeleton assembly and cell-cycle regulation. CCT has a classic chaperonin architecture, with two heterogeneous 8-membered rings stacked back-to-back, enclosing a folding cavity. However, the mechanism by which CCT assists folding is distinct from other chaperonins, with no hydrophobic wall lining a potential Anfinsen cage, and a sequential rather than concerted ATP hydrolysis mechanism. We have solved the crystal structure of yeast CCT in complex with actin at 3.8 A resolution, revealing the subunit organisation and the location of discrete patches of co-evolving 'signature residues' that mediate specific interactions between CCT and its substrates. The intrinsic asymmetry is revealed by the structural individuality of the CCT subunits, which display unique configurations, substrate binding properties, ATP-binding heterogeneity and subunit-subunit interactions. The location of the evolutionarily conserved N terminus of Cct5 on the outside of the barrel, confirmed by mutational studies, is unique to eukaryotic cytosolic chaperonins. PMID- 21701562 TI - Genome-wide function of THO/TREX in active genes prevents R-loop-dependent replication obstacles. AB - THO/TREX is a conserved nuclear complex that functions in mRNP biogenesis and prevents transcription-associated recombination. Whether or not it has a ubiquitous role in the genome is unknown. Chromatin immunoprecipitation (ChIP) chip studies reveal that the Hpr1 component of THO and the Sub2 RNA-dependent ATPase have genome-wide distributions at active ORFs in yeast. In contrast to RNA polymerase II, evenly distributed from promoter to termination regions, THO and Sub2 are absent at promoters and distributed in a gradual 5' -> 3' gradient. This is accompanied by a genome-wide impact of THO-Sub2 deletions on expression of highly expressed, long and high G+C-content genes. Importantly, ChIP-chips reveal an over-recruitment of Rrm3 in active genes in THO mutants that is reduced by RNaseH1 overexpression. Our work establishes a genome-wide function for THO-Sub2 in transcription elongation and mRNP biogenesis that function to prevent the accumulation of transcription-mediated replication obstacles, including R-loops. PMID- 21701564 TI - Vitamin D in adipose tissue and serum 25-hydroxyvitamin D after roux-en-Y gastric bypass. AB - Vitamin D is stored in body fat. The purpose of this study was to determine vitamin D concentration in abdominal fat of obese patients who underwent roux-en Y gastric bypass (RYGB), and to describe changes in serum 25-hydroxyvitamin D (25(OH)D) levels in relation to loss of body fat. Subjects from a single clinic who were scheduled for RYGB were invited into the study. Abdominal subcutaneous, omental, and mesenteric fat were obtained at time of surgery. Adipose vitamin D(2) and vitamin D(3) concentrations were measured by high-performance liquid chromatography (HPLC). Weight and serum 25(OH)D were assessed at baseline and every 3 months up to 1 year. Seventeen subjects were included, and fat samples were available from eleven. Total vitamin D content in subcutaneous abdominal fat was 297.2 +/- 727.7 ng/g tissue, and a wide range was observed (4-2,470 ng/g). Both vitamin D(2) and vitamin D(3) were detected in some of the fat samples. At baseline, 25(OH)D was 23.1 +/- 12.6 ng/ml. Average weight loss was 54.8 kg at 12 months, of which ~40 kg was fat mass. Despite daily vitamin D intake of >=2,500 IU throughout the study, no significant increase in serum 25(OH)D was observed, with mean serum concentration of 25(OH)D at 1 year of 26.2 +/- 5.36 ng/ml (P = 0.58). We conclude that vitamin D in adipose tissue does not significantly contribute to serum 25(OH)D despite dramatic loss of fat mass after RYGB. PMID- 21701563 TI - DNA methylation status predicts cell type-specific enhancer activity. AB - Cell-selective glucocorticoid receptor (GR) binding to distal regulatory elements is associated with cell type-specific regions of locally accessible chromatin. These regions can either pre-exist in chromatin (pre-programmed) or be induced by the receptor (de novo). Mechanisms that create and maintain these sites are not well understood. We observe a global enrichment of CpG density for pre-programmed elements, and implicate their demethylated state in the maintenance of open chromatin in a tissue-specific manner. In contrast, sites that are actively opened by GR (de novo) are characterized by low CpG density, and form a unique class of enhancers devoid of suppressive effect of agglomerated methyl-cytosines. Furthermore, treatment with glucocorticoids induces rapid changes in methylation levels at selected CpGs within de novo sites. Finally, we identify GR-binding elements with CpGs at critical positions, and show that methylation can affect GR DNA interactions in vitro. The findings present a unique link between tissue specific chromatin accessibility, DNA methylation and transcription factor binding and show that DNA methylation can be an integral component of gene regulation by nuclear receptors. PMID- 21701565 TI - A genome-wide association study of BMI in American Indians. AB - Numerous studies have been done to understand genetic contributors to BMI, but only a limited number of studies have been done in nonwhite groups such as American Indians. A genome-wide association study (GWAS) for BMI was therefore performed in Pima Indians. BMI measurements from a longitudinal study of 1,120 Pima Indians and 454,194 single-nucleotide polymorphisms (SNPs) from the 1 million Affymetrix SNP panel were used (35% of SNPs were excluded due to minor allele frequency <0.05). Data included BMI measured at multiple examinations collected from 1965 to 2004, as well as the maximum BMI at one of these visits. General and within-family tests were performed using a maximum-likelihood based mixed model procedure. No SNP reached a genome-wide significance level (estimated at P < 4.94 * 10(-7)). For repeated measures analyses, the strongest associations for general and within-family tests mapped to two different regions on chromosome 6 (rs9342220 (P = 1.39 * 10(-6)) and rs7758764 (P = 2.51 * 10(-6)), respectively). For maximum BMI, the strongest association for the general tests mapped to chromosome 4 (rs17612333; P = 1.98 * 10(-6)) and to chromosome 3 (rs11127958; P = 1.53 * 10(-6)) for the within-family tests. Further analysis is important because only a few of these regions have been previously implicated in a GWAS and genetic susceptibility may differ by ethnicity. PMID- 21701566 TI - Transcriptional metabolic inflexibility in skeletal muscle among individuals with increasing insulin resistance. AB - Disturbances in skeletal muscle lipid metabolism may play an important role in development of insulin resistance (IR). The aim was to investigate transcriptional control of skeletal muscle fatty acid (FA) metabolism in individuals with the metabolic syndrome (MetS) with varying degrees of insulin sensitivity (S(I)). 122 individuals with MetS (NCEP-ATP III criteria) at age 35 70 years, BMI 27-38 kg/m(2) were studied (subgroup EU-LIPGENE study). Individuals were divided into quartiles of S(I) measured during a frequently sampled insulin modified intravenous glucose tolerance test. Skeletal muscle normalized mRNA expression levels of genes important in skeletal muscle FA handling were analyzed with quantitative real-time PCR. The expression of sterol regulatory element binding protein 1c (SREBP1c), acetyl-CoA carboxylase 2 (ACC2), diacylglycerol acyltransferase (DGAT1), and nuclear respiration factor (NRF) was higher in the lowest two quartiles of S(I) (<50th) compared with the highest two quartiles of S(I) (>50th). Interestingly, peroxisome proliferator-activated receptor coactivator 1alpha (PGC1alpha), peroxisome proliferator-activated receptor alpha (PPARalpha), and muscle carnitine palmitoyl transferase 1b (mCPT1), important for oxidative metabolism, showed a complex mRNA expression profile; levels were lower in both the most "insulin sensitive" (IS) as well as the most "IR" individuals. Lipoprotein lipase (LPL) mRNA was reduced in the lowest quartile of S(I). Enhanced gene expression of SREBP1c and ACC2 in the IR state suggests a tendency towards FA storage rather than oxidation. From the lower expression of PGC1alpha, PPARalpha, and mCPT1 in both the most "IS" as well as the most "IR" individuals, it may be speculated that "IS" subjects do not need to upregulate these genes to have a normal FA oxidation, whereas the most "IR" individuals are inflexible in upregulating these genes. PMID- 21701567 TI - Longitudinal associations between key dietary behaviors and weight gain over time: transitions through the adolescent years. AB - Previous studies have yielded inconsistent results when documenting the association between key dietary factors and adolescent weight change over time. The purpose of this study was to examine the extent to which changes in adolescent sugar-sweetened beverage (SSB), diet soda, breakfast, and fast-food consumption were associated with changes in BMI and percent body fat (PBF). This study analyzed data from a sample of 693 Minnesota adolescents followed over 2 years. Random coefficient models were used to examine the relationship between dietary intake and BMI and PBF and to separate cross-sectional and longitudinal associations. Adjusting for total physical activity, total energy intake, puberty, race, socioeconomic status, and age, cross-sectional findings indicated that for both males and females, breakfast consumption was significantly and inversely associated with BMI and PBF, and diet soda intake was significantly and positively associated with BMI and PBF among females. In longitudinal analyses, however, there were fewer significant associations. Among males there was evidence of a significant longitudinal association between SSB consumption and PBF; after adjustment for energy intake, an increase of one serving of SSB per day was associated with an increase of 0.7 units of PBF among males. This study adds to previous research through its methodological strengths, including adjustment for physical activity and energy intake assessed using state-of-the art methods (i.e., accelerometers and 24-h dietary recalls), as well as its evaluation of both BMI and PBF. Additional research is needed to better understand the complex constellation of factors that contribute to adolescent weight gain over time. PMID- 21701568 TI - Serum amyloid A induces lipolysis by downregulating perilipin through ERK1/2 and PKA signaling pathways. AB - Serum amyloid A (SAA) is not only an apolipoprotein, but also a member of the adipokine family with potential to enhance lipolysis. The purpose of this study was to explore how SAA facilitates lipolysis in porcine adipocytes. We found that SAA increased the phosphorylation of perilipin and hormone-sensitive lipase (HSL) after 12-h treatment and decreased perilipin expression after 24-h treatment, and these effects were prevented by extracellular signal-regulated kinase (ERK) or protein kinase A (PKA) inhibitors in primary adipocyte cell culture. SAA treatment decreased HSL and adipose triglyceride lipase (ATGL) expression. SAA treatment also activated ERK and PKA by increasing the phosphorylation of these kinases. Moreover, SAA significantly increased porcine adipocyte glycerol release and lipase activity, which was inhibited by either ERK (PD98059) or PKA (H89) inhibitors, suggesting that ERK and PKA were involved in mediating SAA enhanced lipolysis. SAA downregulated the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA, which was reversed by the ERK inhibitor. We performed a porcine perilipin promoter assay in differentiated 3T3-L1 adipocytes and found that SAA reduced the porcine perilipin promoter specifically through the function of its PPAR response element (PPRE), and this effect was reversed by the ERK inhibitor. These findings demonstrate that SAA-induced lipolysis is a result of downregulation of perilipin and activation of HSL via ERK/PPARgamma and PKA signaling pathways. The finding could lead to developing new strategies for reducing human obesity. PMID- 21701569 TI - Postpartum changes in body composition. AB - Parity is associated with weight retention and has long-lasting and detrimental effects on the health of women. Previous studies have shown that increasing parity was independently associated with an increased prevalence of metabolic syndrome. Postpartum weight is made up of several components including uterine and mammary tissues, body water (intracellular (ICW) and extracellular water (ECW)), and fat. These components change in variable amounts postpartum, thereby distinctly affecting the interpretation of individual weight retention; however, it is unclear which components contribute to weight retention. The aims of this longitudinal study were to evaluate changes in body composition during the postpartum period and to investigate their effects on weight retention. This prospective study examined 41 healthy, pregnant women who gave birth at Korea University Guro Hospital. We measured body composition at 2 days, 2 weeks, and 6 weeks postpartum using bioelectrical impedance analysis. Weight decreased during this postpartum period (P < 0.001); the postpartum weight retention from prepregnancy to 6 weeks postpartum was 4.43 +/- 4.0 kg. Among various body composition components, ECW, ICW, total body water, and fat-free mass (FFM) decreased postpartum. However, fat mass (FM) and visceral fat area, the components that experienced the greatest changes, increased postpartum. Our results demonstrate that the postpartum period is associated with a preferential accumulation of adipose tissue in the visceral compartment, even though overall body weight is decreased. Further studies are needed to evaluate the changes in body composition over longer time periods and their long-term effects on health. PMID- 21701570 TI - Genome-wide association of BMI in African Americans. AB - Recent genome-wide association studies (GWAS) have identified multiple novel loci associated with obesity in Europeans but results in other ethnicities are less convincing. Here, we report a two-stage GWAS of BMI in African Americans. The GWAS was performed using the Affymetrix 6.0 platform in 816 nondiabetic and 899 diabetic nephropathy subjects. 746,626 single-nucleotide polymorphisms (SNPs) were tested for association with BMI after adjustment for age, gender, disease status, and population structure. Sixty high scoring SNPs that showed nominal association in both GWAS cohorts were further replicated in 3,274 additional subjects in four replication cohorts and a meta-analysis was computed. Meta analysis of 4,989 subjects revealed five SNPs (rs6794092, rs268972, rs2033195, rs815611, and rs6088887) at four loci showing consistent associations in both GWAS (P < 0.0001) and replication cohorts (P < 0.05) with combined P values range from 2.4 * 10(-6) to 5 * 10(-5). These loci are located near PP13439-TMEM212, CDH12, MFAP3-GALNT10, and FER1L4 and had effect sizes between 0.091 and 0.167 s.d. unit (or 0.67-1.24 kg/m(2)) of BMI for each copy of the effect allele. Our findings suggest the presence of novel loci potentially associated with adiposity in African Americans. Further replication and meta-analysis in African Americans and other populations will shed light on the role of these loci in different ethnic populations. PMID- 21701571 TI - B cell-activating factor controls the production of adipokines and induces insulin resistance. AB - Visceral adipose tissue (VAT) inflammation has been linked to the pathogenesis of insulin resistance and metabolic syndrome. VAT has recently been established as a new component of the immune system and is involved in the production of various adipokines and cytokines. These molecules contribute to inducing and accelerating systemic insulin resistance. In this report, we investigated the role of B cell activating factor (BAFF) in the induction of insulin resistance. We investigated BAFF levels in the sera and VAT of obese mice. In obese mice, the BAFF levels were preferentially increased in VAT and sera compared to these levels in normal control mice. Next, we treated mice with BAFF to analyze its influence on insulin sensitivity. BAFF impaired insulin sensitivity in normal mice. Finally, we investigated the mechanisms underlying insulin resistance induced by BAFF in adipocytes. BAFF also induced alterations in the expression levels of genes related to insulin resistance in adipocytes. In addition, BAFF directly affected the glucose uptake and phosphorylation of insulin receptor substrate-1 in adipocytes. We propose that autocrine or paracrine BAFF and BAFF-receptor (BAFF R) interaction in VAT leads to impaired insulin sensitivity via inhibition of insulin signaling pathways and alterations in adipokine production. PMID- 21701572 TI - Chronic neutrophilic leukaemia: an Egyptian case. AB - Chronic neutrophilic leukaemia (CNL) is a rare myeloproliferative disorder of elderly patients characterised by sustained neutrophilia. The diagnosis of CNL requires the exclusion of BCR/ABL positive chronic myelogenous leukaemia and leukemoid reaction. We present here a case of a 61-year-old Egyptian man with CNL and 21 months of follow-up. The main symptom of our patient was purpura. Splenomegaly, hepatomegaly and lymph node enlargement were not detected at presentation or throughout the patient's course. Thrombocytopenia was a considerable problem in our patient, causing recurrent bleeding and affecting the hydroxyurea dose adjustment. While hydroxyurea decreased the total leucocytic count, it could not affect the fatal course of the disease. The survival course of our patient extended to 21 months after presentation. The cause of death was attributed to disease progression. PMID- 21701573 TI - Simultaneous bilateral avulsion fractures of the anterior superior iliac spines in an adolescent sprinter. AB - A 16-year-old boy presented to the emergency department with sudden onset of bilateral hip pain while performing in a 100 m sprint race. Examination revealed diffuse swelling and tenderness at both anterior superior iliac spines (ASIS). Pelvic x ray revealed bilateral displaced avulsion fractures of the ASIS at the origin of the sartorius muscle. He was managed conservatively with analgesia and bed rest with both hips held partially flexed at approximately 60 degrees . Further x rays showed good healing and no further displacement of the avulsed fragments. Following physiotherapy he had a full range of hip movements at 6 weeks post-injury. He was able to return to full activity by 18 weeks post injury. PMID- 21701574 TI - New therapies and management strategies in the treatment of asthma: patient focused developments. AB - It is increasingly recognized that large proportions of patients with asthma remain poorly controlled with daily symptoms, limitation in activities, or severe exacerbations despite traditional treatment with inhaled corticosteroids and other agents. This suggests that there is considerable scope for the refinement of traditional guidelines on the use of inhaled therapies in asthma and also a need for the development of novel therapeutic agents, particularly for the treatment of severe asthma. This review aims to discuss a range of emerging treatment approaches in asthma. Firstly, we will set the scene by highlighting the importance of achieving good asthma control in a patient-focused manner and discussing recent work that has furthered our understanding of asthma phenotypes and paved the way for patient-specific treatments. Secondly, we will review new strategies to better use the existing therapies such as inhaled corticosteroids and long-acting beta(2)-agonists that remain the mainstay of treatment for most patients. Finally, we will review the novel therapies that are becoming available, both pharmacological and interventional, and discuss their likely place in the management of this complex disease. PMID- 21701575 TI - Reconciling apparent conflicts between mitochondrial and nuclear phylogenies in African elephants. AB - Conservation strategies for African elephants would be advanced by resolution of conflicting claims that they comprise one, two, three or four taxonomic groups, and by development of genetic markers that establish more incisively the provenance of confiscated ivory. We addressed these related issues by genotyping 555 elephants from across Africa with microsatellite markers, developing a method to identify those loci most effective at geographic assignment of elephants (or their ivory), and conducting novel analyses of continent-wide datasets of mitochondrial DNA. Results showed that nuclear genetic diversity was partitioned into two clusters, corresponding to African forest elephants (99.5% Cluster-1) and African savanna elephants (99.4% Cluster-2). Hybrid individuals were rare. In a comparison of basal forest "F" and savanna "S" mtDNA clade distributions to nuclear DNA partitions, forest elephant nuclear genotypes occurred only in populations in which S clade mtDNA was absent, suggesting that nuclear partitioning corresponds to the presence or absence of S clade mtDNA. We reanalyzed African elephant mtDNA sequences from 81 locales spanning the continent and discovered that S clade mtDNA was completely absent among elephants at all 30 sampled tropical forest locales. The distribution of savanna nuclear DNA and S clade mtDNA corresponded closely to range boundaries traditionally ascribed to the savanna elephant species based on habitat and morphology. Further, a reanalysis of nuclear genetic assignment results suggested that West African elephants do not comprise a distinct third species. Finally, we show that some DNA markers will be more useful than others for determining the geographic origins of illegal ivory. These findings resolve the apparent incongruence between mtDNA and nuclear genetic patterns that has confounded the taxonomy of African elephants, affirm the limitations of using mtDNA patterns to infer elephant systematics or population structure, and strongly support the existence of two elephant species in Africa. PMID- 21701576 TI - Predicting species diversity of benthic communities within turbid nearshore using full-waveform bathymetric LiDAR and machine learners. AB - Epi-macrobenthic species richness, abundance and composition are linked with type, assemblage and structural complexity of seabed habitat within coastal ecosystems. However, the evaluation of these habitats is highly hindered by limitations related to both waterborne surveys (slow acquisition, shallow water and low reactivity) and water clarity (turbid for most coastal areas). Substratum type/diversity and bathymetric features were elucidated using a supervised method applied to airborne bathymetric LiDAR waveforms over Saint-Simeon-Bonaventure's nearshore area (Gulf of Saint-Lawrence, Quebec, Canada). High-resolution underwater photographs were taken at three hundred stations across an 8-km(2) study area. Seven models based upon state-of-the-art machine learning techniques such as Naive Bayes, Regression Tree, Classification Tree, C 4.5, Random Forest, Support Vector Machine, and CN2 learners were tested for predicting eight epi macrobenthic species diversity metrics as a function of the class number. The Random Forest outperformed other models with a three-discretized Simpson index applied to epi-macrobenthic communities, explaining 69% (Classification Accuracy) of its variability by mean bathymetry, time range and skewness derived from the LiDAR waveform. Corroborating marine ecological theory, areas with low Simpson epi-macrobenthic diversity responded to low water depths, high skewness and time range, whereas higher Simpson diversity relied upon deeper bottoms (correlated with stronger hydrodynamics) and low skewness and time range. The degree of species heterogeneity was therefore positively linked with the degree of the structural complexity of the benthic cover. This work underpins that fully exploited bathymetric LiDAR (not only bathymetrically derived by-products), coupled with proficient machine learner, is able to rapidly predict habitat characteristics at a spatial resolution relevant to epi-macrobenthos diversity, ranging from clear to turbid waters. This method might serve both to nurture marine ecological theory and to manage areas with high species heterogeneity where navigation is hazardous and water clarity opaque to passive optical sensors. PMID- 21701577 TI - ELOVL6 genetic variation is related to insulin sensitivity: a new candidate gene in energy metabolism. AB - BACKGROUND: The elongase of long chain fatty acids family 6 (ELOVL6) is an enzyme that specifically catalyzes the elongation of saturated and monounsaturated fatty acids with 12, 14 and 16 carbons. ELOVL6 is expressed in lipogenic tissues and it is regulated by sterol regulatory element binding protein 1 (SREBP-1). OBJECTIVE: We investigated whether ELOVL6 genetic variation is associated with insulin sensitivity in a population from southern Spain. DESIGN: We undertook a prospective, population-based study collecting phenotypic, metabolic, nutritional and genetic information. Measurements were made of weight and height and the body mass index (BMI) was calculated. Insulin resistance was measured by homeostasis model assessment. The type of dietary fat was assessed from samples of cooking oil taken from the participants' kitchens and analyzed by gas chromatography. Five SNPs of the ELOVL6 gene were analyzed by SNPlex. RESULTS: Carriers of the minor alleles of the SNPs rs9997926 and rs6824447 had a lower risk of having high HOMA_IR, whereas carriers of the minor allele rs17041272 had a higher risk of being insulin resistant. An interaction was detected between the rs6824447 polymorphism and the intake of oil in relation with insulin resistance, such that carriers of this minor allele who consumed sunflower oil had lower HOMA_IR than those who did not have this allele (P = 0.001). CONCLUSIONS: Genetic variations in the ELOVL6 gene were associated with insulin sensitivity in this population based study. PMID- 21701578 TI - Chemical linkage to injected tissues is a distinctive property of oxidized avidin. AB - We recently reported that the oxidized avidin, named AvidinOX(r), resides for weeks within injected tissues as a consequence of the formation of Schiff's bases between its aldehyde groups and tissue protein amino groups. We also showed, in a mouse pre-clinical model, the usefulness of AvidinOX for the delivery of radiolabeled biotin to inoperable tumors. Taking into account that AvidinOX is the first oxidized glycoprotein known to chemically link to injected tissues, we tested in the mouse a panel of additional oxidized glycoproteins, with the aim of investigating the phenomenon. We produced oxidized ovalbumin and mannosylated streptavidin which share with avidin glycosylation pattern and tetrameric structure, respectively and found that neither of them linked significantly to cells in vitro nor to injected tissues in vivo, despite the presence of functional aldehyde groups. The study, extended to additional oxidized glycoproteins, showed that the in vivo chemical conjugation is a distinctive property of the oxidized avidin. Relevance of the high cationic charge of avidin into the stable linkage of AvidinOX to tissues is demonstrated as the oxidized acetylated avidin lost the property. Plasmon resonance on matrix proteins and cellular impedance analyses showed in vitro that avidin exhibits a peculiar interaction with proteins and cells that allows the formation of highly stable Schiff's bases, after oxidation. PMID- 21701579 TI - Effects of the training dataset characteristics on the performance of nine species distribution models: application to Diabrotica virgifera virgifera. AB - Many distribution models developed to predict the presence/absence of invasive alien species need to be fitted to a training dataset before practical use. The training dataset is characterized by the number of recorded presences/absences and by their geographical locations. The aim of this paper is to study the effect of the training dataset characteristics on model performance and to compare the relative importance of three factors influencing model predictive capability; size of training dataset, stage of the biological invasion, and choice of input variables. Nine models were assessed for their ability to predict the distribution of the western corn rootworm, Diabrotica virgifera virgifera, a major pest of corn in North America that has recently invaded Europe. Twenty-six training datasets of various sizes (from 10 to 428 presence records) corresponding to two different stages of invasion (1955 and 1980) and three sets of input bioclimatic variables (19 variables, six variables selected using information on insect biology, and three linear combinations of 19 variables derived from Principal Component Analysis) were considered. The models were fitted to each training dataset in turn and their performance was assessed using independent data from North America and Europe. The models were ranked according to the area under the Receiver Operating Characteristic curve and the likelihood ratio. Model performance was highly sensitive to the geographical area used for calibration; most of the models performed poorly when fitted to a restricted area corresponding to an early stage of the invasion. Our results also showed that Principal Component Analysis was useful in reducing the number of model input variables for the models that performed poorly with 19 input variables. DOMAIN, Environmental Distance, MAXENT, and Envelope Score were the most accurate models but all the models tested in this study led to a substantial rate of mis classification. PMID- 21701580 TI - Dynamics of tropomyosin in muscle fibers as monitored by saturation transfer EPR of bi-functional probe. AB - The dynamics of four regions of tropomyosin was assessed using saturation transfer electron paramagnetic resonance in the muscle fiber. In order to fully immobilize the spin probe on the surface of tropomyosin, a bi-functional spin label was attached to i,i+4 positions via cysteine mutagenesis. The dynamics of bi-functionally labeled tropomyosin mutants decreased by three orders of magnitude when reconstituted into "ghost muscle fibers". The rates of motion varied along the length of tropomyosin with the C-terminus position 268/272 being one order of magnitude slower then N-terminal domain or the center of the molecule. Introduction of troponin decreases the dynamics of all four sites in the muscle fiber, but there was no significant effect upon addition of calcium or myosin subfragment-1. PMID- 21701581 TI - Tyrosine kinase syk non-enzymatic inhibitors and potential anti-allergic drug like compounds discovered by virtual and in vitro screening. AB - In the past decade, the spleen tyrosine kinase (Syk) has shown a high potential for the discovery of new treatments for inflammatory and autoimmune disorders. Pharmacological inhibitors of Syk catalytic site bearing therapeutic potential have been developed, with however limited specificity towards Syk. To address this topic, we opted for the design of drug-like compounds that could impede the interaction of Syk with its cellular partners while maintaining an active kinase protein. To achieve this challenging task, we used the powerful potential of intracellular antibodies for the modulation of cellular functions in vivo, combined to structure-based in silico screening. In our previous studies, we reported the anti-allergic properties of the intracellular antibody G4G11. With the aim of finding functional mimics of G4G11, we developed an Antibody Displacement Assay and we isolated the drug-like compound C-13, with promising in vivo anti-allergic activity. The likely binding cavity of this compound is located at the close vicinity of G4G11 epitope, far away from the catalytic site of Syk. Here we report the virtual screen of a collection of 500,000 molecules against this new cavity, which led to the isolation of 1000 compounds subsequently evaluated for their in vitro inhibitory effects using the Antibody Displacement Assay. Eighty five compounds were selected and evaluated for their ability to inhibit the liberation of allergic mediators from mast cells. Among them, 10 compounds inhibited degranulation with IC50 values <= 10 uM. The most bioactive compounds combine biological activity, significant inhibition of antibody binding and strong affinity for Syk. Moreover, these molecules show a good potential for oral bioavailability and are not kinase catalytic site inhibitors. These bioactive compounds could be used as starting points for the development of new classes of non-enzymatic inhibitors of Syk and for drug discovery endeavour in the field of inflammation related disorders. PMID- 21701582 TI - Toxicity testing in the 21 century: defining new risk assessment approaches based on perturbation of intracellular toxicity pathways. AB - The approaches to quantitatively assessing the health risks of chemical exposure have not changed appreciably in the past 50 to 80 years, the focus remaining on high-dose studies that measure adverse outcomes in homogeneous animal populations. This expensive, low-throughput approach relies on conservative extrapolations to relate animal studies to much lower-dose human exposures and is of questionable relevance to predicting risks to humans at their typical low exposures. It makes little use of a mechanistic understanding of the mode of action by which chemicals perturb biological processes in human cells and tissues. An alternative vision, proposed by the U.S. National Research Council (NRC) report Toxicity Testing in the 21(st) Century: A Vision and a Strategy, called for moving away from traditional high-dose animal studies to an approach based on perturbation of cellular responses using well-designed in vitro assays. Central to this vision are (a) "toxicity pathways" (the innate cellular pathways that may be perturbed by chemicals) and (b) the determination of chemical concentration ranges where those perturbations are likely to be excessive, thereby leading to adverse health effects if present for a prolonged duration in an intact organism. In this paper we briefly review the original NRC report and responses to that report over the past 3 years, and discuss how the change in testing might be achieved in the U.S. and in the European Union (EU). EU initiatives in developing alternatives to animal testing of cosmetic ingredients have run very much in parallel with the NRC report. Moving from current practice to the NRC vision would require using prototype toxicity pathways to develop case studies showing the new vision in action. In this vein, we also discuss how the proposed strategy for toxicity testing might be applied to the toxicity pathways associated with DNA damage and repair. PMID- 21701583 TI - SHP-2 promotes the maturation of oligodendrocyte precursor cells through Akt and ERK1/2 signaling in vitro. AB - BACKGROUND: Oligodendrocyte precursor cells (OPCs) differentiate into oligodendrocytes (OLs), which are responsible for myelination. Myelin is essential for saltatory nerve conduction in the vertebrate nervous system. However, the molecular mechanisms of maturation and myelination by oligodendrocytes remain elusive. METHODS AND FINDINGS: In the present study, we showed that maturation of oligodendrocytes was attenuated by sodium orthovanadate (a comprehensive inhibitor of tyrosine phosphatases) and PTPi IV (a specific inhibitor of SHP-2). It is also found that SHP-2 was persistently expressed during maturation process of OPCs. Down-regulation of endogenous SHP-2 led to impairment of oligodendrocytes maturation and this effect was triiodo-L-thyronine (T3) dependent. Furthermore, over-expression of SHP-2 was shown to promote maturation of oligodendrocytes. Finally, it has been identified that SHP-2 was involved in activation of Akt and extracellular-regulated kinases 1 and 2 (ERK1/2) induced by T3 in oligodendrocytes. CONCLUSIONS: SHP-2 promotes oligodendrocytes maturation via Akt and ERK1/2 signaling in vitro. PMID- 21701584 TI - Isolation by elevation: genetic structure at neutral and putatively non-neutral loci in a dominant tree of subtropical forests, Castanopsis eyrei. AB - BACKGROUND: The distribution of genetic diversity among plant populations growing along elevational gradients can be affected by neutral as well as selective processes. Molecular markers used to study these patterns usually target neutral processes only, but may also be affected by selection. In this study, the effects of elevation and successional stage on genetic diversity of a dominant tree species were investigated controlling for neutrality of the microsatellite loci used. METHODOLOGY/PRINCIPAL FINDINGS: Diversity and differentiation among 24 populations of Castanopsis eyrei from different elevations (251-920 m) and successional stages were analysed by eight microsatellite loci. We found that one of the loci (Ccu97H18) strongly deviated from a neutral model of differentiation among populations due to either divergent selection or hitchhiking with an unknown selected locus. The analysis showed that C. eyrei populations had a high level of genetic diversity within populations (A(R) = 7.6, H(E) = 0.82). Genetic variation increased with elevation for both the putatively selected locus Ccu97H18 and the neutral loci. At locus Ccu97H18 one allele was dominant at low elevations, which was replaced at higher elevations by an increasing number of other alleles. The level of genetic differentiation at neutral loci was similar to that of other Fagaceae species (F(ST) = 0.032, = 0.15). Population differentiation followed a model of isolation by distance but additionally, strongly significant isolation by elevation was found, both for neutral loci and the putatively selected locus. CONCLUSIONS/SIGNIFICANCE: The results indicate higher gene flow among similar elevational levels than across different elevational levels and suggest a selective influence of elevation on the distribution of genetic diversity in C. eyrei. The study underlines the importance to check the selective neutrality of marker loci in analyses of population structure. PMID- 21701585 TI - In search of an uncultured human-associated TM7 bacterium in the environment. AB - We have identified an environmental bacterium in the Candidate Division TM7 with >=98.5% 16S rDNA gene homology to a group of TM7 bacteria associated with the human oral cavity and skin. The environmental TM7 bacterium (referred to as TM7a like) was readily detectable in wastewater with molecular techniques over two years of sampling. We present the first images of TM7a-like cells through FISH technique and the first images of any TM7 as viable cells through the STARFISH technique. In situ quantification showed TM7 concentration in wastewater up to five times greater than in human oral sites. We speculate that upon further characterization of the physiology and genetics of the TM7a-like bacterium from environmental sources and confirmation of its genomic identity to human associated counterparts it will serve as model organisms to better understand its role in human health. The approach proposed circumvents difficulties imposed by sampling humans, provides an alternative strategy to characterizing some diseases of unknown etiology, and renders a much needed understanding of the ecophysiological role hundreds of unique Bacteria and Archaea strains play in mixed microbial communities. PMID- 21701586 TI - Hepatitis E virus seroprevalence among blood donors in southwest Switzerland. AB - AIM: The aim of this study was to determine the seroprevalence of Hepatitis E virus (HEV) among blood donors in southwest Switzerland. BACKGROUND: HEV is recognized as a food-borne disease in industrialized countries, transmitted mainly through pork meat. Cases of transmission through blood transfusion have also been reported. Recent studies have revealed seroprevalence rates of 13.5%, 16.6% and 20.6% among blood donors in England, France and Denmark, respectively. METHODS: We analyzed 550 consecutive blood donor samples collected in the region of Lausanne, canton of Vaud, Switzerland, for the presence of anti-HEV IgG, using the MP Diagnostics HEV ELISA kit. For each donor, we documented age, sex and alanine aminotransferase (ALT) value. RESULTS: The study panel was composed of 332 men (60.4%) and 218 women (39.6%). Overall, anti-HEV IgG was found in 27 of 550 samples (4.9%). The seroprevalence was 5.4% (18/332) in men and 4.1% (9/218) in women. The presence of anti-HEV IgG was not correlated with age, gender or ALT values. However, we observed a peak in seroprevalence of 5.3% in individuals aged 51 to 70 years old. CONCLUSIONS: Compared with other European countries, HEV seroprevalence among blood donors in southwest Switzerland is low. The low seroprevalence may be explained by the sensitivity of commercial tests used and/or the strict regulation of animal and meat imports. Data regarding HEV prevalence in Swiss livestock are lacking and merit exploration. PMID- 21701587 TI - Id1 interacts and stabilizes the Epstein-Barr virus latent membrane protein 1 (LMP1) in nasopharyngeal epithelial cells. AB - The EBV-encoded latent membrane protein 1 (LMP1) functions as a constitutive active form of tumor necrosis factor receptor (TNFR) and activates multiple downstream signaling pathways similar to CD40 signaling in a ligand-independent manner. LMP1 expression in EBV-infected cells has been postulated to play an important role in pathogenesis of nasopharyngeal carcinoma. However, variable levels of LMP1 expression were detected in nasopharyngeal carcinoma. At present, the regulation of LMP1 levels in nasopharyngeal carcinoma is poorly understood. Here we show that LMP1 mRNAs are transcribed in an EBV-positive nasopharyngeal carcinoma (NPC) cell line (C666-1) and other EBV-negative nasopharyngeal carcinoma cells stably re-infected with EBV. The protein levels of LMP1 could readily be detected after incubation with proteasome inhibitor, MG132 suggesting that LMP1 protein is rapidly degraded via proteasome-mediated proteolysis. Interestingly, we observed that Id1 overexpression could stabilize LMP1 protein in EBV-infected cells. In contrary, Id1 knockdown significantly reduced LMP1 levels in cells. Co-immunoprecipitation studies revealed that Id1 interacts with LMP1 by binding to the CTAR1 domain of LMP1. N-terminal region of Id1 is required for the interaction with LMP1. Furthermore, binding of Id1 to LMP1 suppressed polyubiquitination of LMP1 and may be involved in stabilization of LMP1 in EBV infected nasopharyngeal epithelial cells. PMID- 21701589 TI - Exome sequencing reveals comprehensive genomic alterations across eight cancer cell lines. AB - It is well established that genomic alterations play an essential role in oncogenesis, disease progression, and response of tumors to therapeutic intervention. The advances of next-generation sequencing technologies (NGS) provide unprecedented capabilities to scan genomes for changes such as mutations, deletions, and alterations of chromosomal copy number. However, the cost of full genome sequencing still prevents the routine application of NGS in many areas. Capturing and sequencing the coding exons of genes (the "exome") can be a cost effective approach for identifying changes that result in alteration of protein sequences. We applied an exome-sequencing technology (Roche Nimblegen capture paired with 454 sequencing) to identify sequence variation and mutations in eight commonly used cancer cell lines from a variety of tissue origins (A2780, A549, Colo205, GTL16, NCI-H661, MDA-MB468, PC3, and RD). We showed that this technology can accurately identify sequence variation, providing ~95% concordance with Affymetrix SNP Array 6.0 performed on the same cell lines. Furthermore, we detected 19 of the 21 mutations reported in Sanger COSMIC database for these cell lines. We identified an average of 2,779 potential novel sequence variations/mutations per cell line, of which 1,904 were non-synonymous. Many non synonymous changes were identified in kinases and known cancer-related genes. In addition we confirmed that the read-depth of exome sequence data can be used to estimate high-level gene amplifications and identify homologous deletions. In summary, we demonstrate that exome sequencing can be a reliable and cost effective way for identifying alterations in cancer genomes, and we have generated a comprehensive catalogue of genomic alterations in coding regions of eight cancer cell lines. These findings could provide important insights into cancer pathways and mechanisms of resistance to anti-cancer therapies. PMID- 21701588 TI - Plant Hsp90 proteins interact with B-cells and stimulate their proliferation. AB - BACKGROUND: The molecular chaperone heat shock protein 90 (Hsp90) plays an important role in folding stabilization and activation of client proteins. Besides, Hsp90 of mammals and mammalian pathogens displays immunostimulatory properties. Here, we investigated the role of plant-derived Hsp90s as B-cell mitogens by measuring their proliferative responses in vitro. METHODOLOGY: Plant cytosolic Hsp90 isoforms from Arabidopsis thaliana (AtHsp81.2) and Nicotiana benthamiana (NbHsp90.3) were expressed in E. coli. Over-expression of recombinant plant Hsp90s (rpHsp90s) was confirmed by SDS-PAGE and western blot using and anti AtHsp81.2 polyclonal anti-body. Both recombinant proteins were purified by Ni-NTA affinity chromatography and their identity confirmed by MALDI-TOF-TOF. Recombinant AtHsp81.2 and NbHsp90.3 proteins induced prominent proliferative responses in spleen cells form BALB/c mice. Polymyxin-B, a potent inhibitor of lipopolysaccharide (LPS), did not eliminate the rpHsp90-induced proliferation. In addition, in vitro incubation of spleen cells with rpHsp90 led to the expansion of CD19-bearing populations, suggesting a direct effect of these proteins on B lymphocytes. This effect was confirmed by immunofluorescence analysis, where a direct binding of rpHsp90 to B- but not to T-cells was observed in cells from BALB/c and C3H/HeN mice. Finally, we examined the involvement of Toll Like Receptor 4 (TLR4) molecules in the rpHsp90s induction of B-cell proliferation. Spleen cells from C3H/HeJ mice, which carry a point mutation in the cytoplasmic region of TLR4, responded poorly to prAtHsp90. However, the interaction between rpHsp90 and B-cells from C3H/HeJ mice was not altered, suggesting that the mutation on TLR4 would be affecting the signal cascade but not the rpHsp90-TLR4 receptor interaction. CONCLUSIONS: Our results show for the first time that spleen cell proliferation can be stimulated by a non-pathogen-derived Hsp90. Furthermore, our data provide a new example of a non-pathogen-derived ligand for TLRs. PMID- 21701590 TI - Coccidioidomycosis incidence in Arizona predicted by seasonal precipitation. AB - The environmental mechanisms that determine the inter-annual and seasonal variability in incidence of coccidioidomycosis are unclear. In this study, we use Arizona coccidioidomycosis case data for 1995-2006 to generate a timeseries of monthly estimates of exposure rates in Maricopa County, AZ and Pima County, AZ. We reveal a seasonal autocorrelation structure for exposure rates in both Maricopa County and Pima County which indicates that exposure rates are strongly related from the fall to the spring. An abrupt end to this autocorrelation relationship occurs near the the onset of the summer precipitation season and increasing exposure rates related to the subsequent season. The identification of the autocorrelation structure enabled us to construct a "primary" exposure season that spans August-March and a "secondary" season that spans April-June which are then used in subsequent analyses. We show that October-December precipitation is positively associated with rates of exposure for the primary exposure season in both Maricopa County (R = 0.72, p = 0.012) and Pima County (R = 0.69, p = 0.019). In addition, exposure rates during the primary exposure seasons are negatively associated with concurrent precipitation in Maricopa (R = -0.79, p = 0.004) and Pima (R = -0.64, p = 0.019), possibly due to reduced spore dispersion. These associations enabled the generation of models to estimate exposure rates for the primary exposure season. The models explain 69% (p = 0.009) and 54% (p = 0.045) of the variance in the study period for Maricopa and Pima counties, respectively. We did not find any significant predictors for exposure rates during the secondary season. This study builds on previous studies examining the causes of temporal fluctuations in coccidioidomycosis, and corroborates the "grow and blow" hypothesis. PMID- 21701591 TI - Detection of human bocavirus mRNA in respiratory secretions correlates with high viral load and concurrent diarrhea. AB - Human bocavirus (HBoV) is a parvovirus recently identified in association with acute respiratory infections (ARI). Despite its worldwide occurrence, little is known on the pathogenesis of HBoV infections. In addition, few systematic studies of HBoV in ARI have been conducted in Latin America. Therefore, in order to test whether active viral replication of human bocavirus is associated with respiratory diseases and to understand the clinical impact of this virus in patients with these diseases, we performed a 3-year retrospective hospital-based study of HBoV in outpatients and inpatients with symptoms of Acute Respiratory Infections (ARI) in Brazil. Nasopharyngeal aspirates (NPAs) from 1015 patients with respiratory symptoms were tested for HBoV DNA by PCR. All samples positive for HBoV were tested by PCR for all other respiratory viruses, had HBoV viral loads determined by quantitative real time PCR and, when possible, were tested by RT-PCR for HBoV VP1 mRNA, as evidence of active viral replication. HBoV was detected in 4.8% of patients, with annual rates of 10.0%, 3.0% and 3.0% in 2005, 2006 and 2007, respectively. The range of respiratory symptoms was similar between HBoV-positive and HBoV-negative ARI patients. However, a higher rate of diarrhea was observed in HBoV-positive patients. High HBoV viral loads (>108 copies/mL) and diarrhea were significantly more frequent in patients with exclusive infection by HBoV and in patients with detection of HBoV VP1 mRNA than in patients with viral co-infection, detected in 72.9% of patients with HBoV. In summary, our data demonstrated that active HBoV replication was detected in a small percentage of patients with ARI and was correlated with concurrent diarrhea and lack of other viral co-infections. PMID- 21701592 TI - Dia2 controls transcription by mediating assembly of the RSC complex. AB - BACKGROUND: Dia2 is an F-box protein found in the budding yeast, S. cerevisiae. Together with Skp1 and Cul1, Dia2 forms the substrate-determining part of an E3 ubiquitin ligase complex, otherwise known as the SCF. Dia2 has previously been implicated in the control of replication and genome stability via its interaction with the replisome progression complex. PRINCIPAL FINDINGS: We identified components of the RSC chromatin remodelling complex as genetic interactors with Dia2, suggesting an additional role for Dia2 in the regulation of transcription. We show that Dia2 is involved in controlling assembly of the RSC complex. RSC belongs to a group of ATP-dependent nucleosome-remodelling complexes that controls the repositioning of nucleosomes. The RSC complex is expressed abundantly and its 17 subunits are recruited to chromatin in response to both transcription activation and repression. In the absence of Dia2, RSC-mediated transcription regulation was impaired, with concomitant abnormalities in nucleosome positioning. CONCLUSIONS: Our findings imply that Dia2 is required for the correct assembly and function of the RSC complex. Dia2, by controlling the RSC chromatin remodeller, fine-tunes transcription by controlling nucleosome positioning during transcriptional activation and repression. PMID- 21701593 TI - Serial histopathological examination of the lungs of mice infected with influenza A virus PR8 strain. AB - Avian influenza H5N1 and pandemic (H1N1) 2009 viruses are known to induce viral pneumonia and subsequent acute respiratory distress syndrome (ARDS) with diffuse alveolar damage (DAD). The mortality rate of ARDS/DAD is extremely high, at approximately 60%, and no effective treatment for ARDS/DAD has been established. We examined serial pathological changes in the lungs of mice infected with influenza virus to determine the progress from viral pneumonia to ARDS/DAD. Mice were intranasally infected with influenza A/Puerto Rico/8/34 (PR8) virus, and their lungs were examined both macro- and micro-pathologically every 2 days. We also evaluated general condition, survival rate, body weight, viral loads in lung, and surfactant proteins in serum. As a result, all infected mice died within 9 days postinfection. At 2 days postinfection, inflammation in alveolar septa, i.e., interstitial pneumonia, was observed around bronchioles. From 4 to 6 days postinfection, interstitial pneumonia with alveolar collapse expanded throughout the lungs. From 6 to 9 days postinfection, DAD with severe alveolar collapse was observed in the lungs of all of dying and dead mice. In contrast, DAD was not observed in the live infected-mice from 2 to 6 days postinfection, despite their poor general condition. In addition, histopathological analysis was performed in mice infected with a dose of PR8 virus which was 50% of the lethal dose for mice in the 20-day observation period. DAD with alveolar collapse was observed in all dead mice. However, in the surviving mice, instead of DAD, glandular metaplasia was broadly observed in their lungs. The present study indicates that DAD with severe alveolar collapse is associated with death in this mouse infection model of influenza virus. Inhibition of the development of DAD with alveolar collapse may decrease the mortality rate in severe viral pneumonia caused by influenza virus infection. PMID- 21701594 TI - Immune activation, CD4+ T cell counts, and viremia exhibit oscillatory patterns over time in patients with highly resistant HIV infection. AB - The rates of immunologic and clinical progression are lower in patients with drug resistant HIV compared to wild-type HIV. This difference is not fully explained by viral load. It has been argued that reductions in T cell activation and/or viral fitness might result in preserved target cells and an altered relationship between the level of viremia and the rate of CD4+ T cell loss. We tested this hypothesis over time in a cohort of patients with highly resistant HIV. Fifty four antiretroviral-treated patients with multi-drug resistant HIV and detectable plasma HIV RNA were followed longitudinally. CD4+ T cell counts and HIV RNA levels were measured every 4 weeks and T cell activation (CD38/HLA-DR) was measured every 16 weeks. We found that the levels of CD4+ T cell activation over time were a strong independent predictor of CD4+ T cell counts while CD8+ T cell activation was more strongly associated with viremia. Using spectral analysis, we found strong evidence for oscillatory (or cyclic) behavior in CD4+ T cell counts, HIV RNA levels, and T cell activation. Each of the cell populations exhibited an oscillatory behavior with similar frequencies. Collectively, these data suggest that there may be a mechanistic link between T cell activation, CD4+ T cell counts, and viremia and lends support for the hypothesis of altered predator-prey dynamics as a possible explanation of the stability of CD4+ T cell counts in the presence of sustained multi-drug resistant viremia. PMID- 21701595 TI - Transmitted drug resistance in the CFAR network of integrated clinical systems cohort: prevalence and effects on pre-therapy CD4 and viral load. AB - Human immunodeficiency virus type 1 (HIV-1) genomes often carry one or more mutations associated with drug resistance upon transmission into a therapy-naive individual. We assessed the prevalence and clinical significance of transmitted drug resistance (TDR) in chronically-infected therapy-naive patients enrolled in a multi-center cohort in North America. Pre-therapy clinical significance was quantified by plasma viral load (pVL) and CD4+ cell count (CD4) at baseline. Naive bulk sequences of HIV-1 protease and reverse transcriptase (RT) were screened for resistance mutations as defined by the World Health Organization surveillance list. The overall prevalence of TDR was 14.2%. We used a Bayesian network to identify co-transmission of TDR mutations in clusters associated with specific drugs or drug classes. Aggregate effects of mutations by drug class were estimated by fitting linear models of pVL and CD4 on weighted sums over TDR mutations according to the Stanford HIV Database algorithm. Transmitted resistance to both classes of reverse transcriptase inhibitors was significantly associated with lower CD4, but had opposing effects on pVL. In contrast, position specific analyses of TDR mutations revealed substantial effects on CD4 and pVL at several residue positions that were being masked in the aggregate analyses, and significant interaction effects as well. Residue positions in RT with predominant effects on CD4 or pVL (D67 and M184) were re-evaluated in causal models using an inverse probability-weighting scheme to address the problem of confounding by other mutations and demographic or risk factors. We found that causal effect estimates of mutations M184V/I (-1.7 log10pVL) and D67N/G (-2.1[3?CD4] and 0.4 log10pVL) were compensated by K103N/S and K219Q/E/N/R. As TDR becomes an increasing dilemma in this modern era of highly-active antiretroviral therapy, these results have immediate significance for the clinical management of HIV-1 infections and our understanding of the ongoing adaptation of HIV-1 to human populations. PMID- 21701596 TI - Brown adipose tissue in humans is activated by elevated plasma catecholamines levels and is inversely related to central obesity. AB - BACKGROUND: Recent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in controlling obesity. It is known that beta-adrenoceptor-UCP1 system regulates BAT in rodent, but its influence in adult humans remains to be shown. The present study is to determine whether BAT activity can be independently stimulated by elevated catecholamines levels in adult human, and whether it is associated with their adiposity. METHODOLOGY/PRINCIPAL FINDINGS: We studied 14 patients with pheochromocytoma and 14 normal subjects who had performed both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and plasma total metanephrine (TMN) measurements during 2007-2010. The BAT detection rate and the mean BAT activity were significantly higher in patients with elevated TMN levels (Group A: 6/8 and 6.7+/-2.1 SUVmean. g/ml) than patients with normal TMN concentrations (Group B: 0/6 and 0.4+/-0.04 SUVmean. g/ml) and normal subjects (Group C: 0/14 and 0.4+/-0.03 SUVmean.g/ml). BAT activities were positively correlated with TMN levels (R = 0.83, p<0.0001) and were inversely related to body mass index (R = -0.47, p = 0.010), visceral fat areas (R = -0.39, p = 0.044), visceral/total fat areas (R = -0.52, p = 0.0043) and waist circumferences (R = -0.43, p = 0.019). Robust regression revealed that TMN (R = 0.81, p<0.0001) and waist circumferences (R = -0.009, p = 0.009) were the two independent predictors of BAT activities. CONCLUSIONS/SIGNIFICANCE: Brown adipose tissue activity in adult human can be activated by elevated plasma TMN levels, such as in the case of patients with pheochromocytoma, and is negatively associated with central adiposity. PMID- 21701597 TI - Overexpression of AtBMI1C, a polycomb group protein gene, accelerates flowering in Arabidopsis. AB - Polycomb group protein (PcG)-mediated gene silencing is emerging as an essential developmental regulatory mechanism in eukaryotic organisms. PcGs inactivate or maintain the silenced state of their target chromatin by forming complexes, including Polycomb Repressive Complex 1 (PRC1) and 2 (PRC2). Three PRC2 complexes have been identified and characterized in Arabidopsis; of these, the EMF and VRN complexes suppress flowering by catalyzing the trimethylation of lysine 27 on histone H3 of FLOWER LOCUS T (FT) and FLOWER LOCUS C (FLC). However, little is known about the role of PRC1 in regulating the floral transition, although AtRING1A, AtRING1B, AtBMI1A, and AtBMI1B are believed to regulate shoot apical meristem and embryonic development as components of PRC1. Moreover, among the five RING finger PcGs in the Arabidopsis genome, four have been characterized. Here, we report that the fifth, AtBMI1C, is a novel, ubiquitously expressed nuclear PcG protein and part of PRC1, which is evolutionarily conserved with Psc and BMI1. Overexpression of AtBMI1C caused increased H2A monoubiquitination and flowering defects in Arabidopsis. Both the suppression of FLC and activation of FT were observed in AtBMI1C-overexpressing lines, resulting in early flowering. No change in the H3K27me3 level in FLC chromatin was detected in an AtBMI1C overexpressing line. Our results suggest that AtBMI1C participates in flowering time control by regulating the expression of FLC; moreover, the repression of FLC by AtBMI1C is not due to the activity of PRC2. Instead, it is likely the result of PRC1 activity, into which AtBMI1C is integrated. PMID- 21701598 TI - Prevalence of antibodies to 2009 pandemic influenza A (H1N1) virus in German adult population in pre- and post-pandemic period. AB - BACKGROUND: In order to detect levels of pre-existing cross-reactive antibodies in different age groups and to measure age-specific infection rates of the influenza A (H1N1) 2009 pandemic in Germany, we conducted a seroprevalence study based on samples from an ongoing nationwide representative health survey. METHODOLOGY/PRINCIPAL FINDINGS: We analysed 845 pre-pandemic samples collected between 25 Nov 2008 and 28 Apr 2009 and 757 post-pandemic samples collected between 12 Jan 2010 and 24 Apr 2010. Reactive antibodies against 2009 pandemic influenza A (H1N1) virus (pH1N1) were detected using a haemagglutination inhibition test (antigen A/California/7/2009). Proportions of samples with antibodies at titre >= 40 and geometric mean of the titres (GMT) were calculated and compared among 6 age groups (18-29, 30-39, 40-49, 50-59, 60-69, >= 70 years). The highest proportions of cross-reactive antibodies at titre >= 40 before the pandemic were observed among 18-29 year olds, 12.5% (95% CI 7.3-19.5%). The highest increase in seroprevalence between pre- and post-pandemic was also observed among 18-29 year olds, 29.9% (95% CI 16.7-43.2%). Effects of sampling period (pre- and post-pandemic), age, sex, and prior influenza immunization on titre were investigated with Tobit regression analysis using three birth cohorts (after 1976, between 1957 and 1976, and before 1957). The GMT increased between the pre- and post-pandemic period by a factor of 10.2 (95% CI 5.0-20.7) in the birth cohort born after 1976, 6.3 (95% CI 3.3-11.9) in those born between 1957 and 1976 and 2.4 (95% CI 1.3-4.3) in those born before 1957. CONCLUSIONS/SIGNIFICANCE: We demonstrate that infection rates differed among age groups and that the measured pre-pandemic level of cross-reactive antibodies towards pH1N1 did not add information in relation to protection and prediction of the most affected age groups among adults in the pandemic. PMID- 21701599 TI - FTY720 reduces post-ischemic brain lymphocyte influx but does not improve outcome in permanent murine cerebral ischemia. AB - BACKGROUND: The contribution of neuroinflammation and specifically brain lymphocyte invasion is increasingly recognised as a substantial pathophysiological mechanism after stroke. FTY720 is a potent treatment for primary neuroinflammatory diseases by inhibiting lymphocyte circulation and brain immigration. Previous studies using transient focal ischemia models showed a protective effect of FTY720 but did only partially characterize the involved pathways. We tested the neuroprotective properties of FTY720 in permanent and transient cortical ischemia and analyzed the underlying neuroimmunological mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: FTY720 treatment resulted in substantial reduction of circulating lymphocytes while blood monocyte counts were significantly increased. The number of histologically and flow cytometrically analyzed brain invading T- and B lymphocytes was significantly reduced in FTY720 treated mice. However, despite testing a variety of treatment protocols, infarct volume and behavioural dysfunction were not reduced 7d after permanent occlusion of the distal middle cerebral artery (MCAO). Additionally, we did not measure a significant reduction in infarct volume at 24 h after 60 min filament-induced MCAO, and did not see differences in brain edema between PBS and FTY720 treatment. Analysis of brain cytokine expression revealed complex effects of FTY720 on postischemic neuroinflammation comprising a substantial reduction of delayed proinflammatory cytokine expression at 3d but an early increase of IL 1beta and IFN-gamma at 24 h after MCAO. Also, serum cytokine levels of IL-6 and TNF-alpha were increased in FTY720 treated animals compared to controls. CONCLUSIONS/SIGNIFICANCE: In the present study we were able to detect a reduction of lymphocyte brain invasion by FTY720 but could not achieve a significant reduction of infarct volumes and behavioural dysfunction. This lack of neuroprotection despite effective lymphopenia might be attributed to a divergent impact of FTY720 on cytokine expression and possible activation of innate immune cells after brain ischemia. PMID- 21701600 TI - High-resolution X-ray structure of the trimeric Scar/WAVE-complex precursor Brk1. AB - The Scar/WAVE-complex links upstream Rho-GTPase signaling to the activation of the conserved Arp2/3-complex. Scar/WAVE-induced and Arp2/3-complex-mediated actin nucleation is crucial for actin assembly in protruding lamellipodia to drive cell migration. The heteropentameric Scar/WAVE-complex is composed of Scar/WAVE, Abi, Nap, Pir and a small polypeptide Brk1/HSPC300, and recent work suggested that free Brk1 serves as a homooligomeric precursor in the assembly of this complex. Here we characterized the Brk1 trimer from Dictyostelium by analytical ultracentrifugation and gelfiltration. We show for the first time its dissociation at concentrations in the nanomolar range as well as an exchange of subunits within different DdBrk1 containing complexes. Moreover, we determined the three-dimensional structure of DdBrk1 at 1.5 A resolution by X-ray crystallography. Three chains of DdBrk1 are associated with each other forming a parallel triple coiled-coil bundle. Notably, this structure is highly similar to the heterotrimeric alpha-helical bundle of HSPC300/WAVE1/Abi2 within the human Scar/WAVE-complex. This finding, together with the fact that Brk1 is collectively sandwiched by the remaining subunits and also constitutes the main subunit connecting the triple-coil domain of the HSPC300/WAVE1/Abi2/ heterotrimer to Sra1(Pir1), implies a critical function of this subunit in the assembly process of the entire Scar/WAVE-complex. PMID- 21701601 TI - Patient Safety Culture: A Review of the Nursing Home Literature and Recommendations for Practice. AB - Patient safety culture (PSC) is a critical factor in creating high-reliability health-care organizations. Most PSC research studies to date have been conducted in acute care settings; however, nursing home studies have recently begun to appear in the literature. Nursing homes differ from hospitals in a number of ways, including the population they serve, the medical model of care, and having the vast majority of direct care provided by non-licensed certified nursing assistants. Research has shown that nursing home PSC differs in important ways from PSC in acute care institutions. Recent PSC studies conducted in nursing homes and related quality and safety research can guide recommendations for nursing homes wishing to evaluate their own PSC. Relationships between PSC measurement, quality improvement, and workforce issues are potentially important and may influence clinical outcomes. PMID- 21701602 TI - Mechanisms Linking Early Experience and the Emergence of Emotions: Illustrations From the Study of Maltreated Children. AB - Emotions are complex processes that are essential for survival and adaptation. Recent studies of children and animals are shedding light on how the developing brain learns to rapidly respond to signals in the environment, assess the emotional significance of this information, and in so doing adaptively regulate subsequent behavior. Here, I describe studies of children and nonhuman primates who are developing within emotionally aberrant environments. Examining these populations provides new insights on the ways in which social or interpersonal contexts influence development of the neural systems underlying emotional behavior. PMID- 21701603 TI - Sex Differences in Trajectories of Offending Among Puerto Rican Youth. AB - Although sex is one of the strongest correlates of crime, contentions remain regarding the necessity of sex-specific theories of crime. The current study examines delinquent trajectories across sex among Puerto Rican youth socialized in two different cultural contexts (Bronx, United States and San Juan, Puerto Rico). Results indicate: similar substantive offending trajectories across males and females within each cultural context; that males exhibit a higher frequency of offending and higher levels of risk factors for delinquency; and there more similarities than differences in how risk/protective factors relate to patterns of offending across male versus female youth. Study limitations and implications for sex-specific criminological theories are also discussed. PMID- 21701604 TI - Anti-metallothionein IgG and levels of metallothionein in autistic children with GI disease. AB - AIM: To assess both serum concentration of metallotionein (MT) and anti metallothionein (anti-MT) immunoglobulin G (IgG) in autistic children with gastrointestinal (GI) symptoms and controls, and to test the hypothesis that there is an association between the presence of MT, anti-MT IgG, and inflammatory GI disease seen in many children with autistic spectrum disorder (ASD). SUBJECTS AND METHODS: ELISAs were used to measure serum MT and anti-MT IgG in 41 autistic children with chronic digestive disease (many with ileo-colonic lymphoid nodular hyperplasia [LNH] and inflammation of the colorectum, small bowel, and/or stomach), and 33 controls (17 age-matched autistic children with no GI disease and 16 age-matched children without autism or GI disease). RESULTS: Ten of 41 autistic children with chronic digestive disease had high serum concentration of MT compared to only one of the 33 controls (p < 0.01). Thirteen of the 41 autistic children with chronic digestive disease had anti-MT IgG compared to only four of 33 controls (p < 0.01). Nine of 10 (90%) of autistic children with GI disease with high MT levels had a regressive onset (compared to the expected 25 of 41, or 61%, in this group) (p < 0.05), whereas only nine of 13 of the autistic children with GI disease and anti-MT IgG had a regressive onset (70%) which was not significantly higher than the expected. We didn't find any correlation between severity of GI disease and MT concentration or anti-MT IgG. DISCUSSION: These results suggest a relationship between MT, anti-MT IgG and GI disease seen in many ASD individuals. PMID- 21701605 TI - Polycystic ovary syndrome and its impact on women's quality of life: More than just an endocrine disorder. AB - In the past, polycystic ovary syndrome has been looked at primarily as an endocrine disorder. Studies now show that polycystic ovary syndrome is a metabolic, hormonal, and psychosocial disorder that impacts a patient's quality of life. It is extremely important to holistically treat these patients early on to help them deal with the emotional stress that is often overlooked with polycystic ovary syndrome. Early diagnosis and long term management can help control polycystic ovary syndrome so that women can still live a healthy active life and avoid long-term complications such as metabolic syndrome and cardiovascular diseases. PMID- 21701606 TI - Severe hepatotoxic adverse reaction in a healthy schoolgirl after treatment with flucloxacillin. AB - This is the first detailed description of a severe hepatotoxic reaction in a previously healthy 9-year-old schoolgirl after ingestion of some flucloxacillin tablets. She was clinically well within one week and alanine aminotransferase in serum was normalized in one month. Follow up for more than one year was normal. PMID- 21701607 TI - Use of X-ray fluoroscopy in orthopedic operations: The patient's perspective. AB - We collected data from 50 patients who had orthopedic trauma surgery involving X ray fluoroscopy. All patients were interviewed post-operatively. The aim of the study was to find out what patients thought of orthopedic trauma surgery, the radiation involved, and their concerns post-trauma surgery. Were they given information about the procedures? Did the surgery follow the Department of Health, UK guidelines? That is, consent should be informed, etc. Results showed that most of the patients were unaware of the fact that they were X-rayed during the operation; hence the emphasis on informed consent should be stressed. Most of the patients were unaware about the availability of any protective clothing (lead shield). Even some female patients were unaware of the harmful effects of the radiation on the fetus. Hence, we recommend that more information and education be given to orthopedic trauma patients regarding X-rays. PMID- 21701608 TI - Long-term use of rosuvastatin: a critical risk benefit appraisal and comparison with other antihyperlipidemics. AB - Rosuvastatin represents the latest inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase introduced in clinical practice for the treatment of hypercholesterolemia. In comparative trials, across dose ranges this statin reduced low-density lipoprotein (LDL) cholesterol and total cholesterol significantly more than atorvastatin, simvastatin, and pravastatin, and triglycerides significantly more than simvastatin and pravastatin. In healthy subjects with normal LDL cholesterol and elevated C-reactive protein, rosuvastatin treatment significantly decreased the incidence of cardiovascular events. Its chemical and pharmacokinetic properties (with a low lipophilicity and poor capacity to inhibit cytochrome P450 enzymes) suggest a very limited penetration in extrahepatic tissues with a lower risk of muscle toxicity and unlike metabolically mediated drug-drug interactions. This article reviews the most recent data on the pharmacologic and clinical properties of rosuvastatin, in order to enable the correct use of this statin for the treatment of hypercholesterolemia. PMID- 21701609 TI - Information technology in pharmacovigilance: Benefits, challenges, and future directions from industry perspectives. AB - Risk assessment during clinical product development needs to be conducted in a thorough and rigorous manner. However, it is impossible to identify all safety concerns during controlled clinical trials. Once a product is marketed, there is generally a large increase in the number of patients exposed, including those with comorbid conditions and those being treated with concomitant medications. Therefore, postmarketing safety data collection and clinical risk assessment based on observational data are critical for evaluating and characterizing a product's risk profile and for making informed decisions on risk minimization. Information science promises to deliver effective e-clinical or e-health solutions to realize several core benefits: time savings, high quality, cost reductions, and increased efficiencies with safer and more efficacious medicines. The development and use of standard-based pharmacovigilance system with integration connection to electronic medical records, electronic health records, and clinical data management system holds promise as a tool for enabling early drug safety detections, data mining, results interpretation, assisting in safety decision making, and clinical collaborations among clinical partners or different functional groups. The availability of a publicly accessible global safety database updated on a frequent basis would further enhance detection and communication about safety issues. Due to recent high-profile drug safety problems, the pharmaceutical industry is faced with greater regulatory enforcement and increased accountability demands for the protection and welfare of patients. This changing climate requires biopharmaceutical companies to take a more proactive approach in dealing with drug safety and pharmacovigilance. PMID- 21701611 TI - Pharmacist-documented interventions during the dispensing process in a primary health care facility in Qatar. AB - OBJECTIVES: To characterize prescribing error interventions documented by pharmacists in four pharmacies in a primary health care service in Qatar. METHODS: The study was conducted in a primary health care service in the State of Qatar in the period from January to March 2008. Pharmacists in four clinics within the service used online, integrated health care software to document all clinical interventions made. Documented information included: patient's age and gender, drug therapy details, the intervention's details, its category, and its outcome. Interventions were categorized according to the Pharmaceutical Care Network Europe Classification of drug-related problems (DRP). RESULTS: The number of patients who had their prescriptions intercepted were 589 (0.71% of the total 82,800 prescriptions received). The intercepted prescriptions generated 890 DRP related interventions (an average of 1.9% DRPs identified across the four clinics). Fifty-four percent of all interventions were classified as drug choice problems, and 42% had safety problems (dose too high, potential significant interaction). The prescriber accepted the intervention in 53% of all interventions, and the treatment was changed accordingly. Interventions as a result of transcription errors, legality and formulary issues were eliminated from this study through the use of computerized physician order entry (CPOE). CONCLUSIONS: Documenting and analyzing interventions should be a routine activity in pharmacy practice setting in primary health care services. Educational outreach visits and other strategies can improve prescribing practices and enhance patient safety. PMID- 21701612 TI - 29 gauge needles improve patient satisfaction over 27 gauge needles for daily glatiramer acetate injections. AB - Using three surveys, a comparative assessment of needle performance and patient preference for 27-gauge (G) and 29G needles for glatiramer acetate administration for multiple sclerosis therapy was performed. Eligible patients participated in a specialty pharmacy program and administered glatiramer acetate for >=1 month. In Survey 1 on the 27G needle, 545 (82.70%) patients reported no needle problems, 106 (16.09%) cited one type (dull, bent, or broken), five (0.76%) cited two types, and three (0.46%) cited all three types. In Survey 2 on the 29G needle, 553 (98.05%) indicated no problems, two (0.35%) cited dull needles, and nine (1.60%) cited bent needles. On the 29G needles versus 27G needles pain comparison, 219 (38.83%) reported the 29G needle was a little better, and 155 (27.48%) reported it was a lot better than the 27G. For injection-site experiences, 515 patients (91.31%) reported no, very slight, or mild reactions with the 29G needle. In Survey 3, over 76% of patients preferred the 29G to the 27G needle and significantly fewer patients reported one or more problems with the 29G needle compared to patients reporting problems with the 27G needle (P < 0.00001). In conclusion, significantly fewer patients reported problems after 30 days of use of the 29G than the 27G needle. Fewer injection-site experiences occurred with the 29G needle and the 29G needle was preferred overall. PMID- 21701610 TI - Prevention of NSAID-related upper gastrointestinal toxicity: a meta-analysis of traditional NSAIDs with gastroprotection and COX-2 inhibitors. AB - BACKGROUND: Traditional NSAIDs (tNSAIDs) and COX-2 inhibitors (COX-2s) are important agents for the treatment of a variety or arthritic conditions. The purpose of this study was to systematically review the effectiveness of misoprostol, H2-receptor antagonists (H2RAs), and proton pump inhibitors (PPIs) for the prevention of tNSAID related upper gastrointestinal (GI) toxicity, and to review the upper gastrointestinal (GI) safety of COX-2s. METHODS: An extensive literature search was performed to identify randomized controlled trials (RCTs) of prophylactic agents used for the prevention of upper GI toxicity, and RCTs that assessed the GI safety of the newer COX-2s. Meta-analysis was performed in accordance with accepted techniques. RESULTS: 39 gastroprotection and 69 COX-2 RCTs met inclusion criteria. Misoprostol, PPIs, and double doses of H2RAs are effective at reducing the risk of both endoscopic gastric and duodenal tNSAID induced ulcers. Standard doses of H2RAs are not effective at reducing the risk of tNSAID-induced gastric ulcers, but reduce the risk of duodenal ulcers. Misoprostol is associated with greater adverse effects than the other agents, particularly at higher doses. COX-2s are associated with fewer endoscopic ulcers and clinically important ulcer complications, and have fewer treatment withdrawals due to GI symptoms than tNSAIDS. Acetylsalicylic acid appears to diminish the benefit of COX-2s over tNSAIDs. In high risk GI patients, tNSAID with a PPI or a COX-2 alone appear to offer similar GI safety, but a strategy of a COX-2 with a PPI appears to offer the greatest GI safety. CONCLUSION: Several strategies are available to reduce the risk of upper GI toxicity with tNSAIDs. The choice between these strategies needs to consider patients' underlying GI and cardiovascular risk. PMID- 21701613 TI - Beyond the black box: drug- and device-associated hypersensitivity events. AB - BACKGROUND: Drug- and device-associated hypersensitivity reactions are serious toxicities that can result in respiratory failure or acute cardiac ischemic events, or even severe hypersensitivity syndromes such as Stevens-Johnson syndrome. These toxicities are usually poorly described in the "black box" warnings section of the product labels. METHODS: Adverse event reports contained in databases maintained by the Project on Medical Research on Adverse Drug Events and Reports (Med-RADAR), product labels, safety advisories disseminated by pharmaceutical manufacturers, the Food and Drug Administration (FDA), and the Centers for Disease Control and Prevention (CDC) were reviewed. RESULTS: Adverse event reports identified three health care workers who developed nevirapine associated Stevens-Johnson syndrome following occupational exposure to HIV infected blood or blood products; four persons with localized hypersensitivity and fatal cardiac events associated with rapamycin- or paclitaxel-coated coronary artery stent placements; and six persons with breast cancer who developed severe or fatal anaphylaxis after receiving adjuvant chemotherapy with Cremophor-EL containing paclitaxel. Safety advisories from the FDA, CDC, and the relevant pharmaceutical manufacturers were ambiguous in their description in "black box" warning sections of package inserts describing these serious and potentially fatal toxicities. CONCLUSION: Improvements are needed in pharmacovigilance and subsequent dissemination of safety advisories for drug/device-associated hypersensitivity reactions. PMID- 21701615 TI - Antihypertensive drugs and erectile dysfunction as seen in spontaneous reports, with focus on angiotensin II type 1 receptor blockers. AB - AIM: To describe spontaneously reported cases of erectile dysfunction (ED) in association with angiotensin II type I blockers (ARB) and other antihypertensive drugs. SUBJECTS AND METHODS: All spontaneously reported cases of ED submitted to the Swedish Medical Products Agency (MPA) between 1990 and 2006, where at least one antihypertensive drug was the suspected agent, were scrutinized. Patient demographics, drug treatment and adverse reactions were recorded. Using the Bayesian Confidence Propagation Neural Network (BCPNN) method, the information component (IC) was calculated. RESULTS: Among a total of 225 reports of ED, 59 involved antihypertensive drugs including ARB (9 cases) as suspected agents. A positive IC value was found indicating that ED was reported more often in association with antihypertensive drugs classes, except for angiotensin converting enzyme inhibitors, compared with all other drugs in the database. Positive dechallenge was reported in 43 cases (72%). DISCUSSION: All classes of major antihypertensive drugs including ARB were implicated as suspected agents in cases of ED. Few risk factors were identified. The relatively high reporting of ED in association with ARB is in contrast with previous studies, suggesting that ARB have neither a positive nor any effect on ED. This discrepancy suggests that further studies are warrnted on this potential adverse reaction to ARB. PMID- 21701614 TI - Dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: safety, tolerability, and efficacy. AB - Although glycemic control is an important and effective way to prevent and minimize the worsening of diabetes-related complications, type 2 diabetes is a progressive disease which often proves difficult to manage. Most affected patients will eventually require therapy with multiple medications in order to reach appropriate glycemic targets. The dipeptidyl peptidase-4 (DPP-4) inhibitors constitute a relatively new class of oral medications for the treatment of type 2 diabetes, which has become widely incorporated into clinical practice. This review summarizes the available data on the efficacy, safety, and tolerability of these medications. PMID- 21701616 TI - Clinical safety and tolerability issues in use of triazole derivatives in management of fungal infections. AB - There has been an increase in the number of patients susceptible to invasive fungal infections (IFIs) leading to a greater need for effective, well tolerated, and easily administered antifungal agents. The advent of triazoles has revolutionized the care of patients requiring treatment or prophylaxis for IFIs. However, triazoles have been associated with a number of adverse events and significant drug-drug interactions. While commonly used, physicians and patients should be aware of the distinct properties of these agents in order to ensure that patients are optimally treated with the least amount of toxicity possible. Clinicians should have a full understanding of the basic pharmacokinetics, absorption, and bioavailability of triazoles. Moreover, knowledge of the drug drug interactions and potential toxicities of each agent is critical prior to administering a triazole. Careful history taking, thorough review of the patient's medication list, and detailed discussion with the patients and their families about the efficacy, safety, and tolerability of these agents should be performed. Clinicians treating patients with triazoles should closely follow them, monitor pertinent laboratory tests, and consider measuring drug levels as needed. This article will review the basic pharmacokinetic properties and most frequently encountered adverse events and pitfalls associated with triazoles in clinical practice. PMID- 21701617 TI - Management of glucocorticoid-induced osteoporosis: prevalence, and emerging treatment options. AB - An excess amount of glucocorticoids represents the primary and most frequent etiological factor influencing secondary osteoporosis. Patients receiving glucocorticoids, but also those with the endogenous form of hypercorticism, are at high risk for the loss of bone density, with the subsequent occurrence of pathological fractures. In this review, we summarize the currently available methods of prevention and the treatment of glucocorticoid-induced osteoporosis. We also include a proposal for both a prophylactic and therapeutic approach that takes into account the risk factors typical for long-term users of glucocorticoids. PMID- 21701618 TI - Safety and efficacy of laropiprant and extended-release niacin combination in the management of mixed dyslipidemias and primary hypercholesterolemia. AB - Statins form the cornerstone of pharmaceutical cardiovascular disease prevention. However, despite very effective statin intervention, the majority of events remain unpreventable. In some cases statin therapy alone is insufficient to achieve adequate lipid levels whereas other patients are unable to tolerate statins. This calls for additional treatment options. Niacin has a long history of success in reducing low-density lipoprotein cholesterol and triglycerides, and increasing high-density lipoprotein cholesterol. It was the first lipid-lowering drug to demonstrate a reduction in cardiovascular events, and remains the only one that has consistently shown benefits on surrogate outcomes when added to background therapies of other lipid-lowering drugs, including statins. Niacin's uptake in clinical practice has been less successful due to its side-effect profile, most notable being flushing. The uncovering of the mechanism by which flushing is induced, together with the development of a prostaglandin D(2) receptor inhibitor (laropiprant) which reduces this downstream flushing effect of niacin, has sparked new promise in therapeutic lipid management. It provides an additional treatment option into managing lipid abnormalities. The uptake in clinical practice of the niacin-laropiprant combination will depend on the relative improvements experienced by the patient in the side-effect profile compared to other treatment options, as well as on the the keenly-awaited outcome studies currently underway. Until these data become available guidelines and recommendations are unlikely to change and niacin's position in therapeutic cardiovascular risk prevention will be determined by clinician opinion and experience, and patient preferences. PMID- 21701619 TI - Efficacy, safety and tolerability of combination therapy with timolol and dorzolamide in glaucoma and ocular hypertension. AB - Combination pharmacotherapy has simplified and improved glaucoma medication regimens. This update focuses on the previous and recent studies on efficacy and tolerability profile of dorzolamide-timolol in adult ocular hypertension and open angle glaucoma patients. Dorzolamide-timolol has been shown to be efficacious and well tolerated in clinical trials and the adverse effects reflect those of the individual components. PMID- 21701620 TI - Safety and clinical efficacy of everolimus in the treatment of advanced renal cell carcinoma (RCC). AB - Renal cell carcinoma (RCC) is one of the most lethal genitourinary malignancies. Recently, there has been a paradigm shift in the management of advanced RCC. New targeted therapies including vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors have been developed which have shown promising results in a patient population who otherwise had very few options for treatment. The first mTOR inhibitor, temsirolimus, an intravenous prodrug, has shown improved overall survival in poor prognosis patients. More recently, an oral mTOR inhibitor, everolimus (RAD 001), has been developed which has been shown to delay disease progression in patients with metastatic RCC who have progressed on other targeted therapies. Although a survival advantage in phase III trials is seen with everolimus, associated systemic toxicities, while generally well tolerated, are not insignificant. These include mucositis, hyperglycemia, hyperlipidemia, and pneumonitis. Despite the side effects, emerging evidence points to everolimus as the optimal second-line treatment for patients with advanced renal cell carcinoma. PMID- 21701621 TI - Incorrect description of mode of excretion of linagliptin. PMID- 21701622 TI - Development of indicators for identifying adverse drug events in an Indian tertiary care teaching hospital. AB - OBJECTIVE: Adverse drug events (ADEs) are drug-related events which continue to pose serious challenges to the safety of patients. There are a number of ways to monitor ADEs, and the use of indictors to screen them provides an alternative method for detecting them. This method helps to assess the safety of drugs by the manual record review technique. The aim of this work was to develop a list of indicators to use in medical units of the study hospital to identify ADEs. SETTING: Tertiary care teaching hospital in India. METHOD: An initial list of ADE indicators based on published literature was developed by a panel of three experts. The list of indicators was subjected to review by a Delphi panel of five members. The Delphi panel reviewed the list of valid indicators and also suggested an addition of new indicators. The final list of indicators was used to review 100 previously documented ADE case reports. The case reports were screened for the presence of any of the indicators from the list. Parameters studied included number of indicators per case report and the most used indicators. RESULTS: From the literature, a 72 item indicator list was initially prepared which was further narrowed down to a list of 63 items. The Delphi panel conducted a review with these 63 items. At the end of review, and after addition and deletion of indicators, a 49 item indicator list was finalized. When this list of indicators was used for the review of ADE case reports, 42 indicators were identified. On average, three indicators were present in the reviewed case reports. CONCLUSION: An indicator list was developed for identification of ADEs in the study setup. The relevance of this indicator list was demonstrated by the presence of these indicators in the previously documented ADE reports. This is the first study from India to report on the development of ADE indicators, which might provide an alternative method to detecting ADEs in the setup of future studies. PMID- 21701623 TI - Efficacy, tolerability and safety of biologic therapy in rheumatoid disease: patient considerations. AB - Rheumatoid arthritis (RA) is a systemic inflammatory disease in which chronic inflammation leads to joint destruction and extra-articular complications. Early and effective inhibition of inflammation is critical in order to prevent the progressive joint damage that occurs rapidly after onset of the disease. In the past, treatment for this purpose was limited to conventional disease-modifying antirheumatic drugs (DMARDs), which were often suboptimal. Within the last decade however, the development of biologic therapies, targeted against cytokines and cells involved in the inflammatory process, has revolutionized the management of RA. Disease remission is now an achievable goal in newly diagnosed patients. Since the advent of the first tumor necrosis factor-alpha inhibitor in 1999, other biologics have proved necessary as individuals respond to varying degrees with different therapies. Several are now available for the treatment of patients with RA that remains active despite DMARD treatment. This article reviews the evidence, over the last decade, of the efficacy and safety of biologic therapies used in this context, and the recent clinical data supporting the use of biologic therapy earlier in the disease process as first-line therapy. PMID- 21701625 TI - A danger of induction of Brugada syndrome during pill-in-the-pocket therapy for paroxysmal atrial fibrillation. AB - Rhythm control therapy by sodium channel blockers is widely performed for the treatment of paroxysmal atrial fibrillation. Here, we present a case of acquired Brugada syndrome by pill-in-the-pocket treatment using pilsicainide. It is important that this therapy should be applied only after confirming the drug safety to the patients. PMID- 21701624 TI - Safety and tolerability of zoledronic acid and other bisphosphonates in osteoporosis management. AB - Bisphosphonates (BPs) are widely used in the treatment of postmenopausal osteoporosis and other metabolic bone diseases. They bind strongly to bone matrix and reduce bone loss through inhibition of osteoclast activity. They are classified as nitrogen- and non-nitrogen-containing bisphosphonates (NBPs and NNBPs, respectively). The former inhibit farnesyl diphosphate synthase while the latter induce the production of toxic analogs of adenosine triphosphate. These mechanisms of action are associated with different antifracture efficacy, and NBPs show the most powerful action. Moreover, recent evidence indicates that NBPs can also stimulate osteoblast activity and differentiation. Several randomized control trials have demonstrated that NBPs significantly improve bone mineral density, suppress bone turnover, and reduce the incidence of both vertebral and nonvertebral fragility fractures. Although they are generally considered safe, some side effects are reported (esophagitis, acute phase reaction, hypocalcemia, uveitis), and compliance with therapy is often inadequate. In particular, gastrointestinal discomfort is frequent with the older daily oral administrations and is responsible for a high proportion of discontinuation. The most recent weekly and monthly formulations, and in particular the yearly infusion of zoledronate, significantly improve persistence with treatment, and optimize clinical, densitometric, and antifracture outcomes. PMID- 21701626 TI - Antidepressant-associated sexual dysfunction: impact, effects, and treatment. AB - Sexual dysfunction is a common side effect of antidepressants and can have significant impact on the person's quality of life, relationships, mental health, and recovery. The reported incidence of sexual dysfunction associated with antidepressant medication varies considerably between studies, making it difficult to estimate the exact incidence or prevalence. The sexual problems reported range from decreased sexual desire, decreased sexual excitement, diminished or delayed orgasm, to erection or delayed ejaculation problems. There are a number of case reports of sexual side effects, such as priapism, painful ejaculation, penile anesthesia, loss of sensation in the vagina and nipples, persistent genital arousal and nonpuerperal lactation in women. The focus of this article is to explore the incidence, pathophysiology, and treatment of antidepressant iatrogenic sexual dysfunction. PMID- 21701627 TI - Phosphodiesterase-5 inhibitors in management of pulmonary hypertension: safety, tolerability, and efficacy. AB - Pulmonary arterial hypertension (PAH) is a progressive disease that causes severe disability and has no cure. Over the past 20 years, a variety of treatment options have evolved for the management of PAH. With an expanded therapeutic armamentarium come more complex decisions regarding treatment options. Agent selection depends upon several factors including efficacy, side effect profile, and cost, as well as convenience of administration. We have undertaken a review of phosphodiesterase-5 (PDE-5) inhibitors in PAH with a focus on efficacy and safety. A literature search was conducted using the Medline and Cochrane Central Register of Controlled Trials databases (1966-February 2010) for relevant randomized clinical studies. Overall, 10 studies met our inclusion criteria. Sildenafil was the most commonly studied agent, followed by tadalafil and vardenafil. Most trials found that the PDE-5 inhibitors significantly improved exercise capacity and lowered pulmonary pressures. However, there were conflicting results regarding these agents' impact on improving cardiac function and functional class. Overall, these medications were effective and well tolerated with a relatively benign side effect profile. The PDE-5 inhibitors are an important option in treating PAH. While most of the published clinical data involved sildenafil, the other PDE-5 inhibitors show promise as well. Further studies are needed to determine the optimal doses of this therapeutic drug class, as well as its effects as adjunctive therapy with other agents in PAH. PMID- 21701628 TI - Profound thrombocytopenia after primary exposure to eptifibatide. AB - Eptifibatide is a glycoprotein IIb/IIIa receptor antagonist used to reduce the incidence of ischemic events in patients with acute coronary syndromes and those undergoing percutaneous coronary intervention. A minority of patients given eptifibatide develop acute, profound thrombocytopenia (<20,000 cells/mm(3)) within a few hours of receiving the drug. This case report discusses a patient who developed profound thrombocytopenia within hours of receiving eptifibatide for the first time. The Naranjo algorithm classified the likelihood that this patient's thrombocytopenia was related to eptifibatide as probable. Profound thrombocytopenia is an uncommon but clinically important complication of eptifibatide. This case report emphasizes the importance of monitoring platelet counts routinely at baseline and within 2-6 hours of eptifibatide administration. PMID- 21701629 TI - Safety and clinical efficacy of golimumab in the treatment of arthritides. AB - Golimumab is a human anti-tumor necrosis factor (TNF)-alpha monoclonal antibody that was recently approved for the treatment of patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. This review covers the published clinical trial data on the use of golimumab for the approved indications mentioned above with respect to efficacy and safety. The various ongoing trials for golimumab have yielded promising results in terms of efficacy and safety in methotrexate-naive and -resistant patients with rheumatoid arthritis, as well as in patients who were previously treated with other anti-TNF agents. In addition, the efficacy of golimumab in psoriatic arthritis and ankylosing spondylitis has also been demonstrated. The real safety information will be available only once the drug has been used in many more patients, who frequently have comorbid conditions. PMID- 21701630 TI - Antiepileptic drugs and suicidality. AB - The risk of suicide in patients with epilepsy is significantly higher than the general population. There are many hypotheses as to the reasons for this, but the potential role of anti-epileptic drugs (AEDs) in increasing suicidality has recently been brought into question. In 2008, the U.S. Food and Drug Administration (FDA) published a warning after a meta-analysis of data from all clinical trials involving AEDs found a suicidality risk of 0.43 per 1000 patients in active drug arms of these clinical trials compared to a rate in the placebo arm of 0.22. While an increased risk for individual AEDs was found in two, the FDA decided to issue a warning for the entire AED class. While this decision and the meta-analysis findings have been considered controversial, and have created concern that this stated risk may dissuade use of AEDs by patients who would benefit from them, it has led to increased awareness of the risk of suicidality and psychiatric co-morbidity in this patient group. In this article, the association of epilepsy and AEDs with psychiatric disease and suicidality are reviewed, perspective as to the significance and limitations of the FDA's findings are discussed, and some options for suicidality screening and their potential utility in clinical care are evaluated. PMID- 21701631 TI - Risk management of risk management: Combining proton pump inhibitors with low dose aspirin. AB - Low-dose aspirin is widely used in the primary and secondary prevention of cardiovascular events, but is associated with a range of upper gastrointestinal side effects. In this review, we summarize the rationale for low-dose aspirin therapy, quantify the risk for upper gastrointestinal side effects, identify the risk factors involved, and provide an overview of preventive strategies, thereby focusing on the rationale and clinical utility of combining proton-pump inhibitors with low-dose aspirin. PMID- 21701632 TI - Safety and tolerability of antipsychotics: focus on amisulpride. AB - The introduction of the atypical antipsychotic drugs represents an important advance in the treatment of schizophrenia, because the therapeutic efficacy, tolerability, and safety profiles of these agents seem to be superior to that of the classical neuroleptics. As would be predicted from the pharmacologic profile of a pure D(2)/D(3) receptor blocker, amisulpride is an atypical antipsychotic agent, effective for positive and negative symptoms, which can bring about additional improvement in the social functioning and quality of life of patients with schizophrenia. Amisulpride is effective in acute schizophrenia as determined by Clinical Global Impression scores. The major concern regarding the safety of the atypical antipsychotics is related to their propensity to induce weight gain and alter glucose and lipid metabolism. Amisulpride has one of the lowest potentials for weight gain of all the antipsychotic agents, and is associated with clearly lower use of antiparkinsonian medication and with fewer dropouts due to adverse events than conventional antipsychotics. Amisulpride is well tolerated with regard to anxiety and insomnia, and not notably different from placebo. Amisulpride has a pronounced prolactin-elevating effect which appears to be independent of dosage and duration of administration. Hyperprolactinemia rapidly reverses following amisulpride discontinuation. Amisulpride benefits patients with negative symptoms, and is the only antipsychotic to demonstrate efficacy in patients with predominantly negative symptoms. Amisulpride maintains its efficacy when used for medium/long-term treatment, as demonstrated in studies of up to 12 months. In terms of relevance of the effects, superiority is observed for quality of life, social adaptation, and functioning, as measured by the Quality of Life and Functional Status Questionnaire scales. In conclusion, amisulpride is an antipsychotic agent with proven efficacy and good tolerability. Moreover, this drug can help people with schizophrenia to attain social reinsertion. PMID- 21701633 TI - Glargine and detemir: Safety and efficacy profiles of the long-acting basal insulin analogs. AB - Diabetes mellitus is a growing public health concern in the US and worldwide. Insulin therapy is the cornerstone of diabetes therapy, and the use of basal insulins will increase as clinicians strive to help their patients reach glycemic goals. Basal insulins have been continually improved upon over the years, and the long-acting basal insulin analogs, glargine and detemir, have many pharmacokinetic and pharmacodynamic advantages over neutral protamine Hagedorn insulin, namely, less variable absorption profiles, a less pronounced peak in effect, and a longer duration of action. Overall, glargine and detemir do not differ greatly in their safety and efficacy profiles. Major differences between the two include lower within-subject variability, lower risk of hypoglycemia, and a weight-sparing effect with insulin detemir. This review summarizes data from the key pharmacokinetic and pharmacodynamic studies, as well as clinical and observational studies to elucidate the role of each basal insulin analog in therapy. PMID- 21701634 TI - Insomnia medication use and the probability of an accidental event in an older adult population. AB - OBJECTIVE: This study examined the risk of accidental events in older adults prescribed a sedating antidepressant, long-acting benzodiazepine, short-acting benzodiazepine, and nonbenzodiazepine, relative to a reference group (selective melatonin receptor agonist). METHODS: This was a retrospective cohort analysis of older adults (>=65 years) with newly initiated pharmacological treatment of insomnia. Data were collected from the Thomson MarketScan((r)) Medicare Supplemental and Coordination of Benefits databases (January 1, 2000, through June 30, 2006). Probit models were used to evaluate the probability of an accidental event. RESULTS: Data were analyzed for 445,329 patients. Patients taking a long-acting benzodiazepine (1.21 odds ratio [OR]), short-acting benzodiazepine (1.16 OR), or nonbenzodiazepine (1.12 OR) had a significantly higher probability of experiencing an accidental event during the first month following treatment initiation compared with patients taking the reference medication (P < 0.05 for all). A significantly higher probability of experiencing an accidental event was also observed during the 3-month period following the initiation of treatment (1.62 long-acting benzodiazepine, 1.60 short-acting benzodiazepine, 1.48 nonbenzodiazepine, and 1.56 sedating antidepressant; P < 0.05). CONCLUSIONS: Older adults taking an SAD or any of the benzodiazepine receptor agonists appear to have a greater risk of an accidental event compared with a reference group taking an MR. PMID- 21701635 TI - Interaction between clopidogrel and proton-pump inhibitors and management strategies in patients with cardiovascular diseases. AB - Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin has been successful in reducing ischemic events in a wide range of patients with cardiovascular diseases. However, the anti-ischemic effects of DAPT may also be associated with gastrointestinal (GI) complications including ulceration and bleeding particularly in 'high risk' and elderly patients. Current guidelines recommend the use of proton-pump inhibitors (PPIs) to reduce the risk of GI bleeding in patients treated with DAPT. However, pharmacodynamic studies suggest an effect of PPIs on clopidogrel metabolism with a resultant reduction in platelet inhibitory effects. Similarly, several observational studies have demonstrated reduced clopidogrel benefit in patients who coadministered PPIs. Although recent US Food and Drug Administration and European Medicines Agency statements discourage PPI (particularly omeprazole) and clopidogrel coadministration, the 2009 AHA/ACC/SCAI PCI guidelines do not support a change in current practice in the absence of adequately powered prospective randomized clinical trial data. The data regarding pharmacologic and clinical interactions between PPI and clopidogrel therapies are herein examined and treatment strategies are provided. PMID- 21701637 TI - Essential medicines for children: Should we focus on a priority list of medicines for the present? PMID- 21701636 TI - TNF-alpha inhibitors: are they carcinogenic? AB - Biologic therapy has increasingly been used in the treatment of chronic diseases. Tumor necrosis factor (TNF) is a cytokine implicated in the pathogenesis of rheumatoid arthritis and inflammatory bowel disease. Anti-TNF therapy is being used in the treatment of these conditions. Since the introduction of anti-TNF agents, there have been many case reports of development of malignancy after the initiation of anti-TNF therapy. With increasing case reports, there is growing concern that anti-TNF therapy, albeit useful in the treatment of these chronic conditions, might be associated with the development of malignancy in patients. In this review we examine the different anti-TNF agents and different studies to evaluate any possible association between use of any anti-TNF agent and development of malignancy. PMID- 21701638 TI - Evaluation of nootropic and neuroprotective effects of low dose aspirin in rats. AB - OBJECTIVE: To evaluate the nootropic and neuroprotective effects of aspirin in Sprague Dawley rats. MATERIALS AND METHODS: Retention of conditioned avoidance response (CAR) and central 5-HT-mediated behavior (lithium-induced head twitches) were assessed using repeated electroconvulsive shock (ECS) in rats. Rats were divided into eight groups: control (pretreated with distilled water), scopolamine (0.5 mg/kg i.p.), ECS (150 V, 50 Hz sinusoidal with intensity of 210 mA for 0.5 s) pretreated, aspirin (6.75 mg/kg orally) pretreated, combined scopolamine and aspirin pretreated, ondansetron (0.36 mg/kg orally) pretreated, combined ECS and ondansetron pretreated and combined ECS and aspirin pretreated groups. Data was analyzed by the chi-square test and ANOVA. RESULTS: Findings show that administration of single ECS daily for consecutive 8 days results in enhancement of 5-HT-mediated behavior (lithium-induced head twitches) and in disruption of the retention of CAR. Aspirin and ondansetron administration significantly increased the retention of conditioned avoidance response compared to control. Ondansetron and aspirin significantly prevented ECS-induced attenuation of the retention of conditioned avoidance response also. On the other hand, ondansetron and aspirin significantly retarded the ECS-induced enhancement of 5-HT-mediated behavior. CONCLUSION: Inhibition of the serotonergic transmission by aspirin is responsible for its nootropic and neuroprotective actions. PMID- 21701639 TI - Pharmacokinetic and pharmacodynamic drug interactions of carbamazepine and glibenclamide in healthy albino Wistar rats. AB - AIMS: To find out the pharmacokinetic and pharmacodynamic drug interaction of carbamazepine, a protype drug used to treat painful diabetic neuropathy with glibenclamide in healthy albino Wistar rats following single and multiple dosage treatment. MATERIALS AND METHODS: Therapeutic doses (TD) of glibenclamide and TD of carbamazepine were administered to the animals. The blood glucose levels were estimated by GOD/POD method and the plasma glibenclamide concentrations were estimated by a sensitive RP HPLC method to calculate pharmacokinetic parameters. RESULTS: In single dose study the percentage reduction of blood glucose levels and glibenclamide concentrations of rats treated with both carbamazepine and glibenclamide were significantly increased when compared with glibenclamide alone treated rats and the mechanism behind this interaction may be due to inhibition of P-glycoprotein mediated transport of glibenclamide by carbamazepine, but in multiple dose study the percentage reduction of blood glucose levels and glibenclamide concentrations were reduced and it may be due to inhibition of P glycoprotein mediated transport and induction of CYP2C9, the enzyme through which glibenclamide is metabolised. CONCLUSIONS: In the present study there is a pharmacokinetic and pharmacodynamic interaction between carbamazepine and glibenclamide was observed. The possible interaction involves both P-gp and CYP enzymes. To investigate this type of interactions pre-clinically are helpful to avoid drug-drug interactions in clinical situation. PMID- 21701640 TI - Effects of fluoxetine and escitalopram on C-reactive protein in patients of depression. AB - OBJECTIVE: To study the anti-inflammatory activity of fluoxetine and escitalopram in newly diagnosed patients of depression and also to evaluate the association between depression and inflammation. MATERIALS AND METHODS: Ninety-eight newly diagnosed patients of depression were recruited as cases. From these, 48 had started treatment with fluoxetine (20 mg/day) and 50 had started treatment with escitalopram (20 mg/day). After 2 months of treatment of these patients, Hamilton rating scale for depression (HRSD scale), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cell (WBC) count were measured and compared to their respective baseline values before starting treatment. One hundred healthy volunteers were recruited as controls and their baseline of CRP, ESR and WBC count were measured and compared with their respective baseline values of cases. Severity of depression was measured by HRSD scale and anti inflammatory activity was measured by reduction CRP, ESR and WBC count. RESULTS: On baseline comparison between cases and controls, there were significant increases in the levels of CRP (P = 0.014), ESR (P = 0.023) and WBC count (P = 0.020) in cases. In fluoxetine (20 mg/day) treatment group, there was a significant reduction in the levels of CRP (P = 0.046), ESR (P = 0.043) and WBC count (P = 0.021) after 2 months of treatment but no significant reduction in HRSD scale (P = 0.190). Similarly, in escitalopram treatment group, there was a significant reduction in CRP (P = 0.041), ESR (P = 0.030) and WBC count (P = 0.017) after 2 months of treatment but no significant reduction in HRSD scale (P = 0.169). CONCLUSION: In newly diagnosed patients of depression, inflammatory markers such as CRP, ESR and WBC count were significantly raised and Selective serotonin reuptake inhibitors SSRIs such as fluoxetine and escitalopram reduced them independent of their antidepressant effect. So, SSRIs have some anti inflammatory activity independent of their antidepressant action. PMID- 21701641 TI - The incidence and nature of drug-related hospital admission: A 6-month observational study in a tertiary health care hospital. AB - OBJECTIVE: To assess and evaluate the frequency, severity and classification of drug-related problems (DRP) resulting in hospitalization in an internal medicine department of a large tertiary care hospital and to identify any patient, prescriber, drug, and system factors associated with these events. MATERIALS AND METHODS: A prospective and descriptive study carried out in Department of Medicine, Government Medical College, Jagdalpur. The DRP and relevant data were recorded on the personal record of every individual patient, filled during the course of treatment. RESULT: A total of 3560 patient's records were analyzed. Among them118 admissions were due to DRP. The most common DRP noted was noncompliance in part of patient's i.e 55 (46.6%). Statistically significant correlations were found in the number of prescribed drugs and over the counter drugs (OTC) used by patients. CONCLUSION: The DRP that attributed to hospital admission are mostly avoidable through proper patient education and strengthening the need of pharmacovigilance with little more vigilance in patient care. PMID- 21701642 TI - Adverse drug reactions in inpatients of internal medicine wards at a tertiary care hospital: A prospective cohort study. AB - OBJECTIVE: To find out incidence of adverse drug reactions (ADR) in patients of internal medicine wards and study various aspects of ADR, e.g., causality, mortality, drugs commonly causing ADR in internal medicine wards of Guru Gobind Singh Hospital, Jamnagar, a tertiary care hospital. MATERIALS AND METHODS: This was prospective, observational study carried out at Department of Medicine, Shri Meghji Pethraj Shah Medical College attached with Guru Gobind Singh Hospital, a tertiary care teaching hospital, Jamnagar, Gujarat over a period of 6 months. For statistical analysis, ADR were analyzed by using Chi-square test. RESULTS: Out of total 860 patients admitted, 830 were analyzed as they met the inclusion criteria. A total of 45 (5.42%) patients developed 47 ADR. Among them, 27 (3.25 %) (95% CI, 2.03, 4.47%) patients due to ADR required hospital admission in medicine ward (ADR Ad), 18 (2.17%) (95% CI, 1.17%-3.17%) patients developed ADR while already hospitalized in medicine ward (ADR In). Most of the fatal and life threatening reactions occurred due to chemotherapeutic agents. Majority of patients discontinued suspected drug and recovered from ADR. CONCLUSION: Fatal and life-threatening adverse reactions reported in the present as well as other studies underline the importance of such studies and need for creating awareness among health professionals about looking for and reporting such reactions. PMID- 21701643 TI - Adverse drug reactions of nonsteroidal anti-inflammatory drugs in orthopedic patients. AB - OBJECTIVES: To identify the ADRs due to NSAIDs and to know how to monitor the drug's effect. MATERIALS AND METHODS: A descriptive study was undertaken in the Orthopedic Outpatients Department of a tertiary care teaching hospital. Hundred patients were enrolled in this study to observe the risk of adverse drug reactions (ADRs) due to NSAIDs. All the ADRs were further analyzed in relation to age and sex, type of drug and its pattern. Probability scale was used for the causality assessment of the ADRs. RESULTS: 26% of the 100 patients developed ADR due to NSAIDs. There was not much of a difference in the number of the ADRs in relation to the gender. Diclofenac was the highest prescribed drug (65 patients), followed by paracetamol (12), nimesulide (10), ibuprofen (6), piroxicam (5) and Etoricoxib (2). Diclofenac accounted for the maximum number (73%) of ADRs, followed by nimesulide (16%), paracetamol (7%), and Etoricoxib (4%). CONCLUSION: Pharmacovigilance improves recognition of ADRs by the medical students. It allows the treating physician to identify the ADR associated with drugs, in particular, with the ones considered relatively safe and with those commonly prescribed by the medical and non-health professionals. PMID- 21701645 TI - Protocol for middle cerebral artery occlusion by an intraluminal suture method. PMID- 21701644 TI - Pharmacological evidences for the stimulation of calcium-sensing receptors by nifedipine in gingival fibroblasts. AB - OBJECTIVE: To investigate pharmacologically whether CaSRs are involved in the Ca(2+) antagonist-induced [Ca(2+)]i elevation in gingival fibroblasts. MATERIALS AND METHODS: Gin-1 cells, normal human gingival fibroblasts, were used as the material. The [Ca(2+)] i was measured with fura-2/AM, a Ca(2+)-sensitive fluorescent dye. RESULTS: At first, we confirmed the existence of CaSRs in these cells by showing that [Ca(2+)] i was elevated by high concentrations of extracellular Ca(2+) and by prototypic agonists of the CaSR such as gentamicin. The action of gentamicin was antagonized by inhibitors of phospholipase C (PLC), inositol trisphosphate (IP(3)) receptors, NSCCs, and, importantly, by the CaSR antagonist, NPS2390. Furthermore, the action of gentamicin was potentiated by activators of PLC and protein kinase C (PKC). This confirmed the pathway components mediating Ca(2+) responses to a known agonist of the CaSR. We then investigated whether nifedipine (an L-type Ca(2+) channel blocker) stimulates CaSRs to elevate [Ca(2+)] i via a similar mechanism. Nifedipine Ca(2+) responses were dose-dependently blocked by NPS2390 and by the same inhibitors of PLC, IP(3) receptors, and NSCCs that disrupted the action of gentamicin. Calphostin C (a PKC inhibitor) and TMB-8 (an inhibitor of Ca(2+) release from stores) also inhibited the nifedipine-induced [Ca(2+)] i elevation. CONCLUSION: These findings suggest that CaSRs are involved in the nifedipine-induced [Ca(2+)] i elevation in gingival fibroblasts. PMID- 21701646 TI - Atorvastatin-induced acute pancreatitis. AB - Atorvastatin-induced acute pancreatitis (AP) is one of the rare adverse effects available in the literature. We report a case of 53-year-old patient developed AP after treatment with atorvastatin monotherapy which resolved after drug withdrawal. Extensive workup on AP failed to reveal any other etiology for it. To our knowledge, this is one of the rare case reports of AP caused due to atorvastatin monotherapy and it further strengthens the fact that statins may cause AP. There is need of continued reporting of such a rare adverse effect of atorvastatin for increasing awareness and to manage and avoid the same. PMID- 21701647 TI - Data transformation. PMID- 21701648 TI - Author's reply. PMID- 21701649 TI - Critical appraisal of irrational drug combinations: A call for awareness in undergraduate medical students. PMID- 21701650 TI - Fingolimod (FTY720): First approved oral therapy for multiple sclerosis. PMID- 21701651 TI - Prediction of activity spectra for substances. PMID- 21701652 TI - Frequency distribution. PMID- 21701654 TI - Journal of Laboratory Physicians (JLP): Success Story Despite Many Challenges. PMID- 21701656 TI - Human immunodeficiency virus infection among tuberculosis patients in mumbai. AB - BACKGROUND: Human Immunodeficiency Virus (HIV) is the most powerful risk factor for the progression of Mycobacterium tuberculosis infection to Tuberculosis (TB) disease. TB accelerates the progression of HIV infection to AIDS and shortens the survival of such patients. AIM: To determine the seroprevalence of HIV infection among TB confirmed patients in a tertiary care center in Mumbai in view of the significance of HIV in TB. Its association with gender and age was also determined. MATERIALS AND METHODS: Blood samples were collected by venipuncture from 432 TB patients and their HIV status was determined. HIV antibody detection was carried out as per Strategy III, National AIDS Control Organisation (NACO) guidelines. Statistical analysis was carried out by applying the Chi-square test. RESULTS AND CONCLUSION: Of the 432 patients screened, 9% (39) were HIV positive. The prevalence of co-infection was higher among females (9.4%) than the male (8.7%) patients and highest amongst those aged 21to40 years (13.7%). Co-infection was found to be statistically highly associated with age (p < 0.05). This high prevalence calls for routine screening of TB patients for HIV infection. PMID- 21701655 TI - Quorum sensing and Bacterial Pathogenicity: From Molecules to Disease. AB - Quorum sensing in prokaryotic biology refers to the ability of a bacterium to sense information from other cells in the population when they reach a critical concentration (i.e. a Quorum) and communicate with them. The "language" used for this intercellular communication is based on small, self-generated signal molecules called as autoinducers. Quorum sensing is thought to afford pathogenic bacteriaa mechanism to minimize host immune responses by delaying theproduction of tissue-damaging virulence factors until sufficientbacteria have amassed and are prepared to overwhelm host defensemechanisms and establish infection. Quorum sensing systems are studied in a large number of gram-negative bacterial species belonging to alpha, beta, and gamma subclasses of proteobacteria. Among the pathogenic bacteria, Pseudomonas aeruginosa is perhaps the best understood in terms of the virulence factors regulated and the role the Quorum sensing plays in pathogenicity. Presently, Quorum sensing is considered as a potential novel target for antimicrobial therapy to control multi/all drug-resistant infections. This paper reviews Quorum sensing in gram positive and gram negative bacteria and its role in biofilm formation. PMID- 21701657 TI - Pancytopenia: a clinico hematological study. AB - BACKGROUND: Pancytopenia is a relatively common hematological entity. It is a striking feature of many serious and life-threatening illnesses, ranging from simple drug-induced bone marrow hypoplasia, megaloblastic anemia to fatal bone marrow aplasias and leukemias. The severity of pancytopenia and the underlying pathology determine the management and prognosis. Thus, identification of the correct cause will help in implementing appropriate therapy. OBJECTIVES: To study the clinical presentations in pancytopenia due to various causes; and to evaluate hematological parameters, including bone marrow aspiration. MATERIALS AND METHODS: It was a prospective study, and 104 pancytopenic patients were evaluated clinically, along with hematological parameters and bone marrow aspiration in Hematology Unit, Department of Pathology, JJMMC, Davanagere, during the period of September 2005 to September 2007. RESULTS: Among 104 cases studied, age of patients ranged from 2 to 80 years with a mean age of 41 years, and male predominance. Most of the patients presented with generalized weakness and fever. The commonest physical finding was pallor, followed by splenomegaly and hepatomegaly. Dimorphic anemia was the predominant blood picture. Bone marrow aspiration was conclusive in all cases. The commonest marrow finding was hypercellularity with megaloblastic erythropoiesis. The commonest cause for pancytopenia was megaloblastic anemia (74.04%), followed by aplastic anemia (18.26%). CONCLUSION: Thepresent study concludes that detailed primary hematological investigations along with bone marrow aspiration in cytopenic patients are helpful for understanding disease process and to diagnose or to rule out the causes of cytopenia. These are also helpful in planning further investigations and management. PMID- 21701658 TI - Significance of histopathology in leprosy patients with 1-5 skin lesions with relevance to therapy. AB - BACKGROUND: Patients with 1-5 skin lesions are clinically categorized as paucibacillary for treatment purposes. For betterment and adequate treatment of patients, this grouping needs further study. AIM: To study a group of leprosy patients with 1-5 skin lesions, compare clinical details with histopathological findings and bacteriological status of the skin to evaluate the relevance of this grouping. MATERIALS AND METHODS: Two-year study involving 31 patients of leprosy with 1-5 skin lesions was included in this study. A number of skin lesions were recorded. Skin biopsies were taken in all patients. The biopsies were evaluated for the type of pathology and acid fast bacilli (AFB) status. RESULTS: Of 31 patients, 19 (61.2%) had single skin lesion, 7 (22.5%) had two lesions, 4 (12.9%) had three lesions, and only one (3.22%) had four lesions, there were no patients with five lesions. Of the 31 patients, 30 (96.7%) were clinically diagnosed as borderline tuberculoid and one patient (3.22%) has tuberculoid leprosy. Skin smears were negative for AFB in all patients. The histological diagnoses were: TT 1 (3.22%), BT 24 (77.41%), and IL 6 (19.2%). AFB were found in 2 (6.45%) out of 31 skin biopsies. Clinicopathological correlation was 76.6% in the BT group. CONCLUSION: Tissue biopsy findings in 1-5 skin lesions which were not considered relevant for treatment purposes until now should be given a status in the categorization and assessment of severity of the disease. The significance of finding of AFB and histopathology of multibacillary (MB) type of leprosy in tissue biopsies, in patients grouped as PB should be resolved so that patients could be given the drug therapy and duration of therapy they warrant. PMID- 21701659 TI - Inducible Clindamycin Resistance in Staphylococcus aureus Isolated from Clinical Samples. AB - INTRODUCTION: The resistance to antimicrobial agents among Staphylococci is an increasing problem. This has led to renewed interest in the usage of Macrolide Lincosamide-Streptogramin B (MLS(B)) antibiotics to treat Staphylococcus aureus (S. aureus) infections. The resistance to macrolide can be mediated by msr A gene coding for efflux mechanism or via erm gene encoding for enzymes that confer inducible or constitutive resistance to MLS(B)antibiotics. In vitro routine tests for clindamycin susceptibility may fail to detect inducible clindamycin resistance due to erm genes resulting in treatment failure, thus necessitating the need to detect such resistance by a simple D test on a routine basis. MATERIALS AND METHODS: One hundred and ninety S. aureus isolates were subjected to routine antibiotic susceptibility testing including oxacillin (1 ug) and cefoxitin (30 ug) by modified Kirby Bauer disc diffusion method. Inducible resistance to clindamycin in S. aureus was tested by 'D test' as per CLSI guidelines. RESULTS: Twenty (10%) isolates showed inducible clindamycin resistance, 18 (9%) showed constitutive resistance while remaining 16 (8%) showed MS phenotype. Inducible resistance and constitutive resistance were found to be higher in MRSA as compared to MSSA (20%, 16% and 6%, 6%, respectively). CONCLUSION: Clindamycin is kept as a reserve drug and is usually advocated in severe MRSA infections depending upon the antimicrobial susceptibility results. This study showed that D test should be used as a mandatory method in routine disc diffusion testing to detect inducible clindamycin resistance in Staphylococci for the optimum treatment of patients. PMID- 21701660 TI - Lipoprotein (a) and other Lipid Profile in Patients with Thrombotic Stroke: Is it a Reliable Marker? AB - BACKGROUND: Cerebrovascular disease (CVD) and coronary heart disease (CHD) cause 40%-50% of deaths in developed countries with CVD causing 10%-12% of deaths. Though increased Lipoprotein (a) is a risk factor in developing CHD, its role is poorly defined in etiopathogenesis of CVD. AIMS: To find the association of lipoprotein (a) and lipid profile in thrombotic stroke patients after acute phase. SETTINGS AND DESIGN: The study was conducted at Kasturba Medical College, Manipal. Twenty one cases of thrombotic stroke and 18 cases of age and sex matched controls were taken for the study. Informed consent was taken from both case and control. MATERIALS AND METHODS: Overnight fasting sample was collected from both case and control. Serum was separated and parameters such as total cholesterol, triglycerides, high density lipoproteins-C, low density lipoprotein C, lipoprotein (a), fasting blood sugars were estimated. STATISTICAL ANALYSIS: Data were analyzed by SPSS software, Student's t-test, standard deviation (SD), and standard error of mean (SEM), P-value <0.05 is considered to be significant. RESULTS: In this study, we found no statistical significant differences in serum lipid and lipoprotein (a) profile between controls and thrombotic stroke patients. CONCLUSIONS: Highest frequency (38%) of stroke was found in the age group of 7080 years. There were other associated risk factors such as diabetes in five cases (24%), hypertension in nine cases (43%), and family history of stroke in four cases. However, further studies are required to evaluate the importance of serum Lp(a) estimation in the assessment as a risk factor for thrombotic stroke. PMID- 21701661 TI - Comparison of disc diffusion methods for the detection of extended-spectrum Beta lactamase-producing enterobacteriaceae. AB - BACKGROUND: Resistance to broad-spectrum beta lactams, mediated by extended spectrum beta lactamases (ESBLs), is an increasing problem world wide. This resistance poses problems for in vitro testing and reporting. Increased prevalence of ESBLs among Enterobacteriaceae creates a great need for laboratory testing methods that will accurately identify their presence. MATERIALS AND METHODS: During the study, the Enterobacteriaceae isolated were tested for the presence of ESBL by the National Committee for Clinical Laboratory Standards (NCCLS) screening test, Jarlier double disc synergy (approximation) test (DDST) and NCCLS phenotypic confirmatory test (PCT), and compared their efficiency in detection. RESULTS: A total of 313 Enterobacteriaceae were isolated and tested for the presence of ESBL. NCCLS PCT identified 200 (63.89%) as ESBL producers and DDST identified 176 (56.23%), with a P-value of <0.001. Among the screening agents, ceftazidime had a better sensitivity (89.49%) and specificity (95.74%). CONCLUSIONS: Close monitoring of the susceptibility pattern of isolates and careful spacing with specific discs can identify many ESBL producers. Ceftazidime has a better sensitivity and specificity as a screening agent. A combination of different tests can be useful for accurate identification. PMID- 21701662 TI - Horizontal Transfer of Antimicrobial Resistance by Extended-Spectrum beta Lactamase-Producing Enterobacteriaceae. AB - BACKGROUND: The purpose of this work was to study the acquisition of new antibiotic-resistant genes carried by extended spectrum beta-lactamase (ESBL) producing Enterobacteriaceae via horizontal transfer to understand their rampant spread in the hospitals and in the community. MATERIALS AND METHODS: A retrospective analysis of 120 ESBL screen-positive isolates of Escherichia coli and Klebsiella pneumoniae, which were subjected to antimicrobial susceptibility testing, was carried out. The Double Disc Synergy Test (DDST) and Inhibitor Potentiation Disc Diffusion Test (IPDD) were employed for confirmation of ESBL activity. The transferability of the associated antibiotic resistance for amoxicillin, amikacin, gentamicin, cefotaxime and ceftriaxone was elucidated by intra- and intergenus conjugation in Escherichia coli under laboratory as well as under simulated environmental conditions. Transformation experiments using plasmids isolated by alkaline lysis method were performed to study the transferability of resistance genes in Klebsiella pneumoniae isolates. RESULTS: ESBL production was indicated in 20% each of the Escherichia coli and Klebsiella pneumoniae isolates. All the ESBL isolates showed co- resistance to various other groups of antibiotics, including 3GC antibiotics, though all the isolates were sensitive to both the carbapenems tested. Conjugation-mediated transfer of resistance under laboratory as well as environmental conditions at a frequency of 3-4 * 10(-5), and transformation-mediated dissemination of cefotaxime and gentamicin resistance shed light on the propensity of ESBL producers for horizontal transfer. CONCLUSIONS: The transfer of resistant markers indicated availability of a large pool of resistance genes in the hospital setting as well as in the environment, facilitating long-term persistence of organisms. PMID- 21701663 TI - Actinomycetes mycetoma. AB - Mycetoma is a chronic infection, frequently seen in tropical and sub-tropical countries and is considered as an occupational disease. Nocardia species though it can infect immunocompetent individuals, it most commonly affects immunocompromised patients. A 50-year-old male, farmer presented to our hospital with serosanguineous discharging swelling over the dorsum of right foot. We have isolated Nocardia asteroides from the tissue sample. Speciation of this isolate was carried out based on phenotypic methods. Hereby we report a case of Actinomycetes Mycetoma in an immunocompetent individual. PMID- 21701664 TI - A Rare Case of Fungal Maxillary Sinusitis due to Paecilomyces lilacinus in an Immunocompetent Host, Presenting as a Subcutaneous Swelling. AB - Paecilomyces is a colonizing fungal species which usually causes keratitis, endocarditis, sinusitis, nephritis, fungemia, cutaneous, and subcutaneous infections in immunocompromised host. Very rarely, it causes similar infection in immunocompetent host without any risk factors. We report a case of maxillary sinusitis due to Paecilomyces lilacinus in a 65-year-old immunocompetent male, who presented with a subcutaneous swelling below the left eye. The lesion was excised by surgery and treated with itraconazole for 6 months based on culture and sensitivity. After 1 year of follow up, he is free of symptoms with no evidence of recurrence. PMID- 21701665 TI - An association between hypoplastic myelodysplastic syndrome and T-prolymphocytic leukaemia. AB - Myelodysplastic syndrome (MDS) represents one of the most challenging health related problems in the elderly, characterized by dysplastic morphology in the bone marrow in association with ineffective hematopoiesis. Hypoplastic MDS (h MDS) accounts for 12-17% of all patients with MDS and has yet to be shown to alter the disease course or prognosis. The concept that T-cell-mediated autoimmunity contributes to bone marrow failure in MDS has been widely accepted due to hematologic improvement after immunosuppressive therapy. T-cell expansion is known to occur in these patients, but development of chronic T-cell disorders, especially T-prolymphocytic leukemia (PLL) in a hypocellular MDS is extremely rare, which has an aggressive course. The possible explanation for the association between the two disorders is that T-PLL might arise from a clonally arranged MDS stem cell. We report a unique case of h-MDS with non-progressive pancytopenia and severe hypocellular marrow for 2 years, followed by T-PLL within few months. PMID- 21701666 TI - Uncommon manifestations of Endocervical Malignant Mixed Mullerian Tumor with Incidental Bilateral Fallopian Tube Carcinoma. AB - A 43-year-old perimenopausal lady presented with bleeding per vagina and lower abdominal pain. On evaluation, she had cervical polyp, which expelled spontaneously during the per speculum examination. Histopathology revealed malignant mixed Mullerian tumor. Extended hysterectomy with salphingo oophorectomy was carried out, which showed bilateral fallopian tube carcinoma and leiomyoma uterus. The patient was treated with carboplatin regime and found to be disease-free for 1 year. This case presented because of a rare combination of the lesions. PMID- 21701667 TI - Epignathus with fetiform features. AB - Epignathus is an extremely rare oropharyngeal teratoma that commonly arises from the palate, leading to a high mortality (80-100%) due to airway obstruction in the neonatal period. We present a case of epignathus immature teratoma with fetiform features, originating from basisphenoid in a 28-week preterm male baby, who succumbed to death immediately after birth. Since epignathus is a life threatening condition at the time of delivery, a prenatal diagnosis is essential to coordinate the treatment and appropriate management by securing the airway, either by endotracheal intubation or tracheostomy followed by complete resection of the tumor. PMID- 21701668 TI - Extrarenal nephroblastoma. PMID- 21701669 TI - Microbial profile of sugarcane juice sold at rohtak, haryana with special reference to bile esculin azide medium. PMID- 21701670 TI - A Case of Salmonella typhi Infection Leading to Miscarriage. PMID- 21701671 TI - Elizabethkingia meningosepticum : An Emerging Cause of Septicemia in Critically III Patients. PMID- 21701672 TI - An Investigation of Pulsatile Flow Past Two Cylinders as a Model of Blood Flow in an Artificial Lung. AB - Pulsatile flow across two circular cylinders with different geometric arrangements is studied experimentally using the particle image velocimetry method and numerically using the finite element method. This investigation is motivated the need to optimize gas transfer and fluid mechanical impedance for a total artificial lung, in which the right heart pumps blood across a bundle of hollow microfibers. Vortex formation was found to occur at lower Reynolds numbers in pulsatile flow than in steady flow, and the vortex structure depends strongly on the geometric arrangement of the cylinders and on the Reynolds and Stokes numbers. PMID- 21701673 TI - A Surrogate for Debye-Waller Factors from Dynamic Stokes Shifts. AB - We show that the short-time behavior of time-resolved fluorescence Stokes shifts (TRSS) are similar to that of the intermediate scattering function obtained from neutron scattering at q near the peak in the static structure factor for glycerol. This allows us to extract a Debye-Waller (DW) factor analog from TRSS data at times as short as 1 ps in a relatively simple way. Using the time-domain relaxation data obtained by this method we show that DW factors evaluated at times >= 40 ps can be directly influenced by alpha relaxation and thus should be used with caution when evaluating relationships between fast and slow dynamics in glassforming systems. PMID- 21701674 TI - Mini ways to stop a virus: microRNAs and HIV-1 replication. AB - Cellular restriction of HIV-1 replication has traditionally been thought of as protein mediated: APOBEC3G hypermutates HIV-1 genomic RNA, but is counteracted by Vif; Tetherin inhibits the release of budding virions but is counteracted by Vpu. In recent years, new evidence suggesting that miRNAs and other components of the miRNA pathway act as HIV-1 restriction factors has come to light, along with the identification of strategies that HIV-1 employs to surmount these host obstacles. In this article, we summarize and discuss the literature to date regarding the complex relationship between HIV-1 and miRNA-mediated inhibition. PMID- 21701675 TI - MicroRNA-145 regulates human corneal epithelial differentiation. AB - BACKGROUND: Epigenetic factors, such as microRNAs, are important regulators in the self-renewal and differentiation of stem cells and progenies. Here we investigated the microRNAs expressed in human limbal-peripheral corneal (LPC) epithelia containing corneal epithelial progenitor cells (CEPCs) and early transit amplifying cells, and their role in corneal epithelium. METHODOLOGY/PRINCIPAL FINDINGS: Human LPC epithelia was extracted for small RNAs or dissociated for CEPC culture. By Agilent Human microRNA Microarray V2 platform and GeneSpring GX11.0 analysis, we found differential expression of 18 microRNAs against central corneal (CC) epithelia, which were devoid of CEPCs. Among them, miR-184 was up-regulated in CC epithelia, similar to reported finding. Cluster miR-143/145 was expressed strongly in LPC but weakly in CC epithelia (P = 0.0004, Mann-Whitney U-test). This was validated by quantitative polymerase chain reaction (qPCR). Locked nucleic acid-based in situ hybridization on corneal rim cryosections showed miR-143/145 presence localized to the parabasal cells of limbal epithelium but negligible in basal and superficial epithelia. With holoclone forming ability, CEPCs transfected with lentiviral plasmid containing mature miR-145 sequence gave rise to defective epithelium in organotypic culture and had increased cytokeratin-3/12 and connexin-43 expressions and decreased ABCG2 and p63 compared with cells transfected with scrambled sequences. Global gene expression was analyzed using Agilent Whole Human Genome Oligo Microarray and GeneSpring GX11.0. With a 5-fold difference compared to cells with scrambled sequences, miR-145 up-regulated 324 genes (containing genes for immune response) and down-regulated 277 genes (containing genes for epithelial development and stem cell maintenance). As validated by qPCR and luciferase reporter assay, our results showed miR-145 suppressed integrin beta8 (ITGB8) expression in both human corneal epithelial cells and primary CEPCs. CONCLUSION/SIGNIFICANCE: We found expression of miR-143/145 cluster in human corneal epithelium. Our results also showed that miR-145 regulated the corneal epithelium formation and maintenance of epithelial integrity, via ITGB8 targeting. PMID- 21701677 TI - Remote data retrieval for bioinformatics applications: an agent migration approach. AB - Some of the approaches have been developed to retrieve data automatically from one or multiple remote biological data sources. However, most of them require researchers to remain online and wait for returned results. The latter not only requires highly available network connection, but also may cause the network overload. Moreover, so far none of the existing approaches has been designed to address the following problems when retrieving the remote data in a mobile network environment: (1) the resources of mobile devices are limited; (2) network connection is relatively of low quality; and (3) mobile users are not always online. To address the aforementioned problems, we integrate an agent migration approach with a multi-agent system to overcome the high latency or limited bandwidth problem by moving their computations to the required resources or services. More importantly, the approach is fit for the mobile computing environments. Presented in this paper are also the system architecture, the migration strategy, as well as the security authentication of agent migration. As a demonstration, the remote data retrieval from GenBank was used to illustrate the feasibility of the proposed approach. PMID- 21701676 TI - Using regulatory and epistatic networks to extend the findings of a genome scan: identifying the gene drivers of pigmentation in merino sheep. AB - Extending genome wide association analysis by the inclusion of gene expression data may assist in the dissection of complex traits. We examined piebald, a pigmentation phenotype in both human and Merino sheep, by analysing multiple data types using a systems approach. First, a case control analysis of 49,034 ovine SNP was performed which confirmed a multigenic basis for the condition. We combined these results with gene expression data from five tissue types analysed with a skin-specific microarray. Promoter sequence analysis of differentially expressed genes allowed us to reverse-engineer a regulatory network. Likewise, by testing two-loci models derived from all pair-wise comparisons across piebald associated SNP, we generated an epistatic network. At the intersection of both networks, we identified thirteen genes with insulin-like growth factor binding protein 7 (IGFBP7), platelet-derived growth factor alpha (PDGFRA) and the tetraspanin platelet activator CD9 at the kernel of the intersection. Further, we report a number of differentially expressed genes in regions containing highly associated SNP including ATRN, DOCK7, FGFR1OP, GLI3, SILV and TBX15. The application of network theory facilitated co-analysis of genetic variation with gene expression, recapitulated aspects of the known molecular biology of skin pigmentation and provided insights into the transcription regulation and epistatic interactions involved in piebald Merino sheep. PMID- 21701679 TI - Weak spatial and temporal population genetic structure in the rosy apple aphid, Dysaphis plantaginea, in French apple orchards. AB - We used eight microsatellite loci and a set of 20 aphid samples to investigate the spatial and temporal genetic structure of rosy apple aphid populations from 13 apple orchards situated in four different regions in France. Genetic variability was very similar between orchard populations and between winged populations collected before sexual reproduction in the fall and populations collected from colonies in the spring. A very small proportion of individuals (~2%) had identical multilocus genotypes. Genetic differentiation between orchards was low (F(ST)<0.026), with significant differentiation observed only between orchards from different regions, but no isolation by distance was detected. These results are consistent with high levels of genetic mixing in holocyclic Dysaphis plantaginae populations (host alternation through migration and sexual reproduction). These findings concerning the adaptation of the rosy apple aphid have potential consequences for pest management. PMID- 21701680 TI - Exploring tree-habitat associations in a Chinese subtropical forest plot using a molecular phylogeny generated from DNA barcode loci. AB - Elucidating the ecological mechanisms underlying community assembly in subtropical forests remains a central challenge for ecologists. The assembly of species into communities can be due to interspecific differences in habitat associations, and there is increasing evidence that these associations may have an underlying phylogenetic structure in contemporary terrestrial communities. In other words, by examining the degree to which closely related species prefer similar habitats and the degree to which they co-occur, ecologists are able to infer the mechanisms underlying community assembly. Here we implement this approach in a diverse subtropical tree community in China using a long-term forest dynamics plot and a molecular phylogeny generated from three DNA barcode loci. We find that there is phylogenetic signal in plant-habitat associations (i.e. closely related species tend to prefer similar habitats) and that patterns of co-occurrence within habitats are typically non-random with respect to phylogeny. In particular, we found phylogenetic clustering in valley and low slope habitats in this forest, indicating a filtering of lineages plays a dominant role in structuring communities in these habitats and we found evidence of phylogenetic overdispersion in high-slope, ridge-top and high-gully habitats, indicating that distantly related species tended to co-occur in these high elevation habitats and that lineage filtering is less important in structuring these communities. Thus we infer that non-neutral niche-based processes acting upon evolutionarily conserved habitat preferences explain the assembly of local scale communities in the forest studied. PMID- 21701678 TI - Gene expression profiling of preovulatory follicle in the buffalo cow: effects of increased IGF-I concentration on periovulatory events. AB - The preovulatory follicle in response to gonadotropin surge undergoes dramatic biochemical, and morphological changes orchestrated by expression changes in hundreds of genes. Employing well characterized bovine preovulatory follicle model, granulosa cells (GCs) and follicle wall were collected from the preovulatory follicle before, 1, 10 and 22 h post peak LH surge. Microarray analysis performed on GCs revealed that 450 and 111 genes were differentially expressed at 1 and 22 h post peak LH surge, respectively. For validation, qPCR and immunocytochemistry analyses were carried out for some of the differentially expressed genes. Expression analysis of many of these genes showed distinct expression patterns in GCs and the follicle wall. To study molecular functions and genetic networks, microarray data was analyzed using Ingenuity Pathway Analysis which revealed majority of the differentially expressed genes to cluster within processes like steroidogenesis, cell survival and cell differentiation. In the ovarian follicle, IGF-I is established to be an important regulator of the above mentioned molecular functions. Thus, further experiments were conducted to verify the effects of increased intrafollicular IGF-I levels on the expression of genes associated with the above mentioned processes. For this purpose, buffalo cows were administered with exogenous bGH to transiently increase circulating and intrafollicular concentrations of IGF-I. The results indicated that increased intrafollicular concentrations of IGF-I caused changes in expression of genes associated with steroidogenesis (StAR, SRF) and apoptosis (BCL-2, FKHR, PAWR). These results taken together suggest that onset of gonadotropin surge triggers activation of various biological pathways and that the effects of growth factors and peptides on gonadotropin actions could be examined during preovulatory follicle development. PMID- 21701681 TI - Subdivisions of the auditory midbrain (n. mesencephalicus lateralis, pars dorsalis) in zebra finches using calcium-binding protein immunocytochemistry. AB - The midbrain nucleus mesencephalicus lateralis pars dorsalis (MLd) is thought to be the avian homologue of the central nucleus of the mammalian inferior colliculus. As such, it is a major relay in the ascending auditory pathway of all birds and in songbirds mediates the auditory feedback necessary for the learning and maintenance of song. To clarify the organization of MLd, we applied three calcium binding protein antibodies to tissue sections from the brains of adult male and female zebra finches. The staining patterns resulting from the application of parvalbumin, calbindin and calretinin antibodies differed from each other and in different parts of the nucleus. Parvalbumin-like immunoreactivity was distributed throughout the whole nucleus, as defined by the totality of the terminations of brainstem auditory afferents; in other words parvalbumin-like immunoreactivity defines the boundaries of MLd. Staining patterns of parvalbumin, calbindin and calretinin defined two regions of MLd: inner (MLd.I) and outer (MLd.O). MLd.O largely surrounds MLd.I and is distinct from the surrounding intercollicular nucleus. Unlike the case in some non songbirds, however, the two MLd regions do not correspond to the terminal zones of the projections of the brainstem auditory nuclei angularis and laminaris, which have been found to overlap substantially throughout the nucleus in zebra finches. PMID- 21701682 TI - Identification of fast-evolving genes in the scleractinian coral Acropora using comparative EST analysis. AB - To identify fast-evolving genes in reef-building corals, we performed direct comparative sequence analysis with expressed sequence tag (EST) datasets from two acroporid species: Acropora palmata from the Caribbean Sea and A. millepora from the Great Barrier Reef in Australia. Comparison of 589 independent sequences from 1,421 A. palmata contigs, with 10,247 A. millepora contigs resulted in the identification of 196 putative homologues. Most of the homologous pairs demonstrated high amino acid similarities (over 90%). Comparisons of putative homologues showing low amino acid similarities (under 90%) among the Acropora species to the near complete datasets from two other cnidarians (Hydra magnipapillata and Nematostella vectensis) implied that some were non orthologous. Within 86 homologous pairs, 39 exhibited dN/dS ratios significantly less than 1, suggesting that these genes are under purifying selection associated with functional constraints. Eight independent genes showed dN/dS ratios exceeding 1, while three deviated significantly from 1, suggesting that these genes may play important roles in the adaptive evolution of Acropora. Our results also indicated that CEL-III lectin was under positive selection, consistent with a possible role in immunity or symbiont recognition. Further studies are needed to clarify the possible functions of the genes under positive selection to provide insight into the evolutionary process of corals. PMID- 21701684 TI - Global diversity of Ascidiacea. AB - The class Ascidiacea presents fundamental opportunities for research in the fields of development, evolution, ecology, natural products and more. This review provides a comprehensive overview of the current knowledge regarding the global biodiversity of the class Ascidiacea, focusing in their taxonomy, main regions of biodiversity, and distribution patterns. Based on analysis of the literature and the species registered in the online World Register of Marine Species, we assembled a list of 2815 described species. The highest number of species and families is found in the order Aplousobranchia. Didemnidae and Styelidae families have the highest number of species with more than 500 within each group. Sixty percent of described species are colonial. Species richness is highest in tropical regions, where colonial species predominate. In higher latitudes solitary species gradually contribute more to the total species richness. We emphasize the strong association between species richness and sampling efforts, and discuss the risks of invasive species. Our inventory is certainly incomplete as the ascidian fauna in many areas around the world is relatively poorly known, and many new species continue to be discovered and described each year. PMID- 21701683 TI - Long-term programming of antigen-specific immunity from gene expression signatures in the PBMC of rhesus macaques immunized with an SIV DNA vaccine. AB - While HIV-1-specific cellular immunity is thought to be critical for the suppression of viral replication, the correlates of protection have not yet been determined. Rhesus macaques (RM) are an important animal model for the study and development of vaccines against HIV/AIDS. Our laboratory has helped to develop and study DNA-based vaccines in which recent technological advances, including genetic optimization and in vivo electroporation (EP), have helped to dramatically boost their immunogenicity. In this study, RMs were immunized with a DNA vaccine including individual plasmids encoding SIV gag, env, and pol alone, or in combination with a molecular adjuvant, plasmid DNA expressing the chemokine ligand 5 (RANTES), followed by EP. Along with standard immunological assays, flow based activation analysis without ex vivo restimulation and high-throughput gene expression analysis was performed. Strong cellular immunity was induced by vaccination which was supported by all assays including PBMC microarray analysis that identified the up-regulation of 563 gene sequences including those involved in interferon signaling. Furthermore, 699 gene sequences were differentially regulated in these groups at peak viremia following SIVmac251 challenge. We observed that the RANTES-adjuvanted animals were significantly better at suppressing viral replication during chronic infection and exhibited a distinct pattern of gene expression which included immune cell-trafficking and cell cycle genes. Furthermore, a greater percentage of vaccine-induced central memory CD8+ T cells capable of an activated phenotype were detected in these animals as measured by activation analysis. Thus, co-immunization with the RANTES molecular adjuvant followed by EP led to the generation of cellular immunity that was transcriptionally distinct and had a greater protective efficacy than its DNA alone counterpart. Furthermore, activation analysis and high-throughput gene expression data may provide better insight into mechanisms of viral control than may be observed using standard immunological assays. PMID- 21701685 TI - Beneficial effects of resistance exercise on glycemic control are not further improved by protein ingestion. AB - PURPOSE: To investigate the mechanisms underpinning modifications in glucose homeostasis and insulin sensitivity 24 h after a bout of resistance exercise (RE) with or without protein ingestion. METHODS: Twenty-four healthy males were assigned to a control (CON; n = 8), exercise (EX; n = 8) or exercise plus protein condition (EX+PRO; n = 8). Muscle biopsy and blood samples were obtained at rest for all groups and immediately post-RE (75% 1RM, 8*10 repetitions of leg-press and extension exercise) for EX and EX+PRO only. At 24 h post-RE (or post-resting biopsy for CON), a further muscle biopsy was obtained. Participants then consumed an oral glucose load (OGTT) containing 2 g of [U-13C] glucose during an infusion of 6, 6-[2H2] glucose. Blood samples were obtained every 10 min for 2 h to determine glucose kinetics. EX+PRO ingested an additional 25 g of intact whey protein with the OGTT. A final biopsy sample was obtained at the end of the OGTT. RESULTS: Fasted plasma glucose and insulin were similar for all groups and were not different immediately post- and 24 h post-RE. Following RE, muscle glycogen was 26+/-8 and 19+/-6% lower in EX and EX+PRO, respectively. During OGTT, plasma glucose AUC was lower for EX and EX+PRO (75.1+/-2.7 and 75.3+/-2.8 mmol.L-1?120 min, respectively) compared with CON (90.6+/-4.1 mmol.L-1?120 min). Plasma insulin response was 13+/-2 and 21+/-4% lower for EX and CON, respectively, compared with EX+PRO. Glucose disappearance from the circulation was ~12% greater in EX and EX+PRO compared with CON. Basal 24 h post-RE and insulin-stimulated PAS AS160/TBC1D4 phosphorylation was greater for EX and EX+PRO. CONCLUSIONS: Prior RE improves glycemic control and insulin sensitivity through an increase in the rate at which glucose is disposed from the circulation. However, co-ingesting protein during a high-glucose load does not augment this response at 24 h post-exercise in healthy, insulin-sensitive individuals. PMID- 21701686 TI - Haloquadratum walsbyi: limited diversity in a global pond. AB - BACKGROUND: Haloquadratum walsbyi commonly dominates the microbial flora of hypersaline waters. Its cells are extremely fragile squares requiring >14%(w/v) salt for growth, properties that should limit its dispersal and promote geographical isolation and divergence. To assess this, the genome sequences of two isolates recovered from sites at near maximum distance on Earth, were compared. PRINCIPAL FINDINGS: Both chromosomes are 3.1 MB in size, and 84% of each sequence was highly similar to the other (98.6% identity), comprising the core sequence. ORFs of this shared sequence were completely synteneic (conserved in genomic orientation and order), without inversion or rearrangement. Strain specific insertions/deletions could be precisely mapped, often allowing the genetic events to be inferred. Many inferred deletions were associated with short direct repeats (4-20 bp). Deletion-coupled insertions are frequent, producing different sequences at identical positions. In cases where the inserted and deleted sequences are homologous, this leads to variant genes in a common synteneic background (as already described by others). Cas/CRISPR systems are present in C23(T) but have been lost in HBSQ001 except for a few spacer remnants. Numerous types of mobile genetic elements occur in both strains, most of which appear to be active, and with some specifically targetting others. Strain C23(T) carries two ~6 kb plasmids that show similarity to halovirus His1 and to sequences nearby halovirus/plasmid gene clusters commonly found in haloarchaea. CONCLUSIONS: Deletion-coupled insertions show that Hqr. walsbyi evolves by uptake and precise integration of foreign DNA, probably originating from close relatives. Change is also driven by mobile genetic elements but these do not by themselves explain the atypically low gene coding density found in this species. The remarkable genome conservation despite the presence of active systems for genome rearrangement implies both an efficient global dispersal system, and a high selective fitness for this species. PMID- 21701688 TI - The slow-releasing hydrogen sulfide donor, GYY4137, exhibits novel anti-cancer effects in vitro and in vivo. AB - The slow-releasing hydrogen sulfide (H2S) donor, GYY4137, caused concentration dependent killing of seven different human cancer cell lines (HeLa, HCT-116, Hep G2, HL-60, MCF-7, MV4-11 and U2OS) but did not affect survival of normal human lung fibroblasts (IMR90, WI-38) as determined by trypan blue exclusion. Sodium hydrosulfide (NaHS) was less potent and not active in all cell lines. A structural analogue of GYY4137 (ZYJ1122) lacking sulfur and thence not able to release H2S was inactive. Similar results were obtained using a clonogenic assay. Incubation of GYY4137 (400 uM) in culture medium led to the generation of low (<20 uM) concentrations of H2S sustained over 7 days. In contrast, incubation of NaHS (400 uM) in the same way led to much higher (up to 400 uM) concentrations of H2S which persisted for only 1 hour. Mechanistic studies revealed that GYY4137 (400 uM) incubated for 5 days with MCF-7 but not IMR90 cells caused the generation of cleaved PARP and cleaved caspase 9, indicative of a pro-apoptotic effect. GYY4137 (but not ZYJ1122) also caused partial G2/M arrest of these cells. Mice xenograft studies using HL-60 and MV4-11 cells showed that GYY4137 (100-300 mg/kg/day for 14 days) significantly reduced tumor growth. We conclude that GYY4137 exhibits anti-cancer activity by releasing H2S over a period of days. We also propose that a combination of apoptosis and cell cycle arrest contributes to this effect and that H2S donors should be investigated further as potential anti cancer agents. PMID- 21701687 TI - Intranasal delivery of E-selectin reduces atherosclerosis in ApoE-/- mice. AB - Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE-/- mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE-/- mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL 10 and immunosuppressive antibody isotypes. Intranasal administration of E selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke. PMID- 21701689 TI - Pharmacological blockade of serotonin 5-HT7 receptor reverses working memory deficits in rats by normalizing cortical glutamate neurotransmission. AB - The role of 5-HT7 receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT7 antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT7 receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission. PMID- 21701691 TI - Simulated atmospheric N deposition alters fungal community composition and suppresses ligninolytic gene expression in a northern hardwood forest. AB - High levels of atmospheric nitrogen (N) deposition may result in greater terrestrial carbon (C) storage. In a northern hardwood ecosystem, exposure to over a decade of simulated N deposition increased C storage in soil by slowing litter decay rates, rather than increasing detrital inputs. To understand the mechanisms underlying this response, we focused on the saprotrophic fungal community residing in the forest floor and employed molecular genetic approaches to determine if the slower decomposition rates resulted from down-regulation of the transcription of key lignocellulolytic genes, by a change in fungal community composition, or by a combination of the two mechanisms. Our results indicate that across four Acer-dominated forest stands spanning a 500-km transect, community scale expression of the cellulolytic gene cbhI under elevated N deposition did not differ significantly from that under ambient levels of N deposition. In contrast, expression of the ligninolytic gene lcc was significantly down regulated by a factor of 2-4 fold relative to its expression under ambient N deposition. Fungal community composition was examined at the most southerly of the four sites, in which consistently lower levels of cbhI and lcc gene expression were observed over a two-year period. We recovered 19 basidiomycete and 28 ascomycete rDNA 28S operational taxonomic units; Athelia, Sistotrema, Ceratobasidium and Ceratosebacina taxa dominated the basidiomycete assemblage, and Leotiomycetes dominated the ascomycetes. Simulated N deposition increased the proportion of basidiomycete sequences recovered from forest floor, whereas the proportion of ascomycetes in the community was significantly lower under elevated N deposition. Our results suggest that chronic atmospheric N deposition may lower decomposition rates through a combination of reduced expression of ligninolytic genes such as lcc, and compositional changes in the fungal community. PMID- 21701690 TI - Diffusion MRI of structural brain plasticity induced by a learning and memory task. AB - BACKGROUND: Activity-induced structural remodeling of dendritic spines and glial cells was recently proposed as an important factor in neuroplasticity and suggested to accompany the induction of long-term potentiation (LTP). Although T1 and diffusion MRI have been used to study structural changes resulting from long term training, the cellular basis of the findings obtained and their relationship to neuroplasticity are poorly understood. METHODOLOGY/PRINCIPAL FINDING: Here we used diffusion tensor imaging (DTI) to examine the microstructural manifestations of neuroplasticity in rats that performed a spatial navigation task. We found that DTI can be used to define the selective localization of neuroplasticity induced by different tasks and that this process is age-dependent in cingulate cortex and corpus callosum and age-independent in the dentate gyrus. CONCLUSION/SIGNIFICANCE: We relate the observed DTI changes to the structural plasticity that occurs in astrocytes and discuss the potential of MRI for probing structural neuroplasticity and hence indirectly localizing LTP. PMID- 21701692 TI - Group living enhances individual resources discrimination: the use of public information by cockroaches to assess shelter quality. AB - In group-living organisms, consensual decision of site selection results from the interplay between individual responses to site characteristics and to group members. Individuals independently gather personal information by exploring their environment. Through social interaction, the presence of others provides public information that could be used by individuals and modulates the individual probability of joining/leaving a site. The way that individual's information processing and the network of interactions influence the dynamics of public information (depending on population size) that in turn affect discrimination in site quality is a central question. Using binary choice between sheltering sites of different quality, we demonstrate that cockroaches in group dramatically outperform the problem-solving ability of single individual. Such use of public information allows animals to discriminate between alternatives whereas isolated individuals are ineffective (i.e. the personal discrimination efficiency is weak). Our theoretical results, obtained from a mathematical model based on behavioral rules derived from experiments, highlight that the collective discrimination emerges from competing amplification processes relying on the modulation of the individual sheltering time without shelters comparison and communication modulation. Finally, we well demonstrated here the adaptive value of such decision algorithm. Without any behavioral change, the system is able to shift to a more effective strategy when alternatives are present: the modification of the spatio-temporal distributions of individuals leading to the collective selection of the best resource. This collective discrimination implying such parsimonious and widespread mechanism must be shared by many group living-species. PMID- 21701693 TI - Fospropofol Disodium for Sedation in Elderly Patients Undergoing Flexible Bronchoscopy. AB - BACKGROUND: Fospropofol disodium is a water-soluble prodrug of propofol. A subset analysis was undertaken of elderly patients (>=65 y) undergoing flexible bronchoscopy, who were part of a larger multicenter, randomized, double-blind study. METHODS: Patients received fentanyl citrate (50 mcg) followed by fospropofol at initial (4.88mg/kg) and supplemental (1.63mg/kg) doses. The primary end point was sedation success (3 consecutive Modified Observer's Assessment of Alertness/Sedation scores of <=4 and procedure completion without alternative sedative or assisted ventilation). Treatment success, time to fully alert, patient and physician satisfaction, and safety/tolerability were also evaluated. RESULTS: In the elderly patients subset (n=61), sedation success was 92%, the mean time to fully alert was 8.0+/-10.9 min, and memory retention was 72% during recovery, and these were comparable with the younger patients subgroup (age, <65 y). Sedation-related adverse events occurred in 23% of the elderly and 18% of the younger patients (age, <65 y) group. Hypoxemia occurred in 26% of the elderly and 18% of the younger patients group, but no escalation of care was required. CONCLUSIONS: Fospropofol provided safe and effective sedation, rapid time to fully alert, and high satisfaction in this elderly subset undergoing flexible bronchoscopy, which was comparable with outcomes in younger patients. PMID- 21701694 TI - Power of permutation tests using generalized additive models with bivariate smoothers. AB - In spatial epidemiology, when applying Generalized Additive Models (GAMs) with a bivariate locally weighted regression smooth over longitude and latitude, a natural hypothesis is whether location is associated with an outcome. An approximate chi-square test (ACST) is available but has an inflated type I error rate. Permutation tests provide alternatives. This research evaluated powers of ACST and four permutation tests: the conditional (CPT), fixed span (FSPT), fixed multiple span (FMSPT), and unconditional (UPT) permutation tests. For CPT, the span size was determined by minimizing the Akaike Information Criterion (AIC) and was held constant for models applied to permuted datasets. For FSPT, a single span was selected a priori. For FMSPT, GAMs were applied using 3-5 different spans selected a priori and the significance cutoff was reduced to account for multiple testing. For UPT, the span was selected by minimizing the AIC for observed and for permuted datasets. Data with a cluster of increased/decreased risk centered in a study region were simulated. ACST and CPT had high power estimates when applied with reduced significance cutoffs to adjust for inflated type I errors. FSPT power depended on the span size; FMSPT power estimates were slightly lower. Overall, UPT had low power. PMID- 21701695 TI - The timing of mothers' employment after childbirth. PMID- 21701696 TI - Adolescent Academic Adjustment Factors and the Trajectories of Cigarette Smoking from Adolescence to the Mid-thirties. AB - Knowledge of early predictors which differentiate between various longitudinal smoking patterns might facilitate designing more effective interventions. Using data from 806 participants, we examined the association of three adolescent academic adjustment factors, Educational Aspirations and Expectations; Perception of School Achievement; and Trouble at School, to five trajectories of cigarette use covering 23 years from adolescence to adulthood. The five trajectory groups were: heavy/continuous smokers, late starters, quitter/decreasers, occasional smokers, and nonsmokers. Each academic factor predicted smoking trajectory group membership. Each academic factor was significantly associated with being a heavy/continuous smoker rather than a member of other trajectory groups. Behavioral academic factors also differentiated quitter/decreasers from late starters, occasional smokers, and nonsmokers. Adolescents manifesting academic maladjustment risk becoming early, chronic smokers. Prevention and intervention efforts targeting educational maladjustment may decrease cigarette smoking. PMID- 21701697 TI - Activity-Based Protein Profiling (ABPP) and Click Chemistry (CC)-ABPP by MudPIT Mass Spectrometry. AB - Activity-based protein profiling (ABPP) is a chemical proteomic method for functional interrogation of enzymes within complex proteomes. This Unit presents a protocol for in vitro and in vivo labeling using ABPP and Click Chemistry (CC) ABPP probes for in-depth profiling using the Multi-dimensional Protein Identification Technology (MudPIT) analysis platform. PMID- 21701698 TI - Mixed Membership Stochastic Blockmodels. AB - Observations consisting of measurements on relationships for pairs of objects arise in many settings, such as protein interaction and gene regulatory networks, collections of author-recipient email, and social networks. Analyzing such data with probabilisic models can be delicate because the simple exchangeability assumptions underlying many boilerplate models no longer hold. In this paper, we describe a latent variable model of such data called the mixed membership stochastic blockmodel. This model extends blockmodels for relational data to ones which capture mixed membership latent relational structure, thus providing an object-specific low-dimensional representation. We develop a general variational inference algorithm for fast approximate posterior inference. We explore applications to social and protein interaction networks. PMID- 21701699 TI - Gene therapy for myocardial infarction-associated congestive heart failure: how far have we got? AB - With the advancement of vectors, delivery methods, and newly identified molecular targets, preclinical studies have shown that gene transfer is effective in improving left ventricular contractility and attenuating deleterious left ventricular remodeling in myocardial infarction-associated congestive heart failure (CHF). We are optimistic that these favorable effects will also be seen when tested in patients with CHF associated with myocardial infarction, as well as in patients with CHF from other etiologies. Gene therapy has the potential to be tailored to meet the needs of individual patients. Moreover, when used in conjunction with pharmacological and device management of the patient with CHF, it provides hope for a brighter future for the 23 million patients worldwide with this devastating disease. PMID- 21701700 TI - Excitatory and Inhibitory Influence of Pathways in the Pelvic Nerve on Bladder Activity in Rats with Bladder Outlet Obstruction. AB - OBJECTIVES: This study was undertaken to investigate whether chronic bladder outlet obstruction (BOO) in female rats influences the tonic parasympathetic excitatory or inhibitory reflex control of bladder activity. METHODS: Bladder activity during isovolumetric cystometry (1.5-12 mL) was examined after transection of dorsal and ventral lumbosacral spinal roots (L4-S4) and administration of hexamethonium, a ganglionic blocking agent, in urethane anesthetized female rats with sympathectomy and BOO. RESULTS: Lumbosacral dorsal root transection abolished reflex bladder contractions, but did not influence intravesical baseline pressure. However, ventral root transection after dorsal root transection decreased baseline intravesical pressure (y: % change) at low bladder volumes (x) and increased pressure at high volumes. The calculated (y = 1.9x - 16.5) transition volume was 9 mL. Administration of hexamethonium (100 mg/kg, intraperitoneally) after dorsal and ventral root transection increased the amplitude and decreased the frequency of myogenic bladder contractions. CONCLUSION: The bladder is tonically excited or inhibited depending upon bladder volume by the interactions between a parasympathetic preganglionic pathway in the pelvic nerve and a peripheral reflex. However, in rats with BOO, the volume at which the response shifts from excitation to inhibition was very large, and tonic function of the parasympathetic preganglionic pathway was weak compared to previously reported results in rats without BOO. The persistence of reflex tonic excitatory control of bladder tone over a broad range of bladder volumes may be one of the reasons for overactivity of the bladder with outlet obstruction. PMID- 21701701 TI - Cognitive Style Moderates Attention to Attribution-Relevant Stimuli. AB - Individuals with negative cognitive style are at high risk for depressive disorders; however, the mechanisms linking cognitive vulnerability to depression are not fully understood. Here, we use an attentional blink task to test whether stimuli associated with negative attributions are especially salient to individuals with high negative cognitive style. We found that individuals high in negative cognitive style were able to attend to negative attribution words during a period of time when attentional resources would ordinarily be depleted. These individuals were not more likely than those with low or moderate negative cognitive style to detect neutral and negative non-self-relevant words during this period. These data suggest that cognitive style modulates the saliency of material that is relevant to negative attributions, and these alterations in information processing may link cognitive style to development of depression. PMID- 21701702 TI - Influence of brain-derived neurotrophic factor and apolipoprotein E genetic variants on hemispheric and lateral ventricular volume of young healthy adults. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) and apolipoprotein E (ApoE) are thought to be implicated in a variety of neuronal processes, including cell growth, resilience to noxious stimuli and synaptic plasticity. A Val to Met substitution at codon 66 in the BDNF protein has been associated with a variety of neuropsychiatric conditions. The ApoE4 allele is considered a risk factor for late-onset Alzheimer's disease, but its effects on young adults are less clear. We sought to investigate the effects of those two polymorphisms on hemispheric and lateral ventricular volumes of young healthy adults. METHODS: Hemispheric and lateral ventricular volumes of 144 healthy individuals, aged 19-35 years, were measured using high resolution magnetic resonance imaging and data were correlated with BDNF and ApoE genotypes. RESULTS: There were no correlations between BDNF or ApoE genotype and hemispheric or lateral ventricular volumes. CONCLUSION: These findings indicate that it is unlikely that either the BDNF Val66Met or ApoE polymorphisms exert any significant effect on hemispheric or lateral ventricular volume. However, confounding epistatic genetic effects as well as relative insensitivity of the volumetric methods used cannot be ruled out. Further imaging analyses are warranted to better define any genetic influence of the BDNF Val6Met and ApoE polymorphism on brain structure of young healthy adults. PMID- 21701704 TI - Aluminium in UK rivers: a need for integrated research related to kinetic factors, colloidal transport, carbon and habitat. AB - Dissolved aluminium concentrations ([Al]) in the <0.45 MUm filtered fraction are described for 54 UK river sites covering rural, acidic/acid sensitive, agricultural and urban typologies, and wide pH range (4 to 11). High [Al] occurred under acidic conditions and for acid runoff neutralised by bicarbonate rich groundwater. Thermodynamic analysis indicates Al hydroxide/hydroxy-silicate oversaturation at circumneutral pH across the rivers, but undersaturation at lower/higher pH. The oversaturation reflects in part the presence of Al bearing colloids as indicated by (1) [Al] being correlated with components associated with both lithogenic (Fe, Ti and lanthanides) colloids and organic carbon, (2) baseflow studies using cross-flow ultrafiltration and (3) comparison of our data with Acid Waters Monitoring Network (AWMN) information on labile and non-labile Al. Tree harvesting and emission reductions of SO(x) in acidic and acid sensitive catchments in mid-Wales led to acidification reversal, lower [Al] and changing [H(+)] - [Al] relationships. The [Al] decline was confined to acidic conditions while [Al] increased during the later part of the monitoring period with a peak around 2002 for moorland and forested systems. Colloidal production across the flow range was indicated late in the record by comparison of our data with information collected by the AWMN for a site in mid-Wales. This production seems interlinked with organic carbon and with dissolved CO(2) changes. In order for further understanding of Al hydrogeochemistry in river systems there is a need to integrate research that moves from equilibrium to kinetic and colloidal consideration including the critical issues of organic and inorganic controls within the context of bioavailability and aquatic stress. The colloidal Al may well be of low environmental concern to fish and other factors such as habitat may well be critical. PMID- 21701706 TI - Flexible quantum dot sensitized solar cell by electrophoretic deposition of CdSe quantum dots on ZnO nanorods. AB - We report on a flexible quantum dot-sensitized solar cell (QDSSC) based on ZnO nanorods with a length of 2 MUm. Due to the good coverage of CdSe QDs on ZnO by the electrophoretic deposition method, a maximum power conversion efficiency of ~1% is achieved for the flexible QDSSC. PMID- 21701705 TI - Small delay, big waves: a minimal delayed negative feedback model captures Escherichia coli single cell SOS kinetics. AB - BACKGROUND: How exactly does an organism coordinate its responses to differing environmental conditions, especially when several responses and physiological priorities are potentially conflicting? Recently, single cell results have been published on the kinetics of the bacterial SOS response. Based on these, we construct a relatively simple mathematical model for the regulatory control of the mutagenic elements of the Escherichia coli DNA repair system. METHODS: We employ one first order delay differential equation for the dynamics of the activation level of mutagenic gene repair and one first order ordinary differential equation for the dynamics of the level of DNA damage. After manual adjustment of parameters, our model qualitatively reproduces the UV dose dependent RecA expression peak occurrence, peak amplitude and peak timing. Parameter noise captures qualitatively the fluctuations observed in the experimental data. Quantitative agreement is achieved for timing of the three response peaks for different doses of UV. CONCLUSIONS: A delayed negative feedback is likely to play a primary role in the regulation of the E. coli mutagenic gene repair. The model presented in this paper is an example of how a delayed regulatory mechanism establishes control over a critical organismic response with negative secondary effects. PMID- 21701703 TI - Analysis of Somatic Mutations in Cancer: Molecular Mechanisms of Activation in the ErbB Family of Receptor Tyrosine Kinases. AB - The ErbB/EGFR/HER family of kinases consists of four homologous receptor tyrosine kinases which are important regulatory elements in many cellular processes, including cell proliferation, differentiation, and migration. Somatic mutations in, or over-expression of, the ErbB family is found in many cancers and is correlated with a poor prognosis; particularly, clinically identified mutations found in non-small-cell lung cancer (NSCLC) of ErbB1 have been shown to increase its basal kinase activity and patients carrying these mutations respond remarkably to the small tyrosine kinase inhibitor gefitinib. Here, we analyze the potential effects of the currently catalogued clinically identified mutations in the ErbB family kinase domains on the molecular mechanisms of kinase activation. Recently, we identified conserved networks of hydrophilic and hydrophobic interactions characteristic to the active and inactive conformation, respectively. Here, we show that the clinically identified mutants influence the kinase activity in distinctive fashion by affecting the characteristic interaction networks. PMID- 21701707 TI - Effects of strong and weak hydrogen bond formation on VCD spectra: a case study of 2-chloropropionic acid. AB - The vibrational circular dichroism (VCD) spectrum of S-(-) and R-(+)-2 chloropropionic acid is thoroughly analyzed. Besides the VCD spectrum of the monomer, the dimers (stabilized by strong hydrogen bonds) and the 2 chloropropionic acid-CHCl(3) complexes (stabilized by a weak hydrogen bond) are studied both experimentally (in solution and in low-temperature Ar matrix) and by quantum chemical computations. It is shown that dimer formation drastically changes, and even weak complex formation can also substantially affect the overall shape of the VCD spectrum. The present and previous results can be generalized for the practice of absolute configuration determination of carboxylic acids by VCD spectroscopy. For these measurements, if bulky groups do not block dimer formation, comparison of the computed spectra of the dimers with the experimental spectra recorded in relatively concentrated (~0.1 mol dm(-3)) solutions is suggested. Our study also shows that due to the stabilization of monomers and/or the formation of weak complexes, the VCD spectrum recorded in CHCl(3) is more complex and, like in the present case, can have a lower intensity than that of the spectrum recorded in CCl(4). Therefore, if solubility allows, CCl(4) is a much preferred solvent over CHCl(3). PMID- 21701708 TI - "Union is strength": how weak hydrogen bonds become stronger. AB - Recently reported rotational spectroscopic studies on small dimers and oligomers bound by weak hydrogen bonds show that the driving forces, the spatial arrangement and the dynamical features displayed are very different from those involved in stronger and conventional hydrogen bonds. The very small binding energies (similar to those of van der Waals interactions) imply that the stabilization of the dimer is often obtained by networks of weak hydrogen bonds. Even in the presence of multiple bonds the partner molecules show a high degree of internal freedom within the complex. This paper analyses several examples of molecular adducts bound by weak hydrogen bonds formed in free jet expansions and recently characterized by rotational spectroscopy. They include weakly bound complexes of weak donors with strong acceptors (C-H...O,N, S-H...O,N), strong donors (O-H, N-H) with weak acceptors such as the halogen atoms and pi systems but also the elusive interactions between weak donors and weak acceptors (C H...pi and C-H...halogen). Examples are also given where rotational spectroscopy highlights that weak hydrogen bonds are extremely important in chiral recognition phenomena and as driving forces of the conformational landscape of important biomolecules. PMID- 21701709 TI - Transforming ligands into transcriptional regulators: building blocks for bifunctional molecules. AB - The human body is comprised of several hundred distinct cell types that all share a common genomic template. This diversity arises from regulated expression of individual genes. The first critical step in this process is transcription and is governed by a large number of transcription factors. Small molecules that can alter transcription hold tremendous utility as chemical probes and therapeutics. To fully realize their potential, however, artificial transcription factors must be able to orchestrate protein recruitment at gene promoters just like their natural counterparts. This tutorial review surveys the discovery of small ligands (drug-like molecules and short peptides) that bind transcriptional coregulatory proteins, and thus comprise one of the two essential characteristics of a transcription factor. By joining these ligands to DNA-targeting moieties, one can construct a bifunctional molecule that recruits its protein target to specific genes and controls gene transcription. PMID- 21701710 TI - Electron-beam evaporated silicon as a top contact for molecular electronic device fabrication. AB - This paper discusses the electronic properties of molecular devices made using covalently bonded molecular layers on carbon surfaces with evaporated silicon top contacts. The Cu "top contact" of previously reported carbon/molecule/Cu devices was replaced with e-beam deposited Si in order to avoid Cu oxidation or electromigration, and provide further insight into electron transport mechanisms. The fabrication and characterization of the devices is detailed, including a spectroscopic assessment of the molecular layer integrity after top contact deposition. The electronic, optical, and structural properties of the evaporated Si films are assessed in order to determine the optical gap, work function, and film structure, and show that the electron beam evaporated Si films are amorphous and have suitable conductivity for molecular junction fabrication. The electronic characteristics of Si top contact molecular junctions made using different molecular layer structures and thicknesses are used to evaluate electron transport in these devices. Finally, carbon/molecule/silicon devices are compared to analogous carbon/molecule/metal junctions and the possible factors that control the conductance of molecular devices with differing contact materials are discussed. PMID- 21701711 TI - A study of the ethene-ozone reaction with photoelectron spectroscopy: measurement of product branching ratios and atmospheric implications. AB - The ozone-ethene reaction has been investigated at low pressure in a flow-tube interfaced to a u.v. photoelectron spectrometer. Photoelectron spectra recorded as a function of reaction time have been used to estimate partial pressures of the reagents and products, using photoionization cross-sections for selected photoelectron bands of the reagents and products, which have been measured separately. Product yields compare favourably with results of other studies, and the production of oxygen and acetaldehyde have been measured as a function of time for the first time. A reaction scheme developed for the ozone-ethene reaction has been used to simulate the reagents and products as a function of time. The results obtained are in good agreement with the experimental measurements. For each of the observed products, the simulations allow the main reaction (or reactions) for production of that product to be established. The product yields have been used in a global model to estimate their global annual emissions in the atmosphere. Of particular interest are the calculated global annual emissions of formaldehyde (0.96 +/- 0.10 Tg) and formic acid, (0.05 +/- 0.01 Tg) which are estimated as 0.04% and 0.7% of the total annual emission respectively. PMID- 21701712 TI - Voltammetry and in situ scanning tunnelling spectroscopy of osmium, iron, and ruthenium complexes of 2,2':6',2''-terpyridine covalently linked to Au(111) electrodes. AB - We have studied self-assembled molecular monolayers (SAMs) of complexes between Os(II)/(III), Fe(II)/(III), and Ru(II)/(III) and a 2,2',6',2''-terpyridine (terpy) derivative linked to Au(111)-electrode surfaces via a 6 acetylthiohexyloxy substituent at the 4'-position of terpy. The complexes were prepared in situ by first linking the terpy ligand to the surface via the S-atom, followed by addition of suitable metal compounds. The metal-terpy SAMs were studied by cyclic voltammetry (CV), and in situ scanning tunnelling microscopy with full electrochemical potential control of substrate and tip (in situ STM). Sharp CV peaks were observed for the Os- and Fe complexes, with interfacial electrochemical electron transfer rate constants of 6-50 s(-1). Well-defined but significantly broader peaks (up to 300 mV) were observed for the Ru-complex. Addition of 2,2'-bipyridine (bipy) towards completion of the metal coordination spheres induced voltammetric sharpening. In situ STM images of single molecular scale strong structural features were observed for the osmium and iron complexes. As expected from the voltammetric patterns, the surface coverage was by far the highest for the Ru-complex which was therefore selected for scanning tunnelling spectroscopy. These correlations displayed a strong peak around the equilibrium potential with systematic shifts with increasing bias voltage, as expected for a sequential two-step in situ ET mechanism. PMID- 21701713 TI - Unexpected size distribution of Ba(H2O)n clusters: why is the intensity of the Ba(H2O)1 cluster anomalously low? AB - An experimental and theoretical study on the reactivity of neutral Ba atoms with water clusters has been conducted to unravel the origin of the irregular intensity pattern observed in one-photon ionization mass spectra of a Ba(H(2)O)(n)/BaOH(H(2)O)(n-1) (n = 1-4) cluster distribution, which was generated in a laser vaporization-supersonic expansion source. The most remarkable irregular feature is the finding for n = 1 of a lower intensity for the Ba(+)(H(2)O)(n) peak with respect to that of BaOH(+)(H(2)O)(n-1), which is opposite to the trend for n = 2-4. Rationalization of the data required consideration of a distinct behavior of ground-state and electronically excited state Ba atoms in inelastic and reactive Ba + (H(2)O)(n) encounters that can occur in the cluster source. Within this picture, the generation of Ba(H(2)O)(n) (n > 1) association products results from stabilizing collisions with atoms of the carrier gas, which are favored by intramolecular vibrational redistribution that operates on the corresponding collision intermediates prior to stabilization; the latter is unlikely to occur for Ba + (H(2)O) encounters. Overall, this interpretation is consistent with additional in-source laser excitation and quenching experiments, which aimed to explore qualitatively the effect of perturbing the Ba atom electronic state population distribution on the observed intensity pattern, as well as with the energetics of various possible reactions for the Ba + H(2)O system that derive from high level ab initio calculations. PMID- 21701714 TI - Infrared differential absorption Lidar (DIAL) measurements of hydrocarbon emissions. AB - We report the application of an infrared (IR) differential absorption Lidar (DIAL) system (also capable of ultra violet measurements) built at the National Physical Laboratory (NPL), UK, to field measurements of total site emissions (controlled and fugitive) from petrochemical and landfill installations. The validation of the IR-DIAL was carried out via a series of controlled field experiments including comparison to GC analysis and tests against controlled methane releases from a test stack, all detailing agreements on the order of +/ 20%. In volatile organic compound (VOC) measurements at a UK petrochemical site it was found that the American Petroleum Institute's methodology of the time for calculating the emitted flux underestimated by a factor of 2.4. Also, in a similar field trial it was found that scaling traditional point measurements at easily accessible flanges and valves to represent all flanges and valves on a site led to an underestimation by a factor of 6. In addition to petrochemical examples we also report field measurements from a landfill site to demonstrate the advantageous of the DIAL technique for monitoring area emission sources. In this case study it was found that active (still being filled) cells resulted in significantly greater VOC emission rates (30 kg h(-1)) than closed (<= 10 kg h( 1)). PMID- 21701715 TI - The effects of oligonucleotide overhangs on the surface hybridization in DNA films: an impedance study. AB - While oligonucleotide hybridization and effects of nucleobase mismatches have been the intense focus of a number of electrochemical studies, the effects of the target strand length on the electrochemical response of oligonucleotide films have not been addressed yet. In this report, we have studied the electrochemical impedance of the oligonucleotide films having overhangs on either the target or the surface bound capture strand. Each system gives different impedance responses, which were interpreted with the help of modified Randles' equivalent. Results indicate that comparable sizes of target and capture strands ensure the higher hybridization efficiency and film order. The presence of nucleobase overhangs at the bottom of the film causes lower changes in charge transfer resistance (DeltaR(CT)) after hybridization due to lower hybridization efficiency and presumably non-uniformity in the film. Nucleobase overhangs at the top of the film result in higher DeltaR(CT) due to higher film order and accumulation of negative charges but appear not to cause any steric congestion. PMID- 21701716 TI - Evidence for alpha-helices in the gas phase: a case study using Melittin from honey bee venom. AB - Gas phase methodologies are increasingly used to study the structure of proteins and peptides. A challenge to the mass spectrometrist is to preserve the structure of the system of interest intact and unaltered from solution into the gas phase. Small peptides are very flexible and can present a number of conformations in solution. In this work we examine Melittin a 26 amino acid peptide that forms the active component of honey bee venom. Melittin is haemolytic and has been shown to form an alpha-helical tetrameric structure by X-ray crystallography [M. Gribskov et al., The RCSB Protein Data Bank, 1990] and to be helical in high concentrations of methanol. Here we use ion mobility mass spectrometry, molecular dynamics and gas-phase HDX to probe its structure in the gas phase and specifically interrogate whether the helical form can be preserved. All low energy calculated structures possess some helicity. In our experiments we examine the peptide following nano-ESI from solutions with varying methanol content. Ion mobility gives collision cross sections (CCS) that compare well with values found from molecular modelling and from other reported structures, but with inconclusive results regarding the effect of solvent. There is only a slight increase in CCS with charge, showing minimal coloumbically driven unfolding. HDX supports preservation of some helical content into the gas phase and again shows little difference in the exchange rates of species sprayed from different solvents. The [M + 3H](3+) species has two exchanging populations both of which exhibit faster exchange rates than observed for the [M + 2H](2+) species. One interpretation for these results is that the time spent being analysed is sufficient for this peptide to form a helix in the 'ultimate' hydrophobic environment of a vacuum. PMID- 21701717 TI - N-H...pi hydrogen-bonding and large-amplitude tipping vibrations in jet-cooled pyrrole-benzene. AB - The N-H...pi hydrogen bond is an important intermolecular interaction in many biological systems. We have investigated the infrared (IR) and ultraviolet (UV) spectra of the supersonic-jet cooled complex of pyrrole with benzene and benzene d(6) (Pyr.Bz, Pyr.Bz-d(6)). DFT-D density functional, SCS-MP2 and SCS-CC2 calculations predict a T-shaped and (almost) C(s) symmetric structure with an N H...pi hydrogen bond to the benzene ring. The pyrrole is tipped by omega(S(0)) = +/-13 degrees relative to the surface normal of Bz. The N...ring distance is 3.13 A. In the S(1) excited state, SCS-CC2 calculations predict an increased tipping angle omega(S(1)) = +/-21 degrees . The IR depletion spectra support the T-shaped geometry: The NH stretch is redshifted by -59 cm(-1), relative to the "free" NH stretch of pyrrole at 3531 cm(-1), indicating a moderately strong N H...pi interaction. The interaction is weaker than in the (Pyr)(2) dimer, where the NH donor shift is -87 cm(-1) [Dauster et al., Phys. Chem. Chem. Phys., 2008, 10, 2827]. The IR C-H stretch frequencies and intensities of the Bz subunit are very similar to those of the acceptor in the (Bz)(2) dimer, confirming that Bz acts as the acceptor. While the S(1)<-S(0) electronic origin of Bz is forbidden and is not observable in the gas-phase, the UV spectrum of Pyr.Bz in the same region exhibits a weak 0 band that is red-shifted by 58 cm(-1) relative to that of Bz (38 086 cm(-1)). The origin appears due to symmetry-breaking of the pi electron system of Bz by the asymmetric pyrrole NH...pi hydrogen bond. This contrasts with (Bz)(2), which does not exhibit a 0 band. The Bz moiety in Pyr.Bz exhibits a 6a band at 0 + 518 cm(-1) that is about 20* more intense than the origin band. The symmetry breaking by the NH...pi hydrogen bond splits the degeneracy of the nu(6)(e(2g)) vibration, giving rise to 6a' and 6b' sub-bands that are spaced by ~6 cm(-1). Both the 0 and 6 bands of Pyr.Bz carry a progression in the low-frequency (10 cm(-1)) excited-state tipping vibration omega', in agreement with the change of the omega tipping angle predicted by SCS MP2 and SCS-CC2 calculations. PMID- 21701718 TI - Proton mobility and stability of water clusters containing the bisulfate anion, HSO4(-)(H2O)n. AB - Bisulfate water clusters, HSO(4)(-)(H(2)O)(n), have been studied both experimentally by a quadrupole time-of-flight mass spectrometer and by quantum chemical calculations. For the cluster distributions studied, there are some possible "magic number" peaks, although the increase in abundance compared to their neighbours is small. Experiments with size-selected clusters with n = 0-25, reacting with D(2)O at a center-of-mass energy of 0.1 eV, were performed, and it was observed that the rate of hydrogen/deuterium exchange is lower for the smallest clusters (n < 8) than for the larger (n > 11), with a transition taking place in the range n = 8-11. We propose that the protonic defect of the bisulfate ion remains rather stationary unless the degree of hydration reaches a given level. In addition, it was observed that H/D scrambling becomes close to statistically randomized for the larger clusters. Insight into this size dependency was obtained by B3LYP/6-311++G(2d,2p) calculations for HSO(4)( )(H(2)O)(n) with n = 0-10. In agreement with experimental observations, these calculations suggest pronounced effectiveness of a ''see-saw mechanism'' for pendular proton transfer with increasing HSO(4)(-)(H(2)O)(n) cluster size. PMID- 21701720 TI - Preparation of LiCoO2 concaved cuboctahedra and their electrochemical behavior in lithium-ion battery. AB - LiCoO(2) concaved cuboctahedra with a size of about 1.0 MUm were hydrothermally prepared from CoCO(3) and LiOH.H(2)O at 150 degrees C. Field-emitting scanning electron microscope (FESEM) images show that the cuboctahedra consisted of four hexagonal plates, with angles of 70.5 degrees in neighboring plates. Electron diffraction (ED) patterns of the hexagonal plates show 1 0 0 diffraction of LiCoO(2) in rhombohedral phase and 2 2 0 diffraction in spinel phase, which means LiCoO(2) concaved cuboctahedra are comprised of two intergrown phases. The electrochemical performance of these concaved cuboctahedra of LiCoO(2) at a rate of 0.5 C demonstrated first run charge/discharge capacities of 155 and 141 mAh g( 1) and a stable discharge capacity of 114 mAh g(-1) after 100 cycles. After that, FESEM images show the LiCoO(2) concaved cuboctahedra have undergone no significant change. At a temperature of 120 degrees C and under the same conditions, only a small amount of LiCoO(2) concaved cuboctahedron appeared. As the temperature rose to 180 degrees C, flower-like LiCoO(2) microstructures with a size of about 1.0 MUm were formed, constructed of irregular plates. The electrochemical performance of the products prepared at 120 degrees C and 180 degrees C indicates lower stability than that of LiCoO(2) concaved cuboctahedra. PMID- 21701719 TI - Energetics and dynamics of proton transfer reactions along short water wires. AB - Proton transfer (pT) reactions in biochemical processes are often mediated by chains of hydrogen-bonded water molecules. We use hybrid density functional calculations to study pT along quasi one-dimensional water arrays that connect an imidazolium-imidazole proton donor-acceptor pair. We characterize the structures of intermediates and transition states, the energetics, and the dynamics of the pT reactions, including vibrational contributions to kinetic isotope effects. In molecular dynamics simulations of pT transition paths, we find that for short water chains with four water molecules, the pT reactions are semi-concerted. The formation of a high-energy hydronium intermediate next to the proton-donating group is avoided by a simultaneous transfer of a proton from the donor to the first water molecule, and from the first water molecule into the water chain. Lowering the dielectric constant of the environment and increasing the water chain length both reduce the barrier for pT. We study the effect of the driving force on the energetics of the pT reaction by changing the proton affinity of the donor and acceptor groups through halogen and methyl substitutions. We find that the barrier of the pT reaction depends linearly on the proton affinity of the donor but is nearly independent of the proton affinity of the acceptor, corresponding to Bronsted slopes of one and zero, respectively. PMID- 21701721 TI - A dual channel gas chromatograph for atmospheric analysis of volatile organic compounds including oxygenated and monoterpene compounds. AB - A dual channel gas chromatograph with flame ionisation detectors has been used extensively for analysis of volatile organic compounds in the atmosphere and forms the basis of two monitoring instruments contributing VOC data to the World Meteorological Organisation - Global Atmosphere Watch network. Recent modifications to the methodology have broadened the scope of the instrument; to incorporate measurements of selected monoterpenes, and achieve improved accuracy in the measurement of oxygenated volatile organic compounds. Analysis of selected monoterpenes has been achieved without any significant loss of resolution of the non-methane hydrocarbons or oxygenated compounds. Quantification of 64 different VOCs of varying functionalities are reported with detection limits in the range 1 5 parts per trillion. Here we present a summary of the instrumental and calibration details for the methodology, which continues to be used on many field projects, along with a discussion of the associated measurement uncertainties. PMID- 21701722 TI - A Teflon microreactor with integrated piezoelectric actuator to handle solid forming reactions. AB - We present a general inexpensive method for realizing a Teflon stack microreactor with an integrated piezoelectric actuator for conducting chemical synthesis with solid products. The microreactors are demonstrated with palladium-catalyzed C-N cross-coupling reactions, which are prone to clogging microchannels by forming insoluble salts as by-products. Investigations of the ultrasonic waveform applied by the piezoelectric actuator reveal an optimal value of 50 kHz at a load power of 30 W. Operating the system at these conditions, the newly developed Teflon microreactor handles the insoluble solids formed and no clogging is observed. The investigated reactions reach full conversion in very short reaction times and high isolated yields are obtained (>95% yield). PMID- 21701724 TI - Heterostructured CIGS-Au nanoparticles: from Au-CIGS side-by-side structure to Au core/CIGS-shell configuration. AB - Heterostructured Au-Copper Indium Gallium Selenide (CIGS) nanoparticles (nps) with Au-CIGS side-by-side and Au-core/CIGS-shell configurations have been synthesized in a controllable manner using seed mediated growth. Detailed microstructure analysis reveals that (112) planes in the tetragonal chalcopyrite CIGS serve as the predominant termination surfaces during single phase CIGS nanoparticle growth. Preferential nucleation of Au on such planes determines the Au-CIGS side-by-side configuration when the pre-synthesized CIGS nps are used as the seeds for further Au growth. Reversing the growth sequence by employing Au nano-seeds results in Au-core/CIGS-shell configuration, as determined by the non preferential nucleation of CIGS on the spherical Au nanoparticle surface. The different morphological configurations of the heterostructures are found to modify the surface plasmon resonance of Au in the corresponding samples. PMID- 21701725 TI - Synthesis of alanine-based colorimetric sensors and enantioselective recognition of aspartate and malate anions. AB - Two chiral colorimetric sensors (1,2) were synthesized and characterized by spectroscopic techniques and their enantioselective recognition of chiral dicarboxylic anions (D/L-aspartate and D/L-malate) was examined by UV-vis and (1)H NMR spectroscopy. Interaction of the receptors 1 and 2 with the enantiomers of aspartate or malate caused different color changes, and they act as optical chemosensors for the recognition of D-aspartate vs. L-aspartate and d-malate vs.l malate. Receptor 1 exhibits high enantioselective binding for aspartate anions [K(A(D))/K(A(L)) = 12.15]. PMID- 21701726 TI - Molecular dynamics simulations of the Salmonella typhi Vi antigenic polysaccharide and effects of the introduction of a zwitterionic motif. AB - A series of hexasaccharides corresponding to the Vi capsular polysaccharide, a polymer of alpha-(1->4)-galacturonic acid, and analogs containing a zwitterionic motif with various degrees of acetylation at positions 3 have been modeled. When submitted to molecular dynamics simulations in a water box, all the structures visited only two quite restricted regions of the phi/psi conformational space both corresponding to extended geometries without any tendency towards supercoiling. The most stable conformation showed a clockwise helix arrangement of substituents on the molecular surface whereas the opposite arrangement was observed for the other conformation. The flexibility of the system and the hydrophobic character of the molecular surface are modulated by the 3-O-acetyl groups that confer rigidity to the system. In the zwitterionic analogs, the introduction of positive charges in the place of the acetamido groups alters the hydrophobicity that can be regained by methylation of the amino groups. The needed molecular flexibility can be obtained by the complete deacetylation at positions 3. PMID- 21701727 TI - An organocatalytic ionic liquid. AB - The carbene concentration in 1-ethyl-3-methylimidazolium-acetate ionic liquid is sufficiently high to act as a catalyst in benzoin condensation, hydroacylation and also in oxidation of an alcohol by using CO(2) and air. This observation reveals the potential of ionic liquid organocatalysts, uniting the beneficial properties of these two families of compounds. PMID- 21701728 TI - Photoremovable chiral auxiliary. AB - A new concept of a photoremovable chiral auxiliary (PCA), based on the chiral benzoin chromophore, is introduced. This moiety can control the asymmetric formation of a Diels-Alder adduct, and then be removed in a subsequent photochemical step in high chemical and quantum yields. Selective formation of the products at up to 96% ee was observed in the presence of a Lewis acid catalyst in the case of a 2-methoxybenzoinyl chiral auxiliary. PMID- 21701729 TI - Biaxial nematic phases in fluids of hard board-like particles. AB - We use density-functional theory, of the fundamental-measure type, to study the relative stability of the biaxial nematic phase, with respect to non-uniform phases such as smectic and columnar, in fluids made of hard board-like particles with sizes sigma(1) > sigma(2) > sigma(3). A restricted-orientation (Zwanzig) approximation is adopted. Varying the ratio kappa(1) = sigma(1)/sigma(2) while keeping kappa(2) = sigma(2)/sigma(3), we predict phase diagrams for various values of kappa(2) which include all the uniform phases: isotropic, uniaxial rod- and plate-like nematics, and biaxial nematic. In addition, spinodal instabilities of the uniform phases with respect to fluctuations of the smectic, columnar and plastic-solid types are obtained. In agreement with recent experiments, we find that the biaxial nematic phase begins to be stable for kappa(2)? 2.5. Also, as predicted by previous theories and simulations on biaxial hard particles, we obtain a region of biaxiality centred at kappa(1)~kappa(2) which widens as kappa(2) increases. For kappa(2)? 5 the region kappa(2)~kappa(1) of the packing fraction vs. kappa(1) phase diagrams exhibits interesting topologies which change qualitatively with kappa(2). We have found that an increasing biaxial shape anisotropy favours the formation of the biaxial nematic phase. Our study is the first to apply FMT theory to biaxial particles and, therefore, it goes beyond the second-order virial approximation. Our prediction that the phase diagram must be asymmetric in the neighbourhood of kappa(1)~kappa(2) is a genuine result of the present approach, which is not accounted for by previous studies based on second order theories. PMID- 21701730 TI - Solvatochromic dissociation of non-covalent fluorescent organic nanoparticles upon cell internalization. AB - Amorphous red-emitting materials involving solvatochromic small molecules have been processed by the reprecipitation method as non-doped nanospheres characterized by a remarkably low polydispersity. Their mean diameter could simply be tuned by the concentration of the organic solution giving rise to time stable dispersion of 85-200 nm-sized nanoparticles. Time-resolved measurements performed on solid nanoparticles showed significant size-dependence effects of the emission lifetime and maxima evidencing populations with distinct molecular conformations. Nanoparticle internalization has proved successful in NIH-3T3 murine fibroblasts with normal toxicity effects after 48 h. Fluorescence confocal microscopy under one- and two-photon excitations revealed dual emission enabling localization of the organic material within the plasma membrane and the cytoplasm. Model experiments resorting to suspended artificial lipid bilayers allowed us to conclude on the dissolution of nanoparticles by the phospholipid membrane during the internalization process. They let us to assume that uptake of hydrophobic nanoparticles by living cells implies an endocytosis mechanism operating through the formation of plasmic vesicles. PMID- 21701731 TI - Computing the 7Li NMR chemical shielding of hydrated Li+ using cluster calculations and time-averaged configurations from ab initio molecular dynamics simulations. AB - Ab initio molecular dynamics (AIMD) simulations have been used to predict the time-averaged Li NMR chemical shielding for a Li(+) solution. These results are compared to NMR shielding calculations on smaller Li(+)(H(2)O)(n) clusters optimized in either the gas phase or with a polarizable continuum model (PCM) solvent. The trends introduced by the PCM solvent are described and compared to the time-averaged chemical shielding observed in the AIMD simulations where large explicit water clusters hydrating the Li(+) are employed. Different inner- and outer-coordination sphere contributions to the Li NMR shielding are evaluated and discussed. It is demonstrated an implicit PCM solvent is not sufficient to correctly model the Li shielding, and that explicit inner hydration sphere waters are required during the NMR calculations. It is also shown that for hydrated Li(+), the time averaged chemical shielding cannot be simply described by the population-weighted average of coordination environments containing different number of waters. PMID- 21701732 TI - Band gap engineering of double-cation-impurity-doped anatase-titania for visible light photocatalysts: a hybrid density functional theory approach. AB - In this study, we have used cation-passivated codoping of Nb with Ga/In and also of W with Zn/Cd to modulate the band structure of anatase-TiO(2) to extend absorption to longer visible-light wavelengths. We adopted generalized Kohn-Sham theory with the Heyd-Scuseria-Ernzerhof (HSE06) hybrid functional for exchange and correlation. It has been found that (W, Cd)-doped TiO(2) should be a strong candidate for visible-light photocatalyst materials owing to the largest extent of band gap narrowing and the formation of continuum band, without movement of the valence band. It is argued that this design principle for band-edge modification can also be applied to other wide-band-gap semiconductors. PMID- 21701733 TI - Synthesis and molecular structure of piperazidine-bridged bis(phenolate) samarium(II) complex and its reactivity to carbodiimides. AB - The reaction of Sm[N(TMS)(2)](2)(THF)(2) with H(2)L (L = 1,4-bis(2-hydroxy-3-tert butyl-5-methyl-benzyl)-piperazidine) afforded [SmL(HMPA)(2)](4).8THF 2 upon treatment with 2 equivalents of HMPA (hexamethyl phosphoric triamide). X-ray crystallographic analysis of 2 reveals a tetrametallic macrocyclic structure, which represents the first example of a crystal structure of a Sm(II) complex stabilized by heteroatom bridged bis(phenolate) ligands. Reduction of carbodiimides RNCNR (R = (i)Pr and Cy) by [SmL](2)(THF) 1, which was formed in situ by the reaction of Sm[N(TMS)(2)](2)(THF)(2) with H(2)L in THF, yielded the Sm(III) complex with an oxalamidinate ligand [LSm{(N(i)Pr)(2)CC(N(i)Pr)(2)}SmL].THF 3 for (i)PrNCN(i)Pr and the Sm(III) complex with a diamidocarbene ligand [LSm(MU-CyNCNCy)SmL].5.5THF 4 for CyNCNCy. PMID- 21701734 TI - Synthesis and electrochemical properties of bipyrimidine bridged triruthenium complexes. AB - A new MU(4)-bpym-bridged dimer of an oxoacetao-triruthenium complex with carbonyl, [{Ru(3)O(CH(3)COO)(5)(CO)(py)}(2)(MU(4)-bpym)], was synthesized. The complex possesses two stable mixed-valence states associated with Ru(3)(III,III,II)/Ru(3)(III,II,II) and Ru(3)(III,III,III)/Ru(3)(III,III,II). The IR-spectroelectrochemistry reveals nu(CO) spectra in five oxidation states, Ru(3)(III,III,III)-Ru(3)(III,III,III) to Ru(3)(III,II,II)-Ru(3)(III,II,II) and both the mixed-valence states show a spectrum indicating medium interaction between the Ru(3) units. PMID- 21701735 TI - Synthesis, structure and magnetic properties of nanocrystalline YMnO3. AB - Nanocrystalline YMnO(3) has been prepared by wet chemical synthesis routes to obtain crystallites with sizes from 20 nm to bulk material. The crystal structure of hexagonal YMnO(3) nanocrystallites smaller than 80 nm deviates from bulk material in terms of unit cell distortion and unit cell volume. The ferrielectric displacements of Y(3+) cations along the polar c-axis decays progressively with decreasing size below 100 nm. Indications of weak ferromagnetism in the form of a narrow hysteresis loop and enhanced magnetic susceptibility below 43 K in 20 nm YMnO(3) nanoparticles is attributed to extrinsic effects. Low-temperature annealing of the 20 nm crystallites in an oxidizing atmosphere removed all traces of ferromagnetism, showing that this is not a size-induced property. Finally, formation of the competing metastable orthorhombic phase and the thermodynamically stable hexagonal phase is discussed with respect to oxidizing or reducing conditions during synthesis. PMID- 21701736 TI - Structure and properties of an eight-coordinate Mn(II) complex that demonstrates a high water relaxivity. AB - An air-stable eight-coordinate (8C) Mn(II)N(8) complex has been synthesized utilizing an N(4) imidazole/imine ligand. The 8C dodecahedral geometry is structurally robust as the Mn complex is stable to air, NO(g), and potential coordinating anions. The structural, spectroscopic and water relaxivity properties of this complex are reported. PMID- 21701737 TI - Microwave synthesis and inherent stabilization of metal nanoparticles in 1-methyl 3-(3-carboxyethyl)-imidazolium tetrafluoroborate. AB - The synthesis of Co-NPs and Mn-NPs by microwave-induced decomposition of the metal carbonyls Co(2)(CO)(8) and Mn(2)(CO)(10), respectively, yields smaller and better separated particles in the functionalized IL 1-methyl-3-(3-carboxyethyl) imidazolium tetrafluoroborate [EmimCO(2)H][BF(4)] (1.6 +/- 0.3 nm and 4.3 +/- 1.0 nm, respectively) than in the non-functionalized IL 1-n-butyl-3-methylimidazolium tetrafluoroborate [Bmim][BF(4)]. The particles are stable in the absence of capping ligands (surfactants) for more than six months although some variation in particle size could be observed by TEM. PMID- 21701738 TI - Naked-eye visible and fluorometric dual-signaling chemodosimeter for hypochlorous acid based on water-soluble p-methoxyphenol derivative. AB - The oxidation of a simple p-methoxyphenol derivative by HClO induces an intramolecular charge transfer from the end phenyl units to the middle benzoquinone, which leads to colorimetric and fluorescent changes. This detection can be run in aqueous solution with high selectivity over other reactive oxygen species. PMID- 21701739 TI - Molecular controlled nano-devices. AB - In this perspective we present several examples of the ability to control electronic and magnetic properties of nano-devices by adsorbing on their surfaces organized self-assembled monolayers (SAM) of organic molecules. The work presented focuses on research in which we were involved and is aimed at demonstrating the ability to control physical properties of metal and semiconductor films by complementing them with the properties of a SAM. The organization of molecules on a surface produces a pseudo two-dimensional dipole layer, owing to the dipolar property of each of the molecules. The field confined in the layer could be enormous, however the molecules are either depolarized or charge is transferred between the substrate and the layer so as to reduce the energy of the dipole layer. This charge transfer process can be exploited for the use of hybrid-organic-inorganic devices as sensors, as wavelength specific light detectors, or for varying the critical temperature in semiconductor ferromagnets. The concept presented here, for combining electronic properties of organic molecules with those of the inorganic substrate, is another venue toward "molecular controlled electronics". PMID- 21701740 TI - Peroxy radical isomerization in the oxidation of isoprene. AB - We report experimental evidence for the formation of C(5)-hydroperoxyaldehydes (HPALDs) from 1,6-H-shift isomerizations in peroxy radicals formed from the hydroxyl radical (OH) oxidation of 2-methyl-1,3-butadiene (isoprene). At 295 K, the isomerization rate of isoprene peroxy radicals (ISO2*) relative to the rate of reaction of ISO2* + HO2 is k(isom)(295)/(k(ISO2*+HO2)(295)) = (1.2 +/- 0.6) x 10(8) mol cm(-3), or k(isom)(295) ? 0.002 s(-1). The temperature dependence of this rate was determined through experiments conducted at 295, 310 and 318 K and is well described by k(isom)(T)/(k(ISO2*+HO2)(T)) = 2.0 x 10(21) exp(-9000/T) mol cm(-3). The overall uncertainty in the isomerization rate (relative to k(ISO2*+HO2)) is estimated to be 50%. Peroxy radicals from the oxidation of the fully deuterated isoprene analog isomerize at a rate ~15 times slower than non deuterated isoprene. The fraction of isoprene peroxy radicals reacting by 1,6-H shift isomerization is estimated to be 8-11% globally, with values up to 20% in tropical regions. PMID- 21701741 TI - Structural design and facile synthesis of a highly efficient catalyst for formic acid electrooxidation. AB - The pathway of formic acid electrooxidation strongly depends on the amount of three neighbouring Pt or Pd atoms in the surface of Pd- or Pt-based catalysts. Here, Pt decorated Pd/C nanoparticles (the optimal atomic ratio, Pd : Pt = 20 : 1) were designed and then synthesized through a facile galvanic replacement reaction where the amount of three neighbouring Pt or Pd atoms markedly decreased. As a result, discontinuous Pd and Pt atoms suppressed CO formation and exhibited unprecedented catalytic activity and stability toward formic acid electrooxidation while the cost was almost the same as that of Pd/C. PMID- 21701742 TI - Occurrence of orthophosphate monoesters in lake sediments: significance of myo- and scyllo-inositol hexakisphosphate. AB - Orthophosphate monoesters often constitute a significant fraction of total phosphorus in lake sediments. The knowledge on the specific composition and recalcitrance of these compounds is however limited. The main aim was therefore to identify and quantify specific orthophosphate monoesters in sediment from 15 Danish lakes by solution (31)P NMR spectroscopy. The four most quantitatively important orthophosphate monoesters were myo-inositol hexakisphosphate (myo IP(6)), scyllo-inositol hexakisphosphate (scyllo-IP(6)) alpha-glycerophosphate (alpha-GP) and beta-glycerophosphate (beta-GP). The compounds were identified in 9, 4, 8 and in all 15 lakes, respectively. In total these four components made up 46-100% of the orthophosphate monoester pool. The glycerophosphates (GPs) are most likely degradation products of phospholipids, created as an artifact by the alkaline extraction procedure used for (31)P NMR spectroscopy, while the inositol hexakisphosphates (IPs) are naturally occurring compounds. There was a significant positive correlation between myo-IP(6) and total aluminium in the sediment and a negative correlation between myo-IP(6) and lake water pH, suggesting that myo-IP(6) is stabilized in the sediment by adsorption at slightly acidic or neutral conditions. In three lakes, the depth distribution of the orthophosphate monoesters was investigated. The content of scyllo-IP(6) and myo IP(6) was constant with sediment depth in two of the lakes while the content of myo-IP(6) decreased with depth in one of the lakes. In all cases the IPs seem to be preserved with sediment depth to a higher extent than the orthophosphate diesters and especially the GPs suggesting that IPs can be a sink for phosphorus in the lake ecosystem or at least delay P-recycling for years. PMID- 21701743 TI - Controlled synthesis of a large fraction of metallic single-walled carbon nanotube and semiconducting carbon nanowire networks. AB - Controlled synthesis of both single-walled carbon nanotube and carbon nanowire networks using the same CVD reactor and Fe/Al(2)O(3) catalyst by slightly altering the hydrogenation and temperature conditions is demonstrated. Structural, bonding and electrical characterization using SEM, TEM, Raman spectroscopy, and temperature-dependent resistivity measurements suggest that the nanotubes are of a high quality and a large fraction (well above the common 33% and possibly up to 75%) of them are metallic. On the other hand, the carbon nanowires are amorphous and semiconducting and feature a controlled sp(2)/sp(3) ratio. The growth mechanism which is based on the catalyst nanoisland analysis by AFM and takes into account the hydrogenation and temperature control effects explains the observed switch-over of the nanostructure growth modes. These results are important to achieve the ultimate control of chirality, structure, and conductivity of one-dimensional all-carbon networks. PMID- 21701744 TI - Luminescent cyclometalated gold(III) complexes. AB - Many luminescent gold(I) compounds are known, but in the vast majority of gold(III) complexes reported until recently, room temperature emission in fluid solution does not occur. As for other d(8) and d(6) metals, the key to obtaining gold(III) compounds with favorable luminescence properties seems to be the use of cyclometalating ligands that ensure very strong ligand fields. Recent progress in this emerging research field is discussed, and where appropriate, comparison to isoelectronic platinum(II) complexes and their photophysical properties is made. PMID- 21701745 TI - Highly dispersed MoO(x) on carbon nanotube as support for high performance Pt catalyst towards methanol oxidation. AB - HPMo self-assembly on carbon nanotubes followed by decomposition is used to fabricate highly dispersed MoO(x)/CNTs as a support for high performance of a Pt catalyst towards methanol oxidation. PMID- 21701746 TI - Reduced graphene oxide as capturer of dyes and electrons during photocatalysis: surface wrapping and capture promoted efficiency. AB - To elucidate the roles of graphene in photoelectric events and mass transfer during photocatalytic process is important for engineering graphene-semiconductor hybrid photocatalyst. Here, we demonstrated reduced graphene oxide (RGO) capturing dyes and photoinduced electrons during photocatalytic degradation of organic dyes in water. It captures dyes from water through adsorption and desorption irreversible hysteresis, and captures photoinduced electrons from semiconductor through surface junction. The RGO was attached to the surface of TiO(2) in the form of surface wrapping. After one-step photocatalytic reduction of graphene oxide (GO) and TiO(2) in ethanol-water solvent under UV irradiation, the RGO wrapped TiO(2) hybrid (graphene-w-TiO(2)) photocatalyst was obtained. Using visible absorption spectroscopy, we also demonstrated these captured dyes were degraded during photocatalysis. The photocatalytic test showed the RGO significantly improved the photocatalytic activity of this hybrid photocatalyst. PMID- 21701747 TI - Surface plasmon enhanced energy transfer in metal-semiconductor hybrid nanostructures. AB - We report a type of hybrid nanostructures composed of ZnO nanoparticles, CdSe/ZnS core/shell quantum dots (QDs), and Ag nanoprisms. With ultraviolet light illumination, the energy absorbed by ZnO nanoparticles was transferred to the CdSe/ZnS core/shell QDs inducing a photoluminescence (PL) emission. To enhance the PL emission, Ag nanoprisms were doped in the ZnO nanoparticles and the QDs. Enhanced energy transfer from the ZnO nanoparticles to the QDs via the surface plasmon effect of the Ag nanoprisms was also demonstrated. The PL emission dependence was investigated as a function of the doped Ag nanoprism concentration and a 7.4 times PL enhancement was obtained at an Ag nanoprism concentration of 5 * 10(-8) M. PMID- 21701748 TI - High-order graphene oxide nanoarchitectures. AB - We fabricate unique photoluminescent three dimensional graphene oxide (GO) architectures, so-called GO flowers, by self-assembly onto silicon substrates via solvent-mediated volume-controlled growth. The GO flowers exhibited bright photoluminescence and a photoresponse demonstrating their potential for advanced optical and electronic applications, such as advanced photovoltaic devices and organic light emitting diodes. PMID- 21701749 TI - Synthesis of a new class of ribose functionalized dinucleotide cap analogues for biophysical studies on interaction of cap-binding proteins with the 5' end of mRNA. AB - mRNAs of primitive eukaryotes such as Caenorhabditis elegans and Ascaris summ possess two different caps at their 5' terminus. They have either a typical cap which consists of 7-methylguanosine linked via a 5',5'-triphosphate bridge to the first transcribed nucleotide (MMG cap) or an atypical hypermethylated form with two additional methyl groups at the N2 position (TMG cap). Studies on interaction between the 5' end of mRNA and proteins that specifically recognize its structure have been carried out for several years and they often require chemically modified cap analogues. Here, we present the synthesis of five novel dinucleotide MMG and TMG cap analogues designed for binding studies using biophysical methods such as electron spin resonance (ESR) and surface plasmon resonance (SPR). New analogues were prepared by derivatization of the 2',3'-cis diol of the second nucleotide in the cap structure with levulinic acid, and coupling of the obtained acetal through its carboxylic group with 4-amino-2,2,6,6-tetramethylpiperidine-1 oxyl (4-amino TEMPO), ethylenediamine (EDA) or (+)-biotinyl-3,6,9 trioxaundecanediamine (amine-PEO(3)-biotin). PMID- 21701750 TI - Defining oxyanion reactivities in base-promoted glycosylations. AB - Saccharide oxyanions obtained by base treatment could be employed in glycosylation to give oligosaccharides with high stereo- and regioselectivities. PMID- 21701751 TI - An L-proline functionalized metallo-organic triangle as size-selective homogeneous catalyst for asymmetry catalyzing aldol reactions. AB - A homochiral metal-organic triangle Co-Pro1 was achieved via self-assembly by incorporating a L-proline moiety within the corresponding ligand. Co-Pro1 comprised L-proline moieties as asymmetric catalytic active sites and a helical like cavity, it worked as an asymmetric catalyst to prompt aldol reactions with size-, stereo- and enantioselectivity. PMID- 21701752 TI - Solid-phase synthesis of BODIPY dyes and development of an immunoglobulin fluorescent sensor. AB - The diversification of the BODIPY scaffold has been hindered by its controversial adaptability to solid-phase chemistry. Herein we report the first solid-phase synthesis of a BODIPY library in high purities. We screened the library against a set of proteins, identified an immunoglobulin fluorescent sensor (Ig Orange) and confirmed its binding by SPR experiments. PMID- 21701753 TI - Ultrathin titania coating for high-temperature stable SiO2/Pt nanocatalysts. AB - The facile synthesis of silica supported platinum nanoparticles with ultrathin titania coating to enhance metal-support interactions suitable for high temperature reactions is reported, as thermal and structure stability of metal nanoparticles is important for catalytic reactions. PMID- 21701754 TI - The rise, fall and reinvention of combinatorial chemistry. AB - Combinatorial chemistry provides a powerful tool for the rapid creation of large numbers of synthetic compounds. Ideally, these libraries should be a rich source of bioactive molecules, but there is the general feeling that the initial promise of combinatorial chemistry has not yet been realized. In particular, enthusiasm for conducting unbiased (non-structure-guided) screens of large libraries for protein or RNA ligands has waned. A central challenge in this area is to devise methods for the synthesis of chemically diverse, high-quality libraries of molecules with many of the desirable features of natural products. These include diverse functionality, a significant representation of chiral sp(3) centers that provide conformational bias to the molecule, significant skeletal diversity, and good pharmacokinetic properties. However, these libraries must be easy to make from cheap, readily available building blocks, ideally those that would support convenient hit optimization/structure reactivity relationship studies. Meeting these challenges will not be easy. Here I review some recent advances in this area and provide some thoughts on likely important developments in the next few years. PMID- 21701755 TI - Tuning the surface composition of novel metal vanadates and its effect on the catalytic performance. AB - Tuning the surface composition of metal vanadates using different cations leads to the development of a new class of highly effective catalysts tested in the ammoxidation of 2-methylpyrazine. Especially, an enrichment of V in the near surface region is beneficial for improved selectivity. With this approach, a knowledge based optimisation of the catalysts was possible for the first time, which indeed led to highly efficient novel LaVO(x) catalysts with a high yield of 2-cyanopyrazine (>=85%) and extremely high space-time-yields (ca. 525 g kg h( 1)). PMID- 21701757 TI - The primary step in the ultrafast photodissociation of the methyl iodide dimer. AB - This paper shows the results of combined experimental and theoretical work that have unravelled the mechanism of ultrafast ejection of a methyl group from a cluster, the methyl iodide dimer (CH(3)I)(2). Ab initio calculations have produced optimized geometries for the dimer and energy values and oscillator strengths for the excited states of the A band of (CH(3)I)(2). These calculations have allowed us to describe the blue shift that had been observed in the past in this band. This blue shift has been experimentally determined with higher precision than in all previously reported experiments, since it has been measured through its effect upon the kinetic energy release of the fragments using femtosecond velocity map imaging. Observations of the reaction branching ratio and of the angular nature of the fragment distribution indicate that two main changes occur in A-band absorption in the dimer with respect to the monomer: a substantial change in the relative absorption to different states of the band, and, more importantly, a more efficient non-adiabatic crossing between two of those states. Additionally, time resolved experiments have been performed on the system, obtaining snapshots of the dissociation process. The apparent retardation of more than 100 fs in the dissociation process of the dimer relative to the monomer has been assigned to a delay in the opening of the optical detection window associated with the resonant multiphoton ionization detection of the methyl fragment. PMID- 21701756 TI - Supramolecular hydrogels based on the epitope of potassium ion channels. AB - Imparting aromatic-aromatic interactions to the potassium binding epitope affords a supramolecular hydrogelator that responds to the K(+) concentration by self assembly into nanofibers of different widths and crosslinking patterns, which illustrates a simple approach to generate biomimic materials based on tunable, hierarchical self-assembly of small molecules. PMID- 21701758 TI - Tethered bilayer lipid micromembranes for single-channel recording: the role of adsorbed and partially fused lipid vesicles. AB - A mercury-supported bilayer lipid micromembrane was prepared by anchoring a thiolipid monolayer to a mercury cap electrodeposited on a platinum microdisc about 20 MUm in diameter; a lipid monolayer was then self-assembled on top of the thiolipid monolayer either by vesicle fusion or by spilling a few drops of a lipid solution in chloroform on the cap and allowing the solvent to evaporate. Single-channel recording following incorporation of the alamethicin channel forming peptide exhibits quite different features, depending on the procedure followed to form the distal lipid monolayer. The "spilling" procedure, which avoids the formation of adsorbed or partially fused vesicles, yields very sharp single-channel currents lasting only one or two milliseconds. These are ascribed to ionic flux into the hydrophilic spacer moiety of the thiolipid. Conversely, the vesicle-fusion procedure yields much longer single-channel openings analogous to those obtained with conventional bilayer lipid membranes, albeit smaller. This difference in behavior is explained by ascribing the latter single-channel currents to ionic flux into vesicles adsorbed and/or partially fused onto the tethered lipid bilayer, via capacitive coupling. PMID- 21701759 TI - First-principles study of fluoroform adsorption on a hexagonal ice (0001) surface: weak hydrogen bonds-strong structural effects. AB - For isolated fluoroform (F(3)CH) molecules adsorbed on a hexagonal ice (0001) surface the properties of blue- and red-shifting hydrogen bonds were studied using static density functional theory (DFT) calculations and Car-Parrinello molecular dynamics (CP-MD) simulations. A systematic search by starting from many initial configurations was performed to determine the lowest-energy structures of F(3)CH on the ice surface, and for the optimized geometries the vibrational frequencies were calculated. The local minima structures are analyzed in terms of their coordination to the surface, with special focus on identifying blue shifting hydrogen bonds via their spectroscopic signature of an increased frequency of the C-H fundamental stretching vibration. Subsequently, by CP-MD simulations the stability of the lowest-energy configurations at finite temperatures was verified and possible transformation pathways connecting the local minima structures were explored. PMID- 21701760 TI - Pattern formation in phase separating binary mixtures. AB - We experimentally investigate the interplay of thermodynamics with hydrodynamics during phase separation of (quasi-) binary mixtures. Well defined patterns emerge while slowly crossing the cloud point curve. Depending on the material parameters of the experimental system, two distinct scenarios are observed. In quasi-binary mixtures of methanol-hexane patterns appear before macroscopic phase separation sets in. In course of time the patterns turn faint while the overall turbidity of the sample increases until the mixtures become completely turbid. We attribute this pattern formation to a latent heat induced instability resembling a Rayleigh Benard instability. This is confirmed by calorimetric data and an estimate of its Rayleigh number. Mixtures of C(4)E(1)-water doped with decane phase separate under heating. After passing the cloud point curve these mixtures first become homogenously turbid. While clearing up, pattern formation is observed. We attribute this type of pattern formation to an interfacial tension induced Benard Marangoni instability. The occurrence of the two scenarios is supported by the relevant dimensionless numbers. PMID- 21701761 TI - Synthesis and fluorescence emission of neutral and anionic di- and tetra carboranyl compounds. AB - A new family of photoluminescent neutral and anionic di-carboranyl and tetra carboranyl derivatives have been synthesized and characterized. The reaction of alpha,alpha'-bis(3,5-bis(bromomethyl)phenoxy-m-xylene with 4 equiv. of the monolithium salt of 1-Ph-1,2-C(2)B(10)H(11) or 1-Me-1,2-C(2)B(10)H(11) gives the neutral tetracarboranyl-functionalized aryl ether derivatives closo-1 and closo 2, respectively. The addition of the monolithium salt of 1-Ph-1,2-closo C(2)B(10)H(11) to alpha,alpha,'-dibromo-m-xylene or 2,6-dibromomethyl-pyridine gives the corresponding di-carboranyl derivatives closo-3 and closo-4. These compounds, which contain four or two closo clusters, were degraded using the classical method, KOH in EtOH, affording the corresponding nido species, which were isolated as potassium or tetramethylammonium salts. All the compounds were characterized by IR, (1)H, (11)B and (13)C NMR spectroscopy, and the crystal structure of closo-3 was analysed by X-ray diffraction. The carboranyl fragments are bonded through CH(2) units to different organic moieties, and their influence on the photoluminescent properties of the final molecules has been studied. All the closo- and nido-carborane derivatives exhibit a blue emission under ultraviolet excitation at room temperature in different solvents. The fluorescence properties of these closo and nido-derivatives depend on the substituent (Ph or Me) bonded to the C(cluster), the solvent polarity, and the organic unit bearing the carborane clusters (benzene or pyridine). In the case of nido-derivatives, an important effect of the cation is also observed. PMID- 21701762 TI - Morphological phase separation in unstable thin films: pattern formation and growth. AB - We present results from a comprehensive numerical study of morphological phase separation (MPS) in unstable thin liquid films on a 2-dimensional substrate. We study the quantitative properties of the evolution morphology via several experimentally relevant markers, e.g., correlation function, structure factor, domain-size and defect-size probability distributions, and growth laws. Our results suggest that the late-stage morphologies exhibit dynamical scaling, and their evolution is self-similar in time. We emphasize the analogies and differences between MPS in films and segregation kinetics in unstable binary mixtures. PMID- 21701763 TI - A triad [FeFe] hydrogenase system for light-driven hydrogen evolution. AB - A novel molecular triad [FeFe]-H(2)ase 1, and its model complexes 2 and 3 have been successfully constructed. The multistep PET and long-lived Fe(i)Fe(0) species were found to be responsible for the better performance of triad 1 than that of 2 with 3 for light-driven H(2) evolution. PMID- 21701764 TI - Microfluidic lipid membrane formation on microchamber arrays. AB - We present a simple method to form free-standing lipid membranes on arrayed microchambers (>100). The formed membranes are perpendicular to an imaging plane with control of solute concentration on each side of the membranes. This platform let us quantitatively detect membrane transport of non-charged fluorescent molecules, induced by membrane proteins. PMID- 21701765 TI - Effects of Zn(II) complex with vitamins C and U, and carnitine on metabolic syndrome model rats. AB - The insulinomimetic activity of a Zn(ii) complex is reported. The effects of the Zn(ii) complex with ascorbic acid (Vitamin C; VC), methylmethionine sulfonium chloride (Vitamin U; VU) and l-carnitine were assessed in diet-induced metabolic syndrome model rats. Zn(VU)(2)Cl(2) and Zn(VC)Cl(2) were suggested to be useful supplementary materials for preventing metabolic syndrome by reducing visceral adipose tissues or accelerating blood fluidity. PMID- 21701766 TI - The impact of P-substituents on the structures, spectroscopic properties, and reactivities of POCOP-type pincer complexes of nickel(II). AB - The room temperature reaction of NiBr(2)(NCCH(3))(x) with the pincer-type ligand POCHOP(Ph) gave the new pincer complex (POCOP(Ph))NiBr (1, POCOP(Ph) = kappa(P), kappa(C), kappa(P)-2,6-{Ph(2)PO}(2)C(6)H(3)). Complex 1 reacts with AgX to give the analogous Ni-X derivatives (X = CN, 2; OSO(2)CF(3), 3; OC(O)CH(3), 4; ONO(2), 5), whereas complex 3 reacts with phenylacetylene and NEt(3) to give the Ni-CCPh derivative 6. On the other hand, reaction of 1 or 3 with RLi or RMgI did not afford the desired Ni-R derivatives, giving instead the corresponding iodo and hydroxo derivatives. Complexes 1-6 have been characterized by NMR, IR, and UV-Vis spectroscopy and X-ray crystallography. The solid state structural and IR data indicate that Ni-C(sp) interaction is dominated by ligand-to-metal sigma-donation in 2 and 6. Cyclic voltammetry measurements indicate that complexes 3 and 4 display reversible redox behaviour (Ni(II)/Ni(III)); comparison of the E(0)(1/2) values for these complexes and their POCOP(i-Pr) analogues shows that both the X ligands and the P-substituent have a considerable impact on the ease of oxidation in this family of complexes. PMID- 21701767 TI - On the theoretical understanding of the unexpected O2 activation by nanoporous gold. AB - Several pure and Ag-doped gold surfaces were used as models of nanoporous gold catalysts where O(2) was suggested to be activated. Density functional theory (DFT) calculations show that residual Ag on Au is able to promote adsorption and to dissociate thermodynamically favorable O(2) with high rate constants. PMID- 21701768 TI - A glycoprotein from Porphyra yezoensis produces anti-inflammatory effects in liposaccharide-stimulated macrophages via the TLR4 signaling pathway. AB - The purpose of this study was to investigate the antioxidant and anti inflammatory effects of a glycoprotein isolated from the alga Porphyra yezoensis in LPS-stimulated RAW 264.7 mouse macrophages. First, we extracted a novel material with antioxidant activity from P. yezoensis, confirmed by SDS-PAGE to be a glycoprotein, which we named P. yezoensis glycoprotein (PGP). PGP inhibited the production of NO and ROS and expression of iNOS, COX-2, TNF-alpha and IL-1beta, which are involved in the pathogenesis of many inflammation-associated human diseases, including septic shock, hemorrhagic shock and rheumatoid arthritis. Next, we determined the mechanisms behind the antioxidant and anti-inflammatory activities of PGP. We focused on the Toll-like receptor 4 (TLR4) signaling pathway because it is well-known to induce the pro-inflammatory proteins that trigger MAPK and NF-kappaB activation in lipopolysaccharide (LPS)-induced oxidative events. PGP treatment reduced the formation of the TLR4-IRAK4 and TLR4 TRIF binding complexes in response to LPS. Moreover, it inhibited LPS-induced activation and nuclear translocation of NF-kappaB by abrogating IkappaB phosphorylation. PGP also suppressed the phosphorylation of ERK1/2 and JNK in a dose-dependent manner. These results suggest that PGP exerts its anti inflammatory effects by modulating TLR4 signaling and thus inhibiting the activation of NF-kappaB and MAP kinases. PMID- 21701769 TI - Bee venom phospholipase A2 prevents prion peptide induced-cell death in neuronal cells. AB - Bee venom phospholipase A2 (bvPLA2) is a prototypic group III enzyme which consists of unique N-terminal and C-terminal domains and a central secretory PLA2 (sPLA2) domain. This sPLA2 domain is highly homologous with human group III sPLA2. Current evidence suggests that group III sPLA2 may affect some neuronal functions, such as neuritogenesis, neurotransmitter release and neuronal survival. The prion diseases are neurodegenerative disorders characterized by the conversion of the normal cellular prion (PrPC) to the misfolded isoform scrapie prion protein (PrPSc). PrPSc accumulation in the central nervous system (CNS) leads to neurotoxicity by inhibition of the PI3K/AKT pathway or activation of p38 mitogen-activated protein kinase (MAPK) pathways. In the present study, we found that bvPLA2 inhibited prion protein (PrP) fragment (106-126)-induced neuronal cell death. PrP(106-126)-mediated increase of p-p38 MAPK and cleaved caspases and decrease of p-AKT were blocked by bvPLA2 treatment. These results indicate that increasing PLA2, including the group III sPLA2 is key to regulating PrP(106-126) mediated neurotoxicity. Taken together, the results of this study suggest that specific modulation of PLA2 appears to prevent neuronal cell death caused by prion peptides. PMID- 21701770 TI - Endosialin: a novel malignant cell therapeutic target for neuroblastoma. AB - Endosialin emerged recently as a potential therapeutic target for sarcoma. Since some sarcoma subtypes, such as Ewing's sarcoma, show characteristics of neuroendocrine differentiation, we wondered whether cancers with neuro-endocrine properties and/or neuroectodermal origin, such as neuroblastoma, small cell lung cancer and melanoma, may express endosialin. Endosialin protein expression was surveyed in neuroblastoma, small cell lung cancer and melanoma in human clinical specimens by immunohistochemistry (IHC) and in human cell lines by flow cytometry. Side population cells were examined to determine whether cancer stem cells can express endosialin. Endosialin-expressing neuroblastoma cell lines were implanted in immunodeficient mice and allowed to grow. The xenograft tumors were resected and tested for endosialin expression by IHC. In human clinical specimens, vascular endosialin staining was observed in neuroblastoma, small cell lung cancer and melanoma. Malignant cell staining was strongest in neuroblastoma, weak in melanoma and rare in small cell lung cancer. In human cell lines, endosialin was detected in neuroblastoma cell lines, including cancer stem cell like side population (SP) cells, but was absent in melanoma and was both rare and weak in small cell lung cancer. Human neuroblastoma xenograft tumors were found to be positive for endosialin. Our work suggests that endosialin may be a suitable therapeutic target for neuroblastoma. PMID- 21701771 TI - Heterogeneity of colorectal cancers and extraction of discriminator gene signatures for personalized prediction of prognosis. AB - Dissected specimens of colorectal cancer (CRC) have been intensively studied using molecular sketches (gene signatures) to obtain a set of discriminator gene signatures for accurate prognosis prediction in individual patients. The discriminators obtained so far are not universally applicable, as the gene sets reflect the method and site of the study. In this study, we show that dissected stage II and III CRC samples are significantly heterogeneous in molecular sketches, and are not appropriate sources for discriminator extraction unless handled individually. To search for an accurate discriminator gene set for prediction of metastases, we need to start with less heterogeneous stage II CRC. We examined 198 (92 stage II and 106 stage III) CRC dissected samples for the predictability of discriminator gene signatures by analyzing stage II CRC alone, stage III alone, or in combination. The best predictive power of discriminator genes was obtained only when these genes were extracted and validated with stage II CRC samples. An accurate discriminator gene set for the prediction of CRC metastases can be obtained by focusing on stage II CRC samples. PMID- 21701772 TI - Hedgehog signaling pathway regulates the growth of ovarian cancer spheroid forming cells. AB - The hedgehog (Hh) pathway has been shown to be activated in numerous malignancies as well as in cancer stem cells. We sought to determine the importance of the Hh pathway in regulating growth and development of ovarian cancer spheroid-forming cells (SFCs). Ovarian cancer cell lines (ES2, TOV112D, OV90, and SKOV3) as well as a normal ovarian epithelial cell line (IOSE80) were grown in non-adherent growth conditions to form SFCs. Western blot analysis was used to determine the expression of Hh pathway proteins SMOH, PTCH, GLI1. SFCs were treated with Hh agonists (SHH and IHH) as well as an Hh inhibitor (cyclopamine) to determine changes in spheroid growth and survival. All ovarian cancer cell lines readily formed spheroids in non-adherent growth conditions while IOSE80 failed to form SFCs. Compared to IOSE80, ovarian cancer cell lines demonstrated significant activation of the Hh pathway as defined by increased expression of intranuclear GLI1. Both Hh agonists demonstrated significant increases in spheroid volume of at least 42-fold for SHH-treated cells and 46-fold for IHH-treated cells. With regard to survival, SFCs were 30-50% more resistant to cyclopamine than their corresponding monolayer cells. Despite this resistance, inhibition of the Hh pathway with cyclopamine prevented further growth of SFCs with a 10-, 5-, and 4 fold restriction in growth for ES2, SKOV3, and TOV112D, respectively. The hedgehog pathway appears to be important in regulating growth of ovarian cancer spheroid-forming cells. The activation and inhibition of this pathway demonstrates significant correlation to enhanced growth and growth restriction, respectively. PMID- 21701773 TI - Combination effects of distinct cores in 11q13 amplification region on cervical lymph node metastasis of oral squamous cell carcinoma. AB - Lymph node metastasis (LNM) in oral squamous cell carcinoma (OSCC) is known to associate with a significant decrease of 5-year survival. Genetic factors related to the difference of the LNM status in the OSCC have been not fully elucidated. Array-based comparative genomic hybridization (CGH) with individual gene-level resolution and real-time quantitative polymerase chain reaction (QPCR) were conducted using primary tumor materials resected from 54 OSCC patients with (n=22) or without (n=32) cervical LNM. Frequent gain was observed at the 11q13 region exclusively in patients with cervical LNM, which was confirmed by real time QPCR experiments using 11 genes (TPCN2, MYEOV, CCND1, ORAOV1, FGF4, TMEM16A, FADD, PPFIA1, CTTN, SHANK2 and DHCR7) in this region. It was revealed that two distinct amplification cores existed, which were separated by a breakpoint between MYEOV and CCND1 in the 11q13 region. The combination of copy number amplification at CTTN (core 2) and/or TPCN2/MYEOV (core 1), selected from each core, was most significantly associated with cervical LNM (P=0.0035). Two amplification cores at the 11q13 region may have biological impacts on OSCC cells to spread from the primary site to local lymph nodes. Further study of a larger patient series should be conducted to validate these results. PMID- 21701774 TI - RNA interference against granulin-epithelin precursor prevents hepatocellular carcinoma growth: its application as a therapeutic agent. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. However, little is known regarding the molecular mechanism of HCC development and progression and effective therapeutic methods. Recently, the granulin-epithelin precursor (GEP) was reported as a novel growth factor that can control HCC cell proliferation. Using the CAPSID program, we designed three small interfering RNAs (siRNAs) targeting the GEP gene (GEP-siRNA1, 2 and 3) and examined their tumor regression and suppression effects on cell proliferation. GEP-siRNA1 exhibited the strongest anti-proliferative effect among the GEP-siRNAs, in a time-dependent manner. To increase the biostability of the siRNA, we also constructed a short hairpin RNA (shRNA) using an H1/TO promoter with the same sequence of GEP-siRNA1 (GEP-shRNA). GEP-shRNA decreased the expression levels of GEP and tumor cell growth via cell cycle arrest at the G2/M stage and down-regulation of the cell proliferation proteins cyclin D1 and alpha-tubulin. Furthermore, GEP-shRNA inhibited tumor growth significantly after intratumoral injection into tumor bearing Balb/C nude mice. Taken together, these results represent the first therapeutic application of RNA interference to GEP, which is a promising target molecule for HCC treatment, as an approach for the suppression of HCC cell proliferation. PMID- 21701775 TI - Identification of novel molecular targets regulated by tumor suppressive miR 1/miR-133a in maxillary sinus squamous cell carcinoma. AB - Based on our microRNA (miRNA) expression signature analysis of maxillary sinus squamous cell carcinoma (MSSCC), we found that miR-1 and miR-133a were significantly reduced in tumor tissues. Quantitative real-time RT-PCR revealed that the expression levels of miR-1 and miR-133a were significantly downregulated in clinical MSSCC tumor tissues compared with normal tissues. We focused on the functional significance of miR-1 and miR-133a in cancer cells and identification of the novel cancer networks regulated by these miRNAs in MSSCC. Restoration of downregulated miRNAs (miR-1 or miR-133a) in cancer cells revealed that both miRNAs significantly inhibited cancer cell proliferation and induced cell apoptosis. Molecular target identification of these miRNAs showed that transgelin 2 (TAGLN2) and purine nucleoside phosphorylase (PNP) were regulated by miR-1 and miR-133a. Both TAGLN2 and PNP mRNA expression levels were significantly upregulated in clinical MSSCC tumor tissues. Silencing studies of target genes demonstrated that both genes inhibited cancer cell proliferation. The identification of novel miR-1/miR-133a-regulated cancer pathways could provide new insights into potential molecular mechanisms of MSSCC oncogenesis. PMID- 21701777 TI - The effect of a novel antagonist of growth hormone releasing hormone on cell proliferation and on the key cell signaling pathways in nine different breast cancer cell lines. AB - Growth hormone releasing hormone (GHRH) antagonists have been developed for the treatment of various cancers. We investigated the effects of a novel GHRH antagonist, MIA-602, on nine breast cancer cell lines, differing in their expression for estrogen-, progesterone- and HER-2 receptors. We detected the presence of pituitary-type GHRH receptors (pGHRH-R) on 6 of the 9 breast cancer cell lines. The main splice variant of pGHRH-R, SV1, was found on all 9 cell lines. MTT assay showed that following treatment with MIA-602, cell viability decreased significantly in all 9 cell lines. The reduction in cell viability was greater in cells positive for both pGHRH-R and SV1, than in cells positive for only SV1, but the difference was not significant. Using Western blotting, we demonstrated that the levels of phospho-Akt, -GSK3beta and -ERK1/2 decreased significantly following exposure to MIA-602 and the level of phospho-p38 increased after treatment. The reduction of the phosphorylated anti-apoptotic proteins was significantly greater in cells where both pGHRH-R and SV1 were present, than where only SV1 was expressed. In conclusion, our study shows that MIA-602 is effective against a wide range of breast cancer cells in vitro, independently of their receptor positivity, suggesting the potential use of GHRH antagonists also in the treatment of triple-negative breast cancer. The effect of MIA-602 was mediated nearly as well in tumors that expressed only the SV1 receptor compared to those in which both SV1 and pGHRH-R were present, although a difference could be detected at the level of cell signaling. PMID- 21701776 TI - Transforming growth factor-beta-induced protein (TGFBI) suppresses mesothelioma progression through the Akt/mTOR pathway. AB - As an uncommon cancer, mesothelioma is very hard to treat with a low average survival rate owing to its usual late detection and being highly invasive. The link between asbestos exposure and the development of mesothelioma in humans is unequivocal. TGFBI, a secreted protein that is induced by transforming growth factor-beta in various human cell types, has been shown to be associated with tumorigenesis in various types of tumors. It has been demonstrated that TGFBI expression is markedly suppressed in asbestos-induced tumorigenic cells, while an ectopic expression of TGFBI significantly suppresses tumorigenicity and progression in human bronchial epithelial cells. In order to delineate a potential role of TGFBI in mediating the molecular events that occur in mesothelioma tumorigenesis, we generated stable TGFBI knockdown mutants from the mesothelium cell line Met-5A by using an shRNA approach, and secondly created ectopic TGFBI overexpression mutants from the mesothelioma cell line H28 in which TGFBI is absent. We observed that in the absence of TGFBI, the knockdown mesothelial and mesothelioma cell lines exhibited an elevated proliferation rate, enhanced plating efficiency, increased anchorage-independent growth, as well as an increased cellular protein synthesis rate as compared with their respective controls. Furthermore, cell cycle regulatory proteins c-myc/cyclin D1/phosphor-Rb were upregulated; a more active PI3K/Akt/mTOR signaling pathway was also detected in TGFBI-depleted cell lines. These findings suggest that TGFBI may repress mesothelioma tumorigenesis and progression via the PI3K/Akt signaling pathway. PMID- 21701778 TI - Predictive factors for the occurrence of idiopathic menorrhagia: evidence for a hereditary trait. AB - The aim of the present study was to assess predictive factors for occurrence of idiopathic menorrhagia (IM), a disease characterized by abnormal endometrial blood vessel morphology. It was hypothesized that IM exhibits familial clustering (suggesting inheritance) and is associated with other vascular abnormalities, primarily cutaneous hemangiomas. Women with IM (n=152) and healthy, regularly menstruating (n=56) women answered a questionnaire concerning menstrual pattern, susceptibility to bleeding and family history of abnormal gynecological bleeding. Factor analysis with principal component extraction was used to separate predictive factors that may be associated with IM. A total of 35 different items were analyzed. A strong association was found between IM and a family history of heavy menstrual bleeding (r=0.68), but not with cutaneous vascular abnormalities. Our results revealed that a family history of heavy menstrual bleeding may have the highest predictive value for the diagnosis of IM, indicating a hereditary trait. PMID- 21701779 TI - Analysis of CCL5 expression in classical Hodgkin's lymphoma L428 cell line. AB - CCL5 is one of the chemoattractant cytokines involved in inflammatory observed in both diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin's lymphoma (CHL). However, the pathological effects of CCL5 remain unclear. To gain a better understanding of the role of CCL5 in CHL and DLBCL, we examined the expression of CCL5 in the CHL cell line L428 and the DLBCL cell lines Ly1 and Ly8, as well as its chemotactic effect on CD4+ T cells. CCL5 mRNA expression was detected by real time quantitative RT-PCR. Intracellular CCL5 protein expression was analyzed using confocal microscopy, and CCL5 protein secretion was detected by ELISA. The chemotactic function of CCL5 was assessed using a Transwell coculture system, and the number of migrated CD4+ T cells was counted. Moreover, the p-ikBalpha and p65 levels of NF-kB signaling molecules in these lymphoma cell lines were detected by Western blotting. The results showed that CCL5 mRNA and protein expression in the L428 cells was significantly higher than in Ly1 and Ly8 cells (p<0.05). L428 cells secreted more CCL5 than the Ly1 or Ly8 cells, and the secreted CCL5 was capable of inducing CD4+ T cell migration. The expression levels of the NF-kB transcription factors p65 and p-ikBalpha were examined in these lymphoma cells. L428, Ly1 and Ly8 cells expressed similar levels of p65, while p-ikBalpha expression was higher in the L428 cells than in the Ly1 or Ly8 cells, indicating that a high CCL5 expression may be related to the increased activity of the NF-kB signaling pathway in L428 cells. PMID- 21701780 TI - Serum levels of beta-catenin as a potential marker for genotype 4/hepatitis C associated hepatocellular carcinoma. AB - The global rising incidence of hepatocellular carcinoma (HCC), which parallels the increase of hepatitis C virus (HCV) prevalence, has sparked a renewed interest in discovering additional HCC serum markers. In this study, we investigated the clinical use of serum E-cadherin, ICAM, MMP-2, VEGF, OPN and beta-catenin as potential diagnostic makers for HCV/genotype 4-associated HCC. Twenty cases of healthy subjects, 11 cases with asymptomatic HCV/genotype 4 carriers (ASC), 28 chronic hepatitis (CH) cases and 32 patients with HCC were enrolled in this study. Serum levels of proteins were measured by a sandwich enzyme-linked (ELISA) assay. The diagnostic accuracy of each candidate marker was evaluated using receiver-operating characteristic (ROC) curve analysis, reporting the area under the curve (AUC) and its 95% confidence interval (CI). We demonstrated that serum beta-catenin levels were significantly elevated in patients with HCC compared to those with CH, ASC and healthy controls. Among the six studied markers, beta-catenin was also found to be the only marker that can significantly discriminate between patients with HCC and those with CH; therefore, beta-catenin could be considered as a potential marker for early diagnosis of HCV-associated HCC in patients infected with HCV genotype 4. PMID- 21701781 TI - Downregulation of discoidin domain receptor 2 in A375 human melanoma cells reduces its experimental liver metastasis ability. AB - Discoidin domain receptors (DDR1 and DDR2) are tyrosine kinase receptors for fibrillar collagen implicated in postnatal development, tissue repair, and primary and metastatic cancer progression. While DDR1 has been described in tumor cells, DDR2 has been localized in the tumor stroma, but its presence in the tumor cells remains unknown. The aim of this study was to elucidate the role of DDR2 signaling in tumor cells during hepatic metastasis progression. DDR2 expression and phosphorylation in cultured human A375 melanoma cells was documented by Western blot analysis. A375 cells were stably transfected with a small interfering RNA (siRNA) against DDR2 and two clones were selected: A375R2-70 and A375R2-40, with 70 and 40% of the DDR2 protein expression respectively, compared to mock-transfected cells (A375R2-100). Development of experimental liver metastasis by intrasplenic inoculation of A375R2-70 and A37R2-40 clones was reduced by 60 and 75%, respectively, measured as tumor volume, compared to livers injected with A375R2-100 cells. Accordingly, A375R2-70 and A37R2-40 clones showed reduced in vitro gelatinase activity and JNK phosphorylation, compared to mock transfected cells, with maximal inhibition in A375R2-40. Additionally, A375 melanoma, SK-HEP hepatoma and HT-29 colon carcinoma human cell lines transiently transfected with siRNA against DDR2 also showed reduced proliferation and migration rates compared to mock-transfected ones. In conclusion, DDR2 promotes A375 melanoma metastasis to the liver and the underlying mechanism implicates regulation of metalloproteinase release, cell growth and chemotactic invasion of the host tissue. PMID- 21701782 TI - Cytokeratins negatively regulate the invasive potential of lung cancer cell lines. AB - Lung cancer cells express several cytokeratins (CKs) that are subdivided into type I (CK9-23) and type II (CK1-8) subclasses. The functions of CKs in lung cancer cells have not been fully elucidated. The purpose of this study was to investigate the role of CKs in the invasion of lung cancer cells. We investigated the expression levels of CK7, 8, 18 and 19 in 12 non-small cell lung cancer (NSCLC) and seven SCLC cell lines by quantitative immunoblotting. The expression levels of these four CKs were significantly higher in the NSCLC cells. The NSCLC cell line HI1017 expressed CK8 and 18; A549 cells expressed CK7, 8, 18 and 19, respectively. Invasive sublines of HI1017 and A549 were established by repeated selection of invasive cells using a membrane invasion chamber system. The invasive cell lines showed lower expression levels of CKs compared with the parental cells. Exogenous CK19 also resulted in a decrease in invasiveness of the HI1017 cells. Suppression of either CK8 or CK18 by short interfering RNAs led to a decrease in the total CKs and increased invasiveness of both the HI1017 and A549 cells. A549 cells expressed very low levels of CK19. Suppression of CK19 affected neither invasive ability nor total CK amount in the A549 cells. Our observations indicate that CK expression levels were inversely associated with invasiveness of the NSCLC cell lines, and suggest that expression levels of dominant CKs may affect invasive ability. PMID- 21701783 TI - Asterosaponin 1 induces endoplasmic reticulum stress-associated apoptosis in A549 human lung cancer cells. AB - Asterosaponin 1, a new cytostatic agent from starfish, possesses several bioactivities including an antitumor effect. The aim of this study was to investigate the potential anti-proliferative and pro-apoptotic activity of asterosaponin 1 in A549 human lung cancer cells, as well as the potential mechanisms. The results showed that asterosaponin 1 inhibited the proliferation of A549 cells in a dose-dependent manner, and the cytostatic activity resulted from the induction of apoptotic cell death. Asterosaponin 1 increased ER dilation and cytosolic Ca2+ concentration, and enhanced the expression of the ER molecular chaperones GRP78 and GRP94 in a dose- and time-dependent manner. In addition, asterosaponin 1 treated A549 cells exerted increased expression and activity of CHOP, caspase-4 and JNK, three essential ER-associated apoptotic molecules. In summary, these results demonstrated that asterosaponin 1 inhibits the proliferation of A549 cells through induction of ER stress-associated apoptosis, making asterosaponin 1 a candidate new anticancer drug for lung cancer therapy. PMID- 21701784 TI - A polymorphism of the interferon-gamma-inducible protein 30 gene is associated with hyperglycemia in severely obese individuals. AB - A previous expression profiling of visceral adipose tissue (VAT) revealed that the immune response gene interferon-gamma-inducible protein 30 (IFI30) gene was 1.72-fold more highly expressed in non-diabetic severely obese men with the metabolic syndrome as compared to those without. Given the importance of low grade inflammation in obesity-related metabolic complications, we hypothesized that variants in the IFI30 gene are associated with cardiovascular disease (CVD) risk factors. A detailed genetic investigation was performed at the IFI30 locus by sequencing its promoter, exons and intron-exon junction boundaries using DNA of 25 severely obese men. Among the 21 sequence-derived single-nucleotide polymorphisms (SNPs), 5 tagged SNPs (covering 100% of the common SNPs identified) were genotyped in two independent samples of severely obese patients (total n = 1,283). Using a multistage experimental design, chi-square analyses and logistic regressions were performed to compare genotype frequencies and compute odds ratios (OR) for low and high CVD risk groups (dyslipidemia, hyperglycemia/diabetes and hypertension). A significant association was observed with the non-synonymous SNP rs11554159 (p.R76Q), where GA individuals showed lower risk (OR = 0.67; P = 0.0009) for hyperglycemia/diabetes as compared to homozygotes for the major allele (GG). No association was observed between rs11554159 and VAT IFI30 mRNA levels (P = 0.81), and the expression levels were not correlated with fasting plasma glucose levels (P = 0.31) in 112 non-diabetic severely obese women. The localization of rs11554159 near the active site of IFI30 suggests a functional effect of this SNP. This study showed a novel association between rs11554159 (p.R76Q) polymorphism at the IFI30 locus and the risk of hyperglycemia/diabetes in severely obese individuals. PMID- 21701785 TI - Novel variant Pro143Ala in HTRA2 contributes to Parkinson's disease by inducing hyperphosphorylation of HTRA2 protein in mitochondria. AB - Mutations in the gene encoding the mitochondrial protein high temperature requirement A2 (HTRA2) are inconsistently associated with a risk of Parkinson's disease (PD). We assessed the presence of HTRA2 mutations among patients with PD and performed functional assay of identified mutations or variants. Among the total 1,373 subjects, the entire HTRA2 coding region was sequenced in 113 early onset PD (EOPD), 20 familial PD patients and 150 control subjects. An additional 390 sporadic late-onset PD patients and 700 controls were subsequently screened to validate possible mutations found in the first set. We identified two novel heterozygous variants, c.427C > G (Pro143Ala) and c.906 +3 G > A, in 2 (1.5%) EOPD patients. The missense variant, Pro143Ala, was also observed in one late onset PD patient but was absent in total 850 control subjects (relative risk 2.3, 95% CI 1.5-2.8, P = 0.04). Expressing Pro143Ala variant of HTRA2 in primary dopaminergic neurons causes neurite degeneration. Following exposure to rotenone, the ultra-structural mitochondrial abnormality, the percentage of mitochondrial dysfunction and apoptosis in cells carrying the HTRA2 Pro143Ala variant was significantly higher than wild-type cells. Mechanistically, protein level of phosphorylated HTRA2 was increased in cells carrying the Pro143Ala variant, suggesting Pro143Ala variant promotes HTRA2 phosphorylation with resultant mitochondrial dysfunction. Our results support a biologically relevant role of HTRA2 in PD susceptibility in Taiwanese. Further large-scale association studies are warranted to confirm the role of HTRA2 Pro143Ala variant in the risk of PD. PMID- 21701786 TI - Risk factors for autism: translating genomic discoveries into diagnostics. AB - Autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in communication and reciprocal social interaction, and the presence of restricted and repetitive behaviors. The spectrum of autistic features is variable, with severity of symptoms ranging from mild to severe, sometimes with poor clinical outcomes. Twin and family studies indicate a strong genetic basis for ASD susceptibility. Recent progress in defining rare highly penetrant mutations and copy number variations as ASD risk factors has prompted early uptake of these research findings into clinical diagnostics, with microarrays becoming a 'standard of care' test for any ASD diagnostic work-up. The ever changing landscape of the generation of genomic data coupled with the vast heterogeneity in cause and expression of ASDs (further influenced by issues of penetrance, variable expressivity, multigenic inheritance and ascertainment) creates complexity that demands careful consideration of how to apply this knowledge. Here, we discuss the scientific, ethical, policy and communication aspects of translating the new discoveries into clinical and diagnostic tools for promoting the well-being of individuals and families with ASDs. PMID- 21701787 TI - A regulatory domain is required for Foxn4 activity during retinogenesis. AB - Foxn4, a member of the N-family forkhead transcription factors, controls fate decision in mouse retina and spinal cord as well as in zebrafish heart. Analysis of Foxn4 amino acid sequence revealed the presence of a region homologous to the activation domain of its close relative Foxn1 in between C-terminal amino acids 402 and 455 of Foxn4 protein. The requirement of Foxn4 putative activation domain remains to be elucidated. Using a gain-of function approach in rat and chick retinal explants, we report that deletion of Foxn4 putative activation domain results in a complete loss of its activity during retinogenesis. Target promoter transcription assay indicates that this domain is critical for Foxn4 transcriptional regulatory properties in vitro. Accordingly, in chick retinal explants, this domain is required for proper regulation of target retinogenic factors expression by Foxn4. Thus, our study demonstrates that the domain between amino acids 402 and 455 is necessary for Foxn4 transcriptional activity both in vitro and in the retina. PMID- 21701788 TI - Neuroprotective effect of cyclooxygenase inhibitors in ICV-STZ induced sporadic Alzheimer's disease in rats. AB - Sporadic Alzheimer's disease is an age-related neurological and psychiatric disorder characterized by impaired energy metabolism. Oxidative stress and neuroinflammation have been implicated in pathophysiology of sporadic type of dementia. The central streptozotocin administration induces behavioral and biochemical alterations resembling those in sporadic type of Alzheimer's patients. The present study was designed to investigate the effects of chronic pretreatment with cyclooxygenase-1 or cyclooxygenase-2 or cyclooxygenase-3 selective inhibitors on cognitive dysfunction and oxidative stress markers in intracerebroventricular streptozotocin-treated rats. Chronic treatment with valeryl salicylate (5 and 10 mg/kg, i.p.) and etoricoxib (5 and 10 mg/kg, i.p.) on a daily basis for a period of 21 days, beginning 1 h prior to first intracerebroventricular streptozotocin injection, significantly improved streptozotocin-induced cognitive impairment. However, phenacetin (20 and 40 mg/kg, i.p.) failed to restore the cognitive performances of streptozotocin treated rats. Besides, improving cognitive dysfunction, chronic administration of highly selective cyclooxygenase-1 and/or cyclooxygenase-2 inhibitors (valeryl salicylate and etoricoxib, respectively), but not cyclooxygenase-3 inhibitor (phenacetin), significantly reduced elevated malondialdehyde, nitrite levels, and restored reduced glutathione and superoxide dismutase levels. Furthermore, cyclooxygenase-1 and/or cyclooxygenase-2 inhibitors significantly increased the survival of pyramidal neurons. In summary, we demonstrate for the first time that both cyclooxygenase-1 and cyclooxygenase-2 isoforms, but not cyclooxygenase-3, are involved in the progression of neuronal damage in intracerebroventricular streptozotocin-treated rats. PMID- 21701789 TI - Prothrombin G20210A and factor V Leiden polymorphisms in stroke. AB - The molecular epidemiology of stroke is critically lacking in the developing world. We explored the relationships between genetics polymorphism and risk for ischemic stroke among the residents of Casablanca, Morocco. Ninety-one stroke patients matched 1:2 for their age, gender, and ethnic background to 182 healthy controls who were genotyped for the prothrombin G20210A mutation and factor V (FV) Leiden and were assessed for conventional risk factors for stroke. No significant association was found between prothrombin gene mutation with stroke (p = .054). Regarding stroke subtypes, significant relationships between patients with a large artery disease subtype of stroke and this mutation was found compared to controls (p = .046). As a genetic risk factor to develop this event, a strong association was observed when adjusted for conventional vascular risk factors (adjusted OR, 4.3; p = .029). No FV Leiden was found. We suggest that prothrombin mutation but not FV Leiden should be considered as a modest genetic risk factor for large artery disease stroke subtype in the Moroccan population. PMID- 21701790 TI - Sall3 correlates with the expression of TH in mouse olfactory bulb. AB - Sall3 is a member of a gene family with homology to the spalt gene of Drosophila melanogaster, encoding transcription factors, and acts as downstream target of hedgehog. Vertebrate homologues of spalt have been shown to be involved in development of the limbs and nervous system and several organs including the kidney and heart; mutations in the genes are implicated in several human genetic disorders. Recent studies have shown a total loss of olfactory bulb (OB) dopaminergic (DA) neurons in Sall3-null mice. We assume that tyrosine hydroxylase (TH) may be regulated by Sall3 in OB. In this study, we find that Sall3 and TH co localize in glomerular layer (GL) of OB. Furthermore, we demonstrate a significant induction of the proximal TH promoter transcription activity by Sall3 in dual-luciferase reporter assay and a reduction of TH expression level in Sall3 deficient cell lines. Collectively, these findings support the notion that Sall3 correlates with the expression of TH in mouse OB and may have a role in OB DA neuron development by regulating TH gene expression. The results from this study may advance our understanding of the molecular pathways of OB in the DA neuron development and differentiation. PMID- 21701791 TI - A random comparative study of terbinafine versus griseofulvin in patients with tinea capitis in Western China. AB - OBJECTIVE: To compare the efficacy and safety of terbinafine with griseofulvin in the treatment of tinea capitis in Western China. METHODS: Children (2-14 years of age) with clinically diagnosed and potassium hydroxide microscopy-confirmed tinea capitis were randomized into three groups: group GRI4 received 4 weeks of griseofulvin; group TBF2 received 2 weeks of terbinafine; and Group TBF4 received 4 weeks of terbinafine. Clinical and mycological evaluations were done in 0, 2, 4, and 8 weeks and 1 year after therapy started. The isolated pathogenic fungi were evaluated for in vitro susceptibility by detecting the minimal inhibitory concentration (MIC) against terbinafine, griseofulvin, itraconazole, and ketoconazole. RESULTS: The clinical effectiveness rate of GRI4, TBF2, and TBF4 were 100% (95% CI-confidence interval: 82-100%), 96.3% (95% CI: 81-100%), and 100%(95% CI: 85-100%), respectively, at week 8 and 100% after 1 year for the 3 groups; clinical cure rates were 84.2%(95% CI: 77-99%), 85.2%(95% CI: 71-98%), and 78.3%(95% CI: 61-95%), respectively, at week 8 and 100% after 1 year for all agents; mycological cure rates were 100%(95% CI: 74-100%), 95.0%(95% CI: 74 100%), and 94.1%(95% CI: 50-93%) at week 8 and 100% after 1 year for the 3 groups. In vitro, all patient-derived cultures were sensitive to the four antifungal agents. CONCLUSION: Data from the clinical trial and in vitro antifungal activity indicated that terbinafine is efficacious and well tolerated in the treatment for Trichophyton infections (T. violaceum; Arthroderma vanbreuseghemii; and T. tonsurans) of the scalp, i.e., a 2- to 4-week course of terbinafine is as effective as a 4-week course of griseofulvin; in fact, a 2-week course of terbinafine is sufficient. Terbinafine is an effective alternative to griseofulvin against tinea capitis of Trichophyton infections. PMID- 21701792 TI - Phenotypic and molecular identification of Sporothrix isolates from an epidemic area of sporotrichosis in Brazil. AB - Sporotrichosis has significantly increased in Brazil in the last decade, particularly in the state of Rio de Janeiro, with the occurrence of an epidemic related to zoonotic transmission from cats to humans. Recently, four new phylogenetic species were incorporated into the Sporothrix species complex based on the phenotypic and molecular characteristics, and a new species name (Sporothrix brasiliensis) was proposed for some of the Sporothrix isolates from this epidemic. This study describes the characterization of 246 isolates obtained from patients attending the Laboratory of Infectious Dermatology, IPEC-FIOCRUZ, between 1998 and 2008, together with one environmental sample. Two hundred and six of the isolates (83.4%) were characterized as S. brasiliensis, 15 (6.0%) as S. schenckii, and one (0.5%) as S. mexicana. Twenty-five isolates (10.1%) could not be identified according to their phenotype and were classified as Sporothrix spp. The calmodulin gene was sequenced to confirm the identity of these isolates. The molecular analysis demonstrated that 24 of the isolates were S. brasiliensis, with the remainder being a S. globosa isolate. The isolate characterized phenotypically as S. mexicana was clustered on the S. schenckii clade. The correlation between molecular data and phenotypic characteristics described in this study is fundamental to the identification of the Sporothrix complex. PMID- 21701793 TI - Investigating the candidacy of lipopolysaccharide-based glycoconjugates as vaccines to combat Mannheimia haemolytica. AB - Inner core lipopolysaccharide (LPS) has been shown to be conserved in the majority of veterinary strains from the species Mannheimia haemolytica, Actinobacillus pleuropneumoniae and Pasteurella multocida and as such is being considered as a possible vaccine antigen. The proof-in-principle that a LPS-based antigen could be considered as a vaccine candidate has been demonstrated from studies with monoclonal antibodies raised to the inner core LPS of Mannheimia haemolytica, which were shown to be both bactericidal and protective in a mouse model of disease. In this study we confirm and extend the candidacy of the inner core LPS by demonstrating that it is possible to elicit functional antibodies against Mannheimia haemolytica wild-type strains following immunisation of rabbits with glycoconjugates elaborating the conserved inner core LPS antigen. The present study describes a conjugation strategy that uses amidases produced by Dictyostelium discoideum, targeting the amino functionality created by the amidase activity as the attachment point on the LPS molecule. To protect the amino functionality on the phosphoethanolamine (PEtn) residue of the inner core, we developed a novel blocking and unblocking strategy with t-butyl oxycarbonyl. A maleimide-thiol linker strategy with the thiol linker on the carboxyl residues of the carrier protein and the maleimide linker on the carbohydrate resulted in a high loading of carbohydrates per carrier protein. Immunisation derived antisera from rabbits recognised fully extended Mannheimia haemolytica LPS and whole cells from serotypes 1 and 2, despite a somewhat immunodominant response to the linkers also being observed. Moreover, bactericidal activity was demonstrated to a strain elaborating the immunising carbohydrate antigen and crucially to wild-type cells of serotypes 1 and 2, thus further supporting the consideration of inner core LPS as a potential vaccine antigen to combat disease caused by Mannheimia haemolytica. PMID- 21701794 TI - Experimental approaches for high-resolution in vivo imaging of islet of Langerhans biology. AB - Under physiological conditions and in the pathogenesis of diabetes mellitus systemic influences play a substantial role for function and survival of cells of the islet of Langerhans. Therefore, in vivo studies to understand islet biology are indispensible and imaging techniques are increasingly used for this purpose. Among the diverse imaging modalities currently only laser scanning microscopy (LSM) allows resolution and visualization of individual cells and cellular processes. To overcome limited tissue penetration and working distance of LSM and enable in vivo investigations of islet cell physiology, various experimental approaches have been developed. Especially, the recently developed imaging platforms have significantly improved the possibility to study islets at a cellular level in vivo, and provided novel insight into islet biology in health and disease. The various approaches, their applications, and reported results, as well as their limitations are reviewed in this article. PMID- 21701795 TI - 18F-FDG PET versus PET/CT as a diagnostic procedure for clinical suspicion of large vessel vasculitis. PMID- 21701796 TI - Indirect comparison of etanercept, infliximab, and adalimumab for psoriatic arthritis: mixed treatment comparison using placebo as common comparator. AB - Psoriatic arthritis (PsA) is a chronic inflammatory joint disorder that is commonly associated with skin psoriatic lesions and can lead to severe disability. Current pharmacologic therapy for PsA includes TNFalpha-blocking agents for patients who are intolerant of or have an inadequate response to conventional disease-modifying antirheumatic drugs. Currently, there are no published randomized controlled trials providing a head-to-head comparison of the effectiveness of the three TNFalpha-blocking agents used most often to treat patients with PsA (adalimumab, etanercept, and infliximab). In this study, we have performed the first indirect comparison among these biologic agents, in this setting, using a mixed treatment comparison analysis of the data from pivotal trials regarding efficacy profiles of adalimumab, etanercept, and infliximab evaluated as American College of Rheumatology (ACR) 20 response. Our results suggest that etanercept is expected to provide the greatest ACR20 response among the anti-TNFalpha agents compared with placebo in the treatment of patients with PsA unresponsive to conventional treatments. This analysis may be relevant for clinical decision-making, hence improving the management of PsA patients. PMID- 21701797 TI - Relationship between psoriatic arthritis and moderate-severe psoriasis: analysis of a series of 166 psoriatic arthritis patients selected from a hospital population. AB - The aim of the study was to assess the prevalence of moderate to severe psoriasis (MS-P) in patients with psoriatic arthritis (PsA) and the relationship between MS P and other variables related to arthritis. One hundred sixty-six consecutive patients with PsA periodically monitored at a university hospital's PsA unit in northeastern Spain were included in the study. Patients with psoriasis were classified as having MS-P when systemic treatment for skin was required. Clinical criteria for treatment indication was BSA >10 and/or PASI >14 and/or psoriasis affecting a very sensitive area of the body. Demographic and clinical data related to arthritis were assessed, including PsA pattern, age of onset of psoriasis and arthritis, disease activity index, and treatment required over the course of the disease. Moderate-severe psoriasis were more prevalent in women (p = 0.027). One hundred nine patients (65.7%) had psoriatic nail disease, and MS-P was more frequent in these patients (40 (77%) vs. 69 (61%), p = 0.028). Patients with spondyloarthropathy were significantly associated with MS-P (7 (16%) vs. 3 (3%), p = 0.014). No statistical association was observed between severe psoriasis and the age of onset of psoriasis or arthritis, involvement of distal interphalangeal joints, laboratory findings (HLA B27, RF), functional class, or disease activity indices. We report a high prevalence of severe psoriasis among patients with psoriatic arthritis, higher in women and patients with psoriatic nail disease and axial spondyloarthropathy. PMID- 21701798 TI - Methanolic extract of leaves of Jasminum grandiflorum Linn modulates oxidative stress and inflammatory mediators. AB - The leaves of Jasminum grandiflorum (JG) are in clinical use in Ayurveda for wound management. Since, oxidative stress and inflammation are the primary causes in delayed wound healing, so here its antioxidant and anti-inflammatory activities have been investigated using in vitro as well as in vivo models. The solvent-free methanolic extract of dried leaves of JG were tested for its trapping capacity toward pre-generated ABTS*+ radicals, instantly generated superoxide and hydroxyl radicals, along with metal chelation property, reducing power and total phenolic content. Further, it was tested on LPS-induced nitric oxide and cell viability, on primary culture of rat peritoneal macrophages. Its anti-inflammatory property was also tested on carrageenan-induced paw edema in rats. This extract significantly inhibited iron-induced lipid peroxidation and trapped ABTS*+, superoxide and OH radicals. It significantly inhibited nitric oxide (NO) release, without affecting the cell viability at 800 MUg/ml concentration and reduced the formation of paw edema in rats. Thus, it could be suggested that the aforesaid anti-inflammatory properties of JG leaves are associated to its high phenolic content (2.25+/-0.105 mg/l of gallic acid equivalent), reducing power and its free radical-scavenging property. PMID- 21701799 TI - Ectopic mandibular third molar in subcondylar region: report of a rare case. AB - BACKGROUND: A tooth is ectopic if it is malpositioned due to congenital factors or displaced by the presence of pathology. Recent literature review suggests only 14 cases of ectopic mandibular third molar in the condylar region. Most have been treated using an extra-oral or endoscopic approach. Patients with an ectopic tooth impaction can remain asymptomatic over the course of their lifetime. But when such a tooth is accompanied by a cyst, patients can experience significant morbidity and require intervention. CASE REPORT: This report presents a case of ectopic mandibular third molar in the left subcondylar region associated with pain and trismus. DISCUSSION: Ectopic eruption of teeth is rare and reported in the mandibular condyle, coronoid process, orbit, palate, nasal cavity, nasal septum, chin and the maxillary antrum. Management of such cases should be meticulously planned on the basis of the position and type of the ectopic tooth and related potential trauma which could be caused by surgical intervention. PMID- 21701801 TI - Intravenous dexmedetomidine for treatment of intraoperative penile erection. AB - BACKGROUND: Intraoperative penile erections following the initiation of either regional or general anaesthesia is rare; however, when it occurs in patients undergoing urologic procedures it may delay, or even cancel the planned surgery. The aetiology is unclear. Various treatments proposed for producing detumescence are not always effective. Use of intracavernous alpha-adrenergic agonists is an efficient and rapid but short-lasting treatment. Furthermore, repeated intracavernous injections of vasoactive drugs may be harmful. Dexmedetomidine is a potent, selective alpha(2)-adrenoreceptor agonist. In our study, we evaluated the effect of dexmedetomidine on intraoperative penile erection. METHODS: Penile erection developed during an endoscopic procedure in 12 more than 7,800 patients. Anaesthesia used was general in 3 patients, epidural in 1 patient and spinal in 8 patients. The erection rigidity was evaluated by the operating urologist. Dexmedetomidine was diluted in normal saline to a concentration of 4 MUg/ml. In all of the cases, 0.5 MUg/kg dexmedetomidine was injected intravenously. RESULTS: The incidence of intraoperative penile erection was 0.34% for general anaesthesia, 0.11% spinal anaesthesia and 1.72% epidural anaesthesia at our institution. Detumescence was achieved in 9 patients during the first 5 min and in one patient at the 9th minute after a single intravenous dexmedetomidine (83%). There was no detumescence in two patients after 15 min (17%). CONCLUSION: This study demonstrated that 0.5 MUg/kg intravenous injection of dexmedetomidine is a simple, effective and safe method for immediate relief of intraoperative penile erection with high success rate. PMID- 21701802 TI - Population densities in relation to bladder cancer mortality rates in America from 1950 to 1994. AB - OBJECTIVE: Previous studies have reported that bladder cancer risks are elevated in industrial and urban areas. The cause is believed to be the result of occupational exposure from industries located in urban areas. Recent studies suggest that traffic air pollution may also increase bladder cancer risks. The study purpose is to investigate the relationship between bladder cancer mortality and population density of counties in America. Another objective is to explore traffic air pollution and industrial exposures as risk factors. MATERIALS AND METHODS: Bladder cancer mortality rates for white men and women from 1950 to 1994 and population densities (population per 10 square miles) of 2,248 counties were the basis of the study. A linear regression analysis was performed to evaluate the relationship between bladder cancer mortality rates and population densities after log transforming the population density data set. In addition, the counties were divided into quartiles based on bladder cancer mortality rates. Mean population density values with 95% confidence intervals for the quartiles were computed. RESULTS: Correlation coefficients (R) between bladder cancer mortality rates and the population densities were R = .37, P < .001 for men and R = .28, P < .001 for women. In addition, population densities increased with increasing bladder cancer mortality rates across all quartiles. The mean population density of the highest quartile was more than ten times higher than the lowest. CONCLUSIONS: In this study, we found a strong association between bladder cancer mortality and population density. Traffic air pollution is a potential cause. PMID- 21701803 TI - Polymer-mediated immunocamouflage of red blood cells: effects of polymer size on antigenic and immunogenic recognition of allogeneic donor blood cells. AB - Developing a practical means of reducing alloimmunization in chronically transfused patients would be of significant clinical benefit. Immunocamouflaging red blood cells (RBCs) by membrane grafting of methoxypoly(ethylene glycol) (mPEG) may reduce the risk of allo-immunization. The results of this study showed that antibody recognition of non-ABO antigens was significantly reduced in an mPEG-dose- and polymer size-dependent manner, with higher molecular weight mPEGs providing better immunoprotection. Furthermore, in vivo immunogenicity was significantly reduced in mice serially transfused with mPEG-modified xenogeneic (sheep; sRBCs), allogeneic (C57Bl/6), or syngeneic (Balb/c) RBCs. Following a primary transfusion of sRBCs, mice receiving mPEG-sRBCs showed a >90% reduction in anti-sRBC IgG antibody levels. After two transfusions, mice receiving mPEG sRBCs showed reductions of >80% in anti-sRBC IgG levels. Importantly, mPEG modified autologous cells did not induce neoantigens or an immune (IgG or IgM) response. These data suggest that the global immunocamouflage of RBCs by polymer grafting may provide a safe and cost-effective means of reducing the risk of alloimmunization. PMID- 21701804 TI - Molecular variation and evolution of the tyrosine kinase domains of insulin receptor IRa and IRb genes in Cyprinidae. AB - The insulin receptor (IR) gene plays an important role in regulating cell growth, differentiation and development. In the present study, DNA sequences of insulin receptor genes, IRa and IRb, were amplified and sequenced from 37 representative species of the Cyprinidae and from five outgroup species from non-cyprinid Cypriniformes. Based on coding sequences (CDS) of tyrosine kinase regions of IRa and IRb, molecular evolution and phylogenetic relationships were analyzed to better understand the characteristics of IR gene divergence in the family Cyprinidae. IRa and IRb were clustered into one lineage in the gene tree of the IR gene family, reconstructed using the unweighted pair group method with arithmetic mean (UPGMA). IRa and IRb have evolved into distinct genes after IR gene duplication in Cyprinidae. For each gene, molecular evolution analyses showed that there was no significant difference among different groups in the reconstructed maximum parsimony (MP) tree of Cyprinidae; IRa and IRb have been subjected to similar evolutionary pressure among different lineages. Although the amino acid sequences of IRa and IRb tyrosine kinase regions were highly conserved, our analyses showed that there were clear sequence variations between the tyrosine kinase regions of IRa and IRb proteins. This indicates that IRa and IRb proteins might play different roles in the insulin signaling pathway. PMID- 21701805 TI - Non-Smad signaling pathways. AB - Transforming growth factor-beta (TGFbeta) is a key regulator of cell fate during embryogenesis and has also emerged as a potent driver of the epithelial mesenchymal transition during tumor progression. TGFbeta signals are transduced by transmembrane type I and type II serine/threonine kinase receptors (TbetaRI and TbetaRII, respectively). The activated TbetaR complex phosphorylates Smad2 and Smad3, converting them into transcriptional regulators that complex with Smad4. TGFbeta also uses non-Smad signaling pathways such as the p38 and Jun N terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways to convey its signals. Ubiquitin ligase tumor necrosis factor (TNF)-receptor-associated factor 6 (TRAF6) and TGFbeta-associated kinase 1 (TAK1) have recently been shown to be crucial for the activation of the p38 and JNK MAPK pathways. Other TGFbeta induced non-Smad signaling pathways include the phosphoinositide 3-kinase-Akt mTOR pathway, the small GTPases Rho, Rac, and Cdc42, and the Ras-Erk-MAPK pathway. Signals induced by TGFbeta are tightly regulated and specified by post translational modifications of the signaling components, since they dictate the subcellular localization, activity, and duration of the signal. In this review, we discuss recent findings in the field of TGFbeta-induced responses by non-Smad signaling pathways. PMID- 21701806 TI - Formalin for haemorrhagic radiation-induced proctitis. PMID- 21701807 TI - Diagnostic accuracy of C-reactive protein and white blood cell counts in the early detection of inflammatory complications after open resection of colorectal cancer: a retrospective study of 1,187 patients. AB - PURPOSE: Although widely used, there is a lack of evidence concerning the diagnostic accuracy of C-reactive protein (CRP) and white blood cell counts (WBCs) in the postoperative period. The aim of this study was to evaluate the diagnostic accuracy of CRP and WBCs in predicting postoperative inflammatory complications after open resection of colorectal cancer. METHODS: In this retrospective study, clinical data and the CRP and WBCs, routinely measured until postoperative day 5 (POD 5), were available for 1,187 patients who underwent colorectal cancer surgery between 1997 and 2009. Using the receiver-operating characteristic (ROC) methodology, the diagnostic accuracy was evaluated according to the area under the curve (AUC). RESULTS: Three hundred forty-seven patients (29.2%; 95% CI, 26.7-31.9%) developed various inflammatory complications. Anastomotic leakage occurred in 8.0% (95% CI, 6.1-9.1%) of patients. The CRP level on POD 4 (AUC 0.76; 95% CI, 0.71-0.81) had the highest diagnostic accuracy for the early detection of inflammatory complications. With a cutoff of 123 mg/l, the sensitivity was 0.66 (95% CI, 0.56-0.74), and the specificity was 0.77 (95% CI, 0.71-0.82). The diagnostic accuracy of the WBC was significantly lower compared to CRP. CONCLUSION: Measurement of CRP on POD 4 is recommended to screen for inflammatory complications. CRP values above 123 mg/l on POD 4 should raise suspicion of inflammatory complications, although the discriminatory performance was insufficient to provide a single threshold that could be used to correctly predict inflammatory complications in clinical practice. WBC measurement contributes little to the early detection of inflammatory complications. PMID- 21701808 TI - Laparoscopic surgery for rectal cancer: a single-centre experience of 120 cases. AB - INTRODUCTION: For colorectal surgeons, laparoscopic rectal cancer surgery poses a new challenge. The defence of the questionable oncological safety tempered by the impracticality of the long learning curve is rapidly fading. As a unit specialising in minimally invasive surgery, we have routinely undertaken rectal cancer surgery laparoscopically since 2005. METHODS: Patients undergoing surgery for rectal cancer between June 2005 and February 2010 were retrospectively reviewed from a prospectively maintained colorectal cancer database. RESULTS: One hundred and thirty patients underwent surgery for rectal cancer during the study period. One hundred and twenty patients had a laparoscopic resection, six were converted to open (conversion rate 5%) and 10 had a planned primary open procedure. Fifty four were low rectal tumours and 76 were upper rectal tumours. One hundred and thirteen patients had an anterior resection (87%), 17 patients an abdomino-perineal resection (13%) and 62 of the 130 patients (47.6%) had neoadjuvant radiotherapy. The median lymph node retrieval rate was 12 (9-14), five patients (3.8%) had a positive circumferential margin and the clinical anastomotic leak rate was 3.8% (n = 5 patients). There was no significant difference in the stated parameters for neoadjuvant versus non-neoadjuvant patients and for upper versus lower rectal tumours. Ninety three percent of mesorectal excision specimens were complete on pathological assessment. CONCLUSIONS: During the study period, 92% of rectal cancers underwent a laparoscopic resection with low rates of morbidity and acceptable short-term oncological outcomes. This data supports the view that laparoscopic surgery for rectal cancer can be safely delivered in mid-volume centres by surgeons who have completed the learning curve for laparoscopic colorectal surgery. PMID- 21701809 TI - Laparoscopic fistula excision and omentoplasty for high rectovaginal fistulas: a prospective study of 40 patients. AB - AIM: The aim of this study is to prospectively evaluate 40 patients with a high rectovaginal fistula treated by a laparoscopic fistula division and closure, followed by an omentoplasty. PATIENTS AND METHODS: Forty patients with a rectovaginal fistula, between the middle third of the rectum and the posterior vaginal fornix, resulting from different causes (IBD, iatrogenic and birth trauma) were treated by a laparoscopic excision of the fistula and insertion of an omentoplasty in the rectovaginal septum. The patients completed the gastrointestinal quality of life index questionnaire (GIQLI) and the Cleveland Clinic incontinence score (CCIS). All tests were performed at regular intervals after treatment. RESULTS: In 38 (95%) patients with a median age of 53 years (range 33-72), the surgical procedure was feasible. In two patients, the fistula was closed without an omentoplasty, and a diverting stoma was performed. The median follow-up was 28 months (range 10-35). Two patients (5%) developed a recurrent fistula. In one patient, the interposed omentum became necrotic and was successfully treated laparoscopically. In another patient, an abscess developed, which needed drainage procedures. The mean CCIS was 9 (range 7-10) before treatment and 10 (range 7-13) after treatment (p = 0.5 Wilcoxon). The median GIQLI score was 85 (range 34-129) before treatment and 120 (range75-142) after treatment (p = 0.0001, Wilcoxon). CONCLUSIONS: Laparoscopic fistula excision combined with omentoplasty is a good treatment modality with a high healing rate for high rectovaginal fistulas and an acceptable complication rate. PMID- 21701810 TI - Homology modeling, molecular dynamics and QM/MM study of the regulatory protein PhoP from Corynebacterium pseudotuberculosis. AB - Corynebacterium pseudotuberculosis is a facultatively intracellular Gram-positive bacterium that causes caseous lymphadenitis, principally in sheep and goats, though sometimes in other species of animals, leading to considerable economic losses. This pathogen has a TCS known as PhoPR, which consists of a sensory histidine kinase protein (PhoR) and an intracellular response regulator protein (PhoP). This system is involved in the regulation of proteins present in various processes, including virulence. The regulation is activated by PhoP protein phosphorylation, an event that requires a magnesium (Mg(2+)) ion. Here we describe the 3D structure of the regulatory response protein (PhoP) of C. pseudotuberculosis through molecular modeling by homology. The model generated provides the first structural information on a full-length member of the OmpR/PhoP subfamily. Classical molecular dynamics was used to investigate the stability of the model. In addition, we used quantum mechanical/molecular mechanical techniques to perform (internal, potential) energy optimizations to determine the interaction energy between the Mg(2+) ion and the structure of the PhoP protein. Analysis of the interaction energy residue by residue shows that Asp-16 and Asp-59 play an important role in the protein-Mg(2+) ion interactions. These results may be useful for the future development of a new vaccine against tuberculosis based on genetic attenuation via a point mutation that results in the polar residue Asp-16 and/or Asp-59 being replaced with a nonpolar residue in the DNA-binding domain of PhoP of C. pseudotuberculosis. PMID- 21701811 TI - The effects of detraining on blood adipokines and antioxidant enzyme in Korean overweight children. AB - The present study examined the change to clarify the effects of detraining on the concentration of lipid profiles, serum adipokines and antioxidant enzyme gene expression in Korean overweight children. The subjects were normal children (n = 19) and obese children (n = 20) who were further subdivided into the overweight training (OT) group (n = 10) and the overweight detraining (OD) group (n = 10). Maximal oxygen uptake (VO(2)max); body composition; lipid profiles (TG, TC); adipokines (adiponectin and leptin); antioxidants (blood and gene expressions SOD and GPX) were measured before, 12 weeks, and 24 weeks after the exercise program. Body mass index (BMI) and %fat were significantly higher in the OD group only. However, waist hip ration (WHR) and systolic blood pressure (SBP) were significantly decreased in the OT group. TG was significantly decreased in the OT group. There was a significant difference in TG level between the two groups. Besides, adiponectin was significantly increased in both the OT group and the OD group. Furthermore, leptin was significantly decreased in the OT group. There was a significant difference in leptin level between the two groups. In training groups, the expression of SOD was significantly increased after a 12- and 24-week period (p < 0.05). However, detraining group was significantly increased after a 12-week only (p < 0.05). In addition, GPX was significantly increased after a 24 week only in the training group (p < 0.05). Thus, detraining showed that negative effected on body composition and lipid profiles and maintained of uniform period on adipokines and antioxidant enzyme the protein and expression. PMID- 21701812 TI - Clinical practice : diagnosis and treatment of functional constipation. AB - Childhood functional constipation has an estimated prevalence of 3% in the Western world and is probably the most common gastrointestinal complaint in children. It is characterized by infrequent painful defecation, faecal incontinence and abdominal pain. Only less than 5% of children with constipation have an underlying disease. Only recently two evidence-based guidelines (the Netherlands and Great Britain) have been developed concerning the diagnostic and therapeutic approach for childhood constipation which we both discuss in this article. At present, a thorough medical history and complete physical exam are usually sufficient to confirm the diagnosis of functional constipation. Further laboratory or radiological investigations should only be performed in case of doubt, to exclude an underlying disease. Treatment of childhood constipation consists of four steps: (1) education, (2) disimpaction, (3) prevention of re accumulation of faeces and (4) follow-up. Surprisingly, there is only limited evidence that laxative treatment is better than placebo in children with constipation. However, according to the available evidence, the Dutch guideline recommends lactulose for children <1 year as first-choice treatment. For children below the age of older than 1 year, both lactulose and polyethylene glycol (PEG) with or without electrolytes can be used as first-choice treatment. According to the National Institute for Health and Clinical Excellence guideline, PEG plus electrolytes is the first-choice treatment for all ages. CONCLUSION: Children with functional constipation should be diagnosed and treated according to recently developed evidence-based guidelines. PMID- 21701813 TI - Tolerance to cannabinoid-induced behaviors in mice treated chronically with ethanol. AB - RATIONALE: Chronic ethanol (EtOH) treatment decreases the motor-impairing effects of cannabinoids and downregulates the cannabinoid type 1 (CB1) receptor. However, these studies have been limited to measures of ataxia and analysis of CB1 expression from whole-brain or hippocampal preparations. OBJECTIVE: To more fully assess the interactions between ethanol and cannabinoids, a tetrad of four well characterized cannabinoid-induced behaviors (hypolocomotion, antinociception, hypothermia, and catalepsy) was measured in mice following EtOH treatment. Additionally, immunoblotting assessed CB1 protein in tissue from nine brain regions associated with these behaviors and the addiction neurocircuitry. MATERIALS AND METHODS: Male C57Bl/6J mice were administered EtOH (0, 2, or 4 g/kg; intraperitoneally (i.p.)) twice daily for 10 days. Tetrad behaviors induced by the CB1 agonist WIN 55212-2 (3 mg/kg, i.p.) were measured in subjects 1 or 10 days following the last EtOH injection. In a separate group of animals, tissue was collected at the same time points for immunoblot analysis. RESULTS: EtOH treated mice were less sensitive to the hypothermic, hypolocomotive, and antinociceptive effects of WIN, and this effect reversed to control levels over a 10-day abstinence period. EtOH treatment did not affect WIN-induced catalepsy. CB1 protein expression was significantly altered in several brain areas including the hypothalamus, periaqueductal gray, ventral tegmental area, and cerebellum. CONCLUSIONS: These results show that chronic EtOH treatment significantly affects the behavioral sensitivity to cannabinoid drugs and alters CB1 expression in several brain regions. Furthermore, these effects are selective as some behaviors and brain regions display an altered response while others do not. PMID- 21701814 TI - Effects of pramipexole on the reinforcing effectiveness of stimuli that were previously paired with cocaine reinforcement in rats. AB - RATIONALE: Dopamine D(2)-like agonists maintain responding when substituted for cocaine in laboratory animals. However, these effects appear to be mediated by an interaction with stimuli that were previously paired with cocaine reinforcement (CS). OBJECTIVES: To evaluate the extent to which the pramipexole-maintained and pramipexole-induced responding are influenced by cocaine-paired stimuli. METHODS: Rats were trained to nosepoke for cocaine under fixed ratio 1 (FR1) or progressive ratio (PR) schedules of reinforcement. In FR1-trained rats, pramipexole was substituted for cocaine with injections either paired with CSs, or delivered in their absence. The capacity of experimenter-administered pramipexole to induce FR1 and PR responding for CS presentation was evaluated. The effects of altering stimulus conditions, as well as pretreatments with D(2)- (L: -741,626) and D(3)-preferring (PG01037) antagonists on pramipexole-induced PR responding were also evaluated. RESULTS: When substituted for cocaine, pramipexole maintained responding at high rates when injections were paired with CSs, but low rates when CSs were omitted. Similarly, experimenter-administered pramipexole induced dose-dependent increases in FR1 or PR responding, with high rates of responding observed when the CS was presented, and low rates of responding when CS presentation was omitted. D(2) and D(3) antagonists differentially affected pramipexole-induced PR responding, with L: -741,626 and PG01037 producing rightward, and downward shifts in the dose-response curve for CS-maintained responding, respectively. CONCLUSIONS: These data indicate that pramipexole is capable of enhancing the reinforcing effectiveness of conditioned stimuli, and raise the possibility that similar mechanisms are responsible for the increased occurrence of impulse control disorders in patients being treated with pramipexole. PMID- 21701815 TI - Sodium benzoate, a metabolite of cinnamon and a food additive, upregulates neuroprotective Parkinson disease protein DJ-1 in astrocytes and neurons. AB - DJ-1 (PARK7) is a neuroprotective protein that protects cells from oxidative stress. Accordingly, loss-of-function DJ-1 mutations have been linked with a familial form of early onset Parkinson disease. Mechanisms by which DJ-1 level could be enriched in the CNS are poorly understood. Recently we have discovered anti-inflammatory activity of sodium benzoate (NaB), a metabolite of cinnamon and a widely-used food additive. Here we delineate that NaB is also capable of increasing the level of DJ-1 in primary mouse and human astrocytes and human neurons highlighting another novel neuroprotective effect of this compound. Reversal of DJ-1-inducing effect of NaB by mevalonate, farnesyl phosphate, but not cholesterol and ubiquinone, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the induction of DJ-1 by NaB. Accordingly, either an inhibitor of p21(ras) farnesyl protein transferase (FPTI) or a dominant-negative mutant of p21(ras) alone was also able to increase the expression of DJ-1 in astrocytes suggesting an involvement of p21(ras) in DJ 1 expression. However, an inhibitor of geranyl geranyl transferase (GGTI) and a dominant-negative mutant of p21(rac) had no effect on the expression of DJ-1, indicating the specificity of the effect. Similarly lipopolysaccharide (LPS), an activator of small G proteins, also inhibited the expression of DJ-1, and NaB and FPTI, but not GGTI, abrogated LPS-mediated inhibition. Together, these results suggest that NaB upregulates DJ-1 via modulation of mevalonate metabolites and that p21(ras), but not p21(rac), is involved in the regulation of DJ-1. PMID- 21701816 TI - Non-surgical treatment of osteoarthritis-related pain in the elderly. AB - Osteoarthritis (OA), the third most common diagnosis in the elderly [1], causes significant pain leading to disability and decreased quality of life in subjects 65 years and older [2]. Traditionally, clinicians have relied heavily on the use of non-steroidal anti-inflammatory drugs (NSAIDs) to treat the pain of OA, as numerous studies have proven these agents to be effective. The cardiovascular, gastrointestinal, renal and hepatic toxicities of NSAIDs have limited their use, particularly in the elderly. Acetaminophen has been recommended as initial therapy due to relative safety. Several other topical, oral and intra-articular agents are available today, with use limited by efficacy and side effect profiles. Many non-pharmacologic approaches are available but underused, and may be attractive choices to avoid poly-pharmacy in older patients. We will attempt to highlight the evidence behind available non-surgical therapies for OA while paying specific attention to issues in geriatric patients. PMID- 21701817 TI - Insulitis in the human endocrine pancreas: does a viral infection lead to inflammation and beta cell replication? AB - Defining the role of viruses in the aetiopathogenesis of human type 1 diabetes has been an elusive goal for more than 40 years, although indirect evidence is mounting that viruses have an important modulatory role in the development of the disease through their interaction with the innate immune system. In this issue of Diabetologia, Willcox et al. provide histopathological evidence that the islets of Langerhans in seven young patients with recent-onset disease expressed the enteroviral protein VP1 and report that this marker is preferentially present in islets that show signs of enhanced replicative activity. They suggest that insulitis may be the common factor linking beta cell replication and VP1 positivity, with persistent virus infection leading to chemokine secretion, infiltration of immune cells (insulitis) and pro-inflammatory cytokine-induced beta cell replication. PMID- 21701818 TI - Nuclear factor of activated T cells mediates oxidised LDL-induced calcification of vascular smooth muscle cells. AB - AIMS/HYPOTHESIS: Vascular calcification is a prominent feature of both atherosclerosis and diabetes, and is clinically associated with osteoporosis. The expression of bone-regulatory factors and the impact of oxidative stress in aortic calcification are well-documented. Recently, nuclear factor of activated T cells (NFAT) cytoplasmic, calcineurin-dependent 1 (NFATc1) was identified in calcified aortic valves and has been implicated in vascular calcification. Therefore, we assessed the mechanisms of osteogenic transdifferentiation of vascular smooth muscle cells induced by oxidised LDL (oxLDL) and evaluated the role of NFAT in this process. METHODS: Human coronary artery smooth muscle cells (HCASMCs) were cultured for 21 days in medium supplemented with oxLDL. NFAT was inhibited using the NFAT inhibitor VIVIT, or by knockdown with small interfering RNA (siRNA). Osteogenic transdifferentiation was assessed by gene expression, matrix mineralisation and alkaline phosphatase activity. RESULTS: Exposure to oxLDL caused the transformation of HCASMCs towards an osteoblast-like phenotype based on increased mineral matrix formation and RUNX2 expression. NFATc1 blockade completely prevented oxLDL-induced osteogenic transformation of HCASMCs as well as oxLDL-induced stimulation of osteoblast differentiation. In contrast, matrix mineralisation induced by osteogenic medium was independent of the NFAT pathway. Of note, oxLDL-conditioned medium from HCASMCs transferred to bone cells promoted osteoblast mineralisation. Consistent with these in vitro findings, diabetic rats with a twofold increase in oxidised lipid levels displayed higher aortic calcium concentrations and increased expression of osteogenic markers and production of NFATc1. CONCLUSIONS/INTERPRETATION: Our results identify the NFAT signalling pathway as a novel regulator of oxLDL-induced transdifferentiation of vascular smooth muscle cells towards an osteoblast-like phenotype. PMID- 21701819 TI - Influence of dietary carbohydrate level on endocrine status and hepatic carbohydrate metabolism in the marine fish Sparus sarba. AB - Silver sea bream, Sparus sarba, were fed two diets of different carbohydrate levels (2 and 20% dextrin) for 4 weeks, and the effects on organ indices, liver composition, serum metabolite and hormone levels and gene expression profile of key enzymes of carbohydrate metabolism in the liver were investigated. By using real-time PCR, mRNA expression levels of carbohydrate metabolic enzymes including glucokinase (GK, glycolysis), glucose-6-phosphatase (G6Pase, gluconeogenesis), glycogen synthase (GS, glycogenesis), glycogen phosphorylase (GP, glycogenolysis) and glucose-6-phosphate dehydrogenase (G6PDH, pentose phosphate pathway) in liver of sea bream have been examined, and it was found that high dietary carbohydrate level increased mRNA level of GK but decreased mRNA levels of G6Pase and GP. However, mRNA levels of GS and G6PDH were not significantly influenced by dietary carbohydrate. Silver sea bream fed high dietary carbohydrate had higher hepatosomatic index (HSI), liver glycogen and protein, but there were no significant changes in gonadosomatic index (GSI), serum glucose and protein level, as well as liver lipid and moisture level. Pituitary growth hormone (GH) and hepatic insulin-like growth factor I (IGF-I) transcript abundance were assayed by real-time PCR, and it was found that both parameters remained unchanged in fish fed different dietary carbohydrate levels. Serum triiodothyronine (T(3)) and thyroxine (T(4)) were not significantly affected by dietary carbohydrate levels, but lower serum cortisol level was found in fish fed high dietary carbohydrate level. These results suggest that silver sea bream is able to adapt to a diet with high carbohydrate content (up to 20% dextrin), the consumption of which would lead to fundamental re-organization of carbohydrate metabolism resulting in hepatic glycogen deposition. PMID- 21701820 TI - The effect of water temperature on gamete maturation and gamete quality in the European grayling (Thymalus thymallus) based on experimental data and on data from wild populations. AB - To investigate the effect of water temperature on gamete maturation and gamete quality, European grayling (Thymalus thymallus) were held under different temperature regimes prior to spawning. Maturation of males and females and their gamete quality depended strongly on temperature regime. The highest percentages of maturing fish and highest gamete quality were obtained under a creek water temperature regime with natural seasonal fluctuations. In warmed creek water (3-4 degrees C), at a constant temperature of 8-9 degrees C, and under an abruptly increasing temperature, regime maturation rates and gamete quality were reduced. The effect was more pronounced in females than in males. The spawning dates of different wild Austrian grayling populations were also correlated with water temperature data collected during the last 10-15 years. The mean spawning date expressed as the number of days from 21 December until spawning ranged from 98 to 111 days for lower elevation populations, while it was considerably delayed for an alpine population. All populations spawned at water temperatures of 5.5-7.2 degrees C. Regression analysis indicated that spawning date correlated with (1) the overall mean water temperature from 21 December until spawning, (2) the mean water temperature during both the last 10 days and 15 days before spawning, and (3) the difference between mean January temperature and that of the last 15 days before spawning. The regression functions indicate that an increase in water temperature from 21 December to spawning of 1 degrees C advances spawning by 51/2 days, and an increase of 1 degrees C in the last 10-15 days advances spawning by 31/2 days. PMID- 21701821 TI - Benefits of Helicobacter pylori cagE genotyping in addition to cagA genotyping: a Bulgarian study. AB - Associations of Helicobacter pylori cagE status with complex patient characteristics remain to be elucidated in Eastern Europe. The aim of this study was to assess the frequencies of cagE gene and cagA/cagE combinations in H. pylori strains from symptomatic Bulgarian patients and to improve cagA detection. cagA and cagE genotypes were evaluated in 219 patients with single-strain infections. In total, 84.9% of strains were cagA (+), while 68.5% were cagE (+). cagA (+), cagE (+), and cagA (+)/cagE (+) strains were more prevalent in peptic ulcer (93.8%, 84.4%, and 84.4%) compared with nonulcer patients (81.3%, 61.9%, and 61.3%, respectively). In elderly patients, cagE (+) and cagA (+)/cagE (+) strains were 1.9-fold more common than in the 12 children evaluated. Only 10% of the elderly subjects harbored low-virulence cagA (+)/cagE (-) strains compared with 16.8% of adults and 41.7% of children. Intriguingly, prevalence of the cagA (+)/cagE (-) genotype was 2.1-fold lower in men than in women, suggesting a higher frequency of more virulent strains in men. The presence of both cag genes and combinations was not linked to strain susceptibility to clarithromycin or metronidazole, place of residence, or prior therapy. Use of an extra primer pair increased cagA detection in 14.7% of 31 cagA (-) strains. In conclusion, use of a second primer pair for the cagA gene can be recommended in countries with common cagA (+) strains. Although both cag genes were linked to severe diseases in Bulgarian patients, the best discrimination of virulent strains was obtained by the cagA/cagE combination or by the cagE gene alone. cagE prevalence increased gradually with patient age, while the cagA (+)/cagE (-) genotype, implying a disrupted cag pathogenicity island, was associated with both younger age and female gender. PMID- 21701822 TI - Paternal deprivation prior to adolescence and vulnerability to pituitary adenomas. AB - It has been reported that women with prolactinoma were exposed, early in life, to an environment characterized by an absent or violent father. The present study was designed to evaluate whether paternal absence or violent paternal behavior were more prevalent in patients with pituitary adenomas (prolactinoma, acromegaly, non-secreting adenoma and Cushing's disease) compared to a control population. We conducted an observational case-control multicenter study. We interviewed 395 patients with prolactinoma (296 females and 99 males), 130 with acromegaly (87 females and 43 males), 237 with non-secreting adenoma (144 females and 93 males) and 68 with Cushing's disease (61 females and 7 males) and 365 patients from the same clinics with nodular thyroid disease or lymphocytic thyroiditis with euthyroidism as controls. Violent or absent fathers were significantly more prevalent in patients with prolactinoma or acromegaly than in controls (P = 0.001 and P = 0.002, respectively) but not in patients with non secreting adenoma or corticotrophinoma. Absent fathers in prolactinoma and acromegaly versus controls: P = 0.001 and P = 0.119. Violent fathers in prolactinoma and acromegaly versus controls: P = 0.069 and P = 0.001. The prevalence of absent or violent fathers was also significantly higher in prolactinoma and acromegaly when compared to non-secreting adenoma (P = 0.039 and P = 0.033, respectively). Paternal deprivation before adolescence may be a risk factor for prolactinoma and acromegaly but not for non-secreting pituitary adenomas or Cushing's disease. PMID- 21701824 TI - Age-related macular degeneration and genetic polymorphisms of glutathione S transferases M1 (GSTM1) and T1 (GSTT1). AB - The aim of this study is to understand the multifactorial causes of age-related macular degeneration (ARMD), and, therefore, it is reasonable to investigate whether genetic polymorphisms of antioxidant enzymes (GSTM1 and GSTT1) contribute to the development of ARMD. This study consisted of 112 subjects (44 females, 68 males) with exudative ARMD, who were recruited from Khalili Hospital ophthalmic clinic in Shiraz (southern Iran), referred by vitreoretinal surgeon. Also 112 sex matched controls (44 females, 68 males) were randomly selected from unrelated volunteers in the same clinic. We excluded patients and controls with cataract or past history of cataract surgery, asthma, past history of malignancy, cardiovascular disease that on medication and known cases of glaucoma, because these traits were associated with GSTM1 and/or GSTT1 polymorphisms. There was no association between polymorphisms of neither GSTM1 nor GSTT1 and risk of ARMD. The combination genotypes of GSTM1 and GSTT1 were not associated with the risk of ARMD. We considered the time of deterioration of vision as the time of onset of exudative ARMD. The Kaplan-Meier analysis revealed that there was significant difference between genotypes of GSTM1 (log rank statistic = 7.03, df = 1, P = 0.008). The age at onset among GSTM1 null genotype was lower than the active genotype of GSTM1. Our results support the hypothesis that the protein encoded by the GSTM1 gene might have a protective function against oxidative stress in retina. Since the age at onset is influenced by the GSTM1 polymorphism, this implies that GSTM1 is a modifier gene. PMID- 21701825 TI - Polymorphisms of beta-lactoglobulin promoter region in three Sicilian goat breeds. AB - Several beta-lactoglobulin (BLG) polymorphisms have been described within the proximal promoter region and coding region of the caprine gene, although no genetic variants affecting the protein amino acid composition and/or expression level have been characterized so far. Binding sites for several transcription factors (TFs) are present in the BLG promoter region. The aims of this work were to sequence the full-length promoter region of three Sicilian goat breeds in order to identify polymorphisms, analyze the identified haplotypes, search for differences between breeds for the presence of polymorphisms in this gene region, search for putative TFs binding sites, and check if polymorphisms lay within the identified TFs binding sites. The promoter region of BLG gene in Sicilian goat breeds showed high level of polymorphism due to the presence of 36 single nucleotide polymorphisms (SNPs). Association between polymorphic sites was computed within the whole sample analyzed and 18 haplotypes were inferred. Binding sites for three milk protein binding factors (MPBFs) and four nuclear factor-I (NF-I) were found within BLG promoter region based on the ovine sequence. The identification of some SNPs within TFs binding sites allowed hypothesizing the loss of TFs. Further studies are in progress to evaluate the effect of these mutations on binding affinity of TFs, the functional interaction of the TFs with the goat BLG promoter, and the relationship of the polymorphisms with BLG gene expression and milk production and composition. PMID- 21701826 TI - Identification and expression analysis of CjLTI, a novel low temperature responsive gene from Caragana jubata. AB - Using rapid amplification of cDNA ends, a full length cDNA (CjLTI) was cloned from apical buds of Caragana jubata, a plant species that grows under extreme cold. The cDNA obtained was 573 bp long consisting of an open reading frame of 351 bp encoding 116 amino acids. Homology analysis did not exhibit significant similarity with any sequence at NCBI database, therefore it was deduced as a novel gene. Secondary structure analysis suggested that the deduced CjLTI contained 25.86% alpha-helices, 4.31% beta-turns, 6.90% extended strands, and 62.93% random coils. The hydropathy profile suggested CjLTI to be a hydrophobic protein having characteristic features of signal peptides at N-terminus. The gene exhibited down-regulation at 5 min of exposure to low temperature (LT, 4 +/- 3 degrees C) followed by a strong up-regulation after 15 min and onwards. Methyl jasmonate (MJ) lead to up-regulation of CjLTI starting at 5 min onwards. The gene exhibited up- and down-regulation of expression pattern in response to abscisic acid (ABA) and salicylic acid (SA). Mild drought stress slightly up-regulated gene expression and at severe drought (up to 115% reduction in leaf water potential) slight down-regulation of gene expression was observed. These results suggested CjLTI to be a LT responsive gene wherein MJ, ABA and SA pathways might be involved in regulating the gene expression. PMID- 21701827 TI - p38 MAPK regulates calcium signal-mediated lipid accumulation through changing VDR expression in primary preadipocytes of mice. AB - In the present study we have examined whether p38 mitogen activated protein kinase (p38 MAPK) signal pathway interacts with calcium signal on lipid accumulation in primary preadipocytes of mice. The primary preadipocytes were treated with p38 MAPK inhibitor SB203580, blockers and excitomotors of calcium channel for 24 h, respectively. Intracellular triglyceride (TG) content was measured by triglyceride kit and lipid accumulation was determined by Oil Red O staining. Meanwhile, the mRNA expressions of peroxisome proliferators-activated receptor gamma (PPARgamma) gene, fatty acid synthetase (FAS) gene, lipoprotein lipase (LPL) gene, vitamin D receptor (VDR) gene and extracellular Ca(2+)-sensing receptor (CaSR) gene were analyzed with real-time PCR. The protein content and phosphorylation of VDR and p38 were tested with Western Blotting. The data showed that intracellular TG content and the mRNA expression levels of PPARgamma, FAS, LPL in N group and L group as well as FAS, LPL in C group were increased significantly (P < 0.01) compared to the control. On the contrary, intracellular TG content and the mRNA expression levels of PPARgamma, FAS in B group as well as intracellular TG content and PPARgamma, FAS, LPL in SB group and B+SB group were decreased significantly (P < 0.01). VDR mRNA expression and protein content were decreased in B, C, and SB added groups (P < 0.01). In addition, p38 phosphorylation levels increased in N and L groups (P < 0.01) and decreased in SB added groups (P < 0.01). These findings suggest that p38 MAPK pathway through regulating VDR mRNA expression participates in mediation of calcium signal and affects calcium signal regulating lipid accumulation in mice preadipocytes through changing PPARgamma, FAS and LPL mRNA expression. In addition, calcium signal have a feedback effect in phosphorylation of p38. PMID- 21701828 TI - Association between HFE polymorphisms and susceptibility to Alzheimer's disease: a meta-analysis of 22 studies including 4,365 cases and 8,652 controls. AB - Whether the variations in the hemochromatosis (HFE) gene increase Alzheimer's disease (AD) risk is still undetermined. We performed a meta-analysis in order to systematically summarize the possible association. Studies were identified by searching PUBMED, Web of Science and EMBASE databases complemented with screening the references of the retrieved studies. The association was measured using random-effect or fixed-effect odds ratio (OR) combined with 95% confidence intervals (CIs) according to the studies' heterogeneity. For C282Y polymorphism, we did not find any association using data from 22 studies including 4,365 cases and 8,652 controls. For H63D polymorphism, on the basis of 2,795 cases and 7,424 controls from 17 studies, we observed a significant association (allele contrast: OR = 0.902, 95% CI = 0.819-0.994, P = 0.037; minor-allele-dominant model: OR = 0.887, 95% CI = 0.790-0.996, P = 0.043). No publication bias was detected in this meta-analysis. The synthesis of available evidence supports mutant of HFE H63D polymorphism plays a protective role for AD risk. PMID- 21701829 TI - Genetic polymorphism analysis of killer cell immunoglobulin-like receptor genes in the Chinese Uygur population. AB - Human killer cell immunoglobulin-like receptors are expressed in natural killer cells and subsets of T lymphocytes. They regulate these cells upon interaction with human leukocyte antigen class I molecules and other ligands presented by target cells. KIR gene frequencies and haplotype distributions have been shown to differ significantly between populations from different geographical regions and ethnic origins, which relates to functional variations in the immune response. We have investigated KIR gene frequencies and genotype diversities of 15 KIR genes (KIR2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DS1, 2DS2, 2DS3, 2DS4, ID, 2DS5, 3DL1, 3DL2, 3DL3, 3DS1) and two pseudogenes (KIR3DP1 and 2DP1) in 120 unrelated healthy individuals of the Uygur population living in the Xinjiang autonomous region of China. All individuals were typed positive for the four framework loci KIR3DL3, 2DL4, 3DL2 and KIR3DP1, while activating genes (KIR2DS1, 2DS2, 2DS3, 2DS5 and KIR3DS1) indicated some variation in this population. KIR3DS1 was found in a higher frequency in the studied population than in other groups from China. Linkage disequilibrium among KIR genes displayed a wide range. chi(2) analysis, conducted among non-ubiquitous genes, based on the KIR gene frequency data from our study population and previously published population data, revealed significant differences in the KIR2DL1, 2DL2, 2DL3, 2DL5, 3DL1, 2DS1, 2DS2, 2DS3, 2DS5, and 3DS1 genes. A neighbor-joining phylogenic tree, built using the observed carrier frequencies data of 13 KIR loci (KIR2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 3DL1, 3DL2, 3DL3, 2DS1, 2DS2, 2DS3, 2DS5, and 3DS1), showed relationships between the population studied and other previously reported populations. The present study can therefore be valuable for enriching the ethnical gene information resources of the KIR gene pool, for population origin studies and for KIR-related clinical practice. PMID- 21701830 TI - Molecular characterization and expression analysis of dihydroflavonol 4-reductase (DFR) gene in Saussurea medusa. AB - Dihydroflavonol 4-reductase (DFR), which catalyzes the reduction of dihydroflavonols to leucoanthocyanins, is a key enzyme in the biosynthesis of anthocyanidins, proanthocyanidins, and other flavonoids of importance in plant development and human nutrition. This study isolated a full length cDNA encoding DFR, designated as SmDFR (GenBank Accession No. EF600682), by screening a cDNA library from a red callus line of Saussurea medusa, which is an endangered, traditional Chinese medicinal plant with high pharmacological value. SmDFR was functionally expressed in yeast (Saccharomyces cerevisiae) to confirm that SmDFR can readily reduce dihydroquercetin (DHQ) and dihydrokampferol (DHK), but it could not reduce dihydromyricetin (DHM). The deduced SmDFR structure shared extensive sequence similarity with previously characterized plant DFRs and phylogenetic analysis showed that it belonged to the plant DFR super-family. SmDFR also possessed flavanone 4-reductase (FNR) activity and can catalyze the conversion of eridictyol to luteoforol. Real-time PCR analysis showed that the expression level of SmDFR was higher in flowers compared with both leaves and roots. This work greatly enhances our knowledge of flavonoid biosynthesis in S. medusa and marks a major advance that could facilitate future genetic modification of S. medusa. PMID- 21701831 TI - Differential expression of MMP-2 and -9 and their inhibitors in fetal lung cells exposed to mechanical stretch: regulation by IL-10. AB - STUDY OBJECTIVES: Abnormal remodeling of the extracellular matrix (ECM) has been implicated in the pathogenesis of bronchopulmonary dysplasia. However, the contribution of lung parenchymal cells to ECM remodeling after mechanical injury is not well defined. The objective of these studies was to investigate in vitro the release of MMP-2 and -9 and their respective inhibitors TIMP-2 and -1, and to explore potential regulation by IL-10. DESIGN: Mouse fetal epithelial cells and fibroblasts isolated on E18-19 of gestation were exposed to 20% cyclic stretch to simulate lung injury. MMP-2 and MMP-9 activity were investigated by zymography and ELISA. TIMP-1 and TIMP-2 abundance were analyzed by Western blot. RESULTS: We found that mechanical stretch increased MMP-2 and decreased TIMP-2 in fibroblasts, indicating that excessive stretch promotes MMP-2 activation, expressed as the MMP-2/TIMP-2 ratio. Incubation with IL-10 did not change MMP-2 activity. In contrast, mechanical stretch of epithelial cells decreased MMP-9 activity and the MMP-9/TIMP-1 ratio by 60-70%. When IL-10 was added, mechanical stretch increased the MMP-9/TIMP-1 ratio by 50%. CONCLUSIONS: We conclude that mechanical stretch differentially affects MMP-2/9 and their inhibitors in fetal lung cells. IL-10 modulates MMP-9 activity through a combination of effects on MMP-9 and TIMP-1 levels. PMID- 21701832 TI - The relationship of the BODE index to oxygen saturation during daily activities in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: The frequency of oxygen desaturation during daily activities in chronic obstructive pulmonary disease (COPD) is poorly defined. The BODE index predicts survival in COPD. The purpose of this study was to determine the relationship between BODE scores and oxygen saturation during daily activities. METHODS: Seventy-eight patients with COPD (FEV(1) = 37%) underwent ambulatory oximetry and activity monitoring. We defined four activity categories: Walking, Slow-Intermittent-Walking (SIW), Active-Not-Walking (ANW), and Rest. We quantified oxygen desaturation during activity using a desaturation index (DSI = % time oxygen saturation <90%). BODE scores were categorized into three groups: group I (0-3), II (4-6), and III (7-10). RESULTS: The percentage of patients demonstrating oxygen desaturation (DSI >= 10%) during each activity was 55% for Walking, 35% for SIW, 15% for ANW, and 28% for Rest. There was a strong association between BODE score and desaturation for Walking and SIW. During Walking, 21, 44, and 86% of patients in BODE groups I, II, and III, respectively, demonstrated desaturation. The DSI for Walking and SIW was increased in patients in BODE groups II and III compared to group I (P < 0.006, P < 0.007, respectively). BODE score was also linked to long-term oxygen therapy (LTOT) usage; the majority of patients not on LTOT (89%) had a BODE score <7. The majority of patients on LTOT (84%) demonstrated desaturation during Walking, but 42% of patients not on LTOT also demonstrated desaturation. In this subgroup of patients not on LTOT, all patients with a BODE score >= 7 demonstrated desaturation during Walking. CONCLUSIONS: The link between the BODE index and oxygen desaturation during daily activities suggests that desaturation is linked to disease severity. Our data suggest that patients with a BODE score >= 7 should be evaluated for desaturation during daily activities. Use of the BODE index to screen for exertional desaturation may have value as a tool that can lead to the earlier identification of patients who may be candidates for LTOT. PMID- 21701834 TI - Long-term lead elimination from plasma and whole blood after poisoning. AB - OBJECTIVE: Blood lead (B-Pb), one of the most used toxicological biomarker all kind, has serious limitations. Thus, the objective is to evaluate whether plasma lead (P-Pb) is more adequate. METHODS: A long-term follow-up study of five cases of lead poisoning. P-Pb was analysed by inductively coupled plasma mass spectrometry. Kinetics after end of exposure was modelled. RESULTS: P-Pb at severe poisoning was about 20 MUg/L; haematological effects at about 5 MUg/L. Biological half-time of P-Pb was about 1 month; B-Pb decay was much slower. CONCLUSION: P-Pb is a valuable biomarker of exposure to and risk, particularly at high exposure. PMID- 21701833 TI - Occupational exposure to diisononyl phthalate (DiNP) in polyvinyl chloride processing operations. AB - PURPOSE: Diisononyl phthalate (DiNP) is primarily used as a plasticizer in polyvinyl chloride (PVC) materials. While information is available on general population exposure to DiNP, occupational exposure data are lacking. We present DiNP metabolite urinary concentrations in PVC processing workers, estimate DiNP daily intake for these workers, and compare worker estimates to other populations. METHODS: We assessed DiNP exposure in participants from two companies that manufactured PVC materials, a PVC film manufacturer (n = 25) and a PVC custom compounder (n = 12). A mid-shift and end-shift urine sample was collected from each participant and analyzed for the DiNP metabolite mono(carboxy isooctyl) phthalate (MCiOP). Mixed models were used to assess the effect on MCiOP concentrations of a worker being assigned to (1) a task using DiNP and (2) a shift where DiNP was used. A simple pharmacokinetic model was used to estimate DiNP daily intake from the MCiOP concentrations. RESULTS: Creatinine-adjusted MCiOP urinary concentrations ranged from 0.42-80 MUg/g in PVC film and from 1.11 13.4 MUg/g in PVC compounding. PVC film participants who worked on a task using DiNP (n = 7) had the highest MCiOP geometric mean (GM) end-shift concentration (25.2 MUg/g), followed by participants who worked on a shift where DiNP was used (n = 11) (17.7 MUg/g) as compared to participants with no task (2.92 MUg/g) or shift (2.08 MUg/g) exposure to DiNP. The GM end-shift MCiOP concentration in PVC compounding participants (4.80 MUg/g) was comparable to PVC film participants with no task or shift exposure to DiNP. Because no PVC compounding participants were assigned to tasks using DINP on the day sampled, DiNP exposure in this company may be underestimated. The highest DiNP intake estimate was 26 MUg/kg/day. CONCLUSION: Occupational exposure to DiNP associated with PVC film manufacturing tasks were substantially higher (sixfold to tenfold) than adult general population exposures; however, all daily intake estimates were less than 25% of current United States or European acceptable or tolerable daily intake estimates. Further characterization of DiNP occupational exposures in other industries is recommended. PMID- 21701835 TI - Effects of shock waves on oxidative stress, antioxidant enzyme and element levels in kidney of rats. AB - The aim of this study was to investigate the effect of extracorporeal shock wave lithotripsy (ESWL) on kidney oxidative stress and trace element levels of adult rats. Twelve male Wistar albino rats were divided equally into two groups. First group was used as control. The right-side kidneys of animals in second group were treated with 2,000 18-kV shock waves under anesthesia. Localization of the right kidney was achieved following contrast medium injection through a tail vein under flouroscopy control. The animals were sacrificed 72 h after the ESWL treatment, and the kidneys were taken. Malondialdehyde level was higher in the ESWL group than in the control. Reduced glutathione levels, superoxide dismutase, and glutathione peroxidase activities were lower in the ESWL group than those of the control. Fe, Cu, Pb, Mn, Cd, and Ni levels were lower in the ESWL group than in the control, although Mg level was higher in the ESWL group than in the control. In conclusion, the result of the present study indicated that ESWL treatment produced oxidative stress in the kidney and caused impairments on the antioxidant and trace element levels in the kidneys of rats. PMID- 21701836 TI - Fertility sparing surgery for ovarian tumors in children and young adults. AB - OBJECTIVES: To study the outcome of fertility conserving surgery for ovarian tumors in children and young adults (<= 20 years) over 6 years (2003-2009). METHODS: This prospective study included 183 patients diagnosed with ovarian cysts or tumors requiring surgical excision. Ovarian cystectomy/ovariectomy was carried out followed by frozen section histopathology. Malignant cases were subjected to staging laparotomy and fertility sparing surgery. RESULTS: The median age at diagnosis was 17 years (range 7-20 years). 160/183 (87.4%) were non neoplastic ovarian cysts or benign tumors. In 131/160 (81.8%) of non-neoplastic and benign tumors, it was possible to preserve the affected ovary. Twenty cases (11%) were diagnosed as primary malignant ovarian tumors, 2/183 (1.1%) were borderline tumors and 1 case (0.55%) was metastatic colonic carcinoma. The median follow up of cases with primary malignant ovarian tumors was 36 months. During this period, two recurrences (9.1%) were detected, both of the germ cell type (immature teratoma and yolk sac tumor). Recurrent cases were managed by local excision and lymph node sampling followed by chemotherapy. CONCLUSION: Fertility sparing surgery for malignant ovarian tumors in children and young adults has excellent prognosis and should be attempted whenever possible. PMID- 21701838 TI - Advances in adolescent substance abuse treatment. AB - Alcohol and other drug use among adolescents has been a public health problem for decades. Although some substance use may be developmentally routine, a concerning number of adolescents meet criteria for a substance use disorder and could greatly benefit from a quality treatment experience. However, parents and health care providers want evidence of the efficacy of adolescent-specific treatment programs. This review summarizes four factors surrounding the efficacy of current adolescent treatment programs: 1) adolescent-specific treatment services; 2) the variety of therapeutic modalities; 3) relapse and recovery rates; and 4) the need for evidence-based, quality assessments and research. Current adolescent treatment efforts are summarized, and the recent literature regarding the efficacy of adolescent treatment and recovery rates is discussed. PMID- 21701837 TI - Alpha-defensin DEFA1A3 gene copy number elevation in Danish Crohn's disease patients. AB - BACKGROUND AND PURPOSE OF STUDY: Extensive copy number variation is observed for the DEFA1A3 gene encoding alpha-defensins 1-3. The objective of this study was to determine the involvement of alpha-defensins in colonic tissue from Crohn's disease (CD) patients and the possible genetic association of DEFA1A3 with CD. METHODS: Two-hundred and forty ethnic Danish CD patients were included in the study. Reverse transcriptase PCR assays determined DEFA1A3 expression in colonic tissue from a subset of patients. Immunohistochemical analysis identified alpha defensin peptides in colonic tissue. Copy number of DEFA1A3 and individual alleles, DEFA1 and DEFA3, were compared with those for controls, by use of combined real-time quantitative PCR and pyrosequencing, and correlated with disease location. RESULTS: Inflammatory-dependent mRNA expression of DEFA1A3 (P < 0.001), and the presence of alpha-defensin peptides, were observed in colonic tissue samples. Higher DEFA1A3 gene copy number (CD: mean copy number, 7.2 vs. controls 6.7; P < 0.001) and individual DEFA1 alleles (CD mean copy number 5.6 vs. controls 5.1; P < 0.01) were associated with CD, with strong association with colonic location (P < 0.001). CONCLUSIONS: Alpha-defensins are involved in the inflammation of CD, with local mRNA and peptide expression. In combination with the findings that a high DEFA1A3 copy number is significantly linked to CD, these results suggest that a high DEFA1A3 copy number might be important in hindering the normal inflammatory response in CD, particularly colonic CD. PMID- 21701839 TI - Updates on attention-deficit/hyperactivity disorder and learning disorders. AB - The relationship of attention-deficit/hyperactivity disorder (ADHD) to learning disorders was reviewed and included reading disability, mathematics learning disability, and nonverbal learning disability. Genetic, neuroimaging, and neuropsychological functioning were examined for each disorder, along with a discussion of any existing literature when ADHD co-occurred with the disorder. All the disorders were found to frequently co-occur with ADHD. A review of the underlying neuroanatomic and neurofunctional data found specific structures that frequently co-occur in these disorders with others that are specific to the individual diagnosis. Aberrations in structure and/or function were found for the caudate, corpus callosum, and cerebellum, making these structures sensitive for the disorder but not specific. Suggestions for future research, particularly in relation to intervention, are provided. PMID- 21701840 TI - Protein tyrosine phosphatase non-receptor type 14 is a novel sperm-motility biomarker. AB - PURPOSE: To understand the molecular basis of sperm-motility and to identify related novel motility biomarkers. METHODS: Two-dimensional electrophoresis (2DE) followed by Reverse-phase-nano-high-performance liquid chromatography electrospray ionization tandem mass spectrometry (RP-nano-HPLC-ESI-MS/MS) were applied to establish the human sperm proteome. Then the sperm proteome of moderate-motile human sperm fraction and that of good-motile human sperm fraction from pooled spermatozoa of forty normozoospermic donors (Group 1 subjects) were compared to identify the dysregulated proteins. Among these down-regulated proteins, Protein tyrosine phosphatase non-receptor type 14 (PTPN14) was chosen to reconfirm by Western blotting and semi-quantitative reverse transcription polymerase chain reaction. For clinical application, Western blotting and real time reverse transcription polymerase chain reaction was performed to compare the expression level of PTPN14 in (Group 2 subjects) nine normozoospermic controls and thirty-three asthenozoospermic patients (including 21 mild asthenozoospermic cases and 12 severe cases). Finally, bioinformatic tools prediction and immunofluorescence assay were performed to elucidate the potential localization of PTPN14. RESULTS: The expression levels of three proteins were observed to be lower in the moderate-motile sperm fraction than in good-motile sperm of group 1 subjects. Among three proteins with persistent down-regulation in the moderate motile sperm, we reconfirmed that the expression level of PTPN14 was significantly lower in both mRNA and protein levels from the moderate-motile sperm fraction. Further, down-regulation of PTPN14 was found at the translational and transcriptional level in the asthenozoospermic men. Finally, Bioinformatic tools prediction and immunofluorescence assay showed that PTPN14 maybe predominantly localized at the mitochondria in the midpiece of human ejaculated sperm. CONCLUSIONS: Proteomics tools were applied to identify three possible sperm motility-related proteins. Among these proteins, PTPN14 was highly likely a novel sperm-motility biomarker and a potential mitochondrial protein. PMID- 21701841 TI - Pregnancy after PGD for recessive dystrophic epidermolysis bullosa inversa: genetics and preimplantation genetics. PMID- 21701842 TI - Recognition of inferiorly dislocated fast pathways guided by three-dimensional electro-anatomical mapping. AB - PURPOSE: Slow pathway (SP) ablation of atrioventricular (AV) nodal reentrant tachycardia (AVNRT) can be complicated by unexpected AV block even at sites >10 mm inferior to the bundle of His (HB), and one cause is thought to be the inferior dislocation of an antegrade fast pathway (A-FP). We assessed locations of FPs guided by CARTO. METHODS: Sites of FPs were mapped guided by CARTO before SP ablation in 18 patients with slow-fast AVNRT. The A-FP was defined as the site with the minimum interval between the stimulus and HB potential when pace mapping in the right atrial septum. RESULTS: The A-FP was 7.9 +/- 7.5 mm inferior and 2.9 +/- 5.0 mm posterior to the HB. In 6 of 18 patients (33%), the A-FP was inferiorly dislocated >10 mm to the HB. SP ablation was successfully performed in all patients at sites >10 mm from both the HB and the A-FP without AV block. In the inferiorly dislocated A-FP group, A-FPs seemed to be positioned much more on atrial sites and sufficiently posterior to SP ablation sites. CONCLUSIONS: The A FP inferiorly dislocated >10 mm to the HB in one third of patients with AVNRT and seemed to be positioned deep on atrial sites. It is again emphasized that SP ablation within the triangle of Koch should be performed at a very ventricular annulus site, particularly in the inferiorly dislocated A-FP group. PMID- 21701843 TI - Food rationing affects dietary selenium bioaccumulation and life cycle performance in the mayfly Centroptilum triangulifer. AB - Selenium effects in nature are mediated by the relatively large bioconcentration of aqueous Se by primary producers and smaller, yet critical, dietary transfers to primary consumers. These basal processes are then propagated through food webs to higher trophic levels. Here we quantified the movement of dissolved Se (as selenite) to periphyton, and used the resultant periphyton as a food source for conducting full life-cycle dietary Se exposures to the mayfly Centroptilum triangulifer. Periphyton bioconcentrated Se ~2,200-fold from solution in a log linear fashion over dissolved Se concentrations ranging from 1.1 to 23.1 MUg L( 1). We examined the influence of two feeding ration levels (1x and 2x) on trophic transfer, tissue Se concentrations, maternal transfer, and functional endpoints of mayfly performance. Mayflies fed a lesser ration (1x) displayed greater trophic transfer factors (mean TTF, 2.8 +/- 0.4) than mayflies fed 2x rations (mean TTF, 1.1 +/- 0.3). In 1x exposures, mayflies exhibited significant (p < 0.05) reductions in survivorship and total body mass at dietary [Se] >= 11.9 MUg g(-1), reduced total fecundity at >= 4.2 MUg g(-1), and delayed development at >= 27.2 MUg g(-1). Mayflies fed a greater ration (2x) displayed reduced tissue Se concentrations (apparently via growth dilution) relative to 1x mayflies, with no significant effects on performance. These results suggest that the influence of Se on mayfly performance in nature may be tied to food resource availability and quality. Furthermore, nutritional status is an important consideration when applying laboratory derived estimates of toxicity to risk assessments for wild populations. PMID- 21701844 TI - In situ spatio-temporal changes in pollution-induced community tolerance to zinc in autotrophic and heterotrophic biofilm communities. AB - Pollution-induced community tolerance (PICT) uses increased tolerance in populations at contaminated sites as an indicator of contaminant effects. However, given the broad structural and functional complexity that characterizes biological communities, the acquisition of PICT could vary with (i) target community, (ii) intensity of toxicant exposure, (iii) the species succession stage, and (iv) the physicochemical characteristics of the studied site. To assess the spatio-temporal changes of zinc-induced tolerance in fluvial biofilm communities, we conducted an in situ study in Osor River (North-East Catalonia, Spain), which has zinc contamination. Biofilms were developed for 5 weeks in a non-metal-polluted site, and were then transferred to different sites in Osor River with different levels of zinc contamination. The spatio-temporal changes of biofilm PICT to zinc was determined using photosynthetic activity bioassays and respiration-induced aerobic bioassays at T(0), and at 1, 3 and 5 weeks of exposure. We also performed physicochemical characterization of the sites, taxonomic analysis of diatoms, bacterial and fungal diversity and profiled pigments of phototrophic communities. We used multivariate ordination to analyze results. In addition to natural species succession, the intensity of metal pollution exerted structural pressure by selecting the most metal-tolerant species, but differently depending on the type of biofilm. Zn-tolerance values indicated that exposure to high levels of zinc had effects that were similar to a longer exposure to lower levels of zinc. PMID- 21701845 TI - Vitellogenin-like gene expression in freshwater amphipod Gammarus fossarum (Koch, 1835): functional characterization in females and potential for use as an endocrine disruption biomarker in males. AB - The induction of vitellogenin (Vtg) synthesis is widely accepted as a biomarker of estrogenic exposure in male and juvenile fish. Vtg synthesis has emerged as an interesting endpoint to assess endocrine disruptor (ED) effects in crustaceans. However, studies reporting induction of Vtg in male crustaceans are lacking. This study investigated the expression of the Vtg gene in a freshwater amphipod, Gammarus fossarum, using calibrated real-time reverse transcription polymerase chain reaction (real-time RT PCR). First, we described the basal pattern of expression in healthy male and female organisms at different reproductive moult stages, in order to validate the function of this gene. Females expressed from 200 to 700 times more Vtg transcripts than males, depending on the female reproductive stage. Females displayed significant elevation of Vtg mRNA levels at the end of the inter-moult phase and at the beginning of the pre-moult phase. Second, male gammarids were exposed to the estrogenic compound nonylphenol (NP) (0.05, 0.5, 5 and 50 MUg L(-1)) and to the anti-androgen cyproterone (1, 10, 100 and 1000 MUg L(-1)) for 2, 4, 8 and 16 days. Both chemicals altered the pattern of interindividual variability of Vtg gene expression in males with strong induction in some individuals. Finally, the impact of urban wastewater treatment plants (WWTP) on male Vtg gene expression was assessed in organisms transplanted in the field during in situ bioassay campaigns in three different watersheds. Induction of the Vtg mRNA level was observed in males transplanted downstream from WWTP effluent discharge in two of the three study sites. PMID- 21701846 TI - Locomotor-respiratory coupling patterns and oxygen consumption during walking above and below preferred stride frequency. AB - Locomotor respiratory coupling patterns in humans have been assessed on the basis of the interaction between different physiological and motor subsystems; these interactions have implications for movement economy. A complex and dynamical systems framework may provide more insight than entrainment into the variability and adaptability of these rhythms and their coupling. The purpose of this study was to investigate the relationship between steady state locomotor-respiratory coordination dynamics and oxygen consumption [Formula: see text] of the movement by varying walking stride frequency from preferred. Twelve male participants walked on a treadmill at a self-selected speed. Stride frequency was varied from 20 to +20% of preferred stride frequency (PSF) while respiratory airflow, gas exchange variables, and stride kinematics were recorded. Discrete relative phase and return map techniques were used to evaluate the strength, stability, and variability of both frequency and phase couplings. Analysis of [Formula: see text] during steady-state walking showed a U-shaped response (P = 0.002) with a minimum at PSF and PSF - 10%. Locomotor-respiratory frequency coupling strength was not greater (P = 0.375) at PSF than any other stride frequency condition. The dominant coupling across all conditions was 2:1 with greater occurrences at the lower stride frequencies. Variability in coupling was the greatest during PSF, indicating an exploration of coupling strategies to search for the coupling frequency strategy with the least oxygen consumption. Contrary to the belief that increased strength of frequency coupling would decrease oxygen consumption; these results conclude that it is the increased variability of frequency coupling that results in lower oxygen consumption. PMID- 21701847 TI - Mass spectrometry based metabolomics to identify potential biomarkers for resistance in barley against fusarium head blight (Fusarium graminearum). AB - Resistance in Triticeae to fusarium head blight (FHB) is quantitatively inherited. Metabolomics as a tool was used to better understand the mechanisms of resistance and to identify potential FHB resistance biomarker metabolites in barley. Five FHB-resistant two-row barley genotypes (CIho 4196, Zhedar-1, Zhedar 2, Fredrickson, and Harbin-2r) and one FHB-susceptible genotype (CH 9520-30) were each inoculated with either pathogen-suspension or mock-solution. Disease severity, quantified as the proportion of spikelets diseased, varied among genotypes, being the greatest in CH 9520-30. Spikelets were sampled, metabolites extracted with aqueous methanol, and analyzed using an LC-ESI-LTQ-Orbitrap system. A pair wise, resistant vs. susceptible, t-test identified 1774 significant treatment peaks. Canonical discriminant analysis of peak abundance allowed the genotypes to be sorted into three clusters: (i) CH9520-30, (ii) Harbin-2r, (iii) the remaining four genotypes. The t-test was further used to identify resistance-related (RR) and pathogenesis-related (PR) metabolites. The pathogen-produced virulence factor deoxynivalenol (DON), and its detoxification product, DON-3-O-glucoside (D3G) were designated as resistance indicator (RI) metabolites. Metabolites (RR, PR, or RI) occurring in at least two resistant genotypes, showing a two-fold or greater abundance in resistant vs. susceptible lines, and also known to have plant defense functions were selected as potential FHB resistance biomarker metabolites. These included phenylalanine, p-coumaric acid, jasmonate, linolenic acid, total DON produced (TDP), and the proportion of DON converted to D3G (PDC). Total DON was the lowest in CIho 4196, while PDC was the highest in Zhedar-2. The application of RR, PR, and RI metabolites as potential biomarkers to enhance resistance is discussed. PMID- 21701848 TI - Rot and Agr system modulate fibrinogen-binding ability mainly by regulating clfB expression in Staphylococcus aureus NCTC8325. AB - Staphylococcus aureus is an important human pathogen that causes a variety of diseases, ranging from localized skin infections to life-threatening systemic infections. The success of S. aureus as a pathogen is partly due to its ability to adhere to a wide range of host tissues by binding to host extracellular matrix proteins such as fibrinogen, fibronectin, and collagen. Staphylococcus aureus expresses two proteins that can bind specifically to fibrinogen, clumping factors A and B (ClfA and ClfB). Repressor of toxins (Rot) is known to be a global regulator of virulence gene expression in S. aureus. The translation of Rot is regulated by the staphylococcal accessory gene regulator (Agr) quorum-sensing system. In this study, we demonstrated that Rot and the Agr system in S. aureus NCTC8325 can affect the bacterial binding ability to human fibrinogen (Fg) under different bacterial growth phases. Our real-time RT-PCR results indicated that both Rot and the Agr system have no significant effect on clfA expression. However, Rot is an activator of clfB, and Agr/RNAIII can regulate clfB expression via Rot. Gel shift data further suggested that Rot might regulate clfB expression by directly binding to the promoter region of clfB. Moreover, Rot and the Agr system exhibited consistent regulatory effects on clfB transcription and bacterial Fg-binding ability, suggesting that Rot and the Agr system might affect bacterial Fg-binding ability mainly through regulating clfB transcription. PMID- 21701849 TI - Technological applications of chlorophyll a fluorescence for the assessment of environmental pollutants. AB - Chlorophyll a fluorescence has been extensively studied over the last few years. As demonstrated, this phenomenon is closely related to the state of photosystem II, which plays a leading role in the photosynthetic process, and therefore it has become a powerful tool to investigate this complex and any damage occurring in it as a result of physical or chemical stresses. This means that by using photosynthetic organisms as biological probes, one can consider chlorophyll a fluorescence as one of the techniques of choice to reveal the presence of some hazardous toxicants widely spread in the environment. Herbicides, pesticides, and heavy metals, whose concentration in water and food products is generally subject to extremely severe restrictions, are a concrete example of compounds detectable by chlorophyll a fluorescence. These dangerous substances react with the photosystem II, modifying the fluorescence emitted and giving responses which vary in a concentration-dependent manner. The possibility of performing easy, fast, and direct measurements of the fluorescence, even under light conditions, has opened new frontiers for the analysis in situ of pollutants. The aim of this review is to give an overview of the different techniques based on chlorophyll a fluorescence spectrometry, focusing in particular on those which represented the starting point for applications addressed to the assessment of toxic compounds in environmental samples. PMID- 21701850 TI - Wipe sampling procedure coupled to LC-MS/MS analysis for the simultaneous determination of 10 cytotoxic drugs on different surfaces. AB - A simple wipe sampling procedure was developed for the surface contamination determination of ten cytotoxic drugs: cytarabine, gemcitabine, methotrexate, etoposide phosphate, cyclophosphamide, ifosfamide, irinotecan, doxorubicin, epirubicin and vincristine. Wiping was performed using Whatman filter paper on different surfaces such as stainless steel, polypropylene, polystyrol, glass, latex gloves, computer mouse and coated paperboard. Wiping and desorption procedures were investigated: The same solution containing 20% acetonitrile and 0.1% formic acid in water gave the best results. After ultrasonic desorption and then centrifugation, samples were analysed by a validated liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in selected reaction monitoring mode. The whole analytical strategy from wipe sampling to LC-MS/MS analysis was evaluated to determine quantitative performance. The lowest limit of quantification of 10 ng per wiping sample (i.e. 0.1 ng cm(-2)) was determined for the ten investigated cytotoxic drugs. Relative standard deviation for intermediate precision was always inferior to 20%. As recovery was dependent on the tested surface for each drug, a correction factor was determined and applied for real samples. The method was then successfully applied at the cytotoxic production unit of the Geneva University Hospitals pharmacy. PMID- 21701851 TI - Monitoring allostery in D2O: a necessary control in studies using hydrogen/deuterium exchange to characterize allosteric regulation. AB - There is currently a renewed focus aimed at understanding allosteric mechanisms at atomic resolution. This current interest seeks to understand how both changes in protein conformations and changes in protein dynamics contribute to relaying an allosteric signal between two ligand binding sites on a protein (e.g., active and allosteric sites). Both nuclear magnetic resonance (NMR), by monitoring protein dynamics directly, and hydrogen/deuterium exchange, by monitoring solvent accessibility of backbone amides, offer insights into protein dynamics. Unfortunately, many allosteric proteins exceed the size limitations of standard NMR techniques. Although hydrogen/deuterium exchange as detected by mass spectrometry (H/DX-MS) offers an alternative evaluation method, any application of hydrogen/deuterium exchange requires that the property being measured functions in both H(2)O and D(2)O. Due to the promising future H/DX-MS has in the evaluation of allosteric mechanisms in large proteins, we demonstrate an evaluation of allosteric regulation in D(2)O. Exemplified using phenylalanine inhibition of rabbit muscle pyruvate kinase, we find that binding of the inhibitor is greatly reduced in D(2)O, but the effector continues to elicit an allosteric response. PMID- 21701852 TI - Single-trial classification of antagonistic oxyhemoglobin responses during mental arithmetic. AB - Near-infrared spectroscopy (NIRS) is a non-invasive optical technique that can be used for brain-computer interfaces (BCIs) systems. A common challenge for BCIs is a stable and reliable classification of single-trial data, especially for cognitive (mental) tasks. With antagonistic activation pattern, recently found for mental arithmetic (MA) tasks, an improved online classification for optical BCIs using MA should become possible. For this investigation, we used the data of a previous study where we found antagonistic activation patterns (focal bilateral increase of [oxy-Hb] in the dorsolateral prefrontal cortex in parallel with a [oxy-Hb] decrease in the medial area of the anterior prefrontal cortex) in eight subjects. We used the [oxy-Hb] responses to search for the best antagonistic feature combination and compared it to individual features from the same regions. In addition, we investigated the use of antagonistic [deoxy-Hb], total hemoglobin [Hbtot] and pairs of [oxy-Hb] and [deoxy-Hb] features as well as the existence of a group-related feature set. Our results indicate that the use of the antagonistic [oxy-Hb] features significantly increases the classification accuracy from 63.3 to 79.7%. These results support the hypothesis that antagonistic hemodynamic response patterns are a suitable control strategy for optical BCI, and that only two prefrontal NIRS channels are needed for good performance. PMID- 21701853 TI - An EEG-based real-time cortical functional connectivity imaging system. AB - In the present study, we introduce an EEG-based, real-time, cortical functional connectivity imaging system capable of monitoring and tracing dynamic changes in cortical functional connectivity between different regions of interest (ROIs) on the brain cortical surface. The proposed system is based on an EEG-based dynamic neuroimaging system, which is capable of monitoring spatiotemporal changes of cortical rhythmic activity at a specific frequency band by conducting real-time cortical source imaging. To verify the implemented system, we performed three test experiments in which we monitored temporal changes in cortical functional connectivity patterns in various frequency bands during structural face processing, finger movements, and working memory task. We also traced the changes in the number of connections between all possible pairs of ROIs whose correlations exceeded a predetermined threshold. The quantitative analysis results were consistent with those of previous off-line studies, thereby demonstrating the possibility of imaging cortical functional connectivity in real time. We expect our system to be applicable to various potential applications, including real-time diagnosis of psychiatric diseases and EEG neurofeedback. PMID- 21701854 TI - Effects of inferior oblique muscle-weakening surgery on the Bielschowsky head tilt phenomenon in patients with superior oblique palsy habitually fixating with the paretic eye. AB - PURPOSE: To evaluate the usefulness of inferior oblique (IO) weakening surgery on a paretic eye for correcting vertical deviation in three positions of gaze by comparing the surgical results in 2 types of unilateral superior oblique (SO) palsy. METHODS: The patients were divided into 2 groups: 27 patients fixated with the paretic eye and 61 patients fixated with the non-paretic eye (control). The former had hypotropia and the latter hypertropia. All patients underwent IO recession of the paretic eye. We compared the corrective effects, percentage changes in the decrease of vertical deviation of the primary position (PP), vertical deviation on ipsilateral head tilt, i.e., the Bielschowsky head-tilt phenomenon (BHP), and differences in vertical deviation between ipsilateral and contralateral head tilt (BHTD) relative to the preoperative values between the 2 groups. RESULTS: Mean percentage decrease in vertical deviation of the BHP and BHTD in the control group was larger at 3, 6, and 12 months, but no significant difference was observed between the 2 groups except for the BHP at 12 months (52% for case vs. 70% for control, p = 0.04). CONCLUSIONS: IO weakening in the paretic eye was effective irrespective of the preferred eye for fixation on PP and head tilt position. PMID- 21701855 TI - Effects of oblique muscle surgery on the rectus muscle pulley. AB - PURPOSE: To determine the position of rectus muscle pulleys in Japanese eyes and to evaluate the effect of oblique muscle surgery on rectus muscle pulleys. METHODS: Quasi-coronal plane MRI was used to determine area centroids of the 4 rectus muscles. The area centroids of the rectus muscles were transformed to 2 dimensional coordinates to represent pulley positions. The effects of oblique muscle surgery on the rectus muscle pulley positions in the coronal plane were evaluated in 10 subjects with cyclovertical strabismus and, as a control, pulley locations in 7 normal Japanese subjects were calculated. RESULTS: The mean positions of the rectus muscle pulleys in the coronal plane did not significantly differ from previous reports on normal populations, including Caucasians. There were significant positional shifts of the individual horizontal and vertical rectus muscle pulleys in 3 (100%) patients with inferior oblique advancement, but not in eyes with inferior oblique recession and superior oblique tendon advancement surgery. The surgical cyclorotatory effect was significantly correlated with the change in the angle of inclination formed by the line connecting the vertical rectus muscles (p = 0.0234), but weakly correlated with that of the horizontal rectus muscles. CONCLUSIONS: The most important factor that affects the pulley position is the amount of ocular torsion, not the difference in surgical procedure induced by oblique muscle surgery. PMID- 21701856 TI - Chronic expanding hematoma might be a potential insidious challenge for orthopedic surgeon. AB - Chronic expanding hematomas can cause alarm both to the physician and to the patient because they simulate the growth of a malignant tumor. It is not always possible to bring back the cause to a specific traumatic event that the patient can remember. At this purpose, it is important to have a precise diagnosis when dealing with a growing mass and to exclude any malignancy before processing any treatment. In this article, we report the case of a young patient admitted to our department with a suspected soft tissue sarcoma, but imaging study and histological examination revealed to be hematoma. The authors want to emphasize the necessity of performing a complete clinical and instrumental study when surgeon has to deal with a growing mass. From accurate analysis of imaging, it is often possible to discriminate between malignancy and other benign forms. PMID- 21701857 TI - Measles incidence rate and a phylogenetic study of contemporary genotype H1 measles strains in China: is an improved measles vaccine needed? AB - The incidence of measles in China has increased over the last decade. To evaluate the genetic variation of measles strains, 16 measles wild-type virus strains were isolated from 14 vaccinated cases and 2 nonvaccinated cases in Jilin Province during 2005-2006, and their nucleoprotein (N) and hemagglutinin (H) genes were amplified by RT-PCR. The amplified products were sequenced and compared with the Edmonston virus and the existing vaccine strains (Changchun-47 and Shanghai-191). The results showed that the variation rate between the vaccine and wild-type strains was 9.8-12.0% in the N gene and 5.9-6.9% in the H gene, respectively. In addition, cross-neutralization assays revealed that although sera obtained from infants following primary vaccination effectively neutralized vaccine strains, the capacity in neutralizing H1 wild-type measles virus isolates was decreased fourfold. Antigenic ratios testing revealed that the antigenic relatedness between wild-type measles viruses and existing vaccine strains was notably low. These data suggest that the increased incidence of measles in Jilin Province may be attributed to the antigenic drift between wild-type and vaccine strains. Our findings strengthen the recommendation of supplemental immunization with existing vaccines and also strongly suggest a need for developing new vaccines to better control measles virus outbreaks. PMID- 21701858 TI - Bacterial expression of antigenic sites A and D in the spike protein of transmissible gastroenteritis virus and evaluation of their inhibitory effects on viral infection. AB - The spike (S) protein is a key structural protein of coronaviruses including, the porcine transmissible gastroenteritis virus (TGEV). The S protein is a type I membrane glycoprotein located in the viral envelope and is responsible for mediating the binding of viral particles to specific cell receptors and therefore specific cell types. It is also an important immune target for the host in neutralizing the virus. Four antigenic sites A, B, C, and D that reside near the N-terminal domain have been defined in the S protein. Of these, the region encoding antigenic sites A and to a lesser extent D, herein defined as S-AD, are most critical in eliciting host neutralizing antibodies. Herein, we enzymatically amplified, cloned, and expressed the S-AD fragment from TGEV in the prokaryotic expression vector, pET-30a. Maximum protein expression was achieved at 30 degrees C over a 5-h period post-induction. Rabbit polyclonal antiserum was generated using recombinant S-AD (rS-AD) protein. In contrast to prior studies showing no activity with bacterially produced S protein, results indicated that polyclonal serum recognized TGEV-infected cells and reduced infection by 100%. Furthermore, the truncated rS-AD peptide was able to bind to the surface of cells from swine testes in a competitive manner and completely inhibit viral infection. PMID- 21701859 TI - Molecular cloning, characterization, and expression analysis of resistance gene candidates in Kaempferia galanga L. AB - Majority of the plant disease resistance genes expresses cytoplasmic receptor like proteins characterized by an N-terminal nucleotide-binding site (NBS) and a leucine-rich repeat (LRR) domain. Degenerative primers based on these conserved motifs were used to isolate NBS type sequences in Kaempferia galanga. Cloning and sequencing identified 12 Kaempferia NBS-type sequences called resistance gene candidates (RGCs) classified into four classes. The amino acid sequences of the RGCs detected the presence of conserved domains, viz., kinase-1a, kinase-2, and hydrophobic GLPL, categorizing them with the NBS-LRR class gene family. Structural and phylogenetic characterization grouped the RGCs with the non-toll interleukin receptor (non-TIR) subclasses of the NBS sequences. Reverse transcription PCR with 10 Kaempferia RGC specific primers revealed 7 out of 10 Kaempferia RGCs to be expressive. The isolation and characterization of Kaempferia RGCs has been reported for the first time in this study. This will provide a starting point towards characterization of candidate resistance genes in Kaempferia and can act as a source pool for disease resistance development in other asexually reproducing plants. PMID- 21701860 TI - Magnaporthe oryzae populations adapted to finger millet and rice exhibit distinctive patterns of genetic diversity, sexuality and host interaction. AB - In this study, host-specific forms of the blast pathogen Magnaporthe oryzae in sub-Saharan Africa (SSA) were characterised from distinct cropping locations using a combination of molecular and biological assays. Finger millet blast populations in East Africa revealed a continuous genetic variation pattern and lack of clonal lineages, with a wide range of haplotypes. M. oryzae populations lacked the grasshopper (grh) element (96%) and appeared distinct to those in Asia. An overall near equal distribution (47-53%) of the mating types MAT1-1 and MAT1-2, high fertility status (84-89%) and the dominance of hermaphrodites (64%) suggest a strong sexual reproductive potential. Differences in pathogen aggressiveness and lack of cultivar incompatibility suggest the importance of quantitative resistance. Rice blast populations in West Africa showed a typical lineage-based structure. Among the nine lineages identified, three comprised ~90% of the isolates. Skewed distribution of the mating types MAT1-1 (29%) and MAT1-2 (71%) was accompanied by low fertility. Clear differences in cultivar compatibility within and between lineages suggest R gene-mediated interactions. Distinctive patterns of genetic diversity, sexual reproductive potential and pathogenicity suggest adaptive divergence of host-specific forms of M. oryzae populations linked to crop domestication and agricultural intensification. PMID- 21701861 TI - Degradation of o-toluidine by fluidized-bed Fenton process: statistical and kinetic study. AB - BACKGROUND, AIM, AND SCOPE: The optimal conditions of o-toluidine degradation by fluidized-bed Fenton process were determined using Box-Behnken designs (BBD). The BBD can be used to find the optimal conditions in multivariable systems. The optimal conditions obtained by the design were further applied in the kinetic analysis of o-toluidine oxidation in fluidized-bed Fenton process. MATERIALS AND METHODS: The 1.35-L fluidized-bed reactor used in all experiments was a cylindrical vessel with an inlet, outlet, and recirculation pump. The o-toluidine was determined by high-performance liquid chromatography. RESULTS AND DISCUSSION: Analytical results indicated that pH, Fe(2+), and H(2)O(2) were significant factors in o-toluidine and chemical oxygen demand (COD) removal, but loading carrier was not. The pH significantly affected not only o-toluidine degradation, but also total iron removal. The predicted conditions for optimal removal of 1 mM of o-toluidine using 100 g of carriers were pH 3 +/- 0.5, 1 mM of Fe(2+), and 17 mM of H(2)O(2). Removal of o-toluidine and COD in the actual experiment was higher than predicted, whereas removal of total iron was slightly lower. The kinetic study showed that the initial rate and rate constant (k) of o-toluidine degradation in the fluidized-bed Fenton process correlated Fe(2+) concentration. In the Fe(2+)/H(2)O(2) stage, high concentration of H(2)O(2) produced a scavenging effect. CONCLUSIONS: The predicted removal efficiencies of o-toluidine and COD were 90.2% and 41.4%, respectively. Moreover, the removals of o-toluidine and COD in the actual experiment were 99.8% and 61.8%, respectively. PMID- 21701862 TI - Possible use of Serratia marcescens in toxic metal biosorption (removal). AB - BACKGROUND, AIM AND SCOPE: Metal pollution is a serious problem for environmental safety and programmes of monitoring and bioremediation are needed. Among the processes of bioremediation, the use of microbes to remove and degrade contaminants is considered a biotechnological approach to clean up polluted environments. AIM: The aim of this study was to evaluate the ability of Serratia marcescens in Pb, Cd and Cr removal and the potential use of these bacteria in toxic metal bioremediation from polluted environments. METHODS: A short-term study (120 min) was carried out to study the bacterial growth in the presence of sub-inhibitory concentrations of each metal analysed and the kinetics of metal biosorption in S. marcescens strain. In addition, metal influence on the biosynthesis of the red pigment 'prodigiosina' by S. marcescens was monitored. RESULTS: The results obtained in this study show metals biosorption by S. marcescens (range: 0.0133-0.213 MUg/g for Pb; 0.097-0.1853 MUg/g for Cd; and 0.105-0.176 MUg/g for Cr) and confirm the possible use of this bacterium to realize bioremediation processes, especially for Pb removal, and as a bioindicator of metal pollution. PMID- 21701863 TI - [Asymptomatic infections in man: a Trojan horse for the introduction and spread of mosquito-borne arboviruses in non-endemic areas?]. AB - In mosquito-borne arbovirus infections in man the asymptomatic cases are much more frequent than the symptomatic ones, but their true role in the introduction and subsequent spread of such diseases in non-endemic areas remains to be clarified. We have collected pertinent data from English and French literature from 1952 to 2010 through Pubmed and other bibliographic sources. Data were analysed to assess if viremia in asymptomatic human arbovirus infections might be sufficient to represent a true risk for introduction in non-endemic areas. During dengue and chikungunya fever outbreaks, humans are believed to be the only vertebrate hosts. Since a very large number of individuals are infected and since viremic levels are known to vary by many orders of magnitude in symptomatic patients, it is reasonable to augur that a proportion of asymptomatic cases might reach levels of viremia sufficient to infect competent mosquitoes. Moreover, in both dengue and chikungunya fever, nosocomial infections have been identified representing an alternative opportunity for virus introduction in non-endemic areas. In zoonotic mosquito-borne arbovirus infections such as Japanese encephalitis or West Nile infection, the situation is quite different since humans are considered as "dead-end" hosts. However, the very large number of asymptomatic cases arising during outbreaks and the existence of newly recognised ways of contamination (blood transfusion, organ transplantation, transplacental way etc.) may also ensure their introduction and subsequent spread in new areas. PMID- 21701864 TI - Transverse and tangential orientation of predicted transmembrane fragments 4 and 10 from the human multidrug resistance protein (hMRP1/ABCC1) in membrane mimics. AB - The human multidrug-resistance-associated protein 1 (hMRP1/ABCC1) belongs to the large ATP-binding cassette transporter superfamily. In normal tissues, hMRP1 is involved in tissue defense, whereas, in cancer cells, it is overproduced and contributes to resistance to chemotherapy. We previously investigated the folding properties of the predicted transmembrane fragments (TM) TM16, and TM17 from membrane-spanning domain 2 (MSD2). These TMs folded only partially as an alpha helix and were located in the polar headgroup region of detergent micelles used as membrane mimics (Vincent et al. in Biochim Biophys Acta 1768:538-552, 2007; de Foresta et al. in Biochim Biophys Acta 1798:401-414, 2010). We have now extended these studies to TM4 and TM10, from MSD0 and MSD1, respectively. TM10 may be involved in the substrate translocation pathway whereas the role of TM4 is less predictable, because few studies have focused on MSD0, a domain present in some hMRP1 homologs only. Each TM contained a single Trp residue (W142 or W553) acting as an intrinsic fluorescent probe. The location and dynamics of the TMs in dodecylphosphocholine (DPC) or n-dodecyl-beta-D: -maltoside (DDM) micelles were studied by Trp steady-state and time-resolved fluorescence, including quenching experiments. Overall TM structure was analyzed by far-UV circular dichroism studies in detergent micelles and TFE. TM10 behaved similarly to TM16 and TM17, with an interfacial location in micelles consistent with a possible role in lining the transport pore. By contrast, TM4 behaved like a classical TM fragment with a high alpha-helical content, and its transmembrane insertion did not require its interaction with other TMs. PMID- 21701865 TI - Secondary structure determination by FTIR of an archaeal ubiquitin-like polypeptide from Natrialba magadii. AB - The ubiquitin protein belongs to the beta-grasp fold family, characterized by four or five beta-sheets with a single alpha-helical middle region. Ubiquitin like proteins (Ubls) are structural homologues with low sequence identity to ubiquitin and are widespread among both eukaryotes and prokaryotes. We previously demonstrated by bioinformatics that P400, a polypeptide from the haloalkaliphilic archaeon Natrialba magadii, has structural homology with both ubiquitin and Ubls. This work examines the secondary structure of P400 by Fourier transform infrared spectroscopy (FTIR). After expression in Escherichia coli, recombinant P400 (rP400) was separated by PAGE and eluted pure from zinc-imidazole reversely stained gels. The requirement of high salt concentration of this polypeptide to be folded was corroborated by intrinsic fluorescence spectrum. Our results show that fluorescence spectra of rP400 in 1.5 M KCl buffer shifts and decreases after thermal denaturation as well as after chemical treatment. rP400 was lyophilized and rehydrated in buffer containing 1.5 M KCl before both immunochemical and FTIR tests were performed. It was found that rP400 reacts with anti-ubiquitin antibody after rehydration in the presence of high salt concentrations. On the other hand, like ubiquitin and Ubls, the amide I' band for rP400 shows 10% more of its sequence to be involved in beta-sheet structures than in alpha-helix. These findings suggest that P400 is a structural homologue of the ubiquitin family proteins. PMID- 21701866 TI - Stereotactic radiosurgery of essential trigeminal neuralgia using Leksell Gamma Knife model C with automatic positioning system: technical nuances and evaluation of outcome in 130 patients with at least 2 years follow-up after treatment. AB - The objective of the present study was the evaluation of outcome in 130 patients with essential trigeminal neuralgia, who were treated using Leksell Gamma Knife model C with automatic positioning system and followed at least 24 months thereafter. Radiosurgery was guided by fused thin-sliced magnetic resonance (MR) and "bone window" computed tomographic (CT) images. In all cases, retrogasserian part of the trigeminal nerve at the level of trigeminal incisura was selected as a target, and one 4-mm collimator was used for delivery of the maximum irradiation dose of 90 Gy. The coordinates of the isocenter were adjusted for positioning of the nerve in the center of 80% isodose area, and were corrected in each individual case with regard to presence of distortion artifacts on MR images. Initial relief of the typical paroxysmal facial pain was marked in 127 patients (98%) within a median interval of 3 weeks after treatment. However, in 23 patients the pain re-appeared later on. Overall, at the time of the last follow-up 112 patients (86%) were pain-free, including 86 who remained both pain- and medication-free after initial radiosurgery. In 31 cases (24%), treatment was complicated by facial hypesthesia and/or paresthesia. In conclusion, radiosurgery of essential trigeminal neuralgia results in a high rate of initial pain relief, but pain recurrences and associated complications are not uncommon. The outcome may be influenced by various technical nuances; therefore, treatment should be preferably done in specialized clinical centers with sufficient expertise in the management of this disorder. PMID- 21701867 TI - Unique sacral location of an arteriovenous fistula of the filum terminale associated with diastematomyelia and lowered spinal cords. PMID- 21701868 TI - The italian communist party and the "lysenko affair" (1948-1955). AB - This article explores the impact of the VASKhNIL conference upon the cultural policy of the Italian Communist Party (PCI) and Italian communist biology, with particular attention to the period between 1948 and 1951. News of the Moscow session did not appear in the Italian news media until October, 1948, and for the next three years party biologists struggled over whether to translate the official transcript of the proceedings, The Situation in Biological Science, into Italian. This struggle reveals the complex efforts of the PCI to confirm the ideological and political connection with the Soviet Union, without completely alienating significant milieus of the democratic and antifascist culture in Italy. The apparent impossibility of doing both is indicated by the fact that the project was finally abandoned in March-April, 1951. The article is divided into three sections, each focused on different actors and their response to Lysenkoism. The first section outlines the features of the PCI's pro-Lysenko campaign, with particular regard to the intellectual militancy and organizational commitment of Emilio Sereni, head of PCI's Cultural Commission between 1948 and 1951. The second section analyzes the reaction of the three most important figures in Italian communist biology during this period, Massimiliano Aloisi, Franco Graziosi and Emanuele Padoa. The third section interprets the decision not to publish a translation of The Situation in Biological Science as a consequence of the conflicts between PCI cultural program and the editorial policy of the left-wing publishing house Giulio Einaudi Editore. PMID- 21701869 TI - Effects of propionic acid and pH on ethanol fermentation by Saccharomyces cerevisiae in cassava mash. AB - The effects of propionic acid on ethanol and glycerol production by Saccharomyces cerevisiae in cassava mash were examined along with the influence of pH (4.0, 5.0, and 6.0) and of dissolved solids content (22%, 25%, and 27%). Inhibition by propionic acid increased as solids content increased and medium pH declined. Complete inhibition of ethanol fermentation was observed in mashes at pH 4.0 (60 mM propionic acid for 22% solids and 45 mM for 25% and 27%). Glycerol production linearly decreased with increased undissociated propionic acid concentration in all mashes at all pH levels, which partly contributed to increased final ethanol production when propionic acid concentration in mashes was low (<= 30 mM). PMID- 21701871 TI - Influence of illumination on settlement of diatom Navicula sp. AB - Diatoms are responsible for biofouling, which causes many problems in various marine industries. This study examined the effects of different light conditions (intensity, incident direction, time of illumination) on the settling behavior of the marine diatom Navicula sp. on glass surfaces. The density of this diatom's settlement on glass was strongly influenced by light conditions. Moreover, very weak light emitted on the bottom of the culture dish could also rapidly inhibit diatom settlement. These phenomena were explained by spatial interference between chloroplast and holdfast-like structures inside the thecae. The holdfast-like structure is observed to be responsible for diatom locomotion and hence the settlement behavior. It was proposed that the interrelation of illumination and attachment of diatoms allowed them to better adapt to the habitat with higher efficiency of attachment and successive reproduction. PMID- 21701870 TI - Very long-term follow-up of adults treated in infancy for hydrocephalus. AB - PURPOSE: The purpose of this study is to perform a population-based, very long term follow-up of adults who had been shunt treated for hydrocephalus in infancy. METHODS: The 72 children with hydrocephalus born in 1967-1978 in western Sweden, who had participated in a follow-up at school age, were re-examined at 30-43 years of age. The 29 with mental retardation were described in terms of developmental level and survival, whereas the remaining 43 were invited to take part in a follow-up and 28 accepted. The assessments included a semi-structured interview pertaining to medical issues, academic achievements and social function. RESULTS: Six children had died, i.e. a mortality rate of 8%. Mental retardation was present in 29 (40%), severe (IQ <50) in 13 and mild (IQ 50-70) in 16. Four of the 28 (14%) had cerebral palsy and 8 (28%) had other motor problems. Five (18%) had epilepsy and nine (32%) had visual impairments. A total of 20 (71%) reported some kind of health problem. Repeated revisions of the shunt had been performed in 23 (82%). Many worried about their shunt and requested a systematic medical follow-up. Nineteen subjects (68%) lived with a partner and 16 (57%) were parents. The majority had completed secondary school and 9 (32%) had completed university studies, while 18 (64%) worked full time, equal to the general population. CONCLUSION: In general, the group of normally gifted individuals with hydrocephalus, who had been shunt treated during infancy, was functioning well as adults and participated in society to the same extent as other people. PMID- 21701872 TI - Is intravascular ultrasound beneficial for percutaneous coronary intervention of bifurcation lesions? Evidence from a 4,314-patient registry. AB - BACKGROUND: Coronary bifurcations remain a challenging lesion subset for percutaneous coronary intervention (PCI). It is unclear whether intravascular ultrasound (IVUS) guidance can improve PCI results in bifurcations. We aimed to compare IVUS-guided PCI versus standard PCI in a large registry of patients undergoing PCI for bifurcations in the drug-eluting stent era. METHODS: A multicenter, retrospective study was conducted enrolling consecutive patients undergoing bifurcation PCI between January 2002 and December 2006 at 22 centers. The primary end-point was the long term rate of major adverse cardiac events [MACE, i.e. death, myocardial infarction or target lesion revascularization (TLR)]. RESULTS: A total of 4,314 patients were included, 226 (5.2%) undergoing IVUS-guided PCI, and 4,088 (94.8%) standard PCI. Early (30-day) outcomes were similar in the two groups, with MACE in 1.3 versus 2.1%, respectively, death in 0.9 versus 1.0%, and stent thrombosis in 0 versus 0.6% (all p > 0.05). After 24 +/- 15 months, unadjusted rates of MACE were 17.7 versus 16.4%, with death in 2.7 versus 4.9%, myocardial infarction in 4.4 versus 3.7%, TLR in 15.0 versus 12.3%, and stent thrombosis in 3.1 versus 2.7% (all p > 0.05). Even at multivariable Cox proportional hazard analysis with propensity score adjustment, IVUS was not associated with any statistically significant impact on the risk of MACE, death, myocardial infarction, TLR (neither on the main branch nor on the side branch), or stent thrombosis (all p > 0.05). CONCLUSIONS: Despite a sound rationale to choose stent size, optimize stent expansion and guide kissing inflation, IVUS usage during PCI for coronary bifurcation lesions was not associated with significant clinical benefits in this large retrospective study. PMID- 21701873 TI - Massive ascites generation following pacemaker infection: a case report. PMID- 21701874 TI - Revision hip arthroplasty using a cementless modular tapered stem. AB - PURPOSE: Here we report the short-term clinical and radiological results of the Profemur(r)-R cementless modular revision stem. METHODS: Between June 2002 and May 2006, 68 revision hip arthroplasties were consecutively performed using this stem. Survival at a mean follow-up of 5.2 years was 94%. According to the Paprosky classification, the femoral defect was classified as type 1 in 39 hips (57.3%), type 2 in 18 hips (26.5%), type 3A in ten hips (14.7%) and type 3B in one hip (1.5%). RESULTS: The Harris Hip Score was 49.57 before surgery and averaged 78.28 at the latest follow-up. The Merle d'Aubigne score improved from 9.15 preoperatively to 14.30 postoperatively. Stem stability rated according to the Agora Roentgenographic Assessment (ARA) scoring system averaged 5.22, suggesting a high likelihood of a durable implant. CONCLUSION: The revision prosthesis examined in this study can be considered a viable and useful option in revision hip arthroplasty, even in patients with bony femoral defects. PMID- 21701875 TI - Isolated mesopic rod and cone electroretinograms realized with a four-primary method. AB - The purpose of this study was to evaluate the feasibility of measuring rod and cone electroretinograms (ERGs) at a single mesopic adaptation level. To accomplish this, a four-primary photostimulator was implemented using a commercially available ERG system (Diagnosys ColorDome) to generate three types of stimuli that temporally modulated rods alone, cones alone, and rods and cones simultaneously. For each stimulus type, ERGs were recorded as a function of temporal frequency (2, 4, 8, or 16 Hz) and mesopic light levels (0.02, 0.16, or 1.26 cd/m(2)) in normal observers and patients with retinitis pigmentosa (RP) or cone-rod degeneration. The normal observers ERG waveforms showed a clear periodic pattern, mirroring the sinusoidal stimuli. At all light levels, rod responses were always higher than cone responses for temporal frequencies between 2 and 8 Hz, suggesting that rods dominated the responses. Cone responses were minimal at the lowest light level and increased with increases in light level. The amplitude of the response to the combined stimuli was intermediate between that of the isolated cone and the isolated rod stimuli for all light levels. Good receptoral isolation was confirmed by the results showing (1) minimal or no rod ERGs but recordable cone ERGs in the patients and (2) high correlation between the ERG amplitudes obtained from the four-primary method and those from the ISCEV standard clinical protocol in normal observers. PMID- 21701877 TI - Neuronal model with distributed delay: analysis and simulation study for gamma distribution memory kernel. AB - A single neuronal model incorporating distributed delay (memory)is proposed. The stochastic model has been formulated as a Stochastic Integro-Differential Equation (SIDE) which results in the underlying process being non-Markovian. A detailed analysis of the model when the distributed delay kernel has exponential form (weak delay) has been carried out. The selection of exponential kernel has enabled the transformation of the non-Markovian model to a Markovian model in an extended state space. For the study of First Passage Time (FPT) with exponential delay kernel, the model has been transformed to a system of coupled Stochastic Differential Equations (SDEs) in two-dimensional state space. Simulation studies of the SDEs provide insight into the effect of weak delay kernel on the Inter Spike Interval(ISI) distribution. A measure based on Jensen-Shannon divergence is proposed which can be used to make a choice between two competing models viz. distributed delay model vis-a-vis LIF model. An interesting feature of the model is that the behavior of (CV(t))((ISI)) (Coefficient of Variation) of the ISI distribution with respect to memory kernel time constant parameter eta reveals that neuron can switch from a bursting state to non-bursting state as the noise intensity parameter changes. The membrane potential exhibits decaying auto correlation structure with or without damped oscillatory behavior depending on the choice of parameters. This behavior is in agreement with empirically observed pattern of spike count in a fixed time window. The power spectral density derived from the auto-correlation function is found to exhibit single and double peaks. The model is also examined for the case of strong delay with memory kernel having the form of Gamma distribution. In contrast to fast decay of damped oscillations of the ISI distribution for the model with weak delay kernel, the decay of damped oscillations is found to be slower for the model with strong delay kernel. PMID- 21701876 TI - Phenotypic expression of X-linked retinoschisis in Chinese families with mutations in the RS1 gene. AB - To assess the clinical features of and identify genetic defects in six Chinese families with X-linked retinoschisis (XLRS). Patients were recruited from ophthalmic clinics in Peking Union Medical College Hospital. A cohort of six unrelated families was identified. Clinical evaluation was performed on eight affected males (six probands) and five female carriers. Genomic DNA was extracted from peripheral leukocytes. All exons and the flanking introns of the RS1 gene were amplified by polymerase chain reaction and screened for mutations by direct DNA sequencing. One hundred control X chromosomes were screened by direct sequencing to exclude nonpathogenic polymorphisms. Typical foveal schisis was found in all eight patients, while peripheral schisis was noted in six patients. The six probands displayed electronegative electroretinography (ERG) in the standard combined response, while the remaining two patients showed non recordable waveforms. Two novel mutations (W112X and S134P) and three previously identified missense mutations (R102Q, R200H, and R213W) were found. None of these novel nucleotide variations were observed in any of 100 ethnically matched control chromosomes. Chinese patients with XLRS displayed variability in phenotypes. Novel mutations in RS1 were associated with these patients. Identification of the disease-causing mutations in suspected families can help to confirm the diagnosis for the patients and recommend genetic counseling for the female carriers. In addition, genetic testing could provide important information for future treatment. PMID- 21701878 TI - Role of CAMKII in reinforcement learning: a computational model of glutamate and dopamine signaling pathways. AB - Timely release of dopamine (DA) at the striatum seems to be important for reinforcement learning (RL) mediated by the basal ganglia. Houk et al. (in: Houk et al (eds) Models of information processing in the basal ganglia, (1995) proposed a cellular signaling pathway model to characterize the interaction between DA and glutamate pathways that have a role in RL. The model simulation results, using GENESIS KINETIKIT simulator, point out that there is not only prolongation of duration as proposed by Houk et al. (1995), but also an enhancement in the amplitude of autophosphorylation of CaMKII. Further, the autophosphorylated form of CaMKII may form a basis for the "eligibility trace" condition required in RL. This simulation study is the first of its kind to support the comprehensive theoretical proposal of Houk et al. (1995). PMID- 21701879 TI - Different CHEK2 germline mutations are associated with distinct immunophenotypic molecular subtypes of breast cancer. AB - Germline mutations in BRCA1 were already linked to basal-like subtype of immunophenotypic molecular classification of breast cancer (BC). However, it is not known whether mutations in other BC susceptibility genes are associated with molecular subtypes of this cancer. We tested the hypothesis that distinct mutations in another BC susceptibility gene involved in DNA repair, i.e., CHEK2 may be associated with particular immunophenotypic molecular subtypes of this cancer. Two groups of patients: 1255 with BCs and 5496 healthy controls were genotyped for four CHEK2 mutations (I157T and three truncating mutations: 1100delC, IVS2 + 1G > A, del5395). BCs were tested by immunohistochemistry on tissue microarrays for ER, PR, HER-2, EGFR, and CK5/6 and were assigned to appropriate subtypes of immunophenotypic molecular classification. There was a significant association between CHEK2 mutations and the immunophenotypic molecular classification (P = 0.004). CHEK2-associated cancers were predominantly luminal (108/117 = 92.3%). CHEK2-I157T variant was associated with the luminal A subtype (P = 0.01), whereas CHEK2-truncating mutations were associated with the luminal B subtype (P = 0.005). Comparing the prevalence of CHEK2 mutations in BC with controls revealed that carriers of an I157T variant had OR of 1.80 for luminal A subtype and carriers of truncating mutations had OR of 6.26 for luminal B subtype of BC. To our knowledge, this is the first study showing that specific mutations in the same susceptibility gene are associated with different immunophenotypic molecular subtypes of BC. This association represents independent evidence supporting the biological significance of immunophenotypic molecular classification of BC. PMID- 21701880 TI - Low-intensity infrared laser increases plasma proteins and induces oxidative stress in vitro. AB - Low-intensity laser therapy is based on the excitation of endogenous chromophores in biotissues and free-radical generation could be involved in its biological effects. In this work, the effects of the low-intensity infrared laser on plasma protein content and oxidative stress in blood from Wistar rats were studied. Blood samples from Wistar rats were exposed to low-intensity infrared laser in continuous wave and pulsed-emission modes at different fluencies. Plasma protein content and two oxidative stress markers (thiobarbituric acid-reactive species formation and myeloperoxidase activity) were carried out to assess the effects of laser irradiation on blood samples. Low-intensity infrared laser exposure increases plasma protein content, induces lipid peroxidation, and increases myeloperoxidase activity in a dose- and frequency-dependent way in blood samples. The low-intensity infrared laser increases plasma protein content and oxidative stress in blood samples, suggesting that laser therapy protocols should take into account fluencies, frequencies, and wavelengths of the laser before beginning treatment. PMID- 21701881 TI - Cross-sectional imaging of acute abdominal conditions in the oncologic patient. AB - Cross-sectional imaging of acute abdominal conditions encompasses a broad differential diagnosis, including traumatic, inflammatory, and infectious etiologies. In addition, an underappreciated contributor to the acute abdomen is oncologic disease and its treatment. Oncologic patients are at increased risk in the development of numerous acute abdominal conditions due to a combination of tumor invasion, sequelae of treatment, and altered immune response. Cross sectional imaging of the oncologic patient poses several unique challenges due to the need to be able to evaluate surgically altered anatomy, evaluation of treatment response, and potential untoward effects of neoplasia and its treatment. The radiologist plays a pivotal role in the multidisciplinary approach to cancer diagnosis and management. In addition to diagnosis and follow-up assessment of disease response, the radiologist should be familiar with the imaging findings of acute conditions affecting the oncologic patient to optimize patient care. Recognition of key imaging findings can allow prompt diagnosis and facilitate treatment for potentially lethal abdominal conditions in the complex oncologic patient, thereby reducing morbidity and mortality. PMID- 21701883 TI - Ivabradine and nightmares: a previously unreported adverse reaction. PMID- 21701882 TI - Warfarin drug interactions: a comparative evaluation of the lists provided by five information sources. AB - PURPOSE: Detecting potential drug interactions can lead to early interventions that protect patients from serious drug-related problems. The aim of this study was to evaluate the agreement among the lists of warfarin interactions provided by five information sources. METHODS: The lists of warfarin interactions and the corresponding severity ratings and documentation levels presented by the three compendia and by the World Health Organization (WHO) Model Formulary were all compared, and each list was compared to that provided on the package insert of Marevan, a brand of warfarin. The compendia used were: Drug Interaction Facts, Drug Interactions: Analysis and Management and DRUG-REAX. A kappa coefficient was used to calculate the agreement among the sources. RESULTS: A total of 537 interactions were listed. Only 13 (2.4%) were common to the five sources. The global Fleiss' kappa coefficient was -0.0080, which indicated poor agreement. Eleven warfarin interactions appeared only in the Marevan package insert. Importantly, 243 interactions (45.3% of the total) were deemed significant in at least one compendium. Only two warfarin interactions were reported as critical by all three compendia and by WHO. The most critical interactions cited by the compendia were missing from the package insert. CONCLUSIONS: Poor agreement was found among five sources listing warfarin interactions. Potentially severe clinical consequences might occur due to these discrepant recommendations. Finally, the lack of standard terminology and clinical guidance, as well as the possible inaccuracy of severity ratings and documentation might contribute to heterogeneous procedures in clinical practice. PMID- 21701884 TI - Mutation analysis of KRAS prior to targeted therapy in colorectal cancer: development and evaluation of quality by a European external quality assessment scheme. AB - In Europe, the use of anti-EGFR monoclonal antibodies is restricted to Kirsten RAS (KRAS) wild-type colorectal tumors. Information on the KRAS status of the patients tumor is thus key for clinical practice; however, there is little guidance or definition on which KRAS mutations to assess and how to assess them. To ensure the consistency and the quality of KRAS test results in Europe, an interlaboratory control network needs to be set up. This pilot study aimed to identify the variables that need to be assessed in a quality control scheme and to provide a first assessment in a selected set of laboratories. Fourteen different tumor cases were circulated between 13 laboratories by a central laboratory acting as the referent for the mutation status determination. This study illustrated that of 13 experienced laboratories that perform KRAS testing only ten correctly identified the KRAS in all 14 cases that were circulated. There was no harmonization in DNA isolation and KRAS mutation detection method between the laboratories. These results indicate that future standardization is needed in KRAS mutation detection methodology. An expansion of the European Society of Pathology KRAS program could identify areas of difficulty in KRAS testing and provide the basis for harmonization. PMID- 21701885 TI - Concentrations of polycyclic aromatic hydrocarbon in the surface sediments from inter-tidal areas of Kenting coast, Taiwan. AB - The main objective of this study was to investigate the concentrations of polycyclic aromatic hydrocarbons (PAHs) in inter-tidal sediments of the Kenting coast, Taiwan, to assess the levels and origin of PAHs, and to provide useful information on the potential ecological risk of PAHs to benthic organisms. The total concentrations of 38 PAHs ranged from 0.2 to 493 ng/g dry weight. The high variation in total PAH concentrations was caused by the sand content of the sediment in the area. Compared with other coasts and bays in the world, the concentrations of PAHs in the inter-tidal surface sediment of the Kenting coast is low to moderate. Based on the sediment quality guidelines, the total PAH concentrations were below the effects range low value, indicating that the PAH levels in the Kenting area were within minimal effects ranges for benthic organisms. Principal component analysis and isomer ratios were analyzed to identify the contamination source in the inter-tidal surface sediment of the Kenting coast. The results of compounds' pattern and origin analysis suggest that the source of PAHs in the inter-tidal surface sediment of the Kenting coast is the combustion of petroleum and biomass. PMID- 21701886 TI - Determination of cobalt, nickel and iron at trace level in natural water samples by in-column chelation-reversed phase high-performance liquid chromatography. AB - This paper reports the utilization of 4-(2-pyridylazo) resorcinol (PAR) as a chelating reagent for in-column derivatization and the determination of trace Co, Fe, and Ni ions by reversed-phase high-performance liquid chromatography with photodiode array detector. A good separation of Co, Fe, and Ni chelates were achieved by using an Inertsil ODS-3 column and a mobile phase, consisted of methanol-THF-water mixture (50:5:45) containing ammonium acetate buffer (pH 5.0) and PAR. After full optimization, good repeatability of retention times (relative standard deviation (RSD) < 0.05%) and peak areas (RSD < 1.7%) was achieved as well as a good linearity (r (2) > 0.9991). The detection limits (S/N = 3), expressed as micrograms per liter, were 0.50 (Co), 9.07 (Fe), and 2.00 (Ni). The applicability and the accuracy of the developed method were estimated by the analysis of spiked water samples and certified reference material BCR 715 wastewater-SRM. PMID- 21701888 TI - Geostatistical 3-dimensional integration of measurements of soil magnetic susceptibility. AB - In soil magnetometry, two types of measurements are usually performed. The first type is measurements performed on the soil surface, frequently using an MS2D sensor. The second type includes measurements of magnetic susceptibility carried out in the soil profile, usually to a depth of about 30 cm. Up to now, such measurement results were analyzed separately. However, it is possible and advantageous to integrate these two types of measurements. The goal of the study was to integrate measurements of magnetic susceptibility performed on the soil surface and in the soil profile. More specifically, the goal was to obtain 3 dimensional spatial distributions of magnetic susceptibility of the topsoil horizon. Results show that it is possible to effectively integrate measurements of magnetic susceptibility performed on the soil surface and in the soil profile. Moreover, the 3-dimensional spatial distribution that is obtained shows the magnetic susceptibility of the top 20 cm of soil, which includes the soil horizons where most of the heavy metals are accumulated. The analysis of such a spatial distribution can be very helpful in delineating areas where the heightened magnetic susceptibility is a result of the influence of anthropogenic pollution from those areas where it results from lithogenic origin. It is possible to investigate where the volumes of soil with heightened magnetic susceptibility are located in the soil profile and in this way investigate which characteristic type of soil profile it is. PMID- 21701887 TI - Characterization of different road dusts in opencast coal mining areas of India. AB - Dust from haul and transport roads are the major source of air pollution in opencast coal mining areas. Dust generated during mining operations pollutes air which causes different health problems. Various available techniques are implemented in the field to minimize and control dust in mining areas. However, they are not very effective because dust deposited on road surfaces are not removed by these techniques. For effective control of dust in opencast mining areas, it has to be regularly collected from road surfaces and may be converted into solid form, and subsequently can be used as a domestic fuel considering its physicochemical properties. The present paper describes a comparative study of qualitative and quantitative aspects of road dust samples of four coalfields of India. The pH of the dust was found to be in the range of 5.1-7.7. Moisture, ash, volatile matter, fixed carbon, water-holding capacity, bulk density, and specific gravity of dust samples were found to be in the range of 0.5-3.0%, 45-76%, 12.6 20.0%, 10.2-45.3%, 21.17-31.71%, 1.15-1.70, and 1.73-2.30 g cm(-3), respectively. Observing the overall generation and characteristics of coal dust, it is suggested that coal dust from haul and transport roads of mining areas can be effectively collected and used as domestic fuel. PMID- 21701889 TI - Assessing the risk posed by high-turbidity water to water supplies. AB - The objective of this study is to assess the risk of insufficient water supply posed by high-turbidity water. Several phenomena can pose risks to the sufficiency of a water supply; this study concerns risks to water treatment plants from particular properties of rainfall and raw water turbidity. High turbidity water can impede water treatment plant operations; rainfall properties can influence the degree of soil erosion. Thus, water turbidity relates to rainfall characteristics. Exceedance probabilities are presented for different rainfall intensities and turbidities of water. When the turbidity of raw water is higher than 5,000 NTU, it can cause operational problems for a water treatment plant. Calculations show that the turbidity of raw water at the Ban-Sin water treatment plant will be higher than 5,000 NTU if the rainfall intensity is larger than 165 mm/day. The exceedance probability of high turbidity (turbidity >5,000 NTU) in the Ban-Sin water treatment plant is larger than 10%. When any water treatment plant cannot work regularly, its ability to supply water to its customers is at risk. PMID- 21701890 TI - Long-term seasonal changes of the Danube River eco-chemical status in the region of Serbia. AB - Seasonal spatial and temporal changes of selected eco-chemical parameters in section of the Danube River flowing through Serbia were analyzed. Data for electrical conductivity (EC), dry and suspended matter, residue on ignition, chemical oxygen demand (COD), biochemical oxygen demand (BOD-5), ultraviolet extinction, dissolved oxygen (DO), oxygen saturation, pH, nitrates, total phosphorus, and nitrogen were collected between 1992 and 2006. The use of monthly medians combined with linear regression and two-sided t test has been proven to be the best approach for resolving trends from natural variability of investigated parameters and for determining trend significance. Patterns of temporal changes between different months were examined. It was also determined that spatial trends of some parameters oscillate in predictable manner, increasing in one part of the year and declining in the other. Regression slope coefficients, an excellent indicator for determining when the water quality is changing the most along the course of the Danube, reach their maximum during summer for temperature (t), electric conductivity, nitrates, and total N, while in the same season suspended matter, COD, BOD-5, DO, and oxygen saturation coefficients reach their minimum. Correlations for used data sets of selected parameters were analyzed for better understanding of their behavior and mutual relations. It was observed that as Danube flows through Serbia, its general eco chemical status either stagnates or improves, but the rate of river self purification often depends on the season of the year. PMID- 21701892 TI - Fish scales as indicators of wastewater toxicity from an international water channel Tung Dhab drain. AB - The effect of wastewater exposure on scales and chromatophores of freshwater fish Channa punctatus was studied using wastewater dilutions (60-100%) from an international water channel Tung Dhab drain at an interval of 15 and 30 days. The exposed fish showed significant alterations such as uprooted and damaged lepidonts and dispersal of chromatophores. These observations strongly suggest that fish scales can be successfully employed as indicators of wastewater pollution. PMID- 21701891 TI - Spatial distribution and multiple sources of heavy metals in the water of Chaohu Lake, Anhui, China. AB - In this study, a survey for the spatial distribution of heavy metals in Chaohu Lake of China was conducted. Sixty-two surface water samples were collected from entire lake including three of its main river entrances. This is the first systematic report concerning the content, distribution, and origin of heavy metals (Cu, Cr, Cd, Hg, Zn, and Ni) in the Chaohu Lake water. The results showed that heavy metals (Cu, Cr, Zn, and Ni) concentrations in the estuary of Nanfei River were relatively higher than those in the other areas, while content of Hg is higher in the southeast lake than northwest lake. Moreover, Cd has locally concentration in the surface water from the entire Chaohu Lake. The heavy metal average concentrations, except Hg, were lower than the cutoff values for the first-grade water quality (China Environment Quality Standard) which was set as the highest standard to protect the social nature reserves. The Hg content is between the grades three and four water quality, and other heavy metals contents are higher than background values. The aquatic environment of Chaohu Lake has apparently been contaminated. Both the cluster analysis (CA) and correlation analysis provide information about the origin of heavy metals in the Lake. Our findings indicated that agricultural activities and adjacent plants chimneys may contribute the most to Cd and Hg contamination of Chaohu Lake, respectively. PMID- 21701893 TI - A case study of trace metals in suspended particulate matter and biota before wastewater treatment plant from the Izmir Bay, Turkey. AB - The concentrations of trace metals (Cu, Zn, Mn, Ni, and Fe) from suspended particulate matter (SPM) and biota in Izmir Bay (Eastern Aegean Sea) were studied in order to evaluate the environmental impact of the anthropogenic metals before building of Wastewater Treatment Plant. SPM samples were collected in wet and dry periods from Izmir Bay. Metal concentrations in SPM (Cu, 0.36-2.19; Mn, 0.07 11.3; Ni, 0.43-7.81; Zn, 7.33-269; Fe, 1.00-266 MUg dm(-3)) were comparable to those reported for other moderately polluted bays. Maximum metal concentrations in SPM were observed during summer season. SPM metal concentrations displayed a clear spatial trend with values increasing with proximity to urban centers. Cu and Zn concentrations in SPM were especially high in the inner bay. SPM were found to be contaminated by Zn. The vertical profile of Mn, Zn, and Ni concentrations in SPM had a maximal value at the upper layer and decreased to minimal value at the bottom layer of the inner bay in summer, in contrast to the observed pattern of Fe and Cu. Maximum Cu concentrations were obtained in Penaeus kerathurus. Also, maximum Zn and Fe concentrations were found in Mytilus galloprovincialis. Relatively high Cu levels were found in Sardina pilcardus and Mullus barbatus than other fish species. Besides, Cu levels were lower in Diplodus annularis and Merluccius merluccius. Finally, metal levels in biota tissues were lower than the limits of European Dietary Standards and Guidelines. PMID- 21701894 TI - Trophic states of creeks and their relationship to changes in water level in Xixi National Wetland Park, China. AB - Urban wetland parks are a new type of urban park that have developed rapidly in recent years and have caught the attention of multiple governmental departments. The objective of this paper was to describe the trophic states of creeks and their relationship to water levels in an urban wetland park in Xixi, China. The study was based on temporal and spatial data collected monthly between March 2009 and March 2010. The results indicated that: (1) water quality significantly changed from upstream to downstream in study creeks. From upstream to downstream, water quality of creeks I and III improved; however, the water quality of creek IV and V declined; (2) trophic states in Xixi creeks differed according to seasons. Overall, the nutrition in creeks was measured at the slight eutrophication level. Nutrition was highest in summer and lowest in winter; (3) the relationship between water quality and water level differed dramatically between creeks. Water quality and water level in creek I was significantly negatively correlated, while no obvious trends were observed in other creeks. In order to improve water quality in creeks, the valid technique is to strengthen the management of inflowing water quality and then control water levels. PMID- 21701895 TI - Spinocerebellar ataxia types 1, 2, 3 and 6: the clinical spectrum of ataxia and morphometric brainstem and cerebellar findings. AB - To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1-3), speech (item 4) and the limb kinetic subscore (items 5-8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose-finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders. PMID- 21701897 TI - Synthesis of hydroxyferrocifen and its abilities to protect DNA and to scavenge radicals. AB - The aim of this work was to clarify the effect of the position of the hydroxyl group on the antioxidant capacity of hydroxyferrocifen by means of a chemical kinetic method. Propionylferrocene and benzoylferrocene condensed with 4 hydroxydiphenylketone, 3,4-dihydroxydiphenylketone, and 4,4' dihydroxydiphenylketone to form FP3, FP4, FB3, and FB4 with a single hydroxyl group and FP34, FP44, FB34, and FB44 with two hydroxyl groups. These hydroxyferrocifens were applied in Cu(2+)/glutathione (GSH)-induced, hydroxyl radical (.OH)-induced, and 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH) induced oxidation of DNA, and in trapping 2,2'-azinobis(3-ethylbenzothiazoline-6 sulfonate) cationic radical (ABTS(+.)). It was found that these hydroxyferrocifens acted as prooxidants in Cu(2+)/GSH-induced oxidation of DNA and exhibited very weak effects on .OH-induced oxidation of DNA. FP3, FP4, FB3, and FB4 can only retard the rate of AAPH-induced oxidation of DNA, whereas FP44, FB44, FB34, and FP34 can trap 11.9, 7.1, 6.2, and 4.9 radicals, respectively, in AAPH-induced oxidation of DNA. The ability to trap ABTS(+.) followed the order FB4 > FP44 > FB34 > FB44 > FP34. It was concluded that two hydroxyl groups at the para position of two benzene rings rather than at the ortho position in the same benzene ring were beneficial for hydroxyferrocifen to increase the antioxidant capacity. PMID- 21701896 TI - Inositol 1,4,5-trisphosphate receptor-mediated calcium release in Purkinje cells: from molecular mechanism to behavior. AB - The inositol 1,4,5-trisphosphate (IP(3)) receptor is highly expressed in cerebellar Purkinje cells and mediates conspicuous calcium release from intracellular calcium stores. Receptor stimulation, such as through mGluR1, activates the G(q)-PLC pathway, which leads to IP(3)-induced calcium release and subsequent cellular responses, including cerebellar long-term depression in Purkinje cells. Recent studies have demonstrated the regulatory mechanisms of IP(3) receptor, revealing activation via IP(3) and Ca(2+), inactivation via high concentrations of Ca(2+), and modulation by various proteins that bind to the IP(3) receptor. Novel calcium imaging techniques and caged compounds provide analysis of calcium signals at the single spine level in relation to the induction of long-term depression. Genetically encoded indicators for calcium or IP(3) could provide alternate Ca(2+) or IP(3) imaging, in particular, for in vivo observations. IP(3)-induced calcium release participates in early development of dendritic branch formation, and loss-of-function mutations or hyper-activation could result various diseases. The IP(3) receptor plays a central role in calcium signaling in Purkinje cells, affecting a wide variety of cellular functions, including development, plasticity, maintenance of synaptic functions, and cerebellar motor control. PMID- 21701898 TI - Differential effects of 1alpha,25-dihydroxycholecalciferol on MCP-1 and adiponectin production in human white adipocytes. AB - BACKGROUND/AIM: Obesity is characterized by a low-grade inflammation in white adipose tissue (WAT), which promotes insulin resistance. Low serum levels of 1alpha,25-dihydroxycholecalciferol (DHCC) associate with insulin resistance and higher body mass index although it is unclear whether vitamin D supplementation improves insulin sensitivity. We investigated the effects of DHCC on adipokine gene expression and secretion in adipocytes focusing on two key factors with pro inflammatory [monocyte chemoattractant protein-1 (MCP-1/CCL2)] and anti inflammatory [adiponectin (ADIPOQ)] effects. METHODS: Pre-adipocytes were isolated from human subcutaneous WAT and cultured until full differentiation. Differentiated adipocytes were either pre-treated with DHCC (10(-7) M) and subsequently incubated with tumor necrosis factor-alpha (TNFalpha, 100 ng/mL) or concomitantly incubated with TNFalpha/DHCC. MCP1 and adiponectin mRNA expression was measured by RT-PCR and protein release by ELISA. RESULTS: DHCC was not toxic and did not affect adipocyte morphology or the mRNA levels of adipocyte-specific genes. TNFalpha induced a significant increase in CCL2 mRNA and protein secretion, while DHCC alone reduced CCL2 mRNA expression (~25%, p < 0.05). DHCC attenuated TNFalpha-induced CCL2 mRNA expression in both pre-incubation (~15%, p < 0.05) and concomitant (~60%, p < 0.01) treatments. TNFalpha reduced ADIPOQ mRNA (~80%) and secretion (~35%). DHCC alone decreased adiponectin secretion to a similar degree (~35%, p < 0.05). Concomitant treatment with DHCC/TNFalpha for 48 h had an additive effect, resulting in a pronounced reduction in adiponectin secretion (~70%). CONCLUSIONS: DHCC attenuates MCP-1 and adiponectin production in human adipocytes, thereby reducing the expression of both pro- and anti inflammatory factors. These effects may explain the difficulties so far in determining the role of DHCC in insulin sensitivity and obesity in humans. PMID- 21701900 TI - Epidemiology of respiratory infections caused by atypical bacteria in two Kenyan refugee camps. AB - Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella spp. are common causes of atypical pneumonia; however, data about these atypical pathogens are limited in the refugee setting. Paired nasopharyngeal and oropharyngeal specimens were collected from patients with respiratory illness presenting to healthcare centers in two refugee camps in Kenya. The specimens were tested for C. pneumoniae, M. pneumoniae, and Legionella spp. as well as eight respiratory viruses. Atypical pathogens were detected in 5.5% of the specimens of which 54% were co-infected with at least one of the eight viruses tested. Patients positive for atypical bacteria co-infected with virus were significantly more likely to have severe acute respiratory illness than patients infected with only atypical bacteria (P = 0.04). While the percentage of atypical pathogens identified was lower than expected, we found a significant relationship between atypical bacterial-viral co-infection and severity of disease in this refugee population. PMID- 21701899 TI - Efficient expression of a Paenibacillus barcinonensis endoglucanase in Saccharomyces cerevisiae. AB - The endoglucanase coded by celA (GenBank Access No. Y12512) from Paenibacillus barcinonensis, an enzyme with good characteristics for application on paper manufacture from agricultural fibers, was expressed in Saccharomyces cerevisiae by using different domains of the cell wall protein Pir4 as translational fusion partners, to achieve either secretion or cell wall retention of the recombinant enzyme. Given the presence of five potential N-glycosylation sites in the amino acid sequence coded by celA, the effect of glycosylation on the enzymatic activity of the recombinant enzyme was investigated by expressing the recombinant fusion proteins in both, standard and glycosylation-deficient strains of S. cerevisiae. Correct targeting of the recombinant fusion proteins was confirmed by Western immunoblot using Pir-specific antibodies, while enzymatic activity on carboxymethyl cellulose was demonstrated on plate assays, zymographic analysis and colorimetric assays. Hyperglycosylation of the enzyme when expressed in the standard strain of S. cerevisiae did not affect activity, and values of 1.2 U/ml were obtained in growth medium supernatants in ordinary batch cultures after 24 h. These values compare quite favorably with those described for other recombinant endoglucanases expressed in S. cerevisiae. This is one of the few reports describing the expression of Bacillus cellulases in S. cerevisiae, since yeast expressed recombinant cellulases have been mostly of fungal origin. It is also the first report of the yeast expression of this particular endoglucanase. PMID- 21701901 TI - Murine gamma herpes virus 68 infection promotes fatty liver formation and hepatic insulin resistance in C57BL/6J mice. AB - PURPOSE: Murine gamma herpes virus 68 (MHV68) is a naturally occurring mouse pathogen that is homologous to Epstein-Barr virus. This study was designed to determine the correlation between MHV68 infection and lipid accumulation and insulin resistance in livers of C57BL/6J mice, and to explore the underlying mechanisms. METHODS: C57BL/6J mice fed a high fat diet were randomly assigned to receive either MHV68 or phosphate buffered saline treatment. Insulin sensitivities were evaluated by glucose tolerance tests. Serum was analyzed for lipids and cytokines. Liver was taken for histology and lipid analysis. Quantitative RT-PCR and western blotting were used to measure expression of hepatic mammalian target of rapamycin (mTOR), ribosomal S6 kinase 1 (S6K1), insulin receptor substrate-1 (IRS-1), sterol regulatory element binding protein-1 (SREBP1), fatty acid synthase (FAS), and acetyl CoA carboxylase (ACC). RESULTS: MHV68 infection promoted fatty liver, hypertriglyceridemia, insulin resistance, and hyperinsulinemia in association with elevated inflammatory cytokines. In the livers of MHV68-infected C57BL/6J mice, SREBP1, FAS, ACC levels were increased. MHV68 infection also inhibited total IRS-1 expression and increased serine phosphorylation levels of IRS-1, which is parallel to the over activation of mTOR signaling pathway. Sirolimus, a specific inhibitor of mTOR pathway, inhibited MHV68-induced hepatic expression of serine p-IRS-1, increased total IRS-1 levels and improved MHV68-induced hepatic insulin resistance. CONCLUSION: In C57BL/6J mice, MHV68 infection promotes fatty liver formation and hepatic insulin resistance, which can be ameliorated by sirolimus. PMID- 21701902 TI - Hepatitis B surface antigen: association with sustained response to peginterferon alfa-2a in hepatitis B e antigen-positive patients. AB - PURPOSE: Patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, who achieve HBeAg seroconversion 6 months after completing 48 weeks of peginterferon alfa-2a therapy, have an increased chance of clearing hepatitis B surface antigen (HBsAg) during long-term treatment-free follow-up. This analysis aimed to determine whether HBsAg quantification during treatment could be used to identify posttreatment response. METHODS: Patients (n = 399) treated with peginterferon alfa-2a (180 MUg/week) alone or in combination with lamivudine (100 mg/day) for 48 weeks during a large, randomized study were included in this retrospective analysis. Receiver-operating characteristic analyses were used to identify baseline and on-treatment HBsAg levels associated with response (HBeAg seroconversion 6 months posttreatment). RESULTS: Baseline HBsAg levels were lower in patients achieving posttreatment response than in nonresponders (3.97 and 4.21 IU/mL, respectively, p = 0.039). Two baseline HBsAg cutoff levels (5,000 and 50,000 IU/mL) provided a positive predictive value of 42% and a negative predictive value of 77%. HBsAg decline was significantly greater during and posttreatment in responders than in nonresponders (p < 0.0001). HBeAg seroconversion rates 6 months posttreatment were significantly higher in patients with HBsAg < 1,500 IU/mL at weeks 12 and 24 (56.7 and 54.4%, respectively) versus patients with HBsAg 1,500-20,000 IU/mL (32.3 and 26.1%, respectively) or HBsAg < 20,000 IU/mL (16.3 and 15.4%, respectively) (all p < 0.0001 and <0.0001). CONCLUSIONS: HBsAg levels at baseline strongly associated with posttreatment response were not identified. Low HBsAg levels during peginterferon alfa-2a therapy were associated with high rates of posttreatment response. On-treatment HBsAg quantification may, therefore, help guide patient management in the future. PMID- 21701903 TI - Temporal dynamics of primary motor cortex gamma oscillation amplitude and piper corticomuscular coherence changes during motor control. AB - In recent years, the use of non-invasive techniques (EEG/MEG) to measure the ~80 Hz ("gamma") oscillations generated by the primary motor cortex during motor control has been well validated. However, primary motor cortex gamma oscillations have yet to be systematically compared with lower frequency (30-50 Hz, 'piper') corticomuscular coherence in the same tasks. In this paper, primary cortex gamma oscillations and piper corticomuscular coherence are compared for three types of movements: simple abductions of the index finger, repetitive abductions of the index finger of different extents and frequencies and static abduction of the index finger at two different force levels. For simple movements, piper coherence and gamma amplitude followed very similar time courses with coherence appearing at approximately half the frequency of cortical gamma oscillations. No evidence of 2:1 phase-phase coupling was observed. A similar pattern of results was observed for repetitive movements varying in size and frequency; however, during the production of static force, the time courses became dissociated. During these movements, EMG piper amplitude was sustained for the entire contraction; gamma power showed a burst at onset but no piper corticomuscular coherence was observed. For these data, this dissociation suggests that while primary motor cortex gamma oscillations and piper corticomuscular coherence may often co-occur during the production of dynamic movements, they probably reflect different functional processes in motor control. PMID- 21701904 TI - RNA editing restores critical domains of a group I intron in fern mitochondria. AB - In the leptosporangiate fern Osmunda regalis, cox1 gene is disrupted by a 1071 nucleotide-long group I intron that is homologous to the Marchantia polymorpha cox1 intron 4 (cox1i395g1). This intron, which shares 89% sequence identity with its bryophyte counterpart, lost the capacity to encode for a maturase due to insertion/deletion mutations. The cox1 coding region is interrupted by a stop codon in both exons. The cox1 transcript undergoes 58 C-to-U and 13 U-to-C conversions, including the suppression of two stop codons that result in the recovery of a functional cox1 ORF. Interestingly, 4 C-to-U conversions found in mRNA precursors showed that the O. regalis cox1i395g1 intron is efficiently edited. These modifications improved the sequence identity with the Marchantia cox1i395 intron. In particular, the RNA editing events affect regions involved in secondary and tertiary structures of the intron, restoring three base pairing in the structural P5a and P9 helices, and correcting a highly conserved U in the P7 helix that contributes to the catalytic core. Moreover, cox1 intron orthologous from three different fern species were found to be edited by both C-to-U and U-to C conversions in P7 and P9. Thus, RNA editing helps to correct the conserved domains of group I introns in "true ferns", suggesting a possible link between editing and splicing. We present here the first experimental evidence of RNA editing concerning a group I intron in plant organelles. PMID- 21701905 TI - Performance of a commercial nucleic acid amplification test with extrapulmonary specimens for the diagnosis of tuberculosis. AB - The laboratory diagnosis of tuberculosis (TB) on extrapulmonary specimens is particularly challenging. A number of commercial nucleic acid amplification tests able to detect and identify Mycobacterium tuberculosis (MTB) complex directly from respiratory secretions have been developed, but their use on extrapulmonary samples still calls for validation. The BDProbeTec ET Mycobacterium tuberculosis Complex Direct Detection Assay (DTB) was applied to 918 consecutive extrapulmonary specimens (collected from 863 patients), including 84 gastric aspirates, 145 urine, 136 sterile body fluids, 83 cerebrospinal (CSF) fluids, 237 fine-needle aspirates, 175 pus, 56 biopsies, and two stool specimens. The results were compared with those of acid-fast staining and culture (solid plus liquid media), setting the combination of culture and clinical diagnosis as the gold standard. Ninety-two specimens yielded culture positive for MTB and 24 (smear- and culture-negative) were from patients with TB clinical diagnosis. Of these, 96 were DTB-positive, including all of those from culture-negative TB cases. From 26 specimens, nontuberculous mycobacteria were grown. Two of these specimens were positive by the DTB assay. Finally, of the 776 samples that were smear- and culture-negative for acid-fast bacilli (AFB), collected from patients for whom the diagnosis of TB was excluded, six were DTB-positive. The overall sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) of extrapulmonary samples were 82.7, 99.0, 92.3, and 97.8%, respectively. Although, at present, amplification assays cannot replace culture techniques, DTB proved to be rapid and specific for the detection of MTB in extrapulmonary samples. PMID- 21701906 TI - Enhancing labour force participation for people living with HIV: a multi perspective summary of the research evidence. AB - Labour force participation has been identified as a critical social and health issue facing people living with HIV/AIDS (PHAs). We conducted a scoping study (a form of literature synthesis that summarizes research findings, research activity, and identifies literature strengths and gaps) on labour force participation for PHAs, guided by a community advisory committee. We summarized information from 243 peer-reviewed articles and 42 reports from the grey literature, and synthesized the evidence into a preliminary conceptual framework with five components: (1) the meaning of work, (2) key factors (barriers and facilitators) influencing labour force participation, (3) factors affecting vulnerable populations, (4) strategies and supports for returning to or sustaining work, and (5) outcomes (benefits and risks) of labour force participation for individuals and employers. The framework supports the development of labour force initiatives requiring collaborative efforts in multiple domains (health, employment, community) by PHAs, rehabilitation professionals, employers, insurers, and policy makers. PMID- 21701907 TI - Pharmacogenomics and multiple sclerosis: moving toward individualized medicine. AB - Notwithstanding the availability of disease-modifying treatments including interferon-beta, glatiramer acetate, and natalizumab, a considerable proportion of multiple sclerosis (MS) patients experience continued progression of disease, clinical relapses, disease activity on MRI, and adverse effects. Application of gene expression, proteomic or genomic approaches is universally accepted as a suitable strategy toward the identification of biomarkers with predictive value for beneficial/poor clinical response to therapy and treatment risks. This review focuses on recent progress in research on the pharmacogenomics of disease modifying therapies for MS. Although MS drug response biomarkers are not yet routinely implemented in the clinic, the diversity of reported, promising molecular markers is rapidly increasing. Even though most of these markers await further validation, given time, this research is likely to empower neurologists with an enhanced armamentarium to facilitate rational decisions on therapy and patient management. PMID- 21701908 TI - Associations between relational aggression, depression, and suicidal ideation in a child psychiatric inpatient sample. AB - The current study examined relations between relational aggression, depressive symptoms, and suicidal ideation in a child clinical population. Participants included 276 children (M(age) = 9.55 years; 69% Male) who were admitted to a child psychiatric inpatient facility. Findings suggested that relational aggression was associated with depressive symptoms, which in turn was associated with suicidal ideation. The test of indirect effects suggested that depressive symptoms fully accounted for the link between relational aggression and suicidal ideation. Moreover, these relations were found when also controlling for the variance associated with overt aggression, history of abuse, and social problems. Current findings appear to suggest that relational aggression is linked to depressive symptoms, which is linked to suicidal ideation within a clinical population, and as such there may be clinical utility in assessing relational aggression. PMID- 21701909 TI - Affective determinants of anxiety and depression development in children and adolescents: an individual growth curve analysis. AB - The tripartite model (in Clark and Watson, J Abnorm Psychol 100:316-336, 1991) comprises Negative Affect (NA), Positive Affect (PA), and Physiological Hyperarousal (PH), three temperamental-based dimensions. The current study examined the tripartite model's assumptions that (a) NA interacts with PA to predict subsequent depressive (but not anxiety) symptom developments and (b) NA interacts with PH to predict subsequent anxiety (but not depressive) symptom developments in a sample of 243 community and referred children and adolescents (42.8% boys; M age = 10.87 years, SD = 1.83). Results confirmed that individuals with a combined high NA/low PA profile display the least favorable course of depressive -but not anxiety- symptoms. In contrast with the model, the combination of NA and PH influenced the development of depression, but not anxiety. Relations were not moderated by sex or sample. Results revealed that the assessment of the tripartite components is warranted as it can help to identify children at risk for an unfavorable depressive symptom course. PMID- 21701911 TI - Characterization and factors associated with sleep quality in adolescents with bipolar I disorder. AB - Sleep disturbance is an early marker for bipolar disorder (BD) onset in youth. We characterized sleep quality in adolescents experiencing mania within the last 6 12 months. We examined the association between mood and sleep in 27 adolescents with BD and 24 matched healthy controls (HC). Subjects were assessed by parent and teen report of sleep, a semi-structured clinical interview, the Young Mania Rating Scale (YMRS), and the Childhood Depression Rating Scale (CDRS-R). Average BD youth YMRS (mean 20.3 +/- 7.3) and CDRS-R (mean 42.4 +/- 14.1) scores indicated they were still ill at time of assessment. Compared to HCs, adolescents with BD have distinct patterns of prolonged sleep onset latency, frequent nighttime awakenings, and increased total time awake. Mood symptoms, specifically excessive guilt, self-injurious behavior, and worsening evening mood, interfered with sleep. Further studies are needed to determine whether early regulation of sleep would improve long-term outcome in BD youth. PMID- 21701910 TI - Noncardiac chest pain in children and adolescents: a biopsychosocial conceptualization. AB - Pediatric NCCP may be characterized by recurrent pain accompanied by emotional distress and functional impairment. This paper reviews and critiques literature on pediatric noncardiac chest pain (NCCP) and introduces a theoretical conceptualization to guide future study of NCCP in children and adolescents. A developmentally informed biopsychosocial conceptualization of NCCP etiology is proposed based on a synthesis of empirical evidence and clinical observations of pediatric NCCP within the context of relevant findings from the broader pediatric pain and anxiety literature. Multiple factors from biological, psychological, social, familial, and developmental domains are potentially relevant to the etiology of this ailment. This article concludes with directions for future research and clinical implications. PMID- 21701912 TI - Administration of hepatocyte growth factor increases reelin and disabled 1 expression in the mouse cerebral cortex: an in vivo study. AB - Hepatocyte growth factor (HGF) and its receptor, c-Met, are widely expressed in the developing brain. HGF also known as scatter factor enhances cell proliferation and cell growth, and stimulates cell migration and motility. Neurons and glia produced in the neuroepithelium migrate along radial glial fibers into the cortical plate. Reelin, a glycoprotein which is produced by Cajal Retzius cells in the marginal zone directs neuronal migration indirectly via the radial glial cells. It has been demonstrated that Disabled 1 functions downstream of reelin in a tyrosin kinase signal transduction pathway that controls appropriate cell positioning in the developing brain. In this study, administration of HGF on reelin and Disabled 1 expression in the cerebral cortex has been studied. Using Western blot, it was shown that the expression of reelin and Disabled 1 is increased in response to infusion of HGF when compared to control group. It is concluded that HGF is essential for reelin and Disabled 1 expression in the cerebral cortex of the newborn mouse. Moreover, this method may be applied to the other factors, allowing identification of molecules involved in neural cell migration. PMID- 21701913 TI - Predictors of rehospitalization in high-utilizing patients in the VA psychiatric medical system. AB - 233 high-service-utilizing (HSU) psychiatric patients were recruited during an inpatient psychiatric treatment. They completed a questionnaire related to their treatment beliefs and were tracked via computerized medical records over 2 years. During the follow-up period, 79.8% were readmitted for additional inpatient psychiatric treatment. Survival analysis techniques were used to examine patients' rates of readmittance during the follow-up period. Number of previous year inpatient psychiatric days served as a significant predictor of readmittance status and time to readmission. The survival plot was split by previous-year inpatient days to examine the effect of this variable on readmission. Implications of findings are discussed. PMID- 21701914 TI - Parity and total, ischemic heart disease and stroke mortality. The Adventist Health Study, 1976-1988. AB - In a prospective study with information about life style and reproductive factors, we assessed the relationship between parity and total, ischemic heart disease, and stroke mortality. The large majority of the 19,688 California Seventh-day Adventist women included did not smoke or drink alcohol, 31 percent never ate meat and physical activity was relatively high. Cox proportional hazard analysis was conducted with parity as the main independent variable and with adjustment for a number of other possible confounders. During follow-up from 1976 through 1988, there were 3,122 deaths; 782 deaths from ischemic heart disease and 367 deaths due to stroke. There were no relationships between parity and total mortality (P-value for overall effect of parity = 0.32). Grand multiparous women (>4 children) had somewhat increased ischemic heart disease mortality (MRR = 1.45, 95% CI: 1.15, 1.84) before adjustment for educational level. After adjustment for educational level and marital status, there were no relationship with mortality from ischemic heart disease (P = 0.29) or stroke (P = 0.72). In parous women, there were, after adjustment for age at first delivery, some suggestions of an increased total mortality in women with one child. For ischemic heart disease and stroke mortality, no associations were found. Stratified and adjusted analyses confirmed these results. Thus, we found no consistent relationships between parity and total, ischemic heart disease or stroke mortality. However, a longer follow-up would have been helpful and the conclusions may be somewhat influenced by the lifestyle of the women included. PMID- 21701915 TI - Habitat selection, reproduction and predation of wintering lemmings in the Arctic. AB - Snow cover has dramatic effects on the structure and functioning of Arctic ecosystems in winter. In the tundra, the subnivean space is the primary habitat of wintering small mammals and may be critical for their survival and reproduction. We have investigated the effects of snow cover and habitat features on the distributions of collared lemming (Dicrostonyx groenlandicus) and brown lemming (Lemmus trimucronatus) winter nests, as well as on their probabilities of reproduction and predation by stoats (Mustela erminea) and arctic foxes (Vulpes lagopus). We sampled 193 lemming winter nests and measured habitat features at all of these nests and at random sites at two spatial scales. We also monitored overwinter ground temperature at a subsample of nest and random sites. Our results demonstrate that nests were primarily located in areas with high micro topography heterogeneity, steep slopes, deep snow cover providing thermal protection (reduced daily temperature fluctuations) and a high abundance of mosses. The probability of reproduction increased in collared lemming nests at low elevation and in brown lemming nests with high availability of some graminoid species. The probability of predation by stoats was density dependent and was higher in nests used by collared lemmings. Snow cover did not affect the probability of predation of lemming nests by stoats, but deep snow cover limited predation attempts by arctic foxes. We conclude that snow cover plays a key role in the spatial structure of wintering lemming populations and potentially in their population dynamics in the Arctic. PMID- 21701916 TI - Improvement of the thermostability and enzymatic activity of cholesterol oxidase by site-directed mutagenesis. AB - Site-directed mutagenesis was applied to enhance the thermostability and enzymatic activity of cholesterol oxidase (ChOx) isolated from Brevibacterium sp. Three amino acid residues (Q153E, F128L, and S143H) located near the FAD-binding site of the enzyme were substituted based on structural analysis. The specific activity of the two-sites mutant Q153E/F128L increased by 11.6% and the relative activity increased by 47% when grown for 2 h at 50 degrees C. This mutant is a potential industrial strain for producing ChOx. PMID- 21701917 TI - Sequence analysis of the Lactobacillus temperate phage Sha1. AB - Bacteriophage Sha1, a newly isolated temperate phage from a mitomycin-C-induced lysate of Lactobacillus plantarum isolated from Kimchi, has an isometric head (58 nm * 60 nm) and a long tail (259 nm * 11 nm). The double-strand DNA genome of the phage Sha1 was 41,726 base pairs (bp) long, with a G+C content of 40.61%. Bioinformatic analysis of Sha1 shows that this phage contains 58 putative open reading frames (ORFs). Sha1 can be classified as a member of the large family Siphoviridae by genomic structure and morphology. To our knowledge, this is the first report of genomic sequencing and characterization of temperate phage Sha1 from wild-type L. plantarum isolated from kimchi in Korea. PMID- 21701918 TI - Concerns about inherited risk of breast cancer prior to diagnosis in Japanese patients with breast complaints. AB - The purpose of this study was to reveal characteristics that underlie patients' expressions of concern about their genetic risk of breast cancer at an initial outpatient clinic visit prior to a definitive diagnosis of cancer. A total of 233 women, at their initial outpatient clinic visits, participated in semi-structured and open-ended interviews that surveyed their anxieties, worries, thoughts, and feelings. Each patient completed a self-administered survey comprising questions about her family history of breast cancer and responded to a questionnaire that assessed psychological distress. Patients were divided into those who expressed concerns about inherited risk of breast cancer during the interview (expression group, n = 39) and those who did not (non-expression group, n = 194). Although patients in the expression group tended to have higher rates of breast cancer in their families, patients without a family history of breast cancer also expressed concerns. We used qualitative content analysis to identify the emotions and thoughts of patients expressing these concerns. Patients with a family history of breast cancer experienced anxiety/worry, risk-reducing behavior, acceptance, objective fact, and denial, whereas patients without a family history of breast cancer experienced anxiety/worry, risk-reducing behavior, surprise/shock, acceptance, objective fact, denial, optimistic thought, regret, and realistic thought. Some patients in the breast clinic had concerns about their inherited risk of cancer, despite lacking a family history of breast cancer. Health care professionals should inquire about family histories and provide appropriate support and counseling to patients as needed, regardless of the patient's genetic risk for the disease. PMID- 21701919 TI - A QM/MM study of the binding of RAPTA ligands to cathepsin B. AB - We have carried out quantum mechanical (QM) and QM/MM (combined QM and molecular mechanics) calculations, as well as molecular dynamics (MD) simulations to study the binding of a series of six RAPTA (Ru(II)-arene-1,3,5-triaza-7-phosphatricyclo [3.3.1.1] decane) complexes with different arene substituents to cathepsin B. The recently developed QM/MM-PBSA approach (QM/MM combined with Poisson-Boltzmann solvent-accessible surface area solvation) has been used to estimate binding affinities. The QM calculations reproduce the antitumour activities of the complexes with a correlation coefficient (r (2)) of 0.35-0.86 after a conformational search. The QM/MM-PBSA method gave a better correlation (r (2) = 0.59) when the protein was fixed to the crystal structure, but more reasonable ligand structures and absolute binding energies were obtained if the protein was allowed to relax, indicating that the ligands are strained when the protein is kept fixed. In addition, the best correlation (r (2) = 0.80) was obtained when only the QM energies were used, which suggests that the MM and continuum solvation energies are not accurate enough to predict the binding of a charged metal complex to a charged protein. Taking into account the protein flexibility by means of MD simulations slightly improves the correlation (r (2) = 0.91), but the absolute energies are still too large and the results are sensitive to the details in the calculations, illustrating that it is hard to obtain stable predictions when full flexible protein is included in the calculations. PMID- 21701920 TI - Transcervical videoscopic esophageal dissection during two-field minimally invasive esophagectomy: early patient experience. AB - BACKGROUND: Transhiatal (two-field) esophagectomy reduces cardiopulmonary complications by avoiding thoracic access, but requires blind mediastinal dissection. The authors developed a minimally invasive esophagectomy (MIE) technique applying single-incision laparoscopy technology to better visualize the thoracic esophageal dissection. This is performed using laparoscopy and simultaneous transcervical videoscopic esophageal dissection (TVED). Our aim is to demonstrate feasibility of two-field MIE with TVED and improve recovery in high-risk patients. METHODS: We performed a retrospective cohort study of eight patients who underwent two-field MIE with TVED over 10 months. The majority were male (N = 6) with mean age of 63 +/- 12 years. Mean body mass index (BMI) was 30.2 +/- 5.1 kg/m(2). Indications for operation were: high-grade dysplasia (N = 2), adenocarcinoma (N = 6) with one receiving neoadjuvant chemoradiation. Using the Charlson comorbidity index, three patients were low risk and five were high risk. TVED was performed with a modified single-incision access device across the left neck. The mediastinal esophagus was dissected distally and circumferentially with simultaneous transabdominal laparoscopy for gastric conduit creation and distal esophageal dissection. RESULTS: Mean operative time was 292 min (range 194 375 min). Three obese patients required temporary abdominal desufflation to avoid extrinsic mediastinal compression. Mean estimated blood loss was 119 mL (range 25 400 mL). A median of 23 lymph nodes (range 13-29) was harvested. Median intensive care unit (ICU) stay was 1 day (range 1-5 days), and median overall stay was 7 days (range 5-16 days). The three low-risk patients had no major complications. Three of five high-risk patients had major complications, including two cervical anastomotic leaks. Major complications were seen in three of four obese patients (BMI >30 kg/m(2)). There were no mortalities. CONCLUSIONS: The TVED approach may avoid the morbidity of transthoracic esophageal dissection by improving esophageal visualization. Complications with TVED appear to correlate with obesity and comorbidities. Although TVED appears feasible, a larger experience is required. PMID- 21701922 TI - Decreased incidence of isolated tumor cells in lymph nodes after laparoscopic resection for colorectal cancer. AB - BACKGROUND: Laparoscopic surgery has potential for less tumor cell spread because of the no-touch technique. We assessed the effect of the surgical approach (open versus no-touch laparoscopic) on the presence of tumor cells in sentinel lymph nodes (SN) of patients with stage I and II colorectal cancer. METHODS: A single center consecutive prospective series of patients operated on for colorectal cancer was analyzed. After conventional hematoxylin and eosin (H&E) staining, 107 patients without lymphatic metastases were included; 59 patients had open surgery, and 48 patients underwent laparoscopic resection. Patients in the laparoscopic group underwent a no-touch medial to lateral approach, whereas the conventional lateral to medial approach was applied in open surgery. A SN procedure was performed in all patients. The SNs were immunohistochemically analyzed for presence of occult tumor cells (OTC). According to the American Joint Committee on Cancer (AJCC) these tumor cells were divided into micrometastases (0.2-2 mm) or isolated tumor cells (ITC, < 0.2 mm). RESULTS: In ten patients micrometastases were found, equally distributed between the two groups. However, ITC were more often found after open surgery (18 versus 5 patients, p = 0.03). Presence of OTC was related to depth of tumor invasion and tumor diameter > 3.5 cm. Logistic regression analysis identified lymphovascular invasion as a predictor for micrometastases [odds ratio (OR) 18.4], whereas open resection was predictive for presence of ITC (OR 3.3). CONCLUSIONS: No-touch medial to lateral laparoscopic surgery results in less isolated tumor cells in lymph nodes compared with open lateral to medial surgery in patients with stage I and II colorectal cancer. PMID- 21701921 TI - Laparoscopic extraperitoneal rectal cancer surgery: the clinical practice guidelines of the European Association for Endoscopic Surgery (EAES). AB - BACKGROUND: The laparoscopic approach is increasingly applied in colorectal surgery. Although laparoscopic surgery in colon cancer has been proved to be safe and feasible with equivalent long-term oncological outcome compared to open surgery, safety and long-term oncological outcome of laparoscopic surgery for rectal cancer remain controversial. Laparoscopic rectal cancer surgery might be efficacious, but indications and limitations are not clearly defined. Therefore, the European Association for Endoscopic Surgery (EAES) has developed this clinical practice guideline. METHODS: An international expert panel was invited to appraise the current literature and to develop evidence-based recommendations. The expert panel constituted for a consensus development conference in May 2010. Thereafter, the recommendations were presented at the annual congress of the EAES in Geneva in June 2010 in a plenary session. A second consensus process (Delphi process) of the recommendations with the explanatory text was necessary due to the changes after the consensus conference. RESULTS: Laparoscopic surgery for extraperitoneal (mid- and low-) rectal cancer is feasible and widely accepted. The laparoscopic approach must offer the same quality of surgical specimen as in open surgery. Short-term outcomes such as bowel function, surgical-site infections, pain and hospital stay are slightly improved with the laparoscopic approach. Laparoscopic resection of rectal cancer is not inferior to the open in terms of disease-free survival, overall survival or local recurrence. Laparoscopic pelvic dissection may impair genitourinary and sexual function after rectal resection, like in open surgery. CONCLUSIONS: Laparoscopic surgery for mid and low-rectal cancer can be recommended under optimal conditions. Still, most level 1 evidence is for colon cancer surgery rather than rectal cancer. Upcoming results from large randomised trials are awaited to strengthen the evidence for improved short-term results and equal long-term results in comparison with the open approach. PMID- 21701923 TI - Prognostic factors associated with mortality in patients undergoing emergency surgery for abdominal aortic aneurysms. AB - PURPOSE: Surgical mortality rates following emergency surgery for ruptured abdominal aortic aneurysms (AAAs) remain high. This study investigated the mortality rate and identified prognostic factors affecting mortality in patients undergoing emergency repair of AAAs in our hospital. METHODS: Between January 2005 and June 2010, a total of 42 patients underwent emergency surgery for AAAs and were included in this retrospective study. The following variables concerning each patient were collected by chart review and compared between survivors and nonsurvivors: age; gender; preoperative levels of hemoglobin (Hb), hematocrit (Ht), platelets (Plts), base excess (BE), and serum glucose and lactate; presence of preoperative shock defined as hypotension (systolic blood pressure of less than 80 mmHg); incidence of blood transfusion, whether AAA was ruptured or impending; interval from admission to the hospital or arrival in the operating room until aortic cross-clamping; surgical duration; and volume of intraoperative blood loss and transfusion, total fluid infusion, and urine output. RESULTS: Nine patients died within 30 days postoperatively, a 30-day mortality rate of 21.4%. Among these nine nonsurvivors, eight had shown persistent preoperative shock (P = 0.0004 vs. survivors). Compared with the survivors, nonsurvivors were significantly older (P = 0.0052) and had lower preoperative levels of Hb/Ht (P < 0.0001), Plts (P = 0.0003), and BE (P < 0.0001), an elevated lactate level (P = 0.0048), shorter interval from admission (P = 0.0459) or arrival in the operating room (P = 0.0288) until aortic clamping, and intraoperatively more hemorrhage (P = 0.0038) associated with larger amounts of blood transfusion (P = 0.0083) and less urine output (P = 0.0004). CONCLUSIONS: The authors clarified that certain features such as age, persistent preoperative shock, and greater amounts of transfusion associated with greater blood loss and anemia were factors affecting the mortality in patients undergoing emergency surgery for AAAs. It might be of great importance to correct preoperative shock and anemia caused by massive bleeding before the onset of hemodynamic deterioration. PMID- 21701924 TI - Temporal and spatial distribution of cattle anthrax outbreaks in Zimbabwe between 1967 and 2006. AB - This retrospective study aimed to assess the spatial and temporal distribution of anthrax and to identify risk areas in Zimbabwe. The data were extracted from the monthly and annual reports of the Division of Livestock Production and Veterinary Services for the period 1967 to 2006. The data were analyzed in relation to temporal and spatial factors. The hot-dry season was found to be significantly (X (2)=847.8, P<0.001) associated with the occurrence of anthrax in cattle, and the disease was found to be approximately three times more likely to occur during this season compared to other seasons. Anthrax outbreaks demonstrated a gradual temporal increase from an annual mean of three outbreaks for the 5-year period (1967-1971) to 42 for the 5-year period (2002-2006). Similarly, the data demonstrated a spatial increase in the number of districts affected by anthrax between 1967 and 2006, with 12 districts affected for the 10-year period (1967 1976) that expanded to 42 districts for the 10-year period (1997-2006). The majority of outbreaks (83.7%) were recorded in rural areas, and 11 districts were found to be at a higher risk than others. There is need to develop differential vaccination strategy, other control strategies and preventive recommendations to reduce anthrax in high-risk districts. In the medium- to low-risk districts, maintenance of effective surveillance systems and improvement of awareness is very important to detect and contain outbreaks early. PMID- 21701925 TI - Development and validation of a reference table for prediction of postoperative mortality rate in patients treated with radical cystectomy: a population-based study. AB - PURPOSE: The existing literature suggests that the postoperative mortality (POM) rate in radical cystectomy (RC) patients does not exceed 3%. We sought to develop and externally validate a reference table that quantifies POM after RC. METHODS: We identified 12,274 patients treated with RC, between 1998 and 2007, within the Nationwide Inpatient Sample database. A total of 6188 (50.4%) randomly selected patients was used as the development cohort. Logistic regression analysis for prediction of POM adjusted for: age, sex, race, Charlson comorbidity index (CCI), urinary diversion type, year of surgery, annual hospital caseload, location/teaching status of hospital, region and bed size of hospital. The reference table was developed by using stepwise variable removal to identify the most accurate and parsimonious model. The model was externally validated in 6086 (49.6%) patients. RESULTS: POM occurred in 2.4% of patients. POM proportion increased with increasing age (<=59: 0.6% vs. 60-69: 1.6% vs. 70-79: 3.1% vs. >=80: 4.6%, P < 0.001), and higher CCI (CCI 0: 1.7% vs. CCI 1: 3.0% vs. CCI 2: 4.2% vs. CCI 3: 4.3% vs. CCI >= 4: 12.1%, P < 0.001). In multivariable analyses, only age and CCI remained as independent predictors of POM, after stepwise variable removal. The discrimination accuracy of the reference table in predicting POM was 70%. CONCLUSIONS: Age and CCI represent the foremost determinants of POM after RC. The developed reference table is capable of predicting POM after RC, in an individualized fashion. The accuracy of the model is good (70%), and it is highly generalizable. PMID- 21701926 TI - Role of radiation in intermediate-risk rectal cancer. AB - The treatment of rectal cancer has greatly evolved during the last several decades as a result of the understanding of the pathways of cancer spread, natural history of the disease, stages prognosis and prognostic markers. The tendency is clearly to move toward a more personalized approach to these patients based on preoperative staging and response to therapy. Although in the past we have been adding more treatment modalities to surgery to the point that every stage II/III cancer was treated with neoadjuvant chemo and radiotherapy followed by radical surgery by total mesorectal excision with or without sphincter preservation and more chemotherapy to follow, more recently this algorithm has been under discussion and scrutiny. Two of the major topics of controversy are: the use of local excision or even a watch-and-wait approach after a clinical complete response and the need for radiotherapy in the intermediate risk group. In this manuscript we will present the historical perspective that has brought the treatment of rectal cancer to the current standard of care and present the evidence supporting further investigation in the intermediate risk group. PMID- 21701927 TI - Survival and quality of life of patients with resected pancreatic adenocarcinoma treated with adjuvant interferon-based chemoradiation: a phase II trial. AB - PURPOSE: We conducted a phase II trial to assess the survival duration and quality of life of patients who received adjuvant interferon-based chemoradiation for pancreatic adenocarcinoma after pancreaticoduodenectomy. METHODS: Patients with a performance status of 0 or 1 were enrolled to receive interferon-alfa-2b (3 million units MWF), cisplatin (30 mg/m(2), 6 doses) and 5-fluorouracil (5-FU; 175 mg/m(2)/day), concurrent with external-beam radiation (50.4 Gy) and followed by 2 courses of systemic 5-FU. The protocol was modified to include an optional 9 day break in the middle of chemoradiation. Quality of life was assessed by use of validated instruments. RESULTS: Twenty-eight patients were eligible for analysis. The operation of 15 (54%) patients was performed at other institutions. All patients had T3 tumors, 22 (79%) had positive lymph nodes and 4 (14%) had positive (R1) margins. 24 (86%) patients completed therapy. In all, 25 (89%) patients experienced grade 3 toxicity and 3 (11%) patients were hospitalized. The most common grade 3 events were leukopenia (15, 54%) and neutropenia (12, 43%). No grade 4 toxicity occurred. Overall quality of life decreased during chemoradiation but returned to baseline thereafter and was stable throughout surveillance. 19 patients have died; the median follow-up of the 9 survivors is 62 months. The median OS duration of treated patients was 42.3 (95% confidence interval 30.5-54.2) months. CONCLUSIONS: Adjuvant interferon-based chemoradiation can be delivered safely and tolerably-though with substantial reversible toxicity to patients of good performance status at an experienced cancer center. Therapy may be associated with an improvement in overall survival. PMID- 21701928 TI - Outcomes for patients who develop both breast and colorectal cancer. AB - BACKGROUND: Patients diagnosed with both breast and colorectal cancer are not uncommon and will likely be seen more often as the population ages and treatment modalities improve. Survival outcomes for such patients have not been previously reported. METHODS: The 1988-2007 Surveillance, Epidemiology, and End Results data were used to identify women diagnosed with both breast and colorectal cancer. Disease-specific survival rates were compared. RESULTS: We identified 4,835 women who were diagnosed with both breast and colorectal cancer. Of these, 2,844 (58.8%) were diagnosed with breast cancer first and 1,807 (37.4%) were diagnosed with colorectal cancer first; 184 (3.8%) had synchronous cancers. At 5 years following the second cancer diagnosis, 163 (3.4%) died of breast cancer and 477 (9.9%) died of colorectal cancer (P < 0.05). Comparing primary site groups between years 1 and 5 after the second cancer diagnosis showed that the relative risk of death from breast cancer declined by 46%, though it did not reach statistical significance (P = 0.24), while it significantly increased by 46% for colorectal cancer death (P = 0.0004). These findings persisted regardless of patient age, stage at diagnosis, or breast tumor histology. CONCLUSION: For women diagnosed with both breast and colorectal cancer, the cumulative risk of death at 5 years following the second cancer diagnosis is 3 times more likely to be due to colorectal cancer than to breast cancer. Colorectal cancer specific mortality increases with time, while breast cancer specific mortality decreases with time. Consideration should be given to these findings when discussing prognosis and making treatment decisions. PMID- 21701929 TI - The role of cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) in patients with high-grade appendiceal carcinoma and extensive peritoneal carcinomatosis. AB - BACKGROUND: Patients with peritoneal mucinous carcinomatosis (PMCA) of appendiceal origin and extensive disease are commonly advised against CRS/HIPEC. We hypothesize that CRS/HIPEC is a beneficial treatment for this group. METHODS: Retrospective analysis of 134 patients with appendiceal cancer treated with CRS/HIPEC was performed from a prospective database. Extent of disease, measured by peritoneal cancer index (PCI), was related to completeness of cytoreduction (CC), lymph node (LN) status, and prior surgery score (PSS). Overall survival (OS) was estimated by Kaplan-Meier curves. Test differences were calculated using log-rank test. RESULTS: A total of 77 patients (57%) had PMCA. Mean follow-up was 22 months with a median of 18 months. OS was 88%, 56%, and 40% for 1, 3, and 5 years, respectively. 68% had PCI >= 20. LN metastasis was found in 44% of patients in PCI >= 20 and PCI < 20 groups. 73% and 60% of patients had PSS of 2 or 3 in PCI >= 20 and PCI < 20 groups, respectively (P = .196). Complete cytoreduction was achieved in 65% of PCI >= 20 group and 96% of PCI < 20 group (P = .004). With complete cytoreduction, the 5-year OS was 45% in PCI >= 20 group and 66% in PCI < 20 group (P = .139). 18 of 19 patients with incomplete cytoreduction had PCI >= 20, with 3- and 5-year OS of 27% and 0%. Hazard ratios (by Cox regression) were 2.8 (95% confidence interval [95% CI] 0.8-10.2) and 3.6 (95% CI 1.5-8.8) for PCI < 20 and complete cytoreduction, respectively. CONCLUSIONS: Meaningful long-term survival could be achieved in patients with PMCA even with extensive peritoneal disease. PCI >= 20 should not be used as an exclusion criterion when selecting these patients for CRS/HIPEC, and every effort should be made to achieve complete cytoreduction. PMID- 21701930 TI - Molecular profiling of direct xenograft tumors established from human pancreatic adenocarcinoma after neoadjuvant therapy. AB - BACKGROUND: Pancreatic adenocarcinoma is among the most resistant of human cancers, yet specific mechanisms of treatment resistance remain poorly understood. Models to study pancreatic cancer resistance remain limited and should reflect in vivo changes that occur within patient tumors. We sought to identify consistent, differentially expressed genes between treatment of naive pancreatic tumors and those exposed to neoadjuvant therapy using a strict, in vivo direct xenograft model system. METHODS: Over a 42-week period, 12 untreated and treated patient tumors were successfully engrafted into NOD/SCID mice. RNA from each treatment group (5 untreated and 4 treated) was isolated in triplicate and subjected to global gene expression analysis. Consistent gene expression changes with treatment were identified and confirmed using RT-PCR and immunohistochemistry. RESULTS: Engraftment of untreated patient tumors was more frequent than treated tumors (17 of 21 versus 16 of 49, P = .0002) but without differences in observed time until tumor formation. The histology of patient tumors was recapitulated in direct xenograft tumors. Relative to untreated tumors, treated tumors consistently demonstrated more than a 2-fold reduction in TGFbeta-R2 mRNA expression and more than a 5-fold increase in IGFBP3 expression (P < .0218) and were confirmed by immunohistochemistry. CONCLUSION: Engraftment of human pancreatic tumors into immunodeficient mice prior to and following neoadjuvant therapy is possible and provides an in vivo platform for comparison of global gene expression patterns. The decreased TGFbeta-R2 expression and increased IGFBP3 expression among direct xenograft tumors derived from treated tumors relative to untreated tumors suggests a role in therapy resistance and warrants further study. PMID- 21701931 TI - Risk and predictors of malignancy in women with endometrial polyps. AB - BACKGROUND: Endometrial polyps commonly affect premenopausal and postmenopausal women and carry a small risk of cancer. Consensus guidelines to direct the management of women with endometrial polyps are lacking. We examined the risk of malignancy in symptomatic and asymptomatic women with endometrial polyps. METHODS: Institutional databases were analyzed to identify women with pathologically confirmed endometrial polyps diagnosed from 2002 to 2007. Demographic, clinical, and pathologic outcomes were reviewed. The most significant pathologic diagnosis was recorded for each subject. Endometrial hyperplasia and cancer were characterized as arising in the polyp or the adjacent endometrium. Factors associated with atypical hyperplasia and cancer were analyzed. RESULTS: A total of 1011 women with endometrial polyps were identified. On pathology review, 964 (95.4%) polyps were reported as benign, 13 (1.3%) as hyperplasia without atypia, 5 (0.5%) as hyperplasia with atypia, and 13 (1.3%) as endometrial cancer. The only clinical or demographic factor associated with atypical hyperplasia and cancer was menopausal status (P = .02). Among premenopausal women the risk of cancer or atypical hyperplasia was 0.9% in patients without bleeding and 1.0% in women with bleeding. In postmenopausal women cancer or atypical hyperplasia was found in 1.9% of patients without bleeding and in 3.8% of women with bleeding. CONCLUSIONS: The risk of endometrial cancer in women with endometrial polyps is 1.3%, while cancers confined to a polyp were found in only 0.3%. The risk is greatest in postmenopausal women with vaginal bleeding. PMID- 21701932 TI - Radiofrequency-assisted hepatic resection. AB - BACKGROUND: The only curative procedure to date for liver tumors is surgical resection, which remains a major procedure with marked morbidity and mortality. Radiofrequency (RF) has increasingly been used for both ablation and resection. On the basis of this technique, a new bipolar RF device, Habib 4X, has been developed and used clinically. We present our technique of liver resection with this device in a patient with colorectal liver metastases. METHODS: A patient with situs inversus who had colorectal liver metastases in her left lobe underwent left lateral segmentectomy with the new device, a four-electrode bipolar resection device that uses RF energy for tissue necrosis. After laparotomy and intraoperative ultrasound, the plane resection was marked 1 cm away from the edge of the lesion. Coagulative desiccation was performed along this plane using this sealer connected to a RF generator. The necrosed band of parenchyma was then divided with a scalpel and resection completed. RESULTS: The length of the procedure was 105 minutes; resection time was 35 minutes. Total blood loss was 100 ml. No blood transfusions were required, and the patient was not admitted to the intensive care unit after surgery. The patient was discharged 10 days after surgery without any surgical complications. CONCLUSIONS: We think that RF-assisted liver resection with this new device is safe and effective. It is quicker than conventional RF and may reduce overall hospital stay in liver resection patients. PMID- 21701933 TI - Stochastic modeling of adipogenesis in 3T3-L1 cultures to determine probabilities of events in the cell's life cycle. AB - 3T3-L1 preadipocytes are often being used in research of adipose-related diseases such as obesity, insulin resistance, and hyperlipidemia. We developed a stochastic model that simulated differentiation of four 3T3-L1 culture conditions distinct by the insulin concentration in the differentiation medium (2.5, 5, 7.5, or 10 MUg/mL). The model simulated culture behavior and the accumulation of lipid droplets in the maturing cells from the day of induction of differentiation through 28 days after that. The cellular processes including cell adhesion, mitosis, growing after undergoing mitosis, commitment to the adipocyte lineage, and apoptosis were referred to as stochastic events in the modeling. By minimizing the error between our model and experimental results, we found that the probability for becoming committed to the adipocyte lineage in a single division and the probability for growing after undergoing mitosis were 0.02 and 0.8, respectively, regardless of the insulin concentration. The probability for undergoing mitosis was equal to 0.2 and 0.4 in cultures that had insulin concentrations of 2.5 and 5-10 MUg/mL in the differentiation medium, respectively; hence the insulin concentration affected the probability for mitosis in the 3T3-L1 cells. The model and resulted probabilities now allow quantitative and visual predictions of adipogenesis in 3T3-L1 cultures, toward computational design of cell culturing protocols. PMID- 21701934 TI - Combined experimental and mathematical approach for development of microfabrication-based cancer migration assay. AB - Migration of cancer cells is a key determinant of metastasis, which is correlated with poor prognosis in patients. Evidence shows that cancer cell motility is regulated by stromal cell interactions. To quantify the role of homotypic and heterotypic cell-cell interaction in migration, a two-dimensional migration assay has been developed by microfabrication techniques. Two breast cancer cell lines, MDA-MB-231 and MDA-MB-453, were used to develop micropatterns of cancer cells (cell islands) that revealed distinct migration profiles in this assay. Although the individual migration rates of these cells showed only a sevenfold difference, MDA-MB-453 islands migrated significantly lower than MDA-MB-231 islands, indicating differential regulation of migration in isolated cells vs. islands. Island size had the greatest impact on migration, primarily for MDA-MB-231 cells. Migration of MDA-MB-231 islands was decreased by interaction with homotypic cells, and significantly more by heterotypic non-cancer-associated fibroblasts. In addition, a mathematical model of island migration in multi-cellular population has been developed using Stefan-Maxwell's equation. The model showed qualitative agreement with experimental results and predicted a biphasic relation between cell densities and island sizes. The combined experimental and mathematical model can be used to quantitatively study the impact of cell-cell interactions on migration. PMID- 21701935 TI - Intracellular delivery of mitomycin C with targeted polysaccharide conjugates against multidrug resistance. AB - Intracellular targeted conjugates of xyloglucan and mitomycin C (MMC) were synthesized with a lysosomally degradable peptide spacer and galactosamine, a terminal moiety that can be used to target polymeric conjugates to hepatoma. The content of the MMC was about 3.5% (mol) in this conjugate. In an in vitro cytotoxicity experiment, the targeted prodrugs have higher cytotoxicity than free MMC against the drug resistant HepG2 cells. In a human tumor xenograft nude mouse model, the targeted prodrugs generated higher therapeutic effect than non targeted prodrugs or free MMC. Together, these results suggest that targeted prodrugs, which have improved transfer efficiency and hepatocyte specificity, may be useful for the reversion of drug resistant HepG2 cells. PMID- 21701936 TI - Empowering Latino church leaders to deal with the HIV-AIDS crisis: a strengths oriented service model. AB - Ideology and attitudes of Latino church leaders in the United States toward HIV/AIDS are explored. A qualitative approach utilized with emergent categories including: a desire within the Latino church for greater acceptance of HIV/AIDS sufferers, the supposed contaminating influence of HIV/AIDS individuals over other church members, and the feelings of helplessness many church members experience in relation to the HIV/AIDS crisis. Understanding ideological resistance that prevents engagement is here identified and a strategy of empowerment of church leaders is recommended to overcome it including: adopting a strengths-oriented service model that focuses on resources religious denominations already have, as opposed to a financially driven, medically oriented service model that highlights what churches often do not have; church leaders educating health care agencies on how to use religious beliefs to motivate church members to work on behalf of HIV/AIDS patients; the power of doctrinal ideology in affecting church and civil society's response to HIV/AIDS. PMID- 21701937 TI - Metabolic changes following 500 MUg monthly administration of calcidiol: a study in normal females. AB - This study was performed to investigate the effect of monthly oral administration of 500 MUg of calcidiol (25-hydroxyvitamin D(3)) for 4 months on both serum vitamin D levels and sequential changes of parameters of calcium metabolism; 18 normal women aged 24-72 years were investigated. There was a significant increase of serum 25(OH)D after the first administration; thereafter all values persisted significantly higher compared to the basal value (P < 0.001). Mean 1,25(OH)(2)D serum levels peaked at day 3 and then tended to stabilize following day 30. During the first month, all mean values observed following the initial administration were significantly higher than basal values. The first calcidiol dose produced a significant reduction of serum PTH levels (P < 0.001), which then remained constant over time. Concerning serum calcium and phosphorus, we were not able to demonstrate any significant change during the entire observation period. Considering the single values for both serum ionized and total calcium, the values of Ca(2+) exceeded upper limits of normal on only two occasions. Regarding biochemical markers of bone remodeling, mean changes of serum bone isoenzyme of alkaline phosphatase activity showed a significant trend to decrease, starting at day 30. No significant changes of serum CTX values were noted. Overall, 24-h urinary excretion of calcium did not change, seven values exceeding the threshold of 4 mg/kg body weight. Monthly administration of 500 MUg of 25-hydroxyvitamin D(3) may be considered an alternative for vitamin D repletion, without any detrimental effect. PMID- 21701938 TI - Experimental stimulation of bone healing with teriparatide: histomorphometric and microhardness analysis in a mouse model of closed fracture. AB - Fracture consolidation is a crucial goal to achieve as early as possible, but pharmacological stimulation has been neglected so far. Teriparatide has been considered for this purpose for its anabolic properties. We set up a murine model of closed tibial fracture on which different doses of teriparatide were tested. Closed fracture treatment avoids any bias introduced by surgical manipulations. Teriparatide's effect on callus formation was monitored during the first 4 weeks from fracture. Callus evolution was determined by histomorphometric and microhardness assessment. Daily administration of 40 MUg/kg of teriparatide accelerated callus mineralization from day 9 onward without significant increase of sizes, and at day 15 the microhardness properties of treated callus were similar to those of bone tissue. Teriparatide considerably improved callus consolidation in the very early phases of bone healing. PMID- 21701939 TI - Pharmaceutical patents, R&D incentives and access to new drugs: new ways of progress at the crossroad. PMID- 21701940 TI - Cost-effectiveness of lapatinib plus capecitabine in women with HER2+ metastatic breast cancer who have received prior therapy with trastuzumab. AB - BACKGROUND: In a phase III trial of women with HER2+ metastatic breast cancer (MBC) previously treated with trastuzumab, an anthracycline, and taxanes (EGF100151), lapatinib plus capecitabine (L+C) improved time to progression (TTP) versus capecitabine monotherapy (C-only). In a trial including HER2+ MBC patients who had received at least one prior course of trastuzumab and no more than one prior course of palliative chemotherapy (GBG 26/BIG 03-05), continued trastuzumab plus capecitabine (T+C) also improved TTP. METHODS: An economic model using patient-level data from EGF100151 and published results of GBG 26/BIG 03-05 as well as other literature were used to evaluate the incremental cost per quality adjusted life-year [QALY] gained with L+C versus C-only and versus T+C in women with HER2+ MBC previously treated with trastuzumab from the UK National Health Service (NHS) perspective. RESULTS: Expected costs were L28,816 with L+C, L13,985 with C-only and L28,924 with T+C. Corresponding QALYs were 0.927, 0.737 and 0.896. In the base case, L+C was estimated to provide more QALYs at a lower cost compared with T+C; cost per QALY gained was L77,993 with L+C versus C-only. In pairwise probabilistic sensitivity analyses, the probability that L+C is preferred to C-only was 0.03 given a threshold of L30,000. The probability that L+C is preferred to T+C was 0.54 regardless of the threshold. CONCLUSIONS: When compared against capecitabine alone, the addition of lapatinib has a cost effectiveness ratio exceeding the threshold normally used by NICE. Compared with T+C, L+C is dominant in the base case and approximately equally likely to be cost effective in probabilistic sensitivity analyses over a wide range of threshold values. PMID- 21701941 TI - Observed externalizing behavior: a developmental comparison of genetic and environmental influences across three samples. AB - Estimates of genetic and environmental influences on externalizing behavior are markedly inconsistent. In an attempt to refine and extend our knowledge of externalizing behavior, the current study examined the etiology of externalizing behavior using observational data in middle childhood and adolescence from three twin and sibling samples. Observational ratings offer a unique perspective on externalizing behavior rarely examined within behavioral genetic designs. Shared environmental influences were significant and moderate to large in magnitude across all three samples (i.e., 44, 77, and 38%), while genetic influences (31%) were significant only for the adolescent sample. All three samples showed greater shared environmental influences and less genetic influence than is typically found when examining self-, parent-, and teacher-reports of externalizing behavior. These findings are consistent with other reports that have found evidence for shared environmental influences on measures of child externalizing behavior-in direct contrast to a commonly held perception that shared environmental factors do not have significant influences on behavior beyond early childhood. PMID- 21701942 TI - Social defeat or social resistance? Reaction to fear of crime and violence among people with severe mental illness living in urban 'recovery communities'. AB - This article is propelled by recent theory positing that 'social defeat' is a common experience for people with severe mental illness, potentially affecting course and outcome. The primary objective is to investigate how far fear of crime and violence contributes toward 'social defeat' among people with mental illness. This is done through examining 6 years of ethnographic data collected from a sample of urban-dwelling people with severe mental illness, all securely-housed in apartments located in small scale "recovery communities." Findings suggest that many participants living in the highest crime neighborhoods report that they deliberately restrict their temporal and spatial movement as a consequence of such crime. This hinders aspects of their recovery. Nevertheless, participants actively confront the nefarious affects of neighborhood crime by engaging in various empowering strategies of resistance. These include confronting disruptive people, fortifying homes, moving around the neighborhood in small groups and carrying objects such as umbrellas and canes that can be used in self-defense. Some reported that fear of crime directly contributed to the development of a rich and gratifying domestic life, centered on hospitality and religion. I conclude that participants partake in valiant and durable "social resistance," and may better be perceived as imaginative and resourceful resistors, rather than passive victims of "social defeat." An influential factor fostering such resistance is the "recovery community' itself, which creates secure and reliable housing within a micro-community in which participants could thrive. PMID- 21701943 TI - Ultrasound-assisted liposuction as a safe and effective method for the removal of siliconomas. PMID- 21701944 TI - A modified technique combining excision of the levator muscle and tarsus for blepharoptosis in Asians: a 6-year experience with 116 cases. AB - BACKGROUND: In patients with blepharoptosis, the function of levator muscle is insufficient or completely absent, causing blepharoptosis in various degrees. For mild or moderate blepharoptosis, levator advancement or resection is commonly performed. However, in severe cases, undercorrection results and recurrence often occur even a great length of levator muscle is resected. Because the levator muscle makes the upper eyelid move in a physiologic direction, exerting the function of residual levator muscle is still a more preferred approach for correction of blepharoptosis. This study combined tarsus resection with levator resection. The resected tarsus can offset the amount of the levator excised, making this technique applicable for severe cases. METHODS: This study included 116 patients (175 eyelids) with moderate or severe ptosis who underwent combined excision of the levator muscle and the tarsus. For cases of bilateral blepharoptosis with different levator functions between the two eyelids, surgery was performed for more severe side first and for the other side 6 months later. Postoperatively, the correction and symmetry results were evaluated and analyzed using chi-square testing by SPSS (version 10.0). RESULTS: Adequate or normal correction was achieved in 149 eyelids (85.1%). The difference in correction results did not differ significantly between moderate and severe cases. With a two-stage operation, 98 patients (84.5%) obtained good or fair asymmetry results, and no statistically significant difference existed between the bilateral and unilateral cases. CONCLUSION: The described technique appears to be effective for both moderate and severe ptosis, with better biomechanics and a satisfying aesthetic outcome. PMID- 21701945 TI - miRNA expression profiles in keloid tissue and corresponding normal skin tissue. AB - BACKGROUND: Because the molecular mechanism behind keloid pathogenesis is still largely unknown, the clinical management of keloids remains problematic. miRNA (microRNA) is a novel class of small regulatory RNA that has emerged as post transcriptional gene repressors and participants in diverse pathophysiological processes of skin disease. In the present study we aimed to investigate expression profiles of miRNA in keloid tissue and to develop a further understanding of the molecular mechanism involved in the pathogenesis of keloids. METHODS: miRNA expression profiles in 12 pairs of keloid tissue and corresponding normal skin tissue were analyzed through a mammalian miRNA microarray containing established whole human mature and precursor miRNA sequences. Real-Time quantitative PCR was performed to confirm the array results. The putative targets of differentially expressed miRNA were functionally annotated by bioinformatics approaches. RESULTS: miRNA microarray analysis identified 32 differentially expressed miRNAs, and a total of 23 miRNAs exhibited higher expression, while 9 miRNAs demonstrated lower expression in keloid tissue than in normal skin tissue. Functional annotations of differentially expressed miRNA targets revealed that they were enriched in several signaling pathways important for scar wound healing. CONCLUSION: This study showed that the expressions of many miRNAs were altered in keloid tissue, and their expression profiling may provide a useful clue for exploring the pathogenesis of keloids. miRNAs might partly contribute to the etiology of keloids by affecting several signaling pathways relevant to scar wound healing. PMID- 21701946 TI - Analysis of migrated hydrogel used for breast augmentation revealed prolamin (a cereal seed storage protein). AB - BACKGROUND: We report on a case of leakage and migration to the upper abdomen of an unknown injected material that was used for breast augmentation. It was revealed to be prolamin by Fourier transform infrared (FTIR) analysis and pyrolysis gas chromatography/mass spectrometry (PY-GC/MS). METHODS: A 35-year-old woman who had undergone mammary augmentation by transaxillary injection 8 years previously presented with a decreased size of her left breast and a palpable mass in the left upper quadrant (LUQ). Mammogram and ultrasonography showed multiple dense masses and several hypoechoic areas, respectively. Abdominal ultrasound showed a hypoechoic lesion between the subcutaneous layer and the abdominal wall muscles. When the left breast and the lump in the LUQ were explored, 90 and 160 cc of yellow, sticky, granular gel gushed out. FTIR analysis and PY-GC/MS were used to investigate the component of the removed gel. RESULTS: When this gel was analyzed by FTIR with the transmittance mode, intensity bands appeared at 3295.2 (NH2), 2927.2 (CH), 1650 (C=C), 1544.6 (C-C), and 1403.1 (C-N) cm(-1). The result showed a 93.84% match with purified zein, a 91.19% match with zein from corn, and a 90.27% match with poly(N-methyl acrylamide). FTIR with the attenuated total reflectance (ATR) mode revealed that the gel matched with wheat gluten flour. Based on the result of PY-GC/MS, the gel was suspected to be protein. CONCLUSION: This is the first such report on performing chemical analysis of a leaked injected gel from human breast implantation. The removed gel from the breast augmentation was revealed to be prolamin, which is a cereal seed storage protein. We think FTIR might be a useful tool for analyzing and confirming extracted materials that were previously injected to the body. PMID- 21701947 TI - Toward a scalable holographic word-form representation. AB - Phenomena in a variety of verbal tasks--for example, masked priming, lexical decision, and word naming--are typically explained in terms of similarity between word-forms. Despite the apparent commonalities between these sets of phenomena, the representations and similarity measures used to account for them are not often related. To show how this gap might be bridged, we build on the work of Hannagan, Dupoux, and Christophe, Cognitive Science 35:79-118, (2011) to explore several methods of representing visual word-forms using holographic reduced representations and to evaluate them on their ability to account for a wide range of effects in masked form priming, as well as data from lexical decision and word naming. A representation that assumes that word-internal letter groups are encoded relative to word-terminal letter groups is found to predict qualitative patterns in masked priming, as well as lexical decision and naming latencies. We then show how this representation can be integrated with the BEAGLE model of lexical semantics (Jones & Mewhort, Psychological Review 114:1-37, 2007) to enable the model to encompass a wider range of verbal tasks. PMID- 21701948 TI - Mining twitter: a source for psychological wisdom of the crowds. AB - Over the last few years, microblogging has gained prominence as a form of personal broadcasting media where information and opinion are mixed together without an established order, usually tightly linked with current reality. Location awareness and promptness provide researchers using the Internet with the opportunity to create "psychological landscapes"--that is, to detect differences and changes in voiced (twittered) emotions, cognitions, and behaviors. In our article, we present iScience Maps, a free Web service for researchers, available from http://maps.iscience.deusto.es/ and http://tweetminer.eu/ . Technologically, the service is based on Twitter's streaming and search application programming interfaces (APIs), accessed through several PHP libraries, and a JavaScript frontend. This service allows researchers to assess via Twitter the effect of specific events in different places as they are happening and to make comparisons between cities, regions, or countries regarding psychological states and their evolution in the course of an event. In a step-by-step example, it is shown how to replicate a study on affective and personality characteristics inferred from first names (Mehrabian & Piercy, Personality and Social Psychology Bulletin, 19, 755-758 1993) by mining Twitter data with iScience Maps.Results from the original study are replicated in both world regions we tested (the western U.S. and the U.K./Ireland); we also discover base rate of names to be a confound that needs to be controlled for in future research. PMID- 21701949 TI - WoMMBAT: A user interface for hierarchical Bayesian estimation of working memory capacity. AB - The change detection paradigm has become an important tool for researchers studying working memory. Change detection is especially useful for studying visual working memory, because recall paradigms are difficult to employ in the visual modality. Pashler (Perception & Psychophysics, 44, 369-378, 1988) and Cowan (Behavioral and Brain Sciences, 24, 87-114, 2001) suggested formulas for estimating working memory capacity from change detection data. Although these formulas have become widely used, Morey (Journal of Mathematical Psychology, 55, 8-24, 2011) showed that the formulas suffer from a number of issues, including inefficient use of information, bias, volatility, uninterpretable parameter estimates, and violation of ANOVA assumptions. Morey presented a hierarchical Bayesian extension of Pashler's and Cowan's basic models that mitigates these issues. Here, we present WoMMBAT (Working Memory Modeling using Bayesian Analysis Techniques) software for fitting Morey's model to data. WoMMBAT has a graphical user interface, is freely available, and is cross-platform, running on Windows, Linux, and Mac operating systems. PMID- 21701950 TI - Fever and deep venous thrombosis. Findings from the RIETE registry. AB - Fever is a presenting sign in some patients with acute deep venous thrombosis (DVT), but its influence on outcome has not been thoroughly investigated. RIETE is an ongoing, international, observational registry of consecutive patients with symptomatic, objectively confirmed, acute venous thromboembolism. The aim of the present study was to assess the prevalence of fever in patients with acute DVT, and to compare their outcome during the first month of therapy, according to the presence or absence of fever. As of September 2009, 14,480 patients with symptomatic DVT have been enrolled in RIETE. Of these, 707 (4.9%) had fever at presentation. During the 30-day study period, 448 patients (3.1%) died, 171 (1.2%) developed DVT recurrences, 376 (2.6%) had pulmonary embolism, and 384 (2.6%) had a major bleeding. Patients initially presenting with fever had a higher mortality (5.8% vs. 2.9%; odds ratio: 2.6; 95% CI 1.9-3.5) than those without fever. Among the causes of death, pulmonary embolism (0.7% vs. 0.1%) and infection (1.1% vs. 0.3%) were significantly more common in patients presenting with fever. Multivariate analysis confirmed that DVT patients with fever had an increased mortality (hazard ratio: 2.00; 95% CI 1.44-2.77) irrespectively of the patient's age, body weight, and risk factors for VTE. Fever is not uncommon in patients with DVT, and carries a worse outcome. PMID- 21701951 TI - Return to work expectations of workers on long-term non-work-related sick leave. AB - INTRODUCTION: Despite suggestions that worker perception might be the best predictor of return to work (RTW), there still is limited research on time to RTW in workers with lengthy non-work-related sick leave. METHODS: Prospective cohort study of 663 workers with a current long-term non-work-related sick leave episode recruited during the first medical visit in a mutua (Spanish health insurance company) and followed until their sick leave episode ended. Workers completed a baseline questionnaire regarding their perceptions of sick leave episode and expectations of RTW (i.e., health status, work ability, expectations and time required to RTW, self-efficacy and self-perceived connection between health and job). Time to RTW was established based on the mutua's register. Cox regression models were used to examine the associations of worker perception and expectation of RTW with time to RTW within the study population as a whole as well as in three diagnostic subgroups (i.e., musculoskeletal disorders, mental disorders and other physical conditions). RESULTS: As a whole, time to RTW was longer for workers reporting poor health [hazard ratio (HR) = 0.71, 95%CI 0.59-0.85], extremely reduced work ability (HR = 0.69, 95%CI 0.53-0.88), a longer period of time required to RTW (HR = 0.36, 95%CI 0.25-0.52) and lack of expectation of returning to the same job (HR = 0.13, 95%CI 0.06-0.31). Workers with musculoskeletal and other physical conditions showed a similar pattern to whole study population, while workers with mental disorders did not. CONCLUSION: Self required time and RTW expectations are important prognostic factors in sick listed workers by all types of health conditions certified as non-work-related. Questioning the workers on their perceptions and expectations of RTW during medical visits could help health care professionals to identify individuals at risk of long-term sickness absence and facilitate triage and management of the patient. PMID- 21701952 TI - Quantitative assessment of bone defect healing by multidetector CT in a pig model. AB - OBJECTIVE: To evaluate multidetector CT volumetry in the assessment of bone defect healing in comparison to histopathological findings in an animal model. MATERIALS AND METHODS: In 16 mini-pigs, a circumscribed tibial bone defect was created. Multidetector CT (MDCT) of the tibia was performed on a 64-row scanner 42 days after the operation. The extent of bone healing was estimated quantitatively by MDCT volumetry using a commercially available software programme (syngo Volume, Siemens, Germany).The volume of the entire defect (including all pixels from -100 to 3,000 HU), the nonconsolidated areas (-100 to 500 HU), and areas of osseous consolidation (500 to 3,000 HU) were assessed and the extent of consolidation was calculated. Histomorphometry served as the reference standard. RESULTS: The extent of osseous consolidation in MDCT volumetry ranged from 19 to 92% (mean 65.4 +/- 18.5%). There was a significant correlation between histologically visible newly formed bone and the extent of osseous consolidation on MDCT volumetry (r = 0.82, P < 0.0001). A significant negative correlation was detected between osseous consolidation on MDCT and histological areas of persisting defect (r = -0.9, P < 0.0001). CONCLUSION: MDCT volumetry is a promising tool for noninvasive monitoring of bone healing, showing excellent correlation with histomorphometry. PMID- 21701953 TI - Engineering broad-spectrum resistance against RNA viruses in potato. AB - RNA silencing technology has become the tool of choice for inducing resistance against viruses in plants. A significant discovery of this technology is that double-stranded RNA (dsRNA), which is diced into small interfering RNAs (siRNAs), is a potent trigger for RNA silencing. By exploiting this phenomenon in transgenic plants, it is possible to confer high level of virus resistance by specific targeting of cognate viral RNA. In order to maximize the efficiency and versatility of the vector-based siRNA approach, we have constructed a chimeric expression vector containing three partial gene sequences derived from the ORF2 gene of Potato virus X, Helper Component Protease gene of Potato virus Y and Coat protein gene of Potato leaf roll virus. Solanum tuberosum cv. Desiree and Kuroda were transformed with this chimeric gene cassette via Agrobacterium tumefaciens mediated transformation and transgenic status was confirmed by PCR, Southern and double antibody sandwich ELISA detection. Due to simultaneous RNA silencing, as demonstrated by accumulation of specific siRNAs, the expression of partial triple gene sequence cassette depicted 20% of the transgenic plants are immune against all three viruses. Thus, expression of a single transgene construct can effectively confer resistance to multiple viruses in transgenic plants. PMID- 21701954 TI - Gene expression profiling supports the role of Repin1 in the pathophysiology of metabolic syndrome. AB - Congenic BB rat strains carrying a SHR segment (D4Got41-Tacr1; 60.5-122.8 Mb; BB.4S) or a WOKW segment (D4Got41-Fabp1; 60.5-104.6 Mb; BB.4W) of chromosome 4 within the BB/OK background develop facets of the metabolic syndrome when compared with their parental BB/OK rats. To narrow down potential genes involved in the pathophysiology of metabolic syndrome, gene expression studies in adipose tissues of BB/OK, BB.4S, and BB.4W rats were initiated. Total RNA of subcutaneous and epididymal adipose tissue of BB/OK (n=10), congenic BB.4S (n=8), and BB.4W (n=9) males at an age of 4 weeks was isolated. The mRNA expression of 92 genes involved in obesity, insulin resistance and other metabolic traits was measured by RT-PCR. Significant differences in gene expression were only found in Repin1 in both adipose tissues. Congenic BB.4W showed significantly lower gene expression than did BB.4S and BB/OK. Our findings and newly published findings of Repin1 in 3T3-L1 adipocytes support the hypothesis that Repin1 may affect the development of facets of the metabolic syndrome. PMID- 21701955 TI - A survey of ethical and professional challenges experienced by Spanish health care professionals that provide genetic counseling services. AB - Genetic testing is increasingly applied for diagnosis and clinical treatment. In some countries, genetic counseling services are provided by professionals with specific training in this discipline, whereas other countries have no teaching programs and counseling is offered by physicians, nurses, pharmacists or biochemists. This counseling raises more and more ethical dilemmas for health professionals at their clinics. The purpose of this study was to analyze the characteristics of Spanish professionals devoted to providing genetic counseling services and to investigate the frequency of the ethical dilemmas they face. Results from 72 survey respondents revealed this counseling is provided by an almost even number of male and female professionals, mostly physicians with many years of professional experience. The overall frequency of the ethical dilemmas encountered was not high. The most frequent dilemmas corresponded to emotional responses by patients, informed consent, uncertainty about test results, and limitations on health-care resources. The frequency of dilemmas involving discrimination and provider directiveness was very low. Additional findings, practice implications, and research recommendations are presented. PMID- 21701956 TI - Clinical use of the Surgeon General's "My Family Health Portrait" (MFHP) tool: opinions of future health care providers. AB - This study examined medical students' and house officers' opinions about the Surgeon General's "My Family Health Portrait" (MFHP) tool. Participants used the tool and were surveyed about tool mechanics, potential clinical uses, and barriers. None of the 97 participants had previously used this tool. The average time to enter a family history was 15 min (range 3 to 45 min). Participants agreed or strongly agreed that the MFHP tool is understandable (98%), easy to use (93%), and suitable for general public use (84%). Sixty-seven percent would encourage their patients to use the tool; 39% would ensure staff assistance. Participants would use the tool to identify patients at increased risk for disease (86%), record family history in the medical chart (84%), recommend preventive health behaviors (80%), and refer to genetics services (72%). Concerns about use of the tool included patient access, information accuracy, technical challenges, and the need for physician education on interpreting family history information. PMID- 21701957 TI - Personality traits associated with genetic counselor compassion fatigue: the roles of dispositional optimism and locus of control. AB - Compassion fatigue (CMF) arises as a consequence of secondary exposure to distress and can be elevated in some health practitioners. Locus of control and dispositional optimism are aspects of personality known to influence coping style. To investigate whether these personality traits influence CMF risk, we surveyed 355 genetic counselors about their CMF, locus of control orientation, and degree of dispositional optimism. Approximately half of respondents reported they experience CMF; 26.6% had considered leaving their job due to CMF symptoms. Mixed-method analyses revealed that genetic counselors having an external locus of control and low optimism were at highest risk for CMF. Those at highest risk experienced moderate-to-high burnout, low-to-moderate compassion satisfaction, and tended to rely on religion/spirituality when coping with stress. CMF risk was not influenced by years in practice, number of genetic counselor colleagues in the workplace, or completion of graduate training in this area. Recommendations for practice and education are outlined. PMID- 21701958 TI - A case study of liberation among Latino immigrant families who have children with disabilities. AB - Latino immigrant families with children with disabilities experience multiple sources of oppression during their settlement process in the United States. Unfair social structures and dominant cultural values and norms and the way they influence the immigrants' personal life stories generate a cycle of oppression very difficult to break. This paper presents a case study of how a group of Latino parents carried out a process of liberation fueled by the generation of empowering community narratives (critical awareness leading to transformative action) that resulted from a community-university partnership. Participants initiated a process that led them to discover their own stories of oppression and create new stories; to deconstruct the dominant cultural narratives and modify existing ones; and to understand contexts for power sharing. This joint reflection and increased awareness propelled group members to take action by founding a grassroots organization to redress some of the injustices that were partly responsible for their oppression, thus generating shifts at the personal, relational, and collective levels. In light of the theory of liberation, we discuss the participants' development of critical awareness that led them to take action to address their unmet needs. PMID- 21701959 TI - Tree-ring-based reconstruction of precipitation in the Changling Mountains, China, since A.D.1691. AB - Seven different tree-ring parameters were obtained from Chinese pine (Pinus tabulaeformis) in the Changling Mountains, China. The chronologies were analyzed individually and then compared with each other. The climate response analysis shows that total precipitation (September-July) is the main factor limiting the radial growth of Chinese pine in the Changling Mountains. Thus, the residual earlywood width chronology was used to estimate precipitation (September-July) for the period AD 1691-2006, and explained 46.9% of the precipitation variance. Drought events in our reconstruction are compared to historical archives for Gansu and north-central China. The results reveal the climatic extremes over much of Gansu. Some events have had profound impacts on the Gansu people over the past several centuries. Spatial analysis shows that the precipitation reconstruction has strong common signals for North-central China. The reconstructed series is correlated significantly with Helan Mountains Palmer drought severity index (PDSI), as well as with previous results from Jiuquan, Shandan, Huashan, Luya Mountains, and even the state of Mongolia. Our results suggest that some dry periods are coincident with solar minima over the past several hundred years. Multitaper spectral analysis reveals the existence of significant 24.4-year, 12.2 year, and 2.4- to 3.4-year periods of variability. PMID- 21701960 TI - Application of pharmaceutical QbD for enhancement of the solubility and dissolution of a class II BCS drug using polymeric surfactants and crystallization inhibitors: development of controlled-release tablets. AB - The aim of this study was to apply quality by design (QbD) for pharmaceutical development of felodipine solid mixture (FSM) containing hydrophilic carriers and/or polymeric surfactants, for easier development of controlled-release tablets of felodipine. The material attributes, the process parameters (CPP), and the critical quality attributes of the FSMs were identified. Box-Behnken experimental design was applied to develop space design and determine the control space of FSMs that have maximum solubility, maximum dissolution, and ability to inhibit felodipine crystallization from supersaturated solution. Material attributes and CPP studied were the amount of hydroxypropyl methylcellulose (HPMC; X(1)), amount of polymeric surfactants Inutec(r)SP1 (X(2)), amount of Pluronic(r)F-127 (X(3)) and preparation techniques, physical mixture (PM) or solvent evaporation (SE; X(4)). There is no proposed design space formed if the Pluronic(r) content was below 45.1 mg and if PM is used as the preparation technique. The operating ranges, for robust development of FSM of desired quality, of Pluronic(r), Inutec(r)SP1, HPMC, and preparation technique, are 49 50, 16-23, 83-100 mg, and SE, respectively. The calculated value of f2 was 56.85, indicating that the release profile of the controlled-release (CR) tablet (CR-6) containing the optimized in situ-formed FSM was similar to that of the target release profile. Not only did the ternary mixture of Pluronic(r), HPMC with Inutec(r)SP1 enhance the dissolution rate and inhibit crystallization of felodipine, but also they aided Carbopol(r)974 in controlling felodipine release from the tablet matrix. It could be concluded that a promising once-daily CR tablets of felodipine was successfully designed using QbD approach. PMID- 21701961 TI - Invasive Streptococcus pneumoniae infections in children in Kamikawa and Soya subprefecture, Hokkaido, Japan, 2000-2010, before the introduction of the 7 valent pneumococcal conjugate vaccine. AB - We evaluated 103 cases of invasive pneumococcal disease (IPD) encountered in 99 children (two developed the disease twice and one, three times) treated in the northern district of Hokkaido (Kamikawa and Soya subprefecture) from April 2000 until March 2010, before the introduction of the 7-valent pneumococcal conjugate vaccine. The main diseases were as follows: pneumonia, 54 cases (52.9%); occult bacteremia, 34 cases (33.3%); meningitis, five cases (4.9%). There were 42 cases during the first half of the study period (from April 2000 to March 2005) and 61 during the second half (from April 2005 to March 2010). The IPD morbidity rate for the 10-year period was 41.3 per 100,000 population in children <5 years and 79.2 per 100,000 population in children <2 years. Serotype analysis of the 77 strains was performed. The most frequent serotype isolated was 6B (31.2%), followed by 23F (14.3%), 19F (13.0%), 9V (7.8%), 6A (7.8%), and 14 (3.9%). The number of strains that could potentially be covered by heptavalent pneumococcal conjugate vaccine was 55 (71.4%), and the number of strains that could potentially be covered by 13-valent pneumococcal conjugate vaccine was 64 (83.1%). Analysis of penicillin-binding protein (PBP) genes was performed of the 82 strains. The percentages of resistant bacteria caused by PBP gene mutations were 42.7% (35 strains) for gPRSP, 48.8% for gPISP (40 strains), and 8.5% for gPSSP (7 strains). PMID- 21701962 TI - Microstructuration stages during gelation of gelatin under shear. AB - We study gelation under shear of aqueous gelatin by measuring the evolution of the apparent viscosity, thus extending the previous study by de Carvalho and Djabourov (W. de Carvalho, M. Djabourov, Rheol. Acta 36, 591 (1997)). From a set of experiments under constant stress, we deduce that the microstructure evolves through the following succession of regimes: i) nucleation and growth until crowding of a microgel suspension; ii) coalescence into strata parallel to the flow; iii) gradual thickening of these strata via transverse cross-linking until the flow finally localizes into two interfacial sliding bands which close sequentially. The transition between these regimes occurs at characteristic viscosity values. This scenario is fully confirmed by experiments performed at constant shear rates. We expect it to be relevant for all materials forming thermoreversible gels. PMID- 21701963 TI - Screening for ligands of C-type lectin-like receptors. AB - In order to execute their immune functions, leukocytes interact with a broad range of cell types through cell surface receptors, such as those of the immunoglobulin and C-type lectin families, or indirectly through soluble factors. The characterization of activating and inhibitory counterparts of NK cell receptors on myeloid cells, as well as the identification of their physiological ligands, has provided new insights into the underlying mechanisms of immunity and homeostasis. Here, we describe methodology that can be employed to screen for endogenous ligands of type-II C-type lectin-like receptors using reporter cells and Fc fusion proteins. PMID- 21701964 TI - Yeast surface display of lamprey variable lymphocyte receptors. AB - The variable lymphocyte receptors (VLRs) of lamprey and hagfish comprise leucine rich repeat modules, instead of the immunoglobulin-like domain building blocks of antibodies and T-cell receptors in jawed vertebrates. Both types of vertebrate rearranging antigen receptors are similarly diverse, with repertoires that can potentially exceed 10(14) unique receptors. In order to characterize antigen binding properties of the VLRs, we developed a high-throughput yeast surface display platform for the isolation of monoclonal VLRs. We have isolated VLRs that specifically bind hen egg lysozyme, beta-galactosidase, cholera toxin subunit B, R-phycoerythrin, and the blood group trisaccharides A and B, with binding affinities in the mid-nanomolar to mid-picomolar range. VLRs may, thus, be excellent single-chain alternatives to Ig-based antibodies for biotechnology applications. PMID- 21701965 TI - Identification of scavenger receptor ligands. AB - Scavenger receptors (SRs) are structurally diverse but functionally related innate immune receptors involved in defence and clearance mechanisms. Their broad specificity relies on evolutionarily conserved pattern recognition domains which interact with a variety of microbial, apoptotic and modified self ligands. Studies of immune functions of SR-expressing cells require the identification of interaction partners for SRs. We have developed an ELISA-based method which allows for large-scale high-throughput screening of complex mixtures. The assay successfully identified bacterial and plasma ligands for macrophage scavenger receptor A and can be adapted to screen for novel exogenous or endogenous ligands for any immune receptor of interest. PMID- 21701966 TI - Construction, expression, and purification of chimeric protein reagents based on immunoglobulin fc regions. AB - Recombinant fusion proteins incorporating experimental protein domains fused to immunoglobulin Fc regions have become widely utilized in studies of protein ligand interactions. The advantages of these systems include an inherent increase in avidity provided by the multimerization of Fc regions, combined with robust detection methods based on numerous commercially available secondary reagents directed against the Fc tag. We describe a set of methods for subcloning, expression, and purification of chimeric protein reagents containing a protein domain (or domains) of interest fused to a C-terminal moiety derived from the Fc region of either IgG or IgM. PMID- 21701968 TI - Analysis of receptor-ligand interactions by surface plasmon resonance. AB - Many immunological responses are often regulated by cell surface receptors in cell-cell recognition events. Such immune receptors on the cell surface typically exhibit low-affinity and fast-kinetic ligand interactions (e.g., K (d) in the MUM range, k (off) = 10(-2) to 20 s(-1)). Real-time surface plasmon resonance (SPR) detection systems are generally useful for determining these binding parameters. However, several technical points should be considered because the determination of low-affinity binding and fast kinetics is often rather difficult. Here, we introduce a general procedure for SPR experiments and, moreover, show typical examples for ligand binding of immune cell surface receptors, including experimentally useful tips. We also show how to determine the thermodynamic characteristics using the nonlinear van't Hoff and Arrhenius analyses. These affinity, kinetic, and thermodynamic parameters of immune-receptor binding are important for understanding immunological events as well as developing drugs and vaccines. PMID- 21701967 TI - Innate immune receptors for nucleic acids. AB - The innate immune system has evolved to detect microbes and sterile tissue damage with the help of a series of signaling receptors. One key strategy is to detect infectious microbes or host cell damage by recognizing nucleic acids that are modified or appear in compartment normally devoid of nucleic acids. Here, we describe two methods that allow studying the molecular interaction between various nucleic acid recognizing signaling receptors with their ligands. A ligand pull-down assay can be used to show a known interaction between a ligand and its receptor or the method can be utilized as a discovery approach to identify an unknown receptor to a given ligand. An AlphaScreen experiment can be set up to assess the ligand binding affinity to a given receptor. PMID- 21701969 TI - Cell-based reporter assay to analyze activation of Nod1 and Nod2. AB - Nod1 and Nod2 are pattern recognition receptors of the mammalian innate immune system. They respond to bacterial peptidoglycan fragments and are implicated in host defense against a variety of -different bacterial pathogens. Recent studies furthermore support additional functions of these proteins in the control of adaptive immune responses and intestinal homeostasis. Activation of Nod1 and Nod2 by their cognate elicitors triggers inflammatory responses driven by the activation of NF-kappaB and MAPK pathways. In this chapter, we describe a quick and reliable cell-based assay using a luciferase reporter to measure Nod1- and Nod2-mediated NF-kappaB activation. The described protocol was successfully applied to analyze the influences of overexpressed proteins and siRNA-mediated knock-down to provide new insights into the regulation of Nod1/2-specific signaling pathways. Furthermore, this method is well suited for downscaling to high-throughput screening applications. PMID- 21701970 TI - Determining FcepsilonRI diffusional dynamics via single quantum dot tracking. AB - Single-particle tracking (SPT) using fluorescent quantum dots (QDs) provides high resolution spatial-temporal information on receptor dynamics that cannot be obtained through traditional biochemical techniques. In particular, the high brightness and photostability of QDs make them ideal probes for SPT on living cells. We have shown that QD-labeled IgE can be used to characterize the dynamics of the high-affinity IgE Receptor. Here, we describe protocols for (1) coupling QDs to IgE, (2) tracking individual QD-bound receptors, and (3) analyzing one- and two-color tracking data. PMID- 21701971 TI - Ratiometric analysis of subcellular recruitment of Fc receptors during phagocytosis. AB - Numerous immune receptors have the ability to mediate phagocytosis of large particles by triggering dynamic local rearrangement of the cytoskeleton and cell membrane. Different receptors can be differentially recruited to sites of particle binding, which in turn can have important functional consequences with respect to engulfment and downstream signaling. Using Fcgamma receptor-mediated phagocytosis of IgG-coated particles as a model, we describe a method for analyzing nascent phagocytic cups and quantifying relative receptor levels at sites of phagocytosis. This technique is based on a ratiometric analysis of subcellular localization of exogenously expressed receptors carrying different fluorescent protein tags. This approach could be applied more generally to the analysis of surface membrane protein localization in the context of any dynamic cellular process. PMID- 21701972 TI - Assessment of the recycling of the membrane-bound chemokine, CX3CL1. AB - Fractalkine (CX(3)CL1) is a membrane-anchored chemokine whose N-terminus contains a unique CX(3)C motif that is cleaved and released. The membrane-bound form functions as an adhesion molecule and the secreted form as a chemotactic factor. Like other chemokines, CX(3)CL1 is regulated at the levels of transcription and translation. Recent evidence points to additional functional regulation by cellular trafficking owing to the unique transmembrane structure. CX(3)CL1 is the only chemokine known to undergo constitutive internalization. To understand mechanisms governing the regulation and processing of such membrane-bound proteins, it is vital to study their subcellular distribution and transport. The methods outlined in this chapter describe (1) transfection of mammalian cells with plasmids encoding the expression of green fluorescent protein-tagged CX(3)CL1; (2) immunofluorescence antibody labeling as well as fluorescence recovery after photobleaching to study internalization of CX(3)CL1 by endocytosis; and (3) acid-stripping assays to study the recycling of internalized CX(3)CL1 back to the plasma membrane. Together, these methods allow for the examination of subcellular distribution and traffic of recycling membrane proteins. PMID- 21701973 TI - Measuring immune receptor mobility by fluorescence recovery after photobleaching. AB - The coordinated effort of cells in the immune system relies heavily on surface receptor interactions. Immune receptor mobility provides vital information on the function and responses of immune cells, and these measurements shed light on their interactions with other membrane, cytosolic, and extracellular matrix proteins. These measurements can be obtained using the fluorescence recovery after photobleaching (FRAP) technique in living cells. We describe here general approaches for FRAP using green fluorescent protein fusion proteins. PMID- 21701974 TI - Probing the plasma membrane structure of immune cells through the analysis of membrane sheets by electron microscopy. AB - This chapter describes a method to generate plasma membrane sheets that are large enough to visualize the membrane architecture and perform quantitative analyses of protein distributions. This procedure places the sheets on electron microscopy grids, parallel to the imaging plane of the microscope, where they can be characterized by transmission electron microscopy. The basic principle of the technique is that cells are broken open ("ripped") through mechanical forces applied by the separation of two opposing surfaces sandwiching the cell, with one of the surfaces coated onto an EM grid. The exposed inner membrane surfaces can then be visualized with electron dense stains and specific proteins can be detected with gold conjugated probes. PMID- 21701975 TI - Rapamycin-based inducible translocation systems for studying phagocytosis. AB - Phagocytosis is an immune receptor-mediated process whereby cells engulf large particles. The process is dynamic and requires several localized factors acting in concert with and sequentially after the engagement of immune receptors to envelope the particle. Once the particle is internalized, the nascent -phagosome undergoes a series of events leading to its maturation to the microbicidal phagolysosome. Investigating these dynamic and temporally controlled series of events in live cells requires noninvasive methods. The ability to rapidly recruit the proteins of interest to the sites of phagocytosis or to nascent phagosomes would help dissect the regulatory mechanisms involved during phagocytosis. Here, we describe a general approach to express in RAW264.7 murine macrophages, a genetically encoded rapamycin--induced heterodimerization system. In the presence of rapamycin, tight association between FK506-binding protein (FKBP) and FKBP rapamycin-binding protein (FRB) is observed. Based on this principle, a synthetic system consisting of a targeting domain attached to FKBP can recruit a protein of interest fused to FRB upon the addition of rapamycin. Previously, this technique has been used to target lipid-modifying enzymes and small GTPases to the phagosome or plasma membrane. The recruitment of the FRB module can be monitored by fluorescent microscopy if a fluorescent protein is fused to the FRB sequence. While the focus of this chapter is on phagocytic events, this method can be employed to study any organelle of interest when the appropriate targeting sequence is used. PMID- 21701976 TI - Micropatterned ligand arrays to study spatial regulation in Fc receptor signaling. AB - Fc receptor signaling plays a fundamental role in immune responses. A plethora of Fc -receptors (e.g., Fc gamma, Fc-alpha, and Fc-epsilon) are expressed on different immune cells, including natural killer cells, macrophages, mast cells, and neutrophils. Receptor clustering and activation by multivalent ligands or opsonized particles induce a signaling cascade that leads to targeted secretion of chemical mediators (i.e., histamine, cytokines, and chemokines) and phagocytosis, among other responses. Spatial targeting and compartmentalization are common mechanisms of regulation in Fc receptor signaling. However, the tools for studying these dynamic interactions have been limited. To overcome these limitations in our model system, microfabricated surfaces containing spatially defined ligands are used to cluster- and activate IgE receptors (FcepsilonRI), involved in allergic responses by mast cells. Micron-scale control of cell activation allows investigation of spatially regulated mechanisms for intracellular signaling with -fluorescence microscopy. This approach in conjunction with biochemical techniques has proven to be valuable for investigating immune receptor signaling. PMID- 21701977 TI - CELLISA: reporter cell-based immunization and screening of hybridomas specific for cell surface antigens. AB - Monoclonal antibodies (mAbs) specific for cell surface antigens are an invaluable tool to study immune receptor expression and function. Here, we outline a generalized reporter cell-based approach to the generation and high-throughput screening of mAbs specific for cell surface antigens. Termed CELLISA, this technology hinges upon the capture of hybridoma supernatants in mAb arrays that facilitate ligation of an antigen of interest displayed on BWZ reporter cells in the form of a CD3zeta-fusion chimeric antigen receptor (zCAR); in turn, specific mAb-mediated cross-linking of zCAR on BWZ cells results in the production of beta galactosidase enzyme (beta-gal), which can be assayed colorimetrically. Importantly, the BWZ reporter cells bearing the zCAR of interest may be used for immunization as well as screening. In addition, serial immunizations employing additional zCAR- or native antigen-bearing cell lines can be used to increase the frequency of the desired antigen-specific hybridomas. Finally, the use of a cohort of epitope-tagged zCAR (e.g., zCAR(FLAG)) variants allows visualization of the cell surface antigen prior to immunization, and coimmunization using these variants can be used to enhance the immunogenicity of the target antigen. Employing the CELLISA strategy, we herein describe the generation of mAb directed against an uncharacterized natural killer cell receptor protein. PMID- 21701979 TI - Transfection-based genomic readout for identifying rare transcriptional splice variants. AB - Understanding the transcriptome, defined as the complete transcriptional component of the genome, is far more complex than originally considered. Even with the near fully resolved human and mouse genomes, for which extensive databases of transcribed sequence data (e.g., expressed sequence tags) are available, it is presently not possible to experimentally recover or computationally predict the full range of transcription products that derive from multiexon genes. Many genes are tightly regulated, which could include alternative processing of RNA, and lead to significant underrepresentation of many transcripts. A multitude of factors in addition to cell lineage- and developmental stage-specific expression as well as shortcomings in computational methods result in a less than complete understanding of transcriptional complexity. Here, we describe an approach to predict and evaluate a more complete repertoire of transcriptional products that derive from specific genetic loci with attention toward analysis of immune receptor genes. This approach is particularly useful in identifying gene products, including alternative splice forms, that originate from complex multigene families. PMID- 21701978 TI - Use of colloidal silica-beads for the isolation of cell-surface proteins for mass spectrometry-based proteomics. AB - Chaney and Jacobson first introduced the colloidal silica-bead protocol for the coating of cellular plasma membranes in the early 1980s. Since then, this method has been successfully incorporated into a wide range of in vitro and in vivo applications for the isolation of cell-surface proteins. The principle is simple cationic colloidal silica microbeads are introduced to a suspension or monolayer of cells in culture. Electrostatic interactions between the beads and the negatively charged plasma membrane, followed by cross-linking to the membrane with an anionic polymer, ensure attachment and maintain the native protein conformation. Cells are subsequently ruptured, and segregation of the resulting plasma membrane sheets from the remaining- cell constituents is achieved by ultracentrifugation through density gradients. The resulting membrane-bead pellet is treated with various detergents or chaotropic agents (i.e., urea) to elute bound proteins. If proteomic profiling by mass spectrometry is desired, proteins are denatured, carbamidomethylated, and digested into peptides prior to chromatography. PMID- 21701980 TI - Characterizing somatic hypermutation and gene conversion in the chicken DT40 cell system. AB - The secondary immunoglobulin gene diversification processes, somatic hypermutation (SHM), immunoglobulin gene conversion (GCV), and class switch recombination, are important for efficient humoral immune responses. They require the action of activation-induced cytidine deaminase, an enzyme that deaminates cytosine in the context of single-stranded DNA. The chicken DT40 B-cell line is an important model system for exploring the mechanisms of SHM and GCV, as both processes occur constitutively without the need for stimulation. In addition, standard gene targeting strategies can be used for defined manipulations of the DT40 genome. Thus, these cells represent an excellent model of choice for genetic studies of SHM and GCV. Problems arising from defects in early B-cell development that are of concern when using genetically engineered mice are avoided in this system. Here, we describe how to perform gene targeting in DT40 cells and how to determine the effects of such modifications on SHM and GCV. PMID- 21701981 TI - Characterizing immune receptors from new genome sequences. AB - Genome sequences are quickly being generated from a variety of organisms and provide researchers with an abundance of previously inaccessible information and an important source of insight into immune mechanisms. There are a variety of methods to accurately characterize genes from new genome sequences, but immune receptors pose special challenges for these techniques. Immune receptors, particularly those that directly recognize pathogens, often diverge rapidly among species and are commonly found in large, complex multigene families. Because of these characteristics, immune receptors tend to be overlooked or misannotated in large-scale genomic surveys. We describe here a computational strategy to characterize homologs of immune receptors and also to identify putative novel receptors from newly assembled genome sequences. The description of these protocols is aimed at a typical immunologist, and a substantial knowledge of bioinformatics is not expected. The approach is based on using low-stringency sequence searches to identify divergent homologs. For receptors with multiple domains, the intersection of low-stringency searches can be used to identify divergent receptor sequences with high confidence. For multigene families, these predictions can be refined using sequence conservation among gene family paralogs. This strategy has recently been useful in identifying novel expansions in immune receptors in a number of animal genomes and will likely continue to revolutionize our view of animal immunity as new genomes emerge. PMID- 21701982 TI - Molecular phylogenetic diversity of Bacillus community and its temporal-spatial distribution during the swine manure of composting. AB - In order to obtain the diversity and temporal-spatial distribution of Bacillus community during the swine manure composting, we utilized traditional culture methods and the modern molecular biology techniques of polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and -denaturing gradient gel electrophoresis (PCR-DGGE). Bacillus species were firstly isolated from the composting. Based on temperature changes, the temporal-spatial characteristics of total culturable Bacillus were remarkable that the number of the culturable Bacillus detected at the high-temperature stage was the highest in each layer of the pile and that detected in the middle layer was the lowest at each stage of composting respectively. The diversity of cultivated Bacillus species isolated from different composting stages was low. A total of 540 isolates were classified by the RFLP method and partial 16S rDNA sequences. They affiliated to eight species including Bacillus subtilis, Bacillus cereus, Bacillus thuringiensis, Bacillus anthracis, Bacillus megaterium, Bacillus licheniformis, Bacillus pumilus, and Bacillus circulans. The predominant species was B. subtilis, and the diversity of culturable Bacillus isolated in the middle-level samples at temperature rising and cooling stages was the highest. The DGGE profile and clone library analysis revealed that the temporal-spatial distribution of Bacillus community was not obvious, species belonging to the Bacillus were dominant (67%) with unculturable bacteria and B. cereus was the second major culturable Bacillus species. This study indicated that a combination of culture and culture independent approaches could be very useful for monitoring the diversity and temporal-spatial distribution of Bacillus community during the composting process. PMID- 21701983 TI - Identification of phenylalkane derivatives when Mycobacterium neoaurum and Rhodococcus erythropolis were cultured in the presence of various phenylalkanes. AB - Phenylalkanes are ubiquitously found in nature as pollutants originating from oil, gas oil and petrol. Rising commercial demand for mineral oil fractions has led to the increased prevalence of environmental contamination, whereby these particular hydrocarbons are encountered by bacteria which have subsequently developed sophisticated metabolic routes for purposes of degradation. Herein a detailed analysis of these metabolic pathways in the degradation of phenylalkanes by Mycobacterium neoaurum and Rhodococcus erythropolis highlighted preponderance for the formation of certain metabolites of which 17 were identified and whereby striking differences were noticed depending specifically upon the length of the substrate's alkyl chain. Although the degradation of even-numbered phenylalkane substrates was assumed to result in the generation of phenylacetic acid formed due to substrate terminal oxidation and subsequent beta-oxidation, cultures of M. neoaurum and R. erythropolis were determined in an extracellular accumulation of odd-numbered acidic metabolites, suggesting a simultaneous presence of sub terminal degradation mechanisms. However, results obtained from biotransformation assays containing even-chained phenylalkanoic acid intermediates as substrates revealed exclusive beta-oxidative mechanisms and no generation of odd-numbered degradation products. R. erythropolis in contrast to M. neoaurum also proved viable for hydroxylation of the aromatic ring of metabolites. Interestingly, the generation of phenylacetic acid and subsequently 2-hydroxyphenyl acetic acid was monitored and entailed the presence of the lactone intermediate 2-coumaranone. These results enhance our understanding of the degradation of phenylalkanes and illustrate the potential application of such species in the bioremediation of these common environmental pollutants and in the strains' diverse abilities to transform mineral oil compounds to new valuable products. PMID- 21701984 TI - Versatility and application of anaerobic ammonium-oxidizing bacteria. AB - With the unique cell compartmentalization and the ability to simultaneously oxidize ammonium and reduce nitrite into nitrogen gas, anaerobic ammonium oxidizing (anammox) bacteria have challenged our recognitions of microorganism. The research conducted on these bacteria has been extended from bench-scale tryouts to full-scale reactor systems. This review addresses the recently discovered versatile properties of anammox bacteria and the applications and obstacles of implementing the anammox process in ammonia-rich wastewater treatment. We also discuss the merits and drawbacks of traditional and anammox based processes for nitrogen removal and suggest areas for improvement. PMID- 21701985 TI - siRNA targeting mCD14 inhibits TNF-alpha, MIP-2, and IL-6 secretion and NO production from LPS-induced RAW264.7 cells. AB - Innate immunity plays a key role in protecting a host against invading microorganism, including Gram-negative bacteria. Cluster of differentiation antigen 14 (CD14) is an important innate immunity molecule, existing as a soluble (sCD14) and membrane-associated (mCD14) protein. Endotoxin [lipopolysaccharide (LPS)] is recognized as a key molecule in the pathogenesis of sepsis and septic shock caused by Gram negative bacteria. Emerging evidences indicate that upstream inhibition of bacterial LPS/Toll-like receptor 4(TLR4)/CD14-mediated inflammation pathway is an effective therapeutic approach for attenuating damaging immune activation. RNA interference (RNAi) provides a promising approach to down regulate gene expression specifically. To explore the possibility of using RNAi against mCD14 as a strategy for inhibiting the secretion of cytokines and the nitric oxide (NO) production from LPS-activated RAW264.7 cells, four different short interfering RNA (siRNA) molecules corresponding to the sequence of mCD14 gene were designed and synthesized. We then tested the inhibition effects of these siRNA molecules on mCD14 expression by real-time quantitative RT-PCR and Western blot. After effective siRNA molecule (mCD14-siRNA-224), which is capable of reducing messenger RNA (mRNA) accumulation and protein expression of mCD14 specifically, was identified, RAW264.7 cells pretreated with mCD14-siRNA-224 were stimulated with LPS, and the secretion of tumor necrosis factor alpha (TNF alpha), macrophage inflammatory protein-2 (MIP-2) and interleukin-6 (IL-6) and the NO production were evaluated. The results indicated that mCD14-siRNA-224 effectively inhibited TNF-alpha, MIP-2, and IL-6 release and NO production from LPS-stimulated RAW 264.7 cells by down-regulating mRNA accumulation and protein expression of mCD14 specifically. These findings provide useful information for the development of RNAi-based prophylaxis and therapy for endotoxin-related diseases. PMID- 21701986 TI - Review of mass transfer aspects for biological gas treatment. AB - This contribution reviews the mass transfer aspects of biotechnological processes for gas treatment, with an emphasis on the underlying principles and technical feasible methods for mass transfer enhancements. Understanding of the mass transfer behavior in bioreactors for gas treatment will result in improved reactor designs, reactor operation, and modeling tools, which are important to maximize efficiency and minimize costs. Various methods are discussed that show the potential for a more effective treatment of compounds with poor water solubility. PMID- 21701987 TI - Characterization of pediatric liver lesions with gadoxetate disodium. AB - Gadoxetate disodium (Gd-EOB-DTPA) is a relatively new hepatobiliary MRI contrast agent. It is increasingly used in adults to characterize hepatic masses, but there is little published describing its use in children. The purpose of this paper is to describe our pediatric MRI protocol as well as the imaging appearance of pediatric liver lesions using gadoxetate disodium. As a hepatocyte-specific MRI contrast agent, Gd-EOB-DTPA has the potential to improve characterization and provide a more specific diagnosis of pediatric liver masses. PMID- 21701988 TI - Comparative analysis of cerebrospinal fluid adenosine deaminase activity in meningitis. AB - AIM: The purpose is to determine the cut-off value of adenosine deaminase (ADA) activity in cerebrospinal fluid (CSF) of patients with tuberculous and non tuberculous meningitis, and to assess its value in differential diagnosis. MATERIAL AND METHODS: This study was conducted in 91 patients with meningitis in two university hospitals in Turkey. 24 patients had tuberculous meningitis (TBM), 25 purulent meningitis (PM), 25 aseptic meningitis (AM) and 17 neurobrucellosis (BM). ADA activity of CSF was quantified by colorimetry. RESULTS: In our study, mean ADA values in CSF were 28.34 +/- 14.83 IU/L in TB cases, 8.71 +/- 5.83 IU/L in BM, 6.18 +/- 2.54 IU/L in PM and 3.43 +/- 3.48 U/L in AM cases. If we accept for CSF ADA an activity cut-off value of 12.5 IU/L for differential diagnosis of TBM and BM, its sensitivity was 92% and specificity was 88%. If we accept 12.35 IU/L for differential diagnosis of TBM and PM, its sensitivity was 92% and specificity was 100%. If we accept 6.45 IU/L for differential diagnosis of TBM and AM, its sensitivity was 100% and specificity was 92%. Additionally, we examined the cases after dividing them into two groups, viz. TB and non-TB. If we accept an ADA activity cut-off level of 11 IU/L for differential diagnosis of TB and non-TB by applying ROC analysis, its sensitivity was 92% and specificity was 90%. CONCLUSION: The sensitivity and specificity for CSF ADA activity are markedly high in differential diagnosis of TB from non-TB. Hence CSF ADA activity may be used as a simple, cost-effective and reliable test for early differential diagnosis of TB. PMID- 21701989 TI - Rita Levi-Montalcini and the discovery of NGF, the first nerve cell growth factor. AB - The nerve growth factor (NGF) is a signaling protein, discovered by Rita Levi Montalcini in the early 1950's for its effect on growth and differentiation of specific populations of neurons of the peripheral nervous system. Originally identified as neurite outgrowth-stimulating factor, later studies revealed that the purified molecule has a number of target cells in the central nervous system and on nonneuronal cells. Moreover, recent studies showed the potential therapeutic properties of NGF in neuropathies of the central and peripheral nervous system and diseases of the eye and skin. Here I briefly describe the discovery of NGF, the early studies of Rita LeviMontalcini, a pioneer in modern neuroscience, and my scientific and human experience working in her laboratory for over 40 years. PMID- 21701990 TI - Targeting NGF pathway for developing neuroprotective therapies for multiple sclerosis and other neurological diseases. AB - Inflammation is the first line of defense against injury and infection and works both by controlling the ongoing pathological processes and by promoting neuroprotection and regeneration. When the inflammatory response is hyper activated, it plays a pivotal role in the pathophysiology of many neurological diseases, as it can also be a source of additional injury to host cells. Since neurons lack the ability to divide and recover poorly from injury, they are extremely vulnerable to auto destructive immune and inflammatory processes, and this side effect is fundamental to the outcome of neurological diseases. Inappropriate immune responses are responsible for diseases such as Multiple Sclerosis (MS), Alzheimer's disease (AD) or Parkinson's disease (PD) and for the increased disability after brain trauma or stroke. However, in certain circumstances immune responses in the brain might have a neuroprotective effect, possibly mediated by the release of trophic factors from inflammatory and/or glial cells. The nerve growth factor (NGF) was the first neurotrophin discovered for its stimulatory effect on differentiation, survival, and growth of neurons in peripheral and central nervous system. This factor can protect axons and myelin from inflammatory damage and also can modulate the immune system, reducing the enhanced excitotoxicity during acute inflammatory activation. Therefore, because its neuroprotective activity and immunomodulatory effects, NGF may represent a new therapeutic approach for the treatment of numerous brain disorders. PMID- 21701991 TI - Sensory impairment in mental retardation: a potential role for NGF. AB - Sensory impairment is defined as the inability to interpret outside stimuli such as visual, auditory, verbal, sense of touch, taste or smell or feelings of pain. This leads to absence of sensation and neuronal coordination. The impairment may be caused by ageing and other physiological changes, accident or injuries or can be found in some cases of mental retardation (MR) also referred to as intellectual disability. Known cases of MR involving inability to accurately interpret an outside source or stimuli are: Fragile-X syndrome; Tuberous sclerosis complex (TSC) with associated autism spectrum disorder (ASD); Rett syndrome; Autism and ASD with or without MR; Chromosome 22q13.3 deletion syndrome; familial dysautonomia, Prader-Willi's syndrome, Williams syndrome. In this review we will discuss in particular form of ASD and altered sensory sensitivity. The role of NGF in causing pronociceptive activity and its role in peripheral sensitisation is discussed under the light of its involvement in forms of MR where loss of pain perception is a main feature due to mutations to NGF receptors or NGF genes during development. Other forms of MR with altered sensory impairment will be considered as well as additional potential mechanisms involved. PMID- 21701992 TI - The nerve growth factor administrated as eye drops activates mature and precursor cells in subventricular zone of adult rats. AB - The possibility to take advantage from the nerve growth factor (NGF) ability to induce recovery of damaged tissue has been largely explored in animal models and humans. Recently, the successful use of the ocular administration of NGF in ophthalmology, and the evidences that from the eyes NGF can access to the brain have stimulated new fields of research and open further perspectives to the clinical application of this neurotrophin. In our previous studies we have demonstrated the efficacy of NGF eye drop treatment to improved behavioural deficits and recover structural and biochemical alterations occurring follow brain lesion in animals. Since NGF exerts neuroreparative effects in brain by acting on mature neurons and neuronal precursors localised in germinal subventricular zone (SVZ), the present study has been aimed to evaluate the effects of NGF eye drop administration on the expression of the mitotic marker Ki67 in brain of adult rats. We found that a single ocular administration (10 MUl) of 200 MUg/mL NGF solution is sufficient to enhance the distribution of Ki67 positive cells also expressing p75 neurotrophin receptors in the proliferating layer of the SVZ. In addition, NGF treatment induces an increase of levels of brain derived neurotrophic factor (BDNF) in forebrain. This data further supports the efficacy of ocular applied NGF to affect brain activities and suggests that NGF also by inducing local factors, including BDNF, can activate the machinery regulating the proliferation and maturation of neuronal precursor in brain. PMID- 21701993 TI - Release of growth factors by neuronal precursor cells as a treatment for diseases with tau pathology. AB - The intraneuronal accumulation of the microtubule associated protein tau in a hyperphosphorylated state and the extracellular deposit of betaamyloid protein constitute the defining neuropathological signature of Alzheimer's disease, the most common type of dementia in ageing Homo sapiens.There is accumulating evidence suggesting that transplantation of embryonic and adult derived neuronal precursor cells (NPCs) has a major role for cell based repair strategies in models of acute and chronic injury. In order to determine whether NPCs could rescue tau related neuronal cell death NPCs were transplanted into the transgenic mouse cortex of transgenic mice expressing human P301S tau protein at 2 month of age and the effect followed 2 and 3 months after transplantation. The results demonstrated that following transplantation mouse NPCs differentiated into astrocytes and exerted a neuroprotective effect. In particular, the expression of ciliary neurotrophic factor, nerve growth factor and glial cell derived neurotrophic factor was increased near the transplanted cells. A nonsignificant increase of brain derived neurotrophic factor expression was instead found in the area of the cortex where neuronal death was rescued. PMID- 21701994 TI - Brain ischemia, neurogenesis, and neurotrophic receptor expression in primates. AB - Generation of new neurons persists in the normal adult mammalian brain, with neural stem/progenitor cells residing in at least two brain regions: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG). Adult neurogenesis is well documented in the rodent, and has also been demonstrated in vivo in nonhuman primates and humans. Brain injuries such as ischemia affect neurogenesis in adult rodents as both global and focal ischemic insults enhance the proliferation of progenitor cells residing in SGZ or SVZ. We addressed the issue whether an injury triggered activation of endogenous neuronal precursors also takes place in the adult primate brain. We found that the ischemic insult increased the number of progenitor cells in monkey SGZ and SVZ, and caused gliogenesis in the ischemia-prone hippocampal CA1 sector. To better understand the mechanisms regulating precursor cell division and differentiation in the primate, we analyzed the expression at protein level of a panel of potential regulatory molecules, including neurotrophic factors and their receptors. We found that a fraction of mitotic progenitors were positive for the neurotrophin receptor TrkB, while immature neurons expressed the neurotrophin receptor TrkA. Astroglia, ependymal cells and blood vessels in SVZ were positive for distinctive sets of ligands/receptors, which we characterized. Thus, a network of neurotrophic signals operating in an autocrine or paracrine manner may regulate neurogenesis in adult primate SVZ. We also analyzed microglial and astroglial proliferation in postischemic hippocampal CA1 sector. We found that proliferating postischemic microglia in adult monkey CA1 sector express the neurotrophin receptor TrkA, while activated astrocytes were labeled for nerve growth factor (NGF), ligand for TrkA, and the tyrosine kinase TrkB, a receptor for brain derived neurotrophic factor (BDNF). These results implicate NGF and BDNF as regulators of postischemic glial proliferation in adult primate hippocampus. PMID- 21701995 TI - Neuroprotection by human umbilical cord blood-derived progenitors in ischemic brain injuries. AB - Stem cells have an extremely high potential to treat many devastating diseases, including neuronal injuries. Albeit the need for human neuronal stem cells, their quantities are very limited by relying on early human embryos as the main source. Therefore, progenitors of other origins, such as human umbilical cord blood (CB) are being considered. In the last decade, various populations isolated from the CB were reported to differentiate in vitro towards a neural phenotype. The conditions to induce the cell differentiation are not conclusive and may include addition of chemicals, cytokines and growth factors, including the nerve growth factor (NGF). Some CB cells were found to express the TrkANGF receptor, suggesting an endogenous role for this growth factor also in the CB environment. The ability of CB and derived stem cell populations to protect against neurological deficits was shown, both in vitro and in vivo, in models of ischemic brain injuries. In rodent models of stroke, heatstroke, brain trauma and brain damage at birth, CB cells either by intravenous injection or intrastriatal transplantation, were found to reduce the infarct size and the neurological deficits caused by the injury. The restorative effects of CB were suggested to be mediated by mechanisms other than cell replacement. Some of the proposed mechanisms involve reduced inflammation, nerve fiber reorganization by trophic actions, increased cell survival and enhanced angiogenesis. Furthermore, treatment with CB was found to have a therapeutic window of days compared with the present 36 hour window for the treatment of stroke with clinically available tools such as recombinant tissue plasminogen activator. Considering the encouraging results with whole CB and derived cells transplantation in ischemic injury models and since CB is widely available and have been used clinically, they may be an excellent source of cells for treatment of human brain ischemic disorders. PMID- 21701996 TI - Electroacupucture and nerve growth factor: potential clinical applications. AB - The nerve growth factor (NGF) is a neurotrophin regulating the survival and function peripheral sensory and sympathetic neurons and of forebrain cholinergic neurons. Both peripheral neuropathies and brain cholinergic dysfunctions could benefit from NGFbased therapies, but the clinical use of NGF has been so far hampered by the development of important side effects, like hyperalgesia and autonomic dysfunctions. Acupuncture is a therapeutic technique and is a part of traditional Chinese medicine. Western descriptions of the clinical efficacy of acupuncture on pain, inflammation, motor dysfunction, mood disorders, and seizures are based on the stimulation of several classes of sensory afferent fibers and the consequent activation of physiological processes similar to those resulting from physical exercise or deep massage. Recently, it has been shown that peripheral sensory stimulation by electroacupuncture (EA) could improve brain NGF availability and utilization, at the same time counteracting the major sideeffects induced by NGF administration. This review focuses on the emerging links between EA and NGF with special emphasis on the work carried out in the last decade in our laboratory, investigating the role of NGF as a mediator of EA effects in the central nervous system and as a modulator of sensory and autonomic activity. PMID- 21701997 TI - The metabotrophic NGF and BDNF: an emerging concept. AB - The field of neurotrophins, particularly, nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), has witnessed a number of breakthroughs in recent years. There is evidence now that NGF and BDNF mediate multiple biological phenomena, ranging from the Rita Levi Montalcini's neurotrophic through immunotrophic to epitheliotrophic and nociceptive effects. In 2003 we, for the first time, enriched the "NGFome" with one more expression presented in our concept of NGF metabotrophicity, also that of BDNF. This envisages that these two factors may operate as metabotrophins, that is, involved in the maintenance of cardiometabolic homeostasis (glucose and lipid metabolism as well as energy balance, cardioprotection, and wound healing). Recent results also demonstrated that the circulating and/or tissue levels of NGF and BDNF are altered in cardiometabolic diseases (atherosclerosis, obesity, type 2 diabetes, metabolic syndrome, and type 3 diabetes). Altogether, a hypothesis of metabotrophic deficit due to the reduction of NGF/BDNF availability and/or utilization was raised, and implicated in the pathogenesis of cardiometabolic diseases. This may cultivate a novel pathogenic and therapeutic thinking for these diseases. PMID- 21701998 TI - NGF and romantic love. AB - Romantic love is the catalyst behind the spread of the human life. The neurobiology of love embraces the hypothesis that what we call "romantic attachment" or "romantic love" may be at least in part the expression of biological factors. A corollary of this hypothesis states that it is possible to learn much about the nature of human love by studying the molecules involved in the expression of social and affiliative behaviours. Under this theoretical framework, we have investigated the changes in plasma neurotrophin levels in subjects with early stage romantic love. A positive association between the intensity of early romantic feelings and serum levels of nerve growth factor (NGF) has been identified. These findings link love with biologically relevant pathways for neuron survival and illuminate the biochemical correlates of such a complex feeling that so deeply affects our own lives. The progresses in the neurobiology of love suggest that this kind of research may open a new window onto our understanding of the very nature of human romantic bonding. PMID- 21702000 TI - Neuroprotective role of nerve growth factor in hypoxicischemic injury. From brain to skin. AB - Hypoxic-ischemic injuries (HII) of the brain, optic pathways, and skin are frequently associated with poor neurological and clinical outcome. Unfortunately, no new therapeutic approaches have been proposed for these conditions. Recently, experimental and clinical studies showed that nerve growth factor (NGF) can improve neurological deficits, visual loss and skin damage after HII. Based on these studies, we report the effects of NGF administration in different lesions of the brain, optic pathways and skin. 2.5S NGF purified and lyophilized from male mouse submaxillary glands was utilized for the treatment. NGF administration was started in absence of recovery after conventional and standardized treatment. One mg NGF was administered via the external catheter into the brain, by drop administration in the eye, and by subcutaneous administration in the skin. We treated 4 patients: 2 children with hypoxic-ischemic brain damage, an adult patient with an optic glioma-induced visual loss and a child with a severe crush syndrome of the lower left limb. After NGF treatment, we observed an amelioration of both neurological and electrophysiological function of the brain, a subjective and objective improvement of visual function, and a gradual improvement of ischemic skin lesion. No side effects were related to NGF treatment in all patients studied. Our observation shows that NGF administration may be an effective and safe adjunct therapy in patients with severe HII. The beneficial and prolonged effect on nerve function suggests a neuroprotective mechanism exerted by NGF on the residual viable neurological pathways of these patients. PMID- 21702001 TI - Clinical applications of NGF in ocular diseases. AB - Nerve Growth Factor (NGF) and its receptors TrkA and p75 are expressed in physiological states in the anterior and posterior segments of the human eye, where they exert several tissue-specific functions. The roles played by NGF in the homeostasis of the eye and in vision are, therefore, crucial and have been widely investigated both in vitro and in vivo, with growing evidence of an NGF pathway alteration in several ocular diseases. In this review we describe the functions of NGF in health and diseases states of the eye, and discuss the potential therapeutic effectiveness of NGF in preliminary clinical reports performed in severe ocular diseases unresponsive to any standard treatment. In fact, pharmacodynamic studies showing that NGF administered topically on the ocular surface affects not only the ocular surface but is also able to reach the retina, optic nerve and brain, recently opened new perspectives for the treatment of challenging ocular surface diseases, optic nerve diseases, and degenerative diseases of the retina currently lacking an effective therapy. PMID- 21702003 TI - Dietary effects on development of the human mandibular corpus. AB - The extent to which the mandibular corpus exhibits developmental plasticity has important implications for interpreting variation in adult and juvenile mandibular morphology in the archaeological and paleontological record. Here, we examine ontogenetic changes in mandibular corpus breadth, rigidity, and strength in two population samples with contrasting diets: late prehistoric Tigara from Point Hope, Alaska, characterized by a very demanding masticatory regime, and proto-historic Arikara from the Sully Site in South Dakota, with a less demanding regime. A total of 52 juvenile and 11 adult Tigara, and 32 juvenile and 10 adult Arikara were included in the study. Juveniles ranged in age from 1 to 17 years, with good representation of younger (1-6-year-old) juveniles (20 Arikara, 18 Tigara). Superoinferior and buccolingual external and cortical bone breadths of mandibles were measured at the Pm(4) -M(1) and M(1) -M(2) junctions using calipers and biplanar radiographs, respectively. An asymmetrical hollow beam model was employed to reconstruct cross sections and calculate bending rigidities and strengths in the sagittal and transverse planes. Among adults, Tigara have greater transverse corpus width, bending rigidity, and strength, and ratios of transverse to sagittal dimensions than Arikara. This shape difference develops gradually during growth, with only weak trends among young juveniles, increasing to near-adult contrasts among adolescents. These results support a role for functional mechanical loading of the mandible during growth in producing adult differences in mandibular corpus morphology. PMID- 21702002 TI - The effects of a long-term psychosocial stress on reproductive indicators in the baboon. AB - Psychosocial stress is thought to negatively impact fecundity, but human studies are confounded by variation in nutrition and lifestyle. Baboons offer a useful model to test the effect of prolonged mild stress on reproductive indicators in a controlled setting. Following relocation from social groups to solitary housing, a previously documented stressful event for nonhuman primates, daily urine samples, tumescence, and menstrual bleeding were monitored in twenty baboons (Papio sp.) for 120-150 days. Specimens were assayed for estrone conjugates (E1C), pregnanediol-3-glucuronide (PDG), follicle-stimulating hormone (FSH), and cortisol. Linear mixed effects models examined (1) the effects of stress on frequency of anovulation, hormone levels, tumescence and cycle length, and (2) the relationship of cortisol with reproductive indicators. Despite cortisol levels indicative of stress, anovulation was negligible (1% in 102 cycles). PDG, FSH, cycle length, and tumescence declined during the first four cycles, but began recovery by the fifth. Cortisol was negatively associated with FSH but not associated with PDG, E1C or tumescence. Ovulation, E1C, and luteal phase length were not affected. Tumescence tracked changes in FSH and PDG, and thus may be a useful indicator of stress on the reproductive axis. Elevated cortisol was associated with reduced FSH, supporting a model of cortisol action at the hypothalamus rather than the gonad. After four to five menstrual cycles the reproductive indicators began recovery, suggesting adjustment to new housing conditions. In conclusion, individual housing is stressful for captive baboons, as reflected by cortisol and reproductive indicators, although ovulation, a relatively direct proxy for fecundity, is unaffected. PMID- 21702004 TI - Interleukin-27 in rheumatic diseases: friend or foe? Comment on the article by Pickens et al. PMID- 21702005 TI - Bilateral asymmetry of the humerus during growth and development. AB - The development of handedness throughout growth can be investigated by using bilateral asymmetry of the humerus as a proxy for this trait. A large skeletal sample of nonadults from English archaeological sites was examined using standard metric techniques to assess when right-sided asymmetry first appears in the human skeleton. Results of this work indicate a change in directional asymmetry during growth and development, with infants and young children exhibiting no significant asymmetry and older children and adolescents demonstrating right-sidedness. This trend is consistent with what has been observed in previous studies of upper limb asymmetry in skeletal material and behaviorally in living children, adding further strength to the premise that biomechanical forces strongly influence bilateral asymmetry in the upper limb bones. Variability in the magnitude of asymmetry between different features of the humerus was also noted. This characteristic can be explained by differing degrees of genetic canalization, with length and articular dimensions being more strongly canalized than diaphyseal properties. PMID- 21702006 TI - Suppression of collagen-induced arthritis in growth arrest and DNA damage inducible protein 45beta-deficient mice. AB - OBJECTIVE: Growth arrest and DNA damage-inducible protein 45beta (GADD45beta) is involved in stress responses, cell cycle regulation, and oncogenesis. Previous studies demonstrated that GADD45beta deficiency exacerbates K/BxN serum-induced arthritis and experimental allergic encephalomyelitis (EAE) in mice, indicating that GADD45beta plays a suppressive role in innate and adaptive immune responses. To further understand how GADD45beta regulates autoimmunity, we evaluated collagen-induced arthritis in GADD45beta-/- mice. METHODS: Wild-type (WT) and GADD45beta-/- DBA/1 mice were immunized with bovine type II collagen (CII). Serum anticollagen antibody levels were quantified by enzyme-linked immunosorbent assay. Expression of cytokines and matrix metalloproteinases in the joint and spleen was determined by quantitative polymerase chain reaction. The in vitro T cell cytokine response to CII was measured by multiplex analysis. CD4+CD25+ Treg cells and Th17 cells were quantified using flow cytometry. RESULTS: GADD45beta-/- mice showed significantly lower arthritis severity and joint destruction compared with WT mice. MMP-3 and MMP-13 expression was also markedly reduced in GADD45beta /- mice. However, serum anti-CII antibody levels were similar in both groups. FoxP3 and interleukin-10 (IL-10) expression was increased 2-3-fold in splenocytes from arthritic GADD45beta-/- mice compared with those from WT mice. Flow cytometric analysis showed greater numbers of CD4+CD25+ Treg cells in the spleen of GADD45beta-/- mice than in the spleen of WT mice. In vitro studies showed that interferon-gamma and IL-17 production by T cells was significantly decreased in GADD45beta-/- mice. CONCLUSION: Unlike passive K/BxN arthritis and EAE, GADD45beta deficiency in CIA was associated with lower arthritis severity, elevated IL-10 expression, decreased IL-17 production, and increased numbers of Treg cells. The data suggest that GADD45beta plays a complex role in regulating adaptive immunity and, depending on the model, either enhances or suppresses inflammation. PMID- 21702008 TI - Distinct features of circulating microparticles and their relationship to clinical manifestations in systemic lupus erythematosus. AB - OBJECTIVE: Characterization of the abundance, origin, and annexin V (AnxV) binding capabilities of circulating microparticles (MPs) in SLE patients and healthy controls and to determine any associations with clinical parameters. METHODS: Seventy unselected SLE patients and 29 sex- and age-matched healthy control subjects were included in the study. MPs were isolated from citrate treated plasma and characterized by flow cytometry using AnxV or antibodies to platelet, leukocyte, or endothelial cell surface markers. RESULTS: SLE patients had significantly increased concentrations of AnxV-nonbinding (AnxV-) MPs (P<0.0001), while the concentrations of total MPs (P=0.011) and AnxV-binding (AnxV+) MPs (P<0.0001) were decreased, as compared with controls. Based on flow cytometric characteristics, 2 subgroups of AnxV- MPs could be discerned: AnxV- cell-derived MPs (CDMPs) and AnxV- MPs of unknown nature (UNMPs). Both fractions were significantly increased in SLE patients (P=0.007 and P=0.0018, respectively). Platelet- and leukocyte-derived MPs were decreased in the SLE patients (P<0.0001), whereas no difference was observed for endothelial cell derived MPs (P=0.14). The concentrations of AnxV- CDMPs correlated with the concentrations of endothelial cell-derived MPs, the disease activity score, active nephritis, hypertension, history of arterial thrombosis, and triglyceride levels (P<0.05 for all comparisons). CONCLUSION: The concentrations and composition of MPs in SLE patients differ markedly from those in healthy subjects. Overall MP numbers were significantly decreased, but two distinct subpopulations of AnxV- MPs were significantly increased. These findings call for further characterization of MPs in SLE patients to elucidate their role in disease pathogenesis. PMID- 21702009 TI - Changes in Rab3D expression and distribution in the acini of Sjogren's syndrome patients are associated with loss of cell polarity and secretory dysfunction. AB - OBJECTIVE: Oral and ocular dryness are frequent and serious symptoms of Sjogren's syndrome (SS) that reflect problems in secretion due to glandular dysfunction. Exocytosis, an important process in the secretory pathway, requires the participation of Rab family GTPases. This study was undertaken to analyze the expression and localization of Rab3D and Rab8A and to examine their correlation with acinar cell polarity and glandular secretory function. METHODS: Nineteen patients with SS and 17 controls were evaluated. Levels of Rab3D and Rab8A messenger RNA (mRNA) and protein were determined by real-time polymerase chain reaction and Western blotting. Subcellular localization of proteins was determined by indirect immunofluorescence analysis. RESULTS: In patients with SS, total Rab3D protein levels decreased significantly, while mRNA levels remained unchanged. For Rab8A, no changes in either mRNA or protein levels were detected. In serous acini of labial salivary glands from patients with SS, the following 4 patterns of Rab3D staining were distinguishable: severely decreased, distribution throughout the cytoplasm, distribution throughout the cytoplasm combined with loss of nuclear polarity, and normal apical localization. Basal localization of Rab8A was not modified. Rab3D changes were accompanied by apicobasolateral redistribution of ezrin, loss of nuclear polarity, thicker Golgi stacks, and mucin 7 accumulation in the cytoplasm. Finally, low Rab3D protein levels correlated with alterations in scintigraphy measurements. CONCLUSION: Our findings indicate that Rab3D regulates the exocytosis of many components critical for the maintenance of oral physiology. Hence, the changes observed in Rab3D expression and distribution are likely to contribute to the decrease in or loss of saliva components (i.e., mucins), which may explain the variety of oral and ocular symptoms associated with SS. PMID- 21702010 TI - Role of the MICA polymorphism in systemic lupus erythematosus. AB - OBJECTIVE: To study the genetic contribution of major histocompatibility complex class I polypeptide-related sequence A (MICA), important in natural killer (NK) cell function, in patients with systemic lupus erythematosus (SLE). METHODS: Japanese patients with SLE (n=716), those with rheumatoid arthritis (RA) (n=327), and healthy control subjects (n=351) were genotyped for the Val129 Met polymorphism (rs1051792) and transmembrane (TM) alanine-encoding GCT repeats, termed A4, A5, A5.1, A6, and A9, in the MICA gene. Recombinant human MICA-GST fusion proteins were tested on the NK cell line NK92MI for the expression of NK group 2, member D (NKG2-D), NK cell-mediated cytotoxicity, and interferon-gamma (IFNgamma) production. RESULTS: The MICA 129Met allele, TMA9 allele, and 129Met/Met genotype were positively associated with SLE (corrected P [Pcorr]=0.01 and odds ratio [OR] 1.3, Pcorr=0.003 and OR 1.6, and Pcorr=0.02 and OR 1.8, respectively), while the MICA 129Val allele was negatively associated with SLE (Pcorr=0.01, OR 0.8). The MICA 129Met;A9 haplotype was also associated with SLE (Pcorr=0.0006, OR 1.8), and there was an additive genetic effect between the MICA 129Met;A9 haplotype and HLA-DRB1*15:01. When NK92MI cells were incubated in vitro with recombinant human disease-associated 129Met;A9 (the combination of polymorphisms at 129Met and TMA9), expression of NKG2-D on NK92MI cells and cytotoxicity of the NK cells were inhibited, but production of IFNgamma from NK92MI cells was enhanced. CONCLUSION: The MICA polymorphism is genetically associated with SLE, and MICA appears to contribute to the pathogenesis of SLE by modulating NK cell function. PMID- 21702011 TI - Clinical outcomes after withdrawal of anti-tumor necrosis factor alpha therapy in patients with juvenile idiopathic arthritis: a twelve-year experience. AB - OBJECTIVE: To estimate the length of time to disease flare and the likelihood of achieving clinical remission after discontinuation of treatment with tumor necrosis factor alpha (TNFalpha) blockers in patients with juvenile idiopathic arthritis (JIA). METHODS: We conducted a retrospective chart review in a cohort of patients with JIA treated with TNFalpha inhibitors between January 1, 1998 and November 1, 2009. Demographic information, laboratory data, and medication exposure were extracted using a standardized tool. Outcomes of interest were based on preliminary criteria for remission in JIA. RESULTS: One hundred seventy one patients with 255 discrete episodes of anti-TNFalpha treatment were reviewed. The median duration of patient observation was 59.7 months (range 5.8-211.2 months). Among patients in whom disease was inactive after discontinuation of anti-TNFalpha therapy, 50% had persistently inactive disease at 6 months, and 33% had clinical remission at 12 months. The median duration of anti-TNFalpha therapy after inactive disease was obtained was 6.1 months (range 0-67.9 months). No significant association was observed between the time to disease flare after cessation of treatment with TNFalpha antagonists and the length of time from the diagnosis of JIA to the initiation of anti-TNFalpha therapy, the duration of therapy following the onset of inactive disease, or the total duration of treatment with TNFalpha antagonists prior to discontinuation. The category of JIA, sex, and age at diagnosis were not associated with the risk of relapse. CONCLUSION: One-third of patients with JIA can successfully undergo withdrawal of treatment with TNFalpha antagonists and be spared the cost and potential morbidity of treatment for at least 12 months. Further studies are needed to identify factors to accurately identify these patients. PMID- 21702012 TI - Cytosolic phospholipase A2 induction and prostaglandin E2 release by interleukin 1beta via the myeloid differentiation factor 88-dependent pathway and cooperation of p300, Akt, and NF-kappaB activity in human rheumatoid arthritis synovial fibroblasts. AB - OBJECTIVE: Cytosolic phospholipase A2 (cPLA2) is a rate-limiting enzyme that plays a critical role in the biosynthesis of eicosanoids. The aim of this study was to investigate the mechanisms underlying interleukin-1beta (IL-1beta)-induced cPLA2 expression in human rheumatoid arthritis synovial fibroblasts (RASFs). METHODS: Synovial tissue was obtained from patients with RA who were undergoing joint replacement surgery. In a mouse model of IL-1beta-mediated inflammatory arthritis, neutrophil infiltration, bone erosion, and cPLA2 expression in ankle synovium were analyzed by immunohistochemistry. IL-1beta-induced cPLA2 expression was determined by Western blotting, real-time polymerase chain reaction, and gene promoter assay using pharmacologic inhibitors and transfection with short hairpin RNAs or small interfering RNAs. The recruitment of NF-kappaB and p300 to the cPLA2 promoter was determined by chromatin immunoprecipitation assay. Prostaglandin E2 (PGE2) biosynthesis was evaluated by enzyme-linked immunosorbent assay. RESULTS: IL-1beta-induced cPLA2 expression and PGE2 release were mediated through a myeloid differentiation factor 88 (MyD88)/c-Src-dependent matrix metalloproteinase (MMP)/heparin-binding epidermal growth factor (HB-EGF) cascade linking to transactivation of the EGF receptor (EGFR)/phosphatidylinositol 3 kinase (PI 3-kinase)/Akt, p300, and NF-kappaB p65 pathways. IL-1beta also stimulated Akt phosphorylation and nuclear translocation. Activation of Akt eventually led to the acetylation of histone residues by phosphorylation and recruitment of p300 and enhanced its histone acetyltransferase activity on the NF kappaB elements of the cPLA2 promoter. IL-1beta-induced NF-kappaB transcriptional activity was mediated through a PI 3-kinase/Akt-dependent cascade. Up-regulation of cPLA2 by IL-1beta increased PGE(2) biosynthesis in RASFs. CONCLUSION: IL-1beta induced cPLA2 expression is mediated through activation of the MyD88/c-Src, MMP/HB-EGF, EGFR/PI 3-kinase/Akt, p300, and NF-kappaB pathways. These results provide insights into the mechanisms underlying IL-1beta-enhanced joint inflammatory responses in RA and may inspire new targeted therapeutic approaches. PMID- 21702013 TI - Impaired suppression of synovial fluid CD4+CD25- T cells from patients with juvenile idiopathic arthritis by CD4+CD25+ Treg cells. AB - OBJECTIVE: Natural CD4+CD25+FoxP3+ Treg cells play a crucial role in maintaining immune homeostasis and controlling autoimmunity. In patients with juvenile idiopathic arthritis (JIA), inflammation occurs despite the increased total numbers of Treg cells in the synovial fluid (SF) compared to the peripheral blood (PB). This study was undertaken to investigate the phenotype of CD4+ T cells in PB and SF from JIA patients, the function of synovial Treg cells, and the sensitivity of PB and SF CD4+CD25- effector T cells to the immunoregulatory properties of Treg cells, and to study the suppression of cytokine secretion from SF effector T cells by Treg cells. METHODS: The phenotypes of effector T cells and Treg cells of PB and SF from JIA patients and healthy donors were determined by flow cytometry. The functionality of isolated Treg cells and effector T cells was quantified in (3) H-thymidine proliferation assays. Cytokine levels were analyzed using Bio-Plex Pro assay. RESULTS: Compared to PB, SF showed significantly elevated numbers of activated and differentiated CD4+CD45RO+ T cells. Sensitivity of SF effector T cells to the suppressive effects of Treg cells from both PB and SF was impaired, correlating inversely with the expression of CD69 and HLA-DR. However, SF effector T cell cytokine secretion was partly suppressed by SF Treg cells. CONCLUSION: Our findings indicate that regulation is impaired in the SF of patients with JIA, as shown by the resistance of effector T cells to immunoregulation by functional Treg cells. This resistance of the SF effector T cells might be due to their activated phenotype. PMID- 21702014 TI - "Yo soy yo y mi circunstancia" ("I am I and my circumstance") (Jose Ortega y Gasset, Spanish philosopher [1883-1955]): comment on the article by Falk et al. PMID- 21702015 TI - Biosimilars: the debate continues. PMID- 21702017 TI - On publication policy, combination therapy, and the European League Against Rheumatism recommendations for the management of rheumatoid arthritis: comment on the article by Graudal et al. PMID- 21702016 TI - Increased synovial expression of nuclear receptors correlates with protection in pristane-induced arthritis: a possible novel genetically regulated homeostatic mechanism. AB - OBJECTIVE: To use microarray analyses of gene expression to characterize the synovial molecular pathways regulated by the arthritis regulatory locus Cia25 and to determine how it operates to control disease severity and joint damage. METHODS: Synovial tissues from DA rats and DA.ACI(Cia25) rats obtained 21 days after induction of pristane-induced arthritis were used for RNA extraction and hybridization to Illumina RatRef-12 Expression BeadChips (22,228 genes). Genes with a P value<=0.01 and a fold difference in expression>=1.5 between DA rats and DA.ACI(Cia25) rats were considered significant. RESULTS: Interleukin-1beta (IL 1beta) (7.4-fold), IL-6 (67-fold), Ccl2, Cxcl10, Mmp3, Mmp14, and innate immunity genes were expressed at increased levels in DA rats and at significantly lower levels in DA.ACI(Cia25) congenic rats. DA.ACI(Cia25) rats had increased expression of 10 nuclear receptor (NR) genes, including those known to interfere with NF-kappaB activity and cytokine expression, such as Lxra, Pparg, and Rxrg. DA.ACI(Cia25) rats also had increased expression of NR targets, suggesting increased NR activity. While Vdr was not differentially expressed, a Vdr expression signature was detected in congenic rats, along with up-regulation of mediators of vitamin D synthesis. CONCLUSION: This is the first description of the association between increased synovial levels of NRs and arthritis protection. The expression of NRs was inversely correlated with the expression of key mediators of arthritis, suggesting reciprocally opposing effects either via NF-kappaB or at the genomic level in the synovial tissue. We consider that the NR signature may have an important role in maintaining synovial homeostasis and an inflammation-free tissue. These processes are regulated by the Cia25 gene and suggest a new function for this gene. PMID- 21702018 TI - Recommendations for publication of genetic association studies in Arthritis & Rheumatism. PMID- 21702020 TI - Short-term and long-term outcomes of interstitial lung disease in polymyositis and dermatomyositis: a series of 107 patients. AB - OBJECTIVE: This study was undertaken to assess the characteristics and outcome of interstitial lung disease (ILD) in polymyositis/dermatomyositis (PM/DM) and to determine variables predictive of ILD deterioration in PM/DM. METHODS: Among 348 consecutive patients with PM/DM, 107 patients with ILD were identified by medical records search in 4 medical centers. All patients underwent pulmonary function tests (PFTs) and pulmonary high-resolution computed tomography (HRCT) scan. RESULTS: ILD onset preceded PM/DM clinical manifestations in 20 patients, was identified concurrently with PM/DM in 69 patients, and occurred after PM/DM onset in 18 patients. Patients with ILD could be divided into 3 groups according to their presenting lung manifestations: patients with acute lung disease (n = 20), patients with progressive-course lung signs (n = 55), and asymptomatic patients with abnormalities consistent with ILD evident on PFTs and HRCT scan (n = 32). We observed that 32.7% of the patients had resolution of pulmonary disorders, whereas 15.9% experienced ILD deterioration. Factors that predicted a poor ILD prognosis were older age, symptomatic ILD, lower values of vital capacity and diffusing capacity for carbon monoxide, a pattern of usual interstitial pneumonia on HRCT scan and lung biopsy, and steroid-refractory ILD. The mortality rate was higher in patients with ILD deterioration than in those without ILD deterioration (47.1% versus 3.3%). CONCLUSION: Our findings indicate that ILD results in high morbidity in PM/DM. Our findings also suggest that more aggressive therapy may be required in PM/DM patients presenting with factors predictive of poor ILD outcome. PMID- 21702021 TI - High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. AB - OBJECTIVE: Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in ~40% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome. METHODS: An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype phenotype associations. RESULTS: Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2%). Estimates of the level of mosaicism ranged from 4.2% to 35.8% (mean +/- SD 12.1 +/- 7.9%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms. CONCLUSION: Somatic NLRP3 mutations were identified in 69.2% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome. PMID- 21702022 TI - Genetic evidence of the regulatory role of parathyroid hormone-related protein in articular chondrocyte maintenance in an experimental mouse model. AB - OBJECTIVE: Parathyroid hormone-related protein (PTHrP) regulates the rate of differentiation of growth chondrocytes and is also expressed in articular chondrocytes. This study tested the hypothesis that PTHrP might have a regulatory role in articular chondrocyte maintenance. METHODS: Control sequences of growth differentiation factor 5 were used to delete PTHrP from articular chondrocytes in the mid-region of mouse articular cartilage. Mice with conditional deletion of PTHrP (knockout [KO]) and littermate control mice were evaluated for degenerative changes using both a time-course design and destabilization of the medial meniscus (DMM) technique. A total histologic score of degenerative changes was determined for the femoral and tibial articular surfaces (total maximum score of 60). RESULTS: The time-course study revealed degenerative changes in only a minority of the KO mice. In the DMM model, male KO mice were highly susceptible to DMM-induced degenerative changes (mean +/- SEM total histologic score 45 +/- 2.7 in KO mice versus 23 +/- 1.4 in controls; P < 0.0001 by Mann-Whitney U test), with virtually no overlap between groups. PTHrP normally functions in a feedback loop with Indian hedgehog (IHH), in which a reduction in one signaling partner induces a compensatory increase in the other. A number of phenotypic and functional markers were documented in KO mice to suggest that the IHH-PTHrP axis is capable of compensating in response to a partial Cre-driven PTHrP deletion, a finding that underscores the need to subject the mouse articular cartilage to a destabilizing challenge in order to elicit frankly degenerative findings. CONCLUSION: PTHrP may regulate articular chondrocyte maintenance in mice. PMID- 21702023 TI - Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan. AB - Eosinophilia-myalgia syndrome (EMS) is characterized by subacute onset of myalgias and peripheral eosinophilia, followed by chronic neuropathy and skin induration. An epidemic of EMS in 1989 was linked to consumption of L-tryptophan that had originated from a single source. Following the ban by the Food and Drug Administration (FDA) on the sale of L-tryptophan, the incidence of EMS declined rapidly. Moreover, no new cases have been described since the FDA ban was lifted in 2005. We report the clinical, histopathologic, and immunogenetic features of a new case of L-tryptophan-associated EMS, along with evidence of activated transforming growth factor beta and interleukin-4 signaling in the lesional skin. PMID- 21702024 TI - Increased density of sympathetic nerve fibers in metabolically activated fat tissue surrounding human synovium and mouse lymph nodes in arthritis. AB - OBJECTIVE: To investigate the density of sympathetic nerve fibers in and the metabolic activation of fat tissue surrounding human synovium in rheumatoid arthritis (RA)/osteoarthritis (OA) and in the draining lymph nodes of arthritic and normal mice. METHODS: Using immunofluorescence and immunohistochemistry, the density of sympathetic nerve fibers and the presence of nerve repellent factors were investigated. The metabolic activation of fat tissue was estimated by the occurrence of small-vacuole adipocytes, expression of beta3-adrenoceptors, and adipose tissue weight. RESULTS: The density of sympathetic nerve fibers was markedly increased in fat tissue surrounding RA synovium compared with that in fat tissue surrounding OA synovium. In adipose tissue adjacent to draining lymph nodes, the density of sympathetic nerve fibers was higher in arthritic mice compared with normal mice. In human synovium and mouse draining lymph nodes, the 2 sympathetic nerve repellent factors, semaphorin 3C and semaphorin 3F, were highly expressed. In arthritic compared with normal mice, the fat tissue around lymph nodes was markedly lighter, adipocytes had more fragmented lipid droplets, and fat tissue demonstrated high expression of beta3-adrenoceptors. CONCLUSION: This study demonstrated an increased density of sympathetic nerve fibers in metabolically activated fat tissue surrounding human RA synovium and the draining lymph nodes of arthritic mice. Because sympathetic neurotransmitters stimulate lipolysis, the repulsion of sympathetic nerve fibers from inflamed regions and their increased occurrence in fat tissue probably represent an adaptive program to support the proinflammatory process by releasing energy-rich substrates. PMID- 21702025 TI - Inhibition of enzymatic hydrolysis by residual lignins from softwood--study of enzyme binding and inactivation on lignin-rich surface. AB - Lignin-derived inhibition is a major obstacle restricting the enzymatic hydrolysis of cell wall polysaccharides especially with softwood lignocellulosics. Enzyme adsorption on lignin is suggested to contribute to the inhibitory effect of lignin. The interaction of cellulases with softwood lignin was studied in the present work with commercial Trichoderma reesei cellulases (Celluclast) and lignin-rich residues isolated from steam pretreated softwood (SPS) by enzymatic and acid hydrolysis. Both lignin preparations inhibited the hydrolysis of microcrystalline cellulose (Avicel) and adsorbed the major cellulases present in the commercial cellulase mixture. The adsorption phenomenon was studied at low temperature (4 degrees C) and at the typical hydrolysis temperature (45 degrees C) by following activities of free and lignin-bound enzymes. Severe inactivation of the lignin-bound enzymes was observed at 45 degrees C, however at 4 degrees C the enzymes retained well their activity. Furthermore, SDS-PAGE analysis of the lignin-bound enzymes indicated that very strong interactions form between the residue and the enzymes at 45 degrees C, because the enzymes were not released from the residue in the electrophoresis. These results suggest that heat-induced denaturation may take place on the surface of softwood lignin at the hydrolysis temperature. PMID- 21702026 TI - Well plate microfluidic system for investigation of dynamic platelet behavior under variable shear loads. AB - The study of platelet behavior in real-time under controlled shear stress offers insights into the underlying mechanisms of many vascular diseases and enables evaluation of platelet-focused therapeutics. The two most common methods used to study platelet behavior at the vessel wall under uniform shear flow are parallel plate flow chambers and cone-plate viscometers. Typically, these methods are difficult to use, lack experimental flexibility, provide low data content, are low in throughput, and require large reagent volumes. Here, we report a well plate microfluidic (WPM)-based system that offers high throughput, low reagent consumption, and high experimental flexibility in an easy to use well plate format. The system consists of well plates with an integrated array of microfluidic channels, a pneumatic interface, an automated microscope, and software. This WPM system was used to investigate dynamic platelet behavior under shear stress. Multiple channel designs are presented and tested for shear loads with whole blood to determine their applicability to study thrombus formation. Normal physiological shear (0.1-20 dyn/cm(2) ) and pathological shear (20-200 dyn/cm(2) ) devices were used to study platelet behavior in vitro under various shear, matrix coating, and monolayer conditions. The high physiological relevance, low blood consumption, and increased throughput create a valuable technique available to vascular biology researchers. The approach also has extensibility to other research areas including inflammation, cancer biology, and developmental/stem cell research. PMID- 21702027 TI - Effect of sulfur oxyanions on lignocellulose-derived fermentation inhibitors. AB - Recent results show that treatments with reducing agents, including the sulfur oxyanions dithionite and hydrogen sulfite, efficiently improve the fermentability of inhibitory lignocellulose hydrolysates, and that the treatments are effective when the reducing agents are added in situ into the fermentation vessel at low temperature. In the present investigation, dithionite was added to medium with model inhibitors (coniferyl aldehyde, furfural, 5-hydroxymethylfurfural, or acetic acid) and the effects on the fermentability with yeast were studied. Addition of 10 mM dithionite to medium containing 2.5 mM coniferyl aldehyde resulted in a nine-fold increase in the glucose consumption rate and a three-fold increase in the ethanol yield. To investigate the mechanism behind the positive effects of adding sulfur oxyanions, mixtures containing 2.5 mM of a model inhibitor (an aromatic compound, a furan aldehyde, or an aliphatic acid) and 15 mM dithionite or hydrogen sulfite were analyzed using mass spectrometry (MS). The results of the analyses, which were performed by using UHPLC-ESI-TOF-MS and UHPLC LTQ/Orbitrap-MS/MS, indicate that the positive effects of sulfur oxyanions are primarily due to their capability to react with and sulfonate inhibitory aromatic compounds and furan aldehydes at low temperature and slightly acidic pH (such as 25 degrees C and pH 5.5). PMID- 21702028 TI - Evaluation of nanoparticle-immobilized cellulase for improved ethanol yield in simultaneous saccharification and fermentation reactions. AB - Ethanol yields were 2.1 (P = 0.06) to 2.3 (P = 0.01) times higher in simultaneous saccharification and fermentation (SSF) reactions of microcrystalline cellulose when cellulase was physisorbed on silica nanoparticles compared to enzyme in solution. In SSF reactions, cellulose is hydrolyzed to glucose by cellulase while yeast simultaneously ferments glucose to ethanol. The 35 degrees C temperature and the presence of ethanol in SSF reactions are not optimal conditions for cellulase. Immobilization onto solid supports can stabilize the enzyme and promote activity at non-optimum reaction conditions. Mock SSF reactions that did not contain yeast were used to measure saccharification products and identify the mechanism for the improved ethanol yield using immobilized cellulase. Cellulase adsorbed to 40 nm silica nanoparticles produced 1.6 times (P = 0.01) more glucose than cellulase in solution in 96 h at pH 4.8 and 35 degrees C. There was no significant accumulation (<250 ug) of soluble cellooligomers in either the solution or immobilized enzyme reactions. This suggests that the mechanism for the immobilized enzyme's improved glucose yield compared to solution enzyme is the increased conversion of insoluble cellulose hydrolysis products to soluble cellooligomers at 35 degrees C and in the presence of ethanol. The results show that silica-immobilized cellulase can be used to produce increased ethanol yields in the conversion of lignocellulosic materials by SSF. PMID- 21702029 TI - Abstracts of the Annual Scientific Meetings of the Association of Surgeons from the Netherlands. Najaarsvergadering. November 26, 2010. Ede, The Netherlands. PMID- 21702030 TI - Abstracts of the Association of Surgeons from the Netherlands (ASN). Chirurgendagen. May 19-20, 2011. Veldhoven, The Netherlands. PMID- 21702031 TI - Heterotrophs grown on the soluble microbial products (SMP) released by autotrophs are responsible for the nitrogen loss in nitrifying granular sludge. AB - In this work, nitrogen loss in the nitrite oxidation step of the nitrification process in an aerobic-granule-based reactor was characterized with both experimental and modeling approaches. Experimental results showed that soluble microbial products (SMP) were released from the nitrite-oxidizing granules and were utilized as a carbon source by the heterotrophs for denitrification. This was verified by the fluorescence in situ hybridization (FISH) analysis. Microelectrode tests showed that oxygen diffusion limitation did result in an anoxic micro-zone in the granules and allowed sequential utilization of nitrate as an electron acceptor for heterotrophic denitrification with SMP as a carbon source. To further elucidate the nitrogen loss mechanisms, a mathematic model was formulated to describe the growth of nitrite oxidizers, the formation and consumption of SMP, the anoxic heterotrophic growth on SMP and nitrate, as well as the oxygen transfer and the substrate diffusion in the granules. The results clearly indicate that the heterotrophs grown on the SMP released by the autotrophs are responsible for the nitrogen loss in the nitrifying granules, and give us a better understanding of the aerobic granules for nitrogen removal. Biotechnol. Bioeng. 2011;108: 2844-2852. (c) 2011 Wiley Periodicals, Inc. PMID- 21702032 TI - One-step production of unacetylated sophorolipids by an acetyltransferase negative Candida bombicola. AB - Sophorolipids from the non-pathogenic yeast Candida bombicola are applied commercially as biodegradable, eco-friendly surface active agents. These sophorolipids are produced by cultivation in presence of a hydrophobic carbon source and are always constituted of a mixture of structurally related molecules. For some applications however, certain structural variants perform better than others. Acetylation of the sophorolipid molecule is such a parameter that gains interest because of its influence on water solubility, foaming properties, and biological activity. Fully unacetylated sophorolipids therefore are interesting metabolites but cannot be produced in a pure way by conventional cultivation. Here we report the identification of the acetyltransferase gene AT, responsible for acetylation of de novo synthesized sophorolipids in Candida bombicola. By the creation of a Deltaat deletion mutant, we could create a yeast strain producing purely unacetylated sophorolipids with a yield of 5 +/- 0.7 g/L using rapeseed oil as hydrophobic carbon source. In contrast to the chemical production of unacetylated sophorolipids used nowadays, the microbial production leads to mainly lactonic sophorolipids, in addition to minor amounts of acidic sophorolipids. PMID- 21702033 TI - A mechanistic model for rational design of optimal cellulase mixtures. AB - A model-based framework is described that permits the optimal composition of cellulase enzyme mixtures to be found for lignocellulose hydrolysis. The rates of hydrolysis are shown to be dependent on the nature of the substrate. For bacterial microcrystalline cellulose (BMCC) hydrolyzed by a ternary cellulase mixture of EG2, CBHI, and CBHII, the optimal predicted mixture was 1:0:1 EG2:CBHI:CBHII at 24 h and 1:1:0 at 72 h, at loadings of 10 mg enzyme per g substrate. The model was validated with measurements of soluble cello oligosaccharide production from BMCC during both single enzyme and mixed enzyme hydrolysis. Three-dimensional diagrams illustrating cellulose conversion were developed for mixtures of EG2, CBHI, CBHII acting on BMCC and predicted for other substrates with a range of substrate properties. Model predictions agreed well with experimental values of conversion after 24 h for a variety of enzyme mixtures. The predicted mixture performances for substrates with varying properties demonstrated the effects of initial degree of polymerization (DP) and surface area on the performance of cellulase mixtures. For substrates with a higher initial DP, endoglucanase enzymes accounted for a larger fraction of the optimal mixture. Substrates with low surface areas showed significantly reduced hydrolysis rates regardless of mixture composition. These insights, along with the quantitative predictions, demonstrate the utility of this model-based framework for optimizing cellulase mixtures. PMID- 21702034 TI - Frequency of cervical intraepithelial neoplasia treatment in a well-screened population. AB - Treatment of cervical intraepithelial neoplasia (CIN) detectable at screening has helped reduce the incidence of cervical cancer, but has also led to overtreatment. The estimates of overtreatment have often focused on a particular grade of CIN or age group. The aim of this paper was to provide a nationwide population-based estimate of the frequency of CIN treatment per prevented cervical cancer case in a well-screened population. We retrieved the data from the Danish National Population, Patient, Health Insurance, Pathology, and Cancer Registers, and calculated annual age-standardized CIN treatment rates. We estimated the frequency of CIN treatment per prevented cervical cancer case by comparing the cumulative life-time risk of CIN treatment from 1996 onward, with the difference in the cumulative life-time risks of cervical cancer in the prescreening and the screening periods. Since 1996, more than 5,000 CIN treatments were undertaken annually in the population of about 2.2 million women aged 15-84 years, and at present 5.2 CIN treatments are undertaken per 1,000 women aged 20-49. About six women have undergone CIN treatment for each prevented cervical cancer. The frequency of CIN treatment increased after 2004 and at present almost eight women are treated per prevented cervical cancer case. Screening, though effective in reducing the incidence of cervical cancer, leads also to a considerable burden of CIN treatment. Future trends in CIN treatment should be closely monitored. PMID- 21702035 TI - The emerging epidemic of estrogen-related cancers in young women in a developing Asian country. AB - The incidence of breast and genital tract cancers is increasing among Taiwanese women, but the age specificity and histopathological features of these cancers have not been determined. We used a descriptive epidemiological method and data from the Taiwan Cancer Registry (1979-2007) to examine secular trends in the age specific incidences of female breast cancer, three major female genital tract cancers and the histopathological subtypes of these cancers. Age-specific incidence rates in the United States (1978-2002) were used as an external reference, and the incidence rates of all malignancies and of malignant brain tumors were used as internal references. We found that age-adjusted incidence rates of female breast, uterine, and ovarian cancers increased in Taiwan from 1979 to 2007, whereas the incidence of cervical cancer decreased after 1998. The largest increase was observed for ductal and lobular carcinomas of the breast and endometrioid carcinomas of the uterus and ovary in women <=55 years, all of these tumors show a high prevalence of hormone receptor expressions. In addition, hormone-receptor-positive rates of breast cancer were uniquely higher in younger, as opposed to older, Taiwanese women. These findings indicate that estrogen related cancers rapidly emerge in young women in Taiwan and that incidence rates are catching up with that of women living in the United States. PMID- 21702036 TI - Time since first sexual intercourse and the risk of cervical cancer. AB - Young age at first sexual intercourse (AFI) is an important risk factor for cervical cancer, but no simple statistical model of its influence has been established. We investigated the relationship between risk of cervical carcinoma and time since first intercourse using data on monogamous women (5,074 cases and 16,137 controls) from the International Collaboration of Epidemiological Studies of Cervical Cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from pooled data on 20 studies using conditional logistic regression. The OR for invasive cervical carcinoma is approximately proportional to the square of time since first intercourse (exponent 1.95, 95% CI: 1.76-2.15) up to age 45. First cervical infection with human papillomavirus (HPV) often occurs soon after first sexual intercourse, so early AFI is a reasonable proxy for early age at first exposure to HPV. In addition, age-specific incidence rates of cervical cancer in unscreened populations remain fairly constant above age 45. Cervical cancer thus resembles other cancers caused by strong early-stage carcinogens, with incidence rates proportional to a power of time since first exposure and also resembles cancers of the breast and other hormone-dependent epithelia, where a similar flattening of age-specific incidence rates is seen at the time menopausal changes start. Taken together, these observations suggest that HPV vaccination may prevent the majority of cervical cancers by delaying HPV infection without necessarily providing lifetime protection against HPV. PMID- 21702038 TI - ROS implication in a new antitumor strategy based on non-thermal plasma. AB - Non-thermal plasma (NTP) is generated by ionizing neutral gas molecules/atoms leading to a highly reactive gas at ambient temperature containing excited molecules, reactive species and generating transient electric fields. Given its potential to interact with tissue or cells without a significant temperature increase, NTP appears as a promising approach for the treatment of various diseases including cancer. The aim of our study was to evaluate the interest of NTP both in vitro and in vivo. To this end, we evaluated the antitumor activity of NTP in vitro on two human cancer cell lines (glioblastoma U87MG and colorectal carcinoma HCT-116). Our data showed that NTP generated a large amount of reactive oxygen species (ROS), leading to the formation of DNA damages. This resulted in a multiphase cell cycle arrest and a subsequent apoptosis induction. In addition, in vivo experiments on U87MG bearing mice showed that NTP induced a reduction of bioluminescence and tumor volume as compared to nontreated mice. An induction of apoptosis was also observed together with an accumulation of cells in S phase of the cell cycle suggesting an arrest of tumor proliferation. In conclusion, we demonstrated here that the potential of NTP to generate ROS renders this strategy particularly promising in the context of tumor treatment. PMID- 21702037 TI - Boswellic acid inhibits growth and metastasis of human colorectal cancer in orthotopic mouse model by downregulating inflammatory, proliferative, invasive and angiogenic biomarkers. AB - Numerous cancer therapeutics were originally identified from natural products used in traditional medicine. One such agent is acetyl-11-keto-beta-boswellic acid (AKBA), derived from the gum resin of the Boswellia serrata known as Salai guggal or Indian frankincense. Traditionally, it has been used in Ayurvedic medicine to treat proinflammatory conditions. In this report, we hypothesized that AKBA can affect the growth and metastasis of colorectal cancer (CRC) in orthotopically implanted tumors in nude mice. We found that the oral administration of AKBA (50-200 mg/kg) dose-dependently inhibited the growth of CRC tumors in mice, resulting in decrease in tumor volumes than those seen in vehicle-treated mice without significant decreases in body weight. In addition, we observed that AKBA was highly effective in suppressing ascites and distant metastasis to the liver, lungs and spleen in orthotopically implanted tumors in nude mice. When examined for the mechanism, we found that markers of tumor proliferation index Ki-67 and the microvessel density cluster of differentiation (CD31) were significantly downregulated by AKBA treatment. We also found that AKBA significantly suppressed nuclear factor-kappaB (NF-kappaB) activation in the tumor tissue and expression of proinflammatory (cyclooxygenase-2), tumor survival (bcl-2, bcl-xL, inhibitor of apoptosis (IAP-1) and survivin), proliferative (cyclin D1), invasive (intercellular adhesion molecule 1 and matrix metalloproteinase-9) and angiogenic C-X-C (CXC) receptor 4 and vascular endothelial growth factor) biomarkers. When examined for serum and tissue levels of AKBA, a dose-dependent increase in the levels of the drug was detected, indicating its bioavailability. Thus, our findings suggest that this boswellic acid analog can inhibit the growth and metastasis of human CRC in vivo through downregulation of cancer-associated biomarkers. PMID- 21702039 TI - The protective role of polymorphism MKK4-1304 T>G in nasopharyngeal carcinoma is modulated by Epstein-Barr virus' infection status. AB - MKK4 is a candidate tumor suppressor, which acts as a critical mediator of Epstein-Barr Virus (EBV)-induced c-Jun N-terminal kinase (JNK) activation. Functional polymorphism MKK4 -1304T>G has been showed to be protective in colorectal cancer or lung cancer. We hypothesized that genetic variants in the MKK4 promoter were associated with the risk of nasopharyngeal carcinoma (NPC). Two common polymorphisms in MKK4, -1304T>G and -1044A>T were genotyped in two independent case-control panels of Eastern and Southern Chinese populations, totally containing 1237 NPC and 1328 controls. We found that compared to the most common -1304TT genotype, carriers of variant genotypes (-1304TG+GG) were associated with a significantly reduced risk for NPC in total subjects (adjusted OR = 0.78; 95%CI = 0.67-0.94). Further stratification analysis showed that the protective effect was more pronounced in EBV negative status (adjusted OR = 0.51; 95%CI = 0.41-0.68) but restrained in those with EBV infection (adjusted OR = 1.05; 95%CI = 0.88-1.26), and that the -1304GG variant genotypes interacted with EBV negative status on reducing cancer risk (p = 0.011). However, no significant association was observed between the -1044A>T polymorphism and risk of NPC. Our data suggest that the protective role of genetic variant MKK4 -1304T>G is restrained in NPC with EBV infection. These findings implicate the role of EBV and MKK4 -1304 T>G interaction as a causative factor for the NPC. PMID- 21702040 TI - Genome structure-based screening identified epigenetically silenced microRNA associated with invasiveness in non-small-cell lung cancer. AB - MicroRNA (miRNA) expression is frequently altered in human cancers. To search for epigenetically silenced miRNAs in non-small-cell lung cancer (NSCLC), we mapped human miRNAs on autosomal chromosomes and selected 55 miRNAs in silico. We treated six NSCLC cell lines with the DNA methylation inhibitor 5-aza-2' deoxycytidine (5-aza-CdR) and determined the expressions of the 55 miRNAs. Fourteen miRNAs were decreased in the cancer cell lines and were induced after 5 aza-CdR treatment. After a detailed DNA methylation analysis, we found that mir 34b and mir-126 were silenced by DNA methylation. Mir-34b was silenced by the DNA methylation of its own promoter, whereas mir-126 was silenced by the DNA methylation of its host gene, EGFL7. A chromatin immunoprecipitation assay revealed H3K9me2 and H3K9me3 in mir-34b and EGFL7, and H3K27me3 in EGFL7. The overexpression of mir-34b and mir-126 decreased the expression of c-Met and Crk, respectively. The 5-aza-CdR treatment of lung cancer cell line resulted in increased mir-34b expression and decreased c-Met protein. We next analyzed the DNA methylation status of these miRNAs using 99 primary NSCLCs. Mir-34b and mir 126 were methylated in 41 and 7% of all the cases, respectively. The DNA methylation of mir-34b was not associated with c-Met expression determined by immunohistochemistry, but both mir-34b methylation (p = 0.007) and c-Met expression (p = 0.005) were significantly associated with lymphatic invasion in a multivariate analysis. The DNA methylation of mir-34b can be used as a biomarker for an invasive phenotype of lung cancer. PMID- 21702041 TI - Alcohol drinking and primary liver cancer: a pooled analysis of four Japanese cohort studies. AB - Because studies of the association between alcohol intake and the risk of primary liver cancer use varying cut-off points to classify alcohol intake, it is difficult to precisely quantify this association by meta-analysis of published data. Furthermore, there are limited data for women in prospective studies of the dose-specific relation of alcohol intake and the risk of primary liver cancer. We analyzed original data from 4 population-based prospective cohort studies encompassing 174,719 participants (89,863 men and 84,856 women). After adjustment for a common set of variables, we used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of primary liver cancer incidence according to alcohol intake. We conducted a meta-analysis of the HRs derived from each study. During 1,964,136 person-years of follow-up, 804 primary liver cancer cases (605 men and 199 women) were identified. In male drinkers, the multivariate-adjusted HRs (95% CI) for alcohol intakes of 0.1-22.9, 23.0-45.9, 46.0-68.9, 69.0-91.9 and >=92.0 g/day, as compared to occasional drinkers, were 0.88 (0.57-1.36), 1.06 (0.70-1.62), 1.07 (0.69-1.66), 1.76 (1.08 2.87) and 1.66 (0.98-2.82), respectively (p for trend = 0.015). In women, we observed a significantly increased risk among those who drank >=23.0 g/day, as compared to occasional drinkers (HR: 3.60; 95% CI: 1.22-10.66). This pooled analysis of data from large prospective studies in Japan indicates that avoidance of (1) heavy alcohol drinking (>=69.0 g alcohol/day) in men and (2) moderate drinking (>=23.0 g alcohol/day) in women may reduce the risk of primary liver cancer. PMID- 21702042 TI - MiR-34a chemosensitizes bladder cancer cells to cisplatin treatment regardless of p53-Rb pathway status. AB - MiR-34a is a downstream effector of p53 that has been shown to target several molecules associated with cell cycle and cell survival pathways. As alterations in these pathways are frequent in muscle invasive transitional cell carcinoma of the bladder (MI-TCC), for example mutation or loss of p53 and Rb, the goal of this study was to determine whether manipulation of miR-34a expression levels could abrogate the effect of these alterations and sensitize bladder cancer cells to chemotherapy. We demonstrate that transfection of T24, TCCSUP and 5637 with pre-miR-34a followed by cisplatin treatment results in a dramatic reduction in clonogenic potential and induction of senescence compared to treatment with cisplatin alone. Molecular analyses identified Cdk6 and sirtuin (SIRT)-1 as being targeted by miR-34a in MI-TCC cells, however, inhibition of Cdk6 and SIRT-1 was not as effective as pre-miR-34a in mediating chemosensitization. Analysis of 27 preneoadjuvant chemotherapy patient samples revealed many of the patients who subsequently did not respond to treatment (based on surgical resection postchemotherapy and 5-year survival data) express lower levels of miR-34a, however, a statistically significant difference between the responder and nonresponder groups was not observed (p = 0.1174). Analysis of eight sets of pre- and postneoadjuvant chemotherapy patient samples determined miR-34a expression increased postchemotherapy in only two of the eight patients. The combined data indicate that elevation of miR-34a expression levels before chemotherapy would be of benefit to MI-TCC patients, particularly in a setting of low miR-34a expression. PMID- 21702043 TI - Phosphorylation of vasodilator-stimulated phosphoprotein Ser239 suppresses filopodia and invadopodia in colon cancer. AB - In colorectal cancer, the antitumorigenic guanylyl cyclase C (GCC) signalome is defective reflecting ligand deprivation from downregulation of endogenous hormone expression. Although the proximal intracellular mediators of that signal transduction system, including cyclic guanosine monophosphate (cGMP) and cGMP dependent protein kinase (PKG), are well characterized, the functional significance of its distal effectors remain vague. Dysregulation of ligand dependent GCC signaling through vasodilator-stimulated phosphoprotein (VASP), an actin-binding protein implicated in membrane protrusion dynamics, drastically reduced cGMP-dependent VASP phosphorylation levels in colorectal tumors from patients. Restoration of cGMP-dependent VASP phosphorylation by GCC agonists suppressed the number and length of locomotory (filopodia) and invasive (invadopodia) actin-based organelles in human colon cancer cells. Membrane organelle disassembly reflected specific phosphorylation of VASP Ser239, the cGMP/PKG preferred site, and rapid VASP removal from tumor cell protrusions. Importantly, VASP Ser239 phosphorylation inhibited the proteolytic function of invadopodia, reflected by suppression of the cancer cell ability to digest DQ collagen IV embedded in Matrigel. These results demonstrate a previously unrecognized role for VASP Ser239 phosphorylation, a single intracellular biochemical reaction, as an effective mechanism which opposes tumor cell shape promoting colon cancer invasion and metastasis. Reconstitution of physiological cGMP circuitry through VASP, in turn, represents an attractive targeted approach for patients with colorectal cancer. PMID- 21702044 TI - Humoral response to catumaxomab correlates with clinical outcome: results of the pivotal phase II/III study in patients with malignant ascites. AB - The trifunctional antibody catumaxomab is a targeted immunotherapy for the intraperitoneal treatment of malignant ascites. In a Phase II/III trial in cancer patients (n = 258) with malignant ascites, catumaxomab showed a clear clinical benefit vs. paracentesis and had an acceptable safety profile. Human antimouse antibodies (HAMAs), which could be associated with beneficial humoral effects and prolonged survival, may develop against catumaxomab as it is a mouse/rat antibody. This post hoc analysis investigated whether there was a correlation between the detection of HAMAs 8 days after the fourth catumaxomab infusion and clinical outcome. HAMA-positive and HAMA-negative patients in the catumaxomab group and patients in the control group were analyzed separately for all three clinical outcome measures (puncture-free survival, time to next puncture and overall survival) and compared to each other. There was a strong correlation between humoral response and clinical outcome: patients who developed HAMAs after catumaxomab showed significant improvement in all three clinical outcome measures vs. HAMA-negative patients. In the overall population in HAMA-positive vs. HAMA negative patients, median puncture-free survival was 64 vs. 27 days (p < 0.0001; HR 0.330), median time to next therapeutic puncture was 104 vs. 46 days (p = 0.0002; HR 0.307) and median overall survival was 129 vs. 64 days (p = 0.0003; HR 0.433). Similar differences between HAMA-positive and HAMA-negative patients were seen in the ovarian, nonovarian and gastric cancer subgroups. In conclusion, HAMA development may be a biomarker for catumaxomab response and patients who developed HAMAs sooner derived greater benefit from catumaxomab treatment. PMID- 21702045 TI - Downregulation and growth inhibitory role of FHL1 in lung cancer. AB - Four and a half Lin-11, Isl-1, Mac-3 (LIM) protein 1 (FHL1) has been linked to carcinogenesis. However, the role of FHL1 in lung cancer remains unclear and the detailed mechanism underlying its tumor suppressive role is poorly understood. The purpose of this study was to examine FHL1 expression in lung cancer patients and to investigate how it was associated with lung cancer cell growth. Immunoblotting and immunohistochemistry showed that FHL1 protein was downregulated in over 90% of 80 lung cancer patients. FHL1 expression was strongly correlated with tumor histological types (p < 10(-4) ) and the differentiation of the tumor (p = 0.002). FHL1 inhibited anchorage-dependent and independent growth of human lung cancer cell lines. The inhibitory effects of FHL1 on lung cancer cell growth were associated with both the G1 and the G2/M cell cycle arrest concomitant with a marked inhibition of cyclin A, cyclin B1 and cyclin D as well as the induction of the cyclin dependent kinase inhibitors p21 (WAF1/CIP1) and p27 (Kip1). Direct intratumoral injection of an adenovirus expressing FHL1 dramatically suppressed the growth of A549 lung cancer cells in nude mice. Our data suggest that reduced expression of FHL1 may play an important role in the development and progression of lung cancer and that FHL1 may be a useful target for lung cancer gene therapy. PMID- 21702046 TI - Uptake of faecal immunochemical test screening among nonparticipants in a flexible sigmoidoscopy screening programme. AB - Screening programmes based on single modality testing may prevent individuals with a preference for a different test from participating. We conducted a population-based trial to determine whether nonparticipants in flexible sigmoidoscopy (FS) screening were willing to attend faecal immunochemical test (FIT) screening. In total, 8,407 subjects were invited in a primary FS screening programme. Invitees did not know at the time of FS invitation that nonparticipants would be offered FIT screening. A total of 4,407 nonparticipants of FS screening were invited for FIT screening (cut-off 50 ng haemoglobin/ml). The participation rate to FS screening was 31% [95% confidence interval (CI): 30 32%]. Among the FS nonparticipants 25% (CI: 24-26%) did attended FIT screening. The participation rate of the two-stage recruitment for FS and FIT screening was 45% (CI: 44-46%). FIT screenees were older (p = 0.02), more often women (p < 0.001) and had a lower social economic status (p = 0.01) than FS screenees. The detection rate (DR) for advanced adenoma was 3.5% (CI: 2.5-4.8%), and for colorectal cancer (CRC) it was 0.3% (CI: 0.1-0.8%) among participants to FIT screening. The DR of the two-stage recruitment was 6.1% (n = 202) for an advanced adenoma and 0.5% (n = 16) for a CRC. In conclusion, offering FIT screening to nonparticipants in a FS screening programme increases the overall participation rate considerably, as a quarter of nonparticipants of FS screening was willing to attend FIT screening. The participation rate remains lower for primary FIT screening in the same population (62%). Women in the target population were more likely to refuse FS than FIT screening. Countries introducing FS screening should be aware of these preferences. PMID- 21702047 TI - Mapping the zinc-transporting system in mammary cells: molecular analysis reveals a phenotype-dependent zinc-transporting network during lactation. AB - The mammary epithelial cell transitions from a non-secreting to a terminally differentiated, secreting cell during lactation. Zinc (Zn) is a key modulator of phenotypic transition as it regulates over 300 biological functions including transcription, translation, energy transformation, intracellular signaling, and apoptosis. In addition, Zn must be redirected from normal cellular functions into the secretory compartment, as many components of the secretory system are Zn dependent and an extraordinary amount of Zn is secreted (1-3 mg Zn/day) into milk. Herein, we utilized a "systems biology" approach of genomic and proteomic profiling to explore mechanisms through which Zn is reallocated during phenotype transition in the lactating mammary gland from mice and cultured mammary cells. Nine Zn transporters play key roles in Zn redistribution within the network during lactation. Protein abundance of six Zip (Zip3, Zip5, Zip7, Zip8, Zip10, Zip11) and three ZnT (ZnT2, ZnT4, ZnT9) proteins was expanded >2-fold during lactation, which was not necessarily reflected by changes in mRNA expression. Our data suggest that Zip5, Zip8, and Zip10 may be key to Zn acquisition from maternal circulation, while multiple Zip proteins reuptake Zn from milk. Confocal microscopy of cultured mammary cells identified the Golgi apparatus (modulated in part by ZnT5, Zip7, and Zip11) and the late endosomal compartment (modulated in part by ZnT2 and Zip3) as key intracellular compartments through which Zn is reallocated during lactation. These results provide an important framework for understanding the "Zn-transporting network" through which mammary gland Zn pools are redistributed and secreted into milk. PMID- 21702048 TI - Human peripheral blood lymphocytes and fibroblasts as Notch3 expression models. AB - Notch3 is a single pass transmembrane protein belonging to the Notch receptor family. Notch proteins are involved in a very conserved signaling system (Notch signaling) with a broad spectrum of functions, from cell proliferation and differentiation to apoptosis. Mutations in Notch3 gene are linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a disorder characterized by stroke and dementia in young adults. Studies evaluating Notch3 expression in human differentiated cells and adult tissues have shown high Notch3 levels only in vascular smooth muscle cells (VSMC). However, it has been hypothesized that Notch3 is ubiquitously expressed in adult human tissues. Our aim was to evaluate Notch3 expression in human peripheral blood lymphocytes (PBLs) and fibroblasts from normal healthy subjects. In both cell types, we examined the expression of Notch3 by reverse transcriptase polymerase chain reaction (RT-PCR) and quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, we assessed Notch3 protein expression by Western blot analysis. RT-PCR and qRT-PCR analysis showed the presence of Notch3 mRNA in both cell types. Western blot analysis confirmed Notch3 protein expression in PBLs and fibroblasts though showing different profiles. Our data support the expression of Notch3 in adult human cell types, and suggests that PBLs and fibroblasts could provide readily available cells for the study of the role of Notch3 expression in the pathogenetic mechanisms leading to different human disease. PMID- 21702049 TI - Comparison of the skeletal effects induced by daily administration of PTHrP (1 36) and PTHrP (107-139) to ovariectomized mice. AB - We here compared the changes induced by subcutaneous injection of PTHrP (1-36) or PTHrP (107-139) (80 ug/kg/day, 5 days/week for 4 or 8 weeks) in bone histology and bone remodeling factors, and in bone marrow cells (BMCs) ex vivo, in ovariectomized (OVX) mice. We also examined the osteogenic effects of these peptides in mouse mesenchymal C3H10T1/2 cells under oxidative stress condition in vitro, which recapitulates the effects of OVX. We confirmed that PTHrP (1-36) exerts bone anabolic actions, as assessed by bone histology and osteoblast differentiation markers in the long bones and plasma from OVX mice. PTHrP (107 139) was also efficient in stimulating several bone formation parameters, and it dramatically decreased bone resorption markers. Moreover, both PTHrP peptides modulate DKK-1 and Sost/sclerostin in osteoblast-like UMR-106 cells highly expressing these Wnt pathway inhibitors, related to their osteogenic action in this in vivo scenario. Administration of either PTHrP peptide improved osteogenic differentiation in BMCs from OVX mice ex vivo and in mouse mesenchymal C3H10T1/2 cells under oxidative stress condition in vitro. These data demonstrate that PTHrP (1-36) and PTHrP (107-139) can exert similar osteogenic effects in the appendicular skeleton of OVX mice. Our results suggest that these effects might occur in part by modulating the Wnt pathway. These findings lend credence to the notion that the osteogenic action of PTHrP (107-139) is likely a consequence of its anti-resorptive and anabolic features, and further support the usefulness of PTHrP (1-36) as a bone anabolic peptide in the setting of estrogen-depletion. PMID- 21702050 TI - The calcineurin-nuclear factor of activated T cells signaling pathway mediates the effect of corticotropin releasing factor and urocortins on catecholamine synthesis. AB - The biological effects of the Corticotropin-releasing factor (CRF) family of neuropeptides are mediated by mobilization of [Ca(2+)]. Aim of the current work was to examine if the calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway is involved in the effect of CRF peptides in catecholamine synthesis and secretion from PC12 rat pheochromocytona cells, a model for the study of adrenal catecholamine production. PC12 cells express both types of CRF receptors. Our data are as follows: (a) The calcineurin inhibitor cyclosporine A (CsA) blocked norepinephrine secretion induced by ligands of either CRF type 1 (CRF(1)) or 2 (CRF(2)) receptors on PC12 cells. (b) Silencing NFAT2 expression using a selective NFAT2 siRNA blocked CRF(1) and CRF(2) -induced NE production. (c) CRF ligands induced NFAT transcriptional activity in cells transfected with a luciferase reporter construct controlled by NFAT binding elements (NFAT-Luc). (d) CsA completely blocked the stimulatory effect of CRF(1) and CRF(2) ligands on NFAT activity in NFAT-Luc transfected cells. (e) PKA, PKC, p38-MAPK, Tpl2, Ha Ras, and AKT1 were crucial intermediates for both CRF(1) and CRF(2)-induced NFAT activation. Interestingly, MEK1/2 and ERK1/2 were crucial only for the CRF(2) induced NFAT activation. (f) p38-MAPK and Tpl2 were crucial intermediates for both CRF(1) and CRF(2)-induced norepinephrine production, while AKT1 affected only CRF(2)-induced norepinephrine production. In conclusion, our data suggest that CRF(1) and CRF(2) ligands activate the transcription factor NFAT and its activation is prerequisite for CRF-induced catecholamine production from chromaffin cells. PMID- 21702051 TI - Advanced approach to build the design space for the primary drying of a pharmaceutical freeze-drying process. AB - This paper deals with the design space of a pharmaceutical freeze-drying process. Mathematical modeling is used to investigate the effect of the operating conditions [shelf temperature (T(shelf)) and chamber pressure (P(c))] on product temperature (that has to remain below a limit value) and sublimation flux (that has to be lower than a level that would cause choked flow). The algorithm takes into account the variation of the design space with time due to the increase in the dried layer thickness. Besides T(shelf) and P(c), the dried layer thickness is used as the third coordinate of the diagram, thus resulting in just one graph that can be used to build recipes with variable operating conditions, as well as to analyze the effect of process failures. Such results are compared with those obtained when the variation of the design space with time is not accounted for; in this case, the design space comprises those operating conditions that fulfill the operation constraints throughout primary drying, thus giving a much more conservative recipe when designing the process or potentially misleading results when analyzing process failures. Finally, the proposed method has been used to design, and experimentally validate, a recipe for a pharmaceutical formulation. PMID- 21702052 TI - Mathematical modeling of variables involved in dissolution testing. AB - Dissolution testing is an important technique used for development and quality control of solid oral dosage forms of pharmaceutical products. However, the variability associated with this technique, especially with USP apparatuses 1 and 2, is a concern for both the US Food and Drug Administration and pharmaceutical companies. Dissolution testing involves a number of variables, which can be divided into four main categories: (1) analyst, (2) dissolution apparatus, (3) testing environment, and (4) sample. Both linear and nonlinear models have been used to study dissolution profiles, and various mathematical functions have been used to model the observed data. In this study, several variables, including dissolved gases in the dissolution medium, off-center placement of the test tablet, environmental vibration, and various agitation speeds, were modeled. Mathematical models including Higuchi, Korsmeyer-Peppas, Weibull, and the Noyes Whitney equation were employed to study the dissolution profile of 10 mg prednisone tablets (NCDA #2) using the USP paddle method. The results showed that the nonlinear models (Korsmeyer-Peppas and Weibull) accurately described the entire dissolution profile. The results also showed that dissolution variables affected dissolution rate constants differently, depending on whether the tablets disintegrated or dissolved. PMID- 21702053 TI - Impact of CYP3A5*3 and CYP2C8-HapC on paclitaxel/carboplatin-induced myelosuppression in patients with ovarian cancer. AB - The influence of genetic variants on paclitaxel-induced toxicity is of considerable interest for reducing adverse drug reactions. Recently, the genetic variants CYP2C8*3, CYP2C8-HapC, and CYP3A5*3 were associated with paclitaxel induced neurotoxicity. We, therefore, investigated the impact of CYP2C8-HapC and CYP3A5*3 on paclitaxel/carboplatin-induced myelosuppression and neurotoxicity. Thirty-three patients from a prospective pharmacokinetics study were genotyped using pyrosequencing. Patients with variant alleles of CYP2C8-HapC were found to have significantly lower nadir values of both leukocytes and neutrophils (p < 0.05) than patients with the wild-type genotype. CYP3A5*3/*1 patients were shown to have borderline, significantly lower nadir values of leukocytes (p = 0.07) than *3/*3 patients. Combining the two genotypes resulted in a significant correlation with both leukopenia and neutropenia (p = 0.01). No effect of these genetic variants on neurotoxicity could be shown in this rather small study, but their importance for paclitaxel-induced toxicity could be confirmed. PMID- 21702054 TI - Partial purification and characterisation of cysteine protease in wheat germ. AB - BACKGROUND: Proteases have become an essential part of the modern food and feed industry, being incorporated in a large and diversified range of products for human and animal consumption. The objective of this study was to purify and characterise a protease from wheat germ. RESULTS: After purification a single protease of molecular weight 61-63 kDa (determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis) was obtained. The purified protease had optimal activity at 50 degrees C and maintained its activity completely after incubation at 30 degrees C for 30 min, while over 47% of the activity was lost after incubation at 80 degrees C for 30 min. The purified protease had optimal activity and maintained maximum stability at pH 5.5, while the activity decreased after incubation for 30 min at other pH values. The protease was inhibited by Mg(2+), Mn(2+), Ba(2+) and iodoacetic acid and stimulated by Li(+), Ca(2+), Cu(2+), beta-mercaptoethanol and dithiothreitol, while Zn(2+), L-cysteine and glutathione had no significant effect on its activity. At pH 5.5 the enzyme had a K(m) of 0.562 mg mL(-1) with casein as substrate and showed higher affinity to casein than to bovine serum albumin, ovalbumin and gelatin. CONCLUSION: The purified enzyme from wheat germ was identified as a cysteine protease. PMID- 21702055 TI - Correlation between isotopic and meteorological parameters in Italian wines: a local-scale approach. AB - BACKGROUND: Since the beginning of the 1980s deuterium nuclear magnetic resonance and carbon-13 mass spectrometry have proved to be reliable techniques for detecting adulteration and for classifying natural products by their geographic origin. Scientific literature has so far mainly focused on data acquired at regional level where isotopic parameters are correlated to climatic mean data relative to large territories. RESULTS: Nebbiolo and Barbera wine samples of various vintages and from different areas within the Piedmont region (northern Italy) were analysed using SNIF-NMR and GC-C-IRMS and a large set of meteorological parameters were recorded by means of weather stations placed in fields where the grapes were grown. Correlations between isotopic ((2)H and (13)C) data and several climatic parameters at a local level (mean temperature, total rainfall, mean humidity and thermal sums) were attempted and some linear correlations were found. CONCLUSIONS: Mean temperature and total rainfall were found to be correlated to isotopic ((2)H and (13)C) abundance in linear direct and inverse proportions respectively. Lower or no correlations between deuterium and carbon-13 abundances and other meteorological parameters such as mean humidity and thermal sums were found. Moreover, wines produced from different grape varieties in the same grape field showed significantly different isotopic values. PMID- 21702056 TI - 1-MCP suppresses ethylene biosynthesis and delays softening of 'Hami' melon during storage at ambient temperature. AB - BACKGROUND: 'Hami' melon is susceptible to softening during postharvest storage at ambient temperature, which enhances postharvest deterioration and limits transportation and storage. To look for a method of softening control, the effect of 1-methylcyclopropene (1-MCP) on regulating postharvest softening of 'Hami' melon fruit was investigated. RESULTS: 1-MCP treatment at 1 uL L(-1) significantly reduced ethylene production and maintained higher levels of fruit firmness. It also markedly inhibited the accumulation of 1-aminocyclopropane-1 carboxylic acid (ACC) and maintained lower activities of ACC synthase and ACC oxidase. In addition, 1-MCP treatment reduced the activities of fruit-softening enzymes such as pectin methyl esterase, polygalacturonase, endo-1,4-beta glucanase and beta-galactosidase. CONCLUSION: 1-MCP was effective in suppressing ethylene production and delaying fruit softening in 'Hami' melon by decreasing the activities of ethylene biosynthesis enzymes and inhibiting fruit-softening enzymes. PMID- 21702057 TI - Stevens-Johnson syndrome after lenalidomide therapy for multiple myeloma: a case report and a review of treatment options. AB - Stevens- Johnson syndrome (SJS) is a severe and life-threatening condition. Although allopurinol, an antihyperuricemia drug, is the drug most commonly associated with SJS, more than 100 different causative drugs have been reported. Among hematologic drugs recently introduced into the market, drugs such as rituximab, imatinib, and bortezomib are reported. Here, we describe a patient with SJS while receiving lenalidomide in combination with prednisolone for treatment-naive multiple myeloma. Although SJS has been reported rarely as an adverse reaction to Lenalidomide, this drug should be considered in the etiology of SJS, and the increased number of prescriptions of Lenalidomide for the therapy of multiple myeloma has to stress the awareness of its potentially serious side effects. PMID- 21702058 TI - Protective effect of thalidomide against N-methyl-D-aspartate-induced retinal neurotoxicity. AB - Thalidomide, an inhibitor of tumor necrosis factor-alpha (TNF-alpha) production, has been indicated to be useful for many inflammatory and oncogenic diseases. In the present study, we examined whether thalidomide (50 mg/kg/day, p.o.) has a protective effect against N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity in rats. A morphometric analysis showed that systemic administration of thalidomide protects neural cells in the ganglion cell layer (GCL) in a dose-dependent manner and significantly decreases the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) positive cells in GCL and in the inner nuclear layer (INL). ELISA showed that thalidomide significantly suppressed the elevation of TNF-alpha 6 and 24 hr after an NMDA injection. Western blot analysis revealed a significant increase in nuclear factor-kappaB (NF-kappaB) p65 level in the retinas treated with NMDA at 24 hr after the injection, but not at 6 or 72 hr. Furthermore, an increase in p JNK and p-p38 levels was also observed in the retina after NMDA injection. Thalidomide suppressed the increased expressions of NF-kappaB p65, p-JNK, and p p38 after NMDA injection. Immunohistochemical analysis showed that thalidomide attenuated NF-kappaB p65 immunoreactivity in the GCL induced by NMDA treatment. In the NMDA-treated group, translocation of NF-kappaB p65 from the cytoplasm to the nucleus was detected in TUNEL-positive cells exposed to NMDA treatment. These results suggest new indications for thalidomide against neurodegenerative diseases. PMID- 21702059 TI - Toxicity of methylmercury injected into eggs when dissolved in water versus corn oil. AB - In a previous study, the embryotoxicity of methylmercury dissolved in corn oil was compared among 26 species of birds. Corn oil is not soluble in the water based matrix that constitutes the albumen of an egg. To determine whether the use of corn oil limited the usefulness of this earlier study, a comparison was made of the embryotoxicity of methylmercury dissolved in corn oil versus water. Mallard (Anas platyrhynchos) and chicken (Gallus gallus) eggs were injected with methylmercury chloride dissolved in corn oil or water to achieve concentrations of 0, 0.2, 0.4, 0.8, and 1.6 ug/g mercury in the egg on a wet weight basis. Hatching success at each dose of mercury was compared between the two solvents. For mallards, 16.4% of the eggs injected with 1.6 ug/g mercury dissolved in water hatched, which was statistically lower than the 37.6% hatch rate of eggs injected with 1.6 ug/g mercury dissolved in corn oil, but no differences in hatching success were observed between corn oil and water at any of the other doses. With chicken eggs, no significant differences occurred in percentage hatch of eggs between corn oil and water at any of the mercury doses. Methylmercury dissolved in corn oil seems to have a toxicity to avian embryos similar to that of does methylmercury dissolved in water. Consequently, the results from the earlier study that described the toxicity of methylmercury dissolved in corn oil to avian embryos were probably not compromised by the use of corn oil as a solvent. PMID- 21702060 TI - CINE turbo spin echo imaging. AB - High-resolution turbo spin echo (TSE) images have demonstrated important details of carotid artery morphology; however, it is evident that pulsatile blood and wall motion related to the cardiac cycle are still significant sources of image degradation. Although ECG gating can reduce artifacts due to cardiac-induced pulsations, gating is rarely used because it lengthens the acquisition time and can cause image degradation due to nonconstant repetition time. This work introduces a relatively simple method of converting a conventional TSE acquisition into a retrospectively ECG-correlated cineTSE sequence. The cineTSE sequence generates a full sequence of ECG-correlated images at each slice location throughout the cardiac cycle in the same scan time that is conventionally used by standard TSE sequences to produce a single image at each slice location. The cineTSE images exhibit reduced pulsatile artifacts associated with a gated sequence but without the increased scan time or associated nonconstant repetition time effects. PMID- 21702061 TI - Myocardial first-pass perfusion: influence of spatial resolution and heart rate on the dark rim artifact. AB - Myocardial perfusion images can be affected by the dark rim artifact. This study aimed to evaluate the effects of the spatial resolution and heart rate on the transmural extent of the artifact. Six pigs under anesthesia were scanned at 1.5T using an echo-planar imaging/fast gradient echo sequence with a nonselective saturation preparation pulse. Three short-axis slices were acquired every heart beat during the first pass of a contrast agent bolus. Two different in-plane spatial resolutions (2.65 and 3.75 mm) and two different heart rates (normal and tachycardia) were used, generating a set of four perfusion scans. The percentage drop of signal in the subendocardium compared to the epicardium and the transmural extent of the artifact were extracted. Additionally, the signal-to noise and the contrast-to-noise ratios were evaluated. The signal drop as well as the width of the dark rim artifact increased with decreased spatial resolution and with increased heart rates. No significant slice-to-slice variability was detected for signal drop and width of the rim within the four considered groups. signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) ratios decreased with increasing spatial resolution. In conclusion, low spatial and temporal resolution could be correlated with increased extent of the dark-rim artifact and with lower SNR and CNR. PMID- 21702062 TI - Optimization of b-value sampling for diffusion-weighted imaging of the kidney. AB - Diffusion-weighted imaging (DWI) involves data acquisitions at multiple b values. In this paper, we presented a method of selecting the b values that maximize estimation precision of the biexponential analysis of renal DWI data. We developed an error propagation factor for the biexponential model, and proposed to optimize the b-value samplings by minimizing the error propagation factor. A prospective study of four healthy human subjects (eight kidneys) was done to verify the feasibility of the proposed protocol and to assess the validity of predicted precision for DWI measures, followed by Monte Carlo simulations of DWI signals based on acquired data from renal lesions of 16 subjects. In healthy subjects, the proposed methods improved precision (P = 0.003) and accuracy (P < 0.001) significantly in region-of-interest based biexponential analysis. In Monte Carlo simulation of renal lesions, the b-sampling optimization lowered estimation error by at least 20-30% compared with uniformly distributed b values, and improved the differentiation between malignant and benign lesions significantly. In conclusion, the proposed method has the potential of maximizing the precision and accuracy of the biexponential analysis of renal DWI. PMID- 21702063 TI - Nonlinear registration of diffusion-weighted images improves clinical sensitivity of functional diffusion maps in recurrent glioblastoma treated with bevacizumab. AB - Diffusion-weighted imaging estimates of apparent diffusion coefficient (ADC) have shown sensitivity to brain tumor cellularity as well as response to therapy. Functional diffusion maps (fDMs) exploit these principles by examining voxelwise changes in ADC within the same patient over time. Currently, the fDM technique involves linear image registration of ADC maps from subsequent follow-up times to pretreatment ADC maps; however, misregistration of ADC maps due to geometric distortions as well as mass effect from growing tumor can confound fDM measurements. In this study, we compare the use of a nonlinear registration scheme to the current linear fDM technique in 70 patients with recurrent glioblastoma multiforme treated with bevacizumab. Results suggest that nonlinear registration of pretreatment ADC maps to post-treatment ADC maps improves the clinical predictability, sensitivity, and specificity of fDMs for both progression-free and overall survival. PMID- 21702064 TI - Short echo-time 3D radial gradient-echo MRI using concurrent dephasing and excitation. AB - Ultrashort echo-time imaging and sweep imaging with Fourier transformation are powerful techniques developed for imaging ultrashort T(2) species. However, it can be challenging to implement them on standard clinical MRI systems due to demanding hardware requirements. In this article, the limits of what is possible in terms of the minimum echo-time and repetition time with 3D radial gradient echo sequences, which can be readily implemented on a standard clinical scanner, are investigated. Additionally, a new 3D radial gradient-echo sequence is introduced, called COncurrent Dephasing and Excitation (CODE). The unique feature of CODE is that the initial dephasing of the readout gradient is performed during RF excitation, which allows CODE to effectively achieve echo-times on the order of ~0.2 ms and larger in a clinical setting. The minimum echo-time achievable with CODE is analytically described and compared with a standard 3D radial gradient-echo sequence. CODE was implemented on a clinical 3 T scanner (Siemens 3 T MAGNETOM Trio), and both phantom and in vivo human knee images are shown for demonstration. PMID- 21702065 TI - Human brain iron mapping using atlas-based T2 relaxometry. AB - Several in vivo quantitative MRI techniques have been proposed as surrogate measures to map iron content in the human brain. The majority of in vivo quantitative MRI iron mapping methods used the age-dependent iron content data based on postmortem data. In this work, we fused atlas-based human brain volumetry obtained on a large cohort of healthy adults using FreeSurfer with T(2) relaxation time measurements. We provide a brain atlas-based T(2) relaxation time map, which was subsequently used along with published postmortem iron content data to obtain a map of iron content in subcortical and cortical gray matter. We have also investigated the sensitivity of the linear model relating transverse relaxation rate with published iron content to the number of regions used. Our work highlights the challenges encountered on using the simple model along with postmortem data to infer iron content in several brain regions where postmortem iron data are scant (e.g., corpus callosum, amygdale). PMID- 21702066 TI - Reconstruction of fully three-dimensional high spatial and temporal resolution MR temperature maps for retrospective applications. AB - Many areas of MR-guided thermal therapy research would benefit from temperature maps with high spatial and temporal resolution that cover a large three dimensional volume. This article describes an approach to achieve these goals, which is suitable for research applications where retrospective reconstruction of the temperature maps is acceptable. The method acquires undersampled data from a modified three-dimensional segmented echo-planar imaging sequence and creates images using a temporally constrained reconstruction algorithm. The three dimensional images can be zero-filled to arbitrarily small voxel spacing in all directions and then converted into temperature maps using the standard proton resonance frequency shift technique. During high intensity focused ultrasound heating experiments, the proposed method was used to obtain temperature maps with 1.5 mm * 1.5 mm * 3.0 mm resolution, 288 mm * 162 mm * 78 mm field of view, and 1.7 s temporal resolution. The approach is validated to demonstrate that it can accurately capture the spatial characteristics and time dynamics of rapidly changing high intensity focused ultrasound-induced temperature distributions. Example applications from MR-guided high intensity focused ultrasound research are shown to demonstrate the benefits of the large coverage fully three dimensional temperature maps, including characterization of volumetric heating trajectories and near- and far-field heating. PMID- 21702067 TI - Optimizing signal-to-noise ratio of high-resolution parallel single-shot diffusion-weighted echo-planar imaging at ultrahigh field strengths. AB - The potential signal-to-noise ratio (SNR) gain at ultrahigh field strengths offers the promise of higher image resolution in single-shot diffusion-weighted echo-planar imaging the challenge being reduced T(2) and T(2) * relaxation times and increased B(0) inhomogeneity which lead to geometric distortions and image blurring. These can be addressed using parallel imaging (PI) methods for which a greater range of feasible reduction factors has been predicted at ultrahigh field strengths-the tradeoff being an associated SNR loss. Using comprehensive simulations, the SNR of high-resolution diffusion-weighted echo-planar imaging in combination with spin-echo and stimulated-echo acquisition is explored at 7 T and compared to 3 T. To this end, PI performance is simulated for coil arrays with a variable number of circular coil elements. Beyond that, simulations of the point spread function are performed to investigate the actual image resolution. When higher PI reduction factors are applied at 7 T to address increased image distortions, high-resolution imaging benefits SNR-wise only at relatively low PI reduction factors. On the contrary, it features generally higher image resolutions than at 3 T due to smaller point spread functions. The SNR simulations are confirmed by phantom experiments. Finally, high-resolution in vivo images of a healthy volunteer are presented which demonstrate the feasibility of higher PI reduction factors at 7 T in practice. PMID- 21702068 TI - Comparison of gadoxetic acid-enhanced dynamic imaging and diffusion-weighted imaging for the preoperative evaluation of colorectal liver metastases. AB - PURPOSE: To retrospectively compare the diagnostic accuracy for the detection of colorectal liver metastases between gadoxetic acid-enhanced MRI (EOB-MRI) and diffusion-weighted imaging (DWI) on 3.0 Tesla (T) system, and then to determine whether a combination of the two techniques may improve the diagnostic performance. MATERIALS AND METHODS: Forty-seven patients underwent MR imaging at 3.0T, including DWI (DWI set) and dynamic and hepatobiliary phase EOB-MRI (EOB set) for the preoperative evaluation of colorectal liver metastases. All suspicious metastases were confirmed by hepatic surgery. Two blinded readers independently reviewed three different image sets, which consisted of DWI set, EOB set, and combined set. The accuracy was assessed by the area (Az) under the alternative-free response receiver operating characteristic curve, and the sensitivity and positive predictive value (PPV) were calculated. RESULTS: We found a total of 78 confirmed colorectal liver metastases in 42 of 47 patients. Each reader noted higher diagnostic accuracy of combined set of EOB-MRI and DWI than DWI set and EOB set, without statistical significance. Regardless of the size of colorectal liver metastasis, each reader detected significantly more metastases on combined set than on DWI set, and PPV was significantly higher with DWI set than with EOB set or with combined set for one reader. CONCLUSION: EOB MRI was more useful for the detection of colorectal liver metastases, while DWI was more useful for their characterization. The combination of EOB-MRI and DWI showed significantly higher accuracy and sensitivity for the preoperative detection of small colorectal liver metastases than DWI. PMID- 21702069 TI - Spontaneous reports of assumed herbal hepatotoxicity by black cohosh: is the liver-unspecific Naranjo scale precise enough to ascertain causality? AB - PURPOSE: Causality assessment of cases with herbal hepatotoxicity represents a major regulatory challenge and included, in the past, the application of a diagnostic algorithm consisting of causality evaluation methods with either liver specific or liver-unspecific characteristics. To evaluate various causality assessing methods in cases with suspected herbal hepatotoxicity, two different scales were now used for reasons of comparison. METHODS: We used the liver specific scale of the updated Council for International Organizations of Medical Sciences (CIOMS) as well as the Naranjo scale that is not organ specific and therefore not liver specific. Both scales were applied to 22 cases of spontaneous reports with initially assumed herbal hepatotoxicity caused by black cohosh, used for menopausal symptoms. RESULTS: The analysis shows that causality was either unlikely (n = 6) or excluded (n = 16), using the updated CIOMS scale. There were various confounding variables: pre-existing liver diseases (n = 6) including genuine autoimmune hepatitis or alcoholic or cardiac hepatopathy; hepatotoxicity induced by interferon or fluoxetine (n = 2); marginally increased serum activities of alanine aminotransferase (n = 2) or gamma-glutamyltranspeptidase (n = 2) of unassessable causality; a mixed group consisting of unassessable cases (n = 6) and cases with questionable, poorly documented hepato-biliary diseases (n = 3); and rosuvastin-induced rhabdomyolysis (n = 1). These confounding factors were not recognized by the Naranjo scale. CONCLUSIONS: Structured hepatotoxicity specific causality assessment methods such as the updated CIOMS scale are the preferred tools for causality assessment of assumed herbal hepatotoxicity and should replace the liver-unspecific Naranjo scale. Applying the updated CIOMS scale to cases with initially assumed hepatotoxicity by BC, causality was now found either unlikely or excluded. PMID- 21702070 TI - The knowledge, perceptions and practice of pharmacovigilance amongst community pharmacists in Lagos state, south west Nigeria--flaws with the methodology. PMID- 21702071 TI - Neuroleptic malignant syndrome controversies revisited--what is the incidence of neuroleptic malignant syndrome? PMID- 21702073 TI - Underreporting of recognized adverse drug reactions by primary care physicians: an exploratory study. AB - PURPOSE: This study evaluated the magnitude of underreporting of adverse drug reactions (ADRs) and investigated possible reporting patterns according to patient characteristics and the type of reaction based on the integration of information obtained from primary care electronic medical records (EMRs) and the Spanish Pharmacovigilance System. METHODS: This investigation was a descriptive retrospective study analysing ADRs recorded in 2005 in the EMRs from six health centers in Zaragoza (Aragon, Spain) with a covered population of 126,838 subjects. The associations between the probability of reporting and the reaction and drug type were studied using logistic regression models adjusted by age and sex. RESULTS: The total number of ADRs recorded in the EMRs was 543, of which 65.7% were reported to the Spanish Pharmacovigilance System. Positive associations were found between the probability of reporting an ADR and advanced age of patients (OR for >=76 years = 2.0; 95%CI 1.1-3.6), involvement of the reproductive system (OR = 7.9; 95%CI 1.02-60.2) and involvement of psychiatric disorders (OR = 4.0; 95%CI 1.4-11.6). Negative associations were found between reporting an ADR and early age of patients (OR for 0-14 years = 0.2; 95%CI 0.1 0.6) and the use of antimicrobial drugs (OR = 0.6; 95%CI 0.4-0.9). CONCLUSIONS: This study tackles an important public health problem directly related to patients' safety and highlights the utility of EMRs for investigating the current significance of ADR underreporting. It also makes us think that primary care physicians seem to have selective reporting patterns based on their familiarity with the reaction type and the drug causing the reaction as well as on the age of patients. PMID- 21702074 TI - Bisphenol A and estrone-induced developmental effects in early chick embryos. AB - Endocrine disruptors, especially estrogenic substances, are thought to affect the reproduction and development of animals, including humans. We therefore assessed whether bisphenol A (BPA) or estrone (E1) had any adverse effects on chick embryogenesis. Fertilized eggs of white Leghorns were obtained within 24 h after laying. Embryos were administered 0.1, 1.0, and 10.0 mM BPA, and administered 10, 100 nM, and 1 MUM E1, and incubated for 48 h at 37 +/- 0.5 degrees C and >80% relative humidity with one rotation per hour. The embryos were excised, fixed in 70% ethanol and viewed under a stereomicroscope. Their morphological abnormalities and numbers of somites were recorded. There were no significant difference in the average number of somites in embryos administered BPA and controls. Abnormal embryogenesis, however, showed dose-related increases caused by BPA and E1. PMID- 21702075 TI - Acute toxicity and bioconcentration of fungicide tebuconazole in zebrafish (Danio rerio). AB - This research work investigated the bioconcentration of tebuconazole [(+/-)-alpha [2-(4-chlorophenyl)ethyl]-alpha-(1,1-dimethylethyl)-1H-1,2,4-triazole-1-ethanol] fungicide in zebrafish (Danio rerio) under laboratory conditions and a first order kinetic pesticide dissipation in the water. The concentrations of tebuconazole fitted to an equivalent nonlinear kinetic type model which allowed the calculation of the following parameters: bioconcentration factor (38.80 L kg( 1) ), time to reach maximum fish concentration (6 days), maximum concentration in fish (0.0075 MUg mg(-1) ), half-life in fish (24 days) and time needed for the fish to eliminate 95% of the maximum concentration (105 days). These calculations permitted the establishment of theoretical reference limit values for human consumption of fish and the establishment of safe limits for the water pesticide concentration. The data would also be useful in safe strategies associated with fishery activities that are conducted in aquatic regions close to crops using tebuconazole. The information will contribute to enlarge the tebuconazole toxicokinetics database of aquatic organisms. PMID- 21702076 TI - ISTA 14--impact of antibiotics from pig slurry on soil microbial communities, including the basidiomycete Trametes versicolor. AB - Livestock slurry containing antibiotics is a source of contamination of agricultural soils, with possible effects on soil function and micro-organisms. Extracellular oxido-reductases and hydrolases from the fungus T. versicolor and fungal growth were monitored in liquid cultures in the presence of tetracycline, lincomycine, sulfadiazine and ciprofloxacin for 10 days, in order to assess the suitability of these enzymes as biomarkers. Among the conditions of treatment, statistical analysis demonstrated an increase in manganese-dependent peroxidase after exposure to sulfadiazine at 1 mg/L when compared with the control. Acid phosphatase activity was decreased by lincomycine at 1 or 10 mg/L. Conversely, beta-glucosidase activity increased in the presence of this antibiotic at 10 mg/L. In Terrestrial Model Ecosystems spiked with contaminated pig slurry, lincomycine at the concentration of 8 or 80 MUg/kg dry soil, and ciprofloxacin at 250 ng/kg dry soil decreased the activity of soil dehydrogenase, when compared with a green slurry treatment, over 28-day incubations. Laccase activity was similarly decreased in the presence of the highest concentration of antibiotics. We determined bacterial and fungal biomasses using Q-PCR. Bacterial biomass was increased in the presence of lincomycine at 80 MUg/kg whatever the time of exposure, and to a lesser extent in the presence of ciprofloxacin at 250 ng/kg, but only at day 28. In contrast, both antibiotics, whatever their concentrations, did not modify fungal biomass in soil. In conclusion, we were unable to demonstrate important effects of antibiotics at concentrations found in the agricultural environment. PMID- 21702077 TI - Evaluation of the incidence of the G143A mutation and cytb intron presence in the cytochrome bc-1 gene conferring QoI resistance in Botrytis cinerea populations from several hosts. AB - BACKGROUND: Previous studies have shown that resistance of Botrytis cinerea to QoI fungicides has been attributed to the G143A mutation in the cytochrome b (cytb) gene, while, in a part of the fungal population, an intron has been detected at codon 143 of the gene, preventing QoI resistance. During 2005-2009, 304 grey mould isolates were collected from strawberry, tomato, grape, kiwifruit, cucumber and apple in Greece and screened for resistance to pyraclostrobin and for the presence of the cytb intron, using a novel real-time TaqMan PCR assay developed in the present study. RESULTS: QoI-resistant phenotypes existed only within the population collected from strawberries. All resistant isolates possessed the G143A mutation. Differences were observed in the genotypic structure of cytb. Individuals possessing the intron were found at high incidence in apple fruit and greenhouse-grown tomato and cucumber populations, whereas in the strawberry population the intron frequency was lower. Cultivation of QoI resistant and QoI-sensitive isolates for ten culture cycles on artificial nutrient medium in the presence or absence of fungicide selection showed that QoI resistance was stable. CONCLUSIONS: The results of the study suggest that a high risk for selection of QoI-resistant strains exists in crops heavily treated with QoIs, in spite of the widespread occurrence of the cytb intron in B. cinerea populations. The developed real-time TaqMan PCR constitutes a powerful tool to streamline detection of the mutation by reducing pre- and post-amplification manipulations, and can be used for rapid screening and quantification of QoI resistance. PMID- 21702078 TI - Hyperglycemia, hypoxia and their combination exert oxidative stress and changes in antioxidant gene expression: studies on cultured rat embryos. AB - INTRODUCTION: Hyperglycemia and hypoxia are well-known teratogens that may affect many animal species, including man. We hypothesize that a combination of hypoxia and hyperglycemia will increase embryonic damage produced by either factor individually. We investigated the interrelationship between hyperglycemia and hypoxia and their effects on genes involved in the balance of embryonic redox status. METHODS: Rat embryos (10.5-day-old) were cultured for 28 hr in culture medium with about 6 mg/ml of glucose and 20% oxygen (hyperglycemia), with 10% oxygen (hypoxia) and 2.4 g/ml glucose (normal) or a combination of both 6 mg/ml glucose and 10% oxygen. Antioxidant capacity was determined by activity and gene expression of antioxidant enzymes: Cu/Zn SOD, Mn-SOD, CAT, and GSH-px using real time PCR. RESULTS: Hyperglycemia, hypoxia, or their combination, decreased embryonic growth and induced a high rate (62-78%) of anomalies mainly of the nervous system, heart, and limbs. CAT mRNA and GSH-px mRNA were decreased in the malformed embryos exposed to hyperglycemia, to hypoxia or their combination. CAT mRNA was also decreased in the nonmalformed embryos subjected to hyperglycemia and hypoxia. Cu/Zn SOD mRNA was increased in all experimental embryos whether malformed or not, whereas Mn-SOD was drastically decreased. Total SOD and CAT like activity were changed very little in the experimental embryos compared to controls. CONCLUSIONS: Both hyperglycemia, hypoxia, and their combination reduce embryonic growth and development, induce embryonic anomalies, and modify the expression of the principle antioxidant genes. However, hypoxia does not seem to enhance the damaging effects of hyperglycemia except its effects of embryonic growth. PMID- 21702079 TI - The quality of privately banked cord blood. PMID- 21702080 TI - Titania-hydroxyapatite nanocomposite coatings support human mesenchymal stem cells osteogenic differentiation. AB - In addition to mechanical and chemical stability, the third design goal of the ideal bone-implant coating is the ability to support osteogenic differentiation of mesenchymal stem cells (MSCs). Plasma-sprayed TiO(2)-based bone-implant coatings exhibit excellent long-term mechanical properties, but their applications in bone implants are limited by their bioinertness. We have successfully produced a TiO(2) nanostructured (grain size <50 nm) based coating charged with 10% wt hydroxyapatite (TiO(2)-HA) sprayed by high-velocity oxy-fuel. On Ti64 substrates, the novel TiO(2)-HA coating bond 153* stronger and has a cohesive strength 4* higher than HA coatings. The HA micro- and nano-sized particles covering the TiO(2)-HA coating surface are chemically bound to the TiO(2) coating matrix, producing chemically stable coatings under high mechanical solicitations. In this study, we elucidated the TiO(2)-HA nanocomposite coating surface chemistry, and in vitro osteoinductive potential by culturing human MSCs (hMSCs) in basal and in osteogenic medium (hMSC-ob). We assessed the following hMSCs and hMSC-ob parameters over a 3-week period: (i) proliferation; (ii) cytoskeleton organization and cell-substrate adhesion; (iii) coating-cellular interaction morphology and growth; and (iv) cellular mineralization. The TiO(2) HA nanocomposite coatings demonstrated 3* higher hydrophilicity than HA coatings, a TiO(2)-nanostructured surface in addition to the chemically bound HA micron- and nano-sized rod to the surface. hMSCs and hMSC-ob demonstrated increased proliferation and osteoblastic differentiation on the nanostructured TiO(2)-HA coatings, suggesting the TiO(2)-HA coatings nanostructure surface properties induce osteogenic differentiation of hMSC and support hMSC-ob osteogenic potential better than our current golden standard HA coating. PMID- 21702081 TI - Use of Bayesian belief networks for dealing with ambiguity in integrated groundwater management. AB - In integrated groundwater management, different knowledge frames and uncertainties need to be communicated and handled explicitly. This is necessary in order to select efficient adaptive groundwater management strategies. In this connection, Bayesian belief networks allow for integration of knowledge, for engaging stakeholders and for dealing with multiple knowledge frame uncertainties. This is illustrated for the case of the Upper Guadiana Basin, Spain, where Bayesian belief networks with stakeholder involvement were used for dealing with the ambiguities related to sustainable groundwater exploitation. PMID- 21702084 TI - Spectroscopic detection of beta -sheet structure in nascent Abeta oligomers. AB - Deep-UV resonance Raman (UVRR) spectroscopy and circular dichroism (CD) were employed to study the secondary structure of Abeta(1-42) in fresh samples with increasing fractions of oligomeric peptide. A feature with a minimum at ~217 nm appeared in CD spectra of samples containing oligomeric Abeta(1-42). UVRR spectra more closely resembled those of disordered proteins. The primary difference between UVRR spectra was the ratio of the 1236 cm(-1) to 1260 cm(-1) amide III peak intensities, which shifted in favor of the 1236 cm(-1) band as the fraction of oligomeric peptide increased. PMID- 21702085 TI - Impact of obesity on functioning among women with systemic lupus erythematosus. AB - OBJECTIVE: Obesity is associated with high rates of disability in the general population. The nature of the relationship between obesity and disability in systemic lupus erythematosus (SLE), a condition with a high background rate of disability, is unknown. METHODS: Data were from 2 interviews, 4 years apart, of a longitudinal cohort of individuals with SLE (n = 716 women). Body mass index (BMI) was calculated from self-reported height and weight; obesity was classified by usual (BMI >=30) and revised (BMI >=26.8) definitions. Three measures of functioning were examined: the Short Form 36 (SF-36) Health Survey physical function (PF) subscale, Valued Life Activities (VLA) Disability Questionnaire, and employment. Multivariate analyses controlled for demographics, SLE duration and disease activity, glucocorticoid use, depression, and comorbidities. Prospective analyses also controlled for baseline function. RESULTS: At a BMI of >=30, 27.8% of the subjects were obese; at a BMI of >=26.8, 40.6% of the subjects were obese. Regardless of obesity definition, obese women exhibited poorer baseline function, with decrements ranging from 20-33% depending on the functional measure and obesity definition. With a BMI of >=26.8, the adjusted SF 36 PF scores were 4.3 points lower for obese women (P < 0.0001), VLA difficulty was 0.09 higher (P = 0.01), and odds of employment were 80% of nonobese women (odds ratio 0.8, 95% confidence interval 0.5-1.1). At the 4-year followup, women who were obese at baseline had poorer function and experienced greater functional declines. CONCLUSION: Obesity was associated with clinically significant negative effects on function, both concurrently and prospectively. This negative impact occurred at a lower BMI than is often considered problematic clinically. Because of the high rate of SLE-related disability, addressing preventable risk factors such as obesity may improve long-term SLE outcomes. PMID- 21702086 TI - Reproducibility of musculoskeletal ultrasound for determining monosodium urate deposition: concordance between readers. AB - OBJECTIVE: Criteria for sonographic diagnosis of monosodium urate (MSU) crystal deposition have been developed, but the interreader reproducibility of this modality is not well established. We therefore assessed agreement using a systematic approach. METHODS: Fifty male subjects ages 55-85 years were recruited during primary care visits to an urban Veterans Affairs hospital, and were assessed by musculoskeletal ultrasound (US) of the knees and first metatarsophalangeal (MTP) joints to evaluate for the double contour sign and tophi as evidence of MSU crystal deposition. Images were read by 2 blinded rheumatologists trained in musculoskeletal US, and the degree of concordance was determined for individual subjects, total joints, femoral articular cartilage (FAC), and first MTP joints. Subjects were further categorized into 3 diagnostic groups: gout, asymptomatic hyperuricemia (no gout, serum uric acid [UA] >=6.9 mg/dl), and controls (no gout, serum UA <=6.8 mg/dl), and reader concordance within these 3 groups was assessed. RESULTS: We observed almost perfect agreement between readers for 1) individual subjects (yes/no; n = 50, 100% agreement, kappa = 1.000), 2) total joints (n = 200, 99% agreement, kappa = 0.942), 3) FAC (n = 100, 99% agreement, kappa = 0.942), and 4) first MTP joints (n = 100, 99% agreement, kappa = 0.942). Furthermore, findings by side (right/left) and diagnostic group (gout, asymptomatic hyperuricemia, control) showed substantial to almost perfect concordance for all measures. MSU deposition was seen most commonly in gout patients, and deposition was also seen in some subjects with asymptomatic hyperuricemia, but in only 1 control. CONCLUSION: Musculoskeletal US is reliable for detecting MSU deposition in FAC and first MTP joints in gout and asymptomatic hyperuricemia. PMID- 21702088 TI - Collisions and chronic pain: The solution is finding the problem. Comment on the article by Jones et al. PMID- 21702087 TI - Quadriceps weakness, patella alta, and structural features of patellofemoral osteoarthritis. AB - OBJECTIVE: To determine the relationship between quadriceps weakness and cartilage damage and bone marrow lesions (BMLs) in the patellofemoral joint (PFJ) and if this relationship is modified by patella alta. METHODS: The Multicenter Osteoarthritis Study is a cohort study of persons ages 50-79 years with or at risk of knee osteoarthritis. Concentric knee extensor strength was measured using an isokinetic dynamometer. Patella alta was measured using the Insall-Salvati ratio (ISR) on the lateral radiograph, and cartilage damage and BMLs were graded on magnetic resonance imaging in the PFJ. We determined the association between quadriceps weakness with cartilage damage and BMLs in the PFJ among knees with (ISR >=1.2) and without (ISR <1.2) patella alta using multiple binomial regression. RESULTS: A total of 807 knees were studied (mean age 62 years, body mass index 30 kg/m(2) , ISR 1.10) and 64% were from women. Compared with the knees in the highest strength tertile, those in the lowest had 10.2% (95% confidence interval [95% CI] 3, 18), 9.1% (95% CI 2, 16), and 7.1% (95% CI 1, 13) higher prevalence of lateral PFJ cartilage damage, medial PFJ cartilage damage, and lateral PFJ BMLs, respectively. The association between quadriceps weakness with cartilage damage and BMLs was not different between knees with and without patella alta in the lateral PFJ. CONCLUSION: Quadriceps weakness was associated with PFJ cartilage damage and BMLs. While both patella alta and quadriceps weakness were associated with PFJ damage, the combination of the two was not associated with more damage than either of these factors alone. PMID- 21702089 TI - A 60-year-old woman with headache, confusion, and hallucinations. PMID- 21702090 TI - Very early improvements in the wrist and hand assessed by power Doppler sonography predicting later favorable responses in tocilizumab-treated patients with rheumatoid arthritis. AB - OBJECTIVE: To investigate the response of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) by ultrasonographic evaluation of changes in the wrist and hand, and to determine whether such assessments during early TCZ treatment predict later clinical outcome. METHODS: Thirty-two RA patients about to receive TCZ treatment were examined by ultrasound at baseline and after 2 weeks using the Outcome Measures in Rheumatology Clinical Trials semiquantitative scoring of 22 joints (both wrists, proximal interphalangeal joints 1-5, and metacarpophalangeal joints 1-5) as well as clinical and laboratory variables, leading to a calculation of composite indexes. The aim was to determine whether methotrexate treatment and clinical, laboratory, and ultrasonographic evaluation after 2 weeks of TCZ treatment predict treatment outcome at 24 weeks, as assessed by the Disease Activity Score in 28 joints (DAS28). RESULTS: Changes of ultrasound scores after 2 weeks were found to be correlated with changes in DAS28 at 24 weeks (r = 0.545-0.622, P < 0.05). The change of sum power Doppler scores after 2 weeks of treatment was identified as the variable most closely correlated with the change in DAS28 at 24 weeks (r = 0.622, P < 0.05). CONCLUSION: The best predictors after 2 weeks of favorable treatment outcome at 24 weeks were improved power Doppler scores. Methotrexate treatment and composite indexes did not predict favorable treatment outcome in this study. PMID- 21702091 TI - [Pathomorphosis of the mammary gland tissue during radical interventions using high-frequency electrosurgical welding]. AB - High-frequency electric welding of a live soft tissues (HFEW LST) is applied widely in all surgical specialties. Its application in surgery of mammary gland cancer constitutes a perspective trend. The impact of HFEW LST and monopolar electrocoagulation on tissues while performing radical operations in patients women for mammary gland cancer was studied up. Basing on analysis of pathomorphological investigations data, the possibility and perspective of the welding technologies application, while performing radical operations on mammary glands, were established. PMID- 21702092 TI - [Endoscopic surgery of the duodenal large papilla tumors]. AB - The results of endoscopic papillectomy, performed in 17 patients for tumors of duodenal large papilla in 2005-2010 yrs, were studied up. In 7 (41.2%) patients complications have occurred, including hemorrhage--in 4 (23.5%). All the patients are alive. PMID- 21702093 TI - [Hypothermal sanation in acute peritonitis]. AB - Comparative analysis of treatment of 78 patients, suffering an acute peritonitis, was conducted for studying of practical significance of hypertonic peritoneal enteric sanation (PES). In 40 patients (control group) the conventional methods of treatment were used and in 38 (the main group)--the treatment was conducted on the PES background. Such clinical indices, as the patient state, body temperature, respiration rate, pulse and intestinal peristalsis, while the PES application, have had normalized earlier. As well the raising of the survival capacity of an organism, suffering critical state, was noted. Relaparotomy was conducted in 17.5% of patients control group and in 7.9% of the main; the complications rate had constituted accordingly 27.5 and 15.7%, mortality - 22.5 and 15.8%, the stationary treatment duration--(17.2 +/- 1.02) and (12.4 +/- 0.7) days. Due to its simplicity the method may be applied in every clinic, not depending on its equipment. PMID- 21702094 TI - [Individualized prognosis of the infectious acute pancreatitis]. AB - The results of treatment of 125 patients, suffering severe forms of an acute pancreatitis (AP) are analyzed. Basing on the patients complex examination data, using the method of logistic regression, a mathematic model of individualized prognosis of the AP infected form presence after their admittance to hospital, was elaborated. PMID- 21702095 TI - Re: Pergolizzi et al., 2010: the role of urine drug testing for patients on opioid therapy. PMID- 21702096 TI - Myrmecomorphomania. AB - Ants are so abundant that mimicking them has become a profitable way of life for many species. Florian Maderspacher and Marcus Stensmyr take a trip into the world of ant mimicry PMID- 21702097 TI - Iva Tolic-Norrelykke. PMID- 21702098 TI - Renewable energy: Making fuels for the future. PMID- 21702099 TI - Mini-MCR issue and proceedings of SCS-09, Second International Symposium on Combinatorial Sciences in Biology, Chemistry, Catalysts and Materials. September 19-22, 2001. Beijing, China. PMID- 21702100 TI - Proceedings of the 4th International Breast Cancer Conference (IBCC4). January 30 February 1, 2010. Paris, France. PMID- 21702101 TI - Safe and sound. PMID- 21702102 TI - [Some adjuvants added to local anesthetics improve the duration and quality of epidural anesthesia]. PMID- 21702103 TI - [Mechanisms of postoperative pain]. PMID- 21702104 TI - [Neuroanesthesia: bench to bedside]. PMID- 21702105 TI - [Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice]. PMID- 21702106 TI - [Correct knowledge of invasive manipulations focusing on minimally invasive central venous catheterization]. PMID- 21702107 TI - [Balance between glutamatergic excitation and GABAergic inhibition in the brain regulates hypnotic and amnestic actions of general anesthetics, and pain thresholds]. PMID- 21702108 TI - Ask the doctor. I am 53. I've had fibroids for some time but have experienced heavy menstrual bleeding lately. A recent ultrasound showed fibroids and polyps. My doctor presented me with three choices: do nothing and monitor the situation with ultrasounds (which have been part of my annual gynecological exams for a while); get a hysterectomy; or get a new procedure, which I think involves freezing the fibroids and polyps. I am not sure what to do. PMID- 21702109 TI - Ask the doctor. I have started noticing more coconut oil at the grocery store and have heard it is better for you that a lot of other oils. Is that true? PMID- 21702111 TI - Joint replacement surgery: how to avoid weight gain afterward. PMID- 21702110 TI - Ask the doctor. My doctor recently advised me to start taking an 81-mg aspirin once a day. I am physically active 62-year-old and have been a vegetarian-mostly vegan-for 35 years. My BMI is less than 24, my HDL is over 70, and my Framingham risk score is 8%. My only problems are systolic blood pressure in the 130s and an occasional episode of arrhythmia. I'd really rather not take aspirin. Am I being foolish in questioning my doctor's advice? PMID- 21702112 TI - Scoliosis: its not only a children's condition. This spinal deformity can also cause pain in adults. PMID- 21702113 TI - Insulin therapy: friend, not foe. It's time to dispel common myths about insulin treatment for people with type 2 diabetes. PMID- 21702114 TI - What men should know about overactive bladder. PMID- 21702116 TI - I've been walking every day for a month, but my blood pressure is not going down. What's going on? PMID- 21702115 TI - Off-label prescribing explained. Why your doctor may recommend meds that aren't FDA-approved for your condition. PMID- 21702117 TI - [Treatment of chronic myeloid leukemia with imatinib]. PMID- 21702118 TI - [Mechanism and overcome against drug resistance to imatinib for treatment of chronic myeloid leukemia]. PMID- 21702119 TI - [Changes of the storage stability of ketones collected on activated coconut carbon in environmental ketone measurement]. AB - The storage stability for six ketones was studied on four activated coconut carbons commonly used for air sampling in Japan. As the ratios of the enol form of cyclohexanone and methyl ethyl ketone are high, the ketones showed drastic losses during storage (storage stability), which could be attributed to catalytic oxidation and chemisorption. Moreover, adsorbed water caused a further decrease in recoveries of the ketones from the carbons. Because keto-enol tautomerism and hydration are catalyzed by acid or base, the relationships between the recoveries of the ketones from the carbons and pH in the aqueous solution of the carbons and the ignition residue of the carbons were investigated. As a result, the intensity of acidity or basicity of the carbons correlated with the loss of the ketones during storage, but the ignition residue of the carbons did not. Therefore, these results lead us to the conclusion that a more neutral coconut carbon is more suitable for the collection of aliphatic ketones, and activated coconut carbons are not suitable for cyclohexanone. PMID- 21702120 TI - [Management of patients with bronchial foreign bodies]. AB - The aspiration of foreign bodies into the bronchus frequently occurs in children as well as in elderly people. Foreign bodies in the airway not only cause chronic cough and pneumonia, but also result in life-threatening conditions, such as dyspnea and cyanosis. This report presents the clinical characteristics of 6 patients with bronchial foreign bodies who were treated between 2006 and 2010, including 4 male and 2 female patients. The age of the patients ranged from 8 to 83 years old. Foreign bodies were located in the right bronchial tree in all the patients. Chest X-rays showed pneumonia or atelectasis in 5 out of 6 patients. The foreign bodies were an artificial teeth or a tooth in 5 patients, and a fish bone in 1 patient. Five patients had fiberoptic bronchoscopy under local anesthesia, although an 8-year-old girl required general anesthesia with a laryngeal mask. Surgery was needed in only one case. Bronchial foreign bodies present a large range of symptoms, from trivial symptoms to irreversible damage to the bronchus and the lung, which can be life threatening. Nonspecific respiratory symptoms may be mistakenly attributed to other medical diagnoses unless there is a clear history of aspiration. However, an early diagnosis is very important, because inflammatory granulation due to long-term impaction of foreign bodies makes its removal difficult. PMID- 21702121 TI - [Filtration performance of dust respirators against nanoparticles]. AB - It is necessary to consider protective measures, such as dust respirators, against the inhalation of nanoparticle aerosols. Industrial hygienists and workers handling nanomaterials are concerned about the filteration performance of dust respirators in protecting against nanoparticles, the size of which is less than 100 nm. We developed a filteration performance evaluating system using titanium dioxide nanoparticle aerosols ranging from 15 to 220 nm in diameter. The system, which includes two models of DS1 class and four models of DS2 class, was used to measure the collection efficiencies of dust respirators. These tested dust respirators had been certified by the Japanese government. In the dust respirators, there were no samples that showed less collection efficiency than the standard certified collection efficiency (80% for DS1 and 95% for DS2). PMID- 21702122 TI - [Progress in B-cell targeting therapy for the treatment of systemic lupus erythematosus]. AB - Systemic lupus erythematosus (SLE) is a representative systemic autoimmune disease characterized by multi-organ manifestation. Although the etiology of the disease remains unclear, the activation of autoreactive T cells and production of antibodies by B cells are mainly involved in the pathological processes of the disease. B cell depletion therapy using anti-CD20 antibody rituximab has shown a rapid onset of effect and prolonged efficacy in refractory SLE, emerging as a promising new agent for the treatment of SLE. We also reported that rituximab is safe for the treatment of active SLE in a domestic pilot study and a multi-center phase I/II clinical trial. In regard to the mechanism underlying the efficacy of rituximab, it has been reported that the drug caused peripheral depletion of memory B cells and plasma cells. We found that rituximab efficiently depleted naive and memory B cells and decreased co-stimulatory molecules on B cells and memory T cells. Recovered B cells in patients in long-term remission were dominated by naive B cells with an increased ratio of naive T cells, and co stimulatory molecules remained low. These findings indicate that the reconstitution of the B cell compartment results in the inhibition of T cell activation by memory B cells, which leads to the sustained remission of SLE by rituximab. Although the recent placebo-controlled trials such as EXPLORER with rituximab in SLE did not achieve satisfactory results, other evidence continues to be published in support of the notion that B cell depletion could be useful for refractory SLE. In addition, other B-cell targeted therapies, such as CD22 and agents that interrupt B-T-cell interaction, including belimumab, also have potential of the therapeutic application. PMID- 21702123 TI - [A case of dyshidrosiform pemphigoid]. AB - We report a case of dyshydrosiform pemphigoid. Multiple small bullae were noticed in the bilateral hands and feet of an 85 year old Japanese male about 1 month before admission to hospital, and these lesions gradually worsened and expanded generally. Clinical appearance on the initial examination showed a collection of erosions, bullae, and pustules with haemorrhagic pompholyx. Serum anti-BP180 antibody index was more than 150. Histopathologic appearance of the bullous leision revealed a subepidermal bulla with an inflammatory infiltrate and fibrinous exudate, with aggregated eosinophils, neutrophils, and lymphocytes in the upper dermis. In direct immunofluorescence, the epidermal basement membrane was stained strongly for complement C3 and weakly for IgG. Based on these features, especially from the particular clinical aspects, we finally diagnosed one subtype of bullous pemphigoid, namely dyshidrosiform pemphigoid. Although he got better by orally taking steroids, the eruptions recurred just after tapering off. Thereafter, he died due to worsened general condition partly complicated by pancreatitis. PMID- 21702124 TI - [Physical characteristics of female nursing students in the first year at university]. AB - We measured the physique and physical fitness of 528 first year female nursing students in order to develop a plan for the health education and health promotion of nursing students. We also conducted a questionnaire survey of their health condition and athletic activities. The results showed that, compared to the national average for the same age group, the female nursing students had lower body weight, greater agility, and less muscle strength. In addition, they had little experience of athletic activities in junior and senior high school, and a high percentage of them were concerned about their physical fitness. PMID- 21702125 TI - [How to reduce unnecessary orders of laboratory tests]. AB - The medical insurance system in Japan has been focusing on how to reduce the annual increases in medical expenses. In this context, the circumstances in the laboratory department in large hospitals have been growing more strict. Therefore, medical staff working in large hospitals need to know how to reduce the expenditure consumed in laboratory tests. In this paper we report economical loss resulted from physicians' excessive test-orders and suggest how to manage the problem. PMID- 21702126 TI - [A case of late-onset schizophrenia with the predominant symptom of delusional perception of the color of food]. AB - Herein, we report the case of a woman in her late 60s with late-onset schizophrenia in which the predominant symptom was delusional perception of the color of food based on a delusional "rule of colors" system constructed by the patient. This paranoid type schizophrenia is considered a core type of schizophrenia in which first-rank Schneiderian symptoms are initially exhibited. After approximately four years, the chronic phase, characterized by a poor social function, is reached. In this respect, the main psychopathological characteristics of the present case of late-onset schizophrenia are the same as those of typical cases of schizophrenia in young patients. In this study, the patient's delusional "rule of colors" system is analyzed according to Matussek's theory of delusional perception. PMID- 21702127 TI - [Schizophrenia and idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome)]. AB - Idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome, or GS) is a relatively common congenital hyperbilirubinemia occurring in 3-7% of the world's population. It has been recognized as a benign familial condition in which hyperbilirubinemia occurs in the absence of structural liver disease or hemolysis, and the plasma concentration of conjugated bilirubin is normal. Recently, it has been reported that unconjugated bilirubin exhibited neurotoxicity in the developing nervous system. The 'neurodevelopmental hypothesis' of schizophrenia proposes that an as-yet-unidentified event occurs in utero or during early postnatal life. We have observed that patients suffering from schizophrenia frequently present with an increased unconjugated bilirubin plasma concentration when admitted to the hospital. As a result, we noticed a relationship between unconjugated bilirubin and the etiology of, and vulnerability to, schizophrenia. Our reported findings suggest that there are significant biological and clinical character differences between schizophrenic patients with and without GS. From the viewpoint of the heterogeneity of schizophrenia, there may be a poor outcome for the subtype of schizophrenia with GS. PMID- 21702128 TI - [Development of new therapeutic drugs based on the pathophysiology of schizophrenia]. AB - Cognitive deficits in schizophrenia are the core symptoms of this disorder, and are strongly correlated with decreased QOL in patients. Antipsychotic drugs have been used therapeutically for positive symptoms, including hallucinations and delusions. However, many patients treated with antipsychotic drugs fail to recover from cognitive deficits. Therefore, a number of new therapeutic drugs for cognitive deficits in schizophrenia are currently being developed around the world. A number of studies suggest that nicotine, a major component of cigarettes, could improve cognitive deficits in patients with schizophrenia. Accumulating evidence suggests that the alpha7 subtype of nicotinic receptors (alpha7 nAchRs) play a role in the pathophysiology of schizophrenia, as well as deficits in auditory evoked potential P50 in patients with schizophrenia. We have reported that the antiemetic drug tropisetron (alpha7 nAchR agonist and 5-HT3 receptor antagonist) improved auditory P20-N40 deficits in DBA/2 mice, and cognitive deficits after administration of the NMDA receptor antagonist phencyclidine. Furthermore, a single administration of tropisetron was associated with improved auditory P50 deficits in non-smoking patients with schizophrenia. Moreover, a randomized, double-blind, placebo-controlled study demonstrated that tropisetron significantly improved auditory P50 deficits and attention deficits in patients with schizophrenia. In this paper, the author will discuss the therapeutic potential of alpha7 nAChR agonists for cognitive deficits in patients with schizophrenia. PMID- 21702129 TI - [Improvements in spontaneity and social functioning in patients with schizophrenia after cognitive training]. AB - Cognitive rehabilitation approaches are in the spotlight as a novel strategy for promoting social participation in patients with schizophrenia, as the connection between cognitive deficits and functional outcomes in schizophrenia has been consistently demonstrated over the last decade. Divergent thinking is typically applied when someone is confronted with questions that do not have a single fixed answer. We identified divergent thinking deficits in patients with schizophrenia using qualitative measures involving idea and design fluency tests, and found that the impairment in generating high-quality responses on divergent thinking tasks was an important determinant of poor community functioning among patients. Based on our findings, we suggested that divergent thinking was an important neurocognitive skill that deserves consideration as a potential target for intervention, and developed a training program specifically for divergent thinking deficits in patients with schizophrenia. We evaluated the effects of this program on measures of divergent thinking (e.g., fluency measures), negative symptoms, and social functioning. After the training program, participants in the divergent thinking program had significantly greater improvements on measures of idea fluency, negative symptoms, and interpersonal relations than the participants in the control program. These results suggest that interventions for divergent thinking in patients with schizophrenia may lead to improvements in patients' social functioning. In recent years, intrinsic motivation has become a focus of attention as a critical mechanism for explaining the relationship between neurocognition and psychosocial functioning in patients with schizophrenia. Divergent thinking is thought to be relevant to spontaneity and intrinsic motivation. The training program for divergent thinking deficits may have achieved its effects on negative symptoms and social functioning through an improvement in spontaneity and intrinsic motivation. The potential of the cognitive training program to enhance patients' quality of life is discussed. PMID- 21702131 TI - [Training program for clinical psychologists in general hospital settings]. AB - Physicians in hospitals are so exhausted that mental healthcare providers other than physicians, such as psychologists, might be necessary. A clinical education program for psychologists in general hospitals has been developed. Applicants should be at Level 2 of Stoltenberg & McNeil's IDM (Integrated Development Model) model. Seven domains of objectives are introduced. Core competencies are multi dimensional knowledge, understanding dynamics and collaborating, and communication skills with challenging patients. Sustainable education strategies and evaluation methods are discussed. A TV-based education program is useful for the purpose of acquiring general medical knowledge. PMID- 21702130 TI - [Promoting "successful aging" in community psychiatric care]. AB - Recently, patients with schizophrenia have been progressively aging in a way similar to that of the general population. In Japan, community mental health care has become more active in the context of the policy of promoting the discharge of patients from psychiatric hospitals. Patients with chronic schizophrenia who have been discharged are already approaching old age. "Successful aging" may be a key concept in their community-based psychiatric care. Successful aging does not emphasize a loss of youth, but focuses on gains and growth achieved with aging. In the Sasagawa Project, 78 patients with schizophrenia were gradually transferred from a psychiatric hospital to a community dwelling. Eight years have passed since the project began. Elder patients (>60 years old) showed stable psychiatric symptoms and were rarely readmitted to the psychiatric ward. They were, however, more often readmitted to hospital due to physical disease (for example, lifestyle-related disease or fracture) than were middle -aged patients (<60 years old). Elder patients cannot simultaneously receive mental health services under the Services and Support for Persons with Disabilities Act, and long-term care under the Long-Term Care Insurance Act. We hope that the government will establish a new system and institutions that address the needs of elder psychiatric patients. Elder patients with schizophrenia have an optimistic view of their own aging, but they are not sufficiently prepared for old age. In the mental health care of aging psychiatric patients, it is necessary to not only control psychiatric symptoms, but also promote and improve their quality of life by maintaining their ability to continue living in the community (for example, by supporting their preparations for old age). PMID- 21702132 TI - [Collaboration between psychiatrists and clinical psychologists for efficient delivery of cognitive behavioral therapy in Japan]. AB - Cognitive-behavioral therapy (CBT) is an evidence-based psychotherapy which leads to recovery in over 50% of patients with depression and anxiety disorders. It is, therefore, the first-line treatment for those disorders. In April 2010 we began a beacon project, called "Increasing Access for Psychological Therapies" (IAPT), in Chiba, Japan. In the Chiba IAPT project, we lead the cognitive-behavioral therapy training and provide individual CBT supervision, based on the system of IAPT in the UK. It is important to differentiate between counseling services and psychiatric services under the Medical Practitioners Act. To improve mental health in Japan, we will establish national standards for certification of clinical professionals trained in the science and art of CBT, and develop a law related to national licensing of cognitive-behavioral therapists. PMID- 21702133 TI - [Kidney and systemic diseases]. PMID- 21702134 TI - [I. Metabolic disease: 1. Diabetic nephropathy]. PMID- 21702135 TI - [I. Metabolic disease: 2. Hyperuricemia and chronic kidney disease]. PMID- 21702136 TI - [I. Metabolic disease: 3. Glycogen storage diseases]. PMID- 21702138 TI - [II. Autoimmune disease: 1. Systemic lupus erythematosus]. PMID- 21702137 TI - [I. Metabolic disease: 4. Lipid metabolism abnormalities]. PMID- 21702139 TI - [II. Autoimmune disease: 2. Renal disturbance in rheumatoid arthritis]. PMID- 21702140 TI - [II. Autoimmune disease: 3. Polyarteritis nodosa and Wegener's granulomatosis]. PMID- 21702141 TI - [II. Autoimmune disease: 4. ANCA associated gulomerulonephritis/nephritis]. PMID- 21702142 TI - [II. Autoimmune disease: 5. Sjogren's syndrome]. PMID- 21702143 TI - [II. Autoimmune disease: 6. Henoch-Schonlein purpura nephritis]. PMID- 21702144 TI - [III. Paraproteinemia: 1. Multiple myeloma]. PMID- 21702145 TI - [III. Paraproteinemia: 2. Amyloidosis]. PMID- 21702146 TI - [III. Paraproteinemia: 3. Cryoglobulinemia]. PMID- 21702147 TI - [IV. Others: 1. Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)]. PMID- 21702148 TI - [IV. Others: 2. Glomerulonephritis associated with viral hepatitis]. PMID- 21702149 TI - [IV. Others: 4. Human immunodeficiency virus associated renal dysfunction]. PMID- 21702150 TI - [IV. Others: 5. MRSA-associated glomerulonephritis]. PMID- 21702151 TI - [IV. Others: 6. Malignancy and kidney injury]. PMID- 21702152 TI - [IV. Others: 7. Drug induced nephrotoxicity]. PMID- 21702153 TI - [Discussion meeting on recent progress of systemic diseases in chronic kidney disease]. PMID- 21702154 TI - [Solitary fibrous tumor (SFT) of the pleura associated with hypoglycemia at the second recurrence]. PMID- 21702155 TI - [A case of purpura fulminans caused by sepsis with Streptococcus pneumoniae]. PMID- 21702156 TI - [A case of autoimmune pancreatitis diagnosed at the time of relapse which happened twelve years after the initial onset]. PMID- 21702157 TI - [Relapsing Helicobacter cinaedi bacteremia in a non-immunocompromised patient]. PMID- 21702158 TI - [A case of fever of unknown origin that diagnosed as early-phase of Takayasu arteritis by FDG-PET/CT]. PMID- 21702159 TI - [A case of acute renal failure due to interstitial nephritis likely induced by rabeprazole]. PMID- 21702160 TI - [Recent advances in sleep apnea]. PMID- 21702161 TI - [Current status of clinical infectious diseases education: what is needed for effective education in infectious diseases in a global era?]. PMID- 21702162 TI - [Cutting edge of interventional endoscopy in pancreaticobiliary diseases]. PMID- 21702163 TI - [Roles of the cAMP sensor Epac2A in insulin secretion]. PMID- 21702164 TI - [Stroke]. PMID- 21702165 TI - [Report from the 10th Tokai Chapter Educational Seminar; remarkable infectious disease]. PMID- 21702166 TI - [A case with anterior chest oppression complicated with various symptoms]. PMID- 21702167 TI - [Diagnosis at a glance]. PMID- 21702169 TI - [The board of medical specialties system in The Japanese Society of Internal Medicine and training curriculum in internal medicine]. PMID- 21702168 TI - [Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial]. PMID- 21702170 TI - [Clinical outcomes cochlear reimplantation]. AB - To clarify the clinical features of cochlear reimplantation and surgical changes in auditory performance, we retrospectively reviewed 10 of 252 cochlear implantation surgeries-6 adults and 4 children-among 129 children and 123 adults done between April 1987 and May 2009. Mean duration from initial implantation to reimplantation was 50.3 months in children and 89 months in adults, most commonly due to hard failure and implant exposure/infection (33%) in children and to hard failure (75%) in adults. The initial device implanted was the Nucleus multichannel implant (CI22M, CI24M, or CI24R). The second implant in 7 was the same or an upgrade of the same manufacturer's device, and in 2 children the HiRes 90K (Hifocus 1j) and in 1 adult the Clarion 1.2. Full initial and reinsertion succeeded in 8 cases but reinsertion proved difficult in 2 due to severe intracochlear granulation and osteoneogenseis. Auditory performance analyzed in 7 cases was mostly equal to or better than before reimplantation, although differences were not statistically significant. Reinsertion is rarely difficult, but electrode choice is important in preparing for difficult reinsertion. Post reinsertion auditory performance is satisfactory with some exceptions. PMID- 21702171 TI - [A case report on cervical neuroblastoma with ataxia]. AB - We present a case of pediatric primary cervical neuroblastoma (NB), which is extremely rare. A 3-year-old girl with ataxia but no nasal obstruction, dysphagia, or stridor was diagnosed with cervical NB. Diagnostic results including clinical chemistry, full blood count, and serology, were normal. Ataxia worsened within a few days after onset and was not cured by steroids or intravenous immunoglobulin, delaying a definite diagnosis until a tumor was detected. Opsoclonus-myoclonus syndrome is typified by opsoclonus with myoclonus and ataxia, primarily associated with neuroblastoma. Brain stem cell and cerebellum dysfunction is thought to be due to an autoimmune mechanism. Following chemotherapy and selective neck dissection, the girl has had no recurrence or adverse sequelae. Ataxia disappeared during chemotherapy. We suggest that neuroblastoma should be considered in any child with unexpected by prolonged ataxia. PMID- 21702172 TI - [Clinical review of 8 patients with tuberculous peritonitis]. AB - OBJECTIVE: With the progress of anti-tuberculous therapy, tuberculous peritonitis (TBP) has become a rare manifestation of active tuberculosis. Its early diagnosis is difficult due to lack of pathognomonic findings and specific symptoms. However, early diagnosis is important for effective treatment and for reducing fatality. MATERIALS AND METHOD: We retrospectively reviewed medical records of eight patients who were hospitalized with TBP in National Hospital Organization Omuta National Hospital during the periods between 2001 and 2009. RESULTS: Three patients were males and five were females. The age of the patients ranged between 28 and 80 years old (average 67.3 years). The most common presenting findings were abdominal distention seen in four patients and loss of appetite in five patients. Blood examination suggested that most patients were in poor nutrition. Three patients were diagnosed based on bacteriological examination, two based on histopathological findings of caseating granulomas, two based on the elevation of adenosine deaminase activity in ascitic fluid and one based on clinical diagnosis. The most common CT findings were thin lines along mesenteric vessels representing thickened mesenteric leaves and smooth uniform peritoneal thickening. Most patients were treated with isoniazid, rifampicin and ethambutol for 9 months with/without pyrazinamide initially. Seven patients completed anti tuberculous therapy successfully and were cured. However, one patient died of the deterioration of tuberculosis. CONCLUSION: TBP should be considered for diagnosis, in patients with non-specific abdominal symptoms. Adenosine deaminase activity in ascitic fluid and CT images are considered to be useful for the diagnosis of TBP in patients in whom bacteriological and histopathological examinations are difficult to perform. PMID- 21702173 TI - [A study on preventive measures against tuberculosis in care facilities for the elderly in a Tokyo metropolitan district]. AB - OBJECTIVES: To promote early detection of tuberculosis (TB) in care facilities for the elderly, we studied the pattern of occurrence of TB cases and the preventive measures taken against TB at the care facilities in a Tokyo Metropolitan District in 2008. METHODS: Registration cards and contact examination records of the public health center of the district were reviewed. We also made a self-administered questionnaire survey to gather information about the preventive measures against TB at 40 facilities in our district. (The questionnaire response rate was 100%.) RESULTS: A total of 4 TB cases were reported in 3 facilities in the study period. Two of the 3 facilities were fee based homes. Adequate implementation of preventive measures against TB was not found at any of these 3 facilities. Secondary infection to care workers was also reported. Of the 40 facilities, 90% undertook annual routine TB examination with radiophotography. However, several facilities did not perform comparative X-ray readings, and had residents who did not comply with the examination. In regard to daily health monitoring, many facilities did not check for fever and/or respiratory symptoms. Many fee-based homes did not implement sufficient preventive measures against TB. CONCLUSION: In the care facilities for the elderly in this district, the TB prevention program was not adequately implemented, so that new TB cases were not rare, leading to the transmission of infection to the facility staff. Especially, fee-based homes' practice was poor. It is an important mission of a public health center to provide these facilities in the district with information about current TB problem and its prevention, as well as technical support for it. PMID- 21702174 TI - [Treatment and isolation of non-adherent and/or infectious tuberculosis patients under the infectious diseases control law]. AB - OBJECTIVES: To clarify the present situation regarding isolation of tuberculosis (TB) patients who do not comply with hospital treatment or adhere to treatment. METHODS: A mailed questionnaire survey to 252 hospitals having tuberculosis beds. RESULTS: Answers were returned from 160 hospitals. Answers from 146 hospitals, excluding 14 that had closed their TB wards, were analyzed. Experiences of defaulters were reported from 35 hospitals. Seven of these defaulting patients were homeless, 4 were foreign-born, and 2 had other problems, but for 15 cases no problem was known. Fourteen hospitals reported that the burden of medical fee payment was one of the causes of defaulting. Defaulting occurred in hospitals even having close cooperation with public health centers over DOTS. For chronic excretors under long-term hospitalization, 31 (20.4%) hospitals allow home isolation, whereas 78 (51.3 %) refuse discharge from the TB ward even for a short period. However, 69 (45.4%) answered that home isolation could be allowed under certain conditions. Only 17 (11.2%) think that current TB hospitals are appropriate for long-term hospitalization, and 63 (41.4%) feel that the improvement of the facilities for that purpose is needed. Seventy-two (48.3%) hospitals answered that confinement under detention should be mandatory, while 70 were against it. CONCLUSION: Since 2007 hospital treatment of tuberculosis patients has been mandatory under the Infectious Diseases Control Law in Japan, but this study revealed that there are patients who leave the hospital in violation of the law. There is also a problem of non-infectious but non-compliant patients who are discharged for ambulatory treatment being likely to default and develop relapse. Because these patients are likely to develop M(X)DR-TB and may threaten the community, certain effective legal actions including hospitalization under detention should be imposed on them. At the same time, for chronic excretors with XDR-TB, home isolation should be allowed from the point of view of human rights, under clear conditions for infection prevention, together with the provision of a financial subsidy. PMID- 21702175 TI - [The relationship between the nutritional states of tuberculosis patients at the time of their admission to tuberculosis wards and their treatment results]. AB - OBJECTIVES: To prospectively investigate the relationship between the nutritional states of tuberculosis patients at the time of their admission to tuberculosis wards and their treatment outcomes. PATIENTS AND METHODS: We observed body mass index (BMI), peripheral blood lymphocyte count, serum albumin concentration, and induration size in the PPD skin test of a total of 107 tuberculosis patients after they had been newly admitted to NHO Omuta National Hospital during the period from Aug. 2004 to Jul. 2006. Based on these indices, the patients were divided into four groups according to their nutritional states: severely impaired, moderately impaired, mildly impaired or normal. RESULTS: It was shown that the worse the nutritional state was on admission, the higher the mortality rate from all causes including tuberculosis. There has been no relapse case in patients from this group who have completed tuberculosis treatment despite their poor nutritional states at the start of the treatment. CONCLUSION: This prospective study of the relationship between the nutritional states of tuberculosis patients on admission and their treatment outcomes reproduced the results obtained from a retrospective study that we had previously reported. The assessment method of the nutritional state that was used in our study was proven to be useful for predicting the prognosis of tuberculosis patients. PMID- 21702176 TI - [Legal enforcement for non-adherent tuberculosis patients]. AB - PURPOSE: To investigate the conditions that would allow for coercive measures for persistently non-adherent tuberculosis patients. METHOD: Literature review of the jurisprudential and medical papers, mainly of the United States. RESULT: We found relevant items in the following categories related to conditions allowing for coercive measures: truthful adequate purpose of the coercive measures, scientific evidence or prospects of effectiveness of the measures, individual risk assessment, existence of significant risk, proportionality principle, least restrictive alternative principle, and procedural due process. CONCLUSION: To establish a system of coercive measures for persistently non-adherent tuberculosis patients in Japan, we would first need to accomplish many tasks, including a significant broadening of the support services for tuberculosis patients. PMID- 21702177 TI - [Pneumonitis induced by rifampicin]. AB - An 86-year-old male with pulmonary tuberculosis developed fever, rash, and interstitial pneumonia 3 weeks after the beginning of treatment with isoniazid (INH), rifampicin (RFP), and ethambutol (EB). Chest CT showed new infiltration shadows that were diffuse bilateral ground-glass opacities mixed with dense consolidation and septal thickening, accompanied by a small amount of pleural effusion. Drug-induced pneumonitis was suspected, and therefore the antituberculous regimen was discontinued. The radiologic findings and symptoms improved promptly. A provocation trial with RFP lead to fever, diarrhea, and rash. Therefore, RFP was considered to be the causative drug. INH and EB were reintroduced without any recurrence of the symptoms. Clinicians should be aware not only of paradoxical reactions but also of drug-induced pneumonitis, when a new pulmonary infiltrate develops in the course of tuberculosis treatment. PMID- 21702178 TI - [Tuberculosis annual report 2009--series 2. TB in foreigners]. AB - Statistics on tuberculosis (TB) in foreigners in Japan have been collected since 1998. The number of foreign TB patients increased from 739 in 1998 to 938 in 2009. In contrast, the number of Japanese TB patients decreased during this period. Hence, the proportion of foreigners among TB patients increased from 2.1% in 1998 to 4.0% in 2009, excluding those of unknown nationality. Especially, the proportion of foreigners among TB patients aged 20-29 years increased greatly from 9.1% in 1998 to 25.4% in 2009. Although the number of nationalities was 38, the majority of patients in 2009 were from China (28.4%), the Philippines (23.6%) and Korea (13.8%). The number of foreign TB patients aged 20-29 years was 427, accounting for 45.5% of all foreign TB patients in 2009. Eighty-one percent of foreign TB patients aged 20-29 years had developed TB within 5 years of entering Japan. The equivalent proportions in those aged 30-39 years and 40-49 years were 49% and 29%. Regarding occupation, 37.2% of foreign TB patients aged 20-29 years were students, 27.2% were full-time workers and 11.7% were part-time workers. PMID- 21702179 TI - [Foot and mouth disease virus keeps lurking around the corner]. PMID- 21702180 TI - [Bladder warning]. PMID- 21702181 TI - [Specializing or continued education? Continued education for small animal veterinarians]. PMID- 21702182 TI - [Trends from the GD monitoring]. PMID- 21702183 TI - [Castration with anesthesia in the clinic]. PMID- 21702184 TI - [Are parasite egg counts in horses repeatable?]. PMID- 21702185 TI - [Blood work identifies left over ovarian tissue]. PMID- 21702186 TI - [Animal feed expert and veterinarians need to sit at the table together]. PMID- 21702187 TI - [What do you really earn?]. PMID- 21702188 TI - [Toxoplasmosis in cats can be avoided]. PMID- 21702189 TI - [Alternatives for antibiotics?]. PMID- 21702190 TI - [Flexibility in veterinary practice (WUD)]. PMID- 21702191 TI - [Honors council: yearly report and arbitration results]. PMID- 21702192 TI - [Q fever in petting zoos]. PMID- 21702193 TI - [Cancer fund for animals stimulates education and research]. PMID- 21702194 TI - [The nurse, cornerstone of nursing care organization]. PMID- 21702195 TI - [Preadolescence, myth or reality?]. PMID- 21702196 TI - [Toward humanizing pediatric nursing]. PMID- 21702197 TI - [Breastfeeding, a factor in preventing postpartum depression]. PMID- 21702198 TI - [Team competence and knowledge to serve the child]. PMID- 21702199 TI - [Care until the end of life]. AB - When there is no more hope of a cure during a child's treatment, the curative period makes way for a palliative phase through to the last moments of the child's life. This phase is both difficult and fundamental for the child and his/her family, as well as for the caregivers, who must continue to provide care without any hope of curing the child. This phase determines how the period of mourning which follows the loss of a loved one is experienced, particularly for the family. PMID- 21702200 TI - [Paediatric palliative care, definition and regulations]. AB - The implementation of paediatric palliative care aims to fulfil objectives regarding the support provided for the child and his/her family in all aspects of care. It is guided by regulations and recommendations relating to pain relief, quality of life and support for families. PMID- 21702201 TI - [Supporting the siblings of a child suffering from cancer]. AB - As soon as a child is diagnosed with cancer, the family dynamics are overturned. The parents, destabilised by their feelings of powerlessness, must establish a dialogue with the caregivers, and the siblings must be supported from the moment the diagnosis is made. A psychoanalyst should be brought in early on in the end of-life phase to offer support to the family members undergoing this ordeal. PMID- 21702202 TI - [The role of the nursing team caring for a child approaching the end of life]. AB - In a general paediatric department, nurses may have to care for children suffering from severe life-threatening illnesses. When supporting the child and his/her parents, sometimes until the end of life, they must learn to manage their emotions and adopt a position which is both sympathetic and professional. PMID- 21702203 TI - [The community hospital dealing with a child at the end of life]. PMID- 21702204 TI - [Lois or the end of life of a child suffering from cancer]. AB - Lois, suffering from a malignant tumour, was supported until his death by a general paediatric department, with the collaboration of a mobile continuing care and support team and surrounded by his parents. The particularity of this multi disciplinary support lies in the fact that the family experienced the birth of their daughter at the same time. PMID- 21702205 TI - [Playing games to help deal with the end of life]. AB - Allowing a child to play until the end of his/her life, such is the objective which a paediatric nursing team has set itself The games must enable the child and his family to organise psychologically the emotional chaos provoked by impending death. They question and provide an answer to an intolerable situation- the end of a child's life. PMID- 21702206 TI - [Teaching a teenager approaching the end of life]. AB - When a teenager is diagnosed with a life-threatening condition, priority is given to the provision of care, but the continuation of the adolescent's education is also encouraged, through the hospital school. Thereby, like all children of his age, Issem, suffering from an osteosarcoma, will sit his secondary school exams and will be supported to the end by his teachers. Personal accounts. PMID- 21702207 TI - [Associated structures in pediatric palliative care, a key factor in patient management]. PMID- 21702208 TI - [Paliped, a palliative care team in action]. PMID- 21702209 TI - [Psychomotor therapy in paediatric palliative care]. AB - Present for around ten years in specialised paediatric departments, most psychomotor therapists have already been confronted with children approaching the end of life. In this context, psychomotor therapy takes into account the individuality of each child within his/her family dynamics, for global and personalised support. PMID- 21702210 TI - [Home hospital care for children suffering from serious neurological pathologies]. AB - The return home of seriously ill very young children causes worry and upheaval in the family. The home hospital care team supports the child and his/her family enabling links to be forged between them, whatever the outcome of the illness, whilst respecting the rhythm of each family member. The situation of Flora, 14 months, illustrates this support. PMID- 21702211 TI - [Home support for a child receiving palliative care provided by a self-employed nurse]. AB - Complex and demanding, paediatric palliative care at home is beginning to develop. How can a self-employed nurse, by definition isolated, care for a child approaching the end of life and his/her family at home? What resources and tools does the nurse have to provide this support? PMID- 21702212 TI - [The nutritional care of a child suffering from neuroblastoma]. AB - Children are growing people. When they are suffering from cancer, they are often malnourished. Their nutritional care must be adapted and form an integral part of the overall treatment. The diet of Lea, a young girl suffering from neuroblastoma, was enriched and adjusted in order to take into account the side effects of her treatment. PMID- 21702213 TI - [Pain in children: some progress, continuity to be monitored]. AB - The fight against pain in children has progressed significantly since the 1980s. The setting up of pain prevention plans, the issuing of good practice recommendations, the development of new treatments as well as the training of professionals in particular account for this progress. However, caregivers must remain vigilant in order that the quality of care provided to a child in pain remains a priority. PMID- 21702215 TI - Retraction. PMID- 21702214 TI - Stroke. Foreword. PMID- 21702216 TI - [Abstracts of the XXIV National Congress for association evaluation, management, organisation, sante (Emois). Nancy, France. March 17-18, 2011]. PMID- 21702217 TI - Stem cell therapies for type 1 diabetes mellitus. AB - The present review discusses the use of autologous hematopoietic stem cell transplantation (HSCT) for the treatment of diabetes mellitus type 1 (DM 1). It has been observed that high dose immunosuppression followed by HSCT shows better results among other immunotherapeutic treatments for the disease as the patients with adequate beta cell reserve achieve insulin independence. However, this response is not maintained and reoccurrence of the disease is major a major challenge to use HSCT in future to prevent or control relapse of DM 1. PMID- 21702218 TI - Islet-specific microRNAs in pancreas development, regeneration and diabetes. AB - Diabetes is a chronic and slowly progressive disease that is presently reaching epidemic proportions in several parts of the world. Multiple aspects including genetic and lifestyle changes have been identified as the key factors leading to the development of type 1 and type 2 diabetes. Although molecular mechanisms underlying the pathogenesis of diabetes remain unclear, recent discoveries in understanding post-transcriptional gene regulation by microRNAs (miRNAs) has opened a new area of research. MicroRNAs have been implicated as new players in pathogenesis as well as complications of diabetes. MiRNAs have been shown to be necessary not only during embryonic development of insulin-producing cells, transcription of (pro-)insulin gene and insulin secretion, but also in development of insulin resistance and diabetes. The present review summarizes the findings related to understanding the role of miRNAs in endocrine pancreas development, pancreas regeneration, islet function and diabetes. PMID- 21702219 TI - Cellular reprogramming of somatic cells. AB - The process of 'cell reprogramming' can be achieved by somatic cell nuclear transfer, cell fusion with embryonic stem cells, exposure to stem cell extracts, or by inducing pluripotentcy mediated by defined factors giving rise to what are termed induced pluripotent stem cells. More recently, the fate of a somatic cell can be directly induced to uptake other cell fates, termed lineage-specific reprogramming, without the need to de-differentiate the cells to a pluripotent state. In this review we will describe the different methods of reprogramming somatic cells. PMID- 21702220 TI - Radioiodide uptake and sodium iodide symporter expression in breast carcinoma. AB - Breast cancer is a common malignancy in women all over the world and novel therapeutic approaches are required for the treatment of patients who become refractory to conventional therapies. Thyroid cancer is being treated successfully with radioiodine since many years. The iodide is transported inside the thyroid epithelial cell via sodium iodide symporter (NIS) which is a trans membrane protein. The present study was aimed to explore the uptake of radioiodide (RAI) and the expression of NIS in breast tissues of invasive ductal carcinoma patients. Breast tissues from tumor region (Tu-Br) as well as corresponding normal region (N-Br) were collected from patients of invasive ductal carcinoma. In vitro RAI uptake, its efflux and NIS expression were studied. The uptake of RAI (1.98+/-1.75 x 10(5) cpm/g) in Tu-Br was significantly higher as compared to that observed in N-Br (0.31+/-0.27 x 10(5) cpm/g) and fast efflux was observed in the tissue samples. NIS gene expression was positive in 41.66% (10/24) samples of Tu-Br. None of the N-Br samples expressed NIS gene. In 14 samples of Tu-Br, RAI uptake as well as NIS expression was studied. In 50% of these Tu-Br samples RAI uptake as well as of NIS gene expression was positive. The results indicate that RAI uptake is significantly higher in breast tumor tissues as compared to their normal counterpart and in future radioiodine may be an important agent for treatment of breast cancer. PMID- 21702221 TI - No effect of low-level lasers on in vitro myoblast culture. AB - Effects of phototherapy using low-level lasers depend on irradiation parameters and the type of laser used. The aim of the present study was to evaluate the effect of phototherapy on the proliferation of cultured C2C12 myoblasts under different nutritional conditions using low-level GaAlAs and InGaAlP lasers with different parameters and incubation periods. C2C12 cells cultured in regular and nutrient-deficient medium were irradiated with low-level GaAlAs (780 nm) and InGaA1P (660 nm) lasers with energy densities of 3.8, 6.3 and 10 J/cm2, and 3.8, 10 and 17.5 J/cm2, respectively. Cell proliferation was assessed 48 and 72 h after irradiation by MTT assay. There were no significant differences in cell proliferation between laser-treated myoblasts and control cultures for any of the parameters and incubation periods. Further studies are necessary to determine the correct laser parameters for optimizing the biostirhulation of myoblasts. PMID- 21702222 TI - Differential gene expression in pepper (Capsicum annuum) exposed to UV-B. AB - In the present paper, complementary DNA-amplified fragment length polymorphism (cDNA-AFLP) was used to examine and identify differentially expressed genes in Capsicum annuum exposed to UV-B irradiation. Around 4000 transcript derived fragments (TDFs) were visualized and in total 183 TDFs were isolated, sequenced and analyzed by Blast 2 go. Among these TDFs, 84 of them showed homology to known genes. There were 43 TDFs showing up-regulated expression, 24 TDFs showing down regulated expression and 29 TDFs showing both up-regulated and down-regulated expression, respectively. Some of these TDFs were found to be in response/related to UV-B stress, including carbonic anhydrase, calcium-dependent protein, thionin like protein, bzip protein and so on. In particular, chlorophyll a/b binding protein (Capcab) responding to UV-B stress was cloned. It was concluded that Capcab could play a protective role in plant anti-UV-B and maintaining photosynthetic rate under UV-B stress. PMID- 21702223 TI - Sorbitan ester niosomes for topical delivery of rofecoxib. AB - The aim of the present investigation is to encapsulate rofecoxib in niosomes and incorporate the prepared niosomes into dermal gel base for sustained therapeutic action. Niosomes were prepared by lipid film hydration technique and were analyzed for size, entrapment efficiency and drug retention capacity. Niosomal vesicles were then incorporated into blank carbopol gel to form niosomal gel. The in vitro permeation study across pig skin was performed using Keshary-Chien glass diffusion cell. The size and entrapment efficiency of the niosomal vesicles increased with gradual increase in HLB value of nonionic surfactants used. Maximum drug entrapment was observed with Span 20 with HLB value of 8.6 and drug leakage from vesicles was less at refrigerated condition than at the room temperature. Higher proportion of cholesterol made the niosomal formulation more stable with high drug retention properties. The niosomal gel showed a prolong drug release behavior compared to plain drug gel. Differential scanning calorimetric study of drug loaded gel and pig skin after permeation study confirmed inertness of carbopol gel base toward rofecoxib and absence of drug metabolism in the skin during permeation study, respectively. The niosomal formulations were successfully prepared by lipid film hydration technique using cholesterol and Span as nonionic surfactant. Presence of cholesterol made niosomes more stable with high drug entrapment efficiency and retention properties. The lower flux value of niosomal gel as compared to plain drug gel across pig skin assured the prolong drug release behavior with sustained action. PMID- 21702224 TI - Sub-chronic diclofenac sodium induced alterations of alkaline phosphatase activity in serum and skeletal muscle of mice. AB - The present study has been carried on changes in activity of alkaline phosphatase in serum and gastrocnemius muscle of mice after sub-chronic use of diclofenac. Mice in experimental group received diclofenac (10 mg/kg body wt /day) for 30 days while control group received normal saline. Alkaline phosphatase was assayed in muscle and serum and its activity was localized histochemically in muscle. Results showed that diclofenac induced changes in specific activity of alkaline phosphatase at different periods of treatment variably compared to control group. Specific activity of alkaline phosphatase decreased significantly in gastrocnemius initially (48.74%), increased thereafter (132.96%) and slight decrease (13.97%) was noticed after 30 days. In serum, the specific activity of alkaline phosphatase decreased slightly after 10 days (18.78%), increased in the middle of the treatment period (132.04%) as well as showed increase (109.09%) compared to control group after 30 days stage of investigation. These findings were also confirmed by electrophoretic studies in muscle. PMID- 21702225 TI - Hepatoprotective and antioxidant properties of Suaeda maritima (L.) dumort ethanolic extract on concanavalin-A induced hepatotoxicity in rats. AB - Hepatoprotective and antioxidant properties of Suaeda maritima (L.) Dumort on concanavalin-A induced stress in Wistar albino rats have been reported. Rats were administered with ethanolic extract of Suaeda maritimna at the concentration of 75, 150 and 300 mg/kg of body wt. for 9 days and concanavalin-A was administrated (iv) 12 mg/kg on 9th day. Rats in concanavalin-A administered group showed elevated levels of AST, ALT, ALP and bilurubin. Pretreatment of rats with ethanolic extract (300 mg/kg) significantly reduced these serum parameters compared to concavalin-A administered group. Histopathological examination of liver sections showed that, normal liver architecture was disturbed by hepatotoxin intoxication. The extract treated group and silymarin treated group retained the normal cell architecture, although less visible changes were observed. Preliminary phytochemical analysis showed the presence of triterpenioids and may be responsible for the hepatoprotective activity. The LD50 was calculated as 3 g/kg of the body weight. IC50 values of hydroxyl (52.21+/ 1.32 microg/ml) and nitric oxide radicals (09.14+/-0.94 microg/ml) scavenging results showed comparable activity with vitamin-C. Results of this study may be useful for the development of herbal medicine from Suaeda maritima for the treatment of hepatitis. PMID- 21702227 TI - In silico designing of insecticidal small interfering RNA (siRNA) for Helicoverpa armigera control. AB - Helicoverpa armigera, a polyphagous lepidopteron insect pest causes severe yield loss in cotton, legumes, tomato, okra and other crops. Application of chemical pesticides although effective, has human health and environmental safety concerns. Moreover, development of resistance against most of the available pesticides is compelling to look for alternative strategies. Adoption of Bt transgenic crops have resulted in reduction in pesticide consumption and increasing crop productivity. However, sustainability of Bt transgenic crops is threatened by the emergence of insect resistance. In the present study potential insecticidal siRNA were identified in six H. armigera horrhonal pathway genes. Out of over 2000 computationally identified siRNA, 16 most promising siRNA were selected that address the biosafety concerns and have high potential of targeted gene silencing. These siRNA will be useful for chemical synthesis, in insect feeding assays and knockdown the target H. armigera hormone biosynthesis, consequently obstructing the completion of insect life cycle. The siRNA have a great potential of deployment to control H. annrmigera alone as well as with Bt for insect resistance management. PMID- 21702226 TI - Anti-ulcerogenic and proton pump (H+, K+ ATPase) inhibitory activity of Kolaviron from Garcinia kola Heckel in rodents. AB - Anti-ulcer potential and proton pump inhibitory activity of kolaviron (KV) isolated from Garcinia kola Heckel has been evaluated using different ulcer models. Cold-restraint (CRU), aspirin (ASP), alcohol (AL), pyloric ligation (PL) induced gastric ulcer models were used to assess anti-ulcerogenic activity of KV in rats. Effects of KV on gastric juice for free and total acidity, peptic activity and mucin secretion were also evaluated. The H+, K+-ATPase activity was assayed in gastric microsomes, spectrophotometrically. Results of this study showed that KV (200 mg/kg) reduced the incidence of ulcers in CRU (69.0%), PL (67.6%), ASP (68.6%) and AL (51.5%). Reductions were also observed in free acidity (32.6%), total acidity (56.2%) and peptic activity (35.4%) with increase in mucin secretion by 40.1%. KV inhibited the H+,K+-ATPase activity with IC50 of 43.8 microg/ml compared with omeprazole with IC50 of 32.3 microg/ml. KV showed both cytoprotective and anti-secretory potentials against peptic ulcer models, and a proton pump inhibitory activity. KV may emerge as a potent anti-ulcer compound. PMID- 21702228 TI - Eating disorders: an emerging psychopathology. PMID- 21702229 TI - Molecular detection and epidemiology of extended-spectrum beta-lactamase genes prevalent in clinical isolates of Klebsiella pneumoniae and E coli from Trinidad and Tobago. AB - OBJECTIVE: The epidemiology of Extended-spectrum beta-lactamase (ESBL) producing E coli and K pneumoniae is complex and varies among hospitals and countries. This study aimed at describing the molecular detection and epidemiology of ESBL subtypes prevalent in clinical isolates of K pneumonia and E coli in Trinidad and Tobago. METHODS: Over 36-months, isolates of E coli and K pneumoniae from clinical specimens of patients processed at a regional tertiary hospital in the country,were identified using standard microbiological methods. MicroScan System (Siemens, USA) was used to determine MIC values while E-test (AB Biodisk, Sweden) assays phenotypically confirmed ESBL production. K pneumoniae (n = 65) and E coli (n = 25) isolates confirmed as ESBL producers were further subjected to multiplex PCR and PFGE tests to determine the ESBL subtypes and clonal relatedness. RESULTS: Female patients (67.8%) and urine samples (65%) yielded most ESBL isolates, with over 90% recovered from the hospital's medicine and surgery facilities. All ESBL isolates including all K pneumoniae producing ESBLs were 100% susceptible to carbapenems and amikacin antimicrobials. Polymerase Chain Reaction detected 100% blaTEM genes, 4.1% blasHv and 37.5% blaCTX_M genes among E coli isolates. Similarly, 84.3% blaTEM, 34.5% blaSHV and 58.8% blaCTX-M genes were detected in K pneumoniae. Pulsed-field gel electrophoresis (PFGE) results showed diverse and unrelated clones. CONCLUSIONS: In this the first report of molecular characterization and epidemiology ofESBL subtypes in E coli and K pneumoniae isolates in Trinidad and Tobago, the CTX-M, mainly phylogenetically group 1 type, was most predominant. Most ESBL isolates were still susceptible to carbapenems and aminoglycosides and their spread appears to be polyclonal and clonally unrelated. PMID- 21702230 TI - Cytotoxic activity of selected West Indian medicinal plants against a human leukaemia cell line. AB - OBJECTIVE: To assess the cytotoxic activities of crude extracts and solvent fractions of Spermacoce verticillata, Ficus pumila and Flemingia strobilifera against a MT-4 human leukaemia cancer cell line. METHODS: Crude extracts of dried leaves of S verticillata, F pumila and F strobilifera were made by exhaustive methanol extraction, fractions were obtained from sequential extraction of the crude extract using solvents of increasing polarity. Dose responses corresponding to cell survival following 72-hour exposure to the extracts were determined using a leukaemia cancer cell line (MT-4). Cell viability was assessed using the MTT[3 (4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] assay reading absorbances at 570 nm. Comparisons were made with controls and cell survival, in each sample well, was determined based on the ratio of the absorbance of the sample to the control. RESULTS: Crude extracts of S verticillata, F pumila and F strobilifera displayed cytotoxicity and the IC50 values were 89 microg/ml, 131 microg/ml and 81 microg/ml, respectively. The petroleum ether and chloroform fractions of the crude extracts of S verticillata and F strobilifera showed potent cytotoxic activity but the highest cytotoxic activity was found in the chloroform and butanol fractions of F pumila with IC50 values of 23 microg/ml and 26 microg/ml, respectively. CONCLUSION: The crude extracts of S verticillata, F pumila and F strobilifera were shown to be cytotoxic to the leukaemia cell line, MT-4 and IC50 values were determined. Fractionation of the crude extracts by solvent-solvent extraction enabled determination of the active fractions and their IC50 values. We propose that cytotoxic activity may be due to antioxidant compounds previously isolated from these plants. PMID- 21702231 TI - Comparative antimicrobial activity of two new mutacins. AB - OBJECTIVES: To compare the in vitro activity of mutacins D-123.1 and F-59.1 against different bacteria including antibiotic-resistant strains, in order to evaluate their application potential. DESIGN AND METHODS: The antibacterial activity spectrum of purified F-59.1 and the MIC and MBC of F-59.1 and D-123.1 against target bacteria were determined. RESULTS: Most bacteria were inhibited by the purified mutacins. Mutacin F-59.1 shows a relatively wide activity spectrum. Mutacin D-123.1 has low Minimum Inhibitory Concentrations [MICs] (0.25-4 microg/ml) against human pathogens while F-59.1 has higher MICs (3.2-12.8 microg/ml) mainly against food-borne pathogens. CONCLUSION: The effectiveness of mutacins D-123.1 and F-59.1 against human and food-borne pathogens is demonstrated. Mutacin D-123.1 shows potential as a new antibiotic while F-59.1 shows promising application in food products. PMID- 21702232 TI - A randomized, controlled, open-label trial evaluating the efficacy and safety of chloroquine in the treatment of giardiasis in children. AB - BACKGROUND: Giardia duodenalis is among the commonest protozoan parasites in the intestinal tract of humans and may cause significant morbidity worldwide. Although there are several antigiardial agents, treatment failures have been commonly reported. OBJECTIVE: To compare the efficacy and safety of chloroquine (CQ) versus metronidazole (MTZ) in the treatment of children with confirmed G duodenalis mono-infection. METHODS: A randomized, controlled, open-label trial was carried out at the Cuban Institute of Gastroenterology. One hundred and twenty-two children were randomly assigned to receive either CQ (10 mg/Kg bodyweight twice a day for five days) or MTZ [15 mg/Kg bodyweight divided in three daily does for five days]. All children were asked to provide three faecal samples on days 3, 5 and 7 after treatment completion. Children were considered to be cured, if no Giardia trophozoites or cysts were found in any of the three post-treatment faecal specimens evaluated by direct wet mounts and/or after Ritchie concentration techniques. RESULTS: The frequency of cure was a little higher for CQ than for MTZ but the difference was not statistically significant. Headache was more common in patients treated with CQ as was bitter taste. Yellowish colouration of the urine was more frequent in the MTZ treated group. CONCLUSION: Chloroquine, for five days, is as efficacious as the recommended treatment with MTZ in children infected with G duodenalis. PMID- 21702233 TI - Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2) A randomised, placebo-controlled trial. AB - BACKGROUND: Tranexamic acid can reduce bleeding in patients undergoing elective surgery. We assessed the effects of early administration of a short course of tranexamic acid on death, vascular occlusive events, and the receipt of blood transfusion in trauma patients. METHODS: This randomised controlled trial was undertaken in 274 hospitals in 40 countries. 20 211 adult trauma patients with, or at risk of significant bleeding were randomly assigned within 8 h of injury to either tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Randomisation was balanced by centre, with an allocation sequence based on a block size of eight, generated with a computer random number generator Both participants and study staff (site investigators and trial coordinating centre staff) were masked to treatment allocation. The primary outcome was death in hospital within 4 weeks of injury, and was described with the following categories: bleeding, vascular occlusion (myocardial infarction, stroke and pulmonary embolism), multiorgan failure, head injury, and other AL analyses were by intention to treat. This study is registered as ISRCTN86750102, Clinicaltrials.gov NCT00375258, and South African Clinical Trial Register DOH-27 0607-1919. RESULTS: 10096 patients were allocated to tranexamic acid and 10 115 to placebo, of whom 10060 and 10067, respectively, were analysed. All-cause mortality was significantly reduced with tranexamic acid (1463 [14.5%] tranexamic acid group vs 1613 [160%] placebo group; relative risk 0.91, 95% CI 085-097; p = 00035). The risk of death due to bleeding was significantly reduced (489 [49%] vs 574 [5-7%]; relative risk 0-85, 95% CI 0.76-0.96; p = 0-0077). CONCLUSION: Tranexamic acid safely reduced the risk of death in bleeding trauma patients in this study On the basis of these results, tranexamic acid should be considered for use in bleeding trauma patients. PMID- 21702234 TI - Cardiovascular disease risk factors in menopausal Jamaican black women after hysterectomy and bilateral oophorectomy: an observational study. AB - OBJECTIVE: To determine differences in prevalence of cardiovascular risks and diseases in black Jamaican postmenopausal women who had hysterectomy (hysgroup) compared with those without (control). METHOD: Eight hundred and nine (809) women (hysterectomized (HYSGRP) = 403; non-hysterectomized (controls) = 406) were enrolled. Sociodemographic information and lifestyle history, measured blood pressure, waist hip ratio, body mass index, fasting blood glucose, total and HDL cholesterol were obtained. RESULTS: Of the 809 women, complete cardiovascular risk data were available in 341 controls and 328 in the HYSGRP group. There was no difference in mean age, blood pressure and body mass indices between the subjects excluded and the subjects in the data analytical sample. A significantly lower proportion of women in the control group exercised, attained post-secondary education and were of higher parity. Systolic (mean diference with 95% CI; 6 (3, 9) mmHg and diastolic (3 (1, 5) mmHg) blood pressure were lower in the HYSGRP compared with controls but total cholesterol (0.2 (0.07 to 0.4) mmol/L was greater HDL cholesterol was not different between both groups 1.3 mmol/L (SD 0.3) vs 1.3 mmol/L [SD 0.4] (p = 0.8435). There was no difference in the prevalence of diabetes, hypertension and high waist-hip ratio in hysterectomized women compared with controls adjusting for hormone replacement therapy usage, cigarette smoking, exercise and educational status. Within the HYSGRP there was also no diference in cardiovascular disease or risk in women who had bilateral oophorectomy compared with women who had at least an ovary preserved at time of operation. CONCLUSION: Hysterectomy was not associated with an increased risk of cardiovascular disease. This must be taken cautiously since data did not allow for analysis on duration of menopause. PMID- 21702235 TI - Knowledge of students attending a high school in Pretoria, South Africa, on diet, nutrition and exercise. AB - OBJECTIVE: The objective of this study was to ascertain the knowledge of students on the composition of a healthy diet, daily nutritional requirements and the importance of regular exercise. METHOD: A cross-sectional survey using a self administered questionnaire with closed and open-ended questions to assess students 'knowledge on diet, nutrition and exercise was conducted. The study group were students of Tswaing High School in Pretoria, South Africa, who were in attendance on a particular day when the study was conducted and who consented to participate in the study Only 500 students of the school participated in the study RESULTS: Results showed that 77% of the students do not have adequate knowledge on diet, nutrition and exercise while 23% of the students showed satisfactory knowledge. Approximately 26% and 16% of the students reported that they participated in rigorous and moderate exercise respectively The study also showed that the majority of the students were however not engaged in physical activities. CONCLUSION: Students at Tswaing High School do not have adequate knowledge on nutrition, diet and exercise. Their views on what exercise entails were found not to be satisfactory. Programmes/ information or seminars that could assist to inform students on the importance of diet and exercise are therefore suggested. PMID- 21702236 TI - Substance use among university students at the St Augustine campus of the University of the West Indies. AB - OBJECTIVE: Substance use and abuse is a well known public health risk that peaks in persons between 18 and 25 years of age and is prevalent among university students. While this has been repeatedly documented in developed nations, there have been limited studies in the English-speaking Caribbean. This study therefore sought to assess the prevalence of alcohol, tobacco and marijuana use among university students in the English-speaking Caribbean and any associated risk factors. METHODS: The study was designed as a descriptive, cross-sectional study to assess substance use in full-time, undergraduate students of The University of the West Indies (UWI), Trinidad and Tobago, over a six-month period. Questionnaires were distributed and students asked to self-report on their use of alcohol, tobacco and marijuana during the preceding six months. RESULTS: The six month prevalence rate for alcohol was 70% and 28% of students were identified as regular users. Binge drinking was estimated at 31%. Muslims were least likely to have used alcohol when compared to other religious groupings. The prevalence rate for tobacco and marijuana was 17% and 13%, respectively Ten per cent used all three substances. The use of all three substances was associated with multiple problems. CONCLUSION: We conclude that substance use is common among many students of the UWI but generally lower than reports from other regions of the world. Despite this, substance use is associated with a number of problems and immediate educational interventions may be necessary to assist students in making informed and responsible choices. PMID- 21702237 TI - Knowledge, attitude and practice of emergency contraceptive pills among tertiary level students in Trinidad: a cross-sectional survey. AB - OBJECTIVE: The objective of this study was to estimate the general knowledge, attitude and practice of Emergency Contraceptive pills (ECs) among tertiary level students in Trinidad. METHOD: A 32-item questionnaire was constructed to assess knowledge, attitudes and practice of EC. There were 76 medical and 160 non medical students who volunteered to fill-up the questionnaire. This survey was conducted by graduate students under supervision of the Department of Mathematics and Computer Science, UWI, St Augustine. RESULTS: Eighty-four per cent of the students were less than 25 years of age, 64% were Christians and 92% were single. Sixty-three per cent were female and there were more females in the non-medical group than the medical students group but the numbers were not significant. Eighty-one per cent used condoms as the main type of contraception. Only 63% had heard of ECs before and only 9% had heard of ECs from medical sources. Among the factors that related to attitude towards EC, only two factors were significant. Sixty-two per cent of students felt that increased EC use would increase promiscuity (p = 0.013) but 59% also felt that ECs should be made more easily available (p = 0.014). CONCLUSION: The general level of their knowledge about ECs was poor. The general attitude of students towards ECs was positive. This study will help policy-makers by providing evidence-based knowledge to promote EC use among university students. PMID- 21702238 TI - Interdisciplinary communication in the intensive care unit at the University Hospital of the West Indies. AB - OBJECTIVE: To assess the perceptions of physicians and nurses working full-time in the Intensive Care Unit (ICU) at the University Hospital of the West Indies (UHWI) regarding interdisciplinary communication. METHOD: A cross-sectional survey of all medical personnel working full-time in the ICU was conducted in January 2008 using a self-administered, validated questionnaire. Data on perceived communication, teamwork and leadership, comprehension of patient care goals, perceived effectiveness and satisfaction were collected and analysed using the SPSS Version 14. Internal reliability was tested using Cronbach's alpha score and differences and correlations were assessed using Pearson's Chi-square and correlation analysis. RESULTS: Ninety-five per cent (105/111) of questionnaires were completed. More doctors than nurses experienced open communication with other staff members (73% vs 32%; p < 0.01), with less openness occurring with increasing seniority. More doctors (53%) than nurses (32%) reported receiving inaccurate information from doctors (p < 0.05), with 67% and 51% respectively receiving incorrect information from nurses (p < 0.05). Communication across shifts was felt to be better amongst doctors than nurses (73% vs 63%). Only 50% of doctors compared to 88% of nurses felt they received relevant information quickly (p < 0.05). More nurses than doctors (86% vs 63%; p < 0.01) felt that they had a good understanding of patient care goals. Negative perceptions of the leadership characteristics of consultants (62% amongst doctors and 74% of nurses) and sisters (79% and 73%, respectively) were high. CONCLUSIONS: Communication within the ICU, UHWI, is unsatisfactory with an overall poor perception of senior leadership. Improvement in staff morale and leadership training may create a working environment where team members can communicate openly without fear of chastisement. PMID- 21702239 TI - Mental illness and public health: exploring the role of general hospital physicians at a teaching hospital in Jamaica. AB - OBJECTIVES: Against the public health implications of untreated mental illness among general hospital inpatients, this study aimed firstly to examine hospital physicians' level of referral to a psychiatric service, and secondly, to explore the extent of these doctors' knowledge of psychiatric issues by comparing their reasons for referring patients with patients' final psychiatric diagnoses. METHODS: Over a one-year period, data were collected on all patients referred to a consultation liaison psychiatric service at a multi-disciplinary teaching hospital. Reasons for referral and final psychiatric diagnosis were recorded. Official hospital census data were also used in the calculation of referral rates. Chi-square or Fisher's Exact tests were used as appropriate to explore potential associations between reasons for referral and psychiatric diagnosis. Statistical significance was taken at the 0.05 level. RESULTS: The referral rate was 1.5%. Strange and disruptive behaviour as reasons for referral were strongly associated with the presence of underlying medical conditions as the cause of mental disturbance. Anxiety and psychotic symptoms as reasons for referral were associated with anxiety and psychotic disorders respectively. Depression was often given as a reason for referral when clinical depression was absent, but adjustment issues were prominent. CONCLUSIONS: The psychiatric service was underutilized. Generally, the psychiatric knowledge of physicians was fair However, closer attention to underlying medical conditions as a potential cause for psychiatric, disturbance, as well as to the difference between maladjustment and depression, seems warranted. It is possible that clinicians were less able to detect mild to moderate cases of psychiatric illness. PMID- 21702240 TI - Exposure to airborne asbestos in Jamaican hospitals. AB - OBJECTIVE: Asbestos is an established human carcinogen and has been identified at 16 of 26 Jamaican hospitals surveyed. We sought to determine if hospital employees are exposed and if current asbestos exposure in Jamaican hospitals differed by job category. METHOD: At two of the largest hospitals with more than 10 permanent maintenance workers and where over 67% of bulk samples analysed contained asbestos, three groups of employees selected by stratified random sampling participated in a personal air sampling study for asbestos. One hundred and thirty-two personal air samples and 32 area samples were collected and analysed for asbestos fibres utilizing phase contrast microscopy (PCM) and transmission electron microscopy (TEM). RESULTS: Twenty-four (14.6%) air samples had fibre counts above the limit of detection (LOD) for the analytical method (PCM), ranging from 0.002 f/cc to 0.013 f/cc. The fibres met the dimensional characteristics of asbestos fibres. There was no difference in the median fibre concentration to which the groups of employees were exposed. Further testing of samples which had fibre counts above the LOD using TEM confirmed that the fibres were not asbestos. CONCLUSION: Despite not finding asbestos fibres in the air samples, most of the asbestos containing building material (ACBM) found in the hospitals was friable and in a poor condition indicative of fibre release. We recommend an ongoing monitoring programme for airborne asbestos fibres in hospitals until an abatement programme can be undertaken by the regulatory agencies in the country. PMID- 21702241 TI - Oral steroid therapy for frozen shoulder. AB - BACKGROUND: Since frozen shoulder is characterized by spontaneous recovery, no precise treatment strategy exists. Both conservative therapy and arthroscopic surgery is available, but the time required for recovery varies considerably. This study looks at the possible early symptom relief with oral steroid therapy. SUBJECTS AND METHODS: The subjects were 76 patients aged 33 to 73 years at the beginning of the study. The duration of the frozen shoulder was one to 15 months (mean 5.7 months) and hypertension was noted in 13 patients as a complicated disorder. A single course of steroid therapy consisted of a total dose of 105 mg of prednisolone over approximately a three-week period by the dose-tapering method. The number of courses varied with the degree of symptom relief but the rest period between courses was always approximately four weeks. The results were assessed on the basis of the Japanese Orthopaedic Association (JOA) score, but the principal evaluations were pain and range of motion. RESULTS: The average ranges of motion before treatment were 102.8 degrees of forward flexion 11.3 degrees of external rotation and internal, rotation was at the buttocks. However, after one course of treatment, forward flexion was 136 degrees, external rotation was 33.7 degrees, and internal rotation was limited to the buttocks in only six cases. CONCLUSION: The results of oral steroid therapy for frozen shoulder were highly satisfactory. However, sufficient care is required in explaining the method of administration and the adverse effects such as the osteonecrosis of the femoral head or osteoporosis. PMID- 21702242 TI - Time equals myocardium: are we in time? AB - OBJECTIVE: To determine the door to thrombolysis time of patients who presented to the Adult Priority Care Facility of the Eric Williams Medical Sciences Complex from February 1-May 31, 2008. METHOD: The patients who presented to the Adult Priority Care Facility of the Eric Williams Medical Sciences Complex with cardiac type chest pain and ST segment elevation that met the international criteria and had positive troponin test were interviewed and their notes reviewed to obtain the relevant information. RESULTS: Fifty-one patients were treated with ST segment elevation myocardial infarctions; 78.4% were thrombolysed. Patients were: 59.75 years old, 68.6% male and 66.7% were of East Indian extraction The average time to thrombolysis was 5 hours and 31 minutes from the onset of chest pain. The average door to thrombolysis time was 2 hours and 7 minutes with 20% of patients having a door to thrombolysis time of 30 minutes. The time to thrombolysis from the onset of chest pain and the door to thrombolysis times were adversely affected by the health facility to which the patient first presented CONCLUSION: The majority of patients presented within the thrombolysis window. Early recognition of symptoms of myocardial infarction and arrival at a healthcare facility is not being achieved by the majority of patients. The systems that are responsible for the transport, triage and treatment of patients who present with chest pain are inadequate and require urgent review and overhaul to achieve the goals outlined by the American Heart Association and the American College of Cardiologist. PMID- 21702243 TI - The effects of viewing pro-eating disorder websites: a systematic review. AB - OBJECTIVE: To determine health-related effects of viewing pro-eating disorder (Pro-ED) websites. METHODS: A systematic review was carried out addressing: 1. The effect of viewing pro-ED websites on eating disorder behaviour 2. The effect of viewing pro-ED websites on viewers' negative and positive affect. RESULTS: Seven studies were included. Pro-ED viewers compared with controls showed higher levels of dieting and exercise (3 studies, 2 suggesting causation); higher levels of drive for thinness, body dissatisfaction and perfectionism (2 studies, both associative); a reduced likelihood of binging/purging (one study); increased negative affect (two studies); and a positive correlation between viewing pro-ED websites, disease duration and hospitalisations (one study). CONCLUSION: Viewing pro-ED websites may increase eating disorder behaviour but might not cause it. It may cause increased negative affect after a single short website exposure. For those with eating disorders, viewing is positively correlated with disease duration and hospitalisations. Professionals should be aware of these sites and their potential damage for health. PMID- 21702244 TI - Compartment syndrome as a complication of the lithotomy position. AB - Compartment syndrome is a rare but serious complication of surgical procedures performed in the lithotomy position. Preventive measures include careful placement of the patient's legs and limited elevation. Early diagnosis is based on vigilance and close postoperative follow-up, especially after prolonged surgery. Finally, postoperative analgesia does not delay the diagnosis, if the patient's needs are assessed carefully. PMID- 21702245 TI - Iatrogeny: why patients come to harm. AB - latrogeny remains a constant challenge to all members of the health team who must be made aware from the onset of their roles and responsibility to their patients with particular reference to patients' rights and well-being. Physicians, as the acknowledged leaders of the health team, have the greatest role in this respect; their training and involvement in supervising and monitoring members of their health teams must reflect an acknowledgement of this responsibility. The protection of the legacy associated with the medical profession for ethical behaviour and acting in the patient's best interest remains a challenge which must be addressed in the face of changing societal dynamics where rights and responsibilities are in a constant state of evolution. Medical schools must be at the forefront of responding to these challenges and reflect this by constant review of their training programmes. PMID- 21702246 TI - The relationship between healthcare services and the political economy with reference to the Jamaican experience. AB - The availability of and equitable access to, health services have challenged healthcare providers with a greater degree of urgency since the end of World War II. Prior to that time, concepts such as equity and social justice were just that, concepts but no real attempts were ever made to operationalize them. Goods and services were still produced and distributed based on market forces, that is, one's ability and willingness to pay for something. Health in that context was a service, some say a commodity, to be bought and sold, hence its availability was not necessarily commensurate with its accessibility. PMID- 21702247 TI - The Faculty of Medical Sciences, St Augustine, and its contribution to human resource development in the Caribbean. AB - INTRODUCTION: The University of the West Indies (UWI), Faculty of Medical Sciences (FMS), St Augustine campus, began teaching its undergraduate programme in October 1989, in three Schools: Medicine, Dentistry and Veterinary Medicine. The first batch of students graduated in 1994. A four-year Pharmacy Programme commenced in 1995, producing its first graduates in 1999 and ten years later an accelerated Bachelor of Science in Nursing was started and saw its first graduates in 2006. In its twenty years of existence, the FMS has graduated 2380 students from its undergraduate programmes. The facuhy has thus strengthened the human resource capacity in the health sector of most of the contributing territories of the Caribbean region and the vast majority of the undergraduates have been from Trinidad and Tobago. OBJECTIVE: To present a longitudinal study of the number of graduates from 1994 to 2008, and to highlight the number of doctors, dentists, veterinarians, pharmacists and nurses in the region and beyond, who have graduated from the programmes of the FMS. RATIONALE: The FMS, St Augustine, plays an important role in producing qualified health personnel. The study is a compilation of graduates from the UWI, FMS, St Augustine from 1994 to 2008. The first batch, which started in 1989, graduated in 1994. No other compilation of this type exists for other faculties. METHODS: Data were obtained by harvesting the names of graduates from the graduation booklets, and by cross checking administration records of the Faculty's Office. RESULTS: The study shows that fifteen of the sixteen contributing Caribbean territories have had graduates from the FMS, St Augustine, with Anguilla the one exception. Other graduates have come from beyond the region, including 16 developed and developing nations. CONCLUSION: The FMS, St Augustine, serves a key role in providing health professionals for the region. PMID- 21702248 TI - Escitalopram related erectile dysfunction and spontaneous ejaculation during micturition. PMID- 21702249 TI - Foreign body aspiration in children--a report of five cases. PMID- 21702250 TI - Penicillin V-induced drug rash with eosinophilia and systemic symptoms. AB - DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), previously named "drug hypersensitivity syndrome", is a severe adverse drug reaction characterized by skin rash, fever lymph node enlargement and internal organ involvement. We report on a 7-year old girl who developed DRESS syndrome caused by penicillin V treatment. PMID- 21702251 TI - The importance of smoking cessation as part of lung cancer control measures in Japan. PMID- 21702252 TI - The necessity for urgent suicide prevention measures in Japan based on current high rates in a review from 1980-2007. PMID- 21702253 TI - Does mild hepatitis on liver biopsy warrant immediate combination anti viral therapy in chronic hepatitis C patients? AB - BACKGROUND: Not all patients with histologically mild chronic Hepatitis C progress to cirrhosis. Many patients being treated on the basis of raised ALT and positive PCR alone may not be actually requiring it. METHODS: All adult patients suffering from chronic Hepatitis C, qualifying for combination interferon ribavirin therapy, under went liver biopsies. Tissue samples were sent to Armed Forces Institute of Pathology (AFIP) Rawalpindi for histopathology. Reporting was done according to modified Ishaq score. RESULTS: Total number of patients was 147. Out of these, 75 (51%) were female and 72 (49%) were male. Mean age of females and males were 35.1 +/- 8.12 and 36.31 +/- 8.56 year respectively. Out of these, 19 (12.9%) were stage zero, 61 (41.5%) at stage 1, and 31 (21.1%) at stage 2 of modified fibrotic Ishaq score. In all, 111 (75.5%) of the patients were < or = 2 of modified Ishaq fibrotic score in either sex or 80 (54.4%) < or = 1 of modified Ishaq fibrotic stage. The necroinflammatory score has been divided into minimal (0-3), mild (4-8), moderate (9-13), and severe (14-18). About the same number of our patients (74%) had minimal to mild inflammation. CONCLUSION: Since the majority of the patients have fibrotic score less than 3, so it will be cost effective to individualise their treatment on liver histpathology. Patients with low fibrotic score and minimal to mild inflammation may not be treated, but only monitored with serial ALT and liver biopsy every 4-5 years. Treatment may be started if there is increase in fibrosis on surveillance biopsy. However, there is a need to conduct prospective studies in similar group of patients to evaluate the natural course of disease in untreated patients. PMID- 21702254 TI - Anxiolytic effect of midazolam premedication assessed by clinical and platelet aggregation profiles. AB - BACKGROUND: It is well documented that surgery is associated with increased anxiety, which has an adverse impact on patient's outcome. This study was designed to assess the anxiolytic effect of midazolam in pre-anaesthetic medication by using clinical and platelet aggregation profiles. METHODS: Sixty ASA I and II female patients aged between 35 and 60 years undergoing elective abdominal hysterectomy were randomly divided into two equal groups. Group I received placebo as pre-medication while group II received 0.15 mg/kg midazolam as pre-medication 1 hour preoperatively. They were monitored for visual analogue scale (VAS) for anxiety, observer's anxiety criteria, sedation score, blood pressure, heart rate and platelet aggregation profile immediately before and 1 hour after pre-medication. RESULTS: There was statistically significant difference with respect to VAS of anxiety, observer's anxiety criteria, sedation scores, systolic and diastolic blood pressure (p<0.05). Heart rate was higher in the midazolam group but this was not statistically significant. There was no statistical significant difference in platelet aggregation profile in the two groups. CONCLUSION: Findings of the study suggest midazolam is a good anxiolytic for pre-medication and its effect on platelet aggregation profile needs to be further evaluated. PMID- 21702255 TI - Digoxin as a rescue drug in intra aortic balloon pump and inotrope dependent patients. AB - BACKGROUND: In absence of cardiac transplant program in our country, when patients with poor left ventricular (LV) functions undergo coronary revascularisation surgery, they are on one or more inotropic supports with intra aortic balloon pump (IABP) at the time of weaning off from cardiopulmonary bypass (CPB). Post-operatively, due to the poor LV function, many of these patients become dependent on inotropic supports and IABP and eventually have a poor outcome. We used digoxin in these patients as a rescue drug, where more than one attempts to wean them off IABP and inotropic support had failed. Objective of the study was to evaluate the efficacy of digoxin as a rescue drug in intra-aortic balloon pump (IABP) and inotropic support-dependent, post-CABG patients in terms of improvement in their left ventricular ejection fraction (LVEF), serum lactate and mixed venous oxygen saturation. METHODS: It is a descriptive case series conducted at Department of Cardiac Anesthesia & Intensive Care, Armed Forces Institute of Cardiology and National Institute of Heart Diseases, Rawalpindi, Pakistan, from 1 Nov 2002 to 31 Dec 2007. Thirty post-coronary re-vascularisation patients who were inotrope and IABP dependant and could not be weaned off from supports were given a trial of digoxin to see any improvement in the cardiac functions. Mixed venous oxygen saturation (SvO2), serum lactate levels and left ventricular ejection fraction (LVEF) in the bed side echo were monitored at predigoxin stage and then at three intervals: at serum digoxin level of up to 0.5 nanog/ml; then up to 1.0 nanog/ml and then up to 1.5 nanog/ml. Paired sample t test was applied and 2-tailed significance was calculated. RESULTS: Significant improvement was seen in the mean SvO2, serum lactate levels and LVEF when patient's serum digoxin level were around 1.5 nanog/dL. Clinically, 20 out of 30 patients (66.67%) improved with digoxin administration and were ultimately weaned off from IABP and inotropic supports. There was no significant correlation between patient's improvement and presence of diabetes mellitus or hypertension. However, pre-operative IABP placement had a significant correlation as 6 out of 8 patients (75%) were successfully weaned off at digoxin levels around 1.5 nanog/mL. CONCLUSION: Improvement in significant number of patients suggests that digoxin can be used as a rescue drug in IABP and inotropic support dependent patients after CABG surgery especially in countries where heart transplant program does not exist. However, more clinical trials with larger sample size are recommended for further evaluation. PMID- 21702256 TI - Role of 64-slice multi detector computed tomography for non-invasive visualisation of coronary artery bypass grafts for follow up in post CABG patients. AB - BACKGROUND: Coronary artery bypass graft surgery is a commonly performed revascularization procedure in ischemic heart disease patients. Conventional coronary angiography is an invasive method for evaluation of grafts in such patients. Non-invasive evaluation of grafts in post CABG patient has been made possible with the advent of 64-Slice Multi Detector Computed Tomography (MDCT) The Objective of the study was to non-invasively assess the graft patency with MDCT. METHODS: Sixty post CABG patients (52 male, 8 female) with atypical chest pain or stable angina were evaluated with MDCT for graft patency. The grafts were considered as patent if there was continuous lumen visualisation at origin, in the body and at its insertion with native recipient vessels. Grafts were defined as blocked when only stumps were seen. They were classified as stenotic if there was > or = 50% diameter narrowing. RESULTS: The mean age of the patients was 60.1 +/- 9.7 years, mean duration since CABG was 8.01 +/- 6 years. Total number of grafts assessed was 175 including 124 (71%) venous grafts and 51 (28.9%) arterial grafts. A total of 82/124 (66.1%) venous grafts and 47/51 (92%) arterial grafts were patent. Forty-two (34%) venous grafts were blocked whereas 4 arterial grafts were not developed. Arterial grafts patency was 92% and venous grafts patency was 67.7% after a mean follow up of 8.01 +/- 6 years. CONCLUSION: The study shows that 64 slice MDCT can be used for the evaluation of patency and occlusion of venous and arterial grafts in post CABG patients for follow up. PMID- 21702258 TI - Assessment of pregnancy outcome in primigravida: comparison between booked and un booked patients. AB - BACKGROUND: Primigravida (PG), defined as a woman who conceives for the first time, is in a high-risk group. Objective of this study was to evaluate the pregnancy outcome in booked and un-booked primigravida. METHODS: This was a hospital based comparative study conducted in Women and Children Hospital Abbottabad from May 1998 to November 1999. A total of 322 patients were included in the study. Inclusion criteria was all primigravida, both booked as well as un booked patients. Evaluation was done by taking detailed history, clinical examination and relevant investigations. Antenatal, intrapartum and postnatal complications were noted in the mothers. Perinatal morbidity and mortality was assessed in both the groups. RESULTS: Out of 322 cases, 52 patients were booked and 270 patients were un-booked. Majority of un-booked patients belonged to the rural areas and were from lower socioeconomic group, between the age group of 15 35 years. The rate of instrumental deliveries was high (87.5%) in un-booked patients as compared to booked patients (12.5%). Caesarean section rate in un booked patients was higher (76.5%) as compared to booked patients (23.5%). Twenty three (20%) patients of un-booked group presented in emergency mainly with obstructed labour. Twenty-two (19.8%) patients had pregnancy induced hypertension, while foetuses of 48 (43.2%) patients developed foetal distress. Antipartum haemorrhage was present in 12 (10.8%) patients, while prolonged labour with foetal distress was noted in 26 (23.4%) patients in un-booked group. Postpartum haemorrhage and puerperal pyrexia was more common in un-booked patients (7.7% and 18.6% respectively). Perinatal mortality was high in un-booked patients (19.5%) as compared to booked patients. CONCLUSION: Primigravida are high-risk patients. Comprehensive antenatal care should be provided in this group of patients to have better maternal and foetal outcome. PMID- 21702257 TI - Experience of extracorporeal shockwave lithotripsy for kidney and upper ureteric stones by electromagnetic lithotriptor. AB - BACKGROUND: Extracorporeal Shock Wave Lithotripsy (ESWL) is a non-invasive treatment of urinary stones which breaks them, by using externally applied, focused, high intensity acoustic pulse, into smaller pieces so that they can pass easily through ureter. Shock wave generation, focusing, coupling and stone localisation by fluoroscope or ultrasound are the basic components of ESWL. ESWL has some complications and is contraindicated in certain situations. The aim of this study was to evaluate the effectiveness and safety of ESWL in kidney and upper ureteric stones by Electromagnetic Lithotriptor. METHODS: All adult patients with renal and upper ureteric stones having a diameter of up to 1 Cm were included in the study. Basic evaluation such as history, examination, ultrasound and excretory urography were performed. Electromagnetic lithotripsy was done and data were collected on a printed proforma from 1st January 2008 to 30th March 2009 in Institute of Kidney Diseases, Peshawar. RESULTS: Out of a total of 625 patients 463 were male and 162 were female; 67.36% of patients were having renal stones, 23.84% upper ureteric and 8.8% both renal and ureteric stones. Complications noted were renal colic in 9.76%, haematuria in 3.2%, steinstrasse in 2.72%, and fever in 1.12% of patients. The stone free rate was 89% and 7% of patients were having stone fragments <4 mm. ESWL failed in 4% of patients. CONCLUSION: ESWL is a safe and effective way of treating kidney and upper ureteric stones. PMID- 21702259 TI - Minimal change disease, the leading cause of glomerulopathies in paediatric population at Peshawar. AB - BACKGROUND: Glomerulonephritis (GN) is a relatively rare disease with numerous subtypes. Most regional nephrology centres see only a limited number of patients with each type of GN every year. The objective of this study was to find out the pattern of glomerulopathies in paediatric population, undergoing renal biopsy in Peshawar. METHODS: This was a prospective study carried out at the Department of Nephrology, Khyber Teaching Hospital, Peshawar from May 2002 to May 2004. Ultrasound guided percutanous renal biopsies were carried out in patients with the findings of: 1) Nephrotic range proteinuria in children, 2) Non-nephrotic range proteinuria with evidence of hypertension/haematuria/deranged renal function or active sediments on urine microscopy, 3) Steroid resistant nephrotic syndrome in children, and 4) Children with nephrotic syndrome who were not tolerant of steroid therapy or were considered for immunosuppressive drugs. RESULTS: A total of 155 renal biopsies were taken. Out of these 90 were male patients and 65 were female. The most common histopathological lesion among children population was Minimal Change Disease (42.66%) followed by Focal Segmental Glomerulosclerosis (25.33%) and Membranous Glomerulonephritis (16.0%). Nephrotic range proteinuria was most prevalent in Minimal Change Disease and Membranous Glomerulonephritis followed by Focal Segmental Glomerulosclerosis. Non nephrotic range proteinuria was mostly seen in patients with Membranoprolifirative Glomerulonephritis. CONCLUSION: In paediatric population, Minimal Change Disease is the most commonly encountered glomerulopathy, followed by Focal Segmental Glomerulosclerosis and Membranous Glomerulonephritis. PMID- 21702260 TI - Open cholecystectomy without intraperitoneal drainage. AB - BACKGROUND: Cholecystectomy through laparotomy with or without intra-peritoneal drain has been the standard operation for the gall bladder disease for the last 100 years. It implies removal of gall bladder and is performed mainly for symptomatic gall stones. The Objectives was to analyse the outcome of open cholecystectomy without drain in term of complications. METHODS: Patients who underwent open cholecystectomy without drainage from January 2005 to December 2008, at Department of Surgery, Liaquat University Hospital, Jamshoro, Pakistan were included in the study. This was a 4 years prospective analysis of open cholecystectomy performed without drainage on 212 patients. Patients were randomly allocated for the procedure who presented with uncomplicated Cholelithiasis. Exclusion Criteria included carcinoma gall bladder, empyema gall bladder, Choledocholithiasis and porcelain gall bladder. All these patients underwent open cholecystectomy under general anaesthesia through various incisions. Operative time, post operative complications and hospital stay were recorded on a performa and analysed using SPSS-13. RESULTS: Two hundred and twelve patients, 199 females (93.9%) and 13 males (6.13%), age range 15 to 70 years, underwent open cholecystectomy without drainage for uncomplicated cholelithiasis. The most common complication observed includes seroma (5.66%), followed by surgical site infection both superficial and deep (3.30%) and bile leakage (1.14%). However biliary peritonitis, sub hepatic abscess and Wattman Walter's syndrome were not observed in any case. Mean operating time was 35 minutes. Mean hospital stay was 1.5 days with no mortality during the period of hospitalisation. The overall complications rate and hospital stay was significantly less when compared to open cholecystectomy with intra-peritoneal drain. CONCLUSION: In selected cases with a dry gall bladder bed, routine use of intra peritoneal drainage is unnecessary. PMID- 21702261 TI - Frequency of anxiety and psychosocial stressful events in patients with acute myocardial infraction. AB - BACKGROUND: The impact of psychological factors in acute coronary events is only now emerging. A growing body of evidence attests to the influence of emotional and stress-related psychosocial factors in the aetiology of Coronary Artery Disease (CAD) and morbidity and mortality among individuals with coronary heart disease. The objectives were to look for the frequency of anxiety and psychosocial stressful events in patients with acute myocardial infarction. METHODS: Two hundred consecutive patients of Acute Myocardial Infarction (AMI) without complications who presented to the Coronary Care Unit of Cardiology Department, Lady Reading Hospital Peshawar, and 200 healthy controls among relatives of patients were assessed on Holmes Rahe Social scale (HRS) and Hospital Anxiety and Depression Scale (HADS) scale for the presence of anxiety and stressful life events in period preceding AMI. RESULTS: Sixty-three percent of the patients were male in both groups. Mean age of patients was 59 years while that of controls was 52 years. For scores of anxiety on HADS, 34% of the controls had normal score compared to of the 19% AMI group (p<0.001), while 57% of the AMI patients had abnormal score compared to 39% of the control group (p<0.001). The number events reported on HRS scale in patients with AMI were significantly more (4.2 +/- 2) compared to the number of events (2.7 +/- 1.6) in the control group with (p<0.001). Scores for the number of events on HRS scale were significantly less (98 +/- 64) in controls compared to (158 +/- 5.8) in group with AMI (p<0.001). Anxiety was diagnosed in 70% of the female patients compared to 50% of the male patients. CONCLUSION: Significant number of patients with acute myocardial infarction when assessed on standard scales had anxiety and stressful life events in the weeks preceding the event. These were more common in female than male patients. PMID- 21702262 TI - Assessment of hepatitis B vaccination status in doctors of services hospital, Lahore. AB - BACKGROUND: Hepatitis B is the most common serious infection of the liver and can lead to premature death from liver cancer or liver failure. Of the two billion people who have been infected with Hepatitis B virus, more than 350 million have chronic infection. The objectives of this study were to assess the Hepatitis B vaccination status, reasons for non-compliance and the risk of exposure to doctors at a tertiary care hospital. METHODS: Three hundred and twenty-two doctors were selected from the various departments of the hospital by simple random sampling. They were given a self-administered questionnaire after taking verbal consent. Some doctors refused to fill-in the questionnaire while some others were on leave during the time of study and the remaining 215 doctors responded to the questionnaire. RESULTS: A total of 215 doctors, (age range 22-59 years) responded to the questionnaire. Amongst them 11.6% had not received even a single dose of Hepatitis B vaccine while 14.4% had not completed the required course of vaccination. Most common reason cited by doctors for non-immunisation was that they had not thought about it. Consultants were more likely of the other doctors to have received completed vaccination (83.9% versus 69.9%) (p<0.05). They were also significantly more likely to know their antibody titre after completing vaccination. Needle stick injuries were common. One hundred and forty five doctors in the study admitted having received at least one needle prick/sharp injury. Of them, 51.6% had received a needle prick/sharp injury more than once. CONCLUSION: Despite the availability of an effective vaccine in the market doctors continue to remain non-vaccinated. It is the lack of awareness and carelessness on part of doctors coupled with the negligence of the risk that has led them being incompletely vaccinated. There is a need to ensure that every doctor is completely vaccinated against Hepatitis B before he/she enters professional practice. PMID- 21702263 TI - Frequency of left atrial and appendage clot in patients with severe mitral stenosis. AB - BACKGROUND: Left atrial thrombus is common in patients with mitral stenosis and atrial fibrillation; but how frequent it is in our population? The objective of study was to see the frequency of left atrial and appendage clot on trans oesophageal echocardiography in symptomatic patients with severe mitral stenosis planned for PTMC. METHODS: Trans-oesophageal echocardiographic data retrieved from computer database Cardiology department, Lady Reading Hospital, Peshawar from August 1998 to Mach 2008. Patients admitted for PTMC under went trans oesophageal echocardiography for detection of left atrial and appendage clot and quantification of mitral regurgitation. Data was analyzed on SPSS. RESULTS: Out of 1544 patients, males were 608 (39.4%), females were 936 (60.6%). Mean age was 30.84 +/- 12.6. Mean age of males was 30.56 +/- 13.1 years and females were 31.02 +/- 12.6 years. Minimum age was 8 years and maximum was 76 years. The mean LA size was 43.82 +/- 2.12 mm.Atrial fibrillation was observed in 289 (18.7%).Overall clot was seen in 224 (14.5%) patients. Left atrial appendage clot seen in 202 (89.73%).LA clot seen in 9 (4.02%). LAA/LA clot seen in 14 (6.25%). No significant difference was observed for clot among the gender distribution (p=0.42). Significant correlation was observed for clot in patients with AF and LA size > or = 45 mm, (p>0.001). CONCLUSION: The frequency of left atrial and appendage clots on trans-oesophageal echocardiography in patients with severe mitral stenosis is common and more frequent in patients with AF and LA size > or = 45 mm. PMID- 21702264 TI - False positivity of serological tests for hepatitis C virus. AB - BACKGROUND: Hepatitis C virus infection is now one the common infection in Pakistan. Patients are routinely screened by antibody assays. Objective of this study was to assess the viremia in patients labelled as anti-HCV positive by ELISA. METHODS: It this retrospective study patients labelled as anti HCV positive by ELISA were assessed for HCV RNA by polymerase chain reaction. The 254 HCV positive cases which were analysed by MEIA method on AxSYM System were selected for RNA extraction by RT-PCR upon Cepheid thermal cycler using TaqMan technology and subsequent for amplification. RESULTS: Out of 254 anti HCV positive by ELISA, viremia was shown in 211 patients; the remaining 43 (16.92%) samples were false positive. CONCLUSION: Out of a total 254 anti HCV positive patients, 211 had viremia by RT-PCR. The false positivity noted was 16.9%. PMID- 21702265 TI - Laparoscopic cholecystectomy: an experience at Lady Reading Hospital, Peshawar. AB - BACKGROUND: Laparoscopic Cholecystectomy originally a minimal invasive surgical technique involving less hospital stay less economical burden decreased post op complication and early mobility. The objective was to analyse data of patients undergoing laparoscopic cholecystectomy at a surgical setup. METHODS: This study was conducted at the Department of Surgery, Lady Reading Hospital, Peshawar from 11th January 2006 till 10th January 2009. Patients aged above 14 year, presenting in the outpatient department with clinical and ultrasonographic evidence of cholecystitis and undergoing laparoscopic cholecystectomy were included in the study. The procedure performed was predominantly the four port technique for laparoscopic cholecystectomy. A proforma was prepared to collect preoperative, operative, and postoperative data. Operative data included the technique used and the difficulties ascertained during those procedures. Data was analysed using SPSS-13.0. RESULTS: Of 421 patients, 387 patients fulfilled the criteria for admission to undergo the procedure. The mean age of all patients was 38.6 +/- 7.1 year ranging from 16 years to 72 year with a male to female ratio of 1:8.09. During the first six months 57 patients underwent the procedure for which the mean operating time was 67.4 min. During the last six months the mean operating time was 39.1 +/- 8.9 minutes. The overall rate of conversion of laparoscopic cholecystectomy was 6.4%. In comparison the last six months of the study showed one case (1.16%) in 86 patients being converted to open cholecystectomy. The most common cause foe conversion of the laparoscopic procedure to an open cholecystectomy was dense adhesions making dissection of the triangle of Calot's difficult. In 73 cases (21.4%) the gall bladder was perforated during dissection of gall bladder from the gall bladder bed. CONCLUSION: The out comes of this study during the last six months is comparable to studies conducted at more experienced centres making laparoscopic more than just an early experience in this part of the world. PMID- 21702266 TI - Plasma homocysteine in patients of migraine without aura. AB - BACKGROUND: Few studies have studied the role of homocysteine in migraineurs and have produced conflicting results. The MTHFR C677T genotype has been associated with increased risk of migraine in selected clinical samples. We assessed the association of the MTHFR C677T variant with migraine, the corresponding homocysteine levels and their correlation. METHOD: We studied 27 random adult migraineurs with aura (MWA), migraine without aura (MWOA), and 32 non-migraineurs (controls) from Lahore, Pakistan in this pilot study which is still under progress. RESULTS: We found significant differences in homocysteine levels between various diagnostic groups (K-W test: p=0.005). One-way ANOVA, post-hoc tests revealed significant differences in homocysteine levels between Non migraineurs, MWA (p=0.002, CI: 1.93 - 9.19) and MWoA (p=0.002, CI: -9.19 - -1.9). We found a significant association between the migraine group and C677T-MTHFR variant mutant allele (C/T) (p=0.039). We did not find a significant association between C677T-MTHFR variant and homocysteine levels. CONCLUSION: In this pilot study, we found plasma homocysteine levels to be significantly associated with MWOA. Additionally, plasma homocysteine levels were lower in MWA than in MWOA. Furthermore, we did not find a relationship between homocysteine levels and the MTHFR variant (SNP rs1801133). Lastly, there may be a relationship between the MTHFR variant (SNP rs1801133) and migraine in this population. PMID- 21702267 TI - Frequency of sputum positive AFB cases among patients of pulmonary tuberculosis in tertiary care hospitals of northern Pakistan. AB - OBJECTIVE: This study was aimed to find out the frequency of sputum positive Acid Fast Bacilli (AFB) cases among pulmonary tuberculosis patients and to determine those patients who are the potential source of transmitting infection. METHODS: This study was conducted in four medical units of Khyber Teaching Hospital, Peshawar and Chest Unit, Ayub Teaching Hospital, Abbottabad in collaboration with the pathology unit of Khyber Teaching Hospital, Peshawar, and Kohat Institute of Medical Sciences, Kohat. Three specimens of sputum were collected for three consecutive days in the morning and were transported immediately to the laboratory along with full details of the patients. RESULTS: Out of two hundred total patients studied, 104 patients (52%) were sputum AFB positive. Among the 104 patients 60 patients (57.4%) were females. Sixty-four (61.52%) individuals were between 20-50 years. Majority of the patients were from poor, deprived and lower social class. Fifty-two (50%) patients had monthly income of less than Rs. 4,000; only 8 patients (7.67%) had monthly income of more than Rs. 12,000). Forty eight patients <46.12% were house wives, 10 patients (9.61%) were unemployed. Most of the patients were under weight for their age and height. 24 patients (23.06%) were below 42 kg. The maximum (53.84%) number of patients was in weight range of 43-50 kg. CONCLUSION: Sputum AFB positive pulmonary tuberculosis is more in individuals of low socioeconomic group and in females. The patients put their children and family members at risk of tuberculosis infection. For the control of this disease early diagnosis of active disease and their treatment under supervision is important. PMID- 21702268 TI - Reverse ulnar parametacarpal artery flap for soft tissue defects of hand. AB - BACKGROUND: Burn injuries and post burn contractures of the little fingers and areas around are quite common. Release of these contractures may lead to full thickness soft tissue defects which need soft tissue cover. Similarly, mechanical trauma and also road traffic accidents, quite often lead to soft tissue defects of hand. Objective of this study was to evaluate the role of reverse ulnar parametacarpal artery flap in providing soft tissue cover for various full thickness soft tissue defects at the base of little finger and adjacent areas on palmar and dorsal aspects. METHODS: It was an observational study, conducted at Department of Plastic Surgery, Services Hospital, Lahore. Study included ten cases with three females and seven male patients. Six of the patients had severe post-burn contractures of little finger, two had the involvement of the adjacent palm areas as well and one case had contracture along the mid palm crease. One case had post mechanical trauma soft tissue defect at dorsal aspect of 4th web space. Contractures were released and resulting soft tissue defects were reconstructed with reverse ulnar parametacarpal artery flap. Age ranged from 9 to 42 years with a mean age of 20.3 years. RESULTS: This flap was utilised in ten cases. All flaps survived, one of the cases developed epidermolysis of whole of the flap which healed uneventfully. CONCLUSION: Flap is a local option to cover the soft tissue defects of little finger and areas around thus involves the same operative field. Skin texture and features of the donor site also resemble the recipient area. The defect site is closed primarily. PMID- 21702269 TI - Small gut atresia in neonates. AB - BACKGROUND: Small gut atresia is a common neonatal surgical problem. Early diagnosis and timely management of the neonate can reduce mortality and morbidity in these patients. The aim of this study was to note the causes of mortality and morbidity in these neonates. METHODS: This was a prospective study conducted at Lady Reading Hospital (LRH) Peshawar from August 2007 to August 2009. All patients with small gut atresia were included in this study. Neonates having intestinal obstruction due to another cause were excluded from this study. The diagnosis of small gut atresia was usually established peroperatively as other causes of intestinal obstruction like meconium ileus or meconium plug syndrome etc. in neonatal period mimic small gut atresia. RESULTS: A total of 40 neonates with small gut Atresia were included in this study. Among them 28 were males and 12 were females. Age of presentation ranged from 1 to 8 days. Weight of the neonates ranged from 1.8-2.8 Kg with the mean weight of 2.43 Kg. Peroperatively type-III(a) Atresia was the commonest type 20 (50%). Resection and end to end anastomosis was done in 31 cases. Nine neonates needed ileostomy. Financial constraints, late presentation, aspiration, sepsis, gut perforation and gangrene were the main contributors to death of these neonates. CONCLUSION: Neonates having small gut atresia should be treated at a centre equipped for dealing neonates during all stages of management. PMID- 21702270 TI - Detection of cerebral atrophy in type-II diabetes mellitus by magnetic resonance imaging of brain. AB - BACKGROUND: Diabetes is a metabolic disorder that affects many systems in the body. Cerebral atrophy is one of the complications of diabetes and research is on going to find out its aetiopathological factors. The main aim of the study was to determine the frequency of cerebral atrophy in type-II diabetes mellitus using magnetic resonance imaging of the brain. METHODS: One hundred diabetic patients (Random blood sugar >126 mg/dl) were recruited in this study after the informed consent from every patient. Duration of diabetes was five years and more in all the patients as determined by their glycosylated haemoglobin which was >6 in all the patients. All the patients were undergone MRI of brain using 1.5 Tesla power magnetic resonance imaging machine ofPicker Company. Evan's index, a specific parameter for measurement of cerebral atrophy was calculated on MR images and was used in this study. RESULTS: In male group the frequency of cerebral atrophy was 22 (47%) and in female group it was found to be 23 (43%). When we study the overall population the frequency was found to be 45 (45%). The results are well in concordance with the previous data published on this issue. CONCLUSIONS: Cerebral atrophy, a complication of long standing diabetes is quite frequent in our population and is well diagnosed by MRI. PMID- 21702271 TI - Comparison of ambulatory and inpatient cleft lip surgery for adults. AB - BACKGROUND: Ambulatory cleft lip repair after its acceptance in developed countries is also becoming popular in developing world. This study was performed to compares the outcomes of ambulatory cleft lip repair with the inpatient group for adult patients. Objectives were to compare outcome after ambulatory and inpatient cleft lip surgery for adults with respect to perioperative complications (Early: pain, oedema of upper lip, bleeding, nausea or vomiting, infection, dehiscence; Late: visible scar and white roll discrepancy), to compare the economic benefits, and evaluate patient satisfaction in terms of acceptance for ambulatory surgery. METHODS: This comparative study is carried out in Plastic Surgery Department, King Edward Medical University, Mayo Hospital, Lahore. The study included 80 adult patients fulfilling inclusion criteria and were randomly divided into two groups, i.e., Ambulatory (Group-A, n=40) and Inpatient (Group-B, n=40). Those belonging to ambulatory group were worked up on OPD basis, advised to report on morning of surgery, operated under loco-regional anaesthesia and were discharged on same day. Patients of inpatient group were admitted two days before surgery, worked up in ward, operated under general anaesthesia and were discharged on 2nd day. RESULTS: Ambulatory cleft lip surgery can be easily performed under loco-regional anaesthesia. Perioperative complications between these groups were comparable. Hospital stay was significantly reduced in ambulatory surgery. The patients felt more satisfied after ambulatory than inpatient surgery. CONCLUSION: Ambulatory cleft lip repair for adults is as safe as inpatient surgery. It is dependable option and can be successfully performed in our setup. It should be considered whenever possible due to cost effectiveness, reduction of waiting lists, earlier discharge and better utilisation of hospital resources. PMID- 21702272 TI - Clinical and radiological findings in Arnold Chiari malformation. AB - BACKGROUND: The Chiari Malformation I (CMI) is a disorder of uncertain origin that has been traditionally defined as downward herniation of the cerebellar tonsils through the foramen magnum. The anomaly is a leading cause of syringomyelia and occurs inassociation with osseus abnormalities at the craniovertebral junction. In contrast to other Chiari malformations, CMI tends to present in the second or third decade of life and is sometimes referred to as the 'adult-type' Chiari malformation. The objective was to document clinical and radiological findings in Arnold Chiari Malformation-I. METHOD: This was a descriptive study carried out in Ayub Teaching Hospital Abbottabad at Neurosurgery Department during July 2008-July 2010. We examined a prospective cohort of 60 symptomatic patients. All patients underwent magnetic resonance imaging of the head and spine. RESULTS: There were 40 female and 20 male patients. The age of onset was 24.9 +/- 15.8 years. Common associated radiological problems included syringomyelia (60%), scoliosis (25%), and basilarinvagination (12%), increased cervical lordosis 5 (8.5%), and Klippel Feil syndrome 2 (3.3%). The most consistent magnetic resonance imaging findings were obliteration of the retrocerebellar cerebrospinal fluid spaces (70% patients), tonsillar herniation of at least 5 mm (100% patients), and varying degrees of post fossa anomalies. Linical manifestations were headaches, pseudotumor-like episodes, a Meniere's disease-like syndrome, lower cranial nerve signs, and spinal cord disturbances in the absence of syringomyelia. CONCLUSION: These data support accumulating evidence that CMI is a disorder of the para-axial mesoderm that is characterised by underdevelopment of the posterior cranial fossa and overcrowding of the normally developed hindbrain. Tonsillar herniation of less than 5 mm does not exclude the diagnosis. Clinical manifestations of CMI seem to be related to cerebrospinal fluid disturbances (which are responsible for headaches, pseudotumor-like episodes, endolymphatic hydrops, syringomyelia, and hydrocephalus) and direct compression of nervous tissue. PMID- 21702273 TI - Importance of physical examination in early detection of lump in breast in women of different age groups. AB - BACKGROUND: The spectrum of breast lesions in adolescents varies markedly from that for adults, with the former lesions being overwhelmingly benign. Fine needle biopsy can be used to distinguish benign and malignant tumour. STUDY DESIGN: This study examined the characteristics and outcome of women with different age groups in whom physical examination was their sole method of lump in breast detection. PATIENTS AND METHODS: A total of 200 patients were included in the study. These were divided into 3 groups. Group A was consisting of 75 girls with age of pubescent. Group B included 69 suspected breast cancer women with age range 26-38 years. Fifty-six suspected breast cancer women with age range 41-60 year were included as group C. Study was carried out in patients admitted in the Department/Out-door of Surgery, Sir Ganga Ram Hospital, Lahore, Pakistan. Study period was 6 months. All women received a physical examination by a breast surgeon. Proforma including demographic and clinical characteristics were filled. The diagnosis for patients in this study was achieved by core needle biopsy using a 14-gauge cutting needle. RESULTS: It was observed that early age at menarche (<15 year) plays an important role in developing both type of tumour, i.e., benign or malignant. Body Mass Index (BMI) with a range of 19-25 may be a risk factor in developing both type of tumours especially in pubescent and reproductive age, while BMI>25 may be a risk factor in peri/post menopausal women. Active life style is more important with increasing age as it decreases the risk of developing tumour state. Family history was more common in women with peri/post menopausal status as compared to other age groups. Clinical characteristics showed that lump size <2.5 cm was more common in both pubescent and reproductive age. While lump size with a range of 2.5-5.0 cm, was observed in all groups of patients. Fibroadenoma is observed in almost all women with pubesenct age while both benign and malignant tumour observed in women with reproductive age. Malignant tumour was observed mostly in women with peri/post menopausal status. CONCLUSION: Study concluded that early detection or clinical examination with FNA cut out the patients from harassment of malignancy and complications especially in the pubescent age. It is also found that Physical examination remain the useful indicators of prognosis in diagnosing cancer. Further research is needed to fully understand the reasons for variations in breast disease outcomes i.e. malignant or benign. PMID- 21702274 TI - Frequency of otitis media in patients of nasal polypi. AB - BACKGROUND: Otitis media is a common disease encountered in ENT practice. Its incidence has fallen in the developed world. It is expected that nasal polypi causes Eustachian tube dysfunction which in turn leads to negative middle ear pressure causing to develop otitis media with effusion or recurrent otitis media. The objective of this study was to find the frequency of Otitis Media in patients of nasal polypi. SUBJECTS AND METHODS: It was a cross-sectional study. Seventy patients with bilateral nasal polypi were taken for study from OPD of ENT Department, Fauji Foundation Hospital Rawalpindi. Purposive (non-probability) sampling was done keeping p=4%. There were 24 (34.3%) males and 46 (65.7%) females included in the study. Age range was 26-38 years. Tympanometry was done in every patient to look for signs of Otitis media. Duration of study was from 24th Apr 2008 to 30th Jul 2009. RESULTS: In our study, all patients were having bilateral nasal polypi. Age range was between 26 and 38 years. Frequency of patients having retracted tympanic membrane on right side was 25 (35.7%), and those who developed it on left side was 30 (42.9%). However, 35 (50%) of the 70 patients were having retraction of tympanic membrane whether right or left. This shows frequency of otitis media in patients of nasal polypi was found to be 50%. CONCLUSION: Frequency of developing otitis media in patients of nasal polypi is quite high. Nasal problems lead to development of ear diseases. PMID- 21702275 TI - Role of interleukin-1 in pathogenesis of radicular cyst. AB - BACKGROUND: Interleukin-1 (IL-1) is one of the cytokines produced by macrophages, monocytes and dentritc cells. Macrophages are present in apical granuloma and the wall of the radicular cyst. This cytokine causes the cyst expansion and is involved in proliferation of fibroblasts in the cyst wall and stimulate the fibroblasts to produce more prostaglandin. Radicular cyst is the most common cyst of the jaws which is usually associated with necrotic pulp of the tooth. The cyst formation requires proliferation of the epithelial rest cells of Malassez present in the periodontal ligament. Proliferation of epithelial rest cells of Malassez is an essential event in the Pathogenesis of radicular cyst. Objective of the study was to investigate the effect of IL-1 on epithelial cell proliferation which is an important factor in the pathogenesis of radicular cyst. METHODS: The cyst walls of 20 radicular cysts were removed and were cultured in vitro to grow the epithelial cells. The culture were rapidly contaminated and dominated by growth of fibroblasts. Therefore another cell line was used for the experiments. RESULTS: The result showed that proliferation was stimulated with increased in a biphasic manner with maximum stimulation at 1.25 nanog/ml, beyond this concentration proliferation was decreased. CONCLUSION: IL-1 had a proliferative effect on epithelial cells at low concentrations which may be playing a role in evoking an inflammatory reaction and stimulating the epithelial cell rests of Malassez to proliferate to form radicular cyst. PMID- 21702276 TI - Frequency of causes of ascites in patients admitted at medical unit of a tertiary medical care facility. AB - BACKGROUND: Ascites can be defined as accumulation of free fluid in the peritoneal cavity. It is the most common complication of cirrhosis and is associated with a poor quality of health, increased risks of infections, renal failure and a poor long-term outcome. This descriptive analytical study was conducted on one hundred and fifty diagnosed patients of ascites consecutively admitted in medical unit of tertiary care facility attached to Muhammad Medical College, Mirpur Khas, Sindh, from Oct 2006 to Sep 2008. METHODS: Special proforma was prepared containing patients' basic information, history, clinical findings and investigations necessary to diagnose the cause of ascites. Patients with ascites due to perforation and intraperitoneal bleeding were excluded from the study. Serum-ascitic albumin gradient (SAAG) was calculated and patients were grouped into high and low SAAG groups. The obtained data was analysed using SPSS- 11. RESULTS: In this study 150 patients of ascites were included. Patients were arranged in two groups. High SAAG 'high portal pressure' group and low SAAG 'low portal pressure' group. In high SAAG group patients included were 128 (85.33%), and in low SAAG group patients included were 22 (14.66%). In high SAAG group, out of 128 (85.33%) patients 122 (81.33%) were of cirrhotic ascites, [(viral hepatitis B, C and combined 105 (70%), alcoholic 7 (4.66%), cryptogenic 10 (6.66%)], heart failure ascitic patients were 5 (3.33%), and constrictive pericarditis 1 (0.66). In low SAAG group out of 22 (14.66%) patients malignant ascites was (primary peritoneal carcinomatosis and metastasis) 11 (7.33%), tuberculous ascites was 10 (6.66%), and ascites due to nephrotic syndrome was 1 (0.66%). CONCLUSION: As large number of cases of ascites are due to cirrhosis of liver that has little or no cure in developing countries. Media and NGO's should further work to increase awareness of this deadly problem. PMID- 21702277 TI - Frequency and types of bodily medico-legal injuries in a rural area. AB - BACKGROUND: The primary objective of the study was to know the types and frequency of the bodily medico legal injuries in a rural setup. METHODS: Data was retrospectively collected by selecting 55 cases consecutively. Data of injury types was analysed. RESULTS: The number of injured males in this study was 48 (87.3%) while the females were 7 (12.7%). The most common type of injuries were shajja (45.9% among males and 71.4% among females). CONCLUSIONS: Our study shows relatively true picture of frequency and types of injuries. It was observed that male population is more prone to violence than females owing to the conservative life style of women in our society. PMID- 21702278 TI - Management of ruptured amoebic liver abscess: 22-years experience. AB - BACKGROUND: Amoebiasis affects approximately 10% of the population all over the world. Amoebic liver abscess (ALA) is the commonest complication of amoebiasis affecting 3-9% victims. It is an ancient disease as Hippocrates notified large hepatic abscesses likely to be amoebic abscesses. Objective of this study was to see the efficacy of conservative treatment in the management of ruptured amoebic liver abscess. METHODS: Record of 1,083 patients of amoebic liver abscess, who were treated and managed at Liaquat University Hospital between January 1986 and December 2007, was reviewed retrospectively. Amongst these, 36 (3.32%) patients, found to have intra-peritoneal rupture of the liver abscess were included in this study. The record of these patients was reviewed. The patients were divided into group A and B depending upon the mode of treatment employed. Group A included 16 (44.44%) patients in whom exploratory laparotomy was performed while group B included 20 (55.55%) patients who were treated conservatively. RESULTS: Group A consisted of 16 (44.4%) patients who underwent laparotomy for acute peritonitis due to non-availability of ultrasound in the initial period of the study. In group B, all twenty patients were treated conservatively after a diagnosis of ruptured amoebic liver abscess made by ultrasound guided percutaneous aspiration of pus. These patients were treated with ultrasound guided aspiration of pus with placement of peritoneal drain under local anaesthesia. Six patients in group A died compared to one patient in group B. the overall mortality of ruptured amoebic liver abscess was 19.4%. It was higher in patients treated surgically (37.5%) compared to patients who were treated conservatively (5%). CONCLUSION: Conservative treatment is an effective modality of treatment for ruptured liver abscess with minimum mortality and mortality if diagnosis is made early. PMID- 21702279 TI - Morbidity and mortality associated with obstetric hysterectomy. AB - BACKGROUND: Obstetric hysterectomy still complicates a substantial number of pregnancies in third world countries and is a significant cause of obstetric morbidity and mortality. This study was carried out to evaluate in our setup the frequency of obstetric hysterectomy, its indication, risk factors, complication, morbidity, mortality and avoidable factors. METHODS: A descriptive study of all patients who under went obstetric hysterectomy was conducted from 1st May, 2004 to 31st October, 2005 at Gynaecology and Obstetric Unit-II, III of Liaquat University of Medical and Health Science Hospital, Hyderabad. After collecting the data on pre-designed proforma the data was fed to SPSS in the form of frequency distribution tables and percentages were calculated. Statistical analysis of data was performed by using Chi-square test. The level of significance was taken as p<0.05. RESULTS: During the study time period there were total 6495 deliveries and 41 cases of obstetric hysterectomy were identified, giving a frequency of 0.63% or 1 in 158 deliveries. Most of patients were from rural areas (82.92%), un-booked 73.17%), uneducated (95%), lower socioeconomical class (92.69%), 25-29 years age (48.78%) multiparae (56.10%), have to travel a distance of <100 km to reach hospital and referred late (51%) by healthcare providers (doctors). Majority of hysterectomies were performed due to ruptured uteri (51.21%). There were 5 maternal and 26 perinatal deaths; all were due to severity of conditions necessitating hysterectomy. CONCLUSION: Incidence of obstetric hysterectomy in our woman is very high. The reason being many avoidable factors such as high parity, inadequate maternity and family planning services, lack of proper referral system, un-booked status, mismanaged labour, illiteracy on the part of woman herself, family and health care providers are not taken care of during pregnancy, labour and puerperium. PMID- 21702280 TI - Maternal morbidity and perinatal outcome with twin pregnancy. AB - BACKGROUND: Multiple pregnancy still warrants special attention as it is associated with increasing risk for mother and foetus. Preterm delivery increases the risk for baby. This study was conducted to evaluate the risks of pregnancy complications and adverse perinatal outcome in women with twin pregnancy. METHODS: It was 2 years observational study from July 2007 to July 2009 at Department of Obstetrics and Gynaecology, Liaquat University Hospital, Jamshoro. All women admitted to the labour ward with multiple pregnancy after 28 weeks gestation were included in the study. Main outcome measures were maternal complications (i.e., anaemia, preterm labour, pregnancy induced hypertension, postpartum haemorrhage etc.), perinatal morbidity and mortality. All data collected was analysed using SPSS-16. RESULTS: Incidence of multiple pregnancy in this study was 1.44%. Majority of women 52 (81%) were un-booked and only 12 (18%) were booked; 54 (84%) women presented with preterm labour, 10 (15.6%) were at > or = 36 weeks of gestation. Fifty-four (84%) patients presented with preterm labour. Anaemia was found in 42 (65.6%), and hypertension was noted in 31.2% cases. Abruptio placentae occurred in 6.2% of cases, prematurity was the major problem (54, 84.3%). Majority presented between 28-35 weeks gestation, 10 (15.6%) delivered at 36 weeks or above. The most common cause of neonatal death was very low birth weight (in 32.8% cases), followed by sepsis and jaundice. CONCLUSION: Multiple pregnancy is associated with increasing risk for mother and foetus. Preterm delivery increases the risk for baby. PMID- 21702281 TI - Comparative analysis of attitudes and perceptions about rape among male and female university students. AB - BACKGROUND: Rape and other forms of violence against women have been reported to be common in Pakistan, and police is often reluctant to register a rape complaint. We assessed and compared the attitudes and perceptions of male and female university students towards rape of females by males. METHODS: A cross sectional survey with convenience sampling was conducted among the male and female students of Quide-e-Azam University, Islamabad. A structured, self administered, anonymous and pre-tested questionnaire was used with close-ended questions. Students were asked about their attitudes and beliefs regarding characteristics of the female rape victims, male perpetrators and contexts in which this type of violence is more or less likely. Interviewers approached conveniently-selected participants and explained the objectives of the survey, while emphasising voluntary participation in this study. Data was analysed for frequencies and counts, while Chi-square test was used to for pairwise comparisons between male and female students with STATA 9. RESULTS: Five hundred and four students, 247 male and 257 female, completed the questionnaire. Male students were more likely to believe that strong character of a woman would ostensibly shield her from the advances of a rapist; only young and pretty women get raped; woman's willingness is present in rape. About 25% of students also believed that a raped woman is not worthy of becoming another man's wife. One third of students believed that there could be no rape in marital context. CONCLUSION: Rape myths were common in our educated study respondents with significant gender differences. Attitudes and beliefs blaming the female victim of rape were more common in males. PMID- 21702282 TI - A new approach for estimation of body mass index using waist and hip circumference in type 2 diabetes patients. AB - BACKGROUND: Body mass index (BMI), derived by dividing weight (Kg) by the square of height (m), is a useful anthropometric parameter, with multiple applications. It is dependent upon accurate measurement of its component parameters. Where measurement of height and weight with calibrated instruments is not possible, other objective parameters are required to maintain accuracy. OBJECTIVES: We aimed to propose an alternate prediction model for the estimation of BMI based on statistical linear regression equation using hip and waist circumferences. Our objective was to ascertain the accuracy of estimated BMI when compared with observed BMI of patients, and to propose a model for BMI prediction which would overcome problems encountered in the prediction of body mass index of critically ill or immobile patients, needed for applications such as BMI based calculations in ventilation protocols in ICUs. METHODS: This cross sectional survey was done by reviewing hospital records of adult subjects of both genders (n=24,485; 10,687 males and 13,798 females), aged 20 years and above, who were diagnosed with type 2 diabetes. Two different prediction models were designed for males and females keeping morphological and physiological differences in gender. The measured waist and hip circumference values were used to estimate BMI. RESULTS: Data analysis revealed a significant linear relationship between BMI, waist and hip circumference in all categories [waist circumference (r=0.795, p=0.000), hip circumference (r=0.838, p=0.000)]. Estimated regression models for males and females were BMI=-10.71+0.212 (hip cir)+0.170 (waist circumference); and BMI= 15.168+0.143 (hip circumference)+0.30 (waist circumference) respectively. CONCLUSION: Estimation of BMI using this prediction model based upon measured waist and hip circumferences, is an alternate and reliable method for the calculation of BMI. PMID- 21702283 TI - Postmenopausal bleeding: causes and risk of genital tract malignancy. AB - BACKGROUND: Postmenopausal bleeding (PMB) is bleeding occurring after 6-12 months of amenorrhea in a woman of age where the menopause can be expected. Objectives of this study were to ascertain various causes and prevalence of genital organ malignancy in patients presenting with postmenopausal bleeding. METHODS: A prospective observational study carried out in the Department of Obstetrics and Gynaecology, Fauji Foundation Hospital, Rawalpindi comprising of 167 consecutive cases presenting with postmenopausal bleeding one year after menopause. Women having undergone hysterectomy and bilateral salpingo-oophorectomy, receiving radiotherapy or chemotherapy, suffered trauma to the genital tract, having coagulation disorder or on anticoagulant or hormone replacement therapy were excluded. Detailed history was obtained and a thorough clinical examination was conducted. Data were entered into hospital computer database (Medix) system. Mean +/- SD were calculated for age, percentage was calculated for types of histopathological findings. RESULTS: The commonest cause of PMB was atrophic endometritis and vaginitis 33 (21.2%). Overall incidence of various genital tract malignancies was 25 (16.0%). CONCLUSION: The overall incidence of genital tract malignancies in patients presenting with PMB is high (16.0%), therefore, it needs to be taken seriously and requires prompt and thorough investigations. PMID- 21702284 TI - Quality of life in patients with obturator prostheses. AB - BACKGROUND: Oral cancer has a profound impact on the quality of life for patients and their families. Functionally, the mouth is an important organ for speech, swallowing, chewing, taste and salivation. These functions become compromised due to surgical ablation of the tumour. Obturator prosthesis is a common prosthdontic rehabilitative option for maxillectomy patients. The purpose of this study was to investigate how patients with maxillofacial defects evaluate their quality of life after maxillectomy and prosthodontic therapy with obturator prostheses. METHODS: Thirty patients were included in the study (11 female, 19 male). The patients were interviewed by using a standardised questionnaire developed by University of Washington (UW-QOL). The detailed questionnaire was adjusted for obturator patients and internalised most parts of obturator functioning scale (OFS). RESULTS: Quality of life after prosthodontic therapy with obturator prostheses was 54 +/- 22.9% on average. Functioning of the obturator prosthesis, impairment of ingestion, speech and appearance, the extent of therapy, and the existence of pain had significant impact on the quality of life (p<0.005). CONCLUSION: Orofacial rehabilitation of patients with maxillofacial defects using obturator prostheses is an appropriate treatment modality. To improve the situation of patients prior to and after maxillectomy sufficient information about the treatment, adequate psychological care and speech therapy should be provided. PMID- 21702285 TI - Assessment of knowledge about evidence based medicine in medical students and doctors in a Pakistani health care setting. AB - BACKGROUND: Evidence based practice promotes self assessment and ensures delivery of up to date care to patients. The concept of Evidence Based Medicine (EBM) in developing countries is still in its infancy where strong opinions drive patient care. METHODS: We conducted a cross sectional survey to explore the knowledge, perceptions and attitudes regarding EBM in final year medical students and physicians of our institution. The survey was distributed to all students and residents of the college and the affiliated hospital. RESULTS: The response rate was 57% (74/130). Seventy-one percent (53/74) of respondents were not aware of EBM. Out of these, 38 were medical students and 15 were house officers. Only 16 (9 students and 7 doctors) admitted that they had heard about EBM. Those who heard about EBM recognised its importance in patient care. Teaching at both under and postgraduate level was strongly suggested. Participants recognised the need for EBM skills and expertise. Financial constraint was considered as the main hindrance in practicing EBM. CONCLUSION: The concept of EBM is still alien to most of the students and residents at our institution. There is need for incorporating formal teaching of EBM at all levels of medical education. PMID- 21702286 TI - Prevalence of hypertension among obese and non-obese patients with coronary artery disease. AB - BACKGROUND: Globally, obesity is now recognised as an epidemic. The degree of obesity is proportional to the rate of development of cardiovascular diseases, hence, resulting in a dramatic increase in morbidity and mortality. Apart from obesity, hypertension is another well recognised risk factor contributing to coronary artery disease (CAD). The precise prevalence of obesity-related hypertension varies with age, race and gender; and is yet unknown in our population. The objective of this study was to determine the prevalence of hypertension in obese and non-obese patients with diagnosed CAD. METHODS: This hospital based descriptive study was conducted in Cardiology Department of Postgraduate Medical Institute, Lady Reading Hospital, Peshawar from 15th March 2007 to 30th May 2008. A total of 200 patients with diagnosed CAD were enrolled, 100 were found obese and 100 non-obese. RESULTS: Among these, a total of 111 (55.5%) were found to be hypertensive, 66 (59.46%) of these were obese and 45 (40.54%) non-obese (p=0.003). CONCLUSION: Obese patients with CAD had significantly more frequent hypertension. PMID- 21702287 TI - Clinical usefulness of Tc-99m hexakis 2-methoxyisobutyl isonitrile gated spect in patients with dilated cardiomyopathy: retrospective analysis. AB - BACKGROUND: In Dilated cardiomyopathy the heart is enlarged and ventricles are dilated. Gated myocardial perfusion single photon emission computed tomography is considered state of the art for myocardial perfusion imaging. A retrospective analysis was conducted to evaluate patients with dilated cardiomyopathy with Tc 99m sestamibi gated myocardial perfusion single photon emission computed tomography to evaluate its clinical utility. METHODS: A 10 year retrospective medical record review was done from 1991 to 2001 at Wake Forest University, North Carolina, USA. Eligibility criteria included a diagnosis of dilated cardiomyopathy and availability of coronary angiography and Tc-99m sestamibi cardiac imaging results. 26 cases were selected for the final review and inclusion in the study. The study was done with standard protocols for cardiac sestamibi imaging. RESULTS: A total of 26 cases were included in the final analysis. Cases were divided into two main groups. Group-A included 16 patients with no correlation between Tc-99m sestamibi and cardiac catheterisation reports. Group-B included 10 patients with good correlation between the above tests. There were no significant differences between the left ventricular ejection fraction, angina history, sex distribution and diabetic status between the two groups. We applied Wilcoxon Signed Rank Test and z-test to quantify the difference between the two groups. Data was tabulated and z-test was performed. The calculated p value was <0.0001. This is significantly less than the tabulated p-value at 5% level of significance, i.e., 1.96. Significant differences exist between Group-A and Group-B. CONCLUSION: Tc-99m sestamibi is an excellent agent for investigating myocardial perfusion in dilated cardiomyopathy. The reversible and fixed perfusion defects (small to medium sized) seen in dilated cardiomyopathy after performance of Tc-99m sestamibi gated single photon emission computed tomography imaging may not be due to coronary artery disease. Tc-99m sestamibi single photon emission computed tomography is useful as a routine non-invasive technique to evaluate myocardial function in dilated cardiomyopathy. PMID- 21702288 TI - Ultrasound guided fine needle aspiration cytology versus core biopsy in the preoperative assessment of non-palpable breast lesions. AB - BACKGROUND: Breast screening is a method of detecting breast cancer at a very early stage. Most of the lesions detected by screening are not malignant. Objective of this study was to compare ultrasound guided fine needle aspiration cytology and core biopsy in the preoperative assessment of non-palpable breast lesions. METHODS: The study was conducted prospectively at Department of Radiology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pakistan from March 2004 to February 2005. All the patients underwent fine needle aspiration cytology and core biopsy. Later on, all of them had excision biopsy/mastectomy. Prospectively 80 patients were studied; information was collected on a specifically designed form according to inclusion criteria. The patient age, sex, medical record number and side of lesion were recorded. Clinical history of duration of lump was also taken. Informed consent was obtained. RESULTS: The age of patients were ranges from 20-71 years, with mean of 44.31 +/- 11.002 and the maximum number of patients 28 (35.3%) was between the ages 50-59 years. The sensitivity of FNAC was 92.85%, while the specificity of was 90% and the accuracy rate was 92.1%. The sensitivity of core biopsy was 94.64%, specificity 91.30% and accuracy rate was 94.87%. CONCLUSION: Fine Needle Aspiration has been found to be an extremely useful method for the diagnosis of lumps of breast. The accuracy and the sensitivity of diagnosis on fine needle aspiration cytology were high. PMID- 21702289 TI - Calcium status in premenopausal and postmenopausal women. AB - BACKGROUND: In postmenopausal women, the two major causes of bone loss are oestrogen deficiency after menopause and age related processes. Bone turnover increases to high levels and oestrogen deficiency may induce calcium loss by indirect effects on extra skeletal calcium homeostasis. Objective of this study was to evaluate calcium status in pre-menopausal and postmenopausal women. METHODS: This cross sectional study was carried out in 34 premenopausal women and 33 postmenopausal women, in Department of Physiology, Services Institute of Medical Sciences, Lahore. Height and weight of each woman were taken to find out the body mass index (BMI). Serum calcium, parathyroid hormone and calcitonin levels of each subject were determined. RESULTS: Premenopausal women were obese (BMI>30 Kg/m2) while postmenopausal women were overweight (BMI>25 Kg/m2). Serum calcium levels were significantly lower in postmenopausal women than in pre menopausal women, while serum parathyroid hormone levels were significantly higher in postmenopausal woman. Serum calcitonin level was not significantly different in the two groups. CONCLUSION: Postmenopausal women are calcium deficient and have increased bone turnover as indicated by increased serum parathyroid hormone levels. PMID- 21702290 TI - Significance of chest pain without ST changes during exercise treadmill testing. AB - BACKGROUND: Exercise treadmill test is interpreted as positive or negative for ischemia in the presence or absence of ST depression respectively. This study was conducted to evaluate the diagnostic value of chest pain without ST depression during exercise treadmill test. METHODS: A total of 180 patients who had abnormal exercise treadmill test result and subsequently underwent coronary angiography were studied. Patients were categorised as having ST depression and angina (group A), only ST depression (group B) and only angina (group C). Coronary angiograms of all patients were assessed and compared. RESULTS: Out of 180 patients [159 (88.3%) men and 21 (11.7%) women], 84 patients were in Group A, 64 in Group B and 32 in Group C. Characteristics like age, sex distribution and risk factors were similar in three groups. Significant coronary artery disease was seen in 77 (91.7%), 40 (62.5%) and in 25 (78.1%) patients in groups A, B and C respectively (p=0.02). Triple vessel disease was seen in 21 (25%), 11 (17.2%) and 5 (15.6%) patients in groups A, B and C respectively. Significant disease of left anterior descending artery was seen in 61 (72.6%), 26 (40.6%) and 23 (71.9%) in groups A, B and C respectively (p=0.001). CONCLUSION: Occurrence of both ST depression and angina during exercise treadmill test has strong association with angiographic coronary artery disease whereas occurrence of either of the two has similar association with angiographic coronary artery disease with a trend towards more disease in the latter. PMID- 21702291 TI - Pre-examination stress in second year medical students in a government college. AB - BACKGROUND: Pre-examination Stress is a common condition faced by students prior to exams and is quite predominant among medical students. Many studies have been conducted to assess the impact of stress on students prior to examinations. This study however aims to determine the behavioural and physiological changes occurring in the second year medical students during the pre-examination period. METHODS: Questionnaires were distributed among students to review the changes that occurred in medical students related to their behaviour, physical activities and functions just before exams. Duration of study was two months from October November, 2009. The questionnaire was divided into two parts. The first part contained demographic information about the patient, the second part contained opinions of students experiencing pre-examination stress. SPSS was used for data management and approval from the Ethical Review Board of Dow University of Health Sciences was obtained before starting the research. RESULTS: The data for this study was collected from 226 students of 2nd year MBBS, Dow Medical College, Karachi on specially designed questionnaires. Among the 226 students 22.1% were male while 77.9% were female with mean age 20 +/- 1 years. Changes observed in pre-examination period included anorexia, nausea, fatigue (54.87%), changed concentration span (80.09%), increased irritability (68.14%), mood swings (50.88%), disturbed menstrual cycle (15.91%), disturbed sleep cycle (80.97%), increased intake of caffeine/energy drinks (38.94%), disturbed metabolism (46.02%), aggravated skin problems such as acne (12.83%). Among the 226 students 42.04% did regular exercise and 76.12% prayed regularly. Both of these factors helped them in coping with stress. CONCLUSION: Majority included in our research experienced stress prior to exams but the signs and symptoms varied greatly. Irritability, increased intake of caffeine/energy drinks, and disturbed sleep cycle seemed to dominate physiological and behavioural changes in the pre examination period. PMID- 21702292 TI - Physical trauma--a leading cause of medico legal cases at DHQ Hospital Abbottabad. AB - BACKGROUND: Trauma is one of leading cause of suffering to mankind. No study has yet been done to see the incidence, pattern of injury, outcome and declaration according to Qisas and Diyat in the city of Abbottabad. The objectives of the study were to determine the frequency of age and sex with type of lesion and causative weapon after trauma in a medico-legal clinic and to find the impact on the commonest target organs in the study area. METHODS: This cross-sectional study was conducted at District Headquarter Hospital, Abbottabad between 1st January 2004 and 31st December 2004. Cases presenting for medico legal examination in Medico-legal Department of DHQ Hospital Abbottabad. Patients were selected on basis of purposive sampling technique. Physical trauma group was sub divided into firearms, sharp, blunt and road traffic accident. This group was further classified according to age, sex, area of body involved, type of weapon, seasonal prevalence, and whether injuries were declared according to Qisas and Diyat ordinance. RESULTS: A total of 759 cases of physical trauma reported for medico-legal examination. Out of 759 cases of physical trauma, 3.4% cases of firearm weapon, 7.9% cases of sharp weapon, 16.2% of road traffic accidents, and 72.5% of blunt weapon presented in the medico-legal clinic. Male preponderance with 97% was noted. Two-third of victims were between 10 and 39 years of age. The months of May-July and October-December showed slightly elevated number of cases. The head and neck was the most commonly involved area. No case was certified according to Qisas and Diyat Ordinance. CONCLUSION: Physical trauma constitutes the leading cause to the mankind which makes about 91.6% of cases. Males between 10 to 39 years of age are most likely to be victims. The face and head is the most affected area. PMID- 21702293 TI - In vitro antibacterial activity of onion (Allium cepa) against clinical isolates of Vibrio cholerae. AB - BACKGROUND: Cholera is a major public health problem in developing countries of the world. Bacterial resistance, lack of surveillance data and proper microbiological facilities are major problems regarding diagnosis of cholera. The spread of microbial drug resistance is a global public health challenge that results in increased illness and death rate. Newer antimicrobials or agents are urgently required to overcome this problem. This work was therefore done to investigate the antimicrobial potential of onion against thirty-three clinical isolates of Vibrio cholerae. METHODS: The extract was prepared by reflux extraction method. Antibacterial screening of clinical isolates of V. cholerae was done by agar well diffusion method. Agar dilution method was used to assess the Minimum Inhibitory Concentration (MIC). RESULTS: All tested strains of V. cholerae were sensitive to onion (Allium cepa) extracts of two types (purple and yellow). Purple type of extract had MIC range of 19.2-21.6 mg/ml. The extract of yellow type onion had an MIC range of 66-68.4 mg/ml. CONCLUSION: The results indicated that onion (Allium cepa) has an inhibitory effect on V. cholerae. Keeping in view the anti-bacterial activity of this compound can be exploited as a therapeutic agent in an animal model. This finding is a positive point for further investigation of this herb of traditional medicine. PMID- 21702294 TI - Relationship of glycaemia and triglycerides with BMI in diabetic patients. AB - BACKGROUND: Diabetes mellitus (DM) is a metabolic disorder characterised by chronic hyperglycaemia with disturbances in carbohydrate, fat and protein metabolism arising from defect in insulin secretion or action or both. The clinical guidelines recommend measurement of BMI as "vital signs" for evaluating the obese and diabetic patients. METHODS: This study was carried out on 160 diabetics, which were divided on the basis of BMI into obese (120) and non-obese (40) diabetics from Peshawar district. All patients had their triglycerides and glucose checked after over night fast. RESULTS: The serum triglyceride in diabetics having BMI >30 (obese) was increased as compared to patients having BMI <30 (non-obese). The comparison of serum glucose level in obese diabetics was found to be significantly raised as compared to non-obese diabetics. CONCLUSIONS AND RECOMMENDATIONS: It was concluded that dyslipidemia is common in all diabetics. The abnormal triglyceride level can improve with good glycaemic control, but do not reach the normal state. Good glycaemic control, Reducing BMI, periodic checkups of lipids and blood glucose are recommended for all diabetics in order to avoid complications. PMID- 21702295 TI - Frequency of hepatitis B and C in patients undergoing elective surgery. AB - BACKGROUND: Viral Hepatitis (HBV and HCV) is a major health problem affecting approximately two billion population worldwide. It is one of the single most important cause of chronic liver disease and hepato-cellular carcinoma in Pakistan and worldwide and is now spreading beyond endemic dimensions. This study was carried out to assess the frequency of Hepatitis B and C infection in patients undergoing elective surgical operations, and to evaluate the associated risk factors. METHODS: This was a descriptive study, conducted at Surgical Department of Ghulam Muhammad Mahar Medical College Hospital, Sukkur, from April 2009 to March 2010. All patients who were admitted in the Surgical Department for elective surgical operations were included in the study. The patients were screened for HBsAg and Anti-HCV using immunochromatography (ICT) method. Those who were weak positive by ICT were further confirmed by ELISA. RESULTS: Total 913 patients were admitted in Surgical Department during study period for elective operations and were screened for HBsAg and Anti-HCV. Out of these, 572 (62.65%) were male and 341 (37.34%) were female. Mean age of these patients was 40 years. After screening, 33 (3.61%) patients were found HBsAg positive and 117 (12.8%) were Anti-HCV positive, while 9 (0.98%) were positive for both. Hepatitis-B was found in 21 (2.3%) males and 12 (1.3%) females, and Hepatitis-C was found in 68 (7.44%) males and 49 (5.36%) female patients. Parenteral injections by quacks, previous surgery, blood transfusion and shaving by barbers were found to be the risk factors. CONCLUSION: Our message is: 'Prevention is better than cure'. It is essential to prevent spread of Hepatitis B and C by screening every patient before surgery and counselling the patients. The doctors and paramedical staff must follow proper ethical practice ensuring use of sterile disposables where indicated and protecting patients and themselves from these viral infections. PMID- 21702296 TI - Surgical management of tuberculous small bowel obstruction. AB - BACKGROUND: Acute intestinal obstruction due to tuberculosis is a common surgical problem in our community. Emergency surgery is usually required and surgical procedure depends upon the location and extent of the disease. The aim of this study was to determine the commonly involved region of intestine and different surgical procedures tailored. METHODS: Thirty patients operated upon for acute intestinal obstruction in emergency with operative and histopathological findings suggestive of tuberculosis were included in the study. Demographic profile, operative findings, details of surgical procedure, complications and post-op hospital stay were recorded. The patients were followed for 6 months. RESULTS: Intestinal tuberculosis is more common in young female, with male to female ratio of 1:1.5. Stricture of the small bowel was found in 50% of the cases. The next common finding was ileocaecal tuberculosis found in 40% of patients. Strictruplasty was performed in 11 (36.33%). The right hemicolectomy, limited ileocaecal resection and segmental bowel resection with end to end anastomosis were performed in four patients each. Other procedures were release of adhesions and bands in 4 patients, ileotransverse bypass in 1 patient and loop ileiostomy in 2 patients. Major complication in 10 patient and mortality rate was 10%. CONCLUSION: Because of non-specific clinical features, ignorance and malpractice intestinal tuberculosis presents late. Ileocecal tuberculosis is becoming less common as compared to small bowel strictures. Less radical surgery gives better results. Post operative complications and mortality are related to the perforation of the intestine at the time of surgery. PMID- 21702297 TI - Correlation between plasma thyroid hormones and liver enzymes level in thyrotoxic cases and controls in Hazara Division. AB - BACKGROUND: Thyrotoxicosis is defined as increased synthesis and secretion of thyroid hormones; when associated with defused goitre it is known as grave's disease. Hepatic changes in thyrotoxiosis are fatty changes, cirrhosis and centrilobular necrosis, resulting in elevated serum levels of liver specific enzymes ALT, AST and ALK. Objective of the study was to determine a correlation between plasma levels of 3 liver enzymes, and thyroid hormones in thyrotoxic cases, and matched controls in Hazara Division. METHODS: This study was conducted at Ayub Teaching Hospital Abbottabad from 1st July 2004 to 30th June 2007. The controls were selected from staff and students of Ayub Medial College Abbottabad. Fifty cases of thyrotoxicosis and 50 controls were included in this study by convenience sampling. Their thyroid profile for T3, T4, TSH and liver enzymes profile for ALT, AST, ALK were determined and analysed for a correlation. RESULTS: Mean T3 of cases was 5.23 +/- 1.95 and of controls 1.95 +/- 0.35. Mean T4 of case was 248.88 +/- 62.75, and of controls was 113.40 +/- 19.01. Mean TSH of cases was 0.07 +/- 0.25 and that of controls was 2.24 +/- 0.80. Mean ALT of cases was 38.78 +/- 4.96 while that of controls was 23.98 +/- 5.27. Mean AST of cases was 39.76 +/- 5.05 and of controls was 26.52 +/- 4.49. Mean ALK of cases was 299.68 +/- 22.32 and of controls was 155.10 +/- 37.07. CONCLUSION: Although liver enzymes levels were slightly elevated in many thyrotoxic cases, no significant correlation emerged between any of the thyroid hormones and any of the liver enzymes, either in cases or controls. PMID- 21702298 TI - Outcome of cervical disectomy and fusion with stabilization in single level cervical disc. AB - BACKGROUND: Cervical radiculopathy is a common and distressing problem. Only those patients who failed conservative treatment should undergo surgery. The anterior cervical disectomy is the procedure which offers maximal exposure of the disc space. It easily removes the portion of disc which compresses the nerve root. Possibility of developing late kyphosis from disc space collapse supported the fusion procedure after single level disectomy. The goal of instrumentation is to provide immediate stability, increase fusion rate, prevent graft failure, improve rehabilitation process and possibly no need for external orthosis. Objective of study was To see the results and complications of cervical disectomy thru anterior approach and fusion and stabilisation with titanium made plate. METHODS: This was a prospective study, comprised of 32 patients admitted during period from 2005-2008. Patients presented with radiculopathy or radiculo myelopathy were evaluated. MRI was carried out in all the cases. Each patient was carefully evaluated to confirm clinico-radiological correlation and patients with significant disc and failure of conservative treatment were included in the study. RESULTS: Males were 28 (87.5%) and female were 4 (12.5%). Twenty patients (62.5%) were in fourth decade. C5-6 was involved in 18 (56.25%) patients. No significant postoperative complications noted. Persistent neck and back pain noted in patients in disectomy group without plating. CONCLUSION: Anterior cervical disectomy, fusion and stabilisation with plating is a safe and easy procedure in single level cervical disc disease without significant complications. PMID- 21702299 TI - Frequency of pericardial effusion in patients with first myocardial infarction and its effects on in-hospital morbidity and mortality. AB - BACKGROUND: Pericardial effusion (PE) is not an uncommon finding in serial echocardiographic evaluation of patients with AMI, especially when infarction is anterior and extensive. The objective of this study was to determine the frequency of pericardial effusion after first myocardial infarction and its effects on in-hospital morbidity and mortality. METHODS: This descriptive study was performed in the Department of Cardiology, PGMI, LRH Peshawar, from July 2007 to December 2007. Main outcome measure was frequency of pericardial effusion. RESULTS: Out of 200 patients with first acute myocardial infarction (AMI), mean age was 56 +/- 18 (28-90 years). Majority of patients (31.5%) were in the age range of 51-60 years. Males were 65.5% and 34.5% were females. Pericardial effusion was found in 4.5% patients on day 0, in 12.5% patients on day 2 and in 15% patients on day 4. Left ventricular failure was documented in 19 (9.5%) patients without and 42 (21%) patients with pericardial effusion (p<0.05%). Cardiogenic shock was reported in 5 (2.5%) patients without and 16 (8%) in patients with pericardial effusion and mitral regurgitation was found in 3 (1.5%) patients in each group. Death was recorded in 1 (0.5%) patient without pericardial effusion and was 1.5% (n=3) in patients with pericardial effusion. CONCLUSIONS: Pericardial effusion was seen in one third of the patients with first acute myocardial infarction. In acute phase of myocardial infarction, the chances of development of pericardial effusion increases as the time passes. Left ventricular failure was the commonest in-hospital morbidity followed by cardiogenic shock and mitral regurgitation. In-hospital mortality was more in patients with pericardial effusion. PMID- 21702300 TI - Myocardial infarction in young versus older adults: clinical characteristics and angiographic features. AB - BACKGROUND: Coronary artery disease is now frequently encountered in young adult population. However, being a relatively uncommon entity, not many studies are available in this regard. Therefore, the present study was designed to evaluate the clinical characteristics and angiographic features of patients less than 40 years of age with a history of myocardial infarction and compare them to patients older than 40 years. METHODS: A total of 281 patients who underwent coronary angiography from April, 2009 to December, 2009, were included in this study. The patients were divided into two groups on the basis of age. Group A included patients 40 years of age or younger. Group B included patients older than 40 years. Both the groups were compared with respect to gender, hypertension, diabetes mellitus and extent and severity of coronary artery disease as assessed on coronary angiography. RESULTS: Of the total 281 patients, 45 (16%) were < or =40 years old (Group-A) and 236 (84%) were older than 40 years (Group-B). There was no significant difference between the two groups with respect to the risk factors like gender, hypertension and diabetes mellitus. On coronary angiography, the two groups neither differed in the number of totally occluded vessels, nor in the severity of the culprit lesion. There were only 3 patients in group-A (6.7%) and 5 patients in group-B (2.1%) with normal coronaries (p=NS). Majority (60%) of the patients in group-A had no significant disease or single vessel disease while majority (69%) of the patients in group-B had two or more vessels involved (p<0.001 ). As far as the number of lesions in the coronary arteries is concerned, 62.3% patients had 2 or lesser lesions in group-A while 68.6% patients in group-B had three or more lesions (p=0.001). CONCLUSION: These data suggest that in our study, young patients with MI do not have significantly high prevalence of normal coronaries compared to older patients. Young patients are similar to the older patients with respect to severity of CAD. Lesser number of coronaries is involved and there is lesser number of lesions per patient in young patients compared to older ones. PMID- 21702301 TI - Relationship of awards in multiple choice questions and structured answer questions in the undergraduate years and their effectiveness in evaluation. AB - BACKGROUND: A number of evaluation tools for assessing the cognitive and affective domains in accordance with Bloom's taxonomy are available for summative assessment. At the University of Health Sciences, Lahore, Multiple Choice Questions (MCQs) and Structured Answer Questions (SAQs) are used for the evaluation of the cognitive domain at all six hierarch levels of taxonomy using the tables of specifications to ensure content validity. The rationale of having two evaluation tools seemingly similar in their evaluative competency yet differing in feasibility of construction, administration and marking is being challenged in this study. METHODS: The MCQ and SAQ awards of the ten percent sample population amounting to 985 students in fifteen Medical and Dental Colleges across Punjab were entered into SPSS-15 and correlated according to the cognitive and affective level of assessment in relation to the Bloom's taxonomy and their grouping in the Tables of Specifications, using parametric tests. 3494 anonymously administered questionnaires were analyzed using ethnograph. RESULTS: No statistically significant difference was found in the mean marks obtained by the students when MCQs and SAQs were compared according to their groupings in the Tables of Specifications at all levels of cognitive hierarchical testing. End-of yearcognitive level testing targets set were not met and more questions were set at the lower cognitive testing levels. Expenses incurred in setting MCQs and SAQs were comparable but conduct and assessment costs for MCQs and SAQs were 6% and 94% of the total respectively. In both MCQs and SAQs students performed better at higher cognitive testing levels whereas the SAQs and MCQs were able to marginally test the lower levels of affective domain only. Student's feedback showed that attempting MCQs required critical thinking, experience and practice. CONCLUSION: MCQs are more cost effective means at levels of cognitive domain assessment. PMID- 21702303 TI - Medical image registration: basic science and clinical implications. AB - Image Registration is a process of aligning two or more images so that corresponding feature can be related objectively. Integration of corresponding and complementary information from various images has become an important area of computation in medical imaging. Merging different images of the same patient taken by different modalities or acquired at different times is quite useful in interpreting lower resolution functional images, such as those provided by nuclear medicine, in determining spatial relationships of structures seen in different modalities. This will help in planning surgery and longitudinal follow up. The aim of this article was to introduce image registration to all those who are working in field of medical sciences in general and medical doctors in particular; and indicate how and where this specialty is moving to provide better health care services. PMID- 21702302 TI - Outcome of 'basic life support training' in a busy district general hospital. AB - BACKGROUND: In view of the recently increasing terrorist attacks, hospitals have to devote an increased attention to Disaster Management. An effective way to do this is by preparing disaster plans and training 'hospital staff response team'. Most of the District General Hospitals (DGH) act as first point of contact in emergency. Our practical experience revealed that if the staff is not trained well for an organised and structured response, rather than help they can become an unnecessary hindrance. In the current scenario we felt a dire need to train as many staff members as possible in Basic life support (BLS). The objective was to train as well as assess the feasibility of training these skills to a mixed ability group of health professionals in a busy DGH. METHODS: Twelve training sessions of 1 hour/week were planned. Twenty-nine candidates with mixed ability health workers (5 Medical Officers, 10 Nurses, 9 Nursing Assistants, 2 LHV, 3 Ayahs) were enrolled. Each session was planned as initial 20 min lecture presentation followed by practical demonstration and 30 minutes hands on training with final 10 minutes for feedback. Final Assessment was performed by an independent assessor. Post training feedback was acquired through an open ended questionnaire. RESULTS: The outcome of training showed 24 participants fully trained and successful in first attempt. There were total 5 drop-outs during the training program. CONCLUSION: It is feasible to run this program regularly in a District General Hospital with few adjustments in the administrative arrangements. Results of training can be much more improved if institutional commitment is linked to such training pursuits and 'protected teaching time' is ensured. PMID- 21702304 TI - Colouterine fistula with a foreign body. AB - Foreign bodies in vagina are known to have been inserted by the patient herself or by some other person; as an aid to masturbation, sexual intercourse or sexual assault. The two most common items retained in adult females are tampons and burst condoms. Since long, vaginal deliveries and Obstetric and Gynaecological interventions have been associated with vesicovaginal and rectovaginal fistulae. We present a case of a 24 years old Pakistani woman with a colouterine fistula. Although vesicouterine fistulae have rarely been reported previously, world literature has only a few documented cases of colouterine fistula. PMID- 21702305 TI - Band heterotopia. AB - Band heterotopias are one of the rarest groups of congenital disorder that result in variable degree of structural abnormality of brain parenchyma. Band of heterotopic neurons result from a congenital or acquired deficiency of the neuronal migration. MRI is the examination of choice for demonstrating these abnormalities because of the superb gray vs. white matter differentiation, detail of cortical anatomy and ease of multiplanar imaging. We report a case of band heterotopia that showed a bilateral band of gray matter in deep white matter best demonstrated on T2 Wt. and FLAIR images. PMID- 21702306 TI - An AIDS patient with multiple opportunistic infections. AB - A patient was diagnosed having advanced acquired immunodeficiency syndrome (AIDS) who suffered from various pulmonary and extrapulmonary infective complications. A number of opportunistic infections were diagnosed and prompt treatment was initiated. Due to his low CD4+ lymphocyte count that carries a higher morbidity and mortality, he experienced clinical worsening even with treatment and could not survive through this Black Death. PMID- 21702307 TI - Visceral leishmaniasis: adult population of Abbottabad at risk now. AB - Leishmaniasis is a disease complex caused by the parasite of genus Leishmania. Visceral Leishmaniasis is caused by Leishmania donovani transmitted to human by sand fly. Some wild animals and human reservoir is the major reservoir in most of the cases. The disease is prevalent in different parts of the world including India, Nepal, Bangladesh, Sudan and Brazil. It has also been reported from Northern half of Pakistan. In Hazara Division, it has been reported from Galiat, Battagram, Kaladhaka, Kohistan, Balakot, Kaghan and adjoining areas of Azad Jammu & Kashmir. A focus of visceral Leishmaniasis was detected in villages located about 15 Km from Abbottabad city in year 2000. Sporadic cases were reported from the suburbs of Abbottabad but not from Abbottabad city. All these cases and cases from the other parts of Pakistan were children <12 years of age and the disease was not seen in adults except only one child, 11 year old. We report the 1st case from this area which is 16 years old girl. PMID- 21702308 TI - Decompression sickness after air break in prebreathe described with a survival model. AB - INTRODUCTION: A perception exists in aerospace that a brief interruption in a 100% oxygen prebreathe (PB) by breathing air has a substantial decompression sickness (DCS) consequence. The consequences of an air break during PB on the subsequent hypobaric DCS outcomes were evaluated. The hypothesis was that asymmetrical and not symmetrical nitrogen (N2) kinetics was best to model the distribution of subsequent DCS survival times after PBs that included air breaks. METHODS: DCS survival times from 95 controls for a 60-min PB prior to 2- or 4-h exposures to 4.37 psia (9144 m; 30,000 ft) were analyzed along with 3 experimental conditions: 10-min air break (N = 40), 20-min air break (N = 40), or 60-min air break (N = 32) 30 min into the PB followed by 30 min of PB. Ascent rate was 1524 m x min(-1) and all 207 exposures included light exercise at 4.37 psia. Various computations of decompression dose were evaluated; either the difference or ratio of P1N2 and P2, where P1N2 was computed tissue N2 pressure to account for the PB and P2 was altitude pressure. RESULTS: Survival times were described with an accelerated log logistic model with asymmetrical N2 kinetics defining P1N2--P2 as best decompression dose. Exponential N2 uptake during the air break was described with a 10-min half time and N2 elimination during PB with a 60-min half time. CONCLUSION: A simple conclusion about compensation for air break is not possible because the duration and location of a break in a PB is variable. The resulting survival model is used to compute additional PB time to compensate for an air break in PB within the range of tested conditions. PMID- 21702309 TI - Cardiac arrhythmias during aerobatic flight and its simulation on a centrifuge. AB - INTRODUCTION: It is well known that accelerations during centrifuge training and during flight can provoke cardiac arrhythmias. Our study was designed to investigate both the similarities and differences between heart rhythm disturbances during flights and centrifuge tests. METHOD: There were 40 asymptomatic, healthy pilots who performed two training flights and were also tested in a human centrifuge according to a program of rapid onset rate acceleration (ROR) and of centrifuge simulation of the actual acceleration experienced in flight (Simulation). During the flight and centrifuge tests ECG was monitored with the Holter method. ECG was examined for heart rhythm changes and disturbances. RESULTS: During flights, premature ventricular contractions (PVCs) were found in 25% of the subjects, premature supraventricular contractions (PSVCs) and PVCs with bigeminy in 5%, and pairs of PVCs in 2.5% of subjects. During the centrifuge tests, PVCs were experienced by 45% of the subjects, PSVCs and pairs of PVCs by 7.5%, and PVCs with bigeminy by 2.5%. Sinus bradycardia was observed during flights and centrifuge tests in 7.5% of subjects. DISCUSSION: Comparative evaluation of electrocardiographic records in military pilots during flights and centrifuge tests demonstrated that: 1) there were no clinically significant arrhythmias recorded; and 2) the frequency and kind of heart rhythm disturbances during aerobatic flight and its simulation on a centrifuge were not identical and did not occur repetitively in the same persons during equal phases of the tests. PMID- 21702311 TI - Development and validation of a web-based questionnaire for surveying skydivers. AB - INTRODUCTION: Parachuting injuries are well-known medical problems in military and recreational skydiving. However, little is known about sub-clinical incidents such as those involving the opening shock. To date, there is no validated questionnaire for epidemiological purposes that identifies relevant exposures among skydivers. A web-based platform has been recognized as a convenient approach for data collection in the Swedish skydiving population. The present aim was, therefore, to validate such a web-based questionnaire for wide assessment of pain incidents and related risks among Swedish skydivers. METHODS: Initially, a web-based questionnaire was developed and piloted with 102 skydivers. Content and face validity were then systematically assessed by an independent panel of seven experts in three developing stages before the form was finalized by the present authors in a consensus panel. The reviewers were medical (N = 5) and skydiving (N = 2) experts. Content validity was rated on a four-point Likert-type ordinal scale. The item content validity index (I-CVI) was the proportion of experts rating an item as acceptable (score 3-4) while scale-CVI was the proportion of acceptable items in the questionnaire. Face validity was achieved with open-ended reviews. RESULTS: Of the 19 items in the final web-based questionnaire, 18 reached an I-CVI of 0.86 or higher, with the last item reaching an I-CVI of 0.71. The overall scale-CVI was 0.95. Face validity for the final version was assessed as 'good' or 'really good'. CONCLUSIONS: The present web-based questionnaire is considered valid for further use in studies investigating epidemiological and clinical aspects among skydivers. PMID- 21702310 TI - Protective effect of hydrogen-rich saline on decompression sickness in rats. AB - INTRODUCTION: Hydrogen (H2) has been reported to be effective in the treatment of oxidative injury, which plays an important role in the process of decompression sickness (DCS). This study was designed to test whether H2-rich saline (saline saturated with molecular hydrogen) protected rats against DCS. METHODS: Models of DCS were induced in male Sprague-Dawley rats weighing 300-310 g. H2-rich (0.86 mmol x L(-1)) saline was administered intraperitoneally (10 ml x kg(-1)) at 24 h, 12 h, immediately before compression, and right after fast decompression. RESULTS: H2-rich saline significantly decreased the incidence of DCS from 67.57 to 35.14% and partially counteracted the increases in the total concentration of protein in the bronchoalveolar lavage from 0.33 +/- 0.05 to 0.14 +/- 0.01 mg x ml(-1) (mean +/- SD; P < 0.05), myeloperoxidase activity from 0.86 +/- 0.16 to 0.44 +/- 0.13 U/g, levels of malondialdehyde (MDA) from 0.80 +/- 0.10 to 0.48 +/- 0.05 nmol x mg(-1), 8-hydroxydeoxyguanosine from 253.7 +/- 9.3 to 191.2 +/- 4.8 pg x mg(-1) in the lungs, and MDA level from 1.77 +/- 0.20 to 0.87 +/- 0.23 nmol x mg(-1) in the spinal cord in rat DCS models. The histopathology results also showed that H2-rich saline ameliorated DCS injuries. DISCUSSION: It is concluded that H2-rich saline may have a protective effect against DCS, possibly due to its antioxidant action. PMID- 21702312 TI - Weight loss in humans in space. AB - INTRODUCTION: Bodyweight loss during spaceflight has been observed among astronauts since the early space missions. Considerable mission data has been accumulated, including data from female astronauts, on the many Shuttle and International Space Station missions. The purpose of this study was to investigate the association between observed weight loss during spaceflight and potential covariate factors. METHODS: We performed a statistical analysis of the association between bodyweight change and plausible clinical and mission covariates, using data obtained from the NASA Longitudinal Study of Astronaut Health (LSAH). RESULTS: We confirmed that spaceflight is associated with weight change (-2.1 +/- 0.1%, N = 514). Prospective predictors of weight loss included: being a first-time astronaut, preflight bodyweight and BMI, routinely performing preflight exercise sessions lasting greater than 1 h, and baseline levels of cholesterol, potassium, and chloride. Severe space motion sickness was significantly associated with greater weight loss. Unexpectedly, a higher number of extravehicular activities per mission protected against weight loss. Mission duration had the strongest association with bodyweight change (-2.4 +/- 0.4% per 100 d in space). DISCUSSION: On average, space missions are associated with cumulative loss of bodyweight over time. Unless effective countermeasures are implemented, significant weight loss will be a likely outcome in a subset of astronauts as mission durations increase. New predictors of intra-mission bodyweight changes and other associated factors are identified. PMID- 21702313 TI - Metabolic syndrome and carotid artery intima-media thickness in military pilots. AB - BACKGROUND: The common carotid artery intima-media thickness (CCAIMT) is an independent predictor of cardiovascular events and diabetes mellitus in apparently healthy men. The relationship between features of metabolic syndrome (MS) and CCAIMT is not fully understood. We conducted this study to assess the cross-sectional relationship between CCAIMT and MS parameters in military pilots during their regular annual medical physical examinations. METHODS: There were 179 pilots (ages 39.69 +/- 5.56 yr) free of cardiovascular disease and diabetes mellitus included in our study. MS was defined according to the International Diabetes Federation criteria. The CCAIMT was measured in the posterior wall of both common carotid arteries within 1 cm proximal to the carotid bulbus, by high resolution B-mode ultrasonography. RESULTS: We identified MS in 51 (28.5%) and CCAIMT > or = 0.9 mm in 72.1% of subjects, and found the means of CCAIMT in subjects grouped according to the absence and presence of 3, 4, and 5 MS features to be 0.98, 1.05, 1.14, and 1.18 mm respectively, with statistically significant differences between those without and those with 4 and 5 components, as well as between those with MS and those with 5 MS features. A simple logistic regression analyses showed that HDL-c, triglycerides, triglycerides/HDL-c, pulse pressure, and smoking were not associated with CCAIMT > or = 0.9 mm, while multiple logistic regression analysis indicated that total cholesterol and body mass index were independent predictors of CCAIMT. CONCLUSIONS: The increase in MS features in our study group correlated with the increase in CCAIMT and total cholesterol and body mass index were identified as the independent predictors of CCAIMT. PMID- 21702314 TI - Adrenocortical and immune responses following short- and long-duration spaceflight. AB - INTRODUCTION: Short-term spaceflight is associated with significant but reversible immunological alterations. However, little information exists on the effects of long-duration spaceflight on neuroimmune responses. METHODS: We collected multiple pre- and postflight samples from Shuttle and International Space Station (ISS) crewmembers in order to compare adrenocortical and immune responses between short- (approximately 11 d) and long-duration (approximately 180 d) spaceflight. RESULTS: In Shuttle crewmembers, increased stress hormone levels and altered leukocyte subsets were observed prior to launch and at landing. Additionally, typical stress-induced shifts in leukocyte and lymphocyte subsets, as well as the percentage of T-cells capable of producing intracellular IFN-gamma were also decreased just before launch and immediately after landing. Plasma IL-10 levels were increased before launch but not postflight. No preflight changes occurred in ISS crewmembers, but long-duration crewmembers exhibited significantly greater spikes in both plasma and urinary cortisol at landing as compared to Shuttle crewmembers. The percentage of T-cells capable of producing intracellular IFN-gamma was decreased in ISS crewmembers. Plasma IL-10 was increased postflight. Unexpectedly, stress-induced shifts in lymphocyte subpopulations were absent after long-duration flights despite significantly increased stress hormones at landing. CONCLUSION: Our results demonstrate significant differences in neuroimmune responses between astronauts flying on short-duration Shuttle missions versus long-duration ISS missions, and they agree with prior studies demonstrating the importance of mission duration in the magnitude of these changes. PMID- 21702315 TI - Operator selection for unmanned aerial systems: comparing video game players and pilots. AB - INTRODUCTION: Popular unmanned aerial system (UAS) platforms such as the MQ-1 Predator and MQ-9 Reaper have experienced accelerated operations tempos that have outpaced current operator training regimens, leading to a shortage of qualified UAS operators. To find a surrogate to replace pilots of manned aircraft as UAS operators, this study evaluated video game players (VGPs), pilots, and a control group on a set of UAS operation relevant cognitive tasks. METHODS: There were 30 participants who volunteered for this study and were divided into 3 groups: experienced pilots (P), experienced VGPs, and a control group (C). Each was trained on eight cognitive performance tasks relevant to unmanned flight tasks. RESULTS: The results indicated that pilots significantly outperform the VGP and control groups on multi-attribute cognitive tasks (Tank mean: VGP = 465 +/- 1.046 vs. P = 203 +/- 0.237 vs. C = 351 +/- 0.601). However, the VGPs outperformed pilots on cognitive tests related to visually acquiring, identifying, and tracking targets (final score: VGP = 594.28 +/- 8.708 vs. P = 563.33 +/- 8.787 vs. C = 568.21 +/- 8.224). Likewise, both VGPs and pilots performed similarly on the UAS landing task, but outperformed the control group (glide slope: VGP = 40.982 +/- 3.244 vs. P = 30.461 +/- 2.251 vs. C = 57.060 +/- 4.407). CONCLUSIONS: Cognitive skills learned in video game play may transfer to novel environments and improve performance in UAS tasks over individuals with no video game experience. PMID- 21702316 TI - Post-traumatic stress disorder after a submarine accident. AB - INTRODUCTION: Although submarine accidents occur rarely, they sometimes result in many casualties. Although there are numerous reports on behavioral health consequences following surface vessel accidents, few studies have focused on these issues in the unique context of submarines. This paper reviews the history of significant acknowledged submarine accidents and reports the results of a behavioral health assessment following one recent accident. METHODS: In 2007, a French nuclear-powered submarine (SNA Rubis) suffered a collision during a diving exercise off Toulon, France. All of the crew were individually assessed by a psychiatric team following the event for defusing. A follow-up assessment by auto questionnaire was only conducted 8 mo after the accident using an anonymous subjective survey tool, the French version of the post-traumatic checklist scale (PCLS). RESULTS: Of the 50 male crew, 48 (average age 28.8 +/- 4.3 yr) completed the questionnaire. Most of the crew (95.8%) had talked about the accident with close relations or work colleagues, but only three discussed it with a doctor. Median PCLS score was 19 (range 17-45); 83.3% of the crew had scores < or = 29; one subject met the criteria for PTSD. DISCUSSION: Whether or not PTSD is an occupational hazard in submariners, this report highlights the difficulties in conducting behavioral health follow-up after serious accidents. PMID- 21702317 TI - Metabolic consequences of garments worn to protect against post-spaceflight orthostatic intolerance. AB - INTRODUCTION: Astronauts have worn an inflatable antigravity suit (AGS) during Space Shuttle re-entry and landing to protect against hypotension and syncope, but ambulation with an inflated AGS requires significant effort and may prevent successful completion of an unaided emergency egress from the vehicle. NASA is considering the use of alternative garments to provide protection against post spaceflight orthostatic intolerance. The purpose of this study was to compare the metabolic cost of walking in NASA's current AGS with that of walking in a commercially available elastic compression garment (thigh-high stockings), a candidate garment for use after exploration missions. METHODS: There were 10 volunteers (5 men, 5 women) who walked on a treadmill at 5.6 km x h(-1) for 5 min, a simulation of unaided egress previously used in our laboratory, in 3 different conditions presented in random order: wearing exercise clothes, wearing elastic compression garments, and wearing the AGS. Oxygen consumption (Vo2), carbon dioxide production (Vco2), and ventilation (V(E)) were compared using repeated-measures ANOVA and Tukey's Honestly Significant Difference test. RESULTS: Vo2 while wearing the AGS was 12% greater than when wearing the elastic compression garments and 15% greater than while wearing exercise clothes. There were no differences between the elastic compression garments and exercise clothes only conditions. Vco2 and VE also were greater while walking in the AGS than walking in the elastic compression garments or exercise clothes. CONCLUSIONS: Wearing elastic compression garments as a countermeasure to post-spaceflight orthostatic intolerance may not impair unaided egress from a space vehicle. PMID- 21702318 TI - Jacob Jongbloed (1895-1974): a Dutch pioneer of aviation medicine. AB - Jacob Jongbloed (nick-named "Janus") was a Dutch aviation physiologist and avid aviator. While lack of funding hindered his work tremendously, he nonetheless became an important figure in aeromedical research between World War I and II, chiefly in the field of the effects of acceleration on the human organism. Most of his work was published in Dutch and German journals, rendering him an unknown force in the English-speaking world. Only after World War II did he make a name for himself in Anglo-American circles, primarily due to his involvement in various international organizations dealing with aeromedical matters and his part in developing the first Dutch heart-lung machine. Due to his many posts and his scientific work in the field, he could be regarded as the "father" of Dutch aviation medicine. PMID- 21702319 TI - Translational research: an emerging trend in biomedical science. PMID- 21702320 TI - You're the flight surgeon: cystic fibrosis. PMID- 21702321 TI - This month in aerospace medicine history. PMID- 21702322 TI - Anticaries potential of commercial fluoride rinses as determined by fluoridation and remineralization efficiency. AB - OBJECTIVE: The objective of this work was to compare the anticaries potential of several currently marketed fluoride-containing mouthrinse products using two in vitro approaches: 1) fluoride uptake studies of demineralized human enamel samples after exposure to rinse products; and 2) microhardness studies of sound enamel samples after exposure to the rinse products and demineralizing agents. METHODS: Four currently marketed rinse products, formulated at 100 ppm F, were evaluated in fluoride uptake studies relative to a negative (water) rinse control (Study 1). The same rinse products were evaluated in microhardness studies (Study 2) against a positive control, ACT Anticavity rinse, which is formulated with 225 ppm F and carries the ADA Seal of Acceptance as an effective anticavity mouthrinse. Test products included ACT Total Care rinse (pH = 6.34), Listerine Total Care rinse (pH = 3.57), Crest Pro-Health for Me rinse (pH = 3.33), and Crest Pro-Health Complete rinse (pH = 3.43). RESULTS: Study 1-Samples treated with any of the fluoride-containing rinses showed significantly higher (p < 0.05) levels of fluoride uptake than the negative (water) control. Two of the products (Crest Pro-Health for Me and Crest Pro-Health Complete) showed significantly higher (p < 0.05) levels of fluoride uptake into demineralized enamel than the other marketed rinses (Listerine Total Care and ACT Total Care). Study 2-Samples treated with the same two rinse products (Crest Pro-Health For Me and Crest Pro Health Complete) showed significantly lower mineral loss than the other rinse products, as well as the positive control. CONCLUSION: Results of these in vitro studies indicate that the Crest mouthrinse products evaluated here are capable of providing significantly better fluoridation of demineralized enamel, as well as significantly better protection against the initiation and progression of demineralization, compared to the other marketed fluoride-containing mouthrinse products tested. PMID- 21702323 TI - A clinical investigation of the association of a biochemical chairside assay and periodontal parameters. AB - OBJECTIVE: This study examines the relationship between the values of a research use only biochemical assay that detects sulfur/protein compounds in gingival crevicular fluid (GCF) and clinical measures of periodontal status. METHODS: Seventy-five subjects were enrolled; two were excluded. Mean age (SD) was 44.73 (19.61); age range, 23 to 85; men, 55%; white, 44%. Periodontal evaluations, including plaque index (PI), gingival index (GI), clinical periodontal attachment levels (AL), and bleeding on probing (BOP) were performed on six sites per tooth. Subjects were divided into three groups: periodontally healthy (no loss of attachment and no gingival bleeding, 18 subjects); gingivitis (no loss of attachment and presence of gingival bleeding, 32 subjects); and periodontitis (loss of attachment > 5 mm in five or more teeth, 23 subjects). Gingival crevicular fluid was collected from four separate sites, one site per quadrant, and processed for sulfur compounds (GCF.tx) and protein compounds (GCF.pt). RESULTS: Analysis of variance showed that GCF.pt scores differed between the three periodontal groups (p = 0.01). Ad hoc Tukey HSD test showed periodontally diseased subjects (gingivitis and periodontitis) had higher GCF.pt scores than periodontally healthy subjects (p = 0.05). Correlation analysis showed moderate significant associations between clinical periodontal measures and both GCF.tx and GCF.pt scores. CONCLUSION: Our results suggest that a chairside biochemical assay, capable of measuring sulfur and protein levels in GCF, has potential as an adjunct diagnostic test for periodontal diseases. PMID- 21702324 TI - Rapid desensitizing efficacy of a stannous-containing sodium fluoride dentifrice. AB - OBJECTIVE: To evaluate the efficacy of an experimental stannous-containing sodium fluoride dentifrice (1450 ppm fluoride) in the reduction of dentinal hypersensitivity over a three-day period as compared to a positive control dentifrice containing 8% arginine, calcium carbonate, and 1450 ppm fluoride as sodium monofluorophosphate. METHODS: This study, conducted in China, had a controlled, randomized, examiner-blind, two-treatment, parallel-group design. Eighy-one healthy adult subjects with moderate dentinal hypersensitivity were enrolled, two bicuspid or cuspid teeth in different quadrants demonstrating reproducible thermal (cold air) sensitivity with a score of > 1 on the SchiffAir Sensitivity Scale were chosen for each subject. Subjects also assessed their own level of pain on a Visual Analog Scale (VAS). Subjects were randomized to treatment with either the experimental or positive control dentifrice. At the baseline visit, sensitivity to thermal stimuli was assessed by both the examiner (Schiff Air Sensitivity) and the subject (pain VAS), and subjects were instructed to brush with their assigned study dentifrice according to the manufacturer's instructions provided. Immediately after brushing, thermal sensitivity for each enrolled tooth was reassessed by both examiner and subject. Subjects used their assigned dentifrices at home for three days, after which thermal sensitivity was reassessed by both examiner and subject. Subjects received an oral soft tissue examination at baseline and on Day 3. RESULTS: Forty subjects in the experimental group and 41 subjects in the positive control group completed all study procedures. On the Schiff Air Sensitivity Scale, the experimental dentifrice provided statistically significant (p < 0.001) reductions of 14.8% and 54.1% in sensitivity relative to the positive control dentifrice immediately after first use and at Day 3, respectively. On the pain VAS, the experimental dentifrice provided statistically significant (p < 0.001) reductions of 22.3% and 74.1% in sensitivity relative to the positive control dentifrice immediately after first use and at Day 3, respectively. No adverse events were reported for any subject. CONCLUSION: An experimental stannous-containing sodium fluoride dentifrice provided significantly better dentin hypersensitivity relief relative to a positive control dentifrice both immediately and after three days of product use. PMID- 21702325 TI - Fast onset sensitivity relief of a 0.454% stannous fluoride dentifrice. AB - OBJECTIVE: To evaluate the efficacy ofa stannous fluoride dentifrice as compared to a negative control dentifrice in the reduction of dentinal hypersensitivity after immediate use, and after three days and two weeks of use. METHODS: This was a controlled, randomized, examiner-blind, two-treatment, parallel group study conducted among healthy adult male and female subjects with moderate dentinal hypersensitivity. Subjects with at least two sensitive teeth demonstrating reproducible sensitivity to both thermal stimuli (SchiffAir Sensitivity Scale score of > 1) and tactile stimuli (Yeaple probe 10 grams) were randomized to treatment with either a 0.454% stannous fluoride (SnF,) dentifrice (experimental group) or a 0.76% sodium monofluorophosphate dentifrice (negative control group). At baseline, subjects received an oral soft tissue examination, were assessed for tooth sensitivity, and were instructed, according to manufacturer's product instructions, to brush with their assigned dentifrice thoroughly twice a day (morning and evening). Subjects performed their first product use on site under supervision. Immediately following the first treatment, both examiner and subject assessed sensitivity to thermal stimuli for each enrolled tooth using the Schiff Air Sensitivity Scale and air visual analog scale (VAS), respectively. Thermal sensitivity was also assessed (by both examiner and subject) at the Day 3 and Week 2 study visits, together with tactile sensitivity (Yeaple probe) and oral soft tissue exams of the mouth. RESULTS: One-hundred and eleven subjects were enrolled and randomized to one of the two treatment groups. Immediately after the first use, the SnF, dentifrice provided statistically significant (p < 0.0001) reductions in sensitivity relative to the negative control dentifrice of 13.8% for the thermal Schiff Air Sensitivity Scale and 14.6% for the air VAS. The SnF, dentifrice also provided statistically significant (p < 0.0001) reductions in sensitivity relative to the negative control at Day 3 and at Week 2 based on the thermal Schiff Air Sensitivity Scale (31.8% and 61.3%, respectively) and the thermal air VAS (34.8% and 66.6%, respectively). For the tactile Yeaple probe, the SnF2 dentifrice demonstrated significantly (p < 0.0001) better sensitivity scores relative to the negative control at Day 3 and Week 2, with improvements of 186% and 239%, respectively. Both dentifrices were well tolerated. CONCLUSION: An experimental 0.454% SnF2 dentifrice provides significantly better immediate and ongoing sensitivity relief relative to a negative control dentifrice. PMID- 21702326 TI - Comparison of fluoride uptake into tooth enamel from two fluoride varnishes containing different calcium phosphate sources. AB - OBJECTIVE: The objective of this in vitro study was to compare two 5% sodium fluoride varnishes, each containing different sources of calcium and phosphate, for their ability to deliver fluoride into treated sound tooth enamel and adjacent, but untreated demineralized enamel. METHODS: Six sets of 12 bovine enamel cores were mounted in plexiglass rods and the exposed surfaces were polished. Synthetic lesions were formed in the surface of three sets by soaking in thickened, pH 5.0, 1M lactic acid, 50% saturated with calcium hydroxyapatite. A fluoride varnish containing tri-calcium phosphate (TCP) was applied to one set of sound enamel cores, and a second, delivering amorphous calcium phosphate (ACP), was applied to another. A third set of sound enamel cores was water treated. Each treated sound core was paired with an untreated lesioned core, and the pairs were soaked in artificial saliva for 24 hours at 37 degrees C. The treated cores, but not their lesioned counterparts, were initially soaked in 1.0 N KOH saturated with calcium phosphate for 18 hours. Each core was separately etched with 1.0 N perchloric acid for exactly 15 seconds, and fluoride measured by an ion-sensitive electrode after neutralizing with NaOH and buffering in TISAB II. The amount of calcium extracted was also determined by atomic absorption spectrophotometry as a measure of etch depth. RESULTS: Fluoride uptake average was 1677 +/- 193 ppm, 455 + 38 ppm, and 44 +/- 5 ppm for the sound enamel cores treated with ACP varnish, TCP varnish, and water treatment, respectively. Fluoride uptake into the demineralized enamel averaged 5567 +/- 460 ppm, 2126 +/ 126 ppm, and 49 -/+ 4 ppm for demineralized enamel paired with the sound cores treated with ACP varnish, TCP varnish, and water, respectively. The differences between the ACP varnish, the TCP varnish, and the water treatments were statistically significant (p < 0.05). CONCLUSION: The ACP varnish formulation delivers statistically significantly more fluoride to both intact and demineralized enamel than the formulation containing TCP. PMID- 21702327 TI - Interproximal access efficacy of one vibrating and two powered oscillating rotating toothbrushes. AB - OBJECTIVE: A new toothbrush, with elongated fine bristles and a vibrating bristle field, has been designed and developed. In this study, the new product was compared to two commercially available powered, oscillating-rotating toothbrushes for efficacy using a laboratory method that has been predictive of clinical plaque removal. METHODS: Interproximal access efficacy (IAE) is a measure of the ability of toothbrush bristles to access interproximal sites and remove simulated plaque from these areas. In this assay, an artificial plaque-covered pressure sensitive substrate was placed around anterior- and posterior-shaped teeth, and tooth brushing was conducted using both horizontal and vertical brushing motions. Three toothbrushes were evaluated: the new toothbrush, Aquafresh Between Teeth Buzz (also marketed as Dr.BEST Vibration Zwischenzahn) and two powered toothbrushes with oscillating-rotating brush heads (Oral-B Vitality Precision Clean and Oral-B Professional Care 6000). Twenty-four tests on each product group were conducted, and results for all brushing comparisons were statistically analyzed using Tukey's test for pair-wise comparisons, with a significance level of alpha = 0.05. RESULTS: In all tests conducted, the Aquafresh Between Teeth Buzz toothbrush was consistently and statistically superior to the Oral-B Vitality Precision Clean and Oral-B Professional Care 6000 products (p < 0.05). CONCLUSION: The new toothbrush tested had significantly higher overall efficacy in the IAE assay compared to two marketed powered products. Based on the demonstrated efficacy and the predictability of this laboratory IAE assay, the new toothbrush should provide effective cleansing of the dental interproximal sites. PMID- 21702328 TI - Preparatory processes and compensatory effort in older and younger participants in a driving-like dual task. AB - OBJECTIVE: The nature of increased-age-related dual-task interference was examined during a driving-like dual task in the laboratory. BACKGROUND: Previous research revealed age-related deficits in dual tasks especially when cognitive and motor demands are involved. The specific contributions of sensory input, working memory demands, and/or coordination of motor responses to dual-task interference are not clear and should be clarified in the present study. METHOD: Younger and older participants performed a driving-like tracking task and a visually cued attention task within a dual task. Behavioral and electrophysiological data were recorded during task performance. RESULTS: Overall tracking performance was lower for the older versus younger participants. This age-related decline was particularly pronounced in the time interval after the stimulus when the attention task demanded a motor response. In contrast, older participants tracked relatively better than the younger participants in the time interval preceding the stimulus. In the attention task, the older versus younger participants showed increased responses times and rates of false alarms and misses, suggesting a deficit in retaining the context in the cue-stimulus interval. The electroencephalogram data suggest that the older participants invested more resources than the younger participants in dual-task management during the cue-stimulus interval. CONCLUSION: Evidence was found for increased motor interference and a deficient context processing as well as for an increased investment of processing resources in the older compared with the younger group. APPLICATION: The results suggest that in-vehicle information systems for older drivers should be designed to support cue maintenance and that simultaneous motor demands should not be required. PMID- 21702329 TI - Maximizing players' anticipation by applying the proximity-compatibility principle to the design of video games. AB - OBJECTIVE: Two experiments were conducted to investigate elements of the spatial design of video game interfaces. BACKGROUND: In most video games, both the objects and the background scene are moving. Players must pay attention to what appears in the background to anticipate events while looking at head-up displays. According to the proximity-compatibility principle, game-related information should be placed as close as possible to the anticipation zone. METHOD: Participants played a video game where they had to anticipate the upward movement of obstacles. The score location was manipulated. The average vertical gaze position and dispersion were used to assess anticipation and extent of visual scanning, respectively. RESULTS: Putting the score at the bottom rather than the top of the game window, within the anticipation zone, was expected to minimize attentional moves. Experiment I revealed lower average gaze positions and reduced extent of visual scanning in that condition, but the score performance did not improve significantly. Experiment 2 demonstrated that players' performance increased compared with the bottom condition when the score was displayed just below but outside the game window, despite an increased extent of visual scanning. CONCLUSION: Positioning the score just outside the anticipation zone facilitated anticipation of the movement of obstacles and led to better performance than when the score overlapped with the game anticipation zone. APPLICATION: For games requiring visual anticipation, contextual information should be located in the direction of anticipation but not within the anticipation zone. This recommendation complements the proximity compatibility principle for simple dynamic displays. PMID- 21702330 TI - Vibrotactile "on-thigh" alerting system in the cockpit. AB - BACKGROUND: Alerts in the cockpit must be robust, difficult to ignore, and easily recognized. Tactile alerts can provide means to direct the pilot's attention in the already visual-auditory overloaded cockpit environment. OBJECTIVE: This research examined the thigh as a placement for vibrotactile display in the cockpit. The authors (a) report initial findings concerning the loci and properties of the display, (b) evaluate the added value of tactile cuing with respect to the existing audiovisual alerting system, and (c) address the issue of tactile orienting--whether the cue should display "flight" or "fight" orienting. The tactor display prototype was developed by a joint venture of Israel Aerospace Industries, Lahav Division, and the Ben Gurion University of the Negev (patent pending 11/968,405). A vibrotactile display mounted on the thigh provided directional cues in the vertical plane. Two vibrotactile display modes (eight and four tactors) and two response modes (compatible, i.e., fight [toward vibrotactile cue], and inverse, i.e., flight [away from vibrotactile cue]) were evaluated. RESULTS: Vertical directional orienting can be achieved by a vibrotactile display assembled on the thigh. The four-tactor display mode and the compatible response mode produced more accurate results. CONCLUSION: Tactile cues can provide directional orienting in the vertical plane. The benefit of adding compatible tactile cues compared with visual and auditory cues alone has yet to be reinforced. Nevertheless, fight mode, that is, directing the way to escape from hazardous situations, was preferred. APPLICATION: Potential applications include providing directional collision alerts within the vertical plane, assisting pilot's elevation control, or navigation. PMID- 21702331 TI - The effects of arousing negative and neutral picture stimuli on target detection in a vigilance task. AB - OBJECTIVES: The present study was designed to explore whether target detection in a vigilance task is influenced by task-irrelevant negative emotional and neutral picture stimuli and to test predictions derived from the boredom-mindlessness versus resource depletion accounts of vigilance performance. BACKGROUND: Previous research indicates that emotional stimuli can capture spatial attention. Research on the effect of negative emotional and neutral visual stimuli on temporal aspects of attention has not, however, been researched in detail. METHOD: For this study, 51 participants (15 men and 36 women) were assigned at random to one of three vigilance conditions: a visual vigil with task-irrelevant negative arousing pictures, a visual vigil with task-irrelevant neutral pictures, or a no picture visual vigil control. Vigilance performance was assessed in all conditions. RESULTS: Overall performance efficiency was negatively influenced by the negative-arousing pictures and was interpreted to favor resource depletion to boredom-mindlessness accounts of vigilance performance. CONCLUSION: Task unrelated negative emotional stimuli appear to impair absolute levels of target detections in a vigilance task. APPLICATION: In monitoring settings where negative emotional stimuli are present, the intrusion of negative emotional stimuli should be mitigated via alterations in the system design, or if this is implausible, the monitors may need additional stress coping and emotional resilience training. PMID- 21702332 TI - Modeling the control of attention in visual workspaces. AB - OBJECTIVE: The present study developed and validated a stochastic model of overt attention within a visual workspace. BACKGROUND: Technical specifications and recommended practices for the design of visual warning systems emphasize the role of alert salience. Task demands and display context can modulate alert noticeability, however, meaning that salience alone does not guarantee attention capture. METHOD: A stochastic model integrated elements from existing models of visual attention to predict attentional behavior in dynamic environments.Validation studies tested the predictions of the new model against scanning data from a high-fidelity simulator study and behavioral data from an alert detection experiment. RESULTS: The model accurately predicted the steady state distribution of attention within a simulated cockpit as well as the effects of color similarity, eccentricity, and dynamic visual noise on miss rates and response times in the alert detection task. CONCLUSION: The model successfully predicts attentional behavior in complex visual workspaces with the use of parameter values selected by either the modeler or a subject matter expert. APPLICATION: The model provides a tool to test the effectiveness of visual alerts in various display configurations and with varying task demands. PMID- 21702333 TI - Viewpoint tethering for remotely operated vehicles: effects on complex terrain navigation and spatial awareness. AB - OBJECTIVE: The effect of viewpoint on the navigation of complex terrain and on spatial awareness was examined with the use of a simulated remotely operated vehicle. BACKGROUND: The ability to build terrain models in real time may soon allow remote vehicular control from any viewpoint. A virtual tether couples the viewpoint to the vehicle's position and orientation, but shows more of the terrain than a fully immersive egocentric display. In this sense, it provides visual momentum by providing a view that incorporates egocentric and exocentric qualities. METHOD: For this study, 12 participants navigated a simulated vehicle across complex virtual terrain using five different display viewpoints: egocentric, dynamic tether, rigid tether, 3-D exocentric, and 2-D exocentric. While navigating, participants had to avoid being seen by simulated enemy units. After the navigation task, participants' spatial awareness was assessed using a recognition task. RESULTS: The tethered displays minimized the time during which the participant's vehicle was visible to enemy positions. The egocentric display was more effective than exocentric displays (2-D or 3-D) for navigation, and the exocentric displays were more effective than egocentric for time seen during navigation and the recognition task. The tethered displays produced intermediate results for navigation and recognition. CONCLUSION: Viewpoint tethering produced the most effective displays for minimizing time seen, but tethered displays were less effective than egocentric and exocentric displays for navigation and recognition, respectively. APPLICATION: A tethered display is recommended for applications in which it is necessary to understand the relation of nearby locations to one's own location. PMID- 21702334 TI - Influence of task combination on EEG spectrum modulation for driver workload estimation. AB - OBJECTIVE: This study investigates the feasibility of using a method based on electroencephalography (EEG) for deriving a driver's mental workload index. BACKGROUND: The psychophysiological signals provide sensitive information for human functional states assessment in both laboratory and real-world settings and for building a new communication channel between driver and vehicle that allows for driver workload monitoring. METHODS: An experiment combining a lane-change task and n-back task was conducted. The task load levels were manipulated in two dimensions, driving task load and working memory load, with each containing three task load conditions. RESULTS: The frontal theta activity showed significant increases in the working memory load dimension, but differences were not found with the driving task load dimension. However, significant decreases in parietal alpha activity were found when the task load was increased in both dimensions. Task-related differences were also found. The driving task load contributed more to the changes in alpha power, whereas the working memory load contributed more to the changes in theta power. Additionally, these two task load dimensions caused significant interactive effects on both theta and alpha power. CONCLUSION: These results indicate that EEG technology can provide sensitive information for driver workload detection even if the sensitivities of different EEG parameters tend to be task dependent. APPLICATION: One potential future application of this study is to establish a general driver workload estimator that uses EEG signals. PMID- 21702335 TI - Where's the emotion? How sport psychology can inform research on emotion in human factors. AB - OBJECTIVE: The aim of this study was to demonstrate how research on emotion in sport psychology might inform the field of human factors. BACKGROUND: Human factors historically has paid little attention to the role of emotion within the research on human-system relations. The theories, methods, and practices related to research on emotion within sport psychology might be informative for human factors because fundamentally, sport psychology and human factors are applied fields concerned with enhancing performance in complex, real-world domains. METHOD: Reviews of three areas of theory and research on emotion in sport psychology are presented, and the relevancy of each area for human factors is proposed: (a) emotional preparation and regulation for performance, (b) an emotional trait explanation for risk taking in sport, and (c) the link between emotion and motor behavior. Finally, there are suggestions for how to continue cross-talk between human factors and sport psychology about research on emotion and related topics in the future. RESULTS: The relevance of theory and research on emotion in sport psychology for human factors is demonstrated. CONCLUSION: The human factors field and, in particular, research on human-system relations may benefit from a consideration of theory and research on emotion in sport psychology. APPLICATION: Theories, methods, and practices from sport psychology might be applied usefully to human factors. PMID- 21702336 TI - Effects of ethanol exposure on spatial learning in mice during synaptogenesis. AB - BACKGROUND: The effects of exposure to ethanol (EtOH) on spatial learning in mice during synaptogenesis and changes after maturation are not well understood. In this study, we used a water maze test to evaluate the effects of EtOH exposure on spatial learning during synaptogenesis period. METHODS: One-week-old pups from dams not exposed to EtOH during pregnancy were given 2 dorsal subcutaneous injections of 2.5 g/kg EtOH at a 2-h interval. At 8 h (n=6) and 24 h (n=5) after the first EtOH injection, the brains were perfused and fixed. The brain tissue sections were analyzed by TUNEL assay to detect DNA fragmentation and by immunohistochemistry to detect activated caspase-3. In addition, at 5 h (n=10), 8 h (n=5), and 24 h (n=7) after the first EtOH injection, blood and cerebral EtOH concentrations were measured by headspace gas chromatography. A water maze test was performed at age 7 weeks and 12 weeks. RESULTS: In neonatal EtOH exposure group, mice had a prolonged time to reach the platform compared to a control group. This trend was similar both trials of age 7 weeks and age 12 weeks. At 24 h after EtOH injection in the neonatal EtOH exposure group, the incidence of TUNEL and activated caspase-3 positive cells was 6.1 +/- 1.8% and 6.4 +/- 1.0%, respectively, in the cerebral cortex, 1.6 +/- 0.9% and 1.2 +/- 0.9%, respectively, in the hippocampus, and 11.0 +/- 4.4% and 16.3 +/- 7.8%, respectively, in the thalamus. In blood and cerebral tissue from mice treated with EtOH, as in the neonatal EtOH exposure group, EtOH remained at 0.93 +/- 0.79 mg/g and 0.96 +/- 0.78 mg/g, respectively, after 24 h. CONCLUSIONS: The impairment in spatial learning due to EtOH exposure during the neonatal periods did not tend to improve after reaching maturity. Impairment in spatial learning after maturity in mice exposed to EtOH during synaptogenesis is likely due to apoptosis of brain neurons caused by EtOH. PMID- 21702337 TI - Effect of coffee extracts on plasma fibrinolysis and platelet aggregation. AB - We have previously reported on study results showing that certain types of coffee have the activity to enhance fibrinolysis. This report covers the activity of 10 types of hot water extracts of coffee on human tissue-type plasminogen activator producing cells. Particularly strong activity (29-35 times the control amount) was observed for Blue Mountain, Yunnan and Kilimanjaro beans. It was found that the hot water extracts have anti-thrombin activity, and that coffee components have anti-platelet aggregation activity, although weak. It was revealed that there is no activity affecting tissue-type plasminogen activator producing cells in the coffee components chlorogenic acid, caffeine, quinic acid, trigonelline hydrochloride, 5-(hydroxymethyl)-2-furfuryl and caffeic acid. It was also revealed that there is activity in fractions with a molecular weight of 10,000 or less. This could also be inferred from the fact that oral administration of such fractions of coffee to human subjects resulted in a shortening of their plasma ELT (p<0.05). PMID- 21702338 TI - Association of parental factors with student smoking and alcohol use in Japan. AB - A nationwide survey was conducted on smoking and alcohol use among junior and senior high school students and their parents in Japan. The analyses were performed to assess whether parents' smoking or drinking behavior, health knowledge, and attitude toward their children's smoking or drinking behavior influenced their children's behavior using linked datasets of students and parent answers. The number of schools that responded was 24 out of 40 sampled schools. A total of 11,362 questionnaire data sets from students and parents were applied to the analyses. The influence of parental factors including smoking, alcohol use, knowledge, and attitudes were used as the covariates on students' smoking or alcohol use as independent variables. The data were analyzed using a multiple logistic analysis. The analysis revealed that the parental attitudes of children's smoking or alcohol use were important risk factors as well as parental smoking or drinking behaviors. Conversely, the parental attitude toward warning children of the hazard of smoking or alcohol use was a significant preventive factor for the outcome of their children's behavior. PMID- 21702339 TI - Case of Bowen's disease accompanying syringofibroadenoma. AB - Syringofibroadenoma is an extremely rare benign lesion with distinct histopathological features and variable clinical presentations. Most cases of syringofibroadenoma are thought to be benign skin appendage tumor with eccrine ductal differentiation, however, some syringofibroadenomas are suspected to be a reactive process. Herein, we report the first case of Bowen's disease accompanying syringofibroadenoma, which is suspected to be a reactive process, in a 78-year-old Japanese man. The precise nature of syringofibroadenoma accompanying carcinoma is still controversial. Syringofibroadenoma is thought to be a pre-existing neoplastic condition in some cases. In contrast, syringofibroadenoma is also considered to occur in a reactive process involving several inflammatory dermatoses and skin tumors, and the term "reactive syringofibroadenomatous hyperplasia" has been proposed. In this report, we summarize the clinicopathological features of carcinoma accompanying syringofibroadenoma and discuss the nature of syringofibroadenoma. PMID- 21702340 TI - Measurement method for hydroxylated polychlorinated biphenyls in the blood of Yusho patients by liquid chromatography-electrospray tandem mass spectrometry. AB - Hydroxylated polychlorinated biphenyls (OH-PCBs) are formed as major metabolites of PCBs by cytochrome P450 enzyme-mediated oxidation. It has been reported that their total concentration in serum samples of Yusho patients ranged from 390 to 1300 pg/g. We developed a measurement method for OH-PCBs in blood samples by LC/MS/MS. This method is effective at determining the concentrations of PCDDs, PCDFs, Co-PCBs and OH-PCBs from the same sample without special treatment of the sample. The concentration of OH-PCBs in the blood of Yusho patients was examined using this method. The major OH-PCB metabolites were 4-OH-CB187 (54-906 pg/g wet), 4-OH-CB146 + 3-OH-CB153 (32-527 pg/g-wet), 4-OH-CB109 (ND-229 pg/g-wet) and 4'-OH-CB172 (ND-143 pg/g-wet). The total OH-PCBs ranged from 95 to 1740 pg/g-wet. PMID- 21702341 TI - Evaluation of certain food additive and contaminants. AB - This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of various flavouring agents, with a view to concluding as to safety concerns and to preparing specifications for identity and purity. The Committee also evaluated the risk posed by two food contaminants, with the aim of deriving tolerable intakes where appropriate and advising on risk management options for the purpose of public health protection. The first part of the report contains a general discussion of the principles governing the toxicological evaluation of and assessment of dietary exposure to food additives (particularly flavouring agents) and contaminants. A summary follows of the Committee's evaluations of technical, toxicological and dietary exposure data for 12 groups of flavouring agents (alicyclic ketones, secondary alcohols and related esters; alicyclic primary alcohols, aldehydes, acids and related esters; aliphatic acyclic and alicyclic alpha-diketones and related alpha-hydroxyketones; aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances; aliphatic and aromatic amines and amides; aliphatic lactones; aliphatic primary alcohols, aldehydes, carboxylic acids, acetals and esters containing additional oxygenated functional groups; aliphatic secondary alcohols, ketones and related esters and acetals; aromatic substituted secondary alcohols, ketones and related esters; benzyl derivatives; phenol and phenol derivatives; and simple aliphatic and aromatic sulfides and thiols) and two food contaminants (cadmium and lead). Specifications for the following food additives were revised: activated carbon, cassia gum, indigotine, steviol glycosides, sucrose esters of fatty acids, sucrose monoesters of lauric, palmitic or stearic acid and titanium dioxide. Specifications for the following flavouring agents were revised: 4 carvomenthol and 5,6,7,8-tetrahydroquinoxaline. Annexed to the report are tables summarizing the Committee's recommendations for dietary exposures to and toxicological evaluations of the flavouring agents and contaminants considered. PMID- 21702342 TI - About-face? About time. PMID- 21702343 TI - NMC to keep student records in bid to ensure fitness to practise. PMID- 21702344 TI - Listening panel finds that speed of NHS change is biggest worry. PMID- 21702345 TI - Older people interventions bring role of patient nutrition into focus. PMID- 21702346 TI - Heavy workloads prevent focus on non-communicable diseases. PMID- 21702347 TI - International Nurses' Day: an ideal chance to promote the profession. PMID- 21702348 TI - A worldwide quest for improvement. PMID- 21702349 TI - Game on for 2012 target. AB - An appeal for volunteers to undertak health-related roles at the London 2012 met with an overwhelming response. PMID- 21702350 TI - Get yourself connected. AB - New technology is increasingly being used to help meet growing demands for health care. But it is not without its problems. PMID- 21702351 TI - Surface details. AB - Their physical symptoms can be obvious, but the psychological effects of chronic skin conditions are less well known. PMID- 21702352 TI - A 'can do' attitude. AB - The outgoing director of army nursing services has had a long and illustrious career focusing on children in disaster zones. PMID- 21702353 TI - Applying the preferred priorities for care document in practice. AB - Patient choice and control should be central to the delivery of high-quality, end of life care. Advance care planning (ACP) is a process through which a patient's choices and preferences for care can be discussed and documented. It also enables patients to express what they would want to happen to them in the event that they lose capacity to make decisions. This article focuses on the use of the patient held Preferred Priorities for Care (PPC) document, an example of an ACP tool. This article aims to provide a greater understanding of the PPC document as an end of life care tool and increase practitioners' knowledge, confidence and competence in undertaking ACP conversations with patients and their carers. Four case studies are provided to link theory to practice. PMID- 21702354 TI - Diet and lifestyle as trigger factors for the onset of heartburn. AB - AIM: To examine prospectively the role of reported trigger factors on symptom onset in patients with heartburn and highlight the role of these factors in the management of heartburn in the primary care setting. METHOD Twenty-two patients with heartburn and 50 controls were recruited in Bedfordshire, UK. A seven-day symptom and trigger diary was completed by patients and controls. RESULTS: Patients reported a collection of heartburn symptoms varying in severity and time of day. Aspects of diet and lifestyle perceived as trigger factors included large meals, time of eating and posture. Multiple trigger factors were reported for heartburn. CONCLUSION: Although symptom onset varies between individuals, consideration should be given to trigger factors in the management of heartburn symptoms. PMID- 21702355 TI - Reducing infection associated with central venous access devices. AB - Catheter-related bloodstream infection is a recognised complication associated with central venous access devices, and increases patient morbidity and mortality. The national evidence-based epic2 guidelines remain the most comprehensive guidance on the prevention of infection associated with central venous access devices. This article discusses how evidence-based care can reduce the risk of catheter-related bloodstream infection. PMID- 21702356 TI - Screening for MRSA. PMID- 21702357 TI - Bank of success. PMID- 21702358 TI - Access all areas. PMID- 21702359 TI - A Euro card could open doors. PMID- 21702360 TI - Gold nanoparticle based microbial detection and identification. AB - Microorganisms belong to one of the biggest threats to humanity. Rapid detection and identification of microbes in environmental, food and clinical samples is required for safety purposes as well as diagnosis of infectious diseases. Conventional techniques for microbial detection, though reliable and gold standard, are time consuming, expensive and unsuitable for field situations. Advent of novel techniques involving Nanotechnology has been promising for the development of rapid and low cost strategies for rapid detection and identification of microbes with higher sensitivity. Gold nanoparticles find a significant place in medicine, material sciences as well as diagnostics for their unique optical and physiochemical properties. This review focuses at recent advancements in the development of gold nanoparticle based assays for microbial detection and identification. PMID- 21702361 TI - Enhanced osteoblast adhesion on polymeric nano-scaffolds for bone tissue engineering. AB - Bone tissue engineering is an interdisciplinary field which is emerged for the development of viable substitutes that restore and maintain the function of human bone tissues. The success of bone tissue engineering depends on designing of the scaffolds. The polymer-based composite scaffolds containing micro- and nano structures could provide a platform influencing osteoblastic cell adhesion, spreading, proliferation, and differentiation. Osteoblasts may adhere strongly to the nano-structures than micro-structures in the scaffolds due to the large surface area, better osteo-integrative property and mechanical reliability etc. In this review we are focusing the factors such as pore size, surface topography and roughness, protein adsorption and wettability of nano-structures and their interaction with cell surface integrins molecules. A better understanding of the interactions of nano-structures with osteoblastic cells will have potential applications in the regeneration of bone. PMID- 21702362 TI - Different active biomolecules involved in biosynthesis of gold nanoparticles by three fungus species. AB - In this paper, the intracellular gold nanoparticles were biosynthesized using three fungi including Aureobasidium pullulans (A. pullulans), Fusarium sp. and Fusarium oxysporum (F. oxysporum) after immersion the fungal cells in AuCl4- ions solution. UV-vis and FTIR spectrum, and biochemical compositions analysis of Au nano-fungal cells suggested that active biomolecules of reducing sugar of A. pullulans, and proteins in Fusarium sp. and F. oxysporum were tested positive of providing the function of the reduction of AuCI4- ions and the formation of the gold crystals. SDS-PAGE analysis of purified protein from gold nanoparticles synthesized by three fungi showed that three proteins with molecular weight (WM) about 100 kDa, 25 kDa and 19 kDa were in the gold nanoparticles by Fusarium sp. and two proteins with WM about 25 kDa and 19 kDa were in gold nanoparticles of F oxysporum. Further, three purified fungal proteins with WM about 100 kDa, 25 kDa and 19 kDa from gold nanoparticles by Fusarium sp. identified by LC-MS/MS, named plasma membrane ATPase, 3-glucan binding protein and glyceraldehyde-3-phosphate dehydrogenase, respectively. The Au nano-fungal cells ultrathin sections of Fusarium sp. and F. oxysporum showed that the gold nanoparticles mainly produced in intracellular vacuoles of fungal cells. The growth of gold nanoparticles in three fungal cells indicated the reducing sugar led to the gold nanoparticles in spherical morphology and proteins benefited to the gold aggregates. PMID- 21702363 TI - Study of the effect of formulation parameters/variables to control the nanoencapsulation of hydrophilic drug via double emulsion technique. AB - Preparation of biodegradable nanoparticles containing active molecule is now taking much attention of researchers. The aim of the present work is to achieve the nanosize particles for the first time by double emulsion (W1/O/W2,) evaporation method to encapsulate hydrophilic substance using high performance stirring apparatus. A fluorescent stable hydrophilic agent (Stilbene derivative) was used as a model drug to be encapsulated. For this purpose, PCL (polycaprolactone) was chosen as polymer in this study. Several kinds of stabilizers [triton-405, tween 80, poloxamer, PVP (polyvinylpyrrolidone), PEG (poly ethylene glycol) & PVA (poly vinyl alcohol)] were investigated and the results indicate that the PVA (0.5% concentration) leads to the most stable double emulsion with the particle size in nano range. Different parameters affecting the size of particles have been studied such as stirring time (for 1st and 2nd emulsion), stirring speed (for 1st and 2nd emulsion), polymer and stabilizer concentrations etc. After duration of one month, the encapsulation efficiency of obtained particles was estimated using U.V. analysis. Transmission Electron Microscopy (TEM) showed that the prepared particles were spherical in shape. The size and size distribution were found to be submicron and ranging from 150 to 400 nm. PMID- 21702364 TI - Genomic analysis of cytotoxicity response to nanosilver in human dermal fibroblasts. AB - The aim of this paper was to investigate the molecular mechanisms of interaction between nanosilver and human dermal fibroblasts-fetal (HDF-f) at the level of gene expression. After HDF-f was treated with nanosilver for 1, 4 and 8 h, the cellular response was evaluated with methylthiazoltetrazolium (MTT) assay and flow cytometry analysis. Global gene expression profiles were examined using Illumina Human-6_V3 Expression BeadChip Array and the results were verified by quantitative real-time polymerase chain reaction (RT-PCR). The obtained differential expressed genes were analyzed by the integration of clustering, gene ontology (GO) and biological pathway analysis. The results suggest that nanosilver may cause disruption of cytoskeleton and cellular membrane, disturbance of energy metabolism and gene expression associated pathways, and DNA damage accompanied by cell cycle arrest. When the nanoparticle-cell interaction mechanisms induced by nanogold in our previous research were compared with nanosilver in the present study, both the similarities and differences underlying biological processes and gene regulations were found. The research also suggests that the genomics research can provide a convenient and efficient approach to the understanding of cytotoxicity mechanisms of nanomaterials. PMID- 21702365 TI - Fabrication of porous chitosan/poly(vinyl alcohol) reinforced single-walled carbon nanotube nanocomposites for neural tissue engineering. AB - With the ability to form a nano-sized fibrous structure with large pore sizes mimicking the extracellular matrix (ECM), electrospinning was used to fabricate chitosan/poly(vinyl alcohol) nanofibers reinforced by single-walled carbon nanotube (SWNT-CS/PVA) for potential use in neural tissue engineering. Moreover, ultrasonication was performed to fabricate highly dispersed SWNT/CS solution with 7%, 12%, and 17% SWNT content prior to electrospinning process. In the present study, a number of properties of CS/PVA reinforced SWNTs nanocomposites were evaluated. The in vitro biocompatibility of the electrospun fiber mats was also assessed using human brain-derived cells and U373 cell lines. The results have shown that SWNTs as reinforcing phase can augment the morphology, porosity, and structural properties of CS/PVA nanofiber composites and thus benefit the proliferation rate of both cell types. In addition, the cells exhibit their normal morphology while integrating with surrounding fibers. The results confirmed the potential of SWNT-CS/PVA nanocomposites as scaffold for neural tissue engineering. PMID- 21702366 TI - Preparation of anti-CD40 antibody modified magnetic PCL-PEG-PCL microspheres. AB - Antibody modified magnetic polymeric microspheres have potential biomedical application. In this paper, anti-CD40 antibody modified magnetic poly(epsilon caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCL-PEG-PCL, PCEC) microspheres were prepared. First, PCL-PEG-PCL triblock copolymer was synthesized by ring-opening polymerization, followed by reaction with succinic anhydride, creating carboxylated PCL-PEG-PCL copolymer. Then, magnetite nanoparticles were encapsulated into carboxylated PCL-PEG-PCL microspheres, forming magnetic PCL-PEG-PCL microspheres with carboxyl group on their surface. Catalyzed by EDC/NHS, the anti-CD40 antibody was linked to these magnetic PCL-PEG PCL microspheres, thus forming anti-CD40 modified PCL-PEG-PCL microspheres. These anti-CD40 antibody modified magnetic PCL-PEG-PCL microspheres may have potential application in cell separation. PMID- 21702367 TI - Analysis of CpG island methylation using rolling Circle amplification (RCA) product microarray. AB - Here we report a method for methylation analysis using rolling circle amplification (RCA) product microarray. We treated DNA samples with bisulfite and designed, for each CpG region in the target gene, a pair of padlock probes with one matching to the CpG sites derived from methylated CpG region, and the other matching to the TpG sites derived from their corresponding unmethylated allele. The padlock probes were hybridized to the PCR products of the bisulfite-treated genomic DNA, and were subsequently ligated to form single-strand, circular template for RCA reaction. The RCA products were immobilized on the slide to fabricate DNA microarray which hybridized a pair of universal dual-color probes to detect the methylation status of the CpG islands in the target gene. We tested the RCA product microarray with two tumor-related genes, P16 and IGFBP7, and successfully analyzed the methylation status of the CpG islands in the two genes. The microarray data were further confirmed by methylation-specific PCR analysis. Our results demonstrated that the RCA product microarray was hopeful for high throughput detection of CpG island methylation. PMID- 21702368 TI - Nanoparticulate delivery can improve peroral bioavailability of cyclosporine and match Neoral Cmax sparing the kidney from damage. AB - Cyclosporine (CsA) as an immunosuppressant has demonstrated immense potential in the field of organ transplantation and autoimmune disorders, despite the nephrotoxicity. The present investigation is an attempt to develop biodegradable nanoparticles entrapping CsA that can match Cmax of Neora, the most potent formulation available to date. The Cmax and AUC0-72 of CsA administered as nanoparticles demonstrated an increase with increase in the dose administered, however the relative bioavailability decreased. The Cmax and AUC0-72 increased from 682 to 1073 ng/ml and 34854 to 55322 ng . h/ml, respectively whereas, the relative bioavailability decreased from 120 to 64%. On the other hand, the increase in initial CsA loading (10-30% w/w of polymer) recorded a proportional increase in Cmax and AUC0-72, from 494 to 1101 ng/ml and 17774 to 51763 ng . h/ml, respectively. The relative bioavailability also increased from 31 to 89%. The CsA nanoparticles at 30% CsA loading w/w of polymer and at 30 mg/Kg single dose demonstrated comparable Cmax of Neoral at 15 mg/Kg, which upon chronic administration over a period of 30 days daily dosing showed low nephrotoxicity to that exhibited by Neoral. The reduced toxicity of nanoparticulate CsA indicated by lower blood urea nitrogen, plasma creatinine and glomerular damage, was due to delay in Tmax as result of slow release of the CsA from the nanoparticles. The investigation unlocks the potential of polymeric nanoparticles in oral delivery of CsA. PMID- 21702369 TI - Chemical stability and cytotoxicity of human insulin loaded in cationic DPPC/CTA/DDAB liposomes. AB - Liposomes were prepared from DPPC (dipalmitoyl phosphatidyl choline) mixed with Chol (cholesterol) and CTA [cholest-5-en-3-ol(3beta)(trimethylammonio) acetate] or DDAB (dioctadecyl dimethyl ammonium bromide) at various molar ratios by chloroform film method with sonication. The most physical stable (no sedimentation with an average zeta potential value of 47.7+/-1.44 mV) liposomal formulation (DPPC/CTA/DDAB at 7:2:1 molar ratio) was selected to load with human insulin (0.45 mg/mL) by the freeze dried empty liposomes (FDELs) method with the entrapment efficiency of human insulin of 62.72% (determined by gel filtration). Liposomes were spherical shape with unilamellar structure and an average size of 2.26+/-0.87 microm determined by TEM. The percentages of insulin remaining in liposomes when stored at 4+/-2, 30+/-2 and 45+/-2 degrees C for 4 months were 26.21, 36.86 and 15.75% which were higher than human insulin solution of 6.13, 11.31 and 2.61 times, respectively. The percentages of entrapment of human insulin were 62.72 at initial and at 31.72, 64.10 and 8.10 when kept at 4+/-2, 30+/-2 and 45+/-2 degrees C, respectively, for 4 months. The synthesized cationic lipid, CTA, and the DPPC/Chol/CTA liposomes loaded with human insulin demonstrated no cytotoxicity on normal human skin fibroblast but some cytotoxic effects on mouth epidermal cancer cell line. This study has demonstrated the enhancement of chemical stability of human insulin with no cytotoxicity when loaded this protein in cationic DPPC/CTA/DDAB liposomes. The results indicated the potential application of this cationic liposomal formulation for topical therapeutic use. PMID- 21702371 TI - Biocompartmental (medial and lateral) displaced bucket-handle meniscal tears with associated anterior cruciate ligament rupture. PMID- 21702370 TI - Anti-angiogenic effects of betulinic acid administered in nanoemulsion formulation using chorioallantoic membrane assay. AB - Betulinic acid (3beta, hydroxy-lup-20(29)-en-28-oic acid, BA), a pentacyclic triterpenoid, is derived from a widely distributed natural anticancer compound betulin. It has selective anticancer activity against several tumor cells, and recently it was shown that it also possess anti-angiogenic effects. The objective of this study was to formulate betulinic acid, a poorly aqueous-soluble compound, in flax-seed oil containing nanoemulsion formulation for enhanced delivery efficiency and to effectively inhibit the tumor angiogenic process. The nanoemulsion was prepared using high pressure homogenization method with a Microfludizer processor. The betulinic acid nanoemulsion was studied for the effect on the angiogenic process by performing the in vivo chick embryo chorioallantoic membrane (CAM) assay. The sample volume of 1 microl and 5 microl of the blank and BA nanoemulsions were applied directly on the CAM. The preliminary results from macroscopic, morphological and immunohistochemical evaluations have shown that morphological change was produced in the CAM mesenchyme with a negative impact on the normal growth of the capillaries. Betulinic acid does possess anti-angiogenic activity in a dose dependent manner, and the nanoemulsion formulation maintained this effect. PMID- 21702372 TI - Preventing suicide among returning combat veterans: a moral imperative. PMID- 21702373 TI - Making sense of resilience. PMID- 21702374 TI - Strategic alliances: innovation in Naval cardiovascular surgery and the power of partnerships. PMID- 21702375 TI - Patient preferences for the delivery of military mental health services. AB - OBJECTIVE: Knowledge of patients' preferences of military mental health care is required to inform service planning. The objective was to inform service planning by quantifying, and identifying predictors of, patient preferences for mental health care providers and location of facilities. METHOD: Sociodemographic and service characteristics and concerns about stigma were investigated for patients presenting to 4 U.K. Armed Forces Departments of Community Mental Health over a 2 months period (n = 163). RESULTS: 5% preferred to be seen by a uniformed mental health clinician, 30% by a nonuniformed clinician, and 65% reported no preference. Gender and service were associated with care provider preference and service was associated with location preference. CONCLUSION: The Armed Forces need to explore and identify ways of accommodating their patients' preference, especially regarding the uniformed status of their care provider, to achieve good engagement and acceptability. PMID- 21702376 TI - An intervention to increase mental health treatment engagement among OIF Veterans: a pilot trial. AB - OBJECTIVES: Previous research has documented a stigma associated with mental health problems that interferes with the decision to seek treatment. This study assesses the feasibility of an intervention designed to increase treatment initiation among veterans reporting mental health problems. METHODS: Participants were 27 Operation Iraqi Freedom National Guard soldiers who screened positive for 1 of the following disorders as assessed by the Mini International Neuropsychiatric Interview: depression, posttraumatic stress disorder, generalized anxiety disorder, panic disorder and/or at-risk drinking. An intervention was administered using a cognitive-behavioral model to modify beliefs that may interfere with treatment-seeking behavior. Beliefs and treatment seeking behavior were assessed post-intervention. RESULTS: Participants were significantly more likely to report that they intended to seek mental health treatment post-intervention (p < 0.012), suggesting that a cognitive-behavioral model focusing on modifying treatment-interfering beliefs holds promise for increasing mental health treatment-seeking among returning Veterans in need. CONCLUSIONS: Given the high rates of mental health symptoms post-deployment and the low likelihood of treatment-seeking among Veterans, interventions designed to increase treatment-initiation such as those explored in this article are critically needed. PMID- 21702377 TI - Early psychosocial intervention following operational deployment: analysis of a free text questionnaire response. AB - BACKGROUND: United Kingdom Armed Forces personnel currently undertake arduous operational tours that can make homecoming psychologically challenging. To assist them in this transition, they undergo a process of "decompression" before returning to their base unit. This article reports their subjective impression of the process. METHODS: Personnel completed a brief survey at the end of the decompression process conducted in Cyprus in 2008 and this study reports the analysis of the free text element of the questionnaire. RESULTS: 6,734 comments were available for analysis from a total of 11,304 questionnaires. Although responses were largely positive, significant numbers indicated that decompression could be improved by allowing personnel more choice, improving air transport out of theatre, and greater flexibility in harmonizing decompression activities with the operational role and military characteristics of decompressing units. CONCLUSION: Although decompression is generally viewed positively by participants, elements of the process could be further developed to improve acceptability. PMID- 21702378 TI - Effects of transcendental meditation in veterans of Operation Enduring Freedom and Operation Iraqi Freedom with posttraumatic stress disorder: a pilot study. AB - We conducted an uncontrolled pilot study to determine whether transcendental meditation (TM) might be helpful in treating veterans from Operation Enduring Freedom or Operation Iraqi Freedom with combat-related posttraumatic stress disorder (PTSD). Five veterans were trained in the technique and followed for 12 weeks. All subjects improved on the primary outcome measure, the Clinician Administered PTSD Scale (mean change score, 31.4; p = 0.02; df = 4). Significant improvements were also observed for 3 secondary outcome measures: Clinician's Global Inventory-Severity (mean change score, 1.60; p < 0.04; df = 4), Quality of Life Enjoyment and Satisfaction Questionnaire (mean change score, -13.00; p < 0.01; df = 4), and the PTSD Checklist-Military Version (mean change score, 24.00; p < 0.02; df = 4). TM may have helped to alleviate symptoms of PTSD and improve quality of life in this small group of veterans. Larger, placebo-controlled studies should be undertaken to further determine the efficacy of TM in this population. PMID- 21702379 TI - Significant indicators of intent to leave among Army Dental Corps junior officers. AB - OBJECTIVE: To identify the significant predictors associated with Army Dental Corps junior officers' intent to leave (ITL) the military. METHODS: A secondary data analysis of the 2009 Army Dental Officer Retention Survey was conducted. Frequencies, bivariate, linear, and logistic regression analyses were calculated. RESULTS: Forty-six percent of junior officers completed the survey (N = 577; n = 267). Fifty-eight percent of respondents reported an ITL the military before retirement. The following variables were positively associated (p < 0.05) with ITL: unit of assignment, specialty training status or area of concentration, military lifestyle, and residency training. Age and benefits were negatively associated with ITL. CONCLUSION: This study suggests that ITL is a multifactorial issue. PMID- 21702380 TI - Civilian employment among recently returning Afghanistan and Iraq National Guard veterans. AB - OBJECTIVE: National Guard service members face deactivation from active duty soon after they return to the United States and rapid entry into the civilian workforce; therefore, it is important to examine employment among these Veterans. METHODS: The sample included 585 National Guard service members. Bivariate and multivariable analyses were conducted examining the associations between mental health symptoms, alcohol use, number of deployments, and combat exposure with employment status and full-time versus part-time employment as outcomes. RESULTS: Forty-one percent of National Guard service members were employed 45 to 60 days following demobilization. Among those who were employed, 79% were employed full time. Age, family income, and combat exposure were associated with employment; income and health status were associated with part-time versus full-time employment. CONCLUSIONS: Mental health status may not be strongly associated with initiating civilian employment among National Guard service members; however, better mental health status is associated with being employed full-time versus part-time. PMID- 21702381 TI - Triage and air evacuation strategy for mass casualty events: a model based on combat experience. AB - BACKGROUND: Management of combat casualties should optimize outcomes by appropriate patient triage, prehospital care, and rapid transport to the most capable medical facility, while avoiding overwhelming individual facilities. METHODS: Planning the medical support for the campaign was done by the medical department of the IDF Southern command in cohort with the medical department of the Homefront command. Data collection and analysis were done by the Trauma Branch of the Medical corp. RESULTS: 339 soldiers were injured, among them were 10 fatalities. Five hospitals received casualties, although the 2 regional hospitals received 84% of the primary evacuation load. The majority of urgently injured soldiers (90%) were evacuated by air, as opposed to 59% of non-urgently injured soldiers. CONCLUSIONS: In a cross border setting, airlifting the urgent casualties to farther away level I trauma centers provides appropriate care for them, while not crossing the "surge capacity" line for the near-by medical centers. PMID- 21702382 TI - Traumatic noncombat-related hand injuries in U.S. troops in the combat zone. AB - BACKGROUND: The epidemiology of traumatic, nonbattle, Combat Zone hand injuries has not been well explored. METHODS: This was a retrospective chart review of Emergency Department visits occurring at the Ibn Sina Hospital in Baghdad Iraq. RESULTS: During the 24-month period from May 2007 to June 2009, 7,520 patients were seen at the Ibn Sina Hospital Emergency Department. Three hundred thirty-one cases met the inclusion criteria. Seventy-four cases were found to have required near-term evacuation from area of operation. CONCLUSIONS: Traumatic, nonbattle hand injuries are common and appear to be a significant problem in the Combat Zone. Injuries occurring because of the closure of vehicle doors, hatches, and turrets make up a large portion of these injuries and represent an optimal area of intervention for possible injury mitigation. PMID- 21702383 TI - Laboratory evaluation of 10 heat and moisture exchangers using simulated aeromedical evacuation conditions. AB - Heat and moisture exchangers (HMEs) are used for airway humidification in mechanically ventilated patients and have been evaluated only under hospital conditions. U.S. Air Force aeromedical evacuation transports are performed under rugged conditions further complicated by the cold and dry environment in military aircrafts, and HMEs are used to provide airway humidification for patients. This study evaluated 10 commercial HMEs using a test system that simulated aeromedical evacuation conditions. Although the American National Standards Institute recommends inspired air to be at an absolute humidity value of > or = 30 mg/L for mechanically ventilated patients, the highest absolute humidity by any HME was approximately 20 mg/L. Although none of the HMEs were able to maintain a temperature high enough to achieve the humidity standard of the American National Standards Institute, the clinical significance of this standard may be less important than the relative humidity maintained in the respired air, especially on evacuation flights of short duration. PMID- 21702384 TI - For combat wounded: extremity trauma therapies from the USAISR. PMID- 21702385 TI - Core temperature changes in service members with and without amputations during the Army 10-Miler. AB - The purpose of this case study was to assess differences in core temperature between individuals with and without amputations during a 10-mile run. Decreased body surface area and increased energy needs for ambulation may increase heat production and risk of heat injury for individuals with amputations. Two runners, 1 with and 1 without amputation, completed a 10-mile road race. Anthropometrics, body composition, and energy expenditure were collected before the run. Core temperature and activity were measured continually during the event. Maximum core temperature for the runner with amputation was 38.4 degrees C and for the runner without amputation was 37.9 degrees C. Despite the higher temperature, the runner with amputation completed the run at a slower pace than the one without amputation, indicating that higher core body temperatures may be achieved in individuals with amputation at similar workloads. These data suggest that future research is needed to elucidate differences in core temperature in individuals with amputations. PMID- 21702386 TI - The 1-mile walk test is a valid predictor of VO(2max) and is a reliable alternative fitness test to the 1.5-mile run in U.S. Air Force males. AB - The purpose of this study was to assess the validity of the 1-mile walk (Rockport Walk Test) as a predictor of VO(2max) and determine whether the 1-mile walk is a reliable alternative to the 1.5-mile run in moderately fit to highly fit U.S. Air Force males. Twenty-four (33.0 +/- 1.5 years) males completed a maximal treadmill VO(2max) (50.3 +/- 1.4 mL/ kg/min), 1-mile walk, and 1.5-mile run. For the 1-mile walk, there were no significant differences between measured and predicted VO(2max) (p = 0.177, r = 0.817). There were no significant differences (p = 0.573) between points scored in the Air Force Fitness Test for the 1-mile walk and 1.5-mile run tests. In conclusion, the 1-mile walk test is a valid predictor of VO(2max) and can be used as an alternative fitness test to the 1.5-mile run in assessing cardiovascular fitness in Air Force males. PMID- 21702387 TI - Review: the influence of armed conflict on the development of critical care medicine. AB - This manuscript reviews the historic underpinnings of critical care medicine (CCM) during armed conflict, the means and techniques healthcare providers in the military have used to practice CCM in austere environments, and the ongoing developments in the practice of CCM by military health care clinicians. These developments influence contemporary civilian trauma practice and practice in intensive care units and vice versa. A symbiosis between civilian and military intensivists and traumatologists involves much crosstalk and sharing of experiences and best practices that has influenced and improved care in combat zones and in civilian emergency departments, operating rooms, and intensive care units. PMID- 21702388 TI - An evaluation of the delivery of clinical preventive services in the Joint Task Force National Capital Region Medical. AB - The Walter Reed Army Institute of Research General Preventive Medicine Residency conducted a performance improvement study to evaluate clinical preventive services (CPSs) in the National Capital Region. This study focused on enhancing medical care through quality management of both the process and measurement of service delivery, thereby improving the overall quality of a service by examining its constituent parts. Screening mammography and pneumococcal immunization were the CPSs selected for evaluation, and 9 of 40 military treatment facilities (MTFs) were visited. Mammography completion ranged from 64% to 81%. The process of providing mammography to eligible enrollees varied greatly among MTFs, and the majority did not utilize all identified steps deemed critical for mammography completion. Pneumococcal immunization ranged from 0% to 21%. There was a positive correlation between CPS completion, the number of eligible enrollees, and the use of critical steps. Recommendations include using critical steps to evaluate and improve MTFs' CPS processes. PMID- 21702389 TI - Complementary and alternative medicine in a military primary care clinic: a 5 year cohort study. AB - Previous studies have found that complementary and alternative medication (CAM) use is common. We enrolled 500 adults presenting to a primary care military clinic. Subjects completed surveys before the visit, immediately afterwards, at 2 weeks, 3 months, and 5 years. Over 5 years, 25% used CAM for their presenting symptom. Most (72%) reported that CAM helped their symptom. Independent predictors of CAM use included female sex (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.1-3.7), college educated (OR, 3.4; 95% CI, 1.8-6.3), more severe symptoms (OR, 1.14; 95% CI, 1.01-1.28), and persistence of symptom beyond 3 months (OR, 3.9; 95% CI, 2.0-7.5). We concluded that a quarter of military primary care patients use CAM over 5 years of follow-up and most find it helpful. CAM users tend to be female and better educated. Patients with more severe symptoms or symptoms that persist beyond 3 months are also more likely to turn to CAM. PMID- 21702390 TI - Orthopedic surgery in the United States Army: a historical review. AB - The contribution of American military surgeons to the development of orthopedic surgery has not previously been explored. The experiences of American military surgeons in conflicts from the Civil War to Iraq and Afghanistan have advanced the orthopedic discipline, resulting in important developments within the field, as well as scientific discoveries that have benefited both the civilian and military communities. From advances in wound care, to spinal surgery, intramedullary nailing of long bone fractures, and external fixation, American military surgeons have been pioneers of orthopedic surgery. The goal of this review was to survey the American military orthopedic experience from the American Revolution to the wars in Iraq and Afghanistan. PMID- 21702391 TI - Botulinum toxin type A for nonsurgical lateral release in patellofemoral pain syndrome: a case study. AB - SETTING: Outpatient rehabilitation clinic. PATIENT: A 37-year-old physically active male. CASE DESCRIPTION: The patient presented with anterior left knee pain, exacerbated when climbing stairs, sitting, and running. Exam showed lateral tracking patellae and palpable crepitus. One hundred fifty units of botulinum toxin A was injected into his left vastus lateralis. He underwent a 12-week home exercise program targeting the vastus medialis (VM). ASSESSMENT/RESULTS: Visual analog scale decreased from 70 to 0 on a 150-mm scale, from initial until 8 weeks postinjection. Functional Index Questionnaire increased from 5 to 16 over the same period. Knee torque and surface electromyography findings showed increased activity of the VM during knee extension. CONCLUSION: Botulinum injection into the vastus lateralis in conjunction with VM strengthening may provide more effective treatment of patellofemoral pain syndrome. Further study is needed to explore this novel treatment of patellofemoral pain syndrome. PMID- 21702392 TI - Ocular vaccinia: a consequence of unrecognized contact transmission. AB - A patient developed severe ocular vaccinia via autoinoculation after acquiring unrecognized contact-transmitted vaccinia from wrestling with vaccinated members of his unit. This case highlights both the need to reinforce infection-control measures among vaccinees and the need for providers to be familiar with the identification and treatment of cutaneous and ocular vaccinia infection. PMID- 21702393 TI - Implementation of a protocol to reduce occurrence of retained sponges after vaginal delivery. AB - BACKGROUND: Retained sponges (gossypiboma) following vaginal delivery are an uncommon occurrence. Although significant morbidity from such an event is unlikely, there are many reported adverse effects, including symptoms of malodorous discharge, loss of confidence in providers and the medical system, and legal claims. OBJECTIVE: To report a protocol intended to reduce the occurrence of retained sponges following vaginal delivery. METHODS: After identification of limitations with existing delivery room protocols, we developed a sponge count protocol to reduce occurrence of retained vaginal sponges. We report our experience at Naval Medical Center Portsmouth, a large tertiary care military treatment facility with our efforts to implement a sponge count protocol to reduce retained sponges following vaginal delivery. CONCLUSIONS: With appropriate pre-implementation training, protocols which incorporate post-delivery vaginal sweep and sponge counts are well accepted by the health care team and can be incorporated into the delivery room routine. PMID- 21702394 TI - Rates of gonorrhea and Chlamydia in U.S. military personnel deployed to Iraq and Afghanistan (2004-2009). AB - The increased incidence of sexually transmitted infections has historically been associated with military personnel at war. The incidence of gonorrhea and Chlamydia in personnel deployed in the current wars in Iraq and Afghanistan has not been reported. An electronic records' review of testing done from January 2004 to September 2009 revealed higher rates of Chlamydia than gonorrhea, especially among females who deploy to Iraq. Additionally, increasing Chlamydia rates were noted over the study. Overall, the rates of gonorrhea and Chlamydia were the same or lower than age- and year-matched U.S. rates reported by the Center for Disease Control and Prevention. Ongoing education with emphasis on prevention and treatment are needed, as are development of specific projects to define the risk factors and timing of acquisition of sexually transmitted infections in combat zones. PMID- 21702395 TI - Vitamin D status in veterans with inflammatory bowel disease: relationship to health care costs and services. AB - Vitamin D deficiency is a global pandemic associated with increased health care costs and could play a role in the pathogenesis and management of inflammatory bowel disease. This study examined vitamin D status in veterans with ulcerative colitis (UC) and Crohn's disease (CD) and assessed its relationship to health care costs and service utilization. Veteran patients (n = 125) with UC or CD and with an available 25-hydroxyvitamin D level were studied. CD patients were more likely to be vitamin D insufficient than the UC group. Despite the higher vitamin D levels among UC patients, they were significantly more likely to utilize laboratory and pharmacy services compared with CD patients, whereas patients with CD had significantly higher radiology and pharmacy costs. Thus, it is likely that disease-specific characteristics rather than vitamin D status determine the costs of health care services in veterans with established inflammatory bowel disease. PMID- 21702396 TI - The nonhealing scar. AB - Pyogenic granulomas are common benign skin growths often present at sites of trauma. They can be difficult to treat in austere environments. A case report of a pyogenic granuloma in an austere environment has not previously been published. We submit this work to describe a case of a pyogenic granuloma arising from a properly treated laceration in an austere environment and to review current treatment options. Multiple treatment modalities are available to providers with limited resources to include topical Imiquimod, ethanol injection, silver nitrate application, and oral steroids. PMID- 21702397 TI - Spice: a legal marijuana equivalent. AB - Spice, an herbal mixture containing synthetic cannabinoids, is a legal drug increasingly abused by adolescents and young adults for its narcotic-like effects. A paucity of English language literature exists on the clinical effects of Spice use. A case report of substance-induced psychosis and a summary of available literature follows later. PMID- 21702398 TI - Does palliative care improve outcomes for patients with incurable illness? A review of the evidence. AB - Patients with incurable illness experience considerable physical and psychological distress, which negatively impacts their quality of life. Palliative care clinicians primarily seek to alleviate suffering, enhance coping with symptoms, and enable informed decision making. In this article, we review the efficacy of various palliative care interventions to improve patients' quality of life, physical and psychological symptoms, satisfaction with care, family caregiver outcomes, health-service utilization, and quality of end-of-life care. We have identified 22 randomized studies that evaluate the efficacy of various palliative care interventions. Palliative care research has been hampered by methodological challenges related to attrition and missing data due to progressive illness and death. In addition, interventions to date have varied widely in the focus and extent of services, with only eight studies entailing direct clinical care by palliative care specialists, making comparisons across trials challenging. Despite these limitations, accumulating evidence shows that palliative care interventions do improve patients' quality of life, satisfaction with care, and end-of-life outcomes. Five of seven studies which examined quality of life as a primary outcome reported a statistically significant difference favoring the palliative care intervention. Ten studies examined patient and/or family caregiver satisfaction with care, and seven of these reported greater satisfaction with palliative care intervention. However, data are lacking to support the benefit of palliative interventions for reducing patients' physical and psychological symptoms. We conclude the review by discussing the major obstacles and future directions in evaluating and implementing standardized palliative care interventions. PMID- 21702399 TI - Standards for palliative care programs, interventions, and outcomes: not quite there yet. PMID- 21702400 TI - Facilitating hospice discussions: a six-step roadmap. AB - Hospice programs provide comprehensive, compassionate care to dying patients and their families. However, many patients do not enroll in hospice, and those who do generally receive hospice care only in the last weeks of life. Although patients and families rely on their physicians to discuss hospice, there is often inadequate communication between patients and physicians about end-of-life issues. We describe a Six-Step Roadmap for navigating discussions about hospice adapted from the SPIKES protocol for delivering bad news: setting up the discussion, assessing the patient's perception, inviting a patient to discuss individual goals and needs, sharing knowledge, empathizing with the patient's emotions, and summarizing and strategizing the next steps. PMID- 21702401 TI - I wish that things were different... redux. PMID- 21702403 TI - An exploratory pilot study of palliative medicine compared to anesthesia-pain consultation for pain in patients with cancer. AB - Oncologists often manage cancer-associated symptoms including pain. When symptoms are severe, anesthesia-pain medicine (APM) and/or palliative medicine (PM) can effectively treat symptoms. Nevertheless, symptom management may be suboptimal, leading to diminished quality of life (QOL). We assessed the value of PM vs. APM consultation in cancer patients referred for pain management alone. Patients referred to an APM-based Cancer Pain Clinic (CPC) over an 8-month period were evaluated by PM or APM based on the first available appointment. Symptoms and QOL were assessed by the MD Anderson Symptom Inventory and Linear Analog Self Assessment at baseline and 4-6 weeks after initial encounter. Data were analyzed on an available-case basis. Sixty-two patients (37 PM, 25 APM) completed the initial survey, with 48 patients (31 PM, 17 APM) completing followup. Mean pain score improved from 7.97 to 5.47 in the PM group (P < 0.0001) and from 7.1 to 4.5 (P = 0.29) in the APM group. The PM group demonstrated a clinically significant improvement in 8/19 symptoms vs. 3/19 in the APM group and in 3/5 QOL parameters in the PM group vs. 1/5 in the APM group. Our small sample size weakens our power and ability to detect significant differences between the groups. Only one follow up symptom-assessment point was obtained. PM consultation is as effective as APM in improving cancer pain but may be more effective with symptom management and improving QOL. PMID- 21702402 TI - A phase III randomized, double-blind, placebo-controlled study of pilocarpine for vaginal dryness: North Central Cancer Treatment group study N04CA. AB - Vaginal dryness is a common problem for which effective and safe nonestrogenic treatments are needed. Based on preliminary promising data that pilocarpine attenuated vaginal dryness, the current trial was conducted. A double-blind, placebo-controlled, randomized trial design was used to compare pilocarpine, at target doses of 5 mg twice daily and 5 mg four times daily, with a placebo. Vaginal dryness was recorded by patient-completed questionnaires at baseline and weekly for 6 weeks after study initiation. The primary endpoint for this study was the area under the curve summary statistic composed of the longitudinal responses obtained at baseline and through the 6 weeks of treatment to a numerical analogue scale asking patients to rate their perceived amount of vaginal dryness. The primary analysis was carried out by a single t test using a two-side alternative to compare the collective pilocarpine treatment arms with the collective placebo arms. A total of 201 patients enrolled in this trial. The primary analysis, comparing vaginal dryness symptoms in the collective pilocarpine arms against the placebo arm, did not reveal any benefit for the pilocarpine treatment. This finding was confirmed by other secondary analyses. Toxicity evaluation revealed more nausea, sweating, rigors, and urinary frequency with the pilocarpine arms compared with the placebo arm. PMID- 21702404 TI - A physician's personal experience with neck cancer: deciding whether to share my diagnosis. PMID- 21702405 TI - Disdaining the coward terrors. PMID- 21702406 TI - Caring for Alzheimer's disease patients from a physician/legislator's perspective. PMID- 21702407 TI - What can the physician offer the patient presenting with dementia? PMID- 21702408 TI - New developments in the search for a cure. PMID- 21702409 TI - Standing in the gap: the primary care physician and Alzheimer's disease. PMID- 21702410 TI - Can Alzheimer's or vascular dementia be prevented with control of vascular risk factors? PMID- 21702411 TI - The predisposing factors, biological markers, neuroimaging techniques and medical complications associated with Alzheimer's disease. AB - With increased longevity and increased prevalence of diabetes, hypertension, heart disease, and obesity, dementia is likely to raise three to fourfold. The diagnosis of the Alzheimer's type dementia is being challenged as the majority of the dementias appear to be of the mixed type. Biological and genetic factors combined with life style choices play a role in the development of the dementias. The drugs in current use to modify the symptoms have had little impact. Today's research challenges the long held amyloid theory of Alzheimer 's disease. Research has been inconsistent and more support is needed to help us identify preventable and modifiable factors of the disease. PMID- 21702412 TI - Pathologic diagnosis of Alzheimer disease. PMID- 21702413 TI - Completing the continuum of quality dementia care: end-of-life care. PMID- 21702414 TI - "Training" a workforce to care for people in West Virginia with Alzheimer's disease and related dementias. PMID- 21702415 TI - The West Virginia Alzheimer's Disease Registry: helping West Virginia cope. PMID- 21702416 TI - Major trauma in West Virginia dementia patients injury patterns, discharge dispositions and implications for treatment and injury prevention. AB - Our study examines injury patterns, treatment implications, discharge disposition, and injury prevention for trauma patients with dementia. It is a retrospective observational study of trauma patients at the Jon Michael Moore Trauma Center at West Virginia University Hospitals. Causes of injury, injuries sustained, and discharge disposition were examined in 286 trauma patients with a pre-existing diagnosis of dementia and 5,865 trauma patients without dementia. All patients included in this study were 40 years of age or older. Injury data were compiled for patients with dementia. Causes of injury and discharge disposition were compared for the two groups. PMID- 21702417 TI - Driving assessment results in patients with a diagnosis of dementia. PMID- 21702418 TI - Caregiver stress: an important and overlooked health issue. PMID- 21702419 TI - Filling an unmet need: a support group for early stage/ young onset Alzheimer's disease and related dementias. PMID- 21702420 TI - The patient's perspective: diagnosing and treating Alzheimer's disease. PMID- 21702421 TI - Caregivers, take care of yourselves--resources for family caregivers. PMID- 21702422 TI - Dementia in West Virginia: a review of the data. PMID- 21702423 TI - Doctor: world traveler--kidnapping, ransom, and extortion. Insurance coverage available/keeping you, your family, or your business covered. PMID- 21702424 TI - 2011 Alzheimer's disease facts and figures. PMID- 21702425 TI - Diffusion of innovations in long-term care measurement battery. AB - Poor understanding of factors influencing integration of new practices into long term care (LTC) hinders timely implementation of evidence-based practices (EBPs). Using the Diffusion of Innovations (DOI) framework, a new instrument measuring staff perceptions of an EBP was developed as part of a DOI-LTC measurement battery and tested in a cross-sectional survey of North Carolina LTC nursing personnel. Valid questionnaires were received from 95 licensed nurses and 102 certified nursing assistants (CNAs). Internal consistency reliability for five of seven subscales was acceptable (Cronbach's alpha coefficient = 0.77 to 0.95). Perception of innovation attributes was associated with intention to adopt the new practice (Spearman rho correlation: licensed nurses = 0.41 to 0.68, p < 0.0001; CNAs = 0.26 to 0.54, p = 0.05 to <0.0001). The DOI-LTC measurement battery represents a promising new approach to studying implementation of EBPs in LTC. Future work should examine its responsiveness to interventions that facilitate implementation of EBPs in LTC. PMID- 21702426 TI - Providing nursing leadership in a community residential mental health setting. AB - The worldwide burden of mental illness is increasing. Strong leadership is increasingly emerging as a core component of good mental health nursing. The aim of this article is to demonstrate the ways in which nurses can provide strong and consistent leadership in a values-based practice environment that embodies respect for individuals' dignity and self-determination within a community residential mental health service, which provides a structural foundation for effective action. This is accomplished through the presentation of two vignettes, which highlight how the seemingly impossible becomes possible when an economic paradigm such as agency theory is exchanged for a sociological and psychological paradigm found in leadership as stewardship at the point of service. It is through stronger nursing leadership in mental health that stigma and discrimination can be reduced and better access to treatments and services can be gained by those with mental illness. Nurse leadership in mental health services is not new, but it is still relatively uncommon to see residential services for "high needs" individuals being led by nurses. How nurses meet the challenges faced by mental health services are often at the heart of effective leadership skills and strategies. PMID- 21702427 TI - Simulation to enhance care of patients with psychiatric and behavioral issues: use in clinical settings. AB - Nurses with a medical-surgical clinical focus often care for patients with psychiatric and behavioral issues in acute care hospitals. This article describes how hospital staff and nursing and theater department faculty joined forces to develop realistic simulated psychiatric scenarios for use by practicing nurses. PMID- 21702428 TI - Integrated physical and mental health care at a nurse-managed clinic: report from the trenches. AB - The Health and Wellness Center (HWC), located in Joliet, Illinois, is a nurse managed universally accessible primary health care center funded by a grant from the Health Resources and Services Administration. The goals of the HWC are to improve access to quality primary health care services for all patients, including those who are uninsured and underserved, and to develop and implement a model of nurse-managed primary health care that integrates both physical and mental health assessment and treatment. After 5 years of developing and using this model, it is clear that integration requires strategic supports from the financial, political, and professional sectors to be considered a cost-effective model of health care delivery. Recommendations for policy and practice change are offered based on the author's experiences of providing integrated health care at the HWC and the health care industry's responses to uninsured or underinsured patients' needs. PMID- 21702431 TI - Worldwide standards for nursing education: one answer to a critical need. PMID- 21702432 TI - A service-learning project facilitating leadership and management skills. PMID- 21702433 TI - Understanding ligninase-mediated reactions of endocrine disrupting chemicals in water: reaction rates and quantitative structure-activity relationships. AB - We have verified in our previous work that lignin peroxidase (LiP) mediates effective removal of selected natural and synthetic estrogens. The efficiency of these reactions was greatly enhanced in the presence of veratryl alcohol (VA), a chemical that is produced along with LiP by certain white rot fungi, for example, Phanerochaete chrysosporium. In this study, we systematically evaluated the kinetic behaviors of LiP-mediated reactions for six endocrine disrupting compounds (EDCs), that is, steroid estrogens and their structural analogs, in both the presence and absence of VA. Resulting kinetic parameters were then correlated with structural features of LiP/substrate binding complexes, as quantified using molecular simulation, to create quantitative structure-activity relationship (QSAR) equations. These equations suggest that binding distance between a substrate's phenolic proton and deltaN of HIS47's imidazole ring plays an important role in modulating substrate reactivity toward LiP in both the presence and absence of VA. This information provides insight into an important enzymatic reaction process that occurs in the natural environment affecting EDC transformation, a process that may be used in engineered systems to achieve EDC removal from water. PMID- 21702434 TI - Improvements in proteomic metrics of low abundance proteins through proteome equalization using ProteoMiner prior to MudPIT. AB - Ideally, shotgun proteomics would facilitate the identification of an entire proteome with 100% protein sequence coverage. In reality, the large dynamic range and complexity of cellular proteomes results in oversampling of abundant proteins, while peptides from low abundance proteins are undersampled or remain undetected. We tested the proteome equalization technology, ProteoMiner, in conjunction with Multidimensional Protein Identification Technology (MudPIT) to determine how the equalization of protein dynamic range could improve shotgun proteomics methods for the analysis of cellular proteomes. Our results suggest low abundance protein identifications were improved by two mechanisms: (1) depletion of high abundance proteins freed ion trap sampling space usually occupied by high abundance peptides and (2) enrichment of low abundance proteins increased the probability of sampling their corresponding more abundant peptides. Both mechanisms also contributed to dramatic increases in the quantity of peptides identified and the quality of MS/MS spectra acquired due to increases in precursor intensity of peptides from low abundance proteins. From our large data set of identified proteins, we categorized the dominant physicochemical factors that facilitate proteome equalization with a hexapeptide library. These results illustrate that equalization of the dynamic range of the cellular proteome is a promising methodology to improve low abundance protein identification confidence, reproducibility, and sequence coverage in shotgun proteomics experiments, opening a new avenue of research for improving proteome coverage. PMID- 21702435 TI - Podophyllotoxin and deoxypodophyllotoxin in Juniperus bermudiana and 12 other Juniperus species: optimization of extraction, method validation, and quantification. AB - The lignans podophyllotoxin and deoxypodophyllotoxin are secondary metabolites with potent pharmaceutical applications in cancer therapy. However, the supply of podophyllotoxin from its current natural source, Podophyllum hexandrum, is becoming increasingly problematic, and alternative sources are therefore urgently needed. So far, podophyllotoxin and deoxypodophyllotoxin have been found in some Juniperus species, although at low levels in most cases. Moreover, extraction protocols deserve optimization. This study aimed at developing and validating an efficient extraction protocol of podophyllotoxin and deoxypodophyllotoxin from Juniperus species and applying it to 13 Juniperus species, among which some had never been previously analyzed. Juniperus bermudiana was used for the development and validation of an extraction protocol for podophyllotoxin and deoxypodophyllotoxin allowing extraction yields of up to 22.6 mg/g DW of podophyllotoxin and 4.4 mg/g DW deoxypodophyllotoxin, the highest values found in leaf extract of Juniperus. The optimized extraction protocol and HPLC separation from DAD or MS detections were established and validated to investigate podophyllotoxin and deoxypodophyllotoxin contents in aerial parts of 12 other Juniperus species. This allowed either higher yields to be obtained in some species reported to contain these two compounds or the occurrence of these compounds in some other species to be reported for the first time. This efficient protocol allows effective extraction of podophyllotoxin and deoxypodophyllotoxin from aerial parts of Juniperus species, which could therefore constitute interesting alternative sources of these valuable metabolites. PMID- 21702436 TI - Multitude of morphological dynamics of giant multilamellar vesicles in regulated nonequilibrium environments. AB - Lipid giant vesicles (GVs) exhibit biologically relevant morphological dynamics such as growth and division under certain conditions without any sophisticated molecular machineries employed by the current organisms. Nonequilibrium conditions are essential for the emergence of dynamic behaviors, which are normally generated by the addition of stimulating materials or by the change of some physical conditions. Therefore, an experimental method that allows flexible control of external conditions is desirable. Here we report a new and simple perfusion device for light microscopy observation that simultaneously realizes such control and tracking of individual phospholipid GVs for the long-term. We apply this device to the study of the morphological dynamics of POPC-based giant multilamellar vesicles (GMVs) under a monotonic and gradual increase of surfactant concentration; thereby we reveal the existence of multiple pathways in the slow solubilization processes, whose frequencies depend on the compositions of GMVs. This perfusion device would offer an unprecedented control of external conditions in the studies of GVs and might help us characterize the physicochemical origins of rich morphological dynamics of living cells. PMID- 21702437 TI - Electroluminescence enhancement in polymer light-emitting diodes through inelastic scattering of oppositely charged bipolarons. AB - Combining the one-dimensional tight-binding Su-Schrieffer-Heeger (SSH) model and the extended Hubbard model (EHM), the scattering and combination of oppositely charged bipolarons in conjugated polymers are investigated using a nonadiabatic evolution method. On the basis of this physical picture, bipolarons can scatter into a singlet biexcitonic state, in which two electrons and two holes are trapped together by a lattice distortion. This biexcitonic state can emit one photon to an exciton state, which can subsequently decay to the ground state. The results indicate that the scattering and combination of oppositely charged bipolarons may provide guidance for improving the internal quantum efficiency for electroluminescence to as high as 75% in polymer light-emitting diodes. PMID- 21702438 TI - beta-Cyclodextrin dimers linked through their secondary faces with rigid spacer arms as hosts for bile salts. AB - A convenient synthesis of beta-cyclodextrin dimers in which the two cyclodextrin units are linked by rigid tethers of relatively short length through their secondary sides is reported. Compounds hexa-2,4-diynediyl- and 1,4 phenylenediethyne-briged beta-cyclodextrin dimers are obtained in good yields from mono-2-O-propargyl-beta-cyclodextrin through Pd-mediated oxidative homo- and heterocoupling reactions. Isothermal titration calorimetry and NMR spectroscopy (PGSE and 2D-ROESY) are used to determine the thermodynamic parameters (K, DeltaH, and TDeltaS degrees ) for the complexation of such beta-cyclodextrin dimers with sodium cholate, deoxycholate, and chenodeoxycholate as well as to estimate the size of the supramolecular structures. The binding of bile salts is enhanced relative to that of native beta-cyclodextrin. Although chenodeoxycholate salt binds in a 1:1 fashion, cholate and deoxycholate salts bind in a 1:2 sequential mode. PMID- 21702439 TI - Magic-angle spinning NMR of a class I filamentous bacteriophage virus. AB - The fd bacteriophage is a filamentous virus that is widely used for bio- and nanotechnology applications ranging from phage display to battery materials. The possibility of obtaining a detailed description of its structural properties regardless of its state is therefore essential not only for understanding its physical arrangement and its bacterial infection process but also for many other applications. Here we present a study of the fd phage by magic-angle spinning solid-state NMR. While current structures rely on a Y21M mutant, experiments performed on a strain bearing a wild-type capsid report on high symmetry of the phage and lack of explicit subunit polymorphism. Chemical shift analysis confirmed that the coat protein mostly consists of a rigid right-handed curved alpha-helix (residues 6-47 of 50), preceded by a flexible loop-structured N terminus. We were able to qualitatively assign the resonances belonging to the DNA, including the deoxyribose sugars and the thymine bases. These chemical shifts are consistent with base stacking and a C2'-endo/C3'-exo sugar pucker. PMID- 21702440 TI - Formation of (3+1) G-quadruplexes with a long loop by human telomeric DNA spanning five or more repeats. AB - Structural studies of human telomeric repeats represent an active field of research with potential applications toward the development of specific telomeric quadruplex-targeting drugs for anticancer treatment. To date, high-definition structures were limited to DNA sequences containing up to four GGGTTA repeats. Here we investigate the formation of G-quadruplexes in sequences spanning five to seven human telomeric repeats using NMR, UV, and CD spectroscopy. A (3+1) G quadruplex with a long propeller loop was isolated from a five-repeat sequence utilizing a guanine-to-inosine substitution. A simple approach of selective site specific labeling of guanine residues was devised to rigorously determine the folding topology of the oligonucleotide. The same scaffold could be extrapolated to six- and seven-repeat sequences. Our results suggest that long human telomeric sequences consisting of five or more GGGTTA repeats could adopt (3+1) G quadruplex structures harboring one or more repeat(s) within a single loop. We report on the formation of a Watson-Crick duplex within the long propeller loop upon addition of the complementary strand, demonstrating that the long loop could serve as a new recognition motif. PMID- 21702441 TI - Nanoscale control of phase variants in strain-engineered BiFeO3. AB - Development of magnetoelectric, electromechanical, and photovoltaic devices based on mixed-phase rhombohedral-tetragonal (R-T) BiFeO(3) (BFO) systems is possible only if the control of the engineered R phase variants is realized. Accordingly, we explore the mechanism of a bias induced phase transformation in this system. Single point spectroscopy demonstrates that the T -> R transition is activated at lower voltages compared to T -> -T polarization switching. With phase field modeling, the transition is shown to be electrically driven. We further demonstrate that symmetry of formed R-phase rosettes can be broken by a proximal probe motion, allowing controlled creation of R variants with defined orientation. This approach opens a pathway to designing next-generation magnetoelectronic and data storage devices in the nanoscale. PMID- 21702442 TI - Synthetic studies on polymaxenolides: synthesis and structure elucidation of nominal epoxyafricanane and other africane-type sesquiterpenoids. AB - A racemic total synthesis of the sesquiterpenoid unit of the hybrid marine natural product polymaxenolide has been achieved based on a three-component assembly followed by ring-closing metathesis as the key steps. However, the spectral data of our product synthesized from Delta(9(15))-africanene by epoxidation were not identical with those of the natural product named epoxyafricanane. The structure confirmation of the synthetic nominal epoxyafricanane is described. PMID- 21702443 TI - Laser patterning of epitaxial graphene for Schottky junction photodetectors. AB - Large-area patterning of epitaxial graphene for Schottky junction photodetectors has been demonstrated with a simple laser irradiation method. In this method, semimetal-semiconductor Schottky junctions are created in a controllable pattern between epitaxial graphene (EG) and laser-modified epitaxial graphene (LEG). The zero-biased EG-LEG-EG photodetector exhibits a nanosecond and wavelength independent photoresponse in a broad-band spectrum from ultraviolet (200 nm) through visible to infrared light (1064 nm), distinctively different from conventional photon detectors. An efficient external photoresponsivity (or efficiency) of ~0.1 A.W(-1) is achieved with a biased interdigitated EG-LEG-EG photodetector. The fabrication method presented here opens a viable route to carbon optoelectronics for a fast and highly efficient photoconductive detector. PMID- 21702444 TI - Alkoxide-catalyzed reduction of ketones with pinacolborane. AB - The reduction of ketones with pinacolborane (4,4,5,5-tetramethyl-1,3,2 dioxaborolane) is catalyzed by 5 mol % NaOt-Bu at ambient temperature. The reaction is high yielding and general, providing complete conversion of aryl and dialkyl ketones. Although spectroscopic studies of the active hydride source in benzene-d(6) were complicated due to poor solubility, the data are consistent with the active hydride source being the trialkoxyborohydride, which is believed to be present in low concentration under the reaction conditions. Performing analogous studies in tetrahydrofuran resulted in a complex equilibrium between several different boron-containing species in which the trialkoxyborohydride compound was the major species. PMID- 21702445 TI - Thermally driven ionic aggregation in poly(ethylene oxide)-based sulfonate ionomers. AB - A series of sulfonate polyester ionomers with well-defined poly(ethylene oxide) spacer lengths between phthalates and alkali metal cations as counterions are designed for improved ionic conductivity. Ion conduction in these chemically complex materials is dominated by the polymer mobility and the state of ionic aggregation. While the aggregation decreases dramatically at room temperature as the cation size increases from Li to Na to Cs, the extents of ionic aggregation of these ionomers are comparable at elevated temperatures. Both the Na and Cs ionomers exhibit thermally reversible transformation upon heating from 25 to 120 degrees C as isolated ion pairs aggregate. This seemingly counterintuitive aggregation of ions on heating is driven by the fact that the dielectric constant of all polar liquids decreases on heating, enhancing Coulomb interactions between ions. PMID- 21702446 TI - Anticancer potency of cytotoxic drugs after exposure to high-intensity focused ultrasound in the presence of microbubbles and hematoporphyrin. AB - Chemotherapy is undertaken perioperatively to improve the efficacy of high intensity focused ultrasound (HIFU) for solid tumors. HIFU at a sufficient intensity for tissue ablation has recently been applied for drug delivery; ultrasonic cavitation plays an important part in HIFU and drug delivery. Hematoporphyrin and microbubbles are adjuncts because they aid cavitation. The effect of HIFU (1.0 MHz; 12,999 W/cm(2) in continuous waves), in the presence of hematoporphyrin and/or microbubbles, on the anticancer potency of 5-fluorouracil, cisplatin, paclitaxel, mitomycin C or adriamycin, was investigated. Insonated adriamycin resulted in a lower death rate of human cancer cells HO-8910 (45.85 +/ 2.65% vs 34.84 +/- 1.21%, p < 0.05), which was exacerbated when employing hematoporphyrin (34.84 +/- 1.21% vs 23.09 +/- 7.82%, p < 0.05) or hematoporphyrin combined with microbubbles (34.84 +/- 1.21% vs. 8.79 +/- 3.69%, p < 0.05); the therapeutic activity was not affected when adding microbubbles alone. High performance liquid chromatography detected a smaller peak area after subjecting adriamycin to HIFU with the use of hematoporphyrin alone or combined with microbubbles. The other drugs were not affected. Hematoporphyrin, microbubbles and adriamycin increased the throughput of hydroxyl radicals resulting from cavitation as determined by iodine and methylene blue assays. These data suggested that the anticancer activity of a drug may be decreased by HIFU exposure (particularly in the presence of hematoporphyrin and microbubbles). Cavitation produced reactive species that attacked drug molecules, thereby decreasing their antitumor potency; this process was enhanced if the drug itself generated free radicals under insonation. PMID- 21702447 TI - Polarizability and internal charge transfer in thiophene-triphenylamine hybrid pi conjugated systems. AB - Extended star-shaped conjugated systems consisting of dicyanovinyl electron acceptor units connected to a triphenylamine core by means of thiophene (T), thienylenevinylene (TV), and bithiophene (BT) conjugating spacers have been synthesized. The analysis of the electronic properties of the molecules by UV-vis absorption spectroscopy, cyclic voltammetry, and theoretical calculations shows that the electronic properties of the systems depend on the length and rigidity of the conjugating spacer. PMID- 21702448 TI - Electrogenerated chemiluminescence of conjugated polymer films from patterned electrodes. AB - A new phenomenon is presented in which electrogenerated chemiluminescence (ECL) is generated and propagates laterally as self-reinforcing waves as a result of the oxidation of a poly(9,9-dioctylfluorene-co-benzothiadiazole) thin film. In an ordered array of Au electrode posts that act as effective ECL nucleation sites, soliton-like waves were observed to expand from each site and annihilate upon collision with each other. Simulations of the ECL response supported the experimental observations that the ECL waves propagate at a constant speed. A correlated diffusion mechanism involving the correlated motion of ions, injected holes, and solvent molecules is proposed to interpret the experimental data qualitatively. A rapid increase in the diffusion coefficient of these species in the polymer results in a sharp interface between non-oxidized and oxidized polymer phases wherein the electrochemical (EC) oxidation and mass transport of all pertinent species take place. EC oxidation of conjugated polymers of this type has important implications for the understanding of these materials and their modes of operation in EC conjugated polymer devices. PMID- 21702450 TI - Effect of salt on the equilibrium and nonequilibrium features of polyelectrolyte/surfactant association. AB - The impact of an electrolyte on aqueous mixtures of oppositely charged macromolecules and surfactants is usually explained by assuming an equilibrium association between the components. In this work, it is shown that the nonequilibrium character of polyelectrolyte/surfactant systems plays a crucial role in the interpretation of the effect of salt. Experimental investigations of mixtures of sodium poly(styrenesulfonate) (PSS) and hexadecyltrimethylammonium bromide (CTAB) reveal two distinct effects of added sodium chloride (NaCl). At small and moderate NaCl concentrations, the major impact of the electrolyte is manifested in the reduction of the kinetically stable composition range in which the PSS/CTAB mixtures are trapped in the nonequilibrium colloidal dispersion state. The application of high salt concentrations, however, primarily affects the equilibrium phase properties through considerably decreasing the amount of surfactant bound to the polyelectrolyte. PMID- 21702451 TI - Crystal structures of the cyclic oligoesters from 6,8-dioxabicyclo[3.2.1]octan-7 one. 3. The cyclic pentamer. PMID- 21702453 TI - Controlling electron trap depth to enhance optical properties of persistent luminescence nanoparticles for in vivo imaging. AB - Focusing on the use of nanophosphors for in vivo imaging and diagnosis applications, we used thermally stimulated luminescence (TSL) measurements to study the influence of trivalent lanthanide Ln(3+) (Ln = Dy, Pr, Ce, Nd) electron traps on the optical properties of Mn(2+)-doped diopside-based persistent luminescence nanoparticles. This work reveals that Pr(3+) is the most suitable Ln(3+) electron trap in the diopside lattice, providing optimal trap depth for room temperature afterglow and resulting in the most intense luminescence decay curve after X-ray irradiation. This luminescence dependency toward the electron trap is maintained through additional doping with Eu(2+), allowing UV-light excitation, critical for bioimaging applications in living animals. We finally identify a novel composition (CaMgSi(2)O(6):Eu(2+),Mn(2+),Pr(3+)) for in vivo imaging, displaying a strong near-infrared afterglow centered on 685 nm, and present evidence that intravenous injection of such persistent luminescence nanoparticles in mice allows not only improved but highly sensitive detection through living tissues. PMID- 21702452 TI - Conjugation of cRGD peptide to chlorophyll a based photosensitizer (HPPH) alters its pharmacokinetics with enhanced tumor-imaging and photosensitizing (PDT) efficacy. AB - The alpha(v)beta(3) integrin receptor plays an important role in human metastasis and tumor-induced angiogenesis. Cyclic Arg-Gly-Asp (cRGD) peptide represents a selective alpha(v)beta(3) integrin ligand that has been extensively used for research, therapy, and diagnosis of neoangiogenesis. For developing photosensitizers with enhanced PDT efficacy, we here report the synthesis of a series of bifunctional agents in which the 3-(1'-hexyloxyethyl)-3 devinylpyropheophorbide a (HPPH), a chlorophyll-based photosensitizer, was conjugated to cRGD and the related analogues. The cell uptake and in vitro PDT efficacy of the conjugates were studied in alpha(v)beta(3) integrin overexpressing U87 and 4T1 cell lines whereas the in vivo PDT efficacy and fluorescence-imaging potential of the conjugates were compared with the corresponding nonconjugated photosensitizer HPPH in 4T1 tumors. Compared to HPPH, the HPPH-cRGD conjugate in which the arginine and aspartic acid moieties were available for binding to two subunits of alpha(v)beta(3) integrin showed faster clearance, enhanced tumor imaging and enhanced PDT efficacy at 2-4 h postinjection. Molecular modeling studies also confirmed that the presence of the HPPH moiety in HPPH-cRGD conjugate does not interfere with specific recognition of cRGD by alpha(v)beta(3) integrin. Compared to U87 and 4T1 cells the HPPH-cRGD showed significantly low photosensitizing efficacy in A431 (alpha(v)beta(3) negative) tumor cells, suggesting possible target specificity of the conjugate. PMID- 21702454 TI - Universal electrostatic origin of cation ordering in A2BO4 spinel oxides. AB - The crystal structures of A(2)BO(4) spinel oxides are classified as either normal or inverse, representing different distributions of the A and B cations over the tetrahedrally and octahedrally coordinated cation sites. These structures undergo characteristic structural changes as a function of temperature: (i) the nominally disordered inverse structure orders crystallographically at low T, and (ii) at finite temperatures, both inverse and normal develop characteristic distributions of cations associated with order-disorder structural changes. We show here that all of these universal features emerge naturally from a simple point-ion electrostatic (PIE) model with a single adjustable parameter. Monte Carlo simulations of the PIE Hamiltonian provide quantitative order-disorder characteristic temperatures. We show that, with the help of the PIE model, the magnitude of the temperatures can be inferred from the nominal charges of the atomic species in the spinel. Indeed, we show that characteristic order-disorder temperatures in 3-2 spinels (nominal charges Z(A) = 3 and Z(B) = 2) are approximately an order of magnitude lower than in 2-4 spinels, thus explaining why typical 3-2 samples exhibit much larger degrees of disorder than those belonging to the 2-4 class. PMID- 21702455 TI - Which one among the Pt-containing anticancer drugs more easily forms monoadducts with G and A DNA bases? A comparative study among oxaliplatin, nedaplatin, and carboplatin. AB - The platination processes of DNA bases with second- and third-generation Pt(II) anticancer drugs have been investigated using density functional theory (DFT) combined with the conductor-like dielectric continuum model (CPCM) approach, in order to describe their binding mechanisms and to obtain detailed data on the reaction energy profiles. Although there is no doubt that a Pt-N7 bond forms during initial attack, the energetic profiles for the formation of the monofunctional adducts are not known. Herein, a direct comparison between the rate of formation of the monofunctional adducts of the second- and third generation anticancer drugs with guanine (G) and adenine (A) DNA bases has been made in order to spotlight possible common or different behavior. The guanine as target for platination process is confirmed to be preferred over adenine for all the investigated compounds and for both the hydrolyzed forms considered in our investigation. The preference for G purine base is dominated by electronic factors and promoted by a more favorable hydrogen-bonds pattern, confirming the important role played by H-bonds in determining both structural and kinetic control on the purine platination process. PMID- 21702458 TI - Chiral N,N'-dioxides: new ligands and organocatalysts for catalytic asymmetric reactions. AB - Homochiral catalysts that can effect asymmetric transformations are invaluable in the production of optically active molecules. Researchers are actively pursuing the design of new ligands and organocatalysts by exploiting concepts derived from the application of bifunctional and C(2)-symmetric catalysts. Many homochiral catalysts containing amines, ethers, alcohols, and phosphines as electron-pair donors have been successfully developed. Amine N-oxides are highly polar substances. Despite their pronounced capacity as electron-pair donors, N-oxides have been underutilized in asymmetric reactions; they have only made a visible impact on the field in the preceding decade. Systematic studies have instead largely focused on pyridine- or quinoline-based scaffolds in organosilicon and coordination chemistry. The application of chiral tertiary amine N-oxides has not been widely pursued because of the difficulty of controlling the chirality at the tetrahedral nitrogen of the N-oxide moiety. In this Account, we outline the design of a new family of C(2)-symmetric N,N'-dioxides from readily available chiral amino acids. We then discuss the application of these chiral amine N oxides as useful metal ligands and organocatalysts for asymmetric reactions. The high nucleophilicity of the oxygen in N-oxides is ideal for organocatalytic reactions that rely on nucleophilic activation of organosilicon reagents. These catalysts have been successfully applied in the asymmetric addition of trimethylsilylcyanide to aldehydes, ketones, aldimines, and ketimines, with good yields and excellent enantioselectivities. Asymmetric organocatalytic chlorination of beta-ketoesters with N-chlorosuccinimide has also been achieved through hydrogen bond activation. The molecular framework of these N,N'-dioxides, with their multiple O-donors, also serves as a new tetradentate ligand that can coordinate a range of metal ions, including Cu(I), Cu(II), Ni(II), Mg(II), Fe(II), Co(II), In(III), Sc(III), La(III), Y(III), Nd(III), and others. These versatile metal complexes are efficient catalysts for a variety of asymmetric reactions. Asymmetric cycloadditions have been achieved with these chiral Lewis acid catalysts. We have also found success with asymmetric nucleophilic additions to C?O or C?N bonds; substrates include 3-substituted 2-oxindoles, alkenes, enamides, enecarbamates, diazoacetate esters, nitroalkanes, glycine Schiff bases, and phosphate. Notably, the first catalytic asymmetric Roskamp reaction was realized, which was successful because of the high efficiency of the catalyst. Asymmetric conjugate additions between alpha,beta-unsaturated compounds and nucleophiles such as nitroalkane, malonate, thioglycolate, and indoles have been accomplished. The first asymmetric haloamination of chalcones was discovered, and the reaction proceeded with high regio- and enantioselectivity. In some cases, we were able to reduce the catalyst loading to just 0.01-0.05 mol % while maintaining excellent outcomes. Some particularly interesting phenomena were observed over the course of the research. These include a remarkable amplification of the asymmetry in a sulfa-Michael reaction, as well as the reversal of enantioselectivity after alteration of the central metal or the subunits of the ligand in two other reactions. These unusual results have facilitated a deeper understanding of the catalytic mechanism. PMID- 21702456 TI - Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. AB - Because of a preconceived notion that eliminating reactive metabolite (RM) formation with new drug candidates could mitigate the risk of idiosyncratic drug toxicity, the potential for RM formation is routinely examined as part of lead optimization efforts in drug discovery. Likewise, avoidance of "structural alerts" is almost a norm in drug design. However, there is a growing concern that the perceived safety hazards associated with structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be over exaggerated. In addition, the multifactorial nature of idiosyncratic toxicity is now well recognized based upon observations that mechanisms other than RM formation (e.g., mitochondrial toxicity and inhibition of bile salt export pump (BSEP)) also can account for certain target organ toxicities. Hence, fundamental questions arise such as: When is a molecule that contains a structural alert (RM positive or negative) a cause for concern? Could the molecule in its parent form exert toxicity? Can a low dose drug candidate truly mitigate metabolism-dependent and -independent idiosyncratic toxicity risks? In an effort to address these questions, we have retrospectively examined 68 drugs (recalled or associated with a black box warning due to idiosyncratic toxicity) and the top 200 drugs (prescription and sales) in the United States in 2009 for trends in physiochemical characteristics, daily doses, presence of structural alerts, evidence for RM formation as well as toxicity mechanism(s) potentially mediated by parent drugs. Collectively, our analysis revealed that a significant proportion (~78-86%) of drugs associated with toxicity contained structural alerts and evidence indicating that RM formation as a causative factor for toxicity has been presented in 62-69% of these molecules. In several cases, mitochondrial toxicity and BSEP inhibition mediated by parent drugs were also noted as potential causative factors. Most drugs were administered at daily doses exceeding several hundred milligrams. There was no obvious link between idiosyncratic toxicity and physicochemical properties such as molecular weight, lipophilicity, etc. Approximately half of the top 200 drugs for 2009 (prescription and sales) also contained one or more alerts in their chemical architecture, and many were found to be RM-positive. Several instances of BSEP and mitochondrial liabilities were also noted with agents in the top 200 category. However, with relatively few exceptions, the vast majority of these drugs are rarely associated with idiosyncratic toxicity, despite years of patient use. The major differentiating factor appeared to be the daily dose; most of the drugs in the top 200 list are administered at low daily doses. In addition, competing detoxication pathways and/or alternate nonmetabolic clearance routes provided suitable justifications for the safety records of RM-positive drugs in the top 200 category. Thus, while RM elimination may be a useful and pragmatic starting point in mitigating idiosyncratic toxicity risks, our analysis suggests a need for a more integrated screening paradigm for chemical hazard identification in drug discovery. Thus, in addition to a detailed assessment of RM formation potential (in relationship to the overall elimination mechanisms of the compound(s)) for lead compounds, effects on cellular health (e.g., cytotoxicity assays), BSEP inhibition, and mitochondrial toxicity are the recommended suite of assays to characterize compound liabilities. However, the prospective use of such data in compound selection will require further validation of the cellular assays using marketed agents. Until we gain a better understanding of the pathophysiological mechanisms associated with idiosyncratic toxicities, improving pharmacokinetics and intrinsic potency as means of decreasing the dose size and the associated "body burden" of the parent drug and its metabolites will remain an overarching goal in drug discovery. PMID- 21702459 TI - Photoluminescence of dense nanocrystalline titanium dioxide thin films: effect of doping and thickness and relation to gas sensing. AB - The photoluminescence (PL) of dense nanocrystalline (anatase) TiO(2) thin films is reported as a function of calcination temperature, thickness, and tungsten and nickel doping. The dependence of the optical absorption, Raman spectra, and PL spectra on heat treatment and dopants reveals the role of oxygen vacancies, crystallinity, and phase transformation in the performance of TiO(2) films used as gas sensors. The broad visible PL from defect states of compact and undoped TiO(2) films is found to be much brighter and less sensitive to the presence of oxygen than that of mesoporous films. The dense nanocrystalline grains and the nanoparticles comprising the mesoporous film are comparable in size, demonstrating the importance of film morphology and carrier transport in determining the intensity of defect photoluminescence. At higher calcination temperatures, the transformation to rutile results in the appearance of a dominant near-infrared peak. This characteristic change in the shape of the PL spectra demonstrates efficient capture of conduction band electrons by the emerging rutile phase. The W-doped samples show diminished PL with quenching on the red side of the emission spectrum occurring at lower concentration and eventual disappearance of the PL at higher W concentration. The results are discussed within the context of the performance of the TiO(2) thin films as CO gas sensors and the chemical nature of luminescent defects. PMID- 21702460 TI - Catalytic mechanism of water oxidation with single-site ruthenium heteropolytungstate complexes. AB - Catalytic water oxidation to generate oxygen was achieved using all-inorganic mononuclear ruthenium complexes bearing Keggin-type lacunary heteropolytungstate, [Ru(III)(H(2)O)SiW(11)O(39)](5-) (1) and [Ru(III)(H(2)O)GeW(11)O(39)](5-) (2), as catalysts with (NH(4))(2)[Ce(IV)(NO(3))(6)] (CAN) as a one-electron oxidant in water. The oxygen atoms of evolved oxygen come from water as confirmed by isotope labeled experiments. Cyclic voltammetric measurements of 1 and 2 at various pH's indicate that both complexes 1 and 2 exhibit three one-electron redox couples based on ruthenium center. The Pourbaix diagrams (plots of E(1/2) vs pH) support that the Ru(III) complexes are oxidized to the Ru(V)-oxo complexes with CAN. The Ru(V)-oxo complex derived from 1 was detected by UV-visible absorption, EPR, and resonance Raman measurements in situ as an active species during the water oxidation reaction. This indicates that the Ru(V)-oxo complex is involved in the rate-determining step of the catalytic cycle of water oxidation. The overall catalytic mechanism of water oxidation was revealed on the basis of the kinetic analysis and detection of the catalytic intermediates. Complex 2 exhibited a higher catalytic reactivity for the water oxidation with CAN than did complex 1. PMID- 21702461 TI - Controllable and reversible inversion of the electronic structure in nickel N confused porphyrin: a case when MCD matters. AB - Nickel N-confused tetraphenylporphyrin, 1, and nickel 2-N-methyl-N-confused tetraphenylporphyrin, 1-Me, exhibit unusual sign-reversed (positive-to-negative intensities in ascending energy) MCD spectra in the Q-type band region, suggesting a rare DeltaHOMO < DeltaLUMO relationship between pi and pi* MOs in the porphyrin core. Simple and reversible deprotonation of the external NH proton in 1 dramatically changes the electronic structure of the porphyrin core into the DeltaHOMO > DeltaLUMO combination characteristic for the meso (tetraaryl)porphyrins. DFT, time-dependent DFT, and semiempirical ZINDO/S calculations on 1, 1-Me, and 1(-) confirm the experimental finding and successfully explain the MCD pattern in the target compounds. PMID- 21702462 TI - Synthesis of shape-controlled monodisperse wurtzite CuIn(x)Ga(1-x)S2 semiconductor nanocrystals with tunable band gap. AB - Monodisperse wurtzite CuIn(x)Ga(1-x)S(2) nanocrystals have been synthesized over the entire composition range using a facile solution-based method. Depending on the chemical composition and synthesis conditions, the morphology of the nanocrystals can be controlled in the form of bullet-like, rod-like, and tadpole like shapes. The band gap of the nanocrystals increases linearly with increasing Ga concentration, with band gap values for the end members being close to those observed in the bulk. Colloidal suspensions of the nanocrystals are attractive for use as inks for low-cost fabrication of thin film solar cells by spin or spray coating. PMID- 21702463 TI - Dissociation of H2NCH dication in a strong laser field. AB - Ab initio classical molecular dynamics calculations have been used to simulate the dissociation of H(2)NCH(2+) in a strong laser field. The frequencies of the continuous oscillating electric field were chosen to be omega = 0.02, 0.06, and 0.18 au (2280, 760, and 253 nm, respectively). The field had a maximum strength of 0.03 au (3.2 * 10(13) W cm(-2)) and was aligned with the CN bond. Trajectories were started with 100 kcal/mol of vibrational energy above zero point and were integrated for up to 600 fs at the B3LYP/6-311G(d,p) level of theory. A total of 200 trajectories were calculated for each of the three different frequencies and without a field. Two dissociation channels are observed: HNCH(+) + H(+) and H(2)NC(+) + H(+). About one-half to two-thirds of the H(+) dissociations occurred directly, while the remaining indirect dissociations occurred at a slower rate with extensive migration of H(+) between C and N. The laser field increased the initial dissociation rate by a factor of ca. 1.4 and decreased the half-life by a factor of ca. 0.75. The effects were similar at each of the three frequencies. The HNCH(+) to H(2)NC(+) branching ratio decreased from 10.6:1 in the absence of the field to an average of 8.4:1 in the laser field. The changes in the rates and branching ratios can be attributed to the laser field lowering the reaction barriers as a result of a difference in polarizability of the reactant and transition states. PMID- 21702464 TI - Unprecedented zeolite-like framework topology constructed from cages with 3-rings in a barium oxonitridophosphate. AB - A novel oxonitridophosphate, Ba(19)P(36)O(6+x)N(66-x)Cl(8+x) (x ~ 4.54), has been synthesized by heating a multicomponent reactant mixture consisting of phosphoryl triamide OP(NH(2))(3), thiophosphoryl triamide SP(NH(2))(3), BaS, and NH(4)Cl enclosed in an evacuated and sealed silica glass ampule up to 750 degrees C. Despite the presence of side phases, the crystal structure was elucidated ab initio from high-resolution synchrotron powder diffraction data (lambda = 39.998 pm) applying the charge flipping algorithm supported by independent symmetry information derived from electron diffraction (ED) and scanning transmission electron microscopy (STEM). The compound crystallizes in the cubic space group Fm 3c (no. 226) with a = 2685.41(3) pm and Z = 8. As confirmed by Rietveld refinement, the structure comprises all-side vertex sharing P(O,N)(4) tetrahedra forming slightly distorted 3(8)4(6)8(12) cages representing a novel composite building unit (CBU). Interlinked through their 4-rings and additional 3-rings, the cages build up a 3D network with a framework density FD = 14.87 T/1000 A(3) and a 3D 8-ring channel system. Ba(2+) and Cl(-) as extra-framework ions are located within the cages and channels of the framework. The structural model is corroborated by (31)P double-quantum (DQ) /single-quantum (SQ) and triple-quantum (TQ) /single-quantum (SQ) 2D correlation MAS NMR spectroscopy. According to (31)P{(1)H} C-REDOR NMR measurements, the H content is less than one H atom per unit cell. PMID- 21702465 TI - Highly loaded silicone nanocomposite exhibiting quick thermoresponsive optical behavior. AB - Bulk silicone nanocomposites with thermoresponsive optical behavior were fabricated using silica nanoparticle fillers within a cross-linked silicone matrix. Silica nanoparticles (25 nm diameter) were surface-modified, allowing for even distribution at 6-24 wt % within and covalent bonding to the silicone matrix. Utilizing the temperature-dependent match/mismatching of the refractive indices of the silica nanoparticle filler and the silicone matrix, bulk nanocomposites are highly transparent at room temperature and demonstrate significant increases in opacity with increasing temperature up to 100-150 degrees C. Such a response could be cycled quickly and repeatedly with no detrimental effect on the material. PMID- 21702466 TI - Molecular structure of hydrazoic acid with hydrogen-bonded tetramers in nearly planar layers. AB - Hydrazoic acid (HN(3))--potentially explosive, highly toxic, and very hygroscopic -is the simplest covalent azide and contains 97.7 wt % nitrogen. Although its molecular structure was established decades ago, its crystal structure has now been solved by X-ray diffraction for the first time. Molecules of HN(3) are connected to each other by hydrogen bonds in nearly planar layers parallel to (001) with stacking sequence A, B, ... The layer distance, at 2.950(1) A, is shorter than that in 2H-graphite [3.355(2) A]. The hydrogen bonds N-H...N are of great interest, since the azido group consists of three homonuclear atoms with identical electronegativity, but different formal charges. These hydrogen bonds are bifurcated into moderate ones with ~2.0 A and into weak ones with ~2.6 A. The moderate ones build up tetramers (HN(3))(4) in a nearly planar net of eight membered rings. To the best of our knowledge, such a network of tetramers of a simple molecule is unique. PMID- 21702467 TI - Hybrid cell adhesive material for instant dielectrophoretic cell trapping and long-term cell function assessment. AB - Dielectrophoresis (DEP) for cell manipulation has focused, for the most part, on approaches for separation/enrichment of cells of interest. Advancements in cell positioning and immobilization onto substrates for cell culture, either as single cells or as cell aggregates, has benefited from the intensified research efforts in DEP (electrokinetic) manipulation. However, there has yet to be a DEP approach that provides the conditions for cell manipulation while promoting cell function processes such as cell differentiation. Here we present the first demonstration of a system that combines DEP with a hybrid cell adhesive material (hCAM) to allow for cell entrapment and cell function, as demonstrated by cell differentiation into neuronlike cells (NLCs). The hCAM, comprised of polyelectrolytes and fibronectin, was engineered to function as an instantaneous cell adhesive surface after DEP manipulation and to support long-term cell function (cell proliferation, induction, and differentiation). Pluripotent P19 mouse embryonal carcinoma cells flowing within a microchannel were attracted to the DEP electrode surface and remained adhered onto the hCAM coating under a fluid flow field after the DEP forces were removed. Cells remained viable after DEP manipulation for up to 8 d, during which time the P19 cells were induced to differentiate into NLCs. This approach could have further applications in areas such as cell-cell communication, three-dimensional cell aggregates to create cell microenvironments, and cell cocultures. PMID- 21702468 TI - Friction force spectroscopy as a tool to study the strength and lateral diffusion of protein layers. AB - We present a method to study the strength of layers of biological molecules in liquid medium. The method is based on the Friction Force Spectroscopy operation mode of the Atomic Force Microscope. It works by scratching the sample surface at different applied loads while registering the evolution of the sample topography and of the friction between probe and sample. Results are presented for BSA and beta-casein monolayers on hydrophobic surfaces. We show how the simultaneous monitoring of topography and friction allows detecting differences not only between the strength of both types of layers, but also between the lateral diffusion of the proteins within these layers. Specifically, beta-casein is shown to form stronger layers than BSA. The yield strengths calculated for both of these systems are in the range 50-70 MPa. Moreover, while no lateral diffusion is observed for BSA, we show that beta-casein diffuses along the hydrophobic substrates at a rate higher than the scan velocity of the tip (16 MUm s(-1) in our case). PMID- 21702469 TI - Engineering polymeric aptamers for selective cytotoxicity. AB - Chemotherapy strategies thus far reported can result in both side effects and drug resistance. To address both of these issues at the cellular level, we report a molecular engineering strategy, which employs polymeric aptamers to induce selective cytotoxicity inside target cells. The polymeric aptamers, composed of both multiple cell-based aptamers and a high ratio of dye-labeled short DNA, exploit the target recognition capability of the aptamer, enhanced cell internalization via multivalent effects, and cellular disruption by the polymeric conjugate. Importantly, the polymer backbone built into the conjugate is cytotoxic only inside cells. As a result, selective cytotoxicity is achieved equally in both normal cancer cells and drug-resistant cells. Control assays have confirmed the nontoxicity of the aptamer itself, but they have also shown that the physical properties of the polymer backbone contribute to target cell cytotoxicity. Therefore, our approach may shed new light on drug design and drug delivery. PMID- 21702470 TI - Significant FRET between SWNT/DNA and rare earth ions: a signature of their spatial correlations. AB - Significant acceleration of the photoluminescence (PL) decay rate was observed in water solutions of two rare earth ions (REIs), Tb and Eu. We propose that the time-resolved PL spectroscopy data are explained by a fluorescence resonance energy transfer (FRET) between the REIs. FRET was directly confirmed by detecting the induced PL of the energy acceptor, Eu ion, under the PL excitation of the donor ion, Tb, with FRET efficiency reaching 7% in the most saturated solution, where the distance between the unlike REIs is the shortest. Using this as a calibration experiment, a comparable FRET was measured in the mixed solution of REIs with single-wall nanotubes (SWNTs) wrapped with DNA. From the FRET efficiency of 10% and 7% for Tb and Eu, respectively, the characteristic distance between the REI and SWNT/DNA was obtained as 15.9 +/- 1.3 A, suggesting that the complexes are formed because of Coulomb attraction between the REI and the ionized phosphate groups of the DNA. PMID- 21702471 TI - Role of coordination geometry in dictating the barrier to hydride migration in d6 square-pyramidal iridium and rhodium pincer complexes. AB - Syntheses of the olefin hydride complexes [(POCOP)M(H)(olefin)][BAr(f)(4)] (6a-M, M = Ir or Rh, olefin = C(2)H(4); 6b-M, M = Ir or Rh, olefin = C(3)H(6); POCOP = 2,6-bis(di-tert-butylphosphinito)benzene; BAr(f) = tetrakis(3,5 trifluoromethylphenyl)borate) are reported. A single-crystal X-ray structure determination of 6b-Ir shows a square-pyramidal coordination geometry for Ir, with the hydride ligand occupying the apical position. Dynamic NMR techniques were used to characterize these complexes. The rates of site exchange between the hydride and the olefinic hydrogens yielded DeltaG(++) = 15.6 (6a-Ir), 16.8 (6b Ir), 12.0 (6a-Rh), and 13.7 (6b-Rh) kcal/mol. The NMR exchange data also established that hydride migration in the propylene complexes yields exclusively the primary alkyl intermediate arising from 1,2-insertion. Unexpectedly, no averaging of the top and bottom faces of the square-pyramidal complexes is observed in the NMR spectra at high temperatures, indicating that the barrier for facial equilibration is >20 kcal/mol for both the Ir and Rh complexes. A DFT computational study was used to characterize the free energy surface for the hydride migration reactions. The classical terminal hydride complexes, [M(POCOP)(olefin)H](+), are calculated to be the global minima for both Rh and Ir, in accord with experimental results. In both the Rh ethylene and propylene complexes, the transition state for hydride migration (TS1) to form the agostic species is higher on the energy surface than the transition state for in-place rotation of the coordinated C-H bond (TS2), while for Ir, TS2 is the high point on the energy surface. Therefore, only for the case of the Rh complexes is the NMR exchange rate a direct measure of the hydride migration barrier. The trends in the experimental barriers as a function of M and olefin are in good agreement with the trends in the calculated exchange barriers. The calculated barriers for the hydride migration reaction in the Rh complexes are ~2 kcal/mol higher than for the Ir complexes, despite the fact that the energy difference between the olefin hydride ground state and the agostic alkyl structure is ~4 kcal/mol larger for Ir than for Rh. This feature, together with the high barrier for interchange of the top and bottom faces of the complexes, is proposed to arise from the unique coordination geometry of the agostic complexes and the strong preference for a cis-divacant octahedral geometry in four-coordinate intermediates. PMID- 21702472 TI - A computational study of the oxidation of SO2 to SO3 by gas-phase organic oxidants. AB - We have studied the oxidation of SO(2) to SO(3) by four peroxyradicals and two carbonyl oxides (Criegee intermediates) using both density functional theory, B3LYP, and explicitly correlated coupled cluster theory, CCSD(T)-F12. All the studied peroxyradicals react very slowly with SO(2) due to energy barriers (activation energies) of around 10 kcal/mol or more. We find that water molecules are not able to catalyze these reactions. The reaction of stabilized Criegee intermediates with SO(2) is predicted to be fast, as the transition states for these oxidation reactions are below the free reactants in energy. The atmospheric relevance of these reactions depends on the lifetimes of the Criegee intermediates, which, at present, is highly uncertain. PMID- 21702473 TI - Demetalation of a single organometallic complex. AB - Single lead-phthalocyanine molecules adsorbed to ultrathin lead islands on Ag(111) are demetalized by transferring the lead atom of the inner macrocycle to the tip of a scanning tunneling microscope. Reactants and products are discriminated by their images and spectroscopic fingerprints. PMID- 21702474 TI - High-resolution Fourier transform infrared absorption spectroscopy of the nu6 band of c-C3H2. AB - The gas-phase high-resolution absorption spectrum of the nu(6) band of cyclopropenylidene (c-C(3)H(2)) has been observed using a Fourier transform infrared spectrometer for the first time. The molecule has been produced by microwave discharge in an allene (3.3 Pa) and Ar (4.0 Pa) mixture inside a side arm glass tube. The observed spectrum shows a pattern of c-type ro-vibrational transitions in which the Q-branch lines strongly and distinctly stand out in the spectrum. A combined least-squares analysis of the observed 216 ro-vibrational transitions together with 28 millimeter-wave rotational transitions from the previous study has resulted in an accurate determination of the molecular constants in the nu(6) state. The band center is found to be at 776.11622(13) cm( 1) with one standard deviation in parentheses, which is 2.3% lower than the matrix isolation value. The intensity ratio I(3)(nu(3))/I(6)(nu(6)) obtained from the observed nu(3) and nu(6) bands, 1.90(9), is somewhat lower than the ratio estimated from ab initio (2.4-2.6) and DFT (2.8) calculations. PMID- 21702475 TI - Nanoparticle-functionalized polymer platform for controlling metastatic cancer cell adhesion, shape, and motility. AB - Controlling and understanding the changes in metastatic cancer cell adhesion, shape, and motility are of paramount importance in cancer research, diagnosis, and treatment. Here, we used gold nanoparticles (AuNPs) as nanotopological structures and protein nanocluster forming substrates. Cell adhesion controlling proteins [in this case, fibronection (Fn) and ephrinB3] were modified to AuNPs, and these particles were then modified to the layer-by-layer (LbL) polymer surface that offers a handle for tuning surface charge and mechanical property of a cell-interfacing substrate. We found that metastatic cancer cell adhesion is affected by nanoparticle density on a surface, and ~140 particles per 400 MUm(2) (~1.7 MUm spacing between AuNPs) is optimal for effective metastatic cell adhesion. It was also shown that the AuNP surface density and protein nanoclustering on a spherical AuNP are controlling factors for the efficient interfacing and signaling of metastatic cancer cells. Importantly, the existence of nanotopological features (AuNPs in this case) is much more critical in inducing more dramatic changes in metastatic cell adhesion, protrusion, polarity, and motility than the presence of a cell adhesion protein, Fn, on the surface. Moreover, cell focal adhesion and motility-related paxillin clusters were heavily formed in cell lamellipodia and filopodia and high expression of phospho paxillins were observed when the cells were cultured on either an AuNP or Fn modified AuNP polymer surface. The ephrin signaling that results in the decreased expression of paxillin was found to be more effective when ephrins were modified to the AuNP surface than when ephrinB3 was directly attached to the polymer film. The overall trend for cell motility change is such that a nanoparticle-modified LbL surface induces higher cell motility and the AuNP modification to the LbL surface results in more pronounced change in cell motility than Fn or ephrin modification to the LbL surface. PMID- 21702476 TI - Taste modulating N-(1-methyl-4-oxoimidazolidin-2-ylidene) alpha-amino acids formed from creatinine and reducing carbohydrates. AB - Recent investigations led to the discovery of N-(1-methyl-4-oxoimidazolidin-2 ylidene)aminopropionic acid as a taste modulator enhancing the typical thick-sour mouthdryness and mouthfulness imparted by stewed beef juice. In the present study, systematic model reactions were targeted toward the generation of a series of N-(1-methyl-4-oxoimidazolidin-2-ylidene)-alpha-amino acids by Maillard-type reactions between creatinine and ribose, glucose, methylglyoxal, or glyoxal, respectively. By application of a comparative taste dilution analysis on fractions isolated from thermally treated creatinine/carbohydrate mixtures by means of hydrophilic liquid interaction chromatography (HILIC), a total of nine N (1-methyl-4-oxoimidazolidin-2-ylidene)-alpha-amino acids were identified by means of LC-MS, LC-TOF-MS, and 1D/2D NMR experiments. Six of the nine creatinine glycation products were previously not reported in the literature. Whereas creatinine exhibited a bitter taste, none of the N-(1-methyl-4-oxoimidazolidin-2 ylidene)-alpha-amino acids imparted any intrinsic taste activity up to levels of 10 mmol/L (in water). Depending strongly on their chemical structure, these N-(1 methyl-4-oxoimidazolidin-2-ylidene)-alpha-amino acids induced a thick-sour, mouthdrying orosensation and mouthfulness enhancement when evaluated in model broth with recognition thresholds ranging from 31 to >1000 MUmol/L. PMID- 21702477 TI - Analysis of isomeric forms of oxidized triacylglycerols using ultra-high performance liquid chromatography and tandem mass spectrometry. AB - Detailed studies on the regioisomeric structures of oxidized species of triacylglycerols (TAG), formed in food during storage and processing, have not been published thus far. In this study, an analytical approach based on efficient ultra-high-performance liquid chromatographic (UHPLC) separation of different isomers of oxidized TAG species and their tandem mass spectrometric analysis was created. A linear solvent gradient based on acetonitrile and acetone was used in the UHPLC method. A novel method utilizing positive ion ESI using ammonia supplemented in the nebulizer gas was used to produce ammonium adduct ions for mass spectrometric analysis. With the UHPLC method used, different regioisomers of TAG species containing oxidized linoleic or oleic acid could be efficiently resolved. Differences in the fragmentation patterns of many of the oxidized TAG isomers could be demonstrated by the tandem mass spectrometric method. On the basis of the results, the approach enables regiospecific analysis of oxidized TAG molecules. PMID- 21702478 TI - Relationship between red wine grade and phenolics. 2. Tannin composition and size. AB - Commercial red wines ( Vitis vinifera L. cv. Shiraz) produced during the 2009 vintage underwent winemaker assessment for allocation grade soon after production. The wines were then subjected to phenolic analysis to measure wine color (total anthocyanin, SO(2) nonbleachable pigment, and wine color density) and tannins (concentration, composition, and average degree of polymerization). A positive relationship was found between wine phenolic concentration and projected bottle price. Tannin compositional analysis suggested that there was specifically a relationship between wine grade and skin-derived tannins. These results suggest that maximization of skin tannin concentration and/or proportion is related to an increase in projected wine bottle price. PMID- 21702479 TI - Analysis of alkylamides in Echinacea plant materials and dietary supplements by ultrafast liquid chromatography with diode array and mass spectrometric detection. AB - Alkylamides are a class of compounds present in plants of the genus Echinacea (Asteraceae), which have been shown to have high bioavailability and immunomodulatory effects. Fast analysis to identify these components in a variety of products is essential to profile products used in clinical trials and for quality control of these products. A method based on ultrafast liquid chromatography (UFLC) coupled with diode array detection and electrospray ionization mass spectrometry was developed for the analysis of alkylamides from the roots of Echinacea angustifolia (DC.) Hell., Echinacea purpurea (L.) Moench, and commercial dietary supplements. A total of 24 alkylamides were identified by LC-MS. The analysis time for these components is 15 min. Compared to the alkylamide profiles determined in the Echinacea root materials, the commercial products showed a more complex profile due to the blending of root and aerial parts of E. purpurea. This versatile method allows for the identification of alkylamides in a variety of Echinacea products and presents the most extensive characterization of alkylamides in E. angustifolia roots so far. PMID- 21702480 TI - Characterization of the bound volatile extract from baby kiwi (Actinidia arguta). AB - The glycosidically bound volatile fraction of baby kiwi ( Actinidia arguta ) was studied. Glycosidic precursors were isolated from juice by adsorption onto an Amberlite XAD-2 column. After enzymatic hydrolysis with Rapidase AR2000, the released aglycones were analyzed by GC-MS. Alcohols, terpenoids, and benzenoids were the most abundant compound classes. Aromatic compounds and norisoprenoids showed the highest concentrations. Major compounds were 2,5-dimethyl-4-hydroxy 3(2H)-furanone (Furaneol), benzyl alcohol, 3-hydroxy-beta-damascone, hexanal, and (Z)-3-hexen-1-ol. Precursors of aroma compounds including benzoic acid, cinnamic acid, and coniferyl alcohol were also found. Eugenol, raspberry ketone, and 4 vinylguaiacol were identified for the first time in the fruit of an Actinidia species. The high concentration of 2,5-dimethyl-4-hydroxy-3(2H)-furanone in bound form (95.36 MUg/kg) is particularly interesting and justifies further investigation. PMID- 21702481 TI - Molecular dynamics simulation and binding energy calculation for estimation of oligonucleotide duplex thermostability in RNA-based therapeutics. AB - For oligonucleotide-based therapeutics, a thorough understanding of the thermodynamic properties of duplex formation is critical to developing stable and potent drugs. For unmodified small interfering RNA (siRNA), DNA antisense oligonucleotide (AON) and locked nucleic acid (LNA), DNA/LNA modified oligonucleotides, nearest neighbor (NN) methods can be effectively used to quickly and accurately predict duplex thermodynamic properties such as melting point. Unfortunately, for chemically modified olignonucleotides, there has been no accurate prediction method available. Here we describe the potential of estimating melting temperature (T(m)) for nonstandard oligonucleotides by using the correlation of the experimental T(m) with the calculated duplex binding energy (BE) for oligonucleotides of a given length. This method has been automated into a standardized molecular dynamics (MD) protocol through Pipeline Pilot (PP) using the CHARMm component in Discovery Studio (DS). Results will be presented showing the correlation of the predicted data with experiment for both standard and chemically modified siRNA and AON. PMID- 21702483 TI - Observation of oscillatory resistance behavior in coupled Bernal and rhombohedral stacking graphene. AB - We report on the first observation of an anomalous temperature-dependent resistance behavior in coupled Bernal and rhombohedral stacking graphene. At low temperature regime (<50 K) the temperature-dependent resistance exhibits a drop while at high-temperature regions (>250 K), the resistance increases. In the transition region (50-250 K) an oscillatory resistance behavior was observed. This property is not present in any layered graphene structures other than five layer. We propose that the temperature-dependent resistance behavior is governed by the interplay of the Coulomb and short-range scatterings. The origin of the oscillatory resistance behavior is the ABCAB and ABABA stacking configurations, which induces tunable bandgap in the five-layer graphene. The obtained results also indicate that a perpendicular magnetic field opens an excitonic gap because of the Coulomb interaction-driven electronic instabilities, and the bandgap of the five-layer graphene is thermally activated. Potentially, the observed phenomenon provides important transport information to the design of few-layer graphene transistors that can be manipulated by a magnetic field. PMID- 21702482 TI - An integrated computational analysis of the structure, dynamics, and ligand binding interactions of the human galectin network. AB - Galectins, a family of evolutionarily conserved animal lectins, have been shown to modulate signaling processes leading to inflammation, apoptosis, immunoregulation, and angiogenesis through their ability to interact with poly-N acetyllactosamine-enriched glycoconjugates. To date 16 human galectin carbohydrate recognition domains have been established by sequence analysis and found to be expressed in several tissues. Given the divergent functions of these lectins, it is of vital importance to understand common and differential features in order to search for specific inhibitors of individual members of the human galectin family. In this work we performed an integrated computational analysis of all individual members of the human galectin family. In the first place, we have built homology-based models for galectin-4 and -12 N-terminus, placental protein 13 (PP13) and PP13-like protein for which no experimental structural information is available. We have then performed classical molecular dynamics simulations of the whole 15 members family in free and ligand-bound states to analyze protein and protein-ligand interaction dynamics. Our results show that all galectins adopt the same fold, and the carbohydrate recognition domains are very similar with structural differences located in specific loops. These differences are reflected in the dynamics characteristics, where mobility differences translate into entropy values which significantly influence their ligand affinity. Thus, ligand selectivity appears to be modulated by subtle differences in the monosaccharide binding sites. Taken together, our results may contribute to the understanding, at a molecular level, of the structural and dynamical determinants that distinguish individual human galectins. PMID- 21702484 TI - Three-stage transformation pathway from nanodiamonds to fullerenes. AB - The dynamics of structure evolution of nanodiamonds ranging from 22 to 318 atoms of various shapes is studied by density functional tight-binding molecular dynamics. The spherical and cubic nanodiamonds can be transformed into fullerene like structures upon heating. A number of the transformed fullerenes consist of pentagons and hexagons only. Others contain squares, heptagons, and octagons. One simulated fullerene is an isomer of C(60). The temperature of the transformation depends on the size, shape, and orientation of initial cluster. To be transformed into onion-like fullerenes, the spherical nanodiamonds should have 200 atoms or more, while the cubic ones require 302 atoms or more. The time-resolved energy profiles of all the transformations clearly reveal three-stage transformation character. During the first stage, the energy reduces quickly due to converting sp(3) carbon with dangling bond at the surface into sp(2) one, and the formation of partial sp(2) envelope wrapping the cluster. For the second stage, energy decreases slowly. The remaining interior carbon atoms come to the surface through the hole in the sp(2) envelope, and similar amount of sp(3) and sp(2) atoms coexist. The third stage involves the closure of holes, accompanied by the detachment of C(2) molecules and carbon chains from the edges. The energy decreases relatively fast in this stage. The proposed three-stage transformation pathway holds for all the simulations performed in this work, including those with the instant heating. PMID- 21702485 TI - Universal scaling and Fano resonance in the plasmon coupling between gold nanorods. AB - The plasmon coupling between metal nanocrystals can lead to large plasmon shifts, enormous electric field enhancements, and new plasmon modes. Metal nanorods, unlike spherical ones, possess a transverse and a longitudinal plasmon mode owing to their geometrical anisotropy. Consequently, the plasmon coupling between metal nanorods is much more complicated than that between nanospheres. For the latter, experimental approaches, simple scaling relationships, and exact analytic solutions have been developed for describing the plasmon coupling. In this study, we have carried out extensive finite-difference time-domain simulations to understand the plasmon coupling in the dimers of Au nanorods that are aligned along their length axes. The effects of the gap distance, longitudinal plasmon energy, and end shape of the nanorod monomers on the plasmon coupling have been scrutinized. The coupling energy diagrams show a general anticrossing behavior. All of them can be rescaled into one simple and universal hyperbolic formula. A theoretical model based on two interacting mechanical oscillators has been developed to understand the plasmon coupling between two arbitrarily varying Au nanorods. This model, together with the universal equation, allows for the determination of the coupled plasmon energies of Au nanorod dimers with high accuracies. Furthermore, the Fano interference has been observed in the nanorod heterodimers, with its behavior being dependent on the gap distance and plasmon energies of the nanorod monomers. Our results will be useful for predicting the coupled plasmon energies of metal nanorod dimers in a variety of plasmonic applications and understanding the Fano resonance in plasmonic nanostructures. PMID- 21702486 TI - Nanocrystalline 3C-SiC electrode for biosensing applications. AB - Silicon carbide has been proved as a candidate for power and high-frequency devices. In this paper, we show the application of nanocrystalline 3C-SiC as an electrochemical electrode and its electrochemical functionalization for biosensing applications. SiC electrodes show a wider potential window and lower background current than glassy carbon electrodes. The surface can be electrochemically functionalized with diazonium salts, as confirmed by electrochemical techniques and X-ray photoelectron spectroscopy. The nitrophenyl film is used as linker layer to bond DNA molecule to SiC. These results show that 3C-SiC can be an interesting transducer material for applications in electro- and bioelectrochemical applications. PMID- 21702487 TI - Aluminum foils: the contrasting characters of hyperconjugation and steric repulsion in aluminum dimetallocenes. AB - The novel sandwich complex Cp2*Al2I2, which was recently synthesized by Minasian and Arnold, has been characterized using ab initio and density functional methods. A large family of related compounds was also investigated. Although a few Al(II)-Al(II) bonds are known, this is the first such bond to be supported by Cp-type ligands. In addition, in the remarkable Cp4*Al4 synthesis by Roesky, Cp2*Al2I2 is the Al(II) intermediate; Cp4*Al4 is important as a precursor to novel organoaluminum species. Halogen and ligand effects on the Al-Al bond in Cp2*Al2I2 were systematically explored by studying a series of 20 Cp2*Al2I2 derivatives using density functional theory with relativistic basis sets for the halogens. Comparison was made with the focal point treatment, which uses extrapolation to estimate the full configuration interaction and complete basis set limit energy. Torsional potential energy curves, natural population analyses, and enthalpies of hydrogenation were computed. Using the focal point approach, torsional barriers were computed with 0.05 kcal mol(-1) uncertainty. The interplay of steric and electronic effects on the torsional potential energy curves, enthalpies of dehydrogenation reactions, and geometries is discussed. In species with small ligands (R = H, Me), hyperconjugative effects determine the torsional landscape, whereas steric repulsions dominate in species with Cp* alkyl ligands. Species with Cp ligands represent an intermediate case, thus providing insight into how ligands modulate the structures and properties of small metal clusters. PMID- 21702488 TI - Oriented reconstitution of a membrane protein in a giant unilamellar vesicle: experimental verification with the potassium channel KcsA. AB - We report a method for the successful reconstitution of the KcsA potassium channel with either an outside-out or inside-out orientation in giant unilamellar vesicles, using the droplet-transfer technique. The procedure is rather simple. First, we prepared water-in-oil droplets lined with a lipid monolayer. When solubilized KcsA was encapsulated in the droplet, it accumulated at monolayers of phosphatidylglycerol (PG) and phosphoethanolamine (PE) but not at a monolayer of phosphatidylcholine (PC). The droplet was then transferred through an oil/water interface having a preformed monolayer. The interface monolayer covered the droplet so as to generate a bilayer vesicle. By creating chemically different lipid monolayers at the droplet and oil/water interface, we obtained vesicles with asymmetric lipid compositions in the outer and inner leaflets. KcsA was spontaneously inserted into vesicles from the inside or outside, and this was accelerated in vesicles that contained PE or PG. Integrated insertion into the vesicle membrane and the KcsA orientation were examined by functional assay, exploiting the pH sensitivity of the opening of the KcsA when the pH-sensitive cytoplasmic domain (CPD) faces toward acidic media. KcsA loaded from the inside of the PG-containing vesicles becomes permeable only when the intravesicular pH is acidic, and the KcsA loaded from the outside becomes permeable when the extravesicular pH is acidic. Therefore, the internal or external insertion of KcsA leads to an outside-out or inside-out configuration so as to retain its hydrophilic CPD in the added aqueous side. The CPD-truncated KcsA exhibited a random orientation, supporting the idea that the CPD determines the orientation. Further application of the droplet-transfer method is promising for the reconstitution of other types of membrane proteins with a desired orientation into cell-sized vesicles with a targeted lipid composition of the outer and inner leaflets. PMID- 21702489 TI - Kinetics of the self reaction of cyclohexyl radicals. AB - The kinetics of the self-reaction of cyclohexyl radicals was studied by laser photolysis/photoionization mass spectroscopy. Overall rate constants were obtained in direct real-time experiments in the temperature region 303-520 K and at bath gas (helium with up to 5% of radical precursors) densities (3.00-12.0) * 10(16) molecules cm(-3). Cyclohexyl radicals were produced by a combination of the 193 nm photolysis of oxalyl chloride ((CClO)(2)) with the subsequent fast reaction of Cl atoms with cyclohexane, and their initial concentrations were determined from real-time profiles of HCl. The observed overall c-C(6)H(11) + c C(6)H(11) rate constants demonstrate negative temperature dependence, which can be described by the following expressions: k(1) = 4.8 * 10(-12) exp(+542 K/T) cm(3) molecule(-1) s(-1), with estimated uncertainty of 16% over the 303-520 K temperature range. The fraction of disproportionation equal to 41 +/- 7% was determined at 305 K; analysis of earlier experimental determinations of the disproportionation-to-recombination branching ratio leads to recommending this room-temperature value for other temperatures. The corresponding temperature dependences of the recombination (1a, bicyclohexyl product) and the disproportionation (1b, cyclohexene and cyclohexane products) channels are k(1a) = 2.8 * 10(-12) exp(+542 K/T) and k(1b) = 2.0 * 10(-12) exp(+542 K/T) cm(3) molecule(-1) s(-1), with estimated uncertainties of 20% and 29%, respectively. PMID- 21702490 TI - Characterization of the singlet and triplet excited states of 3-chloro-4 methylumbelliferone. AB - An extensive photophysical characterization of 3-chloro-4-methylumbelliferone (3Cl4MU) in the ground-state, S(0), first excited singlet state, S(1), and lowest triplet state, T(1), was undertaken in water, neutral ethanol, acidified ethanol, and basified ethanol. Quantitative measurements of quantum yields (fluorescence, phosphorescence, intersystem crossing, internal conversion, and singlet oxygen formation) together with lifetimes were obtained at room and low temperature in water, dioxane/water mixtures, and alcohols. The different transient species were assigned and a general kinetic scheme is presented, summarizing the excited-state multiequilibria of 3Cl4MU. In water, the equilibrium is restricted to neutral (N*) and anionic (A*) species, both in the ground (pK(a) = 7.2) and first excited singlet states (pK(a)* = 0.5). In dioxane/water mixtures (pH ca. 6), substantial changes of the kinetics of the S(1) state were observed with the appearance of an additional tautomeric T* species. In low water content mixtures (mixture 9:1 v:v), only the neutral (N*) and tautomeric (T*) forms of 3Cl4MU are observed, whereas at higher water content mixtures (water mole fraction superior to 0.45), all three species N*, T*, and A* coexist in the excited state. In the triplet state, in the nonprotic and nonpolar solvent dioxane, the observed transient signals were assigned as the triplet-triplet transition of the neutral form, N*(T(1)) -> N*(T(n)). In water, two transient species were observed and are assigned as the triplets of the neutral N*(T(1)) and the anionic form, A*(T(1)) (also obtained in basified ethanol). The phosphorescence spectra and decays of 3Cl4MU, in neutral, acidified, and basified solutions, demonstrate that only these two species N*(T(1)) and A*(T(1)) exist in the lowest lying triplet state, T(1). The radiative channel was found dominant for the deactivation of the anionic species, whereas with the neutral the S(1) ? S(0) internal conversion competes with fluorescence. For both N* and A* the intersystem crossing yield represents a minor deactivation channel for S(1). PMID- 21702491 TI - Solvent dependent fluorescent properties of a 1,2,3-triazole linked 8 hydroxyquinoline chemosensor: tunable detection from zinc(II) to iron(III) in the CH3CN/H2O system. AB - A triazole-containing 8-hydroxyquinoline (8-HQ) ether 2 was efficiently synthesized in two steps from the "click" strategy. Compound 2 gave a strong fluorescence (Phi = 0.21) in nonprotic solvent like CH(3)CN, and a weak fluorescence (Phi = 0.06) in protic solvent like water. In water, a more than 100 nm red shift of the fluorescence maximum was observed for compound 2 in comparison with that in CH(3)CN. This fluorescence difference may be attributed to the intermolecular photoinduced proton transfer (PPT) process involving the protic solvent water molecules. Similarly, this intermolecular PPT process was also observed in the high-water-content CH(3)CN aqueous solution (e.g., CH(3)CN/H(2)O = 5/95, v/v). The water content in the CH(3)CN/H(2)O binary solvent mixture greatly affected the fluorescence intensity (e.g., Phi = 0.06 and 0.25 when CH(3)CN/H(2)O = 5/95 and 95/5, v/v, respectively) and emission wavelength. Using this interesting property, by simple variation of the water content in the CH(3)CN aqueous solution, compound 2 was tuned from a selective "turn-on" fluorescent sensor for Zn(2+) (CH(3)CN/H(2)O = 5/95, v/v) to a ratiometric one for Zn(2+) and a selective "turn-off" one for Fe(3+) (CH(3)CN/H(2)O = 95/5, v/v) over a wide range of pH value. In high-water-content (CH(3)CN/H(2)O = 5/95, v/v) aqueous solution compound 2 shows a selective "turn-on" response toward Zn(2+), with a 10-fold enhancement in the fluorescence intensity at 428 nm and a 62 nm blue shift of the emission maximum (490 to 428 nm) due to the inhibition of intermolecular PPT process upon chelating with Zn(2+). However, in a less polar solvent (CH(3)CN/H(2)O = 95/5, v/v) in which compound 2 has high fluorescence (quantum yield =0.25), it shows a ratiometric response toward Zn(2+), with a continuous decrease of the fluorescence intensity at 399 nm and an increase at 423 nm. More interestingly, in this case, it also exhibits a very sensitive, selective, and ratiometric fluorescence quenching in the presence of Fe(3+), with an 81 nm red shift of the emission maximum (399 to 480 nm) in a wide range of pH through a metal ligand charge transfer (MLCT) effect. PMID- 21702492 TI - Sampling multiple scoring functions can improve protein loop structure prediction accuracy. AB - Accurately predicting loop structures is important for understanding functions of many proteins. In order to obtain loop models with high accuracy, efficiently sampling the loop conformation space to discover reasonable structures is a critical step. In loop conformation sampling, coarse-grain energy (scoring) functions coupling with reduced protein representations are often used to reduce the number of degrees of freedom as well as sampling computational time. However, due to implicitly considering many factors by reduced representations, the coarse grain scoring functions may have potential insensitivity and inaccuracy, which can mislead the sampling process and consequently ignore important loop conformations. In this paper, we present a new computational sampling approach to obtain reasonable loop backbone models, so-called the Pareto optimal sampling (POS) method. The rationale of the POS method is to sample the function space of multiple, carefully selected scoring functions to discover an ensemble of diversified structures yielding Pareto optimality to all sampled conformations. The POS method can efficiently tolerate insensitivity and inaccuracy in individual scoring functions and thereby lead to significant accuracy improvement in loop structure prediction. We apply the POS method to a set of 4-12-residue loop targets using a function space composed of backbone-only Rosetta and distance-scale finite ideal-gas reference (DFIRE) and a triplet backbone dihedral potential developed in our lab. Our computational results show that in 501 out of 502 targets, the model sets generated by POS contain structure models are within subangstrom resolution. Moreover, the top-ranked models have a root mean square deviation (rmsd) less than 1 A in 96.8, 84.1, and 72.2% of the short (4-6 residues), medium (7-9 residues), and long (10-12 residues) targets, respectively, when the all-atom models are generated by local optimization from the backbone models and are ranked by our recently developed Pareto optimal consensus (POC) method. Similar sampling effectiveness can also be found in a set of 13-residue loop targets. PMID- 21702493 TI - Study on the binding of propiconazole to protein by molecular modeling and a multispectroscopic method. AB - Propiconazole (PCZ) is an N-substituted triazole used as a fungicide on fruits, grains, seeds, hardwoods, and conifers. Although the triazole fungicides have shorter half-lives and lower bioaccumulation than the organochlorine pesticides, possible detrimental effects on the aquatic ecosystem and human health also exist. To evaluate the toxicity of PCZ at the protein level, its effects on human serum albumin (HSA) were characterized by molecular modeling and multispectroscopic method. On the basis of the fluorescence spectra, PCZ exhibited remarkable fluorescence quenching, which was attributed to the formation of a complex. The thermodynamic parameters DeltaH and DeltaS were calculated to be -14.980 KJ/mol and 26.966 J/(mol K), respectively, according to the van't Hoff equation, which suggests hydrophobic and electrostatic interactions are the predominant intermolecular forces in stabilizing the PCZ protein complex. Furthermore, HSA conformation was slightly altered in the presence of PCZ. These results indicated that PCZ indeed affected the conformation of HSA. PMID- 21702494 TI - Comparison of the relaxation of sessile drops driven by harmonic and stochastic mechanical excitations. AB - Currently, there is no conclusive evidence regarding the global equilibrium condition of vibrated drops. However, it is well-known that vibration of sessile drops effectively reduces the contact angle hysteresis. In this work, applying a recent methodology for evaluating the most-stable contact angle, we examined the impact of the type of excitation signal (random signal versus periodical signal) on the values of the most-stable contact angle for polymer surfaces. Using harmonic signals, the oscillation frequency affected the postvibration contact angle. Instead, the white noise signal enabled sessile drops to relax regardless of their initial configuration. In spite of that, the values of most-stable contact angle obtained with different signals mostly agreed. We concluded that not only the amount of relaxation can be important for relaxing a sessile drop but also the rate of relaxation. Together with receding contact angle, most stable contact angle, measured with the proposed methodology, was able to capture the thermodynamic changes of "wetted" polymer surfaces. PMID- 21702495 TI - DNA sensing by amplifying the number of near-infrared emitting, oligonucleotide encapsulated silver clusters. AB - A bifunctional oligonucleotide integrates in situ synthesis of a fluorogenic silver cluster with recognition of a target DNA sequence. With the template C(3)AC(3)AC(3)GC(3)A, a complex forms with 10 silver atoms that possesses electronic transitions in the near-infrared and that is detected at nanomolar concentrations using diode laser excitation. Pendant to this cluster encoding region, the recognition component binds a target DNA strand through hybridization, and decoupling of these two regions of the composite sensor renders a modular sensor for specific oligonucleotides. A target is detected using a quencher strand that bridges the cluster template and recognition components and disturbs cluster binding, as indicated by static quenching. Competitive displacement of the quencher by the target strand restores the favored cluster environment, and our key finding is that this exchange enhances emission through a proportional increase in the number of emissive clusters. DNA detection is also accomplished in serum-containing buffers by taking advantage of the high brightness of this fluorophore and the inherently low endogenous background in the near-infrared spectral region. Cluster stability in this biological environment is enhanced by supplementing the solutions with Ag(+). PMID- 21702496 TI - Infrared absorption spectra of the CO(2)/H(2)O complex in a cryogenic nitrogen matrix--detection of a new bending frequency. AB - Infrared absorption spectra have been measured for the mixture of CO(2) and H(2)O in a cryogenic nitrogen matrix. The 1:1 CO(2)/H(2)O complex has been observed. Each structure of this complex should have two bending frequencies corresponding to the CO(2) fundamental bending mode (nu(2)). In this work, three bending frequencies corresponding to the CO(2) fundamental bending mode (nu(2)) have been detected; one of them at 660.3 cm(-1) is reported here for the first time. This finding helps confirm the existence of two structures for this complex. A new feature attributed to a CO(2) and H(2)O complex is observed at 3604.4 cm(-1) and is tentatively assigned to the CO(2)/H(2)O complex band corresponding to the CO(2) combination mode (nu(3) + 2nu(2)). In addition, a band that belongs to a CO(2) and H(2)O complex is detected at 3623.8 cm(-1) for the first time and is tentatively assigned to the (CO(2))(2)/H(2)O complex band corresponding to the symmetric stretching mode (nu(1)) of H(2)O. PMID- 21702497 TI - Gas-bubble effects on the formation of colloidal iron oxide nanocrystals. AB - This paper reports that gas bubbles can be used to tailor the kinetics of the nucleation and growth of inorganic-nanocrystals in a colloidal synthesis. We conducted a mechanistic study of the synthesis of colloidal iron oxide nanocrystals using gas bubbles generated by boiling solvents or artificial Ar bubbling. We identified that bubbling effects take place through absorbing local latent heat released from the exothermic reactions involved in the nucleation and growth of iron oxide nanocrystals. Our results show that gas bubbles display a stronger effect on the nucleation of iron oxide nanocrystals than on their growth. These results indicate that the nucleation and growth of iron oxide nanocrystals may rely on different types of chemical reactions between the iron oleate decomposition products: the nucleation relies on the strongly exothermic, multiple-bond formation reactions, whereas the growth of iron oxide nanocrystals may primarily depend upon single-bond formation reactions. The identification of exothermic reactions is further consistent with our results in the synthesis of iron oxide nanocrystals with boiling solvents at reaction temperatures ranging from 290 to 365 degrees C, by which we determined the reaction enthalpy in the nucleation of iron oxide nanocrystals to be -142 +/- 12 kJ/mol. Moreover, our results suggest that a prerequisite for effectively suppressing secondary nucleation in a colloidal synthesis is that the primary nucleation must produce a critical amount of nuclei, and this finding is important for a priori design of colloidal synthesis of monodispersed nanocrystals in general. PMID- 21702498 TI - Investigations on the 4-quinolone-3-carboxylic acid motif. 4. Identification of new potent and selective ligands for the cannabinoid type 2 receptor with diverse substitution patterns and antihyperalgesic effects in mice. AB - Experimental evidence suggests that selective CB2 receptor modulators may provide access to antihyperalgesic agents devoid of psychotropic effects. Taking advantage of previous findings on structure-activity/selectivity relationships for a class of 4-quinolone-3-carboxamides, further structural modifications of the heterocyclic scaffold were explored, leading to the discovery of the 8 methoxy derivative 4a endowed with the highest affinity and selectivity ever reported for a CB2 ligand. The compound, evaluated in vivo in the formalin test, behaved as an inverse agonist by reducing at a dose of 6 mg/kg the second phase of the formalin-induced nocifensive response in mice. PMID- 21702499 TI - Novel benzoxazine and benzothiazine derivatives as multifunctional antihyperlipidemic agents. AB - Atherosclerosis is a multifactorial disease with several mechanisms participating in its manifestation. To address this disorder, we applied a strategy involving the design of a single chemical compound able to simultaneously modulate more than one target. We hereby present the development of novel benzoxazine and benzothiazine derivatives that significantly inhibit in vitro microsomal lipid peroxidation and LDL oxidation as well as squalene synthase activity (IC(50) of 5 16 MUM). Further, these compounds show antidyslipidemic and antioxidant properties in vivo, decreasing total cholesterol, LDL, triglyceride, and MDA levels of hyperlipidemic rats by 26-74%. Finally, by determination of their in vivo concentration (up to 24 h) in target tissues (blood/liver), it is shown that compounds reach their targets in the low micromolar range. The new compounds seem to be interesting multifunctional molecules for the development of a new pharmacophore for disease-modifying agents useful in the treatment of atherosclerosis. PMID- 21702500 TI - Effect of beta-phenylethyl isothiocyanate from cruciferous vegetables on growth inhibition and apoptosis of cervical cancer cells through the induction of death receptors 4 and 5. AB - Cruciferous vegetables have been shown to have the possibility to protect against multistep carcinogenesis. beta-Phenylethyl isothiocyanate (PEITC) is one component of these vegetables demonstrated to help fight many types of cancer. The present study examined the apoptotic effects of PEITC and its molecular mechanism in human cervical cancer cell lines (HEp-2 and KB). PEITC induced apoptosis to inhibit cell proliferation. According to the protein chip assay, PEITC increased the expression of the death receptors (DR4 and DR5) and cleaved caspase-3 compared to the DMSO treatment group. PEITC also induced caspase-8 and truncated BID. PEITC down-regulated the phosphorylation of extracellular-related kinase (ERK)1/2, whereas neither phospho-c-Jun NH(2)-terminal kinases (JNK) nor phospho-p38 MAPK was changed. The role of ERK in PEITC-induced apoptosis was also investigated using MEK inhibitor (PD98059). PD98059 increased the expression of DR4 and DR5, activated caspase-3, and cleaved PARP. In addition, PEITC decreased the phosphorylation of MEK. Therefore, the apoptotic mechanism of PEITC in cervical cancer cells involves the induction of DR4 and DR5 through the inactivation of ERK and MEK. PMID- 21702501 TI - Adsorption and reduction of glutathione disulfide on alpha-Al2O3 nanoparticles: experiments and modeling. AB - Glutathione disulfide (GSSG; gamma-GluCysGly disulfide) was used as a physiologically relevant model molecule to investigate the fundamental adsorption mechanisms of polypeptides onto alpha-alumina nanoparticles. Its adsorption/desorption behavior was studied by enzymatic quantification of the bound GSSG combined with zeta potential measurements of the particles. The adsorption of GSSG to alumina nanoparticles was rapid, was prevented by alkaline pH, was reversed by increasing ionic strength, and followed a nearly ideal Langmuir isotherm with a standard Gibbs adsorption energy of -34.7 kJ/mol. Molecular dynamics simulations suggest that only one of the two glutathionyl moieties contained in GSSG binds stably to the nanoparticle surface. This was confirmed experimentally by the release of GSH from the bound GSSG upon reducing its disulfide bond with dithiothreitol. Our data indicate that electrostatic interactions via the carboxylate groups of one of the two glutathionyl moieties of GSSG are predominantly responsible for the binding of GSSG to the alumina surface. The results and conclusions presented here can provide a base for further experimental and modeling studies on the interactions of biomolecules with ceramic materials. PMID- 21702502 TI - Mehercules, adhuc Bacchus! The debate on wine proteomics continues. AB - The proteome of untreated white wines (a Recioto made with Garganega grapes from the Veneto region) was explored in depth via capture with combinatorial peptide ligand libraries (CPLL) at four different pH values: pH 2.2, 3.8, 7.2, and 9.3. The combined data on the discoveries in the four CPLL eluates, as well as in the collected bottle sediment, allowed the identification of 106 unique gene products belonging to Vitis vinifera, as well as of an additional 11 proteins released by the S. cerevisiae used in the fermentation process. Among the residual grape proteins detected in the Recioto wine, ca. 30% were categorized as medium to high abundance species, vs 70% low-abundance ones. The detection of so many low abundance species suggests that proteomic (coupled to peptidomic) data might be used for typing high-quality products (grand crus) to assess their genuineness and protect them from fraudulent imitations. PMID- 21702503 TI - Conformational flexibility of DNA. AB - Pulsed Electron-Electron Double Resonance (PELDOR) on double-stranded DNA (ds DNA) was used to investigate the conformational flexibility of helical DNA. Stretching, twisting, and bending flexibility of ds-DNA was determined by incorporation of two rigid nitroxide spin labels into a series of 20 base pair (bp) DNA duplexes. Orientation-selective PELDOR experiments performed at both X band (9 GHz/0.3 T) and G-band (180 GHz/6.4 T) with spin label distances in the range of 2-4 nm allowed us to differentiate between different simple models of DNA dynamics existing in the literature. All of our experimental results are in full agreement with a dynamic model for ds-DNA molecules, where stretching of the molecule leads to a slightly reduced radius of the helix induced by a cooperative twist-stretch coupling. PMID- 21702504 TI - Resistive switching behavior and multiple transmittance states in solution processed tungsten oxide. AB - In this work, a tungsten oxide (WO(x)) film is prepared using a thiourea-assisted solution process. We demonstrate a device composed of fluorine doped tin oxide (FTO)-glass/WO(x)/electrolyte/indium-tin oxide (ITO)-glass stacking electrochromic (EC) structure and Al electrodes that are locally patterned and interposed between the WO(x) film and electrolyte, which form an Al(top electrode)/WO(x)/FTO(bottom electrode) resistance random access memory (RRAM) unit. According to transmission electron microscopy and X-ray photoelectron spectroscopy analyses, the WO(x) film contains nanosize pores and metallic tungsten nanoclusters which are scattered within the tungsten oxide layer and concentrated along the interface between the Al electrode and WO(x) film. With application of voltage to the ITO electrode, multiple transmittance states are achieved for the EC unit due to the different quantity of intercalated Li ions in the WO(x) film. As for the Al/WO(x)/FTO RRAM unit, a bipolar nonvolatile resistive switching behavior is attained by applying voltage on the Al top electrode, showing electrical bistability with an ON/OFF current ratio up to 1 * 10(4). PMID- 21702505 TI - Influence of cultivar and concentration of selected phenolic constituents on the in vitro chemiopreventive potential of olive oil extracts. AB - One of the main olive oil phenolic compounds, hydroxytyrosol (3,4-DHPEA), exerts in vitro chemopreventive activities (antiproliferative and pro-apoptotic) on tumor cells through the accumulation of H(2)O(2) in the culture medium. However, the phenol composition of virgin olive oil is complex, and 3,4-DHPEA is present at low concentrations when compared to other secoiridoids. In this study, the in vitro chemopreventive activities of complex virgin olive oil phenolic extracts (VOO-PE, derived from the four Italian cultivars Nocellara del Belice, Coratina, Ogliarola, and Taggiasca) were compared to each other and related to the amount of the single phenolic constituents. A great chemopreventive potential among the different VOO-PE was found following this order: Ogliarola > Coratina > Nocellara > Taggiasca. The antiproliferative and pro-apoptotic activities of VOO-PE were positively correlated to the secoiridoid content and negatively correlated to the concentration of both phenyl alcohols and lignans. All extracts induced H(2)O(2) accumulation in the culture medium, but this phenomenon was not responsible for their pro-apoptotic activity. When tested in a complex mixture, the olive oil phenols exerted a more potent chemopreventive effect compared to the isolated compounds, and this effect could be due either to a synergistic action of components or to any other unidentified extract constituent. PMID- 21702506 TI - Absolute quantification of intracellular glycogen content in human embryonic stem cells with Raman microspectroscopy. AB - We present a method to perform absolute quantification of glycogen in human embryonic stem cells (hESCs) in situ based on the use of Raman microspectroscopy. The proposed quantification method was validated by comparison to a commonly used commercial glycogen assay kit. With Raman microspectroscopy, we could obtain the glycogen content of hESCs faster and apparently more accurately than with the kit. In addition, glycogen distributions across a colony could be obtained. Raman spectroscopy can provide reliable estimates of the in situ glycogen content in hESCs, and this approach should also be extensible to their other biochemical constituents as well as to other cell types. PMID- 21702507 TI - Synthesis of N-substituted 3,5-bis(arylidene)-4-piperidones with high antitumor and antioxidant activity. AB - A series of 3,5-bis(arylidene)-4-piperidone (DAP) compounds are considered as synthetic analogues of curcumin for anticancer properties. We performed structure activity relationship studies by synthesizing a number of DAPs N-alkylated or acylated with nitroxides or their amine precursors as potent antioxidant moieties. Both subtituents on arylidene rings and on piperidone nitrogen (five- or six-membered, 2- or 3-substituted or 3,4-disubstituted isoindoline nitroxides) were varied. The anticancer efficacy of the new DAP compounds was tested by measuring their cytotoxicity to cancer cell lines A2780 and MCF-7 and to the H9c2 cell line. The results showed that all DAP compounds induced a significant loss of cell viability in the human cancer cell lines tested; however, only pyrroline appended nitroxides (5c (Selvendiran, K.; Tong, L.; Bratasz, A.; Kuppusamy, L. M.; Ahmed, S.; Ravi, Y.; Trigg, N. J.; Rivera, B. K.; Kalai, T.; Hideg, K.; Kuppusamy, P. Mol. Cancer Ther. 2010, 9, 1169-1179), 5e, 7, 9) showed limited toxicity toward noncancerous cell lines. Computer docking simulations support the biological activity tested. These results suggest that antioxidant-conjugated DAPs will be useful as a safe and effective anticancer agent for cancer therapy. PMID- 21702508 TI - Are carbon nanotube effects on green algae caused by shading and agglomeration? AB - Due to growing production, carbon nanotubes (CNT) may soon be found in a broad range of products and thus in the environment. In this work, an algal growth test was developed to determine effects of pristine and oxidized CNT on the green algae Chlorella vulgaris and Pseudokirchneriella subcapitata. CNT suspensions were prepared in algal test medium and characterized taking into account the suspension age, the reduced light transmittance of nanoparticle suspensions defined as shading of CNT and quantified by UV/vis spectroscopy, and the agglomeration of the CNT and of the algal cells. Growth inhibition and photosynthetic activity were investigated as end points. Growth of C. vulgaris was inhibited with effect concentrations of 50% (EC(50)) values of 1.8 mg CNT/L and of 24 mg CNT/L in well dispersed and in agglomerated suspensions, respectively, and 20 mg CNT/L and 36 mg CNT/L for P. subcapitata, respectively. However, the photosynthetic activity was not affected. Growth inhibition was highly correlated with the shading of CNT and the agglomeration of algal cells. This suggests that the reduced algal growth might be caused mainly by indirect effects, i.e. by reduced availability of light and different growth conditions caused by the locally elevated algal concentration inside of CNT agglomerates. PMID- 21702509 TI - A near-IR reversible fluorescent probe modulated by selenium for monitoring peroxynitrite and imaging in living cells. AB - We have developed a near-IR reversible fluorescent probe containing an organoselenium functional group that can be used for the highly sensitive and selective monitoring of peroxynitrite oxidation and reduction events under physiological conditions. The probe effectively avoids the influence of autofluorescence in biological systems and gave positive results when tested in both aqueous solution and living cells. Real-time images of cellular peroxynitrite were successfully acquired. PMID- 21702510 TI - Butyronitrile-based electrolyte for dye-sensitized solar cells. AB - We elaborated a new electrolyte composition, based on butyronitrile solvent, that exhibits low volatility for use in dye-sensitized solar cells. The strong point of this new class of electrolyte is that it combines high efficiency and excellent stability properties, while having all the physical characteristics needed to pass the IEC 61646 stability test protocol. In this work, we also reveal a successful approach to control, in a sub-Nernstian way, the energetics of the distribution of the trap states without harming cell stability by means of incorporating NaI in the electrolyte, which shows good compatibility with butyronitrile. These excellent features, in conjunction with the recently developed thiophene-based C106 sensitizer, have enabled us to achieve a champion cell exhibiting 10.0% and even 10.2% power conversion efficiency (PCE) under 100 and 51.2 mW.cm(-2) incident solar radiation intensity, respectively. We reached >95% retention of PCE while displaying as high as 9.1% PCE after 1000 h of 100 mW.cm(-2) light-soaking exposure at 60 degrees C. PMID- 21702511 TI - Conformational states of ADP ribosylation factor 1 complexed with different guanosine triphosphates as studied by 31P NMR spectroscopy. AB - Guanine nucleotide binding proteins (GNB-proteins) play an essential role in cellular signaling, acting as molecular switches, cycling between the inactive, GDP-bound form and the active, GTP-bound form. It has been shown that conformational equilibria also exist within the active form of GNB-proteins between conformational states with different functional properties. Here we present (31)P NMR data on ADP ribosylation factor 1 (Arf1), a GNB-protein involved in Golgi traffic, promoting the coating of secretory vesicles. To investigate conformational equilibria in active Arf1, the wild type and switch I mutants complexed with GTP and a variety of commonly used GTP analogues, namely, GppCH(2)p, GppNHp, and GTPgammaS, were analyzed. To gain deeper insight into the conformational state of active Arf1, we titrated with Cu(2+)-cyclen and GdmCl and formed the complex with the Sec7 domain of nucleotide exchange factor ARNO and an effector GAT domain. In contrast to the related proteins Ras, Ral, Cdc42, and Ran, from (31)P NMR spectroscopic view, Arf1 exists predominantly in a single conformation independent of the GTP analogue used. This state seems to correspond to the so-called state 2(T) conformation, according to Ras nomenclature, which is interacting with the effector domain. The exchange of the highly conserved threonine in position 48 with alanine led to a shift of the equilibrium toward a conformational state with typical properties obtained for state 1(T) in Ras, such as interaction with guanine nucleotide exchange factors, a lower affinity for nucleoside triphosphates, and greater sensitivity to chaotropic agents. In active Arf1(wt), the effector interacting conformation is strongly favored. These intrinsic conformational equilibria of active GNB-proteins could be a fine-tuning mechanism of regulation and thereby an interesting target for the modulation of protein activity. PMID- 21702512 TI - Preparation of silica-encapsulated hollow gold nanosphere tags using layer-by layer method for multiplex surface-enhanced raman scattering detection. AB - The use of silica shells offers many advantages in surface-enhanced Raman scattering (SERS)-based biological sensing applications due to their optical transparency, remarkable stability in environmental media, and improved biocompatibility. Here, we report a novel layer-by-layer method for the preparation of silica-hollow gold nanosphere (HGN) SERS tags. Poly(acrylic acid) was used to stabilize Raman reporter-tagged HGNs prior to the adsorption of a coupling agent, after which a silica shell was deposited onto the particle surface using Stober's method. Importantly, competitive adsorption of the Raman reporter molecules and coupling agents, which results in unbalanced loading of reporter molecules on individual nanoparticles, was avoided using this method. As a result, the loading density of reporter molecules could be maximized. In addition, HGNs exhibited strong enhancement effects from the individual particles because of their ability to localize the surface electromagnetic fields through pinholes in the hollow particle structures. The proposed layer-by-layer silica encapsulated HGN tags showed strong SERS signals as well as excellent multiplexing capabilities. PMID- 21702514 TI - Novel quinoxaline-based organic sensitizers for dye-sensitized solar cells. AB - Novel quinoxaline-based organic sensitizers using vertical (RC-21) and horizontal (RC-22) conjugation between an electron-donating triphenylamine unit and electron accepting quinoxaline unit have been synthesized and used for dye-sensitized solar cells (DSSCs), leading to the relatively high power conversion efficiencies of 3.30 and 5.56% for RC-21 and RC-22, respectively. This result indicates that the quinoxaline electron-accepting unit is quite a promising candidate in organic sensitizers. PMID- 21702542 TI - Communication: non-adiabatic coupling and resonances in the F + H2 reaction at low energies. AB - Quantum reactive scattering calculations on accurate potential energy surfaces predict that at energies below ~5 meV, the reaction of F atoms with H(2) is dominated by the Born-Oppenheimer (BO) forbidden reaction of the spin-orbit excited F((2)P(1/2)) atom. This non-BO dominance is amplified by low-energy resonances corresponding to quasi-bound states of the HF(v = 3, j = 3) + H product channel. Neglect of non-adiabatic coupling between the electronic states of the F atom leads to a qualitatively incorrect picture of the reaction dynamics at low energy. PMID- 21702543 TI - Communication: observation of homonuclear propensity in collisional relaxation of the 13C12CD2 (v2=1) isotopologue of acetylene by stimulated Raman spectroscopy. AB - We report the first experimental observation of homonuclear propensity in collisional relaxation of a polyatomic molecule. A pump-probe stimulated Raman setup is used to pump population to a single rotational level of the v(2) = 1 vibrationally excited state in (13)C(12)CD(2) and then monitor the redistribution of the rotational population that has taken place after a fixed delay. The Q branch of the 2nu(2)-nu(2) band shows a pattern of intensity alternation between the even and the odd rotational components, with the greater intensities always corresponding to the rotational levels with the same parity as the one where all the population was initially deposited. The effect can be explained by the existence of a propensity rule that favors collisional relaxation between rovibrational levels of the same parity. PMID- 21702513 TI - Triazole bridges as versatile linkers in electron donor-acceptor conjugates. AB - Aromatic triazoles have been frequently used as pi-conjugated linkers in intramolecular electron transfer processes. To gain a deeper understanding of the electron-mediating function of triazoles, we have synthesized a family of new triazole-based electron donor-acceptor conjugates. We have connected zinc(II)porphyrins and fullerenes through a central triazole moiety--(ZnP-Tri C(60))--each with a single change in their connection through the linker. An extensive photophysical and computational investigation reveals that the electron transfer dynamics--charge separation and charge recombination--in the different ZnP-Tri-C(60) conjugates reflect a significant influence of the connectivity at the triazole linker. Except for the m4m-ZnP-Tri-C(60)17, the conjugates exhibit through-bond photoinduced electron transfer with varying rate constants. Since the through-bond distance is nearly the same for all the synthesized ZnP-Tri C(60) conjugates, the variation in charge separation and charge recombination dynamics is mainly associated with the electronic properties of the conjugates, including orbital energies, electron affinity, and the energies of the excited states. The changes of the electronic couplings are, in turn, a consequence of the different connectivity patterns at the triazole moieties. PMID- 21702544 TI - Communication: state-to-state differential cross sections for H2O(B) photodissociation. AB - Quantum state-to-state differential cross sections, along with the absorption spectrum and product internal state distributions, have been calculated for the photodissociation of H(2)O in its B band on a new set of ab initio potential energy surfaces in a diabatic representation. The theoretical attributes are in good agreement with the recent experimental data, shedding light on the non adiabatic dissociation dynamics. PMID- 21702545 TI - Second-order dispersion interactions in pi-conjugated polymers. AB - We calculate the ground state and excited state second-order dispersion interactions between parallel pi-conjugated polymers. The unperturbed eigenstates and energies are calculated from the Pariser-Parr-Pople model using CI-singles theory. Based on large-scale calculations using the molecular structure of trans polyacetylene as a model system and by exploiting dimensional analysis, we find that: (1) For inter-chain separations, R, greater than a few lattice spacings, the ground-state dispersion interaction, DeltaE(GS), satisfies, DeltaE(GS)~L(2)/R(6) for L ? R and DeltaE(GS)~L/R(5) for R ? L, where L is the chain length. The former is the London fluctuating dipole-dipole interaction while the latter is a fluctuating line dipole-line dipole interaction. (2) The excited state screening interaction exhibits a crossover from fluctuating monopole-line dipole interactions to either fluctuating dipole-dipole or fluctuating line dipole-line dipole interactions when R exceeds a threshold R(c), where R(c) is related to the root-mean-square separation of the electron-hole excitation. Specifically, the excited state screening interaction, DeltaE(n), satisfies, DeltaE(n) ~ L/R(6) for R(c) < L ? R and DeltaE(n) ~ L(0)/R(5) for R(c) < R ? L. For R < R(c) < L, DeltaE(n) ~ R(-nu), where nu ? 3. We also investigate the relative screening of the primary excited states in conjugated polymers, namely the n = 1, 2, and 3 excitons. We find that a larger value of n corresponds to a larger value of DeltaE(n). For example, for poly(para-phenylene), DeltaE(n = 1) ? 0.1 eV, DeltaE(n = 2) ? 0.6 eV, and DeltaE(n = 3) ? 1.2 eV (where n = 1 is the 1(1)B(1) state, n = 2 is the m(1)A state, and n = 3 is the n(1)B(1) state). Finally, we find that the strong dependence of DeltaE(n) on inter-chain separation implies a strong dependency of DeltaE(n) on density fluctuations. In particular, a 10% density fluctuation implies a fluctuation of 13 meV, 66 meV, and 120 meV for the 1(1)B(1), m(1)A state, and n(1)B(1) states of poly(para phenylene), respectively. Our results for the ground-state dispersion are applicable to all types of conjugated polymers. However, our excited state results are only applicable to conjugated polymers, such as the phenyl-based class of light emitting polymers, in which the primary excitations are particle hole (or ionic) states. PMID- 21702546 TI - Further evidences of the quality of double-hybrid energy functionals for pi conjugated systems. AB - Despite numerous interesting efforts along decades to improve the accuracy of density functionals with broad applicability, such as B3LYP, there are still large sets of molecular systems where improvements are badly needed. We select pi conjugated systems as an example of the latter due to the subtle interplay between some physical effects affecting possibly most of the calculations: self interaction or delocalization error, medium-range correlation signatures, dispersive-like weak interactions, and static correlation effects. We further assess a recently proposed modification of the B2-PLYP double-hybrid functional, called B2pi-PLYP, that is expected to yield substantial progress for this kind of systems. Generally speaking, when compared with other more popular and older density functionals, double hybrids behave particularly accurate for pi conjugated systems without suffering the large errors that are common in former yet conventional methods. PMID- 21702547 TI - A coupled cluster approach with excitations up to six orbital pairs: the formulation and test applications for bond breaking processes. AB - The formalism of the coupled cluster (CC) method with excitations up to six orbital pairs (CC6P) and its illustrative applications are presented. By definition, CC6P includes connected excitations from full singles, doubles, triples, and partial quadruples, pentuples, and hextuples. CC6P and its approximate variants (CC6P-4, CC6P-5, and CC6P-6a) have the similar computational cost as the CC singles, doubles, and triples (CCSDT). They have been applied to investigate the potential energy surfaces for bond dissociation processes in four small molecules (F(2), H(2)O, N(2), and F(2)(+)). In comparison with full configuration interaction results, CC6P and its approximate variants are demonstrated to provide very accurate descriptions for the single-bond breaking process in F(2). While for multi-bond breaking processes, these methods provide considerable improvement over CCSDT. PMID- 21702548 TI - Initial value representation for the SU(n) semiclassical propagator. AB - The semiclassical propagator in the representation of SU(n) coherent states is characterized by isolated classical trajectories subjected to boundary conditions in a doubled phase space. In this paper, we recast this expression in terms of an integral over a set of initial-valued trajectories. These trajectories are monitored by a filter that collects only the appropriate contributions to the semiclassical approximation. This framework is suitable for the study of bosonic dynamics in n modes with fixed total number of particles. We exemplify the method for a Bose-Einstein condensate trapped in a triple-well potential, providing a detailed discussion on the accuracy and efficiency of the procedure. PMID- 21702549 TI - Pointing the way to the products? Comparison of the stress tensor and the second derivative tensor of the electron density. AB - The eigenvectors of the electronic stress tensor can be used to identify where new bond paths form in a chemical reaction. In cases where the eigenvectors of the stress tensor are not available, the gradient-expansion-approximation suggests using the eigenvalues of the second derivative tensor of the electron density instead; this approximation can be made quantitatively accurate by scaling and shifting the second-derivative tensor, but it has a weaker physical basis and less predictive power for chemical reactivity than the stress tensor. These tools provide an extension of the quantum theory of atoms and molecules from the characterization of molecular electronic structure to the prediction of chemical reactivity. PMID- 21702550 TI - Study of ultrafast dynamics of 2-picoline by time-resolved photoelectron imaging. AB - The dynamics of electronically excited states in 2-picoline is studied using femtosecond time-resolved photoelectron imaging spectroscopy. The internal conversion from the S(2) state to the vibrationally excited S(1) state is observed in real time. The secondarily populated high vibronic S(1) state deactivates further to the S(0) state. Photoelectron energy and angular distributions reveal the feature of ionization from the singlet 3p Rydberg states. In addition, variation of time-dependent anisotropy parameters indicates the rotational coherence of the molecule. PMID- 21702551 TI - Electron correlation and relativistic effects in atomic structure calculations of the thorium atom. AB - Relativistic two-component ab initio calculations have been performed for the Th atom. The spin free low lying states have been calculated at state-averaged complete active space self-consistent field (SA-CASSCF) and multi-state complete active space second-order perturbation (MS-CASPT2) level of theories using different sets of active orbitals. The spin-orbit states have been computed using Douglas-Kroll type of atomic mean-field integral approach. The effects of dynamic electron correlation have been studied at the MS-CASPT2 level. The energy levels of spin-orbit states below 30,000 cm(-1) obtained by the inclusion of dynamic electron correlation are in very good agreement with the experimental values. The radiative properties such as weighted transition probabilities (gA) and oscillator strengths (gf) among several spin-orbit states have been calculated at the SA-CASSCF and MS-CASPT2 levels and are expected to be very helpful for future experiments. PMID- 21702552 TI - Complete experimental rovibrational eigenenergies of HCN up to 6880 cm(-1) above the ground state. AB - The [H,C,N] molecular system is a very important model system to many fields of chemical physics and the experimental characterization of highly excited vibrational states of this molecular system is of special interest. This paper reports the experimental characterization of all 3822 eigenenergies up to 6880 cm(-1) relative to the ground state in the HCN part of the potential surface using high temperature hot gas emission spectroscopy. The spectroscopic constants for the first 71 vibrational states including highly excited bending vibrations up to v(2) = 10 are reported. The perturbed eigenenergies for all 20 rotational perturbations in the reported eigenenergy range have been determined. The 11,070 eigenenergies up to J = 90 for the first 123 vibrational substates are included as supplement to this paper. We show that a complete ab initio rovibrational analysis for a polyatomic molecule is possible. Using such an analysis we can understand the molecular physics behind the Schrodinger equation for problems for which perturbation theoretical calculations are no more valid. We show that the vibrational structure of the linear HCN molecule persists approximately up to the isomerization barrier and only above the barrier the accommodation of the vibrational states to the double well structure of the potential takes place. PMID- 21702553 TI - Magnetic susceptibility of alkali-tetracyanoquinodimethane salts and extended Hubbard models with bond order and charge density wave phases. AB - The molar spin susceptibilities chi(T) of Na-tetracyanoquinodimethane (TCNQ), K TCNQ, and Rb-TCNQ(II) are fit quantitatively to 450 K in terms of half-filled bands of three one-dimensional Hubbard models with extended interactions using exact results for finite systems. All three models have bond order wave (BOW) and charge density wave (CDW) phases with boundary V = V(c)(U) for nearest-neighbor interaction V and on-site repulsion U. At high T, all three salts have regular stacks of TCNQ(-) anion radicals. The chi(T) fits place Na and K in the CDW phase and Rb(II) in the BOW phase with V ~ V(c). The Na and K salts have dimerized stacks at T < T(d) while Rb(II) has regular stacks at 100 K. The chi(T) analysis extends to dimerized stacks and to dimerization fluctuations in Rb(II). The three models yield consistent values of U, V, and transfer integrals t for closely related TCNQ(-) stacks. Model parameters based on chi(T) are smaller than those from optical data that in turn are considerably reduced by electronic polarization from quantum chemical calculation of U, V, and t of adjacent TCNQ(-) ions. The chi(T) analysis shows that fully relaxed states have reduced model parameters compared to optical or vibration spectra of dimerized or regular TCNQ( ) stacks. PMID- 21702554 TI - Semiclassical initial value representation study of internal conversion rates. AB - Internal conversion is an inherently quantum mechanical process. To date, "on the fly" computation of internal conversion rates is limited to harmonic approximations, which would seem to be especially unsuitable, given that the typical transition to the ground electronic state occurs at energies which are far from the harmonic limit. It is thus of interest to study the applicability of the semiclassial initial value representation (SCIVR) approach which is in principle amenable to on the fly studies even with "many" degrees of freedom. In this paper we study the applicability of the Herman-Kluk (HK) SCIVR to a model system with two coupled and anharmonic degrees of freedom. We find that (a) the HK SCIVR is a good approximation to the exact quantum dynamics; (b) computation of the first order correction to the HK-SCIVR approximation corroborates the accuracy; (c) by studying a large parameter range, we find that the harmonic approximation is mostly unsatisfactory; and (d) for the specific model used, the coupling between the modes was found to be relatively unimportant. These results imply that the HK-SCIVR methodology is a good candidate for on the fly studies of internal conversion processes of "large" molecules. PMID- 21702555 TI - High-resolution Fourier-transform infrared spectroscopy of the Coriolis coupled ground state and nu7 mode of ketenimine. AB - High resolution FTIR spectra of the short lived species ketenimine have been recorded in the regions 390-1300 cm(-1) and 20-110 cm(-1) using synchrotron radiation. Two thousand six hundred sixty transitions of the nu(7) band centered at 693 cm(-1) and 126 far-IR rotational transitions have been assigned. Rotational and centrifugal distortion parameters for the nu(7) mode were determined and local Fermi and b-axis Coriolis interactions with 2nu(12) are treated. A further refinement of the ground state, nu(12) and nu(8) parameters was also achieved, including the treatment of previously unrecognized ac-axis and ab-axis second order perturbations to the ground state. PMID- 21702556 TI - Theoretical studies of the tunneling splitting of malonaldehyde using the multiconfiguration time-dependent Hartree approach. AB - Full dimensional multi-configuration time-dependent Hartree calculations of the zero point energy and the tunneling splitting of malonaldehyde using a recently published potential energy surface [Y. Wang, B. J. Braams, J. M. Bowman, S. Carter, and D. P. Tew, J. Chem. Phys. 128, 224314 (2008)] are reported. The potential energy surface has been approximated by a modified version of the n mode representation and careful convergence check has been performed to ensure accurate results. The obtained value for the splitting (23.4 cm(-1)) is in acceptable agreement with the experimental value of 21.583 cm(-1). The computed zero-point-energy is 14,670 cm(-1) which is lower than previous results of Wang et al., but likely to be about 4 cm(-1) too low because of shortcomings of the n mode representation of the potential. The energies reported in this abstract contain a correction to account for neglected vibrational angular momentum terms. PMID- 21702557 TI - First principles study of the ground and excited states of FeO, FeO+, and FeO(-). AB - Through a variety of highly correlated methods combined with large basis sets we have studied the electronic structure of FeO, FeO(+), and FeO(-). In particular, we have constructed complete potential energy curves for 48, 24, and 4 states for the FeO, FeO(+), and FeO(-) species, respectively, at the multireference level of theory. For all states examined we report energetics, common spectroscopic parameters, and dipole moments. Overall our results are in good agreement with experiment, but we have encountered as well interesting differences between experiment and theory deserving further investigation. PMID- 21702558 TI - Vibronic effects on the 1t(1) -> 3s Rydberg excitation in CF4 induced by electron impact. AB - We report a theoretical study of vibronic effects on the 1t(1) -> 3s Rydberg excitation in CF(4) induced by electron impact. The generalized oscillator strength for the excitation has been calculated using theoretical wave functions at the equation-of-motion coupled cluster singles and doubles level. In the calculation vibronic effects have been taken into account by evaluating the electronic transition moment along the individual normal coordinates. The present calculation successfully reproduces our recent experimental result [N. Watanabe, D. Suzuki, and M. Takahashi, J. Chem. Phys. 134, 064307 (2011)] over the full momentum transfer region studied. By examining contributions from individual normal modes, the asymmetric stretching mode is found to play a leading role in the 1t(1) -> 3s transition at small momentum transfer. PMID- 21702559 TI - False estimates of stimulated Raman pumping efficiency caused by the optical Stark effect. AB - One technique for measuring the fraction of molecules pumped to the excited state in stimulated Raman pumping (SRP) is to record the depletion of molecules in the lower state by resonance enhanced multiphoton ionization (REMPI). The presence of electric fields on the order of 10(7) V/cm arising from the pulsed SRP laser beams is sufficient to shift the line position of the REMPI transition to such an extent that the estimate of the pumping efficiency is overestimated unless this shift is accounted for. PMID- 21702560 TI - Interactions of a Mn atom with halogen atoms and stability of its half-filled 3d shell. AB - Using density functional theory with hybrid exchange-correlation potential, we have calculated the geometrical and electronic structure, relative stability, and electron affinities of MnX(n) compounds (n = 1-6) formed by a Mn atom and halogen atoms X = F, Cl, and Br. Our objective is to examine the extent to which the Mn-X interactions are similar and to elucidate if/how the half-filled 3d-shell of a Mn atom participates in chemical bonding as the number of halogen atoms increases. While the highest oxidation number of the Mn atom in fluorides is considered to be +4, the maximum number of halogen atoms that can be chemically attached in the MnX(n)(-) anions is 6 for X = F, 5 for X = Cl, and 4 for X = Br. The MnCl(n) and MnBr(n) neutrals are superhalogens for n >= 3, while the superhalogen behavior of MnF(n) begins with n = 4. These results are explained to be due to the way different halogen atoms interact with the 3d electrons of Mn atom. PMID- 21702561 TI - Molecular dynamics simulation of the dielectric constant of water: the effect of bond flexibility. AB - The role of bond flexibility on the dielectric constant of water is investigated via molecular dynamics simulations using a flexible intermolecular potential SPC/Fw [Y. Wu, H. L. Tepper, and G. A. Voth, J. Chem. Phys. 128, 024503 (2006)]. Dielectric constants and densities are reported for the liquid phase at temperatures of 298.15 K and 473.15 K and the supercritical phase at 673.15 K for pressures between 0.1 MPa and 200 MPa. Comparison with both experimental data and other rigid bond intermolecular potentials indicates that introducing bond flexibility significantly improves the prediction of both dielectric constants and pressure-temperature-density behavior. In some cases, the predicted densities and dielectric constants almost exactly coincide with experimental data. The results are analyzed in terms of dipole moments, quadrupole moments, and equilibrium bond angles and lengths. It appears that bond flexibility allows the molecular dipole and quadrupole moment to change with the thermodynamic state point, and thereby mimic the change of the intermolecular interactions in response to the local environment. PMID- 21702562 TI - Compressional, temporal, and compositional behavior of H2-O2 compound formed by high pressure x-ray irradiation. AB - X-ray irradiation was found to convert H(2)O at pressures above 2 GPa into a novel molecular H(2)-O(2) compound. We used optical Raman spectroscopy to explore the behavior of x-ray irradiated H(2)O samples as a function of pressure, time, and composition. The compound was found to be stable over a period of two years, as long as high pressure conditions (>2 GPa) were maintained. The Raman shifts for the H(2) and O(2) vibrons behaved differently from pure H(2) and O(2) as pressure was increased on the compound up to 70 GPa, indicating that it remains a distinct, molecular compound. Based on spectra taken from different locations in a single sample, it appears that multiple forms of the H(2)-O(2) compound exist. The structure and composition of the starting material plays an important role in compound formation, as we found that hydrogen-filled ice clathrate C(2) (H(2))H(2)O did not undergo the same dissociation as observed in ice VII upon x ray irradiation until pressure was increased to above 10 GPa. PMID- 21702563 TI - Correlation between boson peak and anomalous elastic behavior in GeO2 glass: an in situ Raman scattering study under high-pressure. AB - We present low-frequency Raman scattering of pure GeO(2) glass under pressure up to 4 GPa, corresponding to an elastic transformation. Intensity variation and frequency shift of the boson peak are analysed and compared to the Debye model. The decrease of the boson peak intensity scaled by the Debye energy is correlated to the elastic anomalous properties under pressure up to 1.5 GPa, and interpreted as an elastic homogenisation process at the local scale. We emphasize similarities between a-GeO(2) and a-SiO(2) behavior under pressure, and compare our results to other experiments, numerical studies, and predictions of several models concerning amorphous systems. PMID- 21702564 TI - Uniform saturation of a strongly coupled spin system by two-frequency irradiation. AB - The theoretical basis of two-frequency saturation is given here in the framework of Provotorov theory. The parameters influencing the saturation efficiency are discussed and studied experimentally using a liquid-crystalline test system. It is shown that double-frequency irradiation can be extremely efficient when the irradiation frequencies are placed at opposite sides of the characteristic frequency of the spin system, and that the frequency separation in the double frequency irradiation can be varied over a large range. Provotorov theory is also shown to provide good insights into the experimental findings, which would otherwise be difficult to obtain from simulations. PMID- 21702565 TI - The effect of geometry on cluster polarizability: studies of sodium, copper, and silicon clusters at shape-transition sizes. AB - The electronic properties of Na(16), Cu(16,) and Si(20-28) clusters were calculated using density functional theory with the generalized gradient approximation (GGA) of Perdew-Burke-Ernzerhof. These clusters are special, as transitions in cluster shape occur at these sizes in the Na(n), Cu(n), and Si(n) cluster systems, respectively. Low-energy isomers that are comparable in stability, but possess distinctly different shapes, exist at each of these sizes, making these sets of isomers useful as probes of geometrical effects on cluster properties. Results for ionization potentials, electron affinities, and polarizabilities are shown to have a characteristic dependence on cluster shape. An analysis of the results reveals a close relationship between polarizability and cluster volume for all the isomers studied, despite the differences in cluster type and geometry. This relationship accounts for variations in polarizabilities among isomers of the same size, but different shapes, whereas previously published rules relating the polarizability to other cluster properties do not. PMID- 21702566 TI - Roles of translational and reorientational modes in translational diffusion of high-pressure water: comparison with soft-core fluids. AB - The dynamics of two soft-core fluids that show the increase in diffusivity with isothermal compression is studied with the mode-coupling theory (MCT). The anomalous density dependence of the diffusivity of these fluids is reproduced by the theory, and it is ascribed to the decrease in the first peak of the structure factor. The mechanism is quite different from that of high-pressure water revealed by MCT on molecular liquids described by the interaction-site model [T. Yamaguchi, S.-H. Chong, and F. Hirata, J. Chem. Phys., 119, 1021 (2003)]. The structures used in that study, calculated by the reference interaction-site model integral equation theory, showed the increase in the height of the first peak of the structure factor between oxygen atoms, whereas the structure obtained by molecular dynamics (MD) simulations shows the decrease in the peak height. In this work, calculations with MCT are performed on the simple fluids whose structure factor is the same as that between oxygen atoms of water from MD simulation, in order to clarify the role of translational structure on the increase in diffusivity with compression. The conclusion is that both the translational and reorientational modes contribute to the increase in diffusivity, and the effect of the latter is indispensable for the anomaly alone at least above freezing temperature. PMID- 21702567 TI - Statistical thermodynamics of fluids with both dipole and quadrupole moments. AB - New Gibbs ensemble simulation data for a polar fluid modeled by a square-well potential plus dipole-dipole, dipole-quadrupole, and quadrupole-quadrupole interactions are presented. This simulation data is used in order to assess the applicability of the multipolar square-well perturbation theory [A. L. Benavides, Y. Guevara, and F. del Rio, Physica A 202, 420 (1994)] to systems where more than one term in the multipole expansion is relevant. It is found that this theory is able to reproduce qualitatively well the vapor-liquid phase diagram for different multipolar moment strengths, corresponding to typical values of real molecules, except in the critical region. Hence, this theory is used to model the behavior of substances with multiple chemical bonds such as carbon monoxide and nitrous oxide and we found that with a suitable choice of the values of the intermolecular parameters, the vapor-liquid equilibrium of these species is adequately estimated. PMID- 21702568 TI - Significant substitution effects in dipolar and non-dipolar supercritical fluids. AB - Vibrational Raman spectra of C=C stretching modes of ethylene derivates (cis C(2)H(2)Cl(2), cis-stilbene, and trans-stilbene) were measured in supercritical fluids along an isotherm as functions of their densities. The substitution effect of the Raman shift is so significant that a difference among three solutes can be 20 times and is observed similarly in dipolar (CHF(3)) and non-dipolar (CO(2)) fluids. In particular, the shifts of trans-stilbene were enormously large among all systems for studies of vibrational spectroscopies of supercritical fluids and were equivalent to those of typical hydrogen-bonded fluids. Such large shifts arising from the significant attractive energy between solute and solvent molecules were attributed to a site-selective solvation around a phenyl group, which was driven by a dispersion force in the absence of steric hindrance. We found that the absence of steric hindrance causes the significant local density augmentation. To the best of our knowledge, Raman experiments and their theoretical analysis are the first ones quantifying how the difference of steric hindrance produces solvation structures in solution as well as supercritical solutions. PMID- 21702569 TI - Hydrophobic interactions with coarse-grained model for water. AB - Integral equation theory is applied to a coarse-grained model of water to study potential of mean force between hydrophobic solutes. Theory is shown to be in good agreement with the available simulation data for methane-methane and fullerene-fullerene potential of mean force in water; the potential of mean force is also decomposed into its entropic and enthalpic contributions. Mode coupling theory is employed to compute self-diffusion coefficient of water as well as diffusion coefficient of a dilute hydrophobic solute; good agreement with molecular dynamics simulation results is found. PMID- 21702570 TI - Origins of dihydrogen binding to metal-inserted porphyrins: electric polarization and Kubas interaction. AB - Using density functional theory calculations, we have investigated the interactions between hydrogen molecules and metalloporphyrins. A metal atom, such as Ca or Ti, is introduced for incorporation in the central N(4) cavity. Within local density approximation (generalized gradient approximation), we find that the average binding energy of H(2) to the Ca atom is about 0.25 (0.1) eV/H(2) up to four H(2) molecules, whereas that to the Ti atom is about 0.6 (0.3) eV per H(2) up to two H(2) molecules. Our analysis of orbital hybridization between the inserted metal atom and molecular hydrogen shows that H(2) binds weakly to Ca porphyrin through a weak electric polarization in dihydrogen, but is strongly hybridized with Ti-porphyrin through the Kubas interaction. The presence of d orbitals in Ti may explain the difference in the interaction types. PMID- 21702571 TI - In situ conductance measurements of copper phthalocyanine thin film growth on sapphire [0001]. AB - The current flowing through a thin film of copper phthalocyanine vacuum deposited on a single crystal sapphire [0001] surface was measured during film growth from 0 to 93 nm. The results, expressed as conductance vs. nominal film thickness, indicate three distinct film growth regions. Conductive material forms below about 5 nm and again above 35 nm, but in the intermediate thicknesses the film conductance was observed to decrease with increasing film thickness. With the aid of ac-AFM topology images taken ex situ, the conductance results are explained based on the Stranski-Krastanov (2D + 3D) film growth mechanism, in which the formation of a thin wetting layer is followed by the growth of discrete islands that eventually coalesce into an interpenetrating, conductive network. PMID- 21702572 TI - State-to-state dynamics at the gas-liquid metal interface: rotationally and electronically inelastic scattering of NO[2Pi(1/2)(0.5)] from molten gallium. AB - Jet cooled NO molecules are scattered at 45 degrees with respect to the surface normal from a liquid gallium surface at E(inc) from 1.0(3) to 20(6) kcal/mol to probe rotationally and electronically inelastic scattering from a gas-molten metal interface (numbers in parenthesis represent 1sigma uncertainty in the corresponding final digits). Scattered populations are detected at 45 degrees by confocal laser induced fluorescence (LIF) on the gamma(0-0) and gamma(1-1) A(2)Sigma <- X(2)Pi(Omega) bands, yielding rotational, spin-orbit, and lambda doublet population distributions. Scattering of low speed NO molecules results in Boltzmann distributions with effective temperatures considerably lower than that of the surface, in respectable agreement with the Bowman-Gossage rotational cooling model [J. M. Bowman and J. L. Gossage, Chem. Phys. Lett. 96, 481 (1983)] for desorption from a restricted surface rotor state. Increasing collision energy results in a stronger increase in scattered NO rotational energy than spin-orbit excitation, with an opposite trend noted for changes in surface temperature. The difference between electronic and rotational dynamics is discussed in terms of the possible influence of electron hole pair excitations in the conducting metal. While such electronically non-adiabatic processes can also influence vibrational dynamics, the gamma(1-1) band indicates <2.6 * 10(-4) probability for collisional formation of NO(v = 1) at surface temperatures up to 580 K. Average translational to rotational energy transfer is compared from a hard cube model perspective with previous studies of NO scattering from single crystal solid surfaces. Despite a lighter atomic mass (70 amu), the liquid Ga surface is found to promote translational to rotational excitation more efficiently than Ag(111) (108 amu) and nearly as effectively as Au(111) (197 amu). The enhanced propensity for Ga(l) to transform incident translational energy into rotation is discussed in terms of temperature-dependent capillary wave excitation of the gas-liquid metal interface. PMID- 21702573 TI - Polarizable Poisson-Boltzmann equation: the study of polarizability effects on the structure of a double layer. AB - We incorporate ion polarizabilities into the Poisson-Boltzmann equation by modifying the effective dielectric constant and the Boltzmann distribution of ions. The extent of the polarizability effects is controlled by two parameters, gamma(1) and gamma(2); gamma(1) determines the polarization effects in a dilute system and gamma(2) regulates the dependence of the polarizability effects on the concentration of ions. For a polarizable ion in an aqueous solution gamma(1) ~ 0.01 and the polarizability effects are negligible. The conditions where gamma(1) and/or gamma(2) are large and the polarizability is relevant involve the low dielectric constant media, high surface charge, and/or large ionic concentrations. PMID- 21702574 TI - Molecular theory on dielectric constant at interfaces: a molecular dynamics study of the water/vapor interface. AB - Though the local dielectric constant at interfaces is an important phenomenological parameter in the analysis of surface spectroscopy, its microscopic definition has been uncertain. Here, we present a full molecular theory on the local field at interfaces with the help of molecular dynamics simulation, and thereby provide microscopic basis for the local dielectric constant so as to be consistent to the phenomenological three-layer model of interface systems. To demonstrate its performance, we applied the theory to the water/vapor interface, and obtained the local field properties near the interface where the simple dielectric model breaks down. Some computational issues pertinent to Ewald calculations of the dielectric properties are also discussed. PMID- 21702575 TI - Atomistic insights into aqueous corrosion of copper. AB - Corrosion is a fundamental problem in electrochemistry and represents a mode of failure of technologically important materials. Understanding the basic mechanism of aqueous corrosion of metals such as Cu in presence of halide ions is hence essential. Using molecular dynamics simulations incorporating reactive force field (ReaxFF), the interaction of copper substrates and chlorine under aqueous conditions has been investigated. These simulations incorporate effects of proton transfer in the aqueous media and are suitable for modeling the bond formation and bond breakage phenomenon that is associated with complex aqueous corrosion phenomena. Systematic investigation of the corrosion process has been carried out by simulating different chlorine concentration and solution states. The structural and morphological differences associated with metal dissolution in the presence of chloride ions are evaluated using dynamical correlation functions. The simulated atomic trajectories are used to analyze the charged states, molecular structure and ion density distribution which are utilized to understand the atomic scale mechanism of corrosion of copper substrates under aqueous conditions. Increased concentration of chlorine and higher ambient temperature were found to expedite the corrosion of copper. In order to study the effect of solution states on the corrosion resistance of Cu, partial fractions of proton or hydroxide in water were configured, and higher corrosion rate at partial fraction hydroxide environment was observed. When the Cl(-) concentration is low, oxygen or hydroxide ion adsorption onto Cu surface has been confirmed in partial fraction hydroxide environment. Our study provides new atomic scale insights into the early stages of aqueous corrosion of metals such as copper. PMID- 21702576 TI - Heat conduction across molecular junctions between nanoparticles. AB - We investigate the problem of heat conduction across molecular junctions connecting two nanoparticles, both in vacuum and in a liquid environment, using classical molecular dynamics simulations. In vacuum, the well-known result of a length independent conductance is recovered; its precise value, however, is found to depend sensitively on the overlap between the vibrational spectrum of the junction and the density of states of the nanoparticles that act as thermal contacts. In a liquid environment, the conductance is constant up to a crossover length, above which a standard Fourier regime is recovered. PMID- 21702577 TI - Thermodynamic factors limiting the preservation of aromaticity of adsorbed organic compounds on Si(100): example of the pyridine. AB - Using pyridine as an example, a thermodynamic analysis of the low temperatures adsorption of aromatic organic molecules with a N atom on the Si(100) surface is presented. This study is restricted to the case of an equilibrium with the gas phase. Dative attachment which is the only way to preserve aromaticity is the more stable form of adsorbed pyridine in dilute solutions at low temperatures. Two factors limit the domain of stability of dative attachment: repulsive interactions between dative bonds prevent them from being present in concentrated solutions while aromaticity contributes to a decrease in the entropy, which explains the vanishing of dative bonds at high temperatures even in dilute solutions. PMID- 21702578 TI - Heterogeneous critical nucleation on a completely wettable substrate. AB - Heterogeneous nucleation of a new bulk phase on a flat substrate can be associated with the surface phase transition called wetting transition. When this bulk heterogeneous nucleation occurs on a completely wettable flat substrate with a zero contact angle, the classical nucleation theory predicts that the free energy barrier of nucleation vanishes. In fact, there always exists a critical nucleus and a free-energy barrier as the first-order prewetting transition will occur even when the contact angle is zero. Furthermore, the critical nucleus changes its character from the critical nucleus of surface phase transition below bulk coexistence (undersaturation) to the critical nucleus of bulk heterogeneous nucleation above the coexistence (oversaturation) when it crosses the coexistence. Recently, Sear [J. Chem. Phys. 129, 164510 (2008)] has shown, by a direct numerical calculation of nucleation rate, that the nucleus does not notice this change when it crosses the coexistence. In our work, the morphology and the work of formation of critical nucleus on a completely wettable substrate are re examined across the coexistence using the interface-displacement model. Indeed, the morphology and the work of formation changes continuously at the coexistence. Our results support the prediction of Sear and will rekindle the interest on heterogeneous nucleation on a completely wettable substrate. PMID- 21702579 TI - Scale-free center-of-mass displacement correlations in polymer melts without topological constraints and momentum conservation: a bond-fluctuation model study. AB - By Monte Carlo simulations of a variant of the bond-fluctuation model without topological constraints, we examine the center-of-mass (COM) dynamics of polymer melts in d = 3 dimensions. Our analysis focuses on the COM displacement correlation function C(N)(t)~?(t) (2)h(N)(t)/2, measuring the curvature of the COM mean-square displacement h(N)(t). We demonstrate that C(N)(t) ~ (R(N)/T(N))(2)(rho*/rho) f(x = t/T(N)) with N being the chain length (16 <= N <= 8192), R(N) ~ N(1/2) is the typical chain size, T(N) ~ N(2) is the longest chain relaxation time, rho is the monomer density, rho(*)~N/R(N) (d) is the self density, and f(x) is a universal function decaying asymptotically as f(x) ~ x( omega) with omega = (d + 2) * alpha, where alpha = 1/4 for x ? 1 and alpha = 1/2 for x ? 1. We argue that the algebraic decay NC(N)(t) ~ -t(-5/4) for t ? T(N) results from an interplay of chain connectivity and melt incompressibility giving rise to the correlated motion of chains and subchains. PMID- 21702580 TI - Exploration of the relationship between topology and designability of conformations. AB - Protein structures are evolutionarily more conserved than sequences, and sequences with very low sequence identity frequently share the same fold. This leads to the concept of protein designability. Some folds are more designable and lots of sequences can assume that fold. Elucidating the relationship between protein sequence and the three-dimensional (3D) structure that the sequence folds into is an important problem in computational structural biology. Lattice models have been utilized in numerous studies to model protein folds and predict the designability of certain folds. In this study, all possible compact conformations within a set of two-dimensional and 3D lattice spaces are explored. Complementary interaction graphs are then generated for each conformation and are described using a set of graph features. The full HP sequence space for each lattice model is generated and contact energies are calculated by threading each sequence onto all the possible conformations. Unique conformation giving minimum energy is identified for each sequence and the number of sequences folding to each conformation (designability) is obtained. Machine learning algorithms are used to predict the designability of each conformation. We find that the highly designable structures can be distinguished from other non-designable conformations based on certain graphical geometric features of the interactions. This finding confirms the fact that the topology of a conformation is an important determinant of the extent of its designability and suggests that the interactions themselves are important for determining the designability. PMID- 21702581 TI - Hydrodynamic screening near planar boundaries: effects on semiflexible polymer dynamics. AB - The influence of hydrodynamic screening near a surface on the dynamics of a single semiflexible polymer is studied by means of Brownian dynamics simulations and hydrodynamic mean field theory. The polymer motion is characterized in terms of the mean squared displacements of the end-monomers, the end-to-end vector, and the scalar end-to-end distance. In order to control hydrodynamic screening effects, the polymer is confined to a plane at a fixed separation from the wall. When gradually decreasing this separation, a crossover from Zimm-type towards Rouse (free-draining) polymer dynamics is induced. However, this crossover is rather slow and the free-draining limit is not completely reached--substantial deviations from Rouse-like dynamics are registered in both simulations and theory -even at distances of the polymer from the wall on the order of the monomer size. Remarkably, the effect of surface-induced screening of hydrodynamic interactions sensitively depends on the type of dynamic observable considered. For vectorial quantities such as the end-to-end vector, hydrodynamic interactions are important and therefore surface screening effects are sizeable. For a scalar quantity such as the end-to-end distance, on the other hand, hydrodynamic interactions are less important, but a pronounced dependence of dynamic scaling exponents on the persistence length to contour length ratio becomes noticeable. Our findings are discussed against the background of single-molecule experiments on f-actin [L. Le Goff et al., Phys. Rev. Lett. 89, 258101 (2002)]. PMID- 21702582 TI - Quantification of macroscopic quantum superpositions within phase space. AB - Based on phase-space structures of quantum states, we propose a novel measure to quantify macroscopic quantum superpositions. Our measure simultaneously quantifies two different kinds of essential information for a given quantum state in a harmonious manner: the degree of quantum coherence and the effective size of the physical system that involves the superposition. It enjoys remarkably good analytical and algebraic properties. It turns out to be the most general and inclusive measure ever proposed that it can be applied to any types of multipartite states and mixed states represented in phase space. PMID- 21702583 TI - Majorana fermions in equilibrium and in driven cold-atom quantum wires. AB - We introduce a new approach to create and detect Majorana fermions using optically trapped 1D fermionic atoms. In our proposed setup, two internal states of the atoms couple via an optical Raman transition-simultaneously inducing an effective spin-orbit interaction and magnetic field-while a background molecular BEC cloud generates s-wave pairing for the atoms. The resulting cold-atom quantum wire supports Majorana fermions at phase boundaries between topologically trivial and nontrivial regions, as well as "Floquet Majorana fermions" when the system is periodically driven. We analyze experimental parameters, detection schemes, and various imperfections. PMID- 21702584 TI - All nonclassical correlations can be activated into distillable entanglement. AB - We devise a protocol in which general nonclassical multipartite correlations produce a physically relevant effect, leading to the creation of bipartite entanglement. In particular, we show that the relative entropy of quantumness, which measures all nonclassical correlations among subsystems of a quantum system, is equivalent to and can be operationally interpreted as the minimum distillable entanglement generated between the system and local ancillae in our protocol. We emphasize the key role of state mixedness in maximizing nonclassicality: Mixed entangled states can be arbitrarily more nonclassical than separable and pure entangled states. PMID- 21702585 TI - Fully distrustful quantum bit commitment and coin flipping. AB - In the distrustful quantum cryptography model the parties have conflicting interests and do not trust one another. Nevertheless, they trust the quantum devices in their labs. The aim of the device-independent approach to cryptography is to do away with the latter assumption, and, consequently, significantly increase security. It is an open question whether the scope of this approach also extends to protocols in the distrustful cryptography model, thereby rendering them "fully" distrustful. In this Letter, we show that for bit commitment-one of the most basic primitives within the model-the answer is positive. We present a device-independent (imperfect) bit-commitment protocol, where Alice's and Bob's cheating probabilities are ?0.854 and 3/4, which we then use to construct a device-independent coin flipping protocol with bias ?0.336. PMID- 21702586 TI - Quantum state tomography of an itinerant squeezed microwave field. AB - We perform state tomography of an itinerant squeezed state of the microwave field prepared by a Josephson parametric amplifier (JPA). We use a second JPA as a preamplifier to improve the quantum efficiency of the field quadrature measurement from 2% to 36%+/-4%. Without correcting for the detection inefficiency we observe a minimum quadrature variance which is 68(-7)(+9)% of the variance of the vacuum. We reconstruct the state's density matrix by a maximum likelihood method and infer that the squeezed state has a minimum variance less than 40% of the vacuum, with uncertainty mostly caused by calibration systematics. PMID- 21702587 TI - Experimental state tomography of itinerant single microwave photons. AB - A wide range of experiments studying microwave photons localized in superconducting cavities have made important contributions to our understanding of the quantum properties of radiation. Propagating microwave photons, however, have so far been studied much less intensely. Here we present measurements in which we reconstruct the quantum state of itinerant single photon Fock states and their superposition with the vacuum by analyzing moments of the measured amplitude distribution up to fourth order. Using linear amplifiers and quadrature amplitude detectors, we have developed efficient methods to separate the detected single photon signal from the noise added by the amplifier. From our measurement data we have also reconstructed the corresponding Wigner function. PMID- 21702588 TI - Spin transport in a one-dimensional anisotropic Heisenberg model. AB - We analytically and numerically study spin transport in a one-dimensional Heisenberg model in linear-response regime at infinite temperature. It is shown that as the anisotropy parameter Delta is varied spin transport changes from ballistic for Delta<1 to anomalous at the isotropic point Delta=1, to diffusive for finite Delta>1, ending up as a perfect isolator in the Ising limit of infinite Delta. Using perturbation theory for large Delta a quantitative prediction is made for the dependence of diffusion constant on Delta. PMID- 21702589 TI - Collision-number statistics for transport processes. AB - Physical observables are often represented as walkers performing random displacements. When the number of collisions before leaving the explored domain is small, the diffusion approximation leads to incongruous results. In this Letter, we explicitly derive an explicit formula for the moments of the number of particle collisions in an arbitrary volume, for a broad class of transport processes. This approach is shown to generalize the celebrated Kac formula for the moments of residence times. Some applications are illustrated for bounded, unbounded and absorbing domains. PMID- 21702590 TI - Gravity Probe B: final results of a space experiment to test general relativity. AB - Gravity Probe B, launched 20 April 2004, is a space experiment testing two fundamental predictions of Einstein's theory of general relativity (GR), the geodetic and frame-dragging effects, by means of cryogenic gyroscopes in Earth orbit. Data collection started 28 August 2004 and ended 14 August 2005. Analysis of the data from all four gyroscopes results in a geodetic drift rate of 6601.8+/-18.3 mas/yr and a frame-dragging drift rate of -37.2+/-7.2 mas/yr, to be compared with the GR predictions of -6606.1 mas/yr and -39.2 mas/yr, respectively ("mas" is milliarcsecond; 1 mas=4.848*10(-9) rad). PMID- 21702591 TI - Reduced basis catalogs for gravitational wave templates. AB - We introduce a reduced basis approach as a new paradigm for modeling, representing and searching for gravitational waves. We construct waveform catalogs for nonspinning compact binary coalescences, and we find that for accuracies of 99% and 99.999% the method generates a factor of about 10-10(5) fewer templates than standard placement methods. The continuum of gravitational waves can be represented by a finite and comparatively compact basis. The method is robust under variations in the noise of detectors, implying that only a single catalog needs to be generated. PMID- 21702592 TI - A new Tolman test of a cosmic distance duality relation at 21 cm. AB - Under certain general conditions in an expanding universe, the luminosity distance (d(L)) and angular diameter distance (d(A)) are connected by the Etherington relation as d(L)=d(A)(1+z)2. The Tolman test suggests the use of objects of known surface brightness, to test this relation. In this Letter, we propose the use of a redshifted 21 cm signal from disk galaxies, where neutral hydrogen (HI) masses are seen to be almost linearly correlated with surface area, to conduct a new Tolman test. We construct simulated catalogs of galaxies, with the observed size-luminosity relation and realistic redshift evolution of HI mass functions, likely to be detected with the planned Square Kilometer Array. We demonstrate that these observations may soon provide the best implementation of the Tolman test to detect any violation of the cosmic distance duality relation. PMID- 21702593 TI - Holographic Josephson junctions. AB - We construct a gravitational dual of a Josephson junction. Calculations on the gravity side reproduce the standard relation between the current across the junction and the phase difference of the condensate. We also study the dependence of the maximum current on the temperature and size of the junction and reproduce familiar results. PMID- 21702594 TI - QCD phase diagram according to the center group. AB - We study an effective theory for QCD at finite temperature and density which contains the leading center symmetric and center symmetry breaking terms. The effective theory is studied in a flux representation where the complex phase problem is absent and the model becomes accessible to Monte Carlo techniques also at finite chemical potential. We simulate the system by using a generalized Prokof'ev-Svistunov worm algorithm and compare the results to a low temperature expansion. The phase diagram is determined as a function of temperature, chemical potential, and quark mass. The shape and quark mass dependence of the phase boundaries are as expected for QCD. The transition into the deconfined phase is smooth throughout, without any discontinuities or critical points. PMID- 21702595 TI - Model-independent calculation of radiative neutron capture on lithium-7. AB - The radiative neutron capture on lithium-7 is calculated model independently using a low-energy halo effective field theory. The cross section is expressed in terms of scattering parameters directly related to the S-matrix elements. It depends on the poorly known p-wave effective range parameter r(1). This constitutes the largest uncertainty in traditional model calculations. It is explicitly demonstrated by comparing with potential model calculations. A single parameter fit describes the low-energy data extremely well and yields r(1)~-1.47 fm(-1). PMID- 21702596 TI - In-medium similarity renormalization group for nuclei. AB - We present a new ab initio method that uses similarity renormalization group (SRG) techniques to continuously diagonalize nuclear many-body Hamiltonians. In contrast with applications of the SRG to two- and three-nucleon interactions in free space, we perform the SRG evolution "in medium" directly in the A-body system of interest. The in-medium approach has the advantage that one can approximately evolve 3,...,A-body operators using only two-body machinery based on normal-ordering techniques. The method is nonperturbative and can be tailored to problems ranging from the diagonalization of closed-shell nuclei to the construction of effective valence-shell Hamiltonians and operators. We present first results for the energies of 4He, 16O, and 40Ca, which have accuracies comparable to coupled-cluster calculations. PMID- 21702597 TI - Wigner crystals of 229Th for optical excitation of the nuclear isomer. AB - We have produced laser-cooled Wigner crystals of 229Th3+ in a linear Paul trap. The magnetic dipole (A) and electric quadrupole (B) hyperfine constants for four low-lying electronic levels and the relative isotope shifts with respect to 232Th3+ for three low-lying optical transitions are measured. Using the hyperfine B constants in conjunction with prior atomic structure calculations, a new value of the spectroscopic nuclear electric quadrupole moment Q=3.11(16) eb is deduced. These results are a step towards optical excitation of the low-lying isomer level in the 229Th nucleus. PMID- 21702598 TI - Quantum optomechanics of a Bose-Einstein antiferromagnet. AB - We investigate the cavity optomechanical properties of an antiferromagnetic Bose Einstein condensate, where the role of the mechanical element is played by spin wave excitations. We show how this system can be described by a single rotor that can be prepared deep in the quantum regime under realizable experimental conditions. This system provides a bottom-up realization of dispersive rotational optomechanics, and opens the door to the direct observation of quantum spin fluctuations. PMID- 21702599 TI - Synchronized cluster formation in coupled laser networks. AB - We experimentally investigate the phase dynamics of laser networks with homogenous time-delayed mutual coupling and establish the fundamental rules that govern their state of synchronization. We identified a specific substructure that imposes its synchronization state on the entire network and show that for any coupling configuration the network forms at most two synchronized clusters. Our results indicate that the synchronization state of the network is a nonlocal phenomenon and cannot be deduced by decomposing the network into smaller substructures, each with its individual synchronization state. PMID- 21702600 TI - Transverse electromagnetic modes in aperture waveguides containing a metamaterial with extreme anisotropy. AB - We use metamaterials with extreme anisotropy to solve the fundamental problem of light transport in deep subwavelength apertures. By filling a simply connected aperture with an anisotropic medium, we decouple the cutoff frequency and the group velocity of modes inside apertures. In the limit of extreme anisotropy, all modes become purely transverse electromagnetic modes, free from geometrical dispersion, propagate with a velocity controlled by the transverse permittivity and permeability, and have zero cutoff frequency. We analyze physically realizable cases for a circular aperture and show a metamaterial design using existing materials. PMID- 21702601 TI - Photonic band gaps in one-dimensionally ordered cold atomic vapors. AB - We experimentally investigate the Bragg reflection of light at one-dimensionally ordered atomic structures by using cold atoms trapped in a laser standing wave. By a fine-tuning of the periodicity, we reach the regime of multiple reflection due to the refractive index contrast between layers, yielding an unprecedented high reflectance efficiency of 80%. This result is explained by the occurrence of a photonic band gap in such systems, in accordance with previous predictions. PMID- 21702602 TI - Multistable attractors in a network of phase oscillators with three-body interactions. AB - Three-body interactions have been found in physics, biology, and sociology. To investigate their effect on dynamical systems, as a first step, we study numerically and theoretically a system of phase oscillators with a three-body interaction. As a result, an infinite number of multistable synchronized states appear above a critical coupling strength, while a stable incoherent state always exists for any coupling strength. Owing to the infinite multistability, the degree of synchrony in an asymptotic state can vary continuously within some range depending on the initial phase pattern. PMID- 21702603 TI - Wrinkling hierarchy in constrained thin sheets from suspended graphene to curtains. AB - We show that thin sheets under boundary confinement spontaneously generate a universal self-similar hierarchy of wrinkles. From simple geometry arguments and energy scalings, we develop a formalism based on wrinklons, the localized transition zone in the merging of two wrinkles, as building blocks of the global pattern. Contrary to the case of crumpled paper where elastic energy is focused, this transition is described as smooth in agreement with a recent numerical work [R. D. Schroll, E. Katifori, and B. Davidovitch, Phys. Rev. Lett. 106, 074301 (2011)]. This formalism is validated from hundreds of nanometers for graphene sheets to meters for ordinary curtains, which shows the universality of our description. We finally describe the effect of an external tension to the distribution of the wrinkles. PMID- 21702604 TI - Vortex stretching as a mechanism for quantum kinetic energy decay. AB - A pair of perturbed antiparallel quantum vortices, simulated using the three dimensional Gross-Pitaevskii equations, is shown to be unstable to vortex stretching. This results in kinetic energy K(?psi) being converted into interaction energy E(I) and eventually local kinetic energy depletion that is similar to energy decay in a classical fluid, even though the governing equations are Hamiltonian and energy conserving. The intermediate stages include the generation of vortex waves, their deepening, multiple reconnections, the emission of vortex rings and phonons, and the creation of an approximately -5/3 kinetic energy spectrum at high wave numbers. All of the wave generation and reconnection steps follow from interactions between the two original vortices. A four vortex example is given to demonstrate that some of these steps might be general. PMID- 21702605 TI - Magnetic control of particle injection in plasma based accelerators. AB - The use of an external transverse magnetic field to trigger and to control electron self-injection in laser- and particle-beam driven wakefield accelerators is examined analytically and through full-scale particle-in-cell simulations. A magnetic field can relax the injection threshold and can be used to control main output beam features such as charge, energy, and transverse dynamics in the ion channel associated with the plasma blowout. It is shown that this mechanism could be studied using state-of-the-art magnetic fields in next generation plasma accelerator experiments. PMID- 21702606 TI - Observation of peak neoclassical toroidal viscous force in the DIII-D tokamak. AB - Observation of a theoretically predicted peak in the neoclassical toroidal viscosity (NTV) force as a function of toroidal plasma rotation rate Omega is reported. The NTV was generated by applying n=3 magnetic fields from internal coils to low Omega plasmas produced with nearly balanced neutral beam injection. Locally, the peak corresponds to a toroidal rotation rate Omega(0) where the radial electric field E(r) is near zero as determined by radial ion force balance. PMID- 21702607 TI - Ballistic focusing of polyenergetic protons driven by petawatt laser pulses. AB - By using a thick (250 MUm) target with 350 MUm radius of curvature, the intense proton beam driven by a petawatt laser is focused at a distance of ~1 mm from the target for all detectable energies up to ~25 MeV. The thickness of the foil facilitates beam focusing as it suppresses the dynamic evolution of the beam divergence caused by peaked electron flux distribution at the target rear side. In addition, reduction in inherent beam divergence due to the target thickness relaxes the curvature requirement for short-range focusing. Energy resolved mapping of the proton beam trajectories from mesh radiographs infers the focusing and the data agree with a simple geometrical modeling based on ballistic beam propagation. PMID- 21702608 TI - First observation of edge localized modes mitigation with resonant and nonresonant magnetic perturbations in ASDEX Upgrade. AB - First experiments with nonaxisymmetric magnetic perturbations, toroidal mode number n=2, produced by newly installed in-vessel saddle coils in the ASDEX Upgrade tokamak show significant reduction of plasma energy loss and peak divertor power load associated with type-I edge localized modes (ELMs) in high confinement mode plasmas. ELM mitigation is observed above an edge density threshold and is obtained both with magnetic perturbations that are resonant and not resonant with the edge safety factor profile. Compared with unperturbed type I ELMy reference plasmas, plasmas with mitigated ELMs show similar confinement, similar plasma density, and lower tungsten impurity concentration. PMID- 21702609 TI - Measurement of the ionization state and electron temperature of plasma during the ablation stage of a wire-array Z pinch using absorption spectroscopy. AB - Wire-array plasmas were investigated in the nonradiative ablation stage via x-ray absorption spectroscopy. A laser-produced Sm plasma was used to backlight Al wire arrays. The Sm spectrum was simultaneously observed by two spectrometers: one recorded the unattenuated spectrum and the other the transmission spectrum with 1.45-1.55 keV K-shell absorption lines. Analysis of absorption spectra revealed electron temperature in the range of 10-30 eV and the presence of F-, O-, N- and C-like Al ions in the absorbing plasma. A comparison of this electron temperature with the postprocessed absorption spectra of a 2D MHD simulation yields results in general agreement with the data analysis. PMID- 21702610 TI - Ion velocity distribution function investigated inside an unstable magnetized plasma exhibiting a rotating nonlinear structure. AB - The frequent situation where a strongly nonlinear rotating structure develops in a linear magnetized plasma column is investigated experimentally with emphasis on the ion velocity distribution function (IVDF). Most often, a mode m=2 appears exhibiting a large density and potential perturbation with angular frequency slightly above the ion cyclotron frequency. For the first time the spatiotemporal evolution of the IVDF is studied using time-resolved laser induced fluorescence to explore the ion's interaction with the nonlinear wave propagating inside the column and at the origin of plasma transport outside the limiter. The ion fluid exhibits an alternance from azimuthal to radial velocity due to the electric field inside the rotating structure. A fluid model also allows us to locally reconstruct the self-consistent electric field evolution which contradicts all existing theories. PMID- 21702611 TI - Universal thermometry for quantum simulation. AB - Quantum simulation is a highly ambitious program in cold atom research currently being pursued in laboratories worldwide. The goal is to use cold atoms in optical lattices to simulate models for unsolved strongly correlated systems, so as to deduce their properties directly from experimental data. An important step in this effort is to determine the temperature of the system, which is essential for deducing all thermodynamic functions. This step, however, remains difficult for lattice systems at the moment. Here, we propose a method based on a generalized fluctuation-dissipation theorem. It does not rely on numerical simulations and gives a universal thermometry scheme for quantum gas systems including mixtures and spinor gases, provided that the local density approximation is valid. PMID- 21702612 TI - Equivalence of the boson peak in glasses to the transverse acoustic van Hove singularity in crystals. AB - We compare the atomic dynamics of the glass to that of the relevant crystal. In the spectra of inelastic scattering, the boson peak of the glass appears higher than the transverse acoustic (TA) singularity of the crystal. However, the density of states shows that they have the same number of states. Increasing pressure causes the transformation of the boson peak of the glass towards the TA singularity of the crystal. Once corrected for the difference in the elastic medium, the boson peak matches the TA singularity in energy and height. This suggests the identical nature of the two features. PMID- 21702613 TI - Energy landscape of fullerene materials: a comparison of boron to boron nitride and carbon. AB - Using the minima hopping global geometry optimization method on the density functional potential energy surface we show that the energy landscape of boron clusters is glasslike. Larger boron clusters have many structures which are lower in energy than the cages. This is in contrast to carbon and boron nitride systems which can be clearly identified as structure seekers. The differences in the potential energy landscape explain why carbon and boron nitride systems are found in nature whereas pure boron fullerenes have not been found. We thus present a methodology which can make predictions on the feasibility of the synthesis of new nanostructures. PMID- 21702614 TI - Phonon spectra, nearest neighbors, and mechanical stability of disordered colloidal clusters with attractive interactions. AB - We investigate the influence of morphology and size on the vibrational properties of disordered clusters of colloidal particles with attractive interactions. Spectral features of the vibrational modes are found to depend strongly on the average number of nearest neighbors, NN, but only weakly on the number of particles in each glassy cluster. In particular, the median phonon frequency, omega(med), is constant for NN<2 and then grows linearly with NN for NN>2. This behavior parallels concurrent observations about local isostatic structures, which are absent in clusters with NN<2 and then grow linearly in number for NN>2. Thus, cluster vibrational properties appear to be strongly connected to cluster mechanical stability, and the scaling of omega(med) with NN is reminiscent of the jamming transition. Simulations of random networks of springs corroborate observations. PMID- 21702615 TI - Mechanism of coarsening and bubble formation in high-genus nanoporous metals. AB - Coarsening of crystalline nanoporous metals involves complex changes in topology associated with the reduction of genus via both ligament pinch-off and void bubble formation. Although void bubbles in metals are often associated with vacancy agglomeration, we use large-scale kinetic Monte Carlo simulations to show that both bubble formation and ligament pinch-off are natural results of a surface-diffusion-controlled solid-state Rayleigh instability that controls changes in the topology of the porous material during coarsening. This result is used to find an effective activation energy for coarsening in nanoporous metals that is associated with the reduction of topological genus, and not the reduction of local surface roughness. PMID- 21702616 TI - Explosive percolation is continuous, but with unusual finite size behavior. AB - We study four Achlioptas-type processes with "explosive" percolation transitions. All transitions are clearly continuous, but their finite size scaling functions are not entirely holomorphic. The distributions of the order parameter, i.e., the relative size s(max)/N of the largest cluster, are double humped. But-in contrast to first-order phase transitions-the distance between the two peaks decreases with system size N as N(-eta) with eta>0. We find different positive values of beta (defined via (s(max)/N)~(p-p(c))beta for infinite systems) for each model, showing that they are all in different universality classes. In contrast, the exponent Theta (defined such that observables are homogeneous functions of (p p(c))N(Theta)) is close to-or even equal to-1/2 for all models. PMID- 21702617 TI - Tailoring the structure of water at a metal surface: a structural analysis of the water bilayer formed on an alloy template. AB - Recent studies show that structures based on the traditional "icelike" water bilayer are not stable on flat transition metal surfaces and, instead, more complex wetting layers are formed. Here we show that an ordered bilayer can be formed on a SnPt(111) alloy template and determine the structure of the water layer by low energy electron diffraction. Close agreement is found between experiment and the structure calculated by density functional theory. Corrugation of the alloy surface allows only alternate water molecules to chemisorb, stabilizing the H-down water bilayer by reducing the metal-hydrogen repulsion compared to a flat surface. PMID- 21702618 TI - Dynamical signatures of edge-state magnetism on graphene nanoribbons. AB - We investigate the edge-state magnetism of graphene nanoribbons using projective quantum Monte Carlo simulations and a self-consistent mean-field approximation of the Hubbard model. The static magnetic correlations are found to be short ranged. Nevertheless, the correlation length increases with the width of the ribbon such that already for ribbons of moderate widths we observe a strong trend towards mean-field-type ferromagnetic correlations at a zigzag edge. These correlations are accompanied by a dominant low-energy peak in the local spectral function and we propose that this can be used to detect edge-state magnetism by scanning tunneling microscopy. The dynamic spin structure factor at the edge of a ribbon exhibits an approximately linearly dispersing collective magnonlike mode at low energies that decays into Stoner modes beyond the energy scale where it merges into the particle-hole continuum. PMID- 21702619 TI - Protected nodal electron pocket from multiple-Q ordering in underdoped high temperature superconductors. AB - A multiple wave vector (Q) reconstruction of the Fermi surface is shown to yield a profoundly different electronic structure to that characteristic of single wave vector reconstruction, despite their proximity in energy. We consider the specific case in which ordering is generated by Q(x)=[2pia,0] and Q(y)=[0,2pib] (in which a=b=1/4)-similar to those identified in neutron diffraction and scanning tunneling microscopy experiments-and more generally show that an isolated pocket adjacent to the nodal point k(nodal)=[+/-pi/2,+/-pi/2] is a protected feature of such a multiple-Q model, potentially corresponding to the nodal "Fermi arcs" observed in photoemission and the small size of the electronic heat capacity found in high magnetic fields-importantly, containing electron carriers which can yield negative Hall and Seebeck coefficients observed in high magnetic fields. PMID- 21702620 TI - Hole localization in molecular crystals from hybrid density functional theory. AB - We use first-principles computational methods to examine hole trapping in organic molecular crystals. We present a computational scheme based on the tuning of the fraction of exact exchange in hybrid density functional theory to eliminate the many-electron self-interaction error. With small organic molecules, we show that this scheme gives accurate descriptions of ionization and dimer dissociation. We demonstrate that the excess hole in perfect molecular crystals forms self-trapped molecular polarons. The predicted absolute ionization potentials of both localized and delocalized holes are consistent with experimental values. PMID- 21702621 TI - Optical detection of spin transport in nonmagnetic metals. AB - We determine the dynamic magnetization induced in nonmagnetic metal wedges composed of silver, copper, and platinum by means of Brillouin light scattering microscopy. The magnetization is transferred from a ferromagnetic Ni80Fe20 layer to the metal wedge via the spin pumping effect. The spin pumping efficiency can be controlled by adding an insulating interlayer between the magnetic and nonmagnetic layer. By comparing the experimental results to a dynamical macroscopic spin-transport model we determine the transverse relaxation time of the pumped spin current which is much smaller than the longitudinal relaxation time. PMID- 21702622 TI - Phantom force induced by tunneling current: a characterization on Si(111). AB - Simultaneous measurements of tunneling current and atomic forces provide complementary atomic-scale data of the electronic and structural properties of surfaces and adsorbates. With these data, we characterize a strong impact of the tunneling current on the measured force on samples with limited conductivity. The effect is a lowering of the effective gap voltage through sample resistance which in turn lowers the electrostatic attraction, resulting in an apparently repulsive force. This effect is expected to occur on other low-conductance samples, such as adsorbed molecules, and to strongly affect Kelvin probe measurements when tunneling occurs. PMID- 21702623 TI - Electrical excitation of surface plasmons. AB - We exploit a plasmon mediated two-step momentum down-conversion scheme to convert low-energy tunneling electrons into propagating photons. Surface plasmon polaritons (SPPs) propagating along an extended gold nanowire are excited on one end by low-energy electron tunneling and are then converted to free-propagating photons at the other end. The separation of excitation and outcoupling proves that tunneling electrons excite gap plasmons that subsequently couple to propagating plasmons. Our work shows that electron tunneling provides a nonoptical, voltage-controlled, and low-energy pathway for launching SPPs in nanostructures, such as plasmonic waveguides. PMID- 21702624 TI - Hotspot decorations map plasmonic patterns with the resolution of scanning probe techniques. AB - In high definition mapping of the plasmonic patterns on the surfaces of nanostructures, the diffraction limit of light remains an important obstacle. Here we demonstrate that this diffraction limit can be completely circumvented. We show that upon illuminating nanostructures made of nickel and palladium, the resulting surface-plasmon pattern is imprinted on the structures themselves; the hotspots (regions of local field enhancement) are decorated with overgrowths, allowing for their subsequent imaging with scanning-probe techniques. The resulting resolution of plasmon pattern imaging is correspondingly improved. PMID- 21702625 TI - Retention of the tetragonal to orthorhombic structural transition in F substituted SmFeAsO: a new phase diagram for SmFeAs(O(1-x)F(x)). AB - In this Letter we propose a new phase diagram for the SmFeAs(O(1-x)F(x)) system, based on careful analysis of synchrotron powder diffraction data, SQUID, and muon spin rotation measurements. The tetragonal to orthorhombic structural transition is slightly affected by F content and is retained for the superconducting samples, even at optimal doping. These findings relate the AFM transition on a different ground with respect to the structural one and suggests that orbital ordering could be the driving force for symmetry breaking. PMID- 21702626 TI - Asymmetric Berry-phase interference patterns in a single-molecule magnet. AB - A Mn(4) single-molecule magnet displays asymmetric Berry-phase interference patterns in the transverse-field (H(T)) dependence of the magnetization tunneling probability when a longitudinal field (H(L)) is present, contrary to symmetric patterns observed for H(L)=0. Reversal of H(L) results in a reflection of the transverse-field asymmetry about H(T)=0, as expected on the basis of the time reversal invariance of the spin-orbit Hamiltonian which is responsible for the tunneling oscillations. A fascinating motion of Berry-phase minima within the transverse-field magnitude-direction phase space results from a competition between noncollinear magnetoanisotropy tensors at the two distinct Mn sites. PMID- 21702627 TI - Diffusion-induced bistability of driven nanomechanical resonators. AB - We study nanomechanical resonators with frequency fluctuations due to diffusion of absorbed particles. The diffusion depends on the vibration amplitude through inertial effect. We find that, if the diffusion coefficient D is sufficiently large, the resonator response to periodic driving displays bistability. The lifetime of the coexisting vibrational states exponentially increases with increasing D and displays a scaling dependence on the parameters close to bifurcation points. PMID- 21702628 TI - Quantum quench in the transverse-field Ising chain. AB - We consider the time evolution of observables in the transverse-field Ising chain after a sudden quench of the magnetic field. We provide exact analytical results for the asymptotic time and distance dependence of one- and two-point correlation functions of the order parameter. We employ two complementary approaches based on asymptotic evaluations of determinants and form-factor sums. We prove that the stationary value of the two-point correlation function is not thermal, but can be described by a generalized Gibbs ensemble (GGE). The approach to the stationary state can also be understood in terms of a GGE. We present a conjecture on how these results generalize to particular quenches in other integrable models. PMID- 21702629 TI - Monomer-dimer mixture on a honeycomb lattice. AB - We study a monomer-dimer mixture defined on a honeycomb lattice as a toy model for the spin-ice system in a magnetic field. In a low-doping region of monomers, the effective description of this system is given by the dual sine-Gordon model. In intermediate- and strong-doping regions, the Potts lattice gas theory can be employed. Synthesizing these results, we construct a renormalization-group flow diagram, which includes the stable and unstable fixed points corresponding to M5 and M6 in the minimal models of the conformal field theory. We perform numerical transfer-matrix calculations to determine a global phase diagram and also to proffer evidence to check our prediction. PMID- 21702630 TI - Propagation of spin information at the supramolecular scale through heteroaromatic linkers. AB - We report an in-depth study on how spin information propagates at supramolecular scale through a family of heteroaromatic linkers. By density-functional theory calculations, we rationalize the behavior of a series of Cr7Ni dimers for which we are able to systematically change the aromatic linker thus tuning the strength of the magnetic interaction, as experimentally shown by low temperature micro SQUID and specific heat measurements. We also predict a cos2 dependence of the magnetic coupling on the twisting angle between the aromatic cycles in bicyclic linkers, a mechanism parallel to charge transport on similar systems [L. Venkataraman et al., Nature (London) 442, 904 (2006)]. PMID- 21702631 TI - Skyrmions in a doped antiferromagnet. AB - Magnetization and magnetoresistance have been measured in insulating antiferromagnetic La2Cu0.97Li0.03O4 over a wide range of temperatures, magnetic fields, and field orientations. The magnetoresistance step associated with a weak ferromagnetic transition exhibits a striking nonmonotonic temperature dependence, consistent with the presence of Skyrmions. PMID- 21702632 TI - Exciton polarization, fine-structure splitting, and the asymmetry of quantum dots under uniaxial stress. AB - We derive a general relation between the fine-structure splitting (FSS) and the exciton polarization angle of self-assembled quantum dots under uniaxial stress. We show that the FSS lower bound under external stress can be predicted by the exciton polarization angle and FSS under zero stress. The critical stress can also be determined by monitoring the change in exciton polarization angle. We confirm the theory by performing atomistic pseudopotential calculations for the InAs/GaAs quantum dots. The work provides deep insight into the dot asymmetry and their optical properties and a useful guide in selecting quantum dots with the smallest FSS, which are crucial in entangled photon source applications. PMID- 21702633 TI - Phonon-mediated coupling of InGaAs/GaAs quantum-dot excitons to photonic crystal cavities. AB - We demonstrate that the emission characteristics of site-controlled InGaAs/GaAs single quantum dots embedded in photonic crystal slab cavities correspond to single confined excitons coupled to cavity modes, unlike previous reports of similar systems based on self-assembled quantum dots. By using polarization resolved photoluminescence spectroscopy at different temperatures and a theoretical model, we show that the exciton-cavity interaction range is limited to the phonon sidebands. Photon-correlation and pump-power dependence experiments under nonresonant excitation conditions further establish that the cavity is fed only by a single exciton. PMID- 21702634 TI - Connection between noise-induced symmetry breaking and an information-decoding function for intracellular networks. AB - The biological function of noise-induced symmetry breaking (NISB) is still unclear even though it may potentially occur in noisy intracellular systems. In this work, I demonstrate that information decoding from a noisy signal is a potential biological function of NISB by revealing that NISB naturally emerges from an optimal information-decoding dynamics and that several intracellular networks can be identified with the information-decoding dynamics. I also propose a mean first passage time profile as a way to experimentally identify NISB. PMID- 21702635 TI - Subdiffusion of a sticky particle on a surface. AB - Conventional diffusion (DeltaR2(t))=2Dt gives way to subdiffusion (DeltaR2(t))~t(MU), 02 h television/day (OR: 1.57; 95% CI: 1.15-2.14), not eating breakfast daily (OR: 2.86; 95% CI: 1.93-4.23), drinking >3 glasses/day sugared drinks (OR: 1.23; 95% CI: 1.01-1.50) on weekdays and not participating in organized sports (OR: 1.32; 95% CI: 1.09-1.59). This odds was however lower among children eating <2 fruit/day (OR: 0.83; 95% CI: 0.69-1.00) on weekends. The association between neighbourhood and overweight altered slightly after adjustment for socio-demographic and behavioural characteristics during weekdays (OR: 1.42; 95% CI: 1.05-1.92) and weekends (OR: 1.50; 95% CI; 1.11-2.02). CONCLUSION: Three neighbourhoods with higher prevalence of overweight were identified. A small part of the association between overweight and neighbourhood is explained by socio-demographic factors and unhealthy behaviours measured in this study. Neighbourhoods with higher overweight prevalence are a priority setting for targeted interventions to prevent overweight. The association between neighbourhood and overweight needs to be explored further to understand the role the neighbourhood can play in tackling overweight. PMID- 21702714 TI - Inhaled muscarinic antagonists for respiratory diseases: a review of patents and current developments (2006 - 2010). AB - INTRODUCTION: Because tiotropium has demonstrated clinical benefits as a long term maintenance treatment for chronic obstructive pulmonary disease (COPD), the number of patent applications of new chemical entities with antimuscarinic activity has significantly increased, along with the number of compounds that have reached clinical development. AREAS COVERED: This review summarizes the current status of long-acting muscarinic antagonists (LAMA) in clinical development for COPD, and the associated patent literature since 2006, with a focus on new chemical entities. EXPERT OPINION: In recent years, companies have taken different approaches to obtain compounds with high potency, long duration of action and minimal systemic exposure. Several strategies for minimizing adverse effects due to systemic exposure have been identified (quaternization, higher rate of plasma hydrolysis and degradation, increased plasma protein binding). The beneficial effects beyond bronchodilation that may be provided in the treatment of COPD patients with a LAMA, and the advantages of combination therapies, such as LAMA + LABA and LAMA + corticosteroids, have also been taken into account in recent studies. PMID- 21702716 TI - The mTOR protein as a target in thyroid cancer. AB - INTRODUCTION: The mammalian target of rapamycin (mTOR) protein is a downstream effector of the phosphatidilinositol-3 kinase (PI3K)/Akt pathway, which regulates not only cell proliferation and viability, but also iodide uptake in thyroid cells. Genetic alterations in the PI3K/Akt/mTOR pathway are common during thyroid cancer progression, and thus, these proteins are attractive targets for cancer therapy. So far, specific mTOR inhibitors, such as rapamycin analogs, have been developed and studied as anti-cancer agents. AREAS COVERED: This review discusses evidence that justifies the potential use of mTOR signaling pathway inhibitors as therapeutic agents for thyroid cancer. EXPERT OPINION: In the near future, mTOR targeted drugs might represent a new approach for the therapy of thyroid cancer patients; rapamycin analogs have already been developed and are currently being clinically tested. Besides the antiproliferative action of mTOR inhibition, the stimulatory effect on thyroid iodide uptake can also be useful in the treatment of recurrent thyroid cancer. Therefore, if rapamycin analogs are able to increase iodide uptake in thyroid cancer, either alone or in combination with other agents, this will represent a new approach for the treatment of thyroid cancer, which may possibly improve the treatment of patients in which radioiodine therapy is not effective. PMID- 21702715 TI - Farnesyl pyrophosphate synthase modulators: a patent review (2006 - 2010). AB - INTRODUCTION: Farnesyl pyrophosphate synthase (FPPS, also known as farnesyl diphosphate synthase (FDPS)) is one of the key enzymes involved in the mevalonate pathway and as such is widely expressed. FPPS modulators, specifically FPPS inhibitors, are useful in treating a number of diseases, including bone-related disorders characterized by excessive bone resorption, for example, osteoporosis, cancer metathesis to bone and infectious diseases caused by certain parasites. AREAS COVERED: This review covers structures and applications of novel FPPS modulators described in the patent literature from 2006 to 2010. Patents disclosing new formulations and uses of existing FPPS inhibitors are also reviewed. Thirty-three patents retrieved from the USPTO, EP and WIPO databases are examined with the goal of defining current trends in drug discovery related to FPPS inhibition, and its therapeutic effects. EXPERT OPINION: Bisphosphonates (BPs) continue to dominate in this area, although other types of modulators are making their appearance. Remarkable for their high bone mineral affinity, BPs are structural mimics of the dimethylallyl pyrophosphate substrate of FPPS, and constitute the major type of FPPS inhibitor currently used in the clinic for treatment of bone-related diseases. Lipophilic BPs and new classes of non-BP FPPS inhibitors (salicylic acid and quinoline derivatives) have been introduced as possible alternatives for treatment of soft tissue diseases, such as some cancers. Novel formulations, fluorescent diagnostic probes and new therapeutic applications of existing FPPS inhibitors are also areas of significant patent activity, demonstrating growing recognition of the versatility and underdeveloped potential of these drugs. PMID- 21702717 TI - Rational combinations of enzastaurin with novel targeted agents for patients with B-cell non-Hodgkin's lymphoma. PMID- 21702718 TI - Divergent activities of osteogenic BMP2, and tenogenic BMP12 and BMP13 independent of receptor binding affinities. AB - Ectopic expression of recombinant human bone morphogenetic protein 2 (rhBMP2) induces osteogenesis, while ectopic expression of rhBMP12 and rhBMP13 induces the formation of tendon-like tissue. Despite their different in vivo activities, all three ligands bound to the type I bone morphogenic protein receptors (BMPRs), activin receptor-like kinase (ALK)-3 and ALK6, and to the type II BMPRs, activin receptor type-2A, activin receptor type-2B, and BMPR2, with similar affinities. Treatment of C3H10T1/2 cells with rhBMP2 activated SMAD signaling and induced expression of osteoblast markers including osteocalcin mRNA (Ocn). In contrast, treatment with rhBMP12 or rhBMP13 resulted in a dose-dependent induction of a tendon-specific gene (Thbs4) expression with no detectable activation of SMAD 1, 5, and 8. Differential regulation of Thbs4 and Ocn has potential utility as an in vitro biomarker for induction of tenogenic signaling. Such an assay also permits the ability to distinguish between the activities of different BMPs and may prove useful in studies on the molecular mechanisms of BMP tenogenic activity. PMID- 21702719 TI - Induced elastic matrix deposition within three-dimensional collagen scaffolds. AB - The structural stability of a cyclically distending elastic artery and the healthy functioning of vascular smooth muscle cells (SMCs) within are maintained by the presence of an intact elastic matrix and its principal protein, elastin. The accelerated degradation of the elastic matrix, which occurs in several vascular diseases, coupled with the poor ability of adult SMCs to regenerate lost elastin, can therefore adversely impact vascular homeostasis. Similarly, efforts to tissue engineer elastic matrix structures are constrained by our inability to induce adult cells to synthesize tropoelastin precursors and to crosslink them into architectural mimics of native elastic matrices, especially within engineered constructs where SMCs/fibroblasts primarily deposit collagen in abundance. In this study, we have shown that transforming growth factor-beta1 (TGF-beta1) and hyaluronan oligomers (HA-o) synergistically enhance elastic matrix deposition by adult rat aortic SMCs (RASMCs) seeded within nonelastogenic, statically loaded three-dimensional gels, composed of nonelastogenic type-I collagen. While there was no substantial increase in production of tropoelastin within experimental cases compared to the nonadditive control cultures over 3 weeks, we observed significant increases in matrix elastin deposition; soluble matrix elastin in constructs that received the lowest doses of TGF-beta1 with respective doses of HA-o, and insoluble matrix at the highest doses that corresponded with elevated lysyl-oxidase protein quantities. However, despite elastogenic induction, overall matrix yields remained poor in all experimental cases. At all provided doses, the factors reduced the production of matrix metalloproteinases (MMP)-9, especially the active enzyme, though MMP-2 levels were lowered only in constructs cultured with the higher doses of TGF-beta1. Immuno-fluorescence showed elastic fibers within the collagen constructs to be discontinuous, except at the edges of the constructs. Von Kossa staining revealed no calcific deposits in any of the cases. This study confirms the benefits of utilizing TGF-beta1 and HA-o in inducing matrix elastin synthesis by adult RASMCs over nonadditive controls, within a collagenous environment, that is not inherently conducive to elastogenesis. PMID- 21702721 TI - Going paperless: implementing an electronic laboratory notebook in a bioanalytical laboratory. AB - AIT Bioscience, a bioanalytical CRO, implemented a highly configurable, Oracle based electronic laboratory notebook (ELN) from IDBS called E-WorkBook Suite (EWBS). This ELN provides a high degree of connectivity with other databases, including Watson LIMS. Significant planning and training, along with considerable design effort and template validation for dozens of laboratory workflows were required prior to EWBS being viable for either R&D or regulated work. Once implemented, EWBS greatly reduced the need for traditional quality review upon experiment completion. Numerous real-time error checks occur automatically when conducting EWBS experiments, preventing the majority of laboratory errors by pointing them out while there is still time to correct any issues. Auditing and reviewing EWBS data are very efficient, because all data are forever securely (and even remotely) accessible, provided a reviewer has appropriate credentials. Use of EWBS significantly increases both data quality and laboratory efficiency. PMID- 21702720 TI - Targeting human inducible regulatory T cells (Tr1) in patients with cancer: blocking of adenosine-prostaglandin E2 cooperation. AB - INTRODUCTION: Emerging data suggest that human inducible regulatory T cells (Tr1) produce adenosine and prostaglandin E(2) and that these factors cooperate in mediating immune suppression. AREAS COVERED: Human Tr1 present in human tumors or blood of cancer patients express ectonucleotidases, CD39 and/or CD73, hydrolyze ATP to adenosine and are COX-2 positive. Expression of CD39 and/or CD73 on human tumors favors expansion and suppressor functions of Tr1. Adenosine and PGE(2) signal via adenosine 2A receptor (A(2A)R) and prostaglandin E(2) receptor 2 (EP(2)R) expressed on effector T (Teff) cells, suppressing their anti-tumor functions by a common mechanism involving upregulation of cytosolic cAMP levels and protein kinase A (PKA) type I activation. The frequency and activity of circulating CD4(+)CD39(+) and CD4(+)COX-2(+) Treg subsets increase in advanced disease and also following oncologic therapies. EXPERT OPINION: Pharmacologic blocking of adenosine-PGE(2) collaboration provides a clinically-feasible strategy for disarming of Treg. Used in conjunction with conventional anti-cancer drugs or immune interventions, pharmacologic inhibitors could improve outcome of oncologic therapies. PMID- 21702722 TI - Using E-WorkBook Suite to implement quality control in real time: expanding the role of electronic laboratory notebooks within a bioanalysis laboratory. AB - In order to support the increasing number of software tools within the bioanalytical (BA) laboratory, electronic laboratory notebooks (ELNs) have to provide more than just paper replacement capabilities. ELN solutions must provide additional functionality to justify deployment in BA laboratories that currently depend on sophisticated instrument software and laboratory information management systems for the capture, analysis and reporting of data. This article reviews how E-WorkBook Suite is positioned to provide functionality not found in other ELN solutions, namely managing workflow execution and tracking quality control compliance in real time. These capabilities are demonstrated by descriptions of a routine BA laboratory process; the registration of a test article, its use in preparing a stock solution and the verification of a balance instrument for weighing the test article. The software solution, in this configuration, guides the analyst through the process and enforces business rules that ensure compliance with specified SOP guidelines. This case study reviews the implementation in a bioanalytical CRO and highlights the use of E-WorkBook Suite in areas that remain unsupported by other software solutions. PMID- 21702724 TI - Sustained informal care: the feasibility, construct validity and test-retest reliability of the CarerQol-instrument to measure the impact of informal care in long-term care. AB - OBJECTIVES: This study analyses feasibility, construct validity and test-retest reliability of the Care-related Quality of Life (CarerQol)-instrument among informal caregivers of long-term care (LTC) users. The CarerQol measures the impact of informal care by assessing happiness (CarerQol-VAS) and describing burden dimensions (CarerQol-7D). METHODS: Data was gathered among informal caregivers of patients obtaining day care or living in a LTC facility in the Netherlands with two questionnaires sent with a two-week interval (n test = 108, n retest = 100). Percentages of missing values indicated feasibility of the CarerQol. Construct validity assessed the extent to which differences in background characteristics were reflected in happiness scores (CarerQol-VAS) with univariate and multivariate statistics. Additionally, construct validity was tested with assessing the correlation between the CarerQol and the Self-Rated Burden (SRB) scale. Percentages of complete agreement between CarerQol scores at test and retest, Cohen's kappa coefficients (kappa value) and Intraclass Correlation Coefficients (ICCs) were used to assess reliability. RESULTS: In this study, 3.7% was missing on the CarerQol. CarerQol-VAS was positively associated with caregivers' age and health, and negatively with SRB score. The percentage of complete agreement of CarerQol-VAS between the measure moments was 60% and between 76% and 96% for CarerQol-7D. kappa value and ICC of CarerQol-VAS were 0.52 and 0.86, and ranged between 0.55 and 0.94 for CarerQol-7D. CONCLUSION: The CarerQol measures the impact of informal care among carers of LTC users in a feasible, valid and reliable way. PMID- 21702723 TI - Innovations in research for treatment of late-life anxiety. AB - OBJECTIVES: While psychosocial interventions for late-life anxiety show positive outcomes, treatment effects are not as robust as in younger adults. To date, the reach of research has been limited to academic and primary care settings, with homogeneous samples. This review examines recently funded and ongoing late-life anxiety research that uses innovative approaches to reach unique patient populations and tailor treatment content and delivery options to meet the unique needs of older adults. METHOD: A systematic search was conducted using electronic databases of funded clinical trials to identify ongoing psychosocial intervention studies targeting older adults with anxiety. The principal investigators (PIs) of the studies were contacted for study details and preliminary data, if available. In some cases, the PIs of identified studies acted as referral sources in identifying additional studies. RESULTS: Eleven studies met inclusion criteria and represented three areas of innovation: new patient groups, novel treatment procedures, and new treatment-delivery options. Studies and their associated theoretical bases are discussed, along with preliminary results reported in published papers or conference presentations. CONCLUSION: Psychosocial intervention trials currently in progress represent promising new strategies to facilitate engagement and improve outcomes among unique subsets of older adults with anxiety. Continued investigation of evidence-based treatments for geriatric anxiety will allow greater understanding of how best to tailor the interventions to fit the needs of older adults. PMID- 21702725 TI - Quality of sleep and day-time sleepiness in chronic hemodialysis: a study of 400 patients. AB - OBJECTIVE: Impaired sleep has potential health consequences in chronic hemodialysis patients. To date, this issue has not been examined in studies involving a large number of subjects. This study aimed to identify factors associated with poor sleep quality and excessive day-time sleepiness (EDS) in dialysis patients. MATERIAL AND METHODS: This cross-sectional observational study involved 400 patients (59% male) from three hemodialysis centers (SD-HEMOFOR). Quality of sleep was evaluated by the Pittsburgh Sleep Quality Index (PSQI), EDS by the Epworth Sleepiness Scale (ESS), risk of obstructive sleep apnea (OSA) by the Berlin questionnaire and comorbidity severity by the Charlson Comorbidity Index (CCI). RESULTS: Poor sleep quality (PSQI >5) was found in 227 individuals (57%) and was associated with older age (p = 0.001), diabetes (p = 0.03), heart failure (p < 0.005), hypoalbuminemia (p = 0.01), low transferrin saturation (TSAT) (p = 0.009), higher CCI score (p = 0.01) and depression (p < 0.005). Independent factors were older age, heart failure, low TSAT and depressive symptoms. Day-time somnolence was present in 108 patients (27%) and was independently associated with stroke [odds ratio (OR) = 2.84, CI 1.03-7.76), lower hemoglobin concentration (OR = 2.45, CI 0.95-3.03) and high risk of OSA (OR = 1.65, CI 1.03-2.63). High risk of OSA (n = 120; 30%), was associated with hypertension (p < 0.001), overweight/obesity (p = 0.001), older age (p = 0.003) and symptoms of depression (p = 0.01). CONCLUSIONS: Poor sleep quality and EDS were prevalent on chronic hemodialysis. Heart failure, low TSAT and depressive symptoms were independently associated with poor sleep quality. Stroke, anemia and high risk of OSA were independently associated with EDS. These results provide new insight into possible treatment strategies. PMID- 21702726 TI - A longitudinal investigation of the predictability of the three-factor model of the Important People Inventory. AB - OBJECTIVE: Because of psychometric limitations and varied adaptations of the Important People Inventory (IP; a measure of alcohol social support), Groh et al. (7) performed factor analyses and created a three-factor model (i.e., Support for Drinking from Network Members, Drinking Behaviors of Network Members, and General Social Support). This present study examined the ability of the three-factor model to predict alcohol use. METHODS: This study consisted of 293 women and 604 men who were US residents of a network of self-run recovery homes known as Oxford House (OH). Logistic regression models were run. The first model examined which of the three IP factors was the best predictor of alcohol use over a 4-month period; next, models compared Drinking Behaviors of Network Members (the three factor model) and Network Support for Drinking from Network Members (the original two-factor model) as predictors of 4-month alcohol use. RESULTS: Of the three factors measuring general support, network drinking behaviors, and support for drinking, Drinking Behaviors of Network Members was the only significant predictor of alcohol use over a 4-month period. Additionally, this component was a better predictor of drinking than the Support for Drinking from Network Members summary score from the original model. CONCLUSIONS: Compared to the original model, this new three-factor model of the IP is shorter, has stronger internal reliability, and is a better predictor of alcohol use over time. It is strongly recommended that researchers continue to explore the utility of this new model. PMID- 21702727 TI - Reasons for psychiatric medication prescription for new nursing home residents. AB - OBJECTIVES: This article focuses on justification of psychoactive medication prescription for NH residents during their first three months post-admission. METHOD: We extracted data from 73 charts drawn from a convenience sample of individuals who were residents of seven nursing homes (NHs) for at least three months during 2009. Six focus groups with NH staff were conducted to explore rationales for psychoactive medication usage. RESULTS: Eighty-nine percent of the residents who received psychoactive medications during the first three months of residence had a psychiatric diagnosis, and all residents who received psychoactive medications had a written physician's order. Mental status was monitored by staff, and psychoactive medications were titrated based on changes in mental status. One concern was that no Level II Preadmission Screening and Annual Resident Review (PASRR) evaluations were completed during the admissions process. Further, while 73% had mental health diagnoses at admission, 85% of the NH residents were on a psychoactive medication three months after admission, and 19% were on four or more psychoactive medications. Although over half of the residents had notes in their charts regarding non-psychopharmacological strategies to address problem behaviors, their number was eclipsed by the number receiving psychopharmacological treatment. CONCLUSIONS: While the results suggest that NHs may be providing more mental health care than in the past, psychopharmacological treatment remains the dominant approach, perhaps because of limited mental health training of staff, and lack of diagnostic precision due to few trained geriatric mental health professionals. A critical review of the role of the PASRR process is suggested. PMID- 21702728 TI - Peritoneal dialysis in transplant recipient patients: outcomes and management. AB - Transplant recipient patients performing dialysis represent a growing population in the integrated model of renal replacement therapy. This includes both patients with kidney allograft loss and non-renal organ transplant recipients requiring dialysis. Although a number of possible advantages of peritoneal dialysis over haemodialysis could hypothetically favour its choice when starting dialysis, peritoneal dialysis penetration is relatively residual in this population. Questions about its safety and adequacy in these patients can explain this fact. The purpose of this review is to address unfounded fears and document evidence that peritoneal dialysis should be considered a viable and safe choice in patients returning to dialysis. Specific issues that still need further investigation are also discussed. PMID- 21702729 TI - Modeling of latent structure of indomethacin solid dispersion tablet using Bayesian networks. AB - BACKGROUND: When designing pharmaceutical products, the relationships between causal factors and pharmaceutical responses are intricate. A Bayesian network (BN) was used to clarify the latent structure underlying the causal factors and pharmaceutical responses of a tablet containing solid dispersion (SD) of indomethacin (IMC). METHOD: IMC, a poorly water-soluble drug, was tested with polyvinylpyrrolidone as the carrier polymer. Tablets containing a SD or a physical mixture of IMC, different quantities of magnesium stearate, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose, and subjected to different compression force were selected as the causal factors. The pharmaceutical responses were the dissolution properties and tensile strength before and after the accelerated test and a similarity factor, which was used as an index of the storage stability. RESULT: BN models were constructed based on three measurement criteria for the appropriateness of the graph structure. Of these, the BN model based on Akaike's information criterion was similar to the results for the analysis of variance. To quantitatively estimate the causal relationships underlying the latent structure in this system, conditional probability distributions were inferred from the BN model. The responses were accurately predicted using the BN model, as reflected in the high correlation coefficients in a leave-one-out cross-validation procedure. CONCLUSION: The BN technique provides a better understanding of the latent structure underlying causal factors and responses. PMID- 21702730 TI - Treatment of unstable distal radius fractures with the volar locking plate. AB - BACKGROUND: Open reduction and internal fixation using an interlocking plate system has gained popularity for the treatment of dorsally displaced distal radius fractures. PURPOSE: To evaluate the functional and radiological results of treating unstable distal radius fractures with the volar locking plate. PATIENTS AND METHODS: A retrospective review was conducted of patients from one institution using the volar locking plate to treat intra-articular and extra articular distal radius fractures. Unstable distal radius fractures in 15 patients, comprising 3 men and 12 women with a mean age of 64.4 years (34-76 years), were treated with a volar locking compression plate (Acu-Loc distal radius plate system; Acumed, Oregon, USA) and followed up for a minimum of 1 year. Fractures were classified using the AO classification. Radiographic parameters of preoperative, postoperative, and final follow-up radiographs were compared. The time to initiation of active range of motion was determined. Final follow-up range of motion and complications were reported. RESULTS: At final functional assessment, the scores of 5 patients were excellent, 7 patients good, and 3 patients fair according to Cooney's Clinical Scoring Chart. No non-union or infection occurred. Rupture of the flexor pollicis longus tendon occurred in 1 patient. CONCLUSION: Treatment of unstable distal radius fractures with a volar locking plate leads to satisfactory results, provided the operative technique is carefully performed to prevent complications. PMID- 21702731 TI - Delivery of cefotaxime to the brain via intranasal administration. AB - The purpose of this study was to investigate the plausibility of delivery of cefotaxime to the brain via intranasal administration. In vitro permeation studies were carried out using Franz diffusion cells, and the effect of different concentrations of chitosan (0.1% w/v and 0.25% w/v) on drug permeation across the bovine olfactory mucosa was determined. Samples were collected from the receiver compartment at different time points and analyzed using HPLC. The amount of cefotaxime that permeated across the olfactory mucosa when 0.25% w/v of chitosan was used as a permeation enhancer was ~1.5- and ~2-fold higher at the end of the first hour and second hour, respectively, over control (29.56 +/- 6.18 ug/cm(2)). There was no significant enhancement in drug permeation when 0.1% w/v chitosan was used as the permeation enhancer. Pharmacokinetic studies were carried out using Sprague-Dawley rats. Cefotaxime solution with 0.25% w/v chitosan (40 mg/kg) was administered intravenously (i.v.) to rats in groups 1 and 3 and intranasally to those in group 2 and 4. The time course of drug in the brain was investigated by performing microdialysis in rats of groups 1 and 2. Blood samples were withdrawn from rats in groups 3 and 4, and cefotaxime in plasma was analyzed using HPLC after extraction with a hydrochloric acid-chloroform:1-pentanol (3:1) and phosphate buffer solvent system. Pharmacokinetic parameters were calculated using the trapezoidal rule. The results imply that the drug levels attained in the brain following i.v. and intranasal administrations were comparable. These results suggest that intranasal administration of cefotaxime could be a potential method of delivering antibacterial agents because of it being noninvasive and patient compliant. PMID- 21702732 TI - Development and evaluation of intestinal targeted mucoadhesive microspheres of Bacillus coagulans. AB - BACKGROUND: Intestinal targeted mucoadhesive microsphere of probiotics may provide numerous associated health benefits. AIM: To develop mucoadhesive microspheres that will deliver viable probiotic cells into gut protectively against harsh environmental conditions of stomach for extended period. MATERIALS AND METHODS: Core mucoadhesive microspheres of Bacillus coagulans were prepared using hypromellose, following coacervation and phase separation technique and were then coated with hypromellose phthalate to achieve their site-specific release. Microspheres were evaluated for percent yield, entrapment efficiency, surface morphology, particle size and size distribution, flow property, swelling property, mucoadhesion property by the in vitro wash-off and the ex vivo mucoadhesive strength tests, in vitro release profile and release kinetic, in vivo probiotic activity, and stability. The values for kinetic constant and regression coefficient of model-dependent approaches and the difference factor, the similarity factor, and the Rescigno index of model-independent approaches were determined for accessing and comparing in vitro performance. RESULTS: Microsphere formulation batches have percent yield value between 56.26% and 69.13% and entrapment efficiency value between 66.95% and 77.89%. Microspheres were coarser with spherical shape having mean particle size from 28.03 to 48.31 MUm. In vitro B. coagulans release profile follows zero-order kinetics and depends on the grade of hypromellose and the B. coagulans-to-hypromellose ratio. Experimental microspheres rendered adequate stability to B. coagulans at room temperature. CONCLUSION: Microspheres had delivered B. coagulans in simulated intestinal condition following zero-order kinetics, protectively in simulated gastric condition, exhibiting appreciable mucoadhesion in intestinal condition, which could be useful to achieve site-specific delivery for extended period. PMID- 21702733 TI - Keeping up with genetic discoveries in amyotrophic lateral sclerosis: the ALSoD and ALSGene databases. AB - Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous disorder that shows a characteristic dichotomy of familial forms typically displaying Mendelian inheritance patterns, and sporadic ALS showing no or less obvious familial aggregation. While the former is caused by rare, highly penetrant, and pathogenic mutations, risk for sporadic ALS is probably the result of the combined effects of common polymorphisms with minor to moderate effect sizes. Owing to recent advances in high-throughput genotyping and sequencing technologies, genetic research in both fields is evolving at a rapidly increasing pace making it more and more difficult to follow and evaluate the most significant progress in the field. To alleviate this problem, our groups have created dedicated and freely available online databases, ALSoD ( http://alsod.iop.kcl.ac.uk/ ) and ALSGene ( http://www.alsgene.org ), which provide systematic and in-depth qualitative and quantitative overviews of genetic research in both familial and sporadic ALS. This review briefly introduces the background and main features of both databases and provides an overview of the currently most compelling genetic findings in ALS derived from analyses using these resources. PMID- 21702735 TI - Isolated bulbar phenotype of amyotrophic lateral sclerosis. AB - Typical bulbar-onset ALS generally portends a poor prognosis. To determine whether a relatively isolated bulbar phenotype (IBP) may have a better prognosis, patients with bulbar onset presentations were prospectively assessed, with IBP defined by an absence of limb progression over an initial six-month period. Clinical features and neurophysiological characteristics were compared. From a cohort of 300 consecutive referrals, 32 patients with bulbar onset disease (21 females, 11 males) were identified and compared to 23 age-matched control subjects. In total, patients were followed for 54 months. Twelve patients were identified with IBP (nine female, three male) and 20 had more typical bulbar ALS (12 female, eight male). Clinically, IBP was characterized by greater female predominance and upper motor neuron bulbar involvement. Compound motor action potential amplitudes were preserved in IBP compared to bulbar ALS (IBP, 7.1 mV; bulbar ALS, 4.2 mV, p <0.05), as was the neurophysiological index (IBP, 1.2; bulbar ALS 0.5, p <0.05). Furthermore, short interval intracortical inhibition was normal in IBP and reduced in typical bulbar ALS. In conclusion, patients with IBP were typically female with prominent upper motor neuron bulbar features and had normal cortical excitability. Biomarkers of cortical excitability may prove useful for further classifying ALS. PMID- 21702734 TI - Uncovering amyotrophic lateral sclerosis phenotypes: clinical features and long term follow-up of upper motor neuron-dominant ALS. AB - The aim of our study was to analyse the natural history and clinical features of upper motor neuron- dominant (UMN-D) ALS. We studied a large series of sporadic ALS patients admitted in a single referral centre over a 23-year period. UMN-D phenotype was compared with other ALS forms, including classic ALS, flail arm and progressive muscular atrophy. Seven hundred and thirty-four sporadic ALS patients were included of which 163 had UMN-D ALS. The mean age of onset in UMN-D ALS (52 years) was 10 years lower than in classic ALS (61.4 years, p < 0.0001); sex ratio by age groups significantly differed with respect to other phenotypes. The pattern of spread of lower motor neuron signs in UMN-D was characterized by early involvement of upper limb muscles and late impairment of respiratory muscles. Duration of the disease was longer in the UMN-D group (56 months) than in classic ALS (33 months, p < 0.001). The UMN-D phenotype was a strong independent predictor of long survival. In summary, UMN-D ALS showed significant differences in age of onset, sex ratio, pattern of spreading and prognosis with respect to other ALS forms, most probably reflecting biological differences. PMID- 21702738 TI - How to deal with a crying patient? A study from a primary care setting in Croatia, using the 'critical incident technique'. AB - BACKGROUND: Expression of strong emotions by patients is not a rare event in medical practice, however, there are few studies describing general practitioner (GP) communication with a crying patient. OBJECTIVE: The aim of this study was to describe GP behaviour with a patient who cries in a family practice setting. METHODS: A semi-qualitative study was conducted on 127 Croatian GP trainees, 83.5% female, and 16.5% male. The study method used was the 'critical incident technique.' GP trainees described their recent experience with patients who cried in front of them. Textual data were explored inductively using content analysis to generate categories and explanations. RESULTS: All 127 (100.0%) GP trainees initially let patients cry, giving them verbal (81.9%) and/or nonverbal support (25.9%). GP trainees (69.3%) encouraged their patients to verbalize and to describe the problem. Most GP trainees (87.4%) tried to establish mutual problem understanding. Approximately half of the GP trainees (55.1%) made a joint management plan. A minor group (14.2%) tried to maintain contact with the patient by arranging follow-up appointments. The vast majority of GP trainees shared their patient's emotion of sadness (92.9%). Some GP trainees were caught unaware or unprepared for patient's crying and reacted awkwardly (4.7%), some were indifferent (3.9%) or even felt guilty (3.1%). CONCLUSION: GP trainees' patterns of communication with crying patients can be described in five steps: (a) let the patient cry; (b) verbalization of emotions and facilitation to express the problem; (c) mutual understanding and solution finding; (d) evaluation- maintaining contact; and (e) personal experience of great emotional effort. PMID- 21702736 TI - ALSUntangled No. 11: Nu Tech Mediworld. PMID- 21702739 TI - A strategy for reducing particulate contamination on opening glass ampoules and development of evaluation methods for its application. AB - A single-dose glass ampoule was developed for ease of administration. When glass ampoules are opened, resulting in contamination by particulate matter. Reducing its contamination may minimize the risk in patients due to particulates. This study reports on an attempt to reduce insoluble particulate contamination by developing methods for the precise measurement of this. A vacuum machine (VM) was used to reduce the level of insoluble particulate contamination, and a microscopy, scanning electron microscopy-energy dispersive X-ray spectrometer (SEM-EDS) and inductively coupled plasma-atomic emission spectrometer (ICP-AES) were used to evaluate the level of reduction. The method permitted the insoluble particle content to be reduced by up to 87.8 and 89.3% after opening 1 and 2 mL ampoules, respectively. The morphology of the glass particulate contaminants was very sharp and rough, a condition that can be harmful to human health. The total weight of glass particles in the opened ampoules was determined to be 104 +/- 72.9 MUg and 30.5 +/- 1.00 MUg after opening 1 and 2 mL-ampoules when the VM was operated at highest power. The total weights were reduced to 53.6 and 50.6%, respectively for 1 and 2 mL-ampoules, compared to opening by hand. The loss of ampoule contents on opening by the VM was 6.50 and 4.67% for 1 and 2 mL-ampoules, respectively. As a result, the VM efficiently reduced glass particulate contamination and the evaluation methods used were appropriate for quantifying these levels of contamination. PMID- 21702740 TI - Mupirocin calcium microencapsulation via spray drying: feed solvent influence on microparticle properties, stability and antimicrobial activity. AB - OBJECTIVES: The aim of this research was to design a controlled release, spray dried, mupirocin calcium-loaded microparticles (MP) with acrylic polymer and assess the influence of a feed solvent at preselected drug:polymer proportions (1:5 and 2:1 (w/w)) on the performance and stability of the prepared MP. METHODS: Physicochemical properties of MP were assessed using modulated differential scanning calorimetry (MDSC), and thermogravimetric analyses (TGA), Fourier transformed infrared spectroscopy (FTIR) and X-ray analyses and were correlated with drug release. Morphology and particle size were determined using low-angle laser light scattering and a scanning electron microscope. A time-kill assay was conducted on two strains of Staphylococcus aureus to evaluate the antimicrobial activity of MP. RESULTS AND DISCUSSION: The MP formed solid dispersions without apparent drug crystallization. Drug-polymer miscibility, morphology, drug release and consequently antimicrobial activity were dependent on drug loading (DL) and the used solvent. The superior control of drug release from MP was achieved for the higher DL (2:1 (w/w) drug:polymer proportion) using solvents in the following order: methanol ~ methanol:ethanol (50:50, w/w) > isopropanol:acetone (40:60, w/w). Moreover, a time-kill assay performed on S. aureus (ATCC 29213) and methicillin-resistant S. aureus strains confirmed the prolonged release and preservation of antimicrobial activity of the microencapsulated drug. The physical aging of the solid dispersion after 10 months of storage had negligible impact on the MP performance. CONCLUSIONS: Acrylic-based MP were confirmed as suitable microcarriers for prolonged drug release using a well-established spray drying technique, while solvent influence was strongly related to the DL employed. PMID- 21702741 TI - Integrating health literacy into occupational therapy: findings from a scoping review. AB - This paper aims to report ways of integrating health literacy into occupational therapy practice. Health literacy is defined as the ability to access, understand, evaluate, and communicate information as a way to promote, maintain, and improve health in various settings over the life-course. A scoping study of the scientific and grey literature on health and, specifically, occupational therapy and health promotion was done from 1980 to May 2010. Five databases were searched by combining key words (i) "health literacy" with (ii) "rehabilitation", "occupational therapy", or "health promotion". Data were extracted from 44 documents: five textbooks, nine reports, and 29 articles. The literature on health literacy needs enhancing in both quantity and quality. Nevertheless, six ways of integrating health literacy into occupational therapy practice were identified (frequency; %): occupational therapists should (i) be informed about and recognize health literacy (27; 61.4), (ii) standardize their practice (10; 22.7), (iii) make information accessible (37; 84.1), (iv) interact optimally with clients (26; 59.1), (v) intervene (29; 65.9) and (vi) collaborate to increase health literacy (21; 47.7). Since health literacy can directly impact on intervention efficacy, further studies are needed on how to integrate health literacy into occupational therapy practice. PMID- 21702742 TI - Participation in day centres for people with psychiatric disabilities: characteristics of occupations. AB - People with psychiatric disabilities (PD) are a vulnerable group, and should be offered support and rehabilitation when needed. Day centres that provide individually matched daily occupations are an important link to provide that. The present study aimed at gaining knowledge regarding the occupations performed in day centres, in terms of the participants' descriptions of what they were doing. Eighty-eight persons with PD completed a time-use diary that focused on the most recent day. The participants were selected from six different day centres, meeting-place-oriented as well as more work-oriented ones. By qualitative content analysis six categories were identified, representing the occupations performed; social occupations, maintenance occupations, creative occupations, manufacturing occupations, service occupations, and information-focused occupations. A main theme termed ?being at the day centre means participating in occupations with different levels of demand? was also discerned. The day centres served as a social meeting point and an opportunity to be involved in occupations with different levels of demand. This study highlights the role day centres could play in the rehabilitation of people with PD, and the potential that lies in the knowledge of the levels of occupational demands when meeting individual occupational needs and when analysing and planning interventions. PMID- 21702744 TI - With this special issue, the International Journal of Psychoanalysis joins the celebrations for the centenary of the International Psychoanalytical Association. PMID- 21702743 TI - Abeta42 oligomers, but not fibrils, simultaneously bind to and cause damage to ganglioside-containing lipid membranes. AB - Abeta (amyloid-beta peptide) assembles to form amyloid fibres that accumulate in senile plaques associated with AD (Alzheimer's disease). The major constituent, a 42-residue Abeta, has the propensity to assemble and form soluble and potentially cytotoxic oligomers, as well as ordered stable amyloid fibres. It is widely believed that the cytotoxicity is a result of the formation of transient soluble oligomers. This observed toxicity may be associated with the ability of oligomers to associate with and cause permeation of lipid membranes. In the present study, we have investigated the ability of oligomeric and fibrillar Abeta42 to simultaneously associate with and affect the integrity of biomimetic membranes in vitro. Surface plasmon field-enhanced fluorescence spectroscopy reveals that the binding of the freshly dissolved oligomeric 42-residue peptide binds with a two step association with the lipid bilayer, and causes disruption of the membrane resulting in leakage from vesicles. In contrast, fibrils bind with a 2-fold reduced avidity, and their addition results in approximately 2-fold less fluorophore leakage compared with oligomeric Abeta. Binding of the oligomers may be, in part, mediated by the GM1 ganglioside receptors as there is a 1.8-fold increase in oligomeric Abeta binding and a 2-fold increase in permeation compared with when GM1 is not present. Atomic force microscopy reveals the formation of defects and holes in response to oligomeric Abeta, but not preformed fibrillar Abeta. The results of the present study indicate that significant membrane disruption arises from association of low-molecular-mass Abeta and this may be mediated by mechanical damage to the membranes by Abeta aggregation. This membrane disruption may play a key role in the mechanism of Abeta-related cell toxicity in AD. PMID- 21702745 TI - In all questions, my interest is not in the individual people but in the analytic movement as a whole. It will be hard enough here in Europe in the times to come to keep it going. After all, we are just a handful of people who really have that in mind. AB - The paper tries to deal with the difficult and at times contradictory decisions that the then leaders of the IPA, S. Freud, A. Freud, E. Jones etc. had to adopt as whether or not to clearly inform the readers of Die Internationale Zeitschrift fur Psychoanalyse and the International Journal of Psychoanalysis, the official scientific periodicals of the IPA, of the tragic events concerning first the German Psychoanalytic Society and then the Vienna Psychoanalytic Society and the newborn Italian Psychoanalytic Society and other European psychoanalytic societies during the years 1933-1945. Because of the anti-Jewish persecution by the Nazi and fascist regimes the IPA had to face the extremely difficult task of helping its Continental Jewish members to emigrate to the USA, Great Britain and other countries in order to save their lives and to allow psychoanalysis to survive, with enormous radical consequences for the scientific and sociocultural future developments of the discipline.The following notes are dedicated to those non-Aryans and Aryans who could not find a proper rescue and whose graves became the wind which scattered the ashes of their bodies with the smoke coming out of the chimneys of the Nazi gas chambers. PMID- 21702746 TI - Narcissism, hypochondria and the problem of alternative theories. AB - This paper is an experiment in conceptual integration and clinical theory testing. Its argument is that narcissism and sexual object love develop from a single source and continue to interact during childhood development and adult life (Freud) and that drives in their oedipal and other formations are not merely disintegration products of narcissism (Kohut). Material from two analyses, supplemented by material from two others, indicate that narcissistic injury was a significant factor in the neuroses of these patients but that aggressive and libidinal conflicts were also decisive such that their hypochondriac symptoms were compositions of their interacting causality. As a result these neuroses are negative instances of Kohut's theory of narcissism. The hypochondriac symptoms as they emerged could not have had the structure and dynamics they actually had nor could the analytic process these patients underwent have achieved the far reaching and durable amelioration of these symptoms that occurred. On the positive side, these analyses are but two inductive instances that support Freud's theory. However, one major difficulty of the faddishness of psychoanalytic theorizing is that much of worth is lost from general theories that turn out not to be supportable. The clinical material from these two cases which disprove basic elements of self-psychology metapsychology also require adjustments to classical theory that integrate the contributions of self psychology to psychoanalytic clinical theory. PMID- 21702747 TI - Psychoanalysis and the university: a difficult relationship. AB - A critique of present-day isolation of psychoanalytic institutes and of their lack of emphasis on research and scientific development is followed with concrete proposals for reorienting psychoanalytic education toward university settings, with the ultimate purpose of bringing together psychoanalytic theory and scientific contributions with the contemporary contributions of neurobiological science and the humanities. Efforts already under way in this direction and practical recommendations for further steps to integrate psychoanalytic education and research within university settings are outlined. PMID- 21702748 TI - Psychoanalysis in the university: the natural home for education and research. AB - Psychoanalysis as a theory of human mental functioning and a derived therapeutic for disturbed functioning would have its natural home in the university, and Freud gave evidence of harboring such an ambition. But the sociopolitical structure of the early 20th century Austro-Hungarian Empire precluded this, and analysis developed, by default, its part-time, private practice-based educational structure. Psychoanalytic penetration of academic psychiatry in the United States after World War II made possible a counter-educational structure, the department of psychiatry-affiliated psychoanalytic institute within the country's medical schools. This paper outlines, beyond these, other more ambitious vistas (David Shakow, Anna Freud, The Menninger Foundation, Emory University [US], APdeBA [Argentina]), conceptions even closer to the ideal (idealized) goal of full-time placement within the university with strong links to medicine, to the behavioral sciences, and to the humanities. PMID- 21702749 TI - Psychoanalysis and the United States research university: current trends. AB - In this essay the author describes the status of the humanities within United States research universities, and notes that there is a place in the research university for clinical analysts with non-quantitative research interests, who are seen as humanities scholars by other humanities specialists. He discusses the current trend in psychoanalytic research in the United States, which perpetuates an historically well-known divide between quantitative and non-quantitative investigators, and causes non-quantitative clinician-researcher analysts to seek a workplace outside organized analysis, as it exists within the American Psychoanalytic Association. He goes on to describe the way a clinical analyst with a strong non-quantitative research commitment has found a supportive home for his investigations in a humanities institute in a research university. That analyst has been welcomed as a colleague by university-based humanities scholars, and has found that those collegial relationships offer creative freedom and interdisciplinary stimulation. The author notes that a cadre of analysts, enriched by such experiences, will be better equipped to bridge the divide which exists between non-quantitative and quantitative analytic researchers, for the benefit of psychoanalytic research in the future. The author also illustrates the benefits experienced by university-based humanities scholars when they collaborate with clinical analysts, and suggests this makes stronger ties between psychoanalysis and research universities more likely in the future. PMID- 21702750 TI - Seeing bodies in pain: from Hippocrates to Freud. AB - The study of pain has a history as long as that of Western medicine. In the 20th and 21st centuries much has been made about the epistemological problem of seeing somatic as well as psychic pain in the clinical setting. The two schools seem to be those which rely on self-reporting and those that rely on the interpretation of visual materials (expression or brain scans) by trained specialists. That this problem was central to the 19th century study of pain is clear as these origins (especially Darwin) are often cited in today's literature as 'proof' of their validity. That the problem was also central to one of the early 20th century thinkers most indebted to Darwin, Sigmund Freud, is less well known and how he resolved this paradox of self-reporting versus seeing seems to have been overlooked. PMID- 21702751 TI - From the dreams of a generation to the theory of dreams: Freud's Roman dreams. AB - In The Interpretation of Dreams, Freud's interpretation of oedipal desires does not occur at the expense of historical and personal desires, which are always there as a backdrop. In the relentless examination of his own dreams that Freud makes in order to show the mechanisms inherent in all oneiric deformation, we are also led to another, specifically historical, aspect of the issue of Jewish emancipation, which he experiences at first hand. By analysing his own dreams, Freud not only shows us the mechanisms governing dream formation, but also develops a pointed critique of his contemporary society and its prejudices. PMID- 21702752 TI - A virtual training institute in Eastern Europe. AB - This is a short outline of the development of psychoanalysis and of analytic training in Eastern Europe after the fall of the Iron Curtain. The Han Groen Prakken Psychoanalytic Institute for Eastern Europe was founded by the IPA and the EPF in 2002 to organize and coordinate this. The activity of such an unusual training institute, virtual and time-limited up to the birth of new IPA study groups, is described with the problems it has had to face, from shuttle analysis to research of this unusual training, from initial outreach activity to formation of new analytic groups, from unavoidable plurality of analytic approaches of an international staff to the need for systematic teaching, from criteria for selection of candidates in such a large area with many languages, cultures and histories, to the integration of new analysts and groups in the international analytic community. These problems are part of the challenge implicit in the globalization, with its unavoidable push to enlarge to the whole humanity the psychoanalytic theory and praxis. Such an experience is now used in Latin America, but may also soon have its application in other continents. Freedom of mind is a basic need of all humans and psychoanalysis still has much to say about this. PMID- 21702753 TI - The training of psychoanalysts in Latin American countries without IPA institutions: antecedents, experiences and problems encountered. AB - ILAP (The Latin American Institute of Psychoanalysis) is a relatively recent project of the IPA and FEPAL (The Latin American Psychoanalytical Federation). Its formal origin, marked by the signature of a memorandum recording an agreement between the presidents of both institutions, Claudio Eizirik and Alvaro Rey de Castro respectively, dates from January 2006, but the governing body of ILAP was formed in December of the same year. Given this, we might say that as of December 2008 ILAP had effectively existed for two years. This is a short and very intense period and for that reason the time for general assessment, conclusions, and suggestions for change has not yet come. We shall simply give a critical history of the project, its antecedents, what it has realized, and the difficulties and limitations encountered hitherto, as well as sketch future perspectives. PMID- 21702754 TI - The challenge of professional identity for Chinese clinicians in the process of learning and practicing psychoanalytic psychotherapy: the discussion on the frame of Chinese culture. AB - One important element in psychoanalysis, which is derived from Western culture, is individualization: the independency and autonomy of an individual are highly valued. However, one of the significant essences in Chinese culture is that the collective interests transcend the individual interests and the interests of social groups are more important than those of families. Therefore, when learning and practicing psychoanalytic psychotherapy, Chinese clinicians inevitably experience conflicts derived from this difference of cultural values. This article attempts to use a historical perspective to discuss the current challenges of professional identity for Chinese clinicians learning and practicing psychoanalytic psychotherapy and psychoanalysis. PMID- 21702755 TI - A camera inside a monastery: reflections on Of Gods and Men [Des Hommes et des Dieux]. PMID- 21702756 TI - Induction of bone formation by Escherichia coli-expressed recombinant human bone morphogenetic protein-2 using block-type macroporous biphasic calcium phosphate in orthotopic and ectopic rat models. AB - BACKGROUND AND OBJECTIVE: The potential of the Escherichia coli-expressed recombinant human bone morphogenetic protein-2 (ErhBMP-2) to support new bone formation/maturation using a block-type of macroporous biphasic calcium phosphate (bMBCP) carrier was evaluated in an orthotopic and ectopic rat model. MATERIAL AND METHODS: Critical-size (Phi 8 mm) calvarial defects and subcutaneous pockets in 32 Sprague-Dawley rats received implants of rhBMP-2 (2.5 MUg) in a bMBCP carrier or bMBCP alone (control). Implant sites were evaluated using histological and histometric analysis following 2- and 8-wk healing intervals (eight animals/group/interval). RESULTS: ErhBMP-2/bMBCP supported significantly greater bone formation at 2 and 8 wk (10.8% and 25.4%, respectively) than the control at 2 and 8 wk (5.3% and 14.0%, respectively) in calvarial defects (p < 0.01). Bone formation was only observed for the ErhBMP-2/bMBCP ectopic sites and was significantly greater at 8 wk (7.5%) than at 2 wk (4.5%) (p < 0.01). Appositional and endochondral bone formation was usually associated with a significant increase in fatty marrow at 8 wk. The bMBCP carrier showed no evidence of bioresorption. CONCLUSION: ErhBMP-2/bMBCP induced significant bone formation in both calvarial and ectopic sites. Further study appears to be required to evaluate the relevance of the bMBCP carrier. PMID- 21702757 TI - Patch testing in children with hand eczema. A 5-year multicentre study in Spain. AB - BACKGROUND: Hand eczema is common in children, but affected children are seldom patch tested. Relatively few studies have assessed patch testing in the paediatric population, and none has specifically evaluated its use in hand eczema in children. OBJECTIVES: The aim of this study was to determine the prevalence of contact allergy in children with hand eczema, and to identify the most frequent allergens and their relevance. MATERIAL AND METHODS: We performed a 5-year retrospective study of children (aged 0-15 years) with hand eczema tested with the Spanish baseline series at the Dermatology Departments of 11 Spanish hospitals. RESULTS: During the study period, 11 729 patients were patch tested, of whom 480 were children. Hand eczema was present in 111 (23.1%) of the children and in 3437 (30.5%) of the adults. Of the children with hand eczema, 46.8% had at least one positive reaction in the patch tests. Current relevance was found for 78% of the allergens detected. The most common allergens were nickel sulfate, methylchloroisothiazolinone/methylisothiazolinone, and fragrance mix I. Allergic contact dermatitis was the most frequent diagnosis (36%), followed by atopic dermatitis. CONCLUSIONS: Allergic contact dermatitis was the most usual diagnosis in our series of children with hand eczema. We recommend patch testing of all children with chronic hand eczema, as is already performed in adults. PMID- 21702758 TI - Patch testing in fixed drug eruptions--a 20-year review. AB - BACKGROUND: The fixed drug eruption is a common adverse drug reaction. Clear identification of the culprit drug is not always possible in the clinical setting, and oral rechallenge may induce new lesions or severe reactions. OBJECTIVES: The main purpose of this study was to evaluate the diagnostic value of patch testing in establishing an aetiological diagnosis in fixed drug eruptions. METHOD: A retrospective analysis was conducted evaluating 52 patients (17M/35F, mean age 53+/-17 years) with clinical diagnoses of fixed drug eruptions submitted to patch tests in a 20-year period in a Dermatology Department. Nonsteroidal anti-inflammatory drugs (NSAID) were clinically suspected in 90.4% of the cases, followed by antibiotics (28.9%) and paracetamol (15.4%). RESULTS: Patch tests on pigmented lesions were reactive in 21 patients (40.4%), 20 of those to NSAID (nimesulide, piroxicam and etoricoxib) and 1 to an antihistamine (cetirizine). All patch tests using other drugs were negative, even under conditions of high clinical suspicion. Oral rechallenge allowed confirmation of drug imputability in 5 of 31 test-negative cases. Cross reactivity was frequently observed between piroxicam and other oxicams, and between different antihistamines. CONCLUSIONS: Patch testing was shown to be a simple and safe method to confirm drug imputabililty in fixed drug eruption, mainly when NSAID or multiple drugs are suspected. Persistent lack of reactivity to drug classes such as antibiotics and allopurinol represent an important limitation. PMID- 21702759 TI - Identification of a novel HLA-C*02 allele, HLA-C*02:02:09. AB - We report HLA-C*02:02:09 as a novel allele with a transition C->T at position 354. PMID- 21702760 TI - Co-occurrence of argyrophilic grain disease in sporadic amyotrophic lateral sclerosis. AB - AIMS: Phosphorylated TDP-43 (pTDP-43) is the pathological protein responsible for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Recently, it has been reported that accumulation of pTDP-43 can occur in the brains of patients with argyrophilic grain disease (AGD), in which phosphorylated 4-repeat tau is the pathological protein. To elucidate the association of ALS with AGD, we examined the brains from 37 consecutively autopsied patients with sporadic ALS (age range 45-84 years, mean 71.5 +/- 9.0 years). METHODS: Sections from the frontotemporal lobe were stained with the Gallyas-Braak method and also immunostained with antibodies against phosphorylated tau, 4-repeat tau and pTDP 43. RESULTS: Fourteen (38%) of the 37 ALS patients were found to have AGD. With regard to staging, 5 of these 14 cases were rated as I, 4 as II and 5 as III. pTDP-43 immunohistochemistry revealed the presence of positive neuronal and glial cytoplasmic inclusions in the affected medial temporal lobe in many cases (93% and 64%, respectively). On the other hand, pTDP-43-positive small structures corresponding to argyrophilic grains were observed only in one case. A significant correlation was found between AGD and the Braak stage for neurofibrillary pathology (stage range 0-V, mean 2.1). However, there were no significant correlations between AGD and any other clinicopathological features, including dementia. CONCLUSIONS: The present findings suggest that co-occurrence of AGD in ALS is not uncommon, and in fact comparable with that in a number of diseases belonging to the tauopathies or alpha-synucleinopathies. PMID- 21702761 TI - Tooth tissue engineering: optimal dental stem cell harvest based on tooth development. AB - Our long-term objective is to devise reliable methods to generate biological replacement teeth exhibiting the physical properties and functions of naturally formed human teeth. Previously, we demonstrated the successful use of tissue engineering approaches to generate small, bioengineered tooth crowns from harvested pig and rat postnatal dental stem cells (DSCs). To facilitate characterizations of human DSCs, we have developed a novel radiographic staging system to accurately correlate human third molar tooth developmental stage with anticipated harvested DSC yield. Our results demonstrated that DSC yields were higher in less developed teeth (Stages 1 and 2), and lower in more developed teeth (Stages 3, 4, and 5). The greatest cell yields and colony-forming units (CFUs) capability was obtained from Stages 1 and 2 tooth dental pulp. We conclude that radiographic developmental staging can be used to accurately assess the utility of harvested human teeth for future dental tissue engineering applications. PMID- 21702762 TI - The relationship between motor competence, physical fitness and self-perception in children. AB - AIM: The aim of the current research was to explore the relationship between motor competence, physical fitness and self-perception, and to study to which extent this relationship may vary by gender. METHODS: A sample of 67 children (mean age 11.46 years, SD 0.27) completed Harter's Self-Perception Profile for Children (SPPC), the Movement Assessment Battery for Children (MABC) and the Test of Physical Fitness (TPF) to assess self-perception, motor competence and physical fitness. RESULTS: The SPPC was stronger related to total score on TPF than to total score on MABC. However, when looking at boys and girls separately, this result was found for the boys only. In the group in general, total scores on both TPF and MABC correlated significantly with three of the domains of SPPC (social acceptance, athletic competence and physical appearance) and general self worth. This relationship varied by gender. Interestingly, TPF was highest correlated with perception of athletic competence in boys but with perception of social acceptance in girls. A high and significant correlation was found between physical fitness and motor competence for both genders. CONCLUSION: The results indicated a strong relationship between physical fitness, motor competence and self-perception in children that varied by gender. This implies that all these factors are essential contributions in order to facilitate participation in physical activity in children. PMID- 21702765 TI - Returning to a new home. PMID- 21702763 TI - Cross-border marriage and disparities in early childhood development in a population-based birth cohort study: the mediation of the home environment. AB - BACKGROUND: Taiwan has experienced a large influx of cross-border marriage migrants in recent years. The majority have been women in their childbearing ages and have come from countries with lower average standards of living than Taiwan. This trend has changed the ethnic composition of children who live in Taiwan, and it has generated considerable social concern over the future health status of Taiwan's citizens. This study aimed to examine: (1) whether there are disparities in development between children reared in families characterized by cross-border marriages and children reared in families with two Taiwanese-born parents; and (2) whether the quality of home environment explains the group differences in early childhood development. METHODS: Data came from the Taiwan Birth Cohort Study. A total of 19,499 participants who completed 6-month, 18-month and 3-year surveys were included for analysis. Cross-border marriage status was defined by mother's original nationality and categorized into three broad groups: Taiwanese born, Chinese cross-border and South-East Asian (SEA) cross-border. Early childhood development was measured at age 3 years, and covered the domains of gross motor, fine motor, language and socio-emotional competence. Hierarchical linear regressions were used to examine the mediation effects of the home environment. RESULTS: Children of Chinese and SEA cross-border groups scored lower in fine motor, language and socio-emotional competence than those of their Taiwanese-born counterpart at age 3 years. Chinese-Taiwanese group differences in all three developmental domains became insignificant after the addition of home environment, while SEA-Taiwanese group differences in fine motor and language development remained, yet were noticeably reduced. The mediation of home environment was further confirmed using the Sobel test. CONCLUSIONS: Home environment plays a central role in reducing the disparities in developmental outcomes among children of different marriage groups. Interventions should be directed towards enhancing the quality of early home environment for children reared in families of cross-border marriages. PMID- 21702766 TI - Do We "do"? AB - A normative framework for modeling causal and counterfactual reasoning has been proposed by Spirtes, Glymour, and Scheines (1993; cf. Pearl, 2000). The framework takes as fundamental that reasoning from observation and intervention differ. Intervention includes actual manipulation as well as counterfactual manipulation of a model via thought. To represent intervention, Pearl employed the do operator that simplifies the structure of a causal model by disconnecting an intervened-on variable from its normal causes. Construing the do operator as a psychological function affords predictions about how people reason when asked counterfactual questions about causal relations that we refer to as undoing, a family of effects that derive from the claim that intervened-on variables become independent of their normal causes. Six studies support the prediction for causal (A causes B) arguments but not consistently for parallel conditional (if A then B) ones. Two of the studies show that effects are treated as diagnostic when their values are observed but nondiagnostic when they are intervened on. These results cannot be explained by theories that do not distinguish interventions from other sorts of events. PMID- 21702767 TI - The large-scale structure of semantic networks: statistical analyses and a model of semantic growth. AB - We present statistical analyses of the large-scale structure of 3 types of semantic networks: word associations, WordNet, and Roget's Thesaurus. We show that they have a small-world structure, characterized by sparse connectivity, short average path lengths between words, and strong local clustering. In addition, the distributions of the number of connections follow power laws that indicate a scale-free pattern of connectivity, with most nodes having relatively few connections joined together through a small number of hubs with many connections. These regularities have also been found in certain other complex natural networks, such as the World Wide Web, but they are not consistent with many conventional models of semantic organization, based on inheritance hierarchies, arbitrarily structured networks, or high-dimensional vector spaces. We propose that these structures reflect the mechanisms by which semantic networks grow. We describe a simple model for semantic growth, in which each new word or concept is connected to an existing network by differentiating the connectivity pattern of an existing node. This model generates appropriate small world statistics and power-law connectivity distributions, and it also suggests one possible mechanistic basis for the effects of learning history variables (age of acquisition, usage frequency) on behavioral performance in semantic processing tasks. PMID- 21702768 TI - Sketches from a design process: creative cognition inferred from intermediate products. AB - Novice designers produced a sequence of sketches while inventing a logo for a novel brand of soft drink. The sketches were scored for the presence of specific objects, their local features and global composition. Self-assessment scores for each sketch and art critics' scores for the end products were collected. It was investigated whether the design evolves in an essentially random fashion or according to an overall heuristic. The results indicated a macrostructure in the evolution of the design, characterized by two stages. For the majority of participants, the first stage is marked by the introduction and modification of novel objects and their local and global aspects; the second stage is characterized by changes in their global composition. The minority that showed the better designs has a different strategy, in which most global changes were made in the beginning. Although participants did not consciously apply these strategies, their self-assessment scores reflect the stages of the process. PMID- 21702769 TI - Perception as abduction: turning sensor data into meaningful representation. AB - This article presents a formal theory of robot perception as a form of abduction. The theory pins down the process whereby low-level sensor data is transformed into a symbolic representation of the external world, drawing together aspects such as incompleteness, top-down information flow, active perception, attention, and sensor fusion in a unifying framework. In addition, a number of themes are identified that are common to both the engineer concerned with developing a rigorous theory of perception, such as the one on offer here, and the philosopher of mind who is exercised by questions relating to mental representation and intentionality. PMID- 21702770 TI - Does the world leak into the mind? Active externalism, "internalism" and epistemology. AB - One of the arguments for active externalism (also known as the extended mind thesis) is that if a process counts as cognitive when it is performed in the head, it should also count as cognitive when it is performed in the world. Consequently, mind extends into the world. I argue for a corollary: We sometimes perform actions in our heads that we usually perform in the world, so that the world leaks into the mind. I call this internalism. Internalism has epistemological implications: If a process gives us an empirical discovery when it is performed in the world, it will also give us an empirical discovery when it is performed in the head. I look at a simple example that highlights this implication. I then explore the relation between internalism and active externalism in more detail and conclude by comparing internalism with mental modeling. PMID- 21702771 TI - A memory-based theory of verbal cognition. AB - The syntagmatic paradigmatic model is a distributed, memory-based account of verbal processing. Built on a Bayesian interpretation of string edit theory, it characterizes the control of verbal cognition as the retrieval of sets of syntagmatic and paradigmatic constraints from sequential and relational long-term memory and the resolution of these constraints in working memory. Lexical information is extracted directly from text using a version of the expectation maximization algorithm. In this article, the model is described and then illustrated on a number of phenomena, including sentence processing, semantic categorization and rating, short-term serial recall, and analogical and logical inference. Subsequently, the model is used to answer questions about a corpus of tennis news articles taken from the Internet. The model's success demonstrates that it is possible to extract propositional information from naturally occurring text without employing a grammar, defining a set of heuristics, or specifying a priori a set of semantic roles. PMID- 21702772 TI - Idea habitats: how the prevalence of environmental cues influences the success of ideas. AB - We investigate 1 factor that influences the success of ideas or cultural representations by proposing that they have a habitat, that is, a set of environmental cues that encourages people to recall and transmit them. We test 2 hypotheses: (a) fluctuation: the success of an idea will vary over time with fluctuations in its habitat, and (b) competition: ideas with more prevalent habitats will be more successful. Four studies use subject ratings and data from newspapers to provide correlational support for our 2 hypotheses, with a negative factoid, positive rumor, catchphrases, and variants of a proverb. Three additional experimental studies manipulate the topic of actual conversations and find empirical support for our theory, with catchphrases, proverbs, and slang. The discussion examines how habitat prevalence applies to a more extensive class of ideas and suggests how habitats may influence the process by which ideas evolve. PMID- 21702773 TI - Information sources for noun learning. AB - Why are some words easier to learn than others? And what enables the eventual learning of the more difficult words? These questions were addressed for nouns using a paradigm in which adults were exposed to naturalistic maternal input that was manipulated to simulate access to several different information sources, both alone and in combination: observation of the extralinguistic contexts in which the target word was used, the words that co-occurred with the target word, and the target word's syntactic context. Words that were not accurately identified from observation alone were both abstract (e.g., music) and concrete (e.g., tail). Whether a noun could be learned from observation depended on whether it labeled a basic-level object category (BLOC). However, the difference between BLOC labels and non-BLOC labels was eliminated when observation was supplemented with linguistic context. Thus, although BLOC labels can be learned from observation alone, non-BLOC labels require richer linguistic context. These findings support a model of vocabulary growth in which an important role is played by changes in the information to which learners have access. PMID- 21702774 TI - Consequences of the serial nature of linguistic input for sentenial complexity. AB - All other things being equal the parser favors attaching an ambiguous modifier to the most recent possible site. A plausible explanation is that locality preferences such as this arise in the service of minimizing memory costs-more distant sentential material is more difficult to reactivate than more recent material. Note that processing any sentence requires linking each new lexical item with material in the current parse. This often involves the construction of long-distance dependencies. Under a resource-limited view of language processing, lengthy integrations should induce difficulty even in unambiguous sentences. To date there has been little direct quantitative evidence in support of this perspective. This article presents 2 self-paced reading studies, which explore the hypothesis that dependency distance is a fundamental determinant of reading complexity in unambiguous constructions in English. The evidence suggests that the difficulty associated with integrating a new input item is heavily determined by the amount of lexical material intervening between the input item and the site of its target dependents. The patterns observed here are not straightforwardly accounted for within purely experience-based models of complexity. Instead, this work supports the role of a memory bottleneck in language comprehension. This constraint arises because hierarchical linguistic relations must be recovered from a linear input stream. PMID- 21702775 TI - Processing coordinated structures: incrementality and connectedness. AB - We recorded participants' eye movements while they read sentences containing verb phrase coordination. Results showed evidence of immediate processing disruption when a reflexive pronoun embedded in the conjoined verb phrase mismatched the sentence subject. We argue that this result is incompatible with models of human parsing that employ only bottom-up parsing procedures, even when flexible constituency is employed. Models need to incorporate a mechanism similar to the adjoining operation in Tree-Adjoining Grammar, in which one structure is inserted into another. PMID- 21702776 TI - Introduction to the 2004 rumelhart prize special issue honoring john R. Anderson. PMID- 21702777 TI - Human symbol manipulation within an integrated cognitive architecture. AB - This article describes the Adaptive Control of Thought-Rational (ACT-R) cognitive architecture (Anderson et al., 2004; Anderson & Lebiere, 1998) and its detailed application to the learning of algebraic symbol manipulation. The theory is applied to modeling the data from a study by Qin, Anderson, Silk, Stenger, & Carter (2004) in which children learn to solve linear equations and perfect their skills over a 6-day period. Functional MRI data show that: (a) a motor region tracks the output of equation solutions, (b) a prefrontal region tracks the retrieval of declarative information, (c) a parietal region tracks the transformation of mental representations of the equation, (d) an anterior cingulate region tracks the setting of goal information to control the information flow, and (e) a caudate region tracks the firing of productions in the ACT-R model. The article concludes with an architectural comparison of the competence children display in this task and the competence that monkeys have shown in tasks that require manipulations of sequences of elements. PMID- 21702778 TI - Rational analyses of information foraging on the web. AB - This article describes rational analyses and cognitive models of Web users developed within information foraging theory. This is done by following the rational analysis methodology of (a) characterizing the problems posed by the environment, (b) developing rational analyses of behavioral solutions to those problems, and (c) developing cognitive models that approach the realization of those solutions. Navigation choice is modeled as a random utility model that uses spreading activation mechanisms that link proximal cues (information scent) that occur in Web browsers to internal user goals. Web-site leaving is modeled as an ongoing assessment by the Web user of the expected benefits of continuing at a Web site as opposed to going elsewhere. These cost-benefit assessments are also based on spreading activation models of information scent. Evaluations include a computational model of Web user behavior called Scent-Based Navigation and Information Foraging in the ACT Architecture, and the Law of Surfing, which characterizes the empirical distribution of the length of paths of visitors at a Web site. PMID- 21702779 TI - An activation-based model of sentence processing as skilled memory retrieval. AB - We present a detailed process theory of the moment-by-moment working-memory retrievals and associated control structure that subserve sentence comprehension. The theory is derived from the application of independently motivated principles of memory and cognitive skill to the specialized task of sentence parsing. The resulting theory construes sentence processing as a series of skilled associative memory retrievals modulated by similarity-based interference and fluctuating activation. The cognitive principles are formalized in computational form in the Adaptive Control of Thought-Rational (ACT-R) architecture, and our process model is realized in ACT-R. We present the results of 6 sets of simulations: 5 simulation sets provide quantitative accounts of the effects of length and structural interference on both unambiguous and garden-path structures. A final simulation set provides a graded taxonomy of double center embeddings ranging from relatively easy to extremely difficult. The explanation of center-embedding difficulty is a novel one that derives from the model' complete reliance on discriminating retrieval cues in the absence of an explicit representation of serial order information. All fits were obtained with only 1 free scaling parameter fixed across the simulations; all other parameters were ACT-R defaults. The modeling results support the hypothesis that fluctuating activation and similarity-based interference are the key factors shaping working memory in sentence processing. We contrast the theory and empirical predictions with several related accounts of sentence-processing complexity. PMID- 21702780 TI - Modeling parallelization and flexibility improvements in skill acquisition: from dual tasks to complex dynamic skills. AB - Emerging parallel processing and increased flexibility during the acquisition of cognitive skills form a combination that is hard to reconcile with rule-based models that often produce brittle behavior. Rule-based models can exhibit these properties by adhering to 2 principles: that the model gradually learns task specific rules from instructions and experience, and that bottom-up processing is used whenever possible. In a model of learning perfect time-sharing in dual tasks (Schumacher et al., 2001), speedup learning and bottom-up activation of instructions can explain parallel behavior. In a model of a complex dynamic task (Carnegie Mellon University Aegis Simulation Program [CMU-ASP], Anderson et al., 2004), parallel behavior is explained by the transition from serially organized instructions to rules that are activated by both top-down (goal-driven) and bottom-up (perceptually driven) factors. Parallelism lets the model opportunistically reorder instructions, leading to the gradual emergence of new task strategies. PMID- 21702781 TI - A multitasking general executive for compound continuous tasks. AB - As cognitive architectures move to account for increasingly complex real-world tasks, one of the most pressing challenges involves understanding and modeling human multitasking. Although a number of existing models now perform multitasking in real-world scenarios, these models typically employ customized executives that schedule tasks for the particular domain but do not generalize easily to other domains. This article outlines a general executive for the Adaptive Control of Thought-Rational (ACT-R) cognitive architecture that, given independent models of individual tasks, schedules and interleaves the models' behavior into integrated multitasking behavior. To demonstrate the power of the proposed approach, the article describes an application to the domain of driving, showing how the general executive can interleave component subtasks of the driving task (namely, control and monitoring) and interleave driving with in-vehicle secondary tasks (radio tuning and phone dialing). PMID- 21702782 TI - A strategy-based interpretation of stroop. AB - Most accounts of the Stroop effect (Stroop, 1935) emphasize its negative aspect, namely, that in particular situations, processing of an irrelevant stimulus dimension interferes with participants' performance of the instructed task. In contrast, this paper emphasizes the fact that, even with that interference, participants actually can (and usually do) exert enough control to perform the instructed task. An Adaptive Control of Thought-Rational (ACT-R) model of the Stroop task interprets this as a kind of learned strategic control. Specifically, the concept of utility is applied to the two processes that compete in the Stroop task, and a utility-learning mechanism serves to update the corresponding utility values according to experience and hence influence the competition. This model both accounts for various extant Stroop results and makes novel predictions about when people can reduce their susceptibility to Stroop interference. These predictions are tested in three experiments that involve a double-response variant of the Stroop task. PMID- 21702783 TI - Cultural differences in belief bias associated with deductive reasoning? AB - Norenzayan, Smith, Jun Kim, and Nisbett (2002) investigated cultural differences in the use of intuitive versus formal reasoning in 4 experiments. Our comment concerns the 4th experiment where Norenzayan et al. reported that, although there were no cultural differences in accuracy on abstract logical arguments, Koreans made more errors than U.S. undergraduates in judging the logical validity of concrete arguments. Norenzayan et al. concluded that Koreans are less likely than European Americans to decontextualize an argument's content from its logical structure, as Koreans were more likely to consider the believability of the conclusion when assessing an argument's validity (a belief bias). Notably, Korean participants were more conservative (less likely to say an argument is valid) than European American participants when assessing arguments. An analysis of the average of the hit and correct rejection rates in each of the conditions (abstract, concrete-believable, concrete-nonbelievable) revealed that, contrary to conclusions of Norenzayan et al., European Americans were no better than Koreans at determining the validity of concrete deductive arguments with conclusions varying in believability. PMID- 21702784 TI - Concurrent cognitive task modulates coordination dynamics. AB - Does a concurrent cognitive task affect the dynamics of bimanual rhythmic coordination? In-phase coordination was performed under manipulations of phase detuning and movement frequency and either singly or in combination with an arithmetic task. Predicted direction-specific shifts in stable relative phase from 0 degrees due to detuning and movement frequency were amplified by the cognitive task. Nonlinear cross-recurrence analysis suggested that this cognitive influence on the locations of the stable points or attractors of coordination entailed a magnification of attractor noise without a reduction in attractor strength. An approximation to these findings was achieved through parameter changes in a motion equation in relative phase. Results are discussed in terms of dual-task performance as limited resources, dynamics rather than chronometrics, and reparameterization rather than degradation. PMID- 21702785 TI - Practice and forgetting effects on vocabulary memory: an activation-based model of the spacing effect. AB - An experiment was performed to investigate the effects of practice and spacing on retention of Japanese-English vocabulary paired associates. The relative benefit of spacing increased with increased practice and with longer retention intervals. Data were fitted with an activation-based memory model, which proposes that each time an item is practiced it receives an increment of strength but that these increments decay as a power function of time. The rate of decay for each presentation depended on the activation at the time of the presentation. This mechanism limits long-term benefits from further practice at higher levels of activation and produces the spacing effect and its observed interactions with practice and retention interval. The model was compared with another model of the spacing effect (Raaijmakers, 2003) and was fit to some results from the literature on spacing and memory. PMID- 21702786 TI - Physically distributed learning: adapting and reinterpreting physical environments in the development of fraction concepts. AB - Five studies examined how interacting with the physical environment can support the development of fraction concepts. Nine- and 10-year-old children worked on fraction problems they could not complete mentally. Experiments 1 and 2 showed that manipulating physical pieces facilitated children's ability to develop an interpretation of fractions. Experiment 3 demonstrated that when children understood a content area well, they used their interpretations to repurpose many environments to support problem solving, whereas when they needed to learn, they were prone to the structure of the environment. Experiments 4 and 5 examined transfer after children had learned by manipulating physical pieces. Children who learned by adapting relatively unstructured environments transferred to new materials better than children who learned with "well-structured" environments that did not require equivalent adaptation. Together, the findings reveal that during physically distributed learning, the opportunity to adapt an environment permits the development of new interpretations that can advance learning. PMID- 21702787 TI - Dissociations in performance on novel versus irregular items: single-route demonstrations with input gain in localist and distributed models. AB - Four pairs of connectionist simulations are presented in which quasi-regular mappings are computed using localist and distributed representations. In each simulation, a control parameter termed input gain was modulated over the only level of representation that mapped inputs to outputs. Input gain caused both localist and distributed models to shift between regularity-based and item-based modes of processing. Performance on irregular items was selectively impaired in the regularity-based modes, whereas performance on novel items was selectively impaired in the item-based modes. Thus, the models exhibited double dissociations without separable processing components. These results are discussed in the context of analogous dissociations found in language domains such as word reading and inflectional morphology. PMID- 21702788 TI - On the experiential link between spatial and temporal language. AB - How do we understand time and other entities we can neither touch nor see? One possibility is that we tap into our concrete, experiential knowledge, including our understanding of physical space and motion, to make sense of abstract domains such as time. To examine how pervasive an aspect of cognition this is, we investigated whether thought about a nonliteral type of motion called fictive motion (FM; as in The road runs along the coast) can influence thought about time. Our results suggest that FM uses the same structures evoked in understanding literal motion, and that these literal aspects of FM influence temporal reasoning. PMID- 21702789 TI - Action alters shape categories. AB - Two experiments show that action alters the shape categories formed by 2-year olds. Experiment 1 shows that moving an object horizontally (or vertically) defines the horizontal (or vertical) axis as the main axis of elongation and systematically changes the range of shapes seen as similar. Experiment 2 shows that moving an object symmetrically (or asymmetrically) also alters shape categories. Previous work has shown marked developmental changes in object recognition between 1 and 3 years of age. These results suggest a role for action in this developmental process. PMID- 21702790 TI - Deontic reasoning with emotional content: evolutionary psychology or decision theory? AB - Three experiments investigated the contrasting predictions of the evolutionary and decision-theoretic approaches to deontic reasoning. Two experiments embedded a hazard management (HM) rule in a social contract scenario that should lead to competition between innate modules. A 3rd experiment used a pure HM task. Threatening material was also introduced into the antecedent, p, of a deontic rule, if p then must q. According to the evolutionary approach, more HM responses (Cosmides & Tooby, 2000) are predicted when p is threatening, whereas decision theory predicts fewer. All 3 experiments were consistent with decision theory. Other theories are discussed, and it is concluded that they cannot account for the behavior observed in these experiments. PMID- 21702791 TI - Content differences for abstract and concrete concepts. AB - Concept properties are an integral part of theories of conceptual representation and processing. To date, little is known about conceptual properties of abstract concepts, such as idea. This experiment systematically compared the content of 18 abstract and 18 concrete concepts, using a feature generation task. Thirty-one participants listed characteristics of the concepts (i.e., item properties) or their relevant context (i.e., context properties). Abstract concepts had significantly fewer intrinsic item properties and more properties expressing subjective experiences than concrete concepts. Situation components generated for abstract and concrete concepts differed in kind, but not in number. Abstract concepts were predominantly related to social aspects of situations. Properties were significantly less specific for abstract than for concrete concepts. Thus, abstractness emerged as a function of several, both qualitative and quantitative, factors. PMID- 21702792 TI - An experimental study of the emergence of human communication systems. AB - The emergence of human communication systems is typically investigated via 2 approaches with complementary strengths and weaknesses: naturalistic studies and computer simulations. This study was conducted with a method that combines these approaches. Pairs of participants played video games requiring communication. Members of a pair were physically separated but exchanged graphic signals through a medium that prevented the use of standard symbols (e.g., letters). Communication systems emerged and developed rapidly during the games, integrating the use of explicit signs with information implicitly available to players and silent behavior-coordinating procedures. The systems that emerged suggest 3 conclusions: (a) signs originate from different mappings; (b) sign systems develop parsimoniously; (c) sign forms are perceptually distinct, easy to produce, and tolerant to variations. PMID- 21702793 TI - Comparing Multiple Paths to Mastery: What is Learned? AB - Contemporary theories of learning postulate one or at most a small number of different learning mechanisms. However, people are capable of mastering a given task through qualitatively different learning paths such as learning by instruction and learning by doing. We hypothesize that the knowledge acquired through such alternative paths differs with respect to the level of abstraction and the balance between declarative and procedural knowledge. In a laboratory experiment we investigated what was learned about patterned letter sequences via either direct instruction in the relevant patterns or practice in solving letter sequence extrapolation problems. Results showed that both types of learning led to mastery of the target task as measured by accuracy performance. However, behavioral differences emerged in how participants applied their knowledge. Participants given instruction showed more variability in the types of strategies they used to articulate their knowledge as well as longer solution times for generating the action implications of that knowledge as compared to the participants given practice. Results are discussed regarding the implications for transfer, generalization, and procedural application. Learning theories that claim generality should be tested against cross-scenario phenomena, not just parametric variations of a single learning scenario. PMID- 21702794 TI - The One-to-One Constraint in Analogical Mapping and Inference. AB - Theories of analogical reasoning have assumed that a 1-to-1 constraint discourages reasoners from mapping a single element in 1 analog to multiple elements in another. Empirical evidence suggests that reasoners sometimes appear to violate the one-to-one constraint when asked to generate mappings, yet virtually never violate it when asked to generate analogical inferences. However, few studies have examined analogical inferences based on nonisomorphic analogs, and their conclusions are suspect due to methodological problems. We sought to elicit mixed inferences that could result from combining information from 2 possible mappings. Participants generated 2-to-1 correspondences when asked for explicit mappings, but did not produce mixed inferences. Multiple correspondences appear to arise from multiple isomorphic mappings, rather than from a single homomorphic mapping. PMID- 21702795 TI - Viewing a map versus reading a description of a map: modality-specific encoding of spatial information. AB - This study investigated whether brain neural activity that accompanied the processing of previously learned map information was influenced by the modality in which the spatial parameters of the maps were originally learned. Participants learned a map by either viewing it directly or by reading an equivalent verbal description. Following learning, the participants' ability to use their spatial knowledge was tested in a spatial orientation task. Electrophysiological recordings identified significant effects of prior learning modality on event related brain activity within 300 ms following the presentation of map orientation instructions. The results indicate that modality-specificity in spatial memory is present at a very early stage of processing. PMID- 21702796 TI - The emergence of words: attentional learning in form and meaning. AB - Children improve at word learning during the 2nd year of life-sometimes dramatically. This fact has suggested a change in mechanism, from associative learning to a more referential form of learning. This article presents an associative exemplar-based model that accounts for the improvement without a change in mechanism. It provides a unified account of children's growing abilities to (a) learn a new word given only 1 or a few training trials ("fast mapping"); (b) acquire words that differ only slightly in phonological form; (c) generalize word meanings preferentially along particular dimensions, such as object shape (the "shape bias"); and (d) learn 2nd labels for already-named objects, despite a persisting resistance to doing so ("mutual exclusivity"). The model explains these improvements in terms of increased attention to relevant aspects of form and meaning, which reduces memory interference. The interaction of associations and reference in word learning is discussed. PMID- 21702797 TI - How should a speech recognizer work? AB - Although researchers studying human speech recognition (HSR) and automatic speech recognition (ASR) share a common interest in how information processing systems (human or machine) recognize spoken language, there is little communication between the two disciplines. We suggest that this lack of communication follows largely from the fact that research in these related fields has focused on the mechanics of how speech can be recognized. In Marr's (1982) terms, emphasis has been on the algorithmic and implementational levels rather than on the computational level. In this article, we provide a computational-level analysis of the task of speech recognition, which reveals the close parallels between research concerned with HSR and ASR. We illustrate this relation by presenting a new computational model of human spoken-word recognition, built using techniques from the field of ASR that, in contrast to current existing models of HSR, recognizes words from real speech input. PMID- 21702798 TI - Semantic interpretation as computation in nonmonotonic logic: the real meaning of the suppression task. AB - Interpretation is the process whereby a hearer reasons to an interpretation of a speaker's discourse. The hearer normally adopts a credulous attitude to the discourse, at least for the purposes of interpreting it. That is to say the hearer tries to accommodate the truth of all the speaker's utterances in deriving an intended model. We present a nonmonotonic logical model of this process which defines unique minimal preferred models and efficiently simulates a kind of closed-world reasoning of particular interest for human cognition. Byrne's "suppression" data (Byrne, 1989) are used to illustrate how variants on this logic can capture and motivate subtly different interpretative stances which different subjects adopt, thus indicating where more fine-grained empirical data are required to understand what subjects are doing in this task. We then show that this logical competence model can be implemented in spreading activation network models. A one pass process interprets the textual input by constructing a network which then computes minimal preferred models for (3-valued) valuations of the set of propositions of the text. The neural implementation distinguishes easy forward reasoning from more complex backward reasoning in a way that may be useful in explaining directionality in human reasoning. PMID- 21702799 TI - The role of embodied intention in early lexical acquisition. AB - We examine the influence of inferring interlocutors' referential intentions from their body movements at the early stage of lexical acquisition. By testing human participants and comparing their performances in different learning conditions, we find that those embodied intentions facilitate both word discovery and word meaning association. In light of empirical findings, the main part of this article presents a computational model that can identify the sound patterns of individual words from continuous speech, using nonlinguistic contextual information, and employ body movements as deictic references to discover word meaning associations. To our knowledge, this work is the first model of word learning that not only learns lexical items from raw multisensory signals to closely resemble infant language development from natural environments, but also explores the computational role of social cognitive skills in lexical acquisition. PMID- 21702800 TI - Uncovering the richness of the stimulus: structure dependence and indirect statistical evidence. AB - The poverty of stimulus argument is one of the most controversial arguments in the study of language acquisition. Here we follow previous approaches challenging the assumption of impoverished primary linguistic data, focusing on the specific problem of auxiliary (AUX) fronting in complex polar interrogatives. We develop a series of corpus analyses of child-directed speech showing that there is indirect statistical information useful for correct auxiliary fronting in polar interrogatives and that such information is sufficient for distinguishing between grammatical and ungrammatical generalizations, even in the absence of direct evidence. We further show that there are simple learning devices, such as neural networks, capable of exploiting such statistical cues, producing a bias toward correct AUX questions when compared to their ungrammatical counterparts. The results suggest that the basic assumptions of the poverty of stimulus argument may need to be reappraised. PMID- 21702801 TI - The seeds of spatial grammar in the manual modality. AB - Sign languages modulate the production of signs in space and use this spatial modulation to refer back to entities-to maintain coreference. We ask here whether spatial modulation is so fundamental to language in the manual modality that it will be invented by individuals asked to create gestures on the spot. English speakers were asked to describe vignettes under 2 conditions: using gesture without speech, and using speech with spontaneous gestures. When using gesture alone, adults placed gestures for particular entities in non-neutral locations and then used those locations to refer back to the entities. When using gesture plus speech, adults also produced gestures in non-neutral locations but used the locations coreferentially far less often. When gesture is forced to take on the full burden of communication, it exploits space for coreference. Coreference thus appears to be a resilient property of language, likely to emerge in communication systems no matter how simple. PMID- 21702802 TI - Looking to understand: the coupling between speakers' and listeners' eye movements and its relationship to discourse comprehension. AB - We investigated the coupling between a speaker's and a listener's eye movements. Some participants talked extemporaneously about a television show whose cast members they were viewing on a screen in front of them. Later, other participants listened to these monologues while viewing the same screen. Eye movements were recorded for all speakers and listeners. According to cross-recurrence analysis, a listener's eye movements most closely matched a speaker's eye movements at a delay of 2 sec. Indeed, the more closely a listener's eye movements were coupled with a speaker's, the better the listener did on a comprehension test. In a second experiment, low-level visual cues were used to manipulate the listeners' eye movements, and these, in turn, influenced their latencies to comprehension questions. Just as eye movements reflect the mental state of an individual, the coupling between a speaker's and a listener's eye movements reflects the success of their communication. PMID- 21702803 TI - Processes of similarity judgment. AB - Similarity underlies fundamental cognitive capabilities such as memory, categorization, decision making, problem solving, and reasoning. Although recent approaches to similarity appreciate the structure of mental representations, they differ in the processes posited to operate over these representations. We present an experiment that differentiates among extant structural accounts of similarity in their ability to account for patterns of similarity ratings. These data pose a challenge for transformation-based models and all but one mapping-based model, the Similarity as Interactive Activation and Mapping (SIAM) model of similarity. PMID- 21702804 TI - Distinguishing between causes and enabling conditions-through mental models or linguistic cues? AB - The mental model theory of naive causal understanding and reasoning (Goldvarg & Johnson-Laird, 2001, Cognitive Science, 25, 565-610) claims that people distinguish between causes and enabling conditions on the basis of sets of models that represent possible causal situations. In the tasks used to test this hypothesis, however, the proposed set of models was confounded with linguistic cues that frame which event to assume as given (the enabling condition) and which to consider as responsible for the effect under this assumption (the cause). By disentangling these two factors, we were able to show that when identifying causes and enabling conditions in these tasks, people rely strongly on the linguistic cues but not on the proposed set of models and that this set of models does not even reflect people's typical interpretation of the tasks. We propose an alternative explanation that integrates syntactic and causal considerations. PMID- 21702805 TI - Acknowledgment: guest reviewers. PMID- 21702806 TI - Editorial statement. PMID- 21702807 TI - Animal foraging and the evolution of goal-directed cognition. AB - Foraging- and feeding-related behaviors across eumetazoans share similar molecular mechanisms, suggesting the early evolution of an optimal foraging behavior called area-restricted search (ARS), involving mechanisms of dopamine and glutamate in the modulation of behavioral focus. Similar mechanisms in the vertebrate basal ganglia control motor behavior and cognition and reveal an evolutionary progression toward increasing internal connections between prefrontal cortex and striatum in moving from amphibian to primate. The basal ganglia in higher vertebrates show the ability to transfer dopaminergic activity from unconditioned stimuli to conditioned stimuli. The evolutionary role of dopamine in the modulation of goal-directed behavior and cognition is further supported by pathologies of human goal-directed cognition, which have motor and cognitive dysfunction and organize themselves, with respect to dopaminergic activity, along the gradient described by ARS, from perseverative to unfocused. The evidence strongly supports the evolution of goal-directed cognition out of mechanisms initially in control of spatial foraging but, through increasing cortical connections, eventually used to forage for information. PMID- 21702808 TI - Idiomatic syntactic constructions and language learning. AB - This article explores the influence of idiomatic syntactic constructions (i.e., constructions whose phrase structure rules violate the rules that underlie the construction of other kinds of sentences in the language) on the acquisition of phrase structure. In Experiment 1, participants were trained on an artificial language generated from hierarchical phrase structure rules. Some participants were given exposure to an idiomatic construction (IC) during training, whereas others were not. Under some circumstances, the presence of an idiomatic construction in the input aided learners in acquiring the phrase structure of the language. Experiment 2 provides a replication of the first experiment and extends the findings by showing that idiomatic constructions that strongly violate the predictive dependencies that define the phrase structure of the language do not aid learners in acquiring the structure of the language. Together, our data suggest that (a) idiomatic constructions aid learners in acquiring the phrase structure of a language by highlighting relevant structural elements in the language, and (b) such constructions are useful cues to learning to the extent that learners can keep their knowledge of the idiomatic construction separate from their knowledge of the rest of the language. PMID- 21702809 TI - The role of functionality in the mental representations of engineering students: some differences in the early stages of expertise. AB - As engineers gain experience and become experts in their domain, the structure and content of their knowledge changes. Two studies are presented that examine differences in knowledge representation among freshman and senior engineering students. The first study examines recall of mechanical devices and chunking of components, and the second examines whether seniors represent devices in a more abstract functional manner than do freshmen. The most prominent differences between these 2 groups involve their representation of the functioning of groups of electromechanical components and how these groups of components interact to produce device behavior. Seniors are better able to construct coherent representations of devices by focusing on the function of sets of components in the device. The findings from these studies highlight some ways in which the structure and content of mental representations of design knowledge differ during the early stages of expertise acquisition. PMID- 21702810 TI - A model of plausibility. AB - Plausibility has been implicated as playing a critical role in many cognitive phenomena from comprehension to problem solving. Yet, across cognitive science, plausibility is usually treated as an operationalized variable or metric rather than being explained or studied in itself. This article describes a new cognitive model of plausibility, the Plausibility Analysis Model (PAM), which is aimed at modeling human plausibility judgment. This model uses commonsense knowledge of concept-coherence to determine the degree of plausibility of a target scenario. In essence, a highly plausible scenario is one that fits prior knowledge well: with many different sources of corroboration, without complexity of explanation, and with minimal conjecture. A detailed simulation of empirical plausibility findings is reported, which shows a close correspondence between the model and human judgments. In addition, a sensitivity analysis demonstrates that PAM is robust in its operations. PMID- 21702811 TI - Modeling recognition memory using the similarity structure of natural input. AB - The natural input memory (NIM) model is a new model for recognition memory that operates on natural visual input. A biologically informed perceptual preprocessing method takes local samples (eye fixations) from a natural image and translates these into a feature-vector representation. During recognition, the model compares incoming preprocessed natural input to stored representations. By complementing the recognition memory process with a perceptual front end, the NIM model is able to make predictions about memorability based directly on individual natural stimuli. We demonstrate that the NIM model is able to simulate experimentally obtained similarity ratings and recognition memory for individual stimuli (i.e., face images). PMID- 21702812 TI - Formalization and analysis of reasoning by assumption. AB - This article introduces a novel approach for the analysis of the dynamics of reasoning processes and explores its applicability for the reasoning pattern called reasoning by assumption. More specifically, for a case study in the domain of a Master Mind game, it is shown how empirical human reasoning traces can be formalized and automatically analyzed against dynamic properties they fulfill. To this end, for the pattern of reasoning by assumption a variety of dynamic properties have been specified, some of which are considered characteristic for the reasoning pattern, whereas some other properties can be used to discriminate among different approaches to the reasoning. These properties have been automatically checked for the traces acquired in experiments undertaken. The approach turned out to be beneficial from two perspectives. First, checking characteristic properties contributes to the empirical validation of a theory on reasoning by assumption. Second, checking discriminating properties allows the analyst to identify different classes of human reasoners. PMID- 21702813 TI - Deferred Interpretations: Why Starting Dickens is Taxing but Reading Dickens Isn't. AB - Comprehenders often need to go beyond conventional word senses to obtain an appropriate interpretation of an expression. We report an experiment examining the processing of standard metonymies (The gentleman read Dickens) and logical metonymies (The gentleman began Dickens), contrasting both to the processing of control expressions with a conventional interpretation (The gentleman met Dickens). Eye movement measures during reading indicated that standard (producer for-product) metonymies were not more costly to interpret than conventional expressions, but logical metonymies were more costly to interpret than both standard metonymies and conventional expressions. These results indicate that constructing alternative senses is sometimes taxing and that not all types of deferred interpretations are processed in the same way. The results suggest that a critical factor in determining the attendant cost of constructing alternative senses is whether compositional operations must generate unexpressed semantic structure to realize an extended sense of an expression. PMID- 21702814 TI - Processing reflexives and pronouns in picture noun phrase. AB - Binding theory (e.g., Chomsky, 1981) has played a central role in both syntactic theory and models of language processing. Its constraints are designed to predict that the referential domains of pronouns and reflexives are nonoverlapping, that is, are complementary; these constraints are also thought to play a role in online reference resolution. The predictions of binding theory and its role in sentence processing were tested in four experiments that monitored participants' eye movements as they followed spoken instructions to have a doll touch a picture belonging to another doll. The instructions used pronouns and reflexives embedded in picture noun phrases (PNPs) containing possessor phrases (e.g., Pick up Ken. Have Ken touch Harry's picture of himself). Although the interpretations assigned to pronouns were generally consistent with binding theory, reflexives were frequently assigned interpretations that violated binding theory. In addition, the timing and pattern of eye movements were inconsistent with models of language processing that assume that binding theory acts as an early filter to restrict the referential domain. The interpretations assigned to reflexives in PNPs with possessors suggest that they are binding-theory-exempt logophors, a conclusion that unifies the treatment of reflexives in PNPs. PMID- 21702815 TI - The Isolation, Primacy, and Recency Effects Predicted by an Adaptive LTD/LTP Threshold in Postsynaptic Cells. AB - An item that stands out (is isolated) from its context is better remembered than an item consistent with the context. This isolation effect cannot be accounted for by increased attention, because it occurs when the isolated item is presented as the first item, or by impoverished memory of nonisolated items, because the isolated item is better remembered than a control list consisting of equally different items. The isolation effect is seldom experimentally or theoretically related to the primacy or the recency effects-that is, the improved performance on the first few and last items, respectively, on the serial position curve. The primacy effect cannot easily be accounted for by rehearsal in short-term memory because it occurs when rehearsal is eliminated. This article suggests that the primacy, the recency, and the isolation effects can be accounted for by experience-dependent synaptic plasticity in neural cells. Neurological empirical data suggest that the threshold that determines whether cells will show long-term potentiation (LTP) or long-term depression (LTD) varies as a function of recent postsynaptic activity and that synaptic plasticity is bounded. By implementing an adaptive LTP-LTD threshold in an artificial neural network, the various aspects of the isolation, the primacy, and the recency effects are accounted for, whereas none of these phenomena are accounted for if the threshold is constant. This theory suggests a possible link between the cognitive and the neurological levels. PMID- 21702816 TI - Modeling the Development of Children's Use of Optional Infinitives in Dutch and English Using MOSAIC. AB - In this study we use a computational model of language learning called model of syntax acquisition in children (MOSAIC) to investigate the extent to which the optional infinitive (OI) phenomenon in Dutch and English can be explained in terms of a resource-limited distributional analysis of Dutch and English child directed speech. The results show that the same version of MOSAIC is able to simulate changes in the pattern of finiteness marking in 2 children learning Dutch and 2 children learning English as the average length of their utterances increases. These results suggest that it is possible to explain the key features of the OI phenomenon in both Dutch and English in terms of the interaction between an utterance-final bias in learning and the distributional characteristics of child-directed speech in the 2 languages. They also show how computational modeling techniques can be used to investigate the extent to which cross-linguistic similarities in the developmental data can be explained in terms of common processing constraints as opposed to innate knowledge of universal grammar. PMID- 21702817 TI - Aging and the use of context in ambiguity resolution: complex changes from simple slowing. AB - Older and younger adults' abilities to use context information rapidly during ambiguity resolution were investigated. In Experiments 1 and 2, younger and older adults heard ambiguous words (e.g., fires) in sentences where the preceding context supported either the less frequent or more frequent meaning of the word. Both age groups showed good context use in offline tasks, but only young adults demonstrated rapid use of context in cross-modal naming. A 3rd experiment demonstrated that younger and older adults had similar knowledge about the contexts used in Experiments 1 and 2. The experiment results were simulated in 2 computational models in which different patterns of context use were shown to emerge from varying a single speed parameter. These results suggest that age related changes in processing efficiency can modulate context use during language comprehension. PMID- 21702818 TI - Diversity and unity of modularity. AB - Since the publication of Fodor's (1983) The Modularity of Mind, there have been quite a few discussions of cognitive modularity among cognitive scientists. Generally, in those discussions, modularity means a property of specialized cognitive processes or a domain-specific body of information. In actuality, scholars understand modularity in many different ways. Different characterizations of modularity and modules were proposed and discussed, but they created misunderstanding and confusion. In this article, I classified and analyzed different approaches to modularity and argued for the unity of modularity. Modularity is a multidimensional property consisting of features from several dimensions specifying different aspects of cognition. Among those, there are core features of modularity, and these core features form a cross-dimensional unity. Despite the diverse and liberal characterizations, modularity contributes to cognitive science because of the unity of the core features. PMID- 21702819 TI - Culture and change blindness. AB - Research on perception and cognition suggests that whereas East Asians view the world holistically, attending to the entire field and relations among objects, Westerners view the world analytically, focusing on the attributes of salient objects. These propositions were examined in the change-blindness paradigm. Research in that paradigm finds American participants to be more sensitive to changes in focal objects than to changes in the periphery or context. We anticipated that this would be less true for East Asians and that they would be more sensitive to context changes than would Americans. We presented participants with still photos and with animated vignettes having changes in focal object information and contextual information. Compared to Americans, East Asians were more sensitive to contextual changes than to focal object changes. These results suggest that there can be cultural variation in what may seem to be basic perceptual processes. PMID- 21702820 TI - A hierarchical bayesian model of human decision-making on an optimal stopping problem. AB - We consider human performance on an optimal stopping problem where people are presented with a list of numbers independently chosen from a uniform distribution. People are told how many numbers are in the list, and how they were chosen. People are then shown the numbers one at a time, and are instructed to choose the maximum, subject to the constraint that they must choose a number at the time it is presented, and any choice below the maximum is incorrect. We present empirical evidence that suggests people use threshold-based models to make decisions, choosing the first currently maximal number that exceeds a fixed threshold for that position in the list. We then develop a hierarchical generative account of this model family, and use Bayesian methods to learn about the parameters of the generative process, making inferences about the threshold decision models people use. We discuss the interesting aspects of human performance on the task, including the lack of learning, and the presence of large individual differences, and consider the possibility of extending the modeling framework to account for individual differences. We also use the modeling results to discuss the merits of hierarchical, generative and Bayesian models of cognitive processes more generally. PMID- 21702821 TI - With the future behind them: convergent evidence from aymara language and gesture in the crosslinguistic comparison of spatial construals of time. AB - Cognitive research on metaphoric concepts of time has focused on differences between moving Ego and moving time models, but even more basic is the contrast between Ego- and temporal-reference-point models. Dynamic models appear to be quasi-universal cross-culturally, as does the generalization that in Ego reference-point models, FUTURE IS IN FRONT OF EGO and PAST IS IN BACK OF EGO. The Aymara language instead has a major static model of time wherein FUTURE IS BEHIND EGO and PAST IS IN FRONT OF EGO; linguistic and gestural data give strong confirmation of this unusual culture-specific cognitive pattern. Gestural data provide crucial information unavailable to purely linguistic analysis, suggesting that when investigating conceptual systems both forms of expression should be analyzed complementarily. Important issues in embodied cognition are raised: how fully shared are bodily grounded motivations for universal cognitive patterns, what makes a rare pattern emerge, and what are the cultural entailments of such patterns? PMID- 21702822 TI - The recognition of phonologically assimilated words does not depend on specific language experience. AB - In a series of 5 experiments, we investigated whether the processing of phonologically assimilated utterances is influenced by language learning. Previous experiments had shown that phonological assimilations, such as /lean#bacon/ -> [leam bacon], are compensated for in perception. In this article, we investigated whether compensation for assimilation can occur without experience with an assimilation rule using automatic event-related potentials. Our first experiment indicated that Dutch listeners compensate for a Hungarian assimilation rule. Two subsequent experiments, however, failed to show compensation for assimilation by both Dutch and Hungarian listeners. Two additional experiments showed that this was due to the acoustic properties of the assimilated utterance, confirming earlier reports that phonetic detail is important in compensation for assimilation. Our data indicate that compensation for assimilation can occur without experience with an assimilation rule, in line with phonetic-phonological theories that assume that speech production is influenced by speech-perception abilities. PMID- 21702823 TI - The coordinated interplay of scene, utterance, and world knowledge: evidence from eye tracking. AB - Two studies investigated the interaction between utterance and scene processing by monitoring eye movements in agent-action-patient events, while participants listened to related utterances. The aim of Experiment 1 was to determine if and when depicted events are used for thematic role assignment and structural disambiguation of temporarily ambiguous English sentences. Shortly after the verb identified relevant depicted actions, eye movements in the event scenes revealed disambiguation. Experiment 2 investigated the relative importance of linguistic/world knowledge and scene information. When the verb identified either only the stereotypical agent of a (nondepicted) action, or the (nonstereotypical) agent of a depicted action as relevant, verb-based thematic knowledge and depicted action each rapidly influenced comprehension. In contrast, when the verb identified both of these agents as relevant, the gaze pattern suggested a preferred reliance of comprehension on depicted events over stereotypical thematic knowledge for thematic interpretation. We relate our findings to language comprehension and acquisition theories. PMID- 21702824 TI - Memory and mystery: the cultural selection of minimally counterintuitive narratives. AB - We hypothesize that cultural narratives such as myths and folktales are more likely to achieve cultural stability if they correspond to a minimally counterintuitive (MCI) cognitive template that includes mostly intuitive concepts combined with a minority of counterintuitive ones. Two studies tested this hypothesis, examining whether this template produces a memory advantage, and whether this memory advantage explains the cultural success of folktales. In a controlled laboratory setting, Study 1 found that an MCI template produces a memory advantage after a 1-week delay, relative to entirely intuitive or maximally counterintuitive cognitive templates. Using archival methods, Study 2 examined the cognitive structure of Grimm Brothers folktales. Compared to culturally unsuccessful folktales, those that were demonstrably successful were especially likely to fit an MCI template. These findings highlight the role of human memory processes in cultural evolution. PMID- 21702825 TI - Arrows in comprehending and producing mechanical diagrams. AB - Mechanical systems have structural organizations-parts, and their relations-and functional organizations-temporal, dynamic, and causal processes-which can be explained using text or diagrams. Two experiments illustrate the role of arrows in diagrams of mechanical systems. In Experiment 1, people described diagrams with or without arrows, interpreting diagrams without arrows as conveying structural information and diagrams with arrows as conveying functional information. In Experiment 2, people produced sketches of mechanical systems from structural or functional descriptions. People spontaneously used arrows to indicate functional processes in diagrams. Arrows can play a powerful role in augmenting structural diagrams to convey dynamic, causal, or functional information. PMID- 21702826 TI - Is the brain a quantum computer? AB - We argue that computation via quantum mechanical processes is irrelevant to explaining how brains produce thought, contrary to the ongoing speculations of many theorists. First, quantum effects do not have the temporal properties required for neural information processing. Second, there are substantial physical obstacles to any organic instantiation of quantum computation. Third, there is no psychological evidence that such mental phenomena as consciousness and mathematical thinking require explanation via quantum theory. We conclude that understanding brain function is unlikely to require quantum computation or similar mechanisms. PMID- 21702827 TI - Bringing cognitive science into education, and back again: the value of interdisciplinary research. PMID- 21702828 TI - Relations, objects, and the composition of analogies. AB - This research addresses the kinds of matching elements that determine analogical relatedness and literal similarity. Despite theoretical agreement on the importance of relational match, the empirical evidence is neither systematic nor definitive. In 3 studies, participants performed online evaluations of relatedness of sentence pairs that varied in either the object or relational match. Results show a consistent focus on relational matches as the main determinant of analogical acceptance. In addition, analogy does not require strict overall identity of relational concepts. Semantically overlapping but nonsynonymous relations were commonly accepted, but required more processing time. Finally, performance in a similarity rating task partly paralleled analogical acceptance; however, relatively more weight was given to object matches. Implications for psychological theories of analogy and similarity are addressed. PMID- 21702829 TI - Uncertainty about the rest of the sentence. AB - A word-by-word human sentence processing complexity metric is presented. This metric formalizes the intuition that comprehenders have more trouble on words contributing larger amounts of information about the syntactic structure of the sentence as a whole. The formalization is in terms of the conditional entropy of grammatical continuations, given the words that have been heard so far. To calculate the predictions of this metric, Wilson and Carroll's (1954) original entropy reduction idea is extended to infinite languages. This is demonstrated with a mildly context-sensitive language that includes relative clauses formed on a variety of grammatical relations across the Accessibility Hierarchy of Keenan and Comrie (1977). Predictions are derived that correlate significantly with repetition accuracy results obtained in a sentence-memory experiment (Keenan & Hawkins, 1987). PMID- 21702830 TI - An embodied model for sensorimotor grounding and grounding transfer: experiments with epigenetic robots. AB - The grounding of symbols in computational models of linguistic abilities is one of the fundamental properties of psychologically plausible cognitive models. In this article, we present an embodied model for the grounding of language in action based on epigenetic robots. Epigenetic robotics is one of the new cognitive modeling approaches to modeling autonomous mental development. The robot model is based on an integrative vision of language in which linguistic abilities are strictly dependent on and grounded in other behaviors and skills. It uses simulated robots that learn through imitation the names of basic actions. Robots also learn higher order action concepts through the process of grounding transfer. The simulation demonstrates how new, higher order behavioral abilities can be autonomously built on previously grounded basic action categories following linguistic interaction with human users. PMID- 21702831 TI - The interpretation of classically quantified sentences: a set-theoretic approach. AB - We present a set-theoretic model of the mental representation of classically quantified sentences (All P are Q, Some P are Q, Some P are not Q, and No P are Q). We take inclusion, exclusion, and their negations to be primitive concepts. We show that although these sentences are known to have a diagrammatic expression (in the form of the Gergonne circles) that constitutes a semantic representation, these concepts can also be expressed syntactically in the form of algebraic formulas. We hypothesized that the quantified sentences have an abstract underlying representation common to the formulas and their associated sets of diagrams (models). We derived 9 predictions (3 semantic, 2 pragmatic, and 4 mixed) regarding people's assessment of how well each of the 5 diagrams expresses the meaning of each of the quantified sentences. We report the results from 3 experiments using Gergonne's (1817) circles or an adaptation of Leibniz (1903/1988) lines as external representations and show them to support the predictions. PMID- 21702832 TI - Unsupervised discovery of nonlinear structure using contrastive backpropagation. AB - We describe a way of modeling high-dimensional data vectors by using an unsupervised, nonlinear, multilayer neural network in which the activity of each neuron-like unit makes an additive contribution to a global energy score that indicates how surprised the network is by the data vector. The connection weights that determine how the activity of each unit depends on the activities in earlier layers are learned by minimizing the energy assigned to data vectors that are actually observed and maximizing the energy assigned to "confabulations" that are generated by perturbing an observed data vector in a direction that decreases its energy under the current model. PMID- 21702833 TI - Perception of auditory motion affects language processing. AB - Previous reports have demonstrated that the comprehension of sentences describing motion in a particular direction (toward, away, up, or down) is affected by concurrently viewing a stimulus that depicts motion in the same or opposite direction. We report 3 experiments that extend our understanding of the relation between perception and language processing in 2 ways. First, whereas most previous studies of the relation between perception and language processing have focused on visual perception, our data show that sentence processing can be affected by the concurrent processing of auditory stimuli. Second, it is shown that the relation between the processing of auditory stimuli and the processing of sentences depends on whether the sentences are presented in the auditory or visual modality. PMID- 21702834 TI - Flexible conceptual projection of time onto spatial frames of reference. AB - Flexibility in conceptual projection constitutes one of the most challenging issues in the embodiment and conceptual metaphor literatures. We sketch a theoretical proposal that places the burden of the explanation on attentional dynamics in interaction with mental models in working memory that are constrained to be maximally coherent. A test of this theory is provided in the context of the conceptual projection of time onto the domain of space. Participants categorized words presented at different spatial locations (back-front, left-right) as referring to the past or to the future. Responses were faster when the irrelevant word location was congruent with the back-past, front-future metaphoric mapping. Moreover, when a new highly task-relevant spatial frame of reference was introduced, it changed the projection of past and future onto space in a way that was congruent with the new frame (past was now projected to left space and future to right space), as predicted by the theory. This study shows that there is substantial flexibility in conceptual projection and opens a venue to study metaphoric variation across tasks, individuals, and cultures as the result of attentional dynamics. PMID- 21702835 TI - Metacognitive control and optimal learning. AB - The notion of optimality is often invoked informally in the literature on metacognitive control. We provide a precise formulation of the optimization problem and show that optimal time allocation strategies depend critically on certain characteristics of the learning environment, such as the extent of time pressure, and the nature of the uptake function. When the learning curve is concave, optimality requires that items at lower levels of initial competence be allocated greater time. On the other hand, with logistic learning curves, optimal allocations vary with time availability in complex and surprising ways. Hence there are conditions under which optimal strategies will be relatively easy to uncover, and others in which suboptimal time allocation might be expected. The model can therefore be used to address the question of whether and when learners should be able to exercise good metacognitive control in practice. PMID- 21702836 TI - Introduction to the 2005 rumelhart prize special issue honoring paul smolensky. PMID- 21702837 TI - Harmony in linguistic cognition. AB - In this article, I survey the integrated connectionist/symbolic (ICS) cognitive architecture in which higher cognition must be formally characterized on two levels of description. At the microlevel, parallel distributed processing (PDP) characterizes mental processing; this PDP system has special organization in virtue of which it can be characterized at the macrolevel as a kind of symbolic computational system. The symbolic system inherits certain properties from its PDP substrate; the symbolic functions computed constitute optimization of a well formedness measure called Harmony. The most important outgrowth of the ICS research program is optimality theory (Prince & Smolensky, 1993/2004), an optimization-based grammatical theory that provides a formal theory of cross linguistic typology. Linguistically, Harmony maximization corresponds to minimization of markedness or structural ill-formedness. Cognitive explanation in ICS requires the collaboration of symbolic and connectionist principles. ICS is developed in detail in Smolensky and Legendre (2006a); this article is a precis of and guide to those volumes. PMID- 21702838 TI - Early child grammars: qualitative and quantitative analysis of morphosyntactic production. AB - This article reports on a series of 5 analyses of spontaneous production of verbal inflection (tense and person-number agreement) by 2-year-olds acquiring French as a native language. A formal analysis of the qualitative and quantitative results is developed using the unique resources of Optimality Theory (OT; Prince & Smolensky, 2004). It is argued that acquisition of morphosyntax proceeds via overlapping grammars (rather than through abrupt changes), which OT formalizes in terms of partial rather than total constraint rankings. Initially, economy of structure constraints take priority over faithfulness constraints that demand faithful expression of a speaker's intent, resulting in child production of tense that is comparable in level to that of child-directed speech. Using the independent Predominant Length of Utterance measure of syntactic development proposed in Vainikka, Legendre, and Todorova (1999), production of agreement is shown first to lag behind tense then to compete with tense at an intermediate stage of development. As the child's development progresses, faithfulness constraints become more dominant, and the overall production of tense and agreement becomes adult-like. PMID- 21702839 TI - Phonotactics and articulatory coordination interact in phonology: evidence from nonnative production. AB - A core area of phonology is the study of phonotactics, or how sounds are linearly combined. Recent cross-linguistic analyses have shown that the phonology determines not only phonotactics but also the articulatory coordination or timing of adjacent sounds. In this article, I explore how the relation between coordination and phonotactics affects speakers producing nonnative sequences. Recent experimental results (Davidson 2005, 2006) have shown that English speakers often repair unattested word-initial sequences (e.g., /zg/, /vz/) by producing the consonants with a less overlapping coordination. A theoretical account of the experimental results employs Gafos's (2002) constraint-based grammar of coordination. In addition to Gafos's Alignment constraints establishing temporal relations between consonants, a family of Release constraints is proposed to encode phonotactic restrictions. The interaction of Alignment and Release constraints accounts for why speakers produce nonnative sequences by failing to adequately overlap the articulation of the consonants. The optimality theoretic analysis also incorporates floating constraints to explain why speakers are not equally accurate on all unattested clusters. PMID- 21702840 TI - Faithful contrastive features in learning. AB - This article pursues the idea of inferring aspects of phonological underlying forms directly from surface contrasts by looking at optimality theoretic linguistic systems (Prince & Smolensky, 1993/2004). The main result proves that linguistic systems satisfying certain conditions have the faithful contrastive feature property: Whenever 2 distinct morphemes contrast on the surface in a particular environment, at least 1 of the underlying features on which the 2 differ must be realized faithfully on the surface. A learning procedure exploiting the faithful contrastive feature property, contrast analysis, can set the underlying values of some features, even where featural minimal pairs do not exist, but is nevertheless fundamentally limited in what it can set. This work suggests that observation of surface contrasts between pairs of words can contribute to the learning of underlying forms, while still supporting the view that interaction with the phonological mapping will be necessary to fully determine underlying forms. PMID- 21702841 TI - Dynamics of phonological cognition. AB - A fundamental problem in spoken language is the duality between the continuous aspects of phonetic performance and the discrete aspects of phonological competence. We study 2 instances of this problem from the phenomenon of voicing neutralization and vowel harmony. In each case, we present a model where the experimentally observed continuous distinctions are linked to the discreteness of phonological form using the mathematics of nonlinear dynamics. PMID- 21702842 TI - Learning phonology with substantive bias: an experimental and computational study of velar palatalization. AB - There is an active debate within the field of phonology concerning the cognitive status of substantive phonetic factors such as ease of articulation and perceptual distinctiveness. A new framework is proposed in which substance acts as a bias, or prior, on phonological learning. Two experiments tested this framework with a method in which participants are first provided highly impoverished evidence of a new phonological pattern, and then tested on how they extend this pattern to novel contexts and novel sounds. Participants were found to generalize velar palatalization (e.g., the change from [k] as in keep to [t??S] as in cheap) in a way that accords with linguistic typology, and that is predicted by a cognitive bias in favor of changes that relate perceptually similar sounds. Velar palatalization was extended from the mid front vowel context (i.e., before [e] as in cape) to the high front vowel context (i.e., before [i] as in keep), but not vice versa. The key explanatory notion of perceptual similarity is quantified with a psychological model of categorization, and the substantively biased framework is formalized as a conditional random field. Implications of these results for the debate on substance, theories of phonological generalization, and the formalization of similarity are discussed. PMID- 21702843 TI - The import and export of cognitive science. PMID- 21702844 TI - How known constructions influence the acquisition of other constructions: the german passive and future constructions. AB - This article suggests evidence for and reasons why prior acquisition may either facilitate or inhibit acquisition of a new construction. It investigates acquisition of the German passive and future constructions which contain a lexical verb with either the auxiliary sein "to be" or werden "to become", and are related through these to potential supporting constructions. We predicted that a supported construction should be acquired earlier, faster, and unusually rapidly. An inhibited construction should show an extended depressed usage. We analyzed a dense corpus of a German boy between 2;0 and 5;0. He acquired the sein before the werden-passive. The former was supported by his prior acquisition of the sein copula, whereas the werden-passive itself supported one werden copula construction. He acquired the werden-future extremely slowly due to the hindrance of a semantically identical construction. These results fit with an emergentist approach in which apparently "sudden" acquisition is still due to gradual learning mechanisms. PMID- 21702845 TI - Errors of Omission in English-Speaking Children's Production of Plurals and the Past Tense: The Effects of Frequency, Phonology, and Competition. AB - How do English-speaking children inflect nouns for plurality and verbs for the past tense? We assess theoretical answers to this question by considering errors of omission, which occur when children produce a stem in place of its inflected counterpart (e.g., saying "dress" to refer to 5 dresses). A total of 307 children (aged 3;11-9;9) participated in 3 inflection studies. In Study 1, we show that errors of omission occur until the age of 7 and are more likely with both sibilant regular nouns (e.g., dress) and irregular nouns (e.g., man) than regular nouns (e.g., dog). Sibilant nouns are more likely to be inflected if they are high frequency. In Studies 2 and 3, we show that similar effects apply to the inflection of verbs and that there is an advantage for "regular-like" irregulars whose inflected form, but not stem form, ends in d/t. The results imply that (a) stems and inflected forms compete for production and (b) children generalize both product-oriented and source-oriented schemas when learning about inflectional morphology. PMID- 21702846 TI - Pictures and spoken descriptions elicit similar eye movements during mental imagery, both in light and in complete darkness. AB - This study provides evidence that eye movements reflect the positions of objects while participants listen to a spoken description, retell a previously heard spoken description, and describe a previously seen picture. This effect is equally strong in retelling from memory, irrespective of whether the original elicitation was spoken or visual. In addition, this effect occurs both while watching a blank white board and while sitting in complete darkness. This study includes 4 experiments. The first 2 experiments measured eye movements of participants looking at a blank white board. Experiment 1 monitors eye movements of participants on 2 occasions: first, when participants listened to a prerecorded spoken scene description; second, when participants were later retelling it from memory. Experiment 2 first monitored eye movements of participants as they studied a complex picture visually, and then later as they described it from memory. The second pair of experiments (Experiments 3 and 4) replicated Experiments 1 and 2 with the only difference being that they were executed in complete darkness. This method of analysis differentiated between eye movements that are categorically correct relative to the positions of the whole eye gaze pattern (global correspondence) and eye movements that are only locally correct (local correspondence). The discussion relates the findings to the current debate on mental imagery. PMID- 21702847 TI - Decision making and confidence given uncertain advice. AB - We study human decision making in a simple forced-choice task that manipulates the frequency and accuracy of available information. Empirically, we find that people make decisions consistent with the advice provided, but that their subjective confidence in their decisions shows 2 interesting properties. First, people's confidence does not depend solely on the accuracy of the advice. Rather, confidence seems to be influenced by both the frequency and accuracy of the advice. Second, people are less confident in their guessed decisions when they have to make relatively more of them. Theoretically, we develop and evaluate a type of sequential sampling process model-known as a self-regulating accumulator that accounts for both decision making and confidence. The model captures the regularities in people's behavior with interpretable parameter values, and we show its ability to fit the data is not due to excessive model complexity. Using the model, we draw conclusions about some properties of human reasoning under uncertainty. PMID- 21702848 TI - The Action-Sentence Compatibility Effect: It's All in the Timing. AB - When participants are asked to make sensibility judgments on sentences that describe action toward the body (i.e., "Mark dealt the cards to you") or away from the body (i.e., "You dealt the cards to Mark"), they are faster to respond when the response requires an arm movement in the same direction as the action described by the sentence. This congruence effect is known as the Action-Sentence Compatibility Effect (ACE). This study reports 4 experiments that extend our understanding of the ACE by exploring how the time at which one prepares the motor response required for the sensibility judgment affects the magnitude of the ACE. Results show that the ACE arises only when participants have the opportunity to plan their motor response while they are processing the sentence. PMID- 21702849 TI - Phonological abstraction in the mental lexicon. AB - A perceptual learning experiment provides evidence that the mental lexicon cannot consist solely of detailed acoustic traces of recognition episodes. In a training lexical decision phase, listeners heard an ambiguous [f-s] fricative sound, replacing either [f] or [s] in words. In a test phase, listeners then made lexical decisions to visual targets following auditory primes. Critical materials were minimal pairs that could be a word with either [f] or [s] (cf. English knife nice), none of which had been heard in training. Listeners interpreted the minimal pair words differently in the second phase according to the training received in the first phase. Therefore, lexically mediated retuning of phoneme perception not only influences categorical decisions about fricatives (Norris, McQueen, & Cutler, 2003), but also benefits recognition of words outside the training set. The observed generalization across words suggests that this retuning occurs prelexically. Therefore, lexical processing involves sublexical phonological abstraction, not only accumulation of acoustic episodes. PMID- 21702850 TI - Acknowledgment: guest reviewers. PMID- 21702851 TI - Oral microflora in infants delivered vaginally and by caesarean section. AB - BACKGROUND. Early in life, vaginally delivered infants exhibit a different composition of the gut flora compared with infants delivered by caesarean section (C-section); however, it is unclear whether this also applies to the oral cavity. AIM. To investigate and compare the oral microbial profile between infants delivered vaginally and by C-section. DESIGN. This is a cross-sectional case control study. Eighty-four infants delivered either vaginally (n = 42) or by C section (n = 42) were randomly selected from the 2009 birth cohort at the County Hospital in Halmstad, Sweden. Medically compromised and premature children (<32 weeks) were excluded. The mean age was 8.25 months (range 6-10 months), and parents were asked to complete a questionnaire on socioeconomic factors, lifestyle, and hygiene habits. Saliva was collected and analysed using checkerboard DNA-DNA hybridization. RESULTS. A higher prevalence of salivary Streptococcus salivarius, Lactobacillus curvata, Lactobacillus salivarius, and Lactobacuillus casei was detected in infants delivered vaginally (P < 0.05). The caries-associated bacteria Streptococcus mutans and Streptococcus sobrinus were detected in 63% and 59% of all children, respectively. CONCLUSION. A significantly higher prevalence of certain strains of health-related streptococci and lactobacilli was found in vaginally delivered infants compared with infants delivered by C-section. The possible long-term effects on oral health need to be further investigated. PMID- 21702852 TI - Limited phenotypic variation of hypocalcified amelogenesis imperfecta in a Danish five-generation family with a novel FAM83H nonsense mutation. AB - BACKGROUND. Autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI) is a disease with severe dental manifestations. OBJECTIVES. The aims were by means of a genome-wide linkage scan to search for the gene underlying the ADHCAI phenotype in a Danish five-generation family and to study the phenotypic variation of the enamel in affected family members. RESULTS. Significant linkage was found to a locus at chromosome 8q24.3 comprising the gene FAM83H identified to be responsible for ADHCAI in other families. Subsequent sequencing of FAM83H in affected family members revealed a novel nonsense mutation, p.Y302X. Limited phenotypic variation was found among affected family members with loss of translucency and discoloration of the enamel. Extensive posteruptive loss of enamel was found in all teeth of affected subjects. The tip of the cusps on the premolars and molars and a zone along the gingival margin seemed resistant to posteruptive loss of enamel. We have screened FAM83H in another five unrelated Danish patients with a phenotype of ADHCAI similar to that in the five-generation family, and identified a de novo FAM83H nonsense mutation, p.Q452X in one of these patients. CONCLUSION. We have identified a FAM83H mutation in two of six unrelated families with ADHCAI and found limited phenotypic variation of the enamel in these patients. PMID- 21702853 TI - The ability of pulp sensibility tests to evaluate the pulp status in primary teeth. AB - BACKGROUND. Accurate determination of the pulp status is the most important part of conservative pulp therapy. AIM. The aim of this study was to assess the ability of thermal and electrical pulp tests to assess the pulp status in primary teeth. DESIGN. Seventy-eight primary molar teeth in 36 children were investigated. Fifty-six teeth had unknown pulp status in need of endodontic treatment, and 22 were intact teeth with no signs of pulp disease. Cold, hot and electrical pulp testing (EPT) were performed on each tooth. The gold standard was established by direct inspection of the pulp after an access cavity had been made. The sensitivity, specificity, positive and negative predictive values for each test and different sequential combinations of pulp testing were calculated. Sequential combination test analysis was used for data analysis. RESULTS. The highest accuracy was found for EPT, followed by heat and cold tests. No significant difference was found between the accuracy of EPT and the heat test (P values > 0.05); however, the accuracy of EPT was significantly higher than that of the cold test (P-value< 0.05). CONCLUSION. Based on this study, EPT can be used as a reliable test for diagnosing the pulp status in primary teeth. PMID- 21702854 TI - Effects of silver diamine fluoride on dentine carious lesions induced by Streptococcus mutans and Actinomyces naeslundii biofilms. AB - BACKGROUND. Silver diamine fluoride (SDF) has been shown to be a successful treatment for arresting caries. However, the mechanism of SDF is to be elucidated. AIM. To characterize the effects of SDF on dentine carious induced by Streptococcus mutans and Actinomyces naeslundii. DESIGN. Thirty-two artificially demineralized human dentine blocks were inoculated: 16 with S. mutans and 16 with A. naeslundii. Either SDF or water was applied to eight blocks in each group. Biofilm morphology, microbial kinetics and viability were evaluated by scanning electron microscopy, colony forming units, and confocal microscopy. The crosssection of the dentine carious lesions were assessed by microhardness testing, scanning electron microscopy with energy-dispersive x-ray spectroscopy and Fourier transform infrared spectroscopy. RESULTS. Biofilm counts were reduced in SDF group than control (P < 0.01). Surfaces of carious lesions were harder after SDF application than after water application (P < 0.05), in S. mutans group, Ca and P weight percentage after SDF application than after water application (P < 0.05). Lesions showed a significantly reduced level of matrix to phosphate after SDF treatment (P < 0.05). CONCLUSION. Present study showed that SDF posses an anti-microbial activity against cariogenic biofilm of S. mutans or A. naeslundii formed on dentine surfaces. SDF slowed down demineralization of dentine. This dual activity could be the reason behind clinical success of SDF. PMID- 21702855 TI - Salivary flow rate and oral findings in Prader-Willi syndrome: a case-control study. AB - BACKGROUND. Prader-Willi syndrome (PWS) is a rare complex multisystemic genetic disorder. AIM. The objective of this study was to provide a systematic assessment of whole saliva secretion and oral manifestations associated with PWS. DESIGN. Fifty individuals (5-40 years) with PWS and an age- and sex-matched control group were included. Whole saliva was collected. All participants underwent an anamnestic interview. Radiological and dental clinical examinations were carried out to identify hypodontia, dental caries, enamel defects and gingival inflammation. RESULTS. Mean whole salivary flow rate was 0.12 +/- 0.11 mL/min in the study group compared with 0.32 +/- 0.20 mL/min in the control group (P < 0.001). Hypodontia was significantly more common in PWS (P < 0.001), and dental caries in the age group >19 years was significantly lower in PWS (P = 0.04) compared with the controls. There was no significant difference in the prevalence of dental caries in the primary dentition or in the frequency of enamel defects in the permanent dentition between the two groups. Median Gingival Index was significantly higher in the Prader-Willi group compared with the controls (P = 0.02). CONCLUSIONS. Low salivary flow is a consistent finding in PWS. Nevertheless, despite dry mouth and dietary challenges, dental caries is not increased in Norwegian individuals with PWS. PMID- 21702856 TI - RNAi-mediated inhibition of the desmosomal cadherin (desmoglein 3) impairs epithelial cell proliferation. AB - OBJECTIVES: Desmoglein 3 (Dsg3) is a desmosomal adhesion protein expressed in basal and immediate suprabasal layers of skin. Importance of Dsg3 in cell-cell adhesion and maintenance of tissue integrity is illustrated by findings of keratinocyte dissociation in the autoimmune disease, pemphigus vulgaris, where autoantibodies target Dsg3 on keratinocyte surfaces and cause Dsg3 depletion from desmosomes. However, recognition of possible participation of involvement of Dsg3 in cell proliferation remains controversial. Currently, available evidence suggests that Dsg3 may have both anti- and pro-proliferative roles in keratinocytes. The aim of this study was to use RNA interference (RNAi) strategy to investigate effects of silencing Dsg3 in cell-cell adhesion and cell proliferation in two cell lines, HaCaT and MDCK. MATERIALS AND METHODS: Cells were transfected with siRNA, and knockdown of Dsg3 was assessed by western blotting, fluorescence-activated cell sorting and confocal microscopy. Cell-cell adhesion was analysed using the hanging drop/fragmentation assay, and cell proliferation by colony forming efficiency, BrdU incorporation, cell counts and organotypic culture. RESULTS: Silencing Dsg3 caused defects in cell-cell adhesion and concomitant reduction in cell proliferation in both HaCaT and MDCK cells. CONCLUSION: These findings suggest that Dsg3 depletion by RNAi reduces cell proliferation, which is likely to be secondary to a defect in cell-cell adhesion, an essential function required for cell differentiation and morphogenesis. PMID- 21702857 TI - Regulation of pre-adipocyte proliferation and apoptosis by the small leucine-rich proteoglycans, biglycan and decorin. AB - Evidence for a functional role for extracellular matrix (ECM) proteins in adipose tissue is demonstrated in dynamic changes in expression of ECM genes during adipocyte differentiation and in obesity. Components of the ECM may regulate adipose cell number expansion by restricting pre-adipocyte proliferation, regulating apoptosis and inhibiting adipogenesis. Although pre-adipocytes express multiple proteoglycans, their role in pre-adipocyte proliferation up to now has remained unknown. The study described here was conducted to characterize roles of small leucine-rich proteoglycans (SLRPs) in adipocyte proliferation. Pre adipocytes were seeded on plates coated with biglycan and decorin and were allowed to differentiate. In addition, pre-adipocytes were incubated on plates coated with biglycan, decorin, or fibronectin and measurements were made of cell proliferation and apoptosis. We are able to report that SLRPs decorin and biglycan did not affect differentiation of our 3T3-L1 cells; however, biglycan and decorin did reduce proliferation of pre-adipocytes, partly by induction of apoptosis. Furthermore, anti-proliferative capabilities of decorin and biglycan were nullified with removal of GAG side-chains suggesting that the chains played key roles in anti-proliferative effects of the SLRPs. We also found that co treatment of decorin or biglycan with the proteoglycan fibronectin restored normal proliferation, an indication that multiple ECM proteins may act in concert to regulate overall proliferation rates of pre-adipocytes. These studies indicate that SLRPs may compose a regulatory factor in adipose tissue expansion, through hyperplasia. PMID- 21702858 TI - Effects of tumour necrosis factor-alpha on activity and nitric oxide synthase of endothelial progenitor cells from peripheral blood. AB - The aim of this investigation was to determine whether tumour necrosis factor alpha (TNF-alpha) has any effect on endothelial progenitor cells (EPCs). Total mononuclear cells were isolated from peripheral blood by Ficoll density gradient centrifugation, and then the cells were plated on fibronectin-coated culture dishes. After 7 days culture, attached cells were stimulated with tumour necrosis factor-alpha (final concentrations: 0, 10, 20, 50 and 100 mg/l) for 0, 6, 12, 24 and 48 h. EPCs were characterized as adherent cells double positive for DiLDL uptake and lectin binding, by direct fluorescence staining. EPC proliferation and migration were assayed using the MTT assay and modified Boyden chamber assay, respectively. EPC adhesion assay was performed by re-plating those cells on fibronectin-coated dishes, and adherent cells were counted. Tube formation activity was assayed using a tube formation kit. Levels of apoptosis were revealed using an annexin V apoptosis detection kit. Vascular endothelial growth factor Receptor-1 (VEGF-R1) and stromal derived factor-1 (SDF-1) mRNA, assessed by real-time RT-PCR inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) were assayed by western blot analysis. Incubation of EPCs with tumour necrosis factor-alpha reduced EPC proliferation, migration, adhesion, tube formation capacity, iNOS and eNOS in concentration- and time-dependent manners. Tumour necrosis factor-alpha reduced proliferation, migration, adhesion and tube formation capacity of EPCs. TNF-alpha increased EPC apoptosis level, reduced VEGF-R1 and SDF-1 mRNA expression; tumour necrosis factor-alpha also reduced iNOS and eNOS in the EPCs. PMID- 21702859 TI - Effects of enamel matrix proteins on proliferation, differentiation and attachment of human alveolar osteoblasts. AB - OBJECTIVES: Enamel matrix proteins (EMPs) have been demonstrated to promote periodontal regeneration. However, effects of EMPs on human alveolar osteoblasts (hAOBs), up to now, have still been unclear. The purpose of this study was to investigate influence of EMPs on proliferation, differentiation and attachment of hAOBs in vitro. MATERIALS AND METHODS: EMPs were extracted using the acetic acid method, hAOBs were obtained and cultured in vitro. Cell proliferation, alkaline phosphatase (ALP) activity, mRNA expression of osteogenic markers and cell attachment were measured in the absence and in the presence of EMPs (50, 100 and 200 MUg/ml). RESULTS: EMPs increased proliferation of hAOBs; however, they inhibited ALP activity and mRNA expression of osteogenic markers (collagen I, ALP, runt-related protein 2, osteocalcin, bone sialoprotein and osteopontin). Meanwhile, EMPs hindered hAOBs' attachment. These effects occurred in EMPs concentration-dependent manner. CONCLUSIONS: These results indicate that EMPs may inhibit osteoblastic differentiation and attachment to prevent ankylosis and allow other cell types to regenerate periodontal tissues. PMID- 21702860 TI - Changes in quality of life among newly diagnosed breast cancer patients in Taiwan. AB - AIM: To examine changes in quality of life among patients with breast cancer and factors related to it, during the first three months after diagnosis. BACKGROUND: Numerous studies have examined quality of life among cancer survivors or among patients with cancer after aggressive treatment; such research has demonstrated that quality of life in the third month after surgery can significantly predict quality of life in the long run. In contrast, changes in quality of life causes among patients during the acute treatment phase have not been well studied. DESIGN: Prospective longitudinal study. METHODS: Newly diagnosed patients with breast cancer were recruited during 2008-2009. Sixty-one cases completed the four data collections on the day before operation and one, two and three months after surgery. Data were collected using the Functional Living Index-Cancer, Symptom Distress Scale, the Self-Efficacy Scale and a 0-10 Anxiety Numeric Rating Scale. Generalized Estimating Equations were applied for data analysis. RESULTS: There were significant changes in quality of life over the three months following surgery, and the worst quality of life was observed in the first month after surgery. Less advanced stages of cancer, lower anxiety, less symptom distress and higher perceived self-efficacy in the preoperative interview could significantly predict which patients experienced more positive quality of life trends. Fatigue, limited shoulder function and perceived poor appearance were the most significant factors predicting changes of quality of life. CONCLUSION: Preoperative physical and psychological factors, as well as sense of self-efficacy for managing the cancer, are important factors for predicting changes in patients' quality of life. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers should be alert to factors contributing to changes of quality of life among patients receiving chemotherapy. Interventions based on these results should be developed and their effectiveness tested for their impact on breast cancer patients' quality of life. Clinical interventions based on these results should be developed to improve breast cancer patients' quality of life. PMID- 21702861 TI - A randomised controlled clinical trial of repositioning, using the 30 degrees tilt, for the prevention of pressure ulcers. AB - BACKGROUNDL: Pressure ulcers are common, costly and impact negatively on individuals. Pressure is the prime cause, and immobility is the factor that exposes individuals to pressure. International guidelines advocate repositioning; however, there is confusion surrounding the best method and frequency required. DESIGN: A pragmatic, multi-centre, open label, prospective, cluster-randomised controlled trial was conducted to compare the incidence of pressure ulcers among older persons nursed using two different repositioning regimens. METHOD: Ethical approval was received. Study sites (n=12) were allocated to study arm using cluster randomisation. The experimental group (n=99) were repositioned three hourly at night, using the 30 degrees tilt; the control group (n=114) received routine prevention (six-hourly repositioning, using 90 degrees lateral rotation). Data analysis was by intention to treat; follow-up was for four weeks. RESULTS: All participants (n=213) were Irish and white, among them 77% were women and 65% aged 80 years or older. Three patients (3%) in the experimental group and 13 patients (11%) in the control group developed a pressure ulcer (p=0.035; 95% CI 0.031-0.038; ICC=0.001). All pressure ulcers were grade 1 (44%) or grade 2 (56%). Mobility and activity were the highest predictors of pressure ulcer development (beta=-0.246, 95% CI=-0.319 to -0.066; p=0.003); (beta=0.227, 95% CI=0.041-0.246; p = 0.006). CONCLUSION: Repositioning older persons at risk of pressure ulcers every three hours at night, using the 30 degrees tilt, reduces the incidence of pressure ulcers compared with usual care. The study supports the recommendations of the 2009 international pressure ulcer prevention guidelines. RELEVANCE TO CLINICAL PRACTICE: An effective method of pressure ulcer prevention has been identified; in the light of the problem of pressures ulcers, current prevention strategies should be reviewed. It is important to implement appropriate prevention strategies, of which repositioning is one. PMID- 21702862 TI - Lifestyle behaviours and psychosocial well-being of Chinese adolescents in Hong Kong and Guangzhou, China: a cross-sectional comparative survey. AB - AIMS: To describe and compare the lifestyle behaviours and psychosocial well being of Chinese adolescents aged 10-19 in the two cities of Hong Kong and Guangzhou and to identify the factors that most influence adolescents' lifestyle patterns in these two cities. BACKGROUND: Health-promoting lifestyle behaviours of adolescents are influenced by economic growth and societal changes. DESIGN: A cross-sectional comparative survey. METHODS: The Chinese version of the Adolescent Lifestyle Questionnaire was used to measure the adolescents' lifestyle behaviours and psychosocial well-being in the primary and secondary schools. RESULTS: A total of 2014 adolescents aged 10-19 responded to the survey in Hong Kong (n = 1008) and Guangzhou (n = 1006). Adolescents in Guangzhou practised healthier lifestyle behaviours and psychosocial well-being than adolescents in Hong Kong, with statistically significant differences in all the seven dimensions. Adolescents in Guangzhou, when compared with those in Hong Kong, obtained higher mean scores in 'physical participation' (9.6 vs. 8.9, p < 0.001), 'nutrition' (20.2 vs. 17.6, p < 0.001), 'social support' (19.6 vs. 18.9, p = 0.001), 'stress management' (9.6 vs. 9.3, p = 0.022), 'identity awareness' (25.7 vs. 23.5, p < 0.001), 'health practices awareness' (9.2 vs. 8.3, p < 0.001) and 'safety' (21.6 vs. 20.6, p < 0.001). Demographic factors that contributed to adolescents' lifestyle behaviours were living in Guangzhou (OR = 1.92, 95% CI 1.56, 2.44), being in the younger age group (10-14 years old) (OR = 2.44, 95% CI 2.00, 3.03) and living with both parents (OR = 1.92, 95% CI 1.12, 3.27). CONCLUSIONS: Socio-economic disparities, family composition and age group are the key factors associated with adolescents' healthy lifestyle behaviours. Further research is needed to understand the complex causal pathways between ethnicity, social environment and health behaviours. RELEVANCE TO CLINICAL PRACTICE: Parental lifestyles inevitably influence the lifestyles of their young. Therefore, nurses should emphasise the health education of both parents and youth as future parents and support parents in modelling health-promoting lifestyles. PMID- 21702863 TI - Being concerned: caregiving for Taiwanese mothers of a child with cerebral palsy. AB - AIMS AND OBJECTIVES: This article explores the Chinese social context and provides insight into Taiwanese mothers' challenging experiences when a disabled child is born into their families. BACKGROUND: International research indicates that barriers to maternal caregiving for a disabled child revolve around challenging relationships. Giving birth to a disabled child creates a huge challenge for mothers in Chinese society. DESIGN: Data were collected using in depth interviews and journaling methods. A hermeneutic phenomenological approach, informed by the philosophical world views of Heidegger and Gadamer, provided theoretical guidance in revealing and interpreting mothers' experiences. METHOD: Interviews were carried out with a purposeful sample of 15 mothers who were primary caregivers for a child aged between 0-18 years who was diagnosed with cerebral palsy and used Mandarin or Taiwanese as their primary language. RESULTS: Shared meanings revealed four modes of being concerned: (1) experiencing burden as a sole primary caregiver; (2) managing the challenges by balancing demands; (3) being marginalised by others; and (4) encountering limited or no professional support. CONCLUSIONS: Taiwanese mothers face the strain of managing barriers to caregiving in contexts in which their children are not supported or acknowledged as being important contributors to family and Chinese society at large. This study highlights how the family can be important to caregiving mothers in traditional Chinese family life. Poor support and dynamics will emerge when family members regard disability as a loss of face or a stigma. RELEVANCE TO CLINICAL PRACTICE: By learning from Taiwanese mothers who accommodate barriers to caregiving on a daily basis, nurses can seize the impetus to explore ways of reconceptualising nursing practice with families and people with disabilities. The aim is to explore ways that will ultimately align intentions and caring processes and foster coping and positive reward in caring, thereby creating a context that is stress reducing and therapeutic. PMID- 21702864 TI - Narratives of the heart: telling the story of children with a cardiac condition through a bead program. AB - AIMS: To present and discuss the significance of a bead program in assisting families to put together the story of a child's journey through cardiac intervention. The main focus of the article is the importance to families of developing a narrative in making sense of the experience of discovering their child has a cardiac condition and how this is enhanced by the bead program. BACKGROUND: The Heart Beads Program involved giving families beads related to procedures and processes the children undergo while they are in hospital. Research on narratives related to illness suggests that forming a narrative that incorporates the health condition facilitates the ability to talk about these experiences and helps to make sense of and deal with the stressors related to such traumatic life events. DESIGN: A qualitative methodology was used to evaluate the program employing semi-structured interviews and content analysis following a grounded theory approach. METHODS: Interviews were undertaken with 11 families to highlight their experiences of being involved in the Heart Beads Program. Themes were identified from the interviews and critical discussion was used to structure and connect the themes. RESULTS: The major theme that emerged from the analysis of the interviews was the importance of the beads in enabling the telling of the child's story. Five subthemes were identified in this theme: symbolism, encouraging/uplifting, acknowledgement, connection with others and imagining the future. The themes are outlined and expressed through specific comments from interviews. CONCLUSIONS: The Heart Beads are seen as presenting a significant way for children and families to comprehend their time in hospital as part of the child's life story. RELEVANCE TO CLINICAL PRACTICE: The program can offer the opportunity for health care professionals to relate to the child and family's story and to engage with that story in a person centred way. PMID- 21702865 TI - Reduced sleep quality in healthy girls at risk for depression. AB - Depression is characterized by sleep difficulties, but the extent to which subjective and objective sleep disturbances precede depression are unclear. This study was designed to examine perceptions of sleep quality in addition to actigraphy- and diary-measured sleep variables in healthy girls at low and high familial risk for major depressive disorder. Forty-four healthy daughters and their mothers completed a week of daily sleep diary and actigraphy; 24 girls had mothers with no history of psychopathology (low risk, mean age 14.92 years), and 20 girls had mothers with recurrent depression during the daughter's lifetime (high risk, mean age 14.12 years). All daughters had no current or past psychopathology. High-risk girls reported significantly poorer subjective sleep quality than did low-risk girls (P = 0.001). The two groups of participants did not differ in actigraphy- or diary-measured sleep duration, onset latency or snooze duration. Healthy girls at high familial risk for depression report poorer sleep quality than do girls at low risk for depression, despite the absence of group differences in objective sleep disturbances as measured by actigraphy or daily diary. This pattern of findings may reflect a broader cognitive or physiological phenotype of risk for depression. PMID- 21702866 TI - Loss of PKCdelta results in characteristics of Sjogren's syndrome including salivary gland dysfunction. AB - OBJECTIVES: Chronic infiltration of lymphocytes into the salivary and lacrimal glands of patients with Sjogren's syndrome (SS) leads to destruction of acinar cells and loss of exocrine function. Protein kinase C-delta (PKCdelta) is known to play a critical role in B-cell maintenance. Mice in which the PKCdelta gene has been disrupted have a loss of B-cell tolerance, multiple organ lymphocytic infiltration, and altered apoptosis. To determine whether PKCdelta contributes to the pathogenesis of SS, we quantified changes in indicators of SS in PKCdelta-/- mice as a function of age. Salivary gland histology, function, the presence of autoantibodies, and cytokine expression were examined. MATERIALS AND METHODS: Submandibular glands were examined for the presence of lymphocytic infiltrates, and the type of infiltrating lymphocyte and cytokine deposition was evaluated by immunohistochemistry. Serum samples were tested by autoantibody screening, which was graded by its staining pattern and intensity. Salivary gland function was determined by saliva collection at various ages. RESULTS: PKCdelta-/- mice have reduced salivary gland function, B220+ B-cell infiltration, anti-nuclear antibody production, and elevated IFN-gamma in the salivary glands as compared to PKCdelta+/+ littermates. CONCLUSIONS: PKCdelta-/- mice have exocrine gland tissue damage indicative of a SS-like phenotype. PMID- 21702867 TI - Effect of leptin on differentiation of human dental stem cells. AB - OBJECTIVES: Mesenchymal stem cells (MSCs) were identified in adult human periodontal ligament and dental pulp that are considered as potential stem cell sources for future clinical applications in dentistry. Leptin is known as an important regulator of mesenchymal differentiation. The objective of this study was to elucidate the role of leptin on proliferation and differentiation of dental MSCs. MATERIALS AND METHODS: Enhancement of cemento/odontoblastic differentiation of dental stem cells by leptin was confirmed by alizarin red S staining and alkaline phosphatase activity staining. In contrast, leptin reduced adipogenesis in both dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) confirmed by oil red O staining and RT-PCR. The expression of adipogenic markers, lipoprotein lipase and proliferator-activated receptor gamma2 (PPARgamma2), were suppressed in PDLSCs incubated on media supplemented with leptin for 2 weeks. RESULTS: Leptin had a relatively stronger osteogenesis promoting effect and adipogenesis suppressing effect in PDLSCs than in DPSCs. CONCLUSIONS: Collectively, leptin had a relatively stronger promoting effect on cemento/odontoblastic differentiation and a suppressing effect on adipogenesis in PDLSCs than in DPSCs. This study has provided evidence that leptin acts as an important modulator of dental MSCs differentiation. PMID- 21702868 TI - Applying lessons learnt from the 'DOTS' Tuberculosis Model to monitoring and evaluating persons with diabetes mellitus in Blantyre, Malawi. AB - The global burden of diabetes mellitus (DM) is immense and predicted to reach 438 million by 2030, with 80% of the cases being in the developing world. The management of chronic non-communicable diseases like DM is poor in most resource limited settings, and the 'directly observed therapy, short course' (DOTS) framework for tuberculosis control has been proposed as a feasible way to improve this situation. In late 2009, aspects of the DOTS model were applied to the management of persons with DM in the diabetes clinic in Queen Elizabeth Central Hospital, Blantyre, Malawi, and a point-of-care electronic medical record system was set up to support and monitor patients in care. This is the first quarterly and cumulative report of persons with DM registered for care stratified by treatment outcomes, complications and medication history up to 31 December 2010. There were 170 new patients registered between October and December 2010, with 1864 ever registered by 31 December 2010. Most patients were alive and in care; 3 died, 53 defaulted and 3 transferred out. Of those on oral hypoglycaemic agents, metformin was most commonly used. Complications were common. The monitoring and evaluation will be further refined, and at the same time, the systems developed in Blantyre will be expanded to other parts of the country. PMID- 21702869 TI - Phenotypic characterization of mononuclear blood cells from pregnant Gabonese and their newborns. AB - OBJECTIVES: As many studies have analysed the immunological phenotype of either neonatal cord or maternal blood during pregnancy, but few have compared paired maternal and neonatal samples, we designed and conducted such a study in a Central African setting. METHODS: We used flow cytometric analyses with blood samples from pairs of Gabonese mothers and their newborns to determine the cellular composition of mononuclear cells as well as the activation status of T and B lymphocytes and antigen-presenting cells. RESULTS: The results indicate higher activation levels of neonatal cells involved in the first-line defence against pathogens such as natural killer cells, while the neonatal T- and B-cell compartment as well as the neonatal monocyte subpopulations shows a less mature phenotype. CONCLUSIONS: Our findings likely reflect a specific neonatal defence mechanism that compensates for otherwise poorly developed immune responses at birth, especially important in an area with a high burden of infectious agents such as Gabon. The data contribute to the establishment of reference values for the mother-neonate relationship in African regions that have similar environmental characteristics. PMID- 21702870 TI - Do poor people use poor quality providers? Evidence from the treatment of presumptive malaria in Nigeria. AB - OBJECTIVE: To determine the differences in the quality of treatment for presumptive malaria received by different socio-economic status (SES) groups in Nigeria. METHODS: The study was conducted in southeast Nigeria. A household survey was used to collect data on patterns of use of different providers for treatment of adult and childhood malaria. The quality of services provided by different provider types was assessed using treatment vignettes. Quality scores for the different providers were computed based on their responses to the different points raised in the vignettes. Patterns of household treatment seeking for fever were disaggregated by SES, and then weighted by quality score to indicate the overall quality-weighted utilization by SES and the average quality of a visit by a member of each SES group. Equity ratios (poorest/least poor) provided the measure of inequity in quality-weighted utilization of different providers. RESULTS: In treatment of adult malaria, higher SES groups used more of public and private hospitals, while lower SES groups used more of traditional healers. In case of children, higher SES used more of healthcare centres and private hospitals and lower SES groups used more of pharmacy shops. The lowest quality of services was measured among laboratories, patent medicine dealers (PMDs), mixed goods shops and pharmacies, all of which are private. The highest scores were observed among the two types of public providers (public hospital and healthcare centres). The quality of treatment services utilised by consumers decreased as SES decreased. However, when the quantity normalized index was used this SES disparity almost disappeared. The resulting equity ratio was 0.96 for adults and 0.94 for children. CONCLUSION: Everybody used poor quality malaria treatment services but the poor people used providers with poor quality malaria treatment services more than others. The major driver of disparities in use of different providers by different SES was the greater number of visits of the higher SES groups, rather than the higher quality of the providers they used. Interventions should be developed to improve quality of treatment seeking behaviour and provision practices. PMID- 21702871 TI - Is routine dengue vector surveillance in central Brazil able to accurately monitor the Aedes aegypti population? Results from a pupal productivity survey. AB - OBJECTIVE: To assess how well the Aedes aegypti infestation rapid survey, Levantamento Rapido de Indice para Aedes aegypti (LIRAa), is able to accurately estimate dengue vector densities and target the most important breeding sites in Goiania, Brazil. METHODS: In February 2009, a pupal productivity survey was conducted in 2 districts of the city of Goiania, central Brazil. The results were compared to those of LIRAas conducted in the same districts during the months before and after the pupal productivity survey. RESULTS: In the pupal productivity survey, 2,024 houses were surveyed and 2,969 water-holding containers were inspected. Discarded small water containers most frequently contained immature Ae. aegypti. The most pupal-productive containers were elevated water tanks, roof gutters and water holding roofs. Combined, these three containers accounted for <40% of all positive containers but produced >70% of all pupae. In the two districts where the pupal productivity survey was conducted, the house indices were 5.1 and 4.6 and the Breteau indices were 5.9 and 6.0. In contrast, the two LIRAs conducted in the same two districts resulted in an average house index of 1.5 and Breteau index of 2.5, with discarded items identified as the most frequently infested container type. CONCLUSION: Both the LIRAa and the pupal productivity survey identified discarded items as being most frequently infested with immature stages of Ae. aegypti, but the pupal productivity survey showed that elevated containers produced the greatest proportion of Ae. aegypti pupae (a proxy measure of adult vector density) and that the values of the Stegomyia indices were substantially underestimated by LIRAa. Although both surveys differ considerably in terms of sampling method and manpower, in the case of this study the LIRAa did not accurately identify or target the containers that were the most important to adult mosquito production. PMID- 21702872 TI - American ginseng improves neurocognitive function in senescence-accelerated mice: possible role of the upregulated insulin and choline acetyltransferase gene expression. AB - AIM: To investigate the effects of American ginseng on neurocognitive function and glucose regulation in senescence-accelerated mice. METHODS: Male senescence resistant inbred strains (SAMR1) and senescence-prone inbred strains (SAMP10) mice were divided into five groups and fed either a control diet or an American ginseng-supplemented diet (1% or 2% g/g) from 6 weeks to 10 months of age. Bodyweight, levels of fasting plasma glucose (FPG) and grading scores were monitored every month and neurocognitive functions were evaluated at 9 months of age with a KUROBOX apparatus using a stress-free positive cue task. Gene expressions of peroxisome proliferator-activated receptor delta (PPAR-delta), insulin, choline acetyltransferase (ChAT) and amyloid precursor protein (APP) in the brain were measured by real-time quantitative reverse transcription polymerase chain reaction assays. RESULTS: American ginseng decreased FPG in SAMR1 mice, but increased FPG in SAMP10 mice. Correct visit ratios were higher in both SAMR1 and SAMP10 strains consuming an American ginseng-supplemented diet. Gene upregulation of insulin and ChAT in the brain, but not of PPAR-delta or APP, was evident in American ginseng-fed groups. CONCLUSION: Daily consumption of American ginseng induced an enhancement in neurocognitive function in senescence accelerated mice, which could be related to the upregulation of insulin and ChAT gene expression in the brain. Geriatr Gerontol Int 2012; 12: 123-130. PMID- 21702873 TI - Visual and hearing impairment among rural elderly of south India: a community based study. AB - AIM: Of India's population, 76.6 million (7.2%) are aged above 60 years. Increasing age is associated with increasing disability and functional impairments such as low vision, loss of mobility and hearing impairment. Hence, the purpose of this paper is to study the prevalence of hearing and visual impairment among a rural elderly population in South India and its association with selected variables. METHODS: This was a cross-sectional study of elderly persons in two villages of Bangalore District, Karnataka, South India. Elderly persons identified were administered a questionnaire for assessment of demographic details, health and function related information. Visual acuity was checked using Snellen's E chart for distant vision. Hearing was assessed using pure tone audiometry. RESULTS: Two hundred and fifty-seven (12.2%) of the population were elderly in these two villages. Seventy-two (32.4%) of the elderly persons were facing problems completely or partially in at least one of the activities and 10 (4.5%) elderly persons had cognitive impairment. Sixty-two (35.4%) of the elderly had low vision and 22 (12.6%) were blind. On assessment with pure tone audiometry, 117 (66.9%) of the elderly persons had some degree of hearing impairment. Forty-three (24.6%) of the elderly had disabling hearing impairment. Forty-seven (26.9%) of the elderly had combined low vision associated with hearing impairment and 18 (10.2%) had combined blindness along with hearing impairment. As age advanced there was a significant increase in visual, hearing and combined impairments. CONCLUSION: Visual and hearing impairment are important health problems among elderly persons in rural areas of South India. PMID- 21702875 TI - In-home controls of pacemakers in debilitated elderly patients. AB - AIM: We assessed the efficacy, reliability and cost of an in-home control service, devoted to debilitated patients with pacemakers, during long-term follow up. METHODS: We admitted 802 patients (mean age 87.8 +/- 6.9 years) with pacemakers into our program, which were monitored periodically during in-home visits by nurses. During these controls, patients underwent a standard electrocardiogram with and without magnet, during which stimulation intervals were measured. In-home pacemaker assessments were performed by a portable programmer only for patients with Biotronik pacemakers. Electrocardiograms and technical data were evaluated at hospital, and a report was sent by mail to the patient. Moreover, we compared the costs for the hospital, patients and society between in-home and ambulatory assessments. RESULTS: During 80 months of follow up, 2418 controls were performed. The monthly average of patients who were followed at home was 283.9 +/- 23.9. The mean number of controls per month was 30.2 +/- 10 (range 4-51). One hundred and twenty-three pacemakers were replaced due to battery exhaustion, after a mean device longevity of 7.4 years (range 4.9 12.4 years). Four hundred and sixty-eight patients died (8.7% annual mortality). Fifteen patients (annual incidence 0.3%) were invited to in-hospital visits for reprogramming. The cumulative cost for in-home assessment were 20.5% lower than conventional in-hospital controls and 66.5% lower if patients are transported by ambulance. CONCLUSION: Elderly debilitated patients can be monitored by effective and reliable pacemaker assessments at home, alleviating them and their families from the issues that are associated with their transfer from the home to the hospital and concurrently reducing overall costs. PMID- 21702874 TI - Critical tooth number without subjective dysphagia. AB - AIM: To assess the critical tooth number (CTN) required for prevention of subjective dysphagia caused by oral impairments and to evaluate the relationship between this CTN and mortality. METHODS: The baseline study was performed with residents aged 40-89years (n=5,643; 2224 men and 3419 women) in Miyako Islands, Okinawa, in 1987. Dental examinations were performed by dentists, and subjective dysphagia was asked. We recorded the cause and year of death of participants who died during the next 15years. RESULTS: The average functional tooth number of participants with and without subjective dysphagia declined with age in both sexes. The CTN for each respective age group (40s, 50s, 60s, 70s and 80s) not including the denture group were 20.0, 17.5, 14.0, 11.8 and 10.1 in men and 19.0, 14.7, 12.7, 9.5 and 4.0 in women. These CTN were significant factors of 15-year mortality in both sexes (P<0.05). The hazard ratios were 0.72 (95% confidence interval=0.55-0.93) in men and 0.71 (0.51-0.99) in women. CONCLUSION: In aged people, the minimum number of functional teeth needed to avoid subjective dysphagia might not be as high as in young people. PMID- 21702877 TI - Effects of infant massage on HIV-infected mothers and their infants. AB - PURPOSE. To determine the feasibility of implementing an infant massage intervention and to evaluate the preliminary effects of infant massage on HIV infected mothers and their infants. DESIGN AND METHODS. In this two-group, randomized controlled pilot study, intervention group mothers were taught to perform infant massage daily for 10 weeks. RESULTS. Infant massage training had a positive impact on maternal depression, parental distress, and infant growth along with facilitating more optimal parent-child interactions. PRACTICE IMPLICATIONS. Infant massage, a quick, easy, and inexpensive intervention, is feasible in a clinic setting and may benefit human immunodeficiency virus infected mothers and their infants. PMID- 21702878 TI - Parenting children with hypoplastic left heart syndrome: finding a balance. AB - PURPOSE. This study described the role normalization played for parents related to their young children with hypoplastic left heart syndrome. DESIGN AND METHODS. The data source for this secondary analysis was 30 interviews with 16 parents. RESULTS. Three themes were identified: normalization, parental perception of child vulnerability, and optimistic appraisal. Parents engaged in a balancing act between worrying about their children's vulnerability and marveling at their children's survival, using normalization as a coping strategy. PRACTICE IMPLICATIONS. Nurses can collaborate with parents to determine strategies to restore a sense of normalcy to simultaneously promote child independence and parent well-being. PMID- 21702879 TI - Effectiveness and feasibility of using the computerized interactive virtual space in reducing depressive symptoms of Hong Kong Chinese children hospitalized with cancer. AB - PURPOSE. To examine the effectiveness and feasibility of using the computerized interactive virtual space in reducing depressive symptoms of children hospitalized with cancer. DESIGN AND METHODS. A nonequivalent control group design was employed. Children (8-16 years of age; n= 122) admitted to a pediatric oncology ward during a 14-month period were recruited. RESULTS. The results support the effectiveness and feasibility of using the computerized interactive virtual space in reducing depressive symptoms of children hospitalized with cancer. PRACTICE IMPLICATIONS. The results heighten the awareness in nurses of the importance of integrating play activities as an essential component of holistic and quality nursing care. PMID- 21702880 TI - The relationships among body size, biological sex, ethnicity, and healthy lifestyles in adolescents. AB - PURPOSE. The purposes of this study were to (a) determine whether actual weight, biological sex, and race/ethnicity were related to differences of weight perception, nutrition and activity knowledge, perceived difficulty, attitudes, and choices about living a healthy lifestyle in adolescents; and (b) describe the relationships among these variables. DESIGN AND METHODS. This was a cross sectional descriptive, correlational design with 404 adolescents. RESULTS. Perception of weight was more accurate in overweight adolescents. Teens who reported difficulty in leading a healthy lifestyle reported less healthy choices, attitudes, and knowledge. PRACTICE IMPLICATIONS. Findings suggest tailored interventions should consider biological sex and race/ethnicity. PMID- 21702881 TI - Illness-specific anxiety: implications for functioning and utilization of medical services in adolescents with inflammatory bowel disease. AB - PURPOSE. Adolescents with inflammatory bowel disease (IBD) may be at heightened risk for developing anxiety and depression. This cross-sectional pilot study examined the relationship between anxiety and depression and health-related behaviors. METHODS. Thirty-six adolescents with diagnosed IBD, ages 12-17, and their parents were recruited from two pediatric gastroenterology medical centers. RESULTS. Clinical levels of anxiety (22%) and depressive symptoms (30%) were reported by patients. Regression analyses revealed that IBD-specific anxiety was significantly associated with greater utilization of medical services and worsened psychosocial functioning. PRACTICE IMPLICATIONS. Results provide preliminary support that IBD-specific anxiety may play an important role in disease management, yet concerns are rarely systematically assessed by health professionals. PMID- 21702882 TI - Involving fathers in research. AB - Scientific Inquiry provides a forum to facilitate the ongoing process of questioning and evaluating practice, presents informed practice based on available data, and innovates new practices through research and experimental learning. PMID- 21702883 TI - Cross-age peer mentoring approach to impact the health outcomes of children and families. AB - Family-Centered Care provides a forum for sharing information about basic components of caring for children and families, including respect, information sharing, collaboration, family-to-family support, and confidence building. PMID- 21702884 TI - Disaster preparedness for children with special healthcare needs and disabilities. AB - Ask the Expert provides research-based answers to practice questions submitted by JSPN readers. PMID- 21702885 TI - Obstructive right ventricular outflow tract hemangioma in an adolescent. AB - Cardiac tumors are rare in children, but they are being diagnosed with increasing frequency and great accuracy with wide array of imaging modalities. Cardiac rhabdomyoma and myxoma are the most common tumors in children and adults, respectively. Cardiac hemangiomas comprise about 2.8% of all primary cardiac tumors and fewer than 100 cases have been reported in the literature. We report a successful resection of cardiac hemangioma in the right ventricular outflow tract in an adolescent, presented with moderate to severe obstruction. PMID- 21702886 TI - Iatrogenic ST elevation during percutaneous closure of a coronary artery fistula. AB - Coronary artery fistulae are an uncommon anomaly and, while frequently asymptomatic, may require interventional therapy. Transcatheter approaches for closure of coronary artery fistulae are now commonly used, with various methods of fistula occlusion described, including detachable coils. During a percutaneous procedure to occlude a symptomatic left anterior descending coronary artery to pulmonary artery fistula, the patient experienced chest discomfort with anterior ST segment elevation. We demonstrate an unusual, unique and striking ECG abnormality complicating the delivery of coils designed to occlude the fistula in the absence of coronary artery injury. The mechanisms of the procedural ECG changes are discussed, as are potential alternate diagnoses and associated therapy. PMID- 21702887 TI - A case of tricuspid atresia with normally related great vessels and coarctation of the aorta. AB - Tricuspid atresia is a congenital cardiac anomaly that is most commonly associated with normally related great vessels and less commonly with transposition of the great vessels. When tricuspid atresia is associated with dextro-transposition of the great vessels, there is a high incidence of coarctation of the aorta. This report documents the rare case of a newborn male with tricuspid atresia and normally related great arteries with both pulmonary stenosis and coarctation of the aorta. PMID- 21702888 TI - Relief of right ventricle to pulmonary artery conduit compression by chest wall resection. AB - Many congenital heart defects require reconstruction of the right ventricular outflow tract utilizing a right ventricle to pulmonary artery conduit. One of the challenges with these conduits is the development of conduit stenosis. This phenomenon is quite common and typically results from a combination of progressive calcification, fibrosis, and/or the relative size mismatch that occurs with patient growth. However, extrinsic compression is much less common and a much more difficult problem to address. Chest wall resection and reconstruction is an option for alleviating external conduit compression that provides good results. PMID- 21702889 TI - Typical atrial flutter in an atypical patient. AB - Arrhythmias in adult congenital heart disease (ACHD) pose unique procedural challenges, especially with intravascular access. We report a unique case of ablation via a left-sided hepatic vein approach in a patient with situs inversus totalis. A 28-year-old woman with situs inversus totalis, ventriculoseptal defect, and dextro-transposition of the great arteries underwent ablation for documented narrow-complex tachycardia. Because of bilateral iliac venous occlusions, the coronary sinus (CS) was accessed through the left internal jugular vein. Rapid atrial pacing resulted in a tachycardia with an atrial cycle length of 225 msec and 2:1 atrioventricular association. Entrainment from the proximal and distal CS was consistent with typical atrial flutter around the left sided tricuspid valve. Because of the iliac vein occlusions, access for ablation was obtained via a left-sided hepatic vein (Figure 1). Resetting from the cavotricuspid isthmus and three-dimensional electroanatomic mapping (Figure 2) confirmed typical atrial flutter, which, given the dextrocardia, occurred in a clockwise fashion around the tricuspid valve. Ablation was performed at the cavotricuspid isthmus resulting in arrhythmia termination and isthmus block. This case highlights the many unusual challenges that patients with ACHD can pose to the proceduralist, including atypical cardiac anatomy and difficult intravascular access. Unusual and creative approaches are often necessary to treat these patients successfully. PMID- 21702890 TI - A different therapeutic strategy for severe tetralogy of Fallot with origin of the left pulmonary artery from the ascending aorta: stenting of the right ventricular outflow tract before complete repair. AB - The origin of pulmonary artery branches (particularly the left pulmonary artery) from the ascending aorta is a rare condition. We detected prominent hypoplasia of the main and right pulmonary arteries in a 3.5-month-old 3.7 kg female infant who had tetralogy of Fallot with origin of the left pulmonary artery in the ascending aorta. In order to ensure the development of the right pulmonary artery, a stent was put in that extended from the right ventricular outflow tract to the right pulmonary artery. During follow-up, after the patient's right pulmonary artery had developed sufficiently, a complete repair surgery was done. It is common practice for patients with abnormal origin of the left pulmonary artery to perform the complete repair using the direct reimplantation technique. However, we think that another possibility is to implant the stent in patients with hypoplastic pulmonary artery and branches in the early stages, wait for a short period of time and perform the complete repair surgery before permanent pulmonary hypertension develops. PMID- 21702891 TI - Complementing institutional with localised strategies for climate change adaptation: a South-North comparison. AB - Climate change and disasters pose a serious risk to sustainable development. In the South, local coping strategies are an important element of adaptation to climate and disaster risk. Such strategies have emerged because of the limited assistance provided by urban actors and associated social security and governance systems. In the North, in contrast, local coping strategies are comparatively poorly developed. However, the extent of the changing climatic conditions is also reducing the capacity of Northern institutions to deal with climatic extremes and variability, which emphasises the need for more local-level engagement in the North. This paper analyses the differences in local and institutional responses to climate change and disasters in a Southern and a Northern city (San Salvador, El Salvador, and Manchester, United Kingdom, respectively), and highlights how the lessons learned might be translated into an improved distributed governance system; that is, an 'integrated engagement model', where local and institutionalised responses support rather than hinder each other, as is currently the case. PMID- 21702892 TI - Coping strategies and risk manageability: using participatory geographical information systems to represent local knowledge. AB - The accumulated knowledge and perceptions of communities 'at risk' are key elements in managing disaster risk at the local level. This paper demonstrates that local knowledge of flood hazards can be structured systematically into geographic information system (GIS) outputs. When combined with forecasting models and risk scenarios, they strengthen the legitimacy of local knowledge of at-risk populations. This is essential for effective disaster risk reduction practices by external actors, local non-governmental organisations (NGOs) and municipal authorities. The research focused on understanding coping strategies and 'manageability' of flood hazards as defined by communities. 'Manageability' is how people experience flooding in relation to their household capacity and the coping mechanisms available. The research in the Philippines highlights the significance of localised factors, including socioeconomic resources, livelihoods, seasonality and periodicity, for understanding manageability. The manageability concept improves practice at the municipal level by legitimising local coping strategies, providing better indicators, and developing understanding of flooding as a recurrent threat. PMID- 21702893 TI - Cyclone preparedness and response: an analysis of lessons identified using an adapted military planning framework. AB - The United Kingdom uses the Defence Lines of Development (DLOD) framework to analyse and understand the key components and costs of a military capability. Rooted in the Resource Based View (RBV) of a firm, an adapted DLOD approach is employed to explore, analyse and discuss the preparedness, planning and response strategies of two markedly different countries (Australia and Bangladesh) when faced with a major cyclone event of a comparable size. Given the numerous similarities in the challenges facing military forces in a complex emergency and humanitarian agencies in a natural disaster, the paper demonstrates the applicability of the DLOD framework as an analysis and planning tool in the cyclone preparedness planning and response phases, and more broadly within the disaster management area. In addition, the paper highlights the benefit to disaster managers, policymakers and researchers of exploiting comparative cross learning opportunities from disaster events, drawn from different sectors and countries. PMID- 21702894 TI - Is Ankyrin a genetic risk factor for psychiatric phenotypes? AB - BACKGROUND: Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336) as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482) was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression. METHODS: We genotyped three single nucleotide polymorphisms (SNPs) in ANK3 (rs9804190, rs10994336, and rs10761482) in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes. RESULTS: We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015) but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification. CONCLUSION: Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases. PMID- 21702895 TI - The new wave: time to bring EEG to the emergency department. AB - Emergency electroencephalography (EEG) is indicated in the diagnosis and management of non-convulsive status epilepticus (NCSE) underlying an alteration in the level of consciousness. NCSE is a frequent, treatable, and under-diagnosed entity that can result in neurological injury. This justifies the need for EEG availability in the emergency department (ED). There is now emerging evidence for the potential benefits of EEG monitoring in various acute conditions commonly encountered in the ED, including convulsive status after treatment, breakthrough seizures in chronic epilepsy patients who are otherwise controlled, acute head trauma, and pseudo seizures. However, attempts to allow for routine EEG monitoring in the ED face numerous obstacles. The main hurdles to an optimized use of EEG in the ED are lack of space, the high cost of EEG machines, difficulty of finding time, as well as the expertise needed to apply electrodes, use the machines, and interpret the recordings. We reviewed the necessity for EEGs in the ED, and to meet the need, we envision a product that is comprised of an inexpensive single-use kit used to wirelessly collect and send EEG data to a local and/or remote neurologist and obtain an interpretation for managing an ED patient. PMID- 21702896 TI - Neuroprotective and anti-oxidant effects of caffeic acid isolated from Erigeron annuus leaf. AB - BACKGROUND: Since oxidative stress has been implicated in a neurodegenerative disease such as Alzheimer's disease (AD), natural antioxidants are promising candidates of chemopreventive agents. This study examines antioxidant and neuronal cell protective effects of various fractions of the methanolic extract of Erigeron annuus leaf and identifies active compounds of the extract. METHODS: Antioxidant activities of the fractions from Erigeron annuus leaf were examined with [2,2-azino-bis(3-ethylbenz thiazoline-6-sulfonic acid diammonium salt)] (ABTS) and ferric reducing antioxidant power (FRAP) assays. Neuroprotective effect of caffeic acid under oxidative stress induced by H2O2 was investigated with [3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) and lactate dehydrogenase (LDH) assays. RESULTS: This study demonstrated that butanol fraction had the highest antioxidant activity among all solvent fractions from methanolic extract E. annuus leaf. Butanol fraction had the highest total phenolic contents (396.49 mg of GAE/g). Caffeic acid, an isolated active compound from butanol fraction, showed dose-dependent in vitro antioxidant activity. Moreover, neuronal cell protection against oxidative stress induced cytotoxicity was also demonstrated. CONCLUSION: Erigeron annuus leaf extracts containing caffeic acid as an active compound have antioxidative and neuroprotective effects on neuronal cells. PMID- 21702897 TI - Physical health behaviours and health locus of control in people with schizophrenia-spectrum disorder and bipolar disorder: a cross-sectional comparative study with people with non-psychotic mental illness. AB - BACKGROUND: People with mental illness experience high levels of morbidity and mortality from physical disease compared to the general population. Our primary aim was to compare how people with severe mental illness (SMI; i.e. schizophrenia spectrum disorders and bipolar disorder) and non-psychotic mental illness perceive their: (i) global physical health, (ii) barriers to improving physical health, (iii) physical health with respect to important aspects of life and (iv) motivation to change modifiable high-risk behaviours associated with coronary heart disease. A secondary aim was to determine health locus of control in these two groups of participants. METHODS: People with SMI and non-psychotic mental illness were recruited from an out-patient adult mental health service in London. Cross-sectional comparison between the two groups was conducted by means of a self-completed questionnaire. RESULTS: A total of 146 people participated in the study, 52 with SMI and 94 with non-psychotic mental illness. There was no statistical difference between the two groups with respect to the perception of global physical health. However, physical health was considered to be a less important priority in life by people with SMI (OR 0.5, 95% CI 0.2-0.9, p = 0.029). There was no difference between the two groups in their desire to change high risk behaviours. People with SMI are more likely to have a health locus of control determined by powerful others (p < 0.001) and chance (p = 0.006). CONCLUSIONS: People with SMI appear to give less priority to their physical health needs. Health promotion for people with SMI should aim to raise awareness of modifiable high-risk lifestyle factors. Findings related to locus of control may provide a theoretical focus for clinical intervention in order to promote a much needed behavioural change in this marginalised group of people. PMID- 21702898 TI - Metagenomic biomarker discovery and explanation. AB - This study describes and validates a new method for metagenomic biomarker discovery by way of class comparison, tests of biological consistency and effect size estimation. This addresses the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities, which is a central problem to the study of metagenomics. We extensively validate our method on several microbiomes and a convenient online interface for the method is provided at http://huttenhower.sph.harvard.edu/lefse/. PMID- 21702899 TI - Accounting for the mortality benefit of drug-eluting stents in percutaneous coronary intervention: a comparison of methods in a retrospective cohort study. AB - BACKGROUND: Drug-eluting stents (DES) reduce rates of restenosis compared with bare metal stents (BMS). A number of observational studies have also found lower rates of mortality and non-fatal myocardial infarction with DES compared with BMS, findings not observed in randomized clinical trials. In order to explore reasons for this discrepancy, we compared outcomes after percutaneous coronary intervention (PCI) with DES or BMS by multiple statistical methods. METHODS: We compared short-term rates of all-cause mortality and myocardial infarction for patients undergoing PCI with DES or BMS using propensity-score adjustment, propensity-score matching, and a stent-era comparison in a large, integrated health system between 1998 and 2007. For the propensity-score adjustment and stent era comparisons, we used multivariable logistic regression to assess the association of stent type with outcomes. We used McNemar's Chi-square test to compare outcomes for propensity-score matching. RESULTS: Between 1998 and 2007, 35,438 PCIs with stenting were performed among health plan members (53.9% DES and 46.1% BMS). After propensity-score adjustment, DES was associated with significantly lower rates of death at 30 days (OR 0.49, 95% CI 0.39 - 0.63, P < 0.001) and one year (OR 0.58, 95% CI 0.49 - 0.68, P < 0.001), and a lower rate of myocardial infarction at one year (OR 0.72, 95% CI 0.59 - 0.87, P < 0.001). Thirty day and one year mortality were also lower with DES after propensity-score matching. However, a stent era comparison, which eliminates potential confounding by indication, showed no difference in death or myocardial infarction for DES and BMS, similar to results from randomized trials. CONCLUSIONS: Although propensity score methods suggested a mortality benefit with DES, consistent with prior observational studies, a stent era comparison failed to support this conclusion. Unobserved factors influencing stent selection in observational studies likely account for the observed mortality benefit of DES not seen in randomized clinical trials. PMID- 21702900 TI - Oxytocin may be useful to increase trust in others and decrease disruptive behaviours in patients with Prader-Willi syndrome: a randomised placebo controlled trial in 24 patients. AB - BACKGROUND: Prader-Willi syndrome (PWS) is a complex neurodevelopmental genetic disorder with hypothalamic dysfunction, early morbid obesity with hyperphagia, and specific psychiatric phenotypes including cognitive and behavioural problems, particularly disruptive behaviours and frequent temper outbursts that preclude socialization. A deficit in oxytocin (OT)-producing neurons of the hypothalamic paraventricular nucleus has been reported in these patients. METHODS: In a double blind, randomised, placebo-controlled study, 24 adult patients with PWS received a single intranasal administration of 24 IU of OT or placebo and were tested 45 min later on social skills. Behaviours were carefully monitored and scored using an in-house grid as follows: over the two days before drug administration, on the half-day following administration, and over the subsequent two days. All patients were in a dedicated PWS centre with more than ten years of experience. Patients are regularly admitted to this controlled environment. RESULTS: Patients with PWS who received a single intranasal administration of OT displayed significantly increased trust in others (P = 0.02) and decreased sadness tendencies (P = 0.02) with less disruptive behaviour (P = 0.03) in the two days following administration than did patients who received placebo. In the half-day following administration, we observed a trend towards less conflict with others (p = 0.07) in the OT group compared with the placebo group. Scores in tests assessing social skills were not significantly different between the two groups. CONCLUSIONS: This study needs to be reproduced and adapted. It nevertheless opens new perspectives for patients with PWS and perhaps other syndromes with behavioural disturbances and obesity. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT01038570. PMID- 21702901 TI - Hydroxylation of recombinant human collagen type I alpha 1 in transgenic maize co expressed with a recombinant human prolyl 4-hydroxylase. AB - BACKGROUND: Collagens require the hydroxylation of proline (Pro) residues in their triple-helical domain repeating sequence Xaa-Pro-Gly to function properly as a main structural component of the extracellular matrix in animals at physiologically relevant conditions. The regioselective proline hydroxylation is catalyzed by a specific prolyl 4-hydroxylase (P4H) as a posttranslational processing step. RESULTS: A recombinant human collagen type I alpha-1 (rCIalpha1) with high percentage of hydroxylated prolines (Hyp) was produced in transgenic maize seeds when co-expressed with both the alpha- and beta- subunits of a recombinant human P4H (rP4H). Germ-specific expression of rCIalpha1 using maize globulin-1 gene promoter resulted in an average yield of 12 mg/kg seed for the full-length rCIalpha1 in seeds without co-expression of rP4H and 4 mg/kg seed for the rCIalpha1 (rCIalpha1-OH) in seeds with co-expression of rP4H. High-resolution mass spectrometry (HRMS) analysis revealed that nearly half of the collagenous repeating triplets in rCIalpha1 isolated from rP4H co-expressing maize line had the Pro residues changed to Hyp residues. The HRMS analysis determined the Hyp content of maize-derived rCIalpha1-OH as 18.11%, which is comparable to the Hyp level of yeast-derived rCIalpha1-OH (17.47%) and the native human CIa1 (14.59%), respectively. The increased Hyp percentage was correlated with a markedly enhanced thermal stability of maize-derived rCIalpha1-OH when compared to the non hydroxylated rCIalpha1. CONCLUSIONS: This work shows that maize has potential to produce adequately modified exogenous proteins with mammalian-like post translational modifications that may be require for their use as pharmaceutical and industrial products. PMID- 21702902 TI - Blood pressure to height ratios as simple, sensitive and specific diagnostic tools for adolescent (pre)hypertension in Nigeria. AB - BACKGROUND: The age-, gender-, and height-percentile requirements of the 'gold standard' for the diagnosis of (pre)hypertension in adolescents make it time consuming for clinicians and difficult-to-use by non-professionals. Simplified diagnostic tools are therefore needed. The use of blood pressure-to-height ratio (BPHR)--systolic BPHR (SBPHR) and diastolic BPHR (DBPHR)--has been reported in Han adolescents, but it requires validation in other racial groups. The diagnostic accuracy of SBPHR and DBPHR in a population of 1,173 Nigerian adolescents aged 11-17 years, was therefore studied. METHODS: Blood pressures were measured using standard procedures and (pre)hypertension were defined according to international recommendations. ROC curve analyses were used to assess the diagnostic accuracy of BPHR in defining (pre)hypertension in this population. Sex-specific threshold values for SBPHR and DBPHR were determined, and thereafter used to define (pre)hypertension. The sensitivity/specificity of this method was determined. RESULTS: The accuracies of SBPHR and DBPHR in diagnosing (pre)hypertension, in both sexes, was > 92%. The optimal thresholds for diagnosing prehypertension were 0.72/0.46 in boys and 0.73/0.48 in girls; while for hypertension, they were 0.75/0.51 in boys and 0.77/0.50 in girls. The sensitivity and specificity of this method were > 96%. CONCLUSIONS: The use of BPHR is valid, simple and accurate in this population. Race-specific thresholds are however needed. PMID- 21702903 TI - Questionnaire-based approach to assess schoolchildren's physical fitness and its potential role in exploring the putative impact of helminth and Plasmodium spp. infections in Cote d'Ivoire. AB - BACKGROUND: Disability weights (DWs) are important for estimating burden of disease in terms of disability-adjusted life years. The previous practice of eliciting DWs by expert opinion has been challenged. More recent approaches employed quality of life (QoL) questionnaires to establish patient-based DWs, but results are ambiguous. METHODS: In early 2010, we administered a questionnaire pertaining to physical fitness to 200 schoolchildren in Cote d'Ivoire. Helminth and Plasmodium spp. infections were determined and schoolchildren's physical fitness objectively measured in a maximal multistage 20 m shuttle run test. Associations between objectively measured and self-reported physical fitness and between self-reported physical fitness and infection status were determined. Spearman rank correlation coefficient, uni- and multivariable linear regression models adjusting for children's age and sex, ambient air temperature and humidity, Fisher's test, chi(2) and t-test statistics were used for statistical analysis. RESULTS: The prevalence of Schistosoma haematobium, Plasmodium spp., Schistosoma mansoni, hookworm and Ascaris lumbricoides in 167 children with complete parasitological results was 84.4%, 74.9%, 54.5%, 14.4% and 1.2%, respectively. High infection intensities and multiple species parasite infections were common. In the 137 children with complete data also from the shuttle run test, we found statistically significant correlations between objectively measured and self-reported physical fitness. However, no statistically significant correlation between the children's parasitic infection status and self-reported physical fitness was identified. An attrition analysis revealed considerably lower self-reported physical fitness scores of parasitized children who were excluded from shuttle run testing due to medical concerns in comparison to parasitized children who were able to successfully complete the shuttle run test. CONCLUSIONS: Our QoL questionnaire proofed valid to assess children's physical fitness in the current study area. Reasons why no differences in self reported physical fitness in children with different parasitic infections were found are manifold, but do not preclude the use of QoL questionnaires in the elicitation of DWs. Indeed, the questionnaire was particularly useful in assessing physical fitness of those children, who were - supposedly due to parasitic infections - unable to complete the shuttle run test. Hence, we encourage others to use QoL questionnaires to determine not only physical fitness, but also more subtle morbidities. PMID- 21702905 TI - Can we monitor heart attack in the troponin era? Evidence from a population-based cohort study. AB - BACKGROUND: Troponins (highly sensitive biomarkers of myocardial damage) increase counts of myocardial infarction (MI) in clinical practice, but their impact on trends in admission rates for MI in National statistics is uncertain. METHODS: Cases coded as MI or other cardiac diagnoses in the Hospital Morbidity Data Collection (MI-HMDC) in Western Australia in 1998 and 2003 were classified using revised criteria for MI developed by an International panel convened by the American Heart Association (AHA criteria) using information on symptoms, ECGs and cardiac biomarkers abstracted from samples of medical notes. Age-sex standardized rates of MI-HMDC were compared with rates of MI based on AHA criteria including troponins (MI-AHA) or traditional biomarkers only (MI-AHAck). RESULTS: Between 1998 and 2003, rates of MI-HMDC decreased by 3.5% whereas rates of MI-AHA increased by 17%, a difference largely due to increased false-negative cases in the HMDC associated with marked increased use of troponin tests in cardiac admissions generally, and progressively lower test thresholds. In contrast, rates of MI-AHAck declined by 18%. CONCLUSIONS: Increasing misclassification of MI-AHA by the HMDC may be due to reluctance by clinicians to diagnose MI based on relatively small increases in troponin levels. These influences are likely to continue. Monitoring MI using AHA criteria will require calibration of commercially available troponin tests and agreement on lower diagnostic thresholds for epidemiological studies. Declining rates of MI-AHA ck are consistent with long-standing trends in MI in Western Australia, suggesting that neither MI-HMDC nor MI-AHA reflect the true underlying population trends in MI. PMID- 21702904 TI - Rare human papillomavirus 16 E6 variants reveal significant oncogenic potential. AB - The aim of this study was to determine whether low prevalence human papillomavirus (HPV) 16 E6 variants differ from high prevalence types in their functional abilities. We evaluated functions relevant to carcinogenesis for the rarely-detected European variants R8Q, R10G and R48W as compared to the commonly detected L83V. Human immortalized keratinocytes (NIKS) stably transduced with the E6 variants were used in most functional assays. Low and high prevalence E6 variants displayed similar abilities in abrogation of growth arrest and inhibition of p53 elevation induced by actinomycin D. Differences were detected in the abilities to dysregulate stratification and differentiation of NIKS in organotypic raft cultures, modulate detachment induced apoptosis (anoikis) and hyperactivate Wnt signaling. No distinctive phenotype could be assigned to include all rare variants. Like L83V, raft cultures derived from variants R10G and R48W similarly induced hyperplasia and aberrantly expressed keratin 5 in the suprabasal compartment with significantly lower expression of keratin 10. Unlike L83V, both variants, and particularly R48W, induced increased levels of anoikis upon suspension in semisolid medium. R8Q induced a unique phenotype characterized by thin organotypic raft cultures, low expression of keratin 10, and high expression of keratins 5 and 14 throughout all raft layers. Interestingly, in a reporter based assay R8Q exhibited a higher ability to augment TCF/beta-catenin transcription. The data suggests that differences in E6 variant prevalence in cervical carcinoma may not be related to the carcinogenic potential of the E6 protein. PMID- 21702906 TI - The increase of methicillin-resistant Staphylococcus aureus (MRSA) and the presence of an unusual sequence type ST49 in slaughter pigs in Switzerland. AB - BACKGROUND: In years past, methicillin-resistant S. aureus (MRSA) has been frequently detected in pigs in Europe, North America and Asia. Recent, yet sporadic studies have revealed a low occurrence of MRSA in Switzerland. In 2009, a monitoring survey of the prevalence and genetic diversity of methicillin resistant S. aureus (MRSA) in slaughter pigs in Switzerland was conducted using methods recommended by the EU guidelines, and using a sampling strategy evenly distributed throughout the year and representative of the Swiss slaughter pig population. Monitoring should determine if the overall prevalence of MRSA in the entire country is increasing over the years and if specific multi-resistant MRSA clones are spreading over the country. RESULTS: In 2009, the nasal cavities of eight out of 405 randomly selected pigs were positive for MRSA, representing a prevalence of 2.0% (95% CI 0.9-3.9). The following year, 23 out of 392 pigs were positive for MRSA [5.9% prevalence (95% CI 3.8-8.7)]. Three multilocus sequence types (ST), four spa types and two types of staphylococcal cassette chromosome mec (SCCmec) elements were detected. The most frequent genotypes were ST398 (MLST)-(spa)t034-V(SCCmec) (n=18) and ST49-t208-V (n=7), followed by ST398-t011-V (n=4), ST398-t1451-V (n=1), and ST1-t2279-IVc (n=1). The isolates displayed resistance to beta-lactams [mecA, (31/31); blaZ, (19/31)]; tetracycline [tet(M), (31/31); tet(K), (30/31)] (n=31); macrolides and lincosamides [erm(C) (4/31) or erm(A) (18/31)] (n=22); tiamulin [vga(A)v (9/31) or unknown mechanism (18/31)] (n=27); trimethoprim [dfr(G) (18/31); spectinomycin [ant(9)-Ia (19/31) or unknown mechanism (3/31)] (n=22); streptomycin [str (19/31)]; sulphamethoxazole (7/31) and ciprofloxacin (n=1) (mechanisms not determined). CONCLUSIONS: This study is the first to describe the presence of MRSA ST49 in slaughter pigs, and to demonstrate a significant and nearly three-fold increase of MRSA prevalence in pigs within two years. The presence of a specific clonal lineage of MRSA from Switzerland suggests that it has been selected in Swiss pig husbandry. Effective hygiene measures should be enhanced within the entire pig production chain to suppress the spread of these pathogens into the community. PMID- 21702907 TI - A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes. AB - BACKGROUND: Detection of mutations by DNA sequencing can be facilitated by scanning methods to identify amplicons which may have mutations. Current scanning methods used for the detection of germline sequence variants are laborious as they require post-PCR manipulation. High resolution melting (HRM) is a cost effective rapid screening strategy, which readily detects heterozygous variants by melting curve analysis of PCR products. It is well suited to screening genes such as BRCA1 and BRCA2 as germline pathogenic mutations in these genes are always heterozygous. METHODS: Assays for the analysis of all coding regions and intron-exon boundaries of BRCA1 and BRCA2 were designed, and optimised. A final set of 94 assays which ran under identical amplification conditions were chosen for BRCA1 (36) and BRCA2 (58). Significant attention was placed on primer design to enable reproducible detection of mutations within the amplicon while minimising unnecessary detection of polymorphisms. Deoxyinosine residues were incorporated into primers that overlay intronic polymorphisms. Multiple 384 well plates were used to facilitate high throughput. RESULTS: 169 BRCA1 and 239 BRCA2 known sequence variants were used to test the amplicons. We also performed an extensive blinded validation of the protocol with 384 separate patient DNAs. All heterozygous variants were detected with the optimised assays. CONCLUSIONS: This is the first HRM approach to screen the entire coding region of the BRCA1 and BRCA2 genes using one set of reaction conditions in a multi plate 384 well format using specifically designed primers. The parallel screening of a relatively large number of samples enables better detection of sequence variants. HRM has the advantages of decreasing the necessary sequencing by more than 90%. This markedly reduced cost of sequencing will result in BRCA1 and BRCA2 mutation testing becoming accessible to individuals who currently do not undergo mutation testing because of the significant costs involved. PMID- 21702908 TI - Global transcriptome response in Lactobacillus sakei during growth on ribose. AB - BACKGROUND: Lactobacillus sakei is valuable in the fermentation of meat products and exhibits properties that allow for better preservation of meat and fish. On these substrates, glucose and ribose are the main carbon sources available for growth. We used a whole-genome microarray based on the genome sequence of L. sakei strain 23K to investigate the global transcriptome response of three L. sakei strains when grown on ribose compared with glucose. RESULTS: The function of the common regulated genes was mostly related to carbohydrate metabolism and transport. Decreased transcription of genes encoding enzymes involved in glucose metabolism and the L-lactate dehydrogenase was observed, but most of the genes showing differential expression were up-regulated. Especially transcription of genes directly involved in ribose catabolism, the phosphoketolase pathway, and in alternative fates of pyruvate increased. Interestingly, the methylglyoxal synthase gene, which encodes an enzyme unique for L. sakei among lactobacilli, was up-regulated. Ribose catabolism seems closely linked with catabolism of nucleosides. The deoxyribonucleoside synthesis operon transcriptional regulator gene was strongly up-regulated, as well as two gene clusters involved in nucleoside catabolism. One of the clusters included a ribokinase gene. Moreover, hprK encoding the HPr kinase/phosphatase, which plays a major role in the regulation of carbon metabolism and sugar transport, was up-regulated, as were genes encoding the general PTS enzyme I and the mannose-specific enzyme II complex (EIIman). Putative catabolite-responsive element (cre) sites were found in proximity to the promoter of several genes and operons affected by the change of carbon source. This could indicate regulation by a catabolite control protein A (CcpA)-mediated carbon catabolite repression (CCR) mechanism, possibly with the EIIman being indirectly involved. CONCLUSIONS: Our data shows that the ribose uptake and catabolic machinery in L. sakei is highly regulated at the transcription level. A global regulation mechanism seems to permit a fine tuning of the expression of enzymes that control efficient exploitation of available carbon sources. PMID- 21702909 TI - Very low prevalence of epidermal growth factor receptor (EGFR) protein expression and gene amplification in Saudi breast cancer patients. AB - BACKGROUND: Breast cancers which demonstrate EGFR protein expression, gene amplification and/or gene mutations may benefit therapeutically from tyrosine kinase inhibitors. In Western studies, EGFR protein expression has been demonstrated in 7-36% of breast cancer patients, while gene amplification has been found in around 6% of cases and mutations were either absent or extremely rare. Studies addressing EGFR protein expression and gene amplification in Saudi breast cancer patients are extremely scanty and the results reported have been mostly non-conclusive. Herein we report the prevalence of EGFR protein expression and gene amplification in a cohort of Saudi breast cancer patients. FINDINGS: We noticed a remarkably low incidence of EGFR protein expression (1.3%) while analyzing the spectrum of molecular subtypes of breast cancer in a Saudi population by immunohistochemistry. Also, EGFR gene amplification could not be demonstrated in any of 231 cases studied using silver enhanced in situ hybridization. CONCLUSIONS: The extremely low incidence of EGFR protein expression and gene amplification in Saudi breast cancer patients as compared to Western populations is most probably ethnically related as supported by our previous finding in the same cohort of a spectrum of molecular breast cancer types that is unique to the Saudi population and in stark contrast with Western and other regionally based studies. Further support to this view is provided by earlier studies from Saudi Arabia that have similarly shown variability in molecular breast cancer subtype distribution between Saudi and Caucasian populations as well as a predominance of the high-grade pathway in breast cancer development in Middle East women. More studies on EGFR in breast cancer are needed from different regions of Saudi Arabia before our assumption can be confirmed, however. PMID- 21702910 TI - Automated Bayesian model development for frequency detection in biological time series. AB - BACKGROUND: A first step in building a mathematical model of a biological system is often the analysis of the temporal behaviour of key quantities. Mathematical relationships between the time and frequency domain, such as Fourier Transforms and wavelets, are commonly used to extract information about the underlying signal from a given time series. This one-to-one mapping from time points to frequencies inherently assumes that both domains contain the complete knowledge of the system. However, for truncated, noisy time series with background trends this unique mapping breaks down and the question reduces to an inference problem of identifying the most probable frequencies. RESULTS: In this paper we build on the method of Bayesian Spectrum Analysis and demonstrate its advantages over conventional methods by applying it to a number of test cases, including two types of biological time series. Firstly, oscillations of calcium in plant root cells in response to microbial symbionts are non-stationary and noisy, posing challenges to data analysis. Secondly, circadian rhythms in gene expression measured over only two cycles highlights the problem of time series with limited length. The results show that the Bayesian frequency detection approach can provide useful results in specific areas where Fourier analysis can be uninformative or misleading. We demonstrate further benefits of the Bayesian approach for time series analysis, such as direct comparison of different hypotheses, inherent estimation of noise levels and parameter precision, and a flexible framework for modelling the data without pre-processing. CONCLUSIONS: Modelling in systems biology often builds on the study of time-dependent phenomena. Fourier Transforms are a convenient tool for analysing the frequency domain of time series. However, there are well-known limitations of this method, such as the introduction of spurious frequencies when handling short and noisy time series, and the requirement for uniformly sampled data. Biological time series often deviate significantly from the requirements of optimality for Fourier transformation. In this paper we present an alternative approach based on Bayesian inference. We show the value of placing spectral analysis in the framework of Bayesian inference and demonstrate how model comparison can automate this procedure. PMID- 21702911 TI - A progressive increase in cardiovascular risk assessed by coronary angiography in non-diabetic patients at sub-diabetic glucose levels. AB - OBJECTIVE: Diabetes mellitus type 2 (DM2) is a risk factor for coronary heart disease (CHD). While there is a clear correlation of fasting blood glucose (FBG) and 2 h post-challenge blood glucose values (2h-BG) with microvascular complications, the risk for CHD conferred by glucose dysregulation antecedent to DM2 is less clear. Therefore, we investigated associations of FBG and 2h-BG values with the prevalence of CHD assessed by coronary angiography as the most sensitive diagnostic tool. RESEARCH DESIGN AND METHODS: Coronary angiography was performed in 1394 patients without known DM. Capillary blood glucose was analyzed before and 2 h after an oral glucose tolerance test. Associations between FBG as well as 2h-BG levels and the risk for CHD were assessed by logistic regression analysis. RESULTS: 1064 (75%) of patients were diagnosed with CHD. 204 (15%) were diagnosed with so far unknown DM2, 274 (20%) with isolated impaired fasting glucose (IFG), 188 (13%) with isolated impaired glucose tolerance (IGT) and 282 (20%) with both, IGT and IFG. We found a continuous increase in the risk for CHD with fasting and post-challenge blood glucose values even in the subdiabetic range. This correlation did however not suggest clear cut-off values. The increase in risk for CHD reached statistical significance at FBG levels of > 120 mg/dl (Odds Ratio of 2.7 [1.3-5.6] and 2h-BG levels > 140 mg/dl (141-160 mg/dl OR 1.8 [1.1-2.9], which was however lost after adjusting for age, sex and BMI. CONCLUSIONS: In our study population we found a continuous increased risk for CHD at fasting and 2h-BG levels in the sub-diabetic glucose range, but no clear cut off values for cardiovascular risk. PMID- 21702913 TI - Human resources for maternal, newborn and child health: from measurement and planning to performance for improved health outcomes. AB - BACKGROUND: There is increasing attention, globally and in countries, to monitoring and addressing the health systems and human resources inputs, processes and outputs that impede or facilitate progress towards achieving the Millennium Development Goals for maternal and child health. We reviewed the situation of human resources for health (HRH) in 68 low- and middle-income countries that together account for over 95% of all maternal and child deaths. METHODS: We collected and analysed cross-nationally comparable data on HRH availability, distribution, roles and functions from new and existing sources, and information from country reviews of HRH interventions that are associated with positive impacts on health services delivery and population health outcomes. RESULTS: Findings from 68 countries demonstrate availability of doctors, nurses and midwives is positively correlated with coverage of skilled birth attendance. Most (78%) of the target countries face acute shortages of highly skilled health personnel, and large variations persist within and across countries in workforce distribution, skills mix and skills utilization. Too few countries appropriately plan for, authorize and support nurses, midwives and community health workers to deliver essential maternal, newborn and child health-care interventions that could save lives. CONCLUSIONS: Despite certain limitations of the data and findings, we identify some key areas where governments, international partners and other stakeholders can target efforts to ensure a sufficient, equitably distributed and efficiently utilized health workforce to achieve MDGs 4 and 5. PMID- 21702912 TI - The risk of child and adolescent overweight is related to types of food consumed. AB - BACKGROUND/AIMS: To investigate the association between the risk of overweight and the consumption of food groups in children and adolescents. METHODS: We studied 1764 healthy children and adolescents (age 6-19y) attending 16 Seventh Day Adventist schools and 13 public schools using a 106-item non-quantitative food frequency questionnaire from the late 1980 Child-Adolescent Blood Pressure Study. Logistic regression models were used to compute the risk of overweight according to consumption of grains, nuts, vegetables, fruits, meats/fish/eggs, dairy, and, low nutrient-dense foods (LNDF). RESULTS: The frequency of consumption of grains, nuts, vegetables and LNDF were inversely related to the risk of being overweight and dairy increased the risk. Specifically, the odds ratio (95% CI) for children in the highest quartile or tertile of consumption compared with the lowest quartile or tertile were as follows: grains 0.59(0.41 0.83); nuts 0.60(0.43-0.85); vegetables 0.67(0.48-0.94); LNDF 0.43(0.29-0.63); and, dairy 1.36(0.97, 1.92). CONCLUSION: The regular intake of specific plant foods may prevent overweight among children and adolescents. PMID- 21702914 TI - Sequential FDG-PET and induction chemotherapy in locally advanced adenocarcinoma of the Oesophago-gastric junction (AEG): the Heidelberg Imaging program in Cancer of the oesophago-gastric junction during Neoadjuvant treatment: HICON trial. AB - BACKGROUND: 18-Fluorodeoxyglucose-PET (18F-FDG-PET) can be used for early response assessment in patients with locally advanced adenocarcinomas of the oesophagogastric junction (AEG) undergoing neoadjuvant chemotherapy. It has been recently shown in the MUNICON trials that response-guided treatment algorithms based on early changes of the FDG tumor uptake detected by PET are feasible and that they can be implemented into clinical practice. Only 40%-50% of the patients respond metabolically to therapy. As metabolic non-response is known to be associated with a dismal prognosis, metabolic non-responders are increasingly treated with alternative neoadjuvant chemotherapies or chemoradiation in order to improve their clinical outcome. We plan to investigate whether PET can be used as response assessment during radiochemotherapy given as salvage treatment in early metabolic non-responders to standard chemotherapy. METHODS/DESIGN: The HICON trial is a prospective, non-randomized, explorative imaging study evaluating the value of PET as a predictor of histopathological response in metabolic non responders. Patients with resectable AEG type I and II according to Siewerts classification, staged cT3/4 and/or cN+ and cM0 by endoscopic ultrasound, spiral CT or MRI and FDG-PET are eligible. Tumors must be potentially R0 resectable and must have a sufficient FDG-baseline uptake. Only metabolic non-responders, showing a < 35% decrease of SUV two weeks after the start of neoadjuvant chemotherapy are eligible for the study and are taken to intensified taxane-based RCT (chemoradiotherapy (45 Gy) before surgery. 18FDG-PET scans will be performed before ( = Baseline) and after 14 days of standard neoadjuvant therapy as well as after the first cycle of salvage docetaxel/cisplatin chemotherapy (PET 1) and at the end of radiochemotherapy (PET2). Tracer uptake will be assessed semiquantitatively using standardized uptake values (SUV). The percentage difference DeltaSUV = 100 (SUV Baseline - SUV PET1)/SUV Baseline will be calculated and assessed as an early predictor of histopathological response. In a secondary analysis, the association between the difference SUV PET1 - SUV PET2 and histopathological response will be evaluated. DISCUSSION: The aim of this study is to investigate the potential of sequential 18FDG-PET in predicting histopathological response in AEG tumors to salvage neoadjuvant radiochemotherapy in patients who do not show metabolic response to standard neoadjuvant chemotherapy. PMID- 21702915 TI - In utero protein restriction causes growth delay and alters sperm parameters in adult male rats. AB - BACKGROUND: Recent studies have supported the concept of "fetal programming" which suggests that during the intrauterine development the fetus may be programmed to develop diseases in adulthood. The possible effects of in utero protein restriction on sexual development of rat male offspring were evaluated in the present study. METHODS: Pregnant Wistar rats were divided into two experimental groups: one group treated with standard chow (SC, n = 8, 17% protein) and the other group treated with hypoproteic chow (HC, n = 10, 6% protein) throughout gestation. After gestation the two experimental groups received standard chow. To evaluate the possible late reproductive effects of in utero protein restriction, the male offspring of both groups were assessed at different phases of sexual development: prepubertal (30 days old); peripubertal (60 days old); adult (90 days old). Student's t-test and Mann-Whitney test were utilized. Differences were considered significant when p < 0.05. RESULTS: We found that in utero protein restriction reduced the body weight of male pups on the first postnatal day and during the different sexual development phases (prepubertal, peripubertal and adult). During adulthood, Sertoli cell number, sperm motility and sperm counts in the testis and epididymal cauda were also reduced in HC. Furthermore, the numbers of sperm presenting morphological abnormalities and cytoplasmic drop retention were higher in HC. CONCLUSIONS: In conclusion, in utero protein restriction, under these experimental conditions, causes growth delay and alters male reproductive-system programming in rats, suggesting impairment of sperm quality in adulthood. PMID- 21702916 TI - The risk factor profile of women with secondary infertility: an unmatched case control study in Kigali, Rwanda. AB - BACKGROUND: Secondary infertility is a common, preventable but neglected reproductive health problem in resource-poor countries. This study examines the association of past sexually transmitted infections (STIs) including HIV, bacterial vaginosis (BV) and factors in the obstetric history with secondary infertility and their relative contributions to secondary infertility. METHODS: Between November 2007 and May 2009 a research infertility clinic was set up at the Kigali University Teaching Hospital in Rwanda. Cases were defined as sexually active women aged 21-45 years presenting with secondary infertility (n = 177), and controls as multiparous women in the same age groups who recently delivered (n = 219). Participants were interviewed about socio-demographic characteristics and obstetric history using structured questionnaires, and were tested for HIV and reproductive tract infections (RTIs). RESULTS: Risk factors in the obstetric history for secondary infertility were lack of prenatal care in the last pregnancy, the first pregnancy before the age of 21 years, a history of unwanted pregnancy, a pregnancy with other than current partner, an adverse pregnancy outcome, stillbirth, postpartum infection and curettage. Presence of HIV, herpes simplex virus type 2 (HSV-2), or Treponema pallidum antibodies, and bacterial vaginosis (BV), were significantly more common in women in secondary infertile relationships than those in fertile relationships. The population attributable fractions (PAF%) for obstetric events, HIV, other (STIs), and BV were 25%, 30%, 27%, and 14% respectively. CONCLUSIONS: The main finding of this study is that obstetric events, HIV and other STIs contribute approximately equally to secondary infertility in Rwanda. Scaling up of HIV/STI prevention, increased access to family planning services, improvement of prenatal and obstetric care and reduction of stillbirth and infant mortality rates are all likely to decrease secondary infertility in sub-Saharan Africa. PMID- 21702917 TI - Variations in salinity tolerance of malaria vectors of the Anopheles subpictus complex in Sri Lanka and the implications for malaria transmission. AB - BACKGROUND: Anopheles subpictus sensu lato, a widespread vector of malaria in Asia, is reportedly composed of four sibling species A-D based on distinct cytogenetic and morphological characteristics. However An. subpictus species B specimens in Sri Lanka are termed An. subpictus B/ An. sundaicus because of recent genetic data. Differences in salinity tolerance and coastal/inland prevalence of An. subpictus sibling species that were not previously established in Sri Lanka are presented here. RESULTS: Specimens with morphological characteristics of all four Indian An. subpictus sibling species were found in Sri Lanka. Sibling species A, C and D tended to be predominant in inland, and An. subpictus species B/An. sundaicus, in coastal localities. Sibling species C was predominant in both adult and larval inland collections. Larvae of An. subpictus B/An. sundaicus were found in inland and coastal sites, including a lagoon, with salinity varying from 0 to 30 ppt. An. subpictus sibling species A, C and D larvae were present in water of salinity between 0 to 4 ppt. An. subpictus C, D and An. subpictus B/An. sundaicus larvae showed compatible differential salinity tolerance in laboratory tests. The first instar larvae of An. subpictus B/An. sundaicus showed 100% survival up to 15 ppt in comparison to species C and D where the corresponding values were 3 ppt and 6 ppt respectively. However all third instar larvae of An. subpictus B/An. sundaicus survived up to 30 ppt salinity whereas An. subpictus C and D tolerated up to 4 ppt and 8 ppt salinity respectively. CONCLUSIONS: The results suggest that An. subpictus species B/An. sundaicus breed in fresh, brackish and nearly saline water while An. subpictus species C and D do so in fresh and less brackish waters in Sri Lanka, as in India. Because of the established role of An. sundaicus s.l. and An. subpictus s.l. as malaria vectors, the findings indicate a need for greater monitoring of brackish water breeding habitats in Asia. Tolerance to 15 ppt salinity may also constitute a simple method for differentiating An. subpictus B/An. sundaicus larvae from those of An. subpictus species C and D in field studies. PMID- 21702918 TI - Tocotrienol rich fraction supplementation improved lipid profile and oxidative status in healthy older adults: A randomized controlled study. AB - BACKGROUND: Vitamin E supplements containing tocotrienols are now being recommended for optimum health but its effects are scarcely known. The objective was to determine the effects of Tocotrienol Rich Fraction (TRF) supplementation on lipid profile and oxidative status in healthy older individuals at a dose of 160 mg/day for 6 months. METHODS: Sixty-two subjects were recruited from two age groups: 35-49 years (n = 31) and above 50 years (n = 31), and randomly assigned to receive either TRF or placebo capsules for six months. Blood samples were obtained at 0, 3rd and 6th months. RESULTS: HDL-cholesterol in the TRF supplemented group was elevated after 6 months (p < 0.01). Protein carbonyl contents were markedly decreased (p < 0.001), whereas AGE levels were lowered in the > 50 year-old group (p < 0.05). Plasma levels of total vitamin E particularly tocopherols were significantly increased in the TRF-supplemented group after 3 months (p < 0.01). Plasma total tocotrienols were only increased in the > 50 year old group after receiving 6 months of TRF supplementation. Changes in enzyme activities were only observed in the > 50 year-old group. SOD activity was decreased after 3 (p < 0.05) and 6 (p < 0.05) months of TRF supplementation whereas CAT activity was decreased after 3 (p < 0.01) and 6 (p < 0.05) months in the placebo group. GPx activity was increased at 6 months for both treatment and placebo groups (p < 0.05). CONCLUSION: The observed improvement of plasma cholesterol, AGE and antioxidant vitamin levels as well as the reduced protein damage may indicate a restoration of redox balance after TRF supplementation, particularly in individuals over 50 years of age. PMID- 21702919 TI - Comparative expression profiling of E. coli and S. aureus inoculated primary mammary gland cells sampled from cows with different genetic predispositions for somatic cell score. AB - BACKGROUND: During the past ten years many quantitative trait loci (QTL) affecting mastitis incidence and mastitis related traits like somatic cell score (SCS) were identified in cattle. However, little is known about the molecular architecture of QTL affecting mastitis susceptibility and the underlying physiological mechanisms and genes causing mastitis susceptibility. Here, a genome-wide expression analysis was conducted to analyze molecular mechanisms of mastitis susceptibility that are affected by a specific QTL for SCS on Bos taurus autosome 18 (BTA18). Thereby, some first insights were sought into the genetically determined mechanisms of mammary gland epithelial cells influencing the course of infection. METHODS: Primary bovine mammary gland epithelial cells (pbMEC) were sampled from the udder parenchyma of cows selected for high and low mastitis susceptibility by applying a marker-assisted selection strategy considering QTL and molecular marker information of a confirmed QTL for SCS in the telomeric region of BTA18. The cells were cultured and subsequently inoculated with heat-inactivated mastitis pathogens Escherichia coli and Staphylococcus aureus, respectively. After 1, 6 and 24 h, the cells were harvested and analyzed using the microarray expression chip technology to identify differences in mRNA expression profiles attributed to genetic predisposition, inoculation and cell culture. RESULTS: Comparative analysis of co expression profiles clearly showed a faster and stronger response after pathogen challenge in pbMEC from less susceptible animals that inherited the favorable QTL allele 'Q' than in pbMEC from more susceptible animals that inherited the unfavorable QTL allele 'q'. Furthermore, the results highlighted RELB as a functional and positional candidate gene and related non-canonical Nf-kappaB signaling as a functional mechanism affected by the QTL. However, in both groups, inoculation resulted in up-regulation of genes associated with the Ingenuity pathways 'dendritic cell maturation' and 'acute phase response signaling', whereas cell culture affected biological processes involved in 'cellular development'. CONCLUSIONS: The results indicate that the complex expression profiling of pathogen challenged pbMEC sampled from cows inheriting alternative QTL alleles is suitable to study genetically determined molecular mechanisms of mastitis susceptibility in mammary epithelial cells in vitro and to highlight the most likely functional pathways and candidate genes underlying the QTL effect. PMID- 21702920 TI - Adjuvant radio-chemotherapy for extrahepatic biliary tract cancers. AB - BACKGROUND: Extrahepatic biliary duct cancers (EBDC) are uncommon malignancies characterized by a poor prognosis with high rate of loco-regional recurrence. The purpose of the present study is to assess the feasibility and the potential impact of adjuvant radiotherapy (RT) in a series of patients treated in one institution. METHODS: Twenty three patients with non-metastatic bile duct cancer treated surgically with curative intent (4 gallbladder, 7 ampullary and 12 cholangiocarcinoma) received 3D conformal external beam RT to a median total dose of 50.4 Gy. Concurrent chemotherapy based on 5-FU was delivered to 21 patients (91%). Surgical margins were negative in 11 patients (48%), narrow in 2 (9%), and microscopically involved in 8 (35%). Eleven patients (55%) had metastatic nodal involvement. The average follow-up time for all patients was 30 months (ranging from 3-98). RESULTS: Acute gastrointestinal grade 2 toxicity (RTOG scale) was recorded in 2 patients (9%). Nausea or vomiting grade 1 and 2 was observed in 8 (35%) and 2 patients (9%) respectively. Only one patient developed a major late radiation-induced toxicity. The main pattern of recurrence was both loco-regional and distant (liver, peritoneum and/or lung). No difference was observed in loco regional control according to the tumor location. The 5-year actuarial loco regional control rate was 48.3% (67% and 30% for patients operated on with negative and positive/narrow/unknown margins respectively, p=0.04). The 5-year actuarial overall survival was of 35.9% for the entire group (61.4% in case of negative margins and 16.7% in case of positive/narrow/unknown margins, p=0.07). CONCLUSIONS: Postoperative RT with 50-60 Gy is feasible with acceptable acute and late toxicities. The potential benefit observed in our series may support the use of adjuvant RT in patients with locally advanced disease. Prospective randomized trials are warranted to confirm definitively the role of RT in this tumor location. PMID- 21702921 TI - Comparative diffusion assay to assess efficacy of topical antimicrobial agents against Pseudomonas aeruginosa in burns care. AB - BACKGROUND: Severely burned patients may develop life-threatening nosocomial infections due to Pseudomonas aeruginosa, which can exhibit a high-level of resistance to antimicrobial drugs and has a propensity to cause nosocomial outbreaks. Antiseptic and topical antimicrobial compounds constitute major resources for burns care but in vitro testing of their activity is not performed in practice. RESULTS: In our burn unit, a P. aeruginosa clone multiresistant to antibiotics colonized or infected 26 patients over a 2-year period. This resident clone was characterized by PCR based on ERIC sequences. We investigated the susceptibility of the resident clone to silver sulphadiazine and to the main topical antimicrobial agents currently used in the burn unit. We proposed an optimized diffusion assay used for comparative analysis of P. aeruginosa strains. The resident clone displayed lower susceptibility to silver sulphadiazine and cerium silver sulphadiazine than strains unrelated to the resident clone in the unit or unrelated to the burn unit. CONCLUSIONS: The diffusion assay developed herein detects differences in behaviour against antimicrobials between tested strains and a reference population. The method could be proposed for use in semi routine practice of medical microbiology. PMID- 21702922 TI - Lymph node-derived donor encephalitogenic CD4+ T cells in C57BL/6 mice adoptive transfer experimental autoimmune encephalomyelitis highly express GM-CSF and T bet. AB - Experimental autoimmune encephalomyelitis (EAE) is a relevant animal model for the human demyelinating inflammatory disorder of the central nervous system (CNS), multiple sclerosis (MS). Induction of EAE by adoptive transfer allows studying the role of the donor T lymphocyte in disease pathogenesis. It has been challenging to reliably induce adoptive transfer EAE in C57BL/6 (H-2b) mice. The goal of this study was to develop a reproducible and high yield protocol for adoptive transfer EAE in C57BL/6 mice. A step-wise experimental approach permitted us to develop a protocol that resulted in a consistent relatively high disease incidence of ~70% in recipient mice. Donor mice were immunized with myelin oligodendrocyte glycoprotein (MOG)p35-55 in complete Freund's adjuvant (CFA) followed by pertussis toxin (PT). Only lymph node cells (LNC) isolated at day 12 post immunization, and restimulated in vitro for 72 hours with 10 MUg/mL of MOGp35-55 and 0.5 ng/mL of interleukin-12 (IL-12) were able to transfer disease. The ability of LNC to transfer disease was associated with the presence of inflammatory infiltrates in the CNS at day 12. Interferon gamma (IFNgamma) was produced at comparable levels in cell cultures prepared from mice at both day 6 and day 12 post immunization. By contrast, there was a trend towards a negative association between IL-17 and disease susceptibility in our EAE model. The amount of GM-CSF secreted was significantly increased in the culture supernatants from cells collected at day 12 post immunization versus those collected at day 6 post immunization. Activated CD4+ T cells present in the day 12 LNC cultures maintained expression of the transcription factor T-bet, which has been shown to regulate the expression of the IL-23 receptor. Also, there was an increased prevalence of MOGp35-55-specific CD4+ T cells in day 12 LNC after in vitro re stimulation. In summary, encephalitogenic LNC that adoptively transfer EAE in C57BL/6 mice were not characterized by a single biomarker in our study, but by a composite of inflammatory markers. Our data further suggest that GM-CSF expression by CD4+ T cells regulated by IL-23 contributes to their encephalitogenicity in our EAE model. PMID- 21702923 TI - Genetic mechanisms involved in the evolution of the cephalopod camera eye revealed by transcriptomic and developmental studies. AB - BACKGROUND: Coleoid cephalopods (squids and octopuses) have evolved a camera eye, the structure of which is very similar to that found in vertebrates and which is considered a classic example of convergent evolution. Other molluscs, however, possess mirror, pin-hole, or compound eyes, all of which differ from the camera eye in the degree of complexity of the eye structures and neurons participating in the visual circuit. Therefore, genes expressed in the cephalopod eye after divergence from the common molluscan ancestor could be involved in eye evolution through association with the acquisition of new structural components. To clarify the genetic mechanisms that contributed to the evolution of the cephalopod camera eye, we applied comprehensive transcriptomic analysis and conducted developmental validation of candidate genes involved in coleoid cephalopod eye evolution. RESULTS: We compared gene expression in the eyes of 6 molluscan (3 cephalopod and 3 non-cephalopod) species and selected 5,707 genes as cephalopod camera eye specific candidate genes on the basis of homology searches against 3 molluscan species without camera eyes. First, we confirmed the expression of these 5,707 genes in the cephalopod camera eye formation processes by developmental array analysis. Second, using molecular evolutionary (dN/dS) analysis to detect positive selection in the cephalopod lineage, we identified 156 of these genes in which functions appeared to have changed after the divergence of cephalopods from the molluscan ancestor and which contributed to structural and functional diversification. Third, we selected 1,571 genes, expressed in the camera eyes of both cephalopods and vertebrates, which could have independently acquired a function related to eye development at the expression level. Finally, as experimental validation, we identified three functionally novel cephalopod camera eye genes related to optic lobe formation in cephalopods by in situ hybridization analysis of embryonic pygmy squid. CONCLUSION: We identified 156 genes positively selected in the cephalopod lineage and 1,571 genes commonly found in the cephalopod and vertebrate camera eyes from the analysis of cephalopod camera eye specificity at the expression level. Experimental validation showed that the cephalopod camera eye-specific candidate genes include those expressed in the outer part of the optic lobes, which unique to coleoid cephalopods. The results of this study suggest that changes in gene expression and in the primary structure of proteins (through positive selection) from those in the common molluscan ancestor could have contributed, at least in part, to cephalopod camera eye acquisition. PMID- 21702924 TI - Molecular role of GATA binding protein 4 (GATA-4) in hyperglycemia-induced reduction of cardiac contractility. AB - BACKGROUND: Diabetic cardiomyopathy, a diabetes-specific complication, refers to a disorder that eventually leads to left ventricular hypertrophy in addition to diastolic and systolic dysfunction. In recent studies, hyperglycemia-induced reactive oxygen species (ROS) in cardiomyocytes have been linked to diabetic cardiomyopathy. GATA binding protein 4 (GATA-4) regulates the expression of many cardio-structural genes including cardiac troponin-I (cTnI). METHODS: Streptozotocin-induced diabetic rats and H9c2 embryonic rat cardiomyocytes treated with a high concentration of glucose (a D-glucose concentration of 30 mM was used and cells were cultured for 24 hr) were used to examine the effect of hyperglycemia on GATA-4 accumulation in the nucleus. cTnI expression was found to be linked to cardiac tonic dysfunction, and we evaluated the expression levels of cTnI and GATA-4 by Western blot analysis. RESULTS: Cardiac output was lowered in STZ-induced diabetic rats. In addition, higher expressions of cardiac troponin I (cTnI) and phosphorylated GATA-4 were identified in these rats by Western blotting. The changes were reversed by treatment with insulin or phlorizin after correction of the blood sugar level. In H9c2 cells, ROS production owing to the high glucose concentration increased the expression of cTnI and GATA-4 phosphorylation. However, hyperglycemia failed to increase the expression of cTnI when GATA-4 was silenced by small interfering RNA (siRNA) in H9c2 cells. Otherwise, activation of ERK is known to be a signal for phosphorylation of serine105 in GATA-4 to increase the DNA binding ability of this transcription factor. Moreover, GSK3beta could directly interact with GATA-4 to cause GATA-4 to be exported from the nucleus. GATA-4 nuclear translocation and GSK3beta ser9 phosphorylation were both elevated by a high glucose concentration in H9c2 cells. These changes were reversed by tiron (ROS scavenger), PD98059 (MEK/ERK inhibitor), or siRNA of GATA-4. Cell contractility measurement also indicated that the high glucose concentration decreased the contractility of H9c2 cells, and this was reduced by siRNA of GATA-4. CONCLUSIONS: Hyperglycemia can cause systolic dysfunction and a higher expression of cTnI in cardiomyocytes through ROS, enhancing MEK/ERK-induced GATA-4 phosphorylation and accumulation in the cell nucleus. PMID- 21702925 TI - Role of the SaeRS two-component regulatory system in Staphylococcus epidermidis autolysis and biofilm formation. AB - BACKGROUND: Staphylococcus epidermidis (SE) has emerged as one of the most important causes of nosocomial infections. The SaeRS two-component signal transduction system (TCS) influences virulence and biofilm formation in Staphylococcus aureus. The deletion of saeR in S. epidermidis results in impaired anaerobic growth and decreased nitrate utilization. However, the regulatory function of SaeRS on biofilm formation and autolysis in S. epidermidis remains unclear. RESULTS: The saeRS genes of SE1457 were deleted by homologous recombination. The saeRS deletion mutant, SE1457DeltasaeRS, exhibited increased biofilm formation that was disturbed more severely (a 4-fold reduction) by DNase I treatment compared to SE1457 and the complementation strain SE1457saec. Compared to SE1457 and SE1457saec, SE1457DeltasaeRS showed increased Triton X-100 induced autolysis (approximately 3-fold) and decreased cell viability in planktonic/biofilm states; further, SE1457DeltasaeRS also released more extracellular DNA (eDNA) in the biofilms. Correlated with the increased autolysis phenotype, the transcription of autolysis-related genes, such as atlE and aae, was increased in SE1457DeltasaeRS. Whereas the expression of accumulation associated protein was up-regulated by 1.8-fold in 1457DeltasaeRS, the expression of an N-acetylglucosaminyl transferase enzyme (encoded by icaA) critical for polysaccharide intercellular adhesin (PIA) synthesis was not affected by the deletion of saeRS. CONCLUSIONS: Deletion of saeRS in S. epidermidis resulted in an increase in biofilm-forming ability, which was associated with increased eDNA release and up-regulated Aap expression. The increased eDNA release from SE1457DeltasaeRS was associated with increased bacterial autolysis and decreased bacterial cell viability in the planktonic/biofilm states. PMID- 21702926 TI - Difference in the distribution pattern of substrate enzymes in the metabolic network of Escherichia coli, according to chaperonin requirement. AB - BACKGROUND: Chaperonins are important in living systems because they play a role in the folding of proteins. Earlier comprehensive analyses identified substrate proteins for which folding requires the chaperonin GroEL/GroES (GroE) in Escherichia coli, and they revealed that many chaperonin substrates are metabolic enzymes. This result implies the importance of chaperonins in metabolism. However, the relationship between chaperonins and metabolism is still unclear. RESULTS: We investigated the distribution of chaperonin substrate enzymes in the metabolic network using network analysis techniques as a first step towards revealing this relationship, and found that as chaperonin requirement increases, substrate enzymes are more laterally distributed in the metabolic. In addition, comparative genome analysis showed that the chaperonin-dependent substrates were less conserved, suggesting that these substrates were acquired later on in evolutionary history. CONCLUSIONS: This result implies the expansion of metabolic networks due to this chaperonin, and it supports the existing hypothesis of acceleration of evolution by chaperonins. The distribution of chaperonin substrate enzymes in the metabolic network is inexplicable because it does not seem to be associated with individual protein features such as protein abundance, which has been observed characteristically in chaperonin substrates in previous works. However, it becomes clear by considering this expansion process due to chaperonin. This finding provides new insights into metabolic evolution and the roles of chaperonins in living systems. PMID- 21702927 TI - Identity of zinc finger nucleases with specificity to herpes simplex virus type II genomic DNA: novel HSV-2 vaccine/therapy precursors. AB - BACKGROUND: Herpes simplex type II (HSV-2) is a member of the family herpesviridae. Human infection with this double stranded linear DNA virus causes genital ulcerative disease and existing treatment options only serve to resolve the symptomatology (ulcers) associated with active HSV-2 infection but do not eliminate latent virus. As a result, infection with HSV-2 follows a life-long relapsing (active versus latent) course. On the basis of a primitive bacterium anti-phage DNA defense, the restriction modification (R-M) system, we previously identified the Escherichia coli restriction enzyme (REase) EcoRII as a novel peptide to excise or irreversibly disrupt latent HSV-2 DNA from infected cells. However, sequences of the site specificity palindrome of EcoRII 5'-CCWGG-3' (W = A or T) are equally present within the human genome and are a potential source of host-genome toxicity. This feature has limited previous HSV-2 EcoRII based therapeutic models to microbicides only, and highlights the need to engineer artificial REases (zinc finger nucleases-ZFNs) with specificity to HSV-2 genomic DNA only. Herein, the therapeutic-potential of zinc finger arrays (ZFAs) and ZFNs is identified and modeled, with unique specificity to the HSV-2 genome. METHODS AND RESULTS: Using the whole genome of HSV-2 strain HG52 (Dolan A et al.,), and with the ZFN-consortium's CoDA-ZiFiT software pre-set at default, more than 28,000 ZFAs with specificity to HSV-2 DNA were identified. Using computational assembly (through in-silico linkage to the Flavobacterium okeanokoites endonuclease Fok I of the type IIS class), 684 ZFNs with specificity to the HSV-2 genome, were constructed. Graphic-analysis of the HSV-2 genome-cleavage pattern using the afore-identified ZFNs revealed that the highest cleavage-incidence occurred within the 30,950 base-pairs (~between the genomic context coordinates 0.80 and 1.00) at the 3' end of the HSV-2 genome. At approximately 3,095 bp before and after the 5' and 3' ends of the HSV-2 genome (genomic context coordinates 0.02 and 0.98, respectively) were specificity sites of ZFNs suited for the complete excision of over 60% of HSV-2 genomic material from within infected human cells, through the process of non-homologous end joining (NHEJ). Furthermore, a model concerning a recombinant (ICP10-PK mutant) replication competent HSV-2 viral vector for delivering and transducing a diploid copy (or pair) of the HSV-2-genome-specific ZFN genotype within neuronal tissue, is presented. CONCLUSION: ZFNs with specificity to HSV-2 genomic DNA that are precursors of novel host-genome expressed HSV-2 gene-therapeutics or vaccines were identified. PMID- 21702928 TI - Novel multiplex technology for diagnostic characterization of rheumatoid arthritis. AB - INTRODUCTION: The aim of this study was to develop a clinical-grade, automated, multiplex system for the differential diagnosis and molecular stratification of rheumatoid arthritis (RA). METHODS: We profiled autoantibodies, cytokines, and bone-turnover products in sera from 120 patients with a diagnosis of RA of < 6 months' duration, as well as in sera from 27 patients with ankylosing spondylitis, 28 patients with psoriatic arthritis, and 25 healthy individuals. We used a commercial bead assay to measure cytokine levels and developed an array assay based on novel multiplex technology (Immunological Multi-Parameter Chip Technology) to evaluate autoantibody reactivities and bone-turnover markers. Data were analyzed by Significance Analysis of Microarrays and hierarchical clustering software. RESULTS: We developed a highly reproducible, automated, multiplex biomarker assay that can reliably distinguish between RA patients and healthy individuals or patients with other inflammatory arthritides. Identification of distinct biomarker signatures enabled molecular stratification of early-stage RA into clinically relevant subtypes. In this initial study, multiplex measurement of a subset of the differentiating biomarkers provided high sensitivity and specificity in the diagnostic discrimination of RA: Use of 3 biomarkers yielded a sensitivity of 84.2% and a specificity of 93.8%, and use of 4 biomarkers a sensitivity of 59.2% and a specificity of 96.3%. CONCLUSIONS: The multiplex biomarker assay described herein has the potential to diagnose RA with greater sensitivity and specificity than do current clinical tests. Its ability to stratify RA patients in an automated and reproducible manner paves the way for the development of assays that can guide RA therapy. PMID- 21702929 TI - Detection of early Alzheimer's disease in MCI patients by the combination of MMSE and an episodic memory test. AB - BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous clinical entity that comprises the prodromal phase of Alzheimer's disease (Pr-AD). New biomarkers are useful in detecting Pr-AD, but they are not universally available. We aimed to investigate baseline clinical and neuropsychological variables that might predict progression from MCI to AD dementia. METHODS: All patients underwent a complete clinical and neuropsychological evaluation at baseline and every 6 months during a two-year follow-up period, with 54 out of 109 MCI patients progressing to dementia (50 of them progressed to AD dementia), and 55 remaining as stable MCI (S-MCI). RESULTS: A combination of MMSE and California Verbal Learning Test Long Delayed Total Recall (CVLT-LDTR) constituted the best predictive model: subjects scoring above 26/30 on MMSE and 4/16 on CVLT-LDTR had a negative predictive value of 93.93% at 2 years, whereas those subjects scoring below both of these cut-off scores had a positive predictive value of 80.95%. CONCLUSIONS: Pr-AD might be distinguished from S-MCI at baseline using the combination of MMSE and CVLT-LDTR. These two neuropsychological predictors are relatively brief and may be readily completed in non-specialist clinical settings. PMID- 21702930 TI - Conceptual frameworks and empirical approaches used to assess the impact of health research: an overview of reviews. AB - BACKGROUND: How to assess the impact of research is of growing interest to funders, policy makers and researchers mainly to understand the value of investments and to increase accountability. Broadly speaking the term "research impact" refers to the contribution of research activities to achieve desired societal outcomes. The aim of this overview is to identify the most common approaches to research impact assessment, categories of impact and their respective indicators. METHODS: We systematically searched the relevant literature (PubMed, The Cochrane Library (1990-2009)) and funding agency websites. We included systematic reviews, theoretical and methodological papers, and empirical case-studies on how to evaluate research impact. We qualitatively summarised the included reports, as well the conceptual frameworks. RESULTS: We identified twenty-two reports belonging to four systematic reviews and 14 primary studies. These publications reported several theoretical frameworks and methodological approaches (bibliometrics, econometrics, ad hoc case studies). The "payback model" emerged as the most frequently used. Five broad categories of impact were identified: a) advancing knowledge, b) capacity building, c) informing decision-making, d) health benefits, e) broad socio-economic benefits. For each proposed category of impact we summarized a set of indicators whose pros and cons are presented and briefly discussed. CONCLUSIONS: This overview is a comprehensive, yet descriptive, contribution to summarize the conceptual framework and taxonomy of an heterogeneous and evolving area of research. A shared and comprehensive conceptual framework does not seem to be available yet and its single components (epidemiologic, economic, and social) are often valued differently in different models. PMID- 21702931 TI - Multigenic phylogeny and analysis of tree incongruences in Triticeae (Poaceae). AB - BACKGROUND: Introgressive events (e.g., hybridization, gene flow, horizontal gene transfer) and incomplete lineage sorting of ancestral polymorphisms are a challenge for phylogenetic analyses since different genes may exhibit conflicting genealogical histories. Grasses of the Triticeae tribe provide a particularly striking example of incongruence among gene trees. Previous phylogenies, mostly inferred with one gene, are in conflict for several taxon positions. Therefore, obtaining a resolved picture of relationships among genera and species of this tribe has been a challenging task. Here, we obtain the most comprehensive molecular dataset to date in Triticeae, including one chloroplastic and 26 nuclear genes. We aim to test whether it is possible to infer phylogenetic relationships in the face of (potentially) large-scale introgressive events and/or incomplete lineage sorting; to identify parts of the evolutionary history that have not evolved in a tree-like manner; and to decipher the biological causes of gene-tree conflicts in this tribe. RESULTS: We obtain resolved phylogenetic hypotheses using the supermatrix and Bayesian Concordance Factors (BCF) approaches despite numerous incongruences among gene trees. These phylogenies suggest the existence of 4-5 major clades within Triticeae, with Psathyrostachys and Hordeum being the deepest genera. In addition, we construct a multigenic network that highlights parts of the Triticeae history that have not evolved in a tree-like manner. Dasypyrum, Heteranthelium and genera of clade V, grouping Secale, Taeniatherum, Triticum and Aegilops, have evolved in a reticulated manner. Their relationships are thus better represented by the multigenic network than by the supermatrix or BCF trees. Noteworthy, we demonstrate that gene-tree incongruences increase with genetic distance and are greater in telomeric than centromeric genes. Together, our results suggest that recombination is the main factor decoupling gene trees from multigenic trees. CONCLUSIONS: Our study is the first to propose a comprehensive, multigenic phylogeny of Triticeae. It clarifies several aspects of the relationships among genera and species of this tribe, and pinpoints biological groups with likely reticulate evolution. Importantly, this study extends previous results obtained in Drosophila by demonstrating that recombination can exacerbate gene-tree conflicts in phylogenetic reconstructions. PMID- 21702932 TI - The importance of measuring psychosocial functioning in schizophrenia. AB - BACKGROUND: Schizophrenia is among the most disabling of mental illnesses and frequently causes impaired functioning. We explore issues of definition and terminology, and the relationship between social functioning, cognition, and psychopathology considering relevant research findings. METHODS: The present article describes measures of social functioning and outlines their psychometric properties. It considers their usefulness in research and clinical settings. Treatment aims and objectives are explored in the context of cognitive and social functioning. Finally, we identify areas for developing research and refining the measurement of social functioning. RESULTS: The definition and measurement of social functioning in schizophrenia remains a complex and disputed area. The relationships between symptoms, cognitive functioning and social functioning are complex but we are beginning to understand them better. Scales for measuring functioning in clinical practice must be brief and sensitive to change and the Personal and Social Performance (PSP) scale may offer several advantages in these regards. Brief cognitive assessments focusing upon the domains most commonly affected in schizophrenia, such as verbal memory and executive functions, should be coadministered with measures of functioning. CONCLUSIONS: The use of validated scales for schizophrenia that are sensitive to change over the course of the illness and its treatment, should allow for a better understanding of patients' functional disabilities, enabling better and more comprehensive monitoring and evaluation of both pharmacological and non-pharmacological treatment strategies. PMID- 21702933 TI - Digging deeper into lymphatic vessel formation in vitro and in vivo. AB - BACKGROUND: Abnormal lymphatic vessel formation (lymphangiogenesis) is associated with different pathologies such as cancer, lymphedema, psoriasis and graft rejection. Lymphatic vasculature displays distinctive features than blood vasculature, and mechanisms underlying the formation of new lymphatic vessels during physiological and pathological processes are still poorly documented. Most studies on lymphatic vessel formation are focused on organism development rather than lymphangiogenic events occurring in adults. We have here studied lymphatic vessel formation in two in vivo models of pathological lymphangiogenesis (corneal assay and lymphangioma). These data have been confronted to those generated in the recently set up in vitro model of lymphatic ring assay. Ultrastructural analyses through Transmission Electron Microscopy (TEM) were performed to investigate tube morphogenesis, an important differentiating process observed during endothelial cell organization into capillary structures. RESULTS: In both in vivo models (lymphangiogenic corneal assay and lymphangioma), migrating lymphatic endothelial cells extended long processes exploring the neighboring environment and organized into cord-like structures. Signs of intense extracellular matrix remodeling were observed extracellularly and inside cytoplasmic vacuoles. The formation of intercellular spaces between endothelial cells led to tube formation. Proliferating lymphatic endothelial cells were detected both at the tips of sprouting capillaries and inside extending sprouts. The different steps of lymphangiogenesis observed in vivo are fully recapitulated in vitro, in the lymphatic ring assay and include: (1) endothelial cell alignment in cord like structure, (2) intracellular vacuole formation and (3) matrix degradation. CONCLUSIONS: In this study, we are providing evidence for lymphatic vessel formation through tunneling relying on extensive matrix remodeling, migration and alignment of sprouting endothelial cells into tubular structures. In addition, our data emphasize the suitability of the lymphatic ring assay to unravel mechanisms underlying lymphangiogenesis. PMID- 21702934 TI - Value of high-sensitivity C-reactive protein in low risk chest pain observation unit patients. AB - OBJECTIVE: High-sensitivity C-reactive protein (hs-CRP) rises with cardiac injury/ischemia. We evaluated its efficacy in aiding in the identification of an acute coronary syndrome (ACS) in patients (pts) admitted to the chest pain unit (CPU) for possible ACS. METHODS: Retrospective study of all patients admitted to the CPU with chest pain who underwent hs-CRP testing as part of their CPU evaluation from January 2004 to October 2008. Patients were low risk for ACS (compatible symptoms, nondiagnostic initial ECG, and negative cTnI). ACS was diagnosed by positive functional study, cardiac catheterization, or cardiac event during 30-day follow-up. Positive hs-CRP was defined based on local laboratory levels (>1.0 mg/l or >3.0 mg/l), and population-based and prior study values >2.0 mg/l. Chi-square analysis was performed, and odds ratios (OR) are presented. Multivariate analysis was done to determine whether hs-CRP was independently associated with the diagnosis of ACS. Cardiac risk factors, demographics, and diagnosis of ACS were included in the model. Medians with IQR are presented for continuous data. Ninety-five percent confidence intervals are presented where applicable. RESULTS: A total of 958 patients had hs-CRP testing as part of their CPEU evaluation. Excluded from the analysis were 39 patients lost to follow-up. The final cohort comprised 478 (52%) women and 441 (48%) men with a median age of 56 (IQR 48-64). ACS was diagnosed in 128 (13.4%). The median cohort hs-CRP value was 2.2 mg/l (IQR 0.7, 5.8) and 2.3 mg/l (IQR 0.6, 5.9) in those with and without ACS, respectively. In the multivariate analysis hs-CRP was not independently associated with the diagnosis of ACS (0.99; 95% CI 0.98 - 1.01). CONCLUSION: In large patient cohort managed in a single-center CPU, measurement of hs-CRP did not enhance the diagnostic accuracy for ACS. Routine hs-CRP as a diagnostic tool should not be recommended in the CPU setting. PMID- 21702935 TI - Genetic variants in the MRPS30 region and postmenopausal breast cancer risk. AB - BACKGROUND: Genome-wide association studies have identified several genomic regions that are associated with breast cancer risk, but these provide an explanation for only a small fraction of familial breast cancer aggregation. Genotype by environment interactions may contribute further to such explanation, and may help to refine the genomic regions of interest. METHODS: We examined genotypes for 4,988 SNPs, selected from recent genome-wide studies, and four randomized hormonal and dietary interventions among 2,166 women who developed invasive breast cancer during the intervention phase of the Women's Health Initiative (WHI) clinical trial (1993 to 2005), and one-to-one matched controls. These SNPs derive from 3,224 genomic regions having pairwise squared correlation (r2) between adjacent regions less than 0.2. Breast cancer and SNP associations were identified using a test statistic that combined evidence of overall association with evidence for SNPs by intervention interaction. RESULTS: The combined 'main effect' and interaction test led to a focus on two genomic regions, the fibroblast growth factor receptor two (FGFR2) and the mitochondrial ribosomal protein S30 (MRPS30) regions. The ranking of SNPs by significance level, based on this combined test, was rather different from that based on the main effect alone, and drew attention to the vicinities of rs3750817 in FGFR2 and rs7705343 in MRPS30. Specifically, rs7705343 was included with several FGFR2 SNPs in a group of SNPs having an estimated false discovery rate < 0.05. In further analyses, there were suggestions (nominal P < 0.05) that hormonal and dietary intervention hazard ratios varied with the number of minor alleles of rs7705343. CONCLUSIONS: Genotype by environment interaction information may help to define genomic regions relevant to disease risk. Combined main effect and intervention interaction analyses raise novel hypotheses concerning the MRPS30 genomic region and the effects of hormonal and dietary exposures on postmenopausal breast cancer risk. PMID- 21702936 TI - Evaluation of an early detection tool for social-emotional and behavioral problems in toddlers: The Brief Infant Toddler Social and Emotional Assessment - A cluster randomized trial. AB - BACKGROUND: The prevalence of social-emotional and behavioral problems is estimated to be 8 to 9% among preschool children. Effective early detection tools are needed to promote the provision of adequate care at an early stage. The Brief Infant-Toddler Social and Emotional Assessment (BITSEA) was developed for this purpose. This study evaluates the effectiveness of the BITSEA to enhance social emotional and behavioral health of preschool children. METHODS AND DESIGN: A cluster randomized controlled trial is set up in youth health care centers in the larger Rotterdam area in the Netherlands, to evaluate the BITSEA. The 31 youth health care centers are randomly allocated to either the control group or the intervention group. The intervention group uses the scores on the BITSEA and cut off points to evaluate a child's social-emotional and behavioral health and to decide whether or not the child should be referred. The control group provides care as usual, which involves administering a questionnaire that structures the conversation between child health professionals and parents. At a one year follow up measurement the social-emotional and behavioral health of all children included in the study population will be evaluated. DISCUSSION: It is hypothesized that better results will be found, in terms of social-emotional and behavioral health in the intervention group, compared to the control group, due to more adequate early detection, referral and more appropriate and timely care. TRIAL REGISTRATION: Current Controlled Trials NTR2035. PMID- 21702937 TI - Mathematical method to build an empirical model for inhaled anesthetic agent wash in. AB - BACKGROUND: The wide range of fresh gas flow - vaporizer setting (FGF - FD) combinations used by different anesthesiologists during the wash-in period of inhaled anesthetics indicates that the selection of FGF and FD is based on habit and personal experience. An empirical model could rationalize FGF - FD selection during wash-in. METHODS: During model derivation, 50 ASA PS I-II patients received desflurane in O2 with an ADU(r) anesthesia machine with a random combination of a fixed FGF - FD setting. The resulting course of the end-expired desflurane concentration (FA) was modeled with Excel Solver, with patient age, height, and weight as covariates; NONMEM was used to check for parsimony. The resulting equation was solved for FD, and prospectively tested by having the formula calculate FD to be used by the anesthesiologist after randomly selecting a FGF, a target FA (FAt), and a specified time interval (1 - 5 min) after turning on the vaporizer after which FAt had to be reached. The following targets were tested: desflurane FAt 3.5% after 3.5 min (n = 40), 5% after 5 min (n = 37), and 6% after 4.5 min (n = 37). RESULTS: Solving the equation derived during model development for FD yields FD=-(e(-FGF*-0.23+FGF*0.24)*(e(FGF*-0.23)*FAt*Ht*0.1 e(FGF*-0.23)*FGF*2.55+40.46-e(FGF*-0.23)*40.46+e(FGF*-0.23+Time/-4.08)*40.46 e(Time/-4.08)*40.46))/((-1+e(FGF*0.24))*(-1+e(Time/-4.08))*39.29). Only height (Ht) could be withheld as a significant covariate. Median performance error and median absolute performance error were -2.9 and 7.0% in the 3.5% after 3.5 min group, -3.4 and 11.4% in the 5% after 5 min group, and -16.2 and 16.2% in the 6% after 4.5 min groups, respectively. CONCLUSIONS: An empirical model can be used to predict the FGF - FD combinations that attain a target end-expired anesthetic agent concentration with clinically acceptable accuracy within the first 5 min of the start of administration. The sequences are easily calculated in an Excel file and simple to use (one fixed FGF - FD setting), and will minimize agent consumption and reduce pollution by allowing to determine the lowest possible FGF that can be used. Different anesthesia machines will likely have different equations for different agents. PMID- 21702938 TI - Supplementation with xylanase and beta-xylosidase to reduce xylo-oligomer and xylan inhibition of enzymatic hydrolysis of cellulose and pretreated corn stover. AB - BACKGROUND: Hemicellulose is often credited with being one of the important physical barriers to enzymatic hydrolysis of cellulose, and acts by blocking enzyme access to the cellulose surface. In addition, our recent research has suggested that hemicelluloses, particularly in the form of xylan and its oligomers, can more strongly inhibit cellulase activity than do glucose and cellobiose. Removal of hemicelluloses or elimination of their negative effects can therefore become especially pivotal to achieving higher cellulose conversion with lower enzyme doses. RESULTS: In this study, cellulase was supplemented with xylanase and beta-xylosidase to boost conversion of both cellulose and hemicellulose in pretreated biomass through conversion of xylan and xylo oligomers to the less inhibitory xylose. Although addition of xylanase and beta xylosidase did not necessarily enhance Avicel hydrolysis, glucan conversions increased by 27% and 8% for corn stover pretreated with ammonia fiber expansion (AFEX) and dilute acid, respectively. In addition, adding hemicellulase several hours before adding cellulase was more beneficial than later addition, possibly as a result of a higher adsorption affinity of cellulase and xylanase to xylan than glucan. CONCLUSIONS: This key finding elucidates a possible mechanism for cellulase inhibition by xylan and xylo-oligomers and emphasizes the need to optimize the enzyme formulation for each pretreated substrate. More research is needed to identify advanced enzyme systems designed to hydrolyze different substrates with maximum overall enzyme efficacy. PMID- 21702939 TI - BioAssay Ontology (BAO): a semantic description of bioassays and high-throughput screening results. AB - BACKGROUND: High-throughput screening (HTS) is one of the main strategies to identify novel entry points for the development of small molecule chemical probes and drugs and is now commonly accessible to public sector research. Large amounts of data generated in HTS campaigns are submitted to public repositories such as PubChem, which is growing at an exponential rate. The diversity and quantity of available HTS assays and screening results pose enormous challenges to organizing, standardizing, integrating, and analyzing the datasets and thus to maximize the scientific and ultimately the public health impact of the huge investments made to implement public sector HTS capabilities. Novel approaches to organize, standardize and access HTS data are required to address these challenges. RESULTS: We developed the first ontology to describe HTS experiments and screening results using expressive description logic. The BioAssay Ontology (BAO) serves as a foundation for the standardization of HTS assays and data and as a semantic knowledge model. In this paper we show important examples of formalizing HTS domain knowledge and we point out the advantages of this approach. The ontology is available online at the NCBO bioportal http://bioportal.bioontology.org/ontologies/44531. CONCLUSIONS: After a large manual curation effort, we loaded BAO-mapped data triples into a RDF database store and used a reasoner in several case studies to demonstrate the benefits of formalized domain knowledge representation in BAO. The examples illustrate semantic querying capabilities where BAO enables the retrieval of inferred search results that are relevant to a given query, but are not explicitly defined. BAO thus opens new functionality for annotating, querying, and analyzing HTS datasets and the potential for discovering new knowledge by means of inference. PMID- 21702941 TI - Folic acid use in pregnant patients presenting to the emergency department. AB - BACKGROUND: The US Preventive Services Task Force has recommended daily folic acid supplementation for women planning on becoming pregnant in an effort to prevent fetal neural tube defects. We evaluated pregnant patients presenting to the emergency department to determine rates of folic acid supplementation. METHODS: We surveyed a convenience sample of pregnant patients who presented to the University of Utah Emergency Department (ED) between 1 January 2008, and 30 April 2009, regarding pregnancy history and prior medical care. RESULTS: One hundred thirty-five patients participated in the study. Eighty-four patients (62.2%) reported current folic acid supplementation. Sixty-six patients identified themselves as Caucasian and 69 as non-Caucasian race. There was a significant difference in folic acid use between Caucasian and non-Caucasian women (p = 0.035). The majority of Caucasian women (71.2%) reported daily folic acid use versus approximately one-half of non-Caucasian women (53.6%). Both groups were similar in accessing a primary care provider (PCP) for pregnancy care prior to the ED visit (53% vs. 49.3%, p = 0.663), and rates of folic acid use were similar in those who had seen a PCP (85.7% vs. 76.5%, p = 0.326). Language did not have a significant association with folic acid use. CONCLUSION: A large percentage of pregnant ED patients did not report current folic use, and there was a significant difference between Caucasian and non-Caucasian women in rates of folic acid supplementation. This study highlights the potential role of the ED in screening patients for folic acid supplementation. PMID- 21702940 TI - Cell subset prediction for blood genomic studies. AB - BACKGROUND: Genome-wide transcriptional profiling of patient blood samples offers a powerful tool to investigate underlying disease mechanisms and personalized treatment decisions. Most studies are based on analysis of total peripheral blood mononuclear cells (PBMCs), a mixed population. In this case, accuracy is inherently limited since cell subset-specific differential expression of gene signatures will be diluted by RNA from other cells. While using specific PBMC subsets for transcriptional profiling would improve our ability to extract knowledge from these data, it is rarely obvious which cell subset(s) will be the most informative. RESULTS: We have developed a computational method (Subset Prediction from Enrichment Correlation, SPEC) to predict the cellular source for a pre-defined list of genes (i.e. a gene signature) using only data from total PBMCs. SPEC does not rely on the occurrence of cell subset-specific genes in the signature, but rather takes advantage of correlations with subset-specific genes across a set of samples. Validation using multiple experimental datasets demonstrates that SPEC can accurately identify the source of a gene signature as myeloid or lymphoid, as well as differentiate between B cells, T cells, NK cells and monocytes. Using SPEC, we predict that myeloid cells are the source of the interferon-therapy response gene signature associated with HCV patients who are non-responsive to standard therapy. CONCLUSIONS: SPEC is a powerful technique for blood genomic studies. It can help identify specific cell subsets that are important for understanding disease and therapy response. SPEC is widely applicable since only gene expression profiles from total PBMCs are required, and thus it can easily be used to mine the massive amount of existing microarray or RNA-seq data. PMID- 21702942 TI - Allometric scaling of dietary linoleic acid on changes in tissue arachidonic acid using human equivalent diets in mice. AB - BACKGROUND: It is hypothesized that dietary linoleic acid (LA) promotes chronic and acute diseases in humans by enriching tissues with arachidonic acid (AA), its downstream metabolite, and dietary studies with rodents have been useful for validation. However, levels of LA in research diets of rodents, as published in the literature, are notoriously erratic making interspecies comparisons unreliable. Therefore, the ability to extrapolate the biological effects of dietary LA from experimental rodents to humans necessitates an allometric scaling model that is rooted within a human equivalent context. METHODS: To determine the physiological response of dietary LA on tissue AA, a mathematical model for extrapolating nutrients based on energy was used, as opposed to differences in body weight. C57BL/6J mice were divided into 9 groups fed a background diet equivalent to that of the US diet (% energy) with supplemental doses of LA or AA. Changes in the phospholipid fatty acid compositions were monitored in plasma and erythrocytes and compared to data from humans supplemented with equivalent doses of LA or AA. RESULTS: Increasing dietary LA had little effect on tissue AA, while supplementing diets with AA significantly increased tissue AA levels, importantly recapitulating results from human trials. CONCLUSIONS: Thus, interspecies comparisons for dietary LA between rodents and humans can be achieved when rodents are provided human equivalent doses based on differences in metabolic activity as defined by energy consumption. PMID- 21702943 TI - Tridimensional model structure and patterns of molecular evolution of Pepino mosaic virus TGBp3 protein. AB - BACKGROUND: Pepino mosaic virus (PepMV) is considered one of the most dangerous pathogens infecting tomatoes worldwide. The virus is highly diverse and four distinct genotypes, as well as inter-strain recombinants, have already been described. The isolates display a wide range on symptoms on infected plant species, ranging from mild mosaic to severe necrosis. However, little is known about the mechanisms and pattern of PepMV molecular evolution and about the role of individual proteins in host-pathogen interactions. METHODS: The nucleotide sequences of the triple gene block 3 (TGB3) from PepMV isolates varying in symptomatology and geographic origin have been analyzed. The modes and patterns of molecular evolution of the TGBp3 protein were investigated by evaluating the selective constraints to which particular amino acid residues have been subjected during the course of diversification. The tridimensional structure of TGBp3 protein has been modeled de novo using the Rosetta algorithm. The correlation between symptoms development and location of specific amino acids residues was analyzed. RESULTS: The results have shown that TGBp3 has been evolving mainly under the action of purifying selection operating on several amino acid sites, thus highlighting its functional role during PepMV infection. Interestingly, amino acid 67, which has been previously shown to be a necrosis determinant, was found to be under positive selection. CONCLUSIONS: Identification of diverse selection events in TGB3p3 will help unraveling its biological functions and is essential to an understanding of the evolutionary constraints exerted on the Potexvirus genome. The estimated tridimensional structure of TGBp3 will serve as a platform for further sequence, structural and function analysis and will stimulate new experimental advances. PMID- 21702944 TI - Dexmedetomidine provides renoprotection against ischemia-reperfusion injury in mice. AB - INTRODUCTION: Acute kidney injury following surgery incurs significant mortality with no proven preventative therapy. We investigated whether the alpha2 adrenoceptor agonist dexmedetomidine (Dex) provides protection against ischemia reperfusion induced kidney injury in vitro and in vivo. METHODS: In vitro, a stabilised cell line of human kidney proximal tubular cells (HK2) was exposed to culture medium deprived of oxygen and glucose. Dex decreased HK2 cell death in a dose-dependent manner, an effect attenuated by the alpha2 adrenoceptor antagonist atipamezole, and likely transduced by phosphatidylinositol 3-kinase (PI3K-Akt) signaling. In vivo C57BL/6J mice received Dex (25 MUg/kg, intraperitoneal (i.p.)) 30 minutes before or after either bilateral renal pedicle clamping for 25 minutes or right renal pedicle clamping for 40 minutes and left nephrectomy. RESULTS: Pre or post-treatment with Dex provided cytoprotection, improved tubular architecture and function following renal ischemia. Consistent with this cytoprotection, dexmedetomidine reduced plasma high-mobility group protein B1 (HMGB-1) elevation when given prior to or after kidney ischemia-reperfusion; pretreatment also decreased toll-like receptor 4 (TLR4) expression in tubular cells. Dex treatment provided long-term functional renoprotection, and even increased survival following nephrectomy. CONCLUSIONS: Our data suggest that Dex likely activates cell survival signal pAKT via alpha2 adrenoceptors to reduce cell death and HMGB1 release and subsequently inhibits TLR4 signaling to provide reno-protection. PMID- 21702945 TI - Haemodynamic goal-directed therapy and postoperative infections: earlier is better. A systematic review and meta-analysis. AB - INTRODUCTION: Infectious complications are the main causes of postoperative morbidity. The early timing of their promoting factors is the rationale for perioperative strategies attempting to reduce them. Our aim was to determine the effects of perioperative haemodynamic goal-directed therapy on postoperative infection rates. METHODS: We performed a systematic review and meta-analysis. MEDLINE, EMBASE, The Cochrane Library and the DARE databases were searched up to March 2011. Randomised, controlled trials of major surgery in adult patients managed with perioperative goal-directed therapy or according to routine haemodynamic practice were included. Primary outcome measure was specific type of infection. RESULTS: Twenty-six randomised, controlled trials with a combined total of 4,188 participants met our inclusion criteria. Perioperative goal directed therapy significantly reduced surgical site infections (pooled OR 0.58, 95% CI 0.46 to 0.74; P < 0.0001), pneumonia (pooled OR 0.71, 95% CI 0.55 to 0.92; P = 0.009), and urinary tract infections (pooled OR 0.44, 95% CI 0.22 to 0.84; P = 0.02). A significant benefit was found regarding total infectious episodes (OR 0.40, 95% CI 0.28 to 0.58; P < 0.00001). CONCLUSIONS: Flow-directed haemodynamic therapy designed to optimise oxygen delivery protects surgical patients against postoperative hospital-acquired infections and must be strongly encouraged, particularly in the high-risk surgical population. PMID- 21702947 TI - British Columbia hospitals: examination and assessment of payment reform (B CHeaPR). AB - BACKGROUND: Accounting for 36% of public spending on health care in Canada, hospitals are a major target for cost reductions through various efficiency initiatives. Some provinces are considering payment reform as a vehicle to achieve this goal. With few exceptions, Canadian provinces have generally relied on global and line-item budgets to contain hospital costs. There is growing interest amongst policy-makers for using activity based funding (ABF) as means of creating financial incentives for hospitals to increase the 'volume' of care, reduce cost, discourage unnecessary activity, and encourage competition. British Columbia (B.C.) is the first province in Canada to implement ABF for partial reimbursement of acute hospitalization. To date, there have been no formal examinations of the effects of ABF policies in Canada. This study proposal addresses two research questions designed to determine whether ABF policies affect health system costs, access and hospital quality. The first question examines the impact of the hospital funding policy change on internal hospital activity based on expenditures and quality. The second question examines the impact of the change on non-hospital care, including readmission rates, amount of home care provided, and physician expenditures. METHODS/DESIGN: A longitudinal study design will be used, incorporating comprehensive population-based datasets of all B.C. residents; hospital, continuing care and physician services datasets will also be used. Data will be linked across sources using anonymized linking variables. Analytic datasets will be created for the period between 2005/2006 and 2012/2013. DISCUSSION: With Canadian hospitals unaccustomed to detailed scrutiny of what services are provided, to whom, and with what results, the move toward ABF is significant. This proposed study will provide evidence on the impacts of ABF, including changes in the type, volume, cost, and quality of services provided. Policy- and decision-makers in B.C. and elsewhere in Canada will be able to use this evidence as a basis for policy adaptations and modifications. The significance of this proposed study derives from the fact that the change in hospital funding policy has the potential to affect health system costs, residents' access to care and care quality. PMID- 21702948 TI - Strengthening systems for communicable disease surveillance: creating a laboratory network in Rwanda. AB - BACKGROUND: The recent emergence of a novel strain of influenza virus with pandemic potential underscores the need for quality surveillance and laboratory services to contribute to the timely detection and confirmation of public health threats. To provide a framework for strengthening disease surveillance and response capacities in African countries, the World Health Organization Regional Headquarters for Africa (AFRO) developed Integrated Disease Surveillance and Response (IDSR) aimed at improving national surveillance and laboratory systems. IDSR emphasizes the linkage of information provided by public health laboratories to the selection of relevant, appropriate and effective public health responses to disease outbreaks. METHODS: We reviewed the development of Rwanda's National Reference Laboratory (NRL) to understand essential structures involved in creating a national public health laboratory network. We reviewed documents describing the NRL's organization and record of test results, conducted site visits, and interviewed health staff in the Ministry of Health and in partner agencies. Findings were developed by organizing thematic categories and grouping examples within them. We purposefully sought to identify success factors as well as challenges inherent in developing a national public health laboratory system. RESULTS: Among the identified success factors were: a structured governing framework for public health surveillance; political commitment to promote leadership for stronger laboratory capacities in Rwanda; defined roles and responsibilities for each level; coordinated approaches between technical and funding partners; collaboration with external laboratories; and use of performance results in advocacy with national stakeholders. Major challenges involved general infrastructure, human resources, and budgetary constraints. CONCLUSIONS: Rwanda's experience with collaborative partnerships contributed to creation of a functional public health laboratory network. PMID- 21702946 TI - Prevention of ventilator-associated pneumonia, mortality and all intensive care unit acquired infections by topically applied antimicrobial or antiseptic agents: a meta-analysis of randomized controlled trials in intensive care units. AB - INTRODUCTION: Given the high morbidity and mortality attributable to ventilator associated pneumonia (VAP) in intensive care unit (ICU) patients, prevention plays a key role in the management of patients undergoing mechanical ventilation. One of the candidate preventive interventions is the selective decontamination of the digestive or respiratory tract (SDRD) by topical antiseptic or antimicrobial agents. We performed a meta-analysis to investigate the effect of topical digestive or respiratory tract decontamination with antiseptics or antibiotics in the prevention of VAP, of mortality and of all ICU-acquired infections in mechanically ventilated ICU patients. METHODS: A meta-analysis of randomised controlled trials was performed. The U.S. National Library of Medicine's MEDLINE database, Embase, and Cochrane Library computerized bibliographic databases, and reference lists of selected studies were used. Selection criteria for inclusion were: randomised controlled trials (RCTs); primary studies; examining the reduction of VAP and/or mortality and/or all ICU-acquired infections in ICU patients by prophylactic use of one or more of following topical treatments: 1) oropharyngeal decontamination using antiseptics or antibiotics, 2) gastrointestinal tract decontamination using antibiotics, 3) oropharyngeal plus gastrointestinal tract decontamination using antibiotics and 4) respiratory tract decontamination using antibiotics; reported enough data to estimate the odds ratio (OR) or risk ratio (RR) and their variance; English language; published through June 2010. RESULTS: A total of 28 articles met all inclusion criteria and were included in the meta-analysis. The overall estimate of efficacy of topical SDRD in the prevention of VAP was 27% (95% CI of efficacy = 16% to 37%) for antiseptics and 36% (95% CI of efficacy = 18% to 50%) for antibiotics, whereas in none of the meta-analyses conducted on mortality was a significant effect found. The effect of topical SDRD in the prevention of all ICU-acquired infections was statistically significant (efficacy = 29%; 95% CI of efficacy = 14% to 41%) for antibiotics whereas the use of antiseptics did not show a significant beneficial effect. CONCLUSIONS: Topical SDRD using antiseptics or antimicrobial agents is effective in reducing the frequency of VAP in ICU. Unlike antiseptics, the use of topical antibiotics seems to be effective also in preventing all ICU-acquired infections, while the effectiveness on mortality of these two approaches needs to be investigated in further research. PMID- 21702949 TI - The evolution of health policy guidelines for assisted reproduction in the Republic of Ireland, 2004-2009. AB - This analysis reports on Irish regulatory policies for in vitro fertilisation (IVF) from 2004-2009, in the context of membership changes within the Medical Council of Ireland. To achieve this, the current (2009) edition of the Guide to Professional Conduct & Ethics was compared with the immediately preceding version (2004). The statutory composition of the Medical Council from 2004-2009 was also studied. Content analysis of the two editions identified the following differences: 1) The 2004 guide states that IVF "should only be used after thorough investigation has failed to reveal a treatable cause of the infertility", while the 2009 guide indicates IVF "should only be used after thorough investigation has shown that no other treatment is likely to be effective"; 2) The 2004 stipulation stating that fertilized ovum (embryo) "must be used for normal implantation and must not be deliberately destroyed" is absent from the 2009 guidelines; 3) The option to donate "unused fertilised ova" (embryos) is omitted from the 2009 guidelines; 4) The 2009 guidelines state that ART should be offered only by "suitably qualified professionals, in appropriate facilities, and according to the international best practice"; 5) The 2009 guidelines introduce criteria that donations as part of a donor programme should be "altruistic and non-commercial". These last two points represent original regulatory efforts not appearing in the 2004 edition. The Medical Practitioners Act 2007 reduced the number of physicians on the Medical Council to 6 (of 25) members. The ethical guidelines from 2004 preceded this change, while the reconstituted Medical Council published the 2009 version. Between 2004 and 2009, substantial modifications in reproductive health policy were incorporated into the Medical Council's ethical guidelines. The absence of controlling Irish legislation means that patients and IVF providers in Ireland must rely upon these guidelines by default. Our critique traces the evolution of public policy on IVF during a time when the membership of the Medical Council changed radically; reduced physician contribution to decision-making was associated with diminished protection for IVF-derived embryos in Ireland. Considerable uncertainty on IVF practice in Ireland remains. PMID- 21702950 TI - The HIV-1 Rev/RRE system is required for HIV-1 5' UTR cis elements to augment encapsidation of heterologous RNA into HIV-1 viral particles. AB - BACKGROUND: The process of HIV-1 genomic RNA (gRNA) encapsidation is governed by a number of viral encoded components, most notably the Gag protein and gRNA cis elements in the canonical packaging signal (psi). Also implicated in encapsidation are cis determinants in the R, U5, and PBS (primer binding site) from the 5' untranslated region (UTR). Although conventionally associated with nuclear export of HIV-1 RNA, there is a burgeoning role for the Rev/RRE in the encapsidation process. Pleiotropic effects exhibited by these cis and trans viral components may confound the ability to examine their independent, and combined, impact on encapsidation of RNA into HIV-1 viral particles in their innate viral context. We systematically reconstructed the HIV-1 packaging system in the context of a heterologous murine leukemia virus (MLV) vector RNA to elucidate a mechanism in which the Rev/RRE system is central to achieving efficient and specific encapsidation into HIV-1 viral particles. RESULTS: We show for the first time that the Rev/RRE system can augment RNA encapsidation independent of all cis elements from the 5' UTR (R, U5, PBS, and psi). Incorporation of all the 5' UTR cis elements did not enhance RNA encapsidation in the absence of the Rev/RRE system. In fact, we demonstrate that the Rev/RRE system is required for specific and efficient encapsidation commonly associated with the canonical packaging signal. The mechanism of Rev/RRE-mediated encapsidation is not a general phenomenon, since the combination of the Rev/RRE system and 5' UTR cis elements did not enhance encapsidation into MLV-derived viral particles. Lastly, we show that heterologous MLV RNAs conform to transduction properties commonly associated with HIV-1 viral particles, including in vivo transduction of non-dividing cells (i.e. mouse neurons); however, the cDNA forms are episomes predominantly in the 1 LTR circle form. CONCLUSIONS: Premised on encapsidation of a heterologous RNA into HIV-1 viral particles, our findings define a functional HIV-1 packaging system as comprising the 5' UTR cis elements, Gag, and the Rev/RRE system, in which the Rev/RRE system is required to make the RNA amenable to the ensuing interaction between Gag and the canonical packaging signal for subsequent encapsidation. PMID- 21702951 TI - AMDORAP: non-targeted metabolic profiling based on high-resolution LC-MS. AB - BACKGROUND: Liquid chromatography-mass spectrometry (LC-MS) utilizing the high resolution power of an orbitrap is an important analytical technique for both metabolomics and proteomics. Most important feature of the orbitrap is excellent mass accuracy. Thus, it is necessary to convert raw data to accurate and reliable m/z values for metabolic fingerprinting by high-resolution LC-MS. RESULTS: In the present study, we developed a novel, easy-to-use and straightforward m/z detection method, AMDORAP. For assessing the performance, we used real biological samples, Bacillus subtilis strains 168 and MGB874, in the positive mode by LC orbitrap. For 14 identified compounds by measuring the authentic compounds, we compared obtained m/z values with other LC-MS processing tools. The errors by AMDORAP were distributed within +/-3 ppm and showed the best performance in m/z value accuracy. CONCLUSIONS: Our method can detect m/z values of biological samples much more accurately than other LC-MS analysis tools. AMDORAP allows us to address the relationships between biological effects and cellular metabolites based on accurate m/z values. Obtaining the accurate m/z values from raw data should be indispensable as a starting point for comparative LC-orbitrap analysis. AMDORAP is freely available under an open-source license at http://amdorap.sourceforge.net/. PMID- 21702952 TI - Breathing adapted radiotherapy: a 4D gating software for lung cancer. AB - PURPOSE: Physiological respiratory motion of tumors growing in the lung can be corrected with respiratory gating when treated with radiotherapy (RT). The optimal respiratory phase for beam-on may be assessed with a respiratory phase optimizer (RPO), a 4D image processing software developed with this purpose. METHODS AND MATERIALS: Fourteen patients with lung cancer were included in the study. Every patient underwent a 4D-CT providing ten datasets of ten phases of the respiratory cycle (0-100% of the cycle). We defined two morphological parameters for comparison of 4D-CT images in different respiratory phases: tumor volume to lung-volume ratio and tumor-to-spinal cord distance. The RPO automatized the calculations (200 per patient) of these parameters for each phase of the respiratory cycle allowing to determine the optimal interval for RT. RESULTS: Lower lobe lung tumors not attached to the diaphragm presented with the largest motion with breathing. Maximum inspiration was considered the optimal phase for treatment in 4 patients (28.6%). In 7 patients (50%), however, the RPO showed a most favorable volumetric and spatial configuration in phases other than maximum inspiration. In 2 cases (14.4%) the RPO showed no benefit from gating. This tool was not conclusive in only one case. CONCLUSIONS: The RPO software presented in this study can help to determine the optimal respiratory phase for gated RT based on a few simple morphological parameters. Easy to apply in daily routine, it may be a useful tool for selecting patients who might benefit from breathing adapted RT. PMID- 21702953 TI - Classification of breast tissue in mammograms using efficient coding. AB - BACKGROUND: Female breast cancer is the major cause of death by cancer in western countries. Efforts in Computer Vision have been made in order to improve the diagnostic accuracy by radiologists. Some methods of lesion diagnosis in mammogram images were developed based in the technique of principal component analysis which has been used in efficient coding of signals and 2D Gabor wavelets used for computer vision applications and modeling biological vision. METHODS: In this work, we present a methodology that uses efficient coding along with linear discriminant analysis to distinguish between mass and non-mass from 5090 region of interest from mammograms. RESULTS: The results show that the best rates of success reached with Gabor wavelets and principal component analysis were 85.28% and 87.28%, respectively. In comparison, the model of efficient coding presented here reached up to 90.07%. CONCLUSIONS: Altogether, the results presented demonstrate that independent component analysis performed successfully the efficient coding in order to discriminate mass from non-mass tissues. In addition, we have observed that LDA with ICA bases showed high predictive performance for some datasets and thus provide significant support for a more detailed clinical investigation. PMID- 21702954 TI - A cross-sectional survey of water and clean faces in trachoma endemic communities in Tanzania. AB - BACKGROUND: Face washing is important to interrupt the transmission of trachoma, the leading infectious cause of blindness worldwide. We aimed to assess the household and personal factors that affected water use and face washing practices in Kongwa, Tanzania. METHODS: We conducted a household water use survey in 173 households (329 children) in January, 2010. Self reported data on water use practices, observed water in the household, and observed clean faces in children were collected. Contingency table analyses and logistic regression analyses were used to measure associations between unclean faces and risk factors. RESULTS: We found that women are recognized as primary decision makers on water use in a household, and respondents who reported laziness as a reason that others do not wash children's faces were significantly more likely to have children with clean faces. Washing was reported as a priority for water use in most households. Sixty four percent (95% Confidence Interval = 59%-70%) of children had clean faces. CONCLUSIONS: Attitudes toward face washing and household water use appear to have changed dramatically from 20 years ago when clean faces were rare and men made decisions on water use in households. The sources of these attitudinal changes are not clear, but are positive changes that will assist the trachoma control program in strengthening its hygiene efforts. PMID- 21702956 TI - Reliability of a tool for measuring theory of planned behaviour constructs for use in evaluating research use in policymaking. AB - BACKGROUND: Although measures of knowledge translation and exchange (KTE) effectiveness based on the theory of planned behavior (TPB) have been used among patients and providers, no measure has been developed for use among health system policymakers and stakeholders. A tool that measures the intention to use research evidence in policymaking could assist researchers in evaluating the effectiveness of KTE strategies that aim to support evidence-informed health system decision making. Therefore, we developed a 15-item tool to measure four TPB constructs (intention, attitude, subjective norm and perceived control) and assessed its face validity through key informant interviews. METHODS: We carried out a reliability study to assess the tool's internal consistency and test-retest reliability. Our study sample consisted of 62 policymakers and stakeholders that participated in deliberative dialogues. We assessed internal consistency using Cronbach's alpha and generalizability (G) coefficients, and we assessed test retest reliability by calculating Pearson correlation coefficients (r) and G coefficients for each construct and the tool overall. RESULTS: The internal consistency of items within each construct was good with alpha ranging from 0.68 to alpha = 0.89. G-coefficients were lower for a single administration (G = 0.34 to G = 0.73) than for the average of two administrations (G = 0.79 to G = 0.89). Test-retest reliability coefficients for the constructs ranged from r = 0.26 to r = 0.77 and from G = 0.31 to G = 0.62 for a single administration, and from G = 0.47 to G = 0.86 for the average of two administrations. Test-retest reliability of the tool using G theory was moderate (G = 0.5) when we generalized across a single observation, but became strong (G = 0.9) when we averaged across both administrations. CONCLUSION: This study provides preliminary evidence for the reliability of a tool that can be used to measure TPB constructs in relation to research use in policymaking. Our findings suggest that the tool should be administered on more than one occasion when the intervention promotes an initial 'spike' in enthusiasm for using research evidence (as it seemed to do in this case with deliberative dialogues). The findings from this study will be used to modify the tool and inform further psychometric testing following different KTE interventions. PMID- 21702955 TI - Cucurbitacin-I (JSI-124) activates the JNK/c-Jun signaling pathway independent of apoptosis and cell cycle arrest in B leukemic cells. AB - BACKGROUND: Cucurbitacin-I (JSI-124) is potent inhibitor of JAK/STAT3 signaling pathway and has anti-tumor activity in a variety of cancer including B cell leukemia. However, other molecular targets of JSI-124 beyond the JAK/STAT3 pathway are not fully understood. METHODS: BJAB, I-83, NALM-6 and primary CLL cells were treated with JSI-124 as indicated. Apoptosis was measured using flow cytometry for accumulation of sub-G1 phase cells (indicator of apoptosis) and Annexin V/PI staining. Cell cycle was analyzed by FACS for DNA content of G1 and G2 phases. Changes in phosphorylation and protein expression of p38, Erk1/2, JNK, c-Jun, and XIAP were detected by Western blot analysis. STAT3 and c-Jun genes were knocked out using siRNA transfection. VEGF expression was determined by mRNA and protein levels by RT-PCR and western blotting. Streptavidin Pull-Down Assay was used to determine c-Jun binding to the AP-1 DNA binding site. RESULTS: Herein, we show that JSI-124 activates c-Jun N-terminal kinase (JNK) and increases both the expression and serine phosphorylation of c-Jun protein in the B leukemic cell lines BJAB, I-83 and NALM-6. JSI-124 also activated MAPK p38 and MAPK Erk1/2 albeit at lower levels than JNK activation. Inhibition of the JNK signaling pathway failed to effect cell cycle arrest or apoptosis induced by JSI 124 but repressed JSI-124 induced c-Jun expression in these leukemia cells. The JNK pathway activation c-Jun leads to transcriptional activation of many genes. Treatment of BJAB, I-83, and NALM-6 cells with JSI-124 lead to an increase of Vascular Endothelial Growth Factor (VEGF) at both the mRNA and protein level. Knockdown of c-Jun expression and inhibition of JNK activation significantly blocked JSI-124 induced VEGF expression. Pretreatment with recombinant VEGF reduced JSI-124 induced apoptosis. CONCLUSIONS: Taken together, our data demonstrates that JSI-124 activates the JNK signaling pathway independent of apoptosis and cell cycle arrest, leading to increased VEGF expression. PMID- 21702957 TI - Integrating an internet-mediated walking program into family medicine clinical practice: a pilot feasibility study. AB - BACKGROUND: Regular participation in physical activity can prevent many chronic health conditions. Computerized self-management programs are effective clinical tools to support patient participation in physical activity. This pilot study sought to develop and evaluate an online interface for primary care providers to refer patients to an Internet-mediated walking program called Stepping Up to Health (SUH) and to monitor participant progress in the program. METHODS: In Phase I of the study, we recruited six pairs of physicians and medical assistants from two family practice clinics to assist with the design of a clinical interface. During Phase II, providers used the developed interface to refer patients to a six-week pilot intervention. Provider perspectives were assessed regarding the feasibility of integrating the program into routine care. Assessment tools included quantitative and qualitative data gathered from semi structured interviews, surveys, and online usage logs. RESULTS: In Phase I, 13 providers used SUH and participated in two interviews. Providers emphasized the need for alerts flagging patients who were not doing well and the ability to review participant progress. Additionally, providers asked for summary views of data across all enrolled clinic patients as well as advertising materials for intervention recruitment. In response to this input, an interface was developed containing three pages: 1) a recruitment page, 2) a summary page, and 3) a detailed patient page. In Phase II, providers used the interface to refer 139 patients to SUH and 37 (27%) enrolled in the intervention. Providers rarely used the interface to monitor enrolled patients. Barriers to regular use of the intervention included lack of integration with the medical record system, competing priorities, patient disinterest, and physician unease with exercise referrals. Intention-to-treat analyses showed that patients increased walking by an average of 1493 steps/day from pre- to post-intervention (t = (36) = 4.13, p < 0.01). CONCLUSIONS: Providers successfully referred patients using the SUH provider interface, but were less willing to monitor patient compliance in the program. Patients who completed the program significantly increased their step counts. Future research is needed to test the effectiveness of integrating SUH with clinical information systems over a longer evaluation period. PMID- 21702958 TI - Increased gene sampling strengthens support for higher-level groups within leaf mining moths and relatives (Lepidoptera: Gracillariidae). AB - BACKGROUND: Researchers conducting molecular phylogenetic studies are frequently faced with the decision of what to do when weak branch support is obtained for key nodes of importance. As one solution, the researcher may choose to sequence additional orthologous genes of appropriate evolutionary rate for the taxa in the study. However, generating large, complete data matrices can become increasingly difficult as the number of characters increases. A few empirical studies have shown that augmenting genes even for a subset of taxa can improve branch support. However, because each study differs in the number of characters and taxa, there is still a need for additional studies that examine whether incomplete sampling designs are likely to aid at increasing deep node resolution. We target Gracillariidae, a Cretaceous-age (~100 Ma) group of leaf-mining moths to test whether the strategy of adding genes for a subset of taxa can improve branch support for deep nodes. We initially sequenced ten genes (8,418 bp) for 57 taxa that represent the major lineages of Gracillariidae plus outgroups. After finding that many deep divergences remained weakly supported, we sequenced eleven additional genes (6,375 bp) for a 27-taxon subset. We then compared results from different data sets to assess whether one sampling design can be favored over another. The concatenated data set comprising all genes and all taxa and three other data sets of different taxon and gene sub-sampling design were analyzed with maximum likelihood. Each data set was subject to five different models and partitioning schemes of non-synonymous and synonymous changes. Statistical significance of non-monophyly was examined with the Approximately Unbiased (AU) test. RESULTS: Partial augmentation of genes led to high support for deep divergences, especially when non-synonymous changes were analyzed alone. Increasing the number of taxa without an increase in number of characters led to lower bootstrap support; increasing the number of characters without increasing the number of taxa generally increased bootstrap support. More than three quarters of nodes were supported with bootstrap values greater than 80% when all taxa and genes were combined. Gracillariidae, Lithocolletinae + Leucanthiza, and Acrocercops and Parectopa groups were strongly supported in nearly every analysis. Gracillaria group was well supported in some analyses, but less so in others. We find strong evidence for the exclusion of Douglasiidae from Gracillarioidea sensu Davis and Robinson (1998). Our results strongly support the monophyly of a G.B.R.Y. clade, a group comprised of Gracillariidae + Bucculatricidae + Roeslerstammiidae + Yponomeutidae, when analyzed with non synonymous changes only, but this group was frequently split when synonymous and non-synonymous substitutions were analyzed together. CONCLUSIONS: 1) Partially or fully augmenting a data set with more characters increased bootstrap support for particular deep nodes, and this increase was dramatic when non-synonymous changes were analyzed alone. Thus, the addition of sites that have low levels of saturation and compositional heterogeneity can greatly improve results. 2) Gracillarioidea, as defined by Davis and Robinson (1998), clearly do not include Douglasiidae, and changes to current classification will be required. 3) Gracillariidae were monophyletic in all analyses conducted, and nearly all species can be placed into one of six strongly supported clades though relationships among these remain unclear. 4) The difficulty in determining the phylogenetic placement of Bucculatricidae is probably attributable to compositional heterogeneity at the third codon position. From our tests for compositional heterogeneity and strong bootstrap values obtained when synonymous changes are excluded, we tentatively conclude that Bucculatricidae is closely related to Gracillariidae + Roeslerstammiidae + Yponomeutidae. PMID- 21702959 TI - Consistent two-dimensional visualization of protein-ligand complex series. AB - BACKGROUND: The comparative two-dimensional graphical representation of protein ligand complex series featuring different ligands bound to the same active site offers a quick insight in their binding mode differences. In comparison to arbitrary orientations of the residue molecules in the individual complex depictions a consistent placement improves the legibility and comparability within the series. The automatic generation of such consistent layouts offers the possibility to apply it to large data sets originating from computer-aided drug design methods. RESULTS: We developed a new approach, which automatically generates a consistent layout of interacting residues for a given series of complexes. Based on the structural three-dimensional input information, a global two-dimensional layout for all residues of the complex ensemble is computed. The algorithm incorporates the three-dimensional adjacencies of the active site residues in order to find an universally valid circular arrangement of the residues around the ligand. Subsequent to a two-dimensional ligand superimposition step, a global placement for each residue is derived from the set of already placed ligands. The method generates high-quality layouts, showing mostly overlap-free solutions with molecules which are displayed as structure diagrams providing interaction information in atomic detail. Application examples document an improved legibility compared to series of diagrams whose layouts are calculated independently from each other. CONCLUSIONS: The presented method extends the field of complex series visualizations. A series of molecules binding to the same protein active site is drawn in a graphically consistent way. Compared to existing approaches these drawings substantially simplify the visual analysis of large compound series. PMID- 21702960 TI - Neuronal and glial markers are differently associated with computed tomography findings and outcome in patients with severe traumatic brain injury: a case control study. AB - INTRODUCTION: Authors of several studies have studied biomarkers and computed tomography (CT) findings in the acute phase after severe traumatic brain injury (TBI). However, the correlation between structural damage as assessed by neuroimaging and biomarkers has not been elucidated. The aim of this study was to investigate the relationships among neuronal (Ubiquitin carboxy-terminal hydrolase L1 [UCH-L1]) and glial (glial fibrillary acidic protein [GFAP]) biomarker levels in serum, neuroradiological findings and outcomes after severe TBI. METHODS: The study recruited patients from four neurotrauma centers. Serum samples for UCH-L1 and GFAP were obtained at the time of hospital admission and every 6 hours thereafter. CT scans of the brain were obtained within 24hrs of injury. Outcome was assessed by Glasgow Outcome Scale (GOS) at discharge and at 6 months. RESULTS: 81 severe TBI patients and 167 controls were enrolled. The mean serum levels of UCH-L1 and GFAP were higher (p < 0.001) in TBI patients compared to controls. UCH-L1 and GFAP serum levels correlated significantly with Glasgow Coma Scale (GCS) and CT findings. GFAP levels were higher in patients with mass lesions than in those with diffuse injury (2.95 +/- 0.48 ng/ml versus 0.74 +/- 0.11 ng/ml) while UCH-L1 levels were higher in patients with diffuse injury (1.55 +/- 0.18 ng/ml versus 1.21 +/- 0.15 ng/ml, p = 0.0031 and 0.0103, respectively). A multivariate logistic regression showed that UCH-L1 was the only independent predictor of death at discharge [adjusted odds ratios 2.95; 95% confidence interval, 1.46-5.97], but both UCH-L1 and GFAP levels strongly predicted death 6 months post-injury. CONCLUSIONS: Relationships between structural changes detected by neuroimaging and biomarkers indicate each biomarker may reflect a different injury pathway. These results suggest that protein biomarkers could provide better characterization of subjects at risk for specific types of cellular damage than that obtained with neuroimaging alone, as well as provide valuable information about injury severity and outcome after severe TBI. PMID- 21702961 TI - In vivo versus in vitro protein abundance analysis of Shigella dysenteriae type 1 reveals changes in the expression of proteins involved in virulence, stress and energy metabolism. AB - BACKGROUND: Shigella dysenteriae serotype 1 (SD1) causes the most severe form of epidemic bacillary dysentery. Quantitative proteome profiling of Shigella dysenteriae serotype 1 (SD1) in vitro (derived from LB cell cultures) and in vivo (derived from gnotobiotic piglets) was performed by 2D-LC-MS/MS and APEX, a label free computationally modified spectral counting methodology. RESULTS: Overall, 1761 proteins were quantitated at a 5% FDR (false discovery rate), including 1480 and 1505 from in vitro and in vivo samples, respectively. Identification of 350 cytoplasmic membrane and outer membrane (OM) proteins (38% of in silico predicted SD1 membrane proteome) contributed to the most extensive survey of the Shigella membrane proteome reported so far. Differential protein abundance analysis using statistical tests revealed that SD1 cells switched to an anaerobic energy metabolism under in vivo conditions, resulting in an increase in fermentative, propanoate, butanoate and nitrate metabolism. Abundance increases of transcription activators FNR and Nar supported the notion of a switch from aerobic to anaerobic respiration in the host gut environment. High in vivo abundances of proteins involved in acid resistance (GadB, AdiA) and mixed acid fermentation (PflA/PflB) indicated bacterial survival responses to acid stress, while increased abundance of oxidative stress proteins (YfiD/YfiF/SodB) implied that defense mechanisms against oxygen radicals were mobilized. Proteins involved in peptidoglycan turnover (MurB) were increased, while beta-barrel OM proteins (OmpA), OM lipoproteins (NlpD), chaperones involved in OM protein folding pathways (YraP, NlpB) and lipopolysaccharide biosynthesis (Imp) were decreased, suggesting unexpected modulations of the outer membrane/peptidoglycan layers in vivo. Several virulence proteins of the Mxi-Spa type III secretion system and invasion plasmid antigens (Ipa proteins) required for invasion of colonic epithelial cells, and release of bacteria into the host cell cytosol were increased in vivo. CONCLUSIONS: Global proteomic profiling of SD1 comparing in vivo vs. in vitro proteomes revealed differential expression of proteins geared towards survival of the pathogen in the host gut environment, including increased abundance of proteins involved in anaerobic energy respiration, acid resistance and virulence. The immunogenic OspC2, OspC3 and IpgA virulence proteins were detected solely under in vivo conditions, lending credence to their candidacy as potential vaccine targets. PMID- 21702962 TI - Newly diagnosed incident dizziness of older patients: a follow-up study in primary care. AB - BACKGROUND: Dizziness is a common complaint of older patients in primary care, yet not much is known about the course of incident dizziness. The aim of the study was to follow-up symptoms, subjective impairments and needs of older patients (>=65) with incident dizziness and to determine predictors of chronic dizziness. Furthermore, we analysed general practitioners' (GPs') initial diagnoses, referrals and revised diagnoses after six months. METHODS: An observational study was performed in 21 primary care practices in Germany, including a four-week and six-month follow-up. A questionnaire comprising characteristic matters of dizziness and a series of validated instruments was completed by 66 participants during enrollment and follow-up (after 1 month and 6 months). After six months, chart reviews and face-to-face interviews were also performed with the GPs. RESULTS: Mean scores of dizziness handicap, depression and quality of life were not or only slightly affected, and did not deteriorate during follow-up; however, 24 patients (34.8%) showed a moderate or severe dizziness handicap, and 43 (62.3%) showed a certain disability in terms of quality of life at the time of enrollment. In multivariate analysis, n = 44 patients suffering from chronic dizziness (dependent variable, i.e. relapsing or persistent at six months) initially had a greater dizziness handicap (OR 1.42, 95%CI 1.05-1.47) than patients with transient dizziness. GPs referred 47.8% of the patients to specialists who detected two additional cases of benign paroxysmal positional vertigo (BPPV). CONCLUSIONS: New-onset dizziness relapsed or persisted in a considerable number of patients within six months. This was difficult to predict due to the patients' heterogeneous complaints and characteristics. Symptom persistence does not seem to be associated with deterioration of the psychological status in older primary care patients. Management strategies should routinely consider BPPV as differential diagnosis. PMID- 21702963 TI - Dietary flaxseed administered post thoracic radiation treatment improves survival and mitigates radiation-induced pneumonopathy in mice. AB - BACKGROUND: Flaxseed (FS) is a dietary supplement known for its antioxidant and anti-inflammatory properties. Radiation exposure of lung tissues occurs either when given therapeutically to treat intrathoracic malignancies or incidentally, such as in the case of exposure from inhaled radioisotopes released after the detonation of a radiological dispersion devise (RDD). Such exposure is associated with pulmonary inflammation, oxidative tissue damage and irreversible lung fibrosis. We previously reported that dietary FS prevents pneumonopathy in a rodent model of thoracic X-ray radiation therapy (XRT). However, flaxseed's therapeutic usefulness in mitigating radiation effects post-exposure has never been evaluated. METHODS: We evaluated the effects of a 10%FS or isocaloric control diet given to mice (C57/BL6) in 2 separate experiments (n = 15-25 mice/group) on 0, 2, 4, 6 weeks post a single dose 13.5 Gy thoracic XRT and compared it to an established radiation-protective diet given preventively, starting at 3 weeks prior to XRT. Lungs were evaluated four months post-XRT for blood oxygenation levels, inflammation and fibrosis. RESULTS: Irradiated mice fed a 0%FS diet had a 4-month survival rate of 40% as compared to 70-88% survival in irradiated FS-fed mouse groups. Additionally, all irradiated FS-fed mice had decreased fibrosis compared to those fed 0%FS. Lung OH-Proline content ranged from 96.5 +/- 7.1 to 110.2 +/- 7.7 MUg/ml (Mean +/- SEM) in all irradiated FS-fed mouse groups, as compared to 138 +/- 10.8 MUg/ml for mice on 0%FS. Concomitantly, bronchoalveolar lavage (BAL) protein and weight loss associated with radiation cachexia was significantly decreased in all FS-fed groups. Inflammatory cell influx to lungs also decreased significantly except when FS diet was delayed by 4 and 6 weeks post XRT. All FS-fed mice (irradiated or not), maintained a higher blood oxygenation level as compared to mice on 0%FS. Similarly, multiplex cytokine analysis in the BAL fluid revealed a significant decrease of specific inflammatory cytokines in FS-fed mice. CONCLUSIONS: Dietary FS given post-XRT mitigates radiation effects by decreasing pulmonary fibrosis, inflammation, cytokine secretion and lung damage while enhancing mouse survival. Dietary supplementation of FS may be a useful adjuvant treatment mitigating adverse effects of radiation in individuals exposed to inhaled radioisotopes or incidental radiation. PMID- 21702964 TI - Population dynamics, structure and behavior of Anopheles darlingi in a rural settlement in the Amazon rainforest of Acre, Brazil. AB - BACKGROUND: Anopheles darlingi is the major vector of malaria in South America, and its behavior and distribution has epidemiological importance to biomedical research. In Brazil, An. darlingi is found in the northern area of the Amazon basin, where 99.5% of the disease is reported. METHODS: The study area, known as Ramal do Granada, is a rural settlement inside the Amazon basin in the state of Acre. Population variations and density have been analysed by species behaviour, and molecular analysis has been measured by ND4 mitochondrial gene sequencing. RESULTS: The results show higher density in collections near a recent settlement, suggesting that a high level of colonization decreases the vector presence. The biting activity showed higher activity at twilight and major numbers of mosquitos in the remaining hours of the night in months of high density. From a sample of 110 individual mosquitoes, 18 different haplotypes were presented with a diversity index of 0.895, which is higher than that found in other Anopheles studies. CONCLUSIONS: An. darlingi depends on forested regions for their larval and adult survival. In months with higher population density, the presence of mosquitoes persisted in the second part of the night, increasing the vector capacity of the species. Despite the intra-population variation in the transition to rainy season, the seasonal distribution of haplotypes shows no change in the structure population of An. darlingi. PMID- 21702965 TI - Evaluation of stepping stones as a tool for changing knowledge, attitudes and behaviours associated with gender, relationships and HIV risk in Karnataka, India. AB - BACKGROUND: Stepping Stones training aims to help individuals explore sexual relationships and recognize gender inequalities, the structural drivers of the HIV epidemic, in order to understand risk behaviours and to seek solutions to factors that increase HIV vulnerability. Despite earlier studies suggesting the success of Stepping Stones, little data exist to show diffusion to trainees' social networks or the wider community. METHODS: A mixed-methods evaluation of this approach was undertaken using in-depth interviews of trainees and friends, and polling booth surveys in 20 villages where Stepping Stones training took place and in another 20 villages with no Stepping Stones intervention. RESULTS: The interview respondents and their friends reported significant changes in their relationships after training, and benefit from discussion of gender, sexuality, condom use and HIV vulnerability issues. However, though diffusion of this knowledge at the level of personal contacts was strong, the evaluation revealed that diffusion to the community level was limited. CONCLUSIONS: The qualitative part of this study reflects other studies in different settings, in that SS participants gained immensely from the training. Wider behaviour change is a challenging goal that many programmes fail to attain, with most interventions too limited in scope and intensity to produce larger community effects. This may have contributed to the fact that we observed few differences between interventions and non-intervention villages in this study. However, it is also possible that we had excessive expectations of individual change at the community level, and that it might have been more appropriate to have had broader community level rather than individual behavioural change indicators. We suggest that SS could be enhanced by efforts to better engage existing community opinion leaders, to empower and train participants as community change agents, and to support the development of village-level action plans that combat sexual stereotyping and risky behaviours that lead to unhealthy sexual relationships. PMID- 21702966 TI - Computable visually observed phenotype ontological framework for plants. AB - BACKGROUND: The ability to search for and precisely compare similar phenotypic appearances within and across species has vast potential in plant science and genetic research. The difficulty in doing so lies in the fact that many visual phenotypic data, especially visually observed phenotypes that often times cannot be directly measured quantitatively, are in the form of text annotations, and these descriptions are plagued by semantic ambiguity, heterogeneity, and low granularity. Though several bio-ontologies have been developed to standardize phenotypic (and genotypic) information and permit comparisons across species, these semantic issues persist and prevent precise analysis and retrieval of information. A framework suitable for the modeling and analysis of precise computable representations of such phenotypic appearances is needed. RESULTS: We have developed a new framework called the Computable Visually Observed Phenotype Ontological Framework for plants. This work provides a novel quantitative view of descriptions of plant phenotypes that leverages existing bio-ontologies and utilizes a computational approach to capture and represent domain knowledge in a machine-interpretable form. This is accomplished by means of a robust and accurate semantic mapping module that automatically maps high-level semantics to low-level measurements computed from phenotype imagery. The framework was applied to two different plant species with semantic rules mined and an ontology constructed. Rule quality was evaluated and showed high quality rules for most semantics. This framework also facilitates automatic annotation of phenotype images and can be adopted by different plant communities to aid in their research. CONCLUSIONS: The Computable Visually Observed Phenotype Ontological Framework for plants has been developed for more efficient and accurate management of visually observed phenotypes, which play a significant role in plant genomics research. The uniqueness of this framework is its ability to bridge the knowledge of informaticians and plant science researchers by translating descriptions of visually observed phenotypes into standardized, machine-understandable representations, thus enabling the development of advanced information retrieval and phenotype annotation analysis tools for the plant science community. PMID- 21702967 TI - Classical risk factors of cardiovascular disease among Chinese male steel workers: a prospective cohort study for 20 years. AB - BACKGROUND: Cardiovascular disease (CVD) constitutes a major public health problem in China and worldwide. We aimed to examine classical risk factors and their magnitudes for CVD in a Chinese cohort with over 20 years follow-up. METHODS: A cohort of 5092 male steelworkers recruited from 1974 to 1980 in Beijing of China was followed up for an average of 20.84 years. Cox proportional hazards regression model were used to evaluate the risk of developing a first CVD event in the study participants who were free of CVD at the baseline. RESULTS: The multivariable-adjusted hazard ratio (HR) associated with every 20 mmHg rise in systolic blood pressure (SBP) was 1.63 in this Chinese male population, which was higher than in Caucasians. Compared to non-smokers, men who smoked not less than one-pack-a-day had a HR of 2.43 (95% confidence interval [CI], 1.75-3.38). The HR (95% CI) for every 20 mg/dl increase in total serum cholesterol (TC) and for every point rise in body mass index (BMI) was 1.13 (1.04-1.23) and 1.06 (1.02 1.09), respectively. CONCLUSIONS: Our study documents that hypertension, smoking, overweight and hypercholesterolemia are major conventional risk factors of CVD in Chinese male adults. Continued strengthening programs for prevention and intervention on these risk factors are needed to reduce the incidence of CVD in China. PMID- 21702968 TI - Phosphoproteomic analysis of apoptotic hematopoietic stem cells from hemoglobin E/beta-thalassemia. AB - BACKGROUND: Hemoglobin E/beta-thalassemia is particularly common in Southeast Asia and has variable symptoms ranging from mild to severe anemia. Previous investigations demonstrated the remarkable symptoms of beta-thalassemia in terms of the acceleration of apoptotic cell death. Ineffective erythropoiesis has been studied in human hematopoietic stem cells, however the distinct apoptotic mechanism was unclear. METHODS: The phosphoproteome of bone marrow HSCs/CD34+ cells from HbE/beta-thalassemic patients was analyzed using IMAC phosphoprotein isolation followed by LC-MS/MS detection. Decyder MS software was used to quantitate differentially expressed proteins in 3 patients and 2 normal donors. The differentially expressed proteins from HSCs/CD34+ cells were compared with HbE/beta-thalassemia and normal HSCs. RESULTS: A significant change in abundance of 229 phosphoproteins was demonstrated. Importantly, the analysis of the candidate proteins revealed a high abundance of proteins that are commonly found in apoptotic cells including cytochrome C, caspase 6 and apoptosis inducing factors. Moreover, in the HSCs patients a significant increase was observed in a specific type of phosphoserine/threonine binding protein, which is known to act as an important signal mediator for the regulation of cell survival and apoptosis in HbE/beta-thalassemia. CONCLUSIONS: Our study used a novel method to investigate proteins that influence a particular pathway in a given disease or physiological condition. Ultimately, phosphoproteome profiling in HbE/beta thalassemic stem cells is an effective method to further investigate the cell death mechanism of ineffective erythropoiesis in beta-thalassemia. Our report provides a comprehensive phosphoproteome, an important resource for the study of ineffective erythropoiesis and developing therapies for HbE/beta-thalassemia. PMID- 21702969 TI - Image-guided versus blind corticosteroid injections in adults with shoulder pain: a systematic review. AB - BACKGROUND: Corticosteroid injections can be performed blind (landmark-guided) or with image guidance, and this may account for variable clinical outcomes. The objective of this study was to assess the effectiveness and safety of image guided versus blind corticosteroid injections in improving pain and function among adults with shoulder pain. METHODS: MEDLINE, the Cochrane Controlled Trials Register and EMBASE were searched to May 2010. Additional studies were identified by searching bibliographies of shortlisted articles. Search items included blind, landmark, anatomical, clinical exam, image-guided, ultrasound, fluoroscopy, steroid injection, frozen shoulder, random allocation, randomized controlled trial (RCT) and clinical trial.Randomized controlled studies comparing image guided versus blind (landmark-guided) corticosteroid shoulder injections that examined pain, function and/or adverse events were included. Independent extraction was done by two authors using a form with pre-specified data fields, including risk of bias appraisal. Conflicts were resolved by discussion. The decision to pool data was based on assessment of clinical design homogeneity. When warranted, studies were pooled under a random-effects model. RESULTS: Two RCTs for pain, function and adverse events (n = 101) met eligibility criteria. No serious threats to validity were found. Both trials compared ultrasound-guided versus landmark-guided injections and were judged similar in clinical design. Low to moderate heterogeneity was observed: shoulder pain I2 = 60%, function I2 = 22%. A meta-analysis demonstrated greater improvement with ultrasound-guided injections at 6 weeks after injection in both pain (mean difference = 2.23 [95% CI: 1.27, 3.18]), as assessed with a 0 to 10 visual analogue scale, and shoulder function (standardised mean difference = 1.09 [95% CI: 0.61, 1.57]) as assessed with shoulder function scores. Although more adverse events (all mild) were reported with landmark-guided injections, the difference was not statistically significant (risk ratio = 0.20 [95% CI: 0.04, 1.13]).This review was only based on two moderate-sized trials. Blinding of patients was not performed in both trials, causing some risk of bias in outcome assessment since primary endpoints were wholly or partially patient-reported. CONCLUSION: There is a paucity of RCTs on image-guided versus landmark-guided corticosteroid shoulder injections examining pain, function and adverse events. In this review, patients who underwent image-guided (ultrasound) injections had statistically significant greater improvement in shoulder pain and function at 6 weeks after injection. Image-guided (ultrasound) corticosteroid injections potentially offer a significantly greater clinical improvement over blind (landmark-guided) injections in adults with shoulder pain. However, this apparent benefit requires confirmation from further studies (adequately-powered and well-executed RCTs). PMID- 21702970 TI - Implication of human papillomavirus-66 in vulvar carcinoma: a case report. AB - INTRODUCTION: Vulvar cancer in older women is seldom associated with human papillomavirus infection. CASE PRESENTATION: We present the case of an 80-year old Greek Caucasian woman with an undetermined obstetric and gynecologic history. The patient underwent radical vulvectomy and bilateral inguinal lymphadenectomy for a vulvar carcinoma. A human papillomavirus infection was suggested on the basis of histological and cytological examinations followed by human papillomavirus DNA typing, which revealed the presence of human papillomavirus 66. CONCLUSION: Even though human papillomavirus-16 and human papillomavirus-18 are most frequently implicated in the pathogenesis of vulvar carcinoma, human papillomavirus-66 can also be regarded as a causative factor. Suspicious lesions should be biopsied, and in the presence of carcinoma, vulvectomy with bilateral lymphadenectomy, if necessary, must be performed. Furthermore, polymerase chain reaction assay analysis with clinical arrays in cytological samples is an accurate test for the detection of a wide range of human papillomavirus genotypes and can be used to verify the infection and specify the human papillomavirus type implicated. PMID- 21702971 TI - Myofibrillogenesis regulator 1 (MR-1) is a novel biomarker and potential therapeutic target for human ovarian cancer. AB - BACKGROUND: Myofibrillogenesis regulator 1 (MR-1) is overexpressed in human cancer cells and plays an essential role in cancer cell growth. However, the significance of MR-1 in human ovarian cancer has not yet been explored. The aim of this study was to examine whether MR-1 is a predictor of ovarian cancer and its value as a therapeutic target in ovarian cancer patients. METHODS: Reverse transcription polymerase chain reaction (PCR) and quantitative real-time PCR were used to detect MR-1 mRNA levels in tissue samples from 26 ovarian cancer patients and 25 controls with benign ovarian disease. Anti-MR-1 polyclonal antibodies were prepared, tested by ELISA and western blotting, and then used for immunohistochemical analysis of the tissue samples. Adhesion and invasion of 292T cells was also examined after transfection of a pMX-MR-1 plasmid. Knockdown of MR 1 expression was achieved after stable transfection of SKOV3 cells with a short hairpin DNA pGPU6/GFP/Neo plasmid against the MR-1 gene. In addition, SKOV3 cells were treated with paclitaxel and carboplatin, and a potential role for MR-1 as a therapeutic target was evaluated. RESULTS: MR-1 was overexpressed in ovarian cancer tissues and SKOV3 cells. 293T cells overexpressed MR-1, and cellular spread and invasion were enhanced after transfection of the pMX-MR-1 plasmid, suggesting that MR-1 is critical for ovarian cancer cell growth. Knockdown of MR 1 expression inhibited cell adhesion and invasion, and treatment with anti-cancer drugs decreased its expression in cancer cells. Taken together, these results provide the first evidence of the cellular and molecular mechanisms by which MR-1 might serve as a novel biological marker and potential therapeutic target for ovarian cancer. CONCLUSIONS: MR-1 may be a biomarker for diagnosis of ovarian cancer. It may also be useful for monitoring of the effects of anti-cancer therapies. Further studies are needed to clarify whether MR-1 is an early diagnostic marker for ovarian cancer and a possible therapeutic target. PMID- 21702972 TI - Human immunodeficiency virus infection and autoimmune hepatitis during highly active anti-retroviral treatment: a case report and review of the literature. AB - INTRODUCTION: The emergence of hepatic injury in patients with human immunodeficiency virus infection during highly active therapy presents a diagnostic dilemma. It may represent treatment side effects or autoimmune disorders, such as autoimmune hepatitis, emerging during immune restoration. CASE PRESENTATION: We present the case of a 42-year-old African-American woman with human immunodeficiency virus infection who presented to our emergency department with severe abdominal pain and was found to have autoimmune hepatitis. A review of the literature revealed 12 reported cases of autoimmune hepatitis in adults with human immunodeficiency virus infection, only three of whom were diagnosed after highly active anti-retroviral treatment was initiated. All four cases (including our patient) were women, and one had a history of other autoimmune disorders. In our patient (the one patient case we are reporting), a liver biopsy revealed interface hepatitis, necrosis with lymphocytes and plasma cell infiltrates and variable degrees of fibrosis. All four cases required treatment with corticosteroids and/or other immune modulating agents and responded well. CONCLUSION: Our review suggests that autoimmune hepatitis is a rare disorder which usually develops in women about six to eight months after commencing highly active anti-retroviral treatment during the recovery of CD4 lymphocytes. It represents either re-emergence of a pre-existing condition that was unrecognized or a de novo manifestation during immune reconstitution. PMID- 21702973 TI - Obstructive azoospermia as an unusual complication associated with herniorrhaphy of an omphalocele: a case report. AB - INTRODUCTION: Iatrogenic damage to the seminal tract is one of the causes of obstructive azoospermia, which can be an indication for reconstruction surgery. We present a case of obstructive azoospermia as an unusual complication after neonatal herniorrhaphy of an omphalocele. CASE PRESENTATION: A 30-year-old Japanese man was diagnosed with obstructive azoospermia. He had undergone herniorrhaphy of an omphalocele immediately after birth. Reconstruction surgery of both seminal tracts was performed to pursue the possibility of naturally achieved pregnancy. Intra-operative findings demonstrated that both vasa deferentia were interrupted at the internal inguinal rings, although the abdominal end of the right vas leading to the seminal vesicle was found in the abdominal cavity. The discharge from the stump of the testicular end had no sperm, although the right epididymal tubules were dilated with motile sperm. Therefore, we performed right-sided vasovasostomy in the internal inguinal ring and ipsilateral epididymovasostomy simultaneously. CONCLUSION: To the best of our knowledge, this is the first report describing obstructive azoospermia as an unusual complication of herniorrhaphy of an omphalocele. It is important to pay attention to the existence of seminal tracts in such surgery as well as in inguinal herniorrhaphy. PMID- 21702974 TI - Systemic lupus erythematosus presenting with eosinophilic enteritis: a case report. AB - INTRODUCTION: Systemic lupus erythematosus (SLE) is a multisystem disorder that may present with various symptoms. It may involve the gastrointestinal tract in a variety of ways; some of the most well-known ones are transaminitis, lupus mesenteric vasculitis, lupus enteritis and mesenteric vascular leakage. We describe a case of a patient with SLE who presented with a five-month history of diarrhea caused by eosinophilic enteritis. To the best of our knowledge, there are few cases reported in the literature of patients with SLE who initially present with chronic diarrhea due to eosinophilic enteritis. CASE PRESENTATION: A 38-year-old Persian Iranian woman was admitted with a five-month history of diarrhea and abdominal pain. A physical examination showed nothing abnormal. Initially, she had only lymphopenia and mild eosinophilia. No autoimmune or infectious etiology was detected to justify these abnormalities. A thorough evaluation was not helpful in finding the etiology, until she developed a scalp lesion similar to discoid lupus erythematosus. Computed tomography showed small bowel wall thickening. Briefly, she manifested full-blown SLE, and it was revealed that the diarrhea was caused by eosinophilic enteritis. CONCLUSION: Considering SLE in a patient who presents with chronic diarrhea and lymphopenia may be helpful in earlier diagnosis and therapy. This is an original case report of interest to physicians who practice internal medicine, family medicine and gastroenterology. PMID- 21702975 TI - Minimally invasive surgery - maximal exposure to research. PMID- 21702976 TI - Pulmonary interstitial emphysema presenting in a woman on the intensive care unit: case report and review of literature. AB - INTRODUCTION: Pulmonary interstitial emphysema is a life-threatening form of ventilator-induced lung injury. We present one of the few reported adult cases of pulmonary interstitial emphysema in a woman with respiratory failure admitted to our intensive care unit. CASE PRESENTATION: An 87-year-old Caucasian woman with a diagnosis of community-acquired pneumonia was admitted to our intensive care unit requiring invasive ventilation. The combination of a poor oxygenation index and bilateral alveolar/interstitial infiltrates on a chest radiograph fulfilled the criteria for adult respiratory distress syndrome; the cause was thought to be a combination of the direct pneumonic pulmonary injury and extrapulmonary severe sepsis. By day seven, the fraction of inspired oxygen, peak airway and positive end expiratory pressures weaned sufficiently to allow an uncomplicated percutaneous tracheostomy. On day 10, problems with ventilation necessitated recruitment maneuvers with a Mapleson C circuit, after which dramatic surgical emphysema was noted. An upper airway bronchoscopy showed no obvious tracheal wall injury, and computed tomography of her chest showed extensive surgical emphysema, perivascular emphysema and peribronchial emphysema, which were consistent with a diagnosis of pulmonary interstitial emphysema. Over the following days, despite protective ventilatory strategies and intercostal tube thoracostomy, lung compliance along with oxygenation deteriorated and our patient died on day 14. CONCLUSION: The development of pulmonary interstitial emphysema is a rare but real risk when caring for patients with worsening lung compliance on the intensive care unit. Improved awareness of the condition, early protective ventilation strategies and timely treatment of any of the lethal complications will hopefully result in improved survival from the condition in adults. PMID- 21702977 TI - Long-term respiratory follow-up of H1N1 infection. AB - BACKGROUND: The first case of 2009 pandemic influenza A (H1N1) virus infection was documented in our Hospital on 10th August 2009. METHODS AND FINDINGS: Real time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) testing was used to confirm the diagnosis. All patients were treated with oseltamivir from the first day of hospitalization. Upon admission 12/44 had local patchy shadowing in their chest x-ray and additionally antibiotic regimen was added to these patients as pneumonia was suspected based on clinical evidence. In total 44 patients were hospitalized 15/44 had asthma, 6/44 COPD, 5/44 leukemia. Lung function was evaluated with forced vital capacity, forced expiratory volume in 1 sec and diffused carbon monoxide upon discharge and every 3 months, until 6 months of observation was completed after discharge. The purpose of this retrospective cohort study was to evaluate whether influenza A (H1N1) had an impact on the respiratory capacity of the infected patients. CONCLUSIONS: An improvement of pulmonary function tests was observed between the first two measurements, implicating an inflammatory pathogenesis of influenza A (H1N1) to the respiratory tract. This inflammation was not associated with the severity or clinical outcome of the patients. All patients had a mild clinical course and their respiratory capacity was stable between the second and third measurement, suggesting that the duration of respiratory inflammation was two months. Early treatment with antiviral agents and vaccination represent the mainstay of management. PMID- 21702978 TI - Exploring internal features of 16S rRNA gene for identification of clinically relevant species of the genus Streptococcus. AB - BACKGROUND: Streptococcus is an economically important genus as a number of species belonging to this genus are human and animal pathogens. The genus has been divided into different groups based on 16S rRNA gene sequence similarity. The variability observed among the members of these groups is low and it is difficult to distinguish them. The present study was taken up to explore 16S rRNA gene sequence to develop methods that can be used for preliminary identification and can supplement the existing methods for identification of clinically-relevant isolates of the genus Streptococcus. METHODS: 16S rRNA gene sequences belonging to the isolates of S. dysgalactiae, S. equi, S. pyogenes, S. agalactiae, S. bovis, S. gallolyticus, S. mutans, S. sobrinus, S. mitis, S. pneumoniae, S. thermophilus and S. anginosus were analyzed with the purpose to define genetic variability within each species to generate a phylogenetic framework, to identify species-specific signatures and in-silico restriction enzyme analysis. RESULTS: The framework based analysis was used to segregate Streptococcus spp. previously identified upto genus level. This segregation was validated using species specific signatures and in-silico restriction enzyme analysis. 43 uncharacterized Streptococcus spp. could be identified using this approach. CONCLUSIONS: The markers generated exploring 16S rRNA gene sequences provided useful tool that can be further used for identification of different species of the genus Streptococcus. PMID- 21702979 TI - Antioxidant activity relationship of phenolic compounds in Hypericum perforatum L. AB - BACKGROUND: The St John's Wort (Hypericum perforatum; Clusiaceae) has been used in traditional and modern medicine for a long time due to its high content of biologically active phenolics. The purpose of this work was to develop a method for their fractionation and identification, and to determine the most active antioxidant compounds in plant extract. RESULTS: An LC-MS method which enables fast qualitative and semiquantitative analysis was developed. The composition determined is in agreement with the previous results, where 6 flavonoids, 4 naphthodianthrones and 4 phloroglucinols have been identified. Significant antioxidant activity was determined for most of the fractions by DPPH assay (the lowest IC50 of 0.52 MUg/ml), NO scavenging (6.11 MUg/ml), superoxide scavenging (1.86 MUg/ml), lipid peroxidation (0.0079 MUg/ml) and FRAP (the highest reduction capacity of 104 mg Fe equivalents/g) assays. CONCLUSION: LC-MS technique has been successfully applied for a quick separation and identification of the major components of H. perforatum fractions. Majority of the fractions analyzed have expressed a very high antioxidative activity when compared to synthetic antioxidants. The antioxidant activity could be attributed to flavonoids and phenolic acids, while phloroglucinols and naphthodianthrones showed no significant activity. It is demonstrated that it is possible to obtain, by fractionation, H. perforatum preparations with significantly increased phloroglucinols-to-naphthodianthrones ratio (up to 95:5). PMID- 21702980 TI - TFRC and ACTB as the best reference genes to quantify Urokinase Plasminogen Activator in breast cancer. AB - BACKGROUND: Biomedical researchers have long looked for ways to diagnose and treat cancer patients at the early stages through biomarkers. Although conventional techniques are routinely applied in the detection of biomarkers, attitudes towards using Real-Time PCR techniques in detection of many biomarkers are increasing. Normalization of quantitative Real-Time PCR is necessary to validate non-biological alteration occurring during the steps of RNA quantification. Selection of variably expressed housekeeping genes (HKs) will affect the validity of the data. The aim of the present study was to identify uniformly expressed housekeeping genes in order to use in the breast cancer gene expression studies. Urokinase Plasminogen Activator was used as a gene of interest. FINDINGS: The expression of six HKs (TFRC, GUSB, GAPDH, ACTB, HPRT1 and RPLP0) was investigated using geNorm and NormFinder softwares in forty breast tumor, four normal and eight adjacent tissues. RPLP0 and GAPDH revealed maximum M value, while TFRC demonstrated lowest M value. CONCLUSIONS: In the present study the most and the least stable genes were TFRC and RPLP0 respectively. TFRC and ACTB were verified as the best combination of two genes for breast cancer quantification. The result of this study shows that in each gene expression analysis HKs selection should be done based on experiment conditions. PMID- 21702981 TI - Protein kinase CK2alpha is overexpressed in colorectal cancer and modulates cell proliferation and invasion via regulating EMT-related genes. AB - BACKGROUND: Protein kinase CK2 is a highly conserved, ubiquitous protein serine/threonine kinase that phosphorylates many substrates and has a global role in numerous biological and pathological processes. Overexpression of the protein kinase CK2alpha subunit (CK2alpha) has been associated with the malignant transformation of several tissues, with not nearly as much focus on the role of CK2alpha in colorectal cancer (CRC). The aims of this study are to investigate the function and regulatory mechanism of CK2alpha in CRC development. METHODS: Expression levels of CK2alpha were analyzed in 144 patients (104 with CRC and 40 with colorectal adenoma) by immunohistochemistry. Proliferation, senescence, motility and invasion assays as well as immunofluorescence staining and western blots were performed to assess the effect of CK2alpha in CRC. RESULTS: The immunohistochemical expression of nuclear CK2alpha was stronger in tumor tissues than in adenomas and normal colorectal tissues. Suppression of CK2alpha by small interfering RNA or the CK2alpha activity inhibitor emodin inhibited proliferation of CRC cells, caused G0/G1 phase arrest, induced cell senescence, elevated the expression of p53/p21 and decreased the expression of C-myc. We also found that knockdown of CK2alpha suppressed cell motility and invasion. Significantly, CK2alpha inhibition resulted in beta-catenin transactivation, decreased the expression levels of vimentin and the transcription factors snail1 and smad2/3, and increased the expression of E-cadherin, suggesting that CK2alpha regulates the epithelial-mesenchymal transition (EMT) process in cancer cells. CONCLUSIONS: Our results indicate that CK2alpha plays an essential role in the development of CRC, and inhibition of CK2alpha may serve as a promising therapeutic strategy for human CRC. PMID- 21702982 TI - Canadian children's and youth's pedometer-determined steps/day, parent-reported TV watching time, and overweight/obesity: the CANPLAY Surveillance Study. AB - BACKGROUND: This study examines associations between pedometer-determined steps/day and parent-reported child's Body Mass Index (BMI) and time typically spent watching television between school and dinner. METHODS: Young people (aged 5-19 years) were recruited through their parents by random digit dialling and mailed a data collection package. Information on height and weight and time spent watching television between school and dinner on a typical school day was collected from parents. In total, 5949 boys and 5709 girls reported daily steps. BMI was categorized as overweight or obese using Cole's cut points. Participants wore pedometers for 7 days and logged daily steps. The odds of being overweight and obese by steps/day and parent-reported time spent television watching were estimated using logistic regression for complex samples. RESULTS: Girls had a lower median steps/day (10682 versus 11059 for boys) and also a narrower variation in steps/day (interquartile range, 4410 versus 5309 for boys). 11% of children aged 5-19 years were classified as obese; 17% of boys and girls were overweight. Both boys and girls watched, on average, < 40 minutes of television between school and dinner on school days. Adjusting for child's age and sex and parental education, the odds of a child being obese decreased by 20% for every extra 3000 steps/day and increased by 21% for every 30 minutes of television watching. There was no association of being overweight with steps/day, however the odds of being overweight increased by 8% for every 30 minutes of additional time spent watching television between school and dinner on a typical school day. DISCUSSION: Television viewing is the more prominent factor in terms of predicting overweight, and it contributes to obesity, but steps/day attenuates the association between television viewing and obesity, and therefore can be considered protective against obesity. In addition to replacing opportunities for active alternative behaviours, exposure to television might also impact body weight by promoting excess energy intake. CONCLUSIONS: In this large nationally representative sample, pedometer-determined steps/day was associated with reduced odds of being obese (but not overweight) whereas each parent-reported hour spent watching television between school and dinner increased the odds of both overweight and obesity. PMID- 21702983 TI - Joint effect of longevity-associated mitochondrial DNA 5178 C/A polymorphism and alcohol consumption on risk of hyper-LDL cholesterolemia in middle-aged Japanese men. AB - BACKGROUND: Combined effects between mitochondrial DNA 5178 (Mt5178) C/A polymorphism and alcohol consumption on the risk of hypertension or hyperuricemia have been reported. The objective of this study was to investigate whether Mt5178 C/A polymorphism modulates the effects of alcohol consumption on the risk of dyslipidemia. METHODS: A total of 394 male subjects were selected from among individuals visiting the hospital for regular medical check-ups. After Mt5178 C/A genotyping, a cross-sectional study assessing the combined effect of Mt5178 polymorphism and alcohol consumption on the risk of dyslipidemia was conducted. RESULTS: For men with Mt5178C, alcohol consumption was significantly and negatively associated with the risk of hyper-low-density lipoprotein (LDL) cholesterolemia (serum LDL cholesterol >= 140 mg/dl) (P for trend = 0.015). After adjustment for age, body mass index (BMI), habitual smoking, coffee consumption and use of antihypertensive medicine, the odds ratio (OR) for hyper-LDL cholesterolemia was significantly lower in daily drinkers with Mt5178C than non drinkers with Mt5178C (OR = 0.360, 95% confidence intervals: 0.153-0.847). A significant and negative association between alcohol consumption and serum LDL cholesterol levels was also observed in Mt5178C genotypic men (P for trend < 0.01). On the other hand, the association between Mt5178A genotype and risk of hyper-LDL cholesterolemia does not appear to depend on alcohol consumption. CONCLUSIONS: For Mt5178C genotypic men, alcohol consumption may reduce the risk of hyper-LDL cholesterolemia. PMID- 21702984 TI - Chromatin structure characteristics of pre-miRNA genomic sequences. AB - BACKGROUND: MicroRNAs (miRNAs) are non-coding RNAs with important roles in regulating gene expression. Recent studies indicate that transcription and cleavage of miRNA are coupled, and that chromatin structure may influence miRNA transcription. However, little is known about the relationship between the chromatin structure and cleavage of pre-miRNA from pri-miRNA. RESULTS: By analysis of genome-wide nucleosome positioning data sets from human and Caenorhabditis elegans (C. elegans), we found an enrichment of positioned nucleosome on pre-miRNA genomic sequences, which is highly correlated with GC content within pre-miRNA. In addition, obvious enrichments of three histone modifications (H2BK5me1, H3K36me3 and H4K20me1) as well as RNA Polymerase II (RNAPII) were observed on pre-miRNA genomic sequences corresponding to the active promoter miRNAs and expressed miRNAs. CONCLUSION: Our results revealed the chromatin structure characteristics of pre-miRNA genomic sequences, and implied potential mechanisms that can recognize these characteristics, thus improving pre miRNA cleavage. PMID- 21702986 TI - Milk sharing: from private practice to public pursuit. AB - After only six months, a commerce-free internet-based milk-sharing model is operating in nearly 50 countries, connecting mothers who are able to donate breast milk with the caregivers of babies who need breast milk. Some public health authorities have condemned this initiative out of hand. Although women have always shared their milk, in many settings infant formula has become the "obvious" alternative to a mother's own milk. Yet an internationally endorsed recommendation supports mother-to-mother milk sharing as the best option in place of a birth mother's milk. Why then this rejection? Several possibilities come to mind: 1) ignorance and prejudice surrounding shared breast milk; 2) a perceived challenge to the medical establishment of a system where mothers exercise independent control; and 3) concern that mother-to-mother milk sharing threatens donor milk banks. We are not saying that milk sharing is risk-free or that the internet is an ideal platform for promoting it. Rather, we are encouraging health authorities to examine this initiative closely, determine what is happening, and provide resources to make mother-to-mother milk sharing as safe as possible. Health authorities readily concede that life is fraught with risk; accordingly, they promote risk-reduction and harm-minimisation strategies. Why should it be any different for babies lacking their own mothers' milk? The more that is known about the risks of substituting for breast milk, the more reasonable parental choice to use donor milk becomes. We believe that the level of intrinsic risk is manageable through informed sharing. If undertaken, managed and evaluated appropriately, this made-by-mothers model shows considerable potential for expanding the world's supply of human milk and improving the health of children. PMID- 21702985 TI - Characterization of surface proteins of Cronobacter muytjensii using monoclonal antibodies and MALDI-TOF Mass spectrometry. AB - BACKGROUND: Cronobacter spp. is a newly emerging pathogen that causes meningitis in infants and other diseases in elderly and immunocompromised individuals. This study was undertaken to investigate surface antigenic determinants in Cronobacter spp. using monoclonal antibodies (MAbs) and MALDI-TOF Mass spectrometry. RESULTS: Spleenocytes from mice that were immunized with heat-killed (20 min, 80 degrees C) Cronobacter cells were fused with SP2 myeloma cells. Five desirable MAbs (A1, B5, 2C2, C5 and A4) were selected. MAbs A1, B5, 2C2 and C5 were of IgG2a isotype while A4 was an IgM. Specificity of the MAbs was determined by using immunoblotting with outer membrane protein preparations (OMPs) extracted from 12 Cronobacter and 6 non-Cronobacter bacteria. All MAbs recognized proteins with molecular weight ranging between 36 and 49 kDa except for one isolate (44) in which no OMPs were detected. In addition, MAbs recognized two bands (38-41 kDa) in four of the non-Cronobacter bacteria. Most of the proteins recognized by the MAbs were identified by MALDI-TOF peptide sequencing and appeared to be heterogeneous with the identities of some of them are still unknown. All MAbs recognized the same epitope as determined by an additive Index ELISA with their epitopes appeared to be conformational rather than sequential. Further, none of the MAbs recognized purified LPS from Cronobacter spp. Specificity of the MAbs toward OMPs was further confirmed by transmission electron microscopy. CONCLUSIONS: Results obtained in this study highlight the immunological cross reactivity among Cronobacter OMPs and their Enterobacteriaceae counterparts. Nevertheless, the identity of the identified proteins appeared to be different as inferred from the MALDI-TOF sequencing and identification. PMID- 21702987 TI - Indoor solid fuel use and tuberculosis in China: a matched case-control study. AB - BACKGROUND: China ranks second among the 22 high burden countries for tuberculosis. A modeling exercise showed that reduction of indoor air pollution could help advance tuberculosis control in China. However, the association between indoor air pollution and tuberculosis is not yet well established. A case control study was conducted in Anhui, China to investigate whether use of solid fuel is associated with tuberculosis. METHODS: Cases were new sputum smear positive tuberculosis patients. Two controls were selected from the neighborhood of each case matched by age and sex using a pre-determined procedure. A questionnaire containing demographic information, smoking habits and use of solid fuel for cooking or heating was used for interview. Solid fuel (coal and biomass) included coal/lignite, charcoal, wood, straw/shrubs/grass, animal dung, and agricultural crop residue. A household that used solid fuel either for cooking and (/or) heating was classified as exposure to combustion of solid fuel (indoor air pollution). Odds ratios and their corresponding 95% confidence limits for categorical variables were determined by Mantel-Haenszel estimate and multivariate conditional logistic regression. RESULTS: There were 202 new smear positive tuberculosis cases and 404 neighborhood controls enrolled in this study. The proportion of participants who used solid fuels for cooking was high (73.8% among cases and 72.5% among controls). The majority reported using a griddle stove (85.2% among cases and 86.7% among controls), had smoke removed by a hood or chimney (92.0% among cases and 92.8% among controls), and cooked in a separate room (24.8% among cases and 28.0% among controls) or a separate building (67.8% among cases and 67.6% among controls). Neither using solid fuel for cooking (odds ratio (OR) 1.08, 95% CI 0.62-1.87) nor using solid fuel for heating (OR 1.04, 95% CI 0.54-2.02) was significantly associated with tuberculosis. Determinants significantly associated with tuberculosis were household tuberculosis contact (adjusted OR, 27.23, 95% CI 8.19-90.58) and ever smoking tobacco (adjusted OR 1.64, 96% CI 1.01-2.66). CONCLUSION: In a population where the majority had proper ventilation in cooking places, the association between use of solid fuel for cooking or for heating and tuberculosis was not statistically significant. PMID- 21702988 TI - Exploring the experiences and coping strategies of international medical students. AB - BACKGROUND: Few studies have addressed the challenges that international medical students face and there is a dearth of information on the behavioural strategies these students adopt to successfully progress through their academic program in the face of substantial difficulties of language barrier, curriculum overload, financial constraints and assessment tasks that require high proficiency in communication skills. METHODS: This study was designed primarily with the aim of enhancing understanding of the coping strategies, skill perceptions and knowledge of assessment expectations of international students as they progress through the third and fourth years of their medical degree at the School of Medicine, University of Tasmania, Australia. RESULTS: Survey, focus group discussion and individual interviews revealed that language barriers, communication skills, cultural differences, financial burdens, heavy workloads and discriminatory bottlenecks were key factors that hindered their adaptation to the Australian culture. Quantitative analyses of their examination results showed that there were highly significant (p < 0.001) variations between student performances in multiple choice questions, short answer questions and objective structured clinical examinations (70.3%, 49.7% & 61.7% respectively), indicating existence of communication issues. CONCLUSIONS: Despite the challenges, these students have adopted commendable coping strategies and progressed through the course largely due to their high sense of responsibility towards their family, their focus on the goal of graduating as medical doctors and their support networks. It was concluded that faculty needs to provide both academic and moral support to their international medical students at three major intervention points, namely point of entry, mid way through the course and at the end of the course to enhance their coping skills and academic progression. Finally, appropriate recommendations were made. PMID- 21702989 TI - Cost of non-persistence with oral bisphosphonates in post-menopausal osteoporosis treatment in France. AB - BACKGROUND: During the last decade, oral bisphosphonates (BP) became the most widely prescribed pharmacologic class for post-menopausal osteoporosis. However, many surveys revealed the important issue of poor persistence with those drugs resulting in a failure of treatment to reduce fracture risk sufficiently. Using a published Markov model, this study analyses the economic impact of non persistence with bisphosphonates in the context of the introduction of generics in France. METHODS: Direct costs of vertebral, hip and wrist fracture were assessed and included in an existing 10-year Markov model developed to analyse consequences of non-persistence. Three alternatives of comparison were set: no treatment, real-world persistence, and ideal persistence. Simulated patients' characteristics matched those from a French observational study and the real world adherence alternative employed persistence data from published database analysis. The risk of fracture of menopausal women and the risk reduction associated with the drugs were based on results reported in clinical trials. Incremental cost-effectiveness ratios (ICERs) were calculated first between real world adherence and no treatment alternatives, and second between ideal and real world persistence alternatives. The cost of non-persistence was defined as the difference between total cost of ideal and real-world persistence alternatives. RESULTS: Within fractured women population, mean costs of 10-year management of fracture were significantly different between the three alternatives with ?7,239 (+/- ?4,783), ?6,711 (+/- ?4,410) and ?6,134 (+/- ?3,945) in the no-treatment, the real-world and ideal persistence alternatives, respectively (p < 0.0001). Cost-effectiveness ratio for real-world treatment persistence compared with no treatment alternative was found dominant and as well, alternative of ideal persistence dominated the former. Each ten percentage point of persistence gain amounted to ?58 per patient, and extrapolation resulted in a global annual cost of non-persistence of over ?30 million to the French health care system, with a substantial transfer from hospital to pharmacy budgets. CONCLUSION: Within term, improving persistence with oral bisphosphonates should be economically dominant on levels currently known in real-world. Given this potential savings, ambitious adherence-enhancing interventions should be considered in osteoporotic patients. PMID- 21702990 TI - Specific and sensitive quantitative RT-PCR of miRNAs with DNA primers. AB - BACKGROUND: MicroRNAs are important regulators of gene expression at the post transcriptional level and play an important role in many biological processes. Due to the important biological role it is of great interest to quantitatively determine their expression level in different biological settings. RESULTS: We describe a PCR method for quantification of microRNAs based on a single reverse transcription reaction for all microRNAs combined with real-time PCR with two, microRNA-specific DNA primers. Primer annealing temperatures were optimized by adding a DNA tail to the primers and could be designed with a success rate of 94%. The method was able to quantify synthetic templates over eight orders of magnitude and readily discriminated between microRNAs with single nucleotide differences. Importantly, PCR with DNA primers yielded significantly higher amplification efficiencies of biological samples than a similar method based on locked nucleic acids-spiked primers, which is in agreement with the observation that locked nucleic acid interferes with efficient amplification of short templates. The higher amplification efficiency of DNA primers translates into higher sensitivity and precision in microRNA quantification. CONCLUSIONS: MiR specific quantitative RT-PCR with DNA primers is a highly specific, sensitive and accurate method for microRNA quantification. PMID- 21702991 TI - The conjugative plasmid of a bean-nodulating Sinorhizobium fredii strain is assembled from sequences of two Rhizobium plasmids and the chromosome of a Sinorhizobium strain. AB - BACKGROUND: Bean-nodulating Rhizobium etli originated in Mesoamerica, while soybean-nodulating Sinorhizobium fredii evolved in East Asia. S. fredii strains, such as GR64, have been isolated from bean nodules in Spain, suggesting the occurrence of conjugative transfer events between introduced and native strains. In R. etli CFN42, transfer of the symbiotic plasmid (pRet42d) requires cointegration with the endogenous self-transmissible plasmid pRet42a. Aiming at further understanding the generation of diversity among bean nodulating strains, we analyzed the plasmids of S. fredii GR64: pSfr64a and pSfr64b (symbiotic plasmid). RESULTS: The conjugative transfer of the plasmids of strain GR64 was analyzed. Plasmid pSfr64a was self-transmissible, and required for transfer of the symbiotic plasmid. We sequenced pSfr64a, finding 166 ORFs. pSfr64a showed three large segments of different evolutionary origins; the first one presented 38 ORFs that were highly similar to genes located on the chromosome of Sinorhizobium strain NGR234; the second one harbored 51 ORFs with highest similarity to genes from pRet42d, including the replication, but not the symbiosis genes. Accordingly, pSfr64a was incompatible with the R. etli CFN42 symbiotic plasmid, but did not contribute to symbiosis. The third segment contained 36 ORFs with highest similarity to genes localized on pRet42a, 20 of them involved in conjugative transfer. Plasmid pRet42a was unable to substitute pSfr64a for induction of pSym transfer, and its own transfer was significantly diminished in GR64 background. The symbiotic plasmid pSfr64b was found to differ from typical R. etli symbiotic plasmids. CONCLUSIONS: S. fredii GR64 contains a chimeric transmissible plasmid, with segments from two R. etli plasmids and a S. fredii chromosome, and a symbiotic plasmid different from the one usually found in R. etli bv phaseoli. We infer that these plasmids originated through the transfer of a symbiotic-conjugative-plasmid cointegrate from R. etli to a S. fredii strain, and at least two recombination events among the R. etli plasmids and the S. fredii genome. As in R. etli CFN42, the S. fredii GR64 transmissible plasmid is required for the conjugative transfer of the symbiotic plasmid. In spite of the similarity in the conjugation related genes, the transfer process of these plasmids shows a host-specific behaviour. PMID- 21702992 TI - Zinc finger protein ZBTB20 expression is increased in hepatocellular carcinoma and associated with poor prognosis. AB - BACKGROUND: Our previous studies showed that ZBTB20, a new BTB/POZ-domain gene, could negatively regulate alpha feto-protein and other liver-specific genes, concerning such as bio-transformation, glucose metabolism and the regulation of the somatotropic hormonal axis. The aim of this study is to determine the potential clinical implications of ZBTB20 in hepatocellular carcinoma (HCC). METHODS: Quantitative real-time RT-PCR and Western blot analyses were used to detect expression levels of ZBTB20 in 50 paired HCC tumorous and nontumorous tissues and in 20 normal liver tissues. Moreover, expression of ZBTB20 was assessed by immunohistochemistry of paired tumor and peritumoral liver tissue from 102 patients who had undergone hepatectomy for histologically proven HCC. And its relationship with clinicopathological parameters and prognosis was investigated. RESULTS: Both messenger RNA and protein expression levels of ZBTB20 were elevated significantly in HCC tissues compared with the paired non-tumor tissues and normal liver tissues. Overexpressed ZBTB20 protein in HCC was significantly associated with vein invasion (P=0.016). Importantly, the recurrence or metastasis rates of HCCs with higher ZBTB20 expression were markedly greater than those of HCCs with lower expression (P=0.003, P=0.00015, respectively). Univariate and multivariate analyses revealed that ZBTB20 overexpression was an independent prognostic factor for HCC. The disease-free survival period and over-all survival period in patients with overexpressed ZBTB20 in HCC was significantly reduced. CONCLUSIONS: The expression of ZBTB20 is increased in HCC and associated with poor prognosis in patients with HCC, implicating ZBTB20 as a candidate prognostic marker in HCC. PMID- 21702993 TI - The comparison of grey-scale ultrasonic and clinical features of hepatoblastoma and hepatocellular carcinoma in children: a retrospective study for ten years. AB - BACKGROUND: Hepatoblastoma (HBL) and hepatocellular carcinoma (HCC) are respectively the first and the second most common pediatric malignant liver tumors. The purpose of this study was to evaluate the combined use of the ultrasound examination and the assessment of the patients' clinical features for differentiating HBL from HCC in children. METHODS: Thirty cases of the confirmed HBL and 12 cases of the confirmed HCC in children under the age of 15 years were enrolled into our study. They were divided into the HBL group and the HCC group according to the histological types of the tumors. The ultrasonic features and the clinical manifestations of the two groups were retrospectively analyzed, with an emphasis on the following parameters: onset age, gender (male/female) ratio, positive epatitis-B-surface-antigen (HBV), alpha-fetoprotein increase, and echo features including septa, calcification and liquefaction within the tumors. RESULTS: Compared with the children with HCC, the children with HBL had a significantly younger onset age (8.2 years vs. 3.9 years, P < 0.001) and a significantly smaller frequency of positive HBV (66.7% vs. 13.3%, P < 0.001). The septa and liquefaction were more frequently found in HBL than in HCC (25/30, 83.3% vs. 2/12, 16.7%, P < 0.001; 17/30, 56.7% vs. 3/12, 25%, P = 0.02). When a combination of the liquefaction, septa, negative HBV and onset age smaller than 5 years was used in the evaluation, the sensitivity was raised to 90%, the accuracy was raised to 88%, and the negative predictive value was raised to 73%. CONCLUSION: Ultrasonic features combined with clinical manifestations are valuable for differentiating HBL from HCC in children. PMID- 21702994 TI - The actions of exogenous leucine on mTOR signalling and amino acid transporters in human myotubes. AB - BACKGROUND: The branched-chain amino acid (BCAA) leucine has been identified to be a key regulator of skeletal muscle anabolism. Activation of anabolic signalling occurs via the mammalian target of rapamycin (mTOR) through an undefined mechanism. System A and L solute carriers transport essential amino acids across plasma membranes; however it remains unknown whether an exogenous supply of leucine regulates their gene expression. The aim of the present study was to investigate the effects of acute and chronic leucine stimulation of anabolic signalling and specific amino acid transporters, using cultured primary human skeletal muscle cells. RESULTS: Human myotubes were treated with leucine, insulin or co-treated with leucine and insulin for 30 min, 3 h or 24 h. Activation of mTOR signalling kinases were examined, together with putative nutrient sensor human vacuolar protein sorting 34 (hVps34) and gene expression of selected amino acid transporters. Phosphorylation of mTOR and p70S6K was transiently increased following leucine exposure, independently to insulin. hVps34 protein expression was also significantly increased. However, genes encoding amino acid transporters were differentially regulated by insulin and not leucine. CONCLUSIONS: mTOR signalling is transiently activated by leucine within human myotubes independently of insulin stimulation. While this occurred in the absence of changes in gene expression of amino acid transporters, protein expression of hVps34 increased. PMID- 21702995 TI - Lung cancer in HIV patients and their parents: a Danish cohort study. AB - BACKGROUND: HIV patients are known to be at increased risk of lung cancer but the risk factors behind this are unclear. METHODS: We estimated the cumulative incidence and relative risk of lung cancer in 1) a population of all Danish HIV patients identified from the Danish HIV Cohort Study (n = 5,053) and a cohort of population controls matched on age and gender (n = 50,530) (study period; 1995 - 2009) and 2) their parents (study period; 1969 - 2009). Mortality and relative risk of death after a diagnosis of lung cancer was estimated in both populations. RESULTS: 29 (0.6%) HIV patients vs. 183 (0.4%) population controls were diagnosed with lung cancer in the observation period. HIV patients had an increased risk of lung cancer (adjusted incidence rate ratio (IRR); 2.38 (95% CI; 1.61 - 3.53)). The IRR was considerably increased in HIV patients who were smokers or former smokers (adjusted IRR; 4.06 (95% CI; 2.66 - 6.21)), male HIV patients with heterosexual route of infection (adjusted IRR; 4.19 (2.20 - 7.96)) and HIV patients with immunosuppression (adjusted IRR; 3.25 (2.01 - 5.24)). Both fathers and mothers of HIV patients had an increased risk of lung cancer (adjusted IRR for fathers; 1.31 (95% CI: 1.09 - 1.58), adjusted IRR for mothers 1.35 (95% CI: 1.07 - 1.70)). Mortality after lung cancer diagnose was increased in HIV patients (adjusted mortality rate ratio 2.33 (95%CI; 1.51 - 3.61), but not in the parents. All HIV patients diagnosed with lung cancer were smokers or former smokers. CONCLUSION: The risk was especially increased in HIV patients who were smokers or former smokers, heterosexually infected men or immunosuppressed. HIV appears to be a marker of behavioural or family related risk factors that affect the incidence of lung cancer in HIV patients. PMID- 21702996 TI - Assessing the association between all-cause mortality and multiple aspects of individual social capital among the older Japanese. AB - BACKGROUND: Few prospective cohort studies have assessed the association between social capital and mortality. The studies were conducted only in Western countries and did not use the same social capital indicators. The present prospective cohort study aimed to examine the relationships between various forms of individual social capital and all-cause mortality in Japan. METHODS: Self administered questionnaires were mailed to subjects in the Aichi Gerontological Evaluation Study (AGES) Project in 2003. Mortality data from 2003 to 2008 were analyzed for 14,668 respondents. Both cognitive and structural components of individual social capital were collected: 8 for cognitive social capital (trust, 3; social support, 3; reciprocity, 2) and 9 for structural social capital (social network). Cox proportional hazard models stratified by sex with multiple imputation were used. Age, body mass index, self-rated health, current illness, smoking history, alcohol consumption, exercise, equivalent income and education were used as covariates. RESULTS: During 27,571 person-years of follow-up for men and 29,561 person-years of follow-up for women, 790 deaths in men and 424 in women were observed. In the univariate analyses for men, lower social capital was significantly related to higher mortality in one general trust variable, all generalised reciprocity variables and four social network variables. For women, lower social capital was significantly related to higher mortality in all generalised reciprocity and four social network variables. After adjusting for covariates, lower friendship network was significantly associated with higher all cause mortality among men (meet friends rarely; HR = 1.30, 95%CI = 1.10-1.53) and women (having no friends; HR = 1.81, 95%CI = 1.02-3.23). Among women, lower general trust was significantly related to lower mortality (most people cannot be trusted; HR = 0.65, 95%CI = 0.45-0.96). CONCLUSIONS: Friendship network was a good predictor for all-cause mortality among older Japanese. In contrast, mistrust was associated with lower mortality among women. Studies with social capital indices considering different culture backgrounds are needed. PMID- 21702997 TI - Modulation of the Chlamydia trachomatis in vitro transcriptome response by the sex hormones estradiol and progesterone. AB - BACKGROUND: Chlamydia trachomatis is a major cause of sexually transmitted disease in humans. Previous studies in both humans and animal models of chlamydial genital tract infection have suggested that the hormonal status of the genital tract epithelium at the time of exposure can influence the outcome of the chlamydial infection. We performed a whole genome transcriptional profiling study of C. trachomatis infection in ECC-1 cells under progesterone or estradiol treatment. RESULTS: Both hormone treatments caused a significant shift in the sub set of genes expressed (25% of the transcriptome altered by more than 2-fold). Overall, estradiol treatment resulted in the down-regulation of 151 genes, including those associated with lipid and nucleotide metabolism. Of particular interest was the up-regulation in estradiol-supplemented cultures of six genes (omcB, trpB, cydA, cydB, pyk and yggV), which suggest a stress response similar to that reported previously in other models of chlamydial persistence. We also observed morphological changes consistent with a persistence response. By comparison, progesterone supplementation resulted in a general up-regulation of an energy utilising response. CONCLUSION: Our data shows for the first time, that the treatment of chlamydial host cells with key reproductive hormones such as progesterone and estradiol, results in significantly altered chlamydial gene expression profiles. It is likely that these chlamydial expression patterns are survival responses, evolved by the pathogen to enable it to overcome the host's innate immune response. The induction of chlamydial persistence is probably a key component of this survival response. PMID- 21702998 TI - Combined mRNA expression levels of members of the urokinase plasminogen activator (uPA) system correlate with disease-associated survival of soft-tissue sarcoma patients. AB - BACKGROUND: Members of the urokinase-type plasminogen activator (uPA) system are up-regulated in various solid malignant tumors. High antigen levels of uPA, its inhibitor PAI-1 and its receptor uPAR have recently been shown to be associated with poor prognosis in soft-tissue sarcoma (STS) patients. However, the mRNA expression of uPA system components has not yet been comprehensively investigated in STS patients. METHODS: The mRNA expression level of uPA, PAI-1, uPAR and an uPAR splice variant, uPAR-del4/5, was analyzed in tumor tissue from 78 STS patients by quantitative PCR. RESULTS: Elevated mRNA expression levels of PAI-1 and uPAR-del4/5 were significantly associated with clinical parameters such as histological subtype (P = 0.037 and P < 0.001, respectively) and higher tumor grade (P = 0.017 and P = 0.003, respectively). In addition, high uPAR-del4/5 mRNA values were significantly related to higher tumor stage of STS patients (P = 0.031). On the other hand, mRNA expression of uPA system components was not significantly associated with patients' survival. However, in STS patients with complete tumor resection (R0), high PAI-1 and uPAR-del4/5 mRNA levels were associated with a distinctly increased risk of tumor-related death (RR = 6.55, P = 0.054 and RR = 6.00, P = 0.088, respectively). Strikingly, R0 patients with both high PAI-1 and uPAR-del4/5 mRNA expression levels showed a significant, 19 fold increased risk of tumor-related death (P = 0.044) compared to the low expression group. CONCLUSION: Our results suggest that PAI-1 and uPAR-del4/5 mRNA levels may add prognostic information in STS patients with R0 status and distinguish a subgroup of R0 patients with low PAI-1 and/or low uPAR-del4/5 values who have a better outcome compared to patients with high marker levels. PMID- 21702999 TI - HPV types, HIV and invasive cervical carcinoma risk in Kampala, Uganda: a case control study. AB - BACKGROUND: While the association of human papillomavirus (HPV) with cervical cancer is well established, the influence of HIV on the risk of this disease in sub-Saharan Africa remains unclear. To assess the risk of invasive cervical carcinoma (ICC) associated with HIV and HPV types, a hospital-based case-control study was performed between September 2004 and December 2006 in Kampala, Uganda. Incident cases of histologically-confirmed ICC (N=316) and control women (N=314), who were visitors or care-takers of ICC cases in the hospital, were recruited. Blood samples were obtained for HIV serology and CD4 count, as well as cervical samples for HPV testing. HPV DNA detection and genotyping was performed using the SPF10/DEIA/LiPA25 technique which detects all mucosal HPV types by DEIA and identifies 25 HPV genotypes by LiPA version 1. Samples that tested positive but could not be genotyped were designated HPVX. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by logistic regression, adjusting for possible confounding factors. RESULTS: For both squamous cell carcinoma (SCC) and adenocarcinoma of the cervix, statistically significantly increased ORs were found among women infected with HPV, in particular single HPV infections, infections with HPV16-related types and high-risk HPV types, in particular HPV16, 18 and 45. For other HPV types the ORs for both SCC and adenocarcinoma were not statistically significantly elevated. HIV infection and CD4 count were not associated with SCC or adenocarcinoma risk in our study population. Among women infected with high-risk HPV types, no association between HIV and SCC emerged. However, an inverse association with adenocarcinoma was observed, while decrease in CD4 count was not associated with ICC risk. CONCLUSIONS: The ORs for SCC and adenocarcinoma were increased in women infected with HPV, in particular single HPV infections, infections with HPV16- and 18-related types, and high-risk HPV types, specifically HPV16, 18 and 45. HIV infection and CD4 count were not associated with SCC or adenocarcinoma risk, but among women infected with high risk HPV types there was an inverse association between HIV infection and adenocarcinoma risk. These results suggest that HIV and CD4 count may have no role in the progression of cervical cancer. PMID- 21703000 TI - Telephone and face to face methods of assessment of veteran's community reintegration yield equivalent results. AB - BACKGROUND: The Community Reintegration of Service Members (CRIS) is a new measure of community reintegration developed to measure veteran's participation in life roles. It consists of three sub-scales: Extent of Participation (Extent), Perceived Limitations with Participation (Perceived), and Satisfaction with Participation (Satisfaction). Testing of the CRIS measure to date has utilized in person administration. Administration of the CRIS measure by telephone, if equivalent to in-person administration, would be desirable to lower cost and decrease administrative burden. The purpose of this study was to test the equivalence of telephone and in-person mode of CRIS administration. METHODS: A convenience sample of 102 subjects (76% male, 24% female, age mean = 49 years, standard deviation = 8.3) were randomly assigned to received either telephone interview at Visit 1 and in-person interview at Visit 2, or in-person interview at Visit 1 and telephone interview a Visit 2. Both Visits were conducted within one week. Intraclass correlation coefficients, ICC (2,1), were used to evaluate correspondence between modes for both item scores and summary scores. ANOVAs with mode order as a covariate were used to test for presence of an ordering effect. RESULTS: ICCs (95%CI) for the subscales were 0.92 (0.88-0.94) for Extent, 0.85 (0.80-0.90) for Perceived, and 0.89 (0.84-0.93) for Satisfaction. No ordering effect was observed. CONCLUSION: Telephone administration of the CRIS measure yielded equivalent results to in-person administration. Telephone administration of the CRIS may enable lower costs of administration and greater adoption. PMID- 21703002 TI - Periodic lateralized epileptiform discharges as manifestation of pneumococcal meningoencephalitis. AB - Periodic Lateralized Epileptiform Discharges (PLEDs) are usually seen in the context of destructive structural lesions of the cortex, more frequently in acute ischemic stroke and less common in tumours and meningoencephalitis, specially herpes simplex virus. Its origin and prognosis are uncertain but it is known that PLEDs are linked to epilectic seizures, including status epilepticus.We report on a 75-year old woman with pneumococcal meningoencephalitis who presented altered level of consciousness, acute focal deficits, convulsive seizures and PLEDs in left hemisphere. The finding of PLEDs on the electroencephalogram is related to focal lesions of heterogeneous origin, which up to date, have not been documented in pneumococcal infections of the central nervous system. Our case highlights the importance of identifying and addressing any modifiable etiologic factors of PLEDs. PMID- 21703001 TI - Patient education integrated with acupuncture for relief of cancer-related fatigue randomized controlled feasibility study. AB - BACKGROUND: Cancer-related fatigue (CRF) is a prominent clinical problem. There are calls for multi-modal interventions. METHODS: We assessed the feasibility of delivering patient education integrated with acupuncture for relief of CRF in a pilot randomized controlled trial (RCT) with breast cancer survivors using usual care as control. Social cognitive and integrative medicine theories guided integration of patient education with acupuncture into a coherent treatment protocol. The intervention consisted of two parts. First, patients were taught to improve self-care by optimizing exercise routines, improving nutrition, implementing some additional evidence-based cognitive behavioral techniques such as stress management in four weekly 50-minute sessions. Second, patients received eight weekly 50-minute acupuncture sessions. The pre-specified primary outcome, CRF, was assessed with the Brief Fatigue Inventory (BFI). Secondary outcomes included three dimensions of cognitive impairment assessed with the FACT-COGv2. RESULTS: Due to difficulties in recruitment, we tried several methods that led to the development of a tailored recruitment strategy: we enlisted oncologists into the core research team and recruited patients completing treatment from oncology waiting rooms. Compared to usual care control, the intervention was associated with a 2.38-point decline in fatigue as measured by the BFI (90% Confidence Interval from 0.586 to 5.014; p <0.10). Outcomes associated with cognitive dysfunction were not statistically significant. CONCLUSIONS: Patient education integrated with acupuncture had a very promising effect that warrants conducting a larger RCT to confirm findings. An effective recruitment strategy will be essential for the successful execution of a larger-scale trial. TRIAL REGISTRATION: NCT00646633. PMID- 21703003 TI - The effectiveness of manual stretching in the treatment of plantar heel pain: a systematic review. AB - BACKGROUND: Plantar heel pain is a commonly occurring foot complaint. Stretching is frequently utilised as a treatment, yet a systematic review focusing only on its effectiveness has not been published. This review aimed to assess the effectiveness of stretching on pain and function in people with plantar heel pain. METHODS: Medline, EMBASE, CINAHL, AMED, and The Cochrane Library were searched from inception to July 2010. Studies fulfilling the inclusion criteria were independently assessed, and their quality evaluated using the modified PEDro scale. RESULTS: Six studies including 365 symptomatic participants were included. Two compared stretching with a control, one study compared stretching to an alternative intervention, one study compared stretching to both alternative and control interventions, and two compared different stretching techniques and durations. Quality rating on the modified Pedro scale varied from two to eight out of a maximum of ten points. The methodologies and interventions varied significantly between studies, making meta-analysis inappropriate. Most participants improved over the course of the studies, but when stretching was compared to alternative or control interventions, the changes only reached statistical significance in one study that used a combination of calf muscle stretches and plantar fascia stretches in their stretching programme. Another study comparing different stretching techniques, showed a statistically significant reduction in some aspects of pain in favour of plantar fascia stretching over calf stretches in the short term. CONCLUSIONS: There were too few studies to assess whether stretching is effective compared to control or other interventions, for either pain or function. However, there is some evidence that plantar fascia stretching may be more effective than Achilles tendon stretching alone in the short-term. Appropriately powered randomised controlled trials, utilizing validated outcome measures, blinded assessors and long-term follow up are needed to assess the efficacy of stretching. PMID- 21703004 TI - Feasibility and validity of accelerometer measurements to assess physical activity in toddlers. AB - BACKGROUND: Accelerometers are considered to be the most promising tool for measuring physical activity (PA) in free-living young children. So far, no studies have examined the feasibility and validity of accelerometer measurements in children under 3 years of age. Therefore, the purpose of the present study was to examine the feasibility and validity of accelerometer measurements in toddlers (1- to 3-year olds). METHODS: Forty-seven toddlers (25 boys; 20 +/- 4 months) wore a GT1M ActiGraph accelerometer for 6 consecutive days and parental perceptions of the acceptability of wearing the monitor were assessed to examine feasibility. To investigate the validity of the ActiGraph and the predictive validity of three ActiGraph cut points, accelerometer measurements of 31 toddlers (17 boys; 20 +/- 4 months) during free play at child care were compared to directly observed PA, using the Observational System for Recording Physical Activity in Children-Preschool (OSRAC-P). Validity was assessed using Pearson and Spearman correlations and predictive validity using area under the Receiver Operating Characteristic curve (ROC-AUC). RESULTS: The feasibility examination indicated that accelerometer measurements of 30 toddlers (63.8%) could be included with a mean registration time of 564 +/- 62 min during weekdays and 595 +/- 83 min during weekend days. According to the parental reports, 83% perceived wearing the accelerometer as 'not unpleasant and not pleasant' and none as 'unpleasant'. The validity evaluation showed that mean ActiGraph activity counts were significantly and positively associated with mean OSRAC-P activity intensity (r = 0.66; p < 0.001; n = 31). Further, the correlation among the ActiGraph activity counts and the OSRAC-P activity intensity level during each observation interval was significantly positive (rho = 0.52; p < 0.001; n = 4218). Finally, the three sedentary cut points exhibited poor to fair classification accuracy (ROC-AUC: 0.56 to 0.71) while the three light PA (ROC-AUC: 0.51 to 0.62) and the three moderate-to-vigorous PA cut points (ROC-AUC: 0.53 to 0.57) demonstrated poor classification accuracy with respect to detecting sedentary behavior, light PA and moderate-to-vigorous PA, respectively. CONCLUSIONS: The present findings suggest that ActiGraph accelerometer measurements are feasible and valid for quantifying PA in toddlers. However, further research is needed to accurately identify PA intensities in toddlers using accelerometry. PMID- 21703005 TI - Phylogenetic analysis of porcine parvoviruses from swine samples in China. AB - BACKGROUND: Porcine parvovirus (PPV) usually causes reproductive failure in sows. The objective of the present study was to analyze the phylogenetic distribution and perform molecular characterization of PPVs isolated in China, as well as to identify two field strains, LZ and JY. The data used in this study contained the available sequences for NS1 and VP2 from GenBank, as well as the two aforementioned Chinese strains. RESULTS: Phylogenetic analysis shows that the PPV sequences are divided into four groups. The early Chinese PPV isolates are Group I viruses, and nearly all of the later Chinese PPV isolates are Group II viruses. LZ belongs to group II, whereas the JY strain is a Group III virus. This is the first report on the isolation of a Group III virus in China. The detection of selective pressures on the PPV genome shows that the NS1 and VP2 genes are under purifying selection and positive selection, respectively. Moreover, the amino acids in the VP2 capsid are highly variable because of the positive selection. CONCLUSIONS: Our study provides new molecular data on PPV strains in China, and emphasizes the importance of etiological studies of PPV in pigs. PMID- 21703006 TI - Integrative network analysis reveals active microRNAs and their functions in gastric cancer. AB - BACKGROUND: MicroRNAs (miRNAs) are a class of endogenous, small and highly conserved noncoding RNAs that control gene expression either by degradation of target mRNAs or by inhibition of protein translation. They play important roles in cancer progression. A single miRNA can provoke a chain reaction and further affect protein interaction network (PIN). Therefore, we developed a novel integrative approach to identify the functional roles and the regulated PIN of oncomirs. RESULTS: We integrated the expression profiles of miRNA and mRNA with the human PIN to reveal miRNA-regulated PIN in specific biological conditions. The potential functions of miRNAs were determined by functional enrichment analysis and the activities of miRNA-regulated PINs were evaluated by the co expression of protein-protein interactions (PPIs). The function of a specific miRNA, miR-148a, was further examined by clinical data analysis and cell-based experiments. We uncovered several miRNA-regulated networks which were enriched with functions related to cancer progression. One miRNA, miR-148a, was identified and its function is to decrease tumor proliferation and metastasis through its regulated PIN. Furthermore, we found that miR-148a could reduce the invasiveness, migratory and adhesive activities of gastric tumor cells. Most importantly, elevated miR-148a level in gastric cancer tissues was strongly correlated with distant metastasis, organ and peritoneal invasion and reduced survival rate. CONCLUSIONS: This study provides a novel method to identify active oncomirs and their potential functions in gastric cancer progression. The present data suggest that miR-148a could be a potential prognostic biomarker of gastric cancer and function as a tumor suppressor through repressing the activity of its regulated PIN. PMID- 21703007 TI - PlantPhos: using maximal dependence decomposition to identify plant phosphorylation sites with substrate site specificity. AB - BACKGROUND: Protein phosphorylation catalyzed by kinases plays crucial regulatory roles in intracellular signal transduction. Due to the difficulty in performing high-throughput mass spectrometry-based experiment, there is a desire to predict phosphorylation sites using computational methods. However, previous studies regarding in silico prediction of plant phosphorylation sites lack the consideration of kinase-specific phosphorylation data. Thus, we are motivated to propose a new method that investigates different substrate specificities in plant phosphorylation sites. RESULTS: Experimentally verified phosphorylation data were extracted from TAIR9-a protein database containing 3006 phosphorylation data from the plant species Arabidopsis thaliana. In an attempt to investigate the various substrate motifs in plant phosphorylation, maximal dependence decomposition (MDD) is employed to cluster a large set of phosphorylation data into subgroups containing significantly conserved motifs. Profile hidden Markov model (HMM) is then applied to learn a predictive model for each subgroup. Cross-validation evaluation on the MDD-clustered HMMs yields an average accuracy of 82.4% for serine, 78.6% for threonine, and 89.0% for tyrosine models. Moreover, independent test results using Arabidopsis thaliana phosphorylation data from UniProtKB/Swiss Prot show that the proposed models are able to correctly predict 81.4% phosphoserine, 77.1% phosphothreonine, and 83.7% phosphotyrosine sites. Interestingly, several MDD-clustered subgroups are observed to have similar amino acid conservation with the substrate motifs of well-known kinases from Phospho.ELM-a database containing kinase-specific phosphorylation data from multiple organisms. CONCLUSIONS: This work presents a novel method for identifying plant phosphorylation sites with various substrate motifs. Based on cross-validation and independent testing, results show that the MDD-clustered models outperform models trained without using MDD. The proposed method has been implemented as a web-based plant phosphorylation prediction tool, PlantPhos http://csb.cse.yzu.edu.tw/PlantPhos/. Additionally, two case studies have been demonstrated to further evaluate the effectiveness of PlantPhos. PMID- 21703008 TI - Evaluation of several adjuvants in avian influenza vaccine to chickens and ducks. AB - The effects of three different adjuvants, mineral oil, MontanideTM ISA 70M VG, and MontanideTM ISA 206 VG, were evaluated on reverse genetics H5N3 avian influenza virus cell cultured vaccine. The immune results of SPF chickens after challenging with highly pathogenic avian influenza (HPAI) virus demonstrated that mineral oil adjuvant group and 70M adjuvant group provided 100% protection efficiency, but 206 adjuvant group provided only 40%. Statistical analysis indicated that the protection effects of mineral oil adjuvant group and the 70M adjuvant showed no significant difference to each other, but with significant difference to 206 adjuvant group. All three groups could induce high titres of antibody after immunizing SPF ducks, but there was no significant difference among them. The immunization effect of 70M adjuvant group on SPF chickens were the best and showed significant difference compared with optimized 70Mi MontanideTM eight series adjuvants groups. These results suggest that 70M adjuvant could be a novel adjuvant for preparing avian influenza vaccine. PMID- 21703009 TI - Real-time PCR assay and rapid diagnostic tests for the diagnosis of clinically suspected malaria patients in Bangladesh. AB - BACKGROUND: More than 95% of total malaria cases in Bangladesh are reported from the 13 high endemic districts. Plasmodium falciparum and Plasmodium vivax are the two most abundant malaria parasites in the country. To improve the detection and management of malaria patients, the National Malaria Control Programme (NMCP) has been using rapid diagnostic test (RDT) in the endemic areas. A study was conducted to establish a SYBR Green-based modified real-time PCR assay as a gold standard to evaluate the performance of four commercially-available malaria RDTs, along with the classical gold standard- microscopy. METHODS: Blood samples were collected from 338 febrile patients referred for the diagnosis of malaria by the attending physician at MatirangaUpazila Health Complex (UHC) from May 2009 to August 2010. Paracheck RDT and microscopy were performed at the UHC. The blood samples were preserved in EDTA tubes. A SYBR Green-based real-time PCR assay was performed and evaluated. The performances of the remaining three RDTs (Falcivax, Onsite Pf and Onsite Pf/Pv) were also evaluated against microscopy and real-time PCR using the stored blood samples. RESULT: In total, 338 febrile patients were enrolled in the study. Malaria parasites were detected in 189 (55.9%) and 188 (55.6%) patients by microscopy and real-time PCR respectively. Among the RDTs, the highest sensitivity for the detection of P. falciparum (including mixed infection) was obtained by Paracheck [98.8%, 95% confidence interval (CI) 95.8 99.9] and Falcivax (97.6%, 95% CI 94.1-99.4) compared to microscopy and real-time PCR respectively. Paracheck and Onsite Pf/Pv gave the highest specificity (98.8%, 95% CI 95.7-99.9) compared to microscopy and Onsite Pf/Pv (98.8, 95% CI 95.8 99.9) compared to real-time PCR respectively for the detection of P. falciparum. On the other hand Falcivax and Onsite Pf/Pv had equal sensitivity (90.5%, 95% CI 69.6-98.8) and almost 100% specificity compared to microscopy for the detection of P. vivax. However, compared to real-time PCR assay RDTs and microscopy gave low sensitivity (76.9%, 95% CI 56.4-91) in detecting of P. vivax although a very high specificity was obtained (99-100%). CONCLUSION: The results of this study suggest that the SYBR Green-based real-time PCR assay could be used as an alternative gold standard method in a reference setting. Commercially-available RDTs used in the study are quite sensitive and specific in detecting P. falciparum, although their sensitivity in detecting P. vivax was not satisfactory compared to the real-time PCR assay. PMID- 21703010 TI - Patient and general practitioner attitudes to taking medication to prevent cardiovascular disease after receiving detailed information on risks and benefits of treatment: a qualitative study. AB - BACKGROUND: There are now effective drugs to prevent cardiovascular disease and guidelines recommend their use. Patients do not always choose to accept preventive medication at levels of risk reduction recommended in guidelines. The purpose of the study was to identify and explore the attitudes of patients and general practitioners towards preventative medication for cardiovascular disease (CVD) after they have received information about it; to identify implications for practice and prescribing. METHODS: Qualitative interviews with GPs and patients following presentation of in depth information about CVD risks and the absolute effects of medication. SETTING: GP practices in Birmingham, United Kingdom. RESULTS: In both populations: wide variation on attitudes to preventative medication; concerns about unnecessary drug taking & side effects; preferring to consider lifestyle changes first. In patient population: whatever their attitudes to medication were, the vast majority explained that they would ultimately do what their GP recommended; there was some misunderstanding of the distinction between curative and preventative medication. A common theme was the degree of trust in their doctors' judgement and recommendations, which contrasted with scepticism of the role of pharmaceutical companies and academics. Scepticism in guidelines was also common among doctors although many nevertheless recommended treatment for their patients CONCLUSIONS: A guideline approach to prescribing preventative medication could be against the interests and preferences of the patient. GPs must take extra care to explain what preventative medication is and why it is recommended, attempt to discern preferences and make recommendations balancing these potentially conflicting concerns. PMID- 21703011 TI - Altered efficacy of AT1R-targeted treatment after spontaneous cancer cell-AT1R upregulation. AB - BACKGROUND: Targeting of the renin angiotensin system (RAS) reduces tumour growth in experimental models of cancer. We aimed to establish if combined targeting of the 'classical' and 'alternative' arms of the RAS could result in synergistic inhibition of colorectal cancer (CRC) liver metastases. METHODS: Immediately following induction of CRC liver metastases through intrasplenic injection of murine CRC cells, treatment with irbesartan (AT1R blocker; 50 mg/kg/day s.c.), captopril (ACE inhibitor; 750 mg/kg/day i.p.), CGP42112A (AT2R agonist; 0.6 MUg/kg/hr i.p.), and/or ANG-(1-7) (24 MUg/kg/hr i.p.) began and continued for 21 days. Liver to body weight ratio and/or stereology were used as a measure of tumour burden. Immunohistochemistry was used to determine AT1R and VEGF expression as well as proliferation (Ki67), apoptosis (active caspase 3) and angiogenesis (CD34). RESULTS: Combined RAS therapies failed to improve upon single arm therapies. However, while irbesartan previously inhibited tumour growth in this model, in the current experiments irbesartan failed to affect tumour burden. Subsequent analysis showed a cancer-cell specific upregulation of the angiotensin II type I receptor (AT1R) in irbesartan-insensitive compared to irbesartan-sensitive tumours. The upregulation of AT1R was associated with an increase in proliferation and VEGF expression by cancer cells. While animals bearing irbesartan-sensitive tumours showed a marked decrease in the number of proliferating cells in the liver and VEGF-expressing infiltrating cells in the tumour following AT1R treatment, these were unchanged by treatment in animals bearing irbesartan-insensitive (high AT1R expressing) tumours. CONCLUSIONS: Although the results do not support increased efficacy of combined treatment, they provide intriguing evidence of the importance of RAS expression in determining patient response and tumour growth potential and suggest that components of the RAS could be used as biomarkers to aid in patient selection. PMID- 21703012 TI - Ethnic differences in body fat distribution among Asian pre-pubertal children: a cross-sectional multicenter study. AB - BACKGROUND: Ethnic differences in body fat distribution contribute to ethnic differences in cardiovascular morbidities and diabetes. However few data are available on differences in fat distribution in Asian children from various backgrounds. Therefore, the current study aimed to explore ethnic differences in body fat distribution among Asian children from four countries. METHODS: A total of 758 children aged 8-10 y from China, Lebanon, Malaysia and Thailand were recruited using a non-random purposive sampling approach to enrol children encompassing a wide BMI range. Height, weight, waist circumference (WC), fat mass (FM, derived from total body water [TBW] estimation using the deuterium dilution technique) and skinfold thickness (SFT) at biceps, triceps, subscapular, supraspinale and medial calf were collected. RESULTS: After controlling for height and weight, Chinese and Thai children had a significantly higher WC than their Lebanese and Malay counterparts. Chinese and Thais tended to have higher trunk fat deposits than Lebanese and Malays reflected in trunk SFT, trunk/upper extremity ratio or supraspinale/upper extremity ratio after adjustment for age and total body fat. The subscapular/supraspinale skinfold ratio was lower in Chinese and Thais compared with Lebanese and Malays after correcting for trunk SFT. CONCLUSIONS: Asian pre-pubertal children from different origins vary in body fat distribution. These results indicate the importance of population-specific WC cut-off points or other fat distribution indices to identify the population at risk of obesity-related health problems. PMID- 21703013 TI - Stratified sampling design and loss to follow-up in survival models: evaluation of efficiency and bias. AB - BACKGROUND: Longitudinal studies often employ complex sample designs to optimize sample size, over-representing population groups of interest. The effect of sample design on parameter estimates is quite often ignored, particularly when fitting survival models. Another major problem in long-term cohort studies is the potential bias due to loss to follow-up. METHODS: In this paper we simulated a dataset with approximately 50,000 individuals as the target population and 15,000 participants to be followed up for 40 years, both based on real cohort studies of cardiovascular diseases. Two sample strategies--simple random (our golden standard) and Stratified by professional group, with non-proportional allocation- and two loss to follow-up scenarios--non-informative censoring and losses related to the professional group--were analyzed. RESULTS: Two modeling approaches were evaluated: weighted and non-weighted fit. Our results indicate that under the correctly specified model, ignoring the sample weights does not affect the results. However, the model ignoring the interaction of sample strata with the variable of interest and the crude estimates were highly biased. CONCLUSIONS: In epidemiological studies misspecification should always be considered, as different sources of variability, related to the individuals and not captured by the covariates, are always present. Therefore, allowance must be made for the possibility of unknown confounders and interactions with the main variable of interest in our data. It is strongly recommended always to correct by sample weights. PMID- 21703014 TI - Immunoproteomic analysis of bacterial proteins of Actinobacillus pleuropneumoniae serotype 1. AB - BACKGROUND: Actinobacillus pleuropneumoniae (APP) is one of the most important swine pathogens worldwide. Identification and characterization of novel antigenic APP vaccine candidates are underway. In the present study, we use an immunoproteomic approach to identify APP protein antigens that may elicit an immune response in serotype 1 naturally infected swine and serotype 1 virulent strain S259-immunized rabbits. RESULTS: Proteins from total cell lysates of serotype 1 APP were separated by two-dimensional electrophoresis (2DE). Western blot analysis revealed 21 immunoreactive protein spots separated in the pH 4-7 range and 4 spots in the pH 7-11 range with the convalescent sera from swine; we found 5 immunoreactive protein spots that separated in the pH 4-7 range and 2 in the pH 7-11 range with hyperimmune sera from S259-immunized rabbits. The proteins included the known antigens ApxIIA, protective surface antigen D15, outer membrane proteins P5, subunit NqrA. The remaining antigens are being reported as immunoreactive proteins in APP for the first time, to our knowledge. CONCLUSIONS: We identified a total of 42 immunoreactive proteins of the APP serotype 1 virulent strain S259 which represented 32 different proteins, including some novel immunoreactive factors which could be researched as vaccine candidates. PMID- 21703015 TI - Molecular epidemiology of dengue viruses in southern China from 1978 to 2006. AB - To investigate molecular epidemiology of dengue viruses (DENV) in southern China, a total of 14 dengue isolates were collected in southern China during each epidemic year between 1978 and 2006 and their full-length genome sequences were obtained by using RT-PCR method. The E gene sequences from additional 6 dengue fever patients in Guangzhou in 2006 were also obtained by using RT-PCR method. Combined with DENVs sequences published in GenBank, phylogenetic analysis and recombination analysis were performed. One hundred and twenty-five E gene sequences and 60 complete genome sequences published in the GenBank were also involved. Phylogenetic analysis showed that there was a wide genetic diversity of DENVs isolated in southern China. DENV-1 strains exist in almost all of the clades of genotype I and IV except the Asia 1 clade of genotype I; DENV-2 stains are grouped into four of the five genotypes except American genotype. DENV-4 strains are grouped into 2 genotypes (I and II). Phylogenetic analysis also showed that all DENV-4 isolates and two DENV-2 isolates were closely related to the prior isolates from neighboring Southeast Asia countries. The DENV-1 strain isolated during the 2006 epidemic is highly homologous to the strains isolated during the 2001 epidemic.Recombination analysis showed no inter-serotype recombination, but 22 intra-serotype recombination events were found across the 32 complete genomes of all Chinese isolates. The study suggested that dengue fever epidemic in Southern China over the past 30 years presented two important modes, 1) imported-cases-induced endemic prevalence; 2) endogenous epidemic outbreak with natural epidemic focus. Recombination may play an important role in dengue virus evolution and adaptation. PMID- 21703017 TI - Consumer input into research: the Australian Cancer Trials website. AB - BACKGROUND: The Australian Cancer Trials website (ACTO) was publicly launched in 2010 to help people search for cancer clinical trials recruiting in Australia, provide information about clinical trials and assist with doctor-patient communication about trials. We describe consumer involvement in the design and development of ACTO and report our preliminary patient evaluation of the website. METHODS: Consumers, led by Cancer Voices NSW, provided the impetus to develop the website. Consumer representative groups were consulted by the research team during the design and development of ACTO which combines a search engine, trial details, general information about trial participation and question prompt lists. Website use was analysed. A patient evaluation questionnaire was completed at one hospital, one week after exposure to the website. RESULTS: ACTO's main features and content reflect consumer input. In February 2011, it covered 1, 042 cancer trials. Since ACTO's public launch in November 2010, until the end of February 2011, the website has had 2, 549 new visits and generated 17, 833 page views. In a sub-study of 47 patient users, 89% found the website helpful for learning about clinical trials and all respondents thought patients should have access to ACTO. CONCLUSIONS: The development of ACTO is an example of consumers working with doctors, researchers and policy makers to improve the information available to people whose lives are affected by cancer and to help them participate in their treatment decisions, including consideration of clinical trial enrolment. Consumer input has ensured that the website is informative, targets consumer priorities and is user-friendly. ACTO serves as a model for other health conditions. PMID- 21703016 TI - Accuracy of malaria rapid diagnostic tests in community studies and their impact on treatment of malaria in an area with declining malaria burden in north-eastern Tanzania. AB - BACKGROUND: Despite some problems related to accuracy and applicability of malaria rapid diagnostic tests (RDTs), they are currently the best option in areas with limited laboratory services for improving case management through parasitological diagnosis and reducing over-treatment. This study was conducted in areas with declining malaria burden to assess; 1) the accuracy of RDTs when used at different community settings, 2) the impact of using RDTs on anti malarial dispensing by community-owned resource persons (CORPs) and 3) adherence of CORPs to treatment guidelines by providing treatment based on RDT results. METHODS: Data were obtained from: 1) a longitudinal study of passive case detection of fevers using CORPs in six villages in Korogwe; and 2) cross sectional surveys (CSS) in six villages of Korogwe and Muheza districts, north eastern, Tanzania. Performance of RDTs was compared with microscopy as a gold standard, and factors affecting their accuracy were explored using a multivariate logistic regression model. RESULTS: Overall sensitivity and specificity of RDTs in the longitudinal study (of 23,793 febrile cases; 18,154 with microscopy and RDTs results) were 88.6% and 88.2%, respectively. In the CSS, the sensitivity was significantly lower (63.4%; chi2=367.7, p<0.001), while the specificity was significantly higher (94.3%; chi2=143.1, p<0.001) when compared to the longitudinal study. As determinants of sensitivity of RDTs in both studies, parasite density of<200 asexual parasites/MUl was significantly associated with high risk of false negative RDTs (OR>=16.60, p<0.001), while the risk of false negative test was significantly lower among cases with fever (axillary temperature >=37.5 degrees C) (OR<=0.63, p<=0.027). The risk of false positive RDT (as a determinant of specificity) was significantly higher in cases with fever compared to afebrile cases (OR>=2.40, p<0.001). Using RDTs reduced anti malarials dispensing from 98.9% to 32.1% in cases aged >=5 years. CONCLUSION: Although RDTs had low sensitivity and specificity, which varied widely depending on fever and parasite density, using RDTs reduced over-treatment with anti malarials significantly. Thus, with declining malaria prevalence, RDTs will potentially identify majority of febrile cases with parasites and lead to improved management of malaria and non-malaria fevers. PMID- 21703018 TI - Spatial patterns of malaria in a land reform colonization project, Juruena municipality, Mato Grosso, Brazil. AB - BACKGROUND: In Brazil, 99% of malaria cases are concentrated in the Amazon, and malaria's spatial distribution is commonly associated with socio-environmental conditions on a fine landscape scale. In this study, the spatial patterns of malaria and its determinants in a rural settlement of the Brazilian agricultural reform programme called "Vale do Amanhecer" in the northern Mato Grosso state were analysed. METHODS: In a fine-scaled, exploratory ecological study, geocoded notification forms corresponding to malaria cases from 2005 were compared with spectral indices, such as the Normalized Difference Vegetation Index (NDVI) and the third component of the Tasseled Cap Transformation (TC_3) and thematic layers, derived from the visual interpretation of multispectral TM-Landsat 5 imagery and the application of GIS distance operators. RESULTS: Of a total of 336 malaria cases, 102 (30.36%) were caused by Plasmodium falciparum and 174 (51.79%) by Plasmodium vivax. Of all the cases, 37.6% (133 cases) were from residents of a unique road. In total, 276 cases were reported for the southern part of the settlement, where the population density is higher, with notification rates higher than 10 cases per household. The local landscape mostly consists of open areas (38.79 km2). Training forest occupied 27.34 km2 and midsize vegetation 7.01 km2. Most domiciles with more than five notified malaria cases were located near areas with high NDVI values. Most domiciles (41.78%) and malaria cases (44.94%) were concentrated in areas with intermediate values of the TC_3, a spectral index representing surface and vegetation humidity. CONCLUSIONS: Environmental factors and their alteration are associated with the occurrence and spatial distribution of malaria cases in rural settlements. PMID- 21703020 TI - Modeling and measuring intracellular fluxes of secreted recombinant protein in Pichia pastoris with a novel 34S labeling procedure. AB - BACKGROUND: The budding yeast Pichia pastoris is widely used for protein production. To determine the best suitable strategy for strain improvement, especially for high secretion, quantitative data of intracellular fluxes of recombinant protein are very important. Especially the balance between intracellular protein formation, degradation and secretion defines the major bottleneck of the production system. Because these parameters are different for unlimited growth (shake flask) and carbon-limited growth (bioreactor) conditions, they should be determined under "production like" conditions. Thus labeling procedures must be compatible with minimal production media and the usage of bioreactors. The inorganic and non-radioactive 34S labeled sodium sulfate meets both demands. RESULTS: We used a novel labeling method with the stable sulfur isotope 34S, administered as sodium sulfate, which is performed during chemostat culivations. The intra- and extracellular sulfur 32 to 34 ratios of purified recombinant protein, the antibody fragment Fab3H6, are measured by HPLC-ICP-MS. The kinetic model described here is necessary to calculate the kinetic parameters from sulfur ratios of consecutive samples as well as for sensitivity analysis. From the total amount of protein produced intracellularly (143.1 MUg g-1 h-1 protein per yeast dry mass and time) about 58% are degraded within the cell, 35% are secreted to the exterior and 7% are inherited to the daughter cells. CONCLUSIONS: A novel 34S labeling procedure that enables in vivo quantification of intracellular fluxes of recombinant protein under "production like" conditions is described. Subsequent sensitivity analysis of the fluxes by using MATLAB, indicate the most promising approaches for strain improvement towards increased secretion. PMID- 21703019 TI - Transcription and translation of human F11R gene are required for an initial step of atherogenesis induced by inflammatory cytokines. AB - BACKGROUND: The F11 Receptor (F11R; aka JAM-A, JAM-1) is a cell adhesion protein present constitutively on the membrane surface of circulating platelets and within tight junctions of endothelial cells (ECs). Previous reports demonstrated that exposure of ECs to pro-inflammatory cytokines causes insertion of F11R molecules into the luminal surface of ECs, ensuing with homologous interactions between F11R molecules of platelets and ECs, and a resultant adhesion of platelets to the inflamed ECs. The main new finding of the present report is that the first step in this chain of events is the de-novo transcription and translation of F11R molecules, induced in ECs by exposure to inflammatory cytokines. METHODS: The experimental approach utilized isolated, washed human platelet suspensions and cultured human venous endothelial cells (HUVEC) and human arterial endothelial cells (HAEC) exposed to the proinflammatory cytokines TNF-alpha and/or IFN-gamma, for examination of the ability of human platelets to adhere to the inflamed ECs thru the F11R. Our strategy was based on testing the effects of the following inhibitors on this activity: general mRNA synthesis inhibitors, inhibitors of the NF-kappaB and JAK/STAT pathways, and small interfering F11R-mRNA (siRNAs) to specifically silence the F11R gene. RESULTS: Treatment of inflamed ECs with the inhibitors actinomycin, parthenolide or with AG-480 resulted in complete blockade of F11R- mRNA expression, indicating the involvement of NF-kappaB and JAK/STAT pathways in this induction. Transfection of ECs with F11R siRNAs caused complete inhibition of the cytokine-induced upregulation of F11R mRNA and inhibition of detection of the newly- translated F11R molecules in cytokine-inflamed ECs. The functional consequence of the inhibition of F11R transcription and translation was the significant blockade of the adhesion of human platelets to inflamed ECs. CONCLUSION: These results prove that de novo synthesis of F11R in ECs is required for the adhesion of platelets to inflamed ECs. Because platelet adhesion to an inflamed endothelium is crucial for plaque formation in non-denuded blood vessels, we conclude that the de-novo translation of F11R is a crucial early step in the initiation of atherogenesis, leading to atherosclerosis, heart attacks and stroke. PMID- 21703021 TI - Allele coding in genomic evaluation. AB - BACKGROUND: Genomic data are used in animal breeding to assist genetic evaluation. Several models to estimate genomic breeding values have been studied. In general, two approaches have been used. One approach estimates the marker effects first and then, genomic breeding values are obtained by summing marker effects. In the second approach, genomic breeding values are estimated directly using an equivalent model with a genomic relationship matrix. Allele coding is the method chosen to assign values to the regression coefficients in the statistical model. A common allele coding is zero for the homozygous genotype of the first allele, one for the heterozygote, and two for the homozygous genotype for the other allele. Another common allele coding changes these regression coefficients by subtracting a value from each marker such that the mean of regression coefficients is zero within each marker. We call this centered allele coding. This study considered effects of different allele coding methods on inference. Both marker-based and equivalent models were considered, and restricted maximum likelihood and Bayesian methods were used in inference. RESULTS: Theoretical derivations showed that parameter estimates and estimated marker effects in marker-based models are the same irrespective of the allele coding, provided that the model has a fixed general mean. For the equivalent models, the same results hold, even though different allele coding methods lead to different genomic relationship matrices. Calculated genomic breeding values are independent of allele coding when the estimate of the general mean is included into the values. Reliabilities of estimated genomic breeding values calculated using elements of the inverse of the coefficient matrix depend on the allele coding because different allele coding methods imply different models. Finally, allele coding affects the mixing of Markov chain Monte Carlo algorithms, with the centered coding being the best. CONCLUSIONS: Different allele coding methods lead to the same inference in the marker-based and equivalent models when a fixed general mean is included in the model. However, reliabilities of genomic breeding values are affected by the allele coding method used. The centered coding has some numerical advantages when Markov chain Monte Carlo methods are used. PMID- 21703022 TI - Evidence of a pharmacodynamic EEG profile in rats following clonidine administration using a nonlinear analysis. AB - BACKGROUND: Changes caused by clonidine in rodent electroencephalograms (EEG) have been reported with some inconsistency. For this reason, a pre-clinical study was conducted in order to confirm previous findings with both a standard spectral analysis and a sleep stage scoring procedure. In addition, a nonlinear technique for analysing the time-varying signals was implemented to compare its performance against conventional approaches. RESULTS: The nonlinear method succeeds in quantifying all dose-related responses from the data set relying solely on the EEG trace. CONCLUSIONS: Nonlinear approaches can deliver a suitable alternative to the sleep-stage scoring methods commonly used for drug effect detection. PMID- 21703023 TI - Reconsidering low-dose aspirin therapy for cardiovascular disease: a study protocol for physician and patient behavioral change. AB - BACKGROUND: There are often disparities between current evidence and current practice. Decreasing the gap between desired practice outcomes and observed practice outcomes in the healthcare system is not always easy. Stopping previously recommended or variably recommended interventions may be even harder to achieve than increasing the use of a desired but under-performed activity. For over a decade, aspirin has been prescribed for primary prevention of cardiovascular disease and for patients with the coronary artery disease risk equivalents; yet, there is no substantial evidence of an appropriate risk-benefit ratio to support this practice. This paper describes the protocol of a randomized trial being conducted in six primary care practices in the Denver metropolitan area to examine the effectiveness of three interventional strategies to change physician behavior regarding prescription of low-dose aspirin. METHODS: All practices received academic detailing, one arm received clinician reminders to reconsider aspirin, a second arm received both clinician and patient messages to reconsider aspirin. The intervention will run for 15 to 18 months. Data collected at baseline and for outcomes from an electronic health record will be used to assess pre- and post-interventional prescribing, as well as to explore any inappropriate decrease in aspirin use by patients with known cardiovascular disease. DISCUSSION: This study was designed to investigate effective methods of changing physician behavior to decrease the use of aspirin for primary cardiovascular disease prevention. The results of this study will contribute to the small pool of knowledge currently available on the topic of ceasing previously supported practices. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01247454. PMID- 21703024 TI - Virus-like particle production with yeast: ultrastructural and immunocytochemical insights into Pichia pastoris producing high levels of the hepatitis B surface antigen. AB - BACKGROUND: A protective immune response against Hepatitis B infection can be obtained through the administration of a single viral polypeptide, the Hepatitis B surface antigen (HBsAg). Thus, the Hepatitis B vaccine is generated through the utilization of recombinant DNA technology, preferentially by using yeast-based expression systems. However, the polypeptide needs to assemble into spherical particles, so-called virus-like particles (VLPs), to elicit the required protective immune response. So far, no clear evidence has been presented showing whether HBsAg assembles in vivo inside the yeast cell into VLPs or later in vitro during down-stream processing and purification. RESULTS: High level production of HBsAg was carried out with recombinant Pichia pastoris using the methanol inducible AOX1 expression system. The recombinant vaccine was isolated in form of VLPs after several down-stream steps from detergent-treated cell lysates. Search for the intracellular localization of the antigen using electron microscopic studies in combination with immunogold labeling revealed the presence of HBsAg in an extended endoplasmic reticulum where it was found to assemble into defined multi-layered, lamellar structures. The distance between two layers was determined as ~6 nm indicating that these lamellas represent monolayers of well ordered HBsAg subunits. We did not find any evidence for the presence of VLPs within the endoplasmic reticulum or other parts of the yeast cell. CONCLUSIONS: It is concluded that high level production and intrinsic slow HBsAg VLP assembly kinetics are leading to retention and accumulation of the antigen in the endoplasmic reticulum where it assembles at least partly into defined lamellar structures. Further transport of HBsAg to the Golgi apparatus is impaired thus leading to secretory pathway disfunction and the formation of an extended endoplasmic reticulum which bulges into irregular cloud-shaped formations. As VLPs were not found within the cells it is concluded that the VLP assembly process must take place during down-stream processing after detergent-mediated disassembly of HBsAg lamellas and subsequent reassembly of HBsAg into spherical VLPs. PMID- 21703025 TI - Immunotherapeutic role of Ag85B as an adjunct to antituberculous chemotherapy. AB - BACKGROUND: Immunotherapy to enhance the efficiency of the immune response in tuberculosis patients and to eliminate the persisters could be an additional valuable strategy to complement anti-mycobacterial chemotherapy. This study was designed to assess the immunotherapeutic potential of Ag85B as an adjunct to chemotherapy and its effect against active and persister bacteria left after therapy in mouse model of tuberculosis. METHODS: 6-8 week old female Balb/c mice were infected with Mycobacterium tuberculosis and treated with chemotherapy or immunotherapy. Protective efficacy was measured in terms of bacterial counts in lungs and spleen. Immune correlates of protection in terms of Th1 and Th2 cytokines were measured by ELISA. RESULTS: Therapeutic effect of Ag85B was found to be comparable to that of short term dosage of antituberculous drugs (ATDs). The therapeutic effect of ATDs was augmented by the simultaneous treatment with rAg85B and moreover therapy with this protein allowed us to reduce ATD dosage. This therapy was found to be effective even in case of drug persisters. The levels of antigen specific IFNgamma and IL-12 were significantly increased after immunotherapy as compared to the basal levels; moreover antigen specific IL-4 levels were depressed on immunotherapy with Ag85B. CONCLUSION: We demonstrated in this study that the new combination approach using immunotherapy and concurrent chemotherapy should offer several improvements over the existing regimens to treat tuberculosis. The therapeutic effect is associated not only with initiating a Th1 response but also with switching the insufficient Th2 immune status to the more protective Th1 response. PMID- 21703026 TI - Perceived and desired weight, weight related eating and exercising behaviours, and advice received from parents among thin, overweight, obese or normal weight Australian children and adolescents. AB - BACKGROUND: Thin children are less muscular, weaker, less active, and have lower performance in measures of physical fitness than their normal weight peers. Thin children are also more frequently subjected to teasing and stigmatization. Little is known about thin children's weight perceptions, desired weight and attitudes and behaviours towards food and exercise. The study aimed to compare perceived weight status, desired weight, eating and exercise behaviours and advice received from parents among thin, overweight, obese or normal weight Australian children and adolescents. METHODS: The sample included 8550 school children aged 6 to 18 years selected from every state and territory of Australia. The children were weighed, measured and classified as thin, normal, overweight or obese using international standards. The main outcome measures were perceived and desired weight, weight related eating and exercising behaviours, and advice received from parents. RESULTS: The distribution of weight status was - thin 4.4%; normal weight 70.7%; overweight 18.3%; and obese 6.6%. Thin children were significantly shorter than normal weight, overweight or obese children and they were also more likely to report regularly consuming meals and snacks. 57.4% of thin children, 83.1% of normal weight children, 63.7% of overweight and 38.3% of obese children perceived their weight as "about right". Of the thin children, 53.9% wanted to be heavier, 36.2% wanted to stay the same weight, and 9.8% wanted to weigh less. Thin children were significantly less likely than obese children to respond positively to statements such as "I am trying to get fitter" or "I need to get more exercise." Parents were significantly less likely to recommend exercise for thin children compared with other weight groups. CONCLUSIONS: Thin children, as well as those who are overweight or obese, are less likely than normal weight children to consider their weight "about right'. Thin children differ from children of other weights in that thin children are less likely to desire to get fitter or be encouraged to exercise. Both extremes of the spectrum of weight, from underweight to obese, may have serious health consequences for the individuals, as well as for public health policy. Health and wellness programs that promote positive social experiences and encourage exercise should include children of all sizes. PMID- 21703027 TI - High fat diet intake during pre and periadolescence impairs learning of a conditioned place preference in adulthood. AB - BACKGROUND: Brain regions that mediate learning of a conditioned place preference (CPP) undergo significant development in pre and periadolescence. Consuming a high fat (HF) diet during this developmental period and into adulthood can lead to learning impairments in rodents. The present study tested whether HF diet intake, consumed only in pre and periadolescence, would be sufficient to cause impairments using a CPP procedure. METHODS: Rats were randomly assigned to consume a HF or a low fat (LF) diet during postnatal days (PD) 21-40 and were then placed back on a standard lab chow diet. A 20-day CPP procedure, using HF Cheetos(r) as the unconditioned stimulus (US), began either the next day (PD 41) or 40 days later (PD 81). A separate group of adult rats were given the HF diet for 20 days beginning on PD 61, and then immediately underwent the 20-day CPP procedure beginning on PD 81. RESULTS: Pre and periadolescent exposure to a LF diet or adult exposure to a HF diet did not interfere with the development of a HF food-induced CPP, as these groups exhibited robust preferences for the HF Cheetos(r) food-paired compartment. However, pre and periadolescent exposure to the HF diet impaired the development of a HF food-induced CPP regardless of whether it was assessed immediately or 40 days after the exposure to the HF diet, and despite showing increased consumption of the HF Cheetos(r) in conditioning. CONCLUSIONS: Intake of a HF diet, consumed only in pre and periadolescence, has long-lasting effects on learning that persist into adulthood. PMID- 21703029 TI - Maximum inspiratory pressure, a surrogate parameter for the assessment of ICU acquired weakness. AB - BACKGROUND: Physical examination has been advocated as a primary determinant of ICU-acquired weakness (ICU-AW). The purpose of the study is to investigate ICU-AW development by using Maximum Inspiratory Pressure (MIP) as a surrogate parameter of the standardized method to evaluate patients' peripheral muscle strength. METHODS: Seventy-four patients were recruited in the study and prospectively evaluated in a multidisciplinary university ICU towards the appearance of ICU-AW. APACHE II admission score was 16 +/- 6 and ICU stay 26 +/- 18 days. ICU-AW was diagnosed with the Medical Research Council (MRC) scale for the clinical evaluation of muscle strength. MIP was measured using the unidirectional valve method, independently of the patients' ability to cooperate. RESULTS: A significant correlation was found between MIP and MRC (r = 0.68, p < 0.001). Patients that developed ICU-AW (MRC<48) had a longer weaning period compared to non ICU-AW patients (12 +/- 14 versus 2 +/- 3 days, p < 0.01). A cut-off point of 36 cmH2O for MIP was defined by ROC curve analysis for ICU-AW diagnosis (88% sensitivity,76% specificity). Patients with MIP below the cut-off point of 36 cmH2O had a significant greater weaning period (10 +/- 14 versus 3 +/- 3 days, p = 0.004) also shown by Kaplan-Meier analysis (log-rank:8.2;p = 0.004). CONCLUSIONS: MIP estimated using the unidirectional valve method may be a potential surrogate parameter for the assessment of muscle strength compromise, useful for the early detection of ICU-AW. PMID- 21703028 TI - Breakpoint characterization of large deletions in EXT1 or EXT2 in 10 multiple osteochondromas families. AB - BACKGROUND: Osteochondromas (cartilage-capped bone tumors) are by far the most commonly treated of all primary benign bone tumors (50%). In 15% of cases, these tumors occur in the context of a hereditary syndrome called multiple osteochondromas (MO), an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped bone tumors at children's metaphyses. MO is caused by various mutations in EXT1 or EXT2, whereby large genomic deletions (single-or multi-exonic) are responsible for up to 8% of MO-cases. METHODS: Here we report on the first molecular characterization of ten large EXT1 and EXT2-deletions in MO-patients. Deletions were initially identified using MLPA or FISH analysis and were subsequently characterized using an MO-specific tiling path array, allele-specific PCR-amplification and sequencing analysis. RESULTS: Within the set of ten large deletions, the deleted regions ranged from 2.7 to 260 kb. One EXT2 exon 8 deletion was found to be recurrent. All breakpoints were located outside the coding exons of EXT1 and EXT2. Non-allelic homologous recombination (NAHR) mediated by Alu-sequences, microhomology mediated replication dependent recombination (MMRDR) and non-homologous end-joining (NHEJ) were hypothesized as the causal mechanisms in different deletions. CONCLUSIONS: Molecular characterization of EXT1- and EXT2-deletion breakpoints in MO-patients indicates that NAHR between Alu-sequences as well as NHEJ are causal and that the majority of these deletions are nonrecurring. These observations emphasize once more the huge genetic variability which is characteristic for MO. To our knowledge, this is the first study characterizing large genomic deletions in EXT1 and EXT2. PMID- 21703030 TI - Trochanteric osteotomy versus posterolateral approach: function the first year post surgery. A pilot study. AB - BACKGROUND: Although no prospective studies have compared functional results of trochanteric osteotomy and a non-trochanteric approach, most surgeons feel that trochanteric osteotomy is outdated in simple hip arthroplasty. Reasons not to perform an osteotomy include the fear of longer rehabilitation and worse (final) functional outcome. METHOD: This prospective study examines differences in rehabilitation between posterolateral and trochanteric approach one year post surgery using questionnaires (WOMAC, SF-36, HHS) and functional tests (walking, climbing stairs, rising from sitting, and strength tests). Of the 109 patients 24 had a trochanteric osteotomy: the selected approach was based on the surgeon's preference. The trochanteric osteotomy group included more patients with developmental dysplasia of the hip. Before the start of the study no power analysis was performed. RESULTS: Data from the questionnaires showed no significant differences between the two groups at 3, 6 and 12-months follow-up. At 3-months follow-up patients in the trochanteric osteotomy group scored lower on the functional tests. This difference had disappeared at 6 and 12-months follow-up, except for abduction force which remained lower in the trochanteric osteotomy group in patients with a non union of the TO. CONCLUSION: For simple hip arthroplasty an approach without osteotomy seems a logical choice. Although the power of this study is low, in experienced hands trochanteric osteotomy seems to give good functional results at 6-12 months post surgery if trochanteric union is obtained. Therefore, one should not hesitate to perform an osteotomy in difficult cases. PMID- 21703031 TI - Analysis of the photosynthetic apparatus in transgenic tobacco plants with altered endogenous cytokinin content: a proteomic study. AB - BACKGROUND: Cytokinin is a plant hormone that plays a crucial role in several processes of plant growth and development. In recent years, major breakthroughs have been achieved in the elucidation of the metabolism, the signal perception and transduction, as well as the biological functions of cytokinin. An important activity of cytokinin is the involvement in chloroplast development and function. Although this biological function has already been known for 50 years, the exact mechanisms remain elusive. RESULTS: To elucidate the effects of altered endogenous cytokinin content on the structure and function of the chloroplasts, chloroplast subfractions (stroma and thylakoids) from transgenic Pssu-ipt and 35S:CKX1 tobacco (Nicotiana tabacum) plants with, respectively, elevated and reduced endogenous cytokinin content were analysed using two different 2-DE approaches. Firstly, thykaloids were analysed by blue-native polyacrylamide gel electrophoresis followed by SDS-PAGE (BN/SDS-PAGE). Image analysis of the gel spot pattern thus obtained from thylakoids showed no substantial differences between wild-type and transgenic tobacco plants. Secondly, a quantitative DIGE analysis of CHAPS soluble proteins derived from chloroplast subfractions indicated significant gel spot abundance differences in the stroma fraction. Upon identification by MALDI-TOF/TOF mass spectrometry, these proteins could be assigned to the Calvin-Benson cycle and photoprotective mechanisms. CONCLUSION: Taken together, presented proteomic data reveal that the constitutively altered cytokinin status of transgenic plants does not result in any qualitative changes in either stroma proteins or protein complexes of thylakoid membranes of fully developed chloroplasts, while few but significant quantitative differences are observed in stroma proteins. PMID- 21703032 TI - The assessment of efficacy of porcine reproductive respiratory syndrome virus inactivated vaccine based on the viral quantity and inactivation methods. AB - BACKGROUND: There have been many efforts to develop efficient vaccines for the control of porcine reproductive and respiratory syndrome virus (PRRSV). Although inactivated PRRSV vaccines are preferred for their safety, they are weak at inducing humoral immune responses and controlling field PRRSV infection, especially when heterologous viruses are involved. RESULTS: In all groups, the sample to positive (S/P) ratio of IDEXX ELISA and the virus neutralization (VN) titer remained negative until challenge. While viremia did not reduce in the vaccinated groups, the IDEXX-ELISA-specific immunoglobulin G increased more rapidly and to significantly greater levels 7 days after the challenge in all the vaccinated groups compared to the non-vaccinated groups (p < 0.05). VN titer was significantly different in the 106 PFU/mL PRRSV vaccine-inoculated and binary ethylenimine (BEI)-inactivated groups 22 days after challenge (p < 0.05). Consequently, the inactivated vaccines tested in this study provided weak memory responses with sequential challenge without any obvious active immune responses in the vaccinated pigs. CONCLUSIONS: The inactivated vaccine failed to show the humoral immunity, but it showed different immune response after the challenge compared to mock group. Although the 106 PFU/mL-vaccinated and BEI-inactivated groups showed significantly greater VN titers 22 days after challenge, all the groups were already negative for viremia. PMID- 21703033 TI - Agreement between pedometer and accelerometer in measuring physical activity in overweight and obese pregnant women. AB - BACKGROUND: Inexpensive, reliable objective methods are needed to measure physical activity (PA) in large scale trials. This study compared the number of pedometer step counts with accelerometer data in pregnant women in free-living conditions to assess agreement between these measures. METHODS: Pregnant women (n = 58) with body mass index >=25 kg/m(2) at median 13 weeks' gestation wore a GT1M Actigraph accelerometer and a Yamax Digi-Walker CW-701 pedometer for four consecutive days. The Spearman rank correlation coefficients were determined between pedometer step counts and various accelerometer measures of PA. Total agreement between accelerometer and pedometer step counts was evaluated by determining the 95% limits of agreement estimated using a regression-based method. Agreement between the monitors in categorising participants as active or inactive was assessed by determining Kappa. RESULTS: Pedometer step counts correlated moderately (r = 0.36 to 0.54) with most accelerometer measures of PA. Overall step counts recorded by the pedometer and the accelerometer were not significantly different (medians 5961 vs. 5687 steps/day, p = 0.37). However, the 95% limits of agreement ranged from -2690 to 2656 steps/day for the mean step count value (6026 steps/day) and changed substantially over the range of values. Agreement between the monitors in categorising participants to active and inactive varied from moderate to good depending on the criteria adopted. CONCLUSIONS: Despite statistically significant correlations and similar median step counts, the overall agreement between pedometer and accelerometer step counts was poor and varied with activity level. Pedometer and accelerometer steps cannot be used interchangeably in overweight and obese pregnant women. PMID- 21703034 TI - Carotid axillary bypass in a patient with blocked subclavian stents: a case report. AB - INTRODUCTION: Surgical treatment of symptomatic occlusive lesions of the proximal subclavian artery is infrequently necessary. Carotid subclavian bypass has gained popularity and is now considered standard treatment when stenting is not possible. Exposure of the subclavian artery and bypass grafting onto it is difficult, as the vessel is delicate, thin-walled and located deep in the supraclavicular fossa. The thoracic duct and brachial plexus are in close proximity to the left subclavian artery and are therefore susceptible to damage. Distal grafting to the axillary artery instead of the subclavian artery has the potential of avoiding some of these risks. Infraclavicular exposure of the axillary artery is more straightforward. The vessel wall is thicker and is easier to handle. In this case report, we describe a patient with a left proximal subclavian occlusion which was stented twice and blocked on both occasions. The patient underwent a carotid axillary bypass, as grafting onto the subclavian artery was impossible because of the two occluded metal stents. CASE PRESENTATION: A 56-year-old Caucasian woman, a heavy smoker, presented acutely with left arm numbness and pain and blood pressure discrepancies in both arms. A diagnosis of subclavian stenosis was confirmed on the basis of a computed tomographic scan and a magnetic resonance angiogram. The patient had undergone subclavian artery stenting twice, and unfortunately the stents blocked on both occasions. The patient underwent carotid axillary bypass surgery. She had an uneventful recovery and was able to return to a full, normal life. CONCLUSION: Carotid axillary bypass appears to be a good alternative to carotid subclavian bypass in the treatment of symptomatic proximal stenosis or occlusion of the subclavian artery. PMID- 21703035 TI - Giant mediastinal mature teratoma with increased exocrine pancreatic activity presenting in a young woman: a case report. AB - INTRODUCTION: Mediastinal mature teratoma is a benign, slow-growing tumor typically affecting 20- to 40-year-old adults. Fluid examination from the cystic masses rarely shows enzymatic activity as we describe in this report. CASE PRESENTATION: We report a case of a giant mediastinal germ cell tumor (measuring 15 cm * 14 cm * 8 cm) detected in a 35-year-old Caucasian woman. Microscopic examination showed that the lesion resembled a mature cystic teratoma with areas of pancreatic tissue with mature ductal and acinar structures intermixed with islets of Langerhans. Fluid from the cysts in the mass was examined after removal showed amylase activity of 599 U/l despite normal serum levels. The post operative period was free of complications, and the patient was discharged on post-operative day 10. CONCLUSION: Complete surgical removal is the treatment of choice for mature cystic teratomas, with optimal results and acceptable surgical risk. Exocrine pancreatic function may be an aid to pre-operative or intra operative diagnosis; however, these findings have no impact on survival or the therapeutic pathway. PMID- 21703036 TI - Name that prostate cancer drug. PMID- 21703037 TI - Legends in urology. PMID- 21703038 TI - Isoniazid resistance among Bacillus Calmette Guerin strains: implications on bladder cancer immunotherapy related infections. AB - Bacillus Calmette Guerin (BCG) immunotherapy is widely used for treatment of superficial bladder transitional cell carcinoma. Infectious complications while rare can be serious and severe disseminated infections as well as sepsis has been reported. There are no standard guidelines to direct therapy of these complications. Isoniazid is a commonly and widely used component of the various treatment regimens. Various strains of BCG are used for treatment of bladder cancer as well as vaccinations. These strains have evolved because of repeated subcultures in various laboratories in the world and have been shown to exhibit phenotypic differences in their immunogenicity as well as recently in susceptibility to various antimycobacterial agents. In this article, we review the resistance of BCG strains to various antimycobacterial agents. Some of these strains including the BCG Connaught strain, which is widely used in the United States, Canada and some other parts of the world for bladder cancer therapy exhibit intrinsic resistance to isoniazid. Although the clinical relevance of these differences is unclear, recent studies have questioned the role of isoniazid in treatment of infections after vaccination with these strains. Also, use of isoniazid in combination therapy for these infections may lead to the development of resistance to other antimycobacterial agents. We conclude that isoniazid may not be a suitable agent for empiric treatment of infections related to intravesical immunotherapy for bladder cancer with these strains and further studies are needed to clarify its role. PMID- 21703039 TI - Management of bulbar urethral strictures: review of current practice. AB - Male urethral stricture disease is one of the common conditions encountered in the day-to-day urological practice. It can present at any age and has a wide range of etiological factors including infection, trauma and instrumentation. It usually manifests itself as lower urinary tract symptoms or urinary tract infections with significant impairment in the quality of life. There are several treatment options for this condition and these mainly depend on the site, length, the underlying cause and previous treatment. The management of bulbar urethral strictures has greatly evolved over the last few decades with more patients being offered reconstructive surgical operations as a primary treatment option. This article provides an overview on the management of bulbar urethral strictures and the wide range of surgical procedures offered to the patients. PMID- 21703040 TI - New findings in localized and advanced prostate cancer: AUA 2011 review. AB - The 2011 American Urological Association (AUA) annual meeting took place in Washington, DC, USA, on May 14-19. It is the largest gathering of urologists in the world, providing unparalleled access to groundbreaking research, new guidelines and the latest advances in urologic medicine. The opportunity to exchange knowledge among urologists on a worldwide level was provided by participation of more than 80 countries in this scientific meeting. As one of the most important subjects, there were more than 500 presented studies in prostate cancer. In this review we will highlight some of the findings and the clinical significance of a few of these abstracts concerning prostate cancer staging and markers. PMID- 21703041 TI - Recording urinary flow and lower urinary tract symptoms using sonouroflowmetry. AB - INTRODUCTION: To assess the accuracy of sonouroflow (SUF), an at-home, wireless based acoustic system for recording lower urinary tract symptoms (LUTS) and urinary flow rate, and to compare test-to-test variability in flow parameters recorded using this new portable method with those obtained by conventional uroflowmetry. MATERIALS AND METHODS: An initial pilot study evaluated the technical feasibility of the SUF system. Subsequently, test-to-test variability was compared between sonourograms (SUFm) and standard uroflowmetry recordings. Uroflowmetry tests were performed at the urology office at pre-set times. SUF tests were performed at home on a schedule in keeping with the subjects' normal habits. RESULTS: In the initial feasibility study, 94% of SUFm recordings obtained from male volunteers displayed regular bell-shaped flow curves comparable to those recorded by standard uroflowmetry; significant variability was noted among female volunteers. In the comparative study, the coefficient of variation for SUFm-derived values was significantly lower for voiding time (p < 0.001) and significantly higher for average flow rate (p = 0.009) than that obtained from standard uroflowmetry recordings; maximum flow rate and time to maximum flow were not significantly different between methods. Box-and-whisker plots showed reduced test-to-test variability in the SUFm dataset for voiding time, maximum flow rate and time to maximum flow rate in 62.5%, 43.75% and 56%, respectively, of study subjects. CONCLUSIONS: The SUF system is easy to use and yields results comparable to those of standard uroflowmetry. Integration of recordings of LUTS with flow parameters and lower test-to-test variability suggest the potential of SUF for clinical applications. PMID- 21703042 TI - Urodynamic parameters evolution after artificial urinary sphincter implantation for post-radical prostatectomy incontinence with concomitant bladder dysfunction. AB - INTRODUCTION: Urodynamic assessment is strongly recommended before artificial urinary sphincter (AUS) implantation. Detrusor overactivity (DO) and/or hypersensitivity and/or mild loss of compliance are frequently demonstrated in post prostatectomy incontinence. The aim of this study was to evaluate urodynamic parameter changes before and after AUS implantation in patients with urinary incontinence post-radical prostatectomy (RP) and concomitant urodynamic bladder abnormalities. MATERIALS AND METHODS: We performed a retrospective review of charts pre- and post-AUS implantation. Sixteen out of a cohort of 52 patients met our inclusion criteria: stress urinary incontinence (SUI) due to RP and bladder dysfunction (early bladder sensation and/or low compliance and/or small bladder capacity and/or the presence of DO). RESULTS: The mean age of these 16 patients was 68 +/- 6.3 years, and the duration of incontinence was 3 +/- 2.7 years. The number of pads/day was 5.7 +/- 2.3 before AUS implantation, and 1 +/- 0.7 after implantation. Average time for the last post-implantation UDS was 43 months (range 7 to 73 months). Comparison of pre- and post-AUS implantation urodynamic parameters revealed statistically significant improvement in bladder capacity from 271 +/- 117 to 295.6 +/- 151 mL (p = 0.05), bladder compliance from 7.6 +/- 3.95 to 12.5 +/- 10.3 mL/cmH2O (p = 0.03), and decrease in DO from 50% to 25% on cystometrograms. CONCLUSION: Preoperative urodynamic abnormalities improved after AUS implantation. Thus, mild bladder dysfunction should not be a contraindication to AUS placement for SUI post-RP. PMID- 21703043 TI - Anatomical and histological equivalence of the human, canine, and bull vas deferens. AB - INTRODUCTION: Several animal models have been utilized for in-vitro experimentation and surgical training exercises of the vas deferens. The canine model is currently the standard for both in-vivo and ex-vivo study. Due to increasing costs associated with experimentation on canines, and in keeping with the principles of refine, reduce, and replace, a novel model that is cost effective and easily obtained is desired. We compared morphology of the bull vas deferens to that of the human and the canine. MATERIALS AND METHODS: Bilateral vas deferens tissue from the human (n = 6), canine (n = 6), and bull (n = 5) were compared. Outer diameter (OD), inner diameter (ID), and microscopic measurements of the luminal mucosa and muscularis were then determined from each of these tissues. Histological comparisons were performed by a single pathologist. Data was analyzed using Two One-sided Tests (TOST) Analysis of Equivalence. RESULTS: According to the TOST statistical analysis, the vassal ID was equivalent for all three species. Similarly, equivalent microscopic measurements were noted for both vassal mucosal (human-canine and human-bull) and muscularis thicknesses (canine bull). Lastly, all three species had similar histological characteristics. CONCLUSIONS: The vas deferens' of the human, canine, and bull are equivalent in many ways, including histological similarities. It is reasonable to conclude that the bull vas could be substituted for the human vas for both in-vitro testing and microscopic vasovasostomy simulation exercises. Specimens are cost-effective, provide ample tissue length, and are easy to obtain. PMID- 21703044 TI - Transurethral resection of the prostate (TURP) with low dose spinal anesthesia in outpatients: a 5 year review. AB - INTRODUCTION: Spinal anesthesia for ambulatory transurethral resection of the prostate (TURP) is a well established technique. The following study examines data over a 5 year period at a major Canadian tertiary academic center. The purpose of the study is to review our experience and complications associated with spinal anesthesia using combined low dose local anesthetic + narcotic for ambulatory TURP procedures. METHODS: Medical records were reviewed retrospectively on all ambulatory TURP patients over a 5 year period between January 2000 and September 2005 in our Surgical Day Care Center. All spinal anesthetics were reviewed and based on dosage, classified into low dose bupivacaine (< 10 mg; Group LD-B), conventional dose lidocaine (> 35 mg; Group CD L) or low dose lidocaine (<= 35 mg; Group LD-L). Primary end points of interest were duration of spinal block and duration of postanesthesia care unit (PACU) stay. RESULTS: A total of 1064 TURPs were performed during the study period. Within this cohort of 334 spinal anesthetics administered, 27 were excluded for lack of data leaving 307 cases for analysis. Patient demographics were normally distributed. Mean doses of spinal local anesthetics administered were: Group LD-B 7.3 +/- 2 mg, Group CD-L 52.2 +/- 13 mg and Group LD-L 29 +/- 5.2 mg. Intrathecal fentanyl was often added to the local anesthetic as an adjunct. Block regression times (Group LD-B 273 +/- 98 mins, Group CD-L 174 +/- 47 mins and Group LD-L 159 +/- 45 mins) and discharge times (Group LD-B 309 +/- 94 mins, Group CD-L 230 +/- 71 mins and Group LD-L 227 +/- 75 mins) were significantly lesser in both lidocaine groups compared to Group LD-B (p <0.05). The frequency of prolonged spinal blocks (> 3 hr) in Groups LD-L, CD-L and LD-B was 23%, 43% and 83% respectively (p < 0.05). CONCLUSION: Low dose spinal anesthesia with bupivacaine and lidocaine were well tolerated for short duration TURP. Low dose bupivacaine and conventional dose lidocaine were associated with significantly longer block duration, longer PACU stay and higher frequency of prolonged blocks compared with low dose lidocaine for spinal anesthesia. PMID- 21703045 TI - EDITORIAL COMMENT Re: Transurethral resection of the prostate (TURP) with low dose spinal anesthesia in outpatients: a 5 year review. PMID- 21703046 TI - The role of vitamin D, estrogen, calcium sensing receptor genotypes and serum calcium in the pathogenesis of prostate cancer. AB - INTRODUCTION: Prostate cancer is the second leading cause of cancer death among men in developed countries. Estrogen receptor-alpha (ER-alpha), vitamin D receptor (VDR), and the calcium-sensing receptor (CaSR), partly through their effects on calcium levels are implicated in the proliferation and carcinogenesis in the prostate gland. VDR, ER-alpha and CaSR genes show polymorphisms in humans that appear to have clinical significance in many pathological conditions, such as prostate cancer. Our aim was to evaluate the role of ER-alpha (PvuII, XbaI), VDR (BsmI) and CaSR (A986S) gene polymorphisms and serum calcium levels in the pathogenesis of prostate cancer. MATERIAL AND METHODS: Two hundred four patients with prostate cancer and 102 healthy controls were recruited into a hospital based case control study. After genotyping, the relationship between the individual genotypes and prostate cancer was investigated. RESULTS: Both the ER alpha XbaI and the VDR BsmI polymorphisms were significantly related to the risk of prostate cancer. An age adjusted logistic regression limited to controls and patients not receiving bisphosphonate therapy showed that higher corrected serum calcium and the VDR Bb/BB genotypes independently increased the risk of prostate cancer. CONCLUSIONS: ER-alpha XbaI and VDR BsmI genetic polymorphisms had a significant association with the risk of prostate cancer. Both VDR BsmI genotypes and serum calcium levels were independently related to the risk of prostate cancer, suggesting an influence of VDR on the development of this malignancy. PMID- 21703047 TI - Urolithiasis in the elderly. AB - OBJECTIVES: Urolithiasis is an increasing problem in patients >= 80 years. Our objective was to compare patients >= 80 years with urolithiasis to a younger cohort in terms of presentation and management. METHODS: Patients referred to a tertiary care stone clinic for management of urolithiasis over a 5 year period were reviewed. Data collected on clinical parameters for patients >= 80 years were compared with a random sample of those < 80 years. RESULTS: There were 26 patients >= 80 years and 102 in the sample < 80 years; mean age was 83.5 +/- 0.6 and 50.1 +/- 1.3 years, respectively. The older group had more comorbidities. The presenting complaint was more often flank pain in younger patients. Patients >= 80 years had larger stones. Early ureteric stent insertion was more likely in the elderly compared with the younger group (27% versus 7%, p < 0.01). Definitive therapy for patients >= 80 years was most often percutaneous nephrolithotomy (PCNL) (23%) compared with only 9% in the younger group. In contrast, the most common definitive treatment modality used for patients < 80 years was extracorporeal shock wave lithotripsy (ESWL) (35% versus 8%, p < 0.01). There was no difference in intraoperative complications. Thirty nine percent of the older group was managed as outpatients. More of the older group had postoperative complications but all were minor. CONCLUSION: Urolithiasis in the elderly is challenging to treat because they have more comorbidities and are less likely to present with classic symptoms of renal colic. This may lead to later presentation with larger and more complex stone disease. Early ureteric stent is often required and definitive PCNL is more likely than in the younger cohort. Despite these issues most can be treated safely and often as an outpatient. PMID- 21703048 TI - Effect on sexual function of a vacuum erection device post-prostatectomy. AB - INTRODUCTION: Treatment of erectile dysfunction (ED) subsequent to bilateral nerve sparing robotic prostatectomy (BNSRP) with tadalafil plus a vacuum erection device (VED) may improve return of sexual function. MATERIALS AND METHODS: Men with prostate cancer who had BNSRP were randomized to receive tadalafil, 20 mg three times weekly, or tadalafil plus a VED, 10 minutes unbanded per day for at least 5 days weekly. Treatments started 1 month after surgery; clinic visits were at 1, 3, 6, 9 and 12 months. Patients were requested to attempt intercourse at least twice before each visit. At every visit patients completed the International Index of Erectile Function (IIEF-5) questionnaire and a penile hardness scale (1-4) and were questioned as to their ability to have vaginal penetration and intercourse to orgasm. RESULTS: Thirteen men started the combination regimen, and there were no dropouts; 10 patients started the tadalafil treatment, and three men dropped out. The mean IIEF-5 at months 6, 9 and 12 were significantly higher for the combination group, while the penile hardness scores were significantly greater for the combination group at 6 and 9 months. After 12 months 92% of combination patients responded yes to the vaginal penetration question versus 57% of the tadalafil group; corresponding figures were 92% and 29%, respectively, for intercourse to orgasm. Compliance to the VED was superior to that of tadalafil. CONCLUSION: Men with ED subsequent to BNSRP had a more rapid and complete return of sexual function when treated with tadalafil plus VED versus tadalafil alone. PMID- 21703049 TI - Management of post-prostatectomy erectile dysfunction. AB - The management of post-prostatectomy erectile function has been debated since the nerve sparing radical prostatectomy was first introduced. A number of penile rehabilitation protocols have been proposed with varying degrees of success and patient satisfaction. My management of post-prostatectomy erectile dysfunction has evolved based on an honest and critical appraisal of the literature and my own experience and research. A review of major studies published on the topic of post-prostatectomy penile rehabilitation is included here, in addition to a critical evaluation of my own clinical practice. After evaluating the efficacy of these various approaches, it is clear to me that a nerve sparing procedure is only one of many factors involved in recovering erectile function. Moreover, in addition to assessing a patient's goals and their motivation for erectile function after prostatectomy, setting appropriate patient expectations is paramount to avoiding patient frustration. A frank evaluation and discussion with a patient and their partner is paramount to managing these expectations. A "one size fits all" approach is not appropriate. Herein, I discuss the evolution of my approach to managing post-prostatectomy erectile dysfunction. PMID- 21703050 TI - Robot-assisted laparoscopic excision of a pelvic extragastrointestinal stromal tumor: a case report and literature review. AB - A 61-year-old male presented with long standing urinary frequency and the sensation of incomplete emptying. Computed tomography (CT) revealed a 9.5 cm x 7.9 cm x 6.9 cm pelvic mass behind the bladder and abutting the rectum. The mass was excised using a robotic-assisted laparoscopic approach. Pathologic examination of the mass demonstrated an extragastrointestinal stromal tumor (EGIST), an extremely rare entity. To the best of our knowledge, this is the first EGIST to be found in the rectovesicular pouch of a male and the first to be resected robotically. Our case adds to the understanding of EGISTs and their possible origin and demonstrates that robotic-assisted resection of large pelvic masses can be safe and potentially curative. PMID- 21703051 TI - Surgical resection of a virilizing adrenal mass with extensive tumor thrombus. AB - Adrenocortical carcinoma with tumor thrombus and concomitant testosterone production is a rare entity. We describe a case of a 53-year-old woman with a testosterone producing left-sided adrenocortical carcinoma with tumor extending to the right atrium and tumor embolus to the right pulmonary artery. To our knowledge, there exist no such reported cases in the medical literature. We describe our use of techniques derived from transplant surgery for the removal of this mass. Critical components for successful resection included early renal artery ligation, hepatic mobilization off the inferior vena cava, and minimization of cardiopulmonary bypass time thus eliminating the need for deep hypothermic circulatory arrest. PMID- 21703052 TI - Late presentation of posterior urethral valves. AB - Late presenting posterior urethral valves are very rare and often present ambiguously. The consequence of late detection can be profoundly detrimental, resulting in persistent voiding dysfunction and/or renal failure. We present an unusual case of a patient with posterior urethral valves who presented at the age of 28 years. We review the literature and discuss the clinical features, diagnosis, and treatment of this condition. PMID- 21703053 TI - Hydrocele: an atypical presentation of metastatic sarcomatoid renal cell carcinoma. AB - Herein is a case of a 55-year-old man who presented with epididymitis. He subsequently failed medical management for the suspected infection and progressed to develop an acute scrotum and sonographic findings consistent with a pyocele. Concurrent computed tomography (CT), obtained for persistent abdominal pain, revealed a large enhancing upper pole renal mass suspicious for malignancy. He was taken for emergent scrotal exploration to drain the presumptive pyocele. However, during scrotal exploration, no purulence or evidence of infection was seen. Although, seemingly unrelated to the renal mass, the thickened hydrocele sac was excised and sent as a specimen. Pathology of the sac revealed a diagnosis of metastatic sarcomatoid renal cell carcinoma. Appropriate chemotherapy was initiated based on the scrotal pathology, circumventing the need for a CT directed retroperitoneal lymph node biopsy or nephrectomy. PMID- 21703054 TI - Laparoendoscopic single-site surgery of the kidney: an initial experience. AB - INTRODUCTION: Laparoendoscopic single-site surgery (LESS) has emerged as a natural progression from standard laparoscopy toward minimization of surgical morbidity. We present our initial experience with LESS renal surgery in order to assess safety, feasibility, and early postoperative outcomes. MATERIALS AND METHODS: Patients undergoing LESS renal surgery by a single surgeon from November 2008 to June 2010 were retrospectively identified. Safety, feasibility, and early outcomes were analyzed. Pain parameters were assessed using morphine equivalents used and visual analog pain scores (VAPS). RESULTS: LESS procedures included 13 radical nephrectomy (1 bilateral), 5 simple nephrectomy (1 bilateral), 2 partial nephrectomy, 2 renal biopsy, and 1 renal cryoablation. Of 17 renal tumors, 15 were renal cell carcinoma and 2 had known renal vein involvement. Mean patient age was 55.4 years and mean BMI was 25.5 kg/m2. Mean operative time was 131 minutes (38-230), median estimated blood loss was 50 mL, and median length of stay was 2 days. There was one intraoperative transfusion and one conversion to conventional laparoscopy. The postoperative complication rate was 12% with two Clavien grade > 2 complications. Mean morphine equivalent dose of intravenous narcotics was 21.7 mg, and mean VAPS scores were 4.3, 3.5, and 2.9/10 on POD#0, #1, and day of discharge, respectively. CONCLUSIONS: LESS surgery is safe and feasible for a wide variety of renal surgeries. Despite the selection bias of this early experience, postoperative outcomes and pain scores appear comparable to those reported for standard laparoscopy. Prospective studies comparing LESS to standard laparoscopic renal surgery are needed for definitive assessment. PMID- 21703055 TI - Open clinical uro-oncology trials in Canada. PMID- 21703056 TI - Clinical presentations of schistosoma hematobium: three case reports and review. AB - Urinary schistosomiasis is a prevalent parasitic infection in certain areas of Africa and the Middle East. It could present with common as well as unusual urological symptoms, which poses a considerable diagnostic challenge in countries where there is relative low incidence of the disease. We describe three unusual cases of urinary schistosomiasis identified in patients presenting to a London hospital. One patient was found to have schistosomiasis in the seminal vesicles following surgery for prostatic adenocarcinoma. Another was found to have schistosoma-related granulomatous inflammation within a urachal cyst. Thirdly a patient was found to have simultaneous occurrence of transitional cell carcinoma and schistosomiasis of the bladder. We review the literature on the presentations of the parasite and its association with malignancy. In conclusion, awareness of the disease prevalence, clinical and histopathological features will help to avoid missing the diagnosis. PMID- 21703057 TI - Staying current with trauma treatment. PMID- 21703058 TI - Characteristics of dental clinics in US children's hospitals. AB - PURPOSE: This study's purpose was to describe the workforce, patient, and service characteristics of dental clinics affiliated with US children's hospitals belonging to the National Association of Children's Hospital and Related Institutions (NACHRI). METHODS: A 2-stage survey mechanism using ad hoc questionnaires sought responses from hospital administrators and dental clinic administrators. Questionnaires asked about: (1) clinic purpose; (2) workforce; (3) patient population; (4) dental services provided; (5) community professional relations; and (5) relationships with medical services. RESULTS: Of the 222 NACHRI-affiliated hospitals, 87 reported comprehensive dental clinics (CDCs) and 64 (74%) of CDCs provided data. Provision of tertiary medical services was significantly related to presence of a CDC. Most CDCs were clustered east of the Mississippi River. Size, workload, and patient characteristics were variable across CDCs. Most were not profitable. Medical diagnosis was the primary criterion for eligibility, with all but 1 clinic treating special needs children. Most clinics (74%) had dental residencies. Over 75% reported providing dental care prior to major medical care (cardiac, oncology, transplantation), but follow up care was variable. CONCLUSIONS: Many children's hospitals reported comprehensive dental clinics, but the characteristics were highly variable, suggesting this element of the pediatric oral health care safety net may be fragile. PMID- 21703059 TI - A preliminary analysis of the US dental health care system's capacity to treat children with special health care needs. AB - PURPOSE: The purpose of this study was to use existing data to determine capacity of the US dental care system to treat children with special health care needs (CSHCN). METHODS: A deductive analysis using recent existing data was used to determine the: possible available appointments for CSHCN in hospitals and educational programs/institutions; and the ratio of CSHCN to potential available and able providers in the United States sorted by 6 American Academy of Pediatric Dentistry (AAPD) districts. RESULTS: Using existing data sets, this analysis found 57 dental schools, 61 advanced education in general dentistry programs, 174 general practice residencies, and 87 children's hospital dental clinics in the United States. Nationally, the number of CSHCN was determined to be 10,221,436. The distribution, on average, of CSHCN per care source/provider ranged from 1,327 to 2,357 in the 6 AAPD districts. Children's hospital dental clinics had fewer than 1 clinic appointment or 1 operating room appointment available per CSHCN. The mean number of CSHCN patients per provider, if distributed equally, was 1,792. CONCLUSIONS: The current US dental care system has extremely limited capacity to care for children with special health care needs. PMID- 21703060 TI - Congenital aplasia of the major salivary glands: literature review and case report. AB - Congenital aplasia of the major salivary glands is rare, and there have been few cases of the condition reported to date. In many cases, absence of the salivary glands is associated with syndromes involving the ectodermal tissues. The xerostomia encountered in affected children is usually associated with increased risk for caries and infections of the soft tissues. The purpose of this paper was to describe the case of a 10-year-old boy with bilateral aplasia of the submandibular and parotid salivary glands and the preventive and restorative treatment rendered. This case study demonstrates the importance of timely diagnosis of this condition in order to prevent the serious oral complications from xerostomia. PMID- 21703061 TI - Evaluation of pediatric dentistry guidelines using the AGREE instrument. AB - PURPOSE: Guidelines are used to inform clinical practice and improve the quality of health care. Poorly developed guidelines may emphasize the incorrect intervention. The purpose of this paper was to evaluate the quality of pediatric dentistry guidelines using the AGREE instrument. METHODS: A search was carried out to identify pediatric dentistry guidelines up to November 2007. Three independent assessors evaluated the guidelines using the AGREE tool. RESULTS: Fifty-seven guidelines produced by 11 organisations were evaluated. Most guidelines assessed were of poor quality, as determined by the AGREE instrument. CONCLUSIONS: Consideration should be given to using the AGREE instrument in the development of new guidelines and review of existing guidelines. PMID- 21703062 TI - A retrospective study of a modified 1-minute formocresol pulpotomy technique part 1: clinical and radiographic findings. AB - PURPOSE: The purpose of this study was to assess the clinical and radiographic outcomes of a 1-minute application of full-strength Buckley's formocresol with concurrent hemostasis using the medicated cotton pledget in human primary teeth. METHODS: Using a retrospective chart review, clinical and radiographic data were available for 557 primary molars in 320 patients. Descriptive statistics and survival analysis were used to assess outcomes. RESULTS: Overall clinical success, radiographic success, and cumulative 5-year survival rates were approximately 99%, 90%, and 87%, respectively. Internal root resorption (~5%) and pulp canal obliteration (~2%) were the most frequently observed radiographic failures. Thirty-nine teeth were extracted due to clinical and or radiographic failure. Mandibular molars were 6 times more prone to radiographic failure than maxillary molars. CONCLUSIONS: Success rates for the modified technique are comparable to techniques that use the 5-minute diluted or full-strength solutions reported in the literature. This 1-minute full-strength formocresol technique is an acceptable alternative to published traditional techniques. PMID- 21703063 TI - A retrospective study of a modified 1-minute formocresol pulpotomy technique part 2: effect on exfoliation times and successors. AB - PURPOSE: The purposes of this study were to evaluate the: effect of a 1-minute application of full-strength Buckley's formocresol with concur- rent hemostasis using the medicated cotton pledget in human primary teeth on their successors; and exfoliation times compared to the contralateral nonpulpotomized tooth. METHODS: Using a retrospective chart review, clinical and radiographic data were available for 557 primary molars in 320 patients. RESULTS: There was no difference between treated and control teeth in the number of enamel defects of succedaneous teeth (P<.45). Approximately 66% exfoliated at the same time as their contralateral counterpart and approximately 29% exfoliated earlier (P<.001). CONCLUSIONS: This 1-minute technique showed a tendency toward early exfoliation, but no effect on clinical management, and no increase in incidence of defects on succedaneous teeth was observed. The 1-minute full-strength formocresol technique may be considered an acceptable alternative to the 5-minute formocresol pulpotomy. PMID- 21703064 TI - Visionaries or dreamers? The story of infant oral health. AB - PURPOSE: To review the early history of the promotion of oral health for infants and toddlers, the impact of the AAPD guideline on infant oral health care and ways to maximize health outcomes. METHODS: Review of the literature. RESULTS: Concepts on primary prevention and early intervention were reported as early as the 19th century. Progress to positively impact the oral health of children has been made. Nevertheless, the advice of early scholars and clinicians that oral care and prevention must begin early with the caregivers and the emergence of the infant's first tooth have not been fully embraced by the profession. CONCLUSIONS: A historical perspective on oral health care for infants and toddlers has been presented. There is a need to move away from the surgical approach of managing oral disease and embrace the concepts of primary care beginning perinatally while more broadly addressing social determinants of health. PMID- 21703065 TI - Use of chlorhexidine gel (0.2%) to control gingivitis and candida species colonization in human immunodeficiency virus-infected children: a pilot study. AB - PURPOSE: The purpose of this study was to evaluate chlorhexidine to control gingivitis and Candida species (spp.) in children infected with the human immunodeficiency virus (HIV) and their acceptance of the therapy. METHODS: Twenty six HIV+ children were selected, and oral exam-established biofilm, gingival indexes, and stimulated saliva were collected for Candida ssp. identification. The children brushed their teeth for 21 days with chlorhexidine gel (0.2%). Salivary samples, biofilm, and gingival indexes were collected after 21-days and again 35 days after ceasing gel use. The children answered a questionnaire about the therapy. RESULTS: All children tested positive for Candida and gingivitis. After 21 days, Candida counts and gingivitis decreased in 25 and 26 children, respectively. Mean reduction was approximately 68% for Candida spp. and 74% for gingivitis. Thirty-five days after discontinuing gel use, gingivitis and Candida spp. increased in 13 and 16 patients, respectively. Considering the Candida spp., the heavy growth was lower in the first re-evaluation. Candida albicans was the most frequent species. Approximately 85% did not experience inconvenience with the gel, and approximately 48% thought it was good for tooth-brushing. CONCLUSION: Chlorhexidine therapy may be an option to treat and pre- vent gingivitis and reduce yeast counts in children infected with HIV. PMID- 21703066 TI - Effects of deep sedation on behaviors and side effects in children undergoing different dental procedures. AB - PURPOSE: The purpose of this study was to determine behavioral characteristics and side effects in children undergoing restorative dental treatment with or without dental extractions under deep sedation. METHODS: This study comprised 68 healthy 4- to 7-year-old children; 34 each were assigned to extraction and restorative groups. Children's behaviors were assessed using the following scales: (1) modified Frankl scale (preoperative period); (2) modified Houpt behavior rating scale (venipuncture period); and (3) modified Wilton behavior scale (recovery period). All complications observed during and after sedation were also recorded. RESULTS: The occurrence of agitation was higher in the extraction group; however, this difference was statistically significant only at 15 minutes after completion of sedation. In both groups, the most common side effects observed were: involuntary movement (during sedation); sleepiness; agitation and dizziness (during the early recovery period); irritability; crying; and sleepiness (following hospital discharge). CONCLUSIONS: Agitation may be observed during procedures involving extractions. Few side effects were observed during and after the sedation procedure in both groups. PMID- 21703067 TI - Success rates of mineral trioxide aggregate, ferric sulfate, and formocresol pulpotomies: a 24-month study. AB - PURPOSE: The purpose of this study was to evaluate the total success rates of mineral trioxide aggregate (MTA), ferric sulfate (FS), and formocresol (FC) as pulpotomy agents in primary molars. METHODS: A randomized, split-mouth study design was used in 32 healthy 5- to 7-year-old children with 128 carious primary molars without clinical or radiographic evidence of pulp degeneration. The pulpotomy agents were assigned as follows: Group 1=MTA; Group 2=FS; Group 3=1:5 diluted Buckley's FC; and Group 4=zinc oxide eugenol (ZOE) base. Clinical and radiographic follow-up at 6, 12, and 24 months used the following criteria: pain; swelling; sinus tract; mobility; internal root resorption; and furcation and/or periapical bone destruction. The data were analyzed using chi-square. RESULTS: No significant differences in success rates were found among the groups at 6 and 12 months. Success rates in groups 1 to 4 at 24 months were 96%, 88%, 88%, and 68% respectively. There was a significant difference (P<.001) between the MTA and ZOE groups at 24 months. CONCLUSIONS: ZOE, as the only pulpotomy medicament, had a significantly lower success rate than MTA. No significant differences were observed, among the 3 experimental materials (MTA, FC, and FS) at 2 years follow up. PMID- 21703069 TI - The work of advocacy. PMID- 21703068 TI - Enamel defects in the complete primary dentition of children born at term and preterm. AB - PURPOSE: This study's purpose was to compare the frequency of enamel defects (ED) in the complete primary dentition (CDD) of term children (TC) and preterm children (PTC) and to analyze neonatal factors associated with ED in PTC. METHODS: The study group was formed by 45 PTC, cared for at the Follow-up Clinic for Preterm Children of the Federal University of Sao Paulo, Brazil. The control group included 46 school-children born at term. RESULTS: ED was more frequent in PTC (87%) than in TC (44%; P<.05). All 34 PTC with tracheal intubation at birth presented ED, showing a strong association between both. The variable was not included in the regression model. To analyze neonatal factors associated with ED in PTC, a model of logistic regression was adjusted. Malnutrition at term corrected age increased the risk of ED in PTC 7.8 times. Opacity (white/cream) and hypoplasia (missing enamel) were frequent types of ED in this series. PTC and TC presented with high ED frequencies. CONCLUSIONS: The frequencies of enamel defects were elevated in term and preterm children, but were higher in the latter. Tracheal intubation was strongly associated with enamel defects, and extrauterine growth restriction significantly increased the risk for enamel defects in preterm children. PMID- 21703070 TI - An alternative explanation for the prevalence and distribution of enamel defects. PMID- 21703071 TI - Marginal microleakage of triage sealant under different moisture contamination. AB - PURPOSE: Glass ionomer sealants (GISs) are promoted in pediatric dentistry for their moisture-friendly properties. This study's purpose was to investigate the marginal leakage of a glass ionomer sealant (Fuji Triage) under different moisture environments. METHODS: Eighty extracted teeth were distributed into 4 groups: (1) control; (2) saliva contamination with 1-second air-thinning; (3) saliva contamination with 10 seconds of air-drying; and (4) saliva contamination with reconditioning. Sealants were placed after contamination. All extracted teeth underwent thermocycling followed by 1% methylene blue dye and distilled water wash. All extracted teeth were then sectioned buccolingually into 3 cross sections and examined at 60X under a stereomicroscope. Microleakage was assessed using a dye penetration scoring system (score=0-3). Data were analyzed with Kruskal-Wallis and Mann-Whitney tests. RESULTS: The control group showed significantly lower marginal leakage than the other 3 groups (P<.02). There was no statistically significant difference among the 3 contaminated groups (P>.34). CONCLUSIONS: Fuji Triage sealant had the least marginal leakage under a moisture controlled environment. When saliva was introduced during the application of the material, microleakage significantly increased. When contamination occurred, 1 second air-thinning of the saliva, 10-second air-drying of the saliva, or reconditioning before sealant application did not show a difference in decreasing microleakage. PMID- 21703072 TI - Comparison of enamel defects in the primary and permanent dentitions of children from a low-fluoride District in Australia. AB - PURPOSE: The purpose of this study was to compare developmental defects of enamel (DDE) in the primary and permanent dentitions of children from a low-fluoride district. METHODS: A total of 517 healthy schoolchildren were examined using the modified DDE criteria. RESULTS: The prevalence of DDE in the primary and permanent dentition was 25% and 58%, respectively (P<.001). The mean number of teeth with enamel opacity per subject was approximately threefold compared to that affected by enamel hypoplasia (3.1+/-3.8 vs 0.8+/-1.4, P<.001 in the primary dentition and 3.6+/-4.7 vs 1.2+/-2.2, P<.001 in the permanent dentition). Demarcated opacities (83%) were predominant compared to diffuse opacities (17%), while missing enamel was the most common type of enamel hypoplasia (50%), followed by grooves (31%) and enamel pits (19%) (P=.04). In the permanent dentition, diffuse and demarcated opacities were equally frequent, while enamel grooves were the commonest type of hypoplasia (52%), followed by missing enamel (35%) and enamel pits (5%; P<.001). CONCLUSIONS: In a low-fluoride community, developmental defects of enamel were twice as common in the permanent dentition vs the primary dentition. In the primary dentition, the predominant defects were demarcated opacities and missing enamel, while in the permanent dentition, the defects were more variable. PMID- 21703073 TI - Bonding of resin composite to caries-affected dentin after Carisolv((r)) treatment. AB - PURPOSE: The purpose of this study was to investigate the effect of Carisolv((r)) on resin composite adhesion on caries-affected dentin. METHODS: Carious lesion specimens (N =46) were prepared from 45 extracted primary molars: Group 1 (N =23) chemomechanical (Carisolv((r))) treatment; Group 2 (N =23)-rotary instrumentation; and Group 3 (N =23)-caries-free specimens from 20 noncarious primary molars. After caries removal (Groups 1 and 2) or washing and drying (Group 3), a resin composite rod (2-mm high, 0.975-mm diameter) was bonded vertically to dentin. Specimens were stressed at constant displacement (1.0 mm/minute) to failure; treated surfaces were examined under a scanning electron microscope. RESULTS: The mean (+/-SD) microshear bond strengths of resin composite to dentin were: Group 1=6.69 (+/-4.08) MPa; Group 2=10.31 (+/-5.47) MPa; and Group 3=7.16 (+/-6.64) MPa. The mean bond strength of resin composite of Group 2 significantly exceeded that of Groups 1 (P=.02) and 3 (P=.01); Groups 1 and 3 did not differ significantly. There was no significant association between failure mode and treatment type (P=.22) or mean bond strength (P=.44). Carisolv((r)) removed the smear layer or limited its formation, producing demineralization incompletely infiltrated by resin composite. CONCLUSION: Chemomechanical treatment of caries-affected dentin of primary teeth did not adversely affect resin composite bonding. PMID- 21703074 TI - Dental maturity of Caucasian children in the Indianapolis area. AB - PURPOSE: The purpose of this study was to compare chronologic and dental age using Demirjian's method. METHODS: Two hundred and fifty-seven panoramic radiographs of healthy 5- to 17.5-year-old Caucasian children in the Indianapolis area were evaluated using Demirjian's 7 tooth method. RESULTS: The intraclass correlation coefficient (ICC) for agreement with Demirjian was 0.94 (95% confidence interval [CI]: 0.87, 0.97). The ICC for repeatability of the investigator was 0.97 (95% CI=0.95, 0.99). Calculated dental age was significantly greater than chronologic age by 0.59 years (P<.001). There was no significant difference in the mean difference in ages between sexes (P=.73). Medicaid subjects had a significantly higher (P<.001) mean difference (0.82 years) than private insurance subjects (0.32 years). There was a significant negative correlation between the chronologic age and the difference in ages (r= 0.29, P<.001). Overweight (P<.001) and obese (P=.004) subjects were significantly more dentally advanced than normal (P=.35) and underweight (P=.42) subjects. CONCLUSIONS: Demirjian's method has high inter- and intraexaminer repeatability. Caucasian children in the Indianapolis area are more advanced dentally than the French-Canadian children studied by Demirjian. Difference between dental age and chronologic age varies depending on the age of the child, socioeconomic status, and body mass index. PMID- 21703075 TI - Validation of a child dental pain questionnaire instrument for the self-reporting of toothache in Children. AB - PURPOSE: The purpose of the present study was to test the reliability and validity of a novel child dental pain questionnaire (child-DPQ). METHODS: The child-DPQ is structured to measure toothache using 3 subscales: (1) prevalence; (2) severity; and (3) impact on daily life. It was tested on 174 8- and 9-year old children. The instrument's reliability was assessed by testing internal and test-retest consistency, and its validity was assessed by testing construct and discriminant validity. Specifically, discriminant validity was tested by comparing the mean scores of 2 clinical groups: (1) absent or treated caries (N =110); and (2) untreated caries (N =64). RESULTS: Internal consistency was confirmed by a Cronbac's alpha coefficient of 0.93. Test-retest reliability was found to be highly reproducible (intraclass correlation coefficient=0.99). The construct validity was satisfactory, demonstrating highly significant correlations among the global indicator, the total score, and subscale scores (P<.001). The child-DPQ score was able to discriminate between the 2 clinical groups (P<.001). CONCLUSION: The present study provides evidence for the reliability and validity of the child dental pain questionnaire in assessing the impact of toothache on the daily life of children. PMID- 21703076 TI - Mixed dentition cavitated caries incidence and dietary intake frequencies. AB - PURPOSE: This study examined risk factors for children having new cavitated caries between 5 and 9 years old. METHODS: Subjects were Iowa Fluoride Study cohort children (mostly Caucasian and of relatively high socioeconomic status) with both primary and mixed dentition caries exams and at least 2 diet diaries recorded between 5 and 8 years old (N=198). Using surface-specific transitions, combined counts of new cavitated caries (d(2-3)f and/or D(2-3)F) were determined from 4 primary second molars, 8 permanent incisors, and 4 permanent molars. Food and beverage intake frequencies were abstracted. Other factors were assessed using periodic questionnaires. Logistic regression identified predictors of new cavitated caries. RESULTS: Thirty-seven percent had new cavitated caries. The mean new cavitated caries count for all children was 1.17 surfaces (+/-2.28 SD). In multivariable logistic regression, the following were significantly associated (P<.10) with having new cavitated caries: noncavitated caries experience at 5 years old (odds ratio [OR]=2.67, P=.03); cavitated caries experience at 5 years old (OR=3.39, P=.004); greater processed starch at snack frequency (OR=3.87, P=.07); being older (OR=1.68, P=.04); and less frequent tooth-brushing (P=.001). CONCLUSION: Results suggested that increased tooth-brushing frequency and reduced consumption of processed starches as snacks may reduce caries incidence in younger school-aged children. PMID- 21703077 TI - Osteoporosis: an increasing concern in pediatric dentistry. AB - Increasing numbers of children are being affected by low bone density and osteoporosis. Bone fractures are the main reason for hospitalization between 10 and 14 years of age and, over the past 3 decades, there has been an increase in the incidence of fractures in children. Childhood factors such as lifestyle, diet, chronic illness, and medications have a vital short-term impact on bone health and a long-term effect on the achievement of peak bone mass, with the potential for morbidity in adulthood. The primary forms of osteoporosis consist of rare inherited conditions, but the secondary forms are becoming more common given that chronically ill children are surviving longer. This subject should be of interest to pediatric dentists, because low mineral density and osteoporosis, together with drugs used to treat them (eg, bisphosphonates), may cause adverse effects in the oral cavity. Furthermore, the pediatric dentist is an important health care professional to counsel patients about healthy lifestyles that can help prevent the condition from an early age. PMID- 21703078 TI - Two-year survival rates of proximal atraumatic restorative treatment restorations in relation to glass ionomer cements and Postrestoration meals consumed. AB - PURPOSE: The purpose of this study was to investigate the influence of 3 glass ionomer cement (GIC) brands and the postrestoration meal consumed on the survival rate of proximal atraumatic restorative treatment (ART) restorations. METHODS: A total of 804 proximal restorations were placed in primary molars by trained operators and assistants using 3 GIC brands. The materials' mixing/placement times, the room temperature and the postrestoration meal consumed by the subjects were documented. The restorations were evaluated soon after placement and after 2 years by trained and calibrated evaluators. RESULTS: After 2 years, approximately 31% of the restorations had survived. There were no statistically significant differences in the survival rate of the restorations in relation to the GIC brands. The postrestoration meal consumed, which was of "hard consistency," was associated with significantly lower survival rate of the restorations. CONCLUSIONS: The survival rate of the proximal restorations was not significantly affected by the glass ionomer cement brands used, but was significantly influenced by the consistency of the next meal consumed by each child. PMID- 21703079 TI - Methemoglobinemia in a newborn: a case report. AB - The purpose of this report was to describe a case of methemoglobinemia involving different systemic complications as a result of local anesthetic injection with lidocaine in a 2-day-old female patient. Acquired methemoglobinemia is considered a major, potentially life-threatening complication. There are several reports of this complication related to anesthetic agents, most commonly prilocaine and benzocaine. It can involve patients of different ages, but it is more common in children 6-years-old and younger, particularly those younger than 3 months. Widely used in dental practices for pain management, lidocaine is considered to be one of the safest anesthetic agents. Although rare, complications of lidocaine administration need to be addressed properly, and adequate training in diagnosis and management of these complications should be provided. Providers should weigh the risk and benefit of using these agents. PMID- 21703080 TI - Oral & maxillofacial manifestations in pediatric esthesioneuroblastoma-report of a case and review of literature. AB - Esthesioneuroblastoma (ENB) is a rare, malignant neoplasm arising from the olfactory epithelial cells, with only approximately 100 pediatric cases being reported in the literature since its original description in 1924. As a result of its origin high in the nasal cavity, most patients have non-specific symptoms, precluding early diagnosis and leading to the development of locally advanced disease that usually has been found to involve the orbital cavity, paranasal sinuses, and anterior cranial fossa in children. The purpose of this paper was to report a rare case of pediatric esthesioneuroblastoma diagnosed following the patient's dental complaints, wherein local invasion of the tumor into the maxillofacial region was noticed before its extension into other vital structures. PMID- 21703081 TI - Conservative surgical treatment of an aggressive calcifying cystic odontogenic maxillary tumor in the young permanent dentition. AB - Calcifying cyst odontogenic tumor (CCOT) is a rare benign cystic neoplasm of odontogenic origin whose treatment depends on the lesion's localization and histological type. The purpose of this report was to describe a case of extensive calcifying cyst odontogenic tumor involving the maxilla of a 12-year old female patient and the treatment option adopted. The lesion was associated with an impacted first premolar, and the roots of the canine and second premolar were divergently displaced. An incisional biopsy revealed the presence of a highly cellular, densely fibrous connective tissue, with diffuse infiltration of mononuclear inflammatory cells. Cystic marsupialization and extraction of the impacted premolar were performed. No signs of lesion recurrence were noted after 28 months. Therefore, marsupialization should be considered when planning CCOT treatment, primarily in young patients with large lesions, to avoid mutilations and tooth loss. PMID- 21703082 TI - Infantile refsum disease with enamel defects: a case report. AB - The purpose of this paper was to present the case of a 15-year-old female diagnosed with infantile Refsum disease (IRD) that presented with generalized enamel defects in the primary and permanent dentition. IRD is an inherited autosomal recessive disorder characterized by aberrant peroxisome function. IRD patients present with multiple clinical manifestations, including: retinitis pigmentosa; nystagmus; sensorineural hearing loss; mental and developmental delays; neuromotor defects; and cerebral ataxia. Craniofacial abnormalities reported include: high forehead; hypoplastic supraorbital ridges; epicanthal folds; midface hypoplasia; and large anterior fontanelle. At present, there is only one known report of dental anomaly associated with this syndrome. This represents the first known reported case in the pediatric dental literature. PMID- 21703083 TI - The demands of a working day among female professional ballet dancers. AB - Professional classical ballet dancers typically face long working days, and many complain of fatigue, particularly as a possible cause of injury. However, little information exists regarding the true physiological demands on dancers. The aim of the present study was therefore to ascertain the daily workload of professional female ballet dancers in terms of work intensity and rest data. Information regarding a single "work day" was obtained from 51 female dancers in one company using a multiple accelerometer. Data were examined for the amount of time spent at work intensities measured in metabolic equivalents (METS)deemed sedentary, low, moderate, and high, and the length of each period at rest. Results indicated significant differences between dancer rankings (corps de ballet, first artist, soloist, and principal) for mean exercise intensity and the percentage of time spent at sedentary intensity (< 3 METS), moderate intensity (3 6 METS) (p < 0.005), and vigorous intensity (6-9 METS) (p < 0.05). The ratios of time spent below 1.5 METS versus time spent above 1.5 METS ("rest" vs. "work") were also significantly different (p < 0.001) between rankings. When rest periods throughout the working day were analyzed, 90% of dancers were found to spend less than 60 consecutive minutes resting at any one time; for 33.3% of dancers this was less than 20 minutes. Results also revealed significant differences (p < 0.05) between dancer rankings for the greatest amount of rest at any one time during the day. It was concluded that female professional classical ballet dancers' ranking in their companies should be considered in devising work-rest schedules to help them to avoid fatigue and resultant injuries. PMID- 21703084 TI - Performance anxiety experiences of professional ballet dancers: the importance of control. AB - Performance anxiety research abounds in sport psychology, yet has been relatively sparse in dance. The present study explores ballet dancers' experiences of performance anxiety in relation to: 1. symptom type, intensity, and directional interpretation; 2. experience level (including company rank); and 3. self confidence and psychological skills. Fifteen elite ballet dancers representing all ranks in one company were interviewed, and qualitative content analysis was conducted. Results revealed that cognitive anxiety was more dominant than somatic anxiety, and was unanimously interpreted as debilitative to performance. Somatic anxiety was more likely to be interpreted as facilitative, with the majority of dancers recognizing that a certain amount of anxiety could be beneficial to performance. Principal dancers suffered from higher intensities of performance anxiety than corps de ballet members. Feeling out of control emerged as a major theme in both the experience of anxiety and its interpretation. As a result, prevention or handling of anxiety symptoms may be accomplished by helping dancers to feel in control. Dancers may benefit from education about anxiety symptoms and their interpretation, in addition to psychological skills training incorporating cognitive restructuring strategies and problem-focussed coping to help increase their feelings of being in control. PMID- 21703085 TI - Energetic efficiency, menstrual irregularity, and bone mineral density in elite professional female ballet dancers. AB - Sports that emphasize low body weight for optimal performance, such as ballet, are associated with an increased prevalence of the female athlete triad (FT). Previous research in this area that involves dancers has been limited; the majority of studies have been performed on adolescents training in classical ballet, and not professional adult dancers. The purpose of this study is to compare the physical and behavioral characteristics of female elite ballet dancers to sedentary, recreationally active non-dancing controls, with regard to characteristics of the FT and energetic efficiency. Women aged 18 to 35 years were recruited as participants. The dancers (N = 15) and non-dancing controls (N = 15) were pair-matched via age (dancers: 24.3 +/- 1.3 years; controls: 23.7 +/- 0.9 years), body mass index (dancers: 18.9 +/- 0.2; controls: 19.4 +/- 0.2 kg/m 2 ), and fat-free mass (dancers: 44.3 +/- 0.8; controls: 44.1 +/- 0.9 kg). Assessments included habitual dietary intake using 4-day food records, self reported physical activity, psychometric measures of eating behaviors, health and menstrual history, body composition and bone density (dual energy x-ray absorptiometry), and resting metabolic rate (RMR) assessed by indirect calorimetry. Characteristics of the FT, specifically menstrual irregularities (6 of 15 dancers reported irregular or no menses; 1 of 15 controls reported irregular menses) and low energy availability, were more prevalent in dancers than in pair-matched controls. Despite having a similar fat-free mass (FFM), dancers had a significantly lower absolute RMR (dancers: 1367 +/- 27; controls: 1454 +/- 34 kcal/d; p <= 0.05) and significantly lower RMR relative to FFM (dancers: 30.9 +/- 0.6; controls: 33.1 +/- 0.8 kcal/kg fat-free mass/d; p <= 0.05). Energy intake between dancers (1577 +/- 89 kcal/d) and pair-matched controls (2075 +/- 163 kcal/d) also differed significantly (p <= 0.01). Six of the 15 dancers met the criteria for the FT (including low bone mineral density, menstrual irregularities, and eating pathology accompanied by low energy availability) and, therefore, represent a population of individuals afflicted with this disorder. These findings provide insight as to the metabolic impact of chronic energy restriction, and suggest that alterations in RMR (i.e., energetic efficiency) may be an indicator of low energy availability. Future larger-scale studies are warranted to address this possibility. Interventions aimed at increasing energy availability in elite female ballet dancers may be needed to promote optimal health status. PMID- 21703086 TI - Spinal reflex adaptation in dancers changes with body orientation and role of pre synaptic inhibition. AB - Dancers undergo specific activity-dependent neuromuscular adaptations following long-term training that allow them to develop the refined motor skills required for success in dance. The spinal stretch reflex circuit has demonstrated specific adaptations following prolonged dance training. Adaptations in the spinal stretch reflex can be studied using H-reflex methodology, first described by Paul Hoffmann in 1910. This article discusses H-reflex methodology and presents data that examine the neural mechanisms that contribute to adaptations in the spinal stretch reflex with dance training. Two groups of subjects, modern dancers (N = 5) and untrained controls (N = 5), were tested. On one-half of the trials common peronal nerve (CPN) conditioning of the soleus H-reflex was used to assess one spinal mechanism, pre-synaptic inhibition; the other half tested the soleus H reflex only (unconditioned). The dependent variables were the H(max)/M(max) ratios, unconditioned and with CPN conditioning, expressed as percent values. The results revealed three main findings: 1. Modern dancers had smaller H(max)/M(max) ratios than control subjects; 2. The H(max)/M(max) ratio was smaller in standing posture than in prone among both dancers and controls; and 3. Pre-synaptic inhibition was not different between dancers and controls in standing. In conclusion, modern dancers have smaller H-reflexes than untrained controls, but pre-synaptic inhibition does not appear to explain this difference. PMID- 21703087 TI - Trait anxiety and achievement goals as predictors of self-reported health in dancers. AB - Psychological characteristics associated with interpreting situations as stressful can impact people's physical health. The present investigation focused on trait anxiety and achievement goals as two such characteristics that may predict health outcomes in dancers, a group prone to chronic stress and injury. Students enrolled in a university dance program (N = 109) completed measures of trait anxiety, achievement goals for dance classes, and current health at the start of an academic term. Health was assessed again at the end of the term. Greater trait anxiety predicted poorer health at the end of the term when controlling for initial health. In addition, the more dancers wanted to avoid performing worse than others (performance-avoidance goals), the poorer was their physical health at term's end. It is concluded that anxiety and performance avoidance goals may hinder dancers' ability to cope with the physical stress associated with a dance career. PMID- 21703088 TI - Perceived autonomy support, motivation regulations and the self-evaluative tendencies of student dancers. AB - Limited research has considered the social-environmental and motivational processes predictive of self evaluations and body-related concerns. Evidence suggests that low self-esteem, poor body evaluations, and associated anxieties are particularly prevalent among the student dance population. Grounded in self determination theory (SDT), this study examined the relationships among perceptions of autonomy support, motivation regulations, and self-evaluations of body-related concerns in the context of vocational dance. Three hundred and ninety-two dancers completed questionnaires regarding their perceptions of autonomy support in their dance school, reasons for engaging in dance, self esteem, social physique anxiety (SPA), and body dissatisfaction. Structural equation modeling analyses revealed that perceived autonomy support predicted intrinsic motivation (+) and amotivation (-). Extrinsic regulation positively predicted SPA. Amotivation mediated the associations between perceptions of autonomy support and dancers' self-esteem, SPA, and body dissatisfaction. The utility of SDT in understanding predictors of self-worth, physical evaluations, and associated concerns was supported. Moreover, this study provides preliminary evidence supporting the applicability of SDT in dance contexts. PMID- 21703089 TI - A within-subject analysis of the effects of remote cueing on pelvic alignment in dancers. AB - Many professionals who treat and train dancers believe that good alignment at the pelvis can facilitate movement efficiency and reduce injury risk in a variety of dance genres. This study evaluated the effects of a remote cueing technique on pelvic alignment for dancers in a university-based professional training program. Two female dancers participated in 20-minute individualized observation and training sessions twice a week for eight weeks. Pelvic alignment improved to criterion levels for both dancers, suggesting that individualized approaches may have special utility in training dancers. PMID- 21703090 TI - Pelvis and hip three-dimensional kinematics in grand battement movements. AB - Dancers frequently sustain hip injuries, including labral tears, coxa saltans, stress fractures, tendinosis, and joint disease. High velocity kicks (grand battement), with extreme abduction and external rotation (ER), may stress the hip, sacroiliac joint, and surrounding soft tissue. However, three-dimensional kinematic dance descriptions are limited. The purpose of this study was to describe the kinematics of the pelvis and hip in grand battement movements in healthy dancers. Seventeen advanced-level college dancers performed three battement conditions: battement devant to the front, a la seconde to the side, and derriere to the back. Data were collected with a 5-camera motion capture system. Repeated measures ANOVA (p < 0.05) compared peak pelvis and hip angular displacement and hip and toe velocity for all conditions and planes. Three dimensional hip to pelvic ratios were calculated. There were differences in pelvic angular displacement between conditions in all planes (p < 0.00). Battement devant posterior pelvic tilt exceeded that of battement seconde. Both were opposite in direction from the anterior pelvic tilt of battement derriere. All conditions demonstrated pelvic obliquity toward the stance limb, with battement derriere greater than devant and seconde. Battement derriere transverse plane pelvic displacement exceeded that found in devant and seconde. There were also differences in hip angular displacement between conditions in all planes (p < 0.00). Battement derriere hip extension differed from battement devant and seconde flexion. The hip abducted in all conditions, with battement seconde exceeding devant and derriere. In the transverse plane, the hip rotated internally in battement seconde and externally in battement derriere and devant. In battement devant and seconde, peak hip ER decreased relative to baseline, while increasing at the peak of battement derriere. Battement peak velocities were relatively low. The ratio of hip to pelvic angular sagittal plane motion was 4.1, 2.6, and 0.5 in battement devant, seconde, and derriere respectively; 0.9, 2.6, and 1.5 in the frontal plane; and 0.6, 8.5, and 0.2 in the transverse plane. This confirms that pelvic motion provides a large proportion of the battement movement. PMID- 21703091 TI - Bone mineral density and body composition of collegiate modern dancers. AB - This study investigates body composition (BC), bone mineral density (BMD), eating behaviors, and menstrual dysfunction in collegiate modern dancers. Thirty-one female collegiate modern dance majors (D), 18 to 25 years of age, and 30 age matched controls (C) participated in the study. BC and BMD were measured using dual energy x-ray absorptiometry (DXA). Upper and lower body strength was assessed by chest and leg press one-repetition maximum tests. Participants completed three-day food records, and the diet was analyzed using nutritional software. Menstrual dysfunction (MD) and history of eating disorder (ED) data were collected via questionnaires. BC and BMD variables were analyzed using MANCOVA and frequency of ED and MD by Chi-Square analysis. BMD was greater in D than C at the spine (1.302 +/- 0.135 g/cm(2) vs. 1.245 +/- 0.098 g/cm(2)), and both the right hip (1.163 +/- 0.111 g/cm(2) vs. 1.099 +/- 0.106 g/cm(2)) and left hip (1.160 +/- 0.114 g/cm(2) vs. 1.101 +/- 0.104 g/cm(2); p <= 0.05). Total body fat percentage was lower in D than C (25.9 +/- 4.2% vs. 32.0 +/- 5.9%; p <= 0.05), and percent of fat distributed in the android region was also lower in D than C (28.0 +/- 6.2% vs. 37.6 +/- 8.6%; p <= 0.05). With regard to diet composition, only percent fat intake was lower in D than C (27.54 +/- 6.8% vs. 31.5 +/- 7.4%, p <= 0.05). A greater incidence of ED was reported by D than C (12.9% vs. 0%; p <= 0.05), as well as a greater incidence of secondary amenorrhea (41.9% vs 13.3%; p <= 0.05). No differences were found for incidence of primary amenorrhea, oligomenorrhea, or use of birth control. Strength values were higher in D than C for both chest press (30.1 +/- 0.9 kg vs. 28.4 +/- 1.0 kg; p <= 0.05) and leg press (170.7 +/- 4.2 kg vs.163.1 +/- 3.9 kg; p <= 0.05). It is concluded that the dancers in our study had a healthy body weight, yet reported a higher incidence of eating disorders and menstrual dysfunction, than non-dancers. These dancers' higher BMD may be attributable to the mechanical loading and increased strength associated with practicing modern dance. Further, modern dancers had lower centrally located body fat, which decreases the risk for cardiovascular and metabolic diseases. PMID- 21703092 TI - Case studies in cervicothoracic spine function evaluation and treatment of two dancers with mechanical neck pain. AB - It has been reported that manual therapy directed at the thoracic spine followed by exercise may improve outcomes in patients with mechanical neck pain. At this point, there is little available data on dancers with neck pain, and it is unclear whether this type of treatment is appropriate for restoring the rigorous level of activity required of the dancer. The purpose of this study was to review the evaluation, clinical decision-making process, and treatment of two dancers one with acute and the other with chronic neck pain-who fell into the classification of patients who might benefit from an intervention to the thoracic spine. The two participants were a musical theater dancer with an acute onset of neck pain and a retired dancer who was an active dance company director with an 11-year history of chronic neck pain. Both participants went through a standard examination and were treated with mobilizations to the upper thoracic spine followed by therapeutic exercises. In both cases, successful outcomes were achieved immediately after treatment and up to six months after discharge from physical therapy. PMID- 21703093 TI - The effects of nutrition, puberty and dancing on bone density in adolescent ballet dancers. AB - Ballet dancers have on average a low bone mineral content (BMC), with elevated fracture-risk, low body mass index (BMI) for age (body mass index, kg/m2), low energy intake, and delayed puberty. This study aims at a better understanding of the interactions of these factors, especially with regard to nutrition. During a competition for pre-professional dancers we examined 127 female participants (60 Asians, 67 Caucasians). They averaged 16.7 years of age, started dancing at 5.8 years, and danced 22 hours/week. Assessments were made for BMI, BMC (DXA), and bone mineral apparent density (BMAD) at the lumbar spine and femoral neck, pubertal stage (Tanner score), and nutritional status (EAT-40 questionnaire and a qualitative three-day dietary record). BMI for age was found to be normal in only 42.5% of the dancers, while 15.7% had a more or less severe degree of thinness (12.6% Grade2 and 3.1% Grade 3 thinness). Menarche was late (13.9 years, range 11 to 16.8 years). Food intake, evaluated by number of consumed food portions, was below the recommendations for a normally active population in all food groups except animal proteins, where the intake was more than twice the recommended amount. In this population, with low BMI and intense exercise, BMC was low and associated with nutritional factors; dairy products had a positive and non-dairy proteins a negative influence. A positive correlation between BMAD and years since menarche confirmed the importance of exposure to estrogens and the negative impact of delayed puberty. Because of this and the probable negative influence of a high intake of non-dairy proteins, such as meat, fish, and eggs, and the positive association with a high dairy intake, ballet schools should promote balanced diets and normal weight and should recognize and help dancers avoid eating disorders and delayed puberty caused by extensive dancing and inadequate nutrition. PMID- 21703094 TI - Ground reaction forces in ballet dancers landing in flat shoes versus pointe shoes. AB - Reports in the literature suggest an abundance of lower extremity injuries in ballet dancers; however, few studies have identified the underlying causes of these injuries. Excessive ground reaction forces and shoe type are two potential contributing factors. Eighteen collegiate female ballet majors volunteered for this study. Each participant performed 12 trials of a basic ballet jump, six trials in flat shoes and 6 trials in pointe shoes, landing on a force plate. Ground reaction force (Newtons) and jump height (centimeters) were assessed for each trial. The mean ground reaction force and jump height for each shoe condition was used for statistical analysis. Two dependent t-tests were conducted to determine differences between the shoe types, one for ground reaction force and one for jump height. Alpha level was set at p < .05. We found that the ground reaction force was significantly higher when landing in flat shoes than in pointe shoes (p = .003). There was no significant difference in jump height between the two shoe conditions. This leads us to believe that the increase in ground reaction force was produced primarily by the shoe type. PMID- 21703095 TI - Development and evaluation of an educational intervention program for pre professional adolescent ballet dancers: nutrition for optimal performance. AB - The purpose of this investigation was to develop, implement, and evaluate a theoretically based nutritional education intervention through a DVD lecture series (three 30-minute classes) in summer intensive programs for pre professional, adolescent ballet dancers. Objectives of this intervention program were to increase knowledge of basic sports nutrition principles and the Female Athlete Triad and promote self-efficacy for adopting healthier dietary habits. Dancers ranging from 13 to 18 years old who were attending summer intensive programs affiliated with professional ballet companies were recruited. Group One (n = 231) participated in the nutrition education program, while Group Two the control participants (n = 90) did not. Assessments of the participants' dietary status consisted of a demographic questionnaire, a Sports Nutrition Knowledge and Behavior Questionnaire, and a Food Frequency Questionnaire. The intervention group was assessed at baseline, immediately post-program, and at six weeks post program. The control group was assessed at baseline and at six weeks post baseline. The intervention program was effective at increasing nutrition knowledge, perceived susceptibility to the Female Athlete Triad, and self efficacy constructs. Improvements in dietary intake were also observed among intervention group participants. To improve overall health and performance nutrition education should be incorporated into the training regimens of adolescent dancers. This potentially replicable DVD-based program may be an effective, low-cost mechanism for doing that. PMID- 21703096 TI - Injury, imagery, and self-esteem in dance healthy minds in injured bodies? AB - The purpose of this study was to investigate a selection of psychological variables (help-seeking behaviors, mental imagery, self-esteem) in relation to injury among UK dancers. We recruited 216 participants from eight dance styles and six levels of involvement. It was found that 83.5% of the participants had experienced at least one injury in the past year. The most common response to injury was to inform someone, and most continued to dance when injured, albeit carefully. Physical therapy was the most common treatment sought when an injury occurred (38.1%), and dancers seemed to follow recommendations offered. Injured and non-injured dancers did not differ in their imagery frequencies (facilitative, debilitative, or injury-related) and scored similarly (and relatively high) in self-esteem. Neither facilitative nor debilitative imagery was correlated with self-esteem, but dancers who engaged in more facilitative imagery in general also reported doing so when injured. Altogether, it appears that injury is not related to dancers' self-esteem or imagery, at least not when injuries are mild or moderate. Even so, such conclusions should be made with caution, given that most dancers do sustain at least one injury each year. PMID- 21703097 TI - Effect of footwear on dancers: a systematic review. AB - Dancers need their feet to be healthy and pain-free; therefore, the footwear they use is of great importance. Footwear has the potential to enhance or restrict movement and impact the dancer's body in various ways. To evaluate the effects of footwear on dancers, in particular the effects on foot motion and injury during dance movements, we undertook a systematic review of the literature. The major databases were searched for articles on theatrical dance styles and dance footwear. Sixteen articles were selected for inclusion in this study, ten on ballet and the remainder covering a variety of other genres. The contribution of dance shoes to the quality of dance movement is a relatively unexplored subject; little experimental research has been done. Prospective scientific evidence is needed to support or disprove traditional beliefs regarding the effects of footwear on dance performance and dancers' health. PMID- 21703098 TI - Empiric treatment of chronic cough in adults. AB - Cause-directed treatment is the mainstay of the current diagnostic approaches for chronic cough. However, empiric therapy has also been advocated in several recent guidelines for the management of chronic cough in adults. This study was designed to evaluate the usefulness of empiric therapy for chronic cough in adults. A literature review is given to discuss the issues related to empiric therapy for chronic cough in adults, including the benefits and limitations of empiric therapy, empiric treatment for the common causes of chronic cough, and the selection of management strategies. Empiric therapy for chronic cough in adults, because of its simplicity and less expense, provides the convenience for doctors in the clinics with limited facilities. It can be used either alone or in combination. When used properly, it can avoid the excessive laboratory investigations and reach the therapeutic success rate similar to cause-directed treatment. Empiric therapy is a simple and useful means for the management of chronic cough in adults and can be used as a surrogate for cause-directed therapy. PMID- 21703099 TI - Comparison of the Multi-Test II and ComforTen allergy skin test devices. AB - The performance of different devices for percutaneous allergy skin testing may have statistically and clinically significant differences. We compared two multihead allergy skin testing devices: Multi-Test II (Lincoln Diagnostics, Decatur, IL) and ComforTen (Hollister-Stier Laboratories, Spokane, WA). Skin tests with glycerinated histamine (6 mg/mL base) and glycerinated saline were applied to 30 adults using Multi-Test II on the volar surface of one forearm and ComforTen on the opposite forearm. For each device, data were obtained from 150 histamine sites and 90 negative control sites. Defining a positive result using cutoff wheal sizes of either 5-mm versus 3-mm inclusive, respective results for Multi-Test II sensitivity were 97% versus 100% with specificity of 100% versus 97%, whereas corresponding ComforTen sensitivity increased from 26 to 82% with specificity of 100% versus 99%. For Multi-Test II versus ComforTen, histamine mean (SD) wheal sizes were 7.47 (1.72) mm versus 3.93 (1.59) mm (p = 0.00), mean coefficients of variation (CV) were 23.0% versus 40.5%, and pooled estimates of variance were 1.42 versus 1.29. Comparing results at different test head positions, there was no statistically significant variation in histamine wheal sizes with either device. Multi-Test II had notably lower CV, greater wheal size, and higher sensitivity but similar specificity to ComforTen. Consequently, Multi Test II had superior performance at both 3- and 5-mm wheal cutoffs. Because ComforTen had a low sensitivity at the 3-mm and, particularly, at the 5-mm wheal cutoff, skin testing with this device might result in underdiagnosis of allergy using either cutoff. PMID- 21703100 TI - Reliability of skin test results when read at different time points. AB - Percutaneous skin testing to determine allergies is usually read 15-20 minutes after placement, but the time to reading may be prolonged because of clinic duties or emergencies. The objective of the study was to compare skin-prick testing (SPT) wheal and flare reactions at 10, 30, and 40 minutes with the standard 20 minutes to determine if extended time from placement to reading skin tests interferes with clinical significance. Fifty-three subjects undergoing routine aeroallergen SPT for allergy symptoms were tested with allergen extracts, histamine, and a negative control solution. Based on these results, SPTs can be read up to 40 minutes after placement but are more reliable when read between 20 and 30 minutes after placement. Skin testing to determine IgE-mediated or immediate hypersensitivity can be read up to 30 minutes without significant loss of reliability. PMID- 21703101 TI - The effect of intranasal carbon dioxide on the acute response to nasal challenge with allergen. AB - Intranasal carbon dioxide (CO(2)) was shown to reduce symptoms of seasonal allergic rhinitis (SAR). This study was designed to evaluate the effect of CO(2) on nasal allergen challenge. We conducted a randomized, controlled, crossover trial in 12 subjects with SAR outside their pollen season. Thirty minutes after a 20-second exposure to CO(2) or no exposure, subjects underwent a unilateral, localized, nasal allergen challenge. Filter paper disks were placed on the nasal septum to deliver a sham challenge followed by 2 increasing doses of either grass or ragweed allergen. Secretions were collected from both sides of the septum to evaluate the nasonasal reflex and were assayed for histamine. Nasal and eye symptoms were recorded. The primary outcome measure was the contralateral, reflex, secretory response to allergen as measured by secretion weights. Secondary outcome measures included ipsilateral nasal secretion weights, nasal and eye symptoms, levels of histamine in nasal secretions, and eosinophils in nasal scrapings. Subjects reported a transient burning sensation during exposure to CO(2). Compared with no treatment, active treatment resulted in a significant reduction in sneezes (p = 0.05), contralateral secretion weights (p = 0.04), and bilateral runny nose symptoms (p = 0.01). Ipsilateral secretion weights were numerically reduced. Histamine levels in ipsilateral nasal secretions increased significantly when the subjects received sham treatment but did not increase after pretreatment with CO(2). Treatment with nasal CO(2) resulted in partial reduction of the acute response to allergen challenge. Reflex responses were reduced, supporting an effect on neuronal mechanisms, which predict usefulness in the treatment of allergic rhinitis. Registered with the U.S. National Institutes of Health clinicaltrials.gov. Identifier: NCT00618410. PMID- 21703102 TI - Eotaxin, but not IL-8, is increased in upper and lower airways of allergic rhinitis subjects after nasal allergen challenge. AB - The aim of this study was to assess the impact of a single nasal allergen challenge (NAC) on levels of eotaxin and IL-8 and the inflammatory cells in upper and lower airways of allergic rhinitis (AR) patients. Twenty-four AR patients and 12 control subjects entered a sequential nasal placebo challenge and NAC study, out of the pollen season. Nasal lavage fluid (NLF) was obtained at baseline, 15 minutes, and 1, 5, and 24 hours postchallenge. Before and 24 hours after placebo/allergen challenge induced sputum was performed. NLF and induced sputum were evaluated for total cell count (TCC) and differential cell count and analyzed for concentrations of eotaxin and IL-8 using ELISA method. NAC in AR subjects was associated with significantly increased sputum (p = 0.008) and NLF (p < 0.001) eotaxin levels. Post-NAC IL-8 levels were significantly increased in NLF (p < 00001) but not in sputum (p = 0.080) of AR subjects. Increased eotaxin levels in NLF positively correlated with the increased TCC and eosinophils. Positive correlations were also found between NLF increased eotaxin level and sputum TCC, eosinophils, and macrophages. NAC is associated with the increased levels of eotaxin in lower airways of AR subjects. Allergen-induced secretion of eotaxin in nasal mucosa of AR subjects is involved in determining the cellular character of both upper and lower airway inflammation. PMID- 21703103 TI - Camel milk: an alternative for cow's milk allergy in children. AB - Treatment of cow's milk allergy (CMA) in children includes avoidance of cow's milk and providing a milk substitute. This study was designed to determine whether CMA children could safely consume camel's milk as an alternative, and skin-prick test (SPT) to camel's milk could be a reliable tool in selecting them. Between April 2007 and February 2010, children with confirmed CMA seen at the Allergy-Immunology Clinic, Hamad Medical Corp., were enrolled into this prospective cohort study. Subjects had a detailed history and medical examination, complete blood count with differential count, total serum IgE, and specific IgE test and SPT to cow's milk. Patients with positive SPT and an elevated cow's milk-specific IgE had negative SPT to camel's milk. Of 35 children (23 male and 12 female children) aged 4-126 months (median, 21 months), 23 patients (65.7%) presented with acute urticaria, 17 (48.6%) with atopic dermatitis, 9 (25.7%) with anaphylaxis, 8 (22.9%) with failure to thrive, and 5 (14.3%) with chronic vomiting. Twenty-eight patients (80%) had family history of allergy. Twenty-six patients (74.3%) were breast-fed for <=18 months. Mean white blood cell count was 9860.5 cells/MUL, absolute eosinophil count was 1219 cells/MUL, IgE was 682 IU/mL, and cow's milk-specific IgE was 22.01 kU/L. Only 7 patients (20%) had positive SPT to camel's milk and 28 (80%) were negative to camel's milk. All patients with negative SPT took camel's milk without any reactions. In children with CMA, SPT is a reliable clinical test in ruling out reactivity to camel's milk so these children could safely take camel's milk as an alternative nutrient. PMID- 21703104 TI - Selective cyclooxygenase-2 inhibitor cross-reactivity in aspirin-exacerbated respiratory disease. AB - Aspirin-induced asthma (AIA) is a severe and difficult-to-treat allergic disease in which acute asthma attacks are induced by nonsteroidal anti-inflammatory drugs. Patients with AIA rarely experience asthma attacks when taking celecoxib, a specific inhibitor of cyclooxygenase (COX) 2. A 33-year-old woman had a severe asthma attack with hypoxia and lost consciousness after oral provocation testing with 15 mg of aspirin and also with 50 mg of celecoxib. After 2 months of treatment with 10 mg/day of oral prednisolone, 1600 MUg/day of inhaled fluticasone propionate, montelukast as a leukotriene receptor antagonist (LTRA), and long-term beta-agonist, we again challenged her with a provocation test with up to 200 mg of celecoxib; this time there were neither allergic symptoms nor decrease in forced expiratory volume in 1 second. Patients with severe or poorly controlled asthma may experience asthma attacks even if using selective COX-2 inhibitors. However, treatment with steroids and an LTRAs may inhibit asthma attacks induced by celecoxib. PMID- 21703105 TI - Increasing the impact of quality improvement science: learning from the past and changing the future. PMID- 21703106 TI - Impact factor in general practice. PMID- 21703107 TI - Practice-based small group learning: what are the motivations to become and continue as a facilitator? A qualitative study. AB - INTRODUCTION: Practice-based small group learning (PBSGL) originated in Canada and has spread to Scotland. After a successful pilot in 2004, there has been rapid growth in the number of participants in Scotland, particularly among general practitioners (GPs). Growth of participant numbers has required the recruitment and retention of trained peer facilitators who help PBSGL groups to learn. It was not known what the perceptions and experiences of PBSGL facilitators were; in particular what had motivated them to become and continue as facilitators. METHOD: Two focus groups of PBSGL facilitators were held; their discussions were audio-recorded and transcribed with permission. Data generated were coded, and themes were constructed from these codes. RESULTS: Participants found facilitation work to be enjoyable and useful. They had positive past experiences of problem-based learning and of small group learning. Older facilitators had experiences gained through their involvement in GP registrar training. Some of the younger facilitators saw the programme as being a method to enhance and advance their careers. There were anxieties about recruiting new PBSGL groups from potential members relatively unknown to facilitators. Once groups were established, facilitators felt there was little need for further support. DISCUSSION: Participants were enthusiastic about PBSGL facilitation, suggesting that the programme will continue and may grow further. Their positive perceptions and experiences should reassure potential new facilitators. PMID- 21703108 TI - Building high functioning clinical teams through quality improvement initiatives. AB - BACKGROUND: Team-based care has consistently been associated with improved clinical outcomes. However, strategies for promoting and sustaining a team-based approach in family medicine practice are more elusive. METHODS: We conducted a longitudinal time series cohort study of 30 primary care providers in seven practices to assess the sequential addition of three different chronic disease management feedback reports over 24 months, culminating in a team-based quality improvement intervention linked to feedback, assessing clinical performance and self-reported effectiveness. RESULTS: The proportion of patients at their low density lipoprotein target (<100 mg/dL) improved over the 24-month study period (P<0.001) but the rate of clinical improvement was more modest when feedback data were only presented at an individual and at a team level. When feedback reports were linked to a team-based quality improvement intervention, the results were more robust and were sustained for 12 months following the intervention cycle. Surveyed clinicians reported that the individual and team reports impacted both on their own practice approach and on team functioning. CONCLUSIONS: These findings suggest a strategic role for clinical performance feedback linked to team initiated quality improvement initiatives for improving both clinical outcomes and clinical team-based care. PMID- 21703109 TI - Does a general practitioner support unit reduce admissions following medical referrals from general practitioners? AB - BACKGROUND: Emergency medical admissions to UK hospitals have been increasing steadily over the past few decades and there are likely to be a proportion of these admissions that are avoidable. This evaluation aims to demonstrate whether a general practitioner support unit (GPSU) reduces general practitioner (GP) referred emergency medical admissions to an acute hospital. METHODS: The GPSU comprises a team of GPs based in the hospital with the purpose of providing alternatives to admission for medical referrals from community GPs. This is an observational study of patients referred and admitted to the Medical Admissions Unit (MAU) of an acute hospital over two six-month periods, in 2007 prior to and in 2008 after the introduction of the GPSU. RESULTS: The number of GP referrals to the MAU per day decreased by 1.55 (confidence interval -2.45 to -0.51) patients with the GPSU in place. The number admitted to the hospital per day from MAU decreased by a mean of 0.48 patients but with confidence intervals that included the null hypothesis (-1.39 to 0.44). In comparison, non-GP admissions that were not targeted by the GPSU increased by 3.99 per day (2.64 to 5.33). CONCLUSION: An acute GP led service run from within the hospital to provide support to community GPs led to a modest reduction in the number of GP admissions to the MAU, but did not reduce the number of GP admissions to the hospital wards. PMID- 21703110 TI - The prevalence of co-administration of clopidogrel and proton pump inhibitors. AB - BACKGROUND: Recent studies have suggested that proton pump inhibitors (PPIs) may inhibit the antiplatelet activity of clopidogrel, increasing the risk of major cardiovascular events in patients taking clopidogrel and PPIs together. AIM: The primary aim of this study was to determine the prevalence of co-prescription of clopidogrel and PPIs amongst residents of aged-care facilities in New South Wales, Australia. METHODS: One-year prescription records of 791 aged-care residents were analysed for prevalence of co-prescribing of clopidogrel and PPIs, and aspirin with clopidogrel and PPIs. Prevalence of co-prescribing of clopidogrel, aspirin and PPI in diabetic patients and clopidogrel with various CYP2C19 inhibitors was also examined. RESULTS: Of the 791 residents studied, 60 were prescribed clopidogrel, 248 were on aspirin and 326 were prescribed a PPI. Among residents who were prescribed PPIs, 155 were prescribed omeprazole, 72 pantoprazole, 15 lansoprazole, 44 esomeprazole and 51 rabeprazole. Eleven of these residents had taken more than one PPI during the study period. Thirty-nine residents took a combination of clopidogrel and a PPI (any PPI) for a mean 203 days (SD 12). Thirteen residents were on the combination of aspirin and clopidogrel for a mean of 202 days (SD 111). Nine residents took the combination of clopidogrel, aspirin and a PPI (any PPI) for a mean of 173 days (SD 81). Only one patient on clopidogrel was receiving a CYP2C19 inhibitor in addition to a PPI. CONCLUSIONS: A significant number of residents in this cohort were taking a combination of clopidogrel and a PPI, mainly omeprazole. Residents who were on the combination of clopidogrel and a PPI, with or without aspirin, were on these combinations for a significantly long duration, which could increase their risk of adverse cardiovascular events. PMID- 21703111 TI - Raising achievement: educating physicians to address effects of at-risk drinking on common diseases. AB - BACKGROUND: Despite a high prevalence, internists rarely screen for at-risk drinking. A contributing factor is likely to be physicians' limited understanding of the negative effects that at-risk drinking can have on common clinical conditions managed on a daily basis. OBJECTIVE: To develop and conduct a pre-post pilot evaluation of a web-based educational programme to educate and support physicians to assess alcohol use in patients with sleep disorders, depression and hypertension. METHODS: An expert panel developed a programme that addressed: 1) screening for alcohol use; 2) evidence on effect of alcohol on hypertension, sleep disorders and depression; 3) brief interventions for at-risk drinking with patient education materials; and 4) codes for payment of brief alcohol interventions. From an internist network, 17 physicians were recruited for a pilot test of the web-based educational programme. All participants were surveyed at baseline and at an end point three months after the intervention about attitudes, knowledge and beliefs about at-risk drinkers and effects of alcohol on hypertension, sleep disorders and depression. RESULTS: Among the 17 study physicians: 1) most believed that at-risk drinking affected their ability to treat hypertension, sleep disorders and depression (77% at baseline and 65% at end point); 2) nearly all were aware that at-risk drinking affects hypertension, sleep disorders and depression (94% at baseline and 94% at end point); and 3) 94% rated the educational programme positively at the end point. Frustration with managing at-risk alcohol use decreased (from 71% at baseline to 53% at end point) and study physicians' self-reported screening for at-risk drinking increased for new patients (from 47% at baseline to 71% at end point) and established patients (from 35% at baseline to 47% at end point). CONCLUSION: This pilot of a web-based educational programme for internists was well received by study physicians. The programme increased screening for at-risk drinking while reducing frustration in dealing with this condition. Future work needs to evaluate this highly accessible programme in diverse practices and assess patient-related outcomes. PMID- 21703112 TI - Design of a quality and performance improvement project for small primary care practices: reflections on the Center for Practice Innovation. AB - BACKGROUND: Small practices often lack the human, financial and technical resources to make necessary practice improvements and infrastructure investments in order to achieve sustainable change that promotes quality and efficiency. AIMS: To report on an effort to assist small primary care practices in improving quality of care and efficiency of practice management to meet the needs of patients, improve physician satisfaction and enhance the ability of these small practices to survive. METHODS: We report on an intervention design and the reflections of the implementers on what they learned and what went well or poorly during implementation. Results of the intervention are reported separately (in Quality in Primary Care). Thirty practices underwent the entire intervention. The practices were selected on the basis of practice size, diversity in patient factors, apparent dedication to making practice improvements and geographic location. The main components of the intervention were two site visits to the participating practices by Center for Practice Innovation (CPI); now known as the Centre for Practice Improvement and Innovation, team members. The CPI team provided ongoing advice and support in focus areas selected by practices after initial site visit and assessment. RESULTS: A customised session focusing on the practice report and on helping practices to think about which areas they wished to improve was more effective in engaging practices than didactic presentation. Quality and practice management improvements were observed in information posting, patient education, staff communication and patient safety practices. Having a strong physician champion and a strong office manager determined to make quality improvement changes were important elements for successful change. In addition, practices with greater stability of staff and strong finances were more likely to meet project goals. CONCLUSIONS: Small practices today are facing a range of important challenges. The CPI sought to provide successful guidance to small practices with evidence of positive change in some clinical measures, patient satisfaction and practice motivation to implement quality of care and practice management improvements. PMID- 21703113 TI - Erythropoietin receptor positive circulating progenitor cells and endothelial progenitor cells in patients with different stages of diabetic retinopathy. AB - OBJECTIVE: To investigate the possible involvement of erythr opoietin (EPO)/erythropoietin receptor (EPOR) system in neovascularization and vascular regeneration in diabetic retinopathy (DR). METHODS: EPOR positive circulating progenitor cells (CPCs: CD34(+)) and endothelial progenitor cells (EPCs: CD34(+)KDR(+)) were assessed by flow cytometry in type 2 diabetic patients with different stages of DR. The cohort consisted of age- and sex-matched control patients with out diabetes ( n=7),non-proliferative DR (NPDR, n=7),non proliferative DR (PDR, n=8), and PDR complicated with diabetic nephr opathy (PDR DN, n=7). RESULTS: The numbers of EPOR(+) CPCs and EPOR(+) EPCs were reduced remarkably in NPDR compared with the control group (both Pu0.01), whereas rebounded in PDR and PDR-DN groups in varyingdegrees. Similar changes were observed in respect of the proportion of EPOR(+)CPCs in CPCs (NPDR vs. control, Pu0.01) and that of EPOR(+) EPCs in EPCs (NPDR vs. control, Pu0.05). CONCLUSION: Exogenous EPO, mediated via the EPO/EPOR system of EPCs, may alleviate the impaired vascular regeneration in NPDR, whereas it might aggravate retinal neovascularization in PDR due to a rebound of EPOR(+)EPCs associated with ischemia. PMID- 21703114 TI - Inhibition of SIRT1 increases EZH2 protein level and enhances the repression of EZH2 on target gene expression. AB - OBJECTIVE: To study the regulatory rolesof SIRT1 on EZH2 expression and the further effects on EZH 2' s repression of target gene expression. METHODS: The stable SIRT1 RNAi and Control RNAi HeLa cells were established by infection with retroviruses expressing shSIRT1 and shLuc respectively followed by puromycin selection. EZH2 protein level was detected by Western blot in either whole cell lysate or the fractional cell extract. Reverse transcription-polymerase chain reaction was performed to detect the mRNA level of EZH2. Cycloheximide was used to treat SIRT1 RNAi and Control RNAi cells for protein stability assay. Chromatin immunoprecipitation(ChIP) assay was applied to measure enrichment of SIRT1, EZH2, and trimethylated H3K27 (H3K27me3) at SATB1 promoter in SIRT1 RNAi and Control RNAi cells. RESULTS: Western blot results showed that EZH2 protein level increased upon SIRT1 depletion. Fractional extraction results showed unchanged cytoplasmic fraction and increased chromatin fraction of EZH2 protein in SIRT1 RNAi cells. The mRNA level of EZH2 was not affected by knockdown of SIRT1. SIRT1 recruitment was not detected at the promoter regionof EZH2 gene locus. The protein stability assay showed that the protein stability of EZH2 increases upon SIRT1 knockdown. Upon SIRT1 depletion, EZH2 and H3K27me3 recruitment at SATB1 promoter increases and the mRNA level of SATB1 decreases. CONCLUSIONS: Depletion of SIRT1 increases the protein stability of EZH2. The regulation of EZH2 protein level by SIRT1 affects the repressive effects of EZH2 on the target gene expression. PMID- 21703115 TI - Correlation between acute coronary syndrome classification and multi-detector CT characterization of plaque. AB - OBJECTIVE: To determine if multi-detector CT (MDCT) characterization of plaque is correlated with the classification of acute coronary syndrome (ACS). METHODS: Altogether 1900 patients were examined by MDCT from December 2007 to May 2009, of whom 95 patients fulfilled the criteria of ACS. Those patients were divided into the discrete plaque group ( n=61) and diffuse plaque group ( n=34) based on the findings in MDCT. The clinical diagnosis of ACS and CT results were analyzed, including segment stenosis score, segment involvement score, 3-vessel plaque score, left main score, calcification score, and remodeling index. The incidences of major adverse cardiac events in follow-up period were also recorded. RESULTS: The patients of the diffuse plaque group were older than those of the discrete plaque group ( Pu0.0001). The diffuse plaque group presented more cases of hypertension, peripheral artery disease, diabetes, and heart failure than discrete plaque group (all P<0.05). All the 5 patients with ST-segment elevation myocardial infarction were found in discrete plaque group. The segment stenosis score of the discrete plaque group was lower than that of the diffuse plaque group(5.15+/-3.55 vs. 14.91+/-5.37, Pu0.001). The other four scores demonstrated significant inter-group difference as well (all P<0.05). The remodeling index of thediscrete plaque group was higher (1.12+/-0.16 vs.0.97+/-0.20, Pu0.05). Follow up data showed that major adverse cardiac events occurred more frequently in diffuse plaque group than in discrete group (29.41% vs. 11.48%, P=0.0288). CONCLUSIONS: Characteristics of discrete and diffuse plaques may be significantly different among different classes of ACS. The diffuse plaque may present higher risk, correlated to higher mortality. The diagnosis of discrete and diffuse plaques by MDCT would provide a new insight into the prognosis and treatment of ACS. PMID- 21703116 TI - alpha-GalCer administration after allogeneic bone marrow transplantation improves immune reconstitution in mice. AB - OBJECTIVE: To explore the effect of alpha- galactosyleramide( alpha-GalCer ) on immune reconstitution under acute graft-versus-host disease (aGVHD). METHODS: BALB/c mice were transplanted wit hallogeneic C57BL/6 bone marrow cells and splenocytes (both 1*10(7))after receiving lethal total-body irradiation. alpha GalCer (100 ug/kg) or vehicle (dimethylsulfoxide) was administered intraperitoneally immediately after transplantation. The effects of alpha-GalCer on immune reconstitution,proliferation of T cells and B cells, hematopoiesis,and thymic microenvironment were assessed. RESULTS: The alpha-GalCer group exhibited higher percentages of CD3(+),CD4(+), CD8(+), B220(+), CD40(+), and CD86(+)cells compared with the vehicle group . The number of colony forming unit per 1000 CD34(+) cells in the alpha-GalCer group was higher than in the vehicle group ( P=0.0012).In vitro proliferation assays showed that the alpha-GalCer group had higher percentages of CD3(+), CD4(+), CD8(+),and B220(+) cells compared with the vehicle group. As for the results of in vivo proliferation assays, the numbers of CD3(+), CD4(+), CD8(+), and B220(+)cells were higher in the alpha-GalCer group than in the normal group ,especially the number of B220(+) cells ( P=0.007).Significant difference was not found in thymocyte count between the alpha-GalCer group and the vehicle group, nor in the percentages of CD3(+), CD4(+), and CD8(+) cells. CONCLUSION: Administration of alpha-GalCer after allogeneic bone marrow transplantation may promote immune reconstitution in the presence of aGVHD. PMID- 21703117 TI - Risk factors analysis on traumatic brain injury prognosis. AB - OBJECTIVE: To investigate the independent risk factors of traumatic brain injury (TBI) prognosis. METHODS: A retrospective analysis was performed in 885 hospitalized TBI patients from January 1, 2003 to January 1,2010 in the First Affiliated Hospital of Medical College of Xi'an Jiaotong University .Single factor and logisticregression analysis were conducted to evaluate the association of different variables with TBI outcome. RESULTS: The single-factor analysis revealed significant association between several variables and TBI outcome, including age ( P=0.044 for the age group 40-60, Pu0.001 for the age group >=60), complications ( P<0.001), cerebrospinal fluid leakage( P<0.001), Glasgow Coma Scale(GCS) ( P<0.001), pupillary light reflex ( P<0.001), shock ( P<0.001), associated extra-craniallesions ( P=0.01), subdural hematoma ( P<0.001), cerebral contusion ( P<0.001), diffuse axonal injury ( P<0.001), and subarachnoid hemorrhage( P<0.001), suggesting theinfluence of those factors on the prognosis of TBI. Furthermore, logistic regression analysis identified age, GCS score, pupillary light reflex, subdural hematoma,and subarachnoid hemorrhage as independent risk factors of TBI prognosis. CONCLUSION: Age, GCS score, papillary lightreflex, subdural hematoma, and subarachnoid hemorrhage may be risk factors influencing the prognosis of TBI. Paying attention to those factors might improve the outcome of TBI in clinical treatment. PMID- 21703118 TI - Magnetic resonance urography and X-ray urography findings of congenital megaureter. AB - OBJECTIVE: To observe the imaging findings of congenital megaureter in order to enhance the understanding of this disease. METHODS: Image data of 5 patients with congenital megaureter and 2 misdiagnosed patients were analyzed, and image findings of congenital megaureter were summarized.Elscint Prestig 2.0T superconductive magnetic resonance urography (MRU) with conventional sequence (spin-echo, T1WI560 ms/16 ms; fast spin-echo, T2WI 9600 ms/96 ms ) was performed. Raw data were acquired with fastspin-echo sequence from heavy T2-weighted image (9600 ms/120 ms). Post-processing method of MRU was the maximum intensity projection with three-dimensional reconstruction in the workstation. Intravenous pyelography (IVP) was conducted, in which X-rayfilms were taken 7 minutes, 15 minutes, and 30 minutes after injecting contrast agent, exceptthat in 2 patients the films were taken delayed at 60 and 90 minutes .X-ray retrograde pyelography was performed on 2 patients, successful in one butfailed in the other. RESULTS: The dilated ureter showed hypointensity on T1-weighted images and hyperintensity on T2-weighted images in conventional MRI. The mass wall was intact, uniform in thickness, and showing hypointensity on T1-weighted and T2-weighted images. The MRU images showed a retroperitoneal mass appearing as an elongated tubular cystic structure spreading from kidney to bladder. MRU also revealed dilated calices and renal pelvis, pelviureteric obstruction, and renal duplication. The main signs of congenital megaureter in X-urography was significant dilatation of ureter, or normal renal pelvis with ureter dilatation, hydronephrosis, deformity, and displacement. CONCLUSIONS: MRU with X-urography could visualizethe characteristics of congenital megaureter, including the dilation of renal pelvis and ureter, calculi, urinary tract duplication, and stenosis location. The two techniques can complement each other in disease diagnosis and provide more detailed information for preoperative treatment. PMID- 21703119 TI - Changes of nerve growth factor in amniotic fluid and correlation with ventriculomegaly. AB - OBJECTIVE: To detect the change of nerve growth factor (NGF) level in human amniotic fluid during gestation, and to explore the relationship between this change and fetal ventriculomegaly (VM). METHODS: The studied subjects (collected from 2004 to 2007) were divided into four groups, including the second-trimester pregnancy group (n=113), third-trimester pregnancy group (n=110), fetal cerebral VM group (n=12), and healthy control group (n=12) which matched with the VM group in gestational weeks. The amniotic fluid specimens were obtained during amniocentesis or cesarean section. The NGF levels in amniotic fluid were detected with enzyme-linked immunosorbent assay. RESULTS: A significantly negative correlation was found between gestational age and the NGF level in amniotic fluid (r=-0.6149, P<0.0001). The NGF level in patients with fetal VM was significantly lower than that in healthy controls (33.95±29.24 pg/mL vs. 64.73±16.21 pg/mL, P=0.024). CONCLUSION: NGF levels in amniotic fluid may be a sensitive marker for fetal VM. PMID- 21703120 TI - Application of positron emission tomography molecular probes in hepatocellular carcinoma biological imaging. AB - Biological behavior is a hot issue in hepatocellular carcinoma (HCC) study. Positron emission tomography (PET), a biological imaging technique, has been widely applied in many types of tumors. It is capable of noninvasive detection of biological behavior. Different radiotracers provide different information of HCC, including glucose/lipid metabolism, DNA synthesis, and apoptosis. In addition, radiotracer uptake relates to biological and clinical prognostic markers. In this article we review the application of several existing and novel radiotracers in PET in HCC study. PMID- 21703121 TI - C-peptide and diabetic encephalopathy. AB - With the changes of life style, diabetes and its complications have become a major cause of morbidity and mortality. It is reasonable to anticipate a continued rise in the incidence of diabetes and its complications along with the aging of the population, increase in adult obesity rate, and other risk factors. Diabetic encephalopathy is one of the severe microvascular complications of diabetes, characterized by impaired cognitive functions, and electrophysiological, neurochemical, and structural abnormalities. It may involve direct neuronal damage caused by intracellular glucose. However, the pathogenesis of this disease is complex and its diagnosis is not very clear. Previous researches have suggested that chronic metabolic alterations, vascular changes, and neuronal apoptosis may play important roles in neuronal loss and damaged cognitive functions. Multiple factors are responsible for neuronal apoptosis, such as disturbed insulin growth factor (IGF) system, hyperglycemia, and the aging process. Recent data suggest that insulin/C-peptide deficiency may exert a primary and key effect in diabetic encephalopathy. Administration of C-peptide partially improves the condition of the IGF system in the brain and prevents neuronal apoptosis in the hippocampus of diabetic patients. Those findings provide a basis for application of C-peptide as a potentially effective therapy for diabetes and diabetic encephalopathy. PMID- 21703122 TI - Breast fibromatosis after hydrophilic polyacrylamide gel injection for breast augmentation: a case report and review of the literature. PMID- 21703123 TI - Clinical treatment and anatomy study of maxillary first molars with five root canals. PMID- 21703124 TI - Immediate surgical intervention for penile fracture: a case report and literature review. PMID- 21703125 TI - Dental epidemic diseases and oral health knowledge in people with disabilities: a survey in a southwest city of China. PMID- 21703127 TI - Dental caries experience among 15-year-old adolescents in north-west Russia. AB - OBJECTIVES: To estimate the prevalence and experience of dental caries among 15 year-old adolescents in north-west Russia between 2007 and 2008. STUDY DESIGN: A cross-sectional study. METHODS: In total, 352 adolescents at the age of 15 were selected at random from 3 urban and 4 rural areas in the Arkhangelsk region. Girls comprised 53.4% of the sample. Caries experience was assessed at D3 level by a single calibrated examiner and was estimated as a sum of decayed, missing and filled teeth (DMFT). RESULTS: The prevalence of caries was 91.8% with a mean DMFT of 4.92. On average, there were 2.61 decayed, 0.13 missing and 2.18 filled teeth per participant. No gender differences in the prevalence of caries in any of the settings or in the full sample were observed. In urban areas, the average number of decayed teeth was lower (2.15 vs. 2.95, p=0.006), while the number of filled teeth was greater (2.71 vs. 1.79, p<0.001) than in rural areas. CONCLUSIONS: Under assumption of the representativeness of the sample, no improvements in the overall caries prevalence among 15-year-old children in the Arkhangelsk region occurred since 1997-1998. Urban-rural variations, but not gender variations, in caries experience were observed. The levels are considerably higher than those in neighbouring Nordic countries and the Russian average. Urgent public health measures on both population and individual levels are needed to improve the situation. PMID- 21703126 TI - Health consumption in Sami-speaking municipalities with regard to cancer and radiotherapy. AB - OBJECTIVES: The objective of this study was to document that the Sami people, constituting an ethnic minority in northern Norway, experience an equally available specialist health care service as the one offered to Norwegians in general. We aimed to use cancer and radiotherapy treatment as the instrument to clarify the situation. STUDY DESIGN: A retrospective registry-based study. METHODS: The 8 municipalities included in the administration area of the Sami language law were matched with a control group of 11 municipalities. Population data (numbers, sex and age) were accessed from Statistics Norway. Data on cancer incidence, prevalence and survival during the 10-year time period 1999-2008 were derived from the Cancer Registry of Norway (CRN). Five years overall survival was calculated for patients diagnosed in the time period 1999-2003. Furthermore, data on radiotherapy (RT) and treatment intention were recorded for the time period 1999-2008. RESULTS: The Sami-speaking municipalities had a significantly lower incidence of cancer. Breast (RR 0.82 [95% CI 0.76-0.89]) and lung cancer (females RR 0.55 [95% CI 0.52-0.58], males RR 0.64 [95% CI 0.60-0.68]) were significantly less frequent. The Sami group had experienced a significant increase (Sami 54.5% [95% CI 49.2-61.7], controls 24.1% [95% CI 21.7-26.5]) in the prevalence of cancer during the last 10 years. Five years overall survival was similar among both the Sami and control groups. In both groups, 28% of cancer patients underwent radiotherapy. CONCLUSIONS: The Sami in northern Norway had a lower risk of cancer but experienced the same use of radiotherapy in their cancer treatment as Norwegians in general. PMID- 21703128 TI - Establishing the psychometric properties and preferences for the Northern Pain Scale. AB - OBJECTIVES: A culturally relevant, evidence-based pain assessment scale in Inuktitut is needed. Psychometric properties and preferences for the Northern Pain Scale (NorthPS), a revised version of the Wong-Baker FACES scale, were examined. STUDY DESIGN: This repeated-measures, within-subjects study involved 2 face-to-face interviews held 2 weeks apart. METHODS: Participants were recruited from 2 schools and a community centre in Pangnirtung, Nunavut, Canada. Three pain scales (NorthPS, FACES and a numerical rating scale) were used to rate the pain portrayed in an adapted version of the Charleston Pediatric Pain Pictures (NorthCPPP, a series of 17 cartoon vignettes). RESULTS: The study involved 188 participants ranging in age from 5 to 83 years. Compared with the established FACES and numerical scales, the concurrent validity of the NorthPS was acceptable, with all 3 pain scales producing similar scores for the North CPPP vignettes. The youngest children were slightly more accurate during the second interview; otherwise, scoring accuracy was similar during both interviews. Accuracy was also similar across pain scales. Spearman correlations between NorthPS and other scales were lowest for the "No" pain vignettes, and for the youngest children. Internal consistency was acceptable for the NorthPS when compared with FACES and numerical scales. FACES was preferred by the majority of children and NorthPS was preferred by the majority of adults. CONCLUSIONS: NorthPS, a pain scale adapted to Inuit language and culture, was validated using the NorthCPPP with children and adults. The NorthPS is a well-understood, culturally and linguistically adapted option for the assessment of pain for Inuktitut speaking children and adults. PMID- 21703129 TI - Climate change health assessment: a novel approach for Alaska Native communities. AB - OBJECTIVES: Develop a process for assessing climate change impacts on public health that identifies climate-health vulnerabilities and mechanisms and encourages adaptation. STUDY DESIGN: Multi-stakeholder, participatory, qualitative research. METHODS: A Climate Change Health Assessment (CCHA) was developed that involved 4 steps: (1) scoping to describe local conditions and engage stakeholders; (2) surveying to collect descriptive and quantitative data; (3) analysis to evaluate the data; and (4) planning to communicate findings and explore appropriate actions with community members. The health effects related to extreme weather, thinning ice, erosion, flooding, thawing permafrost and changing conditions of water and food resources were considered. RESULTS: The CCHA process was developed and performed in north-west Arctic villages. Refinement of the process took place in Point Hope, a coastal Inupiat village that practices whaling and a variety of other traditional subsistence harvest practices. Local observers identified climate change impacts that resulted in damaged health infrastructure, compromised food and water security and increased risk of injury. Priority health issues included thawing traditional ice cellars, diminished quality of the community water source and increased safety issues related to sea ice change. The CCHA increased awareness about health vulnerability and encouraged informed planning and decision-making. CONCLUSION: A community-scale assessment process guided by observation-based data can identify climate health impacts, raise awareness and encourage adaptive actions, thereby improving the response capacity of communities vulnerable to climate change. PMID- 21703130 TI - Alaska Native adolescent views on cervical cancer, the human papillomavirus (HPV), genital warts and the quadrivalent HPV vaccine. AB - OBJECTIVES: To understand the knowledge levels, attitudes and perceptions of Alaska Native adolescent girls about cervical cancer, HPV, genital warts and the HPV vaccine. STUDY DESIGN: A qualitative study. METHODS: Seventy-nine in-depth interviews were conducted with adolescent females aged 11 through 18 years in 4 communities in Alaska. The convenience sample was recruited through word of mouth, posters and flyers distributed in community schools, medical clinics and stores. RESULTS: Many of those surveyed didn't know the purpose of a vaccine and were not familiar with basic knowledge about HPV, genital warts and cervical cancer. After learning about cervical cancer and HPV, most teens felt that someone their age had an average likelihood of contracting the diseases and that having the disease would be quite bad. Most teens said they were interested in vaccination. When asked if they would get a vaccine, older teens most commonly cited concerns about side effects or doubts about vaccine efficacy, while younger teens were afraid the shot would hurt. Most teens stated that they preferred to learn about health topics such as these through television programming, followed by the Internet, brochures and posters. CONCLUSIONS: The findings provide valuable information on how to inform adolescents about the vaccine and alleviate their concerns. The design of an educational campaign should vary depending on the age of the adolescents. For younger teens, distribution of information should be at school using a brochure or curriculum, while for older teens a web page may be more appropriate. PMID- 21703131 TI - An interactive two-step training and management model of point-of-care glucose testing in northern Finland. AB - OBJECTIVES: To assess an interactive 2-step training and management model for nurses in glucose point-of-care testing (POCT). STUDY DESIGN: The training of the nursing staff by the point-of-care coordinator of the laboratory started with interactive sessions with contact persons who subsequently trained their nursing colleagues at the Oulu University Hospital in northern Finland. The 2-step training model was applied in blood glucose testing as a pilot study. METHODS: Functional quality was assessed through interviews with clinical contact persons and a questionnaire was given to the trained nurses. Technical quality was assessed through control measurements by laboratory and nursing staff. RESULTS: Training succeeded because of basic resources (trainers' knowledge and skills, organized contents of training and place), interpersonal communication and high quality interactions. Nurses were especially satisfied with the prerequisite training of the contact persons (mean score 1.58, Likert scale from -2 to +2, strongly disagree - strongly agree). Day-to-day repeatabilities of less than 3% were achieved in control measurements by both nursing and laboratory staff. CONCLUSIONS: The interactive 2-step training and management model could be implemented in the clinical units using a reasonable amount of laboratory resources. The goal of good functional and technical quality in point-of-care testing in the clinical units was achieved. Despite successful implementation, POCT needs continuous support from the laboratory. PMID- 21703132 TI - Pan-Arctic TV Series on Inuit wellness: a northern model of communication for social change? AB - OBJECTIVES: This paper provides highlights of a utilization-focused evaluation of a collaborative Pan-Arctic Inuit Wellness TV Series that was broadcast live in Alaska and Canada in May 2009. This International Polar Year (IPY) communication and outreach project intended to (1) share information on International Polar Year research progress, disseminate findings and explore questions with Inuit in Alaska, Canada and Greenland; (2) provide a forum for Inuit in Alaska, Canada and Greenland to showcase innovative health and wellness projects; (3) ensure Inuit youth and adult engagement throughout; and (4) document and reflect on the overall experience for the purposes of developing and "testing" a participatory communication model. STUDY DESIGN: Utilization-focused formative evaluation of the project, with a focus on overall objectives, key messages and lessons learned to facilitate program improvement. METHODS: Participant observation, surveys, key informant interviews, document review and website tracking. RESULTS: Promising community programs related to 3 themes - men's wellness, maternity care and youth resilience - in diverse circumpolar regions were highlighted, as were current and stillevolving findings from ongoing Arctic research. Multiple media methods were used to effectively deliver and receive key messages determined by both community and academic experts. Local capacity and new regional networks were strengthened. Evidence-based resources for health education and community action were archived in digital formats (websites and DVDs), increasing accessibility to otherwise isolated individuals and remote communities. CONCLUSIONS: The Pan-Arctic Inuit Wellness TV Series was an innovative, multi-dimensional communication project that raised both interest and awareness about complex health conditions in the North and stimulated community dialogue and potential for increased collaborative action. Consistent with a communication for social change approach, the project created new networks, increased motivation to act and provided new tools to do so, and increased local community involvement and "voice" in the discussion and dissemination of successful strategies to promote Inuit wellness. PMID- 21703133 TI - [New antiarrthythmics in atrial fibrillation]. AB - Atrial fibrillation is the most common cardiac arrhythmia responsible for a significant morbidity and mortality. In recent years, progress has been made in determining the genetic abnormalities, the use of anticoagulants as a component of a primary treatment strategy in many patients who have a high risk of recurrence and for thromboembolism, and newer and safer antiarrthythmics are now available. The aim of this paper is to discuss about this topic and antiarrhythmic therapy. PMID- 21703134 TI - [Regarding the paper "Hospital readmission of diabetic patients"]. PMID- 21703135 TI - [Comments about the paper "Effect of milk products consumption in mother during breastfeeding"]. PMID- 21703136 TI - [Comment about the paper "Diabetes nortality in insured population..."]. PMID- 21703137 TI - ["h" index: a necessary criterion in researcher evaluation]. PMID- 21703138 TI - [Style and quality of life in patients with type 2 diabetes]. AB - BACKGROUND: Diabetes mellitus type 2 (DM2) is the main cause of morbi-mortality, and disability in our country. The life style (LS) is the pattern of conduct that can or cannot affect the health; LS influences on the DM2 incidence and affects the quality of life of the diabetic patient. The purpose was to evaluate the quality and LS in patients with DM2. METHODS: A cross-sectional study in 150 patients with DM2 was carried out. The quality and LS were measured. RESULTS: The sample aged 53.5+/-6.6 years, 72.7% aged 50 to 59 years; 45.3% were women; an average of 8+/-2.08 years in the disease's evolution was found. The 84% belonged to a supporting group, 8.7% were in SODHI groups and 7.3% to other group. The affected domains of LS were physical activity (48.1%), Self-esteem (57.8%), Self perception (68.3%), Diet (68.7%) and attachment to the treatment (73.5%). The most affected domains of quality of life were physical, social relations and environmental. Spirituality and believes obtained greater qualifications. CONCLUSIONS: There was little adhesion to support groups. It is necessary to improve life styles on physical activity, self-esteem, diet and attachment to the treatment. PMID- 21703139 TI - [Frequency and clinical outcome of odontogenic cervicofacial infection]. AB - OBJECTIVE: To measure frequency, mortality, hospitals stay and the requirement of attention in the intensive care unit (ICU) of patients with cervical infections. METHODS: A descriptive, observational and transversal study was carried out. We analyzed the database of patients admitted to Emergency Room of High Specialty Hospital, with cervical and facial infection with odontogenic origin, during a year period. RESULTS: In three cases were ambulatory and 19 where hospitalized; only three required ICU attention. The average of hospital stay was 6.3 days and the mortality of 8.3%. CONCLUSIONS: The mortality is significant in patients who require ICU and whose age is older than 60 years. Therefore this group of patients required a rapid multidisciplinary care to improve their expectations for survival expectancy. PMID- 21703140 TI - [Analysis of an outbreak of Burkholderia cepacia for risk stratification]. AB - BACKGROUND: The possibility of nosocomial infection is determined by factors relating to the patient, the presence and degree of immunodeficiency, and interventions that become stronger the risk. A nosocomial outbreak is the emergence of an unusual case of a specific disease and is due to an infectious agent only. Our objective was to analyze the risk of Burkholderia cepacia with a risk stratification criterion in a pediatric intensive care unit (ICU). METHODS: An epidemiological outbreak, transverse, retrospective study was done. We included 71 patients from a pediatric ICU. Attack rate and fatality rate was obtained. We applied Fisher exact test with a level of significance p<0.05. RESULTS: Regardless the risk stratification the Burkholderia cepacia infection showed no significant difference. The attack rate was 23.94, and the fatality rate in infected patient was 29.41. Candida albicans coinfection was present in 50% of the cases; other kind of bacteria infection in 50% was also seen. Therefore the treatment was the combination of different antimicrobials. CONCLUSIONS: The paediatric intensive care patient is exposed to nosocomial infection including Burkholderia cepacia independent of its risk rating. Attachment and the monitoring of standard precautions with isolation strategy is suggested as a good preventive measure. PMID- 21703141 TI - [The effectiveness of the percutaneous discectomy in the treatment of pain secondary to disc herniation]. AB - BACKGROUND: Percutaneous discectomy has shown to be useful for relief the radicular pain due to a disk hernia, which is a common condition in the general population. The objective was to evaluate the efficacy of percutaneous discectomy in radicular pain caused by disk hernia. METHODS: A descriptive study was done. The records of percutaneous discectomy patients from a two years period were analyzed including those who had a pain intensity scored by a Analog Visual Scale (VAS), those with daily taken analgesics, before and after the procedure were registered. Dose in milligrams (mg) of analgesic intake were converted to equivalent dosages for 24 hours oral morphine. Pain intensity and medication take before and after the procedure were compared. RESULTS: VAS average previous to the procedure was 6.29 and after it descended to 2.86. The mean of medication intake before discectomy was 30.32 mg and after the procedure was 12.75 mg. DISCUSSION: We found pain improvement in a high percentage of patients reflected by a decrease in VAS and the medication needed. PMID- 21703142 TI - [Assessment of comorbidity in elderly]. AB - The objective was to offer to the clinical researchers who work on elderly and health field a review of the main instruments use for assessment the presence of comorbidity in elderly. A systematic quest at Medline using keywords was made. A group of experts on geriatric and internal medicine physicians was integrated for the evaluation of paper found. The group analyzed the structure, clinical utility, clinimetrics properties, focus on elderly patients. This communication included the four main tools: Charlson's comorbidity index, Geriatric index of comorbidity, Kaplan-Feinstein's index and Cumulative Illness Rating Scale Geriatric (CIRS-G). Each of them showed adequate clinometric properties, although, the assessment of CIRS-G requires a health professional more skilled on clinical examination, all of these indexes have been shown to have a good predictive value about functional impairment and mortality. However, the choice of the index by researchers depends on the context of the study. PMID- 21703144 TI - [Clinical geriatric assessment in primary care medicine]. AB - BACKGROUND: The Comprehensive Geriatric Assessment (CGA) included the physical, psychic and social environment. The purpose was to describe the use of CGA in primary care. METHODS: A descriptive transversal study was carried out. "Timed-up and-go"; Barthel index and the Lawton and Brody scales were used. The minimental state examination and the Yesavage scale were used for the mental performance. The Gijon instrument was used for the social and family environmental evaluation. RESULTS: Average age was 64 years. In 83% the caretaker was a direct relative, and 65% were hospitalized within the last year. The 84% had multiple pathology, 93% poly-pharmacy, 71% overweight or obesity, 68% visual deficit, 35% hearing deficiency, 68% were prone to falls; 86% had some degree of dependency on daily life activities; 38% had a mild deterioration of the cognitive state and 27% moderate; 37% suffers mild depression and 17% a established depression and 35% had a social-family risk. Among physicians 72% knew the CGA concept, 72% preferred not to perform it due to lack of time and 67% point out fo not having the tools for it. CONCLUSIONS: The studied population showed some grade of bio psycho-social deterioration and the lack use of CGA. PMID- 21703143 TI - [Clinical research II. Studying the process (the diagnosis test)]. AB - A diagnosis test is carried out to establish the presence of health or illness. In the latter it could grade the severity. Due to its importance in clinical decisions, the diagnosis test is evaluated by mathematical strategies. We estimate the sensitivity and specificity once we know the existence or not of the disease, but we act in the reverse direction; with the presence "X" test positive or negative we estimate the presence of the disease, therefore, we use the positive and negative predictive values. Mathematical strategy allow us to quantify the observation, but it requires judgment to determine the quality making use of a minimum of features: a) selection under the same criteria for cases and controls; b) the inclusion of the full spectrum of disease severity (from mild to the most serious, ensuring that all levels have an enough number of subjects); c) the interpretation of both, the gold standard and the new tool of diagnosis, it must be blind and conducted by experts; d) the interpretation of results should show us what is their application in everyday clinical practice; e) the reproducibility must be checked. Do not forget that usually, we treat only one patient at once, what enforce us to have full knowledge of the performance of the diagnostic test, and to consider all clinical aspects for its proper implementation. PMID- 21703145 TI - [Intelligence quotient related with congenital hypotyroidism etiology]. AB - BACKGROUND: In Mexico, the congenital hypothyroidism (CH) is a public health problem that has a national incidence ranging from 1:1951 to 1:2458 live births. It is the main endocrine cause of mental retardation. The objective was to evaluate the intelligence coefficient (IQ) of patients with CH using the Wechsler Scale (WS) and to correlate the degree of involvement with its etiology. METHODS: We included patients with CH diagnosed by neonatal screening and treated by who attended the test of Wechsler. Data were obtained from the clinical records. Statistical descriptive were used. RESULTS: We included 15 male (21.7%) and 54 females (78.3%) patients. According to the dysgenesis aetiology was secondary in 51 patients (89.9%) and different from dysgenesis in 18 (26.1%). The age at diagnosis was 12.4 days. The initial replacement dose was 10-5 mg/kg/day. The average age at time of psychometric assessment was 6.4 years. The severity of hypothyroidism was 29 mild, 26 moderate and 14 severe. The mean IQ was 99.47. There was no relationship between IQ and the severity of hypothyroidism (p=0.31), age of initiation of treatment (p=0.271) and etiology (p=0.127). CONCLUSIONS: No relationship was found between the etiology nor the severity of CH with IQ. PMID- 21703146 TI - [Cystic neoplasm of the pancreas: a ten years experience]. AB - BACKGROUND: Pancreatic cystic lesions (PCL) are identified in 1 % of patients who undergo abdominal computed tomography scans, because it is difficult to discriminate clinically between benign and malignant PCL. The PCL must be distinguished from inflammatory pseudocysts, which can have a similar radiographic appearance. The aim of this study was to review the incidence of PCL during 10 years. METHODS: Nineteen consecutive patients who underwent surgical resection of a cystic lesion of the pancreas during a 10-year period were reviewed. RESULTS: From 1998, 434 patients underwent to pancreatic surgery, 103 (25.75%) resulted with neoplasm of the pancreas and a PCL was diagnosed in 19 of them (18.44%). They were more common in women (n=15, 79%). The pathologic diagnosis was mucinous cystadenoma (n=6, 31.5%) followed by serous cystadenoma and solid cystic papilar tumor (n=4, 21%). Mucinous cystadenocarcinoma was diagnosed in a 77 year-old man and a serous cystadenocarcinoma was diagnosed in a 53 years-old woman; cystic degeneration of two insulinomas were diagnosed in a 71 year-old woman and a 32 year-old man (5.26%). CONCLUSIONS: PCLs represent a spectrum of associated diseases. The incidence of serous cystadenoma is lower in our experience. PMID- 21703147 TI - [Clinical and social factors related with a long labor disability]. AB - OBJECTIVE: To determine the factors associated with a longer labor disability (LLD) due to a labor accident. METHODS: A cases and controls study was made. All the patients who presented a disability certificate for over thirty days due to a labor accident were included. The socio-demographic, labor characteristics and diagnoses were analyzed. A bivariate statistical analysis was made. RESULTS: There were 32 cases; average age was 34 years; 27 were men (84.4%) and 5 women (15.6%); the predominant schooling was the upper middle level in 40%, the economical level was poor in 40%, the 19.1% worked as a store assistant. The anatomic region most affected was the wrist-hand in 19 cases (27.9%) and the more frequent diagnoses were: injuries 33%, fractures 32.4% and inadequate skills 23.5%. Associated factors were the lack of training (OR: 1.6 IC: 1.08-2.47), working in the afternoon or at night shift (OR: 4.19 CI: 1.04-20 .07) and being a man (OR: 1.4 CI: 0.66-2.9). CONCLUSIONS: It was observed that sex, not training and the schedule of working were associated with a LLD. PMID- 21703150 TI - [Fetal hydrops diagnosed by ultrasonographics images. A case report]. AB - We reported a non-immune case of fetal hydrops diagnosed at the 15th week of pregnancy with ultrasonographic images. Follow-up was made but the death in utero occurred at the week 16. The treatment with the induct conduction labor was carrying out and finally an abortion was performed. The pathological study of the product was made. With this case, we point out the importance of ultrasound screening in the first quarter of pregnancy for an early diagnosis with high probability of aneuploidy and high morbidity and mortality malformations was highlighted. PMID- 21703148 TI - [Thyroid incidentaloma frequency in a university hospital]. AB - BACKGROUND: The prevalence of thyroid incidentaloma is variable and always created the dilemma of how to manage them. The objective was to determine the frequency of thyroid incidentalomas in a University Hospital. METHODS: A descriptive, transversal, prospective study was done; a non-probabilistic sample was used with patients who met the following criteria: >18 years, indiscriminate sex, and an image that included neck: ultrasound, computed tomography and/or magnetic resonance. Patients with known or suspected thyroid nodule or any other thyroid disease and pregnant women were excluded. Descriptive statistics were used. RESULTS: 153 patients who had the criterion; 11 patients had an incidentaloma (7.18%). Females were more frequent with seven cases (63.6%), the mean age was 56.9 years. Morphologically only a single thyroid nodule was detected. The nodules were smaller than 1.5 cm. CONCLUSIONS: The prevalence documented in our study is smaller than other reports, it is proposed monitoring patients with thyroid incidentalomas according to current consensus guidelines. PMID- 21703149 TI - [Clinical and therapeutic approach to Klippel-Feil syndrome in the primary care medicine]. AB - A case of Klippel-Feil syndrome in a female nine years is informed. The patient presented a clinical picture compatible with Klippel-Feil syndrome: short neck with joint movements diminished and low hair implantation. We showed the diagnostics and treatment approach at the primary medicine level, the follow-up until the presence of clinical manifestations of the main clinical problems associated. The liver, cardiovascular, audiology, and muscle-bones are describe and finally some aspects of her physical rehabilitation. PMID- 21703151 TI - [Mature mesenteric teratoma in an adult male. A case report]. AB - Mesenteric teratoma matures in adulthood are extremely rare. The spectrum of differential diagnosis for intra-abdominal cystic lesions in male patients is limited and its occurrence is less than in female counterparts, being so a diagnostic problem for daily medical practice. The purpose of this study is to present this entity as an infrequent tumor, which can become a diagnostic challenge. Here we present a case of a mature teratoma occurring in the mesenteric root in a 50 year old man. PMID- 21703152 TI - [Clinical guideline for detection and diagnosis of hypertensive pregnancy disease]. AB - Hypertensive disorders in pregnancy (HDP) are the main complication and cause of maternal and perinatal death. Pre-eclampsia represents a 34%, according to the Secretaria de Salud de Mexico. To offer the family physicians tools for the opportune detection and diagnosis of HDP a clinical guideline was developmented. Clinical questions were formulated and structured. A standardized sequence to search for Practice Guidelines, based on the key words: hypertensive disorders in pregnancy, pre-eclampsia. Tripdatabase, MDConsult, National Guideline Clearinghouse, Scottish Intercollegiate Guidelines Network, National Institute for Health and Clinical Excellence were used. In addition, Cochrane Library Plus, Science Direct and OVID were used. Most of the recommendations were taken from guidelines selected and supplemented with the remaining material. The information is expressed in levels of evidence and grade of recommendation according to the characteristics of the study design and type of publications. To reduce morbidity and mortality from HDP health professionals should identify risk factors; conduct a close monitoring and early diagnosis. It is essential to provide information to the pregnant patient on alarm data and behavior to follow. This clinical practice guide offers current evidence for screening and diagnosis of HDP in primary care. PMID- 21703153 TI - [Outpatient medical attention demand due to diabetes mellitus in the health primary care]. AB - Outpatient visits for medical attention because of Diabetes mellitus in the Instituto Mexicano del Seguro Social became very important for the magnitude that it represents. There is a clear increasing tendency for the coming years. The available data indicates a higher frequency and increased demand of women. Higher number of patients is observed between 40 and 59 years old. However, earlier age groups present considerable amount of cases. Having the number of patients allows knowing the average of consultations per patient, this parameter allows having an estimate of the follow up by the physician and it must be part of the evaluation of the medical attention programs. Diabetes mellitus is strongly associated with obesity, this condition affects a high percentage of diabetic patients in the Institution and weight loss must be encouraged. PMID- 21703154 TI - Activated protein C resistance and its correlation with thrombophlebitis in Behcet's disease. AB - Patients with Behcet's disease (BD) have been recognized to be at an increased risk of thrombosis and thrombotic complications have been reported in 12%-40% of patients. The precise pathogenetic mechanisms underlying the thrombotic tendency of BD are not known. In recent researches, it is reported that procoagulant mutations might play a role in thrombotic process in BD patients. We aimed to evaluate the frequency of activated protein C resistance (APCR) in our BD patients and to investigate the association between thrombophlebitis and APCR. The study included 116 patients with BD who fulfilled the International Study Group criteria and 70 healthy individuals as a control group. APCR levels were measured by the clotting method. APCR levels were 129.63 +/- 39.70 and 152.26 +/- 22.62 in BD patients and control group, respectively (P<0.01). APCR was found in 47.4% and 8.6% of BD patients and control group, respectively (P<0.01). There was no statistically significant difference regarding APCR levels between patients with thrombophlebitis and without thrombophlebitis (46.4% vs. 48.3%). We found the frequency of APCR to be increased in BD patients with or without thrombophlebitis. The lack of association between thrombophlebitis and APCR in our series of BD patients suggests that some factors like endothelial abnormalities other than thrombophilia play a major role in the pathogenesis of thrombosis in BD. PMID- 21703155 TI - Epicutaneous patch test results in children and adults with allergic contact dermatitis in Karlovac county: a retrospective survey. AB - The aim of the study was to evaluate the results of epicutaneous patch testing with a standard series of contact allergens in children suspected to have allergic contact dermatitis (ACD), and to compare the results of patch testing between children and adults. Clinical records of children defined as patients aged <=18 years and adults examined at Department of Dermatology and Venereology, Karlovac General Hospital, for suspicion of ACD during the 1994-2009 period were reviewed. Epicutaneous patch testing with a standard series of contact allergens, manufactured by the Institute of Immunology, Zagreb, Croatia, was performed in group 1 consisting of 412 children (274 female and 138 male, mean age 13.4 years, range 4-18 years) and group 2 consisting of 4440 adult patients (2918 female and 1522 male, mean age 40.3 years, range 19-81 years). The most common six allergens differed between the two groups. Adult subjects were divided into three age subgroups: 19-40 (n=1708), 41-60 (n=1570) and 61-81 (n=1162 subjects). The high sensitization rate in younger subgroup and lower sensitization rate in the oldest group compared to adult patient group as a whole was statistically significant (P<0.05). In children, the most common positive reactions were recorded to nickel sulfate (25.4%), thimerosal (17.8%), cobalt chloride (11.6%), fragrance mix (8.9%), white mercury precipitate (6.2%), formaldehyde (4.7%) and other allergens (25.4%). In adult patients, positive reactions were most common to nickel sulfate (32.6%), cobalt chloride (10.8%), fragrance mix (9.0%), wood tars (7.1%), potassium dichromate (6.6%), balsam of Peru (5.1%) and other allergens (28.8%). The group of children included 179 (43.4%) atopic subjects (according to Hanifin and Rajka criteria) and 233 (56.6%) non-atopic subjects. There was no statistically significant between-group difference and no statistically significant difference in nickel sulfate, cobalt chloride, fragrance mix and balsam of Peru sensitization between children and adult patients. A higher sensitization rate in children versus adults was recorded for thimerosal, white mercury precipitate and formaldehyde. Less frequent sensitization in children versus adults was found for wood tars and potassium dichromate. It is concluded that pediatric ACD exists and is more common than previously recognized. Sensitization to allergens differs between children and adults. PMID- 21703156 TI - Perifolliculitis capitis abscedens et suffodiens in a caucasian: diagnostic and therapeutic challenge. AB - Perifolliculitis capitis abscedens et suffodiens or dissecting cellulitis of the scalp is a rare, chronic destructive folliculitis of the scalp, characterized by painful nodules, purulent drainage, sinus tracts, keloid formation and cicatricial alopecia. The cause of the disease is unknown, but it is similar in many features to hidradenitis suppurativa and acne conglobata. In our case report, the patient's dermatologic appearance included one slightly erythematous, infiltrated alopecic area with draining lesions in the right parietal part of the scalp with a few alopecic areas in other parts of the scalp. The identification of the infectious agent, repeated swabs and KOH examination/or fungal cultures and tissue sampling for histopathologic analysis were necessary to confirm the diagnosis of perifolliculitis capitis abscedens et suffodiens. The patient received systemic antibiotics (azithromycin and amoxicillin-clavulanate) and oral antimycotic therapy (fluconazole), followed by a long period of oral isotretinoin with local skin care, which led to resolution and thus inhibited the evolution to scarring and nodular stage of the disease. Thus, such combined approach could be useful for other patients with these dermatologic problems. PMID- 21703157 TI - Granulomatous response due to anabolic steroid injections. AB - Injected corticosteroids can sometimes lead to a granulomatous reaction. This is apparently also true for anabolic steroids, which are often used by bodybuilders, although we have not found any histologic report on such a phenomenon. We report a case of a granulomatous reaction in a 30-year-old male bodybuilder having undergone anabolic steroid injections. Foreign bodies typical of steroids were found, together with areas of calcification and ossification with lamellar bone. Multivacuolated macrophages were found in the fibrous tissue close to these areas of calcification and ossification. PMID- 21703158 TI - Axillary basal cell carcinoma: case report and literature review. AB - Axillary basal cell carcinoma (BCC) has been rarely reported. The axilla is a site that is less likely to be monitored by the patient, thus there is a potential for delay in diagnosis and treatment. Surgical excision is the most widely used treatment method for its effectiveness, simplicity and histologic control. BCC is easily treated when it is detected early. There are 33 cases of axillary BCCs reported in the literature, and only one case has been reported in Asia. Herein we report on the second case of primary axillary BCC in an Asian female. PMID- 21703159 TI - Delusion of parasitosis: case report and current concept of management. AB - Delusions of parasitosis (DP) is a primary psychiatric disorder, a type of monosymptomatic hypochondriac psychosis in which patients believe that 'bugs' or 'parasites' have infested their skin or that they have even spread into their visceral organs. Patients with DP usually approach different medical specialists, mostly dermatologists and primary care physicians because of symptoms presenting as crawling under their skin. Therefore, the exact prevalence of DP is unknown. It is believed that it is a rare disorder but different studies indicate that the prevalence is greater than presented. The etiology of this disorder is still unclear. Patients with DP come to a physician with a stereotypic history. Usually the patient has previously addressed many other different specialists and symptoms are usually present for several months to years. The main cutaneous symptom is crawling, biting and pruritus due to 'burrowing of parasites, insects or bugs' under the skin. Patients with DP are rare but can be very challenging for making the correct diagnosis and for the treatment as well. It is essential to distinguish primary from secondary disorder since the approach to these patients is different. Dermatologists who have good knowledge in diagnosis, both dermatologic and psychodermatologic, and who dare prescribe antipsychotics after consulting liaison-psychiatrist, can have good results in treating patients with DP. When treating patients with DP, multidisciplinary approach by collaboration between a dermatologist and a psychiatrist is necessary to provide complete and meaningful treatment for these patients. PMID- 21703160 TI - Psoriasis vulgaris - an inflammatory skin disease and/or benign epidermal hyperplasia. AB - Psoriasis vulgaris (PV) is a systemic inflammatory disease in which immune and genetic factors are involved in the pathogenesis. Some treatment approaches in PV patients have been similar to therapy of some tumors. This fact has led to a new scientific approach to PV not only as an inflammatory disease, but also as a benign epidermal hyperplasia or a benign tumor. In this article, we hypothesize that there has been a parallel between some benign tumors and neoplasms and PV. The aim of this article is to present the approach to PV as an inflammatory disease as well as benign epidermal hyperplasia or tumor, and to introduce a new meaning. PMID- 21703161 TI - Bullous cutaneous larva migrans. PMID- 21703162 TI - Poroid hidradenoma. PMID- 21703166 TI - Vascular invasion leaves its mark in hepatocellular carcinoma. PMID- 21703167 TI - Evaluation of the gut barrier to intestinal bacteria in non-alcoholic fatty liver disease. PMID- 21703168 TI - A major step towards effective treatment evaluation in primary biliary cirrhosis. PMID- 21703170 TI - Does adherence to hepatitis B antiviral treatment correlate with virological response and risk of breakthrough? PMID- 21703171 TI - IL-33--a cytokine which balances on a knife's edge? PMID- 21703172 TI - Who pulls the trigger: JNK activation in liver lipotoxicity? PMID- 21703173 TI - Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography. AB - BACKGROUND & AIMS: Patients with acute liver injury/failure (ALI/ALF) are assumed to have a bleeding diathesis on the basis of elevated INR; however, clinically significant bleeding is rare. We hypothesized that patients with ALI/ALF have normal hemostasis despite elevated INR. METHODS: Fifty-one patients with ALI/ALF were studied prospectively using thromboelastography (TEG), which measures the dynamics and physical properties of clot formation in whole blood. ALI was defined as an INR >=1.5 in a patient with no previous liver disease, and ALF as ALI with hepatic encephalopathy. RESULTS: Thirty-seven of 51 patients (73%) had ALF and 22 patients (43%) underwent liver transplantation or died. Despite a mean INR of 3.4+/-1.7 (range 1.5-9.6), mean TEG parameters were normal, and 5 individual TEG parameters were normal in 32 (63%). Low maximum amplitude, the measure of ultimate clot strength, was confined to patients with platelet counts <126*10(9)/L. Maximum amplitude was higher in patients with ALF than ALI and correlated directly with venous ammonia concentrations and with increasing severity of liver injury assessed by elements of the systemic inflammatory response syndrome. All patients had markedly decreased procoagulant factor V and VII levels, which were proportional to decreases in anticoagulant proteins and inversely proportional to elevated factor VIII levels. CONCLUSIONS: Despite elevated INR, most patients with ALI/ALF maintain normal hemostasis by TEG, the mechanisms of which include an increase in clot strength with increasing severity of liver injury, increased factor VIII levels, and a commensurate decline in pro- and anticoagulant proteins. PMID- 21703175 TI - In vitro selection and characterization of HCV replicons resistant to multiple non-nucleoside polymerase inhibitors. AB - BACKGROUND & AIMS: To delay or prevent the selection of HCV drug-resistant variants, combination therapy will be needed. Our aim was to determine the antiviral efficacy of various combinations of non-nucleoside polymerase inhibitors (NNI) (that have a different allosteric binding site) and the barrier towards resistance development of such combinations. METHODS: Short-term antiviral combination assays were performed in a checkerboard format. Resistance selection experiments employing HCV replicons were performed using two different protocols: (i) a short-term treatment with fixed concentrations and (ii) a long term treatment with increasing concentrations. RESULTS: All pair-wise combinations of NNI resulted in an additive antiviral effect in short-term antiviral assays. Combination treatment of two NNIs markedly reduced or even prevented the emergence of double resistant colonies. However, double and even triple NNI-resistant variants emerged readily when relatively low starting concentrations were used in a long-term selection protocol. Genotyping confirmed the presence of the previously published resistance mutations. For some NNI, different signature mutations appeared depending on the other NNI in the particular combination. Remarkably, variants that were selected to be resistant to three different classes of NNIs [a thiophene carboxylic acid (TCA), a benzimidazole (JT-16), and a benzofuran (HCV-796)] proved resistant to yet a fourth class of NNIs (benzothiadiazines). CONCLUSIONS: Double and even triple NNI resistant HCV replicons can be readily selected with a stepwise resistance selection protocol. Depending on the particular combination, different signature mutations may arise for some NNI. Resistance to three classes of NNI resulted in resistance to yet a fourth class. PMID- 21703174 TI - Cdc42 and Rac1 are major contributors to the saturated fatty acid-stimulated JNK pathway in hepatocytes. AB - BACKGROUND & AIMS: Saturated free fatty acid (SFA)-stimulated c-Jun NH(2) terminal kinase (JNK) activation is associated with the pathogenesis of non alcoholic fatty liver disease (NAFLD). However, the mechanisms responsible for the effects of SFA are incompletely understood. The goal of this study was to determine the molecular mechanisms by which SFA induce JNK activation in hepatocytes. METHODS: We used siRNA-mediated knockdown in Hepa1c1c7 and AML12 cell lines, as well as primary mouse hepatocytes for these studies. RESULTS: The current model for JNK activation by SFA involves endoplasmic reticulum (ER) stress, which induces JNK activation through an inositol requiring enzyme 1 (IRE1alpha) Apoptosis Regulating Kinase 1 (ASK1)-dependent mechanism. Here, we find that SFA-induced JNK activation is not inhibited in the absence of IRE1alpha and ASK1. Instead we show that activation of the small GTP-binding proteins Cdc42 and Rac1 is required for SFA-stimulated MLK3-dependent activation of JNK in hepatocytes. In addition, we demonstrate that SFA-induced cell death in hepatocytes is independent of IRE1alpha, but dependent on Cdc42, Rac1, and MLK3. CONCLUSIONS: Our results demonstrate that Cdc42 and Rac1, rather than ER stress, are important components of a SFA-stimulated signaling pathway that regulates MLK3-dependent activation of JNK in hepatocytes. PMID- 21703176 TI - Interleukin-28B genetic variants in identification of hepatitis C virus genotype 1 patients responding to 24 weeks peginterferon/ribavirin. AB - BACKGROUND & AIMS: A substantial proportion of hepatitis C virus genotype 1 (HCV 1) patients achieved a sustained virological response (SVR, HCV RNA seronegative throughout 24 weeks of post-treatment follow-up) after 24 weeks peginterferon/ribavirin therapy. We explored the role of interleukin-28B genotype in identifying patients who responded to the regimen. METHODS: Interleukin-28B rs8099917 genotype was determined in 226 HCV-1 patients with 24 weeks peginterferon/ribavirin. RESULTS: Compared to patients with rs8099917 TG/GG genotype, those with TT genotype had significantly higher rapid virological response (RVR, HCV RNA seronegative at treatment week 4, 54.0% vs. 17.9%, p<0.001) and SVR (64.7% vs. 25.6%, p<0.001) rates, and lower relapse rate (28.0% vs. 54.5%, p=0.01). Logistic regression analysis revealed that the strongest factor predictive of a RVR was the carriage of rs8099917 TT genotype (odds ratio/ 95% confidence intervals [OR/CI]: 6.24/2.34-16.63), followed by lower viral loads (OR/CI: 5.29/2.81-9.93) and age (OR/CI:0.94/0.91-9.97). The most important factor predictive of an SVR was the attainment of a RVR (OR/CI: 22.23/9.22-53.58), followed by the carriage of rs8099917 TT genotype (OR/CI: 3.38/1.18-9.65), lower viral loads (OR/CI: 2.23/1.00-4.93) and ribavirin exposure dose (OR/CI: 1.17/1.06 1.30). The determinant power of rs8099917 genotype on SVR was mainly restricted to non-RVR patients, particularly those with higher baseline viral loads. Combination of the two pretreatment predictors, interleukin-28B genotype and baseline viral loads, could predict treatment efficacy with a positive predictive value of 80% and a negative predictive value of 91%. CONCLUSIONS: Interleukin-28B genotype could help identifying patients who are or are not candidates for an abbreviated regimen before treatment. PMID- 21703178 TI - Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a common cause of abnormal LFTs in primary care, but there are no data defining its contribution nor reporting the range of NAFLD severity in this setting. This study seeks to calculate the range of disease severity of NAFLD in a primary care setting. METHODS: Adult patients with incidental abnormal LFTs, in the absence of a previous history, or current symptoms/signs of liver disease were prospectively recruited from eight primary care practices in Birmingham. NAFLD was diagnosed as fatty liver on ultrasound, negative serological liver aetiology screen, and alcohol consumption <=30 and <=20 g/day in males and females, respectively. The NAFLD Fibrosis Score (NFS) was calculated to determine the presence or absence of advanced liver fibrosis in subjects identified with NAFLD. RESULTS: Data from 1118 adult patients were analysed. The cause of abnormal LFTs was identified in 55% (614/1118) of subjects, with NAFLD (26.4%; 295/1118) and alcohol excess (25.3%; 282/1118) accounting for the majority. A high NFS (>0.676) suggesting the presence of advanced liver fibrosis was found in 7.6% of NAFLD subjects, whereas 57.2% of NAFLD patients had a low NFS (<-1.455) allowing advanced fibrosis to be confidently excluded. CONCLUSIONS: NAFLD is the commonest cause of incidental LFT abnormalities in primary care (26.4%), of whom 7.6% have advanced fibrosis as calculated by the NFS. This study is the first of its kind to highlight the burden of NAFLD in primary care and provide data on disease severity in this setting. PMID- 21703177 TI - Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients. AB - BACKGROUND & AIMS: Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-alpha (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia. METHODS: 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count >=80*10(9)/L and an absolute neutrophil count (ANC) >=1500/mm(3). Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294). RESULTS: 6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p=10(-10)). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV) induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p=10(-12), p=10(-7)) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=-0.28, p=10( 17)) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia. CONCLUSIONS: Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified. PMID- 21703179 TI - Smoking as an independent risk factor of liver fibrosis in primary biliary cirrhosis. AB - BACKGROUND & AIMS: Smoking has been identified as a potential predisposition factor for primary biliary cirrhosis (PBC). However, it remains unclear whether it is associated with more active and severe disease. Our aim was to assess the relationships between smoking and the severity of the elementary histological lesions, as well as the biochemical and immunological features of PBC. METHODS: Smoking history data were collected from 223 PBC patients using a standardized questionnaire. Histological data were available in 164 patients at presentation. Liver fibrosis and histological inflammatory activity were semi-quantified according to a METAVIR-based classification system. Odds ratios (OR) were assessed using a logistic regression analysis. RESULTS: Smoking history prior to diagnosis was reported in 58 patients (26%). Twenty-five patients (11%) were active smokers at diagnosis. Male gender (OR, 4.5), alcohol intake >20 g/d (OR, 4.2), and F3-F4 fibrosis stage (OR, 2.7), but not inflammatory grade, bile duct changes, biochemical or immunological features, were associated with smoking history. Smoking intensity was significantly higher in patients with F3-F4 stage (8.1+/-14.2 pack-years vs. 3.0+/-7.0 pack-years; p=0.01). Adjusted logistic regression identified smoking history and smoking intensity as independent risk factors of advanced fibrosis. Each pack-year of increase in smoking intensity was associated with a 5.0% (95% CI, 1.3-8.7%) increased likelihood of advanced fibrosis. CONCLUSIONS: Smoking increases, in a dose-dependent fashion, the risk of liver fibrosis in PBC without apparent increase in the histological inflammatory activity, bile duct lesions, biochemical, and immunological features of the disease. PBC patients should be strongly encouraged not to smoke. PMID- 21703180 TI - Effect of HBV polymerase inhibitors on renal function in patients with chronic hepatitis B. AB - BACKGROUND & AIMS: Therapy of chronic hepatitis B with HBV-polymerase inhibitors, in particular tenofovir or adefovir, may affect renal function. To assess renal function more accurately in the normal range, we used the recently validated, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula to calculate the estimated glomerular filtration rate (eGFR). METHODS: Patient subgroups included: patients with HBV-monoinfection treated with lamivudine (n=36), adefovir (n=32), entecavir (n=32), or tenofovir (n=37). HBsAg-positive untreated patients (n=60) served as control. For comparison HIV-monoinfected patients treated with tenofovir (n=120) or zidovudine (n=52) based antiretroviral therapy and antiretroviral naive patients (n=109) were assessed. CKD-EPI equation was used to calculate eGFR. In a more sensitive approach, we modeled the individual change in eGFR over time with linear mixed effects models (LME). RESULTS: Yearly predicted median changes in individual eGFR according to the LME model were: HBV untreated -2.05 ml/min, HBV lamivudine -0.92 ml/min, HBV adefovir -1.02 ml/min, HBV entecavir -1.00 ml/min, and HBV tenofovir -0.92 ml/min (p<0.01 for HBV untreated vs. HBV treated). In HIV-monoinfected patients: HIV untreated -0.62 ml/min, HIV treated with tenofovir -2.64 ml/min, HIV treated with zidovudine -1.0 ml/min (p=0.017 for tenofovir vs. no treatment, p<0.001 for tenofovir vs. zidovudine). CONCLUSIONS: Therapy of HBV infection irrespective of medication seems to result in a milder decrease of renal function. In contrast tenofovir as part of HIV combination therapy seems to impair renal function in this Caucasian population. PMID- 21703181 TI - Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese. AB - BACKGROUND & AIMS: Morbid obesity is frequently associated with low grade systemic inflammation, increased macrophage accumulation in adipose tissue (AT), obstructive sleep apnea (OSA), and nonalcoholic fatty liver disease (NAFLD). It has been suggested that chronic intermittent hypoxia (CIH) resulting from OSA could be an independent factor for early stage of NAFLD in addition to other well recognized factors (dyslipidemia or insulin resistance). Moreover, macrophage accumulation in AT is associated with local hypoxia in fat tissue. We hypothesized that the association between CIH and morbid obesity could exert additional specific deleterious effects both in the liver and adipose tissues. METHODS: One hundred and one morbidly obese subjects were prospectively recruited and underwent bariatric surgery during which a liver needle biopsy as well as surgical subcutaneous and omental AT biopsies were obtained. Oxygen desaturation index (ODI) quantified the severity of nocturnal CIH. RESULTS: Histopathologic analysis of liver biopsies demonstrated that NAFLD lesions (ballooning of hepatocytes, lobular inflammation), NAFLD activity score (NAS), and fibrosis were significantly more severe in patients with the highest ODI tertile (p values <=0.001 for all hepatic lesions). In multivariate analysis, after adjustment for age, obesity, and insulin resistance status, CIH remained independently associated with hepatic fibrosis, fibroinflammation, and NAS. By contrast, no association was found between CIH, macrophage accumulation, and adipocytes size in both subcutaneous and omental adipose tissue. CONCLUSIONS: In morbidly obese patients, CIH was strongly associated with more severe liver injuries but did not worsen obesity induced macrophage accumulation in adipose tissue depots. PMID- 21703182 TI - Threshold for toxicity from hyperammonemia in critically ill children. AB - BACKGROUND & AIMS: Hyperammonemia results from reduction of hepatocyte function or enzyme of urea cycle deficiency. Hyperammonemia contributes to cerebral edema that may lead to cerebral herniation. The threshold of toxicity of ammonemia is unknown. METHODS: We conducted a retrospective observational study in our pediatric intensive care unit. All children who developed hyperammonemia from January 2000 to April 2009 were included. Clinical and laboratory data at admission, specific treatments implemented, and ammonemias the first 7 days after inclusion were collected. The outcome assessed was 28 day mortality. Risk of mortality was estimated by a logistic regression model. RESULTS: Ninety patients with liver failure (63.3%) and primary or secondary urea cycle defect (23.3%) were included. Patients with urea cycle defects were more likely to receive ammonia scavengers than patients with liver failure (47.6% versus 3.5%). The 28 day mortality rate was 31.1%. Risk of mortality increased according to the ammonemia within 48 h: odds ratio 1.5, 1.9, 3.3, 2.4 for ammonemia above 100, 150, 200, and 300 MUmol/L, respectively. Peak ammonemia >=200 MUmol/L within the first 48 h was an independent risk factor for mortality, with greater risk found in liver failure than in urea cycle defect. CONCLUSIONS: Our study identifies a threshold of exposure to ammonia (>=200 MUmol/L) above which mortality increases significantly, especially in liver failure. Specific treatments of hyperammonemia are rarely used in liver failure when compared with urea cycle defect even though use of ammonia scavengers may help to decrease ammonemia. PMID- 21703183 TI - Protective role of IL-33/ST2 axis in Con A-induced hepatitis. AB - BACKGROUND & AIMS: We used Concanavalin A-induced liver injury to study the role of Interleukin 33 and its receptor ST2 in the induction of inflammatory pathology and hepatocellular damage. METHODS: We tested susceptibility to Concanavalin A induced hepatitis in ST2 deficient and wild type BALB/c mice and analyzed the effects of single injection of Interleukin 33 as evaluated by liver enzyme test, quantitative histology, mononuclear cell infiltration, cytokine production, intracellular staining of immune cells, and markers of apoptosis in the liver. RESULTS: ST2 deficient mice developed significantly more severe hepatitis and had significantly higher number of mononuclear cells in the liver, CD4+ and CD8+ T cells, NKp46+ and CD3+NKp46+ cells, and F4/80+ macrophages. The level of pro inflammatory cytokines in the sera and number of TNF alpha, IFN gamma, and IL-17 producing cells was higher in ST2 deficient mice. In contrast, number of CD4+Foxp3+ cells was statistically higher in wild type mice. Additionally, treatment of wild type mice with single (1 MUg) injection of Interleukin 33 led to attenuation of the liver injury and milder infiltration of mononuclear cells, increase in total number of liver CD4+Foxp3+ cells and IL-4 producing CD4+ T cells. Interleukin 33 also suppressed the activation of caspase 3, prevented the expression of BAX, and enhanced the expression of antiapoptotic Bcl-2 in the liver. CONCLUSIONS: We concluded that Interleukin 33/ST2 axis downregulated Concanavalin A-induced liver injury and should be evaluated as potential target in fulminant hepatitis in humans. PMID- 21703184 TI - SOCS1 controls liver regeneration by regulating HGF signaling in hepatocytes. AB - BACKGROUND & AIMS: Frequent repression of the Socs1 (suppressor of cytokine signaling 1) gene in hepatocellular carcinoma (HCC) and increased susceptibility of SOCS1-deficient mice to hepatocarcinogens suggest a tumor suppressor role for SOCS1 in the liver, but the underlying mechanisms remain unclear. Here we investigated the role of SOCS1 in regulating hepatocyte proliferation following partial hepatectomy and HGF stimulation. METHODS: Because Socs1(-/-) mice die prematurely due to deregulated IFNgamma signaling, we used Socs1(-/-)Ifng(-/-) mice to study the role of SOCS1 in liver regeneration following partial hepatectomy. We examined the activation of signaling molecules downstream of IL-6 and hepatocyte growth factor (HGF) receptors in the regenerating liver, primary hepatocytes, and in human hepatoma cells. We examined the interaction between SOCS1 and the HGF receptor c-Met by reciprocal immunoprecipitation. RESULTS: Socs1(-/-)Ifng(-/-) mice displayed accelerated liver regeneration with increased DNA synthesis compared to Ifng(-/-) and wild type mice. The regenerating liver of Socs1(-/-)Ifng(-/-) mice did not show increased IL-6 signaling, but displayed earlier phosphorylation of Gab1, a signaling adaptor downstream of c-Met. Following HGF stimulation, hepatocytes from Socs1(-/-)Ifng(-/-) mice displayed increased phosphorylation of c-Met and Gab1, cell migration and proliferation. Accordingly, SOCS1 overexpression attenuated HGF-induced phosphorylation of c Met, Gab1, and ERK1/2 in hepatoma cells, and decreased their proliferation and migration. SOCS1 interacted with the Tpr-Met, an oncogenic form of the Met receptor. CONCLUSIONS: SOCS1 attenuates c-Met signaling and thus negative regulation of HGF signaling could be an important mechanism underlying the anti tumor role of SOCS1 in the liver. PMID- 21703185 TI - Altered composition of fatty acids exacerbates hepatotumorigenesis during activation of the phosphatidylinositol 3-kinase pathway. AB - BACKGROUND & AIMS: Some clinical findings have suggested that systemic metabolic disorders accelerate in vivo tumor progression. Deregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is implicated in both metabolic dysfunction and carcinogenesis in humans; however, it remains unknown whether the altered metabolic status caused by abnormal activation of the pathway is linked to the protumorigenic effect. METHODS: We established hepatocyte-specific Pik3ca transgenic (Tg) mice harboring N1068fs*4 mutation. RESULTS: The Tg mice exhibited hepatic steatosis and tumor development. PPARgamma-dependent lipogenesis was accelerated in the Tg liver, and the abnormal profile of accumulated fatty acid (FA) composition was observed in the tumors of Tg livers. In addition, the Akt/mTOR pathway was highly activated in the tumors, and in turn, the expression of tumor suppressor genes including Pten, Xpo4, and Dlc1 decreased. Interestingly, we found that the suppression of those genes and the enhanced in vitro colony formation were induced in the immortalized hepatocytes by the treatment with oleic acid (OA), which is one of the FAs that accumulated in tumors. CONCLUSIONS: Our data suggest that the unusual FA accumulation has a possible role in promoting in vivo hepato-tumorigenesis under constitutive activation of the PI3K pathway. The Pik3ca Tg mice might help to elucidate molecular mechanisms by which metabolic dysfunction contributes to in vivo tumor progression. PMID- 21703186 TI - Survival after radiofrequency ablation and salvage transplantation in patients with hepatocellular carcinoma and Child-Pugh A cirrhosis. AB - BACKGROUND & AIMS: In patients with hepatocellular carcinoma (HCC) within the Milan criteria, liver transplantation (LT) may be the best therapeutic option. However, the shortage of grafts, leads to attempt liver resection (LR) or radiofrequency ablation (RFA) as a first-line treatment for patients with Child Pugh A cirrhosis. METHODS: We report results, obtained between 2000 and 2007 from a single center, involving 67 patients (mean age: 57 years) eligible for LT, who were treated with RFA, followed by LT if there was recurrence or liver failure. RESULTS: Eighty three tumors were treated (mean size: 29+/-9 mm; 16 binodular forms). RFA achieved complete ablation in 96% of nodules. No mortality occurred. During a post-RFA median follow-up of 48 months, 38 patients experienced recurrence, corresponding to a 5-year recurrence rate of 58%. Of these, 14 patients did not receive a transplant because they fell outside the Milan criteria, 21 were transplanted, and 3 were treated by RFA after refusing LT. Binodularity (95% CI HR=2, 1.0-4.0; p=0.049) was the unique risk factor for recurrence. By the study's end-point, 24 patients had undergone LT (21 for HCC recurrence and three for liver failure). No HCC recurrence occurred after LT. Among the 43 non-transplant patients, 12 died due to HCC progression, and 27 were alive without detectable viable tumor. The probability rates for 5-year overall and tumor-free survival were 74% and 69%, respectively. CONCLUSIONS: First line RFA followed by salvage LT allows survival figures that are at least as good as a first-line LT, while limiting the number of grafts. PMID- 21703187 TI - Liver disease in adult patients with cystic fibrosis: a frequent and independent prognostic factor associated with death or lung transplantation. AB - BACKGROUND & AIMS: Increased life expectancy in patients with cystic fibrosis (CF) allows better knowledge of non-pulmonary complications like liver disease (CFLD). However, few data have been published in large adult cohorts. The aim of this study was to estimate the prevalence and the prognosis of CFLD in adult CF patients. METHODS: A retrospective analysis of a monocentric cohort of adult CF patients prospectively followed, at least every year, was performed. CFLD was diagnosed using published composite criteria. If cirrhosis was suspected, upper digestive endoscopy was realized to assess the presence of portal hypertension. RESULTS: A cohort of 285 adult CF patients was followed during 4.8 +/- 3.6 years. Among them, 90 had CFLD at the beginning of follow-up and 23 a suspicion of cirrhosis. Factors independently associated with liver disease at baseline were history of meconium ileus, pancreatic insufficiency, chronic colonization with Burkholderia cepacia and the number of IV antibiotic courses per year. Nine patients developed liver decompensation during follow-up, all with a suspicion of cirrhosis at baseline. Six patients underwent liver transplantation alone and three patients combined liver and lung transplantation. Factors independently associated with death or lung transplantation at baseline were liver disease, BMI, forced expiratory volume in 1 second and number of IV antibiotic courses per year. CONCLUSIONS: CFLD was present at baseline in one third of adult patients with CF with a marked risk of liver decompensation during follow-up. Moreover, CFLD at baseline appears as an independent factor associated with death or lung transplantation. PMID- 21703188 TI - Association of polymorphisms in the promoter regions of TNF-alpha (-308) with susceptibility to hepatitis E virus and TNF-alpha (-1031) and IFN-gamma (+874) genes with clinical outcome of hepatitis E infection in India. AB - BACKGROUND & AIMS: Hepatitis E virus (HEV) is the predominant cause of acute viral hepatitis (AVH-E) and acute liver failure (ALF-E) among adults from developing countries. Pathogenesis of hepatitis E is poorly understood. Earlier, we showed association of elevated serum levels of TNF-alpha, IFN-gamma, and IL-12 with ALF-E. The role of TNF-alpha and IFN-gamma gene promoter polymorphisms with disease severity was investigated. METHODS: The study population included 374 anti-HEV negative apparently healthy controls, 136 subclinical hepatitis E, 353 AVH-E, and 25 ALF-E patients. Polymorphisms at promoter regions of TNF-alpha 308G/A, TNF-alpha-1031T/C, and IFN-gamma+874T/A were investigated employing allelic discrimination/SNaPshotTM methods. RESULTS: ALF-E patients were younger with significantly higher ALT levels when compared to other categories. Genotype TNF-alpha-308AA frequency was significantly higher among subclinical and clinical hepatitis E than the controls (p=0.03, 0.0007). No significant difference was observed among AVH-E/ALF-E groups. The -308A allele was significantly higher in HEV-infected individuals; fatal ALF patients showed higher frequency than the recovered (p=0.024). TNF-alpha-1031CC, IFN-gamma+874TT, and IFN-gamma+874TA genotypes were significantly associated with clinical disease. With respect to the controls, genotype+874TA was more frequent in subclinical infection (p=0.005) while+874AA frequency was lower in the AVH-E category (p=0.003). CONCLUSIONS: The data reveal association of TNF-alpha-308AA genotype with susceptibility to HEV and that of TNF-alpha-1031CC and IFN-gamma+874TT and TA with clinical disease, irrespective of the outcome. Higher -308A allele frequency was associated with susceptibility to HEV and the fatal outcome of ALF-E. PMID- 21703190 TI - Embolization of hepatocellular carcinoma with drug-eluting beads: doxorubicin tissue concentration and distribution in patient liver explants. AB - BACKGROUND & AIMS: To follow the local tissue delivery of doxorubicin in HCC explants from patients embolized with drug-eluting beads and to compare it with histologic modifications. METHODS: Six patients with HCC underwent chemoembolization with doxorubicin-eluting beads (caliber 100-300 MUm, dose 75 150 mg) followed by liver transplantation at different time points (8 h to 36 days). On sections of the explanted liver, the tissue concentration of doxorubicin was determined radially around bead-occluded vessels with microspectrofluorimetry. The intra/peritumoral location of the beads and the modifications of the surrounding tissue were determined on an adjacent hematein eosin-saffron-stained section and compared to drug measurements. RESULTS: Doxorubicin was detected in the tissue surrounding the beads at all times of explantation. The drug impregnates an area of at least 1.2 mm in diameter around the occluded vessel. The tissue concentration of drug ranges from 5 MUM at 8 h to 0.65 MUM at 1 month. In patient transplanted at 8 h, no major tissue modification was observed and we found 42% of the beads occluding intratumoral vessels. Drug concentration was not different around intratumoral and peritumoral occluded vessels. After 9-14 days, necrosis was present around 37% of vessels and at 32-36 days, around 40% of vessels. Necrotic tissue was associated with a deeper penetration and a higher concentration of the drug than non necrotized areas, though statistically significant only at 32-36 days. CONCLUSIONS: Doxorubicin eluting beads provide a sustained delivery of drug for a period of 1 month and local tissue concentrations above cytotoxic threshold in HCC-bearing livers. PMID- 21703189 TI - Regulation of placenta growth factor by microRNA-125b in hepatocellular cancer. AB - BACKGROUND & AIMS: microRNAs (miRNAs) are a class of small noncoding RNAs that can regulate gene expression by translation repression or mRNA degradation. Our aim was to evaluate the role of aberrantly expressed miRNAs in hepatocellular cancer (HCC). METHODS: miRNA expression in HCC tissues and cells was evaluated by qPCR array and Taqman miRNA assay. Cell proliferation, motility, invasion, and the angiogenesis index were quantitated using commercial assays. DNA methylation status, matrix metalloproteinases (MMPs) mRNA expression was quantitated by real time PCR analysis. RESULTS: miRNA profiling identified a decrease in miR-125b expression in HCC tumor tissues and cell lines. The expression of miR-125b was significantly increased by the methylation inhibitor 5-aza-2'-deoxycytidine in HCC cells but not in normal controls, suggesting that the expression of miR-125b could be epigenetically modulated. Methylation-specific PCR revealed hypermethylation status of miR-125b in HCC cells compared to non-malignant controls. Cell proliferation, anchorage-independent growth, cell migration, invasion, and angiogenesis were significantly decreased by the introduction of miR-125b precursor in HCC cell lines. Placenta growth factor was identified as a target of miR-125b by bioinformatics analysis and experimentally verified using luciferase reporter constructs. Overexpression of miR-125b in HCC cells decreased PIGF expression, and altered the angiogenesis index. Furthermore, modulation of miR-125b also distorted expression of MMP-2 and -9, the mediators of enzymatic degradation of the extracellular matrix. CONCLUSIONS: Our studies showing epigenetic silencing of miR-125b contributes to an invasive phenotype provide novel mechanistic insights and identify a potential target mechanism that could be manipulated for therapeutic benefit in HCC. PMID- 21703191 TI - Interaction of bile salts with rat canalicular membrane vesicles: evidence for bile salt resistant microdomains. AB - BACKGROUND & AIMS: Canalicular phosphatidylcholine and cholesterol secretion requires the coordinate action of the ATP binding cassette transporters: the bile salt export pump (Bsep) for bile salts (BS) and the phosphatidylcholine translocator multidrug resistance protein 2 (Mdr2). After their secretion, phosphatidylcholine and BS form mixed micelles acting as acceptors for canalicular cholesterol. We have shown that the canalicular liver plasma membrane (cLPM) contains lipid raft enriched in sphingomyelin and cholesterol. As BS have detergent properties and their concentration in the canaliculus is very high, we tested the hypothesis that the canalicular membrane contains BS resistant microdomains. METHODS: Isolated cLPMs were extracted at 4 degrees C with different BS or detergents and subjected to flotation in sucrose step gradients followed by Western blotting and lipid composition analysis. RESULTS: Incubating cLPMs with increasing taurocholate concentrations revealed the presence of BS resistant microdomains. These microdomains were found with different BS in the presence and absence of lipids and contained the raft markers reggie-1/-2 and caveolin-1 and canalicular transporters Bsep, Mrp2, and Abcg5, the latter independent of the presence of lipids. BS resistant microdomains contain mainly cholesterol, phosphatidylcholine, and phosphatidylethanolamine. Extraction of cLPMs with a mixture of different BS similar to rat bile revealed a comparable microdomain composition. CONCLUSIONS: cLPM contains BS resistant microdomains potentially protecting the cLPM against the detergent action of BS. Combination of different BS has no synergistic effect on microdomain composition. PMID- 21703192 TI - Chemical composition of hepatic lipids mediates reperfusion injury of the macrosteatotic mouse liver through thromboxane A(2). AB - BACKGROUND & AIMS: Chemical composition of hepatic lipids is an evolving player in steatotic liver ischemia/reperfusion (I/R) injury. Thromboxane A(2) (TXA(2)) is a vasoactive pro-inflammatory lipid mediator derived from arachidonic acid (AA), an omega-6 fatty acid (Omega-6 FA). Reduced tolerance of the macrosteatotic liver to I/R may be related to increased TXA(2) synthesis due to the predominance of Omega-6 FAs. METHODS: TXA(2) levels elicited by I/R in ob/ob and wild type mice were assessed by ELISA. Ob/ob mice were fed Omega-3 FAs enriched diet to reduce hepatic synthesis of AA and TXA(2) or treated with selective TXA(2) receptor blocker before I/R. RESULTS: I/R triggered significantly higher hepatic TXA(2) production in ob/ob than wild type animals. Compared with ob/ob mice on regular diet, Omega-3 FAs supplementation markedly reduced hepatic AA levels before ischemia and consistently blunted hepatic TXA(2) synthesis after reperfusion. Sinusoidal perfusion and hepatocellular damage were significantly ameliorated despite downregulation of heme oxygenase-1. Hepatic transcript and protein levels of IL-1beta and neutrophil recruitment were significantly diminished after reperfusion. Moreover, TXA(2) receptor blockage conferred similar protection without modification of the histological pattern of steatosis. A stronger protection was achieved in the steatotic compared with lean animals. CONCLUSIONS: Enhanced I/R injury in the macrosteatotic liver is explained, at least partially, by TXA(2) mediated microcirculatory failure rather than size related mechanical compression of the sinusoids by lipid droplets. TXA(2) blockage may be a simple strategy to include steatotic organs and overcome the shortage of donor organs for liver transplantation. PMID- 21703194 TI - Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. AB - BACKGROUND & AIMS: The biochemical response to ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC) correlates with the long-term prognosis and thus could allow the identification of the patients needing new therapeutic approaches. Due to variation in both endpoints and studied populations, there is still no full agreement on the definition of the biochemical response. The aim of our study was to determine, in a population of patients with only early-stage disease, the best biochemical criteria of response to UDCA allowing to predict the absence of poor outcome, as defined by liver-related death, liver transplantation, complications of cirrhosis, or histological evidence of cirrhosis development. METHODS: The efficiency of several combinations of serum bilirubin, alkaline phosphatase (ALP), and aspartate aminotransferase (AST) threshold values to predict outcome was assessed after 1 year of UDCA in 165 patients with early-stage PBC followed up for an average 7 years. The Barcelona, Paris, Rotterdam, and Toronto criteria were also assessed. RESULTS: The most accurate discrimination of the patients according to the multiple endpoints was given by the following criteria: ALP and AST<=1.5* upper limit of normal, with a normal bilirubin level. Responders and non-responders were equally distributed, while all adverse events were observed in non-responders (p<0.001). These criteria remained valid when early PBC was defined by both normal bilirubin and albumin concentrations at baseline. CONCLUSIONS: This study defines the best efficient biochemical response to UDCA that identifies patients with early PBC at very low risk of long-term development of liver failure or cirrhosis. PMID- 21703193 TI - Hepatocyte gamma-catenin compensates for conditionally deleted beta-catenin at adherens junctions. AB - BACKGROUND & AIMS: Wnt/beta-catenin signaling is important in liver physiology. Moreover, beta-catenin is also pivotal in adherens junctions (AJ). Here, we investigate hepatocyte-specific beta-catenin conditional null mice (KO) for any alterations in AJ and related tight junctions (TJ). METHODS: Using gene array, PCR, Western blot, immunohistochemistry, immunofluorescence, and co immunoprecipitation, we compare and contrast the composition of AJ and TJ in KO and littermate wild-type (WT) control livers. RESULTS: We show association of E cadherin with beta-catenin in epithelial cells of WT livers, which is lost in the KOs. While total levels of alpha-catenin, E-cadherin, and F-actin were modestly decreased, KO livers show increased gamma-catenin/plakoglobin. By co immunoprecipitation, E-cadherin/beta-catenin/F-actin association was observed in WT livers, while the association of E-cadherin/gamma-catenin/F-actin was evident in KO livers. gamma-Catenin was localized at the hepatocyte membrane at baseline in the KO liver. While gamma-catenin gene expression remained unaltered, an increase in serine- and threonine-phosphorylated, but not tyrosine-phosphorylated gamma-catenin was observed in KO livers. A continued presence of gamma-catenin at the hepatocyte membrane, without any nuclear localization, was observed in liver regeneration after partial hepatectomy at 40 and 72 h, in both KO and WT. Analysis of TJ revealed lack of claudin-2 and increased levels of JAM-A and claudin-1 in KO livers. CONCLUSIONS: beta-Catenin adequately maintains AJ in the absence of beta-catenin in hepatocytes; however, it lacks nuclear localization. Moreover, beta-catenin/claudin-2 may be an important mechanism of crosstalk between the AJ and TJ. PMID- 21703195 TI - Impact of insulin resistance on sustained response in HCV patients treated with pegylated interferon and ribavirin: a meta-analysis. AB - BACKGROUND & AIMS: Recent studies suggested that SVR rates might be lower in HCV patients with insulin resistance (IR) than in patients without IR, but the extent of the impact of IR on treatment response has not been established. We aimed to confirm the role of IR assessed by the homoeostasis model assessment (HOMA-IR) on SVR and to determine its magnitude. METHODS: We performed meta-analysis of studies evaluating the impact of IR in HCV patients treated with pegylated interferon and ribavirin. RESULTS: Fourteen studies involving 2732 patients were included. SVR was less frequent in patients with IR than in patients without IR (mean difference: -19.6%, 95% CI: -29.9% to -9.4%, p<0.001). In sensitivity analyses according to HCV-1 patients, patients with IR also less frequently attained a SVR than patients without IR (mean difference: -13.0%, 95% CI: -22.6% to -3.4%, p=0.008). In addition, the baseline HOMA-IR index was lower in responders than in non-responders (mean difference: -0.92, 95% CI: -1.53 to 0.32, p<0.001). In sensitivity analyses restricted to HCV-1 patients, the baseline HOMA-IR index remained lower in responders than in non-responders (mean difference: -0.63, 95% CI: -1.13 to -0.14, p<0.001). CONCLUSIONS: HCV patients with IR have a 20% lower SVR than patients without IR. The baseline HOMA-IR index is a major determinant of SVR. PMID- 21703196 TI - EASL and mRECIST responses are independent prognostic factors for survival in hepatocellular cancer patients treated with transarterial embolization. AB - BACKGROUND & AIMS: Standard RECIST criteria may not be the optimal method to assess response to loco-regional therapy for hepatocellular cancer (HCC). EASL and mRECIST, which measure changes in arterialized tumor, have been proposed. Here we compare the three criteria and their associations with survival. METHODS: Response was determined using RECIST 1.1, EASL, and mRECIST criteria in 83 consecutive patients with HCC undergoing palliative therapy with transarterial (chemo) embolization. Results were compared at the first assessment after therapy. Cox regression and Kaplan-Meier survival analyses were used to explore differences in overall survival between the responders and non-responders defined by each method. RESULTS: There was a good correlation between EASL and mRECIST with overall response rates; 58% and 57%, and target lesion responses; 74% and 73%, respectively. There was a poor correlation with RECIST 1.1 with overall and target response rates of 7%. Overall and target lesion progression rates were similar for all three assessments; 27% and 2% for both EASL and mRECIST and 28% and 6% for RECIST 1.1. There was a significant association between survival and overall EASL and mRECIST responses, which was retained in multivariate analysis. EASL response was associated with a 44% risk reduction and mRECIST with a 42% reduction. There was no significant association between survival for RECIST 1.1 responses or target EASL and mRECIST responses. CONCLUSIONS: When measured at a single, early time point post-therapy, EASL and mRECIST overall response rates are associated with survival and should be used in preference to RECIST 1.1 or target responses. PMID- 21703197 TI - c-Met activation through a novel pathway involving osteopontin mediates oncogenesis by the transcription factor LSF. AB - BACKGROUND & AIMS: Understanding the molecular pathogenesis of hepatocellular carcinoma (HCC) would facilitate development of targeted and effective therapies for this fatal disease. We recently demonstrated that the cellular transcription factor Late SV40 Factor (LSF) is overexpressed in more than 90% of human HCC cases, compared to the normal liver, and plays a seminal role in hepatocarcinogenesis. LSF transcriptionally upregulates osteopontin (OPN) that plays a significant role in mediating the oncogenic function of LSF. The present study aims at a better understanding of LSF function by analyzing the signaling pathway modulated by LSF. METHODS: Phospho-receptor tyrosine kinase (RTK) array was performed to identify which receptor tyrosine kinases are activated by LSF. Immunohistochemical analysis using tissue microarray was performed to establish correlation among LSF, OPN, and phospho-c-Met levels in HCC patients. Co immunoprecipitation analysis was performed to check OPN-induced CD44 and c-Met interaction. Inhibition studies using chemicals and siRNAs were performed in vitro and in vivo using nude mice xenograft models to establish the importance of c-Met activation in mediating LSF function. RESULTS: Secreted OPN, induced by LSF, activates c-Met via a potential interaction between OPN and its cell surface receptor CD44. A significant correlation was observed among LSF, OPN, and activated c-Met levels in HCC patients. Chemical or genetic inhibition of c-Met resulted in profound abrogation of LSF-mediated tumorigenesis and metastasis in nude mice xenograft studies. CONCLUSIONS: The present findings elucidate a novel pathway of c-Met activation during hepatocarcinogenesis and support the rationale of using c-Met inhibitors as potential HCC therapeutics. PMID- 21703198 TI - Beneficial IL28B genotype associated with lower frequency of hepatic steatosis in patients with chronic hepatitis C. AB - BACKGROUND & AIMS: IL28B polymorphisms have been associated with both treatment induced and spontaneous clearance of hepatitis C virus (HCV). We previously found that LDL cholesterol levels were higher in chronic hepatitis C (CHC) patients with the CC genotype at the rs12979860 polymorphism, located proximal to the IL28 gene. Here we analyzed the association of steatosis with IL28B genotype in treatment naive patients with CHC. METHODS: Two independent cohorts of 145 genotype 1 infected patients from an antifibrotic study and 180 genotype 1 patients from Duke were analyzed for the presence and severity of steatosis in relation to the rs12979860 polymorphism at the IL28B locus. TaqMan assay based genotyping classified three groups CC, CT, and TT. RESULTS: CC genotype was associated with a lower prevalence of steatosis. In the antifibrotic study, steatosis was found in 47.6% (50/105) of IL28B non-CC vs. 22.5% (9/40; p=0.008) in CC patients. Similarly, steatosis was found in 67.4% (89/132) of non-CC patients compared to only 39.6% (19/48; p=0.001) of CC patients in the Duke cohort. CONCLUSIONS: IL28B CC genotype is associated with less pronounced disturbances of lipid metabolism, as reflected both in serum lipoprotein levels and hepatic steatosis, in HCV infection. PMID- 21703200 TI - The role of thiazolidinediones in non-alcoholic steatohepatitis - a systematic review and meta analysis. AB - BACKGROUND & AIMS: Non alcoholic steatohepatitis (NASH) has no approved pharmacological therapy. Insulin sensitisers such as thiazolidinediones ameliorate insulin resistance and are a potential therapeutic option. We performed a systematic review and meta-analysis of the effect of thiazolidinediones on histological and biochemical variables in NASH. METHODS: Two reviewers searched Medline, Embase, Cochrane Central, international meeting abstracts, reference lists, and contacted experts. Inclusion criteria were randomized trials of people with NASH receiving thiazolidinediones, compared with placebo or other treatments. Methodological quality was assessed in domains suggested by the Cochrane Collaboration. The primary outcome was histological improvement (fibrosis, steatosis, inflammation, hepatocellular ballooning, and NAS score). Secondary outcomes included change in alanine transaminase, insulin resistance, body mass index, weight, and adverse events. Meta-analysis used random effects with dichotomous outcomes as relative risk (RR) and continuous outcomes as mean difference (MD), both with 95% confidence intervals (CI). RESULTS: Of seven randomized trials (n=489) with histological outcomes, four were placebo controlled (n=355). Methodological quality was variable although better for placebo controlled studies. Treated participants showed improvement in fibrosis (RR 1.38, CI 1.01-1.89), steatosis (RR 2.03, CI 1.57-2.62), inflammation (RR 1.71, CI 1.32-2.21), and hepatocellular ballooning (RR 1.62, CI 1.15-2.28). Treatment increased weight by an average of 4.4 kg (CI 2.6-5.2 kg). Adverse event reporting was inconsistent and only one trial assessed quality of life. CONCLUSIONS: Thiazolidinediones modestly improve histological variables including fibrosis and hepatocellular ballooning, but at the cost of significant weight gain. Trials of longer duration and reporting of patient oriented outcomes would be informative. PMID- 21703199 TI - Diagnosis, treatment and survival of patients with hepatorenal syndrome: a survey on daily medical practice. AB - BACKGROUND & AIMS: Hepatorenal syndrome (HRS) is a severe complication of cirrhosis with ascites. The International Ascites Club recommended strict diagnostic criteria and treatment with vasoconstrictors and albumin. Aim of this prospective cohort study was to investigate the prevalence of HRS, diagnostic criteria, treatment and 3-month outcome in the daily-clinical-practice. METHODS: Two-hundred-fifty-three patients with cirrhosis and renal failure consecutively admitted to 21 Italian hospitals were recruited. RESULTS: The prevalence of HRS was 45.8% (30% type-1 and 15.8% type-2). In 36% of cases HRS was presumed because not all diagnostic criteria could be fulfilled. In 8% of cases HRS was superimposed on an organic nephropathy. Patients with HRS type-1 were younger and showed higher leukocyte count, higher respiratory rates, and worse liver function scores. Sixty-four patients with HRS type-1 received vasoconstrictors (40 terlipressin and 24 midodrine/octreotide). A complete response was obtained in 19 cases (30%) and a partial response in 13 (20%). Age was the only independent predictor of response (p=0.033). Three-month survival of patients with HRS type-1 was 19.7%. Survival was better in patients who responded to therapy. Age (p=0.017), bilirubin (p=0.012), and creatinine increase after diagnostic volume expansion (p=0.02) independently predicted death. The mortality rate was 97% among patients with at least two negative predictors. CONCLUSIONS: The diagnostic criteria of HRS in our daily-clinical-practice could not be completely fulfilled in one third of cases. The treatment with vasoconstrictors and albumin was widely implemented. Mortality was strongly predicted by simple baseline variables. PMID- 21703201 TI - The predictive value of IL28B gene polymorphism for spontaneous clearance in a single source outbreak cohort is limited in patients carrying the CCR5Delta32 mutation. AB - BACKGROUND & AIMS: The CCR5Delta32 mutation has been suspected to adversely affect outcomes of HCV infection, although reports have remained controversial. Here, we investigated the relative genetic contributions of the CCR5Delta32 deletion and the IL28B rs12979860 polymorphisms to spontaneous clearance of hepatitis C in a single-source outbreak. METHODS: We retrieved 396 Caucasian women (119 women with spontaneous HCV clearance) who had been infected with HCV genotype 1-contaminated anti-D immunoglobulin in 1978, and determined their IL28B and CCR5 alleles. RESULTS: IL28B CC, CT, and TT genotypes were found in 35.4%, 50%, and 14.6% of patients and corresponded to spontaneous clearance rates of 50%, 21.2%, and 12.1% (Chi(2)=38.7, p=5.0*10(-10)), respectively. CCR5 WT/WT, WT/Delta32, and Delta32/Delta32 genotypes were observed in 76%, 22.7%, and 1.3% of patients and corresponded to clearance rates of 33.2%, 21.2%, and 0% (Chi(2)=6.9, p=0.009), respectively. In a stepwise forward-conditional multivariate regression model both CCR5 (OR 2.1, p=0.01 for WT/WT) and IL28B genetic variants (OR 4.3, p=4.6*10(-10) for the C/C genotype) were identified as independent predictors of spontaneous HCV clearance. Importantly, favorable response rates were associated with the IL28B CC genotype only in CCR5 wild-type homozygous women, while HCV clearance in CCR5Delta32 carriers remained poor even in patients with the rs12979860 CC genotype. CONCLUSIONS: Both IL28B rs1297860 and CCR5Delta32 allelic variants are independent genetic determinants of spontaneous HCV clearance. The variable relative distribution between IL28B rs1297860 and CCR5Delta32 allelic variants in different populations may have masked the role of the CCR5Delta32 mutation in some studies. PMID- 21703202 TI - Hepatitis C in the general population of various ethnic origins living in the Netherlands: should non-Western migrants be screened? AB - BACKGROUND & AIMS: Little is known about the HCV prevalence in non-Western migrant populations. To determine whether targeted HCV screening and prevention programs for migrants are needed, we examined HCV prevalence and determinants among non-Western, Western migrants, and the native Dutch population in the Netherlands. METHODS: Data were obtained from four surveys: (1) 3895 heterosexual visitors recruited during biannual surveys at the STI-clinic Amsterdam, 2007 2009; (2) random sample of 4563 pregnant women in Amsterdam, 2003; (3) population based random sample of 1309 inhabitants of Amsterdam, 2004; (4) population-based random sample of 4428 people living in the Netherlands, 2006-2007. Characteristics associated with HCV-positivity were examined and phylogenetic analysis was used to obtain insight in the geographical origin of HCV strains. RESULTS: HCV seroprevalence in the four surveys was low (0.3-0.6%). In total 4860/14,195 (34%) were non-Western and 9329/14,195 (66%) Western participants (including Dutch). First-generation non-Western migrants were more likely to be HCV-positive (0.7-2.3%) than Western participants (0.1-0.4%). Except for survey 3, second-generation non-Western migrants had a lower HCV prevalence than first generation migrants, comparable to Western migrants and the Dutch population. Phylogenetic analysis showed that the majority of the HCV-positive, first generation non-Western non-European migrants were infected with endemic strains which are rarely observed in Europe. CONCLUSIONS: First-generation non-Western migrants are at increased risk for HCV. Phylogenetic analysis suggests that transmission likely took place in the country of origin, causing introduction but no further transmission of endemic HCV strains in the Netherlands. HCV screening and prevention programs should target first-generation, but not second generation, non-Western migrants. PMID- 21703203 TI - Gene-expression signature of vascular invasion in hepatocellular carcinoma. AB - BACKGROUND & AIMS: Vascular invasion is a major predictor of tumor recurrence after surgical treatments for hepatocellular carcinoma (HCC). While macroscopic vascular invasion can be detected by radiological techniques, pre-operative detection of microscopic vascular invasion, which complicates 30-40% of patients with early tumors, remains elusive. METHODS: A total of 214 patients with hepatocellular carcinoma who underwent resection were included in the study. By using genome-wide gene-expression profiling of 79 hepatitis C-related hepatocellular carcinoma samples (training set), a gene-expression signature associated with vascular invasion was defined. The signature was validated in formalin-fixed paraffin-embedded tissues obtained from an independent set of 135 patients with various etiologies. RESULTS: A 35-gene signature of vascular invasion was defined in the training set, predicting vascular invasion with an accuracy of 69%. The signature was independently associated with the presence of vascular invasion (OR 3.38, 95% CI 1.48-7.71, p=0.003) along with tumor size (diameter greater than 3 cm, OR 2.66, 95% CI 1.17-6.05, p=0.02). In the validation set, the signature discarded the presence of vascular invasion with a negative predictive value of 0.77, and significantly improved the diagnostic power of tumor size alone (p=0.045). CONCLUSIONS: The assessment of a gene expression signature obtained from resected biopsied tumor specimens improved the diagnosis of vascular invasion beyond clinical variable-based prediction. The signature may aid in candidate selection for liver transplantation, and guide the design of clinical trials with experimental adjuvant therapies. PMID- 21703204 TI - Role of cardiac myofilament proteins titin and collagen in the pathogenesis of diastolic dysfunction in cirrhotic rats. AB - BACKGROUND & AIMS: Significance of diastolic dysfunction in cirrhotic cardiomyopathy has been brought to the forefront with several reports of unexpected heart failure following liver transplantation and transjugular intrahepatic portosystemic stent-shunt, but the etiology remains unclear. The present study investigated the role of passive tension regulators - titin and collagen - in the pathogenesis of this condition. METHODS: Cirrhosis was induced by bile duct ligation (BDL) in rats, while controls underwent bile duct inspection with no ligation. Four weeks after operation, cardiac mRNA and protein levels of titin, collagen, and protein kinase A (PKA) were determined. Diastolic function was examined in isolated right ventricular cardiomyocytes, while passive tension was examined in right ventricular trabeculae muscles. RESULTS: In BDL animals, diastolic return velocity was significantly decreased, relaxation time increased and passive tension increased. However, no significant difference in mRNA and protein levels of titin was observed. PKA mRNA and protein levels were significantly decreased in BDL animals. Collagen levels were also significantly altered in the BDL group. CONCLUSIONS: Therefore, diastolic dysfunction exists in cirrhosis with alterations in titin modulation, PKA levels, and collagen configuration contributing to the pathogenesis of this condition. PMID- 21703205 TI - Treatment of newborn G6pc(-/-) mice with bone marrow-derived myelomonocytes induces liver repair. AB - BACKGROUND & AIMS: Several studies have shown that bone marrow-derived committed myelomonocytic cells can repopulate diseased livers by fusing with host hepatocytes and can restore normal liver function. These data suggest that myelomonocyte transplantation could be a promising approach for targeted and well tolerated cell therapy aimed at liver regeneration. We sought to determine whether bone marrow-derived myelomonocytic cells could be effective for liver reconstitution in newborn mice knock-out for glucose-6-phosphatase-alpha. METHODS: Bone marrow-derived myelomonocytic cells obtained from adult wild type mice were transplanted in newborn knock-out mice. Tissues of control and treated mice were frozen for histochemical analysis, or paraffin-embedded and stained with hematoxylin and eosin for histological examination or analyzed by immunohistochemistry or fluorescent in situ hybridization. RESULTS: Histological sections of livers of treated knock-out mice revealed areas of regenerating tissue consisting of hepatocytes of normal appearance and partial recovery of normal architecture as early as 1 week after myelomonocytic cells transplant. FISH analysis with X and Y chromosome paints indicated fusion between infused cells and host hepatocytes. Glucose-6-phosphatase activity was detected in treated mice with improved profiles of liver functional parameters. CONCLUSIONS: Our data indicate that bone marrow-derived myelomonocytic cell transplant may represent an effective way to achieve liver reconstitution of highly degenerated livers in newborn animals. PMID- 21703206 TI - A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection. AB - BACKGROUND & AIMS: In the Asia-Pacific region, perinatal transmission of the hepatitis B virus (HBV) is the primary cause of chronic hepatitis B infection. Despite the use of HBIG and HBV vaccination, HBV perinatal transmission (PT) occurs in 10-30% of infants born to highly viremic mothers. We evaluated the efficacy and safety of LTD use during late pregnancy in reducing HBV transmission in highly viremic HBeAg+mothers. METHODS: Two hundred and twenty-nine HBeAg+HBV DNA levels>1.0*10(7) copies/ml mothers received telbivudine 600 mg/day from week 20 to 32 of gestation (n=135) or served as untreated controls (n=94). All infants in both arms received 200 IU of HBIg within 12 h postpartum and recombinant HBV vaccine of 20 MUg at 0, 1, and 6 months. HBsAg and HBV DNA results of infants at week 28 were used to determine perinatal transmission rate. All telbivudine treated subjects were registered in the Antiretroviral Pregnancy Registry. RESULTS: Telbivudine treatment was associated with a marked reduction in serum HBV DNA and hepatitis B e antigen (HBeAg) levels and normalization of elevated ALT levels before delivery. A striking decline of HBV DNA levels started from treatment onset to week 4, and sustained in a low level since week 12. Forty-four (33%) of the 135 telbivudine-treated mothers and none (0%) of the untreated controls had polymerase chain reaction-undetectable viremia (DNA<500 copies/ml) at delivery. Seven months after delivery, the incidence of perinatal transmission was lower in the infants that completed follow-up born to the telbivudine-treated mothers than to the controls (0% vs. 8%; p=0.002). HBV DNA levels were only detectable in HBsAg+infants. No significant differences in anti-HBs levels were observed during postnatal follow-up. No serious adverse events were noted in the telbivudine-treated mothers or their infants. CONCLUSIONS: Telbivudine used during pregnancy in CHB HBeAg+highly viremic mothers can safely reduce perinatal HBV transmission. Telbivudine was well-tolerated with no safety concerns in the telbivudine-treated mothers or their infants on short term follow up. These data support the use of telbivudine in this special population. PMID- 21703207 TI - Ablation of c-FLIP in hepatocytes enhances death-receptor mediated apoptosis and toxic liver injury in vivo. AB - BACKGROUND & AIMS: Apoptosis is crucially involved in acute and chronic liver injury, including viral, cholestatic, toxic, and metabolic liver disease. Additionally, dysregulation of apoptosis signaling pathways has been implicated in hepatocarcinogenesis. The most prominent members of the apoptosis-mediating tumor necrosis factor receptor superfamily are the TNF-R1 (CD120a) and the CD95 (Apo-1/Fas) receptor. Although extensively studied, the intracellular signaling events in hepatocytes are only incompletely understood. METHODS: To examine the role of the caspase-8 homolog cellular FLICE-inhibitory protein (c-FLIP) in liver injury, we generated mice with hepatocyte specific deletion of c-FLIP. Three models of acute liver injury were employed: the agonistic anti-CD95 antibody Jo2, d-galactosamine and LPS (GalN/LPS), and concanavalin A. RESULTS: Conditional ablation of c-FLIP in hepatocytes augmented liver injury and cell death in all three models of liver injury. CD95- and GalN/LPS-induced liver injury was ameliorated by a pancaspase inhibitor, while ConA-induced injury was unaffected by caspase inhibition. Augmented activation of the MAPK JNK was observed in parallel to liver injury in c-FLIP knockout mice in all injury models; however, inhibition of JNK only affected TNF- and ConA-mediated injury. CONCLUSIONS: In summary, c-FLIP is a central regulator of cell death in hepatocytes, involving increased activation of caspases and the MAPK JNK. PMID- 21703208 TI - DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH. AB - BACKGROUND & AIMS: Intestinal bacterial overgrowth and increased permeability are features of non alcoholic steatohepatitis (NASH). Bacterial endotoxin has been shown to promote NASH progression. Application of dextran sulfate sodium (DSS) is a colitis model in mice characterized by damage of the intestinal barrier. This study was designed to investigate if application of DSS aggravates experimental NASH. METHODS: Male C57bl/6 mice were allocated into four experimental groups receiving either (I) standard chow (SC), (II) a high fat (HF) diet, (III) SC+DSS (1% in the drinking water), and (IV) HF+DSS for 12 weeks. RESULTS: DSS treatment caused inflammation and proinflammatory gene expression (IL-1beta, IL-17, TNF) in the colon. Expression of colonic antimicrobial peptide Cramp was significantly induced in SC+DSS mice, whereas expression was blocked in the HF+DSS group. Endotoxin levels were elevated in SC+DSS and HF mice but further augmented in the HF+DSS group. In line with this, increased hepatic TLR4 and TLR9 mRNA levels were detected in HF+DSS mice. The histological analysis revealed hepatic steatosis in both HF groups. Hepatic inflammation was more severe in HF+DSS mice, reflected by histology and analysis of proinflammatory gene expression (TNF and MCP-1). HF+DSS mice showed increased hepatic fibrosis by sirius red staining, hepatic collagen I expression, and alpha-SMA positive cells accompanied by higher p47(phox), TIMP-1, TGF-beta, Pai-1, and alpha-SMA mRNA expression. CONCLUSIONS: Induction of an intestinal inflammation in experimental NASH promotes LPS translocation, hepatic inflammation, and fibrogenesis probably due to inhibition of intestinal antimicrobial peptides. These findings underscore the pathophysiological role of the gut-liver axis in the progression of NASH. PMID- 21703209 TI - Rat liver sinusoidal endothelial cells (LSECs) express functional low density lipoprotein receptor-related protein-1 (LRP-1). AB - BACKGROUND & AIMS: The low density lipoprotein receptor-related protein-1 (LRP-1) is a large, multifunctional endocytic receptor from the LDL receptor family, highly expressed in liver parenchymal cells (PCs), neurons, activated astrocytes, and fibroblasts. The aim of the study was to investigate if liver sinusoidal endothelial cells (LSECs), highly specialized scavenger cells, express LRP-1. METHODS: To address this question, experiments were performed in vivo and in vitro to determine if receptor associated protein (RAP) and trypsin-activated alpha(2)-macroglobulin (alpha(2)M*) were endocytosed in LSECs. RESULTS: Both ligands were cleared from the circulation mainly by the liver. Hepatocellular distribution of intravenously administered ligands, assessed after magnetic bead cell separation using LSEC- and KC-specific antibodies, showed that PCs contained 93% and 82% of liver-associated (125)I-RAP and (125)I-alpha(2)M*, whereas 5% and 11% were associated with LSECs. Uptake of RAP and alpha(2)M* in the different liver cell population in vitro was specific and followed by degradation. The uptake of (125)I-RAP was not inhibited by ligands to known endocytosis receptors in LSECs, while uptake of (125)I-alpha(2)M* was significantly inhibited by RAP, suggesting the involvement of LRP-1. Immunofluorescence using LRP-1 antibody showed positive staining in LSECs. Ligand blot analyses using total cell proteins and (125)I-RAP followed by mass spectrometry further confirmed and identified LRP 1 in LSECs. CONCLUSIONS: LSECs express functional LRP-1. An important implication of our findings is that LSECs contribute to the rapid removal of blood borne ligands for LRP-1 and may thus play a role in lipid homeostasis. PMID- 21703210 TI - Demographics and outcomes of severe herpes simplex virus hepatitis: a registry based study. AB - BACKGROUND & AIMS: Herpes simplex virus hepatitis is a rare, but severe disease, thus far only documented by case reports and short series. The present study was based on the SRTR registry, and included all listed patients for liver transplantation from 1985 to 2009 with a diagnosis of HSV hepatitis. METHODS: We assessed demographics and outcome of all listed patients, and further conducted a case-control study, matching each transplanted patient with 10 controls. Matching criteria included: transplant status, MELD score +/-5, transplant date +/-6 months, and age at transplant +/-5 years. During the study period, 30 patients were listed for HSV hepatitis. Of the 30 listed patients, seven recovered spontaneously and five died, prior to transplantation. The remaining 10 children and eight adults were transplanted. RESULTS: The chance of recovery was significantly higher in children than in adults (7/19 vs. 0/11, p=0.02). In children, survival was similar between HSV patients and the matched controls (5 year survival: 69% vs. 64%, p=0.89). Conversely, survival was poor in adult HSV (5-year survival: 38% vs. 65%, p=0.006), with 62% of them dying within the first 12 months. All three reported post-transplant deaths in children were independent from HSV. Among the seven adult post-transplant deaths, four were related to infection (bacterial, fungal, or viral). CONCLUSIONS: Children listed for HSV hepatitis have a significantly better survival than adults both prior and after liver transplantation. While HSV fulminant hepatitis is an appropriate indication for liver transplantation in children, it should only be performed in selected adult patients in otherwise good condition. PMID- 21703211 TI - Cytosolic phospholipase A(2)alpha protects against Fas- but not LPS-induced liver injury. AB - BACKGROUND & AIMS: Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) is a rate limiting key enzyme controlling the release of arachidonic acid (AA) substrate for the synthesis of prostaglandins and leukotrienes. This study was designed to explore the role of hepatocyte cPLA(2)alpha in Fas-mediated liver injury, in vivo. METHODS: Transgenic mice with targeted expression of cPLA(2)alpha under control of the albumin-promoter enhancer and wild-type mice were injected intraperitoneally with anti-Fas antibody Jo2 or lipopolysaccharide plus d galactosamine and monitored for liver injury and survival at various time points. RESULTS: The cPLA(2)alpha Tg mice resist Fas-induced liver failure, as reflected by the lower serum transaminase levels, fewer apoptotic hepatocytes, reduced caspase activation, and reduced PARP cleavage when compared to the matched wild type mice. Inhibition of cPLA(2)alpha by its pharmacological inhibitor, pyrrolidine, enhanced Jo2-induced liver injury in both cPLA(2)alpha Tg and wild type mice. Hepatic overexpression of cPLA(2)alpha increases the expression of EGFR in the liver and the EGFR inhibitor, AG1478, exacerbated Jo2-mediated liver injury. The cPLA(2)alpha transgenic mice develop more prominent liver tissue damage than wild-type mice after LPS/d-galactosamine injection. CONCLUSIONS: Hepatocyte cPLA(2)alpha protects against Fas-induced liver injury and this effect is mediated at least in part through the upregulation of EGFR. PMID- 21703212 TI - Integrative assessment of potential effects of dioxins and related compounds in wild Baikal seals (Pusa sibirica): application of microarray and biochemical analyses. AB - We have previously indicated that accumulation of chlorinated dioxins and related compounds (DRCs) induced cytochrome P450 (CYP) 1A1, 1A2 and 1B1 isozymes in the liver of wild Baikal seals (Pusa sibirica). Here we attempt to assess the potential effects of DRCs triggered by the induction of these CYP1 isozymes in this species, using an integrative approach, combining gene expression monitoring and biochemical assays. To screen genes that may potentially respond to the exposure of DRCs, we constructed a custom cDNA oligo array that can target mRNAs in Baikal seals, and monitored hepatic mRNA expression levels in the wild population. Correlation analyses between the hepatic total 2,3,7,8 tetrachlorodibenzo-p-dioxin toxic equivalents (TEQs) and mRNA levels supported our previous findings that high accumulation of DRCs induces the transcription of CYP1A1, CYP1A2 and CYP1B1 genes. In addition, our integrative assessment indicated that the chronic exposure to DRCs may alter the hepatic transcript levels of genes related to oxidative stress, Fe ion homeostasis, and inflammatory responses. The expression levels of CYP1A2 showed significant positive correlations with levels of malondialdehyde, a biomarker of lipid peroxidation, and of etheno-dA, a DNA adduct, suggesting that the lipid peroxidation may be enhanced through the production of reactive oxygen species (ROS) triggered by CYP1A2 induction. Moreover, there was a positive correlation between heme oxygenase activities and malondialdehyde levels, suggesting the prompted heme degradation by ROS. Fetuin-A levels, which are suppressed by inflammation, showed a significant negative correlation with TEQ levels, and hepcidin levels, which are conversely increased by inflammation, had significant positive correlations with malondialdehyde and etheno-dA levels, implying the progression of inflammation by DRC-induced oxidative stress. Taken together, we propose here that wild Baikal seals may suffer from effects of chronic exposure to DRCs on the induction of CYP1 isozymes, followed by increased oxidative stress, heme degradation and inflammation. PMID- 21703214 TI - Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma. AB - BACKGROUND & AIMS: It is not clear whether risk for hepatocellular carcinoma can be accurately determined from long-term changes in serum levels of hepatitis B virus (HBV) DNA or alanine aminotransferase (ALT). METHODS: We measured serum levels of HBV DNA and ALT at enrollment and during follow-up analysis of 3160 participants in the REVEAL-HBV study. Development of hepatocellular carcinoma was determined from follow-up examinations and computerized linkage with National Cancer Registry and National Death Certification profiles. Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. RESULTS: During 38,330 person-years of follow-up, 81 participants developed hepatocellular carcinoma (incidence rate, 211.3/100,000 person-years). The risk for hepatocellular carcinoma was only slightly higher for participants whose follow-up levels of HBV DNA spontaneously decreased to <10,000 copies/mL compared with those with baseline levels of HBV DNA<10,000 copies/mL (control group; HR, 2.25; 95% CI, 0.68-7.37). Compared with the control group, the HRs (95% CI) for long-term levels of HBV DNA that persisted at 10,000 to 100,000 copies/mL, decreased to/persisted at 100,000 to 1,000,000 copies/mL, or decreased to/persisted at 1,000,000 to 10,000,000 copies/mL were 3.12 (1.09 8.89), 8.85 (3.85-20.35), and 16.78 (7.33-38.39), respectively. A gradient in ALT level was significantly associated with hepatocellular carcinoma risk: from all low-normal, to ever high-normal, to transient abnormal, to persistent abnormal (Ptrend<.001). CONCLUSIONS: Long-term changes in serum levels of HBV DNA and ALT are independent predictors of risk for hepatocellular carcinoma. Regular monitoring of levels of HBV DNA and ALT is important in clinical management of chronic carriers of HBV. PMID- 21703213 TI - Matrix metalloproteinase-9 inhibition reduces inflammation and improves motility in murine models of postoperative ileus. AB - BACKGROUND & AIMS: Matrix metalloproteinase (MMP)-9, a member of the gelatinase family of MMPs, mediates leukocyte migration during inflammation. Inflammation contributes to development of postoperative ileus (POI), which is caused by physical disturbances to the bowel during abdominal surgery. We evaluated the role of MMP-9 in POI and investigated whether disruption of MMP-9 or administration of an inhibitor of MMP-9 activity reduced cellular inflammation and bowel dysmotility in rat and mouse models of POI. METHODS: Mice and rats underwent laparotomy and bowel manipulation; bowel tissues were collected 3 to 24 hours later and analyzed by real-time reverse-transcriptase polymerase chain reaction, immunoblot, in situ zymography, and functional analyses. RESULTS: Bowel manipulation resulted in a time-dependent increase in MMP-9 expression within the intestinal muscularis; increases in MMP-9 messenger RNA were inducible nitric oxide synthase dependent. Immunoblot analyses confirmed the presence of the proenzyme and the catalytically active form of MMP-9. Administration of MMP-2/MMP 9 II, a dual active-site inhibitor, reduced the number of myeloperoxidase positive immune cells that infiltrated the muscularis and prevented the surgically induced reduction in bowel smooth muscle contractility. Zymography analysis, performed in muscularis whole mounts in situ, indicated that MMP-9 and not MMP-2 mediated the gelatinase activity observed in infiltrating cells. MMP-9 knockout mice were protected from the inflammation and dysmotility associated with POI. CONCLUSIONS: MMP-9 mediates cellular inflammatory responses within the intestinal muscularis in mouse and rat models of POI. Inhibition of MMP-9 activity reduced recruitment of immune cells to the intestinal muscularis, preventing loss of smooth muscle contractility. Induction of MMP-9 expression requires inducible nitric oxide synthase. PMID- 21703215 TI - Transseptal access and atrial fibrillation ablation guided by intracardiac echocardiography in patients with atrial septal closure devices. AB - BACKGROUND: Percutaneous positioning of closure devices is a well-established treatment of atrial septal defects (ASDs). However, patients who have undergone the procedure are at increased risk for developing atrial fibrillation (AF), and treatment by catheter ablation is underutilized due to the perceived difficulty of obtaining transseptal access in the presence of the closure device. OBJECTIVE: The purpose of this study was to report the acute and long-term results of radiofrequency catheter ablation of AF in patients with ASD closure devices. METHODS: Thirty-nine patients (age 54 +/- 6 years, 72% males) with drug refractory AF (33% paroxysmal, 51% persistent, 16% long-standing persistent) and ASD closure devices (82% Amplatzer, 18% CardioSEAL) underwent radiofrequency catheter ablation. A double transseptal access guided by intracardiac echocardiography was obtained in all patients. RESULTS: In 35 of 39 patients (90%), the transseptal access was obtained in a portion of the native septum, whereas in 4 of 39 patients (10%), a direct access through the device was required. The latter group had a significantly longer time for achieving the double transseptal access (73.6 +/- 1.1 minutes vs. 4.3 +/- 0.4 minutes, P < .001), longer fluoroscopy time (122 +/- 5 minutes vs. 80 +/- 8 minutes, P < .001), and total procedural time (4.1 +/- 0.2 hours vs. 3.1 +/- 0.3 hours, P < .001). At follow-up of 14 +/- 4, months the overall success rate was 77% (85% in paroxysmal AF, 73% in nonparoxysmal AF). Transthoracic contrast-enhanced echocardiography with the Valsalva maneuver, performed between 3 and 6 months after the procedure, failed to detect shunt in all patients. CONCLUSION: Radiofrequency catheter ablation of AF is feasible, safe, and effective in patients with ASD closure devices. Transseptal access can be obtained in portions of the native septum in the majority of cases. Direct transseptal puncture of the device is feasible and safe but requires longer time for each transseptal access. PMID- 21703216 TI - Intra-atrial thrombolysis of left atrial thrombus guided by intracardiac echocardiography during catheter ablation of atrial fibrillation. PMID- 21703217 TI - Role of repeat procedures for catheter ablation of postinfarction ventricular tachycardia. AB - BACKGROUND: In patients with ischemic heart disease, ventricular tachycardia (VT) is associated with increased mortality and morbidity. Catheter ablation is useful for reducing VT therapies but remains challenging, and recurrences are common. OBJECTIVE: The purpose of this study was to assess the prognosis and safety of repeat catheter ablation procedures for postinfarct VT and to determine clinical and procedural predictors of outcomes. METHODS: From a total of 280 patients undergoing catheter ablation of postinfarct VT at one center, 107 consecutive patients having a repeat procedure after one or more prior failed catheter ablation procedures (PFCA group) were compared to 173 patients who underwent a single catheter ablation (SCA group) in the same study period. RESULTS: Of the PFCA group, 75 (70.1%) had one procedure and 32 (29.9%) had two or more prior ablations. Ventricular function and age were similar between groups. Periprocedural complications occurred in 11.2% of patients in the PFCA group and 8.7% of patients in the SCA group (P = .484). The 1-year VT recurrence rate was higher in the PFCA group compared to the SCA group (32.6% vs 16.6%, P = .001). On multivariable analysis, prior ablation (hazard ratio [HR] 1.84, P = .018), left ventricular ejection fraction (HR 1.04, P = .019), and mean number of induced VTs (HR 1.17, P = .043) were independent predictors of VT recurrence. CONCLUSION: Failure of initial ablation does not preclude subsequent successful ablation for postinfarct VT. Whether healing of prior lesions, change in arrhythmic substrate, or changes in antiarrhythmic therapy are factors that influence recurrence warrants further study. PMID- 21703218 TI - Ablation of epicardial ventricular arrhythmias from nonepicardial sites. AB - BACKGROUND: Idiopathic epicardial ventricular arrhythmias can be targeted from the coronary venous system or the pericardial space, the endocardium, or the aortic sinus cusps. OBJECTIVE: The purpose of this study was to analyze systematically the contribution of ablation at sites other than the epicardium to eliminate an arrhythmia originating in the epicardium. METHODS: In a consecutive patient series of 33 patients (14 women, age 51 +/- 14 years, ejection fraction 51% +/- 9%) with epicardial ventricular arrhythmias, mapping and ablation was performed via the cardiac venous system/pericardial space, the aortic sinus cusp, and the left ventricular endocardium. An arrhythmia was defined as epicardial if the earliest onset of activation and a matching pace-map (>=10/12 leads) were identified in the epicardium. RESULTS: In 12/33 patients (36%), either an endocardial approach alone (n = 3) or a combined endocardial/epicardial (n = 6), cusp/endocardial (n = 1), or cusp/epicardial (n = 2) approach was required to eliminate the ventricular arrhythmias. In 10 of 33 patients (30%), epicardial ablation alone was effective in eliminating epicardial ventricular arrhythmias. Ablation was ineffective due to failure to reach the site of origin with the ablation catheter in 5 of 33 patients (15%), the site of origin was too close to an epicardial artery or the phrenic nerve in 3 patients (6%), and power delivery was insufficient in 3 patients (9%). CONCLUSION: About one-third of epicardial arrhythmias require ablation from sites other than the epicardium to eliminate the arrhythmia focus. PMID- 21703219 TI - Unroofed coronary sinus or coronary sinus on the roof? Successful implantation of biventricular implantable defibrillator in anomalous coronary venous drainage. PMID- 21703220 TI - Spatial analysis of scrub typhus infection and its association with environmental and socioeconomic factors in Taiwan. AB - We analyzed the spatial distribution of human cases of scrub typhus on the main island of Taiwan from 2003 to 2008 and implemented an island-wide survey of scrub typhus vectors (trombiculid chiggers) in 2007 and 2008. The standardized incidence rate 'SIR' incorporating inter-district variations in population, gender and age was correlated with environmental and socioeconomic variables. Higher incidence and SIR rates were clustered in the less developed, mountainous regions of central and eastern Taiwan. Higher SIRs were also associated with a higher proportion of dry-field farmers in the population, a higher normalized difference vegetation index (NDVI) and lower mean annual temperature, but was not associated with rainfall. Small mammal hosts in high-SIR districts harbored more chiggers and had higher rates of seropositivity against Orientia tsutsugamushi Hyashi, the etiologic agent of scrub typhus, compared to low-SIR districts. The concurrence of a higher proportion of dry-field farmers and higher NDVI has likely led to the clustering of scrub typhus in the mountainous regions of Taiwan. Further individual-level study of the risk factors associated with scrub typhus, and a better understanding of the effect of environmental factors on chigger abundance, should help to prevent scrub typhus in Taiwan. PMID- 21703221 TI - Seroprevalence and risk factors for canine toxocariasis by detection of specific IgG as a marker of infection in dogs from Salvador, Brazil. AB - Toxocara canis is a highly prevalent worldwide canine nematode responsible for enzootic and zoonotic infections. It is considered to be one of the main agents of human visceral and ocular larva migrans. False negative diagnosis may occur because adult infected dogs with "dormant" larvae may have negative fecal test results since they usually do not shed parasite eggs in their stools. During pregnancy, the larvae become active and infect the offspring through the placenta. A serological test can distinguish infected animals, thus increasing the accuracy of the diagnosis for epidemiological studies and prophylactic purposes. In the present work a serological investigation was carried out to study the risk factors for the acquisition of this infection in 301 dogs inhabiting the city of Salvador, northeast Brazil. A validated questionnaire was applied to the donors and caretakers to assess animal management practices. All dogs were submitted to clinical evaluation and blood collection. Serum samples were analyzed for IgG antibodies against excretory-secretory products of T. canis larvae, used as antigens, by indirect ELISA. The overall seroprevalence of anti T. canis IgG antibodies was 82.7%. Risk factors for T. canis infection included sex, area of origin within the city, homemade leftover food intake, failure to receive regular vaccination against infectious diseases and lack of preventive anti-helminthic treatment. Most of these risk factors suggest a lack of veterinary care and poverty. The high frequency of seropositivity found for toxocariasis in dogs suggests that results based on parasitological fecal examination could underestimate the actual prevalence of the infection. PMID- 21703222 TI - Gold nanoparticle-based signal amplification for biosensing. AB - Colloidal gold nanoparticles (AuNPs), with unique properties such as highly resonant particle plasmons, direct visualization of single nanoclusters by scattering of light, catalytic size enhancement by silver deposition, conductivity, and electrochemical properties, are very attractive materials for several applications in biotechnology. Furthermore, as excellent biological tags, AuNPs can be easily conjugated with biomolecules and retain the biochemical activity of the tagged biomolecules, making AuNPs ideal transducers for several biorecognition applications. The goal of this article is to review recent advances of using AuNPs as labels for signal amplification in biosensing applications. We focus on the signal amplification strategies of AuNPs in biosensing/biorecognition, more specifically, on the main optical and electrochemical detection methods that involve AuNP-based biosensing. Particular attention is given to recent advances and trends in sensing applications. PMID- 21703223 TI - Nitrogen dioxide solubility and permeation in lipid membranes. AB - Nitrogen dioxide (()NO(2)) is an important oxidant molecule in biology that is produced by several biological processes, and it is also an important air pollutant. It can oxidize proteins and lipids with important consequences on their biological functions. Despite its relevance, the interaction of ()NO(2) with the cell barrier, the lipid membrane, is poorly understood. For instance, can lipid membranes limit ()NO(2) diffusion? To estimate the permeability of lipid membranes to ()NO(2) it is necessary to learn more about its solubility in the lipid phase. However, experimental data on ()NO(2) solubility is very limited. To improve our knowledge on this matter, we used a mixed approach consisting in calculating the solubility of ()NO(2) and related diatomic and triatomic gases (()NO, O(2), CO(2), etc.) in different solvents using quantum calculations and Tomasi's Polarizable Continuum Model and validating and correcting these results using experimental data available for the related gases. This approach led to an estimated partition coefficient for ()NO(2) of 2.7 between n-octanol and water, and 1.5 between lipid membranes and water, meaning that ()NO(2) is a moderately hydrophobic molecule (less than ()NO, more than CO(2)). Based on the solubility-diffusion permeability theory, the permeability coefficient was estimated to be 5 cms(-1), up to 4000 times higher than that of peroxynitrous acid. It is concluded that lipid membranes are not significant barriers to ()NO(2) transport. PMID- 21703224 TI - T-quaternary structure of oxy human adult hemoglobin in the presence of two allosteric effectors, L35 and IHP. AB - The cooperative O(2)-binding of hemoglobin (Hb) have been assumed to correlate to change in the quaternary structures of Hb: T(deoxy)- and R(oxy)-quaternary structures, having low and high O(2)-affinities, respectively. Heterotropic allosteric effectors have been shown to interact not only with deoxy- but also oxy-Hbs causing significant reduction in their O(2)-affinities and the modulation of cooperativity. In the presence of two potent effectors, L35 and inositol hexaphosphate (IHP) at pH 6.6, Hb exhibits extremely low O(2)-affinities (K(T)=0.0085mmHg(-1) and K(R)=0.011mmHg(-1)) and thus a very low cooperativity (K(R)/K(T)=1.3 and L(0)=2.4). (1)H-NMR spectra of human adult Hb with these two effectors were examined in order to determine the quaternary state of Hb in solution and to clarify the correlation between the O(2)-affinities and the structural change of Hb caused by the heterotropic effectors. At pH 6.9, (1)H-NMR spectrum of deoxy-Hb in the presence of L35 and IHP showed a marker of the T quaternary structure (the T-marker) at 14ppm, originated from inter- dimeric alpha(1)beta(2)- (or alpha(2)beta(1)-) hydrogen-bonds, and hyperfine-shifted (hfs) signals around 15-25ppm, caused by high-spin heme-Fe(II)s. Upon addition of O(2), the hfs signals disappeared, reflecting that the heme-Fe(II)s are ligated with O(2), but the T-marker signals still remained, although slightly shifted and broadened, under the partial pressure of O(2) (P(O2)) of 760mmHg. These NMR results accompanying with visible absorption spectroscopy and visible resonance Raman spectroscopy reveal that oxy-Hb in the presence of L35 and IHP below pH 7 takes the ligated T-quaternary structure under the P(O2) of 760mmHg. The L35 concentration dependence of the T-marker in the presence of IHP indicates that there are more than one kind of L35-binding sites in the ligated T-quaternary structure. The stronger binding sites are probably intra-dimeric binding sites between alpha(1)G- and beta(1)G-helices, and the other weaker binding site causes the R->T transition without release of O(2). The fluctuation of the tertiary structure of Hb seems to be caused by both the structural perturbation of alpha(1)beta(1) (or alpha(2)beta(2)) intra-dimeric interface, where the stronger L35-binding sites exist, and by the IHP-binding to the alpha(1)alpha(2)- (or beta(1)beta(2)-) cavity. The tertiary structural fluctuation induced by the allosteric effectors may contribute to the significant reduction of the O(2) affinity of oxy-Hb, which little depends on the quaternary structures. Therefore, the widely held assumptions of the structure-function correlation of Hb - [the deoxy-state]=[the T-quaternary structure]=[the low O(2)-affinity state] and [the oxy-state]=[the R-quaternary structure]=[the high O(2)-affinity state] and the O(2)-affiny of Hb being regulated by the T/R-quaternary structural transition - are no longer sustainable. This article is part of a Special Issue entitled: Allosteric cooperativity in respiratory proteins. PMID- 21703225 TI - Dipole potential as a driving force for the membrane insertion of polyacrylic acid in slightly acidic milieu. AB - In this work, we report on the interaction of polyacrylic acid with phosphatidylcholine bilayers and monolayers in slightly acidic medium. We found that adsorption of polyacrylic acid on liposomes composed of egg lecithin at pH 4.2 results in the formation of small pores permeable for low molecular weight solutes. However, the pores were impermeable for trypsin indicating that no solubilization of liposomes occurred. The pores were permeable for both positively charged trypsin substrate N-benzoyl-l-arginine ethyl ester and negatively charged pH-indicator pyranine. Two lines of evidence were obtained confirming the involvement of the membrane dipole potential in the insertion of polyacrylic acid into lipid bilayer. (i) Addition of phloretin, a molecule which is known to decrease dipole potential of lipid bilayer, reduced the rate of a polyacrylic acid induced leakage of pyranine from liposomes. (ii) Direct measurements of air/lipid monolayer/water interface surface potential using Kelvin probe showed that adsorption of polyacrylic acid at pH 4.2 induced a decrease in both boundary and dipole potential by 37 and 62mV for ester lipid dioleoylphosphatidylcholine (DOPC). Replacement of DOPC by ether lipid 1,2-di-O oleyl-sn-glycero-3-phosphocholine (DiOOPC) which is known to form monolayers and bilayers with only minor dipole component of membrane potential showed that addition of PAA produced similar response in the boundary potential (by 50mV) but negligible response in dipole potential of monolayer. These observations agree with our assumption that dipole potential is an important driving force for the insertion of polyacids into biological membranes. PMID- 21703226 TI - Nature of plasmalemmal functional "hemichannels". AB - The molecular identity of the protein forming "hemichannels" at non-junctional membranes is disputed. The family of gap junction proteins, innexins, connexins, and pannexins share several common features, including permeability characteristics and sensitivity to blocking agents. Such overlap in properties renders the identification of which of these protein species actually establishes the non-junctional membrane conductance and permeability quite complicated, especially because in vertebrates pannexins and connexins have largely overlapping distributions in tissues. Recently, attempts to establish criteria to identify events that are "hemichannel" mediated and those to allow the distinction between connexin- from pannexin-mediated events have been proposed. Here, I present an update on that topic and discuss the most recent findings related to the nature of functional "hemichannels" focusing on connexin43 and pannexin1. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics. PMID- 21703227 TI - Modulation of chromatin modifying factors' gene expression in embryonic and induced pluripotent stem cells. AB - Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are a promising source of cells for regenerative medicine because of their potential of self renew and differentiation. Multiple evidences highlight the relationship of chromatin remodeling with stem cell properties, differentiation programs and reprogramming for iPSC obtention. With the purpose of finding chromatin modifying factors relevant to these processes, and based on ChIP on chip studies, we selected several genes that could be modulated by Oct4, Sox2 and Nanog, critical transcription factors in stem cells, and studied their expression profile along the differentiation in mouse and human ESCs, and in mouse iPSCs. In this work, we analyzed the expression of Gcn5l2, GTF3C3, TAF15, ATF7IP, Myst2, HDAC2, HDAC3, HDAC5, HDAC10, SUV39H2, Jarid2, and Bmi-1. We found some genes from different functional groups that were highly modulated, suggesting that they could be relevant both in the undifferentiated state and during differentiation. These findings could contribute to the comprehension of molecular mechanisms involved in pluripotency, early differentiation and reprogramming. We believe that a deeper knowledge of the epigenetic regulation of ESC will allow improving somatic cell reprogramming for iPSC obtention and differentiation protocols optimization. PMID- 21703228 TI - The role of runt-related transcription factor 2 (Runx2) in the late stage of odontoblast differentiation and dentin formation. AB - Runx2, of the Runx family, is an essential transcription factor that controls bone and tooth development by regulating osteoblast and odontoblast differentiation. However, the function of Runx2 in late stage odontoblast differentiation is not clear. We studied the function of Runx2 in dentinogenesis by generating transgenic mice expressing Runx2 specifically in odontoblasts. We observed dentin formation in postnatal day 3 (P3), P7 and P28 mice and measured the expression levels of Runx2 and matrix proteins in dentin. The odontoblasts in transgenic mice (Tg) lost their tall columnar shape and polarization and dentinal tubules were absent. The dental pulp chamber was dramatically enlarged and the dentin in Tg mice was thinner. Osteoblast-like cells were seen instead of normal odontoblasts and were embedded in a bone-like matrix, indicating that dentin formation was replaced with bone. Predentin was disorganized possessing lacunae that contained odontoblasts. The mandibular molars of Tg mice showed noticeable defects by Micro-CT. Using quantitative real-time PCR, the expression of dentin matrix proteins, particularly dentin sialophosphoprotein (DSPP), was found to be upregulated in 3-day-old Tg mice and downregulated at 1 month of age. These findings indicate that Runx2 inhibited odontoblast terminal differentiation and induced transdifferentiation of odontoblasts to osteoblasts at the late cell differentiation stage. Therefore, Runx2 should be inhibited in odontoblasts to encourage normal cell maturation, differentiation and dentinogenesis. PMID- 21703229 TI - Sphingolipid synthesis is involved in autophagy in Saccharomyces cerevisiae. AB - In eukaryotes, autophagy is a conserved protein degradation system that degrades cytoplasmic components by encompassing them with double-membrane structures, called autophagosomes, and delivering them to the lytic compartments of vacuoles/lysosomes. Certain Atg proteins are known to be involved in autophagy, yet the identity and function of lipid molecules involved remain largely unknown. We investigated the involvement of sphingolipids in autophagy using Saccharomyces cerevisiae. Inhibiting synthesis of the simplest complex sphingolipid, inositol phosphorylceramide (IPC), resulted in reduced autophagic activities. Similar results were obtained using myriocin, an inhibitor of the first step in sphingolipid synthesis. Our results indicate that sphingolipids, especially IPC, are required for autophagy. Inhibition of sphingolipid synthesis had no effect on formation of Atg12-Atg5 or Atg8-phosphatidylethanolamine conjugates, on maturation of vacuolar proteases, or on formation of the pre-autophagosomal structure (PAS). These results suggest that sphingolipids are not involved in the cellular signaling that leads to formation of the PAS, but may be involved in the process of autophagosome formation. PMID- 21703230 TI - Defective GATA-3 expression in Th2 LCR-deficient mice. AB - Th2 cell differentiation is critically influenced by transcription factor GATA-3 and by various cis-acting elements including enhancers, silencers and a locus control region (LCR) in the Th2 cytokine locus. Th2 LCR-deficient Th2 cells completely lost the expression of GATA-3 and the phosphorylation of STAT6. Histone 3 lysine 4 (H3-K4) was hypomethylated in the gata3 locus in these cells. GATA-3 and STAT6 bound several regulatory regions in the gata3 locus and transactivated the expression of the gata3 gene. These results suggest that Th2 differentiation program stimulates feed-forward regulation of gata3 gene expression. PMID- 21703231 TI - GntR family regulators of the pathogen of fish tuberculosis Mycobacterium marinum. AB - Mycobacterium marinum is a slow-growing pathogenic mycobacterium. It was first isolated by Aronson in 1926 from fish, fish mycobacteriosis or called fish tuberculosis is the common causative agent of bacterial disease in many species of freshwater and marine fish. M. marinum can infect wild fish, aquaculture and ornamental fish, and it has a close relative of the causative agent of human tuberculosis, Mycobacterium tuberculosis. The recently sequenced genome of M. marinum has been shown to contain several putative GntR regulators. This family named after gluconate regulator has a helix-turn-helix structure. Characterization of transcription regulators and their network is an important step towards the complete understanding of cellular physiology. The regulator of this family shares a similar and conserved N-terminal DNA-binding domain, but has a highly diverse C-terminal effector-binding and oligomerization domain. According to the heterogeneity, we classify the M. marinum GntR family to four subfamilies: FadR, HutC, MocR, and YtrA, and these regulators are encoded by 8, 3, 1 and 1 genes, respectively. Thus this study extends the annotation of M. marinum GntR family proteins, and can help to understand the pathogenic role of this family in M. marinum and facilitate future drug design against this pathogen. PMID- 21703232 TI - Regulation of human hepatocellular carcinoma cells by Spred2 and correlative studies on its mechanism. AB - Members of the Spred gene family are negative regulators of the Ras/Raf-1/ERK pathway, which has been associated with several features of the tumor malignancy. However, the effect of Spred genes on hepatocellular carcinoma (HCC) remains uninvestigated. In the present work, we analyzed the in vitro and in vivo effects of Spred2 expression on the hepatic carcinoma cell line, SMMC-7721. In addition to attenuated ERK activation, which inhibited the proliferation and migration of unstimulated and HGF-stimulated SMMC-7721 cells. Adenovirus-mediated Spred2 overexpression induced the activation of caspase-3 and apoptosis, as well as reduced the expression level of Mcl-1. Most importantly, the knockdown of Spred2 markedly enhanced tumor growth in vivo. In conclusion, these results suggest that Spred2 could qualify as a potential therapeutic target in HCC. PMID- 21703233 TI - Sperm-specific C-terminal processing of the proteasome PSMA1/alpha6 subunit. AB - We previously reported that the ascidian sperm proteasome degrades the egg-coat protein extracellularly during fertilization. In order to explore an extracellular transport signal, we purified the proteasome from ascidian sperm and compared its subunit structure with egg and muscle proteasomes. The results showed that PSMA1/alpha6 subunit of the sperm proteasome is distinct from egg and muscle proteasomes. LC/MS/MS analysis revealed that the C-terminal 16 residues of sperm alpha6 subunit are processed. Whereas sperm-specific paralogous genes of alpha subunits are reported, its sperm-specific C-terminal processing is a newly discovered novel post-translational modification of the proteasome. PMID- 21703234 TI - Recombinant Gaussia luciferase with a reactive cysteine residue for chemical conjugation: expression, purification and its application for bioluminescent immunoassays. AB - The mutated recombinant Gaussia luciferase (hgGLase) having the hinge sequence with a reactive cysteine residue at the carboxyl terminal region was purified from Escherichia coli cells by nickel-chelate affinity chromatography and hydrophobic chromatography. The biotinylated hgGLase (Biotin-hgGLase) was prepared by chemical conjugation with a maleimide activated biotin and apply to bioluminescent immunoassay. In the streptavidin and biotin complex system using Biotin-hgGLase, the measurable range of alpha-fetoprotein as a model analyte was 0.02-100ng/ml with the coefficient of variation between 2.5% and 5.2%. The sensitivity of Biotin-hgGLase was similar to that by using the detection system of aequorin, alkaline phosophatase and horseradish peroxidase as a label enzyme. PMID- 21703235 TI - Differential ligand-dependent activation and a role for Y322 in aryl hydrocarbon receptor-mediated regulation of gene expression. AB - The aryl hydrocarbon receptor (AHR) mediates the toxic effects of halogenated aromatic hydrocarbons (HAHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF) and 2,3,7,8 tetrachlorodibenzofuran (2,3,7,8-TCDF). Non-traditional activators, including omeprazole (Omp), are thought to regulate AHR action through phosphorylation rather than binding to the receptor. In this study, we examined the ability of these compounds to induce AHR-dependent regulation of cytochrome P450 1A1 (CYP1A1) and CYP1B1 in T-47D human breast cancer cells. The role of Y322, a residue implicated in Omp-dependent activation of AHR was also investigated. All four compounds induced CYP1A1 and CYP1B1 mRNA expression, with Omp differing from the HAHs. Chromatin immunoprecipitation assays revealed ligand- and gene selectivity in the recruitment patterns of AHR coactivators. We also found that residue Y322 of human AHR was important for maximum activation of AHR by 2,3,7,8 TCDD and 2,3,4,7,8-PeCDF, but required for 2,3,7,8-TCDF and Omp in an AHR deficient MCF-7 human breast cancer cell line. In summary, this study provides evidence for context- and ligand-selective differences in coactivator recruitment in AHR-regulated gene expression and reveal an important role of Y322 in AHR activation. PMID- 21703236 TI - Transglutaminase-mediated internal protein labeling with a designed peptide loop. AB - Post-translational internal protein labeling was explored through the insertion of a 13-mer peptidyl loop specifically recognized by microbial transglutaminase (MTG). The peptidyl loop included one lysine residue (abbreviated as the K-loop), and was designed and inserted into two different regions of the protein bacterial alkaline phosphatase (BAP). MTG-mediated selective labeling of a lysine residue in the K-loop was achieved with a functional Gln-donor substrate. Internal protein labeling in the vicinity of the active site of BAP (residues 91-93) markedly decreased the activity of the enzyme. Conversely, insertion of the K loop at a site distal from the active site (residues 219-221) afforded site specific and covalent internal protein labeling without impairing the activity of the enzyme. PMID- 21703237 TI - Role of Meis1 in mitochondrial gene transcription of pancreatic cancer cells. AB - Pre-B-cell leukemia transcription factor (PBX)/three-amino-acid loop extension (TALE) class transcription factors [PBX1-4, Meis homeobox (Meis) 1-3, pbx/knotted 1 homeobox (Prep) 1, 2] are involved in tumorigenesis and metastasis. To investigate further the function of PBX/TALE class transcription factors, mRNA expression profile after downregulation of each mRNA expression by siRNA transfection in pancreatic cancer cell line, Panc-1, was examined. Downregulation of Meis1 resulted in downregulation of mitochondrial genes, but those of PBX1 and PBX2 did not. Quantitative reverse transcription polymerase chain reaction confirmed downregulation of mitochondrial genes by Meis1 siRNA transfection. Chromatin immunoprecipitation assay revealed the binding of Meis1 to the mitochondrial promoter region that contained the putative Meis1 binding site. Luciferase reporter assay showed the increase of luciferase activity of a construct containing the Meis1 binding site compared with that with shorter fragment without Meis1 binding region. These findings indicate that Meis1 works as a transcription factor for mitochondrial genes in pancreatic cancer cells. PMID- 21703238 TI - Arsenic trioxide regulates the apoptosis of glioma cell and glioma stem cell via down-regulation of stem cell marker Sox2. AB - Knowledge of the mechanism by which arsenic trioxide exerts the anti-tumor effects may help in designing a more effective regimen for therapy. Transcription factor Sox2, a key gene implicated in maintaining the "stemness" of embryonic and adult stem cells, plays an important role in the carcinogenesis and maintenance of glioblastoma. Here, we found that the expression of Sox2 at transcriptional level was decreased during As(2)O(3)-induced glioma cell apoptosis. And, the ectopic expression of Sox2 attenuated the apoptotic effect of As(2)O(3) on glioma cell. Furthermore, As(2)O(3) inhibited the self-renewal of glioma stem cells, and efficiently induces the apoptosis of glioma stem cells, at least, partly through down-regulation of Sox2. These data identify a previously unrecognized mechanism of the anti-tumor effects of arsenic trioxide. PMID- 21703239 TI - Mitochondrial DNA as a non-invasive biomarker: accurate quantification using real time quantitative PCR without co-amplification of pseudogenes and dilution bias. AB - Circulating mitochondrial DNA (MtDNA) is a potential non-invasive biomarker of cellular mitochondrial dysfunction, the latter known to be central to a wide range of human diseases. Changes in MtDNA are usually determined by quantification of MtDNA relative to nuclear DNA (Mt/N) using real time quantitative PCR. We propose that the methodology for measuring Mt/N needs to be improved and we have identified that current methods have at least one of the following three problems: (1) As much of the mitochondrial genome is duplicated in the nuclear genome, many commonly used MtDNA primers co-amplify homologous pseudogenes found in the nuclear genome; (2) use of regions from genes such as beta-actin and 18S rRNA which are repetitive and/or highly variable for qPCR of the nuclear genome leads to errors; and (3) the size difference of mitochondrial and nuclear genomes cause a "dilution bias" when template DNA is diluted. We describe a PCR-based method using unique regions in the human mitochondrial genome not duplicated in the nuclear genome; unique single copy region in the nuclear genome and template treatment to remove dilution bias, to accurately quantify MtDNA from human samples. PMID- 21703240 TI - Protein acetylation in prokaryotes increases stress resistance. AB - Acetylation of lysine residues is conserved in all three kingdoms; however, its role in prokaryotes is unknown. Here we demonstrate that acetylation enables the reference bacterium Escherichia coli to withstand environmental stress. Specifically, the bacterium reaches higher cell densities and becomes more resistant to heat and oxidative stress when its proteins are acetylated as shown by deletion of the gene encoding acetyltransferase YfiQ and the gene encoding deacetylase CobB as well as by overproducing YfiQ and CobB. Furthermore, we show that the increase in oxidative stress resistance with acetylation is due to the induction of catalase activity through enhanced katG expression. We also found that two-component system proteins CpxA, PhoP, UvrY, and BasR are associated with cell catalase activity and may be responsible as the connection between bacterial acetylation and the stress response. This is the first demonstration of a specific environmental role of acetylation in prokaryotes. PMID- 21703241 TI - A population of BJ fibroblasts escaped from Ras-induced senescence susceptible to transformation. AB - Oncogenic stimuli such as H-Ras induce oncogene-induced senescence (OIS) in fibroblasts to protect against transformation. Here we found that a population of the human diploid fibroblasts can escape from OIS induced by H-RasV12. We designated these OIS-escaped cells as OISEC (OIS-escaped cells). OISEC lost the expression of p16 which plays an important role for cell cycle arrest for induction of senescence, but OISEC preserved the p16 expression machinery and exhibited senescence by the treatment with hydrogen peroxide (H(2)O(2)) as stress induced premature senescence (SIPS). OISEC did not possess anchorage-independent growth potential, and functional disruption of p53 and Rb by SV40 early region encoding large T and small t antigens, induced the aneuploidy phenotype and colony-forming potential of OISEC together with the exhibition of in vivo tumor formation. Finally, we also found that the distinctive feature of OISEC is expression of transcription factors, Oct3/4, SOX2, and Nanog which is closely related to stem-like cell features. This study highlights the presence of a cell population which escaped from OIS, and this OISEC may transform into malignant cancer cells by the additional hits of several genes in vivo. PMID- 21703242 TI - The presence of 5-hydroxymethylcytosine at the gene promoter and not in the gene body negatively regulates gene expression. AB - 5-Hydroxymethylcytosine (5hmC) was recently described as a stable modification in mammalian DNA. 5hmC is formed by the enzymatic oxidation of 5-methylcytosine (5meC). Overwhelming evidence supports the notion that 5meC has a negative effect on transcription; however, only recently has the effect that 5hmC has on transcription begun to be studied. Using model substrates including the CMV(IE) promoter and a generic gene body we have directly assessed the effect that 5hmC, both at the promoter and in the gene body, has on in vitro gene transcription. We show that the presence of the 5hmC modifications strongly represses transcription. We also demonstrate that the inhibition of transcriptional activity is primarily due to the presence of 5hmC in the promoter and that 5hmC in the gene body has a minimal effect on transcription. Thus, we propose that the presence of 5hmC in promoter prevents the binding of essential transcription factors or recruits factors that repress transcription. PMID- 21703243 TI - TRPV1 agonist piperine but not olvanil enhances glutamatergic spontaneous excitatory transmission in rat spinal substantia gelatinosa neurons. AB - We examined the effects of TRPV1 agonists olvanil and piperine on glutamatergic spontaneous excitatory transmission in the substantia gelatinosa (SG) neurons of adult rat spinal cord slices with the whole-cell patch-clamp technique. Bath applied olvanil did not affect the frequency and amplitude of spontaneous excitatory postsynaptic current (sEPSC), and unchanged holding currents at -70 mV. On the other hand, superfusing piperine reversibly and concentration dependently increased sEPSC frequency (half-maximal effective concentration: 52.3 MUM) with a minimal increase in its amplitude. This sEPSC frequency increase was almost repetitive at an interval of more than 20 min. Piperine at a high concentration produced an inward current in some neurons. The facilitatory effect of piperine was blocked by TRPV1 antagonist capsazepine. It is concluded that piperine but not olvanil activates TRPV1 channels in the central terminals of primary-afferent neurons, resulting in an increase in the spontaneous release of l-glutamate onto SG neurons. PMID- 21703244 TI - Identification of transcriptional regulatory elements required for the Mup2 expression in circadian clock mutant mice. AB - The suprachiasmatic nuclei in the mammalian brain function as the regulators of circadian rhythm and coordinate the peripheral oscillators. Losses of clock genes alter gene expression and behavior. Here, we investigated whether disruption of the circadian clock and glucocorticoid signals would influence the gene expression of major urinary protein (Mup) in mice. Both Mup2 mRNA and protein showed biphasic rhythms with similar phase relationships. However, the peak of the rhythm is shifted in mPeriod2 circadian clock mutant mice. We identified two E-boxes and one glucocorticoid response element (GRE) as regulatory elements for Mup2 transcription. While CLOCK binds to the E-boxes constantly, glucocorticoid receptor was capable of binding to the GRE in a timely manner. All together, our results indicate that Mup2 expression is regulated by both the circadian clock and glucocorticoid. PMID- 21703245 TI - A model capturing novel strand symmetries in bacterial DNA. AB - Chargaff's second parity rule for short oligonucleotides states that the frequency of any short nucleotide sequence on a strand is approximately equal to the frequency of its reverse complement on the same strand. Recent studies have shown that, with the exception of organellar DNA, this parity rule generally holds for double-stranded DNA genomes and fails to hold for single-stranded genomes. While Chargaff's first parity rule is fully explained by the Watson Crick pairing in the DNA double helix, a definitive explanation for the second parity rule has not yet been determined. In this work, we propose a model based on a hidden Markov process for approximating the distributional structure of primitive DNA sequences. Then, we use the model to provide another possible theoretical explanation for Chargaff's second parity rule, and to predict novel distributional aspects of bacterial DNA sequences. PMID- 21703246 TI - Cytoprotective roles of ERK and Akt in endoplasmic reticulum stress triggered by subtilase cytotoxin. AB - Subtilase cytotoxin (SubAB) is the prototype of a distinct AB(5) toxin family produced by Shiga toxigenic Escherichia coli. Recent reports disclosed pro apoptotic pathways triggered by SubAB, whereas its anti-apoptotic signals have not been elucidated. In the present study, we investigated pro-survival signaling elicited by SubAB, especially focusing on extracellular signal-regulated kinase (ERK) and Akt. We found that SubAB activated ERK and Akt, and inhibition of individual kinases enhanced SubAB-triggered apoptosis. SubAB induced endoplasmic reticulum (ER) stress, and other ER stress inducers mimicked the stimulatory effects of SubAB on ERK and Akt. Attenuation of ER stress reduced SubAB-induced phosphorylation of these kinases, suggesting involvement of the unfolded protein response (UPR). SubAB induced activation of protein kinase-like ER kinase (PERK) and phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha), and phosphorylation of eIF2alpha by salubrinal caused activation of ERK and Akt, leading to cell survival. Dominant-negative inhibition of PERK enhanced SubAB-induced apoptosis and reduced phosphorylation of ERK and Akt. Furthermore, the anti-apoptotic effect of eIF2alpha was significantly reversed by inhibition of ERK and Akt. These results suggest cytoprotective roles of ERK and Akt in SubAB-triggered, ER stress-mediated apoptosis. PMID- 21703247 TI - Suppression of human CD4+ T cell activation by 3,4-dimethoxycinnamonyl anthranilic acid (tranilast) is mediated by CXCL9 and CXCL10. AB - 3,4-dimethoxycinnamonyl-anthranilic acid (tranilast) is an orally available anti allergic drug with structural and functional homologies to immunosuppressive catabolites of the essential amino acid tryptophan and broad anti-inflammatory properties. It has recently been shown to be effective in animal models of multiple sclerosis and rheumatoid arthritis, two autoimmune diseases that are mediated by auto-aggressive Th1-polarized CD4+ T lymphocytes. Here we demonstrate potent suppressive effects of tranilast on the function of naive human CD4+ T cells. Tranilast inhibited inhibits activation and proliferation of purified CD4+ T cells stimulated through the T cell receptor with an EC50 of less than 10 MUM, a concentration that is well below plasma levels achieved after oral administration of approved doses of 200-600 mg in humans. The antiproliferative effects were less potent on naive CD8+ T cells. Suppression of CD4+ and CD8+ T cell proliferation was associated with an inhibition of T cell activation. Cytokine analyses of naive CD4+ T cells revealed that tranilast interferes with the production of cyto- and chemokines driven by signal transducer and activator of transcription 1 (STAT1), notably chemokine (C-X-C motif) ligands (CXCL) 9 and 10. Tranilast limited STAT1 phosphorylation in activated T cells and supplementation of CXCL9 or CXCL10 reversed the anti-proliferative effects of tranilast. These data imply CXCL9 and CXCL10 as novel therapeutic targets of tranilast in Th1-mediated autoimmune diseases and identify phospho-STAT1 and its target chemokines CXCL9 and CXCL10 as potential markers for monitoring the bioactivity of tranilast in humans. PMID- 21703248 TI - The aromatic ketone 4'-hydroxychalcone inhibits TNFalpha-induced NF-kappaB activation via proteasome inhibition. AB - Chalcones are aromatic ketones, known to exhibit anti-microbial, anti inflammatory and anti-cancer activities. The aim of this study was to investigate the anti-inflammatory and anti-cancer activity of 4'-hydroxychalcone. Here, we report that 4'-hydroxychalcone inhibits TNFalpha-induced NF-kappaB pathway activation in a dose-dependent manner. To investigate the underlying molecular mechanisms we demonstrate that 4'-hydroxychalcone inhibits proteasome activity in a dose-dependent manner but has no effect on IKK activity. Results show that 4' hydroxychalcone inhibits TNFalpha-dependent degradation of IkappaBalpha and subsequently prevents p50/p65 nuclear translocation leading to 4'-hydroxychalcone inhibited expression of NF-kappaB target genes. Most importantly, inhibition of NF-kappaB activation by 4'-hydroxychalcone is not leukemia cell-type specific and has no significant effect on non-transformed cell viability, thus highlighting the compound's potential in both prevention and treatment. PMID- 21703250 TI - Pathways of cholesterol oxidation via non-enzymatic mechanisms. AB - Cholesterol has many functions, including those that affect biophysical properties of membranes, and is a precursor to hormone synthesis. These actions are governed by enzymatic pathways that modify the sterol nucleus or the isooctyl tail. The addition of oxygen to the cholesterol backbone produces its derivatives known as oxysterols. In addition to having an enzymatic origin, oxysterols can be formed in the absence of enzymatic catalysis in a pathway usually termed "autoxidation," which has been known for almost a century and observed under various experimental conditions. Autoxidation of cholesterol can occur through reactions initiated by free radical species, such as those arising from the superoxide/hydrogen peroxide/hydroxyl radical system and by non-radical highly reactive oxygen species such as singlet oxygen, HOCl, and ozone. The susceptibility of cholesterol to non-enzymatic oxidation has raised considerable interest in the function of oxysterols as biological effectors and potential biomarkers for the non-invasive study of oxidative stress in vivo. PMID- 21703249 TI - Mangiferin attenuates methylmercury induced cytotoxicity against IMR-32, human neuroblastoma cells by the inhibition of oxidative stress and free radical scavenging potential. AB - Mangiferin (MGN), a C-glucosylxanthone was investigated for its ability to protect against methylmercury (MeHg) induced neurotoxicity by employing IMR-32 (human neuroblastoma) cell line. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] and clonogenic cell survival assays confirmed the efficacy of MGN supplementation in attenuating MeHg-induced cytotoxicity. Pre treatment with MGN significantly (p<0.01) inhibited MeHg-induced DNA damage (micronuclei, olive tail moment and % tail DNA) thereby demonstrating MGN's antigenotoxic potential. Also, pre-treatment with MGN significantly reduced MeHg induced oxidative stress, intra-cellular Ca(2+) influx and inhibited depolarization of mitochondrial membrane. MGN pre-treated cells demonstrated a significant (p<0.05) increase in the GSH and GST levels followed by a significant (p<0.05) decrease in malondialdehyde (MDA) formation. In addition, inhibition of MeHg induced apoptotic cell death by MGN was demonstrated by microscopic, Annexin V FITC and DNA fragmentation assays and further confirmed by western blot analysis. The present findings indicated the protective effect of MGN against MeHg induced toxicity, which may be attributed to its anti-genotoxic, anti apoptotic and anti-lipid peroxidative potential plausibly because of its free radical scavenging ability, which reduced the oxidative stress and in turn facilitated the down-regulation of mitochondrial apoptotic signalling pathways. PMID- 21703251 TI - Functional lipidomics of oxidized products from polyunsaturated fatty acids. AB - Because of their high degree of unsaturation, polyunsaturated fatty acids (PUFA) in mammals, with mainly 18, 20 and 22 carbons, can easily be autooxidized, and converted into many oxidized derivatives and degradation products. This short review reports on some of those relevant to the evaluation of oxidative stress in situ. In addition, the enzyme-dependent oxygenation by both dioxygenases and monooxygenases is briefly reviewed by functional and/or metabolic categories, pointing out the structure variety and the analytical approaches. PMID- 21703252 TI - Metalloproteinases in metabolic syndrome. AB - Experimental and clinical evidence supports the concept that metalloproteinases (MMPs), beyond different physiologic functions, also play a role in the development and rupture of the atherosclerotic plaque. Interest in MMPs has been rapidly increasing during the last years, especially as they have been proposed as biomarkers of vulnerable plaques. Different components of the metabolic syndrome (MS) have been identified as possible stimulus for the synthesis and activity of MMPs, like pro-inflammatory and pro-oxidant state, hyperglycemia, hypertension and dyslipidemia. On the other hand, anti-inflammatory cytokines like adiponectin are inversely associated with MMPs. Among the several MMPs studied, collagenases (MMP-1 and MMP-8) and gelatinases (MMP-2 and MMP-9) are the most associated with MS. Our aim was to summarize and discuss the relation between different components of the MS on MMPs, as well as the effect of the cluster of the metabolic alterations itself. It also highlights the necessity of further studies, in both animals and humans, to elucidate the function of novel MMPs identified, as well as the role of the known enzymes in different steps of metabolic diseases. Understanding the mechanisms of MS impact on MMPs and vice versa is an interesting area of research that will positively enhance our understanding of the complexity of MS and atherosclerosis. PMID- 21703253 TI - Subcutaneous rather than visceral adipose tissue thickness of the abdomen correlates with alterations in serum fatty acid profile in Japanese women. PMID- 21703254 TI - APOE haplotypes are associated with human longevity in a Central Italy population: evidence for epistasis with HP 1/2 polymorphism. AB - BACKGROUND: Apolipoprotein E (APOE) functional haplotypes determined by rs429358 and rs7412 SNPs have been extensively studied and found to be one of the most consistent association in human longevity studies. However, the search for longevity-determining genes in human has largely neglected the operation of genetic interactions. METHODS: APOE haplotypes have been determined for 1072 unrelated healthy individuals from Central Italy, 18-106 years old, divided into three gender-specific age classes defined according to demographic information and accounting for the different survival between sexes. The epistasis between APOE haplotypes and Haptoglobin (HP) 1/2 polymorphism was tested according to three-way contingency table analysis by a log-linear model. RESULTS: APOE genotype and haplotype distributions differ significantly along the age classes (Genotype: p=0.014; Haplotype: p=0.005) with APOE*epsilon4 genotype status and haplotype displaying negative association (Genotype: O.R.=0.377, p=0.002, Haplotype: O.R.=0.447, p=0.005). A significant interaction between APOE*epsilon4 genotype status, HP 1/2 genotype and age classes is reported (p=0.006). CONCLUSION: APOE haplotypes are significantly associated with longevity in our population. Of note, HP*1/*1 genotype seems to protects APOE*epsilon4 carriers from age-related negative selection. Collectively, these results also suggest and claim for further investigations on APOE/HP interaction in other age-related diseases such as Alzheimer's disease, atherosclerosis and Parkinson's disease. PMID- 21703255 TI - IL-16 rs11556218 gene polymorphism is associated with coronary artery disease in the Chinese Han population. AB - OBJECTIVE: Our aim was to investigate the association between IL-16 gene polymorphisms (rs4778889 C/T and rs11556218 G/T) and coronary artery disease (CAD). DESIGN AND METHODS: The initial cohort consisted of 300 CAD patients and 397 controls from the Chinese Han population. Genotyping was performed by using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). The positive association between polymorphism and CAD was replicated in another independent cohort, which included 424 CAD cases and 332 controls. RESULTS: In the initial study, the allele and genotype frequencies of rs4778889 were not different between in CAD and controls (P>0.05). However, The G allele frequency of rs11556218 was significantly higher in the CAD cases than in the controls (CAD, 46.8% vs. controls, 22.8%, P<0.001). The risk of CAD was significantly higher in the G allele carriers than in the non-carriers (P<0.001, adjusted odds ratio = 7.27; 95% confidence interval, 4.13-12.8). In the replication cohort, G carriers of rs11556218 also had a higher risk of CAD (P = 0.005, adjusted OR = 2.33; 95% confidence interval, 1.45-3.74). CONCLUSION: Our study suggested that IL-16 rs11556218 G/T polymorphism is significantly associated with the risk of CAD in the Chinese Han population. PMID- 21703256 TI - Effects of hydrochlorothiazide on cardiac remodeling in a rat model of myocardial infarction-induced congestive heart failure. AB - Heart failure is a major cause of morbidity and mortality worldwide. Diuretics are regarded as the first-line treatment for patients with heart failure because they provide symptomatic relief. However, the specific benefits of diuretics and their effects on heart failure survival remain unclear. This study was designed to investigate the potential of hydrochlorothiazide to improve cardiac remodeling compared with spironolactone. Heart failure was produced by ligation of the left anterior descending coronary artery in male Sprague-Dawley rats. Two weeks after coronary artery ligation, 55 rats were randomly divided into four groups: sham operated group (n=10), control group (n=15), hydrochlorothiazide group (12.5 mg/kg/day, n=15) and spironolactone group (20 mg/kg/day, n=15). Cardiac function was assessed by echocardiography and Millar catheter after treatment with drugs for 8 weeks. Compared with the control group, ejection fraction and left ventricular end-systolic pressure were significantly improved in the hydrochlorothiazide and spironolactone treatment groups (P<0.05). In addition, hydrochlorothiazide and spironolactone reduced collagen volume fraction and proinflammatory cytokine levels. Moreover, gene and protein expression of TGF beta1, Smad2, Smad3 and Smad7 (P<0.05) were also reduced. Nevertheless, no significant differences were observed between the hydrochlorothiazide and spironolactone groups. These results suggest that hydrochlorothiazide improves cardiac remodeling as effectively as spironolactone by reducing proinflammatory cytokine levels and inhibiting the TGF-beta signaling pathway in post-myocardial infarction congestive heart failure. Moreover, the effects of the drugs on the TGF-beta signaling pathway are likely to result from inhibited TGF-beta and R Smads expression rather than increased Inhibitory-Smad7 expression. PMID- 21703258 TI - Fentanyl activates hypoxia-inducible factor 1 in neuronal SH-SY5Y cells and mice under non-hypoxic conditions in a MU-opioid receptor-dependent manner. AB - Hypoxia-inducible factor 1 (HIF-1) is the main transcription factor responsible for hypoxia-induced gene expression. Perioperative drugs including anesthetics have been reported to affect HIF-1 activity. However, the effect of fentanyl on HIF-1 activity is not well documented. In this study, we investigated the effect of fentanyl and other opioids on HIF-1 activity in human SH-SY5Y neuroblastoma cells, hepatoma Hep3B cells, lung adenocarcinoma A549 cells and mice. Cells were exposed to fentanyl, and HIF-1 protein expression was examined by Western blot analysis using anti-HIF-1alpha and beta antibodies. HIF-1-dependent gene expression was investigated by semi-quantitative real-time reverse transcriptase (RT)-PCR (qRT-PCR) and luciferase assay. Furthermore, fentanyl was administered intraperitoneally and HIF-1-dependent gene expression was investigated by qRT-PCR in the brains and kidneys of mice. A 10-MUM concentration of fentanyl and other opioids, including 1 MUM morphine and 4 MUM remifentanil, induced HIF-1alpha protein expression and HIF-1 target gene expression in an opioid receptor dependent manner in SH-SY5Y cells with activity peaking at 24h. Fentanyl did not augment HIF-1alpha expression during hypoxia-induced induction. HIF-1alpha stabilization assays and experiments with cycloheximide revealed that fentanyl increased translation from HIF-1alpha mRNA but did not stabilize the HIF-1alpha protein. Furthermore, fentanyl induced HIF-1 target gene expression in the brains of mice but not in their kidneys in a naloxone-sensitive manner. In this report, we describe for the first time that fentanyl, both in vitro and in vivo, induces HIF-1 activation under non-hypoxic conditions, leading to increases in expression of genes associated with adaptation to hypoxia. PMID- 21703257 TI - Interruption of mitochondrial complex IV activity and cytochrome c expression activated O2.--mediated cell survival in silibinin-treated human melanoma A375-S2 cells via IGF-1R-PI3K-Akt and IGF-1R-PLC gamma-PKC pathways. AB - Silibinin was reported to have high cyto-toxicity in many malignant cell lines, however, it showed low cyto-toxicity in treatment of human melanoma A375-S2 cells and even protected these cells against certain stress insults. Reactive oxygen species was reported to have controversial effects on cancer chemotherapy. In this study we investigated the mechanism of reactive oxygen species generation and the role of reactive oxygen species in protecting cells against silibinin induced cyto-toxicity in A375-S2 cells. We found that silibinin induced the generation of large amount of superoxide anion (O(2)(?-)) and small amount of hydrogen peroxide (H(2)O(2)) through down-regulating the activity of mitochondrial complex IV and the protein level of cytochrome c. We also discovered that O(2)(?-) generation activated insulin like growth factor-1 receptor (IGF-1R) and its down-stream phosphatidylinositol 3-kinases-Akt (PI3K Akt) and phospholipase C gamma-protein kinase C (PLC gamma-PKC) signaling pathways, which were augmented by H(2)O(2) scavenger catalase. Scavenging O(2)(? ) by superoxide dismutase (SOD) or inhibition of IGF-1R-PI3K-Akt and IGF-1R-PLC gamma-PKC signaling pathways increased cell apoptosis. Therefore, O(2)(?-) mediated cell resistance to silibinin via activating IGF-1R-PI3K-Akt and IGF-1R PLC gamma-PKC pathways in silibinin treated A375-S2 cells. PMID- 21703259 TI - Inhibition of vascular endothelial growth factor (VEGF)-induced endothelial proliferation, arterial relaxation, vascular permeability and angiogenesis by dobesilate. AB - Vascular endothelial growth factor (VEGF) is a key factor in angiogenesis and vascular permeability which is associated with many pathological processes. 2,5 hydroxybenzene sulfonate (DHBS; dobesilate) is a small molecule with anti angiogenic activity that has been described as an inhibitor of fibroblast growth factors (FGF). The aim of the present study was to evaluate the effects of DHBS on VEGF-induced actions. The effects of DHBS were evaluated on VEGF-induced proliferation in human umbilical vein endothelial cells (HUVEC) and rat aorta relaxation, as well as on in vivo VEGF-induced skin vascular permeability and neovascularization in rats. DHBS at 50 and 100 MUM concentration significantly inhibited the proliferation of HUVEC induced by VEGF (10 ng/ml), without significantly affecting HUVEC proliferation in the absence of VEGF. Rapid VEGF induced activation of Akt in HUVEC was also prevented by DHBS (100 MUM). Additionally, DHBS (2 MUM) specifically inhibited the relaxation of rat aorta induced by VEGF (0.1 to 30 ng/ml), but not endothelium-dependent relaxation to acetylcholine (1 nM to 10 MUM). The in vivo enhancement of vascular permeability caused by VEGF injection (50 MUl at 10 ng/ml) in rat skin was also inhibited by DHBS co-administration (200 MUM) (74.8+/-3.8% inhibition of dye extravasation). Administration of DHBS (200 mg/kg/day; i.p.) also reduced VEGF-induced angiogenesis in vivo. DHBS inhibits main responses elicited in vitro and in vivo by VEGF. As a dual antagonist of VEGF and FGF activities, DHBS could be of therapeutic interest in the treatment of diseases related to VEGF/FGF overproduction and excessive angiogenesis. PMID- 21703260 TI - 20(S)-Protopanaxadiol, a metabolite of ginsenosides, induced cell apoptosis through endoplasmic reticulum stress in human hepatocarcinoma HepG2 cells. AB - 20(S)-Protopanaxadiol (PPD), a metabolite of ginsenosides, has been demonstrated to possess cytotoxic effects on several cancer cell lines. The molecular mechanism is, however, not well understood. In this study, we have shown that PPD inhibits cell growth and induces apoptosis in human hepatocarcinoma HepG2 cells. PPD-treated cells showed a massive cytoplasmic vacuolization and a dramatic change of endoplasmic reticulum (ER) morphology. The induction of ER stress is associated with the upregulation of ER stress-associated genes and proteins. PPD activates the unfolded protein response (UPR) through the phosphorylation of PERK and eIF2alpha, the splicing of XBP1 mRNA, and the cleavage of AFT6. PPD also induces the intrinsic and extrinsic apoptotic pathways. It activates DR5, caspase 8, -9, -3, and promotes the cleavage of PARP while it downregulates Bcl-2, Bcl x(L) and mitochondrial membrane potential. Knockdown of one of the three UPR limbs by specific siRNAs did not affect PPD-induced apoptosis, which was however, significantly suppressed by the downregulation of CHOP. Western blot analysis showed that PPD-stimulated downregulation of Bcl-2 protein, increase of DR5 protein, activation of caspase-8 and cleavage of PARP were significantly inhibited in CHOP siRNA-transfected cells. Taken together, we have identified ER as a molecular target of PPD and our data support the hypothesis that PPD induces HepG2 cell apoptosis through the ER stress pathway. PMID- 21703261 TI - Volumetric effects of motor cortex injury on recovery of ipsilesional dexterous movements. AB - Damage to the motor cortex of one hemisphere has classically been associated with contralateral upper limb paresis, but recent patient studies have identified deficits in both upper limbs. In non-human primates, we tested the hypothesis that the severity of ipsilesional upper limb motor impairment in the early post injury phase depends on the volume of gray and white matter damage of the motor areas of the frontal lobe. We also postulated that substantial recovery would accompany minimal task practice and that ipsilesional limb recovery would be correlated with recovery of the contralesional limb. Gross (reaching) and fine hand motor functions were assessed for 3-12 months post-injury using two motor tests. Volumes of white and gray matter lesions were assessed using quantitative histology. Early changes in post-lesion motor performance were inversely correlated with white matter lesion volume indicating that larger lesions produced greater decreases in ipsilesional hand movement control. All monkeys showed improvements in ipsilesional hand motor skill during the post-lesion period, with reaching skill improvements being positively correlated with total lesion volume indicating that larger lesions were associated with greater ipsilesional motor skill recovery. We suggest that reduced trans-callosal inhibition from the lesioned hemisphere may play a role in the observed skill improvements. Our findings show that significant ipsilesional hand motor recovery is likely to accompany injury limited to frontal motor areas. In humans, more pronounced ipsilesional motor deficits that invariably develop after stroke may, in part, be a consequence of more extensive subcortical white and gray matter damage. PMID- 21703264 TI - The hot mustard receptor's role in gut motor function. PMID- 21703262 TI - Insulin resistance impairs nigrostriatal dopamine function. AB - Clinical studies have indicated a link between Parkinson's disease (PD) and Type 2 Diabetes. Although preclinical studies have examined the effect of high-fat feeding on dopamine function in brain reward pathways, the effect of diet on neurotransmission in the nigrostriatal pathway, which is affected in PD and parkinsonism, is less clear. We hypothesized that a high-fat diet, which models early-stage Type 2 Diabetes, would disrupt nigrostriatal dopamine function in young adult Fischer 344 rats. Rats were fed a high fat diet (60% calories from fat) or a normal chow diet for 12 weeks. High fat-fed animals were insulin resistant compared to chow-fed controls. Potassium-evoked dopamine release and dopamine clearance were measured in the striatum using in vivo electrochemistry. Dopamine release was attenuated and dopamine clearance was diminished in the high fat diet group compared to chow-fed rats. Magnetic resonance imaging indicated increased iron deposition in the substantia nigra of the high fat group. This finding was supported by alterations in the expression of several proteins involved in iron metabolism in the substantia nigra in this group compared to chow-fed animals. The diet-induced systemic and basal ganglia-specific changes may play a role in the observed impairment of nigrostriatal dopamine function. PMID- 21703263 TI - An angiogenic inhibitor, cyclic RGDfV, attenuates MPTP-induced dopamine neuron toxicity. AB - We previously demonstrated that several dopamine (DA) neurotoxins produced punctate areas of FITC-labeled albumin (FITC-LA) leakage in the substantia nigra and striatum suggesting blood brain barrier (BBB) dysfunction. Further, this leakage was co-localized with alphavbeta3 integrin up-regulation, a marker for angiogenesis. This suggested that the FITC-LA leakage might have been a result of angiogenesis. To assess the possible role of angiogenesis in DA neuron loss, we treated mice with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and on the following day treated with cyRGDfV, a cyclic peptide that binds to integrin alphavbeta3 and prevents angiogenesis. Post-treatment for 3 days (b.i.d.) with cyRGDfV blocked the MPTP-induced upregulation of integrin beta3 immunoreactivity (a marker for angiogenesis), leakage of FITC-LA into brain parenchyma (a marker for BBB disruption) as well as the down regulation of Zona Occludin-1 (ZO-1; a marker for tight junction integrity). In addition, cyRGDfV also completely prevented tyrosine hydroxylase immunoreactive cell loss (a marker for DA neurons) and markedly attenuated the up-regulation of activated microglia (Iba1 cell counts and morphology). These data suggest that cyRGDfV, and perhaps other anti angiogenic drugs, are neuroprotective following acute MPTP treatment and may suggest that compensatory angiogenesis and BBB dysfunction may contribute to inflammation and DA neuron loss. PMID- 21703265 TI - Angle-resolved low coherence interferometry for detection of dysplasia in Barrett's esophagus. PMID- 21703266 TI - Targeting serotonin synthesis to treat irritable bowel syndrome. PMID- 21703267 TI - Lineage tracing evidence for transdifferentiation of acinar to duct cells and plasticity of human pancreas. AB - BACKGROUND & AIMS: Animal studies have indicated that pancreatic exocrine acinar cells have phenotypic plasticity. In rodents, acinar cells can differentiate into ductal precursors that can be converted to pancreatic ductal adenocarcinoma or insulin-producing endocrine cells. However, little is known about human acinar cell plasticity. We developed nongenetic and genetic lineage tracing methods to study the fate of human acinar cells in culture. METHODS: Human exocrine tissue was obtained from organ donors, dissociated, and cultured. Cell proliferation and survival were measured, and cell phenotypes were analyzed by immunocytochemistry. Nongenetic tracing methods were developed based on selective binding and uptake by acinar cells of a labeled lectin (Ulex europaeus agglutinin 1). Genetic tracing methods were developed based on adenoviral introduction of a Cre-lox reporter system, controlled by the amylase promoter. RESULTS: Both tracing methods showed that human acinar cells can transdifferentiate into cells that express specific ductal markers, such as cytokeratin 19, hepatocyte nuclear factor 1beta, SOX9, CD133, carbonic anhydrase II, and cystic fibrosis transmembrane conductance regulator. Within 1 week of culture, all surviving acinar cells had acquired a ductal phenotype. This transdifferentiation was decreased by inhibiting mitogen-activated protein kinase signaling. CONCLUSIONS: Human acinar cells have plasticity similar to that described in rodent cells. These results might be used to develop therapeutic strategies for patients with diabetes or pancreatic cancer. PMID- 21703268 TI - An in vitro model for evaluating peripheral regulation of growth in fish: effects of 17beta-estradiol and testosterone on the expression of growth hormone receptors, insulin-like growth factors, and insulin-like growth factor type 1 receptors in rainbow trout (Oncorhynchus mykiss). AB - A central component of growth coordination in vertebrates is the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) system. To date, most studies on the control of vertebrate growth have focused on regulation of pituitary GH production and release. In this study, we used liver, muscle, and gill tissue from sexually immature rainbow trout incubated in vitro to evaluate the extrapituitary effects of 17beta-estradiol (E2) and testosterone (T) on mRNA and functional expression of growth hormone receptors (GHR), insulin-like growth factors 1 and 2 (IGF-1, IGF-2), and type 1 IGF receptors (IGFR1). E2 significantly decreased steady-state levels of GHR1, GHR2, and IGF-1 mRNAs in liver as well as of GHR1 and GHR2 mRNAs in muscle and of IGF-1 and IGF-2 mRNAs in gill in a time- and concentration-dependent manner. E2 had no effect on levels of IGFR1 mRNAs in muscle or on GHR and IGFR1 mRNAs in gill. Functional expression of GHRs as assessed by (125)I-GH binding capacity was reduced by E2 in liver and muscle; however, E2 did not affect (125)I-IGF-1 binding capacity in muscle or (125)I-GH and (125)I-IGF-1 binding capacity in gill. By contrast, T increased steady-state levels of GHR1, GHR2, IGF-1, and IGF-2 mRNAs in liver, of GHR1, GHR2, IGFR1A, and IGFR1B in muscle, and of GHR1, GHR2, IGF-1, IGF-2, IGFR1A, and IGFR1B mRNAs in gill in a time- and concentration-dependent manner. Binding capacity of (125)I-GH in liver and of (125)I-GH and (125)I-IGF-1 in both muscle and gill also was increased by T. These data indicate that E2 and T directly affect peripheral aspects of the GH-IGF system, and suggest, at least in immature rainbow trout, that E2 reduces hepatic sensitivity to GH as well as reduces peripheral production of IGFs and that T increases peripheral sensitivity to GH and IGF as well as increases peripheral production of IGFs. PMID- 21703269 TI - Role of chicken Pit-1 isoforms in activating growth hormone gene. AB - In the present study, we expressed chicken (ch) Pit-1alpha (chPit-1alpha) and chPit-1gammain vitro to compare the roles of chPit-1s in the transcription of the chicken growth hormone (chGH) gene. Both green fluorescence protein (GFP)-fused chPit-1gamma and GFP-fused chPit-1alpha were localized in the nuclei of COS-7 cells. In a luciferase reporter gene assay, both chPit-1alpha and chPit-1gamma transactivated the chGH promoter, and chPit-1alpha showed a more potent effect than chPit-1gamma. On the other hand, an increase of cellular cAMP induced by forskolin promoted transactivation of the chGH gene with chPit-1alpha and chPit 1gamma to similar extents. These results suggest that chPit-1gamma may modulate the basal promoter activity of the chGH gene to the same degree as chPit-1alpha; however, a structural difference observed at the N-terminus transactivation domains in chPit-1alpha and chPit-1gamma could be associated with the efficiency of basal activation of the chGH promoter. PMID- 21703270 TI - Insulin-like peptides in the mosquito Anopheles stephensi: identification and expression in response to diet and infection with Plasmodium falciparum. AB - Insulin-like peptides (ILPs) regulate a multitude of biological processes, including metabolism and immunity to infection, and share similar structural motifs across widely divergent taxa. Insulin/insulin-like growth factor signaling (IIS) pathway elements are similarly conserved. We have shown that IIS regulates reproduction, innate immunity, and lifespan in female Anopheles stephensi, a major mosquito vector of human malaria. To further explore IIS regulation of these processes, we identified genes encoding five ILPs in this species and characterized their expression in tissues. Antisera to ILP homologs in Anopheles gambiae were used to identify cellular sources in An. stephensi females by immunocytochemistry. We analyzed tissue-specific ILP transcript expression in young and older females, in response to different feeding regimens, and in response to infection with Plasmodiumfalciparum with quantitative reverse transcriptase-PCR assays. While some ILP transcript changes were evident in older females and in response to blood feeding, significant changes were particularly notable in response to hormonal concentrations of ingested human insulin and to P. falciparum infection. These changes suggest that ILP secretion and action may be similarly responsive in Plasmodium-infected females and potentially alter metabolism and innate immunity. PMID- 21703271 TI - Involvement of thyroid hormones in the control of larval metamorphosis in Sicyopterus lagocephalus (Teleostei: Gobioidei) at the time of river recruitment. AB - After oceanic migration, post-larvae of the amphidromous Sicyopterus lagocephalus recruit to rivers in Reunion Island. As they enter the river mouth, post-larvae undergo many morphological, physiological and behavioural changes. These drastic changes, which allow them to change feeding regime and to colonise the juvenile and adult freshwater habitat, are defined as metamorphosis. The endocrine control of these changes has never been investigated in Gobioid fish. Here, we investigated whether thyroid hormones (TH) influence metamorphosis in recruiting S.lagocephalus. An analytical study was first performed on a cohort of 2400 fish caught at post-larval stage 1 and maintained for 37 days after capture in a flume tank (fluvarium), which replicates as closely as possible the natural conditions. Biometrical parameters (total and standard lengths, corner of mouth angle, body mass and condition factor) and whole-body thyroxine (T(4)) and triiodothyronine (T(3)) contents were measured on fish, sampled at regular intervals during these 37 days (192 fish). TH levels, measured by radioimmunoassays, were highest when morphological changes, such as the change in the position of the mouth, were most important. An experimental approach was then used to test the effect of the hormonal treatment (T(4) or thiourea, TU, a TH inhibitor) on biometrical parameters of 576 post-larvae. The change in the position of the mouth was significantly accelerated in the T(4)-treated post-larvae, while it was significantly delayed in the TU-treated post-larvae, compared to controls. Our study suggests that S.lagocephalus post-larva undergoes a true metamorphic event under the control of thyroid hormones at the time of its recruitment into the river. PMID- 21703272 TI - Discovery of a new reproductive hormone in teleosts: pituitary adenylate cyclase activating polypeptide-related peptide (PRP). AB - Pituitary adenylate cyclase-activating polypeptide (PACAP)-related peptide (PRP) is a peptide encoded with PACAP in the same precursor protein. Non-mammalian PRPs were previously termed growth hormone-releasing hormone (GHRH)-like peptide, and was regarded as the mammalian GHRH homologue in non-mammalian vertebrates until the discovery of authentic GHRH genes in teleosts and amphibians. Although a highly specific receptor for PRP, which is lost in mammals, is present in non mammals, a clear function of PRP in vertebrates remains unknown. Using goldfish as a model, here we show the expression of PRP and its cognate receptor in the brain-pituitary-gonadal (BPG) axis, thus suggesting a function of goldfish (gf) PRP in regulating reproduction. We found that gfPRP controls the expression of reproductive hormones in the brain, pituitary and ovary. Goldfish PRP exerts stimulatory effects on the expression of salmon gonadotropin-releasing hormone (sGnRH) in the brain, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in pituitary primary culture cells, but inhibits the expression of LH in the ovary. Using the same technique, we showed that gfPRP did not alter the mRNA level of growth hormone in the pituitary primary culture. In summary, we have discovered the first function of vertebrate PRP in regulating reproduction, which provides a new research direction in studying the neuroendocrine control of reproduction not only in teleosts, but also in other non-mammalian vertebrates. PMID- 21703273 TI - Effects of breeding season, testosterone and ACTH on the corticosterone response of free-ranging male fence lizards (Sceloporus undulatus). AB - An attenuated stress response during the breeding season has been reported for several vertebrate species, but the underlying physiological mechanism has received little attention, particularly in reptiles. Modulation could involve changes in the capacity of the adrenal gland to secrete glucocorticoids in addition to upstream changes in the pituitary or hypothalamus. In this study the magnitude of the corticosterone response to capture and confinement was compared between the breeding and postbreeding season in adult male eastern fence lizards, Sceloporus undulatus. Males were captured in both seasons and subjected to the identical stressor of 4h of confinement. Plasma corticosterone levels in response to confinement were significantly lower in the breeding than the postbreeding season. The effect of testosterone on the stress response was tested by experimentally elevating plasma testosterone levels via silastic implants in free living males during the postbreeding season. Males with experimentally elevated testosterone exhibited significantly weaker corticosterone responses to 1h of confinement than sham-implanted males. Finally the capacity of the adrenal glands to secrete corticosterone during the breeding season was tested by challenging males with adrenocorticotropin (ACTH) injections. In spite of naturally suppressed corticosterone responses during the breeding season, males nonetheless responded robustly to ACTH. Altogether these results suggest that modulation resides upstream of the adrenal gland, as has been shown in some arctic-breeding avian species, and likely involves seasonal changes in testosterone levels. PMID- 21703274 TI - Measurement of the total proANP product in mammals by processing independent analysis. AB - The cellular processing of natriuretic propeptides is attenuated in heart disease, resulting in release of a mixture of unprocessed precursor, partially processed fragments, and the bioactive hormone. Here, we report a species independent method for quantification of pro-atrial natriuretic peptide (proANP) and its products irrespective of variable post-translational processing. The processing-independent assay (PIA) was developed raising mono-specific antibodies against the C-terminus of sequence 1-16 in proANP. The assay procedure included plasma extraction followed by tryptic cleavage, which releases the assay epitope from the N-terminal region. The PIA was tested in elderly patients with symptoms of heart failure (n=450), in pigs with acute myocardial infarction (n=21), and in normal dogs and dogs with heart failure (n=77). The epitope specificity permitted reliable measurement in man, dog, cat and pig. In human plasma, the PIA correlated well with an established proANP analysis (r=0.86, P<0.0001) but with a 5.5-fold difference in plasma level (P<0.0001). In pigs, the PIA measured 9.2 fold higher concentrations compared to a human assay (804 versus 87pmol/L, P<0.0001). The basal proANP concentration was 396pmol/L in dogs: a dramatic increase was seen in canine heart failure. Our new processing- and species independent proANP assay allows for the measurement of the total proANP product, irrespective of changes in post-translational maturation. We suggest that this tool should be used for comparative studies between human patients and porcine and canine models of human cardiac disease. PMID- 21703275 TI - A strategic and systematic approach for the determination of biosensor regeneration conditions. AB - Determining the optimal conditions for surface regeneration is fundamental for performance of efficient and robust protein-protein interaction kinetic studies. We devised a systematic methodology comprised of an automated seven-cycle analyte and buffer injection Biacore scheme and data interpretation algorithm. The efficiency and utility is illustrated using an antigen/monoclonal antibody interaction that required ultimately six pulses of acid for regeneration. This technique has broad applicability to any biosensor assay that requires regeneration of a surface. PMID- 21703276 TI - Parental care, cost of reproduction and reproductive skew: a general costly young model. AB - Understanding the mechanisms by which animals resolve conflicts of interest is the key to understanding the basis of cooperation in social species. Conflict over reproductive portioning is the critical type of conflict among cooperative breeders. The costly young model represents an important, but underappreciated, idea about how an individual's intrinsic condition and cost of reproduction should affect the resolution of conflict over the distribution of reproduction within a cooperatively breeding group. However, dominant control in various forms and fixed parental care (offspring fitness dependent solely on total brood size) are assumed in previous versions of costly young models. Here, we develop a general costly young model by relaxing the restrictive assumptions of existing models. Our results show that (1) when the complete-control assumption is relaxed, the costly young model behaves very differently from the original model, and (2) when the fixed parental care assumption is relaxed, the costly young costly care model displays similar predictions to the tug-of-war model, although the underlying mechanisms causing these similar patterns are different. These results, we believe, help simplify the seemingly divergent predictions of different reproductive skew models and highlight the importance of studying the group members' intrinsic conditions, costs of producing young, and costs of parental care for understanding breeding conflict resolution in cooperatively breeding animals. PMID- 21703277 TI - RNA templating of molecular assembly and covalent modification patterning in early molecular evolution and modern biosystems. AB - The Direct RNA Template (DRT) hypothesis proposes that an early stage of genetic code evolution involved RNA molecules acting as stereochemical recognition templates for assembly of specific amino acids in sequence-ordered arrays, providing a framework for directed covalent peptide bond formation. It is hypothesized here that modern biological precedents may exist for RNA-based structural templating with functional analogies to hypothetical DRT systems. Beyond covalent molecular assembly, an extension of the DRT concept can include RNA molecules acting as dynamic structural template guides for the specific non covalent assembly of multi-subunit complexes, equivalent to structural assembly chaperones. However, despite numerous precedents for RNA molecules acting as scaffolds for protein complexes, true RNA-mediated assembly chaperoning appears to be absent in modern biosystems. Another level of function with parallels to a DRT system is possible if RNA structural motifs dynamically guided specific patterns of catalytic modifications within multiple target sites in a pre-formed polymer or macromolecular complex. It is suggested that this type of structural RNA templating could logically play a functional role in certain areas of biology, one of which is the glycome of complex organisms. If any such RNA templating processes are shown to exist, they would share no necessary evolutionary relationships with events during early molecular evolution, but may promote understanding of the practical limits of biological RNA functions now and in the ancient RNA World. Awareness of these formal possibilities may also assist in the current search for functions of extensive non-coding RNAs in complex organisms, or for efforts towards artificial rendering of DRT systems. PMID- 21703278 TI - A model of plasma membrane flow and cytosis regulation in growing pollen tubes. AB - A model of cytosis regulation in growing pollen tubes is developed and simulations presented. The authors address the question on the minimal assumptions needed to describe the pattern of exocytosis and endocytosis reported recently by experimental biologists. Biological implications of the model are also treated. Concepts of flow and conservation of membrane material are used to pose an equation system, which describes the movement of plasma membrane in the tip of growing pollen tubes. After obtaining the central equations, relations describing the rates of endocytosis and exocytosis are proposed. Two cytosis receptors (for exocytosis and endocytosis), which have different recycling rates and activation times, suffice to describe a stable growing tube. Simulations show a very good spatial separation between endocytosis and exocytosis, in which separation is shown to depend strongly on exocytic vesicle delivery. In accordance to measurements, most vesicles in the clear zone are predicted to be endocytic. Membrane flow is essential to maintain cell polarity, and bi directional flow seems to be a natural consequence of the proposed mechanism. For the first time, a model addressing plasma membrane flow and cytosis regulation were posed. Therefore, it represents a missing piece in an integrative model of pollen tube growth, in which cell wall mechanics, hydrodynamic fluxes and regulation mechanisms are combined. PMID- 21703279 TI - Using the concept of pseudo amino acid composition to predict resistance gene against Xanthomonas oryzae pv. oryzae in rice: an approach from chaos games representation. AB - To evaluate the possibility of an unknown protein to be a resistant gene against Xanthomonas oryzae pv. oryzae, a different mode of pseudo amino acid composition (PseAAC) is proposed to formulate the protein samples by integrating the amino acid composition, as well as the Chaos games representation (CGR) method. Some numerical comparisons of triangle, quadrangle and 12-vertex polygon CGR are carried to evaluate the efficiency of using these fractal figures in classifiers. The numerical results show that among the three polygon methods, triangle method owns a good fractal visualization and performs the best in the classifier construction. By using triangle + 12-vertex polygon CGR as the mathematical feature, the classifier achieves 98.13% in Jackknife test and MCC achieves 0.8462. PMID- 21703280 TI - Estrogen signaling in testicular cells. AB - Aromatase transforms irreversibly androgens into estrogens and is present in the endoplasmic reticulum of various tissues including the mammalian testis. In rat all testicular cells except peritubular cells express aromatase. Indeed in adult rat germ cells (pachytene spermatocytes and round spermatids) we have demonstrated the presence of a functional aromatase (transcript, protein and biological activity) and the estrogen output is equivalent to that of Leydig cells. In addition in the adult rat, transcripts of aromatase vary according to the germ cell type and to the stages of seminiferous epithelium. By contrast with the androgen receptors mainly localized in somatic cells, estrogen receptors (ERs) are described in most of the testicular cells including germ cells. Moreover, besides the presence of high affinity ERalpha and/or ERbeta,? a rapid membrane effect has been recently reported and we demonstrated that GPR30 (a transmembrane intracellular estrogen receptor) is expressed in adult rat pachytene spermatocytes. Therefore estrogens through both GPR30 and ERalpha are able to activate the rapid EGFR/ERK/c-jun signaling cascade, which in turn triggers an apoptotic mitochondrial pathway involving an increase in Bax expression and a concomitant reduction of cyclin A1 and B1 gene levels. In another study in round spermatids of adult rat we have shown that the rapid membrane effect of estradiol is also efficient in controlling apoptosis and maturation / differentiation of these haploid germ cells. In man the presence of a biologically active aromatase and of estrogen receptors has been reported in Leydig cells, but also in immature germ cells and ejaculated spermatozoa. Thus the role of estrogen (intracrine, autocrine and / or paracrine) in spermatogenesis (proliferation, apoptosis, survival and maturation) and more generally, in male reproduction is now evidenced taking into account the simultaneous presence of a biologically active aromatase and the widespread distribution of estrogen receptors especially in haploid germ cells. PMID- 21703281 TI - Adenosine A(2A)R modulates cardiovascular function by activating ERK1/2 signal in the rostral ventrolateral medulla of acute myocardial ischemic rats. AB - AIMS: To investigate the cardiovascular regulatory mechanism of adenosine A(2A) receptor (A(2A)R) in the rostral ventrolateral medulla (RVLM) in acute myocardial ischemic (AMI) rats. MAIN METHODS: The animal model of AMI was established by ligating the left anterior descending coronary artery (LAD). The A(2A)R expression was examined by immunohistochemistry, western blot and real-time PCR. CGS21680 and SCH58261 (an agonist and antagonist of A(2A)R) were respectively microinjected into the RVLM. In a subgroup of rats, PD98059 (an antagonist of extracellular signal-regulated kinase (ERK1/2)) was microinjected prior to CGS21680 administration. Phosphorylation of ERK1/2 was examined by western blot. KEY FINDINGS: Our results demonstrated that A(2A)R immunoreactive positive neurons, the expressions of protein and mRNA of A(2A)R in the RVLM of AMI group were increased compared with the sham group. Microinjection CGS21680 into the RVLM inhibited mean arterial pressure (MAP) and heart rate (HR) in both AMI and sham groups. The inhibition was significantly greater in AMI group than in sham group. The cardiovascular effects of CGS21680 mentioned above were almost abolished by prior administration of PD98059. The increase of ERK1/2 in the RVLM with the cardiovascular responses was induced by CGS21680 in AMI rats; this effect was also blocked by SCH58261. SIGNIFICANCE: This study reveals that the activated A(2A)R in the RVLM underlies the depressor and bradycardiac responses in AMI rats via phosphorylation of ERK1/2 increasing. PMID- 21703282 TI - Rapid signaling responses in Sertoli cell membranes induced by follicle stimulating hormone and testosterone: calcium inflow and electrophysiological changes. AB - This minireview describes the rapid signaling actions of follicle stimulating hormone (FSH) and testosterone in immature Sertoli cells mainly related to Ca(2+) inflow and the electrophysiological changes produced by hormones. The rapid membrane actions of FSH occur in a time frame of seconds to minutes, which include membrane depolarization and the stimulation of (45)Ca(2+) uptake. These effects can be prevented by pertussis toxin (PTX), suggesting that they are likely mediated by Gi-protein coupled receptor activation. Furthermore, these effects were inhibited by verapamil, a blocker of the L-type voltage-dependent Ca(2+) channel (VDCC). Finally, FSH stimulation of (45)Ca(2+) uptake was inhibited by the (phosphoinositide 3-kinase) PI3K inhibitor wortmannin. These results suggest that the rapid action of FSH on L-type Ca(2+) channel activity in Sertoli cells from pre-pubertal rats is mediated by the Gi/Gbetagamma/PI3Kgamma pathway, independent of its effects on insulin-like growth factor type I (IGF-I). Testosterone depolarizes the membrane potential and increases the resistance and the (45)Ca(2+) uptake in Sertoli cells of the seminiferous tubules of immature rats. These actions were nullified by diazoxide (K(+)(ATP) channel opener). Testosterone actions were blocked by both PTX and the phospholipase C (PLC) inhibitor U73122, suggesting the involvement of PLC - phosphatidylinositol 4-5 bisphosphate (PIP2) hydrolysis via the Gq protein in the testosterone-mediated pathway. These results indicate that testosterone acts on the Sertoli cell membrane through the K(+)(ATP) channels and PLC-PIP2 hydrolysis, which closes the channel, depolarizes the membrane and stimulates (45)Ca(2+) uptake. These results demonstrate the existence of rapid non-classical pathways in immature Sertoli cells regulated by FSH and testosterone. PMID- 21703284 TI - Abnormal neural oscillations in schizotypy during a visual working memory task: support for a deficient top-down network? AB - Neural oscillatory deficits have been proposed to be a core feature of schizophrenia spectrum disorders. In this study we aimed to confirm this by examining early evoked oscillatory patterns in the EEG theta, beta and gamma bands in individuals with high schizotypal personality trait scores. We carried out an event-related experiment using a computerised delayed matching to sample working memory (WM) task on a sample of volunteers scoring high or low on the Schizotypal Personality Questionnaire (SPQ). Phase-locking factor (PLF), a measure of network synchronisation, was reduced in the beta and gamma bands in two distinct topographical regions (fronto-central and centraloccipital). In addition, signal power in the beta band was decreased in the high schizotypy group in the same fronto-occipital network. These findings suggest that abnormalities in functional connectivity, already described in schizophrenia, extend to schizotypy. Further, the pattern and latency of the altered neural oscillations in the high schizotypy group suggests a deficient modulation of the sensory processing by higher-order structures. Such top-down deficits have been reported in schizophrenia and this data supports the idea that top-down dysfunction is a vulnerability trait that is independent of disease course, medication or symptom severity. PMID- 21703283 TI - Vascular hyperpermeability in response to inflammatory mustard oil is mediated by Rho kinase in mice systemically exposed to arsenic. AB - The mechanisms underlying vascular dysfunction and cardiovascular disease induced by chronic arsenic exposure are not completely understood. We have previously shown that mice chronically fed sodium arsenite are hypersensitive to the permeability-increasing effects of inflammatory mustard oil. The aim of this study was to investigate whether RhoA/Rho kinase (ROCK)-mediated vascular leakage (hyperpermeability) is induced by mustard oil in mice systemically exposed to arsenic. Animals were orally fed water (control group) or sodium arsenite for 8weeks. We compared the blood pressure and microvessel density of the ears between these two groups. Both control and arsenic groups exhibited a similar mean arterial pressure and microvessel density. Microvessel permeability changes that occurred following mustard oil treatment in the presence of Y-27632, a ROCK inhibitor, were quantified using the Evans blue (EB) technique and vascular labeling with carbon particles. Both the excessive leakiness of EB and the high density of carbon-labeled microvessels upon stimulation with mustard oil in the arsenic-fed mice were reduced by Y-27632 treatment. However, RhoA and ROCK2 expression levels were similar between control and arsenic-fed mice. We further investigated ROCK2 levels and ROCK activity in the ears following mustard oil challenge. ROCK2 levels in mouse ears treated with mustard oil were higher in the arsenic group as compared with the control group. Following mustard oil application, ROCK activity was significantly higher in the arsenic-fed mice compared with the control mice. These findings indicate that increased ROCK2 levels and enhanced ROCK activity are responsible for mustard oil-induced vascular hyperpermeability in arsenic-fed mice. PMID- 21703285 TI - Impact of novelty and type of material on recognition in healthy older adults and persons with mild cognitive impairment. AB - The goal of this study was to assess the effect of novelty on correct recognition (hit minus false alarms) and on recollection and familiarity processes in normal aging and amnestic mild cognitive impairment (MCI). Recognition tasks compared well-known and novel stimuli in the verbal domain (words vs. pseudowords) and in the musical domain (well-known vs. novel melodies). Results indicated that novel materials associated with lower correct recognition and lower recollection, an effect that can be related to its lower amenability to elaborative encoding in comparison with well-known items. Results also indicated that normal aging impairs recognition of well-known items, whereas MCI impairs recognition of novel items only. Healthy older adults showed impaired recollection and familiarity relative to younger controls and individuals with MCI showed impaired recollection relative to healthy older adults. The recollection deficit in healthy older adults and persons with MCI and their impaired recognition of well known items is compatible with the difficulty both groups have in encoding information in an elaborate manner. In turn, familiarity deficit could be related to impaired frontal functioning. Therefore, novelty of material has a differential impact on recognition in persons with age-related memory disorders. PMID- 21703286 TI - fMRI evidence of a relationship between hypomania and both increased goal sensitivity and positive outcome-expectancy bias. AB - BACKGROUND: Mania is argued to stem from the dysfunctional processing of reward. Investigation of hypomania in healthy samples has the potential to offer refined insight into the particular aspects of reward processing in mania that are dysfunctional. METHOD: In this study, fMRI was employed in contrasting a sample of 12 unmedicated subclinical hypomanic individuals with a sample of 12 unmedicated controls in order to investigate reward-related processing in a reinforcement-learning task. RESULTS: Four findings in the hypomania-prone group relative to the control group supported atypical reward processing. Firstly, striatal activation that correlated with reward value and prediction error was stronger in response to cues and outcomes respectively, consistent with hypomania being related to an enhanced perception of the value of goals that may lead to reward. Secondly, value-related medial temporal activation was stronger in response to cues, suggesting that in hypomania-prone individuals, stimuli in memory were represented in accordance with their perceived value. Thirdly, these effects failed to be modulated by the actual value of outcomes, suggesting that hypomania is related to a decreased ability to discriminate between cues differing in value. Fourthly, increased insula activation in response to expected, but absent, reward was consistent with a bias towards expecting positive outcomes in decision-making. CONCLUSION: Together, the findings suggest that enhanced perception and representation of goal-value that nonetheless fails to discriminate on the basis of actual goal-value, coupled with a positive outcome-expectancy bias, could be causally related to insatiable and indiscriminate reward seeking in mania. PMID- 21703288 TI - Social stress and reproductive success in the female Syrian hamster: endocrine and behavioral correlates. AB - In many mammal species, reproduction is not shared equally among the members of a social unit. Even though reproductive skew seems unlikely in females of solitary species, this phenomenon could result from environmental factors. Although solitary in the wild, captive Syrian hamsters (Mesocricetus auratus) are generally housed in groups. We investigated whether social stress produces some degree of reproductive skew in this solitary species and whether female reproductive success varies as a function of social rank. To assess the physiological relationship between social stress and fertility, we monitored reproductive hormones and glucocorticoids of solitary and pair-housed females during pregnancy by means of recently established non-invasive methods for measuring hormone metabolites in the feces. The patterns of fecal progesterone, estrogen and glucocorticoid metabolites were similar to those found in blood and reported in the literature for pregnant hamsters. As expected, dominant females had higher breeding success than subordinate females. However the rate of reproductive failure was also very high among the singly housed females of our control group. The number of pups per litter, the average sex-ratio in each group, and the mean weight of pups did not differ significantly among groups. Glucocorticoid concentrations were unaffected by housing and social rank and the few differences between the endocrine profiles of singly- and pair-housed females are not sufficient to explain the observed difference in breeding success. It is likely that social isolation impairs reproduction in the same manner as subordination. Our findings suggest that social isolation of animals accustomed to group living was equally as disturbing as cohabitation with an unknown conspecific. PMID- 21703287 TI - Disrupted functional connectivity for controlled visual processing as a basis for impaired spatial working memory in schizophrenia. AB - Although regional brain abnormalities underlying spatial working memory (SWM) deficits in schizophrenia have been identified, little is known about which brain circuits are functionally disrupted in the SWM network in schizophrenia. We investigated SWM-related interregional functional connectivity in schizophrenia using functional magnetic resonance imaging (fMRI) data collected during a memory task that required analysis of spatial information in object structure. Twelve schizophrenia patients and 11 normal control subjects participated. Patients had SWM performance deficits and deficient neural activation in various brain areas, especially in the high SWM load condition. Examination of the covariation of regional brain activations elicited by the SWM task revealed evidence of functional disconnection between prefrontal and posterior visual association areas in schizophrenia. Under low SMW load, we found reduced functional associations between dorsolateral prefrontal cortex (DLPFC) and inferior temporal cortex (ITC) in the right hemisphere in patients. Under high SWM load, we found evidence for further functional disconnection in patients, including additional reduced functional associations between left DLPFC and right visual areas, including the posterior parietal cortex (PPC), fusiform gyrus, and V1, as well as between right inferior frontal cortex and right PPC. Greater prefrontal-posterior cortical functional connectivity was associated with better SWM performance in controls, but not in patients. These results suggest that prefrontal-posterior functional connectivity associated with the maintenance and control of visual information is central to SWM, and that disruption of this functional network underlies SWM deficits in schizophrenia. PMID- 21703289 TI - Pontine and thalamic influences on fluid rewards: III. Anticipatory contrast for sucrose and corn oil. AB - An anticipatory contrast effect (ACE) occurs when, across daily trials, an animal comes to respond less than normally to a first stimulus when it is followed shortly by a second, more preferred solution. Classically, ACE is studied using a low (L) concentration of saccharin or sucrose, followed by access to a higher (H) concentration of sucrose. Subjects in the control condition have two bouts of access to the weaker solution presented on the same schedule. The ACE is measured by the difference in intake of the first bout low solution between subjects in the low-low (L-L) vs. the low-high (L-H) conditions. Here we used this paradigm with sham feeding rats and determined that nutritional feedback was unnecessary for the development of ACE with two concentrations of sucrose or with two concentrations of corn oil. Next we showed that ibotenic acid lesions centered in the orosensory thalamus spared ACEs for both sucrose and corn oil. In contrast, lesions of the pontine parabrachial nuclei (PBN), the second central relay for taste in the rat, disrupted ACEs for both sucrose and corn oil. Although the sensory modalities needed for the oral detection of fats remain controversial, it appears that the PBN is involved in processing the comparison of disparate concentrations of sucrose and oil reward. PMID- 21703290 TI - Pontine and thalamic influences on fluid rewards: I. Operant responding for sucrose and corn oil. AB - The reward strength of orosensory sucrose and corn oil was measured using fixed and progressive ratio operant schedules. Because the orosensory effects of the stimuli were of interest, Experiment 1 compared operant responses for sucrose in sham and real feeding rats. The results demonstrated that rats would work for sucrose solutions without the accompanying postingestive effects. Furthermore, the break points for high concentrations of sucrose (1.0 M or 2.0 M) were significantly higher in sham feeding rats than in real feeding controls. Experiment 2 investigated the role of the parabrachial nucleus (PBN) and of the thalamic orosensory area (TOA) in sucrose and corn oil reward. During free access, rats with PBN lesions (PBNx) licked significantly less sucrose solution than their controls, but both groups ingested a similar volume of corn oil emulsion. When an operant was imposed, these same PBNx rats failed to respond for sucrose and continued only modestly for corn oil. In contrast, the TOA lesioned rats (TOAx) showed no impairment in responding for sucrose or corn oil during either the free access or operant sessions. Furthermore, rats with TOA lesions demonstrated significantly higher break points for sucrose than did their controls. Together, the data imply that the PBN but not the TOA is critical for the perception of, or responding to the reward value of sucrose and corn oil. PMID- 21703291 TI - Sulfur amino acid metabolism in doxorubicin-resistant breast cancer cells. AB - Although methionine dependency is a phenotypic characteristic of tumor cells, it remains to be determined whether changes in sulfur amino acid metabolism occur in cancer cells resistant to chemotherapeutic medications. We compared expression/activity of sulfur amino acid metabolizing enzymes and cellular levels of sulfur amino acids and their metabolites between normal MCF-7 cells and doxorubicin-resistant MCF-7 (MCF-7/Adr) cells. The S-adenosylmethionine/S adenosylhomocysteine ratio, an index of transmethylation potential, in MCF-7/Adr cells decreased to ~10% relative to that in MCF-7 cells, which may have resulted from down-regulation of S-adenosylhomocysteine hydrolase. Expression of homocysteine-clearing enzymes, such as cystathionine beta-synthase, methionine synthase/methylene tetrahydrofolate reductase, and betaine homocysteine methyltransferase, was up-regulated in MCF-7/Adr cells, suggesting that acquiring doxorubicin resistance attenuated methionine-dependence and activated transsulfuration from methionine to cysteine. Homocysteine was similar, which is associated with a balance between the increased expressions of homocysteine clearing enzymes and decreased extracellular homocysteine. Despite an elevation in cysteine, cellular GSH decreased in MCF-7/Adr cells, which was attributed to over-efflux of GSH into the medium and down-regulation of the GSH synthesis enzyme. Consequently, MCF-7/Adr cells were more sensitive to the oxidative stress induced by bleomycin and menadione than MCF-7 cells. In conclusion, our results suggest that regulating sulfur amino acid metabolism may be a possible therapeutic target for chemoresistant cancer cells. These results warrant further investigations to determine the role of sulfur amino acid metabolism in acquiring anticancer drug resistance in cancer cells using chemical and biological regulators involved in sulfur amino acid metabolism. PMID- 21703293 TI - Distractor-induced blindness for orientation changes and coherent motion. AB - The conscious perception of simple visual stimuli can be modulated by the presence of distractors. In the motion blindness paradigm, the detection of coherent motion is impaired when task-irrelevant motion distractors are presented prior to the target. Aim of this study was to examine the feature specificity of the distractor effect. For this reason, targets were either defined by motion coherence ("motion blindness") or orientation changes ("orientation blindness"). In a series of three experiments we show that distractors have to share the feature characteristics of the target in order to reduce its detectability. However, independent inhibition sets for visual features can be activated if the targets' characteristics are ambiguous. PMID- 21703292 TI - Gestational lead exposure selectively decreases retinal dopamine amacrine cells and dopamine content in adult mice. AB - Gestational lead exposure (GLE) produces supernormal scotopic electroretinograms (ERG) in children, monkeys and rats, and a novel retinal phenotype characterized by an increased number of rod photoreceptors and bipolar cells in adult mice and rats. Since the loss of dopaminergic amacrine cells (DA ACs) in GLE monkeys and rats contributes to supernormal ERGs, the retinal DA system was analyzed in mice following GLE. C57BL/6 female mice were exposed to low (27 ppm), moderate (55 ppm) or high (109 ppm) lead throughout gestation and until postnatal day 10 (PN10). Blood [Pb] in control, low-, moderate- and high-dose GLE was <= 1, <= 10, ~25 and ~40 MUg/dL, respectively, on PN10 and by PN30 all were <= 1 MUg/dL. At PN60, confocal-stereology studies used vertical sections and wholemounts to characterize tyrosine hydroxylase (TH) expression and the number of DA and other ACs. GLE dose-dependently and selectively decreased the number of TH immunoreactive (IR) DA ACs and their synaptic plexus without affecting GABAergic, glycinergic or cholinergic ACs. Immunoblots and confocal revealed dose-dependent decreases in retinal TH protein expression and content, although monoamine oxidase-A protein and gene expression were unchanged. High-pressure liquid chromatography showed that GLE dose-dependently decreased retinal DA content, its metabolites and DA utilization/release. The mechanism of DA selective vulnerability is unknown. However, a GLE-induced loss/dysfunction of DA ACs during development could increase the number of rods and bipolar cells since DA helps regulate neuronal proliferation, whereas during adulthood it could produce ERG supernormality as well as altered circadian rhythms, dark/light adaptation and spatial contrast sensitivity. PMID- 21703294 TI - Higher levels of heat shock proteins in longer-lived mammals and birds. AB - Cellular stress resistance is generally associated with longevity, but the mechanisms underlying this phenotype are not clear. In invertebrate models there is a clear role for heat shock proteins (Hsps) and organelle-specific unfolded protein responses (UPR) in longevity. However, this has not been demonstrated in vertebrates. Some Hsp amino acid sequences are highly conserved amongst mammals and birds. We used antibodies recognizing conserved regions of Hsp60 (primarily mitochondrial), Hsp70 (primarily cytosolic), GRP78 (Bip) and GRP94 (endoplasmic reticulum) to measure constitutive levels of these proteins in brain, heart and liver of 13 mammalian and avian species ranging in maximum lifespan from 3 to 30 years. In all three tissues, the expression of these proteins was highly correlated with MLSP, indicating higher basal levels of Hsp expression are characteristic of longer-lived species. We also quantified the levels of Hsp60, Hsp70 and GRP78 in brain and heart tissue of young adult (6-7 month old) Snell dwarf mice and normal littermates. Snell dwarf mice are characterized by a single gene mutation that is associated with an ~50% increase in lifespan. However, neither Hsp60, nor Hsp70, nor GRP78 levels were elevated in brain or heart tissue from Snell dwarf mice compared to normal littermates. PMID- 21703295 TI - Considerations for the use of cellular electrophysiology models within cardiac tissue simulations. AB - The use of mathematical models to study cardiac electrophysiology has a long history, and numerous cellular scale models are now available, covering a range of species and cell types. Their use to study emergent properties in tissue is also widespread, typically using the monodomain or bidomain equations coupled to one or more cell models. Despite the relative maturity of this field, little has been written looking in detail at the interface between the cellular and tissue level models. Mathematically this is relatively straightforward and well-defined. There are however many details and potential inconsistencies that need to be addressed, in order to ensure correct operation of a cellular model within a tissue simulation. This paper will describe these issues and how to address them. Simply having models available in a common format such as CellML is still of limited utility, with significant manual effort being required to integrate these models within a tissue simulation. We will thus also discuss the facilities available for automating this in a consistent fashion within Chaste, our robust and high-performance cardiac electrophysiology simulator. It will be seen that a common theme arising is the need to go beyond a representation of the model mathematics in a standard language, to include additional semantic information required in determining the model's interface, and hence to enhance interoperability. Such information can be added as metadata, but agreement is needed on the terms to use, including development of appropriate ontologies, if reliable automated use of CellML models is to become common. PMID- 21703296 TI - Adriamycin-related anxiety-like behavior, brain oxidative stress and myelotoxicity in male Wistar rats. AB - Chemotherapeutic regimens have been indicated to negatively impact the quality of life for patients. Adriamycin (ADR) is an effective chemotherapeutic agent widely employed for the treatment of human's malignancies; however, it may cause serious side effects. The present study was aimed at investigating the effects of acute administration of ADR on cognitive alterations, brain oxidative status and immune dysregulation in male Wistar rats. Treated animals received a single intraperitoneal injection of ADR (7 mg/kg). Control ones received physiological saline only. Behavioral effects were tested in the elevated plus-maze and the open field which showed that drug-treated rats displayed anxious behavior and deteriorations in the locomotive and exploratory activities over the 72 h following ADR injection as compared to controls. Assessment of brain antioxidant capacity in ADR-injected animals revealed an increase in glutathione-S transferase activities and malondialdehyde levels while a decrease in glutathione concentrations when compared with the vehicle-treated group. Our results indicated that ADR administration decreased total leukocyte, lymphocyte and granulocyte counts, while enhanced monocyte levels. Moreover, white blood cells (WBC) relative counts in ADR-treated rats showed a significant increase in monocytes and granulocytes and a decrease in lymphocytes as compared to controls. This study suggests that ADR-related cognitive impairments are associated with brain oxidative stress and myelosuppression. PMID- 21703298 TI - Behavioral consequences of the mGlu5 receptor antagonist MTEP in immature rats. AB - High doses of mGluR5 antagonists have anticonvulsant effects in multiple seizure models in both adult and immature animals. Data on potential behavioral effects in immature animals are very scarce. The present study investigated whether an antagonist of mGluR5 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) in doses proven to be anticonvulsant affects behavior in immature rats. Animals aged 12, 18 and 25 days received MTEP in doses of 20 and 40 mg/kg i. p. The sensorimotor performance was tested at 15 and 60 min after dosing. Locomotor exploratory behavior was tested at 20 and 65 min after dosing. An elevated plus maze was used to examine an adaptive form of learning and anxiety-like behavior in 18- and 25-day-old rats at 15, 60 min and 24h. MTEP slightly affected sensorimotor performance, regardless of age. In the open field test, MTEP decreased transiently locomotor-exploratory behavior but did not affect the habituation - a simple form of nonassociative learning. In the elevated plus maze, the drug did not impair transfer latency, an indicator of an adaptive form of learning and memory. An anxiolytic-like effect was observed at 60 min after drug administration. In conclusion, no severe impairment was observed after high anticonvulsant doses of mGlu5 antagonist MTEP in immature animals. PMID- 21703297 TI - Decreased response to social defeat stress in MU-opioid-receptor knockout mice. AB - Substantial evidence exists that opioid systems are involved in stress response and that changes in opioid systems in response to stressors affect both reward and analgesia. Reportedly, mice suffering chronic social defeat stress subsequently show aversion to social contact with unfamiliar mice. To further examine the role of opioid systems in stress response, the behavioral and neurochemical effects of chronic social defeat stress (psychosocial stress) were evaluated in MU-opioid-receptor knockout (MOR-KO) mice. Aversion to social contact was induced by chronic social defeat stress in wild-type mice but was reduced in MOR-KO mice. Moreover, basal expression of brain-derived neurotrophic factor (BDNF) mRNA in MOR-KO mice hippocampi was significantly lower than in wild type mice. Psychosocial stress significantly decreased BDNF mRNA expression in wild-type mice but did not affect BDNF expression in MOR-KO mice; no difference in basal levels of plasma corticosterone was observed. These results suggest that the MU-opioid receptor is involved in the behavioral sequelae of psychosocial stress and consequent regulation of BDNF expression in the hippocampus, and may play an important role in psychiatric disorders for which stress is an important predisposing or precipitating factor, such as depression, posttraumatic stress disorder, and social anxiety disorder. PMID- 21703299 TI - Chemical analysis and study of immunoenhancing and antioxidant property of a glucan isolated from an alkaline extract of a somatic hybrid mushroom of Pleurotus florida and Calocybe indica variety APK2. AB - A water-soluble glucan isolated from an alkaline extract of fruit bodies of a somatic hybrid mushroom PCH9FB of Pleurotus florida and Calocybe indica var. APK2 strains showed antioxidant properties with immune activation of macrophage, splenocyte, and thymocyte. On the basis of acid hydrolysis, methylation, periodate oxidation and NMR studies ((1)H, (13)C, DEPT-135, DQF-COSY, TOCSY, NOESY, ROESY, HMQC, and HMBC) the structure of the repeating unit of the glucan was established as: [structure: see text]. PMID- 21703300 TI - Molecular cloning and characterization of interferon regulatory factor 1 (IRF-1), IRF-2 and IRF-5 in the chondrostean paddlefish Polyodon spathula and their phylogenetic importance in the Osteichthyes. AB - The interferon regulatory factor (IRF) with its 10 members is a very important gene family related to innate immunity. Currently, most fish IRFs reported are from bony fish (teleosts). Cloning and sequencing of IRFs from chondrosteans, the so-called "ancient fish" including sturgeon, paddlefish, bichir and gar, are absent from the literature. In this study, three IRF genes PsIRF-1, PsIRF-2 and PsIRF-5, were cloned and characterized from the paddlefish (Polyodon spathula). PsIRF-1 includes an open reading frame (ORF) of 972 bp that encodes a putative protein of 324 amino acids; PsIRF-2 includes an ORF of 1023 bp encoding 341 amino acids and PsIRF-5 includes an ORF of 1491 bp that encodes 497 amino acids. The PsIRF-5 gene structure is similar to those in mammals but differs from those in teleosts in the first and second exons. Phylogenetic studies of the putative amino acid sequences of PsIRF-1, PsIRF-2 and PsIRF-5 based on the neighbor joining and Bayesian inference method for Osteichthyes found widely accepted inter-relationships among actinopterygians and tetrapods. Reverse Transcription Polymerase Chain Reaction (RT-PCR) analysis of PsIRF-1, PsIRF-2 and PsIRF-5 in different paddlefish tissues shows higher levels of expression in gill, spleen and head kidney. Poly (I: C) (polyinosinic-polycytidylic acid) stimulation in vivo up-regulated PsIRF-1 and PsIRF-2 expression, while PsIRF-5 gene expression did not respond to the challenge of Poly (I: C). PMID- 21703301 TI - Characterization of a scavenger receptor cysteine-rich-domain-containing protein of the starfish, Asterina pectinifera: ApSRCR1 acts as an opsonin in the larval and adult innate immune systems. AB - Proteins containing a scavenger receptor cysteine-rich (SRCR) domain (SRCR proteins) play an important role in the innate immune system of various metazoan animals. In the starfish Asterina pectinifera, mesenchyme cells and coelomocytes govern the two distinct innate immune systems of the larvae and adults, respectively. Here we identify a cDNA encoding a protein containing nine SRCR domains termed ApSRCR1, and present characterization of the molecular structure, expression, subcellular localization and function of ApSRCR1 protein during ontogenesis of this animal. ApSRCR1 protein is a membrane-type protein with a predicted molecular mass of approximately 120 kDa. During ontogenesis, ApSRCR1 protein is de novo synthesized and localizes to cytoplasmic vesicles in both mesenchyme cells and coelomocytes without translation of maternal mRNA; however, the net production and modification by N-glycosylation of ApSRCR1 protein differs in each cell type. In both types of cell, functional inhibition of ApSRCR1 protein leads to incompetent bacterial clearance and failure of aggregate formation. However, this inhibitory effect is weaker in the mesenchyme cells than in the coelomocytes. In the bacteria-sensitized adult, ApSRCR1 protein is up regulated and digested to enable its secretion into the coelomic fluid. This secreted form of ApSRCR1 protein can apparently bind to bacteria. Overall, we show that ApSRCR1 protein is finely regulated for expression not only during development but also in a sensitive innate immunological situation, and thereupon acts as an opsonin for bacteria to different extents in the larvae and adults of A. pectinifera. PMID- 21703303 TI - Glycerophospholipids and glycerophospholipid-derived lipid mediators: a complex meshwork in Alzheimer's disease pathology. AB - An increasing body of evidence suggested that intracellular lipid metabolism is dramatically perturbed in various cardiovascular and neurodegenerative diseases with genetic and lifestyle components (e.g., dietary factors). Therefore, a lipidomic approach was also developed to suggest possible mechanisms underlying Alzheimer's disease (AD). Neural membranes contain several classes of glycerophospholipids (GPs), that not only constitute their backbone but also provide the membrane with a suitable environment, fluidity, and ion permeability. In this review article, we focused our attention on GP and GP-derived lipid mediators suggested to be involved in AD pathology. Degradation of GPs by phospholipase A(2) can release two important brain polyunsaturated fatty acids (PUFAs), e.g., arachidonic acid and docosahexaenoic acid, linked together by a delicate equilibrium. Non-enzymatic and enzymatic oxidation of these PUFAs produces several lipid mediators, all closely associated with neuronal pathways involved in AD neurobiology, suggesting that an interplay among lipids occurs in brain tissue. In this complex GP meshwork, the search for a specific modulating enzyme able to shift the metabolic pathway towards a neuroprotective role as well as a better knowledge about how lipid dietary modulation may act to slow the neurodegenerative processes, represent an essential step to delay the onset of AD and its progression. Also, in this way it may be possible to suggest new preventive or therapeutic options that can beneficially modify the course of this devastating disease. PMID- 21703302 TI - Examination of the stimulatory signaling potential of a channel catfish leukocyte immune-type receptor and associated adaptor. AB - Expressed by various subsets of myeloid and lymphoid immune cells, channel catfish (Ictalurus punctatus) leukocyte immune-type receptors (IpLITRs) are predicted to play a key role in the initiation and termination of teleost cellular effector responses. These type I transmembrane proteins belong to the immunoglobulin superfamily and display features of immunoregulatory receptors with inhibitory and/or stimulatory signaling potential. Expanding on our previous work, which demonstrated that putative stimulatory IpLITR-types associated with the catfish adaptor proteins IpFcRgamma and FcRgamma-L, this study focuses on the functional significance of this immune receptor-adaptor signaling complex. Specifically, we generated an epitope-tagged chimeric receptor construct by fusing the extracellular domain of IpLITR 2.6b with the transmembrane region and cytoplasmic tail of IpFcRgamma-L. This chimera was stably expressed in a rat basophilic leukemia (RBL) cell line, RBL-2H3, and following cross-linking of the surface receptor with an anti-hemagglutinin monoclonal antibody or opsonized microspheres, the chimeric teleost receptor induced cellular degranulation and phagocytic responses, respectively. Site-directed mutagenesis of the immunoreceptor tyrosine-based activation motif encoded within the cytoplasmic tail of the chimera confirmed that these functional responses were dependent on the phosphorylated tyrosines within this motif. Using a combination of phospho specific antibodies and pharmacological inhibitors, we also demonstrate that the IpLITR/IpFcRgamma-L-induced degranulation response requires the activity of Src homology 2 domain containing protein tyrosine phosphatases, phosphatidylinositol 3-kinase, protein kinase C, and mitogen-activated protein kinases but appears independent of the c-Jun N-terminal kinase and p38 MAP kinase pathways. In addition to this first look at stimulatory IpLITR-mediated signaling and its influence on cellular effector responses, the advantage of generating RBL-2H3 cells stably expressing a functional IpLITR-adaptor chimera will be discussed. PMID- 21703304 TI - Anopheles gambiae mosquito isolated neurons: a new biological model for optimizing insecticide/repellent efficacy. AB - To understand better the mode of action of insecticides and repellents used in vector-borne diseases control, we developed a new biological model based on mosquito neurons isolated from adults Anopheles gambiae heads. This cellular model is well adapted to multidisciplinary approaches: electrophysiology, pharmacology, molecular biology and biochemical assays. Using RT-PCR, we demonstrated that isolated neurons express the nicotinic acetylcholine receptor subunit alpha1 (Agalpha1 nAchR), two acetylcholinesterases (AChE-1 and AChE-2) and three voltage-gated ion channels required for membrane excitability (AgCav1, AgNav1 and AgKv1). In order to correlate the expression of the different transcripts, encoding functional AgNav channel, nAChR receptor and AChE enzymes detected by RT-PCR, with electrophysiological activity we used patch-clamp technique. We revealed that AgNav and AChE which are targeted by insecticide and/or repellent were sensitive to the pyrethroid permethrin and to the repellent DEET, respectively. In addition, using colorimetric method, we also showed that AChE was sensitive to the carbamate propoxur. These results indicated that this novel neuronal mosquito model will lead to molecular and functional characterization of insecticide/repellent targets and appears as a powerful tool to investigate the development of highly specific and effective strategies for disease vector control. PMID- 21703305 TI - Propagation of classical swine fever virus in vitro circumventing heparan sulfate adaptation. AB - Amplification of natural virus isolates in permanent cell lines can result in adaptation, in particular enhanced binding to heparan sulfate (HS)-containing glycosaminoglycans present on most vertebrate cells. This has been reported for several viruses, including the pestivirus classical swine fever virus (CSFV), the causative agent of a highly contagious hemorrhagic disease in pigs. Propagation of CSFV in cell culture is essential in virus diagnostics and research. Adaptation of CSFV to HS-binding has been related to amino acid changes in the viral E(rns) glycoprotein, resulting in viruses with altered replication characteristics in vitro and in vivo. Consequently, a compound blocking the HS containing structures on cell surfaces was employed to monitor conversion from HS independency to HS-dependency. It was shown that the porcine PEDSV.15 cell line permitted propagation of CSFV within a limited number of passages without adaptation to HS-binding. The selection of HS-dependent CSFV mutants was also prevented by propagation of the virus in the presence of DSTP 27. The importance of these findings can be seen from the altered ratio of cell-associated to secreted virus upon acquisition of enhanced HS-binding affinity, a phenotype proposed previously to be related to virulence in the natural host. PMID- 21703306 TI - Development of a one step real time RT-PCR assay to detect and quantify Dugbe virus. AB - A one-step real time quantitative RT-PCR (qRT-PCR) assay was developed to detect all published Dugbe virus (DUGV) genomes of the Nairovirus genus. Primers and probes were designed to detect specific sequences on the most conserved regions of the S segment. The limit of detection of the assay was 10 copies per reaction which is an improvement of 3 log(10)FFU/mL over the sensitivity of conventional RT-PCR. The specificity of the primers and probe was confirmed with the closely related Nairoviruses CCHFV and Hazara virus, and on the non-related viruses Coronavirus and Influenza A virus. This qRT-PCR assay was used to screen nucleic acids extracted from 498 ticks collected in the Republic of Chad. One sample was found positive suggesting that DUGV is present in this part of the world. The molecular assay developed in this study is sensitive, specific and rapid and can be used for research and epidemiological studies. PMID- 21703307 TI - International interlaboratory trials on rabies diagnosis: an overview of results and variation in reference diagnosis techniques (fluorescent antibody test, rabies tissue culture infection test, mouse inoculation test) and molecular biology techniques. AB - Interlaboratory trials on rabies diagnosis were organised in 2009 and in 2010 by the European Union Reference Laboratory (EURL) for rabies. In 2009, two panels of virus samples were sent to participating laboratories to compare results on reference diagnosis techniques and on RT-PCR. A single panel was sent in 2010 to test FAT (fluorescent antibody test), RTCIT (rabies tissue culture infection test) and RT-PCR techniques. The virus panels included the RABV, EBLV-1, EBLV-2 and ABLV strains. Results revealed that laboratories produced the highest proportion of concordant results using RT-PCR (90.5%) and FAT (87.1%), followed by RTCIT (70.0%) and MIT (35.0%) in 2009 and in FAT (85.0%) and RT-PCR (80.6%) followed by RTCIT (77.3%) in 2010. Errors were only observed in bat strains (i.e. none in the RABV strain) for the RT-PCR or FAT techniques, highlighting the need to improve diagnosis most specifically in such strains. RT-PCR was the technique showing the lowest rate of false negative results in either trial year, while RTCIT and MIT (performed in 2009 only) were the techniques with the lowest proportion of false positive results. Nevertheless, the FAT technique represented a good compromise with both satisfactory sensitivity and specificity, as only a few false positive (1.6% in 2009, 5.8% in 2010) and false negative results (1.6% in both 2009 and 2010) were detected. The analysis of technical questionnaires describing the protocols used by participating laboratories revealed variation in the methods used that may induce inconsistencies in the results. In this study, the number of readers for FAT slide examination was identified as a factor affecting significantly the results of laboratories, suggesting that two independent readers are necessary for routine rabies diagnosis. Our findings highlight the need for all rabies diagnostic laboratories to improve harmonisation of procedures. PMID- 21703308 TI - Fluorescein and radiolabeled Function-Spacer-Lipid constructs allow for simple in vitro and in vivo bioimaging of enveloped virions. AB - Tools that can aid in vitro and in vivo imaging and also noninvasively determine half-life and biodistribution are required to advance clinical developments. A Function-Spacer-Lipid construct (FSL) incorporating fluorescein (FSL-FLRO4) was used to label vesicular stomatitis virus (VSV), measles virus MV-NIS (MV) and influenza virus (H1N1). The ability of FSL constructs to label these virions was established directly by FACScan of FSL-FLRO4 labeled VSV and MV, and indirectly following labeled H1N1 and MV binding to a cells. FSL-FLRO4 labeling of H1N1 was shown to maintain higher infectivity of the virus when compared with direct fluorescein virus labeling. A novel tyrosine (125)I radioiodinated FSL construct was synthesized (FSL-(125)I) from FSL-tyrosine. This was used to label VSV (VSV FSL-(125)I), which was infused into the peritoneal cavity of laboratory mice. Bioscanning showed VSV-FSL-(125)I to localize in the liver, spleen and bloodstream in contrast to the free labels FSL-(125)I or (125)I, which localized predominantly in the liver and thyroid respectively. This is a proof-of-principle novel and rapid method for modifying virions and demonstrates the potential of FSL constructs to improve in vivo imaging of virions and noninvasively observe in vivo biodistribution. PMID- 21703309 TI - Mutations in HCV non-structural genes do not contribute to resistance to nitazoxanide in replicon-containing cells. AB - Nitazoxanide (NTZ) exhibits potent antiviral activity against hepatitis C virus (HCV) in cell culture. Previously, HCV replicon-containing cell lines resistant to NTZ were selected, but transfer the HCV NTZ-resistance phenotype was not observed following transfection of whole cell RNA. To further explore the nature of the resistance of HCV to NTZ, full length HCV replicon sequences were obtained from two NTZ-resistant (NTZ-11, TIZ-9), and the parental (RP7) cell lines. Numerous nucleotide changes were observed in individual HCV genomes relative to the RP7 HCV consensus sequence, but no common mutations in the HCV non-structural genes or 3'-UTR were detected. A cluster of single nucleotide mutations was found within a 5-base portion of the 5'-UTR in 20/21 HCV replicon sequences from both resistant cell lines. Three mutations (5'-UTR G17A, G18A, C20U) were individually inserted into CON1 ('wild-type') HCV replicons, showed reduced replication (5 to 50-fold), but none conferred resistance to NTZ. RP7, NTZ-11, and TIZ-9 were cured of HCV genomes by serial passage under interferon. Transfection of cured NTZ-11 and TIZ-9 with either whole cell RNAs from RP7, NTZ-11, or TIZ-9, 'wild-type' or the 5'-UTR mutation-containing replicon RNAs exhibited an NTZ-resistance phenotype. TIZ (the active metabolite of NTZ) was found to be inactive against the activity of HCV polymerase, protease, and helicase in enzymatic assays. These data confirm previous speculations that HCV resistance to NTZ is not due to mutations in the virus, and demonstrate that HCV resistance and most likely the antiviral activity of TIZ are due to interactions with cellular target(s). PMID- 21703310 TI - Extracellular loops 1 and 3 and their associated transmembrane regions of the calcitonin receptor-like receptor are needed for CGRP receptor function. AB - The first and third extracellular loops (ECL) of G protein-coupled receptors (GPCRs) have been implicated in ligand binding and receptor function. This study describes the results of an alanine/leucine scan of ECLs 1 and 3 and loop associated transmembrane (TM) domains of the secretin-like GPCR calcitonin receptor-like receptor which associates with receptor activity modifying protein 1 to form the CGRP receptor. Leu195Ala, Val198Ala and Ala199Leu at the top of TM2 all reduced alphaCGRP-mediated cAMP production and internalization; Leu195Ala and Ala199Leu also reduced alphaCGRP binding. These residues form a hydrophobic cluster within an area defined as the "minor groove" of rhodopsin-like GPCRs. Within ECL1, Ala203Leu and Ala206Leu influenced the ability of alphaCGRP to stimulate adenylate cyclase. In TM3, His219Ala, Leu220Ala and Leu222Ala have influences on alphaCGRP binding and cAMP production; they are likely to indirectly influence the binding site for alphaCGRP as well as having an involvement in signal transduction. On the exofacial surfaces of TMs 6 and 7, a number of residues were identified that reduced cell surface receptor expression, most noticeably Leu351Ala and Glu357Ala in TM6. The residues may contribute to the RAMP1 binding interface. Ile360Ala impaired alphaCGRP-mediated cAMP production. Ile360 is predicted to be located close to ECL2 and may facilitate receptor activation. Identification of several crucial functional loci gives further insight into the activation mechanism of this complex receptor system and may aid rational drug design. PMID- 21703312 TI - High-throughput DNA isolation method for detection of Xylella fastidiosa in plant and insect samples. AB - We report an inexpensive, high-throughput method for isolating DNA from insect and plant samples for the purpose of detecting Xylella fastidiosa infection. Existing methods often copurify inhibitors of DNA polymerases, limiting their usefulness for PCR-based detection assays. When compared to commercially available kits, the method provides enhanced pathogen detection at a fraction of the cost. PMID- 21703311 TI - Parathyroid hormone and the regulation of cell cycle in colon adenocarcinoma cells. AB - Parathyroid hormone (PTH) functions as a major mediator of bone remodeling and as an essential regulator of calcium homeostasis. In this study, we investigated the role of PTH in the regulation of the cell cycle in human colon adenocarcinoma Caco-2 cells. Flow cytometry analysis revealed that PTH (10(-8)M, 12-24h) treatment increases the number of cells in the G0/G1 phase and diminishes the number in both phases S and G2/M. In addition, analysis by Western blot showed that the hormone increases the expression of the inhibitory protein p27Kip1 and diminishes the expression of cyclin D1, cyclin D3 and CDK6. However, the amounts of CDK4, p21Cip1, p15INK4B and p16INK4A were not different in the absence or presence of PTH. Inhibitors of PKC (Ro-318220, bisindolylmaleimide and chelerythine), but not JNK (SP600125) and PP2A (okadaic acid and calyculin A), reversed PTH response in Caco-2 cells. Taken together, our results suggest that PTH induces G0/G1 phase arrest of Caco-2 intestinal cells and changes the expression of proteins involved in cell cycle regulation via the PKC signaling pathway. PMID- 21703313 TI - Development of an adenovirus vector lacking the expression of virus-associated RNAs. AB - A major limitation of the use of adenovirus (Ad) vectors is the innate immune response, which causes inflammatory cytokine production and tissue damages. To overcome this limitation, it is necessary to develop safer Ad vectors that are less likely to induce innate immunity. The Ad genome encodes two non-coding small RNAs, virus-associated (VA)-RNA I and VA-RNA II, which are transcribed by RNA polymerase III and promote Ad replication. Recently, we reported that VA-RNAs are produced in the cells transduced with a conventional first-generation (E1 deleted) Ad vector (FG-Ad) and trigger innate immune responses through intracellular nucleic acid sensors. In the present study, we have developed a VA RNA-deleted Ad (AdDeltaVR) vector, in which the transcriptional control elements of the VA-RNA-expression were deleted. Although conventional HEK293 cells did not support the propagation of the AdDeltaVR vectors, HEK293 transformants inducibly expressing VA-RNA I (VR293 cells) with appropriate induction of VA-RNA I expression allowed the propagation of the AdDeltaVR vector. The AdDeltaVR vector showed high transduction efficiency comparable to that of the conventional FG-Ad vector in the cultured cells. The AdDeltaVR vector may be a safer alternative to the FG-Ad vector. PMID- 21703314 TI - Situation-specific cognitive behavioural self-therapy for erroneously suspected allergy or intolerance to a food. A short self-assessment tool. AB - The recall of personal experiences relevant to a claim of food allergy or food intolerance is assessed by a psychologically validated tool for evidence that the suspected food could have caused the adverse symptom suffered. The tool looks at recall from memory of a particular episode or episodes when food was followed by symptoms resulting in self-diagnosis of food allergy or intolerance compared to merely theoretical knowledge that such symptoms could arise after eating the food. If there is detailed recall of events that point to the food as a potential cause of the symptom and the symptom is sufficiently serious, the tool user is recommended to seek testing at an allergy clinic or by the appropriate specialist for a non-allergic sensitivity. If what is recalled does not support the logical possibility of a causal connection between eating that food and occurrence of the symptom, then the user of the tool is pointed to other potential sources of the problem. The user is also recommended to investigate remedies other than avoidance of the food that had been blamed. PMID- 21703315 TI - Antimicrobial proline-rich peptides from the hemolymph of marine snail Rapana venosa. AB - Hemolymph of Rapana venosa snails is a complex mixture of biochemically and pharmacologically active components such as peptides and proteins. Antimicrobial peptides are gaining attention as antimicrobial alternatives to chemical food preservatives and commonly used antibiotics. Therefore, for the first time we have explored the isolation, identification and characterisation of 11 novel antimicrobial peptides produced by the hemolymph of molluscs. The isolated peptides from the hemolymph applying ultrafiltration and reverse-phase high performance liquid chromatography (RP-HPLC) have molecular weights between 3000 and 9500 Da, determined by mass spectrometric analysis. The N-terminal sequences of the peptides identified by Edman degradation matched no peptides in the MASCOT search database, indicating novel proline-rich peptides. UV spectra revealed that these substances possessed the characteristics of protein peptides with acidic isoelectric points. However, no Cotton effects were observed between 190 and 280 nm by circular dichroism spectroscopy. Four of the pro-rich peptides also showed strong antimicrobial activities against tested microorganisms including Gram positive and Gram-negative bacteria. PMID- 21703316 TI - High content analysis to determine cytotoxicity of the antimicrobial peptide, melittin and selected structural analogs. AB - Antimicrobial peptides (AMPs) are naturally occurring entities with potential as pharmaceutical candidates and/or food additives. They are present in many organisms including bacteria, insects, fish and mammals. While their antimicrobial activity is equipotent with many commercial antibiotics, current limitations are poor pharmacokinetics, stability and potential toxicology issues. Most elicit antimicrobial action via perturbation of bacterial membranes. Consequently, associated cytotoxicity in human cells is reflected by their capacity to lyse erythrocytes. However, more rigorous toxicological assessment of AMPs is required in order to predict potential failure at a later stage of development. We describe a high-content analysis (HCA) screening protocol recently established for determination and prediction of safety in pharmaceutical drug discovery. HCA is a powerful, multi-parameter bioanalytical tool that amalgamates the actions of fluorescence microscopy with automated cell analysis software in order to understand multiple changes in cellular health. We describe the application of HCA in assessing cytotoxicity of the cytolytic alpha-helical peptide, melittin, and selected structural analogs. The data shows that structural modification of melittin reduces its cytotoxic action and that HCA is suitable for rapidly identifying cytotoxicity. PMID- 21703317 TI - Antimicrobial and antibiofilm activity of pleurocidin against cariogenic microorganisms. AB - Dental caries is a common oral bacterial infectious disease of global concern. Prevention and treatment of caries requires control of the dental plaque formed by pathogens such as Streptococcus mutans and Streptococcus sobrinus. Pleurocidin, produced by Pleuronectes americanus, is an antimicrobial peptide that exerts broad-spectrum activity against pathogenic bacteria and fungi. Moreover, pleurocidin shows less hemolysis and is less toxic than other natural peptides. In the present study, we investigated whether pleurocidin is an effective antibiotic peptide against common cariogenic microorganisms and performed a preliminary study of the antimicrobial mechanism. We assayed minimal inhibitory concentration (MIC), minimal bactericide concentration (MBC) and bactericidal kinetics and performed a spot-on-lawn assay. The BioFlux system was used to generate bacterial biofilms under controllable flow. Fluorescence microscopy and confocal laser scanning microscopy (CLSM) were used to analyze and observe biofilms. Scanning electron microscopy was used to observe the bacterial membrane. MIC and MBC results showed that pleurocidin had different antimicrobial activities against the tested oral strains. Although components of saliva could affect antimicrobial activity, pleurocidin dissolved in saliva still showed antimicrobial effects against oral microorganisms. Furthermore, pleurocidin showed a favorable killing effect against BioFlux flow biofilms in vitro. Our findings suggest that pleurocidin has the potential to kill dental biofilms and prevent dental caries. PMID- 21703318 TI - FK506 ameliorates cell death features in Huntington's disease striatal cell models. AB - Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by striatal neurodegeneration, involving apoptosis. FK506, an inhibitor of calcineurin (or protein phosphatase 3, formerly known as protein phosphatase 2B), has shown neuroprotective effects in several cellular and animal models of HD. In the present study, we show the protective effects of FK506 in two striatal HD models, primary rat striatal neurons treated with 3-nitropropionic acid (3-NP) and immortalized striatal STHdh cells derived from HD knock-in mice expressing normal (STHdh(7/7)) or full-length mutant huntingtin (FL-mHtt) with 111 glutamines (STHdh(111/111)), under basal conditions and after exposure to 3-NP or staurosporine (STS). In rat striatal neurons, FK506 abolished 3-NP-induced increase in caspase-3 activation, DNA fragmentation/condensation and necrosis. Nevertheless, in STHdh(111/111) cells under basal conditions, FK506 did not prevent, in a significant manner, the release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria, or alter Bax/Bcl-2 ratio, but significantly reverted caspase-3 activation. In STHdh(111/111) cells treated with 0.3mM 3-NP or 25 nM STS, linked to high necrosis, exposure to FK506 exerted no significant effects on caspase-3 activation. However, treatment of STHdh(111/111) cells exposed to 10nM STS with FK506 effectively prevented cell death by apoptosis and moderate necrosis. The results suggest that FK506 may be neuroprotective against apoptosis and necrosis under mild cell death stimulus in the presence of FLmHtt. PMID- 21703319 TI - Inducible astrocytic glucose transporter-3 contributes to the enhanced storage of intracellular glycogen during reperfusion after ischemia. AB - Glucose is a necessary source of energy to sustain cell activities and homeostasis in the brain, and enhanced glucose transporter (GLUT) activities are protective of cells during energy depletion including brain ischemia. Here we investigated whether and if so how the astrocytic expression of GLUTs crucial for the uptake of glucose changes in ischemic conditions. Under physiological conditions, cultured astrocytes primarily expressed GLUT1, and GLUT3 was only detected at extremely low levels. However, exposure to ischemic stress increased the expression of not only GLUT1 but also GLUT3. During ischemia, cultured astrocytes significantly increased production of the transcription factor nuclear factor-kappaB (NF-kappaB), leading to an increase in GLUT3 expression. Moreover, astrocytic GLUT3 was responsible for the enhanced storage of intracellular glucose during reperfusion, resulting in increased resistance to lethal ischemic stress. These results suggested that astrocytes promptly increase GLUT3 production in situations such as ischemia, and much glucose is quickly taken up, possibly contributing to the protection of astrocytes from ischemic damage. PMID- 21703320 TI - Expected epidemiological impact of the introduction of a partially effective HIV vaccine among men who have sex with men in Australia. AB - A trial of the ALVAC-AIDSVAX HIV vaccine was recently found to be partially effective in preventing HIV transmission among study participants in Thailand. The success of this trial means that vaccination may become a viable intervention for the prevention of HIV infection in the medium-term future. Assuming that the vaccine has similar relative protective effectiveness per exposure event for reducing transmission among men who have sex with men (MSM) in high-income settings we investigated the potential population-level impact of rolling out such a vaccine among MSM in New South Wales, Australia. Using a detailed individual-based transmission model that simulates a population of sexually active MSM it was found that one-off intervention of 60% or 30% coverage of a vaccine with characteristics like the ALVAX-AIDSVAX vaccine would likely reduce the cumulative incidence of HIV by 9.6% and 5.1%, respectively, over a 10-year period. Due to the waning of vaccine efficacy, a booster vaccination could be required to maintain this reduction in incidence over the long term. If the previously vaccinated population is given a booster vaccine, with the same protection conferred as with the initial vaccination, every 5 years or every 2 years then the cumulative incidence over 10 years for 60% coverage could be reduced by 14.4% and 22.8%, respectively. Such a weak vaccine, with boosting, may be a potential intervention strategy for the prevention of HIV infection in MSM in high-income countries if further trials show boosting to be safe, acceptable, and cost-effective. However, the moderately low population-level impact suggests that a public health strategy involving such a vaccine should be supplemented with other biomedical and educational strategies. PMID- 21703321 TI - The potential impact of RV144-like vaccines in rural South Africa: a study using the STDSIM microsimulation model. AB - BACKGROUND: The only successful HIV vaccine trial to date is the RV144 trial of the ALVAC/AIDSVAX vaccine in Thailand, which showed an overall incidence reduction of 31%. Most cases were prevented in the first year, suggesting a rapidly waning efficacy. Here, we predict the population level impact and cost effectiveness of practical implementation of such a vaccine in a setting of a generalised epidemic with high HIV prevalence and incidence. METHODS: We used STDSIM, an established individual-based microsimulation model, tailored to a rural South African area with a well-functioning HIV treatment and care programme. We estimated the impact of a single round of mass vaccination for everybody aged 15-49, as well as 5-year and 2-year re-vaccination strategies for young adults (aged 15-29). We calculated proportion of new infections prevented, cost-effectiveness indicators, and budget impact estimates of combined ART and vaccination programmes. RESULTS: A single round of mass vaccination with a RV144 like vaccine will have a limited impact, preventing only 9% or 5% of new infections after 10 years at 60% and 30% coverage levels, respectively. Revaccination strategies are highly cost-effective if vaccine prices can be kept below 150 US$/vaccine for 2-year revaccination strategies, and below 200 US$/vaccine for 5-year revaccination strategies. Net cost-savings through reduced need for HIV treatment and care occur when vaccine prices are kept below 75 US$/vaccine. These results are sensitive to alternative assumptions on the underlying sexual network, background prevention interventions, and individual's propensity and consistency to participate in the vaccination campaign. DISCUSSION: A modestly effective vaccine can be a cost-effective intervention in highly endemic settings. To predict the impact of vaccination strategies in other endemic situations, sufficient knowledge of the underlying sexual network, prevention and treatment interventions, and individual propensity and consistency to participate, is key. These issues are all best addressed in an individual based microsimulation model. PMID- 21703322 TI - The potential impact of a moderately effective HIV vaccine with rapidly waning protection in South Africa and Thailand. AB - BACKGROUND: Although published data from the recent ALVAC/AIDSVAX trial in Thailand (RV144) indicated the HIV vaccine provided very modest protection overall (31.2%), new analysis of trial data has suggested higher efficacy levels earlier in the follow-up period. CDC and UNAIDS organized several modeling research teams to explore the implications of the trial results and potential utility of this vaccine. METHODS: We explored the impact of a vaccine with moderate but rapidly waning protection (78%, 1.43 years) using an exponential decay function fit to trial data. We varied program coverage levels (20-80%), vaccine efficacy (30-90%), timing (single or multi-year programs), targeting (general or populations at higher risk), and background levels of all other prevention programs (constant or scaled-up). We simulated these various vaccination scenarios in two representative countries using demographic projections generated with Spectrum modeling software. We assumed the vaccine becomes available in 2020 and target coverage is achieved by 2025. RESULTS: A general vaccination strategy in South Africa covering 60% of the population, for example, would prevent 3.0 million infections between 2020 and 2030-36% of expected infections-and would be very effective, requiring only 39 vaccinations/infection averted. The same strategy in Thailand would prevent 81,000 infections-35% of expected infections-but would require 1725 vaccinations/infection averted. Targeting only populations at higher risk of exposure in Thailand would reduce total vaccinations given by more than ten-fold and would still prevent 52,000 infections-23% of expected infections-while requiring only 220 vaccinations/infection averted. Outcomes were sensitive to program coverage, vaccine efficacy and background levels of all other prevention programs. CONCLUSIONS: A vaccine with rapidly waning protection could have a substantial impact on the epidemic in South Africa and Thailand. Due to the short duration of effect, large numbers of vaccinations would be needed to maintain high population coverage levels. Further research into the immunological effects of booster vaccinations is warranted. PMID- 21703323 TI - Assessment of margin of exposure based on biomarkers in blood: an exploratory analysis. AB - In chemical risk assessment, exposures in humans are often compared to no observed-adverse-effect levels or benchmark doses for sensitive adverse responses ("points of departure") in laboratory species to assess whether a sufficient "margin of exposure" (MOE) is attained to ensure safety. Conventionally, the default target MOE based on external dose is drawn from uncertainty factors of 10 each for inter- and intra-species extrapolation. The increasing availability of blood-based biomonitoring data in humans as well as measured and modeled blood concentrations in laboratory animals in key studies underlying chemical risk assessments may allow assessments of MOE to be made by comparing blood concentrations of parent compound in humans compared to those in the laboratory species at the point of departure for the risk assessment. This exploratory analysis provides an initial evaluation of whether the default MOE of 100 typically applied on an external dose basis is protective when applied on the basis of comparison of blood concentrations between laboratory animals and humans. The evaluation is conducted using a generic physiologically-based pharmacokinetic model of the structure typically applied to volatile organic compounds. Additional considerations relative to other classes of compounds are also addressed. Based on this evaluation, for chemicals with characteristics consistent with the modeling conducted here under certain conditions, the default MOE of 100 is more protective when applied to comparative blood concentrations than when applied on an external dose basis. Depending upon the chemical characteristics, the toxicokinetic components of the inter- and/or intra-species uncertainty factor could be reduced or eliminated when inter- and intra-species comparisons and extrapolations are made based on blood concentrations of parent compound of interest. PMID- 21703324 TI - Effects of S-equol and natural S-equol supplement (SE5-OH) on the growth of MCF-7 in vitro and as tumors implanted into ovariectomized athymic mice. AB - Hormone replacement therapy (HRT) for treatment of menopausal symptoms is controversial because of reported breast cancer resulting from estrogen treatment and consequent estrogenic stimulation. S-equol, a natural metabolite of the soy isoflavone daidzein produced by intestinal bacteria, has been shown to ameliorate menopausal symptoms, with relatively low concomitant estrogenic receptor stimulation. Although synthesis of equol produces the racemate, the S-isomer may be produced in commercial amounts by bacterial fermentation of soy germ, during the production of the supplement SE5-OH. This study aims to investigate the effects of S-equol and SE5-OH on the growth of MCF-7 in vitro and in vivo. In vitro, purified S-equol, and the isoflavonoid mixture present in SE5-OH stimulated estrogenic transcriptional activity and proliferation of MCF-7-E10 cells, similar to that observed for genistein (another soy isoflavone), but at concentrations from 10(4)-fold to 10(6)-fold higher than seen with 17beta estradiol (E2). Ovariectomized (OVX) mice implanted with MCF-7-E10 cells were fed diets containing 250 or 500 ppm of purified S-equol, isoflavonoid mixture, or genistein. There were no significant differences in tumor growth between the treatment groups and control group. These results suggest that S-equol and natural S-equol in the supplement (SE5-OH), do not promote the progression of breast cancer. PMID- 21703325 TI - Comparative antihemolytic and radical scavenging activities of strawberry tree (Arbutus unedo L.) leaf and fruit. AB - The present study reports the antioxidant properties of Arbutus unedo L. leaf and fruit extracts using different in vitro assays including (i) reducing power, (ii) scavenging effect on DPPH free radicals, and (iii) inhibitory effect on AAPH induced hemolysis and lipid peroxidation in human erythrocytes. All assays demonstrated antioxidant efficiency for A. unedo L. aqueous extracts, being consistently higher in the leaf. EC(50) values for reducing power and DPPH radical scavenging activities were, respectively, 0.318 +/- 0.007 and 0.087 +/- 0.007 mg/mL for leaf, and 2.894 +/- 0.049 and 0.790 +/- 0.016 mg/mL for fruit extracts. Under the oxidative action of AAPH, A. unedo leaf and fruit extracts protected the erythrocyte membrane from hemolysis (IC(50) of 0.062 +/- 0.002 and 0.430 +/- 0.091 mg/mL, respectively) and decreased the levels of malondialdehyde, a breakdown product of lipid peroxidation (IC(50) of 0.075 +/- 0.014 and 0.732 +/ 0.452 mg/mL, respectively). In accordance with antioxidant activity, phenolic content was found to be significantly higher in leaf extract. To our knowledge, this is the first time that the antioxidant activity of A. unedo species is evaluated using human biological membranes. Overall, our results suggest that A. unedo leaves are a promising source of natural antioxidants with potential application in diseases mediated by free radicals. PMID- 21703326 TI - The antioxidant protection of CELLFOOD against oxidative damage in vitro. AB - CELLFOOD (CF) is an innovative nutritional supplement containing 78 ionic/colloidal trace elements and minerals combined with 34 enzymes and 17 amino acids, all suspended in a solution of deuterium sulfate. The aim of this study was to investigate, for the first time, the antioxidant properties of CF in vitro in different model systems. Three pathophysiologically relevant oxidants were chosen to evaluate CF protection against oxidative stress: hydrogen peroxide, peroxyl radicals, and hypochlorous acid. Both biomolecules (GSH and plasmid DNA) and circulating cells (erythrocytes and lymphocytes) were used as targets of oxidation. CF protected, in a dose-dependent manner, both GSH and DNA from oxidation by preserving reduced GSH thiol groups and supercoiled DNA integrity, respectively. At the same time, CF protected erythrocytes from oxidative damage by reducing cell lysis and GSH intracellular depletion after exposure to the oxidant agents. In lymphocytes, CF reduced the intracellular oxidative stress induced by the three oxidants in a dose-dependent manner. The overall in vitro protection of biomolecules and cells against free radical attacks suggests that CF might be a valuable coadjuvant in the prevention and treatment of various physiological and pathological conditions related to oxidative stress, from aging to atherosclerosis, from neurodegeneration to cancer. PMID- 21703327 TI - Induction of CCAAT/enhancer-binding protein-homologous protein by cigarette smoke through the superoxide anion-triggered PERK-eIF2alpha pathway. AB - Cigarette smoke triggers apoptosis through oxidative stress- and endoplasmic reticulum (ER) stress-dependent induction of CCAAT/enhancer-binding protein homologous protein (CHOP) (Tagawa et al., 2008. Free Radic. Biol. Med. 45, 50 59). We investigated roles of individual reactive oxygen/nitrogen species in the transcriptional induction of CHOP by cigarette smoke. Exposure of bronchial epithelial cells to O(2)(-), ONOO(-) or H(2)O(2) induced expression of CHOP, whereas NO alone did not. Induction of CHOP mRNA by cigarette smoke extract (CSE) was attenuated by scavengers for O(2)(-), ONOO(-) or NO, whereas scavenging H(2)O(2) did not affect the induction of CHOP. Like CSE, O(2)(-) and ONOO(-) caused activation of the CHOP gene promoter. Scavengers for O(2)(-), ONOO(-) or NO attenuated CSE-triggered activation of the CHOP gene promoter. CSE, O(2)(-) and ONOO(-) induced phosphorylation of protein kinase-like ER kinase (PERK) and eukaryotic translation initiation factor 2alpha (eIF2alpha) and caused induction of downstream activating transcription factor 4 (ATF4). Scavengers for O(2)(-), ONOO(-) or NO attenuated induction of ATF4 by CSE. Furthermore, dominant-negative inhibition of the PERK-eIF2alpha pathway exclusively suppressed CSE-triggered induction of CHOP and consequent apoptosis. These results suggest that O(2)(-) and ONOO(-) are selectively involved in CSE-triggered induction of CHOP and that the PERK-eIF2alpha pathway plays a crucial role in the induction of CHOP and apoptosis downstream of the particular reactive oxygen species. PMID- 21703328 TI - Transcriptomics identifies differences between ultrapure non-dioxin-like polychlorinated biphenyls (PCBs) and dioxin-like PCB126 in cultured peripheral blood mononuclear cells. AB - Polychlorinated biphenyls (PCBs) remain ubiquitously present in human lipids despite the ban on their production and use. Their presence can be chemically monitored in peripheral blood samples of the general population. We tested whether in vitro exposure to different PCB congeners induced different gene expression profiles in peripheral blood cells. We have isolated peripheral blood mononuclear cells (PBMC) from whole blood of 8 healthy individuals and exposed these cells in vitro to individual non-dioxin-like (NDL)-PCB congeners (PCB52, 138 or 180; 10MUM) or dioxin-like (DL)-PCB congener PCB126 (1MUM) during 18h. Differential gene expression response was measured using Agilent whole-human genome microarrays. Two-way ANOVA analysis of the data showed that both gender and PCB exposure are important factors influencing gene expression responses in blood cells. Hierarchical cluster analysis of genes influenced by PCB exposure, revealed that DL-PCB126 induced a different gene expression response compared to the NDL-PCBs. Biological interpretation of the results revealed that exposure to PCB126 induced the AhR signaling pathway, whereas the induction of nuclear receptor pathways by the NDL-PCBs was limited in blood cells. Nevertheless, molecular responses of blood cells to individual PCB congeners revealed significantly expressed genes that play a role in biological functions and processes known to be affected by PCB exposure in vivo. Observed gene expression changes in this in vitro model were found to be related to hepatotoxicity, immune and inflammatory response and disturbance of lipid and cholesterol homeostasis. PMID- 21703329 TI - In vivo and in vitro function of human UDP-galactose 4'-epimerase variants. AB - Type III galactosemia results from reduced activity of the enzyme UDP-galactose 4'-epimerase. Five disease-associated alleles (G90E, V94M, D103G, N34S and L183P) and three artificial alleles (Y105C, N268D, and M284K) were tested for their ability to alleviate galactose-induced growth arrest in a Saccharomyces cerevisiae strain which lacks endogenous UDP-galactose 4'-epimerase. For all of these alleles, except M284K, the ability to alleviate galactose sensitivity was correlated with the UDP-galactose 4'-epimerase activity detected in cell extracts. The M284K allele, however, was able to substantially alleviate galactose sensitivity, but demonstrated near-zero activity in cell extracts. Recombinant expression of the corresponding protein in Escherichia coli resulted in a protein with reduced enzymatic activity and reduced stability towards denaturants in vitro. This lack of stability may result from the introduction of an unpaired positive charge into a bundle of three alpha-helices near the surface of the protein. The disparities between the in vivo and in vitro data for M284K hGALE further suggest that there are additional, stabilising factors present in the cell. Taken together, these results reinforce the need for care in the interpretation of in vitro, enzymatic diagnostic tests for type III galactosemia. PMID- 21703330 TI - Effects of gender and age on anterior commissure volume. AB - The purpose of this study was to measure the average anterior commissure (AC) volume of normal subjects in their 20s or 40s and to determine the effects of gender and age on AC volume. Magnetic resonance brain images were obtained for 93 people in their 20s (46 men, 47 women) and 87 in their 40s (36 men, 51 women). To investigate the effect of gender and age on AC volume, two-way analysis of variance, which used gender (two levels) and age (two levels) as independent variables, was employed. For subjects in their 20s, there was no difference in AC volume between genders, but for those in their 40s, the AC volume of males was less than that of females. There was no difference in AC volume between females in their 20s or 40s; however, the AC volume of men in their 40s was less than that for those in their 20s. There were gender-influenced differences in AC volume changes related to aging. PMID- 21703331 TI - The localization and physiological effects of cannabinoid receptor 1 in the brain stem auditory system of the chick. AB - Fast, temporally-precise, and consistent synaptic transmission is required to encode features of acoustic stimuli. Neurons of nucleus magnocellularis (NM) in the auditory brain stem of the chick possess numerous adaptations to optimize the coding of temporal information. One potential problem for the system is the depression of synaptic transmission during a prolonged stimulus. The present study tested the hypothesis that cannabinoid receptor 1 (CB1) signaling may limit synaptic depression at the auditory nerve-NM synapse. In situ hybridization was used to confirm that CB1 mRNA is expressed in the cochlear ganglion; immunohistochemistry was used to confirm the presence of CB1 protein in NM. These findings are consistent with the common presynaptic locus of CB1 in the brain. Rate-dependent synaptic depression was then examined in a brain slice preparation before and after administration of WIN 55,212-2 (WIN), a potent CB1 agonist. WIN decreased the amplitude of excitatory postsynaptic currents (EPSCs) and also reduced depression across a train of stimuli. The effect was most obvious late in the pulse train and during high rates of stimulation. This CB1-mediated influence could allow for lower, but more consistent activation of NM neurons, which could be of importance for optimizing the coding of prolonged, temporally-locked acoustic stimuli. PMID- 21703332 TI - Differential modulation of the glutamate-nitric oxide-cyclic GMP pathway by distinct neurosteroids in cerebellum in vivo. AB - The glutamate-nitric oxide (NO)-cGMP pathway mediates many responses to activation of N-methyl-d-aspartate (NMDA) receptors, including modulation of some types of learning and memory. The glutamate-NO-cGMP pathway is modulated by GABAergic neurotransmission. Activation of GABA(A) receptors reduces the function of the pathway. Several neurosteroids modulate the activity of GABA(A) and/or NMDA receptors, suggesting that they could modulate the function of the glutamate NO-cGMP pathway. The aim of this work was to assess, by in vivo microdialysis, the effects of several neurosteroids with different effects on GABA(A) and NMDA receptors on the function of the glutamate-NO-cGMP pathway in cerebellum in vivo. To assess the effects of the neurosteroids on the glutamate-NO-cGMP pathway, they were administered through the microdialysis probe before administration of NMDA and the effects on NMDA-induced increase in extracellular cGMP were analyzed. We also assessed the effects of the neurosteroids on basal levels of extracellular cGMP. To assess the effects of neurosteroids on nitric oxide synthase (NOS) activity and on NMDA-induced activation of NOS, we also measured the effects of the neurosteroids on extracellular citrulline. Pregnanolone and tetrahydrodeoxy corticosterone (THDOC) behave as agonists of GABA(A) receptors and completely block NMDA-induced increase in cGMP. Pregnanolone but not THDOC also reduced basal levels of extracellular cGMP. Pregnenolone did not affect extracellular cGMP or its increase by NMDA administration. Pregnenolone sulfate increased basal extracellular cGMP and potentiated NMDA-induced increase in cGMP, behaving as an enhancer of NMDA receptors activation. Allopregnanolone and dehydroepiandrosterone sulphate behave as antagonists of NMDA receptors, increasing basal cGMP and blocking completely NMDA-induced increase in cGMP. Dehydroepiandrosterone sulphate seems to do this by activating sigma receptors. These data support the concept that, at physiological concentrations, different neurosteroids may rapidly modulate, in different ways and by different mechanisms, the function of the glutamate-NO-cGMP pathway and, likely, some forms of learning and memory modulated by this pathway. PMID- 21703333 TI - Molecular simulations probing Kushecarpin A as a new lipoxygenase inhibitor. AB - Zizyphus oxyphylla Edgew is used in Pakistan as a folk medicinal remedy for inflammatory conditions, pains especially rheumatic pain, fevers, allergy and diabetes. The aim of the current study was to scientifically validate the folk use of Z. oxyphylla Edgew by using the isolated compound in vitro and in vivo levels. Kushecarpin A was isolated from ethyl acetate fraction of the plant crude extract. Molecular docking simulations predicted Kushecarpin A as a potential new lipoxygenase (LOX) inhibitor. Kushecarpin A showed significant lipoxygenase inhibition (IC(50): 7.2 +/- 0.02 MUM) thus validated computational prediction. It also exhibited significant and highly significant inhibition (p < 0.05 and p < 0.01) of carrageenan-induced hind paw oedema at the doses of 5, 10 and 20 mg/kg. Kushecarpin A seems to be a potentially new anti-inflammatory compound responsible for anti-inflammatory activities of Z. oxyphylla Edgew. In vitro and in vivo anti-inflammatory inflammatory activities were found in good agreement with the folk medicinal use of Z. oxyphylla Edgew in inflammatory disorders. PMID- 21703334 TI - The complete mitochondrial genome of the leafminer Liriomyza sativae (Diptera: Agromyzidae): great difference in the A+T-rich region compared to Liriomyza trifolii. AB - The complete mitochondrial genome sequence of Liriomyza sativae Blanchard (15,551bp) was determined and analyzed in this study. The circular genome contained 37 genes including 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes and an A+T-rich region. The initiation codons of COI and ND1 were 'ATCA' and 'GTG', respectively. ND2 gene used the truncated termination codon 'T'. All the tRNA genes had the typical cloverleaf secondary structures except for tRNA(Ser(AGN)) gene, which was found with the absence of a DHU arm. In addition, a tRNA-like secondary structure (tRNA(Met)) was found in the A+T-rich region. The great difference was that the length of L. sativae A+T-rich region was 597bp shorter than that of Liriomyza trifolii (Burgess). Meanwhile, some minor differences such as 'TATA' block were also observed in L. sativae in contrast to 'TACA' block in L. trifolii. There were also some essential structure elements such as 'TATA' block, 'G(A)(n)T' block, poly-T stretch and stem-and-loop structure in the A+T-rich region of L. sativae mitochondrial genome. PMID- 21703335 TI - Yeast cell cycle transcription factors identification by variable selection criteria. AB - Identifying cell cycle transcription factors (TFs) is important for understanding the transcriptional regulation of the cell cycle process which controls the growth and development of all organisms. Existing computational approaches for identifying cell cycle TFs are mainly based on methods with a fixed selection criterion. That is, the same criterion was applied to each TF to determine whether it is a cell cycle TF or not. Since the characteristic of each TF may be quite different, it is not suitable to use a fixed selection criterion in identifying cell cycle TFs. Instead of using a fixed selection criterion, we propose a method with variable selection criteria to identify cell cycle TFs in yeast by integrating the ChIP-chip and cell cycle gene expression data. Our method is shown to outperform five existing methods which used the same ChIP-chip dataset as we did. Fifteen cell cycle TFs were identified by our approach, 12 of which are known cell cycle TFs, while the remaining three (Hap4, Reb1 and Tye7) are novel cell cycle TFs. The biological significance of our predictions is shown by four lines of indirect evidence derived from the protein-protein interaction data, TF mutant data, ChIP-chip data and the results of the previous computational studies. PMID- 21703336 TI - Ochratoxin A at nanomolar concentration perturbs the homeostasis of neural stem cells in highly differentiated but not in immature three-dimensional brain cell cultures. AB - Ochratoxin A (OTA), a fungal contaminant of basic food commodities, is known to be highly cytotoxic, but the pathways underlying adverse effects at subcytotoxic concentrations remain to be elucidated. Recent reports indicate that OTA affects cell cycle regulation. Therefore, 3D brain cell cultures were used to study OTA effects on mitotically active neural stem/progenitor cells, comparing highly differentiated cultures with their immature counterparts. Changes in the rate of DNA synthesis were related to early changes in the mRNA expression of neural stem/progenitor cell markers. OTA at 10nM, a concentration below the cytotoxic level, was ineffective in immature cultures, whereas in mature cultures it significantly decreased the rate of DNA synthesis together with the mRNA expression of key transcriptional regulators such as Sox2, Mash1, Hes5, and Gli1; the cell cycle activator cyclin D2; the phenotypic markers nestin, doublecortin, and PDGFRalpha. These effects were largely prevented by Sonic hedgehog (Shh) peptide (500ngml(-1)) administration, indicating that OTA impaired the Shh pathway and the Sox2 regulatory transcription factor critical for stem cell self renewal. Similar adverse effects of OTA in vivo might perturb the regulation of stem cell proliferation in the adult brain and in other organs exhibiting homeostatic and/or regenerative cell proliferation. PMID- 21703337 TI - Interaction of bispyridinium compounds with the orthosteric binding site of human alpha7 and Torpedo californica nicotinic acetylcholine receptors (nAChRs). AB - Standard treatment of poisoning by organophosphorus (OP) nerve agents with atropine and oximes lacks efficacy with different nerve agents. A direct pharmacologic intervention at the nicotinic acetylcholine receptor (nAChR) was proposed as an alternative therapeutic approach and promising in vitro and in vivo results were obtained with the bispyridinium compound SAD-128. In addition, a number of SAD-128 analogues improved neuromuscular transmission of soman poisoned diaphragms in vitro. We investigated the interaction of six of these SAD 128 analogues with the orthosteric binding site of the human alpha7 nAChR and Torpedo californica nAChR with a high-throughput assay using radioactive ligands. The determined affinity constants indicate a weak interaction of three test compounds (K(i) in the micromolar range) with both receptors, but no interaction could be recorded with the other three test compounds. The six SAD-128 analogues showed a low intrinsic inhibitory potency with human acetylcholinesterase (IC50 > 400 MUM). In conclusion, the results of the present study do not indicate a correlation between the affinity to the orthosteric binding site and the functional improvement of neuromuscular transmission and it is assumed that other mechanisms contribute to the therapeutic effect of the tested compounds. PMID- 21703338 TI - Homogeneous diffusion layer model of dissolution incorporating the initial transient phase. AB - Purpose of this paper is to describe characteristic features of dissolution data by using homogeneous model of dissolution with initial transient phase. To achieve the goal we consider a random lag time before the homogeneous phase of the dissolution begins. The resulting dissolution profiles are characterized by sigmoidal shape commonly observed in empirical dissolution data. Furthermore, probability distribution of repeated measurements at fixed time is deduced from the model and function describing variability of the data in dependency on time is proposed. Three examples with normal, exponential and gamma probability distribution of the lag time are presented. All the models are pairwise compared with the Weibull function with high similarity between them. The result offers an alternative interpretation for the frequently found fit of the Weibull model to experimental data. PMID- 21703339 TI - Evaluation of protein stability and in vitro permeation of lyophilized polysaccharides-based microparticles for intranasal protein delivery. AB - Biocompatible microparticles prepared by lyophilization were developed for intranasal protein delivery. To test for the feasibility of this formulation, stability of the incorporated protein and enhancement of in vitro permeation across the nasal epithelium were evaluated. Lyophilization was processed with hydroxypropylmethylcellulose (HPMC) or water soluble chitosan (WCS) as biocompatible polymers, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and d-alpha tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) as permeation enhancers, sugars as cryoprotectants and lysozyme as the model protein. As a result, microparticles ranging from 6 to 12MUm were developed where the maintenance of the protein conformation was verified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism and fluorescence intensity detection. Moreover, in vitro bioassay showed that the lysozyme activity was preserved during the preparation process while exhibiting less cytotoxicity in primary human nasal epithelial (HNE) cells. Results of the in vitro release study revealed slower release rate in these microparticles compared to that of the lysozyme itself. On the other hand, the in vitro permeation study exhibited a 9-fold increase in absorption of lysozyme when prepared in lyophilized microparticles with HPMC, HP-beta-CD and TPGS 1000 (F4 2). These microparticles could serve as efficient intranasal delivery systems for therapeutic proteins. PMID- 21703340 TI - A pharmaceutical study of doxorubicin-loaded PEGylated nanoparticles for magnetic drug targeting. AB - One of the new strategies to improve cancer chemotherapy is based on new drug delivery systems, like the polyethylene glycol-coated superparamagnetic iron oxide nanoparticles (PEG-SPION, thereafter called PS). In this study, PS are loaded with doxorubicin (DOX) anticancer drug, using a pre-formed DOX-Fe(2+) complex reversible at lower pH of tumour tissues and cancer cells. The DOX loaded PS (DLPS, 3% w/w DOX/iron oxide) present a hydrodynamic size around 60nm and a zeta potential near zero at physiological pH, both parameters being favourable for increased colloidal stability in biological media and decreased elimination by the immune system. At physiological pH of 7.4, 60% of the loaded drug is gradually released from the DLPS in ~2h. The intracellular release and distribution of DOX is followed by means of confocal spectral imaging (CSI) of the drug fluorescence. The in vitro cytotoxicity of the DLPS on MCF-7 breast cancer cells is equivalent to that of a DOX solution. The reversible association of DOX to the SPION surface and the role of polymer coating on the drug loading/release are discussed, both being critical for the design of novel stealth magnetic nanovectors for chemotherapy. PMID- 21703341 TI - Reversal of multidrug resistance by co-delivery of tariquidar (XR9576) and paclitaxel using long-circulating liposomes. AB - One of the major obstacles to the success of cancer chemotherapy is the multidrug resistance (MDR) often resulting due to the overexpression of drug efflux transporter pumps such as P-glycoprotein (P-gp). Highly efficacious third generation P-gp inhibitors, like tariquidar, have shown promising results in overcoming the MDR. However, P-gp is also expressed in normal tissues like blood brain barrier, gastrointestinal track, liver, spleen and kidney. To maximize the efficacy of P-gp inhibitor and reduce the systemic toxicity, it is important to limit the exposure of P-gp inhibitors and the anticancer drugs to normal tissues and increase their co-localization with tumor cells. In this study, we have investigated the co-delivery of the P-gp inhibitor, tariquidar, and cytotoxic drug, paclitaxel, into tumor cells to reverse the MDR using long-circulating liposomes. Tariquidar- and paclitaxel-loaded long-circulating liposomes showed significant resensitization of the resistant variant for paclitaxel, which could be correlated with an increased accumulation of paclitaxel in tumor cells. These results suggest that the co-delivery of the P-gp inhibitor, tariquidar, and the cytotoxicity inducer, paclitaxel, looks like a promising approach to overcome the MDR. PMID- 21703342 TI - Utilization of in vitro methods to determine the biocompatibility of intraocular lens materials. AB - In vitro methods for measuring the adhesion and viability of lens epithelial cells on implant devices are needed to assess material biocompatibility. We investigated whether the use of confocal microscopy and spectrophotometric methods could determine the viability and adhesion of cells on a silicone biomaterial. Human lens epithelial cells adhered to silicone were treated with 0.01% benzalkonium chloride (cationic surfactant), 0.1% sodium dodecyl sulfate (anionic surfactant), and 10% Tween 20 (nonionic surfactant). Cell viability was then assessed using two fluorescent dyes (calcein and ethidium homodimer-1). Adhesion was determined directly by measuring the number of attached cells after surfactant treatment and by an indirect method that utilized the colorimetric agent crystal violet. The number of viable cells remaining on the biomaterial was determined both immediately after exposure and after the cells were allowed to grow for 1 day following surfactant exposure. The measurements for adhesion showed that the anionic surfactant weakened cell surface binding more than the cationic or nonionic surfactant. This study demonstrated that confocal microscopy in conjunction with crystal violet as an indirect colorimetric indicator can quantify the viability and adhesion of human lens epithelial cells attached to a material surface. PMID- 21703343 TI - Fine particulate matter from urban ambient and wildfire sources from California's San Joaquin Valley initiate differential inflammatory, oxidative stress, and xenobiotic responses in human bronchial epithelial cells. AB - Environmental particulate matter (PM) exposure has been correlated with pathogenesis of acute airway inflammatory disease such as asthma and COPD. PM size and concentration have been studied extensively, but the additional effects of particulate components such as biological material, transition metals, and polycyclic aromatic hydrocarbons could also impact initial disease pathogenesis. In this study, we compared urban ambient particulate matter (APM) collected from Fresno, California with wildfire (WF) particulate matter collected from Escalon, California on early transcriptional responses in human bronchial epithelial cells (HBE). Global gene expression profiling of APM treated HBE activated genes related to xenobiotic metabolism (CYP 1B1), endogenous ROS generation and response genes (DUOX1, SOD2, PTGS2) and pro-inflammatory responses associated with asthma or COPD such as IL-1alpha, IL-1beta, IL-8, and CCL20. WF PM treatments also induced a pro-inflammatory gene response, but elicited a more robust xenobiotic metabolism and oxidative stress response. Inhibitor studies targeting endotoxin, ROS, and trace metals, found endotoxin inhibition had modest selective inhibition of inflammation while inhibition of hydrogen peroxide and transition metals had broad effects suggesting additional interactions with xenobiotic metabolism pathways. APM induced a greater inflammatory response while WF PM had more marked metabolism and ROS related responses. PMID- 21703344 TI - Distribution of vascular endothelial growth factor receptor-3/Flt4 mRNA in adult rat central nervous system. AB - Vascular endothelial growth factor receptor (VEGFR)-3/Flt4 binds VEGF-C and VEGF D with high affinity. It has been suggested to be involved in neurogenesis and adult neuronal function. However, little is known about the localization of VEGFR 3 in the adult central nervous system (CNS). The present study presents, to our knowledge, the first detailed mapping of VEGFR-3 mRNA expression in adult rat brain and spinal cord by using in situ hybridization and reverse transcription polymerase chain reaction analysis (RT-PCR). Varying VEGFR-3 expression intensity was detected in functionally diverse nuclei, with the highest levels in the mitral cells of the olfactory bulb, piriform cortex, anterodorsal thalamic nucleus, several nuclei of the hypothalamus, and the brainstem cranial nerve nuclei. VEGFR-3 mRNA was abundantly expressed in the ventral motor neurons of the spinal cord and in some circumventricular organs such as the median eminence and the area postrema. Moreover, the locus coeruleus and some of the nuclei of the reticular formation showed moderate-to-high hybridization signals. VEGFR-3 expression appeared to be localized mostly within neurons, but weak labeling was also found in some astrocytes. In particular, VEGFR-3 was highly expressed in ependymal cells of the ventral third ventricle and the median eminence, which were co-labeled with vimentin but not with glial fibrillary acidic protein, suggesting that these cells are tanycytes. RT-PCR analysis revealed similar levels of VEGFR-3 expression in all regions of the adult rat CNS. The specific but widespread distribution of VEGFR-3 mRNA in the adult rat CNS suggests that VEGFR-3 functions more broadly than expected, regulating adult neuronal function playing important roles in tanycyte function. PMID- 21703345 TI - HIF-1alpha stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells. AB - The "angiogenic switch" during tumor progression is increasingly recognized as a milestone event in tumorigenesis, although the surprising prometastatic effect of antiangiogenic therapies has recently shaken the scientific community. Tumor hypoxia has been singled out as a possible responsible factor in this prometastatic effect, although the molecular pathways are completely unknown. We report herein that human melanoma cells respond to hypoxia through a deregulation of the mitochondrial release of reactive oxygen species (ROS) by the electron transfer chain complex III. These ROS are mandatory to stabilize hypoxia inducible factor-1alpha (HIF-1alpha), the master transcriptional regulator of the hypoxic response. We found that melanoma cells sense hypoxia-enhancing expression/activation of the Met proto-oncogene, which drives a motogenic escape program. Silencing analyses revealed a definite hierarchy of this process, in which mitochondrial ROS drive HIF-1alpha stabilization, which in turn activates the Met proto-oncogene. This pathway elicits a clear metastatic program of melanoma cells, enhancing spreading on extracellular matrix, motility, and invasion of 3D matrices, as well as growth of metastatic colonies and the ability to form capillary-like structures by vasculogenic mimicry. Both pharmacological and genetic interference with mitochondrial ROS delivery or Met expression block the hypoxia-driven metastatic program. Hence, we propose that hypoxia-driven ROS act as a primary driving force to elicit an invasive program exploited by aggressive melanoma cells to escape from a hypoxic hostile environment. PMID- 21703346 TI - Bioavailability and variability of biphasic insulin mixtures. AB - Absorption of subcutaneously administered insulin is associated with considerable variability. Some of this variability was quantitatively explained for both soluble insulin and insulin suspensions in a recent contribution to this journal (Soeborg et al., 2009). In the present article, the absorption kinetics for mixtures of insulins is described. This requires that the bioavailability of the different insulins is considered. A short review of insulin bioavailability and a description of the subcutaneous depot thus precede the presentation of possible mechanisms associated with subcutaneous insulin degradation. Soluble insulins are assumed to be degraded enzymatically in the subcutaneous tissue. Suspended insulin crystals form condensed heaps that are assumed to be degraded from their surface by invading macrophages. It is demonstrated how the shape of the heaps affects the absorption kinetics. Variations in heap formation thus explain some of the additional variability associated with suspended insulins (e.g. NPH insulins) compared to soluble insulins. The heap model also describes how increasing concentrations of suspended insulins lead to decreasing bioavailability and lower values of Cmax. Together, the findings constitute a comprehensive, quantitative description of insulin absorption after subcutaneous administration. The model considers different concentrations and doses of soluble insulin, including rapid acting insulin analogues, insulin suspensions and biphasic insulin mixtures. The results can be used in both the development of novel insulin products and in the planning of the treatment of insulin dependent diabetic patients. PMID- 21703348 TI - Counter-intuitive enhancement in the dissolution of indomethacin with the incorporation of cohesive poorly water-soluble inorganic salt additives. AB - The objective of this work was to investigate the influence of various micronized poorly water-soluble inorganic materials on the dissolution and de-agglomeration behaviour of a micronized, poorly water-soluble model drug, indomethacin, from lactose interactive mixtures. Dissolution of indomethacin was studied using the USP paddle method and the data were modelled with multi-exponential equations using a nonlinear least squares algorithm in order to obtain key parameter estimates. The dispersion of indomethacin mixtures was measured by laser diffraction. The addition of aluminium hydroxide and calcium phosphate to binary mixtures of indomethacin counter-intuitively improved the dissolution rate of indomethacin due to significant increases in both the estimated initial concentration and dissolution rate constant of dispersed particles of indomethacin. While some enhancement was due to pH changes in the dissolution medium, the presence of these poorly water-soluble inorganic salts caused de agglomeration. Average particle size distributions indicated that the presence of aluminium hydroxide within the matrix of indomethacin had reduced the agglomerate concentration whilst increasing the dispersed particle concentration. These findings provide the first evidence of the ability of poorly water-soluble inorganic salts to enhance the de-agglomeration and dissolution of micronized powders, potentially translating to improved bioavailability of poorly water soluble drugs. PMID- 21703347 TI - Tryptophan-mPEGs: novel excipients that stabilize salmon calcitonin against aggregation by non-covalent PEGylation. AB - Protein aggregation, which is triggered by various factors, is still one of the most prevalent problems encountered during all stages of protein formulation development. In this publication, we present novel excipients, tryptophan-mPEGs (Trp-mPEGs) of 2 and 5 kDa molecular weight and suggest their use in protein formulation. The synthesis and physico-chemical characterization of the excipients are described. Possible cytotoxic and hemolytic activities of the Trp mPEGs were examined. Turbidity, 90 degrees static light scatter, intrinsic fluorescence, fluorescence after staining the samples with Nile Red and fluorescence microscopy were used to study the inhibitory effect of the Trp-mPEGs on the aggregation of salmon calcitonin (sCT) in different buffer systems and at various molar ratios. Aggregation of sCT was reduced significantly with increasing concentrations of Trp-mPEG 2 kDa. A 10-fold molar excess of Trp-mPEG 2 kDa suppressed almost completely the aggregation of sCT in 10mM sodium citrate buffer (pH 6) for up to 70 h. Trp-mPEG 5 kDa also reduced the aggregation of sCT, though less pronounced than Trp-mPEG 2 kDa. Low aggregation of sCT was measured after approximately 10 days in 10mM sodium citrate buffer, pH 5, with a 10-fold molar excess of Trp-mPEG 2 kDa. This paper shows that Trp-mPEGs are potent excipients in reducing the aggregation of sCT. Trp-mPEGs are superior to dansyl PEGs concerning the stabilization of sCT in a harsh environment, wherein sCT is prone to aggregation. Trp-mPEGs might therefore also be used for stabilization of other biopharmaceuticals prone to aggregation. PMID- 21703349 TI - The molecular identification of factor H and factor I molecules in rainbow trout provides insights into complement C3 regulation. AB - The complement system in vertebrates plays a crucial role in the elimination of pathogens. To regulate complement on self-tissue and to prevent spontaneous activation and systemic depletion, complement is controlled by both fluid-phase and membrane-bound inhibitors. One such inhibitor, complement factor I (CFI) regulates complement by proteolytic cleavage of components C3b and C4b in the presence of specific cofactors. Complement factor H (CFH), the main cofactor for CFI, regulates the alternative pathway of complement activation by acting in the breakdown of C3b to iC3b. To gain further insight into the origin of C3 regulation in bony fish we have cloned and characterized the CFI and CFH1 cDNAs in the rainbow trout (Oncorhynchus mykiss). In this study we report the primary sequence, the tissue expression profile, the polypeptide domain architecture and the phylogenetic analysis of trout CFI and CFH1 genes. The deduced amino acid sequences of trout CFI and CFH1 polypeptides exhibit 42% and 32% identity with human orthologs, respectively. RNA expression analysis showed that CFI is expressed differentially in trout tissues, while liver is the main source of CFH1 expression. Our data indicate that factor H and I genes have emerged during evolution as early as the divergence of teleost fish. PMID- 21703350 TI - Effects of transcranial direct current stimulation (tDCS) on human regional cerebral blood flow. AB - Transcranial direct current stimulation (tDCS) can up- and down-regulate cortical excitability depending on current direction, however our abilities to measure brain-tissue effects of the stimulation and its after-effects have been limited so far. We used regional cerebral blood flow (rCBF), a surrogate measure of brain activity, to examine regional brain-tissue and brain-network effects during and after tDCS. We varied the polarity (anodal and cathodal) as well as the current strength (0.8 to 2.0mA) of the stimulation. Fourteen healthy subjects were randomized into receiving either anodal or cathodal stimulation (two subjects received both, one week apart) while undergoing Arterial Spin Labeling (ASL) in the MRI scanner with an alternating off-on sampling paradigm. The stimulating, MRI-compatible electrode was placed over the right motor region and the reference electrode over the contralateral supra-orbital region. SPM5 was used to process and extract the rCBF data using a 10mm spherical volume of interest (VOI) placed in the motor cortex directly underneath the stimulating scalp electrode. Anodal stimulation induced a large increase (17.1%) in rCBF during stimulation, which returned to baseline after the current was turned off, but exhibited an increase in rCBF again in the post-stimulation period. Cathodal stimulation induced a smaller increase (5.6%) during stimulation, a significant decrease compared to baseline (-6.5%) after cessation, and a continued decrease in the post stimulation period. These changes in rCBF were all significant when compared to the pre-stimulation baseline or to a control region. Furthermore, for anodal stimulation, there was a significant correlation between current strength and the increase in rCBF in the on-period relative to the pre-stimulation baseline. The differential rCBF after-effects of anodal (increase in resting state rCBF) and cathodal (decrease in resting state rCBF) tDCS support findings of behavioral and cognitive after-effects after cathodal and anodal tDCS. We also show that tDCS not only modulates activity in the brain region directly underlying the stimulating electrode but also in a network of brain regions that are functionally related to the stimulated area. Our results indicate that ASL may be an excellent tool to investigate the effects of tDCS and its stimulation parameters on brain activity. PMID- 21703351 TI - Using a symbolic process model as input for model-based fMRI analysis: locating the neural correlates of problem state replacements. AB - In this paper, a model-based analysis method for fMRI is used with a high-level symbolic process model. Participants performed a triple-task in which intermediate task information needs to be updated frequently. Previous work has shown that the associated resource - the problem state resource - acts as a bottleneck in multitasking. The model-based method was used to locate the neural correlates of 'problem state replacements'. To analyze the fMRI data, we fit the computational process model to the behavioral data and regressed the model's activity against the fMRI data. The brain region responsible for the temporary representation of problem states, the inferior parietal lobule, and the brain region responsible for long-term storage of problem states, the inferior frontal gyrus were thus identified. These results show that model-based fMRI analyses can be performed using high-level symbolic cognitive models, enabling fine-grained exploratory fMRI research. PMID- 21703352 TI - Neural regions associated with self control and mentalizing are recruited during prosocial behaviors towards the family. AB - Prosocial decisions can be difficult because they often involve personal sacrifices that do not generate any direct, immediate benefits to the self. The current study used functional magnetic resonance imaging (fMRI) to understand how individuals decide to provide support to others. Twenty-five participants were scanned as they completed a task in which they made costly decisions to contribute money to their family and noncostly decisions to accept personal monetary rewards. Decisions to contribute to the family recruited brain regions involved in self-control and mentalizing, especially for individuals with stronger family obligation preferences. Psychophysiological interaction (PPI) analyses revealed that individuals with stronger family obligation preferences showed greater functional coupling between regions involved in self-control and mentalizing with the ventral striatum, a region involved in reward processing. These findings suggest that prosocial behavior may require both social cognition and deliberate effort, and the application of these processes may result in greater positive reinforcement during prosocial behavior. PMID- 21703354 TI - Coupling between spontaneous (resting state) fMRI fluctuations and human oculo motor activity. AB - The recent discovery of incessant spontaneous fluctuations in human brain activity (also termed resting state fMRI) has been a focus of intense research in brain imaging. The spontaneous BOLD activity shows organized anatomical specialization as well as disruption in a number of brain pathologies. The link between the spontaneous fMRI fluctuations and human behavior is therefore of acute interest and importance. Here we report that a highly significant correlation exists between spontaneous BOLD fluctuations and eye movements which occur subliminally and spontaneously in the absence of any visual stimulation. Of the various eye movement parameters tested, we found robust and anatomically consistent correlations with both the amplitude and velocity of spontaneous eye movements. Control experiments ruled out a contribution of spatial and visual attention as well as smooth pursuit eye movements to the effect. The consistent anatomical specificity of the correlation patterns and their tight temporal link at the proper hemodynamic delay argues against a non-neuronal explanation of the effect, such as cardiac or respiratory cycles. Our results thus demonstrate a link between resting state and spontaneously emerging subconscious oculo-motor behavior. PMID- 21703353 TI - Imaging of sialidase activity in rat brain sections by a highly sensitive fluorescent histochemical method. AB - Sialidase (EC 3.2.1.18) removes sialic acid from sialoglycoconjugates. Since sialidase extracellularly applied to the rat hippocampus influences many neural functions, including synaptic plasticity and innervations of glutamatergic neurons, endogenous sialidase activities on the extracellular membrane surface could also affect neural functions. However, the distribution of sialidase activity in the brain remains unknown. To visualize extracellular sialidase activity on the membrane surface in the rat brain, acute brain slices were incubated with 5-bromo-4-chloroindol-3-yl-alpha-d-N-acetylneuraminic acid (X Neu5Ac) and Fast Red Violet LB (FRV LB) at pH 7.3. After 1h, myelin-abundant regions showed intense fluorescence in the rat brain. Although the hippocampus showed weak fluorescence in the brain, mossy fiber terminals in the hippocampus showed relatively intense fluorescence. These fluorescence intensities were attenuated with a sialidase-specific inhibitor, 2,3-dehydro-2-deoxy-N acetylneuraminic acid (DANA, 1mM). Additionally, the fluorescence intensities caused by X-Neu5Ac and FRV LB were correlated with the sialidase activity measured with 4-methylumbelliferyl-alpha-d-N-acetylneuraminic acid (4MU-Neu5Ac), a classical substrate for quantitative measurement of sialidase activity, in each brain region. Therefore, staining with X-Neu5Ac and FRV LB is specific for sialidase and useful for quantitative analysis of sialidase activities. The results suggest that white matter of the rat brain has intense sialidase activity. PMID- 21703355 TI - Spurious 99% bootstrap and jackknife support for unsupported clades. AB - Quantifying branch support using the bootstrap and/or jackknife is generally considered to be an essential component of rigorous parsimony and maximum likelihood phylogenetic analyses. Previous authors have described how application of the frequency-within-replicates approach to treating multiple equally optimal trees found in a given bootstrap pseudoreplicate can provide apparent support for otherwise unsupported clades. We demonstrate how a similar problem may occur when a non-representative subset of equally optimal trees are held per pseudoreplicate, which we term the undersampling-within-replicates artifact. We illustrate the frequency-within-replicates and undersampling-within-replicates bootstrap and jackknife artifacts using both contrived and empirical examples, demonstrate that the artifacts can occur in both parsimony and likelihood analyses, and show that the artifacts occur in outputs from multiple different phylogenetic-inference programs. Based on our results, we make the following five recommendations, which are particularly relevant to supermatrix analyses, but apply to all phylogenetic analyses. First, when two or more optimal trees are found in a given pseudoreplicate they should be summarized using the strict consensus rather than frequency-within-replicates approach. Second jackknife resampling should be used rather than bootstrap resampling. Third, multiple tree searches while holding multiple trees per search should be conducted in each pseudoreplicate rather than conducting only a single search and holding only a single tree. Fourth, branches with a minimum possible optimized length of zero should be collapsed within each tree search rather than collapsing branches only if their maximum possible optimized length is zero. Fifth, resampling values should be mapped onto the strict consensus of all optimal trees found rather than simply presenting the >= 50% bootstrap or jackknife tree or mapping the resampling values onto a single optimal tree. PMID- 21703356 TI - In vitro interactions between Fusarium verticillioides and Ustilago maydis through real-time PCR and metabolic profiling. AB - The goal of this research was to determine mechanisms of interaction between endophytic strains of Fusarium verticillioides (Sacc.) Nirenberg and the pathogen, Ustilago maydis (DC) (Corda). Endophytic strains of the fungus F. verticillioides are commonly found in association with maize (Zea mays) and when co-inoculated with U. maydis, often lead to decreased disease severity caused by the pathogen. Here, we developed methods (liquid chromatography-mass spectrometry) to evaluate changes in relative concentration of metabolites produced during in vitro interactions between the endophyte and pathogen. Fungi were grown on two different media, in single and in confronted cultures. We used real-time PCR (qPCR) assays to measure relative changes in fungal biomass, that occurred in confronted cultures compared to single cultures. The results showed that most secondary metabolites are constitutively produced by each species. Metabolite profiles are complex for U. maydis (twenty chromatographic peaks detected) while relatively fewer compounds were detected for F. verticillioides (six chromatographic peaks). In confronted cultures, metabolite ratio (metabolite concentration/biomass) generally increases for U. maydis metabolites while no significant changes were observed for most F. verticillioides metabolites. The results show that F. verticillioides is a strong antagonist of U. maydis as its presence leads to large reductions in U. maydis biomass. We infer that few U. maydis metabolites likely serve antibiotic functions against F. verticillioides. The methods described here are sufficiently sensitive to detect small changes in biomass and metabolite concentration associated with differing genotypes of the interacting species. PMID- 21703357 TI - Nitric oxide activates Nrf2 through S-nitrosylation of Keap1 in PC12 cells. AB - Nitric oxide (NO) exerts bifunctional effects on cell survival. While a high concentration of NO is cytotoxic, a relatively low concentration of NO promotes cytoprotection and cell survival. However, the molecular mechanism underlying the cytoprotective effect of NO remains poorly understood. One of the transcription factors that confer cellular protection against oxidative stress is NF-E2-related factor 2 (Nrf2), which is sequestered in the cytoplasm by forming an inactive complex with Klech-like ECH-associated protein 1 (Keap1). Previous studies suggested that various stimuli could induce the dissociation of Nrf2 from Keap1 in cytosol and/or promote its nuclear translocation by activating several upstream kinases. NO-mediated thiol modification in Keap1 has also been proposed as a possible mechanism of Nrf2 activation. Since NO can modify the function or activity of target proteins through S-nitrosylation of cysteine, we attempted to investigate whether the cytoprotective effect of NO is mediated through Nrf2 activation by directly modifying cysteine residues of Keap1. Our present study reveals that treatment of rat pheochromocytoma (PC12) cells with an NO donor S nitroso-N-acetylpenicillamine (SNAP) induced nuclear translocation and DNA binding of Nrf2. Under the same experimental conditions, there was NO-mediated S nitrosylation of Keap1 observed, which coincided with the Nrf2 activation. Moreover, SNAP treatment caused phosphorylation of Nrf2, and pharmacological inhibition of protein kinase C (PKC) abolished the phosphorylation and nuclear localization of Nrf2. In conclusion, NO can activate Nrf2 by S-nitrosylation of Keap1 and alternatively by PKC-catalyzed phosphorylation of Nrf2 in PC12 cells. PMID- 21703358 TI - Polymorphisms in nitric-oxide synthase 3 may influence the risk of urinary bladder cancer. AB - Nitric oxide (NO) is an important biological messenger known to influence several types of human cancers. NO formation is catalyzed by three different nitric oxide synthase (NOS) enzymes. In this study we analyzed if the NOS3 promoter polymorphism -786T>C (rs2070744) and the NOS3 Glu298Asp polymorphism in exon 7 (rs1799983) influence risk and pathogenesis of urinary-bladder cancer. Allelic discrimination and DNA sequencing were used to determine the -786T>C and the Glu298Asp NOS3 genotypes in 359 urinary-bladder cancer patients, from a population-based patient material, and 164 population controls. Patient genotypes were combined with information on tumor stage, grade, stage and grade progression and cancer-specific death, using a 5-year clinical follow-up. A threefold increased odds ratio for bladder cancer was found in homozygous carriers of the C allele of the -786T>C promoter polymorphism (p=0.017). No increased bladder cancer risk was found for the Glu298Asp polymorphism, but there was an association between the Glu298Asp and tumor grade (p=0.040). Our results suggest that the NOS3 promoter polymorphism -786T>C may influence bladder cancer risk. PMID- 21703359 TI - Influence of genetic variation of the beta2-adrenergic receptor on lung diffusion in patients with cystic fibrosis. AB - RATIONALE: Cystic fibrosis (CF) is a disease that adversely affects the lung resulting in a reduction in lung diffusion. Stimulation of the beta(2)-adrenergic receptors mediates mucociliary clearance and bronchodilation. We sought to determine the influence of an inhaled beta-agonist on the diffusing capacity of the lungs for carbon monoxide (DLCO), alveolar-capillary membrane conductance (D(M)), pulmonary capillary blood volume (Vc), and peripheral oxygen saturation (SaO(2)) in subjects with CF, when compared to matched healthy subjects, according to genetic variation of the beta(2)-adrenergic receptor (ADRB2). METHODS: To determine this we recruited 18 subjects with CF and 20 healthy subjects (age = 23 +/- 7 vs. 24+/-4years; ht = 168 +/- 8 vs. 174 +/- 12 cm; wt = 64 +/- 16 vs. 70 +/- 13 kg; BMI = 23 +/- 4 vs. 23+/-3 kg/m(2); FEV(1) = 72 +/- 27 vs. 92 +/- 12%pred; VO(2peak) = 45 +/- 25 vs. 99 +/- 24%pred, p < 0.05 for FEV(1) and VO(2peak), mean +/- SD, for CF and healthy, respectively). The study involved measurement of DLCO, D(M), V(C) and SaO(2) before and 30, 60, and 90 min following the administration of inhaled albuterol. Subjects were stratified according to genetic variation of ADRB2, Gln(27)Gln vs. Glu(27)Glu/Gln(27)Glu. RESULTS: Within the healthy group, there were no differences in DLCO, D(M), V(C), D(M)/V(C) at baseline or in response to albuterol according to genetic variation of the ADRB2 at amino acid 27. Within the CF group, the Glu(27)Glu/Gln(27)Glu group had higher D(M)/V(C) and SaO(2) when compared to the Gln(27)Gln group at baseline (p < 0.05). Both genotype groups demonstrated a significant decline in V(C) and an improvement in D(M)/V(C) and SaO(2) in response to albuterol. Subjects with the Glu(27) genotype experienced a greater improvement in D(M)/V(C) with albuterol when compared to subjects homozygous for Gln at amino acid 27. CONCLUSION: These results suggest that there are differences in lung diffusion and peripheral SaO(2) according to genetic variation of the ADRB2 at position 27 which could play a potential role in dosing options or adjustments that may be required according to genotype. PMID- 21703361 TI - Physiology and mRNA expression in rainbow trout (Oncorhynchus mykiss) after long term exposure to the new antifoulant medetomidine. AB - Medetomidine is under evaluation for use as an antifouling agent, and its effects on non-target aquatic organisms are therefore of interest. In this study, rainbow trout was exposed to low (0.5 and 5.0nM) concentrations of medetomidine for up to 54 days. Recently we have reported on effects on paleness and melanophore aggregation of medetomidine in these fish. Here, specific growth rates were investigated together with a broad set of physiological parameters including plasma levels of growth hormone (GH), insulin-like growth factor-I (IGF-I) and leptin, glucose and haemoglobin (Hb), hematocrit (Ht), condition factor, liver and heart somatic indexes (LSI, HSI). Hepatic enzyme activities of CYP1A (EROD activity), glutathione S-transferases (GST) and glutathione reductase (GR) were also measured. Additionally, hepatic mRNA expression was analysed through microarray and quantitative PCR in fish sampled after 31 days of exposure. Medetomidine at both concentrations significantly lowered blood glucose levels and the higher concentration significantly reduced the LSI. The mRNA expression analysis revealed few differentially expressed genes in the liver and the false discovery rate was high. Taken together, the results suggest that medetomidine at investigated concentrations could interfere with carbohydrate metabolism of exposed fish but without any clear consequences for growth. PMID- 21703362 TI - Detection of chromosomal abnormalities using high resolution arrays in clinical cancer research. AB - In clinical cancer research, high throughput genomic technologies are increasingly used to identify copy number aberrations. However, the admixture of tumor and stromal cells and the inherent karyotypic heterogeneity of most of the solid tumor samples make this task highly challenging. Here, we propose a robust two-step strategy to detect copy number aberrations in such a context. A spatial mixture model is first used to fit the preprocessed data. Then, a calling algorithm is applied to classify the genomic segments in three biologically meaningful states (copy loss, copy gain and modal copy). The results of a simulation study show the good properties of the proposed procedure with complex patterns of genomic aberrations. The interest of the proposed procedure in clinical cancer research is then illustrated by the analysis of real lung adenocarcinoma samples. PMID- 21703360 TI - Attenuation of multi-targeted proliferation-linked signaling by 3,3' diindolylmethane (DIM): from bench to clinic. AB - Emerging evidence provide credible support in favor of the potential role of bioactive products derived from ingesting cruciferous vegetables such as broccoli, brussel sprouts, cauliflower and cabbage. Among many compounds, 3,3' diindolylmethane (DIM) is generated in the acidic environment of the stomach following dimerization of indole-3-carbinol (I3C) monomers present in these classes of vegetables. Both I3C and DIM have been investigated for their use in preventing, inhibiting, and reversing the progression of cancer - as a chemopreventive agent. In this review, we summarize an updated, wide-ranging pleiotropic anti-tumor and biological effects elicited by DIM against tumor cells. It is unfeasible to point one single target as basis of cellular target of action of DIM. We emphasize key cellular and molecular events that are effectively modulated in the direction of inducing apoptosis and suppressing cell proliferation. Collectively, DIM orchestrates signaling through Ah receptor, NF kappaB/Wnt/Akt/mTOR pathways impinging on cell cycle arrest, modulation of key cytochrome P450 enzymes, altering angiogenesis, invasion, metastasis and epigenetic behavior of cancer cells. The ability of DIM to selectively induce tumor cells to undergo apoptosis has been observed in preclinical models, and thus it has been speculated in improving the therapeutic efficacy of other anticancer agents that have diverse molecular targets. Consequently, DIM has moved through preclinical development into Phase I clinical trials, thereby suggesting that DIM could be a promising and novel agent either alone or as an adjunct to conventional therapeutics such as chemo-radio and targeted therapies. An important development has been the availability of DIM formulation with superior bioavailability for humans. Therefore, DIM appears to be a promising chemopreventive agent or chemo-radio-sensitizer for the prevention of tumor recurrence and/or for the treatment of human malignancies. PMID- 21703363 TI - The in vivo behavior and antitumor activity of doxorubicin-loaded poly(gamma benzyl l-glutamate)-block-hyaluronan polymersomes in Ehrlich ascites tumor bearing BalB/c mice. AB - The in vivo efficacy of doxorubicin (DOX)-loaded poly(gamma-benzyl l-glutamate) block-hyaluronan (PBLG(23)-b-HYA(10))-based polymersomes (PolyDOX) was evaluated. Samples were efficiently labeled with technetium-99m radionuclide with good stability for in vivo studies. PolyDOX enhanced circulation time compared to free DOX. Biodistribution studies revealed selective accumulation of PolyDOX in the Ehrlich ascites tumor (EAT) as a result of passive accumulation and active targeting (CD44-mediated endocytosis) in EAT-bearing mice. Toxicity studies demonstrated PolyDOX is a safe drug carrier, and no hemolysis was observed with PolyDOX equivalent to 200 MUg/mL of free DOX. PolyDOX dominantly controlled tumor growth by delaying doubling time of EATs compared to free DOX over 30 days after treatment. PolyDOX also increased life span six times more than free DOX. Hence, it is reasonable to expect that higher DOX levels attributable to PolyDOX improve the therapeutic index and reduce side effects due to site-specific drug accumulation. FROM THE CLINICAL EDITOR: In this preclinical project, doxorubicin loaded polymersomes enhanced intracellular uptake of doxorubicin in a murine model of Ehrlich Ascites Tumor (EAT) through CD44 receptor mediated endocytosis, resulting in prolonged Tumor Doubling Time and increase in life span of mice. PMID- 21703364 TI - How do we develop nanopharmaceuticals under open innovation? AB - It is incumbent on nanomedicine researchers to understand how to develop their ideas into commercial drugs; success to date has not been as good as funders would have liked. This article attempts to outline, perhaps for the first time, some of the expertise that the pharmaceutical sector has acquired to facilitate translation. It is hoped this explanation will start to improve the planning required at an early stage to develop nanopharmaceuticals and to encourage researchers and their institutions to devise a development plan. PMID- 21703365 TI - Genetic and evolutionary characterization of norovirus from sewage and surface waters in Cordoba City, Argentina. AB - Noroviruses (NoVs) are among the most common viral agents that cause gastroenteritis in humans of all ages worldwide. They are excreted in the feces and introduced into environmental waters as raw or treated sewage. In this work, sewage and water samples collected from the Suquia River in the city of Cordoba, Argentina, were evaluated for the presence of NoV. Phylogenetic analysis demonstrated that the main genotype detected was GII.4, belonging to the widely distributed 2006b variant, followed by strains related to the putative recombinant GII.g virus. Detected NoVs were more phylogenetically related with recent viruses from other countries than with previous local sequences, suggesting a rapid and wide spread of viral strains that prevents a geographically structured phylogeny. A Bayesian coalescent analysis demonstrated that variants isolated in this work have a most recent common ancestor placed in 2007-2008 with estimated substitution rates of 3.7-5.8*10(-3)s/s/y. Environmental samples showed a mixture of both viral types, pointing up to the co-circulation and the risk of mixed infections and recombination. This is the first report on the detection and characterization of NoV in sewage and river water in Argentina. PMID- 21703366 TI - The role of mitochondrial membrane potential in ischemic heart failure. AB - The molecular events occurring during myocardial infarction and cardioprotection are described with an emphasis on the changes of the mitochondrial membrane potential (DeltaPsi(m)). The low DeltaPsi(m) values of the normal beating heart (100-140 mV) are explained by the allosteric ATP-inhibition of cytochrome c oxidase (CcO) through feedback inhibition by ATP at high [ATP]/[ADP] ratios. During ischemia the mechanism is reversibly switched off by signaling through reactive oxygen species (ROS). At reperfusion high DeltaPsi(m) values cause a burst of ROS production leading to apoptosis and/or necrosis. Ischemic preconditioning is suggested to cause additional phosphorylation of CcO, protecting the enzyme from immediate dephosphorylation via ROS signaling. PMID- 21703367 TI - Critical hydrogen bonds and protonation states of pyridoxal 5'-phosphate revealed by NMR. AB - In this contribution we review recent NMR studies of protonation and hydrogen bond states of pyridoxal 5'-phosphate (PLP) and PLP model Schiff bases in different environments, starting from aqueous solution, the organic solid state to polar organic solution and finally to enzyme environments. We have established hydrogen bond correlations that allow one to estimate hydrogen bond geometries from (15)N chemical shifts. It is shown that protonation of the pyridine ring of PLP in aspartate aminotransferase (AspAT) is achieved by (i) an intermolecular OHN hydrogen bond with an aspartate residue, assisted by the imidazole group of a histidine side chain and (ii) a local polarity as found for related model systems in a polar organic solvent exhibiting a dielectric constant of about 30. Model studies indicate that protonation of the pyridine ring of PLP leads to a dominance of the ketoenamine form, where the intramolecular OHN hydrogen bond of PLP exhibits a zwitterionic state. Thus, the PLP moiety in AspAT carries a net positive charge considered as a pre-requisite to initiate the enzyme reaction. However, it is shown that the ketoenamine form dominates in the absence of ring protonation when PLP is solvated by polar groups such as water. Finally, the differences between acid-base interactions in aqueous solution and in the interior of proteins are discussed. This article is part of a special issue entitled: Pyridoxal Phosphate Enzymology. PMID- 21703368 TI - Mass spectrometry based approach for identification and characterisation of fluorescent proteins from marine organisms. AB - We present here a new analytical strategy for identification and characterisation of fluorescent proteins from marine organisms. By applying basic proteomics tools it is possible to screen large sample collections for fluorescent proteins of desired characteristics prior to gene cloning. Our methodology which includes isolation, spectral characterisation, stability testing, gel-based separation and mass spectrometric identification was optimised on samples collected during the Danish Galathea 3 expedition. Four corals of the Fungia, Sarcophyton and Acropora species emitting green fluorescence were tested. Each of the fluorescent extracts behaves differently under denaturing conditions but complete fluorescence loss was not observed. Optimised electrophoretic conditions yielded effective separation of active fluorescent proteins in both 1DE and 2DE. Mass spectrometric analysis of the proteins in the fluorescent spots excised directly from unstained 2DE gels provides sequence information that might be sufficient to design degenerate primers for gene cloning. Identified fluorescent proteins are in agreement with the coral species determined by visual examination of the samples. The presented methodology is a viable alternative to direct gene cloning for the discovery of novel fluorescent proteins and will be further validated on other samples collected during the Galathea 3 expedition. PMID- 21703369 TI - MRM assay for quantitation of complement components in human blood plasma - a feasibility study on multiple sclerosis. AB - As a proof-of-principle study, a multiple reaction monitoring (MRM) assay was developed for quantitation of proteotypic peptides, representing seven plasma proteins associated with inflammation (complement components and C-reactive protein). The assay development and the sample analysis were performed on a linear ion trap mass spectrometer. We were able to quantify 5 of the 7 target proteins in depleted plasma digests with reasonable reproducibility over a 2 orders of magnitude linear range (RSD<=25%). The assay panel was utilized for the analysis of a small multiple sclerosis sample cohort with 10 diseased and 8 control patients. PMID- 21703371 TI - Developing healthy eating behaviors: why is it so difficult? PMID- 21703370 TI - The Sox2 high mobility group transcription factor inhibits mature osteoblast function in transgenic mice. AB - We have previously shown that in osteoblasts Sox2 expression can be induced by Fgfs, and can inhibit Wnt signaling and differentiation. Furthermore, in mice in which Sox2 is conditionally deleted in the osteoblastic lineage, bones are osteopenic, and Sox2 inactivation in cultured osteoblasts leads to a loss of proliferative ability with a senescent phenotype. To help understand the role of Sox2 in osteoblast development we have specifically expressed Sox2 in bone from a Col1alpha1 promoter, which extended Sox2 expression into more mature osteoblasts. In long bones, trabecular cartilage remodeling was delayed and the transition from endochondral to cortical bone was disrupted, resulting in porous and undermineralized cortical bone. Collagen deposition was disorganized, and patterns of osteoclast activity were altered. Calvarial bones were thinner and parietal bones failed to develop the diploic space. Microarray analysis showed significant up- or downregulation of a variety of genes coding for non collagenous extracellular matrix proteins, with a number of genes typical of mature osteoblasts being downregulated. Our results position Sox2 as a negative regulator of osteoblast maturation in vivo. PMID- 21703372 TI - Our nutrition literacy challenge: making the 2010 dietary guidelines relevant for consumers. PMID- 21703373 TI - Opening up opportunities through work in public policy. PMID- 21703374 TI - More on mice and men: fructose could put brakes on a vicious cycle leading to obesity in humans. PMID- 21703376 TI - Eating disorders in an obesogenic environment. PMID- 21703377 TI - Eating disorders in adolescence: when should prevention occur? PMID- 21703378 TI - Dieting and disordered eating behaviors from adolescence to young adulthood: findings from a 10-year longitudinal study. AB - BACKGROUND: Disordered eating behaviors are prevalent in adolescence and can have harmful consequences. An important question is whether use of these behaviors in adolescence sets the pattern for continued use into young adulthood. OBJECTIVE: To examine the prevalence and tracking of dieting, unhealthy and extreme weight control behaviors, and binge eating from adolescence to young adulthood. DESIGN: Population-based, 10-year longitudinal study (Project EAT-III: Eating Among Teens and Young Adults, 1999-2010). PARTICIPANTS/SETTING: The study population included 2,287 young adults (55% girls, 52% nonwhite). The sample included a younger group (mean age 12.8+/-0.7 years at baseline and 23.2+/-1.0 years at follow-up) and an older group (mean age 15.9+/-0.8 at baseline and 26.2+/-0.9 years at follow-up). STATISTICAL ANALYSES PERFORMED: Longitudinal trends in prevalence of behaviors were tested using generalized estimating equations. Tracking of behaviors were estimated using the relative risk of behaviors at follow-up given presence at baseline. RESULTS: In general, the prevalence of dieting and disordered eating was high and remained constant, or increased, from adolescence to young adulthood. Furthermore, behaviors tended to track within individuals and, in general, participants who engaged in dieting and disordered eating behaviors during adolescence were at increased risk for these behaviors 10 years later. Tracking was particularly consistent for the older girls and boys transitioning from middle adolescence to middle young adulthood. CONCLUSIONS: Study findings indicate that disordered eating behaviors are not just an adolescent problem, but continue to be prevalent among young adults. The tracking of dieting and disordered eating within individuals suggests that early use is likely to set the stage for ongoing use. Findings suggest a need for both early prevention efforts before the onset of harmful behavioral patterns as well as ongoing prevention and treatment interventions to address the high prevalence of disordered eating throughout adolescence and young adulthood. PMID- 21703379 TI - Health literacy is associated with healthy eating index scores and sugar sweetened beverage intake: findings from the rural Lower Mississippi Delta. AB - BACKGROUND: Although health literacy has been a public health priority area for more than a decade, the relationship between health literacy and dietary quality has not been thoroughly explored. OBJECTIVE: To evaluate health literacy skills in relation to Healthy Eating Index (HEI) scores and sugar-sweetened beverage (SSB) consumption while accounting for demographic variables. DESIGN: Cross sectional survey. PARTICIPANTS/SETTING: A community-based proportional sample of adults residing in the rural Lower Mississippi Delta. METHODS: Instruments included a validated 158-item regional food frequency questionnaire and the Newest Vital Sign (scores range 0 to 6) to assess health literacy. STATISTICAL ANALYSES PERFORMED: Descriptive statistics, analysis of variance, and multivariate linear regression. RESULTS: Of 376 participants, the majority were African American (67.6%), without a college degree (71.5%), and household income level <$20,000/year (55.0%). Most participants (73.9%) scored in the two lowest health literacy categories. The multivariate linear regression model to predict total HEI scores was significant (R(2)=0.24; F=18.8; P<0.01), such that every 1 point increase in health literacy was associated with a 1.21-point increase in HEI scores, while controlling for all other variables. Other significant predictors of HEI scores included age, sex, and Supplemental Nutrition Assistance Program participation. Health literacy also significantly predicted SSB consumption (R(2)=0.15; F=6.3; P<0.01) while accounting for demographic variables. Every 1 point in health literacy scores was associated with 34 fewer kilocalories per day from SSBs. Age was the only significant covariate in the SSB model. CONCLUSIONS: Although health literacy has been linked to numerous poor health outcomes, to our knowledge this is the first investigation to establish a relationship between health literacy and HEI scores and SSB consumption. Our study suggests that understanding the causes and consequences of limited health literacy is an important factor in promoting compliance to the Dietary Guidelines for Americans. PMID- 21703380 TI - Dietary intake in Head Start vs non-Head Start preschool-aged children: results from the 1999-2004 National Health and Nutrition Examination Survey. AB - OBJECTIVE: To determine whether dietary intakes of children enrolled in Head Start programs differ from those of children not attending preschool or children in non-Head Start programs. DESIGN: Using data from the 1999-2004 National Health and Nutrition Examination Survey, low-income, 3- to 5-year-old children were categorized into one of four preschool groups: Head Start (n=184), non-Head Start (n=189), past preschool (n=193), and no preschool (n=384). Total nutrient intakes were calculated using 24-hour parental recalls. STATISTICAL ANALYSES PERFORMED: Mean macronutrient and micronutrient intakes were compared across groups and the percentage of children not meeting Recommended Dietary Allowances (RDAs) were calculated. Multivariate logistic regression was used to evaluate the relationship between preschool group and likelihood of not meeting dietary guidelines. RESULTS: Many children did not meet the RDA for folate (20.5%), vitamin A (39.7%), vitamin E (79.7%), calcium (40.2%), iron (28.8%), and potassium (90.8%). Compared with the other preschool groups, Head Start children had lower mean protein, saturated fat, riboflavin, calcium, and phosphorous intakes. The greatest differences in intake were observed between Head Start participants and no-preschool children. Multivariate analyses demonstrated an association between Head Start and inadequate intake of protein, thiamin, riboflavin, niacin, calcium, and selenium. CONCLUSIONS: Compared with other low income children, those in Head Start programs appear to be at greater risk for not meeting the RDA for several key vitamins and minerals. These differences in diet quality may present an opportunity for Head Start programs to enhance nutrition in this student population. PMID- 21703381 TI - Traditional foods and practices of Spanish-speaking Latina mothers influence the home food environment: implications for future interventions. AB - This study aimed to obtain in-depth information from low-income, Spanish-speaking Latino families with young children to guide the development of culturally appropriate nutrition interventions. Focus groups were used to assess parent's knowledge about healthful eating, the home food environment, perceived influences on children's eating habits, food purchasing practices, and commonly used strategies to promote healthful eating among their children. Thirty-four Latino parents (33 women; 27 born in Mexico; 21 food-insecure) of preschool-aged children participated in four focus group discussions conducted in Spanish by a trained moderator. The focus groups were audiotaped, transcribed, translated, and coded by independent raters. Results suggest that in general, parents were very knowledgeable about healthful eating and cited both parents and school as significant factors influencing children's eating habits; at home, most families had more traditional Mexican foods available than American foods; cost and familiarity with foods were the most influential factors affecting food purchasing; many parents had rules regarding sugar intake; and parents cited role modeling, reinforcement, and creative food preparation as ways to encourage children's healthful eating habits. Finally, parents generated ideas on how to best assist Latino families through interventions. Parents indicated that future interventions should be community based and teach skills to purchase and prepare meals that include low-cost and traditional Mexican ingredients, using hands-on activities. In addition, interventions could encourage and reinforce healthy food related practices that Latino families bring from their native countries. PMID- 21703382 TI - Children's intake of fruit and selected energy-dense nutrient-poor foods is associated with fathers' intake. AB - Parental dietary intake, lifestyle behavior, and parenting style influence a child's weight status. Few studies have examined associations between parent child dietary intake, or specific father-child associations. This cross-sectional study examined associations between father-child dietary intakes of fruit, vegetables, and selected energy-dense nutrient-poor foods. The study population consisted of overweight fathers with 50 father-child dyads included in the analysis; median (interquartile range) age of fathers was 39+/-8.0 years; body mass index was 32.7+/-5.3; and their primary school-aged children (n=50) (54% boys aged 8.5+/-3.0 years, body mass index z score 0.6+/-1.6) who had been targeted to participate in the Healthy Dads, Healthy Kids pilot trial in the Hunter region, New South Wales, Australia in 2008. Dietary intakes of fathers and children were assessed using validated food frequency questionnaires, with mothers reporting their child's food intake. Descriptive statistics were reported and Spearman's rank order correlations used to test the strength of associations between father-child intakes. Fathers' median (interquartile range) daily fruit and vegetable intakes were 0.9 (1.5) and 2.2 (1.3) servings/day, respectively, whereas children consumed 2.1 (2.4) fruit and 2.9 (2.1) vegetable servings/day. Moderately-strong positive correlations were found between father-child fruit intakes (r=0.40, P<0.01), cookies (r=0.54, P<0.001), and potato chips (r=0.33, P<0.05). There were no associations between intakes of vegetables, ice cream, chocolate, or french fries (P>0.05). Children's intakes of fruit and some energy dense nutrient-poor foods but not vegetables were related to their father's intakes. The targeting of fathers should be tested in experimental studies as a potential strategy to improve child and family eating habits. PMID- 21703383 TI - Performance of the quantitative food frequency questionnaire used in the Brazilian center of the prospective study Natural History of Human Papillomavirus Infection in Men: The HIM Study. AB - The Natural History of Human Papillomavirus (HPV) Infection in Men: The HIM Study is a prospective multicenter cohort study that, among other factors, analyzes participants' diet. A parallel cross-sectional study was designed to evaluate the validity and reproducibility of the quantitative food frequency questionnaire (QFFQ) used in the Brazilian center from the HIM Study. For this, a convenience subsample of 98 men aged 18 to 70 years from the HIM Study in Brazil answered three 54-item QFFQ and three 24-hour recall interviews, with 6-month intervals between them (data collection January to September 2007). A Bland-Altman analysis indicated that the difference between instruments was dependent on the magnitude of the intake for energy and most nutrients included in the validity analysis, with the exception of carbohydrates, fiber, polyunsaturated fat, vitamin C, and vitamin E. The correlation between the QFFQ and the 24-hour recall for the deattenuated and energy-adjusted data ranged from 0.05 (total fat) to 0.57 (calcium). For the energy and nutrients consumption included in the validity analysis, 33.5% of participants on average were correctly classified into quartiles, and the average value of 0.26 for weighted kappa shows a reasonable agreement. The intraclass correlation coefficients for all nutrients were greater than 0.40 in the reproducibility analysis. The QFFQ demonstrated good reproducibility and acceptable validity. The results support the use of this instrument in the HIM Study. PMID- 21703384 TI - A medical nutrition therapy primer for childhood asthma: current and emerging perspectives. AB - Asthma is the most common chronic disease in children. Prevalence has increased in the past 2 decades and has reached a plateau of approximately 9% of children in the United States, affecting about 6.7 million children. The increased prevalence of childhood asthma has paralleled the increased prevalence in childhood obesity. Changes in diet have also been implicated in the increased prevalence of asthma, among other risk factors. The main symptoms of asthma (ie, wheezing, coughing, and chest tightness) require medical evaluation and monitoring. The cornerstone of asthma management is medication therapy, frequently consisting of inhaled bronchodilators and corticosteroids and, when needed, therapy of corticosteroids by mouth. As part of the multidisciplinary management of this chronic disease, nutrition assessment and follow-up in childhood asthma is necessary to identify and address relevant nutrition-related problems. These problems can involve food-medication interactions, obesity, gastroesophageal reflux disease, food allergies, and other issues; therefore, individualized medical nutrition therapy is warranted. Finally, counseling to achieve a healthy balanced diet is recommended for overall health and weight management. A recent but small number of descriptive investigations agree that adherence to a Mediterranean dietary pattern can be associated with a decreased risk of current asthma symptoms in children. Although this evidence is promising, food interventions are required to substantiate an evidence-based foundation for medical nutrition therapy in childhood asthma. At this time, there is no known health risk if a Mediterranean diet is adopted. PMID- 21703386 TI - Where can I find resources on the local food movement? PMID- 21703385 TI - Dietary supplement use within a multiethnic population as measured by a unique inventory method. AB - Use of dietary supplements is widespread, yet intakes from supplements are difficult to quantify. The Supplement Reporting study utilized a unique inventory method to quantify dietary supplement use across 1 year in a sample of 397 supplement users. Interviewers visited participants' homes in 2005-2006 to record supplement purchases and the number of pills in each supplement bottle every 3 months. Total use for the year was calculated from these inventories. Participants in this observational study were older adults (average age 68 years) from the Multiethnic Cohort in Hawaii and Los Angeles, CA, with approximately equal representation of men and women and six ethnic groups (white, Japanese American, Hawaiian, African American, Latinos born in the United States, and Latinos born elsewhere). The most commonly used supplement type was one-a-day multivitamins/minerals, which were taken at least once during the year by 83% of men and 73% of women. Other common supplements were vitamin C, fish oil, vitamin E, and bone or joint supplements. Participants used a median of seven (women) and five and a half (men) different supplements during the year. There were few differences in supplement use across ethnic groups for men, but use tended to be highest for white and Japanese-American women. Use of nonvitamin/nonmineral supplements was common among these older adults, sometimes at high doses. When assessing intakes, supplement use should be correctly quantified because users tend to take many different supplements and nutrient intakes from supplements can be substantial. The inventory method may help improve the measurement of supplement use. PMID- 21703387 TI - The International American Journal of Ophthalmology. PMID- 21703388 TI - Floaters and the quality of life. PMID- 21703390 TI - Restoring dystrophin expression in duchenne muscular dystrophy muscle progress in exon skipping and stop codon read through. AB - The identification of the Duchenne muscular dystrophy gene and protein in the late 1980s led to high hopes of rapid translation to molecular therapeutics. These hopes were fueled by early reports of delivering new functional genes to dystrophic muscle in mouse models using gene therapy and stem cell transplantation. However, significant barriers have thwarted translation of these approaches to true therapies, including insufficient therapeutic material (eg, cells and viral vectors), challenges in systemic delivery, and immunological hurdles. An alternative approach is to repair the patient's own gene. Two innovative small-molecule approaches have emerged as front-line molecular therapeutics: exon skipping and stop codon read through. Both approaches are in human clinical trials and aim to coax dystrophin protein production from otherwise inactive mutant genes. In the clinically severe dog model of Duchenne muscular dystrophy, the exon-skipping approach recently improved multiple functional outcomes. We discuss the status of these two methods aimed at inducing de novo dystrophin production from mutant genes and review implications for other disorders. PMID- 21703391 TI - Compartment-specific remodeling of splenic micro-architecture during experimental visceral leishmaniasis. AB - Progressive splenomegaly is a hallmark of visceral leishmaniasis in humans, canids, and rodents. In experimental murine visceral leishmaniasis, splenomegaly is accompanied by pronounced changes in microarchitecture, including expansion of the red pulp vascular system, neovascularization of the white pulp, and remodeling of the stromal cell populations that define the B-cell and T-cell compartments. Here, we show that Ly6C/G(+) (Gr-1(+)) cells, including neutrophils and inflammatory monocytes, accumulate in the splenic red pulp during infection. Cell depletion using monoclonal antibody against either Ly6C/G(+) (Gr-1; RB6) or Ly6G(+) (1A8) cells increased parasite burden. In contrast, depletion of Ly6C/G(+) cells, but not Ly6G(+) cells, halted the progressive remodeling of Meca 32(+) and CD31(+) red pulp vasculature. Strikingly, neither treatment affected white pulp neovascularization or the remodeling of the fibroblastic reticular cell and follicular dendritic cell networks. These findings demonstrate a previously unrecognized compartment-dependent selectivity to the process of splenic vascular remodeling during experimental murine visceral leishmaniasis, attributable to Ly6C(+) inflammatory monocytes. PMID- 21703392 TI - Unique ectopic lymph node-like structures present in human primary colorectal carcinoma are identified by immune gene array profiling. AB - We hypothesized that immune gene-related signatures would predict the presence of unique histological features of lymphoid cell infiltrates in colorectal carcinoma (CRC) that correlate with clinical parameters. Metagene analysis with gene chip technology was performed on 326 CRCs, which were then sorted by low versus high gene scores. Microscopically, CRCs with a high gene score revealed a marked host immune response organized, remarkably, as lymphoid follicles. Proliferation involved both B and T cells. In every case, the presence of CD79a(+) B-cell precursors was identified, suggesting that the lymphoid follicles represent newly formed, ectopic lymph node-like structures. CD21(+) dendritic cells were present within the follicular germinal centers, and CD3(+) T cells were localized mainly in the parafollicular cortex zone surrounding the B-cell area of the follicles. A strong correlation between a 12-chemokine gene subset of the molecular profile and the presence of ectopic lymph node-like structures was associated with better patient survival independent of tumor staging, site location, microsatellite instability or stability, and patient treatment. These findings suggest beneficial, intratumoral immune cell priming and raise the possibility of immunotherapy intervention decisions based on molecular signatures that can identify the presence of tumor-localized, ectopic lymph node-like structures. PMID- 21703393 TI - Protein-coding and microRNA biomarkers of recurrence of prostate cancer following radical prostatectomy. AB - An important challenge in prostate cancer research is to develop effective predictors of tumor recurrence following surgery to determine whether immediate adjuvant therapy is warranted. To identify biomarkers predictive of biochemical recurrence, we isolated the RNA from 70 formalin-fixed, paraffin-embedded radical prostatectomy specimens with known long-term outcomes to perform DASL expression profiling with a custom panel that we designed of 522 prostate cancer-relevant genes. We identified a panel of 10 protein-coding genes and two miRNA genes (RAD23B, FBP1, TNFRSF1A, CCNG2, NOTCH3, ETV1, BID, SIM2, LETMD1, ANXA1, miR-519d, and miR-647) that could be used to separate patients with and without biochemical recurrence (P < 0.001), as well as for the subset of 42 Gleason score 7 patients (P < 0.001). We performed an independent validation analysis on 40 samples and found that the biomarker panel was also significant at prediction of biochemical recurrence for all cases (P = 0.013) and for a subset of 19 Gleason score 7 cases (P = 0.010), both of which were adjusted for relevant clinical information including T-stage, prostate-specific antigen, and Gleason score. Importantly, these biomarkers could significantly predict clinical recurrence for Gleason score 7 patients. These biomarkers may increase the accuracy of prognostication following radical prostatectomy using formalin-fixed specimens. PMID- 21703394 TI - Abnormal cell properties and down-regulated FAK-Src complex signaling in B lymphoblasts of autistic subjects. AB - Recent studies suggest that one of the major pathways to the pathogenesis of autism is reduced cell migration. Focal adhesion kinase (FAK) has an important role in neural migration, dendritic morphological characteristics, axonal branching, and synapse formation. The FAK-Src complex, activated by upstream reelin and integrin beta1, can initiate a cascade of phosphorylation events to trigger multiple intracellular pathways, including mitogen-activated protein kinase-extracellular signal-regulated kinase and phosphatidylinositol 3-kinase Akt signaling. In this study, by using B lymphoblasts as a model, we tested whether integrin beta1 and FAK-Src signaling are abnormally regulated in autism and whether abnormal FAK-Src signaling leads to defects in B-lymphoblast adhesion, migration, proliferation, and IgG production. To our knowledge, for the first time, we show that protein expression levels of both integrin beta1 and FAK are significantly decreased in autistic lymphoblasts and that Src protein expression and the phosphorylation of an active site (Y416) are also significantly decreased. We also found that lymphoblasts from autistic subjects exhibit significantly decreased migration, increased adhesion properties, and an impaired capacity for IgG production. The overexpression of FAK in autistic lymphoblasts countered the adhesion and migration defects. In addition, we demonstrate that FAK mediates its effect through the activation of Src, phosphatidylinositol 3-kinase-Akt, and mitogen-activated protein kinase signaling cascades and that paxillin is also likely involved in the regulation of adhesion and migration in autistic lymphoblasts. PMID- 21703395 TI - Two-photon imaging within the murine thorax without respiratory and cardiac motion artifact. AB - Intravital microscopy has been recognized for its ability to make physiological measurements at cellular and subcellular levels while maintaining the complex natural microenvironment. Two-photon microscopy (TPM), using longer wavelengths than single-photon excitation, has extended intravital imaging deeper into tissues, with minimal phototoxicity. However, due to a relatively slow acquisition rate, TPM is especially sensitive to motion artifact, which presents a challenge when imaging tissues subject to respiratory and cardiac movement. Thoracoabdominal organs that cannot be exteriorized or immobilized during TPM have generally required the use of isolated, pump-perfused preparations. However, this approach entails significant alteration of normal physiology, such as a lack of neural inputs, increased vascular resistance, and leukocyte activation. We adapted techniques of intravital microscopy that permitted TPM of organs maintained within the thoracoabdominal cavity of living, breathing rats or mice. We obtained extended intravital TPM imaging of the intact lung, arguably the organ most susceptible to both respiratory and cardiac motion. Intravital TPM detected the development of lung microvascular endothelial activation manifested as increased leukocyte adhesion and plasma extravasation in response to oxidative stress inducers PMA or soluble cigarette smoke extract. The pulmonary microvasculature and alveoli in the intact animal were imaged with comparable detail and fidelity to those in pump-perfused animals, opening the possibility for TPM of other thoracoabdominal organs under physiological and pathophysiological conditions. PMID- 21703396 TI - Suppression of chronic damage in renal allografts by Liver X receptor (LXR) activation relevant contribution of macrophage LXRalpha. AB - Liver X receptors (LXR)-alpha,beta regulate intracellular cholesterol homeostasis and inhibit inflammatory gene expression. We studied the effects of the LXRalpha,beta-agonist GW3965 on acute and chronic organ damage in the F344-LEW rat kidney transplantation model. In addition, to gain LXR isoform and cell specific insights BALB/c kidneys were transplanted into mice with macrophage overexpression of LXRalpha (mLXRalpha-tg) and evaluated 7 and 42 days after transplantation. After 56 days GW3965 improved significantly function and morphology of rat kidney allografts by substantial reduction of mononuclear cell infiltrate and fibrosis; in vitro GW3965 reduced inflammatory activity of bone marrow-derived macrophages (BMDMs) and alloreactivity of T cells. Kidneys transplanted into mLXRalpha-tg mice were also protected from development of chronic allograft dysfunction. Similarly to GW3965-activated BMDMs, mLXRalpha-tg macrophages secreted significantly less monocyte chemoattractant protein 1 and macrophage inflammatory protein 1beta. Interestingly, 7 days after transplantation, when the total number of intragraft macrophages did not differ, evidently more arginase 1- and mannose receptor C type 1-positive cells were found in LXR rat and mice kidney allografts; in vitro both LXR activation by GW3965 and mLXRalpha overexpression accentuated the induction of alternative activation of BMDMs by IL-4/IL-13, suggesting an additional mechanism by LXRs to prevent graft damage. The results highlight the relevance of macrophage LXRalpha in allograft rejection and prevention of fibrosis. PMID- 21703397 TI - Dual blockade of the homeostatic chemokine CXCL12 and the proinflammatory chemokine CCL2 has additive protective effects on diabetic kidney disease. AB - Monocyte/ chemoattractant protein-1/chemokine ligand (CCL) 2 and stromal cell derived factor-1/CXCL12 both contribute to glomerulosclerosis in mice with type 2 diabetes mellitus, through different mechanisms. CCL2 mediates macrophage-related inflammation, whereas CXCL12 contributes to podocyte loss. Therefore, we hypothesized that dual antagonism of these chemokines might have additive protective effects on the progression of diabetic nephropathy. We used chemokine antagonists based on structured l-enantiomeric RNA (so-called Spiegelmers) ie, the CCL2-specific mNOX-E36 and the CXCL12-specific NOX-A12. Male db/db mice, uninephrectomized at the age of 6 weeks, received injections of Spiegelmer, both Spiegelmers, nonfunctional control Spiegelmer, or vehicle from the age of 4 months for 8 weeks. Dual blockade was significantly more effective than monotherapy in preventing glomerulosclerosis. CCL2 blockade reduced glomerular leukocyte counts and renal-inducible nitric oxide synthase or IL-6 mRNA expression. CXCL12 blockade maintained podocyte numbers and renal nephrin and podocin mRNA expression. Consistently, CXCL12 blockade suppressed nephrin mRNA up regulation in primary cultures of human glomerular progenitors induced to differentiate toward the podocyte lineage. All previously mentioned parameters were significantly improved in the dual-blockade group, which also suppressed proteinuria and was associated with the highest levels of glomerular filtration rate. Blood glucose levels and body weight were identical in all treatment groups. Dual chemokine blockade can have additive effects on the progression of diabetic kidney disease when the respective chemokine targets mediate different pathomechanisms of disease (ie, inflammation and progenitor differentiation toward the podocyte lineage). PMID- 21703398 TI - Lung-targeted overexpression of the NF-kappaB member RelB inhibits cigarette smoke-induced inflammation. AB - Acute lung inflammation can be caused by a variety of respirable agents, including cigarette smoke. Long-term cigarette smoke exposure can cause chronic obstructive pulmonary disease (COPD), a serious illness that affects >10 million Americans. Cigarette smoke is a known inducer of inflammation and is responsible for approximately 90% of all COPD cases. RelB, a member of the NF-kappaB family, attenuates cigarette smoke-induced inflammatory mediator production in mouse lung fibroblasts in vitro. We hypothesized that overexpression of RelB in the airways of mice would dampen acute smoke-induced pulmonary inflammation. Mice received a recombinant adenovirus encoding RelB by intranasal aspiration to induce transient RelB overexpression in the lungs and were subsequently exposed to mainstream cigarette smoke. Markers of inflammation were analyzed after smoke exposure. Neutrophil infiltration, normally increased by smoke exposure, was significantly and potently decreased after RelB overexpression. Cigarette smoke-induced proinflammatory cytokine and chemokine production, cyclooxygenase-2 expression, and prostaglandin E(2) production were also significantly decreased in the context of RelB overexpression. The expression of intercellular adhesion molecule 1, an NF-kappaB-dependent protein, was decreased, indicating a potential mechanism through which RelB can regulate inflammatory cell migration. Therefore, increased expression and/or activation of RelB could be a novel therapeutic strategy against acute lung inflammation caused by respirable agents and possibly against chronic injury, such as COPD. PMID- 21703399 TI - Ischemic cardiomyopathy following seizure induction by domoic Acid. AB - Exposure to the excitotoxin domoic acid (DOM) has been shown to produce cardiac lesions in both clinical and animal studies. We have previously shown that DOM failed to directly affect cardiomyocyte viability and energetics, but the development of this cardiomyopathy has remained unexplained. The present study compared effects of high-level seizure induction obtained by intraperitoneal (2 mg/kg) or intrahippocampal (100 pmol) bolus administration of DOM on development of cardiac pathologies in a rat model. Assessment of cardiac pressure derivatives and coronary flow rates revealed a significant time-dependent decrease in combined left ventricular (LV) systolic and diastolic function at 1, 3, 7, and 14 days after intraperitoneal administration and at 7 and 14 days after intrahippocampal DOM administration. LV dysfunction was matched by a similar time dependent decrease in mitochondrial respiratory control, associated with increased proton leakage, and in mitochondrial enzyme activities. Microscopic examination of the LV midplane revealed evidence of progressive multifocal ischemic damage within the subendocardial, septal, and papillary regions. Lesions ranged from reversible early damage (vacuolization) to hypercontracture and inflammatory necrosis progressing to fibrotic scarring. Plasma proinflammatory IL 1alpha, IL-1beta, and TNF-alpha cytokine levels were also increased from 3 days after seizure induction. The observed cardiomyopathies did not differ between intraperitoneal and intrahippocampal groups, providing strong evidence that cardiac damage after DOM exposure is a consequence of a seizure-evoked autonomic response. PMID- 21703400 TI - Plexiform lesions in pulmonary arterial hypertension composition, architecture, and microenvironment. AB - Pulmonary arterial hypertension (PAH) is a debilitating disease with a high mortality rate. A hallmark of PAH is plexiform lesions (PLs), complex vascular formations originating from remodeled pulmonary arteries. The development and significance of these lesions have been debated and are not yet fully understood. Some features of PLs resemble neoplastic disorders, and there is a striking resemblance to glomeruloid-like lesions (GLLs) in glioblastomas. To further elucidate PLs, we used in situ methods, such as (fluorescent) IHC staining, three dimensional reconstruction, and laser microdissection, followed by mRNA expression analysis. We generated compartment-specific expression patterns in the lungs of 25 patients (11 with PAH associated with systemic shunts, 6 with idiopathic PAH, and 8 controls) and GLLs from 5 glioblastomas. PLs consisted of vascular channels lined by a continuously proliferating endothelium and backed by a uniform myogenic interstitium. They also showed up-regulation of remodeling associated genes, such as HIF1a, TGF-beta1, VEGF-alpha, VEGFR-1/-2, Ang-1, Tie-2, and THBS1, but also of cKIT and sprouting-associated markers, such as NOTCH and matrix metalloproteinases. The cellular composition and signaling seen in GLLs in neural neoplasms differed significantly from those in PLs. In conclusion, PLs show a distinct cellular composition and microenvironment, which contribute to the plexiform phenotype and set them apart from other processes of vascular remodeling in patients with PAH. Neoplastic models of angiogenesis seem to be of limited use in further study of plexiform vasculopathy. PMID- 21703401 TI - Migration of fibrocytes in fibrogenic liver injury. AB - CD45(+) and collagen I-positive (Col(+)) fibrocytes are implicated in fibrogenesis in skin, lungs, and kidneys. Fibrocyte migration in response to liver injury was investigated using bone marrow (BM) from chimeric mice expressing luciferase (Col-Luc->wt) or green fluorescent protein (Col-GFP->wt) under control of the alpha1(I) collagen promoter and enhancer, respectively. Monitored by luciferase expression, recruitment of fibrocytes was detected in CCl(4)-damaged liver and in spleen. Migration of CD45(+)Col(+) fibrocytes was regulated by chemokine receptors CCR2 and CCR1, as demonstrated, respectively, by 50% and 25% inhibition of fibrocyte migration in Col-Luc(CCR2-/-)->wt and Col Luc(CCR1-/-)->wt mice. In addition to CCR2 and CCR1, egress of BM CD45(+)Col(+) cells was regulated by transforming growth factor-beta1 (TGF-beta1) and liposaccharide in vitro and in vivo, which suggests that release of TGF-beta1 and increased intestinal permeability have important roles in fibrocyte trafficking. In the injured liver, fibrocytes gave rise to (myo)fibroblasts. In addition, a BM population of CD45(+)Col(+) cells capable of differentiation into fibrocytes in culture was identified. Egress of CD45(+)Col(+) cells from BM was detected in the absence of injury or stress in aged mice but not in young mice. Development of liver fibrosis was also increased in aged mice and correlated with high numbers of liver fibrocytes. In conclusion, in response to liver injury, fibrocytes migrate from BM to the liver. Their migration is regulated by CCR2 and CCR1 but is compromised with age. PMID- 21703402 TI - Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. AB - Complications of acute respiratory distress syndrome (ARDS) are common among critically ill patients infected with highly pathogenic influenza viruses. Macrophages and neutrophils constitute the majority of cells recruited into infected lungs, and are associated with immunopathology in influenza pneumonia. We examined pathological manifestations in models of macrophage- or neutrophil depleted mice challenged with sublethal doses of influenza A virus H1N1 strain PR8. Infected mice depleted of macrophages displayed excessive neutrophilic infiltration, alveolar damage, and increased viral load, later progressing into ARDS-like pathological signs with diffuse alveolar damage, pulmonary edema, hemorrhage, and hypoxemia. In contrast, neutrophil-depleted animals showed mild pathology in lungs. The brochoalveolar lavage fluid of infected macrophage depleted mice exhibited elevated protein content, T1-alpha, thrombomodulin, matrix metalloproteinase-9, and myeloperoxidase activities indicating augmented alveolar-capillary damage, compared to neutrophil-depleted animals. We provide evidence for the formation of neutrophil extracellular traps (NETs), entangled with alveoli in areas of tissue injury, suggesting their potential link with lung damage. When co-incubated with infected alveolar epithelial cells in vitro, neutrophils from infected lungs strongly induced NETs generation, and augmented endothelial damage. NETs induction was abrogated by anti-myeloperoxidase antibody and an inhibitor of superoxide dismutase, thus implying that NETs generation is induced by redox enzymes in influenza pneumonia. These findings support the pathogenic effects of excessive neutrophils in acute lung injury of influenza pneumonia by instigating alveolar-capillary damage. PMID- 21703403 TI - The immune-modulating cytokine and endogenous Alarmin interleukin-33 is upregulated in skin exposed to inflammatory UVB radiation. AB - The cellular and molecular mechanisms by which UV radiation modulates inflammation and immunity while simultaneously maintaining skin homeostasis is complex and not completely understood. Similar to the effects of UV, IL-33 has potent immune-modulating properties that are mediated by the downstream induction of cytokines and chemokines. We have discovered that exposure of mice in vivo or human skin samples ex vivo to inflammatory doses of UVB induced IL-33 expression within the epidermal and dermal skin layers. Using a combination of murine cell lines and primary human cells, we demonstrate that both UV and the oxidized lipid platelet activating factor induce IL-33 expression in keratinocytes and dermal fibroblasts. Highlighting the significance of these results, we found that administering IL-33 to mice in vivo suppressed the induction of Th1-mediated contact hypersensitivity responses. This may have consequences for skin cancer growth because UV-induced squamous cell carcinomas that evade immunological destruction were found to express significantly higher levels of IL-33. Finally, we demonstrate that dermal mast cells and skin-infiltrating neutrophils closely associate with UV-induced IL-33-expressing fibroblasts. Our results therefore identify and support a role for IL-33 as an important early danger signal produced in response to inflammation-inducing UV radiation. PMID- 21703404 TI - Therapeutic DNA vaccine reduces schistosoma mansoni-induced tissue damage through cytokine balance and decreased migration of myofibroblasts. AB - Helminths are known to elicit a wide range of immunomodulation characterized by dominant Th2-type immune responses. Our group previously showed that a DNA vaccine encoding the mycobacterial 65-kDa heat shock protein (DNA-hsp65) showed immunomodulatory properties. We also showed, using a helminth-tuberculosis (TB) co-infection model, that the DNA-hsp65 vaccine protected mice against TB. We next investigated the mechanistic role of the vaccine during helminth-TB co-infection. Clinically, helminth infection causes type 2 granulomas in the lung. Mice were immunized with DNA-hsp65 while they were submitted to the type 2 granuloma induction protocol by Schistosoma mansoni eggs infusion. In this work we investigated the effects of DNA-hsp65 on the pathology and immune response during the development of type 2 granuloma induced by S. mansoni eggs. Histologic analyses of lung parenchyma showed that the DNA-hsp65 vaccine protected mice against exacerbated fibrosis induced by Schistosoma eggs, and decreased the size of the granulomas. These changes were correlated with a reduction in the number of T cells specific for the egg antigens in the lung and also with modulation of Th2 cytokine expression. Taken together, our results showed that the adjuvant properties of the DNA-hsp65 vaccine regulated the immune response in this Th2 model, and resulted in a preserved lung parenchyma. PMID- 21703405 TI - Differential host determinants contribute to the pathogenesis of 2009 pandemic H1N1 and human H5N1 influenza A viruses in experimental mouse models. AB - Influenza viruses are responsible for high morbidities in humans and may, eventually, cause pandemics. Herein, we compared the pathogenesis and host innate immune responses of a seasonal H1N1, two 2009 pandemic H1N1, and a human H5N1 influenza virus in experimental BALB/c and C57BL/6J mouse models. We found that both 2009 pandemic H1N1 isolates studied (A/Hamburg/05/09 and A/Hamburg/NY1580/09) were low pathogenic in BALB/c mice [log mouse lethal dose 50 (MLD(50)) >6 plaque-forming units (PFU)] but displayed remarkable differences in virulence in C57BL/6J mice. A/Hamburg/NY1580/09 was more virulent (logMLD(50) = 3.5 PFU) than A/Hamburg/05/09 (logMLD(50) = 5.2 PFU) in C57BL/6J mice. In contrast, the H5N1 influenza virus was more virulent in BALB/c mice (logMLD(50) = 0.3 PFU) than in C57BL/6J mice (logMLD(50) = 1.8 PFU). Seasonal H1N1 influenza revealed marginal pathogenicity in BALB/c or C57BL/6J mice (logMLD(50) >6 PFU). Enhanced susceptibility of C57BL/6J mice to pandemic H1N1 correlated with a depressed cytokine response. In contrast, enhanced H5N1 virulence in BALB/c mice correlated with an elevated proinflammatory cytokine response. These findings highlight that host determinants responsible for the pathogenesis of 2009 pandemic H1N1 influenza viruses are different from those contributing to H5N1 pathogenesis. Our results show, for the first time to our knowledge, that the C57BL/6J mouse strain is more appropriate for the evaluation and identification of intrinsic pathogenicity markers of 2009 pandemic H1N1 influenza viruses that are "masked" in BALB/c mice. PMID- 21703406 TI - Increased serum enzyme levels associated with kupffer cell reduction with no signs of hepatic or skeletal muscle injury. AB - Macrophage colony-stimulating factor (M-CSF) is a hematopoietic growth factor that is responsible for the survival and proliferation of monocytes and the differentiation of monocytes into macrophages, including Kupffer cells (KCs) in the liver. KCs play an important role in the clearance of several serum enzymes, including aspartate aminotransferase and creatine kinase, that are typically elevated as a result of liver or skeletal muscle injury. We used three distinct animal models to investigate the hypothesis that increases in the levels of serum enzymes can be the result of decreases in KCs in the apparent absence of hepatic or skeletal muscle injury. Specifically, neutralizing M-CSF activity via a novel human monoclonal antibody reduced the CD14(+)CD16(+) monocyte population, depleted KCs, and increased aspartate aminotransferase and creatine kinase serum enzyme levels in cynomolgus macaques. In addition, the treatment of rats with clodronate liposomes depleted KCs and led to increased serum enzyme levels, again without evidence of tissue injury. Finally, in the osteopetrotic (Csf1(op)/Csf1(op)) mice lacking functional M-CSF and having reduced levels of KCs, the levels of serum enzymes are higher than in wild-type littermates. Together, these findings support a mechanism for increases in serum enzyme levels through M-CSF regulation of tissue macrophage homeostasis without concomitant histopathological changes in either the hepatic or skeletal system. PMID- 21703407 TI - IL-17-induced pulmonary pathogenesis during respiratory viral infection and exacerbation of allergic disease. AB - Severe respiratory syncytial virus (RSV) infections are characterized by airway epithelial cell damage, mucus hypersecretion, and Th2 cytokine production. Less is known about the role of IL-17. We observed increased IL-6 and IL-17 levels in tracheal aspirate samples from severely ill infants with RSV infection. In a mouse model of RSV infection, time-dependent increases in pulmonary IL-6, IL-23, and IL-17 expression were observed. Neutralization of IL-17 during infection and observations from IL-17(-/-) knockout mice resulted in significant inhibition of mucus production during RSV infection. RSV-infected animals treated with anti-IL 17 had reduced inflammation and decreased viral load, compared with control antibody-treated mice. Blocking IL-17 during infection resulted in significantly increased RSV-specific CD8 T cells. Factors associated with CD8 cytotoxic T lymphocytes, T-bet, IFN-gamma, eomesodermin, and granzyme B were significantly up regulated after IL-17 blockade. Additionally, in vitro analyses suggest that IL 17 directly inhibits T-bet, eomesodermin, and IFN-gamma in CD8 T cells. The role of IL-17 was also investigated in RSV-induced exacerbation of allergic airway responses, in which neutralization of IL-17 led to a significant decrease in the exacerbated disease, including reduced mucus production and Th2 cytokines, with decreased viral proteins. Taken together, our data demonstrate that IL-17 plays a pathogenic role during RSV infections. PMID- 21703408 TI - The melanocortin agonist AP214 exerts anti-inflammatory and proresolving properties. AB - Synthetic and natural melanocortin (MC) peptides afford inhibitory properties in inflammation and tissue injury, but characterization of receptor involvement is still elusive. We used the agonist AP214 to test MC-dependent anti-inflammatory effects. In zymosan peritonitis, treatment of mice with AP214 (400 to 800 MUg/kg) inhibited cell infiltration, an effect retained in MC receptor type 1, or MC(1), mutant mice but lost in MC(3) null mice. In vitro, cytokine release from zymosan stimulated macrophages was affected by AP214, with approximately 80%, 30%, and 40% reduction in IL-1beta, tumor necrosis factor-alpha, and IL-6, respectively. Inhibition of IL-1beta release was retained in MC(1) mutant cells but was lost in MC(3) null cells. Furthermore, AP214 augmented uptake of zymosan particles and human apoptotic neutrophils by wild-type macrophages: this proresolving property was lost in MC(3) null macrophages. AP214 displayed its pro-efferocytotic effect also in vivo. Finally, in a model of inflammatory arthritis, AP214 evoked significant reductions in the clinical score. These results indicate that AP214 elicits anti-inflammatory responses, with a preferential effect on IL-1beta release. Furthermore, we describe for the first time a positive modulation of an MC agonist on the process of efferocytosis. In all cases, endogenous MC(3) is the receptor that mediates these novel properties of AP214. These findings might clarify the tissue-protective properties of AP214 in clinical settings and may open further development for novel MC agonists. PMID- 21703409 TI - Low-dose exposure of C57BL/6 mice to burkholderia pseudomallei mimics chronic human melioidosis. AB - Burkholderia pseudomallei is the etiological agent of human melioidosis, a disease with a broad spectrum of clinical manifestations ranging from fatal septicemia to chronic localized infection or asymptomatic latent infection. Most clinical and immunological studies to date have focused on the acute disease process; however, little is known about pathology and immune response in chronic melioidosis. Here, we have developed a murine model of chronic disease by challenging C57BL/6 mice intranasally with a low dose of B. pseudomallei and monitoring them up to 100 days postinfection. Bacterial burdens were heterogeneous in different animals at all time points, consistent with the spectrum of clinical severity observed in humans. Proinflammatory cytokines such as gamma interferon (IFN-gamma), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-alpha) were induced during chronic infection, and histopathological analysis showed features in common with human melioidosis. Interestingly, many of these features were similar to those induced by Mycobacterium tuberculosis in humans, such as development of a collagen cord that encapsulates the lesions, the presence of multinucleated giant cells, and granulomas with a caseous necrotic center, which may explain why chronic melioidosis is often misdiagnosed as tuberculosis. Our model now provides a relevant and practical tool to define the immunological features of chronic melioidosis and aid in the development of more effective treatment of this disease in humans. PMID- 21703410 TI - Cavia porcellus as a model for experimental infection by Trypanosoma cruzi. AB - The guinea pig (Cavia porcellus) is a natural reservoir for Trypanosoma cruzi but has seldom been used as an experimental infection model. We developed a guinea pig infection model for acute and chronic Chagas disease. Seventy-two guinea pigs were inoculated intradermally with 10(4) trypomastigotes of T. cruzi strain Y (experimental group); 18 guinea pigs were used as control group. Eight animals from the experimental group and two from the control group were sacrificed 5, 15, 20, 25, 40, 55, 115, 165, and 365 days after inoculation. During the acute phase (15 to 55 days), we observed parasitemia (with a peak on day 20) and positive IgM and IgG Western blots with anti-shed acute-phase antigen bands. The cardiac tissue showed vasculitis, necrosis (on days 40 to 55), moderate to severe inflammation, and abundant amastigote nests. Smaller numbers of amastigote nests were also present in kidney, brain, and other organs. In the early chronic phase (115 to 165 days), parasitemia disappeared and anti-T. cruzi IgG antibodies were still detectable. In cardiac tissue, the number of amastigote nests and the grade of inflammation decreased. In the chronic phase (365 days), the cardiac tissue showed vasculitis and fibrosis; detectable parasite DNA was associated with higher grades of inflammation. The experimental T. cruzi infection model in guinea pigs shows kinetics and pathologic changes similar to those of the human disease. PMID- 21703411 TI - Phosphodiesterase-4 inhibition combined with isoniazid treatment of rabbits with pulmonary tuberculosis reduces macrophage activation and lung pathology. AB - Tuberculosis (TB) is responsible for significant morbidity and mortality worldwide. Even after successful microbiological cure of TB, many patients are left with residual pulmonary damage that can lead to chronic respiratory impairment and greater risk of additional TB episodes due to reinfection with Mycobacterium tuberculosis. Elevated levels of the proinflammatory cytokine tumor necrosis factor-alpha and several other markers of inflammation, together with expression of matrix metalloproteinases, have been associated with increased risk of pulmonary fibrosis, tissue damage, and poor treatment outcomes in TB patients. In this study, we used a rabbit model of pulmonary TB to evaluate the impact of adjunctive immune modulation, using a phosphodiesterase-4 inhibitor that dampens the innate immune response, on the outcome of treatment with the antibiotic isoniazid. Our data show that cotreatment of M. tuberculosis infected rabbits with the phosphodiesterase-4 inhibitor CC-3052 plus isoniazid significantly reduced the extent of immune pathogenesis, compared with antibiotic alone, as determined by histologic analysis of infected tissues and the expression of genes involved in inflammation, fibrosis, and wound healing in the lungs. Combined treatment with an antibiotic and CC-3052 not only lessened disease but also improved bacterial clearance from the lungs. These findings support the potential for adjunctive immune modulation to improve the treatment of pulmonary TB and reduce the risk of chronic respiratory impairment. PMID- 21703412 TI - Dual functions of prostaglandin D2 in murine contact hypersensitivity via DP and CRTH2. AB - Prostaglandin D2 (PGD2) exerts its effects through two distinct receptors: the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and the D prostanoid (DP) receptor. Our previous study demonstrated that CRTH2 mediates contact hypersensitivity (CHS) in mice. However, the function of DP receptor remains to be fully established. In this study, we examine the pathophysiological roles of PGD2 using DP-deficient (DP(-/-)) and CRTH2/DP deficient (CRTH2(-/-)/DP(-/-)) mice to elucidate receptor-mediated PGD2 action in CHS. We observed profound exacerbation of CHS in DP(-/-) mice. CRTH2(-/-)/DP(-/-) mice showed similar exacerbation, but to a lesser extent. These symptoms were accompanied by increased production of interferon-gamma and IL-17. The increase in IL-17 producing gammadelta T cells was marked and presumably contributed to the enhanced CHS. DP deficiency promoted the in vivo migration of dendritic cells to regional lymph nodes. A DP agonist added to DCs in vitro was able to inhibit production of IL-12 and IL-1beta. Interestingly, production of IL-10 in dendritic cells was elevated via the DP pathway, but it was lowered by the CRTH2 pathway. Collectively, PGD2 signals through CRTH2 to mediate CHS inflammation, and conversely, DP signals to exert inhibitory effects on CHS. Thus, we report opposing functions for PGD2 that depend on receptor usage in allergic reactions. PMID- 21703413 TI - Time-course and regional analyses of the physiopathological changes induced after cerebral injection of an amyloid beta fragment in rats. AB - Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid beta protein (Abeta) formed by pathological processing of the Abeta precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated Abeta fragment 25-35 (Abeta(25 35)) in rats. Using a combined biochemical, behavioral, and morphological approach, we analyzed the peptide effects after 1, 2, and 3 weeks in the hippocampus, cortex, amygdala, and hypothalamus. The scrambled Abeta(25-35) peptide was used as negative control. The aggregated forms of Abeta peptides were first characterized using electron microscopy, infrared spectroscopy, and Congo Red staining. Intracerebroventricular injection of Abeta(25-35) decreased body weight, induced short- and long-term memory impairments, increased endocrine stress, cerebral oxidative and cellular stress, neuroinflammation, and neuroprotective reactions, and modified endogenous amyloid processing, with specific time-course and regional responses. Moreover, Abeta(25-35), the presence of which was shown in the different brain structures and over 3 weeks, provoked a rapid glial activation, acetylcholine homeostasis perturbation, and hippocampal morphological alterations. In conclusion, the acute intracerebroventricular Abeta(25-35) injection induced substantial central modifications in rats, highly reminiscent of the human physiopathology, that could contribute to physiological and cognitive deficits observed in AD. PMID- 21703414 TI - Bmp6 regulates retinal iron homeostasis and has altered expression in age-related macular degeneration. AB - Iron-induced oxidative stress causes hereditary macular degeneration in patients with aceruloplasminemia. Similarly, retinal iron accumulation in age-related macular degeneration (AMD) may exacerbate the disease. The cause of retinal iron accumulation in AMD is poorly understood. Given that bone morphogenetic protein 6 (Bmp6) is a major regulator of systemic iron, we examined the role of Bmp6 in retinal iron regulation and in AMD pathogenesis. Bmp6 was detected in the retinal pigment epithelium (RPE), a major site of pathology in AMD. In cultured RPE cells, Bmp6 was down-regulated by oxidative stress and up-regulated by iron. Intraocular Bmp6 protein injection in mice up-regulated retinal hepcidin, an iron regulatory hormone, and altered retinal labile iron levels. Bmp6(-/-) mice had age-dependent retinal iron accumulation and degeneration. Postmortem RPE from patients with early AMD exhibited decreased Bmp6 levels. Because oxidative stress is associated with AMD pathogenesis and down-regulates Bmp6 in cultured RPE cells, the diminished Bmp6 levels observed in RPE cells in early AMD may contribute to iron build-up in AMD. This may in turn propagate a vicious cycle of oxidative stress and iron accumulation, exacerbating AMD and other diseases with hereditary or acquired iron excess. PMID- 21703416 TI - beta-catenin dosage is a critical determinant of tracheal basal cell fate determination. AB - The purpose of this study was to determine whether beta-catenin regulates basal cell fate determination in the mouse trachea. Analysis of TOPGal transgene reporter activity and Wnt/beta-catenin pathway gene expression suggested a role for beta-catenin in basal cell proliferation and differentiation after naphthalene-mediated Clara-like and ciliated cell depletion. However, these basal cell activities occurred simultaneously, limiting precise determination of the role(s) played by beta-catenin. This issue was overcome by analysis of beta catenin signaling in tracheal air-liquid interface cultures. The cultures could be divided into two phases: basal cell proliferation and basal cell differentiation. A role for beta-catenin in basal cell proliferation was indicated by activation of the TOPGal transgene on proliferation days 3 to 5 and by transient expression of Myc (alias c-myc). Another peak of TOPGal transgene activity was detected on differentiation days 2 to 10 and was associated with the expression of Axin 2. These results suggest a role for beta-catenin in basal to ciliated and basal to Clara-like cell differentiation. Genetic stabilization of beta-catenin in basal cells shortened the period of basal cell proliferation but had a minor effect on this process. Persistent beta-catenin signaling regulated basal cell fate by driving the generation of ciliated cells and preventing the production of Clara-like cells. PMID- 21703417 TI - P-cadherin promotes liver metastasis and is associated with poor prognosis in colon cancer. AB - P-cadherin belongs to the family of classic cadherins, which is important for maintaining cellular localization and tissue integrity. Recently, it has become evident that P-cadherin contributes to the oncogenesis of many tumor types, including melanoma, prostate, breast, and colon carcinomas. Although cadherin switching is a crucial step in metastasis, the role of P-cadherin in colon cancer metastasis to the liver is unknown. In this study, we performed gene expression analysis and found that the level of P-cadherin was higher in tissue from liver metastases of colon cancer than in the corresponding primary colon cancer tissues. IHC analysis also showed that P-cadherin expression was significantly higher in liver metastases than in paired primary colorectal cancer tumors. Knockdown of P-cadherin in colon cancer cells inhibited wound healing, proliferation, and colony formation and resulted in developing fewer liver metastatic foci and reducing the tumor burden in vivo. Inhibition of P-cadherin expression also induced the up-regulation of E-cadherin and the down-regulation of beta-catenin and its downstream target molecules, including survivin and c Myc. In summary, these results uncover a novel function of P-cadherin in the regulation of colon cancer metastasis to the liver, suggesting that blocking the activity of P-cadherin or its associated signaling may be a valuable target for the treatment of hepatic metastases of colon carcinomas. PMID- 21703415 TI - Effects of age and heart failure on human cardiac stem cell function. AB - Currently, it is unknown whether defects in stem cell growth and differentiation contribute to myocardial aging and chronic heart failure (CHF), and whether a compartment of functional human cardiac stem cells (hCSCs) persists in the decompensated heart. To determine whether aging and CHF are critical determinants of the loss in growth reserve of the heart, the properties of hCSCs were evaluated in 18 control and 23 explanted hearts. Age and CHF showed a progressive decrease in functionally competent hCSCs. Chronological age was a major predictor of five biomarkers of hCSC senescence: telomeric shortening, attenuated telomerase activity, telomere dysfunction-induced foci, and p21(Cip1) and p16(INK4a) expression. CHF had similar consequences for hCSCs, suggesting that defects in the balance between cardiomyocyte mass and the pool of nonsenescent hCSCs may condition the evolution of the decompensated myopathy. A correlation was found previously between telomere length in circulating bone marrow cells and cardiovascular diseases, but that analysis was restricted to average telomere length in a cell population, neglecting the fact that telomere attrition does not occur uniformly in all cells. The present study provides the first demonstration that dysfunctional telomeres in hCSCs are biomarkers of aging and heart failure. The biomarkers of cellular senescence identified here can be used to define the birth date of hCSCs and to sort young cells with potential therapeutic efficacy. PMID- 21703419 TI - Metastatic progression of prostate cancer and e-cadherin regulation by zeb1 and SRC family kinases. AB - Expression of E-cadherin is used to monitor the epithelial phenotype, and its loss is suggestive of epithelial-mesenchymal transition (EMT). EMT triggers tumor metastasis. Exit from EMT is marked by increased E-cadherin expression and is considered necessary for tumor growth at sites of metastasis; however, the mechanisms associated with exit from EMT are poorly understood. Herein are analyzed 185 prostate cancer metastases, with significantly higher E-cadherin expression in bone than in lymph node and soft tissue metastases. To determine the molecular mechanisms of regulation of E-cadherin expression, three stable isogenic cell lines from DU145 were derived that differ in structure, migration, and colony formation on soft agar and Matrigel. When injected into mouse tibia, the epithelial subline grows most aggressively, whereas the mesenchymal subline does not grow. In cultured cells, ZEB1 and Src family kinases decrease E-cadherin expression. In contrast, in tibial xenografts, E-cadherin RNA levels increase eight- to 10-fold despite persistent ZEB1 expression, and in all ZEB1-positive metastases (10 of 120), ZEB1 and E-cadherin proteins were co-expressed. These data suggest that transcriptional regulation of E-cadherin differs in cultured cells versus xenografts, which more faithfully reflect E-cadherin regulation in cancers in human beings. Furthermore, the aggressive nature of xenografts positive for E-cadherin and the frequency of metastases positive for E-cadherin suggest that high E-cadherin expression in metastatic prostate cancer is associated with aggressive tumor growth. PMID- 21703418 TI - Expression and regulation of the DeltaN and TAp63 isoforms in salivary gland tumorigenesis clinical and experimental findings. AB - The TP63 gene, a TP53 homologue, encodes for two main isoforms by different promoters: one retains (TA) and the other lacks (DeltaN) the transactivation domain. p63 plays a critical role in the maintenance of basal and myoepithelial cells in ectodermally derived tissues and is implicated in tumorigenesis of several neoplastic entities. However, the biological and regulatory roles of these isoforms in salivary gland tumorigenesis remain unknown. Our results show a reciprocal expression between TA and DeltaN isoforms in both benign and malignant salivary tumors. The most dominantly expressed were the DeltaN isoforms, whereas the TA isoforms showed generally low levels of expression, except in a few tumors. High DeltaNp63 expression characterized tumors with aggressive behavior, whereas tumors with high TAp63 expression were significantly smaller and less aggressive. In salivary gland cells, high expression of DeltaNp63 led to enhanced cell migration and invasion and suppression of cell senescence independent of TAp63 and/or TP53 gene status. We conclude the following: i) overexpression of DeltaNp63 contributes to salivary tumorigenesis, ii) DeltaNp63 plays a dominant negative effect on the TA isoform in the modulation of cell migration and invasion, and iii) the DeltaN isoform plays an oncogenic role and may represent an attractive target for therapeutic intervention in patients with salivary carcinomas. PMID- 21703420 TI - Fusion tyrosine kinase NPM-ALK Deregulates MSH2 and suppresses DNA mismatch repair function novel insights into a potent oncoprotein. AB - The fusion tyrosine kinase NPM-ALK is central to the pathogenesis of ALK-positive anaplastic large cell lymphoma (ALK(+)ALCL). We recently identified that MSH2, a key DNA mismatch repair (MMR) protein integral to the suppression of tumorigenesis, is an NPM-ALK-interacting protein. In this study, we found in vitro evidence that enforced expression of NPM-ALK in HEK293 cells suppressed MMR function. Correlating with these findings, six of nine ALK(+)ALCL tumors displayed evidence of microsatellite instability, as opposed to none of the eight normal DNA control samples (P = 0.007, Student's t-test). Using co immunoprecipitation, we found that increasing levels of NPM-ALK expression in HEK293 cells resulted in decreased levels of MSH6 bound to MSH2, whereas MSH2.NPM ALK binding was increased. The NPM-ALK.MSH2 interaction was dependent on the activation/autophosphorylation of NPM-ALK, and the Y191 residue of NPM-ALK was a crucial site for this interaction and NPM-ALK-mediated MMR suppression. MSH2 was found to be tyrosine phosphorylated in the presence of NPM-ALK. Finally, NPM-ALK impeded the expected DNA damage-induced translocation of MSH2 out of the cytoplasm. To conclude, our data support a model in which the suppression of MMR by NPM-ALK is attributed to its ability to interfere with normal MSH2 biochemistry and function. PMID- 21703421 TI - Prostate epithelial Pten/TP53 loss leads to transformation of multipotential progenitors and epithelial to mesenchymal transition. AB - Loss of PTEN and loss of TP53 are common genetic aberrations occurring in prostate cancer. PTEN and TP53 contribute to the regulation of self-renewal and differentiation in prostate progenitors, presumptive tumor initiating cells for prostate cancer. Here we characterize the transformed phenotypes resulting from deletion of the Pten and TP53 tumor suppressors in prostate epithelium. Using the PB-Cre4(+)Pten(fl/fl)TP53(fl/fl) model of prostate cancer, we describe the histological and metastatic properties of primary tumors, transplanted primary tumor cells, and clonal cell lines established from tumors. Adenocarcinoma was the major primary tumor type that developed, which progressed to lethal sarcomatoid carcinoma at approximately 6 months of age. In addition, basal carcinomas and prostatic urothelial carcinomas were observed. We show that tumor heterogeneity resulted, at least in part, from the transformation of multipotential progenitors. CK8+ luminal epithelial cells were capable of undergoing epithelial to mesenchymal transition in vivo to sarcomatoid carcinomas containing osseous metaplasia. Metastasis rarely was observed from primary tumors, but metastasis to lung and lymph nodes occurred frequently from orthotopic tumors initiated from a biphenotypic clonal cell line. Androgen deprivation influenced the differentiated phenotypes of metastases. These data show that one functional consequence of Pten/TP53 loss in prostate epithelium is lineage plasticity of transformed cells. PMID- 21703422 TI - Human renal cell carcinoma induces a dendritic cell subset that uses T-cell crosstalk for tumor-permissive milieu alterations. AB - Tissue dendritic cells (DCs) may influence the progression of renal cell carcinoma (RCC) by regulating the functional capacity of antitumor effector cells. DCs and their interaction with T cells were analyzed in human RCC and control kidney tissues. The frequency of CD209(+) DCs in RCCs was found to be associated with an unfavorable T(H)1 cell balance in the tissue and advanced tumor stages. The CD209(+) DCs in RCC were unusual because most of them co expressed macrophage markers (CD14, CD163). The phenotype of these enriched-in renal-carcinoma DCs (ercDCs) could be reiterated in vitro by carcinoma-secreted factors (CXCL8/IL-8, IL-6, and vascular endothelial growth factor). ErcDCs resembled conventional DCs in costimulatory molecule expression and antigen cross presentation. They did not suppress cognate cytotoxic T-lymphocyte function and did not cause CD3zeta down-regulation, FOXP3 induction, or T-cell apoptosis in situ or in vitro; thus, they are different from classic myeloid-derived suppressor cells. ErcDCs secreted high levels of metalloproteinase 9 and used T cell crosstalk to increase tumor-promoting tumor necrosis factor alpha and reduce chemokines relevant for T(H)1-polarized lymphocyte recruitment. This modulation of the tumor environment exerted by ercDCs suggests an immunologic mechanism by which tumor control can fail without involving cytotoxic T-lymphocyte inhibition. Pharmacologic targeting of the deviated DC differentiation could improve the efficacy of immunotherapy against RCC. PMID- 21703423 TI - Combination therapy of an inhibitor of group VIA phospholipase A2 with paclitaxel is highly effective in blocking ovarian cancer development. AB - We and others have shown that calcium-independent phospholipase A(2) (iPLA(2)) is involved in epithelial ovarian cancer (EOC). Hence, we propose that iPLA(2) is a potential effective and novel target for EOC. We tested this concept and found that bromoenol lactone (BEL), a selective inhibitor of iPLA(2), significantly inhibited EOC metastatic tumor growth in mouse xenograft models using human SKOV3 and HEY ovarian cancer cells. Moreover, the combination of BEL with paclitaxel (PTX), one of the most commonly used therapeutic agents in EOC, almost completely blocked tumor development in the xenograft mouse model. BEL showed no detectable cytotoxic effects in mice. Another iPLA(2) inhibitor, FKGK11, also inhibited tumor development in the xenograft mouse model, supporting that the major target of action was iPLA(2). The additional effects of BEL with PTX in vivo likely stem from their distinct cellular effects. BEL and FKGK11 reduced adhesion, migration, and invasion of EOC cells in vitro; the reduced ability to adhere, migrate, and invade seems to increase the vulnerability of tumor cells to PTX. These results provide an important basis for the development of new treatment modalities for EOC. PMID- 21703424 TI - NPAS3 demonstrates features of a tumor suppressive role in driving the progression of Astrocytomas. AB - Malignant astrocytomas, the most common primary brain tumors, are predominantly fatal. Improved treatments will require a better understanding of the biological features of high-grade astrocytomas. To better understand the role of neuronal PAS 3 (NPAS3) in diseases in human beings, it was investigated as a candidate for astrocytomagenesis based on the presence of aberrant protein expression in greater than 70% of a human astrocytoma panel (n = 433) and most notably in surgically resected malignant lesions. In subsequent functional studies, it was concluded that NPAS3 exhibits features of a tumor-suppressor, which drives the progression of astrocytomas by modulating the cell cycle, proliferation, apoptosis, and cell migration/invasion and has a further influence on the viability of endothelial cells. Of clinical importance, absence of NPAS3 expression in glioblastomas was a significantly negative prognostic marker of survival. In addition, malignant astrocytomas lacking NPAS3 expression demonstrated loss of function mutations, which were associated with loss of heterozygosity. While overexpressed NPAS3 in malignant glioma cell lines significantly suppressed transformation, the converse decreased expression considerably induced more aggressive growth. In addition, knockdown NPAS3 expression in a human astrocyte cell line in concert with the human papillomavirus E6 and E7 oncogenes induced growth of malignant astrocytomas. In conclusion, NPAS3 drives the progression of human malignant astrocytomas as a tumor suppressor and is a negative prognostication marker for survival. PMID- 21703425 TI - RREB1 transcription factor splice variants in urologic cancer. AB - RREB1 is an alternatively spliced transcription factor implicated in Ras signaling and cancer. Little is known about the expression of RREB1 isoforms in cell lines or human tumors, or about the clinical relevance of the latter. We have developed tools for IHC of RREB1 protein isoform-specific amplification of RREB1 mRNA and selective knockdown of RREB1 isoforms and use these to provide new information by characterizing RREB1 expression in bladder and prostate cancer cell lines and human tissue samples. Previously described splice variants RREB1alpha, RREB1beta, RREB1gamma, and RREB1delta were identified, as well as the novel variant RREB1epsilon. Total and isoform-specific mRNA expression was lower in most but not all tumors, compared with normal tissues. RREB1 IHC performed on a bladder cancer TMA did not indicate a relationship between total RREB1 expression and overall survival after radical cystectomy for invasive bladder cancer. In contrast, in vitro proliferation studies using the UMUC-3 bladder cancer cell line after selective isoform-specific knockdown of expression indicate that RREB1alpha is not necessary for proliferation, but that RREB1beta may be required. These contributions should accelerate progress in the nascent RREB1 field by providing new reagents while also providing clues to the role of RREB1 isoforms in human cancer and raising the possibility of isoform-specific roles in human carcinogenesis and progression. PMID- 21703426 TI - Modeling colon adenocarcinomas in vitro a 3D co-culture system induces cancer relevant pathways upon tumor cell and stromal fibroblast interaction. AB - Activated tumor stroma participates in tumor cell growth, invasion, and metastasis. Normal fibroblasts and cancer-associated fibroblasts (CAFs) have been shown to display distinct gene expression signatures. This molecular heterogeneity may influence the way tumor cells migrate, proliferate, and survive during tumor progression. To test this hypothesis and to better understand the molecular mechanisms that control these interactions, we established a three dimensional (3D) human cell culture system that recapitulates the tumor heterogeneity observed in vivo. Human colon tumor cells were grown as multicellular spheroids and subsequently co-cultured with normal fibroblasts or CAFs in collagen I gels. This in vitro model system closely mirrors the architecture of human epithelial cancers and allows the characterization of the tumor cell-stroma interactions phenotypically and at the molecular level. Using GeneChip analysis, antibody arrays, and enzyme-linked immunosorbent assays, we demonstrate that the interaction of colon cancer cells with stromal fibroblasts induced different highly relevant cancer expression profiles. Genes involved in invasion, extracellular matrix remodeling, inflammation, and angiogenesis were differentially regulated in our 3D carcinoma model. The modular setup, reproducibility, and robustness of the model make it a powerful tool to identify target molecules involved in signaling pathways that mediate paracrine interactions in the tumor microenvironment and to validate the influence of these molecular targets during tumor growth and invasion in the supporting stroma. PMID- 21703427 TI - Slow disease progression in a C57BL/6 pten-deficient mouse model of prostate cancer. AB - Prostate-specific deletion of Pten in mice has been reported to recapitulate histological progression of human prostate cancer. To improve on this model, we introduced the conditional ROSA26 luciferase reporter allele to monitor prostate cancer progression via bioluminescence imaging and extensively backcrossed mice onto the albino C57BL/6 genetic background to address variability in tumor kinetics and to enhance imaging sensitivity. Bioluminescence signal increased rapidly in Pten(p-/-) mice from 3 to 11 weeks, but was much slower from 11 to 52 weeks. Changes in bioluminescence signal were correlated with epithelial proliferation. Magnetic resonance imaging revealed progressive increases in prostate volume, which were attributed to excessive fluid retention in the anterior prostate and to expansion of the stroma. Development of invasive prostate cancer in 52-week-old Pten(p-/-) mice was rare, indicating that disease progression was slowed relative to that in previous reports. Tumors in these mice exhibited a spontaneous inflammatory phenotype and were rapidly infiltrated by myeloid-derived suppressor cells. Although Pten(p-/-) tumors responded to androgen withdrawal, they failed to exhibit relapsed growth for up to 1 year. Taken together, these data identify a mild prostate cancer phenotype in C57BL/6 prostate-specific Pten-deficient mice, reflecting effects of the C57BL/6 genetic background on cancer progression. This model provides a platform for noninvasive assessment of how genetic and environmental risk factors may affect disease progression. PMID- 21703430 TI - [Education and training of young psychiatrists: is there time for research?]. PMID- 21703428 TI - Targeting protease-activated receptor-1 with cell-penetrating pepducins in lung cancer. AB - Protease-activated receptors (PARs) are G-protein-coupled receptors that are activated by proteolytic cleavage and generation of a tethered ligand. High PAR1 expression has been documented in a variety of invasive cancers of epithelial origin. In the present study, we investigated the contribution of the four PAR family members to motility of lung carcinomas and primary tumor samples from patients. We found that of the four PARs, only PAR1 expression was highly increased in the lung cancer cell lines. Primary lung cancer cells isolated from patient lung tumors migrated at a 10- to 40-fold higher rate than epithelial cells isolated from nonmalignant lung tissue. Cell-penetrating pepducin inhibitors were generated against the first (i1) and third (i3) intracellular loops of PAR1 and tested for their ability to inhibit PAR1-driven migration and extracellular regulated kinase (ERK)1/2 activity. The PAR1 pepducins showed significant inhibition of cell migration in both primary and established cell lines similar to silencing of PAR1 expression with short hairpin RNA (shRNA). Unlike i1 pepducins, the i3 loop pepducins were effective inhibitors of PAR1 mediated ERK activation and tumor growth. Comparable in efficacy with Bevacizumab, monotherapy with the PAR1 i3 loop pepducin P1pal-7 provided significant 75% inhibition of lung tumor growth in nude mice. We identify the PAR1-ERK1/2 pathway as a feasible target for therapy in lung cancer. PMID- 21703429 TI - Lung-residing metastatic and dormant neuroblastoma cells. AB - The mechanism by which dormant tumor cells can begin growing after long periods of inactivity and accelerate disease recurrence is poorly understood. The present study characterizes dormant neuroblastoma (NB) cells, as well as metastatic cells, which reside in the same organ microenvironment. A xenograft model of human NB consisting of variants that generate nonmetastatic local tumors in the orthotopic inoculation site and variants that generate lung metastatic NB (MetNB) cells was developed in our laboratory. The present study shows that lungs of mice inoculated with nonmetastatic NB variants contain disseminated neuroblastoma (DisNB) human cells. Both DisNB and MetNB variants expressed a similar tumorigenicty phenotype in vivo, whereas the MetNB variants produced a heavy metastatic load and the DisNB variants produced no or little metastasis. A comparative in vitro characterization of MetNB and DisNB cells revealed similarities and differences. DisNB, but not MetNB cells, expressed the minimal residual disease markers PHOX2B and TH. MetNB cells demonstrated higher migratory capacity, an elevated matrix metalloproteinase (MMP) secretion, and a higher constitutive phosphorylation of extracellular signal-regulated kinase (ERK) than DisNB cells. We suggest that characteristics common to both MetNB and DisNB cells were acquired relatively early in the metastatic process and the characteristics that differ between these variants were acquired later. We hypothesize that the DisNB cells are metastasis precursors, which may progress toward metastasis under certain microenvironmental conditions. PMID- 21703431 TI - [Relationship between insight and self-reported quality of life among shizophrenic patients]. AB - BACKGROUND: Shizophrenia is a long-lasting condition with either episodic or continuous evolution that can result in physical, psychological, and social problems related to both the disease itself and the potential side-effects of treatments. These various aspects should be taken into account when assessing the outcome of medical management of patients suffering from schizophrenia. Subjective criteria, such as quality of life (QoL) measurements, should be considered an important focus for evaluation in this population. A major subgroup of patients with schizophrenia lacks insight of having a mental disorder or symptoms of a mental disorder. Studies on the relationship between insight and QoL have produced inconsistent results. While some studies found positive associations between insight and QoL, others found negative ones. Some possible explanations for the discrepancies between these findings can be expressed: differing patients' characteristics, heterogeneous insight or QoL measures, sample size and methodological differences. None of the previous research studies have looked at relationships between insight and QoL, as assessed respectively using the scale to assess unawareness of mental disorder (SUMD, a widely multidimensional insight questionnaire), and the S-QoL (a disease-specific patient-based instrument). AIM OF THE STUDY: The aim of this study was to assess the impact of insight into illness on the self-reported QoL as determined by schizophrenic patients, while taking into account the key confounding factors. METHODOLOGY: This study incorporated a cross-sectional design and took place in the psychiatric department of a French public university teaching hospital (Marseille, France). The inclusion criteria were: diagnosis of schizophrenia or schizoaffective disorder (DSM-IV-R), age over 18, native French speaker, agreement to participate. The following data were recorded: sociodemographic parameters (age, gender, marital status, education level, occupational activity), clinical data (in- or out-patient, clinical form), and psychopathology (Positive And Negative Syndrome Scale, PANSS). Insight was assessed using the Scale to assess Unawareness of Mental Disorder (SUMD), a standardised expert-rating scale based on a patient interview describing nine domains. The S-QoL is a self administered disease-specific instrument validated from patients' views that includes 41 items and describes eight dimensions (psychological well-being, self esteem, family relationships, relationships with friends, resilience, physical well-being, autonomy, and sentimental life), and yielding a global index score. RESULTS: One hundred and fifty-three patients were enrolled (mean age 37.6, standard deviation 11.2). Patients with good insight generally reported a lower global QoL score, whatever the insight domains. Insight of mental disorder is the most important domain affecting QoL levels. Psychological well-being, self esteem, physical well-being, and autonomy scores were significantly lower for subjects with good insight. Multivariate analysis showed that insight of mental disorder is the only parameter linked to the S-QoL index. No links were found between other insight domains and S-QoL index. CONCLUSION: Patients with good insight might realise consequences of their mental illness with restrictions in daily living and alteration of their QoL, while patients with poor insight might partially overrate their QoL and present themselves as more competent. PMID- 21703432 TI - [Pain and depression: cognitive and behavioural mediators of a frequent association]. AB - LITERATURE FINDINGS: The comorbidity between chronic pain and depression is high: in the general population setting, the odds ratio for suffering from one of these disorders when suffering from the other is estimated around 2.5. For chronic pain patients consulting in pain clinics, the comorbidity rate reaches one third to half of the patients. For the International Association for the Study of Pain (IASP), pain consists in an emotional as well as a sensory dimension, both of them have to be assessed systematically. Likewise, affective disorders must be systematically depicted in chronic pain patients. The reasons for such comorbidity are complex and result from the conjunction of common risk factors (environmental and genetic vulnerability factors) and of a bidirectional causality. THE TRANSACTIONAL MODEL OF STRESS AND COPING OF LAZARUS ET FOLKMAN: The appraisal stress model (Lazarus and Folkman, 1984) offers an opportunity to understand how chronic pain can cause depression. Pain is conceptualized as a chronic stress. Its appraisal in terms of loss, injustice, incomprehensibility or changes (primary appraisal), and in terms of control (secondary evaluation) determine how the subject will cope with pain. Several personality traits as optimism, hardiness or internal locus of control play a protective role on these evaluations, whereas others (neuroticism, negative affectivity or external locus of control) are risk factors for depression. Low perceived social support is also related to depression. On the contrary, self-efficiency is linked with low levels of depression. Self-management therapies focus on increase of perceived control of pain by the patient in order to improve his/her motivation to change, and to let the patient become active in the management of his/her pain. CONCLUSION: According to Lazarus and Folkman (1984), coping strategies are the constantly changing cognitive and behavioural efforts to manage specific external and/or internal demands that are appraised as taxing on or exceeding the resources of the person. Pain patients can use a wide variety of pain coping strategies: problem versus emotion focused strategies or cognitive versus behavioural strategies. Some of them are highly dysfunctional, such as catastrophizing (cognitive strategy) or avoidance (behavioural strategy). Their preferential use can lead to the development of a depressive episode. The "fear-avoidance model" (Vlayen, 2000) explains pain chronicization by a vicious circle that begins with the pain catastrophizing; this leads to fear of pain, which in turn leads to avoidance and finally to pain and depression. This is why some behavioural cognitive interventions focus on the reduction of catastrophizing and avoidance. Some functional pain coping strategies were identified: they are active strategies centred on problem resolution such as distraction, reinterpretation or ignorance of pain sensations, acceptance, and exercise and task persistence. New therapeutic interventions focus on the development of better coping strategies such as distraction, relaxation and acceptance. PMID- 21703433 TI - [Attention deficit disorder: multidisciplinary observational study over 1 year]. AB - INTRODUCTION: In France, attention deficit disorder (ADHD) has traditionally met with two opposing approaches (biological and psychoanalytic). This conflict led us to conduct a multidisciplinary observational study, on a group of 36 children over a period of 1 year. METHODS: Thirty-six children with ADHD diagnostic (DSM IV), not treated by MPH were included. Initial "multi-field" evaluation (T0) consisted of: neuro-paediatric consultation (Conners questionnaire, Child Behaviour Checklist, reading and writing scores by French tests); semi-structured child psychiatric interview (DSM-IV axis I), structural hypothesis (CFTMEA), existence of narcissistic fragility, parents/child interactions; neuropsychological standardized evaluation (attention and executive functions); psychodynamic interview and projective tests (Rorscharch, CAT or TAT). A therapeutic project is proposed combining MPH and psychotherapy according to the results. A new evaluation 1 year later (T1) included a consultation and a neuropsychological evaluation. RESULTS T0: All parental questionnaires appreciating attention deficit and hyperactivity/impulsivity were significantly pathological. The neuropsychological evaluation showed usual characteristics of ADHD with individual differences. The psychiatric evaluation revealed the frequency of comorbidity in axis I (23% of children with more than two diagnoses, 57% with anxiety disorder, 23 and 3% with oppositional and conduct disorder). FOLLOW UP (T1): Thirty-one children were re-examined (20 treated by MPH and 11 not treated because of parental refusal or particular psychopathological situations). Psychoanalytical psychotherapy, proposed to 28 children, was undertaken with only 19. An improvement in scores for attention and executive tests was registered only in the treated group. DISCUSSION: The tests confirm deficits of attention and executive functions without correlation with the scores of questionnaires, underlining the need for a neuropsychological evaluation to objectify attention disorders. Projective tests refine and enrich psychiatric evaluation and showed that half of the children had borderline organization. However, structural hypotheses were heterogeneous, suggesting the need for specific therapeutic projects to be devised according to each child. The treated children were the only ones to improve attention deficit. On the other hand, the scores of anxiety are not improved by MPH, emphasizing the indications of psychotherapy if comorbidity is present. Psychotherapeutic care was carried out only among part of the population, because of parental reservations, exacerbated by differences of opinion among professionals and lack of access. CONCLUSION: This study is innovative, providing precise data on ADHD from a multidisciplinary perspective. Psychopathological comorbidity is high in this population, so the concept of ADHD cannot be limited to a cognitive point of view. These elements and doubts regarding the efficacy of behavioural therapies suggest the need for a rigorous evaluation of analytical psychotherapies independent of MPH to treat attention deficit. PMID- 21703434 TI - [The FAQ self-report is a valid instrument to characterize endophenotypes of the autistic spectrum in parents of children with autism]. AB - BACKGROUND: We have previously developed the FAQ self-report, an adaptation of the Baron-Cohen's Autism Quotient self-report, in order to detect traits of the autistic spectrum in the parents and siblings of children with autism. We have previously shown that parents of children with autism show significant differences in their global scores and in their social functioning scores according to their answers to the FAQ self-report. OBJECTIVE: Our aim was to validate the FAQ self-report in a population of control parents, and to confirm our previous results concerning parents of children with autism. METHODOLOGY: Hundred and twenty-seven adults (67 female, 60 male), parents of children with normal development were recruited in the general population. They were asked to fulfill the 40 questions of the FAQ self-report at two different times. Sixty-six parents of children with autism were asked to fulfill the FAQ self-report, for group comparisons. Statistical factor analysis and test-retest reliability analysis was performed with the Matlab toolbox((c)) software. RESULTS: Statistical factor analysis and test-retest reliability show that the FAQ is structured in two main factors, socialization and communication on one hand, rigidity and imagination on the other, with good test-retest reliability. Further comparison between parents of children with autism and control parents shows a significant difference between the two groups for the socialization and communication domain, and for the global score. We show for the first time that scores of the parents of children with autism remain unchanged from infancy to adulthood. CONCLUSION: The FAQ is the first French validated self-report focused on the detection of traits of the autistic spectrum in parents and siblings of children with autism. It is structured in two main factors, corresponding to imagination/rigidity, which are negatively correlated, and communication and socialization, which are positively correlated. The FAQ is therefore a reliable instrument to measure endophenotypes associated with the autistic spectrum in parents of children with autism, and may be useful in genetic studies. PMID- 21703435 TI - [Influence of paternal age in schizophrenia]. AB - BACKGROUND: Schizophrenia is an aetiologically heterogeneous syndrome, with a strong genetic component. Despite a reduced fertility in this disorder, its prevalence is maintained and could be explained by de novo genetic mutations. Advanced paternal age (APA) is a major source of new mutations in human beings and could thus be associated with an increased risk of developing schizophrenia in offspring. New mutations related to APA have been implicated as a cause of sporadic cases in several autosomal dominant diseases and also in neurodevelopmental diseases, autism, intellectual disabilities, and social functioning. The aim of the present study was to summarize the results of studies investigating the role of APA, and to discuss some interpretations. METHODS: All relevant studies were identified through the National Library of Medicine (PubMed((r)) database). Keywords used for research were "age" and "schizophrenia" linked to "paternal or father". We have identified and analysed eight cohort studies, five case-control studies, two meta-analyses, and one review concerning different father's mutations potentially transmitted, two studies comparing paternal age at conception between sporadic versus familial cases of schizophrenia. All studies selected have been published between 2000 and 2009. RESULTS: After controlling for several confounding factors including maternal age, the relative risk of schizophrenia increased from 1.84 to 4.62 in offspring of fathers with an older age of fatherhood. Mother's age showed no significant effects after adjusting for paternal age. There was a significant association between paternal age and risk of developing schizophrenia, there was a weaker association with psychosis. DISCUSSION: The results of these different studies are confirmed by two recent meta-analyses which found an increased risk of schizophrenia in offspring of fathers older than 35 years. Two main hypotheses could explain these results. The first one is based on the presence of new mutations in the spermatogonia, possibly because of accumulating replication errors in spermatogonial cell lines. This hypothesis is confirmed by Malaspina et al. (2002) [19], who found that patients without a family history of schizophrenia had significantly older fathers than probands with a positive family history of schizophrenia. However, this result has not been confirmed by other studies, and paternal age effect could be also explained by a mechanism called imprinting, which is a form of gene regulation. The second hypothesis is based on the fact that fathers with schizophrenia spectrum personality disorder, known to be genetically related to schizophrenia, could have an advanced age at conception. However, regarding this hypothesis, advanced maternal age at conception should be a risk factor for schizophrenia, and this is not the case. Thus, the first hypothesis seems more plausible than the second. APA has been identified as a risk factor for other psychiatric disorders such as autism, bipolar disorder, obsessive-compulsive disorder, and phobia, and thus seems to be a non-specific risk factor. Furthermore, its association with impaired neurocognitive outcomes during infancy and childhood in normal populations raises the question of the phenotype linked to APA. CONCLUSION: APA at conception appears to be a risk factor for schizophrenia. This risk factor probably interacts with genetic factors in a gene-environment interaction. To date, there is no validated cut-off at which the risk is significantly increased in offspring. In the future, studies could benefit from analyzing the phenotype related to APA. PMID- 21703436 TI - [Relapse in schizophrenia: an exploratory study of the joint conceptions of patients, parents and caregivers]. AB - INTRODUCTION: The question of the course of schizophrenia relapses, is of considerable interest in different clinical and social areas such as prognosis, quality of life, therapeutic relationship, psychoeducation, rehabilitation and so on. The more the schizophrenic relapses, the higher the level of handicap. Although there is a widespread agreement that it is essential to detect early signs of relapses in order to prevent them, there still remain theoretical and methodological difficulties in identifying these signs because they are personal, heterogeneous and not always specific to psychosis. That is why the notion of "relapse signature" seems relevant by taking into account differentiated and personal assessment of early signs of relapse. This implies the consideration of the different visions of relapse given by patients, parents and caregivers. OBJECTIVE: We propose a qualitative study of the joint appraisal of patients, patients' parents and medical staff. The aim of this study is to regroup the expertises in order to further our understanding of the early signs of relapse. We assume that patients and parents are able to describe signs that are not considered as pathological symptoms, but refer to a personal manner of initiating the relapse process. This should then help in designing early intervention and provide reinforced therapeutic alliance and more positive responses to psychoeducation programs. METHOD: We have interviewed 30 subjects divided in three groups: 10 schizophrenic patients, 10 caregivers (including physicians, psychologists and nurses) and 10 parents of schizophrenics. The patients met the following criteria: patients with a diagnosis of schizophrenia (DSM IV criteria), under neuroleptic treatment, and stabilized. The mean duration of illness was 15 years. The patients as well as caregivers were recruited in two external hospital structures. All the subjects gave their written consent for this study and its methods. We did not recruit parents who were not living with their schizophrenic child or who did not see or have frequent contact with him or her for this study. We conducted a semistructured interview and analysed the transcripts of the narratives provided by our three groups on the definition of relapse and early signs of relapse. Recorded interviews were processed using the Alceste Method, a computer program of textual analysis that identifies the word patterns most frequently used by the subjects. Alceste creates classes of words using a hierarchical descending classification. The description of each class is presented in the form of a word list (with the value of the word's Chi(2) association in this class). We assessed the awareness of problems using the 8-Q. RESULTS: The three groups described relapses as a distressed, even traumatic experience. This experience is shared by the patients' siblings who sometimes mention violent situations and difficulties at home. The analysis showed that each group uses a compartmentalized universe of speech. This raises the question of the communication and the sharing of information between the different groups. Parents who didn't live the relapse of their children and the caregivers gave prepsychotic or psychotic symptoms of relapse. Conversely, parents who had lived relapse(s) of their children gave nonspecific and very personalized signs of relapse (e.g., "When she relapses, our daughter eats much more cheese than usually"). The patients with a low level of awareness of his/her problem were able to describe early signs of relapse. They described mood and sleep disturbances. This is an unexpected result and calls for a debate on the need or not to have good insight in order to follow a psychoeducation program. CONCLUSION: This study insists on the complementarity of different conceptions of all persons involved in schizophrenic relapse in order to identify as accurately as possible the "relapse signature" of patients. According to us, and in order to promote suitable subjective data to increase insight, compliance and therapeutic alliance, psychoeducation programs should rely on these personal criteria rather than propose systematic programs. Then the relapse signature could be the first step to the appropriation of the course of illness and control of psychotic symptoms by schizophrenic patients. PMID- 21703437 TI - [Evaluation of the characteristics of addiction to online video games among adolescents and young adults]. AB - OBJECTIVES: The objectives of this study are to assess the social characteristics, coping strategies, self-esteem and depressive symptoms in a population-dependent and not dependent on video games online, in order to investigate the correlations existing between these characteristics. METHOD: The study was conducted among 193 subjects. Data were collected through a global questionnaire constituted of several scales. The global questionnaire consisted of a sociodemographic part (age, sex, social status, most played game, number of hours per week devoted to the game), a questionnaire assessing dependence and abuse according to the DSM -IV-TR, the feeling of social belonging scale (or ESAS which was doubled to collect information about the belonging in real life and virtual life), the Ways of coping check-list (WCCL), the Rosenberg self-esteem scale (EES), the Quality of interpersonal relations scale (EQRI), the UCLA Loneliness scale and the Center for epidemiologic studies depression scale (CES D). The questionnaire was broadcasted on the Internet, specifically in the forums dedicated to "massively multiplayer online role-playing games" and in young people's forums in specific subject headings. RESULTS: The results show that there are significant differences between the two populations, especially regarding the social characteristics, depressive symptoms, self-esteem and coping strategies. In the entire population, 66 subjects (42%) were considered dependent on online video games and 92 subjects (58%) were not considered dependent. In the dependent population, the number of hours spent playing per week, the score of social belonging in the virtual life, the coping focused on the emotion, the score of loneliness or social isolation and the score obtained on the CES-D appeared more important than the scores obtained by the non-dependent. Moreover, the average age, the scores of social belonging in real life, self-esteem and sub dimensions "family" and "friends" of the quality of interpersonal relations scale are lower than those obtained by the non-dependent. Furthermore, the number of hours of play per week, the feeling of social belonging, self-esteem, quality of family relationships and loneliness are predictive factors of addiction to video games online. CONCLUSION: These results suggest that one of the crucial issues in dependence is the monitoring of game practice. Indeed, dependence on video games is based on a real hardware that needs to be controlled and managed by a third party before the emergence of a dependency. Therefore the results of this study suggest the establishment of better prevention, especially among parents who are confronted in majority with a world and a technology that is unknown or too complicated. In the case of a proven addiction, the study proposes care therapy focused on the social link, especially the family link, and a particular care to work on self-esteem. PMID- 21703438 TI - [Life-events incidence in Alzheimer disease: preliminary study on the ABORD program]. AB - INTRODUCTION: Alzheimer disease has been studied according to several approaches: neurological, cognitive, or psychodynamic. Investment in the latter is sparse although it provides an essential clinical overview for global understanding of the disease. OBJECTIVES AND METHODS: This study followed the Alzheimer Observation Bank of Research and Data (ABORD) programme, which began in the 1980s. Fifty-nine subjects suffering from Alzheimer disease were compared to 31 control subjects, in order to search for an association between vulnerability factors linked to the life story and future clinical outbreak of Alzheimer disease. The study was carried out with an 11-item questionnaire on difficult life events. They concerned childhood, stress inductive situations, separation or bereavement experiences, family background or psychiatric history. RESULTS: Control subjects experienced less difficult events (Chi(2)=5.87; P<0.05). An accumulation of deleterious life events can impact on psychic economy. Pathogenic factors appear, sick people have more often been placed before the age of 10 (Chi(2)=5.06; P<0.01), and recognize more psychiatric family history and/or psychic vulnerability (Chi(2)=5.06; P<0.05). Difficult life events can impact on the subject's ability to grieve, and so the elaboration of losses linked with ageing can become difficult and exceed the psychic ability of the subject, which can be further disrupted by cerebral lesions or pathogenic factors. Hence, the subject could make an unconscious choice of a rescue mental running, which appears in the development of Alzheimer. A protective factor has been found: spiritual practice referring to a form of faith or philosophical adherence (Chi(2)=5.64; P<0.05). PMID- 21703439 TI - [Alcohol and epilepsy: a case report between alcohol withdrawal seizures and neuroborreliosis]. AB - OBJECTIVES: This work consists in a study of the links between alcohol, a psychoactive substance and different related epileptic manifestations in order to clarify predominant factors both on conceptual, clinical and therapeutic levels. BACKGROUND: If alcohol is a frequent risk factor for seizures, its scientific evidence is less clear and ad hoc literature is rich in controversies and not firmly supported by systematic surveys. Alcohol has variable roles in the physiopathological determinism of seizures, the nosographical status of which needs to be clarified: alcohol withdrawal seizures, alcoholic epilepsy, and sometimes symptomatic epilepsy caused by coincidental disorders. METHODS: A synthesis of relevant literature describing the links between alcohol and epilepsy is illustrated by a clinical case: a patient admitted in our psychiatric ward for chronic alcoholism had had two seizures questioning their nosographical status. An infectious process with protean neurological manifestations, neuroborreliosis, was diagnosed. DISCUSSION: Three distinct clinical pictures illustrate the links between alcohol and epilepsy: the first, convulsive inebriation corresponds to a seizure during severe acute alcohol intoxication. The second deals with alcohol withdrawal seizures following a partial or complete sudden withdrawal of alcohol; these are the clinical features the most documented in the literature representing, with delirium tremens, the main complication of alcohol withdrawal. The third clinical picture, alcoholic epilepsy, is characterized by repetitive seizures in patients presenting alcohol abuse without former history of epilepsy or other potentially epileptic disorder, and without relationship to alcohol withdrawal or acute alcohol intoxication. Acute and chronic effects of alcohol on central nervous system have been depicted, while a unified classification of alcohol related seizures has been recently established by Bartolomei. This classification based on the Ballenger hypothesis of kindling (1978) could explain withdrawal and hazardous seizures as clinical expressions of the same epileptogenic process over different stages. Although theoretically criticized, such a model offers a conceptual interest while able to unify the varied understanding of convulsive crises related to alcohol, and a practical one, whilst being a basis for a therapeutic approach. Our clinical case illustrates the delay in the diagnosis established after two iterative generalized seizures, 72 hours after the beginning of a programmed weaning of a patient presenting alcohol dependency. If the withdrawal seizure hypothesis was underlined, some data led to symptomatic epilepsy. Firstly atypia, the well supervised preventive treatment of convulsion did not avoid seizures. Secondly, the EEG showed focal anomalies strongly linked in the literature with a cerebral disorder, which was confirmed by MRI; thirdly, cognitive alterations, which are not usual in alcohol dependency, were observed clinically and confirmed by neuropsychological tests. Finally a neuroborreliosis was diagnosed, while the main neuropsychiatric complications of Lyme disease were described. In accordance with the recommendations made by some authors, it appeared legitimate to consider neuroborreliosis as a potential differential diagnosis of every atypical psychiatric disorder, the interest of such an identification laying in the existence of a specific treatment. PMID- 21703440 TI - [8th neuroplasticity International Workshop, October 23-24, 2010]. PMID- 21703441 TI - [Legal counselling and depression - the experience of a legal advisor]. PMID- 21703442 TI - p63 and epithelial metaplasia: a gutsy choice. AB - Barrett's esophagus is an epithelial metaplasia associated with an increased risk for cancer, but its underlying mechanisms have been debated. Now Wang et al. (2011) suggest an intriguing explanation for this puzzle: a population of residual embryonic cells, lacking the transcription factor p63, migrates and repopulates a normal tissue damaged by inflammation or gastroesophageal reflux. PMID- 21703443 TI - Stress signaling etches heritable marks on chromatin. AB - Transgenerational inheritance of epigenetic states allows organisms to pass on adaptive responses to the environment to their offspring. Seong et al. (2011) now reveal how stress-induced signaling through dATF-2 disrupts heterochromatin and leaves heritable marks that influence patterns of gene expression in subsequent generations. PMID- 21703444 TI - Stuck in the middle: drugging the ubiquitin system at the e2 step. AB - The discovery of a small-molecule allosteric inhibitor of the CDC34 ubiquitin conjugating enzyme (E2) by Ceccarelli et al. raises the possibility that it will be generally feasible to selectively inhibit ubiquitin transfer at this central step in the ubiquitin pathway. PMID- 21703445 TI - The pessimist's and optimist's views of adult neurogenesis. AB - The reports by Bonaguidi et al. (in this issue of Cell) and Encinas et al. (in Cell Stem Cell) come to differing conclusions about whether and how the proliferation of radial glia-like stem cells of the adult hippocampus impacts their long-term potential for neurogenesis. PMID- 21703446 TI - Life at the leading edge. AB - Cell migration requires sustained forward movement of the plasma membrane at the cell's front or "leading edge." To date, researchers have uncovered four distinct ways of extending the membrane at the leading edge. In lamellipodia and filopodia, actin polymerization directly pushes the plasma membrane forward, whereas in invadopodia, actin polymerization couples with the extracellular delivery of matrix-degrading metalloproteases to clear a path for cells through the extracellular matrix. Membrane blebs drive the plasma membrane forward using a combination of actomyosin-based contractility and reversible detachment of the membrane from the cortical actin cytoskeleton. Each protrusion type requires the coordination of a wide spectrum of signaling molecules and regulators of cytoskeletal dynamics. In addition, these different protrusion methods likely act in concert to move cells through complex environments in vivo. PMID- 21703447 TI - Residual embryonic cells as precursors of a Barrett's-like metaplasia. AB - Barrett's esophagus is an intestine-like metaplasia and precursor of esophageal adenocarcinoma. Triggered by gastroesophageal reflux disease, the origin of this metaplasia remains unknown. p63-deficient mice, which lack squamous epithelia, may model acid-reflux damage. We show here that p63 null embryos rapidly develop intestine-like metaplasia with gene expression profiles similar to Barrett's metaplasia. We track its source to a unique embryonic epithelium that is normally undermined and replaced by p63-expressing cells. Significantly, we show that a discrete population of these embryonic cells persists in adult mice and humans at the squamocolumnar junction, the source of Barrett's metaplasia. We show that upon programmed damage to the squamous epithelium, these embryonic cells migrate toward adjacent, specialized squamous cells in a process that may recapitulate early Barrett's. Our findings suggest that certain precancerous lesions, such as Barrett's, initiate not from genetic alterations but from competitive interactions between cell lineages driven by opportunity. PMID- 21703449 TI - Inheritance of stress-induced, ATF-2-dependent epigenetic change. AB - Atf1, the fission yeast homolog of activation transcription factor-2 (ATF-2), contributes to heterochromatin formation. However, the role of ATF-2 in chromatin assembly in higher organisms remains unknown. This study reveals that Drosophila ATF-2 (dATF-2) is required for heterochromatin assembly, whereas the stress induced phosphorylation of dATF-2, via Mekk1-p38, disrupts heterochromatin. The dATF-2 protein colocalized with HP1, not only on heterochromatin but also at specific loci in euchromatin. Heat shock or osmotic stress induced phosphorylation of dATF-2 and resulted in its release from heterochromatin. This heterochromatic disruption was an epigenetic event that was transmitted to the next generation in a non-Mendelian fashion. When embryos were exposed to heat stress over multiple generations, the defective chromatin state was maintained over multiple successive generations, though it gradually returned to the normal state. The results suggest a mechanism by which the effects of stress are inherited epigenetically via the regulation of a tight chromatin structure. PMID- 21703448 TI - Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. AB - Ion channel mutations are an important cause of rare Mendelian disorders affecting brain, heart, and other tissues. We performed parallel exome sequencing of 237 channel genes in a well-characterized human sample, comparing variant profiles of unaffected individuals to those with the most common neuronal excitability disorder, sporadic idiopathic epilepsy. Rare missense variation in known Mendelian disease genes is prevalent in both groups at similar complexity, revealing that even deleterious ion channel mutations confer uncertain risk to an individual depending on the other variants with which they are combined. Our findings indicate that variant discovery via large scale sequencing efforts is only a first step in illuminating the complex allelic architecture underlying personal disease risk. We propose that in silico modeling of channel variation in realistic cell and network models will be crucial to future strategies assessing mutation profile pathogenicity and drug response in individuals with a broad spectrum of excitability disorders. PMID- 21703450 TI - Insights into the micromechanical properties of the metaphase spindle. AB - The microtubule-based metaphase spindle is subjected to forces that act in diverse orientations and over a wide range of timescales. Currently, we cannot explain how this dynamic structure generates and responds to forces while maintaining overall stability, as we have a poor understanding of its micromechanical properties. Here, we combine the use of force-calibrated needles, high-resolution microscopy, and biochemical perturbations to analyze the vertebrate metaphase spindle's timescale- and orientation-dependent viscoelastic properties. We find that spindle viscosity depends on microtubule crosslinking and density. Spindle elasticity can be linked to kinetochore and nonkinetochore microtubule rigidity, and also to spindle pole organization by kinesin-5 and dynein. These data suggest a quantitative model for the micromechanics of this cytoskeletal architecture and provide insight into how structural and functional stability is maintained in the face of forces, such as those that control spindle size and position, and can result from deformations associated with chromosome movement. PMID- 21703451 TI - The INAD scaffold is a dynamic, redox-regulated modulator of signaling in the Drosophila eye. AB - INAD is a scaffolding protein that regulates signaling in Drosophila photoreceptors. One of its PDZ domains, PDZ5, cycles between reduced and oxidized forms in response to light, but it is unclear how light affects its redox potential. Through biochemical and structural studies, we show that the redox potential of PDZ5 is allosterically regulated by its interaction with another INAD domain, PDZ4. Whereas isolated PDZ5 is stable in the oxidized state, formation of a PDZ45 "supramodule" locks PDZ5 in the reduced state by raising the redox potential of its Cys606/Cys645 disulfide bond by ~330 mV. Acidification, potentially mediated via light and PLCbeta-mediated hydrolysis of PIP(2), disrupts the interaction between PDZ4 and PDZ5, leading to PDZ5 oxidation and dissociation from the TRP Ca(2+) channel, a key component of fly visual signaling. These results show that scaffolding proteins can actively modulate the intrinsic redox potentials of their disulfide bonds to exert regulatory roles in signaling. PMID- 21703453 TI - A phosphorylation cycle shapes gradients of the DYRK family kinase Pom1 at the plasma membrane. AB - Concentration gradients regulate many cell biological and developmental processes. In rod-shaped fission yeast cells, polar cortical gradients of the DYRK family kinase Pom1 couple cell length with mitotic commitment by inhibiting a mitotic inducer positioned at midcell. However, how Pom1 gradients are established is unknown. Here, we show that Tea4, which is normally deposited at cell tips by microtubules, is both necessary and, upon ectopic cortical localization, sufficient to recruit Pom1 to the cell cortex. Pom1 then moves laterally at the plasma membrane, which it binds through a basic region exhibiting direct lipid interaction. Pom1 autophosphorylates in this region to lower lipid affinity and promote membrane release. Tea4 triggers Pom1 plasma membrane association by promoting its dephosphorylation through the protein phosphatase 1 Dis2. We propose that local dephosphorylation induces Pom1 membrane association and nucleates a gradient shaped by the opposing actions of lateral diffusion and autophosphorylation-dependent membrane detachment. PMID- 21703452 TI - Golgi export of the Kir2.1 channel is driven by a trafficking signal located within its tertiary structure. AB - Mechanisms that are responsible for sorting newly synthesized proteins for traffic to the cell surface from the Golgi are poorly understood. Here, we show that the potassium channel Kir2.1, mutations in which are associated with Andersen-Tawil syndrome, is selected as cargo into Golgi export carriers in an unusual signal-dependent manner. Unlike conventional trafficking signals, which are typically comprised of short linear peptide sequences, Golgi exit of Kir2.1 is dictated by residues that are embedded within the confluence of two separate domains. This signal patch forms a recognition site for interaction with the AP1 adaptor complex, thereby marking Kir2.1 for incorporation into clathrin-coated vesicles at the trans-Golgi. The identification of a trafficking signal in the tertiary structure of Kir2.1 reveals a quality control step that couples protein conformation to Golgi export and provides molecular insight into how mutations in Kir2.1 arrest the channels at the Golgi. PMID- 21703455 TI - SnapShot: Mitochondrial dynamics. PMID- 21703454 TI - A role for the primary cilium in Notch signaling and epidermal differentiation during skin development. AB - Ciliogenesis precedes lineage-determining signaling in skin development. To understand why, we performed shRNA-mediated knockdown of seven intraflagellar transport proteins (IFTs) and conditional ablation of Ift-88 and Kif3a during embryogenesis. In both cultured keratinocytes and embryonic epidermis, all of these eliminated cilia, and many (not Kif3a) caused hyperproliferation. Surprisingly and independent of proliferation, ciliary mutants displayed defects in Notch signaling and commitment of progenitors to differentiate. Notch receptors and Notch-processing enzymes colocalized with cilia in wild-type epidermal cells. Moreover, differentiation defects in ciliary mutants were cell autonomous and rescued by activated Notch (NICD). By contrast, Shh signaling was neither operative nor required for epidermal ciliogenesis, Notch signaling, or differentiation. Rather, Shh signaling defects in ciliary mutants occurred later, arresting hair follicle morphogenesis in the skin. These findings unveil temporally and spatially distinct functions for primary cilia at the nexus of signaling, proliferation, and differentiation. PMID- 21703456 TI - [Update on psoriasis at the Dermatology Day conference, Paris 2010]. PMID- 21703457 TI - [European and British recommendations on the role of biologic interventions in moderate to severe psoriasis]. PMID- 21703458 TI - [News on psoriasis from the 2010 Dermatology Days in Paris]. PMID- 21703459 TI - [The therapeutic benefits of systemic treatment of psoriatic arthritis? The example of golimumab in psoriatic arthritis]. PMID- 21703460 TI - [News on melanoma from the 2010 Dermatology Days in Paris]. PMID- 21703461 TI - [Conclude that clinical trials on the overall effectiveness of interferon? Contribution of recent data]. PMID- 21703462 TI - [The psoriatic continuum: a new concept]. PMID- 21703463 TI - [In practice, how to assess the therapeutic benefits of systemic treatment for psoriasis?]. PMID- 21703464 TI - [Cutaneous lymphoma at the Dermatology Day conference, Paris 2010]. PMID- 21703465 TI - [Management of cutaneous lymphoma ]. PMID- 21703466 TI - [Therapeutic perspectives of cutaneous T-cell lymphoma]. PMID- 21703467 TI - [Current topics in psoriasis]. PMID- 21703468 TI - [Recommendations on the management of psoriatic arthritis]. PMID- 21703469 TI - [Nail psoriasis: a marker of profound inflammation]. PMID- 21703470 TI - [Early detection of psoriatic arthritis: which tools are most practical?]. PMID- 21703471 TI - [Introduction. Inhalation of anti-infective agents in respiratory tract infections]. PMID- 21703472 TI - [Benefits of nebulized therapy: basic concepts]. AB - The main advantage of nebulized drugs is that they are deposited directly into the respiratory tract and thus higher drug concentrations can be achieved in the bronchial tree and pulmonary bed with fewer adverse effects than when the systemic route is used. The effectiveness of nebulization depends on many factors, including the characteristics of the drug to be nebulized (particle size, form, density, and surface tension), the anatomy of the airways, the patient's inhalation technique and the nebulization system employed, among others. The factors determining the particle size produced by a nebulizer include both the characteristics of the solution and the flow velocity of the nebulization system. The higher the flow velocity, the smaller the aerosol particles. The parameter most widely used to measure aerosolized particle size is the mass median aerodynamic diameter. Particles of between 1 and 5 MUm are those with the greatest probability of reaching the site of infection in the bronchial tree and of achieving the desired therapeutic effect. Nebulization systems or apparatus are composed of a nebulization chamber where the liquid to be nebulized is introduced and aerosol and an energy source required to make the nebulizer work are generated. There are three types of nebulization systems: ultrasonic, jet and mesh nebulizers. Of the three, the most effective are mesh nebulizers. These nebulizers are also the most compact, quietest and most rapid, which translates into better patient compliance. PMID- 21703473 TI - [Chronic bronchial infection: the problem of Pseudomonas aeruginosa]. AB - Pathogenic bronchopulmonary colonizations and the exacerbations produced are among the most important causes of reduced pulmonary function in patients with bronchiectasis. The most frequent pathogens in these patients are Haemophilus influenzae and Pseudomonas aeruginosa. Lesions are produced by the local inflammatory process and the vicious circle developed by antigen stimulation, the release of inflammatory mediators, the presence of neutrophils, the increase of bacterial inoculum and the release of bacterial exoproducts. P. aeruginosa has been demonstrated to affect the patients with bronchiectasis and poorest quality of life and to colonize those with the poorest pulmonary function and the highest number of antimicrobial treatments. In bronchiectasis, as in chronic obstructive pulmonary disease (COPD) or cystic fibrosis, P. aeruginosa is able to colonize the respiratory mucosa chronically. Due to the ecological niche occupied by P. aeruginosa and the multitude of cycles with antimicrobial agents to which these patients are subjected, the development of antimicrobial resistance is highly likely, encouraged by the high proportion of hypermutation variants in existence. Likewise, P. aeruginosa naturally grows in the form of biofilms on the mucosal surface, greatly contributing to its persistence. Antimicrobial treatment in patients with bronchiectasis and P. aeruginosa colonization should be based on antimicrobial agents, alone or in combination, that do not lose activity when acting on biofilms. PMID- 21703474 TI - [Inhaled antibiotic therapy in cystic fibrosis]. AB - Cystic fibrosis is the most frequent fatal genetically-transmitted disease among Caucasians. Chronic bronchial infection, especially by Pseudomonas aeruginosa, is the main cause of morbidity and mortality in this disease. Aerosolized antibiotic therapy achieves high drug concentrations in the airway with low toxicity, allowing chronic use. Currently, two antibiotics have been approved for inhalation therapy, tobramycin inhalation solution and colistimethate sodium aerosol. There is less evidence from clinical trials for the latter. The main indication for these drugs is chronic bronchial colonization by P. aeruginosa, although there is increasing evidence of the importance of the primary infection by this bacterium, whether treated by oral or intravenous antibiotics or not. More controversial is the use of aerosolized antibiotic therapy in bacterial prophylaxis or respiratory exacerbations. For many years, intravenous formulations of distinct antibiotics for aerosolized use have been employed, which are in distinct phases of research for use in nebulizer therapy. In addition to being used to treat P. aeruginosa infection, aerosolized antibiotics have been used to treat other pathogens such as methicillin-resistant Staphylococus aureus, Mycobacterium abscessus and Aspergillus fumigatus. PMID- 21703475 TI - [Inhaled antibiotics in the treatment of noncystic fibrosis bronchiectasis]. AB - Inhaled antibiotics are increasingly used in patients with non-cystic fibrosis (CF) bronchiectasis. Currently, there is no formal indication for the use of this therapy in these patients as inhaled antibiotics are currently only indicated in patients with CF. Therefore, prescription in patients with non-CF bronchiectasis will continue to be based on compassionate use until scientific evidence from ongoing clinical trials becomes available. However, the studies performed to date have shown several positive effects on some key parameters such as a reduction in the number of colonies and the quantity and purulence of sputum, improved quality of life and fewer exacerbations, although this therapy has little impact on accelerated loss of pulmonary function. The percentage of eradication varies, with a low rate of resistance. The clearest use of inhaled antibiotics in patients with non-CF bronchiectasis is probably colonization, especially chronic infection with Pseudomonas aeruginosa. Adverse effects are usually mild and consist of local irritation of the airway, although their frequency is greater than that in patients with CF. Currently, various clinical trials are being carried out that aim to establish the indications for inhaled antibiotic therapy in these patients. Due to its special characteristics (high local concentrations of the drug with scarce systemic adverse effects), inhaled antibiotic therapy will undoubtedly be an excellent future option for the management of bronchiectasis, as well as of many other diseases of the airways. PMID- 21703476 TI - [Inhaled antibiotic therapy in other respiratory diseases]. AB - Aerosolized antimicrobial agents have been used in clinical practice since the 1950s. The main advantage and aim of using this route of administration is delivery of the drug to the site of infection in the lung. Achieving this aim may produce high concentrations in the site of infection or colonization and reduce systemic toxicity to a minimum. The most convincing data to support the use of aerosolized antimicrobials comes from their use as maintenance treatment in patients with cystic fibrosis. In addition to this indication, the use of aerosolized antimicrobials has also been studied in the treatment or prevention of a series of other diseases, including noncystic fibrosis bronchiectasis, ventilator-associated pneumonia, prophylaxis against fungal lung infections, mycobacterial lung infections and, more recently, in chronic obstructive pulmonary disease. Although the theoretical bases underlying aerosol antibiotic administration seem convincing, there is insufficient evidence to support its routine use. Due to the gaps in knowledge that persist in the routine use of aerosolized antibiotics, caution should be exercised in situations without clearly established indications for this modality, such as the treatment of patients with cystic fibrosis, bronchiectasis or Pneumocystis pneumonia. PMID- 21703477 TI - [The future of inhaled antibiotic therapy. New products]. AB - Inhaled antibiotics have been used for more than 30 years to treat bronchial colonization or infection, especially in patients with cystic fibrosis and chronic bronchial infection with Pseudomonas. However, major progress in this field has only been made in the last 10 years: the beneficial effects in this indication have been confirmed by scientific evidence, the number of clinical trials has considerably increased, inhaled antibiotic formulations have appeared, administration systems have improved and their use has been broadened to include other infections. The speed of research indicates that major advances will be made in the indications and arsenal of inhaled antibiotics, as well as in the effectiveness of administration systems in the next 10 years. A desirable aim in the immediate future would be to demonstrate the efficacy of inhaled antibiotics in the treatment of any chronic bronchial infection, irrespective of the causative microorganism or the underlying disease and even in the absence of bronchiectasis. The antibiotic effect is related to the concentration achieved in the site of infection. Antibiotic administration through the inhaled route is subject to many variables: the dose administered, the dose that reaches the site of infection, the type of nebulizer used and the patient's characteristics. Many features of the pharmacokinetics of this route remain unknown and, because of its complexity, it should be prescribed and monitored by specialist physicians to avoid underdosing, which could lead to bacterial resistance. PMID- 21703478 TI - [Editorial: French congress on cardiopulmonary bypass and perfusion]. PMID- 21703479 TI - The crystalloid cardioplegia: advantages with a word of caution. AB - Technical success and absence of iatrogenic injury from inadequate myocardial protection are the foremost targets of every cardiac surgical procedure. The current trends of pediatric cardiac surgery are aimed to achieve definitive repair of complex cardiac defects at birth as to avoid the risks related with palliative surgery and to reduce the long term impact of the untreated defect on the cardiac function. Thus, even newborn patients are exposed to a prolonged time of myocardial ischemia. The aim of this paper is to describe the impact of crystalloid HKT Custodiol cardioplegia infusion on myocardial protection in the early and late outcome of newborn patients who underwent arterial switch operation (ASO) for transposition of the great arteries (TGA). PMID- 21703480 TI - [The basis of ischemia-reperfusion and myocardial protection]. AB - The myocardial infarction represents a major cause of mortality. The deleterious phenomena arising during the ischaemia and the reperfusion of the myocardium are studied for more than 40 years. We thought for a long time that the ischaemia was the harmful stage, at the origin of the decrease of the energy stores, the dysregulation of the ionic homeostasis and the metabolic deregulation. We know now that the reperfusion itself is also a source of noxious effects (calcium overload, free radicals production, mitochondrion alteration). To combat these deleterious processes, two maneuvers demonstrated their efficiency by protecting the ischemic myocardium : it is the preconditioning and the postconditionning. PMID- 21703481 TI - [Blood cardioplegia: advantages and disadvantages]. AB - Blood cardioplegia is worldwilde used during cardiac surgery. It provides a safe myocardial protection during this surgery. All along the year blood cardioplegia has been improved but it's of importance to apply it correctly. This can be a disadvantage during some cardiac surgery technics. PMID- 21703482 TI - [MESRCA/MESRRA: material aspects]. AB - Mobile ECMO support for remote cardiac or respiratory assistance (MESRCA and MESRRA) allows mobilization of the medical and paramedical team 24/7 in a very large geographical area. Mobility and autonomy require adapted devices. During many years, teams had to deal with non useful equipment. Recently, thanks to interest of medical world and laboratories, many materials especially suitable for this activity are developed. We describe our local experience and solutions we tented to fi nd to deal with material difficulties. PMID- 21703483 TI - [Mobile unit for cardio-respiratory support]. AB - In order to effectively deal with the increase in cardiac and/or respiratory services outside of Lille CHU (University Hospital), an interdisciplinary medical/surgical procedure has been put in place in collaboration with the emergency medical service (SAMU). This organization makes it possible to respond rapidly to a demand outside the University Hospital, while ensuring safe management of patients. PMID- 21703484 TI - [MCAU/MRAU session: point of view of the pre-hospital Emergency Medical Services, costs assessment]. AB - Since the 1970s, it has become possible to handle patients with serious pulmonary and cardiac failure with extracorporeal membrane oxygenation (ECMO) when conventional treatment fails, but only in specialized centers. When the latter were too far away, the risks of such transport were considered too high until the Mobile Cardiac Assistance Unit (MCAU) and Mobile Respiratory Assistance Unit (MRAU) were created. We are first going to expose the point of view of the pre hospital Emergency Medical Services (EMS). The M.D. in need of such assistance should call the cardiac surgeon of the reference center : if the indication is confirmed, they will call the EMS (Service d'Aide Medicale Urgente, SAMU), and decide together which means is the most appropriate for a quick transportation of the team and the ECMO to the patient's bedside, and then back to the ECMO center, depending on the problems raised by ground vehicles on the one hand and aircrafts or helicopters on the other. Then, we are going to evaluate the cost of such transportation, which is quite considerable. As a conclusion, because of its high cost, the mobile inter-hospital ECMO. service should only be used when the patient is considered too ill to be transported on conventional therapy : in that case, this procedure represents huge progress. PMID- 21703485 TI - Percutaneous mitral repair with the MitraClip. AB - Mitral regurgitation (MR) is associated with poor prognosis and high incidence of clinical events if left untreated. To reduce the invasiveness of the surgical approach, different types of trans-catheter procedures are becoming available. The MitraClip procedure (Abbott Vascular Inc. Menlo Park, CA) is yet the only available at the moment. The procedure is used to treat high risk surgical candidates with either functional or degenerative MR. Recent trials have shown that the procedure is safer than surgery, although less effective. Efficacy of the procedure depends on several factors, including patient selection, anatomy of the valve and the experience of the operators. However, when treating high risk patients a suboptimal repair obtained with low risk can be a acceptable outcome. In the future, novel devices, improved knowledge, more efficient imaging and transcatheter mitral prosthetic valve implantation may expand the indications to those patients currently not treated by MitraClip for anatomical unsuitability, as well as may improve the results both in term of early efficacy and long term durability. PMID- 21703486 TI - [Anesthesia for minimally invasive cardiac procedure]. AB - The objectives are to present the different minimally invasive cardiac surgery techniques to repair the mitral valve, TAVI and MitraClip, as well as the implications for the anaesthetist. Evaluate retrospectively the anaesthesist methods, change in monitoring and how the patients are selected. The mitral valve repair by minithoracotomy and video-surgery requires selective left intubation and monitoring by TEE. The TAVI methods seem to be working best under local anaesthesia and sedation for haemodynamic and neurologic monitoring. The MitraClip surgery requires an extensive monitoring during and after surgery. In conclusion, the care of patients that are candidates for a TAVI requires the same level of expertise as anaesthesiology in cardiac surgery. The number of procedures performed under sedation will increase. These patients require multidisciplinary care (surgeons, cardiologists, sonographers and anaesthesiologists) due to comorbidities, and the possible haemodynamic, neurologic and vascular complications. These patients have an Euroscore greater than 20% and a STS score greater than 10%. In our experience, 80% of the cases are done femorally, 17% of the cases are done through the subsclavian artery (Corevalve((r))). 80% of the patients have surgery with a local anaesthesia and sedation. 20% of the patients get surgery with general anaesthesia. For the Edwards-Sapien((r)) valve, when the femoral approach is impossible, the patient can get surgery with general anaesthesia using the transapical access. PMID- 21703487 TI - Abstract thinking: trauma and the mind-body connection. PMID- 21703488 TI - Standardized interviews for diagnostic assessments of children and adolescents in psychiatric research. PMID- 21703489 TI - Fifty years and counting: celebrating citations to the Journal. PMID- 21703490 TI - Infants remember: war exposure, trauma, and attachment in young children and their mothers. PMID- 21703491 TI - Clinically relevant phenomenology: the nature of psychosis. PMID- 21703492 TI - Posttraumatic stress disorder in infants and young children exposed to war related trauma. AB - OBJECTIVE: Although millions of the world's children are growing up amidst armed conflict, little research has described the specific symptom manifestations and relational behavior in young children exposed to wartime trauma or assessed factors that chart pathways of risk and resilience. METHOD: Participants included 232 Israeli children 1.5 to 5 years of age, 148 living near the Gaza Strip and exposed to daily war-related trauma and 84 controls. Children's symptoms were diagnosed, maternal and child attachment-related behaviors observed during the evocation of traumatic memories, and maternal psychological symptoms and social support were self-reported. RESULTS: PTSD was diagnosed in 37.8% of war-exposed children (n = 56). Children with PTSD exhibited multiple posttraumatic symptoms and substantial developmental regression. Symptoms observed in more than 60% of diagnosed children included nonverbal representation of trauma in play; frequent crying, night waking, and mood shifts; and social withdrawal and object focus. Mothers of children with PTSD reported the highest depression, anxiety, and posttraumatic symptoms and the lowest social support, and displayed the least sensitivity during trauma evocation. Attachment behavior of children in the Exposed-No-PTSD group was characterized by use of secure-base behavior, whereas children with PTSD showed increased behavioral avoidance. Mother's, but not child's, degree of trauma exposure and maternal PTSD correlated with child avoidance. CONCLUSIONS: Large proportions of young children exposed to repeated wartime trauma exhibit a severe posttraumatic profile that places their future adaptation at significant risk. Although more resilient children actively seek maternal support, avoidance signals high risk. Maternal well-being, sensitive behavior, and support networks serve as resilience factors and should be the focus of interventions for families of war-exposed infants and children. PMID- 21703493 TI - Illogical thinking and thought disorder in maltreated children. AB - OBJECTIVE: To examine illogical thinking in children from low-income families with and without histories of child maltreatment. METHOD: Maltreated (n = 91) and nonmaltreated (n = 43) school-age children individually participated in a story game designed to elicit speech samples. Children were instructed to listen to two recorded stories and prompted to retell the story; they then were asked to create their own story from possible topics. Child behavior ratings on the Child Behavior Checklist were completed by research assistants following 35 hours of observation. RESULTS: Maltreated children exhibited more illogical thinking than did nonmaltreated children, and the level of illogical thinking in maltreated children was in the clinically pathological range. The occurrence of multiple subtypes of maltreatment and the chronicity of the maltreatment also were associated with illogical thinking. Dissociation did not differ between groups, although it was related to illogical thinking. CONCLUSION: The ability to formulate ideas and communicate them logically is compromised in children who have been maltreated. These results extend prior research on selective attentional processes and negativity biases in maltreated children. PMID- 21703494 TI - Thought disorder and communication deviance as predictors of outcome in youth at clinical high risk for psychosis. AB - OBJECTIVE: Given the fundamental role of thought disorder in schizophrenia, subtle communication disturbance may be a valuable predictor of subsequent development of psychosis. Here we examined the contribution of thought and communication disturbance to the prediction of outcome in adolescents identified as putatively prodromal for psychosis. METHOD: Transcribed speech samples were elicited from 105 adolescents (54 identified as being at clinical high risk for a first episode of psychosis [CHR], and 51 demographically comparable comparison subjects) and coded for formal thought disorder (FTD) and linguistic cohesion. We then examined the association of baseline FTD/cohesion with conversion to psychosis and social and role outcome at follow-up, approximately 1 year later. RESULTS: At baseline, CHR patients who subsequently converted to psychosis (CHR+) showed an elevated rate of illogical thinking and poverty of content (POC) in their speech, relative to both typically developing controls and CHR patients who did not convert to psychosis (CHR-). CHR+ youth also used significantly less referential cohesion at baseline, indicating that they provide fewer references to persons, objects, or events mentioned in preceding utterances. Multiple regression models indicated that, among measures of FTD/cohesion, illogical thinking was uniquely predictive of subsequent conversion to psychosis, whereas POC and referential cohesion were significant predictors of social and role functioning, respectively. CONCLUSIONS: Despite the absence of fully psychotic symptoms, putatively prodromal individuals evidence signs of communication disturbance that are qualitatively similar to those seen in schizophrenia and are predictive of both conversion to psychosis and psychosocial outcome. These findings suggest that FTD measures have prognostic significance for at-risk youth. PMID- 21703495 TI - Childhood onset schizophrenia: high rate of visual hallucinations. AB - OBJECTIVE: To document high rates and clinical correlates of nonauditory hallucinations in childhood onset schizophrenia (COS). METHOD: Within a sample of 117 pediatric patients (mean age 13.6 years), diagnosed with COS, the presence of auditory, visual, somatic/tactile, and olfactory hallucinations was examined using the Scale for the Assessment of Positive Symptoms (SAPS). We also compared hallucination modality membership (presence/absence) groups on gender, socioeconomic status, ethnicity, age of onset (of psychosis), Full Scale IQ, Verbal IQ, and clinical severity (Children's Global Assessment Scale [CGAS) and Scale for the Assessment of Negative Symptoms [SANS]). RESULTS: A total of 111 COS patients (94.9%) had auditory and 94 patients (80.3%) had visual hallucinations. Somatic/tactile (60.7%) and olfactory (29.9%) hallucinations occurred almost exclusively in patients who also had visual hallucinations. Children who had visual hallucinations had lower IQ, earlier age of onset, and more severe illness relative to children who did not have visual hallucinations. CONCLUSIONS: In this study, we observed that patients with COS have high rates of hallucinations across all modalities. An increased rate of visual hallucinations is associated with greater clinical impairment and greater compromise in overall brain functioning. Somatic and olfactory hallucinations reflect an additive rather than alternative symptom pattern. PMID- 21703496 TI - Identification of genetic loci underlying the phenotypic constructs of autism spectrum disorders. AB - OBJECTIVE: To investigate the underlying phenotypic constructs in autism spectrum disorders (ASD) and to identify genetic loci that are linked to these empirically derived factors. METHOD: Exploratory factor analysis was applied to two datasets with 28 selected Autism Diagnostic Interview-Revised (ADI-R) algorithm items. The first dataset was from the Autism Genome Project (AGP) phase I (1,236 ASD subjects from 618 families); the second was from the AGP phase II (804 unrelated ASD subjects). Variables derived from the factor analysis were then used as quantitative traits in genome-wide variance components linkage analyses. RESULTS: Six factors, namely, joint attention, social interaction and communication, nonverbal communication, repetitive sensory-motor behavior, peer interaction, and compulsion/restricted interests, were retained for both datasets. There was good agreement between the factor loading patterns from the two datasets. All factors showed familial aggregation. Suggestive evidence for linkage was obtained for the joint attention factor on 11q23. Genome-wide significant evidence for linkage was obtained for the repetitive sensory-motor behavior factor on 19q13.3. CONCLUSIONS: This study demonstrates that the underlying phenotypic constructs based on the ADI-R algorithm items are replicable in independent datasets, and that the empirically derived factors are suitable and informative in genetic studies of ASD. PMID- 21703497 TI - Normalization of cortical gray matter deficits in nonpsychotic siblings of patients with childhood-onset schizophrenia. AB - OBJECTIVE: Cortical gray matter (GM) abnormalities in patients with childhood onset schizophrenia (COS) progress during adolescence ultimately localizing to prefrontal and temporal cortices by early adult age. A previous study of 52 nonpsychotic siblings of COS probands had significant prefrontal and temporal GM deficits that appeared to "normalize" by age 17 years. Here we present a replication with nonoverlapping groups of healthy full siblings and healthy controls. METHOD: Using an automated measure and prospectively acquired anatomical brain magnetic resonance images, we mapped cortical GM thickness in nonpsychotic full siblings (n = 43, 68 scans; ages 5 through 26 years) of patients with COS, contrasting them with age-, gender-, and scan interval-matched healthy controls (n = 86, 136 scans). The false-discovery rate procedure was used to control for type I errors due to multiple comparisons. RESULTS: As in our previous study, young nonpsychotic siblings (<17 years) showed significant GM deficits in bilateral prefrontal and left temporal cortices and, in addition, smaller deficits in the parietal and right inferior temporal cortices. These deficits in nonpsychotic siblings normalized with age with minimal abnormalities remaining by age 17. CONCLUSIONS: Our results support previous findings showing nonpsychotic siblings of COS probands to have early GM deficits that ameliorate with time. At early ages, prefrontal and/or temporal loss may serve as a familial/trait marker for COS. Late adolescence appears to be a critical period for greatest localization of deficits in probands or normalization in nonpsychotic siblings. PMID- 21703498 TI - Different neural patterns are associated with trials preceding inhibitory errors in children with and without attention-deficit/hyperactivity disorder. AB - OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is associated with difficulty inhibiting impulsive, hyperactive, and off-task behavior. However, no studies have examined whether a distinct pattern of brain activity precedes inhibitory errors in typically developing (TD) children and children with ADHD. In healthy adults, increased activity in the default mode network, a set of brain regions more active during resting or internally focused states, predicts commission errors, suggesting that momentary lapses of attention are related to inhibitory failures. METHOD: Event-related functional magnetic resonance imaging and a go/no-go paradigm were used to explore brain activity preceding errors in 13 children with ADHD and 17 TD controls. RESULTS: Comparing pre-error with pre correct trials, TD children showed activation in the precuneus/posterior cingulate cortex and parahippocampal and middle frontal gyri. In contrast, children with ADHD demonstrated activation in the cerebellum, dorsolateral prefrontal cortex (DLPFC), and basal ganglia. Between-group comparison for the pre-error versus pre-correct contrast showed that children with ADHD showed greater activity in the cerebellum, DLPFC, and ventrolateral PFC compared with TD controls. Results of region-of-interest analysis confirmed that the precuneus/posterior cingulate cortex are more active in TD children compared with children with ADHD. CONCLUSIONS: These preliminary data suggest that brain activation patterns immediately preceding errors differ between children with ADHD and TD children. In TD children, momentary lapses of attention precede errors, whereas pre-error activity in children with ADHD may be mediated by different circuits, such as those involved in response selection and control. PMID- 21703523 TI - Heart failure with recovered ejection fraction: a distinct clinical entity. AB - BACKGROUND: A subset of patients with heart failure (HF) and preserved left ventricular ejection fraction (EF) previously had EF <40%. We postulated that such "recovered" EF patients would be prevalent in a referral HF population and clinically distinct from those with persistently preserved or reduced EF. METHODS AND RESULTS: We identified all subjects with a clinical diagnosis of HF seen in the advanced heart disease practice at our center from March to October 2008. Patients were classified into 1 of 3 groups based on retrospective review of the medical record: EF persistently >=40% (HF-PEF), EF recovered to >=40% (HF-REF) and low EF, <40% (HF-LEF). Clinical and echocardiographic characteristics were compared across groups using standard chi-square and analysis of variance tests. A total of 358 heart failure patients were identified, including 56 with HF-PEF, 121 with HF-REF, and 181 with HF-LEF. Compared with HF-PEF, HF-REF patients were younger with less atrial fibrillation, hypertension, and diabetes. Also, they tended to have lower systolic blood pressure, better renal function, and larger left ventricular diameter at end diastole. HF-REF patients were more similar to HF-LEF, but were younger and had lower rates of coronary artery disease. Of the 3 groups, HF-REF patients had the mildest reported HF symptoms and fewest previous HF hospitalizations. CONCLUSIONS: Patients with HF-REF comprise a substantial proportion of those with HF and EF >=40% followed in an ambulatory referral practice. These patients appear to be clinically distinct from the residual HF population and should be specifically targeted for further research. PMID- 21703499 TI - Predictors of parental accommodation in pediatric obsessive-compulsive disorder: findings from the Pediatric Obsessive-Compulsive Disorder Treatment Study (POTS) trial. AB - OBJECTIVE: Few studies have examined predictors of parental accommodation (assessed with the Family Accommodation Scale-Parent Report) among families of children with obsessive-compulsive disorder (OCD). No studies have examined this phenomenon using empirically derived subscales of the Family Accommodation Scale Parent Report (i.e., Caregiver Involvement, Avoidance of Triggers). METHOD: Ninety-six youths (and their families) were included in the present study. Parents were asked to complete the Family Accommodation Scale-Parent Report. Families also completed several additional measurements assessing child- and parent-level variables of interest. Regression analyses were used to examine potential predictors of accommodation. RESULTS: Results support prior research suggesting that accommodation is ubiquitous among the families of children with OCD. Analyses revealed that several child-level (i.e., compulsion severity, oppositional behavior, and frequency of washing symptoms) and one parent-level (i.e., symptoms of anxiety) predictors work jointly to provide significant predictive models of parental accommodation. CONCLUSIONS: Clinicians and researchers should be aware of the impact of specific child- and parent-level variables on family accommodation in pediatric OCD and in turn their implications for treatment compliance, adherence, and, by extension, outcome. Study limitations warrant replication and extension of these findings; in particular, researchers may seek to obtain a better understanding of how the various facets of parental accommodation may differentially affect treatment. PMID- 21703524 TI - Incidence, correlates, and consequences of acute kidney injury in patients with pulmonary arterial hypertension hospitalized with acute right-side heart failure. AB - BACKGROUND: Though much is known about the prognostic influence of acute kidney injury (AKI) in left-side heart failure, much less is known about AKI in patients with pulmonary arterial hypertension (PAH). METHODS AND RESULTS: We identified consecutive patients with PAH who were hospitalized at Stanford Hospital for acute right-side heart failure. AKI was diagnosed according to the criteria of the Acute Kidney Injury Network. From June 1999 to June 2009, 105 patients with PAH were hospitalized for acute right-side heart failure (184 hospitalizations). AKI occurred in 43 hospitalizations (23%) in 34 patients (32%). The odds of developing AKI were higher among patients with chronic kidney disease (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.8-8.5), high central venous pressure (OR 1.8, 95% CI 1.1-2.4, per 5 mm Hg), and tachycardia on admission (OR 4.3, 95% CI 2.1-8.8). AKI was strongly associated with 30-day mortality after acute right side heart failure hospitalization (OR 5.3, 95% CI 2.2-13.2). CONCLUSIONS: AKI is relatively common in patients with PAH and associated with a short-term risk of death. PMID- 21703525 TI - Outcomes for women and men who attend a heart failure clinic: results of a 12 month longitudinal study. AB - BACKGROUND: Although prevalence of heart failure (HF) is similar in women and men, more men are admitted to specialized HF clinics, possibly owing to a perception that men benefit more. Our aim was to describe 1-year outcomes in men and women attending specialized HF clinics. METHODS AND RESULTS: We enrolled 531 newly referred patients (mean age 66 years, 26% women) to 1 of 6 HF multidisciplinary clinics in Quebec. Data were collected at time of entry to the clinic and 6 and 12 months later. The 3 main outcomes, mortality, disease evolution (New York Heart Association functional class, quality of life, 6-minute walk), and number of hospital admissions/emergency department visits were analyzed separately. Survival was higher in women than in men (adjusted hazard ratio 2.53, 95% confidence interval 1.10-5.80). Both women and men improved over the 12-month period in terms of quality of life, 6-minute walk, and lower use of hospital and emergency department. Persons who at entry to the clinic had more severe disease showed more improvement. Deterioration over the year was associated with higher number of comorbidities, but not with age or gender. CONCLUSIONS: Both men and women with HF who attend specialized HF clinics improved, including those with more severe disease. PMID- 21703526 TI - The impact of extra cardiac comorbidities on pressure volume relations in heart failure and preserved ejection fraction. AB - BACKGROUND: Extracardiac comorbidities are common in patients with heart failure and a preserved ejection fraction (HFPEF). We sought to evaluate the relationship between comorbidities and ventricular structure and function in patients with HFPEF through evaluation of pressure-volume analysis. METHODS AND RESULTS: Two hundred twenty Chinese patients with a preserved ejection fraction who were either healthy (n = 75), hypertensive without heart failure (HTN; n = 89), or hypertensive with HFPEF (HFPEF; n = 56) were studied. Using echocardiographic measures, estimated end-systolic and end-diastolic pressure-volume relationships, and the area between them as a function of EDP, the isovolumic pressure-volume areas (PVA(iso)), were calculated. Ventricular capacitance, as measured by V(30), was larger in patients with HFPEF compared with normal control subjects and tended to be larger compared with hypertensive control subjects. The presence of diabetes and renal insufficiency was independently associated with greater ventricular capacitance in patients with HFPEF. The PVA(iso) was increased in patients with HFPEF compared with HTN and normal control subjects, and in particular, it was increased in HFPEF patients with multiple comorbidities. CONCLUSIONS: The presence of comorbid conditions is associated with altered pressure-volume relations and enhanced pump function in subjects with HFPEF, supporting an important role for extracardiac comorbidities in the pathophysiology of patients with this condition. PMID- 21703527 TI - Diabetic retinopathy is associated with impaired left ventricular relaxation. AB - BACKGROUND: Diabetic retinopathy (DR) is an independent predictor of heart failure (HF) in patients with diabetes mellitus (DM). However, it is unclear how DR is related to the development of HF. We hypothesized that DR is associated with left ventricular (LV) diastolic dysfunction, which is well recognized to subsequently result in HF. METHODS AND RESULTS: Data were collected in 63 consecutive patients with DM and LV ejection fraction (EF) >=50%. Patients were excluded if they had HF diagnosed according to the modified Framingham criteria. Doppler echocardiographic indices including peak early-diastolic mitral annular movement velocity (E') were obtained in each patient.We also assessed the diastolic index of echocardiographic color kinesis (CK-DI), which proportionally decreases with LV relaxation abnormality independently of LV filling pressure, as recently published. The DM patients were divided into groups without (DM-N; n = 30) and with (DM-DR; n = 33) DR. Age, gender, LV end-diastolic dimension, EF, E/A ratio of the transmitral flow velocity curves, E', and E/E' were not different between DM-N and DM-DR. However, CK-DI was significantly lower in DM-DR than DM N. CONCLUSIONS: DR is associated with LV diastolic dysfunction, and this may at least in part explain the increased incidence of HF in DM patients with DR. PMID- 21703528 TI - Mismatch of right- and left-sided filling pressures in chronic heart failure. AB - BACKGROUND: In patients with advanced heart failure (HF), elevated jugular venous pressure (JVP) is the most reliable sign of elevated left-sided filling pressures. However, discordance between right- and left-sided filling pressures (R-L mismatch) could lead to inadequate or excessive therapy guided by JVP. We determined the prevalence of R-L mismatch in the current era and investigated whether mismatch might be identified from clinical information. METHODS AND RESULTS: Right-sided heart catheterization was performed in 537 consecutive patients hospitalized with advanced HF during complete transplantation evaluation. Patients with high filling pressures were categorized as matched (right atrial pressure (RAP) >=10 mm Hg and pulmonary wedge pressure (PCWP) >=22 mm Hg), high-R mismatch (RAP >=10 but PCWP <22 mm Hg) or high-L mismatch (PCWP >=22 but RAP <10 mm Hg). Among all of the patients, 195 (36%) were matched low and 194 (36%) were matched high, and 148 (28%) had R-L mismatch. Among patients with high filling pressures, 194 (57%) were matched high and 82 (24%) had high-L and 66 (19%) high-R mismatch. Mismatches were not associated with differences in demographic or clinical data, including pulmonary and hepatic function, or severity of valvular regurgitation and right ventricular function by echo. However, among all patients with RAP >=10 mm Hg, pulmonary artery systolic pressure (PASP) was higher in those patients with matched high left- and right sided pressures (59 +/- 12 mm Hg) versus high-R mismatch (41 +/- 13 mm Hg; P < .0001). Similarly among all patients with low RAP, PASP was lower in patients with matched low right- and left-side pressures (33 +/- 11 mm Hg) versus high-L mismatch (53 +/- 13 mm Hg; P < .0001). CONCLUSIONS: R-L mismatch was present in >1 in 4 total patients, and >1 in 3 with elevated filling pressures. Regardless of clinical history, when empiric therapy to optimize volume status to JVP is not effective, additional measurement should be considered to establish the R-L relationship. PMID- 21703529 TI - Improved algorithm to detect fluid accumulation via intrathoracic impedance monitoring in heart failure patients with implantable devices. AB - BACKGROUND: Intrathoracic impedance fluid monitoring has been shown to predict worsening congestive heart failure (CHF) in patients with implantable devices. We developed and externally validated a modified algorithm to identify worsening heart failure (HF) by using intrathoracic impedance. METHODS AND RESULTS: The modified algorithm was developed by using published data from 81 CHF subjects averaging 259 days of follow-up. Device-measured daily impedance was input to both the existing and the modified intrathoracic impedance fluid monitoring algorithms to determine a reference impedance and a fluid index (FI). Separate validation sets included 326 cardiac resynchronization therapy device (CRT-D) patients with an average 333 days of follow-up (group 1) and 104 CRT D/implantable cardioverter/defibrillator (ICD) patients followed for an average of 520 days (group 2). Clinicians and patients in group 2 were blinded to impedance and FI data. HF events included adjudicated HF hospitalizations or emergency room visits. Sensitivity was defined as the percentage of HF events preceded by FI exceeding the predefined threshold (60 Omega-d) within the last 2 weeks. Unexplained detections were FI threshold crossing events not followed by a HF event within 2 weeks. The modified algorithm significantly decreased unexplained detections by 30% (P = .01; GEE) in the development set, 30% (P < .001) in the group 1 validation set, and 43% (P < .001) in group 2. Sensitivity did not change significantly in any group. Simulated monthly review of FI threshold crossings identified subjects at significantly greater risk of worsening HF within the next 30 days. CONCLUSIONS: A modified intrathoracic impedance based fluid detection algorithm lowered the number of unexplained FI threshold crossings and identified patients at significantly increased immediate risk of worsening HF. PMID- 21703530 TI - gamma-Glutamyltransferase rather than total bilirubin predicts outcome in chronic heart failure. AB - BACKGROUND: Gamma-glutamyltransferase (GGT) and total bilirubin (T-Bil) are elevated and of prognostic significance in chronic heart failure (CHF). This study sought to compare these novel cardiovascular risk markers in CHF. METHODS AND RESULTS: We evaluated 1,087 ambulatory patients from our heart failure program. Long-term follow-up was available in 1,056 patients. The combined end point was defined as death of any cause or heart transplantation. Prevalence of elevated GGT was 43% in men and 48% in women, that of T-Bil 17% and 8%, respectively. Both variables were significantly correlated with severity of heart failure. GGT and T-Bil were associated with transplant-free survival in bivariate analysis (P values <.001 and .006, respectively). However, GGT (hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.13-1.44; P < .001), but not T-Bil, remained an independent predictor of prognosis in the multivariate model. Also, categorized GGT levels beyond the gender-specific normal ranges were predictive of the combined end point (HR 1.55, 95% CI 1.23-1.95). Elevation of both GGT and T-Bil further increased the risk of reaching the end point (HR 2.57, 95% CI 1.74 3.18). CONCLUSIONS: GGT and T-Bil are associated with disease severity in CHF. However, only GGT is independently associated with adverse outcome. Our findings further highlight the clinical importance of GGT in cardiovascular disease. PMID- 21703531 TI - Effects of interval cycle training with or without strength training on vascular reactivity in heart failure patients. AB - BACKGROUND: Exercise training confers beneficial effects on vascular reactivity in patients with chronic heart failure (CHF). This randomized study compares the effects of interval cycle training combined with strength training versus interval training alone on vascular reactivity in CHF patients. METHODS: Twenty eight consecutive stable CHF patients (23 males, 53 +/- 10 years, 28.4 +/- 4.1 kg/m(2), left ventricular ejection fraction of 37 +/- 12%) were randomly assigned to 3 times' weekly training sessions for 3 months, consisting of a) 40 minutes of interval cycle training (n = 14), versus b) 20 minutes of similar interval training plus 20 minutes of strength training of the quadriceps, hamstrings, muscles of the shoulder and biceps brachialis (n = 14). The work/recovery ratio of each session was 30/60 seconds. The intensity of interval training was set at 50% of the peak workload achieved at the steep ramp test (consisted of a 25-Watt increase on a cycle ergometer every 10 seconds until exhaustion). All patients underwent maximal, symptom-limited cardiopulmonary exercise testing and ultrasound evaluation of vascular reactivity by flow-mediated vasodilation (FMD) before and after the program. RESULTS: A significant improvement in FMD was observed in the combined training group (P = 0.002), in contrast to the interval training alone group (P = NS); the improvement was significantly greater in the combined training than in the interval training alone group (P < .05). Peak oxygen uptake increased significantly and similarly in both groups, in the interval training group (P = .03), and in the combined training group (P = .006). No significant correlation was found between FMD improvement and cardiopulmonary exercise parameters. CONCLUSIONS: A combined high-intensity, interval cycle exercise with strength training induces a greater beneficial effect on vascular reactivity rather than interval exercise training alone in CHF patients. PMID- 21703532 TI - beta-Adrenergic receptor stimulation and activation of protein kinase A protect against alpha1-adrenergic-mediated phosphorylation of protein kinase D and histone deacetylase 5. AB - INTRODUCTION: Chronic activation of beta(1)-adrenergic receptor (beta(1)-AR) signaling can have deleterious effects on the heart, and animal models overexpressing beta(1)-ARs develop a dilated cardiomyopathy and heart failure. In the classic beta-AR pathway, receptor occupancy by an agonist results in increased cyclic adenosine monophosphate (cAMP) levels and activation of protein kinase A (PKA). However, the role of PKA-dependent signaling in the development and progression of cardiomyopathies and heart failure is controversial, because beta-AR signal transduction is generally desensitized in the failing heart and PKA activity is not increased. METHODS AND RESULTS: Neonatal rat ventricular myocytes were acutely (15 minutes) or chronically (48 hours) treated with isoproterenol, and phosphorylation of protein kinase D (PKD) and histone deacetylase 5 (HDAC5) was measured. Acute beta(1)-AR stimulation or expression of constitutively active (CA) PKA reduced alpha(1)-adrenergic-mediated phosphorylation of HDAC5 and PKD by activation of a phosphatase. Overexpression of CA-PKA also reduced alpha(1)-adrenergic-mediated increased expression of contractile protein fetal isoforms and promoted repression of adult isoforms, but had no effect on alpha(1)-adrenergic-mediated cellular hypertrophy. CONCLUSIONS: These data indicate that the PKA-dependent arm of beta-AR signaling can be antihypertrophic and presumably beneficial, through dephosphorylation of PKD and HDAC5 and reduction of hypertrophic fetal isoform gene expression. PMID- 21703533 TI - Human hepatocyte growth factor (VM202) gene therapy via transendocardial injection in a pig model of chronic myocardial ischemia. AB - BACKGROUND: Hepatocyte growth factor (HGF) may stimulate angiogenesis. We examined the safety and therapeutic potential of the HGF plasmid (VM202) in pigs with chronic myocardial ischemia. METHODS AND RESULTS: We delivered VM202 or vehicle transendocardially to 4 groups of pigs: vehicle control (n = 9); high dose VM202 (n = 9); low-dose VM202 (n = 3); and normal control (no ischemia; n = 1). Pigs were killed 3, 30, and 60 days after injection. No adverse events were associated with VM202 treatment or delivery. Quantitative polymerase chain reaction indicated that heart injection sites had the highest levels of VM202 (day 3), which became almost undetectable by 30-60 days. Most nontarget tissues showed clearance of VM202 plasmid by day 30. Control and VM202-treated pigs did not differ in global functional data. Dobutamine-stressed myocardial-contrast echocardiogram suggested that VM202 may help preserve microvascular perfusion at 30 days; reperfusion velocity in ischemic myocardium decreased significantly in control (baseline to follow-up, 5.1 +/- 1.9 to 2.7 +/- 1.0; P = .031) but not in VM202 groups (high-dose: 3.1 +/- 1.1 vs 3.1 +/- 1.5 [P = .511]; low-dose: 3.8 +/- 1.1 vs 3.9 +/- 1.5 [P = .559]). Linear local shortening increased significantly from day 0 to 30 in VM202-treated versus control pigs (5.0 +/- 4.7% vs 9.2 +/- 7.5% vs 0.9 +/- 5.8% [high-dose, low-dose, control, respectively]; P = .021). CONCLUSIONS: Transendocardial delivery of VM202 was safe and may help to preserve microcirculatory perfusion and improve wall motion. PMID- 21703534 TI - NOD so fast: NLRX1 puts the brake on inflammation. AB - In this issue of Immunity, Allen et al. (2011) and Xia et al. (2011) provide in vivo and biochemical evidence that NLRX1, a member of the nucleotide binding domain and leucine-rich-repeat-containing protein family, functions as a negative regulator of RIG-I and Toll-like receptors. PMID- 21703535 TI - Intracellular trafficking of perforin: to thwart a killer. AB - How do killer cells restrain perforin, the most potent toxin known to biologists, at its point of synthesis in the endoplasmic reticulum, where conditions are ideal for its activation? In this issue of Immunity, Brennan et al. (2011) study its trafficking, offering insights into protective mechanisms. PMID- 21703536 TI - Lymphocyte signaling converges on microtubules. AB - Movement of immunoreceptor microclusters tunes lymphocyte activation, but the underlying mechanisms are incompletely understood. In this issue of Immunity, Schnyder et al. (2011) and Hashimoto-Tane et al. (2011) show that cytoplasmic dynein drives microcluster centralization along microtubules. PMID- 21703537 TI - A fine romance: T follicular helper cells and B cells. AB - T follicular helper (Tfh) cells help B cells to generate affinity-matured antibodies. Three papers in this issue of Immunity (Choi et al., 2011; Kerfoot et al., 2011; Kitano et al., 2011) provide information about the reciprocal relationship between B cells and Tfh cells. PMID- 21703538 TI - Application of ChIP-Seq and related techniques to the study of immune function. AB - Behaviors observed at the cellular level such as development and acquisition of effector functions by immune cells result from transcriptional changes. The biochemical mediators of transcription are sequence-specific transcription factors (TFs), chromatin modifying enzymes, and chromatin, the complex of DNA and histone proteins. Covalent modification of DNA and histones, also termed epigenetic modification, influences the accessibility of target sequences for transcription factors on chromatin and the expression of linked genes required for immune functions. Genome-wide techniques such as ChIP-Seq have described the entire "cistrome" of transcription factors involved in specific developmental steps of B and T cells and started to define specific immune responses in terms of the binding profiles of critical effectors and epigenetic modification patterns. Current data suggest that both promoters and enhancers are prepared for action at different stages of activation by epigenetic modification through distinct transcription factors in different cells. PMID- 21703539 TI - NLRX1 negatively regulates TLR-induced NF-kappaB signaling by targeting TRAF6 and IKK. AB - Tight regulation of NF-kappaB signaling is essential for innate and adaptive immune responses, yet the molecular mechanisms responsible for its negative regulation are not completely understood. Here, we report that NLRX1, a NOD-like receptor family member, negatively regulates Toll-like receptor-mediated NF kappaB activation. NLRX1 interacts with TRAF6 or IkappaB kinase (IKK) in an activation signal-dependent fashion. Upon LPS stimulation, NLRX1 is rapidly ubiquitinated, disassociates from TRAF6, and then binds to the IKK complex, resulting in inhibition of IKKalpha and IKKbeta phosphorylation and NF-kappaB activation. Knockdown of NLRX1 in various cell types markedly enhances IKK phosphorylation and the production of NF-kappaB-responsive cytokines after LPS stimulation. We further provide in vivo evidence that NLRX1 knockdown in mice markedly enhances susceptibility to LPS-induced septic shock and plasma IL-6 level. Our study identifies a previously unrecognized role for NLRX1 in the negative regulation of TLR-induced NF-kappaB activation by dynamically interacting with TRAF6 and the IKK complex. PMID- 21703540 TI - NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-kappaB signaling pathways. AB - The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) proteins regulate innate immunity. Although the positive regulatory impact of NLRs is clear, their inhibitory roles are not well defined. We showed that Nlrx1(-/-) mice exhibited increased expression of antiviral signaling molecules IFN-beta, STAT2, OAS1, and IL-6 after influenza virus infection. Consistent with increased inflammation, Nlrx1(-/-) mice exhibited marked morbidity and histopathology. Infection of these mice with an influenza strain that carries a mutated NS-1 protein, which normally prevents IFN induction by interaction with RNA and the intracellular RNA sensor RIG-I, further exacerbated IL-6 and type I IFN signaling. NLRX1 also weakened cytokine responses to the 2009 H1N1 pandemic influenza virus in human cells. Mechanistically, Nlrx1 deletion led to constitutive interaction of MAVS and RIG-I. Additionally, an inhibitory function is identified for NLRX1 during LPS activation of macrophages where the MAVS-RIG-I pathway was not involved. NLRX1 interacts with TRAF6 and inhibits NF-kappaB activation. Thus, NLRX1 functions as a checkpoint of overzealous inflammation. PMID- 21703541 TI - DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. AB - The innate immune system detects viral infection predominantly by sensing viral nucleic acids. We report the identification of a viral sensor, consisting of RNA helicases DDX1, DDX21, and DHX36, and the adaptor molecule TRIF, by isolation and sequencing of poly I:C-binding proteins in myeloid dendritic cells (mDCs). Knockdown of each helicase or TRIF by shRNA blocked the ability of mDCs to mount type I interferon (IFN) and cytokine responses to poly I:C, influenza A virus, and reovirus. Although DDX1 bound poly I:C via its Helicase A domain, DHX36 and DDX21 bound the TIR domain of TRIF via their HA2-DUF and PRK domains, respectively. This sensor was localized within the cytosol, independent of the endosomes. Thus, the DDX1-DDX21-DHX36 complex represents a dsRNA sensor that uses the TRIF pathway to activate type I IFN responses in the cytosol of mDCs. PMID- 21703542 TI - B cell receptor-mediated antigen gathering requires ubiquitin ligase Cbl and adaptors Grb2 and Dok-3 to recruit dynein to the signaling microcluster. AB - The B cell receptor (BCR) mediates B cell antigen gathering and acquisition for presentation to T cells. Although the amount of antigen presentation to T cells determines the extent of B cell activation, the molecular mechanisms underlying antigen gathering remain unexplored. Here, through a combination of high resolution imaging, genetics and quantitative mass spectrometry, we demonstrate that adaptors Grb2 and Dok-3, and ubiquitin ligase Cbl in signaling BCR microclusters mediate association with the microtubule motor dynein. Furthermore, we visualize the localization and movement of these microclusters on the underlying microtubule network. Importantly, disruption of this network or diminished dynein recruitment in Grb2-, Dok-3-, or Cbl-deficient B cells, does not influence microcluster formation or actin-dependent spreading, but abrogates directed movement of microclusters and antigen accumulation. Thus we identify a surprising but pivotal role for dynein and the microtubule network alongside Grb2, Dok-3, and Cbl in antigen gathering during B cell activation. PMID- 21703543 TI - Dynein-driven transport of T cell receptor microclusters regulates immune synapse formation and T cell activation. AB - When T cells recognize a peptide-major histocompatibility complex on antigen presenting cells (APCs), T cell receptor microclusters (TCR-MCs) are generated and move to the center of the T cell-APC interface to form the central supramolecular activation cluster (cSMAC). cSMAC formation depends on stimulation strength and regulates T cell activation. We demonstrate that the dynein motor complex colocalized and coimmunoprecipitated with the TCR complex and that TCR MCs moved along microtubules (MTs) toward the center of the immune synapse in a dynein-dependent manner to form cSMAC. MTs are located in close proximity to the plasma membrane at the activation site. TCR-MC velocity and cSMAC formation were impaired by dynein or MT inhibitors or by ablation of dynein expression. T cells with impaired cSMAC formation exhibited enhanced cellular activation including protein phosphorylation and interleukin-2 production. These results indicate that cSMAC formation by TCR-MC movement depends on dynein and MTs, and the movement regulates T cell activation. PMID- 21703544 TI - Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens. AB - A prominent feature of sensitizing environmental compounds that cause allergic contact dermatitis is the rapid induction of an innate inflammatory response that seems to provide danger signals for efficient T cell priming. We generated mouse models of mast cell deficiency, mast cell-specific gene inactivation, and mast cell reporter mice for intravital imaging and showed that these adjuvant effects of contact allergens are mediated by mast cells and histamine. Mast cell deficiency resulted in impaired emigration of skin DCs to the lymph node and contact hypersensitivity was dramatically reduced in the absence of mast cells. In addition, mast cell-specific inactivation of the Il10 gene did not reveal any role for mast cell-derived IL-10 in the regulation of contact allergy. Collectively, we demonstrate that mast cells are essential promoters of contact hypersensitivity, thereby highlighting their potential to promote immune responses to antigens entering via the skin. PMID- 21703546 TI - Drosophila sbo regulates lifespan through its function in the synthesis of coenzyme Q in vivo. AB - CoQ is an essential electron carrier in the mitochondrial respiratory chain of both eukaryotes and prokaryotes. It consists of a benzoquinone head group and a hydrophobic polyisoprenoid tail. The genes (COQ1-9) involved in CoQ biosynthesis have been characterized in yeast. In this study, we generated and molecularly characterized a mutant allele of a novel Drosophila gene, sbo, which encodes a protein that is predicted to catalyze the prenylation of p-hydroxybenzoate with the isoprenoid chain during the process of CoQ synthesis. Expression of sbo in yeast rescues the lethality of ?COQ2 mutant cells, indicating that sbo is a functional homolog of COQ2. HPLC results show that the levels of CoQ(9) and CoQ(10) were significantly reduced in sbo heterozygous adult flies. Furthermore, the mean lifespans of males and females heterozygous for sbo are extended by 12.5% and 30.8%, respectively. Homozygous sbo animals exhibit reduced activities of the insulin/insulin-like growth factor signaling (IIS) pathway. Taken together, we conclude that sbo is an essential gene for Drosophila development, mutation of which leads to an extension of lifespan most likely by altering endogenous CoQ biosynthesis. PMID- 21703545 TI - TNF alpha antagonist therapy and safety monitoring. AB - OBJECTIVES: To develop and/or update fact sheets about TNFalpha antagonists treatments, in order to assist physicians in the management of patients with inflammatory joint disease. METHODS: 1. selection by a committee of rheumatology experts of the main topics of interest for which fact sheets were desirable; 2. identification and review of publications relevant to each topic; 3. development and/or update of fact sheets based on three levels of evidence: evidence-based medicine, official recommendations, and expert opinion. The experts were rheumatologists and invited specialists in other fields, and they had extensive experience with the management of chronic inflammatory diseases, such as rheumatoid. They were members of the CRI (Club Rhumatismes et Inflammation), a section of the Societe Francaise de Rhumatologie. Each fact sheet was revised by several experts and the overall process was coordinated by three experts. RESULTS: Several topics of major interest were selected: contraindications of TNFalpha antagonists treatments, the management of adverse effects and concomitant diseases that may develop during these therapies, and the management of everyday situations such as pregnancy, surgery, and immunizations. After a review of the literature and discussions among experts, a consensus was developed about the content of the fact sheets presented here. These fact sheets focus on several points: 1. in RA and SpA, initiation and monitoring of TNFalpha antagonists treatments, management of patients with specific past histories, and specific clinical situations such as pregnancy; 2. diseases other than RA, such as juvenile idiopathic arthritis; 3. models of letters for informing the rheumatologist and general practitioner; 4. and patient information. CONCLUSION: These TNFalpha antagonists treatments fact sheets built on evidence-based medicine and expert opinion will serve as a practical tool for assisting physicians who manage patients on these therapies. They will be available continuously at www.cri-net.com and updated at appropriate intervals. PMID- 21703547 TI - c-Jun binding site identification in K562 cells. AB - Determining the binding sites of the transcription factor is important for understanding of transcriptional regulation. Transcription factor c-Jun plays an important role in cell growth, differentiation and development, but the binding sites and the target genes are not clearly defined in the whole human genome. In this study, we performed a ChIP-Seq experiment to identify c-Jun binding site in the human genome. Forty-eight binding sites were selected to process further evaluation by dsDNA microarray assay. We identified 283 c-Jun binding sites in K562 cells. Data analysis showed that 48.8% binding sites located within 100 kb of the upstream of the annotated genes, 28.6% binding sites comprised consensus TRE/CRE motif (5'-TGAC/GTCA-3', 5'-TGACGTCA-3') and variant sequences. Forty-two out of the selected 48 binding sites were found to bind the c-Jun homodimer in dsDNA microarray analysis. Data analysis also showed that 1569 genes are located in the neighborhood of the 283 binding sites and 191 genes in the neighborhood of the 42 binding sites validated by dsDNA microarray. We consulted 38 c-Jun target genes in previous studies and 16 among these 38 genes were also detected in this study. The identification of c-Jun binding sites and potential target genes in the genome scale may improve our fundamental understanding in the molecular mechanisms underlying the transcription regulation related to c-Jun. PMID- 21703548 TI - Unraveling the Acidithiobacillus caldus complete genome and its central metabolisms for carbon assimilation. AB - Acidithiobacillus caldus is one of the dominant sulfur-oxidizing bacteria in bioleaching reactors. It plays the essential role in maintaining the high acidity and oxidation of reduced inorganic sulfur compounds during bioleaching process. In this report, the complete genome sequence of A. caldus SM-1 is presented. The genome is composed of one chromosome (2,932,225 bp) and four plasmids (pLAtc1, pLAtc2, pLAtc3, pLAtcm) and it is rich in repetitive sequences (accounting for 11% of the total genome), which are often associated with transposable genetic elements. In particular, twelve copies of ISAtfe and thirty-seven copies of ISAtc1 have been identified, suggesting that they are active transposons in the genome. A. caldus SM-1 encodes all enzymes for the central metabolism and the assimilation of carbon compounds, among which 29 proteins/enzymes were identifiable with proteomic tools. The SM-1 fixes CO(2)via the classical Calvin Bassham-Benson (CBB) cycle, and can operate complete Embden-Meyerhof pathway (EMP), pentose phosphate pathway (PPP), and gluconeogenesis. It has an incomplete tricarboxylic acid cycle (TCA). Four putative transporters involved in carbohydrate uptake were identified. Taken together, the results suggested that SM-1 was able to assimilate carbohydrates and this was subsequently confirmed experimentally because addition of 1% glucose or sucrose in basic salt medium significantly increased the growth of SM-1. It was concluded that the complete genome of SM-1 provided fundamental data for further investigation of its physiology and genetics, in addition to the carbon metabolism revealed in this study. PMID- 21703549 TI - Deletion of the topoisomerase III gene in the hyperthermophilic archaeon Sulfolobus islandicus results in slow growth and defects in cell cycle control. AB - Topoisomerase III (topo III), a type IA topoisomerase, is widespread in hyperthermophilic archaea. In order to interrogate the in vivo role of archaeal topo III, we constructed and characterized a topo III gene deletion mutant of Sulfolobus islandicus. The mutant was viable but grew more slowly than the wild type strain, especially in a nutrient-poor medium. Flow cytometry analysis revealed changes of the mutant in growth cycle characteristics including an increase in proportion of cells containing either more than two genome equivalents or less than one genome equivalent in exponentially-growing cultures. As shown by fluorescence microscopy, a fraction of mutant cells in the cultures were drastically enlarged, and at least some of the enlarged cells were apparently capable of resuming cell division. The mutant also shows a different transcriptional profile from that of the wild-type strain. Our results suggest that the enzyme may serve roles in chromosomal segregation and control of the level of supercoiling in the cell. PMID- 21703550 TI - Development of pyrF-based gene knockout systems for genome-wide manipulation of the archaea Haloferax mediterranei and Haloarcula hispanica. AB - The haloarchaea Haloferax mediterranei and Haloarcula hispanica are both polyhydroxyalkanoate producers in the domain Archaea, and they are becoming increasingly attractive for research and biotechnology due to their unique genetic and metabolic features. To accelerate their genome-level genetic and metabolic analyses, we have developed specific and highly efficient gene knockout systems for these two haloarchaea. These gene knockout systems consist of a suicide plasmid vector with the pyrF gene as the selection marker and a uracil auxotrophic haloarchaeon (DeltapyrF) as the host. For in-frame deletion of a target gene, the suicide plasmid carrying the flanking region of the target gene was transferred into the corresponding DeltapyrF host. After positive selection of the single-crossover integration recombinants (pop-in) on AS-168SY medium without uracil and counterselection of the double-crossover pyrF-excised recombinants (pop-out) with 5-fluoroorotic acid (5-FOA), the target gene knockout mutants were confirmed by PCR and Southern blot analysis. We have demonstrated the effectiveness of these systems by knocking out the crtB gene which encodes a phytoene synthase in these haloarchaea. In conclusion, these well-developed knockout systems would greatly accelerate the functional genomic research of these halophilic archaea. PMID- 21703551 TI - Extracardiac symptoms are important manifestations of pediatric myocarditis. PMID- 21703552 TI - Effects of early life stress on neuroendocrine and neurobehavior: mechanisms and implications. AB - Evidence continues to mount that adverse experiences early in life have an impact on brain functions. Early life stress can program the development of the hypothalamic-pituitary-adrenal axis and cause alterations of neurochemistry and signaling pathways involved in regulating neuroplasticity, with resultant neurobehavioral changes. Early life experiences and genetic factors appear to interact in determining the individual vulnerability to mental health disorders. We reviewed the effects of early life stress on neuroendocrine regulation and the relevance to neurobehavioral development. PMID- 21703553 TI - Efficacy of creamatocrit technique in evaluation of premature infants fed with breast milk. AB - BACKGROUND: Most premature babies are discharged with low body weight. Creamatocrit represents the lipid concentration of breast milk. We expected the creamatocrit technique could be applied in the nutrition plan for premature infants who were exclusively fed by human milk. METHODS: Breast milk samples were obtained from the mothers whose babies were admitted to the neonatal intensive care unit or sick baby room. The breast milk provider was enrolled under the criteria of stable breast milk expression 2 weeks after having given birth. Breast milk was collected for 7 consequent days. Creamatocrit technique and calorie analysis were performed on the processed breast milk samples. RESULTS: Fourteen pairs of mothers and infants were enrolled in our study. The median gestational age and birth weight were 29 weeks (27-36 weeks) and 1,393 g (680 3050 g), respectively. The mean calorie and creamatocrit values for all the 98 breast milk samples were 0.67 kcal/mL and 5.98%, respectively. The linear correlation between creamatocrit value and laboratory-measured calories was found to be calories (kcal/mL)=0.39+0.048*creamatocrit (%) (p<0.05). CONCLUSION: We established the relation equation of creamatocrit and calories for the first time in Chinese population, which is convenient and accurate for evaluating calories provided for premature infants fed with breast milk. PMID- 21703555 TI - Pediatric malignant ovarian tumors: 15 years of experience at a single institution. AB - BACKGROUND: Malignant ovarian tumors in children are relatively rare. We reviewed our 15-year experience to understand their clinical presentations, managements, and prognoses. METHODS: There were 15 children who were diagnosed to have malignant ovarian tumors from January 1994 to June 2009 in our hospital. The presenting symptoms, treatments, and outcomes were obtained retrospectively from the medical records. RESULTS: The median age at presentation was 13 years. The most common presenting symptom was abdominal pain, occurring in 10 patients (66.7%). The tumors were in the left side in 10 patients (66.7%). The pathologic diagnoses were yolk sac tumors in four patients, immature teratomas in four, dysgerminomas in three, malignant mixed germ cell tumors in three, and carcinosarcoma in one patient. According to the Federation Internationale de Gynecologie Oncologique classification, seven girls had Stage I, one had Stage II, and seven had Stage III disease. Thirteen patients received chemotherapy with platinum-based regimens. Three patients died of their disease: one of yolk sac tumor, one of malignant mixed germ cell tumor, and one of carcinosarcoma. They all had Stage III disease at diagnosis. The 10-year overall survival and disease free survival rates were 77% and 69%, respectively. CONCLUSIONS: Pediatric malignant ovarian tumors were highly curable disease if they were not in the advanced stage at presentation. Earlier consideration of malignant ovarian tumor in the differential diagnosis of young girls with abdominal pain is important. PMID- 21703554 TI - Clinical presentation of pediatric myocarditis in Taiwan. AB - BACKGROUND: The purposes of this study were to characterize the symptoms and signs of children with myocarditis at the time of presentation to the hospital and to identify the predictors of death. METHODS: This was a 5-year retrospective study in a tertiary hospital. We collected demographic data and clinical symptoms and signs when children with myocarditis presented at the hospital. The outcome for patient was classified as either survival or death, and the predictors of death were identified. RESULTS: Over the 5-year period, 27 children (14 boys and 13 girls) met the definition of clinical myocarditis. The mean age of the myocarditis patients was 9.1+/-5.1 years (range, 0.08-17.9 years), and the maximum age was 10-12 years. The most common presentation was gastrointestinal symptoms. We used extracorporeal membrane oxygenation on nine (33%) children, and pacemaker was implanted in eight (30%). Six (22%) children died in this study, and only one of them was younger than 6 years. The poor prognosis predictors were gastrointestinal symptoms, hepatomegaly, and hypotension. CONCLUSIONS: Pediatric myocarditis presents primarily with gastrointestinal symptoms in Taiwan. Careful check of heart rhythm may provide a useful objective marker of myocarditis. The predictors of a poor prognosis were gastrointestinal symptoms, hepatomegaly, and hypotension. PMID- 21703556 TI - Renal calcification in very low birth weight infants. AB - BACKGROUND: Renal calcification in preterm infants has been described frequently. The etiologic factors have not yet been fully clarified. The objective of this study was to evaluate the incidence of and risk factors for renal calcification in our population. METHODS: We retrospectively reviewed the charts of very low birth weight preterm infants during a 1-year period. Renal ultrasound scans were performed at term or before discharge and at a corrected age of 1 year. RESULTS: Six infants (6%) had renal calcification at term or before discharge compared with 96 who did not. Factors significantly associated with renal calcification included gestational age (26 weeks vs. 29 weeks, p=0.006), birth weight (851 g vs. 1141 g, p=0.004), duration of mechanical ventilation (69 days vs. 29 days, p=0.002), length of intensive care (72 days vs. 41 days, p=0.013), furosemide therapy (33% vs. 3%, p=0.027), and dexamethasone therapy (50% vs. 2% p=0.001). Birth weight and dexamethasone therapy had significant independent association after stepwise logistic regression analysis. Sex, oliguria, acidosis, duration of oxygen therapy, length of hospital stay, nutrition status, and nephrotoxic drugs did not differ between the two groups. Three of the six infants had spontaneous remission of renal calcification, whereas two patients without the finding in neonatal stage had renal calcification at a corrected age of 1 year. CONCLUSION: The incidence of renal calcification in very low birth weight infants in this study was relatively low, and the calcification was transient in one-half of the infants. Extremely premature, sick infants requiring long-term ventilation, and those receiving furosemide or dexamethasone were more likely to have renal calcification. Clinicians should be aware that renal calcification may develop beyond the neonatal stage. PMID- 21703557 TI - Clinical manifestations of primary spontaneous pneumothorax in pediatric patients: an analysis of 78 patients. AB - BACKGROUND: The aims of this investigation were to explore primary spontaneous pneumothorax (PSP) in pediatric patients and to evaluate the clinical manifestations and outcomes of the PSP. METHODS: Seventy-eight patients diagnosed with PSP between January 2004 and December 2009 was retrospectively studied. The clinical data on demographics, diagnostic imaging, therapeutic approach, and outcomes were collected and analyzed. RESULTS: The sex ratio of 78 PSP patients was 7.7:1 (male:female=69:9), and the age distribution concentrated between 15 years and 18 years (66 patients, 84.6%). The most common presenting symptom was chest pain (69 patients, 88.5%). The average body mass index was 18.2+/-1.6 (n=66). Autumn was the more likely attack season for PSP in this study (p=0.005). Twenty-eight patients (35.9%) had tension pneumothorax. Only nine (11.5%) patients had a past history of cigarette smoking. All 21 outpatients received supportive treatment. Out of 57 inpatients, 10 (17.5%) received oxygen therapy, 39 (68.4%) received closed-tube drainage, and 6 (10.5%) received video-assisted thoracoscopic surgery. Apical bleb and subpleural bullae formation were common pathological findings (21 patients, 91.3%). Twenty-four (42.1%) patients experienced a second attack, and six (10.5%) patients had a third attack. CONCLUSION: Pediatric PSP occurred mainly in boys of the late teenage group with lower body mass index. Autumn was the most likely attack season. There was only a small portion of the patients who smoked. There was no evidence to find a correlation between smoking and pediatric PSP attacks. Length of stay was shorter in supportive treatment and closed-tube drainage patients than that in video assisted thoracoscopic surgery-treated patients. The outcomes were satisfactory. PMID- 21703558 TI - Complete blood count reference values of cord blood in Taiwan and the influence of gender and delivery route on them. AB - BACKGROUND: Cord blood banking has become more popular in recent years. Checking cord blood complete blood count (CBC) and white blood cell (WBC) differential counts (DCs) is essential before cryopreserving the cord blood units. Therefore, establishing the normal reference values of cord blood CBC and WBC DC is important in clinical practice and research. OBJECTIVES: To obtain a large-scale population-based normal CBC and WBC DC reference values of healthy neonates' cord blood from a public cord blood bank and to investigate the influence of the gender and delivery route. METHODS: From September 2001 to November 2006, the cord blood of healthy Taiwanese neonates with gestational age 36 weeks and more were collected by Tzu Chi Cord Blood Bank with written informed consents. All cord blood samples were analyzed by Sysmex XE2100 automated hematology analyzer (Sysmex Corporation, Kobe, Japan) to obtain the CBC. The WBC DC was calculated by manual method. We used Student's t test and Mann-Whitney U test for investigating the influences of gender and delivery route on the CBC and WBC DC reference values. The results were presented by mean+/-standard deviation or 2.5-97.5th percentiles. RESULTS: In the study period, totally 5602 cord blood samples were collected eligibly for analysis. The cord blood CBC and WBC DC normal reference values were calculated. The female neonates had significantly higher mean corpuscular volume, platelet count, and WBC count, but lower red blood cell (RBC) count, hemoglobin (Hb), hematocrit, and mean corpuscular Hb concentration values (p<0.001). Newborns through vaginal delivery had significantly higher RBC count, Hb, hematocrit, platelet count, and WBC count (p<0.001). The percentages of some different types WBC were significantly influenced by gender and delivery routes. Male babies had higher lymphocyte, monocyte, eosinophil, basophil, and nucleated RBC ratios than the female neonates. Newborns through cesarean section had significantly lower neutrophil, monocyte, and nucleated RBC ratios, but higher lymphocyte and eosinophil ratios, than newborns through vaginal delivery. CONCLUSION: We successfully obtained the normal CBC and WBC DC reference values of the cord blood in Taiwan. Gender and delivery routes were important confounding factors that influenced the cord blood CBC and WBC DC values. PMID- 21703559 TI - Dipstick urinalysis screening of healthy neonates. AB - BACKGROUND: Renal disease may accidentally be discovered during urinalysis. This study was conducted to examine the usefulness of dipstick urinalysis screening in healthy neonates for the diagnosis of underlying renal disease and to study the magnitude of abnormal urinalysis in apparently healthy neonates. METHODS: In this descriptive study, voided urine samples were obtained from 400 apparently healthy neonates and tested using urine dipstick. The reaction of dipstick strip was read visually by a trained nurse. In cases with an abnormal urine analysis, a second screen test was performed within a week, and for those with persistent abnormalities, complete diagnostic tests were done. RESULTS: On the first urinalysis, 375 (94%) subjects were normal and 25 (6%) had abnormalities: 23 had proteinuria (5.75%), one was blood positive (0.25%), and one was both protein and blood positive (0.25%). Male neonates had a higher proportion of proteinuria than female neonates (p=0.038). In the second examination, proteinuria was found in five (1.25%) neonates, but the proportion of other abnormalities did not change. In follow-up investigations, ureteropelvic junction obstruction and vesicoureteral reflux were recognized in two infants who had blood-positive or combined blood- and protein-positive results on their first tests. CONCLUSION: The findings of this study show that dipstick test during neonatal period could be used for early diagnosis of renal diseases. PMID- 21703560 TI - Interstitial deletions of the short arm of chromosome 4 in a patient with mental retardation and focal seizure. AB - Interstitial deletion of the proximal short arm of chromosome 4 has rarely been described. This defect is associated with variable clinical manifestations, including mental retardation, unusual facial appearance, and minor limb abnormalities. We describe a girl diagnosed with moderate mental retardation and seizures with an interstitial deletion of the short arm of chromosome 4 [46, XX, del(4)(p12p15.2)]. PMID- 21703561 TI - Autonomic dysfunction because of severe tetanus in an unvaccinated child. AB - Tetanus is rare in a country with a national vaccination program. When it does occur, the associated autonomic dysfunction is a challenge for physicians. We report here a case of an unvaccinated 5-year-old boy who suffered from tetanus complicated by autonomic dysfunction, which was successfully controlled by the infusion of magnesium sulfate. This is the first case that demonstrated the therapeutic effect of magnesium sulfate in a child with tetanus. This case highlights the importance of implementing a vaccination program. PMID- 21703562 TI - Mediastinal and retropharyngeal abscesses in a neonate. AB - Mediastinal abscess following retropharyngeal abscess is a rare entity. We report the first neonate presenting with a large mediastinal abscess as a complication of a retropharyngeal abscess. The initial manifestations of this newborn were fever and stridor. The chest sonography revealed a mediastinal mass, and the neck and chest computed tomography showed multiple abscesses in the retropharyngeal space, parapharyngeal space, and superior mediastinum. The mediastinal cystic mass was excised, and antibiotic treatment was completed for 7 weeks. She did well without any sequelae at follow-up clinic. Pediatricians should consider retropharyngeal and mediastinal abscesses among the differential diagnoses when confronting a newborn with fever and stridor. PMID- 21703563 TI - Experience of remifentanil in extremely low-birth-weight babies undergoing laparotomy. AB - Premature babies experience pain and require adequate analgesia for any painful procedure. Fentanyl and morphine resulted in safe and effective anesthesia in the past; however, their pharmacokinetics may be impaired in preterm babies with multiorgan failure. Remifentanil, despite the absence of available pharmacokinetic data in preterm infants and few reports in newborns, demonstrated its advantages in children undergoing either major surgery or minor painful procedures and has been shown to be useful even in neonates, because its elimination is independent of organ function. We report two cases of babies born at 26 weeks' and 27 weeks' gestation, weighing 580 g and 400 g, respectively, undergoing laparotomy for necrotizing enterocolitis. Both received midazolam bolus and remifentanil infusion at high doses. This technique seems to be an advantageous alternative even in extremely low-birth-weight prematures. Furthermore, it becomes a technique of choice in these babies because the available ventilators are often not equipped with halogenated vaporizers. Particularly in intensive care, where there are no scavenger systems, it could allow to operate without moving out the preterm babies and avoiding stress and hypothermia. PMID- 21703564 TI - Why a supplement on biologics in PM&R? PMID- 21703567 TI - Stem cells for central nervous system repair and rehabilitation. AB - The central nervous system (CNS) has limited capacity for self-repair. Current treatments are often incapable of reversing the debilitating effects of CNS diseases that result in permanent and/or progressive physical and cognitive impairments. One promising repair strategy is transplantation of stem cells, which can potentially replace lost neurons and/or glia or promote repair through secretion of trophic factors. Various types of stem cells exist, each with their own advantages and disadvantages. Although no consensus exists regarding the optimal cell type to use, moderate functional improvements have been shown in animal models of CNS diseases using different types of stem cells. However, the precise mechanism of action behind their beneficial effects remains unknown. In addition, many barriers to clinical use still need to be resolved before transplantation of stem cells can be used as effective biologics. These barriers include--depending on the stem cell type--possible tumor formation, difficulty with harvest, limited in vivo differentiation and integration, and ethical issues regarding use. PMID- 21703566 TI - The influence of dietary factors in central nervous system plasticity and injury recovery. AB - Although feeding is an essential component of life, it is only recently that the actions of foods on brain plasticity and function have been scrutinized. There is evidence that select dietary factors are important modifiers of brain plasticity and can have an impact on central nervous system health and disease. Results of new research indicate that dietary factors exert their effects by affecting molecular events related to the management of energy metabolism and synaptic plasticity. Recent study results show that select dietary factors have mechanisms similar to those of exercise, and that, in some cases, dietary factors can complement the action of exercise. Abundant research findings in animal models of central nervous system injury support the idea that nutrients can be taken in through whole foods and dietary supplements to reduce the consequences of neural damage. Therefore, exercise and dietary management appear as a noninvasive and effective strategy to help counteract neurologic and cognitive disorders. PMID- 21703568 TI - Identifying inflammatory targets for biologic therapies for spine pain. AB - The costs associated with treating spine-related conditions are enormous and are trending upward. Current methods employed to treat inflammatory-mediated pain are targeted at alleviating symptoms, rather than correcting the underlying cause of disease. It is clear that a biochemical basis for inflammatory-mediated intervertebral disk, facet joint, and nerve pain exists. Biologic therapies that address the underlying cause of pain could potentially decrease the costs associated with treating spine pathology. MMPs, IL-1, TNF- alpha, IL-6, NGF, bradykinin, prostaglandins, and nitric oxide are implicated in much of the catabolic effects seen in the pathogenesis of inflammatory-mediated pain and are good targets for inhibition. The anticatabolic and anabolic effects of TIMPs, BMPs, TGF- beta, and IGF-1 are targets already shown to favorably impact disk matrix homeostasis. With rapid advances in biomedical technology, these interventions may be available for clinical use in the near future. PMID- 21703565 TI - Progesterone and vitamin d hormone as a biologic treatment of traumatic brain injury in the aged. AB - There is growing recognition that traumatic brain injury is a highly variable and complex systemic disorder that is refractory to therapies that target individual mechanisms. It is even more complex in elderly persons, in whom frailty, previous comorbidities, altered metabolism, and a long history of medication use are likely to complicate the secondary effects of brain trauma. Progesterone, one of the few neuroprotective agents that has shown promise for the treatment of acute brain injury, is now in national and international phase 3 multicenter trials. New findings show that vitamin D hormone (VDH) and VDH deficiency in the aging process (and across the developmental spectrum) may interact with progesterone and treatment for traumatic brain injury. In this article we review the use of progesterone and VDH as biologics-based therapies along with recent studies demonstrating that the combination of progesterone and VDH may promote better functional outcomes than either treatment independently. PMID- 21703569 TI - CDP-choline as a biological supplement during neurorecovery: a focused review. AB - Cytidine 5'-diphosphocholine (CDP-choline or citicoline) is a highly bioavailable compound with potential benefits for aiding neural repair and increasing acetylcholine levels in the central and peripheral nervous system. As a result, many researchers have investigated the use of CDP-choline for various types of neurological insult or conditions, including stroke, traumatic brain injury, and Alzheimer disease. Despite the fact that the safety of the compound has been verified across multiple international studies, evidence for efficacy remains less clear. This may be attributable, at least in part, to several issues, including a lack of randomized clinical trials, a lack of availability of the compound in the United States, and statistical power issues in reported trials. In addition, the fact that CDP-choline has multiple potential points of therapeutic impact makes it an exciting treatment option in theory but also complicates the analysis of efficacy in the sense that multiple mechanisms and time points must be evaluated. Although some clinical conditions do not appear to benefit from CDP-choline treatment, the majority of findings to date have suggested at least minor benefits of treatment. In this review we will examine the evidence in the published literature pertaining to use of CDP-choline in rehabilitation populations and briefly consider the work yet to be done. PMID- 21703570 TI - Industry perspectives on the development of biologics. PMID- 21703571 TI - Surgeon's use of biologics: perception and reality. PMID- 21703572 TI - Leveraging biomarker platforms and systems biology for rehabilomics and biologics effectiveness research. AB - Although traumatic brain injury (TBI) remains a major health problem, with approximately 2 million incidents occurring annually in the United States, no therapeutic agents to treat TBI have been approved by the Food and Drug Administration despite several clinical trials. It is estimated that 3.5 million Americans now have a lifelong condition that might be termed "chronic traumatic brain injury disease.'' Some health care providers categorize TBI as an "event" for which patients require brief periods of rehabilitation with no further treatment. On the contrary, TBI should be seen as a chronic disease process that fits the World Health Organization definition as being a non-reversible pathologic condition requiring special rehabilitation training. Among the major obstacles that contribute to this type of misconception is the absence of brain injury-specific diagnostic biomarker(s) that can indicate and monitor the long term health status of patients with TBI after use of conventional therapeutics and a rehabilitation process. It is of interest that recent advances in genomics, proteomics, and systems biology have enabled us to use these high throughput based approaches in developing biomarkers and therapeutic targets in the area of TBI. One aim of this article is to provide an overview that evaluates the current status of TBI biomarker discovery using neuroproteomics/systems biology techniques, along with their clinical utilization. In addition, we discuss the need for strengthening the role of biomarker-based neuroproteomics/systems biology and its potential utility in the field of rehabilitation, which would lead to the establishment of rehabilomics studies, where biomarkers would indicate and predict the long-term efficacy and health status of patients with chronic TBI conditions. PMID- 21703574 TI - Conclusions on biologics in rehabilitation research and clinical care. PMID- 21703573 TI - Integrating rehabilitation engineering technology with biologics. AB - Rehabilitation engineers apply engineering principles to improve function or to solve challenges faced by persons with disabilities. It is critical to integrate the knowledge of biologics into the process of rehabilitation engineering to advance the field and maximize potential benefits to patients. Some applications in particular demonstrate the value of a symbiotic relationship between biologics and rehabilitation engineering. In this review we illustrate how researchers working with neural interfaces and integrated prosthetics, assistive technology, and biologics data collection are currently integrating these 2 fields. We also discuss the potential for further integration of biologics and rehabilitation engineering to deliver the best technologies and treatments to patients. Engineers and clinicians must work together to develop technologies that meet clinical needs and are accessible to the intended patient population. PMID- 21703576 TI - Rehabilomics: a conceptual framework to drive biologics research. PMID- 21703575 TI - Biologic and plastic effects of experimental traumatic brain injury treatment paradigms and their relevance to clinical rehabilitation. AB - Neuroplastic changes, whether induced by traumatic brain injury (TBI) or therapeutic interventions, alter neurobehavioral outcome. Here we present several treatment strategies that have been evaluated by using experimental TBI models and discuss potential mechanisms of action (ie, plasticity) and how such changes affect function. PMID- 21703577 TI - Anabolic/Catabolic balance in pathogenesis of osteoarthritis: identifying molecular targets. AB - Osteoarthritis is the most common degenerative musculoskeletal disease. In healthy cartilage, a low turnover of extracellular matrix molecules occurs. Proper balance of anabolic and catabolic activities is thus crucial for the maintenance of cartilage tissue integrity and for the repair of molecular damages sustained during daily usage. In persons with degenerative diseases such as osteoarthritis, this balance of anabolic and catabolic activities is compromised, and the extent of tissue degradation predominates over the capacity of tissue repair. This mismatch eventually results in cartilage loss in persons with osteoarthritis. Tissue homeostasis is controlled by coordinated actions and crosstalk among a number of proanabolic and antianabolic and procatabolic and anticatabolic factors. In osteoarthritis, an elevation of antianabolic and catabolic factors occurs. Interestingly, anabolic activity is also increased, but this response fails to repair the tissue because of both quantitative and qualitative insufficiency. This review presents an overview of the anabolic and catabolic activities involved in cartilage degeneration and the interplay among different signaling and metabolic factors. Understanding the basic molecular mechanisms responsible for tissue degeneration is critical to identifying and developing means to efficiently block or reverse the pathobiological symptoms of osteoarthritis. PMID- 21703578 TI - Translating biomarkers research to clinical care: applications and issues for rehabilomics. AB - Traumatic brain injury is a leading cause of morbidity and mortality in adults and children in the United States. Despite steady improvement in our understanding of the pathophysiology of acquired brain injuries, there has been remarkably little improvement in brain injury therapies and/or pharmacologic treatments over the past decade. One of the reasons may be the inability to properly stratify subjects for clinical trials and/or to have real-time assessment of the effectiveness of a given intervention. It has been recognized for several decades that serum biomarkers may allow for more objective subject stratification as well as act as surrogate markers of treatment efficacy. Despite numerous studies, however, biomarkers are not currently part of clinical practice in either acquired brain injury or other neurologic or musculoskeletal disorders. The goals of this review article, therefore, are to use traumatic brain injury as a example to discuss the use of biomarkers in clinical and randomized controlled trials; to briefly discuss the field of neuroproteomics and its interface with neurologic interventions; and to provide an overview of the collaborative pathway between academia and industry, which needs to be an integral part of the translation of biomarkers from the bench to the bedside in any clinical population. Introduction of the concept of rehabilomics and implications of biomarker use for the physical medicine and rehabilitation physician also are discussed. PMID- 21703579 TI - Biomarker development for musculoskeletal diseases. AB - More than one in 4 Americans has a musculoskeletal (MSK) disorder that requires medical diagnosis and treatment. Imaging tools are able to demonstrate structural changes but cannot reflect the disease activity or symptom severity of MSK conditions. This is of paramount concern in the aging population, in which imaging findings have poor correlation with symptoms, and multiple pain generators frequently coexist. Because levels of inflammatory and matrix breakdown products address disease activity, evaluation of biomarkers has the potential to provide assessment of active pain generators above and beyond the changes observable on imaging studies. This fact has stimulated research interest in the search for novel biomarkers of disease activity and response to treatment in body fluids. The goal is to develop panels of multi-biomarkers, which could be used independently or in conjunction with the imaging tools, for the diagnosis, prognosis, and treatment validation in MSK diseases. The current review of MSK biomarkers is organized into 3 mechanistic categories: the metabolites of extracellular matrix of MSK tissues; inflammatory cytokines and chemokines; and pain-related neuropeptides and/or chemicals. Although some representative biomarkers could be used alone, the fact that MSK diseases are multi-tissue disorders that involve the muscles, bones, cartilage, and nerves suggests that panels of biomarkers may have greater potential than any single biomarker used in isolation. As advances in biotechnology make this a reality, multi-biomarker panels that include all 3 categories of biomarkers, used either alone or in combination with imaging tools, has the potential to revolutionize the clinical approach to MSK diseases. PMID- 21703581 TI - Genomic, transcriptomic, and epigenomic approaches to recovery after acquired brain injury. AB - Genomics and its related fields have expanded rapidly, primarily because of the potential utility for clinical decision making and improving our understanding of the pathophysiology of complex conditions. The state of the science and technology associated with this field is such that current and future health care providers, when consulting with new patients about their acquired brain injury and options for rehabilitation, will use genetic information as a routine part of the process, which may include information received from a laboratory report that uses transcriptomic data, informs regarding patient prognosis, and makes recommendations for individualized therapeutic approaches to optimize recovery. This may sound like science fiction, but, in the field of oncology, it is the norm for breast cancer and, more recently, for colon cancer, with expansion to other types of cancer on the horizon as research data continue to contribute to the understanding of the pathophysiology of these conditions. Something similar for rehabilitation after acquired brain injury is much further off on the horizon. However, it is a possibility that will never be realized if the community of scientists and health care providers who work with these patients do not have the knowledge or expertise to embrace genomics and related approaches. This article discusses these approaches, some practical considerations for using such approaches, and what is currently published in this area with regard to brain injury. PMID- 21703580 TI - Cognitive impairment in acquired brain injury: a predictor of rehabilitation outcomes and an opportunity for novel interventions. AB - Cognitive impairment is a common sequela in acquired brain injury and one that predicts rehabilitation outcomes. There is emerging evidence that impairments in cognitive functions can be manipulated by both pharmacologic and nonpharmacologic interventions to improve rehabilitation outcomes. By using stroke as a model for acquired brain injury, we review the evidence that links cognitive impairment to poor rehabilitation outcomes and discuss possible mechanisms to explain this association. Furthermore, we examine nascent promising research that suggests that interventions that target cognitive impairments can lead to better rehabilitation outcomes. PMID- 21703582 TI - Biological basis of exercise-based treatments for musculoskeletal conditions. AB - Exercise-based therapies are the cornerstone of rehabilitation programs. While the benefits of exercise on systemic and tissue function are generally accepted, mechanisms underlying these benefits are sometimes poorly understood. An improved understanding of the effects of mechanical loading on molecular and cellular processes has the potential to lead to more disease-specific and efficacious exercise-based therapies. The purpose of this paper is to review the current literature examining the role of mechanical signaling on muscle and cartilage biology. PMID- 21703583 TI - Exercise after traumatic brain injury: is it a double-edged sword? AB - This article describes the effects of exercise on neural plasticity after traumatic brain injury (TBI). There is strong evidence that indicates that exercise has neuroprotective effects by activating specific neuronal circuits and increasing molecules that enhance synaptic plasticity. Findings obtained from experimental models of TBI are discussed to support the use of exercise as a rehabilitative tool. These studies indicate that injury characteristics are likely to influence the time window for therapeutic exercise. Results of human and animal studies suggest that premature postconcussive exercise may be deleterious by exacerbating postconcussive symptomatology and disrupting restorative processes. A better understanding of the mechanisms that influence exercise after TBI will contribute to improving guidelines for the return to exercise activities and to the successful use of exercise as a therapeutic tool. PMID- 21703584 TI - Biological basis of exercise-based treatments: spinal cord injury. AB - Despite intensive neurorehabilitation, extensive functional recovery after spinal cord injury is unattainable for most individuals. Optimal recovery will likely depend on activity-based, task-specific training that personalizes the timing of intervention with the severity of injury. Exercise paradigms elicit both beneficial and deleterious biophysical effects after spinal cord injury. Modulating the type, intensity, complexity, and timing of training may minimize risk and induce greater recovery. This review discusses the following: (a) the biological underpinning of training paradigms that promote motor relearning and recovery, and (b) how exercise interacts with cellular cascades after spinal cord injury. Clinical implications are discussed throughout. PMID- 21703585 TI - Prolotherapy: a clinical review of its role in treating chronic musculoskeletal pain. AB - Prolotherapy is a technique that involves the injection of an irritant, usually a hyperosmolar dextrose solution, typically in the treatment of chronic painful musculoskeletal conditions. Despite its long history and widespread use as a form of complementary therapy, there still are disparities over its optimal indications and injection preparations. There are, however, numerous studies available regarding the use and efficacy of prolotherapy for various musculoskeletal conditions. The most frequently published indication is in the treatment of chronic low back pain, but there are recent studies that examined its use in the management of refractory tendinopathies as well as osteoarthritis. There is growing evidence to suggest that prolotherapy may be helpful in treating chronic low back pain when coupled with adjunctive therapies, such as spinal manipulation or corticosteroid injections. There is also evidence to suggest that prolotherapy is effective in treating refractory tendinopathies, particularly for lateral epicondylosis and Achilles tendinopathy. Additional larger, randomized controlled trials are needed to make specific recommendations regarding ideal protocols and indications. There is emerging evidence for the use of prolotherapy as a treatment option for osteoarthritis; however, further studies are needed to conclusively demonstrate its efficacy. Overall, prolotherapy remains a promising option for the treatment of painful musculoskeletal conditions, particularly when other standard treatments have proved ineffective. PMID- 21703586 TI - Vitamin K: fracture prevention and beyond. AB - Morbidity and decreased function related to osteoporosis, fracture, cardiovascular disease, stroke, and peripheral vascular disease are encountered by clinicians daily. Although we have seen vast advancement in treatment and management of these conditions, preventative practice has unfortunately served a lesser role in patient care. Increasing the dietary intake of vitamin K may have substantial utility in the prevention of these disease states. Since the discovery of vitamin K in 1935, its primary role was thought to be involved in the synthesis of clotting factors II, VII, IX, and X. Recently, its function in other metabolic pathways has emerged, leading to exploration of its significance beyond coagulation. Vitamin K is essential to bone physiology and prevention of atherosclerosis. It is involved in bone remodeling, cell signaling, apoptosis, arterial calcification, and chemotaxis, and it has anti-inflammatory effects. Conversely, warfarin, a potent vitamin K inhibitor, has demonstrated adverse effects on bone remodeling and atherosclerosis. Natural forms of vitamin K are available in multiple dietary sources, and some structural forms are more readily available for use in metabolic pathways than are others. With regard to supplementation, the specific form of vitamin K is often not disclosed, and the recommended daily value is potentially less than what is physiologically required. On the basis of a review of the literature, it appears advantageous to encourage patients to eat a diet rich in vitamin K; however, the benefit of vitamin K supplementation alone is yet to be thoroughly conveyed. PMID- 21703587 TI - Intervertebral disk repair by protein, gene, or cell injection: a framework for rehabilitation-focused biologics in the spine. AB - Low back pain carries an enormous socioeconomic burden. Current treatment modalities for symptomatic intervertebral disk (IVD) degeneration have limited and often inconsistent clinical benefits. Novel approaches with the potential to halt or even reverse disk degeneration and restore physiologic disk function, such as biological treatments, are therefore very attractive. The following barriers are impeding the development of successful therapeutic interventions: (1) the biology and pathophysiology of disk degeneration are not well understood, and (2) the precise relationship between IVD degeneration and low back pain remains unclear. This article reviews the structural changes that take place during IVD degeneration and their relationship to diskogenic back pain. It also presents treatment modalities that currently are under laboratory investigation and are being studied in clinical trials. The authors of recent studies have shown that the content of large proteoglycans, such as aggrecan and versican, decreases with aging and IVD degeneration, whereas the content of certain small proteoglycans, such as biglycan, increases. Proinflammatory cytokines such as interleukin-1 and tumor necrosis factor-alpha also are associated with IVD degeneration and are potential biomarkers of IVD degeneration and repair. Our group of investigators and others have developed in vitro models of IVD cell and explant culture in addition to in vivo animal models to study IVD degeneration and repair. With the use of these models, we have tested candidate therapeutic agents to assess their therapeutic potential for matrix restoration. When a rabbit annular puncture model of IVD degeneration was used, injections of either bone morphogenetic protein-7 (also known as osteogenic protein-1) or bone morphogenetic protein-14 (also known as growth differentiation factor-5) were shown to be effective in restoring IVD structures. On the basis of these data, the Food and Drug Administration has recently allowed the initiation of Investigational New Drug clinical trials on osteogenic protein-1 and growth differentiation factor-5 in the United States. Protein therapies such as other growth factors, inhibitors of degradation enzymes or cytokines, and cell therapies also are being investigated in laboratory settings with the goal of restoring disk function and alleviating back pain symptoms. These therapies may be used by physiatrists with the skills required to administer intradiskal injections and supervise a comprehensive rehabilitation program after the procedures. Ultimately, the clinical use of any biological treatment discussed in this article would require the collective efforts of clinicians and researchers. PMID- 21703588 TI - Stem cell use in musculoskeletal disorders. AB - Human stem cells derived from bone marrow are currently used in clinical medicine for bone and cartilage repair for injuries such as meniscal tears. New clinical stem cell studies underway include the treatment of patients with spinal cord injuries. Rapid advances in stem cell science are opening new avenues for drug discovery and may lead to new uses of stem cells for other musculoskeletal disorders. PMID- 21703589 TI - Retroactive interference in short-term memory and the word-length effect. AB - Two experiments investigated the possibility that the word-length effect in short term memory (STM) is a consequence of long words generating a greater level of retroactive interference than shorter words. In Experiment 1, six-word lists were auditorily presented under articulatory suppression for immediate serial reconstruction of only the first three words. These three words were always drawn from a single set of middle-length words, whereas the last three positions were occupied by either short or long interfering words. The results showed worse memory performance when the to-be-remembered words were followed by long words. In Experiment 2, a recent-probes task was used, in which recent negative probes matched a target word in trial n-2. The results showed lower levels of proactive interference when trial n-1 involved long words instead of short words, suggesting that long words displaced previous STM content to a greater extent. By two different experimental approaches, therefore, this study shows that long words produce more retroactive interference than short words, supporting an interference-based account for the word-length effect. PMID- 21703592 TI - Outcomes associated with introduction of a shoulder dystocia protocol. AB - The objective of this study was to assess outcomes that are associated with the implementation of a shoulder dystocia protocol that is focused on team response. We identified women who had a shoulder dystocia during 3 time periods: 6 months before (period A), 6 months during (period B), and 6 months after (period C) the institution of a shoulder dystocia protocol. Documentation and health outcomes were compared among the time periods. During the study period, 254 women (77, 100, and 77 in periods A, B, and C, respectively) had a shoulder dystocia. There were no differences among study periods in patient characteristics. However, complete and consistent documentation increased (14% to 50% to 92%; P < .001), and brachial plexus palsy that was diagnosed at delivery (10.1% to 4.0% to 2.6%; P = .03) and at neonatal discharge (7.6% to 3.0% to 1.3%; P = .04) declined. PMID- 21703590 TI - Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting. AB - Genetic mutations responsible for oblique facial clefts (ObFC), a unique class of facial malformations, are largely unknown. We show that loss-of-function mutations in SPECC1L are pathogenic for this human developmental disorder and that SPECC1L is a critical organizer of vertebrate facial morphogenesis. During murine embryogenesis, Specc1l is expressed in cell populations of the developing facial primordial, which proliferate and fuse to form the face. In zebrafish, knockdown of a SPECC1L homolog produces a faceless phenotype with loss of jaw and facial structures, and knockdown in Drosophila phenocopies mutants in the integrin signaling pathway that exhibit cell-migration and -adhesion defects. Furthermore, in mammalian cells, SPECC1L colocalizes with both tubulin and actin, and its deficiency results in defective actin-cytoskeleton reorganization, as well as abnormal cell adhesion and migration. Collectively, these data demonstrate that SPECC1L functions in actin-cytoskeleton reorganization and is required for proper facial morphogenesis. PMID- 21703593 TI - Clinicopathologic predictors for early and late biochemical hypothyroidism after hemithyroidectomy. AB - BACKGROUND: Biochemical hypothyroidism (BH) after hemithyroidectomy is an under recognized complication with a reported incidence of 9% to 43%. This study aimed to identify potential clinicopathologic risk factors associated with early (<12 months after hemithyroidectomy) and late-onset (>=12 months after hemithyroidectomy) BH. METHODS: From 2005 to 2008 there were 263 postsurgical patients who were eligible for analysis. Serum thyroid stimulating hormone (TSH) level was checked regularly after surgery. Postoperative TSH reaching a level higher than 5.5 mIU/L was defined as BH. The overall median follow-up period was 21 months (range, 3-62 mo). Any clinicopathologic factors significantly associated with BH in the univariate analysis were entered into multivariate analysis. A further analysis was performed comparing factors between early and late-onset BH. RESULTS: There were 38 patients who developed subsequent BH, 33 of these cases developed within 2 years. Those patients with BH were significantly older (P = .037), had a higher preoperative TSH level (P < .001), longer follow up period (P < .001), more frequent thyroiditis on histology (P = .043), lighter resected tissue weight (P = .001), and were more likely to have positive antimicrosomal antibodies (P = .043) than those without BH. However, in the multivariate analysis after adjusting for different follow-up periods in the 2 groups, only lighter resected tissue weight (P = .036) and concomitant thyroiditis on histology (P = .005) turned out to be independent factors for BH. Thyroiditis on histology was also the only significant risk factor for developing early onset BH. CONCLUSIONS: Patients with lighter resected tissue weight and concomitant thyroiditis on histology were particularly at risk for subsequent BH. Although not all patients with thyroiditis developed BH, in those who did develop BH it occurred within the first 11 months. PMID- 21703594 TI - Operating room introduction for the novice. AB - BACKGROUND: This study assessed the implementation of a theater induction curriculum through a didactic lecture, an online Second Life operating room, and a simulated operating suite. METHODS: Sixty operating room novices were randomized into 4 groups: control (n = 15), didactic lecture (n = 15), Second Life (n = 15), and simulated operating suite (n = 15). The study followed a pretest and posttest design with a training intervention between operating room attendances. Outcome measures were knowledge, skills, and attitudes, measured using observed behavior and a self-report scale, with knowledge further assessed using multiple-choice questionnaires. RESULTS: The lecture, Second Life, and simulated operating suite groups demonstrated significant improvements in all outcome measures. After the intervention, these 3 groups had significantly higher behavior (P < .001), self-report (P < .05), and knowledge (P < .05) scores than the control group. CONCLUSIONS: This study demonstrates the value of delivering a theater induction curriculum for operating room preparation. PMID- 21703595 TI - n-Butanol extracts of Panax notoginseng suppress LPS-induced MMP-2 expression in periodontal ligament fibroblasts and inhibit osteoclastogenesis by suppressing MAPK in LPS-activated RAW264.7 cells. AB - OBJECTIVE: Periodontitis is a group of inflammatory diseases that affect connective tissue attachments and the supporting bone that surround the teeth. Osteoclasts are responsible for skeletal modeling and remodeling but may also destroy bone in several bone diseases, including osteoporosis and periodontitis. This study examined the anti-inflammatory effects of Panax notoginseng (PN) on periodontal ligament fibroblasts (PDLFs) and RAW264.7 cells under lipopolysaccharide (LPS) induced inflammatory conditions. DESIGN: The effects of PN on PDLFs were determined by measuring the cell viability and mRNA expression of tissue-destructive proteins. The effects of PN on osteoclasts were examined by measuring the following: (1) the cell viability, (2) the formation of Tartrate resistant acid phosphatase (TRAP)(+) multinucleated cells, (3) MAPK signaling pathways, (4) mRNA expression of inflammatory-related proteins and (5) nitric oxide (NO) production. RESULTS: The n-butanol extracts of PN (bPN) increased the cell proliferation of the PDLFs and decreased the mRNA expression of matrix metalloproteinase (MMP)-2 in the PDLFs. bPN inhibited the formation of LPS stimulated TRAP(+) multinucleated cells. bPN also inhibited the LPS-stimulated activation of JNK and ERK signaling, and inhibited the LPS-stimulated degradation of I(K)B in the RAW264.7 cells. In addition, bPN decreased the mRNA expression of MMP-9 and iNOS, which are involved in the range of pathophysiological processes, such as inflammation in the RAW264.7 cells. NO production was also decreased via the inhibition of iNOS. CONCLUSIONS: These findings suggest that bPN has therapeutic effects on bone-destructive processes, such as those that occur in periodontal diseases. PMID- 21703596 TI - Brain energy consumption induced by electrical stimulation promotes systemic glucose uptake. AB - BACKGROUND: Controlled transcranial stimulation of the brain is part of clinical treatment strategies in neuropsychiatric diseases such as depression, stroke, or Parkinson's disease. Manipulating brain activity by transcranial stimulation, however, inevitably influences other control centers of various neuronal and neurohormonal feedback loops and therefore may concomitantly affect systemic metabolic regulation. Because hypothalamic adenosine triphosphate-sensitive potassium channels, which function as local energy sensors, are centrally involved in the regulation of glucose homeostasis, we tested whether transcranial direct current stimulation (tDCS) causes an excitation-induced transient neuronal energy depletion and thus influences systemic glucose homeostasis and related neuroendocrine mediators. METHODS: In a crossover design testing 15 healthy male volunteers, we increased neuronal excitation by anodal tDCS versus sham and examined cerebral energy consumption with 31phosphorus magnetic resonance spectroscopy. Systemic glucose uptake was determined by euglycemic hyperinsulinemic glucose clamp, and neurohormonal measurements comprised the parameters of the stress systems. RESULTS: We found that anodic tDCS-induced neuronal excitation causes an energetic depletion, as quantified by 31phosphorus magnetic resonance spectroscopy. Moreover, tDCS-induced cerebral energy consumption promotes systemic glucose tolerance in a standardized euglycemic hyperinsulinemic glucose clamp procedure and reduces neurohormonal stress axes activity. CONCLUSIONS: Our data demonstrate that transcranial brain stimulation not only evokes alterations in local neuronal processes but also clearly influences downstream metabolic systems regulated by the brain. The beneficial effects of tDCS on metabolic features may thus qualify brain stimulation as a promising nonpharmacologic therapy option for drug-induced or comorbid metabolic disturbances in various neuropsychiatric diseases. PMID- 21703597 TI - A facile synthesis of D-ribo-C(20)-phytosphingosine and its C2 epimer from D ribose. AB - A facile synthetic route to d-ribo-C(20)-phytosphingosine 31 and its C2 epimer 32 is described. The Overman rearrangement of allylic trichloroacetimidates derived from the known ribose derivative 7 has been used as the key step. The subsequent functional group interconversions in rearranged products 14 and 15 followed by Wittig olefination, Pd/C-mediated reduction and the removal of protecting groups successfully constructed the final molecules. PMID- 21703598 TI - Mild acid hydrolysis of fucoidan: characterization by electrophoresis and FT Raman spectroscopy. AB - Along with proteins, lipids, water and minerals, polysaccharides are the main chemical compounds of which macroalgae are built. Among the chemical compounds now widely examined is fucoidan (fucan, fucosan, sulfate fucan or sulfated fucan), a fucose-containing sulfated polysaccharide. Fucoidans isolated from different species have been extensively studied because of their varied biological properties, including anticoagulant and antitumor effects. Methodology based on mild acid hydrolysis can be used as an efficient tool to study the relationship between molecular weight of the sulfated polysaccharides and their biological activities. Anticancer activity of fucoidans can be significantly enhanced by lowering their molecular weight only when they are depolymerized under mild conditions. In this study, fucoidan was identified during extraction with H(2)SO(4) and HCl; its presence was confirmed by FT-Raman spectroscopy in aqueous solution. In particular, shifts at 840cm(-1) were analysed, which are due to the presence of sulfate at the axial C-4 position, as were the shifts at about 811-809cm(-1), for which the sulfated fucoidan is responsible. Shifts of electrophoretic bands of fucoidan resulting from mild acid hydrolysis in H(2)SO(4) and HCl were also analysed. The analytical procedure was developed using apparatus for cellulose acetate membrane electrophoresis and this was supplemented by semi-quantitative analysis. PMID- 21703599 TI - Lysophosphatidic acid enhances antimycobacterial response during in vivo primary Mycobacterium tuberculosis infection. AB - Lysophospholipids may play an important protective role during primary infection of Mycobacterium tuberculosis (MTB) by enhancing innate antimycobacterial immune response of both macrophages and alveolar epithelial cells. Here, we show that treatment with lysophosphatidic acid (LPA) of mice aerogenically infected with MTB immediately after infection results in a significant early reduction of pulmonary CFUs and of histopathological damage in comparison with control mice. In contrast, treatment of acute disease does not result in any improvement of both microbiological and histopathological parameters. Altogether, these results show that LPA treatment can exert protective effect if administrated during primary infection, only. PMID- 21703600 TI - Effects of age, gender and time on receptor expression and anti-Aspergillus functions of human phagocytes. AB - Phagocytes play a central role in immune defense. Their dysfunction predisposes to infections. This study determined the expression level of nine receptors involved in Aspergillus immune response as well as the values of phagocytosis and production of radical oxygen species after Aspergillus stimulation, in a healthy adult population. The expression values of the CD11b, CD11c, CD14, CD18, CD35, CD181, CD182, CD282 and CD284 receptors on peripheral human monocytes and granulocytes was established. A heterogenous expression of the CD282 on granulocytes was observed as CD181, CD182 and CD284 on monocytes. Similarly, we observed considerable variation in the expression of these receptors over time. Only CD282 on granulocytes varied with sex. No variation with age was observed. Adherence of Aspergillus conidia to phagocytes was dependent of individual, sex, age and time. A better characterization of these innate immunity parameters is necessary to develop in the future an immunologic surveillance strategy for transplant recipients. PMID- 21703601 TI - [An atypical presentation of a schwannoma: laparoscopic diagnosis and resection]. PMID- 21703602 TI - [Oesophago-gastric cancer and minimally invasive surgery]. PMID- 21703603 TI - [Ergonomics in laparoscopic surgery and its importance in surgical training]. AB - Despite the many advantages that laparoscopic surgery has for patients, it involves a series of risks for the surgeon. These are related to the reduced freedom of movement and forced postures which lead to greater muscle fatigue than with conventional surgery. In laparoscopic surgery there are few references on the introduction of training programs in ergonomics, despite the numerous advantages demonstrated in other disciplines. The application of ergonomic criteria in the surgical field could have great benefits, both for surgeons and patients. In this work we attempt to review the existing literature and our experience to provide the surgeon with some ergonomic guidelines for body stance and positioning of equipment. We also present a training model based on ergonomics which we have introduced into the training activities carried out in our Centre. PMID- 21703604 TI - Detection improvement for neonatal click evoked otoacoustic emissions by time frequency filtering. AB - This study employed a time-frequency filtering technique to improve click evoked otoacoustic emission (CEOAE) detection at lower frequency bands, and hence to reduce the number of referral cases in neonatal OAE screening. Using this approach the detectability of CEOAEs, in terms of lower frequency SNRs and whole wave reproducibility, was significantly improved. Evaluations of screening outcomes demonstrated this method significantly reduced the overall referral rate, by 2.5 percentage points in initial CEOAE hearing screening. This approach may have potential application in OAE technology and in neonatal hearing screening programmes. PMID- 21703605 TI - Detection of masses in mammogram images using CNN, geostatistic functions and SVM. AB - Breast cancer occurs with high frequency among the world's population and its effects impact the patients' perception of their own sexuality and their very personal image. This work presents a computational methodology that helps specialists detect breast masses in mammogram images. The first stage of the methodology aims to improve the mammogram image. This stage consists in removing objects outside the breast, reducing noise and highlighting the internal structures of the breast. Next, cellular neural networks are used to segment the regions that might contain masses. These regions have their shapes analyzed through shape descriptors (eccentricity, circularity, density, circular disproportion and circular density) and their textures analyzed through geostatistic functions (Ripley's K function and Moran's and Geary's indexes). Support vector machines are used to classify the candidate regions as masses or non-masses, with sensitivity of 80%, rates of 0.84 false positives per image and 0.2 false negatives per image, and an area under the ROC curve of 0.87. PMID- 21703606 TI - Computer-assisted reading of haemagglutination: intensity of the ABH antigens secretion into saliva. AB - We examined 138 saliva samples for the presence or absence of the blood antigens ABH using haemagglutination inhibition methodology. The outcomes of the tests were scanned and examined by special software, which used the HSV colour model, allowed setting the parameters in a way that enabled differentiation of agglutination clusters from suspensions of erythrocytes and subsequently calculated the area of agglutination clusters. The size of the area was (inversely) related to the presence of ABH substances in saliva. Both the secretor phenotypes and the intensity of secretion into saliva were statistically analysed in relation to gender, blood type, blood group genotype frequencies and secretor genotype frequencies. PMID- 21703607 TI - Development of an advanced database for clinical trials integrated with an electronic patient record system. AB - Secondary use of patient databases is essential in healthcare if clinical trials are to progress efficiently to planned time and target and imperative if the planned UK expansion of research and development (R&D) at point of care is to be achieved. Integration of effective databases primarily designed to facilitate patient care with R&D requirements is needed but represents a complex challenge. We present a system that achieves an integrated approach with online management of complex datasets for clinical trials within care records using a specific study as an example to show functionality in practice; illustrating how this system provides an ideal resource to meet the needs of both clinicians and researchers. PMID- 21703608 TI - Follicular loss in endoscopic surgery for ovarian endometriosis: quantitative and qualitative observations. AB - OBJECTIVE: To identify a possible marker of follicular depletion in relation to some histologic parameters of endometriotic cysts. DESIGN: Prospective study. SETTING: Universita Cattolica del Sacro Cuore, Operative Division of Endocrinological Gynecology. PATIENT(S): Seventy-seven patients (aged 20-40 years) with endometrioma. INTERVENTION(S): Patients underwent laparoscopic surgery for ovarian endometriosis. MAIN OUTCOME MEASURE(S): After excision of the cyst wall, involuntarily removed follicles were correlated with age at surgery and with intrinsic histologic parameters of the specimen (thickness and composition of capsule; size of cyst). RESULT(S): There was a statistically significant relationship between patient age and number of follicles in the histologic section, a statistically significant inverse relationship between size of cyst and number of follicles, and no significant correlation between thickness of the capsule and number of follicles. Fibroblastic-type capsule, most frequently found in younger patients, was associated with removal of a significantly higher number of follicles. CONCLUSION(S): Our study suggests that patient age and cyst dimension are related to the histologic composition of the capsule, which is a marker of the aggressiveness of the cyst itself. PMID- 21703610 TI - Polycystic ovary syndrome is associated with negatively variable impacts on domains of health-related quality of life: evidence from a meta-analysis. AB - OBJECTIVE: To systematically review the literature to identify the impact of polycystic ovary syndrome (PCOS) on specific health-related quality of life domains. DESIGN: Meta-analysis. SETTING: N/A. PATIENT(S): The outcomes of 423 patients and 285 controls from 5 articles that used the Short Form 36 (SF-36) questionnaire were used for meta-analysis. INTERVENTION(S): N/A. MAIN OUTCOME MEASURE(S): The SF-36 dimensions including physical function, physical role function, body pain, general health, vitality, social function, emotional role function, and mental health were evaluated. RESULT(S): Compared with controls, women with PCOS had lower scores in all SF-36 dimensions: physical function (mean differences [MD], -5.46; 95% confidence intervals [CI], -8.52, -2.41), physical role function (MD, -5.76; 95% CI, -8.49, -3.03), body pain (MD, -4.55; 95% CI, 7.99, -1.11), general health (MD, -11.34; 95% CI, -19.53, -3.15), vitality (MD, 15.14; 95% CI, -17.43, -12.84), social function (MD, -15.95, 95% CI, -18.57, 13.33), emotional role function (MD, -23.86; 95% CI, -27.51, -20.21), and mental health (MD, -13.83; 95% CI, -16.13, -11.53). CONCLUSION(S): The meta-analysis showed that women with PCOS score lower in each dimension of the SF-36, mostly in the emotional role function. PMID- 21703609 TI - Early growth response-2 expression in uterine leiomyoma cells: regulation and function. AB - OBJECTIVE: To investigate the regulation of early growth response-2 (Egr-2) by transforming growth factor beta3 (TGF-beta3) and its functions in cultured human uterine leiomyoma smooth muscle cells. DESIGN: Laboratory research. SETTING: Academic medical center. PATIENT(S): Primary leiomyoma cells from patients with symptomatic leiomyomata. INTERVENTION(S): Tissue culture followed by RNA and protein analysis. MAIN OUTCOME MEASURE(S): Cell proliferation, alteration in extracellular matrix component expression. RESULT(S): In vivo mRNA levels of Egr 2 were statistically significantly higher in leiomyoma tissues compared with matched myometrial tissues, and showed a statistically significant correlation with TGF-beta3 messenger RNA (mRNA) levels in leiomyoma tissues. In primary leiomyoma smooth muscle cells, TGF-beta3 statistically significantly induced Egr 2 gene expression in a dose-dependent and time-dependent manner. Small interfering RNA (siRNA) knockdown of Egr-2 markedly increased the level of the proliferation marker proliferating cell nuclear antigen and the expression of proto-oncogene c-myc. On the other hand, ablation of Egr-2 stimulated collagen 1A1 and collagen-3A1 transcription and inhibited dermatopontin gene expression. However, the mRNA levels of alpha-smooth muscle actin and fibronectin were not affected by Egr-2 knockdown. CONCLUSION(S): We demonstrated that TGF-beta3 regulated Egr-2 gene expression and presented evidence that Egr-2 decreases collagen production and stimulates dermatopontin gene expression. PMID- 21703611 TI - Life-threatening intraabdominal bleeding after oocyte retrieval successfully managed with angiographic embolization. AB - OBJECTIVE: To report the first case of massive intraabdominal hemorrhage after transvaginal ultrasonographically guided oocyte retrieval that was successfully managed with angiographic uterine artery embolization. DESIGN: Case report. SETTING: Assisted reproduction unit of a tertiary university hospital. PATIENT(S): A 40-year-old woman with a history of primary infertility presented 10 days after oocyte retrieval because of severe abdominal pain, vomiting, and vaginal bleeding for 3 days. She had a history of mild factor VIII deficiency for 3 years. INTERVENTION(S): Evaluation of the intraabdominal hemorrhage with ultrasonography and angiography. Management of oocyte pickup complicated with intraabdominal hemorrhage. MAIN OUTCOME MEASURE(S): Treatment of massive life threatening intraabdominal hemorrhage with bilateral uterine artery embolization. RESULT(S): After transfusion with 2 units of fresh-frozen plasma and packed red blood cell, an interventional radiologist performed percutaneous transcatheter pelvic angiography to detect abnormal vascularization and vascular blush consistent with hemorrhage and then immediate bilateral uterine artery embolization was done. The patient was discharged from the hospital 5 days later without any remarkable complications. CONCLUSION(S): Angiographic uterine artery embolization under fluoroscopic guidance is a successful nonsurgical approach for the treatment of oocyte pickup-induced life-threatening hemorrhage. PMID- 21703612 TI - Occurrence of 47,X,i(X)(q10),Y Klinefelter variant with hypogonadotropic hypogonadism. AB - OBJECTIVE: To report a rare occurrence of 47,X,i(Xq),Y karyotype with hypogonadotropic hypogonadism in a man. DESIGN: Case report. SETTING: Infertility institute. PATIENT(S): Thirty-three-year-old man with primary infertility. INTERVENTION(S): Clinical evaluation, hormone assays, and assessment of X inactivation. MAIN OUTCOME MEASURE(S): Physical examination, semen analysis, and cytogenetic analysis. RESULT(S): The patient showed the classic phenotype of Klinefelter syndrome but with low levels of FSH and LH. The bromodeoxyuridine 33258 Hoechst technique showed faint staining of the long arm of the isochromosome. CONCLUSION(S): This is the first report of co-occurrence of hypogonadotropic hypogonadism with the 47,X,i(X)(q10),Y Klinefelter karyotype variant in a man. PMID- 21703613 TI - Differential effects of estrogen and micronized progesterone or medroxyprogesterone acetate on cognition in postmenopausal women. AB - OBJECTIVE: To investigate possible differential effects of the coadministration of conjugated equine estrogen (CEE) and a placebo (CEE + PL), CEE and medroxyprogesterone acetate (CEE + MPA), or CEE and micronized P (CEE + MP) on aspects of cognitive functioning in naturally postmenopausal women. DESIGN: Double-blind, randomized, controlled trial. SETTING: Gynecologic screening occurred at a university hospital, and neuropsychological testing took place in a university laboratory. PATIENT(S): Twenty-four naturally menopausal women with an intact uterus who had never used hormone therapy were recruited by means of newspaper advertisements. All completed the study. INTERVENTION(S): A battery of mood and neuropsychological tests was administered. Women were randomly assigned to receive CEE + PL (n = 7), CEE + MPA (n = 9), or CEE + MP (n = 8). The tests were readministered 12 weeks later. MAIN OUTCOME MEASURE(S): Standardized tests of mood, verbal memory, working memory, spatial abilities, and visual-spatial sequencing, and assays of serum sex hormone levels. RESULT(S): Mood improved after treatment in all groups. No changes in scores occurred over time in any cognitive test in the group that received CEE + PL. Only the CEE + MP group had a significant decrease in their delayed verbal memory scores from baseline to after treatment. The CEE + MP-treated women performed significantly better on a test of working memory than women in the other two groups. CONCLUSION(S): Coadministration of CEE with MPA or MP caused differential effects on aspects of memory in postmenopausal women. These findings need to be replicated with a larger sample size before their potential clinical implications can be determined. PMID- 21703614 TI - Combined effects of recombinant human BMP-2 and Nell-1 on bone regeneration in rapid distraction osteogenesis of rabbit tibia. AB - Distraction osteogenesis (DO) has been accepted as an effective technique for bone lengthening. However, the long treatment period and possible fibrous union or nonunion hampers its further clinical application. Bone regeneration in DO involves multiple stages of repair and coordinated action of multiple cell types. Consequently, it may be possible to enhance bone regeneration through treatment strategies that target more than one repair process or cell types. The goal of this study was to determine the combined effects of recombinant human bone morephogenetic protein 2 (rhBMP-2) and NEL-like molecule-1 (NELL-1) on bone formation in DO. Unilateral tibiae in 48 rabbits were lengthened for 7days at a rate of 2mm/day after 3-day lag. At the end of distraction, the animals were randomly divided into four groups (n=12) and received phosphate-buffered saline, 50MUg rhNell-1 or 50MUg rhBMP-2, or both 25MUg rhBMP-2 and 25MUg rhNell-1 at the lengthened segment, respectively. After 4-week consolidation bony healing was assessed using histology, radiography, dual energy X-ray absorptiometry, micro CT, and three-point bend testing. Treatment with rhNell-1 and/or rhBMP-2 resulted in better bone formation and higher BMD and BMC than the saline group, whilst excellent bone formation and the highest BMD and BMC was observed in the combined treatment group. Both rhNell-1 and rhBMP-2 groups presented more mature characteristics in the micro-architecture than the saline group, whereas the combined treatment group presented the highest BV/TV, Tb.Th and Tb.N as well as the lowest Tb.Sp. The peak load of the lengthened tibia increased by 71% in the combined treatment group, 54% in the rhBMP-2 group, and 25% in the rhNell-1 group compared to the control group, respectively. This work suggests that BMP-2 and Nell-1 enhance each other's ability and dual delivery of two agents can significantly improve bony healing in tibial DO. PMID- 21703615 TI - Propofol attenuates hypoxia-induced apoptosis in alveolar epithelial type II cells through down-regulating hypoxia-inducible factor-1alpha. AB - To investigate the protective effect of propofol against hypoxia-induced apoptosis in alveolar epithelial type II (ATII) cells and to explore whether hypoxia-inducible factor-1alpha (HIF-1alpha) is involved in this process. Primary cultured rat ATII cells were randomly assigned to one of the following four groups, namely, Group C: treated under normoxia (21% O(2)), Group P(20): treated with propofol (20 MUM) under normoxia (21% O(2)), Group H: treated under hypoxia (5% O(2)), and Group P(20)-H: pre-treated with propofol (20 MUM) before hypoxia exposure (5% O(2)). Apoptosis in ATII cells was detected by Annexin V-FITC binding using FACScan. Expressions of HIF-1alpha and Bnip3L mRNA and protein in ATII cells were examined by quantitative real-time polymerase chain reaction and Western blotting analysis, respectively. Hypoxia exposure (Group H) significantly increased HIF-1alpha protein expression (P<0.01 vs. Group C) and significantly promoted apoptosis in ATII cells (P<0.01 vs. Group C). Expression of Bnip3L, a target gene of HIF-1alpha, was also significantly increased at both mRNA and protein levels in response to hypoxia (P<0.01 vs. Group C). Pretreatment with propofol (20 MUM, Group P(20)-H) significantly decreased HIF-1alpha protein expression (P<0.01 vs. Group H) and significantly inhibited apoptosis in ATII cells (P<0.01 vs. Group H), accompanied by decreased expression of Bnip3L at both mRNA and protein levels (P<0.01 vs. Group H). Propofol (20 MUM) can attenuate hypoxia-induced apoptosis in ATII cells and inhibit HIF-1alpha-hypoxia responsive element (HRE) axis involving Bnip3L, which may partly mediate the cytoprotective effects of propofol. PMID- 21703616 TI - Rigidity of unilateral external fixators--a biomechanical study. AB - INTRODUCTION: External fixation is the primary choice of temporary fracture stabilisation for specific polytrauma patients. Adequate initial fracture healing requires sufficient stability at the fracture site. The purpose of this study was to compare the rigidity of the Dynafix DFS((r)) Standard Fixator (4 joints) with the Orthofix ProCallus Fixator((r)) (2 joints), which differ in possibilities for adapting the configuration for clinical needs. MATERIALS AND METHODS: Both devices were tested 10 times in a standardised model. In steps of 10N, loading was increased to a maximum of 160N in parallel, transversal and axial direction (distraction and compression). Translation resultant and rotation resultant were calculated. RESULTS: With a force of 100N in parallel direction the mean translation resultant (Tr(mean)) of the Dynafix DFS((r)) Standard Fixator (6.65+/ 1.43mm) was significantly higher than the ProCallus Fixator((r)) (3.29+/-0.83mm, p<0.001; Student's t-test). With a maximum load of 60N in transverse direction the Tr(mean) of the Dynafix DFS((r)) Standard Fixator was significantly lower (8.14+/-1.20mm versus 9.83+/-0.63mm, p<0.005). Translation was significantly higher with the Dynafix DFS((r)) Standard Fixator, for both distraction (2.13+/ 0.32mm versus 1.69+/-0.44mm, p<0.05) and compression (1.55+/-1.08mm versus 0.15+/ 0.33mm, p<0.005). The mean rotation resultant (Rr(mean)) at 160N distraction was lower for the Dynafix DFS((r)) Standard Fixator (0.70+/-0.17 degrees versus 0.97+/-0.21 degrees , p<0.005). CONCLUSIONS: Both fixators were most sensitive to transverse forces. The Dynafix DFS((r)) Standard Fixator was less rigid with parallel and axial forces, whereas transverse forces and rotation at distraction forces favoured the Dynafix DFS((r)) Standard Fixator. Repeated heavy loading did not influence the rigidity of both devices. PMID- 21703617 TI - Early alveolar and systemic mediator release in patients at different risks for ARDS after multiple trauma. AB - Alveolar IL-8 has been reported to early identify patients at-risk to develop ARDS. However, it remains unknown how alveolar IL-8 is related to pulmonary and systemic inflammation in patients predisposed for ARDS. We studied 24 patients 2 6h after multiple trauma. Patients with IL-8 >200 pg/ml in bronchoalveolar lavage (BAL) were assigned to the group at high risk for ARDS (H, n = 8) and patients with BAL IL-8 <200 pg/ml to the group at low risk for ARDS (L, n = 16). ARDS developed within 24h after trauma in 5 patients at high and at least after 1 week in 2 patients at low risk for ARDS (p = 0.003). High-risk patients had also increased BAL IL-6, TNF-alpha, IL-1beta, IL-10 and IL-1ra levels (p<0.05). BAL neutrophil counts did not differ between patient groups (H vs. L, 12% (3-73%) vs. 6% (2-32%), p = 0.1) but correlated significantly with BAL IL-8, IL-6 and IL-1ra. High-risk patients had increased plasma levels of pro- but not anti-inflammatory mediators. The enhanced alveolar and systemic inflammation associated with alveolar IL-8 release should be considered to identify high-risk patients for pulmonary complications after multiple trauma to adjust surgical and other treatment strategies to the individual risk profile. PMID- 21703618 TI - Averting maternal death and disability: editor's comment. PMID- 21703619 TI - The effects of ownership, staffing level and organisational justice on nurse commitment, involvement, and satisfaction: a questionnaire study. AB - BACKGROUND: Elderly care systems have undergone a lot of changes in many European countries, including Finland. Most notably, the number of private for-profit firms has increased. Previous studies suggest that employee well-being and the quality of care might differ according to the ownership type. OBJECTIVE: The present study examined whether the ownership type and the staffing level were associated with organisational commitment, job involvement, and job satisfaction. In addition, we examined the potential moderating effect of organisational justice on these associations. DESIGN: Cross-sectional questionnaire study. PARTICIPANTS AND SETTING: 1047 Finnish female staff members aged 18-69 years working in sheltered housing or nursing homes (units n=179). METHODS: The relationships were studied with analyses of covariance (ANCOVA), adjusting for the effects of age and case-mix. RESULTS: Organisational commitment and job satisfaction levels were low in for-profit sheltered homes when justice levels were low, but when justice levels were high, for-profit sheltered homes did not differ from other ownership types. Similarly, organisational justice acted as a buffer against low commitment resulting from low staffing levels. Staffing levels were lowest in public sheltered homes and highest in not-for-profit sheltered homes. CONCLUSION: The results show that organisational justice can act as a buffer against low organisational commitment that results from low staffing levels and working in for-profit sheltered homes. Increasing justice in regard to the management, outcomes, and procedures in the organisation would thus be important. PMID- 21703620 TI - Nurses' perceptions of sexuality in institutionalized elderly: a literature review. AB - BACKGROUND: Institutionalized elderly continue to have the need for sexual expression and intimacy. Nurses often display negative responses when they are confronted with the sexual behavior of residents. They feel ashamed and do not know how to react. This generates feelings of discomfort, resulting in the denial of resident's needs and desires for sexual fulfillment. OBJECTIVES: The objective of this review is to thoroughly analyze the literature about the knowledge, attitudes, and experiences of nursing staff toward sexuality in institutionalized elderly. We shed light onto the relationship between knowledge and attitudes, and determined whether certain demographic factors relate to the knowledge and attitudes of nursing home caregivers. DESIGN: We conducted an extensive search of the electronic databases Medline, Cinahl, Psychinfo, Web of Science, Philosophers Index, Google Scholar, and Invert for papers published between January 1980 and September 2010. A broad range of search keywords was used. FINDINGS: The quantitative studies revealed nursing staff to show rather positive attitudes toward later-life sexuality. However, the extent of the staff's knowledge regarding sexuality in the aged seemed to be very limited. There was no consensus found about the relationship between knowledge and attitudes. As regards the influence of demographic variables, the results were very ambiguous. The qualitative studies showed that caregivers hold rather conservative attitudes toward sexuality in institutionalized elderly. Feelings of discomfort prevailed. The responses to residents' sexual behavior were influenced by the staff's own level of comfort related to sexuality issues and the ethos within the institution where they work. CONCLUSIONS: This review gives us a broad outline of the knowledge, attitudes, and experiences of geriatric nurses toward sexuality in institutionalized elderly. If we want the sexual needs of residents to be recognized, more research is needed. Especially needed are more in-depth qualitative studies that explore the experiences of nurses and managers. The development of a more accurate educational program could increase the knowledge of later-life sexuality and cultivate positive and permissive attitudes toward sexuality in the aged. PMID- 21703621 TI - Synergistic effect of chronic kidney disease and high circulatory norepinephrine level on stroke risk in Japanese hypertensive patients. AB - OBJECTIVE: Evidence is now available about the association between chronic kidney disease (CKD) and stroke. However, less is known about the underlying mechanisms, and there is currently no reliable marker for identifying stroke-prone high-risk patients among CKD patients. METHODS: A total of 514 hypertensive patients aged >50 years (mean, 72.3 years; 37% men) underwent 24-h BP monitoring and measurement of circulatory high-sensitivity C-reactive protein (hs-CRP) and norepinephrine at baseline. CKD was defined as eGFR<60 ml/min/1.73 m(2) using the Cockcroft-Gault equation. RESULTS AND CONCLUSION: During an average of 41 months (1751 person-years), there were 43 stroke events. Compared with hypertensive patients without CKD, those with CKD (n=225) had higher levels of sleep systolic BP (SBP) (125 mmHg vs. 129 mmHg), circulatory hs-CRP (0.12 mg/L vs. 0.20 mg/L) and norepinephrine (332.2 pg/ml vs. 372.8 pg/ml; all P<0.05). On multivariable analysis, the hazard ratio (HR) (95% CI) for stroke in CKD vs. non-CKD was 2.7 (1.2-6.9) (P<0.05). CKD, as well as the baseline presence of silent cerebral infarction, sleep SBP increase, and high hs-CRP level (highest quartile: >=0.42 mg/L) were independently and additively associated with stroke events; above all, there was a synergistic effect of CKD and high norepinephrine level (highest quartile: >=538 pg/ml) on stroke risk (all P<0.05). Among hypertensive patients with CKD, those within the highest quartiles of norepinephrine had a greater stroke risk compared to those who were in the lower quartiles of norepinephrine (HR (95% CI): 2.2 (1.0-4.5); P=0.045). In conclusion, CKD is an independent predictor of stroke in Japanese hypertensive patients; in particular, hypertensive patients with CKD and a high norepinephrine level have a synergistically augmented stroke risk. PMID- 21703622 TI - Novel association analysis between 9 short tandem repeat loci polymorphisms and coronary heart disease based on a cross-validation design. AB - OBJECTIVE: To investigate genes associated with coronary heart disease (CHD) screened with a novel cross-validation design. METHODS: On the basis of age at the onset of the first episode of CHD, stratified sampling by age (<50 years, 50 59 years, 60-69 years, 70-79 years and >80 years) was performed. Alleles of the nine CODIS STR loci including D3S1358, vWA, FGA, D8S1179, D21S11, D18S51, D5S818, D13S317, and D7S820, were determined using the STR Profiler Plus PCR amplification kit. Allele frequencies were compared with a control population. The mean age of patients with and without the alleles was compared. Cross validation was based on differences in both frequency values and ages instead of adjustment procedure for multiple testing. RESULTS: There were statistical differences in frequency values between the CHD group and the control population for three alleles, and also statistical differences in the age at first onset of CHD for two alleles; at least one allele, D21S11-28.2, was statistically different with regards to both frequency values and age. It was confirmed that D21S11-28.2 is truly related with CHD. CONCLUSIONS: A single true CHD-related allele could be discriminated from the sampling errors through cross-validation. It appears that CHD-related genes may be located near to loci D21S11. PMID- 21703623 TI - Low serum magnesium concentrations predict cardiovascular and all-cause mortality. AB - BACKGROUND: Low serum magnesium (Mg(++)) levels are associated with future development of left ventricular hypertrophy independently of common cardiovascular risk factors, as recently demonstrated in the five-year follow-up of the population-based Study of Health in Pomerania (SHIP). As left ventricular hypertrophy has significant prognostic implications, we hypothesized that serum Mg(++) levels are associated with cardiovascular mortality. METHOD AND RESULTS: All-cause mortality and cardiovascular mortality were analyzed in relationship to serum Mg(++) concentrations at baseline by Cox proportional hazard model in SHIP (n=4203, exclusion of subjects with Mg(++) supplementation). The median duration of mortality follow-up was 10.1 years (25th percentile: 9.4 years, 75th percentile: 10.8 years; 38,075 person-years). During the follow-up, 417 deaths occurred. Mortality in subjects with Mg(++)<=0.73 mmol/l was significantly higher for all-cause deaths (10.95 death per 1000 person years), and cardiovascular deaths (3.44 deaths per 1000 person years) in comparison to higher Mg(++) concentrations (1.45 deaths from all-cause per 1000 person years, 1.53 deaths from cardiovascular cause per 1000 person years). This association remained statistically significant after adjustment for multiple cardiovascular risk factors, including arterial hypertension, and antihypertensive therapy including diuretics (log-rank-test p=0.0001 for all-cause mortality, and p=0.0174 for cardiovascular mortality). CONCLUSIONS: Low serum Mg(++) levels are associated with higher all-cause mortality and cardiovascular mortality. This corresponds well with recent findings that hypomagnesemia is associated with the increase of left ventricular mass over the following years. PMID- 21703624 TI - The role of plasma aminothiols in the prediction of coronary microvascular dysfunction and plaque vulnerability. AB - BACKGROUND: Although oxidative stress is considered a key pathogenic step in mediating vascular dysfunction and atherosclerosis development, their association has not been evaluated in human coronary circulation in vivo. Accordingly, we hypothesized that higher oxidative stress would be associated with abnormal coronary epicardial structure and microvascular function. METHODS: We measured coronary flow velocity reserve (CFVR) and hyperemic microvascular resistance (HMR) as indices of microvascular function, and epicardial plaque volume and necrotic core using intravascular ultrasound (IVUS) in 47 patients undergoing cardiac catheterization. Plasma glutathione, cystine and their ratio served as measures of oxidative stress while high-sensitivity C-reactive protein (hs-CRP) served as a measure of inflammation. RESULTS: Lower glutathione, a measure of increased oxidative stress was associated with impaired microvascular function [CFVR (r=0.39, p=0.01) and HMR (r=-0.43, p=0.004)], greater plaque burden (r= 0.32, p=0.03) and necrotic core (r=-0.39, p=0.008). Similarly, higher cystine/glutathione ratio was associated with impaired microvascular function [CFVR (r=-0.29, p=0.04)] and greater necrotic core (r=0.37, p=0.01). In comparison, higher hs-CRP was associated only with greater necrotic core (r=0.45, p=0.003). After multivariate adjustment for age, gender, hypertension, diabetes, acute coronary syndrome presentation, body mass index, tobacco abuse, statin use and hs-CRP, glutathione remained an independent predictor of CFVR, HMR and necrotic core (p<0.05). CONCLUSIONS: Lower plasma glutathione level a measure of increased oxidative stress, was an independent predictor of impaired coronary microvascular function and plaque necrotic core. PMID- 21703625 TI - Ursolic acid causes DNA-damage, p53-mediated, mitochondria- and caspase-dependent human endothelial cell apoptosis, and accelerates atherosclerotic plaque formation in vivo. AB - OBJECTIVE: The plant derived triterpene ursolic acid (UA) has been intensively studied in the past; mainly as an anti-cancer compound and for its cardiovascular protective properties. Based on the controversy of reports suggesting anti angiogenic and cytotoxic effects of UA on one side and cardiovascular and endothelial protective effects on the other side, we decided to assess UA effects on primary human endothelial cells in vitro and atherosclerotic plaque formation in vivo. METHODS AND RESULTS: Our in vitro analyses clearly show that UA inhibits endothelial proliferation and is a potent inducer of endothelial cell death. UA causes DNA-damage, followed by the activation of a p53-, BAK-, and caspase dependent cell-death pathway. Oral application of UA in APO E knockout mice potently stimulated atherosclerotic plaque formation in vivo, which was correlated with decreased serum levels of the athero-protective cytokine IL-5. CONCLUSIONS: Due the potent endothelial cell death inducing activity of UA, a systemic application of UA in the treatment of cardiovascular diseases seems unfavourable. UA as an anti-angiogenesis, anti-cancer and - locally applied - cardiovascular drug may be helpful. The DNA damaging activity of UA may however constitute a serious problem. PMID- 21703626 TI - Optimised loads for the simulation of axial rotation in the lumbar spine. AB - Simplified loading modes (pure moment, compressive force) are usually applied in the in vitro studies to simulate flexion-extension, lateral bending and axial rotation of the spine. The load magnitudes for axial rotation vary strongly in the literature. Therefore, the results of current investigations, e.g. intervertebral rotations, are hardly comparable and may involve unrealistic values. Thus, the question 'which in vitro applicable loading mode is the most realistic' remains open. A validated finite element model of the lumbar spine was employed in two sensitivity studies to estimate the ranges of results due to published load assumptions and to determine the input parameters (e.g. torsional moment), which mostly affect the spinal load and kinematics during axial rotation. In a subsequent optimisation study, the in vitro applicable loading mode was determined, which delivers results that fit best with available in vivo measurements. The calculated results varied widely for loads used in the literature with potential high deviations from in vivo measured values. The intradiscal pressure is mainly affected by the magnitude of the compressive force, while the torsional moment influences mainly the intervertebral rotations and facet joint forces. The best agreement with results measured in vivo were found for a compressive follower force of 720N and a pure moment of 5.5Nm applied to the unconstrained vertebra L1. The results reveal that in many studies the assumed loads do not realistically simulate axial rotation. The in vitro applicable simplified loads cannot perfectly mimic the in vivo situation. However, the optimised values lead to the best agreement with in vivo measured values. Their consequent application would lead to a better comparability of different investigations. PMID- 21703627 TI - Accuracy of generic musculoskeletal models in predicting the functional roles of muscles in human gait. AB - Biomechanical assessments of muscle function are often performed using a generic musculoskeletal model created from anatomical measurements obtained from cadavers. Understanding the validity of using generic models to study movement biomechanics is critical, especially when such models are applied to analyze the walking patterns of persons with impaired mobility. The aim of this study was to evaluate the accuracy of scaled-generic models in determining the moment arms and functional roles of the lower-limb muscles during gait. The functional role of a muscle was described by its potential to contribute to the acceleration of a joint or the acceleration of the whole-body center of mass. A muscle's potential acceleration was defined as the acceleration induced by a unit of muscle force. Dynamic simulations of walking were generated for four children with cerebral palsy and five age-matched controls. Each subject was represented by a scaled generic model and a model developed from magnetic resonance (MR) imaging. Calculations obtained from the scaled-generic model of each subject were evaluated against those derived from the corresponding MR-based model. Substantial differences were found in the muscle moment arms computed using the two models. These differences propagated to calculations of muscle potential accelerations, but predictions of muscle function (i.e., the direction in which a muscle accelerated a joint or the center of mass and the magnitude of the muscle's potential acceleration relative to that of other muscles) were consistent between the two modeling techniques. Our findings suggest that scaled generic models and image-based models yield similar assessments of muscle function in both normal and pathological gait. PMID- 21703628 TI - Development of cadmium/silver/palladium separation by ion chromatography with quadrupole inductively coupled plasma mass spectrometry detection for off-line cadmium isotopic measurements. AB - A separation method was investigated to perform off-line cadmium isotopic measurements on a (109)Ag transmutation target. Ion chromatography (IC) with Q ICPMS detection (quadrupole inductively coupled plasma mass spectrometry detection) was chosen to separate cadmium from the isobarically interfering elements, silver and palladium, present in the sample. The optimization of chromatographic conditions was particularly studied. Several anion and cation columns (Dionex AG11((r)), CS10((r)) and CS12((r))) were compared with different mobile phases (HNO(3), HCl). The separation procedure was achieved with a carboxylate-functionalized cation exchange CS12 column using 0.5 M HNO(3) as eluent. The developed technique yielded satisfactory results in terms of separation factors (greater than 5) and provides an efficient solution to obtain rapidly purified cadmium fractions (decontamination factors higher 100,000 for silver and palladium) which can directly be analyzed by multi collection inductively coupled plasma mass spectrometry (MC ICPMS). By applying the proposed procedure, accurate and precise cadmium isotope ratios were determined for the irradiated (109)Ag transmutation target. PMID- 21703629 TI - Preparation and characterization of lauryl methacrylate-based monolithic microbore column for reversed-phase liquid chromatography. AB - Poly(lauryl methacrylate-co-ethylene dimethacrylate) monoliths were in situ synthesized within the confines of a silicosteel tubing of 1.02 mm i.d. and 1/16" o.d. for microbore reversed-phase HPLC. In order to obtain practically useful monoliths with adequate column efficiency, low flow resistance, and good mechanical strength, some parameters such as total monomer concentration (%T), cross-linking degree (%C) and polymerization temperature were optimized. High efficiency monoliths were successfully obtained by thermal polymerization of a monomer mixture (40%T, 10%C) with a binary porogenic solvent consisting of 1 propanol and 1,4-butandiol (7:4, v/v) at a high temperature of 90 degrees C. The morphology and porous structure of the resulting monoliths were assessed by scanning electron microscope (SEM) and inverse size exclusion chromatography (ISEC), while the column performance was evaluated through the separations of a series of alkylbenzenes in acetonitrile-water (50:50, v/v) eluent. At a normal flow rate of 50 MUL/min (corresponding to 1.66 mm/s), the optimized monolithic columns typically exhibited theoretical plate numbers of 6000 plates/10 cm-long column for amylbenzene (k>40), and the pressure drop was always less than 1 MPa/10 cm. The monoliths, which were chemically anchored to the tube inner wall surface using a bifunctional silylation agent, exhibited adequate mechanical strength of up to 12-13 MPa, and were properly operated at 10 times higher flow rate than normal, reducing the separation time to one tenth. The lauryl methacrylate-based monolithic column was applied to a rapid and efficient separation of ten common proteins such as aprotinin, ribonuclease A, insulin, cytochrome c, trypsin, transferrin, conalbumin, myoglobin, beta-amylase, and ovalbumin in the precipitation-redissolution mode. Using a linear CH(3)CN gradient elution at a flow rate of 500 MUL/min (10-times higher flow rate), 10 proteins were baseline separated within 2 min. PMID- 21703630 TI - Zonal rate model for stacked membrane chromatography. I: characterizing solute dispersion under flow-through conditions. AB - Conventional models of both packed-bed and stacked-membrane chromatography typically attribute elution band broadening to non-idealities within the column. However, when the column length to diameter ratio is greatly reduced, as in stacked-membrane chromatography, variations in solute residence times within the feed-distribution (inlet) and eluent-collection (outlet) manifolds can also contribute to band broadening. We report on a new zonal rate model (ZRM) for stacked-membrane chromatography that improves on existing hold-up volume models that rely on one plug-flow reactor and one stirred-tank reactor in series to describe dispersion of solute during transport into and out of the column. The ZRM radially partitions the membrane stack and the hold-up volumes within the inlet and outlet manifolds into zones to better capture non-uniform flow distribution effects associated with the large column diameter to height ratio. Breakthrough curves from a scaled-down anion-exchange membrane chromatography module using ovalbumin as a model protein were collected at flow rates ranging from 1.5 to 20 mL min(-1) under non-binding conditions and used to evaluate the ZRM as well as previous models. The ZRM was shown to be significantly more accurate in describing protein dispersion and breakthrough. The model was then used to decompose breakthrough data, where it was found that variations in solute residence time distributions within the inlet and outlet manifolds make the dominant contribution to solute dispersion over the recommended range of feed flow rates. The ZRM therefore identifies manifold design as a critical contributor to separation quality within stacked-membrane chromatography units. PMID- 21703631 TI - Preparation of positively charged oil/water nano-emulsions with a sub-PIT method. AB - The phase inversion temperature (PIT) method is generally used to prepare nonionic surfactant stabilized nano-emulsions because of its low energy and surfactant consumption. The emulsion droplets are usually negatively charged because of the selective adsorption of OH(-) onto the droplet surfaces. In this work, positively charged oil/water nano-emulsions were prepared by adding a cationic surfactant to the system. The cationic molecules change the spontaneous curvature of the surfactant layers and raise the PIT above 100 degrees C. The PIT can be depressed by addition of NaBr, as shown by conductivity measurements and equilibrium phase behavior. Therefore, these nano-emulsions can be prepared by the PIT method. We found that the formation of the nano-emulsions did not require a cross-PIT cycle. The mechanism of the emulsification is the formation of mixed swollen micelles that can solubilize all the oil above a "clearing boundary", followed by a stir-quench to a temperature where these droplets become metastable emulsions. The zeta potential of the emulsion droplets can be easily tuned by varying the cationic surfactant concentrations. Due to electrosteric stabilization, the resulting nano-emulsions are highly stable, thus could find significant applications in areas such as pharmaceuticals, cosmetics and food industries. PMID- 21703632 TI - New dimeric cholesteryl-based A(LS)2 gelators with remarkable gelling abilities: organogel formation at room temperature. AB - Three new dimeric cholesterol-based compounds of A(LS)(2) type, where A stands for aromatic component, S steroid moiety, and L a linker connecting the two units, have been designed and prepared. Gelation test in 30 solvents demonstrated that the compounds can gel some of the solvents and form 37 gels, of which 16 form spontaneously at room temperature (~25 degrees C). These gels possess smart thixotropic properties as revealed by rheological studies. FTIR and (1)H NMR measurements revealed that hydrogen bonding is an important driving force for the formation of the gel networks. XRD analysis demonstrated that unlike commonly found layered structures adopted by dimeric cholesterol-based low-molecular mass gelators (LMMGs), one of the gelators created in this study adopts a hexagonal packing structure in its benzene gel. PMID- 21703633 TI - Facile method to synthesize platelet SBA-15 silica with highly ordered large mesopores. AB - Highly ordered mesoporous SBA-15 silica with large pore diameter of 18 nm (nominal BJH pore diameter ~22 nm) and short pore length (~500 nm) was synthesized using a micelle expander 1,3,5-triisopropylbenzene in the absence of ammonium fluoride by employing short initial stirring time at 17 degrees C followed by static aging at low temperature. Scanning and transmission electron microscopies revealed that the material comprised of platelet particles in which large mesopores were nearly flawlessly arranged within uniform domains up to 3 MUm in size. The platelet SBA-15 had the (100) interplanar spacing of 17 nm, high surface area (~470 m(2) g(-1)) and large pore volume (~1.6 cm(3) g(-1)). The hydrothermal treatment at 130 degrees C for 2 days was employed to eliminate constrictions from the pore channels. The control experiment showed that a sample prepared with prolonged stirring had very similar mesoporous properties, but the particle size was smaller and the domains were irregular, proving that the static conditions facilitate the formation of SBA-15 with platelet particle morphology. The absence of ammonium fluoride was also critical in attaining the platelet particle shape. PMID- 21703634 TI - A meta-analysis of two genome-wide association studies identifies 3 new loci for alcohol dependence. AB - Family, twin and adoption studies have clearly demonstrated that genetic factors are important in modulating the vulnerability to alcohol dependence. Several genome-wide association (GWA) studies of alcohol dependence have been conducted; however, few loci have been replicated. A meta-analysis was performed on two GWA studies of 1283 cases of alcohol dependence and 1416 controls in Caucasian populations. Through meta-analysis we identified 131 SNPs associated with alcohol dependence with p<10(-4). The best novel signal was rs6701037 (p=1.86 * 10(-7)) at 1q24-q25 within KIAA0040 gene while the second best novel hit was rs1869324 (p=4.71 * 10(-7)) at 2q22.1 within THSD7B. The third novel locus was NRD1 at 1p32.2 (the top SNP was rs2842576 with p=7.90 * 10(-6)). We confirmed the association of PKNOX2 at 11q24.4 with alcohol dependence. The top hit of PKNOX2 (rs750338 with p=1.47 * 10(-6)) in the meta-analysis was replicated with the Australian Twin-Family Study of 778 families (p=1.39 * 10(-2)) Furthermore, several flanking SNPs of the top hits in the meta-analysis demonstrated borderline associations with alcohol dependence in the family sample (top SNPs were rs2269655, rs856613, and rs10496768 with p=4.58 * 10(-3), 2.1 * 10(-4), and 2.86 * 10(-3) for KIAA0040, NRD1 and THSD7B, respectively). In addition, ALK, CASC4, and SEMA5A were strongly associated with alcohol dependence (p<2 * 10(-5)) in the meta-analysis. In conclusion, we identified three new loci (KIAA0040, THSD7B and NRD1) and confirmed the previous association of PKNOX2 with alcohol dependence. These findings offer the potential for new insights into the pathogenesis of alcohol dependence. PMID- 21703635 TI - The impact of a dedicated single-ventricle home-monitoring program on interstage somatic growth, interstage attrition, and 1-year survival. AB - OBJECTIVE: There has been considerable improvement in survival after the first stage of palliation for single-ventricle heart disease. Yet, interstage mortality continues to plague this population. Home monitoring has been proposed to reduce interstage mortality. We review our experience after creation of a Single Ventricle Program. METHODS: All infants with a single ventricle heart defect who were admitted to Texas Children's Hospital from the inception of the Single Ventricle Program on September 1, 2007, to January 1, 2010, were included in the Single Ventricle Program cohort. Infants with a single ventricle presenting between January 1, 2002, and August 31, 2007, comprised the pre-Single Ventricle Program group. Anatomic, operative, and postoperative details were noted for all patients. End points included in-hospital death after the first stage of palliation, interstage death (defined as after discharge from the first stage of palliation and before the second stage of palliation), and death or heart transplantation by 1 year of age. Interstage weight gain was also compared. RESULTS: A total of 137 infants with a single ventricle were included in the pre Single Ventricle Program cohort, and 93 infants were included in the Single Ventricle Program cohort. Anatomic subtypes were similar between groups. There was significant improvement in rate of interstage weight gain, whereas age at the second stage of palliation was significantly reduced in the Single Ventricle Program group. In-house mortality decreased during the Single Ventricle Program era (P = .021). Interstage mortality did not significantly decrease in the Single Ventricle Program group. However, 1-year transplant-free survival improved during the Single Ventricle Program era (P = .002). CONCLUSIONS: The Single Ventricle Program improved interstage weight gain, thereby allowing for early second-stage palliation at an equivalent patient weight. Interstage mortality was not significantly reduced by our program. However, 1-year transplant-free survival was significantly improved in patients in the Single Ventricle Program. PMID- 21703637 TI - Where is the common sense in aortic valve replacement? A review of hemodynamics and sizing of stented tissue valves. AB - Heated debates revolve around the hemodynamic performance of stented aortic tissue valves. Because the opening area strongly influences the generation of a pressure gradient over the prosthesis, and the outer diameter determines which valve actually fits into the aortic root, it would seem logical that the valve with the greatest opening area in relation to its outer diameter should allow the best hemodynamic performance. Interestingly, neither of these 2 parameters is reflected by the manufacturing companies' size labels or suggested sizing strategies. In addition, it is known that valves with the same size label from different companies may differ significantly in their actual dimension (outer diameter). Finally, the manufacturer-suggested sizing strategies differ so much that expected differences from valve design may get lost because of differences in sizing. These size and sizing differences and the lack of information on the geometric opening area complicate true hemodynamic comparisons significantly. Furthermore, some fluid dynamic considerations regarding the determination of opening area by echocardiography (the effective orifice area) introduce additional obscuring factors in the attempt to compare hemodynamic performance data of different stented tissue valves. We analyzed the true dimensions of different tissue prostheses and the manufacturer-suggested sizing strategies in relation to published effective orifice areas. We have demonstrated how sizing and implantation strategy have much greater impact on postoperative valve hemodynamics than valve brand or type. In addition, our findings may explain the different opinions regarding valve hemodynamics of different tissue valves. PMID- 21703636 TI - Benefits and risks of using clopidogrel before coronary artery bypass surgery: systematic review and meta-analysis of randomized trials and observational studies. AB - OBJECTIVE: The benefits and risks associated with the use of clopidogrel before coronary artery bypass grafting are controversial, and these were investigated in the present meta-analysis. METHODS: A systematic literature search was performed to identify studies on the use of clopidogrel before coronary artery bypass grafting. Meta-analysis was performed according to the Cochrane Handbook for Systematic Reviews. RESULTS: The literature search yielded 3 prospective randomized studies and 17 observational studies with valid data. Randomized studies were post hoc analyses of the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY), Clopidogrel for the Reduction of Events During Observation (CREDO), and Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events trials. Meta-analysis based on these data showed a nonsignificant reduced risk of immediate postoperative composite end point (death, myocardial infarction, or stroke) in the clopidogrel group (risk ratio [RR], 0.77; 95% confidence interval [CI], 0.58-1.04). Data from the CREDO and CLARITY trials showed a similar risk of death (RR, 0.81; 95% CI, 0.20-3.37), myocardial infarction (RR, 0.58; 95% CI, 0.25-1.33), and major bleeding according to Thrombolysis in Myocardial Infarction criteria (RR, 1.48; 95% CI, 0.72-3.04). Meta-analysis of observational studies showed that preoperative exposure to clopidogrel was associated with an increased risk of death (RR, 1.30; 95% CI, 1.02-1.67), reoperation for bleeding (RR, 1.88; 95% CI, 1.37-2.58), blood loss (mean difference, 157.8 mL; 95% CI, 61.9-253.6), need of packed red blood cell transfusion (RR, 1.23; 95% CI, 1.10-1.37), and increased use of blood products. A significantly reduced risk of postoperative myocardial infarction was observed among patients taking clopidogrel (RR, 0.63; 95% CI, 0.48-0.82). CONCLUSIONS: Contrary to the findings of post hoc analyses of randomized trials, observational studies showed that recent exposure to clopidogrel before coronary artery bypass grafting is associated with increased risk of postoperative death, reoperations for bleeding, blood loss, and need of blood transfusions. PMID- 21703639 TI - Long-term tricuspid valve function after Norwood operation. AB - OBJECTIVE: Long-term functional outcomes after Norwood palliation are likely to depend on tricuspid valve performance in the systemic role. We therefore aimed to characterize features associated with tricuspid valve intervention. METHODS: All 219 children (1990-2007) who underwent Norwood stage 1 palliation resulting in a systemic right ventricle were investigated. In parametric competing risks analyses, primary end points included surgical tricuspid valve intervention (repair = 27, replacement = 3) and death (N = 105). All 2705 echocardiogram reports were included in time-related analyses of outcome adjusted for repeated measures. Variable selection used bootstrapping. RESULTS: Approximately 25% of survivors underwent tricuspid valve repair at some point, especially in children with mitral atresia (P = .04, 53% reliability), longer myocardial ischemic time during Norwood (P = .02, 50%), and moderate/severe tricuspid regurgitation immediately post-Norwood (P = .006, 86%). Risk of tricuspid valve intervention was mainly early, but a late risk emerged 10 to 15 years after Norwood. Tricuspid valve intervention was successful in restoring functional natural history to that of the remainder of the cohort. Tricuspid valve intervention did not compromise survival (82% +/- 2% 5 years after tricuspid valve intervention), and right ventricular function was not worse in patients requiring tricuspid valve intervention. Repeat tricuspid valve interventions were undertaken in 6 patients (3 repairs, 3 replacements). At latest follow-up, the degree of tricuspid valve regurgitation was not different between those who did and did not receive intervention. CONCLUSIONS: Tricuspid valve surgery is common after single ventricle palliation for hypoplastic left heart syndrome, necessary in up to 25% of survivors. Mitral atresia and lengthy myocardial ischemic times during Norwood surgery are prominent risks. Right ventricular function was preserved by tricuspid repair. However, the emerging late hazard for tricuspid valve intervention may have implications for long-term outcome and should be explored further. PMID- 21703638 TI - The easier, the better: age, creatinine, ejection fraction score for operative mortality risk stratification in a series of 29,659 patients undergoing elective cardiac surgery. AB - OBJECTIVE: Age, preoperative creatinine value, and ejection fraction are easily arranged in the age, creatinine, ejection fraction score to predict operative mortality in elective cardiac operations, as recently shown. We validate the age, creatinine, ejection fraction score in a large multicentric study. METHODS: We analyzed 29,659 consecutive patients who underwent elective cardiac operations in 14 Italian institutions during the period from 2004 to 2009. The operative (30 day) mortality rate was recorded for the entire population and for subgroups of patients based on the risk distribution. The predicted mortality was assessed using the additive and logistic European System for Cardiac Operative Risk Evaluations, and the age, creatinine, ejection fraction score. Accuracy and clinical performance of the different models were tested. RESULTS: The observed mortality rate was 2.77% (95% confidence interval, 2.59-2.96). The predicted mortality rate was 2.84% (95% confidence interval, 2.79-2.88) for the age, creatinine, ejection fraction score (not significantly different from the observed rate), 6.26% for the additive European System for Cardiac Operative Risk Evaluation, and 9.67% for the logistic European System for Cardiac Operative Risk Evaluation (both significantly overestimated). For all deciles of risk distribution, the European System for Cardiac Operative Risk Evaluation significantly overestimated mortality risk; the age, creatinine, ejection fraction score slightly overestimated the mortality risk in very low-risk patients and significantly underestimated the mortality risk in very high-risk patients, correctly estimating the risk in 7 of 10 deciles. The accuracy of the age, creatinine, ejection fraction score was acceptable (area under the curve of 0.702). In a separate analysis, this value increased to 0.74 by excluding centers that reported no operative mortality. These values were similar or worse for the European System for Cardiac Operative Risk Evaluation. CONCLUSIONS: The age, creatinine, ejection fraction score provides an accuracy level comparable to that of the European System for Cardiac Operative Risk Evaluation, with far superior clinical performance. PMID- 21703640 TI - Rescue surgery for bronchial obstruction after endovascular thoracoabdominal stent implantation. PMID- 21703641 TI - The evolving role of intraoperative balloon pulmonary valvuloplasty in valve sparing repair of tetralogy of Fallot. AB - OBJECTIVE: The late morbidity of pulmonary regurgitation has intensified the interest in valve-sparing repair of tetralogy of Fallot. This study reviewed a single institution's experience with valve-sparing repair and investigated the role of intraoperative balloon valvuloplasty. METHODS: A retrospective chart review identified 238 patients who underwent complete primary repair of tetralogy of Fallot at less than 180 days of age. Patients were divided into 4 groups on the basis of the type of right ventricular outflow tract repair: transannular patch (n = 111), commissurotomy or standard rigid dilation (n = 71), intraoperative balloon pulmonary valvuloplasty (n = 32), or no valvar intervention (n = 24). RESULTS: Baseline demographic and anatomic factors differed among the 4 procedural groups with substantial overlap. Among 142 patients with pulmonary valve hypoplasia (z score, -2 to -4), 37% had valve sparing repair. These patients had significant annular growth over time: z score increased 0.67 and 1.00 per year in the intraoperative balloon valvuloplasty (P < .001) and traditional valve-sparing (P < .001) groups, respectively. Rates of valve growth did not differ across groups, but z scores were 0.58 lower for the balloon valvuloplasty group across all time points (P = .001). Freedom from reintervention and surgery was shorter for the balloon valvuloplasty group than for the other groups (P < .001). CONCLUSIONS: Patients with tetralogy of Fallot and pulmonary valve hypoplasia who undergo valve-sparing repair with intraoperative balloon valvuloplasty have significant longitudinal annular growth, with normalization of annular size over time. Despite application in patients with more hypoplastic valves, balloon valvuloplasty resulted in similar valve growth and pulmonary regurgitation as traditional methods, but higher rates of reintervention. Although the precise role of this technique needs further refinement, it is likely to be most useful in patients with moderate pulmonary stenosis and moderate pulmonary valve dysplasia. PMID- 21703642 TI - [ACTH-independent macronodular adrenal hyperplasia and subclinical Cushing's syndrome]. PMID- 21703643 TI - [Vitamin D and hypertension]. AB - Low levels of vitamin D, defined as levels of 25-hydroxyvitamin D < 20-30 ng/ml, is a prevalent problem in the general population. Besides the classic relation with musculoskeletal disease, vitamin D has been also related to autoimmune diseases, cancer, metabolic diseases or cardiovascular diseases. High blood pressure, as the main cardiovascular risk factor, also has been related to vitamin D deficiency, constituting two prevalent worldwide health problems. Therefore, this article reviews the most important studies that combine both pathologies, the biological mechanism that relate them and the current evidence about the effect of vitamin D supplementation on hypertension. PMID- 21703644 TI - [The paradox of obesity in heart failure: is more weight better?]. PMID- 21703645 TI - [Clinical and molecular study of five families with resistance to thyroid hormones]. AB - BACKGROUND AND OBJECTIVE: Resistance to thyroid hormone (RTH) is a syndrome mostly caused by mutations in thyroid hormone receptor beta gen (THRB). We present five families with RTH phenotype. PATIENTS AND METHODS: THRB gene sequencing. In vitro studies to evaluate the mutants response to thyroid hormones and their dominant negative effect. Mechanism of resistance in patients with RTH without THRB mutations quantifying expression of regulator of calcineurin 2 (ZAKI4) and Kruppel-like factor 9 (BTEB) genes in patients fibroblast cultures. RESULTS: THRB mutations were found in three cases: R243Q, R320C, R429Q. Mutants showed a decreased response to T3. R243Q and R320C had a strong dominant negative effect. One subject without THRB mutation showed changes in ZAKI4 and BTEB expression similar to R320C and the other showed expression levels higher than normal controls. CONCLUSIONS: Three cases of RTH were caused by THRB heterozygous mutations but in two cases mutations were not found. THRB mutation carriers and one of the patients without mutations share a similar mechanism of resistance and in the other subject RTH is TRbeta independent. PMID- 21703646 TI - [Cognitive disorder: a reality in the chronic fatigue syndrome]. PMID- 21703647 TI - [Non-Hodgkin's lymphoma staging: a prospective study of the value of positron emission tomography/computed tomography (PET/CT) versus PET and CT]. AB - BACKGROUND AND OBJECTIVE: To prospectively analyze the diagnostic accuracy of PET/CT in non-Hodgkin's lymphoma (NHL) and to evaluate the most appropriate study protocol of this technique. PATIENTS AND METHOD: Seventy-six biopsy proven NHL patients were enrolled in this prospective study for 3 years. Patients initially underwent a low-dose CT without intravenous contrast, then a PET emission scan and finally a full-dose CT with intravenous contrast. For every patient, two modalities of PET/CT images were reconstructed: a low-dose unenhanced PET/CT and a full-dose enhanced PET/CT. Each modality was evaluated by either of two pairs of readers, different for each modality. Enhanced CT and PET images were evaluated by an independent radiologist and nuclear medicine physician respectively. RESULTS: Agreement between reference standard and techniques was as follows: 52.2% of patients with enhanced CT (kappa=0.458), 46% with PET (kappa=0.335), 75% with low-dose unenhanced PET/CT (kappa=0.664) and 76.8% with full-dose enhanced PET/CT (kappa=0.679), with p<0.001. Although all techniques underestimated the stage in comparison to gold standard, the lowest percentage was for full-dose enhanced PET/CT (20.3%). CONCLUSIONS: PET/CT improved staging accuracy of NHL, being full-dose enhanced PET/CT the most accurate technique in our study. PMID- 21703648 TI - Tracing the development of psychosis and its prevention: what can be learned from animal models. AB - Schizophrenia (SCZ) is a neurodevelopmental disorder manifested symptomatically after puberty whose pharmacotherapy remains unsatisfactory. In recent years, longitudinal structural neuroimaging studies have revealed that neuroanatomical aberrations occur in this disorder and in fact precede symptom onset, raising the exciting possibility that SCZ can be prevented. There is some evidence that treatment with atypical antipsychotic drugs (APDs) prior to the development of the full clinical phenotype reduces the risk of transition to psychosis, but results remain controversial. It remains unknown whether progressive structural brain aberrations can be halted. Given the diagnostic, ethical, clinical and methodological problems of pharmacological and imaging studies in patients, getting such information remains a major challenge. Animal neurodevelopmental models of SCZ are invaluable for investigating such questions because they capture the notion that the effects of early brain damage are progressive. In recent years, data derived from such models have converged on key neuropathological and behavioral deficits documented in SCZ attesting to their strong validity, and making them ideal tools for evaluating progression of pathology following in-utero insults as well as its prevention. We review here our recent studies that use longitudinal in vivo structural imaging to achieve this aim in the prenatal immune stimulation model that is based on the association of prenatal infection and increased risk for SCZ. Pregnant rats were injected on gestational day 15 with the viral mimic polyriboinosinic polyribocytidylic acid (poly I:C) or saline. Male and female offspring were imaged and tested behaviorally on postnatal days (PNDs) 35, 46, 56, 70 and 90. In other experiments, offspring of poly I:C- and saline-treated dams received the atypical antipsychotic drugs (APDs) clozapine or risperidone in two developmental windows: PND 34-47 and PND 48-61, and underwent behavioral testing and imaging at adulthood. Prenatal poly I:C-induced interference with fetal brain development led to aberrant postnatal brain development as manifested in structural abnormalities in the hippocampus, the striatum, the prefrontal cortex and lateral ventricles (LV), as seen in SCZ. The specific trajectories were region-, age- and sex-specific, with females having delayed onset of pathology compared to males. Brain pathology was accompanied by development of behavioral abnormalities phenotypic of SCZ, attentional deficit and hypersensitivity to amphetamine, with same sex difference. Hippocampal volume loss and LV volume expansion as well as behavioral abnormalities were prevented in the offspring of poly I:C mothers who received clozapine or risperidone during the asymptomatic period of adolescence (PND 34-47). Administration at a later window, PNDs 48-61, exerted sex-, region- and drug- specific effects. Our data show that prenatal insult leads to progressive postnatal brain pathology, which gradually gives rise to "symptoms"; that treatment with atypical APDs can prevent both brain and behavioral pathology; and that the earlier the intervention, the more pathological outcomes can be prevented. PMID- 21703649 TI - Blueprint for development of the advanced practice psychiatric nurse workforce. AB - The mental health system is inefficient and ineffective in providing behavioral health care services to the 1 in 4 Americans who have a mental illness or a substance abuse problem. Current health care reform initiatives present a significant opportunity for advanced practice psychiatric nurses-psychiatric mental health (APRN-PMH) to develop action-oriented recommendations for developing their workforce and thereby increasing access to high-quality and full spectrum behavioral health care services. If endorsed by the professional nursing associations and the APRN-PMH workforce, the strategies presented in this paper provide a blueprint for developing the APRN-PMH workforce. Achieving these goals will significantly reform the APRN-PMH workforce, thereby contributing to the overall goal of supporting an integrated model of behavioral health care. No change has as much potential to influence the APRN-PMH workforce as the uniting of all APRN-PMHs in a "Blueprint for APRN-PMH Workforce Development." PMID- 21703650 TI - Nursing diagnoses in elderly residents of a nursing home: a case in Turkey. AB - There are limited studies on nursing diagnoses of the elderly living in nursing homes worldwide. This study aimed to define the most frequent nursing diagnoses in the elderly residents of a nursing home elder care and rehabilitation center. Seventy-four elderly individuals were included in the study. Data were collected using the "Elderly Individual's Introduction Form" between April 2007 to August 2007. The content of the form was based on a guide to gerontologic assessment, and Gordon's Functional Health Patterns. The nursing diagnoses (NANDA-I Taxonomy II) were identified by the 2 researchers separately according to the defining characteristics and the risk factors. The consistency between the nursing diagnoses defined by the 2 researchers was evaluated using Cohen's kappa (kappa). There was an 84.7% agreement about nursing diagnoses defined by the 2 researchers separately. The weighted kappa consistency analyses showed there was an adequate level of consistency (kappa = 0.710), and the findings were significant (p < 0.0001). The most frequent diagnoses were ineffective role performance (86.5%), ineffective health maintenance (81.2%), risk for falls (77%), and impaired physical mobility (73%). The diagnosis of ineffective role performance was more frequent in patients with dementia (x(2) =10.993, df = 1, p = 0.001). There was a very significant relationship between dementia and the diagnosis of impaired verbal communication (x(2) = 32.718, df = 1, p = 0.0001). The relationship between mobility disorder and self-care deficit was also significant (x(2) = 19.411, df = 1, p = 0.0001). To improve quality in patient care, nurses should use nursing diagnoses with a systematic assessment and should help the elderly in health promotion or use of the maximum current potential. PMID- 21703651 TI - Transitions theory: a trajectory of theoretical development in nursing. AB - There have been very few investigations into how any single nursing theory has actually evolved historically. In this paper, a trajectory of theoretical development in nursing is explored through reviewing the theoretical development of a single nursing theory-transitions theory. The literature related to transitions theory was searched and retrieved using multiple databases. Ninety nine papers were analyzed according to type of theory, populations of interest, sources of theorizing, and theoretical methods. Transitions theory originated in research but was initially borrowed. It also arose in research with immigrants and from national and international collaborative research efforts. A product of mentoring, transitions theory is used widely in nursing education, research, and practice. Diverse thoughts related to transitions theory coexist. For future theoretical development in nursing, we need to remain open to new ideas and continue to engage in multiple collaborative efforts. PMID- 21703652 TI - Communication, training, well-being, and commitment across nurse generations. AB - Within a context of global nurse shortages, replacing nurses is difficult; training and retention is a critical concern for healthcare management. Similarities and differences in the impact of supervisor-nurse relationships upon satisfaction with training and development, well-being and affective commitment were examined across 3 different nursing generations in Australia. Nine hundred nurses from 7 private hospitals (small, medium, and large) across Australia responded. Path analysis, using an ordinary least squares approach, and multivariate analysis were used to test the hypotheses. Three factors accounted for almost half the variance of Generation Xs' and Baby Boomers' and a third of Generation Ys' affective commitment. Practical implications for hospital management include differences in generations and the pivotal role of nurse supervisors. For all 3 generations of nurses, supervisor-subordinate communication relationships are important because they contribute to satisfaction with training and development and well-being, but also significantly impact affective commitment. PMID- 21703653 TI - 8,12;8,20-diepoxy-8,14-secopregnane glycosides from roots of Asclepias tuberosa and their effect on proliferation of human skin fibroblasts. AB - A pregnane glycoside fraction from the roots of Asclepias tuberosa L. caused normal human skin fibroblasts to proliferate. This fraction contained 21 pregnane glycosides whose structures were established using NMR spectroscopic analysis and chemical evidence. The aglycones of most of these compounds were identified as 8,12;8,20-diepoxy-8,14-secopregnanes, such as tuberogenin or 5,6 didehydrotuberogenin, the same aglycones as constituents of the aerial parts of this plant. Some of these compounds also caused proliferation of skin fibroblasts. PMID- 21703654 TI - [Other models for training radiologists]. AB - Different models for training radiologists are used in different countries. Considering the trend toward international homogenization, it is important to know the differences and common traits among different countries to enable us to adapt our programs to future changes. We review training programs in radiology in Europe, the United States, Canada, and some Latin American countries. We focus on the selection process, residency programs, research, certification, subspecialization, and maintaining certification. We found a wide variability among countries, although there are more similarities within continents. PMID- 21703655 TI - Morphological and ultrastructural organization of the male genital apparatus of some Aphididae (Insecta, Homoptera). AB - Ultrastructural investigations on the amphigonic reproductive mechanisms in Aphidoidea (Homoptera, Sternorryncha) species, of which little is known in the literature, can provide useful information on their reproductive biology. Morphological and ultrastructural investigations were carried out on the reproductive tract and on spermatozoa from sexually mature males of five species belonging to three subfamilies of Aphidoidea. The organization of the reproductive tract and of spermatozoa appears simple and similar in the examined species. Each testis consists of three follicles containing many cysts arranged in a progressive order of maturation from the distal to the proximal tract; spermiogenesis only occurs in sexually mature males, ending with the organization of sperm bundles. Gametes are neatly arranged in each bundle and kept together by a cap showing a particular organization. The distal tract of each spermiduct is enlarged and full of gametes; close to the testis the two spermiducts merge together, except in Drepanosiphum platanoidis where the spermiducts run independently. The various tracts of each examined gland showed no peculiar differences either in the same species or among the species. Some interesting hypotheses are proposed in this work about the probable roles of the investigated structures in the reproductive mechanisms of these insects. PMID- 21703656 TI - A long-distance RNA-RNA interaction plays an important role in programmed -1 ribosomal frameshifting in the translation of p88 replicase protein of Red clover necrotic mosaic virus. AB - Programmed -1 ribosomal frameshifting (-1 PRF) is one viral translation strategy to express overlapping genes in positive-strand RNA viruses. Red clover necrotic mosaic virus (RCNMV) uses this strategy to express its replicase component protein p88. In this study, we used a cell-free translation system to map cis acting RNA elements required for -1 PRF. Our results show that a small stem-loop structure adjacent to the cap-independent translation element in the 3' untranslated region (UTR) of RCNMV RNA1 is required for -1 PRF. Site-directed mutagenesis experiments suggested that this stem-loop regulates -1 PRF via base pairing with complementary sequences in a bulged stem-loop adjacent to the shifty site. The existence of RNA elements responsible for -1 PRF and the cap independent translation of replicase proteins in the 3' UTR of RNA1 might be important for switching translation to replication and for regulating the ratio of p88 to p27. PMID- 21703657 TI - Natural versus wastewater derived dissolved organic carbon: implications for the environmental fate of organic micropollutants. AB - The interaction of organic micropollutants with dissolved organic carbon (DOC) can influence their transport, degradation and bioavailability. While this has been well established for natural organic carbon, very little is known regarding the influence of DOC on the fate of micropollutants during wastewater treatment and water recycling. Dissolved organic carbon-water partition coefficients (K(DOC)) for wastewater derived and reference DOC were measured for a range of micropollutants using a depletion method with polydimethylsiloxane disks. For micropollutants with an octanol-water partition coefficient (log K(OW)) greater than 4 there was a significant difference in K(DOC) between reference and wastewater derived DOC, with partitioning to wastewater derived DOC over 1000 times lower for the most hydrophobic micropollutants. The interaction of nonylphenol with wastewater derived DOC from different stages of a wastewater and advanced water treatment train was studied, but little difference in K(DOC) was observed. Organic carbon characterisation revealed that reference and wastewater derived DOC had very different properties due to their different origins. Consequently, the reduced sorption capacity of wastewater derived DOC may be related to their microbial origin which led to reduced aromaticity and lower molecular weight. This study suggests that for hydrophobic micropollutants (log K(OW) > 4) a higher concentration of freely dissolved and thus bioavailable micropollutants is expected in the presence of wastewater derived DOC than predicted using K(DOC) values quantified using reference DOC. The implication is that naturally derived DOC may not be an appropriate surrogate for wastewater derived DOC as a matrix for assessing the fate of micropollutants in engineered systems. PMID- 21703658 TI - Effects of titanate nanotubes synthesized by a microwave hydrothermal method on photocatalytic decomposition of perfluorooctanoic acid. AB - Titanate nanotubes (TNTs) were used to remove perfluorooctanoic acid (PFOA) from aqueous solutions in this study. Direct photolysis of PFOA by a 254-nm UV light (400 W) was found effective to decompose PFOA without presence of photocatalysts. Shorter-chain perfluorocarboxylic acids (PFCAs) and fluoride ions were formed during photodecomposition. Addition of TNTs as photocatalysts did not greatly enhance photocatalytic decomposition of PFOA. TNTs mainly act as adsorbents to adsorb PFOA and form TNT-PFOA complexes. It suggested that sodium ions and oxygen atoms on the surfaces of TNTs play important roles in PFOA adsorption. X-ray Photoelectron Spectroscopy (XPS) and Fourier Transform Infrared Spectroscopy (FTIR) analyses indicated that ion-exchange, electrostatic interaction, and hydrophobic interaction all participated in the photocatalytic reaction of PFOA by TNTs. PMID- 21703659 TI - Distribution of Se and its species in Myriophyllum spicatum and Ceratophyllum demersum growing in water containing Se (VI). AB - The uptake of Se (VI) by two aquatic plants, Myriophyllum spicatum L. and Ceratophyllum demersum L., and its effects on their physiological characteristics have been studied. Plants were cultivated outdoors under semi-controlled conditions and in two concentrations of Na selenate solution (20 MUg Se L(-1) and 10 mg Se L(-1)). The higher dose of Se reduced the photochemical efficiency of PSII in both species, while the lower dose had no effect on PSII. Addition of Se had no effect on the amounts of chlorophyll a and b. The concentration of Se in plants grown in 10 mg Se L(-1), averaged 212 +/- 12 MUg Seg(-1) DM in M. spicatum (grown from 8-13 d), and 492 +/- 85 MUg Se g(-1) DM in C. demersum (grown for 31 d). Both species could take up a large amount of Se. The amount of soluble Se compounds in enzyme extracts ranged from 16% to 26% in control, and in high Se solution from 48% to 36% in M. spicatum and C. demersum, respectively. Se-species were determined using HPLC-ICP-MS. The main soluble species in both plants was selenate (~37%), while SeMet and SeMeSeCys were detected at trace levels. PMID- 21703660 TI - Degradation of 4-nonylphenol, 4-t-octylphenol, bisphenol A and triclosan following biosolids addition to soil under laboratory conditions. AB - Land application of biosolids is common practice in many countries, however, there are some potential risks associated with the presence of contaminants within the biosolids. This laboratory study examined the degradation of four commonly found organic compounds, 4-nonylphenol, 4-t-octylphenol, bisphenol A, and triclosan, in soil following the addition of two biosolids over 32 weeks. The pattern of degradation was assessed to determine if it followed a standard first order decay model or if a biphasic model with a degrading and a recalcitrant fraction better described the data. The time taken for the initial concentrations to decrease by 50% (DT50), based on a first-order model, was 12-25 d for 4 nonylphenol, 10-14 d for 4-t-octylphenol, 18-102 d for bisphenol A, and 73-301 d for triclosan. For 4-nonylphenol, bisphenol A and triclosan, the biphasic model fitted the degradation data better than the first-order model, indicating the presence of a degrading fraction and a non-degrading recalcitrant fraction. The recalcitrant fraction for these three compounds at the completion of the 32 week experiment was 17-21%, 24-42%, and 30-51% of the initial concentrations, respectively. For 4-t-octylphenol, the first-order model was sufficient in explaining the degradation data, indicating that no recalcitrant fraction was present. This study showed that biphasic degradation occurred for some organic compounds in biosolids amended soil and that the use of standard first-order degradation models may underestimate the persistence of some organic compounds following land application of biosolids. PMID- 21703661 TI - Effects of dissolution kinetics on bioaccessible arsenic from tailings and soils. AB - Dissolution kinetics of arsenic from soils and tailings were studied under simulated gastrointestinal conditions to determine the effects of residence time, pH and soil composition on the bioaccessibility of arsenic. The samples were sieved to four particle size fractions from bulk to <45 MUm, and included arsenic minerals, soils and tailings with total arsenic concentrations ranging from 19 to 42000 mg kg(-1). The bioaccessible arsenic concentrations varied from 2.8 to 10000 mg kg(-1), and the highest concentrations were associated with the smallest particle size fractions. Kinetic parameters were determined for each sample extracted under gastric conditions (pH=1.8) followed by intestinal conditions (pH=7.0). Under gastric pH conditions, dissolution appeared to be diffusion controlled and followed an exponential curve, whereas a logarithmic or linear model was used to describe the mixed dissolution mechanisms observed under intestinal conditions. Nine of the 13 samples tested reached a steady state bioaccessible arsenic concentration within the 5-h physiologically-based extraction test (PBET). However the bioaccessible arsenic concentrations in four tailings samples increased significantly (p=0.034) between the 5-h and the extended 24-h extraction under intestinal conditions. Since arsenic absorption may occur along the entire digestive tract, assessments based on the standard 5-h PBET extraction may not adequately estimate the risks associated with arsenic absorption in such cases. The slow dissolution kinetics associated with secondary arsenic minerals in some tailings samples may require extending the PBET extractions to longer periods, or extrapolating using the proposed kinetic models, to reach steady state concentrations in simulated gastrointestinal fluids. PMID- 21703662 TI - SIMS(DAIRY): a modelling framework to identify sustainable dairy farms in the UK. Framework description and test for organic systems and N fertiliser optimisation. AB - Multiple demands are placed on farming systems today. Society, national legislation and market forces seek what could be seen as conflicting outcomes from our agricultural systems, e.g. food quality, affordable prices, a healthy environmental, consideration of animal welfare, biodiversity etc., Many of these demands, or desirable outcomes, are interrelated, so reaching one goal may often compromise another and, importantly, pose a risk to the economic viability of the farm. SIMS(DAIRY), a farm-scale model, was used to explore this complexity for dairy farm systems. SIMS(DAIRY) integrates existing approaches to simulate the effect of interactions between farm management, climate and soil characteristics on losses of nitrogen, phosphorus and carbon. The effects on farm profitability and attributes of biodiversity, milk quality, soil quality and animal welfare are also included. SIMS(DAIRY) can also be used to optimise fertiliser N. In this paper we discuss some limitations and strengths of using SIMS(DAIRY) compared to other modelling approaches and propose some potential improvements. Using the model we evaluated the sustainability of organic dairy systems compared with conventional dairy farms under non-optimised and optimised fertiliser N use. Model outputs showed for example, that organic dairy systems based on grass clover swards and maize silage resulted in much smaller total GHG emissions per l of milk and slightly smaller losses of NO(3) leaching and NO(x) emissions per l of milk compared with the grassland/maize-based conventional systems. These differences were essentially because the conventional systems rely on indirect energy use for 'fixing' N compared with biological N fixation for the organic systems. SIMS(DAIRY) runs also showed some other potential benefits from the organic systems compared with conventional systems in terms of financial performance and soil quality and biodiversity scores. Optimisation of fertiliser N timings and rates showed a considerable scope to reduce the (GHG emissions per l milk too). PMID- 21703663 TI - Dichlobenil and 2,6-dichlorobenzamide (BAM) in the environment: what are the risks to humans and biota? AB - Dichlobenil is a herbicide widely used for weed control, mainly in non agricultural areas and in the aquatic environment. When released into the environment, dichlobenil can undergo many processes such as vaporization to air, binding to soil and sediment, as well as degradation to a number of new compounds. The main metabolite is 2,6-dichlorobenzamide (BAM) which is water soluble and causes ground water contamination. It is frequently found in levels exceeding maximum allowed concentrations of pesticides and metabolites in ground water (0.1 MUg/L) set by the European Commission. The environmental distribution of both dichlobenil and BAM was outlined and the risk quotients were calculated for biota and for humans. For organisms living in aquatic habitats, risk quotients were low for both dichlobenil and BAM, approximately 0.02 for dichlobenil and 2.4.10(-4) to 1.3.10(-3) for BAM. For humans, a margin of safety above 15,000 was estimated for dichlobenil. The most unusual and extreme concentration of BAM ever found in ground water is 560 MUg/L. Even at this concentration, the margin of safety for humans was 313 for a 70 kilo man and 56 for a 25 kilo child. The results clearly demonstrate that the risks to biota and humans are very low. PMID- 21703664 TI - An inter-laboratory trial of the unified BARGE bioaccessibility method for arsenic, cadmium and lead in soil. AB - The Bioaccessibility Research Group of Europe (BARGE) has carried out an inter laboratory trial of a proposed harmonised in vitro physiologically based ingestion bioaccessibility procedure for soils, called the Unified BARGE Method (UBM). The UBM includes an initial saliva phase and simulated stomach and intestine compartments. The trial involved the participation of seven laboratories (five European and two North American) providing bioaccessibility data for As (11 samples), Cd (9 samples) and Pb (13 samples) using soils with in vivo relative bioavailability data measured using a swine model. The results of the study were compared with benchmark criteria for assessing the suitability of the UBM to provide data for human health risk assessments. Mine waste and slag soils containing high concentrations of As caused problems of poor repeatability and reproducibility which were alleviated when the samples were run at lower soil to solution ratios. The study showed that the UBM met the benchmark criteria for both the stomach and stomach & intestine phase for As. For Cd, three out of four criteria were met for the stomach phase but only one for the stomach & intestine phase. For Pb two, out of four criteria were met for the stomach phase and none for the stomach & intestine phase. However, the study recommends tighter control of pH in the stomach phase extraction to improve between-laboratory variability, more reproducible in vivo validation data and that a follow up inter-laboratory trial should be carried out. PMID- 21703666 TI - Effects of genistein on gonadotropic cells in immature female rats. AB - The effects of genistein on pituitary gonadotropic cells of immature female rats were examined and compared to actions of the synthetic estrogen, 17alpha ethynylestradiol. Immature female rats received 50mg/kg/bw of genistein in dimethylsulfoxide (DMSO) subcutaneously (s.c.) daily for 3 days at 18, 19 and 20 days of age. A second group was injected with 1MUg/kg of 17alpha-ethynylestradiol in olive oil in the same schedule. The genistein control group received DMSO only, while 17alpha-ethynylestradiol controls were given sterile olive oil only. Changes in cell number per mm(2), cell volume and volume density of follicle stimulating (FSH) and luteinizing (LH) immunolabeled cells were evaluated by morphometry and stereology. Genistein induced significant increases in the number of FSH cells (by 21%) and LH cells (by 20%) per mm(2) compared to corresponding controls. Volumes of FSH and LH cells were significantly increased by 19.7% and 20% and their volume densities by 20% and 20.2%, respectively. Estradiol markedly affected gonadotropes in the same manner, but to a greater extent. It can be concluded that genistein acted as an estrogenic agonist in the pituitaries of immature female rats, and as such, stimulated gonadotropic cells. PMID- 21703665 TI - Diesel vehicle emission and death rates in Tokyo, Japan: a natural experiment. AB - Evidence linking air pollution with adverse cardiopulmonary outcomes is accumulating. However, few studies have been conducted to evaluate whether vehicle emission control improves public health. We thus evaluated the effect of a diesel emission control law on mortality rates in 23 wards of Tokyo metropolitan area, Japan. We obtained daily counts of mortality and concentrations of nitrogen dioxide (NO(2)) and particulate matter less than 2.5 MUm in diameter (PM(2.5)) from April 2003 to December 2008. Time-series and interrupted time-series analysis were employed to analyze the data in two periods: prior to the introduction of tighter restrictions (April 2003 to March 2006) and after the enforcement (April 2006 to December 2008). Concentrations of air pollutants gradually decreased during the study period: from 36.3 ppb (NO(2)) and 22.8 MUg/m(3) (PM(2.5)) to 32.1 ppb and 20.3 MUg/m(3), respectively. Air pollutants were positively associated with circulatory and pulmonary disease mortality, especially cerebrovascular disease. Each same-day PM(2.5) increase of 10 MUg/m(3) was associated with a 1.3% increase in cerebrovascular mortality rate (95% confidence interval: 0.2-2.4). Rate ratios were attenuated after the enforcement in most of the outcomes, probably due to reduced toxicity of the pollutants. In the crude interrupted time-series analysis, reductions of standardized mortality rates after the enforcement were the greatest in high traffic areas. Even after adjustment of longer-time trend, mortality rate from cerebrovascular disease was reduced by 8.50% (p<.001) with dose-response relationship. However, the declines in other cause-specific mortality became equivocal. This natural experiment in Tokyo suggests that emission controls improved air quality. Although suggestive, further data are needed to conclusively demonstrate an impact on mortality rates. PMID- 21703667 TI - Patterns of immunoreactivity specific for gustducin and for NCAM differ in developing rat circumvallate papillae and their taste buds. AB - alpha-Gustducin and neural cell adhesion molecule (NCAM) are molecules previously found to be expressed in different cell types of mammalian taste buds. We examined the expression of alpha-gustducin and NCAM during the morphogenesis of circumvallate papillae and the formation of their taste buds by immunofluorescence staining and laser-scanning microscopy of semi-ultrathin sections of fetal and juvenile rat tongues. Images obtained by confocal laser scanning microscopy in transmission mode were also examined to provide outlines of histology and cell morphology. Morphogenesis of circumvallate papillae had already started on embryonic day 13 (E13) and was evident as the formation of placode. By contrast, taste buds in the circumvallate papillae started to appear between postnatal day 0 (P0) and P7. Although no cells with immunoreactivity specific for alpha-gustducin were detected in fetuses from E13 to E19, cells with NCAM-specific immunoreactivity were clearly apparent in the entire epithelium of the circumvallate papillary placode, the rudiment of each circumvallate papilla and the developing circumvallate papilla itself from E13 to E19. However, postnatally, both alpha-gustducin and NCAM became concentrated within taste cells as the formation of taste buds advanced. After P14, neither NCAM nor alpha gustducin was detectable in the epithelium around the taste buds. In conclusion, alpha-gustducin appeared in the cytoplasm of taste cells during their formation after birth, while NCAM appeared in the epithelium of the circumvallate papilla forming area. However, these two markers of taste cells were similarly distributed within mature taste cells. PMID- 21703668 TI - Are ulcerative and nonulcerative interstitial cystitis/painful bladder syndrome 2 distinct diseases? A study of coexisting conditions. AB - OBJECTIVES: Coexisting conditions associated with interstitial cystitis/painful bladder syndrome (IC/PBS) have not been fully explored by IC/PBS subtypes. We compared comorbid diagnoses/symptoms in women with ulcerative (ULC) and nonulcerative (N-ULC) IC/PBS and controls. METHODS: Adult women with IC/PBS and controls without IC/PBS completed a mailed survey assessing for 21 diagnoses. IC/PBS subtype was determined by hydrodistention reports. Standardized questionnaires assessed IC/PBS symptoms (Interstitial Cystitis Symptom/Problem Indexes [ICSI-PI]) and for undiagnosed fibromyalgia, irritable bowel syndrome, and depression (Symptom Intensity Score [SIS]; Rome III Functional Bowel Questionnaire; Center for Epidemiologic Studies Depression Scale [CES-D]). Data were analyzed using the Pearson chi-square, Fisher exact, Wilcoxon rank test, or Spearman rank correlation coefficient. RESULTS: Of 178 N-ULC IC/PBS patients, 36 ULC IC/PBS patients, and 425 controls, ULC IC/PBS subjects were older (median 63 years; P < .01) and less employed (P < .01), but groups were similar on other demographic characteristics. N-ULC reported more chronic diagnoses (mean 3.5 +/- 2.3) than ULC (2.3 +/- 2.0) and controls (1.2 +/- 1.5) (P < .01). When N-ULC and ULC IC/PBS patients were compared, more N-ULC IC/PBS patients had fibromyalgia (P = .03), migraines (P = .03), temporomandibular joint disorder (P < .01), and higher CES-D (P = .02) and SIS scores (P = .01). The ULC IC/PBS group voided more frequently during the daytime (P = .03) and nighttime (P < .01) and had smaller mean bladder capacity than N-ULC (P < .01). No significant differences were seen between N-ULC and ULC IC/PBS patients on the ICSI-PI and Rome III. CONCLUSIONS: Notable differences in the number of comorbid diagnoses and symptoms were seen between IC/PBS subtypes and controls. Subtypes should continue to be evaluated individually to ascertain other similarities and differences. PMID- 21703669 TI - Charles A. Hoffman, M.D.: physician, leader, humanist. PMID- 21703670 TI - Preoperative stent placement decreases cost of ureteroscopy. AB - OBJECTIVES: To examine the effect of preoperative stent placement on total cost of ureteroscopic stone intervention. Passive ureteral dilation with a preoperative ureteral stent has been proposed as a method to facilitate both upper tract access and stone removal. METHODS: We retrospectively reviewed the records of patients who underwent ureteroscopic stone intervention at our institution from 2005 to 2009. A sample of patients who had undergone stenting before ureteroscopy was selected and nonstented matched controls were used as a comparison group. A cost model was used to compare the total healthcare costs for the prestented and nonstented patients with a large (>1 cm) and small (<=1 cm) stone burden using the actual cost accrued for each patient. Sensitivity analyses were used to examine the robustness of the cost model. RESULTS: A total of 104 patients were included in the present study (45 prestented, 59 not prestented). The median stone size was 1 cm (range 0.3-4). The overall stone clearance rate was 95.8%. The median number of procedures was 1. Pre-stenting significantly decreased the total healthcare cost in patients with stones >1 cm. The median cost for the prestented and nonstented cohorts was $17,706 and $27,806, respectively (P < .01). However, prestenting increased the total cost for smaller stones of <=1 cm, although not significantly. The median cost for the prestented and nonstented cohorts was $10,872 and $12,344, respectively (P = .70). Sensitivity analysis confirmed that the model conclusions are robust. CONCLUSIONS: Preoperative stent placement is cost-effective for successful ureteroscopic treatment of stones >1 cm. PMID- 21703671 TI - Factors associated with parametrial involvement in stage IB1 cervical cancer and identification of patients suitable for less radical surgery. AB - OBJECTIVE: The purpose of the present study was to determine possible factors associated with parametrial spread in patients with stage IB1 cervical cancer and define parameters associated with a low risk for parametrial spread, in order to identify candidates for less radical surgery. PATIENTS AND METHODS: We retrospectively reviewed 200 patients with stage IB1 cervical cancer who had undergone radical hysterectomy (class III) and pelvic lymphadenectomy. RESULTS: Overall, 20 (10.0%) of the 200 patients revealed parametrial spread, of which 11 (55%) had only direct microscopic extension of the disease, 3 (15%) had only disease spread to parametrial lymph nodes, 1 (5%) had both direct microscopic extension and disease spread to parametrial lymph nodes, and 5 (25%) had only tumor emboli within the lymph vascular channels in the parametrial tissue. Elderly age, depth of invasion, tumor size, lymph vascular space invasion (LVSI), positive pelvic nodes, and ovarian metastasis were significantly associated with parametrial involvement. The multivariate analysis model included factors that could be determined by a cone biopsy and showed LVSI, deep stromal invasion, and elderly age to be the independent predictors of parametrial involvement. Ninety one patients had a depth of invasion of <=10 mm and no LVSI, of which only 1 (1.1%) had parametrial involvement. When patients aged <=50 years were further stratified into those with a depth of invasion of <=10 mm and no LVSI, parametrial involvement was found to be 0.0% (0/68). CONCLUSION: Patients with a tumor depth of invasion of <=10 mm, no LVSI, and aged <=50 years, could be considered for less radical surgery such as modified radical hysterectomy or simple hysterectomy with pelvic lymphadenectomy. PMID- 21703672 TI - Efficacy of triage by paramedics: a real-time comparison study. AB - OBJECTIVES: Triage has evolved as an effective method of separating patients who require immediate medical attention from patients with non-urgent problems. The aim of this study was to assess the agreement between paramedics and emergency residents about triage decisions using the 3-level triage (3L) system and the 5 level (5L) Australian triage scale in real time. METHODS: All patients who presented to a central triage area during a 1-week period were triaged by paramedics and emergency residents. The chance-adjusted measure of agreement kappa (kappa) was calculated to evaluate the agreement between triage decisions made by paramedics and by emergency residents. RESULTS: A total of 731 patients were included in the final data analysis. Admitting time and waiting time were significantly consistent in the triage area. Agreement between the triage decisions made by paramedics and by emergency residents was 47% (kappa = 0.47) when using the 3L triage scale and 45% (kappa = 0.45) when using the 5L triage scale across all cases. A strong correlation existed among the general conditions of the patients, the 3L triage scale, and the 5L triage scale. DISCUSSION: Triaging is commonly performed by nurses in the American emergency system, and triage by paramedics is not common. Few studies are available about triage by paramedics, and more studies are necessary. A new triage scale may be necessary for untrained personnel so that all emergency departments can conduct simple triage. PMID- 21703673 TI - Microleakage after thermocycling of cemented crowns--a meta-analysis. AB - OBJECTIVES: Microleakage testing of dental materials is a commonly accepted evaluation technique of margin integrity. Thermocycling has been utilized by many researchers to study the influence of temperature extremes on the marginal gap of cemented restorations. The aim of this investigation was to analyze microleakage data on cemented crowns, published in the dental literature until Dec 2009, to identify methodological factors that might potentially affect the results of in vitro microleakage tests and to compare the results. METHODS: The following databases were included: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1950 to Present, Ovid-MEDLINE(R) 1950 to Present with Daily Update, EMBASE, EBM Reviews - Cochrane Database of Systematic Reviews and Pub Med. The search was limited to articles in English, French, Italian and German published until the end of 2009. Classical reviews, comments, animal studies, in vivo articles and studies investigating restorative materials or milk teeth were excluded. 33 different studies were finally selected. The studies were entered in a database and compared using selected literature criteria: sample, restoration procedures, thermocycling and mechanical cycling, evaluation method. For statistical analysis only 16 studies could be applied. RESULTS: It was not possible to make a quantitative synthesis of most of the data, due to the heterogeneity of the studies concerning methods, treatment and outcome variables. Comparing the main groups of materials (ceramics, gold alloys and base metal alloys), no significant difference in the proportion of teeth without microleakage was found. Furthermore no significant difference in the proportion of teeth showing microleakage less than two third of the wall or teeth showing microleakage including the entire wall was found. Using the mean values in the meta-analysis instead of the proportions does not change the results. Confidence intervals could only be calculated for two materials (gold alloy, metal alloy). No difference between materials was found. SIGNIFICANCE: Comparison of the results from different studies is critical, since there are no generally accepted standards for experimental parameters, such as type and concentration of the storage solution, time of storage, temperature during storage, type and duration of thermal cycling and/or mechanical cycling, and the scoring criteria. There is lack of standardization of experimental conditions, which would ensure confidence in the studies and would further allow better comparability of various results. PMID- 21703674 TI - The European respiratory roadmap. PMID- 21703675 TI - Outpatient management of pulmonary embolism. PMID- 21703676 TI - Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. AB - BACKGROUND: Although practice guidelines recommend outpatient care for selected, haemodynamically stable patients with pulmonary embolism, most treatment is presently inpatient based. We aimed to assess non-inferiority of outpatient care compared with inpatient care. METHODS: We undertook an open-label, randomised non inferiority trial at 19 emergency departments in Switzerland, France, Belgium, and the USA. We randomly assigned patients with acute, symptomatic pulmonary embolism and a low risk of death (pulmonary embolism severity index risk classes I or II) with a computer-generated randomisation sequence (blocks of 2-4) in a 1:1 ratio to initial outpatient (ie, discharged from hospital <=24 h after randomisation) or inpatient treatment with subcutaneous enoxaparin (>=5 days) followed by oral anticoagulation (>=90 days). The primary outcome was symptomatic, recurrent venous thromboembolism within 90 days; safety outcomes included major bleeding within 14 or 90 days and mortality within 90 days. We used a non-inferiority margin of 4% for a difference between inpatient and outpatient groups. We included all enrolled patients in the primary analysis, excluding those lost to follow-up. This trial is registered with ClinicalTrials.gov, number NCT00425542. FINDINGS: Between February, 2007, and June, 2010, we enrolled 344 eligible patients. In the primary analysis, one (0.6%) of 171 outpatients developed recurrent venous thromboembolism within 90 days compared with none of 168 inpatients (95% upper confidence limit [UCL] 2.7%; p=0.011). Only one (0.6%) patient in each treatment group died within 90 days (95% UCL 2.1%; p=0.005), and two (1.2%) of 171 outpatients and no inpatients had major bleeding within 14 days (95% UCL 3.6%; p=0.031). By 90 days, three (1.8%) outpatients but no inpatients had developed major bleeding (95% UCL 4.5%; p=0.086). Mean length of stay was 0.5 days (SD 1.0) for outpatients and 3.9 days (SD 3.1) for inpatients. INTERPRETATION: In selected low-risk patients with pulmonary embolism, outpatient care can safely and effectively be used in place of inpatient care. FUNDING: Swiss National Science Foundation, Programme Hospitalier de Recherche Clinique, and the US National Heart, Lung, and Blood Institute. Sanofi-Aventis provided free drug supply in the participating European centres. PMID- 21703677 TI - Comparative study of digestion methods EPA 3050B (HNO3--H2O2--HCl) and ISO 11466.3 (aqua regia) for Cu, Ni and Pb contamination assessment in marine sediments. AB - Knowing the metal extraction capacity of a digestion method is crucial for a better environmental interpretation of metal concentrations determined in sediments. One of the main problems at the present is the lack of harmonization of information obtained by two of the most popular sediment partial digestion methods: ISO 11466.3 (aqua regia) and EPA 3050B (HNO3--H2O2--HCl). In the present work, the amount of Cu, Ni and Pb leached by using both methods was compared with the total content of those elements in marine sediments collected, as an example, from the Cienfuegos Bay, Cuba. Similar amounts of Cu were extracted by both methods; while leaching of Ni and Pb were different. Generally, the EPA method extracted more Ni than the ISO method. In contrast, Pb was extracted in a larger amount by the ISO method. Some explanations are given for the observed results. X ray Diffraction, X-ray Fluorescence, Particle Induced X-ray Emission Spectrometry and Energy Dispersive X-ray coupled to Scanning Electron Microscopy were employed for this purpose. On the other hand, none of the methods studied extracted simultaneously the fraction of all the metals, probably provided by human activity (Theoretical Anthropogenic Fraction) in both sediments studied. The use of ISO 11466.3 or EPA 3050B is recommended since the analytical performance parameters of both, in combination with Flame Atomic Absorption Spectrometry, are adequate. For a better environmental interpretation of the analytical results, information on the extraction efficiency of the selected method for specific elements and sediments under study should also be provided, together with the determined concentrations. PMID- 21703678 TI - Histopathology of mussels (Mytilus sp.) from the Tamar estuary, UK. AB - This study assessed numerous histological parameters as markers of health status in mussels (Mytilus spp.) collected from several locations along a contamination gradient on the River Tamar and two coastal sites on the north and south coast of Cornwall, UK. Twenty-seven health parameters were assessed including the presence of pathogens, inflammatory lesions, non-specific pathologies and reproductive condition. Logistic regression showed that reproductive condition and inflammatory lesions showed changes indicative of a contamination gradient response. Mussel populations further upstream within the Tamar were relatively less developed compared to mussels situated downstream in the estuary. Compared to coastal locations, mussels sampled within the Tamar also exhibited a higher prevalence of inflammatory lesions that increased at locations situated furthest upstream. Similarly, levels of lipofuscin within the kidney epithelium were highest in mussels sampled within the estuary and Whitsand Bay compared to Trebarwith Strand. The most prevalent pathogens observed during this survey included Rickettsia/Chlamydia-like organisms (R/CLO), gill ciliates including Ancistrum mytili, the copepod Mytilicola intestinalis, Ciliophora-like organisms and Marteilia sp. Marteilia sp. was observed in 31% of the mussels sampled from the Cremyll Ferry site. Generally, the range and prevalence of pathogens was highest from the two estuarine locations at Cremyll Ferry and Wilcove. No significant differences were observed between estuarine sampling sites and Whitsand Bay with respect to median epithelial cell height of digestive tubules, however mussels from Trebarwith Strand did exhibit a reduced median epithelial cell height compared to mussels sampled from other sampling sites. Species genotyping was also undertaken during this study in order to consider any histological differences in relation to species. Results are discussed in relation to histopathology health parameters and biological effects monitoring. PMID- 21703680 TI - Osteoblast and monocyte responses to 444 ferritic stainless steel intended for a magneto-mechanically actuated fibrous scaffold. AB - The rationale behind this work is to design an implant device, based on a ferromagnetic material, with the potential to deform in vivo promoting osseointegration through the growth of a healthy periprosthetic bone structure. One of the primary requirements for such a device is that the material should be non-inflammatory and non-cytotoxic. In the study described here, we assessed the short-term cellular response to 444 ferritic stainless steel; a steel, with a very low interstitial content and a small amount of strong carbide-forming elements to enhance intergranular corrosion resistance. Two different human cell types were used: (i) foetal osteoblasts and (ii) monocytes. Austenitic stainless steel 316L, currently utilised in many commercially available implant designs, and tissue culture plastic were used as the control surfaces. Cell viability, proliferation and alkaline phosphatase activity were measured. In addition, cells were stained with alizarin red and fluorescently-labelled phalloidin and examined using light, fluorescence and scanning electron microscopy. Results showed that the osteoblast cells exhibited a very similar degree of attachment, growth and osteogenic differentiation on all surfaces. Measurement of lactate dehydrogenase activity and tumour necrosis factor alpha protein released from human monocytes indicated that 444 stainless steel did not cause cytotoxic effects or any significant inflammatory response. Collectively, the results suggest that 444 ferritic stainless steel has the potential to be used in advanced bone implant designs. PMID- 21703679 TI - Activation of innate immune responses in a pathogen-mimicking manner by amphiphilic polyanhydride nanoparticle adjuvants. AB - Techniques in materials design, immunophenotyping, and informatics can be valuable tools for using a molecular based approach to design vaccine adjuvants capable of inducing protective immunity that mimics a natural infection but without the toxic side effects. This work describes the molecular design of amphiphilic polyanhydride nanoparticles that activate antigen presenting cells in a pathogen-mimicking manner. Biodegradable polyanhydrides are well suited as vaccine delivery vehicles due to their adjuvant-like ability to: 1) enhance the immune response, 2) preserve protein structure, and 3) control protein release. The results of these studies indicate that amphiphilic nanoparticles possess pathogen-mimicking properties as evidenced by their ability to activate dendritic cells similarly to LPS. Specific molecular descriptors responsible for this behavior were identified using informatics analyses, including the number of backbone oxygen moieties, percent of hydroxyl end groups, polymer hydrophobicity, and number of alkyl ethers. Additional findings from this work suggest that the molecular characteristics mediating APC activation are not limited to hydrophobicity but vary in complexity (e.g., presentation of oxygen-rich molecular patterns to cells) and elicit unique patterns of cellular activation. The approach outlined herein demonstrates the ability to rationally design pathogen-mimicking nanoparticle adjuvants for use in next-generation vaccines against emerging and re-emerging diseases. PMID- 21703681 TI - Selective immobilization of Sonic hedgehog on benzylguanine terminated patterned self-assembled monolayers. AB - Patterned two-component, self-assembled monolayers on gold were produced by UV lithography. An oligo(ethylene glycol) terminated disulfide served as inert matrix reducing unspecific protein adsorption and cell adhesion. The second component of the self-assembled monolayer (SAM) presented a benzylguanine moiety for the immobilization of Sonic hedgehog (Shh) fused to a mutant O(6) alkylguanine-DNA alkyltransferase (SNAP-tagTM). The enzymatic activity of the SNAP-tag allows selective and covalent immobilization of the linked Shh. Time-of flight secondary ion mass spectrometry verified the correct lateral distribution of the benzylguanine head groups in the patterned SAM. The quantification of unspecific and specific protein binding to mixed SAMs showed increased adsorption of albumin with increasing benzylguanine/(ethylene glycol) ratios. However, the immobilization of SNAP-tagged Shh was not blocked by pre-adsorbed albumin. Furthermore, the obtained micro-patterned substrates permitted direct immobilization of SNAP-tagged Shh even in the presence of many competing proteins from conditioned media of transfected HEK293 cells. Therefore, the presented system is suited for the controlled immobilization of fusion proteins from complex mixtures avoiding purification steps. PMID- 21703683 TI - A review of the promises and pitfalls of oocyte and embryo metabolomics. AB - Embryo viability assessment is one of the most important and challenging tasks in IVF. Evaluation of embryo quality is critical when selecting the best embryo(s) to transfer or cryopreserve. Until recently, the only instrument used for embryo evaluation was the inverted light microscope, which provided information based on morphological characteristics. Developmental and morphological information gained from microscopic assessment have been positively associated with IVF outcomes, including pregnancy and implantation rates. However, based on general statistics, it is clear that IVF currently still results in relatively low pregnancy rates, while simultaneously being associated with relatively high multiple implantation rates. Only with novel embryo assessment and selection procedures would it be possible to improve these outcomes. Accordingly, it has been proposed that it is possible to test the culture environment of a developing embryo to gain valuable information regarding its viability. Different approaches have been used. These include the measurement of oxygen consumption by the embryo and testing of the soluble HLA-G in the environment, as it was proposed that secretion of HLA-G is associated with higher implantation rates. Amino acid turnover, which appears to be correlated to blastocyst development, can be measured as an indication of embryo viability. Other approaches, such as time-lapse video observation or cumulus cell gene expression analysis, may be used in the future to gain a broader understanding of embryo viability. Proteomics and metabolomics are also useful tools for assessment of embryo developmental potential. Results from recent studies on predicting embryo viability by analyzing the metabolome of different stage embryos are promising, as increases in pregnancy and implantation rates were obtained using the metabolomic profile for embryo selection. Several novel approaches are currently being developed to aid in viability assessment. These need to be evaluated in prospective clinical trials, while considering their practicality in the clinical laboratory. PMID- 21703682 TI - The role of engineered tendon matrix in the stemness of tendon stem cells in vitro and the promotion of tendon-like tissue formation in vivo. AB - When injured, tendons tend to heal but with poor structure and compromised function. Tissue engineering is a promising approach to enhancing the quality of healing tendons. Our group and others have identified tendon stem cells (TSCs), a type of tendon-specific stem cells which may be optimal for cellular interventions seeking to restore normal structure and function to injured tendons. However, in vitro expanding of TSCs on regular plastic cell culture dishes only yields a limited number of TSCs before they lose the stemness, i.e., the self-renewal capability and multipotency. In this study, we developed a substrate material for TSCs, engineered tendon matrix (ETM) from decellularized tendon tissues. We showed that ETM in vitro was able to stimulate TSC proliferation and better preserve the stemness of TSCs than plastic culture surfaces. In vivo, implantation of ETM-TSC composite promoted tendon-like tissue formation whereas implantation of TSCs alone led to little such tissue formation. Together, the findings of this study indicate that ETM may be used to effectively expand TSCs in vitro and with TSCs, to enhance repair of injured tendons in vivo. PMID- 21703684 TI - Stimulation of serotonergic 5-HT2A receptor signaling increases placental aromatase (CYP19) activity and expression in BeWo and JEG-3 human choriocarcinoma cells. AB - It is known that serotonin can influence the production and function of sex hormones, such as estrogens. Estrogens are critical for maintenance of pregnancy and regulate placental and fetal development. The key enzyme controlling estrogens synthesis during pregnancy is placental aromatase (CYP19). To better understand the regulation of placental aromatase, this study determined whether serotonin is involved in the regulation of this enzyme. BeWo and JEG-3 choriocarcinoma cells were used as models of the human placental trophoblast to evaluate the effects of serotonin and selective 5-HT(2A) receptor agonists on CYP19 activity and expression. Serotonin and selective 5-HT(2A) receptor agonists as well as PKC activation increased aromatase activity and expression in BeWo and JEG-3 cells. Dexamethasone, which regulates aromatase expression via JAK/STAT activation in certain tissues, had no effect. Increased CYP19 gene transcription by 5-HT(2A) receptor and PKC stimulation was mediated by activation of the placental I.1 aromatase promoter. This study shows that the serotonergic system modulates placental aromatase expression, which would result in altered estrogens biosynthesis in trophoblast cells. Future detailed studies of serotonin-estrogen interactions in placenta are crucial for an improved understanding of the endo-, para- and autocrine role of serotonin during pregnancy and fetal development. PMID- 21703685 TI - The significance of isolated Y chromosome loss in bone marrow metaphase cells from males over age 50 years. AB - To further investigate the potential clinical significance of Y chromosome loss as the sole bone marrow karyotype change, we studied 161 Mayo Clinic male patients with 75% or more metaphase cells with Y loss, and correlated the percent Y loss with age and hematopathologic review. In patients with a lymphoproliferative or plasma cell disorder, the negligible proportion of bone marrow involvement cannot account for the observed high proportion of -Y cells. In males with myeloid disease, Y loss appears to often represent the abnormal myeloid clone, which may also harbor acquired genetic changes that are not observed by conventional cytogenetic analysis. PMID- 21703686 TI - Impact of drug label changes on propofol use in pediatrics for moderate conscious sedation. AB - BACKGROUND: Drug product labeling is a critical component of communication regarding the appropriate use of medications. The information contained in a drug label is often complex, including contraindications and warnings that may be difficult to understand. In an attempt to further examine this issue, this article looks at one such difficult-to-understand label concerning anesthetic propofol and its use in the pediatric population. OBJECTIVE: The objective of this study was to describe the use of propofol for moderate conscious sedation (MCS) in pediatric patients (0-17 years) after drug warnings were disseminated. METHODS: This study was a retrospective, observational study from January 2001 to December 2007 that used data from the Premier Perspective Comparative Hospital database. This database includes approximately 425 hospitals with a broad range of hospital types and contains a weighting scheme that allows for the generation of national estimates in the United States. The main outcome measure was use of propofol during hospitalization. RESULTS: The study included 307,779 discharges in which MCS was used. Both the number of discharges for MCS and the percent of discharges using propofol increased from 2001 to 2007. After multivariable adjustment, there was more than a 3-fold increase in the odds of receiving propofol between 2001 and 2007 (odds ratio [OR] = 3.32; 95% CI, 2.96-3.72) for MCS. CONCLUSIONS: The results of this study suggest that the label changes and a "Dear Doctor" letter did not affect propofol utilization. A more cohesive approach to the assessment of safety and the dissemination of label change information to practitioners is needed. PMID- 21703687 TI - Pharyngitis guidelines. PMID- 21703689 TI - The 'art' and 'science' of handcrafting cheese in the United States. AB - Drawing on ethnographic research conducted in the United States, this article demonstrates how American cheesemakers articulate the work of handcrafting cheese as a balance of 'art' and 'science', where art refers to aesthetic creativity and an intuitive ability to interpret observable conditions as a guide for contingent practice, while science refers to the accurate measuring of those conditions as well as meticulous record-keeping and hygiene. Artisanship thus entails a blend of subjective and objective practice and accounting, characterized here as the application of synaesthetic reason. Mutually defining, art and science in the crafting of cheese are far from mutually exclusive. And both are embedded in larger cultural contexts. Artisanship must also acknowledge market-based tastes and cultural understandings of acceptable form. PMID- 21703688 TI - Impact of cigarette smoking on volatile organic compound (VOC) blood levels in the U.S. population: NHANES 2003-2004. AB - The impact of cigarette smoking on volatile organic compound (VOC) blood levels is studied using 2003-2004 National Health and Nutrition Examination Survey (NHANES) data. Cigarette smoke exposure is shown to be a predominant source of benzene, toluene, ethylbenzene, xylenes and styrene (BTEXS) measured in blood as determined by (1) differences in central tendency and interquartile VOC blood levels between daily smokers [>=1 cigarette per day (CPD)] and less-than-daily smokers, (2) correlation among BTEXS and the 2,5-dimethylfuran (2,5-DMF) smoking biomarker in the blood of daily smokers, and (3) regression modeling of BTEXS blood levels versus categorized CPD. Smoking status was determined by 2,5-DMF blood level using a cutpoint of 0.014 ng/ml estimated by regression modeling of the weighted data and confirmed with receiver operator curve (ROC) analysis. The BTEXS blood levels among daily smokers were moderately-to-strongly correlated with 2,5-DMF blood levels (correlation coefficient, r, ranging from 0.46 to 0.92). Linear regression of the geometric mean BTEXS blood levels versus categorized CPD showed clear dose-response relationship (correlation of determination, R(2), ranging from 0.81 to 0.98). Furthermore, the pattern of VOCs in blood of smokers is similar to that reported in mainstream cigarette smoke. These results show that cigarette smoking is a primary source of benzene, toluene and styrene and an important source of ethylbenzene and xylene exposure for the U.S. population, as well as the necessity of determining smoking status and factors affecting dose (e.g., CPD, time since last cigarette) in assessments involving BTEXS exposure. PMID- 21703690 TI - Shrinkage of the scleral canal during cupping reversal in children. AB - PURPOSE: The mechanism of cupping reversal seen after lowering intraocular pressure (IOP) in pediatric glaucoma is unknown. Theories include forward movement of the lamina cribrosa or shrinkage of a stretched scleral canal. Our study aimed to quantify changes in optic disc size occurring in children who had undergone glaucoma surgery. DESIGN: Retrospective, single-center, observational case series. PARTICIPANTS: Children undergoing incisional surgery for pediatric glaucoma at the University of California, Davis. METHODS: The electronic charts of all patients with pediatric glaucoma were reviewed for the presence of RetCam digital optic nerve photographs (Clarity Medical Systems, Pleasanton, CA). Cases in which the photographs (baseline and follow-up after surgical intervention) were of sufficient quality were analyzed. The optic disc margin was outlined manually using ImageJ software. Inter-session changes in magnification were accounted for by drawing a control polygon joining 4 or 5 fixed landmarks (e.g., vessel crossings) to include a second larger area containing the optic nerve. The optic disc area (in pixels adjusted with the control polygon) was compared between baseline and follow-up images. MAIN OUTCOME MEASURES: Change in disc area between baseline and follow-up after surgery. RESULTS: We identified 29 eyes for which baseline and follow-up images were available for analysis. Fifteen eyes of 9 children showed clinically obvious cupping reversal. Fourteen eyes of 12 children showed no cupping reversal. Disc area decreased by 6.8% (95% confidence interval [CI], -10.0 to -3.3) in the obvious reversal group and increased by 4.3% (95% CI, +1.0 to +7.6) in the no reversal group after surgery (P < 0.0001; Student t test). Percent change in disc area is correlated to percent change in IOP (r=0.540; P=0.0025) and axial length (r=0.534; P=0.0028). CONCLUSIONS: When cupping reversal is clinically apparent after successful IOP-lowering surgery for congenital glaucoma, the scleral canal shrinks in area. In contrast, when cupping reversal is not observed, the scleral ring continues to enlarge, indicating ongoing stress on the optic nerve. Clinically obvious cupping reversal is less frequently observed in adults after surgery, which may reflect a lower elasticity of the scleral ring in adults compared with children. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21703691 TI - Analysis of normal peripapillary choroidal thickness via spectral domain optical coherence tomography. AB - PURPOSE: To analyze the normal peripapillary choroidal thickness utilizing a commercial spectral domain optical coherence tomography (OCT) device and determine the intergrader reproducibility of this method. DESIGN: Retrospective, noncomparative, noninterventional case series. PARTICIPANTS: Thirty-six eyes of 36 normal patients seen at the New England Eye Center between April and September 2010. METHODS: All patients underwent high-definition scanning with the Cirrus HD OCT. Two raster scans were obtained per eye, a horizontal and a vertical scan, both of which were centered at the optic nerve. Two independent graders individually measured the choroidal thickness. Choroidal thickness was measured from the posterior edge of the retinal pigment epithelium to the choroid-scleral junction at 500-MUm intervals away from the optic nerve in the superior, inferior, nasal, and temporal quadrants. Statistical analysis was conducted to compare mean choroidal thicknesses. Intergrader reproducibility was assessed by intraclass correlation coefficient and Pearson's correlation coefficient. Average choroidal thickness in each quadrant was compared with retinal nerve fiber layer (RNFL) thickness in their respective quadrants. MAIN OUTCOME MEASURES: Peripapillary choroidal thickness, intraclass coefficient, and Pearson's correlation coefficient. RESULTS: The peripapillary choroid in the inferior quadrant was significantly thinner compared with all other quadrants (P<0.001). None of the other quadrants were significantly different from each other in terms of thickness. The inferior peripapillary choroid was significantly thinner compared with all other quadrants at all distances measured away from the optic nerve (P<0.001). Generally, the peripapillary choroid increases in thickness the farther it was away from the optic nerve and eventually approaching a plateau. The intraclass correlation coefficient ranged from 0.62 to 0.93 and Pearson's correlation coefficient ranged from 0.74 to 0.95 (P<0.001). Neither RNFL thickness nor average age was significantly correlated with average choroidal thickness. CONCLUSIONS: Manual segmentation of the peripapillary choroidal thickness is reproducible between graders, suggesting that this method is accurate. The inferior peripapillary choroid was significantly thinner than all other quadrants (P<0.001). FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21703692 TI - Correlates of perceptual distortions in clinical and non-clinical populations using the Cardiff Anomalous Perceptions Scale (CAPS): associations with anxiety and depression and a re-validation using a representative population sample. AB - Although the literature on hallucinations in psychiatric patients shows clear links with anxiety and depression, associations of affect with a wider array of anomalous perceptual experiences have been much less studied. This study investigated patients with psychosis (N=29) and a non-clinical population (N=193) using the Cardiff Anomalous Perceptions Scale (CAPS), a measure of perceptual distortion and associated distress, intrusiveness and frequency; along with measures of depression, anxiety and worry. The study also allowed a re-validation of the CAPS in a more representative sample of the UK population. Moderate, reliable correlations with depression, anxiety and worry were found in the non clinical population with the association being stronger in psychotic patients. The study re-confirmed that anomalous perceptual experiences are common in the general population and that a significant minority (11.9%) have higher levels than the mean of psychotic patients. Scale reliability and validity were also re confirmed, and the CAPS score was found to be unrelated to age or gender in either sample. As in the original study, factor analysis produced a three-factor solution, although factor theme was not fully replicated: as before, a cluster of first-rank symptoms emerged, but with equivocal evidence for a temporal lobe factor and no replication of a 'chemosensation' component. PMID- 21703693 TI - Multiplex PCR and Genescan analysis to detect immunoglobulin heavy chain gene rearrangement in feline B-cell neoplasms. AB - Lymphoid neoplasms are usually diagnosed on the basis of cytological and histopathological findings. However, in some cases, discrimination of lymphoid neoplasms from reactive lymphoid proliferation is difficult. PCR amplification of complementarity-determining region 3 (CDR3) of the immunoglobulin heavy-chain variable region (IGHV) gene can be used to assess clonality of B-cell populations as a supportive diagnostic tool for B-cell neoplasms. Because of the sequence variation and possible somatic hypermutation of the IGHV gene, sensitivity of the PCR-based assay to detect clonal IGHV gene rearrangement largely depends on the sequences and numbers of primer sets. Prior to the development of an efficient assay, we cloned and sequenced 97 IGHV complementary DNAs (48 IGHV-1 and 49 IGHV 3 clones) from normal cat spleens. On the basis of these sequences, we designed 6 forward primers at the variable region and 5 reverse primers at the joining region. Using each of 6 forward primers and a mixture of 5 reverse primers, we amplified CDR3 of IGHV genes and analyzed the PCR products by conventional PAGE and Genescan analyses using fluorescence-labeled primers. Twenty-six feline B cell neoplasms diagnosed by histopathological and immunohistochemical examinations were subjected to the newly developed analysis of IGHV gene rearrangement. Clonal IGHV gene rearrangement was detected in 22 of 26 (84%) samples by both PAGE and Genescan analyses. To reduce the number of PCR reactions, we constructed a multiplex PCR analysis system using a mixture of IGHV 1- and IGHV-3-specific primers as forward primers and a mixture of 5 joining region reverse primers. Results of the multiplex PCR were 100% concordant with those obtained by each of the singleplex PCRs. The multiplex PCR-based assay and Genescan analysis developed in the present study would be useful and practical tools to detect clonal IGHV gene rearrangement in feline B-cell neoplasms. PMID- 21703694 TI - Exploring factors that affect the age of cochlear implantation in children. AB - OBJECTIVE: Early access to sound through early cochlear implantation has been widely advocated for children who do not derive sufficient benefit from acoustic amplification. Early identification through newborn hearing screening should lead to earlier intervention including earlier cochlear implantation when appropriate. Despite earlier diagnosis and the trend towards early implantation, many children are still implanted well into their preschool years. The purpose of this study was to examine the factors that affected late cochlear implantation in children with early onset permanent sensorineural hearing loss. METHODS: Data were examined for 43 children with cochlear implants who were part of a group of 71 children with hearing loss enrolled in a Canadian outcomes study. Eighteen (41.9%) of the 43 children were identified through newborn screening and 25 (58.1%) through medical referral to audiology. Medical chart data were examined to determine age of hearing loss diagnosis, age at cochlear implant candidacy, and age at cochlear implantation. Detailed reviews were conducted to identify the factors that resulted in implantation more than 12 months after hearing loss confirmation. RESULTS: The median age of diagnosis of hearing loss for all 43 children was 9.0 (IQR: 5.1, 15.8) months and a median of 9.1 (IQR: 5.6, 26.8) months elapsed between diagnosis and unilateral cochlear implantation. The median age at identification for the screened groups was 3.3 months (IQR: 1.4, 7.1) but age at implantation (median 15.8 months: IQR: 5.6, 37.1) was highly variable. Eighteen of 43 children (41.9%) received a cochlear implant more than 12 months after initial hearing loss diagnosis. For many children, diagnosis of hearing loss was not equivalent to the determination of cochlear implant candidacy. Detailed reviews of audiologic profiles and study data indicated that late implantation could be accounted for primarily by progressive hearing loss (11 children), complex medical conditions (4 children) and other miscellaneous factors (3 children). CONCLUSIONS: This study suggests that a substantial number of children will continue to receive cochlear implants well beyond their first birthday primarily due to progressive hearing loss. In addition, other medical conditions may contribute to delayed decisions in pediatric cochlear implantation. PMID- 21703695 TI - Rescue extracorporeal life support as a bridge to reflection in fulminant stress induced cardiomyopathy. PMID- 21703696 TI - Epicardial fat thickness correlates with ApoB/ApoA1 ratio, coronary calcium and carotid intima media thickness in asymptomatic subjects. PMID- 21703697 TI - Coronary artery spasm progressing to acute myocardial infarction in patients with systemic inflammatory disease: a potential association with Kounis syndrome. PMID- 21703698 TI - Furosemide in chronic advanced heart failure: intimate friend or cunning foe? PMID- 21703699 TI - Pulmonary hypertension in left heart disease: a review. AB - Pulmonary hypertension (PH) occurs commonly in patients with left heart disease, and is associated with increased morbidity and mortality. The pathophysiologic mechanisms of PH in left heart disease are complex, and are thought to be a composite of both passive and active components. PH that is disproportionate to the underlying left heart disease may be attributable to reactive pulmonary vascular remodelling. Management of these patients is focused upon treatment of the underlying left heart disease and its associated comorbidities. There is no supporting evidence for the routine use of specific PH therapies in these patients at present. However, there is some suggestion that PDE-5 inhibitors may be useful, but their safety and efficacy needs to be formally evaluated in controlled trials before further recommendations are made. PMID- 21703700 TI - A guide for identification and continuing care of adult congenital heart disease patients in primary care. AB - BACKGROUND: Surgical and other advances in the treatment and care of congenital heart disease have resulted in a significant increase in the number of adults with congenital heart disease (ACHD), many of whom have no regular cardiology follow-up. Optimised care for ACHD patients requires continuity of specialist and shared care and education of practitioners and patients. The challenges for managing ACHD were identified by a Health Needs Assessment in the North West and are addressed within the UK Department of Health's ACHD Commissioning Guide. MATERIALS AND METHODS: An ACHD model of care was recommended in the North West of England and developed by the three North West Cardiac & Stroke Networks. Within this, a Task Group focused on the role of primary care in the identification and continuing care of ACHD patients. A feasibility study demonstrated that existing diagnostic Read Codes can identify ACHD patients on general practice registers. An ACHD Toolkit was developed to provide algorithms to guide the appropriate management of ACHD patients through primary, secondary and/or specialist ACHD care and to improve education/knowledge amongst primary care staff about ACHD and its wider implications. RESULTS: Early findings during the development of this Toolkit illustrate a wide disparity of provision between current and optimal management strategies. Patients lost to follow-up have already been identified and their management modified. CONCLUSIONS: By focusing on identifying ACHD patients in primary care and organising/delivering ACHD services, the ACHD Toolkit could help to improve quality, timeliness of care, patient experience and wellbeing. PMID- 21703701 TI - One-year clinical outcome of patients treated with or without abciximab in rescue coronary angioplasty. AB - BACKGROUND: The clinical results of abciximab administration during rescue angioplasty (PCI) are poorly investigated. METHODS: We evaluated the outcome of 406 consecutive patients undergoing rescue PCI treated with (n=218) or without (n=188) abciximab and a clopidogrel loading dose of 300 mg. The end point was the incidence of major cardiac adverse events (MACE) defined as death, recurrent acute myocardial infarction (AMI) and target vessel revascularization at 30 days and 1 year. The predictors of MACE were also investigated. RESULTS: No differences were found in MACE between the groups treated with or without abciximab at 30 days (15 and 20, p=0.67) and 1 year (23 and 29, p=0.85). Stepwise logistic regression analysis identified: cardiogenic shock (Odds Ratio [OR]=17.8, 95% confidence interval [CI] 5-99, p=0.0001), age (OR=1.099, 95% CI 1.04-1.15, p=0.0001), TIMI flow 0-1 after procedure (OR=5.51, 95% CI 1.72-17.6, p=0.004) as independent predictors of MACE at 30 days. Cox proportional hazards model identified: cardiogenic shock (adjusted hazard ratio [HR]=3.83, 95% confidence interval [CI] 1.76-8.35, p=0.01), age (HR=3.7, 95% CI 1.75-8.3, p=0.01), TIMI flow 0-1 after procedure (HR=1.04, 95% CI 1.01-1.07, p=0.001 as predictors of MACE at 1 year). After propensity score adjustments the predictors of MACE did not change. CONCLUSION: There were no differences in MACE at 30 days and 1 year in patients treated with or without abciximab during rescue PCI after a clopidogrel loading dose of 300 mg. Cardiogenic shock, age and TIMI flow 0 and 1 after PCI were predictors of MACE. PMID- 21703702 TI - Letter to editor: clinical profile and predictors of in-hospital outcome in patients with heart failure. PMID- 21703703 TI - Outcomes of furosemide-mannitol infusion in hospitalized patients with heart failure: an observational single-center cohort study of 122 patients. PMID- 21703704 TI - Inflammatory rebound phenomenon after abrupt withdrawal of statin is a mature point of view but not hypotheses. PMID- 21703705 TI - Intravenous amiodarone facilitates electrical cardioversion in patients with persistent atrial fibrillation pre-treated with oral amiodarone. PMID- 21703706 TI - Aortic root size and sleep apnea in elderly: a cohort study. PMID- 21703707 TI - The human heart: application of the golden ratio and angle. AB - The golden ratio, or golden mean, of 1.618 is a proportion known since antiquity to be the most aesthetically pleasing and has been used repeatedly in art and architecture. Both the golden ratio and the allied golden angle of 137.5 degrees have been found within the proportions and angles of the human body and plants. In the human heart we found many applications of the golden ratio and angle, in addition to those previously described. In healthy hearts, vertical and transverse dimensions accord with the golden ratio, irrespective of different absolute dimensions due to ethnicity. In mild heart failure, the ratio of 1.618 was maintained but in end-stage heart failure the ratio significantly reduced. Similarly, in healthy ventricles mitral annulus dimensions accorded with the golden ratio, while in dilated cardiomyopathy and mitral regurgitation patients the ratio had significantly reduced. In healthy patients, both the angles between the mid-luminal axes of the pulmonary trunk and the ascending aorta continuation and between the outflow tract axis and continuation of the inflow tract axis of the right ventricle approximate to the golden angle, although in severe pulmonary hypertension, the angle is significantly increased. Hence the overall cardiac and ventricular dimensions in a normal heart are consistent with the golden ratio and angle, representing optimum pump structure and function efficiency, whereas there is significant deviation in the disease state. These findings could have anatomical, functional and prognostic value as markers of early deviation from normality. PMID- 21703708 TI - Repeated sudden cardiac death in coronary spasm: is IVUS helpful to decide treatment strategy? PMID- 21703709 TI - Letter by Schoormans et al. regarding article, "recommendations for improving the quality of interdisciplinary care of grown-up with congenital heart disease (GUCH)". PMID- 21703710 TI - Schooling and smoking among the baby boomers - an evaluation of the impact of educational expansion in France. AB - Post-war expansion of education in France transformed the distribution of schooling for the cohorts born between the 1940s and the 1970s. However, throughout this expansion the proportion with the highest levels of qualifications remained stable, providing a natural control group. We evaluate the impact of schooling on smoking, for the beneficiaries of the post-war expansion, by comparing changes in their outcomes across birth cohorts with changes within the control group. We uncover robust evidence that educational expansion contributed to a decline in smoking prevalence of 2.9 points of percentage for men and 3.2 points for women at the turn of the 21st century. Our results also suggest that the persistence of the schooling-smoking gradient is better explained by differences in the education-related opportunity costs of smoking than by differences in information about smoking dangers. PMID- 21703711 TI - The Cancer of the Prostate Risk Assessment (CAPRA) in patients treated with external beam radiation therapy: evaluation and optimization in patients at higher risk of relapse. AB - BACKGROUND: The Cancer of the Prostate Risk Assessment (CAPRA) was developed to predict freedom from biochemical failure (FFBF) following radical prostatectomy (RP). Its utility following external beam radiation therapy (EBRT) has not been externally evaluated. METHODS: A retrospective study of 612 patients treated with dose-escalated EBRT at the University of Michigan Medical Center. RESULTS: Compared to the derivation cohort, EBRT treated patients had higher-risk disease (28% with CAPRA of 6-10 vs. 5%, respectively). A total of 114 patients (19%) had BF with 5-year BF ranging from 7% with CAPRA 0-3 to 35% with CAPRA 7-10. For RT patients the risk of BF at 5-year was similar to 4 surgical cohorts for CAPRA scores 0-2 but lower for all CAPRA scores >= 3. The difference favoring RT increased with increasing CAPRA score reaching a 27-50% absolute improved at 5 years for CAPRA scores of 6-10. On multivariate analysis each CAPRA point increased the risk of BF (p<0.0001) while Gleason pattern 5 in the biopsy also increased BF (p=0.01) and long-term androgen deprivation therapy (ADT) significantly reduced the risk of BF (p=0.015). CONCLUSIONS: Compared to surgical series the risk of BF was lower with dose-escalated EBRT with the greatest difference at the highest CAPRA scores. PMID- 21703712 TI - Choice of primary care provider: results from a population survey in three Swedish counties. AB - Recent reforms in Swedish primary care have involved choice of provider for the population combined with freedom of establishment and privatisation of providers. This study focus to what extent individuals feel they have exercised a choice of provider, why they exercise choice and where they search for information, based on a population survey in three Swedish counties. The design of the study enabled for studying behaviour with respect to differences in time since introduction of the reform and differences in number of alternative providers and establishments of new providers in connection with the reform. About 60% of the population in the three counties felt that they had made a choice of provider in connection with or after the introduction of a reform focusing on choice and privatisation. Establishments of new providers and having enough information increased the likelihood whereas preferences for direct access to a specialist decreased the likelihood of making a choice. The data further suggests that individuals were rather passive in their search for information and tended to choose providers that they previously had been in contact with. This is in line with results from previous studies and poses challenges for county councils governance of reforms. PMID- 21703713 TI - An associative memory approach to medical decision support systems. AB - Classification is one of the key issues in medical diagnosis. In this paper, a novel approach to perform pattern classification tasks is presented. This model is called Associative Memory based Classifier (AMBC). Throughout the experimental phase, the proposed algorithm is applied to help diagnose diseases; particularly, it is applied in the diagnosis of seven different problems in the medical field. The performance of the proposed model is validated by comparing classification accuracy of AMBC against the performance achieved by other twenty well known algorithms. Experimental results have shown that AMBC achieved the best performance in three of the seven pattern classification problems in the medical field. Similarly, it should be noted that our proposal achieved the best classification accuracy averaged over all datasets. PMID- 21703714 TI - Does conservation on farmland contribute to halting the biodiversity decline? AB - Biodiversity continues to decline, despite the implementation of international conservation conventions and measures. To counteract biodiversity loss, it is pivotal to know how conservation actions affect biodiversity trends. Focussing on European farmland species, we review what is known about the impact of conservation initiatives on biodiversity. We argue that the effects of conservation are a function of conservation-induced ecological contrast, agricultural land-use intensity and landscape context. We find that, to date, only a few studies have linked local conservation effects to national biodiversity trends. It is therefore unknown how the extensive European agri environmental budget for conservation on farmland contributes to the policy objectives to halt biodiversity decline. Based on this review, we identify new research directions addressing this important knowledge gap. PMID- 21703715 TI - Neotropical biodiversity: timing and potential drivers. AB - The origin of extant neotropical biodiversity has been a controversial topic since the time of Darwin. In this review, I discuss the timing of, and potential driving factors associated with, diversification using recent evidence from molecular phylogenetics. Although these studies provide new insights into the subject, they are sensitive to dating approaches and targets, and can eventually lead to biased conclusions. A careful analysis suggests that the origin of extant neotropical biodiversity cannot be attributed to the action of one or few events during key time intervals. Rather, it is the result of complex ecological and evolutionary trends initiated by Neogene tectonic events and palaeogeographical reorganisations, and maintained by the action of Pleistocene climatic changes. PMID- 21703716 TI - Cutaneous findings in sporadic and familial autosomal dominant hyper-IgE syndrome: a retrospective, single-center study of 21 patients diagnosed using molecular analysis. AB - BACKGROUND: Recent identification of STAT3 mutations in autosomal dominant (AD) hyper-IgE syndrome (HIES) has improved the clinical, genetic, and molecular classification of the HIES. OBJECTIVE: We sought to characterize the cutaneous signs observed in molecularly diagnosed AD-HIES. METHODS: We conducted a retrospective study of 21 patients with AD-HIES and confirmed STAT3 mutations, treated at Necker-Enfants Malades Hospital, Paris, France. RESULTS: A papulopustular rash on the face and scalp before the age of 2 months was observed in 67% of patients. This "early rash" was distinguished from other neonatal pustular eruptions by crusted papules and pustules, rash intensity, and a continuum with chronic dermatitis. An eczematous dermatitis was almost always present before the age of 18 months (95% of patients) and was mainly confined to the face, scalp, chest, and buttocks. All patients presented with infected dermatitis (Staphylococcus aureus) and 59% had chronic candidiasis of the oral mucosa and nails. Cutaneous herpes virus infections were not unusually severe. Coarse facial skin at puberty, and sometimes at a younger age, with prominent follicular ostia resembling atrophoderma vermiculatum was not related to severe acne or facial abscesses. LIMITATIONS: This was a retrospective study with a small number of patients. CONCLUSION: When associated with serum IgE levels 10 times the age-appropriate level, a neonatal papulopustular rash progressing to a chronic impetiginized eczematous dermatitis that differs from classic atopic dermatitis is highly suggestive of AD-HIES. Early recognition is important for initiation of prophylactic antistaphylococcal and antifungal treatment. PMID- 21703717 TI - Personal protective equipment use and allocation in home health during disasters. AB - BACKGROUND: Home health preparedness for disasters is imperative, including the need to identify essential resources to protect home health professionals from exposure during an event. Access to personal protective equipment (PPE) is expected to be limited during a disaster, and PPE distribution and allocation needs to be prearranged to minimize infection transmission risk. This article outlines the appropriate use and allocation of PPE for home health agencies as part of disaster planning. METHODS: A literature review and Internet search were conducted in July-August 2010. A spreadsheet was created delineating the best practices related to PPE use and allocation identified by each source. Recommendations were divided into themes/domains for simplification and clarity. RESULTS: A total of 46 articles, planning documents/reports, and Web-based training programs were identified and screened. Of these, 28 were deemed relevant, including 12 journal articles and 16 published reports, book chapters, planning documents, or training programs. Themes for PPE use and allocation in home health during disasters in the literature included identifying the types of PPE used in home health, determining PPE needs, storing PPE, allocating PPE when resources are limited or depleted, disposing of PPEl, and educating staff. CONCLUSION: Having access to the correct types and quantities of PPE during a disaster will be essential to home health agencies. The information presented in this article can assist home health agencies in developing emergency management plans that address planning issues related to PPE. PMID- 21703718 TI - [Analysis of maternal morbidity and mortality among patients admitted to Obstetric Intensive Care with severe preeclampsia, eclampsia or HELLP syndrome]. AB - OBJECTIVE: To describe the incidence and clinical and epidemiological profile of patients with severe preeclampsia admitted to Intensive Care. DESIGN: A prospective, observational case series. SETTING: A specific obstetric 8-bed ICU belonging to a university hospital with a total of 55 ICU beds. PATIENTS: A total of 262 patients admitted due to severe preeclampsia, eclampsia or HELLP syndrome. INTERVENTION: Descriptive analysis of the population and complications in the ICU and hospital mortality. RESULTS: The mean patient age was 30.47+/-5.7 years, with the following diagnostico at admission: A total of 78% of the patients with severe preeclampsia, 16% with HELLP syndrome, and 6% with eclampsia, occurring in gestational week 31.85+/-4.45. In turn, 63% of the patients were nulliparous and had a low prevalence of previous diseases. The global complications rate was 14% (9% heart failure, 5% acute renal failure and 2% coagulopathy). Maternal mortality was 1.5% (4 patients), and was associated with non-nulliparous status, the presence of complications, and toast > 71mg/dl. CONCLUSIONS: Severe preeclampsia has a low mortality rate (1.5%), though the complications rate is considerable (14%). The condition develops more often in nulliparous women during the third trimester of pregnancy. PMID- 21703719 TI - [Increasing the number of valid lungs for transplantation: a necessity]. PMID- 21703720 TI - [Acute appendicitis after colonoscopy: coincidence or cause?]. PMID- 21703721 TI - [Esophageal perforation following a biopsy in a patient with eosinophilic esophagitis]. AB - Eosinophilic esophagitis is an underdiagnosed disease that should be suspected in all patients with dysphagia and food impaction. Although these are the leading symptoms, the clinical and endoscopic spectrum is highly varied. Clinicians should be aware of the risk of endoscopy-related complications in this disorder. Precautions should be maximized in endoscopic examinations to avoid iatrogenic damage. We describe the case of a young patient with esophageal stricture and dysphagia who suffered a perforation following a biopsy. PMID- 21703722 TI - [Esophageal perforation after ingestion of a blister-wrapped tablet]. PMID- 21703723 TI - [Cost of screening for hepatocarcinoma in patients with cirrhosis: a prospective study]. AB - INTRODUCTION: Current clinical guidelines recommend biannual screening for hepatocarcinoma in cirrhotic patients; however, the cost of this preventive activity is unknown. OBJECTIVE: To determine the cost of ultrasound screening for hepatocarcinoma in patients with cirrhosis. PATIENTS AND METHOD: Data on patients diagnosed with liver cirrhosis in a population of 245,042 inhabitants were prospectively gathered. The screening tests performed and cases of hepatocarcinoma diagnosed during the annual follow-up were included in the analysis. The cost of these tests was calculated based on the tariffs paid by insurance companies for health coverage of civil servants. RESULTS: In 2009, there were 374 patients with cirrhosis; of these, 99 were aged > 80 years, with a performance status of >2 or associated comorbidities. During the annual follow up, the remaining patients underwent a total of 602 visits (abdominal ultrasound, blood test), four contrast-enhanced computed tomography scans, nine magnetic resonance scans, two scintigraphies, four aspiration biopsies, four radiographs and six contrast ultrasound scans. In our environment, the total estimated cost of these procedures was 37,946 ?, indicating that the cost of a screening program for hepatocellular carcinoma according to the above-mentioned selection criteria is 0.155 ? per inhabitant/year. If only cirrhotic patients suitable for screening are included, the annual cost of screening is 138 ? per patient. CONCLUSION: The cost of an ultrasound screening program for hepatocarcinoma is 0.155 ? per inhabitant/year. These data should be taken into account when considering population-based screening programs. PMID- 21703724 TI - [Effects of vibrotherapy on postural control, functionality and fatigue in multiple sclerosis patients. A randomised clinical trial]. AB - INTRODUCTION: Postural and balance disorders, functionality impairment and fatigue, are the most incapacitating problems in multiple sclerosis (MS) patients. Whole Body Vibration (WBV), through the transmission of mechanical stimuli, appears to be a useful therapeutic tool in the treatment of neurological diseases. The objective of this study is to assess the effect of the WBV on postural control, balance, functionality and fatigue in patients with MS. MATERIAL AND METHODS: A total of 34 patients with mild-moderate MS were randomised into a control group and an intervention group. For the intervention group, the protocol consisted of 5 consecutive days, daily series of 5 periods of 1 minute of duration of WBV at a frequency of 6 Hz. Posturographic assessment using the Sensory Organization Test (SOT) and Motor Control Test (MCT), the Timed Get Up and Go Test, 10 metres Test, the Berg Balance Scale and Krupp's Fatigue Severity Scale were used before and after intervention. RESULTS: The analysis showed improvements in the intervention group for conditions SOT 1, SOT 3 and latency in MCT. In the comparison between groups, only the latency or reaction time in MCT improved significantly in favour of the intervention group (from 173.78+/-12.46 to 161.25+/-13.64 ms; P=.04). No side-effects were found. CONCLUSIONS: The results of this pilot study show that WBV can improve, in the short-term, the time of response to recover the uprightness after sudden disturbances, appearing as a possible therapeutic tool maintaining balance and posture. PMID- 21703725 TI - [Guidelines for molecular diagnosis of Charcot-Marie-Tooth disease]. AB - INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is the most frequent form of inherited neuropathy. In accordance with the inheritance pattern and degree of slowing of motor conduction velocity (MCV) of the median nerve, CMT encompasses five main forms: CMT1 (autosomal dominant [AD] or X-linked transmission and MCV < 38 m/s); CMT2 (AD or X-linked transmission and MCV > 38 m/s); CMT4 (autosomal recessive [AR] and severe slowing of MCV); AR-CMT2 (AR transmission and MCV > 38 m/s); and DI-CMT (intermediate form with AD transmission and MCV between 30 and 40 m/s). In spite of its stereotyped semiological repertoire (basically, symptoms and signs of sensory-motor polyneuropathy and pes cavus), CMT seems to be one of the most complex hereditary neurodegenerative syndromes, 31 causative genes having been cloned. DEVELOPMENT: This paper is aimed at performing a nosological review of the disease, emphasising the guidelines for its molecular diagnosis. Genetic epidemiological studies and genotypes reported in Spanish patients are revised. CONCLUSIONS: In the great majority of CMT cases, mutations involve a reduced number of genes, namely: for CMT1, PMP22, GJB1 and MPZ; for CMT2, MFN2 and GJB1; for CMT4, GDAP1, and NDRG1, HK1 and SH3TC2 (gypsies); for AR-CMT2, GDAP1; and for DI-CMT, GJB1 and MPZ. Given their low prevalence, mutations in other pathogenic genes should be investigated after discarding the previous ones. There is no place for the indiscriminate use of diagnostic CMT genetic panels. PMID- 21703726 TI - Participation rates in the selection of population controls in a case-control study of colorectal cancer using two recruitment methods. AB - OBJECTIVES: Low participation rates in the selection of population controls are an increasing concern for the validity of case-control studies worldwide. METHODS: We conducted a pilot study to assess two approaches to recruiting population controls in a study of colorectal cancer, including a face-to-face interview and blood sample collection. In the first approach, persons identified through a population roster were invited to participate through a telephone call by an interviewer telephoning on behalf of our research center. In the second approach, individuals were identified from the lists of selected family practitioners and were telephoned on behalf of the family practitioner. RESULTS: When the second method was used, participation rates increased from 42% to 57% and the percentage of refusals decreased from 47% to 13%. The reasons for refusing to participate did not differ significantly between the two methods. CONCLUSIONS: Contact through the family practitioner yielded higher response rates in population controls in the study area. PMID- 21703727 TI - [Continuing training plan in a clinical management unit]. AB - Continuing Care Unit (UCA) focused the attention of frail patients, polypathological patients and palliative care. UCA attend patients at home, consulting, day unit, telephone consulting and in two hospitals of the health area. From 2002 UCA began as a management unit, training has been a priority for development. Key elements include: providing education to the workplace, including key aspects of the most prevalent health care problems in daily work, directing training to all staff including organizational aspects of patient safety and the environment, improved working environment, development of new skills and knowledge supported by the evidence-based care for the development of different skills. The unit can be the ideal setting to undertake the reforms necessary conceptual training of professionals to improve the quality of care. PMID- 21703728 TI - [Public health and the market]. PMID- 21703729 TI - [Communication and satisfaction among primiparas in a public health service]. AB - OBJECTIVE: To analyze first-time mothers communication with health professionals, and to explore satisfaction, needs and expectation towards healthcare services. METHOD: Qualitative design using in-deep interviews and phenomenology was used. First-time mothers from Huercal-Overa (Almeria) were intentionally selected in 2010 and were included in the study. A hermeneutic analysis was performed. RESULTS: Six meta-categories were obtained. Saturation of information was found with nine interviews. The meta-categories were the following: 1) Health professionals; 2) Pregnancy, partum and postpartum; 3) Communication; 4) Child nutrition; 5) Feelings; 6) Others. The mothers perceived as exciting this new experience and expressed feelings of fear, anguish and high sensitiveness. These feelings are increased by the information received from the family circle and the professionals which is referred low and contradictory. All professionals were positively considered, specially the midwife. The following negative experiences were identified: contractions, dilation and delivery. The end of the stay at the hospital was considered early and the time for consultation was short for the mothers. There is a demand about more information on breast feeding. Mothers wish health professionals to respect their decisions. CONCLUSIONS: The study found some areas for improvement in the communication between firs-time mothers and health professionals which could be taken into account in satisfaction promotion plans in regards to healthcare services. PMID- 21703730 TI - [Multilevel analysis of the use of oral health services by the pediatric population]. AB - OBJECTIVES: To analyze the variables associated with the use of oral health services in the last year by the population aged 6 to 15 years living in Spain and to determine whether there is variability in the use of these services among autonomous regions and, if so, whether this variability could be explained by variables related to the care model of the distinct autonomous regions. METHODS: A cross-sectional study of the Spanish National Health Survey (2006) was carried out. Independent variables were individual (sociodemographic, dental disease, habits and socioeconomic) and contextual (type of dental care model and prevalence of unemployment in the autonomous region). Association was estimated by multilevel logistic regression. RESULTS: Variance in the use of oral health services among autonomous regions was 0.16 (SE: 0.07), and 4.8% of the total variability was attributable to the autonomous region. The variables included in the model explained 83.11% of the variance. Individual variables associated with an increased likelihood of using dental services were the presence of disease and the frequency of brushing. Individual variables associated with a lower likelihood were age, origin, intake of sugary soft drinks and socioeconomic status. The contextual variables of being covered by a dental care model (of the type Childhood Dental Care Plan) older than 10 years doubled the likelihood of using oral health services compared with those without such coverage (OR=2.47, CI=2.04-2.99). CONCLUSIONS: The use of oral health services during the last year by the pediatric population in Spain is lower than recommended. This use is associated with individual variables (demographic, dental health, habits and socioeconomic factors) and contextual variables (dental care model). PMID- 21703731 TI - Novel 2-thioxothiazolidin-4-one inhibitors of bacterial MurD ligase targeting D Glu- and diphosphate-binding sites. AB - Mur ligases are involved in cytoplasmic steps of bacterial peptidoglycan biosynthesis and are viable targets for antibacterial drug discovery. We have designed and synthesized a focused chemical library of compounds combining the glutamic acid moiety and the 2-thioxothiazolidin-4-one, thiazolidine-2,4-dione, 2 iminothiazolidin-4-one or imidazolidine-2,4-dione ring connected by a benzylidene group. These compounds were designed to target the d-Glu- and the diphosphate binding pockets of the MurD active site and were evaluated for inhibition of MurD ligase from Escherichia coli. The most potent compounds (R)-9 and (S)-9 inhibited MurD with IC(50) values of 45 MUM and 10 MUM, respectively. The specific binding mode of (R)-9 in MurD active site was established by high-resolution NMR spectroscopy. PMID- 21703732 TI - Synthesis and in vitro evaluation of xylene linked carbamoyl bis-pyridinium monooximes as reactivators of organophosphorus (OP) inhibited electric eel acetylcholinesterase (AChE). AB - A series of carbamoyl bis-pyridinium monooximes linked with xylene linker were synthesized and their in-vitro reactivation potential was evaluated against acetylcholinesterase (AChE) inhibited by organophosphorus inhibitors (OP) such as sarin, DFP and VX and the data were compared with reactivation obtained with 2 PAM and obidoxime. Amongst the synthesized compounds, 3-carbamoyl 2'hydroxyiminomethyl-1-1'-(1,4-phenylenedimethyl)-bispyridinium dibromide (5e) 3 carbamoyl-2'hydroxyiminomethy l-1-1'-(1,3-phenylenedimethyl)-bispyridinium dibromide (5k) and 4-carbamoyl-2'hydroxyiminomethyl-1-1'-(1,3-phenylenedimethyl) bispyridinium dibromide (5l) were found to be the most potent reactivators for electric eel AChE inhibited by sarin and DFP. However, in case of VX inhibited AChE, none of the synthesized oximes could surpass the reactivation potential of 2-PAM and obidoxime. The pKa values of all the oximes were determined and correlated with their observed reactivation potential. PMID- 21703733 TI - Synthesis and biological evaluation of the glycoside (25R)-3beta,16beta-diacetoxy 22-oxocholest-5-en-26-yl beta-d-glucopyranoside: a selective anticancer agent in cervicouterine cell lines. AB - The synthesis and biological evaluation of the new cholestane glycoside (25R) 3beta,16beta-diacetoxy-22-oxocholest-5-en-26-yl beta-d-glucopyranoside starting from diosgenin is described. This compound showed selective antiproliferative activity against CaSki, ViBo, and HeLa cervicouterine cancer cells. Its effect on the cell-cycle was determined. The cytotoxic effects of the title compound on cervicouterine cancer cell lines and human lymphocytes indicate that the main cell death process is not necrosis; hence it is not cytotoxic. The title compound induced apoptosis in cervicouterine cancer cells. Importantly, the antiproliferative activity on tumor cells did not affect the proliferative potential of peripheral blood lymphocytes. The title compound showed selective antitumor activity and greater antiproliferative activity than its aglycon, and therefore serves as a promising lead candidate for further optimization. PMID- 21703734 TI - Synthesis and structure-activity relationship of 1- and 2-substituted-1,2,3 triazole letrozole-based analogues as aromatase inhibitors. AB - A series of bis- and mono-benzonitrile or phenyl analogues of letrozole 1, bearing (1,2,3 and 1,2,5)-triazole or imidazole, were synthesized and screened for their anti-aromatase activities. The unsubstituted 1,2,3-triazole 10a derivative displayed inhibitory activity comparable with that of the aromatase inhibitor, letrozole 1. Compound 10a, bearing a 1,2,3-triazole, is also 10000 times more tightly binding than the corresponding analogue 25 bearing a 1,2,5 triazole, which confirms the importance of a nitrogen atom at position 3 or 4 of the 5-membered ring needed for high activity. The effect on human epithelial adrenocortical carcinoma cell line (H295R) proliferation was also evaluated. The compound 10j (IC(50) = 4.64 MUM), a letrozole 1 analogue bearing para cyanophenoxymethylene-1,2,3-triazole decreased proliferation rates of H295R cells by 76 and 99% in 24 and 72 h respectively. Computer calculations, using quantum ab initio structures, suggest a possible correlation between anti-aromatase activity and the distance between the nitrogen in position 3 or 4 of triazole nitrogen and the cyano group nitrogen. PMID- 21703735 TI - Potentially increasing the metabolic stability of drug candidates via computational site of metabolism prediction by CYP2C9: The utility of incorporating protein flexibility via an ensemble of structures. AB - Cytochrome P450 enzymes are responsible for metabolizing many endogenous and xenobiotic molecules encountered by the human body. It has been estimated that 75% of all drugs are metabolized by cytochrome P450 enzymes. Thus, predicting a compound's potential sites of metabolism (SOM) is highly advantageous early in the drug development process. We have combined molecular dynamics, AutoDock Vina docking, the neighboring atom type (NAT) reactivity model, and a solvent accessible surface-area term to form a reactivity-accessibility model capable of predicting SOM for cytochrome P450 2C9 substrates. To investigate the importance of protein flexibility during the ligand-binding process, the results of SOM prediction using a static protein structure for docking were compared to SOM prediction using multiple protein structures in ensemble docking. The results reported here indicate that ensemble docking increases the number of ligands that can be docked in a bioactive conformation (ensemble: 96%, static: 85%) but only leads to a slight improvement (49% vs. 44%) in predicting an experimentally known SOM in the top-1 position for a ligand library of 75 CYP2C9 substrates. Using ensemble docking, the reactivity-accessibility model accurately predicts SOM in the top-1 ranked position for 49% of the ligand library and considering the top-3 predicted sites increases the prediction success rate to approximately 70% of the ligand library. Further classifying the substrate library according to K(m) values leads to an improvement in SOM prediction for substrates with low K(m) values (57% at top-1). While the current predictive power of the reactivity accessibility model still leaves significant room for improvement, the results illustrate the usefulness of this method to identify key protein-ligand interactions and guide structural modifications of the ligand to increase its metabolic stability. PMID- 21703736 TI - Dose estimation and radon action level problems due to nanosize radon progeny aerosols in underground manganese ore mine. AB - One of the essential parameters influencing of the dose conversion factor is the ratio of unattached short-lived radon progeny. This may differ from the value identified for indoor conditions when considering special workplaces such as mines. Inevitably, application of the dose conversion factors used in surface workplaces considerably reduces the reliability of dose estimation in the case of mines. This paper surveyed the concentration of radon and its short-lived radon progeny and identified the unattached fraction of short-lived radon progeny. As well equilibrium factor during the month of August was calculated simultaneously at two extraction faces in a manganese ore mine. During working hours the average radon concentrations were 220 Bq m(-3) and 530 Bq m(-3) at Faces 1 and 2; the average short-lived progeny concentration was 90 Bq m(-3) and 190 Bq m(-3), the average equilibrium factors were 0.46 and 0.36, and the average unattached fractions were 0.21 and 0.17, respectively. The calculated dose conversion factor was between 9 and 27 mSv WLM(-1), but higher values could also be possible. PMID- 21703738 TI - Leaflet to aid postoperative placement of elastics after orthognathic surgery. PMID- 21703737 TI - Tritium concentrations in the atmospheric environment at Rokkasho, Japan before the final testing of the spent nuclear fuel reprocessing plant. AB - This study aimed at obtaining background tritium concentrations in precipitation and air at Rokkasho where the first commercial spent nuclear fuel reprocessing plant in Japan has been under construction. Tritium concentration in monthly precipitation during fiscal years 2001-2005 had a seasonal variation pattern which was high in spring and low in summer. The tritium concentration was higher than that observed at Chiba City as a whole. The seasonal peak concentration at Rokkasho was generally higher than that at Chiba City, while the baseline concentrations of both were similar. The reason for the difference may be the effect of air mass from the Asian continent which is considered to have high tritium concentration. Atmospheric tritium was operationally separated into HTO, HT and hydrocarbon (CH(3)T) fractions, and the samples collected every 3 d-14 d during fiscal year 2005 were analyzed for these fractions. The HTO concentration as radioactivity in water correlated well with that in the precipitation samples. The HT concentration was the highest among the chemical forms analyzed, followed by the HTO and CH(3)T concentrations. The HT and CH(3)T concentrations did not have clear seasonal variation patterns. The HT concentration followed the decline previously reported by Mason and Ostlund with an apparent half-life of 4.8 y. The apparent and environmental half-lives of CH(3)T were estimated as 9.2 y and 36.5 y, respectively, by combining the present data with literature data. The Intergovernmental Panel on Climate Change used the atmospheric lifetime of 12 y for CH(4) to estimate global warming in its 2007 report. The longer environmental half-life of CH(3)T suggested its supply from other sources than past nuclear weapon testing in the atmosphere. PMID- 21703739 TI - Simple technique to minimise facial scarring during extraoral mandibular distraction. PMID- 21703740 TI - Head load carriage and pregnancy in West Africa. AB - BACKGROUND: The postures of the trunk and of the head relative to the trunk adopted during the specific task of head load carriage were measured for a group of pregnant women and a control group of non-pregnant women because this activity was identified as a risk factor for back pain during pregnancy. METHODS: The postural data of the trunk and of the head relative to the trunk were collected using two inclinometer devices and an electrogoniometer, respectively. FINDINGS: During walking, the load on the head caused significantly larger upper trunk extension and smaller flexion of the head relative to the trunk. The amplitude of motion of the upper trunk and of the head relative to the trunk, as measured by the standard deviation of walking angles, was found to decrease as a result of carrying a load on the head and compensated by increased motion at the sacrum. Pregnant women showed larger upper trunk movements than their counterpart in the frontal and sagittal planes during the unloaded walking trials. INTERPRETATION: These posture modifications were believed to be adopted by the subjects to provide better stability for the load during walking. These prolonged postural strains caused by the trunk being displaced from its normal position can lead to muscle fatigue and ultimately to musculoskeletal injuries. The larger movements of the upper trunk for the pregnant women were hypothesized to be due to the enlarged abdomen of pregnant women as it creates a larger moment about L5/S1 and increases instability. PMID- 21703741 TI - Structural stability of different reconstruction techniques following total sacrectomy: a biomechanical study. AB - BACKGROUND: The biomechanical stability of spino-pelvis structure after varying reconstruction methods following total sacrectomy remains poorly defined. The objective of this study was to compare the structural stability of different reconstruction techniques. METHODS: Six fresh human cadavers (L2-pelvis-femora) were used to compare biomechanical stability after reconstruction using four different techniques: (1) sacral rod reconstruction; (2) bilateral fibular flap reconstruction; (3) four-rod reconstruction; and (4) improved compound reconstruction. After total sacrectomy, the construction was carried out using each method once in each cadaver. Structural stiffness was evaluated by linear and angular ranges of motion. L5 relative shift-down displacement, abduction angle on the coronal plane and rotation angle on the sagittal plane, were calculated based on displacement of the identification point under 500N axial loading. Overall stiffness was estimated using load displacement curve. FINDINGS: Improved compound reconstruction resulted in significantly higher stiffness than all three other techniques. The structural stability following bilateral fibular flap reconstruction was superior to that after sacral rod reconstruction. Four rod reconstruction achieved worst stability due to the lack of anterior bracing applied in three other methods. INTERPRETATION: Improved compound reconstruction produces optimal structural stability after total sacrectomy. This finding suggests that both anterior bracing and alternation of screw trajectory are important in achieving optimal structural stability. PMID- 21703742 TI - Reproductive toxicity assessment of surface water of the Tai section of the Yangtze River, China by in vitro bioassays coupled with chemical analysis. AB - Reproductive toxicity of organic extracts of the surface water from the Tai section of the Yangtze River was assessed by in vitro cytotoxity assays and selected persistent organic pollutants including PCBs, OCPs and PAHs were quantified by instrumental analysis. Eleven of the US EPA priority PAHs were detected. Individual PAHs were found to range from 0.7 to 20 ng/L. Concentrations of BaP did not exceed the national drinking water source quality standard of China. However, a 286-fold concentrated organic extract induced significant reproductive toxicity in adult male rats. The morphology of cells, MTT assay and LDH release assay were all affected by exposure to the organic extracts of water. The results of the reproductive toxicity indicated that PAHs posed the greatest risk of the chemicals studied. The compounds present in the water could be bioconcentrated and result in adverse effects. PMID- 21703743 TI - Variations in concentrations and compositions of polycyclic aromatic hydrocarbons (PAHs) in coals related to the coal rank and origin. AB - The release of unburnt coal particles and associated polycyclic aromatic hydrocarbons (PAHs) may cause adverse impacts on the environment. This study assessed variations in the concentration and composition of PAHs in a set of fifty coal samples from eleven coal basins worldwide. The maximum PAH concentrations at high volatile bituminous rank were recorded in samples from a single basin. Considering the entire sample set, the highest PAH concentrations were in fact found outside of this rank range, suggesting that the maceral composition and thus the coal's origin also influenced PAH concentrations. The examination of the PAH compositions revealed that alkylated 2-3 ring PAHs remain dominant compounds irrespective of coal rank or origin. Multivariate analysis based on PAH and maceral content, bulk and maturity parameters allowed the recognition of seven groups with different rank and origin within the coal sample set. PMID- 21703744 TI - Stable carbon isotope analysis (delta13C values) of polybrominated diphenyl ethers and their UV-transformation products. AB - Polybrominated diphenyl ethers (PBDEs) are frequently detected in food and environmental samples. We used compound specific isotope analysis to determine the delta(13)C values of individual PBDEs in two technical mixtures. Within the same technical product (DE-71 or DE-79), BDE congeners were the more depleted in (13)C the higher brominated they were. In contrast, the products of light-induced hydrodebromination of BDE 47 and technical DE-79 were more enriched in (13)C because of more stable bonds between (13)C and bromine. As a result, the delta(13)C values of the irradiated solution progressed diametrically compared to those of the technical synthesis. The ratio of the delta(13)C values of BDE 47 to BDE 99 and of BDE 99 to BDE 153 are thus suggested as indicators to distinguish native technical products from transformation products. Ratios <1 are typical for native congeners (e.g. in DE-71) while the reversed ratio (>1) is typical of transformation products. PMID- 21703745 TI - Qualitative and quantitative evaluation of bony structures based on DICOM dataset. AB - PURPOSE: The aim of this study was to investigate bone mass using different cone beam computed tomographies (CBCTs) combined with image analysis and to determine whether bone quantity or quality was detected. MATERIALS AND METHODS: Different measurements recorded on mandible bones of pigs in the retromolar region were evaluated on ProMax 3D (Planmeca Oy, Finland) and the ILUMATMCT (IMTECTM Imaging, Ardmore, OK) to calculate a calibration curve. The spatial relationships of pig mandible halves relative to adjacent defined anatomical structures were assessed by means of 3D visualization software. In addition to the screenshot, their bone quality was evaluated in accordance with the Lenkholm and Zarb classification. RESULTS: The CBCT calibration curves based on the measurements taken from the ProMax and ILUMA CT showed linear correlation. Huge Hounsfield units intervals were found between the 2 CBCTs and there was no correlation with the computed tomography. Exact information on the micromorphology of the bone cylinders was not available. A subjective correlation according to Lenkholm and Zarb showed overlapping in all groups. CONCLUSIONS: CBCT is a good choice for analyzing bone mass. However, it does not provide any information on bone quality. To obtain information on the microarchitecture of the spongiosa, it is necessary to use a computed tomography with finite element analysis. PMID- 21703746 TI - Omega-shaped (Omega) incision design to enhance gingival esthetics for adjacent implant placement in the anterior region. AB - It is well accepted that achieving an optimal interdental papilla between adjacent implants is esthetically challenging in implant dentistry. In general, there are 2 kinds of interproximal soft tissues that can be present between adjacent implants. One is the true anatomic interdental papilla and the other is a "papilla-like" tissue created by surgical intervention and prosthetic contouring of the tissues. The former is challenging to preserve, and the latter is difficult to create. Multiple techniques have been suggested to create and preserve this volume of interproximal soft tissue between adjacent implants. This article describes another technique to achieve a papilla-like tissue using an omega-shaped (Omega) incision design when implants are placed adjacent to each other in partially edentulous ridges. This incision design is intended to spare an area of soft tissue of approximately 4 mm * 4 mm between the anticipated positions of the adjacent implants. The area of soft tissue that is free from surgical insult later helps in the creation of a papilla-like tissue through interim restorations. Case reports of this technique on long-term partially edentulous ridges are described, with a follow-up period of 3 to 4 years. The technique is relatively simple and does not involve additional surgeries or additional time for healing. PMID- 21703747 TI - Effect of the osteotome technique in cases of deficient edentulous ridge. AB - PURPOSE: The use of dental implants may be limited by lack of sufficient bone. The effectiveness of the alveolar ridge bone-spreading technique in the maxilla was compared with the standard technique. Bone spreading is a technique in which hand osteotomes are used to progressively enlarge the remaining deficient edentulous ridge to enable placement of dental implants. MATERIALS AND METHODS: In the test group (bone spreading), 72 patients received 126 implants. Thirty-six patients with 63 implants placed with conventional implant preparation served as a control group. Measurements of outcome were implant failure and complications after therapy. Kaplan-Meier curves were used to depict time from implant placement to implant failure or complication. RESULTS: Six complications were observed after placement of the implants (3 implant failures, peri-implant inflammation in 2 implants, and 1 exposure of rough implant surface). There was a trend toward more implant failures in the control group. CONCLUSIONS: Results of the ridge-spreading technique seem to be similar to those of the standard technique. However, these results should be regarded with caution because of the small number of complications. PMID- 21703748 TI - Anarchic-hand syndrome: ERP reflections of lost control over the right hemisphere. AB - In patients with the callosal type of anarchic-hand syndrome, the left hand often does not act as intended and counteracts the right hand. Reports are scarce about the underlying neurophysiological mechanisms. We report the case G.H. who developed the syndrome after infarction of the left arteria pericallosa. It has been suggested that the syndrome arises out of lacking inhibition from the dominant left hemisphere on the right hemisphere. Yet, in tests of spatial intelligence G.H. performed much better with his "anarchic" left hand than with his dominant right hand, similar to observations commonly reported in split-brain patients. Left-right manual choice responses and event-related EEG potentials to laterally presented stimuli were measured. Asymmetries were evident in G.H.'s behavior and EEG potentials, different from age-matched healthy participants (n=11). His right-hand responses were fast and unaffected by incompatibility with stimulus location, whereas his left-hand responses were variable and accompanied by a large negative central-midline EEG potential, probably reflecting efforts in initiating the response. G.H.'s visual N1 component peaked earlier and was larger at the right than the left side of the scalp, and the P3 component was distinctly reduced at the right side. Both features occurred independent of side of stimulus presentation and side of responding hand. The effort indicated by the midline negativity and the asymmetrically reduced P3 might directly reflect G.H.'s lack of control on his right hemisphere's processing. The faster visual processing of the right hemisphere suggested by the N1 asymmetry might contribute to "anarchic" processing, making the right hemisphere process stimuli before control impulses exert their effect. These neurophysiological results tend to support the split brain account which assumes that the syndrome arises by the lack of communication between hemispheres that act according to their respective competences. PMID- 21703749 TI - Cardiac arrest patients in the emergency department-National Hospital Ambulatory Medical Care Survey, 2001-2007. AB - AIM OF THE STUDY: Few studies have focused on the full complement of cardiac arrest cases seen in hospital emergency departments (ED). The aims of our study were to describe cardiac arrest visits in the ED by using a nationally representative sample of U.S. adults. METHODS: ED data from the 2001-2007 National Hospital Ambulatory Medical Care Survey (NHAMCS) were analyzed. Cardiac arrest visits were considered to be those with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code of 427.5 as the primary diagnosis. RESULTS AND CONCLUSIONS: From 2001 to 2007, adults in the U.S. made an estimated 600,729,000 ED visits. Of those, 1,001,000 (0.17%) had a primary diagnosis of cardiac arrest. The majority of patients with such visits were dead on arrival or died in the ED (74.0%). The mean age for cardiac arrest visits was 66.7 years (95% confidence interval [CI], 64.6-68.8 years). Women had a lower rate of cardiac arrest visits than men (age-adjusted odds ratio [AOR], 0.6; 95% CI, 0.5-0.8), and the privately insured (AOR, 0.4; 95% CI, 0.2-0.7) and those with government insurance (AOR, 0.5; 95% CI, 0.3-0.9) had a lower proportion of cardiac arrest ED visits than uninsured persons. In addition, increasing age was a significant predictor of cardiac arrest visits. Cardiac arrest visits did not vary significantly by race, geographic region, or metropolitan statistical area. ED visits classified as cardiac arrest represent 1 in 600 visits and these visits differ by age, sex, payment source, and arrival time at the ED. PMID- 21703750 TI - Urinary leukotriene excretion profile in children with exercise-induced asthma compared with controls: a preliminary study. AB - BACKGROUND: Leukotrienes are among the most important mediators associated with inflammatory responses in patients with exercise induced asthma (EIA). The aim of this study was to investigate the impact of exercise on the urinary leukotriene profile. Hence, we compared post exercise changes of urinary leukotriene E4 (LTE4) concentration between children with EIA and healthy controls. METHODS: Ten children with EIA and 15 controls were enrolled. Both groups underwent a standardised exercise challenge test (ECT). LTE4 concentration was measured in urine samples obtained pre and post ECT, using enzyme immunoassay and adjusted by urinary creatinine concentrations. RESULTS: Median (minimum-maximum) pre ECT concentration of LTE4 was 17.82 (7.58-90.23 pg/ml) in EIA and 17.24 (4.64-64.02 pg/ml) in controls, p=0.86. LTE4 concentration post ECT were 23.37 (4.02-93.00 pg/ml) in EIA and 11.74 (0.13-25.09 pg/ml) in controls, p=0.02. Changes of LTE4 concentration post ECT were 2.54 (-31.98 to 43.31 pg/ml) in cases and -13.53 ( 46.00 to 11.02 pg/ml) in controls, p=0.03. There was no significant correlation between basal predicted FEV(1) [%] and changes in LTE4 concentration in cases (i.e., r(s)=0.14) nor controls (i.e., r(s)=0.12). There was a tendency towards more pronounced changes in LTE4 concentration post ECT in children with moderate/mild persistent asthma compared to those with mild but intermittent asthma. CONCLUSIONS: Children with EIA had significantly higher changes of urinary LTE4 concentrations post ECT compared to healthy controls. Urinary measurement of LTE4 may be an interesting and non-invasive option to assess control of EIA in children. PMID- 21703751 TI - Age of sexual debut and central introital dyspareunia. AB - OBJECTIVES: Analysis of characteristics of patients with introital central dyspareunia. Is late coitarche (age at first sexual intercourse) a risk factor for introital dyspareunia? STUDY DESIGN: 145 women attending a vulvo-vaginitis clinic in secondary and tertiary care center in Tienen and Leuven, Belgium, with central introital pain during sexual intercourse. RESULTS: The mean age of the study group was 32 years, and 5% were 60 years of age or older. Of the patients, 51% had primary and 49% secondary dyspareunia. Before referral, two-thirds of the patients had already tried several types of therapy, including psychiatric help in 16% of cases. The study group of patients with central introital dyspareunia had a coitarche at a mean of 18.3 years. 72% of the dyspareunic women with coitarche later than 18 had to regularly interrupt intercourse because of pain, compared with 52% of women with coitarche before 18 (p<0.05). A strong correlation was found between the age of sexual debut and the necessity to interrupt intercourse attempts due to pain (p<0.001). Frequency of intercourse was also found to be inversely related to coitarche. CONCLUSION: Women with introital dyspareunia had their sexual debut at a later age than otherwise comparable women. Late coitarche is inversely related to frequency of attempted intercourse and to the necessity to interrupt intercourse due to pain, suggesting a relation between coitarchal age and severity of dyspareunia. A possible explanation is increased fibrosis and stiffening of the hymenal remnants at the posterior vulvar commissural due to increasing age in primary, and repeated injury by sexual contacts in secondary, central introital dyspareunia patients. PMID- 21703755 TI - Anterior subcutaneous transposition of ulnar nerve with fascial flap and complete excision of medial intermuscular septum in cubital tunnel syndrome: a prospective patient cohort. AB - OBJECTIVE: Regarding the frequency of cubital tunnel syndrome, varieties of treatment modalities, and ambiguity of anterior subcutaneous transposition of ulnar nerve method, we aimed to evaluate the efficacy of this procedure in patients with cubital tunnel syndrome referred to Taleghani hospital between 2006 and 2009. METHODS: This study was a case series including all referred patients with definite diagnosis of cubital tunnel syndrome, treated by anterior subcutaneous transposition. Treatment results were measured according to modified Bishop rating system, and were ranked into excellent, good, fair, and poor. Variables such as gender, age (less/more than 45 years), causation, and initial severity, determined by Dellon criteria preoperatively, were analyzed by Fisher's exact test. RESULTS: This study was performed on 26 eligible cases including 29 elbows, 38% males and 62.1% females, with mean age of 44.5 years (ranging 23-72 years). In a 12 months follow-up post-operatively, 62% showed excellent, 20.7% good, and 17.3% fair, with no poor result. In a 1-12 months follow-up post operatively, results showed improvement, and initial severity and old age were demonstrated to significantly affect treatment results (P<0.07). CONCLUSION: Though considered standard of care, the present study suggests that criteria for surgical techniques of ulnar nerve decompression, e.g. simple decompression vs. more extensive repair as in the present cohort, should be revised by controlled prospective studies. PMID- 21703752 TI - The use of analytical sedimentation velocity to extract thermodynamic linkage. AB - For 25 years, the Gibbs Conference on Biothermodynamics has focused on the use of thermodynamics to extract information about the mechanism and regulation of biological processes. This includes the determination of equilibrium constants for macromolecular interactions by high precision physical measurements. These approaches further reveal thermodynamic linkages to ligand binding events. Analytical ultracentrifugation has been a fundamental technique in the determination of macromolecular reaction stoichiometry and energetics for 85 years. This approach is highly amenable to the extraction of thermodynamic couplings to small molecule binding in the overall reaction pathway. In the 1980s this approach was extended to the use of sedimentation velocity techniques, primarily by the analysis of tubulin-drug interactions by Na and Timasheff. This transport method necessarily incorporates the complexity of both hydrodynamic and thermodynamic nonideality. The advent of modern computational methods in the last 20 years has subsequently made the analysis of sedimentation velocity data for interacting systems more robust and rigorous. Here we review three examples where sedimentation velocity has been useful at extracting thermodynamic information about reaction stoichiometry and energetics. Approaches to extract linkage to small molecule binding and the influence of hydrodynamic nonideality are emphasized. These methods are shown to also apply to the collection of fluorescence data with the new Aviv FDS. PMID- 21703756 TI - Levetiracetam compared to valproic acid: plasma concentration levels, adverse effects and interactions in aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: Both valproic acid and levetiracetam are anti-epileptic drugs, often used either alone or in combination. The present study compares valproate (VPA) with levetiracetam (LEV) as an intravenous (i.v.) anticonvulsant treatment in intensive care patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) with a high risk of seizures. PATIENTS AND METHODS: A prospective, single-center patient registry of 35 intensive care unit (ICU) patients with onset seizure and/or high risk of seizures underwent an anticonvulsive, first-line single treatment regimen either with VPA or LEV. Plasma concentrations (pc), interactions between drugs in the ICU context, adverse effects and seizure occurrences were observed and recorded. RESULTS: A significant decrease in the pc in patients treated with LEV was observed after changing from intravenous (160+/ 51MUmol/l) to enteral liquid application (113+/-58MUmol/l), corresponding to a 70.3% bioavailability for enteral liquid applications. The pc in VPA patients decreased significantly, from (491+/-138MUmol/l) to (141+/-50MUmol/l), after adding meropenem to the therapy (p<0.05). Three epileptic seizures occurred during anticonvulsive therapy in the LEV group, and two in the VPA group, including one non-convulsive status epilepticus (NCSE). CONCLUSION: Though this finding needs further verification, the enteral liquid application of levetiracetam seems to be associated with lower bioavailability than the common oral application of levetiracetam. The use of the antibiotic drug meropenem together with valproic acid leads to lower pc levels in patients treated with of valproic acid. For clinical practice, this indicates the need to monitor the levels of valproic acid in combination with meropenem. PMID- 21703757 TI - Decolorization of reactive textile dyes using water falling film dielectric barrier discharge. AB - Decolorization of reactive textile dyes Reactive Black 5, Reactive Blue 52, Reactive Yellow 125 and Reactive Green 15 was studied using advanced oxidation processes (AOPs) in a non-thermal plasma reactor, based on coaxial water falling film dielectric barrier discharge (DBD). Used initial dye concentrations in the solution were 40.0 and 80.0mg/L. The effects of different initial pH of dye solutions, and addition of homogeneous catalysts (H(2)O(2), Fe(2+) and Cu(2+)) on the decolorization during subsequent recirculation of dye solution through the DBD reactor, i.e. applied energy density (45-315kJ/L) were studied. Influence of residence time was investigated over a period of 24h. Change of pH values and effect of pH adjustments of dye solution after each recirculation on the decolorization was also tested. It was found that the initial pH of dye solutions and pH adjustments of dye solution after each recirculation did not influence the decolorization. The most effective decolorization of 97% was obtained with addition of 10mM H(2)O(2) in a system of 80.0mg/L Reactive Black 5 with applied energy density of 45kJ/L, after residence time of 24h from plasma treatment. Toxicity was evaluated using the brine shrimp Artemia salina as a test organism. PMID- 21703758 TI - Novel thermosensitive flocculanting agent based on pullulan. AB - New thermosensitive polysaccharide (P-g-pNIPAAm) was synthesized by graft polymerization of p(N-isopropylacrylamide) (pNIPAAm) onto pullulan (P) using Ce(IV) ion as initiator. The grafted polysaccharide was characterized by FT-IR and (1)H NMR spectroscopy and elemental analysis. Its flocculation efficiency was studied in a clay suspension, in comparison with p(NIPAAm) homopolymer, as a function of the polymer dose, temperature and settling time. The thermosensitive polysaccharide could induce clay particle flocculation both below and above the lower critical solution temperature (LCST), but the process was more effective above the LCST. A lower value of the residual turbidity at the optimum polymer dose and a wider flocculation window were recorded at temperature above the LCST. The floc size distribution and surface morphology revealed bigger size flocs when the flocculation was performed above the LCST. The re-dispersion effect was negligible for the flocs obtained in the presence of P-g-pNIPAAm. PMID- 21703759 TI - Removal of phenols from aqueous solutions by emulsion liquid membranes. AB - The present study deals with the extraction of phenols from aqueous solutions by using the emulsion liquid membranes technique. Besides phenol, two derivatives of phenol, i.e., tyrosol (2-(4-hydroxyphenyl)ethanol) and p-coumaric acid (4 hydroxycinnamic acid), which are typical components of the effluents produced in olive oil plants, were selected as the target solutes. The effect of the composition of the organic phase on the removal of solutes was examined. The influence of pH of feed phase on the extraction of tyrosol and p-coumaric was tested for the membrane with Cyanex 923 as an extractant. The use of 2% Cyanex 923 allowed obtaining a very high extraction of phenols (97-99%) in 5-6 min of contact time for either single solute solutions or for their mixtures. The removal efficiency of phenol and p-coumaric acid attained equivalent values by using the system with 2% isodecanol, but the removal rate of tyrosol was found greatly reduced. The extraction of tyrosol and p-coumaric acid from their binary mixture was also analysed for different operating conditions like the volume ratio of feed phase to stripping phase (sodium hydroxide), the temperature and the initial concentration of solute in the feed phase. PMID- 21703760 TI - Prophylactic and therapeutic effects of taurine against aluminum-induced acute hepatotoxicity in mice. AB - Aluminum is a well known neurotoxin and a possible candidate of hepatotoxins to humans. Using natural antioxidants against metal-induced hepatotoxicity is a modern approach. In the present study, Aluminum (AlCl(3)) intoxication (a single injection of 25mg Al(3+)/kg, i.p.) for 24h in mice resulted in elevations in serum alanine aminotransferase activity and serum tumor necrosis factor and hepatic malondialdehyde levels. Aluminum reduced the activities of glutathione peroxidase, glutathione S-transferase, quinone oxidoreductase, and catalase in liver. In addition, Al caused hepatic hemorrhage, cellular degeneration as well as necrosis of hepatocytes. Ultrastructure examination showed swelling of mitochondria, derangement of rough endoplasmic reticulum cisternae and pleomorphic nuclei with abnormal chromatin distribution. Taurine, a sulfur containing amino acid was administered to mice daily for 5 days before (at 100mg/kg, i.p.) or 2h after (a single dose of 1g/kg, i.p.) aluminum administration. Treating mice with taurine at either dosing regimens, pre- or post-aluminum administration alleviated aluminum oxidative damaging effects. The rate of recovery was better when taurine was administered prior to Al. Taurine had anaphylactic and therapeutic activity against hepatotoxicity induced by aluminum in mice. PMID- 21703761 TI - Optimization of the cathode material for nitrate removal by a paired electrolysis process. AB - Ni, Cu, Cu(90)Ni(10) and Cu(70)Ni(30) were evaluated as cathode materials for the conversion of nitrate to nitrogen by a paired electrolysis process using an undivided flow-through electrolyzer. Firstly, corrosion measurements revealed that Ni and Cu(70)Ni(30) electrodes have a much better corrosion resistance than Cu and Cu(90)Ni(10) in the presence of chloride, nitrate and ammonia. Secondly, nitrate electroreduction experiments showed that the cupro-nickel electrodes are the most efficient for reducing nitrate to ammonia with a selectivity of 100%. Finally, paired electrolysis experiments confirmed the efficiency of Cu(70)Ni(30) and Cu(90)Ni(10) cathodes for the conversion of nitrate to nitrogen. During a typical electrolysis, the concentration of nitrate varied from 620ppm to less than 50ppm NO(3)(-) with an N(2) selectivity of 100% and a mean energy consumption of 20kWh/kg NO(3)(-) (compared to ~35 and ~220kWh/kg NO(3)(-) with Cu and Ni cathodes, respectively). PMID- 21703762 TI - Sorption of zinc by novel pH-sensitive hydrogels based on chitosan, itaconic acid and methacrylic acid. AB - Novel pH-sensitive hydrogels based on chitosan, itaconic acid and methacrylic acid were applied as adsorbents for the removal of Zn(2+) ions from aqueous solution. In batch tests, the influence of solution pH, contact time, initial metal ion concentration and temperature was examined. The sorption was found pH dependent, pH 5.5 being the optimum value. The adsorption process was well described by the pseudo-second order kinetic. The hydrogels were characterized by spectral (Fourier transform infrared-FTIR) and structural (SEM/EDX and atomic force microscopy-AFM) analyses. The surface topography changes were observed by atomic force microscopy, while the changes in surface composition were detected using phase imaging AFM. The negative values of free energy and enthalpy indicated that the adsorption is spontaneous and exothermic one. The best fitting isotherms were Langmuir and Redlich-Peterson and it was found that both linear and nonlinear methods were appropriate for obtaining the isotherm parameters. However, the increase of temperature leads to higher adsorption capacity, since swelling degree increased with temperature. PMID- 21703763 TI - A simple modeling study of the Ce(IV) regeneration in sulfuric acid solutions. AB - The electrochemical regeneration of Ce(IV) for mediated electrochemical oxidation in sulfuric acid media was investigated in an electrolytic membrane reactor. A simple kinetic model was developed to analyze and simulate the regeneration of Ce(IV) in the electrolysis process. The model was based on the Faraday's law and the mass balance of components in the reactor. The key operating conditions of the initial electrolyte concentration and the regeneration time were analyzed. It was found that the simulating model agreed well with the experimental data for regeneration of Ce(IV). Experimental results showed that Ce(SO4)-2 is the active species. The decomposition of surface complex of Ce(IV) at the anode surface is the rate determining step. Constant-current electrolysis shows that the high proton and Ce(III) concentrations are electrochemically favorable for the regeneration of Ce(IV). The current efficiency for regeneration of Ce(IV) decrease obviously with the increase of SO(4)(2-) concentration from 0.8 to 2.4mol/L. PMID- 21703764 TI - Repetitive transcranial magnetic stimulation for chronic pain: time to evolve from exploration to confirmation? PMID- 21703765 TI - Chronic widespread pain and interference with functioning. PMID- 21703766 TI - Reducing the future threat from (liver) fluke: realistic prospect or quixotic fantasy? AB - The liver fluke remains an economically significant parasite of livestock and is emerging as an important zoonotic infection of humans. The incidence of the disease has increased in the last few years, as a possible consequence of changes to the World's climate. Future predictions suggest that this trend is likely to continue. Allied to the changing pattern of disease, reports of resistance to triclabendazole (TCBZ) have appeared in the literature, although they do not all represent genuine cases of resistance. Nevertheless, any reports of resistance are a concern, because triclabendazole is the only drug that has high activity against the migratory and damaging juvenile stages of infection. How to deal with the twin problems (of increasing incidence and drug resistance) is the overall theme of the session on "Trematodes: Fasciola hepatica epidemiology and control" and of this review to introduce the session. Greater knowledge of fluke epidemiology and population genetics will highlight those regions where surveillance is most required and indicate how quickly resistant populations of fluke may arise. Models of disease risk are becoming increasingly sophisticated and precise, with more refined data analysis programmes and Geographic Information Systems (GIS) data. Recent improvements have been made in our understanding of the action of triclabendazole and the ways in which flukes have become resistant to it. While microtubules are the most likely target for drug action, tubulin mutations do not seem to be involved in the resistance mechanism. Rather, upregulation of drug uptake and metabolism processes appear to be more important and the data relating to them will be discussed. The information may help in the design of new treatment strategies or pinpoint potential molecular markers for monitoring fluke populations. Advances in the identification of novel targets for drugs and vaccines will be made by the various "-omics" technologies that are now being applied to Fasciola. A major area of concern in the current control of fasciolosis is the lack of reliable tests for the diagnosis of drug (TCBZ) resistance. This has led to inaccurate reports of resistance, which is hindering successful disease management, as farmers may be encouraged to switch to less effective drugs. Progress with the development of a number of new diagnostic tests will be reviewed. PMID- 21703767 TI - Effective role of broadcasting systems in prevention of burns due to an Iranian traditional custom: Chaharshanbe-Suri. PMID- 21703768 TI - A system for 3D representation of burns and calculation of burnt skin area. AB - In this paper a computer-based system for burnt surface area estimation (BAI), is presented. First, a 3D model of a patient, adapted to age, weight, gender and constitution is created. On this 3D model, physicians represent both burns as well as burn depth allowing the burnt surface area to be automatically calculated by the system. Each patient models as well as photographs and burn area estimation can be stored. Therefore, these data can be included in the patient's clinical records for further review. Validation of this system was performed. In a first experiment, artificial known sized paper patches were attached to different parts of the body in 37 volunteers. A panel of 5 experts diagnosed the extent of the patches using the Rule of Nines. Besides, our system estimated the area of the "artificial burn". In order to validate the null hypothesis, Student's t-test was applied to collected data. In addition, intraclass correlation coefficient (ICC) was calculated and a value of 0.9918 was obtained, demonstrating that the reliability of the program in calculating the area is of 99%. In a second experiment, the burnt skin areas of 80 patients were calculated using BAI system and the Rule of Nines. A comparison between these two measuring methods was performed via t-Student test and ICC. The hypothesis of null difference between both measures is only true for deep dermal burns and the ICC is significantly different, indicating that the area estimation calculated by applying classical techniques can result in a wrong diagnose of the burnt surface. PMID- 21703769 TI - Multiple-locus variable number of tandem repeats (VNTR) fingerprinting (MLVF) and antibacterial resistance profiles of extended spectrum beta lactamase (ESBL) producing Pseudomonas aeruginosa among burnt patients in Tehran. AB - Extended spectrum beta-lactamase (ESBL)-producing trait was present in 48 out of the 112 (42.8%) Pseudomonas aeruginosa isolates collected from burn wound infections during a 12-month period. The presence of oxa-10, per-1, veb-1 and ges genes and the multiple-locus variable number of tandem repeats (VNTR) fingerprinting (MLVF) of 112 P. aeruginosa strains were determined by PCR and multiplex PCR. Disk diffusion methods were used to determine the susceptibility of the isolates to antimicrobial agents as instructed by CLSI. All ESBL isolates were resistant to aztreonam, cefepime, cefotaxime, cefpodoxime, ceftazidime, ceftriaxone and ofloxacin. Fewer than 60% of ESBL isolates were resistant to imipenem, meropenem, and piperacillin-tazobactam but more than 90% were resistant to amikacin, ciprofloxacin, levofloxacin, ticarcillin and tobramycin. The most prevalent ESBL genes included oxa-10 (70%) and per-1 (50%) followed by veb-1 (31.3%). The gene encodes GES enzyme did not detect in any isolates. A total of 100 P. aeruginosa strains were typed by MLVF typing method. MLVF produced 42 different DNA banding patterns. These data indicate that different MLVF types infect burn wounds in patients at a hospital in Tehran and also suggest an alarming rate of ESBL-producing isolates in this test location. PMID- 21703770 TI - Late-onset rhabdomyolysis in burn patients in the intensive care unit. AB - Rhabdomyolysis (RML), defined as creatine phosphokinase (CPK) >1000 U/L, is relatively common immediately after a significant burn. Late-onset RML, occurring a week or more after a burn, is less well understood and recognised. All patients admitted to the Intensive Care Unit (ICU) following an acute burn between May 2006 and December 2009 were retrospectively identified. Patients with CPK>1000 U/L a week or more after their burn had a detailed notes review. Seventy-six patients were admitted during 43 months. Late-onset RML was demonstrated in 7/76 (9%) patients. They had a similar pattern of normal or mildly raised CPK on admission that resolved over the following days, but suddenly increased sharply to over 1000 U/L, a week or more after their burn, usually around day ten. A severe late-onset RML occurred in 5/76 (7%) patients, with a CPK rise of over 5000 U/L, and all required haemodialysis. Potential triggering factors for late onset RML include sepsis, nephrotoxic drugs and hypophosphataemia. It is important to consider measuring CPK in all patients with the above complications, even after it has previously been observed to be normal, in order to initiate early treatment. PMID- 21703771 TI - Could antioxidants be the "magic pill" for cirrhosis-related complications? A pathophysiological appraisal. AB - Patients with liver cirrhosis are prone to serious complications by almost all systems, leading to high morbidity rates and even death. Although the functional and structural derangement of diverse vital organs developed in the course of advanced liver disease is the result of one entity (cirrhosis) there are various treatment modalities for each system's complications, which are often ineffective. Identification of the link which connects the complications of cirrhosis from diverse systems might lead to a global, simple and more effective treatment approach for patients with cirrhosis. Accumulating evidence from experimental and clinical studies suggests that intestinal barrier dysfunction and subsequent gut-derived endotoxemia represent an important common pathogenetic mechanism in the development of diverse complications of cirrhosis. Intestinal oxidative stress seems to be a pivotal factor of gut barrier dysfunction in cirrhosis through promotion of enterocyte apoptosis, modulation of intestinal tight junctions and impairment of intestinal brush border function. In parallel, oxidative stress plays a fundamental role in the aggravation of liver injury and in the structural and/or functional derangements of diverse organs complicating the course of cirrhosis. Our hypothesis is that antioxidant treatments could prevent in a global way virtually all cirrhosis-related complications acting in two crucial levels in the pathophysiological cascade of events: (a) in a primary level, which is the gut-liver axis by ameliorating gut-derived endotoxemia, through prevention of intestinal oxidative stress and its associated gut barrier dysfunction, concurrently conferring direct antioxidant protection in the liver tissue and (b) in a secondary level, which refers to the diverse organs whose function is affected by liver cirrhosis, by preventing their oxidant-related structural and functional derangements. PMID- 21703772 TI - Recombinant human IGF-1 for patients with schizophrenia. AB - Schizophrenia is a disease where brain connectivity abnormalities are present. Evidence support the fact that these abnormalities are related to demyelination. Experimental and preclinical data support the fact that IGF-1 treatment enhances the myelination process through oligodendrocytes stimulation. Clinical data in patients suffering from demyelinating diseases such as multiple sclerosis show that IGF-1 treatment is safe. Yet, there is no clinical evidence supporting the fact that IGF-1 treatment is efficient in modifying the course of this disease. Clinical evidence supports the fact that patients suffering from schizophrenia present low IGF-1 levels. Accordingly, the administration of IGF-1 for the treatment of schizophrenia symptoms might be an efficient way to treat these symptoms. Subcutaneous recombinant human IGF-1 in the dose of 0.05 mg/kg given twice daily might be administered because this form of treatment has proved its safe profile. According to some evidence, treatment initiation might be more efficient at the disease onset rendering it more appropriate to be tested in patients presenting with first episode psychosis. It can also be tested as an adjuvant treatment to antipsychotic agents. PMID- 21703773 TI - 57th International Congress of Meat Science and Technology: ICoMST 2011. PMID- 21703774 TI - Carcass and meat palatability breed differences and heterosis effects in an Angus Brahman multibreed population. AB - Additive genetic Angus-Brahman differences, heterosis effects, and least squares means for six carcass and six meat palatability traits were estimated using data from 1367 steers from the Angus-Brahman multibreed herd of the University of Florida collected from 1989 to 2009. Brahman carcasses had higher dressing percent (P<0.0001), lower marbling (P<0.0001), smaller ribeye area (P<0.0001), and less fat over the ribeye (P<0.0001) than Angus carcasses. Brahman beef was less tender (P<0.0001), had more connective tissue (P<0.0001), and it was less juicy (P<0.001) than Angus beef. Heterosis increased hot carcass weight (P<0.0001), dressing percent (P<0.017), ribeye area (P<0.0001), fat over the ribeye (P<0.0001), and kidney, pelvic, and heart fat (P<0.01) in Angus-Brahman crossbred steers. Results indicated that crossbred animals with up to 50% Brahman showed limited negative impact on meat quality while maximizing meat yield due to heterosis. PMID- 21703775 TI - Development of a beef flavor lexicon and its application to compare the flavor profile and consumer acceptance of rib steaks from grass- or grain-fed cattle. AB - Ten panelists were selected from the local community to develop a meat lexicon composed of 18 terms that describe flavor attributes found in red meats. This flavor lexicon was used to compare the flavor profile of meat from beef cattle finished on grass or grain. Steaks from grass-fed animals were significantly (P<0.05) higher in barny, bitter, gamey, and grassy flavor, and lower in juicy and umami notes. Gamey, barny, bitter and grassy were some of the attributes inversely correlated to the degree of liking of the meat and therefore can be classified as "negative" attributes. Brothy, umami, roast beef, juicy, browned, fatty and salty are some of the attributes positively correlated to the degree of liking of beef and therefore can be identified as attributes that drive consumers' acceptance. Steaks from grass-fed cattle were rated by consumers as slightly liked (6.08 on a 9-point scale), while steaks from grain-fed animals were rated as moderately liked (7.05 on a 9-point scale). PMID- 21703776 TI - Effects of dietary digestible energy concentration on growth, meat quality, and PPARgamma gene expression in muscle and adipose tissues of Rongchang piglets. AB - This study investigated the effects of dietary digestible energy (DE) concentration (3.20, 3.40, 3.60 & 3.80 M cal/kg) on growth, meat quality, and PPARgamma gene expression in muscle and adipose tissues of Rongchang piglets. There was a quadratic increase in average daily gain and a linear decrease in the ratio of feed intake and gain as dietary DE increased (P<0.05). Increasing dietary DE resulted in a linear increase of back fat thickness and intramuscular fat content (P<0.05). A significant linear or quadratic effect (P<0.01) was detected for shearing force. Increasing dietary DE linearly enhanced the expression of PPARgamma in adipose tissues (P<0.01). These data suggest that dietary DE had an impact on carcass and meat quality of Rongchang piglets. This could be partly due to the increased gene expression of PPARgamma in adipose tissues, which may regulate the fat deposition of whole body. PMID- 21703777 TI - Quality characteristics of Dutch-style fermented sausages manufactured with partial replacement of pork back-fat with pure, pre-emulsified or encapsulated fish oil. AB - Dutch-style fermented sausages were manufactured with 15% and 30% pork back-fat substitution by pure or commercial encapsulated fish oil, either added as such or as pre-emulsified mixture with soy protein isolate. Adding commercial encapsulated fish oil was the most important factor influencing the chemical composition. The fat content was not significantly different between products (p>0.05). The n-6/n-3 ratio decreased from 8.49 in controls to 0.90-2.47 in modified products. Lipid oxidation parameters (propanal and hexanal) showed much higher values for sausages with pure fish oil than for products with encapsulated oil. For the latter, lipid oxidation was similar to controls. Products with encapsulated or pre-emulsified oil were significantly firmer than products from other treatments in physical and sensory analysis (p<0.05). Overall, it is technologically feasible to enrich dry fermented sausages with n-3 fatty acids from fish oil and the application of commercial encapsulated fish oil seems to be the best in retaining overall quality. PMID- 21703778 TI - Effect of lactoferrin and its derivatives against gram-positive bacteria in vitro and, combined with high pressure, in chicken breast fillets. AB - The bactericidal activity of lactoferrin (LF), amidated lactoferrin (AMILF), pepsin digested lactoferrin (PDLF), and its activated (ALF) commercial form, against six strains of three gram-positive bacterial species was investigated. Listeria monocytogenes was most sensitive in vitro, Staphylococcus aureus showed a moderate resistance, and Enterococus faecalis was highly resistant to antimicrobials. When chicken breast fillets were inoculated with L. monocytogenes CECT5725 and treated with antimicrobials, reductions were below 0.5 logCFU/ml in all cases. In combination with high pressure (HHP) treatment at 400 MPa for 10 min, antimicrobials showed a slight additional bactericidal effect, always below 1 logCFU/g. Incorporation of antimicrobials 18 h before or 1 h after HHP treatment generally yielded better results than incorporation 1 h before HHP treatment, although reductions remained below 1.5 logCFU/g in all cases. LF and its derivatives showed a limited potential for pathogen control in meat. PMID- 21703779 TI - Avocado, sunflower and olive oils as replacers of pork back-fat in burger patties: effect on lipid composition, oxidative stability and quality traits. AB - The present study investigates the effects of avocado, sunflower and olive oils used as back-fat replacers, on the fatty acid composition, oxidative stability, volatiles profile and color and texture properties of cooked pork patties. The vegetable oils modified the fatty acid profiles of the patties by lowering the percentages of SFA (from 36.96% to ~25.30%) and reducing the atherogenic index (from 0.41 to ~0.24). Vegetable oils had higher amounts of antioxidant compounds such as tocopherols (10.8-53.9 mg/100 g) than back-fat (5.9 mg/100 g). Consistently, patties manufactured with the oils had significantly lower amounts of lipid and protein oxidation products than control patties. Avocado oil contributed with specific aroma-active terpenes to patties and had a significant impact on particular color and texture parameters. The results from this study highlight the technological applications of the vegetable oils as food ingredients in the design of healthier meat commodities. PMID- 21703780 TI - Magnitude of interfractional vaginal cuff movement: implications for external irradiation. AB - PURPOSE: To quantify the extent of interfractional vaginal cuff movement in patients receiving postoperative irradiation for cervical or endometrial cancer in the absence of bowel/bladder instruction. METHODS AND MATERIALS: Eleven consecutive patients with cervical or endometrial cancer underwent placement of three gold seed fiducial markers in the vaginal cuff apex as part of standard of care before simulation. Patients subsequently underwent external irradiation and brachytherapy treatment based on institutional guidelines. Daily megavoltage CT imaging was performed during each external radiation treatment fraction. The daily positions of the vaginal apex fiducial markers were subsequently compared with the original position of the fiducial markers on the simulation CT. Composite dose-volume histograms were also created by summing daily target positions. RESULTS: The average (+/- standard deviation) vaginal cuff movement throughout daily pelvic external radiotherapy when referenced to the simulation position was 16.2 +/- 8.3 mm. The maximum vaginal cuff movement for any patient during treatment was 34.5 mm. In the axial plane the mean vaginal cuff movement was 12.9 +/- 6.7 mm. The maximum vaginal cuff axial movement was 30.7 mm. In the craniocaudal axis the mean movement was 10.3 +/- 7.6 mm, with a maximum movement of 27.0 mm. Probability of cuff excursion outside of the clinical target volume steadily dropped as margin size increased (53%, 26%, 4.2%, and 1.4% for 1.0, 1.5, 2.0, and 2.5 cm, respectively.) However, rectal and bladder doses steadily increased with larger margin sizes. CONCLUSIONS: The magnitude of vaginal cuff movement is highly patient specific and can impact target coverage in patients without bowel/bladder instructions at simulation. The use of vaginal cuff fiducials can help identify patients at risk for target volume excursion. PMID- 21703781 TI - A beam-specific planning target volume (PTV) design for proton therapy to account for setup and range uncertainties. AB - PURPOSE: To report a method for explicitly designing a planning target volume (PTV) for treatment planning and evaluation in heterogeneous media for passively scattered proton therapy and scanning beam proton therapy using single-field optimization (SFO). METHODS AND MATERIALS: A beam-specific PTV (bsPTV) for proton beams was derived by ray-tracing and shifting ray lines to account for tissue misalignment in the presence of setup error or organ motion. Range uncertainties resulting from inaccuracies in computed tomography-based range estimation were calculated for proximal and distal surfaces of the target in the beam direction. The bsPTV was then constructed based on local heterogeneity. The bsPTV thus can be used directly as a planning target as if it were in photon therapy. To test the robustness of the bsPTV, we generated a single-field proton plan in a virtual phantom. Intentional setup and range errors were introduced. Dose coverage to the clinical target volume (CTV) under various simulation conditions was compared between plans designed based on the bsPTV and a conventional PTV. RESULTS: The simulated treatment using the bsPTV design performed significantly better than the plan using the conventional PTV in maintaining dose coverage to the CTV. With conventional PTV plans, the minimum coverage to the CTV dropped from 99% to 67% in the presence of setup error, internal motion, and range uncertainty. However, plans using the bsPTV showed minimal drop of target coverage from 99% to 94%. CONCLUSIONS: The conventional geometry-based PTV concept used in photon therapy does not work well for proton therapy. We investigated and validated a beam specific PTV method for designing and evaluating proton plans. PMID- 21703782 TI - Radiosurgery of glomus jugulare tumors: a meta-analysis. AB - PURPOSE: During the past two decades, radiosurgery has arisen as a promising approach to the management of glomus jugulare. In the present study, we report on a systematic review and meta-analysis of the available published data on the radiosurgical management of glomus jugulare tumors. METHODS AND MATERIALS: To identify eligible studies, systematic searches of all glomus jugulare tumors treated with radiosurgery were conducted in major scientific publication databases. The data search yielded 19 studies, which were included in the meta analysis. The data from 335 glomus jugulare patients were extracted. The fixed effects pooled proportions were calculated from the data when Cochrane's statistic was statistically insignificant and the inconsistency among studies was <25%. Bias was assessed using the Egger funnel plot test. RESULTS: Across all studies, 97% of patients achieved tumor control, and 95% of patients achieved clinical control. Eight studies reported a mean or median follow-up time of >36 months. In these studies, 95% of patients achieved clinical control and 96% achieved tumor control. The gamma knife, linear accelerator, and CyberKnife technologies all exhibited high rates of tumor and clinical control. CONCLUSIONS: The present study reports the results of a meta-analysis for the radiosurgical management of glomus jugulare. Because of its high effectiveness, we suggest considering radiosurgery for the primary management of glomus jugulare tumors. PMID- 21703784 TI - Methicillin-resistant Staphylococcus pseudintermedius among cats admitted to a veterinary teaching hospital. PMID- 21703785 TI - Tungiasis: a poorly documented tropical dermatosis. AB - Tungiasis is the parasitic skin disease caused by the sand flea Tunga penetrans, also called the jigger flea, found in most intertropical countries. The contamination occurs when walking barefoot in the sand: adult females actively burrow the foot epidermis leading to self-limited lesions responsible for itching or pain. The diagnosis is made on clinical observation and history of travelling to an endemic country. The simple treatment is surgical extraction of the flea. PMID- 21703783 TI - Deficits in default mode network activity preceding error in cocaine dependent individuals. AB - BACKGROUND: Cocaine dependence is associated with cognitive deficits and altered task-related cerebral activation in cognitive performance (see Li and Sinha, 2008, for a review). Relatively little is known whether these individuals are also impaired in regional brain activation of the default mode network (DMN). We demonstrated previously that greater activation of the default brain regions precedes errors in a stop signal task performed by healthy controls (SST, Li et al., 2007). We seek to determine whether individuals with cocaine dependence are impaired in DMN activity, specifically activity preceding error, as compared to the healthy people. We also examine the relation to years of cocaine use. METHODS: Individuals with cocaine dependence (CD, n=23) and demographics-matched healthy controls (HC, n=27) performed a SST that employed a tracking procedure to adjust the difficulty of stop trials and elicit errors approximately half of the time. Blood oxygenation level dependent (BOLD) signals of go trials preceding stop error as compared to those preceding stop success trials were extracted with generalized linear models using statistical parametric mapping. RESULTS: HC showed activation of bilateral precuneus and posterior cingulate cortices and ventromedial prefrontal cortex (vmPFC) preceding errors during the SST. In contrast, despite indistinguishable stop signal performance, CD did not show these error predicting activations. Furthermore, the effect size of error preceding vmPFC activation was inversely correlated with years of cocaine use. CONCLUSIONS: These findings indicate DMN deficits and could potentially add to our understanding of the effects of chronic cocaine use on cerebral functions in cocaine dependence. Work to further clarify potential changes in functional connectivity and gray matter volume is warranted to understand the relevance of DMN to the pathology of cocaine misuse. PMID- 21703786 TI - [Effectiveness and risks related to enteric decolonization with oral streptomycin for glycopeptide-resistant enterocci carriers]. PMID- 21703787 TI - [Measles in the Nantes Teaching Hospital during the 2008-2009 epidemic]. AB - OBJECTIVE: A recent measles epidemic in France incited us to report and describe measles cases requiring hospitalization, to raise the awareness of health professionals on under-diagnosis and frequent complications of this viral disease. DESIGN: We carried out a retrospective and epidemiologic study of measles cases recorded in the Nantes Teaching Hospital between August 2008 and September 2009. All these cases where confirmed by biological diagnosis and recorded by the Teaching Hospital virological laboratory. RESULTS: Thirteen cases of measles (11 adults and two children) were recorded during the study period. Adults were young (mean age 21.4 years); the oldest was 35 years old. We noted two severe cases with viral pneumonia and hypoxemia and one case with bacterial pneumonia. Two female patients were pregnant; one delivered prematurely, in the acute phase of measles, with no complication for the newborn. Two cases occurred in the nursing staff by documented nosocomial transmission. Sixty-nine percent of the patients were not vaccinated whereas the vaccinal status was not documented for 31%. CONCLUSIONS: These cases underline the potential severity of this infection and the difficulty to diagnose measles at the early phase because of lack of awareness of medical staff. It will be necessary to reinforce prevention messages and promote measles vaccination in children as well as in young people and health workers. PMID- 21703788 TI - Reduced-dose chest CT with 3D automatic exposure control vs. standard chest CT: quantitative assessment of emphysematous changes in smokers' lung parenchyma. AB - OBJECTIVES: To determine the capability of reduced-dose chest CT with three dimensional (3D) automatic exposure control (AEC) on quantitative assessment of emphysematous change in smoker' lung parenchyma, compared to standard chest CT. METHODS: Twenty consecutive smoker patients (mean age 62.8 years) underwent CT examinations using a standard protocol (150 mAs) and a protocol with 3D-AEC. In this study, the targeted standard deviations number was set to 160. For quantitative assessment of emphysematous change in lung parenchyma in each subject using the standard protocol, a percentage of voxels less than -950 HU in the lung (%LAA(-950)) was calculated. The 3D-AEC protocol's %LAA was computed from of voxel percentages under selected threshold CT value. The differences of radiation doses between these two protocols were evaluated, and %LAAs(-950) was compared with the 3D-AEC protocol %LAAs. RESULTS: Mean dose length products were 780.2 +/- 145.5 mGy cm (standard protocol), and 192.0 +/- 95.9 (3D-AEC protocol). There was significant difference between them (paired Student's t test, p<0.00001). Meanwhile, only setting -960 HU yielded no significant difference (paired Student's t test, p=0.32) between %LAAs(-950) and 3D-AEC protocol %LAAs. In adopting the feasible threshold CT values of the 3D-AEC protocol, the 3D-AEC protocol %LAAs were significantly correlated with %LAAs(-950) (r = 0.98, p<0.001) and limits of agreement from Bland-Altman analysis was 0.52 +/- 4.3%. CONCLUSIONS: Changing threshold CT values demonstrated that reduced-dose chest CT with 3D-AEC can substitute for the standard protocol in assessments of emphysematous change in smoker' lung parenchyma. PMID- 21703789 TI - CT-guided transthoracic cutting needle biopsy of intrathoracic lesions: comparison between coaxial and single needle technique. AB - PURPOSE: To evaluate the complication rates and diagnostic accuracy of two different CT-guided transthoracic cutting needle biopsy techniques: coaxial method and single needle method. METHODS: This study involved 198 consecutive subjects with 198 intrathoracic lesions. The first 98 consecutive subjects received a single needle cutting technique and the next 100 consecutive subjects received a coaxial technique. Both groups were compared in relation the diagnostic accuracy and complication rates. RESULTS: No significant difference was found between the two groups concerning patient characteristics, lesions and procedure variables. There was a borderline statistical difference in the incidence of pneumothorax at within 24-h post biopsy between patients in the single needle group (5%) and the coaxial group (13%) (P=0.053). Little difference was found in the pneumothorax rate at immediately post biopsy between the two groups, which was 28% in the single needle group and 31% in the coaxial group. There was no significant difference in the hemoptysis rate between the two groups, which was 9.2% in the single needle group and 11% in the coaxial group. Both techniques yielded an overall diagnostic accuracy of 98% for malignant lesions with similar sensitivity (single needle: 96.9% vs. coaxial: 96.4%) and specificity (single needle: 100% vs. coaxial: 100%). CONCLUSION: There is little difference in the pneumothorax rates and bleeding complications between patients who either received a single needle or a coaxial transthoracic cutting biopsy. Both techniques produce an overall diagnostic accuracy of 98% for malignant lesions. PMID- 21703790 TI - Comparison of coronal and axial computed tomography measurements of mediastinal nodes before primary surgery for non-small cell lung cancer. AB - OBJECTIVE: To assess computed tomography (CT) evaluation of mediastinal nodes in non-small cell lung cancer to predict metastatic involvement by measurement of their axis and surface area in the coronal plane, as compared to standard short axis measures in the axial plane. METHODS: Evaluation of mediastinal nodes was retrospectively performed on CT scans of 100 patients before thoracotomy. In all patients, mediastinal dissection was performed in the appropriate stations (n=264) according to the side (59 right, 41 left) of the tumor. Measurements of short axis and surface area of the largest node in each dissected station were performed on axial and coronal planes. RESULTS: By using the standard threshold of axial short axis >=10 mm, sensitivity and specificity were 25% and 98%, respectively. Areas under receiver operating characteristic curves were 0.828 and 0.821 for axial short axis and axial surface area data. For comparison, areas under receiver operating characteristic curves were 0.843 and 0.845 for coronal short axis and coronal surface area data, respectively. So, for a specificity of 98%, sensitivity was 29% for coronal short axis >=11 mm and 33% for coronal surface area >=123 mm(2). When using axial short axis >=10 mm or coronal surface area >=120 mm(2), sensitivity was 45%, whereas specificity remained at 96%. CONCLUSION: Coronal measurements of mediastinal nodes give a slightly albeit non significant improvement of diagnostic accuracy over axial ones. If both axial short axis and coronal surface area are taken into account, accuracy is improved. PMID- 21703791 TI - Prospectively ECG gated CT pulmonary angiography versus helical ungated CT pulmonary angiography: impact on cardiac related motion artifacts and patient radiation dose. AB - OBJECTIVE: To compare prospectively ECG gated CT pulmonary angiography (CTPA) with routine helical ungated CTPA for cardiac related motion artifacts and patient radiation dose. SUBJECTS AND METHODS: Twenty patients with signs and symptoms suspicious for pulmonary embolism and who had a heart rate below 85 were scanned with prospectively ECG gated CTPA. These gated exams were matched for several clinical parameters to exams from twenty similar clinical patients scanned with routine ungated helical CTPA. Three blinded independent reviewers subjectively evaluated all exams for overall pulmonary artery enhancement and for several cardiac motion related artifacts, including vessel blurring, intravascular shading, and double line. Reviewers also measured pulmonary artery intravascular density and image noise. Patient radiation dose for each technique was compared. Fourteen clinical prospectively ECG gated CTPA exams from a second institution were evaluated for the same parameters. RESULTS: Prospectively ECG gated CTPA resulted in significantly decreased motion-related image artifact scores in lung segments adjacent to the heart compared to ungated CTPA. Measured image noise was not significantly different between the two types of CTPA exams. Effective dose was 28% less for prospectively ECG gated CTPA (4.9 mSv versus 6.8 mSv, p=0.02). Similar results were found in the prospectively ECG gated exams from the second institution. CONCLUSION: Compared to routine helical ungated CTPA, prospectively ECG gated CTPA may result in less cardiac related motion artifact in lung segments adjacent to the heart and significantly less patient radiation dose. PMID- 21703792 TI - Agreement of duplex ultrasonography vs. computed tomography angiography for evaluation of native and in-stent SFA re-stenosis--findings from a randomized controlled trial. AB - BACKGROUND: Multidetector CT angiography (CTA) is a non-invasive imaging technique for evaluation of peripheral vascular disease. CTA might be particularly useful for assessment of intermediate- and long-term morphological outcome after endovascular treatment. Validation of CTA vs. the current imaging standard, colour Doppler ultrasonography (CDUS), for quantification of native and in-stent re-stenosis in the superficial femoral artery (SFA) is required. METHODS: Seventy randomized patients who underwent stent implantation (n=47) or balloon angioplasty (n=23) underwent 6-month follow-up with CDUS and CTA. CTA was compared with CDUS in both sub-groups of patients in terms of binary re-stenosis (>50% lumen narrowing) and re-occlusion. Agreement between CTA and CDUS was assessed using Kappa (kappa) statistics with 95% confidence intervals, and correlation coefficients. RESULTS: Binary re-stenosis was detected in 16/70 (22.9%) patients by CTA and 17/70 (24.3%) patients by CDUS (kappa=0.88, 95% CI: 0.80-0.96). Re-stenosis rates after balloon angioplasty were 39.1% (9/23) on CTA and CDUS (kappa=0.82, 95% CI: 0.66-0.98), and after stent implantation 14.9% (7/47) on CTA and 17.0% (8/47) on CDUS (kappa=0.92, 95% CI: 0.84-1.00). Re occlusions were detected in 3/70 (4.3%) patients by both CTA and CDUS (kappa=0.65; 95% CI 0.54-0.76). Significant correlations (r=0.85, p<0.001) were noted between degree of re-stenosis on CTA and peak velocity ratio on CDUS. The correlation coefficient was higher in patients after balloon angioplasty (r=0.94, p<0.001) than in patients after stent implantation (r=0.71, p<0.001). CONCLUSION: CTA and CDUS show excellent agreement for evaluation of native and in-stent re stenosis after endovascular treatment of SFA obstructions. CTA is an appropriate non-invasive imaging modality for follow-up after endovascular therapy. PMID- 21703793 TI - Estimation and comparison of effective dose (E) in standard chest CT by organ dose measurements and dose-length-product methods and assessment of the influence of CT tube potential (energy dependency) on effective dose in a dual-source CT. AB - PURPOSE: To determine effective dose (E) during standard chest CT using an organ dose-based and a dose-length-product-based (DLP) approach for four different scan protocols including high-pitch and dual-energy in a dual-source CT scanner of the second generation. MATERIALS AND METHODS: Organ doses were measured with thermo luminescence dosimeters (TLD) in an anthropomorphic male adult phantom. Further, DLP-based dose estimates were performed by using the standard 0.014mSv/mGycm conversion coefficient k. Examinations were performed on a dual-source CT system (Somatom Definition Flash, Siemens). Four scan protocols were investigated: (1) single-source 120kV, (2) single-source 100kV, (3) high-pitch 120kV, and (4) dual energy with 100/Sn140kV with equivalent CTDIvol and no automated tube current modulation. E was then determined following recommendations of ICRP publication 103 and 60 and specific k values were derived. RESULTS: DLP-based estimates differed by 4.5-16.56% and 5.2-15.8% relatively to ICRP 60 and 103, respectively. The derived k factors calculated from TLD measurements were 0.0148, 0.015, 0.0166, and 0.0148 for protocol 1, 2, 3 and 4, respectively. Effective dose estimations by ICRP 103 and 60 for single-energy and dual-energy protocols show a difference of less than 0.04mSv. CONCLUSION: Estimates of E based on DLP work equally well for single-energy, high-pitch and dual-energy CT examinations. The tube potential definitely affects effective dose in a substantial way. Effective dose estimations by ICRP 103 and 60 for both single-energy and dual-energy examinations differ not more than 0.04mSv. PMID- 21703794 TI - MRI after patellofemoral replacement: the preserved compartments. AB - INTRODUCTION: The aim of this study was to assess the reproducibility of magnet resonance imaging (MRI) analysis of preserved anatomic structures of the knee after patellofemoral replacement (PFR). It was hypothesized that evaluation of cartilage, ligaments, meniscus and tendons would result in high inter-observer reliability after PFR. MATERIAL AND METHODS: MRI, tailored to reduce metallic artefacts of the knee, after PFR was performed in seven patients. Two independent investigators evaluated cartilage, menisci, collateral and cruciate ligaments, the quadriceps and patellar tendons and the presence of joint effusion. The reviewers used a five-point scale to give a degree of confidence to their evaluation of each parameter. Inter-observer reliability was determined by calculation of Cohen's Kappas. RESULTS: Artefact provoked by the implants was not observed. For all assessed structures, there was excellent inter-observer reliability, with high Cohen's Kappas. There were also high levels of inter observer agreement and observer confidence in the evaluation of cartilage, meniscus, tendons, ligaments and joint effusion. CONCLUSION: Tailored MRI allows reproducible analysis of the preserved knee joint structures after PFR. It might prove helpful in assessment of painful knee joints after PFR. PMID- 21703795 TI - Comparison of arterial and venous coronary artery bypass flow measurements using 3-T magnetic resonance phase contrast imaging. AB - OBJECTIVE: Comparison of arterial and venous coronary artery bypass flow measurements using 3-T magnetic resonance (MR) phase contrast in correlation with intraoperative Doppler flow measurements. METHODS: Fifty-six coronary bypasses (right coronary artery n=18, left internal mammary artery to left anterior descending artery n=16, marginal artery n=7, circumflex artery n=7, diagonal artery n=6, left anterior descending artery n=1, and right internal mammary artery to right coronary artery n=1) were studied in 27 asymptomatic patients. In this prospective study, each bypass was studied intra-operatively using Doppler flow measurement. Within one week post surgery, patients were studied using a 3-T MR scanner (Magnetom Verio, Siemens, Erlangen, Germany) using velocity encoded phase-contrast flow measurements. RESULTS: Intraoperative Doppler flow measurements demonstrated regular flow patterns in all vascular territories supplied. All bypasses were patent on MRI and flow measurement results were as follows: median flow 60ml/min (interquartile range (IQR): 37.5-78.5ml/min). For comparison, the corresponding median intraoperative flow was 58ml/min (IQR: 41 80ml/min) (p<0.001; R=0.44). Linear regression analysis demonstrated a significant correlation for venous bypasses (p=0.0002; R=0.48), but not for arterial bypasses (p=0.09; R=0.24). CONCLUSION: This study demonstrated that MR flow measurements of venous bypass grafts agreed more with Doppler than arterial bypass grafts. However, bypass patency was confirmed for all patients. In the future, this technique may be used for non invasive coronary bypass graft follow up. PMID- 21703796 TI - Isolation, identification and antiviral activities of metabolites of calycosin-7 O-beta-D-glucopyranoside. AB - In vivo and in vitro metabolites of calycosin-7-O-beta-D-glucopyranoside in rats were identified using a specific and sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS(n)) method. The parent compound and twelve metabolites were found in rat urine after oral administration of calycosin-7-O-beta-D-glucopyranoside. The parent compound and six metabolites were detected in rat plasma. In heart, liver, spleen, lung and kidney samples, respectively, six, eight, seven, nine and nine metabolites were identified, in addition to the parent compound. Three metabolites, but no trace of parent drug, were found in the rat intestinal flora incubation mixture and feces, which demonstrated cleavage of the glycosidic bond of the parent compound in intestines. The main phase I metabolic pathways of calycosin-7-O-beta-D glucopyranoside in rats were deglycosylation, dehydroxylation and demethylation reactions; phase II metabolism included sulfation, methylation, glucuronidation and glycosylation (probably). Furthermore, two metabolites commonly found in rat urine, plasma and tissues were isolated from feces and characterized by NMR. The antiviral activities of the metabolite calycosin against coxsackie virus B3 (CVB3) and human immunodeficiency virus (HIV) were remarkably stronger than those of calycosin-7-O-beta-D-glucopyranoside. PMID- 21703797 TI - Quantitative determination of lysophosphatidic acids (LPAs) in human saliva and gingival crevicular fluid (GCF) by LC-MS/MS. AB - Lysophosphatidic acid (LPA) is a phospholipid mediator that plays multiple cellular functions by acting through G protein-coupled LPA receptors. LPAs are known to be key mediators in inflammation, and several lines of evidence suggest a role for LPAs in inflammatory periodontal diseases. A simple and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method has been developed and validated to quantify LPA species (LPA 18:0, LPA 16:0, LPA 18:1 and LPA 20:4) in human saliva and gingival crevicular fluid (GCF). LPA 17:0 was used as an internal standard and the LPA species were extracted from saliva by liquid-liquid extraction using butanol. Chromatography was performed using a Macherey-Nagel NUCLEODUR(r) C8 Gravity Column (125 mm * 2.0 mm ID) with a mixture of methanol/water: 75/25 (v/v) containing 0.5% formic acid and 5 mM ammonium formate (mobile phase A) and methanol/water: 99/0.5 (v/v) containing 0.5% formic acid and 5mM ammonium formate (mobile phase B) at a flow rate of 0.5 mL/min. LPAs were detected by a linear ion trap-triple quadrupole mass spectrometer with a total run time of 8.5 min. The limit of quantification (LOQ) in saliva was 1 ng/mL for all LPA species and the method was validated over the range of 1-200 ng/mL. The method was validated in GCF over the ranges of 10-500 ng/mL for LPA 18:0 and LPA 16:0, and 5-500 ng/mL for LPA 18:1 and LPA 20:4. This sensitive LC MS/MS assay was successfully applied to obtain quantitative data of individual LPA levels from control subjects and patients with various periodontal diseases. All four LPA species were consistently elevated in samples obtained from periodontal diseases, which supports a role of LPAs in the pathogenesis of periodontal diseases. PMID- 21703798 TI - Potential of synchrotron X-ray powder diffractometry for detection and quantification of small amounts of crystalline drug substances in pharmaceutical tablets. AB - The purpose of this study was to develop a sensitive system for detection of crystalline drug substances in intact pharmaceutical tablets by X-ray powder diffractometry (XRPD), using synchrotron X-rays. Fenoprofen calcium dihydrate was used as a model compound. The wavelength and path length of X-rays from synchrotron radiation were optimized in order to maximize the potential of the synchrotron radiation. The optimum wavelength and path length for the measurement of fenoprofen calcium dihydrate were found to be 0.69817 A and 6.0 mm, respectively, based on theoretical calculations. Under the optimized conditions, a limit of quantification of 0.05% (RSD=9.4%, n=3) and a limit of detection of 0.02% (RSD=17.3%, n=3), results which are approximately 102 times as sensitive as those obtained using conventional XRPD instruments, were achieved. The technique was also applied to fenoprofen calcium dihydrate detection in intact film-coated tablets, which contained Ti in the coating film, and a limit of detection of 0.02% was again attained. PMID- 21703799 TI - An alternative approach to community consultation for emergency research without informed consent. PMID- 21703800 TI - A new electrocardiographic criteria for emergent reperfusion therapy. AB - The benefit of emergency reperfusion therapy with fibrinolytics or primary percutaneous coronary intervention in patients with ST-segment elevation (STE) acute myocardial infarction (MI) is well known. However, what is not well known are which subgroups of MI patients with ST-segment depression (STD) on the 12 lead electrocardiogram (ECG) may benefit from emergent reperfusion therapy. Current clinical guidelines recommend against administering emergent reperfusion therapy to MI patients with STD on the ECG unless a true posterior MI is suspected. Overlooked subgroups of patients with STD on the initial ECG who may potentially benefit from emergent reperfusion therapy are patients with multilead STD with coexistent STE in lead aVR. This finding has been reported in MI patients with occlusion of the left main artery, occlusion of the proximal left anterior descending artery, and MI in the presence of severe multivessel coronary artery disease. Because these patients have a higher mortality in the setting of MI, we believe that this ECG finding be considered a STEMI equivalent and that patients with this finding receive consideration for emergent reperfusion therapy preferably at a center with both primary percutaneous coronary intervention and coronary artery bypass grafting capability. In this report, we present 3 such patients to heighten the awareness of the emergency physician to this phenomenon. PMID- 21703801 TI - Standard-length catheters vs long catheters in ultrasound-guided peripheral vein cannulation. AB - PURPOSE: Ultrasound (US) is a useful tool for peripheral vein cannulation in patients with difficult venous access. However, few data about the survival of US guided peripheral catheters in acute care setting exist. Some studies showed that the survival rate of standard-length catheters (SC) is poor especially in obese patients. The use of longer than normal catheters could provide a solution to low survival rate. The aim of the present study was to compare US-guided peripheral SCs vs US-guided peripheral long catheters inserted with Seldinger technique (LC) in acute hospitalized patients with difficult venous access. METHODS: This was a prospective, randomized controlled trial. A total of 100 consecutively admitted subjects in an urban High Dependency Unit were randomized to obtain US-guided intravenous access using either SC or LC after 3 failed blind attempts. Primary outcome was catheter failure rate. RESULTS: Success rate was 86% in the SC groups and 84% in the LC group (P=.77). Time requested to positioning venous access resulted to be shorter for SC as opposed to LC (9.5 vs 16.8 minutes, respectively; P=.001). Catheter failure was observed in 45% of patients in the SC group and in 14% of patients in the LC group (relative risk, 3.2; P<.001). CONCLUSIONS: Both SC and LC US-guided cannulations have a high success rate in patients with difficult venous access. Notwithstanding a higher time to cannulation, LC US-guided procedure is associated with a lower risk of catheter failure compared with SC US-guided procedure. PMID- 21703802 TI - Association of mechanical chest compression and prehospital thrombolysis. AB - Pulmonary embolism (PE) is a common cause of sudden death; the use of prehospital thrombolysis is currently a last-resort option and requires a prolonged cardiopulmonary resuscitation (CPR). Novel mechanical devices have recently been introduced that provides automatic mechanical chest compression (AMCC) according to the guidelines and continually without decrease efficiency throughout prolonged resuscitation. A 54 year-old woman with a history of breast cancer experienced sudden chest pain and severe dyspnea. A mobile intensive care unit was dispatched to her home. During physical examination, she suddenly collapsed with pulseless electrical activity as the initial rhythm. Prehospital thrombolysis during CPR combined with use of AMCC was performed based on a strongly suspected diagnosis of massive PE. After 75 minutes of effective CPR, return of spontaneous circulation was attained. After admission to an intensive care unit, computed tomographic scan confirmed bilateral PE. The patient was discharged 3 weeks after CPR in good neurologic condition. To our knowledge, this is the first case describing combined use of thrombolysis and AMCC in out ofhospital cardiac arrest. However, for the time being, prehospital thrombolysis in CPR continues to be a measure that should only be performed on a case-by-case basis based on informed decision. Further studies are needed to evaluate the efficacy and safety of AMCC with thrombolysis and thus prolonged CPR. PMID- 21703803 TI - The rest of the story. PMID- 21703804 TI - Efficiency of the kidney disease outcomes quality initiative guidelines for preemptive vascular access in an academic setting. AB - BACKGROUND: The National Kidney Foundation-Kidney Diseases Outcomes Quality Initiative (KDOQI) for vascular access guidelines state that patients with late stage chronic kidney disease (CKD) should undergo native arteriovenous fistula (AVF) creation at least 6 months before anticipated start of hemodialysis (HD) treatments to obviate the need for other vascular access types, such as grafts or central catheters. OBJECTIVE: The objective of this study was to determine the incidence of HD, the functional patency, and associated morbidity of AVFs in patients with late-stage CKD placed according to KDOQI. METHODS: Consecutive patients with late-stage CKD who underwent AVF creation using KDOQI guidelines for anatomy between January 2003 and December 2007 at two tertiary academic centers were retrospectively evaluated. Baseline demographics, AVF type, and clinical comorbidities were recorded. Patients were stratified into one of four groups (groups A-D) over the follow-up course based on two end points: patency of their AVF and whether or not they began HD. The ideal primary outcome was AVF maturation and use for HD (group A; cumulative functional patency). Other outcomes included AVF patency but no HD (group B), HD with AVF failure (group C), or no HD and AVF abandonment (ie, death, refused hemodialysis, kidney transplant, or fistula failure; group D). Secondary outcomes were time to first cannulation, complications, and secondary interventions. RESULTS: AVFs were created (46% forearm and 54% upper arm) in 150 patients with CKD (85% men, median age 63 years old). At a median follow-up of 10 months, 74 patients (49%) were receiving HD and of these, 48 patients (65%) were using their AVF (group A), whereas 26 patients (35%) were not due to fistula failure (group C). Thirty-four patients (23%) never initiated HD treatments, but had a viable AVF (group B), and 42 patients (28%) never initiated HD and abandoned their AVF (group D). Overall, AVF abandonment was 51%. Mean maturation time of all AVFs successfully cannulated was 285 days (range, 30-1265 days). Complications encountered were maturation failure for cannulation (15%), focal stenosis requiring intervention (13%), inadequate flows on HD (9%), steal syndrome (9%), and thrombosis (8%). Cumulative functional patency for all AVFs was 19% and 27% at 6 and 12 months, respectively, with a mean number of two interventions per AVF (range, 1-10). Mortality during the study was 23%. CONCLUSION: Despite successful creation and maturation of a preemptive AVF in nearly two-thirds of patients who started HD during the follow up and given the following observations: the high overall mortality of the population, the morbidity and costs in secondary procedures of AVF creation, and the high incidence of abandonment, it is unclear if this strategy would demonstrate a benefit in a randomized trial when compared to other access strategies. PMID- 21703806 TI - Short-term results of a randomized trial examining timing of carotid endarterectomy in patients with severe asymptomatic unilateral carotid stenosis undergoing coronary artery bypass grafting. AB - OBJECTIVE: This study evaluated the timing of carotid endarterectomy (CEA) in the prevention of stroke in patients with asymptomatic carotid stenosis >70% receiving a coronary artery bypass graft (CABG). METHODS: From January 2004 to December 2009, 185 patients with unilateral asymptomatic carotid artery stenosis >70%, candidates for CABG, were randomized into two groups. In group A, 94 patients received a CABG with previous or simultaneous CEA. In group B, 91 patients underwent CABG, followed by CEA. All patients underwent preoperative helical computed tomography scans, excluding significant atheroma of the ascending aorta or aortic arch. Baseline characteristics of the patients, type of coronary artery lesion, and preoperative myocardial function were comparable in the two groups. In group A, all patients underwent CEA under general anesthesia with the systematic use of a carotid shunt, and 79 patients had a combined procedure and 15 underwent CEA a few days before CABG. In group B, all patients underwent CEA, 1 to 3 months after CABG, also under general anesthesia and with systematic carotid shunting. RESULTS: Two patients (one in each group) died of cardiac failure in the postoperative period. Operative mortality was 1.0% in group A and 1.1% in group B (P = .98). No strokes occurred in group A vs seven ipsilateral ischemic strokes in group B, including three immediate postoperative strokes and four late strokes, at 39, 50, 58, and 66 days, after CABG. These late strokes occurred in patients for whom CEA was further delayed due to an incomplete sternal wound healing or because of completion of a cardiac rehabilitation program. The 90-day stroke and death rate was 1.0% (one of 94) in group A and 8.8% (eight of 91) in group B (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.01-0.91; P = .02). Logistic regression analysis showed that only delayed CEA (OR, 14.2; 95% CI, 1.32-152.0; P = .03) and duration of cardiopulmonary bypass (OR, 1.06; 95% CI, 1.02-1.11; P = .004) reliably predicted stroke or death at 90 days. CONCLUSIONS: This study suggests that previous or simultaneous CEA in patients with unilateral severe asymptomatic carotid stenosis undergoing CABG could prevent stroke better than delayed CEA, without increasing the overall surgical risk. PMID- 21703807 TI - A biomechanical evaluation of bicortical metal screw fixation versus absorbable interference screw fixation after coracoid transfer for anterior shoulder instability. AB - PURPOSE: The purpose was to evaluate the load to failure of 2 coracoid fixation techniques after transfer of the coracoid to the anterior glenoid neck. METHODS: Ten cadavers (mean age, 87 years; range, 74 to 96 years) underwent the Bristow conjoined tendon tenodesis technique as described by Boileau et al. (bioabsorbable interference screw fixation of a coracoid bone plug) in 1 shoulder and the Latarjet-Patte coracoid transfer popularized by Walch (fixation with 2 screws through a larger piece of the coracoid) in the opposite shoulder. The force on the conjoined tendon required to pull the coracoid off of the anterior glenoid was recorded, along with the mode of construct failure. RESULTS: The median ultimate failure load was 110 N (range, 35 to 170 N) in the interference screw group and 202 N (range, 95 to 300 N) in the bicortical screw group (P = .002). The mode of failure of the interference screw technique was complete avulsion of the bone plug from the socket in 6 cases (60%) and fracture of the bone plug in 4 (40%). The mode of failure of the bone block technique was a vertical fracture through both screw holes in 7 cases (70%), a horizontal fracture through the distal screw hole in 2 (20%), and an intratendinous rupture of the conjoined tendon in 1 (10%). CONCLUSIONS: Fixation of a coracoid bone block to the anterior glenoid neck with 2 bicortical metal screws is stronger than fixation of a coracoid bone plug with an absorbable interference screw. CLINICAL RELEVANCE: These data may influence surgeons' decisions regarding coracoid fixation as well as postoperative rehabilitation after coracoid transfer. PMID- 21703808 TI - [Benefits and safety of perioperative pregabalin: a systematic review]. AB - OBJECTIVE: Perioperative gabapentine administration improves analgesia, reduces postoperative nausea and vomiting, but increases sedation. Pregabalin is also a gabapentinoid, with an improved bioavailability. This systematic review evaluates the analgesic effect and tolerance of perioperative pregabaline. STUDY DESIGN: Systematic review. METHODS: Systematic search in Pubmed database of clinical human randomized controlled studies dealing with perioperative administration of pregabalin. A quantitative review of pregabalin efficiency and an analysis of the main side effects reported in these studies was then performed. RESULTS: Twenty three study arms (884 patients) received at least one dose of pregabalin in 17 studies (totalizing 1577 patients). Pregabalin improved analgesia in 11 of 23 study arms. Pregabalin improved analgesia in three of 12 study arms after ambulatory surgery, and in eight of 11 after major surgery (P=0.04). Two of three studies about chronic postoperative pain revealed improved results in pregabalin groups. Nevertheless, pregabalin did not reduce postoperative nausea/vomiting, pruritus and headache, but increased trouble with vision, drowsiness, severe sedation and dizziness during the first postoperative hours, without severe clinical consequence. Severe sedation seemed clearly dose dependant, while drowsiness, dizziness or visual disturbance did not. CONCLUSION: A favorable benefit risk-ratio is demonstrated only for major surgery (excluding ambulatory surgery). The lack of data concerning tolerance of pregabalin in the elderly and/or in case of renal dysfunction forbids any conclusion in these populations. PMID- 21703809 TI - [Pneumonia associated with health care versus community acquired pneumonia: different entities, distinct approaches]. AB - Healthcare-associated pneumonia (HCAP) is now identified as a unique entity that differs from community-acquired pneumonia (CAP), and in many ways is similar to nosocomial pneumonia (NP). Patients with the diagnosis of CAP and HCAP admitted to our Pneumology Unit during one year were retrospectively analysed. The objective was to compare the characteristics and the approach of these two entities. 197 patients were included, 144 with CAP and 53 with HCAP. Sex, age, comorbilities, Pneumonia Severity Index (PSI) score, radiological involvement, bacteriology, treatment and outcomes were analysed in the 2 groups. Compared to CAP, HCAP was associated with more severe disease, a higher mortality rate and greater length of hospitalization. HCAP differed from CAP mainly in bacteriology and outcomes. PMID- 21703810 TI - [Impact factor and the Portuguese Journal of Pulmonology: knockin' on heaven's door?]. PMID- 21703811 TI - Critical care in Colombia: differences between teaching and nonteaching intensive care units. A prospective cohort observational study. AB - OBJECTIVE: The aim of this study was to determine the differences in the efficacy and efficiency in providing critical care to hospitalized patients in teaching vs nonteaching intensive care units (ICUs) in Colombia. METHODS: A prospective cohort observational study was conducted. LOCATION: This study was conducted in 11 teaching and 8 nonteaching ICUs. From June 1 until December 31, 2005, data on 826 patients admitted consecutively to teaching ICUs and 825 patients admitted to nonteaching ICUs were analyzed. MEASUREMENTS: Acute Physiology and Chronic Health Evaluation II, Simplified Therapeutic Intervention Scoring System, ICU discharge status (dead or alive) and ICU length of stay, and standardized mortality ratios were considered in this study. A logistic regression and robust linear regression were performed. RESULTS: There were no differences in mortality (P = .25). Standardized mortality was less than 1 for both types of units. The teaching ICUs length of stay was 1 day longer (P < .01). Resource use is 25% higher in teaching units (P = .01). When the Simplified Therapeutic Intervention Scoring System score on the last day was from 21 to 35, a higher ratio of patients from the nonteaching ICUs was observed going floor or home when discharged from the ICU (P < .01). CONCLUSIONS: Nonteaching ICUs discharge patients earlier than do teaching ICUs, but the effect of it remains to be clarified with further studies addressing questions as what happens after ICU discharge. PMID- 21703812 TI - Cerebral perfusion pressure, microdialysis biochemistry, and clinical outcome in patients with spontaneous intracerebral hematomas. AB - PURPOSE: The aim of our study was to investigate the roles of cerebral perfusion pressure (CPP) and microdialysis marker values on the clinical outcome of patients with spontaneous intracerebral hematoma. MATERIALS AND METHODS: Twenty seven patients (18 men; mean +/- SD age, 54.17 +/- 10.05 years; 9 women, mean +/- SD age, 65.00 +/- 4.24 years) with a GCS of 8 or less upon admission were included in this study. After a 6-month follow-up period, a linear regression model was applied to evaluate the outcomes using the Glasgow Outcome Scale (GOS). RESULTS: Of the 27 patients, 16 died within the first 6 months after discharge from the hospital. Six patients had a favorable prognosis after 6 months. In the patients who had a favorable outcome (GOS = 4 or GOS = 5), the CPP was above 75.46 mm Hg, and intracranial pressure was below 14.21 mm Hg. No patient with a favorable prognosis had a lactate-pyruvate (L/P) ratio greater than 37.40. An inverse linear relationship was found among the L/P ratio, the CPP, and patient outcome. CONCLUSION: The L/P ratio and CPP were found to be related to patient outcome. In addition, a CPP greater than 75.46 mm Hg and an L/P ratio lower than 37.40 mm Hg were related to a favorable outcome. PMID- 21703813 TI - Rapid response systems: a prospective study of response times. AB - PURPOSE: The purpose of the study was to evaluate the time taken for delivery of each component of care following patient deterioration and to assess the effect on response times of strategies implemented to improve the system. METHODS: A model identifying the sequence of organizational responses following a patient's unexpected clinical deterioration was developed. The time to key events and interventions from initial deterioration was measured for 3 months in 2005 and again in 2006 at a tertiary care hospital with a rapid response team (RRT) in place. Strategies to improve compliance with the RRT system were introduced between the 2 periods. RESULTS: The number of acute deterioration episodes identified increased (61 episodes in 2005; 154 episodes in 2006), but there was no improvement in response times. The 2 components contributing most frequently to delays were the time for nursing staff to call for assistance and, where needed, for physicians to call for higher-level care. Overall, 26% of episodes in 2006 and 30% in 2005 did not receive medical attention within 30 minutes of acute deterioration. CONCLUSIONS: Significant delays in responding to acute deterioration persist despite strategies to facilitate the functioning of the RRT system. Simple strategies such as policy directives are not sufficient to effect change in complex health care systems. PMID- 21703814 TI - Effectiveness of extracorporeal membrane oxygenation when conventional ventilation fails: valuable option or vague remedy? AB - The mortality and morbidity of patients with severe acute respiratory distress syndrome (ARDS) remains high despite the advances in intensive care practice. The low-tidal-volume ventilation strategy (ARDS net protocol) has been shown to be effective in improving survival. Unfortunately, however, some patients have such severe ARDS that they cannot be managed with the ARDS net strategy. In these patients, rescue therapies such as high-frequency ventilation, prone ventilation, nitric oxide, and extracorporeal membrane oxygenation (ECMO) are considered. The CESAR trial has shown that an ECMO-based protocol improved survival without severe disability as compared with conventional ventilation. The recent increased incidence of severe respiratory failure due to H1N1 influenza pandemic has led to an increased use of ECMO. Although several reports showed ECMO use to be encouraging, some scepticism remains. In this article, we reviewed the usefulness of ECMO in patients with severe ARDS in the light of current evidence. PMID- 21703815 TI - Urgent implantable cardioverter defibrillator deactivation by unconventional means. AB - Increasing numbers of patients are receiving implantable cardioverter defibrillators (ICDs); the devices remain fully functional in most terminally ill patients at the time of death. We describe a case of a terminally ill patient with repeated defibrillations who requested urgent ICD deactivation. Nonmedical magnets available in the facility were used to deactivate the ICD and terminate the defibrillations. We then studied various magnetic field sources commonly available in homes, such as ceramic magnets, cell phones, computer hard drives, headsets, and earbuds that potentially may be used to temporarily deactivate an ICD until a device technician is available for reprogramming. We conclude that commonly available magnetic sources may potentially be used to deactivate an ICD. The clinical usefulness of this is speculative and limited to conditions when the need to turn off the device is urgent, and a delay in reprogramming is anticipated. PMID- 21703816 TI - Providing palliative care for cancer patients: the views and exposure of community general practitioners and district nurses in Japan. AB - CONTEXT: The role of general practitioners (GPs) and district nurses (DNs) is increasingly important to achieve dying at home. OBJECTIVES: The primary aim of this region-based representative study was to clarify 1) clinical exposure of GPs and DNs to cancer patients dying at home, 2) availability of symptom control procedures, 3) willingness to participate in out-of-hours cooperation and palliative care consultation services, and 4) reasons for hospital admission of terminally ill cancer patients. METHODS: Questionnaires were sent to 1106 GP clinics and 70 district nursing services in four areas across Japan. RESULTS: Two hundred thirty-five GPs and 56 district nursing services responded. In total, 53% of GPs reported that they saw no cancer patients dying at home per year, and 40% had one to 10 such patients. In contrast, 31% of district nursing services cared for more than 10 cancer patients dying at home per year, and 59% had one to 10 such patients. Oral opioids, subcutaneous opioids, and subcutaneous haloperidol were available in more than 90% of district nursing services, whereas 35% of GPs reported that oral opioids were unavailable and 50% reported that subcutaneous opioids or haloperidol were unavailable. Sixty-seven percent of GPs and 93% of district nursing services were willing to use palliative care consultation services. Frequent reasons for admission were family burden of caregiving, unexpected change in physical condition, uncontrolled physical symptoms, and delirium. CONCLUSION: Japanese GPs have little experience in caring for cancer patients dying at home, whereas DNs have more experience. To achieve quality palliative care programs for cancer patients at the regional level, educating GPs about opioids and psychiatric medications, easily available palliative care consultation services, systems to support home care technology, and coordinated systems to alleviate family burden is of importance. PMID- 21703817 TI - Loperamide. PMID- 21703818 TI - Results of higher power toric intraocular lens implantation. AB - PURPOSE: To evaluate the efficacy, predictability, and safety of coaxial microincision phacoemulsification and toric intraocular lens (IOL) implantation in eyes with high corneal astigmatism. SETTING: Two eye clinics in Germany. DESIGN: Case series. METHODS: Routine cataract extraction using 2.2 mm coaxial phaco equipment and Acrysof toric IOL (3.00 to 6.00 diopters [D] cylinder) implantation were performed. Examinations included optical biometry, Haigis IOL calculation, topography, and objective and subjective refractions. Retroillumination images were used to evaluate IOL alignment. Postoperative examinations were scheduled at 1 week and 3 months. RESULTS: The study enrolled 40 eyes (30 patients). The mean preoperative keratometric cylinder was 3.55 +/- 0.73 D (range 2.64 to 5.39 D) and the mean 3-month postoperative subjective cylinder, 0.67 +/- 0.32 D. The mean logMAR uncorrected distance visual acuity improved from 0.93 to 0.20 and the mean logMAR CDVA, from 0.41 to 0.09. The mean prediction error (spherical equivalent) was +0.14 +/- 0.44 D. The mean IOL rotation between 1 week and 3 months was 0.23 +/- 1.9 degrees clockwise. The mean surgically induced astigmatism was 0.08 +/- 0.41 D. The alignment error was below 10 degrees in 97.5% of cases. The mean vector change in refractive cylinder between 1 week and 3 months was 0.31 +/- 0.19 D. The Alpins correction index was +1.01, indicating a slight tendency toward overcorrection. CONCLUSIONS: Coaxial microincision phacoemulsification with toric IOL safely and predictably reduced high corneal astigmatism and improved surgical outcomes. Thorough planning and precise execution are necessary. PMID- 21703819 TI - A verbal-instruction system to help persons with multiple disabilities perform complex food- and drink-preparation tasks independently. AB - In a recent single-case study, we showed that a new verbal-instruction system, ensuring the automatic presentation of step instructions, was beneficial for promoting the task performance of a woman with multiple disabilities (including blindness). The present study was aimed at replicating and extending the aforementioned investigation with three adults with multiple disabilities. During Part I of the study, the new instruction system was compared with a system requiring the participants to seek instructions on their own. Two tasks were used, one per system. During Part II of the study, the new system was applied with two additional tasks. The results of Part I showed that (a) the participants had a better performance (i.e., in terms of correct steps or task execution time) on the task carried out with the new system than on the task carried out with the comparison/control system, and (b) the performance of this latter task improved rapidly when the new system was used with it. The results of Part II showed satisfactory performance with each of the two tasks carried out directly with the new system. The implications of these data were discussed. PMID- 21703820 TI - ADHD and other associated developmental problems in children with mild mental retardation. The use of the "Five-To-Fifteen" questionnaire in a population-based sample. AB - The aim was to examine the rates and types of parent reported neuropsychiatric problems in children and adolescents with mild mental retardation (MMR) (mild intellectual disability/UK) using the Five-To-Fifteen questionnaire (FTF). The target group comprised all pupils with clinically diagnosed MMR, aged between 7 and 15 years, attending the special schools for children with MMR in two municipalities in a region in the South-West of Sweden. The FTF is a 181-item parent questionnaire with age and gender specific Swedish norms covering eight domains, including the phenomenology of early symptomatic syndromes eliciting neurodevelopmental examinations (ESSENCE), including ADHD, autism, tic syndromes, and various kinds of language, memory, and learning problems. Parents of 63% (39/62) of the eligible target group completed the FTF. After scrutiny of the medical records, 6 of the 39 children were found not to meet criteria for MR. Scores exceeding the 90th centile of the norm group were considered indicative of neuropsychiatric problems. Such high scores are strongly associated with clinically valid ESSENCE/neuropsychiatric disorders. All the examined children with validated MR were reported by their parents to have learning problems. There were very high rates of problems reported in all the other seven FTF domains: perception (88%), language (79%), social skills/autism (76%), memory (67%), emotional problems (58%), motor skills (55%) and executive functions/ADHD (55%). School age children with MMR are all in need of a comprehensive work-up covering not only general cognitive abilities, but also many other areas, including motor skills, executive function/attention, social and emotional/behavioural symptoms/functioning. Such broad assessment (including child screening by parent report with the FTF) will enable a better basis for understanding their special needs of support through life. PMID- 21703821 TI - A kernel-based framework to tensorial data analysis. AB - Tensor-based techniques for learning allow one to exploit the structure of carefully chosen representations of data. This is a desirable feature in particular when the number of training patterns is small which is often the case in areas such as biosignal processing and chemometrics. However, the class of tensor-based models is somewhat restricted and might suffer from limited discriminative power. On a different track, kernel methods lead to flexible nonlinear models that have been proven successful in many different contexts. Nonetheless, a naive application of kernel methods does not exploit structural properties possessed by the given tensorial representations. The goal of this work is to go beyond this limitation by introducing non-parametric tensor-based models. The proposed framework aims at improving the discriminative power of supervised tensor-based models while still exploiting the structural information embodied in the data. We begin by introducing a feature space formed by multilinear functionals. The latter can be considered as the infinite dimensional analogue of tensors. Successively we show how to implicitly map input patterns in such a feature space by means of kernels that exploit the algebraic structure of data tensors. The proposed tensorial kernel links to the MLSVD and features an interesting invariance property; the approach leads to convex optimization and fits into the same primal-dual framework underlying SVM-like algorithms. PMID- 21703822 TI - A study of performance on microarray data sets for a classifier based on information theoretic learning. AB - Gene-expression microarray is a novel technology that allows the examination of tens of thousands of genes at a time. For this reason, manual observation is not feasible and machine learning methods are progressing to face these new data. Specifically, since the number of genes is very high, feature selection methods have proven valuable to deal with these unbalanced-high dimensionality and low cardinality-data sets. In this work, the FVQIT (Frontier Vector Quantization using Information Theory) classifier is employed to classify twelve DNA gene expression microarray data sets of different kinds of cancer. A comparative study with other well-known classifiers is performed. The proposed approach shows competitive results outperforming all other classifiers. PMID- 21703823 TI - Clinical validation of a novel speckle-tracking-based ejection fraction assessment method. AB - BACKGROUND: The aim of this study was to determine the feasibility, accuracy, and reproducibility of a novel tracking-based echocardiographic ejection fraction (EF) assessment method in comparison with traditional methods based on magnetic resonance imaging and echocardiography. METHODS: In a prospective assessment, apical echocardiographic grayscale image loops from 81 patients were read in random order by four experienced readers, blinded to any data of the cases. In three separate sessions, EFs were estimated using biplane tracking-based assessment and according to the modified Simpson's rule, as well as by visual interpretation in three apical views. Data were compared with a reference EF derived from echocardiography and magnetic resonance imaging. RESULTS: On average, no significant difference was found between EF estimates of the different methods. Tracking-based EF assessments were possible in 90% of the patients. Tracking-based EF assessments showed slightly higher deviations from the reference EF than the modified Simpson's rule, while interobserver and intraobserver variability of tracking-based assessment were significantly better. Visual interpretation allowed the fastest EF assessment. Tracking-based EF assessment was approximately twice as fast as the modified Simpson's rule. CONCLUSIONS: Tracking-based EF assessment is feasible, has lower interobserver and intraobserver variability, and is faster than traditional echocardiographic EF quantification. Its minimal demand on user interaction makes it a favorable alternative to traditional echocardiographic approaches, with a particular clinical advantage when reliable follow-up measurements are needed. PMID- 21703824 TI - Attentional disengagement from emotional stimuli in schizophrenia. AB - Previous research indicates that abnormal attention-emotion interactions are related to symptom presentation in individuals with schizophrenia. However, the individual components of attention responsible for this dysfunction are unclear. In the current study we examined the possibility that schizophrenia patients with higher levels of negative symptoms (HI-NEG: n=14) have greater difficulty disengaging attention from unpleasant stimuli than patients with low negative symptoms (LOW-NEG: n=18) or controls (CN: n=27). Participants completed an exogenous emotional cueing task that required them to focus on an initial emotional or neutral cue and subsequently shift attention to a separate location outside of foveal vision to detect a target stimulus (letter). Results indicated that HI-NEG patients had greater difficulty disengaging attention from unpleasant stimuli than CN or LOW-NEG patients; however, behavioral performance did not differ among the groups for pleasant stimuli. Higher self-reported trait negative affect was also associated with greater difficulty disengaging attention from unpleasant stimuli. Abnormalities in disengaging attention from unpleasant stimuli may thus play a critical role in the formation and maintenance of both negative symptoms and trait negative affect in individuals with schizophrenia. PMID- 21703825 TI - Colloidal transport phenomena of milk components during convective droplet drying. AB - Material segregation has been reported for industrial spray-dried milk powders, which indicates potential material migration during drying process. The relevant colloidal transport phenomenon and the underlying mechanism are still under debate. This study extended the glass-filament single droplet drying technique to observe not only the drying behaviour but also the dissolution behaviour of the correspondingly dried single particle. At progressively longer drying stage, a solvent droplet (water or ethanol) was attached to the semi-dried milk particle and the interaction between the solvent and the particle was video-recorded. Based on the different dissolution and wetting behaviours observed, material migration during milk drying was studied. Fresh skim milk and fresh whole milk were investigated using water and ethanol as solvents. Fat started to accumulate on the surface as soon as drying was started. At the initial stage of drying, the fat layer remained thin and the solubility of the semi-dried milk particle was much affected by lactose and protein present underneath the fat layer. Fat kept accumulating at the surface as drying progressed and the accumulation was completed by the middle stage of drying. The results from drying of model milk materials (pure sodium caseinate solution and lactose/sodium caseinate mixed solution) supported the colloidal transport phenomena observed for the milk drying. When mixed with lactose, sodium caseinate did not form an apparent solvent-resistant protein shell during drying. The extended technique of glass filament single droplet approach provides a powerful tool in examining the solubility of individual particle after drying. PMID- 21703827 TI - BMSC and CoQ10 improve behavioural recovery and histological outcome in rat model of Parkinson's disease. AB - OBJECTIVE: This study assessed the ability of a combination treatment of bone marrow stromal cell (BMSC) graft and oral coenzyme (CoQ10) in a rat model of Parkinson's disease (PD) as an appropriate substitute for current Parkinson treatments. The combination treatment was compared to sole treatments of BMSC and CoQ10. MATERIALS AND METHODS: In this experimental study, there were six groups of male Wistar rats: control, sham, lesion, CoQ10, graft BMSC and graft BMSC plus CoQ10. Oral administration of CoQ10 began 1 week before the PD and continued during the entire treatment period. To simulate PD, we injected 6 hydroxydopamine (6OHDA) in rats. BMSC were labelled by 5-bromo-2'-deoxyuridine (Brdu) before transplantation. We assessed behaviour before PD, 2 weeks after PD and 8 weeks after cell transplantation. At the end of the second month of treatment, immunohistochemistry, histology and molecular studies were performed. RESULTS: Behavioural assessment of the CoQ10 group and BMSC group indicated equal recovery in comparison with the lesion group (P<0.01), while the combined treatment of BMSC and CoQ10 showed considerably better recovery compared with the lesion group (P<0.001). There were no signs of gliosis and graft rejection. Immunohistochemistry analysis of Brdu indicated that cells were alive after 2 months of application in host tissue. Cell counts showed significantly greater numbers of neural cells in the combination treatment of BMSC and CoQ10 compared to the other groups. Tyrosine hydroxylase (TH) gene expression levels in the combined therapy group was significantly more than the other experimental groups (P<0.001). CONCLUSION: The combined use of two neuroprotective treatments and cell replacement therapy can be effective in the treatment of PD, at least in experimental settings. PMID- 21703826 TI - In situ gelling hexagonal phases for sustained release of an anti-addiction drug. AB - In this study, fluid precursor formulations for subcutaneous injection and in situ formation of hexagonal phase gels upon water absorption were developed as a strategy to sustain the release of naltrexone, a drug used for treatment of drug addiction. Precursor formulations were obtained by combining BRIJ 97 with propylene glycol (PG, 5-70%, w/w). To study the phase behavior of these formulations, water was added at 10-90% (w/w), and the resulting systems were characterized by polarized light microscopy. Two precursor formulations containing BRIJ:PG at 95:5 (w/w, referred to as BRIJ-95) and at 80:20 (w/w, referred to as BRIJ-80) were chosen. Naltrexone was dissolved at 1% or suspended at 5% (w/w). Precursor formulations were transformed into hexagonal phases when water content exceeded 20%. Water uptake followed second-order kinetics, and after 2-4h all precursor formulations were transformed into hexagonal phases. Drug release was prolonged by the precursor formulations (compared to a drug solution in PBS), and followed pseudo-first order kinetics regardless of naltrexone concentration. The release from BRIJ-80 was significantly higher than that from BRIJ-95 after 48 h. The relative safety of the precursor formulations was assessed in cultured fibroblasts. Even though BRIJ-95 was more cytotoxic than BRIJ-80, both precursor formulations were significantly less cytotoxic than sodium lauryl sulfate (considered moderate-to-severe irritant) at the same concentration (up to 50 MUg/mL). These results suggest the potential of BRIJ based precursor formulations for sustained naltrexone release. PMID- 21703828 TI - A supervised method to assist the diagnosis and monitor progression of Alzheimer's disease using data from an fMRI experiment. AB - OBJECTIVE: The aim of this work is to provide a supervised method to assist the diagnosis and monitor the progression of the Alzheimer's disease (AD) using information which can be extracted from a functional magnetic resonance imaging (fMRI) experiment. METHODS AND MATERIALS: The proposed method consists of five stages: (a) preprocessing of fMRI data, (b) modeling of the fMRI voxel time series using a generalized linear model, (c) feature extraction from the fMRI experiment, (d) feature selection, and (e) classification using the random forests algorithm. In the last stage we employ features that were extracted from the fMRI and other features such as demographics, behavioral and volumetric measures. The aim of the classification is twofold: first to diagnose AD and second to classify AD as very mild and mild. RESULTS: The method is evaluated using data from 41 subjects. The stage of AD is established using the Washington University Alzheimer's Disease Research Center recruitment and assessment procedures. The method classifies a patient as healthy or demented with 84% sensitivity and 92.3% specificity, and the stages of AD with 81% and 87% accuracy for the three class and the four class problem, respectively. CONCLUSIONS: The method is advantageous since it is fully automated and for the first time the diagnosis and staging of the disease are addressed using fMRI. PMID- 21703830 TI - Stopping tamoxifen after 5 years of therapy for early breast cancer: does it alter quality of life? PMID- 21703829 TI - A randomised double-blind placebo-controlled trial to determine the effect of cranberry juice on decreasing the incidence of urinary symptoms and urinary tract infections in patients undergoing radiotherapy for cancer of the bladder or cervix. AB - AIMS: Radical pelvic radiotherapy is one of the main treatment modalities for cancers of the bladder and cervix. The side-effects of pelvic radiotherapy include urinary symptoms, such as urinary frequency and cystitis. The therapeutic effects of cranberry juice in the prevention and treatment of urinary tract infections in general are well documented. The purpose of this study was to evaluate the effectiveness of cranberry juice on the incidence of urinary tract infections and urinary symptoms in patients undergoing pelvic radiotherapy for cancer of the bladder or cervix. MATERIALS AND METHODS: The study was a placebo controlled, double-blind design. Participants were randomised to receive cranberry juice, twice a day (morning and night) for the duration of their radiotherapy treatment and for 2 weeks after treatment (6 weeks in total) or a placebo beverage, for the same duration. RESULTS: The incidence of increased urinary symptoms or urinary tract infections was 82.5% on cranberry and 89.3% on placebo (P=0.240, adjusted odds ratio [cranberry/placebo] 0.48, 95% confidence interval 0.14-1.63). CONCLUSIONS: The power of the study to detect differences was limited by the below target sample size and poor compliance. Further research is recommended, taking cognisance of the factors contributing to the limitations of this study. PMID- 21703831 TI - The postpartum cardiovascular risk factor profile of women with isolated hyperglycemia at 1-hour on the oral glucose tolerance test in pregnancy. AB - BACKGROUND AND AIMS: Women with gestational diabetes mellitus (GDM) have an enhanced cardiovascular risk factor profile at 3-months postpartum and an elevated risk of future cardiovascular disease, as compared to their peers. Recently, it has emerged that even mild dysglycemia on antepartum oral glucose tolerance test (OGTT) predicts an increased risk of future cardiovascular disease, although it is not known whether there exists an identifiable high-risk subgroup within this patient population. Since gestational impaired glucose tolerance (GIGT) due to isolated hyperglycemia at 1-h during the OGTT (1-h GIGT) bears metabolic similarity to GDM, we hypothesized that, like GDM, 1-h GIGT may predict a high-risk postpartum cardiovascular phenotype. METHODS AND RESULTS: In this prospective cohort study, 485 women underwent antepartum OGTT, followed by cardiovascular risk factor assessment at 3-months postpartum. The antepartum OGTT identified 4 gestational glucose tolerance groups: GDM (n = 137); 1-h GIGT (n = 39); GIGT at 2- or 3-h (2/3-h GIGT)(n = 50); and normal glucose tolerance (NGT)(n = 259). After adjustment for age, ethnicity, breastfeeding and waist circumference, mean levels of the following cardiovascular risk factors progressively increased from NGT to 2/3-h GIGT to 1-h GIGT to GDM: LDL cholesterol (p = 0.0026); total cholesterol:HDL (p = 0.0030); apolipoprotein B (p = 0.004); apolipoprotein B:apolipoprotein A1 (p = 0.026); leptin (p = 0.018); and C-reactive protein (p = 0.011). CONCLUSIONS: Amongst women without GDM, 1-h GIGT predicts an enhanced postpartum cardiovascular risk factor profile. It thus emerges, that amongst young women with mild dysglycemia in pregnancy, those with 1-h GIGT may comprise an unrecognized patient population at risk for future cardiovascular disease. PMID- 21703832 TI - Validation of a food frequency questionnaire in Spanish patients with familial hypercholesterolaemia. AB - BACKGROUND AND AIMS: The aim of this study is to validate a semi-quantitative Food Frequency Questionnaire (FFQ) used for general population in Spain, in patients with familial hypercholesterolaemia (FH). SUBJECTS AND METHODS: Subjects with genetic diagnosis of FH were randomly selected from the Spanish FH Registry. They completed an FFQ based in 113 food items at inclusion (FFQ1) and after 1 year (FFQ2), and a 3-day dietary records (DR) every 3 months. Detailed instruction about how to register foods and beverages was given by a trained nutritionist. Each DR and FFQ was systematically coded, and the daily nutrients intake in absolute, percentage and nutrient density terms were estimated using a software system based on food composition tables. Pearson correlation coefficient was calculated with correction-repeated measurements to assess the reproducibility of both FFQ and the four 3-day DRs, as well as the validity of FFQ comparing to the mean of 3 days' DR. RESULTS: A total of 112 subjects (58 females and 54 males, aged 43 +/- 16 years) finished the study. There were no differences between FFQ1, FFQ2 and mean FFQ (FFQa) in mean absolute and percentage values of selected daily nutrients' intake. Comparison between FFQ1, FFQ2, FFQa and the mean of four 3-day DRs was statistically significant in all absolute values, but not in percentage or nutrient density terms. Corrected Pearson correlation coefficient ranged from 0.470 to 0.952 for mean values of all nutrients, except alcohol. CONCLUSION: This study demonstrated that FFQ is a reliable tool to assess the dietary pattern in FH patients. PMID- 21703833 TI - Naturally-occurring phytosterols in the usual diet influence cholesterol metabolism in healthy subjects. AB - BACKGROUND AND AIMS: Modulation of cholesterol absorption is potentially an effective way of lowering blood cholesterol levels and decreasing inherent cardiovascular risk in the general population. It is well established that cholesterol absorption efficiency can be modified by the intake of foods enriched with gram-doses of phytosterols, but little is known about the effects of phytosterols in the usual diet, even though moderate doses have been reported to affect whole-body cholesterol metabolism. A way to indirectly measure cholesterol synthesis and absorption rates is by quantification of serum non-cholesterol sterols. The aim of this study was to investigate the role of naturally occurring phytosterol intake on cholesterol absorption and serum cholesterol concentrations in a Spanish free-living population. METHODS AND RESULTS: A total of 85 healthy volunteers were studied regarding their dietary habits (using a validated food frequency questionnaire), lipid profile and surrogate markers of cholesterol metabolism. Subjects were classified into tertiles of total phytosterol intake, and differences in lipid profile and markers of cholesterol metabolism were assessed by multivariate linear regression models adjusted for various confounders. The estimated daily intake of phytosterols and cholesterol was 489 (median) and 513 (mean) mg, respectively. Both serum low-density lipoprotein (LDL)-cholesterol concentration and sitosterol-to-cholesterol ratio adjusted by sitosterol intake (a surrogate marker of intestinal cholesterol absorption) decreased significantly (p < 0.05, both) across tertiles of phytosterol intake. CONCLUSION: Moderate doses of phytosterols in the habitual diet might have a protective effect on the lipid profile via decreasing cholesterol absorption. PMID- 21703834 TI - Uric acid is predictive of cardiovascular mortality and sudden cardiac death in subjects referred for coronary angiography. AB - BACKGROUND AND AIMS: High serum uric acid (SUA) is suggested to be causally involved in the pathogenesis of vascular disease. The present study aimed to investigate whether SUA independently predicts all-cause mortality, cardiovascular mortality and sudden cardiac death in subjects scheduled for coronary angiography. METHODS AND RESULTS: We studied participants of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. A total of 3245 individuals were included in the analysis. There was a follow-up for all-cause mortality, cardiovascular mortality, and sudden cardiac death with a mean (+/ standard deviation) duration of 7.3 (+/-2.3) years. Sex-specific quartiles of SUA were established and multivariate statistical models were used. A total of 730 deaths occurred during the follow-up. Among these, 473 (64.8%) were accounted for by cardiovascular diseases. Sudden cardiac death occurred in 184 (25.2%) cases. Adjusting for sex and age subjects in the fourth SUA quartile had increased all cause (hazard ratio (HR) = 1.68, p < 0.001) and cardiovascular (HR = 2.00, p < 0.001) mortality compared to individuals in the first quartile. Furthermore, high SUA was a risk factor for sudden cardiac death (HR = 2.27, p < 0.001). These associations remained significant including cardiovascular risk factors and the severity of coronary atherosclerosis as covariates in the models. After additional adjustment for medication use statistical significance for the association between the SUA quartiles and all-cause mortality disappeared. CONCLUSION: High SUA independently indicates increased risk for cardiovascular and sudden cardiac death in subjects referred for coronary angiography. PMID- 21703836 TI - Prenatal effects of natural calcium supplement on Wistar rats during organogenesis period of pregnancy. AB - The potential of oral exposure to calcium and magnesium citrate, a natural product obtained from dolomite, to initiate teratogenesis was analyzed in Wistar rats. Animals received calcium and magnesium citrate oral doses of 250, 500 and 1000 mg/kg during the period of gestation from day 6 to 17 post conception. Maternal, embryo and fetal toxicity was evaluated. Calcium and magnesium citrate exposure did not produce maternal toxicity assessed by clinical observations, body weight gain, food intake, hematology, biochemical parameters and necropsy finding. Signs of embryo-fetal toxicity were not observed. Skeletal and visceral malformations were seen occasionally in all drug-treated and control groups. Skeletal and visceral variations were similar in control and drug-treated groups except for incomplete ossification rib. These finding was spontaneous and unrelated to the drug. In conclusion, in this study we found that the oral exposure to rats of up to 1000 mg/kg of calcium and magnesium citrate during organogenesis did not induce significant maternal and embryo-fetal toxicity. The experimentally derived NOAEL for developmental toxicity was 1000 mg/kg. PMID- 21703835 TI - Relationships between serum total bilirubin levels and metabolic syndrome in Korean adults. AB - BACKGROUND AND AIMS: Metabolic syndrome (MS) is associated with insulin resistance in all parts of its natural history, which is accompanied by oxidative stress. Bilirubin is a potent endogenous antioxidant and cytoprotectant. The current study was performed to identify the major predictors of the total bilirubin level and to assess the relationships between the total bilirubin levels and MS in Korean adults. METHODS AND RESULTS: This is a cross-sectional study involving 12342 adults aged 20 years and over who visited a Health Promotion Center. Physical examinations and laboratory tests including total and direct bilirubin levels were performed. MS was defined based on the modified NCEP ATP III definition and the determinations of the Korean Society for the Study of Obesity. The results showed that hemoglobin had the strongest influence on the total bilirubin levels after adjusting for age, gender, and all other variables. The high-bilirubin group (>=15.4 MUmol/L in males and >=12.1 MUmol/L in females) was associated with significantly decreased odds of MS compared to the low bilirubin group (OR 0.74 [95% CI 0.64-0.86]). High levels of bilirubin also were negatively associated with abdominal obesity and hypertriglyceridemia. The total bilirubin levels decreased with an increase in the number of MS components after adjustment for all covariates. CONCLUSION: Within the physiological range, the serum total bilirubin level was negatively associated with the MS in subjects without overt metabolic or cardiovascular diseases. This may be partially due to the negative association between the total bilirubin level and abdominal obesity and hypertriglyceridemia. PMID- 21703837 TI - In vitro assessment of silver effect on porcine ovarian granulosa cells. AB - The general objective of this in vitro study was to examine the secretory activity (insulin-like growth factor I, IGF-I) of porcine ovarian granulosa cells after Ag addition and to outline the potential intracellular mediators (cyclin B1 and caspase-3) of its effects. Ovarian granulosa cells were incubated with silver nitrate (AgNO(3)) at the doses 0.09, 0.17, 0.33, 0.5 and 1.0 mg/mL for 18 h and compared to the control group without metal addition. The release of IGF-I by granulosa cells was assessed by RIA and expression of cyclin B1 and caspase-3 immunocytochemistry. Our observations show that IGF-I release by granulosa cells was significantly (P<0.05) stimulated by AgNO(3) addition at the doses (0.09-1.0 mg/mL). Similarly to IGF-I the cyclin B1 and caspase-3 expression in ovarian granulosa cells was stimulated by Ag addition (0.09-1.0 mg/mL). In conclusion, the present results indicate, a direct effect of Ag on (1) secretion of growth factor IGF-I, (2) expression of markers of proliferation (cyclin B1) and apoptosis (caspase-3) of porcine ovarian granulosa cells and (3) that the effect of Ag on ovarian cell proliferation could be mediated by IGF-I and cyclin B1. Obtained data indicate the interference of Ag in the pathways of proliferation and apoptosis of porcine ovarian granulosa cells through hormonal and intracellular peptides such as are cyclin B1 and caspase-3. PMID- 21703838 TI - Host epithelial-viral interactions as cause and cure for asthma. AB - Research on the pathogenesis of asthma has concentrated on initial stimuli, genetic susceptibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth muscle) as critical steps leading to disease. Recent evidence indicates that the innate immune cell response to respiratory viruses also contributes to the development of inflammatory airway disease. We further develop this concept by raising the issue that the interaction between host airway epithelial cells and respiratory viruses is another aspect of innate immunity that is also a critical determinant of asthma. We also introduce a rationale for how antiviral performance at the epithelial cell level might be improved to prevent acute infectious illness and chronic inflammatory disease caused by respiratory viruses. PMID- 21703839 TI - Inflammation and mesenchymal stem cell aging. AB - In adults, mesenchymal stromal cells contain tissue-specific multipotent stem cells, MSC, which can be found throughout the body. With advancing age, tight controls of regulatory networks, which guide MSC biology, gradually deteriorate. Aberrations within the MSC microenvironment such as chronic inflammation eventually lead to adverse manifestations, such as the accumulation of fat deposits in bone and muscles, impaired healing and fibrosis after severe injury, or altered hematopoiesis and autoimmunity. MSC can also specifically interact with a large variety of immune cells, and in doing so, they secrete cytoprotective and immunoregulatory molecules, which together with intercellular contacts mediate immune modulatory processes. This review comprehends the current knowledge regarding molecular mechanisms and cellular interactions that occur in stem cell niches, which are jointly shared between MSC and hematopoietic stem and progenitor cells, as well as those intracellular interdependences taking place between mesenchymal and a wide variety of hematopoietic progeny in particular T lymphocytes, which eventually perturb tissue homeostasis and immunology at advanced age. PMID- 21703840 TI - Immune responses in the skin in old age. AB - A marked increase in the susceptibility to cutaneous infections and malignancies has been observed in older humans indicating that cutaneous immunity becomes defective with age. In this review we will focus on recent developments in the understanding of age-related changes in immune function of the skin with a particular emphasis on how alterations in the interaction between cells involved in innate and adaptive immunity leads to decreased cutaneous antigen-specific T cell immunosurveillance. PMID- 21703841 TI - Prevalence of obstructive lung disease in HIV population: a cross sectional study. AB - BACKGROUND: Observational studies have suggested an association between HIV infection and emphysema. AIMS: The primary aim of this study was to estimate the prevalence of obstructive lung disease in HIV-infected patients seen in an outpatient infectious disease clinic. The secondary aim was to estimate the prevalence of Obstructive Lung Disease (OLD) in smokers and non smokers in this population. METHODS: This was a prospective cross-sectional study. Consecutive patients who were seen for routine HIV care underwent spirometry and answered the St. George's Respiratory Questionnaire (SGRQ). Further, we collected information from the charts on demographics, co-morbidities, CD4 cell count, and HIV viral load (current, baseline, etc). RESULTS: This study included 98 HIV-infected patients with mean age of 45 years, (SD: 11) and 84% male. They were seen from November 2008 to May 2009 at Thomas Jefferson University in Philadelphia. According to established criteria, spirometry results were classified as normal in 69% and obstructive in 16.3%. Among those who never smoked, the prevalence of obstructive lung disease on spirometry was 13.6%. The prevalence of obstruction in HIV patients with a history of smoking was 18.5%. Current and ever smokers comprised 21.4% and 55% of the patients respectively. The mean SGRQ total score was 7. The mean SGRQ score in active smokers was 17 and 15 in those subjects with a prior history of smoking. The mean SGRQ score among patients with obstruction in spiromerty was 27.7 in patients with obstruction on spirometry. CONCLUSION: This urban population of HIV-infected persons has a relatively high prevalence of obstructive lung disease as assessed by spirometry. Furthermore, the high prevalence of obstructive lung disease in never smokers may suggest a possible association between HIV infection and emphysema. In addition the SGRQ total score was comparatively higher in patients with obstruction on spirometry. Our data suggests that potentially all patients with HIV should be screened a for OLD. PMID- 21703842 TI - The health, activity, dyspnea, obstruction, age, and hospitalization: prognostic score for stable COPD patients. AB - Multidimensional instruments for determining the severity and prognosis of chronic obstructive pulmonary disease (COPD) must be used in daily clinical practice. OBJECTIVE: To develop and validate a new COPD severity score using variables readily obtained in clinical practice and to compare its predictive capacity with that of other multidimensional indexes. Data collected from a prospective cohort of 611 stable COPD patients were used to derive a clinical prediction rule that was later validated in a separate prospective cohort of 348 patients. In the multivariate analyses, six independent predictive factors were correlated with overall and respiratory mortality: health status, physical activity, dyspnea, airway obstruction (FEV(1)), age, and hospitalizations for COPD exacerbations in the previous two years. These create the HADO-AH score. Based on the beta parameter obtained in the multivariate model, a score was assigned to each predictive variable. The area under the curve for 5-year mortality was 0.79 (95% CI, 0.74-0.83) in the derivation cohort and 0.76 (95% CI, 0.71-0.81) in the validation cohort. The HADO-AH score was a significantly better predictor of mortality than the HADO-score and the Body-mass index, Obstruction, Dyspnea, Exercise-index were statistically significant (p < 0.0004 and p = 0.021, respectively), but was similar to the Age, Dyspnea, and Obstruction-index (p = 0.345). The HADO-AH score provides estimates of all-cause and respiratory mortality that are equal to, or better than, those of other multidimensional instruments. Because it uses only easily accessible measures, it could be useful at all levels of care. PMID- 21703843 TI - History of Bhutan's prohibition of cigarettes: implications for neo prohibitionists and their critics. AB - BACKGROUND: Recently, cigarette neo-prohibitionists have argued that a cigarette ban can be obtained from a de-facto phase-out of cigarettes based on a combination of effective anti-tobacco regulations and high taxes in conjunction with aggressive application of nicotine replacement therapies. The purpose of this study was to ascertain whether these claims were valid in Bhutan, which enacted a national cigarette sales prohibition law in 2004. Did Bhutan from 2004 to 2009 eliminate or nearly eliminate cigarette consumption and avoid a significant cigarette black market and smuggling? METHODS: This study is a historical, qualitative, descriptive statistical, and archival content overview from 2004 to 2009 of smoking prevalence rates and smuggling and black market trends subsequent to the enactment of the Bhutan Penal Code Act of 2004. RESULTS: For adults in Bhutan, tobacco prevalence rates are fairly low compared with other nations but in 2008 remained a serious health issue for those who consumed cigarettes. For minors, tobacco consumption and second hand smoke exposure in 2008 was a significant health issue. In addition, the best available evidence indicates that illegal tobacco smuggling including black market sales due to the sales ban in Bhutan remains robust. CONCLUSIONS: So far, in Bhutan, cigarette neo prohibitionist arguments that stringent anti-tobacco tax and regulatory approaches including a sales prohibition will induce tobacco consumption to cease or nearly cease has not occurred. In addition, the best scientific evidence indicates that a harm reduction-oriented nicotine replacement therapy approach will not be entirely effective. The results of this study provide an important lesson learned for health practitioners and advocates considering or advocating, albeit a gradual, but total cigarette ban as public policy. PMID- 21703844 TI - Regional prediction of long-term landfill gas to energy potential. AB - Quantifying landfill gas to energy (LFGTE) potential as a source of renewable energy is difficult due to the challenges involved in modeling landfill gas (LFG) generation. In this paper a methodology is presented to estimate LFGTE potential on a regional scale over a 25-year timeframe with consideration of modeling uncertainties. The methodology was demonstrated for the US state of Florida, as a case study, and showed that Florida could increase the annual LFGTE production by more than threefold by 2035 through installation of LFGTE facilities at all landfills. The estimated electricity production potential from Florida LFG is equivalent to removing some 70 million vehicles from highways or replacing over 800 million barrels of oil consumption during the 2010-2035 timeframe. Diverting food waste could significantly reduce fugitive LFG emissions, while having minimal effect on the LFGTE potential; whereas, achieving high diversion goals through increased recycling will result in reduced uncollected LFG and significant loss of energy production potential which may be offset by energy savings from material recovery and reuse. Estimates showed that the power density for Florida LFGTE production could reach as high as 10 Wm(-2) with optimized landfill operation and energy production practices. The environmental benefits from increased lifetime LFG collection efficiencies magnify the value of LFGTE projects. PMID- 21703845 TI - Long-period gratings in photonic crystal fiber as an optofluidic label-free biosensor. AB - Using long-period gratings (LPG) inscribed in photonic crystal fiber (PCF) and coupling this structure with an optically aligned flow cell, we have developed an optofluidic refractive index transduction platform for label-free biosensing. The LPG-PCF scheme possesses extremely high sensitivity to the change in refractive index induced by localized binding event in different solution media. A model immunoassay experiment was carried out inside the air channels of PCF by a series of surface modification steps in sequence that include adsorption of poly(allylamine hydrochloride) monolayer, immobilization of anti-rat bone sialoprotein monoclonal primary antibody, and binding interactions with non specific goat anti-rabbit IgG (H+L) and specific secondary goat anti-mouse IgG (H+L) antibodies. These adsorption and binding events were monitored in situ using the LPG-PCF by measuring the shift of the core-to-cladding mode coupling resonance wavelength. Steady and significant resonance changes, about 0.75 nm per nanometer-thick adsorbed/bound bio-molecules, have been observed following the sequence of the surface events with monolayer sensitivity, suggesting the promising potential of LPG-PCF for biological sensing and evaluation. PMID- 21703846 TI - Protein folding mechanisms studied by pulsed oxidative labeling and mass spectrometry. AB - Deciphering the mechanisms of protein folding remains a considerable challenge. In this review we discuss the application of pulsed oxidative labeling for tracking protein structural changes in a time-resolved fashion. Exposure to a microsecond OH pulse at selected time points during folding induces the oxidation of solvent-accessible side chains, whereas buried residues are protected. Oxidative modifications can be detected by mass spectrometry. Folding is associated with dramatic accessibility changes, and therefore this method can provide detailed mechanistic insights. Solvent accessibility patterns are complementary to H/D exchange investigations, which report on the extent of hydrogen bonding. This review highlights the application of pulsed OH labeling to soluble proteins as well as membrane proteins. PMID- 21703847 TI - Reduction of population-based cancer survival estimates by trace back of death certificate notifications: an empirical illustration. AB - BACKGROUND: Survival studies using data from population-based cancer registries allow assessing effectiveness of cancer care on a population level. However, population-based cancer registries differ in the proportion of cases first notified by death certificate, as well as in the efforts to trace back such death certificate notifications (DCN). We aimed to assess the impact of such trace back on population-based cancer survival estimates. MATERIALS AND METHODS: In this study from the population-based Saarland Cancer Registry (Germany) we investigated the survival experience of successfully traced back DCN cases from 1994 to 2003. Five-year relative survival of patients with DCN cancers and the effect of trace back on population-based 5-year relative survival estimates were analysed by age and tumour site. RESULTS: Twelve percent of all cancers were DCN and such cases occurred most often amongst sites with poor prognosis and amongst elderly patients. Approximately half of DCN cases could be successfully traced back. Five-year relative survival of patients with DCN cancers with trace back was 2%. The inclusion of DCN cancers with additional registrations reduced the 5 year relative survival estimate for all cancers combined by 4% points. Reductions were stronger for older patients and highly fatal cancers. CONCLUSIONS: Trace back results in increased inclusion of patients with very poor prognosis. Varying extent of trace back across registries may compromise comparability of cancer survival estimates and should be taken into account in comparative cancer survival studies. PMID- 21703848 TI - The contribution of chest CT-scan at diagnosis in children with unilateral Wilms' tumour. Results of the SIOP 2001 study. AB - BACKGROUND: The SIOP 2001 nephroblastoma study hypothesised that patients with 'CT-only' pulmonary nodules would have the same outcome as patients with localised disease of same stage and histology. PATIENTS: Unilateral Wilms' tumour (WT) patients, who had chest CT scans at diagnosis showing any sized pulmonary nodules undetected on chest X-ray, between November 2001 and November 2009, were selected from the SIOP 2001 database. RESULTS: Among 2532 WT patients, 103 unilateral nephroblastoma patients with CT-only lung lesions were found. Thirty seven patients received preoperative treatment according to the localised-disease protocol, and 66 according to the metastatic-disease protocol. The 3-year event free survival (EFS) was 70% (95% CI: 55-89%) and 77% (95% CI: 66-89%), respectively. Corresponding 3-year overall survival (OS) was 89% (95% CI: 77 100%) and 85% (95% CI: 75-96%), respectively (p-value not significant). EFS and OS of all 2071 patients with true localised disease were 87% (95% CI: 86-89%) and 96% (95% CI: 94-97%), respectively. Patients with metastatic disease (n = 358) had 3-year EFS and OS estimates of 68% (95% CI: 63-74%) and 77% (95% CI: 72-82%), respectively. CONCLUSIONS: EFS and OS of patients with CT-only lung lesions were inferior to that of true localised-disease patients and superior to that of patients with metastatic disease. However, no significant difference was found in EFS and OS between CT-only patients treated for localised or metastatic disease. The clinician's preference to treat patients with CT-only pulmonary nodules as metastatic disease is not evidence-based. Chest CT at diagnosis does not improve outcome but presents paediatric oncologists with a difficult dilemma. PMID- 21703849 TI - Clinical outcome in children and adolescents with Hodgkin lymphoma after treatment with chemotherapy alone - the results of the United Kingdom HD3 national cohort trial. AB - PURPOSE: To assess the efficacy of a standardised hybrid chemotherapy treatment programme for Hodgkin lymphoma (HL) in a national series of children and adolescents. PATIENTS AND METHODS: The 381 assessable patients, treated between March 2000 and April 2005 in the United Kingdom Children's Cancer Study Group trial, were reviewed to evaluate overall survival (OS), disease free survival (DFS) and deaths. Protocol treatment for stages 2-4 offered a hybrid programme of ChlVbPP (chlorambucil, vinblastine, prednisolone, procarbazine) alternating with ABVcD (doxorubicin, bleomycin, vincristine, dacarbazine). Patients with stage I disease only were offered involved field radiation alone or hybrid chemotherapy. RESULTS: With a median follow up of 5.1 years (range 0.5-8.4 years), the 5 years OS and DFS for all patients was 97% and 78%, respectively. By multivariate analysis, mediastinal and stage IV disease at presentation were the only factors that affected achieving a complete response. The 5-year DFS rate for patients with stage IV disease was 55% whilst patients with mediastinal disease had a 2 fold higher risk of an event. CONCLUSIONS: This study demonstrated that multi agent chemotherapy alone is insufficient treatment for patients with mediastinal and stage IV disease. PMID- 21703850 TI - Gene expression analysis of blastemal component reveals genes associated with relapse mechanism in Wilms tumour. AB - Wilms tumour (WT) is a paediatric kidney tumour, composed of blastemal, epithelial and stromal cells, with a relapse rate of approximately 15%. Long-term survival for patients with relapse remains approximately 50%. Current clinical and molecular research is directed towards identifying prognostic factors to define the minimal and intensive therapy for successful treatment of children with low and high risk of relapse, respectively. Blastemal component presents a high level of aggressiveness and responsiveness to chemotherapy. To identify molecular prognostic markers that are predictive of chemotherapy sensitivity in tumour relapse, blastemal-enriched samples from stage III and IV WT, from patients with relapse or without relapse, were analysed for 4608 human genes immobilised on a customised cDNA platform. These analyses revealed 69 differentially expressed genes, and the top nine genes were further evaluated by qRT-PCR in the initial WT samples. TSPAN3, NCOA6, CDO1, MPP2 and MCM2 were confirmed to be down-regulated in relapse WT, and TSPAN3 and NCOA6 were also validated in an independent sample group. Protein expression of MCM2 and NCOA6 were observed in 38% (13 out of 34) and 28% (9 out of 32), respectively, of independent stage III and IV WT blastema samples, without association with relapse. However, a significant association between MCM2 positive staining and chemotherapy as first treatment suggests the involvement of MCM2 with drug metabolism in WT blastemal cells. PMID- 21703851 TI - Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? AB - AIM: Since the introduction of chemotherapy, survival in localised high-grade osteosarcoma has improved considerably. However, there is still no worldwide consensus on a standard chemotherapy approach. In this systematic review evidence for effectiveness of each single drug and the role of response guided salvage treatment of adjuvant chemotherapy are addressed, whereas in a meta-analysis the number of drugs in current protocols is considered. METHODS: A systematic literature search for clinical studies in localised high-grade osteosarcoma was undertaken, including both randomised and non-randomised trials. Historical clinical studies from the pre-chemotherapy era were included for comparison purposes. RESULTS: Nine historical studies showed a long-term survival of 16% after only local treatment. Fifty single agent phase II studies showed high response rates for adriamycin (A, 43%), ifosfamide (Ifo, 33%), methotrexate (M, 32%), cisplatin (P, 26%) but only 4% for etposide (E). In 19 neo-adjuvant studies the mean 5-year event free survival (EFS) was 48% for 2-drug regimens and 58% for ?3 drug regimens, with a 5-year overall survival (OAS) of 62% and 70%, respectively. Meta-analysis showed that ?3 drug regimens including methotrexate plus adriamycin plus cisplatin (plus ifosfamide) (MAP(Ifo)) had significant better outcome (EFS: HR=0.701 (95% confidence interval [95% CI]: 0.615-0.799); OAS: HR=0.792 (95% CI: 0.677-0.926) than 2-drug regimens, but there was no significant difference between MAP and MAPIfo (or plus etoposide). Salvage of poor responders by changing drugs, or intensifying treatment postoperatively has not proven to be useful in this analysis. CONCLUSION: Meta-analysis in patients with localised high-grade osteosarcoma shows that 3-drug regimens, for example MAP are the most efficacious drug regimens. PMID- 21703852 TI - Nitrification potential and population dynamics of nitrifying bacterial biofilms in response to controlled shifts of ammonium concentrations in wastewater trickling filters. AB - Nitrogen removal in wastewater treatment is energy consuming and often carried out in biofilm nitrifying trickling filters (NTFs). We investigated nitrification potential and population dynamics of nitrifying bacteria in pilot-plant NTFs fed with full-scale plant wastewater with high (8-9 mg NH(4)(+)l(-1)) or low (<0.5mg NH(4)(+)l(-1)) ammonium concentrations. After ammonium shifts, nitrification potentials stabilized after 10-43 days depending on feed regime. An NTF fed with 3 days of high, and 4 days of low load per week reached a high nitrification potential, whereas a high load for 1 day a week gave a low potential. Nitrosomonas oligotropha dominated the AOB and changes in nitrification potentials were not explained by large population shifts to other AOBs. Although nitrification potentials were generally correlated with the relative amounts of AOB and NOB, this was not always the case. Ammonium feed strategies can be used to optimize wastewater treatment performance. PMID- 21703853 TI - Cascade bioreactor with submerged biofilm for aerobic treatment of Tunisian landfill leachate. AB - A bioreactor cascade with a submerged biofilm is proposed to treat young landfill leachate of jbel chakir landfill site south west from capital Tunis, Tunisia. The prototype was run under different organic loading charges varying from 0.6 to 16.3 kg TOC m(-3)day(-1). Without initial pH adjustment total organic carbon (TOC) removal rate varied between 65% and 97%. The total reduction of COD reached 92% at a hydraulic retention time of 36 h. However, the removal of total kjeldahl nitrogen for loading charges of 0.5 kg Nm(-3)day(-1) reached 75%. The adjustment of pH to 7.5 improved nitrogen removal to a rate of 85% for loading charge of 1 kg Nm(-3)day(-1). The main bacterial groups responsible for a simultaneous removal of organic carbon and nitrogen belonged to Bacillus, Actinomyces, Pseudomonas and Burkholderia genera. These selected isolates showed a great capacity of degradation at different leachate concentrations of total organic carbon. PMID- 21703854 TI - Enhancing the combustible properties of bamboo by torrefaction. AB - Bamboo has wide range of moisture content, low bulk energy density and is difficult to transport, handle, store and feed into existing combustion and gasification systems. Because of its important fuel characteristics such as low ash content, alkali index and heating value, bamboo is a promising energy crop for the future. The aim of this study was to evaluate the effects of torrefaction on the main energy properties of Bambusa vulgaris. Three different torrefaction temperatures were employed: 220, 250 and 280 degrees C. The elemental characteristics of lignite and coal were compared to the torrefied bamboo. The characteristics of the biomass fuels tend toward those of low rank coals. Principal component analysis of FTIR data showed a clear separation between the samples by thermal treatment. The loadings plot indicated that the bamboo samples underwent chemical changes related to carbonyl groups, mostly present in hemicelluloses, and to aromatic groups present in lignin. PMID- 21703855 TI - Development of an efficient process for the treatment of residual sludge discharged from an anaerobic digester in a sewage treatment plant. AB - In order to reduce the discharge of residual sludge from an anaerobic digester, pre-treatment methods including low-pressure wet-oxidation, Fenton oxidation, alkali treatment, ozone oxidation, mechanical destruction and enzymatic treatment were evaluated and compared. VSS removal efficiencies of greater than 50% were achieved in cases of low-pressure wet-oxidation, Fenton oxidation and alkali treatment. Residual sludge from an anaerobic digester was pre-treated and subjected to thermophilic anaerobic digestion. As a result, the process of low pressure wet-oxidation followed by anaerobic digestion achieved the highest VSS removal efficiency of 83%. The total efficiency of VSS removal of sewage sludge consisting of primary and surplus sludge would be approximately 92%, assuming that the VSS removal efficiency of sewage sludge is 50% in the anaerobic digester of the sewage treatment plant. PMID- 21703857 TI - Perceiving spatial relations via attentional tracking and shifting. AB - Perceiving which of a scene's objects are adjacent may require selecting them with a limited-capacity attentional process. Previous results support this notion [1-3] but leave open whether the process operates simultaneously on several objects or proceeds one by one. With arrays of colored discs moving together, we first tested the effect of moving the discs faster than the speed limit for following them with attentional selection [4]. At these high speeds, participants could identify which colors were present and determine whether identical arrays were aligned or offset by one disc. They could not, however, apprehend which colors in the arrays were adjacent, indicating that attentional selection is required for this judgment. If selection operates serially to determine which colors are neighbors, then after the color of one disc is identified, attention must shift to the adjacent disc. As a result of the motion, attention might occasionally miss its target and land on the trailing disc. We cued attention to first select one or the other of a pair of discs and found the pattern of errors predicted. Perceiving these spatial relationships evidently requires selecting and processing objects one by one and is only possible at low object speeds. PMID- 21703856 TI - The tandem chain extension aldol reaction used for synthesis of ketomethylene tripeptidomimetics targeting hPEPT1. AB - The rationale for targeting the human di-/tripeptide transporter hPEPT1 for oral drug delivery has been well established by several drug and prodrug cases. The aim of this study was to synthesize novel ketomethylene modified tripeptidomimetics and to investigate their binding affinity for hPEPT1. Three related tripeptidomimetics of the structure H-Phe-psi[COCH(2)]-Ser(Bz)-X(aa)-OH were synthesized applying the tandem chain extension aldol reaction, where amino acid derived beta-keto imides were stereoselectively converted to alpha substituted gamma-keto imides. In addition, three corresponding tripeptides, composed of amide bonds, were synthesized for comparison of binding affinities. The six investigated compounds were all defined as high affinity ligands (K(i) values <0.5 mM) for hPEPT1 by measuring the concentration dependent inhibition of apical [(14)C]Gly-Sar uptake in Caco-2 cells. Consequently, the ketomethylene replacement for the natural amide bond and alpha-side chain modifications appears to offer a promising strategy to modify tripeptidic structures while maintaining a high affinity for hPEPT1. PMID- 21703858 TI - What is the most effective type of audio-biofeedback for postural motor learning? AB - Biofeedback is known to improve postural control and reduce postural sway. However, the effects that different biofeedback modes (coding for more or less complex movement information) may have on postural control improvement are still poorly investigated. In addition, most studies do not take into account the effects of spontaneous motor learning from repetition of a task when investigating biofeedback-induced improvement in postural control. In this study, we compared the effects of four different modes of audio-biofeedback (ABF), including direction and/or magnitude of sway information or just a non-specific direction alarm, on the postural sway of 13 young healthy adults standing on a continuously rotating surface. Compared to the non-specific-direction alarm, ABF of continuous postural sway direction and/or amplitude resulted in larger postural sway reduction in the beginning of the experiment. However, over time, spontaneous postural motor learning flattened the effects of the different modes of ABF so that the alarm was as effective as more complex information about body sway. Nevertheless, motor learning did not make ABF useless, since all modes of ABF further reduced postural sway, even after subjects learned the task. All modes of ABF resulted in improved multi-segmental control of posture and stabilized the trunk-in-space. Spontaneous motor learning also improved multi segmental control of posture but not trunk-in-space stabilization as much as ABF. In conclusion, although practice standing on a perturbing surface improved postural stability, the more body sway information provided to subjects using ABF, the greater the additional improvement in postural stability. PMID- 21703859 TI - Manipulation under anaesthesia post total knee replacement: long term follow up. AB - A reduced range of motion post total knee replacement (TKR) is a recognised problem. Manipulation under anaesthesia (MUA) is commonly performed in the stiff post-operative TKR. Long-term results are variable in the literature. We retrospectively reviewed, prospectively collected data on 48 patients followed up since 1996 from one centre, over an average of 7.5 years, (range 1 to 10 years) and report on the long-term results. During the study period 2.3% of TKRs underwent MUA. The mean time to MUA post TKR was 12.3 weeks (range 3 to 48). Pre MUA, the mean flexion was 53 degrees . The mean immediate passive flexion post MUA was 97 degrees , an improvement of 44 degrees (Range 10 degrees to 90 degrees , p<0.05). By 1year, the mean flexion was 87 degrees , an improvement of 34 degrees , (range -15 degrees to 70 degrees , p<0.05). At 10 years the mean flexion was 86 degrees , (range 55 degrees to 100 degrees , p<0.05). We found no difference in the gain in range of motion (ROM) between knees manipulated before or after 12 weeks. Additionally, the gain was no different in stiff knees with a pre TKR ROM <90 degrees , compared to a pre TKR ROM >90 degrees . There were no complications as a result of MUA. However, one patient was eventually revised at 2 years secondary to low grade infection. Our findings show that MUA is a safe and effective method at improving the ROM in a stiff post-operative TKR. The improvement is maintained in the long term irrespective of time to MUA and range of motion pre TKR. PMID- 21703860 TI - Electron microscopy and atomic force microscopy studies of chromatin and metaphase chromosome structure. AB - The folding of the chromatin filament and, in particular, the organization of genomic DNA within metaphase chromosomes has attracted the interest of many laboratories during the last five decades. This review discusses our current understanding of chromatin higher-order structure based on results obtained with transmission electron microscopy (TEM), cryo-electron microscopy (cryo-EM), and different atomic force microscopy (AFM) techniques. Chromatin isolated from different cell types in buffers without cations form extended filaments with nucleosomes visible as separated units. In presence of low concentrations of Mg(2+), chromatin filaments are folded into fibers having a diameter of ~ 30 nm. Highly compact fibers were obtained with isolated chromatin fragments in solutions containing 1-2mM Mg(2+). The high density of these fibers suggested that the successive turns of the chromatin filament are interdigitated. Similar results were obtained with reconstituted nucleosome arrays under the same ionic conditions. This led to the proposal of compact interdigitated solenoid models having a helical pitch of 4-5 nm. These findings, together with the observation of columns of stacked nucleosomes in different liquid crystal phases formed by aggregation of nucleosome core particles at high concentration, and different experimental evidences obtained using other approaches, indicate that face-to face interactions between nucleosomes are very important for the formation of dense chromatin structures. Chromatin fibers were observed in metaphase chromosome preparations in deionized water and in buffers containing EDTA, but chromosomes in presence of the Mg(2+) concentrations found in metaphase (5-22 mM) are very compact, without visible fibers. Moreover, a recent cryo-electron microscopy analysis of vitreous sections of mitotic cells indicated that chromatin has a disordered organization, which does not support the existence of 30-nm fibers in condensed chromosomes. TEM images of partially denatured chromosomes obtained using different procedures that maintain the ionic conditions of metaphase showed that bulk chromatin in chromosomes is organized forming multilayered plate-like structures. The structure and mechanical properties of these plates were studied using cryo-EM, electron tomography, AFM imaging in aqueous media, and AFM-based nanotribology and force spectroscopy. The results obtained indicated that the chromatin filament forms a flexible two dimensional network, in which DNA is the main component responsible for the mechanical strength observed in friction force measurements. The discovery of this unexpected structure based on a planar geometry has opened completely new possibilities for the understanding of chromatin folding in metaphase chromosomes. It was proposed that chromatids are formed by many stacked thin chromatin plates oriented perpendicular to the chromatid axis. Different experimental evidences indicated that nucleosomes in the plates are irregularly oriented, and that the successive layers are interdigitated (the apparent layer thickness is 5-6 nm), allowing face-to-face interactions between nucleosomes of adjacent layers. The high density of this structure is in agreement with the high concentration of DNA observed in metaphase chromosomes of different species, and the irregular orientation of nucleosomes within the plates make these results compatible with those obtained with mitotic cell cryo-sections. The multilaminar chromatin structure proposed for chromosomes allows an easy explanation of chromosome banding and of the band splitting observed in stretched chromosomes. PMID- 21703861 TI - Inflow and outflow occlusion technique of the pulmonary artery and veins for the technically difficult left upper lobectomy. AB - OBJECTIVE: Our objective is to assess the safety of a surgical technique applied to the difficult left upper lobectomy. The inflow-outflow occlusion technique features: dividing the superior pulmonary vein first, then proximal control by clamping the main pulmonary artery (PA), and then distal control by clamping the inferior pulmonary vein. METHODS: A retrospective cohort study of a prospective database was carried out. Patients who underwent left upper lobectomy and required clamping of the vessels were compared to those that did not. RESULTS: Between January 1999 and March 2010,1796 lobectomies were performed and 360 (23%) of these were left upper lobectomies. Of these, 84 (23%) required the inflow outflow occlusion technique. There were 70 (83%) men (median age 65 years). Fifty one patients (61%) required resection of the PA and 33 did not. Heparin was not used in the last 17 patients. These 84 patients were compared to the remaining 276 patients who underwent standard left upper lobectomy. Although the median operative time was longer (150 vs 105 min, p < 0.001) and the median blood loss was greater (120 vs 87 ml, p = 0.03) for the inflow-outflow technique, there were no significant differences in hospital length of stay, morbidity, or mortality between the two groups. CONCLUSION: In our experience, clamping of the inferior pulmonary vein instead of the distal PA achieves safe distal vascular control. It affords greater PA mobility and assessment of the tumor and easier PA repair. This technique can be used even when PA resection is not required. PMID- 21703862 TI - What proportion of lung cancers can be operated by segmentectomy? A computed tomography-based simulation. AB - OBJECTIVE: To estimate the probability that a lung cancer arising in a segment has safety anatomical margin for segmentectomy by using a computed-tomography (CT)-based simulation technique. METHODS: We measured the volume of each segment by dividing a three-dimensional lung model into a segment model. We also measured the volume of particular portions of each segment that were located away from the intersegmental plane by a predefined distance according to a virtual tumor size of 1, 2, or 3 cm. The probability that a lung cancer arising in the segment has safety anatomical margin for segmentectomy (chance to accept segmentectomy) was expressed as the ratio of this particular portion to the entire segment. RESULTS: There was significant variability in segment size (smallest, the right medial basal; largest, the left apicoposterior segment). The chance to accept segmentectomy depended on the segment size and the virtual tumor size; however, irrespective of segment size, there was only a small chance to accept segmentectomy in the bilateral lateral-basal and left anterior segments. Overall, the chance to accept segmentectomy for virtual tumors of 1, 2, and 3 cm in diameter was 33%, 24%, and 18%, respectively. Bisegmentectomy provided 49% chance in resecting virtual tumors that were 2 cm in diameter. CONCLUSION: The chance to accept segmentectomy differed greatly in individual segments; it was minimal if a segment was small or located between neighboring segments. Bisegmentectomy can increase the chance to accept segmentectomy. In addition to these results, our method is useful in identifying tumors having eligibility for segmentectomy. PMID- 21703863 TI - Stressed out about obesity: IRE1alpha-XBP1 in metabolic disorders. AB - The global obesity epidemic is associated with a series of health-threatening diseases including type 2 diabetes. Accumulating evidence suggest that the physiology and homeostasis of the endoplasmic reticulum (ER) is intimately involved in the underlying mechanisms linking obesity and diabetes. Specifically, recent studies indicate a crucial role for the inositol-requiring enzyme 1alpha (IRE1alpha)/X-box binding protein 1 (XBP1) pathway, the most conserved branch of the unfolded protein response (UPR), in glucose and lipid metabolism as well as in insulin function. Focusing on the IRE1alpha-XBP1 pathway, we review recent advances in our understanding of the role of UPR in obesity and obesity associated metabolic disorders. PMID- 21703864 TI - Myeloid cells migrate in response to IL-24. AB - IL-24 (melanoma differentiation associated gene 7 product) is a member of the IL 10 cytokine family that has been reported to possess anti-tumor activity. IL-24 is produced by immune tissues and its expression can be induced in human peripheral blood mononuclear cells by pathogen-associated molecules. While immune cells are known to produce IL-24, the response of immune cells to IL-24 is unclear. Using recombinant human IL-24, we demonstrated that IL-24 induces human monocyte and neutrophil migration, in vitro. An in vivo chemotaxis model showed that IL-24 attracted CD11b positive myeloid cells. To further characterize the chemotactic IL-24 response and type(s) of receptor(s) utilized by IL-24, we treated monocytes with signaling pathway inhibitors. IL-24-induced migration was reduced by pertussis toxin treatment, thus implicating G-protein coupled receptors in this process. Additionally, MEK and JAK inhibitors markedly decreased monocyte migration toward IL-24. These results suggest that IL-24 activates several signaling cascades in immune cells eliciting migration of myeloid cells, which may contribute to the known anti-cancer effects of IL-24. PMID- 21703865 TI - Chronically homeless women report high rates of substance use problems equivalent to chronically homeless men. AB - INTRODUCTION: The U.S. federal government recently committed itself to ending chronic homelessness within 5 years. Women constitute one out of four chronically homeless adults and represent a particularly vulnerable group, but have been little studied. To identify potentially unique needs in this group, we report characteristics and 2-year outcomes in a large sample of male and female chronically homeless adults participating in a multisite, supportive housing program. METHODS: Men and women participating in the outcome evaluation of the 11 site Collaborative Initiative on Chronic Homelessness (n = 714) supportive housing program and who received at least one follow-up assessment were compared on baseline characteristics and up to 2-year follow-up outcomes. Mixed model multivariate regression adjusted outcome findings for baseline group differences. RESULTS: Few significant baseline differences existed between males and females, with both sexes self-reporting very high rates of lifetime mental health (83% women, 74% men) and substance use (68% women, 73% men) problems. Throughout the 2 year follow-up, both men and women dramatically increased the number of days housed, showed minimal changes in substance use patterns, and had modest improvements in mental health outcomes, without significant differences between genders. CONCLUSION: Unlike other U.S. populations, chronically homeless adults do not demonstrate substantial gender differences on mental health or addiction problems. Policy and service delivery must address these remarkably high rates of substance use and mental illness. PMID- 21703866 TI - The role of the obstetrician/gynecologist in the prevention of cardiovascular disease in women. AB - PURPOSE: A qualitative study was conducted to understand the current and potential role of the community obstetrician/gynecologist (OBGYN) in risk factor screening and prevention of cardiovascular disease. METHODS: A total of four focus group discussions were conducted among 46 OBGYN residents and practicing physicians in the mid-Atlantic region. MAIN FINDINGS: Five main thematic areas were identified including scope of practice, professional knowledge and skills in non-reproductive care, potential for liability, logistical and structural barriers, medical practice community, and support for collaborative care. There were no differences between residents and those in practice within and between cities. Comprehensive care was most often defined as excluding chronic medical care issues and most likely as focusing on screening and referring women. The OBGYN recognized their common role as the exclusive clinician for women was, in part, a consequence of patients' nonadherence with primary care referrals. Barriers and strategies were identified within each thematic area. CONCLUSION: Additional training, development of referral networks, and access to local and practice specific data are needed to support an increased role for the OBGYN in the prevention of cardiovascular disease in women. Establishment of evidence based screening and referral recommendations, specific to women across the age spectrum, may enable clinicians to capitalize on this important prevention opportunity. Longer term, and in concert with health care reform, a critical evaluation of the woman's place in the center of her medical home, rather than any one site, may yield improvements in health outcomes for women. PMID- 21703867 TI - Achieving the goals of the national HIV/AIDS strategy: keeping gender in mind. PMID- 21703868 TI - Gender-responsive programming and HIV prevention for women: Centers for Disease Control and Prevention perspective. PMID- 21703869 TI - Comparing sexual minority cancer survivors recruited through a cancer registry to convenience methods of recruitment. AB - PURPOSE: Sexual minority women, defined as having a lesbian or bisexual identity or reporting a preference for a female partner, are not considered by cancer surveillance. This study assesses the representativeness of sexual minority breast cancer survivors, defined as having a lesbian or bisexual identity or reporting a preference for a female partner, who were recruited into a convenience sample compared with a population-based registry sample of sexual minority breast cancer survivors. METHODS: Long-term survivors of non-metastatic breast cancer who self-reported as sexual minority were recruited from a cancer registry and subsequently from the community using convenience recruitment methods. Sexual minority breast cancer survivors who screened eligible participated in a telephone survey about their quality of life and factors associated therewith. RESULTS: Participants in the convenience sample were similar to the registry-based sample with respect to adjustment to cancer, physical health, trust in physician, coping, social support, and sexual minority experiences. Compared with the convenience sample, breast cancer survivors in the registry sample were more likely married, more educated, diagnosed more recently, at an earlier stage of cancer, and more likely treated with breast-conserving surgery; they differed on adjuvant therapies. DISCUSSION: Because sexual minority breast cancer survivors who volunteered for the community-based sample shared most characteristics of the sample recruited from the cancer registry, we concluded that the community sample had comparable representational quality. In the absence of cancer surveillance of sexual minorities, thoughtful convenience recruitment methods provide good representational quality convenience samples. PMID- 21703870 TI - Provision of emergency contraception at student health centers in California community colleges. AB - BACKGROUND: Approximately half of all pregnancies in the United States are unintended, with the highest rates reported among college-age women. The availability of emergency contraception (EC) pills can be an important component of efforts to reduce unintended pregnancy. Student health centers at community colleges can uniquely support student retention and academic achievement among college students by making EC available to reduce the rate of unintended pregnancy and prevent college drop-out. This article highlights findings from an assessment of EC provision in student health centers within the California community college system (n = 73). METHODS: A web-based survey was used to explore the provision of EC, challenges and barriers of EC administration, promotion of EC availability, and attitudes toward EC. FINDINGS: Descriptive statistics conducted revealed that more than 6 out of 10 (62%) student health centers provided EC, 77% of which dispense EC on site during clinic visits. The most common EC promotion methods were providing brochures at the health center (80%) and through information provided at family planning or primary care visits (73%). Challenges to EC administration included a perceived lack of awareness of EC among students (71%), followed by the notion that some students may overutilize EC (40%). Attitudes toward EC provision were more favorable among health center staff whose campuses offered EC than those who did not (p < .05). CONCLUSION: This article provides recommendations for community college health centers to improve access and delivery of EC by addressing issues such as cost and offering more novel EC promotion methods. PMID- 21703871 TI - Development of hepatic pseudotumors for image-guided interventional and surgical research in a large animal model. AB - PURPOSE: Real-time image guidance and navigation have become increasingly important in an era of minimally invasive interventional and surgical procedures in the liver. To develop, test, and implement tools for real-time image guidance, the authors sought to create an in vivo tumor mimic with realistic imaging and treatment capabilities. MATERIALS AND METHODS: Hepatic pseudotumors were created by injecting 1-2 mL of alginate (a hydrocolloid) directly into the liver parenchyma in eight live pigs and two dog cadavers. Tumors were imaged by B-mode ultrasound (US), US elasticity imaging, multi-detector row computed tomography (CT), CT fluoroscopy, and magnetic resonance (MR) imaging to assess imaging capabilities. Procedures performed with the alginate pseudotumors included radiofrequency (RF) ablation and robotic needle guidance. RESULTS: Twenty-four hepatic pseudotumors were created, ranging in size from 10 mm to 28 mm at an average depth of 6 mm. Average time of preparation and insertion was 3 minutes. All tumors were palpable under the surface of the liver and were easily visible on B-mode US, US elasticity imaging, CT, and MR imaging. Tumors were successfully "treated" with RF ablation, and gross examination of the liver showed good encompassment of the tumor by the zone of thermal coagulation. In addition, the pseudotumors allowed for easy introduction of various types of needles, including RF ablation probes and experimental steerable needles. CONCLUSIONS: Alginate pseudotumors can easily be imaged and allow for different procedures to be performed. This model can be used for various research purposes. PMID- 21703872 TI - Evaluation of early imaging response after chemoembolization of hepatocellular carcinoma by phosphorus-31 magnetic resonance spectroscopy-initial experience. AB - PURPOSE: To evaluate the value of phosphorus-31 ((31)P) magnetic resonance (MR) spectroscopy in early monitoring and predicting the response of hepatocellular carcinoma (HCC) after chemoembolization. MATERIALS AND METHODS: The authors evaluated 17 HCC target tumors with (31)P MR spectroscopy before and after chemoembolization. Alterations of phosphorus metabolism were analyzed by the MR spectroscopy analysis package (SAGE 7.0; GE Medical Systems, Milwaukee, Wisconsin). Ratios of the peak areas of phosphomonoesters (PME), phosphodiesters (PDE), and inorganic phosphate (Pi) to the peak area of nucleoside triphosphates (NTP) or the total phosphorus content (TPC) were measured. The changes in these ratios after chemoembolization were calculated from baseline (before chemoembolization). The therapy effect was assessed by computed tomography (CT) or MR imaging 4 weeks after chemoembolization. The ability of phosphorus metabolism in monitoring therapy effect was evaluated by using receiver operating characteristic analysis. RESULTS: Decreases in the PDE/NTP ratio (Wilcoxon signed rank test, P = .024) and the PDE/TPC ratio (Wilcoxon signed rank test, P = .011) that occurred after treatment were the most remarkable changes secondary to chemoembolization. Of the 17 lesions evaluated quantitatively, at the follow-up examination done 4 weeks after chemoembolization, 12 lesions were responsive to chemoembolization, whereas 5 were not. In the responsive group, the PDE/TPC ratio (median 24.15% vs 13.15%; P = .008) was significantly decreased after chemoembolization, whereas the NTP/TPC ratio (median 37.35% vs 49.9%; P = .024) was significantly increased. In the nonresponsive group, phosphorus metabolism had no significant changes after treatment. Results from the receiver operating curve analysis showed that the threshold percentage change of the PDE/NTP (%PDE/NTP) value was -1.25% with 91.7% sensitivity and 100% specificity for identifying tumor response to chemoembolization, and the threshold percentage change of the NTP/TPC (%NTP/NTP) value was 15.3% with 75% sensitivity and 100% specificity. CONCLUSIONS: Phosphorus-31 MR spectroscopy is a promising technique for the noninvasive assessment of HCC response to chemoembolization. Future studies are necessary to confirm these preliminary results. PMID- 21703873 TI - CT-guided navigation of percutaneous hepatic and renal radiofrequency ablation under high-frequency jet ventilation: feasibility study. AB - PURPOSE: Computed tomography (CT)-guided navigation during percutaneous radiofrequency (RF) ablations of liver and kidney lesions is hampered by respiratory motion and time-dependent lesion conspicuity after contrast agent injection. Therefore, target immobilization by general anesthesia with high frequency jet ventilation (HFJV) instead of conventional ventilation (CV) with repeated breath-holds may facilitate and speed up navigation of RF ablation probes. MATERIALS AND METHODS: Nineteen consecutive patients who underwent percutaneous RF ablation of liver (n = 9) or renal tumors (n = 10) with CT guidance under HFJV (n = 9) or CV (n = 10) were included. The choice of the anesthesiologic technique was left to the discretion of the interventionalist. Complexity of the intervention (ie, number of lesions ablated per session, conspicuity of the lesion on nonenhanced CT, and access pathway), volume of the ablated tissue, radiation exposure, and complications were compared between the HFJV and CV groups. RESULTS: In this feasibility study, a statistically significant radiation dose reduction (P < .05) was noted in the HFJV group compared with the CV group for liver and renal RF ablation. No complications were observed in the HFJV group, whereas renal subcapsular hematoma (n = 2) and pulmonary embolism (n = 1) occurred in the CV group. CONCLUSIONS: Percutaneous CT guided navigation of RF ablation probes under HFJV is feasible and safe. It might be advantageous for the treatment of complex kidney and liver tumors, allowing less irradiation exposure to the patient and the interventional radiologist. PMID- 21703874 TI - Spectrum and potential pathogenesis of reversible posterior leukoencephalopathy syndrome. AB - BACKGROUND: Controversy still exists over the etiology and pathophysiology of reversible posterior leukoencephalopathy syndrome (RPLS). This large single center case series aims to describe the clinical and imaging features of RPLS in an attempt to deduce the etiology of the disorder and the mechanisms of brain injury. METHODS: A retrospective chart and imaging review was conducted on 59 cases of RPLS in 55 patients. RESULTS: Five RPLS imaging patterns were observed: posterior predominant (n = 40), anterior predominant (n = 7), diffuse lesion (n = 7), basal ganglia predominant (n = 3), and brainstem/cerebellum predominant patterns (n = 2). RPLS resulted in permanent neurologic deficits in 14 patients and death in 4 patients. Hypertension was seen in 57 (97%) cases, and mean arterial blood pressure exceeded 140 mm Hg in 30 (51%) cases. Follow-up magnetic resonance imaging scans revealed a significant worsening of vasogenic edema in 2 cases, both with persistent hypertension. Magnetic resonance imaging scans revealed areas of ischemia in 14 cases, all within or at areas closely adjacent to vasogenic edema. Diffuse vasculopathy was seen in 8 cases. There was a lack of correlation between the presence of vasculopathy and the degree of vasogenic edema (P = .62), but a correlation was suggested between ischemia and vasculopathy (P = .02). CONCLUSIONS: This study strongly suggests that hypertension-induced vasodilation rather than vasoconstriction-mediated hypoxia is likely the major mechanism responsible for the development of vasogenic edema, and that vasoconstriction may contribute to the development of ischemia in RPLS. PMID- 21703875 TI - Admission leukocytosis in acute cerebral ischemia: influence on early outcome. AB - BACKGROUND: Leukocytes are the first cells that arrive in the stroke region(s), and they increase in peripheral blood. The contribution or leukocytes in the early acute phase of cerebral ischemia has not yet been investigated. METHODS: In consecutive first-ever acute ischemic stroke patients whose symptoms had started <12 hours earlier, we aimed to establish whether admission leukocyte count affects the short-term neurologic outcome, and whether there are differences between the various clinical syndromes of stroke. The National Institutes of Health Stroke Scale (NIHSS) was assessed at admission (NIHSS(0)) and after 72 hours (NIHSS(72)). Modified Rankin scale (mRS) scores were evaluated at discharge. The Spearman rank correlation was used for the correlation between leukocytes and outcome measures. RESULTS: Eight hundred and eleven patients were included (median age 77 years [range 68-82]; 418 [53%] were male; the median NIHSS(0) score was 7 [range 4-12], the median NIHSS(72) score was 6 [range 3-12], and the median mRS score was 2 [range 2-4]). The median leukocyte count at admission was 8100/mm(3) (range 6500-10300). Higher leukocyte levels predicted a worst clinical presentation and a poor functional outcome (NIHSS(0)P < .001; NIHSS(72)P < .001; mRS P < .001). The correlation between leukocyte count and outcome measures remained significant after multivariate analysis (NIHSS(0)P < .001; NIHSS(72)P < .001; mRS P < .008). Focusing on clinical syndromes, a higher leukocyte count predicted severe NIHSS(0) and NIHSS(72) scores in patients with total anterior cerebral stroke (P = .001), partial anterior cerebral stroke (P = .004), or posterior cerebral stroke (P = .026). CONCLUSIONS: An elevated leukocyte count in the acute phase of cerebral ischemia is a significant independent predictor of poor initial stroke severity, poor clinical outcome after 72 hours, and discharge disability. The involved underlying mechanism is still to determined. PMID- 21703876 TI - Ischemic stroke in patients receiving aspirin. AB - BACKGROUND: The widespread use of aspirin-driven vascular prevention strategies does not impede the occurrence of first and recurrent ischemic strokes in numerous subjects. It is not clear what factors are associated with aspirin failure beyond the functional diagnosis of aspirin resistance in selected subjects. Current management guidelines provide little or no recommendations on the proper strategy for subjects who had a stroke while receiving aspirin. We assessed clinical features of subjects who had a first or recurrent stroke while taking aspirin. METHODS: We studied demographic characteristics, vascular risk factors, stroke subtypes, and concomitant medication use in subjects with first or recurrent ischemic strokes. Patients receiving antiplatelet medications other than aspirin and/or oral anticoagulants were excluded from this analysis. RESULTS: Seven hundred and nine patients with first (n = 552) or recurrent (n = 157) ischemic stroke were evaluated. Aspirin was being taken by 29% of first and 48% of recurrent stroke subjects. There was a higher prevalence of hypertension, hypercholesterolemia, and smoking in aspirin users with first and recurrent stroke (P < .05). Diabetes and coronary artery disease were more frequent in aspirin users with first ischemic strokes (P < .003), but not in those who had recurrent ischemic strokes. Aspirin users were more likely to be also receiving statins and antihypertensive drugs (P < .001). CONCLUSIONS: Aspirin failure in ischemic stroke prevention may exceed functional resistance to aspirin and could be associated with a higher prevalence of lacunar stroke, comorbidities, and/or adverse interactions with other drugs. These patients may require a different approach regarding prevention strategies. PMID- 21703877 TI - Cerebrovascular disease and intracranial artery stenosis in patients with symptomatic peripheral artery disease. AB - BACKGROUND: Patients with symptomatic peripheral artery disease (PAD) have an elevated prevalence of internal carotid artery (ICA) stenosis and cerebral infarction, although the correlations between the severity of PAD and cerebral infarction, cerebral white matter lesion (WML), or intracranial or extracranial artery stenosis are unclear. METHODS: We evaluated the prevalence of cardiovascular risk factors, cerebral infarction, and WML on magnetic resonance imaging and intracranial and extracranial carotid artery stenoses on magnetic resonance angiography in patients with symptomatic PAD (n = 136; males/females [M/F] 109/27) and a control group comprised of patients without PAD (n = 92; M/F 57/35). PAD was classified by Fontaine stage (stage II, n = 46; stage III, n = 20; stage IV, n = 70). Cerebral infarctions were classified into symptomatic or asymptomatic groups. WMLs were evaluated according to Fazekas stage. Artery stenosis was classified as normal (no stenosis), mild (stenosis <50%), moderate (stenosis >= 50%), severe (tight stenosis), and obstruction on magnetic resonance angiography. RESULTS: Diabetes mellitus (DM), dyslipidemia, coronary artery disease (CAD), and chronic kidney disease (CKD), as well as symptomatic cerebral infarction and WML, were more frequent in patients with Fontaine III/IV PAD than without PAD. The prevalence rates of cerebral infarction and WML in patients with Fontaine stage II PAD were between those of the control and Fontaine III/IV PAD patients. Supraclinoid and cervical ICA stenoses (>50%) were more frequent in patients with Fontaine stage IV PAD than without PAD. CONCLUSIONS: Our results indicate that patients with advanced PAD have an increased prevalence of symptomatic cerebral infarction, WML, and intracranial and cervical ICA stenosis as well as DM, CAD, and CKD. PMID- 21703878 TI - Blood pressure management and evolution of thrombolysis-associated intracerebral hemorrhage in acute ischemic stroke. AB - BACKGROUND: There is limited knowledge on the radiographic features of thrombolysis-induced hemorrhage. The factors that influence early hematoma expansion have not been elucidated. METHODS: Patients presenting with a symptomatic intracerebral hemorrhage (ICH) as a result of intravenous (IV) thrombolysis with tissue plasminogen activator (tPA) for acute ischemic stroke and had noncontrast computed tomographic (CT) scans of the head were included in this retrospective study. Calculation of hematoma volumes was obtained. Analysis of covariance was used to evaluate for the effect of baseline blood pressure (BP) on initial hematoma volume and further growth. RESULTS: Of 267 patients who were treated with intravenous tPA for acute ischemic stroke at our facility between January 1, 2005 and December 31, 2009, 17 patients developed symptomatic ICH and were included in the final analysis. There was a positive correlation between baseline level of systolic BP after thrombolysis and initial hematoma volume (r = 0.46; P = .03) but not for the diastolic BP (r = 0.07; P = .40). There was a significant increase in mean hematoma volume expansion when comparing results between the first and second CT scans (median 9 hours, 22 minutes; 14.9 +/- 19.6 cm(3) to 26.0 +/- 26.7 cm(3); P = .04). There was also a negative association between the reduction of systolic BP and hematoma growth (r = -0.67; P = .02), but no correlation with change in diastolic BP (r = -0.22; P = .28). CONCLUSIONS: Once diagnosed, thrombolysis-induced symptomatic ICH undergoes significant early expansion in size. Systolic BP may play a role in hematoma expansion. PMID- 21703879 TI - Use of an anti-gravity treadmill in the rehabilitation of the operated achilles tendon: a pilot study. AB - Achilles surgical patients were evaluated using an "anti-gravity" Alter-G (AG) treadmill that allows for reduction of weightbearing pressure on the lower extremity. We studied our hypothesis, which was based on our prior clinical findings, that being able to run on the AG treadmill at 85% of body weight is sufficient to clear patients to run with full body weight outside. Patients undergoing Achilles tendon rupture or insertional repair surgery were prospectively studied. They were compared with a control group that had similar surgeries and a similar rehabilitation program during the same time period: the variable was not using the AG treadmill. The criteria for the study group to be allowed to run outside was being able to run for at least 10 minutes on the AG at 85% of body weight. Each group had 8 patients who underwent surgery for 2 complete tendon ruptures and 6 insertional repairs. There was no significant difference between the AG and control group as to age and postoperative follow up. AG patients began their initial run on the treadmill at 70% of their body weight at 13.9 +/- 3.4 weeks, 85% at 17.6 +/- 3.9 weeks, and outside running at 18.1 +/- 3.9 weeks. The control group's return to running outside time was 20.4 +/- 4.1 weeks. This was not significantly different (p = .27). We confirmed our hypothesis that being able to run at 85% of body weight after Achilles surgery was sufficient to clear patients to run outside. PMID- 21703880 TI - Innovation in diagnostic imaging services: assessing the potential for value based reimbursement. AB - Innovation in the field of diagnostic imaging is based primarily on the availability of new and improved equipment that opens the door for new clinical applications. Payments for these imaging procedures are subject to complex Medicare price control schemes, affecting incentives for appropriate use and innovation. Achieving a "dynamically efficient" health care system-one that elicits a socially optimal amount of innovation-requires that innovators be rewarded in relation to the value they add and can demonstrate with evidence. The authors examine how and whether value-based reimbursement for diagnostic imaging services might better reward innovation explicitly for expected improvements in health and economic outcomes. PMID- 21703881 TI - Influence of population prevalences on numbers of false positives: an overlooked entity. AB - BACKGROUND: Disease prevalence alters the number of true positives (TP), true negatives (TN), false negatives (FN), and false positives (FP), even if the sensitivity and specificity of a test stays the same. METHODS AND MATERIALS: We illustrate this using data for the detection of suspected acute pulmonary embolism (PE) from the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II). We chose PE because of the clinical significance of the disease, the low prevalence of PE in the patient population being tested with CTPA with the widespread adoption of CTPA, and the serious clinical consequences of anticoagulation therapy in FP patients. RESULTS: Based on PIOPED II data (sensitivity 83%, specificity 96%), at a disease prevalence of approximately 5%, the number of FP patients is greater than the number of TP patients. Scaled to the US population, at a disease prevalence of 5%, there would be 139,800 FPs and 3,356,200 TNs. Assuming a mortality rate of 0.5% and a 3.0% rate of major bleeding secondary to anticoagulation therapy for well-controlled patients, if all FP patients received anticoagulation, there would be 699 deaths and 4194 major bleeding complications. CONCLUSIONS: At a prevalence of approximately 5% for PE, the number of FPs approaches or is greater than the number of TPs for CTPA for the detection of suspected acute PE. Patients with FP results may receive unnecessary, potentially harmful treatment with anticoagulation therapy. Population prevalence of disease needs to be taken into account along with the diagnostic accuracy of a test, because this may significantly affect downstream patient outcomes. PMID- 21703882 TI - Cerebral signal intensity abnormalities on T2-weighted MR images in HIV patients with highly active antiretroviral therapy: relationship with clinical parameters and interval changes. AB - RATIONALE AND OBJECTIVES: The aim of this study was to assess the relationship between immune state and cerebral signal intensity abnormalities (SIAs) on T2 weighted magnetic resonance images in subjects with human immunodeficiency virus type 1 infection and highly active antiretroviral therapy. MATERIALS AND METHODS: Thirty-two subjects underwent a total of 109 magnetic resonance studies. The presence of human immunodeficiency virus-associated neurocognitive disorder, categorized CD4(+) T lymphocyte count, and plasma viral load were assessed for relationship with the severity and interval change of SIAs for different anatomic locations of the brain. RESULTS: Subjects with multifocal patterns of SIAs had CD4(+) cell counts < 200 cells/MUL in 66.0%, whereas subjects with diffuse patterns of SIAs had CD4(+) cell counts < 200 cells/MUL in only 31.4% (P < .001). Subjects without SIAs in the basal ganglia had CD4(+) cell counts < 200 cells/MUL in 37.0%, whereas subjects with minor and moderate SIAs in the basal ganglia had CD4(+) cell counts < 200 cells/MUL in 78.3% and 80.0%, respectively (P < .005). The percentage of subjects with CD4(+) cell counts < 200 cells/MUL was 85.7% when there were progressive periventricular SIA changes and 45.5% when periventricular SIA changes were stable in follow-up (P < .05). CONCLUSIONS: The presence and progression of cerebral SIAs on T2-weighted magnetic resonance images reflecting cerebral infection with human immunodeficiency virus are significantly related to impaired immune state as measured by CD4(+) cell count. PMID- 21703883 TI - Acoustic droplet vaporization for enhancement of thermal ablation by high intensity focused ultrasound. AB - RATIONALE AND OBJECTIVES: Acoustic droplet vaporization (ADV) shows promise for spatial control and acceleration of thermal lesion production. The investigators hypothesized that microbubbles generated by ADV could enhance high-intensity focused ultrasound (HIFU) thermal ablation by controlling and increasing local energy absorption. MATERIALS AND METHODS: Thermal lesions were produced in tissue mimicking phantoms using focused ultrasound (1.44 MHz) with a focal intensity of 4000 W . cm(-2) in degassed water at 37 degrees C. The average lesion volume was measured by visible change in optical opacity and by T2-weighted magnetic resonance imaging. In addition, in vivo HIFU lesions were generated in a canine liver before and after an intravenous injection of droplets with a similar acoustic setup. RESULTS: Thermal lesions were sevenfold larger in phantoms containing droplets (3 * 10(5) droplets/mL) compared to phantoms without droplets. The mean lesion volume with a 2-second HIFU exposure in droplet containing phantoms was comparable to that made by a 5-second exposure in phantoms without droplets. In the in vivo study, the average lesion volumes without and with droplets were 0.017 +/- 0.006 cm(3) (n = 4; 5-second exposure) and 0.265 +/- 0.005 cm(3) (n = 3; 5-second exposure), respectively, a factor of 15 difference. The shape of ADV bubbles imaged with B-mode ultrasound was very similar to the actual lesion shape as measured optically and by magnetic resonance imaging. CONCLUSION: ADV bubbles may facilitate clinical HIFU ablation by reducing treatment time or requisite in situ total acoustic power and provide ultrasonic imaging feedback of the thermal therapy. PMID- 21703884 TI - Measuring anisotropic diffusion in kidney using MRI. AB - RATIONALE AND OBJECTIVES: To measure the anisotropic diffusion in kidney and to demonstrate the feasibility of renal tractography. MATERIALS AND METHODS: Diffusion tensor imaging was acquired in kidney from 10 healthy volunteers and 5 patients with chronic kidney disease. Diffusion indices were calculated from the tensor, including fractional anisotropy, intervoxel diffusion coherence, and mean/axial/radial diffusivity. RESULTS: Acquisitions with respiratory triggering could provide improved image quality in all diffusion indices, as compared to that by breathhold. It is sufficient to use five to seven scan averages when the measured diffusion indices converge to a steady state in medulla, which reduced the acquisition time in a triggered measurement down to a clinically tolerable limit. Second, the measured diffusion indices can be affected by the diffusion weighting. An increased diffusion weighting will lead to an underestimation in all diffusion indices. Finally the direction of water diffusion is consistent in the kidney cortex, which was properly reflected in intervoxel diffusion coherence. In a feasibility study in healthy volunteers and patients, renal tractography was performed that visualized the organized renal structure and as it declined with the progress of chronic kidney disease. CONCLUSION: When compared to conventional breath hold technique, the significant improvement in image quality compensated for the prolonged acquisition time. Therefore, triggered acquisition is preferred in a clinical setting because it required less from patient cooperation. PMID- 21703885 TI - Marked variation in venous thromboprophylaxis management for abdominal aortic aneurysm repair; results of survey amongst vascular surgeons in the United kingdom. AB - OBJECTIVES: We aimed to survey the current management of venous thromboprophylaxis in patients undergoing elective surgery for abdominal aortic aneurysm (AAA) by vascular surgeons in the United Kingdom. DESIGN: A questionnaire was designed to investigate anticoagulation strategies in the perioperative period of elective AAA repair, both open and endovascular. This included both chemical and mechanical prophylaxis. A total of 395 questionnaires was posted to the members of the Vascular Society of Great Britain and Ireland. RESULTS: One hundred and seventy-two (44%) valid responses were received. Half of the respondents administered pre-operative chemical prophylaxis at a mean of 13 h prior to AAA surgery. There was a high level of concordance in administration of heparin during surgery and in thromboprophylaxis post-operatively, with 97% giving some form of thromboprophylaxis. However there was a variation in the dose and timing, if administered, of chemical and mechanical prophylaxis. CONCLUSION: The survey revealed diversity in perioperative thromboprophylaxis strategies among vascular surgeons. This suggests that standardisation of pre-operative and post-operative mechanical and chemical thromboprophylaxis may be required which could potentially improve the outcomes in elective management of AAA in the UK. PMID- 21703886 TI - Phenotypic characterisation and 16S rRNA sequence analysis of veterinary isolates of Streptococcus pluranimalium. AB - Forty-two isolates of Streptococcus pluranimalium were identified from cattle (n=38), sheep (n=2), an alpaca (n=1) and a pheasant (n=1) in the United Kingdom. The isolates were confirmed as S. pluranimalium by 16S rRNA sequence analysis but could not be differentiated reliably from Streptococcus acidominimus by phenotypic characterisation using commercial kits routinely used in veterinary laboratories. The alanyl-phenylalanyl-proline arylamidase reaction could be used to differentiate S. pluranimalium (positive) from Aerococcus urinae (negative). PMID- 21703888 TI - Animal welfare: at the interface between science and society. AB - The general concept of animal welfare embraces a continuum between negative/bad welfare and positive/good welfare. Early approaches to defining animal welfare were mainly based on the exclusion of negative states, neglecting the fact that during evolution animals optimised their ability to interact with and adapt to their environment(s). An animal's welfare status might best be represented by the adaptive value of the individual's interaction with a given environmental setting but this dynamic welfare concept has significant implications for practical welfare assessments. Animal welfare issues cannot simply be addressed by means of objective biological measurements of an animal's welfare status under certain circumstances. In practice, interpretation of welfare status and its translation into the active management of perceived welfare issues are both strongly influenced by context and, especially, by cultural and societal values. In assessing whether or not a given welfare status is morally acceptable, animal welfare scientists must be aware that scientifically based, operational definitions of animal welfare will necessarily be influenced strongly by a given society's moral understanding. PMID- 21703887 TI - Tuberculosis due to Mycobacterium bovis and Mycobacterium caprae in sheep. AB - Tuberculosis was diagnosed in three flocks of sheep in Galicia, Spain, in 2009 and 2010. Two flocks were infected with Mycobacterium bovis and one flock was infected with Mycobacterium caprae. Infection was confirmed by the comparative intradermal tuberculin test, bacteriology, molecular analysis and histopathology. Sheep have the potential to act as a reservoir for tuberculosis. PMID- 21703889 TI - Concentration gradient of CXCL10 and CXCL11 between the cerebrospinal fluid and plasma in children with enteroviral aseptic meningitis. AB - BACKGROUND: Lymphocyte migration from the blood into the CNS is mediated by chemokines and chemokine receptors. Chemokines CXCL10 and CXCL11 are important for the recruitment of CXCR3-expressing Th1 lymphocytes to the site of inflammation. AIMS: To determine the concentrations of CXCL10 and CXCL11 in the CSF and plasma of children with enteroviral aseptic meningitis (EV AM) and controls and the contribution of these chemokines to the chemokine concentration gradient between the periphery and the CNS. METHODS: The study included 26 pediatric patients with EV AM and 16 controls in whom CNS infection is excluded by negative CSF examination. Chemokines were quantified by using enzyme immunoassay. Etiological diagnosis of EV AM was based on the detection of enteroviral RNA in the CSF using real-time PCR. RESULTS: CXCL10 (median 12 725 pg/ml) and CXCL11 (median 187 pg/ml) concentrations in CSF of patients with meningitis were significantly higher compared to plasma (median 173 pg/ml and median 110 pg/ml; p < 0.001, p = 0.026 respectively). CXCL10 concentrations in the CSF (median 198 pg/ml) and plasma of controls (median 124 pg/ml) were not significantly different (p = 0.642). CXCL11 concentrations in the CSF of controls (median 89 pg/ml) were significantly lower compared with plasma (median 139 pg/ml, p = 0.004). Chemokine concentration gradient was not influenced by pleocytosis, nor dependent on cytologic CSF formula or the presence of proteinorrachia. CONCLUSION: CXCL10 and CXCL11 concentration gradient between the CSF and plasma in children with EV AM suggests an important role of these chemokines in the T-cells recruitment into the CNS and local immunoreaction. PMID- 21703890 TI - Self-, parent-, and teacher-reported behavioral symptoms in youngsters with Tourette syndrome: a case-control study. PMID- 21703891 TI - Serum insulin, cortisol, leptin, neuropeptide Y, galanin and ghrelin levels in epileptic children receiving oxcarbazepine. AB - PURPOSE: The aim of this study was to investigate whether oxcarbazepine (OXC) monotherapy causes weight gain in epileptic children. METHODS: A total of 22 children with epilepsy (age 3.0-16.4 years) were assigned to OXC therapy. Serum levels of glucose, insulin, cortisol, leptin, neuropeptide Y (NPY), galanin and ghrelin were assessed before OXC therapy (month 0) and after the 6th and 18th months. RESULTS: There was no statistically significant difference in weight standard deviation score (SDS), Height-SDS, BMI-SDS, serum glucose, insulin, cortisol, leptin, NPY, galanin and ghrelin levels between initial values (month 0) and those in the 6th and 18th months after OXC therapy (p > 0.05). CONCLUSIONS: Our results indicate that OXC therapy causes neither weight change nor alterations in serum glucose, insulin, cortisol, leptin, NPY, galanin and ghrelin levels in children with epilepsy. PMID- 21703892 TI - Expression of insulin-like growth factor 1 isoforms in the rabbit oculomotor system. AB - OBJECTIVE: The insulin-like growth factor-1 (IGF-1) gene encodes two isoforms, IGF-1Ea and IGF-1Eb. Both isoforms can regulate skeletal muscle growth and strength. It has been suggested that IGF-Eb may be more potent in promoting skeletal muscle hypertrophy. Precise contractile force regulation is particularly important in the oculomotor system. However, expression of these isoforms in mammalian extraocular muscles (EOMs) is unknown. Here, we examined their expression in rabbit EOMs and the innervating nerve, two potential sources for myogenic growth factors, and compared isoform expression between EOMs and limb skeletal muscles. DESIGN: Expression of IGF-1 isoforms was quantified by real time RT-PCR in adult rabbit EOMs, trochlear and ophthalmic nerves, and compared with expression in rabbit limb skeletal muscles. The presence of mature IGF-1 peptide in the muscles was further examined by Western blot. RESULTS: Both IGF 1Ea and IGF-1Eb were expressed in the EOM and the trochlear nerve. Both isoforms were expressed at significantly higher levels (9-fold) in EOM than in limb skeletal muscle. Transcripts of IGF-1 isoforms, of IGF-1 receptor and of IGF binding proteins showed a gradient distribution along the EOM from proximal to distal. The mature IGF-1 protein showed the same gradient distribution in the EOM. CONCLUSIONS: Expression of relatively abundant amounts of both IGF-1 splicing isoforms in EOMs, and at a significantly higher level than in limb skeletal muscle, underscores the potential relevance of these myogenic growth factors in EOM plasticity and force regulation. PMID- 21703893 TI - Generation of induced pluripotent stem (iPS) cells derived from a murine model of Pompe disease and differentiation of Pompe-iPS cells into skeletal muscle cells. AB - Our study is the first to demonstrate the ability to generate iPS cells from a mouse model of Pompe disease. Initially, mouse tail tip fibroblasts were harvested from male, 8-week-old (GAA) knockout mice, and three reprogramming factors (Oct3/4, Sox2 and Klf4) were transfected into the isolated donor cells using a retroviral vector. These iPS cells also showed decreased levels of GAA enzymatic activity and strong positive staining with periodic acid-Schiff (indicating the accumulation of glycogen) and acid phosphatase (lysosomal activation marker). Pompe-iPS cells were differentiated into skeletal muscle cells in Matrigel(r)-coated plates. Spindle-shaped skeletal muscle cells were successfully generated from Pompe-iPS cells and showed spontaneous contraction and positive staining with the myosin heavy chain antibody. Electron microscopic analysis of the skeletal muscle cells showed typical morphological features, including Z-bands, I-bands, A-bands and H-bands, which were visible in wild-type and Pompe cells. Furthermore, Pompe skeletal muscle cells accumulated massive glycogen in lysosomes. This study indicates that the iPS and skeletal muscle cells generated in this study could also be a useful disease model for studies investigating the pathogenesis and treatment of skeletal muscle in Pompe disease. PMID- 21703894 TI - The pharmacists' role in clinical research. PMID- 21703895 TI - [Primaquine-induced methemoglobinaemia]. PMID- 21703896 TI - Assessing a therapeutic exchange protocol for second-generation antidepressants: clinical results. AB - OBJECTIVE: To design a therapeutic exchange protocol for antidepressants and clinically assess variables, such as: compliance level, frequency of cases with clinically significant increase on the Udvalg-fur-Kliniske-Undersogelser (UKU) psychopharmacological scale, adverse effects analysis, overall analysis of UKU rating development and patients' level of acceptance. Secondary objectives were to correlate psychopharmacological treatment aspects with the pharmacological morbidity level, and evaluate the clinical impact of pharmacotherapeutic optimisation measures. METHOD: The protocol is designed in accordance with a bibliographical review, which was approved by the Pharmacy and Therapeutics Commission. Sequential study was carried out with a sample of 30 patients. Three measurements were taken (base line, at 48-72 hours and at 1-3 weeks) to calculate the pharmacotherapeutic morbidity with the UKU rating scale and the Global Clinical Impression. Pharmacotherapeutic optimisation measures were used for those patients with high pharmacotherapeutic morbidity levels. RESULTS: The compliance level was 73.3%. One patient experienced >=25% increase on the UKU rating scale and another patient suffered from an adverse effect. The final UKU rating reached statistical significance compared with the measurements taken at 48-72 hours (P=.032) and with the base line measurement (P=.007). Patient acceptance was 90%. The impact of optimisation measurements on the pharmacotherapeutic morbidity level was clinically and statistically significant (P<.001). CONCLUSIONS: The proposed protocol has been widely accepted and it is quite certain that it is to be introduced in at a general hospital level. PMID- 21703897 TI - [Coping and management of the disease in patients with diabetes mellitus type 1]. AB - OBJECTIVE: To investigate how patients with DM Type 1 attending a nursing education clinic cope with the disease and to analyse the relationships between the style of coping (CS) and control-self-management of the disease. METHOD: A cross sectional study was performed on all patients attending a diabetes education consultation at the Hospital of Ourense. The sociodemographic and clinical variables, as well as those related to the management of DM were collected. The Medical Questionnaire Coping Strategies of Feifel was used to assess the CS using 3 different models: confrontation (C), avoidance (A) and/or resigned acceptance (RA), and a total coping index (IMCMQ) was established. The data were analysed with SPSS 15.0 statistics program. RESULTS: A total of 51 patients. The average profile of patient is of a male who had been diagnosed with DM for 14.56 years (+/-11.44), and with latest HbA1c levels of 7.5% (+/-1.04). The scores for the CS were: C 21+/-3.4, A 11.73 (+/-3.5), RA 8.47 (+/-1.02); IMCMQ 1.013 (+/-0.23). As for the relationship between the IMCMQ score and the latest HbA1c values, there were significant differences (P=0.01). CONCLUSIONS: Our patients use the CS-C, understood as one in which a person tries to understand and address the situation openly. This style is the most effective and associated with best prognosis. In light of the data obtained, we can infer that our patients have an active and appropriate CS and it has a positive impact on their HbA1c values. PMID- 21703898 TI - [Benchmarking in the emergency unit process in 7 hospitals from different autonomous communities]. AB - OBJECTIVE: To identify and to share the results among hospitals regarding the process of attention at the Emergency Unit, and to detect the practices that explain the differences. MATERIAL AND METHOD: SETTING: 7 hospitals of different regions in Spain. PERIOD OF STUDY: 2005-2007. Firstly the comparability criteria were defined assuring the homotecia in the "emergency process". In order to fulfil the study objectives, 11 criteria were selected and every center sent the information of each one. 7 indicators were identified to compare hospitals processes'. Data regarding all the attentions provided during the study period was analyzed, establishing the benchmark among the centers. Finally, a questionnaire was elaborated for the process analysis, considering all the stages of the process, the resources and the procedures used in every stage, to be fulfilled in each hospital. RESULTS: The homotecia has been verified in the 7 hospitals, with some differences between centers. 7 indicators have been analyzed in the different hospitals, corresponding to 1,526,890 patients attended in the study period. A benchmark has been identified, with the best results in four of seven indicators: % of admissions from urgencies: 8.3%, emergency pressure: 56.14%, emergency length of stay: 2 hs 20min, and % of patients with length stay > 24h: 0.05%. Differences between the stages of the process, resources and procedures used in every stage in the benchmark center have been analyzed. CONCLUSIONS: A set of indicators to compare Emergency Departments has been identified, letting us establish the benchmark. PMID- 21703899 TI - High prevalence of Mycobacterium avium subspecies paratuberculosis ('Indian bison type') in animal attendants suffering from gastrointestinal complaints who work with goat herds endemic for Johne's disease in India. AB - OBJECTIVES: In this study we aimed to estimate the prevalence of Mycobacterium avium subspecies paratuberculosis (MAP) in animal attendants who were chronic colitis patients or who had inflammatory bowel disease and were suspected for Crohn's disease; these animal attendants worked with goat herds endemic for Johne's disease. Microscopic examination and culture tests were used. For comparison purposes a group of healthy human subjects (not suffering with colitis) was also screened. METHODS: Stool samples obtained from 98 human subjects (58 animal attendants suspected for Crohn's disease and 40 healthy humans) were screened for the presence of MAP by microscopic examination and culture. Of the 58 animal attendants screened, 38 had abdominal pain, 29 had suffered episodes of diarrhea, 39 had experienced weight loss, 27 had fever, and 32 had a history of raw milk consumption. Animal attendants had had contact of variable duration with goat herds endemic for Johne's disease (1-5, 6-10, 11-15, and >15 years). Forty stool samples from healthy humans with no symptoms/history of contact with animals were also screened. IS900 PCR and IS1311 PCR restriction endonuclease analysis were used to characterize and genotype the MAP colonies. RESULTS: MAP was recovered from 34 of the 98 human subject stool samples (34.7%). Of the 98 samples, 16.3% (n=16) were acid-fast. None of the 40 healthy human subjects were positive for MAP by microscopy, but five (12.5%) were positive for MAP by culture. Of the 58 animal attendants, 16 (27.6%) were positive by microscopy and 29 (50%) were positive by culture. MAP were recovered from 68.4% of animal attendants with abdominal pain, 72.4% of those with diarrhea, 71.8% of those with weight loss, 44.4% of those with fever, and 46.9% of those who had a history of raw milk consumption. Of the 29 culture-positive animal attendants, 48.3% had worked for >15 years, 27.6% for 11-15 years, 20.7% for 6-10 years, and 3.4% for 1-5 years with goat herds endemic for Johne's disease. Of the 34 culture isolates, 28 (82.4%) showed good quality DNA on agarose gel and were positive by IS900 PCR. Of the 28 IS900-positive DNA samples, 23 (82.1%) were genotyped as 'Indian bison type' and five (17.9%) as 'cattle type'. CONCLUSIONS: The prevalence of MAP was higher in attendants suffering from gastrointestinal problems who worked with goat herds endemic for Johne's disease, than in humans with no history of contact with animals. The risk of developing gastrointestinal problems with clinical symptoms indistinguishable from inflammatory bowel disease was higher in humans who were in contact with goat herds endemic for Johne's disease as compared to healthy humans, and the risk was correlated with the duration of association with the endemic goat herds. PMID- 21703900 TI - Monitoring of bone turnover markers does not improve persistence with ibandronate treatment. AB - OBJECTIVE: To assess if the use of biological marker of bone resorption (CTX) feedback is a mean to improve persistence on monthly oral ibandronate. METHODS: One year prospective multicenter study using a cluster randomisation design with physicians as randomized units into two groups, A and B; in group B, physicians used results of CTX and two standardized messages according to CTX changes from baseline: suboptimal if decrease less than 30% at week 6, positive otherwise. In group A, the follow-up was standard of care. Patients were postmenopausal women, initiating a treatment with ibandronate 150 mg monthly. They were blinded to the study hypotheses and outcome. The outcome was the proportion of patients persistent at 1-year visit. RESULTS: Eighty-eight physicians were randomized in group A and included 346 patients, 75 in group B included 250 patients. The persistence at 1-year was high and not different between the two groups (75.1 and 74.8% P=0.932). There was no difference in the proportion of persistent patients according to the message delivered in the group of patient with CTX information: 77.4 and 74.8% in patients with a suboptimal or positive message respectively. CONCLUSION: This study failed to demonstrate that supporting monitoring of CTX could improve persistence to ibandronate treatment in postmenopausal osteoporosis. KEY MESSAGES: Persistence is a strong determinant of anti osteoporotic treatments efficacy. Monitoring of bone markers is not a mean to improve persistence of an oral bisphosphonate. There is a discrepancy between levels of persistence in clinical studies and real life. PMID- 21703901 TI - The kaleidoscopic presentation of the spondyloarthritis concept in a female patient. AB - Spondyloarthritis is a group of chronic joint diseases that share clinical, pathological and genetic features and is divided into distinct diagnostic entities, including ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease-associated spondyloarthritis, reactive arthritis, juvenile onset and undifferentiated spondyloarthritis. Since the spectrum of spondyloarthritides is wider than the sum of aforementioned disorders suggests, the term "Spondyloarthritis concept" might prove to be appropriate. Here, we present a case in which many features of the spondyloarthritis concept, but also unexpected osteitis in the skull and tibia, emerge during the disease course. A 45-year-old HLA-B27 positive woman with a family history of psoriasis, a former diagnosis of ankylosing spondylitis, reactive arthritis and fulminating acne, was referred to our department with a painful tibial swelling, symmetrical polyarthritis and severe headache. Conventional radiography and bone scintigraphy demonstrated large osteolytic lesions on the left parietal side of the skull and the right anterior tibia. She was treated with surgery and pamidronate. Etanercept treatment was initiated as the arthritis deteriorated and was replaced by infliximab when new onset Crohn's disease became apparent. This case is the illustration of spondyloarthritis as a disease concept, covering the entire spectrum, from ankylosing spondylitis, urogenital reactive arthritis and psoriatic arthritis to inflammatory bowel disease. Cases like this illustrate that the clinical classification of spondyloarthritis patients into distinct diagnostic entities is bypassing the value of the "concept" and provides support for the new classification criteria that were recently proposed. PMID- 21703902 TI - Tooth extraction and oral bisphosphonates: comparison of different surgical protocols. PMID- 21703903 TI - A dental extraction protocol with plasma rich in growth factors (PRGF) in patients on intravenous bisphosphonate therapy: a case-control study. PMID- 21703904 TI - Successful treatment of primary biliary cirrhosis with etanercept in a patient with rheumatoid arthritis. PMID- 21703905 TI - Interleukin-33: a novel player in osteonecrosis of the femoral head? AB - Osteonecrosis of the femoral head (ONFH) is a disabling disease affecting young adults, which usually leads to the destruction of the hip joint. It is mainly due to an inadequate blood supply that causes the death of osteocytes and bone marrow cells. Joint salvaging procedures are numerous but relatively inefficient, justifying the need for new therapeutic strategies. In this regard, the recently discovered interleukin (IL)-33 alarmin appears as a possible target. Indeed, IL 33 seems to be specifically released by necrotic cells, and interestingly, is constitutively expressed in human bone, in particular by osteocytes, osteoblasts and marrow adipocytes. Moreover, recent reports suggesting that IL-33 modulates angiogenesis, vascular permeability, osteoclastogenesis and bone resorption, indicate that IL-33 may play a role in ONFH. PMID- 21703906 TI - Comments on: "Death by biscuit: Exhumation, post-mortem CT, revision of the cause of death 1 year after interment". PMID- 21703907 TI - Influence of orthopaedic drilling parameters on temperature and histopathology of bovine tibia: an in vitro study. AB - Orthopaedic drilling operations without optimum operating parameters by surgeons may cause bone defects such as bone fracture, cracks, osteolysis and tissue loss around the drilling zone. For the sake of optimum drilling parameters, an in vitro study was performed by considering the bone mineral density, bone sex, drill tip angle, drill speed, drill force and feed-rate. The specimens were taken from the drilled sites of fresh male and female calf tibias. The temperature changes at the drill site were investigated throughout the statistical and histopathological analysis. It was observed that the temperature increased with an increasing drill speed and decreased with high feed-rates and applied drill forces. The drilling temperatures of the female bovine tibias were found to be higher than that of the male tibias and the drill speed was found to be a significant parameter on the maximum temperature. Moreover, the maximum temperature increased with an increasing drill tip angle and bone mineral density. Therefore the bone quality around the drill site was found to be worse than the bone samples exposed to low temperatures. PMID- 21703908 TI - Akathisia: An unusual movement disorder in Machado-Joseph disease. PMID- 21703909 TI - Sex in the city: privacy-making practices, spatialized intimacies and the environmental risks of men-who-have-sex-with-men in South India. AB - Employing community-based approaches, the spatialization of sexual risk among men who-have-sex-with-men (MSM) at local cruising spots was explored in South India. To move beyond individualistic and structural deterministic understandings of sexual risk the study examined how erotic associations and networks formed and dissolved as social actors connect to each other through their material world (which includes other bodies). Crowding was important for safely establishing intimacy in public but also created contexts of discrimination and violence, particularly for feminine-acting males. Risk itineraries drawn by MSM anticipated fluctuating levels of risk, enabling them to avoid dangerous situations. Although sexual typologies connected gender nonconforming males to HIV prevention networks, they reinforce the exclusion of men who did not identify with sexual minority identities. Future work must therefore address the HIV prevention needs of men whose identities cannot be readily separated from "the general population". PMID- 21703910 TI - Role of microRNA-155 in autoimmunity. AB - MicroRNAs (miRNAs) have recently emerged as a major class of gene expression regulators linked to most biological functions. MiR-155 is encoded within a region known as B cell integration cluster (Bic) gene, identified originally as a frequent integration site for the avian leukosis virus. Disregulation of endogenous miR-155 has been implicated in the pathogenesis of human cancers. Recently, aberrant expression of miR-155 was observed in many autoimmune conditions, including rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). Moreover, functional analysis demonstrated that miR-155 has powerful regulatory potential in a wide variety of immune cells through targeting specific mRNAs. Since pathogenic immune cells play a pivotal role in pathogenesis of human autoimmune diseases, miR-155 might be a versatile therapeutic target. This review will discuss the current understandings for the role of miR-155 in autoimmunity. PMID- 21703911 TI - Molecular structure, vibrational spectral studies of pyrazole and 3,5-dimethyl pyrazole based on density functional calculations. AB - In this work, the experimental and theoretical vibrational spectra of pyrazole (PZ) and 3,5-dimethyl pyrazole (DMP) have been studied. FTIR and FT-Raman spectra of the title compounds in the solid phase are recorded in the region 4000-400 cm( 1) and 4000-50 cm(-1), respectively. The structural and spectroscopic data of the molecules in the ground state are calculated using density functional methods (B3LYP) with 6-311+G** basis set. The vibrational frequencies are calculated and scaled values are compared with experimental FTIR and FT-Raman spectra. The observed and calculated frequencies are found to be in good agreement. The complete vibrational assignments are performed on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanical (SM) method. 13C and 1H NMR chemical shifts results are compared with the experimental values. PMID- 21703912 TI - Study on the fluorescence enhancement in Lanthanum(III)-carminic acid cetyltrimethylammonium bromide system and its analytical application. AB - A fluorescent enhancement system carminic acid (CA)-La3+-CTAB is found and based on this finding a new fluorimetric method for the determination of CA is developed. Under optimized conditions, the enhanced intensities of fluorescence are quantitatively in proportion to the concentrations of CA in the range of 0.01231-12.31 MUg mL(-1). The detection limit is 10.92 ng mL(-1). Compared with other methods that have been reported to determine CA, this method has high sensitivity, stability and wide linear range. In addition, the luminescence mechanism indicates that the complex of La3+-CA (1:2) forms and solubilizes in CTAB micelle. PMID- 21703913 TI - The study of a single BGC823 cell using Fourier transform infrared microspectroscopic imaging. AB - In order to investigate gastric cancer at cellular and sub-cellular level, a single human gastric adenocarcinoma BGC823 cell was studied by an infrared microscope equipped with a focal plane array (FPA) detector. The spectra showed difference between the nucleus and the endoplasmic reticulum (ER) of the BGC823 cell. The peak of vasPO2- was shifted to a higher wavenumber at the nucleus compared with that at the ER. The height ratios of 2954 cm(-1)/2922 cm(-1) (CH3/CH2) and 1088 cm(-1)/1539 cm(-1) (DNA/amide II) of the nucleus were significantly higher than those of the ER. Furthermore, chemical images reveal the intensity distributions of lipids, proteins and DNA of the single BGC823 cell, and the intense absorptions of proteins and DNA were observed in the nuclear region of the cell while the intense absorption of lipids was found in the ER region of the cell. The Fourier transform infrared (FTIR) microspectroscopic imaging result indicates the study of the single gastric cancer cell at sub-cellular level can be beneficial for knowing gastric cancer more which will be of great importance for the study and diagnosis of gastric cancer. The result also suggests that FPA is a useful tool in the study of a single cell and may be a powerful tool for study and diagnosis of gastric cancer. PMID- 21703914 TI - Growth and characterization of Fe3+-doped bis(thiourea)zinc(II) chloride crystals. AB - Fe3+-doping at ~10 mol% in aqueous medium during crystal growth by slow evaporation solution method in bis(thiourea)zinc(II) chloride (BTZC) leads to form a new compound C2H8Cl2N4S2Zn0.93Fe0.07 (BTZCF) which crystallizes in orthorhombic structure with centrosymmetric space group Pnma though the parent compound BTZC crystallizes in noncentrosymmetric structure with space group Pn2(1)a. The interesting feature observed in this new crystal is that though it crystallizes in centrosymmetric structure, it exhibits positive SHG result (weak signal), quite likely due to possible surface effects or internal stress. The calculated first-order hyperpolarizability is 1.457*10(-30) esu which is ~5.5 times that of urea. Fe3+-doping enhances the transmittance to a significant extent. Comparison of the thermal analysis results by DSC reveals the incorporation of dopant into the crystalline matrix. The high resolution XRD studies reveal that the crystalline quality is improved considerably when the doping level is reached to ~10 mol%. PMID- 21703915 TI - Synthesis, characterization and fluorescence studies of novel bi-phenyl based acrylate and methacrylate. AB - 4-[(1E)-3-(biphenyl-4-yl)buta-1,3-dien-1-yl]phenyl prop-2-enoate (ACH) and 4 [(1E)-3-(biphenyl-4-yl)buta-1,3-dien-1-yl]phenyl 2-methylprop-2-enoate (MCH) was synthesized from biphenyl in three steps and their structures were confirmed by elemental analysis, IR, NMR (1H, 13C, DEPT135, 1H-1H COSY, 1H-13C HSQC and 1H-13C HMBC) spectroscopic techniques. In this present study, various physicochemical characteristics we demonstrate solubility, color, absorbance and fluorescence property of novel biphenyl based acrylate and methacrylate measured in different solvents like benzene, dichloromethane, tetrahydrofuran, acetonitrile, dimethylsulfoxide and ethanol. PMID- 21703916 TI - Inclusion of Paracetamol into beta-cyclodextrin nanocavities in solution and in the solid state. AB - We report on steady-state UV-visible absorption and emission characteristics of Paracetamol, drug used as antipyretic agent, in water and within cyclodextrins (CDs): beta-CD, 2-hydroxypropyl-beta-CD (HP-beta-CD) and 2,6-dimethyl-beta-CD (Me beta-CD). The results reveal that Paracetamol forms a 1:1 inclusion complex with CD. Upon encapsulation, the emission intensity enhances, indicating a confinement effect of the nanocages on the photophysical behavior of the drug. Due to its methyl groups, the Me-beta-CD shows the largest effect for the drug. The observed binding constant showing the following trend: Me-beta-CD>HP-beta-CD>beta-CD. The less complexing effectiveness of HP-beta-CD is due to the steric effect of the hydroxypropyl-substituents, which can hamper the inclusion of the guest molecules. The solid state inclusion complex was prepared by co-precipitation method and its characterization was investigated by Fourier transform infrared spectroscopy, 1H NMR and X-ray diffractometry. These approaches indicated that Paracetamol was able to form an inclusion complex with CDs, and the inclusion compounds exhibited different spectroscopic features and properties from Paracetamol. PMID- 21703917 TI - Vibrational spectroscopic analysis of 2-bromobenzoic and anthranilic acids: a combined experimental and theoretical study. AB - In this work, the vibrational spectral analysis was carried out by using Raman and infrared spectroscopy in the range 100-4000 cm(-1) and 50-4000 cm(-1) respectively, for the title molecules. The molecular structure, fundamental vibrational frequencies and intensity of the vibrational bands are interpreted with the aid of structure optimizations and normal coordinate force field calculations based on Hartee-Fock (HF) and density functional theory (DFT) method and different basis sets combination. The complete vibrational assignments of wavenumbers were made on the basis of potential energy distribution (PED). The scaled B3LYP/6-311++G(d,p) results show the best agreement with the experimental values over the other methods. The effects due to the substitutions of amino group and halogen bond were investigated. The results of the calculations were applied to simulate spectra of the title compounds, which show excellent agreement with observed spectra. PMID- 21703918 TI - Kinetics and mechanism of the heterogeneous catalyzed oxidative decolorization of Acid-Blue 92 using bimetallic metal-organic frameworks. AB - The kinetics study of the oxidative decolorization of Acid-Blue 92 has been investigated by hydrogen peroxide catalyzed with bimetallic metal-organic frameworks. The used metal-organic frameworks (MOF) are [Ph3SnCu(CN)2.L] where L=pyrazine (pyz) 1, methylpyrazine (mepyz) 2, 4,4'-bipyridine (bpy) 3, trans-1,2 bis(4-pyridyl)ethene (tbpe) 4 or 1,2-bis(4-pyridyl)ethane (bpe) 5. The reaction was followed by conventional UV-Vis spectrophotometer at lambdamax=571 nm. The reaction exhibited first-order kinetics with respect to [dye] and [H2O2]. The reactivity of the catalysts depends on the type of the medium and thereafter decreases in strong alkaline media. Addition of NaCl enhances the reaction rate. Also, the irradiation of the reaction with UV-light enhanced the rate of AB-92 mineralization by about 86.9%. The reaction was entropy-controlled as confirmed by the isokinetic relationship. A reaction mechanism was proposed with the formation of free radicals as an oxidant. PMID- 21703919 TI - Leather material found on a 6th B.C. Chinese bronze sword: a technical study. AB - During July to November, 2006, an important archaeological excavation was conducted in Yun country, Hubei province, southern China. Chinese archaeologists found some remnant of leather materials, covered with red pigments, on a 6th century B.C. Chinese bronze sword. To understand the technology/ies that may have been utilized for manufacturing the leathers, a combined of Raman spectroscopy, FT-IR and XRF was thus applied to the remnant of leather materials. Raman analyses showed that red pigment on the leather was cinnabar (HgS). FT-IR and XRF analyses indicated that the content of some elements, such as Ca (existing as CaCO3) and Fe (existing as Fe2O3), were much higher than those in the surrounding grave soil. The results inferred an application of lime depilation and retting, and the Fe-Al compound salt as tanning agent. And it was furthermore implicated that the Fe-Al salt tanning technique had been developed in the middle and late Spring and Autumn Period of China. PMID- 21703920 TI - Synthesis and spectroscopic studies of stable aqueous dispersion of silver nanoparticles. AB - A facile approach for the synthesis of stable aqueous dispersion of silver nanoparticles (AgNPs) using glucose as the reducing agent in water/micelles system, in which cetyltrimethylammonium bromide (CTAB) was used as capping agent (stabilizer) is described. The evolution of plasmon band of AgNPs was monitored under different conditions such as (a) concentration of sodium hydroxide, (b) concentration of glucose, (c) concentration of silver nitrate (d) concentration of CTAB, and (e) reaction time. AgNPs were characterized by UV-visible spectroscopy, transmission electron microscopy (TEM), fluorescence spectroscopy and FT-IR spectroscopy. The results revealed an easy and viable strategy for obtaining stable aqueous dispersion of AgNPs with well controlled shape and size below 30 nm in diameter. PMID- 21703921 TI - Optical spectroscopy studies of the interaction between thiophanate methyl and human serum albumin for biosensor applications. AB - Optical properties of the interaction between thiophanate methyl and human serum albumin have been investigated for biosensor applications. The interaction between human serum albumin (HSA) and thiophanate methyl (MT) was investigated by UV-Vis absorption spectra and atomic force microscopy. The optical constants (refractive index, absorption index, band gap and dielectric properties) of HSA, MT and MT+HSA films were determined using absorbance, transmittance and reflectance spectra. The refractive index dispersion curve (>530 nm) exhibits the normal dispersion. The refractive index of the MT+HSA is higher than both HSA and MT alone due to the highest reflectance of the mixture of MT and HSA. This behavior is indicative of the complex formation between the MT and HSA. PMID- 21703922 TI - Synthesis, spectral and catalytic activity of some manganese(II) bis benzimidazole diamide complexes. AB - Four Mn(II) complexes bound to a neutral bis-benzimidazole diamide ligand N,N' bis(2-methyl benzimidazolyl 2,2'-oxy-diethanamide) (GBOA) have been synthesized and characterized. Anionic ligand associated with the complexes varies as Cl- CH3COO-, SCN- and ClO4-. X-ray structure of one of the complexes [Mn(GBOA)2(H2O)2]Cl(2).4H2O was solved and shows that the Mn(II) ion is hexacoordinate. Two equatorial positions are occupied by benzimidazole imine nitrogen atoms while the other two sites are occupied by amide carbonyl oxygens. The imine nitrogen and carbonyl oxygens are bound to Mn(II) by different arms of the two ligands while axial sites are occupied by two water molecules. Two Cl- anions are outside the coordination sphere and form an extensive 3D H-bonded network. Axially distorted octahedral geometry is confirmed for all the four complexes by low temperature EPR spectroscopy. Distortion parameter D was found to be similar for [Mn(GBOA)2(H2O)2]Cl(2).4H2O and [Mn(GBOA)2(H2O)2].(CH3COO)2.H2O. Cyclic voltammograms have been obtained for all the four complexes and E(1/2) values are dependent on the anionic ligand being in the coordination sphere or outside. [Mn(GBOA)2(H2O)2]Cl(2).4H2O and [Mn(GBOA)2(H2O)2].(CH3COO)2.H2O carry out the selective oxidation of N benzyldimethylamine, and 1-methyl-pyrollidine to their respective carbonyl products with catalytic efficiency of 35-50%. PMID- 21703923 TI - Determination of binding strength for the supramolecular complexation of a designed bisporphyrin with C60, C70 and their derivatives employing absorption spectrophotometric, fluorescence and quantum chemical calculations. AB - The present paper reports the synthesis of a designed bisporphyrin (1), and its supramolecular complexes with C60, C70 and their derivatives, namely, tert-butyl (1,2-methanofullerene)-61-carboxylate (2) and [6,6]-phenyl C70 butyric acid methyl ester (3) in toluene medium. C60, C70 and their derivatives undergo ground state non-covalent interaction with 1 is evidenced from absorption spectrophotometric study in which it is observed that the intensity of the Soret absorption band of 1 decreases considerably in presence of C60, C70 and their derivatives. Steady state fluorescence studies reveal efficient quenching of fluorescence of 1 in presence of fullerenes. The binding constant (K) values of the fullerene/1 complexes follows the trend: 2/110) were reported by 47.5% (95% CI: 37.3-57.7) of the patients. In the sample, 52.6% (95% CI: 0.41-0.60) were overweight or obese, and 53.1% (95% CI: 0.43-0.62) had less than 8 years of formal education. Mainly anxiety, but also neck circumference, was correlated with EDS. Our patients did not exhibit quantitative sleep deprivation. No other epilepsy-related variable showed relationship with EDS. The prevalence of EDS in our population was higher than in similar studies performed in other countries. This finding does not seem to be related to epilepsy itself, but rather to other clinical factors, such as neck circumference, and mainly psychiatric factors, such as anxiety. CONCLUSIONS: Psychiatric comorbidities such as anxiety are linked to EDS and should be recognized and treated. More studies based on objective sleep quality analysis are needed to help elucidate these relationships in the Brazilian population. PMID- 21703936 TI - Prognostic significance of bone markers in patients with lung cancer metastatic to the skeleton: a review of published data. AB - The presence of bone metastases significantly affects clinical outcome and quality of life parameters in patients with lung cancer. In this review, we aimed to evaluate the predictive value of markers of bone turnover in skeletal morbidity and clinical parameters, including disease-free survival (DFS) and overall survival (OS), in patients with lung cancer metastatic to the skeleton who were receiving bisphosphonate treatment. A comprehensive overview of all articles published from 1995 to date in 3 medical databases (PubMed, Scopus, and Cochrane) was performed using the keywords bone markers and lung cancer. Most bone formation markers (including bone alkaline phosphatase [bALP], osteocalcin [OC], and osteoprotegerin [OPG]), most bone absorption markers (including urinary calcium, osteopontin [OPN], receptor activator of nuclear factor kappa-B ligand [RANKL], tartrate-resistant acid phosphatase isoform-5b [TRACP 5b]), and the metabolites of type I collagen had elevated concentrations in patients with lung cancer and bone metastases compared with patients without skeletal involvement. Two large studies showed that urinary N-terminal telopeptide (NTX) levels are a valid diagnostic method for early detection of bone metastases and a more consistent prognosticator than bALP. Treatment with zoledronic acid reduces NTX, TRACP-5b, RANKL, and OPG levels. Furthermore posttherapeutic reduction of urinary NTX levels seems to correlate with lower risk of skeletal-related events (SREs). Levels of markers of bone remodeling reflect the presence of bone metastases and may contribute to early detection of occult skeletal disease or monitor the effect of bisphosphonate treatment. However their ability to predict SREs, as well as DFS and OS, remains debatable. PMID- 21703935 TI - Metabolic tumor volume is an independent prognostic factor in patients treated definitively for non-small-cell lung cancer. AB - PURPOSE: Fluorine-18 flurodeoxyglucose positron emission tomography (FDG-PET) imaging has rapidly become the standard of care for staging patients with lung cancer. We evaluated the prognostic value of metabolic tumor volume (MTV), a measure of tumor burden on FDG-PET imaging, in patients with non-small-cell lung cancer (NSCLC) treated definitively. METHODS AND MATERIALS: A retrospective review identified 61 patients with NSCLC who underwent FDG-PET imaging for pretreatment staging. Metabolically active tumor regions were segmented on the PET scans semiautomatically to calculate the total body MTV. We determined the relationship of overall survival (OS) and progression-free survival (PFS) with MTV in the entire cohort, and in the subgroup treated definitively. RESULTS: The estimated median PFS and OS for the entire cohort were 11.1 months and 18.9 months. Higher MTV was significantly associated with worse OS (P = 0.00075) and PFS (P = 0.00077). For definitively treated patients, when MTV was analyzed as a binary value above or below the median value, 2-year PFS was 60% versus 39.7% (median PFS 34.9 vs. 11.9 months) and 2-year OS was 79.7% versus 33.3% (median OS 41.9 vs. 18.9 months), respectively (log-rank P = 0.12 for PFS and P = 0.066 for OS). When MTV was analyzed as a continuous variable, multivariate Cox proportional hazards analysis demonstrated a trend to worse PFS (hazard ratio [HR] = 1.31; P = 0.12) and significantly worse OS (HR = 1.53; P = 0.018) with increasing MTV after controlling for known prognostic variables. CONCLUSION: Tumor burden as assessed by MTV yields prognostic information on survival beyond that of established prognostic factors in patients with NSCLC treated definitively. PMID- 21703937 TI - The specificity and mechanisms of hemilateral sensory disturbances in complex regional pain syndrome. AB - Hyperalgesia often extends from the affected limb to the ipsilateral forehead in patients with complex regional pain syndrome (CRPS). To investigate whether this is more common in CRPS than other chronic pain conditions, pressure-pain thresholds and sharpness to a firm bristle were assessed on each side of the forehead, at the pain site, and at an equivalent site on the contralateral side in 32 patients with chronic pain other than CRPS (neuropathic or nociceptive limb pain, radicular pain with referral to a lower limb or postherpetic neuralgia), and in 34 patients with CRPS. Ipsilateral forehead hyperalgesia to pressure pain was detected in 59% of CRPS patients compared with only 13% of patients with other forms of chronic pain. Immersion of the CRPS-affected limb in painfully cold water increased forehead sensitivity to pressure, especially ipsilaterally, whereas painful stimulation of the healthy limb reduced forehead sensitivity to pressure pain (albeit less efficiently than in healthy controls). In addition, auditory discomfort and increases in pain in the CRPS-affected limb were greater after acoustic startle to the ear on the affected than unaffected side. These findings indicate that generalized and hemilateral pain control mechanisms are disrupted in CRPS, and that multisensory integrative processes may be compromised. PERSPECTIVE: The findings suggest that hemilateral hyperalgesia is specific to CRPS, which could be diagnostically important. Disruptions in pain control mechanisms were associated with the development of hyperalgesia at sites remote from the CRPS limb. Addressing these mechanisms could potentially deter widespread hyperalgesia in CRPS. PMID- 21703938 TI - Follow-up psychophysical studies in bortezomib-related chemoneuropathy patients. AB - Many frontline chemotherapeutic agents produce robust neuropathy as a dose limiting side effect; however, the persistence of chemotherapy-related sensory disturbances and pain are not well documented. We have previously investigated the qualities of bortezomib-induced pain, and now seek to determine the ongoing nature of this pain. Twenty-six control subjects and 11 patients who had previously been treated with bortezomib and who were experiencing ongoing pain consented to recurring quantitative sensory testing. A pilot immunohistochemistry study of skin innervation was also performed on patient-obtained biopsies. Psychophysical testing in patients revealed persistent changes including decreased skin temperature in the area of pain, diminished touch and sharpness detection, increased pegboard completion times, and decreased sensitivity to skin heating. Additionally, the intensity of pain, as captured by the use of a visual analog scale and pain descriptors, was reported by patients to be unchanged during the retest despite similar morphine equivalent daily doses. The patient skin biopsies displayed a marked decrease in the density of epidermal nerve fibers and Meissner's corpuscles. These results signify a persistent and severe impairment of Abeta, Adelta, and C fibers in patients with chronic bortezomib induced chemoneuropathy. Further, this study reports a loss of both epidermal nerve fibers and Meissner's corpuscles. PERSPECTIVE: The results of this article indicate a persistent, painful peripheral neuropathy in patients treated with bortezomib. Pilot data indicates a loss of nerve fibers innervating the area of pain. This is the first paper to address the persistence, and potential contributing factors, of bortezomib chemoneuropathy. PMID- 21703939 TI - Sequential and base rate analysis of emotional validation and invalidation in chronic pain couples: patient gender matters. AB - The purpose of this study was to examine the extent to which communication patterns that foster or hinder intimacy and emotion regulation in couples were related to pain, marital satisfaction, and depression in 78 chronic pain couples attempting to problem-solve an area of disagreement in their marriage. Sequences and base rates of validation and invalidation communication patterns were almost uniformly unrelated to adjustment variables unless patient gender was taken into account. Male patient couples' reciprocal invalidation was related to worse pain, but this was not found in female patient couples. In addition, spouses' validation was related to poorer patient pain and marital satisfaction, but only in couples with a male patient. It was not only the presence or absence of invalidation and validation that mattered (base rates), but the context and timing of these events (sequences) that affected patients' adjustment. This research demonstrates that sequences of interaction behaviors that foster and hinder emotion regulation should be attended to when assessing and treating pain patients and their spouses. PERSPECTIVE: This article presents analyses of both sequences and base rates of chronic pain couples' communication patterns, focusing on validation and invalidation. These results may potentially improve psychosocial treatments for these couples, by addressing sequential interactions of intimacy and empathy. PMID- 21703940 TI - Stem fracture after total facet replacement in the lumbar spine: a report of two cases and review of the literature. AB - BACKGROUND CONTEXT: A randomized controlled multicenter investigational device exemption clinical trial comparing the total facet arthroplasty system (TFAS) (Archus Orthopedics, Redmond, WA, USA) with posterior fusion was discontinued because of financial reasons. To our knowledge, no clinical outcomes or complications have yet been presented for the TFAS, and no device-related complications have been reported for any other lumbar facet replacement system. PURPOSE: To report and discuss two cases of stem fracture after total facet replacement in the lumbar spine. STUDY DESIGN: Case report and literature review. PATIENT SAMPLE: A 55-year-old man with a body mass index (BMI) of 40 underwent total facet replacement at L4-L5 for Grade 1 spondylolisthesis with stenosis. After 9 months of pain relief, he experienced gradually increasing pain and radiographs showed a broken stem. A 60-year-old woman with a BMI of 31 underwent total facet replacement at L4-L5 for Grade 1 spondylolisthesis with stenosis. She experienced stem fracture 27 months postoperatively. OUTCOME MEASURES: Visual analog scale for pain, Oswestry Disability Index for function, and computed tomography and X-ray for imaging. RESULTS: After TFAS stem breakage, both patients underwent interbody fusion through a transpsoas approach and have done well over 24- and 12-month follow-up periods, respectively. CONCLUSIONS: These are the first cases of stem fracture reported after total facet replacement in the lumbar spine. Biomechanics of TFAS stem breakage may be similar to those of pedicle screw breakage, including fatigue and three-point bending stress. Further biomechanical studies and failure analyses however are needed for adequate understanding to improve the biomechanics of dynamic pedicle-based devices. PMID- 21703941 TI - Superior mesenteric venous thrombosis related to Peterson's hernia. PMID- 21703942 TI - Biochemical control of bone loss and stone-forming propensity by potassium calcium citrate after bariatric surgery. AB - BACKGROUND: Patients undergoing Roux-en-Y gastric bypass (RYGB) surgery are prone to developing bone loss and kidney stones. The goal of the present study was to test the hypothesis that an effervescent formulation of potassium calcium citrate (PCC) would avert metabolic complications by providing bioavailable calcium and alkali. METHODS: A total of 24 patients with RYGB underwent a 2-phase crossover randomized trial comparing PCC and placebo. During the last 2 days of each 2-week phase, the serum and 24-hour urine samples were analyzed for calcium and bone turnover markers, acid base status, and urinary stone risk factors. RESULTS: Compared with placebo, PCC marginally reduced the serum parathyroid hormone level and significantly decreased urinary deoxypyridinoline by 12% (P <.001) and serum type 1 collagen C-telopeptide by 22% (P <.01). PCC significantly increased the net gastrointestinal alkali absorption, citrate, and pH and significantly lowered the urinary net acid excretion (P <.001). The urinary saturation of uric acid decreased significantly (P <.001). The supersaturation of calcium oxalate and brushite did not change despite an increase in calcium and pH. In untreated urine samples with citrate concentrations altered to mimic those of placebo and PCC, calcium oxalate agglomeration was significantly inhibited by PCC. CONCLUSION: In RYGB patients, PCC supplementation inhibited bone resorption by providing bioavailable calcium, reduced the urinary saturation of uric acid, and increased the inhibitor activity against calcium oxalate agglomeration by providing alkali that increased urinary pH and citrate. PMID- 21703944 TI - Use of "glucola alternatives" for cystic fibrosis-related diabetes screening. PMID- 21703943 TI - Replication of ribonucleotide-containing DNA templates by yeast replicative polymerases. AB - The major replicative DNA polymerases of S. cerevisiae (Pols alpha, delta, and E) incorporate substantial numbers of ribonucleotides into DNA during DNA synthesis. When these ribonucleotides are not removed in vivo, they reside in the template strand used for the next round of replication and could potentially reduce replication efficiency and fidelity. To examine if the presence of ribonucleotides in a DNA template impede DNA synthesis, we determined the efficiency with which Pols alpha, delta, and E copy DNA templates containing a single ribonucleotide. All three polymerases can replicate past ribonucleotides. Relative to all-DNA templates, bypass of ribo-containing templates is slightly reduced, to extents that depend on the identity of the ribo and the sequence context in which it resides. Bypass efficiencies for Pols delta and E were increased by increasing the dNTP concentrations to those induced by cellular stress, and in the case of Pol E, by inactivating the 3'-exonuclease activity. Overall, ribonucleotide bypass efficiencies are comparable to, and usually exceed, those for the common oxidative stress-induced lesion 8-oxo-guanine. PMID- 21703945 TI - Rapid determination of gefitinib and its main metabolite, O-desmethyl gefitinib in human plasma using liquid chromatography-tandem mass spectrometry. AB - A novel, rapid and specific liquid chromatography-tandem mass spectrometric (LC MS/MS) method was developed and validated for the simultaneous quantification of gefitinib and its predominant metabolite, O-desmethyl gefitinib in human plasma. Chromatographic separation of analytes was achieved on an Alltima C18 analytical HPLC column (150 mm * 2.1 mm, 5 MUm) using an isocratic elution mode with a mobile phase comprised acetonitrile and 0.1% formic acid in water (30:70, v/v). The flow rate was 300 MUL/min. The chromatographic run time was 3 min. The column effluents were detected by API 4000 triple quadrupole mass spectrometer using electrospray ionization (ESI) in positive mode. Linearity was demonstrated in the range of 5-1000 ng/mL for gefitinib and 5-500 ng/mL for O-desmethyl gefitinib. The intra- and inter-day precisions for gefitinib and O-desmethyl gefitinib were <=10.8% and the accuracies ranged from 89.7 to 104.7% for gefitinib and 100.4 to 106.0% for O-desmethyl gefitinib. This method was used as a bioanalytical tool in a phase I clinical trial to investigate the possible effect of hydroxychloroquine on the pharmacokinetics of gefitinib. The results of this study enabled clinicians to ascertain the safety of the combination therapy of hydroxychloroquine and gefitinib in patients with advanced (Stage IIIB-IV) non small cell lung cancer (NSCLC). PMID- 21703946 TI - Preparation of an immunoaffinity column and its application in sample cleanup for methandrostenolone residues detection. AB - Methandrostenolone (MA) is a steroid used as veterinary medicine on stockbreeding to promote animal growth. The use of MA has been strictly regulated because of its harmful effect on consumers. This paper describes the production of polyclonal antibody (pAb) against MA, the preparation of immunoaffinity column (IAC) and its potential application to the selective extraction of MA residues from animal tissue and feed samples. The produced pAb exhibited good sensitivity to MA with an IC(50) value of 5.6 ng/mL. The cross-reactivity values of the antibody with MA structurally related compounds of testosterone propionate (TP) and trenbolone (TR) were lower than 0.6%. By coupling the produced antibody with CNBr-activated Sepharose 4B, an IAC was prepared. 2% methanol and 80% methanol were selected as loading and eluting solution by optimization. The maximum capacity of the column for MA was approximately 334 ng/mL gel. The average recovery of 20, 40 and 60 ng/mL MA standard solutions from IACs was 97.9% with the relative standard deviation (RSD) among columns of 6.7%. After 3 times of repeated usage, the column capacity and recovery rate still remained 82.0% and 92.6% respectively. The IACs were then challenged with MA-fortified animal tissue and feed samples, recoveries of MA were found to be in the range of 83.5-99.7%. PMID- 21703947 TI - Identification of potassium dehydroandrographolidi succinas and its major metabolites in rat urine by liquid chromatography-tandem mass spectrometry. AB - A rapid, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for identification of potassium dehydroandrographolidi succinas and its metabolites in rat urine. Five male rats were administrated a single dose (100 mg/kg) of potassium dehydroandrographolidi succinas by i.v. injection. The urine were sampled from 0 to 24 h and purified by using Oasis(r) HLB extraction cartridge, then the purified urine samples were separated on a reversed-phase C18 column with a linear gradient and detected by an on-line MS detector. Identification and structural elucidation of the metabolites were performed by comparing their changes in molecular mass (Deltam) and MS/MS spectra with those of the parent drug. Seven metabolites and the parent drug were found in rat urine. All these metabolites were reported for the first time. PMID- 21703948 TI - Sample preparation in separation of the extracellular chitinolytic enzymes of the human intestinal bacterium Clostridium paraputrificum J4 from the culture fluids. AB - Membrane ultrafiltration (UF) was used in sample preparation of the culture fluids of the human intestinal bacterium Clostridium paraputrificum strain J4 containing seven extracellular chitinolytic isoenzymes (38-90 kDa). The subsequent filtration of the bacteria-free supernatants was carried out through Millipore membranes with cut-off 100 and 30 kDa for separation of undigested components of the culture medium and bacterial metabolites with molecular weight higher and lower than that of the target enzymes. The chitinolytic enzymes, which were the minor components in the culture fluids, were concentrated at UF as well. The aim of the research consisted in evaluation of the effect of component composition of bacteria-free supernatants and the chemical nature of membrane active layer on partial fractionation of the chitinolytic enzymes, their recovery in retentates and purification degree. On the basis of the obtained experimental results, the sample preparation procedure of the culture fluids of C. paraputrificum J4 was established to be used further in chromatographic separations of the chitinolytic enzymes. PMID- 21703949 TI - Development and validation of a highly rapid and sensitive LC-MS/MS method for determination of SZ-685C, an investigational marine anticancer agent, in rat plasma--application to a pharmacokinetic study in rats. AB - A sensitive and rapid method was developed and validated for the quantitative analysis of the novel anticancer agent SZ-685C in rat plasma using high performance liquid chromatography/tandem mass spectrometry (LC/MS/MS) in negative ion mode in order to support the following pre-clinical and clinical studies. SZ 685C and the internal standard (IS, emodin) were extracted from rat plasma by a simple liquid-liquid extraction technique using ethyl acetate as extraction solvent. Chromatographic separation was performed on an Elite Hypersil BDS C18 column (100 mm * 2.1 mm i.d., 3 MUm). Elution was carried out using methanol/acetonitrile/2mM ammonium formate (pH 4) (80:15:5 (v/v/v)) at a flow rate of 0.3 mL/min with a run time of 2.5 min. This assay was linear over a concentration range of 50-10,000 ng/mL with a lower limit of quantification of 50 ng/mL. The intra- and inter-batch precision was less than 15% for all quality control samples at concentrations of 100, 1000 and 7500 ng/mL. These results indicate that the method was efficient with a short run time and acceptable accuracy, precision and sensitivity. This method was successfully applied to explore pharmacokinetics of SZ-685C in rats after oral and intravenous administration of this agent. The absolute bioavailability is about 54.8-66.8% and the t(1/2) is 5.7-9.2h, these results provide basic information for further comprehensive pre-clinical research. PMID- 21703950 TI - Quantification of multi-residue levels in peach juices, pulps and peels using dispersive liquid-liquid microextraction based on floating organic droplet coupled with gas chromatography-electron capture detection. AB - In this paper, polychlorinated biphenyl (PCB), organochlorine pesticide (OCP) and pyrethroid pesticides in peach was investigated by comparing their residual level in peach juice, pulps and peels using dispersive liquid-liquid microextraction based on solidification of floating organic droplet (DLLME-SFO) combined with gas chromatography-electron capture detection (GC-ECD). Extraction conditions such as the type of extractant, volume of extractant and dispersant, salt effect and extraction time were optimized. For juice samples, the linearity of the method was obtained in the range of 10-2000 ng L(-1),with determination coefficients>0.99. The limits of detection (LOD) of the method were ranged between 2.8 and 18.5 ng L(-1). For pulp and peel samples, the developed method is linear over the range assayed, 1-20 MUg kg(-1),with coefficients also >0.99. The relative recoveries of compounds analyzed from juice, pulp and peel samples were in the range of 73-106% with a relative standard deviation between 2.6 and 11.8%. The proposed method was applied to the simultaneous analysis of residues in real peach juice, pulp and peel samples. As a result, there were no target analytes found in peach juices and pulps while 3.3 MUg kg(-1) cyhalothrin and 3.5 MUg kg( 1) fenvalerate were found in peels. The experiment results revealed that the pyrethroid residues just deposited on the peels of the fruits, but did not move into pulps and juices. PMID- 21703951 TI - [Treatment of streptococcal tonsillitis with once-a-day amoxicillin: a meta analysis]. AB - INTRODUCTION: The objective of this systematic review is to determine if the treatment of streptococcal pharyngitis with a daily dose of amoxicillin is similar in effectiveness to other dosing schedules (every 6, 8 or 12 hours) of the same antibiotic or penicillin V. MATERIAL AND METHODS: Randomised clinical trials (RCT) comparing amoxicillin (one dose per day) compared to other dosages of amoxicillin (every 8-12 hours) or penicillin V (every 6, 8 or 12 hours). Search databases consulted: Medline, Central, EMBASE and Google Scholar. The results were combined using the risk difference (RD). We measured the effectiveness of each treatment with a negative throat culture on the 14-21th day, being previously positive to group A Streptococcus (under a non-inferiority hypothesis, where the upper limit of the 95% confidence interval [95% CI] of the DR does not exceed 10%) and clinical failure on days 10-21. The results were combined according to a fixed effects model or random depending on whether or not there was heterogeneity. RESULTS: Four RCT met the selection criteria with 1,314 participants (657 received amoxicillin once per day, and 657 received other antibiotics or dosages): a) any positive culture for Streptococcus (14-21st day, 4 RCTs): DR: -0.5% (95% CI: -5.1% to 4.2%; b) persistence of the same serotype (14-21st day, 3 RCT): DR: 0.32% (95% CI: -3.1% to 3.7%; c) clinical failure (2 RCT): DR: 1.7% (95% CI: -1.9% to 5.4%; d) adverse effects (4 RCT): DR: -0.39% (95% CI: -1.5% to 6.8%). There were no statistically significant differences in any comparisons. CONCLUSIONS: Amoxicillin, administered once daily is not inferior to other dosages of the same antibiotic or penicillin V. These results are important because they may facilitate compliance. PMID- 21703952 TI - [Diagnostic value of exhaled nitric oxide measurement in mild asthma]. AB - OBJECTIVES: To assess the diagnostic value of fractional exhaled nitric oxide (FE(NO)) in mild asthma. MATERIAL AND METHODS: Cross-sectional descriptive study in a group of patients with no history of respiratory or allergic illness (control group) and a group of patients with a history of mild asthma with no baseline treatment (asthma group), both aged 6 to 14 years. The following examinations were performed: measurement of FE(NO) using the portable NIOX MINO((r)) device, allergy tests and spirometry. Repeatability of paired FE(NO) measurements was estimated with the intraclass correlation coefficient, the repeatability coefficient and the variation coefficient. The diagnostic value was assessed with the sensitivity, specificity, area under the ROC curve and positive likelihood ratio (LR+) for each cut-off point. RESULTS: Eighty-seven patients were included in the control group and 57 in the asthma group. The mean FE(NO) value was 12.1 ppb (SD 13.5) in the control group and 42.9 ppb (SD 24.5) in asthmatics (P<.001). The intraclass correlation coefficient was 0.98 (95% CI: 0.96-0.99) and of 0.97 (95% CI: 0.92-0.99) in controls and asthmatics, respectively. The repeatability coefficient was 5.5 in controls and 9.2 in asthmatic children, and the median variation coefficient was 8.3% and 6.1%. The optimal cut-off value for FE(NO) was 19 ppb (sensitivity and specificity were 91.4% and 87.2%, respectively). The area under the ROC curve was 0.93 (95% CI: 0.88-0.97) (P<.001) and the LR+ was 7.1. Subclinical sensitisation to pneumoallergens accounted for most false positive cases. CONCLUSIONS: The determination of FE(NO) with NIOX MINO((r)) has an adequate repeatability, especially for healthy patients. For asthmatic patients we recommend determining the average of two measurements. The test has a high diagnostic value in mild asthma. Subclinical sensitisation to pneumoallergens can cause the FE(NO) value to rise to pathologic levels. PMID- 21703953 TI - Two for the price of one: recycling a free flap. AB - Free flaps are now an established, successful, method of reconstruction for complex soft tissue defects. Improvements in microsurgical techniques, anatomical understanding and instruments have resulted in the evolution of free flap surgery to now encompass synchronous double free flap surgery and "free style" type flaps based on perforators. Although there have been reports of a single free flap split in two to reconstruct a defect at a single site, we report what we believe to be the first case of a single free groin flap used to reconstruct two distant and separate defects sequentially. PMID- 21703954 TI - Total auricular reconstruction without skin grafting. AB - Successful ear reconstruction depends on two factors: an ear framework and the skin covering the framework. However, the relative deficiency of skin for coverage of the cartilage framework remains an issue. This new method for total auricular reconstruction is a three-stage operation and involves the use of two tissue expanders. First, two skin expanders are implanted, one underneath the scalp and the other sited behind the microtic ear. At the second stage, after lobule transposition, the two expanded skin flaps (upper and lower) and mastoid fascial flap are raised. At the same time, the autogenous rib cartilage is harvested and the framework constructed. The cartilage framework is then anchored between the upper expanded skin flap and the fascial flap with its inferior pole inserted into the rotated earlobe. The upper expanded skin flap covers the whole anterior surface of the framework and drapes over the margins of the fascial flap, which wrap the framework from beneath. The raw surface of fascial flap is covered with the lower expanded skin flap. The formation of a pseudomeatus and tragus is performed at the third stage. Deficiency of skin is the major problem encountered with the other conventional methods. Our innovations using two tissue expanders in combination with an autogenous rib cartilage framework eliminate this problem completely. PMID- 21703955 TI - Superficial peroneal and sural nerve transfer to tibial nerve for restoration of plantar sensation after complex injuries of the tibial nerve: cadaver feasibility study. AB - BACKGROUND: Nerve reconstruction following lower-extremity nerve injuries usually leads to worse outcomes in comparison with upper-extremity injuries due to the long distances of nerve regeneration. This study was performed to consider the clinical application of distal nerve transfer for the treatment of long gaps of the tibial nerve (TN) and in established compartment syndrome. It aimed to determine the anatomic suitability of transferring the sural nerve (SN) in combination with the superficial peroneal nerve (SPN) to the TN at the level of the tarsal tunnel for restoration of plantar sensation. METHODS: Nine fresh above knee amputated limbs were dissected with the aid of loupe magnification. We focussed on the detailed anatomy of the course of the SN and the SPN from its emergence proximally at the knee level to the foot. Two different regions, suprafascial and subfascial, were described for each nerve. The maximum length of dissection and the length of the nerves in each region were measured. In all dissections, we assessed the feasibility of directly transferring the SN and SPN to the TN at the level of the tarsal tunnel. RESULTS: The average length of the course of the SN was 20.6 cm (SD +/- 2.3 cm) subfascially and 16.4 cm (SD +/- 0.9 cm) suprafascially. For the SPN, the average length was 19.4 cm (SD +/- 1.9 cm) subfascially and 18 cm (SD +/- 2.5 cm) suprafascially. The point of emergence of the nerve from the subfascial course to the suprafascial course was defined as the pivot point for its transfer to the TN. Both the SN and the SPN reached the TN comfortably at the level of the tarsal tunnel, allowing direct co-aptation. CONCLUSION: Distal nerve transfer using the SN in combination with the SPN is an anatomically reliable procedure, being a potential alternative to the use of nerve grafts in reconstruction of long gaps of the TN. In addition, selected patients with compartment syndrome may also benefit from this transfer to restore plantar sensation. PMID- 21703956 TI - [Cinacalcet impact on calcium homeostasis and bone remodeling in 13 renal transplanted patients with hyperparathyroidism and hypercalcaemia]. AB - The purpose of the study is to assess the impact of cinacalcet on calcium and bone remodeling, in post-renal transplanted patients with persistent hypercalcaemia secondary to hyperparathyroidism. Thirteen renal-transplanted adult recipients with a glomerular filtration rate over 30 ml/min/1.73 m(2), a total serum calcium>2.60 mmol/l with ionized calcium>1.31 mmol/l and a parathyroid hormone serum level over 70 pg/ml, were treated with cinacalcet for 4 months followed by a 15-day wash out. The results show that cinacalcet lowers significantly total and ionized calcium respectively from 2,73 (2,67-2,86) to 2,31 (2,26-2,37) mmol/l (P<0.05) and from 1,39 (1,37-1,47) to 1,21 (1,15-1,22) mmol/l (P<0.05) with no alteration of the 24-hour urine calcium/creatinine ratio and no significant expected PTH serum level suppression (153 [115-214,9] and 166 [122-174] pg/ml). On the other hand, fasting urine calcium was significantly decreased from 0,61 (0,27-1,02) to 0,22 (0,15-0,37) (P<0.05) and bone-specific alkaline phosphatases increased from 20,5 (13-46,6) to 33,8 (12-58,9) ng/ml, upon cinacalcet treatment. After its discontinuation, all these effects were reversible. In conclusion, cinacalcet normalizes total and ionized calcium in renal-transplanted recipients with hypercalcemia secondary to hyperparathyroidism through a mechanism that could be independent of PTH serum level suppression. The increase in bone-specific alkaline phosphatases, biochemical markers of bone accretion and the significant decrease in fasting urine calcium suggest the possibility of a beneficial impact of cinacalcet on bone remodeling. PMID- 21703957 TI - A comparison of methods for forensic DNA extraction: Chelex-100(r) and the QIAGEN DNA Investigator Kit (manual and automated). AB - Efficient isolation of DNA from a sample is the basis for successful forensic DNA profiling. There are many DNA extraction methods available and they vary in their ability to efficiently extract the DNA; as well as in processing time, operator intervention, contamination risk and ease of use. In recent years, automated robots have been made available which speed up processing time and decrease the amount of operator input. This project was set up to investigate the efficiency of three DNA extraction methods, two manual (Chelex((r))-100 and the QIAGEN DNA Investigator Kit) and one automated (QIAcube), using both buccal cells and blood stains as the DNA source. Extracted DNA was quantified using real-time PCR in order to assess the amount of DNA present in each sample. Selected samples were then amplified using AmpFlSTR SGM Plus amplification kit. The results suggested that there was no statistical difference between results gained for the different methods investigated, but the automated QIAcube robot made sample processing much simpler and quicker without introducing DNA contamination. PMID- 21703958 TI - Population genetic data and concordance study for the kits Identifiler, NGM, PowerPlex ESX 17 System and Investigator ESSplex in Spain. PMID- 21703959 TI - Management of patients with synchronous liver metastases of colorectal cancer. Clinical practice guidelines. Guidelines of the French society of gastrointestinal surgery (SFCD) and of the association of hepatobiliary surgery and liver transplantation (ACHBT). Short version. PMID- 21703960 TI - A forgotten cause for abdominal pain. PMID- 21703961 TI - Pitfall of hepatitis B surface antigen testing in a kidney transplant recipient presenting hepatitis B reactivation. AB - Diagnosis of hepatitis B virus (HBV) infection based on hepatitis B surface antigen (HBsAg) detection can be hampered in the setting of HBV reactivation in immunocompromized patients with prior serology indicating past cured infection, and can be associated with severe or fulminant and fatal hepatitis. We present a case of HBV reactivation in a renal transplant patient in whom HBsAg failed to be confirmed as a true positive result. One year after transplantation, systematic testing showed HBsAg positivity with a titer at 244 pg/mL, anti-hepatitis B core antibody and concurrent anti-hepatitis B surface antibody positivity. Confirmation of HBsAg detection by seroneutralization did not confirm HBsAg positivity, indicating that HBsAg detection was a false positive result. Notwithstanding, HBV DNA titer in serum was concurrently 8.6 Log IU/mL. HBV DNA sequencing showed a genotype D and several amino acid substitutions within HBsAg, including some previously involved in impaired diagnosis and altered immunogenicity. Although no perturbation of liver biochemical markers was observed, treatment with tenofovir was introduced. One month later, HBV DNA level had decreased by 2.6 Log IU/mL and no clinical and biochemical symptoms of hepatitis had occurred. The present case underlines that serologic diagnosis of HBV reactivation can be tricky in transplant recipients with a prior serology indicating past HBV infection. This prompts to perform HBV DNA testing in case of positive HBsAg testing, regardless of the result of neutralization by anti-HBs antibodies. PMID- 21703962 TI - Will we ever model PSC? - "it's hard to be a PSC model!". AB - Cholangiopathies such as primary sclerosing cholangitis (PSC) represent an important group of liver diseases of the intra- and extrahepatic bile ducts frequently causing end-stage liver disease with significant morbidity and mortality due to limited treatment options. The relatively low incidence of PSC and the difficult accessibility of the human bile duct system for longitudinal studies may represent some of the critical reasons for the lack of profound knowledge in regard to PSC pathophysiology. Therefore, there is an urgent need for reliable, well-defined and easily reproducible animal models to learn more about the pathophysiology of PSC and to test novel treatment modalities. In an ideal world, immunogenetically predisposed animals would develop fibrous obliterative cholangitis of the intra- and extrahepatic bile ducts in association with inflammation of the gut (especially colitis) in a highly reproducible manner allowing to test new drugs. To date, however, no such animal model is available. We aimed to provide a systematic overview of current available rodent models for sclerosing cholangitis and biliary fibrosis and therefore critically analyzed the characteristics of models for chemically-induced cholangitis, knock-out mouse models with cholangitis, cholangitis induced by infectious agents, models of experimental biliary obstruction, models involving enteric bacterial cell-wall components or colitis, and models of primary biliary epithelial and endothelial cell injury. PMID- 21703963 TI - Marker panels for the diagnosis of small hepatocellular carcinoma, a never-ending story. PMID- 21703964 TI - Resolution of cyclic vomiting after appendectomy in a girl. AB - Cyclic vomiting syndrome is a disorder characterized by recurrent, discrete, stereotypical episodes of nausea and vomiting. Although chronic or recurrent appendicitis may be a cause of recurrent abdominal pain, it rarely meets the diagnostic criteria for cyclic vomiting syndrome. Furthermore, mast cell counts are histologically high in chronic appendicitis. We report a 10-year-old Japanese girl with a cyclic pattern of vomiting that met the stringent diagnostic criteria for cyclic vomiting syndrome, and which was resolved after appendectomy. Histopathologic examination of the resected appendix showed not only acute mucosal inflammation but also chronic inflammatory changes. Because we speculated that recurrent or chronic appendicitis may have been related to the patient's vomiting bouts, we also immunohistochemically investigated the density of mast cells in the specimen. We found that the mast cell density was markedly high in the lamina propria of the appendix. In our patient, a type I hypersensitivity reaction with release of mediators by mast cells could have been the initial factor triggering the recurrent appendicitis, and this stressor could have initiated the vomiting cascade. In conclusion, chronic or recurrent appendicitis could be one of the causes of cyclic vomiting, and must be considered in the differential diagnosis of cyclic vomiting syndrome. PMID- 21703965 TI - Words of wisdom: Re: Population-based patterns and predictors of prostate specific antigen screening among older men in the United States. PMID- 21703966 TI - Words of wisdom: Re: Comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer. PMID- 21703967 TI - Words of wisdom: Re: Active surveillance compared with initial treatment for men with low-risk prostate cancer: a decision analysis. PMID- 21703968 TI - Words of wisdom: Re: In vitro production of functional sperm in cultured neonatal mouse testes. PMID- 21703969 TI - Words of wisdom: Re: Does varicocele repair improve male infertility? An evidence based perspective from a randomized, controlled trial. PMID- 21703970 TI - Words of wisdom: Re: Biopsy misidentification identified by DNA profiling in a large multicenter trial. PMID- 21703971 TI - Conflicting impact of alloreactive NK cells on transplantation outcomes after haploidentical transplantation: do the reconstitution kinetics of natural killer cells create these differences? AB - Partially HLA-mismatched related, or HLA-haploidentical, donor stem cell transplantation (SCT) is a feasible therapeutic option for advanced hematologic malignancy patients who lack an HLA-matched related or unrelated donor. Natural killer (NK) cells, a major cell type of the innate immune system, express surface receptors that regulate potent effector functions, such as cytolytic activity and the release of cytokines, and play a central role in the inflammatory response and immunoregulation. Conflicting results have been reported regarding the impact of NK cell alloreactivity on the outcome of haploidentical SCT in leukemic patients. This review summarizes the heterogeneous clinical results and explains the underlying mechanisms with respect to the reconstitution kinetics of NK cells and the interactions between NK cells and T cells. PMID- 21703972 TI - Donor CTLA-4 genotype influences clinical outcome after T cell-depleted allogeneic hematopoietic stem cell transplantation from HLA-identical sibling donors. AB - CTLA-4 (cytotoxic T-lymphocyte antigen-4) plays a pivotal role in inhibiting T cell activation through competitive interaction with B7 molecules and interruption of costimulatory signals mediated by CD28. Polymorphisms on the CTLA 4 gene have been previously associated with autoimmune diseases, predisposition to leukemic relapse, and with graft-versus-host disease (GVHD) or relapse after allogeneic transplant. As CTLA-4 is expressed on T-lymphocytes, the aim of this study was to determine whether the donor CTLA-4 CT60 genotype also influences clinical outcome even after T cell depletion with CD34-positive selection. We studied 136 patient-donor pairs. Overall survival (OS) was worse for those patients who received grafts from a donor with the CT60 AA genotype rather than from a donor with the AG or GG genotype (35.6% vs 49.4%; P = .043). This association was confirmed through multivariate analysis, which identified the donor CT60 genotype as an independent risk factor for OS (P = .008; hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.23-4.08). The donor CT60 AA genotype was also associated with lower disease-free survival, this being related to an increased risk of relapse (P = .001; HR: 3.41, 95% CI: 1.67-6.96) and a trend toward higher transplant-related mortality. These associations were stronger when considering only patients in the early stage of disease. Our results suggest that graft-versus-leukemia (GVL) activity after T cell depletion is conditioned by the donor CTLA-4 genotype. PMID- 21703973 TI - Improvement in oral chronic graft-versus-host disease with the administration of effervescent tablets of topical budesonide-an open, randomized, multicenter study. AB - Chronic graft-versus-host disease (cGVHD) frequently involves oral tissues. Although the mucosal changes may be painful and impair oral function, there is currently no topical therapy available for oral cGVHD that has been proven to work in an evidence-based manner. The aims of this study were to (1) assess the response of patients with oral cGVHD to various doses of a new topical budesonide formulation; (2) evaluate the efficacy and safety of the new topical budesonide formulation in these patients. An open, randomized, multicenter phase II pilot study with 4 treatment arms differing in application frequency and duration was performed. Response to treatment was scored by the clinician and patient using several scales. Oral cGVHD improved in all patients, with a median reduction of 70%. Pain reduction was similar in all study arms. The rate of objective improvement (defined as >=50%) was not significantly different among the 4 study arms. The safety profile was satisfactory. Topical budesonide mouthwash (3 mg/10 mL) improved oral cGVHD in all patients when applied for 5 or 10 minutes, 2 or 3 times daily. The response was similar in all treatment arms. Safety analysis supported a dosing schedule of 3 mg of budesonide 3 times a day for 10 minutes. PMID- 21703974 TI - A prospective study comparing the outcomes and health-related quality of life in adult patients with myeloid malignancies undergoing allogeneic transplantation using myeloablative or reduced-intensity conditioning. AB - We compared the outcomes including health-related quality of life (HRQOL) in adult patients undergoing allogeneic transplantation using myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC). This outcome study was a nonrandomized, prospective, observational noninferiority study, and primarily designed to determine whether RIC was as effective as MAC for myeloid malignancies. Comprehensive longitudinal assessment of HRQOL was done at baseline, day 30, day 100, day 180, and day 365 using validated instruments. A total of 115 patients (MAC, 51; RIC, 64) participated in this study. Of these 115 patients, 105 (91%) participated for HRQOL assessments. The main indication for HCT was acute myeloid leukemia (72%). Except age (median 41 vs 59 years, P < .0001), baseline characteristics were similar in patients undergoing MAC and RIC, respectively. Progression-free survival (PFS) at 1 year was 59% (SE = 7%) and 53% (SE = 6%) for the patients undergoing MAC and RIC, respectively (90% confidence interval [CI] -9% to +21%, P = .53). No significant difference in overall survival (OS), cumulative incidents of acute and chronic graft-versus-host disease (aGVHD, cGVHD), nonrelapse mortality (NRM) or relapse was observed in the 2 cohorts. The trajectory of decline and recovery of HRQOL was similar between the 2 cohorts. We conclude that clinical outcomes and HRQOL in patients with myeloid malignancies undergoing RIC are not inferior to MAC at 1 year. PMID- 21703975 TI - Extramedullary relapse of acute myelogenous leukemia after allogeneic hematopoietic stem cell transplantation: better prognosis than systemic relapse. AB - Allogeneic hematopoietic cell transplantation (HSCT) is considered a curative treatment for acute myelogenous leukemia (AML). Extramedullary relapse after HSCT for AML is a rare event and is less well defined than systemic, hematologic relapse. We retrospectively studied all patients with AML (n = 436) who underwent HSCT at the University of Minnesota between 1996 and 2008 who developed either a bone marrow (BM) or extramedullary (EM) relapse, and examined the incidence and risk factors for BM and EM relapse. Of 128 patients who relapsed post-HSCT, 25 had relapse in EM sites, either isolated (n = 13) or with concurrent BM relapse (n = 12). Relapse sites included bone (n = 1), central nervous system (n = 6), gastrointestinal (n = 4), lymphatic (n = 4), skin (n = 5), genitourinary (n = 1), pulmonary (n = 1), and soft tissue (n = 3). The time to relapse was longer in the EM sites (median, 328 days vs 168 days). Patients with EM relapse were more likely to have had preceding acute graft-versus-host disease (GVHD) (77% vs 49%; P = .03) or chronic GVHD (46% vs 15%; P = .02) compared with those with BM relapse. The 6-month survival postrelapse was significantly better in patients with isolated EM relapse (69%) compared with those with combined EM and BM relapse (8%) or those with BM relapse alone (27%) (P < .01). Compared with local therapy alone, systemic therapy yielded better 6-month survival in patients with EM relapse. This study suggests differing pathogenesis of BM relapse versus EM relapse of AML after allogeneic HSCT. GVHD and its accompanying graft-versus leukemia effect may better protect BM sites, but patients with EM relapse have better responses to combined therapy and improved survival compared with those with BM relapse. PMID- 21703976 TI - Limiting the daily total nucleated cell dose of cryopreserved peripheral blood stem cell products for autologous transplantation improves infusion-related safety with no adverse impact on hematopoietic engraftment. AB - Cryopreserved peripheral blood stem cell (PBSC) products can induce a number of infusion-related adverse reactions, including life-threatening cardiac, neurologic, and other end-organ complications. Preliminary analyses suggested limiting the daily total nucleated cell dose infused might decrease the incidence of these adverse effects. A policy change implemented in December 2007, limiting the total nucleated cell (TNC) dose to <1.63 * 10(9) TNC/kg/day, allowed us to assess the impact of this intervention on infusion-related safety, infusion schedules, engraftment, and costs in cohorts of patients undergoing autologous stem cell transplants (ASCTs) 2 years before (325 ASCTs in 288 patients) and 2 years after the policy change (519 ASCTs in 479 patients). The percentage of autologous transplant patients requiring multiple day infusions increased from 6% to 24%. Concurrently, the incidence of infusion-related grade 3-5 severe infusion related adverse events (SAEs) decreased significantly, from 4% (13 of 325) prepolicy change to 0.6% (3 of 519) postpolicy change (P < .0004). Multiday infusions were not associated with increased time to neutrophil or platelet engraftment or the costs of transplantation. We conclude that limiting the daily TNC dose improved the safety of this procedure without compromising engraftment or increasing the costs of the procedure. PMID- 21703977 TI - The role of anti-HLA antibodies in hematopoietic stem cell transplantation. AB - Donor-specific antihuman leukocyte antigen antibodies (DSHA) have been clearly implicated in graft rejection in solid organ transplantation. Their role in allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains unclear. We summarize here evidence supporting a role for DSHA in graft failure in animal models of allo-HSCT and in clinical settings whenever no full HLA matching occurs. PMID- 21703978 TI - Oxidative stress responses in tilapia (Oreochromis niloticus) exposed to a single dose of pure cylindrospermopsin under laboratory conditions: influence of exposure route and time of sacrifice. AB - Cylindrospermopsin (CYN) is a toxin produced by various cyanobacterial species that are increasingly being found in freshwater systems. Although CYN can have toxic effects in humans, domestic animals and wildlife, it has been subject to very little investigation (particularly in fish). It has been reported to deplete the cellular glutathione content but the role of oxidative stress in the pathogenicity of CYN in fish is unknown. For this reason tilapia fish were exposed to 200 MUg/kg pure CYN through two different exposure routes-gavage and intraperitoneal injection-and sacrificed after 24 h and 5 days. The results showed an increase in NADPH oxidase activity (a biomarker of reactive oxygen species formation), lipid peroxidation (LPO) and protein oxidation; no changes in DNA oxidation; and a reduction in glutathione levels (GSH) and gamma glutamylcysteine synthetase (GCS) activity, the limiting enzyme in glutathione synthesis. The time of sacrifice had a bigger influence on the results than the exposure route because after 5 days some of the biomarkers assayed had recovered their pre-intoxication levels, which was not the case after 24 h. PMID- 21703979 TI - Bezafibrate, a lipid-lowering pharmaceutical, as a potential endocrine disruptor in male zebrafish (Danio rerio). AB - Fibrates are pharmaceuticals commonly used to control hypercholesterolemia in humans and they are frequently detected in the freshwater environment. Since cholesterol is the precursor of all steroid hormones, it is suspected that low cholesterol levels will impact steroidogenesis. However, the effect of fibrates on fish reproductive endocrinology is not clear; therefore the aim of the present study was to evaluate the effect of bezafibrate (BZF) on gonadal steroidogenesis and spermatogenesis of zebrafish (Danio rerio). For this purpose, adult males were exposed orally to 1.7, 33 and 70 mg BZF/g food for 21 days. Blood and gonads were collected after 48 h, 7 days and 21 days to evaluate plasma cholesterol and plasma 11-ketotestosterone (11-KT). The expression of gonadal genes involved in the steroidogenesis was quantified to determine a potential mechanism of action, likewise the effect on spermatogenesis was evaluated by examining gonadal histopathology. A time dependent monotonic decrease in the plasma cholesterol concentration was observed in fish exposed to BZF. Plasma 11-KT decreased significantly after 21 days of exposure in fish exposed to the high concentration of BZF. Different gene expression patterns were observed: down-regulation in ppara and pparg mRNA levels was observed in fish exposed to the higher concentrations after 48 h; however, the expression of pparg increased after 21 days. After 21 days an increase in the star and cyp17a1 mRNA expression was observed in fish exposed to 70 mg BZF/g food. Sampling time and bezafibrate concentration explained 52.4% and 20%, respectively, of the gene expression variability. Gonadal histology revealed the presence of germ cell syncytia in the tubular lumen of fish exposed to bezafibrate and also an increased number of cysts containing spermatocytes, which indicate testicular degeneration. The study shows that bezafibrate exerts a hypocholesterolemic effect in adult male zebrafish and its potential as an endocrine disruptor due to its effect on the gonadal steroidogenesis and spermatogenesis. PMID- 21703980 TI - Relationship between mRNA biomarker candidates and location near a marine municipal wastewater outfall in the benthic indicator species Modiolus modiolus (L.). AB - The deep-sea horse mussel Modiolus modiolus (L.) is a sentinel bivalve species used for the assessment of potential biological exposure to anthropogenic contaminants in benthic environments. Using a combination of endpoints that included gross biological metrics, reproductive status, tissue contaminant load, and mRNA abundance profiles, we characterized variation in the local M. modiolus population situated in different spatial zones relative to a municipal wastewater outfall. Significant differences were observed in reproductive indicators, growth parameters, and abundance of four specific mRNA transcripts representative of stress response or membrane transport (CAT, NET/SCF6, ABCA4 and HSP70) in adductor muscle tissue of animals adjacent to the wastewater outfall. Concentrations of metals and organic chemicals in M. modiolus tissue were generally highest directly at the outfall site with much lower levels at 100-800 m from the outfall. This general pattern did not match the mRNA profiles. HSP70 and ABCA4 mRNA showed increased abundance in all regions adjacent to the municipal outfall compared to the reference site. One site group located within 100-200 m south/south-easterly of the outfall had increased levels of all four transcripts. Some mRNAs showed significant correlations with nickel, arsenic, lead, selenium, copper, and one of thirteen polycyclic aromatic hydrocarbons measured (dibenzo(a,h)-anthracene). Three mRNAs (CAT, NET/SCF6, and ABCA4) were negatively correlated with bis(2-ethylhexyl)phthalate. The data suggest that these benthic organisms are exhibiting biological responses to the outfall and support an alternate interpretation regarding dispersal of contaminants. The potential effects of emerging chemicals of concern entering the receiving environment merits further assessment. PMID- 21703981 TI - Toll-like receptor-9 triggering modulates expression of alpha-4 integrin on human B lymphocytes and their adhesion to extracellular matrix proteins. AB - OBJECTIVE: The interaction of human B lymphocytes as recirculating cells with their microenvironment components including fibronectin is an instrumental process that directs their further responses in an inflammatory milieu or during their development in secondary lymphoid organs. Factors derived from extracellular environment, including those of pathogens, termed pathogen associated molecular patterns, may have effects on this interaction, yet no study to date has addressed these effects. In this study, we explored the effect of Toll-like receptor 9 (TLR9) triggering on the interaction of normal B cells with fibronectin and collagen. MATERIALS AND METHODS: The synthetic analog of TLR9 ligand, CpG-C, was used for stimulating the cells. The expression pattern of very late antigen-4 integrin was studied by fluorescence-activated cell sorting and Western blotting experiments, and cell adhesion was analyzed by fluorometric adhesion assay. RESULTS: CpG at 0.5 MUM upregulated fibronectin receptor (very late antigen-4) expression and cell adhesion, and increasing the CpG concentration did not have further effect. Blocking experiments with TLR9 signaling inhibitor, TTAGGG, anti-alpha4 antibody, and IkappaBalpha phosphorylation inhibitor, Bay 11-7082, confirmed that the CpG-induced induction level was TLR9 (partly), very late antigen-4, and nuclear factor-kappaB-mediated, respectively. CONCLUSIONS: This study indicates that TLR9 triggering on B cells influences their interaction with extracellular matrix, which will be critical in modulating activation of these cells in conditions, such as infections, and gives a basic insight into the contribution of innate immunity elements in B-cell functional responses. PMID- 21703982 TI - Ly6C(+) monocytes are extrahepatic precursors of hepatic stellate cells in the injured liver of mice. AB - OBJECTIVE: We previously reported that hepatic stellate cells (HpSCs) are of hematopoietic origin in liver injury. However, the immediate precursors of HpSCs remain unknown. This study was conducted to elucidate whether terminally differentiated blood cells can differentiate into HpSCs. MATERIALS AND METHODS: We adoptively transferred a variety of cells isolated from enhanced green fluorescent protein (EGFP)-transgenic mice into carbon tetrachloride (CCl(4)) treated nontransgenic mice twice weekly for 2 weeks. We examined the presence of EGFP(+) HpSCs in the injured liver using immunofluorescence analysis. RESULTS: Monocytes, neutrophils, eosinophils, B cells, or T cells from EGFP mice were transferred into CCl(4)-treated mice. Thirty percent of EGFP(+) cells in the livers of mice given Ly6C(high)c-kit(-) monocytes were negative for CD45, but were positive for glial fibrillary acidic protein, desmin, CD146, ADAMTS13, and alpha-smooth muscle actin, well-known markers of HpSCs. EGFP(+)CD45(-) cells were predominantly positive for glial fibrillary acidic protein. Although 48% of EGFP(+) cells were positive for procollagen type I, half of them were CD45(-). In the livers of mice given neutrophils, eosinophils, B cells, or T cells, all of the EGFP(+) cells were CD45(+). The majority of EGFP(+) cells in the nonparenchymal cell fraction purified from the livers of mice given Ly6C(high)c kit(-) monocytes contained lipid droplets and were positive for glial fibrillary acidic protein, desmin, ADAMTS13, and procollagen type I. When Ly6C(+) monocyte depleted peripheral blood total nucleated cells were adoptively transferred into CCl(4)-treated mice, we found no EGFP(+)CD45(-) cells in the liver. CONCLUSIONS: These results suggest that Ly6C(+) monocytes can become HpSCs in the injured liver. PMID- 21703983 TI - Diagnostic microRNAs in myelodysplastic syndrome. AB - OBJECTIVE: The myelodysplastic syndromes (MDS) are aging-associated disorders characterized by ineffective maturation of hematopoietic elements, which are often diagnostically challenging. This study identifies microRNAs (miRNA) and miRNA targets that might represent diagnostic markers for MDS. MATERIALS AND METHODS: This study utilized a total of 42 MDS samples and 45 controls. A discovery set of 20 frozen bone marrow mononuclear cell samples (10 MDS, 10 controls) was profiled on a custom Agilent miRNA microarray. Classifier miRNAs were validated in a separate set of 49 paraffin-embedded particle preparations by real-time polymerase chain reaction (24 MDS, 25 controls). Target prediction analysis was compared to a de novo transcriptional profile of MDS derived from the Microarray Innovations in Leukemia study. c-Myb and Sufu were further investigated by immunohistochemical stains on a set of 26 paraffin-embedded samples. RESULTS: We identified 13 miRNAs of interest from the discovery set, 8 of which proved statistically significant on real-time polymerase chain reaction verification. These eight miRNAs were then examined in an independent real-time polymerase chain reaction validation set. Notably, hsa-miR-378, hsa-miR-632, and hsa-miR-636 demonstrated particularly high discrimination between MDS and normal controls. Target prediction identified potential targets of miRNA regulation that correspond to many of the genes that characterize MDS. Immunohistochemical staining performed on a third validation set confirmed that c-Myb and Sufu are differentially expressed in MDS. CONCLUSIONS: Our data utilize both discovery and validation sets and two complementary platforms to identify miRNAs associated with MDS. We have analyzed predicted targets and identified c-Myb and Sufu as potential diagnostic markers of MDS. PMID- 21703984 TI - Interleukin-15 supports generation of highly potent clinical-grade natural killer cells in long-term cultures for targeting hematological malignancies. AB - OBJECTIVE: Interleukin (IL)-15 is a promising novel cytokine for natural killer (NK) cell activation and survival. We studied the effects of IL-15 compared to IL 2 on NK cells in long-term cultures for clinical translation. MATERIALS AND METHODS: CD56(+)CD3(-) NK cells were expanded with IL-2 or IL-15 for 2 to 4 weeks within lymphokine-activated killer (LAK) cell cultures (LAK-NK) in serum-enriched AIM V or CellGro Stem Cell Growth Medium (SCGM). Cell growth, viability, and NK cell content were monitored and cytotoxicity assessed in a flow cytometric cytotoxicity assay. RESULTS: IL-15 (100-1000 U/mL) could replace IL-2 (1000 U/mL) in AIM V cultures to achieve efficient LAK cell expansion. However, IL-15 stimulated LAK cells exceeded cytotoxicity of IL-2-stimulated LAK cells against K562, notably at later culture points. In the powerful CellGro SCGM, LAK cells expanded over 28 days an average of 905-fold +/- 320-fold standard error of the mean (SEM) for IL-2 (500 U/mL) and 484-fold +/- 98-fold SEM for IL-15 (500 U/mL), and NK cells within such LAK cultures expanded an average of 2320-fold +/- 975 fold SEM for IL-2 and 1084-fold +/- 309-fold SEM for IL-15. Importantly, such IL 15-activated LAK-NK cells retained enhanced cytotoxicity at later culture points against K562 as well. IL-15-stimulated effectors were also highly cytotoxic against hematological targets MOLT-4 and KU812 and nontoxic against autologous nonmalignant cells. Interestingly, IL-15-LAK-NK cells showed overall significant upregulation of the main activating and inhibitory NK cell receptors after long term cytokine stimulation. CONCLUSIONS: Our results demonstrate the potential for IL-15 to support large-scale expansion of clinical-grade LAK-NK effectors, which could retain enhanced longer-term potency and preserve activation receptors in therapy of hematological malignancies. Protocols are readily clinically translatable. PMID- 21703986 TI - Clinical scale expansion of cytokine-induced killer cells is feasible from healthy donors and patients with acute and chronic myeloid leukemia at various stages of therapy. AB - OBJECTIVE: In our clinical studies involving cytokine-induced killer (CIK) cells for patients with hematological malignancies, starting cells came from a heterogeneous group of patients and donors. Here we study the feasibility of expansion and analyzed the characteristics of the end product from starting cells derived from different sources and at different disease states. MATERIALS AND METHODS: Seventy-five clinical scale cultures were grown from 28 patients and 20 donors in Good Manufacturing Practices facilities under CIK condition. RESULTS: CIK cells could be successfully expanded from healthy donors, patients with acute myeloid leukemia recovering from chemotherapy, untreated patients with acute myeloid leukemia or myelodysplastic syndrome with circulating leukemic blasts, and patients with chronic myeloid leukemia on imatinib. Furthermore, CIK cells of donor origin could be expanded from leukapheresis product collected from patients who relapsed post-allogeneic transplantation, thereby offering a useful method of obtaining activated donor cells in patients for whom further donor cells were unavailable. Interestingly, CIK cells cultured from patients with untreated acute myeloid leukemia and myelodysplastic syndrome had a significantly higher proportion of CD3(+)CD56(+) subset and higher fold expansion of CD3(+) cells as compared to other groups of patients or healthy donors. Multivariate analysis showed that fresh starting cells expanded better than frozen-thawed cells, while prior exposure to granulocyte colony-stimulating factor or imatinib before harvesting did not adversely affect CIK cell expansion. CONCLUSIONS: Clinical scale expansion of CIK cells is feasible from both healthy donors and leukemia patients at various stages of treatment. This robust system allows clinical translation using CIK cells as immunotherapy in various clinical settings. PMID- 21703985 TI - Bid is a positive regulator for donor-derived lymphoid cell regeneration in gamma irradiated recipients. AB - OBJECTIVE: Hematopoietic regeneration is regulated by cell survival proteins, such as the Bcl-2 family. Bid, a BH3-only protein of the Bcl-2 family, has multiple cellular functions and is involved in a variety of physiological or pathological conditions. We attempted to define its role in hematopoietic cell repopulation under the stress condition of bone marrow transplantation. MATERIALS AND METHODS: We performed conventional or competitive bone marrow transplantation with donor hematopoietic cells from Bid(-/-) or Bid(+/+) mice. Flow cytometry was used for quantification of hematopoietic stem cells, hematopoietic progenitor cells, and differentiated cells in different lineages (T, B, and myeloid cells). Single cell culture and homing assays were performed to further evaluate hematopoietic stem cell functions. Hematopoietic progenitor cells were also measured by the colony-forming cell culture. RESULTS: Contrary to the widely recognized role of Bid as a pro-apoptotic protein, the absence of Bid significantly reduced the reconstitution of donor hematopoietic cells in gamma irradiated recipients. Interestingly, however, numbers of hematopoietic stem cells and hematopoietic progenitor cells and their functions were not overtly altered. Instead, the regeneration of donor T and B cells was significantly impaired in the absence of Bid. Further analysis indicated an accumulation of the triple-negative T-cell population in the thymus, and pro-B cells in the bone marrow. CONCLUSIONS: Our current study demonstrates a positive impact of Bid on hematopoietic regeneration mainly due to its unique effects on donor lymphopoiesis in the transplant recipients. PMID- 21703987 TI - Prior rituximab administration is associated with reduced rate of acute GVHD after in vivo T-cell depleted transplantation in lymphoma patients. AB - Rituximab is one of the most commonly used drugs in the treatment of B-cell non Hodgkin lymphoma. Because of its ability to target CD20(+) lymphocytes, its use before allogeneic stem cell transplantation seemed to reduce risk of graft-vs. host disease (GVHD) occurrence. We retrospectively analyzed the outcomes of adult patients diagnosed with CD20(+) lymphoproliferative disease undergoing allogeneic stem cell transplantation and receiving, or not receiving, rituximab up to 3 months before transplantation. Analysis on a cohort of 57 patients showed a protective role of rituximab on the occurrence of acute GVHD for those receiving anti-thymocyte globulin during conditioning (n = 39). Grade 2 to 4 and 3 to 4 acute GVHD occurred in 10% vs. 48% (p = 0.03) and 0% vs. 24% (p = 0.08) in the rituximab and no-rituximab groups, respectively. No impact on chronic GVHD was observed. These results confirm a protective role of rituximab on the occurrence of GVHD and enhance further investigation on future studies aimed at reducing GVHD incidence. PMID- 21703988 TI - Synthesis and antibacterial activity of silver nanoparticles against gram positive and gram-negative bacteria. AB - Synthesis of nanosized particles with antibacterial properties is of great interest in the development of new pharmaceutical products. Silver nanoparticles (Ag NPs) are known to have inhibitory and bactericidal effects. In this article we present the synthesis of Ag NPs prepared by chemical reduction from aqueous solutions of silver nitrate, containing a mixture of hydrazine hydrate and sodium citrate as reductants and sodium dodecyl sulfate as a stabilizer. The results of the characterization of the Ag NPs show agglomerates of grains with a narrow size distribution (from 40 to 60 nm), whereas the radii of the individual particles are between 10 and 20 nm. Finally, the antibacterial activity was measured by the Kirby-Bauer method. The results showed reasonable bactericidal activity against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. The standard dilution micromethod, determining the minimum inhibitory concentration leading to inhibition of bacterial growth, is still under way. Preliminary results have been obtained. FROM THE CLINICAL EDITOR: In this paper the synthesis of Ag NPs via chemical reduction from aqueous solutions is discussed. Reasonable bactericidal activity against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus was demonstrated. PMID- 21703989 TI - Liposomes functionalized with acidic lipids rescue Abeta-induced toxicity in murine neuroblastoma cells. AB - The loss of synapses and neurons in Alzheimer's disease (AD) is thought to be at least partly induced by toxic species formed by the amyloid beta (Abeta) peptide; therefore, therapeutics aimed at reducing Abeta toxicity could be of clinical use for treatment of AD. Liposomes are suitable vehicles for therapeutic agents and imaging probes, and a promising way of targeting the various Abeta forms. We tested liposomes functionalized with phosphatidic acid, cardiolipin, or GM1 ganglioside, previously shown to have high Abeta-binding capacity. Mimicking Abeta-induced toxicity in mouse neuroblastoma cell lines, combined with administration of cell viability-modulating agents, we observed that functionalized liposomes rescued cell viability to different extents. We also detected rescue of the imbalance of GSK-3beta and PP2A activity, and reduction in tau phosphorylation. Thus, these liposomes appear particularly suitable for implementing further therapeutic strategies for AD. PMID- 21703990 TI - Cross-linked antioxidant nanozymes for improved delivery to CNS. AB - Formulations of antioxidant enzymes, superoxide dismutase 1 (SOD1, also known as Cu/Zn SOD) and catalase were prepared by electrostatic coupling of enzymes with cationic block copolymers, polyethyleneimine-poly(ethylene glycol) or poly(L lysine)-poly(ethylene glycol), followed by covalent cross-linking to stabilize nanoparticles (NPs). Different cross-linking strategies (using glutaraldehyde, bis-(sulfosuccinimidyl)suberate sodium salt or 1-Ethyl-3-[3 dimethylaminopropyl]carbodiimide hydrochloride with N-hydroxysulfosuccinimide) and reaction conditions (pH and polycation/protein charge ratio) were investigated that allowed immobilizing active enzymes in cross-linked NPs, termed "nanozymes." Bienzyme NPs, containing both SOD1 and catalase were also formulated. Formation of complexes was confirmed using denaturing gel electrophoresis and western blotting; physicochemical characterization was conducted using dynamic light scattering and atomic force microscopy. In vivo studies of (125)I-labeled SOD1-containing nanozymes in mice demonstrated their increased stability in both blood and brain and increased accumulation in brain tissues, in comparison with non-cross-linked complexes and native SOD1. Future studies will evaluate the potential of these formulations for delivery of antioxidant enzymes to the central nervous system to attenuate oxidative stress associated with neurological diseases. FROM THE CLINICAL EDITOR: Formulations of antioxidant enzyme complexes were demonstrated along with their increased stability in both blood and brain and increased accumulation in CNS tissue. Future studies will evaluate the potential of these formulations for antioxidant enzyme deliver to the CNS to attenuate oxidative stress in neurodegenerative diseases. PMID- 21703991 TI - Targeted delivery of liposomal nanocontainers to the peritumoral zone of glioma by means of monoclonal antibodies against GFAP and the extracellular loop of Cx43. AB - The selectivity of PEGylated immunoliposomes based on monoclonal antibodies against GFAP and the E2 extracellular loop of connexin 43 (MAbE2Cx43) with respect to the focus of a glioma was estimated in experiments on animals with intracranial C6 glioma. Stealth immunoliposomes were labeled with 2 alternative labels, a fluorescent (Dil C18) and a paramagnetic (Gd-DTPA) one. Fluorescent labeled liposomal nanocontainers were detected at the periphery of the glioma, where the target antigens were overexpressed, 48 hours after injection. Dynamic T1 MRI of rats injected with paramagnetic immunoliposomes carrying MAbE2Cx43 showed distinct accumulation of the paramagnetic contrast agent at the periphery of the glioma, which began 6 hours after administration. These data suggest that immunoliposomal nanocontainers based on antibodies against GFAP and the E2 extracellular fragment of connexin 43 are suitable for targeted delivery of diagnostic and therapeutic drugs to the peritumoral invasion zone of high-grade gliomas. FROM THE CLINICAL EDITOR: PEGylated immunoliposomes based on monoclonal antibodies against GFAP and the E2 extracellular loop of connexin 43 were investigated in animals with intracranial C6 glioma. These immunoliposomal nanocontainers were found suitable for targeted delivery of diagnostic and therapeutic drugs to the peritumoral invasion zone of high-grade gliomas. PMID- 21703992 TI - AFM study of Escherichia coli RNA polymerase sigma70 subunit aggregation. AB - The self-assembly of Escherichia coli RNA polymerase sigma70 subunit was investigated using several experimental approaches. A novel rodlike shape was reported for sigma70 subunit aggregates. Atomic force microscopy reveals that these aggregates, or sigma70 polymers, have a straight rodlike shape 5.4 nm in diameter and up to 300 nm in length. Atomic force microscopy data, Congo red binding assay, and sodium dodecyl sulfate gel electrophoresis confirm the amyloid nature of observed aggregates. The process of formation of rodlike structures proceeds spontaneously under nearly physiological conditions. E. coli RNA polymerase sigma70 subunit may be an interesting object for investigation of amyloidosis as well as for biotechnological applications that exploit self assembled bionanostructures. Polymerization of sigma70 subunit may be a competitive process with its three-dimensional crystallization and association with core RNA polymerase. FROM THE CLINICAL EDITOR: In this basic science study, the self-assembly of Escherichia coli RNA polymerase sigma70( subunit was investigated using atomic force microscopy and other complementary approaches. PMID- 21703993 TI - Nanoparticles: a boon to drug delivery, therapeutics, diagnostics and imaging. AB - Drug delivery is an interdisciplinary and independent field of research and is gaining the attention of pharmaceutical researchers, medical doctors and industry. A safe and targeted drug delivery could improve the performance of some classic medicines already on the market, and moreover, will have implications for the development and success of new therapeutic strategies such as anticancer drug delivery, peptide and protein delivery and gene therapy. In the last decade, several drug-delivery technologies have emerged and a fascinating part of this field is the development of nanoscale drug delivery devices. Nanoparticles (NPs) have been developed as an important strategy to deliver conventional drugs, recombinant proteins, vaccines and more recently, nucleotides. NPs and other colloidal drug-delivery systems modify the kinetics, body distribution and drug release of an associated drug. This review article focuses on the potential of nanotechnology in medicine and discusses different nanoparticulate drug-delivery systems including polymeric NPs, ceramic NPs, magnetic NPs, polymeric micelles and dendrimers as well as their applications in therapeutics, diagnostics and imaging. FROM THE CLINICAL EDITOR: This comprehensive review focuses on different nanoparticulate drug-delivery systems including polymeric NPs, ceramic NPs, magnetic NPs, polymeric micelles and dendrimers as well as their applications in therapeutics, diagnostics and imaging. PMID- 21703994 TI - Simultaneous basal-bolus delivery of fast-acting insulin and its significance in diabetes management. AB - Insulin delivery relies on subcutaneous or intravascular injection, leading to reduced patient compliance. Transdermal delivery of insulin has been successfully demonstrated but dose accuracy and skin irritation are problematic in addition to the complex basal-bolus delivery profile required by insulin therapy. Here we present a novel intraepidermal delivery technology (delivered site at epidermis layer, <150 MUm) by combining skin pretreatment with short microneedles (<150 MUm in length) and iontophoresis transdermal patch (enhanced transport via electrical field) that can provide a continuous basal dose and on-demand bolus dosing for mealtime insulin needs. To our knowledge, this is the first demonstration of therapeutic equivalence between fast-acting human regular insulin and long-acting insulin with possibilities for on-demand dose adjustment. This new intraepidermal delivery technology is likely to change the therapy regimen of patients suffering from insulin-dependent diabetes mellitus and provide a way to lower cost in comparison with insulin pumps and improve patient compliance. FROM THE CLINICAL EDITOR: The authors present a novel intraepidermal insulin delivery technology by combining skin pretreatment with short microneedles and iontophoresis transdermal patch to provide a continuous basal dose and on-demand bolus dosing. This new method is has the potentials to replace insulin pumps by offering a cost effective alternative with less inconvenience and improved compliance. PMID- 21703995 TI - Linear PEI nanoparticles: efficient pDNA/siRNA carriers in vitro and in vivo. AB - Linear polyethylenimine (lPEI, 25 kDa) nanoparticles' (LPN) series was synthesized by varying percentage of cross-linking with 1,4-butanediol diglycidyl ether (BDE) and their size, surface charge, morphology, pDNA protection/release, cytotoxicity and transfection efficiency were evaluated. Synthesized nanoparticles (NPs) were spherical in shape (size: ~109 - 235 nm; zeta potential: +38 to +16 mV). These NPs showed increased buffering capacity with increasing percent cross-linking and also exhibited excellent transfection efficiency (i.e., ~1.3 - 14.7 folds in case of LPN-5) in comparison with lPEI and the commercial transfection agents used in this study. LPN-5 based GFP-specific siRNA delivery resulted in ~86% suppression of targeted gene expression. These particles were relatively nontoxic in vitro (in cell lines) and in vivo (in Drosophila). In vivo gene expression studies using LPN-5 in Balb/c mice through intravenous injection showed maximum expression of the reporter gene in the spleen. These results together demonstrate the potential of these particles as efficient transfection reagents. FROM THE CLINICAL EDITOR: The authors demonstrate a novel method of synthesizing linear PEI nanoparticles to utilize these as transfection agents. PMID- 21703996 TI - In vivo tumor suppression efficacy of mesoporous silica nanoparticles-based drug delivery system: enhanced efficacy by folate modification. AB - Mesoporous silica nanoparticles (MSNs) have proven to be promising vehicles for drug delivery. However, despite the potential, few studies have extended the success of in vitro studies to animal settings. In this article, we report the efficacy of MSNs using two different human pancreatic cancer xenografts on different mouse species. Significant tumor-suppression effects were achieved with camptothecin-loaded MSNs. Dramatic improvement of the potency of tumor suppression was obtained by surface modifying MSNs with folic acid. Dose dependent tumor suppression was observed, establishing 0.5 mg of CPT-loaded MSNs per mouse as a minimum dose sufficient for achieving complete tumor growth inhibition. Renal excretion of MSNs was also confirmed with transmission electron microscopy (TEM) imaging. These findings highlight attractive features (biocompatibility, renal clearance and high efficacy for delivering anticancer drugs) of MSNs as a drug-delivery system. FROM THE CLINICAL EDITOR: In this study, mesoporous silica nanoparticles are used as chemotherapy delivering agents in two different human pancreatic cancer xenografts and different mouse species. Significant tumor-suppression effects, biocompatibility and efficient renal clearance are demonstrated. PMID- 21703997 TI - BCL9-2 promotes early stages of intestinal tumor progression. AB - BACKGROUND & AIMS: The roles of the 2 BCL9 and 2 Pygopus genes in Wnt to beta catenin signaling are not clear in vertebrates. We examined their expression and function in normal and tumor intestinal epithelia in mice and humans. METHODS: Specific antibodies were generated to characterize the BCL9 and Pygopus proteins in normal intestine and in colon tumors. Targets of BCL9 and Pygopus in colon cancer cells were analyzed using small interfering RNA analysis. Transgenic mice were created that overexpressed BCL9-2 in intestine; these were crossed with APCMin/+ mice to create BCL9-2;APCMin/+ mice. RESULTS: BCL9 and Pygopus2 were expressed in all normal intestinal and colon cancer cells. BCL9-2 was detectable only in the villi, not in the crypts of normal intestine. BCL9-2 was up-regulated in adenomas and in almost all colon tumors, with a concomitant increase of Pygopus2, whereas levels of BCL9 were similar between normal and cancer cells. Transgenic overexpression of BCL9-2 in the intestine of BCL9-2; APCMin/+ mice increased formation of adenomas that progressed to invasive tumors, resulting in reduced survival time. Using small interfering RNA analysis, we found that BCL9s and Pygopus are not targets of Wnt in colon cancer cells, but Wnt signaling correlated with levels of BCL9-2. BCL9-2 regulated expression of beta-catenin dependent and -independent target genes that have been associated with early stages of intestinal tumorigenesis. CONCLUSIONS: BCL9-2 promotes early phases of intestinal tumor progression in humans and in transgenic mice. BCL9-2 increases the expression of a subset of canonical Wnt target genes but also regulates genes that are required for early stages of tumor progression. PMID- 21703998 TI - Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis. AB - BACKGROUND & AIMS: Type 2 diabetes and nonalcoholic steatohepatitis (NASH) are associated with insulin resistance and disordered cholesterol homeostasis. We investigated the basis for hepatic cholesterol accumulation with insulin resistance and its relevance to the pathogenesis of NASH. METHODS: Alms1 mutant (foz/foz) and wild-type NOD.B10 mice were fed high-fat diets that contained varying percentages of cholesterol; hepatic lipid pools and pathways of cholesterol turnover were determined. Hepatocytes were exposed to insulin concentrations that circulate in diabetic foz/foz mice. RESULTS: Hepatic cholesterol accumulation was attributed to up-regulation of low-density lipoprotein receptor via activation of sterol regulatory element binding protein 2 (SREBP-2), reduced biotransformation to bile acids, and suppression of canalicular pathways for cholesterol and bile acid excretion in bile. Exposing primary hepatocytes to concentrations of insulin that circulate in diabetic Alms1 mice replicated the increases in SREBP-2 and low-density lipoprotein receptor and suppression of bile salt export pump. Removing cholesterol from diet prevented hepatic accumulation of free cholesterol and NASH; increasing dietary cholesterol levels exacerbated hepatic accumulation of free cholesterol, hepatocyte injury or apoptosis, macrophage recruitment, and liver fibrosis. CONCLUSIONS: In obese, diabetic mice, hyperinsulinemia alters nuclear transcriptional regulators of cholesterol homeostasis, leading to hepatic accumulation of free cholesterol; the resulting cytotoxicity mediates transition of steatosis to NASH. PMID- 21703999 TI - PAR2 promotes vaccine-induced protection against Helicobacter infection in mice. AB - BACKGROUND & AIMS: Protective immunization limits Helicobacter infection of mice by undetermined mechanisms. Protease-activated receptor 2 (PAR2) signaling is believed to regulate immune and inflammatory responses. We investigated the role of PAR2 in vaccine-induced immunity against Helicobacter infection. METHODS: Immune responses against Helicobacter infection were compared between vaccinated PAR2-/- and wild-type (WT) mice. Bacterial persistence, gastric pathology, and inflammatory and cellular responses were assessed using the rapid urease test (RUT), histologic analyses, quantitative polymerase chain reaction, and flow cytometry, respectively. RESULTS: Following vaccination, PAR2-/- mice did not have reductions in Helicobacter felis infection (RUT values were 0.01+/-0.01 for WT mice and 0.11+/-0.13 for PAR2-/- mice; P<.05). The vaccinated PAR2-/- mice had reduced inflammation-induced stomach tissue damage (tissue damage scores were 8.83+/-1.47 for WT mice and 4.86+/-1.35 for PAR2-/- mice; P<.002) and reduced T helper (Th)17 responses, based on reduced urease-induced interleukin (IL)-17 secretion by stomach mononuclear cells (5182 +/- 1265 pg/mL for WT mice and 350+/ 436 pg/mL for PAR2-/- mice; P<.03) and reduced recruitment of CD4+ IL-17+ T cells into the gastric mucosa of PAR2-/- mice following bacterial challenge (3.7%+/ 1.5% for WT mice and 2.6%+/-1.1% for PAR2-/- mice; P<.05). In vitro, H felis stimulated dendritic cells (DCs) from WT mice induced greater secretion of IL-17 by ovalbumin-stimulated OT-II transgenic CD4+ T cells compared with DCs from PAR2 /- mice (4298+/-347 and 3230+/-779; P<.04), indicating that PAR2-/- DCs are impaired in priming of Th17 cells. Adoptive transfer of PAR2+/+ DCs into vaccinated PAR2-/- mice increased vaccine-induced protection (RUT values were 0.11+/-0.10 and 0.26+/-0.15 for injected and noninjected mice, respectively; P<.03). CONCLUSIONS: PAR2 activates DCs to mediate vaccine-induced protection against Helicobacter infection in mice. PMID- 21704000 TI - Gastroenterology: a field with endless career opportunities for physicians and scientists. PMID- 21704001 TI - Spontaneous, immune-mediated gastric inflammation in SAMP1/YitFc mice, a model of Crohn's-like gastritis. AB - BACKGROUND & AIMS: Crohn's disease (CD) can develop in any region of the gastrointestinal tract, including the stomach. The etiology and pathogenesis of Crohn's gastritis are poorly understood, treatment approaches are limited, and there are not many suitable animal models for study. We characterized the features and mechanisms of chronic gastritis in SAMP1/YitFc (SAMP) mice, a spontaneous model of CD-like ileitis, along with possible therapeutic approaches. METHODS: Stomachs from specific pathogen-free and germ-free SAMP and AKR mice (controls) were evaluated histologically; the presence of Helicobacter spp was tested in fecal pellets by polymerase chain reaction analysis. In vivo gastric permeability was quantified by fractional excretion of sucrose, and epithelial tight junction protein expression was measured by quantitative reverse transcription polymerase chain reaction analysis. The effects of a proton pump inhibitor (PPI) or corticosteroids were measured, and the ability of pathogenic immune cells to mediate gastritis was assessed in adoptive transfer experiments. RESULTS: SAMP mice developed Helicobacter-negative gastritis, characterized by aggregates of mononuclear cells, diffuse accumulation of neutrophils, and disruption of epithelial architecture; SAMP mice also had increased gastric permeability compared with controls, without alterations in expression of tight junction proteins. The gastritis and associated permeability defect observed in SAMP mice were independent of bacterial colonization and reduced by administration of corticosteroids but not a PPI. CD4(+) T cells isolated from draining mesenteric lymph nodes of SAMP mice were sufficient to induce gastritis in recipient SCID mice. CONCLUSIONS: In SAMP mice, gastritis develops spontaneously and has many features of CD-like ileitis. These mice are a useful model to study Helicobacter-negative, immune-mediated Crohn's gastritis. PMID- 21704002 TI - Duodenal mucosal protein kinase C-delta regulates glucose production in rats. AB - BACKGROUND & AIMS: Activation of protein kinase C (PKC) enzymes in liver and brain alters hepatic glucose metabolism, but little is known about their role in glucose regulation in the gastrointestinal tract. We investigated whether activation of PKC-delta in the duodenum is sufficient and necessary for duodenal nutrient sensing and regulates hepatic glucose production through a neuronal network in rats. METHODS: In rats, we inhibited duodenal PKC and evaluated whether nutrient-sensing mechanisms, activated by refeeding, have disruptions in glucose regulation. We then performed gain- and loss-of-function pharmacologic and molecular experiments to target duodenal PKC-delta; we evaluated the impact on glucose production regulation during the pancreatic clamping, while basal levels of insulin were maintained. RESULTS: PKC-delta was detected in the mucosal layer of the duodenum; intraduodenal infusion of PKC inhibitors disrupted glucose homeostasis during refeeding, indicating that duodenal activation of PKC-delta is necessary and sufficient to regulate glucose homeostasis. Intraduodenal infusion of the PKC activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) specifically activated duodenal mucosal PKC-delta and a gut-brain-liver neuronal pathway to reduce glucose production. Molecular and pharmacologic inhibition of duodenal mucosal PKC-delta negated the ability of duodenal OAG and lipids to reduce glucose production. CONCLUSIONS: In the duodenal mucosa, PKC-delta regulates glucose homeostasis. PMID- 21704003 TI - APOC3 polymorphisms and non-alcoholic fatty liver disease: resolving some doubts and raising others. PMID- 21704004 TI - DCD donors: a unique source to significantly increase organ donation. PMID- 21704005 TI - Astrocyte-derived thrombospondin-2 is critical for the repair of the blood-brain barrier. AB - Thrombospondin (TSP)-2-null mice have an altered brain foreign body response (FBR) characterized by increases in inflammation, extracellular matrix deposition, and leakage of the blood-brain barrier (BBB). In the present study, we investigated the role of TSP-2 in BBB repair during the brain FBR to mixed cellulose ester filters implanted in the cortex of wild-type (WT) and TSP-2-null mice for 2 days to 8 weeks. Histological and immunohistochemical analysis revealed enhanced and prolonged neuroinflammation in TSP-2-null mice up to 8 weeks after implantation. In addition, recovery of the BBB was compromised and was associated with increased gelatinolytic activity and low levels of collagen type IV in the basement membranes of TSP-2-null blood vessels. An analysis of protein extracts from implantation sites revealed elevated levels of matrix metalloproteinase (MMP)-2 and MMP-9 in TSP-2-null brains. TSP-2-null astrocytes secreted higher levels of both MMPs in vitro compared with their WT counterparts. Furthermore, TSP-2-null astrocytes were deficient in supporting the recovery of barrier function in WT endothelial cells. Finally, Western blot analysis of astrocytes and brain endothelial cells revealed TSP-2 expression only in the former. Taken together, our observations suggest that astrocyte-derived TSP-2 is critical for the maintenance of physiological MMP-2 and MMP-9 levels during the FBR and contributes to the repair of the BBB. PMID- 21704006 TI - In vivo and in vitro evidence that PPARgamma ligands are antagonists of leptin signaling in breast cancer. AB - Obesity is a major risk factor for the development and progression of breast cancer. Leptin, a cytokine mainly produced by adipocytes, plays a crucial role in mammary carcinogenesis and is elevated in hyperinsulinemia and insulin resistance. The antidiabetic thiazolidinediones inhibit leptin gene expression through ligand activation of the peroxisome proliferator-activated receptor-gamma (PPARgamma) and exert antiproliferative and apoptotic effects on breast carcinoma. In this study, we investigated the ability of PPARgamma ligands to counteract leptin stimulatory effects on breast cancer growth in either in vivo or in vitro models. The results show that activation of PPARgamma prevented the development of leptin-induced MCF-7 tumor xenografts and inhibited the increased cell-cell aggregation and proliferation observed on leptin exposure. PPARgamma ligands abrogated the leptin-induced up-regulation of leptin gene expression and its receptors in breast cancer. PPARgamma-mediated repression of leptin gene involved the recruitment of nuclear receptor corepressor protein and silencing mediator of retinoid and thyroid hormone receptors corepressors on the glucocorticoid responsive element site in the leptin gene expression regulatory region in the presence of glucocorticoid receptor and PPARgamma. In addition, PPARgamma ligands inhibited leptin signaling mediated by MAPK/STAT3/Akt phosphorylation and counteracted leptin stimulatory effect on estrogen signaling. These findings suggest that PPARgamma ligands may have potential therapeutic benefits in the treatment of breast cancer. PMID- 21704007 TI - Keratin 19 epithelial patterns in cirrhotic stroma parallel hepatocarcinogenesis. AB - Cirrhotic septa harbor vessels and inflammatory, fibrogenic, and ductular epithelial cells, collectively referred to as the ductular reaction (DR). Lack of the DR in the stromal compartment around hepatocellular carcinoma (HCC) has been documented; however, the relationship of epithelial keratin 19 (K19) structures to progression of intralesional carcinogenesis has not been explored. K19 immunoreactivity in the stromal compartment around 176 nodules in cirrhotic explants was examined. Quantitative differences (P < 0.0001) were manifested in three distinct histologically identifiable patterns: "complex" around cirrhotic nodules (CN), "attenuated" around dysplastic nodules (DN), and "absent" around HCC. Markers of necrosis or apoptosis could not explain the perinodular K19 epithelial loss; however, multicolor immunolabeling for K19, vimentin, E Cadherin, SNAIL, and fibroblast-specific protein 1 (FSP-1) demonstrated discrepancies in immunophenotype and cytomorphologic features. Variability of cellular features was accompanied by an overall decrease in epithelial markers and significantly increased fractions of SNAIL- and FSP-1-positive cells in the DR around DN when compared with CN (P < 0.0001). Immunolabeling of transforming growth factor-beta signaling components (TGFbetaR1, SMAD3, and pSMAD2/3) demonstrated increased percentages of pSMAD2/3 around DN when compared with CN (P < 0.0001). These findings collectively suggest marked alterations in cellular identity as an underlying mechanism for the reproducible extralesional K19 pattern that parallels progressive stages of intranodular hepatocarcinogenesis. Paracrine signaling is proposed as a link that emphasizes the importance of the epithelial-stromal compartment in malignant progression of HCC in cirrhosis. PMID- 21704008 TI - Dual functionality of myeloperoxidase in rotenone-exposed brain-resident immune cells. AB - Rotenone exposure has emerged as an environmental risk factor for inflammation associated neurodegenerative diseases. However, the underlying mechanisms responsible for the harmful effects of rotenone in the brain remain poorly understood. Herein, we report that myeloperoxidase (MPO) may have a potential regulatory role in rotenone-exposed brain-resident immune cells. We show that microglia, unlike neurons, do not undergo death; instead, they exhibit distinctive activated properties under rotenone-exposed conditions. Once activated by rotenone, microglia show increased production of reactive oxygen species, particularly HOCl. Notably, MPO, an HOCl-producing enzyme that is undetectable under normal conditions, is significantly increased after exposure to rotenone. MPO-exposed glial cells also display characteristics of activated cells, producing proinflammatory cytokines and increasing their phagocytic activity. Interestingly, our studies with MPO inhibitors and MPO-knockout mice reveal that MPO deficiency potentiates, rather than inhibits, the rotenone induced activated state of glia and promotes glial cell death. Furthermore, rotenone-triggered neuronal injury was more apparent in co-cultures with glial cells from Mpo(-/-) mice than in those from wild-type mice. Collectively, our data provide evidence that MPO has dual functionality under rotenone-exposed conditions, playing a critical regulatory role in modulating pathological and protective events in the brain. PMID- 21704009 TI - miR-21 and miR-214 are consistently modulated during renal injury in rodent models. AB - Transforming growth factor (TGF)-beta is one of the main fibrogenic cytokines that drives the pathophysiology of progressive renal scarring. MicroRNAs (miRNAs) are endogenous non-coding RNAs that post-transcriptionally regulate gene expression. We examined the role of TGF-beta-induced expression of miR-21, miRNAs in cell culture models and miRNA expression in relevant models of renal disease. In vitro, TGF-beta changed expression of miR-21, miR-214, and miR-145 in rat mesangial cells (CRL-2753) and miR-214, miR-21, miR-30c, miR-200b, and miR-200c during induction of epithelial-mesenchymal transition in rat tubular epithelial cells (NRK52E). miR-214 expression was robustly modulated in both cell types, whereas in tubular epithelial cells miR-21 was increased and miR-200b and miR 200c were decreased by 58% and 48%, respectively, in response to TGF-beta. TGF beta receptor-1 was found to be a target of miR-200b/c and was down-regulated after overexpression of miR-200c. To assess the differential expression of these miRNAs in vivo, we used the anti-Thy1.1 mesangial glomerulonephritis model and the unilateral ureteral obstruction model in which TGF-beta plays a role and also a genetic model of hypertension, the stroke-prone spontaneously hypertensive rat with and without salt loading. The expressions of miR-214 and miR-21 were significantly increased in all in vivo models, showing a possible miRNA signature of renal damage despite differing causes. PMID- 21704010 TI - MicroRNAs involved in the mitogen-activated protein kinase cascades pathway during glucose-induced cardiomyocyte hypertrophy. AB - Cardiac hypertrophy is a key structural feature of diabetic cardiomyopathy in the late stage of diabetes. Recent studies show that microRNAs (miRNAs) are involved in the pathogenesis of cardiac hypertrophy in diabetic mice, but more novel miRNAs remain to be investigated. In this study, diabetic cardiomyopathy, characterized by hypertrophy, was induced in mice by streptozotocin injection. Using microarray analysis of myocardial tissue, we were able to identify changes in expression in 19 miRNA, of which 16 miRNAs were further validated by real-time PCR and a total of 3212 targets mRNA were predicted. Further analysis showed that 31 GO functions and 16 KEGG pathways were enriched in the diabetic heart. Of these, MAPK signaling pathway was prominent. In vivo and in vitro studies have confirmed that three major subgroups of MAPK including ERK1/2, JNK, and p38, are specifically upregulated in cardiomyocyte hypertrophy during hyperglycemia. To further explore the potential involvement of miRNAs in the regulation of glucose induced cardiomyocyte hypertrophy, neonatal rat cardiomyocytes were exposed to high glucose and transfected with miR-373 mimic. Overexpression of miR-373 decreased the cell size, and also reduced the level of its target gene MEF2C, and miR-373 expression was regulated by p38. Our data highlight an important role of miRNAs in diabetic cardiomyopathy, and implicate the reliability of bioinformatics analysis in shedding light on the mechanisms underlying diabetic cardiomyopathy. PMID- 21704011 TI - Loss of muscarinic M1 receptor exacerbates Alzheimer's disease-like pathology and cognitive decline. AB - Alzheimer's disease (AD) is pathologically characterized by tau-laden neurofibrillary tangles and beta-amyloid deposits. Dysregulation of cholinergic neurotransmission has been implicated in AD pathogenesis, contributing to the associated memory impairments; yet, the exact mechanisms remain to be defined. Activating the muscarinic acetylcholine M(1) receptors (M(1)Rs) reduces AD-like pathological features and enhances cognition in AD transgenic models. To elucidate the molecular mechanisms by which M(1)Rs affect AD pathophysiological features, we crossed the 3xTgAD and transgenic mice expressing human Swedish, Dutch, and Iowa triple-mutant amyloid precursor protein (Tg-SwDI), two widely used animal models, with the M(1)R(-/-) mice. Our data show that M(1)R deletion in the 3xTgAD and Tg-SwDI mice exacerbates the cognitive impairment through mechanisms dependent on the transcriptional dysregulation of genes required for memory and through acceleration of AD-related synaptotoxicity. Ablating the M(1)R increased plaque and tangle levels in the brains of 3xTgAD mice and elevated cerebrovascular deposition of fibrillar Abeta in Tg-SwDI mice. Notably, tau hyperphosphorylation and potentiation of amyloidogenic processing in the mice with AD lacking M(1)R were attributed to changes in the glycogen synthase kinase 3beta and protein kinase C activities. Finally, deleting the M(1)R increased the astrocytic and microglial response associated with Abeta plaques. Our data highlight the significant role that disrupting the M(1)R plays in exacerbating AD related cognitive decline and pathological features and provide critical preclinical evidence to justify further development and evaluation of selective M(1)R agonists for treating AD. PMID- 21704012 TI - Complement regulates CD4 T-cell help to CD8 T cells required for murine allograft rejection. AB - Although induction of CD8 T-cell responses to transplants requires CD4-cell help, how this help is transmitted remains incompletely characterized. In vitro, cognate interactions between CD4 T cells and dendritic cells (DCs) induce C3a and C5a production. CD8(+) T cells lacking C3a receptor (C3aR) and C5a receptor (C5aR) proliferate weakly to allogeneic DCs despite CD4 help, indicating that CD4 cell help is mediated, in part, through DC-derived C3a/C5a acting on CD8(+) T cell-expressed C3aR/C5aR. In support of this concept, augmenting DC C5a/C3a production bypasses the requirement for CD4- and CD40-dependent help to wild-type CD8(+) T cells. CD4-deficient recipients of allogeneic heart transplants prime weak CD8 responses and do not acutely reject their grafts. In contrast, CD4 deficient chimeric mice possessing decay accelerating factor deficient (Daf1(-/ )) bone marrow, in which DC C3a/C5a production is potentiated, acutely reject transplants through a CD8 cell-dependent mechanism. Furthermore, hearts transplanted into CD40(-/-) mice prime weak CD8-cell responses and survive indefinitely, but hearts transplanted into Daf1(-/-)CD40(-/-) recipients undergo CD8 cell-dependent rejection. Together, the data indicate that heightened production and activation of immune cell-derived complement bypasses the need for CD40/CD154 interactions and implicate antigen-presenting cell-produced C5a and C3a as molecular bridges linking CD4 help to CD8(+) T cells. PMID- 21704013 TI - Cloning, expression, and enzymatic activity of Acinetobacter baumannii and Klebsiella pneumoniae acetyl-coenzyme A carboxylases. AB - Pathogenic Gram-negative bacteria are a major public health concern because they are causative agents of life-threatening hospital-acquired infections. Due to the increasing rates of resistance to available antibiotics, there is an urgent need to develop new drugs. Acetyl-coenzyme A carboxylase (ACCase) is a promising target for the development of novel antibiotics. We describe here the expression, purification, and enzymatic activity of recombinant ACCases from two clinically relevant Gram-negative pathogens, Acinetobacter baumannii and Klebsiella pneumoniae. Recombinant ACCase subunits (AccAD, AccB, and AccC) were expressed and purified, and the holoenzymes were reconstituted. ACCase enzyme activity was monitored by direct detection of malonyl-coenzyme A (malonyl-CoA) formation by liquid chromatography tandem mass spectrometry (LC-MS/MS). Steady-state kinetics experiments showed similar k(cat) and K(M) values for both enzymes. In addition, similar IC(50) values were observed for inhibition of both enzymes by a previously reported ACCase inhibitor. To provide a higher throughput assay suitable for inhibitor screening, we developed and validated a luminescence-based ACCase assay that monitors ATP depletion. Finally, we established an enzyme activity assay for the isolated AccAD (carboxyltransferase) subunit, which is useful for determining whether novel ACCase inhibitors inhibit the biotin carboxylase or carboxyltransferase site of ACCase. The methods described here could be applied toward the identification and characterization of novel inhibitors. PMID- 21704014 TI - Sulfo-N-hydroxysuccinimide interferes with bicinchoninic acid protein assay. AB - This study revealed a major interference from sulfo-N-hydroxysuccinimide (sulfo NHS) in the bicinchoninic acid (BCA) protein assay. Sulfo-NHS, a common reagent used in bioconjugation and analytical biochemistry, exhibited absorbance signals and absorbance peaks at 562 nm, comparable to bovine serum albumin (BSA). However, the combined absorbance of sulfo-NHS and BSA was not strictly additive. The sulfo-NHS interference was suggested to be caused by the reduction of Cu(2+) in the BCA Kit's reagent B (4% cupric sulfate) in a manner similar to that of the protein. PMID- 21704015 TI - Quantitative liquid chromatography coupled with tandem mass spectrometry analysis of urinary acylglycines: application to the diagnosis of inborn errors of metabolism. AB - The analysis of urinary acylglycines is an important biochemical tool for the diagnosis of many organic acidemias and mitochondrial fatty acid beta-oxidation defects. A new rapid analytical method has been developed for quantification of acylglycines in urine by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The method requires a simple sample preparation avoiding derivatization. It has high sensitivity, specificity, and throughput capability, and it requires minimal instrument maintenance. The use of chromatographic separation allows us to identify and quantify isomeric compounds that cannot be solved by appropriate multiple reaction monitoring (MRM) transitions. Urinary concentrations of the different acylglycines were determined using deuterated internal standards. The reference interval for the various metabolites was established using 120 healthy controls. The diagnostic usefulness of the method was demonstrated in three patients with propionic acidemia (PA), one patient with isovaleric acidemia (IVA), two patients with beta ketothiolase deficiency (BKTD), one patient with short branched chain amino acid deficiency (SBCAD), four patients with medium chain acyl-coenzyme A dehydrogenase deficiency (MCADD), one patient with isobutyryl-coenzyme A dehydrogenase deficiency (IBDHD), and one patient with multiple acyl-coenzyme A dehydrogenase deficiency (MADD). PMID- 21704016 TI - Fluorescent substrate analog for monitoring chain elongation by undecaprenyl pyrophosphate synthase in real time. AB - Farnesyl pyrophosphate (FPP) is a common substrate for a variety of prenyltransferases for synthesizing isoprenoid compounds. In this study, (2E,6E) 8-O-(N-methyl-2-aminobenzoyl)-3,7-dimethyl-2,6-octandien-1-pyrophosphate (MANT-O GPP), a fluorescent analog of FPP, was synthesized and demonstrated as a satisfactory substrate for Escherichia coli undecaprenyl pyrophosphate synthase (UPPS) with a K(m) of 1.5 MUM and a k(cat) of 1.2s(-1) based on [(14)C]IPP consumption. Interesting, we found that its emission fluorescence intensity at 420 nm increased remarkably during chain elongation, thereby useful for real-time monitoring kinetics of UPPS to yield a K(m) of 1.1 MUM and a k(cat) of 1.0 s(-1), consistent with those measured using radiolabeled substrate. Using this assay, the IC(50) of a known UPPS inhibitor farnesyl thiopyrophosphate (FsPP) was confirmed. Our studies provide a convenient and environmentally friendly alternative for kinetics and inhibition studies on UPPS drug target. PMID- 21704017 TI - Catalytic mechanism and cofactor preference of dihydrodipicolinate reductase from methicillin-resistant Staphylococcus aureus. AB - Given the rapid rise in antibiotic resistance, including methicillin resistance in Staphylococcus aureus (MRSA), there is an urgent need to characterize novel drug targets. Enzymes of the lysine biosynthesis pathway in bacteria are examples of such targets, including dihydrodipicolinate reductase (DHDPR, E.C. 1.3.1.26), which is the product of an essential bacterial gene. DHDPR catalyzes the NAD(P)H dependent reduction of dihydrodipicolinate (DHDP) to tetrahydrodipicolinate (THDP) in the lysine biosynthesis pathway. We show that MRSA-DHDPR exhibits a unique nucleotide specificity utilizing NADPH (K(m)=12MUM) as a cofactor more effectively than NADH (K(m)=26MUM). However, the enzyme is inhibited by high concentrations of DHDP when using NADPH as a cofactor, but not with NADH. Isothermal titration calorimetry (ITC) studies reveal that MRSA-DHDPR has ~20 fold greater binding affinity for NADPH (K(d)=1.5MUM) relative to NADH (K(d)=29MUM). Kinetic investigations in tandem with ITC studies show that the enzyme follows a compulsory-order ternary complex mechanism; with inhibition by DHDP through the formation of a nonproductive ternary complex with NADP(+). This work describes, for the first time, the catalytic mechanism and cofactor preference of MRSA-DHDPR, and provides insight into rational approaches to inhibiting this valid antimicrobial target. PMID- 21704018 TI - Evolution and functional properties of photosystem II light harvesting complexes in eukaryotes. AB - Photoautotrophic organisms, the major agent of inorganic carbon fixation into biomass, convert light energy into chemical energy. The first step of photosynthesis consists of the absorption of solar energy by pigments binding protein complexes named photosystems. Within photosystems, a family of proteins called Light Harvesting Complexes (LHC), responsible for light harvesting and energy transfer to reaction centers, has evolved along with eukaryotic organisms. Besides light absorption, these proteins catalyze photoprotective reactions which allowed functioning of oxygenic photosynthetic machinery in the increasingly oxidant environment. In this work we review current knowledge of LHC proteins serving Photosystem II. Balance between light harvesting and photoprotection is critical in Photosystem II, due to the lower quantum efficiency as compared to Photosystem I. In particular, we focus on the role of each antenna complex in light harvesting, energy transfer, scavenging of reactive oxygen species, chlorophyll triplet quenching and thermal dissipation of excess energy. This article is part of a Special Issue entitled: Photosystem II. PMID- 21704019 TI - Solution structure of a defense peptide from wheat with a 10-cysteine motif. AB - Hevein, a well-studied lectin from the rubber tree Hevea brasiliensis, is the title representative of a broad family of chitin-binding polypeptides. WAMP-1a, a peptide isolated from the wheat Triticum kiharae, shares considerable similarity with hevein. The peptide possesses antifungal, antibacterial activity and is thought to play an important role in the defense system of wheat. Importantly, it features a substitution of the conserved serine residue to glycine reducing its carbohydrate-binding capacity. We used NMR spectroscopy to derive the spatial structure of WAMP-1a in aqueous solution. Notably, the mutation was found to strengthen amphiphilicity of the molecule, associated with its mode of action, an indication of the hevein domain multi-functionality. Both primary and tertiary structure of WAMP-1a suggest its evolutionary origin from the hevein domain of plant chitinases. PMID- 21704020 TI - Identification of the novel bioactive peptides dRYamide-1 and dRYamide-2, ligands for a neuropeptide Y-like receptor in Drosophila. AB - A number of bioactive peptides are involved in regulating a wide range of animal behaviors, including food consumption. Vertebrate neuropeptide Y (NPY) is a potent stimulator of appetitive behavior. Recently, Drosophila neuropeptide F (dNPF) and short NPF (sNPF), the Drosophila homologs of the vertebrate NPY, were identified to characterize the functions of NPFs in the feeding behaviors of this insect. Dm-NPFR1 and NPFR76F are the receptors for dNPF and sNPF, respectively; both receptors are G protein-coupled receptors (GPCRs). Another GPCR (CG5811; NepYR) was indentified in Drosophila as a neuropeptide Y-like receptor. Here, we identified 2 ligands of CG5811, dRYamide-1 and dRYamide-2. Both peptides are derived from the same precursor (CG40733) and have no significant structural similarities to known bioactive peptides. The C-terminal sequence RYamide of dRYamides is identical to that of NPY family peptides; on the other hand, dNPF and sNPF have C-terminal RFamide. When administered to blowflies, dRYamide-1 suppressed feeding motivation. We propose that dRYamides are related to the NPY family in vertebrates, similar to dNPF and sNPF. PMID- 21704021 TI - Integrated cellular pathology--systems biology of human diseases. PMID- 21704023 TI - Autophagy as a mediator of chemotherapy-induced cell death in cancer. AB - Since the 1940s, chemotherapy has been the treatment of choice for metastatic disease. Chemotherapeutic agents target proliferating cells, inducing cell death. For most of the history of chemotherapy, apoptosis was thought to be the only mechanism of drug-induced cell death. More recently, a second type of cell death pathway has emerged: autophagy, also called type II programmed cell death. Autophagy is a tightly regulated process by which selected components of a cell are degraded. It primarily functions as a cell survival adaptive mechanism during stress conditions. However, persistent stress can also promote extensive autophagy, leading to cell death, hence its name. Alterations in the autophagy pathway have been described in cancer cells that suggest a tumor-suppressive function in early tumorigenesis, but a tumor-promoting function in established tumors. Moreover, accumulating data indicate a role for autophagy in chemotherapy induced cancer cell death. Here, we discuss some of the evidence showing autophagy-dependent cell death induced by anti-neoplastic agents in different cancer models. On the other hand, in some other examples, autophagy dampens treatment efficacy, hence providing a therapeutic target to enhance cancer cell killing. In this paper, we propose a putative mechanism that could reconcile these two opposite observations. PMID- 21704024 TI - Metabolism, function and mass spectrometric analysis of bis(monoacylglycero)phosphate and cardiolipin. AB - Polyglycerophospholipids (PGPLs) such as bismonoacylglycerophosphate (BMP) and cardiolipin are important membrane phospholipid species for the maintenance of membrane integrity. While BMP serves as membrane curvature regulator in multivesicular bodies for efficient lysosomal enzyme function, cardiolipin stabilizes the electron transfer complex in the inner mitochondrial membrane, which is crucial for physiological ATP production. Beside their membrane modulatory functions PGPLs play an important role in various signaling events. Although a number of disease associations were found for PGPL species, detailed information about their molecular role still remains unknown. This article reviews the known biological functions of PGPLs and the existing mass spectrometric methods. We discuss the different analytical strategies and how ESI MS/MS can expand our understanding of PGPL homeostasis. PMID- 21704022 TI - Recent advances in gene manipulation and nicotinic acetylcholine receptor biology. AB - Pharmacological and immunological methods have been valuable for both identifying some native nicotinic acetylcholine receptor (nAChR) subtypes that exist in vivo and determining the neurobiological and behavioral role of certain nAChR subtypes. However, these approaches suffer from shortage of subtype specific ligands and reliable immunological reagents. Consequently, genetic approaches have been developed to complement earlier approaches to identify native nAChR subtypes and to assess the contribution of nAChRs to brain function and behavior. In this review we describe how assembly partners, knock-in mice and targeted lentiviral re-expression of genes have been utilized to improve our understanding of nAChR neurobiology. In addition, we summarize emerging genetic tools in nAChR research. PMID- 21704025 TI - Hypertension associated polymorphisms in WNK1/WNK4 are not associated with hydrochlorothiazide response. AB - OBJECTIVES: Our purpose was to investigate whether with-no-K[Lys] kinase (WNK) 1 and WNK4 genetic polymorphisms are associated with both hypertension and diuretics response. DESIGN AND METHODS: Two WNK1 and one WNK4 polymorphisms were detected in two independent populations (n = 1592 and 602) for association with hypertension, and in two clinical trials of hydrochlorothiazide treatment (n = 542 and 274) for association with diuretics response. RESULTS: Two polymorphisms were found to be associated with hypertension risk with odds ratio of 1.55 for WNK1 rs1468326 (P<0.001) and 1.88 for WNK4 rs9916754 (P<0.001) in the first population, and 1.54 for WKN1 rs1468326, and 1.82 for WNK4 rs9916754 in the second population. However, two clinical trials found no relationship between these WNK polymorphisms and systolic/diastolic blood pressure responses to 4 or 8 weeks treatment of hydrochlorothiazide. CONCLUSION: Our findings suggest that hypertension associated polymorphisms in WNK1 and WNK4 may not be predictors for antihypertensive response to diuretics. PMID- 21704026 TI - Vascular endothelial function assessed by a noninvasive ultrasound method and serum asymmetric dimethylarginine concentrations in mild-to-moderate plaque-type psoriatic patients. AB - OBJECTIVES: Our aim was to evaluate vascular endothelial function assessed by serum asymmetric dimethylarginine (ADMA) concentrations and noninvasive ultrasonographic parameters such as flow-mediated dilatation (FMD) and nitroglycerin-induced dilatation (NID) in mild-to-moderate plaque-type psoriatic patients, as rated by the Psoriasis Area and Severity Index. DESIGN AND METHODS: Plaque-type psoriatic patients (n = 29) diagnosed with clinical and/or histopathological findings and control subjects (n = 25) without skin and systemic metabolic diseases were included in the study. RESULTS: There was no statistically significant difference between patients and control subjects in respect to FMD (p = 0.441), NID (p = 0.557), or serum ADMA concentrations (p = 0.225). Also, among the acute-phase reactants, serum C-reactive protein and plasma fibrinogen levels were moderately higher in patients when compared to control subjects (p = 0.008 and p = 0.011, respectively). CONCLUSIONS: Mild-to moderate plaque-type psoriatic patients with low-to-medium grade systemic inflammation did not have evidence of vascular endothelial function. PMID- 21704028 TI - Genistein modulates NF-kappaB-associated renal inflammation, fibrosis and podocyte abnormalities in fructose-fed rats. AB - The study determines the effect of genistein on inflammatory status and expression of nuclear factor-kappa B (NF-kappaB p65), transforming growth factor beta1 (TGF-beta1) and receptor for advanced glycation end products (RAGE) in kidney of fructose-fed rats. Adult male Wistar rats were fed a diet containing either starch or fructose as the source of carbohydrate. Fifteen days later, after confirming the development of insulin resistance in fructose-fed rats, the rats in each dietary group were divided into two and treated with either genistein (1 mg/kg/day) in 30% dimethylsulfoxide (DMSO) or 30% DMSO alone for the next 45 days. The expression of NF-kappaB P(65), TGF-beta1 and RAGE, histochemical localization of alpha-smooth muscle actin (alpha-SMA), levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6(IL-6) and ultrastructural analysis were performed at the end of the experimental period. Fructose-fed rats displayed inflammatory changes in kidney. Increased expression of TGF-beta1 and RAGE in cytosol and NF-kappaB p65 in nuclear fraction were observed. alpha-SMA expression was higher in fructose-fed rat kidney. Proliferation of connective tissue was evident from increased collagen deposition in perivascular and intraglomerular regions. Administration of genistein to fructose-fed rats reduced inflammation, fibrogenesis and NF-kappaB activation. Genistein also mitigated the structural changes such as basement membrane thickening, reduction in podocyte number and loss of glomerular filtration barrier integrity. These findings suggest that genistein prevents inflammation, fibrosis and early nephropathic changes in fructose-fed insulin resistant rats secondary to the attenuation of NF-kappaB activation. PMID- 21704027 TI - Wnt2 signaling is necessary and sufficient to activate the airway smooth muscle program in the lung by regulating myocardin/Mrtf-B and Fgf10 expression. AB - Smooth muscle in the lung is thought to derive from the developing lung mesenchyme. Smooth muscle formation relies upon coordination of both autocrine and paracrine signaling between the budding epithelium and adjacent mesenchyme to govern its proliferation and differentiation. However, the pathways initiating the earliest aspects of smooth muscle specification and differentiation in the lung are poorly understood. Here, we identify the Wnt2 ligand as a critical regulator of the earliest aspects of lung airway smooth muscle development. Using Wnt2 loss and gain of function models, we show that Wnt2 signaling is necessary and sufficient for activation of a transcriptional and signaling network critical for smooth muscle specification and differentiation including myocardin/Mrtf-B and the signaling factor Fgf10. These studies place Wnt2 high in a hierarchy of signaling molecules that promote the earliest aspects of lung airway smooth muscle development. PMID- 21704029 TI - Inhibition of angiogenesis involves in anticancer activity of riccardin D, a macrocyclic bisbibenzyl, in human lung carcinoma. AB - Riccardin D is a novel macrocyclic bisbibenzyl compound extracted from Chinese liverwort plant Dumortiera hirsuta. Our previous studies showed that riccardin D is a DNA topo II inhibitor and has therapeutic potential for treatment of cancers. In this combined in vitro and in vivo study, we examined the inhibitory effects of riccardin D on tumor angiogenesis and the subsequent effect of anticancer activity was evaluated. Incubation with riccardin D weakly inhibited the proliferation of human umbilical vascular endothelial cells (HUVEC) as estimated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The scratch wound experiment showed that riccardin D effectively decreased the motility and migration of HUVEC cells. Riccardin D inhibited the formation of capillary tube as demonstrated by decrease of branch points formed by HUVEC cells on 3-D Matrigel. We examined the levels of angiogenic factors including vascular endothelial growth factor (VEGF), VEGF receptor 2, epidermal growth factor receptor (EGF receptor), and matrix metalloproteinase (MMPs) in HUVEC cells. The expressions of VEGF, phospho-VEGF receptor 2, EGF receptor and MMP-2 were significantly reduced by riccardin D as estimated by Western blot assay and real-time quantitative PCR analysis. The decrease of VEGF was also detected in riccardin D-treated human lung cancer H460 cells. The anticancer activity of riccardin D was then evaluated in a mouse model in which riccardin D delayed the growth of H460 xenografts without obvious toxicity to animals after three weeks injection. To evaluate the role of antiangiogenesis of riccardin D in mice, CD34 immunohistochemical staining was employed to analyze the mean vascular density in H460 xenograft tissues. The number of blood vessels was significantly decreased after riccardin D treatment. These results suggest that riccardin D display the inhibitory effect on growth of human lung carcinoma cells and that the inhibition of angiogenesis may involve in anticancer activity of riccardin D. PMID- 21704030 TI - Bone morphogenetic protein -4 and -5 in pancreatic cancer--novel bidirectional players. AB - Bone morphogenetic proteins (BMPs) are multifunctional signaling molecules that have gained increasing interest in cancer research. To obtain a systematic view on BMP signaling in pancreatic cancer we first determined the mRNA expression levels of seven BMP ligands (BMP2-BMP8) and six BMP specific receptors in pancreatic cancer cell lines and normal pancreatic tissue. BMP receptor expression was seen in all cancer and normal samples. Low expression levels of BMP5 and BMP8 were detected in cancer cells compared to the normal samples, whereas BMP4 expression was elevated in 25% of the cases. The impact of BMP4 and BMP5 signaling on cell phenotype was then evaluated in five pancreatic cancer cell lines. Both ligands suppressed the growth of three cell lines (up to 79% decrease in BMP4-treated PANC-1 cells), mainly due to cell cycle changes. BMP4 and BMP5 concurrently increased cell migration and invasion (maximally a 10.8 fold increase in invaded BMP4-treated PANC-1 cells). The phenotypic changes were typically associated with the activation of the canonical SMAD pathway, although such activation was not observed in the PANC-1 cells. Taken together, BMP4 and BMP5 simultaneously inhibit the growth and promote migration and invasion of the same pancreatic cells and thus exhibit a biphasic role with both detrimental and beneficial functions in pancreatic cancer progression. PMID- 21704031 TI - Ubiquitin-family modifications in the replication of DNA damage. AB - The cell uses specialised Y-family DNA polymerases or damage avoidance mechanisms to replicate past damaged sites in DNA. These processes are under complex regulatory systems, which employ different types of post-translational modification. All the Y-family polymerases have ubiquitin binding domains that bind to mono-ubiquitinated PCNA to effect the switching from replicative to Y family polymerase. Ubiquitination and de-ubiquitination of PCNA are tightly regulated. There is also evidence for another as yet unidentified ubiquitinated protein being involved in recruitment of Y-family polymerases to chromatin. Poly ubiquitination of PCNA stimulates damage avoidance, and, at least in yeast, PCNA is SUMOylated to prevent unwanted recombination events at the replication fork. The Y-family polymerases themselves can be ubiquitinated and, in the case of DNA polymerase eta, this results in the polymerase being excluded from chromatin. PMID- 21704032 TI - Silencing activity of 2'-O-methyl modified anti-MDR1 siRNAs with mismatches in the central part of the duplexes. AB - The thermodynamic properties of siRNA duplexes are important for their silencing activity. siRNAs with high thermodynamic stability of both the central part of the duplex and in the whole, usually display low silencing activity. Destabilization of the central part of the siRNA duplex could increase its silencing activity. However, mismatches located in the central part of the duplex could substantially decrease the amount of RNAi efficacy, hindering active RISC formation and function. In this study, we examined the impact of duplex destabilization by nucleotide substitutions in the central part (7-10 nt counting from the 5'-end of the antisense strand) of the nuclease-resistant siRNA on its silencing activity. PMID- 21704033 TI - The small GTPase Rac1 is involved in the maintenance of stemness and malignancies in glioma stem-like cells. AB - A subpopulation of cancer cells with stem cell properties is responsible for tumor formation, maintenance, and malignant progression; however, the molecular mechanisms underlying the maintenance of cancer stem-like cell properties have remained unclear. Here, we show that the Rho family GTPase Rac1 is involved in the glioma stem-like cell (GSLC) maintenance and tumorigenicity in human glioma. The Rac1-Pak signaling was markedly activated in GSLCs. Knockdown of Rac1 caused reduction of expression of GSLC markers, self-renewal-related proteins and neurosphere formation. Moreover, down-regulation of Rac1 suppressed the migration, invasion, and malignant transformation in GSLCs. Furthermore, inhibition of Rac1 enhanced radiation sensitivity of GSLCs. These results indicate that the small GTPase Rac1 is involved in the maintenance of stemness and malignancies in GSLCs. PMID- 21704034 TI - Iron in evolution. AB - Iron chemistry in the environment and in organisms is entwined. The iron surface minerals in solution for the first billion years of the planet were ferrous compounds. This ion became and has remained a major participant in organisms. The evolution of iron was due to its oxidation to insoluble ferric ions by oxygen released from organisms. The evolution of cellular iron chemistry then required uptake from this oxidised state. Use was expanded from the mainly electron transfer properties in the original reductive cell interior to employment in external oxidative chemistry. The environment/organisms evolution is that of one predictable chemical system. PMID- 21704035 TI - Citrullination of autoantigens: upstream of TNFalpha in the pathogenesis of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by synovial inflammation and destruction of joints. Over 20 years ago, tumour necrosis factor alpha (TNFalpha) was identified as a key player in a cytokine network, whose multifunctional effects could account for both the inflammation and destruction in RA. The remarkable efficacy of TNF inhibitors in the treatment of RA has resulted in extensive research addressing the regulation of TNFalpha production responsible for this excessive production. The discovery of autoimmunity to citrullinated protein/peptide antigens (ACPA) has led the concept that ACPA may be the essential link between disease susceptibility factors and the production of TNFalpha, which ultimately accounts for the disease phenotype. In this review we will consider (1) the mechanisms of citrullination, both physiological and pathological, (2) how known genetic and environmental factors could drive this peculiar form of autoimmunity and (3) how the immune response could lead to excessive production of TNFalpha by the synovial cells and ultimately to the disease phenotype (Fig. 1). PMID- 21704036 TI - Environmental risk factors for inflammatory bowel disease: microbes, diet, and the appendix. PMID- 21704038 TI - Primary conservative therapy in infected pancreatic necrosis: a viable treatment option? PMID- 21704039 TI - Cytosponge for Barrett's esophagus screening: when smart science matches simplicity. PMID- 21704041 TI - The role of virus reactivation in idiosyncratic reactions to drugs. PMID- 21704044 TI - The structure of a monomeric mutant Cks protein reveals multiple functions for a conserved hinge-region proline. AB - Cks (cyclin-dependent kinase subunit) proteins are essential eukaryotic cell cycle regulatory proteins that physically associate with cyclin-dependent kinases (Cdks) to modulate their activity. Cks proteins have also been studied for their ability to form domain-swapped dimers by exchanging beta-strands. Domain swapping is mediated by a conserved beta-hinge region containing two proline residues. Previous structural studies indicate that Cks in its dimer form is unable to bind Cdk, suggesting that the monomer-dimer equilibrium of Cks may have an effect on Cks-mediated Cdk regulation. We present the crystal structure of a proline-to alanine mutant Saccharomyces cerevisiae Cks protein (Cks1 P93A) that preferentially adopts the monomer conformation but surprisingly fails to bind Cdk. Comparison of the Cks1 P93A structure to that of other Cks proteins reveals that Pro93 is critical for stabilizing a multiple beta-turn structure in the hinge region that properly positions an essential Cdk-binding residue. Additionally, we find that these beta-turn formations, conserved in Cks homologs, have implications for the mechanism and preferentiality of strand exchange. Together, our observations suggest that the conservation of Cks hinge-region prolines reflects their functions in forming a Cdk binding interface and that the ability of these prolines to control partitioning between monomer and dimer is a consequence of the beta-turn networks within the hinge. PMID- 21704043 TI - Compartmentation of membrane processes and nucleotide dynamics in diffusion restricted cardiac cell microenvironment. AB - Orchestrated excitation-contraction coupling in heart muscle requires adequate spatial arrangement of systems responsible for ion movement and metabolite turnover. Co-localization of regulatory and transporting proteins into macromolecular complexes within an environment of microanatomical cell components raises intracellular diffusion barriers that hamper the mobility of metabolites and signaling molecules. Compared to substrate diffusion in the cytosol, diffusional restrictions underneath the sarcolemma are much larger and could impede ion and nucleotide movement by a factor of 10(3)-10(5). Diffusion barriers thus seclude metabolites within the submembrane space enabling rapid and vectorial effector targeting, yet hinder energy supply from the bulk cytosolic space implicating the necessity for a shunting transfer mechanism. Here, we address principles of membrane protein compartmentation, phosphotransfer enzyme facilitated interdomain energy transfer, and nucleotide signal dynamics at the subsarcolemma-cytosol interface. This article is part of a Special Issue entitled "Local Signaling in Myocytes". PMID- 21704045 TI - NanoRNAs: a class of small RNAs that can prime transcription initiation in bacteria. AB - It has been widely assumed that all transcription in cells occur using NTPs only (i.e., de novo). However, it has been known for several decades that both prokaryotic and eukaryotic RNA polymerases can utilize small (2 to ~5 nt) RNAs to prime transcription initiation in vitro, raising the possibility that small RNAs might also prime transcription initiation in vivo. A new study by Goldman et al. has now provided the first evidence that priming with so-called "nanoRNAs" (i.e., 2 to ~5 nt RNAs) can, in fact, occur in vivo. Furthermore, this study provides evidence that altering the extent of nanoRNA-mediated priming of transcription initiation can profoundly influence global gene expression. In this perspective, we summarize the findings of Goldman et al. and discuss the prospect that nanoRNA mediated priming of transcription initiation represents an underappreciated aspect of gene expression in vivo. PMID- 21704046 TI - Mutagenicity of secondary oxidation products of 8-oxo-7,8-dihydro-2' deoxyguanosine 5'-triphosphate (8-hydroxy-2'- deoxyguanosine 5'-triphosphate). AB - 8-Oxo-7,8-dihydroguanine (8-hydroxyguanine) is oxidized more easily than normal nucleobases, which can produce spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh). These secondary oxidation products of 8-oxo-7,8-dihydroguanine are highly mutagenic when formed within DNA. To evaluate the mutagenicity of the corresponding oxidation products of 8-oxo-7,8-dihydro-2'-deoxyguanosine 5' triphosphate (8-hydroxy-2'- deoxyguanosine 5'-triphosphate) in the nucleotide pool, Escherichia coli cells deficient in the mutT gene were treated with H(2)O(2), and the induced mutations were analyzed. Moreover, the 2'-deoxyriboside 5'-triphosphate derivatives of Sp and Gh were also introduced into competent E. coli cells. The H(2)O(2) treatment of mutT E. coli cells resulted in increase of G:C -> T:A and A:T -> T:A mutations. However, the incorporation of exogenous Sp and Gh 2'-deoxyribonucleotides did not significantly increase the mutation frequency. These results suggested that the oxidation product(s) of 8-oxo-7,8 dihydro-2'-deoxyguanosine 5'-triphosphate induces G:C -> T:A and A:T -> T:A mutations, and that the 2'-deoxyriboside 5'-triphosphate derivatives of Sp and Gh exhibit quite weak mutagenicity, in contrast to the bases in DNA. PMID- 21704047 TI - Involvement of mismatch repair proteins in adaptive responses induced by N-methyl N'-nitro-N-nitrosoguanidine against gamma-induced genotoxicity in human cells. AB - As humans are exposed to a variety of chemical agents as well as radiation, health effects of radiation should be evaluated in combination with chemicals. To explore combined genotoxic effects of radiation and chemicals, we examined modulating effects of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a direct acting methylating agent, against genotoxicity of gamma-radiation. Human lymphoblastoid TK6 cells and its mismatch-deficient derivative, i.e., MT1 cells, were treated with MNNG for 24h before they were exposed to gamma-irradiation at a dose of 1.0 Gy, and the resulting genotoxicity was examined. In TK6 cells, the pretreatments with MNNG at low doses suppressed frequencies of the thymidine kinase (TK) gene mutation and micronucleus (MN) formation induced by gamma irradiation and thus the dose responses of TK and MN assays were U-shaped along with the pretreatment doses of MNNG. In contrast, the genotoxic effects of MNNG and gamma-irradiation were additive in MT1 cells and the frequencies of TK mutations and MN induction increased along with the doses of MNNG. Apoptosis induced by gamma-radiation was suppressed by the pretreatments in TK6 cells, but not in MT1 cells. The expression of p53 was induced and cell cycle was delayed at G2/M phase in TK6, but not in MT1 cells, by the treatments with MNNG. These results suggest that pretreatments of MNNG at low doses suppress genotoxicity of gamma-radiation in human cells and also that mismatch repair proteins are involved in the apparent adaptive responses. PMID- 21704048 TI - Group II metabotropic glutamate receptor agonists and positive allosteric modulators as novel treatments for schizophrenia. AB - Schizophrenia is a devastating chronic psychotic disorder characterized by positive, negative, and cognitive symptoms. Although the positive symptoms are relatively well controlled by current monoamine-based treatments for schizophrenia, these agents provide only modest efficacy against the negative and cognitive symptoms of the disease. Furthermore serious adverse events have been reported during treatment with antipsychotic drugs. Therefore, novel treatment strategies are needed that provide improved efficacy across the multiple symptom domains of schizophrenia and have improved tolerability/safety profiles. Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays an important role in physiological and pathological processes of the CNS. Group II metabotropic glutamate receptors (mGlu receptors), in particular, have been shown to modulate glutamatergic activity in brain synapses thought to be involved in the pathophysiology of schizophrenia. In recent years a number of selective mGlu2/3 receptor agonists and mGlu2 positive allosteric modulators have been disclosed with demonstrated efficacy in multiple animal models for schizophrenia. Consistent with predictions from pre-clinical animal studies, LY2140023 monohydrate, an mGlu2/3 receptor agonist prodrug, recently demonstrated evidence for antipsychotic activity in phase II proof of concept study. Although additional efficacy and safety studies are needed to understand the therapeutic potential of LY2140023, emerging preclinical and clinical data suggest that activation of group II mGlu receptors is a mechanistically novel and promising approach for the treatment of schizophrenia. PMID- 21704049 TI - Effects of memantine and donepezil on cortical and hippocampal acetylcholine levels and object recognition memory in rats. AB - This preclinical study investigated the ability of memantine (MEM) to stimulate brain acetylcholine (ACh) release, potentially acting synergistically with donepezil (DON, an acetylcholinesterase inhibitor). Acute systemic administration of either MEM or DON to anesthetized rats caused dose-dependent increases of ACh levels in neocortex and hippocampus, and the combination of MEM (5 mg/kg) and DON (0.5 mg/kg) produced significantly greater increases than either drug alone. To determine whether ACh release correlated with cognitive improvement, rats with partial fimbria-fornix (FF) lesions were treated with acute or chronic MEM or DON. Acute MEM treatment significantly elevated baseline hippocampal ACh release but did not significantly improve task performance on a delayed non-match-to sample (DNMS) task, whereas chronic MEM treatment significantly improved DNMS performance but only marginally elevated baseline ACh levels. Acute or chronic treatment with DON (in the presence of neostigmine to allow ACh collection) did not significantly improve DNMS performance or alter ACh release. In order to investigate the effect of adding MEM to ongoing DON therapy, lesioned rats pretreated with DON for 3 weeks were given a single intraperitoneal dose of MEM. MEM significantly elevated baseline hippocampal ACh levels, but did not significantly improve DNMS task scores compared to chronic DON-treated animals. These data indicate that MEM, in addition to acting as an NMDA receptor antagonist, can also augment ACh release; however, in this preclinical model, increased ACh levels did not directly correlate with improved cognitive performance. PMID- 21704050 TI - Intact memory for implicit contextual information in Korsakoff's amnesia. AB - Implicit contextual learning is the ability to acquire contextual information from our surroundings without conscious awareness. Such contextual information facilitates the localization of objects in space. In a typical implicit contextual learning paradigm, subjects need to find a target among a number of distractors during visual search. Some of the configurations of stimuli are repeated during the experiment resulting in faster responses than for novel configurations, without subjects being aware of their repetition. Patients with Korsakoff's syndrome (KS) have been found to show devastating explicit spatial amnesia. Less is know about their implicit spatial memory abilities. The aim of the present research was to examine whether implicit contextual learning is intact in KS. Therefore, eighteen KS patients and twenty-two age-IQ- and education-matched controls performed the Implicit Contextual Learning task and a paradigm intended to assess explicit, spatial working memory, i.e. the Box task. Intact implicit contextual learning was observed in both the control group and the KS patients. In turn KS patients did have markedly lower explicit spatial working memory scores. The implicit learning effect was not related to the spatial working memory scores. Together these results clearly suggest that implicit and explicit spatial memory have a different neurocognitive basis. PMID- 21704051 TI - Coexistence of individual and social learners during range expansion. AB - Individual learning and social learning are two primary abilities supporting cultural evolution. Conditions for their evolution have mostly been studied by investigating gene frequency dynamics, which essentially implies constant population size. Predictions from such "static" models may only be of partial relevance to the evolution of advanced individual learning in modern humans, because modern humans have experienced rapid population growth and range expansion during "out-of-Africa." Here we model the spatial population dynamics of individual and social learners by a reaction-diffusion system. One feature of our model is the inclusion of the possibility that social learners may fail to find an exemplar to copy in regions where the population density is low. Due to this attenuation effect, the invasion speed of social learners is diminished, and various kinds of invasion dynamics are observed. Our primary findings are: (1) individual learners can persist indefinitely when invading environmentally homogeneous infinite space; (2) the occurrence of individual learners at the front may inhibit the spread of social learners. These results suggest that "out of-Africa" may have driven the evolution of advanced individual learning ability in modern humans. PMID- 21704052 TI - Effects of sub-lethal neurite outgrowth inhibitory concentrations of chlorpyrifos oxon on cytoskeletal proteins and acetylcholinesterase in differentiating N2a cells. AB - Previous work in our laboratory has shown that sub-lethal concentrations (1-10 MUM) of chlorpyrifos (CPF), diazinon (DZ) and diazinon oxon (DZO) inhibit the outgrowth of axon-like neurites in differentiating mouse N2a neuroblastoma cells concomitant with altered levels and/or phosphorylation state of axonal cytoskeleton and growth-associated proteins. The aim of the present work was to determine whether chlorpyrifos oxon (CPO) was capable of inhibiting N2a cell differentiation in a similar manner. Using experimental conditions similar to our previous work, sub-lethal concentrations (1-10 MUM) of CPO were found to inhibit N2a cell differentiation. However, unlike previous studies with DZ and DZO, there was a high level of sustained inhibition of acetylcholinesterase (AChE) in CPO treated cells. Impairment of neurite outgrowth was also associated with reduced levels of growth associated protein-43 and neurofilament heavy chain (NFH), and the distribution of NFH in cells stained by indirect immunofluorescence was disrupted. However, in contrast to previous findings for DZO, the absolute level of phosphorylated NFH was unaffected by CPO exposure. Taken together, the findings suggest that sub-lethal concentrations of CPO inhibit axon outgrowth in differentiating N2a cells and that this effect involves reduced levels of two proteins that play key roles in axon outgrowth and maintenance. Although the inhibition of neurite outgrowth is unlikely to involve AChE inhibition directly, further work will help to determine whether the persistent inhibition of AChE by CPO can account for the different effects induced by CPO and DZO on the levels of total and phosphorylated NFH. PMID- 21704053 TI - Genotoxicity in Oreochromis niloticus (Cichlidae) induced by Microcystis spp bloom extract containing microcystins. AB - Studies of genotoxicity in fish caused by cyanobacterial extracts containing microcystins (MCs) can be useful in determining their carcinogenic risk due to a genotoxic mechanism. An extract of cyanobacterial Microcystis ssp, containing MC LR and -LA from a bloom collected in a eutrophic lake, showed genotoxicity to Oreochromis niloticus. DNA damage (comet assay) was significantly induced in peripheral erythrocytes with both tested concentrations of 6.90 MUg kg(-1) bw and 13.80 MUg kg(-1) bw through intraperitoneal injection (ip). There was no micronucleus induction after ip injection at concentrations of 6.90 MUg kg(-1) bw and 13.80 MUg kg(-1) bw. Body exposure resulted in micronucleus induction and DNA damage only at the highest tested concentrations of 103.72 MUg L(-1). Thus, comet assay and ip injection revealed the highest levels of the genotoxicity of MCs. Apoptosis-necrosis test carried out at concentrations of 6.90 MUg kg(-1) bw and 13.80 MUg kg(-1) bw revealed that at low concentrations more apoptosis than necrosis occurred. At higher concentrations more necrosis than apoptosis occurred. PMID- 21704054 TI - Nitrogen starvation of cyanobacteria results in the production of beta-N methylamino-L-alanine. AB - beta-N-Methylamino-L-alanine, an unusual amino acid implicated in neurodegenerative disease, has been detected in cultures of nearly all genera of environmentally ubiquitous cyanobacteria tested. The compound is present within cyanobacterial cells in free and protein-associated forms, with large variations occurring in the concentration of these pools between species as well as within single strains. With a lack of knowledge and supporting data on the regulation of BMAA production and the role of this compound in cyanobacteria, the association between BMAA and cyanobacteria is still subject to debate. In this study we investigated the biosynthesis of BMAA in axenic non-diazotrophic cyanobacterial cultures using the stable isotope 15N. Nitrogen starvation of nutritionally replete cells resulted in an increase in free cellular 15N BMAA suggesting that BMAA may be the result of catabolism to provide nitrogen or that BMAA is synthesised to serve a functional role in the cell in response to nitrogen deprivation. The addition of NO3- and NH4+ to the culture medium following starvation resulted in a decrease of free cellular BMAA without a corresponding increase in the protein-associated fraction. The use of ammonia as a nitrogen source resulted in a more rapid reduction of BMAA when compared to nitrate. This study provides the first data regarding the regulation of intracellular BMAA concentrations in cyanobacteria with results conclusively showing the production of 15N BMAA by an axenic cyanobacterial culture. PMID- 21704056 TI - Global shape processing involves a hierarchy of integration stages. AB - Radial Frequency (RF) patterns can be used to study the processing of familiar shapes, e.g. triangles and squares. Opinion is divided over whether the mechanisms that detect these shapes integrate local orientation and position information directly, or whether local orientations and positions are first combined to represent extended features, such as curves, and that it is local curvatures that the shape mechanism integrates. The latter view incorporates an intermediate processing stage, the former does not. To differentiate between these hypotheses we studied the processing of micro-patch sampled RF patterns as a function of the luminance polarity of successive elements on the contour path. Our first study measures shape after effects involving suprathreshold amplitude RF shapes and shows that alternating the luminance polarity of successive micro patch elements disrupts adaptation of the global shape. Our second study shows that polarity alternations also disrupt sensitivity to threshold-amplitude RF patterns. These results suggest that neighbouring points of the contour shape are integrated into extended features by a polarity selective mechanism, prior to global shape processing, consistent with the view that for both threshold amplitude and suprathreshold amplitude patterns, global processing of RF shapes involves an intermediate stage of processing. PMID- 21704055 TI - Effect of purified Russell's viper venom-factor X activator (RVV-X) on renal hemodynamics, renal functions, and coagulopathy in rats. AB - Acute renal failure (ARF) is the most frequent and a serious complication in victims of Russell's viper snakebites. Russell's viper venom-factor X activator (RVV-X) has been identified as a main procoagulant enzyme involving coagulopathy, which might be responsible for changes in renal hemodynamics and renal functions. Here, we purified RVV-X from crude Russell's viper venom to study renal hemodynamics, renal functions, intravascular clot, and histopathological changes in Sprague-Dawley rats. Changes in renal hemodynamics and renal functions were evaluated by measuring the mean arterial pressure, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), effective renal blood flow (ERBF), renal vascular resistance (RVR), and fractional excretion of electrolytes. After 10 min, rats receiving both crude venom and purified RVV-X decreased GFR, ERPF, and ERBF and increased RVR. These changes correlated to renal lesions. Along with the determination of intravascular clot, rats injected with purified RVV-X increased the average D-dimer level and reached a peak at 10 min, declined temporarily, and then reached another peak at 30 min. The temporal association between clots and renal dysfunction was observed in rats within 10 min after the injection of purified RVV-X. These findings suggested RVV-X as a major cause of renal failure through intravascular clotting in the renal microcirculation. PMID- 21704058 TI - Psychophysical measures of visual acuity in autism spectrum conditions. AB - Previously reported superior visual acuity (VA) in autism spectrum conditions (ASC) may have resulted from methodological settings used (Ashwin, Ashwin, Rhydderch, Howells, & Baron-Cohen, 2009). The current study re-tested whether participants with (N=20) and without (N=20) ASC differ on psychophysical measures of VA. Participants' vision was corrected before acuity measurement, minimising refractive blur. VA was assessed with an ETDRS chart as well as the Freiburg Visual Acuity and Contrast Test (FrACT). FrACT testing was undertaken at 4m (avoiding limitations of pixel-size), using 36 trials (avoiding fatigue). Best corrected VA was significantly better than the initial habitual acuity in both groups, but adults with and without ASC did not differ on ETDRS or FrACT binocular VA. Future research should examine at which level of visual processing sensory differences emerge. PMID- 21704057 TI - Assessment of linear-scale indices for perimetry in terms of progression in early glaucoma. AB - Currently, global indices that summarize the visual field combine sensitivities on a logarithmic (decibel) scale. Recent structure-function models for glaucoma suggest that contrast sensitivity should be converted to a linear scale before averaging across visual field locations, to better relate sensitivity with the number of surviving retinal ganglion cells (RGCs). New indices designed to represent the number of RGCs already lost are described. At least one was found to be a significantly better predictor of subsequent rate of change than traditional Mean Deviation (p=0.014) in participants with glaucomatous optic neuropathy. Issues concerning the creation of optimal global indices are discussed. PMID- 21704059 TI - Enhanced attention amplifies face adaptation. AB - Perceptual adaptation not only produces striking perceptual aftereffects, but also enhances coding efficiency and discrimination by calibrating coding mechanisms to prevailing inputs. Attention to simple stimuli increases adaptation, potentially enhancing its functional benefits. Here we show that attention also increases adaptation to faces. In Experiment 1, face identity aftereffects increased when attention to adapting faces was increased using a change detection task. In Experiment 2, figural (distortion) face aftereffects increased when attention was increased using a snap game (detecting immediate repeats) during adaptation. Both were large effects. Contributions of low-level adaptation were reduced using free viewing (both experiments) and a size change between adapt and test faces (Experiment 2). We suggest that attention may enhance adaptation throughout the entire cortical visual pathway, with functional benefits well beyond the immediate advantages of selective processing of potentially important stimuli. These results highlight the potential to facilitate adaptive updating of face-coding mechanisms by strategic deployment of attentional resources. PMID- 21704060 TI - Effects of environmental context on temporal perception bias in apparent motion. AB - We investigated whether the directional effect on the kappa effect can be attributed to the directional anisotropy of retinotopical space or to the representation of forces provided by environmental contexts (e.g., gravity) in an observed event. We examined whether different contexts with similar directional changes (straight vs. reversed motion) influence the kappa effect in four experiments. The object's motion appeared to depict only forces under the natural laws of physics on a slope (Experiment 1) or on a horizontal plane (Experiment 2) in virtual 3D space. In Experiments 3 and 4, the motion appeared to be subjected to external or self-driving forces additionally influenced by internal forces on a slope (Experiment 3) or a horizontal plane (Experiment 4). The results demonstrated that the directional effect on the kappa effect was observed only in Experiment 1, and not in Experiments 2 and 3, while the kappa effect was preserved. Furthermore, not even the kappa effect was observed in the reversed motion of Experiment 4. The results of the present study suggest that the determining factor of direction in the kappa effect is not a simple anisotropy, but rather the context of observed events. PMID- 21704061 TI - Optokinetic nystagmus is elicited by curvilinear optic flow during high speed curve driving. AB - When analyzing gaze behavior during curve driving, it is commonly accepted that gaze is mostly located in the vicinity of the tangent point, being the point where gaze direction tangents the curve inside edge. This approach neglects the fact that the tangent point is actually motionless only in the limit case when the trajectory precisely follows the curve's geometry. In this study, we measured gaze behavior during curve driving, with the general hypothesis that gaze is not static, when exposed to a global optical flow due to self-motion. In order to study spatio-temporal aspects of gaze during curve driving, we used a driving simulator coupled to a gaze recording system. Ten participants drove seven runs on a track composed of eight curves of various radii (50, 100, 200 and 500m), with each radius appearing in both right and left directions. Results showed that average gaze position was, as previously described, located in the vicinity of the tangent point. However, analysis also revealed the presence of a systematic optokinetic nystagmus (OKN) around the tangent point position. The OKN slow phase direction does not match the local optic flow direction, while slow phase speed is about half of the local speed. Higher directional gains are observed when averaging the entire optical flow projected on the simulation display, whereas the best speed gain is obtained for a 2 degrees optic flow area, centered on the instantaneous gaze location. The present study confirms that the tangent point is a privileged feature in the dynamic visual scene during curve driving, and underlines a contribution of the global optical flow to gaze behavior during active self-motion. PMID- 21704062 TI - High-throughput functional curation of cellular electrophysiology models. AB - Effective reuse of a quantitative mathematical model requires not just access to curated versions of the model equations, but also an understanding of the functional capabilities of the model, and the advisable scope of its application. To enable this "functional curation" we have developed a simulation environment that provides high-throughput evaluation of a mathematical model's functional response to an arbitrary user-defined protocol, and optionally compares the results against experimental data. In this study we demonstrate the efficacy of this simulation environment on 31 cardiac electrophysiology cell models using two test cases. The S1-S2 response is evaluated to characterise the models' restitution curves, and their L-type calcium channel current-voltage curves are evaluated. The significant variation in the response of these models, even when the models represent the same species and temperature, demonstrates the importance of knowing the functional characteristics of a model prior to its reuse. We also discuss the wider implications for this approach, in improving the selection of models for reuse, enabling the identification of models that exhibit particular experimentally observed phenomena, and making the incremental development of models more robust. PMID- 21704063 TI - Multi-scale modeling in biology: how to bridge the gaps between scales? AB - Human physiological functions are regulated across many orders of magnitude in space and time. Integrating the information and dynamics from one scale to another is critical for the understanding of human physiology and the treatment of diseases. Multi-scale modeling, as a computational approach, has been widely adopted by researchers in computational and systems biology. A key unsolved issue is how to represent appropriately the dynamical behaviors of a high-dimensional model of a lower scale by a low-dimensional model of a higher scale, so that it can be used to investigate complex dynamical behaviors at even higher scales of integration. In the article, we first review the widely-used different modeling methodologies and their applications at different scales. We then discuss the gaps between different modeling methodologies and between scales, and discuss potential methods for bridging the gaps between scales. PMID- 21704065 TI - Novel recombinant insulin analogue with flexible C-terminus in B chain. NMR structure of biosynthetic engineered A22G-B31K-B32R human insulin monomer in water/acetonitrile solution. AB - A tertiary structure of recombinant A22(G)-B31(K)-B32(R)-human insulin monomer (insulin GKR) has been characterized by (1)H, (13)C NMR at natural isotopic abundance using NOESY, TOCSY, (1)H/(13)C-GHSQC, and (1)H/(13)C-GHSQC-TOCSY spectra. Translational diffusion studies indicate the monomer structure in water/acetonitrile (65/35vol.%). CSI analysis confirms existence of secondary structure motifs present in human insulin standard (HIS). Both techniques allow to establish that in this solvent recombinant insulin GKR exists as a monomer. Starting from structures calculated by the program CYANA, two different refinement protocols used molecular dynamics simulated annealing with the program AMBER; in vacuum (AMBER_VC), and including a generalized Born solvent model (AMBER_GB). From these calculations an ensemble of 20 structures of lowest energy was chosen which represents the tertiary structure of studied insulin. Here we present novel insulin with added A22(G) amino acid which interacts with beta-turn environment resulting in high flexibility of B chain C-terminus. PMID- 21704064 TI - Same-sex cohabitation under the effects of quinpirole induces a conditioned socio sexual partner preference in males, but not in female rats. AB - The effects of the dopamine D2-type receptor agonist quinpirole (QNP) were examined on the development of conditioned same-sex partner preference induced by cohabitation in rats. In Experiment 1, males received either saline or QNP (1.25mg/kg) and cohabited during three trials with almond-scented stimulus males that were sexually naive. In Experiment 2, males received six trials, and in Experiment 3 received three trials with sexually expert stimulus males. During a final drug-free preference test, males chose between the familiar or a novel male partner. In Experiments 1, 2 and 3 only QNP-treated males displayed a social preference for the familiar male, observed with more time spent together. In Experiment 3 males also displayed a sexual preference observed with more non contact erections when were exposed to their male partner. In Experiment 4 we tested the effects on OVX, E+P primed females that received 1 systemic injection of either saline or QNP during three conditioning trials. In Experiment 5, females received 2 injections 12-h apart during each trial. Results indicated that both saline and QNP-treated females failed to develop partner preference. These data demonstrate that enhanced D2-type receptor activity during cohabitation facilitates the development of conditioned same-sex partner preference in males, but not in female rats. We discuss the implications for same sex partner preferences. PMID- 21704066 TI - Structural features and bioactivities of the chitosan. AB - Fourier transform infrared (FT-IR) spectroscopic studies (3500-600 cm(-1)) showed some different bands of chitosan. The absorption at 3439 cm(-1) is stretching vibration of -OH and -NH(2) bonds, indicating the association of the hydrogen bond between them. The bands at 1659, 1599 and 1321 cm(-1) are attributable to the peaks of stretching vibrations of amide I (nu((C=O))), II (delta((N-H))), and the peak of stretching and bending vibrations of III (nu((C-N))) (delta((N-H))). The chitosan showed strong free radical scavenging activities. Pretreatment with chitosan significantly prevented the decrease of antioxidant enzymes activities and the increase of p-JNK at 3 h after renal ischemia and reduced renal tubular epithelial cell apoptosis. PMID- 21704067 TI - The cluster structure of barley amylopectins of different genetic backgrounds. AB - The unit chains of amylopectin are organized into clusters. In this study, the cluster structure was analysed in detail in four different genotypes of barley, of which two possessed the amo1 genetic background. Amylose content of the barley starches differed from 0 to 32.6%. Isolated amylopectin was hydrolysed with alpha amylase from Bacillus subtilis into domains, defined as groups of clusters, which were size-fractionated by methanol. The domain fractions were further treated with alpha-amylase to release single clusters. Amylopectin, domains and clusters were subsequently treated with phosphorylase and beta-amylase to produce phi,beta limit dextrins and the detailed internal structures of these different structure levels were investigated. Analysis was performed with gel-permeation and anion exchange chromatography. Equal amount of A-chains were detected in all barleys, but the distribution of B-chains differed. At least two types of domain structures were identified in all four barley varieties. Large domains were built up by large clusters and small domains by small clusters. In all four barley samples the number of long chains was small suggesting that shorter chains with a degree of polymerization of 25-35 also are involved in the interconnection of clusters. The cluster structure of the amylopectin correlated with the genetic background. The two barley samples with amo1 genetic background possessed a more dense structure. Internal chain lengths in these two barleys were shorter resulting in larger domains built up by larger clusters. PMID- 21704068 TI - Emotional foundations of music as a non-pharmacological pain management tool in modern medicine. AB - This paper reviews the use of music as an adjuvant to the control of pain, especially in medical procedures. Surgery causes stress and anxiety that exacerbates the experience of pain. Self-report of and physiological measures on post-surgical patients indicate that music therapy or music stimulation reduces the perception of pain, both alone and when part of a multimodal pain management program, and can reduce the need for pharmaceutical interventions. However, multimodal pain therapy, including non-pharmacological interventions after surgery, is still rare in medical practice. We summarize how music can enhance medical therapies and can be used as an adjuvant with other pain-management programs to increase the effectiveness of those therapies. As summarized, we currently know that musical pieces chosen by the patient are commonly, but not always, more effective than pieces chosen by another person. Further research should focus both on finding the specific indications and contra-indications of music therapy and on the biological and neurological pathways responsible for those findings (related evidence has implicated brain opioid and oxytocin mechanisms in affective changes evoked by music). In turn, these findings will allow medical investigators and practitioners to design guidelines and reliable, standardized applications for this promising method of pain management in modern medicine. PMID- 21704069 TI - Glutamatergic modulation of separation distress: profound emotional effects of excitatory amino acids in chicks. AB - Pre-clinical models of brain affective circuits provide relevant evidence for understanding the brain systems that figure heavily in psychiatric disorders. Social isolation and the resulting separation distress contribute to the onset of depression. In this work, the effects of excitatory amino acids (EAA) on isolation-induced distress vocalization (DV) were assessed in young domestic chicks. Both glutamate and quisqualate (QA) produced dose-dependent reductions in DVs, while N-methyl-d-aspartate (NMDA) and kainate (KA) increased DVs. Such a differential pattern of responsiveness may indicate the presence of reciprocal or interacting EAA systems in the brain control of separation distress. Administration of either the NMDA receptor antagonist 2-amino-5-phosphonovalerate (APV) or the broad-spectrum antagonist gamma-d-glutamylglycine (DGG) greatly reduced DVs, as did the antagonist 2-amino-4-phosphonobutyrate (APB). APV did not attenuate the increase in vocalizations seen after NMDA or KA administration. DGG, however, was able to block the increase in calling produced by either of these agonists, suggesting a KA receptor mechanism. KA treatment inhibited the ability of other chicks, or auditory and somatosensory information, to suppress DVs. KA-treated animals exhibited a hyperemotional behavior pattern during which a variety of motivated behaviors were disrupted including reactions to novel objects, approaching the flock, and foraging. They could not sustain a coherent flock-like social cohesion, but exhibited strong fixed-action patterns of flight interspersed with hiding and crouching behaviors. The evident behavioral changes suggest that glutamatergic synapses directly influence sensory, motor and emotional processes in the brain and may be especially important in the integration of environmental stimuli with emotional central state processes of animals. Considering that unresolved social loss and grief have been deemed to be among the main precipitating causes of depression, and glutamate plays a large role in the production of negative effect related to separation distress, these results are consistent with the emerging work targeting glutamate blockade as a way to produce rapid anti-depressant effects. PMID- 21704070 TI - Chronic ethanol treatment alters purine nucleotide hydrolysis and nucleotidase gene expression pattern in zebrafish brain. AB - Ethanol is a widely consumed drug that acts on the central nervous system (CNS), modifying several signal transduction pathways activated by hormones and neurotransmitters. The zebrafish is an experimental model for the study of human diseases and the use of this species in biochemical and behavioral studies on alcoholism and alcohol-dependence has increased recently. However, there are no data concerning the effects of chronic ethanol exposure on the purinergic system, where extracellular nucleotides act as signaling molecules. Purinergic signaling is controlled by a group of enzymes named ectonucleotidases, which include NTPDases and ecto-5'-nucleotidase already characterized in zebrafish brain. The aim of this study was to evaluate nucleotide hydrolysis by NTPDases and ecto-5' nucleotidase after long-term ethanol exposure. Additionally, the gene expression patterns of NTPDases1-3 and 5'-nucleotidase were determined. Animals were exposed to 0.5% ethanol for 7, 14, and 28 days. There were no significant changes in ATP and GTP hydrolysis after all treatments. However, a decrease in ADP (46% and 34%) and GDP (48% and 36%) hydrolysis was verified after 7 and 14 days, respectively. After 7 and 14 days of ethanol exposure, a significant decrease in AMP hydrolysis (48% and 36%) was also observed, whereas GMP hydrolysis was inhibited only after 7 days (46%). NTPDase2_mv and NTPDase3 mRNA transcript levels decreased after 7 and 14 days, respectively. In contrast, ethanol increased NTPDase1, NTPDase2_mq, and NTPDase3 transcript levels after 28 days of exposure. NTPDase2_mg and 5' nucleotidase gene expression was not altered. Therefore, the ectonucleotidase pathway may be a target of chronic ethanol toxicity and the regulation of purinergic system could play a key role in the neurochemical mechanisms underlying the effects of ethanol on the CNS. PMID- 21704071 TI - The nature and consequences of coinfection in humans. AB - OBJECTIVE: Many fundamental patterns of coinfection (multi-species infections) are undescribed, including the relative frequency of coinfection by various pathogens, differences between single-species infections and coinfection, and the burden of coinfection on human health. We aimed to address the paucity of general knowledge on coinfection by systematically collating and analysing data from recent publications to understand the types of coinfection and their effects. METHODS: From an electronic search to find all publications from 2009 on coinfection and its synonyms in humans we recorded data on i) coinfecting pathogens and their effect on ii) host health and iii) intensity of infection. RESULTS: The most commonly reported coinfections differ from infections causing highest global mortality, with a notable lack of serious childhood infections in reported coinfections. We found that coinfection is generally reported to worsen human health (76% publications) and exacerbate infections (57% publications). Reported coinfections included all kinds of pathogens, but were most likely to contain bacteria. CONCLUSIONS: These results suggest differences between coinfected patients and those with single infections, with coinfection having serious health effects. There is a pressing need to quantify the tendency towards negative effects and to evaluate any sampling biases in the coverage of coinfection research. PMID- 21704072 TI - Altered Toll- and Nod-like receptor expression in human middle ear mucosa from patients with chronic middle ear disease. PMID- 21704073 TI - Drugs in porphyria: From observation to a modern algorithm-based system for the prediction of porphyrogenicity. AB - The acute porphyrias are a group of disorders which result from inherited defects in the enzymes of the heme biosynthetic pathway. Affected patients are prone to potentially fatal acute attacks. These attacks are frequently precipitated by exposure to commonly used drugs. Correctly identifying the safety or otherwise of drugs in porphyria is therefore important. In this review we describe how clinical experience and the findings of experimental systems using whole animal or cell culture models have been interpreted to determine porphyrogenicity, that is the potential of a drug to induce an acute attack in a patient carrying a gene for acute porphyria. It is now well established that induction of delta aminolevulinic acid synthase, the rate controlling enzyme of the heme biosynthetic pathway, is fundamental to porphyrogenicity, and that drug-induced hepatic heme depletion via induction or suicidal inactivation of cytochrome P450 is central to this process. The process is now sufficiently well understood that prediction of porphyrogenicity from structural and functional information alone would appear to be justified. PMID- 21704074 TI - Inflammatory processes in schizophrenia: a promising neuroimmunological target for the treatment of negative/cognitive symptoms and beyond. AB - Emerging evidence indicates that schizophrenia is associated with activated peripheral and central inflammatory responses. Such inflammatory processes seem to be influenced by a number of environmental and genetic predisposition factors, and they may critically depend on and contribute to the progressive nature of schizophrenic disease. There is also appreciable evidence to suggest that activated inflammatory responses can undermine disease-relevant affective, emotional, social, and cognitive functions, so that inflammatory processes may be particularly relevant for the precipitation of negative and cognitive symptoms of schizophrenia. Recent clinical trials of anti-inflammatory pharmacotherapy in this disorder provide promising results by showing superior beneficial treatment effects when standard antipsychotic drugs are co-administered with anti inflammatory compounds, as compared with treatment outcomes using antipsychotic drugs alone. Given the limited efficacy of currently available antipsychotic drugs to ameliorate negative and cognitive symptoms, the further exploration of inflammatory mechanisms and anti-inflammatory strategies may open fruitful new avenues for improved treatment of symptoms undermining affective, emotional, social and cognitive functions pertinent to schizophrenic disease. PMID- 21704075 TI - ALS: focus on purinergic signalling. AB - Amyotrophic lateral sclerosis (ALS) is one of the most common neuromuscular diseases. It is devastating and fatal, causing progressive paralysis of all voluntary muscles and eventually death, while sparing cognitive functions. A pathological hallmark of ALS is neuroinflammation mediated by non-neuronal cells in the nervous system, such as microglia and astrocytes that accelerate the disease progression. Scientists have neither found a unique key mechanism, nor an effective treatment against ALS, supposedly because it is a multi-factorial and multi-systemic disease. Extracellular purines and pyrimidines are widespread and powerful physiopathological molecules, signalling to most cell types and directing cell-to-cell communication networks. They are instrumental for instance for neurotransmission, muscle contraction and immune surveillance. Recent work has reported the crucial involvement of purinergic pathways in many neurodegenerative and neuroinflammatory diseases, comprising ALS. Especially P2 receptors for ATP, P1 receptors for adenosine, and nucleotide transporters were found to be modulated in ALS cells and tissues, playing a potential role in the disease. Given the composite cellular cross-talk occurring during ALS and the established action of extracellular purines/pyrimidines as neuron-to-glia alarm signal in the nervous system, a mutual query in these two fields should now be whether, how and when purinergic would meet ALS. In this review, we will highlight the early cellular and molecular purinergic cross-talk that participates to ALS etiopathology, with the conviction that better understanding of purinergic dynamics might provide original research perspectives, stimulate alternative disease modelling, and the design and testing of more powerful targeted therapeutics against this relentlessly progressive disorder. PMID- 21704076 TI - Paired recordings from distant inhibitory neuron pairs by a sequential scanning approach. AB - Simultaneous recordings from connected neuron pairs have brought important insights into synaptic communication between neurons. However, patch clamp recordings from neuron pairs have been largely restricted to brain areas in which connections among nearby neurons exist at a relatively high probability. In the case of more distant connections or in areas in which neurons are connected with low probability, recordings from synaptically connected neuron pairs have remained scarce. Here, we present a method that allows dual recordings from remotely connected neuron pairs by scanning potential presynaptic neurons. The applicability of this new approach was tested in the inhibitory pathway from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO), a sound localization pathway in the auditory brainstem. Using a three-step approach that sequentially combines focal uncaging of glutamate, pressure application of glutamate, and loose patch recordings allowed us to reliably achieve recordings from distant, synaptically connected GABA/glycinergic MNTB-LSO neuron pairs. Our results demonstrate that single MNTB neurons evoke highly variable mono-synaptic responses in developing LSO neurons, and heterogeneous short term synaptic dynamics, suggesting local variations in the refinement of these inhibitory connections. Paired recordings, enabled by scanning of remotely connected pairs, will be highly useful to perform detailed investigations of the synaptic function and plasticity from these circuits during the period of developmental refinement. In general, this method should provide a valuable tool to find connected neurons in other brain areas in which recording from candidate pairs has a low success rate. PMID- 21704077 TI - Spatiotemporal smoothing of single trial MEG data. AB - In MEG experiments an electromagnetic field is measured at a very high temporal resolution in many sensors located in a helmet-shaped dewar, producing a very large dataset. Filtering techniques are commonly used to reduce the noise in the data. In this paper, spatiotemporal smoothing across space and time simultaneously is used, not simply as a pre-processing step, but as the central focus of a modelling technique intended to estimate the structure of the spatial and temporal response to stimulus. A particular advantage of this approach is the ability to study responses from individual replicates, rather than averages. The benefits of this form of smoothing are discussed and simulation used to evaluate its performance. The methods are illustrated on an application with real data. PMID- 21704078 TI - Role of the gut as a primary lymphoid organ. AB - The TCR-alphabeta/gammadelta CD8alphaalpha intraepithelial T lymphocytes (T-IEL) located in the gut mucosa of the small intestine are an abundant population believed to have a major role in ensuring the integrity of the gut wall. Here, we describe their unique characteristics and the controversies regarding the origin and differentiation of these T-IELs. We show how accumulated experimental evidence has finally arrived at a unifying concept, which demonstrates that these cells originate from early thymus precursors that have not yet undergone TCR rearrangement and TCR-alphabeta/gammadelta commitment. These precursors colonize the gut lamina propria during the perinatal period and complete rearrangements and TCR-alphabeta/gammadelta commitment while migrating to the epithelium. Therefore, the gut epithelium, which shares the same embryonic origin as the thymus epithelium, behaves as a primary lymphoid organ responsible for the differentiation of a major local T cell set. PMID- 21704079 TI - NSOM/QD-based fluorescence-topographic image fusion directly reveals nano-spatial peak-valley polarities of CD69 and CD71 activation molecules on cell-membrane fluctuations during T-cell activation. AB - Nano-spatial distribution of cell surface molecules on cell membrane fluctuations during T-cell activation has not been reported. In this study, we innovated application of near-field scanning optical microscopy (NSOM)/quantum dots (QDs) based nanotechnology through three-dimensional image fusion algorithm to merge the simultaneously obtained dual-color fluorescence information and three dimensional topography. This novel imaging system made it possible to visualize nano-spatial distribution and organization of early-activation molecules CD69 and late-activation molecules CD71 on cell-membrane fluctuations during T-cell activation. Interestingly, most CD69 molecules were clustered to form 250-500nm nano-domains polarizing predominantly in the peak of the cell-membrane fluctuations. In contrast, although CD71 molecules were also clustered as 250 500nm nano-domains, they polarized dominantly in the valley of the cell-membrane fluctuations. The peak-valley polarities of CD69 nano-domains and CD71 nano domains implied their different functions. CD69 nano-domains polarizing on membrane-peak fluctuations might serve as transient platforms driving TCR/CD3 induced signaling and activation, whereas CD71 nano-domains distributing in the membrane-valley fluctuations appeared to facilitate iron uptake for increased metabolisms in T-cell activation. Importantly, this NSOM/QD-based fluorescence topographic image fusion provides a powerful tool to visualize nano-spatial distribution of cell-surface molecules on cell-membrane fluctuations and enable better understanding of distribution-function relationship. PMID- 21704080 TI - Development of a quantitative enzyme linked immunosorbent assay for monitoring the Enterovirus 71 vaccine manufacturing process. AB - Enterovirus 71 (EV71), the etiologic agent causes outbreaks with significant mortality in young children in Asia and currently there is no vaccine available. In this study, we report a quantitative enzyme linked immunosorbent assay (Q ELISA) to determine the concentration of the EV71 VP2 antigen. EV71 virus-like particles (VLPs) were produced in the baculovirus expression system and used as the EV71 antigen reference standard. Antisera from both EV71-immunized chickens and rabbits were very efficient and useful as capture antibodies to bind various forms of EV71 antigens, whereas a commercial VP2-specific virus neutralizing monoclonal antibody MAB979 was found to be suitable for quantifying the amount of VP2 antigen. This Q-ELISA was used successfully to determine VP2 content at each stage of EV71 vaccine manufacturing process, particularly during the upstream harvest, downstream purification and viral inactivation steps. The amount of VP2 antigen and the magnitude of neutralizing titers were found to be dose-dependent in mice immunized with vaccine candidates. These results indicate that Q-ELISA could provide off-line timely quantitative measurements of VP2 antigen throughout the production cycle to evaluate critical attributes and conditions that may affect virus yields in culture media, the quality of purification methods, the stability and potency of final vaccine formulations. PMID- 21704081 TI - A specific and sensitive antigen capture assay for NS1 protein quantitation in Japanese encephalitis virus infection. AB - Japanese encephalitis virus (JEV) is a human pathogenic, mosquito-borne flavivirus that is endemic/epidemic in Asia. JEV is rarely detected or isolated from blood or cerebrospinal fluid (CSF), and detection of IgM is generally diagnostic of the infection. The flavivirus nonstructural glycoprotein NS1 is released transiently during flavivirus replication. The aim of this study was to set up a quantitative JEV NS1 antigen capture assay. A soluble hexameric form of JEV NS1 protein was produced in a stable Drosophila S2 cell clone and purified from supernatant fluids. Two IgG1 monoclonal antibodies (MAbs) with high affinity against two different epitopes of JEV NS1 antigen were used to develop an antigen capture assay with a limit of detection of 0.2ngml(-1) NS1. Up to 1MUgml(-1) JEV NS1 protein was released in supernatants of mammalian cells infected with JEV but <10ngml(-1) was released in sera of virus-infected mice before the onset of encephalitis and death. Moreover, NS1 protein was detected at low levels (<10ngml(-1)) in 23.8% of sera and in 10.5% of CSF of patients diagnosed as IgM positive for JEV. This quantitative test of NS1 protein is proposed for highly specific diagnosis of acute infection with JEV genotypes I to IV. PMID- 21704082 TI - Kinematics of obstacle clearance in the rat. AB - Although the rat has become the favourite animal model in preclinical research on locomotion, studies designed to assess the strategy used by rats to avoid obstacle are lacking. Using an optoelectronic 3D motion analysis system, we therefore, compared the step pattern, timing and length variables of locomotor cycles, trajectories and joint angles of limbs when rats step between and over obstacles (3 cm-high) fixed on a treadmill belt (25 cm/s). Motion in all four limbs of adult animals with an initial age of 11 weeks was serially recorded for a period of 10 weeks. The results showed that obstacle clearance is associated with the reorganization of the basic step pattern resulting in increased stride length of all limbs, increased duration of the swing phase of the hindlimbs only, and the appearance of two quadrupedal stance phases. They also revealed that the elevation of limbs above the obstacle not only involves flexion but also displacement of the corresponding girdles. Remarkably, the trajectory of the trailing forelimb to get over the obstacle is almost a mirror image of the trajectory of the leading forelimb. Lastly, all of the parameters measured remained stable over the observation period during which body weight gain reached 100g (one third of the initial body weight). In conclusion, our study may provide a basis for future studies aimed at understanding the neural pathways involved in pathologies associated with deficit/recovery of challenged locomotion in rats. PMID- 21704083 TI - Oral activity of FMRFamide-related peptides on the pea aphid Acyrthosiphon pisum (Hemiptera: Aphididae) and degradation by enzymes from the aphid gut. AB - Insect myosuppressins and myosuppressin analogues were tested for oral toxicity against the pea aphid Acyrthosiphon pisum (Harris) by incorporation into an artificial diet. Acyrthosiphon pisum myosuppressin (Acypi-MS) and leucomyosuppressin (LMS) had significant dose-dependent effects (0.1-0.5MUg peptide/MUl diet) on feeding suppression, mortality, reduced growth and fecundity compared with control insects, but Acypi-MS was more potent than LMS. One hundred percent of aphids had died after 10days of feeding on 0.5MUg Acypi-MS/MUl diet whereas 40% of aphids feeding on 0.5MUg LMS/MUl diet were still alive after 13days. Myosuppressins were degraded by aphid gut enzymes; degradation was most likely due to a carboxypeptidase-like protease, an aminopeptidase and a cathepsin L cysteine protease. The estimated half-life of Acypi-MS in a gut extract was 30min, whereas LMS was degraded more slowly (t1/2=54min). No toxicity was observed when the analogues deltaR(9) LMS and citrolline(9) Acypi-MS or FMRFamide were fed to the pea aphid. These findings not only help to better understand the biological effects of myosuppressins in aphids but also demonstrate the potential use of myosuppressins in a strategy to control aphid pests. PMID- 21704084 TI - Improvement of phylum- and class-specific primers for real-time PCR quantification of bacterial taxa. AB - Mapping the distribution of phylogenetically distinct bacteria in natural environments is of primary importance to an understanding of ecological dynamics. Here we present a quantitative PCR (qPCR) assay for the analysis of higher taxa composition in natural communities that advances previously available methods by allowing quantification of several taxa during the same qPCR run. Existing primers targeting the 16S rRNA gene specific for Firmicutes, Actinobacteria, Bacteroidetes and for the alpha and gamma subdivisions of the Proteobacteria were improved by largely increasing the coverage of the taxon they target without diminishing their specificity. The qPCR assay was validated in vitro testing artificial mixtures of 16S rRNA sequences and used to characterise the composition of natural communities developing in young marine biofilms. The possible contribution of the proposed technique in revealing ecological dynamics affecting higher bacterial taxa is discussed. PMID- 21704085 TI - Reverse transcription-PCR methods significantly impact richness and composition measures of expressed fungal cellobiohydrolase I genes in soil and litter. AB - The importance of soil fungi in complex carbon degradation and the recent identification of genes involved in this process have sparked considerable interest in examining fungal gene expression in situ. Expression of target eukaryotic genes is commonly examined using reverse transcription (RT)-PCR, during which single-stranded (ss) complementary DNA (cDNA) is synthesized from an oligo (dT) primer and the gene of interest is subsequently amplified by PCR using gene specific primers. Another method that is being increasingly employed in environmental gene expression studies is SMART PCR, which generates and amplifies double-stranded (ds) complementary DNA (cDNA) from sscDNA using PCR, prior to gene-specific PCR. We performed a replicated comparison of these two methods using RNA extracted from forest soil and litter to determine if the two approaches yielded comparable results. Richness, composition and reproducibility of gene expression profiles of the fungal glycosyl hydrolase family 7 (GH7) cellobiohydrolase I gene (cbhI) were examined when amplified from sscDNA or dscDNA synthesized using SMART PCR. In the dscDNA libraries from soil or litter samples, richness was significantly reduced and the composition was altered relative to sscDNA libraries. Library composition was significantly more reproducible among replicate sscDNA libraries than among parallel dscDNA libraries from litter. In sum, the reduced richness and altered composition produced in the dscDNA libraries could substantially influence ecological interpretations of the data. Defining the factors underpinning the methodological biases will potentially aid in optimizing the design of gene expression studies in soils and other complex environmental samples. PMID- 21704086 TI - Culture-independent multi-locus variable-number tandem-repeat analysis (MLVA) of Mycoplasma pneumoniae. AB - A PCR approach for multi-locus variable-number tandem-repeat analysis (MLVA) of Mycoplasma pneumoniae directly from respiratory samples was developed and evaluated on 54 specimens from M. pneumoniae-positive pneumonia patients. The method resulted in a clearly identifiable MLVA type in all samples tested and can be used for MLVA without laborious isolation of the pathogen. PMID- 21704087 TI - Detection of virtual pitch up to 5kHz by mice. AB - Natural sounds consist of a component at the fundamental frequency (f0) and its overtones. Pitch is perceived at f0, even when spectral energy at f0 is missing. This missing f0, or 'virtual pitch', is thought to be detected in the auditory cortex and related cortical areas, but the precise neural mechanisms are unknown. One possibility is that virtual pitch can be retrieved from the periodicity of sound waveforms. However, this mechanism requires the temporal accuracy in periodicity detection, and so far the detection of virtual pitch has only been demonstrated at frequencies lower than 1kHz. We investigated the ability of mice to detect virtual pitch up to 5kHz using a two-step sound discrimination test. In the first step of this test, mice were trained to discriminate between tone bursts at 2.5 and 5kHz. In the second step, we tested the ability of mice to discriminate between virtual pitches at 2.5kHz and at 5kHz. It was demonstrated that the performance of mice to discriminate between virtual pitches at 2.5 and 5kHz was significantly affected by previous discrimination learning between tone bursts, indicating that mice can detect virtual pitch up to 5kHz. PMID- 21704088 TI - Effects of novelty stress on hippocampal gene expression, corticosterone and motor activity in mice. AB - Exposure to novelty, a mild psychological stressor, induces neuronal activations in the hippocampus of rodents, which may play an important role in the adaptation to stress. We examined the changes in three parameters, i.e., gene expression in the hippocampus using a RT-PCR method, corticosterone and motor activity, in mice exposed to a new environment for 120min. A sharp and short-lasting increase in the gene expression of a set of stress-related genes previously reported, e.g., Fos and Nr4a1, was observed during the stress, with a similar pattern of changes in corticosterone. The motor activity gradually decreased during the novelty stress, indicating a process of adaptation to the new environment. In addition, in order to minimize the effects of elevated adrenal hormones by the stress, we carried out experiments on adrenalectomized (ADX) mice. However, the adrenalectomy produced minimal changes in the pattern and the magnitude of the gene response after the stress, while the motor activity showed a relatively slower pattern of adaptation in the ADX mice. Hence, the present study suggests that there was a coordinated adaptation process to the new environment in mice, and that the transcriptional response was mediated by neuronal networks rather than by adrenal hormones. PMID- 21704089 TI - Reverse genetics system for Chandipura virus: tagging the viral matrix protein with green fluorescent protein. AB - Chandipura virus (CV; genus Vesiculovirus, family Rhabdoviridae) is an emerging arbovirus, responsible for a number of outbreaks of severe viral encephalitis affecting children in India. A reverse genetics system has been constructed which allows recovery of infectious recombinant CV (rCV) entirely from cDNA. This system was used to construct a virus, rCVE, which has an additional transcription unit encoding green fluorescent protein (EGFP) between the 3rd and 4th CV genes. This virus grew to titres comparable to the parental rCV and stably expressed EGFP in infected cells for at least 4 passages. A second virus, rCVGM, was constructed in which the CV matrix (M) coding region was replaced with the coding region for an EGFP-M fusion protein. Compared to rCV and rCVE, rCVGM was attenuated, giving a small plaque phenotype and lower yield, although it did express the EGFP-M protein in infected cells. Passage of rCVGM resulted in viruses with a standard plaque phenotype which no longer expressed EGFP. Analysis of two of these viruses showed that most or all of the EGFP ORF was deleted. The EGFP-M fusion protein showed cleavage to EGFP-sized and M-sized products, both in rCVGM-infected cells and when expressed from a plasmid. The EGFP-M fusion protein was not detected in virus particles, suggesting it was incompatible with virus assembly, and particles of rCVGM likely contained the M-sized cleavage product in its place. PMID- 21704090 TI - VLPs of Leptopilina boulardi share biogenesis and overall stellate morphology with VLPs of the heterotoma clade. AB - Viruses and virus-like particles (VLPs) of insect parasitoids modify host parasite interactions. The Drosophila wasp, Leptopilina heterotoma, produce 300 nm spiked VLPs that bind to the host's blood cells via surface projections. L. heterotoma is a generalist wasp that attacks over a dozen Drosophila species. Oviposition introduces VLPs into the hemolymph of Drosophila larvae. VLPs lyse hemocytes and obliterate immune signaling in infected larval hosts. L. boulardi, a member of a distinct Leptopilina clade, is a specialist, whose host range is limited to the melanogaster group. As a step toward understanding a potential relationship between venom contents and host range in these wasps, we used electron microscopy to characterize VLPs from the virulent L. boulardi-17 (Lb-17) strain. While the Lb-17 VLPs can neither lyse blood cells nor suppress host defense, their biogenesis is surprisingly similar to that of L. heterotoma. Like L. heterotoma VLPs, L. boulardi VLPs are stellate; but they have fewer spikes, each spike being significantly longer than the spikes in L. heterotoma VLPs. The Lb-17 VLPs possess a dimple, making them clearly distinct from L. heterotoma VLPs. We discuss the significance of these cross-clade differences in VLP morphologies in relation to their biological activities and the host range of the wasp. PMID- 21704091 TI - Serological diagnostics of hepatitis E virus infection. AB - Development of accurate diagnostic assays for the detection of serological markers of hepatitis E virus (HEV) infection remains challenging. In the course of nearly 20 years after the discovery of HEV, significant progress has been made in characterizing the antigenic structure of HEV proteins, engineering highly immunoreactive diagnostic antigens, and devising efficient serological assays. However, many outstanding issues related to sensitivity and specificity of these assays in clinical and epidemiological settings remain to be resolved. Complexity of antigenic composition, viral genetic heterogeneity and varying epidemiological patterns of hepatitis E in different parts of the world present challenges to the refinement of HEV serological diagnostic assays. Development of antigens specially designed for the identification of serological markers specific to acute infection and of IgG anti-HEV specific to the convalescent phase of infection would greatly facilitate accurate identification of active, recent and past HEV infections. PMID- 21704092 TI - Disulfide crosslinked polyion complex micelles encapsulating dendrimer phthalocyanine directed to improved efficiency of photodynamic therapy. AB - Dendrimer phthalocyanine (DPc)-loaded polyion complex micelle (DPc/m) has been developed as photosensitizer (PS) formulation in photodynamic therapy (PDT). Incorporation of DPc into the micelle showed significant enhancement in the in vitro photocytotoxicity. Also, introduction of disulfide crosslinking in the micellar core further improved the in vitro PDT effect of DPc/m. Here, we aim to analyze the mechanism of the enhanced photocytotoxicity of DPc/m, particularly focusing on the photochemical reactions during photoirradiation. As a result, DPc/m has been shown to protect DPc from photobleaching induced by the reactions with serum proteins, although DPc were considerably quenched in the micellar core. Furthermore, the introduction of disulfide crosslinking into the micellar core has demonstrated to improve the efficiency of reactive oxygen species (ROS) production by DPc in the micellar core as well as more effectively prevent the photobleaching of DPc. These effects might lead to effective photochemical reactions by DPc/m, which may account for the enhanced photocytotoxicity. Our findings provide useful knowledge in designing PS formulations for effective PDT. PMID- 21704093 TI - The efficacy of intracranial PLG-based vaccines is dependent on direct implantation into brain tissue. AB - We previously engineered a macroporous, polymer-based vaccine that initially produces GM-CSF gradients to recruit local dendritic cells and subsequently presents CpG oligonucleotides, and tumor lysate to cell infiltrates to induce immune cell activation and immunity against tumor cells in peripheral tumor models. Here, we demonstrate that this system eradicates established intracranial glioma following implantation into brain tissue, whereas implantation in resection cavities obviates vaccine efficacy. Rats bearing seven-day old, intracranial glioma tumors were treated with PLG vaccines implanted into the tumor bed, resulting in retention of contralateral forelimb function (day 17) that is compromised by tumor formation in control animals, and 90% long-term survival (>100 days). Similar benefits were observed in animals receiving tumor resection plus vaccine implants into the adjacent parenchyma, but direct implantation of PLG vaccines into the resection cavity conferred no benefit. This dissociation of efficacy was likely related to GM-CSF distribution, as implantation of PLG vaccines within brain tissue produced significant GM-CSF gradients for prolonged periods, which was not detected after implantation in resection cavities. These studies demonstrate that PLG vaccine efficacy is correlated to GM-CSF gradient formation, which requires direct implantation into brain tissue, and justify further exploration of this approach for glioma treatment. PMID- 21704094 TI - Complement in health and disease. AB - The complement system consists of about 35-40 proteins and glycoproteins present in blood plasma or on cell surfaces. Its main biological function is to recognise "foreign" particles and macromolecules, and to promote their elimination either by opsonisation or lysis. Although historically complement has been studied as a system for immune defence against bacteria, it has an important homeostatic role in which it recognises damaged or altered "self" components. Thus complement has major roles in both immune defence against microorganisms, and in clearance of damaged or "used" host components. Since complement proteins opsonise or lyse cells, complement can damage healthy host cells and tissues. The system is regulated by many endogenous regulatory proteins. Regulation is sometimes imperfect and both too much and too little complement activation is associated with many diseases. Excessive or inappropriate activation can cause tissue damage in diseases such as rheumatoid arthritis, age-related macular degeneration (AMD), multiple sclerosis, ischemia-reperfusion injury (e.g. ischemic stroke). Insufficient complement activity is associated with susceptibility to infection (mainly bacterial) and development of autoimmune disease, like SLE (systemic lupus erythematosus). PMID- 21704095 TI - Role of vascular Kinin B1 and B2 receptors in endothelial nitric oxide metabolism. AB - Kinin B(1) and B(2) receptors play an essential role in inflammatory process and cardiovascular homeostasis. The present study investigated the vascular reactivity and nitric oxide (NO) generation in the isolated mesenteric arteriolar bed from B(1) (B(1)(-/-)) and B(2) receptor (B(2)(-/-)) knockout mice. Endothelial-dependent relaxation was significantly decreased in arterioles from both B(1)(-/-) and B(2)(-/-) in comparison to wild type (WT) mice, with no differences for endothelial-independent relaxating or vasoconstrictor agents. Plasmatic and vascular NO production were markedly reduced in both B(1)(-/-) and B(2)(-/-). In contrast, in the presence of l-arginine, Ca(2+) and co-factors for the enzyme, NO synthase activity was higher in homogenates of mesenteric vessels of B(1)(-/-) and B(2)(-/-). The present study demonstrated that targeted deletion of B(1) or B(2) receptor gene in mice induces important alterations in the vascular reactivity of resistance vessels and NO metabolism. The severe impairment in the endothelial-mediated vasodilation accompanied by decreased NO bioavailability, despite the augmented NOS activity, strongly indicates an exacerbation of NO inactivation in B(1)(-/-) and B(2)(-/-) vessels. The present data provide valuable information in order to clarify the relevance of kinin receptors in regulating vascular physiology and may point to new approaches regarding its correlation with endothelial dysfunction, oxidative stress and NO availability. PMID- 21704096 TI - Analysis of the glucagon receptor first extracellular loop by the substituted cysteine accessibility method. AB - Glucagon is an important hormone for the prevention of hypoglycemia, and contributes to the hyperglycemia observed in diabetic patients, yet very little is known about its receptor structure and the receptor-glucagon interaction. In related receptors, the first extracellular loop, ECL1, is highly variable in length and sequence, suggesting that it might participate in ligand recognition. We applied a variant of the SCAM (Substituted Cysteine Accessibility Method) to the glucagon receptor ECL1 and sequentially mutated positions 197 to 223 to cysteine. Most of the mutations (15/27) affected the glucagon potency, due either to a modification of the glucagon binding site, or to the destabilization of the active receptor conformation. We reasoned that side chains accessible to glucagon must also be accessible to large, hydrophilic cysteine reagents. We therefore evaluated the accessibility of the introduced cysteines to maleimide-PEO(2) biotin ((+)-biotinyl-3-maleimido-propionamidyl-3,6-dioxa-octanediamine), and tested the effect of pretreatment of intact cells with a large cationic cysteine reagent, MTSET ([2-(trimethylammonium)ethyl]methanethiosulfonate bromide), on glucagon potency. Our results suggest that the second and third transmembrane helices (TM2 and TM3) are extended to position 202 and from position 215, respectively, and separated by a short beta stretch (positions 203-209). Glucagon binding induced a conformational change close to TM2: L198C was accessible to the biotin reagent only in the presence of glucagon. Most other mutations affected the receptor activation rather than glucagon recognition, but S217 and D218 (at the top of TM3) were good candidates for glucagon recognition and V221 was very close to the binding site. PMID- 21704098 TI - The extrinsic and intrinsic apoptotic pathways are involved in manganese toxicity in rat astrocytoma C6 cells. AB - Manganese (Mn) is a trace element known to be essential for maintaining the proper function and regulation of many biochemical and cellular reactions. However, chronic exposure to high levels of Mn in occupational or environmental settings can lead to its accumulation in the brain resulting in a degenerative brain disorder referred to as Manganism. Astrocytes are the main Mn store in the central nervous system and several lines of evidence implicate these cells as major players in the role of Manganism development. In the present study, we employed rat astrocytoma C6 cells as a sensitive experimental model for investigating molecular mechanisms involved in Mn neurotoxicity. Our results show that C6 cells undergo reactive oxygen species-mediated apoptotic cell death involving caspase-8 and mitochondrial-mediated pathways in response to Mn. Exposed cells exhibit typical apoptotic features, such as chromatin condensation, cell shrinkage, membrane blebbing, caspase-3 activation and caspase-specific cleavage of the endogenous substrate poly (ADP-ribose) polymerase. Participation of the caspase-8 dependent pathway was assessed by increased levels of FasL, caspase-8 activation and Bid cleavage. The involvement of the mitochondrial pathway was demonstrated by the disruption of the mitochondrial membrane potential, the opening of the mitochondrial permeability transition pore, cytochrome c release, caspase-9 activation and the increased mitochondrial levels of the pro-apoptotic Bcl-2 family proteins. In addition, our data also shows for the first time that mitochondrial fragmentation plays a relevant role in Mn induced apoptosis. Taking together, these findings contribute to a deeper elucidation of the molecular signaling mechanisms underlying Mn-induced apoptosis. PMID- 21704097 TI - Cocaine increases phosphorylation of MeCP2 in the rat striatum in vivo: a differential role of NMDA receptors. AB - Methyl CpG-binding protein-2 (MeCP2) is a transcriptional regulator that binds to methylated DNA at CpG sites and functions to silence DNA transcription. MeCP2 is subject to the phosphorylation modification at serine 421 (S421), which releases MeCP2 from DNA and thus facilitates gene expression. As a transcriptional repressor densely expressed in limbic reward circuits of adult mammalian brains, MeCP2 is recently emerging as a critical epigenetic factor in experience dependent neural plasticity and psychostimulant addiction. In this study, we investigated the regulation of MeCP2 phosphorylation in the rat striatum by the psychostimulant cocaine in vivo. We found that acute systemic injection of cocaine increased MeCP2 phosphorylation at S421 in the rat striatum, including both the caudate putamen and the nucleus accumbens, while cocaine did not affect MeCP2 phosphorylation in the medial prefrontal cortex. The cocaine-stimulated MeCP2 phosphorylation in the nucleus accumbens was a rapid and transient event, as it was evident at 20 min and returned to normal levels 3h after drug injection. The cocaine effect in the caudate putamen was however relatively delayed. Reliable induction of MeCP2 phosphorylation in this region was detected at 60 min. Pretreatment with an N-methyl-d-aspartate (NMDA) glutamate receptor antagonist significantly reduced the cocaine-stimulated MeCP2 phosphorylation in the caudate putamen, although not in the nucleus accumbens. Our data support that MeCP2 is a sensitive target of psychostimulants. Its phosphorylation status is regulated by psychostimulant exposure. NMDA receptors play a region-specific role in linking cocaine to MeCP2 phosphorylation in striatal neurons in vivo. PMID- 21704099 TI - Association analysis of C6 genetic variations and aspirin hypersensitivity in Korean asthmatic patients. AB - There has been increasing evidence that genetic mechanisms contribute to the development of aspirin-intolerant asthma (AIA), a life-threatening disease. The complement component (C6) is a constituent of a biochemical cascade that has been implicated in airway epithelial damage and nasal polyposis, and therefore, may be a risk factor for AIA. To investigate the association between C6 variations and AIA in a Korean asthma cohort, 27 SNPs were selected for genotyping based on previously reported polymorphisms in the HapMap database. Genotyping was carried out using TaqMan assay, and five major haplotypes were obtained in 163 AIA cases and 429 aspirin-tolerant asthma (ATA) controls subjects. Genotype frequency distributions of C6 polymorphisms and haplotypes were analyzed using logistic and regression models. Subsequent analyses revealed a lack of association between C6 genetic variations and AIA. From the initial analyses, marginal associations of rs10512766 (p = 0.04 in co-dominant model) and rs4957374 (p = 0.05 in dominant model) with AIA did not reach the threshold of significance after multiple testing corrections; thus this study failed to find convincing evidence that variations in C6 gene influence the risk of AIA in a Korean population. However, these preliminary results may contribute to the etiology of aspirin hypersensitivity in Korean asthmatic patients. PMID- 21704100 TI - Association of CD209 polymorphisms with tuberculosis in an Indonesian population. AB - Tuberculosis (TB) caused by Mycobacterium tuberculosis is a major cause of morbidity and mortality worldwide. Thus far, many candidate genes have been investigated for their possible association with TB. Dendritic cell-specific ICAM 3 grabbing nonintegrin (DC-SIGN) encoded by CD209 is the major receptor of M tuberculosis on human dendritic cells. Previous studies reported inconsistent results on the association between CD209 polymorphisms and TB. We examined whether 9 single nucleotide polymorphisms (SNPs) of CD209 are associated with TB in 2 southeast Asian populations (Indonesian and Vietnamese) by Fisher's exact test. The SNP at -939 in the promoter region exhibited a significant association with TB in Indonesian (GG vs GA + AA, p = 0.0051, odds ratio [OR] = 0.68, 95% confidence interval [CI] = 0.52-0.89) but not in Vietnamese populations. Further extensive studies are required to confirm the contribution of CD209 polymorphisms to TB susceptibility. PMID- 21704101 TI - Incorporation of 4-1BB ligand into an adenovirus vaccine vector increases the number of functional antigen-specific CD8 T cells and enhances the duration of protection against influenza-induced respiratory disease. AB - T cell based influenza vaccines offer the potential for cross protective immunity to multiple clades of influenza virus. Here we explored the effect of increasing CD8 T cell responses during intranasal vaccination by incorporating a T cell costimulator, 4-1BBL. Inclusion of 4-1BBL in an influenza nucleoprotein (NP) containing adenoviral vector increased the number of NP-specific CD8 T cells and lowered the vaccine dose required for short-term protection from influenza induced disease in mice. At higher vaccine doses, the inclusion of 4-1BBL increased the duration of protection of mice from influenza-induced mortality. Bone marrow chimera experiments revealed that the major effects of 4-1BBL were directly on alphabeta T cells with minor additional effects through cells other than alphabeta T cells. The implications of these findings are that including 4 1BBL or adjuvants that induce 4-1BBL expression may be of benefit in a vaccine setting for enhancing the magnitude and duration of T cell responses to influenza virus. PMID- 21704102 TI - Risk of disability for US army personnel vaccinated against anthrax, 1998-2005. AB - To evaluate the potential for long-term or delayed onset health effects, we extended a previous cohort study of disability separation from the army associated with vaccination against anthrax. Analyses included stratified Cox proportional hazards and multiple logistic regression models. Forty-one percent of 1,001,546 soldiers received at least one anthrax vaccination; 5.21% were evaluated for disability. No consistent patterns or statistically significant differences in risk of disability evaluation, disability determination, or reason for disability were associated with anthrax vaccination. There was a dose-related trend in risk of disability for soldiers with 2 years' service, limited to those entering service in 2000 or later. Divergent patterns in risk suggest confounding by temporal or occupational risks of disability. PMID- 21704103 TI - Temporal development of the humoral immune response to surface antigens of Moraxella catarrhalis in young infants. AB - The primary Moraxella catarrhalis-specific humoral immune response, and its association with nasopharyngeal colonization, was studied in a cohort of infants from birth to 2 years of age. Results indicated that the levels of antigen specific IgG, IgA and IgM showed extensive inter-individual variability over time, with IgM and IgA levels to all 9 recombinant domains, from 7 different OMPs, being relatively low throughout the study period. In contrast, the level of antigen-specific IgG was significantly higher for the recombinant domains Hag358 853, MID764-913, MID962-1200, UspA1557-704 and UspA2165-318 in cord blood compared to 6 months of age (P <= 0.001). This was a most likely a consequence of maternal transmission of antigen-specific IgG to newborn babies, possibly indicating a future role for these 3 surface antigens in the development of an effective humoral immune response to M. catarrhalis. Finally, at 2 years of age, the levels of antigen-specific IgG still remained far below that obtained from cord blood samples, indicating that the immune response to M. catarrhalis has not matured at 2 years of age. We provide evidence that a humoral antibody response to OMPs UspA1, UspA2 and Hag/MID may play a role in the immune response to community acquired M. catarrhalis colonization events. PMID- 21704104 TI - HPV vaccine and adolescent males. AB - In 2009, the United States approved quadrivalent HPV vaccine for males 9-26 years old, but data on vaccine uptake are lacking. We determined HPV vaccine uptake among adolescent males, as well as stage of adoption and vaccine acceptability to parents and their sons. A national sample of parents of adolescent males ages 11 17 years (n=547) and their sons (n=421) completed online surveys during August and September 2010. Analyses used multivariate linear regression. Few sons (2%) had received any doses of HPV vaccine, and most parents and sons were unaware the vaccine can be given to males. Parents with unvaccinated sons were moderately willing to get their sons free HPV vaccine (mean=3.37, SD=1.21, possible range 1 5). Parents were more willing to get their sons vaccinated if they perceived higher levels of HPV vaccine effectiveness (beta=0.20) or if they anticipated higher regret about their sons not getting vaccinated and later developing an HPV infection (beta=0.32). Vaccine acceptability was also modest among unvaccinated sons (mean=2.98, SD=1.13, possible range 1-5). Sons were more willing to get vaccinated if they perceived higher peer acceptance of HPV vaccine (beta=0.39) or anticipated higher regret about not getting vaccinated and later developing an HPV infection (beta=0.22). HPV vaccine uptake was nearly nonexistent a year after permissive national recommendations were first issued for males. Vaccine acceptability was moderate among both parents and sons. Efforts to increase vaccine uptake among adolescent males should consider the important role of peer acceptance and anticipated regret. PMID- 21704106 TI - Free school-based vaccination with HPV vaccine in a Japanese city. PMID- 21704105 TI - Immunogenicity of a combination vaccine containing diphtheria toxoid, tetanus toxoid, three-component acellular pertussis, hepatitis B, inactivated polio virus, and Haemophilus influenzae type b when given concomitantly with 13-valent pneumococcal conjugate vaccine. AB - Two randomized trials of 13-valent pneumococcal conjugate vaccine (PCV13) relative to PCV7 evaluated the immune responses of coadministered antigens comprising Infanrix((r)) hexa/Infanrix((r))-IPV+Hib (diphtheria, tetanus, 3 component acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b). After the 3-dose infant series, immunogenic noninferiority was demonstrated for all concomitantly administered antigens between the PCV13 and PCV7 groups. All antigens elicited good booster responses after the toddler dose except pertussis toxoid; however, 99.6% subjects achieved pertussis toxoid protective antibody level >=5EU/mL in both groups. These results support the concomitant administration of PCV13 and Infanrix hexa/Infanrix IPV+Hib as part of routine immunization schedules. PMID- 21704107 TI - A therapeutic anti-Streptococcus mutans monoclonal antibody used in human passive protection trials influences the adaptive immune response. AB - The adhesin known as Antigen I/II, P1 or PAc of the cariogenic dental pathogen Streptococcus mutans is a target of protective immunity and candidate vaccine antigen. Previously we demonstrated that immunization of mice with S. mutans complexed with anti-AgI/II monoclonal antibodies (MAbs) resulted in changes in the specificity, isotype and functionality of elicited anti-AgI/II antibodies in the serum of immunized mice compared to administration of bacteria alone. In the current study, an anti-AgI/II MAb reported in the literature to confer unexplained long term protection against S. mutans re-colonization following passive immunization in human clinical trials (MAb Guy's 13), and expressed in tobacco plants (MAb Guy's 13 plantibody), was evaluated for its potential immunomodulatory properties. Immunization of BALB/c mice with immune complexes of Guy's 13 plantibody bound to S. mutans whole cells resulted in a similar change in specificity, isotype, and functionality of elicited anti-AgI/II antibodies as had been observed for other immunomodulatory MAbs. This new information, coupled with the recently solved crystal structure of the adhesin, now provides a rational explanation and plausible mechanism of action of passively administered Guy's 13/Guy's 13 plantibody in human clinical trials, and how long-term prevention of S. mutans carriage well past the application period of the therapeutic antibody could have been achieved. PMID- 21704108 TI - Immunogenicity and protective efficacy of a tuberculosis DNA vaccine expressing a fusion protein of Ag85B-Esat6-HspX in mice. AB - Tuberculosis remains a major infectious disease worldwide due to the low efficacy of available vaccine of the Mycobacterium bovis Bacillus Calmette-Guerin (BCG). DNA vaccines are especially promising candidates; however, the efficacy of DNA vaccine expressing single antigen of Mycobacterium tuberculosis (MTb) is limited. In this study, a plasmid DNA vaccine, pAEH, was constructed and designed to express a fusion protein of the Ag85B, Esat6, and HspX of MTb. Its immunogenicity and protective efficacy as well as therapeutic effect were assessed in a mouse model of tuberculosis. Vaccination with the pAEH significantly increased the frequency of peripheral blood CD4(+) and CD8(+) T cells, but not gammadeltaT cells, similar to that of vaccination with the BCG, and induced significantly higher levels of HspX-specific T cell proliferation, as compared with vaccination with BCG or the pHspX. Furthermore, vaccination with the pAEH increased the frequency of Ag85B, Esat6 and HspX-specific IFNgamma-secreting T cells, accompanied by significantly higher levels of IFN-gamma and IL-2 production ex vivo, as compared with that of the BCG or pHspX-vaccinated mice. Apparently, vaccination with the pAEH induced potent Th1 responses in mice. More importantly, vaccination with the pAEH inhibited the replication of virulent MTb in the lungs and spleens, even after MTb infection, and related lung inflammation in mice. Potentially, the newly developed pAEH vaccine may be used for the prevention and therapeutic intervention of MTb infection. PMID- 21704109 TI - Vaccination against 2008/2009 and 2009/2010 seasonal influenza in Spain: coverage among high risk subjects, HCWs, immigrants and time trends from the 2005/2006 campaign. AB - Influenza continues to be a very important cause of morbidity, mortality and a large number of hospitalizations each year, however the compliance with vaccine uptake is low and has barely varied over time among health care workers (HCWs) and people under 65 years of age suffering a chronic condition. Based on data from two nation-wide representative health surveys namely the 2006 Spanish National Health Survey and the 2009 European Health Interview Survey for Spain the aim of this study is to describe influenza vaccination coverage and time trends for the Spanish population as a whole and in recommended populations in four vaccination campaigns: 2005/2006, 2006/2007, 2008/2009 and 2009/2010. Our results show an increasing trend (OR 1.03) in seasonal influenza vaccine coverage for the total population from 2005/2006 to 2009/2010, especially in HCWs (21.8% in 2005/2006; 31.1% in 2009/2010). Coverage in people under 60 with a chronic disease remains low and did not vary significantly during the analyzed period. Immigrants presented a significantly lower probability of having received the influenza vaccine than indigenous people in the 2008/2009 campaign. Different strategies need to be implemented in order to achieve higher coverage levels in these at-risk populations. PMID- 21704110 TI - Selectively willing and conditionally able: HIV vaccine trial participation among women at "high risk" of HIV infection. AB - Efficacy studies of investigational HIV vaccines require enrollment of individuals at 'high risk' for HIV. This paper examines participation in HIV vaccine trials among women at 'high risk' for HIV acquisition. In-depth interviews were conducted with 17 African-American women who use crack cocaine and/or exchange sex for money/drugs to elicit attitudes toward medical research and motivators and deterrents to HIV vaccine trial participation. Interviews were digitally recorded and transcribed; data were coded and compiled into themes. Most women expressed favorable attitudes toward medical research in general. Motivators for trial participation included compensation; personal benefits including information, social services, and the possibility that the trial vaccine could prevent HIV; and altruism. Deterrents included: dislike of needles; distrust; concern about future consequences of participating. In addition, contingencies, care-giving responsibilities, and convenience issues constituted barriers which could impede participation. Respondents described varied, complex perspectives, and individual cases illustrate how these themes played out as women contemplated trial participation. Understanding factors which influence vaccine research participation among women at 'high risk' can aid sites to tailor recruitment procedures to local contexts. Concerns about future reactions can be addressed through sustained community education. Convenience barriers can be ameliorated by providing rides to study visits when necessary, and/or conducting study visits in accessible neighborhood locations. Women in this sample thought carefully about enrolling in HIV vaccine trials given the structural constraints within which they lived. Further research is needed regarding structural factors which influence personal agency and individuals' thinking about research participation. PMID- 21704111 TI - Recombinant HA1 produced in E. coli forms functional oligomers and generates strain-specific SRID potency antibodies for pandemic influenza vaccines. AB - Vaccine production and initiation of mass vaccination is a key factor in rapid response to new influenza pandemic. During the 2009-2010 H1N1 pandemic, several bottlenecks were identified, including the delayed availability of vaccine potency reagents. Currently, antisera for the single-radial immunodiffusion (SRID) potency assay are generated in sheep immunized repeatedly with HA released and purified after bromelain-treatment of influenza virus grown in eggs. This approach was a major bottleneck for pandemic H1N1 (H1N1pdm09) potency reagent development in 2009. Alternative approaches are needed to make HA immunogens for generation of SRID reagents in the shortest possible time. In this study, we found that properly folded recombinant HA1 globular domain (rHA1) from several type A viruses including H1N1pdm09 and two H5N1 viruses could be produced efficiently using a bacterial expression system and subsequent purification. The rHA1 proteins were shown to form functional oligomers of trimers, similar to virus derived HA, and elicited high titer of neutralizing antibodies in rabbits and sheep. Importantly, the immune sera formed precipitation rings with reference antigens in the SRID assay in a dose-dependent manner. The HA contents in multiple H1N1 vaccine products from different manufacturers (and in several lots) as determined with the rHA1-generated sheep sera were similar to the values obtained with a traditionally generated sheep serum from NIBSC. We conclude that bacterially expressed recombinant HA1 proteins can be produced rapidly and used to generate SRID potency reagents shortly after new influenza strains with pandemic potential are identified. PMID- 21704112 TI - Ginkgolide B attenuates ethanol-induced neurotoxicity through regulating NADPH oxidases. AB - Ethanol has long been demonstrated to trigger cell apoptosis in the central nervous system. The over-production of reactive oxygen species (ROS) is considered as one of the most important mechanisms involving in the apoptosis caused by ethanol. Ginkgolide B (GB), which was widely used as a monomer of traditional Chinese medicine, was reported to scavenge free radicals in endothelial cells and smooth muscle cells. But whether GB can prevent ethanol induced neurotoxicity is still unknown. The aim of this study was to investigate effects of GB on ethanol-induced cytotoxicity, oxidative stress and apoptosis and explore potential protective molecular mechanism of GB. It was found that GB inhibited cell injury and apoptosis in a dose-dependent manner in ethanol-treated PC12 cells by MTT and LDH assays. It was also found that activities of caspase-3 increased by ethanol were mostly abrogated by GB. Further, GB decreased the production of ROS and subsequent over-production of lipid peroxides. A significant increase of alcohol dehydrogenase (ADH) and CYP2E1 enzyme activity was found in the ethanol-exposed PC12 cells as compared to controls. However, GB pretreatment did not significantly affect ethanol-induced ADH and CYP2E1 activities. Quantitative real-time PCR and Western blot analysis demonstrated that ethanol treatment resulted in a significant increase in mRNA and protein expression of NADPH oxidases, which are main oxidases producing ROS in neurons. Moreover, expression and activities of NADPH oxidases were down-regulated by GB. These results indicate that ethanol-induced neurotoxicity is ameliorated by GB mainly through regulating expression and activity of NADPH oxidases. PMID- 21704113 TI - Characterization of the mechanisms of HIV-1 Vpr(52-96) internalization in cells. AB - Addition of Vpr C-terminus to various cell types provokes cell apoptosis. This property was recently shown useful to develop inhibitors of cell proliferation. In that context, we investigated the cellular uptake of rhodamine- and fluorescein-labeled Vpr(52-96) peptides to understand the mechanism of Vpr C terminus entry into cells. Dynamic light scattering data indicated that this peptide spontaneously formed polydispersed aggregates in cell culture medium. The fluorescently labeled Vpr(52-96) peptide was efficiently internalized, appearing either as large fluorescent patches in the cytoplasm or in a more diffuse form throughout the cell. Using isothermal titration calorimetry, we demonstrated that Vpr(52-96) can tightly associate with heparin, a glycosaminoglycan analog of heparan sulphate, suggesting a central role of the ubiquitous cell surface associated heparan sulphate proteoglycans for the internalization of Vpr C terminus. Fluorescently-labeled transferrin and methyl-beta-cyclodextrin showed that the Vpr C-terminus was mediated through clathrin- and caveolae/raft dependent endocytosis. We found that Vpr C-terminus uptake was partly blocked at 4 degrees C suggesting the importance of membrane fluidity for Vpr C-terminus entry. In fact, atomic force microscopy and liposome leakage further indicated that the Vpr peptide can destabilize and disrupt model membrane bilayers, suggesting that this mechanism may contribute to the passive entry of the peptide. Finally, using fluorescence lifetime imaging, we found that the Vpr(52 96) peptide was stable in cells for at least 48h, probably as a consequence of the poor accessibility of the peptide to proteolytic enzymes in aggregates. PMID- 21704114 TI - Comparison of antioxidant abilities of magnolol and honokiol to scavenge radicals and to protect DNA. AB - The antioxidant properties of magnolol and honokiol were evaluated in the experimental systems of reducing ONOO(-) and (1)O(2), bleaching beta-carotene in linoleic acid (LH) emulsion, and trapping 2,2'-azinobis(3-ethylbenzothiazoline-6 sulfonate) cationic radical (ABTS(+)*) and 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), and then were applied to inhibit the oxidation of DNA induced by Cu(2+)/glutathione (GSH) and 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH). Magnolol and honokiol were active to reduce ONOO(-) and (1)O(2). Honokiol showed a little higher activity to protect LH and to inhibit Cu(2+)/GSH-induced oxidation of DNA than magnolol. In addition, honokiol exhibited higher activities to trap ABTS(+)* and DPPH than magnolol. In particular, honokiol trapped 2.5 radicals while magnolol only trapped 1.8 radicals in protecting DNA against AAPH induced oxidation. The obtained results suggested that low antioxidant ability of magnolol may be related to the intramolecular hydrogen bond formed between di ortho-hydroxyl groups, which hindered the hydrogen atom in hydroxyl group to be abstracted by radicals. Therefore, the antioxidant capacity of magnolol was lower than that of honokiol. PMID- 21704116 TI - Autonomic regulation and maze-learning performance in older and younger adults. AB - There is growing evidence that centrally modulated autonomic regulation can influence performance on complex cognitive tasks but the specificity of these influences and the effects of age-related decline in these systems have not been determined. We recorded pre-task levels of respiratory sinus arrhythmia (RSA; an index of phasic vagal cardiac control) and rate pressure produce (RPP; an index of cardiac workload) to determine their relationship to performance on a cumulative maze learning task. Maze performance has been shown to reflect executive error monitoring capacity and non-executive visuo-motor processing speed. Error monitoring was predicted by RSA in both older and younger adults but by RPP only in the older group. Non-executive processes were unrelated to either measure. These data suggest that vagal regulation is more closely associated with executive than nonexecutive aspects of maze performance and that, in later life, pre-task levels of cardiac workload also influence executive control. PMID- 21704117 TI - Histone modifications on the adrenergic induction of type II deiodinase in rat pinealocytes. AB - Histone modifications have been shown to play an important role in regulating gene expression. In this study, we investigated the impact of histone modifications on the adrenergic-regulated transcription of type 2 deiodinase (Dio2), a CREB-target gene in the rat pinealocyte. Treatment of pinealocytes with inhibitors of aurora C, a histone kinase, resulted in an inhibitory effect on the adrenergic-stimulated histone H3 Ser10 phosphorylation and Dio2 transcription. Given the established link between histone phosphorylation and acetylation, the role of histone acetylation on the adrenergic-induced Dio2 transcription was investigated. Treatment of pinealocytes with histone deacetylase inhibitors inhibited the adrenergic-induced Dio2 transcription. Chromatin immunoprecipitation with antibodies against acetylated Lys14 of H3 showed an increase in DNA recovery of the promoter region of Dio2 following treatment with trichostatin A. Together, our results indicate that, beside activation of CREB, epigenetic factors such as histone modifications also play an important role in regulating Dio2 transcription. PMID- 21704118 TI - Recent developments in antiandrogens and selective androgen receptor modulators. AB - The androgens testosterone and dihydrotestosterone play an essential role in the development and maintenance of primary and secondary male characteristics. Androgens bind to a specific androgen receptor (AR), a ligand-dependent transcription factor which controls the expression of a large number of downstream target genes. The AR is an essential player in early and late prostate cancer, and may also be involved in some forms of breast cancer. It also represents a drug target for the treatment of hypogonadism. Recent studies furthermore indicate that targeting the AR in pathologies such as frailty syndrome, cachexia or polycystic ovary syndrome may have clinical benefit. Numerous AR ligands with very different pharmacological properties have been identified in the last 40 years and helped to treat several of these diseases. However, progress still needs to be made in order to find compounds with an improved profile with regard to efficacy, differentiation and side-effects. This will only be achieved through a better understanding of the mechanisms involved in normal and aberrant AR signaling. PMID- 21704115 TI - Molecular substrates of action control in cortico-striatal circuits. AB - The purpose of this review is to describe the molecular mechanisms in the striatum that mediate reward-based learning and action control during instrumental conditioning. Experiments assessing the neural bases of instrumental conditioning have uncovered functional circuits in the striatum, including dorsal and ventral striatal sub-regions, involved in action-outcome learning, stimulus response learning, and the motivational control of action by reward-associated cues. Integration of dopamine (DA) and glutamate neurotransmission within these striatal sub-regions is hypothesized to enable learning and action control through its role in shaping synaptic plasticity and cellular excitability. The extracellular signal regulated kinase (ERK) appears to be particularly important for reward-based learning and action control due to its sensitivity to combined DA and glutamate receptor activation and its involvement in a range of cellular functions. ERK activation in striatal neurons is proposed to have a dual role in both the learning and performance factors that contribute to instrumental conditioning through its regulation of plasticity-related transcription factors and its modulation of intrinsic cellular excitability. Furthermore, perturbation of ERK activation by drugs of abuse may give rise to behavioral disorders such as addiction. PMID- 21704119 TI - Angiopoietin 1 reduces rat follicular atresia mediated by apoptosis through the PI3K/Akt pathway. AB - The aim of this study was to determine the effect of the local inhibition of ANGPT1 on steroid production, proliferation and apoptosis of ovarian follicular cells and on the PI3K/AKT pathway. We also examined the effect of ANGPTs on follicular cell apoptosis and proliferation in early antral follicles (EAFs) in culture. Follicular cells expressing PCNA decreased after ANGPT1 Ab treatment. Moreover, ANGPT1 inhibition increased the levels of active caspase 3 and androsterone, but decreased estradiol, AKT phosphorylation and the area of smooth muscle cell actin. In cultured EAFs from prepubertal rats treated with diethylstilbestrol (DES), ANGPT1 increased PCNA and decreased apoptosis while ANGPT2 reversed these effects. These results show that ANGPT1 alters steroidogenesis, reduces ovarian apoptosis, and stimulates cell proliferation in antral follicles. ANGPT1 may exert these roles by regulating ovarian vascular stability and/or by a direct effect on follicular cells, possibly involving the PI3K/AKT pathway. PMID- 21704121 TI - The anatomical characteristics of the stria terminalis in the human brain: a diffusion tensor tractography study. AB - The stria terminalis (ST) connects the amygdale (AM) with the hypothalamus, anterior commissure, preoptic area, and septal region. Many animal studies have reported on the anatomy and function of the ST; in contrast, little is known about its anatomy and function in the human brain. In the current study, we attempted to investigate the anatomical characteristics of the ST in the normal human brain, using diffusion tensor tractography. We recruited 30 healthy volunteers for this study. Diffusion tensor images were scanned using 1.5-T, and the ST was obtained using FMRIB software. Values of fractional anisotropy, mean diffusivity, and tract volume of the ST were measured. STs passed from the AM to the anterior hypothalamus, through the region, around to the anterior margin of the temporal horn of the lateral ventricle, over the posterior and superior margin of the thalamus, behind the anterior commissure. No differences according to the side of the hemisphere and sex in terms of fractional anisotropy, mean diffusivity, and tract volume of the ST (P<0.05) were observed. We identified the ST and observed the anatomical characteristics of the ST in the normal human brain. We believe that the methodology and results reported here would be helpful to researchers and clinicians in this field. PMID- 21704120 TI - Postprandial triglyceride-rich lipoproteins induce hepatic insulin resistance in HepG2 cells independently of their receptor-mediated cellular uptake. AB - Non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance with the molecular basis of this association being not well understood. Here we studied the effect of hepatic triglyceride accumulation induced by postprandial triglyceride-rich lipoproteins (TGRL) on hepatic insulin sensitivity in HepG2 cells. Incubation of HepG2 cells with purified TGRL particles induced hepatocellular triglyceride accumulation paralleled by diminished insulin-stimulated glycogen content and glycogen synthase activity. Accordingly, insulin-induced inhibition of glycogen synthase phosphorylation as well as insulin-induced GSK-3 and AKT phosphorylation were reduced by TGRL. The effects of TGRL were dependent on the presence of apolipoproteins and more pronounced for denser TGRL. Moreover, TGRL effects required the presence of heparan sulfate-proteoglycans on the cell membrane and lipase activity but were independent of the cellular uptake of TGRL particles by receptors of the LDL receptor family. We suggest postprandial lipemia to be an important factor in the pathogenesis of NAFLD. PMID- 21704122 TI - Angiotensin II does not directly affect Abeta secretion or beta-/gamma-secretase activity via activation of angiotensin II type 1 receptor. AB - Recent studies suggest that brain angiotensin II (Ang II), the major effector molecule of the renin-angiotensin system, is implicated in the pathogenesis of Alzheimer's disease (AD). However, it remains unknown whether activation or blockade of the angiotensin II type 1 receptor (AT1R) has an impact on the secretion of amyloid-beta (Abeta), the key molecule in the pathogenesis of AD. In this study, the cell models cultured primary hippocampal neurons and human embryonic kidney 293 cells, were transfected with AT1R and amyloid precursor protein/presenilin-1 (PS1). The effects of activation/blockade of the AT1R on Abeta secretion, PS1 level and beta-/gamma-secretase activity were investigated in different cells. When AT1R was stimulated with Ang II at concentrations from 10nM to 1000nM, only a tendency toward increased Abeta secretion and beta-/gamma secretase activity was noticed in cultured primary hippocampal neurons. However, no significant change in soluble Abeta(40) or Abeta(42), the level of PS1, or secretase activity was found in the cells. Similarly, when the AT1R was blocked by losartan, no significant alteration of Abeta secretion, PS1 levels or secretase activity was detected. In conclusion, this in vitro study demonstrates that Ang II does not directly affect Abeta secretion or secretase activity via activation of AT1R. This study is significantly meaningful for exploring the pharmacologic mechanisms of angiotensin II receptor blockers in AD. PMID- 21704123 TI - Neural correlates of visuo-spatial working memory encoding--an EEG study. AB - The aim of the present electroencephalographic (EEG) study was to investigate neuronal correlates of working memory encoding in a visuo-spatial serial delayed match-to-sample task. A rapid serial visual presentation approach was used to dissociate brain activity related to encoding of visuo-spatial targets and cortical activity evoked by suppression of distracting information. During the task EEG was recorded and steady-state visually evoked potentials (SSVEPs) were calculated. Finally, standardized low-resolution electromagnetic tomography (sLORETA) was used to determine brain regions involved in visuo-spatial working memory encoding. A distributed task-relevant network comprising right temporal, parietal, and occipital areas was identified. Results suggest that activity of this network is amplified during actual encoding of targets into visual working memory, whereas the same network is attenuated in its activation when distracting visual information should be suppressed. Left prefrontal and anterior cingulate cortices do not seem to be involved in encoding of targets but only in suppression of distracting information, likely reflecting activity of an attention-based supervisory system. These results strongly emphasise the linkage between visuo-spatial attention and working memory during amplification of selected and suppression of irrelevant information. PMID- 21704124 TI - Age-related declines in the detection of passive wrist movement. AB - Age-related changes in proprioceptive ability and their contributions to postural instability have been well documented. In contrast, and despite the known importance of proprioceptive feedback in the control of coordinated arm and hand movement, studies focusing on upper limb proprioception in older populations are few and equivocal in their findings. This study focused on kinesthetic awareness about the wrist joint in healthy young and older adults. Passive movement detection thresholds (PMDTs) were twice as high in older compared to young participants. In contrast to previous findings demonstrating asymmetries in static position sense, PMDT did not differ between the dominant and non-dominant wrist joints nor did direction of joint displacement affect PMDT as has been reported for the lower limb. Preliminary analysis indicated that PMDT was significantly higher in older adults categorized as sedentary while active older adults were able to detect passive movement as well as young adults. These findings demonstrate that upper limb kinesthesia is impaired in older adults although the degree of impairment may be influenced by one's level of physical activity. PMID- 21704125 TI - Executive control in Parkinson's disease: effects of dopaminergic medication and deep brain stimulation on anti-cue keypress performance. AB - Using an anti-cue keypress task, we examined executive control in Parkinson's disease (PD) patients treated with deep brain stimulation (DBS) of the subthalamic nucleus (STN) and dopaminergic medication. Across sessions, we varied stimulation (on, off) and dopaminergic medication (on, off). Reaction time (RT) results of the PD patients and their age-matched controls showed a consistent pattern of RT costs and benefits generated by anti-cues with short and long preparation intervals, respectively. This pattern was evident in all sessions, except when DBS stimulation and medication were off. In this condition PD patients showed no RT benefits. These findings are discussed in terms of an executive control process that suppresses the automatic but inappropriate response activation generated by anti-cues. In PD this mechanism is severely compromised but it can be remediated by dopaminergic medication and DBS, suggesting an essential role of the basal ganglia in the selection and suppression of competing responses. PMID- 21704126 TI - Mutation screening of three Chinese families with genetic epilepsy with febrile seizures plus. AB - Genetic epilepsy with febrile seizures plus (GEFS+) is a familial autosomal dominant condition characterized by genetic heterogeneity. Five genes for GEFS+ identified in large families account for only a small proportion of families. Mutation in the majority of families with GEFS+ has not identified yet. The aim of our study is to search for the gene responsible for GEFS+ in three Chinese families by linkage analyses and a sequencing approach and to investigate the importance of coding and noncoding regions variations of four known GEFS+ genes (SCN1A, SCN1B, GABRG2 and SCN2A) in Chinese families. Results showed that a 6-cM candidate interval at 5q33-34 with a maximum LOD scores of 2.043 was identified in families B. Sequencing candidate gene GABRG2 and GABRA1 in this region did not identify a causative mutation. Moreover, no mutation was found in coding and noncoding regions of the four genes in three Chinese families. Besides excluding coding regions of four known GEFS+ genes, we also excluded the possibility of a mutation in the promoter, exon-intron boundaries, 5' untranslated regions (5' UTRs), and 3' UTRs of four known GEFS+ genes in three Chinese families. In conclusion, the present study demonstrates the heterogeneity of the etiologies of GEFS+. There are as yet undiscovered mechanisms underlying GEFS+. PMID- 21704127 TI - Biological targets of isothiocyanates. AB - BACKGROUND: Isothiocyanates are phytochemicals with a broad array of effects in biological systems. Bioactivity includes the stimulation of cellular antioxidant systems, induction of apoptosis and interference with cytokine production and activity. Epidemiological evidence and experimental studies indicate that naturally occurring isothiocyanates and synthetic derivatives have anti-cancer and anti-inflammatory properties. SCOPE OF REVIEW: This review focuses on the molecular targets of isothiocyanates, and how target modification translates into a biological response. MAJOR CONCLUSIONS: Isothiocyanates may mediate their effects via direct protein modification or indirectly by disruption of redox homeostasis and increased thiol oxidation. Some target proteins have been identified, but in-depth searches with new techniques are needed to reveal novel targets. Site-directed mutagenesis and isothiocyanate structure-activity relationships will assist in determining the biological significance of specific modifications. GENERAL SIGNIFICANCE: Target identification is important for rational drug design and exploiting the therapeutic potential of isothiocyanates. It also provides insight into the diverse pathways that these compounds regulate. PMID- 21704128 TI - Left-lateralized N170 response to unpronounceable pseudo but not false Chinese characters-the key role of orthography. AB - A negative event-related potential (ERP) component, known as N170, can be readily recorded over the posterior left brain region when skilled readers are presented with visual words. This left-lateralized word-related N170 has been attributed either to linguistic processes, particularly phonological processing, or to the role of orthographic regularity, emphasizing a perceptual origin. This debate, however, is difficult to resolve in the context of alphabetic scripts because of the tight relations between orthography and phonology. In contrast, Chinese characters have arbitrary mappings between orthographic and sound forms, making it possible to tease apart these two properties of visual words. We therefore addressed this issue by examining ERP responses to Chinese characters and three types of structurally matched but unpronounceable stimuli: pseudo-characters, false-characters, and stroke combinations. A content-irrelevant color matching task was adopted to minimize potentially different top-down modulations across stimulus types. Results show that, relative to false-characters and stroke combinations, real- and pseudo-characters evoked greater N170 in the left posterior brain region. Critically, despite being unpronounceable, pseudo characters produced the same amplitude and left-lateralized N170, just as real characters. These results provide strong evidence that orthography rather than phonology serves as the main driver for the enhanced and left-lateralized N170 to visual words. PMID- 21704129 TI - Walking in circles: navigation deficits from Parkinson's disease but not from cerebellar ataxia. AB - Little is known on the role of neuronal structures for spatial navigation. Our goal was to examine how Parkinson's disease (PD) and cerebellar ataxia, as human lesion models of the basal ganglia and cerebellum, affect spatial navigation round a circular walking path, blindfolded. Twelve subjects with idiopathic PD (ON and OFF medication), eight subjects with cerebellar ataxia and a control group of 20 age-matched healthy subjects participated. All groups performed well when walking around the circle with eyes open. In the eyes-closed condition, control subjects overshot the outlined trajectory but returned to their initial position, thus walking a further distance with eyes closed than with eyes open. When OFF medication, PD subjects navigated a larger radius than controls with eyes closed. When ON levodopa, PD subjects walked a similar distance as controls but with even larger errors in endpoint. Surprisingly, cerebellar patients navigated the circular walking task in the eyes closed condition with even more accuracy (i.e. following the outlined circle) than control and PD subjects. We conclude that blindfolded navigation around a previously seen circle requires intact basal ganglia, but not cerebellar input. PMID- 21704130 TI - Neuroactive steroids: focus on human brain. AB - Studies in experimental animals have revealed important roles of neuroactive steroids in the control of central nervous system functions during physiological and pathological conditions, suggesting that they may represent good candidates for the development of neuroprotective strategies for neurodegenerative and psychiatric disorders. Even if the characterization of the roles played by neuroactive steroids in humans is still at the beginning, several data are already available showing that they may be synthesized within the human CNS. Among the different enzymes, a prominent role is dedicated to aromatase that synthesizes estradiol whose neuroprotective effects have been described in experimental animals. Neuroactive steroid levels are modified by neurodegenerative conditions (i.e. Alzheimer's and Parkinson's diseases, multiple sclerosis) or in other mental diseases (i.e. schizophrenia), and may have an important role in physiological conditions, as the reorganization of grey and white matter during human puberty and adolescence or as a consequence of emotional responses. The interaction of some neuroactive steroids (i.e., allopregnanolone and isopregnanolone) with GABA-A receptor is particularly important in mood disorders. The presumptive role of estradiol and progesterone in neuroprotection is here discussed by comparing contradictory data that have been collected in humans. In conclusion, the state of the art of our knowledge of the role of neuroactive steroids in the normal and pathological human brain suggests several lines of future therapeutic developments in the treatments of neurological, neurodegenerative and affective disorders. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. PMID- 21704131 TI - Genetic, pharmacological and lesion analyses reveal a selective role for corticohippocampal GLUN2B in a novel repeated swim stress paradigm. AB - Glutamate and N-methyl-d-aspartate receptor (NMDAR) dysfunction is strongly implicated in the pathophysiology of mood and anxiety disorders. Treatment with NMDAR antagonists has antidepressant efficacy in treatment-resistant depressives. In preclinical rodent models, NMDAR antagonist administration reduces anxiety- and stress-related behaviors in concert with increases in prefrontal cortical (PFC) dendritic spinogenesis and synaptic proteins. While these effects have been attributed to actions at the NMDAR GluN2B subunit, the precise role of cortical GluN2B in mediating emotional behaviors and stress-responsivity is not fully understood. Here, we employed a novel mutant model in which the GluN2B subunit is postnatally deleted in principal neurons in the cortex and the dorsal CA1 subregion of the hippocampus. GluN2BKO mice were phenotyped on a battery of tests for anxiety-related (light/dark exploration, stress-induced hyperthermia) and antidepressant-sensitive (sucrose preference, novelty-induced hypophagia, single trial forced swim) behaviors. A novel repeated inescapable forced swim paradigm (riFS) was developed to assess behavioral responses to repeated stress in the GluN2BKO mice. For comparison, non-mutant C57BL/6J mice were tested for single trial forced swim behavior after systemic Ro 25-6981 treatment and for riFS behavior after lesions of the ventromedial prefrontal cortex. riFS-induced alterations in corticolimbic GluN2B expression were also examined in C57BL/6J mice. We found that GluN2BKO mice reduced "despair-like" behavior in the riFS procedure, as compared to GluN2BFLOX controls. By contrast, GluN2BKO mice showed minimal alterations on anxiety-like or antidepressant-sensitive assays, including the single-trial forced swim test. In C57BL/6J mice, induction of "despair-like" responses in the riFS test was attenuated by vmPFC lesions, and was associated with changes in limbic GluN2B expression. Collectively, these data suggest that cortical GluN2B plays a major role in modulating adaptive responses to stress. Current findings provide further support for GluN2B as a key mechanism underlying stress responsivity, and a novel pharmacotherapeutic target for stress-related neuropsychiatric disorders. PMID- 21704132 TI - Cell-type-specific sub- and suprathreshold receptive fields of layer 4 and layer 2/3 pyramids in rat primary visual cortex. AB - Connectivity of cortical pyramidal neurons is layer-specific in the primary visual cortex (V1) and this is thought to be reflected in different receptive field (RF) properties of layer 4 and layer 2/3 pyramidal neurons (L4Ps and L2/3Ps, respectively). However, it remains unclear how the two cell populations convert incoming visually driven synaptic inputs into action potential (AP) outputs. Here I compared postsynaptic potentials (PSPs) and AP responses of L4Ps and L2/3Ps in the binocular portion of rat V1 by intrinsic optical imaging (IOI) targeted whole-cell recordings followed by anatomical identification and dendritic reconstructions. L2/3Ps had about 2-fold longer dendritic branches and a higher number of branch points and endings in their apical portions. Functionally, L2/3Ps had more hyperpolarized resting potentials and lower rates of spontaneous APs (medians: 0.07 vs. 0.60 AP/s). PSP responses to optimally oriented moving bars were comparable in terms of amplitude (16.0+/-0.9 vs. 17.3+/ 1.1 mV for L2/3Ps and L4Ps, respectively), reliability and size of the RF. The modulated component of subthreshold responses of L4Ps to optimal sinusoidal drifting gratings was larger and their PSP onset latency in response to bars flashed in the cell's RF center were shorter (60 vs. 86 ms). In contrast to the similarities of PSP responses to moving bars, AP responses of L2/3Ps were more sparse (medians: 0.7 vs. 2.9 APs/stimulus passage), less reliable, but sharper in terms of angular size. Based on the differences of subthreshold inputs, I conclude that L4Ps may receive mostly thalamic inputs, whereas L2/3Ps may receive both thalamic and cortical inputs from layer 4. The comparable subthreshold responses to moving bars are converted by L2/3Ps into sparser but sharper AP outputs possibly by cell-type-specific AP-generating mechanisms or differences in visually driven inhibitory inputs. PMID- 21704133 TI - Caudal nuclei of the rat nucleus of the solitary tract differentially innervate respiratory compartments within the ventrolateral medulla. AB - A substantial array of respiratory, cardiovascular, visceral and somatic afferents are relayed via the nucleus of the solitary tract (NTS) to the brainstem (and forebrain). Despite some degree of overlap within the NTS, specificity is maintained in central respiratory reflexes driven by second order afferent relay neurons in the NTS. While the topographic arrangement of respiratory-related afferents targeting the NTS has been extensively investigated, their higher order brainstem targets beyond the NTS has only rarely been defined with any precision. Nonetheless, the various brainstem circuits serving blood gas homeostasis and airway protective reflexes must clearly receive a differential innervation from the NTS in order to evoke stimulus appropriate behavioral responses. Accordingly, we have examined the question of which specific NTS nuclei project to particular compartments within the ventral respiratory column (VRC) of the ventrolateral medulla. Our analyses of NTS labeling after retrograde tracer injections in the VRC and the nearby neuronal groups controlling autonomic function indicate a significant distinction between projections to the Botzinger complex and preBotzinger complex compared to the remainder of the VRC. Specifically, the caudomedial NTS, including caudal portions of the medial solitary nucleus and the commissural division of NTS project relatively densely to the region of the retrotrapezoid nucleus and rostral ventrolateral medullary nucleus as well as to the rostral ventral respiratory group while avoiding the intervening Botzinger and preBotzinger complexes. Area postrema appears to demonstrate a pattern of projections similar to that of caudal medial and commissural NTS nuclei. Other, less pronounced differential projections of lateral NTS nuclei to the various VRC compartments are additionally noted. PMID- 21704135 TI - Immobilization of Russian VX skin depots by localized cooling: implications for decontamination and medical countermeasures. AB - The chemical weapon nerve agent known as Russian VX (VR) is a potent organophosphorus (OP) compound that is much less studied than its VX analogue with respect to toxicity, as well as to the effectiveness of several known countermeasures against it. An anaesthetized domestic swine model was utilized to assess several approaches in mitigating its toxicity, including the utility of cooling VR treated skin to increase the therapeutic window for treatment. The 6h LD50 for VR topically applied on the ear was 100 MUg/kg. Treatment of VR exposed animals (5 * LD50) with pralidoxime (2PAM) very poorly regenerated inhibited blood cholinesterase activity, but was partially effective in preventing signs of OP poisoning and increasing survival. In contrast, treatment with the Hagedorn oxime HI-6 reactivated cholinesterase, eliminated all signs of poisoning and prevented death. Decontamination with the Reactive Skin Decontaminant Lotion (RSDL) 15 min after VR exposure was completely effective in preventing death. Cooling of the VR exposure sites for 2 or 6h prevented signs of OP poisoning and death during the cooling period. However, these animals died very quickly after the cessation of cooling, unless they were treated with oxime or decontaminated with RSDL. Blood analyses showed that cooling of agent exposure sites delayed the entry of VR into the bloodstream. Medical treatment with HI-6 and to a lesser extent 2PAM, or decontamination with RSDL are effective in protecting against the toxic effects of cutaneous exposure to VR. Immobilizing this agent (and related compounds) within the dermal reservoir by cooling the exposure sites, dramatically increases the therapeutic window in which these medical countermeasures are effective. PMID- 21704134 TI - Rapid antidepressant changes with sleep deprivation in major depressive disorder are associated with changes in vascular endothelial growth factor (VEGF): a pilot study. AB - While conventional antidepressants benefit many patients with major depressive disorder (MDD), as much as eight to 12 weeks can elapse before significant improvements in depressive symptoms are seen. Treatments that act more rapidly in MDD are urgently needed. Sleep deprivation (SD) has been shown to produce a rapid antidepressant response within one day in 50-60% of patients with MDD; thus, identifying its antidepressant mechanism may contribute to the development of antidepressants that act more rapidly. The present study evaluated the effects of 39 h of SD on mood, as well as on plasma levels of brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in patients with MDD. After a drug-free period of at least two weeks, 11 patients (6 males, 5 females; ages 25-62) who met DSM-IV criteria for MDD underwent total SD. Plasma samples for BDNF and VEGF assays were collected on Days 1 (baseline) and 2. The six-item Hamilton Rating Scale for Depression (HAMD-6) was the primary outcome measure. HAMD-6 scores decreased significantly after SD (Day 2). SD was negatively correlated with change in HAMD-6 score and change in VEGF levels, indicating that as depression scores decreased following SD, VEGF plasma levels increased. In contrast, SD did not alter plasma BDNF concentrations, nor was an association found between BDNF levels and clinical improvement on the HAMD-6. These results suggest that SD is associated with mood-related changes in plasma VEGF levels, but not plasma BDNF levels. Further studies using larger sample sizes are needed to confirm these preliminary findings. PMID- 21704136 TI - Correlation between the destruction of tight junction by patulin treatment and increase of phosphorylation of ZO-1 in Caco-2 human colon cancer cells. AB - Patulin is a mycotoxin and its contamination of food has been reported to cause gastrointestinal inflammation, ulcers, and bleeding. The toxicity of patulin is thought to be due to the destruction of tight junctions (TJs) in gastrointestinal tissues. However, the precise mechanism has not been clarified. Here, we investigated the phosphorylation of TJ components. The transepithelial electrical resistance (TER) of Caco-2 human colon cancer cells decreased gradually during the first 24h of treatment with 50MUM patulin. Immunofluorescence microscopy showed that the TJ proteins ZO-1 and claudin-4, but not occludin, had decreased after 24h and decreased from the cell-cell contact regions of TJs after 48h of patulin treatment. Western blotting showed that the level of ZO-1 decreased after 48h of patulin treatment, but the levels of claudin-4 and occludin remained at the initial level until 72h. Phosphorylation of ZO-1 was detected by 24h and increased markedly after 72h of patulin treatment. However, phosphorylation of claudin-4 and occludin was not detected by probing with anti-phosphotyrosine antibody. Immunoprecipitation showed that interaction of ZO-1 with claudin-4 had decreased after 48h and was completely absent after 72h. These results suggest that phosphorylation caused the degradation of ZO-1 protein and the decrease in TER induced by patulin treatment of Caco-2 cells. PMID- 21704137 TI - Effect of brominated flame retardant BDE-47 on androgen production of adult rat Leydig cells. AB - As one of the most abundant polybrominated diphenylethers (PBDEs) detected in adipose tissue and breast milk of humans, 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) is considered as a potential endocrine disruptor. The objective of this study is to explore whether environment-related level of BDE-47 could affect the androgen production in rat Leydig cells. Rat adult Leydig cells (ALCs) were treated with 10(-8) to 10(-4)M BDE-47 in vitro, the production of testosterone (T) and steroidogenic acute regulatory (StAR) protein level were determined. BDE 47 significantly increased basal T production and steroidogenic acute regulatory protein (StAR) level of ALCs after treatment with 10(-4)M BED-47. Overall, LH (0.1ng/ml) stimulated T production in ALCs by 6 folds, however it did not increase T production in BDE-47-treated ALCs when compared to untreated ALC. Both 8-Br-cAMP (for cAMP signaling) and 22R-hydroxycholesterol (22-diol, for P450 cholesterol side chain cleavage enzyme P450scc activity) significantly increased T production in ALCs treated with BDE-47 from 10(-7) to 10(-5)M. The results of this study indicate that environment-related level of BDE-47 in vitro increased T production in a dose-dependent manner. The stimulated effects of BDE-47 on StAR and P450scc might play key roles in BDE-47-mediated stimulation of T production. PMID- 21704138 TI - EGCG-meditated cyto- and genotoxicity in HaCat keratinocytes is impaired by cell mediated clearance of auto-oxidation-derived H2O2: an algorithm for experimental setting correction. AB - Several lines of evidence suggest that besides antioxidant also prooxidant properties are crucially involved in cytotoxic and protective activities of the major green tea catechin epigallocatechin-3-gallate (EGCG) in vitro (Elbling et al., 2011). Furthermore recent data suggest that EGCG induces oxidative stress also in vivo (Li et al., 2010). Here we set out to identify factors modulating cellular effects of EGCG in vitro. Using the HaCat keratinocytes model, we demonstrate that the cytotoxic, genotoxic and signal-activating effects of EGCG are significantly dependent on the ratio of cell number to working volume. Treatment with identical EGCG concentrations at altered experimental settings resulted in IC(50) values differing up to orders of magnitude and could even exert contradictory effects. This effect was based on cell-mediated clearance of autooxidation-derived H(2)O(2) from the supernatant. In order to estimate EGCG/H(2)O(2) concentrations equally effective under different settings, we have rationally derived and experimentally verified a simple algorithm relating concentration, working volume, cell number and - indirectly - exposure time. Algorithm application resulted in similar H(2)O(2) clearance curves from cell supernatants as well as comparable EGCG/H(2)O(2) effects at different settings. Our results demonstrate the importance of standardized experimental settings when investigating cytotoxic and/or beneficial effects of autooxidizing compounds. PMID- 21704139 TI - Drug release behaviors of a pH sensitive semi-interpenetrating polymer network hydrogel composed of poly(vinyl alcohol) and star poly[2-(dimethylamino)ethyl methacrylate]. AB - A series of pH sensitive semi-interpenetrating polymer network (semi-IPN) structural hydrogels composed of poly(vinyl alcohol) (PVA) and 21-arm star poly[2 (dimethylamino)ethyl methacrylate] (star PDMAEMA) with different molecular weight were prepared. Riboflavin was used as a model drug to evaluate the drug loading capacities and drug release behaviors of the semi-IPN structural hydrogels. The molecular weight of the star PDMAEMA polymers was calculated by GPC, and the formation of semi-IPN structure was confirmed by FTIR and SEM. It was found that the molecular weight of star PDMAEMA has significant effect on the structure, swelling ratio and drug release behaviors of the semi-IPN hydrogel at different pH conditions. The results suggested that the PVA/star PDMAEMA-50,000 hydrogel exhibited highest swelling ratio and drug loading capacity. The pH-sensitive semi IPN hydrogel based on star PDMAEMA could be a promising drug delivery system due to the controllable porous structure. PMID- 21704140 TI - Solid lipid nanoparticles suspension versus commercial solutions for dermal delivery of minoxidil. AB - Solid lipid nanoparticles have been reported as possible carrier for skin drug delivery. Solid lipid nanoparticles are produced from biocompatible and biodegradable lipids. Solid lipid nanoparticles made of semi-synthetic triglycerides stabilized with a mixture of polysorbate and sorbitan oleate were loaded with 5% of minoxidil. The prepared systems were characterized for particle size, pH and drug content. Ex vivo skin penetration studies were performed using Franz-type glass diffusion cells and pig ear skin. Ex vivo skin corrosion studies were realized with a method derived from the Corrositex((r)) test. Solid lipid nanoparticles suspensions were compared to commercial solutions in terms of skin penetration and skin corrosion. Solid lipid nanoparticles suspensions have been shown as efficient as commercial solutions for skin penetration; and were non corrosive while commercial solutions presented a corrosive potential. Solid lipid nanoparticles suspensions would constitute a promising formulation for hair loss treatment. PMID- 21704141 TI - Chemical and in vitro enzymatic stability of newly synthesized celecoxib lipophilic and hydrophilic amides. AB - Five celecoxib (CXB) acylamide sodium salts, MP-CXB, Cy-CXB, Bz-CXB, CBz-CXB and FBz-CXB were synthesized and characterized. Two simple, fast and validated RP HPLC methods were developed for simultaneous quantitative determination of the amides and celecoxib in aqueous and biological samples and LOD and LOQ were <=13.6 and <=40ng/mL, respectively. The solubility and logP(app) of the amides, in relevant media, were determined. The chemical hydrolysis, at 60, 70 and 80 degrees C, of MP-CXB was studied at GIT-relevant pH (1.2, 6.8 and 7.4) and of CY CXB was studied at skin relative pH (5.4 and 7.4). Significant hydrolysis was observed for MP-CXB at pH 1.2 only with half-lives 28.28, 11.64 and 3.53h at 60, 70 and 80 degrees C, respectively, with extrapolated half-lives of 2060 and 443h at 25 and 37 degrees C, respectively. The hydrolysis of all amides was studied in rat live homogenate and only Cy-CXB was hydrolyzed with half-life of 3.79h. The hydrolysis of MP-CXB and Cy-CXB was studied in human plasma and neither was hydrolyzed. It is finally suggested that hydrophobic interactions plays a role in the binding of susceptible acylamides to the hepatic hydrolyzing enzyme since only amides with saturated hydrocarbon chains underwent hydrolysis. PMID- 21704142 TI - Investigation of compressibility and compactibility parameters of roller compacted Theophylline and its binary mixtures. AB - Roller compaction is a dry granulation method which results in tablets with inferior tensile strength comparing to direct compaction. The effect of roller compaction on compressibility and compactibility of tablets prepared from Theophylline anhydrate powder, Theophylline anhydrate fine powder and Theophylline monohydrate was investigated by measuring tensile strength of tablets as well as calculating compressibility and compactibility parameters by Leuenberger equation. The tablets under the same conditions were prepared by direct compaction and roller compaction. The binary mixtures of Theophylline anhydrate powder, Theophylline anhydrate fine powder, Theophylline monohydrate and microcrystalline cellulose were prepared in order to determine the optimal ratio of active material and excipients which delivers a sufficient mechanical strength of tablets. Tensile strength of MCC tablets and compactibility parameters calculated by Leuenberger equation after roller compaction was significantly decreased, while THAP, THAFP and THMO tablets showed only a minor reduction in compactibility and compressibility. Adding MCC to a mixture with Theophylline showed that the right choice and ratio of excipients can enable a sufficient mechanical strength of the tablets after roller compaction. PMID- 21704143 TI - Analgesic effects and anti-inflammatory properties of the crude methanolic extract of Schwenckia americana Linn (Solanaceae). AB - AIM OF THE STUDY: To evaluate analgesic effect and anti-inflammatory properties of Schwenckia americana (Solanaceae), a medicinal plant used for treating rheumatic pains and swelling in North-western Nigeria. MATERIALS AND METHODS: Three doses (25mg/kg, 50mg/kg and 100mg/kg) of the crude methanolic extract of Schwenkia americana were evaluated for analgesic and anti-inflammatory activities using acetic acid induced writhing test, formalin induced nociception, and formalin induced hind paw oedema in rats. RESULTS: All doses (25, 50, 100mg/kg) of the extract tested were effective. The extract at the tested doses produced a percentage inhibition of the acetic acid induced abdominal constriction of (53.3, 58.0 and 86.7%), respectively. A percentage inhibition of the formalin induced nociception of 44.00, 56.04, and 56.04% (early phase) and 33.00, 36.63 and 59.71% (late phase) was also produced. The inhibition of oedema formation increased with increasing dosage from 25 to 100mg/kg. The crude extract produced a statistically significant analgesic and anti-inflammatory activity comparable to the effect of standard drug (10mg/kg Piroxicam). CONCLUSION: This study demonstrated the potential analgesic and anti-inflammatory properties of crude methanolic extract of Schwenkia americana thus justifying its traditional usage. PMID- 21704144 TI - Ethnopharmacological survey of medicinal plants in Maden (Elazig-Turkey). AB - AIM OF THE STUDY: This study aimed to identify wild plants collected for medical purposes by the local people of Maden County, located in the Eastern Anatolia Region of Turkey, and to establish the uses and local names of these plants. MATERIALS AND METHODS: Field study was carried out over a period of approximately 2 years (2008-2010). During this period, 131 vascular plant specimens were collected. Demographic characteristics of participants, local plant names, utilized parts and preparation methods of the plants were investigated and recorded. In the scope of the study, the plant species were collected; herbarium materials were prepared; and the specimens were entitled. The Zazas are of the major ethnic group in the region. In addition, the relative importance value of the species was determined and informant consensus factor (FIC) was calculated for the medicinal plants included in the study. RESULTS: A total of 88 medical plants belonging to 41 families were identified in the region. 4 plants out of 88 were recorded to be used for curative purposes for the first time. It was determined that the local names of four different kinds of plants used in Maden were same as the different kinds of plants used in different regions. The most encountered medicinal plant families were Urticaceae (>21%), Rosaceae and Lamiaceae (>17% of use-reports), Asteraceae (>13%), Fabaceae (>8%), Brassicaceae (>7%), Poaceae (>4%); the most common preparations were decoction and infusion. Mentha spicata L. subsp. spicata, Rosa canina L. and Urtica dioica L. was the plants most used by the local people. Anthemis wiedemanniana Fisch. and Mey., Bunium paucifolium DC. var. brevipes (Freyn & Sint.) Hedge & Lam., Tchihatchewia isatidea Boiss., Thymus haussknechtii Velen. were found to be the endemic plants used for medical purposes in Maden, Turkey. The medicinal uses of Bunium paucifolium DC. var. brevipes (Freyn & Sint.) Hedge & Lam., Hippophae rhamnoides L. subsp. caucasica Roussi, Gladiolus atroviolaceus Boiss., Ixiolirion tataricum (Pallas) Herbert subsp. montanum (Labill.) Takht. were recorded for the first time. CONCLUSION: Herbal treatment has become a tradition for the residents of the study region. These plants, which are used in the treatment of many diseases. Comparison of the data obtained in this study from the plants growing in Maden with the experimental data obtained in the previous laboratory studies proved most of the ethnobotanical usages. Literature review showed that curative plants of Maden are used in different parts of the world in the treatment of the same or similar diseases. If a plant is used to treat the same disease in different places across the world then its pharmacologic effect could be accepted. It would be beneficial to conduct pharmacologic studies on such plants. These plants, used in the treatment of many different diseases, are in this region at abundant amounts. Drying enabled local people to use medicinal plants during all seasons of the year. This study identified not only the wild plants collected for medical purposes by local people of Maden County in the Eastern Anatolia Region, but also the uses and local names of these plants. It is tried to generate a source for persons studying in ethnobotany, pharmacology and chemistry sciences by comparing knowledge gained from traditionally used herbs with previous laboratory studies. PMID- 21704145 TI - Pharmacological evaluation of insulin mimetic novel suppressors of PEPCK gene transcription from Paeoniae Rubra Radix. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Paeoniae Rubra Radix (root of Paeonia lactiflora) has been frequently employed in Traditional Chinese Medicine (TCM) as and anti diabetic therapy to enhance blood circulation and dissipate stasis. AIM OF THE STUDY: Previously, we identified a novel hypoglycemic action of a crude extract from Paeoniae Rubra Radix, which also suppressed phosphoenolpyruvate carboxykinase (PEPCK) gene transcription. Therefore, the current investigation intended to elucidate potential active bio-constituents of this herb and mechanisms of action. MATERIALS AND METHODS: Glucocorticoid receptor (GR) nuclear localization, the PEPCK messenger (m)RNA level, pregnane X receptor (PXR) mRNA expression, cAMP-responsive element-binding protein (CREB) serine phosphorylation and DNA binding were evaluated in dexamethasone (Dex) and 8-bromo-cAMP (CA) stimulated H4IIE cells, while efficacy of agents was assessed in a stable cell line containing a green fluorescent protein (GFP) reporter driven by the PEPCK promoter. HPLC profiling, colorimetric assays, and NMR analysis were employed for chemical characterization purpose. RESULTS: An extract of Paeoniae Rubra Radix lacking the insulin mimetic compound, 1,2,3,4,6-penta-O-galloyl-beta-d-glucose (PGG), and termed the non-PGG fraction (NPF), consisting of tannin polymers, suppressed PEPCK expression in the presence of an insulin receptor antagonist (HNMPA-AM(3)), suggesting the action of this fraction is independent of the insulin receptor. Furthermore, Dex-stimulated GR nuclear localization and transactivation were prevented by the NPF. Similarly, CA-stimulated CREB serine phosphorylation and DNA binding were also inhibited by the NPF in H4IIE cells. Hence NPF antagonizes both signaling pathways that induce PEPCK gene transcription. CONCLUSION: In conclusion, the current study proposes that the potent suppressive activity on PEPCK gene transcription observed with Paeoniae Rubra Radix extract, can be attributed to at least two distinct components, namely PGG and NPF. PMID- 21704146 TI - Pharmacokinetics of ferulic acid and potential interactions with Honghua and clopidogrel in rats. AB - AIM OF THE STUDY: Ferulic acid (FA), a compound isolated from herbs, has a big potential to be developed into a useful drug for the treatment of cardiovascular disease. Early estimation of potential drug interaction is critical for drug development. As a common Chinese herb and Western drug respectively, Honghua and clopidogrel are often combined with FA-containing herbs to treat cardiovascular disease in clinical practice. This study aimed to investigate the pharmacokinetics of FA and potential interaction with Honghua and clopidogrel in rats. MATERIALS AND METHODS: The experiments were performed on following three groups: FA alone (10mg/kg, P.O.), combination of FA and Honghua (700 mg/kg, P.O.), combination of FA and clopidogrel (7 mg/kg, P.O.). Blood samples were collected before dosing and at 0, 2, 4, 7, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180 and 210 min after drug administration to determine the plasma drug concentration of FA. RESULTS: FA was rapidly absorbed following oral administration with a mean time to peak plasma concentration (T(max)) of 0.03 h. The corresponding maximum plasma concentration (C(max)) and the area under the concentration-time curve (AUC) were 8174.55 ng/L and 2594.45 h ng/mL respectively. Coadministration of Honghua and clopidogrel resulted in a 63.5% and 79.7% increase in the AUC respectively. The C(max) of FA was significantly increased by coadministration with clopidogrel (74.3%, p<0.01). Moreover, the T(max) of FA when coadministered with Honghua or clopidogrel was 3 and 3.76 times slower than when administered alone. Other pharmacokinetic parameters estimated for FA were also altered by the coadministrations, but no statistically significant differences were observed. CONCLUSION: FA was rapidly absorbed with a low bioavailability after a single oral administration. The pharmacokinetics profile of FA in rats was partly altered by the coadministration of FA with Honghua or clopidogrel. PMID- 21704147 TI - Impaired hypoxic response in senescent mouse brain. AB - Tissue hypoxia leads to activation of endogenous adaptive responses that involve a family of prolyl hydroxylase domain proteins (PHD1-3) with oxygen sensing properties, hypoxia inducible transcription factors (HIFs), and cytoprotective HIF target genes such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF). The hypoxic induction of these genes is regulated by oxygen dependent hydroxylation of HIFalpha subunits by PHDs, which signals their proteasomal degradation. In this study, mice of different age were exposed to hypoxia or subjected to cerebral ischemia after hypoxic pre-conditioning. We found an impaired hypoxic response in the brain, characterized by elevated levels and impaired downregulation of PHD1. Furthermore, an attenuated hypoxic activation of VEGF and EPO, as well as of other HIF-target genes such glucose transporter-1 and carbonic anhydrase 9 was found in senescent brain. Finally, we observed a loss of the protective effect of hypoxic pre-conditioning on subsequent cerebral ischemia with increasing age. Thus, the impaired hypoxic adaptation, resulting in compromised hypoxic activation of neuroprotective factors, could contribute to neurodegenerative processes with increasing age, and might have implications for treating age-related disorders. PMID- 21704148 TI - Development of an animal model for chronic mild hyperhomocysteinemia and its response to oxidative damage. AB - The purpose of this study was to develop a chronic chemically induced model of mild hyperhomocysteinemia in adult rats. We produced levels of Hcy in the blood (30MUM), comparable to those considered a risk factor for the development of neurological and cardiovascular diseases, by injecting homocysteine subcutaneously (0.03MUmol/g of body weight) twice a day, from the 30th to the 60th postpartum day. Controls received saline in the same volumes. Using this model, we evaluated the effect of chronic administration of homocysteine on redox status in the blood and cerebral cortex of adult rats. Reactive oxygen species and thiobarbituric acid reactive substances were significantly increased in the plasma and cerebral cortex, while nitrite levels were reduced in the cerebral cortex, but not in the plasma, of rats subjected to chronic mild hyperhomocysteinemia. Homocysteine was also seen to disrupt enzymatic and non enzymatic antioxidant defenses in the blood and cerebral cortex of rats. Since experimental animal models are useful for understanding the pathophysiology of human diseases, the present model of mild hyperhomocysteinemia may be useful for the investigation of additional mechanisms involved in tissue alterations caused by homocysteine. PMID- 21704150 TI - C-T variant in a miRNA target site of BCL2 is associated with increased risk of human papilloma virus related cervical cancer--an in silico approach. AB - MicroRNAs control gene expression at the posttranscriptional level by base pairing to the 3'-UTR of their target mRNAs, thus leading to mRNA degradation of protein fabrication. We hypothesize, SNPs within miRNAs and their targets could be of significance to an individual's risk of developing cancer. We analyzed in silico SNP information on cervical cancer associated aberrant alleles and further investigated this in a case-control study by examining eleven SNPs from different genes. It was observed that a C to T polymorphism in putative miRNA target site of BCL2 was significantly conspicuous for the aberrant SNP allele in cancer tissues as compared to controls. This study provides evidence that SNPs in miRNA binding sites may play an important role in increasing risk of cancer. The results also paves way for future studies to validate these results in other well characterized populations as well as to explore the biological significance of these particular SNPs. PMID- 21704149 TI - Dietary phytochemicals induce p53- and caspase-independent cell death in human neuroblastoma cells. AB - Neuroblastoma (NB) is the most prevalent pediatric solid tumor and a leading cause of cancer-related death in children. In the present study, a novel cytotoxic role for the dietary compounds, curcumin, andrographolide, wedelolactone, dibenzoylmethane, and tanshinone IIA was identified in human S type NB cells, SK-N-AS and SK-N-BE(2). Mechanistically, cell death appeared apoptotic by flow cytometry; however, these effects proceeded independently from both caspase-3 and p53 activation, as assessed by both genetic (shRNA) and pharmacological approaches. Notably, cell death induced by both curcumin and andrographolide was associated with decreased NFkappaB activity and a reduction in Bcl-2 and Bcl-xL expression. Finally, curcumin and andrographolide increased cytotoxicity following co-treatment with either cisplatin or doxorubicin, two chemotherapeutic agents widely used in the clinical management of NB. Coupled with the documented safety in humans, dietary compounds may represent a potential adjunct therapy for NB. PMID- 21704151 TI - Epigenetic mechanisms in stress and adaptation. AB - Epigenetic mechanisms are processes at the level of the chromatin that control the expression of genes but their role in neuro-immuno-endocrine communication is poorly understood. This review focuses on epigenetic modifications induced by a range of stressors, both physical and psychological, and examines how these variations can affect the biological activity of cells. It is clear that epigenetic modifications are critical in explaining how environmental factors, which have no effect on the DNA sequence, can have such profound, long-lasting influences on both physiology and behavior. A signaling pathway involving activation of MEK-ERK1/2, MSK1, and Elk-1 signaling molecules has been identified in the hippocampus which results in the phospho-acetylation of histone H3 and modification of gene expression including up-regulation of immediate early genes such as c-Fos. This pathway can be induced by a range of challenging experiences including forced swimming, Morris water maze learning, fear conditioning and exposure to the radial maze. Glucocorticoid (GC) hormones, released as part of the stress response and acting via glucocorticoid receptors (GRs), enhance signaling through the ERK1/2/MSK1-Elk-1 pathway and thereby increase the impact on epigenetic and gene expression mechanisms. The role of synergetic interactions between these pathways in adaptive responses to stress and learning and memory paradigms is discussed, in addition we speculate on their potential role in immune function. PMID- 21704152 TI - Zebrafish developmental toxicity assay: A fishy solution to reproductive toxicity screening, or just a red herring? AB - The zebrafish embryotoxicity/teratogenicity assay is described as a useful alternative screening model to evaluate the effect of drugs on embryofoetal development. Fertilized eggs were exposed to different concentrations of 15 compounds with teratogenic (8) and non-teratogenic (7) potential until 96h post fertilization when 28 morphological endpoints and the level of compound uptake was assessed. The majority of drugs testing positive in mammals was also positive in zebrafish (75% sensitivity), while a relative high number of false positives were noted (43% specificity). Compound uptake determination appears useful for clarifying classifications as teratogenic or potential overdose although assay sensitivity could be improved to 71% if the exposure threshold, previously suggested as ~50ng/larvae, is reconsidered. The zebrafish assay shows some potential, though limited in its current form, as a screening tool for developmental toxicity within Janssen drug development. Further assay refinement with respect to endpoints and body burden threshold is required. PMID- 21704153 TI - Altered expression of neuronal tryptophan hydroxylase-2 mRNA in the dorsal and median raphe nuclei of three genetically modified mouse models relevant to depression and anxiety. AB - Depression and anxiety are among the leading causes of societal burden. Abnormalities in 5-hydroxytryptamine (5-HT; serotonin) neurotransmission are known to be associated with depressive and anxiety symptoms. The rostral projections of brainstem dorsal (DRN) and median (MRN) raphe nuclei are the main sources of forebrain 5-HT. The expression, turnover and distribution of tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in 5-HT biosynthesis in the DRN and MRN are complex, in keeping with the existence of different subpopulations of 5-HT neurons in this area. In the present study, we measured the expression of TPH2 mRNA in the DRN and MRN using in situ hybridization in three genetically modified mouse models, all relevant to depression and anxiety, and matched wild-type controls. Our results show quantitative modifications in TPH2 mRNA expression in the three main subregions of the DRN as well as the MRN in relation to changes in serotonergic, glutamatergic and endocannabinoid neurotransmission systems. Thus, there were significant decreases in TPH2 transcript levels in 5-HT transporter (5-HTT)-/- mutant mice, whereas increases were observed in the vesicular glutamate transporter 1 hemi knock out (VGLUT1+/-) and cannabinoid receptor 1 mutant (CB1R-/-) mice. Based on these findings, we suggest that TPH2 mRNA expression is under the influence of multiple messenger systems in relation to presynaptic and/or postsynaptic feedback control of serotonin synthesis that, 5-HTT, VGLUT1 and CB1R seem to be involved in these feedback mechanisms. Finally, our data are in line with previous reports suggesting that TPH2 activity within different raphe subregions is differentially regulated under specific conditions. PMID- 21704154 TI - Neuroprotective mechanisms of cerium oxide nanoparticles in a mouse hippocampal brain slice model of ischemia. AB - Cerium oxide nanoparticles (nanoceria) are widely used as catalysts in industrial applications because of their potent free radical-scavenging properties. Given that free radicals play a prominent role in the pathology of many neurological diseases, we explored the use of nanoceria as a potential therapeutic agent for stroke. Using a mouse hippocampal brain slice model of cerebral ischemia, we show here that ceria nanoparticles reduce ischemic cell death by approximately 50%. The neuroprotective effects of nanoceria were due to a modest reduction in reactive oxygen species, in general, and ~15% reductions in the concentrations of superoxide (O(2)(*-)) and nitric oxide, specifically. Moreover, treatment with nanoceria markedly decreased (~70% reduction) the levels of ischemia-induced 3 nitrotyrosine, a modification to tyrosine residues in proteins induced by the peroxynitrite radical. These findings suggest that scavenging of peroxynitrite may be an important mechanism by which cerium oxide nanoparticles mitigate ischemic brain injury. Peroxynitrite plays a pivotal role in the dissemination of oxidative injury in biological tissues. Therefore, nanoceria may be useful as a therapeutic intervention to reduce oxidative and nitrosative damage after a stroke. PMID- 21704155 TI - Cell-based measurements to assess physiological status of Pseudo-nitzschia multiseries, a toxic diatom. AB - Diatoms of the genus Pseudo-nitzschia are potentially toxic microalgae, whose blooms can trigger amnesic shellfish poisoning. The purpose of this study was to test and adapt different probes and procedures in order to assess the physiological status of Pseudo-nitzschia multiseries at the cell level using flow cytometry. To perform these analyses, probes and procedures were first optimized for concentration and incubation time. The percentage of dead Pseudo-nitzschia cells, the metabolic activity of live cells and their intracellular lipid content were then measured following a complete growth cycle. In addition, chlorophyll autofluorescence and efficiency of photosynthesis (quantum yield) were monitored. The concentration and viability of bacteria present in the medium were also assessed. Domoic acid (DA) was quantified as well. Just before the exponential phase, cells exhibited high metabolic activity, but low DA content. DA content per cell became most abundant at the beginning of the exponential phase when lipid storage was high, which provided a metabolic energy source, and when they were surrounded by a high number of bacteria (high bacteria/P. multiseries ratio). These physiological measurements tended to decrease during exponential phase and until stationary phase, at which time P. multiseries cells did not contain any DA nor store any lipids, and started to die. PMID- 21704157 TI - Niemann-Pick Type C1 deficiency in microglia does not cause neuron death in vitro. AB - Niemann-Pick Type C (NPC) disease is an autosomal recessive disorder that results in accumulation of cholesterol and other lipids in late endosomes/lysosomes and leads to progressive neurodegeneration and premature death. The mechanism by which lipid accumulation causes neurodegeneration remains unclear. Inappropriate activation of microglia, the resident immune cells of the central nervous system, has been implicated in several neurodegenerative disorders including NPC disease. Immunohistochemical analysis demonstrates that NPC1 deficiency in mouse brains alters microglial morphology and increases the number of microglia. In primary cultures of microglia from Npc1(-/-) mice cholesterol is sequestered intracellularly, as occurs in other NPC-deficient cells. Activated microglia secrete potentially neurotoxic molecules such as tumor necrosis factor-alpha (TNFalpha). However, NPC1 deficiency in isolated microglia did not increase TNFalpha mRNA or TNFalpha secretion in vitro. In addition, qPCR analysis shows that expression of pro-inflammatory and oxidative stress genes is the same in Npc1(+/+) and Npc1(-/-) microglia, whereas the mRNA encoding the anti inflammatory cytokine, interleukin-10 in Npc1(-/-) microglia is ~60% lower than in Npc1(+/+) microglia. The survival of cultured neurons was not impaired by NPC1 deficiency, nor was death of Npc1(-/-) and Npc1(+/+) neurons in microglia-neuron co-cultures increased by NPC1 deficiency in microglia. However, a high concentration of Npc1(-/-) microglia appeared to promote neuron survival. Thus, although microglia exhibit an active morphology in NPC1-deficient brains, lack of NPC1 in microglia does not promote neuron death in vitro in microglia-neuron co cultures, supporting the view that microglial NPC1 deficiency is not the primary cause of neuron death in NPC disease. PMID- 21704156 TI - Impairment of benthic diatom adhesion and photosynthetic activity by 2E,4E decadienal. AB - Within biofilms, microorganisms are exposed to a wide range of chemicals released by phototrophic organisms. Those chemicals are likely to influence the dynamics and functioning of biofilms. 2E,4E-decadienal (DD) is a polyunsaturated aldehyde produced by diatoms which is known to induce adverse effects in many aquatic organisms. It has been shown to inhibit the adhesion and motility of one benthic diatom. The aim of this article was to determine if the effects of DD on diatom adhesion were widespread and if it could affect biofilm formation and functioning. The adhesion of 5 of 10 benthic diatom strains was strongly inhibited at 2.5 MUg ml(-1) DD. This indicates a high variability in diatom sensitivity to DD. Several experiments in microcosms showed that the presence of DD diffusing from a substrate decreased biofilm formation. This effect was dose dependent and persisted for 72 h, though the molecule is highly volatile. Using a PHYTO-PAM fluorometer, we also showed that the effective quantum efficiency of charge separation of PSII of biofilms exposed to DD was negatively affected. This indicates a decrease in the efficiency of the photochemical processes. All these results suggest that the presence of DD-producing strains may have a significant impact on the composition and physiology of biofilms. PMID- 21704158 TI - Emergence of the silicon human and network targeting drugs. AB - The development of disease may be characterized as a pathological shift of homeostasis; the main goal of contemporary drug treatment is, therefore, to return the pathological homeostasis back to the normal physiological range. From the view point of systems biology, homeostasis emerges from the interactions within the network of biomolecules (e.g. DNA, mRNA, proteins), and, hence, understanding how drugs impact upon the entire network should improve their efficacy at returning the network (body) to physiological homeostasis. Large, mechanism-based computer models, such as the anticipated human whole body models (silicon or virtual human), may help in the development of such network-targeting drugs. Using the philosophical concept of weak and strong emergence, we shall here take a more general look at the paradigm of network-targeting drugs, and propose our approaches to scale the strength of strong emergence. We apply these approaches to several biological examples and demonstrate their utility to reveal principles of bio-modeling. We discuss this in the perspective of building the silicon human. PMID- 21704159 TI - 17beta-Estradiol-mediated increase in Cu/Zn superoxide dismutase expression in the brain: a mechanism to protect neurons from ischemia. AB - A number of studies have demonstrated that 17beta-estradiol (E(2)) protects the brain from ischemia and yet the mechanism by which this hormone brings about its protective effect is unclear. Interestingly, like E(2), overexpression of the oxidative stress response protein Cu/Zn superoxide dismutase (SOD1), which plays a critical role in regulating reactive oxygen species, also protects the brain from ischemia. Because we previously showed that E(2) treatment of cultured mammary cells increases SOD1 expression, we hypothesized that E(2) might increase SOD1 expression in the brain and that this E(2)-mediated increase in SOD1 expression might help to protect the brain from ischemia. We now show that SOD1 is expressed in cortical neurons, that SOD1 expression is increased by exposure of brain slice cultures to E(2), and that the E(2)-mediated increase in SOD1 expression is further augmented by exposure of brain slice cultures to increased superoxide levels or oxygen and glucose deprivation. Importantly, when cortical neurons are exposed to increased superoxide levels and markers of protein and DNA damage, nitrotyrosine and 8-oxoguanine, respectively, are measured, both protein and DNA damage are reduced. In fact, E(2) reduces nitrotyrosine and 8-oxoguanine levels in brain slice cultures regardless of whether they have or have not been exposed to increased superoxide levels. Likewise, when brain slice cultures are treated with E(2) and deprived of oxygen and glucose, 8-oxoguanine levels are reduced. Taken together, these studies provide a critical link between E(2) treatment, SOD1 expression, and neuroprotection and help to define a mechanism through which E(2)-mediated neuroprotection may be conferred. PMID- 21704160 TI - Features of synergism between mesenchymal stem cells and immunosuppressive drugs in a murine heart transplantation model. AB - BACKGROUND: Mesenchymal stem cells (MSCs) can be used for immunomodulation therapy after solid organ transplantation. Here, we focus on the immunoregulatory potential of combination therapies of MSCs and classic pharmacotherapy to mediate acceptance of solid organ grafts. METHODS: To determine which drugs influence the immunosuppressive effect of MSCs, we assessed the interaction of MSCs and common clinical immunosuppresants (MMF, sirolimus [Srl], and ciclosporin A [CiA]) in a parent-into-F1 cell transfer model. In this model, the transfer of parental strain T cells into semi-allogeneic F1 recipients induces a graft-versus-host reaction (GvHR). Re-isolated CFSE-labelled T lymphocytes were analyzed by flow cytometry. These findings were compared to a fully allogeneic heart transplantation model. RESULTS: We found that MSC treatment alone had no significant effect on allograft survival of heterotopic heart grafts. However, MSCs combined with short-term mycophenolate mofetil (MMF) significantly prolonged graft survival. Quantitative analysis of three different MSC - drug combinations in the F1 model revealed, that only the MSC-MMF combination led to a super additive immunosuppressive effect. We also investigated the effect of MMF and CiA on IFNgamma production of stimulated lymphocytes and found that MMF left the expression of IFNgamma unaffected, whereas CiA completely abolished the production of IFNgamma. CONCLUSION: Our data show that the type of concurrent immunosuppression strongly influences the immunosuppressive effect of MSC, most likely through differential secretion of IFNgamma. A regimen combining MSCs and MMF was most immunosuppressive. PMID- 21704161 TI - Properly scaled and targeted AAV2-NRTN (neurturin) to the substantia nigra is safe, effective and causes no weight loss: support for nigral targeting in Parkinson's disease. AB - Recent analyses of autopsied brains from subjects previously administered AAV2 neurturin (NRTN) gene transfer argues that optimizing the effects of neurotrophic factors in Parkinson's disease (PD) likely requires delivery to both the degenerating cell bodies (in substantia nigra) and their terminals (in striatum). Prior to implementing this novel dosing paradigm in humans, we conducted eight nonclinical experiments with three general objectives: (1) evaluate the feasibility, safety and effectiveness of targeting the substantia nigra (SN) with AAV2-NRTN, (2) better understand and appraise recent warnings of serious weight loss that might occur with targeting the SN with neurotrophic factors, and (3) define an appropriate dose of AAV2-NRTN that should safely and effectively cover the SN in PD patients. Toward these ends, we first determined SN volume for rats, monkeys and humans, and employed these values to calculate comparable dose equivalents for each species by scaling each dose, based on relative SN volume. Using this information, we next injected AAV2-GFP to monkey SN to quantify AAV2 vector distribution and confirm reasonable SN coverage. We then selected and administered a ~200-fold range of AAV2-NRTN doses (and a single AAV2-GDNF dose) to rat SN, producing a wide range of protein expression. In contrast to recent warnings regarding nigra targeting, no dose produced any serious side effects or toxicity, though we replicated the modest reduction in weight gain reported by others with the highest AAV2-NRTN and the AAV2-GDNF dose. A dose-related increase in NRTN expression was seen, with the lower doses limiting NRTN to the peri-SN and the highest dose producing mistargeted NRTN well outside the SN. We then demonstrated that the reduction in weight gain following excessive-doses can be dissociated from NRTN in the targeted SN, and is linked to mistargeted NRTN in the diencephalon. We also showed that prior destruction of the dopaminergic SN neurons via 6-OHDA had no impact on the weight loss phenomenon, further dissociating neurotrophic exposure to the SN as the culprit for weight changes. Finally, low AAV2-NRTN doses provided significant neuroprotection against 6-OHDA toxicity, establishing a wide therapeutic index for nigral targeting. These data support targeting the SN with AAV2-NRTN in PD patients, demonstrating that properly targeted and scaled AAV2-NRTN provides safe and effective NRTN expression. They also provided the means to define an appropriate human equivalent dose for proceeding into an ongoing clinical trial, using empirically based scaling to account for marked differences in SN volume between species. PMID- 21704162 TI - Laboratory of receptor pharmacology. AB - The Laboratory of Receptor Pharmacology studied the GABAB and muscarinic m2/m3 receptors present in primary cultures of rat cerebellar granule cells. From 1985 to 1992, multiple scientists showed the GABAB receptor had, at least, two affinity states, the low affinity receptor inhibiting adenylyl cyclase and the higher affinity receptor increasing intracellular calcium from ryanodine sensitive calcium stores. Muscarinic m2 receptors inhibit adenylyl cyclase and would undergo desensitization using, in part, similar mechanism of desensitization identified for the beta-adrenergic receptor coupled to adenylyl cyclase. Muscarinic m3 receptors increased intracellular calcium levels via inositol 3-phosphate-sensitive intracellular calcium stores. PMID- 21704163 TI - From benzodiazepines to peripheral and brain steroid biosynthesis. AB - From the biochemistry of testicular and adrenal steroids to the mysteries of brain steroid biosynthesis and from pharmacy and pharmacology to neuropharmacology and neurosciences were two transitions in my scientific career where Erminio (Mimo) Costa played a catalytic role. A review of the years and findings that contributed in our understanding of the link between benzodiazepines and neurosteroid biosynthesis that established the pharmacology of neurosteroidogenesis is a testimony to Dr. Costa's will to push the borders of knowledge that inspired us to challenge existing notions and paradigms. PMID- 21704164 TI - Age- and disease-related neuroplasticity of chemically identified neuronal circuits: a tribute to Professor Erminio Costa. AB - The following review highlights a small portion of the research ongoing in my laboratory at the Fidia Georgetown Institute of Neuroscience (FGIN) during the years 1989-1994. Specifically, this work focused on the selective vulnerability of neurons in Alzheimer's disease. At the time, it was known that alpha-amino-3 hydroxy-5-methyl-4-isoaxolepropionate (AMPA) receptors were composed of one or more subunits (GluR1-4). Furthermore, the presence of the GluR2 subunit was known to substantially reduce Ca2+ through AMPA receptors in response to ligand binding. This finding led us to hypothesize that the presence or absence of the GluR2 subunit in the AMPA receptor may have a profound influence on the ability of the cell to gate extracellular Ca2+ and maintain intracellular calcium homeostasis. Furthermore, in Alzheimer's disease we hypothesized that cells at risk for developing AD neuropathology will express certain combinations of glutamate receptor subunits that form channels with increased permeability to Ca2+. In turn, these cells may become more vulnerable to the pathologic consequences of increased intracellular Ca2+ and destabilized intracellular Ca2+ homeostasis. To test this hypothesis we employed anatomical techniques and examined post mortem materials from patients with AD. The results of these studies are summarized in this review. Notably, this review also highlights the valuable collaborations established during my five years at FGIN and pays tribute to the intellectually rich and supportive environment provided by Dr. Costa and colleagues. PMID- 21704165 TI - Laboratory of ion and second messenger imaging: a tribute to the memory of Erminio Costa. AB - When we lost Ermino Costa last year, the end of an era was marked. "Mimo" as we affectionately called him, was looked upon by scores of students, post-doctoral scholars and colleagues with respect and admiration and he was a scientific father figure to many. In this article I reflect upon his time at Georgetown University including his recruitment, formation and leadership of the Fidia Georgetown Institute for Neuroscience (FGIN). The founding of FGIN created a focus upon neurosciences at the university and fostered many new collaborations. My laboratory became associated with the Institute and was involved in common interests concerning ion and second messenger studies and single cell imaging. Mimo's critical support of work and people during his long and illustrious career has significantly impacted not only neuroscience but the people who were so fortunate to have traveled with him along the road to many important and exciting discoveries. PMID- 21704166 TI - The FGIN period: electrophysiological studies. AB - This historical review of the electrophysiology laboratory complemented the activity of the various research teams at the Fidia Georgetown Institute for the Neurosciences and it was the fulfillment of Dr. Erminio Costa's dream to be able to study the inhibitory and excitatory synapse in the central nervous system. These studies were facilitated by the development of the patch clamp technique that allows the functional testing of several of the biochemical and pharmacological hypotheses. The studies described here were the results of the hard work of all the collaborators involved in the projects that will never forget the passionate and stimulating discussion with Dr Costa during and after the development of these projects. PMID- 21704167 TI - Leishmania cell-free protein expression system. AB - Cell-free protein expression is an important tool for a rapid production, engineering and labeling of recombinant proteins. However the complex protocols for preparation of eukaryotic cell-free protein expression systems result in high manufacturing costs and limit their utility. Recently we reported a novel cell free expression system based on the lysate of a fermentable protozoan Leishmania tarentolae. Herein we describe a protocol for high throughput protein expression using Leishmania cell-free lysate. The protocol combines PCR-based synthesis and engineering of translation templates with a combined transcription-translation system. The protocol is adapted to multiwell plate format and allows translation of large protein libraries. In the presented example we translate in vitro and isolate a nearly complete complement of mammalian Rab GTPases. Further applications and developments of the system are discussed. PMID- 21704168 TI - Molecular nuclear therapies for thyroid carcinoma. AB - Thyroid cancer, divided in the subvarieties of papillary and follicular carcinoma, together also called differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC) and anaplastic thyroid carcinoma (ATC), is the most common endocrine malignancy. Over the course of the last seven decades multiple molecular nuclear therapies have been tried to treat the various varieties of thyroid cancer. The sodium iodine symporter (NIS) substrate I-131 is a well known and extremely successful agent to treat DTC, but is not successful in treating other thyroid cancer varieties and some de-differentiated DTC tumors. An alternative to I-131 are radioactively labeled somatostatin analogues, which have predominantly been used to target MTC, but may also be effective in some DTC cases. In experimental preclinical studies the re-induction of NIS expression or transfection with recombinant NIS shows some promise for the treatment of ATC and dedifferentiated DTC. Furthermore, several other potential radioactive NIS substrates are developed. In this review, we will extensively discuss the aforementioned established therapeutic modalities and promising new concepts in molecular nuclear therapy of thyroid carcinoma. PMID- 21704169 TI - Lactococcus lactis as a live vector: heterologous protein production and DNA delivery systems. AB - Lactic acid bacteria (LAB), widely used in the food industry, are present in the intestine of most animals, including humans. The potential use of these bacteria as mucosal delivery vehicles for vaccinal, medical or technological use has been extensively investigated. Lactococcus lactis, a LAB species, is a potential candidate for the production of biologically useful proteins and for plasmid DNA delivery to eukaryotic cells. Several delivery systems have been developed to target heterologous proteins to a specific cell location (i.e., cytoplasm, cell wall or extracellular medium) and more recently to efficiently transfer DNA to eukaryotic cells. A promising application of L. lactis is its use for the development of live mucosal vaccines. Here, we have reviewed the expression of heterologous protein and the various delivery systems developed for L. lactis, as well as its use as an oral vaccine carrier. PMID- 21704170 TI - Preventing protein aggregation by its hyper-acidic fusion cognates in Escherichia coli. AB - Preventing protein aggregation is crucial for various protein studies, and has a large potential for remedy of protein misfolding or aggregates-linked diseases. In this study, we demonstrated the hyper-acidic protein fusion partners, which were previously reported to enhance the soluble expression of aggregation-prone proteins, could also significantly prevent aggregation (or improve the solubility) of disease-associated and amyloid/fibril-forming polypeptides such as TEL-SAM and Abeta42 in Escherichia coli cells. Further and most importantly, the solubility of all poorly soluble target proteins examined was greatly elevated by their corresponding highly soluble hyper-acidic fusion cognates when they were co expressed, in despite of a concomitant compromise of the cognates' solubility. The extent of such a solubility enhancement appeared to be in parallel with the ratio of the levels of co-expressed hyper-acidic fusion cognate and target protein. The hyper-acidic fusion cognates might function as intermolecular solubilizing effectors to prevent aggregation of the target proteins, and a plausible model for interpreting these results is also proposed. PMID- 21704171 TI - NTU-90: a high angular resolution brain atlas constructed by q-space diffeomorphic reconstruction. AB - We present a high angular resolution brain atlas constructed by averaging 90 diffusion spectrum imaging (DSI) datasets in the ICBM-152 space. The spatial normalization of the diffusion information was conducted by a novel q-space diffeomorphic reconstruction method, which reconstructed the spin distribution function (SDF) in the ICBM-152 space from the diffusion MR signals. The performance of this method was examined by a simulation study modeling nonlinear transformation. The result showed that the reconstructed SDFs can resolve crossing fibers and that the accumulated quantitative anisotropy can reveal the relative ratio of the fiber populations. In the in vivo study, the SDF of the constructed atlas was shown to resolve crossing fiber orientations. Further, fiber tracking showed that the atlas can be used to present the pathways of fiber bundles, and the termination locations of the fibers can provide anatomical localization of the connected cortical regions. This high angular resolution brain atlas may facilitate future connectome research on the complex structure of the human brain. PMID- 21704172 TI - Application of multi-source minimum variance beamformers for reconstruction of correlated neural activity. AB - Linearly constrained minimum variance beamformers are highly effective for analysis of weakly correlated brain activity, but their performance degrades when correlations become significant. Multiple constrained minimum variance (MCMV) beamformers are insensitive to source correlations but require a priori information about the source locations. Besides the question whether unbiased estimates of source positions and orientations can be obtained remained unanswered. In this work, we derive MCMV-based source localizers that can be applied to both induced and evoked brain activity. They may be regarded as a generalization of scalar minimum-variance beamformers for the case of multiple correlated sources. We show that for arbitrary noise covariance these beamformers provide simultaneous unbiased estimates of multiple source positions and orientations and remain bounded at singular points. We also propose an iterative search algorithm that makes it possible to find sources approximately without a priori assumptions about their locations and orientations. Simulations and analyses of real MEG data demonstrate that presented approach is superior to traditional single-source beamformers in situations where correlations between the sources are significant. PMID- 21704173 TI - Emotion regulation and brain plasticity: expressive suppression use predicts anterior insula volume. AB - Expressive suppression is an emotion regulation strategy that requires interoceptive and emotional awareness. These processes both recruit the anterior insula. It is not known, however, whether increased use of expressive suppression is associated with increased anterior insula volume. In the present study, high resolution anatomical MRI images were used to calculate insula volumes in a set of 50 healthy female subjects (mean 21.9 years) using both region of interest (ROI) and voxel-based morphometry (VBM) approaches. Participants also completed trait measures of expressive suppression usage, cognitive reappraisal usage, and negative emotional reactivity (the latter two served as control measures). As predicted, both ROI and VBM methods found that expressive suppression usage, but not negative affect and cognitive reappraisal, was positively related to anterior insula volume. These findings are consistent with the idea that trait patterns of emotion processing are related to brain structure. PMID- 21704174 TI - Direct visualization of non-human primate subcortical nuclei with contrast enhanced high field MRI. AB - Subcortical nuclei are increasingly targeted for deep brain stimulation (DBS) and for gene transfer to treat neurological and psychiatric disorders. For a successful outcome in patients, it is critical to place DBS electrodes or infuse viral vectors accurately within targeted nuclei. However current MRI approaches are still limited to localize brainstem and basal ganglia nuclei accurately. By combining ultra-high resolution structural MRI and contrast-enhanced MRI using iron oxide nanoparticles at high field (3T and 7T), we could precisely locate the subcortical nuclei, in particular the subthalamic nucleus in macaques, and validate this location by intracranial electrophysiological mapping. The present data pave the way to a clinical application. PMID- 21704175 TI - Beyond a morphological paradox: complicated phylogenetic relationships of the parrotbills (Paradoxornithidae, Aves). AB - The parrotbills (Paradoxornithidae, meaning "birds of paradox," Aves) are a group of Old World passerines with perplexing taxonomic histories due to substantial morphological and ecological variation at various levels. In this study, phylogenetic relationships of the parrotbills were reconstructed based on sequences of two mitochondrial segments and three nuclear coding regions. Three major clades with characteristic body size and plumage coloration were found in both mtDNA and nuclear gene trees. However, mtDNA phylogeny suggested that the Paradoxornithidae is paraphyletic and relationships among three major parrotbill clades were poorly resolved. On the contrary, apparent and well-supported monophyletic relationships among the three major clades of Paradoxornithidae were revealed by concatenated nuclear dataset. Since paraphyly based on mtDNA data has commonly been found within avian taxa, the conflicting phylogenetic signal between mtDNA and nuclear loci revealed in this study indicates that results obtained from mtDNA dataset alone need to be evaluated with caution. Taxonomic implications of our phylogenetic findings are discussed. These phylogenies also point out areas for future investigation regarding the rapid diversification, morphological evolution and environmental adaptation of various parrotbill species or species complexes. PMID- 21704176 TI - Cognitive dysfunction in depression: neurocircuitry and new therapeutic strategies. AB - Major depressive disorder (MDD) is a disabling medical condition associated with significant morbidity, mortality and public health costs. However, neurocircuitry abnormalities underlying depression remain incompletely understood and consequently current treatment options are unfortunately limited in efficacy. Recent research has begun to focus specifically on cognitive aspects of depression and potential neurobiological correlates. Two fundamental types of cognitive dysfunction observed in MDD are cognitive biases, which include distorted information processing or attentional allocation toward negative stimuli, and cognitive deficits, which include impairments in attention, short term memory and executive functioning. In this article, we present a selective review of current research findings in these domains and examine neuroimaging research that is beginning to characterize the neurocircuitry underlying these biases and deficits. We propose that deficient cognitive functioning, attention biases and the sustained negative affect characteristic of MDD can be understood as arising in part from dysfunctional prefrontal-subcortical circuitry and related disturbances in the cognitive control of emotion. Finally, we highlight potential new pharmacological and non-pharmacological therapeutic strategies for MDD based on an evolving mechanistic understanding of the disorder. PMID- 21704177 TI - Prolonged inactivation of the hippocampus reveals temporally graded retrograde amnesia for unreinforced spatial learning in rats. AB - We investigated whether systems consolidation of spatial memory could be detected in a non-navigational, spatial-learning test that takes advantage of rats' natural propensity to preferentially investigate an object that was displaced relative to spatial cues more than an object that remained stationary. Previous studies using navigational spatial-learning tests have generally failed to reveal temporally-graded retrograde amnesia, possibly because the hippocampus needs to be intact for the retrieval and/or processing of navigational information during the test. In the present study, the hippocampus of rats was kept inactivated, at two sites along its septo-temporal axis (dorsal and intermediate), for four consecutive days, beginning either 3h or 5 days after familiarization to two identical objects in an open field. Rats that had their hippocampus inactivated beginning 5 days but not 3h after familiarization showed evidence that they remembered the previous location of the displaced object. The results suggest that systems consolidation of spatial memories can be detected using a non navigational test of spatial memory. PMID- 21704178 TI - Efficient gene targeting in DeltaCc.ku70 or DeltaCc.lig4 mutants of the agaricomycete Coprinopsis cinerea. AB - Coprinopsis cinerea is a model for studies of sexual development in agaricomycetes (homobasidiomycetes). Efficient gene targeting should facilitate such studies, especially because increasing genome and transcriptome information is now available in C. cinerea. To estimate the frequency of gene disruption by homologous integration in this fungus, we tried to disrupt Cc.wc-2, which encodes a WC-2 homolog, a partner of the fungal blue-light photoreceptor, WC-1. Disruption of Cc.wc-2 did not occur when recipients (protoplasts) of the disrupting construct were prepared from asexual spores, oidia, from the wild type, 326, while it occurred when protoplasts were prepared from mycelial cells from the same strain, albeit at a low frequency (3%). Double-stranded RNA mediated silencing of a ku70 homolog, named Cc.ku70, or the lig4 homolog Cc.lig4 more or less increased the frequency of Cc.wc-2 targeting. On the basis of these results, we disrupted Cc.ku70 using a Cc.lig4-silenced strain. We then disrupted Cc.lig4 using the Cc.ku70 disruptant. We found that the disruption of Cc.ku70 or Cc.lig4 greatly enhanced gene targeting. In addition, this study demonstrates that Cc.wc-2 is involved in blue light perception in this fungus. PMID- 21704179 TI - Mechanisms underlying the vascular relaxation induced by a new nitric oxide generator. AB - Nitric oxide (NO) is a potent vasodilator and it can be generated by the ruthenium complex cis-[Ru(H-dcbpy(-))(2)(Cl)(NO(2)(-))] (DCBPY). The present study aimed to investigate the NO specie generated and to characterize the cellular mechanisms involved on the vasodilatation induced by DCBPY. It was found that at pH 7.4 and 9.4, the NO(+) coordinated to ruthenium (Ru-NO(+)) is converted to NO(2)(-) (Ru-NO(2)(-)), which remains stable. However, the configuration Ru-NO(+) is stable at pH 5.4. It was also verified that the DCBPY complex (Ru-NO(2)(-) configuration) induces vascular relaxation of contracted rat aortic rings in a concentration-dependent manner. Therefore, the potency (pD(2) values) and the maximum relaxant effect (ME) were compared. It was observed that relaxation is more pronounced to Ru-NO(+) configuration, compared with Ru-NO(2)( ), with no difference in ME. On the other hand, the potency of DCBPY (Ru-NO(2)( )) is lower than that of SNP and higher than that of NITRITE, with no difference in ME for all the compounds. Further experiments were conducted using DCBPY in the Ru-NO(2)(-) configuration. It was noted that the relaxation induced by DCBPY is completely blocked by the soluble guanylyl cyclase (sGC) enzyme inhibitor. The non-selective K(+) channel blocker (TEA) diminishes the potency of DCBPY, but it does not change the ME. Incubation with selective radicalar NO (NO()) and extracellular NO scavengers almost abolishes the relaxation induced by DCBPY. The use of a selective nitroxyl (NO(-)) scavenger decreases the potency of DCBPY, but it does not alter the ME. By using confocal microsopy, it was found that DCBPY, SNP, and NITRITE raise the cytosolic NO concentration and reduce the cytosolic Ca(2+) concentration [Ca(2+)]c in rat aortic smooth muscle cells. These effects are not different when DCBPY and SNP are compared, but they are lower for NITRITE. Taken together, our results demonstrate that the compound DCBPY (Ru NO(2)(-)) is an NO generator that promotes relaxation of rat aortic rings due to a reduction in [Ca(2+)]c. The vascular smooth muscle relaxation is dependent on sGC activation. PMID- 21704180 TI - Integration of tight junctions and claudins with the barrier functions of the retinal pigment epithelium. AB - The retinal pigment epithelium (RPE) forms the outer blood-retinal barrier by regulating the movement of solutes between the fenestrated capillaries of the choroid and the photoreceptor layer of the retina. Blood-tissue barriers use various mechanisms to accomplish their tasks including membrane pumps, transporters, and channels, transcytosis, metabolic alteration of solutes in transit, and passive but selective diffusion. The last category includes tight junctions, which regulate transepithelial diffusion through the spaces between neighboring cells of the monolayer. Tight junctions are extraordinarily complex structures that are dynamically regulated. Claudins are a family of tight junctional proteins that lend tissue specificity and selectivity to tight junctions. This review discusses how the claudins and tight junctions of the RPE differ from other epithelia and how its functions are modulated by the neural retina. Studies of RPE-retinal interactions during development lend insight into this modulation. Notably, the characteristics of RPE junctions, such as claudin composition, vary among species, which suggests the physiology of the outer retina may also vary. Comparative studies of barrier functions among species should deepen our understanding of how homeostasis is maintained in the outer retina. Stem cells provide a way to extend these studies of RPE-retinal interactions to human RPE. PMID- 21704181 TI - The ISG15/USP18 ubiquitin-like pathway (ISGylation system) in hepatitis C virus infection and resistance to interferon therapy. AB - The ISG15/USP18 pathway modulates cellular functions and is important for the host innate immune response to chronic viral infections such as Hepatitis C Virus (HCV). Interferon stimulated gene 15 (ISG15) was the first ubiquitin-like protein modifier identified. As in ubiquitination, ISG15 conjugates to target proteins (ISGylation) through the sequential enzymatic action of activating E1, conjugating E2, and ligating E3 enzymes. ISGylation modulates signal transduction pathways and host anti-viral response. The ISGylation process is reversible through the action of an ISG15 protease, USP18. Ubiquitin-like specific protease 18 (USP18) has functions that are both ISG15-dependent and ISG15-independent; the importance of the ISG15/USP18 pathway to chronic HCV infection is illustrated by the consistent finding of increased levels of ISG15 and USP18 in the liver tissue of patients who do not respond to interferon-based treatments. Mechanistically, HCV seems to exploit the ISG15/USP18 pathway to promote viral replication and evade innate anti-viral immune responses. PMID- 21704182 TI - Truncated HER2: implications for HER2-targeted therapeutics. AB - The HER2 receptor is currently one of the flagship therapeutic targets in clinical oncology. Trastuzumab, an antibody targeting HER2, has become a foundation of care in women with HER2-positive breast cancer. However, many women with metastatic breast cancer do not respond to trastuzumab-based therapy. One possible source of trastuzumab resistance is the presence of truncated forms of HER2 in the tumor. Numerous studies suggest that detection of truncated HER2 in the tumor should result in modification of the classical therapeutic approach. Recent development of several promising compounds brings hope that a generation of novel therapeutic modalities against HER2-positive cancers will be delivered in the future. PMID- 21704183 TI - How well do medicinal chemists learn from experience? AB - To an outsider, the exploration of thousands of molecules to find a small number of potential candidate drugs must appear enormously wasteful, but many medicinal chemists would defend this waste as unavoidable. Here, I provide evidence that suggests that modern medicinal chemists are overproductive in that they synthesise many more compounds than are required to achieve the objectives of the project. The difficulties encountered in finding the data for the analysis presented here prompted the design and implementation of a more rigorous approach to capture the essence of a medicinal chemistry program. The result, medicinal chemistry knowledge sharing (MeCKS), was designed to capture and communicate emerging issues and their solutions to the medicinal chemistry community. PMID- 21704184 TI - Getting physical in drug discovery II: the impact of chromatographic hydrophobicity measurements and aromaticity. AB - Here, we review the performance of chromatographic hydrophobicity measurements in a data set of 100,000 GlaxoSmithKline compounds, demonstrating the advantages of the method over octanol-water partitioning and highlighting new insights for drug discovery. The value of chromatographic measurements, versus other hydrophobicity estimates, was supported by improved relationships with solubility, permeation, cytochrome P450s, intrinsic clearance, hERG binding and promiscuity. We also observed marked differentiation of the relative influence of intrinsic and effective hydrophobicity. The summing of hydrophobicity values plus aromatic ring count [logD(pH7.4) (or logP)+#Ar], indicated a wide relevance for simplistic 'property forecast indices' in developability assays, clearly enhanced by chromatographic values; therefore establishing new foundations for enriching property-based drug design. PMID- 21704185 TI - Drug discovery in the next decade: innovation needed ASAP. AB - Pharmaceutical companies must find a better way to increase their output of truly new drugs for the benefit of patients and for their business survival. Here, I highlight a general perspective from within pharmaceutical research as it pertains to research advances in chemistry, biology, pharmacology, pharmacokinetics and toxicology that, if well integrated, stands to put the industry on a productive path. In addition, I provide a complementary perspective on the corporate culture aspect of innovation. I also introduce a new concept, termed 'innovation ASAP' (iASAP; asking powerful questions, seeking the outliers, accepting defeat and populating astutely) and provide support for it using examples of several successful drugs. PMID- 21704186 TI - Phylogenetic relationships of species within the tribe Labiostrongylinea (Nematoda: Cloacinidae) from Australian marsupials based on ribosomal DNA spacer sequence data. AB - Parasitic nematodes of the tribe Labiostrongylinea (Family Cloacinidae) occur in the stomachs of a wide variety of potoroid and macropodid marsupials in Australia, Papua Indonesia and Papua New Guinea. The aim of the present study was to infer the evolutionary relationships of the five genera of labiostrongyline nematodes that occur in Australian potoroids and macropodids using sequence data of the nuclear first and second internal transcribed spacers of ribosomal DNA. The phylogenetic analyses resulted in the separation of the Labiostrongylinea into two major groups reflecting coevolution between hosts and parasites. Two nematode species belonging to the genus Potorostrongylus formed a sister group to the remaining species of the Labiostrongylinea. This genus occurs exclusively in potoroid marsupials, which are considered to be basal to the macropodid marsupials. The second major group included species of Labiostrongylus, Labiosimplex, Labiomultiplex and Parazoniolaimus, all of which occur in macropodids. These species formed two distinct clades, one predominating in the host genera Thylogale and Onychogalea, and the second in the genus Macropus, which includes the more recent macropodids. However, there is also evidence of colonisation by both nematode clades of relatively unrelated hosts. In addition, genetic differences among individuals of Lm. eugenii from geographically isolated populations of M. eugenii, and among Ls. longispicularis from different subspecies of M. robustus suggest the existence of sibling species that may have arisen by allopatric speciation. The broad coevolutionary relationship between the labiostrongyline nematodes and their marsupial hosts therefore represents a mixture of potential cospeciation and colonisation events. PMID- 21704187 TI - Chip-based nanoelectrospray mass spectrometry of brain gangliosides. AB - In the past few years, a considerable effort was invested in interfacing mass spectrometry (MS) to microfluidics-based systems for electrospray ionization (ESI). Since its first introduction in biological mass spectrometry, chip-based ESI demonstrated a high potential to discover novel structures of biomarker value. Therefore, recently, microfluidics for electrospray in conjunction with advanced MS instruments able to perform multistage fragmentation were introduced also in glycolipid research. This review is focused on the strategies, which allowed a successful application of chip technology for ganglioside mapping and sequencing by ESI MS and tandem MS (MS/MS). The first part of the review is dedicated to the progress of MS methods in brain ganglioside research, which culminated with the introduction of two types of microfluidic devices: the NanoMate robot and a polymer microchip for electrospray. In the second part a systematic description of most relevant results obtained by using MS in combination with the two chip systems is presented. Chip-based ESI accomplishments for determination of ganglioside expression and structure in normal brain regions and brain pathologies such as neurodegenerative diseases and primary brain tumors are described together with some considerations upon the perspectives of microfluidics-MS to be routinely introduced in biomedical investigation. PMID- 21704188 TI - n-3 fatty acids ameliorate hepatic steatosis and dysfunction after LXR agonist ingestion in mice. AB - Liver X receptor (LXR) agonists slow atherogenesis, but cause hepatic steatosis and dysfunction in part by increasing expression of sterol regulatory element binding protein 1-c (SREBP1-c), a transcription factor that upregulates fatty acid (FA) synthesis. n-3 FAs decrease hepatic FA synthesis by down-regulating SREBP1-c. To test the hypothesis that n-3 FAs decrease hepatic steatosis in mice given LXR agonist, C57BL/6 mice received daily gavage of an LXR agonist T0901317 (LXR(T)) or vehicle for 4weeks with concomitant intakes chow or high-fat diets enriched in saturated fat (SAT) or n-3 fat (n-3). Mice on LXR(T) and SAT developed hepatomegaly with a large increase in size and number of hepatic lipid droplets; an n-3 diet reduced liver weight/body weight with decreased hepatic steatosis and triglyceride levels. Effects of n-3 diet on hepatic lipogenesis were linked to a blunting of LXR(T) upregulation of hepatic SREBP1-c and FA synthase mRNA. n-3 diets also normalized LXR(T)-mediated increases of plasma ALT and AST levels, whereas SAT diet increased these markers. CONCLUSION: These studies suggest that n-3 FAs when given together with LXR agonists have the potential to improve both hepatic steatosis and hepatotoxicity in humans that might receive LXR agonists to decrease risk of atherosclerosis. PMID- 21704189 TI - Lipid classification, structures and tools. AB - The study of lipids has developed into a research field of increasing importance as their multiple biological roles in cell biology, physiology and pathology are becoming better understood. The Lipid Metabolites and Pathways Strategy (LIPID MAPS) consortium is actively involved in an integrated approach for the detection, quantitation and pathway reconstruction of lipids and related genes and proteins at a systems-biology level. A key component of this approach is a bioinformatics infrastructure involving a clearly defined classification of lipids, a state-of-the-art database system for molecular species and experimental data and a suite of user-friendly tools to assist lipidomics researchers. Herein, we discuss a number of recent developments by the LIPID MAPS bioinformatics core in pursuit of these objectives. PMID- 21704191 TI - The effects of cancer progression on the viscoelasticity of ovarian cell cytoskeleton structures. AB - Alterations in the biomechanical properties and cytoskeletal organization of cancer cells in addition to genetic changes have been correlated with their aggressive phenotype. In this study, we investigated changes in the viscoelasticity of mouse ovarian surface epithelial (MOSE) cells, a mouse model for progressive ovarian cancer. We demonstrate that the elasticity of late-stage MOSE cells (0.549 +/- 0.281 kPa) were significantly less than that of their early stage counterparts (1.097 +/- 0.632 kPa). Apparent cell viscosity also decreased significantly from early (144.7 +/- 102.4 Pa-s) to late stage (50.74 +/- 29.72 Pa s). This indicates that ovarian cells are stiffer and more viscous when they are benign. The increase in cell deformability directly correlates with the progression of a transformed phenotype from a nontumorigenic, benign cell to a tumorigenic, malignant one. The decrease in the level of actin in the cytoskeleton and its organization is directly associated with the changes in cell biomechanical property. FROM THE CLINICAL EDITOR: The authors have investigated changes in the viscoelasticity of mouse ovarian surface epithelial (MOSE) cells and demonstrated that ovarian cells are stiffer and more viscous when they are benign. PMID- 21704192 TI - A comparison of changes to doxorubicin pharmacokinetics, antitumor activity, and toxicity mediated by PEGylated dendrimer and PEGylated liposome drug delivery systems. AB - The pharmacokinetics, biodistribution, and antitumor efficacy of three doxorubicin formulations (doxorubicin in saline, conjugated to a polylysine dendrimer, and encapsulated within a stealth liposome) were investigated in Walker 256 tumor-bearing rats. Liposomal and dendrimer-based delivery systems resulted in more prolonged plasma exposure of total doxorubicin when compared to administration of doxorubicin in saline, although concentrations of free doxorubicin remained low in both cases. Biodistribution profiles revealed enhanced accumulation of dendrimer- and liposome-associated doxorubicin in tumors when compared to doxorubicin alone, although all three doxorubicin formulations reduced tumor growth to a similar extent. Markers of systemic toxicity (spleen weight, white blood cell counts, body weight, and cardiotoxicity) were more pronounced in rats that received doxorubicin and liposomal doxorubicin when compared to dendrimer-doxorubicin. The data provide preliminary evidence that dendrimer-doxorubicin displays similar antitumor efficacy to PEGylated liposomal doxorubicin, but with lower systemic toxicity (resulting from reduced drug exposure to nontarget organs). FROM THE CLINICAL EDITOR: In this manuscript, three different doxorubicin preparations are compared and preliminary evidence suggests that dendrimer-doxorubicin displays similar antitumor efficacy to PEGylated liposomal doxorubicin, but with lower systemic toxicity. PMID- 21704190 TI - The rainbow trout liver cancer model: response to environmental chemicals and studies on promotion and chemoprevention. AB - Rainbow trout (Oncorhynchus mykiss) are an outstanding model of liver cancer induction by environmental chemicals and development of strategies for chemoprevention. Trout have critical and unique advantages allowing for cancer studies with 40,000 animals to determine dose-response at levels orders of magnitude lower than possible in rodents. Examples of two promoters in this model, the dietary supplement dehydroepiandrosterone (DHEA) and industrial chemical perfluorooctanoic acid (PFOA), are presented. In addition, indole-3 carbinol (I3C) and chlorophyllin (CHL) inhibit initiation following exposure to potent human chemical carcinogens (e.g., aflatoxin B(1) (AFB(1))). Two "ED(001)" cancer studies have been conducted, utilizing approximately 40,000 trout, by dietary exposure to AFB(1) and dibenzo[d,e,f,p]chrysene (DBC). These studies represent the two largest cancer studies ever performed and expand the dose response dataset generated by the 25,000 mouse "ED(01)" study over an order of magnitude. With DBC, the liver tumor response fell well below the LED(10) line, often used for risk assessment, even though the biomarker (liver DBC-DNA adducts) remained linear. Conversely, the response with AFB(1) remained relatively linear throughout the entire dose range. These contributions to elucidation of mechanisms of liver cancer, induced by environmental chemicals and the remarkable datasets generated with ED(001) studies, make important contributions to carcinogenesis and chemoprevention. PMID- 21704193 TI - 3,4,5-Tricaffeoylquinic acid inhibits tumor necrosis factor-alpha-stimulated production of inflammatory mediators in keratinocytes via suppression of Akt- and NF-kappaB-pathways. AB - Keratinocytes may play an important role in the pathogenesis of skin disease in atopic dermatitis. Caffeoyl derivatives are demonstrated to have anti inflammatory and anti-oxidant effects. However, the effect of 3,4,5 tricaffeoylquinic acid prepared from Aconium koreanum on the pro-inflammatory cytokine-stimulated keratinocyte responses remains uncertain. In human keratinocytes, we investigated the effect of 3,4,5-tricaffeoylquinic acid on the tumor necrosis factor (TNF)-alpha-stimulated production of inflammatory mediators in relation to the nuclear factor (NF)-kappaB and cell signaling Akt, which regulates the transcription genes involved in immune and inflammatory responses. 3,4,5-Tricaffeoylquinic acid inhibited the TNF-alpha-stimulated production of cytokines (IL-1beta and IL-8) and chemokine (CCL17 and CCL27) in keratinocytes. Bay 11-7085 (an inhibitor of NF-kappaB activation) and Akt inhibitor attenuated the TNF-alpha-induced formation of inflammatory mediators. 3,4,5 Tricaffeoylquinic acid, Bay 11-7085, Akt inhibitor and N-acetylcysteine inhibited the TNF-alpha-induced activation of NF-kappaB, activation of Akt, and formation of reactive oxygen and nitrogen species. The results show that 3,4,5 tricaffeoylquinic acid seems to attenuate the TNF-alpha-stimulated inflammatory mediator production in keratinocytes by suppressing the activation of Akt and NF kappaB pathways which may be mediated by reactive oxygen species. The findings suggest that 3,4,5-tricaffeoylquinic acid may exert an inhibitory effect against the pro-inflammatory mediator-induced skin disease. PMID- 21704194 TI - New mitochondrial tRNA HIS mutation in a family with lactic acidosis and stroke like episodes (MELAS). AB - We report a new mutation in m.12146 A>G in the mt-tRNA(His) in a family with a remarkable clinical history having different degrees of lactic acidosis and stroke-like episodes. Biochemical measurements of a muscle biopsy established an isolated complex IV deficiency, while similar analysis of fibroblasts showed a combined complex I,III and IV deficiency. Transmitochondrial cybrid analysis proved that this tRNA(His) mutation causes the enzymatic deficiency. This family illustrates the complexity of the clinical, biochemical and genetic characteristics of a novel mtDNA encoded disorder, as well as the challenge to prove its pathogenicity. PMID- 21704195 TI - Assessment of upper airway dynamic properties using sternal phrenic nerve magnetic stimulation in awake subjects. AB - To assess upper airway (UA) dynamic properties, magnetic stimulation of the phrenic nerves (MSPN) is usually performed at cervical level or anterior laterally at the neck base. We hypothesized that UA dynamic properties could be effectively assessed by MSPN performed at the sternal level. Instantaneous flow, pharyngeal and mask pressures were recorded in 12 healthy awake subjects. End expiratory MSPN were applied in random order with a non-focal coil placed behind the 7th cervical vertebrae (C7-MS) and at the sternal level (a-MS). The percentage of flow-limited twitches was greater with a-MS (a-MS: 33% and C7-MS: 2%; P<0.0001). For the non flow-limited twitches, maximal inspiratory flow was 36% greater (P<0.001) and isoflow UA resistance was lower with a-MS (0.6+/-0.1 and 0.9+/-0.1 cmH2Ol(-1)s; P=0.02). Maximal inspiratory flow of flow-limited twitches was 78% greater (P=0.05) and isoflow UA resistance tended to be lesser with a-MS (0.9+/-0.3 and 1.8+/-0.7 cmH2Ol(-1)s; P=0.09). a-MS could be a practical approach for assessing UA dynamic properties in awake subjects. PMID- 21704197 TI - Active fluctuation in the cortical cytoskeleton observed by high-speed live-cell scanning probe microscopy. AB - We investigated the dynamics of the cortical cytoskeleton in living cells by analyzing the motion of the endogenous components of the cytoskeleton using scanning probe microscopy (SPM). We performed molecular characterization of the microgranules visualized by SPM in living cells and analyzed the motion of these microgranules via particle tracking. Simultaneous SPM and epifluorescence microscopy observations showed that the microgranules recruited not only actin but also cortactin, which can bind to actin filaments. This indicates condensation of actin filaments at microgranules, leading us to identify them as "cytoskeletal microdomains". High-speed SPM observation and particle-tracking analysis showed that these cytoskeletal microdomains exhibit random walk-like diffusive fluctuations over a timescale of seconds. Inhibition of the molecular motor myosin II, which drives actin filaments, led to subdiffusive fluctuations of the microdomains. These results can be explained by longitudinal sliding of actin filaments stochastically driven by myosin II and the bending motion of the actin filaments in the absence of sliding. Analysis of the cytoskeletal microdomains thus revealed the intrinsic dynamics of the cortical cytoskeleton. PMID- 21704198 TI - Development and optimization of a dual-photoinitiator, emulsion-based technique for rapid generation of cell-laden hydrogel microspheres. AB - A growing number of clinical trials explore the use of cell-based therapies for the treatment of disease and restoration of damaged tissue; however, limited cell survival and engraftment remains a significant challenge. As the field continues to progress, microencapsulation strategies are proving to be a valuable tool for protecting and supporting these cell therapies while preserving minimally invasive delivery. This work presents a novel, dual-photoinitiator technique for encapsulation of cells within hydrogel microspheres. A desktop vortexer was used to generate an emulsion of poly(ethylene glycol) diacrylate (PEGDA) or PEGDA based precursor solution in mineral oil. Through an optimized combination of photoinitiators added to both the aqueous and the oil phase, rapid gelation of the suspended polymer droplets was achieved. The photoinitiator combination provided superior cross-linking consistency and greater particle yield, and required lower overall initiator concentrations compared with a single initiator system. When cells were combined with the precursor solution, these benefits translated to excellent microencapsulation yield with 60-80% viability for the tested cell types. It was further shown that the scaffold material could be modified with cell-adhesive peptides to be used as surface-seeded microcarriers, or additionally with enzymatically degradable sequences to support three dimensional spreading, migration and long-term culture of encapsulated cells. Three cell lines relevant to neural stem cell therapies are demonstrated here, but this technology is adaptable, scalable and easy to implement with standard laboratory equipment, making it a useful tool for advancing the next generation of cell-based therapeutics. PMID- 21704199 TI - Tissue engineering scaffolds containing embedded fluorinated-zeolite oxygen vectors. AB - Efficient oxygen supply is a continuing challenge for the fabrication of successful tissue engineered constructs with clinical relevance. In an effort to enhance oxygen delivery we report the feasibility of using fluorinated zeolite particles embedded in three-dimensional (3-D) polyurethane scaffolds as novel oxygen vectors. First, 1H,1H,2H,2H-perfluorodecyltriethoxysilane was successfully coupled to zeolite framework particles to examine the dose-dependent dissolved oxygen concentration. Following this, the fluorinated-zeolite (FZ) particles were embedded in 3-D tissue engineering polyurethane scaffolds. Our data demonstrates an even distribution of FZ particles in the 3-D scaffolds without affecting the scaffold porosity or pore size. Human coronary artery smooth muscle cell (HCASMC) proliferation on FZ-containing polyurethane (PCU-FZ) scaffolds was significantly greater than on control scaffolds (P=0.05). Remarkably, cell infiltration depths on the PCU-FZ scaffolds was double that on PCU control scaffolds. Taken together, our data suggest the potential of PCU-FZ scaffolds for tissue engineering with enhanced oxygen delivery to cells. PMID- 21704200 TI - Bone bonding ability and handling properties of a titania-polymethylmethacrylate (PMMA) composite bioactive bone cement modified with a unique PMMA powder. AB - One of the challenges of using bioactive bone cements is adjusting their handling properties for clinical application. To resolve the poorer handling properties of bioactive bone cements we developed a novel bioactive bone cement containing a unique polymethylmethacrylate (PMMA) powder, termed SPD-PMMA (40 MUm in diameter), composed of cohered minute particles of PMMA (0.5 MUm). The present study aimed to examine the mechanical and handling properties and the in vivo bone bonding strength of this cement. The titania content of the cement varied from 10 to 30 wt.% (Ts10, Ts20, and Ts30). The mechanical and thermal properties of Ts10 and Ts20 exceeded those of commercially available PMMA cements (PMMAc). The setting properties of Ts20, including a shorter dough time and a working time that was comparable with that of PMMAc, were adequate for clinical application. Hardened cylindrical cement specimens were inserted into rabbit femurs and the interfacial shear strengths were measured by a push-out test at 6, 12, and 26 weeks after the operation. The interfacial shear strength values (in Newtons per square millimeter) of Ts10, Ts20, and Ts30 at 12 weeks and those of Ts20 and Ts30 at 26 weeks were significantly higher than that of PMMAc (P<0.05). These results show that a bioactive titania-PMMA composite bone cement modified by SPD-PMMA particles possesses adequate mechanical and handling properties, as well as osteoconductivity and in vivo bone bonding ability, and can be used for prosthesis fixation. PMID- 21704196 TI - Proliferative versus apoptotic functions of caspase-8 Hetero or homo: the caspase 8 dimer controls cell fate. AB - Caspase-8, the initiator of extrinsically-triggered apoptosis, also has important functions in cellular activation and differentiation downstream of a variety of cell surface receptors. It has become increasingly clear that the heterodimer of caspase-8 with the long isoform of cellular FLIP (FLIP(L)) fulfills these pro survival functions of caspase-8. FLIP(L), a catalytically defective caspase-8 paralog, can interact with caspase-8 to activate its catalytic function. The caspase-8/FLIP(L) heterodimer has a restricted substrate repertoire and does not induce apoptosis. In essence, caspase-8 heterodimerized with FLIP(L) prevents the receptor interacting kinases RIPK1 and -3 from executing the form of cell death known as necroptosis. This review discusses the latest insights in caspase-8 homo versus heterodimerization and the implication this has for cellular death or survival. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome. PMID- 21704201 TI - Protein adsorption and peroxidation of rat retinas under stimulation of a neural probe coated with polyaniline. AB - For the purpose of investigating the potential use of conducting polymers, i.e. polyaniline (PANi), as electrode coating material for improving the function of neural probes, a PANi-coated platinum (Pt) electrode was prepared by the in situ polymerization method. Protein adsorption was observed by atomic force microscopy/scanning electron microscopy and sodium dodecyl sulfate polyacrylamide gel electrophoresis, as well as quantification. Peroxidation of rat retinas was evaluated by determination of conjugated dienes and PLOOH, which were quantified by UV-visible spectrophotometer and high-performance liquid chromatography. The stability of PANi coating for 6 months was also estimated with an in vitro electrical stimulation system. This revealed that: (1) PANi with regular and compact nanoparticles 20-40 nm in diameter was successfully polymerized on the uncoated platinum electrode surface; (2) the PANi-coated Pt electrode adsorbed fewer retinal fragments and induced less peroxidation than the uncoated platinum electrode; (3) in contrast to the uncoated platinum electrode, the PANi-coated Pt electrode surface tended to aggregate retinal fragments rather than spread them, which may help to reduce inflammation and scar formation in long-term implantation; (4) the PANi coating exhibited excellent properties in terms of the intactness and the stable nanoparticle morphology after 6 months' electrical stimulation, while corrosion occurred on the uncoated platinum electrode after 1 month. PMID- 21704202 TI - Strategy for purification of aggregation prone beta-glucosidases from the cell wall of yeast: a preparative scale approach. AB - Purification of biotechnologically important proteins is of vital interest to the biotech industry. beta-Glucosidases, belonging to Family 1 and Family 3 of the glycosylhydrolases, have varied applications as carbohydrate hydrolyzing and synthesizing enzymes. Obtaining high quantities of these enzymes is important for exploring their biosynthetic potential, structural information and catalytic activities. Classical methods for their preparation fail to deliver high yields because of adoption of several/hydroxyapatite chromatography steps. We report here a preparative method for purification of large quantities of two closely related cell bound beta-glucosidases (BGL I and BGL II) from Pichia etchellsii that belong to Family 3 glycosylhydrolases. A combination of ion-exchange and gel filtration chromatography was used to process milligram quantities of protein with recoveries of up to 53%. A simple affinity based separation resulted in resolution of BGL I and BGL II with high recovery and high specific activities of 74IU/mg and 32IU/mg protein respectively. Peptide sequences of BGL II indicated it to be a novel member of Family 3. Methods reported here present a successful strategy for obtaining large quantities of these enzymes. PMID- 21704203 TI - Abundance of tegument surface proteins in the human blood fluke Schistosoma mansoni determined by QconCAT proteomics. AB - The schistosome tegument provides a major interface with the host blood stream in which it resides. Our recent proteomic studies have identified a range of proteins present in the complex tegument structure, and two models of protective immunity have implicated surface proteins as mediating antigens. We have used the QconCAT technique to evaluate the relative and absolute amounts of tegument proteins identified previously. A concatamer comprising R- or K-terminated peptides was generated with [(13)C(6)] lysine/arginine amino acids. Two tegument surface preparations were each spiked with the purified SmQconCAT as a standard, trypsin digested, and subjected to MALDI ToF-MS. The absolute amounts of protein in the biological samples were determined by comparing the areas under the pairs of peaks, separated by 6m/z units, representing the light and heavy peptides derived from the biological sample and SmQconCAT, respectively. We report that aquaporin is the most abundant transmembrane protein, followed by two phosphohydrolases. Tetraspanin Tsp-2 and Annexin-2 are also abundant but transporters are scarce. Sm200 surface protein comprised the bulk of the GPI anchored fraction and likely resides in the secreted membranocalyx. Two host IgGs were identified but in amounts much lower than their targets. The findings are interpreted in relation to the models of protective immunity. PMID- 21704204 TI - Targeting chromatin remodelers: signals and search mechanisms. AB - Chromatin remodeling complexes are ATP-driven molecular machines that change chromatin structure by translocating nucleosomes along the DNA, evicting nucleosomes, or changing the nucleosomal histone composition. They are highly abundant in the cell and numerous different complexes exist that display distinct activity patterns. Here we review chromatin-associated signals that are recognized by remodelers. It is discussed how these regulate the remodeling reaction via changing the nucleosome substrate/product binding affinity or the catalytic translocation rate. Finally, we address the question of how chromatin remodelers operate in the cell nucleus to find specifically marked nucleosome substrates via a diffusion driven target location mechanism, and estimate the search times of this process. This article is part of a Special Issue entitled:Snf2/Swi2 ATPase structure and function. PMID- 21704207 TI - Words of thanks to Dr. Alan H. DeCherney. PMID- 21704208 TI - The Y chromosome in the era of intracytoplasmic sperm injection: a personal review. AB - The Y chromosome contains 60 multicopy genes composed of nine different gene families concentrated in regions of multiple repeat sequences called amplicons arranged in mirror images called palindromes. This pattern is susceptible to deletions caused by homologous recombination with itself, and can explain the presence of small numbers of sperm in otherwise azoospermic men. PMID- 21704205 TI - Functions of the Snf2/Swi2 family Rad54 motor protein in homologous recombination. AB - Homologous recombination is a central pathway to maintain genomic stability and is involved in the repair of DNA damage and replication fork support, as well as accurate chromosome segregation during meiosis. Rad54 is a dsDNA-dependent ATPase of the Snf2/Swi2 family of SF2 helicases, although Rad54 lacks classical helicase activity and cannot carry out the strand displacement reactions typical for DNA helicases. Rad54 is a potent and processive motor protein that translocates on dsDNA, potentially executing several functions in recombinational DNA repair. Rad54 acts in concert with Rad51, the central protein of recombination that performs the key reactions of homology search and DNA strand invasion. Here, we will review the role of the Rad54 protein in homologous recombination with an emphasis on mechanistic studies with the yeast and human enzymes. We will discuss how these results relate to in vivo functions of Rad54 during homologous recombination in somatic cells and during meiosis. This article is part of a Special Issue entitled: Snf2/Swi2 ATPase structure and function. PMID- 21704206 TI - Bone vs. fat: embryonic origin of progenitors determines response to androgen in adipocytes and osteoblasts. AB - Although androgen is considered an anabolic hormone, the consequences of androgen receptor (AR) overexpression in skeletally-targeted AR-transgenic lines highlight the detrimental effect of enhanced androgen sensitivity on cortical bone quality. A compartment-specific anabolic response is observed only in male and not in female AR3.6-transgenic (tg) mice, with increased periosteal bone formation and calvarial thickening. To identify anabolic signaling cascades that have the potential to increase bone formation, qPCR array analysis was employed to define expression differences between AR3.6-tg and wild-type (WT) periosteal tissue. Notably, categories that were significantly different between the two genotypes included axonal guidance, CNS development and negative regulation of Wnt signaling with a node centered on stem cell pathways. Further, fine mapping of AR3.6-tg calvaria revealed that anabolic thickening in vivo is not uniform across the calvaria, occurring only in frontal and in not parietal bones. Multipotent fraction 1 progenitor populations from both genotypes were cultured separately as frontal bone neural crest stem-like cells (fNCSC) and parietal bone mesenchymal stem-like cells (pMSC). Both osteoblastic and adipogenic differentiation in these progenitor populations was influenced by embryonic lineage and by genotype. Adipogenesis was enhanced in WT fNCSC compared to pMSC, but transgenic cultures showed strong suppression of lipid accumulation only in fNCSC cells. Osteoblastogenesis was significantly increased in transgenic fNCSC cultures compared to WT, with elevated alkaline phosphatase (ALP) activity and induction of mineralization and nodule formation assessed by alizarin red and von Kossa staining. Osteocalcin (OC) and ALP mRNA levels were also increased in fNCSC cultures from AR3.6-tg vs. WT, but in pMSC cultures ALP mRNA levels, mineralization and nodule formation were decreased in AR3.6-tg cells. Expression differences identified by array in long bone periosteal tissue from AR3.6-tg vs. WT were recapitulated in the fNCSC samples while pMSC profiles reflected cortical expression. These observations reveal the opposing effects of androgen signaling on lineage commitment and osteoblast differentiation that is enhanced in cells derived from a neural crest origin but inhibited in cells derived from a mesodermal origin, consistent with in vivo compartment-specific responses to androgen. Combined, these results highlight the complex action of androgen in the body that is dependent on the embryonic lineage and developmental origin of the cell. Further, these data these data suggest that the periosteum surrounding long bone is derived from neural crest. PMID- 21704209 TI - Stress relief to augment fertility: the pressure mounts. AB - Current studies have not conclusively demonstrated an objective and consistent marker of an aberrant stress response; an effect of such a stress response on reproductive outcome; or a benefit of counseling on reproductive outcome in such patients. PMID- 21704210 TI - DNA methylation at H19/IGF2 ICR1 in the placenta of pregnancies conceived by in vitro fertilization and intracytoplasmic sperm injection. AB - DNA methylation at H19 ICR1 was investigated in the placenta from pregnancies conceived by in vitro fertilization, intracytoplasmic sperm injection, and from natural conception. Our results showed that there were no significant differences in mean methylation between all pregnancy groups; therefore, assisted reproductive technology may not affect proper imprinting of H19 and IGF2. PMID- 21704211 TI - 5'-(N-ethylcarboxamido) adenosine improves angiogenesis in transplanted human ovarian tissue. AB - To investigate the effect of 5'-(N-ethylcarboxamido) adenosine (NECA), an adenosine agonist, on triggering angiogenesis in transplanted human ovarian tissue, the expression of angiopoietin-1 (Ang1), Ang2, vascular endothelial growth factor 121 (VEGF-121) and VEGF-189 at both gene and protein levels as well as the density of vasculature were studied in tissue fragments grafted to NECA treated and control groups of nude mice. The results showed that NECA treatment triggered down-regulation of Ang1, induced VEGF-189 expression, and stimulated neovascularization, highlighting the beneficial effect of NECA on the process of angiogenesis. PMID- 21704213 TI - Modulation of syndecans in the uterus throughout the menstrual cycle: comparison between endometrium and myometrium. AB - Immunohistochemistry and semiquantitative analysis were used to examine and compare the expression of syndecans 1-4 in the endometrium and myometrium throughout the menstrual cycle. Syndecans molecules show different temporal and spatial expression during the menstrual cycle, and the modulation of syn-2 expression is statistically significantly correlated to morphologic and functional changes of the endometrium, particularly in the periovulatory period. PMID- 21704212 TI - Effects of metformin in adolescents with polycystic ovary syndrome undertaking lifestyle therapy: a pilot randomized double-blind study. AB - Our small study does not support the addition of metformin to the lifestyle of adolescents. Although there are favorable trends toward hyperandrogenism with metformin, these must be balanced against the increased rate of gastrointestinal side effects. However, other treatments were associated with an improved quality of life. PMID- 21704214 TI - Nitrogen vapor shipment of vitrified oocytes: time for caution. AB - Oocyte cryopreservation for fertility preservation, in both medical and elective situations, has significantly increased as freezing technology has improved. Slow freezing techniques demonstrated ~ 50-80% survival of mature oocytes, however vitrification with ~ 97% survival has become the preferred method for oocyte cryopreservation around the world. Our work investigated the effect of transporting cryopreserved oocytes to and from a long-term storage facility. Our findings demonstrate that extra caution should be practiced for vitrified oocytes, especially when handling and transferring between shipping and long-term cryopreservation storage containers. PMID- 21704215 TI - Activation of the immune system and sperm DNA fragmentation are associated with idiopathic oligoasthenoteratospermia in men with couple subfertility. AB - Ejaculates from men without known causes for male subfertility and asymptomatic for genital tract inflammation showed infiltration of macrophages, and their activation state (HLA-DR(+)) was negatively correlated with semen parameters and positively correlated with sperm DNA damage. An activation of the immune system is thus detectable in idiopathic oligoasthenoteratozoospermia of unknown origin. PMID- 21704216 TI - Serum antimullerian hormone in healthy premenopausal women. AB - Antimullerian hormone (AMH) is extensively studied in ovarian aging and pathology; however, little is known about correlates in healthy premenopausal women. We found that AMH levels are strongly inversely associated with age and differed significantly between oral contraceptive pill users and nonusers, whereas no significant associations were seen between AMH and other clinical, behavioral, and anthropometric characteristics and laboratory variables, making it an attractive hormone for clinical applications. PMID- 21704217 TI - Expression and function of fatty acid-binding protein 4 during mouse decidualization. AB - Fatty acid-binding protein 4 (Fabp4) is highly expressed in the secondary decidual zone of mouse decidua and deciduoma and stromal cells under in vitro decidualization. Dtprp, a well-known marker of in vitro decidualization, is diminished by small interfering RNA against Fabp4 and FABP4 inhibitor and stimulated through Fabp4 overexpression. PMID- 21704218 TI - STAFF 2010--Interpreting ST-segment deviation in patients with acute myocardial infarction: from the STAFF 2010 Meeting in Portrush, Northern Ireland--Dewar Finlay and Stafford Warren, Organizers. PMID- 21704219 TI - Influence of the vectorcardiogram synthesis matrix on the power of the electrocardiogram-derived spatial QRS-T angle to predict arrhythmias in patients with ischemic heart disease and systolic left ventricular dysfunction. AB - BACKGROUND AND PURPOSE: Several studies have demonstrated that the spatial mean QRS-T angle (SA) predicts cardiac events and mortality. Spatial mean QRS-T angle is a vectorcardiographic variable. Because in clinical practice, 12-lead standard electrocardiograms (ECGs) are recorded rather than vectorcardiograms (VCGs) according to Frank, VCGs are commonly obtained by synthesizing them from 12-lead ECGs, by using a VCG synthesis matrix. Hence, the thus computed SA is an estimate of the real SA measured in the Frank VCG. Recent studies have shown that Kors VCG synthesis matrix yields better estimates of SA than the inverse Dower VCG synthesis matrix. Our current study aims to compare the predictive power of these SA variants for the occurrence of potentially lethal arrhythmias. METHODS: The study group consisted of patients with ischemic heart disease and left ventricular systolic dysfunction who received an implantable cardioverter defibrillator (ICD) for primary prevention. During follow-up, the occurrence of appropriate device therapy (occurrence of ventricular arrhythmia) was noted. Alternative SAs were computed in VCGs synthesized from standard 12-lead ECGs by using either the inverse Dower matrix (SA-Dower) or the Kors matrix (SA-Kors). Comparison of the predictive power of SA-Dower and SA- Kors was performed by receiver operating characteristic analysis, by Kaplan-Meier analysis, and by univariate and multivariate Cox regression analysis, using every 10th percentile of SA as a cutoff value. RESULTS: The study group consisted of 412 patients (361 men; mean +/- SD age 63 +/- 11 years), in which 56 patients had appropriate ICD therapy during follow-up. Receiver operating characteristic analysis revealed that the area under the curve of SA-Kors was significantly larger than area under the curve of SA-Dower (0.646 vs 0.607, P = .043). The discriminative power of SA Kors for the absence/presence of appropriate ICD therapy in patients during follow-up was generally superior to SA-Dower over a wide range of cutoff values in the Kaplan-Meier analysis and generally yielded stronger hazard ratios in the univariate and multivariate Cox regression analyses. CONCLUSION: If there is no specific reason to use the inverse Dower matrix, VCG synthesis from standard 12 lead ECGs should preferably be done by using the Kors matrix. It is likely to assume that already published studies in which the predictive value of SA-Dower was demonstrated would yield stronger results if the SA-Dower angles were substituted by SA-Kors angles. PMID- 21704220 TI - Optimization of the precordial leads of the 12-lead electrocardiogram may improve detection of ST-segment elevation myocardial infarction. AB - BACKGROUND: For the assessment of patients with chest pain, the 12-lead electrocardiogram (ECG) is the initial investigation. Major management decisions are based on the ECG findings, both for attempted coronary artery revascularization and risk stratification. The aim of this study was to determine if the current 6 precordial leads (V(1)-V(6)) are optimally located for the detection of ST-segment elevation in ST-segment elevation myocardial infarction (STEMI). METHODS: We analyzed 528 (38% anterior [200], 44% inferior [233], and 18% lateral [95]) patients with STEMI with both a 12-lead ECG and an 80-lead body surface map (BSM) ECG (Prime ECG, Heartscape Technologies, Bangor, Northern Ireland). Body surface map was recorded within 15 minutes of the 12-lead ECG during the acute event and before revascularization. ST-segment elevation of each lead on the BSM was compared with the corresponding 12-lead precordial leads (V(1)-V(6)) for anterior STEMI. In addition, for lateral STEMI, leads I and aVL of the BSM were also compared; and limb leads II, III, aVF of the BSM were compared with inferior unipolar BSM leads for inferior STEMI. Leads with the greatest mean ST-segment elevation were selected, and significance was determined by analysis of variance of the mean ST segment. RESULTS: For anterior STEMI, leads V(1), V(2), 32, 42, 51, and 57 had the greatest mean ST elevation. These leads are located in the same horizontal plane as that of V(1) and V(2). Lead 32 had a significantly greater mean ST elevation than the corresponding precordial lead V(3) (P = .012); and leads 42, 51, and 57 were also significantly greater than corresponding leads V(4), V(5), V(6), respectively (P < .001). Similar findings were also found for lateral STEMI. For inferior STEMI, the limb leads of the BSM (II, III, and aVF) had the greatest mean ST-segment elevation; and lead III was significantly superior to the inferior unipolar leads (7, 17, 27, 37, 47, 55, and 61) of the BSM (P < .001). CONCLUSION: Leads placed on a horizontal strip, in line with leads V(1) and V(2), provided the optimal placement for the diagnosis of anterior and lateral STEMI and appear superior to leads V(3), V(4), V(5), and V(6). This is of significant clinical interest, not only for ease and replication of lead placement but also may lead to increased recruitment of patients eligible for revascularization with none or borderline ST-segment elevation on the initial 12-lead ECG. PMID- 21704221 TI - A simulation tool for visualizing and studying the effects of electrode misplacement on the 12-lead electrocardiogram. AB - INTRODUCTION: Studies have shown that between 0.4% and 4% of all 12-lead electrocardiograms (ECGs) are recorded using incorrect electrode positions. Electrode misplacement can cause a misdiagnosis either by concealing a pathology or, on the contrary, by emulating a pathology. Irrespective of this fact, ECG textbooks contain little or no information regarding the effects of electrode misplacement. Moreover, current pedagogic tools, which include physical mannequins, do not allow for the free positioning of electrodes to demonstrate these effects. In recognition of this, an electrode misplacement simulator (EMS) has been developed in this study. METHODS: The EMS is a Web-based simulation developed using the Adobe Flash technology. The software allows the user to position the electrodes anywhere on the torso while rendering the corresponding ECG leads using body surface potential maps. A beta version of the EMS has been made available on the Internet. RESULTS: The EMS has been briefly evaluated by a random selection of delegates (n = 17) from the 37th Annual Conference on Computing in Cardiology. After completing representative tasks and using the EMS for approximately 30 minutes, all 17 participants completed a questionnaire. Overall, the responsiveness of the EMS was rated between 4 and 5 on a Likert scale, 94% of participants rated the "ease of use" between 4 and 5, and 88% of participants also rated the "look and feel" between 4 and 5 on a Likert scale. CONCLUSION: The EMS has the potential to be used to support researchers in enhancing criteria currently used for detecting electrode misplacement. It could also be used to assist academic staff in teaching the effects of electrode misplacement. In this respect, it is currently being used as part of an undergraduate "Clinical Physiology" degree program at the University of Ulster. PMID- 21704222 TI - Predictive power of T-wave alternans and of ventricular gradient hysteresis for the occurrence of ventricular arrhythmias in primary prevention cardioverter defibrillator patients. AB - BACKGROUND AND PURPOSE: Left ventricular ejection fraction lacks specificity to predict sudden cardiac death in heart failure. T-wave alternans (TWA; beat-to beat T-wave instability, often measured during exercise) is deemed a promising noninvasive predictor of major cardiac arrhythmic event. Recently, it was demonstrated that TWA during recovery from exercise has additional predictive value. Another mechanism that potentially contributes to arrhythmogeneity is exercise-recovery hysteresis in action potential morphology distribution, which becomes apparent in the spatial ventricular gradient (SVG). In the current study, we investigated the performance of TWA amplitude (TWAA) during a complete exercise test and of exercise-recovery SVG hysteresis (SVGH) as predictors for lethal arrhythmias in a population of heart failure patients with cardioverter defibrillators (ICDs) implanted for primary prevention. METHODS: We performed a case-control study with 34 primary prevention ICD patients, wherein 17 patients (cases) and 17 patients (controls) had no ventricular arrhythmia during follow up. We computed, in electrocardiograms recorded during exercise tests, TWAA (maximum over the complete test) and the exercise-recovery hysteresis in the SVG. Statistical analyses were done by using the Student t test, Spearman rank correlation analysis, receiver operating characteristics analysis, and Kaplan Meier analysis. Significant level was set at 5%. RESULTS: Both SVGH and TWAA differed significantly (P < .05) between cases (mean +/- SD, SVGH: -18% +/- 26%, TWAA: 80 +/- 46 MUV) and controls (SVGH: 5% +/- 26%, TWAA: 49 +/- 20 MUV). Values of TWAA and SVGH showed no significant correlation in cases (r = -0.16, P = .56) and in controls (r = -0.28, P = .27). Receiver operating characteristics of SVGH (area under the curve = 0.734, P = .020) revealed that SVGH less than 14.8% discriminated cases and controls with 94.1% sensitivity and 41.2% specificity; hazard ratio was 3.34 (1.17-9.55). Receiver operating characteristics of TWA (area under the curve = 0.699, P = .048) revealed that TWAA greater than 32.5 MUV discriminated cases and controls with 93.8% sensitivity and 23.5% specificity; hazard ratio was 2.07 (0.54-7.91). DISCUSSION AND CONCLUSION: Spatial ventricular gradient hysteresis bears predictive potential for arrhythmias in heart failure patients with an ICD for primary prevention, whereas TWA analysis seems to have lesser predictive value in our pilot group. Spatial ventricular gradient hysteresis is relatively robust for noise, and, as it rests on different electrophysiologic properties than TWA, it may convey additional information. Hence, joint analysis of TWA and SVGH may, possibly, improve the noninvasive identification of high-risk patients. Further research, in a large group of patients, is required and currently carried out by our group. PMID- 21704223 TI - DeltaT50--a new method to assess temporal ventricular repolarization variability. AB - BACKGROUND: Increased beat-to-beat variability in cardiac repolarization time is a tentative risk marker of drug-induced torsades de pointes. We developed a new, automatic method based on the temporal variability of the T-wave down slope to assess this variability. METHOD AND RESULTS: Leads V(1) to V(6) of resting electrocardiograms were recorded in 42 healthy subjects (18-68 years, 22 men). The temporal variability at 50% of the T-wave down slope, deltaT50 (1.5 +/- 0.41 milliseconds; range, 0.86-2.66 milliseconds), was measured with an accuracy of 1 millisecond on at least 9 pairs of electrocardiogram complexes with a signal-to noise ratio more than 10 and changes in the R-R interval less than 150 milliseconds. The correlation between repeated measurements of deltaT50 was high. DeltaT50 was measured without corrections for age, sex, heart rate, T-wave amplitude, signal-to-noise ratio, R-R variability, and QTcF because none of these factors explained more than 4% of the within-subject deltaT50 variability. CONCLUSION: The beat-to-beat repolarization variability was measured with high fidelity with the deltaT50 method and was a robust measure in healthy volunteers. PMID- 21704224 TI - Tissue Doppler atrial conduction times and electrocardiogram interlead P-wave durations with varying severity of obstructive sleep apnea. AB - OBJECTIVES: Obstructive sleep apnea (OSA) has been reported to be associated with an increased risk of atrial fibrillation. The aim of this study was to investigate atrial electromechanical couplings in patients with OSA and the relationship between these parameters and P-wave dispersion (Pd). METHODS: One hundred twenty-six patients were enrolled in this study. All patients underwent polysomnographic examination. The apnea-hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of sleep. An AHI score of 5 or more was diagnosed as OSA, and an AHI score of less than 5 was diagnosed as OSA (-). Thirty-nine of the patients had an AHI score of less than 5 (group 1), 42 of the patients had AHI score between 5 and 30 (mild and moderate, group 2), 45 of the patients had an AHI score more than 30 (severe, group 3). Atrial electromechanical coupling (PA), intra-atrial, and interatrial electromechanical delay were measured with tissue Doppler imaging. P-wave dispersion was calculated from 12-lead electrocardiogram. RESULTS: Maximum P-wave duration was higher in group 3 compared with groups 2 and 1 (126.0 +/- 16.7 vs 111.0 +/- 12.5 [P < .001] and 126.0 +/- 16.7 vs 99.9 +/- 10.0 [P < .001], respectively). Maximum P-wave duration was higher in group 2 than in group 1 (111.0 +/- 12.5 vs 99.9 +/- 10.0, P < .001). P-wave dispersion was higher in group 3 compared with groups 2 and 1 (50.9 +/- 11.5 vs 37.0 +/- 8.6 [P < .001] and 50.9 +/- 11.5 vs 27.9 +/- 6.8 [P < .001], respectively). P-wave dispersion was higher in group 2 than in group 1 (37.0 +/- 8.6 vs 27.9 +/- 6.8, P < .001). Minimum P-wave duration did not differ between the groups. Atrial PA at the left lateral mitral annulus (lateral PA), septal mitral annulus (septal PA), and right ventricular tricuspid annulus (RV PA) were significantly higher in group 3 than in group 2 (P < .001, P = .001, and P = .009, respectively). Lateral PA, septal PA, and RV PA were higher in group 2 compared with group 1 (P < .001, P = .003, and P = .009, respectively). Interatrial electromechanical delay (lateral PA - RV PA) was significantly longer in group 3 compared with groups 2 and 1 (33.6 +/- 12.1 vs 22.4 +/- 9.4 [P < .001] and 33.6 +/- 12.1 vs 14.9 +/- 9.2 [P < .001], respectively). Interatrial electromechanical delay was longer in group 2 than in group 1 (22.4 +/- 9.4 vs 14.9 +/- 9.2, P = .001). There was a positive correlation between AHI and Pd, lateral PA, septal PA, RV PA, interatrial electromechanical delay, and left-sided intra-atrial electromechanical delay. CONCLUSION: Prolongation of electromechanical delay and increased Pd are associated with apnea-hypopnea index (AHI) and hence the severity of disease. PMID- 21704225 TI - Combined anterior and inferior ST-segment elevation. Electrocardiographic differentiation between right coronary artery occlusion with predominant right ventricular infarction and distal left anterior descending branch occlusion. PMID- 21704226 TI - Hedgehog signaling and pancreatic tumor development. AB - Numerous signaling pathways are misregulated in pancreatic ductal adenocarcinoma (PDAC), a highly malignant type of cancer. One of these is the Hedgehog (HH) pathway, which is normally involved in patterning processes in the developing embryo. Expression of the main ligand Sonic Hedgehog is an early event in carcinogenesis and correlates with the mutation of the KRAS oncogene, the cardinal molecular feature of pancreatic cancer. Recent data establish a functional role for HH signaling primarily in the tumor microenvironment, where it is involved in myofibroblast differentiation and the induction of stroma derived growth promoting molecules. Given the protumorigenic functions of the abundant stromal desmoplasia typically associated with pancreatic cancer, targeting the HH pathway might prove beneficial in the treatment of the disease. First data using small molecule antagonists of HH signaling in mouse models of pancreatic cancer are promising and reveal a substantial, yet transient, effect on the myofibroblastic stroma. In this review, we try to give an outline on the current knowledge about HH signaling in pancreatic cancer including a perspective of using pharmacological inhibitors of this pathway in the clinic. PMID- 21704227 TI - The microenvironment and molecular biology of the multiple myeloma tumor. AB - Multiple myeloma (MM) is a deadly plasma cell cancer that resides in the bone marrow (BM). Numerous studies have demonstrated the involvement of the BM microenvironment supporting tumor growth, angiogenesis, bone disease and drug resistance. Reciprocal interactions between the different components of the BM microenvironment and the MM cells are necessary to regulate migration, differentiation, proliferation and survival of the malignant plasma cells. In this review we focus on the interactions and molecular mechanisms by which the BM microenvironment exert these effects. Better understanding of these interactions and the study of the epigenetic changes that tumor cells undergo are necessary in order to improve current treatments and for the discovery of new therapies that may eventually lead to a potential cure. PMID- 21704229 TI - Proteolytic control of the oncoprotein transcription factor Myc. AB - The c-Myc oncogene encodes a multifunctional transcription factor that directs the expression of genes required for cell growth and proliferation. Consistent with its potent growth-promoting properties, cells have evolved numerous mechanisms that limit the expression and activity of Myc. One of the most prominent of these mechanisms is proteolysis, which destroys Myc within minutes of its synthesis. The rapid and controlled destruction of Myc keeps its levels low and precisely tied to processes that regulate Myc production. In this review, we discuss how Myc protein stability is regulated and the influence of Myc proteolysis on its function. We describe what is known about how Myc is destroyed by ubiquitin (Ub)-mediated proteolysis, attempt to rationalize the role of different Ub-protein ligases and deubiquitylating enzymes (dUbs) in the regulation of Myc stability, and detail how these processes go awry in cancer. Finally, we discuss how our understanding of Myc regulation by the ubiquitin proteasome system (UPS) can expose strategies for therapeutic intervention in human malignancies. PMID- 21704230 TI - TP53 mutations in human cancer: database reassessment and prospects for the next decade. AB - TP53 mutations are the most frequent genetic alterations found in human cancer. For more than 20 years, TP53 mutation databases have collected over 30,000 somatic mutations from various types of cancer. Analyses of these mutations have led to many types of studies and have improved our knowledge about the TP53 protein and its function. The recent advances in sequencing methodologies and the various cancer genome sequencing projects will lead to a profound shift in database curation and data management. In this paper, we will review the current status of the TP53 mutation database, its application to various fields of research, and how data quality and curation can be improved. We will also discuss how the genetic data will be stored and handled in the future and the consequences for database management. PMID- 21704228 TI - Chromatin insulators: a role in nuclear organization and gene expression. AB - Chromatin insulators are DNA-protein complexes with broad functions in nuclear biology. Based on the ability of insulator proteins to interact with each other, it was originally found that insulators form loops that bring together distant regions of the genome. Data from genome-wide localization studies indicate that insulator proteins can be present in intergenic regions as well as at the 5', introns or 3' of genes, suggesting a variety of roles for insulator loops in chromosome biology. Recent results suggest that insulators mediate intra- and interchromosomal interactions to affect transcription, imprinting, and recombination. Cells have developed mechanisms to control insulator activity by recruiting specialized proteins or by covalent modification of core components. It is then possible that insulator-mediated interactions set up cell-specific blueprints of nuclear organization that may contribute to the establishment of different patterns of gene expression during cell differentiation and development. As a consequence, disruption of insulator activity could result in the development of cancer or other disease states. PMID- 21704232 TI - Common congenital heart disorders in adults: percutaneous therapeutic procedures. AB - The population of adults with unrepaired, palliated, and repaired congenital heart disease is growing. Surgical intervention, once the mainstay of palliative and corrective therapy, has been supplanted in many instances by less invasive trans-catheter techniques. Hybrid procedures involving the symbiotic use of surgical and trans-catheter techniques are increasingly utilized in patients with complex lesions. This article summarizes some of the currently applied trans catheter interventional techniques for pulmonary stenosis, ASD, VSD, and coarctation of the aorta. PMID- 21704233 TI - Early and intensive therapy for management of hyperglycemia and cardiovascular risk factors in patients with type 2 diabetes. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) results in significant morbidity and mortality. Results of recent randomized controlled trials demonstrated the ability of early and intensive therapy to reduce the risk of microvascular complications. However, controversy surrounds the ability of such therapy to reduce the risk for macrovascular complications. OBJECTIVES: This article reviews results from recent clinical trials in patients with T2DM as well as extended follow-up of earlier trials to determine if early, intensive, and individualized therapy aimed at the underlying pathogenesis of the disease could decrease the risk for long-term complications, including cardiovascular disease (CVD). METHODS: Information was obtained by a search of the PUBMED and EMBASE databases using the search terms type 2 diabetes mellitus, glycosylated hemoglobin, pathophysiology of type 2 diabetes, glycemic control, early intervention, multifactorial intervention, cardiovascular disease, beta-cell function, and antidiabetes therapy for the period between 1995 and 2010. Articles dealing with outcomes trials, impact of therapy on microvascular and macrovascular complications, effects of therapeutic agents on the pathophysiology of T2DM, and the impact of agents on CV risk factors were then preferentially selected for in depth review. RESULTS: Large-scale clinical trials in patients with T2DM, although largely negative at 5 years for macrovascular end points, suggested benefit for patients with a shorter duration of T2DM (ie, <10 years) and still supported a treatment strategy of early, intensive, and individualized therapy to prevent long-term complications of the disease. In Steno-2, after 13 years of follow-up, early, intensive, multifactorial therapy was associated with a 56% lower risk of all-cause death (P = 0.02) and a 57% lower risk of death from CVD (P = 0.04). In the 10-year follow-up to the United Kingdom Prospective Diabetes Study, intensive therapy was associated with a significant 15% reduction in the risk of myocardial infarction (P = 0.01) and a significant 13% reduction in the risk of death from any cause (P = 0.007). Therapy should be aimed at correcting underlying pathophysiologic defects, including beta-cell failure and insulin resistance, and should also correct underlying risk factors for CVD whenever possible. CONCLUSIONS: Early and intensive antidiabetes treatment was recommended in patients with T2DM, particularly those with a shorter duration of disease and without a history of CVD. The goal was to safely lower glycosylated hemoglobin to <7%, therefore providing beneficial effects on the risk for complications. Hypoglycemia should be avoided. In addition, less aggressive treatment might be suitable for older patients with longstanding diabetes and a history of CVD events. Clinical trial results also provided support for a second important aspect of individualized treatment for patients with T2DM-multifactorial intervention aimed at controlling CVD risk factors. PMID- 21704235 TI - Multikinase inhibitors in metastatic renal cell carcinoma: indirect comparison meta-analysis. AB - BACKGROUND: Randomized controlled trials (RCTs) of multikinase inhibitors sunitinib, sorafenib, and pazopanib have reported efficacy compared with results from placebo and interferon-alpha (INF-alpha). To date, these drugs have not been compared in head-to-head trials. OBJECTIVE: To review systematically the evidence of clinical effectiveness of multikinase inhibitors in the treatment of metastatic renal cell carcinoma (mRCC) and, via an indirect meta-analysis, to determine an optimal treatment among these agents. METHODS: A systematic literature search of MEDLINE, EMBASE, CANCERLIT, and Cochrane controlled trials register databases was performed. All RCTs of multikinase inhibitors (sorafenib, sunitinib, and pazopanib) used to treat mRCC were included. The study selection, data extraction, and quality assessment were performed independently by 2 reviewers, with all disagreements being resolved by consensus. The effects of multikinase inhibitors on progression-free survival (PFS) were compared using an indirect treatment comparison method with INF-alpha or placebo as a comparator. RESULTS: Four studies were included. Two studies examined sunitinib or sorafenib versus IFN-alpha, and the other 2 studies investigated sorafenib or pazopanib versus placebo. Compared with placebo, 2 interventions reported improvement for PFS (sorafenib: hazard ratio [HR] = 0.44, P = 0.01; pazopanib: HR = 0.46, P = 0.0001), whereas only sunitinib improved PFS over IFN-alpha (HR = 0.539, P = 0.001). An indirect comparison suggests that sunitinib is likely to demonstrate greater clinical benefit than sorafenib in terms of PFS (HR = 0.47; 95% CI, 0.316 0.713; P < 0.001), using IFN-alpha as the comparator. Sorafenib was not statistically different from pazopanib using placebo as the comparator in the indirect comparison (HR = 0.957; 95% CI, 0.657-1.39; P = 0.24). CONCLUSION: Some multikinase inhibitors have a favorably reported PFS for patients with mRCC compared with results using IFN-alpha or placebo. Our findings suggest that sunitinib might offer some clinical benefit over sorafenib in terms of PFS. No statistical difference was found between sorafenib and pazopanib treatments. However, these conclusions are based on 2 indirect comparisons of single RCTs. More RCTs are required to confirm these findings and investigate the clinical effectiveness of multikinase inhibitors in the treatment of mRCC. PMID- 21704236 TI - Longitudinal assessment of estimated glomerular filtration rate in apparently healthy adults: a post hoc analysis from the JUPITER study (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). AB - BACKGROUND: Serum creatinine-based estimates of glomerular filtration rate (eGFR) are frequently used to identify patients with chronic kidney disease and assess cardiovascular risk both in clinical trials and in clinical practice. Although change in eGFR may be useful to assess change in renal function in patients with chronic kidney disease, the utility of serum creatinine-based eGFR is uncertain, particularly among individuals with normal or only mildly impaired renal function. OBJECTIVE: The goal of this study was to examine the relationship between baseline serum creatinine and eGFR, as well as changes in these parameters, in apparently healthy adults in a post hoc analysis of data obtained in participants in the JUPITER study (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). METHODS: JUPITER was a randomized study of rosuvastatin 20 mg versus placebo in apparently healthy adults with high-sensitivity C-reactive protein levels >= 2.0 mg/L, LDL-C <130 mg/dL, and serum creatinine <= 2.0 mg/dL. Changes from baseline in serum creatinine and eGFR, based on the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, were assessed in the entire population and in subsets classified according to baseline eGFR status. RESULTS: Baseline characteristics of the 16,279 JUPITER study participants (mean age, 66 years; 62% men; 72% white; and 58% with a history of hypertension) who had both a baseline and >= 1 postbaseline serum creatinine measurement were similar to the entire population of 17,802 patients who entered the trial. The mean age of the study population was 66 years, 62% were men, 72% were white, and 58% had a history of hypertension. Mean (SD) serum creatinine increased from baseline by 0.08 (0.16) mg/dL and 0.09 (0.14) mg/dL in the rosuvastatin and placebo groups, respectively (P = 0.001) at year 1 and by 0.09 (0.18) and 0.10 (0.16) mg/dL (P = 0.0045) at the final visit. Reductions in MDRD and CKD-EPI eGFR were ~ 0.5 mL/min/1.73 m(2) greater with placebo than with rosuvastatin (P < 0.004) at year 1 and the final visit. The magnitude of eGFR change was closely related to baseline eGFR, with greater reductions among subjects with eGFR >= 60 mL/min/1.73 m(2) in both the rosuvastatin and placebo groups. Among those with an eGFR >= 90 mL/min/1.73 m(2) , mean changes at year 1 and final visit ranged from -16 to -23 mL/min/1.73 m(2) with MDRD and CKD-EPI, respectively; in contrast, mean changes were <1 mL/min/1.73 m(2) in subjects with eGFR <60 mL/min/1.73 m(2) . CONCLUSIONS: In JUPITER, reductions in MDRD or CKD EPI eGFR levels were greater in study participants with higher baseline eGFR levels but less in the rosuvastatin than in the placebo group. Future studies are required to assess the reliability of serum creatinine-based estimates of GFR to assess change in renal function, particularly among individuals with normal serum creatinine levels. PMID- 21704237 TI - Pharmacokinetics of extended-release versus conventional tramadol/acetaminophen fixed-dose combination tablets: an open-label, 2-treatment, multiple-dose, randomized-sequence crossover study in healthy korean male volunteers. AB - BACKGROUND: A fixed-dose combination tablet of tramadol/acetaminophen exhibits both rapid and sustained analgesic effects due to different pharmacologic activities. To prolong analgesia and improve patient convenience, an extended release (ER) tablet of this agent has been developed. OBJECTIVE: The aim of this study was to explore the pharmacokinetic profiles of the new ER tramadol/acetaminophen fixed-dose combination and compare them with those of a conventional immediate-release (IR) formulation after multiple dosing as a Phase I clinical exploratory trial. METHODS: An open-label, randomized, 2-sequence crossover study was conducted in healthy volunteers. All subjects received both formulations for 4 days: either 1 IR tablet (tramadol 37.5 mg/acetaminophen 325 mg) q6h followed by 1 ER tablet (tramadol 75 mg/acetaminophen 650 mg) q12h, or vice versa. A 5-day washout period separated the 2 treatments. Tramadol and acetaminophen concentrations in plasma were determined simultaneously using LC MS/MS, and the pharmacokinetic properties were analyzed by noncompartmental method. To compare the systemic exposure of the 2 formulations, the geometric mean ratios (GMRs) for AUC(0-12,ss) and the 90% CIs were calculated. Adverse events (AEs) were identified through subject interviews, recording of vital signs, physical examinations, 12-lead electrocardiography, and clinical laboratory assessments. RESULTS: Twelve healthy, nonsmoking, Korean male subjects completed the study. The mean (SD) age was 24.4 (5.2) years and the mean body weight was 65.1 (6.0) kg. The T(max,ss) for tramadol was delayed until 3 hours after the ER treatment, compared with 1 hour after the IR treatment, whereas the T(max,ss) of acetaminophen was 30 minutes after each treatment. The mean (SD) of AUC(0-12,ss) in the IR and ER formulations was 2789.0 (507.7) and 2638.7 (469.1) ug/h/L for tramadol and 42,635.0 (8711.2) and 40,394.3 (10,127.7) ug/h/L for acetaminophen, respectively. The GMR of ER to IR for AUC(0-12,ss) was 0.95 (90% CI, 0.91-0.99) for tramadol and 0.94 (90% CI, 0.89-0.99) for acetaminophen. A total of 17 AEs occurred in 9 subjects; all AEs were considered mild or moderate and resolved without medical intervention. The most frequent AEs were headache and dizziness (3 cases each). CONCLUSIONS: The ER formulation displayed a similar AUC(0-12,ss) to that of the IR formulation for tramadol and acetaminophen. PMID- 21704234 TI - Use of biologics in rheumatoid arthritis: current and emerging paradigms of care. AB - BACKGROUND: Improved understanding of rheumatoid arthritis (RA) pathogenesis has led to the development of new biologic treatments that target specific elements of RA inflammatory response. OBJECTIVE: Our aim was to provide a comprehensive review of biologic therapies currently used for the treatment of RA. METHODS: A search of MEDLINE (up to October 2010) was conducted. Preference for article inclusion was given to English language meta-analyses and large, Phase III, randomized controlled trials (RCTs) of biologic treatments in patients with RA. RESULTS: In large RCTs, significantly more patients treated with tumor necrosis factor-alpha (TNF-alpha) antagonists (as monotherapy, or as an adjunct to methotrexate) versus controls (35%-67% vs 9%-33% of patients; P <= 0.01) achieved an American College of Rheumatology 20 response as a primary study end point. However, safety concerns-especially the potential for serious infections and malignancy-remain for TNF-alpha blockade. For example, 1 meta-analysis (>5000 patients) reported a 2-fold increase (95% CI, 1.3-3.1) in the risk of serious infections and a 3.3-fold increase (95% CI, 1.2-9.1) in the risk of malignancy. Abatacept and rituximab (given in combination with methotrexate) may be useful clinical alternatives for RA patients with an inadequate response to TNF-alpha antagonists. These agents do not appear to increase the risk of serious infections (OR, 1.35-1.45; 95% CI, 0.56-3.73), although rituximab may rarely cause progressive multifocal leukoencephalopathy (0.4 cases per 100,000 hospitalizations). CONCLUSIONS: Over the last decade, targeted biologic agents have transformed RA treatment. Although relatively expensive in the short term, the direct costs of these biologics may be offset by slowed disease progression and significant improvements in RA symptoms, physical function, and quality of life. PMID- 21704238 TI - Single-dose relative bioavailability of a new quetiapine fumarate extended release formulation: a postprandial, randomized, open-label, two-period crossover study in healthy Uruguayan volunteers. AB - BACKGROUND: Quetiapine is a dibenzothiazepine derivative that has been established as an effective therapy for schizophrenia and bipolar disorder. A new extended-release (XR) solid formulation of quetiapine was developed in the United Kingdom and a Uruguayan company has developed a branded generic version of the innovator. OBJECTIVE: The goal of the present study was to assess the relative bioavailability of a new XR formulation of quetiapine 300 mg versus the XR reference product after the administration of a high-fat breakfast as required to assume bioequivalence according to the Uruguayan regulatory authority. METHODS: This was a randomized-sequence, open-label, 2-period crossover study performed in healthy Uruguayan volunteers with a washout period of 7 days. One tablet of quetiapine XR 300 mg (test and reference formulations) was administered as a single oral dose, and blood samples were collected over 36 hours. Plasma quetiapine concentration was measured by using HPLC. Plasma concentration-time curves were plotted for each volunteer, and AUC from 0 to 36 hours (AUC(0-36)), AUC(0-infinity), C(max), and T(max) were calculated. A priori bioequivalence requirements were set to require a 90% CI of the test/reference ratios for AUC and C(max) values that were between 0.80 and 1.25. Adverse events were determined using clinical assessment, laboratory test results, and monitoring of vital signs throughout the study. Study subjects were asked to report any adverse events at any time during the study. RESULTS: Twenty-four healthy volunteers (12 men, 12 women) were enrolled and completed the study (mean [SD] age, 31 [6.5] years; weight, 68 [12] kg; height, 1.69 [0.09] m; body mass index, 23.7 [3.2] kg/m(2)). Arithmetic mean (SD) of AUC(0-36), AUC(0-infinity), C(max), and T(max) were 3279 (1169) ng/mL/h, 3731 (1332) ng/mL/h, 341.5 (108.3) ng/mL, and (median [range]) 5.0 (1.5-12.0) hours, respectively, for the test formulation and 3528 (1308) ng/mL/h, 3546 (1350) ng/mL/h, 365.9 (136.4) ng/mL, and (median [range]) 5.0 (2.5 10.0) hours, respectively, for the reference formulation. The geometric mean (90% CI) for the test/reference ratio of the log-transformed AUC(0-36), AUC(0 infinity), and C(max) values were: 0.99 (0.91-1.07), 1.06 (0.95-1.18), and 0.94 (0.84-1.05), respectively. The frequency of reported adverse events was: hypotension (27%), dry mouth (27%), dizziness (10%), headache (7%), and nausea (7%). The difference between formulations was not statistically significant (P > 0.05). CONCLUSIONS: This single-dose study found that the test and reference formulations of quetiapine met the regulatory criteria for bioequivalence among healthy male and female volunteers who took the medicines after a high-fat breakfast. Both products were generally well tolerated. PMID- 21704239 TI - Steady-state pharmacokinetics of once-daily cyclobenzaprine extended release: a randomized, double-blind, 2-period crossover study in healthy volunteers. AB - BACKGROUND: The single-dose pharmacokinetic profile of cyclobenzaprine extended release (CER) has been previously characterized and compared with the pharmacokinetics of cyclobenzaprine immediate-release (CIR) administered 3 times daily for 3 doses. OBJECTIVE: The objective of this study was to characterize the multiple-dose pharmacokinetic properties of once-daily CER 30 mg and CIR 10 mg TID formulations in healthy volunteers. METHODS: In this double-blind, single center, 2-period crossover study, healthy subjects were randomized to dosing sequences with once-daily CER 30 mg or CIR 10 mg TID for 7 days. Subjects crossed over to the alternative regimen following a 14-day washout period. Pharmacokinetic assessments at steady state included area under the plasma cyclobenzaprine concentration-time curve over the dosing interval (AUC(0 tau,ss)), peak plasma cyclobenzaprine concentration (C(max,ss)), time to observed C(max) (T(max,ss)), observed minimum cyclobenzaprine concentration (C(min,ss)), average cyclobenzaprine concentration (C(avg,ss)), accumulation ratio (R(ac)), and terminal elimination half-life (t(1/2)). Tolerability and safety assessments were conducted. RESULTS: A total of 36 subjects were randomized; 34 completed both dosing periods (1 subject was lost to follow-up, 1 withdrew consent). Steady state was reached for CER 30 mg on day 7. Mean C(max,ss), C(min,ss), and C(avg,ss) were 41.1, 21.4, and 31.4 ng/mL, respectively. The median T(max,ss) for CER 30 mg was 7.0 hours, with a mean t(1/2) of 34.8 hours. At steady state, CER produced a sustained plasma cyclobenzaprine concentration with a single peak in plasma concentration during the 24-hour dose interval. The R(ac) for CER was 2.65. Because of a protocol violation (insufficient data), no steady-state pharmacokinetic assessments could be performed for CIR. Most adverse events were mild or moderate in intensity. Somnolence was the most frequently reported adverse event (100% of subjects) in those receiving CER, followed by dry mouth (58%), dizziness (19%), and headache (17%). CONCLUSIONS: Once-daily CER 30 mg delivered sustained plasma cyclobenzaprine levels over 24 hours at steady state. Owing to a protocol violation, steady-state pharmacokinetic properties for CIR could not be assessed. PMID- 21704240 TI - Effects of food intake on the pharmacokinetic properties of dalcetrapib: findings from three phase I, single-dose crossover studies in healthy volunteers. AB - BACKGROUND: Preclinical studies have reported that the relative bioavailability of dalcetrapib, a modulator of cholesteryl ester transfer protein (CETP) inhibitor activity, was ~60% higher when administered in the fed state compared with the fasting state. OBJECTIVE: This article reports on 3 studies conducted to assess the effects of food intake, timing of administration with respect to meals, and meal size and content on the relative bioavailability of dalcetrapib in healthy male subjects. METHODS: Three Phase I studies were performed in healthy subjects: (1) a 2-period crossover study of a single dose of dalcetrapib 900 mg administered in the fed and fasting states (fed versus fasting study [1999]); (2) a 3-period crossover study of a single dose of dalcetrapib 600 mg administered after a light morning meal, a standard evening meal, and a light evening meal (meal timing/size study [2005]); and (3) a 4-period crossover study of a single dose of dalcetrapib 600 mg administered 30 minutes after a high-fat meal or a standard evening meal, and 30 minutes before or 3 hours after the latter (high-fat meal study [2007]). Blood samples for pharmacokinetic analyses (AUC(0-36) or AUC(0-infinity), C(max)) were collected up to 36, 144, and 96 hours after study drug administration in the fed versus fasting, meal timing/size, and high-fat meal studies, respectively. CETP activity was measured using a radioisotopic method in the fed versus fasting study and a fluorometric method in the meal timing/size and high-fat meal studies. Tolerability was assessed using monitoring of adverse events, laboratory parameters, vital signs, and ECG. RESULTS: Six men were enrolled in the fed versus fasting study (mean age, 37 years; mean body mass index [BMI], 23.6 kg/m(2)). Dalcetrapib exposure was increased by 64% (AUC(0-36)) and 126% (C(max)) after administration in the fed state. Eighteen men were enrolled in the analysis of the effects of meal timing and size on the properties of dalcetrapib (mean age, 30.5 years; mean BMI, 25.1 kg/m(2)). When dalcetrapib was administered after a light morning or a light evening meal, comparable values were found for mean dalcetrapib AUC(0-infinity) (7400 and 7860 ng.h/mL, respectively) and C(max) (589 and 552 ng/mL), whereas administration after a standard evening meal was associated with increased AUC(0 infinity) (14.3%-14.7%) and C(max) (25.5%-35.3%). Forty-nine men were included in the analysis in the high-fat meal study (mean age, 32.3 years; mean BMI, 23.9 kg/m(2)). Compared with administration after a standard evening meal, administration after a high-fat evening meal was associated with increased AUC(0 infinity) (34.9%) and C(max) (43.7%). Between-treatment differences in exposure within each study also were reflected in apparent differences in CETP activity. All treatments were generally well tolerated. CONCLUSIONS: Dalcetrapib exposure was increased in the fed state and, to a lesser extent, was dependent on the size and fat content of the meal. Exposure was independent of dosing time. Dalcetrapib was generally well tolerated. PMID- 21704241 TI - Single-dose bioequivalence of 105-mg fenofibric acid tablets versus 145-mg fenofibrate tablets under fasting and fed conditions: a report of two phase I, open-label, single-dose, randomized, crossover clinical trials. AB - BACKGROUND: Fenofibrate is used to treat primary hypercholesterolemia, mixed lipidemia, and hypertriglyceridemia in adults who do not respond to nonpharmacologic measures. Fenofibrate is a prodrug that is rapidly and completely hydrolyzed to fenofibric acid, the active moiety. A new orally administered agent, fenofibric acid, was developed as an alternative to fenofibrate. OBJECTIVE: Two separate studies were conducted to evaluate the bioequivalence of fenofibric acid relative to fenofibrate under fasted and fed (standard breakfast) conditions, characterize the pharmacokinetic profile, and assess the safety and tolerability of fenofibric acid. METHODS: In study 1 (fasted), during each study period, volunteers received a single 105-mg dose of fenofibric acid or single 145-mg dose of fenofibrate (depending on their randomization scheme) after an overnight fast (a minimum fast of 10 hours). A 7 day washout period followed the first treatment period, after which the volunteers received the alternate treatment. Study 2 followed a similar dosing scheme and differed only in that volunteers received their single dose after being fed a standard meal (575 calories, of which 36% were contributed by fat). Serial blood samples in both studies were collected up to 72 hours after drug administration. The pharmacokinetic parameters of interest for assessing bioequivalence were AUC(0-t), AUC(0-infinity), C(max), and T(max). The criterion for a lack of difference between products was a 90% CI between 0.80 and 1.25 for the fenofibric acid:fenofibrate ratios for AUC(0-t), AUC(0-infinity), and C(max.) Tolerability was assessed by adverse events (AEs), laboratory parameters, vital signs, and physical examinations. RESULTS: Volunteers in study 1 (fasted; n = 54) were aged 18 to 43 years; 19 (35%) were men and 35 (65%) were women; mean weight was 155.2 pounds (range, 103.0-267.0 pounds); and 48 (89%) were white, 1 (2%) was black, and 5 (9%) were white/American Indian/Alaskan native/Asian. Volunteers in study 2 (fed; n = 54) were aged 18 to 43 years; 27 (50%) were men and 27 (50%) were women; mean weight was 161.9 pounds (range, 112.0-225.0 pounds); and 51 (94%) were white (including 2 Hispanic) and 3 (6%) were black. The 90% CIs about the ratio of the fenofibric acid geometric mean to the fenofibrate geometric mean were within the 80% and 125% limits for the pharmacokinetic parameters C(max), AUC(0-t), and AUC(0-infinity) of the ln-transformed data in both study 1 (fasted) and study 2. In study 1 (fasted), 14 volunteers (26%) experienced a total of 29 AEs; the most common nonlaboratory AEs were dizziness (6%) and headache (4%). In study 2, 12 volunteers (22%) experienced a total of 19 AEs; the most common nonlaboratory AEs were headache (17%) and dry throat (4%). AEs were generally mild or moderate in intensity. CONCLUSIONS: In these 2 single-dose studies, these healthy volunteers administered a single oral dose of 105-mg fenofibric acid met the US Food and Drug Administration regulatory criteria for assuming bioequivalence to a single oral dose of 145-mg fenofibrate tablets with respect to the rate and extent of fenofibric acid absorption in both fed and fasted states. Fenofibric acid at the dose studied was well tolerated in this population. PMID- 21704243 TI - [The hip throughout history]. PMID- 21704242 TI - Pharmacokinetics and tolerability of etamicastat following single and repeated administration in elderly versus young healthy male subjects: an open-label, single-center, parallel-group study. AB - BACKGROUND: Etamicastat is a new dopamine-beta-hydroxylase (DbetaH) inhibitor currently in clinical development for the treatment of hypertension and heart failure. OBJECTIVES: To evaluate the pharmacokinetics and tolerability of etamicastat after single and repeated administration in elderly subjects (aged >=65 years) relative to young adult healthy controls (aged 18-45 years). METHODS: This was a single-center, open-label, parallel-group study in young male adults (n = 13; mean [SD] age 32.6 [16.4] years; range, 18-44 years; weight 79.0 [16.4] kg; systolic blood pressure 117 [12] mm Hg and diastolic blood pressure 61 [7] mm Hg) and 12 elderly male volunteers (n = 12; age 69.3 [3.3] years; weight 69.2 [9.5] kg; systolic blood pressure 115 [13] mm Hg and diastolic blood pressure 64 [4] mm Hg), conducted in 2 consecutive periods. All subjects were white, except for 1 black elderly subject. In Phase A, subjects received a single dose of 100 mg etamicastat. In Phase B, subjects received 100 mg/d etamicastat for 7 days. The pharmacokinetic parameters of etamicastat and its acetylated metabolite BIA 5 961 were calculated after the single dose of Phase A and the last dose of Phase B. Subjects' N-acetyltransferase type 1 (NAT1) and type 2 (NAT2) genotyping was performed and acetylator status inferred. RESULTS: After a single dose of etamicastat 100 mg, mean (SD) plasma C(max) and plasma AUC(0-infinity) were, respectively, 1.3 (0.5) ng/mL/kg and 12.4 (7.8) ng * h/mL/kg in elderly subjects, and 1.3 (0.4) ng/mL/kg and 10.0 (6.6) ng * h/mL/kg in young subjects. At steady state, C(max) and AUC(0-24) were 1.8 (0.5) ng/mL/kg and 15.0 (6.4) ng * h/mL/kg in elderly subjects, and 1.5 (0.7) ng/mL/kg and 12.5 (6.5) ng * h/mL/kg in young subjects. Elderly/young geometric mean ratios and 90% CIs were, respectively, 0.944 (0.788-1.131) and 1.164 (0.730-1.855) for etamicastat C(max) and AUC(0 infinity) after a single dose, and 1.225 (0.960-1.563) and 1.171 (0.850-1.612) for etamicastat C(max) and AUC(0-24) at steady state. Etamicastat steady-state plasma concentrations were reached after 3 to 4 days of dosing. The mean etamicastat accumulation ratio was 1.7 in both age groups. Following etamicastat single dose, mean (SD) BIA 5-961 C(max) and AUC(0-infinity) were, respectively, 3.5 (2.1) ng/mL/kg and 28.4 (14.7) ng * h/mL/kg in elderly subjects, and 2.5 (1.5) ng/mL/kg and 16.5 (9.7) in young subjects. At steady state, BIA 5-961, C(max), and AUC(0-24) were 4.3 (2.6) ng/mL/kg and 34.6 (17.6) ng * h/mL/kg in elderly subjects, and 3.1 (2.0) ng/mL/kg and 22.2 (11.8) ng * h/mL/kg in young subjects. Large interindividual variability dependent on the NAT2 acetylator status was found in the pharmacokinetic parameters of etamicastat and BIA 5-961. Systemic exposure to etamicastat was higher and systemic exposure to BIA 5-961 was lower in NAT2 poor metabolizers compared with rapid metabolizers. No effect on heart rate and blood pressure was found in the young group. In the elderly, a decrease of supine blood pressure was observed. Postural changes in blood pressure were unaffected. Four adverse events (AEs) were reported by each group: nasopharyngeal pain, sciatica, asthenia, and back pain the elderly group, and headache (2 cases), insomnia, and myopericarditis by the young group. Myopericarditis led to study discontinuation for this subject and was considered to be of probable viral etiology. All other AEs were mild to moderate in intensity. CONCLUSION: The pharmacokinetic profile of etamicastat was not significantly different in these small groups of healthy young versus elderly adult male volunteers. PMID- 21704245 TI - [The acutely limping child]. AB - Acute limping may be the result of multiple pathologies in children. The differential diagnosis varies based on the age of the child. Irrespective of age, the initial imaging work-up includes AP and frog leg radiographs of the pelvis and ultrasound; MRI may sometimes be helpful. In children less than 3 years, infections and trauma are most frequent. MRI is the imaging modality of choice when osteomyelitis is clinically suspected. Between the ages of 3 and 10 years, transient synovitis of the hip and Legg-Calve-Perthes disease are main considerations but infection, inflammation and focal bony lesions are also considered. In children over 10 years, slipped capital femoral epiphysis also is considered. PMID- 21704244 TI - [Developmental dysplasia of the hip]. AB - At one month, the acetabular depth from a standard lateral coronal section is 4.6 +/- 1.0mm. The correlation between experienced and junior radiologists is high (kappa 0.795). A treshhold of 6mm with a Delta (difference between right and left) less than 1.5mm provides a sensitivity of 100% for the detection of DDH at one month. Universal US screening at one month of all high-risk infants in 2009 resulted in a reduction of delayed diagnosis of DDH (zero girls, two boys) in Ille-et-Vilaine due to continuous medical education of general radiologists. PMID- 21704246 TI - [The chronically limping child]. AB - Chronic limping in children usually indicates the presence of an underlying organic lesion. Clinical evaluation establishes the site and type of limping. It may suggest a neurological or mechanical lesion or locoregional etiology at the level of the hip or pelvis. Plain radiographs and ultrasound are firstline imaging techniques. The diagnosis may be delayed either due to ignorance of age specific entities or false positive or negative results on plain films and ultrasound. MRI now plays a major role for diagnosis. Multiple potential underlying etiologies including trauma, infections, arthritides or tumors are best evaluated with MRI. The MRI examination should not be limited only to the hip joint. PMID- 21704247 TI - [Periarticular diseases of the hip in young adults]. AB - Multiple periarticular structures are present around the hip joint: tendons, bursae, muscles and entheses, fascias, nerves and vessels. Periarticular diseases of the hip in young adults include, in decreasing order of functional impairment: posttraumatic lesions of muscles and tendons that should not be overlooked because of the risk of functional sequelae, enthesopathy detected on plain films and ultrasound, snapping hip syndrome frequent in athletes and tunnel syndromes (such as compression of the lateral femoral cutaneous nerve where ultrasound is valuable). The main pitfalls to avoid are the stress fracture, trauma to a pelvic muscle and calcium deposition. PMID- 21704248 TI - [Labral pathology and impingement]. AB - The acetabular labrum, a fibrocartilaginous structure essential to the proper functioning of the hip joint, may be damaged from a variety of conditions including femoroacetabular impingement. FAI is defined by abnormal contact between the femur and acetabulum and is characterized by an underlying morphological abnormality of the femur (dysplastic bump at the head/neck junction, Cam effect), acetabulum (excessive coverage, Pincer effect), or both. The abnormal morphology is suspected on plain films and additional evaluation with either CT or MR arthrography is then performed. The role of the radiologist is to describe the imaging findings while allowing the clinician to make the diagnosis based on clinical symptoms (groin pain, reduced internal rotation). Comprehensive evaluation of the underlying structural abnormalities and associated lesions is important to optimize surgical management with the goal of reducing painful symptoms, improve range of motion and prevent early hip joint degeneration. PMID- 21704249 TI - [Imaging features of pubalgia]. AB - Pubalgia is a generic term used to describe groin pain due to a multitude of different etiologies such as skeletal (microtraumatic pubic symphysis arthropathy), muscular (adductor or rectus abdominis disorders), or abdominal wall (inguinal hernia) disorders. Diagnosis relies mainly on MRI for musculoskeletal disorders and ultrasound for abdominal wall disorders. PMID- 21704250 TI - [Evolution of the pelvis and hip throughout history: from primates to modern man]. AB - The evolution to a bipedal mode of locomotion was accompanied by a verticalization of the spine and a modification in the shape of the pelvis: horizontal curvature and sagittal rotation. Phylogenesis meets ontogenesis: flat bones in fetuses similar to the monkey, australopithecus features at birth and "human-like" features by 7 or 8years of age. These anatomical modifications explain the characteristics of human bipedalism: stable, economical, with hip and knee extension in the standing position with little lateral motion. Some pathologies induce a regression to a more archaic mode of bipedal locomotion. PMID- 21704251 TI - [Transient bone marrow edema of the hip]. AB - Transient bone marrow edema of the hip is characterized by moderate homogeneous low MR signal intensity with ill-defined margins that involves at least a portion of the femoral head. Spin echo T1-weighted images are helpful to exclude other underlying diseases (tumor, infection, necrosis from systemic origin...), for which marrow edema is secondary or no epiphyseal in location. High-resolution fat suppressed T2-weighted or proton density images allow evaluation of the articular cartilage, subchondral bone and subchondal marrow: if the articular cartilage is abnormal, the lesion is irreversible (arthrosis or necrosis); if the subchondral bone is focally interrupted and/or if the femoral is no longer spherical, the lesion is irreversible (necrosis); if a focal linear fluid collection is present under the subchondral bone, the lesion is irreversible (necrosis). Finally, subchondral changes may provide useful prognostic information: the absence of any abnormality other than marrow edema typically indicates that complete resolution is likely; the presence of a focal T2-weighted hypointense lesion immediately next to the subchondral bone suggests an irreversible lesion, especially if it is equal to or thicker than 4mm or the joint space. In some instances, prognosis cannot be reliably determined requiring the need for follow-up imaging. PMID- 21704252 TI - [Hip and pelvic injuries in the elderly]. AB - Fractures of the hip and pelvis are frequent and serious injuries in elderly patients. Due to the aging population, their incidence should double by 2050. Therefore, the social and economical implications of these fractures are significant. Delay in diagnosis increases the associated morbidity and mortality. The purpose is to review the imaging features of these fractures, the imaging techniques (projections, CT) to depict them and their classification based on severity. PMID- 21704253 TI - [Hip degeneration]. AB - Hip degeneration is typically easily diagnosed, based on the combination of clinical findings and plain films showing the four classifical findings: joint space narrowing, osteophytes, subchondral sclerosis and subchondral cysts. Some degenerated hips may have misleading features such as when joint space narrowing is mainly posterior or the main finding is a large subchondral cyst. Rapidly destructive coxopathy results in joint space narrowing and joint destruction over a few months. MRI is helpful in early cases with normal radiographs or in patients with known hip degeneration presenting with acute worsening of symptoms. Follow-up is achieved by measuring the joint space on consecutive radiographs obtained using a standard technique. PMID- 21704254 TI - [Imaging of total hip arthroplasty: normal and pathological imaging features, role of ultrasound, CT and MRI]. AB - Total hip arthroplasty is a frequent procedure with functional outcome that generally is excellent and lasting. Routine imaging follow-up is necessary to detect complications such as loosening and wearing out. Additional imaging with scintigraphy, CT, ultrasound or MRI may be necessary. PMID- 21704255 TI - Getting more grip on genetic risk prediction studies: the GRIPS statement. PMID- 21704256 TI - Clinical trials in India: issues with adherence to CONSORT statements. PMID- 21704257 TI - Extensive increase of microarray signals in cancers calls for novel normalization assumptions. AB - When using microarray data for studying a complex disease such as cancer, it is a common practice to normalize data to force all arrays to have the same distribution of probe intensities regardless of the biological groups of samples. The assumption underlying such normalization is that in a disease the majority of genes are not differentially expressed genes (DE genes) and the numbers of up- and down-regulated genes are roughly equal. However, accumulated evidences suggest gene expressions could be widely altered in cancer, so we need to evaluate the sensitivities of biological discoveries to violation of the normalization assumption. Here, we analyzed 7 large Affymetrix datasets of pair matched normal and cancer samples for cancers collected in the NCBI GEO database. We showed that in 6 of these 7 datasets, the medians of perfect match (PM) probe intensities increased in cancer state and the increases were significant in three datasets, suggesting the assumption that all arrays have the same median probe intensities regardless of the biological groups of samples might be misleading. Then, we evaluated the effects of three currently most widely used normalization algorithms (RMA, MAS5.0 and dChip) on the selection of DE genes by comparing them with LVS which relies less on the above-mentioned assumption. The results showed using RMA, MAS5.0 and dChip may produce lots of false results of down-regulated DE genes while missing many up-regulated DE genes. At least for cancer study, normalizing all arrays to have the same distribution of probe intensities regardless of the biological groups of samples might be misleading. Thus, most current normalizations based on unreliable assumptions may distort biological differences between normal and cancer samples. The LVS algorithm might perform relatively well due to that it relies less on the above-mentioned assumption. Also, our results indicate that genes may be widely up-regulated in most human cancer. PMID- 21704258 TI - Feature importance analysis in guide strand identification of microRNAs. AB - MicroRNA (miRNA) is the negative regulator of gene expression, also known as guide strand of transient miRNA:miRNA* duplex. It is critical in maintaining the normal physiological processes such as development, differentiation, and apoptosis in many organisms. With increasing miRNA data, it is desirable to design methods to identify guide strand based on machine learning algorithms. In this study, the random forest models based on local sequence-structure features were proposed to identify miRNA in four species. The accuracies achieved were 86.51% for Homo sapiens, 81.66% for Ornithorhynchus anatinus, 82.33% for Mus musculus and 85.71% for Schmidtea mediterranea, respectively. Furthermore, the important analysis of feature elements was carried out by using the conditional feature importance strategy. The analysis results revealed that most of the significant elements were related to guanine-cytosine (GC) base pair. We believed that our method could be beneficial to annotate the function of miRNA and help the further understanding of the RNA interference mechanism. PMID- 21704259 TI - On the evolution rate in mammalian mitochondrial genomes. AB - The methods of phylogenetic inference have become more and more realistic and effective since the evolution rate was taken into account. In order to study the evolution rate more comprehensively, all 13 protein coding genes in 123 mammalian mitochondrial genomes are analyzed. The evolution rates of different codon position are analyzed as well. The evolution rate is estimated by Shannon entropy. We find that the distribution of 3rd codon position doesn't follow gamma distribution and the results suggest that it follows a mixed distribution of gamma distribution and normal distribution. The relationship between different codon positions is also studied. We find that there are significant positive correlation between three codon positions. Especially between 1st codon position and 2nd codon position, there is strong linear relationship. PMID- 21704260 TI - A local average connectivity-based method for identifying essential proteins from the network level. AB - Identifying essential proteins is very important for understanding the minimal requirements of cellular survival and development. Fast growth in the amount of available protein-protein interactions has produced unprecedented opportunities for detecting protein essentiality from the network level. Essential proteins have been found to be more abundant among those highly connected proteins. However, there exist a number of highly connected proteins which are not essential. By analyzing these proteins, we find that few of their neighbors interact with each other. Thus, we propose a new local method, named LAC, to determine a protein's essentiality by evaluating the relationship between a protein and its neighbors. The performance of LAC is validated based on the yeast protein interaction networks obtained from two different databases: DIP and BioGRID. The experimental results of the two networks show that the number of essential proteins predicted by LAC clearly exceeds that explored by Degree Centrality (DC). More over, LAC is also compared with other seven measures of protein centrality (Neighborhood Component (DMNC), Betweenness Centrality (BC), Closeness Centrality (CC), Bottle Neck (BN), Information Centrality (IC), Eigenvector Centrality (EC), and Subgraph Centrality (SC)) in identifying essential proteins. The comparison results based on the validations of sensitivity, specificity, F-measure, positive predictive value, negative predictive value, and accuracy consistently show that LAC outweighs these seven previous methods. PMID- 21704261 TI - Identifying novel prostate cancer associated pathways based on integrative microarray data analysis. AB - The development and diverse application of microarray and next generation sequencing technologies has made the meta-analysis widely used in expression data analysis. Although it is commonly accepted that pathway, network and systemic level approaches are more reproducible than reductionism analyses, the meta analysis of prostate cancer associated molecular signatures at the pathway level remains unexplored. In this article, we performed a meta-analysis of 10 prostate cancer microarray expression datasets to identify the common signatures at both the gene and pathway levels. As the enrichment analysis result of GeneGo's database and KEGG database, 97.8% and 66.7% of the signatures show higher similarity at pathway level than that at gene level, respectively. Analysis by using gene set enrichment analysis (GSEA) method also supported the hypothesis. Further analysis of PubMed citations verified that 207 out of 490 (42%) pathways from GeneGo and 48 out of 74 (65%) pathways from KEGG were related to prostate cancer. An overlap of 15 enriched pathways was observed in at least eight datasets. Eight of these pathways were first described as being associated with prostate cancer. In particular, endothelin-1/EDNRA transactivation of the EGFR pathway was found to be overlapped in nine datasets. The putative novel prostate cancer related pathways identified in this paper were indirectly supported by PubMed citations and would provide essential information for further development of network biomarkers and individualized therapy strategy for prostate cancer. PMID- 21704262 TI - The human olfactory receptor 17-40: requisites for fitting into the binding pocket. AB - To gain structural insight on the interactions between odorants and the human olfactory receptor, we did homology modelling of the receptor structure, followed by molecular docking simulation with ligands. Molecular dynamics simulation on the structures resulting from docking served to estimate the binding free energy of the various odorant families. A correlation with the odorous properties of the ligands is proposed. We also investigated which residues were involved in the binding of a set of properly synthesised ligands and which were required for fitting inside the binding pocket. Olfactive stimulation of the olfactory receptor with odorous molecules was also investigated, using calcium imaging or electrophysiological recordings. PMID- 21704263 TI - Multi-nucleation and vectorial folding pathways of large helix protein. AB - At present we have already had the detailed knowledge of the folding of small model proteins, but a unified picture of how large proteins fold is still absent. We simulated the folding of a large eight-helix-bundle protein with a length of 145 amino acids by using a united-residue protein model. We observed a multiple nucleation folding pathway: the formation of secondary structures was followed by the nucleation of helices at the two terminal parts and also at the middle of the chain, and then the nuclei grew and combined with each other to form the tertiary structure. Surprisingly, we also found a vectorial folding pathway that was shown recently for co-translational folding in the ribosome exit tunnel. Furthermore, we found that all three-helix subunits in the chain can fold into native-like conformations independently, especially those at the two terminal parts and the middle of the chain, which may be responsible for the nucleation's. These results may be helpful to understand the folding mechanism of large repeat helical proteins. PMID- 21704264 TI - Exploring the limits of fold discrimination by structural alignment: a large scale benchmark using decoys of known fold. AB - Protein structure comparison by pairwise alignment is commonly used to identify highly similar substructures in pairs of proteins and provide a measure of structural similarity based on the size and geometric similarity of the match. These scores are routinely applied in analyses of protein fold space under the assumption that high statistical significance is equivalent to a meaningful relationship, however the truth of this assumption has previously been difficult to test since there is a lack of automated methods which do not rely on the same underlying principles. As a resolution to this we present a method based on the use of topological descriptions of global protein structure, providing an independent means to assess the ability of structural alignment to maintain meaningful structural correspondances on a large scale. Using a large set of decoys of specified global fold we benchmark three widely used methods for structure comparison, SAP, TM-align and DALI, and test the degree to which this assumption is justified for these methods. Application of a topological edit distance measure to provide a scale of the degree of fold change shows that while there is a broad correlation between high structural alignment scores and low edit distances there remain many pairs of highly significant score which differ by core strand swaps and therefore are structurally different on a global level. Possible causes of this problem and its meaning for present assessments of protein fold space are discussed. PMID- 21704265 TI - Drug-induced glucose-6-phosphate dehydrogenase deficiency-related hemolysis risk assessment. AB - Glucose-6-phosphate dehydrogenase (G6PD) is an essential enzyme that protects human red blood cells from premature destruction caused by oxidative damage. People suffering from G6PD deficiency would be vulnerable to various oxidative substances, such as fava beans and oxidant drugs. Until now, many institutes, organizations or domain experts have compiled low-risk or high-risk drugs collection for patients with G6PD deficiency, mainly from the case report or clinical trails. Recently, we have explored a classification system to predict drug-induced hemolytic potential. In this paper, we screen the normally used over the-counter (OTC) drugs for "high-risk" and "low-risk" ones to G6PD deficient patients by this system. PMID- 21704266 TI - Abstract Next Subvolume Method: a logical process-based approach for spatial stochastic simulation of chemical reactions. AB - The spatial stochastic simulation of biochemical systems requires significant calculation efforts. Parallel discrete-event simulation is a promising approach to accelerate the execution of simulation runs. However, achievable speedup depends on the parallelism inherent in the model. One of our goals is to explore this degree of parallelism in the Next Subvolume Method type simulations. Therefore we introduce the Abstract Next Subvolume Method, in which we decouple the model representation from the sequential simulation algorithms, and prove that state trajectories generated by its executions statistically accord with those generated by the Next Subvolume Method. The experimental performance analysis shows that optimistic synchronization algorithms, together with careful controls over the speculative execution, are necessary to achieve considerable speedup and scalability in parallel spatial stochastic simulation of chemical reactions. Our proposed method facilitates a flexible incorporation of different synchronization algorithms, and can be used to select the proper synchronization algorithm to achieve the efficient parallel simulation of chemical reactions. PMID- 21704267 TI - Information-theoretic approaches to SVM feature selection for metagenome read classification. AB - Analysis of DNA sequences isolated directly from the environment, known as metagenomics, produces a large quantity of genome fragments that need to be classified into specific taxa. Most composition-based classification methods use all features instead of a subset of features that may maximize classifier accuracy. We show that feature selection methods can boost performance of taxonomic classifiers. This work proposes three different filter-based feature selection methods that stem from information theory: (1) a technique that combines Kullback-Leibler, Mutual Information, and distance information, (2) a text mining technique, TF-IDF, and (3) minimum redundancy-maximum-relevance (mRMR). The feature selection methods are compared by how well they improve support vector machine classification of genomic reads. Overall, the 6mer mRMR method performs well, especially on the phyla-level. If the number of total features is very large, feature selection becomes difficult because a small subset of features that captures a majority of the data variance is less likely to exist. Therefore, we conclude that there is a trade-off between feature set size and feature selection method to optimize classification performance. For larger feature set sizes, TF-IDF works better for finer-resolutions while mRMR performs the best out of any method for N=6 for all taxonomic levels. PMID- 21704268 TI - A multiplex approach to the molecular diagnosis of beta-thalassemia. PMID- 21704269 TI - The indicating FTA elute cartridge a solid sample carrier to detect high-risk HPV and high-grade cervical lesions. AB - The clinically validated high-risk human papillomavirus (hrHPV) Hybrid Capture 2 (HC2) and GP5+/6+-PCR assays were analyzed on an Indicating FTA Elute cartridge (FTA cartridge). The FTA cartridge is a solid dry carrier that allows safe transport of cervical samples. FTA cartridge samples were compared with liquid based samples for hrHPV and high-grade cervical intraepithelial neoplasia (CIN) detection. One cervical sample was collected in a liquid-based medium, and one was applied to the FTA cartridge. DNA was eluted directly from the FTA cartridge by a simple elution step. HC2 and GP5+/6+-PCR assays were performed on both the liquid-based and the FTA-eluted DNA of 88 women. Overall agreement between FTA and liquid-based samples for the presence of hrHPV was 90.9% with GP5+/6+-PCR and 77.3% with HC2. The sensitivity for high-grade CIN of hrHPV testing on the FTA cartridges was 84.6% with GP5+/6+-PCR and only 53.8% with HC2. By comparison, these sensitivities on liquid-based samples were 92.3% and 100% for GP5+/6+-PCR and HC2, respectively. Therefore, the FTA cartridge shows reasonably good overall agreement for hrHPV detection with liquid-based media when using GP5+/6+-PCR but not HC2 testing. Even with GP5+/6+-PCR, the FTA cartridge is not yet capable of detecting all high-grade CIN lesions. PMID- 21704270 TI - Efficient DNA extraction for HPV genotyping in formalin-fixed, paraffin-embedded tissues. AB - DNA from archived FFPE can be used for papillomavirus genotyping, but potential problems include paraffin as a physical barrier, DNA cross-linking, and PCR inhibitors. To address these complications, we combined a commercially available DNA isolation kit (Qiagen DNeasy) with a heat treatment and evaluated the resulting DNA with regards to HPV typing. DNA was extracted from 10-MUm sections from 150 FFPE cancer samples. One protocol followed the manufacturer's recommendation, including paraffin removal by xylene and tissue lysis at 56 degrees C. A second section was directly incubated at 120 degrees C and subsequently lysed at 65 degrees C. After spin-column purification, both extracts were tested with a linear array HPV genotyping assay. Additionally, cellular DNA yield, HPV16 DNA copies, and PCR inhibitors were assessed by real-time qPCR assays. Inadequate linear array HPV genotyping assay results were significantly more frequent (P = 0.0003) in xylene-treated (29/150, 19.3%) than in heat-treated extracts (8/150, 5.3%). HPV detection also differed, with 94/150 (62.7%) and 110/150 (73.3%) positive results, respectively (P = 0.0026). The heat method also yielded more PCR-amplifiable cellular DNA (8.2-fold; P < 0.001) and HPV16 copies (6.5-fold; P = 0.009), although PCR inhibitors also had a greater effect (P = 0.035). Aggressive heat treatment demonstrated an advantage over traditional xylene purification protocols, resulting in higher DNA yields and increased sensitivity for HPV testing. PMID- 21704271 TI - Restriction enzyme-mediated enhanced detection of circulating cell-free fetal DNA in maternal plasma. AB - A universal method confirming the presence of circulating cell-free fetal (ccff) DNA in maternal plasma is important in the field of noninvasive prenatal diagnostics. Restriction endonuclease digestion of one allele of a single nucleotide polymorphism (SNP) was used to allow detection of paternal alleles in maternal plasma DNA. Multiplexed genotyping of 92 panethnic high-frequency SNPs predicted >0.99 probability of detecting at least four informative loci per sample. Child-maternal paired DNA samples were used to confirm detection of 2% child's heterozygous DNA in a background of maternal DNA homozygous for the digestible allele. By restriction endonuclease digestion of DNA in a PCR cocktail before thermal cycling, 10 genomic copies of a paternal SNP allele were detectable in a background of 990 maternal SNP alleles. A comparison of 154 pregnant and nonpregnant female plasma DNA samples demonstrated enhanced detection of nondigestible SNP alleles in maternal plasma. Receiver operating characteristic curve analysis showed an optimal detection threshold of four nondigestible SNP alleles in plasma for the confirmation of ccff DNA and 98% sensitivity and 96% specificity at a 95% confidence level. Our study demonstrates the ability of this technique to confirm the presence of paternal alleles from ccff DNA in maternal plasma. PMID- 21704272 TI - Rapid, sensitive, and specific detection of Mycobacterium tuberculosis complex by real-time PCR on paraffin-embedded human tissues. AB - The detection of Mycobacterium tuberculosis complex (MTB) in clinical specimens is important for diagnosing and caring for patients in whom tuberculosis is clinically suspected. We collected 129 FFPE specimens, including 56 nontuberculosis cases, 63 MTB cases, and 10 nontuberculous mycobacteria (NTM) cases determined by acid-fast bacilli (AFB) culture. We performed AFB staining; nested MTB PCR, targeting the IS6110 gene; and real-time MTB PCR, targeting the senX3-regX3 intergenic region in the 129 FFPE specimens. The sensitivity and specificity of AFB staining were 37.0% and 98.2%, respectively, using AFB culture results as the reference standard. The sensitivity and specificity of detecting MTB were 68.3% and 98.5%, respectively, by nested PCR; and 74.6% and 98.5% by real-time PCR, respectively. Among the 129 specimens, four were positive by AFB staining but negative by nested or real-time PCR. NTM grew in all four of these cases by AFB culture. AFB density in FFPE tissue sections significantly correlated with MTB DNA load. Thus, real-time PCR is a useful diagnostic tool for rapid and sensitive MTB detection in FFPE specimens, whereas NTM should be included in differential diagnoses of cases positive by AFB staining but negative by PCR. PMID- 21704273 TI - Comparison of five assays for detection of Clostridium difficile toxin. AB - Performance characteristics of five assays for detection of Clostridium difficile toxin were compared using fresh stool samples from patients with C. difficile infection (CDI). Assays were performed simultaneously and according to the manufacturers' instructions. Patients were included in the study if they exhibited clinical symptoms consistent with CDI. Nonmolecular assays included glutamate dehydrogenase antigen tests, with positive findings followed by the Premier Toxin A and B Enzyme Immunoassay (GDH/EIA), and the C. Diff Quik Chek Complete test. Molecular assays (PCR) included the BD GeneOhm Cdiff Assay, the Xpert C. difficile test, and the ProGastro Cd assay. Specimens were considered true positive if results were positive in two or more assays. For each method, the Youden index was calculated and cost-effectiveness was analyzed. Of 81 patients evaluated, 26 (32.1%) were positive for CDI. Sensitivity of the BD GeneOhm Cdiff assay, the Xpert C. difficile test, the ProGastro Cd assay, C. Diff Quik Chek Complete test, and two-step GDH/EIA was 96.2%, 96.2%, 88.5%, 61.5%, and 42.3%, respectively. Specificity of the Xpert C. difficile test was 96.4%, and for the other four assays was 100%. Compared with nonmolecular methods, molecular methods detected 34.7% more positive specimens. Assessment of performance characteristics and cost-effectiveness demonstrated that the BD GeneOhm Cdiff assay yielded the best results. While costly, the Xpert C. difficile test required limited processing and yielded rapid results. Because of discordant results, specimen processing, and extraction equipment requirements, the ProGastro Cd assay was the least favored molecular assay. The GDH/EIA method lacked sufficient sensitivity to be recommended. PMID- 21704274 TI - Identification of recombinant alleles using quantitative real-time PCR implications for Gaucher disease. AB - Pseudogenes, resulting from duplications of functional genes, contribute to the functional complexity of their parental genes. The glucocerebrosidase gene (GBA), located in a gene-rich region on chromosome 1q 21, is mutated in Gaucher disease. The presence of contiguous, highly homologous pseudogenes for both GBA and metaxin 1 at this locus increases the likelihood of DNA rearrangement. We describe a facile method to identify and analyze recombinant alleles in patients with Gaucher disease. Genomic DNA from 20 patients with recombinant GBA alleles and five controls was evaluated to identify DNA rearrangements or copy number variation using six probes specific for either the GBA gene or pseudogene. Quantitative real-time PCR was performed on genomic DNA, and Southern blot analyses using HincII together with sequencing confirmed the real-time results. Both GBA fusions and duplications could be detected. Different sites of crossover were identified, and alleles resulting from gene conversion could be distinguished from reciprocal recombinant alleles. Quantitative real-time PCR is a sensitive and rapid method to detect fusions and duplications in patients with recombinant GBA alleles. This technique is more sensitive, faster, and cheaper than Southern blot analysis, and can be used in diagnostic laboratories, and to detect other recombinant alleles within the genome. PMID- 21704275 TI - Diagnosis of hydatidiform moles by polymorphic deletion probe fluorescence in situ hybridization. AB - Because products of conception often contain maternal and villous tissues, the determination of maternal and villous genotypes based on genetic polymorphisms can help discern maternal and paternal chromosomal contribution and aid in the diagnosis of hydatidiform moles. Polymorphic deletion probe (PDP) fluorescence in situ hybridization (FISH) probes based on copy number variants are highly polymorphic and allow in situ determination of genetic identity. By using three informative PDPs on chromosomes 2p, 4q, and 8p, we compared maternal with villous genotypes and determined the ploidy of villous tissue. PDP FISH was performed on 13 complete moles, 13 partial moles, 13 nonmolar abortions, and an equivocal hydropic abortion. PDP FISH permitted definitive diagnosis of complete moles in five of 13 cases for which maternal and villous genotypes were mutually exclusive. A complete mole was highly suspected when all three PDP loci showed homozygous villous genotypes. The diagnosis of a complete mole by PDP FISH yielded a theoretical test sensitivity of 87.5%, specificity of 91.8%, an observed test sensitivity of 100%, and specificity of 92.3%. Triploidy was observed in all partial moles, in which diandric triploidy was confirmed in six cases. In the equivocal hydropic abortion, PDP FISH combined with p57 immunofluorescence revealed placental androgenetic/biparental mosaicism. PDP FISH can be used in clinical practice and research studies to subclassify hydatidiform moles and evaluate unusual products of conception. PMID- 21704276 TI - Mutation analysis of SLC26A4 for Pendred syndrome and nonsyndromic hearing loss by high-resolution melting. AB - Pendred syndrome and DFNB4 (autosomal recessive nonsyndromic congenital deafness, locus 4) are associated with autosomal recessive congenital sensorineural hearing loss and mutations in the SLC26A4 gene. Extensive allelic heterogeneity, however, necessitates analysis of all exons and splice sites to identify mutations for individual patients. Although Sanger sequencing is the gold standard for mutation detection, screening methods supplemented with targeted sequencing can provide a cost-effective alternative. One such method, denaturing high-performance liquid chromatography, was developed for clinical mutation detection in SLC26A4. However, this method inherently cannot distinguish homozygous changes from wild type sequences. High-resolution melting (HRM), on the other hand, can detect heterozygous and homozygous changes cost-effectively, without any post-PCR modifications. We developed a closed-tube HRM mutation detection method specific for SLC26A4 that can be used in the clinical diagnostic setting. Twenty-eight primer pairs were designed to cover all 21 SLC26A4 exons and splice junction sequences. Using the resulting amplicons, initial HRM analysis detected all 45 variants previously identified by sequencing. Subsequently, a 384-well plate format was designed for up to three patient samples per run. Blinded HRM testing on these plates of patient samples collected over 1 year in a clinical diagnostic laboratory accurately detected all variants identified by sequencing. In conclusion, HRM with targeted sequencing is a reliable, simple, and cost effective method for SLC26A4 mutation screening and detection. PMID- 21704277 TI - A melting curve analysis--based PCR assay for one-step genotyping of beta thalassemia mutations a multicenter validation. AB - The increasing number of disease-causing mutations demands a simple, direct, and cost-effective diagnostic genotyping technique capable of detecting multiple mutations. This study validated the efficacy of a novel melting curve analysis based genotyping assay (MeltPro HBB assay) for 24 beta-thalassemia mutations in the Chinese population. The diagnostic potential of this assay was evaluated in 1022 pretyped genomic DNA samples, including 909 clinical cases of beta thalassemia minor or major, using a double-blind analysis in a multicenter validation study. Reproducibility of the assay was 100%, and the limit of detection was 10 pg per reaction. All 24 beta-thalassemia mutations were accurately genotyped, and beta-thalassemia genotypes were correctly determined in all 1022 samples, yielding overall sensitivity and specificity of 100%. The concordance rate was 99.4% between this assay and the reference method. It was concluded that the MeltPro HBB assay is useful for reliable genotyping of multiple beta-thalassemia mutations in clinical settings and may have potential as a versatile method for rapid genotyping of known mutations because of its high throughput, accuracy, ease of use, and low cost. PMID- 21704278 TI - KRAS, NRAS, PIK3CA exon 20, and BRAF genotypes in synchronous and metachronous primary colorectal cancers diagnostic and therapeutic implications. AB - Targeted therapy of advanced colorectal carcinoma (CRC) necessitates KRAS genotyping. Because we were interested in diagnostic and therapeutic consequences, we studied the KRAS, NRAS, PIK3CA exon 20, and BRAF genotypes in synchronous and metachronous primary CRCs; in addition, we studied their available metastases. We studied 21 patients with 43 synchronous and 2 metachronous adenocarcinomas of the colorectum (n = 20) and stomach (n = 1). Five patients had liver metastases and one had a distant lymph node metastasis. Genomic DNA was extracted from microdissected tumor tissue. The DNA was analyzed by Sanger sequencing and pyrosequencing. Fifty-seven different neoplastic lesions were genotyped, showing 18 (31.6%) KRAS, 2 (3.5%) NRAS, and 7 (12.3%) BRAF mutations, distributed among 10 (47.6%), 1 (4.8%), and 5 (23.8%) of the patients. An identical genotype of all synchronous primary CRCs was found only in 7 (35%) of the patients; the remainder had dissimilar genotypes in various combinations. Interestingly, a single patient had an unknown KRAS genotype (c.37_39dupGGC). Six patients with 13 primary carcinomas had distant metastases. In three of these patients, the metastasis shared the genotype only with one of the primary tumors, because the other primary tumors had another genotype. Synchronous and metachronous primary CRCs of the same patient have variable KRAS, NRAS, and BRAF genotypes. When metastases occur in these patients, the genotype has diagnostic and therapeutic implications and should be determined from the simultaneous or metachronous distant metastases. PMID- 21704279 TI - Simultaneous genotyping of rs12979860 and rs8099917 variants near the IL28B locus associated with HCV clearance and treatment response. AB - Recent genome-wide association studies have identified two host single-nucleotide polymorphisms (SNPs) near the IL28B gene (rs12979860 C/T and rs8099917 T/G) that are associated with sustained virological response in patients infected with the hepatitis C virus. Herein, we describe a rapid multiplexed dual-color fluorescence resonance energy transfer (FRET) probe assay that accurately genotypes for both SNPs simultaneously. A single-nucleotide extension assay was also developed for verification of genotypes. Agreement (100%) was observed in genotype calls between the FRET and single-nucleotide extension methods for both SNPs, yielding 100% analytical sensitivity and specificity. By using the FRET assay, 443 samples of varying ethnic backgrounds were genotyped and six different compound genotypes (rs12979860/rs8099917) were detected in whites, Asians, Middle Easterners, Hispanics, and African Americans, at the following frequencies: CC/TT (39.2%, 78.9%, 40.0%, 33.9%, and 16.8%), CT/TT (20.8%, 0%, 40%, 9.3%, and 37.0%), TT/TT (2.4%, 0%, 0%, 3.4%, and 35.3%), CT/TG (24.0%, 19.7%, 20%, 39.8%, and 3.4%), TT/TG (8.0%, 1.4%, 0%, 3.4%, and 5.9%), and TT/GG (5.6%, 0%, 0%, 10.2%, and 1.7%), respectively. The multiplexed FRET assay can be used to effectively genotype for both SNPs in a single tube, with high analytical sensitivity and specificity. PMID- 21704280 TI - RNA-stabilized whole blood samples but not peripheral blood mononuclear cells can be stored for prolonged time periods prior to transcriptome analysis. AB - Microarray-based transcriptome analysis of peripheral blood as surrogate tissue has become an important approach in clinical implementations. However, application of gene expression profiling in routine clinical settings requires careful consideration of the influence of sample handling and RNA isolation methods on gene expression profile outcome. We evaluated the effect of different sample preservation strategies (eg, cryopreservation of peripheral blood mononuclear cells or freezing of PAXgene-stabilized whole blood samples) on gene expression profiles. Expression profiles obtained from cryopreserved peripheral blood mononuclear cells differed substantially from those of their nonfrozen counterpart samples. Furthermore, expression profiles in cryopreserved peripheral blood mononuclear cell samples were found to undergo significant alterations with increasing storage period, whereas long-term freezing of PAXgene RNA stabilized whole blood samples did not significantly affect stability of gene expression profiles. This report describes important technical aspects contributing toward the establishment of robust and reliable guidance for gene expression studies using peripheral blood and provides a promising strategy for reliable implementation in routine handling for diagnostic purposes. PMID- 21704281 TI - Population-level incidence and risk factors for pulmonary toxicity associated with amiodarone. AB - Estimates from clinical trials and small observational studies of the incidence of pulmonary toxicity (PT) associated with amiodarone range from 1% to 10%. We report a unique study of the population-based incidence and potential predictors of PT in a real-world atrial fibrillation (AF) population. We conducted a retrospective cohort study of patients >=65 years old discharged with AF using linked administrative databases from Quebec, Canada from 1999 to 2007. "Users" and "nonusers" of amiodarone were identified by prescriptions dispensed within 7 days after hospital discharge. PT was defined through International Classification of Diseases, Ninth Revision and Tenth Revision codes for pulmonary fibrosis, alveolar/interstitial lung disease, and adult respiratory distress syndrome. Potential risk factors for PT were identified using multivariable Cox regression. PT occurred in 250 of 6,460 amiodarone users (3.87%) and 676 of 50,993 nonusers (1.33%). Age-standardized PT incidences were 28.30 and 16.02 per 1,000 person-years in men and women users, respectively, and 14.05 and 8.82 per 1,000 person-years in nonusers, respectively. It was associated with amiodarone exposure at all doses (<=200 mg/day, hazard ratio 1.62, 1.35 to 1.96; >200 mg/day, 1.46, 1.22 to 1.75). Other predictors of PT included increasing age (1.01 per year, 1.00 to 1.02), male gender (1.37, 1.19 to 1.57), chronic obstructive pulmonary disease (2.53, 2.21 to 2.89), and renal disease (1.26, 1.06 to 1.50). In conclusion, the population-based incidence of amiodarone PT is in the lower range of what has been previously reported. However, patients with AF who use amiodarone have an approximately 50% higher risk of PT than nonusers. Clinicians may be able to use the present results to identify patients at higher risk for PT and implement strategies to increase monitoring or select alternative therapy. PMID- 21704282 TI - Left ventricular diastolic function and exercise capacity in community-dwelling adults >=65 years of age without heart failure. AB - Left ventricular diastolic dysfunction (LVDD) has been reported to have strong correlation with exercise capacity. However, this relationship has not been studied extensively in community-dwelling older adults. Data on pulse and tissue Doppler echocardiographic estimates of resting early (E) and atrial (A) transmitral peak inflow and early (Em) mitral annular velocities, and six-minute walk test were obtained from 89 community-dwelling older adults (mean age, 74; range, 65-93 years; 54% women), without a history of heart failure. Overall, 47% had cardiovascular morbidity and 60% had normal diastolic function (E/A 0.75-1.5 and E:Em <10). Among the 36 individuals with LVDD, 83%, 14% and 3% had grade I (E/A <0.75, regardless of E/E(m)), II (E/A 0.75-1.5 and E/E(m) >=10) and III (E/A>1.5 and E/E(m) >=10) LVDD, respectively. Those with LVDD were older (77 versus 73 years; p = 0.001) and had a trend for higher prevalence of cardiovascular morbidity (58% versus 40%; p = 0.083). LVDD negatively correlated with six-minute walk distance (1013 versus 1128 feet; R = -0.25; p = 0.017). This association remained significant despite adjustment for cardiovascular morbidity (R = -0.35; p = 0.048), but lost significance when adjusted for age (R = -0.32; p = 0.105), age and cardiovascular morbidity (R = -0.38; p = 0.161), and additional adjustment for sex, race, body mass index, and systolic blood pressure (R = 0.44; p = 0.365). In conclusion, most community-dwelling older adults without heart failure had normal left ventricular diastolic function or grade-I LVDD. Although LVDD was associated with decreased performance on a six-minute walk test, that association was no longer evident after adjustment for age, body mass index and cardiovascular morbidity. PMID- 21704283 TI - Effect of diastolic dysfunction on early outcomes during elective off-pump coronary artery bypass grafting: a prospective observational study. AB - BACKGROUND: Left ventricular diastolic dysfunction (DD) causes adverse outcomes after cardiac surgery; however, the effects of DD during off-pump coronary artery bypass grafting (OPCAB) are not well understood. We aimed to assess the influence of DD on early mortality and morbidity of patients undergoing OPCAB. METHODS: This prospective observational study included 1,256 patients scheduled for elective OPCAB. The DD of the patients was assessed by transthoracic echocardiography and tissue Doppler imaging. The cohort was classified into four DD groups; normal, mild (relaxation abnormality), moderate (pseudonormal dysfunction), and severe (restrictive abnormality). Study endpoints were major adverse cardiac events and other complications. Multivariate logistic regression was used to evaluate the independent effect of DD on surgical outcomes. RESULTS: The 1,256 patients were grouped as follows: normal diastolic function (n=55, 4.4%), mild DD (n=995, 79.2%), moderate DD (n=169, 13.5%), and severe DD (n=37, 2.9%). Operative strategy did not differ among groups. The prevalence of hypertension, diabetes mellitus, renal failure, low ejection fraction (<35%), myocardial infarction within 30 days, and European System of Cardiac Operative Risk Evaluation score greater than 5 increased significantly with more severe DD. No significant difference was found in 30-day major adverse cardiac events (normal, 1.8%; mild DD, 3.6%; moderate DD, 6.5%; severe DD, 5.4%; p=0.23); however, postoperative renal failure, respiratory complications, respiratory failure, and prolonged hospitalization (more than 12 days: 75th percentile of the study cohort) increased with the severity of DD (p<0.01). Multivariate analysis revealed that severe DD independently predicted respiratory complications (odds ratio 3.68, 95% confidence interval: 1.84 to 20.36, p=0.01) and prolonged hospitalization (odds ratio 5.75, 95% confidence interval: 1.81 to 13.23, p<0.01). CONCLUSIONS: Diastolic dysfunction does not affect 30-day major adverse cardiac events after elective OPCAB. However, severe DD independently predicts respiratory complications and prolonged hospitalization. PMID- 21704284 TI - The interaction between human urotensin II and vasodilator agents in human internal mammary artery with possible clinical implications. AB - BACKGROUND: Graft spasm in the internal mammary artery (IMA) may occur after coronary artery bypass grafting (CABG). We investigated the effect of human urotensin II (hU-II), a cyclic peptide hormone present in human blood and tissues, and the effect of vasodilators on hU-II-mediated response in human IMA. METHODS: Fresh IMA segments (n=114) taken from 50 patients undergoing CABG were studied in a myograph. The interaction between hU-II and various calcium antagonists or glyceryl trinitrate (GTN) was investigated in 2 ways: relaxing effect of vasodilators on the hU-II-induced precontraction and depressing effect of vasodilator agents on the contraction caused by hU-II (n=6 to 10 in each subgroup). RESULTS: Human urotensin II caused contractile response in all human IMA. In potassium chloride-contraction, full (nifedipine: 99.1 %+/-2.7%) or nearly full (diltiazem: 93.5%+/-4.8%) relaxation with 30.9-fold higher potency to nifedipine than to diltiazem (EC50 [effective concentration causing 50% of maximal response] -8.24+/-0.21 vs -6.75+/-0.20 log M, p=0.0002) and in hU-II contraction, nearly full relaxation (nifedipine: 90.6%+/-4.6%; diltiazem: 95.0%+/ 1.7%) with 5.8-fold higher potency to nifedipine than to diltiazem (EC50 -7.55+/ 0.26 vs -6.79+/-0.25 log M, p=0.03) were observed. The GTN caused nearly full relaxation (93.1%+/-4.8%) but GTN pretreatment had limited effect in prevention of the hU-II-induced contraction, whereas diltiazem and nifedipine reduced subsequent contraction to hU-II. CONCLUSIONS: Human urotensin II is a potent vasoconstrictor in human IMA. Calcium antagonists and GTN relax the contraction caused by hU-II with different potencies. However, calcium antagonists are more effective than GTN in preventing the contraction induced by hU-II. These findings may have clinical implications in CABG. PMID- 21704285 TI - Early postoperative severity of illness predicts outcomes after the stage I Norwood procedure. AB - BACKGROUND: We hypothesize that a measure of the immediate postoperative severity of illness after the stage I Norwood operation reflects technical performance or the adequacy of anatomic repair and can serve as a predictor of hospital mortality, reinterventions, and clinical outcomes. METHODS: One hundred thirty five patients undergoing stage I were retrospectively studied (2004 to 2007). The severity of illness on postoperative day 1 (POD1) was measured using the Pediatric Risk of Mortality III (PRISM) scoring system. Technical performance scores (optimal, adequate, inadequate) were calculated before hospital discharge. Hospital mortality, postoperative reinterventions, and complications were recorded. Postoperative reintervention was defined as need for cardiac catheterization laboratory or operating room based procedure that included balloon dilation or repair of arch obstruction, shunt revision, reoperations for bleeding, and extracorporeal membrane oxygenation support. RESULTS: Hospital mortality was 14.1% (n=19). The rate of complications and reinterventions was, respectively, 28.1% (n=38) and 26.7% (n=36). The POD1 PRISM score was associated with technical performance (p=0.003). Higher POD1 PRISM scores were associated with mortality (p<0.001), complications (p<0.001), and reinterventions (p=0.001). The POD1 PRISM score had high discrimination for mortality, complications, reinterventions, and inadequate technical performance (areas under the receiver operating characteristic curve were 0.835, 0.776, 0.773, and 0.710, respectively; p<=0.001 for all). CONCLUSIONS: The severity of illness as measured by PRISM score on POD1 after the stage I Norwood operation has strong association and discrimination with hospital mortality, postoperative reinterventions, inadequate technical performance, and major postoperative complications. It may be used as an early surrogate of technical performance to initiate a search for and correction of technical deficiencies. PMID- 21704286 TI - Aortic valve replacement with Hancock II bioprothesis with and without replacement of the ascending aorta. AB - BACKGROUND: The purpose of this study was to compare the clinical outcomes and valve durability after aortic valve replacement with a Hancock II bioprothesis with and without supracoronary replacement of the ascending aorta (RAA). METHODS: From a cohort of 1,076 patients who had aortic valve replacement with a Hancock II bioprothesis who were prospectively followed for a median of 12.2 years, a propensity score analysis matched patients with and without RAA in a 1:4 ratio. Statistical analysis was performed using the chi2 test or Fisher's exact test for categorical variables, t tests or Wilcoxon rank sum test for continuous variables, and Kaplan-Meier estimates and log rank test for time-to-event data. RESULTS: The propensity score analysis selected 89 patients with RAA and 356 without RAA whose mean age was 66+/-12 years. Preoperative variables were similar in both groups, except that the ascending aorta was aneurysmal in patients who had RAA. Operative mortality was 2.3% and 3.9% in the RAA and non-RAA groups, respectively (p=0.75). Perioperative morbidity was also similar. Only 3 and 13 patients lived beyond 20 years in the RAA and non-RAA groups, respectively. For the non-RAA group and RAA group, respectively, at 10, 15, and 20 years, respectively, the Kaplan-Meier estimates for freedom from death were 62.2%+/ 2.8%, 36.5%+/-3.3%, 20.8%+/-3.6%, and 56.8%+/-6.1%, 31.8%+/-6.7%, 17.2%+/-6.6% (p=0.51); for reoperation on the aortic valve for any reason, 95.3%+/-1.4%, 81.6%+/-3.9%, 70.5%+/-6.4%, and 91.7%+/-3.6, 85.7%+/-6.8%, 53.5%+/-18.8% (p=0.51); and for structural valve degeneration, 98.5%+/-0.9%, 85.0%+/-3.8%, 66.8%+/-7.1%, and 94.4%+/-3.2%, 84.3%+/-7.5%, and 70.2%+/-14.3% (p=0.38). CONCLUSIONS: Aortic valve replacement with a Hancock II bioprothesis with or without RAA has similar clinical outcomes. Supracoronary RAA does not affect the rate of structural valve degeneration of this bioprosthesis. PMID- 21704287 TI - Valve-in-valve hemodynamics of 20-mm transcatheter aortic valves in small bioprostheses. AB - BACKGROUND: Transcatheter aortic valve (TAV) implantation is a treatment for selected patients with failing bioprostheses. We previously showed that currently available SAPIEN (Edwards Lifesciences, Irvine, CA) TAV sizes did not yield acceptable valve-in-valve (VIV) hemodynamics in small degenerated bioprostheses because optimal TAV function requires full stent expansion to its nominal size. The study objective was to determine (1) if 20-mm TAVs provide acceptable hemodynamics in small degenerated bioprostheses and (2) the effect of TAV spatial orientation on valvular hemodynamics and coronary flows. METHODS: Twelve 20-mm TAVs were created for implantation within 19-mm and 21-mm degenerated Carpentier Edwards Perimount (Edwards Lifesciences) and porcine bioprostheses. Degenerated valves were sutured into human homograft roots and mounted in a pulse duplicator. TAVs were implanted within bioprostheses as VIV in standard orientation, in which TAV and bioprosthetic commissures were aligned, and later with 60-degree rotation. RESULTS: The 20-mm TAVs migrated retrograde into the left ventricle after VIV in the 21-mm Perimount bioprostheses. However, 20-mm TAVs in 19-mm Perimount (54.9+/-5.4 to 23.5+/-3.9 mm Hg, p=0.006) and 21-mm porcine bioprostheses (35.2+/-8.9 to 16.8+/-4.1 mm Hg, p=0.03) significantly reduced mean gradients. No significant reduction in pressure gradient occurred after VIV in 19 mm degenerated porcine bioprostheses. Mild regurgitation was observed after VIV. VIV with standard and 60-degree TAV orientation did not significantly alter hemodynamics or coronary flows. CONCLUSIONS: Valve-in-valve hemodynamics with 20 mm TAV improved for 19-mm Perimount and 21-mm porcine but not 19-mm porcine bioprostheses. No significant differences in hemodynamics were noted by orientation with TAV and bioprosthesis commissural alignment or 60-degree rotation. PMID- 21704288 TI - A comparison of Blalock-Taussig shunts with and without closure of the ductus arteriosus in neonates with pulmonary atresia. AB - BACKGROUND: The question of whether to close the patent ductus arteriosus when performing primary modified Blalock-Taussig (MBT) shunt surgery in neonates is still not clearly answered. The aim of this report was to compare the results of closure versus nonclosure of the patent ductus arteriosus during MBT shunt surgery in neonates with pulmonary atresia. METHODS: This retrospective study included neonates with pulmonary atresia who underwent primary MBT shunt surgery through a sternotomy approach at our institution between January 1997 and October 2010. Mortality, resuscitation events, and the need for reintervention within the first 48 postoperative hours were studied as primary outcomes. RESULTS: Sixty-two neonates (mean age 6.9+/-5.5 days) underwent a MBT procedure. The arterial duct was closed surgically in 31 patients, and left open in 31 patients. Compared with patients in whom the PDA was left open, patients with a surgically closed arterial duct had a higher incidence of resuscitation events (29.0% versus 0%, p=0.0012), reinterventions (35.5% versus 3.2%, p=0.0013), and higher early hospital mortality (9.7% versus 0%, p=0.038). Time to extubation and length of hospital stay did not differ between the two groups (p=0.16 and p=0.73, respectively). A trend toward a higher maximum vasoactive-inotropic score in the group with a closed duct was observed (median 13.5 versus 10, p=0.10). CONCLUSIONS: In newborns with pulmonary atresia, ductal closure during MBT shunt procedure is associated with increased incidence of resuscitation events, need for reintervention, and increased mortality during the early postoperative period. PMID- 21704289 TI - Comparison of risk scores to estimate perioperative mortality in aortic valve replacement surgery. AB - BACKGROUND: Transaortic valve implantation has recently been introduced as an alternative to aortic valve replacement (AVR) for high-risk patients with aortic stenosis. However, accurate assessment of surgical risk is critical for appropriate patient selection. We compared the accuracy of The Society of Thoracic Surgeons (STS) risk score, the European System for Cardiac Risk Evaluation (EuroSCORE), and the Veterans Administration (VA) risk score in predicting perioperative mortality after AVR. METHODS: We included 537 consecutive patients who underwent AVR for severe aortic stenosis at the Minneapolis VA Medical Center between 1997 and 2008. Observed and predicted perioperative (30-day) mortality rates were compared. Hosmer-Lemeshow goodness-of fit test and receiver operating characteristic curves were performed to assess the performance of the scores. RESULTS: Perioperative mortality rate was 5.9% (n=32). Predicted mortality rates for the EuroSCORE, STS score, and VA score were 15.6%, 3.6%, and 6.7%, respectively (p=0.001). The EuroSCORE overestimated mortality in all patients, most notably among those with ejection fraction less than 35% (49% predicted versus 9% observed). The EuroSCORE had poor calibration (goodness-of-fit test p<0.008), whereas the STS and the VA scores were well calibrated. However, all three scores displayed good discrimination characteristics per the areas under the receiver operating characteristic curves: STS score 0.73 (95% confidence interval: 0.69 to 0.77); VA score 0.66 (95% confidence interval: 0.62 to 0.70); and EuroSCORE 0.68 (95% confidence interval: 0.64 to 0.72; p>0.05). CONCLUSIONS: The EuroSCORE substantially overestimates perioperative mortality risk in AVR, particularly in patients with low ejection fraction. These data have implications when deciding the appropriate intervention (transaortic valve implantation versus AVR) for high-risk aortic stenosis patients. PMID- 21704290 TI - A randomized trial of a skin sealant to reduce the risk of incision contamination in cardiac surgery. AB - BACKGROUND: Immobilizing skin microbes is a rational approach to reducing contamination of surgical sites by endogenous microorganisms. METHODS: This randomized, controlled, parallel-group, multicenter, open-label clinical trial (ClinicalTrials.gov NCT00467857) enrolled 300 adults scheduled for elective coronary artery bypass graft surgery. Patients received iodine-based skin preparations followed by a cyanoacrylate-based skin sealant or skin preparations alone. Microbiological samples collected from sternal and graft incision sites immediately before any skin preparation, at the wound border after skin incision, and at the incision after fascial closure were evaluated quantitatively. RESULTS: In evaluable patients, mean microbial counts in collected samples increased at the sternal site after fascial closure compared with after skin incision by 0.37 log10 colony-forming units (CFU)/mL in the skin sealant group (n=120) and by 0.57 log10 CFU/mL in the control group (n=132) (p=0.047, Wilcoxon rank sum test). At the graft site, mean microbial counts increased by 0.09 (n=119) and 0.27 (n=127) log10 CFU/mL, respectively (p=0.037). There was a 35.3% relative risk reduction in surgical site infection (SSI) occurring in the skin sealant group (9 of 146 patients, 6.2%) versus the control group (14 of 147 patients, 9.5%). In obese patients (body mass index [BMI]>30.0 to <=37.0 kg/m2), the relative risk reduction for SSI associated with skin sealant was 83.3%. CONCLUSIONS: Pretreatment with skin sealant protects against contamination of the surgical incision by migration of skin microbes. Further data are needed to confirm the impact of this technology on SSI rates in clinical practice. PMID- 21704291 TI - Clinical T2-T3N0M0 esophageal cancer: the risk of node positive disease. AB - BACKGROUND: No consensus exists on the optimal treatment strategy for clinical T2 T3N0M0 esophageal cancer. This study was conducted to determine rates of nodal positivity (N+) and to evaluate results of treatment strategies in this cohort. METHODS: Surgically treated patients with cT2-T3N0M0 esophageal cancer were reviewed. Adequacy of lymph node dissection was assessed by guidelines applied to clinical stage. Survival was determined by Kaplan-Meier analysis. Univariate and multivariate analyses were done for predictors of N+ and survival. RESULTS: We identified 102 patients, 51 cT2N0 and 51 cT3N0, 39 (38%) of whom had induction therapy. Despite being clinically node negative, 61 patients (60%) had nodal metastases. Applied to cT classification, adequate nodal dissection was achieved in 64 patients (63%). Transthoracic esophagectomy was more likely than transhiatal esophagectomy to achieve adequate nodal dissection (69% versus 31%, p=0.005). Adequate nodal dissection was more likely to document pN+ disease in both the surgery alone group (70% versus 50%, p=0.13) and induction therapy group (71% versus 33%, p=0.02). Five-year overall survival was 44% with surgery alone and 55% with induction therapy. On multivariate analysis, pN+ was the strongest predictor of overall survival (relative risk 2.73, confidence interval: 1.29 to 5.78). CONCLUSIONS: Most cT2-T3N0M0 patients have pN+ disease. Despite induction therapy, more than 50% have persistent nodal disease. Transthoracic esophagectomy is more likely to detect pN+ disease and more likely to meet criteria of adequate nodal dissection than is transhiatal esophagectomy. Therefore, the majority of patients with cT2-T3N0M0 should be considered for neoadjuvant protocols and should be treated by transthoracic resection whenever possible. PMID- 21704293 TI - Daily chest roentgenograms are unnecessary in nonhypoxic patients who have undergone pulmonary resection by thoracotomy. AB - BACKGROUND: The purpose of this study is to assess the clinical benefit of performing a daily chest roentgenogram (CXR) on patients who have had a pulmonary resection. METHODS: Patients underwent thoracotomy and pulmonary resection, and all had a daily CXR. The impact the CXR had on their care was evaluated. Hypoxia was defined as a sustained decrease in oxygen saturation of 6% or greater from patient's baseline. RESULTS: Between January 2006 and December 2009, 1,037 patients met the eligibility criteria for this study. Types of resection were wedge in 282 patients, segmentectomy in 146, and lobectomy in 609. Only 20 of the 834 patients (2%) who did not have a pneumothorax on the recovery room CXR had hypoxia, compared with 42 patients (21%) who had a recovery room pneumothorax (odds ratio 10.6, 95% confidence interval: 6.1 to 18.5, p<0.001). Daily CXR changed the care of only 268 of 975 patients (27%) who never had hypoxia compared with 49 of the 62 patients (79%) who were hypoxic (odds ratio 9.2, 95% confidence interval: 4.3 to 13.7, p<0.001). Moreover, the changes in care made by the CXR in the 268 nonhypoxic patients were for small pneumothoraces, and the impact of these changes is dubious. CONCLUSIONS: Daily CXRs are not needed in the vast majority of patients who undergo elective pulmonary resection after thoracotomy. It is of little benefit for patients who do not have a pneumothorax on their recovery room CXR or for patients who do not become hypoxic. PMID- 21704292 TI - Balancing stenosis and regurgitation during mitral valve surgery in pediatric patients. AB - BACKGROUND: The objectives of this study were to evaluate the composite outcome of reoperation or death for mitral valve repair and replacement and to determine the relative importance of regurgitation and stenosis during mitral valve repair to guide intraoperative decision making. METHODS: All consecutive patients undergoing first-time mitral valve surgery from 1990 to 2008 at our institution were reviewed. Those with atrioventricular septal defects were excluded. Intraoperative transesophageal echocardiography was used to assess mitral repairs. Residual mitral valve stenosis (mean gradient) and regurgitation (Grade I=less than mild; Grade II=mild to less than moderate; and Grade III=moderate or greater) were assessed. RESULTS: One hundred-fifty patients were included with median age of 47 months (range, 0.03 to 228 months) and median weight of 14 kg (range, 3-114 kg). Of these, 18 (12%) patients underwent replacement, and 132 (88%) patients underwent primary repair. In-hospital mortality was 6%. Of the patients reviewed, 21% underwent reoperation (repair or replacement) or died. Multivariable proportional hazard modeling adjusted for weight, valve replacement, postrepair mean gradient and grade of regurgitation showed postrepair mitral valve regurgitation to be the predominant predictor of death or reoperation. Compared with patients with mild to moderate mitral regurgitation, those with stenosis, but Grade I regurgitation, were associated with improved outcomes. CONCLUSIONS: Within the limits of our analysis, residual mild mitral valve stenosis was associated with less hazard than mild to moderate regurgitation. Taken together, our data suggest that an intraoperative strategy to minimize mitral valve regurgitation is rational, even at the expense of mild mitral stenosis. PMID- 21704294 TI - Feeding jejunostomy tubes placed during esophagectomy: are they necessary? AB - BACKGROUND: Jejunostomy tubes (JT) are routinely placed at the time of esophagectomy and can be associated with low--but not insignificant--morbidity. Increased emphasis on evidence-based medicine prompted this critical review of JT use during esophagectomy and factors that predict the absolute need for JT. METHODS: All esophagectomies performed at one tertiary care institution from 1995 through 2009 were retrospectively reviewed. Statistical analyses were performed to determine preoperative variables that would assist in selecting patients who should receive a JT. RESULTS: A total of 143 JTs were placed in 151 patients undergoing esophagectomy for carcinoma (83.4%), high-grade dysplasia (13.2%), and perforation (2.6%). Of these, 110 patients (76.9%) had returned to oral intake before discharge (median, 7 days), whereas 33 patients (23.1%) still required tube feedings. Of 8 patients who did not undergo intraoperative JT placement, 6 had resumed oral intake at discharge. Two patients were discharged on total parenteral nutrition. Logistic regression analysis of preoperative variables showed a body mass index of less than 18.5 kg/m2 conferred a likelihood of requiring a JT at discharge (odds ratio, 7.56; p<0.05). Age, sex, albumin level, type of esophagectomy, histology, stage, preoperative neoadjuvant therapy, and type of cancer were not significant predictors of JT need at discharge. CONCLUSIONS: The only absolute indication for JT placement after esophagectomy was a body mass index of less than 18.5 kg/m2. Other patients may have selective JT placement based on the surgeon's judgment. PMID- 21704295 TI - External validation of the recalibrated thoracic revised cardiac risk index for predicting the risk of major cardiac complications after lung resection. AB - BACKGROUND: The recalibrated thoracic revised cardiac risk index (ThRCRI) has been recently proposed as a specific tool for cardiac risk stratification before lung resection. However, the ThRCRI has never been externally validated in a population other than the one from which it was derived. The objective of this study was to validate the ThRCRI in an external population of candidates having undergone major lung resections to assess its reliability for cardiac risk stratification across different samples. METHODS: We analyzed 2,621 patients undergoing lobectomy (2,431) or pneumonectomy (190) in a single center from 2000 to 2009. Patients were grouped into four classes of risk (A, B, C, and D) according to the recalibrated ThRCRI. The outcome variable measured was the occurrence of major cardiac complications (cardiac arrest, complete heart block, acute myocardial infarction, pulmonary edema, cardiac death during admission). Incidence of major cardiac events was assessed in the four risk class groupings to assess the discriminative ability of the index score. RESULTS: The incidence of major cardiac morbidity was 2.2% (59 cases). Patients were grouped into four risk classes according to their recalibrated ThRCRI. Incidence of major cardiac morbidity in risk classes A, B, C, and D were 0.9%, 4.2%, 8%, and 18%, respectively (p<0.0001). CONCLUSIONS: The recalibrated ThRCRI is a reliable instrument that can be used during preoperative workup to differentiate patients needing further cardiologic testing from those who can proceed without any further cardiac testing. PMID- 21704296 TI - Continuous cerebral perfusion for aortic arch repair: hypothermia versus normothermia. AB - BACKGROUND: Deep hypothermia with circulatory arrest (CA) is routinely used for aortic arch repair. Antegrade selective cerebral perfusion (ASCP) has been proposed to avoid neurologic complications. The optimal temperature during aortic arch repair with ASCP is not well established. We therefore compared early outcomes of patients undergoing aortic arch repair associated with intracardiac repair with ASCP either with hypothermia (<28 degrees C, group I; n=70) or normothermia (>34 degrees C, group II; n=40). METHODS: From 2002 to 2008, 110 consecutive patients with interrupted aortic arch (n=40) or coarctation of the aorta (n=70) and cardiac anomalies underwent intracardiac and aortic arch repair without CA. Median age at repair was 12 days. Full cardiopulmonary bypass (CPB), high hematocrit, and high rates of flow were used. ASCP flow was adjusted to maintain arterial pressure at greater than or equal to 50 mm Hg. ASCP was achieved either through a Gore-Tex (W. L. Gore & Associates, Inc., Elkton, MD) graft to the innominate artery (n=36) or by direct cannulation (n=74). An electroencephalogram (EEG) was continuously monitored and 30 patients were monitored by near-infrared spectroscopy (NIRS). RESULTS: Preoperative data were similar in both groups. Group II demonstrated higher ASCP flows (p<0.001). Time to extubation, stay in the intensive care unit (ICU), and postoperative urine output and lactate levels were similar between groups. Mortality was 8.5% in group I versus 10% in group II. During the postoperative course, there were no clinical or electrical neurologic events in either group. CONCLUSIONS: Antegrade selective cerebral perfusion can safely avoid CA. No worse, early, or long-term effects of ASCP with normothermia were found. PMID- 21704297 TI - Retrograde jejunogastric decompression after esophagectomy is superior to nasogastric drainage. AB - BACKGROUND: Nasogastric tubes (NG) are commonly used for maintaining conduit decompression after esophagectomy. We investigated the use of retrograde tube gastrostomy (RG) after esophagectomy. METHODS: Patients underwent either NG or RG placement for postoperative conduit decompression. Both tubes were maintained on low continuous suction. RESULTS: Between 2000 and 2008, 306 patients underwent esophagectomy with reconstruction. One hundred ninety-three patients underwent NG and 113 underwent RG placement. The 2 groups were comparable in age, gender, tumor stage, and smoking status. Patients in the NG group were more likely to have received neoadjuvant therapy and to have a thoracotomy for esophagectomy. The incidence of respiratory complications was lower in the retrograde group compared with the NG group: Pneumonia, 9 of 113(8.0%) vs 50 of 193 (25.9%), p<0.001; respiratory failure requiring bronchoscopy or reintubation, 12 of 113 (10.8%) vs 46 of 193 (23.8%), p=0.004; aspiration, 4 of 113 (3.5%) vs 20 of 193 (10.4%), p=0.045. The incidence of cardiac dysrhythmias was also lower in the retrograde group (18 of 113 [15.9%] vs 69 of 193 [35.8%], p<0.001). The incidence of wound complications, myocardial infarction, stroke, and conduit necrosis anastomotic leak was similar between groups. In a multivariate regression model an NG tube was the strongest predictor for postoperative pneumonia (odds ratio 3.27, 95% confidence interval 1.50 to 7.12). The other predictors were prior chest surgery, smoking, and thoracotomy incision. There were 4 minor complications related to the retrograde tube (wound infection n=1, broken tube requiring endoscopy n=2, tube caught in anastomosis detected intraoperatively n=1). CONCLUSIONS: Retrograde gastrostomy decompression of the conduit after esophagectomy is effective and diminishes complications compared with NG tube drainage. PMID- 21704298 TI - Early outcomes of total pulmonary arterial reconstruction in patients with arterial tortuosity syndrome. AB - BACKGROUND: Arterial Tortuosity Syndrome (ATS) is an autosomal recessive connective tissue disease that can present with complex pulmonary arterial stenosis, causing right ventricular (RV) hypertension and dysfunction. In this study, we review our experience and early outcomes with single stage surgical repair. METHODS: From 2008 to 2010, 7 patients with ATS and severe bilateral pulmonary artery stenosis underwent surgical repair that involved extensive reconstruction of the pulmonary arterial tree bilaterally, including the central, lobar and segmental branches. The clinical records of these patients were reviewed for preoperative data, repair techniques and early clinical outcomes, including reinterventions and recent echocardiographic studies. RESULTS: All 7 patients had bilateral peripheral and central pulmonary artery stenosis with systemic to supra-systemic RV pressure and severe RV dysfunction. Median age at the time of operation was 72 months (range=7 to 120 months). All patients had low RV pressure (<=40% systemic) after the procedure with significant improvement in RV function to normal before hospital discharge. The mean right ventricular/left ventricular pressure ratio decreased from 1.27+/-0.19 to 0.31+/-0.06 postoperatively (p<0.001). There was no mortality. All patients continued regular follow-up at our institution for a mean follow-up period of 17.6+/-9.1 months. All patients were alive and asymptomatic with normal RV function and no evidence of elevated RV pressure on most recent echocardiography. CONCLUSIONS: Complete surgical reconstruction of the pulmonary arterial tree in advanced cases of ATS is a successful intervention with excellent early clinical and hemodynamic outcomes. PMID- 21704299 TI - Is sublobar resection sufficient for carcinoid tumors? AB - BACKGROUND: The existing guidelines for extent of resection of carcinoid tumors are based on other, more malignant non-small cell lung cancers. Because of the small number of patients in any single institution, we analyzed the Surveillance Epidemiology and End Results (SEER) database to study the effect of the extent of resection of these tumors on overall survival. METHODS: All patients with lung cancer in the SEER database from 1973 to 2006 with carcinoid tumors as their only cancer were included. Variables examined included age, race (white, black, others), gender, histologic type (atypical versus typical carcinoid), stage (localized, regional, and distant), extent of resection (sublobar resection, lobectomy, or more extensive) and survival. Univariate analyses (Kaplan-Meier method) were used to select variables for multivariate analysis (Cox regression analysis). Associations were considered significant with an alpha error < 5%. In addition, propensity score-matched Cox regression analysis was performed for patients with typical carcinoid disease. RESULTS: Most patients with carcinoid tumors did not acquire any other cancers (4,785/6,819; 70.2%). Of these, 797 patients had sublobar resection and 2,681 patients had lobectomy or more extensive resections. On univariate analysis, gender (p = 0.014), race (p < 0.001), stage (p < 0.001), histologic type (p < 0.001) and extent of resection (p = 0.04) were associated with overall survival. Multivariate analysis demonstrated that age, gender, race, stage, and histologic type remain statistically associated with overall survival and disease-specific survival, whereas extent of resection is not. Propensity score-matched analysis demonstrates that for typical carcinoid, extent of resection is not associated with overall survival when adjusted for age, gender, race, and stage. CONCLUSIONS: Sublobar resection of carcinoid tumors did not compromise oncologic outcomes in a large population based database. Lobectomy for typical carcinoid tumors is not mandatory as long as complete resection and adequate mediastinal staging are performed. PMID- 21704300 TI - Preoperative beta-blocker usage: is it really worthy of being a quality indicator? AB - BACKGROUND: Since 2007, the use of preoperative beta-blockers has been used as a quality standard for patients undergoing coronary artery bypass graft surgery. Recent studies have called into question of the benefit of empiric preoperative beta-blocker use. METHODS: Data were extracted from our Society of Thoracic Surgeons certified database for patients undergoing isolated coronary artery bypass graft surgery from 2000 to 2008. We compared the outcomes for patients who received preoperative beta-blockers with those of patients who did not. RESULTS: The study group had 12,855 patients, of whom 7,967 (62.0%) were treated preoperatively with beta-blockers. Using propensity matching, we selected two matched groups of 4,474 patients with preoperative beta-blocker use and 4,474 not using preoperative beta-blockers. In the unmatched cohort, only deep sternal infection (0.3% versus 0.5% without beta-blockers; p=0.032), pneumonia (1.9% versus 2.4% without beta-blockers; p=0.039), and intraoperative blood usage (37.2% versus 34.1% without beta-blockers; p<0.001) reached statistically significant difference. In the matched groups, there was no difference between adverse event rates in patients treated with beta-blockers and those who were not. The number of patients requiring intraoperative blood product use was significantly higher among beta-blocker-treated patients (p=0.004). Calculating the adjusted odds ratios showed that in the matched groups, the preoperative use of beta-blockers was not an independent predictor of mortality. CONCLUSIONS: A rational for preoperative beta-blockade exists. However, as with any medical intervention, its application should be tailored to specific clinical scenarios. With no differences in mortality or morbidity, our findings do not support preoperative beta-blockade as a useful quality indicator for coronary artery bypass graft surgery. PMID- 21704301 TI - In vitro study of the properties of Streptococcus mutans in starvation conditions. AB - OBJECTIVES: The present study is to assess Streptococcus mutans survivability in different starvation conditions and to determine the resistance of starved S. mutans to lethal acid and two common anti-caries agents, sodium fluoride (NaF) and chlorhexidine acetate (CHX). METHODS: S. mutans survival rates in sterile water, PBS, sterile saliva, 1/5 strength BHI and BHI were determined at a given time by plate count of viable cell. The resistance of starved S. mutans and control S. mutans to four times the minimal bactericidal concentration (MBC) of NaF, two times the MBC of CHX and acid (pH 2.8) was evaluated and compared respectively. Furthermore, field emission scanning electron microscope (FE-SEM) was used to observe the morphologic characteristics of the starved S. mutans cells. RESULTS: S. mutans showed starvation tolerance under five different starvation conditions, but the bacterial survival rates were different at the same time points. The starved S. mutans exhibited significantly higher resistance (p<0.05) to challenge by anti-caries agents and acid than the control S. mutans. Additionally, starvation resulted in the morphologic modification of S. mutans, and the disruptive degree depended on the change in time. CONCLUSION: The present study indicates that S. mutans displays starvation tolerance, and starvation decreased the susceptibility of S. mutans to NaF, CHX and acid. PMID- 21704303 TI - Tri-phasic modulation of ACh- and NA-maintained calcium plateau by high potassium in isolated mouse submandibular granular convoluted tubular cells. AB - OBJECTIVES: The fact that submandibular glands secrete a large amount of potassium ion upon nerve stimulation has long been recognized, but a physiological role for such high potassium in the saliva has never been systematically investigated. In the present work, high potassium effect has been investigated in the freshly isolated mouse submandibular granular convoluted tubules. DESIGN: Isolated intact mouse submandibular granular convoluted tubules were loaded with Fura-2, and cytosolic calcium concentration in individual tubular cells was measured by microscopic fluorospectrometry. RESULTS: It was found that high potassium had no effect on basal cytosolic calcium concentration, but had a tri-phasic modulation of the calcium plateau maintained by continued stimulation by acetylcholine (ACh) or noradrenaline (NA): a minor initial transient depression, followed by steady increase, completed by a robust calcium rebound spike upon removal of high potassium. The phase of steady increase was blocked without major effect on the plateau by KB-R 7943, a sodium/calcium exchange (NCX) inhibitor. CONCLUSION: These data together suggest that high potassium in saliva bathing the mouse submandibular granular convoluted tubular cells has a potent feedback effect on ACh and NA stimulation, and sodium/calcium exchange is likely to play a major role in this process. Such positive feedback actions of high potassium may suggest a role for enhancing ACh- or NA-stimulated protein factor secretion from the granulated convoluted tubular cells. PMID- 21704302 TI - High resolution of microRNA signatures in human whole saliva. AB - OBJECTIVE: Identifying discriminatory human salivary RNA biomarkers reflective of disease in a low-cost non-invasive screening assay is crucial to salivary diagnostics. Recent studies have reported both mRNA and microRNA (miRNA) in saliva, but little information has been documented on the quality and yield of RNA collected. Therefore, the aim of the present study was to develop an improved RNA isolation method from saliva and to identify major miRNA species in human whole saliva. DESIGN: RNA samples were isolated from normal human saliva using a combined protocol based on the Oragene RNA collection kit and the mirVana miRNA isolation kit in tandem. RNA samples were analysed for quality and subjected to miRNA array analysis. RESULTS: RNA samples isolated from twenty healthy donors ranged from 2.59 to 29.4 MUg/ml saliva and with 1.92-2.16OD(260/280 nm) ratios. RNA yield and concentration of saliva samples were observed to be stable over 48 h at room temperature. Analysis of total salivary RNA isolated from these twenty donors showed no statistical significance between sexes; however, the presence of high-, medium-, and low-yield salivary RNA producers was detected. MiRNA array analysis of salivary RNA detected five abundantly expressed miRNAs, miR-223, miR 191, miR-16, miR-203, and miR-24, that were similarly described in other published reports. Additionally, many previously undetected miRNAs were also identified. CONCLUSION: High quality miRNAs can be isolated from saliva using available commercial kits, and in future studies, the availability of this isolation protocol may allow specific changes in their levels to be measured accurately in various relevant diseases. PMID- 21704304 TI - Susceptibility of Candida albicans and Candida dubliniensis to erythrosine- and LED-mediated photodynamic therapy. AB - The effect of erythrosine- and LED-mediated photodynamic therapy (PDT) on planktonic cultures and biofilms of Candida albicans and Candida dubliniensis was evaluated. Planktonic cultures of standardized suspensions (10(6)cells/mL) of C. albicans and C. dubliniensis were treated with erythrosine concentrations of 0.39 200 MUM and LEDs in a 96-well microtiter plate. Biofilms formed by C. albicans and C. dubliniensis in the bottom of a 96-well microtiter plate were treated with 400 MUM erythrosine and LEDs. After PDT, the biofilms were analysed by scanning electron microscopy (SEM). The antimicrobial effect of PDT against planktonic cultures and biofilms was verified by counting colony-forming units (CFU/mL), and the data were submitted to analysis of variance and the Tukey test (P<0.05). C. albicans and C. dubliniensis were not detectable after PDT of planktonic cultures with erythrosine concentrations of 3.12 MUM or higher. The CFU/mL values obtained from biofilms were reduced 0.74 log(10) for C. albicans and 0.21 log(10) for C. dubliniensis. SEM revealed a decrease in the quantity of yeasts and hyphae in the biofilm after PDT. In conclusion, C. albicans and C. dubliniensis were susceptible to erythrosine- and LED-mediated PDT, but the biofilms of both Candida species were more resistant than their planktonic counterparts. PMID- 21704305 TI - Influence of dose, dose interval and administration route of recombinant human soluble tumour necrosis factor receptor type I on orthodontic tooth movement in rats. AB - OBJECTIVE: To discover the optimal dose, dose interval, and more advantageous administration route of recombinant human soluble tumour necrosis factor receptor type I (rhsTNF-RI) on orthodontic tooth movement. METHODS: Orthodontic tooth movement (OTM) models were established in Sprague-Dawley rats. The maxillary left first molars were given local injections of phosphate-buffered saline (PBS) and four different concentrations of rhsTNF-RI. On day 14, the amount of tooth movement was registered, and tissue sections were stained with haematoxylin-eosin and tartrate-resistant acid phosphatase. After obtaining the optimal dose, the same models were used to investigate the optimal dose interval and more advantageous route of administration. RESULTS: Compared with the control group, the amount of OTM and the number of TRAP-positive cells in the 0.04 MUg/ml group showed no significant changes, whilst were greatly reduced in the other three groups. In the experiment of finding the optimal dose interval, no significant differences were observed in every-two-day and every-three-day injection groups compared to the control. However, every-four-day injection group showed significant difference in the amount of OTM and histological changes. There was no significant difference between local and systemic application of rhsTNF-RI. CONCLUSION: The optimal delivery of rhsTNF-RI was local injection of 0.1 ml at 0.1 MUg/ml every three days. PMID- 21704306 TI - Changes in alcohol intake in response to transdiagnostic cognitive behaviour therapy for eating disorders. AB - OBJECTIVE: The aim of this study was to examine how alcohol intake changes during and after transdiagnostic cognitive behaviour therapy for eating disorders (CBT E). Additionally, the paper considers the relationship between alcohol consumption, eating disorder diagnosis and current major depressive episode at the time of first assessment. METHOD: One hundred and forty nine outpatients with an eating disorder (body mass index over 17.5) were divided into high or low alcohol intake groups (HIG and LIG) according to their intake at pre-treatment assessment. Their alcohol intake and eating disorder psychopathology were examined over the course of treatment and follow-up. RESULTS: There was no difference between the groups on response of the eating disorder to treatment. The HIG significantly reduced their alcohol intake following treatment whilst the intake of the LIG remained stable over the course of treatment and follow-up. There were no group differences in major depression and overall severity of eating disorder at baseline. CONCLUSIONS: The response to CBT-E was not influenced by baseline level of alcohol use. The mean alcohol intake of the heavy drinking subjects decreased without being specifically addressed by the treatment. PMID- 21704307 TI - An initial study of neural responses to monetary incentives as related to treatment outcome in cocaine dependence. AB - BACKGROUND: Although cocaine dependence (CD) involves abnormalities in drug related, reward-based decision making, it is not well understood whether these abnormalities generalize to nondrug-related cues and rewards and how neural functions underlying reward processing in cocaine abusers relate to treatment outcome. METHODS: Twenty CD patients before treatment and 20 matched healthy control (HC) subjects participated in functional magnetic resonance imaging while performing a monetary incentive delay task. Outcomes through 8 weeks were assessed via percent cocaine-negative urine toxicology, self-reported cocaine abstinence, and treatment retention. RESULTS: Among the whole sample, anticipation of working for monetary reward (i.e., reward anticipation) was associated with activation in the ventral striatum (VS), medial frontal gyrus, thalamus, right subcallosal gyrus, right insula, and left amygdala. Cocaine dependence compared with HC participants exhibited greater activation during notification of rewarding outcome (i.e., reward receipt) in left and right VS, right caudate, and right insula. In CD participants during reward anticipation, activation in left and right thalamus and right caudate correlated negatively with percent cocaine-negative urine toxicology, activation in thalamus bilaterally correlated negatively with self-reported abstinence measures, and activation in left amygdala and parahippocampal gyrus correlated negatively with treatment retention. During reward notification, activation in right thalamus, right VS, and left culmen correlated negatively with abstinence and with urine toxicology. CONCLUSIONS: These findings suggest that in treatment-seeking CD participants, corticolimbic reward circuitry is relatively overactivated during monetary incentive delay task performance and specific regional activations related to reward processing may predict aspects of treatment outcome and represent important targets for treatment development in CD. PMID- 21704308 TI - Glial cell response and iNOS expression in the optic nerve head and retina of the rat following acute high IOP ischemia-reperfusion. AB - Acute high IOP ischemia-reperfusion induces the loss of retinal ganglion cells, supporting the hypothesis that the condition of ischemia-reperfusion contributes to the induction and progression of glaucoma. This study investigated morphological changes, glial cell response, and expression of inducible nitric oxide synthase (iNOS) in the optic nerve head and retina of the rat following acute high IOP ischemia-reperfusion. A 60-min ischemic period was administered to the rat eye by raising the IOP, followed by a reperfusion period lasting 2, 5, or 7 days. Histological examination showed that acute high IOP ischemia-reperfusion injury produced optic nerve head and retina damage. In immunohistochemical staining, GFAP and OX-45 were limited to the ganglion cell layer (GCL) or inner nuclear layer (INL) of the control retina and increased to nearly all layers of the retina after acute high IOP ischemia-reperfusion. GFAP and OX-42 were detected at the control optic nerve heads and increased after acute high IOP ischemia-reperfusion. After acute high IOP ischemia-reperfusion, expression of iNOS increased, mostly at the GCL and INL of the retina and at the optic nerve head. Western blot analysis showed that expression of iNOS increased significantly, compared with the control, in the retina and optic nerve head after acute high IOP ischemia-reperfusion. Activation of glial cells and the up regulation of iNOS may contribute to the damage of the retina and optic nerve head of the rat following acute high IOP ischemia-reperfusion. PMID- 21704309 TI - The effects of acetate anion on cellulose dissolution and reaction in imidazolium ionic liquids. AB - Quantum mechanical calculations were carried out to determine the mechanisms for the superiority of the imidazolium acetate-based ionic liquids to the corresponding chloride-based ionic liquids. Our results indicate that the imidazolium cation can react with the acetate anion to generate a carbene, a highly reactive intermediate. The carbene produced then reacts with cellulose to facilitate its dissolution in the ionic liquid solvents in addition to the stronger hydrogen bonds formed between the acetate anion and the hydroxyl groups on cellulose. The mechanisms for the imidazolium cation and acetate anion reactions involve the initial ion pairing of the cation and anion via hydrogen bonding and electrostatic interactions. The hydrogen bond formed between the C2-H on the imidazolium cation and COO(-) of the anion facilitates the transfer of the H(+) to the anion to form a carbene intermediate. PMID- 21704310 TI - Design and synthesis of novel cell wall inhibitors of Mycobacterium tuberculosis GlmM and GlmU. AB - GlmM and GlmU are key enzymes in the biosynthesis of UDP-N-acetyl-d-glucosamine (UDP-GlcNAc), an essential precursor of peptidoglycan and the rhamnose-GlcNAc linker region in the mycobacterial cell wall. These enzymes are involved in the conversion of two important precursors of UDP-GlcNAc, glucosamine-6-phosphate (GlcN-6-P) and glucosamine-1-phosphate (GlcN-1-P). GlmM converts GlcN-6-P to GlcN 1-P, GlmU is a bifunctional enzyme, whereby GlmU converts GlcN-1-P to GlcNAc-1-P and then catalyzes the formation of UDP-GlcNAc from GlcNAc-1-P and uridine triphosphate. In the present study, methyl 2-amino-2-deoxyl-alpha-d glucopyranoside 6-phosphate (1alpha), methyl 2-amino-2-deoxyl-beta-d glucopyranoside 6-phosphate (1beta), two analogs of GlcN-6-P, were synthesized as GlmM inhibitors; 2-azido-2-deoxy-alpha-d-glucopyranosyl phosphate (2) and 2-amino 2,3-dideoxy-3-fluoro-alpha-d-glucopyranosyl phosphate (3), analogs of GlcN-1-P, were synthesized firstly as GlmU inhibitors. Compounds 1alpha, 1beta, 2, and 3 as possible inhibitors of mycobacterial GlmM and GlmU are reported herein. Compound 3 showed promising inhibitory activities against GlmU, whereas 1alpha, 1beta and 2 were inactive against GlmM and GlmU even at high concentrations. PMID- 21704312 TI - Remote protein homology detection and fold recognition using two-layer support vector machine classifiers. AB - Remote protein homology detection and fold recognition refer to detection of structural homology in proteins where there are small or no similarities in the sequence. To detect protein structural classes from protein primary sequence information, homology-based methods have been developed, which can be divided to three types: discriminative classifiers, generative models for protein families and pairwise sequence comparisons. Support Vector Machines (SVM) and Neural Networks (NN) are two popular discriminative methods. Recent studies have shown that SVM has fast speed during training, more accurate and efficient compared to NN. We present a comprehensive method based on two-layer classifiers. The 1st layer is used to detect up to superfamily and family in SCOP hierarchy using optimized binary SVM classification rules. It used the kernel function known as the Bio-kernel, which incorporates the biological information in the classification process. The 2nd layer uses discriminative SVM algorithm with string kernel that will detect up to protein fold level in SCOP hierarchy. The results obtained were evaluated using mean ROC and mean MRFP and the significance of the result produced with pairwise t-test was tested. Experimental results show that our approaches significantly improve the performance of remote protein homology detection and fold recognition for all three different version SCOP datasets (1.53, 1.67 and 1.73). We achieved 4.19% improvements in term of mean ROC in SCOP 1.53, 4.75% in SCOP 1.67 and 4.03% in SCOP 1.73 datasets when compared to the result produced by well-known methods. The combination of first layer and second layer of BioSVM-2L performs well in remote homology detection and fold recognition even in three different versions of datasets. PMID- 21704311 TI - RahU: an inducible and functionally pleiotropic protein in Pseudomonas aeruginosa modulates innate immunity and inflammation in host cells. AB - The aim of this study was to define the functional role of a recently identified RahU protein from Pseudomonas aeruginosa in macrophages and its role in bacterial defense. Recombinant (r)-RahU had no significant effect on cell apoptosis or cell viability in human monocytic THP-1 cells. Gene expression array of murine macrophage cells (RAW 264.7) stimulated with LPS showed modulation of common transcripts (by r-RahU and predisone) involved in inflammation. Functional cellular analysis showed RAW cells incubated with r-RahU at 1.0-10 MUg/ml (0.06 0.6 MUM) inhibited accumulation of nitric oxide (NO) in the presence of LPS by 10 50%. The IC(50) of r-RahU (0.6 MUM) was distinct from the known inhibitors of NO production: prednisone (50 MUM) and L-NMMA (100 MUM). r-RahU also significantly inhibited chemotactic activity of THP-1 cells toward CCL2 or chemotactic supernatants from apoptotic T-cells. These reports show previously unknown pleiotropic properties of RahU in modulating both microbial physiology and host innate immunity. PMID- 21704313 TI - Prevention of menstrual migraine with perimenstrual transdermal 17-beta estradiol: a randomized, placebo-controlled, double-blind crossover study. AB - The effect of treatment with percutaneous E(2) (100 MUg/24 h) during 2 weeks perimenstrually on the number and severity of menstrual migraine attacks was studied in 27 women in a randomized, placebo-controlled, double-blind, crossover trial. We were not able to demonstrate any difference between E(2) supplementation and placebo on the number or severity of migraine attacks, but both regimens showed significant effects compared with before treatment. CLINICAL TRIAL IDENTIFICATION NUMBER: NCT00204074. PMID- 21704314 TI - Current options for preservation of fertility in the male. AB - Modern cancer therapies have greatly improved survival rates in men of reproductive age and younger; however, surgery, chemotherapy, and irradiation may lead to male infertility. Men with cancer should be counseled about fertility preservation before initiating therapy, when possible. Currently, options for male fertility preservation include cryopreservation of semen or testicular tissue. However, prepubertal boys pose a special problem in this area. PMID- 21704315 TI - Another clinical evidence straw on the $4 billion ezetimibe camel's back. PMID- 21704316 TI - Mitral leaflet modeling: Importance of in vivo shape and material properties. AB - The anterior mitral leaflet (AML) is a thin membrane that withstands high left ventricular (LV) pressure pulses 100,000 times per day. The presence of contractile cells determines AML in vivo stiffness and complex geometry. Until recently, mitral valve finite element (FE) models have neglected both of these aspects. In this study we assess their effect on AML strains and stresses, hypothesizing that these will differ significantly from those reported in literature. Radiopaque markers were sewn on the LV, the mitral annulus, and AML in sheep hearts, and their four-dimensional coordinates obtained with biplane video fluoroscopy. Employing in vivo data from three representative hearts, AML FE models were created from the marker coordinates at the end of isovolumic relaxation assumed as the unloaded reference state. AML function was simulated backward through systole, applying the measured trans-mitral pressure on AML LV surface and marker displacements on AML boundaries. Simulated AML displacements and curvatures were consistent with in vivo measurements, confirming model accuracy. AML circumferential strains were mostly tensile (1-3%), despite being compressive (-1%) near the commissures. Radial strains were compressive in the belly (-1 to -0.2%), and tensile (2-8%) near the free edge. These results differ significantly from those of previous FE models. They reflect the synergy of high tissue stiffness, which limits tensile circumferential strains, and initial compound curvature, which forces LV pressure to compress AML radially. The obtained AML shape may play a role not only in preventing mitral regurgitation, but also in optimizing LV outflow fluid dynamics. PMID- 21704317 TI - Liquid phase microextraction applications in food analysis. AB - Over the last years, liquid-phase microextraction (LPME) in its different application modes (single drop microextraction, dispersive liquid-liquid microextraction and hollow fiber-LPME) has been increasingly applied for the extraction of both inorganic and organic analytes from different matrices. Its advantages over conventional extraction procedures (simplicity, effectiveness, rapidity and low consumption of organic solvents) has also attracted its application in the complex food analysis field, in which it has clearly provided good and challenging results. A comprehensive review dealing with those articles published since its introduction till the end of March 2011 is presented, offering also a critical vision of the analytical potential of LPME for the analysis of foods. PMID- 21704318 TI - The development and characterization of protein-based stationary phases for studying drug-protein and protein-protein interactions. AB - Protein-based liquid chromatography stationary phases are used in bioaffinity chromatography for studying drug-protein interactions, the determination of binding affinities, competitive and allosteric interactions, as well as for studying protein-protein interactions. This review addresses the development and characterization of protein-based stationary phase, and the application of these phases using frontal and zonal chromatography techniques. The approach will be illustrated using immobilized heat shock protein 90alpha and the immobilized estrogen related receptor stationary phases. In addition, the review discusses the use of the protein-coated magnetic beads for ligand and protein fishing as well as for the identification of unknown ligands from cellular or botanical extracts. PMID- 21704319 TI - Simultaneous determination of benzotriazoles and ultraviolet filters in ground water, effluent and biosolid samples using gas chromatography-tandem mass spectrometry. AB - A new method using gas chromatography-tandem mass spectrometry (GC-MS/MS) was developed for the determination of four benzotriazoles, i.e. benzotriazole (BT), 5-methylbenzotriazole (5-TTri), 5-chlorobenzotriazole (CBT), 5,6 dimethylbenzotriazole (XTri), and six UV filters, i.e. benzophenone-3 (BP-3), 3 (4-methylbenzylidene)camphor (4-MBC), octyl 4-methoxycinnamate (OMC), 2-(3-t butyl-2-hydroxy-5-methylphenyl)-5-chloro benzotriazole (UV-326), 2-(2'-hydroxy-5' octylphenyl)-benzotriazole (UV-329), and octocrylene (OC) in ground water, effluent and biosolid samples. Solid phase extraction (SPE) and pressurized liquid extraction (PLE) were applied as the preconcentration method for water samples (ground water and effluent) and biosolid samples, respectively. The optimized method allowed us to quantify all target compounds with the method detection limits ranging from 0.29 to 11.02 ng/L, 0.5 to 14.1 ng/L and 0.33 to 8.23 ng/g in tap water, effluent and biosolid samples, respectively. The recoveries of the target analytes in tap water, effluent and biosolid samples were 70-150%, 82-127% and 81-133%, respectively. The developed analytical method was applied in the determination of these target compounds in ground water, effluent and biosolid samples collected from Bolivar sewage treatment plants in South Australia. In effluent samples, the target compounds BT, 5-TTri, CBT, XTri and BP-3 tested were detected with the maximum concentration up to 2.2 MUg/L for BT. In biosolid samples, eight out of ten compounds tested were found to be present at the concentrations ranging between 18.7 ng/g (5-TTri) and 250 ng/g (4 MBC). PMID- 21704320 TI - Design, synthesis and stimuli responsive gelation of novel stigmasterol-amino acid conjugates. AB - An efficient synthesis of three novel stigmasterol-amino acid (glycine, L-leucine and L-phenylalanine) conjugates as stimuli responsive gelators is reported. The gelation properties of the prepared compounds were investigated in a variety of organic as well as aqueous solvents. The most striking finding of our investigation was that the hydrochloride salts of the prepared conjugates acted as gelators, whereas the neutral conjugates were either non-gelators or formed only a weak gel in anisole. The hydrochloride salts of stigmasteryl glycinate and L-leucinate form gels in n-alcohols (n=4-10) and in ethane-1,2-diol, and that of stigmasteryl L-phenylalaninate forms gels in aromatic solvents and in tetrachloromethane. These unique properties of the gelators were explored to prepare stimuli responsive, "acid-base" triggered reversible sol-gel transitions. The gelators and their gels were characterized by liquid and solid-state NMR as well as FT-IR. The morphology of their corresponding xerogels was investigated by SEM. PMID- 21704321 TI - The prognostic significance of electrocardiographic changes in Chagas disease. AB - INTRODUCTION: The meaning of electrocardiographic changes appearing during the clinical follow-up of Chagas disease (ChD) is unknown. In this study, a patient cohort with ChD was followed to describe the electrocardiographic changes that may make it possible to identify patients whose left ventricular function has deteriorated. METHODS: The study sample consisted of a prospective cohort followed since 1998 to 1999, involving 220 patients aged 15 to 55 years, 30 controls, and 190 with ChD, without other comorbidities. The group was reexamined between 2004 and 2006, and new electrocardiograms were obtained for 153 patients, 25 (83%) of 30 in the control group and 128 (72%) of 177 in the ChD group. Electrocardiographic variables associated with a significant decrease in ejection fraction (5% or more) were identified. RESULTS: A significant decrease in ejection fraction was observed in 21 patients in the ChD group (18.7%) but in none of the non-ChD group (P = .024). Only the presence of a new electrocardiographic abnormality and an increase in QRS duration correlated with a decrease in an ejection fraction of 5% or more. QRS duration was correlated with both an increase in left ventricle diastolic diameter and a deterioration in the ejection fraction (r(s) = 0.225, P = .017, and r(s) = -0.300, P < .001). A QRS increase of 5 milliseconds had 77.8% sensitivity and 62.2% specificity for identifying patients with significant decrease in ejection fraction. CONCLUSION: The increase in the duration of the QRS complex and the appearance of new electrocardiographic alterations may help in identifying patients with a significant decrease (of 5% or more) in left ventricle ejection fraction. PMID- 21704322 TI - Functional polymorphism in gamma-glutamylcarboxylase is a risk factor for severe neonatal hemorrhage. AB - A neonate who received vitamin K (VK) supplementation then developed severe late onset bleeding with abnormal prothrombin time and activated partial thromboplastine time. The bleeding was corrected after intravenous VK. Molecular analysis of the gamma-glutamylcarboxylase gene revealed a heterozygous single nucleotide polymorphism, which decreases carboxylase activity and induces VK dependent coagulation deficiency. PMID- 21704323 TI - Vallecular cyst: rare cause of failure to thrive without respiratory distress in an infant. PMID- 21704324 TI - RT-qPCR study on post-mortem brain samples from patients with major psychiatric disorders: reference genes and specimen characteristics. AB - BACKGROUND: Gene expression studies conducted in post-mortem human brain samples have the potential to identify relevant genes implicated in psychiatric disorders. Although reverse transcription quantitative real-time PCR (RT-qPCR) has emerged as the method of choice for specific gene expression studies, it requires the use of stable reference genes, and it is necessary to control for pre- and post-mortem factors to obtain reliable data. OBJECTIVE: The aim of this study was to identify suitable reference genes and specimen characteristics that can be taken into account when comparing mRNA expression data between post-mortem brain specimens from psychiatric patients and controls. METHOD: We used a selection of suitably matched occipital cortex specimens from subjects in each of the following groups: schizophrenia (N = 15), bipolar disorder (N = 13), major depressive disorder (N = 15), and control (N = 15). Quantitative and qualitative RNA analyses were performed prior to RT-qPCR and gene expression stability was evaluated with geNorm and NormFinder. RESULTS: We identified GAPDH, RPS17, RPL30, RPLP0, and TFRC as potential reference genes from a sample plate containing 32 candidates commonly used as reference genes. Further analyses of these 5 genes highlighted that 1) they are suitable reference genes for RT-qPCR studies in these post-mortem brain samples from psychiatric patients, and 2) the RNA quality index is highly correlated with gene expression values (r = -0.681, p < 0.0001). CONCLUSIONS: In addition to controlling for pre- and post-mortem factors and selecting stable reference genes for normalization, sample sets should be matched with regard to RNA quality. PMID- 21704325 TI - Stress distribution on the screws in posterior lumbar fusion of isthmic spondylolisthesis with 2- or 3-vertebra fixation techniques: a biomechanical cadaveric study. AB - BACKGROUND: Two- or three-vertebra fixation techniques are both used in the treatment of spondylolisthesis. However, the number of spinal segments that should be implanted in spondylolisthesis reduction and fixation is still controversial, and there are no published reports on stress distribution on the screws with 2- or 3-vertebra fixation techniques. Understanding stress distribution in screws would be of potential great clinical importance and supply more biomechanical evidence in surgery. The aim of this study was to compare and quantitatively analyze the stress distribution on the screws in 2- or 3-vertebra fixation techniques in cadaveric models of spondylolisthesis. MATERIALS AND METHODS: Sixteen fresh specimens of human lumbar spines were used in this study. The spondylolisthesis model was generated by Panjabi method and fixed with the SINO universal spine system by 2- (group A) or 3-vertebra (group B) fixation technique. Rectangular electrical resistance strain gauges were fixed at upper and lower surface of the root of screws bilaterally. The samples were tested under flexion/extension, left/right lateral bending, and axial compression loading. Stress on the screws was measured by strain gauge monitor, respectively. RESULTS: Under the five different loading conditions, the stress could be compressive stress or tensile stress. Under the compression, flexion, and bending loading condition, the stress in reduction screws in group A is higher than in group B (P < 0.01). However, under the extension loading condition, stress of lower surface in reduction screws in group A is 49% lower than in group B. With regard to the anchor screws, under flexion and lateral bending conditions, stress in group A is lower than in group B (P < 0.05). Under compression and extension loading conditions, stress in group A is slightly higher than in group B, but no significant difference is detected. CONCLUSIONS: In most loading conditions, stress in reduction screws in 2-vertebra fixation technique was higher than in 3 vertebra fixation technique. The 3-vertebra fixation technique might effectively reduce stress on the reduction screws, and decrease the probability of fatigue fractures of the screws. PMID- 21704326 TI - Oncological and functional outcomes of intersphincteric resection for low rectal cancer. AB - BACKGROUND: The intersphincteric resection technique has been used to extend the opportunity for sphincter preservation in patients with very low rectal cancer. The aim of this study is to assess the long-term oncological and functional outcomes of intersphincteric resection. METHODS: Patients with extraperitoneal rectal cancer were treated and retrospectively chart reviewed. The oncological and functional outcomes were evaluated. Comparisons of the overall disease-free survival and recurrence were analyzed for the different surgical procedures. RESULTS: From July 2002 to August 2009, 162 patients with extraperitoneal rectal cancer were retrospectively chart reviewed. One-hundred one patients (62.3%) underwent low anterior resection, 26 patients (16%) received radical proctectomy and intersphincteric resection with coloanal anastomosis, and 23 (14.2%) had abdominoperineal resection. The sphincter preservation rate was 80%. In the intersphincteric resection group, overall survival rates at 3 and 5 y were 83% and 83%, and disease-free survival at 3 and 5 y were 82% and 76%, respectively. The mean stool frequency was 4.7 per 24 h. There were 38.1% of patients suffering from stool fragmentation, and 23.8% had nocturnal defecation. About one-third of the patients required antidiarrheal medications. Overall, 90.8% of patients were satisfied with the functional results of surgery. CONCLUSIONS: Our data show intersphincteric resection for low rectal cancer is feasible and safe. Preoperative radiotherapy may negatively affect symptom-specific quality of life. PMID- 21704327 TI - Transplantation of enteric cells into the aganglionic rodent small intestines. AB - BACKGROUND: Enteric cells, a mixture of cells isolated from the longitudinal and circular muscle of the gut, may contain neural crest stem cells (NCSCs) and therefore may be a potential source to regenerate the enteric nervous system. MATERIALS AND METHODS: Benzylalkonium chloride (BAC) was employed to ablate the myenteric and submucosal plexi of the rodent jejunum. Enteric cells were then injected into this BAC-treated segment of the jejunum either with or without basic fibroblast growth factor (bFGF) mixed in collagen. RESULTS: Expression of peripherin, S100, and synaptophysin were found in all of the cell injection sites. Peripherin and S100 expression appeared in close proximity in ganglion like structures when bFGF was injected simultaneously with enteric cells. Synapses that were formed in the presence of bFGF were elongated compared with those formed in the absence of exogenously delivered bFGF. A small percentage of enteric cells expressed peripherin in the injection site after transplantation. CONCLUSIONS: Enteric cells transplanted with collagen and bFGF in an aganglionic segment of jejunum regenerated ganglion-like structures and may hold potential as a cellular therapeutic for various motility disorders of the gastrointestinal tract. PMID- 21704328 TI - Efficacy of tigecycline and rifampin alone and in combination against Enterococcus faecalis biofilm infection in a rat model of ureteral stent. AB - BACKGROUND: We investigated the efficacy of tigecycline and rifampin alone or combined in preventing ureteral stent infection due to Enterococcus faecalis. MATERIALS AND METHODS: The activities of the two antibiotics were previously studied in vitro in absence or in presence of biofilm. For in vivo research, the study included a control group without bacterial challenge to evaluate the sterility of surgical procedure, a challenged control group that did not receive any antibiotic prophylaxis and, for each bacterial strain, three challenged groups that received: (1) 2 mg/kg intraperitoneal tigecycline, immediately after stent implantation; (2) rifampin-coated ureteral stents where 0.2 cm(2) sterile ureteral stents were incubated in 10 mg/L rifampin solution for 30 min immediately before implantation; and (3) intraperitoneal tigecycline plus rifampin-coated ureteral stent at the above concentrations. Ureteral stents were explanted at d 5 following implantation and biofilm bacteria enumerated. RESULTS: The in vitro studies showed that the biofilm was strongly affected by the presence of rifampin and, in its presence, tigecycline had MICs and MBCs lower than those obtained in the absence of rifampin. Intraperitoneal tigecycline exerted stronger effect than rifampin on bacterial numbers. The combination rifampin plus tigecycline showed efficacies higher than that of each single compound. CONCLUSION: These results highlight the potential usefulness of tigecycline in preventing enterococcal ureteral stent infections and the role of rifampin as an interesting antibiotic enhancer. PMID- 21704329 TI - Epidemiologic trend in elderly domestic injury. AB - BACKGROUND: The elderly constitute about 12% of the American population, with a projected increase of up to 25% in 2050. Elderly domestic injuries have been recognized as a major cause of morbidity and mortality. The objective of this study is to determine the 4-y national trend in elderly domestic injury, and we hypothesize that the home remains a significant source of injury. METHODS: Data on elderly patients >= 65 y was extracted from the National Trauma Data Bank's National Sample Project (NSP). Elderly patients with home injuries were compared with non-home injuries. Subsets of hospitalized patients were analyzed for trends in injury site over a 4 y period. Multivariate analysis was performed to determine the predictors of hospitalization and in-hospital mortality. RESULTS: A total of 98,288 patients, representing a weighed estimate of 472,456 elderly patients were analyzed. Forty-two percent of all injuries in the study population occurred at home, followed by motor vehicle crashes (MVC) at 25%. Home injuries as a proportion of annual injuries increased from 37% in 2003 to 40% in 2006. Majority (57%) were admitted to the floor and 14% to the intensive care unit (ICU). On multivariate analysis, African-Americans and Asians were less likely to be hospitalized (odds ratio (OR) 0.57 and 0.50, respectively, with females 47% less likely than males to die after hospitalization (P < 0.001). CONCLUSIONS: Home injuries remain the most significant source of elderly hospitalizations after trauma. With a rapidly growing elderly population, there is a need to recognize this specific location of injury and create directed preventive measures to avert elderly domestic injuries. PMID- 21704330 TI - Gender-related difference of sevoflurane postconditioning in isolated rat hearts: focus on phosphatidylinositol-3-kinase/Akt signaling. AB - BACKGROUND: Previous studies have reported that female gender confers cardioprotection against ischemia/reperfusion (I/R) injury, partly because estrogen activates phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway. We have previously proven that cardioprotection of sevoflurane postconditioning is mediated by PI3K/Akt pathway in male rats. The purpose of the present study was to determine whether the cardioprotection of sevoflurane postconditioning is influenced by gender, and the role of PI3K/Akt pathway in such gender difference. MATERIALS AND METHODS: Isolated hearts from 2-mo-old male and female SD rats were subjected to ischemia for 40 min and reperfusion for 2 h in the Langendorff apparatus, and were randomly assigned to the following groups: no ischemia/reperfusion (CON), ischemia/reperfusion (I/R), I/R+sevoflurane postconditioning (I/R+SPC), I/R+100 nM wortmannin (I/R+WOR), and I/R+SPC+WOR. Postconditioning was performed with administration of 3.0% sevoflurane at the first 10 min of reperfusion. Left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), and myocardial lactate dehydrogenase (LDH) release were measured. Infarct size was detected by riphenyltetrazolium chloride staining. The protein expression of total Akt (t-Akt) and phosphorylated Akt (Ser(473)) (p-Akt) were determined by Western blot. RESULTS: The I/R group showed lower LVDP and higher LVEDP than CON group in the same gender during reperfusion period. The LDH release and infarct size were smaller in the female I/R group (P < 0.05 versus male I/R group). Sevoflurane postconditioning markedly improved left ventricular function and decreased LDH, infarct size in the male I/R+SPC group (P < 0.05 versus male I/R group) but not in the female I/R+SPC group. Wortmannin abolished the cardioprotection of sevoflurane postconditioning in the male I/R+SPC+Wort group (P < 0.05 versus male I/R+SPC group), and markedly increased the infarct size and LVEDP and decreased LVDP in female rats. The t-Akt protein expression was no significant difference in all groups. The ratio of p Akt/t-Akt expression in the male CON group was a little lower than that in the female CON group, but there was no statistical significance. In male rats, the ratio of p-Akt/t-Akt was no difference between CON and I/R group, but it was higher in I/R+SPC group than that in I/R group (P < 0.05). In female rats, the level of p-Akt was markedly increased by I/R, which was markedly higher than that in male I/R group (P < 0.05). However, p-Akt was not different between I/R and I/R+SPC groups. Wortmannin decreased the p-Akt expression in both male and female rats. CONCLUSIONS: It is concluded that female rat hearts showed greater resistance to I/R injury, and sevoflurane postconditioning developed cardioprotection in male rats but not in female rats. The PI3K/Akt pathway may be involved in the cardioprotection by both sevoflurane postconditioning and gender. PMID- 21704331 TI - Obesity and weight loss at presentation of lung cancer are associated with opposite effects on survival. AB - BACKGROUND: Lung cancer is the second most common neoplasm and the leading cause of cancer deaths in the United States. In cancer, weight loss and obesity are associated with reduced survival. However, the effect of obesity or weight loss at presentation on lung cancer survival has not been well studied. MATERIALS AND METHODS: Using an extensive cancer dataset, we identified 76,086 patients diagnosed with lung cancer during the period of 1998-2002, of which 14,751 patients presented with obesity and/or weight loss. We examined the relationship between survival and weight loss or obesity at diagnosis using univariate and multivariate analysis. RESULTS: Median survival time (MST) for all lung cancer patients was 8.7 mo. Patients presenting with weight loss (15.8%) had shorter MST versus those who did not (6.4 versus 9.2 mo, P < 0.001) and patients with weight loss had significantly shortened MST for all stages and histologic subtypes. In contrast, obese patients at presentation (5.4%) had longer MST relative to non obese patients (13.0 versus 8.6 mo, P < 0.001), which was significant across all stages and histologic subtypes. Multivariate analysis revealed that the absence of weight loss was an independent, positive predictor of improved survival (HR = 0.087, P < 0.001), while the absence of obesity was an independent predictor of worsened survival in lung cancer (HR = 1.16, P < 0.001). CONCLUSIONS: Our results demonstrate an inverse relationship between survival and weight loss at presentation and a potentially protective effect of obesity in lung cancer survival, which could be due to greater physiologic reserves, thereby prolonging life by slowing the progress of cancer cachexia. PMID- 21704332 TI - Assessing the impact of teaching patient safety principles to medical students during surgical clerkships. AB - BACKGROUND: A critical aspect of enhancing patient safety is modifying the healthcare safety culture. We hypothesize that students who participate in safety curricula are knowledgeable regarding patient safety and likely to intervene to avoid patient errors. METHODS: A two-part patient safety curriculum was taught: introductory theories (first year) and a clinically oriented course during surgery rotations (third year). All students participated in the first year introduction and a random cohort of students (62.6%, N = 67) participated in the third year program. Multiple choice tests and web-based surveys were administered. Statistical analysis was carried out using Student's t-test for comparisons of test mean scores and z-test for comparison of the survey data. RESULTS: Students who participated in both years' curricula scored higher on didactic test than those who participated in only the first year course (82.9% versus 75.5%, P < 0.001). More students participating in both portions of the curricula intervened during at least one clinical encounter to avoid a patient error (77% versus 61%, P < 0.05). Students rated junior house-staff more receptive to patient safety suggestions than surgical fellows and faculty (84% versus 66%, P < 0.05); 75% of students rated their surgical clerkship exposure to patient safety somewhat/extremely valuable compared with 54% students who rated the first year exposure as somewhat/extremely valuable (P < 0.05). CONCLUSION: Medical students who have practical applications of patient safety education reinforced during surgery rotations are knowledgeable and willing to intervene in patient safety concerns. Teaching clinically relevant patient safety skills influences positive behavioral changes in medical students' performance on surgical teams. PMID- 21704333 TI - Prolonged cold ischemia enhances alloimmune response to liver grafts. PMID- 21704334 TI - Laparoscopic appendectomy in children with complicated appendicitis: ethnic disparity amid changing trend. AB - BACKGROUND: Laparoscopic appendectomy (LA) has gained acceptance in the treatment of uncomplicated appendicitis in the pediatric population. The role of LA versus open appendectomy (OA) in complicated (perforated) appendicitis has remained controversial. METHODS: A 10-y review of the Nationwide Inpatient Sample (HCUP NIS) and 3 y of non-overlapping data from the Kids' Inpatient Database (KID) (2000, 2003, and 2006) was performed on pediatric patients (age <18 y) with complicated appendicitis. Patients were classified based on gender, race, insurance status, and type of appendectomy performed. Multivariate regression was conducted adjusting for age, race, gender, and type of appendectomy, with mortality and length of hospital stay (LOS) as outcomes. RESULTS: An estimated 72,787 patients met the inclusion criteria with a median age of 11 y. The majorities of the patients were male (59.9%), Caucasian (38.1%), and insured (89.7%). Twenty-nine percent underwent LA while 71% had OA. Proportion of LA increased from 9.9% in 1999 to 46.6% in 2007. On multivariate analysis, African Americans were less likely to undergo LA compared with Caucasians (OR: 0.80, CI = 0.69-0.92, P = 0.002) despite an increased odds of undergoing LA over the last decade from 1998 to 2007 in the entire study population (OR 6.27, 95% CI 4.73 8.30, P = 0.000). Increasing age and gender were also associated with likelihood of receiving LA (OR: 1.08, CI = 1.06-1.10 and OR 1.25, 95% CI 1.18-1.31, P < 0.001). CONCLUSIONS: LA is gradually gaining acceptance over the years as an alternative to OA for complicated appendicitis, However, minority difference still exists in choice of procedure. There is a need to further investigate this disparity as it may be related to access to skilled laparoscopic pediatric surgeons. PMID- 21704335 TI - Magnolol attenuates the lung injury in hypertonic saline treatment from mesenteric ischemia reperfusion through diminishing iNOS. AB - BACKGROUND: Hypertonic saline (HTS) administration can decrease the inflammation following ischemia reperfusion. Magnolol is a potent antioxidant. The present study investigated whether combined treatment of magnolol and HTS could provide further protection in mesenteric ischemia reperfusion injury. METHODS: Male C3H/HeOuJ mice were randomly segregated into the following groups: sham-operated (sham), vehicle treatment and mesenteric ischemia reperfusion (MSIR) (vehicle treated), magnolol treatment and MSIR (magnolol-treated), HTS treatment and MSIR (HTS-treated), as well as co-administration of magnolol plus HTS and MSIR (combined-treated). In MSIR, mice were subjected to mesenteric ischemia for 60 min followed by reperfusion for 30 min. Lung injury was evaluated by lung edema (water ratio) and myeloperoxide (MPO) activity; RNA expression of inducible nitric oxide synthetase (iNOS), TNF-alpha, and IL-6 were assayed by real time RT PCR. The formation of peroxynitrite in plasma was assayed by the peroxynitrite dependent oxidation of dihydrorhodamine 123 (DHR 123) to rhodamine. RESULTS: Compared with those in the sham-treated group, lung edema and MPO activity, expressions of iNOS, TNF-alpha and IL-6, and plasma peroxynitrite were significantly increased in the vehicle-treated group. Significant attenuations of these parameters were found in the magnolol-treated or HTS-treated animals. Combined treatment of magnolol and HTS further suppressed the lung edema, iNOS, and TNF-alpha expressions, and plasma peroxynitrite, compared with the results of a single treatment of magnolol or HTS. CONCLUSIONS: Compared with single-agent use, co-administration of magnolol and HTS further decreases iNOS expression and plasma peroxynitrite as well as the degree of lung injury from MISR. These results may provide another treatment measure for post-injury immunomodulation. PMID- 21704336 TI - The impact of iMedConsent on patient decision-making regarding cholecystectomy and inguinal herniorrhaphy. AB - BACKGROUND: The Veterans Affairs Healthcare System implemented a computer-based tool (iMedConsent) to improve the quality of informed consent in 2004. The impact of this tool on the process of informed consent remains unknown. Our aim was to determine the impact of iMedConsent on patient information preference, anxiety, trust in the surgeon, ambivalence about the surgical decision, and comprehension of procedure-specific risk, benefits, and alternatives. MATERIALS AND METHODS: We prospectively enrolled a consecutive cohort of patients presenting to a general surgery clinic for possible cholecystectomy or inguinal herniorrhaphy from October 2009 to August 2010. We administered questionnaires before and after the clinic visit. RESULTS: Seventy-five patients completed pre-visit questionnaires. After evaluation by the surgeon, 42 patients were offered surgery and documented their informed consent using iMedConsent, of whom 38 (90%) also completed a post visit questionnaire. Among the participants who completed both pre- and post visit questionnaires, participant comprehension of procedure-specific risks benefits and alternatives improved from 50% at baseline to 60% after the clinic visit (P < 0.001). No differences were noted in ambivalence, trust, or anxiety. After the clinic visit, significantly more patients expressed a preference for participating in decision making with their surgeon (98% versus 71%, P = 0.008). However, significantly fewer expressed a preference for knowing all possible details about their illness (25% to 83%, P <= 0.001). CONCLUSIONS: The informed consent process using iMedConsent improves patient comprehension of procedure specific risks, benefits, and alternatives. It also increases patient preferences for participating more actively in the decision-making process. However, the process may provide more detail than patients want regarding their illness. PMID- 21704337 TI - Fighting the risk of developing Parkinson's disease; clinical counseling for first degree relatives of patients with Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) has a long pre-diagnosis phase that may span as long as 10-20 years. The ability to identify at risk populations raises the possibility of early intervention to delay or prevent the onset of motor symptoms. In Israel, there is a large group of Ashkenazi Jews at risk of developing PD due to high frequency of PD associated mutations in 2 genes (GBA and LRRK2). OBJECTIVE: To describe our unique experience with a clinical counseling service for 1st degree relatives of PD patients from the Ashkenazi origin who carry the G2019S mutation in the LRRK2 gene. METHOD: One hundred, self declared, healthy, first degree relatives of PD patients who carry the G2019S mutation in the LRRK2 gene were tested clinically and genetically in a cross sectional study. Those who have requested information on their risk to develop PD were invited to a free of charge, clinical counseling session to provide information on their risk of developing PD and potential risk modifiers that can be applied. Genetic status was not disclosed and the counselor was unaware of the subjects' G2019S mutation status. RESULTS: 46 subjects (mean age 48.2+/-10.7; 46% males) came for clinical counseling provided by a Movement Disorders specialist. Siblings and off-springs of the same proband were seen together. Counseling provided general information about the pre-diagnosis phase of PD, the concept of population at risk and habitual and behavioral recommendations that may delay PD motor symptoms onset. CONCLUSION: A high percentage of individuals at risk for developing PD requested clinical counseling on modifiers of the risk to develop PD. Counseling provided information as well as recommendations for behavioral modifications and drug treatment. Screening population at risk increases the awareness as well as early diagnosis of PD. Prospective information is needed in order to improve our knowledge base and assess the long term impact of such a counseling service. PMID- 21704338 TI - Familial normal pressure hydrocephalus (NPH) with an autosomal-dominant inheritance: a novel subgroup of NPH. AB - Normal pressure hydrocephalus (NPH) has two clinical forms: secondary NPH and idiopathic NPH (iNPH). Most patients with NPH occur sporadically: until now, only two families have been reported to have sibling cases of NPH. We here report a large family with 4 patients with elderly-onset NPH in three generations. All of them had cognitive impairment, gait disturbance, and urinary problems, along with normal pressure of cerebrospinal fluid. Their brain MRI showed enlargement of the ventricles and a disproportional narrowing of the subarachnoid space and cortical sulci at the high convexity of the cerebrum, which are the features of iNPH on MRI. The family interview also disclosed additional 4 patients who were suspected as having NPH. The disease seems to be inherited in an autosomal-dominant fashion. No known causes of secondary NPH were found in any of the patients. This is the first report to show a large family with NPH patients in three generations, who had clinical and MRI features indistinguishable from iNPH. This seems to represent a novel subgroup of NPH, familial NPH. PMID- 21704339 TI - Interstage attrition between bidirectional Glenn and Fontan palliation in children with hypoplastic left heart syndrome. AB - OBJECTIVE: With improving operative mortality for staged palliation of hypoplastic left heart syndrome, interstage death accounts for an increasing proportion of hypoplastic left heart syndrome mortality. We investigated risk factors for death or cardiac transplantation during the interstage period between bidirectional Glenn and Fontan procedures in children with hypoplastic left heart syndrome. METHODS: Patients with hypoplastic left heart syndrome who underwent bidirectional Glenn between August 1995 and June 2007 were screened. Standard risk patients, defined by having been discharged after both Norwood and bidirectional Glenn, were included for analysis. Patient demographic, echocardiographic, cardiac catheterization, and operative data were reviewed. Interstage attrition was defined as death or cardiac transplantation more than 30 days after bidirectional Glenn and before the Fontan procedure. Statistical analysis was carried out using the Student t test, Pearson chi-square correlation, and Cox proportional hazard modeling for multivariable analysis. RESULTS: Ninety-two patients with hypoplastic left heart syndrome were alive at 30 days after bidirectional Glenn. Of these patients, 8 died and 3 underwent cardiac transplantation at a median of 391 days (range, 59-1175 days) after bidirectional Glenn, yielding an interstage attrition rate of 12%. Removing the 7 patients who are still awaiting Fontan (but all of whom are at least 3.5 years after bidirectional Glenn) adjusts the attrition rate to 13%. Interstage attrition did not correlate with hemodynamic data obtained at cardiac catheterization, aortic arch obstruction, or right ventricular dysfunction. Multivariable analysis demonstrated that the presence of moderate or severe tricuspid valve regurgitation (hazard ratio, 6.02; 95% confidence interval, 1.56 23.24; P < .01) and weight z score (hazard ratio, 0.38; 95% confidence interval, 0.16-0.88; P = .02) were independent preoperative risk factors for interstage attrition. CONCLUSIONS: Interstage attrition between bidirectional Glenn and Fontan procedures occurred in 12% of our study population. Moderate or greater tricuspid valve regurgitation and low weight z score at the time of bidirectional Glenn are important risk factors for interstage attrition between the bidirectional Glenn and Fontan procedures in children with hypoplastic left heart syndrome. PMID- 21704340 TI - Split, in situ left internal thoracic artery to revascularize left anterior descending coronary artery system. PMID- 21704341 TI - Giant pseudoaneurysm at the proximal vein graft anastomosis after Bentall procedure for Takayasu arteritis. PMID- 21704342 TI - Susceptibility of fish to Chattonella marina is determined by its tolerance to hypoxia. AB - The harmful alga Chattonella marina has caused massive fish kills and economic losses worldwide. However, the fish kill mechanisms by C. marina have not been identified. The present study has confirmed that a significant elevation of blood osmolality is the universal response in moribund fish exposed to C. marina and the possible reasons leading to contradictory reports were identified. Both osmotic distress and respiratory impairment are important mechanisms leading to fish kill by C. marina. The susceptibility of marine fish to C. marina appears to be inversely related to their tolerance to hypoxia, with the hypoxia intolerant goldlined seabream being the most susceptible, and the hypoxia tolerant green grouper being the most tolerant to C. marina. Further studies in the marine medaka (Oryzias melastigma) showed that fish susceptibility to C. marina is directly related to susceptibility of the fish to hypoxia, but not related to its tolerance to hypersalinity stress. PMID- 21704343 TI - Characterization of organic matter in sediment cores of the Todos os Santos Bay, Bahia, Brazil, by elemental analysis and 13C NMR. AB - The impact of human activity on the sediments of Todos os Santos Bay in Brazil was evaluated by elemental analysis and 13C Nuclear Magnetic Resonance (13C NMR). This article reports a study of six sediment cores collected at different depths and regions of Todos os Santos Bay. The elemental profiles of cores collected on the eastern side of Frades Island suggest an abrupt change in the sedimentation regime. Autoregressive Integrated Moving Average (ARIMA) analysis corroborates this result. The range of depths of the cores corresponds to about 50 years ago, coinciding with the implantation of major onshore industrial projects in the region. Principal Component Analysis of the 13C NMR spectra clearly differentiates sediment samples closer to the Subae estuary, which have high contents of terrestrial organic matter, from those closer to a local oil refinery. The results presented in this article illustrate several important aspects of environmental impact of human activity on this bay. PMID- 21704344 TI - Growth anomalies on Acropora cytherea corals. AB - This ten-year study examined the morphological, physiological, and ecological characteristics of coral growth anomalies on Acropora cytherea on Amuro Island, Okinawa, Japan. The objectives of the study were to assess whether the growth anomalies, identified as diffuse disruptions on the skeleton: (i) were more prevalent on large colonies than on small colonies, (ii) were more common near the center of the colonies than peripherally, (iii) affected colony growth and mortality, and (iv) affected coral-colony fecundity and photosynthetic capacity. We hypothesized that the growth anomalies were signs of the onset of aging. The growth anomalies were more prevalent on colonies>2 m diameter, and were concentrated near the central (older) portions of the colonies. The growth anomalies were also associated with reduced productivity and dysfunctional gametogenesis. Still, the growth anomalies did not appear to affect colony survival. The contact experiments showed that the growth anomalies were not contagious, and were most likely a sign of aging that was exacerbated by thermal stress. PMID- 21704345 TI - Formation of iron plaque on mangrove roots receiving wastewater and its role in immobilization of wastewater-borne pollutants. AB - Iron (Fe) plaque formed on mangrove root increased with wastewater discharge, but the extent was species-specific. For Bruguiera gymnorrhiza, Fe plaque concentration was 0.80 mg g(-1) root d.wt at Day 0 and increased to 4.59, 6.84 and 7.52 mg g(-1) at Day 75 in the fresh water control (FW), synthetic wastewater with pollutant concentrations five times of municipal sewage (5SW) and double of 5SW (10SW) treatments, respectively; the respective increases in Excoecaria agallocha were from 0.70 to 2.37, 10.73 and 13.21 mg g(-1). For Acanthus ilicifolius, similar increase was found in 5SW, but all of the plants were dead in 10SW at Day 75. The concentrations of heavy metals and phosphorus immobilized were positively correlated with the amounts of Fe plaque formed, but the regression coefficients varied among species. The performance of mangrove plants in wastewater treatments was related to the Fe plaque formed and its immobilized wastewater-borne pollutants. PMID- 21704346 TI - Heavy metal concentrations and biomarkers of oxidative stress in native mussels (Mytilus edulis chilensis) from Beagle Channel coast (Tierra del Fuego, Argentina). AB - The aim of this study was to evaluate the usefulness of oxidative stress biomarkers of pollution in native mussels Mytilus edulis chilensis from the Beagle Channel. Spatial and seasonal variations of catalase, glutathione-S transferase and lipid peroxidation in gills and digestive gland were analyzed in relation to environmental parameters, heavy metals in sediment and in tissue. Four sites with anthropogenic impact and a control site were selected and monitored during the four seasons of 2007. We found significant differences among sites in concentrations of dissolved nutrients and heavy metals in sediments, with the highest values recorded at sites with anthropogenic pressure. Different patterns were observed between concentrations of metals in tissues and in sediments suggesting differences in bioavailability. There were also significant differences in biomarker responses among sites, despite the strong seasonal variability. Our results showed relatively moderate levels of pollution in the study area as a result of urban influences. PMID- 21704347 TI - The dynamic insulin sensitivity and secretion test--a novel measure of insulin sensitivity. AB - The objective was to validate the methodology for the dynamic insulin sensitivity and secretion test (DISST) and to demonstrate its potential in clinical and research settings. One hundred twenty-three men and women had routine clinical and biochemical measurements, an oral glucose tolerance test, and a DISST. For the DISST, participants were cannulated for blood sampling and bolus administration. Blood samples were drawn at t = 0, 10, 15, 25, and 35 minutes for measurement of glucose, insulin, and C-peptide. A 10-g bolus of intravenous glucose at t = 5 minutes and 1 U of intravenous insulin immediately after the t = 15 minute sample were given. Fifty participants also had a hyperinsulinemic euglycemic clamp. Relationships between DISST insulin sensitivity (SI) and the clamp, and both DISST SI and secretion and other metabolic variables were measured. A Bland-Altman plot showed little bias in the comparison of DISST with the clamp, with DISST underestimating the glucose clamp by 0.1.10(-2).mg.L.kg( 1).min(-1).pmol(-1) (90% confidence interval, -0.2 to 0). The correlation between SI as measured by DISST and the clamp was 0.82; the c unit for the receiver operating characteristic curve analysis for the 2 tests was 0.96. Metabolic variables showed significant correlations with DISST SI and the second phase of insulin release. The DISST also appears able to distinguish different insulin secretion patterns in individuals with identical SI values. The DISST is a simple, dynamic test that compares favorably with the clamp in assessing SI and allows simultaneous assessment of insulin secretion. The DISST has the potential to provide even more information about the pathophysiology of diabetes than more complicated tests. PMID- 21704348 TI - Overexpression of hepatic 5alpha-reductase and 11beta-hydroxysteroid dehydrogenase type 1 in visceral adipose tissue is associated with hyperinsulinemia in morbidly obese patients. AB - 11-beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone to cortisol, mainly in the liver and visceral adipose tissue (VAT), and has been implicated in several metabolic disorders. The absence of systemic hypercortisolism in central obesity could be due to increased inactivation of cortisol to its tetrahydrometabolites by the hepatic enzymes 5alpha- and 5beta reductases. Our aim was to assess the expression of the reductases in the liver and of 11beta-HSD1 in the liver and VAT in morbidly obese patients and to analyze their association with clinical, anthropometric, and biochemical parameters. Hepatic and VAT samples were obtained during bariatric surgery. 5alpha- and 5beta reductases, 11beta-HSD1, and 18S expression was measured using real-time polymerase chain reaction. Anthropometric and biochemical variables were analyzed. Forty-one patients were recruited (age, 41.8 +/- 10.6 years; body mass index, 42.1 +/- 6.6 kg/m(2); 71% women). The expression of hepatic 5alpha- and 5beta-reductases was positively correlated (r = +0.53, P = .004), and their expression levels were correlated with hepatic 11beta-HSD1 expression (r = +0.61, P < .001 for 5alpha-reductase and r = +0.50, P < .001 for 5beta-reductase). Hepatic 5alpha-reductase was associated with insulin (r = +0.34, P = .015). Visceral adipose tissue 11beta-HSD1 expression was associated with glucose (r = +0.37, P = .025) and insulin (r = +0.54, P = .002). Our results showed that 5alpha-reductase and VAT 11beta-HSD1 expressions were associated with insulinemia. These findings suggest that overexpression of 5alpha-reductase, through a higher inactivation of cortisol in the liver, could have a protective role in preserving hepatic sensitivity to insulin. The overexpression of liver reductases in obesity could be an adaptive response to an increase in cortisol production by the liver and visceral 11beta-HSD1 to avoid systemic hypercortisolism. PMID- 21704349 TI - Alcohol use among 13-year-old adolescents: associated factors and perceptions. AB - OBJECTIVE: To describe the frequency and determinants of alcohol use in a representative sample of 13 years old adolescents, and to analyse qualitatively how adolescents perceive this issue. STUDY DESIGN: Cross-sectional study with quantitative and qualitative components. METHODS: Two thousand and thirty-six adolescents attending schools in a city in Portugal were surveyed using a self reported, structured questionnaire. The qualitative component of the study included 30 semi-structured interviews that intended to assess the reasons for and consequences of drinking as perceived by adolescents, and also the preventive strategies they suggested. RESULTS: Overall, 50.0% of girls and 44.9% of boys reported that they had experimented with alcohol, and 4.7% of girls and 6.6% of boys drink alcohol at least once per month. Most adolescents recognised that drinking alcohol is harmful and an addiction which is difficult to treat, but this perception was not associated with their own behaviour. Adolescents only identified minor and temporary consequences of drinking alcohol, usually related to very high and acute consumption. In order to prevent alcohol abuse and its consequences, adolescents proposed measures based on strict control, legal restrictions and economic measures, some of which are already in place in Portugal. CONCLUSION: A high proportion of adolescents had experimented with alcohol by 13 years of age, showing the importance of starting prevention at an early life stage. The results also reflect the importance of reviewing prevention programmes in schools, highlighting the importance of families. PMID- 21704350 TI - Adipose-derived stromal cell transplantation for treatment of stress urinary incontinence. AB - We aimed to investigate the application of adipose-derived stromal cells in the treatment of stress urinary incontinence (SUI). Animal models of stress urinary incontinence were established with Sprague-Dawley female rats by complete cutting of the pudendal nerve. Rat adipose-derived stromal cells were isolated, cultured and successfully transplanted into animal models. Effects of stem cell transplantation were evaluated through urodynamic testing and morphologic changes of the urethra and surrounding tissues before and after transplantation. Main urodynamic outcome measures were measured. Intra-bladder pressure and leak point pressure were measured during filling phase. Morphologic examinations were performed. Transplantation of adipose-derived stem cells significantly strengthened local urethral muscle layers and significantly improved the morphology and function of sphincters. Urodynamic testing showed significant improvements in maximum bladder capacity, abdominal leak point pressure, maximum urethral closure pressure, and functional urethral length. Morphologic changes and significant improvement in urination control were consistent over time. It was concluded that periurethral injection of adipose-derived stromal cells improves function of the striated urethral sphincter, resulting in therapeutic effects on SUI. Reconstruction of the pelvic floor through transplantation of adipose-derived cells is a minimally invasive and effective treatment for SUI. PMID- 21704351 TI - Co-expression of four baculovirus proteins, IE1, LEF3, P143, and PP31, elicits a cellular chromatin-containing reticulate structure in the nuclei of uninfected cells. AB - Baculovirus DNA replication, transcription, and nucleocapsid assembly occur within a subnuclear structure called the virogenic stroma (VS) that consists of two subcompartments. Specific components of the VS sub-compartments have not been identified except for PP31, a DNA-binding protein that localizes specifically to the electron-dense region of VS. Here, we investigate the dynamic structure of VS using a GFP-tagged PP31 molecule (GFP-PP31). GFP-PP31 localizes to the VS throughout the course of infection. At later times post-infection, a PP31 reticulum distributed within VS was also apparent, indicating that VS sub compartments compose a reticulate structure. Transient expression of PP31 with the viral proteins, IE1, LEF3, and P143, in uninfected cells resulted in the formation of a reticulate structure containing cellular chromatin and the spatial arrangements of the four proteins within the induced reticulum were the same as those within VS reticulum, suggesting that the two reticula are formed by a similar mechanism. PMID- 21704352 TI - Kinetic modelling and microbial community assessment of anaerobic biphasic fixed film bioreactor treating distillery spent wash. AB - Anaerobic digestion, microbial community structure and kinetics were studied in a biphasic continuously fed, upflow anaerobic fixed film reactor treating high strength distillery wastewater. Treatment efficiency of the bioreactor was investigated at different hydraulic retention times (HRT) and organic loading rates (OLR 5-20 kg COD m-3 d-1). Applying the modified Stover-Kincannon model to the reactor, the maximum removal rate constant (U(max)) and saturation value constant (K(B)) were found to be 2 kg m-3 d-1 and 1.69 kg m-3 d-1 respectively. Bacterial community structures of acidogenic and methanogenic reactors were assessed using culture-independent analyses. Sequencing of 16S rRNA genes exhibited a total of 123 distinct operational taxonomic units (OTUs) comprising 49 from acidogenic reactor and 74 (28 of eubacteria and 46 of archaea) from methanogenic reactor. The findings reveal the role of Lactobacillus sp. (Firmicutes) as dominant acid producing organisms in acidogenic reactor and Methanoculleus sp. (Euryarchaeotes) as foremost methanogens in methanogenic reactor. PMID- 21704353 TI - Bioanalytical tools for the evaluation of organic micropollutants during sewage treatment, water recycling and drinking water generation. AB - A bioanalytical test battery was used for monitoring organic micropollutants across an indirect potable reuse scheme testing sites across the complete water cycle from sewage to drinking water to assess the efficacy of different treatment barriers. The indirect potable reuse scheme consists of seven treatment barriers: (1) source control, (2) wastewater treatment plant, (3) microfiltration, (4) reverse osmosis, (5) advanced oxidation, (6) natural environment in a reservoir and (7) drinking water treatment plant. Bioanalytical results provide complementary information to chemical analysis on the sum of micropollutants acting together in mixtures. Six endpoints targeting the groups of chemicals with modes of toxic action of particular relevance for human and environmental health were included in the evaluation: genotoxicity, estrogenicity (endocrine disruption), neurotoxicity, phytotoxicity, dioxin-like activity and non-specific cell toxicity. The toxicity of water samples was expressed as toxic equivalent concentrations (TEQ), a measure that translates the effect of the mixtures of unknown and potentially unidentified chemicals in a water sample to the effect that a known reference compound would cause. For each bioassay a different representative reference compound was selected. In this study, the TEQ concept was applied for the first time to the umuC test indicative of genotoxicity using 4-nitroquinoline as the reference compound for direct genotoxicity and benzo[a]pyrene for genotoxicity after metabolic activation. The TEQ were observed to decrease across the seven treatment barriers in all six selected bioassays. Each bioassay showed a differentiated picture representative for a different group of chemicals and their mixture effect. The TEQ of the samples across the seven barriers were in the same order of magnitude as seen during previous individual studies in wastewater and advanced water treatment plants and reservoirs. For the first time a benchmarking was performed that allows direct comparison of different treatment technologies and covers several orders of magnitude of TEQ from highly contaminated sewage to drinking water with TEQ close or below the limit of detection. Detection limits of the bioassays were decreased in comparison to earlier studies by optimizing sample preparation and test protocols, and were comparable to or lower than the quantification limits of the routine chemical analysis, which allowed monitoring of the presence and removal of micropollutants post Barrier 2 and in drinking water. The results obtained by bioanalytical tools were reproducible, robust and consistent with previous studies assessing the effectiveness of the wastewater and advanced water treatment plants. The results of this study indicate that bioanalytical results expressed as TEQ are useful to assess removal efficiency of micropollutants throughout all treatment steps of water recycling. PMID- 21704354 TI - Effect of two-stage coagulant addition on coagulation-ultrafiltration process for treatment of humic-rich water. AB - A novel two-stage coagulant addition strategy applied in a coagulation ultrafiltration (UF) process for treatment of humic-rich water at neutral pH was investigated in this study. When aluminum sulfate (alum) doses were set at a ratio of 3:1 added during rapid mix stage and half way through flocculation stage, the integrated process of two-stage alum addition achieved almost the same organic matter removal as that of conventional one-stage alum addition at the same overall dose. Whereas membrane fouling could be effectively mitigated by the two-stage addition exhibited by trans-membrane pressure (TMP) developments. The TMP developments were found to be primarily attributed to external fouling on membrane surface, which was closely associated with floc characteristics. The results of jar tests indicated that the average size of flocs formed in two-stage addition mode roughly reached one half larger than that in one-stage addition mode, which implied a beneficial effect on membrane fouling reduction. Moreover, the flocs with more irregular structure and lower effective density resulted from the two-stage alum addition, which caused higher porosity of cake layer formed by such flocs on membrane surface. Microscopic observations of membrane surface demonstrated that internal fouling in membrane pores could be also remarkably limited by two-stage alum addition. It is likely that the freshly formed hydroxide precipitates were distinct in surface characteristics from the aged precipitates due to formation of more active groups or adsorption of more labile aluminum species. Consequently, the flocs could further connect and aggregate to contribute to preferable properties for filtration performance of the coagulation UF process. As a simple and efficient approach, two-stage coagulant addition strategy could have great practical significance in coagulation-membrane processes. PMID- 21704355 TI - Effect of average flow and capacity utilization on effluent water quality from US municipal wastewater treatment facilities. AB - There is increasing interest in decentralization of wastewater collection and treatment systems. However, there have been no systematic studies of the performance of small treatment facilities compared with larger plants. A statistical analysis of 4 years of discharge monthly report (DMR) data from 210 operating wastewater treatment facilities was conducted to determine the effect of average flow rate and capacity utilization on effluent biochemical oxygen demand (BOD), total suspended solids (TSS), ammonia, and fecal coliforms relative to permitted values. Relationships were quantified using generalized linear models (GLMs). Small facilities (40 m3/d) had violation rates greater than 10 times that of the largest facilities (400,000 m3/d) for BOD, TSS, and ammonia. For facilities with average flows less than 40,000 m3/d, increasing capacity utilization was correlated with increased effluent levels of BOD and TSS. Larger facilities tended to operate at flows closer to their design capacity while maintaining treatment suggesting greater efficiency. PMID- 21704356 TI - S100P, von Hippel-Lindau gene product, and IMP3 serve as a useful immunohistochemical panel in the diagnosis of adenocarcinoma on endoscopic bile duct biopsy. PMID- 21704357 TI - Evidence of neuroendocrine disruption in freshwater mussels exposed to municipal wastewaters. AB - The purpose of this study was to test the hypothesis that exposure to municipal effluents can disrupt the neuroendocrine system in Elliptio complanata freshwater mussels. The capacity of ozonation to mitigate these effects was also examined. Mussels were exposed for 14 days to a continuous flow of increasing concentrations of the effluent before and after ozonation. Neuroendocrinal effects were examined by tracking changes in acetylcholinesterase, glutamate, gamma-aminobutyrate, serotonin, dopamine and their respective adenylcyclase activities in synapse membranes, monoamine oxidase and vitellogenin-like proteins. Oxidative stress and damage were examined by superoxide dismutase and lipid peroxidation, respectively, in the visceral tissues. The results revealed that the exposure of freshwater mussels increased the levels of vitellogenin-like proteins in both the primary-treated and ozonated effluents, dopamine and glutamate, and decreased the turnover of the neurostimulant acetylcholine. Moreover, these endpoints were significantly correlated with oxidative stress and damage. A canonical analysis of the responses revealed that dopamine and the neuroexcitatory neuromediators--acetylcholesterase and glutamate--were the endpoints more strongly related with oxidative stress and damage. Mussel morphology and estrogenic biomarkers (vitellogenin-like proteins, gonad lipid stores) were also significantly related, albeit to a lesser extent, to oxidative stress and damage. In general, ozone treatment was not sufficient to mitigate the observed neuroendocrinal effects in freshwater mussels. We conclude that the continuous exposure of freshwater mussels to municipal wastewater effluents leads to neuroendrocinal alterations and to oxidative stress. PMID- 21704358 TI - A method to assess ecosystem services developed from soil attributes with stakeholders and data of four arable farms. AB - Ecosystem-service indicators and related accounting units are crucial for the development of decision frameworks for sustainable land management systems. With a management concept using ecosystem services, land-use expectations can be linked to quantifiable soil features in a defendable and transparent way. A method to define a set of site-specific ecosystem services and indication system for quantification was set-up and run. First, we interviewed a wide group of land users profiting from ecosystem services of the soil at four arable farms in the polder Hoeksche Waard (S-SE of Rotterdam, the Netherlands). Subsequently, site specific ecosystem services were defined and weighted according to land use expectations at different spatial and temporal scales. Second, a practical set of indicators was taken from 'Best Professional Judgment' and used to quantify the performance of the ecosystem services for these four farms. The indicators were derived from biotic and abiotic soil parameters. The performance of ecosystem services was related to a reference situation (MEP: maximum ecological potential) with the same land use and soil type combination (i.e., arable fields on silt loam) taken from the database of our national soil survey. In many cases, the performance of ecosystem services was relatively poor if compared to MEP. However, the performances of natural attenuation and/or climate-related services were better. In addition, the different management of these farms (i.e. conventional, intensive and organic farming) was reflected in the performance of the ecosystem services of their soils. Third, land management measures to improve the targeted ecosystem services were incorporated in the outlined method, but not worked out with illustrative field data in this study. Together with concordant data, we show opportunities for a quantification of ecosystem services to improve land-users' awareness and to assess management sustainability. PMID- 21704359 TI - Comparison of candidate serologic markers for type I and type II ovarian cancer. AB - OBJECTIVE: To examine the value of individual and combinations of ovarian cancer associated blood biomarkers for the discrimination between plasma of patients with type I or II ovarian cancer and disease-free volunteers. METHODS: Levels of 14 currently promising ovarian cancer-related biomarkers, including CA125, macrophage inhibitory factor-1 (MIF-1), leptin, prolactin, osteopontin (OPN), insulin-like growth factor-II (IGF-II), autoantibodies (AAbs) to eight proteins: p53, NY-ESO-1, p16, ALPP, CTSD, B23, GRP78, and SSX, were measured in the plasma of 151 ovarian cancer patients, 23 with borderline ovarian tumors, 55 with benign tumors and 75 healthy controls. RESULTS: When examined individually, seven candidate biomarkers (MIF, Prolactin, CA-125, OPN, Leptin, IGF-II and p53 AAbs) had significantly different plasma levels between type II ovarian cancer patients and healthy controls. Based on the receiver operating characteristic (ROC) curves constructed and area under the curve (AUC) calculated, CA125 exhibited the greatest power to discriminate the plasma samples of type II cancer patients from normal volunteers (AUC 0.9310), followed by IGF-II (AUC 0.8514), OPN (AUC 0.7888), leptin (AUC 0.7571), prolactin (AUC 0.7247), p53 AAbs (AUC 0.7033), and MIF (AUC 0.6992). p53 AAbs levels exhibited the lowest correlation with CA125 levels among the six markers, suggesting the potential of p53 AAbs as a biomarker independent of CA125. Indeed, p53 AAbs increased the AUC of ROC curve to the greatest extent when combining CA125 with one of the other markers. At a fixed specificity of 100%, the addition of p53 AAbs to CA125 increased sensitivity from 73.8% to 85.7% to discriminate type II cancer patients from normal controls. Notably, seropositivity of p53 AAbs is comparable in type II ovarian cancer patients with negative and positive CA125, but has no value for type I ovarian cancer patients. CONCLUSIONS: p53 AAbs might be a useful blood-based biomarker for the detection of type II ovarian cancer, especially when combined with CA125 levels. PMID- 21704360 TI - Problem solving to improve adherence and asthma outcomes in urban adults with moderate or severe asthma: a randomized controlled trial. AB - BACKGROUND: Improving inhaled corticosteroid (ICS) adherence should improve asthma outcomes. OBJECTIVE: In a randomized controlled trial we tested whether an individualized problem-solving (PS) intervention improves ICS adherence and asthma outcomes. METHODS: Adults with moderate or severe asthma from clinics serving urban neighborhoods were randomized to PS (ie, defining specific barriers to adherence, proposing/weighing solutions, trying the best, assessing, and revising) or standard asthma education (AE) for 3 months and then observed for 3 months. Adherence was monitored electronically. Outcomes included the following: asthma control, FEV(1), asthma-related quality of life, emergency department (ED) visits, and hospitalizations. In an intention-to-treat-analysis longitudinal models using random effects and regression were used. RESULTS: Three hundred thirty-three adults were randomized: 49 +/- 14 years of age, 72% female, 68% African American, 7% Latino, mean FEV(1) of 66% +/- 19%, and 103 (31%) with hospitalizations and 172 (52%) with ED visits for asthma in the prior year. There was no difference between groups in overall change in any outcome (P > .20). Mean adherence (61% +/- 27%) decreased significantly (P = .0004) over time by 14% and 10% in the AE and PS groups, respectively. Asthma control improved overall by 15% (P = .002). In both groups FEV(1) and quality of life improved by 6% (P = .01) and 18% (P < .0001), respectively. However, the improvement in FEV(1) only occurred during monitoring but not subsequently after randomization. Rates of ED visits and hospitalizations did not significantly decrease over the study period. CONCLUSION: PS was not better than AE in improving adherence or asthma outcomes. However, monitoring ICS use with provision of medications and attention, which was imposed on both groups, was associated with improvement in FEV(1) and asthma control. PMID- 21704361 TI - Lesional dendritic cells in patients with chronic atopic dermatitis and psoriasis exhibit parallel ability to activate T-cell subsets. AB - BACKGROUND: Atopic dermatitis (AD) and psoriasis represent polar immune diseases. AD is a T(H)2/T(H)22-dominant disease, whereas psoriasis is considered a T(H)1/T(H)17 disease. Local immune deviation is suggested to be regulated by dendritic cell (DC)-induced T-cell polarization and recruitment of specific T cell subsets by chemokines. Although the role of chemokines is well documented, the actual contribution of DCs to activate polar T-cell subsets in human subjects is still a matter of speculation. OBJECTIVE: We sought to elucidate the significance of each cutaneous DC subset in disease-specific T-cell immune deviation. METHODS: We performed a comprehensive analysis of major cutaneous resident (Langerhans cells and blood dendritic cell antigen 1-positive dermal DCs) and inflammatory (inflammatory dendritic epidermal cells and blood dendritic cell antigen 1-negative dermal DCs) DC subsets directly isolated from the lesional skin of patients with AD and those with psoriasis. RESULTS: The ability of each DC subset to expand T(H)1, T(H)2, T(H)17, and T(H)22 subsets was similar between the 2 diseases, despite the association of both with accumulation of resident and inflammatory DCs. We also confirmed differential upregulation of chemokine expression in patients with AD (CCL17, CCL18, and CCL22) and psoriasis (CXCL1, IL-8, and CCL20). The expression of CCL17 and CCL22 was higher in Langerhans cells from patients with AD than from patients with psoriasis, whereas the opposite was observed for CXCL9 and CXCL10. CONCLUSION: Our results suggest that DC polarity does not directly drive differential T-cell subset responses. Alternatively, disease-specific chemokines might recruit specific memory T-cell subsets into the skin, which in turn might be activated and expanded by DCs at the site of inflammation, maintaining differential immune polarity in these diseases. PMID- 21704363 TI - Successful canakinumab treatment identifies IL-1beta as a pivotal mediator in Schnitzler syndrome. PMID- 21704362 TI - Associations among maternal childhood socioeconomic status, cord blood IgE levels, and repeated wheeze in urban children. AB - BACKGROUND: Independent of current socioeconomic status (SES), past maternal SES might influence asthma outcomes in children. OBJECTIVE: We examined associations among the mother's SES in the first 10 years of her life (maternal childhood SES), increased cord blood IgE levels (upper 20% [1.37 IU/mL]), and repeated wheeze (>= 2 episodes by age 2 years) in an urban pregnancy cohort (n = 510). METHODS: Data on sociodemographics, discrimination, financial strain, community violence, interpersonal trauma, and other negative events were obtained prenatally. Prenatal household dust was assayed for cockroach and murine allergens, and traffic-related air pollution was estimated by using spatiotemporal land-use regression. Maternal childhood SES was defined by parental home ownership (birth to 10 years). Maternally reported child wheeze was ascertained at 3-month intervals from birth. Using structural equation models, we examined whether outcomes were dependent on maternal childhood SES directly versus indirect relationships operating through (1) cumulative SES-related adversities, (2) the mother's socioeconomic trajectory (adult SES), and (3) current prenatal environmental exposures. RESULTS: Mothers were largely Hispanic (60%) or black (28%), 37% had not completed high school, and 56% reported parental home ownership. When associations between low maternal childhood SES and repeated wheeze were examined, there were significant indirect effects operating through adult SES and prenatal cumulative stress (beta = 0.28, P = .003) and pollution (beta = 0.24, P = .004; P value for total indirect effects <= .04 for both pathways). Low maternal childhood SES was directly related to increased cord blood IgE levels (beta = 0.21, P = .003). Maternal cumulative adversity (interpersonal trauma) was also associated with increased cord blood IgE levels (beta = 0.19, P = .01), although this did not explain maternal childhood SES effects. CONCLUSION: Lower maternal childhood SES was associated with increased cord blood IgE levels and repeated wheeze through both direct and indirect effects, providing new insights into the role of social inequalities as determinants of childhood respiratory risk. PMID- 21704364 TI - Genetics and phenotyping in chronic sinusitis. AB - Chronic sinusitis with nasal polyposis historically has been treated as a single monolithic clinical disorder. Just as asthma is now accepted as numerous heterogeneous diseases, chronic sinusitis should also be viewed as comprising several diseases with varying causes, with each one characterized by distinct histologic and gene and protein expression patterns. This includes recognition of the need to define these diseases based on the presence or absence of an eosinophilic infiltrate but also on additional distinctions based on unique agents that drive their development and perpetuation. As a collection of heterogeneous diseases, proper differential diagnosis is required to delineate appropriate therapeutic intervention. This review will focus on recognized distinct presentations of chronic sinus disease, including distinguishing the clinical presentations, cellular and molecular characteristics, genetic differences, and current treatment options for each. PMID- 21704365 TI - Metal speciation and toxicity of Tamar Estuary water to larvae of the Pacific oyster, Crassostrea gigas. AB - As part of the PREDICT Tamar Workshop, the toxicity of estuarine waters in the Tamar Estuary (southwest England) was assessed by integration of metal speciation determination with bioassays. High temporal resolution metal speciation analysis was undertaken in situ by deployment of a Voltammetric In situ Profiling (VIP) system. The VIP detects Cd (cadmium), Pb (lead) and Cu (copper) species smaller than 4 nm in size and this fraction is termed 'dynamic' and considered biologically available. Cadmium was mainly present in the dynamic form and constituted between 56% and 100% of the total dissolved concentration, which was determined subsequently in the laboratory in filtered discrete samples. In contrast, the dynamic Pb and Cu fractions were less important, with a much larger proportion of these metals associated with organic ligands and/or colloids (45 90% Pb and 46-85% Cu), which probably reduced the toxicological impact of these elements in this system. Static toxicity tests, based on the response of Crassostrea gigas larva exposed to discrete water samples showed a high level of toxicity (up to 100% abnormal development) at two stations in the Tamar, particularly during periods of the tidal cycle when the influence of more pristine coastal water was at its lowest. Competitive ligand-exchange Cu titrations showed that natural organic ligands reduced the free cupric ion concentration to levels that were unlikely to have been the sole cause of the observed toxicity. Nonetheless, it is probable that the combined effect of the metals determined in this work contributed significantly to the bioassay response. PMID- 21704366 TI - Uniform zwitterionic polymer hydrogels with a nonfouling and functionalizable crosslinker using photopolymerization. AB - We reported previously the design and synthesis of a zwitterionic carboxybetaine dimethacrylate crosslinker, and we showed that its use with zwitterionic carboxybetaine methacrylate led to nonfouling hydrogels with high mechanical properties and high hydration. Now, we use photopolymerization to improve the uniformity of the polymer network, resulting in drastically improved mechanical properties (compressive modulus up to 90 MPa). Furthermore, we designed and synthesized a new functionalizable carboxybetaine dimethacrylate crosslinker, enabling functionalization of the higher strength hydrogels against a nonfouling background. Additionally, the biostability of the carboxybetaine hydrogel systems was tested, and it was found that these hydrogels are stable in oxidative, acidic, and basic environments. PMID- 21704367 TI - Proliferation, differentiation and gene expression of osteoblasts in boron containing associated with dexamethasone deliver from mesoporous bioactive glass scaffolds. AB - Boron is one of the trace elements in the human body which plays an important role in bone growth. Porous mesopore bioactive glass (MBG) scaffolds are proposed as potential bone regeneration materials due to their excellent bioactivity and drug-delivery ability. The aims of the present study were to develop boron containing MBG (B-MBG) scaffolds by sol-gel method and to evaluate the effect of boron on the physiochemistry of B-MBG scaffolds and the response of osteoblasts to these scaffolds. Furthermore, the effect of dexamethasone (DEX) delivery in B MBG scaffold system was investigated on the proliferation, differentiation and bone-related gene expression of osteoblasts. The composition, microstructure and mesopore properties (specific surface area, nano-pore volume and nano-pore distribution) of B-MBG scaffolds have been characterized. The effect of boron contents and large-pore porosity on the loading and release of DEX in B-MBG scaffolds were also investigated. The results have shown that the incorporation of boron into MBG scaffolds slightly decreases the specific surface area and pore volume, but maintains well-ordered mesopore structure and high surface area and nano-pore volume compared to non-mesopore bioactive glass. Boron contents in MBG scaffolds did not influence the nano-pore size distribution or the loading and release of DEX. B-MBG scaffolds have the ability to maintain a sustained release of DEX in a long-term span. Incorporating boron into MBG glass scaffolds led to a controllable release of boron ions and significantly improved the proliferation and bone-related gene expression (Col I and Runx2) of osteoblasts. Furthermore, the sustained release of DEX from B-MBG scaffolds significantly enhanced alkaline phosphatase (ALP) activity and gene expressions (Col I, Runx2, ALP and BSP) of osteoblasts. These results suggest that boron plays an important role in enhancing osteoblast proliferation in B-MBG scaffold system and DEX-loaded B-MBG scaffolds show great potential as a release system to enhance osteogenic property for bone tissue engineering application. PMID- 21704368 TI - Oral bioavailability, therapeutic efficacy and reactive oxygen species scavenging properties of coenzyme Q10-loaded polymeric nanoparticles. AB - The present investigation consists in the development and characterization of CoQ10 loaded PLGA nanoparticles (CoQ10-NPs, size < 100 nm) by a scalable emulsion diffusion-evaporation method. Thermal and crystallinity analysis collectively corroborated that CoQ10 was entrapped into the NPs in amorphous form. The lyophilized CoQ10-NPs were found to be stable for a period of 6 months (at room temperature). In vitro cell culture studies indicated that CoQ10-NPs significantly quenched ROS with nearly 10 fold higher efficacy than free CoQ10. Further, positively charged CoQ10-NPs were localized in two major sources of ROS generation: mitochondria and lysosomes. CoQ10-NPs showed improved oral bioavailability (4.28 times) as compared to free CoQ10. Finally remarkably higher hepatoprotective and anti-inflammatory activity of CoQ10-NPs as compared to free CoQ10 was observed due to mitigation of deleterious effects associated with the generation of free radicals. As elucidated by live noninvasive animal imaging, the higher anti-inflammatory activity of CoQ10-NPs can be attributed to significant accumulation of these NPs in the inflamed tissues. PMID- 21704369 TI - A phosphate-dependent shift in redox state of cerium oxide nanoparticles and its effects on catalytic properties. AB - Cerium oxide nanoparticles (CeNPs) have shown promise as catalytic antioxidants in cell culture and animal models as both superoxide dismutase and catalase mimetics. The reactivity of the cerium (Ce) atoms at the surface of its oxide particle is critical to such therapeutic properties, yet little is known about the potential for a protein or small molecule corona to form on these materials in vivo. Moreover Ce atoms in these active sites have the potential to interact with small molecule anions, peptides, or sugars when administered in culture or animal models. Several nanomaterials have been shown to alter or aggregate under these conditions, rendering them less useful for biomedical applications. In this work we have studied the change in catalytic properties of CeNPs when exposed to various biologically relevant conditions in vitro. We have found that CeNPs are resistant to broad changes in pH and also not altered by incubation in cell culture medium. However to our surprise phosphate anions significantly altered the characteristics of these nanomaterials and shifted the catalytic behavior due to the binding of phosphate anions to cerium. Given the abundance of phosphate in biological systems in an inorganic form, it is likely that the action of CeNPs as a catalyst may be strongly influenced by the local concentration of phosphate in the cells and/or tissues in which it has been introduced. PMID- 21704370 TI - ABCA1 and placental cholesterol efflux. PMID- 21704371 TI - Alemtuzumab based reduced intensity conditioning allogeneic haematopoietic stem cell transplantation for myelofibrosis. AB - We report the results of 11 patients myelofibrosis, who have received a uniform alemtuzumab-based RIC HSCT. The median recipient age was 51 years. Stem cells were obtained from 8 full HLA-matched and 3 HLA-mismatched donors. The 2-year OS and TRM at 2-years was 46% and 54% with no disease relapse observed. For patients with a full HLA-matched donor, the 2-year TRM and OS was 37.5% and 62.5%. All 4 JAK2 V617F mutant positive patients achieved molecular remission after a median of 90 days post-transplant, and the median time to regression of bone marrow fibrosis was 180 days. PMID- 21704372 TI - Validation of a scoring system to establish the probability of myelodysplastic syndrome in patients with unexplained cytopenias or macrocytosis. AB - Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders primarily seen in the elderly that are characterized by ineffective hematopoiesis and a propensity to develop AML. Clinicians may be hesitant to refer older patients with unexplained cytopenias and/or macrocytosis for a bone marrow biopsy (BM), and consequently undiagnosed patients may be deprived access to effective treatments. Previously, we described factors which were independently predictive of a diagnosis of MDS at time of bone marrow: age >=65, mean cell volume (MCV), red cell distribution width (RDW), and lactate dehydrogenase (LDH), and suggested a scoring system to calculate the post-test probability of MDS [1]. In this study we validate this scoring system in a cohort of 313 individuals who underwent bone marrow examinations for the investigation of unexplained cytopenias and or macrocytosis over a 3 year period at our institution (2006-2008). Thirty-two percent of all patients were diagnosed with MDS and 9% had suspected MDS. The post-test likelihood of a diagnosis of MDS increased from 12% when none of the four identified factors were present to 48% when 3 or more factors were present. This scoring system can be used to guide the diagnostic testing of patients presenting with unexplained cytopenias or macrocytosis. PMID- 21704373 TI - Responses of Lyngbya magnifica Gardner to an algaecide exposure in the laboratory and field. AB - Predicting responses of organisms exposed to toxic materials in the field from results produced in laboratory studies and confirming those predictions has been a central question in aquatic toxicology since its inception. A field treatment of a cyanobacterium and laboratory measurements of responses to algaecide exposures provided an opportunity to address that question. This research involved predicting the response of Lyngbya magnifica to an algaecide exposure (Phycomycin SCP) in the laboratory and evaluating that prediction with a comparable exposure in the field. Based on the results from initial laboratory experiments, an effective algaecide and concentration (i.e. 92 mg Phycomycin SCP/g algae) were selected for field application in a farm pond. L. magnifica chlorophyll a and biomass were measured initially and 1, 4, 7, 10, and 21 days after treatment (DAT) for both laboratory and field exposures. Measurements of chlorophyll a decreases in the field treatment at 7, 10, and 21 days after treatment were significantly greater than responses obtained in similar laboratory exposures of Phycomycin SCP. Biomass was significantly decreased in the field at 21 DAT compared to laboratory measurements. This approach can be effective for site specific predictions and can provide valuable information for informed decisions regarding water resource management and should be included in a management plan for increased product efficiency and ecological safety. PMID- 21704374 TI - Regional risk assessment for contaminated sites part 2: ranking of potentially contaminated sites. AB - Environmental risks are traditionally assessed and presented in non spatial ways although the heterogeneity of the contaminants spatial distributions, the spatial positions and relations between receptors and stressors, as well as the spatial distribution of the variables involved in the risk assessment, strongly influence exposure estimations and hence risks. Taking into account spatial variability is increasingly being recognized as a further and essential step in sound exposure and risk assessment. To address this issue an innovative methodology which integrates spatial analysis and a relative risk approach was developed. The purpose of this methodology is to prioritize sites at regional scale where a preliminary site investigation may be required. The methodology aimed at supporting the inventory of contaminated sites was implemented within the spatial decision support sYstem for Regional rIsk Assessment of DEgraded land, SYRIADE, and was applied to the case-study of the Upper Silesia region (Poland). The developed methodology and tool are both flexible and easy to adapt to different regional contexts, allowing the user to introduce the regional relevant parameters identified on the basis of user expertise and regional data availability. Moreover, the used GIS functionalities, integrated with mathematical approaches, allow to take into consideration, all at once, the multiplicity of sources and impacted receptors within the region of concern, to assess the risks posed by all contaminated sites in the region and, finally, to provide a risk-based ranking of the potentially contaminated sites. PMID- 21704375 TI - Chlorinated biphenyls and pesticides in migrating and resident seabirds from East and West Antarctica. AB - The unhatched eggs of the following seabirds were analyzed to quantify PCBs, hexachlorobenzene (HCB), alpha-, beta-, gamma-, delta-hexachlorocyclohexanes (HCHs), o,p' and p,p' isomers of DDT, DDD and DDE: resident Adelie (Pygoscelis adeliae, ADPE) and Emperor (Aptenodytes forsteri, EMPE) penguins, migrating snow petrel (Pagodroma nivea, SNPT) and South Polar skua (Catharacta maccormicki, SPSK) from the Ross Sea (East Antarctica); and migrating Brown skua (Catharacta antartica, BRSK) and resident ADPE from the Brainsfield Strait (West Antarctica). The general aims were to evaluate the contaminant accumulation in eggs of migrating and resident species in the two study areas, and to compare levels in penguins and skuas nesting in East and West Antarctica. PCB congener and HCH and DDT isomer profiles were also assessed. Comparisons were evaluated using seven PCB congeners (IUPAC nos. 28, 52, 101, 118+149, 138, 153, and 180), p,p'-DDE, SigmaDDTs, and SigmaHCHs. Higher contaminant concentrations were detected in migrating seabirds (South polar skua and brown skua)>sub-Antarctic species (snow petrel)>Antarctic species (penguins) from both the sampling sites, suggesting contamination events at lower latitudes for those birds migrating northward. HCHs showed the lowest concentrations in all species (from 0.03+/-0.03 ng/g wet wt in SPSK to 1.81+/-1.23 ng/g wet wt in ADPE from West Antarctica), and PCBs were the most abundant contaminants (from 4.34+/-2.15 ng/g wet wt. in EMPE to 53.41+/ 19.61 ng/g wet wt. in brown skua). Among pesticides, it is relevant the detection of p,p'-DDT in Adelie penguin from West Antarctica and in both species of skua; the detection of this pesticide can confirm its actual use in certain malaria endemic countries from where it is transferred through the long range transport to the polar regions. Contaminants did not show any significant temporal trend during a ten year time span, from 1994/95 to 2004/05, in organisms collected in East Antarctica and they did not indicate any latitudinal gradient along the Ross Sea coasts. PMID- 21704376 TI - Modeling of road traffic noise and estimated human exposure in Fulton County, Georgia, USA. AB - Environmental noise is a major source of public complaints. Noise in the community causes physical and socio-economic effects and has been shown to be related to adverse health impacts. Noise, however, has not been actively researched in the United States compared with the European Union countries in recent years. In this research, we aimed at modeling road traffic noise and analyzing human exposure in Fulton County, Georgia, United States. We modeled road traffic noise levels using the United States Department of Transportation Federal Highway Administration Traffic Noise Model implemented in SoundPLAN(r). After analyzing noise levels with raster, vector and facade maps, we estimated human exposure to high noise levels. Accurate digital elevation models and building heights were derived from Light Detection And Ranging survey datasets and building footprint boundaries. Traffic datasets were collected from the Georgia Department of Transportation and the Atlanta Regional Commission. Noise level simulation was performed with 62 computers in a distributed computing environment. Finally, the noise-exposed population was calculated using geographic information system techniques. Results show that 48% of the total county population [N=870,166 residents] is potentially exposed to 55 dB(A) or higher noise levels during daytime. About 9% of the population is potentially exposed to 67 dB(A) or higher noises. At nighttime, 32% of the population is expected to be exposed to noise levels higher than 50 dB(A). This research shows that large-scale traffic noise estimation is possible with the help of various organizations. We believe that this research is a significant stepping stone for analyzing community health associated with noise exposures in the United States. PMID- 21704377 TI - Analysis as border patrol: chemists along the boundary between pure food and real adulteration. AB - A disputed butter competition in Pennsylvania in 1895 brought the cultural, environmental, and scientific character of the Era of Adulteration to the fore. The incident put a spotlight on the confusing character of adulteration and the increasingly prominent role of chemical analysts in arbitrating that confusion. This article uses the case to explore the role scientific analysts played on the border between pure food products and adulterated ones, arguing that the scientists fighting adulteration gained credibility within a cultural environment where trust and confidence were problematic and an agricultural environment where spatial connections between producers and consumers were difficult to see. They were not just detectors of chemical impurities, but participants in a vital cultural arbitration. Characterizing them for their cultural role helps demonstrate that their practices and identity were (and remain) relevant for more than just detection and eradication, then and in the future. PMID- 21704378 TI - Expression of duck CCL19 and CCL21 and CCR7 receptor in lymphoid and influenza infected tissues. AB - Ducks are the natural host and reservoir of influenza viruses. We are interested in their immune responses to these viruses, to understand host-pathogen interactions and to develop effective agricultural vaccines. We identified duck homologues of the chemokines CCL19 and CCL21 and cloned their cognate receptor, CCR7. Conservation of key features, and expression in lymphoid tissues suggests that these chemokines are the direct orthologues of their mammalian counterparts. Mammalian CCL19 and CCL21 are responsible for the homing of dendritic cells and naive lymphocytes to secondary lymphoid tissues. The contribution of local tertiary lymphoid tissues may be important during influenza infection in ducks. Consistent with leukocyte recruitment, CCL19 and CCL21 transcripts are abundant in lung tissues at 1 day post-infection with highly pathogenic avian influenza A/Vietnam/1203/04 (H5N1) (VN1203). In contrast, expression in lung or intestine tissues infected with low pathogenic A/mallard/BC/500/05 (H5N2) (BC500) is not significant. Recruitment and aggregation of leukocytes is visible in the vicinity of major airways 3 days after infection with VN1203. Chemokine gene expression may serve as a useful marker to evaluate duck immune responses to natural infections and vaccine strains. PMID- 21704379 TI - Inhibition of anthrax toxins with a bispecific monoclonal antibody that cross reacts with edema factor as well as lethal factor of Bacillus anthracis. AB - Bacillus anthracis overwhelms its victims by way of two toxins, namely edema toxin and lethal toxin. Lethal toxin is formed by the combination of protective antigen with lethal factor while edema toxin is formed by the combination of Protective Antigen with edema factor. Overlapping regions between edema factor and lethal factor have been reported in past. For the first time, this study reports characterization of a bispecific monoclonal antibody (mAb), H10, which showed high affinity interaction with both edema factor and lethal factor of B. anthracis. H10 mAb not only neutralized the adenylate cyclase activity of edema toxin but it could also neutralize the cytotoxic activity of lethal toxin. Passive immunization with this antibody gave 100% protection to mice from in vivo challenge with lethal toxin and edema toxin. The results of this study suggest future application of this bispecific monoclonal antibody as passive immunization prophylactics in cases of B. anthracis exposure and infection. PMID- 21704380 TI - Bioactivity studies of rainbow trout (Oncorhynchus mykiss) interleukin-6: effects on macrophage growth and antimicrobial peptide gene expression. AB - Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates hematopoiesis, inflammation, immune responses and bone homeostasis in mammals. Fish IL-6 has been cloned in recent years but to date no functional studies have been reported. Thus, in this paper we present for the first time in fish the functional characterisation of IL-6, using rainbow trout (Oncorhynchus mykiss) as the fish model and with a focus on macrophage effects. Trout IL-6 (tIL-6) expression in macrophages could be induced by proinflammatory agents (LPS, polyI:C, and IL 1beta) and recombinant tIL-6 (rtIL-6) rapidly induced STAT3 phosphorylation and expression of SOCS-1 to -3, CISH and IRF-1, as seen in mammals. However, three findings in this study suggest a novel role of tIL-6 in fish. Firstly, macrophage growth was enhanced by rtIL-6 in vitro, suggesting that IL-6 produced during inflammatory events may promote macrophage proliferation locally. Secondly, rtIL 6 induced the expression of cathelicidin-2, an antimicrobial peptide with immune modulatory function, but down-regulated the expression of IL-1beta and TNF-alpha, indicating a role of IL-6 in host defence and also in limiting inflammation. Thirdly, rtIL-6 induced the expression of hepcidin in macrophages. In mammals hepcidin is antimicrobial but also regulates iron homeostasis by inhibiting iron absorption, and its expression is induced by IL-6 only in hepatocytes but not macrophages. Thus, in fish if IL-6 is induced in patrolling macrophages during sepsis this may act to reduce iron availability by induction of hepcidin expression and lead to iron deficiency, as a means to limit the spread of infection. PMID- 21704381 TI - Uveal melanoma: trends in incidence, treatment, and survival. AB - PURPOSE: To determine trends in incidence, treatment, and survival with primary uveal melanoma in the United States over a 36-year period from 1973 to 2008. DESIGN: Systematic review of existing databases. PARTICIPANTS: A total of 4070 patients with primary uveal melanoma (International Classification of Disease for Oncology [ICD-O-2] codes C69.3 [choroid], C69.4 [ciliary body and iris], and C69.2 [retina]) derived from the Surveillance, Epidemiology, and End Results (SEER) program database in the United States from 1973 to 2008. METHODS: The significance of trends in age-adjusted incidence, treatment, and 5-year relative survival rates were determined using chi-square testing and 95% confidence intervals (CIs). MAIN OUTCOME MEASURES: Age-adjusted incidence, form of treatment (surgery, radiation, or both), and 5-year relative survival rates. RESULTS: There were 4070 cases of uveal melanoma representing 3.1% of all recorded cases of melanoma. The majority of cases (98.3%) were reported by hospital inpatient/outpatient clinics. Histopathologic confirmation was available in 2804 cases (72.1% for all years). The mean age-adjusted incidence of uveal melanoma in the United States was 5.1 per million (95% CI, 4.8-5.3). The majority of cases (97.8%) occurred in the white population. There was a statistically significant variation of age-adjusted incidence between sexes (male = 5.8, 95% CI, 5.5-6.2; and female = 4.4, 95% CI, 4.2-4.7). A decreasing trend was observed in patients treated with surgery alone (93.8% for 1973-1975 vs. 28.3% for 2006-2008), whereas a corresponding increase was seen in those treated with radiation (1.8% for 1973 1975 vs. 62.5% for 2006-2008). No change in the 5-year relative survival rate (81.6%) was observed from 1973 to 2008. CONCLUSIONS: The age-adjusted incidence of uveal melanoma (5.1 per million) has remained unchanged from 1973 to 2008. Despite a shift toward more conservative treatments, survival has not improved during this time period. PMID- 21704383 TI - Stimulation of the nucleus accumbens as behavioral reward in awake behaving monkeys. AB - It has been known that monkeys will repeatedly press a bar for electrical stimulation in several different brain structures. We explored the possibility of using electrical stimulation in one such structure, the nucleus accumbens, as a substitute for liquid reward in animals performing a complex task, namely visual search. The animals had full access to water in the cage at all times on days when stimulation was used to motivate them. Electrical stimulation was delivered bilaterally at mirror locations in and around the accumbens, and the animals' motivation to work for electrical stimulation was quantified by the number of trials they performed correctly per unit of time. Acute mapping revealed that stimulation over a large area successfully supported behavioral performance during the task. Performance improved with increasing currents until it reached an asymptotic, theoretically maximal level. Moreover, stimulation with chronically implanted electrodes showed that an animal's motivation to work for electrical stimulation was at least equivalent to, and often better than, when it worked for liquid reward while on water control. These results suggest that electrical stimulation in the accumbens is a viable method of reward in complex tasks. Because this method of reward does not necessitate control over water or food intake, it may offer an alternative to the traditional liquid or food rewards in monkeys, depending on the goals and requirements of the particular research project. PMID- 21704382 TI - Central and hemicentral retinal vein occlusion: role of anti-platelet aggregation agents and anticoagulants. AB - OBJECTIVE: To investigate systematically the role of anti-platelet-aggregating drugs or anticoagulants in central retinal vein occlusion (CRVO) and hemi-CRVO. DESIGN: Cohort study. PARTICIPANTS: Six hundred eighty-six consecutive patients with CRVO (567 patients, 585 eyes) and nonischemic hemi-CRVO (119 patients, 122 eyes). METHODS: At first visit, all patients had a detailed ophthalmic and medical history (including the use of anti-platelet aggregating drugs or anticoagulants), and comprehensive ophthalmic and retinal evaluation. Visual evaluation was carried out by recording visual acuity, using the Snellen visual acuity chart, and visual fields with a Goldmann perimeter. The same ophthalmic evaluation was performed at each follow-up visit. At the initial visit, CRVO and hemi-CRVO were classified as nonischemic and ischemic. MAIN OUTCOME MEASURES: Visual acuity, visual fields, and severity of retinal hemorrhages. RESULTS: All 3 types of CRVO, showed a significantly greater severity of retinal hemorrhages among aspirin users than nonusers (P<0.001). Initial visual acuity and visual fields were significantly worse in aspirin users than nonusers in nonischemic CRVO and hemi-CRVO, but did not differ for ischemic CRVO. Among patients with nonischemic CRVO who initially had 20/60 or better visual acuity, there was a significant association of aspirin use with visual acuity deterioration. The odds ratio of visual acuity deterioration, adjusting for age, diabetes, ischemic heart disease, and hypertension, for aspirin users relative to nonusers was 2.24 (95% confidence interval [CI], 1.14-4.41; P = 0.020). Of those whose macular edema resolved, overall cumulative visual acuity outcome also suggested a higher percentage with deterioration among aspirin users, odds ratio for deterioration of 3.62 (95% CI, 0.97-13.54; P = 0.05) for aspirin users relative to nonusers. For the nonischemic CRVO patients with 20/70 or worse visual acuity at the initial visit, after resolution of macular edema, improvement in visual acuity was less likely in the aspirin users than in nonusers (odds ratio, 0.18; 95% CI, 0.04-0.72; P = 0.016). CONCLUSIONS: Findings of this study indicate that, for patients with CRVO and hemi-CRVO, the use of aspirin, other anti-platelet aggregating agents, or anticoagulants was associated with a worse visual outcome and no apparent benefit. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21704384 TI - PPARgamma and human trophoblast differentiation. AB - The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear receptor superfamily that controls in a ligand-dependent manner the expression of a large array of genes involved in the control of energy homeostasis and in cell differentiation, proliferation, apoptosis, and the inflammatory process. Unexpectedly, genetic studies performed in mice established that PPARgamma is essential for placental development. In the human placenta, PPARgamma is specifically expressed in the trophoblast, both endocrine villous and invasive extravillous cytotrophoblasts (EVCT). Activation of PPARgamma induces accumulation of lipids, villous trophoblast differentiation and inhibits trophoblast invasiveness. Oxidized LDLs that contain potential PPARgamma ligands, but not native LDL, induce PPARgamma transcriptional activity and inhibit trophoblast invasion in vitro. Recently, human cytomegalovirus (HCMV) was shown to activate trophoblastic PPARgamma for its own replication and consequently inhibits invasiveness of infected cytotrophoblasts. Analysis of PPARgamma target genes revealed trophoblastic factors described to control trophoblast invasiveness and surprisingly chorionic gonadotropin hormone (hCG), known to be mainly produced by the endocrine villous trophoblast. Analysis of hCG gene expression revealed opposite regulation by PPARgamma in the two trophoblast subtypes. Finally, a hyperglycosylated form of hCG (hCG-H) only produced by invasive EVCT was shown to promote trophoblast invasion. Together, these data underscore the major role of PPARgamma and its target genes, such as hCG, in the control of human trophoblast differentiation and invasion, and suggest that over activation of this nuclear receptor following HCMV infection or by excess of ligands at the maternal-fetal interface could impair implantation and placentation and therefore embryonic development. PMID- 21704385 TI - Interaction between interleukin-1 receptor 2 and Toll-like receptor 4, and cervical cytokines. AB - The objective was to assess the impact of genetic variation on cervical cytokine concentrations of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-8 and tumor necrosis factor alpha (TNF-alpha), and first, to determine if these variants interact with polymorphisms in Toll-like receptor 4 (TLR4) that were previously shown to associate with pro-inflammatory cervical cytokine concentrations, and second, to determine if findings are affected by bacterial vaginosis (BV). We examined 183 single nucleotide polymorphisms (SNPs) in 13 cytokine genes and receptors for associations with cervical cytokine levels in 188 African American and European American women. We tested for associations of gene-gene interactions between SNPs in TLR4 and cytokine gene and receptor polymorphisms with cervical pro-inflammatory cytokines. None of the single locus associations were significant after correction for multiple testing in either European Americans or African Americans. However, there were significant gene-gene interactions between IL-1R2 rs485127 and two SNPs in TLR4 (rs1554973 and rs7856729) with IL-1beta after correction for multiple testing. Our study demonstrates that interactions between TLR4 and IL-1R2 are associated with cervical pro-inflammatory cytokine concentrations. These results provide important insights into the possible regulatory mechanisms of the inflammatory response in the presence and absence of microbial disorders such as BV. Additionally, the observed differences in allele frequencies between African Americans and those of European descent may partially explain population disparity in pregnancy-related phenotypes that are cytokine concentration-dependent. PMID- 21704386 TI - Relationship between measures of inhibitory processes in patients with schizophrenia: role of substance abuse disorders. AB - Disruption of prepulse inhibition of the startle response (PPI) has been widely identified in patients with schizophrenia, as well as impairment in many domains of cognitive functioning. However, there is some controversy regarding the relationship between PPI and the different neuropsychological tasks assessing inhibition. This controversy may be due to the influence of other variables, such as substance abuse. We aimed to determine whether differences in inhibition in schizophrenia subjects were related to their pattern of substance use and whether there was a correlation between the changes in each process. PPI and neuropsychological functioning were studied in three groups of subjects with schizophrenia (N=73): tobacco dependents (ToD; n=22), multiple substance abusers (MSUD; n=31) and non-substance abusers (non-SUD; n=20). All subjects were assessed using PPI and neuropsychological tests (Stroop and Wisconsin Card Sorting Test [WCST]). ToD showed better pre-attentive inhibitory function compared to the other two groups, and MSUD showed lower resistance to interference. Furthermore, significant correlations were found between PPI, Stroop, and WCST. Our data suggest that there is a relationship between the different tasks assessing inhibition in schizophrenia, being affected by substance abuse history. We also found differences in inhibition capacity depending on substance abuse in patients with schizophrenia. PMID- 21704387 TI - Negative expectancy appraisals and defeatist performance beliefs and negative symptoms of schizophrenia. AB - Negative symptoms have clear functional implications in schizophrenia and are typically unresponsive to current treatments. The cognitive model of negative symptoms suggests that dysfunctional beliefs are influential in the development and maintenance of negative symptoms and schizophrenia. The current study reports on a preliminary investigation of a new measure of Negative Expectancy Appraisals (specifically beliefs about limited probability of success and perception of limited cognitive resources), and also evaluates whether dysfunctional beliefs are more closely linked to particular subdomains of negative symptoms. Sixty two individuals with schizophrenia completed measures of dysfunctional beliefs and were rated on negative symptoms. Analyses indicated that the endorsement of beliefs regarding low expectations for success and perception of limited resources (Negative Expectancy Appraisals) are robustly associated with diminished experience negative symptoms (avolition, asociality, and anhedonia), but are not associated with negative symptoms reflecting diminished expressivity (blunted affect, alogia). Similarly, Defeatist Performance Beliefs are modestly related to diminished experience, but not diminished expression, negative symptoms. Negative Expectancy Appraisals were also robustly linked to depressive symptoms. Results from the current study provide evidence that dysfunctional beliefs are clearly relevant to consider in relation to negative symptoms, and may represent a fruitful treatment target. PMID- 21704389 TI - Isolated right ventricular infarction as a cause for anterior (V1-V3) ST elevation - review of publications since 2006 and re-appraisal of direct vs reciprocal ST changes. PMID- 21704388 TI - Balancing act: deubiquitinating enzymes in the nervous system. AB - Many pathways important to the nervous system are regulated by the post translational conjugation of ubiquitin to target proteins. The reversal of ubiquitination, or deubiquitination, is equally critical to neuronal function. By countering protein ubiquitination, deubiquitinating enzymes (DUBs) help control neuronal fate determination, axonal pathfinding and synaptic communication and plasticity. The significance of DUBs to the nervous system is underscored by links to various neurological diseases. Owing to cell type or substrate specificity, certain DUBs might also represent therapeutic targets for neurodegeneration. Here, we review recent findings that have shaped our current understanding of emerging functions for DUBs in the nervous system. PMID- 21704390 TI - Regression of non-compaction in left ventricular non-compaction cardiomyopathy by cardiac contractility modulation. PMID- 21704391 TI - Effects of angiotensin II receptor blocker on myocardial endothelial-to mesenchymal transition in diabetic rats. AB - BACKGROUND: Emerging evidence has indicated that the endothelial-to-mesenchymal transition (EndMT) is a crucial event during early stages of cardiac fibrosis. In the present study, we first investigated the influence of Irbesartan (Irb) on myocardial EndMT in diabetic rats. METHODS: Diabetic rats were divided into two groups: the diabetic group (DM) and the Irb-treated group (DM+Irb). Wistar-Kyoto rats served as controls. The pathological changes were investigated by microscopy. Immunofluorescence was performed to evaluate the co-expression of CD31 and fibroblast-specific protein 1 (FSP1). FSP1 and alpha-SMA expressions were detected by RT-PCR and Western blot analysis. EndMT was also studied in human aortic endothelial cells (HAECs) that had been exposed to high glucose (HG) levels. RESULTS: Increased interstitial fibrosis was detected in the DM group. Double labeling revealed CD31 expression in FSP1-positive cells in the DM group, and this expression was diminished by Irb treatment (P<0.05). In vitro, we found that HG stimulated angiotensin II synthesis in HAECs. When HAECs were exposed to HG, some of the cells acquired a spindle-shaped morphology and demonstrated a loss of CD31 labeling, which was attenuated by Irb treatment. FSP1 and alpha-SMA mRNA and protein expression levels were markedly upregulated in diabetic rats compared to controls, and their expressions were inhibited by Irb treatment (P<0.05). CONCLUSION: The results provide the novel insight that an angiotensin II receptor blocker might prevent diabetic cardiomyopathy by abrogating EndMT in diabetic rats. PMID- 21704392 TI - Reduced right ventricular ejection fraction and increased mortality in chronic systolic heart failure patients receiving beta-blockers: insights from the BEST trial. AB - BACKGROUND: Right ventricular ejection fraction (RVEF) < 20% is an independent predictor of poor outcomes in patients with advanced chronic systolic heart failure (HF). The aim of this study was to examine if the adverse effect of abnormally reduced RVEF varies by the receipt of beta-blockers. METHODS: In the Beta-Blocker Evaluation of Survival Trial (BEST), 2708 patients with chronic advanced HF and left ventricular ejection fraction < 35%, receiving standard background therapy with renin-angiotensin inhibition, digoxin, and diuretics, were randomized to receive bucindolol or placebo. Of these 2008 had data on baseline RVEF, and 14% (146/1017) and 13% (125/991) of the patients receiving bucindolol and placebo respectively had RVEF < 20%. RESULTS: Among patients in the placebo group, all-cause mortality occurred in 33% and 43% of patients with RVEF >= 20% and < 20% respectively (unadjusted hazard ratios {HR}, 1.33; 95% confidence intervals {CI}, 0.99-1.78; p = 0.055 and adjusted HR, 0.99; 95% CI, 0.71-1.37; p = 0.934). Among those receiving bucindolol, all-cause mortality occurred in 28% and 49% of patients with RVEF >= 20% and < 20% respectively (unadjusted HR, 2.15; 95% CI, 1.65-2.80; p < 0.001 and adjusted HR, 1.50; 95% CI, 1.08-2.07; p = 0.016). These differences were statistically significant (unadjusted and adjusted p for interaction, 0.016 and 0.053 respectively). CONCLUSIONS: In ambulatory patients with chronic advanced systolic HF receiving renin-angiotensin inhibition, digoxin, and diuretics, RVEF < 20% had no intrinsic association with mortality. However, in those receiving additional therapy with bucindolol, RVEF < 20% had a significant independent association with increased risk of mortality. PMID- 21704393 TI - The regulatory effect of norepinephrine on connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF) expression in cultured cardiac fibroblasts. AB - BACKGROUND: Connective tissue growth factor (CTGF) and vascular endothelial cell growth factor (VEGF) have been implicated as important effectors during cardiac remodeling. This study tested the hypothesis that norepinephrine (NE) induces CTGF and VEGF gene and protein expression in cardiac fibroblasts (CF) and the CTGF/VEGF complex will have an effect on angiogenesis. METHODS AND RESULTS: Rats CF were cultured in NE (0.01 to 100 MUM) for 24h. CTGF and VEGF gene expression were measured by quantitative-PCR. CTGF protein and CTGF/VEGF complex were detected by Western blot. The effect of CTGF/VEGF complex on angiogenesis was detected by endothelial cell tube formation assay. VEGF antigen level, reactive oxygen species (ROS) production were measured by ELISA and DCFH-DiOxyQ assay respectively. NE at 0.01 MUM up-regulated CTGF mRNA and secretory protein expression significantly whereas at 100 MUM both gene and protein were down regulated significantly when compared with controls. At 0.01 to 0.1 MUM of NE, there was no change in VEGF gene and protein level. NE at 100 MUM increased VEGF gene and antigen level and ROS production significantly when compared with controls. CTGF/VEGF complex was found to inhibit the angiogenesis of endothelial cells. CONCLUSIONS: NE regulates CTGF and VEGF expression in a dose-dependent manner and via VEGF can induce angiogenesis. This work suggests NE may have an important role in ventricular remodeling. PMID- 21704394 TI - Soluble epoxide hydrolase and ischemic cardiomyopathy. AB - BACKGROUND: The development of cardiovascular disease has been linked to lowered levels of epoxyeicosatrienoic acids (EETs) in the cardiovascular system. Ischemic cardiomyopathy is caused by atherosclerotic lesions in multi-coronary arteries especially diffusive lesions, which can lead to severe myocardial dysfunction, heart enlargement, heart failure, or arrhythmia, and so on. The EETs are metabolized by the soluble epoxide hydrolase (sEH) encoded by the EPHX2 gene that has several known polymorphisms. CONTENT: The EPHX2 gene polymorphism is associated with sEH catalytic activity and various cardiovascular diseases. sEH is distributed in a variety of organs and tissues and regulated by multiple factors. Research in the area has led to the presence of multiple powerful soluble epoxide hydrolase inhibitors (sEHIs), whose molecular structure and function has been optimized gradually. sEHIs increase EETs' concentration by inhibiting hydration of EETs into their corresponding vicinal diols. EETs are important signaling molecules and known as endothelium-derived hyperpolarizing factors (EDHF). sEHIs have been developed for their ability to prevent atherosclerosis, dilate the coronary artery, promote angiogenesis, ameliorate postischemic recovery of heart contractile function, decrease ischemia/reperfusion injury, modulate postischemic arrhythmia, and prevent heart failure. SUMMARY: sEH is one of the etiological factors of cardiovascular diseases, and plays an important role in the progression of myocardium ischemia. This indicates that sEHIs provide a new method for the prevention and treatment of ischemic cardiomyopathy. PMID- 21704395 TI - Plasma ghrelin levels are closely associated with stenosis severity and morphology of angiographically-detected coronary atherosclerosis in patients with coronary artery disease. PMID- 21704396 TI - Cost-effectiveness of cardiac resynchronization therapy in patients with heart failure: the perspective of a middle-income country's public health system. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) improves symptoms and survival in patients with heart failure (HF). However, the devices used to deliver it are costly and can impose a significant burden to the relatively constrained health budgets of middle-income countries such as Brazil. METHODS: A Markov model was constructed, representing the follow-up of a hypothetical cohort of HF patients, with a 20-year time horizon. Input data were based on information from a Brazilian cohort of 316 HF patients, as well as meta-analyses of data on devices' effectiveness and risks. Stochastic and probabilistic sensitivity analyses were performed for all important variables in the model. Costs were expressed as International Dollars (Int$), by application of current purchasing power parity conversion rate. RESULTS: In the base-case analysis, the incremental cost-effectiveness ratio (ICER) of CRT over medical therapy was Int$ 15,723 per quality-adjusted life years (QALYs) gained. For CRT combined with an implantable cardioverter-defibrillator (ICD), ICER was Int$ 36,940/QALY over ICD alone, and Int$ 84,345/QALY over CRT alone. Sensitivity analyses showed that the model was generally robust, though susceptible to the cost of the devices, their impact on HF mortality, and battery longevity. CONCLUSIONS: CRT is cost-effective for HF patients in the Brazilian public health system scenario. In patients eligible for CRT, upgrade to CRT+ICD has an ICER above the World Health Organization willingness-to-pay threshold of three times the nation's Gross Domestic Product per Capita (Int$ 31,689 for Brazil). However, for ICD eligible patients, upgrade to CRT+ICD is marginally cost-effective. PMID- 21704397 TI - Missing diagnosis of preexcitation syndrome on ECG: clinical and electrophysiological significance. AB - Electrocardiographic criteria of preexcitation syndrome are sometimes not visible on ECG in sinus rhythm (SR). The purpose of the study was to evaluate the significance of unapparent preexcitation syndrome in SR, when overt conduction through accessory pathway (AP) was noted at atrial pacing. METHODS: Anterograde conduction through atrioventricular AP was identified at electrophysiological study (EPS) in 712 patients, studied for tachycardia (n=316), syncope (n=89) or life-threatening arrhythmia (n=55) or asymptomatic preexcitation syndrome (n=252). ECG in SR at the time of EPS was analysed. RESULTS: 78 patients (11%) (group I) had a normal ECG in SR and anterograde conduction over AP at atrial pacing; 634 (group II) had overt preexcitation in SR. Group I was as frequently asymptomatic (35%) as group II (35%), had as frequently tachycardias, syncope or life-threatening arrhythmia as group II (43, 5, 2% vs 43, 13, 8%). AP was more frequently left lateral in group I (57%) than in group II (36%)(p<0.001). AV re entrant tachycardia, atrial fibrillation (AF), antidromic tachycardia were induced as frequently in group I (54, 18, 10%) as in group II (54, 27, 7%). Malignant forms (induced AF with RR intervals between preexcited beats <250ms in control state or <200ms after isoproterenol) were as frequent in group I (11.5%) as II (14%). CONCLUSIONS: The frequency of unapparent preexcitation syndrome represents 11% of our population with anterograde conduction through an AP and could be underestimated. The risk to have a malignant form is as high as in patients with overt preexcitation syndrome in SR. PMID- 21704398 TI - Retention of provided identification for dogs and cats seen in veterinary clinics and adopted from shelters in Oklahoma City, OK, USA. AB - Personalized identification (ID) tags that contain contact information for the dog or cat owner can help assure lost animals are quickly reunited with their owners. The authors have previously reported that while the majority of pet owners stated that ID tags were very important, only a third responded that their pet wears an ID tag. The objective of this study was to evaluate if providing and putting on the pet a free collar and ID tag during an owner's visit to a veterinary hospital or spay/neuter facility increased the likelihood that the pet owners would actually keep the identification on their pet at least 6-8 weeks after they were placed on the pet. A second population of dogs and cats that were adopted from animal control and humane society shelters were also studied to assess retention of a collar and personalized ID tag. Telephone follow-up occurred a mean of 8 weeks after the tag was applied. Retaining and using the tag significantly increased for the veterinary group with 13.8% reporting their pets were currently wearing an ID tag pre-intervention, and 84.3% reporting their pets were currently wearing and ID tag post-intervention. Of the dogs and cats that were adopted, at follow-up 94% of owners reported their pets were currently wearing an ID tag. Approximately 5% of those who participated in the post intervention survey lost a pet and recovered that pet because of the ID tag. This suggests that ID tagging is an effective method to potentially decrease stray intake into shelters and return pets home. The data also support placing tags and collars directly on pets as a method to retain those ID tags and collars on the animals, thus increasing the likelihood they will be returned home if lost or during a disaster. PMID- 21704399 TI - miR-210 as a marker of chronic hypoxia, but not a therapeutic target in prostate cancer. AB - INTRODUCTION: Radiotherapy in combination with medical castration is the standard treatment for high-risk prostate cancer. Some relapses may be explained by the presence of radioresistant clones arising from hypoxic microenvironment. Since microRNAs (miR) are increased upon hypoxia, the aim of this study was to see whether miR-210 is a potential marker for hypoxia and/or a therapeutic target in prostate cancer. METHODS: Human LNCaP, DU145 or PC3 prostate cancer cells were exposed to normoxia or hypoxia for several hours. Gene expression of miR-210, miR 373 and several hypoxia markers were analyzed by Taqman and SYBR green qRT-PCR, respectively. Clonogenic survival after LNA miR-210 inhibitor (78 nM) and concomitant irradiation were evaluated. RESULTS: During anoxia, CAIX and VEGF expressions were dramatically increased. miR-210 expression increased during anoxia exposure, while basal miR-373 expression was low and remained stable upon anoxia. LNA miR-210 inhibitor decreased anoxic miR-210 expression by 90% and clonogenic survival under anoxia (p=0.01). However, no enhanced effect was observed when miR-210 inhibitor was combined with irradiation. CONCLUSION: miR 210 could be an interesting marker of chronic hypoxia irrespective of the androgen dependency and should, therefore, be tested as a prognostic marker in high risk prostate cancer patients. PMID- 21704400 TI - Detection of irradiation-induced, membrane heat shock protein 70 (Hsp70) in mouse tumors using Hsp70 Fab fragment. AB - BACKGROUND AND PURPOSE: The major stress-inducible heat shock protein 70 (Hsp70) is frequently overexpressed in highly aggressive tumors, and elevated intracellular Hsp70 levels mediate protection against apoptosis. Following therapeutic intervention, such as ionizing irradiation, translocation of cytosolic Hsp70 to the plasma membrane is selectively increased in tumor cells and therefore, membrane Hsp70 might serve as a therapy-inducible, tumor-specific target structure. MATERIALS AND METHODS: Based on the IgG1 mouse monoclonal antibody (mAb) cmHsp70.1, we produced the Hsp70-specific recombinant Fab fragment (Hsp70 Fab), as an imaging tool for the detection of membrane Hsp70 positive tumor cells in vitro and in vivo. RESULTS: The binding characteristics of Hsp70 Fab towards mouse colon (CT26) and pancreatic (1048) carcinoma cells at 4 degrees C were comparable to that of cmHsp70.1 mAb, as determined by flow cytometry. Following a temperature shift to 37 degrees C, Hsp70 Fab rapidly translocates into subcellular vesicles of mouse tumor cells. Furthermore, in tumor-bearing mice Cy5.5-conjugated Hsp70 Fab, but not unrelated IN-1 control Fab fragment (IN-1 ctrl Fab), gradually accumulates in CT26 tumors between 12 and 55 h after i.v. injection. CONCLUSIONS: In summary, the Hsp70 Fab provides an innovative, low immunogenic tool for imaging of membrane Hsp70 positive tumors, in vivo. PMID- 21704401 TI - Inhibition of tumor lactate oxidation: consequences for the tumor microenvironment. AB - BACKGROUND AND PURPOSE: Tumor cells are recognized as being highly glycolytic. However, recently it was suggested that lactate produced in hypoxic tumor areas may be taken up by the monocarboxylate transporter MCT1 and oxidized in well oxygenated tumor parts. Furthermore, it was shown that inhibition of lactate oxidation using the MCT1 inhibitor alpha-cyano-hydroxycinnamate (CHC) can radio sensitize tumors possibly by forcing a switch from lactate oxidization to glycolysis in oxygenated cells, which in turn improves tumor oxygenation and indirectly kills radio-resistant hypoxic tumor cells from glucose starvation. MATERIAL AND METHODS: To provide direct evidence for the existence of a targetable energetic symbiosis, mice bearing SiHa or FaDu(dd) tumors were treated with CHC for different time periods. One hour prior to sacrifice, mice were administered with the glucose analog fluorodeoxyglucose (FDG) and the hypoxia marker pimonidazole. Tumor cryosections were analyzed for regional glucose retention (FDG autoradiograms), hypoxia (pimonidazole retention) and glucose and lactate levels (bioluminescence imaging). RESULTS: Treatment did not influence metabolite concentrations, necrosis or extent of hypoxia, but pixel-by-pixel analysis comparing FDG retention and hypoxia (a measure of the apparent in vivo Pasteur effect) showed that CHC treatment caused a transient reduction in the Pasteur effect in FaDu(dd) 1.5 h following CHC administration whereas a reduction was only observed in SiHa following repeated treatments. CONCLUSIONS: In summary, our data show that CHC is able to influence the intratumoral distribution of glucose use between hypoxic and non-hypoxic tumor areas. That is in accordance with a functional tumor lactate-shuttle, but the absence of any detectable changes in hypoxic extent and tissue metabolites was unexpected and warrants further investigation. PMID- 21704402 TI - Oncolytic viruses in radiation oncology. AB - Oncolytic viruses are investigational cancer treatments. They are currently being assessed as single agents or in combination with standard therapies such as external beam radiotherapy - a DNA damaging agent that is a standard of care for many tumour types. Preclinical data indicate that combinations of oncolytic viruses and radiation therapy are promising, showing additional or synergistic antitumour effects in in vitro and in vivo studies. This interaction has the potential to be multifaceted: viruses may act as radiosensitizing agents, but radiation may also enhance viral oncolysis by increasing viral uptake, replication, gene expression and cell death (apoptosis, autophagy or necrosis) in irradiated cells. Phase I and II clinical trials investigating combinations of viruses and radiation therapy have been completed, paving the way for ongoing phase III studies. The aim of this review is to focus on the therapeutic potential of these combinations and to highlight their mechanistic bases, with particular emphasis on the role of the DNA damage response. PMID- 21704403 TI - ALK1 heterozygosity delays development of late normal tissue damage in the irradiated mouse kidney. AB - BACKGROUND AND PURPOSE: Activin receptor-like kinase 1 (ALK1) is a transforming growth factor beta (TGF-beta) receptor, which is mainly expressed in endothelial cells regulating proliferation and migration in vitro and angiogenesis in vivo. Endothelial cells also express the co-receptor endoglin, which modulates ALK1 effects on endothelial cells. Our previous studies showed that mice with reduced endoglin levels develop less irradiation-induced vascular damage and fibrosis, caused by an impaired inflammatory response. This study was aimed at investigating the role of ALK1 in late radiation toxicity. MATERIAL AND METHODS: Kidneys of ALK(+/+) and ALK1(+/-) mice were irradiated with 14 Gy. Mice were sacrificed at 10, 20, and 30 weeks after irradiation and gene expression and protein levels were analyzed. RESULTS: Compared to wild type littermates, ALK1(+/ ) mice developed less inflammation and fibrosis at 20 weeks after irradiation, but displayed an increase in pro-inflammatory and pro-fibrotic gene expression at 30 weeks. In addition, ALK1(+/-) mice showed superior vascular integrity at 10 and 20 weeks after irradiation which deteriorated at 30 weeks coinciding with changes in the VEGF pathway. CONCLUSIONS: ALK1(+/-) mice develop a delayed normal tissue response by modulating the inflammatory response and growth factor expression after irradiation. PMID- 21704404 TI - Ionizing radiation induces migration of glioblastoma cells by activating BK K(+) channels. AB - BACKGROUND AND PURPOSE: Glioblastoma cells express high levels of Ca(2+) activated BK K(+) channels which have been proposed to be indispensable for glioblastoma proliferation and migration. Since migration of glioblastoma cells is reportedly stimulated by ionizing radiation (IR), we tested for an IR-induced increase in BK channel activity and its effect on cell migration. MATERIALS AND METHODS: T98G and U87MG cells were X-ray-irradiated with 0-2 Gy, BK channel activity was assessed by patch-clamp recording, migration by trans-well migration assay, and activation of the Ca(2+)/calmodulin-dependent kinase II (CaMKII) by immunoblotting. RESULTS: IR dose-dependently stimulated migration of glioblastoma cells which was sensitive to the BK channel inhibitor paxilline. Ca(2+) permeabilization of T98G cells activated up to 350 BK channels per cells. Importantly, IR stimulated an increase in BK channel open probability but did not modify the total number of channels. Moreover, IR activated CaMKII in a paxilline sensitive manner. Finally, inhibition of CaMKII by KN-93 abolished the IR stimulated migration. CONCLUSIONS: We conclude that IR stimulates BK channel activity which results in activation of CaMKII leading to enhanced glioblastoma cell migration. PMID- 21704405 TI - Residual DNA and chromosomal damage in ex vivo irradiated blood lymphocytes correlated with late normal tissue response to breast radiotherapy. AB - PURPOSE: To test the association of DNA double-strand break (DSB) repair and chromosomal radiosensitivity in ex vivo irradiated blood lymphocytes with late onset normal tissue responses following breast radiotherapy. METHODS: Breast cancer patients with minimal (controls) or marked late radiotherapy changes (cases) were retrospectively selected. DSB were quantified by gammaH2AX/53BP1 immunofluorescence microscopy 0.5 and 24 h after exposure of unstimulated blood lymphocytes to 0.5 and 4 Gy X-rays, respectively. Chromosomal aberrations were scored in blood lymphocyte metaphases after 6 Gy X-rays. RESULTS: Despite similar foci levels at 0.5 h in cases (n=7) and controls (n=7), foci levels 24 h after 4 Gy irradiation differed significantly between them (foci per cell were 12.8 in cases versus 10.2 in controls, p=0.004). Increased chromosomal radiosensitivity was also observed in cases (aberrations per cell were 5.84 in cases versus 3.79 in controls, p=0.001) with exchange and deletion type aberrations contributing equally to the difference between cases and controls. Residual foci correlated with formation of deletions (Spearman's R=0.589, p=0.027) but not exchanges (R=0.367, p=0.197) in blood lymphocytes from the same patients. CONCLUSIONS: Higher levels of exchange type aberrations observed among radiosensitive breast cancer patients suggest a role for DSB misrepair, in addition to residual damage, as determinants of late normal tissue damage. Correlation of residual foci levels with deletion type aberration yields in the same cohort confirms their mechanistic linkage. PMID- 21704406 TI - Dual targeting of EGFR and focal adhesion kinase in 3D grown HNSCC cell cultures. AB - PURPOSE: Epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK) show frequent overexpression and hyperactivity in various human malignancies including head and neck squamous cell carcinomas (HNSCC). To examine effects of dual EGFR/FAK inhibition on cellular radiosensitivity of HNSCC cells in a more physiological environment, we employed a previously established laminin-rich extracellular matrix (lrECM) based three-dimensional (3D) cell culture model. MATERIALS AND METHODS: UTSCC15 and SAS HNSCC cell lines stably transfected with EGFR-CFP or CFP were used. Single or combined EGFR (Cetuximab, siRNA) and FAK (TAE226, siRNA) inhibition were accomplished prior to measuring clonogenic survival and protein expression and phosphorylation. Immunofluorescence enabled visualization of EGFR-CFP and FAK. RESULTS: Cetuximab resulted in higher radiosensitization in EGFR-CFP overexpressing cell lines than CFP controls. Single EGFR or FAK inhibition mediated radiosensitization, while dual EGFR/FAK targeting further augmented this effect. Despite signaling alterations upon Cetuximab and siRNA knockdown, analysis of protein expression and phosphorylation indicates EGFR and FAK signaling coexistence without obvious overlap. CONCLUSIONS: Combined EGFR/FAK targeting yielded stronger radiosensitization than either approach alone, which might be based on non-overlapping downstream signaling. Whether dual targeting of EGFR and FAK can reasonably be combined with radiotherapy and chemotherapy needs clarification. PMID- 21704407 TI - TRIB3 protein denotes a good prognosis in breast cancer patients and is associated with hypoxia sensitivity. AB - BACKGROUND: Tribbles homolog 3 (TRIB3) is a pseudokinase involved in the regulation of several signaling pathways involved in cell survival and/or cell stress. Here, we determined the correlation between breast cancer prognosis and TRIB3 protein levels and established the role of TRIB3 in cell survival after hypoxia and/or radiotherapy. MATERIAL AND METHODS: TRIB3 mRNA and protein were quantified in a new independent breast cancer patient cohort using QPCR and a new specific avian antibody against TRIB3. In addition, we used siRNA-mediated knockdown of TRIB3 in a colony-forming assay after hypoxia and radiotherapy. RESULTS: TRIB3 mRNA and protein levels did not correlate in breast cancer cell lines or human breast cancer material. We validated our earlier finding that high TRIB3 mRNA denotes a poor prognosis, but found that high TRIB3 protein levels were associated with a good prognosis in breast cancer patients. We also show that knockdown of TRIB3 resulted in an increased survival under hypoxic conditions. CONCLUSION: Whereas mRNA levels of TRIB3 are related with a poor prognosis, TRIB3 protein is associated with a good prognosis in human breast cancer patients, possibly due to the fact that TRIB3 is involved in hypoxia tolerance. PMID- 21704408 TI - Nuclear epidermal growth factor receptor modulates cellular radio-sensitivity by regulation of chromatin access. AB - PURPOSE: Nuclear EGFR is involved in cellular stress management and regulation of cellular radio-sensitivity. The aim of this study was to elucidate the molecular mode of nuclear EGFR action. METHODS: Radiation induced nuclear EGFR-shuttling and EGFR-foci formation was analyzed with immunohistochemistry and confocal microscopy. Composition of gammaH(2)AX-protein complexes was analyzed by western blotting after immuno-precipitation. Functional relevance of nuclear EGFR was analyzed after siRNA mediated depletion of EGFR with respect to activation of ATM, histone H3 acetylation, residual DNA-damage and cell survival after irradiation. RESULTS: Following radiation nuclear EGFR was localized in foci similar to gammaH(2)AX. EGFR co-localized in a sub-fraction of gammaH(2)AX-foci. Analysis of composition of gammaH(2)AX-complexes revealed presence of EGFR, ATM, promyelocytic leukemia protein (PML), histone H3 and hetero-chromatin binding protein (HP1) in response to radiation. Depletion of EGFR protein inhibited ATM activation due to inhibition of acetylase TIP60 activity following irradiation. Consequently, histone H3 acetylation and phosphorylation was blocked and chromatin could not be opened for repair. Thus, residual DNA-damage was increased 24 h after irradiation and cells were radio-sensitized. Comparable results were obtained when cells were treated with EGFR-NLS-peptide, which blocks EGFR nuclear shuttling specifically. CONCLUSIONS: Nuclear EGFR is part of DNA-damage repair complex and is involved in regulation of TIP60-acetylase activity. TIP60 is essential for ATM activation and chromatin relaxation which is a prerequisite for DNA-repair in heterochromatic DNA. Thus interventional EGFR strategies during tumor treatment may also interact with DNA-repair by blocking access to damaged DNA. PMID- 21704409 TI - Retention of gammaH2AX foci as an indication of lethal DNA damage. AB - The application of biological responses of tumours to predict clinical responses to treatment represents a challenging goal with the potential to inform treatment decisions and improve outcome. If tumour cell death is the result of the inability of a cell to repair complex DNA damage, and if gammaH2AX foci mark sites of unrepaired double-strand breaks, then it may be possible to use residual gammaH2AX foci to identify treatment-resistant tumour cells early in the course of therapy. This review will highlight some of the evidence that supports the idea that residual gammaH2AX foci, within certain limitations, may be useful as an early indicator of tumour response to radiotherapy in situ, either alone or in combination with chemotherapy. PMID- 21704410 TI - Inhibition of STAT-3 results in greater cetuximab sensitivity in head and neck squamous cell carcinoma. AB - OBJECTIVE: The inhibition of epidermal growth factor receptor (EGFr) with the monoclonal antibody cetuximab reduces cell proliferation and survival which correlates with increased DNA damage. Since the signal transducer and activator of transcription-3 (STAT-3) is involved in the EGFr-induced signaling pathway, we hypothesized that depletion of STAT-3 may augment cetuximab-induced processes in human head and neck cancer cells. MATERIALS AND METHODS: Human head and neck squamous carcinoma cells (UM-SCC-5) were transfected with short hairpin RNA (shRNA) against STAT-3 (STAT3-2.4 and 2.9 cells). A mutated form of this shRNA was transfected for a control (NEG4.17 cells). Radiosensitivity was assessed by a standard colony formation assay. Proliferation was assessed by daily cell counts following treatment and apoptosis was assessed by an annexin V-FITC assay. The alkaline comet assay was used to assess DNA damage. RESULTS: The STAT-3 knockdown cells (STAT3-2.4 and STAT3-2.9 cells) demonstrated enhanced radiosensitivity compared to control NEG4.17 cells, which correlated with increased apoptosis. Also, the STAT-3 knockdown cells demonstrated decreased proliferation with cetuximab treatments compared to control cells (NEG4.17). The increased cetuximab sensitivity of the STAT-3 knockdown cells correlated with increased apoptosis and DNA damage compared to control cells (NEG4.17). CONCLUSION: These studies revealed that the greater anti-proliferative effects and increased cytotoxicity of cetuximab in the STAT3-2.4 and STAT3-2.9 cells compared to control NEG4.17 cells, may be a result of STAT3-mediated effects on cellular apoptosis and DNA damage. PMID- 21704411 TI - Selection of radioresistant tumor cells and presence of ALDH1 activity in vitro. AB - BACKGROUND: Tumor resistance to radiotherapy has been hypothesized to be mediated by a tumor subpopulation, called cancer stem cells (CSCs). Based on the proposed function of CSCs in radioresistance, we explored the cancer stem cell properties of cells selected for radioresistance phenotype. MATERIALS AND METHODS: A549 and SK-BR-3 cells were radioselected with four single doses of 4 or 3 Gy in intervals of 10-12 days and used for colony formation assay and gamma-H2AX foci formation assay. Expression of putative stem cell markers, i.e. Sox2, Oct4, ALDH1, and CD133 were analyzed using Western blotting. A549 and SK-BR-3 cells sorted based on their ALDH1 activity were analyzed in clonogenic survival assays. RESULTS: Radioselected A549 and SK-BR-3 cells (A549-R, SK-BR-3-R) showed increased radioresistance and A549-R cells presented enhanced repair of DNA-double strand breaks. PI3K inhibition significantly reduced radioresistance of A549-R cells. Cell line specific differences in the expression of the putative CSC markers Sox2 and Oct4 were observed when parental and radioselected cells were compared but could not be directly correlated to the radioresistant phenotype. However, enzyme activity of the putative stem cell marker ALDH1 showed a correlation to radioresistance. CONCLUSIONS: Subpopulations of pooled radioresistant colonies, selected by various radiation exposures were analyzed for the presence of putative stem cell markers. Although the pattern of Sox2, Oct4, and CD133 expression was not generally associated with radioresistance, presence of ALDH1 seems to be indicative for subpopulations with increased radioresistance. PMID- 21704412 TI - Radiobiology goes 3D: how ECM and cell morphology impact on cell survival after irradiation. AB - Translational research is essential to find new therapeutic approaches to improve cancer patient survival. Despite extensive efforts in preclinical studies, many novel therapies fail to turn out to be translational from bench to beside. Therefore, new models better reflecting the conditions in vivo are needed to generate results, which transfer reliably into the clinic. The use of three dimensional (3D) cell culture models has provided new emerging insights into the understanding of cellular behavior upon cancer therapies. Interestingly, cells cultured in a 3D extracellular matrix are more radio- and chemoresistant than cells grown under conventional 2D conditions. In this review, we summarize and discuss underlying mechanisms of this phenomenon including integrin-mediated cell matrix interactions, cell shape, nuclear organization and chromatin structure. Identifying the molecular differences between 2D and 3D cultured cells will offer the opportunity to improve our research and widen our therapeutic possibilities against cancer. PMID- 21704413 TI - Association between single nucleotide polymorphisms in the XRCC1 and RAD51 genes and clinical radiosensitivity in head and neck cancer. AB - PURPOSE: Individual variability in radiosensitivity is large in cancer patients. Single nucleotide polymorphisms (SNPs) in genes involved in DNA repair and in protection against reactive oxygen species (ROS) could be responsible for such cases of radiosensitivity. We investigated the association between the occurrence of acute reactions in 101 patients with squamous cell carcinoma of the head and neck (SCCHN) after radiotherapy (RT) and five genetic polymorphisms: XRCC1 c.1196A>G, XRCC3 c.722C>T, RAD51 (c.-3429G>C, c.-3392G>T), and GSTP1 c.313A>G. MATERIALS AND METHODS: Genetic polymorphisms were detected by high resolution melting analysis (HRMA). The development of acute reactions (oral mucositis, skin erythema and dysphagia) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for biologically effective dose (BED). RESULTS: Development of grade >=2 mucositis was increased in all patients (chemo radiotherapy and radiotherapy alone) with XRCC1-399Gln allele (HR=1.72). The likelihood of developing grade >=2 dysphagia was higher in carriers of RAD51 c. 3429 CC/GC genotypes (HR=4.00). The presence of at least one SNP or the co presence of both SNPs in XRCC1 p.Gln399Arg /RAD51 c.-3429 G>C status were associated to higher likelihood of occurrence of acute toxicities (HR=2.03). CONCLUSIONS: Our findings showed an association between genetic polymorphisms, XRCC1 c.1196A>G and RAD51 c.-3429 G>C, and the development of radiation-induced toxicities in SCCHN patients. PMID- 21704414 TI - DNA methylation changes in cells regrowing after fractioned ionizing radiation. AB - BACKGROUND AND PURPOSE: Repeated exposure to ionizing radiation (IR) can result in adaptive reactions. While DNA methylation changes in adaption to repeated stress exposure are established for a variety of drugs, their role in fractioned ionizing radiation is largely unknown. MATERIAL AND METHODS: MCF7 breast cancer cells were treated 5 times a week with IR in fractions of 2 Gy, resulting in total doses of 10 and 20 Gy. Cells were harvested 48 and 72 h after the last irradiation, as well as after a recovery period of at least 14 d. To identify genes differentially methylated in irradiated versus non-irradiated cells, we used methyl-CpG immunoprecipitation (MCIp) followed by global methylation profiling on CpG island microarrays. RESULTS: MCIp profiling revealed methylation changes in several CpG islands 48 h after FIR with 10 and 20 Gy. Cells receiving a total dose of 10 Gy started regrowing after 14 d and exhibited similar radioresistance as mock-treated cells. Differential methylation of the CpG units associated with FOXC1 (p<0.001) and TRAPPC9 (p<0.001) could be confirmed by time of-flight mass spectrometry (Sequenom). CONCLUSIONS: In summary, these data indicate that regrowth of MCF7 cells after 10 Gy FIR is associated with locus specific alterations in DNA methylation. PMID- 21704415 TI - MRI prostate radiation therapy planning: when the patient distorts his own image (Regarding Lambert et al., Radiother Oncol 2011; 98: 330-334). PMID- 21704416 TI - Radiation combined with hyperthermia induces HSP70-dependent maturation of dendritic cells and release of pro-inflammatory cytokines by dendritic cells and macrophages. AB - PURPOSE: Hyperthermia (HT) treatment of cancer patients was revived over the last years and has been proven to be beneficiary for many cancer entities when applied temperature controlled in multimodal treatments. We examined whether a combination of ionizing irradiation (X-ray) and HT (41.5 degrees C; 1 h) can induce the release of heat shock protein (HSP) 70 by tumor cells and thereby lead to the activation of dendritic cells and macrophages. MATERIAL AND METHODS: Extracellular HSP70 was detected in supernatants (SN) of treated colorectal tumor cells by ELISA. Maturation of dendritic cells (DC) after contact with the SN was measured by flow-cytometry. Phagocytosis assays were conducted to get hints about the immune stimulating potential of the tumor cells after the respective treatments. RESULTS: An increased surface expression of HSP70 was observed after X-ray or X-ray plus HT while the amount of extracellular HSP70 was only increased when HT was given additionally. A high up-regulation of the co-stimulation molecule CD80 and the chemokine receptor CCR7 on DC was measured after contact with SN of X-ray plus HT treated cells. This was dependent on extracellular HSP70. Combined treatments further led to significantly increased phagocytosis rates of macrophages and DC and increased pro-inflammatory cytokine (IL-8 and IL 12) secretion. CONCLUSION: X-ray combined with HT induces HSP70 dependent activation of immune cells and might generate a tumor microenvironment beneficial for cure. PMID- 21704417 TI - State-dependent corrective reactions for backward balance losses during human walking. AB - We investigated corrective reactions for backward balance losses during walking. Several biomechanical studies have suggested that backward falling can be predicted from the horizontal position and velocity of the body center of mass (COM) related to the stance foot. Our hypothesis was that corrective reactions for backward balance losses depend on whether the body moves forward or backward after a perturbation. Using a split-belt treadmill, backward balance losses during walking were induced by rapid decreases of belt speed from 3.5 km/h to 2.5, 2.0, 1.5 and 1.0 km/h. We measured kinematic data and surface electromyography (EMG) during corrective reactions while walking on the treadmill. Phase portrait analysis of COM trajectories revealed that backward balance stability was decreased by the perturbations. When the perturbed belt speed was 1.0 km/h, the COM states at toe-off were significantly lower than the stability limit; a rapid touch-down of the swing foot posterior to the stance foot then occurred, and the gait rhythm was modulated so that the phase advanced. EMG recordings during perturbed steps revealed a bilateral response, including modulation of the swing leg during the recovery. For weaker perturbations, the swing foot placements were anterior to the stance foot and there was a phase delay. In contrast to the bilateral responses for stronger perturbations, unilateral EMG responses were observed for weaker perturbations. The differences in joint kinematics and EMG patterns in the unperturbed swing leg depended on the COM states at toe-off, suggesting the existence of different responses consisting of ongoing swing movements and rapid touch-down. Thus, we conclude that corrective reactions for backward balance losses are not only phase-dependent but also state-dependent. In addition, the control system for backward balance losses predicts the feasibility of forward progression and modulates swing movement and walking rhythm according to backward balance stability. PMID- 21704418 TI - The genome sequence of the lactic acid bacterium, Carnobacterium maltaromaticum ATCC 35586 encodes potential virulence factors. AB - The genus Carnobacterium belongs to the lactic acid bacteria and Carnobacterium maltaromaticum is commonly found in modified atmosphere packed and vacuum packed fish and meat products as well as in live fish. This species has been described as a fish pathogenic organism but human clinical isolates have only been obtained at one occasion. To investigate the virulence potential we sequenced the entire genome of strain ATCC 35586, isolated from a diseased salmon. When comparing the translated gene products of ATCC 35586 to those of Gram positive bacterial pathogens and probiotics as well as the related Carnobacterium sp. AT7 we identified a range of putative virulence genes including genes encoding products involved in adhesion to fibronectin and collagen, capsule synthesis, cell wall modification, iron scavenging mechanisms, haemolysis, invasion and resistance to toxic compounds. Of particular interest was the presence of internalin encoding gene homologues to some of those found in Listeria spp. and Lactobacillus plantarum. Furthermore, the ATCC 35586 strain possesses a gene encoding a product similar to the central Listeria monocytogenes transcriptional regulator PrfA, that in this organism controls virulence gene expression by binding to conserved DNA binding sites. Based on the consensus DNA sequence of this binding site, we identified a total of 65 genes in the ATCC 35586 genome that in the upstream region carry a PrfA binding motif. Among these is one of the internalin encoding genes; two genes encoding products involved in capsule biosynthesis as well as various genes encoding products with metabolic functions. In contrast to L. monocytogenes, the ATCC 35586 strain did not encode other PrfA dependent virulence factors such as listeriolysin O, phospholipases A and B, ActA, listeriolysin O, zinc metallo protease and internalins A and B. In conclusion, C. maltaromaticum ATCC 35586 carries putative virulence genes that may explain its reported ability to infect fish. The findings of this study give no reason for concern regarding human health by the presence of this species in food products. PMID- 21704419 TI - Clinicopathologic features of early lesions of primary cutaneous follicle center lymphoma, diffuse type: implications for early diagnosis and treatment. AB - BACKGROUND: Data on early lesions of primary cutaneous follicle center lymphoma (PCFCL), diffuse type are very limited. OBJECTIVE: We sought to elucidate the early clinicopathologic features of PCFCL, diffuse type. METHODS: Clinical, histologic, immunohistologic, molecular, and fluorescence in situ hybridization data from 24 patients with early lesions of PCFCL, diffuse type (male:female = 19:5; median age: 57 years) were determined. RESULTS: Lesions consisted mostly of solitary or clustered papules and small nodules located on the trunk (21 cases), arm (two cases), and scalp (one case). In 3 patients small papules were located at a distance from the main affected area. All biopsy specimens from early lesions showed aggregates of medium and large centrocytes admixed with small lymphocytes without formation of clear-cut lymph follicles. Staining for Bcl-2 was positive in only 7 cases, one revealing also a rearranged BCL2 signal by fluorescence in situ hybridization. Data on treatment and follow-up were available for 22 patients. At last examination 13 patients were in complete remission (median follow-up: 60 months), 6 were alive with skin disease alone (median follow-up: 60 months), two were alive with skin disease and bone-marrow or lymph node involvement, respectively, and one died of unrelated causes while in complete remission. LIMITATIONS: The retrospective study and the fact that patients were treated at different institutions are limitations. CONCLUSIONS: Early lesions of PCFCL, diffuse type present with characteristic clinicopathologic features. Dermatologists should be alert particularly to the early clinical manifestations of this lymphoma and to the presence of small, inconspicuous lesions at a distance from the main affected area in order to plan treatment properly. PMID- 21704420 TI - Acne treatment and inflammatory bowel disease: what is the evidence? PMID- 21704421 TI - Human herpesvirus 8 is not detectable in lesions of large plaque parapsoriasis, and in early-stage sporadic, familial, and juvenile cases of mycosis fungoides. AB - BACKGROUND: Human herpesvirus (HHV) 8, an essential etiologic agent of Kaposi sarcoma, is also associated with several lymphoproliferative disorders. The involvement of HHV 8 in mycosis fungoides (MF) and large plaque parapsoriasis (LPP) is controversial, with contradictory reports from various countries worldwide. OBJECTIVE: We sought to investigate the presence of the HHV 8 genome in skin lesions of LPP and early-stage sporadic, familial, and juvenile MF in patients in Israel. METHODS: Archival paraffin-embedded and frozen samples from skin biopsies of untreated patients with LPP and early-stage MF performed in 1990 through 2006 were randomly collected from the department of dermatology of a tertiary medical center in central Israel. DNA was extracted, and a TaqMan-based real-time polymerase chain reaction assay specific for the K6 gene region was used to detect the HHV 8 genome. RESULTS: A total of 46 biopsies were sampled from 11 patients with LPP and 35 with early-stage MF (17 adults with sporadic MF, 10 children, and 8 patients with familial MF). In all, 44 samples were negative for HHV 8 DNA; two samples from adults with sporadic MF were positive. LIMITATIONS: The presence of HHV 8 antibodies or virus sequences was not assessed in peripheral blood. CONCLUSION: The results of this study, conducted in a region relatively endemic for HHV 8, support most earlier studies showing a lack of association of HHV 8 infection with LPP and sporadic adult-type MF. To our knowledge, the lack of association of HHV 8 infection with juvenile and familial MF has not been previously reported. PMID- 21704422 TI - Epistaxis after partial middle turbinectomy: the role of sphenopalatine artery ligation. AB - PURPOSE: Extensive nasal polyposis could involve the middle turbinate inducing the surgeon to partially remove it. We initiated this retrospective study to evaluate the effect of a partial middle turbinectomy (PMT) on postoperative epistaxis and if sphenopalatine artery ligation (SPAL) could reduce the risk of bleeding in patients without nasal packing. MATERIAL AND METHODS: Twenty-seven patients with extended bilateral nasal polyposis and submitted to primary functional endoscopic sinus surgery (FESS) with PMT on 40 sides were retrospectively selected. Postoperative bleeding and other complications were evaluated and compared with those of a control group of 27 patients who underwent FESS with middle turbinate preservation on 40 sides. The study group was furthermore divided into 2 groups according to the execution of SPAL. The incidence of postoperative bleeding of both groups and of the 2 parts of the study group was compared using the Fisher exact test. RESULTS: A SPAL was necessary to stop intraoperative bleeding in 21 (52.5%) sides of the study group patients and in 7 (17.5%) of the control group patients. After surgery, epistaxis occurred in 8 cases (20%) in the PMT group (1 submitted to SPAL) and in 2 (5%) of the control group. The comparison with the Fisher exact test confirmed the major tendency of postoperative bleeding in the study group and in those not submitted to SPAL (P < .05). CONCLUSIONS: Partial middle turbinectomy causes a higher incidence of postoperative bleeding in patients who are not packed during the FESS operation. The execution of SPAL greatly reduces this risk. PMID- 21704423 TI - Evaluation of the efficacy of caffeine cessation, nortriptyline, and topiramate therapy in vestibular migraine and complex dizziness of unknown etiology. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of a therapeutic pathway for vestibular migraine (VM) and complex dizziness of undetermined etiology (CDUE) with caffeine cessation and pharmacotherapy. STUDY DESIGN: This study is a retrospective chart review. INTERVENTION(S): Patients were recommended to stop intake of caffeine and other putative migraine-triggering agents. Pharmacotherapy was initiated with nortriptyline or topiramate if symptoms persisted despite diet modification. MAIN OUTCOME MEASURE: Self-reported dizziness is the main outcome measure. RESULTS: Vestibular migraine and CDUE were considered contributing factors to dizziness in 34 and 10, respectively, of 156 patients. Fourteen percent of patients reported improvement in symptoms upon caffeine cessation, whereas 46% of patients reported a reduction in dizziness after nortriptyline therapy (P = .007). Topiramate reduced symptoms in 25% of patients. In total, 75% of VM patients and 56% of patients with CDUE received sufficient benefit from this therapeutic pathway to not progress to other treatments. CONCLUSIONS: Vestibular migraine and CDUE can be treated effectively with a therapeutic pathway consisting of caffeine cessation followed by pharmacotherapy. PMID- 21704424 TI - Group B Streptococcal sepsis: an old or ongoing threat? AB - BACKGROUND: Group B Streptococcus (GBS) is a major cause of severe infections in newborns. Early-onset disease (EOD) occurs within the first week of life, and it is usually vertically transmitted. In late-onset disease (LOD), pathogens may also come from nosocomial sources. We report 3 cases of GBS infection in very low birth weight infants hospitalized by a neonatal intensive care unit (NICU) in Italy. METHODS: The cluster was identified thanks to an active surveillance program; an epidemiologic investigation took place. Pulsed-field gel electrophoresis (PFGE) was used to assess the clonal relatedness of strains. An audit to stress the adherence to isolation precautions and hand hygiene was organized. RESULTS: During a 16-day period, 2 preterm newborns developed GBS LOD; an earlier case of GBS EOD occurred in a baby hospitalized by the same ward. The 3 GBS strains had the same antibiotic susceptibility pattern. The PFGE profiles of the 2 cases of LOD are indistinguishable from each other and closely related with the case of EOD. Strict infection control measures were adopted. CONCLUSION: The implementation of additional infection control measures was able to stop the diffusion of infection; however, clusters like this should remind us the ongoing threat of GBS for the small NICU patients. PMID- 21704425 TI - Hand hygiene in pediatric and neonatal intensive care unit patients: daily opportunities and indication- and profession-specific analyses of compliance. AB - BACKGROUND: Hand hygiene is considered to be the single most effective tool to prevent health care-associated infections. Daily hand hygiene opportunities and compliance for pediatric/neonatal intensive care units (ICU) are currently unknown. METHODS: This was a prospective observational study in pediatric and neonatal ICU patients with analyses of hand hygiene behavior in relation to profession, indication, and shift and correlation with disinfectant usage. RESULTS: Hand hygiene opportunities were significantly higher for pediatric (321/24 hours) than neonatal (194/24 hours; P = .024) patients. Observed compliance rates were 53% (pediatric) and 61% (neonatal) and found to be significantly higher in nurses (57%; 66%) than in physicians (29%, 52%, respectively; P < .001; P = .017, respectively). For neonates, compliance rates were significantly higher before patient contact and aseptic tasks (78%) than after patient, patient body fluid, or patients' surrounding contact (57%; P < .001). Calculating disinfectant usage revealed a 3-fold lower compliance rate of 17%. CONCLUSION: This study provides the first data on opportunities for and compliance with hand hygiene in pediatric/neonatal patients encompassing the whole day and night activities and including a comparison of observed and calculated compliance rates. Observation revealed high compliance especially in nurses and in situations of greatest impact. The data provide a detailed characterization of hand hygiene performance in the neonatal/pediatric ICU setting. PMID- 21704426 TI - Lumen claims of the STERRAD 100NX sterilizer: testing performance limits when processing equipment containing long, narrow lumens. AB - BACKGROUND: According to manufacturers information, the STERRAD 100NX sterilizer a low temperature H(2)O(2) gas plasma sterilizer-can adequately process single channel stainless steel lumens with an inside diameter of 0.7 mm or larger and a maximum length of 500 mm using standard cycle sterilizing conditions. The aim of this study was to qualify the performance of this H(2)O(2) gas plasma sterilizer under different experimental settings representing worst case conditions. METHODS: Inoculated carriers were placed at the midpoint position of specified lumens and then submitted to flex scope sterilizing conditions. To simulate insufficient cleaning or crystalline residues, we added organic and inorganic challenges to our inoculated carriers. RESULTS: For experiments done with unchallenged carriers, quantitative analysis reached a log(10) reduction rate of >=5.71, whereas qualitative results showed no growth in 24 out of 30 biologic indicators tested using flex scope half cycle conditions. Any additional kind of challenge significantly impaired the sterilization outcome. CONCLUSION: The findings of our current study emphasize the importance of a thorough validated cleaning of medical devices as well as timing for cleaning and decontamination before being exposed to the H(2)O(2) sterilization process and, furthermore, the need for strict adherence to manufacturer's recommendations. PMID- 21704427 TI - Preventing catheter-associated urinary tract infection in the zero-tolerance era. AB - BACKGROUND: Catheter-associated urinary tract infection (CAUTI) is one of the most common health care-associated infections in the critical care setting. METHODS: A quasi-experimental study involving multiple interventions to reduce the incidence of CAUTI was conducted in a medical-surgical intensive care unit (ICU) and in 2 step-down units (SDUs). Between June 2005 and December 2007 (phase 1), we implemented some Centers for Disease Control and Prevention-recommended evidence-based practices. Between January 2008 and July 2010 (phase 2), we intervened to improve compliance with these practices at the same time that performance monitoring was being done at the bedside, and we implemented the Institute for Healthcare Improvement's bladder bundle for all ICU and SDU patients requiring urinary catheters. RESULTS: There was a statistically significant reduction in the rate of CAUTI in the ICU, from 7.6 per 1,000 catheter-days (95% confidence interval [CI], 6.6-8.6) before the intervention to 5.0 per 1,000 catheter-days (95% CI, 4.2-5.8; P < .001) after the intervention. There also was a statistically significant reduction in the rate of CAUTI in the SDUs, from 15.3 per 1,000 catheter-days (95% CI, 13.9-16.6) before the intervention to 12.9 per 1,000 catheter-days (95% CI, 11.6-14.2) after the intervention (P = .014). CONCLUSION: Our findings suggest that reducing CAUTI rates in the ICU setting is a complex process that involves multiple performance measures and interventions that can be applied to SDU settings as well. PMID- 21704428 TI - Spread of multidrug carbapenem-resistant Acinetobacter baumannii in different wards of an Italian hospital. AB - BACKGROUND: Multidrug-resistant Acinetobacter baumannii (MDRAB) is an important cause of hospital acquired infection. We describe a 7-month outbreak of a MDRAB infection involving various wards of an Italian hospital and an investigation of the possible source of the infection was conducted. METHODS: A baumannii was isolated from various biological samples from 22 colonized or infected patients, and was identified and characterized for its antibiotic sensitivity. Typing of A baumannii was performed by multilocus sequence typing (MLST). Investigation of the outbreak involved extensive microbiological sampling of the environment. RESULTS: In 50% of cases the infection occurred in the ICU. Invasive procedures were performed in 63.6% of patients. The strain isolated proved to be resistant to all the antibiotics tested, including carbapenems, and displayed the same allelic profile in all patients. None of the 141 samples taken during environmental monitoring showed positivity for A baumannii. CONCLUSION: The results of the present study reveal the importance of strict adherence to control measures by all health care personnel and highlight the fact that regular staff training and frequent revision of control measures are essential to the successful management of an outbreak. PMID- 21704429 TI - Establishing a clinically relevant bioburden benchmark: a quality indicator for adequate reprocessing and storage of flexible gastrointestinal endoscopes. AB - BACKGROUND: Microbiological surveillance of patient-ready flexible endoscopes has been suggested as a tool for endoscope reprocessing quality assurance. However, a proper guideline defining the performance and the frequency of monitoring procedures and specifying how to interpret the results is lacking. MATERIALS AND METHODS: All channels from the 20 flexible gastrointestinal endoscopes (5 gastroscopes, 9 colonoscopes, and 6 duodenoscopes) used at an endoscopy clinic were tested for the presence of bacteria and fungi early every Monday morning over a 7-month period. RESULTS: Bacteria and fungi were detected in 5.7% of the 383 channels tested. Of the 141 scopes tested, 14.1% had detectable growth in at least 1 channel. No significant relationship was detected between the scope or channel type and detection of microorganisms. Over the 7 months of testing, 99.5% of scope channels consistently demonstrated <100 cfu/mL of microbial growth. CONCLUSION: Based on our clinical findings, we recommend 100 cfu/mL as a reliable and routinely achievable cutoff for bioburden residuals in reprocessed endoscope channels. This cutoff is the same as the Canadian cutoff for dialysis water. PMID- 21704430 TI - Health care-associated infections studies project: an American Journal of Infection Control and National Healthcare Safety Network data quality collaboration case study 6. PMID- 21704431 TI - Femoral central venous catheters are not associated with higher rates of infection in the pediatric critical care population. AB - BACKGROUND: Adult data show a difference in central venous catheter (CVC) infection rates between 3 major sites: subclavian (SC), internal jugular (IJ), and femoral veins. We hypothesized that in patients in pediatric intensive care units (PICUs), there is no difference in rates of CVC infection among these three sites, but specifically the femoral compared to all other sites. METHODS: In this retrospective cohort study, data from January 1999 to January 2008 were collected prospectively for internal review and quality assurance. All PICU patients with a CVC were enrolled. The rate of CVC infection was determined using Cox regression survival analysis to account for various durations of CVC placement at the various sites, then adjusted for severity of illness, number of lumens, and patient age. Mortality was compared in patients with a CVC infection versus those without. RESULTS: A total of 4,512 patients with a CVC were enrolled. No site was associated with an increased risk of infection compared with the other sites, with hazard ratios of 0.951 (95% confidence interval [CI], 0.612-1.478) for the SC site, 0.956 (95% CI, 0.593-1.541) for the IJ site, and 1.120 (95% CI, 0.753 1.665) for the femoral site. No significant association between mortality and presence of CVC infection was found when adjusted for age, severity of illness, and duration of CVC placement. An association was found between the presence of a CVC infection and prolonged PICU length of stay (3.98 days longer; P < .001). CONCLUSION: Femoral CVCs are not associated with higher rates of infection in the PICU. In addition, the presence of CVC infection does not affect mortality, but is associated with longer PICU admission. PMID- 21704432 TI - Effectiveness of preventive measures for hemato-oncologic patients undergoing stem cell transplantation during a period of hospital construction. AB - BACKGROUND: Aspergillus spp are ubiquitous spore-forming fungi. Construction work, renovation, demolition, or excavation activities within a hospital or in surrounding areas increase the risk for aspergillus infection in susceptible patients and are the main cause of nosocomial aspergillus outbreaks. METHODS: We investigated the efficacy of infection control measures on the frequency of fungal infection among hemato-oncologic patients undergoing stem cell transplantation during excavation and construction work of an adjacent hospital building. Clinical isolates from these patients obtained before and during the excavation and construction period were analyzed. Preventive measures consisted in the implementation of a multibarrier concept to protect these patients from fungal infection. RESULTS: There was no record of any clinical isolate of Aspergillus spp in the observation period before the beginning of the groundwork. However, 3 clinically significant isolates of Aspergillus spp were detected in respiratory tract specimen of 2 patients after the beginning of excavation and demolition work, which were found to be community acquired. CONCLUSION: Although our data cannot demonstrate the efficacy of infection control measures during construction work, it can be concluded that excavation work close to immunocompromised patients is safe if a bundle of preventive measures is implemented before groundwork. PMID- 21704433 TI - Amyloid beta-induced ER stress is enhanced under mitochondrial dysfunction conditions. AB - Previously we reported that endoplasmic reticulum (ER)-mitochondria crosstalk is involved in amyloid-beta (Abeta)-induced apoptosis. Now we show that mitochondrial dysfunction affects the ER stress response triggered by Abeta using cybrids that recreate the defect in mitochondrial cytochrome c oxidase (COX) activity detected in platelets from Alzheimer's disease (AD) patients. AD and control cybrids were treated with Abeta or classical ER stressors and the ER stress-mediated apoptotic cell death pathway was accessed. Upon treatment, we found increased glucose-regulated protein 78 (GRP78) levels and caspase-4 activation (ER stress markers) which were more pronounced in AD cybrids. Treated AD cybrids also exhibited decreased cell survival as well as increased caspase-3 like activity, poli-ADP-ribose-polymerase (PARP) levels and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells. Finally, we showed that Abeta-induced caspase-3 activation in both cybrid cell lines was prevented by dantrolene, thus implicating ER Ca(2+) release in ER stress-mediated apoptosis. Our results demonstrate that mitochondrial dysfunction occurring in AD patients due to COX inhibition potentiates cell susceptibility to Abeta-induced ER stress. This study further supports the close communication between ER and mitochondria during apoptosis in AD. PMID- 21704434 TI - [Acute cinitapride poisoning]. PMID- 21704435 TI - Synthesis, characterization of some benzazoles bearing pyridine moiety: search for novel anticancer agents. AB - Thirteen novel benzazole derivatives were synthesized as possible anticancer agents. The first intermediate 1,3-benzothiazol-2-ylacetonitrile (2) was synthesized via cyclodeamination reaction of o-aminothiophenol (1) with malononitrile. Also, the second intermediate 5,6-dimethyl-1H-benzimidazol-2 ylacetonitrile (10) was afforded via cyclocondensation reaction between 4,5 dimethyl-1,2-phenylenediamine (9) and ethylcyanoacetate. Nucleophilic reaction of benzimidazolyl NH of compound (10) with ethylcyanoacetate afforded benzimidazolyl 3-oxopropanenitrile (11). On the other hand, methylenation of CH(2) function of compound (10) with dimethylformamide/dimethylacetal afforded benzimidazolylprop-2 enenitrile 12. The synthesis of benzothiazoylpyridines 5a,b and 8a,b as well as benzimidazolylpyridines, 14a,b and 17a-d was carried out through Michael addition of compounds 2 or 10 with arylidenemalononitriles 3a,b and 4a-d. The combination of pharmacophoric anticancer moieties, pyridine and benzazoles was the base on which target compounds 5a,b, 8a,b, 14a,b and 17a-d were designed. Among the synthesized compounds, four derivatives 10 and 17b-d were selected by National Cancer Institute (NCI), USA to be screened for their anticancer activity at a single high dose (10(-5) M) against a panel of 60 cancer cell lines. Compound 17b 4-[p-chlorophenyl]pyridine and 17d 4-[p- methoxyphenyl] pyridine exhibited a broad and moderate antitumor activity against 41 tumor cell lines belonging to the nine subpanels employed and are selected for further evaluation at five dose level screening. PMID- 21704436 TI - Synthesis and cytotoxicity of 2-phenylquinazolin-4(3H)-one derivatives. AB - Thirty 2-phenylquinazolin-4(3H)-one derivatives were prepared and their cytotoxic activities were tested in five human tumor cell lines. Some compounds (5e, 5k, 5t, 6c and 6f) showed relatively high cytotoxic activity. Especially, compound 6c showed the most cytotoxicity against all cell lines tested among the synthesized derivatives, and the inhibitory activity of 6c against HeLa cell was higher than that of adriamycin. The putative mechanism of antitumor action in apoptotic cell death was cell cycle arrest in the G0/G1 phase by compounds 5k, 5v, 5m, 6c, and 6f in HeLa cells. These compounds showed relatively high cytotoxicity in this cell type. PMID- 21704437 TI - Efficacy of hypocaloric parenteral nutrition for surgical patients: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Hypocaloric parenteral nutrition is an underfeeding strategy that lowers energy intake to around 20 kcal/kg/d. It is believed to achieve benefits by modulating metabolic responses and alleviating hyperglycemia. This study aims to systematically review the clinical efficacy of hypocaloric parenteral nutrition on surgical patients. METHODS: Medline, SCI, Embase, Cochrane Library, Chinese Biomedicine Database (CBM) and China Knowledge Resource Integrated Database (CNKI) were searched for studies published before July 1, 2010. Randomized control trials (RCTs) that compared hypocaloric PN with standard or higher energy PN in surgical patients were identified and included. Methodological quality assessment was based on Cochrane Reviewers' Handbook and modified Jadad's Score Scale. Statistical software RevMan 5.0 was used for meta analysis. RESULTS: Five trials met all inclusion criteria and were included in the final meta-analysis. There were significant reductions in infectious complications (RR, 0.60; 95%CI 0.39-0.91, P = 0.02; I(2) = 38%) and length of hospitalization (LOS) associated with receiving hypocaloric PN (MD-2.49 days, 95%CI -3.88 to -1.11, P = 0.0004; I2 = 48%). Stratified analysis of the smaller trials (<60) and larger trials demonstrated that the heterogeneity between trials was mainly associated with sample size. When smaller trials were excluded, hypocaloric PN was associated with reduction in infectious complications (RR, 0.21, 95%CI 0.06-0.72, P = 0.01, I2 = 0%) and shortening of LOS (MD, -2.32 days, 95%CI -3.72 to -0.93, P = 0.001, I2 = 0%). CONCLUSION: Hypocaloric parenteral nutrition may reduce infectious complications and the length of hospitalization in post-operative patients. However, this conclusion is tentative due to patient type and sample size. Furthermore, in terms of hypocaloric PN, the actual energy amount still varies a great deal (from 15 kcal/kg/d to 20 kcal/kg/d). This suggests that further research, including larger randomized clinical trials is required. PMID- 21704438 TI - Spatial distribution of soil radon as a tool to recognize active faulting on an active volcano: the example of Mt. Etna (Italy). AB - This study concerns measurements of radon and thoron emissions from soil carried out in 2004 on the eastern flank of Mt. Etna, in a zone characterized by the presence of numerous seismogenic and aseismic faults. The statistical treatment of the geochemical data allowed recognizing anomaly thresholds for both parameters and producing distribution maps that highlighted a significant spatial correlation between soil gas anomalies and tectonic lineaments. The seismic activity occurring in and around the study area during 2004 was analyzed, producing maps of hypocentral depth and released seismic energy. Both radon and thoron anomalies were located in areas affected by relatively deep (5-10 km depth) seismic activity, while less evident correlation was found between soil gas anomalies and the released seismic energy. This study confirms that mapping the distribution of radon and thoron in soil gas can reveal hidden faults buried by recent soil cover or faults that are not clearly visible at the surface. The correlation between soil gas data and earthquakes depth and intensity can give some hints on the source of gas and/or on fault dynamics. PMID- 21704439 TI - Two error components model for measurement error: application to radon in homes. AB - In this paper, a simple model for analysing variability in radon concentrations in homes is tested. The approach used here involves two error components, representing additive and multiplicative errors, together with variation between houses. We use a Bayesian approach for our analysis and apply this model to two datasets of repeat radon measurements in homes; one based on 3-month long measurements for which the original measurements were close to the current UK Radon Action Level (200 Bq m(-3)), and the other based on 6-month measurement data (from regional and national surveys), for which the original measurements cover a wide range of radon concentrations, down to very low levels. The model with two error components provides a better fit to these datasets than does a model based on solely multiplicative errors. PMID- 21704440 TI - Diagnostic difficulties of a Spitz naevus: a case report. PMID- 21704441 TI - "They don't want our blood": social inclusion and blood donation among African migrants in Australia. AB - The current study examines how feelings of social inclusion influence migrant communities' predisposition to donate blood, focusing specifically on Sub-Saharan African communities in Australia. We begin by explicating the theoretical links between social inclusion, citizenship and blood donation before discussing local and international perspectives of blood donation among African migrant communities. Using qualitative methods comprising nine focus group discussions, held between March and April 2010, we argue that blood donation intentions are mediated by whether or not individuals feel included in their new host society. Real and perceived discrimination experienced by African migrants in their everyday social interactions or in institutional settings can act as a barrier to blood donation. We conclude that removing such barriers, thereby increasing rates of donation in migrant communities, will help to build social capital and inclusion. Strategies for how this can be achieved are outlined. PMID- 21704442 TI - In out-of-hospital cardiac arrest patients, does the description of any specific symptoms to the emergency medical dispatcher improve the accuracy of the diagnosis of cardiac arrest: a systematic review of the literature. AB - AIM: We sought to determine if, in patients with out-of-hospital cardiac arrest (OHCA), the description of any specific symptoms to the emergency medical dispatcher (EMD) improved the accuracy of the diagnosis of cardiac arrest. METHODS: For this systematic review, we searched MEDLINE, EMBASE and the Cochrane Library with no restrictions, and hand-searched the gray literature. Eligible studies included dispatcher interaction with callers reporting OHCA, and reported diagnosis of cardiac arrest. Two independent reviewers used standardized forms and procedures to review papers for inclusion, quality, and to extract data from eligible studies. Findings were peer-reviewed by the International Liaison Committee on Resuscitation. RESULTS: We identified 494 citations; 74 were selected for full evaluation (kappa=0.70) and 23 were included (kappa=0.68), including six before-after, two case-control, and 15 descriptive studies. One before-after study and ten descriptive studies report that inquiring about consciousness and breathing status can help dispatchers recognize cardiac arrest with moderate sensitivity [ranging from 38% to 97%], and high specificity [ranging from 95% to 99%]. One case-control study, three before-after studies, and four observational studies report that abnormal breathing is a significant barrier to cardiac arrest recognition. One before-after study and two descriptive studies report that seizure activity can be a manifestation of cardiac arrest. CONCLUSION: Dispatchers should recognize cardiac arrest when a victim is described as unconscious and not breathing or not breathing normally, and consider cardiac arrest when generalized seizure is described. They should receive specific instructions on how to best recognize the presence of abnormal breathing. PMID- 21704443 TI - Atomic force microscopy analysis of rat pulmonary surfactant films. AB - Pulmonary surfactant facilitates breathing by forming a surface tension reducing film at the air-liquid interface of the alveoli. The objective was to characterize the structure of surfactant films using endogenous rat surfactant. Solid-support surfactant films, at different surface pressures, were obtained using a Langmuir balance and were analyzed using atomic force microscopy. The results showed a lipid film structure with three distinct phases: liquid expanded, liquid ordered and liquid condensed. The area covered by the liquid condensed domains increased as surface pressure increased. The presence of liquid ordered phase within these structures correlated with the cholesterol content. At a surface pressure of 50 mN/m, stacks of bilayers appeared. Several structural details of these films differ from previous observations made with goat and exogenous surfactants. Overall, the data indicate that surfactant films demonstrate phase separation at low surface pressures and multilayer formation at higher pressure, features likely important for normal surfactant function. PMID- 21704444 TI - Identifying the key factors in increasing recycling and reducing residual household waste: a case study of the Flemish region of Belgium. AB - The competent waste authority in the Flemish region of Belgium created the 'Implementation plan household waste 2003-2007' and the 'Implementation plan sustainable management 2010-2015' to comply with EU regulation. It incorporates European and regional requirements and describes strategies, goals, actions and instruments for the collection and treatment of household waste. The central mandatory goal is to reduce and maintain the amount of residual household waste to 150 kg per capita per year between 2010-2015. In literature, a reasonable body of information has been published on the effectiveness and efficiency of a variety of policy instruments, but the information is complex, often contradictory and difficult to interpret. The objective of this paper is to identify, through the development of a binary logistic regression model, those variables of the waste collection scheme that help municipalities to reach the mandatory 150 kg goal. The model covers a number of variables for household characteristics, provision of recycling services, frequency of waste collection and charging for waste services. This paper, however, is not about waste prevention and reuse. The dataset originates from 2003. Four out of 12 variables in the model contributed significantly: income per capita, cost of residual waste collection, collection frequency and separate curbside collection of organic waste. PMID- 21704445 TI - Re: Jurgen Pannek. Mozart, the brain, and the bladder: clinical usefulness of near-infrared spectroscopy for the detection of detrusor overactivity. Eur Urol 2011;59:763-4. PMID- 21704446 TI - Long-term survival after treatment with gemcitabine and oxaliplatin with and without paclitaxel plus secondary surgery in patients with cisplatin-refractory and/or multiply relapsed germ cell tumors. AB - BACKGROUND: Chemotherapy including gemcitabine, oxaliplatin, and/or paclitaxel has shown efficacy in germ cell tumor patients after progression during cisplatin based chemotherapy or relapse after high-dose chemotherapy including complete responses in 5-15%. OBJECTIVE: Most studies have been published with a short follow-up. We present the long-term outcome of two previously reported trials. DESIGN, SETTING, AND PARTICIPANTS: Two phase 2 trials have evaluated chemotherapy with gemcitabine plus oxaliplatin alone (GO) or plus paclitaxel (GOP) including a total of 76 patients (35 GO and 41 GOP). At first publication, 29 patients were still alive and 9 patients (12%) were free of disease after chemotherapy with or without surgery: GO, 3 of 35 (9%) and GOP, 6 of 41 (15%). MEASUREMENTS: Survival and follow-up time were calculated using the Kaplan-Meier method from the beginning of study treatment until the date of death or the date of the last follow-up. RESULTS AND LIMITATIONS: After a median follow-up of 19 mo (2-86 mo) for the 29 patients still alive, 11% of all patients (8 of 76) were free of disease for >2 yr: 1 of 35 patients (3%) after GO and 7 of 41 patients (17%) after GOP. Three patients with complete remission (CR), two after GO and one after GOP, relapsed. Two others treated with GOP were rendered disease free: One patient with partial remission and short follow-up underwent secondary surgery, and another patient, who had relapsed 2 mo after GOP, achieved a CR after salvage treatment. Overall survival time is >=33 mo (range: >= 28-59 mo) in these eight patients. CONCLUSIONS: Long-term survival can be achieved in about 10-15% of patients with cisplatin-refractory or multiply relapsed germ cell tumor with GO(P) chemotherapy. Aggressive secondary surgery following partial remission is a crucial part of this salvage treatment. PMID- 21704447 TI - Predictors of unfavourable repeat biopsy results in men participating in a prospective active surveillance program. AB - BACKGROUND: Active surveillance (AS) protocols for low-risk prostate cancer (PCa) generally include repeat prostate biopsies at predefined follow-up intervals. OBJECTIVE: To study the outcome of routinely obtained 1-yr repeat biopsies and factors predicting reclassification to higher risk, to contribute to risk stratification for men on AS. DESIGN, SETTING, AND PARTICIPANTS: We analysed men with low-risk PCa (clinical stage <= T2, prostate-specific antigen (PSA) <= 10 ng/ml, PSA density <0.2 ng/ml per millilitre, one or two positive biopsy cores, and Gleason score <= 6) who had been included in a prospective AS protocol. INTERVENTIONS: PSA was measured 3-monthly and the first volume-dependent repeat biopsy was scheduled 1 yr after diagnosis, independent of PSA doubling time (PSA DT). Reclassification to higher risk disease on repeat biopsy was defined as Gleason score >= 7 or >= 3 positive cores. MEASUREMENTS: We analysed whether baseline patient characteristics and PSA-DT were associated with reclassification to more aggressive PCa on repeat biopsy. RESULTS AND LIMITATIONS: A first repeat biopsy was taken in 757 patients after median follow-up of 1.03 yr. The results of repeat biopsies were favourable (no or low-risk PCa) in 594 patients (78.5%) and led to reclassification of risk in 163 (21.5%). Analysis showed that reclassification to higher risk was significantly influenced by the number of initial positive cores (two vs one) (odds ratio [OR]: 1.8; p=0.002) and higher PSA density (OR: 2.1; p=0.003). The outcome was not significantly influenced by age, clinical stage, total number of biopsy cores, or PSA. Adding PSA-DT at time of repeat biopsy to the model showed PSA-DT <3 yr to be significantly associated with reclassification to higher risk (OR: 1.7; p=0.015). Data on tumour involvement per biopsy core were not available. CONCLUSIONS: Clinical features at baseline and during follow-up in our AS cohort are significantly associated with short-term reclassification to higher risk on repeat biopsy. These characteristics can potentially be used for risk stratification of men with PCa who are apparently at favourable risk. PMID- 21704448 TI - ICUD-EAU International Consultation on Kidney Cancer 2010: treatment of metastatic disease. AB - CONTEXT: Until the development of novel targeted agents directed against angiogenesis and tumour growth, few treatment options have been available for the treatment of metastatic renal-cell carcinoma (mRCC). OBJECTIVE: This review discusses current targeted therapies for mRCC and provides consensus statements regarding treatment algorithms. EVIDENCE ACQUISITION: Medical literature was retrieved from PubMed up to April 2011. Additional relevant articles and abstract reviews were included from the bibliographies of the retrieved literature. EVIDENCE SYNTHESIS: Targeted treatment for mRCC can be categorized for the following patient groups: previously untreated patients, those refractory to immunotherapy, and those refractory to vascular endothelial growth factor (VEGF) targeted therapy. Sunitinib and bevacizumab combined with interferon alpha are generally considered first-line treatment options in patients with favourable or intermediate prognoses. Temsirolimus is considered a first-line treatment option for poor-risk patients. Either sorafenib or sunitinib may be valid second-line treatments for patients who have failed prior cytokine-based therapies. For patients refractory to treatment with VEGF-targeted therapy, everolimus is now recommended. Pazopanib is a new treatment option in the first- and second-line setting (after cytokine failure). Sequential and combination approaches, and the roles of nephrectomy and tumour metastasectomy will also be discussed. CONCLUSIONS: Increasing clinical evidence is clarifying appropriate first- and second-line treatments with targeted agents for patients with mRCC. Based on phase 2 and 3 trials, a sequential approach is most promising, while combination therapy is still investigational. The role of nephrectomy in mRCC is being evaluated in ongoing phase 3 clinical trials. PMID- 21704449 TI - Outcomes of small renal mass needle core biopsy, nondiagnostic percutaneous biopsy, and the role of repeat biopsy. AB - BACKGROUND: Percutaneous needle core biopsy has become established in the management of small renal masses <= 4 cm (SRMs). Recent series have reported success rates of >= 80%. Nondiagnostic results continue to be problematic. OBJECTIVE: To determine the results of SRM biopsy and the outcomes of nondiagnostic biopsy and repeat biopsy. DESIGN, SETTING, AND PARTICIPANTS: Patients undergoing renal tumor biopsy (RTB) for suspected renal cell carcinoma (RCC) were included in a prospectively maintained database. MEASUREMENTS: The database was analyzed retrospectively to determine the pathology and outcomes of SRM biopsy. Outcomes of patients with nondiagnostic biopsy were determined. Patients undergoing repeat biopsy were identified and their outcomes analyzed. RESULTS AND LIMITATIONS: Three hundred forty-five biopsies were performed (mean diameter: 2.5 cm). Biopsy was diagnostic in 278 cases (80.6%) and nondiagnostic in 67 cases (19.4%). Among diagnostic biopsies, 221 (79.4%) were malignant, 94.1% of which were RCC. Histologic subtyping and grading of RCC was possible in 88.0% and 63.5% of cases, respectively. Repeat biopsy was performed in 12 of the 67 nondiagnostic cases, and a diagnosis was possible in 10 (83.3%). Eight lesions were malignant and two were oncocytic neoplasms. Pathology was available for 15 masses after initial nondiagnostic biopsy; 11 (73%) were malignant. Larger tumor size and a solid nature on imaging predicted a successful biopsy on multivariate analysis. Grade 1 complications were experienced in 10.1% of cases, with no major bleeding and no seeding of the biopsy tract. There was one grade 3a complication (0.3%). This is a retrospective study and some data are unavailable on factors that may affect biopsy success rates. Repeat biopsy was not standard practice prior to this analysis. CONCLUSIONS: RTB can be performed safely and accurately in the investigation of renal masses <= 4 cm. A nondiagnostic biopsy should not be considered a surrogate for the absence of malignancy. Repeat biopsy can be performed with similar accuracy, providing a diagnosis for most patients. PMID- 21704451 TI - A case of chronic inflammatory demyelinating polyneuropathy associated with immune-mediated thrombocytopenia and cutaneous T-cell lymphoma. PMID- 21704452 TI - Zinc recovery and waste sludge minimization from chromium passivation baths. AB - This work reports the feasibility of applying emulsion pertraction technology (EPT) aiming at zinc recovery and waste minimization in the zinc electroplating processes that include Cr (III) passivation. The assessment consists of firstly the lifetime extension of the passivation baths by selective removal of the tramp ions zinc and iron, and secondly, the recovery of zinc for further reuse. Spent passivation baths from a local industry were tested, being the major metallic content: Cr(3+) 9000mg L(-1), Zn(2+) 12,000mg L(-1), Fe(3+) 100mg L(-1). Working in a Liqui-Cel hollow fiber membrane contactor and using the extractant bis(2,4,4 trimethylpentyl) phosphinic acid, reduction of zinc and iron concentrations below 60mg L(-1) and 2mg L(-1), respectively were obtained, while trivalent chromium, the active metal that generates the passivation layer, was retained in the baths. Zinc was selectively transferred to an acidic stripping phase that in the experimental time reached a concentration of 157,000mg L(-1). Zinc recovery by electrowinning from the acidic stripping phase without any pretreatment of the electrolyte solution provided a purity of 98.5%, matching the lower commercial zinc grade. As a result of the extension of the life time of the passivation bath, significant environmental advantages are derived such as minimization of the volume of hazardous wastes and savings in the consumption of raw materials. PMID- 21704453 TI - Three decades of TBT contamination in sediments around a large scale shipyard. AB - Tributyltin (TBT) contamination in sediments was investigated in the vicinity of a large-scale shipyard in the years after the implementation of a total ban on the use of TBT based antifouling paints in Korea. Extremely high level of TBT (36,292ng Sn/g) in surface sediment was found at a station in front of a drydock and near surface runoff outfall of the shipyard. TBT concentration in surface sediments of Gohyeon Bay, where the shipyard is located, showed an apparent decreased TBT concentration gradient from the shipyard towards the outer bay. The vertical distribution of TBT contamination derived from a sediment core analysis demonstrated a significant positive correlation (r(2)=0.88; p<0.001) with the annual tonnage of ship-construction in the shipyard within the past three decades. TBT concentrations at six stations surveyed before (2003) and seven years after (2010) the total ban showed no significant differences (p>0.05). Despite the ban on the use of TBT, including ocean going vessels, surface sediments are still being heavily contaminated with TBT, and its levels well exceeded the sediment quality guideline or screening values. PMID- 21704454 TI - The roles of foam ceramics in suppression of gas explosion overpressure and quenching of flame propagation. AB - In order to substantially suppress the shock waves resulting from gas explosions in coal mines as well as to reveal the mechanism of explosion flame quenching by foam ceramics, a rectangular explosion test pipe was designed, which has a 200mm * 200mm cross-section and is similar in shape to the roadways in coal mines. Explosion flame propagation characteristics in empty pipe and in the presence of Al(2)O(3) and SiC foam ceramics were experimentally investigated. To obtain direct observations, the flame propagation was photographed by a high-speed camera. Furthermore, the mechanism of foam ceramics affecting gas explosion propagation was analyzed. The results demonstrate that the foam ceramics attenuate drastically the maximal explosion overpressure by up to fifty percent; the interconnected micro-network structure of the foam ceramics contribute to quenching gas explosion flame and suppressing shock wave overpressure. These important findings hint that, if properly designed and deployed, this material is expected to be developed into a new suppression and isolation technique against multiple and continuous gas explosions that are presently a grave threat to production safety of coal mines across China and the rest of the world. PMID- 21704455 TI - Assessing the environmental impact of five Pd-based catalytic technologies in removing of nitrates. AB - Emerging technologies involving chemical catalytic processes to remove nitrate from water have proven efficient and cost-effective. However, the environmental impact of noble metals and metals at the nanoscale used in these processes has become a topic of serious concern. The aim of this research was to develop a system for evaluating the environmental impact of technologies associated with Pd based catalytic denitrification. This research performed life cycle assessment (LCA) based on a detailed analysis of the technologies to examine the environmental burden associated with all stages of the removal process. We then applied analytical hierarchy process (AHP) to determine the weights of various burdens. We implemented the proposed system to determine the relative environmental friendliness of 5 processes used for the removal of nitrate. These five methods use Cu-Pd/TNTs, H(2)+Pd-Cu/TiO(2), Pd-Cu/TiO(2), Pd/ZnO, and Pd Cu/FeO as catalysts for the removal of nitrate. The results indicate that the use of palladium and the consumption of electricity have a major environmental impact; while the use of Pd-Cu/TiO(2) as catalyst was the most environmentally friendly of the five processes evaluated. PMID- 21704456 TI - Studies on the removal of arsenic (III) from water by a novel hybrid material. AB - The present work provides a method for removal of the arsenic (III) from water. An ion-exchanger hybrid material zirconium (IV) oxide-ethanolamine (ZrO-EA) is synthesized and characterized which is subsequently used for the removal of selective arsenic (III) from water containing 10,50,100mg/L of arsenic (III) solution. The probable practical application for arsenic removal from water by this material has also been studied. The various parameters affecting the removal process like initial concentration of As (III), adsorbent dose, contact time, temperature, ionic strength, and pH are investigated. From the data of results, it is indicated that, the adsorbent dose of 0.7mg/L, contact time 50min after which the adsorption process comes to equilibrium, temperature (25+/-2), solution pH (5-7), which are the optimum conditions for adsorption. The typical adsorption isotherms are calculated to know the suitability of the process. The column studies showed 98% recovery of arsenic from water especially at low concentration of arsenic in water samples. PMID- 21704457 TI - Trauma and chronic pain: transforming healthcare delivery to provide patient centered and integrative care. PMID- 21704458 TI - Neosporosis in animals--the last five years. AB - Neospora caninum is a protozoan parasite of animals. Until 1988, it was misdiagnosed as Toxoplasma gondii. Since its first recognition in 1984 in dogs and the description of a new genus and species Neospora caninum in 1988, neosporosis has emerged as a serious disease of cattle and dogs worldwide. Abortions and neonatal mortality are a major problem in livestock operations and neosporosis is a major cause of abortion in cattle. This review is focused on current status of neosporosis in animals based on papers published in the last five years. Worldwide seroprevalences are tabulated. Strategies for control and prevention are discussed. PMID- 21704459 TI - Return to work after burn--a prospective study. AB - Return to work (RTW) is one of the most important objectives to strive for in burn rehabilitation. Most individuals do return to work after burn but there is a subgroup that does not. Prospective long-time follow-up studies focusing on RTW after burn are scarce. Consecutive adult burn patients employed before injury (n=58) were included in the present study during hospitalization and subsequently followed up for 12 months. In addition, a structured interview was performed at 2 7 years after burn. At that time; mean 4.5 years (SD 2.0) after burn; 67% of the participants had returned to their work. Predictive variables for time to RTW were length of stay (LOS) at the burn center and fulfilling criteria for Any personality disorder. No RTW was predicted by LOS and having Any anxiety disorder or Any substance use disorder prior to the burn. The non-working group reported lower generic (EQ-5D) and burn-specific (BSHS-B) HRQoL than the working group at every time point. Identification of risk factors associated with difficulties in RTW is required in order to execute individualized vocational rehabilitation. PMID- 21704460 TI - The alternative five-factor model of personality, nicotine dependence and relapse after treatment for smoking cessation. AB - Personality is one of several factors that have been related to the initiation, maintenance and cessation of smoking. This paper aims to analyze the relationship between the alternative five-factor model of personality (AFFM), nicotine dependence (ND), nicotine use (NU) and cessation after twelve months of a cognitive-behavioral therapy combined with medication. In this prospective study, a sample of 103 smokers who were taking part in a workplace smoking cessation intervention, answered the Zuckerman-Kuhlman Personality Questionnaire. ND and NU were measured with the Fagerstrom Test for the Nicotine Dependence (FTND) and the number of cigarettes smoked per day (CPD), respectively. Tobacco cessation was self-reported at twelve months follow-up and biologically confirmed. Results varied according to gender. In men, low scores on Sociability predicted high ND and large number of CPD. In addition, low scores on Sensation Seeking and high scores on Impulsivity predicted also a high smoking rate at baseline. No personality traits were found to explain ND in women, but high Impulsivity Sensation Seeking and General Activity predicted high CPD. Predictors of cessation also differed by gender. Apart from FTND level, high levels on Impulsivity predicted relapse in males. In women, high levels on Sociability predicted relapse. This model correctly classified two thirds of abstainers and relapsers for men and three fourths for women at 12months. Furthermore an interaction between personality and gender was observed. The AFFM appears to have a substantial power for predicting cessation. Personality assessment when beginning treatment for smoking cessation could allow incorporating strategies to improve outcomes. PMID- 21704461 TI - The street cost of drugs and drug use patterns: relationships with sex work income in an urban Canadian setting. AB - BACKGROUND: This study investigated the relationship between drug use and sex work patterns and sex work income earned among street-based female sex workers (FSWs) in Vancouver, Canada. METHODS: We used data from a sample of 129 FSWs who used drugs in a prospective cohort (2007-2008), for a total of 210 observations. Bivariate and multivariable linear regression using generalized estimating equations was used to model the relationship between explanatory factors and sex work income. Sex work income was log-transformed to account for skewed data. RESULTS: The median age of the sample at first visit was 37 years (interquartile range[IQR]: 30-43), with 46.5% identifying as Caucasian, 48.1% as Aboriginal and 5.4% as another visible minority. The median weekly sex work income and amount spent on drugs was $300 (IQR=$100-$560) and $400 (IQR=$150-$780), respectively. In multivariable analysis, for a 10% increase in money spent on drugs, sex work income increased by 1.9% (coeff: 0.20, 95% CIs: 0.04-0.36). FSWs who injected heroin, FSWs with higher numbers of clients and youth compared to older women (<25 versus 25+ years) also had significantly higher sex work income. CONCLUSIONS: This study highlights the important role that drug use plays in contributing to increased dependency on sex work for income among street-based FSWs in an urban Canadian setting, including a positive dose-response relationship between money spent on drugs and sex work income. These findings indicate a crucial need to scale up access and availability of evidence-based harm reduction and treatment approaches, including policy reforms, improved social support and economic choice for vulnerable women. PMID- 21704462 TI - When drugs in the same controlled substance schedule differ in real-world abuse, should they be differentiated in labeling? AB - The prescription drugs regulated in the most restrictive controlled substance schedule for those with an approved therapeutic use vary widely in their real world risk of abuse and harm. Opioid analgesics have the highest rates of abuse, overdose death, drug abuse treatment needs and societal costs in comparison to other Schedule II drugs. Stimulants for attention-deficit/hyperactivity disorders (ADHD) account for substantially lower rates of abuse, harm, and public health impact. The scheduling of drugs is determined by the World Health Organization, the United States Food and Drug Administration, and other regulatory agencies, through a quasi-public process that relies heavily on pre-marketing studies that are conducted in highly controlled clinical settings. We propose that it is increasingly in the interest of science-based regulation and public health to recognize and communicate differences among drugs based on their real-world abuse and public health harm using surveillance data. Appropriate differentiation through labeling of drugs that will likely remain in the same schedule could provide powerful incentives for drug development and research, would aid prescriber/patient decision making by informing them of real differences across drugs within a schedule, and may also contribute to public health efforts to reduce drug abuse. There are risks of course, that include inadvertent perceptions that drugs labeled to be lower in risk are not taken as seriously as others in the same category. Challenges such as these, however, can be overcome and should not serve as barriers to objective communications regarding a drug's actual risks. PMID- 21704463 TI - Methadone maintenance and cancer risk: an Israeli case registry study. AB - OBJECTIVES: This study explored cancer incidence rates in a large cohort of Israeli (Jewish and Arab) opioid-dependent individuals receiving methadone maintenance treatment (MMT), and how the incidences vary by ethnicity and sex. METHOD: The record linkage between the Israel National Addiction Registry (INAR) and the Israel National Cancer Registry (INCR) was performed. Information about the Israeli general population from the Central Bureau of Statistics was used for comparison to match sex and year of birth to the cohort under study. Age standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated. RESULTS: Though the SIR values for aggregated cancer sites for both men and women on MMT did not differ significantly from the corresponding figures in the general population (0.88, 95% CI 0.76-1.00, and 1.06, 95% CI 0.76-1.36, respectively), the risks were substantially increased for lung (1.97, 95% CI 1.13 2.82), larynx (3.62, 95% CI 1.11-6.13) and liver (6.8, 95% CI 1.76-11.83) cancers among Jewish men and for cervix uteri cancer among Jewish women (2.41, 95% CI 0.99-3.84). By contrast, the SIR values for colorectal cancer among Jewish men (0.46, 95% CI 0.09-0.82) and for breast cancer among Jewish women (0.36, 95% CI 0.00-0.71) were significantly lower than expected. CONCLUSIONS: The results suggest that the increased and reduced site-specific cancer risks are counterbalanced, resulting in the absence of the expected excess cancer risk for the entire cohort. The reduced risks for colorectal and breast cancers suggest a protective effect of MMT, warranting further investigation. PMID- 21704464 TI - High-density CT of muscle and liver may allow early diagnosis of childhood-onset Pompe disease. AB - Pompe disease is classified into infantile-, childhood- and adult-onset forms based on onset age and the degree of organ involvement. Differing from the infantile-onset form which is characterized by marked organ involvement, the childhood-onset form usually presents with muscle weakness and elevation of serum creatine kinase (CK), mimicking those of progressive muscular dystrophy. We report our successful early diagnosis and initiation of enzyme replacement therapy (ERT) in a young girl with childhood-onset Pompe disease before the development of skeletal muscle symptoms. She was referred to our hospital at the age of 2 years 4 months because of hyperCKemia detected incidentally. She was active and lacked developmental delay and muscle weakness; however, hepatomegaly was noted. The combination of high-density changes in the liver and skeletal muscle on computed tomography (CT) images was suggestive of glycogen storage disorder, especially childhood-onset Pompe disease. Low alpha-glucosidase (GAA) activity on dried blood spots facilitated the diagnostic process, and genetic analysis of GAA allowed a definitive diagnosis, without performing muscle biopsy. We promptly started ERT at the age of 2 years 6 months. After 1 year, she still had not developed any skeletal muscle symptoms, and serum CK level was almost normal. Since the efficacy of ERT is thought to depend on the extent of muscle damage at its commencement, we expect that ERT may have prevented the manifestation of skeletal muscle involvement in this patient. PMID- 21704465 TI - Evaluation of the small intestinal submucosa covered stent in preventing restenosis after percutaneous transluminal angioplasty in the swine. AB - OBJECTIVE: To compare the performance of small intestinal submucosa (SIS)-covered endografts (SCEs) to bare nitinol stents (BSs) in injured swine iliac arteries. MATERIALS AND METHODS: Twenty-eight nitinol stents were used: 14 externally SCEs and 14 BSs. Devices were implanted in each side of balloon-injured external iliac arteries of 14 swine via carotid approach. Arteriograms were obtained before and after implantation and before animal sacrifice at 4, 8, and 12 weeks. Histopathological and electron microscopy studies of explanted specimens were performed. RESULTS: Implantation of all SCEs and BSs was technically successful, but one SCE and one BS were obstructed at 8 weeks after implantation. At sacrifice, the other 26 stents were patent, with angiogram showing no significant different luminal narrowing between SCEs and BSs. Proliferating cell nuclear antigen (PCNA) immunohistochemistry examination revealed that the percentage of PCNA(+) cells were lower in SCEs (p<0.05). Additionally, histomorphological analysis indicated that the neointima area and percentage of narrowing area were greater in SCEs, but there was no statistical significance. Greater endothelial cell count in SCEs than in BSs per visual field at 4000 times magnification by scanning electron microscope (p<0.05). CONCLUSION: Compared to BSs, no definite decrease of neointima and restenosis was found in SCEs in the present study. However, it is effective in promoting endothelial regeneration and strengthening endothelial function. PMID- 21704466 TI - Endoscopic surgery for plantar fasciitis: application of a deep-fascial approach. AB - PURPOSE: The purpose of this study was to determine the clinical results of deep fascial medial and lateral portals in performing endoscopic surgery for plantar fasciitis. METHODS: In 10 feet in 8 patients who were treated conservatively for more than 6 months with failure to relieve their symptoms, endoscopic surgery was performed. After the patient was placed in the supine position, a medial portal was made 5 mm deep to the plantar fascia and 10 mm anterior to its origin on the calcaneus under fluoroscopy. The lateral portal was established by placing a blunt trocar deep and perpendicular to the plantar fascia. A 2.7-mm-diameter arthroscope was passed through the deep-lateral portal, and the operative devices were inserted through the deep-medial portal. A motorized shaver was used for making a working space to excise the fat tissue along with a portion of the flexor digitorum brevis muscle. If a heel spur existed, it was resected to establish a clear view of the plantar fascia by use of an arthroscopic burr. After exposure of the plantar fascia, its medial half was removed with electric devices such as an Arthro-Knife (ConMed Linvatec, Largo, FL). RESULTS: The mean score on the American Orthopedics Foot and Ankle Society Ankle Hindfoot Scale was 64.2 +/- 6.3 points before surgery and 92.6 +/- 7.1 points at 2 years after surgery (P < .0001). The mean duration to full weight bearing after surgery was 13.9 +/- 8.4 days. All patients returned to full athletic activities by a mean of 10.7 +/- 2.6 weeks. CONCLUSIONS: Endoscopic surgery for plantar fasciitis through a deep-fascial approach allows a wide field of vision and working space, permitting reliable resection of the plantar fascia and heel spur. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 21704467 TI - Biomechanical comparison of arthroscopically performable techniques for suprapectoral biceps tenodesis. AB - PURPOSE: The aim of this study was to biomechanically compare the cyclic and ultimate failure load (UFL) of 4 widely used techniques for arthroscopically performable suprapectoral tenodesis of the long head of the biceps tendon (LHB). METHODS: We used 28 fresh-frozen human cadaveric specimens (mean age, 65 years [range, 43 to 78 years; SD, 6.7 years]; 43% male specimens) to investigate 4 different techniques for LHB tenodesis. All techniques were performed in an open manner, with localization at the entrance of the bicipital groove. Two suture anchor techniques (Healix [DePuy Mitek, Raynham, MA], 5.5 mm, with modified lasso loop stitch; BioSwiveLock [Arthrex, Naples, FL], 5.5 mm, with interlocking Krackow stitch) and two techniques using tenodesis screws (Bio-Tenodesis screw [Arthrex], 8 * 23 mm; Biceptor [Smith & Nephew, Andover, MA], 8 * 25 mm) were investigated. Under a 10-N preload, an axial cyclic load with 100 cycles, 1-Hz frequency, and 50-N maximum load was applied. UFL was evaluated with an axial traction of 0.2 mm/s. LHB displacement during testing was measured by 3 dimensional photogrammetry. RESULTS: All techniques had a mean displacement of less than 3 mm after cyclic loading. The highest UFL was measured with the Bio Tenodesis screw (mean, 218.3 N; range, 134.0 to 313.0 N; SD, 59.7 N) and the lowest with the BioSwiveLock (mean, 111.2 N; range, 60.0 to 156.8 N; SD, 32.3 N). The Healix had the second highest UFL (mean, 187.1 N; range, 144.7 to 245.0 N; SD, 35.5 N), followed by the Biceptor (mean, 173.9 N; range, 147.0 to 209.3 N; SD, 27.2 N). There was no significant difference between the Healix, Bio Tenodesis screw, and Biceptor (P > .05), but the Healix and Bio-Tenodesis screw had a significantly higher UFL than the BioSwiveLock (P < .01). The failure mode was either suture cutout or failure at the anchor-suture-bone interface or of the tendon itself and was generally dependent on technique. CONCLUSIONS: All techniques resisted cyclic testing without a higher grade of displacement, and all devices except the BioSwiveLock had a satisfactory UFL whereas different failure mechanisms were present. The modified lasso-loop stitch provides sufficient tendon fixation and is equivalent to interference screws. CLINICAL RELEVANCE: The lasso-loop suture anchor technique is an appropriate alternative for suprapectoral LHB tenodesis compared with tenodesis screw techniques. PMID- 21704469 TI - Bankart augmentation for capsulolabral deficiency using a split subscapularis tendon flap. AB - Traumatic anterior shoulder instability is a frequent problem and often requires surgical management. In the absence of significant bone deficiency, arthroscopic capsulolabral repair is associated with low recurrence rates and good functional outcome. However, capsulolabral deficiency, particularly after multiple previous attempts at repair, may preclude traditional arthroscopic Bankart techniques. Previous reports have described the use of autograft or allograft augmentation or coracoid transfer in the treatment of this difficult problem. The purpose of this report is to describe a novel technique of arthroscopic Bankart augmentation of capsulolabral deficiency using a split subscapularis tendon flap to reinforce a damaged capsule. In the absence of bone deficiency, this technique can restore anterior shoulder restraint without excessively constraining the glenohumeral joint. PMID- 21704468 TI - Anterior cruciate ligament reconstruction using remnant preservation and a femoral tensioning technique: clinical and magnetic resonance imaging results. AB - PURPOSE: The purpose of this study was to investigate the clinical and magnetic resonance imaging (MRI) results of anterior cruciate ligament (ACL) reconstruction with autogenous hamstring tendon by use of remnant preservation and a femoral tensioning technique. METHODS: A total of 53 patients who had ACL reconstruction by use of remnant ACL stump preservation and a femoral tensioning technique were evaluated. Clinical evaluation at a minimum of 2 years after surgery included range of motion, Lachman test, pivot-shift test, KT-2000 arthrometer testing (MEDmetric, San Diego, CA), and clinical scores. Plain radiographs were evaluated for tunnel enlargement. MRI was obtained for evaluation of graft continuity, cyclops-like mass lesion, and positioning of the tibial tunnel. Second-look arthroscopy was performed in 33 patients. RESULTS: The clinical scores improved postoperatively. There were statistically significant differences between preoperative and postoperative Lachman tests, pivot-shift tests, and KT-2000 arthrometer measurements. Postoperative MRI was available in 48 patients, and it showed intact graft in 45 patients, 2 partial tears, and 1 complete loss of graft. There were cyclops-like mass lesions in 12 patients, but none showed an extension limitation or pain at extension. The position of the tibial tunnel on the sagittal and coronal view was similar to the position of the normal ACL tibial insertion. The measured tibial tunnel widening on the radiographs at final follow-up was 2.2 +/- 1.5 mm. CONCLUSIONS: Reconstruction of the ACL by use of preservation and femoral tensioning of the remnant tissue showed good clinical results without increased concerns regarding incorrect tunnel formation. Postoperative MRI showed an increased incidence of cyclops-like mass lesions, but no clinical significance was observed. LEVEL OF EVIDENCE: Level IV, case series. PMID- 21704470 TI - Precision of tunnel positioning in navigated anterior cruciate ligament reconstruction. AB - PURPOSE: The aim of this study was to validate the precision of navigated tunnel positioning using a fluoroscopy-based computer-assisted technique. METHODS: Ten human cadaveric knees were operated on under operating room conditions. After resection of the anterior cruciate ligament, referenced fluoroscopic images were acquired to plan the tunnel positions according to established radiologic measurement methods. Afterward, femoral and tibial K-wires were placed by use of navigated drill guides without arthroscopic control. Deviations between the planned and actually drilled tunnel positions at the joint level were analyzed by use of both navigated and radiologic assessment methods. RESULTS: Navigated analysis between planned and actually drilled tunnel position showed mean deviations of 0.4 mm (range, 0 to 1 mm; SD, 0.52 mm) at the femur and 0.5 mm (range, 0 to 1 mm; SD, 0.5 mm) at the tibia. The radiologic analysis showed mean deviations for the femoral tunnel of 0.83 mm for the depth (range, 0 to 1.46 mm; SD, 0.46 mm) and 0.54 mm for the height (range, 0 to 1.08 mm; SD, 0.41 mm). At the tibia, deviation of 0.74 mm (range, 0 to 1.2 mm; SD, 0.46 mm) was found. CONCLUSIONS: The fluoroscopy-based navigation system used in this study allows for precise tunnel positioning with deviations of 1 mm or less. CLINICAL RELEVANCE: This technique provides accurate tunnel placement in anterior cruciate ligament surgery. PMID- 21704471 TI - Using magnetic resonance imaging to predict adequate graft diameters for autologous hamstring double-bundle anterior cruciate ligament reconstruction. AB - PURPOSE: To determine whether the preoperative magnetic resonance imaging (MRI) cross-sectional area (CSA) of the hamstring tendons can predict intraoperative bundle diameters during double-bundle anterior cruciate ligament reconstruction. METHODS: A prospective study of 34 patients undergoing anterior cruciate ligament reconstruction with hamstring autografts was performed. CSAs of independent and combined hamstring tendon diameters were correlated to preoperative magnetic resonance images. RESULTS: Intraoperative tendon diameter measurement positively correlated with preoperative MRI tendon CSA measurement for gracilis (P = .0006), semitendinosus (P = .001), and final graft size (P = .001). Double-stranded gracilis grafts greater than or equal to 5 mm in diameter had a mean preoperative MRI gracilis CSA of 9.98 mm(2) compared with a mean of 7.76 mm(2) for grafts less than 5 mm (P = .002). Double-stranded semitendinosus grafts greater than or equal to 6 mm had a mean preoperative MRI tendon CSA of 17.33 mm(2) compared with 14.80 mm(2) for grafts less than 6 mm (P = .02). Final grafts of diameter greater than or equal to 7 mm had a mean preoperative MRI total tendon CSA of 26.54 mm(2) compared with 22.22 mm(2) for grafts under 7 mm (P = .06). CONCLUSIONS: Preoperative MRI is a clinically useful tool to assess hamstring tendon graft diameter. We recommend preoperative CSA threshold values of 10 mm(2) and 17 mm(2) for the gracilis and semitendinosus tendons, respectively, to reliably predict the potential for a double-bundle anterior cruciate ligament reconstruction. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 21704472 TI - Double-row fixation of upper subscapularis tears with a single suture anchor. AB - The recognition of and discussion of operative techniques for subscapularis tendon tears have lagged behind those for the posterosuperior rotator cuff. The advancement of shoulder arthroscopy has provided the opportunity to see the articular side of the rotator cuff and has led to increased recognition of subscapularis tears. Double-row fixation of the posterosuperior rotator cuff has become popular because of improved biomechanical strength, footprint restoration, and tendon healing compared with single-row fixation. Double-row fixation of the subscapularis, however, has been challenging because of the small anterior space overlying the subscapularis. Whereas the subacromial space allows freedom of movement, the limited subcoracoid space makes visualization, instrument manipulation, and knot tying more difficult. We describe a new technique for double-row fixation of the upper subscapularis footprint using a knotless technique without an additional anchor, which eases some of the aforementioned difficulties. The technique is indicated for partial- or full-thickness tears of the upper 50% of the subscapularis tendon and therefore applies to the majority of tears involving the subscapularis tendon. PMID- 21704473 TI - Why repair the subscapularis? A logical rationale. AB - Tears of the subscapularis tendon are now more frequently recognized and are often associated with tears of the posterosuperior rotator cuff tendons. This has been facilitated by arthroscopic approaches, and repair techniques have been developed. In the setting of a rotator cuff repair, when a subscapularis tendon tear is found in continuity with a supraspinatus tendon tear, it is essential to recognize how the repair of both tendon tears can influence the overall security of the entire repair construct. When a repairable subscapularis tendon tear is left unrepaired, the function of the subscapularis muscle will be lost. In addition, the posterosuperior rotator cuff tear will be more difficult to repair, and it will be less securely repaired. When the subscapularis tendon is repaired initially, the posterosuperior rotator cuff repair can be more easily and more reliable achieved. PMID- 21704474 TI - [Ultrasound control of local anaesthetic location after TAP block performed using landmark-based technique: a cohort study]. AB - OBJECTIVE: TAP is a regional anaesthetic technique where local anaesthesic (LA) is injected between the internal oblique and the transversus abdominis muscles in order to block intercostal nerves. The technique originally described, is based on the identification of the lumbar triangle of Petit as the area where to insert the needle before the LA injection. We performed a study to determine, using ultrasonography, the actual location of the LA when TAP block was performed using landmark-based technique. STUDY DESIGN: Prospective and observational study. METHODS: Fifty-two patients scheduled for ileostomy closure surgery under general anaesthesia received a TAP block (20 mL 0.75% ropivacaine) based on standard anatomical landmarks technique. Ultrasonography was used immediately after the block to determine the LA placement. Failed blocks were considered when the patient required intravenous morphine in the immediate postoperative period for pain localised at the operative site. RESULTS: LA solution was injected in the right place in 14 cases out of 52. Only one of these patient received morphine in the postoperative period. In the remaining 38 blocks, the LA was administered in adjacent anatomical structures and 25 failed. Two injections in the peritoneum were observed. CONCLUSION: The localization of LA after the TAP block being performed by landmark-based techniques is highly variable. In the majority of patients, the LA was injected in adjacent anatomical structures with unpredictable block results. This may promote the use of ultrasound-guided technique to perform the TAP block. PMID- 21704475 TI - [Severe trauma patients in a mountain area: an observational study]. AB - OBJECTIVES: The main objective was to estimate the nature, severity and medical care of severe trauma injuries following mountain activities as compared to severe trauma following traffic accident in a mountain area. STUDY DESIGN: We conducted a prospective comparative monocentric observational study at a University Hospital located in the northern Alps area, using the First national study database (French intensive care recorded in severe trauma). PATIENTS AND METHODS: Three hundred and thirty-seven patients were included during a 2-year period from January 2005 to December 2006. Three hundred and thirty-seven patients, including 223 traffic accidents and 114 mountain accidents were included. The survey data was achieved with a standardized method on a period of 30 days after the accident, and recorded in a computerized file for optimal completeness. RESULTS: The study did not show higher severity or mortality rates in patients with mountain accidents. In both groups, we found a peak of mortality for young adults and similar causes of death. However, spinal cord injuries were statistically more frequent in mountain accidents. CONCLUSION: So, it seems important to continuously warn population about dangers of this playground. PMID- 21704476 TI - 4-aminoquinoline analogues and its platinum (II) complexes as antimalarial agents. AB - The high incidence of malaria and drug-resistant strains of Plasmodium have turned this disease into a problem of major health importance. One of the approaches used to control it is to search for new antimalarial agents, such as quinoline derivates. This class of compounds composes a broad group of antimalarial agents, which are largely employed, and inhibits the formation of beta-haematin (malaria pigment), which is lethal to the parasite. More specifically, 4-aminoquinoline derivates represent potential sources of antimalarials, as the example of chloroquine, the most used antimalarial worldwide. In order to assess antimalarial activity, 12 4-aminoquinoline derived drugs were obtained and some of these derivatives were used to obtain platinum complexes platinum (II). These compounds were tested in vivo in a murine model and revealed remarkable inhibition of parasite multiplication values, whose majority ranged from 50 to 80%. In addition they were not cytotoxic. Thus, they may be object of further research for new antimalarial agents. PMID- 21704477 TI - Imaging of the thoracic aorta. AB - Three-dimensional vascular imaging techniques offer a significant advantage over traditional imaging techniques. Spatial resolution of current state-of-the-art allows sufficient depiction of anatomical detail. Pre-operative planning of complex endovascular procedures is facilitated by state-of-the-art imaging. Cone beam CT holds great promise in guiding complex endovascular procedures. PMID- 21704478 TI - Cardiovascular imaging: increasingly efficient. PMID- 21704479 TI - Direct admission to the operating room: an efficient strategy for patients with diagnosed or highly suspected acute type a aortic dissection. AB - BACKGROUND: Acute type A aortic dissection (ATAAD) is a life-threatening condition with a poor acute prognosis, which requires rapid and effective surgical management. The aim of this study is to assess our strategy with regard to this condition. METHODS: According to a regional emergency protocol, patients with diagnosed or highly suspected ATAAD are directly transferred to the cardiac operating room. Transesophageal echocardiography is performed under anaesthesia, and the patient then undergoes surgery if the diagnosis is confirmed. The present retrospective study examines the implementation of this management strategy between January 1, 1990 and December 31, 2009. RESULTS: Out of 380 patients, 245 were directly admitted to the operating room. Three hundred twelve cases of ATAAD, 15 cases of aneurysm of the ascending aorta, 9 cases of acute type B dissection, 4 cases of chronic dissection, 4 cases of hemopericardium, and 7 other diagnoses were observed. In 10 cases, no etiology was found. Nineteen patients died before surgery could be performed. Out of the 307 cases of ATAAD undergoing surgery, 15 patients were operated with cardiac massage (14 cases of aortic rupture). This management strategy was justified in 93.1% of patients (228/245) directly admitted to the operating room, because of the need for surgery or aortic rupture. CONCLUSIONS: Our management strategy enabled patients with ATAAD to receive effective and unselective treatment. Despite appropriate management, the large number of patients still dying before surgery, or undergoing surgery with cardiac massage, justifies and consolidates the need for immediate treatment of this condition. PMID- 21704480 TI - Computed tomography coronary angiography for ostial left main stem stenosis. PMID- 21704481 TI - Birmingham Mid-Head Resection hip arthroplasty in a young man with gigantism. AB - The Birmingham Mid-Head Resection (Smith & Nephew Ltd, Warwick, United Kingdom) arthroplasty is a new bone-conserving procedure that, like hip resurfacing, is used in younger, active patients. We present the case of a young man with Sotos syndrome (cerebral gigantism) with associated extraordinary stature (height, 2.16 m; weight, 157 kg) who underwent Birmingham Mid-Head Resection arthroplasty. The large stature of this patient required a custom manufactured prosthesis (a femoral head 68 mm in diameter with an acetabular cup 76 mm in diameter). We believe this to be the largest metal-on-metal resurfacing articulation and hip arthroplasty reported to date. PMID- 21704482 TI - Comparison of outcomes after bilateral simultaneous total knee arthroplasty using gender-specific and unisex knees. AB - The clinical and radiologic results of a gender-specific total knee arthroplasty design were compared with those of a conventional unisex design in 50 female patients with bilateral osteoarthritis and a minimum follow-up of 2 years. Total knee arthroplasty was performed using a conventional unisex implant in one knee and a gender-specific implant in the other. Clinical outcomes, which included range of motion, Hospital for Special Surgery scores, and Western Ontario and McMaster Universities Osteoarthritis Index scores, were compared. In addition, patients' subjectively preferred sides were noted, and radiologic results based on implant positions, posterior offsets, anterior offsets, and patellofemoral alignments were evaluated. No significant differences were observed between range of motion, Hospital for Special Surgery score, or Western Ontario and McMaster Universities Osteoarthritis Index scores. Patient subjective preferences and radiologic results were also similar for both sides. In conclusion, gender specific knees in female total knee patients showed no advantages over standard unisex knees in terms of clinical or radiologic outcomes. PMID- 21704483 TI - The effect of total hip arthroplasty surgical approach on postoperative gait mechanics. AB - Surgical approach for total hip arthroplasty (THA) is determined by clinician preference from limited prospective data. This study aimed to examine the effect of surgical approach (direct lateral, posterior, and anterolateral) on 6-week postoperative gait mechanics. Thirty-five patients (direct lateral, 8; posterior, 12; anterolateral, 15) were tested preoperatively and 6 weeks after THA. Patients underwent a gait analysis at a self-selected walking speed. A 2-way analysis of variance was used for analysis. Stride length, step length, peak hip extension, and walking speed increased after THA. The 3 surgical approach variables were not significantly different for any of the study variables after THA. All patients showed some increase in selected variables after THA regardless of surgical approach. In this study, surgical approach did not appear to significantly influence the early postoperative gait mechanics that were quantified. PMID- 21704484 TI - Early adverse results with bicompartmental knee arthroplasty: a prospective cohort comparison to total knee arthroplasty. AB - This prospective cohort study compares functional outcomes of bicompartmental knee arthroplasty (BKA) and total knee arthroplasty (TKA) in patients with osteoarthritis (OA) of the patellofemoral and medial compartments. Eligibility criteria included bicompartmental OA with less than grade 2 OA in the lateral compartment and intact cruciate ligaments. Fifty-six patients met eligibility criteria (21 BKA, 33 TKA). Enrolled participants completed Short-Form 12 and Western Ontario and McMaster Universities Osteoarthritis Index assessments at baseline and postoperatively at 3 months, 1 year, and 2 years. In the early postoperative period, the BKA cohort had significantly less pain (P = .020) and better physical function (P = .015). These trends did not continue past 3 months. When adjusting for age, sex, body mass index, and preoperative status, only 3 month Western Ontario and McMaster Universities Osteoarthritis Index stiffness scores significantly differed between cohorts (P = .048). Despite less early stiffness in the BKA cohort, a significantly higher BKA complication rate (P = .045) has led us to recommend TKA for patients with this pattern of OA. PMID- 21704485 TI - Assessing short-term functional outcomes and knee alignment of computer-assisted navigated total knee arthroplasty. AB - This retrospective study examined the relationship between the mechanical axis of the knee throughout its functional arc and functional outcomes in patients with computer-assisted navigation total knee arthroplasty. Data on final intraoperative functional arc alignment were obtained on 76 patients who had computer-assisted navigation total knee arthroplasty over a 2-year period and correlated with scores from postoperative Short Form 12 and Western Ontario and McMaster Universities functional outcome surveys. No correlation was found between functional arc alignment and outcomes from Western Ontario and McMaster Universities or Short Form 12 surveys; however, subgroup analysis of patients with more than 3 degrees average final intraoperative alignment throughout the functional arc of motion demonstrated increased difficulty with daily activities (P = .05). The results indicate that patients with more than 3 degrees average alignment throughout the functional arc of motion perform more poorly with daily activities postoperatively. PMID- 21704486 TI - The Journal of Arthroplasty. Introduction. PMID- 21704487 TI - Clinical comparison of ciliary sulcus and pars plana locations for posterior chamber intraocular lens transscleral fixation. AB - PURPOSE: To compare the clinical outcomes of transscleral fixation of a posterior chamber intraocular lens (PC IOL) in the ciliary sulcus or pars plana. SETTING: Department of Ophthalmology, Seoul National University College of Medicine, Seoul, South Korea. DESIGN: Comparative case series. METHODS: This retrospective chart review comprised eyes having ciliary sulcus or pars plana fixation of a 3 piece foldable acrylic PC IOL between January 2003 and August 2010. The postoperative corrected distance visual acuity (CDVA), efficacy index, safety index, endothelial cell count (ECC), and complication rates in the 2 groups were compared. RESULTS: The ciliary sulcus group comprised 38 eyes and the pars plana group, 56 eyes. There was no significant between-group difference in the postoperative CDVA, efficacy index, safety index, or ECC. The mean spherical equivalent difference was larger in the ciliary sulcus group. Intraocular lens dislocation and pupillary capture of the IOL optic occurred more frequently in the ciliary sulcus group (P=.001 and P=.041, respectively). However, retinal detachment, IOL decentration or tilt, cystoid macular edema, secondary glaucoma, and vitreous hemorrhage did not differ significantly between the 2 groups. CONCLUSION: The pars plana location for PC IOL transscleral fixation was as safe and effective as the ciliary sulcus location. PMID- 21704488 TI - Correction of high myopia with a phakic intraocular lens: interim analysis of clinical and patient-reported outcomes. AB - PURPOSE: To assess uncorrected distance visual acuity (UDVA) and patient-reported outcome changes after bilateral anterior chamber angle-fixated phakic intraocular lens (pIOL) implantation for high myopia. SETTING: Multiple North American surgical centers. DESIGN: Nonrandomized multicenter clinical trials. METHODS: This was a pooled interim analysis of 2 open-label single-arm studies of high myopia patients with bilateral anterior chamber angle-fixated pIOLs. Assessments compared baseline with 6-month, 1-year, and 2-year measurements. Outcomes included binocular UDVA, binocular corrected distance visual acuity (CDVA), satisfaction with vision, spectacle independence, and Refractive Status and Vision Profile (RSVP) questionnaire results. RESULTS: One hundred thirty-eight patients (mean age 37 years, 67% women) completed all 4 assessments. The UDVA at 6 months, 1 year, and 2 years postoperatively was statistically better than the baseline CDVA (0.12 logMAR, 0.11 logMAR, 0.12 logMAR, respectively, versus 0.06 logMAR) (P<.005). The increase in preoperative to postoperative satisfaction with uncorrected vision was significant (P<.0001). Distance vision spectacle independence improved from 0% preoperatively to 94% postoperatively (P<.0001). Patients reported significant improvements in the RSVP overall score (P<.0001) and the following 7 subscales: concern with vision (P<.0001), driving (P<.001), problems with glare (P<.05), optical problems (P <=.001), physical/social functioning (P<.0001), problems with corrective lenses (P<.005), and ocular symptoms (P<.0001). CONCLUSIONS: After pIOL implantation, the UDVA was better than the preoperative CDVA and most patients required no distance vision correction, had improved satisfaction with uncorrected vision, and had improved vision-related quality of life. PMID- 21704489 TI - Impact of the Patient Protection and Affordable Care Act on vascular imaging. AB - Passage of the Patient Protection and Affordable Care Act legislation will impact vascular surgery in many ways. As imaging accounts for 23% of Vascular Surgery Medicare Part B revenues, vascular surgeons will be negatively affected by changes in reimbursement schemes and methodologies proposed by various agencies. The Medicare Payment Advisory Commission is an agency charged by Congress for reviewing Medicare payment policies and recommending changes. Although current recommendations are directed toward "advanced" and more costly imaging services, vascular surgeons and the ultrasound community are advised to watch out for any recommendations that may adversely impact patient access and convenience. PMID- 21704490 TI - Dynamic viscosity of implantable autologous materials into the vocal fold. AB - OBJECTIVE: To compare the dynamic viscosity (DV) of superficial layer of temporalis fascia (SLTF) with that of other biological tissues traditionally used for vocal fold implants to treat vocal fold rigidity. STUDY DESIGN: Experimental. METHOD: Measurement of DV of samples of SLTF, deep layer of temporalis fascia (DLTF), and abdominal fat of 12 cadavers. RESULTS: DV values of the different samples were presented in the following increasing order: SLTF, DLTF, and abdominal fat. There was statistical difference between the samples. CONCLUSION: DV of SLTF is lower than of other tissues tested. PMID- 21704491 TI - Vocal symptoms, voice activity, and participation profile and professional performance of call center operators. AB - PURPOSE: To analyze the phonatory and laryngopharyngeal symptoms reported by call center operators; and quantify the impact of these symptoms on quality of life, and the association between these issues and professional performance, number of monthly calls, and number of missed workdays. METHODS: Call center operators (n=157) from a billing call center completed the Vocal Signs and Symptoms Questionnaire and the Brazilian version of the Voice Activity and Participation Profile (VAPP). The company provided data regarding professional performance, average number of monthly calls, and number of missed workdays for each employee. RESULTS: The mean number of current symptoms (6.8) was greater in the operators than data for the general population (1.7). On average, 4.2 symptoms were attributed to occupational factors. The average number of symptoms did not correlate with professional performance (P=0.571). However, fewer symptoms correlated with decreased missed workdays and higher mean monthly call figures. The VAPP scores were relatively low, suggesting little impact of voice difficulties on call center operator's quality of life. However, subjects with elevated VAPP scores also had poorer professional performance. CONCLUSIONS: The presence of vocal symptoms does not necessarily relate to decreased professional performance. However, an association between higher vocal activity limitation and participation scores and poorer professional performance was observed. PMID- 21704492 TI - Digital voice analysis in patients with advanced Parkinson's disease undergoing deep brain stimulation therapy. AB - INTRODUCTION: An acoustic analysis was conducted of the voice of 25 patients with Parkinson's disease (PD) subjected to deep brain stimulation (DBS) to assess the impact of therapy. MATERIALS AND METHODS: We examined 25 patients with advanced PD under four different conditions: deprived of medical treatment, under medical treatment, and one week and one month after the implant of the DBS electrodes. At the four time points, the patients produced a sustained /a/ and a standard sentence in Spanish, and microphone and electroglottographic recordings were digitally analyzed using the Computerized Speech Lab program. RESULTS: Waveform analysis of the sustained /a/ captured by the microphone indicated a higher fundamental frequency (F(0)) when the patients were under levodopa treatment. The frequency perturbation (jitter) decreased remarkably after the three treatments. Shimmer also fell, but differences were not significant. CONCLUSIONS: Nearly all acoustic analysis parameters during phonation of a sustained /a/ improved after DBS, but the factor that was most sensitive to the impact of both surgical and medical therapy was jitter. PMID- 21704493 TI - Investigating the effects of caffeine on phonation. AB - OBJECTIVE: A core component of vocal hygiene programs is the avoidance of agents that may dry the vocal folds. Clinicians commonly recommend that individuals reduce caffeine intake because of its presumed dehydrating effects on the voice. However, there is little evidence that ingestion of caffeine is detrimental to voice production. The first objective of this study was to evaluate whether caffeine adversely affects voice production. The second objective was to evaluate if caffeine exacerbates the adverse phonatory effects of vocal loading. STUDY DESIGN: Prospective, double-blinded, sham-controlled study. METHODS: Sixteen healthy adults participated in two sessions where they consumed caffeine (caffeine concentration=480 mg) or sham (caffeine concentration=24 mg) beverages. Voice measures (phonation threshold pressure and perceived phonatory effort) were collected. Subjects then completed a vocal loading challenge and voice measures were obtained again. RESULTS: There were no significant differences in voice measures between the caffeine and sham conditions. Ingestion of caffeine did not adversely affect voice production (P>0.05) or exacerbate the detrimental phonatory effects of vocal loading (P>0.05). CONCLUSIONS: Our findings contribute to emerging knowledge on the effects of caffeine on voice production. Recommendations to completely eliminate caffeine from the diet, as a component of a vocal hygiene program, should be evaluated on an individual basis. PMID- 21704494 TI - Consequences of chronic nasal obstruction on the laryngeal mucosa and voice quality of 4- to 12-year-old children. AB - INTRODUCTION: Dysphonia affects 6% to 23% of children, and chronic nasal obstruction may participate in its pathophysiology. OBJECTIVES: To study the effects of chronic nasal obstruction on children's vocal quality. SUBJECTS AND METHODS: Two study groups were formed: nasal obstruction group (NOG), consisting of 60 children aged 4-12 years with important symptoms of chronic nasal obstruction; and a control group (CG), similar in gender and age range, consisting of healthy students without nasal, vocal, or auditory symptoms. The parents answered a questionnaire containing questions concerning their children's vocal qualities. All the children were submitted to perceptual auditory analysis, acoustic vocal analysis, auditory acuity assessment (transient otoacoustic emissions and/or threshold tone audiometry), and videoendoscopic assessment (flexible laryngoscopy and rigid laryngoscopy). RESULTS: The groups were similar in age and gender. Parents reported a dysphonia rate of 76.6% in NOG and a vocal abuse rate of 68.3%. Eight children from NOG (13.34%) showed mild conductive hypoacusia. Laryngeal lesions were detected in 35 children from NOG (58%): inflammatory processes (n=19), mucosal thickening (n=10), nodules (n=5), and cyst (n=1). In children from the NOG were observed higher scores for the Grade, Roughness, Breathiness, Aesthenia, Strain, Instability (GRBAS) perceptual scale (P<0.05), lower maximum phonation time values, and higher values to the s/z ratio, insufficient nasal resonance. CONCLUSIONS: Relevant changes in perceptual auditory and acoustic vocal analyses and in the videolaryngoscopy were detected in children with nasal obstruction. These results showed the importance of the assessment of nasal obstruction in dysphonic children. PMID- 21704495 TI - Can dictionary-based computational models outperform the best linear ones? AB - Approximation capabilities of two types of computational models are explored: dictionary-based models (i.e., linear combinations of n-tuples of basis functions computable by units belonging to a set called "dictionary") and linear ones (i.e., linear combinations of n fixed basis functions). The two models are compared in terms of approximation rates, i.e., speeds of decrease of approximation errors for a growing number n of basis functions. Proofs of upper bounds on approximation rates by dictionary-based models are inspected, to show that for individual functions they do not imply estimates for dictionary-based models that do not hold also for some linear models. Instead, the possibility of getting faster approximation rates by dictionary-based models is demonstrated for worst-case errors in approximation of suitable sets of functions. For such sets, even geometric upper bounds hold. PMID- 21704496 TI - A hierarchical ART network for the stable incremental learning of topological structures and associations from noisy data. AB - In this article, a novel unsupervised neural network combining elements from Adaptive Resonance Theory and topology-learning neural networks is presented. It enables stable on-line clustering of stationary and non-stationary input data by learning their inherent topology. Here, two network components representing two different levels of detail are trained simultaneously. By virtue of several filtering mechanisms, the sensitivity to noise is diminished, which renders the proposed network suitable for the application to real-world problems. Furthermore, we demonstrate that this network constitutes an excellent basis to learn and recall associations between real-world associative keys. Its incremental nature ensures that the capacity of the corresponding associative memory fits the amount of knowledge to be learnt. Moreover, the formed clusters efficiently represent the relations between the keys, even if noisy data is used for training. In addition, we present an iterative recall mechanism to retrieve stored information based on one of the associative keys used for training. As different levels of detail are learnt, the recall can be performed with different degrees of accuracy. PMID- 21704497 TI - Carotid artery stiffness and diastolic function in subjects without known cardiovascular disease. AB - BACKGROUND: The aim of this study was to investigate the relationship between carotid artery stiffness and diastolic function in a cohort of subjects without known cardiovascular risk factors and/or overt cardiovascular disease. METHODS: Ninety-two healthy subjects underwent transthoracic echocardiographic Doppler and carotid echo-tracking studies. Measurements of local arterial stiffness were obtained at left common carotid artery level; stiffness parameter (beta), and pressure-strain elasticity modulus (Ep) were calculated as well as intima-media thickness (IMT). RESULTS: Stiffness parameter and Ep were correlated inversely with transmitral E wave (P < .01), E/A ratio, and septal Em (P < .01) and positively with A wave (P < .001). IMT was also associated with A wave, E/A ratio, Em, and Am but not with E wave. No association was found between IMT, beta, and Ep. The correlation between arterial stiffness and left ventricular diastolic function remained significant after multivariate adjustment for age, sex, pulse pressure, and body mass index, but not with IMT. CONCLUSIONS: In healthy subjects, changes in central carotid stiffness are in line with left ventricular diastolic function independently of age, sex, pulse pressure, and body mass index. PMID- 21704498 TI - Volume visualization using a spatially aware mobile display device. AB - Volume visualization is a difficult three-dimensional task and a significant amount of research is devoted to the development of a suitable computer input device for it. Most of the proposed models use fixed displays, thus rendering extracted slices in orientations unrelated to their real locations within the volume. We present a new device which takes a different approach, as it leaves the volume in a fixed location and demands the user to change his or her posture to explore it from different angles. To implement this, we built a prototype based on a mobile display equipped with sensors that allows it to track its position, which is related to the location of the slice plane within the volume. Therefore, the user can manipulate this plane by displacing and rotating the display, which is a very intuitive method with minimum learning time. Furthermore, the postural changes required to use the device add a new channel of feedback, which effectively helps to reduce the cognitive load imposed on the user. We built a prototype device and tested it with two groups of volunteers who were asked to use it in a medical imaging application. Statistical analysis of the results shows that explorations made with the proposed device were considerably faster with no penalty in precision. We believe that, with further work, the proposed device can be developed into an useful tool for radiology and neurosurgery. PMID- 21704499 TI - Wavelet-based segmentation of renal compartments in DCE-MRI of human kidney: initial results in patients and healthy volunteers. AB - Renal diseases can lead to kidney failure that requires life-long dialysis or renal transplantation. Early detection and treatment can prevent progression towards end stage renal disease. MRI has evolved into a standard examination for the assessment of the renal morphology and function. We propose a wavelet-based clustering to group the voxel time courses and thereby, to segment the renal compartments. This approach comprises (1) a nonparametric, discrete wavelet transform of the voxel time course, (2) thresholding of the wavelet coefficients using Stein's Unbiased Risk estimator, and (3) k-means clustering of the wavelet coefficients to segment the kidneys. Our method was applied to 3D dynamic contrast enhanced (DCE-) MRI data sets of human kidney in four healthy volunteers and three patients. On average, the renal cortex in the healthy volunteers could be segmented at 88%, the medulla at 91%, and the pelvis at 98% accuracy. In the patient data, with aberrant voxel time courses, the segmentation was also feasible with good results for the kidney compartments. In conclusion wavelet based clustering of DCE-MRI of kidney is feasible and a valuable tool towards automated perfusion and glomerular filtration rate quantification. PMID- 21704500 TI - Vitamin D, obesity, and obesity-related chronic disease among ethnic minorities: a systematic review. AB - OBJECTIVE: To assess the association between 25-hydroxyvitamin D (25[OH]D) status and obesity, cardiovascular diseases (CVDs), the metabolic syndrome, and type 2 diabetes mellitus (T2DM) in ethnic minorities. METHODS: Databases searched were CINHAL with full text, Global Health, MEDLINE with full text, and PsycINFO from 1980 through 2010 (February). Studies were included if they 1) targeted immigrants from low- to high-income countries or ethnic minorities, 2) focused primarily on 25(OH)D and its relation to obesity, T2DM, and/or CVDs, and 3) were published in peer-reviewed journals. The influences of key confounders such as age, gender, and ethnicity on any observed relations were also assessed. Due to the heterogeneity of study characteristics, only a narrative synthesis was undertaken. RESULTS: Ethnic minorities had significantly higher rates of vitamin D insufficiency (25[OH]D <50 nmol/L; children 43.6-48.7% versus 10%; adults 30.3 53% versus 13.7-26%) than their white counterparts. None of the studies reported a prevalence of obesity stratified by ethnicity. There was evidence supporting links between vitamin D deficiency and obesity-related chronic diseases, with 14 of 14 studies reporting a statistically significant result with a measurement of obesity, four of five for T2DM, four of five for CVDs, and one of one for the metabolic syndrome. However, the strength of the association varied across ethnic groups depending on the index used to measure adiposity, T2DM, and CVDs. Because most of the included studies were cross-sectional and there were variations in outcome measurements, it was not possible to determine the relative contributions of obesity or vitamin D insufficiency to CVD risk and risk of T2DM or which is the initial driver It is possible both have a role to play. CONCLUSION: Further research specific to migrant populations using randomized controlled trials are required to establish whether causal links between 25(OH)D and obesity-related chronic disease exist, and whether vitamin D supplementation could be valuable in the prevention or treatment of obesity-related diseases. PMID- 21704501 TI - Neurocognitive functions of heavy cannabis using schizophrenia patients. AB - This current study assessed neurocognitive functioning in a carefully selected sample of schizophrenia patients with and without heavy cannabis use and healthy controls. All subjects were negative for any other substance use. Schizophrenia subjects had impaired neurocognitive functions across a wide range of tasks compared to healthy controls. Cannabis using schizophrenia patients had focused impairments on tasks of attention, and the findings suggest an impulsive pattern of response among these patients. PMID- 21704502 TI - Metabolic adaptations to early life protein restriction differ by offspring sex and post-weaning diet in the mouse. AB - BACKGROUND AND AIMS: Low birth weight affects 1 in every 7 babies born globally and can predict a lifetime of increased risk for adverse health outcomes, including cardiovascular disease, hypertension, obesity, diabetes, and metabolic syndrome. Maternal low protein diet during pregnancy and lactation is a well characterized rat model for low birth weight and the subsequent increase in chronic disease risk. However, mice have been relatively understudied in this paradigm and represent a critical resource for investigating the underlying molecular mechanisms that link adverse early life experience and the development of chronic disease. METHODS AND RESULTS: The present manuscript describes a mouse model of low birth weight (maternal consumption of low protein diet (8% protein) through pregnancy and lactation) and characterizes metabolic adaptations (food intake, locomotor activity, oxygen consumption, and glucose tolerance) in male and female offspring. At weaning, mice were maintained either on the control diet or a high fat diet. Notable sex differences were observed, with male mice from the low protein pregnancies showing increased food intake, hyperactivity and increased metabolic rate only when weaned to the high fat diet, while female mice consistently showed increased food intake and were hypometabolic, regardless of post-weaning diet. CONCLUSION: These data identify offspring sex and post-weaning diet as critical variables in the metabolic adaptations to early life protein deficiency, and suggest that females may be more vulnerable to the adverse long term health consequences of low birth weight. PMID- 21704503 TI - Mortality trends in asbestosis, extrinsic allergic alveolitis and sarcoidosis in England and Wales. AB - BACKGROUND: To ascertain the trends in mortality from Asbestosis, Extrinsic Allergic Alveolitis (EAA) and Sarcoidosis in England and Wales, we analysed mortality data from the Office of National Statistics. METHODS: We calculated age and stratum specific mortality rates between 1968 and 2008 and applied these to the 2008 population to generate annual standardised expected number of deaths. Poisson regression was used to calculate annual mortality rate ratios. RESULTS: From 1968 to 2008 there were 1958 registered deaths from Asbestosis, 878 deaths from EAA and 3544 deaths from Sarcoidosis. The Asbestosis mortality rate increased from 0.04 (95% CI 0.03-0.05) in the 1968-1972 calendar period to 0.12 (95% CI 0.10-0.13) in the 2005-2008 period whist the mortality from EAA increased marginally from 0.04 (95% CI 0.03-0.05) in the 1968-1972 calendar period to 0.08 (95% CI 0.07-0.09) in the 2005-2008 period. Mortality from Sarcoidosis increased by approximately 9% a year. DISCUSSION: Our findings show that the mortality from Asbestosis continues to rise in the UK. Overall mortality rates from EAA remained stable throughout the same period but it was higher in males and in older people. There was a slight increase in mortality from Sarcoidosis over the study period which was greater in women. PMID- 21704504 TI - Material and energy recovery in integrated waste management systems: a life-cycle costing approach. AB - A critical assumption of studies assessing comparatively waste management options concerns the constant average cost for selective collection regardless the source separation level (SSL) reached, and the neglect of the mass constraint. The present study compares alternative waste management scenarios through the development of a desktop model that tries to remove the above assumption. Several alternative scenarios based on different combinations of energy and materials recovery are applied to two imaginary areas modelled in order to represent a typical Northern Italian setting. External costs and benefits implied by scenarios are also considered. Scenarios are compared on the base of the full cost for treating the total waste generated in the area. The model investigates the factors that influence the relative convenience of alternative scenarios. PMID- 21704505 TI - Development of a novel biosensing system based on the structural change of a polymerized guanine-quadruplex DNA nanostructure. AB - By inserting an adenosine aptamer into an aptamer that forms a G-quadruplex, we developed an adaptor molecule, named the Gq-switch, which links an electrode with flavin adenine dinucleotide-dependent glucose dehydrogenase (FADGDH) that is capable of transferring electron to a electrode directly. First, we selected an FADGDH-binding aptamer and identified that its sequence is composed of two blocks of consecutive six guanine bases and it forms a polymerized G-quadruplex structure. Then, we inserted a sequence of an adenosine aptamer between the two blocks of consecutive guanine bases, and we found it also bound to adenosine. Then we named it as Gq-switch. In the absence of adenosine, the Gq-switch-FADGDH complex forms a 30-nm high bulb-shaped structure that changes in the presence of adenosine to give an 8-nm high wire-shaped structure. This structural change brings the FADGDH sufficiently close to the electrode for electron transfer to occur, and the adenosine can be detected from the current produced by the FADGDH. Adenosine was successfully detected with a concentration dependency using the Gq switch-FADGDH complex immobilized Au electrode by measuring response current to the addition of glucose. PMID- 21704506 TI - Immobilization of lutetium bisphthalocyanine in nanostructured biomimetic sensors using the LbL technique for phenol detection. AB - This study describes the development of amperometric sensors based on poly(allylamine hydrochloride) (PAH) and lutetium bisphthalocyanine (LuPc(2)) films assembled using the Layer-by-Layer (LbL) technique. The films have been used as modified electrodes for catechol quantification. Electrochemical measurements have been employed to investigate the catalytic properties of the LuPc(2) immobilized in the LbL films. By chronoamperometry, the sensors present excellent sensitivity (20 nA MUM(-1)) in a wide linear range (R(2)=0.994) up to 900 MUM and limit of detection (s/n=3) of 37.5 * 10(-8)M for catechol. The sensors have good reproducibility and can be used at least for ten times. The work potential is +0.3 V vs. saturated calomel electrode (SCE). In voltammetry measurements, the calibration curve shows a good linearity (R(2)=0.992) in the range of catechol up to 500 MUM with a sensitivity of 90 nA MUM(-1) and LD of 8 MUM. PMID- 21704507 TI - Neural mechanisms for filtering self-generated sensory signals in cerebellum-like circuits. AB - This review focuses on recent progress in understanding mechanisms for filtering self-generated sensory signals in cerebellum-like circuits in fish and mammals. Recent in vitro studies in weakly electric gymnotid fish have explored the interplay among anti-Hebbian plasticity, synaptic dynamics, and feedforward inhibition in canceling self-generated electrosensory inputs. Studies of the mammalian dorsal cochlear nucleus have revealed multimodal integration and anti Hebbian plasticity, suggesting that this circuit may adaptively filter incoming auditory information. In vivo studies in weakly electric mormryid fish suggest a key role for granule cell coding in sensory filtering. The clear links between synaptic plasticity and systems level sensory filtering in cerebellum-like circuits may provide insights into hypothesized adaptive filtering functions of the cerebellum itself. PMID- 21704509 TI - The pituitary-Leydig cell axis before and after orchiectomy in patients with stage I testicular cancer. AB - INTRODUCTION: This study investigates the pituitary-Leydig cell axis in patients with stage I testicular germ cell cancer (TGCC) followed with surveillance only, in order to evaluate the risk of Leydig cell dysfunction one year after orchiectomy. PATIENTS AND METHODS: A retrospective evaluation of reproductive hormones in patients with unilateral stage I TGCC (N=72) without relapse diagnosed between 1990 and 2008. A group of healthy males (N=706) served as controls. RESULTS: Before orchiectomy there were no significant differences in luteinizing hormone (LH) and testosterone (T) levels between human chorionic gonadotropin (hCG)-negative patients and controls, although 33% of the patients were outside the 97.5 percentile when using bivariate LH/T evaluation. At 1-year follow-up there was a significant increase in LH (DeltaLH=2.04IU/L, p<0.001), and 57% of the patients had an LH/T relation outside the 97.5 percentile. CONCLUSION: Patients with stage I TGCC are at increased risk of having an LH/T relation outside the normal range one year after orchiectomy, suggesting insufficient Leydig-cell function. Whether a proportion of these patients will develop manifest hypogonadism and benefit from androgen therapy is yet to be clarified. PMID- 21704508 TI - Hierarchical representations in the auditory cortex. AB - Understanding the neural mechanisms of invariant object recognition remains one of the major unsolved problems in neuroscience. A common solution that is thought to be employed by diverse sensory systems is to create hierarchical representations of increasing complexity and tolerance. However, in the mammalian auditory system many aspects of this hierarchical organization remain undiscovered, including the prominent classes of high-level representations (that would be analogous to face selectivity in the visual system or selectivity to bird's own song in the bird) and the dominant types of invariant transformations. Here we review the recent progress that begins to probe the hierarchy of auditory representations, and the computational approaches that can be helpful in achieving this feat. PMID- 21704510 TI - Preoperative chemoradiation followed by surgical resection for resectable pancreatic cancer: a review of current results. AB - BACKGROUND: There has been an interest in the interdisciplinary and multimodality approach that combines chemotherapy and radiation therapy as a preoperative treatment for patients with resectable pancreatic cancer. METHODS: Literature search of databases (Medline and PubMed) to identify published studies of preoperative chemoradiation for resectable pancreatic cancer (potentially resectable and borderline resectable) was undertaken. Response to treatment and survival outcomes was examined as endpoints of this review. RESULTS: Seventeen studies; eight phase II studies, and nine observational studies, comprising of 977 patients were reviewed. Gemcitabine-based chemotherapy with radiotherapy was the most common preoperative regimen. Following preoperative treatment, pancreatic surgical resection was performed in 35-100% (median=61%) of patients after a range of 6-32 weeks (median=7 weeks). Rate of pathological response was complete in 5-15% of patients, partial in 33-60% and minimal in 38-42%. The median overall survival ranged from 12 months to 40 months (median=25 months) with a 5-year overall survival rate ranging between 8% and 36% (median=28%). Patients who underwent chemoradiation but did not undergo surgery survived a median period of 7-11 months (median=9 months). CONCLUSION: Preoperative gemcitabine-based chemoradiation followed by restaging and surgical evaluation for pancreatic resection may identify a sub-population of patients with resectable disease who would benefit the most from surgery. Investigation of this schema of preoperative therapy in a randomized setting of resectable pancreatic cancer is warranted. PMID- 21704511 TI - Novel autotrophic nitrogen removal system using gel entrapment technology. AB - A pilot plant involving a nitritation-anammox process was operated for treating digester supernatant. In the preceding nitritation process, ammonium-oxidizing bacteria were immobilized in gel carriers, and the growth of nitrite-oxidizing bacteria was suppressed by heat-shock treatment. For the following anammox process, in order to maintain the anammox biomass in the reactor, a novel process using anammox bacteria entrapped in gel carriers was also developed. The nitritation performance was stable, and the average nitrogen loading and nitritation rates were 3.0 and 1.7 kg Nm(-3)d(-1), respectively. In the nitritation process, nitrate production was completely suppressed. For the anammox process, the startup time was about two months. Stable nitrogen removal was achieved, and an average nitrogen conversion rate of 5.0 kg Nm(-3)d(-1) was obtained. Since the anammox bacteria were entrapped in gel carriers, stable nitrogen removal performance was attained even at an influent suspended solids concentration of 1500 mg L(-1). PMID- 21704512 TI - Repeated-batch fermentation of lignocellulosic hydrolysate to ethanol using a hybrid Saccharomyces cerevisiae strain metabolically engineered for tolerance to acetic and formic acids. AB - A major challenge associated with the fermentation of lignocellulose-derived hydrolysates is improved ethanol production in the presence of fermentation inhibitors, such as acetic and formic acids. Enhancement of transaldolase (TAL) and formate dehydrogenase (FDH) activities through metabolic engineering successfully conferred resistance to weak acids in a recombinant xylose fermenting Saccharomyces cerevisiae strain. Moreover, hybridization of the metabolically engineered yeast strain improved ethanol production from xylose in the presence of both 30 mM acetate and 20mM formate. Batch fermentation of lignocellulosic hydrolysate containing a mixture of glucose, fructose and xylose as carbon sources, as well as the fermentation inhibitors, acetate and formate, was performed for five cycles without any loss of fermentation capacity. Long term stability of ethanol production in the fermentation phase was not only attributed to the coexpression of TAL and FDH genes, but also the hybridization of haploid strains. PMID- 21704513 TI - Metabolic influence of lead on polyhydroxyalkanoates (PHA) production and phosphate uptake in activated sludge fed with glucose or acetic acid as carbon source. AB - Sludge in a sequential batch reactor (SBR) system was used to investigate the effect of lead toxicity on metabolisms of polyphosphate accumulating organisms (PAOs) and glycogen accumulating organisms (GAOs) communities fed with acetic acid or glucose as their sole carbon source, respectively. Results showed that the effect of lead on substrate utilization of both PAOs and GAOs was insignificant. However, lead substantially inhibited both of phosphate release and uptake of PAOs. In high concentration of acetic acid trials, an abnormal aerobic phosphate release was observed instead of phosphate uptake and the release rate increased with increasing lead concentration. Results also showed that PAOs could normally synthesize polyhydroxybutyrate (PHB) in the anaerobic phase even though lead concentration was 40 mg L(-1). However, they could not aerobically utilize PHB normally in the presence of lead. On the other hand, GAOs could not normally metabolize polyhydroxyvalerate (PHV) in both the anaerobic and aerobic phases. PMID- 21704514 TI - Evaluation of three composting systems for the management of spent coffee grounds. AB - This study was conducted to evaluate the optimum composting approach for the management of spent coffee grounds from the restaurant and ready-to-serve coffee industry. Three composting systems were assessed, including in-vessel composting, vermicomposting bins, and aerated static pile bin composting, over study periods ranging from 47 to 98 days. Total carbon content was reduced by 5-7% in the spent coffee ground treatments across the three composting systems. Nitrogen and other mineral nutrient contents were conserved or enhanced from the initial to the final composts in all the composting systems assessed. Earthworm growth and survival (15-80%) was reduced in all the treatments but mortality rates were lower in coffee treatments with cardboard additions. A decline in earthworm mortality with cardboard additions was the result of reduced exposure to organic compounds and chemicals released through the decomposition of spent coffee grounds. PMID- 21704515 TI - Properties of oil and char derived from slow pyrolysis of Tetraselmis chui. AB - Pyrolysis of biomass is a means to industrially manufacture renewable oil and gas, in addition to biochar for soil amendment and long-term carbon fixation. In this work, oil and char derived from the slow pyrolysis of the unicellular marine diatom Tetraselmis chui are analysed using a variety of techniques. The pyrolytic oil fraction exhibits a wide variety of fatty acids, alkanes, alkenes, amides, aldehydes, terpenes, pyrrolidinines, phytol and phenols, with a high heating value (HHV) of 28 MJ/kg. The biochar produced has a HHV of 14.5 MJ/kg and reveals a number of properties that are potentially valuable from an agronomic point of view, including high cation exchange capacity (CEC), large concentration of N, and a low C:N ratio. The quantity of C in T. chui biochar that can be expected to stabilise in soil amounts to approximately 9%/wt of the original feedstock, leading to a potential net reduction in atmospheric CO(2). PMID- 21704516 TI - Seasonal and wastewater stream variation of trace organic compounds in a dairy processing plant aerobic bioreactor. AB - Bioreactors are often an integral part of dairy factory efforts to reduce the biological oxygen demand of their wastewater. In this study, infeed, mixed liquor and supernatant samples of an aerobic bioreactor used by a dairy factory in South Eastern Australia were analyzed for nutrients and organic compounds using gas chromatography-mass spectrometry and physicochemical analyses. Despite different concentrations of organic inputs into the bioreactor, nutrients and trace organic compounds were reduced significantly (i.e. average concentration of trace organic compounds: infeed=1681 MUg/L; mixed liquor=257 MUg/L; supernatant=23 MUg/L). However, during one sampling period the bioreactor was adversely affected by the organic loading. Trace organic compounds in the samples were predominantly fatty acids associated with animal products. The analyses suggest that it is possible to trace a disruptive input (i.e. infeed with high organic carbon concentrations) into an aerobic bioreactor by measuring concentrations of fatty acids or ammonia. PMID- 21704517 TI - Biofiltration of composting gases using different municipal solid waste-pruning residue composts: monitoring by using an electronic nose. AB - The concentration of volatile organic compounds (VOCs) during the composting of kitchen waste and pruning residues, and the abatement of VOCs by different compost biofilters was studied. VOCs removal efficiencies greater than 90% were obtained using composts of municipal solid waste (MSW) or MSW-pruning residue as biofilter material. An electronic nose identified qualitative differences among the biofilter output gases at very low concentrations of VOCs. These differences were related to compost constituents, compost particle size (2-7 or 7-20mm), and a combination of both factors. The total concentration of VOCs determined by a photoionization analyser and inferred from electronic nose data sets were correlated over an ample range of concentrations of VOCs, showing that these techniques could be specially adapted for the monitoring of these processes. PMID- 21704518 TI - Looking for practical tools to achieve next-future applicability of dark fermentation to produce bio-hydrogen from organic materials in Continuously Stirred Tank Reactors. AB - This study aimed at finding applicable tools for favouring dark fermentation application in full-scale biogas plants in the next future. Firstly, the focus was obtaining mixed microbial cultures from natural sources (soil-inocula and anaerobically digested materials), able to efficiently produce bio-hydrogen by dark fermentation. Batch reactors with proper substrate (1 gL(glucose)(-1)) and metabolites concentrations, allowed high H(2) yields (2.8 +/- 0.66 mol H(2)mol(glucose)(-1)), comparable to pure microbial cultures achievements. The application of this methodology to four organic substrates, of possible interest for full-scale plants, showed promising and repeatable bio-H(2) potential (BHP=202 +/- 3 NL(H2)kg(VS)(-1)) from organic fraction of municipal source separated waste (OFMSW). Nevertheless, the fermentation in a lab-scale CSTR (nowadays the most diffused typology of biogas-plant) of a concentrated organic mixture of OFMSW (126 g(TS)L(-1)) resulted in only 30% of its BHP, showing that further improvements are still needed for future full-scale applications of dark fermentation. PMID- 21704519 TI - Nitrogen and potassium variation on contaminant removal for a vertical subsurface flow lab scale constructed wetland. AB - Lab scale constructed wetlands were used to evaluate organic load removal efficiency. Bioreactors were fed with synthetic wastewater (SW) with varying concentrations of nitrogen and potassium. Reactors were planted with species Phragmites australis. Fed theoretic COD was adjusted to 240.0mg-O(2)L(-1), nitrogen levels were 10 and 40 mg-NL(-1) (ammonium sulfate), potassium levels were 5 and 31 mg-KL(-1) (potassium monobasic phosphate). The higher biomass yield, for 0.5 and 0.775 N:K ratios, was related with higher organic load removal. The ratio N:K showed significant differences for organic load abatement, when 1:0.5 and 1:0.775 N:K ratios were applied, 96.8% efficiency was obtained, whereas N:K ratio of 1:0.125 had efficiency of 92.1% and N:K ratio of 1:3.1 showed an efficiency of 90.5%. For planted bioreactor E(H) decreased in 162.7 mV from sample port to 5 cm down to 35 cm depth, while for the bioreactor without plant showed an E(H) decrement of only 17.7 mV. PMID- 21704520 TI - Conversion of waste produced by the deodorization of palm oil as feedstock for the production of biodiesel using a catalyst prepared from waste material. AB - The distillate produced by deodorization of palm oil (DDPO) is a waste that corresponds to 4% of the product formed in this process. DDPO is 83% free of fatty acids (FFA), making it a good material for biodiesel production. In this paper, a catalyst prepared from a waste material, Amazon flint kaolin, was used for the esterification of DDPO with methanol. Leached metakaolin treated at 950 degrees C and activated with 4M sulfuric acid (labeled as MF9S4) offered maximum esterification activity (92.8%) at 160 degrees C with a DDPO:methanol molar ratio of 1:60 and a 4-h reaction time. The influences of reaction parameters, such as the molar ratio of the reactants, alcohol chain length, temperature, time and the presence of glycerides and unsaponifiable matter, have also been investigated. Based on the catalytic results, esterification of DDPO using MF9S4 can be a cheaper alternative for production of sustainable fuels. PMID- 21704521 TI - Isolation, characterization and evolution of a new thermophilic Bacillus licheniformis for lactic acid production in mineral salts medium. AB - The high fermentation cost of lactic acid is a barrier for polylactic acid (PLA) to compete with the petrochemical derived plastics. In order to lower the cost of lactic acid, the industry needs a microorganism that can ferment various sugars at high temperature (50 degrees C) and at the same time using low cost mineral salts (MS) medium. One such bacterium, BL1, was isolated at 50 degrees C and identified as Bacillus licheniformis. BL1 can ferment glucose to optically pure l lactate with a maximum specific productivity of 7.8 g/hl in LB medium and 0.7 g/hl in MS medium at 50 degrees C. BL1 can also consume 10% and 15% glucose in 20 and 48 h, respectively. After serial transfer of BL1 and BL2 in different concentrations of xylose and MS medium respectively, the final mutant BL3 could efficiently ferment glucose and xylose with specific productivity of 1.9 g/hl and 1.2g/hl in strict MS medium. PMID- 21704522 TI - Internalization of a C17alpha-alkynylestradiol-porphyrin conjugate into estrogen receptor positive MCF-7 breast cancer cells. AB - We hypothesized that expression of nuclear estrogen receptor (ER) in hormone sensitive breast cancer cells could be harnessed synergistically with the tumor accumulating effect of porphyrins to selectively deliver estrogen-porphyrin conjugates into breast tumor cells, and preferentially kill tumor cells upon exposure to visible light. In this study we synthesized a conjugate of C(17alpha) alkynylestradiol and pyropheophorbide and demonstrated that this conjugate is internalized by ER-positive MCF-7 cells while pyropheophorbide did not, suggesting an ER-mediated uptake and internalization of the conjugate by incipient nuclear ER in MCF-7 cells. This study is a direct demonstration of our hypothesis about ER-mediated internalization of estrogen-porphyrin conjugates. PMID- 21704523 TI - Synthesis and antiproliferative activity of novel alpha- and beta dialkoxyphosphoryl isothiocyanates. AB - A series of 15 mostly new dialkoxyphosphoryl alkyl and aralkyl isothiocyanates were synthesized using two alternative strategies, and their in vitro antiproliferative activity against several cancer cell lines (including drug resistant) is here demonstrated. The IC(50) values measured for the new compounds are within the range of 6.3-21.5 MUM, and they are quite similar to the activity of two best and most extensively investigated natural benzyl isothiocyanate (A) and phenethyl isothiocyanate (B). Preliminary studies utilizing the cell cycle and reduced glutathione level analysis performed on A549 lung cancer cell line using representative compounds revealed important differences in the mechanism of action possibly correlated with their chemical properties. Hydrophobic compounds react mainly with the cytosolic glutathione reduced leading to its depletion, causing an oxidative stress and cell cycle arrest in G0/G1 phase. On the other hand, hydrophilic compounds cause moderate cell cycle arrest and massive cell death associated with moderate reduced glutathione depletion. These suggest that significant changes in the chemical structure of isothiocyanates, which do not lead to the significant changes in antiproliferative activity, but simultaneously cause a differences in the mechanism of action are possible. PMID- 21704524 TI - Combining carbochips and mass spectrometry to study the donor specificity for the Neisseria meningitidis beta1,3-N-acetylglucosaminyltransferase LgtA. AB - A library of 11 UDP-N-acetylglucosamine analogs were rapidly screened for their activities as donors for the Neisseria meningitidis beta1,3-N acetylglucosaminyltransferase (LgtA) by direct on-chip reaction and detection with SAMDI-TOF mass spectrometry. Six of the analogs were active in this assay and were analyzed by SAMDI to characterize the kinetics toward LgtA. The analysis revealed that substitutions on C-2, C-4, and C-6 affect the activity of the donors, with bulky groups at these positions decreasing affinity of the donors for the enzyme, and also revealed that activity is strongly affected by the stereochemistry at C-3, but not C-4, of the donor. The study is also significant because it demonstrates that SAMDI can be used to both profile glycosyltransferase activities and to provide a quantitative assessment of enzyme activity. PMID- 21704525 TI - A convenient method to prepare emulsified polyacrylate nanoparticles from powders [corrected] for drug delivery applications. AB - We describe a method to obtain purified, polyacrylate nanoparticles in a homogeneous powdered form that can be readily reconstituted in aqueous media for in vivo applications. Polyacrylate-based nanoparticles can be easily prepared by emulsion polymerization using a 7:3 mixture of butyl acrylate and styrene in water containing sodium dodecyl sulfate as a surfactant and potassium persulfate as a water-soluble radical initiator. The resulting emulsions contain nanoparticles measuring 40-50 nm in diameter with uniform morphology, and can be purified by centrifugation and dialysis to remove larger coagulants as well as residual surfactant and monomers associated with toxicity. These purified emulsions can be lyophilized in the presence of maltose (a non-toxic cryoprotectant) to provide a homogeneous dried powder, which can be reconstituted as an emulsion by addition of an aqueous diluent. Dynamic light scattering and microbiological experiments were carried out on the reconstituted nanoparticles. This procedure allows for ready preparation of nanoparticle emulsions for drug delivery applications. PMID- 21704526 TI - Phenylpropenamide derivatives: anti-hepatitis B virus activity of the Z isomer, SAR and the search for novel analogs. AB - Phenylpropenamides have been reported to be a class of non-nucleoside inhibitors of the hepatitis B virus (HBV). This class of compounds was explored with the objective of developing potent anti-HBV agents, with a novel mechanism of action, that could be combined with nucleos(t)ide analogs currently used to treat HBV infection. To accomplish this objective a series of substituted arylpropenamide derivatives were prepared and the E and Z geometrical isomers were separated. The structural identity of each of the E and Z isomers was determined by single crystal X-ray crystallography. Contrary to previous reports, the activity of this class of molecules resides in the Z isomer. Further structure-activity relationship studies around the active Z isomer identified compounds that displayed potent antiviral activity against HBV with EC(90) value of approximately 0.5 MUM in vitro. Attempts to develop ring constrained analogs did not lead to active HBV inhibitors. PMID- 21704527 TI - Right atrial thrombosis and pulmonary embolism after atrial septal defect repair. AB - A 3-year-old boy underwent surgical closure of a large ostium secundum atrial septal defect. This was complicated with extensive right atrial thrombus formation and pulmonary thromboembolism immediately following surgery. He was managed with emergency surgical thromboembolectomy and anticoagulation. However, new thrombus was formed again immediately. This prompted us to add thrombolysis to his treatment, but with no effect. He died on the fifth postoperative day. A postmortem study confirmed extensive thromboembolism. PMID- 21704528 TI - A paradigm shift in aortic arch surgery, certainly--but corroboration required. PMID- 21704529 TI - Tailored imaging of islet cell tumors of the pancreas amidst increasing options. AB - Pancreatic islet cell tumors are neuroendocrine tumors, which can produce hormones and can arise as part of multiple endocrine neoplasia type 1 or von Hippel-Lindau-disease, two genetically well-defined hereditary cancer syndromes. Currently, technical innovation improves conventional and specific molecular imaging techniques. To organize the heterogeneous results described for the imaging of these tumors, we distinguished three indications (1) imaging of a patient with hormone hypersecretion, (2) search for a pancreatic primary in case of proven neuroendocrine cancer of unknown primary, and (3) screening of asymptomatic mutation carriers. We searched for publications on imaging of islet cell tumors between 1995 and January 2010 and defined a Level of Evidence (LOE) for the applicability of each technique. For each technique, data were analyzed in a Forest plot and arranged per imaging indication and tumor subtype. LOEs are weak for all imaging techniques. Analyses indicate a prominent role for endoscopic ultrasound for all three indications. PMID- 21704530 TI - The effects of skinfold thicknesses and innervation zone on the mechanomyographic signal during cycle ergometry. AB - The purpose of this study was to examine the effects of skinfold (SF) thicknesses at four locations on the vastus lateralis (VL) muscle and the placement of accelerometers relative to the innervation zone (IZ) on the mechanomyographic (MMG) amplitude and mean power frequency (MPF) responses during incremental cycle ergometry. Twenty adults (age+/-SD=23.8+/-3.0 years) participated in the investigation. The MMG signals were detected during incremental cycle ergometry using four accelerometers placed on the right VL. Prior to the cycle ergometer test, SF thicknesses were measured. Simple linear regression analyses and one-way repeated measures analyses of variance (ANOVAs) were performed. The present study found that only 10% of the regression analyses and mean comparisons were significant (p<0.05). Furthermore, the accelerometer placed at the most proximal site (Prox 2) had significantly greater MMG amplitude and MMG MPF than accelerometers placed at more distal sites (Prox 1, Over IZ, and Dist). There were no significant differences, however, in SF thickness between accelerometer placement sites. In addition, the IZ had no effect on MMG amplitude and little effect on MMG MPF values. The results of the present study indicated that the SF thickness values and IZ did not affect the MMG signal. PMID- 21704531 TI - Sticking to one's diet: commentary on "Quining diet qualia" by Keith Frankish. PMID- 21704532 TI - Walking dreams in congenital and acquired paraplegia. AB - To test if dreams contain remote or never-experienced motor skills, we collected during 6 weeks dream reports from 15 paraplegics and 15 healthy subjects. In 9/10 subjects with spinal cord injury and in 5/5 with congenital paraplegia, voluntary leg movements were reported during dream, including feelings of walking (46%), running (8.6%), dancing (8%), standing up (6.3%), bicycling (6.3%), and practicing sports (skiing, playing basketball, swimming). Paraplegia patients experienced walking dreams (38.2%) just as often as controls (28.7%). There was no correlation between the frequency of walking dreams and the duration of paraplegia. In contrast, patients were rarely paraplegic in dreams. Subjects who had never walked or stopped walking 4-64 years prior to this study still experience walking in their dreams, suggesting that a cerebral walking program, either genetic or more probably developed via mirror neurons (activated when observing others performing an action) is reactivated during sleep. PMID- 21704533 TI - Reconstruction of the elbow joint with extracorporeal irradiated bone graft associated with low intensity pulsed ultrasound in malignant soft tissue tumor. PMID- 21704534 TI - Necrosis of the ungual process of great toe as cause for long-standing disabling pain: a case report. AB - We report a case of necrosis of the ungual process of the great toe, which caused longstanding disabling pain in a 34-year-old woman. After a 3-year history of unsuccessful conservative treatment, surgical excision led to complete and persistent relief of the symptoms. Although rare, idiopathic osteonecrosis, even small in size, should be taken into consideration in patients who complain of pain of the foot and lacking conclusive etiologic evidence. PMID- 21704535 TI - Preinjected fluids do not benefit microwave ablation as those in radiofrequency ablation. AB - RATIONALE AND OBJECTIVES: To detect whether the efficacy of microwave ablation (MWA) could be improved by preinjected fluids in an ex vivo porcine liver model. MATERIALS AND METHODS: Ablations were performed for 12 minutes using energy output of impedance-based (power output gradually rose to 200W, maintained until increases in tissue impedance of 20 Omega, reduced to 10W, and switched on again 15 seconds later) in radiofrequency ablation (RFA) or 80 W in MWA. Before ablation, 5 mL of ethanol, distilled water, 0.9% NaCl solution, or 10% NaCl solution (n = 6 each) was injected into the targeted liver tissue. Ablations without fluid injection served as control. The ablation diameter, volume, shape index, and temperature were recorded and compared. RESULTS: Preinjection of 0.9% or 10% NaCl solution resulted in larger coagulation volumes than that of the control group in RFA experiments (28.1 +/- 2.9 cm(3), 45.3 +/- 6.3 cm(3), 20.0 +/ 2.5 cm(3), respectively; P < .05). Ethanol and distilled water had no impact on coagulation volumes in RFA. Preinjection of ethanol or 10% NaCl solution created smaller coagulation volumes than that of the control group in MWA experiments (34.3 +/- 2.0 cm(3), 33.9 +/- 4.1 cm(3), 58.0 +/- 6.6 cm(3), respectively; P < .001). 0.9% NaCl solution and distilled water had no impact on coagulation volumes in MWA. CONCLUSION: In an ex vivo porcine liver, preinjected fluids do not benefit microwave ablation as those in radiofrequency ablation. PMID- 21704536 TI - Normal tissue quantitative T1 and T2* MRI relaxation time responses to hypercapnic and hyperoxic gases. AB - RATIONALE AND OBJECTIVES: Longitudinal (T(1)) and effective transverse (T(2)*) magnetic resonance (MR) relaxation times provide noninvasive measures of tissue oxygenation. The objective for this study was to quantify independent effects of inhaled O(2) and CO(2) on normal tissue T(1) and T(2)* in rabbit liver, kidney, and paraspinal muscle. MATERIALS AND METHODS: Three gas challenges (100% O(2), 10% CO(2) [balance air], and carbogen [90% O(2) + 10% CO(2)]) were delivered to the rabbits in random order to isolate the effects of inspired O(2) and CO(2). During each challenge, quantitative T(1) and T(2)* maps were collected on a 1.5 Tesla MR imaging. Mean changes in T(1) (DeltaT(1)) and T(2)* (DeltaT(2)*) were calculated from regions of interest in each organ. RESULTS: Greatest DeltaT(1) and DeltaT(2)* changes were observed in liver for 10% CO(2) and in kidney for 100% O(2). DeltaT(1) and DeltaT(2)* generally followed predicted patterns when transitioning from air breathing: lower T(1)/higher T(2)* with inspired O(2), higher T(1)/lower T(2)* with inspired CO(2), and variable T(1)/T(2)* changes in the presence of both (ie, carbogen). New observations also emerged: 1) between gas-challenge transitions revealed the greatest significance in DeltaT(2)* for the liver and kidney resulting from the isolation of independent O(2) and CO(2) effects; 2) DeltaT(2)* provided the best sensitivity and detected both tissue oxygenation and blood volume modulation; and 3) DeltaT(1) sensitivity was restricted mainly to tissue oxygenation in the absence of counteracting vasodilatation. CONCLUSION: Robust use of MR relaxation times as noninvasive biomarkers requires an understanding of their relative sensitivity to organ specific physiological responses. PMID- 21704537 TI - Evaluation of global DNA hypomethylation in human prostate cancer and prostatic intraepithelial neoplasm tissues by immunohistochemistry. AB - OBJECTIVE: To identify the differences of 5-methylcytosine (5-MC) level between primary prostate cancer tissues (PCTs), prostate cancer-adjacent benign tissues (PCABTs), low-grade prostatic intraepithelial neoplasia (LGPIN), and high-grade prostatic intraepithelial neoplasia (HGPIN), and further analysis the 5-MC alterations in prostate cancer with pathologic grade and clinical prognosis. MATERIALS AND METHODS: Immunohistochemistry method with a 5-MC monoclonal antibody was used to identify the 5-methylcytosine (5-MC) levels in PCTs, PCABTs, LGPIN, and HGPIN specimens in the present study. Statistical analysis with SPSS software (SPSS Inc., Chicago, IL) was used to compare differences of 5-MC levels in the four groups and evaluate the 5-MC alterations in prostate cancer with pathologic grade and clinical prognosis. RESULTS: We found that 38 of 48 (79.1%) patients studied showed a decrease in 5-MC staining of PCTs compared with PCABTs. The difference in the methylation levels for the PCTs and the PCABTs was highly statistically significant (P < 0.001). Spearman correlation showed there was no statistically significant association between the average score of 5-MC staining and Gleason score sum. Kaplan-Meier survival analysis showed that patient group with no or weak 5-MC staining compared with group with moderate and strong 5-MC staining was associated with better survival of patients, although there was no statistically significant difference between the 2 groups in predicating prognosis (P = 0.385). The average scores of 5-MC staining for LGPIN, HGPIN, PCABTs, and PCTs groups were 6.91, 1.58, 6.63, and 3.10, respectively. The methylation level of HGPIN group, as well as that of PCTs group, was significantly lower than those of LGPIN (P < 0.001; P < 0.001) and PCABTs groups (P < 0.001; P < 0.001), respectively, with the 5-MC levels of PCABTS group similar to that of LGPIN group (P = 0.476). 5-MC levels of HGPIN group was lower than that PCTs group (P = 0.004). CONCLUSIONS: We found that global DNA methylation was low in most prostate cancer compared with benign regions from the same patient's sections. None of the DNA hypomethylation changes in primary cancers were associated with pathologic grade and clinical prognosis. In addition, immunohistochemistry showed that the global methylation was lower in HGPIN compared with LGPIN and methylcytosine staining in HGPIN was lower than that of PCTs. The results suggest that global DNA hypomethylation might play an important role in the process of prostate cancer initiation rather than progression. PMID- 21704538 TI - Urothelial carcinoma at the uretero-enteric junction: multi-center evaluation of oncologic outcomes after radical nephroureterectomy. AB - OBJECTIVE: The natural history of urothelial carcinoma arising at the uretero enteric junction (UEJ) is poorly defined, and the data guiding clinical management of these patients is limited. Therefore, we evaluated oncologic outcomes of patients treated for urothelial carcinoma at the UEJ. METHODS: Utilizing a multi-institutional database of patients treated with radical nephroureterectomy (RNU), we assessed the clinicopathologic parameters and oncologic outcomes of UEJ tumors compared with other upper tract urothelial carcinomas (UTUC). Survival analyses were performed to determine independent predictors of disease recurrence and cancer-specific mortality after RNU. RESULTS: The study included 1,363 patients, 921 men and 442 women with 36 months median follow-up after RNU. Compared with UTUC in the kidney or ureter, UEJ tumors (n = 22) were more likely to demonstrate features of advanced disease, which were proved to be independent predictors of disease recurrence and cancer specific mortality after RNU. The 5 year disease-free survival (DFS) and cancer specific survival (CSS) rates were 25% and 39% in those with UEJ tumors vs. 69% and 73% in those with UTUC in the kidney or ureter (P = 0.001 and P = 0.008, respectively). CONCLUSIONS: UEJ tumors harbor features of locally advanced disease associated with high risk of systemic recurrence and death from cancer after RNU. Our findings suggest the need for integration of systemic therapy into the management paradigm of these patients. PMID- 21704539 TI - Stent-assisted remote iliac artery endarterectomy: an alternative approach to treating combined external iliac and common femoral artery disease. AB - OBJECTIVE: Stent-assisted remote iliac endarterectomy (SA-RIEA) is a hybrid minimally invasive technique for treating patients with combined external iliac and common femoral disease, when the only alternative would be conventional open revascularisation. DESIGN: This was a retrospective, single-centre study. MATERIALS AND METHODS: From January 2004 to April 2010, 155 SA-RIEA procedures were performed. The patients' mean age was 62 (range, 43-86) years. Indications for surgery were: severe claudication in 79 (51%), rest pain in 43 (28%) and gangrene in 33 (21%) cases. The mean length of follow-up was 21 months. RESULT: Initial technical success was achieved in 145 (93.5%) procedures. Ten patients required conversion to a conventional iliofemoral reconstructive procedure. The 1 , 3- and 5-year primary, primary-assisted and secondary patency rates were 80.2%, 74.7% and 69.3%; 84.8%, 82.4% and 78.2%; and 86.8%, 84.2% and 79.6%, respectively. Within the first 30 days, there were no early reocclusions, one (0.6%) perioperative death due to myocardial infarction, five (3.4%) minor wound complications and two (1.3%) limb losses. During follow-up, seven patients underwent open reconstruction due to symptomatic reocclusion, and four were re operated on due to symptomatic restenosis (three percutaneous transluminal angioplasties (PTAs), one reendarterectomy). CONCLUSION: In patients with combined common femoral and external iliac disease, SA-RIEA appears to offer a safe and effective alternative to conventional open surgery. PMID- 21704540 TI - The use of pulsed-field gel electrophoresis to investigate the epidemiology of Mycoplasma bovis in French calf feedlots. AB - Mycoplasma bovis is a major cause of respiratory outbreaks in cattle feedlots. In this study pulsed-field gel electrophoresis (PFGE) was used to trace field strains and provide information on M. bovis patterns of spread in calf feedlots. The suitability of KpnI, MluI and SmaI restriction enzymes was assessed on different sets of strains. The discriminative power of the first two enzymes was first assessed using 28 epidemiologically unrelated strains; stability was 100% on multiple isolates from in vivo experimental infection. Thirty-nine field isolates from six feedlots were then evaluated. In contrast to the unique fingerprints displayed by the unrelated strains, the isolates from the feedlots showed identical patterns at the time of the outbreak of respiratory disease and 4 weeks later. The PFGE typing results suggest that M. bovis strains follow a clonal epidemic spread pattern at the herd level and that the same strain persists in calves of the herd after the clinical signs have disappeared. PMID- 21704541 TI - Distribution of acute phase proteins in the bovine forestomachs and abomasum. AB - Acute phase proteins (APPs) are produced mainly by the liver and their concentration is increased during the systemic inflammatory response. Expression of haptoglobin (Hp), serum amyloid A (SAA), lipopolysaccharide-binding protein (LBP) and alpha-1 acid glycoprotein (AGP) was determined in the mucosa of the normal bovine forestomachs and abomasum by qualitative and quantitative reverse transcriptase-PCR for mRNA and by Western blot analysis and immunohistochemistry for proteins. Although expression of SAA mRNA was evident in the forestomachs and abomasum, SAA protein was identified only in the abomasum. Expression of Hp protein was high in the forestomachs and abomasum, even though expression of Hp mRNA was negligible. The main site of expression of LBP mRNA was the omasum, whereas the highest protein expression was evident in the abomasum. AGP was expressed at low levels in the bovine forestomachs. Western blot analysis revealed a heterogeneous electrophoretic pattern for AGP, LBP and Hp, indicating that different stomach compartments produce isoforms that are different to those expressed by the liver. Expression of APPs by the bovine forestomachs and abomasum may contribute to regulation of the innate immune response against pathogens. PMID- 21704542 TI - Controlling tuberculosis in a llama (Lama glama) herd using clinical signs, tuberculin skin testing and serology. AB - An outbreak of tuberculosis (TB), caused by Mycobacterium bovis, was investigated in a small herd of llamas (Lama glama). Based on three ante-mortem diagnostic methods (clinical signs, tuberculin skin test reactions, and 'Rapid Test' serology), 12 llamas were selected for examination post-mortem. Grossly visible lesions suspicious of TB were observed in eight animals, four of which had exhibited clinical signs, one was a skin test 'reactor', and three had been seropositive. M. bovis was isolated from seven of these eight animals. Clinical signs combined with serology were found to be useful in identifying infected animals, but tuberculin skin testing had limited negative predictive value as four llamas that were subsequently confirmed as infected were not detected using this assay. PMID- 21704543 TI - Partial status epilepticus - rapid genetic diagnosis of Alpers' disease. AB - We describe four children with a devastating encephalopathy characterised by refractory focal seizures and variable liver dysfunction. We describe their electroencephalographic, radiologic, genetic and pathologic findings. The correct diagnosis was established by rapid gene sequencing. POLG1 based Alpers' disease should be considered in any child presenting with partial status epilepticus. PMID- 21704544 TI - Experimental aspects in acquisition of wide bandwidth solid-state MAS NMR spectra of low-gamma nuclei with different opportunities on two commercial NMR spectrometers. AB - The acquisition and different appearances observed for wide bandwidth solid-state MAS NMR spectra of low-gamma nuclei, using (14)N as an illustrative nucleus and employing two different commercial spectrometers (Varian, 14.1T and Bruker, 19.6T), have been compared/evaluated and optimized from an experimental NMR and an electronic engineering point of view, to account for the huge differences in these spectra. The large differences in their spectral appearances, employing the recommended/standard experimental set-up for the two different spectrometers, are shown to be associated with quite large differences in the electronic design of the two types of preamplifiers, which are connected to their respective probes through a 50Omega cable, and are here completely accounted for. This has led to different opportunities for optimum performances in the acquisition of nearly ideal wide bandwidth spectra for low-gamma nuclei on the two spectrometers by careful evaluation of the length for the 50Omega probe-to-preamp cable for the Varian system and appropriate changes to the bandwidth (Q) of the NMR probe used on the Bruker spectrometer. Earlier, we reported quite distorted spectra obtained with Varian Unity INOVA spectrometers (at 11.4 and 14.1T) in several exploratory wide bandwidth (14)N MAS NMR studies of inorganic nitrates and amino acids. These spectra have now been compared/evaluated with fully analyzed (14)N MAS spectra correspondingly acquired at 19.6T on a Bruker spectrometer. It is shown that our upgraded version of the STARS simulation/iterative-fitting software is capable of providing identical sets for the molecular spectral parameters and corresponding fits to the experimental spectra, which fully agree with the electronic measurements, despite the highly different appearances for the MAS NMR spectra acquired on the Varian and Bruker spectrometers. PMID- 21704545 TI - Asymmetric uptake of sepiapterin and 7,8-dihydrobiopterin as a gateway of the salvage pathway of tetrahydrobiopterin biosynthesis from the lumenal surface of rat endothelial cells. AB - Rat aortic endothelial cells were cultured on a porous membrane to form a monolayer sheet. They efficiently accumulated tetrahydrobiopterin (BH(4)) by uptake of sepiapterin but did so only moderately by uptake of dihydrobiopterin. The endothelial cell sheet preferentially took up the pterins from the apical side. Accordingly, a dense accumulation of ENT2-like immunoreactivity was visualized on the apical surface of the cell sheet. The findings suggest that vascular endothelial cells receive BH(4) precursors directly from the blood stream rather than from ablumenal tissues. PMID- 21704546 TI - Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. AB - Antiquitin (ATQ) deficiency is the main cause of pyridoxine dependent epilepsy characterized by early onset epileptic encephalopathy responsive to large dosages of pyridoxine. Despite seizure control most patients have intellectual disability. Folinic acid responsive seizures (FARS) are genetically identical to ATQ deficiency. ATQ functions as an aldehyde dehydrogenase (ALDH7A1) in the lysine degradation pathway. Its deficiency results in accumulation of alpha aminoadipic semialdehyde (AASA), piperideine-6-carboxylate (P6C) and pipecolic acid, which serve as diagnostic markers in urine, plasma, and CSF. To interrupt seizures a dose of 100 mg of pyridoxine-HCl is given intravenously, or orally/enterally with 30 mg/kg/day. First administration may result in respiratory arrest in responders, and thus treatment should be performed with support of respiratory management. To make sure that late and masked response is not missed, treatment with oral/enteral pyridoxine should be continued until ATQ deficiency is excluded by negative biochemical or genetic testing. Long-term treatment dosages vary between 15 and 30 mg/kg/day in infants or up to 200 mg/day in neonates, and 500 mg/day in adults. Oral or enteral pyridoxal phosphate (PLP), up to 30 mg/kg/day can be given alternatively. Prenatal treatment with maternal pyridoxine supplementation possibly improves outcome. PDE is an organic aciduria caused by a deficiency in the catabolic breakdown of lysine. A lysine restricted diet might address the potential toxicity of accumulating alphaAASA, P6C and pipecolic acid. A multicenter study on long term outcomes is needed to document potential benefits of this additional treatment. The differential diagnosis of pyridoxine or PLP responsive seizure disorders includes PLP-responsive epileptic encephalopathy due to PNPO deficiency, neonatal/infantile hypophosphatasia (TNSALP deficiency), familial hyperphosphatasia (PIGV deficiency), as well as yet unidentified conditions and nutritional vitamin B6 deficiency. Commencing treatment with PLP will not delay treatment in patients with pyridox(am)ine phosphate oxidase (PNPO) deficiency who are responsive to PLP only. PMID- 21704547 TI - Stop codon read-through with PTC124 induces palmitoyl-protein thioesterase-1 activity, reduces thioester load and suppresses apoptosis in cultured cells from INCL patients. AB - Infantile neuronal ceroid lipofuscinosis (INCL), a lethal hereditary neurodegenerative lysosomal storage disorder, affects mostly children. It is caused by inactivating mutations in the palmitoyl-protein thioesterase-1(PPT1) gene. Nonsense mutations in a gene generate premature termination codons producing truncated,nonfunctional or deleterious proteins. PPT1 nonsense mutations account for approximately 31% of INCL patients in the US. Currently, there is no effective treatment for this disease. While aminoglycosides such asgentamycin suppress nonsense mutations, inherent toxicity of aminoglycosides prohibits chronic use inpatients. PTC124 is a non-toxic compound that induces ribosomal read-through of premature termination codons. We sought to determine whether PTC124-treatment of cultured cells from INCL patients carrying nonsense mutations in the PPT1 gene would correct PPT1 enzyme-deficiency with beneficial effects. Our results showed that PTC124-treatment of cultured cells from INCL patients carrying PPT1 nonsense-mutations induced PPT1 enzymatic activity in a dose- and time-dependent manner. This low level of PPT1 enzyme activity induced by PTC124 is virtually identical to that induced by gentamycin-treatment. Even though only a modest increase in PPT1 activity was achieved by PTC124-treatment of INCL cells, this treatment reduced the levels of thioester (constituent of ceroid) load. Our results suggest that PTC124-treatment induces PPT1 enzymatic activity in cultured cells from INCL patients carrying PPT1 nonsense-mutations, and this modest enzymatic activity has demonstrable beneficial effects on these cells. The clinical relevance of these effects may be tested in animal models of INCL carrying nonsense mutations in the PPT1 gene. PMID- 21704548 TI - Re: The use of RCT's in manual therapy--are we trying to fit a round peg into a square hole? PMID- 21704549 TI - Structure-based druggability assessment--identifying suitable targets for small molecule therapeutics. AB - A target is druggable if it can be modulated in vivo by a drug-like molecule. The general properties of oral drugs are summarized by the 'rule of 5' which specifies parameters related to size and lipophilicity. Structure-based target druggability assessment consists of predicting ligand-binding sites on the protein that are complementary to these drug-like properties. Automated identification of ligand-binding sites can use geometrical considerations alone or include specific physicochemical properties of the protein surface. Features of a pocket's size and shape, together with measures of its hydrophobicity, are most informative in identifying suitable drug-binding pockets. The recent availability of several validation sets of druggable versus undruggable targets has helped fuel the development of more elaborate methods. PMID- 21704550 TI - Novel biological insights revealed from cell type-specific expression profiling. AB - Transcriptional regulation plays a major role in defining cell identity. Analysis of cell type-resolution expression profiling datasets is moving beyond cataloging gene expression patterns to reveal novel biological insights. Recently developed expression maps of the shoot apical meristem and gametophytes can be used as tools to help define novel cell types and pathways. Already these maps have revealed cell type-specific epigenetic regulatory mechanisms that play important roles in development. Further examples are provided that demonstrate how cell type-specific expression profiling can also be used to uncover genes and pathways in development and response to stress that would be nearly impossible to identify using traditional genetics. PMID- 21704552 TI - Experimental IR and Raman spectra and quantum chemical studies of molecular structures, conformers and vibrational characteristics of nicotinic acid and its N-oxide. AB - FTIR and Raman spectra of nicotinic acid and its N-oxide have been recorded and analyzed. The stabilities, optimized molecular geometries, APT charges and vibrational characteristics for the two possible conformers of nicotinic acid and its N-oxide have been computed using DFT method. The E (trans) conformers of both the molecules are found to be more stable and less polar than their respective Z (cis) conformers. Due to addition of an O atom at the N1 site in nicotinic acid the magnitudes of atomic charges on all the H atomic sites of the nicotinic acid N-oxide molecule are found to increase. Most of the vibrational frequencies have nearly the same magnitude for the two conformers of both the molecules. However, significant changes are noticed in their IR intensities, Raman activities and depolarization ratios of the Raman bands. The calculated frequencies have been correlated with the experimental frequencies. PMID- 21704553 TI - Study binding of Al-curcumin complex to ds-DNA, monitoring by multispectroscopic and voltammetric techniques. AB - In this work a complex of Al3+ with curcumin ([Al(curcumin) (EtOH)2](NO3)2) was synthesized and characterized by UV-vis, FT-IR, elemental analysis and spectrophotometric titration techniques. The mole ratio plot revealed a 1:1 complex between Al3+ and curcumin in solution. For binding studies of this complex to calf thymus-DNA various methods such as: UV-vis, fluorescence, circular dichroism (CD), FT-IR spectroscopy and cyclic voltammetry were used. The intrinsic binding constant of ACC with DNA at 25 degrees C was calculated by UV vis and cyclic voltammetry as 2.1*10(4) and 2.6*10(4), respectively. The thermodynamic studies showed that the reaction is enthalpy and entropy favored. The CD results showed that only the Delta-ACC interacts with DNA and the Delta ACC form has not any tendency to interact with DNA, also the pure curcumin has not any stereoselective interaction with CT-DNA. Fluorimetric studies showed that fluorescence enhancement was initiated by a static process in the ground state. The cyclic voltammetry showed that ACC interact with DNA with a binding site size of 2. From the FT-IR we concluded that the Delta-ACC interacts with DNA via partial electrostatic and minor groove binding. In comparison with previous works it was concluded that curcumin significantly reduced the affinity of Al3+ to the DNA. PMID- 21704551 TI - Protein kinase signaling networks in plant innate immunity. AB - In plants and animals, innate immunity is triggered through pattern recognition receptors (PRRs) in response to microbe-associated molecular patterns (MAMPs) to provide the first line of inducible defense. Plant receptor protein kinases (RPKs) represent the main plasma membrane PRRs perceiving diverse MAMPs. RPKs also recognize secondary danger-inducible plant peptides and cell-wall signals. Both types of RPKs trigger rapid and convergent downstream signaling networks controlled by calcium-activated PKs and mitogen-activated PK (MAPK) cascades. These PK signaling networks serve specific and overlapping roles in controlling the activities and synthesis of a plethora of transcription factors (TFs), enzymes, hormones, peptides and antimicrobial chemicals, contributing to resistance against bacteria, oomycetes and fungi. PMID- 21704554 TI - Multiplex real-time PCR for the detection and quantitation of HTLV-1 and HTLV-2 proviral load: addressing the issue of indeterminate HTLV results. AB - BACKGROUND: Routine diagnosis of Human T Lymphotropic virus (HTLV) infection is primarily serologically based; however the proportion of unresolved and indeterminate Western blot results range from 0.02% to 50% in endemic areas. OBJECTIVES: To validate a sensitive in-house quantitative multiplex real-time assay (mqRT-PCR), capable of detecting and quantifying HTLV-1 and HTLV-2, and use it to differentiate unresolved serological profiles, and monitor infection in HTLV-1 infected patients. STUDY DESIGN: The mqRT-PCR was designed as a single tube assay. Quantitative results were reported as copy number of HTLV provirus per 10(6) cells and the numbers of cells were calculated based on the quantitative result for albumin, of which there are 2 copies/cell. Assay standards were amplified from HTLV-1 infected MT-2 cells and HTLV-2 transfected CEM cells. Blood samples were obtained from HTLV seropositive former blood donors. RESULTS: The mqRT-PCR assay was efficient (98.8-101.2%), reproducible (coefficient of variance<5%) and sensitive to 1 copy for HTLV-1, HTLV-2 and Albumin. The assay resolved the infection profile in 16/17 patients, with undetermined subtype, all of which were reassigned as HTLV-1 infections. In addition, the average PVL detected in patients suffering from HTLV-1 associated HAM/TSP (n=23, 13,450 copies/10(6) cells) was significantly higher than those detected in asymptomatic carriers (n=21, 6665 copies/10(6) cells). CONCLUSIONS: We propose a new testing algorithm for the laboratory diagnosis of HTLV infection, which includes HTLV specific mqRT-PCR for resolving HTLV serological results. Furthermore, quantitation of PVL load by real-time PCR may be useful in assessing the link between infection and disease, and in monitoring patients undergoing therapy. PMID- 21704555 TI - Overnight distribution and motor characteristics of REM sleep behaviour disorder episodes in patients with narcolepsy-cataplexy. AB - OBJECTIVE: The study aimed to examine the temporal distribution of episodes of REM sleep behaviour disorder (RBD) over the night and their motor and polysomnographic (PSG) characteristics in patients with narcolepsy-cataplexy (NC). METHODS: Full-night video-PSG recordings of a continuous series of 37 drug naive NC patients with clinically-documented RBD were examined to detect the occurrences of RBD episodes (disclosed in 27 patients) and to classify their related PSG and motor behaviour features. RESULTS: RBD episodes occurred with comparable frequency in REM sleep periods of the first and second halves of the night, regardless of the length of REM periods, patients' age or disease duration. Vocalisations and pantomimes occurred in comparable proportions of RBD episodes in the two halves of the night, while aggressive-violent movements were significantly more frequent in RBD episodes of the second half of the night. No sleep parameter significantly differed in patients with RBD occurring in the first/second/neither half of the night. CONCLUSIONS: RBD episodes (a) are not an every night phenomenon in NC patients with clinically documented RBD, regardless of their age or disease duration; (b) can occur in any period of REM sleep, regardless of length; and (c) display less violent-aggressive motor features when they occur in the first half of the night. Multi-night studies with dream-report collection may disclose whether this overnight variation in the violent aggressive features in RBD episodes of NC patients is associated with a time-of night-related variation in dream content. PMID- 21704556 TI - Adverse childhood experiences and sleep disturbances in adults. AB - BACKGROUND: Sleep disturbances are associated with an increased risk for many chronic diseases and unhealthy behaviors. A history of adverse childhood experiences (ACEs) is also associated with similar adult health outcomes. We studied the relationship between multiple ACEs and the likelihood of experiencing self-reported sleep disturbances in adulthood. METHODS: We used data from the adverse childhood experiences (ACE) study, a retrospective cohort study of 17,337 adult health maintenance organization members in California who completed a survey about eight ACEs, which included childhood abuse and growing up with various forms of household dysfunction. The self-reported sleep disturbances measured included ever having trouble falling or staying asleep and feeling tired after a good night's sleep. We used an integer count of the number of ACEs (the ACE score) to assess the cumulative impact of these experiences on the likelihood of self-reported sleep disturbances. RESULTS: Thirty-three percent of the cohort reported trouble falling or staying asleep, while 24% reported feeling tired after sleeping. All eight ACE categories were associated with an increased likelihood of self-reported sleep disturbances (p<0.05). Compared to persons with an ACE score of 0, those with an ACE score >= 5 were 2.1 (95% CI: 1.8-2.4) times more likely to report trouble falling or staying asleep and 2.0 (95% CI: 1.7-2.3) times more likely to report feeling tired even after a good night's sleep. The trend for increasing odds for both types of self-reported sleep disturbance with increasing ACE scores was statistically significant (p<0.0001). CONCLUSIONS: Adverse childhood experiences were associated with self-reported sleep disturbances in adulthood, and the ACE score had a graded relationship to these sleep disturbances. A history of ACEs should be obtained for patients with self reported sleep disturbances to coordinate services that ameliorate the long-term effects of these events. PMID- 21704557 TI - Effects of an advanced sleep schedule and morning short wavelength light exposure on circadian phase in young adults with late sleep schedules. AB - OBJECTIVE: We examined the effects of an advanced sleep/wake schedule and morning short wavelength (blue) light in 25 adults (mean age+/-SD=21.8+/-3 years; 13 women) with late sleep schedules and subclinical features of delayed sleep phase disorder (DSPD). METHODS: After a baseline week, participants kept individualized, fixed, advanced 7.5-h sleep schedules for 6days. Participants were randomly assigned to groups to receive "blue" (470nm, ~225lux, n=12) or "dim" (<1lux, n=13) light for 1h after waking each day. Head-worn "Daysimeters" measured light exposure; actigraphs and sleep diaries confirmed schedule compliance. Salivary dim light melatonin onset (DLMO), self-reported sleep, and mood were examined with 2*2 ANOVA. RESULTS: After 6days, both groups showed significant circadian phase advances, but morning blue light was not associated with larger phase shifts than dim-light exposure. The average DLMO advances (mean+/-SD) were 1.5+/-1.1h in the dim light group and 1.4+/-0.7h in the blue light group. CONCLUSIONS: Adherence to a fixed advanced sleep/wake schedule resulted in significant circadian phase shifts in young adults with subclinical DSPD with or without morning blue light exposure. Light/dark exposures associated with fixed early sleep schedules are sufficient to advance circadian phase in young adults. PMID- 21704558 TI - Delayed sleep phase syndrome and depression. PMID- 21704559 TI - Scientific process, pharmacology and drug discovery. AB - Scientific method in drug discovery has centered on generating a hypothesis (target identification) and hypothesis testing (target validation). Traditionally, both processes were performed using animal data, with the basic pharmacologist being pivotal. Many therapeutic areas that rely on human data to validate targets as animal models are seen as poorly predictive. Failures of molecules in Phase III for poor efficacy raise questions about target identification and validation. The clinical pharmacologist, working with the basic pharmacologist can play a major role in aiding target identification and by developing trial designs using small patient populations, mitigating the need for full Phase III studies to test the hypothesis. Technologies such as genomics, non invasive imaging and proteomics are in the forefront of improving target identification and in some cases in providing paradigms for target validation in man. PMID- 21704560 TI - How technology can aid the pharmacologist in carrying out drug discovery. PMID- 21704561 TI - Reprint of: Faculty leadership development: concept or reality? PMID- 21704562 TI - Rifamycin inhibition of WT and Rif-resistant Mycobacterium tuberculosis and Escherichia coli RNA polymerases in vitro. AB - Mycobacterium tuberculosis (MTB) infects over 9 million people globally and claims approximately 2 million lives annually. Rifampin (Rif) is one of the first line anti-tuberculosis drugs that inhibits transcription by binding to the beta subunit (encoded by the rpoB gene) of the prokaryotic RNA polymerase (RNAP). A highly conserved 81 base pair core region among the beta subunit of prokaryotes harbors most of the point mutations leading to rifamycin-resistant (RifR) mutations, where the majority of the clinically relevant MTB RifR mutations result from amino acid substitutions of one of the following three amino acids: betaAsp435, betaHis445, and betaSer450 (MTB numbering). In this study, to determine the direct effect of rifamycins on the MTB RNAP, co-overexpression vectors were constructed to co-express the core subunits of wild-type and RifR mutants of MTB RNAP. The three aforementioned amino acids were each mutated to the most prevalent substitution found in the MTB clinical isolates (Asp435Val, His445Tyr, Ser450Leu) in the rpoB gene via site-directed mutagenesis. After purification via two-step column chromatography, the in vitro activity of the wild-type and RifR mutant MTB RNAPs was assessed via rolling circle transcription assay. The apparent IC(50) values for three key rifamycins (rifampin (Rif), rifabutin (Rbn), and rifaximin (Rfx)) were determined and these results indicate that the mutant RNAPs demonstrate approximately 10(3)-fold or greater loss of affinities for rifamycins relative to wild-type MTB RNAP. Along with the MTB RNAPs, rifamycin inhibition of the Escherichia coli RNAP counterparts was also assessed. Previously, it has been reported that Gram-positive bacteria (particularly mycobacteria) are more sensitive to rifamycins than Gram-negative bacteria. Under our experimental conditions, the rifamycin IC(50)s for wild-type and RifR mutants of MTB and E. coli RNAPs (wild-type and corresponding mutants) were very similar; therefore, the difference in sensitivity toward rifamycins does not reside in the RNAP itself. The correlation between the sensitivity of rifamycins and permeability into cells was evaluated using the wild-type E. coli strains (TG2 and DH5alpha) and a mutant E. coli strain with efflux pump defects (EC2880, tolC(-)/imp(-)). The MICs were drastically lower in the EC2880 strain, consistent with previous reports that the differential sensitivity of MTB and E. coli to rifamycins is not related to the RNAP, but rather has to do with efflux pumps in E. coli. Future work will focus on the elucidation of the molecular interaction of these MTB RifR mutants with rifamycins to provide insight to the design of novel rifamycins. PMID- 21704563 TI - Predictors of adherence to medication in older Korean patients with hypertension. AB - BACKGROUND AND RESEARCH OBJECTIVES: Adherence to a medication regimen is a major factor in achieving adequate blood pressure control for hypertensive patients. However, older adults often report having missed doses, which they attribute to forgetfulness. The purpose of this study was to identify significant factors, including socioeconomic variables, hypertension history, and cognitive functions, contributing to medication adherence among older Korean adults with hypertension. SUBJECTS AND METHOD: This study involved 241 older patients with hypertension from a community senior center during the period from 2008 to 2009. Data were collected through face to face interviews. The association of medication adherence with socioeconomic characteristics, hypertension-related history, knowledge, antihypertensive lifestyle, and memory was assessed by computing odds ratios in logistic regressions. RESULTS AND CONCLUSIONS: Of the 241 patients, 44% were aged 75 or older, and 60% were male. The rate of non-adherence with antihypertensive medication was 41%. Metamemory, adherence to an antihypertensive lifestyle, and employment status, were associated with participants' adherence to antihypertensive medication in both univariate and multivariate analyses. Results suggest that memory functions are a key factor to medication adherence among the Korean elderly population. In contrast to younger adults, unintentional non adherence appears to be a major issue for older adults to keep medicating. Interventions focusing on memory ability, such as strategies for recalling and placing cues, are needed for implementation in the population of older Korean patients with hypertension. Unemployed older people who have hypertensive lifestyles should also be considered a high-risk group for non-adherence to medication. PMID- 21704564 TI - Benign temporo-parieto-occipital junction epilepsy with vestibular disturbance: an underrecognized form of epilepsy? AB - We describe a series of adolescents and adults who share the electroclinical characteristics of a nonlesional, pharmacoresponsive epilepsy manifesting as prominent vestibular disturbances, suggesting a temporo-parieto-occipital (TPO) junction origin. We retrospectively reviewed a database of consecutive patients referred to the epilepsy clinic over a 10-year period with respect to the following criteria: recurrent episodes of paroxysmal vestibular symptoms, normal MRI, and interictal EEG changes over the posterior regions. Fourteen patients were finally selected (10 males, 4 females). Mean age at onset was 26.5 (range: 12-59). The diagnosis of epilepsy was usually delayed until after cardiology and/or otorhinolaryngology workup. The predominant features on interictal scalp EEGs were abnormalities over the posterior areas. All patients responded well to antiepileptic medication. We propose that although further characterization is needed to label it a syndrome, this underdiagnosed form of epilepsy merits recognition. PMID- 21704565 TI - Normal vitamin D and low free estradiol levels in women on enzyme-inducing antiepileptic drugs. AB - Relationships between reproductive hormone levels, bone turnover marker levels, bone mineral density, and rates of bone loss were evaluated in premenopausal women with epilepsy taking enzyme-inducing antiepileptic drugs (EIAEDs: phenytoin or carbamazepine) or lamotrigine. Calciotropic and reproductive hormone levels, bone turnover marker levels, and bone mineral density were measured at baseline and 1 year. Bone mineral density did not differ between groups. Serum calcium (P<0.001) and estrone (P<0.001) levels were lower in the EIAED group. Sex hormone binding globulin levels were higher (P<0.001) and percentage free estradiol levels were lower (P<0.001) in the EIAED group. We detected no relationship between bone mineral density change and calciotropic hormone or bone turnover marker levels. Women with higher sex hormone-binding globulin and lower free estradiol levels sustained more bone loss at the total hip (P=0.04 and P=0.02) and a trend toward more bone loss at the lumbar spine (P=0.07 and P=0.08). These findings suggest that lower estrogen levels may contribute to bone loss in premenopausal women with epilepsy. PMID- 21704566 TI - Evaluation of sleep disturbances in children with epilepsy: a questionnaire-based case-control study. AB - Epilepsy is a chronic neurological disorder accompanied by a wide range of comorbid conditions that can adversely affect the quality of life of children. Sleep disturbances not only predispose children to mood, cognitive, and behavioral impairments, but also have a significant impact on physical health. The aim of this study was to evaluate sleep patterns among Chinese children with epilepsy and healthy subjects in Hong Kong, and examine the relationship between parent-reported sleep problems and specific epilepsy parameters. We conducted a cross-sectional, questionnaire-based, case-control study and included 63 children with epilepsy and 169 healthy children aged between 4 and 12 years. The Children's Sleep Habits Questionnaire (CSHQ) was used as an assessment tool. Our results indicated that children with epilepsy have similar sleep patterns but greater sleep disturbances compared with healthy subjects. Sleep problems should not be overlooked, and a comprehensive review of the sleep habits of this group of patients should be conducted. PMID- 21704567 TI - Clinical evidence on the undertreatment of older and poor performance patients who have advanced non-small-cell lung cancer: is there a role for targeted therapy in these cohorts? AB - A significant proportion of patients who have advanced non-small-cell lung cancer (NSCLC) do not receive treatment even though they may benefit. For instance, studies linking the Surveillance Epidemiology and End Results and Medicare databases show that chemotherapy, even platinum-based doublets, produces a survival benefit in elderly patients who have NSCLC, but only about 30% receive such treatment. Patients with poor performance status and those with significant co-morbidities are also typically undertreated. However, recent clinical evidence suggests that treatment decisions for these populations must be reconsidered. With the emerging availability of validated molecular tools to predict response to specific therapies, the identification of those who may derive substantial benefit from certain interventions is possible even in currently under-served populations. All patients who have advanced NSCLC should be referred for treatment evaluation, even those who are considered ineligible for conventional cytotoxic chemotherapy, and for molecular testing used to match patients with available treatment options. PMID- 21704568 TI - Activity patterns in chronic pain: underlying dimensions and associations with disability and depressed mood. AB - Activity patterns are believed to play an important role in the development and perpetuation of chronic pain. So far, 3 important activity patterns have been studied: avoidance behavior, persistence behavior, and pacing behavior. Yet, empirical evidence is limited and inconclusive about the relationships between these activity patterns and important outcomes. Therefore, the present study was aimed at identifying activity patterns by means of factor analyses and determining their relationship with disability and depressive symptomatology in participants with chronic pain (N = 132). Items across different measurement instruments pertaining to 1 particular activity pattern were aggregated, and submitted to factor analysis. Results from 3 separate factor analyses revealed 6 distinct activity patterns: pain avoidance, activity avoidance, task-contingent persistence, excessive persistence, pain-contingent persistence, and pacing. In line with our hypotheses, pain and activity avoidance, and excessive persistence, were related to higher levels of disability and depressive symptomatology. In contrast to hypotheses, pacing was associated with worse outcomes as well. Interestingly, task-contingent persistence was related to lower levels of disability and depressive symptomatology. When controlling for pain and the other activity patterns, excessive persistence and activity avoidance were the most detrimental in terms of relations with depressed mood or disability. Task contingent persistence appeared to be the least detrimental. PERSPECTIVE: Our findings suggest the existence of several activity patterns, which are differentially related to disability and depressive symptomatology, in participants with chronic pain. The present results are discussed in the light of previous findings, and may provide a new impetus for future studies on activity patterns in chronic pain research. PMID- 21704569 TI - Idiopathic multiple tiny serous retinal pigment epithelial detachments: report of 2 cases and review of the literature. AB - BACKGROUND: Bilateral multiple serous retinal pigment epithelial detachments (PEDs) are a very rare entity. Such conditions may be idiopathic or a presentation of some ocular and/or systemic pathologies. We report 2 unique cases of bilateral multiple serous PEDs without any known cause. Additionally, similar cases of multiple serous idiopathic PEDs reported in the literature were reviewed. CASE REPORT: The patients were middle-age women with no known related ocular and systemic problems. Fundus examination, fluorescein angiography, and optical coherence tomography found innumerable, small, serous, idiopathic PEDs mainly located in the macular area. One woman also had an associated subretinal pigment epithelial hemorrhage in 1 eye, which regressed spontaneously. There are only a few similar cases reported in the literature. CONCLUSION: Idiopathic bilateral, multiple, tiny, serous PEDs in middle-age healthy people are rare entities that may be a variant of central serous choroidopathy in which retinal pigment epithelium is predominantly involved. The visual prognosis seems to be good without any intervention unless complicated by hemorrhages. PMID- 21704570 TI - Brown-McLean syndrome. AB - BACKGROUND: Brown-McLean syndrome is a rare corneal presentation usually resulting from intracapsular cataract extraction or multiple anterior segment surgeries and the passage of time. CASE REPORTS: Two patients presented to our clinic with Brown-McLean syndrome. Both had undergone intracapsular cataract extraction with peripheral iridectomies many years before their current examinations. CONCLUSIONS: Brown-McLean syndrome can be overlooked or misdiagnosed. Although intracapsular cataract extraction is rare in this country today, eye doctors should be made aware of its presence and potential side effects. PMID- 21704571 TI - A rugged and accurate liquid chromatography-tandem mass spectrometry method for quantitative determination of BMS-790052 in plasma. AB - To support toxicokinetic assessments, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of BMS-790052 in rat, dog, monkey, rabbit and mouse K(2)EDTA plasma. The drug was isolated from buffered samples using ISOLUTE C8 96-well solid phase extraction (SPE) plates. Chromatographic separation was achieved on a Waters Atlantis dC18 analytical column (2.1 mm * 50 mm, 5 MUm) with detection accomplished using an API 4000 tandem mass spectrometer in positive ion electrospray and multiple reaction monitoring (MRM) mode. The standard curves, which ranged from 5.00 to 2000 ng/mL for BMS-790052, were fitted to a 1/x(2) weighted linear regression model. The intra-assay precision (%CV) and inter-assay precision (%CV) were within 8.5%, and the assay accuracy (%Dev) was within +/-7.1 for rat, dog, monkey, rabbit and mouse K(2)EDTA plasma. This accurate, precise, and selective SPE/LC-MS/MS method has been successfully applied to analyze several thousands of non-clinical study samples. PMID- 21704572 TI - Simultaneous determination of ginsenoside (G-Re, G-Rg1, G-Rg2, G-F1, G-Rh1) and protopanaxatriol in human plasma and urine by LC-MS/MS and its application in a pharmacokinetics study of G-Re in volunteers. AB - Ginsenoside Re (G-Re) improved the memory function of experimental animals in a preclinical study. Several types of saponins including G-Rg1, G-Rg2, G-F1, G-Rh1, and protopanaxatriol (PPT) may be the metabolites of G-Re according to reports from preclinical trials. In order to support a study of the pharmacokinetics of G Re, an analytical method for G-Re and the co-detection of its probable metabolites using liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and validated. Solid phase extraction was utilized in the sample preparation. Separation of the analytes was achieved using a gradient elution (0.05% formic acid-methanol-acetonitrile, each organic phase containing 0.05% formic acid) at a flow rate of 0.3 mL/min with a retention time of approximately 2.88 min for G-Re. Data were acquired in the multiple reaction mode (MRM) and the linear range of the standard curve of plasma and urine samples for G-Re was 0.05 20 ng/mL with r(2)>=0.99. In the analysis of probable metabolites, G-Re, G-Rg1, G F1, G-Rh1 and PPT were all detected in samples; however, G-Rg2 was not detected. PMID- 21704573 TI - Determination of unbound vismodegib (GDC-0449) concentration in human plasma using rapid equilibrium dialysis followed by solid phase extraction and high performance liquid chromatography coupled to mass spectrometry. AB - A rapid equilibrium dialysis (RED) assay followed by a solid phase extraction (SPE) high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for the quantitative determination of unbound vismodegib in human plasma was developed and validated. The equilibrium dialysis was carried out using 0.3 mL plasma samples in the single-use plate RED system at 37 degrees C for 6h. The dialysis samples (0.1 mL) were extracted using a Strata-X-C 33u Polymeric Strong Cation SPE plate and the resulting extracts were analyzed using reverse-phase chromatography and positive electrospray ionization (ESI) mass spectrometry. The standard curve, which ranged from 0.100 to 100 ng/mL for vismodegib, was fitted to a 1/x(2) weighted linear regression model. The lower limit of quantitation (LLOQ, 0.100 ng/mL) was sufficient to quantify unbound concentrations of vismodegib after dialysis. The intra-assay precision of the LC-MS/MS assay, based on the four analytical QC levels (LLOQ, low, medium and high), was within 7.7% CV and inter-assay precision was within 5.5% CV. The assay accuracy, expressed as %Bias, was within +/-4.0% of the nominal concentration values. Extraction recovery of vismodegib was between 77.9 and 84.0%. The assay provides a means for accurate assessment of unbound vismodegib plasma concentrations in clinical studies. PMID- 21704574 TI - Comments to "the intelligent, painless, "germ-free" colonoscopy: a Columbus' egg for increasing population adherence to colorectal cancer screening?". PMID- 21704575 TI - Classification of Raynaud's disease based on angiographic features. AB - Accurate diagnosis and timely management are crucial to avoid an ischaemic consequence in Raynaud's disease. There is, however, no objective classification of this disorder which guides surgical planning in refractory cases. We propose a new classification system to achieve this. From 2003 to 2009, we treated 178 patients (351 hands) who underwent surgical intervention due to an ischaemic consequence. We analysed the angiographic features of the arterial supply of the hand at three levels: (1) radial or ulnar, (2) palmar arch and common digital and (3) digital vessels. Subsequent surgical interventions were tailored according to disease types, and these included combinations of: digital sympathectomy, balloon angioplasty and end-to-end interposition venous or arterial grafting. We classified Raynaud's disease into six types: type I and II involve the radial or ulnar arteries. Type I (27.3%) showed complete occlusion, while type II (26.2%) involved partial occlusion. Type IIIa (27.1%) showed tortuous, narrowed or stenosed common digital and digital vessels. Type IIIb (1.4%) is a subset which involved the digital vessel of the index finger related to exposure to prolonged vibration. Type IV and V showed global involvement from the main to digital vessels. Type IV (13.7%) showed diffused tortuosity, narrowing and stenosis. Type V (4.3%) is the most severe, with paucity of vessels and very scant flow. Nearly half (47%) of the patients had associated systemic disease. This new classification provides objective and valuable information for decision making regarding choice of surgical procedures for the treatment of patients with Raynaud's disease which had failed conservative therapy. PMID- 21704576 TI - Invited commentary. PMID- 21704577 TI - Popliteal lymphatico-venous anastomosis for lower limb lymphedema to allow patients to adopt the traditional Japanese "seiza" sitting position. PMID- 21704578 TI - The UK plastic surgery trainee. PMID- 21704579 TI - A multidisciplinary cleft palate team in the developing world: performance and challenges. PMID- 21704580 TI - Graves' disease in subjects with type 1 diabetes mellitus: a prevalence study in western Sicily (Italy). AB - OBJECTIVE: To assess the prevalence of Graves' disease in patients with type 1 diabetes mellitus all coming from a defined geographical area (western Sicily Italy) and to investigate the clinical features of these subjects. METHODS: The records of 470 consecutive patients with type 1 diabetes mellitus referred in a 5 year period were analyzed. RESULTS: During the period of the survey, out of 470 patients with type 1 diabetes, 14 (3%) had a previous diagnosis of Graves' disease. There were 9 female and 5 male; these patients showed a high age at diabetes onset (mean 38 years). Diagnosis of Graves' disease was often pre existing or simultaneous to that of diabetes. Vitiligo was coexisting in 4 subjects; none of them presented other autoimmune diseases. Graves' orbitopathy was present in two cases. CONCLUSIONS: Our data confirm the frequent association between Graves' disease and type 1 diabetes. Graves' disease often preceded diagnosis of type 1 diabetes, particularly in female subjects with a high age at diabetes onset; therefore, in these subjects, an active search for the presence of pancreatic autoimmunity is warranted for many years after thyroid dysfunction appearance. PMID- 21704581 TI - [Acute pancreatitis and thrombotic microangiopathy: a two-way association]. AB - Acute pancreatitis and thrombotic microangiopathy is an established association: but which is the cause, which is the consequence? Thanks to two case reports and a literature review, we put to light an unequivocal link. Indeed, thrombotic microangiopathy may be responsible for ischemic pancreatitis. On the other hand, acute pancreatitis, whatever its cause, may trigger thrombotic microangiopathy. In either case, an anti-ADAMTS-13 antibody can be detected: its research is mandatory. PMID- 21704582 TI - New rehabilitation program for intermittent claudication: Interval training with active recovery: pilot study. AB - BACKGROUND: Peripheral arterial disease (PAD) is one of the complications of atherosclerosis. Intermittent claudication is the second stage of PAD. In controlled studies on patients with Stage II PAD, intensive rehabilitation training has proved effective for improving the walking distance in this population. The objective of this prospective study was to determine the effects of treadmill interval training followed by active recovery (low-intensity exercise). METHODS AND RESULTS: Eleven patients with Stage II peripheral arterial disease were included in a rehabilitation program (mean age 68.3+/-10.3 years) for five days a week during two weeks including global exercises, exercises below and above the level of injury. The interval training program consisted of treadmill training for 30minutes twice a day (morning and evening) with a progressively increased intensity: the first week speed was increased and the second week slope was increased. Each session included five six-minute cycles. Each cycle was made of three minutes of active workout followed by three minutes of active recovery. RESULTS: All patients improved their walking distance, from a mean of 610 m (120-1930) at the beginning of the program to a mean of 1252 m (320 2870) at the end (P=0.003). All patients were very motivated by the rehabilitation training program No adverse event was reported. CONCLUSION: This study showed that an interval training program with active recovery was effective and safe for patients with Stage II peripheral arterial disease, the patients' motivation was high. This study must now be validated by a clinical trial. PMID- 21704583 TI - Evaluation of anionic half generation 3.5-6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin. AB - Aquated cisplatin was added to half-generation PAMAM dendrimers and the resultant complexes were purified by centrifuge. The drug-dendrimer complexes were then characterised by 1-D and diffusion (1)H NMR and ICP-AES. The amount of drug bound was found to increase in proportion with dendrimer size: G3.5, 22 cis {Pt(NH(3))(2)} molecules per dendrimer; G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37%, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5'-GMP at temperatures of 60 degrees C for over a week (percentage of drug released 18, 30, 35 and 63%, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6 mg/kg, reduced tumour size by 33% compared to an untreated control group. The G6.5 cisplatin-dendrimer complex was administered at two doses (6 and 8 mg/kg equivalent of cisplatin). Both were well tolerated by the mice. The lower dose displayed comparable activity to cisplatin with a tumour volume reduction of 32%, but the higher dose was significantly more active than free cisplatin with a tumour reduction of 45%. PMID- 21704584 TI - A new cumulene diiron complex related to the active site of Fe-only hydrogenases and its phosphine substituted derivatives: synthesis, electrochemistry and structural characterization. AB - A new cumulene diiron complex related to the Fe-only hydrogenase active site [(MU SCH(2)C(S)CCH(2))Fe(2)(CO)(6)] (1) was obtained by treatment of (MU LiS)(2)Fe(2)(CO)(6) with excess 1,4-dichloro-2-butyne. By controllable CO displacement of 1 with PPh(3) and bis(diphenylphosphino)methane (dppm), mono- and di-substituted complexes, namely [(MU-SCH(2)C(S)CCH(2))Fe(2)(CO)(5)L] (2: L=PPh(3); 3: L=dppm) and [(MU-SCH(2)C(S)CCH(2))Fe(2)(CO)(4)L(2)] (4: L=PPh(3); 5: L=dppm) could be prepared in moderate yields. Treatment of 1 with bis(diphenylphosphino)ethane (dppe) afforded a double butterfly complex [(MU SCH(2)C(S)CCH(2))Fe(2)(CO)(5)](2)(MU-dppe) (7). With dppm in refluxing toluene, a dppm-bridged complex [(MU-SCH(2)C(S)CCH(2))Fe(2)(CO)(4)(MU-dppm)] (6) was obtained. These model complexes were characterized by IR, (1)H, (31)P NMR spectra and the molecular structures of 1, 2 and 5-7 were determined by single crystal X ray analyses. The electrochemistry of 1-3 was studied and the electrocatalytic property of 1 was investigated for proton reduction in the presence of HOAc. PMID- 21704585 TI - EPR investigation of the role of B10 phenylalanine in neuroglobin - evidence that B10Phe mediates structural changes in the heme region upon disulfide-bridge formation. AB - The function of neuroglobin, a member of the vertebrate globin family, is still unknown. In human neuroglobin (NGB), the formation of a disulfide bridge between the CysCD7 and CysD5 is known to affect the heme environment and its ligand binding kinetics. Here, we show by means of EPR that the PheB10 residue plays a key role in transmitting the structural information from the disulfide bridge to the heme-pocket region. While formation of a disulfide bridge in ferric wild-type NGB leads to a considerable change of its EPR parameters, only minor changes are observed in the case of ferric PheB10Leu NGB. Furthermore, wild-type NGB is found to be much more stable in the presence of H(2)O(2) than its PheB10Leu or its HisE7Leu mutants. While tyrosyl radicals are induced in HisE7Leu NGB by the addition of H(2)O(2), this is not the case for wild-type and PheB10Leu NGB. The results will be discussed in terms of the protein's putative functions. PMID- 21704586 TI - Extensive pancreas regeneration following acinar-specific disruption of Xbp1 in mice. AB - BACKGROUND & AIMS: Progression of diseases of the exocrine pancreas, which include pancreatitis and cancer, is associated with increased levels of cell stress. Pancreatic acinar cells are involved in development of these diseases and, because of their high level of protein output, they require an efficient, unfolded protein response (UPR) that mediates recovery from endoplasmic reticulum (ER) stress following the accumulation of misfolded proteins. METHODS: To study recovery from ER stress in the exocrine organ, we generated mice with conditional disruption of Xbp1 (a principal component of the UPR) in most adult pancreatic acinar cells (Xbp1fl/fl). We monitored the effects of constitutive ER stress in the exocrine pancreas of these mice. RESULTS: Xbp1-null acinar cells underwent extensive apoptosis, followed by a rapid phase of recovery in the pancreas that included expansion of the centroacinar cell compartment, formation of tubular complexes that contained Hes1- and Sox9-expressing cells, and regeneration of acinar cells that expressed Mist1 from the residual, surviving Xbp1+ cell population. CONCLUSIONS: XBP1 is required for homeostasis of acinar cells in mice; ER stress induces a regenerative response in the pancreas that involves acinar and centroacinar cells, providing the needed capacity for organ recovery from exocrine pancreas disease. PMID- 21704587 TI - RB and p53 cooperate to prevent liver tumorigenesis in response to tissue damage. AB - BACKGROUND & AIMS: The tumor suppressors retinoblastoma (RB) and p53 are important regulators of the cell cycle. Although human cancer cells inactivate RB and p53 by many mechanisms, the cooperative roles of these proteins in tumorigenesis are complex and tissue specific. We analyzed the cooperation of RB and p53 in liver development and pathogenesis of hepatocellular carcinoma. METHODS: Spontaneous and carcinogen-induced (diethylnitrosamine) tumorigenesis were studied in mice with liver-specific deletions of Rb and/or p53 (Rbf/f;albcre+, p53f/f;albcre+ and Rbf/f; p53f/f;albcre+ mice). Genotype, histologic, immunohistochemical, microarray, quantitative polymerase chain reaction, immunoblot, and comparative genomic hybridization analyses were performed using normal and tumor samples. Comparative microarray analyses were performed against publicly available human microarray data sets. RESULTS: Deletion of RB and p53 from livers of mice deregulated the transcriptional programs associated with human disease. These changes were not sufficient for spontaneous tumorigenesis; potent quiescence mechanisms compensated for loss of these tumor suppressors. In response to hepatocarcinogen-induced damage, distinct and cooperative roles of RB and p53 were revealed; their loss affected cell cycle control, checkpoint response, and genome stability. In damaged tissue, combined loss of RB and p53 resulted in early lesion formation, aggressive tumor progression, and gene expression signatures and histologic characteristics of advanced human hepatocellular carcinoma. CONCLUSIONS: The effects RB and p53 loss are determined by the tissue environment; cell stresses that promote aggressive disease reveal the functions of these tumor suppressors. PMID- 21704588 TI - Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt beta-catenin signaling to slow tumor progression. AB - BACKGROUND & AIMS: Patients with pancreatic ductal adenocarcinoma are deficient in vitamin A, resulting in activation of pancreatic stellate cells (PSCs). We investigated whether restoration of retinol to PSCs restores their quiescence and affects adjacent cancer cells. METHODS: PSCs and cancer cell lines (AsPc1 and Capan1) were exposed to doses and isoforms of retinoic acid (RA) in 2-dimensional and 3-dimensional culture conditions (physiomimetic organotypic culture). The effects of all-trans retinoic acid (ATRA) were studied in LSL-KrasG12D/+;LSL Trp53R172H/+;Pdx-1-Cre mice, a model of human pancreatic ductal adenocarcinoma. RESULTS: After incubation with ATRA, PSCs were quiescent and had altered expression of genes that regulate proliferation, morphology, and motility; genes that encode cytoskeletal proteins and cytokines; and genes that control other functions, irrespective of culture conditions or dosage. In the organotypic model, and in mice, ATRA induced quiescence of PSCs and thereby reduced cancer cell proliferation and translocation of beta-catenin to the nucleus, increased cancer cell apoptosis, and altered tumor morphology. ATRA reduced the motility of PSCs, so these cells created a "wall" at the junction between the tumor and the matrix that prevented cancer cell invasion. Restoring secreted frizzled-related protein 4 (sFRP4) secretion to quiescent PSCs reduced Wnt-beta-catenin signaling in cancer cells and their invasive ability. Human primary and metastatic pancreatic tumor tissues stained strongly for cancer cell nuclear beta-catenin but had low levels of sFRP4 (in cancer cells and PSCs). CONCLUSIONS: RA induces quiescence and reduces motility of PSCs, leading to reduced proliferation and increased apoptosis of surrounding pancreatic cancer cells. RA isoforms might be developed as therapeutic reagents for pancreatic cancer. PMID- 21704589 TI - Hepatitis B virus core promoter mutations contribute to hepatocarcinogenesis by deregulating SKP2 and its target, p21. AB - BACKGROUND & AIMS: Clinical studies have associated hepatitis B virus core promoter (CP) mutations with an increased risk of hepatocellular carcinoma. The CP region overlaps with the HBV X (HBx) gene, which has been implicated in hepatocarcinogenesis. The cyclin kinase inhibitor p21WAF1/CIP1 is an important regulator of cell cycle progression and proliferation. We determined whether HBx mutants that result from mutations in the CP deregulate p21 and these processes. METHODS: We constructed a series of HBx mutants with changes in the CP region that correspond to A1762T/G1764A (TA), T1753A, T1768A, or a combination of these (combo) and expressed them, along with wild-type HBx under control of its endogenous promoter, in primary human hepatocytes (PHHs) and HepG2 cells. We then analyzed the effects of CP mutations on expression and degradation of p21 and the effects on cell cycle progression and proliferation. RESULTS: The combo mutant decreased levels of p21 and increased cyclin E expression in PHHs and HepG2 cells. The combo mutant, but not HBx with single or double CP mutations, accelerated p21 degradation in HepG2 cells. The combo mutant increased expression of S-phase kinase-associated protein 2 (SKP2) in PHHs and Huh7 cells. Silencing of SKP2 abrogated the effects of CP mutations on p21 expression. The kinetics of p21 expression correlated with changes in cell cycle distribution. The combo mutant accelerated cell cycle progression; p21 overexpression restored G1 arrest. CONCLUSIONS: HBx mutants with changes that correspond to a combination of CP mutations up-regulate SKP2, which then down-regulates p21 via ubiquitin-mediated proteasomal degradation. CP mutations might increase the risk of hepatocellular carcinoma via this pathway. PMID- 21704590 TI - Liposome-induced complement activation and related cardiopulmonary distress in pigs: factors promoting reactogenicity of Doxil and AmBisome. AB - Hypersensitivity reactions to liposomal drugs, often observed with Doxil and AmBisome, can arise from activation of the complement (C) system by phospholipid bilayers. To understand the mechanism of this adverse immune reaction called C activation-related pseudoallergy (CARPA), we analyzed the relationship among liposome features, C activation in human serum in vitro, and liposome-induced cardiovascular distress in pigs, a model for human CARPA. Among the structural variables (surface charge, presence of saturated, unsaturated, and PEGylated phospholipids, and cisplatin vs. doxorubicin inside liposomes), high negative surface charge and the presence of doxorubicin were significant contributors to reactogenicity both in vitro and in vivo. Morphological analysis suggested that the effect of doxorubicin might be indirect, via distorting the sphericity of liposomes and, if leaked, causing aggregation. The parallelism among C activation, cardiopulmonary reactions in pigs, and high rate of hypersensitivity reactions to Doxil and AmBisome in humans strengthens the utility of the applied tests in predicting the risk of CARPA. FROM THE CLINICAL EDITOR: The authors studied complement activation-related pseudoallergy (CARPA) in a porcine model and demonstrate that high negative surface charge and drug effects leading to distortion of liposome sphericity might be the most critical factors leading to CARPA. The applied tests might be used to predict CARPA in humans. PMID- 21704591 TI - Protective effect of the apoptosis-sensing nanoparticle AnxCLIO-Cy5.5. AB - The diagnostic utility of the apoptosis-sensing nanoparticle (NP), AnxCLIO-Cy5.5, is well established. Here we sought to define the pathophysiological impact of the nanoparticle (NP) on apoptotic cells. Confocal microscopy showed that AnxCLIO Cy5.5 remained bound to apoptotic cell membranes for 3 hours but by 7 hours had become completely internalized. AnxCLIO-Cy5.5 exposure did not impact energetics, metabolism or caspase-3 activity in apoptotic cells. Gene expression in cells exposed to AnxCLIO-Cy5.5 did not reveal upregulation of pro-inflammatory or cell death pathways. Moreover, exposure to AnxCLIO-Cy5.5 decreased the frequency of membrane rupture of early apoptotic cells. Similarly, in mice exposed to 1 hour of ischemia -reperfusion, the injection of AnxCLIO-Cy5.5 at the onset of reperfusion reduced infarct size/area at risk by 16.2%. Our findings suggest that AnxCLIO-Cy5.5 may protect apoptotic cells by stabilizing their cell membranes and has the potential to become a theranostic agent, capable of both identifying and salvaging early apoptotic cells. From the Clinical Editor: This study demonstrates that AnxCLIO-Cy5.5 nanoparticles may protect apoptotic cells by cell membrane stabilization and have the potential to become a "theranostic agent" capable of identifying and salvaging early apoptotic cells. PMID- 21704592 TI - Gold-doxorubicin nanoconjugates for overcoming multidrug resistance. AB - Multidrug resistance (MDR) is a major clinical obstacle to the success of cancer chemotherapy. Here we developed a gold-doxorubicin (DOX) nanoconjugates system to overcome MDR. Gold nanoparticles (AuNPs) were first PEGylated as Au-PEG-NH(2), and DOX was then grafted onto AuNPs via a cleavable disulfide linkage (Au-PEG-SS DOX). Confocal images revealed that the extent of intracellular uptake of Au-PEG SS-DOX was greater than that of free DOX in the MDR cells, and inductively coupled plasma mass spectroscopy analysis further confirmed that AuNPs significantly increased the level of drug accumulation in MDR cells at a nanoparticles dose greater than 15 MUM. The cytotoxicity study demonstrated that the Au-PEG-SS-DOX nanoconjugates system efficiently released the anticancer drug DOX and enhanced its cytotoxicity against MDR cancer cells. This study highlights the potential of using AuNPs for overcoming of MDR in cancer chemotherapy. FROM THE CLINICAL EDITOR: This study demonstrates that gold nanoparticles can be successfully applied to overcome MDR in cancer chemotherapy. PMID- 21704593 TI - In vivo cancer imaging by poly(ethylene glycol)-b-poly(E-caprolactone) micelles containing a near-infrared probe. AB - Noninvasive near-infrared (NIR) fluorescence imaging is a promising technique for the intraoperative assessment of solid tumor removal. We incorporated a lipophilic NIR probe, 1,1'-dioctadecyltetramethyl indotricarbocyanine iodide (DiR), in poly(ethylene glycol)-b-poly(E-caprolactone) (PEG-b-PCL) micelles, resulting in DiR solubilization in water, occupying nanoscopic PEG-b-PCL micelles. DiR in a self-quenched or nonquenched state showed different kinetics of release from PEG-b-PCL micelles in vitro; however, both obtained high tumor delineation (tumor-to-muscle ratio of 30-43 from collected organs). These results suggest that PEG-b-PCL micelles with DiR are a promising nanosized imaging agent that will provide a basis for enhanced surgical guidance via NIR visualization of tumors. FROM THE CLINICAL EDITOR: In this paper, noninvasive near-infrared fluorescence imaging coupled with specific lipophilic probes is discussed as a promising technique for intraoperative assessment of solid tumor removal, leading to optimized outcomes for in toto removal of tumors. PMID- 21704594 TI - A novel dextran-oleate-cRGDfK conjugate for self-assembly of nanodrug. AB - We report a novel synthetic biocompatible material: a conjugate with a fatty acid substituted dextran decorated with cRGDfK peptide, which was used as a stable coating material instead of the conventional poly(ethylene glycol) for nanodrug preparation. This novel dextran-oleate-cRGDfK conjugate (DO-cRGDfk) could self assemble into a micellar structure in aqueous solution, and was used as a surfactant to formulate nanodrug with poly(d,l-lactic-co-glycolic) acid as matrix to encapsulate paclitaxel with high drug-loading efficiency. The conjugate allowed the fabrication of nanodrug with a targeting moiety on its surface in a simple and robust step. The resultant nanoparticles could induce cellular apoptosis more effectively than that of the commercial paclitaxel formulation, Taxol. Thus, DO-cRGDfk could be used as an alternative to poly(ethylene glycol) as a biocompatible surface coating polymeric material for nanoparticle preparation. FROM THE CLINICAL EDITOR: The authors describe a novel synthetic biocompatible conjugate, which consists of a fatty acid-substituted dextran decorated with cRGDfK peptide. This conjugate was used as a stable coating material for nanodrug preparation, and can be used in place of conventional PEG. PMID- 21704595 TI - In vitro and in vivo evaluation of the inflammatory response to nanoscale grooved substrates. AB - The immune response to an implanted biomaterial is orchestrated by macrophages. In this study various nanogrooved patterns were created by using laser interference lithography and reactive ion etching. The created nanogrooves mimic the natural extracellular matrix environment. Macrophage cell culture demonstrated that interleukin 1beta and TNF-alpha cytokine production were upregulated on nanogrooved substrates. In vivo subcutaneous implantation in a validated mouse cage model for 14 days demonstrated that nanogrooves enhanced and guided cell adhesion, and few multinucleated cells were formed. In agreement with the in vitro results, cytokine production was found to be nanogroove dependent, as interleukin 1beta, TNF-alpha, TGF-beta and osteopontin became upregulated. The results indicate that biomaterial surface texturing, especially at the nanometric scale, can be used to control macrophage activation to induce a wound healing response, rather than a profound inflammatory response. From the Clinical Editor: The authors investigate various nano-grooved patterns that mimic the natural extracellular matrix environment and demonstrate (both in macrophage cultures and in vivo) that interleukin 1beta and TNF-alpha cytokine production is dependent upon surface texturing at the nanometric scale. They propose that modified surfaces may trigger macrophage activation to promote a wound healing response. PMID- 21704596 TI - A Lipo-PEG-PEI complex for encapsulating curcumin that enhances its antitumor effects on curcumin-sensitive and curcumin-resistance cells. AB - A cationic liposome-PEG-PEI complex (LPPC) was used as a carrier for the encapsulation of hydrophobic curcumin to give curcumin/LPPC. Curcumin/LPPC had an average size less than 270 nm and a zeta potential of approximately 40 mV. The LPPC encapsulation efficiency for curcumin was about 45%. The authors found it surprising that the cytotoxic activity of the curcumin/LPPC was fivefold higher than curcumin when tested on curcumin-sensitive cells and 20-fold more active against curcumin-resistant cells. Curcumin/LPPC treatment caused a cell cycle arrest at G2/M phase, which rapidly resulted in apoptosis. The increased cytotoxic activity of curcumin/LPPC is likely attributable to its rapid accumulation in the cell. In vivo, administration of curcumin/LPPC inhibited about 60 - 90% of tumor growth in mice bearing CT-26 or B16F10 cells. These results demonstrate LPPC encapsulation technology is able to enhance the effects of antitumor drugs. Use of this technology may provide a new tool for cancer therapy, especially for drug-resistant cancer. From the Clinical Editor: This team of investigators used a cationic liposome-PEG-PEI complex (LPPC) to encapsulate curcumin. The different delivery method resulted in the five-fold increase of cytotoxic activity against curcumin-sensitive cells and twenty-fold against curcumin-resistant cells. PMID- 21704597 TI - Magnetoliposomes with high USPIO entrapping efficiency, stability and magnetic properties. AB - The DRV technique (followed by extrusion) was used for construction of hydrophilic-USPIO encapsulating liposomes. Magnetoliposomes (ML) were characterized for size, surface charge, entrapment, physical stability and magnetic properties (relaxivity). Results show that nanosized extruded-DRV MLs encapsulate higher amounts of USPIOs in comparison with sonicated vesicles. Fe (III) encapsulation efficiency (EE) is 12%, the highest reported to date for nanosized MLs. EE of MLs is influenced by ML membrane composition and polyethyleneglycol (PEG) coating. PEG-coating increases ML EE and stability; however, r(2)-to-r(1) ratios decrease (in comparison with non-PEGylated MLs). Most ML-types are efficient T2 contrast agents (because r(2)-to-r(1) ratios are higher than that of free USPIOs). Targeted MLs were formed by successfully immobilizing OX-26 monoclonal antibody on ML surface (biotin-streptavidin ligation), without significant loss of USPIOs. Targeted MLs retained their nanosize and integrity during storage for 1 month at 4 degrees C and up to 2 weeks at 37 degrees C. PMID- 21704598 TI - Chitosan enhances the stability and targeting of immuno-nanovehicles to cerebro vascular deposits of Alzheimer's disease amyloid protein. AB - Alzheimer's disease amyloid beta (Abeta) proteins accumulate in the cerebral vasculature and cause cerebral amyloid angiopathy (CAA). The objective of this study was to resolve critical formulation issues in developing nanoparticles (NPs) capable of permeating the blood brain barrier (BBB) and targeting cerebrovascular Abeta proteins. To achieve this objective we designed immuno nanovehicles, which are chitosan-coated poly lactic-co-glycolic acid (PLGA) NPs conjugated with a novel anti-Abeta antibody. Measurements made according to Derjaguin-Landau-Verwey-Overbeek (DLVO) theory indicated that the immuno nanovehicles have a much lower propensity to aggregate than the control nanovehicles. Immuno-nanovehicles showed enhanced uptake at the BBB and better targeting of the Abeta proteins deposited in the CAA model in vitro in comparison with the control nanovehicles. In addition, chitosan enhanced aqueous dispersibility and increased the stability of immuno-nanovehicles during lyophilization, thus transforming them into ideal vehicles for delivering therapeutic and diagnostic agents to the cerebral vasculature ridden with vascular amyloid. FROM THE CLINICAL EDITOR: In this study, the authors report the development of chitosan-coated PLGA nanoparticles conjugated with anti-amyloid antibody to be used as immuno-nanovehicles to image cerebral amyloid angiopathy deposits in vivo. This method enables delivering therapeutic and diagnostic agents to the cerebral vasculature ridden with vascular amyloid. PMID- 21704599 TI - Novel nanostructured lipid-dextran sulfate hybrid carriers overcome tumor multidrug resistance of mitoxantrone hydrochloride. AB - Novel nanostructured lipid-dextran sulfate hybrid carriers (NLDCs) were successfully developed for sustained delivery of water-soluble cationic mitoxantrone hydrochloride (MTO) and overcoming multidrug resistance. The introduction of negative polymer of dextran sulfate sodium significantly improved the encapsulation efficiency (97.4%) and sustained the release of MTO (86.9% at 72 hours). In vivo pharmacokinetics in rats after intravenous administration demonstrated that MTO-loaded NLDCs (MTO-NLDCs) had higher area under the curve and longer half-life than MTO solution (MTO-Sol). In the biodistribution study, NLDCs significantly improved the MTO levels in plasma, spleen, and brain, and decreased the distribution of MTO in heart and kidney. In comparison with MTO Sol, MTO-NLDCs efficiently enhanced cytotoxicity through the higher accumulation of MTO in breast cancer resistance protein (BCRP)-overexpressing MCF-7/MX cells. MTO-NLDCs entered into the resistant cancer cells by the clathrin-mediated endocytosis pathway, which escaped the efflux induced by BCRP transporter and thereby overcame the multidrug resistance of MCF-7/MX cells. FROM THE CLINICAL EDITOR: In this study, novel nanostructured lipid-dextran sulfate hybrid carriers were synthesized and utilized for sustained delivery of mitoxantrone hydrochloride. The utilized methods successfully addressed multidrug resistance to this chemotherapy agent. PMID- 21704600 TI - Formulation and optimization of nanotransfersomes using experimental design technique for accentuated transdermal delivery of valsartan. AB - The purpose of this work was to develop and statistically optimize nanotransfersomes for enhanced transdermal of valsartan vis-a-vis traditional liposomes. Nanotransfersomes bearing valsartan were prepared by conventional rotary evaporation method and characterized for various parameters including entrapment efficiency, vesicles shape, size, size distribution, and skin permeation. In vivo antihypertensive activity conducted on Wistar rats was also taken as a measure of performance of nanotransfersomes and liposomes. Nanotransfersomes proved significantly superior in terms of amount of drug permeated in the skin, with an enhancement ratio of 33.97 +/- 1.25 when compared to rigid liposomes. This was further confirmed through a confocal laser scanning microscopy study. Nanotransfersomes showed better antihypertensive activity in comparison to liposomes by virtue of better permeation through Wistar rat skin. Finally, it could be concluded that the nanotransfersomes accentuates the transdermal flux of valsartan and could be used as a carrier for effective transdermal delivery of valsartan. FROM THE CLINICAL EDITOR: In this paper, the authors discuss the development and optimization of nanotransfersomes for enhanced transdermal of valsartan and demonstrate accentuated transdermal compared to standard preparations. PMID- 21704601 TI - Plasmin is essential in preventing periodontitis in mice. AB - Periodontitis involves bacterial infection, inflammation of the periodontium, degradation of gum tissue, and alveolar bone resorption, which eventually leads to loss of teeth. To study the role of the broad-spectrum protease plasmin in periodontitis, we examined the oral health of plasminogen (Plg)-deficient mice. In wild-type mice, the periodontium was unaffected at all time points studied; in Plg-deficient mice, periodontitis progressed rapidly, within 20 weeks. Morphological study results of Plg-deficient mice revealed detachment of gingival tissue, resorption of the cementum layer, formation of necrotic tissue, and severe alveolar bone degradation. IHC staining showed massive infiltration of neutrophils in the periodontal tissues. Interestingly, doubly deficient mice, lacking both tissue- and urokinase-type plasminogen activators, developed periodontal disease similar to that in Plg-deficient mice; however, mice lacking only tissue- or urokinase-type plasminogen activator remained healthy. Supplementation by injection of Plg-deficient mice with human plasminogen for 10 days led to necrotic tissue absorption, inflammation subsidence, and full regeneration of gum tissues. Notably, there was also partial regrowth of degraded alveolar bone. Taken together, our results show that plasminogen is essential for the maintenance of a healthy periodontium and plays an important role in combating the spontaneous development of chronic periodontitis. Moreover, reversal to healthy status after supplementation of Plg-deficient mice with plasminogen suggests the possibility of using plasminogen for therapy of periodontal diseases. PMID- 21704602 TI - A homogeneous and nonisotopic assay for phosphatidylinositol 4-kinases. AB - Phosphatidylinositol 4-kinases (PI 4-kinases) catalyze the conversion of phosphatidylinositol to phosphatidylinositol 4-phosphate (PtdIns4P). The four known mammalian PI 4-kinases, PI4KA, PI4KB, PI4K2A, and PI4K2B have roles in intracellular lipid and protein trafficking. PI4KA and PI4KB also assist in the replication of several positive-sense RNA viruses. The identification of selective inhibitors of these kinases would be facilitated by assays suitable for high-throughput screening. We describe a homogeneous and nonisotopic assay for PI 4-kinase activity based on the bioluminescent detection of the ADP produced by kinase reactions. We have evaluated this assay with known nonselective inhibitors of PI 4-kinases and show that it performs similar to radiometric assay formats previously described in the literature. In addition, this assay generates Z factor values of >0.7 for PI4KA in a 384-well format, demonstrating its suitability for high-throughput screening applications. PMID- 21704603 TI - Mapping protein interactions by combining antibody affinity maturation and mass spectrometry. AB - Mapping protein interactions by immunoprecipitation is limited by the availability of antibodies recognizing available native epitopes within protein complexes with sufficient affinity. Here we demonstrate a scalable approach for generation of such antibodies using phage display and affinity maturation. We combined antibody variable heavy (V(H)) genes from target-specific clones (recognizing Src homology 2 (SH2) domains of LYN, VAV1, NCK1, ZAP70, PTPN11, CRK, LCK, and SHC1) with a repertoire of 10(8) to 10(9) new variable light (V(L)) genes. Improved binders were isolated by stringent selections from these new "chain-shuffled" libraries. We also developed a predictive 96-well immunocapture screen and found that only 12% of antibodies had sufficient affinity/epitope availability to capture endogenous target from lysates. Using antibodies of different affinities to the same epitope, we show that affinity improvement was a key determinant for success and identified a clear affinity threshold value (60 nM for SHC1) that must be breached for success in immunoprecipitation. By combining affinity capture using matured antibodies to SHC1 with mass spectrometry, we identified seven known binding partners and two known SHC1 phosphorylation sites in epidermal growth factor (EGF)-stimulated human breast cancer epithelial cells. These results demonstrate that antibodies capable of immunoprecipitation can be generated by chain shuffling, providing a scalable approach to mapping protein-protein interaction networks. PMID- 21704605 TI - Unexpected wide substrate specificity of C. perfringens alpha-toxin phospholipase C. AB - Clostridium perfringens phospholipase C (CpPLC), also called alpha-toxin, is the main virulence factor for gas gangrene in humans. The lipase activity serves the bacterium to generate lipid signals in the host eukaryotic cell, and ultimately to degrade the host cell membranes. Several previous reports indicated that CpPLC was specific for phosphatidylcholine and sphingomyelin. Molecular docking studies described in this paper predict favorable interactions of the CpPLC active site with other phospholipids, e.g. phosphatidylethanolamine, phosphatidylinositol and, to a lesser extent, phosphatidylglycerol. On the basis of these predictions, we have performed experimental studies showing alpha-toxin to degrade all the phospholipids mentioned above. The molecular docking data also provide an explanation for the observed lower activity of CpPCL on sphingomyelin as compared to the glycerophospholipids. PMID- 21704604 TI - Structural stability and heme binding potential of the truncated human dual oxidase 2 (DUOX2) peroxidase domain. AB - The essential role of human dual oxidase 2 (hDUOX2) in thyroid hormone biosynthesis defines this member of the NOX/DUOX family, whose absence due to mutation has been directly related to disease, specifically hypothyroidism. Both human DUOX isoforms, hDUOX1 and hDUOX2, are expressed in thyroid tissue; however, hDUOX1 cannot compensate for inactivation of hDUOX2, suggesting that each enzyme is differentially regulated and/or functions in a unique manner. In efforts to uncover relevant structural and functional differences we have expressed and purified the peroxidase domain of hDUOX2(1-599) for direct comparison with the previously studied hDUOX1(1-593). As was shown for hDUOX1, the truncated hDUOX2 domain purifies without a bound heme co-factor and displays no peroxidase activity. However, hDUOX2(1-599) displays greater stability than hDUOX1(1-593). Surprisingly, upon titration with heme, both isoforms bind heme with a low micromolar affinity, demonstrating that they retain a heme binding site. A conformational difference in the full-length protein and/or a protein-protein interaction may be required to increase the heme binding affinity. PMID- 21704606 TI - Checks and balances: interplay of RTKs and PTPs in cancer progression. AB - In recent years, targeted therapies for receptor tyrosine kinases (RTKs) have shown initial promise in the clinical setting for the treatment of several tumors driven by these oncogenic signaling pathways. Unfortunately, clinical relapse due to acquired resistance to these molecular therapeutics is common. An improved understanding of how tumors bypass the inhibitory effects of RTK-targeted therapies has revealed a rich myriad of possible mechanisms for acquired resistance. Protein tyrosine phosphatases (PTPs) can function as oncogenes or tumor suppressors to either enhance or suppress RTK signaling. Recent studies suggest that the loss or gain of function of PTP's can significantly impinge on RTK signaling during tumor progression. Here we review the interplay between RTKs and PTPs as an emerging mechanism for acquired resistance to RTK-targeted therapies, that may aid in the design of improved therapies to prevent and overcome resistance in treatments for cancer patients. PMID- 21704607 TI - Persistent elevation of paraoxonase-1 specific enzyme activity after weight reduction in obese non-diabetic men with metabolic syndrome. AB - BACKGROUND: Paraoxonase-1 (PON1) is an esterase associated with the high-density lipoprotein (HDL) in serum. To date, there have been few reports about circulating PON1 protein concentration and specific activity in subjects with metabolic syndrome (MetS). More importantly, it is unknown whether weight loss could alter PON1 protein expression or specific activity in obese non-diabetic men with MetS. METHODS: We prospectively enrolled a total of 40 obese non diabetic men with MetS. Among them, 22 subjects finished the 3-month course of weight loss program and complied for longer follow-ups post-weight loss at the 3rd, 12th, and 18th month from the beginning of the program. Twenty-six healthy volunteers served as controls. Serum circulating PON1 concentration was measured by an enzyme linked immunosorbent kit (ELISA) and PON1 activity was measured by an automated PON1 activity assay. RESULTS: Obese non-diabetic men with MetS (n=40) had a higher PON1 protein concentration (31.0 +/- 11.3 vs. 24.8 +/- 9.7 MUg/ml, p=0.025) but lower specific enzyme activity (7.5 +/- 4.0 vs. 11.2 +/- 7.2 mU/MUg, p=0.023) than those of the controls. Multivariate regression analysis of baseline PON1 specific activity revealed that adiponectin was a significant positive predictor (p=0.044) while monocyte chemotactic protein-1 (MCP-1) was a negative predictor (p=0.031). After a 3-month weight loss program, obese MetS men (n=22) had a significant weight reduction (95.8 +/- 9.0 to 86.3 +/- 10.4 kg, with a 9.9 +/- 5.4% decrease, p<0.001). PON1 protein decreased significantly after weight loss and kept declining through the 3rd month till the 18th month follow up. PON1 specific enzyme activity (baseline 7.5 +/- 2.6 mU/MUg) increased significantly after weight loss and kept increasing through the 12th month till the 18th month follow-ups (11.8 +/- 6.4 mU/MUg, p=0.001 vs. baseline). CONCLUSIONS: Weight loss by a 3-month diet and exercise program time-sequentially increased PON1 specific enzyme activity in obese non-diabetic men with MetS. PMID- 21704608 TI - Effects of RBC removal and TRIzol of peripheral blood samples on RNA stability. AB - BACKGROUND: Purification of mRNA from stored specimens is very important because results from RT-PCR and microarray analyses are largely affected by the quality of mRNA. Moreover, many preanalytical factors during collection, processing, and storage may affect mRNA quality and the expression of peripheral blood mononuclear cells (PBMC). In this study, we evaluate the effects of RBC removal techniques and TRIzol on RNA quality in blood samples. METHODS: We obtained EDTA blood samples from 50 adult volunteers, and made 10 pools of buffy coats for comparison between protocols and also evaluated RNA quality of clinical samples in biobank. Use of TRIzol and RBC removal (RBC lysis or cell separation) were evaluated their effect on the quality of mRNA from the stored blood samples. RESULTS: RNA integrity with TRIzol was significantly better than that without TRIzol (RIN 4.5 vs. 9.2, respectively; P=0.002). The change in RIN of the PBMC separation method was equivalent to that of the RBC lysis method. After 12 months, IL6 mRNA expression from stored clinical samples in cell separation/TRIzol was stable. CONCLUSIONS: The blood samples frozen in TRIzol after RBC removal preserved RNA quality well. PBMC/TRIzol preservation for storage of blood samples could be a simple protocol for rapid, low-cost biobanking. PMID- 21704609 TI - Effect of genetic polymorphisms on the pharmacokinetics and efficacy of glimepiride in a Korean population. AB - BACKGROUNDS: Glimepiride is a commonly used sulfonylurea hypoglycemic agent. There is considerable interindividual variation in the response to sulfonylurea for patients with type 2 diabetes. The purpose of this study was to investigate whether genetic variations influence the efficacy of glimepiride in healthy Korean subjects. METHODS: A single 2-mg oral dose of glimepiride was administered to 46 healthy volunteers. Serial blood sampling for 12h after oral dosing was performed for determination of plasma glimepiride, glucose and insulin levels. We tested the association of seven single nucleotide polymorphisms (SNPs) in four candidate genes with the efficacy of glimepiride. RESULTS: Pharmacodynamic profiles for plasma glucose and insulin showed no statistically significant differences among genotype groups, and parameters were not different from one another. There were no association of the KCNJ11, NOS1AP, TCF7L2 and ABCC8 gene polymorphisms and the efficacy of glimepiride. CONCLUSIONS: Knowledge of these polymorphisms provides no clinical useful information for the pharmacogenetic therapeutic approach for Korean patients with type 2 diabetes. PMID- 21704610 TI - Detection of circulating tumor cells in peripheral blood from patients with gastric cancer using piRNAs as markers. AB - OBJECTIVE: To investigate the feasibility of detecting circulating cancer cells in peripheral blood from gastric cancer patients using Piwi-interacting RNAs (piRNAs) as markers. DESIGN AND METHODS: Real-time quantitative reverse transcription-polymerase chain reaction was used to analyze piR-651 and piR-823 levels in the peripheral blood of 93 patients with gastric cancer and 32 healthy volunteers. Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic values. RESULTS: The peripheral blood levels of piR-651 and piR-823 in the patients with gastric cancer were significantly lower than those from controls (P<0.001). The piR-651 level in gastric adenocarcinoma was higher than that in gastric signet ring cell carcinoma (P = 0.003). The piR-823 level was positively associated with tumor-node-metastasis stage (P = 0.027) and distant metastasis (P = 0.026). The areas under the ROC curve were 0.841, 0.812 and 0.860 for piR-651, piR-823 and the combination, respectively. CONCLUSIONS: piRNAs may be valuable biomarkers for detecting circulating gastric cancer cells. PMID- 21704611 TI - Analytical performance and clinical concordance of the cancer biomarkers CA 15-3, CA 19-9, CA 125 II, Carcinoembryonic Antigen, and Alpha-Fetoprotein on the Dimension Vista(r) System. AB - OBJECTIVES: We examined analytical characteristics of new CA 15-3, CA 19-9, CA 125 II, Carcinoembryonic Antigen (CEA), and Alpha-Fetoprotein (AFP) assays on the Dimension Vista(r) System. DESIGN AND METHODS: Imprecision studies used CLSI-EP5 A2, Limit of Blank and Limit of Detection used CLSI-EP17 and measurement ranges were determined. Method comparisons were evaluated with Passing-Bablok, least squares regression and residual plots. Reference intervals were determined and valid specimen types, lot-to-lot variability and sample storage stability were defined. Clinical monitoring patterns for each tumor marker in patients were examined. RESULTS: Reproducibility for each method was <6.5%. Limits of Blank and Detection were low. Comparisons between methods showed slopes ranging from 0.89 to 1.32 with low y-intercepts and scatter. Minimal lot-to-lot variability was documented; serum/plasma specimens provide valid results; sample stability at -70 degrees C was >9months. Clinical monitoring patterns correlated with established methods in >89% of cases. CONCLUSIONS: Measurement of CA 15-3, CA 19-9, CA 125 II, CEA and AFP on the Dimension Vista(r) System is an attractive alternative. PMID- 21704612 TI - Use of an automated ACTH assay for the diagnosis of pituitary and adrenal-related diseases. AB - OBJECTIVE: To evaluate Liaison Diasorin's automated ACTH assay. DESIGN: We investigated the limit of quantification (LOQ) and simulated the usage of the analyzer using our ACTH results database. RESULTS: The LOQ was close to the cut off determining Cushing's syndrome ACTH dependency. 25% concentrations of normal subjects were lower than the LOQ. Although biased, the results were concordant with those of an IRMA assay. CONCLUSION: This assay is not sensitive enough to diagnose ACTH-independent Cushing's syndrome. PMID- 21704613 TI - Erythropoiesis versus inflammation in Hereditary Spherocytosis clinical outcome. AB - OBJECTIVES: This study aimed to evaluate the relationship between erythropoiesis and inflammation, in Hereditary Spherocytosis (HS) clinical outcome. DESIGN AND METHODS: We studied 26 controls and 82 HS patients presenting mild (n = 49) and severer (n = 33) HS forms. We evaluated plasma levels of EPO, sTfR, ferritin, iron, folic acid, vitamin B12, TNF-alpha, IFN-gamma, elastase and lactoferrin; leukocyte and reticulocyte counts and RPI were determined. RESULTS: All HS patients showed significantly higher EPO, sTfR, reticulocytes and RPI but only mild HS presented normal hemoglobin levels; the positive significant correlations between EPO and sTfR, reticulocytes and RPI observed in mild HS were not observed in severer HS patients. HS patients presented with higher levels of neutrophils, TNF-alpha, IFN-gamma, elastase, lactoferrin and ferritin. CONCLUSIONS: Our data show HS as a disease linked to enhanced erythropoiesis that is disturbed in the more severe forms, to which inflammation may contribute, at least in part. PMID- 21704614 TI - An elongation factor-like protein (EF-Tu) elicits a humoral response in infiltrating ductal breast carcinomas: an immunoproteomics investigation. AB - OBJECTIVES: In the current study, we have used an immunoproteomics approach to identify proteins that commonly elicit a humoral response in patients with infiltrating ductal carcinomas of the breast. DESIGN AND METHODS: Sera obtained at the time of diagnosis from 40 patients with invasive breast cancer and 42 healthy controls were screened for the presence of IgG antibodies to MCF-7 cell line proteins using a serological proteomics-based approach. RESULTS: An immunoreactive protein detected in sera from 21 of 40 patients was isolated and subsequently identified as elongation factor-Tu. CONCLUSIONS: The immunoproteomic approach implemented here offers a powerful tool for determining novel tumor antigens that induce a humoral immune response in cancer patients. From our findings, the immunoreactive EF-Tu protein and/or the related circulating antibodies may display clinical usefulness as potential diagnostic markers and provide a means for a better understanding of the molecular mechanisms underlying breast cancer development. PMID- 21704615 TI - Serum levels of arginase I are associated with left ventricular function after myocardial infarction. AB - OBJECTIVES: Upregulation of arginase redirects the arginine metabolism from nitric oxide (NO) synthesis to the formation of polyamine and proline, thus causing cardiac dysfunction. NO synthesis is also impaired by asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor. We aimed to evaluate the impact of arginase and ADMA levels on left ventricular function after myocardial infarction (MI). DESIGN AND METHODS: Blood samples from 43 MI patients and 33 controls were used. Arginase I and TNF-alpha were quantified by ELISA; arginine, ADMA and homocysteine concentrations by HPLC; and high-sensitive CRP by immunoassay techniques. RESULTS: Arginase concentrations were higher in MI patients than in controls (121 +/- 73 ng/mL vs 58 +/- 41, p = 0.001) and were negatively associated with left ventricular ejection fraction (r = -0.467, p = 0.019). Significantly low arginine/ADMA ratio was observed in MI patients. CONCLUSION: Induced arginase I after myocardial infarction may deplete the arginine pool. The changes related to arginine metabolism may have a role in ventricular dysfunction. PMID- 21704616 TI - Indispensable role of factor for adipocyte differentiation 104 (fad104) in lung maturation. AB - Factor for adipocyte differentiation 104 (fad104) is a regulator of adipogenesis and osteogenesis. Our previous study showed that fad104-deficient mice died immediately after birth, suggesting fad104 to be essential for neonatal survival. However, the cause of this rapid death is unclear. Here, we demonstrate the role of fad104 in neonatal survival. Phenotypic and morphological analyses showed that fad104-deficient mice died due to cyanosis-associated lung dysplasia including atelectasis. Furthermore, immunohistochemistry revealed that FAD104 was strongly expressed in ATII cells in the developing lung. Most importantly, the ATII cells in lungs were immature, and impaired the expression of surfactant-associated proteins. Collectively, these results indicate that fad104 has an indispensable role in lung maturation, especially the maturation and differentiation of ATII cells. PMID- 21704617 TI - Progesterone attenuates astro- and microgliosis and enhances oligodendrocyte differentiation following spinal cord injury. AB - Reactive gliosis, demyelination and proliferation of NG2+ oligodendrocyte precursor cells (OPC) are common responses to spinal cord injury (SCI). We previously reported that short-term progesterone treatment stimulates OPC proliferation whereas chronic treatment enhances OPC differentiation after SCI. Presently, we further studied the proliferation/differentiation of glial cells involved in inflammation and remyelination in male rats with SCI subjected to acute (3 days) or chronic (21 days) progesterone administration. Rats received several pulses of bromodeoyuridine (BrdU) 48 and 72 h post-SCI, and sacrificed 3 or 21 days post-SCI. Double colocalization of BrdU and specific cell markers showed that 3 days of SCI induced a strong proliferation of S100beta+ astrocytes, OX-42+ microglia/macrophages and NG2+ cells. At this stage, the intense GFAP+ astrogliosis was BrdU negative. Twenty one days of SCI enhanced maturation of S100beta+ cells into GFAP+ astrocytes, but decreased the number of CC1+ oligodendrocytes. Progesterone treatment inhibited astrocyte and microglia /macrophage proliferation and activation in the 3-day SCI group, and inhibited activation in the 21-day SCI group. BrdU/NG2 double labeled cells were increased by progesterone at 3 days, indicating a proliferation stimulus, but decreased them at 21 days. However, progesterone-enhancement of CC1+/BrdU+ oligodendrocyte density, suggest differentiation of OPC into mature oligondendrocytes. We conclude that progesterone effects after SCI involves: a) inhibition of astrocyte proliferation and activation; b) anti-inflammatory effects by preventing microglial activation and proliferation, and c) early proliferation of NG2+ progenitors and late remyelination. Thus, progesterone behaves as a glioactive factor favoring remyelination and inhibiting reactive gliosis. PMID- 21704618 TI - A neuronal transmembrane protein LRFN4 induces monocyte/macrophage migration via actin cytoskeleton reorganization. AB - Leucine-rich repeat and fibronectin type III domain-containing (LRFN) family proteins are thought to be neuronal-specific proteins that play essential roles in neurite outgrowth and synapse formation. Here, we focused on expression and function of LRFN4, the fourth member of the LRFN family, in non-neural tissues. We found that LRFN4 was expressed in a wide variety of cancer and leukemia cell lines. We also found that expression of LRFN4 in the monocytic cell line THP-1 and in primary monocytes was upregulated following macrophage differentiation. Furthermore, we demonstrated that LRFN4 signaling regulated both the transendothelial migration of THP-1 cells and the elongation of THP-1 cells via actin cytoskeleton reorganization. Our data indicate that LRFN4 signaling plays an important role in the migration of monocytes/macrophages. PMID- 21704619 TI - Construction and analysis of a novel peptide tag containing an unnatural N glycosylation site. AB - The addition of N-glycans to clinically used proteins enhances their therapeutic features. Here we report the design of a novel peptide tag with an unnatural N glycosylation site, which may increase the N-glycan content of generally any protein. The designed GlycoTags were attached to A1AT, EPO and AGP and constructs were expressed in HEK293 or CHO cells. Hereby we could prove that the attached unnatural N-glycosylation site is decorated with complex-type N-glycans and that the spacer as well as the C-terminal "tail" sequence are critical for the usage of the novel N-glycosylation site. This demonstrates that the novel GlycoTag is a convenient tool to provide proteins with extra N-glycan moieties by simply adding a peptide tag sequence as small as 22 amino acids. PMID- 21704620 TI - Rac1 takes center stage in pancreatic cancer and ulcerative colitis: quantity matters. PMID- 21704621 TI - Gastrointestinal bleeding in a type 1 neurofibromatosis patient. PMID- 21704623 TI - Polypoid rectal mass in a 21-year-old woman with hematochezia. PMID- 21704622 TI - beta-Catenin and p120 mediate PPARdelta-dependent proliferation induced by Helicobacter pylori in human and rodent epithelia. AB - BACKGROUND & AIMS: Colonization of gastric mucosa by Helicobacter pylori leads to epithelial hyperproliferation, which increases the risk for gastric adenocarcinoma. One H pylori virulence locus associated with cancer risk, cag, encodes a secretion system that transports effectors into host cells and leads to aberrant activation of beta-catenin and p120-catenin (p120). Peroxisome proliferator-activated receptor (PPAR)delta is a ligand-activated transcription factor that affects oncogenesis in conjunction with beta-catenin. We used a carcinogenic H pylori strain to define the role of microbial virulence constituents and PPARdelta in regulating epithelial responses that mediate development of adenocarcinoma. METHODS: Gastric epithelial cells or colonies were co-cultured with the H pylori cag(+) strain 7.13 or cagE(-), cagA(-), soluble lytic transglycosylase(-), or cagA(-)/soluble lytic transglycosylase(-) mutants. Levels of PPARdelta and cyclin E1 were determined by real-time, reverse transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy; proliferation was measured in 3-dimensional culture. PPARdelta and Ki67 expression were determined by immunohistochemical analysis of human biopsies and rodent gastric mucosa. RESULTS: H pylori induced beta-catenin- and p120-dependent expression and activation of PPARdelta in gastric epithelial cells, which were mediated by the cag secretion system substrates CagA and peptidoglycan. H pylori stimulated proliferation in vitro, which required PPARdelta-mediated activation of cyclin E1; H pylori did not induce expression of cyclin E1 in a genetic model of PPARdelta deficiency. PPARdelta expression and proliferation in rodent and human gastric tissue was selectively induced by cag(+) strains and PPARdelta levels normalized after eradication of H pylori. CONCLUSIONS: The H pylori cag secretion system activates beta-catenin, p120, and PPARdelta, which promote gastric epithelial cell proliferation via activation of cyclin E1. PPARdelta might contribute to gastric adenocarcinoma development in humans. PMID- 21704624 TI - Ablate under EUS-guidance when properly indicated. PMID- 21704625 TI - A woman who faints when she eats and drinks. PMID- 21704626 TI - Four gonadotropin releasing hormone receptor genes in Atlantic cod are differentially expressed in the brain and pituitary during puberty. AB - Gonadotropin releasing hormones (GnRH) are an important part of the brain pituitary-gonad axis in vertebrates. GnRH binding to its receptors (GnRH-R) stimulates synthesis and release of gonadotropins in the pituitary. GnRH-Rs also mediate other processes in the central nervous system such as reproductive behavior and neuromodulation. As many as five GnRH-R genes have been identified in two teleost fish species, but the function and phylogenetic relationship of these receptors is not fully understood. To gain a better understanding of the functional relationship between multiple GnRH-Rs in an important aquaculture species, the Atlantic cod (Gadus morhua), we identified four GnRH-Rs (gmGnRH-R) by RT-PCR, followed by full-length cloning and sequencing. The deduced amino acid sequences were used for phylogenetic analysis to identify conserved functional motifs and to clarify the relationship of gmGnRH-Rs with other vertebrate GnRH Rs. The function of GnRH-R variants was investigated by quantitative PCR gene expression analysis in the brain and pituitary of female cod during a full reproductive cycle and in various peripheral tissues in sexually mature fish. Phylogenetic analysis revealed two types of teleost GnRH-Rs: Type I including gmGnRH-R1b and Type II including gmGnRH-R2a, gmGnRH-R2b and gmGnRH-R2c. All four gmGnRH-Rs are expressed in the brain, and gmGnRH-R1b, gmGnRH-R2a and gmGnRH-R2c are expressed in the pituitary. The only GnRH-R differentially expressed in the pituitary during the reproductive cycle is gmGnRH-R2a such that its expression is significantly increased during spawning. These data suggest that gmGnRH-R2a is the most likely candidate to mediate the hypophysiotropic function of GnRH in Atlantic cod. PMID- 21704627 TI - Effect of isolation and conspecific presence in a novel environment on corticosterone concentrations in a social avian species, the zebra finch (Taeniopygia guttata). AB - Zebra finches are a highly social and monogamous avian species. In the present study, we sought to determine the effect of social isolation (separation from the flock) in a novel environment with and without a conspecific present on the adrenocortical activity of paired and unpaired individuals of this species. With regard to paired birds, we hypothesized that the presence of the mate during isolation from the group would act as a social buffer against the stressful effects of isolation. We observed that 10 but not 30 minutes of social isolation resulted in elevated concentrations of corticosterone in unpaired and paired male zebra finches in comparison to baseline concentrations of corticosterone. Furthermore, the presence of a mate during isolation in a novel environment did not have a buffering effect against increases in corticosterone concentrations. Additionally, to compare concentrations of corticosterone in response to isolation (in a novel environment) to a previously well-established stressor, we subjected groups of birds to restraint. We observed that 10 or 30 minutes of restraint led to significantly higher concentrations of corticosterone as compared to baseline. Finally, to rule out the possibility that merely handling a bird would result in significantly elevated concentrations of corticosterone as compared to baseline samples, we measured corticosterone concentrations 10 or 30 minutes after handling involving capture and release only. Our results suggest that handling alone might have contributed to the elevation of corticosterone in birds exposed to 10 minutes but not 30 minutes of restraint. Handling by itself did not account, however, for the elevated corticosterone in birds socially isolated for 10 minutes. PMID- 21704628 TI - Rapid and sensitive detection of cytokines using functionalized gold nanoparticle based immuno-PCR, comparison with immuno-PCR and ELISA. AB - Reliable and simple methods are required for detection of low concentrations of cytokines and some other proteins in complex biological fluids. This is especially important when monitoring the immune responses under various physiological and pathophysiological conditions in vivo or following production of these compounds in in vitro systems. Cytokines and other immunologically active molecules are being predominantly detected by enzyme-linked immunosorbent assays (ELISA) and newly also by immuno-polymerase chain reactions (iPCR). New simplified variants of iPCR have recently been described where antibodies are connected with multiple DNA templates through gold nanoparticles (Au-NPs) to form a new class of detection reagents. In this study we compared functionalized Au-NP based iPCR (Nano-iPCR) with standard ELISA and iPCR for the detection of interleukin (IL)-3 and stem cell factor (SCF). The same immunoreagents (IL-3- and SCF-specific polyclonal antibodies and their biotinylated forms) were used throughout the assays. The obtained data indicate that both Nano-iPCR and iPCR are superior in sensitivity and detection range than ELISA. Furthermore, Nano iPCR is easier to perform than the other two methods. Nano-iPCR was used for monitoring changes in concentration of free SCF during growth of mast cells in SCF-conditioned media. The results show that growing cultures gradually reduce the amount of SCF in supernatant to 25% after 5 days. The combined data indicate that Nano-iPCR assays may be preferable for rapid detection of low concentrations of cytokines in complex biological fluids. PMID- 21704629 TI - Utility of oligoclonal IgG band detection for MS diagnosis in daily clinical practice. AB - An early and accurate diagnosis of multiple sclerosis (MS) is very important, since it allows early treatment initiation, which reduces the activity of the disease. Oligoclonal IgG band (OCGB) detection is a good ancillary tool for MS diagnosis. However, it was argued that its usefulness was limited by the high interlaboratory variability. In the last years, different techniques for OCGB detection have appeared. We performed a blinded aleatorized multicenter study in 19 Spanish hospitals to assess the accuracy and reproducibility of OCGB detection in this new scenario. We studied cerebrospinal fluid (CSF) and serum samples from 114 neurological patients. Every hospital contributed to the study with triplicated pairs of CSF and serum samples of six patients and analyzed 18 different samples. Global analysis rendered a sensitivity of 92.1%, a specificity of 95.1% and a Kappa value of 0.81. This shows that current techniques for OCGB detection have good accuracy and a high interlaboratory reproducibility and thus, represent a good tool for MS diagnosis. When we analyzed separately the different techniques used for OCGB detection, the highest concordance was observed in western blot with alkaline phosphatase detection (kappa=0.91). This indicates that high sensitivity techniques improve the reproducibility of this assay. PMID- 21704631 TI - Fatty acid composition and extreme temperature tolerance following exposure to fluctuating temperatures in a soil arthropod. AB - Ectotherms commonly adjust their lipid composition to ambient temperature to counteract detrimental thermal effects on lipid fluidity. However, the extent of lipid remodeling and the associated fitness consequences under continuous temperature fluctuations are not well-described. The objective of this study was to investigate the effect of repeated temperature fluctuations on fatty acid composition and thermal tolerance. We exposed the springtail Orchesella cincta to two constant temperatures of 5 and 20 degrees C, and a continuously fluctuating treatment between 5 and 20 degrees C every 2 days. Fatty acid composition differed significantly between constant low and high temperatures. As expected, animals were most cold tolerant in the low temperature treatment, while heat tolerance was highest under high temperature. Under fluctuating temperatures, fatty acid composition changed with temperature initially, but later in the experiment fatty acid composition stabilized and closely resembled that found under constant warm temperatures. Consistent with this, heat tolerance in the fluctuating temperature treatment was comparable to the constant warm treatment. Cold tolerance in the fluctuating temperature treatment was intermediate compared to animals acclimated to constant cold or warmth, despite the fact that fatty acid composition was adjusted to warm conditions. This unexpected finding suggests that in animals acclimated to fluctuating temperatures an additional underlying mechanism is involved in the cold shock response. Other aspects of homeoviscous adaptation may protect animals during extreme cold. This paper forms a next step to fully understand the functioning of ectotherms in more thermally variable environments. PMID- 21704630 TI - Thermoperiodic regulation of the circadian eclosion rhythm in the flesh fly, Sarcophaga crassipalpis. AB - We recorded the eclosion time of the flesh fly, Sarcophaga crassipalpis, at different depths in the outdoor soil and under temperature cycles with various amplitudes in the laboratory, to examine the timing adjustment of eclosion in response to temperature cycles and their amplitudes in the pupal stage. In the soil, most eclosions occurred in the late morning, which was consistent with the eclosion time under pseudo-sinusoidal temperature cycles in the laboratory. The circadian clock controlling eclosion was reset by temperature cycles and free-ran with a period close to 24h. This clock likely helps pupae eclose at an optimal time even when the soil temperature does not show clear daily fluctuations. The eclosion phase of the circadian clock progressively advanced as the amplitude of the pseudo-sinusoidal temperature cycle decreased. This response allows pupae located at any depth in the soil to eclose at the appropriate time despite the depth-dependent phase delay of the temperature change. In contrast, the abrupt temperature increase in square-wave temperature cycles reset the phase of the circadian clock to the increasing time, regardless of the temperature amplitude. The rapid temperature increase may act as the late-morning signal for the eclosion clock. PMID- 21704632 TI - A host-plant specialist, Helicoverpa assulta, is more tolerant to capsaicin from Capsicum annuum than other noctuid species. AB - Plant secondary compounds not only play an important role in plant defense, but have been a driving force for host adaptation by herbivores. Capsaicin (8-methyl N-vanillyl-6-nonenamide), an alkaloid found in the fruit of Capsicum spp. (Solanaceae), is responsible for the pungency of hot pepper fruits and is unique to the genus. The oriental tobacco budworm, Helicoverpa assulta (Lepidoptera: Noctuidae), is a specialist herbivore feeding on solanaceous plants including Capsicum annuum, and is one of a very few insect herbivores worldwide capable of feeding on hot pepper fruits. To determine whether this is due in part to an increased physiological tolerance of capsaicin, we compared H. assulta with another specialist on Solanaceae, Heliothis subflexa, and four generalist species, Spodoptera frugiperda, Heliothis virescens, Helicoverpa armigera, and Helicoverpa zea, all belonging to the family Noctuidae. When larvae were fed capsaicin-spiked artificial diet for the entire larval period, larval mortality increased in H. subflexa and H. zea but decreased in H. assulta. Larval growth decreased on the capsaicin-spiked diet in four of the species, was unaffected in H. armigera and increased in H. assulta. Food consumption and utilization experiments showed that capsaicin decreased relative consumption rate (RCR), relative growth rate (RGR) and approximate digestibility (AD) in H. zea, and increased AD and the efficiency of conversion of ingested food (ECI) in H. armigera; whereas it did not significantly change any of these nutritional indices in H. assulta. The acute toxicity of capsaicin measured by injection into early fifth instar larvae was less in H. assulta than in H. armigera and H. zea. Injection of high concentrations produced abdominal paralysis and self cannibalism. Injection of sub-lethal doses of capsaicin resulted in reduced pupal weights in H. armigera and H. zea, but not in H. assulta. The results indicate that H. assulta is more tolerant to capsaicin than the other insects tested, suggesting that this has facilitated expansion of its host range within Solanaceae to Capsicum after introduction of the latter to the Old World about 500 years ago. The increased larval survival and growth due to chronic dietary exposure to capsaicin suggests further adaptation of H. assulta to that compound, the mechanisms of which remain to be investigated. PMID- 21704633 TI - Drosophila male courtship behavior is modulated by ecdysteroids. AB - Temperature-dependent induction of ecdysteroid deficiency in the ecdysoneless mutant ecd(1) adult Drosophila melanogaster results in altered courtship behavior in males. Ecdysteroid deficiency brings about significantly elevated male-male courtship behavior including song production resembling that directed toward females. Supplementation with dietary 20-hydroxyecdysone reduces male-male attraction, but does not change motor activity, courtship patterns or attraction to females. These observations support the hypothesis that reduced levels of ecdysteroids increase the probability that male fruit flies will display courtship behaviors to male stimuli. PMID- 21704634 TI - Galactolipase, phospholipase and triacylglycerol lipase activities in the midgut of six species of lepidopteran larvae feeding on different lipid diets. AB - Galactolipase, phospholipase and triacylglycerol lipase activities were measured from the midgut of six species of lepidopteran larvae, two folivores, Epiphyas postvittana (Tortricidae) and Helicoverpa armigera (Noctuidae); two granivores, Plodia interpunctella (Pyralidae) and Ephestia kuehniella (Pyrallidae); a presumptive carnivore, Galleria mellonella (Pyralidae); and a keratinophage, Tineola bisselliella (Tineidae). Galactolipase has not been previously reported in insects. Galactolipase and phospholipase activities were high in the folivores and triacylglycerol lipase activity was low, matching the high galactolipid content of leaves. Conversely, galactolipase and phospholipase activities were low, but not absent, and triacylglycerol lipase activity high in the four other non-folivorous species, matching the high acylglycerol content of their diets. These data suggest the utility of reclassification, for evolutionary studies, of phytophagous lepidoptera into two feeding classes; folivore and granivore, the latter having similarity to the fungivore line of feeders in terms of its lipase activities and ability to retrieve essential polyunsaturated long chain fatty acids from their diets. All the digestive lipases have alkaline pH optima for activity, matching the pH of the lepidopteran midgut and their amino acid content show modifications likely to stabilize the proteins in that environment. PMID- 21704636 TI - Structure of the RACK1 dimer from Saccharomyces cerevisiae. AB - Receptor for activated C-kinase 1 (RACK1) serves as a scaffolding protein in numerous signaling pathways involving kinases and membrane-bound receptors from different cellular compartments. It exists simultaneously as a cytosolic free form and as a ribosome-bound protein. As part of the 40S ribosomal subunit, it triggers translational regulation by establishing a direct link between protein kinase C and the protein synthesis machinery. It has been suggested that RACK1 could recruit other signaling molecules onto the ribosome, providing a signal specific modulation of the translational process. RACK1 is able to dimerize both in vitro and in vivo. This homodimer formation has been observed in several processes including the regulation of the N-methyl-d-aspartate receptor by the Fyn kinase in the brain and the oxygen-independent degradation of hypoxia inducible factor 1. The functional relevance of this dimerization is, however, still unclear and the question of a possible dimerization of the ribosome-bound protein is still pending. Here, we report the first structure of a RACK1 homodimer, as determined from two independent crystal forms of the Saccharomyces cerevisiae RACK1 protein (also known as Asc1p) at 2.9 and 3.9 A resolution. The structure reveals an atypical mode of dimerization where monomers intertwine on blade 4, thus exposing a novel surface of the protein to potential interacting partners. We discuss the significance of the dimer structure for RACK1 function. PMID- 21704635 TI - Regulation of fat storage and reproduction by Kruppel-like transcription factor KLF3 and fat-associated genes in Caenorhabditis elegans. AB - Coordinated regulation of fat storage and utilization is essential for energy homeostasis, and its disruption is associated with metabolic syndrome and atherosclerosis in humans. Across species, Kruppel-like transcription factors (KLFs) have been identified as key components of adipogenesis. In humans, KLF14 acts as a master transregulator of adipose gene expression in type 2 diabetes and cis-acting expression quantitative trait locus associated with high-density lipoprotein cholesterol. Herein we report that, in Caenorhabditis elegans, mutants in klf-3 accumulate large fat droplets rich in neutral lipids in the intestine; this lipid accumulation is associated with an increase in triglyceride levels. The klf-3 mutants show normal pharyngeal pumping; however, they are sterile or semisterile. We explored important genetic interactions of klf-3 with the genes encoding enzymes involved in fatty acid (FA) beta-oxidation in mitochondria or peroxisomes and FA synthesis in the cytosol, namely acyl-CoA synthetase (acs-1 and acs-2), acyl-CoA oxidase (F08A8.1 and F08A8.2), and stearoyl-CoA desaturase (fat-7). We show that mutations or RNA interference in these genes increases fat deposits in the intestine of acs-1, acs-2, F08A8.1, and F08A8 animals. We further show that acs-1 and F08A8.1 influence larval development and fertility, respectively. Thus, KLF3 may regulate FA utilization in the intestine and reproductive tissue. We demonstrate that depletion of F08A8.1 activity, but not of acs-1, acs-2, F08A8.2, or fat-7 activity, enhances the fat phenotype of the klf-3 mutant. Taken together, these results suggest that klf-3 regulates lipid metabolism, along with acs-1, acs-2, F08A8.1, and F08A8.2, by promoting FA beta-oxidation and, in parallel, may contribute to normal reproductive behavior and fecundity in C. elegans. PMID- 21704637 TI - Structural basis for the function of Tim50 in the mitochondrial presequence translocase. AB - Many mitochondrial proteins are synthesized as preproteins carrying amino terminal presequences in the cytosol. The preproteins are imported by the translocase of the outer mitochondrial membrane and the presequence translocase of the inner membrane. Tim50 and Tim23 transfer preproteins through the intermembrane space to the inner membrane. We report the crystal structure of the intermembrane space domain of yeast Tim50 to 1.83 A resolution. A protruding beta hairpin of Tim50 is crucial for interaction with Tim23, providing a molecular basis for the cooperation of Tim50 and Tim23 in preprotein translocation to the protein-conducting channel of the mitochondrial inner membrane. PMID- 21704639 TI - Evolutionary games in deme structured, finite populations. AB - We describe a fairly general model for the evolutionary dynamics in a sub-divided (or deme structured) population with migration and mutation. The number and size of demes are finite and fixed. The fitness of each individual is determined by pairwise interactions with other members of the same deme. The dynamics within demes can be modeled according to a broad range of evolutionary processes. With a probability proportional to fitness, individuals migrate to another deme. Mutations occur randomly. In the limit of few migrations and even rarer mutations we derive a simple analytic condition for selection to favor one strategic type over another. In particular, we show that the Pareto efficient type is favored when competition within demes is sufficiently weak. We then apply the general results to the prisoner's dilemma game and discuss selected dynamics and the conditions for cooperation to prevail. PMID- 21704638 TI - Rotations of the 2B sub-domain of E. coli UvrD helicase/translocase coupled to nucleotide and DNA binding. AB - Escherichia coli UvrD is a superfamily 1 DNA helicase and single-stranded DNA (ssDNA) translocase that functions in DNA repair and plasmid replication and as an anti-recombinase by removing RecA protein from ssDNA. UvrD couples ATP binding and hydrolysis to unwind double-stranded DNA and translocate along ssDNA with 3' to-5' directionality. Although a UvrD monomer is able to translocate along ssDNA rapidly and processively, DNA helicase activity in vitro requires a minimum of a UvrD dimer. Previous crystal structures of UvrD bound to a ssDNA/duplex DNA junction show that its 2B sub-domain exists in a "closed" state and interacts with the duplex DNA. Here, we report a crystal structure of an apo form of UvrD in which the 2B sub-domain is in an "open" state that differs by an ~160 degrees rotation of the 2B sub-domain. To study the rotational conformational states of the 2B sub-domain in various ligation states, we constructed a series of double cysteine UvrD mutants and labeled them with fluorophores such that rotation of the 2B sub-domain results in changes in fluorescence resonance energy transfer. These studies show that the open and closed forms can interconvert in solution, with low salt favoring the closed conformation and high salt favoring the open conformation in the absence of DNA. Binding of UvrD to DNA and ATP binding and hydrolysis also affect the rotational conformational state of the 2B sub-domain, suggesting that 2B sub-domain rotation is coupled to the function of this nucleic acid motor enzyme. PMID- 21704640 TI - The correlation between infectivity and incubation period of measles, estimated from households with two cases. AB - The generation time of an infectious disease is the time between infection of a primary case and infection of a secondary case by the primary case. Its distribution plays a key role in understanding the dynamics of infectious diseases in populations, e.g. in estimating the basic reproduction number. Moreover, the generation time and incubation period distributions together characterize the effectiveness of control by isolation and quarantine. In modelling studies, a relation between the two is often not made specific, but a correlation is biologically plausible. However, it is difficult to establish such correlation, because of the unobservable nature of infection events. We have quantified a joint distribution of generation time and incubation period by a novel estimation method for household data with two susceptible individuals, consisting of time intervals between disease onsets of two measles cases. We used two such datasets, and a separate incubation period dataset. Results indicate that the mean incubation period and the generation time of measles are positively correlated, and that both lie in the range of 11-12 days, suggesting that infectiousness of measles cases increases significantly around the time of symptom onset. The correlation between times from infection to secondary transmission and to symptom onset could critically affect the predicted effectiveness of isolation and quarantine. PMID- 21704641 TI - Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. AB - AIMS: Cannabidiol (CBD), one of the major constituents in marijuana, has been shown to be extensively metabolized by experimental animals and humans. However, human hepatic enzymes responsible for the CBD metabolism remain to be elucidated. In this study, we examined in vitro metabolism of CBD with human liver microsomes (HLMs) to clarify cytochrome P450 (CYP) isoforms involved in the CBD oxidations. MAIN METHODS: Oxidations of CBD in HLMs and recombinant human CYP enzymes were analyzed by gas chromatography/mass spectrometry. KEY FINDINGS: CBD was metabolized by pooled HLMs to eight monohydroxylated metabolites (6alpha-OH-, 6beta-OH-, 7-OH-, 1"-OH-, 2"-OH-, 3"-OH-, 4"-OH-, and 5"-OH-CBDs). Among these metabolites, 6alpha-OH-, 6beta-OH-, 7-OH-, and 4"-OH-CBDs were the major ones as estimated from the relative abundance of m/z 478, which was a predominant fragment ion of trimethylsilyl derivatives of the metabolites. Seven of 14 recombinant human CYP enzymes examined (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) were capable of metabolizing CBD. The correlations between CYP isoform-specific activities and CBD oxidative activities in 16 individual HLMs indicated that 6beta-OH- and 4"-OH-CBDs were mainly formed by CYP3A4, which was supported by inhibition studies using ketoconazole and an anti-CYP3A4 antibody. The correlation and inhibition studies also showed that CBD 6alpha hydroxylation was mainly catalyzed by CYP3A4 and CYP2C19, whereas CBD 7 hydroxylation was predominantly catalyzed by CYP2C19. SIGNIFICANCE: This study indicated that CBD was extensively metabolized by HLMs. These results suggest that CYP3A4 and CYP2C19 may be major isoforms responsible for 6alpha-, 6beta-, 7 , and/or 4"-hydroxylations of CBD in HLMs. PMID- 21704642 TI - Optimal invasive species management under multiple uncertainties. AB - The management programs for invasive species have been proposed and implemented in many regions of the world. However, practitioners and scientists have not reached a consensus on how to control them yet. One reason is the presence of various uncertainties associated with the management. To give some guidance on this issue, we characterize the optimal strategy by developing a dynamic model of invasive species management under uncertainties. In particular, focusing on (i) growth uncertainty and (ii) measurement uncertainty, we identify how these uncertainties affect optimal strategies and value functions. Our results suggest that a rise in growth uncertainty causes the optimal strategy to involve more restrained removals and the corresponding value function to shift up. Furthermore, we also find that a rise in measurement uncertainty affects optimal policies in a highly complex manner, but their corresponding value functions generally shift down as measurement uncertainty rises. Overall, a rise in growth uncertainty can be beneficial, while a rise in measurement uncertainty brings about an adverse effect, which implies the potential gain of precisely identifying the current stock size of invasive species. PMID- 21704643 TI - Short-term and working memory impairments in aphasia. AB - The aim of the present study is to investigate short-term memory and working memory deficits in aphasics in relation to the severity of their language impairment. Fifty-eight aphasic patients participated in this study. Based on language assessment, an aphasia score was calculated for each patient. Memory was assessed in two modalities, verbal and spatial. Mean scores for all memory tasks were lower than normal. Aphasia score was significantly correlated with performance on all memory tasks. Correlation coefficients for short-term memory and working memory were approximately of the same magnitude. According to our findings, severity of aphasia is related with both verbal and spatial memory deficits. Moreover, while aphasia score correlated with lower scores in both short-term memory and working memory tasks, the lack of substantial difference between corresponding correlation coefficients suggests a possible primary deficit in information retention rather than impairment in working memory. PMID- 21704644 TI - In vivo toxic and lethal cardiovascular effects of a synthetic polymeric 1,3 dodecylpyridinium salt in rodents. AB - APS12-2 is one in a series of synthetic analogs of the polymeric alkylpyridinium salts isolated from the marine sponge Reniera sarai. As it is a potential candidate for treating non small cell lung cancer (NSCLC), we have studied its possible toxic and lethal effects in vivo. The median lethal dose (LD(50)) of APS12-2 in mice was determined to be 11.5mg/kg. Electrocardiograms, arterial blood pressure and respiratory activity were recorded under general anesthesia in untreated, pharmacologically vagotomized and artificially ventilated rats injected with APS12-2. In one group, the in vivo effects of APS12-2 were studied on nerve-evoked muscle contraction. Administration of APS12-2 at a dose of 8mg/kg caused a progressive reduction of arterial blood pressure to a mid-circulatory value, accompanied by bradycardia, myocardial ischemia, ventricular extrasystoles, and second degree atrio-ventricular block. Similar electrocardiogram and arterial blood pressure changes caused by APS12-2 (8mg/kg) were observed in animals pretreated with atropine and in artificially ventilated animals, indicating that hypoxia and cholinergic effects do not play a crucial role in the toxicity of APS12-2. Application of APS12-2 at sublethal doses (4 and 5.5mg/kg) caused a decrease of arterial blood pressure, followed by an increase slightly above control values. We found that APS12-2 causes lysis of rat erythrocytes in vitro, therefore it is reasonable to expect the same effect in vivo. Indeed, hyperkalemia was observed in the blood of experimental animals. Hyperkalemia probably plays an important role in APS12-2 cardiotoxicity since no evident changes in histopathology of the heart were found. However, acute lesions were observed in the pulmonary vessels of rats after application of 8mg/kg APS12 2. Predominant effects were dilation of interalveolar blood vessels and lysis of aggregated erythrocytes within their lumina. PMID- 21704645 TI - Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor 1alpha, suppress amyloid beta-induced neurotoxicity. AB - Alzheimer's disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-beta (Abeta). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1alpha (SDF-1alpha), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress Abeta-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1alpha significantly protected neurons from Abeta-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF 1alpha. Intra-cerebroventricular (ICV) injection of Abeta led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24h following the exposure. The Abeta induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F(2)-isoprostanes, were significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1alpha. Additionally, MIP-2 or SDF-1alpha was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against Abeta neurotoxicity in CXCR2-/- mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. PMID- 21704646 TI - Glutamate, obsessive-compulsive disorder, schizophrenia, and the stability of cortical attractor neuronal networks. AB - A computational neuroscience approach to the symptoms of obsessive-compulsive disorder based on a stochastic neurodynamical framework is described. An increased depth in the basins of attraction of attractor neuronal network states in the brain makes each state too stable, so that it tends to remain locked in that state, and cannot easily be moved on to another state. It is suggested that the different symptoms that may be present in obsessive--compulsive disorder could be related to changes of this type in different brain regions. In integrate and-fire network simulations, an increase in the NMDA and/or AMPA receptor conductances, which increases the depth of the attractor basins, increases the stability of attractor networks, and makes them less easily moved on to another state by a new stimulus. Increasing GABA-receptor activated currents can partly reverse this overstability. There is now some evidence for overactivity in glutamate transmitter systems in obsessive-compulsive disorder, and the hypothesis presented here shows how some of the symptoms of obsessive-compulsive disorder could be produced by the increase in the stability of attractor networks that is produced by increased glutamatergic activity. In schizophrenia, a reduction of the firing rates of cortical neurons caused for example by reduced NMDA receptor function, present in schizophrenia, can lead to instability of the high firing rate attractor states that normally implement short-term memory and attention, contributing to the cognitive and negative symptoms of schizophrenia. Reduced cortical inhibition caused by a reduction of GABA neurotransmission, present in schizophrenia, can lead to instability of the spontaneous firing states of cortical networks, leading to a noise-induced jump to a high firing rate attractor state even in the absence of external inputs, contributing to the positive symptoms of schizophrenia. PMID- 21704647 TI - Screening women aged 40-49 years. AB - Recent recommendations have reignited the debate about mammographic screening in women below age 50 years. Evidence from randomised controlled trials and results from service screening in some countries show a benefit of screening women below age 50 with a screening interval of up to two years. The benefit of such screening in terms of mortality reduction will be lower than that in older women, whilst potential harms include false positive screens and resulting anxiety, risk of overdiagnosis and possible radiation risk. The balance of benefits to possible harms, and the perception of this balance will vary both according to individual priorities and risk. Minimising harms and identifying those women who will benefit most from screening should remain a priority. PMID- 21704648 TI - Attenuation of pro-inflammatory mediators in LPS-stimulated BV2 microglia by chitooligosaccharides via the MAPK signaling pathway. AB - Chitooligosaccharides (COS), depolymerized products of chitosan, has received considerable attention as bioactive material due to their biocompatible, biodegradable, non-toxic and non-allergenic natures. In this study, COS of four different molecular weight ranges (<1, 1-3, 3-5 and 5-10 kDa) were investigated for their abilities to modulate inflammatory mediators in lipopolysaccharides (LPS)-stimulated BV2 microglia. At the concentration of 500 MUg/ml, COS attenuate the productions of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) by inhibiting inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions. Furthermore, the release and expression levels of inflammatory cytokines; including tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) were also attenuated by COS. Notably, the inhibitory activity of COS depends significantly on its molecular weight, with lower molecular weight showed higher activity. In addition, the suppressive effects on the phosphorylation of JNK and p38 mitogen-activated protein kinase (MAPK) by COS were confirmed. These results indicate that COS could be used as an inhibitor in regulating microglial inflammatory responses. Moreover, COS may assist therapeutic treatment of neurodegenerative diseases which accompanied with microglial activation. PMID- 21704649 TI - Study on preparation of beta-cyclodextrin encapsulation tea extract. AB - Microencapsulation of ethanol extract of tea was performed in this study. In order to microencapsulate, beta-cyclodextrin was used as wall material. Ethanol extract of tea was used as the core material. Microcapsules in the solid form were obtained by drying the emulsions. RSM showed that optimal processing parameters were as followings: core material/wall material 1/4, beta-cyclodextrin content 16%, stirring time 30 min and stirring temperature 200 degrees C. Pharmacological activities of beta-cyclodextrin encapsulation tea extract were determined. It was found that beta-cyclodextrin encapsulation tea extract could enhance BMD, BMC and bone Ca, Zn and Cu contents. In addition, beta-cyclodextrin encapsulation tea extract could still reduce blood Ca contents. These results indicated that beta-cyclodextrin encapsulation tea extract was useful for improving bone quality in aged animals. PMID- 21704650 TI - Sodium hyaluronate/chitosan polyelectrolyte complex scaffolds for dental pulp regeneration: synthesis and characterization. AB - In the present study, small-sized porous scaffolds were obtained from the freeze drying of sodium hyaluronate/chitosan polyelectrolyte complexes. The obtained materials were characterized by a set of techniques including attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, swelling determination and weight loss studies. The morphology of the scaffolds was observed using scanning electron microscopy. Thermal characterization of the scaffolds was also performed by dynamic mechanical thermal analysis and thermogravimetric analysis. Finally, the cytotoxic profile of the prepared scaffolds was evaluated in vitro, using mesenchymal stem cells. The results obtained showed that cells adhered to scaffolds and proliferated. This study also confirmed that the degradation by-products of sodium hyaluronate/chitosan scaffold are noncytotoxic, which is fundamental for its application in the biomedical field. PMID- 21704651 TI - Isolation, structural characterization and antioxidant activity of a new water soluble polysaccharide from Acanthophyllum bracteatum roots. AB - ABPS-1, a new water-soluble polysaccharide with molecular weight of 26 kDa and a specific optical rotation of +170 degrees (c 1.0, H(2)O), was extracted from the roots of Acanthophyllum bracteatum by warm water and further successively purified through DEAE-cellulose A52 and Sephadex G-100 columns. Monosaccharide analysis revealed that the ABPS-1 was composed of Glc, Gal and Ara with a relative molar ratio of 1.4:5.2:1.0. Its structural features were elucidated by a combination of FT-IR, methylation and GC-MS analysis, periodate oxidation and Smith degradation, partial acid hydrolysis and (13)C and (1)H NMR spectroscopy. The data obtained indicate that ABPS-1 possessed a backbone of alpha-(1->6) linked Gal with branches attached to O-2 by alpha-1->linked Glc and at O-3 by alpha-1->linked Gal and by alpha-(1->3)-linked Ara. The in vitro antioxidant activity showed that ABPS-1 possesses DPPH radical-scavenging activity in a concentration-dependent manner with an EC(50) value of 2.6 mg/ml. PMID- 21704652 TI - Microwave assisted synthesis of polyacrylamide grafted agar (Ag-g-PAM) and its application as flocculant for wastewater treatment. AB - Grafting of polyacrylamide (PAM) chains was performed onto the backbone of Agar by microwave assisted method, using microwave radiation in synergism with ceric ammonium nitrate (CAN) as the chemical free radical initiator. The intended grafting of the PAM chains were confirmed through intrinsic viscosity study, FTIR spectroscopy and elemental analysis (C, H, N, O & S). Further characterization of the grafted product was done in form of SEM morphology and TGA study. Flocculation efficacy of the synthesized graft copolymers was studied in kaolin suspension, through 'Jar test' procedure. Further, flocculation efficacy of the 'best grade' (as determined by 'jar test' in kaolin suspension) in wastewater was studied for possible application in reduction of pollutant load of wastewater. PMID- 21704653 TI - Continuous nicotinamide administration improves behavioral recovery and reduces lesion size following bilateral frontal controlled cortical impact injury. AB - Previous research has demonstrated considerable preclinical efficacy of nicotinamide (NAM; vitamin B(3)) in animal models of TBI with systemic dosing at 50 and 500 mg/kg yielding improvements on sensory, motor, cognitive and histological measures. The current study aimed to utilize a more specific dosing paradigm in a clinically relevant delivery mechanism: continuously secreting subcutaneous pumps. A bilateral frontal controlled cortical impact (CCI) or sham surgery was performed and rats were treated with NAM (150 mg/kg day) or saline (1 ml/kg) pumps 30 min after CCI, continuing until seven days post-CCI. Rats were given a loading dose of NAM (50mg/kg) or saline (1 ml/kg) following pump implant. Rats received behavioral testing (bilateral tactile adhesive removal, locomotor placing task and Morris water maze) starting on day two post-CCI and were sacrificed at 31 days post-CCI and brains were stained to examine lesion size. NAM-treated rats had reductions in sensory, motor and cognitive behavioral deficits compared to vehicle-treated rats. Specifically, NAM-treated rats significantly improved on the bilateral tactile adhesive removal task, locomotor placing task and the reference memory paradigm of the Morris water maze. Lesion size was also significantly reduced in the NAM-treated group. The results from this study indicate that at the current dose, NAM produces beneficial effects on recovery from a bilateral frontal brain injury and that it may be a relevant compound to be explored in human studies. PMID- 21704654 TI - beta1-noradrenergic system of the central amygdala is involved in state-dependent memory induced by a cannabinoid agonist, WIN55,212-2, in rat. AB - In the present study, we investigated effects of intra-central amygdala (intra CeA) administrations of a beta1-receptor agonist and antagonist, isoprenaline (isoproterenol) and atenolol respectively, on state-dependent memory induced by a cannabioid agonist, WIN55,212-2. This study used a step-through inhibitory avoidance task to assess memory in male Wistar rats. The results showed that post training intra-CeA administrations of different doses of WIN55,212-2 (0.01, 0.05, 0.1 and 0.25MUg/rat) decreased memory as revealed by a decrease in memory retrieval on the test day. The decrease in retrieval induced by post-training WIN55,212-2 (0.25MUg/rat) was reversed by pre-test administration of the same dose of the drug, which was suggestive of drug-induced state-dependent memory. Although pre-test intra-CeA administrations of isoprenaline (0.01, 0.025 and 0.05MUg/rat) alone had no effect, its co-administrations at doses of 0.025 and 0.05MUg/rat with an ineffective dose of WIN55,212-2 (0.1MUg/rat) restored memory retrieval that impaired by post-training WIN55,212-2 (0.25MUg/rat). The results also showed that pre-test intra-CeA administrations of atenolol (0.01, 0.05 and 0.1MUg/rat) alone had no effect, but at dose of 0.1MUg/rat disrupted state dependent memory induced by WIN55,212-2. Moreover, the improving effect of isoprenaline (0.025MUg/rat) on retrieval of state-dependent memory induced by WIN55,212-2 (0.1MUg/rat) was prevented by intra-CeA co-injections of atenolol. Taken together, our results suggest that the CeA may be potentially critical for state-dependent memory induced by WIN55,212-2 and the beta1-noradrenergic receptor mechanism(s) interact with the cannabinergic system in the modulation of this kind of memory in the CeA. PMID- 21704655 TI - Dissociation between neonatal novelty-induced preferential maternal care and enhancement in cognitive, social, and emotional functions. AB - Early life stimulation is known to produce long-lasting changes in the brain and behavior. One such early stimulation method is the neonatal novelty exposure procedure which allows the isolation of the novelty effect from several prominent confounding factors inherent to the neonatal handling procedure. In two previous studies, we found long-lasting novelty effects on different sets of functional measures without accompanying preferential maternal care, even when the observation was made immediately after the novelty manipulation, a time when such preferential care is most likely to be expressed. Here, within a single cohort of Long-Evans male rats, we demonstrate that novelty exposure leads to enhancements across several functional domains, including increased disinhibition to novelty, enhanced spatial and social memory, and reduced aggression, again without the accompaniment of preferential maternal care. These findings extend novelty exposure effects to aggression and replicate previously known novelty exposure effects on spatial and social memory with extension to new developmental stages. Most importantly, these findings do not support the hypothesis that preferential maternal care towards novelty-exposed pups mediates the observed novelty effects. We discuss the possibility that the effects of neonatal novelty exposure are mediated via repeated activation of the hypothalamic-pituitary-adrenal (HPA) axis that serves to inoculate pups for future exposures to novelty and novelty-induced HPA activation and that maternal influence is likely to be expressed via its modulatory role-the mother sets the individual-family specific behavioral and hormonal context to allow the same early life experience to have a family specific effect. PMID- 21704656 TI - Pre- and/or postnatal protein restriction developmentally programs affect and risk assessment behaviors in adult male rats. AB - Developmental programming resulting from a suboptimal intrauterine environment can predispose offspring to a wide-range of lifelong health complications. Little is known about the effects maternal protein restriction during pregnancy and/or lactation has on offspring neurodevelopment. We hypothesized that maternal isocaloric low protein diet during pregnancy and/or lactation would negatively influence male offspring affect and risk assessment behaviors as measured by elevated plus maze and open field tests. Control mothers received 20% casein (C) and restricted mothers (R) 10% casein to provide four groups: CC, RR, CR, and RC (first letter pregnancy diet and second letter lactation diet) to evaluate effects of maternal diet on offspring risk assessment, anxiety and exploratory behaviors. Elevated plus maze results showed an effect of pre- and/or postnatal diet manipulation in open arm time (p<0.05) with increases seen in the RR (157+/ 22.7s), CR (137+/-23.2s) and RC (146.8+/-10.8s) offspring relative to CC (52+/ 8.6s) offspring. This behavior indicates decreased avoidance (less anxiety) and increased exploration by experimental groups. However, in the open field test the RR (17+/-4.2 entries) offspring entered the center zone less than the CC (35+/ 6.6 entries) offspring thus exhibiting increased anxiety with no other groups showing effects. Elevated levels of corticosterone were measured before, during and after immobilization in the RR compared to CC offspring. These findings show protein restriction during critical periods of development negatively program offspring behavior. The underlying anatomical structures affected remain to be elucidated. PMID- 21704657 TI - Antidepressant-like effect of pioglitazone in the forced swimming test in mice: the role of PPAR-gamma receptor and nitric oxide pathway. AB - In this study, the potential antidepressant-like effects of pioglitazone and the possible involvement of peroxisome proliferator-activated receptor gamma (PPARgamma) and nitric oxide system in antidepressant effects of pioglitazone were determined using forced swimming test (FST) in mice. METHOD: After assessment of locomotor activity in open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. Pioglitazone was administered orally with doses (5, 10, 20 and 30 mg/kg) 2 and 4h before FST. To assess the involvement of PPARgamma in the possible antidepressant effect of pioglitazone, GW9662, a PPARgamma antagonist (2mg/kg) was administered before pioglitazone (20mg/kg). For determination of possible role of nitric oxide pathway in this effect, a non-specific NOS inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME, 10mg/kg, i.p.), a specific iNOS inhibitor, aminoguanidine (50mg/kg, i.p.), or a NO precursor, L-arginine (750 mg/kg, i.p.) was co administered with pioglitazone, either 2 or 4h before FST. RESULTS: The immobility time significantly decreased after pioglitazone administration (20 and 30 mg/kg). GW-9662 significantly reversed antidepressant effect of pioglitazone administered 2 and 4h prior to FST. Co-administration of non-effective doses of pioglitazone and l-NAME revealed antidepressant-like effect in FST; while, co administration of non-effective doses of aminoguanidine and pioglitazone did not affect the immobility time. l-Arginine also reversed the antidepressant-like effect of pioglitazone. CONCLUSION: The antidepressant-like effect of pioglitazone on mice in the FST is mediated at least in part through PPARgamma receptors and nitric oxide pathway. PMID- 21704658 TI - A single mild fluid percussion injury induces short-term behavioral and neuropathological changes in the Long-Evans rat: support for an animal model of concussion. AB - Brain concussion is a serious public health concern and is associated with short term cognitive impairments and behavioral disturbances that typically occur in the absence of significant brain damage. The current study addresses the need to better understand the effects of a mild lateral fluid percussion injury on rat behavior and neuropathology in an animal model of concussion. Male Long-Evans rats received either a single mild fluid percussion injury or a sham-injury, and either a short (24h) or long (4 weeks) post-injury recovery period. After recovery, rats underwent a detailed behavioral analysis consisting of tests for rodent anxiety, cognition, social behavior, sensorimotor function, and depression like behavior. After testing all rats were sacrificed and brains were examined immunohistochemically with markers for microglia/macrophage activation, reactive astrocytosis, and axonal injury. Injured rats (mean injury force: 1.20 +/-.03 atm) displayed significant short-term cognitive impairments in the water maze and significantly more anxiolytic-like behavior in the elevated-plus maze compared to sham controls. Neuropathological analysis of the brains of injured rats showed an acute increase in reactive astrogliosis and activated microglia in cortex and evidence of axonal injury in the corpus callosum. There were no significant long term effects on any behavioral or neuropathological measure 4 weeks after injury. These short-term behavioral and neuropathological changes are consistent with findings in human patients suffering a brain concussion, and provide further evidence for the use of a single mild lateral fluid percussion injury to study concussion in the rat. PMID- 21704659 TI - Use of GFP to trace the colonization of Lactococcus lactis WH-C1 in the gastrointestinal tract of mice. AB - A new expression vector for Lactococcus was constructed using nisI as a selection marker and GFP as a reporter protein to explore the colonization characteristics in vivo of Lactococcus lactis WH-C1. By high expression of GFP, it was shown WH C1 could pass through the stomach and survive in the gastrointestinal tract. PMID- 21704660 TI - EEG oscillatory activity associated to monetary gain and loss signals in a learning task: effects of attentional impulsivity and learning ability. AB - This study investigated the influence of individual differences in attentional impulsivity (Att-Imp), learning ability, and learning practice on oscillatory activity and phase synchrony responses to monetary gain and loss signals during an instrumental-learning task in healthy women. We used a trial-by-trial wavelet based time-frequency analysis of the electroencephalographic (EEG) signal to provide amplitude and inter-site phase synchrony measures from 30 electrodes in theta (4-8 Hz, 350-500 ms), alpha (8-12 Hz, 100-200 ms), beta (13-25 Hz, 100-200 ms), and gamma (30-40 Hz, 350-450 ms) time-frequency ranges. Oscillatory amplitude and inter-site phase synchrony were both greater following loss signals as compared to gain signals in theta, beta, and gamma frequency bands. Low Att Imp subjects had higher theta activity within a 350-500 ms time window over frontocentral, and centroparietal sites than high Att-Imp subjects. Monetary gain signals elicited higher theta and gamma activities in high Att-Imp individuals and loss signals elicited higher activities to loss signals in low Att-Imp individuals. Good learners showed enhanced intrahemispheric theta synchrony between frontoparietal, and fronto-occipital sites to monetary loss compared to gain signals. In good learners, monetary loss produced an increase of gamma synchrony that enhanced in the second stage of learning. In low Att-Imp individuals, there was a reduction of theta synchrony during the second stage, as compared with the first stage of learning, between temporal, parietal and fronto parietal brain regions. These findings may offer valuable clues to understand outcome processing, attentional impulsivity, and learning ability. We propose that the punishment-related theta and gamma waves play a leading role in learning process. PMID- 21704661 TI - Performing music can induce greater modulation of emotion-related psychophysiological responses than listening to music. AB - The present study investigated the differential effects of music-induced emotion on heart rate (HR) and its variability (HRV) while playing music on the piano and listening to a recording of the same piece of music. Sixteen pianists were monitored during tasks involving emotional piano performance, non-emotional piano performance, emotional perception, and non-emotional perception. It was found that emotional induction during both perception and performance modulated HR and HRV, and that such modulations were significantly greater during musical performance than during perception. The results confirmed that musical performance was far more effective in modulating emotion-related autonomic nerve activity than musical perception in musicians. The findings suggest the presence of a neural network of reward-emotion-associated autonomic nerve activity for musical performance that is independent of a neural network for musical perception. PMID- 21704662 TI - Retinal ganglion cells survival in a glaucoma model by GDNF/Vit E PLGA microspheres prepared according to a novel microencapsulation procedure. AB - The present experimental work describes the use of a novel protein encapsulation method to achieve protection of the biological factor during the microencapsulation procedure. With this aim, the protein is included in poly(lactic-co-glycolic acid) (PLGA) microspheres without any preliminary manipulation, in contrast to the traditional S/O/W (solid-in-oil-in-water) method where the bioactive substance is first dissolved and then freeze-dried in the presence of lyoprotectors. Furthermore, the presented technique involves the use of an oily additive, vitamin E (Vit E), useful from a technological point of view, by promoting additional protein protection and also from a pharmacological point of view, because of its antioxidant and antiproliferative properties. Application of this microencapsulation technique has been performed for GDNF (glial cell line-derived neurotrophic factor) designed for the treatment of optic nerve degenerative diseases, such as glaucoma, the second leading cause of blindness in the western world. The protein was released in vitro in its bioactive form for more than three months, demonstrated by the survival of their potential target cells (photoreceptors and retinal ganglion cells (RGC)). Moreover, the intravitreal injection of GDNF/Vit E PLGA microspheres in an experimental animal model of glaucoma significantly increased RGC survival compared with GDNF, Vit E or blank microspheres (p<0.01). This effect was present for at least eleven weeks, which suggests that the formulation prepared may be clinically useful as a neuroprotective tool in the treatment of glaucomatous optic neuropathy. PMID- 21704663 TI - Combined MUC1-specific nanobody-tagged PEG-polyethylenimine polyplex targeting and transcriptional targeting of tBid transgene for directed killing of MUC1 over expressing tumour cells. AB - We provide evidence for combining a single domain antibody (nanobody)-based targeting approach with transcriptional targeting as a safe way to deliver lethal transgenes to MUC1 over-expressing cancer cells. From a nanobody immune library, we have isolated an anti-DF3/Mucin1 (MUC1) nanobody with high specificity for the MUC1 antigen, which is an aberrantly glycosylated glycoprotein over-expressed in tumours of epithelial origin. The anti-MUC1 nanobody was covalently linked to the distal end of poly(ethylene glycol)(3500) (PEG(3500)) in PEG(3500)-25kDa polyethylenimine (PEI) conjugates and the resultant macromolecular entity successfully condensed plasmids coding a transcriptionally targeted truncated-Bid (tBid) killer gene under the control of the cancer-specific MUC1 promoter. The engineered polyplexes exhibited favourable physicochemical characteristics for transfection and dramatically elevated the level of Bid/tBid expression in both MUC1 over-expressing caspase 3-deficient (MCF7 cells) and caspase 3-positive (T47D and SKBR3) tumour cell lines and, concomitantly, induced considerable cell death. Neither transgene expression nor cell death occurred when the MUC1 promoter was replaced with the CNS-specific synapsin I promoter. Since PEGylated PEI was only responsible for DNA compaction and played no significant role in direct transfection and cell killing, our attempts overcome previously reported PEI-mediated apoptotic and necrotic cell death, which is advantageous for future in vivo transcriptional targeting as this will minimize (or eliminate) non targeted cell damage. PMID- 21704665 TI - Attitudes, perceptions, and trust. Insights from a consumer survey regarding genetically modified banana in Uganda. AB - Genetically modified (GM) crops and food are still controversial. This paper analyzes consumers' perceptions and institutional awareness and trust toward GM banana regulation in Uganda. Results are based on a study conducted among 421 banana-consuming households between July and August 2007. Results show a high willingness to purchase GM banana among consumers. An explanatory factor analysis is conducted to identify the perceptions toward genetic modification. The identified factors are used in a cluster analysis that grouped consumers into segments of GM skepticism, government trust, health safety concern, and food and environmental safety concern. Socioeconomic characteristics differed significantly across segments. Consumer characteristics and perception factors influence consumers' willingness to purchase GM banana. The institutional awareness and trust varied significantly across segments as well. The findings would be essential to policy makers when designing risk-communication strategies targeting different consumer segments to ensure proper discussion and addressing potential concerns about GM technology. PMID- 21704664 TI - Development of docetaxel-loaded intravenous formulation, Nanoxel-PMTM using polymer-based delivery system. AB - Nanoxel-PMTM, docetaxel-loaded methoxy-poly(ethylene glycol)-block-poly(d,l lactide) (mPEG-PDLLA) micellar formulation was prepared in an effort to develop alternative, less toxic and efficacious Tween 80-free docetaxel formulation, and its pharmacokinetics, efficacy, and toxicity were evaluated in comparison with Taxotere(r) in preclinical studies. The mean diameter of the Nanoxel-PMTM was 10 50 nm and the polydispersity of samples exhibited a narrow size distribution and monodisperse unimodal pattern. Pharmacokinetic study in mice, rats and beagle dogs revealed that Nanoxel-PMTM exhibited similar pharmacokinetic profiles (C(max), AUC, t(1/2), CL, V(ss)) to Taxotere, and the relative mean AUC(t) and C(max) of Nanoxel-PMTM to Taxotere(r) were within 80-120%. Furthermore, excretion study in rats demonstrated that there was no statistically significant difference in the amount excreted in feces or urine as an unmetabolized docetaxel between Nanoxel-PMTM and Taxotere(r). Its pharmacokinetic bioequivalence resulted in comparable anti-tumor efficacy to Taxotere(r) in human lung cancer xenografts H 460 in nude mice as well as in lung, ovary and breast cancer cell lines. Several animal toxicity studies on Nanoxel-PMTM compared with Taxotere(r) were carried out. In single dose rat and dog model and repeated dose mouse model, both Nanoxel PMTM and Taxotere(r) exhibited similar toxic effects on hematology and body weight gain. On the other hand, vehicle related hypersensitivity reactions and fluid retentions were not observed when Nanoxel-PMTM was administered, unlike Taxotere(r), in the beagle dog study. Based on these results, it is expected that Nanoxel-PMTM can reduce side effects of hypersensitivity reactions and fluid retention while retaining antitumor efficacy in cancer patients. Currently, Nanoxel-PMTM is under evaluation for bioequivalence with Taxotere(r) in a multi center, open-label, randomized, crossover study. PMID- 21704666 TI - The effect of pistachio shells as a visual cue in reducing caloric consumption. AB - It was hypothesized that pistachio shells left in sight as visual cues of consumption will cause individuals to consume less. A convenience sample of faculty and staff at a mid-western university (n=118) were recruited as subjects for the study. The subjects were told they were going to evaluate a variety of brands of pistachios and were surveyed at the end of each day to determine their fullness and satisfaction. The subjects were offered pistachios on their desks for an 8-h period on two separate days and were able to consume the pistachios at their leisure during that time. Subjects began each day with a sixteen ounce bowl filled with four ounces of pistachios in the shell. They were also provided with a second sixteen ounce bowl, in which they were instructed to place the empty shells from the pistachios they consumed. Every 2 h throughout the day pistachios were added in two ounce increments. In condition one, the shells remained in the bowls until the end of the day, whereas in condition two, the shell bowls were emptied every 2 h throughout the day. In condition one, subjects consumed an average of 216 calories. In condition two, subjects consumed an average of 264 calories, a difference of 48 calories. Subjects in condition one consumed significantly (p<=.05) fewer calories, yet fullness and satisfaction ratings were not significantly (p>=.05) different between conditions. Leaving pistachio shells as a visual cue to consumption may help consumers consume fewer calories. LEARNING OUTCOMES: Individuals will be aware of the impact of visual cues of dietary intake on total food consumption. PMID- 21704668 TI - Characterisation and toxicological behaviour of Basic Methacrylate Copolymer for GRAS evaluation. AB - Basic Methacrylate Copolymer is a fully polymerised cationic copolymer with taste masking and moisture protection properties. It is used as a pharmaceutical excipient and has potential use as a glazing/coating agent to solid food supplements. This article describes available information on the safety of the substance. Oral administration of radiolabelled copolymer to rats showed the major route of excretion to be via the faeces. Minor absorption may occur at <0.02%. Safety studies revealed no adverse toxicity following repeated administration at up to 2000 mg/kg/day in a sub-chronic study in the rat or 750 mg/kg/day in a sub-acute study in the dog. No reproductive toxicity occurred at up to 1000 mg/kg/day in the rat. The substance shows no evidence of genotoxicity, has low acute toxicity and no irritation or sensitisation potential. As per the FDA approach an ADI of 20 mg/kg bw can be concluded. Daily exposure from use as a food additive is estimated as up to 11.7 mg/kg bw in adults and 13.3 mg/kg bw in children. In view of the high molecular weight of the substance, its lack of absorption and its low toxicity profile, the ADI is deemed adequate. PMID- 21704667 TI - Diversity of factor H-binding protein in Neisseria meningitidis carriage isolates. AB - Several meningococcal vaccines under development for prevention of serogroup B disease target the factor H-binding protein (FHbp), an immunogenic lipoprotein expressed on the surface of Neisseria meningitidis. Based upon sequence and phylogenetic analyses, FHbp can be classified into 3 protein variants (1, 2 or 3) or 2 subfamilies (A or B). The potential effect of FHbp-containing vaccines on meningococcal carriage is not known. We determined the diversity of FHbp among a population of carriage isolates obtained from Georgia and Maryland high school students in 1998 and 2006-2007. Analysis of the fHbp gene sequence from 408 carriage isolates identified 30 different FHbp protein sequences. The majority of carriage isolates harbored FHbp proteins belonging to variant 2/subfamily A. Association between FHbp proteins and genetic lineage was observed among the carriage isolates. However, split decomposition analysis, together with tests of linkage disequilibrium and pairwise homoplasy suggest recombination at fHbp contribute to allelic diversity. Of note, the FHbp proteins in serogroup B vaccines under development are either absent or not well represented in this carriage population. The FHbp genetic repertoire observed in carriage isolate populations will be useful in understanding the potential impact of FHbp containing vaccines on meningococcal carriage. PMID- 21704669 TI - Factors associated with the incidence of erosive wear in upper incisors and lower first molars: a multifactorial approach. AB - OBJECTIVES: The aim was to investigate associations between factors and the incidence of erosive wear in lower first molars and upper incisors, and to investigate whether these associations differ between these locations. METHODS: The study sample of this 3-year longitudinal study consisted of 572 children (mean age 11.9 years, SD=0.9). The permanent dentition was examined for erosive wear according to a modified Lussi-index (1996). Information on biological and behavioural factors was gathered by clinical examinations (at baseline, after 1.5 and 3 years) and by questionnaires (every six months). RESULTS: The incidence of erosive wear in upper incisors over 3 years was 22.2%, for lower first molars the incidence was 14.8%. Multivariate logistic regression analysis showed that carbonated soft drink (OR=1.04) and tooth grinding (OR=2.93) were positively associated with the incidence of erosive wear in upper incisors and milk (OR=0.95) and yoghurt products (OR=0.88) were negatively associated. The incidence of erosive tooth wear in lower first molars was positively associated with alcoholic mixed drink (OR=1.45) and tooth grinding (OR=4.00) and was negatively associated with milk (OR=0.96) and yoghurt products (OR=0.84). The incidence of erosive wear in lower first molar was lower in girls than in boys (OR=0.51). t-Tests on the odds ratios of the factors showed that between the two incidence models only the odds ratios of anterior contact significantly differed. CONCLUSIONS: In the present study, except for anterior contact, no substantial differences in risk factors between the incidence of erosive wear in lower first molars and upper incisors were found. This indicates that the aetiology of erosive wear for the two locations is similar. PMID- 21704670 TI - An idiosyncratic serine ordering loop in methanogen seryl-tRNA synthetases guides substrates through seryl-tRNASer formation. AB - Seryl-tRNA synthetases (SerRS) covalently attach serine to cognate tRNA(Ser). Atypical SerRSs, considerably different from canonical enzymes, have been found in methanogenic archaea. A crystal structure of methanogenic-type SerRS revealed a motif within the active site (serine ordering loop; SOL), which undergoes a notable induced-fit rearrangement during serine binding. The loop rearranges from a disordered conformation in the unliganded enzyme, to an ordered structure comprising an alpha-helix followed by a loop. We performed kinetic and thermodynamic analyses of SerRS variants to establish the role of the SOL in serylation. Thermodynamic data confirmed a linkage between binding of serine and alpha-helix formation, previously described by the crystallographic analysis. The ability of the SOL to adopt the observed secondary structure was recognized as essential for serine activation. Mutation of Gln400, which according to the structural data establishes the main connection between the serine and the SOL, produced only modest kinetic effects. Kinetic data offer new insights into the coupling of the conformational change with active site assembly. Productive positioning of the SOL may be driven by the interaction between Trp396 and the serine alpha-amino group. Rapid kinetics reveals that His250, a non-SOL residue, is essential for transfer of serine to tRNA. Modeling data established that accommodation of the tRNA within the active site may require movement of the SOL. This would enable His250 to assist in productive positioning of the 3'-end of the tRNA for the aminoacyl transfer. Thus, the rearrangements of the SOL conformationally adjust the active site for both reaction steps. PMID- 21704671 TI - The Peptidic GHS-R antagonist [D-Lys(3)]GHRP-6 markedly improves adiposity and related metabolic abnormalities in a mouse model of postmenopausal obesity. AB - It was demonstrated that estrogen deficiency and consuming high fat (HF) diet enhanced orexigenic activity of ghrelin. Therefore, we hypothesized that antagonizing of ghrelin action would attenuate food intake and body weight in mice obese both from ovariectomy (OVX) and feeding a HF diet. Ghrelin receptor antagonist [D-Lys(3)]GHRP-6 after seven days of subcutaneous treatment markedly decreased food intake in OVX mice fed both HF and standard diets; furthermore, it reduced body weight and blood glucose, insulin and leptin, and increased beta hydroxybutyrate level and uncoupling-protein-1 mRNA in brown adipose tissue. Pair feeding revealed that effect of [D-Lys(3)]GHRP-6 was primary anorexigenic. Estrogen supplementation reduced anorexigenic effects of [D-Lys(3)]GHRP-6. OVX [D Lys(3)]GHRP-6 treatment in mice on HF diet resulted in markedly increased circulating level and liver expression of a major metabolic regulator, fibroblast growth factor 21. Our data suggest that ghrelin antagonists could be especially beneficial in individuals with common obesity combined with estrogen deficiency. PMID- 21704673 TI - Neuroprotective effect of bioflavonoid quercetin in 6-hydroxydopamine-induced oxidative stress biomarkers in the rat striatum. AB - An increasing large body of research on Parkinson's disease (PD) has focused on the understanding of the mechanisms behind the potential neuro protection offered by antioxidants and iron chelating agents. In this study, the protective effect of the bioflavonoid quercetin on 6-hydroxydopamine (6-OHDA)-induced model of PD was investigated. PD was induced by a single intracisternal injection of 6 hydroxydopamine (300MUg) to male Sprague-Dawley rats. Quercetin treatment (30mg/kg body weight) over 14 consecutive days markedly increased the striatal dopamine and antioxidant enzyme levels compared with similar measurements in the group treated with 6-OHDA alone. There was a significant decrease in protein carbonyl content in the striatum compared with that of rats that did not receive quercetin. A significant increase in neuronal survivability was also found with quercetin treatment in rats administered 6-OHDA. In conclusion, treatment with quercetin defended against the oxidative stress in the striatum and reduced the dopaminergic neuronal loss in the rat model of PD. PMID- 21704672 TI - The kisspeptin signaling pathway and its role in human isolated GnRH deficiency. AB - Amplification of the neurosecretory activity of the GnRH system is the defining neuroendocrine event for sexual maturation. The physiological mechanisms that drive GnRH secretion at puberty have been difficult to identify but the discovery in 2003 that the G protein coupled receptor KISS1R is a key regulator of pubertal development in mice and men has ushered in a new chapter in reproductive neuroendocrinology. KISS1R is activated by endogenous peptides derived from a precursor protein, kisspeptin. Despite kisspeptin's importance in driving the reproductive cascade, relatively few patients with GnRH deficient states and mutations in the kisspeptin pathway have been described. Yet, these cases, coupled with loss-of-function mouse models, provide unique and complementary information into the biological role of this signaling system in the control of GnRH secretion. This article will examine some of the subtleties in genotype phenotype correlations in both mice and men carrying disabling mutations in the kisspeptin pathway. PMID- 21704674 TI - Histological and functional renal alterations caused by Bothrops alternatus snake venom: expression and activity of Na+/K+-ATPase. AB - BACKGROUND: Acute renal failure is a serious complication of human envenoming by Bothrops snakes. The ion pump Na+/K+-ATPase has an important role in renal tubule function, where it modulates sodium reabsorption and homeostasis of the extracellular compartment. Here, we investigated the morphological and functional renal alterations and changes in Na+/K+-ATPase expression and activity in rats injected with Bothrops alternatus snake venom. METHODS: Male Wistar rats were injected with venom (0.8 mg/kg, i.v.) and renal function was assessed 6, 24, 48 and 72 h and 7 days post-venom. The rats were then killed and renal Na+/K+-ATPase activity was assayed based on phosphate release from ATP; gene and protein expressions were assessed by real time PCR and immunofluorescence microscopy, respectively. RESULTS: Venom caused lobulation of the capillary tufts, dilation of Bowman's capsular space, F-actin disruption in Bowman's capsule and renal tubule brush border, and deposition of collagen around glomeruli and proximal tubules that persisted seven days after envenoming. Enhanced sodium and potassium excretion, reduced proximal sodium reabsorption, and proteinuria were observed 6 h post-venom, followed by a transient decrease in the glomerular filtration rate. Gene and protein expressions of the Na+/K+-ATPase alpha1 subunit were increased 6h post-venom, whereas Na+/K+-ATPase activity increased 6 h and 24 h post-venom. CONCLUSIONS: Bothrops alternatus venom caused marked morphological and functional renal alterations with enhanced Na+/K+-ATPase expression and activity in the early phase of renal damage. GENERAL SIGNIFICANCE: Enhanced Na+/K+-ATPase activity in the early hours after envenoming may attenuate the renal dysfunction associated with venom-induced damage. PMID- 21704675 TI - Effect of protein glutathionylation on neuronal cytoskeleton: a potential link to neurodegeneration. AB - Neurons are highly susceptible to oxidative stress and oxidation of cytoskeletal proteins is considered one of the first steps of neurodegeneration. Protein glutathionylation is a key event in the redox regulation of protein function and constitutes a sensor of tissue oxidative stress in patho-physiological conditions. In this study, we analyzed for the first time tubulin glutathionylation and its relation to neurites degeneration. For this purpose, we exposed motoneuronal cells to the physiological oxidant glutathione disulfide (GSSG) and we analyzed the extent and morphology of axonal changes caused by protein glutathionylation in these cells. Then we studied the effect of glutathionylation on the distribution of stable and dynamic microtubules in the same cells. Our results indicate that oxidative stress conditions determined by an increased intracellular level of oxidized glutathione may cause an alteration of the cytoskeleton organization and function leading to axon degeneration. These findings might contribute to understand the sequence of pathogenic events involved in the axonal degeneration that characterizes many diseases of the nervous system associated with oxidative stress. PMID- 21704677 TI - Midkine regulates amphetamine-induced astrocytosis in striatum but has no effects on amphetamine-induced striatal dopaminergic denervation and addictive effects: functional differences between pleiotrophin and midkine. AB - Midkine (MK), a neurotrophic factor with important roles in survival and differentiation of dopaminergic neurons, is upregulated in different brain areas after administration of different drugs of abuse suggesting MK could modulate drugs of abuse-induced pharmacological or neuroadaptative effects. To test this hypothesis, we have studied the effects of amphetamine administration in MK genetically deficient (MK-/-) and wild-type (MK+/+) mice. In conditioning studies, we found that amphetamine induces conditioned place preference (CPP) similarly in both MK-/- and MK+/+ mice. In immunohistochemistry studies, we found that amphetamine (10 mg/kg, four times, every 2 h) causes a similar striatal dopaminergic denervation in both MK-/- and MK+/+ mice. However, we detected a significant increase of glial fibrillary acidic protein (GFAP)-positive cells in the striatum of amphetamine-treated MK-/- mice compared to MK+/+ mice, suggesting an enhanced amphetamine-induced astrocytosis in absence of endogenous MK. Interestingly, the levels of expression of the MK receptor, receptor protein tyrosine phosphatase (RPTP) beta/zeta, in the striatum were not found to be changed by the drug administration or the mouse genotype. In a similar manner the phosphorylation levels of RPTP beta/zeta substrates with important roles in survival of dopaminergic neurons, Fyn kinase and TrkA, and of the MAP kinases ERK1/2, were unaffected by the drug or the genotype. The data clearly suggest that endogenous MK limits amphetamine-induced astrocytosis through Fyn-, TrkA- and ERK1/2-independent mechanisms and identify previously unexpected functional differences between MK and pleiotrophin, the only other member of the MK family of growth factors, in the modulation of effects of drugs of abuse. PMID- 21704676 TI - A restricted parabrachial pontine region is active during non-rapid eye movement sleep. AB - The principal site that generates both rapid eye movement (REM) sleep and wakefulness is located in the mesopontine reticular formation, whereas non-rapid eye movement (NREM) sleep is primarily dependent upon the functioning of neurons that are located in the preoptic region of the hypothalamus. In the present study, we were interested in determining whether the occurrence of NREM might also depend on the activity of mesopontine structures, as has been shown for wakefulness and REM sleep. Adult cats were maintained in one of the following states: quiet wakefulness (QW), alert wakefulness (AW), NREM, or REM sleep induced by microinjections of carbachol into the nucleus pontis oralis (REM carbachol). Subsequently, they were euthanized and single-labeling immunohistochemical studies were undertaken to determine state-dependent patterns of neuronal activity in the brainstem based upon the expression of the protein Fos. In addition, double-labeling immunohistochemical studies were carried out to detect neurons that expressed Fos as well as choline acetyltransferase, tyrosine hydroxylase, or GABA. During NREM, only a few Fos-immunoreactive cells were present in different regions of the brainstem; however, a discrete cluster of Fos+ neurons was observed in the caudolateral parabrachial region (CLPB). The number of Fos+ neurons in the CLPB during NREM was significantly greater (67.9+/ 10.9, P<0.0001) compared with QW (8.0+/-6.7), AW (5.2+/-4.2), or REM-carbachol (8.0+/-4.7). In addition, there was a positive correlation (R=0.93) between the time the animals spent in NREM and the number of Fos+ neurons in the CLPB. Fos immunoreactive neurons in the CLPB were neither cholinergic nor catecholaminergic; however, about 50% of these neurons were GABAergic. We conclude that a group of GABAergic and unidentified neurons in the CLPB are active during NREM and likely involved in the control of this behavioral state. These data open new avenues for the study of NREM, as well as for the explorations of interactions between these neurons that are activated during NREM and cells of the adjacent pontine tegmentum that are involved in the generation of REM sleep. PMID- 21704679 TI - Vascular endothelial growth factor and platelet derived growth factor modulates the glial response to a cortical stab injury. AB - Traumatic injury to the brain initiates an increase in astrocyte and microglial infiltration as part of an inflammatory response to injury. Increased astrogliosis around the injury impedes regeneration of axons through the injury, while activated microglia release inflammatory mediators. The persistent inflammatory response can lead to local progressive cell death. Modulating the astrocyte and microglial response to traumatic injury therefore has potential therapeutic benefit in brain repair. We examine the modulatory effect of a single bolus of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) in combination on astrocytes and microglia to acute cerebral injury. A combination of VEGF and PDGF (20 pg) was injected into the striatum of adult male Sprague-Dawley rats. The effects of treatment were assessed by quantitative immunofluorescence microscopy analyzing astrocytes and microglia across the stab injury over time. Treatment delayed the onset of astrogliosis in the centre and edge of the stab injury up to day 5; however, increased astrogliosis at areas remote to the stab injury up to day 5 was observed. A persistent astrocytic response was observed in the centre and edge of the stab injury up to day 60. Treatment altered microglia cell morphology and numbers across the stab injury, with a decrease in ramified microglia, but an increase in activated and phagocytic microglia up to day 5 after stab injury. The increased microglial response from 10 until day 60 was comprised of the ramified morphology. Thus, VEGF and PDGF applied at the same time as a stab injury to the brain initially delayed the inflammatory response up to day 5 but evoked a persistent astrogliosis and microglial response up to 60 days. PMID- 21704678 TI - Potassium currents of olfactory bulb juxtaglomerular cells: characterization, simulation, and implications for plateau potential firing. AB - Odor identity is encoded by the activity of olfactory bulb glomeruli, which receive primary sensory input and transfer it to projection neurons. Juxtaglomerular cells (JGCs) may influence glomerular processing via firing of long lasting plateau potentials. Though inward currents have been investigated, little is known regarding potassium current contribution to JGC plateau potentials. We pursued study of these currents, with the overarching goal of creating components for a computational model of JGC plateau potential firing. In conditions minimizing calcium-activated potassium current (I(K(Ca))), we used whole cell voltage clamp and in vitro slice preparations to characterize three potassium currents in rat JGCs. The prominent component I(kt1) displayed rapid kinetics (tau(10%-90% rise), 0.6-2 ms; tau(inactivation), 5-10 ms) and was blocked by high concentration 4-aminopyridine (4-AP) (5 mM) and tetramethylammonium (TEA) (40 mM). It had half maximal activation at -10 mV (V(1/2)max) and little inactivation at rest. I(kt2), with slower kinetics (tau(10%-90% rise), 11-15 ms; tau(inactivation), 100-300 ms), was blocked by low concentration 4-AP (0.5 mM) and TEA (5 mM). The V(1/2)max was 0 mV and inactivation was also minimal at rest. Sustained current I(kt3) showed sensitivity to low concentration 4-AP and TEA, and had V(1/2)max of +10 mV. Further experiments, in conditions of physiologic calcium buffering, suggested that I(K(Ca)) contributed to I(kt3) with minimal effect on plateau potential evolution. We transformed these characterizations into Hodgkin-Huxley models that robustly mimicked experimental data. Further simulation demonstrated that I(kt1) would be most efficiently activated by plateau potential waveforms, predicting a critical role in shaping JGC firing. These studies demonstrated that JGCs possess a unique potassium current profile, with delayed rectifier (I(kt3)), atypical A current (I(kt1)), and D-current (I(kt2)) in accordance with known expression patterns in olfactory bulb (OB) glomeruli. Our simulations also provide an initial framework for more integrative models of JGC plateau potential firing. PMID- 21704680 TI - Time-course of hippocampal granule cell degeneration and changes in adult neurogenesis after adrenalectomy in rats. AB - The hippocampus maintains the remarkable ability to generate new neurons throughout the lifespan. Progenitor cells in the subgranular zone give rise mainly to granule cells that migrate to the granule cell layer and become mature, functionally integrated neurons. Numerous factors are capable of regulating the proliferation and survival of new neurons in the adult hippocampus. Corticosterone is one of the most potent factors. Stress results in a significant decrease in the number of dividing cells and exogenous corticosterone administration produces a similar result. Conversely, removal of circulating glucocorticoids via adrenalectomy has been shown to dramatically increase cell proliferation. However, no studies have examined the long-term effects of adrenalectomy on cell proliferation in the hippocampus. In addition to increasing cell proliferation in the hippocampus, chronic adrenalectomy induces ongoing cell death in the dentate gyrus. In order to determine the time course of cell proliferation and cell death in the dentate gyrus following corticosterone removal we examined the dentate gyrus of rats at several time points following adrenalectomy. We analyzed the number of proliferating cells based on Ki67 labeling and visualized cell death using Fluoro-Jade B. Here we show that although cell proliferation is initially enhanced by adrenalectomy, but the increase is transient; it is no longer apparent by 4 weeks after adrenalectomy. Furthermore, we demonstrate that cell death is pronounced by 3 days after adrenalectomy and continues for at least 23 weeks. PMID- 21704682 TI - Chloride-mediated inhibition of the ictogenic neurones initiating genetically determined absence seizures. AB - Electroclinical investigations in human patients and experimental studies from genetic models demonstrated that spike-and-wave discharges (SWDs) associated with absence seizures have a cortical onset. In the Genetic Absence Epilepsy Rat from Strasbourg (GAERS), SWDs are initiated by the paroxysmal discharges of ictogenic pyramidal neurones located in the deep layers of the somatosensory cortex. However, the cellular and synaptic mechanisms that control the ictal discharges of seizure-initiating neurones remain unclear. Here, by the means of in vivo paired electroencephalographic (EEG) and intracellular recordings in the GAERS cortical focus, we explored the participation of the intracortical inhibitory system in the control of paroxysmal activities in ictogenic neurones. We found that their firing during EEG paroxysms was interrupted by the occurrence of hyperpolarizing synaptic events that reversed in polarity below action potential threshold. Intracellular injection of Cl(-) dramatically increased the amplitude of the paroxysmal depolarizations and the number of generated action potentials, strongly suggesting that the inhibitory synaptic potentials were mediated by GABA(A) receptors. Consistently, we showed that intracellularly recorded GABAergic interneurones fired, during seizures, shortly after (~+8 ms) the discharge of ictogenic neurones and displayed a rhythmic bursting that coincided with the inhibitory synaptic events in neighbouring pyramidal ictogenic cells. In contrast with other forms of epilepsy, our findings suggest that paroxysmal activities in the cortical pyramidal cells initiating absence seizures are negatively controlled by a feedback Cl(-)-mediated inhibition likely resulting from the fast recurrent activation of intracortical GABAergic interneurones by the ictogenic cells themselves. PMID- 21704683 TI - Maintained generalization of delay-specific remembering. AB - According to the discrimination hypothesis (White, 2002), remembering is a delay specific discrimination made at the time of retrieval. In the present experiment the delay-specific nature of the discrimination was made explicit by making correct choices in a delayed matching-to-sample task performed by pigeons conditional on whether the retention interval was short or long. Retention interval was varied over several durations in a maintained generalization test without reinforcement for correct matching responses. Opposing gradients demonstrated generalization of delay-specific remembering, consistent with the view that the temporal dimension of the retention interval can be treated in the same way as non-temporal dimensions of the sample stimulus. PMID- 21704681 TI - Calcium currents of olfactory bulb juxtaglomerular cells: profile and multiple conductance plateau potential simulation. AB - The olfactory glomerulus is the locus of information transfer between olfactory sensory neurons and output neurons of the olfactory bulb. Juxtaglomerular cells (JGCs) may influence intraglomerular processing by firing plateau potentials that support multiple spikes. It is unclear what inward currents mediate this firing pattern. In previous work, we characterized potassium currents of JGCs. We focus here on the inward currents using whole cell current clamp and voltage recording in a rat in vitro slice preparation, as well as computer simulation. We first showed that sodium current was not required to mediate plateau potentials. Voltage clamp characterization of calcium current (I(Ca)) determined that I(Ca) consisted of a slow activating, rapidly inactivating (tau(10%-90% rise) 6-8 ms, tau(inactivation) 38-77 ms) component I(cat1), similar to T-type currents, and a sustained (tau(inactivation)>>500 ms) component I(cat2), likely composed of L type and P/Q-type currents. We used computer simulation to test their roles in plateau potential firing. We robustly modeled I(cat1) and I(cat2) to Hodgkin Huxley schemes (m(3)h and m(2), respectively) and simulated a JGC plateau potential with six conductances: calcium currents as above, potassium currents from our prior study (A-type I(kt1), D-type I(kt2), delayed rectifier I(kt3)), and a fast sodium current (I(Na)). We demonstrated that I(cat1) was required for mediating the plateau potential, unlike I(Na) and I(cat2), and its tau(inactivation) determined plateau duration. We also found that I(kt1) dictated plateau potential shape more than I(kt2) and I(kt3). The influence of these two transient and opposing conductances suggests a unique mechanism of plateau potential physiology. PMID- 21704684 TI - Innovative foraging behaviour in birds: what characterizes an innovator? AB - Innovative foraging behaviour has been observed in many species, but little is known about how novel behaviour emerges or why individuals differ in their propensity to innovate. Here, we investigate these questions by presenting 36 wild-caught adult male Carib grackles (Quiscalus lugubris) with a novel problem solving task. Twenty birds solved the task ("innovators") while 16 did not ("non innovators"). We compared innovators to non-innovators and explored variation in latency to innovate to determine the characteristics of an innovative bird. Innovativeness was not predicted by any morphological trait, but innovators had higher exploration scores and lower object neophobia scores than non-innovators. Within the innovators, latency to innovate was positively correlated with learning speed. Video analysis also revealed a marked difference in the way individuals interacted with the novel apparatus: when innovators contacted the correct part of the apparatus, they continued to do so until they solved the problem. Non-innovators often contacted the correct part of the apparatus, but did not persist in doing so. The importance of obstacle movement cues was confirmed by an experiment where they were manipulated. PMID- 21704685 TI - Phthalate exposure during cold plastisol application--a human biomonitoring study. AB - The phthalates DEHP (Diethylhexyl phthalate), DiNP (Diisononyl phthalate) and DiDP (Diisodecyl phthalate) are constituents of plastisols. We sought to obtain first data on occupational exposures to the above phthalates by analyzing their metabolites in pre- and post-shift urine samples from 5 workers in a car manufacturing plant engaged in seam sealing with a DINP based plastisol. Pre shift samples were collected after a work-free period of at least 2 days. As a comparison group we investigated 10 employees from the same plant. The comparison group had phthalate exposures in the range of the general German population. All plastisol workers had post shift values of DiNP and DiDP metabolites that were approx. 20-times higher, and pre-shift values that were approx. 5-10 times higher than those of the general background exposure. Post-shift values of DiNP metabolites were (median [maximum]: OH-MiNP: 117 [442] MUg/L; oxo-MiNP: 44.3 [175] MUg/L; carboxy-MiNP: 57.8 [286]MUg/L), pre shift values were (OH-MiNP: 26 [164] MUg/L; oxo-MiNP 12.9 [68.6] MUg/L; carboxy-MiNP: 32.3 [103] MUg/L), compared to the comparison group (OH-MiNP: 6.2 [33]MUg/L; oxo-MiNP: 2.8 [16] MUg/L; carboxy-MiNP: 6.5 [31] MUg/L). DiDP values were generally lower. Regarding DEHP we found no significant work related exposure. The dermal exposure route might play an important role for phthalates in plastisols, with possible influences on distribution and elimination kinetics and therefore data interpretation. PMID- 21704686 TI - Acute effects of ethanol on the transfer of nicotine and two dietary carcinogens in human placental perfusion. AB - Many mothers use, against instructions, alcohol during pregnancy. Simultaneously mothers are exposed to a wide range of other environmental chemicals. These chemicals may also harm the developing fetus, because almost all toxic compounds can go through human placenta. Toxicokinetic effects of ethanol on the transfer of other environmental compounds through human placenta have not been studied before. It is known that ethanol has lytic properties and increases the permeability and fluidity of cell membranes. We studied the effects of ethanol on the transfer of three different environmental toxins: nicotine, PhIP (2-amino-1 methyl-6-phenylimidazo(4,5-b)pyridine) and NDMA (N-nitrosodimethylamine) in placental perfusion. We tested in human breast cancer adenocarcinoma cell line MCF-7 whether ethanol affects ABCG2/BCRP, which is also the major transporter in human placenta. We found that the transfer of ethanol is comparable to that of antipyrine, which points to passive diffusion as the transfer mechanism. Unexpectedly, ethanol had no statistically significant effect on the transfer of the other studied compounds. Neither did ethanol inhibit the function of ABCG2/BCRP. These experiments represent only the effects of acute exposure to ethanol and chronic exposure remains to be studied. PMID- 21704687 TI - Manganese in plasma: a promising biomarker of exposure to Mn in welders. A pilot study. AB - BACKGROUND: There is raising concern about the potential neurotoxic effects of manganese (Mn) inhalation exposure in welders. Because most of the airborne particles in welding fume are in the respirable fraction, their bioavailability is likely to be higher than for coarser dust exposure. No well-validated biomarker for Mn exposure is available. OBJECTIVES: To investigate the interest of measuring Mn in plasma (Mn-P) and urine (Mn-U) as biomarkers of exposure in a group of 28 welders whose tasks were only welding-related. METHODS: Ambient air exposure to Mn (Mn-air) was determined by personal full-shift measurements on Monday and Tuesday. On the same days, blood and urine samples were collected before and after the shift. RESULTS: Mn-air varied from 1.3 to 729 MUg/m(3) (GM 27.7). For Mn-U 65% of the values in welders were below the LOQ (0.20 MUg/L). Compared to controls, the welders' Mn-P averaged 33% higher (1.5 vs 2.0 MUg/L). In welders, the after-shift Mn-P values correlated well with Mn-air above 10 MUg/m(3). In spite of similar Mn-air exposure on Monday and Tuesday, the relationships between Mn-air and after-shift Mn-P strikingly differed on Tuesday in that the inflection in the relationship was less obvious and the slope of the regression line (Mn-P after-shift/logMn-air) for a doubling of logMn-air was 2.3 times lower than on Monday. On Monday (the first day of the workweek), a Mn-P value of 2 MUg/L could distinguish Mn-air exposure above or below 20 MUg/m(3) with a sensitivity of 69% and a specificity of 82%. CONCLUSIONS: This preliminary study indicates that Mn-P is a promising biomarker of current exposure to Mn in welders and lends biological plausibility to the intended change for the Mn TLV TWA of 20 MUg/m(3) proposed by ACGIH for respirable Mn particulate. PMID- 21704688 TI - Development of 2-(dimethylamino)ethyl methacrylate-based molecular recognition devices for controlled drug delivery using supercritical fluid technology. AB - This work reports the development of a novel potential body-friendly oral drug delivery system, which consists of a biocompatible molecularly imprinted polymer (MIP), with pH sensitive character and low cross-linking degree (20.2wt%), synthesized and processed in supercritical carbon dioxide. The MIP is synthesized using 2-(dimethylamino)ethyl methacrylate (DMAEMA) as functional monomer and ethylene glycol dimethacrylate (EGDMA) as cross-linker, and ibuprofen as molecular recognition template. The imprinted matrix was able to show a higher affinity towards ibuprofen than its corresponding non-imprinted polymer (NIP) meaning that the molecular imprinting in scCO(2) was efficient even using a low crosslinking degree. MIP showed a significant molecular recognition towards the template, presenting higher drug uptake ability in the supercritical impregnation step, loading 33.1wt% of ibuprofen compared to only 10.2wt% for the NIP polymer. In vitro drug release experiments, simulating an oral administration, showed different release profiles at pH 2.2 and pH 7.4. Zeta potential measurements were performed to both MIP and NIP showing that the imprinting process has a significant influence on the charge of the polymeric particles. Cytotoxicity assays performed with human colorectal carcinoma-derived Caco-2 cells demonstrated that the polymers are biocompatible and could be potentially used in drug delivery applications. PMID- 21704689 TI - Endermatic, epidermatic, enepidermatic-the early history of penetration enhancers. AB - Already at the end of the 18th century, attempts were made to administer drugs transdermally. Several techniques were applied, including rubbing drug substances into the intact or wounded skin. Penetration enhancers were investigated as well, including human and animal body fluids, in particular gastric juice and saliva. In the 19th century, lipophilic solubilizers like chloroform and ether were tried. Although the experiments were mostly done against a pre-rational background some may be worth to be judged under scientific premises. PMID- 21704690 TI - Microencapsulation enhances the anti-ulcerogenic properties of Entada africana leaf extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The antiulcer potentials of most plants still remain largely unexplored, despite their prospects evidenced by their use as ethnomedicine. Entada africana (Mimosaceae) has been widely used in Africa for the treatment of skin infections, wounds, tonic for stomach troubles and against diphtheria-like throat complaints. The aim of the present study was to evaluate the anti-ulcer properties of Entada africana (EA) ethanol leaf extract and to obtain a novel multiparticulate pharmaceutical formulation (ACE) with it. MATERIALS AND METHODS: Ethanol or Indomethacin was administered to rats after oral administration of EA (200, 400 and 800 mg extract/kg b.w), ACE (400 and 800 mg/kg bw), cimetidine (100mg/kg bw), misoprostol (40 MUg/kg bw) or distilled water/saline (vehicle). Anti ulcer property was evaluated by examining and scoring stomach lesions. RESULTS: The extract exhibited significant (P<0.01) cytoprotective effect against ethanol and indomethacin induced gastro ulceration. The microcapsules showed enhanced cytoprotective effect against ethanol and indomethacin induced gastro ulceration. Histopathologically, the effects of EA and ACE on mucus epithelia were mild with reduced neutrophil, eosinophil and lymphocytic infiltration in stomach tissues of rats ulcerated with ethanol. CONCLUSIONS: Our current findings show that EA and its multiparticulate formulation may be a useful preparation in peptic ulcer disease. PMID- 21704691 TI - Psoralea corylifolia protects against testicular torsion/detorsion-induced ischemia/reperfusion injury. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The pathophysiology of testicular torsion detorsion is ischemia-reperfusion injury of the testis. In the course of testicular ischemia and reperfusion, overgeneration of reactive oxygen species is a major initiating component of the testicular spermatogenic injury. Reactive oxygen species regulate many genes whose expression affects cell-cycle regulation, cell proliferation, and apoptosis. The transcription factor cAMP responsive element modulator-tau (CREMtau) plays an essential role in spermatogenesis. Psoralea corylifolia, a medicinal herb with anti-oxidative activity, has been used to treat male reproductive dysfunction in traditional Chinese medicine. In this study, we investigated the effect of Psoralea corylifolia on testicular torsion/detorsion-induced injury. MATERIALS AND METHODS: Sixty adult male Sprague-Dawley rats were randomly divided into 3 groups, each containing 20 rats. Rats in the control group underwent a sham operation of the left testis. In the torsion-detorsion group, the left testis was rotated 720 degrees for 2h. Rats in the treatment group received the same surgical procedure as the torsion-detorsion group, but Psoralea corylifolia was administered orally. Bilateral orchiectomy was performed on half of the rats in each experimental group at 4h after detorsion for measurement of malondialdehyde which is an indicator of intratesticular reactive oxygen species content. Orchiectomy was performed on the remaining rats at 3 months after detorsion for analysis of testicular CREMtau expression and spermatogenesis. RESULTS: Unilateral testicular torsion-detorsion caused a significant increase in malondialdehyde level and caused significant decreases in CREMtau expression and spermatogenesis in ipsilateral testes. Psoralea corylifolia treatment significantly decreased malondialdehyde level and significantly increased CREMtau expression and spermatogenesis in ipsilateral testes, compared with torsion detorsion group. CONCLUSIONS: These results suggest that Psoralea corylifolia may protect testicular spermatogenesis by enhancing CREMtau expression by scavenging reactive oxygen species. PMID- 21704692 TI - Neuroprotective effect of the methanolic extract of Hibiscus asper leaves in 6 hydroxydopamine-lesioned rat model of Parkinson's disease. AB - ETHNOPHARMACOLOGICAL RELEVANCE: While the Hibiscus asper Hook.f. (Malvaceae) is a traditional herb largely used in tropical region of the Africa as vegetable, potent sedative, tonic and restorative, anti-inflammatory and antidepressive drug, there is very little scientific data concerning the efficacy of this. MATERIALS AND METHODS: The antioxidant and antiapoptotic activities of the methanolic extract of Hibiscus asper leaves (50 and 100 mg/kg) were assessed using superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT) specific activities, total glutathione (GSH) content, malondialdehyde (MDA) level (lipid peroxidation) and DNA fragmentation assays in male Wistar rats subjected to unilateral 6-hydroxydopamine (6-OHDA)-lesion. RESULTS: In 6-OHDA-lesioned rats, methanolic extract of Hibiscus asper leaves showed potent antioxidant and antiapoptotic activities. Chronic administration of the methanolic extract (50 and 100 mg/kg, i.p., daily, for 7 days) significantly increased antioxidant enzyme activities (SOD, GPX and CAT), total GSH content and reduced lipid peroxidation (MDA level) in rat temporal lobe homogenates, suggesting antioxidant activity. Also, DNA cleavage patterns were absent in the 6-OHDA-lesioned rats treated with methanolic extract of Hibiscus asper leaves, suggesting antiapoptotic activity. CONCLUSIONS: Taken together, our results suggest that the methanolic extract of Hibiscus asper leaves possesses neuroprotective activity against 6-OHDA-induced toxicity through antioxidant and antiapoptotic activities in Parkinson's disease model. PMID- 21704693 TI - The mechanism of vasorelaxation induced by ethanol extract of Sophora flavescens in rat aorta. AB - AIM OF THE STUDY: Sophora flavescens (SF) is a known medicinal herb for the treatment of cardiovascular symptoms associated with arrhythmia in China. However, the pharmacological action mechanisms involved have not been well studied. The aim of the present study was to define effects of roots of SF on the vascular tension and responsible mechanisms in rat thoracic aorta. MATERIALS AND METHODS: Ethanol extract of the roots of SF (ESF) was examined for their vascular relaxant effect in isolated phenylephrine-precontracted rat thoracic aorta. RESULTS: ESF (0.1-100 MUg/ml) induced relaxation of the phenylephrine precontracted aortic rings in a concentration-dependent manner. Endothelium denudation abolished the ESF-induced vasorelaxation. Pretreatment of the endothelium-intact aortic rings with l-NAME, an inhibitor of nitric oxide synthase, and ODQ, an inhibitor of soluble guanylyl cyclase (sGC), inhibited ESF induced vasorelaxation. ESF increased cGMP levels of the aortic rings in a concentration-dependent manner and the effect was blocked by l-NAME and ODQ. Inhibition of K(+) channels with glibenclamide and tetraethylammonium, cyclooxygenase inhibition with indomethacin, and beta-adrenergic and muscarinic receptors blockade had no effect on the ESF-induced vasorelaxation. CONCLUSION: These findings suggest that ESF relaxes vascular smooth muscle via endothelium dependent NO-sGC-cGMP signaling pathway. PMID- 21704694 TI - Anti-inflammatory effects of methanol extract of Antrodia cinnamomea mycelia both in vitro and in vivo. AB - AIMS OF THE STUDY: Antrodia cinnamomea is a folk medicinal mushroom commonly used in Taiwan for the treatment of several types of cancers and inflammatory disorders. This study aimed to explore the folk use of Antrodia cinnamomea on pharmacological grounds to characterize the scientific basis of anti-inflammatory activity. MATERIALS AND METHODS: The in vitro anti-inflammatory activity of methanol extract of liquid cultured mycelia of Antrodia cinnamomea (MEMAC) was judged by the measurement of the produced levels of pro-inflammatory cytokines and mediators in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and human peripheral blood mononuclear cells (PBMCs). The in vivo anti-inflammatory activity of MEMAC was evaluated using carrageenan-induced hind paw edema in mice, the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the liver and the levels of malondialdehyde (MDA) and nitrite oxide (NO) in the edema paw. The levels of serum NO and TNF-alpha were measured. The MEMAC was administered at the concentrations of 100, 200, and 400mg/kg body weight of mouse. RESULTS: MEMAC inhibited the production of LPS-induced pro inflammatory cytokines (TNF-alpha and IL-6) and mediators (NO and PGE2) in RAW264.7 cells and human PBMCs. Data from Western blotting showed that MEMAC decreased the levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) protein expression in LPS-stimulated RAW264.7 macrophages. In vivo, MEMAC showed significant (p<0.05) anti-inflammatory activity by reducing the edema volume in carrageenan-induced paw edema in mice. MEMAC (400mg/kg) also reduced the carrageenan-induced leukocyte migration (50.92+/-5.71%). Further, MEMAC increased the activities of CAT, SOD, and GPx in the liver tissue and decreased the levels of serum NO and TNF-alpha after carrageenan administration. CONCLUSIONS: Our results showed that MEMAC has the anti-inflammatory property both in vitro and in vivo, suggesting that it may be a potential preventive or therapeutic candidate for the treatment of inflammatory disorders. PMID- 21704695 TI - In vitro neurotoxicity data in human risk assessment of polybrominated diphenyl ethers (PBDEs): overview and perspectives. AB - Polybrominated diphenyl ethers (PBDEs) are flame retardants routinely detected in samples of cord blood and breast milk. Concerns have been raised with regard to the toxicity of both pre- and postnatal exposures towards the developing nervous system. Although there is an increasing body of literature on the disruption of brain cell functions by certain PBDE congeners in vitro, some challenges have yet to be tackled to enable the translation of in vitro findings into their in vivo counterparts. In this paper, we review findings on the PBDE neurotoxicity in human cells and discuss the research gaps to be addressed. Moreover, we propose a scheme for the incorporation of in vitro data in human risk assessment, namely through (i) the determination of in vitro cell benchmark levels; (ii) the consideration of uncertainties in establishing equivalency between the in vitro and the in vivo tissue benchmark levels (e.g., chronic vs. acute exposure, interactions with other chemicals); and (iii) relating tissue benchmark levels to surrogate levels of internal exposure. Alongside the assessment of brain dosimetry following exposure to PBDEs, in vitro neurotoxicity data provide a unique opportunity to evaluate the risks of prenatal and early life exposures on children neurodevelopment. PMID- 21704696 TI - Fluoride-induced death of rat erythrocytes in vitro. AB - Although fluoride (F) in low concentrations is essential for teeth and bone development, its excessive consumption causes numerous deleterious abnormalities in cellular metabolism and physiology often leading to cell death. The present study was performed to establish the toxic F effects inducing the death of rat erythrocytes in vitro. The cells were cultured in the presence of 0.5-16 mM NaF for 1, 5 and 24 h. The progression of erythrocyte death was monitored by cell viability (calcein assay), membrane integrity (hemolysis assay), alterations in the cell morphology (light microscopy) and size (flow cytometry forward scatter), plasma membrane scrambling (annexin V binding). To elucidate the molecular mechanisms underlying F-induced cell death, the cytosolic Ca2+ activity (Fluo-3 fluorescence) and ceramide formation (binding of FITC-labeled antibodies) were determined. Exposure of the rat erythrocytes to NaF considerably suppressed their viability and caused partial cell hemolysis within 24 h. The cells underwent dramatic morphological alterations resulted in appearance of shrunken echinocytes after 1h and swollen spherocytes within 24 h. The development of NaF-induced erythrocyte death was accompanied by progressive PS externalization at the outer cell membrane, ~45% of the cells were annexin V-positive in response to 16 mM NaF within 24 h with a small cell population exhibiting necrotic features. The cell death was preceded by considerable accumulation of the free cytosolic Ca2+, with statistically significant increase in the number of Fluo-3-positive erythrocytes observed as early as during 1-h incubation with 0.5 mM NaF. NaF also induced moderate ceramide formation. Overall, exposure of the rat erythrocytes to NaF triggers rapid progression of their death in a dose- and time-dependent manner, with appearance of apoptotic cells after 1 and 5 h and transition to necrosis within 24 h. An increase in intracellular [Ca2+] appears to be crucial mechanism implicated in development of NaF-induced apoptosis in rat erythrocytes. PMID- 21704697 TI - Deficiency of corticotropin-releasing hormone type-2 receptor alters sleep responses to bacterial lipopolysaccharide in mice. AB - In response to infectious stimuli, enhanced non-rapid eye movement sleep (NREMS) occurs, which is driven by pro-inflammatory cytokines. Those cytokines further elicit the release of corticotropin-releasing hormone (CRH), resulting in the activation of the hypothalamic-pituitary-adrenocortical axis. Signals of CRH are mediated by two receptor types, namely CRH-R1 and -R2. The role of CRH-R1 in wake promoting effects of CRH has been rather clarified, whereas the involvement of CRH-R2 in sleep-wake regulation is poorly understood. To investigate whether CRH R2 interferes with sleep responses to immune challenge, this study examined effects of bacterial lipopolysaccharide (LPS) on sleep in CRH-R2 deficient (KO) mice. CRH-R2 KO mice and control littermates (CL) were implanted with electrodes for recording electroencephalogram (EEG) and electromyogram. After recovery, LPS was applied by intraperitoneal injection at doses of 0.1, 1.0, or 10 MUg at dark onset. In response to LPS injection NREMS of both genotypes was enhanced in a dose-dependent manner. However, CRH-R2 KO mice showed a larger increase, in particular after 10 MUg of LPS compared to CL mice. During postinjection, reduced delta power for NREMS was detected in both genotypes after each dose, but the highest dose evoked a marked elevation of EEG activity in a limited frequency band (4 Hz). However, the EEG power of lower frequencies (1-2 Hz) increased more in CRH-R2 KO than in CL mice. The results indicated that CRH-R2 KO mice show greater NREMS responses to LPS, providing evidence that CRH-R2 participates in sleep-wake regulation via an interaction with the activated immune system. PMID- 21704698 TI - Cytokine and chemokine responses in serum and brain after single and repeated injections of lipopolysaccharide: multiplex quantification with path analysis. AB - Administration of the proinflammatory molecule lipopolysaccharide (LPS) alters transport rates for many peptides across the blood-brain barrier (BBB). We and others have previously shown that effects of LPS on BBB transport are highly dependent on the injection paradigm used, and timing of the study. Cytokine expression in both brain and serum compartments influences the BBB response to an inflammatory stimulus, and mediates changes in BBB transport. Here, we used multianalyte technology to simultaneously determine the responses of 13 cytokines and chemokines (G-CSF, GM-CSF, IL-1alpha, IL-1beta, IL-6, IL-10, IL-13, IP-10, KC, MCP-1, MIP-1alpha, RANTES, and TNF-alpha) in brain and blood to single and repeated injections of LPS and path analysis to determine the major relations among these analytes. Major findings are: (1) in comparison to measurements taken from a time course after a single injection of LPS, the three injection regimen of LPS produced significantly higher levels in brain for G-CSF, IL-1alpha, IL-6, MCP-1, MIP-1alpha, and TNF and in serum for G-CSF, IL-6, and GM-CSF and (2) path analysis distinguished direct from indirect correlations between analyte pairs, with MCP-1, IL-6, G-CSF, and KC mediating relations among these cytokines both within and between serum and brain compartments. These results suggest that potentiation of cytokine levels in brain and serum compartments could play important roles in the regulation of BBB transport, and that our novel application of an established statistical method can be used to assess direct correlations within multiplexed datasets. PMID- 21704699 TI - Changed preference for sweet taste in adulthood induced by perinatal exposure to bisphenol A-A probable link to overweight and obesity. AB - BACKGROUND: The preference of obesity has risen dramatically worldwide over the past decades. Some latest reports showed significant increase of obesity in men compared to women. Implication of environmental endocrine disruptors has been focused more and more. Numerous studies in vitro and vivo implied metabolic actions of bisphenol A (BPA), however much less consideration is given to the possibility of BPA exposure-induced change in gender-specific behaviors which result in obesity and overweight. OBJECTIVES: To examine whether perinatal exposure to BPA at relative dose to environmental levels can influence sweet preference of male and female rats and consequently lead to alteration in bodyweight. METHODS: Rats perinatally exposed to BPA at doses of 0.01, 0.1 and 1.0 mg/L were tested sweet preference for 0.25%, 0.5% saccharin and 15% sucrose by two-bottle choice (water vs. saccharin/sucrose). The food intake, liquid consumption and bodyweight of each rat were monitored daily. At the end of the test, the fat percentage and tail blood pressure were measured. RESULTS: Significant sex difference of preference for 0.25% and 0.5% saccharin was shown in control and all BPA-treated groups (p < 0.001, female vs. male). 0.1 and 1.0 mg/L BPA treatment induced the increase of preference for 0.25% saccharin solution in males, but not in females. 0.1 mg/L BPA treatment increased sucrose preference in males at postnatal day (PND) 70 and 140 (p < 0.05 and p < 0.001, compared to control respectively) but decreased sucrose preference in females at PND 140 (p < 0.05, compared to control). The males treated by BPA showed overweight (p < 0.001), high fat percentage (p < 0.001) and tail blood pressure (p < 0.05) than control at PND 140. CONCLUSION: Perinatal exposure to a low dose of BPA could increase sweet preference of male rats. Calorie intake may be programmed during early life, leading to changes of body weight depending on the gender. Although further researches concerning the mechanism are required, the results of the present study are particularly important with regards to the more significant increasing prevalence of obesity in men and the environmental endocrine disruptors. PMID- 21704700 TI - Production and consumption of methane in freshwater lake ecosystems. AB - The atmospheric concentration of methane (CH(4)), a major greenhouse gas, is mainly controlled by the activities of methane-producing (methanogens) and methane-consuming (methanotrophs) microorganisms. Freshwater lakes are identified as one of the main CH(4) sources, as it was estimated that they contribute to 6 16% of natural CH(4) emissions. It is therefore critical to better understanding the biogeochemical cycling of CH(4) in these ecosystems. In this paper, the effects of environmental factors on methanogenic and methanotrophic rates are reviewed and an inventory of the methanogens and methanotrophs at the genus/species level in freshwater lakes is given. We focus on the anaerobic oxidation of methane, which is a still poorly known process but increasingly reported in freshwater lakes. PMID- 21704701 TI - Taxonomic and functional prokaryote diversity in mildly arsenic-contaminated sediments. AB - Arsenic-resistant prokaryote diversity is far from being exhaustively explored. In this study, the arsenic-adapted prokaryotic community present in a moderately arsenic-contaminated site near Sainte-Marie-aux-Mines (France) was characterized, using metaproteomic and 16S rRNA-encoding gene amplification. High prokaryotic diversity was observed, with a majority of Proteobacteria, Acidobacteria and Bacteroidetes, and a large archaeal community comprising Euryarchaeaota and Thaumarchaeota. Metaproteomic analysis revealed that Proteobacteria, Planctomycetes and Cyanobacteria are among the active bacteria in this ecosystem. Taken together, these results highlight the unsuspected high diversity of the arsenic-adapted prokaryotic community, with some phyla never having been described in highly arsenic-exposed sites. PMID- 21704702 TI - Genome analysis and characterization of zinc efflux systems of a highly zinc resistant bacterium, Comamonas testosteroni S44. AB - A novel and multiple metal(loid)-resistant strain Comamonas testosteroni S44 with a high Zn(2+) resistance level (10 mM) was isolated. To understand the molecular basis for the high zinc resistance, whole genome sequencing was performed and revealed a large number of genes encoding putative metal(loid) resistance proteins, mobile genetic elements (MGEs) and horizontal gene transfer (HGT) events that may have occurred to adapt to a metal(loid)-contaminated environment. In particular, 9 putative Zn(2+) transporters [4 znt operons encoding putative Zn(2+)-translocating P-type ATPases and 5 czc operons encoding putative RND driven (resistance, nodulation, cell division protein family)] tripartite protein complexes were identified. Real-time RT-PCR analysis revealed that the four zntA like genes were all induced by Zn(2+), while czcA genes were either Zn(2+) induced or downregulated by Zn(2+). Furthermore, a zntR1A1 operon encoding a ZntR type regulator and a P-type ATPase was studied in detail. The zntR1 deletion strain (S44DeltazntR1) displayed intermediate resistance to Zn(2+) (6 mM) and accumulated more intracellular Zn(2+). Reporter gene expression assays indicated that ZntR1 responded to Zn(2+), Cd(2+) and Pb(2+), with Zn(2+) being the best inducer. Gene transcription analysis indicated that ZntR1 was a regulator for transcription of zntA1, while other putative ZntR-type regulators may also regulate the transcription expression of zntA1. PMID- 21704703 TI - Mast cell-nerve axis with a focus on the human gut. AB - This paper summarizes the current knowledge on the interactions between intestinal mast cells, enteric neurons and visceral afferents which are part of the gut brain axis. The focus of this review is on the relevance of the mast cell nerve axis in the human intestine. Similarities and important differences in the organization of the mast cell-nerve axis between human and rodents are discussed. Functionally important human mast cell mediators with neural actions in the human ENS are histamine (H1-4 receptors), proteases (PAR1 receptors), several cytokines and chemokines and probably also serotonin (5-HT(3) receptors). On the other hand, mediator release from human intestinal mast cells is modulated by neuropeptides released from enteric and visceral afferent nerves. This article is part of a Special Issue entitled: Mast Cells in Inflammation. PMID- 21704705 TI - Drug retention by inline filters--effect of positively charged polyethersulfone filter membranes on drug solutions with low concentration. AB - OBJECTIVE: The use of infusion filters in pediatrics is controversially discussed. Their application is an excellent opportunity to prevent complications, but there are researchers, who do not see any advantage in using inline filters. This paper describes the interaction of five different drugs with a positively charged as opposed to an uncharged polyethersulfone (PES(+) versus PES(0)) membrane. METHODS: To measure the extent and the mechanism of interaction, PES(+) versus PES(0) membranes and furosemide sodium, potassium canrenoate, digitoxin, digoxin and adenosine, each 30MUmol/l, were investigated. Salt ions with different hydrodynamic radii and different concentrations have been used in the eluents. RESULTS: During furosemide sodium and potassium canrenoate filtration with PES(+), the onset of UV absorption depends on the electrolyte concentration in the eluent: the lower the electrolyte concentration the later the onset of UV absorption. A correlation between the hydrodynamic volume of the different salt ions used and the onset of UV absorption could be proven for both substances: The larger the hydrodynamic volume of the extrinsic ion, the later the onset of the UV absorption if the same electrolyte concentration was used. Due to a higher structural density of PES(+) than PES(0) a delayed onset of UV absorption during filtration of digitoxin and digoxin with the PES(+) membrane could be observed. No correlation between the hydrodynamic volume of the different salt ions used and the onset of UV absorption could be seen. With adenosine neither the filter type nor the electrolyte concentration or the hydrodynamic volume of the salt ions had an influence on the onset time of absorption. CONCLUSION: The results obtained with the anionic drugs investigated are particularly relevant if low drug concentrations in a saltless infusion solution are applied in combination with a charged filter membrane. Therefore, for each infusion formulation, a careful selection of the filter material is essential. PMID- 21704704 TI - Engineering tenofovir loaded chitosan nanoparticles to maximize microbicide mucoadhesion. AB - The objective of this study was to engineer a model anti-HIV microbicide (tenofovir) loaded chitosan based nanoparticles (NPs). Box-Behnken design allowed to assess the influence of formulation variables on the size of NPs and drug encapsulation efficiency (EE%) that were analyzed by dynamic light scattering and UV spectroscopy, respectively. The effect of the NPs on vaginal epithelial cells and Lactobacillus crispatus viability and their mucoadhesion to porcine vaginal tissue were assessed by cytotoxicity assays and fluorimetry, respectively. In the optimal aqueous conditions, the EE% and NPs size were 5.83% and 207.97nm, respectively. With 50% (v/v) ethanol/water as alternative solvent, these two responses increased to 20% and 602 nm, respectively. Unlike small size (182nm) exhibiting burst release, drug release from medium (281 nm) and large (602 nm) sized NPs fitted the Higuchi (r(2)=0.991) and first-order release (r(2)=0.999) models, respectively. These NPs were not cytotoxic to both the vaginal epithelial cell line and L. crispatus for 48h. When the diameter of the NPs decreased from 900 to 188 nm, the mucoadhesion increased from 6% to 12%. However, the combinatorial effect of EE% and percent mucoadhesion for larger size NPs was the highest. Overall, large-size, microbicide loaded chitosan NPs appeared to be promising nanomedicines for the prevention of HIV transmission. PMID- 21704707 TI - Tubular frameworks guiding orderly bone formation in the antler of the red deer (Cervus elaphus). AB - Deer antler is a bony tissue which re-grows every year after shedding. Growth speed and material properties of this tissue are truly remarkable, making it an interesting model for bone regeneration. Surprisingly, not much is known about the ultrastructure of the calcified tissues and the temporal sequence of their development during antler growth. We use a combination of imaging tools based on light and electron microscopy to characterize antler tissue at various stages of development. We observe that mineralized cartilage is first transformed into a bone framework with low degree of collagen fibril ordering at the micron level. This framework has a honeycomb-like appearance with the cylindrical pores oriented along the main antler axis. Later, this tissue is filled with primary osteons, whose collagen fibrils are mainly oriented along the pores, thus improving the antler's mechanical properties. This strongly suggests that to achieve very fast organ growth it is advantageous to have a longitudinal porous framework as an intermediate step in bone formation. The example of antler shows that geometric features of this framework are crucial, and a tubular geometry with a diameter in the order of hundred micrometers seems to be a good solution for fast framework-mediated bone formation. PMID- 21704706 TI - Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord. AB - Dextromethorphan (DM) is a dextrorotary morphinan and a widely used component of cough medicine. Relatively high doses of DM in combination with quinidine are used for the treatment of mood disorders for patients with multiple sclerosis (MS). However, at lower doses, morphinans exert anti-inflammatory activities through the inhibition of NOX2-dependent superoxide production in activated microglia. Here we investigated the effects of high (10 mg/kg, i.p., "DM-10") and low (0.1 mg/kg, i.p., "DM-0.1") doses of DM on the development and progression of mouse experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found no protection by high dose DM treatment. Interestingly, a minor late attenuation by low dose DM treatment was seen in severe EAE that was characterized by a chronic disease course and a massive spinal cord infiltration of CD45(+) cells including T-lymphocytes, macrophages and neutrophils. Furthermore, in a less severe form of EAE, where lower levels of CD4(+) and CD8(+) T-cells, Iba1(+) microglia/macrophages and no significant infiltration of neutrophils were seen in the spinal cord, the treatment with DM-0.1 was remarkably more beneficial. The effect was the most significant at the peak of disease and was associated with an inhibition of NOX2 expression and a decrease in infiltration of monocytes and lymphocytes into the spinal cord. In addition, chronic treatment with low dose DM resulted in decreased demyelination and reduced axonal loss in the lumbar spinal cord. Our study is the first report to show that low dose DM is effective in treating EAE of moderate severity. Our findings reveal that low dose morphinan DM treatment may represent a new promising protective strategy for treating MS. PMID- 21704708 TI - Computer controlled cryo-electron microscopy--TOM2 a software package for high throughput applications. AB - Automated data acquisition expedites structural studies by electron microscopy and it allows to collect data sets of unprecedented size and consistent quality. In electron tomography it greatly facilitates the systematic exploration of large cellular landscapes and in single particle analysis it allows to generate data sets for an exhaustive classification of coexisting molecular states. Here we describe a novel software philosophy and architecture that can be used for a great variety of automated data acquisition scenarios. Based on our original software package TOM, the new TOM(2) package has been designed in an object oriented way. The whole program can be seen as a collection of self-sufficient modules with defined relationships acting in a concerted manner. It subdivides data acquisition into a set of hierarchical tasks, bonding data structure and the operations to be performed tightly together. To demonstrate its capacity for high throughput data acquisition it has been used in conjunction with instrumentation combining the latest technological achievements in electron optics, cryogenics and robotics. Its performance is demonstrated with a single particle analysis case study and with a batch tomography application. PMID- 21704709 TI - Optimal detection of functional connectivity from high-dimensional EEG synchrony data. AB - Computing phase-locking values between EEG signals is a popular method for quantifying functional connectivity. However, this method involves large-scale, high-resolution datasets, which impose a serious multiple testing problem. Standard multiple testing methods fail to exploit the information from the complex dependence structure that varies across hypotheses in spectral, temporal, and spatial dimensions and result in a severe loss of power. They tend to control the false positives at the cost of hiding true positives. We introduce a new approach, called optimal discovery procedure (ODP) for identifying synchrony that is statistically significant. ODP maximizes the number of true positives for a given number of false positives, and thus offers a theoretical optimum for detecting significant synchrony in a multiple testing situation. We demonstrate the utility of this method with PLV data obtained from a visual search study. We also present simulation analysis to confirm the validity and relevance of using ODP in comparison with the standard FDR method for given configurations of true synchrony. We also compare the effectiveness of ODP with our previously published investigation of hierarchical FDR method (Singh and Phillips, 2010). PMID- 21704710 TI - Segmentation of the mouse hippocampal formation in magnetic resonance images. AB - The hippocampal formation plays an important role in cognition, spatial navigation, learning, and memory. High resolution magnetic resonance (MR) imaging makes it possible to study in vivo changes in the hippocampus over time and is useful for comparing hippocampal volume and structure in wild type and mutant mice. Such comparisons demand a reliable way to segment the hippocampal formation. We have developed a method for the systematic segmentation of the hippocampal formation using the perfusion-fixed C57BL/6 mouse brain for application in longitudinal and comparative studies. Our aim was to develop a guide for segmenting over 40 structures in an adult mouse brain using 30 MUm isotropic resolution images acquired with a 16.4 T MR imaging system and combined using super-resolution reconstruction. PMID- 21704711 TI - Developmental cortical thinning in fetal alcohol spectrum disorders. AB - Regional cortical thickness was evaluated using CIVET processing of 3D T1 weighted images (i) to compare the variation in cortical thickness between 33 participants with fetal alcohol spectrum disorders (FASD) aged 6-30 years (mean age 12.3 years) versus 33 age/sex/hand-matched controls, and (ii) to examine developmental changes in cortical thickness with age from children to young adults in both groups. Significant cortical thinning was found in the participants with FASD in large areas of the bilateral middle frontal lobe, pre- and post- central areas, lateral and inferior temporal and occipital lobes compared to controls. No significant cortical thickness increases were observed for the FASD group. Cortical thinning with age in a linear model was observed in both groups, but the locations were different for each group. FASD participants showed thinning with age in the left middle frontal, bilateral precentral, bilateral precuneus and paracingulate, left inferior occipital and bilateral fusiform gyri; while controls showed decreases with age in the bilateral middle frontal gyrus, right inferior frontal gyrus, bilateral precuneus gyrus, and bilateral occipital gyrus. A battery of cognitive assessments of memory, attention, motor, and verbal abilities was conducted with many of the FASD participants, but no significant correlations were found between these cognitive scores and regional cortical thickness. Non-invasive measurements of cortical thickness in children to young adults with FASD have identified both key regions of cortex that may be more deleteriously affected by prenatal alcohol exposure as well as cortical changes with age that differ from normal developmental thinning. PMID- 21704712 TI - BOLD responses to different temporal frequency stimuli in the lateral geniculate nucleus and visual cortex: insights into the neural basis of fMRI. AB - The neural basis of the blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) remains largely unknown after decades of research. To investigate this issue, the unique property of the temporal frequency tuning that could separate neural input and output in the primary visual cortex was used as a model. During moving grating stimuli of 1, 2, 10 and 20Hz temporal frequencies, we measured 9.4-T BOLD fMRI responses simultaneously in the primary visual cortex of area 17 (A17) and area 18 (A18), and the lateral geniculate nucleus (LGN) of isoflurane-anesthetized cat. Our results showed that preferred temporal frequencies of the BOLD responses for A17, A18 and LGN were 3.1Hz, 4.5Hz and 6.0Hz, respectively, which were comparable to the previously reported electrophysiological data. Additionally, the difference of BOLD response onset time between LGN and A17 was 0.5s, which is 18 times larger than the difference of neural activity onset time between these areas. We then compared the frequency-dependent BOLD fMRI response of A17 with tissue partial pressure of oxygen (pO(2)) and electrophysiological data of the same animal model reported by Viswanathan and Freeman (Nature Neuroscience, 2007). The BOLD tuning curve resembled the low frequency band (<12Hz) of local field potential (LFP) tuning curve rather than spiking activity, gamma band (25-90Hz) of LFP, and tissue pO(2) tuning curves, suggesting that the BOLD fMRI signal relates closer to low frequency LFP. PMID- 21704713 TI - Sensitivity and specificity of high-resolution balanced steady-state free precession fMRI at high field of 9.4T. AB - Balanced steady-state free precession (bSSFP) is an attractive fMRI method at high fields due to minimal spatial distortion. To examine sensitivity and specificity of bSSFP fMRI at ultrahigh magnetic field of 9.4T, we performed high resolution pass-band high flip-angle (16 degrees ) bSSFP fMRI with four phase cycling (PC) angles at two repetition times (TR) of 10ms and 20ms and conventional gradient-recalled-echo (GRE) fMRI with TR of 20ms on rat brain during forepaw stimulation. The sensitivity of bSSFP fMRI with TR of 20ms was higher than that of GRE fMRI regardless of PC angle. Because of magnetic field inhomogeneity, fMRI foci were changed with PC angle in bSSFP fMRI, which was more prominent when TR was shorter. Within a middle cortical layer region where magnetic field inhomogeneity was relatively small, the homogeneity of bSSFP fMRI signals was higher at shorter TR. Acquisition of baseline transition-band bSSFP images helped to identify pass- and transition-band regions and to understand corresponding bSSFP fMRI signals. Fourier analysis of the multiple PC bSSFP datasets provided echoes of multiple pathways separately, and the main echo component showed lower sensitivity and better homogeneity than the free induction decay component. In summary, pass-band bSSFP techniques would have advantages over GRE-based fMRI in terms of sensitivity, and may be a good choice for fMRI at ultrahigh fields. PMID- 21704714 TI - Testing the ICA mixing matrix based on inter-subject or inter-session consistency. AB - Independent component analysis (ICA) is increasingly used for analyzing brain imaging data. ICA typically gives a large number of components, many of which may be just random, due to insufficient sample size, violations of the model, or algorithmic problems. Few methods are available for computing the statistical significance (reliability) of the components. We propose to approach this problem by performing ICA separately on a number of subjects, and finding components which are sufficiently consistent (similar) over subjects. Similarity is defined here as the similarity of the mixing coefficients, which usually correspond to spatial patterns in EEG and MEG. The threshold of what is "sufficient" is rigorously defined by a null hypothesis under which the independent components are random orthogonal components in the whitened space. Components which are consistent in different subjects are found by clustering under the constraint that a cluster can only contain one source from each subject, and by constraining the number of the false positives based on the null hypothesis. Instead of different subjects, the method can also be applied on different recording sessions from a single subject. The testing method is particularly applicable to EEG and MEG analysis. PMID- 21704715 TI - Functional micro-ultrasound imaging of rodent cerebral hemodynamics. AB - Healthy cerebral microcirculation is crucial to neuronal functioning. We present a new method to investigate microvascular hemodynamics in living rodent brain through a focal cranial window based on high-frequency ultrasound imaging. The method has a temporal resolution of 40ms, and a 100MUm in-plane and 600MUm through-plane spatial resolution. We use a commercially available high-frequency ultrasound imaging system to quantify changes in the relative cerebral blood volume (CBV) by measuring the scattered signal intensity from an ultrasound contrast agent circulating in the vasculature. Generalized linear model analysis is then used to produce effect size and significance maps of changes in cerebral blood volume upon electrical stimulation of the forepaw. We observe larger CBV increases in the forelimb representation of the primary somatosensory cortex than in the deep gray matter with stimuli as short as 2s (5.1 +/- 1.3% vs. 3.3 +/- 0.6%). We also investigate the temporal evolution of the blood volume changes in cortical and subcortical gray matter, pial vessels and subcortical major vessels, and show shorter response onset times in the parenchymal regions than in the neighboring large vessels (1.6 +/- 1.0s vs. 2.6 +/- 1.3s in the cortex for a 10 second stimulus protocol). This method, which we termed functional micro ultrasound imaging or fMUS, is a novel, highly accessible, and cost-effective way of imaging rodent brain microvascular topology and hemodynamics in vivo at 100micron resolution over a 1-by-1cm field of view with 10s-100s frames per second that opens up a new set of questions regarding brain function in preclinical models of health and disease. PMID- 21704716 TI - Resting state cortical electroencephalographic rhythms in subjects with normal and abnormal body weight. AB - It is well known that resting state regional cerebral blood flow is abnormal in obese when compared to normal-weight subjects but the underlying neurophysiological mechanisms are poorly known. To address this issue, we tested the hypothesis that amplitude of resting state cortical electroencephalographic (EEG) rhythms differ among underweight, normal-weight, and overweight/obese subjects as a reflection of the relationship between cortical neural synchronization and regulation of body weight. Eyes-closed resting state EEG data were recorded in 16 underweight subjects, 25 normal-weight subjects, and 18 overweight/obese subjects. All subjects were psychophysically healthy (no eating disorders or major psychopathologies). EEG rhythms of interest were delta (2 4Hz), theta (4-8Hz), alpha 1 (8-10.5Hz), alpha 2 (10.5-13Hz), beta 1 (13-20Hz), beta 2 (20-30Hz), and gamma (30-40Hz). EEG cortical sources were estimated by low resolution brain electromagnetic tomography (LORETA). Statistical results showed that parietal and temporal alpha 1 sources fitted the pattern underweight>normal weight>overweight/obese (p<0.004), whereas occipital alpha 1 sources fitted the pattern normal-weight>underweight>overweight/obese (p<0.00003). Furthermore, amplitude of the parietal, occipital, and temporal alpha 2 sources was stronger in the normal-weight subjects than in the underweight and overweight/obese subjects (p<0.0007). These results suggest that abnormal weight in healthy overweight/obese subjects is related to abnormal cortical neural synchronization at the basis of resting state alpha rhythms and fluctuation of global brain arousal. PMID- 21704717 TI - Structural-based analysis of dihydrofolate reductase evolution. AB - The evolution of dihydrofolate reductase (DHFR) was studied through a comprehensive structural-based analysis. An amino acid sequence alignment was generated from a superposition of experimentally determined X-ray crystal structures of wild-type (wt) DHFR from the Protein Data Bank (PDB). Using this structure-based alignment of DHFR, a metric was generated for the degree of conservation at each alignment site - not only in terms of amino acid residue, but also secondary structure, and residue class. A phylogenetic tree was generated using the alignment that compared favorably with the canonical phylogeny. This structure-based alignment was used to confirm that the degree of conservation of active-site residues in terms of both sequence as well as structure was significantly greater than non-active site residues. These results can be used in helping to understand the likely future evolution of DHFR in response to novel therapies. PMID- 21704718 TI - Parallel associative processing in the dorsal striatum: segregation of stimulus response and cognitive control subregions. AB - Although evidence suggests that the dorsal striatum contributes to multiple learning and memory functions, there nevertheless remains considerable disagreement on the specific associative roles of different neuroanatomical subregions. We review evidence indicating that the dorsolateral striatum (DLS) is a substrate for stimulus-response habit formation - incremental strengthening of simple S-R bonds - via input from sensorimotor neocortex while the dorsomedial striatum (DMS) contributes to behavioral flexibility - the cognitive control of behavior - via prefrontal and limbic circuits engaged in relational and spatial information processing. The parallel circuits through dorsal striatum interact with incentive/affective motivational processing in the ventral striatum and portions of the prefrontal cortex leading to overt responding under specific testing conditions. Converging evidence obtained through a detailed task analysis and neurobehavioral assessment is beginning to illuminate striatal subregional interactions and relations to the rest of the mammalian brain. PMID- 21704719 TI - Post-translational modification of NMDA receptor GluN2B subunit and its roles in chronic pain and memory. AB - N-methyl-d-aspartate receptors (NMDA receptors) play critical roles in brain functions and diseases. The expression, trafficking, synaptic location and function of different NMDA receptor subtypes are not static, but regulated dynamically in a cell-specific and synapse-specific manner during physiological and pathological conditions. In this review, we will examine recent evidence on the post-translational modulation of NMDA receptors subunit, in particular GluN2B subunit, such as phosphorylation, palmitoylation, and ubiquitination. In parallel, we will overview the roles of these modifications of GluN2B-NMDA receptor subtype in physiological functions, such as learning and memory, and pathophysiological conditions, such as chronic pain, ischemia and neurodegenerative diseases. PMID- 21704720 TI - Fusarium oxysporum Adh1 has dual fermentative and oxidative functions and is involved in fungal virulence in tomato plants. AB - An alcohol dehydrogenase gene, adh1, has been identified in the vascular wilt fungus Fusarium oxysporum f. sp. lycopersici. Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that adh1 is highly expressed in mycelia grown in potato dextrose liquid medium (PDB) under hypoxic conditions, as compared to mycelia grown under aerobic conditions. One spontaneous allyl alcohol resistant (Ally(R)) mutant exhibited insertion of an incomplete F.oxysporum transposable element, while another mutant contained a short (13 nucleotide) deletion, in both cases interrupting the coding region of the adh1 gene. These mutations caused deficiency in Adh activity due to loss of the main constitutive isoform of Adh1, as well as alteration of different physiological parameters related to carbon and energy metabolism, including the ability to use ethanol as a carbon source under aerobic conditions; impaired growth under hypoxic conditions with glucose as the carbon source; and diminished production of ethanol in glucose-containing medium. Interestingly, the adh1 mutations resulted in a significant delay in fungal disease development in tomato plants. Complementation with the wild-type adh1 allele repaired all defects caused by mutation, indicating that the product of the adh1 gene has dual enzymatic functions (fermentative and oxidative), depending on culture conditions, and is also required for full fungal virulence. PMID- 21704721 TI - CefR modulates transporters of beta-lactam intermediates preventing the loss of penicillins to the broth and increases cephalosporin production in Acremonium chrysogenum. AB - The Acremonium chrysogenum cephalosporin biosynthetic genes are divided in two different clusters. The central step of the biosynthetic pathway (epimerization of isopenicillin N to penicillin N) occurs in peroxisomes. We found in the "early" cephalosporin cluster a new ORF encoding a regulatory protein (CefR), containing a nuclear targeting signal and a "Fungal_trans" domain. Targeted inactivation of cefR delays expression of the cefEF gene, increases penicillin N secretion and decreases cephalosporin production. Overexpression of the cefR gene decreased (up to 60%) penicillin N secretion, saving precursors and resulting in increased cephalosporin C production. Northern blot analysis revealed that the CefR protein acts as a repressor of the exporter cefT and exerts a small stimulatory effect over the expression level of cefEF that explains the increased cephalosporin yields observed in transformants overexpressing cefR. In summary, we describe for the first time a modulator of beta-lactam intermediate transporters in A. chrysogenum. PMID- 21704722 TI - Docosahexaenoic acid (DHA) incorporation into the brain from plasma, as an in vivo biomarker of brain DHA metabolism and neurotransmission. AB - Docosahexaenoic acid (DHA) is critical for maintaining normal brain structure and function, and is considered neuroprotective. Its brain concentration depends on dietary DHA content and hepatic conversion from its dietary derived n-3 precursor, alpha-linolenic acid (alpha-LNA). We have developed an in vivo method in rats using quantitative autoradiography and intravenously injected radiolabeled DHA to image net incorporation into the brain of unesterified plasma DHA, and showed with this method that the incorporation rate of DHA equals the rate of brain metabolic DHA consumption. The method has been extended for use in humans with positron emission tomography (PET). Furthermore, imaging in unanesthetized rats using DHA incorporation as a biomarker in response to acute N methyl-D-aspartate administration confirms that regional DHA signaling is independent of extracellular calcium, and likely mediated by a calcium independent phospholipase A(2) (iPLA(2)). Studies in mice in which iPLA(2)-VIA (beta) was knocked out confirmed that this enzyme is critical for baseline and muscarinic cholinergic signaling involving DHA. Thus, quantitative imaging of DHA incorporation from plasma into brain can be used as an in vivo biomarker of brain DHA metabolism and neurotransmission. PMID- 21704723 TI - Identification of HLA-A*02:01-restricted CTL epitopes in Trypanosoma cruzi heat shock protein-70 recognized by Chagas disease patients. AB - CD8(+) cytotoxic T lymphocyte (CTL) response is critical for controlling the infection of the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. Since only a few CD8 antigens have been described in Chagas disease patients, the identification of new class I-restricted epitopes is urgently needed for the development of immunotherapies against T. cruzi infection. In this study, bioinformatic methods were used to predict HLA-A*02:01 binders, and 30 peptides were selected, synthesized and tested for HLA-A*02:01 binding. Among them, sixteen peptides with medium-to-high affinity were assayed for their recognition by CTL from HSP70-immunized or T. cruzi-infected transgenic B6-A2/K(b) mice. Our results show that four immunodominant epitopes (HSP70(210 8), HSP70(255-63), HSP70(316-24) and HSP70(345-53)) are contained in the T. cruzi HSP70 antigen. Indeed two of them (HSP70(210-8) and HSP70(316-24)) were also recognized by CTL of HLA-A*02:01(+) Chagas disease patients, indicating that these peptides are processed and displayed as MHC class I epitopes during the natural history of T. cruzi infection. The HLA-A*02:01 restriction was evidenced using peptide-pulsed K562-A2 cells as antigen-presenting cells. Both cytotoxic and cytokine-secreting activities were detected in response to the former two peptides and, moreover, 10/12 patients (83%) recognized at least one of these two HSP70-derived CD8(+) epitopes. PMID- 21704724 TI - Signal transducer and activator of transcription 5a/b: biomarker and therapeutic target in prostate and breast cancer. AB - The search for new therapeutic strategies for prostate and breast cancer is of significant interest. Signal transducer and activator of transcription 5a/b (Stat5a/b) controls viability and growth of prostate cancer. Nuclear active Stat5a/b expression is clustered to high grade prostate cancers, predicts early disease recurrence and promotes metastatic dissemination of prostate cancer. In breast cancer, the role of Stat5a/b is more complex. In rodent model systems, Stat5a/b may promote malignant transformation and enhance growth of the breast tumors. In contrast, Stat5a/b activation in established human breast cancer positively correlates with tumor differentiation, prevents metastatic dissemination, and predicts favorable clinical outcome of node-negative breast cancer. Here we review the molecular structure and biological functions of Stat5a/b and discuss the potential applications of Stat5a/b for therapy development and as a prognostic marker for prostate and breast cancer. PMID- 21704725 TI - Validation of a genotoxicity test based on p53R2 gene expression in human lymphoblastoid cells. AB - Genotoxicity assessment is important for predicting the carcinogenicity of chemical substances. p53R2 is a p53-regulated gene that is induced by various genotoxic stresses. We previously developed a p53R2-dependent luciferase reporter gene assay in the MCF-7 human breast adenocarcinoma cell line, and demonstrated its ability to detect genotoxic agents. In this paper, we investigate the applicability of the p53R2-based genotoxicity test in the human lymphoblastoid cell line TK6. TK6 cells that express wild-type p53 have been widely used for genetic toxicology studies. To evaluate the performance of the test system in TK6 cells, we referred to 61 of the chemicals on the list of 20 genotoxic and 42 non genotoxic chemicals recommended for the evaluation of modified or new mammalian cell genotoxicity tests by the European Centre for the Validation of Alternative Methods. The overall accordance, sensitivity, and specificity of our results with the ECVAM list were 90% (55/61), 85% (17/20), and 93% (38/41), respectively. These results indicate that the p53R2-based genotoxicity test can detect various types of genotoxic chemicals without compromising its specificity. This test will be a valuable tool for rapid screen for identifying chemicals that may be genotoxic to humans. PMID- 21704726 TI - Genomics and molecular genetics of Clonorchis sinensis: current status and perspectives. AB - Clonorchiasis caused by Clonorchis sinensis is an important foodborne parasitosis of humans and animals, and is predominantly a hepatobiliary disease. Globally, nearly 35 million people were infected with C. sinensis, with approximately 15 million being in China. Patients would chronically present fatigue, jaundice, abdominal discomfort, along with the increased risk of developing into a form of cholangiocarcinoma that is fatal to humans. Treatment of clonorchiasis by praziquantel has been very successful, but this is dependent on early accurate diagnosis and correct species identification. The present article reviews the current status of knowledge in genomics and functional genomics of C. sinensis, and summarizes the main DNA-based techniques for the specific diagnosis of C. sinensis infection and studies of genetic variation in C. sinensis, and provides perspectives for future studies. The advances in genomics and molecular genetics of C. sinensis shed new sight on our understanding of population structure of C. sinensis as well as the prevention and control of clonorchiasis. PMID- 21704727 TI - Diagnostic values of parasite-specific antibody detections in saliva and urine in comparison with serum in opisthorchiasis. AB - Infection by the liver fluke (Opisthorchis viverrini) causes hepatobiliary disease and bile duct cancer (cholangiocarcinoma, CCA) in endemic areas in Southeast Asia. Measurements of humoral immune response particularly parasite specific antibodies are useful not only for serodiagnosis but they have been implicated as risk factors of CCA. In this study, we used indirect Enzyme Immunosorbent Assay (ELISA) to measure O. viverrini-specific immunoglobulins in serum, urine and saliva and assessed efficacies in diagnosis of opisthorchiasis and evaluated the relationship of antibodies among clinical specimens in a sample population in endemic areas in Khon Kaen, Thailand. By employing the Receiver Operation Characteristics (ROC) analysis, diagnostic efficacy based upon the area under the curve (AUC) revealed that serum, salivary IgG and IgA performed better than urine for diagnosis of opisthorchiasis. Seropositive cases were found in both parasite egg-negative as well as O. viverrini egg-positive groups. The levels of serum IgG correlated with intensity of O. viverrini infection (P<0.05). Diagnostic sensitivities based on serum and salivary IgG, IgA also positively associated with the intensity of infection. Correlations between serum antibodies and those in saliva were found to be greater in egg-negative than egg-positive individuals for O. viverrini. Our findings indicated a complex interrelation between antibody responses in different clinical specimens triggered by liver fluke infection. More comprehensive examinations are needed to determine the potential utility of salivary antibody detection which, in combination with the conventional fecal examination method, may better assist in the identification of individuals with opisthorchiasis. Furthermore, it may provide a better indicator of the risk of disease, particularly CCA. PMID- 21704728 TI - Evaluation of liver fluke recombinant cathepsin B-1 protease as a serodiagnostic antigen for human opisthorchiasis. AB - A cathepsin B-like cysteine protease belonging to family C1 is abundantly expressed in the transcriptome and proteome of the carcinogenic liver fluke of humans, Opisthorchis viverrini. This enzyme is present in excretory/secretory (ES) products released by parasites cultured in vitro. This study evaluated the performance of recombinant O. viverrini cathepsin B1 (rOv-CB-1) as an antigen for immunodiagnosis of opisthorchiasis. The full length Ov-CB-1 cDNA was cloned and recombinant protein was produced in catalytically active form in Pichia pastoris. The recombinant Ov-CB-1 (rOv-CB-1) was affinity purified via nickel-NTA chromatography and tested in enzyme-linked immunosorbent assays (ELISA) with human sera from an opisthorchiasis endemic area. Sera from egg-positive O. viverrini infections produced a strong IgG antibody response to rOv-CB-1 both in ELISA and immunoblot analysis. The sensitivity and specificity of the ELISA test was 67% and 81%, respectively. These findings support the feasibility of using recombinant Ov-CB-1 in ELISA for the serodiagnosis of human opisthorchiasis. PMID- 21704729 TI - Oxidative and nitrative DNA damage: key events in opisthorchiasis-induced carcinogenesis. AB - Chronic inflammation induced by liver fluke (Opisthorchis viverrini) infection is the major risk factor for cholangiocarcinoma (CCA) in Northeastern Thailand. Increased levels of proinflammatory cytokines and nuclear factor kappa B that control cyclooxygenase-2 and inducible nitric oxide activities, disturb the homeostasis of oxidants/anti-oxidants and DNA repair enzymes, all of which appear to be involved in O. viverrini-associated inflammatory processes and CCA. Consequently oxidative and nitrative stress-related cellular damage occurs due to the over production of reactive oxygen and nitrogen species in inflamed target cells. This is supported by the detection of high levels of oxidized DNA and DNA bases modified by lipid peroxidation products in both animal and human tissues affected by O. viverrini-infection. Treatment of opisthorchiasis patients with praziquantel, an anti- trematode drug was shown to reduce inflammation-mediated tissue damage and carcinogenesis. The principal mechanisms that govern the effects of inflammation and immunity in liver fluke-associated cholangiocarcinogenesis are reviewed. The validity of inflammation-related biomolecules and DNA damage products to serve as predictive biomarkers for disease risk evaluation and intervention is discussed. PMID- 21704732 TI - Differential effects of the tumor necrosis factor alpha-blocker infliximab and etanercept on immunocompetent cells in vitro. AB - The tumor necrosis factor-alpha (TNFalpha) antagonists infliximab or etanercept are used in the management of chronic inflammatory disorders but have differences in clinical activity. Here we show that both have different effects on immunocompetent cells in vitro. Peripheral blood mononuclear cells (PBMC) from 20 healthy donors were incubated with infliximab or etanercept alone and in a co culture with recall-antigens (BCG, tetanus toxoid [TT]). Expression of the activation marker CD69 on different PBMC-subpopulations was determined by flow cytometry, release of Th1-, Th2- and macrophage/monocyte-related cytokines into the supernatants by ELISA. There were strong inter-individual differences in reactivity of PBMC of the 20 donors towards infliximab and etanercept. On the whole group level, both enhanced IL-10 production but had opposite effects on the TNFalpha- and IFNgamma-secretion; Th2-cytokine-secretion (IL-13, IL-5) was differentially influenced. IL-13 production was significantly reduced by infliximab but not by etanercept. IL-5 secretion was strongly enhanced in individual subjects but was not significantly influenced on the whole group level. Etanercept but not infliximab significantly decreased the CD69-expression by CD8+ T- and CD56+ natural killer(NK)-cells. Co-culture with recall antigens enhanced most of these reactions. Our data indicate that individual predisposition and immunological reactivity may be an important factor influencing the therapeutic efficacy of anti-TNFalpha agents. PMID- 21704731 TI - The contribution of vitamin A to autocrine regulation of fat depots. AB - Morbidity and mortality associated with increased white fat accumulation in visceral fat depots have focused attention on the pathways regulating the development of this tissue during embryogenesis, in adulthood, and while under the influence of obesogenic diets. Adipocytes undergo clonal expansion, differentiation (adipogenesis) and maturation through a complex network of transcriptional factors, most of which are expressed at similar levels in visceral and subcutaneous fat. Rigorous research attempts to unfold the pathways regulating expression and activity of adipogenic transcription factors that act in a fat-depot-specific manner. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is the master regulator of adipogenesis, and is expressed at higher levels in subcutaneous than in visceral depots. PPARgamma expression in adipogenesis is mediated by CCAAT/enhancer binding proteins (C/EBPs) and several transcription factors acting in conjunction with C/EBPs, although alternative pathways through zinc-finger protein-423 (ZFP423) transcription factor are sufficient to induce PPARgamma expression and adipogenesis. Vitamin A and its metabolites, retinaldehyde and retinoic acid, are transcriptionally-active molecules. Retinoic acid is generated from retinaldehyde in adipose tissue by the aldehyde dehydrogenase-1 family of enzymes (Aldh1). In this review, we discuss the role of Aldh1 enzymes in the generation of retinoic acid during adipogenesis, in the regulation of the transcriptional network of PPARgamma in a fat-depot specific manner, and the important contribution of this autocrine pathway in the development of visceral obesity. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism. PMID- 21704733 TI - Pharmacological and biochemical studies on the role of free radicals during stress-induced immunomodulation in rats. AB - The present study was designed to evaluate the role of free radicals in restraint stress (RS)-induced modulation of immune responses in rats. RS significantly suppressed both humoral and cell-mediated immune responses as evidenced by reduced (a) anti-SRBC antibody titre (b) splenic Plaque Forming Cell counts, (c) footpad thickness response, and (d) IFN-gamma and IL-4 levels. Assay for oxidative stress markers in blood showed that there was significant enhancement in plasma corticosterone and products of lipid peroxidation, viz. malondialdehyde and lowered reduced glutathione levels on exposure to RS. Further, this was associated with decreased antioxidant enzyme activity, viz. superoxide dismutase and catalase. These RS-induced changes in immunological and oxidative stress markers were markedly attenuated by pretreatment with the antioxidants, L ascorbic acid (100 and 200 mg/kg) and alpha-tocopherol (30 and 60 mg/kg), by differential degrees. The combination of L-ascorbic acid and alpha-tocopherol was shown to have synergistic effects on reversal of these RS-induced effects. The results suggest that reactive oxygen species may be involved in stress-induced immunomodulation. PMID- 21704734 TI - Protein kinase C beta in postischemic brain mitochondria. AB - PKC is implicated in the regulation of mitochondrial metabolism. We examined the association of PKCbeta with mitochondria and followed postischemic changes in its amount in mitochondria isolated from ischemia-vulnerable (CA1) and ischemia resistant (CA2-4,DG) hippocampus in gerbil model of transient brain ischemia. Our observations suggest that transient ischemic episode induces a significant, rapid and long lasting increase of PKCbeta in mitochondria in CA2-4,DG, which may bespeak neuroprotection. In organotypic hippocampal culture (OHC) model of neurodegeneration, PKCbeta inhibition imposed over NMDA toxicity extended the death area beyond the CA1. These results suggest that PKCbeta might have a protective effect against excitotoxic damage in rat OHC. The pull-down method and LC-MS/MS analysis revealed mitochondrial proteins that can bind directly with PKCbetaIota. The proteins were parts of i) mitochondrial redox carriers forming the electron transport chain including ATP synthase and ii) MPTP: ANT and creatine kinase. PKCbeta acting through mitochondrial proteins could play a role in protecting the cells from death by e.g. influencing ROS and ATP production after ischemia in CA2-4,DG region of the hippocampus. PMID- 21704730 TI - Membrane receptors and transporters involved in the function and transport of vitamin A and its derivatives. AB - The eye is the human organ most sensitive to vitamin A deficiency because of vision's absolute and heavy dependence on vitamin A for light perception. Studies of the molecular basis of vision have provided important insights into the intricate mechanistic details of the function, transport and recycling of vitamin A and its derivatives (retinoid). This review focuses on retinoid-related membrane receptors and transporters. Three kinds of mammalian membrane receptors and transporters are discussed: opsins, best known as vitamin A-based light sensors in vision; ABCA4, an ATP-dependent transporter specializes in the transport of vitamin A derivative; and STRA6, a recently identified membrane receptor that mediates cellular uptake of vitamin A. The evolutionary driving forces for their existence and the wide spectrum of human diseases associated with these proteins are discussed. Lessons learned from the study of the visual system might be useful for understanding retinoid biology and retinoid-related diseases in other organ systems as well. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism. PMID- 21704735 TI - Mitochondrial gene therapy: The tortuous path from bench to bedside. AB - The association of mitochondrial dysfunction with a variety of human diseases and disabilities has been documented. Mitochondrial gene therapy (MGT) seeks to correct the genetic defect in mitochondrial DNA. For successful MGT, an appreciation of the nature of the dysfunction and of the complexities of mitochondrial disease is necessary. This review summarizes the current status of various MGT protocols described in the literature. Although there are many technical difficulties to be overcome, there are indications that some of them will find clinical applications in the near future. PMID- 21704736 TI - Integration of hollow fiber membranes improves nutrient supply in three dimensional tissue constructs. AB - Sufficient nutrient and oxygen transport is a potent modulator of cell proliferation in in vitro tissue-engineered constructs. The lack of oxygen and culture medium can create a potentially lethal environment and limit cellular metabolic activity and growth. Diffusion through scaffold and multi-cellular tissue typically limits transport in vitro, leading to potential hypoxic regions and reduction in the viable tissue thickness. For the in vitro generation of clinically relevant tissue-engineered grafts, current nutrient diffusion limitations should be addressed. Major approaches to overcoming these include culture with bioreactors, scaffolds with artificial microvasculature, oxygen carriers and pre-vascularization of the engineered tissues. This study focuses on the development and utilization of a new perfusion culture system to provide adequate nutrient delivery to cells within large three-dimensional (3D) scaffolds. Perfusion of oxygenated culture medium through porous hollow fiber (HF) integrated within 3D free form fabricated (FFF) scaffolds is proposed. Mouse pre-myoblast (C2C12) cells cultured on scaffolds of poly(ethylene-oxide terephthalate)-poly(butylene-terephthalate) block copolymer (300PEOT55PBT45) integrated with porous HF membranes of modified poly(ether-sulfone) (mPES, Gambro GmbH) is used as a model system. Various parameters such as fiber transport properties, fiber spacing within a scaffold and medium flow conditions are optimized. The results show that four HF membranes integrated with the scaffold significantly improve the cell density and cell distribution. This study provides a basis for the development of a new HF perfusion culture methodology to overcome the limitations of nutrient diffusion in the culture of large 3D tissue constructs. PMID- 21704737 TI - Tuning the dependency between stiffness and permeability of a cell encapsulating hydrogel with hydrophilic pendant chains. AB - The mechanical stiffness of a hydrogel plays a significant role in regulating the phenotype of cells that adhere to its surface. However, the effect of hydrogel stiffness on cells cultured within its matrix is not well understood, because of the intrinsic inverse dependency between the permeability and stiffness of hydrogels. This study therefore presents an advanced biomaterial design strategy to decrease the inverse dependency between permeability and stiffness of a cell encapsulating hydrogel. Hydrogels were made by cross-linking poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) monoacrylate (PEGMA), with PEGMA acting as a pendant polymer chain. Increasing the mass fraction of PEGMA while keeping the total polymer concentration constant led to a decrease in the elastic modulus (E) of the hydrogel, but caused a minimal increase in the swelling ratio (Q). The size and hydrophobicity of the end groups of pendant PEG chains further fine tuned the dependency between Q and E of the hydrogel. Pure PEGDA hydrogels with varying molecular weights, which show the same range of E but a much greater range of Q, were used as a control. Fibroblasts encapsulated in PEGDA-PEGMA hydrogels displayed more significant biphasic dependencies of cell viability and vascular endothelial growth factor (VEGF) expression on E than those encapsulated in pure PEGDA hydrogels, which were greatly influenced by Q. Overall, the hydrogel design strategy presented in this study will be highly useful to better regulate the phenotype and ultimately improve the therapeutic efficacy of a wide array of cells used in various biology studies and clinical settings. PMID- 21704738 TI - Size-dependent transfection efficiency of PEI-coated gold nanoparticles. AB - Gold nanoparticles (Au NPs) are promising vectors for gene delivery applications. In order to gain insight on the influence of particle size on cell transfection, Au NPs were combined with poly(ethylenimine) (PEI) to prepare two sets of PEI coated Au NPs having particle-size distributions centered at about 6 nm (<10nm Au PEI NPs) or 70 nm (<100 nm Au-PEI NPs), respectively. Au-PEI NPs were coupled to a variety of plasmids carrying reporter or suicide genes to prepare Au-PEI NPs/DNA complexes, and human osteosarcoma Saos-2 cells were used to investigate the performance of the Au-PEI NPs as transfection vectors in serum-containing media. The conjugates of DNA with both types of Au-PEI NPs were found to be negatively charged. In spite of the electrostatic repulsion that occurs between the surface of the cell and the surface of the plasmid-conjugated NPs, cell internalization was observed for both kinds of Au-PEI NPs. Cells were efficiently transfected with complexes derived from <10 nm Au-PEI NPs, but not with the <100 nm Au-PEI NPs. Large aggregates of NPs associated with DNA were found in endocytic vesicles of cells incubated with <100 nm Au-PEI NPs, while the success of the smaller Au-PEI NPs as transfection vectors was related to their lower agglomeration state inside cells and to endosomal escape of DNA. PMID- 21704739 TI - Stealth properties of poly(ethylene oxide)-based triblock copolymer micelles: a prerequisite for a pH-triggered targeting system. AB - Evaluation of the biocompatibility of pH-triggered targeting micelles was performed with the goal of studying the effect of a poly(ethylene oxide) (PEO) coating on micelle stealth properties. Upon protonation under acidic conditions, pH-sensitive poly(2-vinylpyridine) (P2VP) blocks were stretched, exhibiting positive charges at the periphery of the micelles as well as being a model targeting unit. The polymer micelles were based on two different macromolecular architectures, an ABC miktoarm star terpolymer and an ABC linear triblock copolymer, which combined three different polymer blocks, i.e. hydrophobic poly(epsilon-caprolactone), PEO and P2VP. Neutral polymer micelles were formed at physiological pH. These systems were tested for their ability to avoid macrophage uptake, their complement activation and their pharmacological behavior after systemic injection in mice, as a function of their conformation (neutral or protonated). After protonation, complement activation and macrophage uptake were up to twofold higher than for neutral systems. By contrast, when P2VP blocks and the targeting unit were buried by the PEO shell at physiological pH, micelle stealth properties were improved, allowing their future systemic injection with an expected long circulation in blood. Smart systems responsive to pH were thus developed which therefore hold great promise for targeted drug delivery to an acidic tumoral environment. PMID- 21704740 TI - Fibronectin layers by matrix-assisted pulsed laser evaporation from saline buffer based cryogenic targets. AB - The deposition of fibronectin (FN) from saline buffer-based cryogenic targets by matrix-assisted pulsed laser evaporation (MAPLE) onto silicon substrates is reported. A uniform distribution of FN was revealed by Ponceau staining after control experiments on nitrocellulose paper. Well-organized particulates with heights from hundreds of nanometers up to more than 1 MUm packed in homogeneous layers were evidenced by optical microscopy and profilometry on Si substrates. Atomic force microscopy images showed regions composed of buffer and FN aggregates forming a compact film. Comparison of infrared spectra of drop-cast and MAPLE-deposited FN confirmed the preservation of composition and showed no degradation of the protein. The protein deposition on Si was confirmed by antibody staining. Small aggregates and fluorescent fibrils were visualized by fluorescence microscopy. Superior attachment of human osteoprogenitor cells cultivated for 3 h proved the presence of stable and intact FN molecules after transfer. PMID- 21704741 TI - Enhanced cellular uptake and in vivo pharmacokinetics of rapamycin-loaded cubic phase nanoparticles for cancer therapy. AB - To date cancer is considered as one of the most devastating diseases due to its high rate of mortality. Preclinical studies have demonstrated that the Akt/mTOR (mammalian target of rapamycin) pathway is activated in cancers and inhibition of this pathway has great potential in anti-cancer therapy. Rapamycin, one of the most potent anti-cancer drugs, blocks Akt/mTOR function and has anti proliferative activity in several cancers. To circumvent problems associated with rapamycin due to its poor water solubility, poor oral bioavailability, low accessibility to cancer tissues and systemic toxicity, rapamycin-loaded cubic nanoparticles (NP) were formulated with vitamin E d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) as an emulsifier for oral delivery. Cubic NP were characterised and these particles demonstrated better cytotoxicity and apoptosis compared with native rapamycin under in vitro conditions due to their enhanced cellular uptake. The molecular impact of particulate systems on the Akt/mTOR pathway were elucidated by immunoblotting. Down-regulation of different anti apoptotic genes of this pathway indicates activation of apoptotic signals leading to MIA PaCa cell death. An in vivo study demonstrated enhanced bioavailability of rapamycin in cubic NP in comparison with native rapamycin in a mouse model with no toxicity and good biocompatibility of void cubic NP at a higher dose of oral administration. Thus, rapamycin-loaded cubic NP can be used as an effective drug delivery system to produce better rapamycin therapeutics for the treatment of cancers. PMID- 21704742 TI - Mechanical properties of functionally graded hierarchical bamboo structures. AB - This paper presents the results of a series of multi-scale experiments and numerical models concerning the mechanical properties of moso culm functionally graded bamboo structures. On the nano- and microscales, nanoindentation techniques are used to study the local variations in the Young's moduli of moso culm bamboo cross-sections. These are then incorporated into finite element models in which the actual variations in Young's moduli are used to model the deformation and fracture of bamboo during fracture toughness experiments. Similarly, the measured gradations in moduli are incorporated into crack bridging models that predict the toughening observed during resistance curve tests. The implications of the results are discussed for the bio-inspired design of structures that mimic the layered, functionally graded structure of bamboo. PMID- 21704743 TI - Distinction of thioredoxin transnitrosylation and denitrosylation target proteins by the ICAT quantitative approach. AB - S-Nitrosylation is a reversible PTM for regulating protein function. Thioredoxin 1 (Trx1) catalyzes either transnitrosylation or denitrosylation of specific proteins, depending on the redox status of the cysteines within its conserved oxidoreductase CXXC motif. With a disulfide bond formed between the two catalytic cysteines, Trx1 is not only inactive as a denitrosylase, but it may also be nitrosylated at Cys73 and serve as a transnitrosylating agent. Identification of Trx1-mediated transnitrosylation or denitrosylation targets will contribute to a better understanding of Trx1's function. Previous experimental approaches based on the attenuation of CXXC oxidoreductase activity cannot readily distinguish Trx1 transnitrosylation targets from denitrosylation targets. In this study, we used the ICAT method in conjunction with the biotin switch technique to differentiate Trx1 transnitrosylation targets from denitrosylation target proteins from neuroblastoma cells. We demonstrate that the ICAT approach is effective for quantitative identification of putative Trx1 transnitrosylation and denitrosylation target peptides. From these analyses, we confirmed reports that peroxiredoxin 1 is a Trx1 transnitrosylation, but not a denitrosylation target, and we found several other proteins, including cyclophilin A to be modulated in this manner. Unexpectedly, we found that many nitrosylation sites are reversibly regulated by Trx1, suggesting a more prominent role for Trx1 in regulating S nitrosylation. PMID- 21704745 TI - iTRAQ-based quantitative proteomic analysis of Thermobifida fusca reveals metabolic pathways of cellulose utilization. AB - Thermobifida fusca is an aerobic, thermophilic, cellulose degrading bacterium identified in heated organic materials. This study applied iTRAQ quantitative proteomic analysis to the cellular and membrane proteomes of T. fusca grown in presence and absence of cellulose to elucidate the cellular processes induced by cellulose nutrient. Using an iTRAQ-based quantitative proteomic approach, 783 cytosolic and 181 membrane proteins expressed during cellulose hydrolysis were quantified with <=1% false discovery rate. The comparative iTRAQ quantification revealed considerable induction in the expression levels and up-regulation of specific proteins in cellulosic medium than non-cellulosic medium. The regulated proteins in cellulosic medium were grouped under central carbohydrate metabolism such as glycolysis/gluconeogenesis, pentose phosphate pathways, citric acid cycle, starch, sugars, pyruvate, propanoate and butanoate metabolism; energy metabolism that includes oxidative phosphorylation, nitrogen, methane and sulfur metabolism; fatty acid metabolism, amino acid metabolic pathways, purine and pyrimidine metabolism, and main cellular genetic information processing functions like replication, transcription, translation, and cell wall synthesis; and environmental information processing (membrane transport and signal transduction). The results demonstrated cellulose induced several metabolic pathways during cellulose utilization. PMID- 21704746 TI - Development of quantitative plasma N-glycoproteomics using label-free 2-D LC MALDI MS and its applicability for biomarker discovery in hepatocellular carcinoma. AB - There has been rapid progress in the development of clinical proteomic methodologies with improvements in mass spectrometric technologies and bioinformatics, leading to many new methodologies for biomarker discovery from human plasma. However, it is not easy to find new biomarkers because of the wide dynamic range of plasma proteins and the need for their quantification. Here, we report a new methodology for relative quantitative proteomic analysis combining large-scale glycoproteomics with label-free 2-D LC-MALDI MS. In this method, enrichment of glycopeptides using hydrazide resin enables focusing on plasma proteins with lower abundance corresponding to the tissue leakage region. On quantitative analysis, signal intensities by 2-D LC-MALDI MS were normalized using a peptide internal control, and the values linked to LC data were treated with DeViewTM software. Our proteomic method revealed that the quantitative dynamic ranged from 102 to 106 pg/mL of plasma proteins with good reproducibility, and the limit of detection was of the order of a few ng/mL of proteins in biological samples. To evaluate the applicability of our method for biomarker discovery, we performed a feasibility study using plasma samples from patients with hepatocellular carcinoma, and identified biomarker candidates, including ceruloplasmin, alpha-1 antichymotrypsin, and multimerin-1. PMID- 21704744 TI - Proteomic profiling of acrolein adducts in human lung epithelial cells. AB - Acrolein (2,3-propenal) is a major indoor and outdoor air pollutant originating largely from tobacco smoke or organic combustion. Given its high reactivity, the adverse effects of inhaled acrolein are likely due to direct interactions with the airway epithelium, resulting in altered epithelial function, but only limited information exists to date regarding the primary direct cellular targets for acrolein. Here, we describe a global proteomics approach to characterize the spectrum of airway epithelial protein targets for Michael adduction in acrolein exposed bronchial epithelial (HBE1) cells, based on biotin hydrazide labeling and avidin purification of biotinylated proteins or peptides for analysis by LC MS/MS. Identified protein targets included a number of stress proteins, cytoskeletal proteins, and several key proteins involved in redox signaling, including thioredoxin reductase, thioredoxin, peroxiredoxins, and glutathione S transferase pi. Because of the central role of thioredoxin reductase in cellular redox regulation, additional LC-MS/MS characterization was performed on purified mitochondrial thioredoxin reductase to identify the specific site of acrolein adduction, revealing the catalytic selenocysteine residue as the target responsible for enzyme inactivation. Our findings indicate that these approaches are useful in characterizing major protein targets for acrolein, and will enhance mechanistic understanding of the impact of acrolein on cell biology. PMID- 21704747 TI - Proteomics of early and late cold shock stress on thermophilic bacterium, Thermus sp. GH5. AB - Thermus sp. GH5 is an aerobic thermophilic bacterium with optimal growth at 70-75 degrees C isolated from a hot spring in Ardabil, North West province of Iran. Due to industrial and biotechnological applications of thermophils, it is very important to know more about their proteomes and metabolomes. Since thermophils live in stressful environments it will be very useful to study their survival mechanisms. There are many reports on stress induced proteins, particularly the well characterized heat shock proteins, but little is known about the functions of proteins induced after a decrease in temperature. In this study, the proteomes of the thermophilic bacterium after a temperature down shift from 75 degrees C to 45 degrees C for 2h and 5h were investigated. We also compared protein profiles of early and late cold shock processes to that of cells grown at 75 degrees C and identified a set of proteins, some of which are involved in metabolic processes such as fatty acid synthesis, pentose phosphate pathway, aromatic component degradation and signal transduction. Our data showed this organism could be tolerating the stress conditions by changing its metabolism and physiology. PMID- 21704748 TI - Identification of Brugia malayi immunogens by an immunoproteomics approach. AB - Filariasis remains a health problem in tropical countries. Identification of immunogens from its causative organism would lead to development of a better diagnostic test, as well as vaccine discovery to effectively prevent this disease. We applied immunoproteomics to define potential immunogens of adult Brugia malayi that were recognized by IgM, IgG1 and IgG4 in sera of patients with four distinct clinical spectra of filariasis, including endemic asymptomatic, lymphangitis, elephantiasis and microfilaremia (n=5/group). Sera of healthy individuals (n=5) from non-endemic area served as the negative control. Brugian proteins were resolved by 2-DE and subjected to 2-D Western blot analysis probed with these sera. A total of 30 immunoreactive proteins recognized by IgM, IgG1 and IgG4 in sera from all four filarial groups were identified by Q-TOF MS and MS/MS analyses. Interestingly, only three immunogens were recognized by IgM in lymphangitis, elephantiasis and microfilaremia, but not in endemic asymptomatic group. IgG1 recognized 20 immunogens in endemic asymptomatic, lymphangitis and microfilaremia (mostly in endemic asymptomatic group), but not in elephantiasis, whereas IgG4 recognized 28 immunogens in all four filarial groups (mostly in microfilaremia). This large data set is an important resource for further development of a new diagnostic test and/or vaccine for filariasis. PMID- 21704750 TI - Detection of multiple cardiac markers with an integrated acoustic platform for cardiovascular risk assessment. AB - This work describes the application of a newly emerged biosensing configuration incorporating a Surface Acoustic Wave device integrated with a multi-channel microfluidic module for the rapid and efficient analysis of cardiac markers. The examined cardiac markers of creatine kinase MB (CK-MB), cardiac reactive protein (CRP), D-dimer and pregnancy-associated plasma protein A (PAPP-A), comprise a group of both established and emerging heart disease proteins, that has never been probed before with any kind of biochip-related platform. The four markers were successfully detected; kinetics and affinity studies on their interactions with the surface immobilized antibodies are also presented. A concentration detection limit of less than 1 nM was achieved, with a dynamic range of more than two orders of magnitude, covering some of the pathological and healthy areas of interest. Mixtures of biomarkers applied to the device surface were used to prove the specificity of each binding event and investigate the microsystem's performance in the presence of complex fluids, towards future utilization with real samples. The simplicity and multiplexing ability of the integrated platform render the system ideal as a potential diagnostic tool for cardiovascular risk assessment, where simultaneous analysis of various protein markers is required. PMID- 21704752 TI - Non-chromatographic screening procedure for arsenic speciation analysis in fish based baby foods by using electrothermal atomic absorption spectrometry. AB - A procedure for the speciation analysis of arsenic in fish-based baby foods is presented. Inorganic arsenic, methylarsonic acid (MA), dimethylarsinic acid (DMA) and arsenobetaine (AB) were determined by electrothermal atomic absorption spectrometry (ETAAS) using suspensions prepared in a 0.01 mol L(-1) tetramethylammonium hydroxide (TMAH) solution. Speciation is based on the use of three different chemically modified ETAAS atomizers to obtain the analytical signals. Using a palladium salt as the chemical modifier, the signal corresponding to the total arsenic concentration is obtained. When palladium is replaced by Ce(IV), the signal is solely due to inorganic arsenic (III and V)+MA. If no signal is obtained in this latter case, it is possible to distinguish between DMA and AB using a zirconium coated atomizer. The signal obtained in this way is due solely to DMA, and the concentration of AB can be obtained by the difference with the total arsenic content. Determinations by ETAAS require the use of the standard additions method. The limits of detection for the determination of AB, DMA and inorganic arsenic (+MA) are 15, 25 and 50 ng g(-1) expressed as arsenic, respectively. These detection limits are good enough for the procedure to be appropriate for the rapid determination of these compounds, avoiding extraction processes and/or chromatographic separations. Data for commercial samples, as well as for four standard reference materials, are given. PMID- 21704751 TI - Using dried-droplet laser ablation inductively coupled plasma mass spectrometry to quantify multiple elements in whole blood. AB - This paper describes a simple procedure for the direct analysis and determination of multiple elements in dried blood samples on a filter membrane using laser ablation coupled with inductively coupled plasma mass spectrometry (LA-ICP-MS). With this technique, we simultaneously quantified 13 elements in whole blood: Be, Mn, Co, Ni, Tl, Bi, Sb, Pb, Cu, Zn, Ba, Mg, and Cd. The measured accuracies was in agreement with the Seronorm CRM certified values, except for Mn, Zn, Ba and Cd, which presented absolute differences higher than the expanded uncertainty for these elements. The within-run precision was less than 5.7% (relative standard deviation, RSD), except for the analyses of Be, and Mn (8.6% and 11.1%, respectively). The reproducibility (between-run precision) was calculated in terms of the RSD obtained for 12 analyses (i.e., four replicates of each sample in three analytical runs). Apart from Be, Mn, and Zn, the reproducibilities of all the elements listed above ranged between 4.0% and 8.5%. In contrast, for Cd, the concentration obtained was significantly different from the certified value; analyses of this element exhibited low reproducibility. Applying the matrix matched calibration method, the accuracy for Cd measured was in agreement with both SRM966 and BCR 635; thus, matrix-matched calibration is a practical means of overcoming matrix-enhancement effects for the quantification of Cd. Sample throughput (ca. 5 min per sample) made it possible to rapidly screen a larger number of samples relative to other techniques that require time-consuming sample preparation steps (e.g., removal of a portion of the solid sample or digestion). PMID- 21704753 TI - A new and efficient variable selection algorithm based on ant colony optimization. Applications to near infrared spectroscopy/partial least-squares analysis. AB - A new variable selection algorithm is described, based on ant colony optimization (ACO). The algorithm aim is to choose, from a large number of available spectral wavelengths, those relevant to the estimation of analyte concentrations or sample properties when spectroscopic analysis is combined with multivariate calibration techniques such as partial least-squares (PLS) regression. The new algorithm employs the concept of cooperative pheromone accumulation, which is typical of ACO selection methods, and optimizes PLS models using a pre-defined number of variables, employing a Monte Carlo approach to discard irrelevant sensors. The performance has been tested on a simulated system, where it shows a significant superiority over other commonly employed selection methods, such as genetic algorithms. Several near infrared spectroscopic experimental data sets have been subjected to the present ACO algorithm, with PLS leading to improved analytical figures of merit upon wavelength selection. The method could be helpful in other chemometric activities such as classification or quantitative structure-activity relationship (QSAR) problems. PMID- 21704754 TI - Classification of amino acids and oligopeptides with the use of multi-mode chemical images obtained with ion selective electrode array. AB - The analysis of amino acids and oligopeptides as important bioanalytes is a significant task in medical diagnostics and proteomic research and currently it is based on chromatographic and electrophoretic methods. In this paper, an approach based on sensor array coupled with titration is proposed for effective recognition of 5 amino acids and 4 oligopeptides. It is shown, that the increase of information gained during measurements of sensors' signals in various pH allows for capturing more data on interaction of amino acids and oligopeptides with various polymeric membranes of potentiometric electrodes used in the array, and that leads to the lowering of classification errors in partial least squares analysis. PMID- 21704755 TI - The use of digital simulation to improve the cyclic voltammetric determination of rate constants for homogeneous chemical reactions following charge transfers. AB - Cyclic voltammetry (CV) is a very useful electrochemical tool used to study reaction systems that include chemical steps that are coupled to electron transfers. This type of system generally involves the chemical reaction of an electrochemically generated free radical. Published methods exist that are used to determine the kinetics of electrochemically initiated chemical reactions from the measurements of the peak current ratio (i(pa)/i(pc)) of a cyclic voltammogram. The published method requires working curves to relate a kinetic parameter to the peak current ratio. In the presented work, a digital simulation package was used to obtain improved working curves for specific working conditions. The curves were compared with the published results for the first- and second-order chemical reactions following the charge transfer step mechanisms. According to the presented results, the previously published working curve is reliable for a mechanism with a first-order chemical reaction; however, a change in the switching potential requires a recalculation of the curve. In the case of mechanisms with a second-order step (dimerisation and disproportionation), several different views exist on how the second-order chemical term should be expressed so that different values of the constant are obtained. Parameters such as electrode type, electrode area, electroactive species concentration, switching potential, scan rate and method for peak current ratio calculation modify the working curves and must always be specified. We propose a standardised method to obtain the most reliable kinetic constant values. The results of this work will permit researchers who handle simulation software to construct their own working curves. Additionally, those who do not have the simulation software could use the working curves described here. The revelations of the presented experiments may be useful to a broad chemistry audience because this study presents a simple and low-cost procedure for the study of free radicals that otherwise should be studied with more sophisticated and expensive techniques, such as ESR or pulse radiolysis. PMID- 21704756 TI - Graphene-based immunosensor for electrochemical quantification of phosphorylated p53 (S15). AB - We reported a graphene-based immunosensor for electrochemical quantification of phosphorylated p53 on serine 15 (phospho-p53(15)), a potential biomarker of gamma radiation exposure. The principle is based on sandwich immunoassay and the resulting immunocomplex is formed among phospho-p53 capture antibody, phospho p53(15) antigen, biotinylated phospho-p53(15) detection antibody and horseradish peroxidase (HRP)-labeled streptavidin. The introduced HRP results in an electrocatalytic response to reduction of hydrogen peroxide in the presence of thionine. Graphene served as sensor platform not only promotes electron transfer, but also increases the surface area to introduce a large amount of capture antibody, thus increasing the detection sensitivity. The experimental conditions including blocking agent, immunoreaction time and substrate concentration have been optimized. Under the optimum conditions, the increase of response current is proportional to the phospho-p53(15) concentration in the range of 0.2-10 ng mL( 1), with the detection limit of 0.1 ng mL(-1). The developed immunosensor exhibits acceptable stability and reproducibility and the assay results for phospho-p53(15) are in good correlation with the known values. This easily fabricated immunosensor provides a new promising tool for analysis of phospho p53(15) and other phosphorylated proteins. PMID- 21704757 TI - Accurate quantification of polycyclic aromatic hydrocarbons in dust samples using microwave-assisted solvent extraction combined with isotope-dilution mass spectrometry. AB - For accurate quantification of polycyclic aromatic hydrocarbons (PAHs) in dust samples, we investigated the use of microwave-assisted solvent extraction (MAE) combined with isotope-dilution mass spectrometry (IDMS) using deuterium-labelled PAHs (D-PAHs). Although MAE with a methanol/toluene mixture (1:3 by volume) at 160 degrees C for 40 min was best for extracting PAHs from tunnel dust among examined, the recovery yields of D-PAHs decreased with increasing molecular weight (<40% for MW>=264; that of deuterium-labelled indeno[123-cd]pyrene (D IcdP) was only 7.1%). Although the residues were extracted a second time, the observed concentrations did not change dramatically (<5%), and the recovery yields of heavier D-PAHs (i.e., MW>=264) were approximately half of those of the first extract, including D-IcdP (3.4%). These results suggest that both partitioning and isotopic equilibria of PAHs and D-PAHs between sample and solvent were achieved for extractable heavier PAHs under the condition. Thus, the observed concentrations of PAHs obtained by MAE-IDMS were reasonable, even though recovery yields of D-PAHs were <50%. From the results of carbon analyses and extractable contents, lower recovery yields of D-PAHs from the tunnel dust were due to a large content of char with low extractable contents. PMID- 21704758 TI - Development of a gas chromatography-mass spectrometry method for the determination of pesticides in gaseous and particulate phases in the atmosphere. AB - A reliable multi-residue method for determining gaseous and particulate phase pesticides in atmospheric samples has been developed. This method, based on full scan gas chromatography-mass spectrometry (GC-MS), allowed the proper determination of sixteen relevant pesticides, in a wide range of concentrations and without the influence of interferences. The pesticides were benfluralin, bitertanol, buprofezin, chlorfenvinphos, chlorpyrifos, chlorpyrifos-methyl, ethalfluralin, fenthion, lindane, malathion, methidathion, propachlor, propanil, pyriproxifen, tebuconazol and trifluralin. Comparisons of two types of sampling filters (quartz and glass fibre) and four types of solid-phase cartridges (XAD-2, XAD-4, Florisil and Orbo-49P) showed that the most suitable supports were glass fibre filter for particulate pesticides and XAD-2 and XAD-4 cartridges for gaseous pesticides (>95% recovery). Evaluations of elution solvents for ultrasonic-assisted extraction demonstrated that isooctane is better than ethylacetate, dichloromethane, methanol or a mixture of acetone:hexane (1:1). Recovery assays and the standard addition method were performed to validate the proposed methodology. Moreover, large simulator chamber experiments allowed the best study of the gas-particle partitioning of pesticides for testing the sampling efficiency for the validation of an analytical multiresidue method for pesticides in air. Satisfactory analytical parameters were obtained, with a repeatability of 5+/-1%, a reproducibility of 13+/-3% and detection limits of 0.05-0.18 pg m(-3) for the particulate phase and 26-88 pg m(-3) for the gaseous phase. Finally, the methodology was successfully applied to rural and agricultural samples in the Mediterranean area. PMID- 21704759 TI - Comparison of silica gel modified with three different functional groups with C 18 and styrene-divinylbenzene adsorbents for the analysis of selected volatile flavor compounds. AB - A comparison of SPE cartridges produced in authors laboratory containing silica modified by addition of three functional moieties with standard C-18 and SDVB cartridges was made in terms of their applicability for the isolation of flavor compounds. Compounds found in wine and grapes were used for model mixture, which was spiked into a grape juice. Functionalized phases for SPE were prepared modifying silica gel with alkoxysilanes with different functional groups: (3 (phenylamino)-propyltrimethoxysilane, octyltriethoxysilane and octadecyl-silane. The functionalization was carried out by the dry method, which resulted 5, 10 and 20 weight parts of initial support. Functionalized phases were characterized using FT-IR, elemental analysis and NMR. Performance for new phases compared to "standard" ones (C-18 and SDVB (styrene-divinylbenzene) varied, depending on the group or type of analyzed compound. They were more efficient in extraction of methyl anthranilate and vanilins. For extraction of terpenes, C-6 alcohols, isoprenoids, benzene derivatives and phenols their efficiency was comparable to that of C-18. Functionalized laboratory-made mixed phases are suitable for extraction of flavor compounds from grape juice. They are suitable for extraction of compounds belonging to different chemical classes with the efficiency comparable to C-18 and SDVB phases. The production of such functionalized phases can be easily performed in the laboratory, at a very low cost, comparing to C-18 or SDVB cartridges. This makes the proposed functionalized phases an interesting alternative, in sample preparation for analysis and particularly in preparative/flash chromatography. PMID- 21704760 TI - Matrix effect in the analysis of drugs of abuse from urine with desorption atmospheric pressure photoionization-mass spectrometry (DAPPI-MS) and desorption electrospray ionization-mass spectrometry (DESI-MS). AB - We have studied the matrix effect within direct analysis of benzodiazepines and opioids from urine with desorption electrospray ionization-mass spectrometry (DESI-MS) and desorption atmospheric pressure photoionization-mass spectrometry (DAPPI-MS). The urine matrix was found to affect the ionization mechanism of the opioids in DAPPI-MS favoring proton transfer over charge exchange reaction. The sensitivity for the drugs in solvent matrix was at the same level with DESI-MS and DAPPI-MS (LODs 0.05-6 MUg mL(-1)) but the decrease in sensitivity due to the urine matrix was higher with DESI (typically 20-160-fold) than with DAPPI (typically 2-15-fold) indicating better matrix tolerance of DAPPI over DESI. Also in MS/MS mode, DAPPI provided better sensitivity than DESI for the drugs in urine. The feasibility of DAPPI-MS/MS was then studied in screening the same drugs from five authentic, forensic post mortem urine samples. A reference measurement with gas chromatography-mass spectrometry (GC-MS) (including pretreatment) revealed 16 findings from the samples, whereas with DAPPI-MS/MS after sample pretreatment, 15 findings were made. Sample pretreatment was found necessary, since only eight findings were made from the same samples untreated. PMID- 21704762 TI - Interaction of soil humic acids with herbicide paraquat analyzed by surface enhanced Raman scattering and fluorescence spectroscopy on silver plasmonic nanoparticles. AB - A study of the interaction between paraquat (methyl viologen) and humic acids, extracted from a soil amended over 30 years with crop residues, cow slurries and cattle manure, was carried out by two emission spectroscopies based on plasmonic effects: surface-enhanced Raman scattering (SERS) and surface-enhanced fluorescence (SEF). To carry out this study Ag nanoparticles were used. The complex formation was tested by analyzing the effect of the herbicide on humic acids, and by varying experimental parameters such as the pH and the laser excitation wavelength. The study of the vibrational bands led to infer information about the interaction mechanism of paraquat with humic acids and to find a correlation between this interaction and the humic acids structural modification induced by the different amendments added to soil. PMID- 21704761 TI - Quantitative analysis of multiple urinary biomarkers of carcinoid tumors through gold-nanoparticle-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - A simple technique for quantitative analysis of four urinary biomarkers, tryptophan (TRP), 5-hydroxytryptophan (5-HTP), 5-hydroxytryptamine (5-HT) and 5 hydroxyindole acetic acid (5-HIAA) of carcinoid tumors is developed using gold nanoparticles as the assisted matrix in surface-assisted laser desorption/ionization time-of-flight mass spectrometry (SALDI-TOF MS). The optimal SALDI conditions for the efficient ionization of those biomarkers are systematically explored by the adjustments of the concentrations of gold nanoparticles and internal standards. The mass spectra with strong signals and minimal background noise are obtained using 1-naphthaleneacetamide (NAD) as the internal standard. The calibration curves of the biomarker concentrations are determined using SALDI-TOF MS and the high linearity is obtained in all samples. For future clinical testing, multiplexed detection of those biomarkers in the urine samples of healthy males is performed. The successful quantitative detections of TRP, 5-HTP, 5-HT and 5-HIAA indicate that our technique provided great potentials to be developed a simple and rapid platform for the tumor biomarker detections. PMID- 21704763 TI - Near infrared and Raman spectroscopy as Process Analytical Technology tools for the manufacturing of silicone-based drug reservoirs. AB - Using near infrared (NIR) and Raman spectroscopy as PAT tools, 3 critical quality attributes of a silicone-based drug reservoir were studied. First, the Active Pharmaceutical Ingredient (API) homogeneity in the reservoir was evaluated using Raman spectroscopy (mapping): the API distribution within the industrial drug reservoirs was found to be homogeneous while API aggregates were detected in laboratory scale samples manufactured with a non optimal mixing process. Second, the crosslinking process of the reservoirs was monitored at different temperatures with NIR spectroscopy. Conformity tests and Principal Component Analysis (PCA) were performed on the collected data to find out the relation between the temperature and the time necessary to reach the crosslinking endpoints. An agreement was found between the conformity test results and the PCA results. Compared to the conformity test method, PCA had the advantage to discriminate the heating effect from the crosslinking effect occurring together during the monitored process. Therefore the 2 approaches were found to be complementary. Third, based on the HPLC reference method, a NIR model able to quantify the API in the drug reservoir was developed and thoroughly validated. Partial Least Squares (PLS) regression on the calibration set was performed to build prediction models of which the ability to quantify accurately was tested with the external validation set. The 1.2% Root Mean Squared Error of Prediction (RMSEP) of the NIR model indicated the global accuracy of the model. The accuracy profile based on tolerance intervals was used to generate a complete validation report. The 95% tolerance interval calculated on the validation results indicated that each future result will have a relative error below +/-5% with a probability of at least 95%. In conclusion, 3 critical quality attributes of silicone-based drug reservoirs were quickly and efficiently evaluated by NIR and Raman spectroscopy. PMID- 21704764 TI - Spectrophotometric determination of various polyanions with polymeric film optodes using microtiter plate reader. AB - Polycation-sensitive membrane optodes based on the chromoionophore 2',7' dichlorofluorescein octadecylester (DCFOE) have previously been developed and used for determination of heparin via a titrimetric method. In this study, it is shown that some other important polyanions such as PPS (pentosan polysulfate), DNA, xanthan, Na-alginate, and carrageenan (food additive) can also be readily determined by using DCFOE-based microtiter plate-format optodes (MPOs) and polycationic titrants that bind these polyanionic species. The optical sensors are prepared with poly(vinyl chloride) (PVC), polyurethane (PU), bis(2 ethylhexyl)sebacate (DOS), and 2',7'-dichlorofluorescein octadecylester (DCFOE) and exhibit reproducible and sensitive absorbance changes in response to the varying polycationic titrant concentrations. Three different polycations; protamine, poly-l-lysine and poly-l-arginine, are employed as titrants. The method has a detection limit of 1 MUg mL(-1), and a dynamic range of 1-40 MUg mL( 1). After the quantitative determinations are successfully demonstrated in buffered solutions, similar titrations are also performed in real samples. The method is validated by recovery studies in these samples. The average polyanion recoveries were quantitative [99.7(+/-1.3) % for pastry cream with vanillin (protamine titrant); 100.4 (+/-3.3) % for pastry gel with strawberry(PLA titrant), and 102.9(+/-2.0) % for pastry gel with strawberry (PLL titrant)]. PMID- 21704765 TI - Determination of N-methylcarbamate insecticides in water samples using dispersive liquid-liquid microextraction and HPLC with the aid of experimental design and desirability function. AB - A rapid and simple method for the extraction and preconcentration of N methylcarbamates (NMCs) (carbofuran, carbaryl and promecarb) in water samples using dispersive liquid-liquid microextraction (DLLME) using chemometrics was developed. Influence variables such as volume of extracting (CHCl(3)) and dispersing solvents (ACN), pH and ionic strength, extraction time and centrifugation time and speed were screened in a 2(7-4) Plackett-Burman design was investigated. The significant variables were optimized by using a central composite design (CCD) combined with desirability function (DF). At optimum conditions values of variables set as 126 MUL chloroform, 1.5 mL acetonitrile, 1 min extraction time, 10 min centrifugation at 4000 rpm min(-1), natural pH, 4.7% (w/v) NaCl, the separation was reached in less than 14 min using a C(18) column and an isocratic binary mobile phase (acetonitrile: water (50:50, v/v)) with flow rate of 1.0 mL min(-1). At optimum conditions method has linear response over 0.001-10 MUg mL(-1) with detection limit between 0.0001 and 0.0005 MUg mL(-1) with relative standard deviations (RSDs) in the range 2.18-5.06% (n=6). PMID- 21704766 TI - Quantitative analysis of essential oils in perfume using multivariate curve resolution combined with comprehensive two-dimensional gas chromatography. AB - The use of multivariate curve resolution (MCR) to build multivariate quantitative models using data obtained from comprehensive two-dimensional gas chromatography with flame ionization detection (GC*GC-FID) is presented and evaluated. The MCR algorithm presents some important features, such as second order advantage and the recovery of the instrumental response for each pure component after optimization by an alternating least squares (ALS) procedure. A model to quantify the essential oil of rosemary was built using a calibration set containing only known concentrations of the essential oil and cereal alcohol as solvent. A calibration curve correlating the concentration of the essential oil of rosemary and the instrumental response obtained from the MCR-ALS algorithm was obtained, and this calibration model was applied to predict the concentration of the oil in complex samples (mixtures of the essential oil, pineapple essence and commercial perfume). The values of the root mean square error of prediction (RMSEP) and of the root mean square error of the percentage deviation (RMSPD) obtained were 0.4% (v/v) and 7.2%, respectively. Additionally, a second model was built and used to evaluate the accuracy of the method. A model to quantify the essential oil of lemon grass was built and its concentration was predicted in the validation set and real perfume samples. The RMSEP and RMSPD obtained were 0.5% (v/v) and 6.9%, respectively, and the concentration of the essential oil of lemon grass in perfume agreed to the value informed by the manufacturer. The result indicates that the MCR algorithm is adequate to resolve the target chromatogram from the complex sample and to build multivariate models of GC*GC-FID data. PMID- 21704767 TI - Investigation into the voltammetric behaviour and detection of selenium(IV) at metal electrodes in diverse electrolyte media. AB - The voltammetric behaviour of selenium(IV) was studied at platinum and gold electrodes in sulphuric acid, perchloric acid and potassium chloride media as a basis for its voltammetric detection. The best voltammetric behaviour was recorded at gold electrodes with perchloric acid as the supporting electrolyte. The concomitant presence of metals, such as copper or lead, and of model biomolecules, such as bovine serum albumin, in the solution resulted in a deterioration of the electrochemical response for selenium(IV). Quantitative detection of selenium(IV) by square wave anodic stripping voltammetry at both a millimetre-sized gold disc electrode and a microband electrode array revealed linear responses to selenium concentration in the ranges 5-15 MUM and 0.1-10 MUM, respectively, with 60s preconcentration. The sensitivities were 6.4 MUA MUM(-1) cm(-2) and 100 MUA MUM(-1) cm(-2) at the disc and the microband array, respectively. The detection limit at the microband electrode array was 25 nM, illustrating the potentiality of such microelectrodes for the development of mercury-free analytical methods for the trace detection of selenium(IV). PMID- 21704768 TI - Analytical aspects of microRNA in diagnostics: a review. AB - MicroRNAs (miRNA) are short (~22 nucleotides) non-coding RNA molecules that regulate gene expression at the post-transcriptional level. Their expression is specific to cells and tissues and is temporally regulated. miRNAs are known to be involved in developmental and physiological processes, and their dysregulation leads to development of diseases. Since their profiles reflect pathological processes, miRNAs have recently been proposed as being useful in diagnostics as biomarkers of the onset, prognosis and risk of diseases, as well as in the classification of different types of cancer. The establishment of miRNA profiles that are representative of diseases and the detection of different types and levels of miRNA in samples are therefore critical milestones in diagnostics. miRNAs can be detected in blood and body fluids as well as in tissues, thus making non-invasive collection of samples possible. For a method to be useful in diagnostics, it should be simple, inexpensive and highly sensitive. Here, we will review current methods of detecting miRNAs and indicate the advantages and disadvantages of each techniques. We will then summarize some of the clinical evidence for the potential application of miRNAs as biomarkers in diagnostics. We conclude providing some general perspectives on the use of miRNAs in clinical situations, including therapeutic applications. PMID- 21704769 TI - An integrated experimental and analytical approach to the chemical state imaging of iron in brain gliomas using X-ray absorption near edge structure spectroscopy. AB - X-ray absorption near-edge structure spectroscopy is used for human neoplastic tissues in order to investigate distributions and chemical states of iron. The specimens used in this study were obtained intraoperatively from brain gliomas of different types and various grades of malignancy and from a control subject. An integrated experimental and analytical approach toward topographic and quantitative analysis in thin freeze-dried cryo-sections is presented. The full XANES spectra at the Fe absorption K edge show the presence of both chemical forms of Fe in the analyzed points of the tissues. The main goal of the work is the chemical state imaging of Fe in tissue areas. Topographic analysis of Fe speciation in the tissues investigated with the use of the XANES technique indicates the presence of microstructures where Fe(2+) is dominant as well as those with a high abundance of the oxidized form of Fe. The quantitative analysis shows that for all cases the content of the oxidized form of Fe is significantly higher in comparison with Fe(2+). The highest level of Fe(3+) is found in the control sample, and the lowest one for the glioma of the highest grade of malignancy. The content of either Fe(2+) or Fe(3+) is increased in low grade gliomas in comparison to high-grade malignant tumors. PMID- 21704770 TI - Optimization of the determination of chemical oxygen demand in wastewaters. AB - Chemical oxygen demand (COD) is one of the most relevant chemical parameters for the management of wastewater treatment facilities including the control of the quality of an effluent. The adequacy of decisions based on COD values relies on the quality of the measurements. Cost effective management of the minor sources of uncertainty can be applied to the analytical procedure without affecting measurement quality. This work presents a detailed assessment of the determination of COD values in wastewaters, according to ISO6060:1989 standard, which can support reduction of both measurement uncertainty and cost of analysis. This assessment includes the definition of the measurement traceability chain and the validation of the measurement procedure supported on sound and objective criteria. Detailed models of the measurement performance, including uncertainty, developed from the Differential Approach, were successfully validated by proficiency tests. The assumption of the measurement function linearity of the uncertainty propagation law was tested through the comparison with the numerical Kragten method. The gathered information supported the definition of strategies for measurement uncertainty or cost reduction. The developed models are available as electronic supplementary material, in an MS-Excel file, to be updated with the user's data. PMID- 21704771 TI - Application of graphene for preconcentration and highly sensitive stripping voltammetric analysis of organophosphate pesticide. AB - Electrochemical reduced beta-cyclodextrin dispersed graphene (beta-CD-graphene) was developed as a sorbent for the preconcentration and electrochemical sensing of methyl parathion (MP), a representative nitroaromatic organophosphate pesticide with good redox activity. Benefited from the ultra-large surface area, large delocalized pi-electron system and the superconductivity of beta-CD graphene, large amount of MP could be extracted on beta-CD-graphene modified electrode via strong pi-pi interaction and exhibited fast accumulation and electron transfer rate. Combined with differential pulse voltammetric analysis, the sensor shows ultra-high sensitivity, good selectivity and fast response. The limit of detection of 0.05 ppb is more than 10 times lower than those obtained from other sorbent based sensors. The method may open up a new possibility for the widespread use of electrochemical sensors for monitoring of ultra-trace OPs. PMID- 21704772 TI - Investigation of DGT as a metal speciation tool in artificial human gastrointestinal fluids. AB - This paper reports the results of an investigation on the performance of the diffusive gradient in thin film technique (DGT) as a speciation tool for trace elements (TEs) in artificial human gastrointestinal fluids. The validity of Cd, Pb, and Zn sampling by DGT in digestive fluids was checked. The TE bioaccessibility in highly contaminated soils was determined using the in vitro Unified Barge Method (UBM) test. DGT devices were deployed in the gastrointestinal solutions obtained after carrying out the UBM test. The computer speciation code JESS (Joint Expert Speciation System) was used to predict the metal speciation of Cd, Pb, and Zn. Combining the in vitro test with the DGT technique and JESS provided an approach to the TE species available for transport across the intestinal epithelium. The gastrointestinal absorption of ingested TE ranged from 8 to 30% for Cd, 0.6 to 11% for Pb, and 0.8 to 7% for Zn and was influenced by TE speciation. In this original approach, the DGT technique was found to be simple and reliable in the investigation of TE chemical speciation in digestive fluids. Extrapolation to the in vivo situation should be undertaken very cautiously and requires further investigation. PMID- 21704773 TI - Extraction tool and matrix effects on arsenic speciation analysis in cell lines. AB - Arsenic glutathione (As-GSH) complexes have been suggested as possible metabolites in arsenic (As) metabolism. Extensive research has been performed on the toxicological and apoptotic effects of As, while few reports exist on its metabolism at the cellular level due to the analytical challenges. In this study, an efficient extraction method for arsenicals from cell lines was developed. Evaluation of extraction tools; vortex, ultrasonic bath and ultrasonic probe and solvents; water, chemicals (methanol and trifluoroacetic acid), and enzymes (pepsin, trypsin and protease) was performed. GSH effect on the stability of As GSH complexes was studied. Arsenic metabolites in dimethylarsino glutathione (DMA(GS)) incubated multiple myeloma cell lines were identified following extraction. Intracellular GSH concentrations of myeloma cell lines were imitated in the extraction media and its corresponding effect on the stability and distribution of As metabolites was studied. An enhancement in both extraction recoveries and time efficiency with the use of the ultrasonic probe was observed. Higher stabilities for the As species in water, pepsin and trypsin were obtained. The presence of 0.5mM GSH in the extraction media (PBS, pH 7.4) could not stabilize the As-GSH complexes compared to the 5mM GSH, where high stabilization of the complexes was observed over a 5 day storage study. Finally, the speciation analysis of the DMA(GS) culture incubated cell lines in the presence or absence of GSH revealed the important role GSH plays in the preservation of DMA(GS) identity. Hence, caution is required during the extraction of arsenicals especially the As-GSH complexes, since their identification is highly dependent on GSH concentration. PMID- 21704774 TI - Quantum dots assisted photocatalysis for the chemiluminometric determination of chemical oxygen demand using a single interface flow system. AB - A novel flow method for the determination of chemical oxygen demand (COD) is proposed in this work. It relies on the combination of a fully automated single interface flow system, an on-line UV photocatalytic unit and quantum dot (QD) nanotechnology. The developed approach takes advantage of CdTe nanocrystals capacity to generate strong oxidizing species upon irradiation with UV light, which fostered a fast catalytic degradation of the organic compounds. Luminol was used as a chemiluminescence (CL) probe for indirect COD assessment, since it is easily oxidized by the QD generated species yielding a strong CL emission that is quenched in the presence of the organic matter. The proposed methodology allowed the determination of COD concentrations between 1 and 35 mg L(-1), with good precision (R.S.D.<1.1%, n=3) and a sampling frequency of about 33 h(-1). The procedure was applied to the determination of COD in wastewater certified reference materials and the obtained results showed an excellent agreement with the certified values. PMID- 21704775 TI - Dicyanostilbene-derived two-photon fluorescence probe for lead ions in live cells and living tissues. AB - A novel two-photon fluorescence probe for Pb(2+) derived from 4-methyl-2,5 dicyano-4'-amino stilbene as a two-photon fluorophore and bis[2-(2 aminophenylsulfanyls)ethyl]amine as a novel Pb(2+) ligand was developed. The probe possesses small molecule size, large two-photon absorption cross-section (1020 GM), noncytotoxic effect, long-wavelength emission at 609 nm, large Stokes shift (209 nm), excellent photostability, moderate water-solubility, good cell permeability, and pH-insensitivity in the biologically relevant pH range. The probe can selectively detect Pb(2+) ions in live cells and living tissues without interference from other metal ions and the membrane-bound probes, and its quenching constant (K(SV)(TP)) is 7.58*10(5) M(-1). PMID- 21704776 TI - Multi-step surface functionalization of polyimide based evanescent wave photonic biosensors and application for DNA hybridization by Mach-Zehnder interferometer. AB - The process of surface functionalization involving silanization, biotinylation and streptavidin bonding as platform for biospecific ligand immobilization was optimized for thin film polyimide spin-coated silicon wafers, of which the polyimide film serves as a wave guiding layer in evanescent wave photonic biosensors. This type of optical sensors make great demands on the materials involved as well as on the layer properties, such as the optical quality, the layer thickness and the surface roughness. In this work we realized the binding of a 3-mercaptopropyl trimethoxysilane on an oxygen plasma activated polyimide surface followed by subsequent derivatization of the reactive thiol groups with maleimide-PEG(2)-biotin and immobilization of streptavidin. The progress of the functionalization was monitored by using different fluorescence labels for optimization of the chemical derivatization steps. Further, X-ray photoelectron spectroscopy and atomic force microscopy were utilized for the characterization of the modified surface. These established analytical methods allowed to derive information like chemical composition of the surface, surface coverage with immobilized streptavidin, as well as parameters of the surface roughness. The proposed functionalization protocol furnished a surface density of 144 fmol mm( 2) streptavidin with good reproducibility (13.9% RSD, n=10) and without inflicted damage to the surface. This surface modification was applied to polyimide based Mach-Zehnder interferometer sensors to realize a real-time measurement of streptavidin binding validating the functionality of the MZI biosensor. Subsequently, this streptavidin surface was employed to immobilize biotinylated single-stranded DNA and utilized for monitoring of selective DNA hybridization. These proved the usability of polyimide based evanescent photonic devices for biosensing application. PMID- 21704778 TI - A membrane-based immunosensor for the analysis of the herbicide isoproturon. AB - A membrane based heterogeneous competitive enzyme-linked immunosorbent assay (ELISA) was used in this work to develop an immunosensor for the detection of a common herbicide, isoproturon. A screen-printed carbon working electrode with carbon counter and silver-silver chloride pseudo-reference electrode was utilized incorporating a membrane fixed into intimate contact with the working electrode to facilitate signal transduction. The membrane containing an immobilized isoproturon-ovalbumin conjugate was laminated onto the carbon working electrode and horseradish peroxidase (HRP) labeled polyclonal antibody was then applied for the competitive assay. Two different amperometric systems, hydroquinone and o phenylenediamine (OPD) mediation reduction were utilised and the properties of the resultant sensors were compared. A flow injection apparatus was also developed utilising the immunosensor. Limits of detection for isoproturon (LLD(90)) were found to be as low as 0.84 ng mL(-1). The senor was also validated using spiked extracted soil samples and also isoproturon contaminated samples. PMID- 21704777 TI - A new light emitting diode-light emitting diode portable carbon dioxide gas sensor based on an interchangeable membrane system for industrial applications. AB - A new system for CO(2) measurement (0-100%) based on a paired emitter-detector diode arrangement as a colorimetric detection system is described. Two different configurations were tested: configuration 1 (an opposite side configuration) where a secondary inner-filter effect accounts for CO(2) sensitivity. This configuration involves the absorption of the phosphorescence emitted from a CO(2) insensitive luminophore by an acid-base indicator and configuration 2 wherein the membrane containing the luminophore is removed, simplifying the sensing membrane that now only contains the acid-base indicator. In addition, two different instrumental configurations have been studied, using a paired emitter-detector diode system, consisting of two LEDs wherein one is used as the light source (emitter) and the other is used in reverse bias mode as the light detector. The first configuration uses a green LED as emitter and a red LED as detector, whereas in the second case two identical red LEDs are used as emitter and detector. The system was characterised in terms of sensitivity, dynamic response, reproducibility, stability and temperature influence. We found that configuration 2 presented a better CO(2) response in terms of sensitivity. PMID- 21704779 TI - Label-free capacitive immunosensors for ultra-trace detection based on the increase of immobilized antibodies on silver nanoparticles. AB - Detection of ultra-trace amounts of antigens by label-free capacitive immunosensors was investigated using electrodes modified with silver nanoparticles (AgNPs) that allows for an increase in the amount of immobilized antibodies. The optimal amount of AgNPs that provided the highest immobilization yield was 48 pmol (in 2.0 mL). The performances of immunosensor electrodes for human serum albumin prepared with AgNPs, were compared to electrodes prepared with gold nanoparticles. The two systems provided the same linear range (1.0*10( 18) to 1.0*10(-10) M) and detection limit (1.0*10(-18) M). The system with AgNPs was used to analyze albumin in urine samples and the results agreed well with the immunoturbidimetric assay (P>0.05). Electrodes modified with AgNPs and appropriate antibodies were tested for their performances to detect analytes of different sizes. For a macromolecule (human serum albumin) the incorporation of AgNPs improved the detection limit from 100 to 1 aM. For small molecules, microcystin-LR and penicillin G, the detection limits were lowered from 100 and 10 fM to 10 and 0.7 fM, respectively. The high sensitivity and very low detection limits are potentially useful for the analysis of toxins or residues present in samples at ultra-trace levels and this method could easily be applied to other affinity pairs. PMID- 21704780 TI - Analysis of urinary neurotransmitters by capillary electrophoresis: sensitivity enhancement using field-amplified sample injection and molecular imprinted polymer solid phase extraction. AB - Capillary electrophoresis (CE) has been investigated for the analysis of some neurotransmitters, dopamine (DA), 3-methoxytyramine (3-MT) and serotonin (5 hydroxytryptamine, 5-HT) at nanomolar concentrations in urine. Field-amplified sample injection (FASI) has been used to improve the sensitivity through the online pre-concentration samples. The cationic analytes were stacked at the capillary inlet between a zone of low conductivity - sample and pre-injection plug - and a zone of high conductivity - running buffer. Several FASI parameters have been optimized (ionic strength of the running buffer, concentration of the sample protonation agent, composition of the sample solvent and nature of the pre injection plug). Best results were obtained using H(3)PO(4)-LiOH (pH 4, ionic strength of 80 mmol L(-1)) as running buffer, 100 MUmol L(-1) of H(3)PO(4) in methanol-water 90/10 (v/v) as sample solvent and 100 MUmol L(-1) of H(3)PO(4) in water for the pre-injection plug. In these conditions, the linearity was verified in the 50-300 nmol L(-1) concentration range for DA, 3-MT and 5-HT with a determination coefficient (r(2)) higher than 0.99. The limits of quantification (10 nmol L(-1) for DA and 3-MT, 5.9 nmol L(-1) for 5-HT) were 500 times lower than those obtained with hydrodynamic injection. However, if this method is applied to the analysis of neurotransmitters in urine, the presence of salts in the matrix greatly reduces the sensitivity of the FASI/CE-UV method.Therefore, a solid phase extraction (SPE) on a dedicated imprinted polymer (MIP) was developed to extract specific neurotransmitters, catecholamines, metanephrines and indolamines, from urine. Matrix salts were thus discarded after sample extraction on AFFINIMIPTM Catecholamine & Metanephrine (100mg) cartridge. Therefore, lower limits of quantification were determined in artificial urine (46 nmol L(-1) for DA, 11 nmol L(-1) for 3-MT and 6 nmol L(-1) for 5-HT).The application of this protocol MIP-SPE/FASI-CE-UV analysis of neurotransmitters in human urine gave rise to electropherograms with a very good base line and signal to noise ratios above 15. PMID- 21704781 TI - The relationship between quality of life and change in mobility 1 year postinjury in individuals with spinal cord injury. AB - OBJECTIVE: To examine quality-of-life (QOL) factors and change in mobility in individuals with traumatic spinal cord injury (SCI) 1 year after injury. DESIGN: Retrospective case study of National SCI Database data. SETTING: SCI Model Systems (SCIMS) sites (N=18). PARTICIPANTS: Subjects (N=1826; age >18y) who presented to an SCIMS site after traumatic SCI between June 2004 and July 2009 and returned for 1-year follow-up. All subjects had FIM mobility data for both assessments. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Assessment of impairment based on Lower-Extremity Motor Score. Assessment of QOL based on Craig Handicap Assessment and Reporting Technique, Patient Health Questionnaire, Satisfaction With Life Scale, Self-perceived Health Status, and pain severity scores. RESULTS: Of the sample, 55 individuals transitioned from walking to wheelchair use within 1 year of discharge. This group had the highest number of individuals from minority groups (52.8%) and the lowest employment rate (7.3%). Compared with individuals who transitioned from wheelchair use to walking or maintained wheelchair use or ambulation, the walking-to-wheelchair transition group had significantly lower QOL scores (P<.01), including higher depression (P<.01) and higher pain severity (P<.001). CONCLUSIONS: Individuals with SCI who transitioned from walking at discharge to wheelchair use within 1 year had low QOL factors, including high pain and depression scores. Rehabilitation professionals should consider encouraging marginal ambulators to work toward functional independence from a wheelchair, rather than primary ambulation during acute inpatient rehabilitation. PMID- 21704782 TI - Efficacy of intra-articular injection of botulinum toxin type A in refractory hemiplegic shoulder pain. AB - OBJECTIVE: To evaluate the efficacy of intra-articular injection of botulinum toxin type A (BTX-A) in relieving hemiplegic shoulder pain (HSP). DESIGN: Pilot study with assessments before and after BTX-A intra-articular injection. SETTING: Hospital rehabilitation department. PARTICIPANTS: Patients (N=5) with HSP refractory to standard treatments and pain score at rest greater than 7 on a pain visual analog scale (VAS) of 0 to 10cm. INTERVENTION: Intra-articular BTX-A injection. MAIN OUTCOME MEASURE: Variation in VAS score at rest and during 90 degrees passive arm abduction 2 and 8 weeks after BTX-A intra-articular injection. RESULTS: Baseline VAS score was 8.7+/-1 at rest and 9.8+/-0.4 during passive arm abduction. It clearly decreased at 2 (1.5+/-1.1 at rest, P=.001; 3+/ 1.2 during arm abduction, P<.001) and 8 weeks (1.5+/-1.2 at rest, P=.001; 2.3+/ 1.1 during arm abduction, P<.001) after BTX-A intra-articular injection. CONCLUSIONS: We found a strong correlation between intra-articular BTX-A injection and pain relief in patients with HSP. This result could provide the rationale for blind randomized controlled trials designed to better evaluate the safety and efficacy of intra-articular BTX-A injection in patients with refractory HSP. PMID- 21704783 TI - Aerobic exercise to improve cognitive function in adults with neurological disorders: a systematic review. AB - OBJECTIVE: To evaluate whether aerobic exercise improves cognition in adults diagnosed with neurologic disorders. DATA SOURCES: The Cochrane Central Register of Controlled Clinical Trials, MEDLINE, CINAHL, PubMed, EMBASE, PEDro, AMED, SPORTDiscus, PsycINFO, ERIC, and Google Scholar, with the last search performed in December 2010. STUDY SELECTION: We included controlled clinical trials and randomized controlled trials with adults diagnosed with a neurologic disorder. Studies were included if they compared a control group with a group involved in an aerobic exercise program to improve cardiorespiratory fitness and if they measured cognition as an outcome. DATA EXTRACTION: Two reviewers independently extracted data and methodologic quality of the included trials. DATA SYNTHESIS: From the 67 trials reviewed, a total of 7 trials, involving 249 participants, were included. Two trials compared the effectiveness of yoga and aerobic exercise in adults with multiple sclerosis. Two trials evaluated the effect of exercise on patients with dementia, and 2 trials evaluated the effectiveness of exercise to improve cognition after traumatic brain injury. One trial studied the effect of a cycling program in people with chronic stroke. Lack of commonality between measures of cognition limited meta-analyses. Results from individual studies show that aerobic exercise improved cognition in people with dementia, improved attention and cognitive flexibility in patients with traumatic brain injury, improved choice reaction time in people with multiple sclerosis, and enhanced motor learning in people with chronic stroke. CONCLUSIONS: There is limited evidence to support the use of aerobic exercise to improve cognition in adults with neurologic disorders. Of the 67 studies retrieved, less than half included cognition as an outcome, and few studies continued the aerobic exercise program long enough to be considered effective. Further studies investigating the effect of aerobic exercise interventions on cognition in people with neurologic conditions are required. PMID- 21704784 TI - Sex differences in lumbopelvic movement patterns during hip medial rotation in people with chronic low back pain. AB - OBJECTIVE: To examine sex differences in lumbopelvic motion and symptom behavior during hip medial rotation in people with low back pain (LBP). We hypothesized that men would demonstrate greater and earlier lumbopelvic motion and would be more likely to report increased symptoms compared with women. DESIGN: Cross sectional observational study. SETTING: University musculoskeletal analysis laboratory. PARTICIPANTS: Persons with chronic LBP (N=59; 30 men, 29 women) were recruited from the community and a university-based physical therapy clinic. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Lumbopelvic rotation range of motion, amount of hip rotation completed before the start of lumbopelvic motion, and provocation of LBP symptoms during the test of prone hip medial rotation were measured. RESULTS: Men demonstrated significantly more lumbopelvic rotation (men, 10.0 degrees +/-5.1 degrees ; women, 4.5 degrees +/-3.9 degrees ; P<.001) and completed less hip rotation before the start of lumbopelvic motion (men, 5.4 degrees +/-3.8 degrees ; women, 16.0 degrees +/-13.2 degrees ; P<.001) compared with women. Additionally, a significantly greater percentage of men (60.0%) than women (34.5%; P=.050) reported increased symptoms with hip medial rotation. CONCLUSIONS: Men could be at greater risk than women for experiencing LBP symptoms related to hip medial rotation as a result of greater and earlier lumbopelvic motion. PMID- 21704785 TI - Reliability and validity of the Shaw gait assessment tool for temporospatial gait assessment in people with hemiparesis. AB - OBJECTIVE: To assess the intra-/interrater reliability and the validity of the free web-based Shaw Gait Assessment Tool (with visual and numerical output) for assessing speed, cadence, step length, and limb advance time in people with hemiplegic gait. DESIGN: Intra-/interrater reliability and concurrent validity with 2 raters using the Shaw Gait Assessment Tool and 1 rater using a multimemory stopwatch. SETTING: Busy outpatient rehabilitation gym at a tertiary care medical center. PARTICIPANTS: Convenience sample of adults with hemiplegic gait after cerebrovascular accident or traumatic brain injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Intraclass correlation coefficients (ICCs) and Pearson product-moment correlation coefficients. RESULTS: ICCs for intrarater reliability ranged from 0.94 (95% CI, 0.88-0.97) to 0.98 (95% CI, 0.96-0.99), (P<.001), and for interrater reliability from 0.95 (95% CI, 0.88-0.98) to 0.99 (95% CI, 0.99-0.99), (P<.001). The Shaw Gait Assessment Tool correlated with the stopwatch for all measured gait parameters with Pearson product-moment correlation coefficients (range, r=0.95 to r= 0.99, P<.001). CONCLUSIONS: The Shaw Gait Assessment Tool is a free, easy-to-use tool that gives reliable and valid results for 4 temporospatial parameters of hemiplegic gait. PMID- 21704786 TI - Long-term effects of structured home-based exercise program on functional capacity and quality of life in patients with intermittent claudication. AB - OBJECTIVES: To evaluate effects of a structured home-based exercise program on functional capacity and quality of life (QoL) in patients with intermittent claudication (IC) after 1-year follow-up, and to compare these results with those from a concurrent control group who received supervised exercise training (SET). DESIGN: Comparative longitudinal cohort study. SETTING: Referral center. PARTICIPANTS: Patients (N=142) with IC. INTERVENTIONS: Structured home-based exercise training or SET. MAIN OUTCOME MEASURES: The maximum (pain-free) walking distance and the ankle-brachial index (ABI) (at rest and postexercise) were measured at baseline and after 6 and 12 months' follow-up. Additionally, QoL was evaluated using a self-administered questionnaire consisting of the Euroqol-5D (scale 0-1), rating scale (scale 0-100), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36; scale 0-100), and the Vascular Quality of Life Questionnaire (VascuQol; scale 1-7). Comparison of the groups was performed with adjustment for the nonrandomized setting using propensity scoring. RESULTS: One hundred forty-two patients with IC started the structured home-based exercise program, of whom 95 (67%) completed 12 months' follow-up. The mean relative improvement compared with baseline was statistically significant after 12 months' follow-up for the maximum and pain-free walking distance (342%, 95% confidence interval [CI], 169-516; P<.01 and 338%, 95% CI, 42-635; P=.03, respectively) and for the ABI postexercise (mean change, .06; 95% CI, .01-.10; P=.02). For the QoL outcomes, the improvement compared with baseline was statistically significant after 12 months for the VascuQol (mean change, .42; 95% CI, .20-.65; P<.01) and for the SF-36 physical functioning (mean change, 5.17; 95% CI, .77-9.56; P=.02). Compared with the structured home-based exercise program, patients in the control group showed significantly better results in the mean relative improvement of maximum and pain-free walking distance and change in the ABI at rest after 12 months' follow-up. CONCLUSIONS: Structured home-based exercise training is effective in improving both functional capacity and QoL in patients with IC and may be considered as a feasible and valuable alternative toSET, since supervised exercise programs are not often available. PMID- 21704787 TI - Sensorimotor and psychosocial correlates of adaptive locomotor performance in older adults. AB - OBJECTIVE: To identify sensorimotor and psychosocial factors independently associated with an inability to perform adaptive walking tasks in older adults. DESIGN: Cross-sectional cohort study. SETTING: Population-based older cohort. PARTICIPANTS: Community-living elderly (N=720; age >=65y) who could walk 7m at self-selected normal speed. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Walking performance was assessed in 4 walking tests: fast walking, obstacle crossing, narrow-based walking, and walking while talking. Possible correlates of the inability to perform the walking test included knee extensor strength, lower limb coordination, Cumulative Somatosensory Impairment Index (CSII), visual acuity and contrast sensitivity, cognition, depression, personal mastery, social support, and years of education. RESULTS: The results of binary logistic regression analyses, adjusted for demographics and self-selected normal speed, demonstrated that poor knee extensor strength was associated with an inability to perform tasks demanding an increase in walking speed (fast walking and obstacle crossing). Both poor lower limb coordination and higher CSII were significantly associated with failure in tests that demanded precise control over foot placement (obstacle crossing and narrow-based walking). Higher CSII was associated with failure in all tests except in the walking while talking. In contrast, poor cognition was associated with an inability to perform walking while talking. Poor personal mastery was the only variable that was associated with failure in all walking tests. CONCLUSIONS: The results demonstrated a systematic and coherent pattern in these associations and indicated possible sensorimotor and psychological parameters that should be specifically investigated and should be intervened if a patient reports a difficulty/inability in walking in certain situations. PMID- 21704788 TI - Minimal chair height standing ability is independently associated with falls in Taiwanese older people. AB - OBJECTIVE: To determine whether a test of minimal chair height standing (MCHS) ability is an important predictor of fall risk in community-dwelling older people living in Taiwan, and whether poor performance in this test is associated with impaired sensorimotor functioning, balance, and mobility in this group. DESIGN: Cross-sectional study. SETTING: Community based. PARTICIPANTS: Community-dwelling participants (N=280; mean age, 74.9y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The MCHS test, which measures the lowest height from which a participant can stand; the Physiological Profile Assessment (PPA); and a range of functional balance and mobility tests. RESULTS: In the 12 months before the study, 81 participants (28.9%) experienced 1 or more falls. The fallers had significantly higher MCHS scores compared with the nonfallers: 29.7+/-9.0 and 25.0+/- 9.2cm, respectively. Fallers also had significantly higher PPA fall risk scores than nonfallers and performed significantly worse in tests of reaction time, standing and leaning balance, and alternate stepping ability. Discriminant function analysis revealed that poor performance in the MCHS and high PPA scores were both independently and significantly associated with falls. These 2 variables correctly classified 64.5% of participants into faller and nonfaller groups. Participants who reported regular squatting performed significantly better in the MCHS test, and multiple regression analysis revealed that impaired knee extension strength, poor single-leg stance ability, and reduced leaning balance were independent predictors of poor MCHS. CONCLUSIONS: In this study, MCHS was an independent risk factor for falls. It is a functional test similar to deep squatting and underpinned by strength and balance. Because the MCHS is quick to administer, it may have scope for clinical application. PMID- 21704789 TI - Validity, responsiveness, and clinically important difference of the ABILHAND questionnaire in patients with stroke. AB - OBJECTIVE: To investigate the criterion-related validity, responsiveness, and clinically important differences of the ABILHAND questionnaire in patients with stroke. DESIGN: Validation and clinimetric study. SETTING: Three medical centers. PARTICIPANTS: Patients with stroke (N=51). INTERVENTIONS: A total of 51 patients with stroke received 1 of 3 upper extremity rehabilitation programs for 4 weeks. MAIN OUTCOME MEASURES: The ABILHAND and the criterion measures, including the Stroke Impact Scale (SIS), FIM, Nottingham Extended Activities of Daily Living (NEADL), and accelerometers, were administered at pretreatment and posttreatment. The score of the ABILHAND, given in logits, was based on the conversion of the ordinal score into a linear measure of ability. RESULTS: Correlation coefficients (Pearson r) were moderate to large between the ABILHAND and SIS physical domains (.54-.66), fair to moderate between the ABILHAND and FIM-motor and NEADL (.28 .48), and moderate between the ABILHAND and accelerometer data (.45-.54). The responsiveness of the ABILHAND was large (standardized response mean=1.27). The minimal clinically important difference range for the ABILHAND was .26 to .35, and 51.0% of the patients showed a positive change that exceeded the lower bound of a clinically important difference after intervention. CONCLUSIONS: The results support that the ABILHAND is an appropriate outcome measure for assessing upper extremity performance in daily activities in patients with stroke and is sensitive to detect change after rehabilitative interventions. The change score of a patient with stroke on the ABILHAND should reach .26 to .35 logits points to be regarded as a clinically important change. PMID- 21704790 TI - Body composition assessment in Taiwanese individuals with poliomyelitis. AB - OBJECTIVES: To measure the changes in the total and regional body fat mass, and assess the clinical usefulness of the body mass index (BMI) in detecting overweight subjects with sequelae of poliomyelitis. DESIGN: Prospective, cross sectional study. SETTING: General community. PARTICIPANTS: Subjects with poliomyelitis (n=17; age range, 42-57y; mean, 47y; 12 men, 5 women) and able bodied people (n=17) matched by sex, age, body weight, and body height participated in the study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Total and regional body composition was measured with dual-energy x-ray absorptiometry. Clinical characteristics such as blood pressure, serum biochemical studies, and habitual behaviors (daily cigarette smoking, alcohol consumption, and exercise regimen) of all participants were evaluated. RESULTS: Compared with able-bodied controls, subjects with poliomyelitis had a 50% greater total body fat mass, significant increases in the regional fat mass in every part of the body, and had the greatest increase of fat mass in the thorax. Nearly all the subjects (94%) with poliomyelitis were obese according to standards of body composition. However, one third of them had a BMI value of less than 25.0kg/m(2). CONCLUSIONS: People with poliomyelitis have a higher prevalence of obesity and a significant increase in total and regional fat mass. Current BMI underestimates the total body fat mass percentage compared with the control; therefore, a population-specific BMI should be used to address the prevalence of obesity in postpolio survivors. PMID- 21704791 TI - Construct validity of the stroke-specific quality of life questionnaire in ischemic stroke patients. AB - OBJECTIVES: To investigate the construct validity of the commonly used 8- and 12 domain versions of the Stroke-Specific Quality of Life (SS-QOL) with a first order factor model. The better-fitted version was further evaluated by a second order factor structure model in order to determine whether a summary score is justified. DESIGN: Cohort study. SETTING: Outpatient stroke clinic. PARTICIPANTS: Patients (N=388) with ischemic stroke. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The SS-QOL. We first conducted confirmatory factor analysis (CFA) to evaluate the construct validity of the first-order 8- or 12-domain versions of the SS-QOL. The better-fitted version was then validated by investigating the second-order health-related quality of life (HRQOL) factor. RESULTS: The 12 domain version, but not the 8-domain version, had sufficient goodness of fit (chi(2)=2041.7, df=1061, chi(2)/df=1.9, comparative fit index [CFI]=0.98, Tucker Lewis index [TLI]=0.98, and root mean square error of approximation=0.05). All items of the 12-domain version showed acceptable factor loadings (>0.40) and were retained. Furthermore, the second-order CFA fit indices of the 12 domains were acceptable (chi(2)=2630.3, df=1115, chi(2)/df=2.4, CFI=0.97, TLI=0.97, root mean square error of approximation=0.06), indicating that a summary score was justified for representing the overall status of HRQOL. CONCLUSIONS: Our results show that the construct validity of the 12-domain SS-QOL is well supported for measuring HRQOL in ischemic stroke patients. Thus, we recommend the 12-domain version of the SS-QOL for use in capturing the multiple impacts of stroke as well as overall HRQOL status on the basis of patients' perspectives. PMID- 21704792 TI - Development of a set of functional hierarchical balance short forms for patients with stroke. AB - OBJECTIVE: To develop a set of 3 hierarchical balance short forms (HBSF; containing sitting, standing, and stepping forms) to measure balance function in patients with stroke. DESIGN: First, we developed the HBSF, based on a previous data set, with each short form containing 6 items. Second, we examined the psychometric properties and efficiency of the HBSF. SETTING: Six teaching hospitals. PARTICIPANTS: Patients with stroke (n=764) for the first part of this study; inpatients and outpatients (n=85) for the second part of this study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We used the item bank (9 sitting-related, 14 standing-related, and 13 stepping-related items) from the Balance Computerized Adaptive Test to develop the HBSF. Both the HBSF and the Berg Balance Scale (BBS) were administered to patients, to determine the concurrent validity and time needed for administration of both measures. Each patient was assessed by 1 of the 3 short forms selected by a rater. RESULTS: The reliability of the HBSF was relatively high (reliability coefficients, .94-.95). The scores of the HBSF were highly correlated with those of the BBS (Spearman rho=.80-.91), supporting the concurrent validity of the HBSF. The average time needed to administer the HBSF was 122 seconds (ie, about 40% of that for the BBS). CONCLUSIONS: Our results provide sufficient evidence that the HBSF is an efficient, reliable, valid, and practical way to measure balance function in patients with stroke. PMID- 21704793 TI - Fatigue and aging with a disability. AB - OBJECTIVE: To compare self-reported fatigue in 4 disability populations with age matched, U.S. population norms. We assessed fatigue and age in a sample of individuals with spinal cord injury (SCI), postpolio syndrome (PPS), multiple sclerosis (MS), and muscular dystrophy (MD). DESIGN: This study used survey responses and published age cohort means for fatigue to test the hypothesis that fatigue would be higher in each of 4 clinical samples than the U.S. population norm. We also hypothesized that, for clinical samples, the mean fatigue reported within age cohorts would be higher than the general U.S. population norms for those age ranges derived in the Patient-Reported Outcomes Measurement Information System (PROMIS). SETTING: Survey responses were collected from participants in the Washington state area. PARTICIPANTS: Participants (N=1836) were persons with MD (n=337), MS (n=580), Post-polio (n=441), and SCI (n=478). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: PROMIS Depression Short Form. RESULTS: Individuals with disabilities reported higher levels of fatigue than the normative PROMIS population. In the normative population, self-reported fatigue was substantially lower in age cohorts from middle age to retirement age. However, individuals with disabilities did not demonstrate this age cohort effect. CONCLUSIONS: Individuals with disabilities are not only at greater risk to experience fatigue, but this risk, relative to normative values, increases with age. More research is needed to determine the specific negative impact of fatigue symptoms on functioning in individuals with disabilities as they age. PMID- 21704794 TI - Urologic dysfunction and neurologic outcome in coma survivors after severe traumatic brain injury in the postacute and chronic phase. AB - OBJECTIVES: To investigate voiding dysfunction and upper urinary tract status in survivors of coma resulting from traumatic brain injury (TBI), and to compare clinical and urodynamic results with neurologic and psychological features as well as functional outcomes. DESIGN: Observational study focused on urologic dysfunction and neurologic outcome in coma survivors after traumatic brain injury in the postacute and chronic phase. SETTING: A postcoma unit in a rehabilitation hospital. PARTICIPANTS: Consecutive patients (N=57) who recovered from coma of traumatic etiology and who were admitted during a 1-year period to a postcoma unit of a rehabilitation hospital. INTERVENTIONS: Patients underwent clinical urologic assessment, urodynamics with the assessment of the Schafer nomogram and the projected isovolumetric detrusor pressure to evaluate detrusor contractility, ultrasound assessment of the lower and upper urinary tract and voiding cystourethrography, routinely performed, according to the International Continence Society Standards. Neurologic variables assessed were brain injury and disability severity, and neuropsychological status. Neuroimaging identified the site of cerebral lesions. MAIN OUTCOME MEASURES: Urinary symptoms, disability by means of the Glasgow Outcome Scale (GOS), and neuropsychological status by means of the Neurobehavioral Rating Scale (NBRS), and the relationships among them. RESULTS: Of the 57 patients studied, 30 had overactive bladder (urge incontinence) symptoms, 28 had detrusor overactivity, and 18 had detrusor underactivity with associated pseudodyssynergia in 15 of these patients. Eleven patients had hypertrophic bladder; 3, bilateral pyelectasia; and 2, vesicoureteral reflux. Disability measured by GOS was severe in 8 patients and moderate in 27, while recovery was good in 22 patients. The mean NBRS total score indicated a mild cognitive impairment. Neuroimaging showed diffuse brain injury in all patients. Statistically significant relationships were found between urge incontinence, detrusor overactivity, and poor neurologic functional outcome, between detrusor overactivity and right hemisphere damage (P=.0001), and between impaired detrusor contractility and left hemisphere injuries (P=.0001). CONCLUSIONS: Most patients who recovered from coma resulting from TBI have symptoms of overactive bladder syndrome and voiding difficulties. These urinary problems correlate with cerebral involvement and neurologic functional outcome. PMID- 21704795 TI - Persistent shoulder pain in the first 6 months after stroke: results of a prospective cohort study. AB - OBJECTIVE: To identify factors associated with persistent poststroke shoulder pain (pPSSP) in the first 6 months after stroke. DESIGN: Prospective inception cohort study. SETTING: Stroke units of 2 teaching hospitals. PARTICIPANTS: Patients (N=31) with a clinical diagnosis of stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The development of pPSSP within the first 6 months after stroke. Clinical assessment of motor, somatosensory, cognitive, emotional, and autonomic functions, undertaken within 2 weeks (t0), at 3 months (t1), and at 6 months (t2) after stroke. RESULTS: Patients with pPSSP (n=9) were compared with patients without pPSSP (n=22). Bivariate logistic regression analyses showed that pPSSP was significantly associated with impaired voluntary motor control (t0, t1, t2), diminished proprioception (t0, t1), tactile extinction (t0), abnormal sensation (t1, t2), spasticity of the elbow flexor muscles (t1, t2), restricted range of motion (ROM) for both shoulder abduction (t2) and shoulder external rotation (t1, t2), trophic changes (t1), and type 2 diabetes mellitus (t0). CONCLUSIONS: These findings suggest a multifactorial etiology of pPSSP. The association of pPSSP with restricted, passive, pain-free ROM and signs indicative of somatosensory sensitization may implicate a vicious cycle of repetitive (micro)trauma that can establish itself rapidly after stroke. Intervention should therefore be focused on maintaining and restoring joint ROM as well as preventing injury and somatosensory sensitization. In this perspective, strategies that aim to intervene simultaneously at various levels of function can be expected to be more effective than treatment directed at merely 1 level. PMID- 21704796 TI - Impaired joint proprioception at higher shoulder elevations in chronic rotator cuff pathology. AB - OBJECTIVES: To assess the degree of impairment of shoulder proprioceptive acuity in individuals with chronic rotator cuff pathology (CRCP), and to examine the effect of impingement-related shoulder pain on acuity using a reliable laboratory technique. DESIGN: Case-control study. SETTING: University human movement laboratory. PARTICIPANTS: A volunteer sample of individuals with CRCP (n=26) were recruited and screened, and compared with age-, sex-, and limb dominance-matched individuals (n=30) who acted as controls. Ten participants with CRCP underwent repeat assessment after 2 days to determine the intrarater reliability of proprioceptive measurement. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Each participant underwent assessment of joint position sense at 40 degrees and 100 degrees of scapular plane abduction using an active position-matching task. Movements were recorded with reflective skin markers and a multidimensional motion analysis system. Self-reported pain intensity associated with the procedure was recorded with a visual analog scale. RESULTS: Intraclass correlation coefficients (model 3,5) between repeat assessments ranged from .54 to .99. On average, those with CRCP demonstrated reduced acuity at 40 degrees and 100 degrees test angles. In comparison with the control group, proprioceptive acuity was significantly impaired (P<.01) at the 100 degrees test angle, where the pain intensity was significantly greater (P<.01). CONCLUSIONS: This study demonstrated impairment of shoulder joint position sense in CRCP. The degree of proprioceptive impairment was greatest at higher elevations in the setting of increased shoulder impingement and pain, which may serve to perpetuate the pathology. These findings provide a theoretic rationale for the continued implementation of proprioceptive rehabilitation programs in managing CRCP. PMID- 21704797 TI - Reproducibility and validity of patient-rated assessment of speech, swallowing, and saliva control in Parkinson's disease. AB - OBJECTIVE: To report on the development and psychometric evaluation of the Radboud Oral Motor Inventory for Parkinson's Disease (ROMP), a newly developed patient-rated assessment of speech, swallowing, and saliva control in patients with Parkinson's disease (PD). DESIGN: Reliability and validity study. SETTING: Tertiary-care Parkinson center for multidisciplinary assessment. PARTICIPANTS: Consecutive community-dwelling patients with PD (n=129) or atypical parkinsonism (AP; n=49; mean +/- SD age, 64+/-9.8y; mean +/- SD disease duration, 7y; median Hoehn and Yahr [HY] stage, 2.5). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: To evaluate reproducibility, 60 patients completed the ROMP twice within a mean of 24+/-12 days. To study validity, another cohort of 118 patients who had completed the ROMP was assessed by both a neurologist (HY stage, Unified Parkinson's Disease Rating Scale III) and speech-language pathologist (severity of dysarthria, dysphagia, drooling) who were blinded to ROMP scores. RESULTS: Confirmatory factor analysis identified the 3 a priori-designed ROMP domains of speech, swallowing, and saliva control. Internal consistency was .95 for the total ROMP and .87 to .94 for the 3 domains or subscales. Intraclass correlation coefficients for reproducibility were .94 and .83 to .92 for the subscales. Construct validity was substantial to good with correlations ranging from .36 to .82. The ROMP differentiated significantly (P<.001) between patients indicated for speech therapy (based on independent assessment) and those who were not and between mild, moderate, and severe PD according to HY stage. CONCLUSIONS: The ROMP provides a reliable and valid instrument to evaluate patient-perceived problems with speech, swallowing, and saliva control in patients with PD or AP. PMID- 21704798 TI - Freezing of gait and activity limitations in people with Parkinson's disease. AB - OBJECTIVES: To investigate the relationships between freezing of gait (FOG) and activity limitations in ambulant people with Parkinson's disease (PD), and to explore the contribution of FOG and gait hypokinesia to activity limitations after adjusting for the effects of disease severity. DESIGN: Retrospective, cross sectional design. SETTING: Participants were recruited from neurologists' clinics and the general public in metropolitan Melbourne, Australia. PARTICIPANTS: Volunteers were screened for eligibility using the following inclusion criteria: diagnosis of idiopathic PD, modified Hoehn and Yahr stages 0 to IV, without dementia. Participants (N=210) were tested (mean age +/- SD, 67.9+/-9.6y; mean PD duration +/- SD, 6.7+/-5.6y; median Hoehn and Yahr stage=2.5). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FOG was measured using the FOG questionnaire. Gait hypokinesia was quantified using both the 6-meter walk test and the Timed Up and Go test. Activity limitation was measured using the modified Unified Parkinson's Disease Rating Scale activities of daily living (ADL) section and the Schwab and England ADL scale. RESULTS: Severity of gait freezing correlated significantly with the level of activity limitation (Spearman correlation coefficient, rho=-.49 to .48; P<.001). A hierarchic regression model showed that disease severity explained 37.5% of the variance in Schwab and England ADL score (P<.001). Gait hypokinesia and FOG severity scores explained an additional 9.1% of the variance in activity limitation (R(2) change=.091; P<.001). CONCLUSIONS: FOG severity and gait hypokinesia were associated with reduced levels of activity after adjusting for disease severity. PMID- 21704799 TI - Effectiveness of interventions for secondary Raynaud's phenomenon: a systematic review. AB - OBJECTIVES: To present an evidence-based overview of the effectiveness of (non)surgical symptomatic interventions to treat secondary Raynaud's phenomenon (RP). DATA SOURCES: The Cochrane Library, PubMed, Embase, PEDro, and CINAHL were searched for relevant systematic reviews and randomized controlled trials (RCTs). STUDY SELECTION: Two reviewers independently applied the inclusion criteria to select potential studies. DATA EXTRACTION: Two reviewers independently extracted data and assessed the methodologic quality. DATA SYNTHESIS: If pooling of data was not possible, a best-evidence synthesis was used to summarize the results. Of the 5 reviews and 19 RCTs included, 1 RCT studied acupuncture and another RCT reported on percutaneous radiofrequency thoracic sympathectomy. All others concentrated on the effectiveness of drugs (oral or intravenous [IV]). It appeared that calcium channel blockers significantly reduce the frequency and severity of Raynaud attacks, and are therefore effective in the treatment of secondary RP. Iloprost (oral and IV) was also found to be effective. Limited evidence was found for atorvastatin. For other traditional and more recently discovered interventions, no clear favorable effects were found. CONCLUSIONS: This review shows that there is clear evidence in favor of calcium channel blockers and iloprost (oral and IV) to treat secondary RP. For all other interventions, only limited, conflicting, or no evidence was found. More high quality, well-designed RCTs are needed in this field, especially for new interventions based on recent knowledge about the pathophysiology of secondary RP. PMID- 21704800 TI - Disorders of consciousness: recommendations are welcome but further guidance is needed. PMID- 21704801 TI - Response to article by American Congress of Rehabilitation Medicine, Brain-Injury Interdisciplinary Special Interest Group, Disorders of Consciousness Task Force. PMID- 21704803 TI - GI endoscopes. AB - The ASGE Technology Committee provides reviews of existing, new, or emerging endoscopic technologies that have an impact on the practice of GI endoscopy. Evidence-based methodology is used, performing a MEDLINE literature search to identify pertinent clinical studies on the topic and a MAUDE (U.S. Food and Drug Administration Center for Devices and Radiological Health) database search to identify the reported complications of a given technology. Both are supplemented by accessing the "related articles" feature of PubMed and by scrutinizing pertinent references cited by the identified studies. Controlled clinical trials are emphasized, but in many cases data from randomized, controlled trials are lacking. In such cases, large case series, preliminary clinical studies, and expert opinions are used. Technical data are gathered from traditional and Web based publications, proprietary publications, and informal communications with pertinent vendors. Technology Status Evaluation Reports are drafted by 1 or 2 members of the ASGE Technology Committee, reviewed and edited by the Committee as a whole, and approved by the Governing Board of the ASGE. When financial guidance is indicated, the most recent coding data and list prices at the time of publication are provided. For this review, the MEDLINE database was searched through September 2010 for articles related to endoscopy by using the key words "gastroscope," "colonoscope," "echoendoscope," "duodenoscope," "choledochoscope," "ultraslim endoscope," "variable stiffness colonoscope," and "wide-angle colonoscope." Technology Status Evaluation Reports are scientific reviews provided solely for educational and informational purposes. Technology Status Evaluation Reports are not rules and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring, or discouraging any particular treatment or payment for such treatment. PMID- 21704804 TI - The role of endoscopy in enteral feeding. PMID- 21704805 TI - The role of endoscopy in gastroduodenal obstruction and gastroparesis. PMID- 21704806 TI - Bleeding after percutaneous endoscopic gastrostomy is linked to serotonin reuptake inhibitors, not aspirin or clopidogrel. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is an invasive procedure that can result in bleeding. Guidelines recommend discontinuing clopidogrel for 7 to 10 days, but not withholding aspirin, before PEG. Serotonin reuptake inhibitors (SRIs) have been associated with an increased risk of GI bleeding. OBJECTIVE: To determine whether there is an association between periprocedural aspirin, clopidogrel, or SRI use and bleeding in patients who underwent PEG tube placement. DESIGN: Retrospective cohort study. SETTING: Large quaternary-care academic medical center. PATIENTS: A total of 990 patients (525 men) with a median age of 69.8 years who underwent PEG from January 1999 to April 2009. INTERVENTIONS: PEG tube placement. MAIN OUTCOME MEASUREMENTS: GI bleeding. RESULTS: Sixteen patients (1.6%) had evidence of bleeding during the first 48 hours after PEG, and 12 patients (1.2%) had evidence of bleeding between 48 hours and 14 days after PEG. Thirty-six patients (3.6%) received high-dose aspirin (>325 mg), 27 patients (2.7%) received clopidogrel (75 mg), and 99 patients (10%) received an SRI before PEG. Twenty-four patients (2.4%) received high-dose aspirin, 25 patients (2.5%) received clopidogrel, and 130 patients (13.1%) received an SRI after PEG. Multivariate analysis demonstrated no association between periprocedural use of aspirin (at any dose) or clopidogrel and post-PEG bleeding. However, SRIs administered 24 hours or less before PEG were associated with a significantly higher odds of post-PEG bleeding (adjusted odds ratio 4.1; 95% CI, 1.1-13.4; P = .04). LIMITATIONS: Retrospective, single-center study with limited statistical power despite a relatively large cohort of patients. CONCLUSIONS: Use of aspirin or clopidogrel before or after PEG was not associated with procedure-related bleeding. SRI use in the 24 hours before PEG was associated with an increased risk of bleeding. PMID- 21704807 TI - Randomized trial on endoscopic resection-cap versus multiband mucosectomy for piecemeal endoscopic resection of early Barrett's neoplasia. AB - BACKGROUND: Endoscopic resection (ER) is an important treatment for high-grade intraepithelial neoplasia and early cancer in Barrett's esophagus. ER-cap requires submucosal lifting and positioning of a snare in the cap, making it technically demanding and laborious. Multiband mucosectomy (MBM) uses a modified variceal band ligator and requires no submucosal lifting or positioning of a snare. OBJECTIVE: To compare ER-cap and MBM for piecemeal ER of early Barrett's neoplasia. DESIGN: Randomized, controlled trial. SETTING: Tertiary-care and community-care centers. PATIENTS: This study involved 84 patients (64 men; median age 70 years) undergoing piecemeal ER of Barrett's neoplasia. INTERVENTION: Piecemeal ER was performed by using ER-cap (n = 42) or MBM (n = 42). MAIN OUTCOME MEASUREMENTS: Safety, efficacy, procedure time, costs. RESULTS: Procedure time (34 vs 50 minutes; P = .02) and costs (?240 vs ?322; P < .01) were significantly less with MBM compared with ER-cap. MBM resulted in smaller resection specimens than ER-cap (18 *13 mm vs 20 * 15 mm; P < .01). Maximum thicknesses of specimens and resected submucosa were not significantly different. There were no clinically relevant bleeding episodes. Four perforations occurred, 3 with ER-cap, 1 with MBM (P = not significant). LIMITATIONS: Potential bias because of different levels of experience among participating endoscopists. CONCLUSION: Piecemeal ER with MBM is faster and cheaper than with ER-cap. Despite the lack of submucosal lifting, MBM appears not to be associated with more perforations. Although MBM results in slightly smaller specimens, the clinical relevance of this may be limited because depth of resections does not differ between both techniques. MBM may thus be preferred for piecemeal ER of early Barrett's neoplasia. ( CLINICAL TRIAL REGISTRATION NUMBER: NTR1435.). PMID- 21704808 TI - Use of antimicrobials for EUS-guided FNA of pancreatic cysts: a retrospective, comparative analysis. AB - BACKGROUND: Pancreatic cystic lesions present a challenge for patients and physicians alike. Morphology alone is inaccurate in discriminating lesion pathology, and use of EUS-guided FNA (EUS-FNA) improves accuracy. Current American Society for Gastrointestinal Endoscopy guidelines recommend prophylactic antibiotics during FNA of cystic lesions to minimize infection risk. However, evidence pertaining to infection risk has been conflicting. The use of prophylactic antibiotics might not be free of other adverse events and might not prevent infection. OBJECTIVE: To assess the impact of antimicrobial therapy for prophylaxis during EUS-FNA of pancreatic cysts. DESIGN: Retrospective cohort study. PATIENTS: This study involved all patients who underwent EUS-FNA of pancreatic cysts at one institution from May 2007 to April 2010. INTERVENTION: Antibiotic prophylaxis for EUS-FNA. MAIN OUTCOME MEASUREMENTS: Infection of a pancreatic cyst, fever, or bacteremia after EUS-FNA. Secondary variables included other complications of the procedure related to the use of prophylaxis (ie, allergic reactions, secondary infections). RESULTS: EUS-FNA was performed on 253 patients in 266 procedures. Antibiotics were used in 88 endoscopy cases (ATB group), whereas no antibiotics were used in 178 cases (NATB group). There were no differences in patient or cyst characteristics between groups. There were 4 major complications in the NATB group (localized bleeding, 2; pancreatitis, 1; bile leakage, 1) and 2 in the ATB group (possible cyst infection, 1; bile leakage, 1) (P = 1.0). Eight mild adverse events were observed in the NATB group and 6 in the ATB group (P = .56). Infections and antibiotic-related complications occurred in 1 (0.6%) (transient fever) in the NATB group and 4 (4.5%) in the ATB group (local allergic reaction, 2; possible cyst infection, 1; Clostridium difficile diarrhea, 1) (P = .04). LIMITATIONS: Retrospective analysis. CONCLUSION: The incidence of infectious complications after EUS-FNA of pancreatic cystic lesions, with or without antibiotic prophylaxis, appears very low. We have not observed a protective effect from periprocedural prophylactic antibiotic administration. PMID- 21704809 TI - Screening for pancreatic cancer in a high-risk population with serum CA 19-9 and targeted EUS: a feasibility study. AB - BACKGROUND: Earlier detection of pancreatic adenocarcinoma is needed. OBJECTIVE: To determine whether early pancreatic neoplasia can be detected in a high-risk population by using CA 19-9 followed by targeted EUS. DESIGN: Prospective cohort study. SETTING: Two academic medical centers. PATIENTS: Eligible patients met age criteria and had at least 1 first-degree relative with pancreatic adenocarcinoma. INTERVENTIONS: A serum CA 19-9 was performed on all patients. EUS was performed if the CA 19-9 level was elevated. FNA of identified lesions was performed. Patients with pancreatic cancer detected by using this screening protocol were compared with patients presenting off-protocol for staging data. Medicare reimbursement rates were used to derive cost data. MAIN OUTCOME MEASUREMENTS: Detection of early pancreatic neoplasia. RESULTS: A total of 546 patients were enrolled. CA 19-9 was elevated in 27 patients (4.9%, 95% CI, 3.2%-7.1%). Neoplastic or malignant findings were detected in 5 patients (0.9%, 95% CI, 0.3% 2.1%), and pancreatic adenocarcinoma in 1 patient (0.2%, 95% CI, 0.005%-1.02%). The patient with pancreatic cancer detected as part of this protocol was 1 of 2 patients presenting to the University of Vermont with stage 1 cancer. The cost to detect 1 pancreatic neoplasia was $8431. The cost to detect 1 pancreatic adenocarcinoma was $41,133. LIMITATIONS: The sample size is adequate only to demonstrate the feasibility of this approach. CONCLUSIONS: Potentially curative pancreatic adenocarcinoma can be identified with this screening protocol. Stage 1 pancreatic cancer is more likely to be detected by using this screening protocol than by using standard means of detection. PMID- 21704810 TI - Colonoscopic yields in 40- to 49-year-old patients with a history of colorectal cancer in a first-degree relative: how high is the risk? PMID- 21704811 TI - Sex preferences for colonoscopists and GI physicians among patients and health care professionals. AB - BACKGROUND: There are indications that many women prefer female health care providers. OBJECTIVE: To determine whether (1) patients and health care professionals have sex preferences for gastroenterologists (for office visit and colonoscopy) and (2) the reasons behind these preferences. DESIGN: Prospective survey. SETTING: Patients from primary care clinics at a Veterans Affairs and a community hospital and health care professionals. PATIENTS: A total of 1364 individuals completed the survey: 840 patients (566 men and 274 women) and 524 health care professionals (211 men and 313 women). MAIN OUTCOME MEASUREMENTS: Sex preferences for colonoscopists and gastroenterologists at a clinic. RESULTS: Women had a stronger sex preference (compared with no preference) for an office visit with a gastroenterologist (44.3%) and for a colonoscopist (53%) than men (23% and 27.8% respectively; P < .001). For health care professionals, there was a significant difference in sex preferences for women and men for a gastroenterologist office visit (30.4% vs 17.6%; P < .001) and for a colonoscopist (43.1% vs 26.1%; P < .001). Of all respondents with a sex preference, the most common reason was embarrassment for both office visit and colonoscopy. For all respondents with a sex preference for colonoscopy, a higher level of education was an independent predictor of patients feeling embarrassed (P = .003). LIMITATIONS: Single city, patient population from only 2 institutions. CONCLUSIONS: Female patients and female health care professionals have sex preferences in choosing a gastroenterologist for an office visit and colonoscopy, and the reasons for this are significantly influenced by their level of education. PMID- 21704812 TI - Neoplasia detection rates after positive fecal occult blood test results are not affected by endoscopy center: a population-based study. AB - BACKGROUND: We previously showed a significant variability in adenoma detection among colonoscopists who were participating in a mass screening program. The reasons for such variability remain largely unknown. OBJECTIVE: To study intercenter variations in neoplasia detection. DESIGN AND SETTING: Secondary analyses of colonoscopy findings from the 2 first rounds of a French screening program: logistic regressions and repeated-measures analyses of variance. MATERIAL: A total of 3487 colonoscopies performed by all 19 endoscopists who performed 30 examinations or more per round at 8 centers (6 private, 2 public). MAIN OUTCOME MEASUREMENTS: Probabilities of detecting 1, 2, or 3 or more adenomas, 1 adenoma 10 mm or larger, or colorectal cancer, as well as the corresponding adjusted (for patient age and sex) per-center detection rates. RESULTS: Endoscopy centers were not significant predictors of the probability of detecting any category of neoplasia with the exception of the 2 adenomas or more category (P < .005). The ranges of the adjusted detection rates for each of these categories were 33.1% to 43.1%, 11.1% to 21.6%, 3.6% to 8.1%, 16.3% to 23.6%, and 8.3% to 12.6%, respectively. When the colonoscopies that were performed by the 11 endoscopists who performed 30 examinations or more per center in 2 or more centers were separately analyzed, no intercenter statistically significant variability was observed with the exception of 1 endoscopist and the 1 adenoma category. In a subgroup of 1100 colonoscopies performed by 6 endoscopists who were working at the same 3 centers, intercenter variability was not statistically significant. LIMITATIONS: Type II error because of sample sizes. CONCLUSIONS: In our setting, intercenter variability did not explain interendoscopist variability for neoplasia detection rate. PMID- 21704813 TI - Antimigration property of a newly designed covered metal stent for esophageal stricture: an in vivo animal study. AB - BACKGROUND: Covered self-expandable metal stents (SEMSs) are associated with a higher migration rate than uncovered SEMSs. OBJECTIVE: The antimigration property of a novel covered SEMS was investigated in a canine esophageal stricture model. DESIGN: The new stent (80 mm in length, 20 or 24 mm in diameter) has multiple protuberances on its body that were designed to be separated from the inner silicone membrane so that they could be embedded into the mucosa after deployment. Twenty-two beagle dogs were subjected to circumferential EMR in the middle esophagus for stricture formation. After 2 weeks, conventional covered stents were inserted in a control group (n = 11), and the newly designed covered SEMSs were inserted in a study group (n = 11). SETTING: Animal laboratory. INTERVENTIONS: Circumferential EMR of the middle esophagus for stricture formation, followed by endoscopic placement of a conventional or newly designed stent. MAIN OUTCOME MEASUREMENTS: Migration, complications, survival, and esophageal histopathology. RESULTS: There was no significant difference in the diameter of the esophageal stricture between the control and study groups (10 mm vs 11 mm, P = .52). Within 3 days, all stents in the control group had migrated, whereas 6 had migrated in the study group (100% vs 55%, P = .035). There were no significant complications directly associated with stent insertion. LIMITATIONS: Complications, survival, and esophageal histopathology could not be compared because all of the conventional stents migrated in the control group within 3 days. CONCLUSIONS: The newly designed covered SEMS is more resistant to migration than the conventional covered SEMS. PMID- 21704814 TI - Advice to program directors and applicants for gastroenterology fellowship application and selection. PMID- 21704815 TI - Are low-volume ERCPists a problem in the United States? A plea to examine and improve ERCP practice-NOW. PMID- 21704816 TI - Feasibility and safety of EUS-guided transgastric/transduodenal gallbladder drainage with single-step placement of a modified covered self-expandable metal stent in patients unsuitable for cholecystectomy. AB - BACKGROUND: Although early laparoscopic cholecystectomy is the treatment of choice for patients with acute cholecystitis, percutaneous cholecystostomy has been performed in patients unsuitable for cholecystectomy. EUS-guided transgastric/transduodenal gallbladder drainage by using a plastic stent and/or nasobiliary drainage may be an alternative effective treatment for these patients, but bile leakage into the peritoneal space causing bile peritonitis is not uncommon during placement of a plastic stent. OBJECTIVE: To evaluate the technical feasibility and safety of EUS-guided transgastric/transduodenal gallbladder drainage with single-step placement of a modified covered self expandable metal stent (CSEMS) in patients with acute cholecystitis who are unsuitable for cholecystectomy. DESIGN: Prospective feasibility study. SETTING: Tertiary-care referral center. PATIENTS: This study involved 15 patients with acute cholecystitis who did not respond to initial medical treatment and were unsuitable for cholecystectomy. INTERVENTION: EUS-guided transgastric/transduodenal gallbladder drainage with single-step placement of a modified CSEMS. MAIN OUTCOME MEASUREMENTS: Technical success, functional success, complications associated with the placement of a metal stent, and recurrence of acute cholecystitis. RESULTS: Modified CSEMSs were successfully placed in all patients through the stomach (n = 10) or duodenum (n = 5). All patients achieved functional success within 3 days of metal stent placement. Pneumoperitoneum occurred in two patients during or after the procedure, but both patients improved with conservative management. During follow-up (median 145 days, range 60-297 days), no patient experienced recurrent cholecystitis. LIMITATIONS: Small patient population without long-term follow-up. CONCLUSION: Placement of a modified CSEMS after EUS-guided transgastric/transduodenal gallbladder drainage may be a feasible and safe alternative to treatments such as percutaneous cholecystostomy in patients with acute cholecystitis who are unsuitable for cholecystectomy. PMID- 21704817 TI - An implantable wireless biosensor for the immediate detection of upper GI bleeding: a new fluorescein-based tool for diagnosis and surveillance (with video). AB - BACKGROUND: Early recurrent hemorrhage after endoscopic intervention for acute upper GI bleeding (UGIB) can approach 20% and leads to increased morbidity and mortality. Little has changed over the past several decades regarding immediate posthemorrhage surveillance, and there has likewise been no significant improvement in outcomes. OBJECTIVE: To develop and test an endoscopically implantable wireless biosensor for real-time detection of fluorescein-labeled blood in ex vivo and in vivo porcine models of UGIB. SETTING: Animal laboratory. DESIGN: Benchtop and acute animal studies. SUBJECTS: Five pigs. INTERVENTIONS: UGIB models were surgically created in living pigs. Biosensors were endoscopically deployed in the stomach using standard endoscopic clips. The ability to detect acute UGIB and estimated blood loss leading to biosensor activation were recorded. Feasibility of wireless data transmission out of the body to an external computer and cell phone was assessed. MAIN OUTCOME MEASUREMENTS: Technical feasibility and immediate complications. RESULTS: A porcine UGIB model was successfully created. Biosensors were able to detect all acute bleeding events and wirelessly transmit out of the body, and successfully sent an emergency text message to the intended cell phone in all cases. Average estimated blood loss leading to biosensor activation was 30 mL (10-75 mL). LIMITATIONS: Animal study; small numbers. CONCLUSIONS: An endoscopically implantable wireless biosensor successfully detected acute hemorrhage in a porcine UGIB model and sent an emergency cell-phone alert in real time. PMID- 21704818 TI - Acute herpes simplex gingivostomatitis and esophagitis (with video). PMID- 21704819 TI - Esophageal stent-induced fistulization to an anterior cervical plate. PMID- 21704820 TI - Gastric metastasis from ovarian carcinoma diagnosed by EUS-FNA biopsy and elastography. PMID- 21704821 TI - Gallstone ileus successfully treated with endoscopic fragmentation by using double-balloon endoscopy (with video). PMID- 21704823 TI - Erythromycin is preferable to metoclopramide as a prokinetic in acute upper GI bleeding. PMID- 21704824 TI - ERCP after Fag Kan Roux-en-Y-hepatojejunostomy in Caroli's syndrome. PMID- 21704825 TI - Avoidance of PEG 3350 in patients with CHF, cirrhosis, and chronic kidney disease. PMID- 21704826 TI - Excessive length of a tube in the stomach: a risk factor for a tangled or knotted tube. PMID- 21704829 TI - Is survivin the potential Achilles' heel of cancer? AB - Survivin, the smallest member of the inhibitors of apoptosis proteins (IAPs), plays an important role in the control of apoptosis, cell division, and cell migration/metastasis. Survivin is expressed and required for normal fetal development but is then generally no longer present in most adult tissues. However, reexpression of survivin is observed in numerous human cancers where presence of the protein is associated with enhanced proliferation, metastasis, poor prognosis, and decreased patient survival. Given the relatively selective expression in cancer cells, but not in normal tissue (tumor-associated antigen), and its importance in tumor cell biology, survivin has emerged as an attractive target for cancer treatment. Here, we discuss some aspects of survivin biology by focusing on why the protein appears to be so important for cancer cells and then discuss strategies that harness this dependence to eradicate tumors and situate survivin as a potential Achilles' heel of cancer. PMID- 21704831 TI - Faulty epithelial polarity genes and cancer. AB - Epithelial architecture is formed in tissues and organs when groups of epithelial cells are organized into polarized structures. The epithelial function and integrity as well as signaling across the epithelial layer is orchestrated by apical junctional complexes (AJCs), which are landmarks for PAR/CRUMBS and lateral SCRIB polarity modules and by dynamic interactions of the cells with underlying basement membrane (BM). These highly organized epithelial architectures are demolished in cancer. In all advanced epithelial cancers, malignant cells have lost polarity and connections to the basement membrane and they have become proliferative, motile, and invasive. Clearly, loss of epithelial integrity associates with tumor progression but does it contribute to tumor development? Evidence from studies in Drosophila and recently also in vertebrate models have suggested that even the oncogene-driven enforced cell proliferation can be conditional, dependant on the influence of cell-cell or cell microenvironment contacts. Therefore, loss of epithelial integrity may not only be an obligate consequence of unscheduled proliferation of malignant cells but instead, malignant epithelial cells may need to acquire capacity to break free from the constraints of integrity to freely and autonomously proliferate. We discuss how epithelial polarity complexes form and regulate epithelial integrity, highlighting the roles of enzymes Rho GTPases, aPKCs, PI3K, and type II transmembrane serine proteases (TTSPs). We also discuss relevance of these pathways to cancer in light of genetic alterations found in human cancers and review molecular pathways and potential pharmacological strategies to revert or selectively eradicate disorganized tumor epithelium. PMID- 21704832 TI - Adult T cell leukemia/lymphoma: FoxP3(+) cells and the cell-mediated immune response to HTLV-1. AB - Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukaemia/lymphoma (ATLL) in ~5% of HTLV-1-infected people. ATLL cells frequently express several molecules that are characteristic of regulatory T cells (Tregs), notably CD4, CD25 and the transcription factor FoxP3. It has therefore recently been suggested that HTLV-1 selectively infects and transforms Tregs. We show that HTLV-1 induces and maintains a high frequency of FoxP3+ T cells by inducing expression of the chemokine CCL22; the frequency is especially high in patients with chronic ATLL. In turn, the FoxP3+ T cells exert both potentially beneficial and harmful effects: they suppress the growth of autologous ATLL clones and may also suppress the host's cytotoxic T lymphocyte response, which normally limits HTLV-1 replication and reduces the risk of HTLV-1-associated diseases. Although ATLL cells may exert immune suppressive effects, we conclude that ATLL is not necessarily a tumour of classical FoxP3+ Tregs. PMID- 21704834 TI - Droplet microfluidics for high-throughput analysis of cells and particles. AB - Droplet microfluidics (DM) is an area of research which combines lab-on-a-chip (LOC) techniques with emulsion compartmentalization to perform high-throughput, chemical and biological assays. The key issue of this approach lies in the generation, over tens of milliseconds, of thousands of liquid vessels which can be used either as a carrier, to transport encapsulated particles and cells, or as microreactors, to perform parallel analysis of a vast number of samples. Each compartment comprises a liquid droplet containing the sample, surrounded by an immiscible fluid. This microfluidic technique is capable of generating subnanoliter and highly monodispersed liquid droplets, which offer many opportunities for developing novel single-cell and single-molecule studies, as well as high-throughput methodologies for the detection and sorting of encapsulated species in droplets. The aim of this chapter is to give an overview of the features of DM in a broad microfluidic context, as well as to show the advantages and limitations of the technology in the field of LOC analytical research. Examples are reported and discussed to show how DM can provide novel systems with applications in high-throughput, quantitative cell and particle analysis. PMID- 21704833 TI - Introduction A: recent advances in cytometry instrumentation, probes, and methods -review. AB - Cytometric techniques are continually being improved, refined, and adapted to new applications. This chapter briefly outlines recent advances in the field of cytometry with the main focus on new instrumentations in flow and image cytometry as well as new probes suitable for multiparametric analyses. There is a remarkable trend for miniaturizing cytometers, developing label-free and fluorescence-free analytical approaches, and designing "intelligent" probes. Furthermore, new methods for analyzing complex data for extracting relevant information are reviewed. PMID- 21704835 TI - Parallel imaging microfluidic cytometer. AB - By adding an additional degree of freedom from multichannel flow, the parallel microfluidic cytometer (PMC) combines some of the best features of fluorescence activated flow cytometry (FCM) and microscope-based high-content screening (HCS). The PMC (i) lends itself to fast processing of large numbers of samples, (ii) adds a 1D imaging capability for intracellular localization assays (HCS), (iii) has a high rare-cell sensitivity, and (iv) has an unusual capability for time synchronized sampling. An inability to practically handle large sample numbers has restricted applications of conventional flow cytometers and microscopes in combinatorial cell assays, network biology, and drug discovery. The PMC promises to relieve a bottleneck in these previously constrained applications. The PMC may also be a powerful tool for finding rare primary cells in the clinic. The multichannel architecture of current PMC prototypes allows 384 unique samples for a cell-based screen to be read out in ~6-10 min, about 30 times the speed of most current FCM systems. In 1D intracellular imaging, the PMC can obtain protein localization using HCS marker strategies at many times for the sample throughput of charge-coupled device (CCD)-based microscopes or CCD-based single-channel flow cytometers. The PMC also permits the signal integration time to be varied over a larger range than is practical in conventional flow cytometers. The signal-to noise advantages are useful, for example, in counting rare positive cells in the most difficult early stages of genome-wide screening. We review the status of parallel microfluidic cytometry and discuss some of the directions the new technology may take. PMID- 21704830 TI - The essential role of evasion from cell death in cancer. AB - The link between evasion of apoptosis and the development of cellular hyperplasia and ultimately cancer is implicitly clear if one considers how many cells are produced each day and, hence, how many cells must die to make room for the new ones (reviewed in Raff, 1996). Furthermore, cells are frequently experiencing noxious stimuli that can cause lesions in their DNA and faults in DNA replication can occur during cellular proliferation. Such DNA damage needs to be repaired efficiently or cells with irreparable damage must be killed to prevent subsequent division of aberrant cells that may fuel tumorigenesis (reviewed in Weinberg, 2007). The detection of genetic lesions in human cancers that activate prosurvival genes or disable proapoptotic genes have provided the first evidence that defects in programmed cell death can cause cancer (Tagawa et al., 2005; Tsujimoto et al., 1984; Vaux, Cory, and Adams, 1988) and this concept was proven by studies with genetically modified mice (Egle et al., 2004b; Strasser et al., 1990a). It is therefore now widely accepted that evasion of apoptosis is a requirement for both neoplastic transformation and sustained growth of cancer cells (reviewed in Cory and Adams, 2002; Hanahan and Weinberg, 2000; Weinberg, 2007). Importantly, apoptosis is also a major contributor to anticancer therapy induced killing of tumor cells (reviewed in Cory and Adams, 2002; Cragg et al., 2009). Consequently, a detailed understanding of apoptotic cell death will help to better comprehend the complexities of tumorigenesis and should assist with the development of improved targeted therapies for cancer based on the direct activation of the apoptotic machinery (reviewed in Lessene, Czabotar, and Colman, 2008). PMID- 21704836 TI - Microfluidic systems for live cell imaging. AB - Microfluidic systems provide many advantages for live cell imaging, including improved cell culture micro-environments, control of flows and dynamic exposure profiles, and compatibility with existing high resolution microscopes. Here, we will discuss our approach for design and engineering of microfluidic cell culture environments as well as interfacing with standard laboratory tools and protocols. We focus on an application specific design concept, whereby a shared fabrication process is used to deliver multiple products for different biological applications. As adoption of advanced in vitro models increases, we envision the use of microfluidic cell culture technology to become commonplace. PMID- 21704838 TI - Label-free resistive-pulse cytometry. AB - Numerous methods have recently been developed to characterize cells for size, shape, and specific cell-surface markers. Most of these methods rely upon exogenous labeling of the cells and are better suited for large cell populations (>10,000). Here, we review a label-free method of characterizing and screening cells based on the Coulter-counter technique of particle sizing: an individual cell transiting a microchannel (or "pore") causes a downward pulse in the measured DC current across that "pore". Pulse magnitude corresponds to the cell size, pulse width to the transit time needed for the cell to pass through the pore, and pulse shape to how the cell traverses across the pore (i.e., rolling or tumbling). When the pore is functionalized with an antibody that is specific to a surface-epitope of interest, label-free screening of a specific marker is possible, as transient binding between the two results in longer time duration than when the pore is unfunctionalized or functionalized with a nonspecific antibody. While this method cannot currently compete with traditional technology in terms of throughput, there are a number of applications for which this technology is better suited than current commercial cytometry systems. Applications include the rapid and nondestructive analysis of small cell populations (<100), which is not possible with current technology, and a platform for providing true point-of-care clinical diagnostics, due to the simplicity of the device, low manufacturing costs, and ease of use. PMID- 21704837 TI - Rise of the micromachines: microfluidics and the future of cytometry. AB - The past decade has brought many innovations to the field of flow and image-based cytometry. These advancements can be seen in the current miniaturization trends and simplification of analytical components found in the conventional flow cytometers. On the other hand, the maturation of multispectral imaging cytometry in flow imaging and the slide-based laser scanning cytometers offers great hopes for improved data quality and throughput while proving new vistas for the multiparameter, real-time analysis of cells and tissues. Importantly, however, cytometry remains a viable and very dynamic field of modern engineering. Technological milestones and innovations made over the last couple of years are bringing the next generation of cytometers out of centralized core facilities while making it much more affordable and user friendly. In this context, the development of microfluidic, lab-on-a-chip (LOC) technologies is one of the most innovative and cost-effective approaches toward the advancement of cytometry. LOC devices promise new functionalities that can overcome current limitations while at the same time promise greatly reduced costs, increased sensitivity, and ultra high throughputs. We can expect that the current pace in the development of novel microfabricated cytometric systems will open up groundbreaking vistas for the field of cytometry, lead to the renaissance of cytometric techniques and most importantly greatly support the wider availability of these enabling bioanalytical technologies. PMID- 21704839 TI - Laser scanning cytometry and its applications: a pioneering technology in the field of quantitative imaging cytometry. AB - Imaging cytometry plays an increasingly important role in all fields of biological and medical sciences. It has evolved into a complex and powerful discipline amalgamating image acquisition technologies and quantitative digital image analysis. This chapter presents an overview of the complex and ever developing landscape of imaging cytometry, highlighting the imaging and quantitative performance of a wide range of available instruments based on their methods of sample illumination and the detection technologies they employ. Each of these technologies has inherent advantages and shortcomings stemming from its design. It is therefore paramount to assess the appropriateness of all of the imaging cytometry options available to determine the optimal choice for specific types of studies. Laser scanning cytometry (LSC), the original imaging cytometry technology, is an attractive choice for analysis of both cellular and tissue specimens. Quantitative performance, flexibility, and the benefits of preserving native sample architecture and avoiding the introduction of artificial signals, particularly in cell-signaling studies and multicolor tissue analysis, are speeding the adoption of LSC and opening up new possibilities for developing sophisticated applications. PMID- 21704840 TI - Analytical capabilities of the ImageStream cytometer. AB - Imaging cytometry has recently become an important achievement in development of flow cytometric technologies. The ImageStream cytometer combines the vast features of classical flow cytometry including an impartial analysis of great number of cells in short period of time which results in strong statistical data output, with essential features of fluorescence microscopy such us collecting of real multiparameter images of analyzed objects. In this chapter, we would like to introduce an overview of imaging cytometry platform and emphasize the potential advantages of using this system for several experimental purposes. Moreover, both well established as well as potential applications of imaging cytometry will be described. Eventually, we would like to illustrate the unique use of ImageStream cytometer for identification and characterization of subpopulations of stem/ progenitor cells present in different biological specimens. PMID- 21704841 TI - Laser scanning cytometry: capturing the immune system in situ. AB - Until recently, it has not been possible to image and functionally correlate the key molecular and cellular events underpinning immunity and tolerance in the intact immune system. Certainly, the field has been revolutionized by the advent of tetramers to identify physiologically relevant specificities of T cells, and the introduction of models in which transgenic T-cell receptor and/or B-cell receptor-bearing lymphocytes are adoptively transferred into normal mice and can then be identified by clonotype-specific antibodies using flow cytometry in vitro, or immunohistochemistry ex vivo. However, these approaches do not allow for quantitative analysis of the precise anatomical, phenotypic, signaling, and functional parameters required for dissecting the development of immune responses in health and disease in vivo. Traditionally, assessment of signal transduction pathways has required biochemical or molecular biological analysis of isolated and highly purified subsets of immune system cells. Inevitably, this creates potential artifacts and does not allow identification of the key signaling events for individual cells present in their microenvironment in situ. These difficulties have now been overcome by new methodologies in cell signaling analysis that are sufficiently sensitive to detect signaling events occurring in individual cells in situ and the development of technologies such as laser scanning cytometry that provide the tools to analyze physiologically relevant interactions between molecules and cells of the innate and the adaptive immune system within their natural environmental niche in vivo. PMID- 21704842 TI - Image cytometry analysis of circulating tumor cells. AB - The majority of cancer-related deaths are as a result of metastatic disease, which has been correlated with the presence of circulating tumor cells (CTCs) in the bloodstream. Therefore the ability to reliably enumerate and characterize these cells could provide useful information about the biology of the metastatic cascade; facilitate patient prognosis; act as a marker of therapeutic response; and/or aid in novel anticancer drug development. Several different techniques have been utilized for the enrichment and detection of these rare CTCs, each having their own unique advantages and disadvantages. In this chapter we will briefly discuss each of these techniques as well as the pros and cons of each approach. In particular, we will provide a comprehensive examination of two image cytometry approaches for CTC analysis that are in routine use in our laboratory; the iCys Laser Scanning Cytometer (Compucyte, Cambridge, MA), and the CellSearch(r) system (Veridex, North Raritan, NJ). The ability to detect, enumerate, and characterize CTCs is an important tool for the study of the metastatic cascade and the improved clinical management of cancer patients. These rare cells could shed light on the basic biology behind this highly lethal process and ultimately change current patient treatment guidelines. PMID- 21704843 TI - Preclinical applications of quantitative imaging cytometry to support drug discovery. AB - Preclinical drug development is actively involved in testing compounds to find cures or to manage the effects of disease, such as diabetes. Animal models, such as the Zucker diabetic fatty (ZDF) rat, are used to measure efficacy of candidate drugs. This animal model was selected because of its clinical and pathological similarities to diabetic human patients. A method using immunofluorescence and laser scanning cytometry (LSC) technology has been used to measure the development of diabetic phenotype in the ZDF rat during a 17-week time course. The expression levels of insulin, glucagon, voltage-dependent anion channel (VDAC), and Ki67 were quantified. Insulin and VDAC expression were reduced in the ZDF animals in comparison to the lean control rats, while no significant change was seen in glucagon and Ki67 expression at week 17. This information is useful in the design of studies to test experimental compounds in this model. Screening drug targets or biomarkers in tissue sections is another important activity in drug development. Tissue microarrays (TMAs) are composed of 60 or more tissue cores from humans or animal models and may contain healthy and/or diseased tissues. Antibodies against target proteins are applied to TMAs using routine immunohistochemical reagents and protocols. The protein expression across the cores, as labeled by immunohistochemistry, is measured using LSC technology. The process provides an efficient and cost-effective method for evaluating multiple targets in a large number of tissue samples. More recently, IHC and LSC have been taken to the next level to quantify biopharmaceutical drug and target co localization in tissue sections. PMID- 21704844 TI - Leveraging image cytometry for the development of clinically feasible biomarkers: evaluation of activated caspase-3 in fine needle aspirate biopsies. AB - Quantitation of activated caspases in xenograft models by laser scanning cytometry has demonstrated mechanism-specific biological activity of Anti-Trail Receptor immunoglobulin therapies in situ. These preclinical data confirmed that caspase activation is an early event that precedes tumor regression. To apply this platform for clinical monitoring of caspase activation using fine needle aspirate (FNA) biopsies, additional assay feasibility and validation experiments need be addressed. Furthermore, important instrument parameters should be considered including the maintenance and operation of the cytometer in a controlled state to ensure aspects like data traceability, reliability, and integrity. In the present chapter we describe a method to evaluate caspase activation in Colo205 cells and fine needle aspirate tumors by slide-based, laser scanning cytometry. This approach can be applied to cell cultures, preclinical and clinical fine needle aspirate material. PMID- 21704845 TI - Automation of the buccal micronucleus cytome assay using laser scanning cytometry. AB - Laser scanning cytometry (LSC) can be used to quantify the fluorescence intensity or laser light loss (absorbance) of localized molecular targets within nuclear and cytoplasmic structures of cells while maintaining the morphological features of the examined tissue. It was aimed to develop an automated LSC protocol to study cellular and nuclear anomalies and DNA damage events in human buccal mucosal cells. Since the buccal micronucleus cytome assay has been used to measure biomarkers of DNA damage (micronuclei and/or nuclear buds), cytokinesis defects (binucleated cells), proliferative potential (basal cell frequency), and/or cell death (condensed chromatin, karyorrhexis, and pyknotic and karyolytic cells), the following automated LSC protocol describes scoring criteria for these same parameters using an automated imaging LSC. In this automated LSC assay, cells derived from the buccal mucosa were harvested from the inside of patient's mouths using a small-headed toothbrush. The cells were washed to remove any debris and/or bacteria, and a single-cell suspension prepared and applied to a microscope slide using a cytocentrifuge. Cells were fixed and stained with Feulgen and Light Green stain allowing both chromatic and fluorescent analysis to be undertaken simultaneously with the use of an LSC. PMID- 21704846 TI - Laser scanning cytometry of mitosis: state and stage analysis. AB - Here we use a concept of cell state, which can be defined as the conjunction of expression levels of an arbitrary number of biomolecules or modifications thereof that oscillate, to classify mitotic cells. We describe detection of cell states with quantitative immunofluorescence measurements performed by laser scanning cytometry. This platform allows both measurement of the cell states, capture of cell images within those states, and subsequent analysis of each image to classify by traditional mitotic stages based on nuclear morphology. PMID- 21704847 TI - Lasers in flow cytometry. AB - Laser technology has advanced tremendously since the first gas lasers were incorporated into early flow cytometers. Gas lasers have been largely replaced by solid-state laser technology, making virtually any desirable visible light wavelength available for flow cytometry. Multiwavelength, white light, and wavelength tunable lasers are poised to enhance our analytical capabilities even further. In this chapter, I summarize the role that lasers play in cytometry, and the practical characteristics that make a laser appropriate for flow cytometry. I then review the latest single wavelength lasers available for flow cytometry, and how they can be used to excite the ever-expanding array of available fluorochromes. Finally, I review the contribution and potential of the latest tunable laser technology to flow cytometry, and show several examples of these novel sources integrated into production instruments. Technical details and critical parameters for successful application of these lasers for biomedical analysis are covered in depth. PMID- 21704850 TI - Quantum dot technology in flow cytometry. AB - The development of quantum dot (QD) technology represents one of the most dramatic advances in flow cytometry history, offering the opportunity for highly multiplexed experiments and allowing better resolution of dimly staining markers. Here, we guide users through the technical aspects of using QDs (including instrumentation and antibody conjugation), demonstrate why QDs are useful in multicolor flow cytometry, and describe some of the challenges investigators may face when adopting this technology. PMID- 21704848 TI - The use of hollow fiber membranes combined with cytometry in analysis of bacteriological samples. AB - To avoid destruction of the implanted biological material it may be separated from host immunological system by enclosure within a permiselective membrane. Two directional diffusion through the membrane of nutrients, metabolic products, as well as bioactive products of encapsulated cells is required to ensure their survival and functional activities. The system of cells encapsulated within the membrane releasing the biologically active substance may be applied either locally to give an opportunity of therapeutic agent activity in the specified place and/or at some convenient site (tissue) for a prolonged period of time.The novel system of bacteria bio-encapsulation using modified membranes, and its assessment by flow cytometry is described and discussed. The encapsulated in membrane bacteria, functioning and releasing their products were evaluated in the systems in vitro and in vivo. The bacteria cells products impact on Eukariotic cells was evaluated. The cytometric evaluation demonstrates the membrane ability to avoid the release of bacteria enclosed within the membrane wall. In experiments with treatment of the bacteria with antibiotic to release products from damaged bacteria it was possible to distinguish stages of the applied antibiotic impact on encapsulated bacteria cells. In E. coli following stages were distinguished: induction of membrane permeability to PI, activation of proteases targeting GFP (protein) and subsequent nucleic acids degradation. In the another experiment the evidence was presented of the cytotoxic activity of live Bacillus subtilis encapsulated within the membrane system. The Bacilus products mediated by secreted listeriolysin O (LLO) on the chosen eukaryotic cells was evaluated. Similar systems releasing bacterial products locally and continuously may selectively affect different types of cells and may have possible application in the anticancer treatment at localized sites. PMID- 21704849 TI - Guide to red fluorescent proteins and biosensors for flow cytometry. AB - Since the discovery of the first red fluorescent protein (RFP), named DsRed, 12 years ago, a wide pallet of red-shifted fluorescent proteins has been cloned and biotechnologically developed into monomeric fluorescent probes for optical microscopy. Several new types of monomeric RFPs that change the emission wavelength either with time, called fluorescent timers, or after a brief irradiation with violet light, known as photoactivatable proteins, have been also engineered. Moreover, RFPs with a large Stokes shift of fluorescence emission have been recently designed. Because of their distinctive excitation and fluorescence detection conditions developed specifically for microscopy, these fluorescent probes can be suboptimal for flow cytometry. Here, we have selected and summarized the advanced orange, red, and far-red fluorescent proteins with the properties specifically required for the flow cytometry applications. Their effective brightness was calculated for the laser sources available for the commercial flow cytometers and sorters. Compatibility of the fluorescent proteins of different colors in a multiparameter flow cytometry was determined. Novel FRET pairs, utilizing RFPs, RFP-based intracellular biosensors, and their application to a high-throughput screening, are also discussed. PMID- 21704851 TI - Background-free cytometry using rare earth complex bioprobes. AB - In the analytical fields of microbiology, disease diagnosis, and antibioterrorism, there are increasing demands for rapid yet inexpensive quantification of rare cells. This has proven to be challenging by the conventional spectral discrimination of using traditional fluorescent probes, since the strong autofluorescence from background cells or particles overlaps spectrally with the probe fluorescence. This is particularly true when the target cell occurs at very low frequency (one in more than 100,000 background cells) representing a needle-in-a-haystack problem. This chapter describes a low-cost solution to overcome this problem by employing a novel detection technology, namely the use of rare-earth (lanthanide) complex bioprobes with luminescence lifetimes in the hundreds of microseconds. Due to this long persistence in lifetime, microsecond duration luminescence can be detected under conditions where fluorescent backgrounds would overwhelm the emission of conventional fluorochromes. The nanosecond duration autofluorescence associated with cells can be suppressed by time-gated detection, allowing detection of long lifetime lanthanide-based bioprobes with minimal background interference. This technology is applicable to a broad range of detection technologies in both cytometry and imaging. In this chapter, we highlight a typical application in the monitoring of the rare microbial pathogens Cryptosporidium parvum and Giardia lamblia against the complex background of concentrated drinking water. We also describe recent nanotechnological developments in the production of rare-earth nanoparticle bioprobes required for this technology. Other applications of rare-earth bioprobes and time-gated flow cytometry will also be discussed. PMID- 21704853 TI - Recent advances in flow cytometric cell sorting. AB - The classification and separation of one cell type or particle from others is a fundamental task in many areas of science. Numerous techniques are available to perform this task; however, electrostatic cell sorting has gained eminence over others because, when combined with the analysis capabilities of flow cytometry it provides flexible separations based on multiple parameters. Unlike competing technologies, such as gradient or magnetic separations that offer much larger total throughput, flow cytometric cell sorting permits selections based on various levels of fluorescent reporters, rather the complete presence or absence of the reporter. As such, this technology has found application in a huge range of fields. This chapter aims to describe the utility of single-cell sorting with particular emphasis given to index sorting. This is followed by two recently developed novel techniques of sorting cells or particles. The first of these is positional sorting which is useful in cell-based studies where sorting can proceed and produce meaningful results without being inherently dependant on prior knowledge of where gates should be set. Secondly, reflective plate sorting is introduced which positionally links multiwell sample and collection plates in a convenient assay format so that cells in the collection plate "reflect" those in the sample plate. PMID- 21704852 TI - Surface-enhanced Raman scattering (SERS) cytometry. AB - Significant advances have been made in the preparation and applications of surface-enhanced Raman scattering (SERS)-active materials for biomolecular analysis. Bright signals, photostability, and narrow spectral features of SERS active materials offer attractive advantages for cytometric analyses. However, SERS cytometry is still in an early stage of development, and advances in both instrumentation and reagents will be necessary to realize its full potential. In this chapter, we discuss the challenges of expanding the numbers of fluorescent labels that can be measured in cytometry, and introduce SERS tags with extremely narrow spectral peaks as an approach to make more efficient use of the optical spectrum and increase the number of parameters in cytometry. PMID- 21704854 TI - Managing pain effectively. PMID- 21704855 TI - "Respect your elders". PMID- 21704856 TI - Osteoporosis--striking the right balance. PMID- 21704858 TI - Lul Riek: helping to improve public health in South Sudan. PMID- 21704859 TI - Triggers of myocardial infarction. PMID- 21704860 TI - Triggers of myocardial infarction. PMID- 21704862 TI - Wireless pulmonary artery haemodynamic monitoring. PMID- 21704863 TI - Wireless pulmonary artery haemodynamic monitoring. PMID- 21704864 TI - Safety and efficacy of zoledronic acid in multiple myeloma. PMID- 21704866 TI - Safety and efficacy of zoledronic acid in multiple myeloma. PMID- 21704867 TI - Decline in neonatal mortality in large poor populations. PMID- 21704869 TI - Rising liver death rate: food for thought. PMID- 21704870 TI - ECDC and the Escherichia coli outbreak in Germany. PMID- 21704871 TI - Treatment of acute postoperative pain. AB - Although postoperative pain remains incompletely controlled in some settings, increased understanding of its mechanisms and the development of several therapeutic approaches have substantially improved pain control in past years. Advances in our understanding of the process of nociception have led to insight into gene-based pain therapy, the development of acute opioid-induced hyperalgesia, and persistent postsurgical pain. Use of specific analgesic techniques such as regional analgesia could improve patient outcomes. We also examine the development of new analgesic agents and treatment modalities and regimens for acute postoperative pain. PMID- 21704872 TI - Treatment of chronic non-cancer pain. AB - Chronic pain is a pervasive problem that affects the patient, their significant others, and society in many ways. The past decade has seen advances in our understanding of the mechanisms underlying pain and in the availability of technically advanced diagnostic procedures; however, the most notable therapeutic changes have not been the development of novel evidenced-based methods, but rather changing trends in applications and practices within the available clinical armamentarium. We provide a general overview of empirical evidence for the most commonly used interventions in the management of chronic non-cancer pain, including pharmacological, interventional, physical, psychological, rehabilitative, and alternative modalities. Overall, currently available treatments provide modest improvements in pain and minimum improvements in physical and emotional functioning. The quality of evidence is mediocre and has not improved substantially during the past decade. There is a crucial need for assessment of combination treatments, identification of indicators of treatment response, and assessment of the benefit of matching of treatments to patient characteristics. PMID- 21704873 TI - Treatment of cancer pain. AB - In patients with active cancer, the management of chronic pain is an essential element in a comprehensive strategy for palliative care. This strategy emphasises multidimensional assessment and the coordinated use of treatments that together mitigate suffering and provide support to the patient and family. This review describes this framework, an approach to pain assessment, and widely accepted techniques to optimise the safety and effectiveness of opioid drugs and other treatments. The advances of recent decades suggest a future that includes increased evidence-based targeting of specific analgesic interventions within an individualised plan of care that is appropriate throughout the course of illness. PMID- 21704874 TI - Bilateral hip pain. PMID- 21704875 TI - Part One: Treatment of type IV thoracoabdominal aneurysms--hybrid technique with debranching is the best option. PMID- 21704876 TI - Part Two: Treatment of type IV thoracoabdominal aneurysms--fenestrated stent graft repair is now the best option. PMID- 21704878 TI - HIV: practical implications for the practicing allergist-immunologist. AB - OBJECTIVES: To review the effects of human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) on allergic diseases and discuss the clinical, pathophysiologic, diagnostic, and therapeutic challenges unique to HIV-infected patients receiving highly active antiretroviral therapy (HAART). DATA SOURCES: The MEDLINE and OVID databases were searched to identify pertinent articles using the following keywords: HIV, AIDS, IgE, allergic rhinitis, adverse drug reaction, asthma, chronic obstructive pulmonary disease, food allergy, and immunization. References from the chosen articles were also examined. STUDY SELECTION: Articles were selected based on their relevance to the subject matter and currency. RESULTS: Human immunodeficiency virus infection causes immunologic alterations that ultimately lead to cell-mediated immune deficiency. In addition, the immune dysfunction caused by HIV also increases the likelihood of developing allergic and other immune-mediated diseases in many patients. HAART is associated with reconstitution of immune system function. While offering protection against infection, immune reconstitution also can provoke immunopathologic conditions. Patients infected with HIV show an increased prevalence of allergic rhinitis, adverse drug reactions, and noninfectious pulmonary complications. The pathophysiology of HIV infection is associated with unique clinical, diagnostic, and therapeutic considerations when treating allergic diseases in HIV-infected patients. CONCLUSIONS: With the use of HAART and the subsequent decrease in infectious complications, HIV-infected patients now live longer and experience common chronic diseases. Evaluation of HIV-infected patients with rhinitis, asthma, and adverse drug reactions may become more frequent as HAART continues to extend the life expectancy of patients living with HIV. Understanding the interactions between HIV and these conditions can facilitate a knowledgeable approach to treating an HIV-infected patient. PMID- 21704879 TI - Current perspectives in HIV therapeutics. PMID- 21704880 TI - Serum leptin and adiponectin levels correlate with exercise-induced bronchoconstriction in children with asthma. AB - BACKGROUND: Exercise-induced bronchoconstriction (EIB), a form of bronchial hyperresponsiveness (BHR), is common in children with asthma or obesity. Epidemiological studies have shown that asthma and obesity are increasing in parallel, but obesity- and adipokine-related effects on inflammation and BHR have not yet been demonstrated in the human airway. OBJECTIVE: To address the relationship between leptin and adiponectin and EIB in children with asthma. METHODS: Eighty-five prepubertal children between the ages of 6 and 10 years were included in our study. They comprised obese with asthma (n = 19), normal weight with asthma (n = 23), obese without asthma (n = 23), and healthy (n = 20). We measured serum leptin and adiponectin levels. We also performed pulmonary function tests: baseline, postbronchodilator inhalation, methacholine inhalation, and exercise. The area under the forced expiratory volume in 1 second (FEV(1)) time curve quantified the severity of EIB over a 20-minute period after exercise (AUC(20)). RESULTS: The obese children had significantly elevated levels of leptin and reduced levels of adiponectin. The maximum decreases in %FEV(1) and AUC(20) after exercise were positively correlated with leptin levels and negatively with serum adiponectin levels in children with asthma. The odds for having EIB were incrementally and significantly higher for children with higher levels of serum leptin. CONCLUSIONS: Levels of the adipocyte-derived hormones leptin and adiponectin are significantly correlated with BHR induced by exercise challenge in children with asthma. Further studies are needed to elucidate whether the changes in leptin and adiponectin levels bear a causal relationship to the EIB/BHR. PMID- 21704881 TI - The RAD score: a simple acute asthma severity score compares favorably to more complex scores. AB - BACKGROUND: Acute asthma severity scores facilitate assessment and implementation of timely and appropriate therapy for pediatric patients but are complex and challenging for clinicians to use at the bedside. OBJECTIVE: To assess whether a simple, bedside acute asthma severity score comprising 3 standard clinical measures performs as well as more comprehensive asthma scores. METHODS: We prospectively enrolled participants 5 to 17 years of age with acute asthma exacerbations. We recorded 3 asthma scores at baseline and after 2 hours of treatment: the Pediatric Asthma Severity Score (PASS), the Pediatric Respiratory Assessment Measure (PRAM), and the RAD score (Respiratory rate; Accessory muscle use; Decreased breath sounds). We assessed each score for criterion validity in predicting baseline percent forced expiratory volume in 1 second (%FEV(1)) and for responsiveness in predicting change of %FEV(1) after 2 hours of treatment using multiple linear regression models adjusted for age, race, sex, and Global Initiative for Asthma chronic control. RESULTS: Of 536 participants included for analyses, median age was 8.8 years, 60% were male, and 58% were African American. The 3 acute asthma scores demonstrated similar criterion validity to explain variation of baseline %FEV(1) (R(2): 0.434 [PASS]; 0.462 [PRAM]; 0.426 [RAD]), but none demonstrated clinically significant responsiveness to change in %FEV(1) (R(2): 0.109 [PASS]; 0.106 [PRAM]; 0.139 [RAD]). CONCLUSIONS: The RAD score, comprising 3 routinely measured bedside clinical parameters, is a simple and easily used instrument for assessing the severity of an acute asthma exacerbation and has comparable criterion validity and improved responsiveness when compared with 2 more complex acute asthma scores. PMID- 21704882 TI - Ocular symptoms in nonspecific conjunctival hyperreactivity. AB - BACKGROUND: Ocular symptoms can be triggered by nonspecific environmental factors, characterizing conjunctival hyperreactivity (CHR). OBJECTIVE: To examine CHR in subjects with ocular symptoms by means of a hyperosmolar conjunctival provocation test (HCPT). METHODS: Sixty-three subjects with ocular complaints (itching, redness, or tearing) were tested for allergy to a common panel of inhalant allergens (Alk Abello-FDA Allergenic, Brazil). They were considered allergic if tests were positive to at least 1 allergen. HCPT with serial diluted glucose concentrations was positive if it produced conjunctival hyperemia up to a 50% solution. Digital images were analyzed by 2 observers who marked redness in the challenged eyes in red (GIMP 2.6.5 software). The number of red dots of the affected eye was compared with the number of blue dots of the control eye. RESULTS: HCPT was positive in 6 of 7 grass pollen-sensitive subjects, in 17 of 20 dust mite-sensitive subjects, and in 10 of 11 subjects who were sensitive to both allergens. HCPT was positive in 33 of 38 allergic subjects (87%) and in 4 of 25 (16%) non-allergic subjects; sensitivity was 87%, and specificity was 84%. Significant correlation (r = 0.96 Pearson; P < .0001) was seen between the number of red dots in 23 digitalized images marked by observers. CONCLUSION: HCPT indentified CHR in allergic as well as in non-allergic subjects. Allergic subjects exhibited more CHR than did non-allergic subjects. Conjunctival hyperreactivity was present in allergic subjects even when they were asymptomatic. Digital images may be useful for objective evaluation of ocular hyperemia in HCPT. PMID- 21704883 TI - Comparison of conventional and component-resolved diagnostics by two different methods (Advia-Centaur/Microarray-ISAC) in pollen allergy. AB - BACKGROUND: Component-resolved diagnostics (CRD) has recently been introduced into clinical allergology. OBJECTIVE: The aim of this study was to assess the contribution that this new diagnostic technique makes to conventional diagnosis in patients with pollen allergy, comparing CRD with conventional technologies, and to compare 2 CRD methods, Advia-Centaur and Microarray-ISAC. METHODS: Serum samples from 120 pollen-allergic patients were obtained. Immunoglobulin (Ig) E to total extracts (CAP System) and individual allergens using both CRD methods were determined. RESULTS: The 3 diagnostic methods were in agreement in 62.5% of cases. In 30%, the CRD modified the conventional diagnosis either by detecting new relevant sensitizations (mainly to Olea) or by ruling out clinically irrelevant sensitizations caused by panallergens. The main differences between the 2 CRD methods were the deficiency in the ISAC version we used (ISAC-CRD-89) to detect sensitizations to Salsola and Plantago and that Advia-Centaur did not detect sensitizations to cypress. For all allergens except for Par j 1, a significant association in the frequency of sensitization was seen with the 2 CRD techniques and good agreement when comparing the results of the 2 methods in all cases. Significant correlation was found in the concentration of specific IgE in the 2 techniques for the most prevalent allergens in our setting. The results of the different profilins analyzed using Microarray-ISAC were superimposable although somewhat lower in the case of Phl p 12. CONCLUSIONS: Component-resolved diagnostics modified the conventional diagnosis in 30% of cases. The results from the 2 CRD methods showed good agreement and correlation for most allergens. PMID- 21704884 TI - Relationship between maternal demoralization, wheeze, and immunoglobulin E among inner-city children. AB - BACKGROUND: Prior research has linked maternal prenatal and postnatal mental health with the subsequent development of asthma in children. However, this relationship has not been examined in inner-city African Americans and Hispanics, populations at high risk for asthma. OBJECTIVE: To determine the relationship of maternal demoralization with wheeze, specific wheeze phenotypes, and seroatopy among children living in a low-income, urban community. METHODS: African American and Dominican women aged 18 to 35 years residing in New York City (the Bronx and Northern Manhattan) were recruited during pregnancy (n = 279). Maternal demoralization (ie, psychological distress) was measured both prenatally and postnatally by validated questionnaire. Outcomes included wheeze, transient (birth to 2.5 years of age), late onset (3-5 years), and persistent (birth to 5 years of age), evaluated via questionnaire and total and indoor allergen specific IgE (at birth and ages 2, 3, and 5 years). Logistic regression with generalized estimating equations assessed the association of demoralization with wheeze and atopy. Multinomial regression explored associations between demoralization and specific wheeze phenotypes. RESULTS: Prenatal demoralization significantly predicted overall wheeze (adjusted odds ratio OR, 1.66; 95% confidence interval [CI], 1.29-2.14), transient wheeze (OR, 2.25; 95% CI, 1.34-3.76), and persistent wheeze (OR, 2.69; 95% CI, 1.52-4.77). No association was found between demoralization and IgE after adjustment (total IgE: OR, 1.04; 95% CI, 0.74-1.45; any specific IgE: OR, 0.96; 95% CI, 0.57-1.60). CONCLUSIONS: In this inner-city cohort, prenatal demoralization was associated with transient and persistent wheeze. Understanding how maternal demoralization influences children's respiratory health may be important for developing effective interventions among disadvantaged populations. PMID- 21704886 TI - Effect of Toll-like receptor 4 gene polymorphisms on work-related respiratory symptoms and sensitization to wheat flour in bakery workers. AB - BACKGROUND: Bakery workers are exposed to flour allergens and endotoxins, which interact to induce allergic responses and respiratory symptoms. We hypothesized that Toll-like receptor 4 (TLR4) may be involved in the development of work related respiratory symptoms and sensitization to wheat flour. OBJECTIVE: To investigate the genetic contribution of TLR4 to respiratory symptoms and sensitization to wheat flour in bakery workers, we performed a genetic association study of TLR4 in Korean bakery workers. METHODS: A total of 381 workers completed a questionnaire regarding work-related symptoms. Skin prick tests with common and occupational allergens were done, and specific antibodies to wheat flour were measured by enzyme-linked immunosorbent assay. Two single nucleotide polymorphisms (SNPs) of the TLR4 gene (-2027A>G and -1608T>C) were genotyped, and the functional effects of the polymorphisms were analyzed using the luciferase reporter and electrophoretic mobility shift assay. RESULTS: Homozygotes for the -2027G and -1608C alleles exhibited a lower prevalence of work-related lower respiratory symptoms than carriers of the -2027AA/AG (P = .007) and -1608TT/TC (P =.021) genotypes. Furthermore, haplotype analysis indicated that workers with the haplotype 2, ht2 [GC], had fewer work-related lower respiratory symptoms (P = .021). The ht2 [GC] construct showed lower promoter activity than the haplotype 1, ht1[AT], in both BEAS-2B (P = .001) and U937 cells (P = .007). CONCLUSION: Bakery workers carrying the TLR4 variants are at lower risk of developing work-related chest symptoms. This finding suggests that the TLR4 gene may be involved in allergic sensitization to wheat flour as well as endotoxin-induced respiratory symptoms in endotoxin-allergen-exposed workers and that carriers of TLR4 variants are less affected by environmental exposure. PMID- 21704885 TI - Congenital alterations of NEMO glutamic acid 223 result in hypohidrotic ectodermal dysplasia and immunodeficiency with normal serum IgG levels. AB - BACKGROUND: Hypomorphic mutations in the nuclear factor-kappaB (NF-kappaB) essential modulator (NEMO) gene result in a variable syndrome of somatic and immunologic abnormalities. Clinically relevant genotype-phenotype associations are essential to understanding this complex disease. OBJECTIVE: To study 2 unrelated boys with novel NEMO mutations altering codon 223 for similarity in phenotype in consideration of potential genotype-phenotype associations. METHODS: Clinical and laboratory features, including cell counts, immunoglobulin quantity and quality, natural killer cell cytotoxicity, and Toll-like and tumor necrosis factor receptor signaling, were evaluated. Because both mutations affected NEMO codon 223 and were novel, consideration was given to new potential genotype phenotype associations. RESULTS: Both patients were diagnosed as having hypohidrotic ectodermal dysplasia and had severe or recurrent infections. One had recurrent sinopulmonary infections and the other necrotizing soft tissue methicillin-resistant Staphylococcus aureus infection and Streptococcus anginosus subdural empyema with bacteremia. NEMO gene sequence demonstrated a 3-nucleotide deletion (c.667_669delGAG) in one patient and a substitution (667G>A) in the other. These findings predict either the deletion of NEMO glutamic acid 223 or it being replaced with lysine, respectively. Both patients had normal serum IgG levels but poor specific antibodies. Natural killer cell cytotoxicity and Toll like and tumor necrosis factor receptor signaling were also impaired. Serious bacterial infection did not occur in both patients after immunoglobulin replacement therapy. CONCLUSIONS: Two different novel mutations affecting NEMO glutamic acid 223 resulted in clinically relevant similar phenotypes, providing further evidence to support genotype-phenotype correlations in this disease. They suggest NEMO residue 223 is required for ectodermal development and immunity and is apparently dispensable for quantitative IgG production but may be required for specific antibody production. PMID- 21704888 TI - Safety of formoterol in adults and children with asthma: a meta-analysis. AB - BACKGROUND: The safety of long-acting beta2 agonists (LABA) for the treatment of persistent asthma remains a topic of ongoing debate. OBJECTIVE: To evaluate the risk of serious asthma-related events among patients treated with formoterol, a meta-analysis of all Novartis-sponsored controlled clinical trials was conducted. METHODS: Forty-five randomized, placebo- and active-controlled, parallel-group or crossover studies with formoterol were included. Background inhaled corticosteroid (ICS) use was permitted in all studies; however, in only 2 studies was ICS randomized as study medication. Sub-analyses of the pooled data were performed according to age (5-12; 13-18; >18 years), baseline ICS use, and lung function. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated between formoterol (twice-daily), albuterol (salbutamol) 4 times per day (active control), and placebo. RESULTS: Patients were randomized to formoterol (n = 5,367), placebo (n = 2,026), and albuterol (n = 976). Two deaths were reported, 1 each in the formoterol (asthma exacerbation) and the placebo (hemorrhagic pancreatitis) groups. No statistically significant differences in serious asthma exacerbations were observed compared with placebo in adolescents and adults. In children, a higher frequency of hospitalizations was observed among patients treated with formoterol compared with placebo (OR 8.4; 95% CI: 1.1-65.3). A trend toward fewer exacerbations was observed among subjects reporting concomitant ICS use at baseline. CONCLUSIONS: This analysis supports current guideline recommendations for the use of LABAs only as add-on therapy to ICS. PMID- 21704887 TI - Persistence of effectiveness of bronchial thermoplasty in patients with severe asthma. AB - BACKGROUND: Bronchial thermoplasty (BT) has been demonstrated to be safe and effective in the treatment of severe persistent asthma out to at least 1 year. Preclinical studies have demonstrated that the reduction in airway smooth muscle after bronchial thermoplasty persists out to at least 3 years. OBJECTIVES: To examine the persistence of effectiveness of BT 2 years posttreatment in subjects with severe asthma. METHODS: Subjects participating in the long-term safety follow-up phase of the Asthma Intervention Research 2 (AIR2) Trial were evaluated by comparing the proportion of subjects who experienced exacerbations, adverse events, or healthcare utilization during the first year (year 1) after BT treatment with the proportion of subjects who experienced the same during the subsequent 12 months (year 2). RESULTS: Severe exacerbations, respiratory adverse events, emergency department visits for respiratory symptoms, and hospitalizations for respiratory symptoms (proportion of subjects experiencing and rates of events), and stability of pre- and post-bronchodilator forced expiratory volume in 1 second (FEV(1)), were comparable between years 1 and 2. The proportion of subjects experiencing severe exacerbations in year 2 after BT was 23.0%, compared with 30.9% in year 1. CONCLUSIONS: The reduction in the proportion of subjects experiencing severe exacerbations after BT is maintained for at least 2 years. Bronchial thermoplasty provides beneficial long-term effects on asthma outcomes in patients with severe asthma. TRIAL REGISTRATION: clinicaltrials.gov, Identifier: NCT00231114. PMID- 21704890 TI - Severe allergic reaction to lactulose in a child with milk allergy. PMID- 21704889 TI - Efficacy of sublingual immunotherapy with house dust mite extract in polyallergen sensitized patients with allergic rhinitis. AB - BACKGROUND: It is suggested that polysensitized patients might not benefit from specific allergic rhinitis immunotherapy as much as monosensitized patients, although further research on this subject is needed. OBJECTIVE: To compare the efficacy of sublingual immunotherapy (SLIT) with standardized house dust mite extract in monosensitized and polysensitized patients with allergic rhinitis. METHODS: Patients who were sensitized to house dust mites and treated with SLIT for house dust mites for at least 1 year between November 2007 and March 2010 were studied. The monoallergen sensitized group was defined as patients who were sensitized to Dermatophagoides pteronyssinus and/or Dermatophagoides farinae (n = 70). The polyallergen sensitized group was defined as patients who were simultaneously sensitized to house dust mites and other allergens (n = 64). A standardized extract of house dust mites was used for immunotherapy. Antiallergic medication and the total nasal symptom score (TNSS), including rhinorrhea, sneezing, nasal obstruction, and itchy nose, were evaluated before and 1 year after SLIT. RESULTS: This study enrolled 134 patients. The TNSS improved significantly after SLIT in both groups, whereas the change in the TNSS did not differ significantly between the groups. The antiallergic medication scores also decreased significantly in both groups, but there was no significant difference between the groups. CONCLUSIONS: In polysensitized allergic rhinitis patients, SLIT for D pteronyssinus and/or D farinae produced improvements in both nasal symptoms and rescue medication scores comparable to those in monosensitized patients, regardless of other positive allergens. SLIT for D pteronyssinus and/or D farinae should be considered in polysensitized allergic rhinitis patients. PMID- 21704891 TI - Bruton syndrome and celiac disease. PMID- 21704892 TI - Spontaneous remission of Schnitzler syndrome. PMID- 21704893 TI - Epinephrine autoinjector delivery systems: an investigation of usability and preference. PMID- 21704894 TI - Immediate allergic reactions to beta-lactams: diagnostic accuracy of skin tests. PMID- 21704895 TI - MOC: We need more data and less hype. PMID- 21704896 TI - Nutrition--the '5th vital assessment'. PMID- 21704897 TI - Science, faith or something else? PMID- 21704898 TI - Is treatment of feline hypertrophic cardiomyopathy based in science or faith? A survey of cardiologists and a literature search. AB - PRACTICAL RELEVANCE: Feline hypertrophic cardiomyopathy (HCM) is the most common cardiac disease of cats. Treatment of HCM is usually directed at controlling signs of congestive heart failure (CHF), preventing occurrence or recurrence of systemic thromboembolism or delaying/preventing/reversing progression of subclinical disease. STUDY OBJECTIVE AND DESIGN: Despite the laudable goals of therapy, however, little objective evidence supporting therapeutic decisions has been published. We, therefore, hypothesized that cardiologists base their treatment strategies on information other than published clinically relevant science. To gain insight into therapeutic decisions that cardiologists and clinicians with an interest in cardiology (n=99) make for cats with HCM, and on what information they base these decisions, we presented participants with, and asked them to select therapy for, 12 hypothetical scenarios of HCM (+/- CHF). Responses and justifications for treatment choices were compiled and compared with the results of a comprehensive literature search for published information about treatment of feline HCM. FINDINGS: Evaluation of the therapeutic strategies chosen for these hypothetical cases of HCM suggests that cardiologists or clinicians with a strong interest in cardiology often prescribe treatments knowing that little documented evidence supports their decisions. PMID- 21704899 TI - Young, male neutered, obese, lame? Non-traumatic fractures of the femoral head and neck. AB - PATIENT GROUP: Young, male neutered, obese cats are predisposed to sustaining spontaneous capital physeal fractures, as well as fractures of the femoral neck secondary to metaphyseal osteopathy. PRACTICAL RELEVANCE: Although femoral head and neck excision generally leads to adequate limb function, and is appropriate for chronic fractures, it is a salvage procedure and irreversible. Ideally, for acute capital physeal fractures an attempt should be made to stabilise the fracture and save the coxofemoral joint. This requires early detection of the femoral fracture. CLINICAL CHALLENGES: Orthopaedic examination in cats can be challenging. Yet thorough assessment is needed to allow localisation of the pathology to the hip joint, and to rule out other orthopaedic conditions such as cranial cruciate ligament rupture. Stabilisation of these types of fracture may also prove challenging. AUDIENCE: This review is aimed at general practitioners who have some experience in orthopaedic surgical procedures, as well as those simply wishing to expand their knowledge of feline orthopaedic conditions. PMID- 21704900 TI - Feline reproduction: problems and clinical challenges. AB - AUDIENCE: Many veterinarians are closely involved with pedigree cat breeding and have become familiar with the unique characteristics of feline reproduction and breeding management. However, even veterinarians who do not have involvement with the pedigree cat fancy require a basic knowledge of the reproductive problems that are most likely to be encountered in working with non-breeding pet cats as well as stray and feral cats. CLINICAL CHALLENGES: This article reviews reproductive problems and challenges in both sexes - namely, ovarian remnant syndrome, mammary fibroadenomatous hyperplasia, congenital anomalies of the reproductive tract and pregnancy diagnosis in the queen, and cryptorchidism and low libido in the tom. EVIDENCE BASE: Feline reproduction has not received the amount of investigation and attention that has been directed at canine reproduction. The result is that less data is available both for description of normal reproduction and for management of common problems. This article reviews most of the available evidence for the conditions discussed. Efforts should focus on making information more readily available to the practitioner and expanding the knowledge base in this important area of feline medicine. PMID- 21704901 TI - WSAVA nutritional assessment guidelines. AB - OBJECTIVES: Careful assessment of the nutritional needs of cats and dogs must be taken into consideration in order to maintain optimum health, be part of a treatment regimen for a diseased state, or to maximize the quality of life in all animals. The goal of these World Small Animal Veterinary Association (WSAVA) Guidelines is that a nutritional assessment and specific nutritional recommendation is made for every patient on every visit. This will become known as the 5th Vital Assessment (5VA), following the four vital assessments of temperature, pulse, respiration and pain that are already addressed on each patient interaction. EVALUATION OF NUTRITIONAL STATUS: A brief screening evaluation of nutritional status can be routinely and seamlessly performed during the history-taking and physical examination of every patient. Nutrition-related risk factors that can be easily identified from the history and physical examination include age (growing or old), suboptimal body condition score (overweight or thin), muscle loss, atypical or homemade diet, medical conditions or changes in appetite. An extended evaluation would follow if one or more risk factors is identified on screening. These guidelines provide criteria with which to evaluate the animal and the diet, as well as key feeding and environmental factors. In addition, recommendations for interpretation, analysis and action are included so that a plan for optimizing the animal's nutritional status can be instituted. TEAM APPROACH: Client compliance with nutritional recommendations requires input from the veterinarian, veterinary technicians/nurses and hospital staff. A team approach to continuous nutritional education, implementation of appropriate protocols, and focused client communication, utilizing these WSAVA Nutritional Assessment Guidelines, is key to reaching this 5VA goal. PMID- 21704902 TI - Vitamin D-dependent non-type 1, non-type 2 rickets in a 3-month-old Cornish Rex kitten. AB - CASE PRESENTATION AND ASSESSMENT: A 3-month-old female Cornish Rex kitten was found to have non-painful swelling of the carpal and tarsal regions when presented for routine neutering. The kitten was smaller in stature and less active than its siblings and, according to the owner, had a bunny-hopping gait, was reluctant to climb stairs and strained during defecation. Radiography of the affected limbs and a subsequent radiographic survey of the entire skeleton demonstrated features consistent with rickets. The three littermates were clinically and radiographically normal. As a nutritionally complete diet was being fed, it seemed most likely that the kitten had an inborn error related to vitamin D metabolism. Serum biochemistry demonstrated reduced total alkaline phosphatase activity and increased concentrations of parathyroid hormone. Concentrations of 1,25- and 25-hydroxycholecalciferol were markedly reduced, confirming the diagnosis of rickets. TREATMENT: The kitten was treated with calcitriol, administered orally once daily, and improved rapidly both clinically and radiologically. Serial laboratory studies suggested that the error in vitamin D metabolism was transient, and, at the time of writing, as an adult, the cat appears to require no ongoing replacement calcitriol therapy. CLINICAL RELEVANCE: This case emphasises the value of examining a full 'calcium profile' via a human or veterinary reference laboratory, and a favourable prognosis in some kittens with rickets makes such investigations worthwhile. Even when finances preclude detailed investigation, trial therapy using a nutritionally complete diet and physiological doses of calcitriol or cholecalciferol is inexpensive and can produce a good response. PMID- 21704903 TI - Malignant melanoma in pleural effusion in a 14-year-old cat. AB - CASE DETAILS: A 14-year-old female cat presented with signs of respiratory distress. Pleural fluid was found on radiographic assessment. Cytologic evaluation of the fluid revealed malignant melanocytosis. The cat had a previous history of a recurrent malignant melanoma near the base of the right ear. Due to declining clinical condition, the cat was euthanized. CLINICAL SIGNIFICANCE: Cutaneous malignant melanomas (or melanosarcomas) are uncommon neoplasms in cats, and knowledge is limited. As far as the authors are aware, there are no previous reports in the veterinary literature of malignant melanocytes being identified in pleural effusion in cats, as they have in dogs. This report suggests that, despite conflicting information in the literature regarding the clinical behavior of cutaneous melanomas in cats, these tumors are capable of recurrence and metastasis. Aggressive treatment may be necessary even, as in this case, if the tumor is well differentiated on histopathology. PMID- 21704904 TI - Use of progesterone-based medications in cats--neutered or otherwise. PMID- 21704905 TI - Liberation by automated movement. PMID- 21704906 TI - Is it solely aquaporins? The mechanisms of brain edema .... PMID- 21704907 TI - The dawn of the hodotopic era in neurosurgery: is there a need to upgrade the operability criteria for brain tumors? PMID- 21704908 TI - Functional validation confirms genomic phenotypes of glioblastoma with implications for targeted therapy. PMID- 21704909 TI - A brain tumor stem cell origin for glioblastoma endothelium. PMID- 21704910 TI - Endovascular neurosurgery in the United States: a survey of 59 vascular neurosurgeons with endovascular training. AB - OBJECTIVE: We sought to assess general aspects of endovascular neurosurgery training, practice, and management for the treatment of intracranial aneurysms, arteriovenous malformations, acute ischemic stroke, and extracranial or intracranial occlusive disease within neurosurgery training and practice in the United States. METHODS: A questionnaire was sent electronically to 80 U.S. neurosurgeons with endovascular training. RESULTS: Fifty-nine surveys (74%) were returned. Survey responses illustrated different practice patterns and varying management of cerebrovascular disorders by neurosurgeons with endovascular training. CONCLUSION: Our findings provide a snapshot of current neurosurgical endovascular practices in the United States. PMID- 21704911 TI - Predictors of functional recovery in African patients with traumatic intracranial hematomas. AB - BACKGROUND: Head injury is a critical public health problem responsible for up to 50% of fatalities among trauma patients and for a large component of continuing care among survivors. Intracranial hematomas are among the most common clinical entities encountered by any neurosurgical service and have a very high mortality rate and extremely poor prognosis among traumatic brain injuries. OBJECTIVE: The purpose of this study was to investigate reliable factors influencing the functional outcome of the patients with traumatic intracranial hematomas (ICHs). METHODS: A retrospective analysis was conducted of consecutive patients presenting at the Kenyatta National Hospital between January 2000 and December 2009. Following ethical approval, the records of patients admitted to the neurosurgical unit and diagnosed with traumatic ICH were retrieved and reviewed. The outcome measure was the Glasgow Outcome Scale (GOS) score at discharge. Data were collected in preformed questionnaires, and the coding and analysis were carried out using SPSS, version 11.5. RESULTS: Of the 608 patients diagnosed with intracranial hematomas during the study period, there was a clear male predominance, with 89.3% male and 10.7% female patients. Majority of the patients (49%) were aged between 26 and 45 years, whereas 5.6% and 9.4% were younger than age 13 years and older than age 61 years, respectively. The most common cause of injury was assault (48%). Good functional recovery was achieved by 280 (46.1%) of the patients in our series, whereas moderate and severe disability accounted for 27% and 6.9%, respectively. Males were more likely to have functional recovery (46.4%) than were females (43.1%), though this finding was not statistically significant (P = 0.069). The proportion of patients who achieved functional recovery seemed to decrease with increasing age. Patients who were involved in motor vehicle accidents were less likely to have functional recovery (33.7%, P = 0.003) than those who fell (53.6%). There was a statistically significant difference in the proportion of patients who achieved functional recovery, with 65.2% of those who had mild head injury as compared to 46% and 15.1% (P <= 0.001) for those with moderate and severe head injury, respectively. Patients who had surgical intervention were more likely to achieve functional outcome (51.2%) as compared to 31.7% in those managed conservatively. Furthermore, the time elapsed from initial trauma to surgery significantly influenced outcome. The type of surgery done was not found to significantly influence patient outcome (P = 0.095). CONCLUSION: An increased risk of poor outcome occurs in patients who are older than age 61 years, have lower preoperative GCS scores, pupillary abnormalities, and a long interval between trauma and decompression. The findings would help clinicians determine management criteria and improve survival. PMID- 21704929 TI - Visualizing the future: enhancing neuroimaging with nanotechnology. AB - Advancements in imaging of the central nervous system have paralleled and propelled neurosurgical practice. These technologic innovations have expanded our understanding of neuroanatomy and neuropathology, helping to refine neurosurgical techniques to be more precise and less invasive. Nanotechnology will play a significant role in the next wave of technology that will continue to improve neurosurgical practice. With specific regard to neuroimaging, nanotechnology has the potential to provide more precise resolution when imaging nervous system malignancies. Nanoparticles may be engineered to noninvasively visualize pathology once found only under a microscope. They will enhance our ability to target new disease processes and thus develop more precise surgical and nonsurgical treatments. This article will discuss the background of nanotechnology's use in imaging of the nervous system, its current status, and future potentials. PMID- 21704930 TI - Cerebral arteriovenous malformations: issues of the interplay between stereotactic radiosurgery and endovascular surgical therapy. AB - Intracranial arteriovenous malformations (AVMs) are congenital lesions frequently diagnosed as a result of hemorrhage or other neurological symptoms. Prevention of such devastating neurological injury has promoted a variety of treatment strategies. The rich history of multimodal therapy in the treatment of AVMs includes microsurgery, endovascular embolization, and stereotactic radiosurgery (SRS). This article reviews the biology and natural history of AVMs, as well as their treatment with both SRS and endovascular neurosurgery. It considers various paradigms and goals of endovascular treatment, along with relevant issues such as the features of an AVM to be targeted. Issues of the interplay between SRS and endovascular neurosurgery include the compartments of an embolized AVM to contain within the radiosurgery plan, the radioprotective and radiosensitizing effects of the embolic agent, the durability of embolization, and the sequencing of embolization with respect to the radiosurgical treatment. Published literature on these topics is sparse, and the flimsiness of the data offers limited guidance. PMID- 21704931 TI - Intracranial venous sinus stenting for benign intracranial hypertension: clinical indications, technique, and preliminary results. AB - OBJECTIVE: The cause of pseudotumor cerebri, or benign intracranial hypertension (BIH), is controversial. We report our results from 18 cases of venous sinus stenting (VSS), the largest series in the literature, with specific focus on the rate of technical success, amelioration of the subjective symptom of headache, attendant complications, and radiographic patency on follow-up. METHODS: Review of our prospectively maintained database identified 18 patients who had undergone 19 VSS procedures for the placement of 30 stents in the past 2.5 years. Indications for treatment included a clinical diagnosis of BIH with venographic demonstration of stenosis. RESULTS: VSS was technically successful in all patients (100%). No patient suffered a permanent complication. Three patients were lost to follow-up. The remaining 15 patients were followed clinically and asked to rate their headache severity on a scale of 1 to 10 both before and after VSS. Overall, 12 patients (80%) qualified their headaches as better after VSS, two stated that they were the same, and one patient said that they were worse. Of 14 patients who underwent follow-up angiography, all demonstrated normal patency of the stented segments. In one of these patients, stenosis was detected on follow-up in the unstented segment of the sigmoid sinus and jugular bulb. CONCLUSIONS: VSS is highly effective (80%) in ameliorating headache associated with BIH. The procedure is associated with a high rate of technical success (100%), a low rate of permanent complications (0), and a high rate of stent patency on follow-up angiography (100%). PMID- 21704932 TI - Language, memory, and verbal fluency changes in patients with aneurysmal subarachnoid hemorrhage: results of a preoperative investigation. AB - OBJECTIVE: To detect changes in speech, verbal fluency, and memory in patients with subarachnoid hemorrhage (SAH) caused by ruptured aneurysms and to analyze the results before surgical or embolization procedure. METHODS: During the period May 2007 to November 2009, 193 patients with anterior aneurysmal SAH admitted to the Department of Neurosurgery, Hospital da Restauracao, Recife, Brazil, were tested for speech, verbal fluency, and memory disturbances after the first week of bleeding and compared with a control group with similar demographics. RESULTS: Patients with aneurysmal SAH differed significantly from the control group in language, verbal fluency, and memory functions before clipping or coiling procedures. There were differences in cognitive performance between patients with different aneurysm sites. CONCLUSIONS: It was possible to characterize the cognitive impairments of each area affected early on in the preoperative period, confirming the assumptions that the aneurysm site could be a determining factor of cognitive impairment. PMID- 21704933 TI - The evolving role of hemodilution in treatment of cerebral vasospasm: a historical perspective. AB - OBJECTIVE: Hypertension, hypervolemia, and hemodilution [HHH] therapy is widely used for prophylactic and therapeutic means in the setting of angiographic or clinical cerebral vasospasm. Hemodilution remains the most controversial aspect of the HHH therapy. METHODS: We performed a literature review to identify the current state of support for hemodilution as a therapeutic modality in treatment of cerebral vasospasm. RESULTS: Over time, evidence has been accumulating against the efficacy of HHH therapy and hemodilution in particular. Although HHH therapy and consequently hemodilution has wide support, the evidence for its effectiveness remains equivocal. CONCLUSIONS: At the time of this study, the burden of evidence appears to be tipped away from hemodilution as a therapeutic modality. PMID- 21704934 TI - Initial experience with the eXtend System: a relocatable frame system for multiple-session gamma knife radiosurgery. AB - OBJECTIVE: To present our initial experience with the Elekta eXtend System, a relocatable frame system for multiple-fraction or serial multiple-session radiosurgery. METHODS: The eXtend System comprises a carbon-fiber frame system known as the eXtend Frame, a vacuum cushion, and a vacuum pump/vacuum surveillance system. The eXtend Frame comprises a carbon-fiber frame, a mouthpiece with dental impression, and a configurable front-piece that accepts the mouthpiece and rigidly attaches to the carbon-fiber frame. Treatment preparation involves creating a dental impression, fitting the patient to the frame system at the Gamma Knife, acquiring a stereotactic computed tomography (CT) scan, and co-registering a volumetric magnetic resonance image. Measurements taken at the time of CT imaging using high-precision electronic probes locate the patient's head within the eXtend frame. These measurements are compared to measurements taken at the time of treatment to ensure the patient is in proper treatment position. Vacuum surveillance interlocks pause the treatment if the patient moves within the eXtend frame. RESULTS: As of June 2010, we have treated four patients at the University of Virginia with the eXtend System. In all cases treated to date, we were able to complete all fractions of the prescribed treatments. In addition, while in some cases repositioning before a given fraction required several attempts, we were able to achieve a radial repositioning error of less than 1 mm without taking new reference measurements and repeating patient setup and imaging. CONCLUSIONS: Gamma Knife radiosurgery (GKRS) has traditionally been a single-fraction treatment modality. The eXtend System expands the range of indications for GKRS to those that may benefit from multi-fraction or serial multi-session techniques. The relocatable eXtend frame can provide non-invasive head fixation while maintaining a high accuracy, high dose, and the steep gradients associated with GKRS. PMID- 21704935 TI - Clinical outcomes of stereotactic radiosurgery in the treatment of patients with metastatic brain tumors. AB - BACKGROUND: Stereotactic radiosurgery (SRS) is a form of radiation therapy that delivers a focused, highly conformal dose of radiation to a single volume, while minimizing damage to the adjacent nervous tissue. The efficacy of SRS has been examined in the treatment of patients diagnosed with brain metastases due to the fact that it is capable of targeting any region in the brain and can irradiate multiple tumors in the same treatment setting in a noninvasive fashion. METHODS: Modern literature was reviewed for studies on SRS in the treatment of patients with brain metastases. RESULTS: After assessing patient age, Karnofsky Performance Score (KPS), control of primary cancer, presence of extracranial metastases, number of brain metastases, location of brain metastases, and size of brain metastases, SRS offers suitable patients a viable, less invasive treatment option. In patients with 1 to 4 brain metastases who have a KPS >=70, the addition of SRS to whole-brain radiation therapy (WBRT) produces increased levels of survival and local tumor control when compared with patients treated with WBRT alone. The available evidence suggests that specific patients treated with SRS alone exhibit superior levels of survival and tumor control when compared with patients treated with WBRT alone. Further evidence in the form of a randomized trial is needed to confirm this observation. Questions remain regarding survival and tumor control in patient groups treated with SRS with or without WBRT. Recently published randomized evidence reported a survival advantage in patients treated with SRS alone. These data differ from other previously published randomized evidence, as well as several prospective and retrospective studies, which reported nonsignificant survival differences. Contrasting evidence also exists pertaining to local and distant tumor control, which warrants further investigation into this matter. The available evidence suggests that in patients with 1 to 2 brain metastases, both SRS alone and SRS with WBRT offer equivalent levels of survival when compared with patients treated with surgery with WBRT. Research has been conducted that reports a survival advantage in patients with 1 to 3 brain metastases that were treated with SRS with WBRT. CONCLUSIONS: SRS can be an advantageous course of treatment in specific patient groups when utilized alone, after surgery, with WBRT, or in combination with either or both of the treatment modalities. Although treatment approaches have been refined, many questions remain unanswered and further clinical evidence is needed to guide physicians in their future treatment decisions regarding treating patients in specific clinical scenarios. PMID- 21704936 TI - Gamma knife surgery in brain melanomas: absence of extracranial metastases and tumor volume strongest indicators of prolonged survival. AB - OBJECTIVE: To review a series of patients who underwent Gamma Knife surgery (GKS) to identify prognostic factors for local growth control and survival. METHODS: During the period 1996-2006, 77 patients (42 men and 35 women) with a total of 143 metastases underwent GKS. A solitary lesion was present in 40 patients (51.9%). RESULTS: Growth control was achieved in 114 of 128 (89.1%) tumors and 59 of 70 (84.3%) patients. The median survival was 7 months (range 0-73 months) after GKS and 67 months (range 4-327 months) from the time of diagnosis. Patients with absence of extracranial disease lived longer than patients with more widespread disease-median 16 months (range 3-52 months) versus 6 months (range 0 73 months; P = 0.014). A total tumor volume of less than 5 cc was associated with longer survival (P = 0.041). Survival was significantly longer in recursive partitioning analysis (RPA) class 1 (22 months) than RPA class 2 (7 months) and RPA class 3 (3 months; P = 0.008). Even in cases of treatment failure with tumor growth or appearance of new metastases, GKS slowed down the cerebral disease with no significant reduction in the duration of survival. CONCLUSIONS: GKS for melanoma brain metastasis provides a high rate of local tumor control. Survival is longest for well-functioning patients with absence of extracranial metastases or with an intracerebral total tumor volume less than 5 cc. PMID- 21704937 TI - Sequelae of autologous fat graft used for reconstruction in skull base surgery. AB - BACKGROUND: The use of an autologous free fat graft is a widely applied technique to obliterate dead space and reinforce dural closure during skull base reconstructions. The associated complications and outcomes of this practice have not been studied. Dissemination of fat in the subarachnoid space resulting in lipoid meningitis has been reported after translabyrinthine approaches, and leakage of liquefied fat is seldom reported in the literature. This study aims to evaluate the morbidity associated with the usage of autologous fat graft in reconstruction of skull base defects based on an extensive experience. METHODS: This study is a retrospective review of 1581 cases in which the senior author (O.A.) used a skull base approach for the resection of tumor. Autologous fat grafts were used for reconstruction in 974 cases and 10 cases (male to female ratio, 4:6) in which there were associated complications were analyzed. RESULTS: Complications included leakage of sterile liquefied fat from fistula (patients 1, 2, 3), delayed cerebrospinal fluid leak after radiation (Patients 5, 6, 9), and postoperative lipoid meningitis (Patients 4, 7, 8, 10). The onset ranged from 11 days to 10 years. Four patients were managed conservatively, and the other six required surgical intervention. All patients had good outcomes after treatment. CONCLUSIONS: The use of autologous fat is associated with a 1% complication rate and should be considered a safe and effective method for skull base reconstruction. However, neurosurgeons should be aware of early and late complications of fat necrosis, including sterile liquefied fat fistula, cerebrospinal fluid leakage, and lipoid meningitis. PMID- 21704938 TI - Harvey Cushing's repair of a dural defect after a traumatic brain injury: novel use of a fat graft. AB - OBJECTIVE: A review of Harvey Cushing's surgical cases at Johns Hopkins Hospital revealed new information about his early work with the use of fat grafts to close dural defects. METHODS: The Johns Hopkins Hospital surgical records from 1896 to 1912 were reviewed. A single case in which Cushing used an autologous fat graft to repair a dural defect in 1912 after a traumatic brain injury was selected for further study. RESULTS: An 18-year-old white female patient presented with recurring seizures in her sleep approximately 12 years after a traumatic brain injury. A depressed skull fracture as a result of this injury was explored by Cushing, and a dural defect was found. Fat was harvested from the thigh of the patient and was sutured in layers to cover the defect. Cushing noted that this was the first of its kind of operation and "probably of very little use." The patient was discharged within 2 weeks after the operation despite recurrence of her seizure episodes. CONCLUSIONS: Despite its questionable functional success, we report herein a previously unpublished operative case by Harvey Cushing's in which an autologous fat graft was used to close a traumatic wound resulting in a dural defect. This report predates currently known published reports of the use of fat to seal dural defects. Cushing recognized that a factor found in fat tissue may aid in wound healing. Contemporary studies indicate the presence of mesenchymal stem cells in fat tissue may be responsible for the accelerated healing and reduced incidence of cerebral spinal fluid leaks after cranial surgery. PMID- 21704939 TI - Lhermitte-Duclos disease associated with dysembryoplastic neuroepithelial tumor differentiation with characteristic magnetic resonance appearance of "tiger striping". AB - BACKGROUND: The simultaneous presence of Lhermitte-Duclos disease (LDD) with focal areas of nodular dysembryoplastic neuroepithelial tumor (DNET) differentiation in the cerebellar hemisphere is reported in a patient who showed the characteristic magnetic resonance imaging (MRI) appearance of "tiger striping". CASE REPORT: A 25-year-old man presented with a 7-month history of holocranial headache, progressive vision diminution, and right-sided cerebellar signs. Computed tomography (CT) scan revealed a hypodense, nonenhancing right cerebellar lesion effacing the fourth ventricle. There were thin hyperdense, linear striations across the tumor with hypodense streaks between them. The third and lateral ventricles were dilated with periventricular lucency. MRI showed the hypointense-to-isointense right cerebellar lesion with linear striations on T1 weighted images. The lesion was hyperintense on T2-weighted images with areas of linear hypointensity streaks running throughout the lesion characteristic of the "tiger striping" effect of LDD. Sagittal MRI revealed tonsillar herniation. Gross total removal of the tumor was accomplished with right paramedian suboccipital craniectomy. The postoperative course was unremarkable, and the patient remained symptom-free at 3-month follow-up examination. Histology revealed the simultaneous presence of LDD with DNET. CONCLUSIONS: To the best of the authors' knowledge, the simultaneous presence of cerebellar LDD with DNET has never been reported before. This case report may point to their common genesis with cortical dysplasia and neuronal migrational abnormalities playing an important role. LDD and DNET may represent different points in the spectrum of the lesion-from being purely hamartomatous to having a greater proliferative potential. The simultaneous presence of LDD and DNET was perhaps responsible for the unusually rapid neurologic deterioration in this patient before surgical intervention. PMID- 21704940 TI - Choroidal fissure cerebrospinal fluid-containing cysts: case series, anatomical consideration, and review of the literature. AB - BACKGROUND: Cerebrospinal fluid (CSF)-containing cysts at the level of the choroidal fissure are rare embryological entities infrequently described in the literature because of their benign nature. On the occasion of a case series, we present an overview of the literature and discuss anatomical and embryological location, imaging characteristics, presenting symptoms, and treatment indication of these lesions. METHODS: We identified, in a retrospective study of a database with 81 patients harboring 86 supratentorial intracranial cysts, six patients with a CSF-containing cyst at the level of the choroidal fissure. In all cases, presenting symptoms were mild and the cysts were considered a fortuitous diagnosis. None of the patients was treated surgically, and the cysts remained stable at radiological follow-up. We performed a literature search for cerebral cysts and choroidal fissure cysts in particular. RESULTS: Only one large study purely addressing choroidal fissure cysts was found in the literature. CONCLUSIONS: CSF-containing cysts at the level of the choroidal fissure may be of the arachnoid or the neuroepithelial type, but pathological confirmation of a CSF containing cyst at this specific location has never been published. Very infrequently they are symptomatic, and surgical treatment is hardly ever necessary. PMID- 21704941 TI - A new classification of complications in neurosurgery. AB - OBJECTIVE: To define and grade neurosurgical and spinal postoperative complications based on their need for treatment. METHODS: Complications were defined as any deviation from the normal postoperative course occurring within 30 days of surgery. A four-grade scale was proposed based on the therapy used to treat the complications: grade I, any non-life-threatening complications treated without invasive procedures; grade II, complications requiring invasive management such as surgical, endoscopic, and endovascular procedures; grade III, life-threatening adverse events requiring treatment in an intensive care unit (ICU); and grade IV, deaths as a result of complications. Each grade was classified as a surgical or medical complication. An observational test of this system was conducted between January 2008 and December 2009 in a cohort of 1190 patients at the Hospital Italiano de Buenos Aires. RESULTS: Of 167 complications, 129 (10.84%) were classified as surgical, and 38 (3.19%) were classified as medical complications. Grade I (mild) complications accounted for 31.73%, grade II (moderate) complications accounted for 25.74%, and grade III (severe) complications accounted for 34.13%. The overall mortality rate was 1.17%; 0.84% of deaths were directly related to surgical procedures. CONCLUSIONS: The authors present a simple, practical, and easy to reproduce way to report negative outcomes based on the therapy administered to treat a complication. The main advantages of this classification are the ability to compare surgical results among different centers and times, the ability to compare medical and surgical complications, and the ability to perform future meta-analyses. PMID- 21704942 TI - Brain abscess: management and outcome analysis of a computed tomography era experience with 973 patients. AB - OBJECTIVE: Brain abscess (BA) is a neurosurgical emergency and despite significant medical advances, it remains a surgical challenge. A single institution's two decade computed tomography era management experience with BA is reported. METHODS: A retrospective analysis of patients with BA, admitted to the Department of Neurosurgery, Wentworth Hospital, Durban, KwaZulu-Natal, South Africa, was performed. The medical records were analyzed for demographic, clinical, neuroimaging, neurosurgical and otolaryngology management, microbiological characteristics, and their relationship to outcome. RESULTS: During a 20-year period (1983-2002), 973 patients were treated. The mean age was 24.36 +/- 15.1 years (range: 0.17-72 years) and 74.2% (n = 722) were men. The mean admission Glasgow Coma Score was 12.5 +/- 2.83. The majority of BAs were supratentorial (n = 872, 89.6%). The causes were otorhinogenic (38.6%), traumatic (32.8%), pulmonary (7%), cryptogenic (4.6%), postsurgical (3.2%), meningitis (2.8%), cardiac (2.7%), and "other" (8.6%). Surgical drainage was performed in 97.1%, whereas 19 patients had nonoperative management. The incidence of BA decreased during the study period. Patient outcomes were good in 81.3% (n = 791), poor in 5.3% (n = 52), and death (13.4%, n = 130) at discharge. The management morbidity, which included postoperative seizures, was 24.9%. Predictors of mortality were cerebral infarction (odds ratio [OR] 31.1), ventriculitis (OR 12.9), coma (OR 6.8), hydrocephalus (OR 5.1), dilated pupils (OR 4.8), bilateral abscesses (OR 3.8), multiple abscesses (OR 3.4), HIV co-infection (OR 3.2), papilledema (OR 2.6), neurological deterioration (OR 2.4), and fever (OR 1.7). CONCLUSIONS: Optimal management of BA involves surgical drainage for medium-to large abscesses (>=2.5 cm) with simultaneous eradication of the primary source, treatment of associated hydrocephalus, and administration of high doses of intravenous antibiotics. The incidence of BA is directly related to poor socioeconomic conditions and therefore, still poses a public health challenge in developing countries. PMID- 21704943 TI - Acute hemicerebellitis with obstructive hydrocephalus in a young adult. AB - BACKGROUND: Acute cerebellitis is a rare entity, described in the pediatric population, usually of viral or autoimmune origin, bilateral and symmetric, and with good prognosis. Only 13 cases of unilateral cerebellitis have been reported thus far. To the best of our knowledge, this is the first case of hemicerebellitis in the literature reported in a young adult that caused acute hydrocephalus requiring surgical treatment. CASE DESCRIPTION: We report an unusual case of an 18-year-old man, without previous infectious symptoms, who developed acute obstructive hydrocephalus secondary to hemicerebellitis. A ventricular drainage was placed. The affected cerebellar hemisphere was later explored and biopsied, and edematous tissue, with an inflammatory reaction of the leptomeninges, was obtained. With corticosteroids and antivirals, the neurologic symptoms disappeared and the MRI evolved to normal in 2 week's time. CONCLUSIONS: Hemicerebellitis must be considered in the differential diagnosis of cerebellar mass lesions, even in young adults. Although rare, clinically significant hydrocephalus may develop. Despite the availability of MRI, a high index of suspicion is still required to accurately diagnose this entity. The histologic substrate seems to be localized meningitis. The edematous reaction of the cerebellar parenchyma supports the usefulness of corticoids in the treatment strategy of this disease. PMID- 21704944 TI - A randomized controlled trial comparing the outcome of burr-hole irrigation with and without drainage in the treatment of chronic subdural hematoma: a preliminary report. AB - BACKGROUND: Burr-hole is the most frequently used neurosurgical treatment for chronic subdural hematoma (CSDH). Few data can be found in the literature confirming the impact of using drainage after evacuation and irrigation of the cavity containing CSDH on the outcome of the patients. It is not clear whether installing such a drainage system would reduce the recurrence rate. OBJECTIVE: The aim of this study was to compare the postoperative recurrence rates and the chance of occurrence of other possible complications between a group treated by burr-hole irrigation without drainage (BI-D) and burr hole-irrigation with drainage (BI+D). MATERIALS AND METHODS: Forty patients experiencing CSDH were included in a randomized controlled trial conducted between June 2007 and July 2009. All underwent surgery and were analyzed in this preliminary report. Twenty patients were assigned to BI+D group and the other 20 to the BD-I group. Inclusion and exclusion criteria are defined, and the cases happened to be well matched. All the epidemiologic, clinical, radiologic, procedure-related, and outcome variables were saved in the data sheaths and analyzed by the use of SPSS v 14. The patients were followed by an independent observer, who visited the patients at 1- and 6-month intervals. RESULTS: There were 28 male and 12 female patients (2.3:1) with the age range between 18 and 96 years (mean, 67 years; SD, 18 years). Glasgow coma scale scores varied between 9 and 15 in 37 patients and less than 9 in the other 3 patients. A history of head trauma was established in 25 patients. Limb weakness, loss of consciousness, and headache were the most common presentations. Recurrence occurred in one patient (5%) in BI+D and in none of the patients in BI-D group after 1-month follow up, without significant statistical difference (P = 0.31). At the end of 6 months there was one more recurrence (5%) in BI-D group, and the recurrence rates became equal. Both patients who experience a recurrence used antiplatelet drugs, and the one in BI-D group also had diabetes. The morbidity and mortality rates were greater in BI+D group, but these finding were not statistically significant (P = 0.37 and 0.73, respectively). There were no significant differences between the two surgical approaches regarding their relation with the recurrence of CSDH, the patient's morbidity, or mortality. The relative risk was greater for BI+D when the primary and secondary outcome measures were taken into account, but it was not significant statistically. CONCLUSION: Type of surgical technique does not seem to be a main variable improving the outcome of such patients and may act as a confounding factor. Age, neurological status, and comorbidities seem to have more significant impact upon the surgical outcome. PMID- 21704945 TI - Reoperations after surgery for lumbar spinal stenosis. AB - OBJECTIVE: To study the indication for reoperations after lumbar decompression, the factors predisposing to redo operations, and the effect of prior instrumentation on developing adjacent level stenosis requiring reoperation. METHODS: Kaplan-Meier analysis was used to compare the median interval to first reoperation. Cox regression was used for multivariate analysis of time to first reoperation. RESULTS: Of 335 patients who underwent surgery for lumbar spinal stenosis, 63 (18%) underwent instrumentation in addition to decompression. There were 50 reoperations performed in 44 patients (13%). Of these 50 reoperations, 26 were at the same level, 14 were at the same level plus an adjacent level, and 10 were at an adjacent level. In 21 reoperations, the indication was adjacent level spinal stenosis; in 16, adjacent level spinal stenosis plus instability; in 9, instability alone; and in 4, disc problem. The risk of reoperation was higher among male patients (hazard ratio [HR] 1.2, 95% confidence interval [CI] 0.586 2.635) and in patients with prior instrumentation (HR 1.7, 95% CI 0.684-4.640). There was no statistical association between prior instrumentation and subsequent risk of reoperation (P = 0.12). There was no association between prior instrumentation and development of adjacent level stenosis requiring reoperation (P = 0.473). CONCLUSIONS: Many patients with spinal stenosis undergo instrumentation because of instability. Most patients in this study underwent reoperation at the same level, and the most common pathology was spinal stenosis. The risk of reoperation was lower in older patients (>=65 years old). Although there was a trend that the risk of reoperation was higher among patients with prior instrumentation, it did not reach statistical significance. In this study, there was no association between prior instrumentation and adjacent level stenosis requiring reoperation. These findings need to be evaluated further in randomized trials. PMID- 21704946 TI - Dysfunctional segmental motion treated with dynamic stabilization in the lumbar spine. AB - OBJECTIVE: To determine the suitability of the application of dynamic stabilization (DS) as a nonfusion technique to address dysfunctional segmental motion (DSM) in the lumbar spine. METHODS: Over a 1-year period, 25 patients were treated with the same assessment and surgical protocol. Inclusion criteria were clinical presentation of DSM with or without stenosis. On preoperative and postoperative plain anteroposterior, lateral, and lateral flexion-extension radiographs, anterior and posterior disc height (DH); anteroposterior diameter of the disc; and global, segmental, apical segment, and below level lordotic angles (LAs) were measured. RESULTS: The study included 9 women and 16 men with a mean age of 43.48 years +/- 7.6. On average, patients had symptoms for 38.04 months +/ 29.6, and mean follow-up was 12.36 months +/- 3.46. The average height of anterior, posterior, and mean intervertebral discs increased significantly (P = 0.002, P = 0.003, and P < 0.0001). There were no significant differences between the preoperative and postoperative global, segmental, apical segment, and below segment LAs in flexion, extension, and neutral positions. At mid-term follow-up, no patients showed new signs of degeneration at the adjacent motion segment. CONCLUSIONS: Overall, the limited radiologic data advocate DS as a nonfusion technique in the treatment of DSM in the lumbar spine. Long-term follow-up is essential, however, to investigate the long-term efficacy of DS in the surgical treatment of DSM. PMID- 21704947 TI - Charles Edouard Brown-Sequard's departure from the Medical College of Virginia: incompatible science or incompatible social views in pre-Civil War southern United States. AB - Charles Edouard Brown-Sequard was one of the most colorful characters in modern physiology. His scientific methods of self-experimentation and animal vivisection led to many great observations, including the eponymous syndrome of hemisection of the spinal cord. Despite his renown, he stayed but one year in his first major academic post. Details of his sojourn at the Medical College of Virginia (now part of Virginia Commonwealth University) in Richmond were divined from perusal of archival material, letters, and from the available literature. His notoriety in the field of physiology landed him a post at the Medical College of Virginia in 1854 as the chair of physiology. During a brief time here, he was able to publish his landmark monograph of 1855 on the pathways of the spinal cord "Experimental and Clinical Researches on the Physiology and Pathology of the Spinal Cord." He had a near-death experience while experimenting on himself to determine the function of the skin. It was rumored that his English was poor, his lectures unintelligible, and his scientific methods disturbing to the neighbors and that for those reasons he was asked to vacate his post. Personal communications and other accounts indicate a different view: his mixed-blood heritage and his views on slavery were unpopular in the pre-Civil War southern United States. These disparate viewpoints lend an insight into the life and career of this pioneer in modern medicine and experimental design and to the clash of science and social views. PMID- 21704948 TI - Surgical management of a giant plexiform neurofibroma of the lower extremity. AB - The authors review their experience with the management of a giant 49-kg (108 lb) neurofibroma of the lower extremity in a 37-year-old male with NF1. The patient presented with right thigh pain, paresthesias, increasing edema, and accelerated growth of the mass. The patient was taken to the operating room, where approximately 39 kg (86 lb) of tumor and 10 L (22 lb) of interstitial fluid was removed. The postoperative course was complicated by cellulitis, delayed wound closure, and recurrent lymphedema. Complications were managed with antibiotics, ultrasound-guided drainage, surgical revision of closure, compressive dressings, passive drainage, and vacuum-assisted wound closure. Giant neurofibromas similar to this tumor require complex intraoperative and postoperative management strategies. Surgical closure is best managed with local flaps, and postoperative lymphedema is best managed with passive drainage and compressive dressings. PMID- 21704949 TI - Hidden semi-Markov models in the computerized decoding of microelectrode recording data for deep brain stimulator placement. AB - OBJECTIVE: To describe an approach to the analysis of deep brain stimulation (DBS) of the subthalamic nucleus (STN) using a hidden semi-Markov model (HsMM) and early results of the analysis of microelectrode recordings for STN DBS. METHODS: The author simulated the anatomy and electrophysiology of STN DBS and built a seven-state model to compare Hidden Markov model (HMM) and HsMM approaches. RESULTS: Accuracy of these competing models was similar for correctly identifying brain nuclei; however, HsMMs showed superior specificity in detecting microelectrode passes traversing the STN. CONCLUSIONS: Further clinical work must be done; however, based on these data, HsMMs may be best suited to computer assisted anatomic delineation for DBS. PMID- 21704950 TI - Systematic review of randomized controlled trials evaluating the efficacy and safety of ginseng. AB - This systematic review aims to evaluate the available evidence from randomized clinical trials of the clinical efficacy and safety of ginseng. Systematic literature searches were performed in 13 databases up to March 2009 without language restriction. All randomized clinical trials evaluating the clinical effects or safety of the use of ginseng monopreparations (Panax ginseng or P. quinquefolium) were considered for inclusion. A total of 411 potentially relevant studies were identified and 57 randomized clinical trials were included. The main indications included glucose metabolism, physical performance, psychomotor function, sexual function, cardiac function, pulmonary disease, and cerebrovascular disease. We found strong evidence of a positive effect of ginseng on glucose metabolism, psychomotor function, and pulmonary disease, whereas evidence suggests that ginseng is not effective at enhancing physical performance. However, ginseng generally has a good safety profile and the incidence of adverse effects seems to be low. In conclusion, our review compiles the evidence on the use of ginseng, finding a strong positive potential for glucose metabolism, psychomotor function, and pulmonary disease, but not for physical performance enhancement. PMID- 21704951 TI - Study of novel threadlike structures on the intestinal fascia of dogs. AB - The primo-vascular system was visualized in the mesentery surrounding the small intestine of a dog using Trypan blue. This structure, which was first observed in a rat, formed a network as primo-vessel branches were joined to primo-nodes. Other characteristic features of the primo-vascular system, such as bundles of tubes with fibrous extracellular matrix in a primo-vessel and a broken-line alignment of rod-shaped nuclei along the primo-vessel, were observed. Blood vessels, lymph vessels, and primo-vessels were present in the same mesentery, and they could clearly be distinguished by histological differences. PMID- 21704952 TI - Expression of keratin 10 in rat organ surface primo-vascular tissues. AB - The primo-vascular system is described as the anatomical structure corresponding to acupuncture meridians and has been identified in several tissues in the body, but its detailed anatomy and physiology are not well understood. Recently, the presence of keratin 10 (Krt10) in primo-vascular tissue was reported, but this finding has not yet been confirmed. In this study, we compared Krt10 expression in primo-vascular tissues located on the surface of rat abdominal organs with Krt10 expression on blood and lymphatic vessels. Krt10 protein (approximately 56.5 kDa) was evaluated by western blot analysis and immunohistochemistry. Krt10 (IR) in the primo-node was visualized as patchy spots around each cell or as a follicle-like structure containing a group of cells. Krt10 IR was also identified in vascular and lymphatic tissues, but its distribution was diffuse over the extracellular matrix of the vessels. Thus Krt10 protein was expressed in all three tissues tested, but the expression pattern of Krt10 in primo-vascular tissue differed from those of blood and lymphatic vascular tissues, suggesting that structural and the regulatory roles of Krt10 in primo-vascular system are different from those in blood and lymphatic vessels. PMID- 21704953 TI - Comparison of electroacupuncture frequency-related effects on heart rate variability in healthy volunteers: a randomized clinical trial. AB - This study aimed to compare the effects of high frequency electroacupuncture (EA) and low-frequency EA on the autonomic nervous system by using a heart rate variability measuring device in normal individuals. Fourteen participants were recruited and each participated in the high-frequency and low-frequency sessions (crossover design). The order of sessions was randomized and the interval between the two sessions was over 2 weeks. Participants received needle insertion with 120-Hz stimulation during the high-frequency session (high-frequency EA group), and with 2-Hz stimulation during the low-frequency session (low-frequency EA group). Acupuncture needles were directly inserted perpendicularly to LI 4 and LI 11 acupoints followed by delivery of electric pulses to these points for 15 minutes. Heart rate variability was measured 5 minutes before and after EA stimulation by a heart rate variability measuring system. We found a significant increase in the standard deviation of the normal-to-normal interval in the high frequency EA group, with no change in the low-frequency EA group. Both the high frequency and low-frequency EA groups showed no significant differences in other parameters including high-frequency power, low-frequency power, and the ratio of low-frequency power to high-frequency power. Based on these findings, we concluded that high-frequency EA stimulation is more effective than low-frequency EA stimulation in increasing autonomic nervous activity and there is no difference between the two EA frequencies in enhancing sympathovagal balance. PMID- 21704954 TI - Anti-spermatogenic activity of ethanol extract of Dalbergia sissoo Roxb. stem bark. AB - The study was undertaken to evaluate the anti-spermatogenic efficacy of ethanol extract of stem bark of Dalbergia sissoo Roxb. For the in vitro study, semen samples were obtained from 15 healthy fertile men aged 25-35 years. Sperm motility was examined by the Sander-Cramer method. A dose-dependent and time dependent effect of ethanol extract on sperm motility and sperm viability were observed. Various concentrations affected the motility of sperm. Ethanol extract at a concentration of 20 mg/mL caused complete immobilization within 3 minutes. Sperm viability and hypo-osmotic swelling was significantly reduced at this concentration. The in vivo studies were carried out on Swiss male albino mice. Ethanol extract at a dose of 200 mg/kg body weight resulted in a significant decrease (p<0.001) in weight of the testis and epididymis. A significant decrease (p<0.01) in sperm motility and sperm count in the epididymis were observed. Histological changes in the epididymis and testis were also investigated. PMID- 21704955 TI - Identification and analysis of differentially expressed genes in mountain cultivated ginseng and mountain wild ginseng. AB - Ginseng is one of the most widely used herbal medicines in the world. Wild ginseng is thought to be more effective than cultivated ginseng in chemoprevention; however, little has been reported on the differences between wild and cultivated ginseng. In the present study we used suppressive subtractive hybridization to identify wild ginseng-specific genes. One of the clones isolated in this screen was the NRT2 gene (designated pNRT2), a high-affinity nitrate transporter. Real-time reverse transcription-polymerase chain reaction results showed that pNRT2 expression was significantly upregulated in wild ginseng compared with cultivated ginseng. However, pNRT2 mRNA levels were similar between mountain cultivated ginseng and mountain wild ginseng. Nitrate is an important nitrogen source for plant growth, and its soil levels can vary in wild environments; thus it is conceivable that pNRT2 expression is upregulated in wild ginseng and may be an important marker of wild ginseng. PMID- 21704956 TI - Effect of Gui-zhi-fu-ling-wan on hot flashes in young patients: a retrospective case series. AB - Hot flashes are one of the main problems in postmenopausal patients. Hormone replacement therapy is the standard treatment for this vasomotor symptom, but long-term estrogen treatment can produce serious adverse effects such as higher risks of cardiovascular disease and breast cancer. For this reason, hormone replacement therapy may not be advisable for young patients. Gui-zhi-fu-ling-wan is an herbal decoction for hot flashes used in traditional Chinese medicine. We have extensive experience treating hot flashes in young women; this preliminary case series evaluates the effectiveness of Gui-zhi-fu-ling-wan for alleviating hot flashes in young patients. In this retrospective case series, we reviewed the medical records of outpatients who visited the Department of Cardiovascular and Neurologic Disease, Kyung Hee Oriental Medical Center for hot flashes from October 1, 2003 to October 1, 2008. Of the 60 cases, 37 met the inclusion criteria. Mean improvement in symptoms, as assessed using the visual analog scale, was 40.4 +/- 28.5%; 51.3% of patients experienced a 50% improvement. According to the secondary analysis, the results of differential diagnosis of cold and hot syndrome and blood stasis syndrome did not affect scores. Only 2.7% of the patients reported adverse events. Our findings suggest that Gui-zhi-fu ling-wan improves hot flashes in young patients in a relatively safe manner. However, rigorous clinical studies are needed to confirm these results. PMID- 21704957 TI - Overview for various aspects of the health benefits of Piper longum linn. fruit. AB - Herbal remedies have become popular, due in part to the lower risk of adverse reactions. Thousands of plants have been used traditionally to treat various diseases. Among them, species of the genus Piper are important medicinal plants used in various systems of medicine. The Piper longum fruit has been used in traditional medicine, including the Ayurvedic system of medicine. Although there are numerous indications for its use, controlled trials are needed to determine its efficacy. The primary constituents isolated from various parts of P. longum are piperine, piperlongumine, sylvatin, sesamin, diaeudesmin piperlonguminine, pipermonaline, and piperundecalidine. It is most commonly used to treat chronic bronchitis, asthma, constipation, gonorrhea, paralysis of the tongue, diarrhea, cholera, chronic malaria, viral hepatitis, respiratory infections, stomachache, bronchitis, diseases of the spleen, cough, and tumors. This study provides detailed information about the P. longum fruit, including phytochemistry, pharmacological profile and safety profile. In view of the commercial, economic, and medicinal importance of the P. longum plant, it is useful for researchers to study the plant in detail. PMID- 21704958 TI - Correlations between fasciology and yin yang doctrine. AB - The aim of this study is to explore the correlations between fasciology and yin yang doctrine. Professor Yuan developed fasciology by three-dimensional reconstruction of connective tissue (fascia) in the trunk and limbs of the human body and tracing back to tissue origins in light of biological evolution and developmental biology. Fasciology states that the human body can be divided into two systems: the supporting-storing system and the functional system. This article elaborates on the roles of the two systems and their mutual relationship. The two systems are used to analyze the yin, the yang, and their relationship. The two systems are promoted but also restricted in different contexts. The supporting-storing system is formed by undifferentiated connective tissue and provides undifferentiated cells and nutrients for differentiated cells of the functional system. Thus, the supporting-storing system could be classified as quiet, similar to yin. The functional system continuously maintains the various functional activities of the human body. Thus, the functional system could be classified as active, similar to yang. In interpreting the yin yang doctrine from the point of view of fasciology, yin can be compared with the supporting-storing system and yang can be compared with the functional system. PMID- 21704959 TI - Divided attention interferes with fulfilling activity-based intentions. AB - Two experiments were conducted to examine the effects of divided attention on activity-based prospective memory. After establishing a goal to fulfill an intention upon completion of an ongoing activity, successful completion of the intention generally suffered when attention was being devoted to an additional task (Experiment 1). Forming an implementation intention at encoding ameliorated the negative effects of divided attention (Experiment 2). The results from the present experiments demonstrate that activity-based prospective memory is susceptible to distraction and that implementing encoding strategies that enhance prospective memory performance can reduce this interference. The current work raises interesting questions about the similarities and differences between event and activity-based prospective memories. PMID- 21704960 TI - Exposure to static magnetic field delays induced preterm birth occurrence in mice. AB - OBJECTIVE: The purpose of this study was to demonstrate that daily 40-minute whole body exposure to an inhomogeneous static magnetic field (SMF) prolongs induced preterm birth (PTB) in mice. STUDY DESIGN: The murine model for PTB induction was performed by the administration of 25 MUg/animal lipopolysaccharide (LPS) intraperitoneally. The applied SMF was an inhomogeneous gradient field with 2.8-476.7 millitesla peak-to-peak magnetic induction range by 10 mm lateral periodicity. During SMF exposure, mice were free to move in their cage. RESULTS: The fetal development and the delivery were normal in animals that were exposed to SMF but not treated with LPS. SMF in these cases did not influence the term of delivery. In LPS-challenged animals, SMF exposure prolonged the time of PTB occurrence from 17.43 h (n = 7) to 21.93 h (n = 15) after the challenge (P < .05). CONCLUSION: Exposure to inhomogeneous SMF may have a valuable effect in the prevention of PTB and may have clinical relevance to humans. PMID- 21704961 TI - Anti-N-methyl-D-aspartate receptor encephalitis complicating ovarian teratomas: a case report. AB - Anti-N-methyl-D-aspartate receptor encephalitis is an emerging disease that affects young women. Its diagnosis can be delayed because of the neuropsychiatric symptoms in the foreground, but early removal of the associated teratoma improves the prognosis. We report the treatment of a patient with anti-N-methyl-D aspartate receptor encephalitis that was related to an ovarian teratoma. PMID- 21704962 TI - The influence of hospital type on induction of labor and mode of delivery. AB - OBJECTIVE: The purpose of this study was to compare labor induction and cesarean delivery rates at term in community vs university hospitals. STUDY DESIGN: A population-based retrospective cohort study of births was performed. Primary outcomes were term gestation at <39 weeks, labor induction, and cesarean delivery. After we adjusted for comorbidities, malpresentation, and previous cesarean delivery, logistic regression assessed the association between hospital type and primary outcomes. RESULTS: Births occur less often in week 37 (n = 24390 [11%] vs 4006 [13%]; adjusted odds ratio [OR], 0.9; 95% confidence interval [CI], 0.8-0.9) and are similar in week 38 in community vs university hospitals. Inductions occur more commonly in community vs university settings at 37 weeks (n = 6440 [27%] vs 757 [19%]; adjusted OR, 1.7; 95% CI, 1.5-1.8) and at 38 weeks (n = 16586 [31%] vs 1530 [21%]; adjusted OR, 1.8; 95% CI, 1.7-1.9). Cesarean rates are no different between hospital types. CONCLUSION: Induction is 70-80% more likely at community vs university hospitals before the optimal gestational age of >= 39 weeks, but cesarean delivery rates do not differ at term. PMID- 21704963 TI - Perioperative bowel management for gynecologic surgery. AB - Postoperative intestinal care after major gynecologic surgery has changed considerably. The purpose of this review was to describe these changes. Our findings are that (1) preoperative mechanical bowel preparation does not lower the risk of anastomotic leakage and infection, (2) elective postoperative nasogastric tube decompression increases postoperative pneumonia and does not decrease the incidence of other postoperative complications, (3) early feeding after major gynecologic surgery reduces hospital stay and does not increase (and may decrease) pneumonia and other postoperative complications, and (4) early feeding, gum chewing, bowel stimulation, alvimopan, and ketorolac may decrease the incidence of postoperative ileus. PMID- 21704964 TI - Monthly ranibizumab for choroidal neovascularizations secondary to angioid streaks in pseudoxanthoma elasticum: a one-year prospective study. AB - PURPOSE: To evaluate the efficacy and safety of monthly intravitreal ranibizumab for the treatment of choroidal neovascularizations (CNV) secondary to angioid streaks (AS) in pseudoxanthoma elasticum (PXE). DESIGN: Twelve-month prospective, open-label, uncontrolled, nonrandomized interventional clinical trial. METHODS: In 7 patients, 1 eye with an active CNV was injected with 0.5 mg ranibizumab monthly over 1 year. Distance and reading visual acuity, reading speed, angiographic findings, and central retinal thickness (CRT) on optical coherence tomography were assessed at each visit. Central retinal light increment sensitivity (LIS) was assessed by microperimetry at baseline, at 6 months, and 3 to 4 months after the last injection. RESULTS: Best-corrected visual acuity increased significantly from baseline to month 12 (20/63 or 61 ETDRS letters to 20/32 or 73 ETDRS letters; P = .012). The effect was maintained 3 months later (61 ETDRS letters to 72 ETDRS letters; P = .055). Reading acuity and speed could be maintained throughout the study. Central LIS improved (6.6 dB, SD +/- 5.9 at baseline to 7.4 dB, SD +/- 6.2 at last follow-up; P < .001). Leakage from active CNVs subsided. Mean change in CRT from baseline to month 12 and 15 was -86 MUm (P = .074) and -65 MUm (P = .182), respectively. No serious adverse events occurred. CONCLUSIONS: Efficacy outcomes indicate a beneficial therapeutic effect of intravitreal ranibizumab on central visual function including retinal LIS. Both the functional and morphologic response based on angiographic and OCT findings to ranibizumab treatment implicate an important pathophysiological role of vascular endothelial growth factor in CNVs secondary to AS in PXE. Intravitreal ranibizumab appears to be a safe and efficacious treatment in these patients. PMID- 21704965 TI - A multicenter randomized controlled fellow eye trial of pulse-dosed difluprednate 0.05% versus prednisolone acetate 1% in cataract surgery. AB - PURPOSE: To compare the effects of 2 corticosteroids on corneal thickness and visual acuity after cataract surgery. DESIGN: Multicenter, randomized, contralateral-eye, double-masked trial. METHODS: Fifty-two patients (104 eyes) underwent bilateral phacoemulsification. The first eye randomly received difluprednate 0.05% or prednisolone acetate 1%; the fellow eye received the alternative. Before surgery, 7 doses were administered over 2 hours; 3 additional doses were given after surgery, before discharge. For the remainder of the day, corticosteroids were administered every 2 hours, then 4 times daily during week 1 and twice daily during week 2. Corneal pachymetry, visual acuity, and corneal edema were evaluated before surgery and at days 1, 15, and 30 after surgery. Endothelial cell counts were evaluated before surgery and at 30 days after surgery. Retinal thickness was evaluated before surgery and at 15 and 30 days after surgery. RESULTS: Corneal thickness at day 1 was 33 MUm less in difluprednate-treated eyes (P = .026). More eyes were without corneal edema in the difluprednate group than in the prednisolone group at day 1 (62% vs 38%, respectively; P = .019). Uncorrected and best-corrected visual acuity at day 1 were significantly better with difluprednate than prednisolone by 0.093 logMAR lines (P = .041) and 0.134 logMAR lines (P < .001), respectively. Endothelial cell density was 195.52 cells/mm(2) higher in difluprednate-treated eyes at day 30 (P < .001). Retinal thickness at day 15 was 7.74 MUm less in difluprednate treated eyes (P = .011). CONCLUSIONS: In this high-dose pulsed-therapy regimen, difluprednate reduced inflammation more effectively than prednisolone acetate, resulting in more rapid return of vision. Difluprednate was superior at protecting the cornea and reducing macular thickening after cataract surgery. PMID- 21704966 TI - Intraocular expression of serum amyloid a and interleukin-6 in proliferative diabetic retinopathy. AB - PURPOSE: Because serum amyloid A can regulate angiogenesis, we searched for an association between serum amyloid A and interleukin-6 (IL-6), as proinflammatory factors, and proliferative diabetic retinopathy (PDR). DESIGN: Retrospective, comparative study. METHODS: Seventy-six patients (76 eyes) with PDR and 31 patients (31 eyes) with nondiabetic ocular disease (control group), including idiopathic epiretinal membranes (8 eyes) and idiopathic macular holes (23 eyes), were enrolled. Enzyme-linked immunosorbent assay, dual-color immunofluorescence staining, and semiquantitative reverse-transcription polymerase chain reaction were used to examine the serum amyloid A and IL-6 levels in vitreous and plasma, expression of protein and mRNA of serum amyloid A in the excised membranes, respectively. RESULTS: Vitreous serum amyloid A and IL-6 levels in the study group were significantly higher than those in the control group (both P < .001), whereas the plasma concentrations of serum amyloid A and IL-6 did not vary significantly between the groups (P = .555 and P = .621, respectively). A significant correlation was observed between the vitreous and plasma levels of serum amyloid A in subjects with PDR (r = 0.525; P < .001). In fibrovascular membranes of the study group, colocalization of endothelial marker CD31 with serum amyloid A and colocalization of fibrillar structure markers fibronectin with serum amyloid A were observed. Expression of serum amyloid A mRNA was significantly higher in fibrovascular membranes with PDR than in idiopathic epiretinal membranes (P = .004). CONCLUSIONS: Serum amyloid A and IL-6 may be involved with the inflammatory process in the development of PDR. Local expression of serum amyloid A may exist in PDR. PMID- 21704967 TI - Patterns of lymph node metastasis and survival for upper esophageal squamous cell carcinoma. AB - BACKGROUND: This study evaluated the clinical results, nodal metastatic patterns, and overall efficacy of esophagectomy with three-field lymph node dissection for upper esophageal squamous cell carcinoma (SCC). METHODS: Between 2001 and 2008, esophagectomy was performed in 497 esophageal cancer patients, of whom 93 underwent esophagectomy with three-field lymph node dissection, without neoadjuvant treatment for upper esophageal SCC. RESULTS: Of these 93 patients, 91 (97.8%) were men, the median age was 65.0 years, and 82 (88.2%) underwent R0 resection with curative intent. In-hospital mortality was 4.3%. Pathologic T N M stages were stage I, 8.6%; stage II, 16.1%; stage III, 75.3%; and stage IV, 0%. The mean numbers of total lymph nodes dissected and, of those, total metastatic lymph nodes per patient were 61.7+/-18.2 and 4.7+/-7.0, respectively. Metastases occurred to the recurrent laryngeal lymph nodes in 43.3%, to the cervical lymph nodes in 46.2%, and to abdominal lymph nodes in 24.7% of patients. Overall 5-year and disease-free survival rates were 43.5% and 34.3%, respectively, and were 50.1% and 37.6%, respectively, for R0 resection. CONCLUSIONS: Recurrent laryngeal lymph node chains are those most commonly affected by nodal metastasis, and the prevalence of cervical lymph node involvement is high, at more than 40%. Esophagectomy with three-field lymph node dissection in patients with upper esophageal SCC can be performed with acceptable morbidity and mortality. Curative R0 resection for upper esophageal SCC achieved a satisfactory 5-year survival rate. PMID- 21704968 TI - Figure-of-eight versus prophylactic sternal weave closure of median sternotomy in diabetic obese patients undergoing coronary artery bypass grafting. AB - BACKGROUND: Sternal dehiscence is a serious and potentially devastating complication after median sternotomy, especially in diabetic obese patients. The optimal technique for sternal closure is unclear in these patients. METHODS: The purpose of this prospective randomized study was to compare the incidence of sternal dehiscence after prophylactic sternal weave and figure-of-eight suturing in diabetic obese patients undergoing coronary artery bypass grafting (CABG). The patients were randomly assigned to group A (figure-of-eight closure; n=75) or group B (sternal weave closure; n=75). RESULTS: There were 8 cases of sternal dehiscence documented: 7 in group A and 1 in group B. In group A, 5 patients had noninfectious sternal dehiscence and 2 patients underwent reoperation because of sternal dehiscence with mediastinitis. Also, 1 of the noninfected patients had deep-seated pain with a feeling of bony crepitus and needed reoperation. The other 4 patients in group A and 1 patient with noninfectious sternal dehiscence in group B were given chest binder support. Pain and bony crepitus decreased in the follow-up period of 1 year. Sternal dehiscence rates were 9.3% in group A and 1.3% in group B. Sternal dehiscence was significantly lower in group B (p<0.05). CONCLUSIONS: Prophylactic sternal weave closure of median sternotomy reduces morbidity from sternal dehiscence in diabetic obese patients undergoing CABG. PMID- 21704969 TI - Appropriate use of emergency department thoracotomy: implications for the thoracic surgeon. AB - BACKGROUND: Practice guidelines for the appropriate use of emergency department thoracotomy (EDT) according to current national resuscitative guidelines have been developed by the American College of Surgeons Committee on Trauma (ACS-COT) and published. At an urban level I trauma center we analyzed how closely these guidelines were followed and their ability to predict mortality. METHODS: Between January 2003 and July 2010, 120 patients with penetrating thoracic trauma underwent EDT at Mount Sinai Hospital (MSH). Patients were separated based on adherence (group 1, n=70) and nonadherence (group 2, n=50) to current resuscitative guidelines, and group survival rates were determined. These 2 groups were analyzed based on outcome to determine the effect of a strict policy of adherence on survival. RESULTS: Of EDTs performed during the study period, 41.7% (50/120) were considered outside current guidelines. Patients in group 2 were less likely to have traditional predictors of survival. There were 6 survivors in group 1 (8.7%), all of whom were neurologically intact; there were no neurologically intact survivors in group 2 (p=0.04). The presence of a thoracic surgeon in the operating room (OR) was associated with increased survival (p=0.039). CONCLUSIONS: A policy of strict adherence to EDT guidelines based on current national guidelines would have accounted for all potential survivors while avoiding the harmful exposure of health care personnel to blood borne pathogens and the futile use of resources for trauma victims unable to benefit from them. Cardiothoracic surgeons should be familiar with current EDT guidelines because they are often asked to contribute their operative skills for those patients who survive to reach the OR. PMID- 21704970 TI - Early outcomes of primary sutureless repair of the pulmonary veins. AB - BACKGROUND: The "sutureless" repair technique has improved outcomes for post repair pulmonary vein (PV) stenosis. The purpose of this study is to determine the early outcomes of primary sutureless repair of pulmonary venoocclusive disease in infants with congenital PV stenosis-hypoplasia or PVs at high risk for progressive stenosis. METHODS: This is a retrospective review of infants who had primary sutureless repair of the PVs from October 2002 to April 2010. RESULTS: Twenty-five infants had primary sutureless repair of the PVs. Eighteen infants had total anomalous pulmonary venous return; 14 with obstruction, 10 with heterotaxy syndrome, and 9 with univentricular anatomy. Seven infants had congenital PV stenosis. There were 24 perioperative survivors (96%; 95% confidence interval [CI], 75% to 99%) and 2 late deaths from extracardiac causes. Follow-up was available on 21 out of 22 survivors at a median duration of 34 months (range, 9 to 100 months). Persistence-recurrence of PV stenosis occurred in 3 veins (3%) of 2 infants (8%). On follow-up echocardiography, right ventricular systolic pressure was normal in 13 out of 14 infants with a biventricular heart and 60% of systemic blood pressure in 1 infant. Kaplan-Meier 1-year cumulative survival was 88% (95% CI, 66% to 96%). Kaplan-Meier cumulative disease-free survival was 96% (95% CI, 75% to 99%) at 30 days and 84% (95% CI, 58% to 95%) at 1 year. By Cox proportional hazards, age, univentricular anatomy, and atrial isomerism-heterotaxy syndrome were not associated with an increased risk of death or persistence-recurrence. One-year disease-free survival was lower in infants with prematurity (p=0.0055) and low birth weight (p=0.0011). CONCLUSIONS: Primary sutureless repair is a feasible, safe, and relatively effective method of addressing congenital PV stenosis and (or) high-risk PVs, particularly in infants with single ventricle anatomy and (or) heterotaxy syndrome. PMID- 21704971 TI - Cytokine expression profile in human lungs undergoing normothermic ex-vivo lung perfusion. AB - BACKGROUND: A donor lung shortage prevents patients from receiving life-saving transplants. Ex-vivo lung perfusion (EVLP) is a viable means of expanding the donor pool by evaluating and potentially improving donor lung function. The metabolic and inflammatory effects of EVLP on human lung tissue are currently unknown. We sought to establish representative cytokine expression in human donor lungs meeting acceptable lung transplant criteria after prolonged normothermic EVLP. METHODS: Seven single human lungs not meeting traditional transplantation criteria for various reasons underwent normothermic EVLP. Lungs were perfused with deoxygenated colloid, rewarmed, and ventilated per standard protocol. Lung function was evaluated every hour. Biopsies were taken at 1, 6, and 12 hours. Inflammatory cytokines were quantitatively measured using a human cytokine magnetic bead-based multiplex assay. RESULTS: All lungs met traditional transplant criteria after EVLP. The partial pressure of arterial oxygen and physiologic lung function significantly improved (p<0.05). No pulmonary edema was formed, and histology demonstrated no evidence of acute lung injury. Interleukin (IL)-6, IL-8, granulocyte colony-stimulating factor, and monocyte chemotactic protein-1 were upregulated, while granulocyte macrophage colony-stimulating factor was downregulated during EVLP (p<0.05). IL-1beta, IL-4, IL-7, IL-12, interferon-gamma, macrophage inflammatory protein-1beta, and tumor necrosis factor-alpha were detectable and unchanged. CONCLUSIONS: Ex-vivo lung perfusion demonstrates the ability to improve oxygenation and physiologic lung function in donor lungs unacceptable for transplantation without injury to the lung. We establish here a cytokine expression profile in human lungs undergoing normothermic EVLP. These data can be used in the future to explore novel targeted therapies for ischemia-reperfusion injury. PMID- 21704972 TI - Impact of preoperative renal dysfunction in patients undergoing off-pump versus on-pump coronary artery bypass. AB - BACKGROUND: The impact of the degree of renal dysfunction (RD) in patients undergoing coronary artery bypass grafting (CABG) ranging from normal to dialysis dependence is not well defined. METHODS: A retrospective review of 14,199 patients undergoing isolated, primary CABG from January 1996 to May 2009 at Emory Healthcare was performed. The estimated glomerular filtration rate (eGFR) was estimated by the Modification of Diet in Renal Disease formula: mild RD (eGFR 60 to 90 mL/min/1.73 m2), moderate RD (eGFR 30 to 59), severe RD (eGFR<30). A propensity scoring was used to balance the groups with 46 preoperative covariates. Multivariable logistic and Cox regression methods were used to determine the independent association of eGFR with mortality. Adjusted odds ratios were calculated for outcomes using the normal eGFR group as the reference. Kaplan-Meier curves were created to estimate long-term survival. RESULTS: A total of 8,086 patients (57.0%) underwent off-pump coronary artery bypass (OPCAB) while 6,113 (43.0%) underwent on-pump CAB. Preoperative RD was common: Normal eGFR (n=3,503/14,199 [24.7%]); mild RD (7,236/14199 [51.0%]); moderate RD (2,860/14,199 [20.1%]); severe RD (283/14,199 [2.0%]); and preoperative dialysis (317/14,199 [2.2%]). Moderate to severe RD or preoperative dialysis was associated with worse adjusted in-hospital mortality: mild RD (odds ratio [OR] 1.42; 95% confidence interval [CI] 0.93 to 2.16; p=not significant); moderate RD (OR 3.55; 95% CI 2.32 to 5.43; p<0.05]; severe RD (OR 8.84; 95% CI 4.92 to 15.9; p<0.05); and dialysis-dependent (OR 9.64; 95% CI 5.45 to 17.0; p<0.05). Adjusted long-term survival was worse across levels of RD. The OPCAB patients with moderate to severe RD had worse long-term survival than on-pump CAB patients; however, the surgery types were similar among normal, mild, and dialysis patients. CONCLUSIONS: Preoperative RD is common in the CABG population and is associated with diminished long-term survival. Improved early outcomes in patients with RD undergoing OPCAB diminished with worsening RD. PMID- 21704973 TI - Results after thoracic endovascular aortic repair in penetrating atherosclerotic ulcers. AB - BACKGROUND: Results after thoracic endovascular aortic repair in penetrating atherosclerotic ulcers are uncertain. METHODS: From 1997 to 2010, 72 patients (median age, 67 years) presented with penetrating atherosclerotic ulcers (symptomatic, 58%; rupture, 36%). Median logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 32. Mean follow-up was 42 months (range, 19 to 56 months). In-hospital mortality, occurrence of endoleaks, reinterventions, and survival were recorded. RESULTS: In hospital mortality was 4%. The primary success rate was 100%. Actuarial survival rates at 1, 5, and 10 years were 93%, 72%, and 60%. The early type I and III endoleak rate was 2.7%. The late type I and III endoleak rate was 4%. One late surgical conversion was performed. Aortic-related actuarial survival was 100% at 1 year and 98.6% at 5 and 10 years. Age older than 75 years (odds ratio, 8.928; 95% confidence interval, 2.05 to 38.93) was an independent predictor of survival. During follow up, 21% of patients underwent a cardiovascular intervention. CONCLUSIONS: Results after thoracic endovascular aortic repair in patients with penetrating atherosclerotic ulcers are excellent for early and late type I and III endoleak formation and aortic-related survival. Patients are mainly limited by age and by the aggressive underlying obliterative atherosclerotic process. PMID- 21704974 TI - The effect of regionalization on outcome in esophagectomy: a Canadian national study. AB - BACKGROUND: Regionalization of specialized surgical services has been proposed to improve outcomes based on the reported association between volume and outcomes. The effect of regionalization of esophagectomy on in-hospital mortality (IHM) and length of stay (LOS) was examined. METHODS: Data from a Canadian database for 6985 patients (74% men; median age, 66 years) who underwent esophagectomy (1998 to 2007) were analyzed with a multivariable mixed model regression controlling for age, sex, Charlson comorbidity index, and year of esophagectomy to evaluate the effect of hospital volume. Volume changes were evaluated within and between hospitals. RESULTS: From 1998 to 2007, the number of hospitals performing esophagectomies decreased (101 to 85). The percentage of patients treated in large-volume (>20 cases/year) centers increased (29% to 61%) and IHM decreased (9.1% to 3.6%). The odds of IHM decreased 64% (95% confidence interval [CI], 51% to 74%), and LOS decreased 38% (95% CI, 34% to 43%). Comparing between hospitals, an increase of 10 cases was associated with a 15% decrease in IHM (95% CI, 6% to 23%, p=0.001) and a 10% increase in LOS (95% CI, 2% to 19%, p=0.01). Within an individual hospital, the relationship between increasing volume and LOS or IHM was not significant. CONCLUSIONS: In-hospital mortality for esophagectomy has decreased in Canada but was not significantly reduced when volume was increased within a given hospital. Improved IHM may be related to selective referral of patients to high-volume hospitals. Although, decreased IHM is not solely attributable to volume changes, our results support regionalization policies for esophagectomy. PMID- 21704975 TI - Evaluation of the vertebrobasilar system in thoracic aortic surgery. AB - BACKGROUND: We evaluated the probability of vertebrobasilar system malperfusion due to occlusion of the left subclavian artery as assessed by preoperative magnetic resonance angiography in patients scheduled to undergo thoracic aortic surgery. METHODS: (Study 1) From January 2000 through March 2009, we studied variations of vertebral arteries in 301 patients scheduled to undergo thoracic aortic surgery. We classified vertebral artery variations into 3 categories according to the findings on preoperative magnetic resonance angiography: connection type, interrupted right vertebral artery, and interrupted left vertebral artery. (Study 2) From February 2007 through January 2010, we evaluated the cerebral complication in 41 patients who had occlusion of the left subclavian artery with a stent graft. RESULTS: (Study 1) On preoperative magnetic resonance angiography, the vertebral artery was classified as connection type in 247 patients, interrupted right vertebral artery in 34, and interrupted left vertebral artery in 20. (Study 2) We performed subclavian obstruction test, left right subclavian artery bypass, or left subclavian artery-left common carotid artery bypass to the 3 patients with interrupted right vertebral artery, respectively. Forty patients (98%) out of 41 patients had no complication after occlusion of the left subclavian artery. CONCLUSIONS: Preoperative magnetic resonance angiography is useful for detection of the patients with high risk of vertebrobasilar system malperfusion due to occlusion of the left subclavian artery. PMID- 21704977 TI - The timed manual wheelchair slalom test: a reliable and accurate performance based outcome measure for individuals with spinal cord injury. AB - OBJECTIVES: To describe the timed manual wheelchair slalom test (MWST) and to quantify its test-retest reliability, standard error of measurement, and minimum detectable change (MDC). DESIGN: Repeated-measures design. SETTING: Pathokinesiology laboratory. PARTICIPANTS: Manual wheelchair users (N=15) with spinal cord injury (SCI) (vertebral levels, C6 to T12; American Spinal Injury Association Impairment Scale: A, B, or C) participated in this study. Participants were 40.7+/-12.6 years of age, measured 1.77+/-.08m in height, weighed 79.6+/-23.9kg, and had been using a manual wheelchair as their primary mode of mobility for 5.9+/-7.5 years. INTERVENTIONS: Participants propelled their own wheelchair at a self-selected maximum velocity along a slalom trajectory (linear length, 18m) defined by 7 cones aligned in a straight line and set 3m, 2m, and 1m apart from one another. Three trials (T=3) of the MWST were performed on 2 separate visits (V=2) 6.3+/-5.4 days apart. The generalizability theory was used to determine the reliability, standard error of measurement, and MDC and to propose testing protocols for the MWST. MAIN OUTCOME MEASURE: The time needed to complete the MWST expressed in seconds. RESULTS: All participants successfully completed the MWST. No adverse effect was reported. The time required to complete the MWST at visits 1 and 2 was 16.8+/-4.4 and 16.5+/-4.3 seconds, respectively. The reliability coefficient (phi=.981) and accuracy (standard error of measurement=3.47%, MDC=8.097%) were high when the time required for a participant to perform 3 MWST trials during a single visit (T=3, V=1) was averaged. CONCLUSIONS: The timed MWST is a safe, reliable, and accurate performance-based outcome measure that can be administered easily and quickly in individuals with SCI who rely on a manually propelled wheelchair for mobility. PMID- 21704976 TI - Gender, race, and socioeconomic status affects outcomes after lung cancer resections in the United States. AB - BACKGROUND: The effect of gender, race, and socioeconomic status on contemporary outcomes after lung cancer resections has not been comprehensively evaluated across the United States. We hypothesized that risk-adjusted outcomes for lung cancer resections would not be influenced by these factors. METHODS: From 2003 to 2007, 129,207 patients undergoing lung cancer resections were evaluated using the Nationwide Inpatient Sample (NIS) database. Multiple regression analysis was used to estimate the effects of gender, race, and socioeconomic status on risk adjusted outcomes. RESULTS: Average patient age was 66.8+/-10.5 years. Women accounted for 5.0% of the total study population. Among racial groups, whites underwent the largest majority of operations (86.2%), followed by black (6.9%) and Hispanic (2.8%) races. Overall the incidence of mortality was 2.9%, postoperative complications were 30.4%, and pulmonary complications were 22.0%. Female gender, race, and mean income were all multivariate correlates of adjusted mortality and morbidity. Black patients incurred decreased risk-adjusted morbidity and mortality compared with white patients. Hispanics and Asians demonstrated decreased risk-adjusted complication rates. Importantly low income status independently increased the adjusted odds of mortality. CONCLUSIONS: Female gender is associated with decreased mortality and morbidity after lung cancer resections. Complication rates are lower for black, Hispanic, and Asian patients. Low socioeconomic status increases the risk of in-hospital death. These factors should be considered during patient risk stratification for lung cancer resection. PMID- 21704978 TI - Rasch analyses of the Activities-specific Balance Confidence Scale with individuals 50 years and older with lower-limb amputations. AB - OBJECTIVES: To explore shortened response formats for use with the Activities specific Balance Confidence (ABC) Scale and then evaluate the unidimensionality of the scale, the item difficulty, the scale for redundancy and content gaps, and the item standard error of measurement (SEM) and internal consistency reliability among aging individuals with a lower-limb amputation living in the community. DESIGN: Secondary analysis of cross-sectional survey and chart review data. SETTING: Outpatient amputee clinics, Ontario, Canada. PARTICIPANTS: Community living adults (N=448; >=50y; mean, 68y) who have used a prosthesis for at least 6 months for a major unilateral lower-limb amputation. Of the participants, 325 (72.5%) were men. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: ABC Scale. RESULTS: A 5-option response format outperformed 4- and 6-option formats. Factor analyses confirmed a unidimensional scale. The distance between response options is not the same for all items on the scale, evident by the Rasch Partial Credit Model (PCM) having a better fit to the data than the Rasch Rating Scale Model. Two items, however, did not fit the PCM within statistical reason. Revising the wording of the 2 items may resolve the misfit and improve the construct validity and lower the standard error of measurement. Overall, the difficulty of the scale's items is appropriate for use with aging individuals with lower-limb amputation, and is most reliable (Cronbach alpha=0.94) for use with individuals with moderately low balance confidence levels. CONCLUSIONS: The ABC Scale with a simplified 5-option response format is a valid and reliable measure of balance confidence for use with individuals aging with a lower-limb amputation. PMID- 21704979 TI - External lid loading for the temporary treatment of paresis of the M. orbicularis oculi: a case report. AB - This clinical note re-introduces external lid loading with the help of a lead weight for the temporary treatment of lagophthalmos. Although simple and effective, the technique is rarely used. Instead of wearing a monoculus, the patient uses an individually tailored lead weight (0.8-mm thickness, 1.0-2.0g) stuck on the lid to enable its closure. Spontaneous ptosis indicates a too-heavy weight. With the musculus (M.) levator palpebrae intact, lid lifting is possible. The effect is gravity dependent; therefore, the patient has to wear the monoculus at night. To minimize the risk for lead intoxication, the surface of the weight is varnished. In the case of persistent M. orbicularis oculi paresis, internal lid loading can follow. Since 1997, a total of 152 lagophthalmos cases have been treated. All patients could close the lid immediately. Almost half the patients had to readjust the weight several times per day because of hooded eyelids. Compliance was high, and partial or complete restoration of M. orbicularis oculi function occurred in 60% of cases. In some subjects, restoration of the M. orbicularis oculi was faster than for the M. orbicularis orbis. External lid loading for the temporary treatment of lagophthalmos is simple and effective. Compared with a monoculus, vision is unimpaired and the aesthetic is more appropriate for most patients. Faster restoration of the M. orbicularis oculi hints at a potentially facilitatory effect of the weight. PMID- 21704980 TI - Bulimic symptomatology: the role of adaptive perfectionism, shape and weight concern, and self-esteem. AB - An interactive model implicating high perfectionism, high weight and shape concern, and low self-esteem in the onset and maintenance of bulimic symptoms (Bardone, Vohs, Abramson, Heatherton, & Joiner, 2000; Vohs, Bardone, Joiner, Abramson, & Heatherton, 1999) has received mixed support. This study aimed to replicate the cross-sectional model in a clinical sample of women with eating disorders, and to investigate whether the model could predict changes in binge eating and purging at the end of treatment. Eating disorder outpatients (n=353) completed measures of perfectionism, weight/shape concern, self-esteem, and bulimic symptoms at pre-treatment and discharge. Contrary to the hypotheses, the three-way interaction did not predict binge eating or purging cross-sectionally or prospectively as a moderator of psychotherapy outcome. It was concluded that the robustness of the interactive model seems questionable and may be impacted by an inadequate conceptualization of the perfectionism construct. PMID- 21704981 TI - Removal of polysialylated neural cell adhesion molecule increases morphine analgesia and interferes with tolerance in mice. AB - Neurons that express high levels of polysialylated neural cell adhesion molecule (PSA-NCAM) in adult spinal substantia gelatinosa also express the MU-opioid receptor. While PSA removal from NCAM by spinal intrathecal injection of endoneuraminidase-N (endo-N) did not detectably change opioid receptor expression, morphine-induced analgesia was significantly increased. This analgesic strengthening was detected as early as 15 min after endo-N treatment and persisted for at least 7 days. In addition, the tolerance that develops with chronic morphine treatment was overcome in the absence of PSA. Interestingly, the same effects on analgesia and tolerance were also produced by selective deletion of the NCAM-180 isoform. PMID- 21704982 TI - Treatment of experimental spinal cord injury with 3beta-methoxy-pregnenolone. AB - The synthetic derivative of pregnenolone MAP4343 (3beta-methoxy-pregnenolone) binds in vitro to microtubule-associated-protein 2 (MAP2), stimulates the polymerization of tubulin, enhances the extension of neurites and protects neurons against neurotoxic agents. Its efficacy was assessed in vivo with the most commonly used thoracic spinal cord compression/contusion models in rats. In the three models used, the post-traumatic subcutaneous injection of MAP4343 significantly improved the recovery of locomotor function after spinal cord injury, as shown by an earlier and more complete recovery compared to vehicle treated rats. The first injection of MAP4343 could be delayed up to 24h after spinal cord injury with maintained efficiency. The improvement was correlated with the preservation of both dendritic trees of motoneurons in the lumbar spinal cord caudally to the injury site, and of MAP2 at lesion site and in the lumbar spinal cord. The results obtained in three different rat models of spinal cord injury demonstrate the beneficial effects of this therapeutic strategy and identify MAP4343 as a potential treatment for acute spinal cord injury. PMID- 21704983 TI - Potential contribution of oxidative stress and inflammation to anxiety and hypertension. AB - Previously, we have published that pharmacological induction of oxidative stress causes anxiety-like behavior in rats and also is associated with hypertension in these animals. Here, we report that sub-chronic induction of oxidative stress via pharmacological induction leads to i) reduction in glyoxalase (GLO)-1 and glutathione reductase (GSR)-1 expression; ii) calpain mediated reduction of brain derived neurotrophic factor (BDNF) levels; iii) NFkappaB mediated upregulation of proinflammatory factors interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha and elevated angiotensin (AT)-1 receptor levels in hippocampus, amygdala and locus coeruleus regions of the brain. Acute oxidative stress has opposite effects. We speculate that regulation of GLO1, GSR1, BDNF, NFkappaB and AT-1 receptor may contribute to anxiety-like behavior and hypertension in rats. PMID- 21704984 TI - A visual processing but no phonological disorder in a child with mixed dyslexia. AB - The case study of Martial, a French 9-year-old boy, who exhibits severe mixed dyslexia and surface dysgraphia is reported. Despite very poor pseudo-word reading, Martial has preserved phonological processing skills as his good oral language, good phoneme awareness and good verbal short-term memory show. He exhibited a strong length effect when reading briefly presented words but no sign of mini-neglect. His letter-string processing abilities were assessed through tasks of whole and partial report. In whole report, Martial could only name a few letters from briefly displayed 5-consonant strings. He showed an initial-position advantage and a sharper than expected left-to-right gradient of performance. He performed better when asked to report a single cued letter within the string but then showed an atypical right-side advantage. The same rightward attentional bias was observed in whole report when top-down control was prevented. Otherwise, Martial showed preserved single letter identification skills and good processing of 5-letter strings when letters were sequentially displayed one at a time. His poor letter-string processing thus reflects a parallel visual processing disorder that is compatible with either a visual attention (VA) span or a visual short term memory disorder. Martial was further engaged in a complex reaching movement task involving VA and simultaneous processing. He performed motor sequences not as a whole but as a succession of independent motor units, suggesting that his attention was not allocated in parallel to the two to-be-reached targets prior to movement execution. Against a more basic motor disorder however, he showed good performance in a task of cyclical pointing movements. The overall findings suggest that Martial suffers from a visual simultaneous processing disorder that disturbs letter identification in strings. Instead of being restricted to letter string processing, this VA disorder might extend to non-verbal task. PMID- 21704985 TI - Contrasting nutrient stocks and litter decomposition in stands of native and invasive species in a sub-tropical estuarine marsh. AB - We compared the influence of invasion by an alien invasive species (Spartina alterniflora, smooth cordgrass) and a native aggressive species (Phragmites australis, common reed) as they have expanded into the native Cyperus malaccensis (shichito matgrass)-dominated wetland ecosystem in the Min River estuary of southeast China. S. alterniflora is a perennial grass native to North America, which has spread rapidly along the southeast coast of China since its introduction in 1979. Our study compared the above and belowground biomass, net primary production, litter decomposition, plant nutrient stocks and soil organic carbon storage of the grasses in three ecosystems: (1) the native ecosystem dominated by C. malaccensis; (2) ecosystems previously dominated by C. malaccensis but presently replaced by P. australis; and (3) ecosystems previously dominated by C. malaccensis but presently replaced by S. alterniflora. Our results demonstrate that the recent invasion (3 years) of the exotic invasive species S. alterniflora has already significantly increased live aboveground biomass and aboveground plant nutrient stocks. However, there was no significant difference in these variables between native aggressive species P. australis and native C. malaccensis. The majority of belowground root Carbon (C), Nitrogen (N) and phosphorus (P) stocks of the three plant species were all distributed in the upper surface layer and there was a decrease with soil depth. There was little difference in litter decomposition rates among the three grass species; they were ranked in the following order: C. malaccensis>S. alterniflora>P. australis. Litter element concentration showed similar patterns for the three species. However, important differences were found between N and P; the litter N concentrations in each of the three species were greater at the end of the 280 days decomposition than at the start, but P concentrations followed a fluctuating pattern during the decomposition period. Soil organic carbon stocks (0-50cm) under S. alterniflora, P. australis and C. malaccensis stands were statistically indistinguishable, which may be due to the invasion of S. alterniflora having been a relatively recent phenomenon. Thus, recent invasion of the exotic species S. alterniflora has already altered the nutrient cycle of C. malaccensis in the ecosystem in the Min River estuary. PMID- 21704986 TI - Effects of different body mass indices on in vitro maturation in women with polycystic ovaries. AB - OBJECTIVE: To evaluate the effect of body mass index (BMI) on in vitro maturation (IVM) outcomes in women with polycystic ovaries. DESIGN: Retrospective, cohort study. SETTING: Tertiary IVF unit. PATIENT(S): One hundred thirteen women with polycystic ovaries. INTERVENTION(S): One hundred sixteen cycles of IVM. Patients were divided into subgroups according to their BMI: underweight, normal weight, overweight, obese, and morbidly obese. We evaluated the effects of BMI on the number of oocytes matured in vivo, maturation rate in vitro, fertilization and cleavage rates, number of embryos transferred, implantation rates, pregnancy rates, and delivery rates. MAIN OUTCOME MEASURE(S): Pregnancy rate and delivery rate. RESULT(S): The number and quality of oocytes among women with different BMIs were similar. There was no significant difference in the endometrial thickness and rates of implantation, pregnancy, and delivery among women with different BMIs. The pregnancy rate in underweight women was 50%, normal weight 47.9%, overweight 29.1%, obese 27.2%, and in morbidly obese women was 30.7%. The miscarriage and delivery rates were also similar. CONCLUSION(S): The results of IVM are independent of BMI. PMID- 21704987 TI - Strongyloidiasis presenting as duodenal obstruction in a patient infected with human T-cell lymphotropic virus type 1. PMID- 21704988 TI - Percutaneous transhepatic cholangioscopy with an ultraslim video upper endoscope with CO(2) insufflation: a feasibility study. PMID- 21704989 TI - An unusual EUS finding of a gastric extraluminal compression. PMID- 21704990 TI - Adverse events during monitored anesthesia care for GI endoscopy: an 8-year experience. AB - BACKGROUND: The importance of sedation during endoscopy is well established. There is no consensus about the best techniques for sedation, which specialist should perform it, and in which location. OBJECTIVE: To provide data on the epidemiology of adverse events during sedation for endoscopy. DESIGN: Retrospective analysis of a prospective database. SETTING: Endoscopy unit of a university hospital. PROCEDURES: A total of 17,999 procedures performed over 8 years. INTERVENTIONS: Sedation for GI endoscopy. MAIN OUTCOME MEASUREMENTS: We recorded the following information: sex, age, body mass index, smoking habits, American Society of Anesthesiologists and Mallampati scores, duration of the procedure, type of sedative drug administered, whether the procedure was performed emergently, and endoscopic interventions during the maneuver. Adverse events were defined as occurrences that warranted intervention and were classified as hypotension, desaturation, bradycardia, hypertension, arrhythmia, aspiration, respiratory depression, vomiting, cardiac arrest, respiratory arrest, angina, hypoglycemia, and/or allergic reaction. RESULTS: Deep sedation with intravenous propofol target controlled infusion pump was the most frequently used means of administering sedation. Adverse events were rare in both the adult (4.5%) and pediatric (2.6%) populations. Six complications occurred in more than 0.1% of adult cases: arterial hypotension, desaturation, bradycardia, arterial hypertension, arrhythmia, and aspiration. Only bradycardia (2.1%) and hypotension (0.44%) occurred in children. Three adult patients (0.017%) died, and no pediatric patients died. Some predictive models for the occurrence of complications are proposed. LIMITATIONS: Retrospective analysis, single-center data collection. CONCLUSIONS: Deep sedation during endoscopic procedures is safe in both adults and children. Our data may be useful for the future planning of new clinical strategies in this setting. PMID- 21704991 TI - Cleaning of occluded pancreatic duct endoprostheses: a new indication for extracorporeal shock wave lithotripsy? AB - BACKGROUND: Pancreatic duct stenting is widely performed for bridging main pancreatic duct obstruction in patients with chronic pancreatitis. The major limitation is early stent occlusion, making regular stent exchange necessary. OBJECTIVE: To date, no measures are available to prevent stent occlusion. The aim of this study was to evaluate the cleansing effect of shock wave application (SWA) on occluded pancreatic duct stents in vitro. DESIGN: In vitro study. PATIENTS: We analyzed occlusion rates of 25 plastic endoprostheses removed from 21 patients with chronic pancreatitis. INTERVENTION: We administered 350 shock wave pulses every 10 mm along the prosthesis, which was stored in a latex balloon filled with gas-free physiologic saline solution, by using a pressure of 42 megapascals. MAIN OUTCOME MEASUREMENTS: After SWA, the occlusion rate was measured again, and the cleansing rate was calculated in comparison with the native prosthesis. RESULTS: The mean (+/- SD) occlusion rate was significantly reduced (64.7 +/- 28.7 [15%-100%]) before SWA vs 9.8 +/- 25.3 [0-100%]) after SWA; P = .038). In 16 of 25 prostheses (64%), cleaning was complete. Four of the remaining 9 prostheses (16%) showed satisfactory cleaning of 95%, on average. Residual clogging material was found mainly at the duodenal tip and the middle of the stent. No significant association was found between patient-related or stent related parameters and the cleansing effect of SWA. LIMITATIONS: In vitro study design. CONCLUSION: SWA is effective in cleaning occluded pancreatic endoprostheses in vitro. Prolongation of stent placement seems possible if regular SWA is performed. Extracorporeal shock wave lithotripsy therefore might become a new indication for patients under treatment with pancreatic endoprostheses. PMID- 21704992 TI - Nonsurgical management of small-bowel polyps in Peutz-Jeghers syndrome with extensive polypectomy by using double-balloon endoscopy. AB - BACKGROUND: The major problem in the management of Peutz-Jeghers syndrome (PJS) is small-bowel polyps, which can cause intussusception and bleeding. Double balloon endoscopy (DBE) enables endoscopic resection of small-bowel polyps. OBJECTIVE: The aim of this study was to determine the efficacy and safety of endoscopic management of small-bowel polyps in PJS patients by using DBE. DESIGN: Retrospective chart review. SETTING: Single university hospital. PATIENTS: Consecutive patients with PJS who underwent multiple sessions of DBE for evaluation or treatment of small-bowel polyps between September 2000 and April 2009. INTERVENTIONS: Endoscopic resection of small-bowel polyps in PJS patients was performed by using DBE. MAIN OUTCOME MEASUREMENTS: Efficacy, safety, and long term laparotomy rate after the procedures were evaluated. RESULTS: Fifteen patients (10 men, mean age 34.0 +/- 15.8 years) underwent DBE for a mean 3.0 +/- 1.0 sessions. The mean numbers of resected polyps larger than 20 mm significantly decreased as sessions advanced (first, 3.6; second, 1.3; third, 0.7; fourth, 0.4; and fifth, 1.0; P = .02). The mean maximum sizes of resected polyps also significantly decreased at each session: 33, 19, 12, 17, and 30 mm (P = .01). One patient had a perforation, but was managed conservatively. Other complications were pancreatitis (n = 2) and bleeding (n = 2). Only 1 patient underwent surgery for intussusception during the study period. LIMITATIONS: This was a small single center retrospective study of short duration. CONCLUSIONS: Endoscopic management of small-bowel polyps in PJS patients by using DBE is safe and effective and avoids urgent laparotomy. PMID- 21704994 TI - Long-term outcome of transoral organ-preserving pharyngeal endoscopic resection for superficial pharyngeal cancer. AB - BACKGROUND: Early detection of pharyngeal cancer has been difficult. We reported that narrow-band imaging (NBI) endoscopy can detect superficial pharyngeal cancer, and these lesions can be treated endoscopically. OBJECTIVE: To assess the safety and long-term efficacy of transoral organ-preserving pharyngeal endoscopic resection (TOPER) for superficial pharyngeal cancer. DESIGN AND SETTING: Retrospective 2-center cohort study. PATIENTS: The study included 104 consecutive patients with superficial pharyngeal cancer. INTERVENTION: TOPER with the patients under general anesthesia. MAIN OUTCOME MEASUREMENTS: Safety of the procedure, long-term survival, clinical outcome. RESULTS: A total of 148 consecutive lesions were resected in 104 patients. There was no severe adverse event. Temporary tracheostomy was required in 17 patients (16%) to prevent airway obstruction. The median fasting period and hospital stay after TOPER were 2 days (range 1-20 days) and 8 days (range 3-58 days), respectively. Ninety-six patients (92%) had no local recurrence or distant metastases. Local recurrence at the primary site developed in 6 patients, but all were resolved by repeat TOPER. With a median follow-up period of 43 months (range 3-96 months), the overall survival rate at 5 years was 71% (95% CI, 59-82). Cause-specific survival rate at 5 years was 97% (95% CI, 93-100). The cumulative development rate of multiple cancers in pharyngeal mucosal sites at 5 years was 22% (95% CI, 12-33). The pharynx was preserved in all patients, and they experienced no loss of function. LIMITATION: Retrospective design. CONCLUSIONS: Peroral endoscopic resection of superficial pharyngeal cancer is a feasible and effective treatment with curative intent. PMID- 21704993 TI - Complications after ERCP in liver transplant recipients. AB - BACKGROUND: Complications of the biliary tract after liver transplantation are successfully managed with ERCP; however, the incidence and risk factors for post ERCP complications remain unknown. OBJECTIVE: To examine the incidence, risk factors, and short-term outcome of post-ERCP complications in liver transplant (LT) recipients. DESIGN: Retrospective evaluation of all ERCPs performed in LT recipients at our institution during a 7-year, 4-month period. SETTING: Tertiary referral center. PATIENTS: A total of 243 ERCPs performed in 121 LT recipients with duct-to-duct anastomosis. MAIN OUTCOME MEASUREMENTS: Incidence of post-ERCP complications. Predictive factors were determined by univariate and multivariate analyses. RESULTS: Overall complications occurred in 22 procedures (9%) (13 mild, 9 moderate): pancreatitis in 9 patients (3.7%), cholangitis in 8 patients (3.3%), postsphincterotomy bleeding in 4 patients (1.6%), and subcapsular hematoma in 1 patient (0.4%). The mean hospitalization for post-ERCP complications was 4.8 days (range 2-11 days). Logistic regression identified mammalian target of rapamycin inhibitors (odds ratio [OR], 4.65; 95% CI, 1.01-21.81; P = .049), serum creatinine level greater than 2 mg/dL (OR, 4.17; 95% CI, 1.07-16.26; P = .04), biliary sphincterotomy (OR, 3.03; 95% CI, 1.07-8.53; P = .037), and more than 2 pancreatic duct contrast injections (OR, 2.95; 95% CI, 1.10-7.91; P = .032) as independent risk factors for post-ERCP complications, whereas steroid therapy (OR, 0.23; 95% CI, 0.08-0.63; P = .004) was an independent protective factor. LIMITATIONS: Single-center retrospective study. CONCLUSIONS: The rate of complications after ERCP in LT recipients seems to be similar to that of non-LT recipients. Complications in this analysis were more common in LT recipients receiving mammalian target of rapamycin inhibitors and those with renal failure, biliary sphincterotomy, and more than 2 pancreatic duct injections, whereas they were less common in those patients on steroid therapy. PMID- 21704995 TI - Treatment of complex fractures of the distal radius: a prospective randomised comparison of external fixation 'versus' locked volar plating. AB - The traditional treatment of severely impacted fractures of the distal radius involves bridging external fixation and maintaining reduction by applying continuous traction. The recent technique using fixed-angle screws within volar plates is reported restore the radial length and the articular profile whilst avoiding joint distraction. It is also believed to produce better and quicker clinical results. To test these claims, we carried out a randomised controlled comparison of the efficiency of external fixation (EF) 'versus' open reduction and internal fixation (ORIF) in treating severely impacted fractures of the distal radius. A total of 39 patients were treated with EF, eventually associated with percutaneous pinning, whereas 36 underwent ORIF with a locked volar plate. There was no significant difference in the two groups with regard to changes in the ulnar variance. Articular reduction was poor in two patients in the EF group with residual step-offs exceeding 2mm; another patient of the EF group suffered a secondary loss of reduction, healing with a severe articular malunion (>2mm). By contrast, articular reduction was satisfactory in all the patients of the ORIF group. The clinical results on the Green and O'Brien rating were significantly better in the ORIF group than in the EF group (p<0.01 at 6 weeks, p<0.05 at 6 months). Nevertheless, open reduction and volar plating did not yield better subjective results than EF. However, although not statistically significant, patients treated by ORIF seemed to resume their usual activities quicker than those treated with EF, suggesting that this technique may be adapted to a greater extent in the case of active, young individuals. PMID- 21704996 TI - Factors influencing neck anteversion during femoral nailing: a retrospective analysis of 220 torsion-difference CTs. AB - BACKGROUND: Rotational malalignment is a well-known complication following intramedullary nailing of femoral shaft fractures. The hypothesis of this study is that various modifiable factors, such as position on the surgical table or nailing technique, influence the incidence of torsional abnormalities. METHODS: For this retrospective study, we analysed the data of 220 consecutive patients with femoral shaft fractures and postoperative torsion-difference computed tomographies (CTs), performed from 2001 to 2009 in our institution. Mean age of the patients was 33+/-15 years. Average delay to surgery was 8+/-11 days. The average postoperative neck anteversion difference between both sides was 11+/-8 degrees . A p value <0.05 was considered to be statistically significant. RESULTS: The average postoperative neck anteversion difference between both sides was not significantly affected from the position of the patient on the surgical table (supine or lateral, p=0.698), the delay till surgery (p=0.989), the nailing technique (antegrade or retrograde, p=0.793; reamed or unreamed, p=0.930), the type of the implant (p=0.885) and the experience of the surgeon (p=0.055). Furthermore, the learning curve regarding this complication was long and not predictable. CONCLUSIONS: We could not identify any risk factors that are associated with an increased incidence of torsional deformities, and thus our hypothesis could not be confirmed. The inability to identify such risk factors renders the prevention of this complication particularly problematic. The invention of new techniques for better intra-operative control of the torsion is probably the only solution to further reduce the incidence of postoperative malrotational deformities. PMID- 21704997 TI - Complications following autologous bone graft harvesting from the iliac crest and using the RIA: a systematic review. AB - Bone grafting is a commonly performed surgical procedure to augment bone regeneration in a variety of cases in orthopaedic and maxillofacial surgery. Autologous bone graft remains to be the 'gold standard' and the iliac crest to be the most common harvesting site. The intramedullary canal of long bones represents another potential site for large volume of autologous bone graft harvesting and is recently being used as an alternative donor site. However, harvesting of autologous bone graft is associated with morbidity and a number of complications. The aim of this systematic review was to collect and summarise the existing data on reported complications after harvesting autologous bone from the iliac crest (anterior and posterior) and the long bone intramedullary canal using the RIA device. We searched the PubMed Medline and Ovid Medline databases, from January 1990 to October 2010, to retrieve all relevant articles. A total of 92 articles (6682 patients) were included in the analysis. Overall, the complication rate following RIA was 6% (14 complications in 233 patients) and 19.37% after iliac crest bone graft harvesting (1249 complications in 6449 patients). The rate of each of the reported complications was assessed and, when the donor site was properly documented, comparison within the anterior and posterior iliac crest donor sites was performed. Although the difference of the overall morbidity rates between the two harvesting sites was not statistically significant (p=0.71); the rates of certain complications were found to significantly differ when anterior or posterior iliac crest was used. The rates of infection (p=0.016), haematoma formation (p=0.002), fracture (p=0.017), and hyperthrophic scar (p=0.017) were significantly higher when the donor site was the anterior iliac crest compared to the posterior iliac crest; whereas the rates of chronic donor site pain (p=0.004) and sensory disturbances (p=0.003) were significantly lower. The incidence of bone graft harvesting related complications can be reduced further if certain principles are followed depending on the performed harvesting methods; but overall the use of RIA device as harvesting method seems a promising alternative with a low complication rate. PMID- 21704998 TI - Bone graft substitutes for articular support and metaphyseal comminution: what are the options? AB - Subchondral and metaphyseal bone defects pose a great challenge for the Orthopaedic surgeon not only because the support for the articular surface has been lost but also because the mechanism for the nourishment of articular cartilage through the subchondral plate is distorted. A number of options are available to the surgeons, none of them perfect. Autografting has an appreciable high rate of harvest site morbidity, allograft is associated with infection transmission and host immunologic response. These realities have stimulated interest in supplying bone replacement materials (demineralised bone matrix, synthetic bone substitutes, bone morphogenic proteins). This paper presents the indications and applications of bone substitutes for metaphyseal defects and subchondral support in orthopaedic trauma. PMID- 21704999 TI - Impact of placenta previa on obstetric outcome. AB - OBJECTIVE: To determine the maternal and perinatal outcome for different types of placenta previa (PP). METHODS: A retrospective review of 132 singleton pregnancies with PP. Outcome measures, including the incidence of obstetric hysterectomy, the neonatal Apgar score, and the neonatal weight, were evaluated by logistic regression analysis. RESULTS: The incidence of PP was 1.0%. Of the women with PP, 51.5% had complete PP, 20.5% had incomplete PP, 5.3% had marginal PP, and 22.7% had a low-lying placenta. Most (93.9%) women were delivered by cesarean delivery. In total, 19.7% women underwent obstetric hysterectomy; of these, 92.3% had complete PP. Mothers with 2 or more previous cesarean deliveries had an increased risk for obstetric hysterectomy (P<0.01). The gestational age at delivery was a significant linear predictor of the 5-minute Apgar score. Mothers with incomplete PP delivered neonates with lower Apgar scores than did mothers with complete PP. CONCLUSION: A history of multiple cesarean deliveries increased the risk for obstetric hysterectomy in women with PP. The type of PP had no effect on maternal and neonatal outcome, with exception of the fact that neonates in the incomplete PP group had lower Apgar scores than neonates in the complete PP group. PMID- 21705000 TI - The status of maternal and newborn care services in Sierra Leone 8 years after ceasefire. AB - OBJECTIVE: To conduct a needs assessment for emergency obstetric care (EmOC) to address the unacceptably high maternal and newborn mortality indices in Sierra Leone 8 years after the end of the civil war. METHODS: From June to August 2008, a cross-sectional survey was conducted of health facilities in Sierra Leone offering delivery services. Assessment tools were local adaptations of tools developed by the Averting Maternal Death and Disability program at Columbia University, New York, USA. RESULTS: There were enough comprehensive EmOC (CEmOC) facilities in the country but they were poorly distributed. There were no basic EmOC (BEmOC) facilities. Few facilities (37% of hospitals and 2% of health centers) were able to perform assisted vaginal delivery (AVD), and 3 potentially BEmOC facilities did not meet the standard only because they did not perform AVD. Severe shortages in staff, equipment, and supplies, and unsatisfactory supply of utilities severely hampered the delivery of quality EmOC services. Demand for maternity and newborn services was low, which may have been related to the poor quality and the high/unpredictable out-of-pocket cost of such services. CONCLUSION: Significant increases in the uptake of institutional delivery services, the linkage of remote health workers to the health system, and the recruitment of midwives, in addition to rapid expansion in the training of health workers (including training in midwifery and obstetric surgery skills), are urgently needed to improve the survival of mothers and newborns. PMID- 21705001 TI - A survey of European intensive care nurses' knowledge levels. AB - BACKGROUND: The application of knowledge to the care of critically ill patients is a hallmark of professional nursing practice. However, the educational preparation of intensive care nurses varies from country to country, and there has been little research that has investigated knowledge levels of European critical care nurses. OBJECTIVE: The aim of this study was to examine the knowledge levels of European intensive care nurses. DESIGN: The study was an international cross-sectional survey, with data collected from 20 European countries. SETTING AND PARTICIPANTS: 318 European intensive care units participated, and data were collected from 1142 intensive care nurses. METHODS: Data were collected between May and December 2009 using a 100-item multiple choice online questionnaire to assess intensive care nursing knowledge. The questionnaire was available in 16 languages, and data were collected in 11 knowledge areas. RESULTS: A response rate of 60% was achieved; the majority of participants was female (77%). The largest groups of nurses had more than five years' experience and were under 30 years of age. The overall mean knowledge score was 66% (SD 12). The main factor that contributed to variance in scores was nurses' length of intensive care experience; in ten categories knowledge scores were progressively higher according to experience. If 50% is considered to be a pass mark, 90% of participants would have passed. However, in only six countries did all participants achieve a 'pass' score, and in five countries more than 10% of participants failed to meet this 'pass' criterion. The knowledge category which scored lowest was respiration and ventilation (mean score 56%, SD 15). CONCLUSIONS: Although knowledge levels differed among countries, there were no major differences. However, the relatively low scores achieved in the respiration/ventilation category are a cause of concern, and suggest that this is an education area that should be prioritised. The results should be considered within the context of each country's healthcare and professional education systems, and strategies should be developed to improve knowledge in several key areas. PMID- 21705002 TI - Effect of heel height on in-shoe localized triaxial stresses. AB - Abnormal and excessive plantar pressure and shear are potential risk factors for high-heeled related foot problems, such as forefoot pain, hallux valgus deformity and calluses. Plantar shear stresses could be of particular importance with an inclined supporting surface of high-heeled shoe. This study aimed to investigate the contact pressures and shear stresses simultaneously between plantar foot and high-heeled shoe over five major weightbearing regions: hallux, heel, first, second and fourth metatarsal heads, using in-shoe triaxial force transducers. During both standing and walking, peak pressure and shear stress shifted from the lateral to the medial forefoot as the heel height increased from 30 to 70mm. Heel height elevation had a greater influence on peak shear than peak pressure. The increase in peak shear was up to 119% during walking, which was about five times that of peak pressure. With increasing heel height, peak posterolateral shear over the hallux at midstance increased, whereas peak pressure at push-off decreased. The increased posterolateral shear could be a contributing factor to hallux deformity. It was found that there were differences in the location and time of occurrence between in-shoe peak pressure and peak shear. In addition, there were significant differences in time of occurrence for the double-peak loading pattern between the resultant horizontal ground reaction force peaks and in-shoe localized peak shears. The abnormal and drastic increase of in-shoe shear stresses might be a critical risk factor for shoe-related foot disorders. In-shoe triaxial stresses should therefore be considered to help in designing proper footwear. PMID- 21705003 TI - Annealing of silica to reduce the concentration of isolated silanols and peak tailing in reverse phase liquid chromatography. AB - Non-porous, colloidal silica particles were annealed at three different temperatures, 800, 900 and 1050 degrees C. The adsorption of lysozyme, a probe of surface roughness, was consistent with progressively reduced surface roughness as temperature increased. The heat treated silica particles were rehydroxylated and then used to pack UHPLC columns. The cationic protein lysozyme was used to probe silanol activity, which exhibited progressively less tailing as the annealing temperature increased. FTIR spectroscopy confirmed that the abundance of isolated silanols on the surface was reduced by annealing at 900 degrees C or 1050 degrees C. FTIR also revealed that there was markedly increased hydrogen bonding of the isolated silanols to neighbors after rehydroxylation. These results combine to support the hypothesis that (a) isolated silanols on silica cause tailing in RP-LC and (b) nonplanar topography gives rise to isolated silanols. PMID- 21705004 TI - Lipidomic profiling of biological tissues using off-line two-dimensional high performance liquid chromatography-mass spectrometry. AB - Lipids are important components in all biological tissues having many essential roles associated with the proper function of the organism. Their analysis in the biological tissues and body fluids is a challenging task due to the extreme sample complexity of polar lipids and to their amphiphilic character. In this work, we describe a new method for the characterization of the lipid composition in various tissues, using off-line two-dimensional coupling of hydrophilic interaction liquid chromatography (HILIC) and reversed-phase (RP) high performance liquid chromatography coupled to electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) mass spectrometry. In the first dimension the total lipid extracts are fractioned using HILIC into individual lipid classes. In total, 19 lipid classes (+3 regioisomeric pairs) that cover a wide range of polarities are separated in one analytical run, which is the highest number of analyzed lipid classes reported so far. The lysophospholipid regioisomers are also separated in HILIC mode followed by the identification based on the characteristic ESI mass spectra. The collected fractions of the various lipid classes are further separated in the RP mode, which offers an excellent resolution of the individual lipid species. Their ESI or APCI mass spectra give correct information on the fatty acid composition and on the individual regioisomeric positions on the glycerol skeleton. Off-line coupling of both modes enables the comprehensive analysis of plant and animal samples as illustrated on the analysis of egg yolk, soya and porcine brain tissues. PMID- 21705005 TI - Practical implications of the "Tanaka" stationary phase characterization methodology using ultra high performance liquid chromatographic conditions. AB - The practical implications of performing column characterization protocols (i.e. Tanaka) and their resultant chromatographic selectivity parameters using small dimension columns (i.e. 50 * 2.1 mm I.D.) at high pressures have been critically compared to those obtained using conventional LC methodology. Retention factors should be corrected for the system extra column volume even when determined on ultra high performance liquid chromatographic (UHPLC) systems with low system volumes. An increase in pressure resulted in a general increase in the retention factor for most analytes, the degree being dependent on the physico/chemical properties of each analyte and the chromatographic conditions employed. However, analytes chromatographed at pH values close to their pK(a) values exhibited a substantial decrease in retention factor. Performing the Tanaka and extended column characterization procedures at pressures that would be encountered during the characterization of small particle sizes packed into 50 * 2.1 mm I.D. column formats at a constant linear velocity according to standard protocols, resulted in comparable chromatographic selectivity parameters to those determined using standard HPLC systems and column formats. However, due to the wide structural diversity of analytes employed in other popular column characterization protocols, it is imperative to demonstrate comparable results when small columns packed with small particle sizes are chromatographed at increased pressure and compared to standard column formats--otherwise erroneous comparisons and conclusions may be made. PMID- 21705006 TI - Innovative high-performance liquid chromatography method development for the screening of 19 antimalarial drugs based on a generic approach, using design of experiments, independent component analysis and design space. AB - An innovative methodology based on design of experiments (DoE), independent component analysis (ICA) and design space (DS) was developed in previous works and was tested out with a mixture of 19 antimalarial drugs. This global LC method development methodology (i.e. DoE-ICA-DS) was used to optimize the separation of 19 antimalarial drugs to obtain a screening method. DoE-ICA-DS methodology is fully compliant with the current trend of quality by design. DoE was used to define the set of experiments to model the retention times at the beginning, the apex and the end of each peak. Furthermore, ICA was used to numerically separate coeluting peaks and estimate their unbiased retention times. Gradient time, temperature and pH were selected as the factors of a full factorial design. These retention times were modelled by stepwise multiple linear regressions. A recently introduced critical quality attribute, namely the separation criterion (S), was also used to assess the quality of separations rather than using the resolution. Furthermore, the resulting mathematical models were also studied from a chromatographic point of view to understand and investigate the chromatographic behaviour of each compound. Good adequacies were found between the mathematical models and the expected chromatographic behaviours predicted by chromatographic theory. Finally, focusing at quality risk management, the DS was computed as the multidimensional subspace where the probability for the separation criterion to lie in acceptance limits was higher than a defined quality level. The DS was computed propagating the prediction error from the modelled responses to the quality criterion using Monte Carlo simulations. DoE-ICA-DS allowed encountering optimal operating conditions to obtain a robust screening method for the 19 considered antimalarial drugs in the framework of the fight against counterfeit medicines. Moreover and only on the basis of the same data set, a dedicated method for the determination of three antimalarial compounds in a pharmaceutical formulation was optimized to demonstrate both the efficiency and flexibility of the methodology proposed in the present study. PMID- 21705007 TI - Fast separations of chiral beta-blockers on a cellulose tris(3,5 dimethylphenylcarbamate)-coated zirconia monolithic column by capillary electrochromatography. AB - Cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC) is an excellent chiral selector for enantioseparation of a wide variety of chiral compounds. The monolithic chiral columns are becoming popular in liquid chromatography and capillary electrochromatography. In this work, we present the fast separation of chiral beta-blockers on a CDMPC-modified zirconia monolithic column by capillary electrochromatography (CEC). The porous zirconia monolithic capillary column was prepared by using the sol-gel technology and then zirconia surface modified with CDMPC. The enantioseparations were performed in reversed-phase (RP) eluents of a phosphate solution (pH 4.4) modified with acetonitrile or alcohol. The enantioseparations of a set of eight chiral beta-blockers were achieved in less than one minute. Influences of the applied voltage, column temperature, concentration of acetonitrile and the type of alcohol as the organic modifier in the mobile phase, and sample injection time on enantioseparation were investigated. CEC separations at the applied voltage of 10 kV and 15 degrees C in the ACN-modified mobile phase provided the best resolutions for the analytes studied. Run-to-run and day-to-day repeatabilities of the column in the RP-CEC separation were less than 1 and 2%, respectively. PMID- 21705008 TI - Polyelectrolyte complexes: bulk phases and colloidal systems. AB - When aqueous solutions of polycations and polyanions are mixed, polyelectrolyte complexes form. These are usually insoluble in water, so that they separate out as a new concentrated polymer phase, called a complex coacervate. The behavior of these complexes is reviewed, with emphasis on new measurements that shed light on their structural and mechanical properties, such as cohesive energy, interfacial tension, and viscoelasticity. It turns out that stoichiometric complexes can be considered in many respects as pseudo-neutral, weakly hydrophobic polymers, which are insoluble in water, but become progressively more soluble as salt is added. In fact, the solubility-enhancing effect of salt is quite analogous to that of temperature for polymers in apolar solvents. Since two-phase systems can be prepared in colloidal form, we also discuss several kinds of colloids or 'microphases' that can arise due to polyelectrolyte complexation, such as thin films, 'zipper' brushes, micelles, and micellar networks. A characteristic feature of these charge-driven two-phase systems is that two polymeric ingredients are needed, but that some deviation from strict stoichiometry is tolerated. This turns out to nicely explain how and when the layer-by-layer method works, how a 'leverage rule' applies to the density of the 'zipper brush', and why soluble complexes or micelles appear in a certain window of composition. As variations on the theme, we discuss micelles with metal ions in the core, due to incorporation of supramolecular coordination polyelectrolytes, and micellar networks, which form a new kind of physical gels with unusual properties. PMID- 21705009 TI - Self-assembly and supramolecular liquid crystals based on organic cation encapsulated polyoxometalate hybrid reverse micelles and pyridine derivatives. AB - The controlled self-assembly of multi-components in one system represents the capability integrating intermolecular interactions and functions of components and is believed the key procedure leading to multifunctional materials finally. In pursuing this goal, we used a double-chain cationic surfactant with a benzoic acid group at the end of one tail to encapsulate Keggin-type polyanion clusters via electrostatic interaction, obtaining uniform supramolecular hybrid reverse micelles, which served as hydrogen-bonding donors. Five pyridine derivatives containing conjugated and non-conjugated groups were chosen as hydrogen-bonding acceptors to bind with reverse micelles. Through mixing with these components according to chemical stoichiometry, the hybrid reverse micelle changed to a new self-assembly precursor through intermolecular hydrogen bonding. The as-prepared reverse micelles bearing conjugated pyridine groups exhibit supramolecular liquid crystal properties, which were characterized by differential scanning calorimetry, polarizing optical microscopy, and X-ray diffraction. The length and number of the alky chain in the pyridine derivatives, as well as the charges of polyoxometalates were also studied with regard to the liquid crystal structure. The synergistic effect of among three components was analyzed, and the liquid crystal properties could be conveniently adjusted through the modification of the hydrogen-bonding acceptor components. PMID- 21705010 TI - Destabilization mechanisms in a triple emulsion with Janus drops. AB - The destabilization mechanism was investigated of a triple Janus emulsion. The inner part of the emulsion consisted of Janus drops of a vegetable oil (VO) and a silicone oil (SO) in an aqueous (W) drop, (VO+SO)/W. This drop, in turn was dispersed in a VO drop forming a double emulsion (VO+SO)/W/VO. Finally, these complex drops generated a complex Janus (SO+VO)/W/VO/SO triple emulsion by being dispersed in a continuous SO phase. The observations were limited to the time dependence of the over-all creaming/sedimentation processes, to the separation of layers of the compounds and to optical microscopy of the drop configuration with time. In the destabilization process the rise of the complex drops, (SO+VO)/W/VO, caused crowding in the upper part of the emulsion, which in turn led to enhanced coalescence, inversion and separation of a dilute vegetable oil emulsion. As a consequence of the separation of VO in the process, the remaining drops contained a greater W fraction and greater density. This change, in turn, resulted in sedimentation of the complex drops to form several high internal ratio morphologies in an SO continuous emulsion in the lower part of the test tube, among them a W/VO/SO emulsion. Finally, an inversion took place into an SO/VO/W double emulsion forming a separate bottom layer. PMID- 21705011 TI - Extension of Langmuir kinetics in dilute solutions to include lateral interactions according to regular solution theory and the Kiselev association model. AB - The influence of lateral non-specific and specific interactions on the kinetics in dilute solutions is analyzed within the framework of the Langmuir model. Regular solution theory is used to derive kinetic equations for dilute solutions (RSK model). RSK equations are modified to include simple Kiselev associative interactions and deviations from the regular solution theory (mRSK model) and LF type energetic heterogeneity (LF-mRSK). Derived models lead to significantly different kinetic behavior than the commonly used FG model or the SRT approach. The influence of the equilibrium uptake u(eq) and coverage theta(eq) on the observed effects of lateral interactions is discussed. A new kind of kinetic plot for data analysis is also presented. The mixed LF-mRSK model is applied to analysis of solute adsorption on mesoporous carbon. PMID- 21705012 TI - Fabrication of large scale two-dimensional colloidal crystal of polystyrene particles by an interfacial self-ordering process. AB - Monolayer films of hexagonal close-packed polystyrene (PS) spheres were formed at the air-water interface through a self-ordering process without using Langmuir trough. The contact angle of PS particles on the surface of water was determined by an interfacial swelling method. It was found that the concentration and the nature of surfactant had an obvious influence on the arrangement of PS particles. PS suspension containing Triton X 100 (TX 100) of an appropriate concentration self-assembled into a closely packed monolayer on the surface of water. Sodium dodecyl sulfonate, an anionic surfactant, had a relative weak influence on the arrangement of pre-dried PS particles, in contrast, had an obvious effect on newly synthesized PS particles. Quantitative ultraviolet-visible (UV-vis) absorption spectrometry indicated that about 3% of the added TX 100 was adsorbed on the PS particle surface. Laser diffraction patterns on the monolayer film were used to investigate the lattice orientation. Ultraviolet-visible-near infrared (UV-vis-NIR) spectra of monolayer films of different sized PS particles displayed that the method presented here was universal for preparation of two-dimensional (2D) colloidal crystals. PMID- 21705013 TI - Electroosmotic-capillary penetration in circular microchannels. AB - Electroosmotic forces can be used to promote penetration of electrolytes in microcapillaries. Analytical solutions for the dynamics of penetration are provided. The investigation includes both the electroosmotic and Poiseuille flows. For horizontal microcapillaries, the expression extends the Lucas-Washburn equation to account for the presence of electroosmotic effects. An analytical solution is also obtained for the case where gravity effects come into play. PMID- 21705014 TI - Pathogenicity of fowl adenovirus in specific pathogen free chicken embryos. AB - Inclusion body hepatitis (IBH) associated with fowl adenovirus (FAdV) infection has a worldwide distribution. The aim of the present study was to determine the pathogenicity of Malaysian FAdV serotype 9 (UPM04217) in specific pathogen free (SPF) embryonated chicken embryos. FAdV (titre 10(5.8)/ml) was inoculated into SPF embryonated chicken eggs (0.1 ml per egg) via the chorioallantoic membrane (CAM). There was 100% embryo mortality within 4-11 days post infection (dpi). The gross and microscopical lesions of the embryo were confined to the liver and were noted at 5, 7, 9 and 11 dpi. The liver was pale with multifocal areas of necrosis, fibrosis and haemorrhage. Microscopically, there was moderate to severe congestion and haemorrhage and severe and diffuse hepatocyte degeneration and necrosis, with intranuclear inclusion bodies (INIBs) and associated inflammation. Haemorrhage, congestion, degeneration, necrosis and hyperplasia of the CAM with INIBs were observed at 5, 7, 9 and 11 dpi. Varying degrees of congestion, haemorrhage, degeneration and necrosis were also observed in the yolk sac, kidney, spleen, heart and bursa of Fabricius. Ultrastructurally, numerous viral particles in the nucleus of hepatocytes were recorded at 7, 9 and 11 dpi, whereas at 5 dpi, fine granular and filamentous INIBs were observed. The INIBs in the CAM were present either as fine granular filamentous structures or as large viral inclusions. FAdV (UPM04217) is therefore highly pathogenic to SPF chicken embryos and the embryonic liver should be used for isolation and propagation of the virus. PMID- 21705015 TI - The prevalence of early repolarization in Wolff-Parkinson-White syndrome with a special reference to J waves and the effects of catheter ablation. AB - We determined the prevalence of J waves in the electrocardiograms (ECG) of 120 patients with Wolff-Parkinson-White syndrome in comparison with J-wave prevalence in a control group of 1936 men and women with comparable demographic and ECG characteristics and with normal atrioventricular conduction. J waves were present only during manifest preexcitation in 22 of 120 patients (18.3%), disappearing after catheter ablation and suggesting that J waves were associated with the presence of preexcitation. J waves were present in 19 (15.8%) of 120 patients only after ablation, apparently having been masked by early depolarization of the preexcited myocardial region, and in 22 patients (18.3%), J waves were not altered significantly by preexcitation. Thus, the overall J-wave prevalence was 52.5% (63/120) and, excluding those apparently due to preexcitation, 34.8% (41/120), both substantially higher than the prevalence (11.5%) in the control group (P < .001 for both). The patients with J waves appearing only during preexcitation were younger, predominantly females. The presence of J waves after ablation was associated with a history of atrial fibrillation and shorter ventricular effective refractory period. It is concluded that the prevalence of J waves is high in patients with Wolff-Parkinson-White syndrome and is influenced by manifest preexcitation. PMID- 21705016 TI - Maternal triglyceride levels during early pregnancy are associated with birth weight and postnatal growth. AB - OBJECTIVE: To investigate whether randomly sampled maternal total cholesterol (TC) and triglycerides (TG) levels during early pregnancy are associated with birth weight (BW) and postnatal growth. STUDY DESIGN: Data were derived from the prospective Amsterdam Born Children and their Development cohort study. Randomly sampled TC and TG levels were determined in early gestation (median, 13; IQR, 12 14 weeks). Outcome measures were BW SDS and weight-for-gestational age; postnatal outcome measures were SDS in weight, length, and body mass index during the first year of life (total n = 2502). RESULTS: The highest TG level was associated with a higher BW SDS (differences 0.20 +/- 0.06 between highest and middle quintile; P = .002) and with a higher prevalence (13%) of an infant large for gestational age compared with middle quintile (9%; P = .04). Infants from mothers in the lowest TG quintile had lower SDS in weight, length, and body mass index until age 3 months, and displayed accelerated postnatal growth patterns. Maternal TC was not associated with BW or postnatal growth. CONCLUSION: High maternal TG levels in the first term of pregnancy were associated with higher BWs and subsequently a higher occurrence of infants large for gestational age, whereas low TG levels were associated with accelerated postnatal growth. PMID- 21705018 TI - White matter alterations in social anxiety disorder. AB - White matter architecture in patients with social anxiety disorder (SAD) has rarely been investigated, but may yield insights with respect to altered structural brain connectivity. Initial evidence points to alterations in the uncinate fasciculus (UF). We applied diffusion tensor imaging in 25 patients with SAD and 25 matched healthy subjects. Whole-brain fractional anisotropy (FA) maps were used for group comparison and voxel-wise correlation with psychometric and clinical measures. Additionally, a region-of-interest analysis of the UF was performed. Patients with SAD had reduced FA compared to healthy subjects in or near the left UF and the left superior longitudinal fasciculus. There were no regions with increased FA in SAD. In the region-of-interest analysis, a negative correlation between FA and trait anxiety was identified in the left and right UF in patients, but not in healthy subjects. No correlations with social anxiety scores were observed. The present study partially confirms previous results pointing to frontal WM alterations in or near the UF in patients with SAD. SAD specific dimensional associations of FA with trait anxiety might reflect general pathological and/or compensatory mechanisms as a function of symptom severity in patients. Future studies should disentangle in which way the identified WM alterations match functional alterations. PMID- 21705019 TI - Microvascular tissue oxygenation and oxidative metabolism changes in the pedicled latissimus dorsi muscle during graded hypoxia: correlation between near infrared and 31P nuclear magnetic resonance spectroscopy. AB - BACKGROUND: In this study, the microvascular tissue oxygenation and oxidative muscle metabolism during graded hypoxia and reoxygenation were examined in a rabbit model by near-infrared (NIR) spectroscopy and correlated with high-energy phosphates measured by (31)P nuclear magnetic resonance (NMR) spectroscopy. MATERIALS AND METHODS: Graded hypoxia was performed in a New Zealand rabbit model (n = 20, 2.0 +/- 0.4 kg) by a stepwise reduction of the fraction of inspired oxygen (FiO(2)) from 0.3 to 0.05 (intervention group versus control group). Recovery and reoxygenation were achieved using FiO(2) of 0.3. A noninvasive NIR spectroscopy sensor and NMR probe was positioned on the surface of the prepared pedicled latissimus dorsi muscle. Microvascular tissue oxygenation (oxyhemoglobin, HbO(2); deoxyhemoglobin, HHb) and redox state of cytochrome oxidase (CytOx) were measured by NIR spectroscopy and correlated with standard values of oxidative muscle metabolism (phosphocreatine, PCr; adenosine triphosphate, ATP) measured by time-resolved (31)P NMR spectroscopy (4.7T). RESULTS: Significant correlation was found between PCr and HbO(2) (r = 0.85, P < 0.001) and HHb (r = -0.75, P < 0.001). beta-ATP levels correlated significantly with CytOx (r = 0.87, P < 0.001). CONCLUSIONS: The data suggest that changes in high-energy phosphates (PCr- and ATP-levels) correlate closely with microvascular tissue oxygenation (HbO(2), HHb, CytOx) measured by NIR spectroscopy. PMID- 21705020 TI - Theory of Mind in Parkinson's disease. AB - Theory of Mind is an important concept within social cognition and refers to the ability to attribute mental states to oneself and others. Other terms for this concept include mentalizing and mind reading. Deficits in Theory of Mind may contribute to behavioral abnormalities, such as paranoia and delusions that are common in dementia. There are several experimental tasks for measuring Theory of Mind. A classical example is the false belief test. Examples of other measures include tests of understanding metaphor, sarcasm, irony, deception, and faux pas, determining what a person is thinking or feeling from photographs of the eye region, and visual perspective taking. There are several anatomical areas related to Theory of Mind. These include regions within the frontal and temporal lobes, and temporoparietal junction. There is a small but emerging literature on Theory of Mind in Parkinson's disease (PD). The data suggest that Theory of Mind is impaired in PD and that the deficits precede the development of dementia. Future studies are needed to better define the nature of the Theory of Mind deficits in PD, as well as the impact of these deficits on clinical disability in this disorder. PMID- 21705021 TI - Blood flow velocities of cerebral arteries in lacunar infarction and other ischemic strokes. AB - Blood flow velocity is an important determinant of vascular hemodynamics. The aim of the present study was to determine the mean flow velocities (MFVs) of cerebral arteries in patients with ischemic stroke, comparing lacunar and nonlacunar infarctions. 388 consecutive patients were examined for lacunar infarction, other subtypes of ischemic stroke, and the presence of underlying internal carotid artery steno-occlusion (ICS). MFVs were measured using transcranial Doppler along the full segments of each cerebral artery including both right and left middle cerebral arteries, basilar artery, and both of the vertebral arteries. The patients were categorized into two major groups: lacunar infarction, and nonlacunar infarction with or without underlying ICS. The characteristics of patients with lacunar infarction (n=83, 21.4%) were significantly different from those with nonlacunar infarctions: younger age, lower prevalence of type 2 diabetes, and lower concentration of plasma total homocysteine. The patients with lacunar infarction had lower MFVs in cerebral arteries than the patients with nonlacunar infarctions, especially in the posterior circulation vessels such as the basilar artery and both vertebral arteries. Different hemodynamics might be pathophysiologically associated with the lacunar infarction, compared with the other subtypes of ischemic stroke. PMID- 21705022 TI - Motor and non-motor correlates of olfactory dysfunction in Parkinson's disease. AB - Hyposmia is highly prevalent in the motor phase of Parkinson's disease (PD) and is an established pre-motor sign of PD that may precede the onset of motor symptoms by as long as 5 years. The data presented here are part of an ongoing study to determine the relationship of the olfactory deficit in PD with both motor and non-motor features of the disease. The study population so far includes 96 patients with a clinical diagnosis of PD (UK PD Society Brain Bank criteria; mean age 64.9 years; mean disease duration 4.8 years). Olfactory testing was performed using the 40-item UPSIT. We analyzed the relationship between UPSIT scores and measures of motor (disease duration, stage and severity) and non-motor (cognitive function, depression, anxiety and sleep) function. In 60 PD patients, [(123)I]FP-CIT SPECT scans were available to assess the relationship between UPSIT scores and striatal dopamine transporter (DAT) binding. Preliminary analyses revealed correlations of the olfactory deficit in PD with both motor and non-motor features, as well as with striatal DAT binding. These data suggest that the olfactory deficit in PD is not stationary by the time the motor phase is entered, but continues to progress over time. Hyposmia may therefore be useful as a marker of disease progression, at least in the early disease stages. PMID- 21705023 TI - Clinical EEG in cognitively impaired patients with Parkinson's Disease. AB - Parkinson's Disease Dementia (PD-D) is one of the most important non-motor signs in advanced PD and is the most influencing factor predicting nursing home placement. PD-related Mild Cognitive Impairment (PD-MCI) is a potential prodromal stage of PD-D. The Grand Total EEG (GTE) score is a rating scale for clinical EEG (Electroencephalography) analyses which is useful in the evaluation of different types of dementia. The purpose of the present study was to investigate the relationship between a short version of the GTE score and severity of cognitive deficits in PD. Nineteen patients with PD underwent neuropsychological testing and resting state EEG. Significant correlations with deteriorating cognition (combined Mini Mental Status Examination/Clock Drawing Test) were found for the overall short GTE score (Spearman Rank correlation, rho=-.6; p<.05) and for the subscore "Frequency of Rhythmic Background Activity" (rho=-.6; p<.05), indicating that these EEG measures increase with deteriorating cognition. PMID- 21705024 TI - Identification of bidirectional gene conversion between SMN1 and SMN2 by simultaneous analysis of SMN dosage and hybrid genes in a Chinese population. AB - Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by programmed motoneuron death. The survival motor neuron 1 (SMN1) gene is an SMA determining gene and SMN2 represents an SMA-modifying gene. Here, we applied capillary electrophoresis to quantify the SMN gene dosage in 163 normal individuals, 94 SMA patients and 138 of their parents. We further quantified exons 7 and 8 in SMN1 and SMN2. We found that the SMA patients carried the highest SMN2 copies, which was inversely correlated with disease severity among its three subtypes. Increased SMN1 was significantly associated with decreased SMN2 in the normal group. We also observed that parents of type I SMA patients had significantly fewer SMN2 copies than those of types II and III patients. The hybrid SMN genes were detected in two normal individuals and one patient and her mother. These results imply that increased SMN2 copies in SMA patient group might be derived from SMN1-to-SMN2 conversion, whereas the trend that normal individuals with higher SMN1 copies simultaneously carry fewer SMN2 copies suggested a reverse conversion, SMN2-to-SMN1. Together with the identification of hybrid SMN genes, our data provided additional evidence to support that SMN1 and SMN2 gene loci are interchangeable between population groups. PMID- 21705017 TI - Socioeconomic status and the likelihood of antibiotic treatment for signs and symptoms of pulmonary exacerbation in children with cystic fibrosis. AB - OBJECTIVE: To determine whether socioeconomic status (SES) influences the likelihood of antibiotic treatment of pulmonary exacerbations in patients with cystic fibrosis (CF). STUDY DESIGN: We used data on 9895 patients <= 18 years old from the Epidemiologic Study of CF. After establishing an individual baseline of clinical signs and symptoms, we ascertained whether antibiotics were prescribed when new signs/symptoms suggested a pulmonary exacerbation, adjusting for sex, presence of Pseudomonas aeruginosa, the number of new signs/symptoms, and baseline disease severity. RESULTS: In a 12-month period, 20.0% of patients <6 years of age, 33.8% of patients 6 to 12 years of age, and 41.4% of patients 13 to 18 years of age were treated with any (oral, intravenous (IV), or inhaled) antibiotics; the percentage receiving IV antibiotics was 7.3%, 15.2%, and 20.9%, respectively. SES had little effect on treatment for pulmonary exacerbation with any antibiotics, but IV antibiotics were prescribed more frequently for patients with lower SES. CONCLUSIONS: SES-related disparities in CF health outcomes do not appear to be explained by differential treatment of pulmonary exacerbations. PMID- 21705025 TI - Induced-hypertension in progressing lacunar infarction. AB - BACKGROUND: Although an early neurological deterioration after lacunar infarction is not rare, its therapeutic options are still undetermined. We investigated the effect of induced-hypertension in lacunar infarction with motor progression. METHODS: We reviewed 82 lacunar infarction patients who experienced motor progression [>= 1-point increase of NIH stroke scale (NIHSS) during hospitalization]. Induced-hypertension using phenylephrine was applied to 52 patients and the others received conventional treatment. Target blood pressure (BP) was defined as a 20% increase of initial systolic BP and motor stabilization time as a period from motor progression to motor stabilization. Good outcome was designated as a modified Rankin disability scale 0-2 at discharge in phenylephrine group. RESULTS: Phenylephrine group (vs. conventional group) had a lower NIHSS motor score after each treatment (p=0.022), a shorter motor stabilization time (p<0.001) and hospitalization period (p=0.047), although there were not significantly different from baseline clinical and laboratory findings (ie. age, sex, risk factors for stroke, initial BPs, and NIHSS motor score) in two groups. In multiple regression analysis, a history of hypertension (odds ratio, OR 7.11, 95% CI 1.43-35.31, p=0.016), achievement of target BP (OR 8.13, 95% CI 1.49-44.45, p=0.016) and motor stabilization time (OR 0.51 per 1-day increase, 95% CI 0.29-0.87, p=0.015) were independent predictors for good outcome in the phenyephrine group. Side effects of phenylephrine treatment were transient chest tightness (n=3) and dysuria (n=2). CONCLUSION: The present study suggests that phenylephrine induced-hypertension can result in early motor restoration without serious side effects in progressing lacunar infarction. PMID- 21705026 TI - Association between kinase insert domain-containing receptor gene polymorphism and haplotypes and ischemic stroke. AB - BACKGROUND: Kinase insert domain-containing receptor (KDR), a type 2 vascular endothelial growth factor receptor, plays a crucial role in angiogenesis and vascular integrity of blood vessels. We evaluated whether single nucleotide polymorphisms (SNPs) and haplotype of kinase insert domain-containing receptor (KDR) are associated with increased risk of ischemic stroke in the Korean population. METHODS: Totals of 501 patients with ischemic stroke and 478 controls were screened for the KDR -604T>C, +1192G>A, and +1719A>T SNPs. Subgroup analysis was performed to determine whether the effect of KDR polymorphism is specific to certain etiological subtypes of ischemic stroke. In addition, haplotype frequencies of these three SNPs were analyzed in stroke patients and controls. RESULTS: The SNP +1719T allele was associated with risk of ischemic stroke in a dose-dependent manner (TT vs. AA: adjusted OR: 1.90, 95% CIs: 1.29-2.81, p=0.001 and false discovery rate (FDR)=0.003). Subgroup analysis showed that the SNP +1719T allele had a slight but significant association with small vessel disease type (TT vs. AA: adjusted OR: 1.91, 95% CIs: 1.11-3.29, p=0.02). There was no association between SNP -604 and SNP +1192 and ischemic stroke risk. In haplotype analysis, the T-G-T (-604/+1192/+1719), T-A-T, and C-G-T haplotypes increased the relative risk of ischemic stroke. CONCLUSIONS: The KDR +1719A>T polymorphism and its haplotypes are possible genetic determinants for the risk of ischemic stroke. PMID- 21705027 TI - Cerebral basis of visual hallucinations in Parkinson's disease: structural and functional MRI studies. AB - The presence of visual hallucinations (VH) is a significant predictor of dementia in Parkinson's disease (PD) and it is associated with a more rapid cognitive decline. Non-demented PD patients with VH present greater neuropsychological impairment than those without VH in domains such as verbal and visual memory, language comprehension, and visuospatial and visuoperceptive functions. Frontal dysfunction has also been described in PD with VH, including deficits in verbal fluency, sustained attention, and inhibition. In PD with VH, structural and functional abnormalities within the primary visual system and visual association areas, including ventral and dorsal pathways, have been reported. Structural MRI studies have shown that non-demented PD patients with VH present grey matter reduction in parieto-occipital areas and the hippocampal head. A follow-up study performed at a mean of 30 months revealed that unlike PD patients without VH, PD patients with VH frequently develop dementia associated with progressive atrophy in limbic, paralimbic and neocortical areas. Functional MRI (fMRI) studies have revealed altered activation in occipito-temporal and frontal areas in response to simple and complex visual stimuli in PD patients with VH, suggesting a marked impairment in bottom-up visual processing, as well as an attentional deficit in the pathophysiology of VH in PD. PMID- 21705028 TI - Expression and prognostic value of NDRG2 in human astrocytomas. AB - OBJECTIVE: The pathological grading system of human astrocytoma is usually used to evaluate the outcomes of brain glioma patients. However, it is true that some astrocytoma patients with similar grades underwent obvious discrepancy in survival. Increasing evidence shows that certain tumor biomarkers are more suitable for prognosis assessment of tumors than the grading system. NDRG2, a member of the N-myc downstream-regulated gene family, plays an important role in cell proliferation and differentiation, but whether it can be used as a biomarker for prognosis assessment of astrocytomas remains unknown. METHODS: Immunohistochemistry and semi-quantitative RT-PCR were performed to examine the expression profile of NDRG2 in human astrocytoma specimens. Spearman correlation coefficient was used to describe the association between NDRG2 expression and the clinical parameters of astrocytoma patients. RESULTS: Our results showed that both protein and mRNA expression levels of NDRG2 were significantly downregulated in astrocytomas. In the analysis of the relationship of NDRG2 expression with pathological grades of astrocytoma and with patient survival rate, we found that NDRG2 expression was negatively correlated with pathological grading but positively with the life span of astrocytoma patients. CONCLUSION: NDRG2 can serve as a potential prognostic biomarker for human astrocytoma. PMID- 21705029 TI - Limbic encephalitis presenting as a post-partum psychiatric condition. AB - OBJECTIVE: We describe a woman who presented with a psychiatric disorder post partum and subsequently developed seizures and cognitive dysfunction prompting further investigation. A diagnosis of limbic encephalitis (LE) was made and antibodies to voltage-gated potassium channel complex (VGKC) detected. These antibodies are found in many non-paraneoplastic patients with LE. Although antibody-mediated conditions tend to present or relapse post-partum, VGKC-LE in the post-partum period has not been described. DESIGN: Case report. RESULTS: Clinical and imaging data were consistent with limbic encephalitis. High titres of anti-VGKC-complex antibodies confirmed the diagnosis of VGKC-LE. CONCLUSION: The similarities between the psychiatric symptomatology of VGKC-LE and post partum psychiatric disorders raise the possibility that some instances of post partum psychiatric conditions are manifestations of immune-mediated, non paraneoplastic LE. PMID- 21705030 TI - Wrong-way deviation: contralateral conjugate eye deviation in acute supratentorial stroke. AB - BACKGROUND AND PURPOSE: Supratentorial stroke can cause conjugate eye deviation directed contralateral to the affected side (wrong-way deviation). It is rare and thought to be associated exclusively with hemorrhagic stroke. We prospectively investigated the clinical features and prognostic significance of this wrong-way deviation. METHODS: Subjects were 12 patients who manifested wrong-way deviation subsequent to supratentorial stroke. These patients were from a group of 968 consecutive patients hospitalized for acute supratentorial stroke during the period April 2007 through March 2010. Clinical features of wrong-way deviation were evaluated. RESULTS: The overall incidence of wrong-way deviation was 1.2%. The causative lesion was a huge intracranial hemorrhage (n=7) or an extensive hemispheric infarction (n=5). Left-sided lesions were most frequent (66.7% of patients). Wrong-way deviation usually appeared a few days after the initial insult and was frequently accompanied by transient downward eye deviation (58.3% of patients). Although the outcomes for patients treated conservatively were generally poor, patients who underwent surgical decompression regained consciousness. CONCLUSION: Wrong-way deviation can result not only from hemorrhagic but also ischemic stroke if the stroke is extensive. Secondary damage to the adjacent rostral brainstem where oculomotor pathways cross over from the contralateral hemisphere can explain the phenomenon, its temporal evolution, and associated eye signs. Immediate surgical decompression may be necessary to improve the prognosis in such cases. PMID- 21705031 TI - Lateral spine radiographs before androgen deprivation treatment detect a high incidence of undiagnosed vertebral fragility fractures in men with advanced prostate cancer. AB - PURPOSE: Baseline bone mineral density scanning in patients about to commence long-term androgen deprivation therapy for advanced/metastatic prostate cancer is reported to show a high incidence of osteoporosis and osteopenia. We investigated the incidence of existing spinal osteoporotic fractures in this population as this is known to be a risk factor for the development of treatment induced fractures. MATERIALS AND METHODS: Since 2003 we performed lateral thoracolumbar x rays on all patients before androgen deprivation therapy for prostate cancer. The heights of T4-L5 vertebral bodies were measured, then reanalyzed by the Eastell method to define grade 1 or worse grade 2 vertebral crush fractures. We used a morphometric algorithm including an age stratified random sample of men with normal thoracolumbar x-rays to quantitatively assess fractures. RESULTS: A total of 202 patients with prostate cancer underwent thoracolumbar x-rays before androgen deprivation therapy. Of the patients 61.9% had 1 or more grade 1 and 60.9% had 1 or more grade 2 wedge fractures. In addition, 46.5% of patients had 1 or more grade 1 and 44.6% had greater than 1 grade 2 biconcavity fractures. Finally 63.9% of patients had 1 or more grade 1 and 47.8% had 1 or more grade 2 compression fractures. With conventional reporting 72.4% of patients had no bony abnormality, 14.9% had 1 and 12.7% multiple vertebral crush fractures. Bone mineral density was significantly less in patients with fracture(s) vs those with no abnormality (p<0.001). CONCLUSIONS: Routine reporting identifies a high incidence of spinal fractures before commencing androgen deprivation therapy, but this is much greater when quantitative assessment is applied. Thoracolumbar x rays identify the risk of treatment induced fracture and allow baseline comparison in individuals who experience back pain on androgen deprivation therapy. We advocate more routine adoption of baseline thoracolumbar x-rays in patients with prostate cancer. PMID- 21705032 TI - Editorial comment. PMID- 21705034 TI - Emanuel Edward Klein's role in the establishment of food preservation standards. AB - OBJECTIVES: To evaluate Emanuel Edward Klein's role in the establishment of food preservation standards in terms of critiques of his work, taking his experimental investigations into account. STUDY DESIGN: Historical revision of Klein's experimental investigations of food preservation. METHODS: Descriptive, comparative and analytical methods were used to evaluate Klein's achievements in public health. RESULTS: Presentation of Klein's six papers on food preservation. CONCLUSION: Klein's experimental work was of significant value for the development of food preservation standards for hams, milk and, most importantly, oysters, mussels and other shellfish. PMID- 21705036 TI - Analysis of a monolithic crystal plate acoustic wave filter. AB - We study thickness-shear and thickness-twist vibrations of a finite, monolithic, AT-cut quartz plate crystal filter with two pairs of electrodes. The equations of anisotropic elasticity are used with the omission of the small elastic constant c(56). An analytical solution is obtained using Fourier series from which the resonant frequencies, mode shapes, and the vibration confinement due to the electrode inertia are calculated and examined. PMID- 21705035 TI - Immunohistochemical demonstration of airway epithelial cell markers of guinea pig. AB - The guinea pig (Cavea porcellus) is a mammalian non-rodent species in the Caviidae family. The sensitivity of the respiratory system and the susceptibility to infectious diseases allows the guinea pig to be a useful model for both infectious and non-infectious lung diseases such as asthma and tuberculosis. In this report, we demonstrated for the first time, the major cell types and composition in the guinea pig airway epithelium, using cell type-specific markers by immunohistochemical staining using the commercial available immunological reagents that cross-react with guinea pig. Our results revealed the availability of antibodies cross-reacting with airway epithelial cell types of basal, non ciliated columnar, ciliated, Clara, goblet and alveolar type II cells, as well as those cells expressing Mucin 5AC, Mucin 2, Aquaporin 4 and Calcitonin Gene Related Peptide. The distribution of these various cell types were quantified in the guinea pig airway by immunohistochemical staining and were comparable with morphometric studies using an electron microscopy assay. Moreover, this study also demonstrated that goblet cells are the main secretory cell type in the guinea pig's airway, distinguishing this species from rats and mice. These results provide useful information for the understanding of airway epithelial cell biology and mechanisms of epithelial-immune integration in guinea pig models. PMID- 21705037 TI - PMN-PT single crystal focusing transducer fabricated using a mechanical dimpling technique. AB - A ~5MHz focusing PMN-PT single crystal ultrasound transducer has been fabricated utilizing a mechanical dimpling technique, where the dimpled crystal wafer was used as an active element of the focusing transducer. For the dimpled focusing transducer, the effective electromechanical coupling coefficient was enhanced significantly from 0.42 to 0.56. The dimpled transducer also yields a -6dB bandwidth of 63.5% which is almost double the bandwidth of the plane transducer. An insertion loss of the dimpled transducer (-18.1dB) is much lower than that of the plane transducer. Finite element simulation also reveals specific focused beam from concave crystal surface. These promising results show that the dimpling technique can be used to develop high-resolution focusing single crystal transducers. PMID- 21705038 TI - Reduced membrane fouling in a novel bio-entrapped membrane reactor for treatment of food and beverage processing wastewater. AB - A novel Bio-Entrapped Membrane Reactor (BEMR) packed with bio-ball carriers was constructed and investigated for organics removal and membrane fouling by soluble microbial products (SMP). An objective was to evaluate the stability of the filtration process in membrane bioreactors through backwashing and chemical cleaning. The novel BEMR was compared to a conventional membrane bioreactor (CMBR) on performance, with both treating identical wastewater from a food and beverage processing plant. The new reactor has a longer sludge retention time (SRT) and lower mixed liquor suspended solids (MLSS) content than does the conventional. Three different hydraulic retention times (HRTs) of 6, 9, and 12 h were studied. The results show faster rise of the transmembrane pressure (TMP) with decreasing hydraulic retention time (HRT) in both reactors, where most significant membrane fouling was associated with high SMP (consisting of carbohydrate and protein) contents that were prevalent at the shortest HRT of 6 h. Membrane fouling was improved in the new reactor, which led to a longer membrane service period with the new reactor. Rapid membrane fouling was attributed to increased production of biomass and SMP, as in the conventional reactor. SMP of 10-100 kDa from both MBRs were predominant with more than 70% of the SMP <100 kDa. Protein was the major component of SMP rather than carbohydrate in both reactors. The new reactor sustained operation at constant permeate flux that required seven times less frequent chemical cleaning than did the conventional reactor. The new BEMR offers effective organics removal while reducing membrane fouling. PMID- 21705039 TI - Analysis of the bacterial community in a laboratory-scale nitrification reactor and a wastewater treatment plant by 454-pyrosequencing. AB - For full understanding of the microbial community in the wastewater treatment bioreactors, one of the feasible and effective ways is to investigate the massive genetic information contained in the activated sludge. In this study, high throughput pyrosequencing was applied to analyze the 16S rRNA gene of bacteria in a laboratory-scale nitrification reactor and a full-scale wastewater treatment plant. In total, 27,458 and 26,906 effective sequence reads of the 16S rRNA gene were obtained from the Reactor and the wastewater treatment plant activated sludge samples respectively. The taxonomic complexities in the two samples were compared at phylum and genus levels. According to the pyrosequencing results, even for a laboratory-scale reactor as simple as that in this study, a small size clone library is far from enough to reflect the whole profile of the bacterial community. In addition, it was found that the commonly used informatics tool "RDP classifier" may drastically assign Nitrosomonas sequences into a wrong taxonomic unit resulting in underestimation of ammonia-oxidizing bacteria in the bioreactors. In this paper the reasons for this mistakenly assignment were analyzed and correction methods were proposed. PMID- 21705040 TI - Occurrence and control of nitrogenous disinfection by-products in drinking water- a review. AB - The presence of nitrogenous disinfection by-products (N-DBPs), including nitrosamines, cyanogen halides, haloacetonitriles, haloacetamides and halonitromethanes, in drinking water is of concern due to their high genotoxicity and cytotoxicity compared with regulated DBPs. Occurrence of N-DBPs is likely to increase if water sources become impacted by wastewater and algae. Moreover, a shift from chlorination to chloramination, an option for water providers wanting to reduce regulated DBPs such as trihalomethanes (THMs) and haloacetic acids (HAAs), can also increase certain N-DBPs. This paper provides a critical review of the occurrence and control of N-DBPs. Data collated from surveys undertaken in the United States and Scotland were used to calculate that the sum of analysed halonitromethanes represented 3-4% of the mass of THMs on a median basis; with Pearson product moment correlation coefficients of 0.78 and 0.83 between formation of dihaloacetonitriles and that of THMs and HAAs respectively. The impact of water treatment processes on N-DBP formation is complex and variable. While coagulation and filtration are of moderate efficacy for the removal of N DBP precursors, such as amino acids and amines, biofiltration, if used prior to disinfection, is particularly successful at removing cyanogen halide precursors. Oxidation before final disinfection can increase halonitromethane formation and decrease N-nitrosodimethylamine, and chloramination is likely to increase cyanogen halides and NDMA relative to chlorination. PMID- 21705041 TI - Risk assessment for human consumption of perfluorinated compound-contaminated freshwater and marine fish from Hong Kong and Xiamen. AB - Perfluorinated compounds (PFCs) are man-made fluoro-surfactants that are identified as global pollutants and can pose health risks to humans and wildlife. Two aspects of risk assessment were conducted in this study, including exposure and response. Exposure was estimated by using the concentrations of PFCs in fish and applying standard exposure factors. Among different PFCs, PFOS, PFOA, PFNA, PFDA, PFUdA and PFTrDA were detected. Total concentrations of PFC in fish ranged from 0.27-8.4 ng g(-1) to 0.37-8.7 ng g(-1) respectively in Hong Kong and Xiamen. The calculated hazard ratio (HR) of PFOS for all fish was less than 1.0. However, the HR for mandarin fish in Hong Kong and bighead carp, grass carp and tilapia in Xiamen, had HR values of approximately 0.5, indicating that frequent consumption of these 4 more contaminated fish species might pose an unacceptable risk to human health. Our data support the notion that the released/disposed chemical pollutants into water systems make fish a source of environmental toxicants to humans. The risks and potential effects of PFCs to health of coastal population in the Pearl River Delta are of concern. PMID- 21705042 TI - Human chorionic gonadotropin (hCG) regulation of galectin-3 expression in endometrial epithelial cells and endometrial stromal cells. AB - Previous investigations on galectin-3 (gal-3) have focused mainly on its role in some malignant tumors. It was believed that gal-3 plays important roles in cell proliferation, apoptosis and adhesion in many cell types. Recently, gal-3 has been recognized as a factor related to endometrial receptivity in the human endometrium and trophoblast during embryo implantation. Human chorionic gonadotropin (hCG) is a specific embryonic hormone providing a signal from the embryo involved in preparing the receptive endometrium for embryo implantation. The current study aimed to determine whether hCG regulates gal-3 expression in endometrial cells. Our results showed that expression of gal-3 in both endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs) could be regulated by hCG in an intricate manner. These results indicate that gal-3 might be regulated by hCG in preparing the endometrium for embryonic implantation. PMID- 21705043 TI - The blood-testis barrier: the junctional permeability, the proteins and the lipids. AB - The elucidation of how individual components of the Sertoli cell junctional complexes form and are dismantled to allow not only individual cells but whole syncytia of germinal cells to migrate from the basal to the lumenal compartment of the seminiferous epithelium without causing a permeability leak in the blood testis barrier is amongst the most enigmatic yet, challenging and timely questions in testicular physiology. The intriguing key event in this process is how the barrier modulates its permeability during the periods of formation and dismantling of individual Sertoli cell junctions. The purpose of this review is therefore to first provide a reliable account on the normal formation, maintenance and dismantling process of the Sertoli cells junctions, then to assess the influence of the expression of their individual proteins, of the cytoskeleton associated with the junctions, and of the lipid content in the seminiferous tubules on the regulation of the their permeability barrier function. To help focus on the formation and dismantling of the Sertoli cell junctions, several considerations are based on data gleaned not only from rodents but from seasonal breeders as well because these animal models are characterized by exhaustive periods of junction assembly during development and the onset of the seasonal re-initiation of spermatogenesis as well as by an extensive junction dismantling period at the beginning of testicular regression, something unavailable in normal physiological conditions in continual breeders. Thus, the modulation of the permeability barrier function of the Sertoli cell junctions is analyzed in the physiological context of the blood-epidydimis barrier and in particular of the blood-testis barrier rather than in the context of a detailed account of the molecular composition and signalisation pathways of cell junctions. Moreover, the considerations discussed in this review are based on measurements performed on seminiferous tubule-enriched fractions gleaned at regular time intervals during development and the annual reproductive cycle. PMID- 21705044 TI - Anatomic retroperitoneoscopic adrenalectomy for selected adrenal tumors >5 cm: our technique and experience. AB - OBJECTIVES: To introduce our experience in using anatomic retroperitoneoscopic adrenalectomy (ARA) for adrenal tumors >5 cm and evaluate this procedure's safety and efficiency. METHODS: Of the 1400 ARAs performed in the past 8 years, 110 were performed on patients who had adrenal tumors with a diameter >5 cm. The perioperative indexes of these patients were retrospectively collected and analyzed. RESULTS: The mean tumor size on postoperative pathologic examination was 7.2 +/- 2.1 cm (range 5-14). Only 1 patient with right-sided adrenal pheochromocytoma (7.8 cm diameter) required conversion to open surgery owing to the tumor's severe adhesions to the liver and inferior vena cava. The mean operative time and evaluated blood loss was 70.8 +/- 18.6 minutes and 81.3 +/- 46.1 mL, respectively. The average postoperative interval to oral intake and drainage withdrawal was 2.1 and 2.2 days, respectively. No patient died during the operation. Major intraoperative complication (ie, injury to the vena cava) occurred in 1 patient, necessitating open surgery. Minor complications during the perioperative period occurred in 10 patients (9.1%). CONCLUSIONS: When performed by experienced surgeons, ARA is a safe and feasible procedure for large adrenal masses with a diameter >7 cm; however, this procedure results in a longer operation time and greater blood loss compared with ARA performed on smaller masses. Open surgery is indicated when the tumor adheres to, or has infiltrated, the surrounding tissues. PMID- 21705045 TI - Development of improved nomogram for prediction of outcome of initial prostate biopsy using readily available clinical information. AB - OBJECTIVES: To construct a nomogram that can be used to estimate the risk of prostate cancer (PCa) and high-grade PCa using readily available clinical information for men undergoing initial extended prostate biopsy (PBx). Many nomograms have been developed to predict the outcome of initial PBx. However, most require information not available at the decision to biopsy. METHODS: From March 2000 to April 2010, 1551 men with a prostate-specific antigen (PSA) of <=10 ng/mL who underwent initial extended PBx were included in the present study. The nomogram predictor variables were patient age, race, prostate-specific antigen (PSA) level, percent free PSA, family history of PCa, and the digital rectal examination findings. The area under the receiver operating characteristic curve was calculated as a measure of discrimination. The calibration was assessed graphically. RESULTS: Of the 1551 men, 606 (39.1%) had PCa on biopsy. The mean value for age, PSA, and percent free PSA was 63.4 years, 5.1 ng/mL, and 21.4%, respectively. Also, 25.1% and 7.8% of patients with positive PBx findings had digital rectal examination abnormalities and a positive family history, respectively. The univariate and multivariate analyses suggested that all 6 risk factors were predictors of PCa in the study cohort (P < .05). The area under the curve for all factors in a model predicting PCa was 0.73 (95% confidence interval 0.71-0.76). The area under the curve for predicting high-grade PCa was 0.71 (95% confidence interval 0.69-0.74). CONCLUSIONS: The present predictive model allows an assessment of the risk of PCa and high-grade PCa for men undergoing initial extended PBx using readily available, noninvasively obtained clinical data. PMID- 21705046 TI - Immunohistochemical analysis of SMARCB1/INI-1 expression in collecting duct carcinoma. AB - OBJECTIVES: Collecting duct carcinoma (CDC) is a rare and aggressive renal tumor with a tendency to involve the renal sinus. CDC displays variable morphologic features that can overlap with those of renal medullary carcinoma. The loss of SMARCB1/INI1 tumor suppressor gene, initially found in pediatric malignant rhabdoid tumors of the central nervous system, kidneys, and soft tissues, was also recently described in renal medullary carcinoma. The current immunohistochemical study assessed SMARCB1/INI1 expression in a series of CDCs. METHODS: A total of 20 archival cases of CDC were used to construct a tissue microarray. Each tumor was spotted 3-7 times; benign tissue from the same specimen was also included when available. The immunoexpression of SMARCB1/INI1 was evaluated using BAF47, a monoclonal mouse antibody directed against the SMARCB1/INI1 gene product. Nuclear staining was considered as indicative of SMARCB1/INI1 expression. RESULTS: The complete loss of SMARCB1/INI1 expression was observed in 3 of 20 cases of CDC. Another 3 cases revealed focal and weak intensity staining. The remaining tumors showed multifocal or diffuse SMARCB1/INI1 expression with variable staining intensity. No significant differences were found in the clinicopathologic and outcome features regarding SMARCB1/INI1 status. CONCLUSIONS: The complete loss of SMARCB1/INI1 immunoexpression was found in 15% of CDC. No differences were found between the SMARCB1/INI1 positive and negative cases regarding the clinicopathologic and outcome features. Our results suggest that some CDC cases might be associated with genetic alterations involving the SMARCB1/INI1 gene. In addition, SMARCB1/INI1 immunoexpression seems to be of limited value in the differential diagnosis of CDC versus renal medullary carcinoma, although these results require additional validation. PMID- 21705047 TI - Colocalycostomy for repair of ureterojejunal fistula. AB - Calycostomy is a procedure used for an inaccessible renal pelvis during pyeloplasty. We report the first case of using an anterior calycostomy to repair a ureterojejeunal fistula in a transverse colon conduit in which the ureter and pelvis were not accessible because of intense fibrosis. PMID- 21705048 TI - Long-term fluoroquinolone use before the prostate biopsy may increase the risk of sepsis caused by resistant microorganisms. AB - OBJECTIVES: To evaluate the effect of long-term fluoroquinolone treatment before the biopsy in terms of post procedure sepsis. Three-week fluoroquinolone management before the biopsy may lower serum prostate specific antigen (PSA) levels and prevent unnecessary biopsies. METHODS: A total of 558 patients were referred to our clinic for transrectal ultrasound (TRUS)-guided prostate biopsy. Of the patients, 205 had received levofloxacin 500 mg once a day for 3 weeks before the biopsy to lower the serum PSA levels (group 1). A total of 353 patients had not received any antibiotics before the procedure (group 2). In terms of the postbiopsy sepsis rate, group 1 and group 2 as well as patients who underwent biopsies in the early period and the latter period of the study were compared. RESULTS: Sepsis was diagnosed in 17 patients (3.0%) after biopsy. Of these patients, 11 (5.4%) and 6 (1.7%) were in group 1 and group 2, respectively (P = .0297, OR: 3.28, 95% CI: 1.10-10.13). Sepsis was diagnosed in 7 patients (1.9%) and 10 patients (5.0%) in the early and the latter period of the study, respectively (P = .0771, OR: 0.38, 95% CI: .13-1.09). Escherichia coli was the causative agent in all patients with a positive culture. In addition, 1 patient also had meticillin-resistant Staphylococcus epidermidis (MRSE). All of the E. coli isolates were resistant to fluoroquinolones, and 55.6% were positive for extended spectrum beta-lactamases (ESBL). CONCLUSIONS: Long-term fluoroquinolone use to prevent unnecessary prostate biopsy may result in postbiopsy sepsis caused by fluoroquinolone resistant microorganisms. PMID- 21705049 TI - Nondismembered pyeloplasty in a pediatric population: results of 34 open and laparoscopic procedures. AB - OBJECTIVE: To assess the outcomes of nondismembered pyeloplasty for ureteropelvic junction obstruction in a pediatric population of children and adolescents. METHODS: Between 2005 and 2009, a total of 129 pyeloplasties were performed at our institution. In all, 34 (24%) renal units underwent primary nondismembered Fenger-type plasty, 22 open (OPEN) and 12 laparoscopic (LAP). Gender distribution, left to right ratio, follow-up period, grade of kidney dilatation and split renal function were similar in both groups. The decision to perform a nondismembered procedure was made by the surgeon intraoperatively. The mean age at surgery was 4.5 years for the OPEN group and 14.2 years for the LAP group. Mean follow-up was 30 months (range 12-70 months). RESULTS: The overall success rate was 91% (95.5% the OPEN group and 83.5% in the LAP group). Secondary surgery was required for 3 renal units. Other complications included pyelonephritis in 3 patients (2 in OPEN and 1 in LAP), ileus in 1 patient (OPEN), and prolonged postoperative pain in 1 patient (LAP). The mean operation time was significantly shorter for open surgery (95 minutes for OPEN vs 179 minutes for LAP; P < .05). There was no significant difference in the length of the postoperative hospital stay (2.5 days for OPEN vs 3 days for LAP). CONCLUSION: Nondismembered pyeloplasty is an effective procedure for curing ureteropelvic junction obstruction in the pediatric population, and can be considered as an option in well selected cases. PMID- 21705050 TI - shRNA targeting PLCepsilon inhibits bladder cancer cell growth in vitro and in vivo. AB - OBJECTIVES: To investigate the role of phospholipase Cepsilon (PLCepsilon) by silencing PLCepsilon with short hairpin RNA (shRNA) in human bladder cancer cells BIU-87 in vitro and in vivo. METHODS: A PLCepsilon shRNA expression vector was transfected into BIU-87 cells, and the expression of PLCepsilon protein was detected by Western blotting. Cell proliferation was determined using the MTT assay, and the cell cycle was detected using flow cytometry. A tumor xenograft experiment was established to evaluate the tumor growth under the condition of PLCepsilon knockdown, and the expression of PLCepsilon, proliferating cell nuclear antigen, and cyclin D1 were detected by Western blotting or immunohistrochemistry. RESULTS: PLCepsilon shRNA reduced the protein level of PLCepsilon, leading to marked proliferation inhibition and significant cell cycle arrest. Furthermore, PLCepsilon shRNA reduced the tumor xenograft growth implanted with BIU-87 cells. The protein expression of PLCepsilon, proliferating cell nuclear antigen, and cyclin D1 were downregulated in the bladder tumor xenograft. CONCLUSIONS: The knockdown of PLCepsilon by shRNA could inhibit bladder tumor growth and might be an alternative approach for human bladder cancer therapy. PMID- 21705051 TI - Immediate and carryover effects of Gram-negative and Gram-positive toxin-induced mastitis on follicular function in dairy cows. AB - This study compared immediate and carryover effects of mastitis induced by Gram negative endotoxin (E. coli LPS) and Gram-positive exosecretions (Staph. aureus ex.) on preovulatory follicle function. Synchronized, uninfected cyclic lactating Holstein cows were treated with PGF(2alpha) on day 6 of the cycle and 36 h later, a dose of either E. coli LPS (n = 8), S. aureus ex. (n = 10), or saline (n = 9) was administered into the mammary gland. Follicular fluids and granulosa cells were aspirated 6 h later from the preovulatory follicles and cows were treated with GnRH. This (cycle 1; immediate effect) was repeated three times (excluding the mammary injections) to induce three 7 d cycles (cycles 2, 3, and 4; carryover effect). E. coli LPS increased body temperature, plasma cortisol concentration, and somatic cell count (SCC), whereas S. aureus ex. induced a minor, subclinical elevation of SCC and slight rise (NS) in body temperature and cortisol concentration. Follicular estradiol, androstenedione, and progesterone concentrations in the E. coli LPS group decreased (P < 0.05) in cycle 1 to about 40%, 13%, and 35%, respectively, of control levels, whereas in the S. aureus ex. group, only estradiol decreased (P < 0.05), to 56% of control concentrations. In cycles 3 and 4, follicular steroids in the E. coli LPS group returned to control concentrations, whereas in the S. aureus ex. group, follicular concentrations of estradiol and androstenedione were lower (P < 0.10) than in controls. In the control group, the concentrations of all follicular and circulating steroids remained stable (P > 0.05) throughout the study. Follicle size was similar in all groups, but the S. aureus ex. treatment caused a decrease (P < 0.02) in the number of follicles developed in cycles 3 and 4. The mRNA expression of steroidogenic genes and LHCGR in the granulosa cells was not affected (P > 0.05) by either treatment during the study, except for a tendency toward lower (P < 0.1) expression in cycle 1 and lower (P < 0.05) expression in cycle 4 of the latter in the S. aureus ex. group. Strain levels, such as SCC and body temperature, following toxin injection correlated well with the magnitude of the immediate decline in follicular steroids. As is typical for Gram-negative clinical events, E. coli LPS-induced acute mastitis caused immediate, short-term, but not long-term impairment of follicular responses, whereas the Gram-positive S. aureus ex.-induced subclinical mastitis exhibited both immediate and carryover disruptive effects on preovulatory follicle function. PMID- 21705052 TI - In vitro effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on ovarian, pituitary, and pineal function in pigs. AB - The aims of the study were: (1) to examine 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and/or prolactin (PRL) effects on in vitro secretion of progesterone (P(4)) and estradiol (E(2)) by luteinized granulosa and theca cells from porcine preovulatory follicles; and (2) to determine the effects of TCDD on PRL, luteinizing hormone (LH), and melatonin luteal phase in pigs. We found that TCDD itself did not affect progesterone secretion, but it abolished the stimulatory effect of PRL in the follicular cells. TCDD stimulated PRL secretion during the luteal phase and inhibited during the follicular phase. Moreover, TCDD increased luteinizing hormone secretion by pituitary cells during the follicular phase. In contrast to protein and steroid hormones, melatonin secretion in vitro was not affected by TCDD. In conclusion, it was found that the pituitary-ovarian axis in pigs is sensitive to TCDD, and the dioxin exhibited a profound ability to disrupt the ovarian actions of prolactin. PMID- 21705053 TI - Effects of reproductive aging and postovulatory aging on the maintenance of biological competence after oocyte vitrification: insights from the mouse model. AB - Cryopreservation of female reproductive cells allows preservation of fertility and provides materials for research. Although freezing protocols have been optimized, and there is a high survival rate after thawing, the in vitro fertilization (IVF) pregnancy rate is still lower in cycles with cryopreserved oocytes, thus highlighting the importance of identifying intrinsic limiting factors characterizing the cells at time of freezing. The aim of the present study is to investigate in the mouse model the impact of reproductive aging and postovulatory aging on oocyte biological competence after vitrification. Metaphase II oocytes were vitrified soon after retrieval from young and reproductively old mice. Part of the oocytes from young animals was vitrified after 6 h incubation (in vitro aged oocytes). All classes of oocytes showed similar survival rate after vitrification. Moreover, vitrification did not alter chromosomal organization in young cells, whereas in vitro aged and old oocytes presented an increase of slightly aberrant metaphase configurations. Compared to fresh young oocytes, in vitro aged and old oocytes showed increased ROS levels which remained unchanged after vitrification. By contrast, cryopreservation significantly increased ROS production in young oocytes. Both the aging processes negatively impacted oocyte ability to undergo pronucleus formation and first cleavage after vitrification by stimulating cellular fragmentation. These results could be helpful for establishing the correct time table for cryopreservation in the laboratory routine and improving its application in reproductively old females. Moreover, our observations highlight the importance of oxidative stress protection during vitrification procedures. PMID- 21705054 TI - The effect of antioxidants on the quality of cryopreserved semen in two salmonid fish, the brook trout (Salvelinus fontinalis) and the rainbow trout (Oncorhynchus mykiss). AB - Until now the supplementation of cryopreservation extenders with antioxidants has not been examined in teleost fish. Therefore, the present study investigated whether addition of antioxidants (catalase, superoxide dismutase, peroxidase, reduced glutathione, reduced methione, mixtures of reduced and oxidized glutathione or methionine) to the cryopreservation extenders could increase the quality of frozen-thawed semen of brook trout, Salvelinus fontinalis, and rainbow trout, Oncorhynchus mykiss. In brook trout and rainbow trout semen post-thaw fertility and motility were evaluated and in brook trout additionally the membrane integrity, DNA integrity, and sperm lipid peroxidation were evaluated. The tested antioxidants affected the motility parameters, DNA integrity, and fertility of cryopreserved semen, but not the membrane integrity. Most of the observed effects were negative and only minor positive effects were found. In brook trout 1.5 mmol/l reduced methionine and a mixture of 1.5 mmol/l oxidized and reduced glutathione increased the swimming velocity of frozen-thawed semen. One hundred U/l catalase, 1.5 mmol/l reduced glutathione, and 1.5 mmol/l reduced methionine slightly, but not statistically significantly increased the semen post thaw fertility. However, these effects were not detectable in rainbow trout. Antioxidative stress or damage seems to play no role during cryopreservation, as also in the lipid peroxidation test no differences were obtained between fresh and cryopreserved semen. Therefore, for routine cryopreservation extender supplementation with antioxidants is not recommended in brook trout and rainbow trout. PMID- 21705055 TI - Effect of conceptus secretions on HOXA10 and PTGS2 gene expression, and PGE2 release in co-cultured luminal epithelial and stromal cells of the porcine endometrium at the time of early implantation. AB - Homeobox A10 (HOXA10) gene expression was demonstrated in the endometrium of adult porcine uteri, however there is little information concerning the role of this gene in the pig. Objectives of the present study were to examine: 1) the expression of HOXA10 in the endometrium of cyclic and early pregnant gilts; 2) the effect of estradiol (E(2)) and progesterone (P(4)) on HOXA10 expression in porcine luminal epithelial (LE) and stromal (ST) cells in vitro; 3) the effect of E(2) and conceptus-exposed medium (CEM) on HOXA10 and prostaglandin endoperoxide synthase (PTGS2) gene expression and prostaglandin (PG) E(2) secretion from LE and ST cells in a co-culture model. The abundance of HOXA10 mRNA was increased on day 15 of pregnancy in comparison to day 15 of the estrous cycle. Moreover, increased HOXA10 mRNA level was detected in ST cells after E(2) and P(4) treatment. E(2) stimulated the expression of HOXA10 in LE cells cultured on collagen and pre-treated with steroids, but not in LE on plastic surfaces. Addition of CEM to LE cells cultured in collagen-coated inserts of the co-culture system resulted in elevated HOXA10 and PTGS2 gene expression and PGE(2) secretion in these cells, but not in ST cells cultured in basal compartments. ST cells directly treated with E(2) or CEM showed higher levels of HOXA10 and PTGS2 expression. Blocking of estrogen receptors with ICI-182,780 did not influence the stimulatory effect of CEM. We conclude that HOXA10 expression in the porcine endometrium is closely related to the implantation process and stimulated by conceptus products. Moreover, the co-culture system of LE and ST cells is a promising model for the study of endometrial response to conceptus-derived factors. PMID- 21705056 TI - L-carnitine enhances oocyte maturation and development of parthenogenetic embryos in pigs. AB - The objective was to determine whether adding L-carnitine in IVM/IVC medium enhanced maturation and developmental competence of porcine oocytes in vitro. Oocyte maturation rates did not differ significantly among groups supplemented with 0, 0.25, 0.5, or 1 mg/mL of L-carnitine added during IVM (although 2 mg/mL of L-carnitine reduced maturation rate). Compared with control oocytes, those treated with 0.5 mg/mL of L-carnitine during IVM had greater (P < 0.05) rates of blastocyst formation after parthenogenetic activation, and these blastocysts had less (P < 0.05) apoptosis. Adding 0.5 mg/mL of L-carnitine during IVM also significantly reduced intracellular reactive oxygen species (ROS), and increased glutathione (GSH) concentrations. With or without glucose supplementation, 0.5 mg/mL of L-carnitine in the IVM medium significantly hastened nuclear maturation of oocytes. Moreover, supplementing the IVM medium with either glucose or L carnitine increased (P < 0.05) percentages of oocytes that reached the metaphase II (MII) stage, relative to a control group. Final maturation rates in IVM medium containing either glucose or L-carnitine were not significantly different. Adding L-carnitine (0 to 2 mg/mL) to IVC medium for activated porcine oocytes did not significantly affect development. However, 0.5 mg/mL of L-carnitine in IVC medium significantly reduced reactive oxygen species levels and apoptosis in activated blastocysts, although glutathione concentrations were not significantly altered. In conclusion, adding L-carnitine during IVM/IVC improved developmental potential of porcine oocytes, and also the quality of parthenogenetic embryos, probably by accelerating nuclear maturation, and preventing oxidative damage and apoptosis. PMID- 21705057 TI - Endocrine profiles of somatic nuclear transfer-derived pregnancies in dairy cattle. AB - In cattle, several hormones and proteins are necessary for maintenance of a normal pregnancy that will result in a viable calf. Deviation from the normal cascade or expected profile of reproductive hormones and proteins may be associated with impairment of somatic nuclear transfer-derived pregnancies and the high rate of fetal loss. The objectives of this study were to characterize maternal plasma concentrations of pregnancy-specific protein B (PSPB), progesterone (P4), estrone sulphate (E(1)S), and estradiol (E2) during the last two-thirds of pregnancy (cloned calves), and to determine associations with gestational abnormalities. Cows with cloned fetuses, produced by either commercial (N = 16) or zona-free (N = 4) cloning techniques, were compared with pregnant animals derived from traditional embryo transfer (N = 6) or AI (N = 6), at various stages of gestation (Days 80, 120, 150, 180, 210, and 240; Day 0 = estrus). Fetal well-being was monitored with ultrasonography throughout gestation. At Day 80, progesterone concentration was lower (P < 0.0001) in nuclear transfer (NT) recipients than in control groups. Mean estrone sulphate concentrations did not vary significantly between NT and control groups. At Day 150, pregnancy-specific protein B concentrations were elevated (P < 0.002) in NT cows. Estradiol concentration was higher in NT recipients than control cows throughout the study period. PMID- 21705058 TI - Infertility in a beef bull due to a failure in the capacitation process. AB - The objective of this case report was to identify the cause of apparent idiopathic infertility in a Red Angus (beef) bull. Semen was collected by electroejaculation and submitted to a series of assays, including evaluation of sperm motility by computer-assisted sperm analysis (CASA), sperm morphology and DNA integrity, semen cryopreservation, AI, IVF, induction of the acrosome reaction, and determination of the level of sperm proteins associated with bull fertility potential. Total (92 +/- 2%) and progressive (79 +/- 4%) sperm motility; sperm concentration (1647 +/- 429 * 10(6) sperm/mL); proportions of morphologically normal sperm (83 +/- 6%) and DNA integrity (96 +/- 2), and acrosome-intact sperm (64 +/- 4%) exceeded minimum acceptable values. Frozen sperm had good total (58.7 +/- 6.7%) and progressive (43.9 +/- 9.2%) motility immediately after thawing. However, AI of 16 heifers resulted in no pregnancies and blastocyst production rate (following IVF using sperm from this infertile bull) was nearly identical to that produced using dead sperm (a control of parthenogenesis; 2 +/- 2 and 2 +/- 3%; respectively P < 0.05). Treatment with a calcium ionophore (A23187) failed to induce the acrosome reaction in sperm from the infertile bull (P < 0.05). Evaluation of several proteins associated with the fertility potential of bulls revealed that the level of Binder Sperm Protein-1 (BSP1), known to be associated with the capacitation process, was much greater on sperm from the infertile bull compared to that of his sire. In conclusion, we inferred that the idiopathic infertility in this bull was caused by a failure to complete the capacitation process. PMID- 21705059 TI - Topographical anatomy and desensitization of the pudendal nerve in adult male dromedary camels. AB - The objectives of this study were to describe the topographical anatomy of the pudendal nerve and to develop techniques of its blocking in adult male dromedary camels. Two cadavers and 30 adult male dromedary camels were used for the description of topographical anatomy and pudendal nerve block techniques, respectively. Results revealed that the pudendal nerve arises from the ventral branches of the 2(nd) and 3(rd) sacral spinal nerves. The nerve had three divisions; dorsal, middle, and ventral. The caudal rectal nerve was a branch of the dorsal division. Three blocking techniques were developed according to the results of topographical anatomy. The first technique was 15 cm cranial to the tail base and 7 cm lateral to the midline. The second was 12 cm cranial to the tail base and 7 cm lateral to the midline. The third was about 3 cm on either sides of the anus. Details and complications of each technique were reported. In conclusion, the anatomy of the pudendal nerve was different from that of cattle and horse. The second technique (12 cm cranial to the tail base and 7 cm lateral to the midline) for pudendal nerve block was superior among the three methods. Duration of nerve blocking was suitable for examination and for performing some surgical procedures in male dromedary camels. PMID- 21705060 TI - Age of acquisition effects on the functional organization of language in the adult brain. AB - Using functional magnetic resonance imaging (fMRI), we neuroimaged deaf adults as they performed two linguistic tasks with sentences in American Sign Language, grammatical judgment and phonemic-hand judgment. Participants' age-onset of sign language acquisition ranged from birth to 14 years; length of sign language experience was substantial and did not vary in relation to age of acquisition. For both tasks, a more left lateralized pattern of activation was observed, with activity for grammatical judgment being more anterior than that observed for phonemic-hand judgment, which was more posterior by comparison. Age of acquisition was linearly and negatively related to activation levels in anterior language regions and positively related to activation levels in posterior visual regions for both tasks. PMID- 21705061 TI - The effect of porcelain thickness and surface liner application on the fracture behavior of a ceramic system. AB - OBJECTIVES: To determine the effect of porcelain thickness and the application of a surface liner (SL) on the flexural strength (sigma) of a ceramic system. METHODS: One hundred twenty bar-shaped specimens of yttria-stabilized zirconia based ceramic were fabricated and randomly divided into two groups according to the application of SL: A - applied; B - not applied. The specimens were further divided according to the porcelain veneer thickness (n=20): 0-0.5mm; 1-1.0mm; 2 2.0mm. All specimens were tested in 3-point bending with the porcelain under tension. The maximum load was recorded at first sign of fracture, the sigma was calculated and the mode of failure was determined. Data was statistically analyzed using one-way ANOVA, Tukey (alpha=0.05) and Weibull distribution. RESULTS: The SL application had no effect (p=0.723) while the porcelain thickness had a significant effect (p=0.000) on the mean sigma values. No significant differences in mean sigma values were found with same porcelain thickness. A 0.5 mm thick porcelain layer (groups A0 and B0) showed greater mean sigma values than other groups. The Weibull modulus (m) ranged from 6 (groups A1 and B2) to 9 (groups A0, A2 and B0). The predominant mode of failure for all groups was fracture initiation at the porcelain surface propagating to the ceramic interface. SIGNIFICANCE: The porcelain thickness influenced the mean sigma values, but the SL had no significant effect on the flexural strength and the mode of failure of the ceramic system examined. PMID- 21705062 TI - Management of type 2 diabetes: new and future developments in treatment. AB - The increasing prevalence, variable pathogenesis, progressive natural history, and complications of type 2 diabetes emphasise the urgent need for new treatment strategies. Longacting (eg, once weekly) agonists of the glucagon-like-peptide-1 receptor are advanced in development, and they improve prandial insulin secretion, reduce excess glucagon production, and promote satiety. Trials of inhibitors of dipeptidyl peptidase 4, which enhance the effect of endogenous incretin hormones, are also nearing completion. Novel approaches to glycaemic regulation include use of inhibitors of the sodium-glucose cotransporter 2, which increase renal glucose elimination, and inhibitors of 11beta-hydroxysteroid dehydrogenase 1, which reduce the glucocorticoid effects in liver and fat. Insulin-releasing glucokinase activators and pancreatic-G-protein-coupled fatty acid-receptor agonists, glucagon-receptor antagonists, and metabolic inhibitors of hepatic glucose output are being assessed. Early proof of principle has been shown for compounds that enhance and partly mimic insulin action and replicate some effects of bariatric surgery. PMID- 21705063 TI - Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION Europe): a cluster-randomised trial. AB - BACKGROUND: Intensive treatment of multiple cardiovascular risk factors can halve mortality among people with established type 2 diabetes. We investigated the effect of early multifactorial treatment after diagnosis by screening. METHODS: In a pragmatic, cluster-randomised, parallel-group trial done in Denmark, the Netherlands, and the UK, 343 general practices were randomly assigned screening of registered patients aged 40-69 years without known diabetes followed by routine care of diabetes or screening followed by intensive treatment of multiple risk factors. The primary endpoint was first cardiovascular event, including cardiovascular mortality and morbidity, revascularisation, and non-traumatic amputation within 5 years. Patients and staff assessing outcomes were unaware of the practice's study group assignment. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00237549. FINDINGS: Primary endpoint data were available for 3055 (99.9%) of 3057 screen-detected patients. The mean age was 60.3 (SD 6.9) years and the mean duration of follow-up was 5.3 (SD 1.6) years. Improvements in cardiovascular risk factors (HbA(1c) and cholesterol concentrations and blood pressure) were slightly but significantly better in the intensive treatment group. The incidence of first cardiovascular event was 7.2% (13.5 per 1000 person-years) in the intensive treatment group and 8.5% (15.9 per 1000 person-years) in the routine care group (hazard ratio 0.83, 95% CI 0.65-1.05), and of all-cause mortality 6.2% (11.6 per 1000 person-years) and 6.7% (12.5 per 1000 person-years; 0.91, 0.69-1.21), respectively. INTERPRETATION: An intervention to promote early intensive management of patients with type 2 diabetes was associated with a small, non-significant reduction in the incidence of cardiovascular events and death. FUNDING: National Health Service Denmark, Danish Council for Strategic Research, Danish Research Foundation for General Practice, Danish Centre for Evaluation and Health Technology Assessment, Danish National Board of Health, Danish Medical Research Council, Aarhus University Research Foundation, Wellcome Trust, UK Medical Research Council, UK NIHR Health Technology Assessment Programme, UK National Health Service R&D, UK National Institute for Health Research, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, Novo Nordisk, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue, Merck. PMID- 21705064 TI - HbA1c 5.7-6.4% and impaired fasting plasma glucose for diagnosis of prediabetes and risk of progression to diabetes in Japan (TOPICS 3): a longitudinal cohort study. AB - BACKGROUND: The clinical relevance of the diagnostic criteria for prediabetes to prediction of progression to diabetes has been little studied. We aimed to compare the prevalence of prediabetes when assessed by the new glycated haemoglobin A(1c) (HbA(1c)) 5.7-6.4% criterion or by impaired fasting glucose, and assessed differences in progression rate to diabetes between these two criteria for prediabetes in a Japanese population. METHODS: Our longitudinal cohort study included 4670 men and 1571 women aged 24-82 years without diabetes at baseline (diabetes was defined as fasting plasma glucose >=7.0 mmol/L, self reported clinician-diagnosed diabetes, or HbA(1c) >=6.5%) who attended Toranomon Hospital (Tokyo, Japan) for a routine health check between 1997 and 2003. Participants with a baseline diagnosis of prediabetes according to impaired fasting glucose (fasting plasma glucose 5.6-6.9 mmol/L) or HbA(1c) 5.7-6.4%, or both, were divided into four groups on the basis of baseline diagnosis of prediabetes. Rate of progression to diabetes was assessed annually. FINDINGS: Mean follow-up was 4.7 (SD 0.7) years. 412 (7%) of 6241 participants were diagnosed with prediabetes on the basis of the HbA(1c) 5.7-6.4% criterion. Screening by HbA(1c) alone missed 1270 (61%) of the 2092 prediabetic individuals diagnosed by a combination of impaired fasting glucose and HbA(1c) 5.7-6.4%. Overall cumulative probability of progression to diabetes did not differ significantly between participants with prediabetes discordantly diagnosed by either HbA(1c) or impaired fasting glucose alone (incidence was 7% for HbA(1c) alone [n=412 individuals and 30 incident cases] and 9% for impaired fasting glucose alone [n=1270, 108 cases]; log-rank test, p=0.3317). Multivariate adjusted hazard ratios for incident diabetes were 6.16 (95% CI 4.33-8.77) for those diagnosed with prediabetes by impaired fasting glucose alone and 6.00 (3.76 9.56) for diagnosis by HbA(1c) alone, and were substantially increased to 31.9 (22.6-45.0) for diagnosis by both impaired fasting glucose and HbA(1c) compared with normoglycaemic individuals. INTERPRETATION: Diagnosis of prediabetes by both the new HbA(1c) criterion and impaired fasting glucose identified individuals with an increased risk of progression to diabetes. Although the new HbA(1c) criterion identified fewer individuals at high risk than did impaired fasting glucose, the predictive value for progression to diabetes assessed by HbA(1c) 5.7 6.4% was similar to that assessed by impaired fasting glucose alone. The two tests used together could efficiently target people who are most likely to develop diabetes and allow for early intervention. FUNDING: Japan Society for the Promotion of Science; Ministry of Health Labor and Welfare, Japan. PMID- 21705065 TI - Glycaemic control and incidence of heart failure in 20,985 patients with type 1 diabetes: an observational study. AB - BACKGROUND: Poor glycaemic control is associated with microvascular and macrovascular complications in type 1 diabetes, but whether glycaemic control is associated with heart failure in such patients is not known. We aimed to assess this association in a large cohort of patients with type 1 diabetes identified from the Swedish national diabetes registry. METHODS: We identified all patients (aged >=18 years) with type 1 diabetes and no known heart failure who were registered in the national diabetes registry between January, 1998, and December, 2003. These patients were followed up until hospital admission for heart failure, death, or end of follow-up on Dec 31, 2009. We calculated incidence categorised by glycated haemoglobin A(1c) (HbA(1c)) values, and we assessed the association between patients' characteristics, including HbA(1c), and heart failure. FINDINGS: In a cohort of 20,985 patients with mean age of 38.6 years (SD 13.3) at baseline, 635 patients (3%) were admitted to hospital with a primary or secondary diagnosis of heart failure during a median follow-up of 9.0 years (IQR 7.3-11.0), with an incidence of 3.38 events per 1000 patient-years (95% CI 3.12-3.65). Incidence increased monotonically with HbA(1c), with a range of 1.42-5.20 per 1000 patient-years between patients in the lowest (<6.5%) and highest (>=10.5%) categories of HbA(1c). In a Cox regression analysis, with adjustment for age, sex, duration of diabetes, cardiovascular risk factors, and baseline or intervening acute myocardial infarction and other comorbidities, the hazard ratio for development of heart failure was 3.98 (95% CI 2.23-7.14) in patients with HbA(1c) of 10.5% or higher compared with a reference group of patients with HbA(1c) of less than 6.5%. Risk of heart failure increased with age and duration of diabetes. Other modifiable factors associated with increased risk of heart failure were smoking, high systolic blood pressure, and raised body-mass index. In a subgroup of 18,281 patients (87%) with data for blood lipids, higher HDL cholesterol was associated with lower risk of heart failure, but there was no association with LDL cholesterol. INTERPRETATION: The positive association between HbA(1c) and risk of heart failure in fairly young patients with type 1 diabetes indicates a potential for prevention of heart failure with improved glycaemic control. FUNDING: AstraZeneca, Novo Nordisk Scandinavia, Swedish Heart and Lung Foundation, and Swedish Research Council. PMID- 21705066 TI - HbA1c and blood glucose for the diagnosis of diabetes. PMID- 21705067 TI - Glycaemia and heart failure in diabetes types 1 and 2. PMID- 21705068 TI - Diet or diet plus physical activity versus usual care in patients with newly diagnosed type 2 diabetes: the Early ACTID randomised controlled trial. AB - BACKGROUND: Lifestyle changes soon after diagnosis might improve outcomes in patients with type 2 diabetes mellitus, but no large trials have compared interventions. We investigated the effects of diet and physical activity on blood pressure and glucose concentrations. METHODS: We did a randomised, controlled trial in southwest England in adults aged 30-80 years in whom type 2 diabetes had been diagnosed 5-8 months previously. Participants were assigned usual care (initial dietary consultation and follow-up every 6 months; control group), an intensive diet intervention (dietary consultation every 3 months with monthly nurse support), or the latter plus a pedometer-based activity programme, in a 2:5:5 ratio. The primary endpoint was improvement in glycated haemoglobin A(1c)(HbA(1c)) concentration and blood pressure at 6 months. Analysis was done by intention to treat. This study is registered, number ISRCTN92162869. FINDINGS: Of 593 eligible individuals, 99 were assigned usual care, 248 the diet regimen, and 246 diet plus activity. Outcome data were available for 587 (99%) and 579 (98%) participants at 6 and 12 months, respectively. At 6 months, glycaemic control had worsened in the control group (mean baseline HbA(1c) percentage 6.72, SD 1.02, and at 6 months 6.86, 1.02) but improved in the diet group (baseline-adjusted difference in percentage of HbA(1c) -0.28%, 95% CI -0.46 to -0.10; p=0.005) and diet plus activity group (-0.33%, -0.51 to -0.14; p<0.001). These differences persisted to 12 months, despite less use of diabetes drugs. Improvements were also seen in bodyweight and insulin resistance between the intervention and control groups. Blood pressure was similar in all groups. INTERPRETATION: An intensive diet intervention soon after diagnosis can improve glycaemic control. The addition of an activity intervention conferred no additional benefit. FUNDING: Diabetes UK and the UK Department of Health. PMID- 21705070 TI - The case for diabetes screening: ADDITION-Europe. PMID- 21705069 TI - National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. AB - BACKGROUND: Data for trends in glycaemia and diabetes prevalence are needed to understand the effects of diet and lifestyle within populations, assess the performance of interventions, and plan health services. No consistent and comparable global analysis of trends has been done. We estimated trends and their uncertainties in mean fasting plasma glucose (FPG) and diabetes prevalence for adults aged 25 years and older in 199 countries and territories. METHODS: We obtained data from health examination surveys and epidemiological studies (370 country-years and 2.7 million participants). We converted systematically between different glycaemic metrics. For each sex, we used a Bayesian hierarchical model to estimate mean FPG and its uncertainty by age, country, and year, accounting for whether a study was nationally, subnationally, or community representative. FINDINGS: In 2008, global age-standardised mean FPG was 5.50 mmol/L (95% uncertainty interval 5.37-5.63) for men and 5.42 mmol/L (5.29-5.54) for women, having risen by 0.07 mmol/L and 0.09 mmol/L per decade, respectively. Age standardised adult diabetes prevalence was 9.8% (8.6-11.2) in men and 9.2% (8.0 10.5) in women in 2008, up from 8.3% (6.5-10.4) and 7.5% (5.8-9.6) in 1980. The number of people with diabetes increased from 153 (127-182) million in 1980, to 347 (314-382) million in 2008. We recorded almost no change in mean FPG in east and southeast Asia and central and eastern Europe. Oceania had the largest rise, and the highest mean FPG (6.09 mmol/L, 5.73-6.49 for men; 6.08 mmol/L, 5.72-6.46 for women) and diabetes prevalence (15.5%, 11.6-20.1 for men; and 15.9%, 12.1 20.5 for women) in 2008. Mean FPG and diabetes prevalence in 2008 were also high in south Asia, Latin America and the Caribbean, and central Asia, north Africa, and the Middle East. Mean FPG in 2008 was lowest in sub-Saharan Africa, east and southeast Asia, and high-income Asia-Pacific. In high-income subregions, western Europe had the smallest rise, 0.07 mmol/L per decade for men and 0.03 mmol/L per decade for women; North America had the largest rise, 0.18 mmol/L per decade for men and 0.14 mmol/L per decade for women. INTERPRETATION: Glycaemia and diabetes are rising globally, driven both by population growth and ageing and by increasing age-specific prevalences. Effective preventive interventions are needed, and health systems should prepare to detect and manage diabetes and its sequelae. FUNDING: Bill & Melinda Gates Foundation and WHO. PMID- 21705071 TI - Diet and exercise for new-onset type 2 diabetes? PMID- 21705072 TI - Type 2 diabetes across generations: from pathophysiology to prevention and management. AB - Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of effective prevention strategies. Diabetes develops because of inadequate islet beta-cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing beta cells to work harder, might also have an important defensive role against nutrient-related toxic effects in tissues such as the heart. Reversal of overnutrition, healing of the beta cells, and lessening of adipose tissue defects should be treatment priorities. PMID- 21705073 TI - Global control of diabetes: information for action. PMID- 21705074 TI - Effect of gold nanoparticle morphology on adsorbed protein structure and function. AB - Many biomedical applications of gold nanoparticles (NPs) rely on proteins that are covalently attached or adsorbed on the NP surface. The biological functionality of the protein-NP conjugate depends on the protein's ability to interact with target molecules, which is affected by NP characteristics such as size, curvature, aspect ratio, morphology, crystal structure, and surface chemistry. In the present study, the effect of gold nanoparticle morphology on the structure and function of adsorbed enzymes, lysozyme (Lyz) and alpha chymotrypsin (ChT), has been investigated. Gold nanospheres (AuNS) were synthesized with diameters 10.6 +/- 1 nm, and gold nanorods (AuNR) were synthesized with dimensions of (10.3 +/- 2) * (36.4 +/- 9) nm. Under saturating conditions, proteins adsorb with a higher surface density on AuNR when compared to AuNS. In the case of Lyz, adsorption on AuNS and AuNR resulted in a 10% and 15% loss of secondary structure, respectively, leading to conjugate aggregation and greatly reduced enzymatic activity. ChT retained most of its secondary structure and activity on AuNS and AuNR at low surface coverages; however, as protein loading approached monolayer conditions on AuNR, a 40% loss in secondary structure and 86% loss of activity was observed. Subsequent adsorption of ChT in multilayers on the AuNR surface allowed the conjugates to recover activity and remain stable. It is clear that AuNP morphology does affect adsorbed protein structure; a better understanding of these differences will be essential to engineer fully functional nanobioconjugates. PMID- 21705075 TI - Wnt5a-mediating neurogenesis of human adipose tissue-derived stem cells in a 3D microfluidic cell culture system. AB - In stem cell biology, cell plasticity refers to the ability of stem cells to differentiate into a variety of cell lineages. Recently, cell plasticity has been used to refer to the ability of a given cell type to reversibly de-differentiate, re-differentiate, or transdifferentiate in response to specific stimuli. These processes are regulated by multiple intracellular and extracellular growth and differentiation factors, including low oxygen. Our recent study showed that 3D microfluidic cell culture induces activation of the Wnt5A/beta-catenin signaling pathway in hATSCs (human Adipose Tissue-derived Stem Cells). This resulted in self renewal and transdifferentiation of hATSCs into neurons. To improve neurogenic potency of hATSCs in response to low oxygen and other unknown physical factors, we developed a gel-free 3D microfluidic cell culture system (3D-MUFCCS). The functional structure was developed for the immobilization of 3D multi cellular aggregates in a microfluidic channel without the use of a matrix on the chip. Growth of hATSCs neurosphere grown on a chip was higher than the growth of control cells grown in a culture dish. Induction of differentiation in the Chip system resulted in a significant increase in the induction of neuronal-like cell structures and the presentation of TuJ or NF160 positive long neuritis compared to control cells after active migration from the center of the microfluidic channel layer to the outside of the microfluidic channel layer. We also observed that the chip neurogenesis system induced a significantly higher level of GABA secreting neurons and, in addition, almost 60% of cells were GABA + cells. Finally, we observed that 1 month of after the transplantation of each cell type in a mouse SCI lesion, chip cultured and neuronal differentiated hATSCs exhibited the ability to effectively transdifferentiate into NF160 + motor neurons at a high ratio. Interestingly, our CHIP/PCR analysis revealed that HIF1alpha-induced hATSCs neurogenesis on the chip. This induction was a result of the direct binding of HIF1alpha to the regulatory regions of the Oct4 and beta-catenin genes in nucleus. In the Chip culture of hATSCs that we developed, a low oxygen microenvironment was induced. The low oxygen level induced HIF1alpha expression, which resulted in increased expression of Wnt5A/beta-catenin and Oct4 via the direct binding of HIF1alpha to the regulatory regions of beta-catenin and Oct4. PMID- 21705076 TI - The stimulation of osteogenic differentiation of human adipose-derived stem cells by ionic products from akermanite dissolution via activation of the ERK pathway. AB - Our previous study indicates that akermanite, a type of Ca-, Mg-, Si-containing bioceramic, can promote the osteogenic differentiation of hASCs. To elucidate the underlying mechanism, we investigated the effect of the extract from akermanite, on proliferation and osteogenic differentiation of hASCs. The original extract was obtained at 200 mg akermanite/ml LG-DMEM and further diluted with LG-DMEM. The final extracts were denoted as 1/2, 1/4, 1/8, 1/16, and 1/32 extracts based on the concentrations of the original extract. The LDH assay and live/dead stain were used to reveal the cytotoxicity of the different extracts on hASCs, while the DNA assay was carried out to quantitatively evaluate the proliferation of cells after being cultured with the extracts for 1, 3 and 7 days. Flow cytometry for cell cycle analysis was carried out on cells cultured in two media (GM and 1/2 extract) in order to further analyze the effect of the extract on cell proliferation behaviors. Osteogenic differentiation of hASCs cultured in the extracts was detected by ALP expression and calcium deposition, and further confirmed by real-time PCR analysis. It was shown that Ca, Mg and Si ions in the extract could suppress the LDH release and proliferation of hASCs, whereas promote their osteogenic differentiation. Such effects were concentration dependent with the 1/4 extract (Ca 2.36 mM, Mg 1.11 mM, Si 1.03 mM) being the optimum in promoting the osteogenic differentiation of hASCs. An immediate increase in ERK was observed in cells cultured in the 1/4 extract and such osteogenic differentiation of hASCs promoted by released ions could be blocked by MEK1-specific inhibitor, PD98059. Briefly, Ca, Mg and Si ions extracted from akermanite in the concentrations of 2.36, 1.11, 1.03 mM, respectively, could facilitate the osteogenic differentiation of hASCs via an ERK pathway, and suppress the proliferation of hASCs without significant cytotoxicity. PMID- 21705077 TI - Tumor eradication in rat glioma and bypass of immunosuppressive barriers using internal radiation with (188)Re-lipid nanocapsules. AB - To date, glioblastoma treatments have only been palliative. In this context, locoregional drug delivery strategies, which allow for blood--brain barrier bypass and reduced systemic toxicity, are of major significance. Recent progress in nanotechnology has led to the development of colloidal carriers of radiopharmaceutics, such as lipid nanocapsules loaded with rhenium-188 (LNC(188)Re-SSS) that are implanted in the brain. In our study, we demonstrated that fractionated internal radiation using LNC(188)Re-SSS triggered remarkable survival responses in a rat orthotopic glioma model (cure rates of 83%). We also highlighted the importance of the radioactivity activity gradient obtained by combining a simple stereotactic injection (SI) with convection-enhanced delivery (CED).We assumed that the immune system played a role in the treatment's efficacy on account of the overproduction of peripheral cytokines, recruitment of immune cells to the tumor site, and memory response in long-term survivor animals. Hence, nanovectorized internal radiation therapy with activity gradients stimulating immune responses may represent a new and interesting alternative for the treatment of solid tumors such as glioblastomas. PMID- 21705078 TI - Deep trophoblast invasion and spiral artery remodelling in the placental bed of the lowland gorilla. AB - In contrast to baboon or rhesus macaque, trophoblast invasion in the human placental bed occurs by the interstitial as well as the endovascular route and reaches as deep as the inner myometrium. We here describe two rare specimens of gorilla placenta. In the light of recent findings in the chimpanzee, we postulated the occurrence of deep invasion in gorilla pregnancy. Tissues were processed for histology (PAS, orcein), lectin staining (Ulex europaeus agglutinin 1) and immunohistochemistry (cytokeratin 7/17, alpha-actin). A specimen of young but undetermined gestational age included deep placental bed tissue, showing interstitial and spiral artery invasion of the inner myometrium as well as the decidua. The cell density and depth of trophoblast invasion was equivalent to a human placental bed of 10-14 weeks. Intraluminal trophoblasts were not seen in any of the invaded vessels, allowing no definite conclusions about the origin of the intramural trophoblast and the time-course of spiral artery invasion. A different late second trimester placenta specimen showed scattered extravillous trophoblast in the basal plate and underlying decidua, as well as a remodelled spiral artery containing intramural trophoblast. Absence of inner myometrial tissue precluded assessment of invasion depth in this later specimen. Despite the limited material we can conclude that key aspects of trophoblast invasion are shared by the three hominid species: gorilla, chimpanzee and human. PMID- 21705079 TI - The trophoblast binucleate cell is the source of maternal circulating C-type natriuretic peptide during ovine pregnancy. AB - Maternal plasma concentrations of C-type natriuretic peptide (CNP) and a co secreted bioinactive amino-terminal fragment (NTproCNP) are elevated during ovine pregnancy. Although the uteroplacental unit has been implicated as a likely source of CNP, the relative contributions of specific uterine and placental tissues, and identity of the cellular site/s of production remain unknown. Therefore, we measured CNP and NTproCNP in intercaruncular uterine tissue and maternal (caruncle) and fetal (cotyledon) placental tissues throughout gestation. Concentrations of CNP forms in placental tissues greatly exceeded those in intercaruncular uterine tissue throughout pregnancy (P < 0.05). Mean caruncular concentrations (CNP 32 +/- 4, NTproCNP 56 +/- 6 pmol g(-1)) peaked at day 60 whereas in the cotyledon there was a progressive increase in CNP forms to peak values (CNP 66 +/- 6, NTproCNP 134 +/- 9 pmol g(-1)) at day 100-135 followed by a sharp decline just prior to term (day 143). At term CNP gene expression was 6 fold greater in placental tissue compared with intercaruncular uterine tissue. Changes in maternal plasma concentration of CNP forms closely followed those in cotyledonary tissue whereas fetal plasma levels fell progressively throughout gestation. Immunohistochemistry revealed staining in binucleate cells (BNC) and around placental blood vessels. CNP's localization to the BNC suggests a novel endocrine role during pregnancy, in addition to its paracrine actions within the placental vasculature. The function of CNP in maternal circulation remains to be determined, but as proposed for other BNC products, may involve manipulation of maternal physiology and placental function to favour fetal growth. PMID- 21705080 TI - Dasatinib is safe and effective in unselected chronic myeloid leukaemia elderly patients resistant/intolerant to imatinib. AB - To highlight dasatinib role in the elderly, 125 unselected patients with CP-CML aged >60 years resistant/intolerant to imatinib were retrospectively evaluated. Grade 3-4 haematological and extra-haematological toxicities were reported in 39 (31.2%) and 34 (27.2%) patients; grade 3-4 haematological toxicity was higher in patients with 140 mg starting dose (50.0% vs 19.6%, p=0.001). Grade 3-4 pleuro pericardial effusions occurred in 10 patients (8.0%). Dose reductions were more common in patients with 140 mg (88.4% vs 26.7%, p<0.001). Of 122 evaluable patients, 72 (59.1%) had cytogenetic response [12 (9.8%) partial, 60 (49.3%) complete]. Overall, 38/60 patients in complete CyR also achieved a molecular response. Cumulative OS at 24 and 48 months were 93.1% (95% CI 88.4-97.8) and 84.2% (95% CI 74.6-93.7). Dasatinib, at the recommended dose of 100mg/day, is effective and safe also in unselected elderly subjects. PMID- 21705081 TI - Multidrug resistance gene expression and ABCB1 SNPs in plasma cell myeloma. AB - Multi-drug resistance (MDR) leads to impaired treatment efficacy in all forms of malignancy. The main forms of MDR are thought to be mediated by the substrate transporting actions of certain adenosine triphosphate binding cassette (ABC) transport proteins. The genes ABCB1, ABCB4, ABCC1, ABCG2 and LRP1 have been identified as the most prominent contributors to clinically significant MDR. To date, no study has investigated the expression of these genes in plasma cell myeloma (PCM), or attempted to relate their expression to the incidence of relapse and/or stage at presentation. Here, we show that ABCB4 may be a prominent mediator of tumour cell MDR within PCM. Additionally, there are three SNPs (rs1045642, rs2032582 and rs1128503) within the most widely studied of these genes, ABCB1, which have been suggested to have a potential impact on OS in PCM and which may form a haplotype in ABCB1. rs1045642 in ABCB1 appears to be the only SNP affecting OS within the PCM patients studied, with minimal linkage disequilibrium demonstrated between it and rs2032582 and rs1128503. PMID- 21705082 TI - Biota-sediment accumulation factors for Dechlorane Plus in bottom fish from an electronic waste recycling site, South China. AB - Biota-sediment accumulation factors (BSAFs) for Dechlorane Plus (DP), a highly chlorinated flame retardant, were determined in three bottom fish species, i.e., crucian carp, mud carp, and northern snakehead from an electronic waste recycling site in South China. The average BSAFs are 0.007, 0.01, and 0.06 for syn-DP, and 0.003, 0.025, and 0.001 for anti-DP in crucian carp, mud carp, and northern snakehead, respectively, suggesting low bioaccumulation potential of DP isomers in these fish. However, the bioaccumulation factors (BAFs) determined previously in the same sample set indicated that both DP isomers were highly bioaccumulative (BAFs>5000) in most of the samples. This implies that BSAF values may be inherently inconsistent affecting their reliability as a bioaccumulation indicator. The BSAFs for DP isomers are two orders of magnitude lower than those (average of 0.43-2.28) for extremely hydrophobic polychlorinated biphenyls (CBs 199, 203, 207 and 208), but are comparable to those (average of 0.0001-0.009) for decabromodiphenyl ether (BDE 209) determined in the same sample set. Despite of the different chemical structures of the three compound classes, significantly negative correlations between logarithm of octanol-water partition coefficients (log K(OW)s) and BSAFs of these chemicals were found, indicating that hydrophobicity is one of the key factors influencing the bioaccumulation of these compounds. PMID- 21705083 TI - Murdered bread, living bread: Doris Grant and the homemade, wholemeal loaf. AB - Doris Grant (1905-2003), a middle-class, British housewife, published numerous books from the 1940s into the 1970s urging her fellow housewives to bake organic, wholemeal bread for their families. This article argues that Grant's arguments defy easy categorization as either 'conservative' or 'progressive'. On the one hand, her targeted appeal to women reflected a traditional, conservative understanding of gender roles: women were, first and foremost, wives and mothers and therefore naturally responsible for family diet and health. On the other hand, Grant also pushed her readers to look beyond their homes and recognize a dangerous food supply system that was impinging on their daily lives. She demanded that her readers reject comfortable complicity in this system and preached the value of individual action in effecting substantive change. PMID- 21705084 TI - Adjusting intraocular pressure for central corneal thickness does not improve prediction models for primary open-angle glaucoma. AB - PURPOSE: To determine if the accuracy of the baseline prediction model for the development of primary open-angle glaucoma (POAG) in patients with ocular hypertension can be improved by correcting intraocular pressure (IOP) for central corneal thickness (CCT). DESIGN: Reanalysis of the baseline prediction model for the development of POAG from the Ocular Hypertension Treatment Study (OHTS) substituting IOP adjusted for CCT using 5 different correction formulae for unadjusted IOP. PARTICIPANTS: A total of 1433 of 1636 participants randomized to OHTS who had complete baseline data for factors in the prediction model: age, IOP, CCT, vertical cup-to-disc ratio (VCDR), and pattern standard deviation (PSD). METHODS: Reanalysis of the prediction model for the risk of developing POAG using the same baseline variables (age, IOP, CCT, VCDR, and PSD) except that IOP was adjusted for CCT using correction formulae. A separate Cox proportional hazards model was run using IOP adjusted for CCT by each of the 5 formulae published to date. Models were run including and excluding CCT. MAIN OUTCOME MEASURES: Predictive accuracy of each Cox proportional hazards model was assessed using the c-statistic and calibration chi-square. RESULTS: C-statistics for prediction models that used IOP adjusted for CCT by various formulas ranged from 0.75 to 0.77, no better than the original prediction model (0.77) that did not adjust IOP for CCT. Calibration chi-square was acceptable for all models. Baseline IOP, whether adjusted for CCT or not, was statistically significant in all models including those with CCT in the same model. The CCT was statistically significant in all models including those with IOP adjusted for CCT in the same model. CONCLUSIONS: The calculation of individual risk for developing POAG in ocular hypertensive individuals is simpler and equally accurate using IOP and CCT as measured, rather than applying an adjustment formula to correct IOP for CCT. PMID- 21705086 TI - Characterization of the cleavage plane in DESCemet's membrane endothelial keratoplasty. AB - PURPOSE: To define the cleavage plane between Descemet's membrane (DM) and posterior corneal stroma in Descemet's membrane endothelial keratoplasty (DMEK) concerning its ultrastructural and immunohistochemical characteristics. DESIGN: Observational, consecutive case series. PARTICIPANTS: Fifteen corneoscleral buttons from donors 71.5+/-4.3 years of age stored in Optisol-GS and used for DMEK surgery in 15 consecutive patients. METHODS: Endothelial cell-DM complexes (EDMs) and corresponding corneoscleral rims were investigated by transmission electron microscopy and immunohistochemistry using a panel of antibodies against adhesive matrix proteins. MAIN OUTCOME MEASURES: Ultrastructural and immunohistochemical characteristics of interface and cleavage plane between DM and posterior stroma. RESULTS: Connection between DM and corneal stroma was mediated predominantly by amorphous material of the interfacial matrix and projecting stromal collagen fibers. After DM stripping, the cleavage plane was located consistently between interfacial matrix and posterior stromal collagen lamellae, providing a largely smooth anterior EDM surface exposing the interfacial zone. Interindividual variations in amount and composition of the interfacial matrix resulted in variable degrees of EDM surface irregularities and variable staining patterns for adhesive matrix proteins such as fibronectin, vitronectin, amyloid P, osteonectin/secreted protein acidic and rich in cysteine (SPARC), fibulin-1, fibulin-2, fibulin-3, fibrillin-1, and keratoepithelin. CONCLUSIONS: The findings provide evidence for the existence of a physiologic cleavage plane between the interfacial matrix, the anteriormost adhesive zone of DM, and the corneal stroma, suggesting a relatively weak attachment that can be disconnected by mechanical forces. Interindividual variations in structure and composition of the interfacial matrix may provide an explanation for the variable attachment of EDM grafts to the recipients' corneal stroma and thus may affect the postoperative clinical outcome. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21705085 TI - Inverse association of vitamin C with cataract in older people in India. AB - OBJECTIVE: To examine the association between vitamin C and cataract in the Indian setting. DESIGN: Population-based cross-sectional analytic study. PARTICIPANTS: A total of 5638 people aged >=60 years. METHODS: Enumeration of randomly sampled villages in 2 areas of north and south India to identify people aged >=60 years. Participants were interviewed for socioeconomic and lifestyle factors (tobacco, alcohol, household cooking fuel, work, and diet); attended a clinical examination, including lens photography; and provided a blood sample for antioxidant analysis. Plasma vitamin C was measured using an enzyme-based assay in plasma stabilized with metaphosphoric acid, and other antioxidants were measured by reverse-phase high-pressure liquid chromatography. MAIN OUTCOME MEASURES: Cataract and type of cataract were graded from digital lens images using the Lens Opacity Classification System III (LOCS III), and cataract was classified from the grade in the worse eye of >=4 for nuclear cataract, >=3 for cortical cataract, and >=2 for posterior subcapsular cataract (PSC). Any cataract was defined as any unoperated or operated cataract. RESULTS: Of 7518 enumerated people, 5638 (75%) provided data on vitamin C, antioxidants, and potential confounders. Vitamin C was inversely associated with cataract (adjusted odds ratio [OR] for highest to lowest quartile = 0.61; 95% confidence interval (CI), 0.51-0.74; P=1.1*10(-6)). Inclusion of other antioxidants in the model (lutein, zeaxanthin, retinol, beta-carotene, and alpha-tocopherol) made only a small attenuation to the result (OR 0.68; 95% CI, 0.57-0.82; P < 0.0001). Similar results were seen with vitamin C by type of cataract: nuclear cataract (adjusted OR 0.66; CI, 0.54-0.80; P < 0.0001), cortical cataract (adjusted OR 0.70; CI, 0.54-0.90; P < 0.002), and PSC (adjusted OR 0.58; CI, 0.45-0.74; P < 0.00003). Lutein, zeaxanthin, and retinol were significantly inversely associated with cataract, but the associations were weaker and not consistently observed by type of cataract. Inverse associations were also observed for dietary vitamin C and cataract. CONCLUSIONS: We found a strong association with vitamin C and cataract in a vitamin C-depleted population. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21705087 TI - Outcomes and risk factors associated with endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. AB - OBJECTIVE: To describe outcomes of and risk factors for endophthalmitis after intravitreal anti-vascular endothelial growth factor (VEGF) injection. DESIGN: Single-center, consecutive, case series and retrospective case-control study. PARTICIPANTS: Between January 1, 2009, and May 31, 2010, 16 vitreoretinal surgeons administered a total of 27 736 injections. During this period, 23 cases of presumed infectious endophthalmitis occurred. Each surgeon used his own preferred injection technique. INTERVENTION: Vitreous or aqueous tap, or both, with intravitreal antibiotic injection and subsequent topical antibiotic and steroid drops. MAIN OUTCOME MEASURES: Visual acuity, bladed lid speculum use, conjunctival displacement, hemisphere of injection, bevacizumab versus ranibizumab, and infectious organism. RESULTS: Seven of 23 cases had positive culture results; 3 grew coagulase-negative Staphylococcus. All cases had pain and vitritis on average 3.4 days (range, 1-6 days) after injection, with no difference between culture-positive and culture-negative groups. Eighteen (78%) of 23 cases had a hypopyon. Fifteen of 23 cases returned to baseline vision (+/-2 lines) within 3 months. Neither lid speculum use (0.10% vs. 0.066% in the no-use group; P = 0.27), conjunctival displacement (0.11% vs. 0.076% in the no displacement group; P = 0.43), hemisphere of injection (0.11% superior vs. 0.079% inferior; P = 0.56), or bevacizumab versus ranibizumab (0.11% vs. 0.066%; P = 0.21) affected risk. Analysis of only culture-positive results yielded similar results. There was no statistically significant difference between the proportion of culture-negative cases after bevacizumab injection (83%) versus ranibizumab injection (55%; P = 0.13). CONCLUSIONS: Most patients in whom presumed infectious endophthalmitis develop after anti-VEGF injection regained baseline vision after treatment. Bladed lid speculum use, conjunctival displacement, hemisphere of injection, and type of anti-VEGF agent did not affect risk. No difference in culture-negative endophthalmitis rates was detected after bevacizumab versus ranibizumab injection. Neither the presence of pain, vitritis, decreased vision, hypopyon, nor the interval between injection and development of symptoms differentiate culture-positive from culture-negative cases. Because a subgroup of patients had poor outcomes, a low threshold for vitreous tap with intravitreal antibiotic injection may be warranted. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21705088 TI - Structural correlates of trait anxiety: reduced thickness in medial orbitofrontal cortex accompanied by volume increase in nucleus accumbens. AB - Structural deficiencies within the medial prefrontal cortex have been shown in anxiety-related psychiatric disorders such as panic disorder, post traumatic stress disorder and obsessive compulsive disorder. In healthy subjects, trait anxiety as the individual's disposition to experience anxiety-relevant feelings or thoughts has been shown to be a risk factor for psychiatric disorders. We aimed at exploring the structural correlates of trait anxiety in normal participants. We acquired high-resolution MRI scans from 34 subjects and used FreeSurfer to obtain a measure of cortical thickness. We correlated cortical thickness with self-rated trait anxiety in a whole brain analysis. Automatic subcortical segmentations of the FreeSurfer pipeline were used to relate nucleus accumbens (NAcc) and amygdala volume to trait anxiety. Trait anxiety was negatively correlated with cortical thickness in the right medial orbitofrontal cortex (mOFC) and positively correlated with the bilateral volume of NAcc. Cortical thickness measures extracted from mOFC were negatively associated with the volume of left NAcc. Since, like in anxiety-related psychiatric disorders, in the healthy sample studied here, trait anxiety was associated with a reduction of cortical thickness in mOFC we suggest that this thinning is a structural precondition rather than a consequence of psychiatric illnesses. PMID- 21705090 TI - A prospective study of the relationship between breastfeeding and postpartum depressive symptoms appearing at 1-5 months after delivery. AB - Despite the fact that more than 90% of mothers in Japan prefer breastfeeding, the breastfeeding rate at 6 months postpartum is as low as approximately 35%. Postpartum depression and bonding disorder are recognized as factors associated with discontinuation of breastfeeding. However, these factors remain controversial. The purpose of the present study was to clarify the effect of postpartum depressive symptoms and bonding on the feeding pattern from 1- to 5 month postpartum. A longitudinal study was conducted at 1- and at 5-month postpartum, in 405 mothers who attended health check at three hospitals in the Tokyo metropolitan area at 1-month postpartum, and completed longitudinal questionnaires. A high proportion of breastfeeding mothers at 1 month postpartum had Edinburgh Postpartum Depression Scale (EPDS) score of >= 9 at 5 months postpartum (p=0.01), and these mothers changed to formula milk-based feeding at 5 month postpartum, when compared with those of the breastfeeding-based group at both 1- and 5-month postpartum,. The appearance of depressive symptoms seems to promote discontinuation of breastfeeding at 5-month postpartum. PMID- 21705089 TI - Depression and associated factors in internal migrant workers in China. AB - BACKGROUND: Internal migrant workers are a large population in China. Current health related studies among this population mainly focused on infectious disease, maternal health and occupational diseases and injuries. However, very limited studies were paid attention to mental health of migrant workers though it is an important public health issue. AIMS: The current study aims to understand prevalence of depression symptoms and factors associated with depression among Chinese migrant workers using novel methods to develop a comprehensive sample. METHODS: Respondent-driven sampling (RDS) was employed to recruit the target population, who are required 1) not to hold a hukou indicative of living in central areas or near suburbs of Chengdu city; 2) to be 16 years or older; 3) not to be a student. The Center for Epidemiologic Depression Scale (CES-D) was used to measure depression symptoms of migrant workers. And then Structural Equation Model (SEM) was applied to explore factors associated with depression among Chinese migrant workers. RESULTS: Among 1180 migrant workers, 23.7% of them had clinically relevant depression symptoms (CES-D score >= 16), and 12.8% were consistent with a clinical diagnosis of depression (CES-D score >= 21). Self rated economic status, city adaptation status, and self-rated health had negative effects on depression. Social economic status (SES) affected depression, and was mediated by self-rated economic status and self-rated health. City adaptation status was affected by length of residence in the city, satisfaction with one's job, and the social support that one could obtain while living in the city. CONCLUSIONS: The findings indicated a higher prevalence of depression symptoms among migrant workers comparing to general population reported by previous studies, identified possible factors associated with depression symptoms, and also explored relationships between these factors. Our study provides a model to understand mental health of Chinese internal migrant workers and to generate important research questions for the future. PMID- 21705091 TI - Is risk for mania associated with increased daydreaming as a form of mental imagery? AB - BACKGROUND: Bipolar disorder and risk for mania are associated with setting high goals and dysregulated goal pursuit. One mechanism mediating between setting high goals and manic symptoms could be daydreaming or more generally, mental imagery. 'Daydreams' (as one form of mental imagery) are characterized by the fact that the content is produced deliberately. Akiskal et al. (1995) reported that daydreaming prospectively predicted a switch from unipolar depression to bipolar disorder. We here hypothesized that risk for mania should also be associated with increased daydreaming after controlling for depression. METHOD: N=249 participants from a non-clinical, community sample completed several self-report measures including the Hypomanic Personality scale and Daydreaming scale. RESULTS: Hierarchical regression revealed that risk for mania predicted daydreaming after controlling for current and former depression. LIMITATIONS: Only self-report measures were used. The sample was a non-clinical, primarily White British sample, which has implications for generalizability. CONCLUSIONS: Despite limitations our results support the hypothesis that vulnerability for mania is associated with daydreaming. Daydreaming was related to mania and depression which highlights that it might be relevant for the etiology or maintenance of mood disorders. PMID- 21705092 TI - Mindfulness, response styles and dysfunctional attitudes in bipolar disorder. AB - BACKGROUND: This study aimed to examine differences between mindfulness, dysfunctional attitudes and response styles in subjects with bipolar disorder, major depressive disorder and controls. METHOD: A total of 192 participants were included in this study: 90 with bipolar disorder, 36 with remitted major depressive disorder and 66 subjects without a current or past history of a mood disorder. RESULTS: After controlling for current mood state and co-morbid anxiety disorders, the groups did not differ on mindfulness or response styles scores, however, those with bipolar disorder scored significantly higher on the Dependency and Achievement subscales of the Dysfunctional Attitudes Scale than the other two groups. LIMITATIONS: Sample sizes were relatively small for the control and remitted major depressive disorder groups making it difficult to draw definitive conclusions. CONCLUSIONS: Participants with bipolar disorder appear to significantly differ from remitted depressives and controls on certain cognitive styles such as Dependency and Achievement on the Dysfunctional Attitudes Scale. Further research may help to understand how these cognitive domains impact on the course and outcome of bipolar disorder. PMID- 21705093 TI - Motivations for body piercings and tattoos - the role of sexual abuse and the frequency of body modifications. AB - Though the popularity of body modification increases, psychosocial data about practitioners of body piercing and tattooing are few and controversial. Most studies used semi-structured interviews and relatively small sample sizes. The aim of this study was to explore psychosocial background information (motivation, sexual abuse) for body modification practises based on a sufficiently large sample. A core group of 432 subjects with body piercings and/or tattoos (readers of a specialised magazine on body modification; mean age: 28 years) was investigated in this study using a 55-item questionnaire. The mean number of body modifications (piercings and tattoos) was nine. Participants with a history of sexual abuse and high users with more than 10 body modifications differed from those without these features with respect to several motivations and consequences of body modification. Participants with sexual abuse often stated that they wanted to overcome certain experiences, and high users were characterised by the feeling of an addiction to continue body modification. Clinicians should include questions on body modifications and their motives in anamnestic schedules. PMID- 21705094 TI - Ethnic variation in the prevalence of depression and anxiety in primary care: a systematic review and meta-analysis. AB - Primary care plays a key role in the detection and management of depression and anxiety. At present it is not clear if the prevalence of depression and anxiety in primary care differs between migrants and ethnic minorities (MI) and natives and ethnic majorities (MA). A systematic review and a meta-analysis of studies comparing the prevalence of depression and anxiety in MI and MA in primary care were performed. Studies were identified by searching MEDLINE, PsychINFO, EMBASE and through hand-search. We included 25 studies, most of which had a relatively small sample size. Significant variations were found in the prevalence of anxiety and depression across studies. Pooled analyses were carried out for 23 studies, based on random-effects models. Pooled RR of depression and anxiety in MI were 1.21 (95% CI 1.04-1.40, p=0.012) and 1.01 (95% CI 0.76-1.32, p=0.971), with high heterogeneity (I2=87.2% and I2=73%). Differences in prevalence rates among studies can be accounted for by inclusion criteria, sampling methods, diagnostic instruments and study design. Further research on larger samples and with culturally adapted instruments is needed to estimate the prevalence of depression and anxiety in MI seeking help for these disorders. PMID- 21705095 TI - Retropharyngeal infections in children. Treatment strategies and outcomes. AB - OBJECTIVE: To optimize the treatment of retropharyngeal infections in children. METHODS: Retrospective chart review of 101 consecutive pediatric cases of retropharyngeal infections referred to our center from January 2006 to July 2009. RESULTS: Two-thirds of patients were males. Their mean age was 52 months (range: 6-163). Upper airway obstruction was observed in three patients. In another child, the infection evolved towards a diffuse cervical cellulitis. Medical treatment was initially planned in 44% of patients. Failures requiring surgical drainage occurred in 18% of them. In 56% of cases, surgical treatment was immediately instigated. It failed in 16% of patients, requiring a second surgical drainage. There was no difference in the duration of fever and of hospital stay between patients initially treated medically or surgically. Both medical and surgical treatment failures were associated with longer durations of fever (p=0.002, and p<0.0001, respectively) and of hospital stay (p=0.0006, and p=0.0005, respectively). Some characteristics of CT-scan anomalies were correlated with treatment failure. A hypodense core surrounded by rim enhancement, with a largest long axis >= 20 mm, was more frequent in case of medical failure (p=0.02). Surgical failure was associated with the same feature, but with a largest long axis >= 30 mm (p=0.05). CONCLUSIONS: The present study suggests that severe complications are rare in pediatric retropharyngeal adenitis, and that CT-scan is a useful tool to choose between medical and surgical treatment. PMID- 21705096 TI - Screening for delayed-onset hearing loss in preschool children who previously passed the newborn hearing screening. AB - OBJECTIVE: The goal of this study was to investigate the prevalence of delayed onset hearing loss in preschool children who previously passed newborn hearing screening in Shanghai, China. METHODS: Between October 2009 and September 2010, 21,427 preschool children were enrolled from five areas of Shanghai, who had passed newborn hearing screening. Children were screened for delayed-onset hearing loss with pediatric audiometers. Children with positive results in initial and re-screening tests were assessed audiologically and for risk indicators according to the Year 2007 Statement of the American Joint Committee on Infant Hearing (JCIH). RESULTS: During the study period, 445 children (2.08%) were referred for audiologic assessment; 16 (0.75/1000, 95% CI 0.38-1.12) had permanent delayed-onset hearing loss. Of these, five (0.23/1000) had bilateral moderate hearing loss; seven (0.33/1000) had mild bilateral hearing loss; and four (0.19/1000) had unilateral moderate or mild hearing loss. JCIH risk indicators were established for six children (6/16, 37.5%), including parental concern regarding speech and language developmental delay, neonatal intensive care unit with assisted ventilation or hyperbilirubinemia, recurrent otitis media with effusion, craniofacial malformation, and family history (n=1 for each). The remaining ten (62.5%) had no related risk factors. CONCLUSIONS: A significant proportion of preschool children have undiagnosed delayed-onset hearing loss. Hearing screening in preschool is recommended for an early detection. PMID- 21705097 TI - Risk stratification by accelerated high-dose dipyridamole stress echocardiography in patients over 70 years of age. AB - BACKGROUND: The non-invasive prognostic assessment of coronary artery disease in patients over 70 years old is an important goal in daily clinical practice. OBJECTIVES: To retrospectively assess the feasibility, the positive and negative predictive values and the accuracy of accelerated high-dose dipyridamole stress echocardiography in patients over 70 years old. METHODS: Three hundred seventy nine patients (226 women; mean age of 75.9+/-4.6 years) underwent dipyridamole stress echocardiography. RESULTS: Follow-up data were available for 313 patients (mean follow-up duration 21+/-15.7 months). Overall feasibility was 97%. Positive predictive values were 30% and 40% for 6 and 12 months of follow-up, respectively. Negative predictive values were 97.7% and 96.7% for 6 and 12 months of follow-up, respectively. Accuracy values were 95.5% and 94.9% for 6 and 12 months of follow-up, respectively. Among the clinical variables, dyslipidemia (OR 5.3; CI 95% 1.3-20.9; p=0.016), coronary artery disease (OR 4.2; CI 95% 1.3-13.3; p=0.014) and a positive stress echo response (OR 9.0; CI 95% 1.7-49.1; p=0.011) were independently associated with the occurrence of a cardiovascular event. A Cox regression model showed that male gender and a positive stress echo response significantly predicted death. CONCLUSIONS: Risk stratification with accelerated high-dose dipyridamole stress echocardiography is feasible in patients over 70 years old. A positive stress echo response, the presence of coronary artery disease, and dyslipidemia positively predicted the occurrence of cardiovascular events. Male gender and a positive stress echo response significantly predicted death. PMID- 21705098 TI - Parathyroid hormone and systolic blood pressure accelerate the progression of aortic valve stenosis in chronic hemodialysis patients. AB - BACKGROUND: Aortic valve stenosis (AS) is a frequent complication contributing to poor prognosis in chronic hemodialysis (CHD) patients. However, little is known regarding the risk factors affecting AS progression. The purpose of this study was to define risk factors affecting AS progression in CHD patients. METHODS: We retrospectively investigated 34 consecutive CHD patients with asymptomatic AS (mild in 9, moderate in 20, severe in 5; aortic valve area (AVA), 1.31+/ 0.31cm(2); mean age, 69+/-8years) who underwent followed-up paired transthoracic echocardiography with period of at least six months apart (22+/-9months). AS progression was evaluated using the absolute reduction in AVA per year. RESULTS: CHD patients were divided into 20 patients with rapid progression (AVA reduction, >0.1cm(2) per year) and 14 with slow progression (AVA reduction, <= 0.1cm(2) per year). Serum parathyroid hormone (PTH) level was significantly higher in patients with rapid progression than in those with slow progression [343+/-489pg/ml vs. 76+/-80pg/ml, P<0.05]. In univariate analysis, AS progression by absolute AVA reduction per year was associated with age, PTH level, initial AVA, systolic blood pressure (SBP), diastolic blood pressure, total cholesterol, and left ventricular diameter at end-diastole and end-systole. Multiple regression analysis indicated that serum PTH level and SBP remained independently associated with AS progression. CONCLUSIONS: AS progression was accelerated in the presence of high PTH and SBP. Careful monitoring and intensive treatment of these parameters may have a beneficial effect on secondary prevention in CHD patients. PMID- 21705099 TI - When cats' ways of life interact with their viruses: a study in 15 natural populations of owned and unowned cats (Felis silvestris catus). AB - In natural populations, virus circulation is influenced by host behavior and physiological characteristics. Cat populations exhibit a great variability in social and spatial structure, the existence of different ways of life within a same population may also result in different epidemiological patterns. To test this hypothesis, we used a logistic regression to analyze the risk factors of Feline immunodeficiency virus (FIV), feline herpes virus (FHV), feline calicivirus (FCV), and feline parvovirus (FPV) infection in owned (fed and sheltered) and unowned (neither fed nor sheltered, unsocialized) cats living in a rural environment in the North Eastern part of France. A serological survey was carried out in 492 non-vaccinated and non-sterilized individuals from 15 populations living in the same area. The prevalence of feline leukemia virus (FeLV) was also studied, but too few were infected to analyze the risk factors of this virus. For each virus, the epidemiological pattern was different in owned and unowned cats. Unowned cats were more frequently infected by directly transmitted viruses like FIV, FHV and FCV (21.22%, 67.66%, 86.52% in unowned cats vs 9.55%, 53.88%, 77.18% in owned cats, respectively), a difference that may be explained by a more solitary and more aggressive behavior in unowned adults, and/or possibly by a higher sensitivity related to a more stressful life. On the contrary, owned cats were more frequently infected with FPV (36.41% in owned cats vs 15.61% in unowned cats), possibly as a result of their concentration around human settlements. The present study showed that owned and unowned cats living in a same area have behavioral and physiological characteristics sufficiently different to influence virus circulation. Pooling different types of cats in a single sample without taking it into account could give a wrong picture of the epidemiology of their viruses. The conclusion of this work can be extended to any epidemiological studies led in wildlife species with flexible behavior as any variations in social or spatial structure, between or within populations, could result in different virus circulation. PMID- 21705101 TI - Poly(glycoamidoamine)s: a broad class of carbohydrate-containing polycations for nucleic acid delivery. AB - In the era of nucleic acid therapeutics, there is an urgent need for non-viral delivery vehicles that can cross the extracellular and intracellular barriers and deliver nucleic acids to specific intracellular regions. This paper reviews the development of a subclass of polymer-based delivery vehicles termed poly(glycoamidoamine)s (PGAAs). The general design of this family consists of carbohydrate residues copolymerized with oligoethyleneamine units, which have proven to be an effective motif that promotes polyplex formation, efficient cellular internalization, high gene expression and low cytotoxicity with cultured cell lines and primary cell types. We then discuss the structure-property relationships of the PGAA class of delivery vehicles and studies aimed at understanding the mechanisms involved in cellular internalization and trafficking. PMID- 21705100 TI - Medicare prospective payment and the volume and intensity of skilled nursing facility services. AB - In 1998, Medicare adopted a per diem Prospective Payment System (PPS) for skilled nursing facility care, which was intended to deter the use of high-cost rehabilitative services. The average per diem decreased under the PPS, but because per diems increased for greater therapy minutes, the ability of the PPS to deter the use of high-intensity services was questionable. In this study, we assess how the PPS affected the volume and intensity of Medicare services. By volume we mean the product of the number of Medicare residents in a facility and the average length-of-stay, by intensity we mean the time per week devoted to rehabilitation therapy. Our results indicate that the number of Medicare residents decreased under PPS, but rehabilitative services and therapy minutes increased while length-of-stay remained relatively constant. Not surprisingly, when subsequent Medicare policy changes increased payment rates, Medicare volume far surpassed the levels seen in the pre-PPS period. PMID- 21705102 TI - 3rd International Symposium on Propionibacteria and Bifidobacteria: dairy and probiotic applications, Oviedo 1-4 June 2010. PMID- 21705103 TI - Scientific summary of the 3rd International Symposium on Propionibacteria and Bifidobacteria: dairy and probiotic applications. PMID- 21705104 TI - Direct-to-consumer advertising (DTCA) for prescription drugs: consumers' attitudes and preferences concerning its regulation in South Korea. AB - OBJECTIVE: To examine consumers' attitudes toward direct-to-consumer advertising (DTCA) for prescription drugs in Korea. METHODS: We conducted a survey of 350 patients visiting community pharmacies to fill their prescriptions. Consumers' attitudes toward DTCA were assessed in terms of whether they felt DTCA was necessary, their trust in the information provided by DTCA, and their intention to use the information provided by DTCA. We examined consumers' preferences regarding the regulation of DTCA and their expectations of the effects of DTCA. RESULTS: About 60% of the respondents responded that DTCA is necessary and that they intended to use the information from DTCA. Less than half of the respondents reported that they would trust DTCA information. About 70% of the participants expressed the need for prior vetting of the DTCA content. Respondents had the highest expectation on the effect of DTCA as an information source for patients. Positive consumer expectations regarding the effects of DTCA were significantly associated with positive consumer attitudes toward DTCA (odds ratio=4.70, 95% confidence interval: 2.25-9.82). CONCLUSIONS: This study provides evidence that consumers in South Korea generally have positive attitudes toward DTCA. However, most of the respondents wanted a prior examination system of DTCA content to ensure that the information conveyed to them via DTCA was trustworthy. Policy makers should be cautious and well-prepared if they decide to introduce DTCA in Korea. PMID- 21705105 TI - Request redirection paradigm in medical image archive implementation. AB - It is widely recognized that the JPEG2000 facilitates issues in medical imaging: storage, communication, sharing, remote access, interoperability, and presentation scalability. Therefore, JPEG2000 support was added to the DICOM standard Supplement 61. Two approaches to support JPEG2000 medical image are explicitly defined by the DICOM standard: replacing the DICOM image format with corresponding JPEG2000 codestream, or by the Pixel Data Provider service, DICOM supplement 106. The latest one supposes two-step retrieval of medical image: DICOM request and response from a DICOM server, and then JPIP request and response from a JPEG2000 server. We propose a novel strategy for transmission of scalable JPEG2000 images extracted from a single codestream over DICOM network using the DICOM Private Data Element without sacrificing system interoperability. It employs the request redirection paradigm: DICOM request and response from JPEG2000 server through DICOM server. The paper presents programming solution for implementation of request redirection paradigm in a DICOM transparent manner. PMID- 21705106 TI - TimeLapseAnalyzer: multi-target analysis for live-cell imaging and time-lapse microscopy. AB - The direct observation of cells over time using time-lapse microscopy can provide deep insights into many important biological processes. Reliable analyses of motility, proliferation, invasive potential or mortality of cells are essential to many studies involving live cell imaging and can aid in biomarker discovery and diagnostic decisions. Given the vast amount of image- and time-series data produced by modern microscopes, automated analysis is a key feature to capitalize the potential of time-lapse imaging devices. To provide fast and reproducible analyses of multiple aspects of cell behaviour, we developed TimeLapseAnalyzer. Apart from general purpose image enhancements and segmentation procedures, this extensible, self-contained, modular cross-platform package provides dedicated modalities for fast and reliable analysis of multi-target cell tracking, scratch wound healing analysis, cell counting and tube formation analysis in high throughput screening of live-cell experiments. TimeLapseAnalyzer is freely available (MATLAB, Open Source) at http://www.informatik.uni ulm.de/ni/mitarbeiter/HKestler/tla. PMID- 21705107 TI - Do all lung adenocarcinomas follow a stepwise progression? AB - Similar to the adenoma-carcinoma sequence of colorectal cancer, lung adenocarcinoma is thought to follow a linear multistep progression, in which a precursor lesion progresses to adenocarcinoma in situ, which is followed by invasive adenocarcinoma. However, lung adenocarcinoma can no longer be considered as a single type of tumor but rather a group of distinct subsets of tumors that arise from different molecular pathways. Consistent with this concept, recent findings revealed that this linear progression might not occur in all lung adenocarcinomas. First, according to the molecular classification based on expression profiling, lung cancer can be divided into at least two subsets; precancerous and in situ lesions share characteristics of molecular expression and clinical features with only one of the two subsets, suggesting that the linear progression is only applicable to the subset in the molecular classification. Second, when EGFR and KRAS were examined based on the progression steps, the mutation rate of KRAS was disproportionally distributed; however, according to the progression schema, gene alterations should be evenly accumulated along the entire progression. Third, by means of comparative genomic hybridization analysis, some adenocarcinoma in situ revealed gene alterations discontinuous to invasive adenocarcinoma. Finally, there were some clinical observations that support that some lesions escape from the progression. In this review, we hypothesize a novel scenario for the progression of lung adenocarcinoma, which does not support a linear progression schema. PMID- 21705108 TI - Nitrogen as an indicator of mass transfer during in-situ gas sparging. AB - Aiming at the stimulation of intrinsic microbial activity, pulses of pure oxygen or pressurized air were recurrently injected into groundwater polluted with chlorobenzene. To achieve well-controlled conditions and intensive sampling, a large, vertical underground tank was filled with the local unconfined sandy aquifer material. In the course of two individual gas injections, one using pure oxygen and one using pressurized air, the mass transfer of individual gas species between trapped gas phase and groundwater was studied. Field data on the dissolved gas composition in the groundwater were combined with a kinetic model on gas dissolution and transport in porous media. Phase mass transfer of individual gas components caused a temporary enrichment of nitrogen, and to a lower degree of methane, in trapped gas leading to the formation of excess dissolved nitrogen levels downgradient from the dissolving gas phase. By applying a novel gas sampling method for dissolved gases in groundwater it was shown that dissolved nitrogen can be used as a partitioning tracer to indicate complete gas dissolution in porous media. PMID- 21705110 TI - Bacterial reduction of alcohol-based liquid and gel products on hands soiled with blood. AB - The antibacterial efficacy of three alcohol-based products (liquid and gel) were tested on the hands with blood and contaminated with Serratia marcescens (ATCC 14756), using EN 1500 procedures in 14 healthy volunteers. The alcohol-based products tested, either gel or liquid-based, reached bacterial reduction levels higher than 99.9% in the presence of blood and did not differ significantly (ANOVA test; P = 0.614). PMID- 21705109 TI - How reliable are national surveillance data? Findings from an audit of Canadian methicillin-resistant Staphylococcus aureus surveillance data. AB - BACKGROUND: The Canadian Nosocomial Infection Surveillance Program (CNISP) has conducted surveillance for incident cases of methicillin-resistant Staphylococcus aureus (MRSA) in sentinel hospitals since 1995. In 2007, a reliability audit of the 2005 data was conducted. METHODS: In 2005, 5,652 cases were submitted to the CNISP from 43 hospitals. A proportional sample of submitted forms (up to 25) from each site were randomly selected. Stratified random sampling was used to obtain the comparison data. The original data were compared with the reabstracted data for congruence on 7 preselected variables. RESULTS: Reabstracted data were received from 30 out of 43 hospitals (70%), providing 443 of the 598 case forms requested (74%). Of these, 397 (90%) had matching case identification numbers. Overall, the percentage of discordant responses was 7.0%, ranging from 3.5% for sex and up to 23.7% for less well-defined variables (eg, where MRSA was acquired). CONCLUSION: Our findings suggest that, in general, the 2005 MRSA data are reliable. However to improve reliability a data quality framework with quality assurance practices, including ongoing auditing should be integrated into the CNISP's surveillance programs. Providing training to data collectors and standard definitions with practical examples may help to improve data quality, especially for those variables that require clinical judgment. PMID- 21705111 TI - Detection and spread of carbapenem-resistant Citrobacter freundii in a teaching hospital in China. AB - BACKGROUND: We examined the detection and spread of carbapenem-resistant Citrobacter freundii in Huashan Hospital, Shanghai, China between 2005 and 2008. METHODS: Twenty-three isolates of carbapenem-resistant C freundii collected in our hospital underwent resistant gene amplification by polymerase chain reaction, followed by minimal inhibitory concentration (MIC) analysis. Molecular epidemiologic analyses included pulsed-field gel electrophoresis and case study. RESULTS: Analysis of MICs with amikacin, gentamicin, cefotaxime, ceftazidime, cefepime, imipenem, meropenem, ertapenem, cefoxitin, piperacillin-tazobactam, and ciprofloxacin characterized the isolates as highly resistant to antimicrobials. Colistin, tigecycline, minocycline, and doxycycline to all C freundii isolates had lower MICs than the other antimicrobials tested, with MIC(50)/MIC(90) values of 0.5/1, 1/1, 4/8, and 4/4 mg/L, respectively. Molecular typing using pulsed field gel electrophoresis classified the isolates into 4 groups, of which 15 isolates belonged to a single clone. In total, all of the isolates produced KPC-2 type carbapenemase, of which most were likely to couple with CTX-M-type extended spectrum beta-lactamases and plasmid-mediated CMY-2-type AmpC enzyme. Subsequent clinical investigations involving the general status of patients, the ward, and antimicrobial and therapeutic outcomes showed that a carbapenem-resistant clone had spread critically in the Department of Neurosurgery. Potential risk factors were identified, including invasive procedures, surgical operations, use of indwelling urine catheters, and number of sickbed changes. CONCLUSION: The spread of carbapenem-hydrolyzing C freundii isolates has emerged in regional hospitals in China. Multidrug-resistant mechanisms of strains severely hamper control efforts. Our findings should alert clinicians to issues involved with preventing the spread of carbapenem-resistant C freundii. PMID- 21705112 TI - Microarray analysis of the astrocyte transcriptome in the aging brain: relationship to Alzheimer's pathology and APOE genotype. AB - Astrocytes contribute to a variety of functions in the brain, including homeostasis, synapse formation, plasticity, and metabolism. Astrocyte dysfunction may disrupt their normal role, including neuronal support, thereby contributing to neurodegenerative pathologies, including Alzheimer's disease (AD). To understand the role of astrocytes in the pathogenesis of age-related disorders, we isolated astrocytes by laser capture microdissection, using glial fibrillary acidic protein (GFAP) as a marker, and characterized the astrocyte transcriptome at different Braak neurofibrillary tangle stages in postmortem temporal cortex samples derived from the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) cohort, using microarray analysis. The largest number of significant, differentially expressed genes were identified when the expression profile of astrocytes from isocortical stages of neurofibrillary tangle pathology (Braak stages V-VI) were compared with entorhinal stages (Braak stages I-II). Dysregulation of genes associated with the actin cytoskeleton, proliferation, apoptosis, and ubiquitin-mediated proteolysis occurred at low Braak stages, while altered regulation of intracellular signaling pathways, including insulin, phosphatidylinositol 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) pathways were primarily associated with high levels of Alzheimer-type pathology, and occurred at lower Braak stages in individuals with the APOEepsilon4 allele. Our findings implicate astrocyte dysfunction in the pathogenesis of neurodegenerative pathology in the aging brain, and provide a basis for future candidate studies based on specific pathways. PMID- 21705114 TI - Synthesis and antitumor activity of new sulfonamide derivatives of thiadiazolo[3,2-a]pyrimidines. AB - New series of sulfonamide derivatives of [1,3,4]thiadiazolo[3,2-a]pyrimidine were synthesized and investigated as antitumor agents. Some of the newly prepared compounds were tested for their in vitro and in vivo antitumor activities. Preliminary biological studies revealed that compounds 4c, 4f, and 4j exhibited the highest affinity to DNA, while compounds 4h,i, 6a-c, 8 and 12-14 exhibited moderate activity. Also, compounds 4j, 4f and 4c showed the highest percentage increase in lifespan of mice inoculated with Ehrlich ascites cells over 5 flurouracil (positive control). The detailed synthesis, spectroscopic and biological data are reported. PMID- 21705113 TI - The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimer's disease. AB - Damage to noradrenergic neurons in the locus coeruleus (LC) is a hallmark of Alzheimer's disease (AD) and may contribute to disease progression. In 5xFAD transgenic mice, which accumulate amyloid burden at early ages, the LC undergoes stress as evidenced by increased astrocyte activation, neuronal hypertrophy, reduced levels of LC-enriched messenger RNAs (mRNAs), and increased inflammatory gene expression. Central nervous system (CNS) noradrenaline (NA) levels in 5 month-old male 5xFAD mice were increased using the NA precursor L-threo-3,4 dihydroxyphenylserine (L-DOPS). After 1 month, L-DOPS treatment improved learning in the Morris water maze test compared with vehicle-treated mice. L-DOPS increased CNS NA levels, and average latency times in the water maze test were inversely correlated to NA levels. L-DOPS reduced astrocyte activation and Thioflavin-S staining; increased mRNA levels of neprilysin and insulin degrading enzyme, and of several neurotrophins; and increased brain-derived neurotrophic factor protein levels. These data demonstrate the presence of LC stress in a robust mouse model of AD, and suggest that raising CNS NA levels could provide benefit in AD. PMID- 21705116 TI - ESPEN 2011: the present and the future. PMID- 21705115 TI - Synthesis and in vitro evaluation of new analogues as inhibitors for phosphodiesterase 10A. AB - A series of analogues were synthesized by optimizing the structure of papaverine. The in vitro PDE10A binding affinity (IC(50)) values for these new analogues were measured; for compounds that have IC(50) value less than 60 nM for PDE10A, the binding affinities (IC(50) value) for PDE3A and PDE3B were tested. Of these analogues, compounds 6a, 6b, 6n, 8b, 8c and 11 displayed relatively higher PDE10A potency with IC(50) value in the range of 28-60 nM. The most potent compound 1-(4 (2-(2-fluoroethoxy)ethoxy)-3-methoxybenzyl)-6,7-dimethoxyisoquinoline (8c) has the IC(50) value of 28 +/- 1.2 nM for PDE10A, 2200 +/- 437 nM for PDE3A and 2520 +/- 210 nM for PDE3B. Compared to papaverine, compound 8c displayed similar PDE10A potency but improved selectivity to PDE10A versus PDE3A and PDE3B. To identify high potent PDE10A inhibitor, further optimization of the structures of these analogues is necessary. PMID- 21705117 TI - Seasonal and spatial variability of polychlorinated biphenyls (PCBs) in vegetation and cow milk from a high altitude pasture in the Italian Alps. AB - The seasonal and spatial variability of polychlorinated biphenyls (PCBs) in vegetation and cow milk was studied in a high altitude pasture in the Alps (1900 m a.s.l.). PCB contamination in vegetation shows a concentration peak in June, which is mainly interpreted as the consequence of a temporary PCB enrichment of the air layer above the ground due to net emission fluxes from the soil. A three compartment dynamic model was developed to test this hypothesis. The North/South enrichment factor in the vegetation was 1.5-1.6 for penta- and hexa-substituted congeners and 1.7 for hepta- and octa-PCBs, according to the effect of temperature on compounds having higher K(oa) values. Milk concentrations followed the vegetation seasonal trend. The congener abundance in milk is in agreement with the biotransformation susceptibility, absorption efficiency and residence time of the different congeners in dairy cows. PMID- 21705118 TI - Methylmercury and dissolved organic carbon relationships in a wetland-rich watershed impacted by elevated sulfate from mining. AB - Methylmercury (MeHg), dissolved organic carbon (DOC), and sulfate (SO(4)(=)) relationships were investigated in the mining-influenced St. Louis River watershed in northeast Minnesota. Fewer wetlands and higher SO(4)(=) in the mining region lead to generally lower availability and solubility of DOC in mining streams compared to non-mining streams. MeHg concentrations, however, are similarly low in mining and non-mining streams during low flow periods, implying that the extra DOC found in non-mining streams carries little MeHg with it during these periods. High water levels elevated MeHg concentrations in both stream types owing to release from wetlands of DOC species that contain MeHg and remain relatively soluble in streams with elevated ionic strength. In-river methylation appeared to be a negligible component of the MeHg budget for the St. Louis River during this study as MeHg and DOC concentrations were intermediate to those observed in its mining-influenced and wetland-dominated tributaries. PMID- 21705119 TI - Assessment of modeled mercury dry deposition over the Great Lakes region. AB - Three sets of model predicted values for speciated mercury concentrations and dry deposition fluxes over the Great Lakes region were assessed using field measurements and model intercomparisons. The model predicted values were produced by the Community Multiscale Air Quality Modeling System for the year 2002 (CMAQ2002) and for the year 2005 (CMAQ2005) and by the Global/Regional Atmospheric Heavy Metals Model for the year 2005 (GRAHM2005). Median values of the surface layer ambient concentration of gaseous elemental mercury (GEM) from all three models were generally within 30% of measurements. However, all three models overpredicted surface-layer concentrations of gaseous oxidized mercury (GOM) and particulate bound mercury (PBM) by a factor of 2-10 at the majority of the 15 monitoring locations. For dry deposition of GOM plus PBM, CMAQ2005 showed a clear gradient with the highest deposition in Pennsylvania and its surrounding areas while GRAHM2005 showed no such gradient in this region; however, GRAHM2005 had more hot spots than those of CMAQ2005. Predicted dry deposition of GOM plus PBM from these models should be treated as upper-end estimates over some land surfaces in this region based on the tendencies of all the models to overpredict GOM and PBM concentrations when compared to field measurements. Model predicted GEM dry deposition was found to be as important as GOM plus PBM dry deposition as a contributor to total dry deposition. Predicted total annual mercury dry deposition were mostly lower than 5 MUg m(-2) to the surface of the Great lakes, between 5 and 15 MUg m(-2) to the land surface north of the US/Canada border, and between 5 and 40 MUg m(-2) to the land surface south of the US/Canada border. Predicted dry deposition from different models differed from each other by as much as a factor of 2 at regional scales and by a greater extent at local scales. PMID- 21705120 TI - Volume depletion versus dehydration: how understanding the difference can guide therapy. AB - Although often used interchangeably, dehydration and volume depletion are not synonyms. Dehydration refers to loss of total-body water, producing hypertonicity, which now is the preferred term in lieu of dehydration, whereas volume depletion refers to a deficit in extracellular fluid volume. In particular, hypertonicity implies intracellular volume contraction, whereas volume depletion implies blood volume contraction. Using a case of hyperglycemic hypertonic nonketosis as an example, we examine the changing composition of body fluid spaces to explore the distinction between dehydration and hypertonicity from volume depletion. PMID- 21705122 TI - Reduction of plasma oxalate levels by oral application of Oxalobacter formigenes in 2 patients with infantile oxalosis. AB - The spectrum of primary hyperoxaluria type I is extremely heterogeneous, ranging from singular to recurrent urolithiasis and early end-stage renal disease (ESRD). In infantile oxalosis, the most devastating form, ESRD occurs as early as within the first weeks of life. No kidney replacement therapy sufficiently removes endogenously overproduced oxalate. However, curative combined liver-kidney transplant often is impracticable in small infants. Oxalobacter formigenes (O formigenes), an anaerobic oxalate-degrading bacterium, is a colonizer of the healthy human colon. Oral administration of O formigenes has been shown to significantly decrease urine and plasma oxalate levels in patients with primary hyperoxaluria. We report compassionate use of O formigenes in two 11-month-old girls with infantile oxalosis and ESRD. They received O formigenes twice a day for 4 weeks (or until transplant). Dialysis regimens were unchanged. Plasma oxalate levels decreased from >110 MUmol/L before to 71.53 MUmol/L under treatment in patient 1 and from >90 to 68.56 MUmol/L (first treatment period) and 50.05 MUmol/L (second treatment period) in patient 2. O formigenes was well tolerated. No serious side effects were reported. Extremely increased plasma oxalate levels in patients with infantile oxalosis may enable intestinal elimination of endogenous oxalate in the presence of O formigenes. Therefore, O formigenes therapy may be helpful as a bridging procedure until transplant in such patients. PMID- 21705123 TI - Evaluation of GFR measurement method as an explanation for differences among GFR estimation equations. PMID- 21705124 TI - Proliferative glomerulonephritis with monoclonal IgG deposits recurs or may develop de novo in kidney allografts. AB - Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMIGD) is a recently recognized glomerular disease. Light microscopy usually resembles membranoproliferative glomerulonephritis. Glomerular deposits are mostly IgG3 kappa; however, unlike in the usual forms of monoclonal immunoglobulin deposition disease, extraglomerular deposits are absent. If PGNMIGD is secondary to the glomerular deposition of circulating monoclonal IgG, it is expected to recur in kidney allografts with the same pattern of monoclonal IgG deposition. We reviewed our kidney biopsy files between January 1, 2003, and January 4, 2010, and identified 21 biopsy specimens with PGNMIGD, mostly with glomerular IgG3 kappa deposits. Of the 21 biopsy specimens, 4 were from kidney allografts; 2 were recurrent and the other 2 were de novo diseases. Recurrent PGNMIGD develops rapidly, causing proteinuria. This rapid recurrence of PGNMIGD in kidney allografts provides further proof that PGNMIGD is secondary to the glomerular deposition of circulating monoclonal IgG. PMID- 21705126 TI - IgA nephropathy: progress before and since Berger. AB - Immunoglobulin A nephropathy (IgAN) is linked inextricably to the name Jean Berger, the Parisian pathologist who published the first description of IgAN in 1968. We reflect on the significance of Berger's first report and consider 40 years of progress in our understanding of IgAN since it was published. We also look back to the days before Berger, when IgAN could not have been identified (because there were no techniques for detecting IgA deposits), classification of glomerulonephritis was even more contentious and confusing than it is today, and it is likely that the literature describing focal glomerulonephritis contained many of the cases we would now identify as IgAN. PMID- 21705125 TI - Aldosterone-induced fibrosis in the kidney: questions and controversies. AB - Over the years, aldosterone has been a favorite topic of renal physiologists given its role in the maintenance of body fluids. Investigators only recently are coming to appreciate a second proinflammatory and profibrotic role for this hormone. Mineralocorticoids such as aldosterone trigger a profibrotic process that in many respects mimics the early phase of wound healing. Depending on the type of cell involved, aldosterone may activate the profibrotic process through classic mineralocorticoid receptors, nonclassic membrane-associated mineralocorticoid receptors, and/or glucocorticoid receptors. In the kidney, the actions of aldosterone can be attenuated by 11-dehydro metabolites of endogenous glucocorticoids generated by isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD-1 and 11beta-HSD-2). Thus, the renal 11beta-HSD isoforms may have 2 functions: to block the improper activation of mineralocorticoid receptors by binding endogenous glucocorticoids and to synthesize agents that limit the actions of aldosterone. Although sodium in the diet has been implicated in aggravating aldosterone-induced renal fibrotic processes, preliminary findings are consistent with the view that aldosterone alone can initiate matrix production in renal tissue even in the absence of active sodium transport. Thus, there is a growing body of laboratory and clinical evidence supporting the use of inhibitors of aldosterone action in patients with both glomerular and tubular diseases. PMID- 21705121 TI - CKD in Hispanics: Baseline characteristics from the CRIC (Chronic Renal Insufficiency Cohort) and Hispanic-CRIC Studies. AB - BACKGROUND: Little is known regarding chronic kidney disease (CKD) in Hispanics. We compared baseline characteristics of Hispanic participants in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC (H-CRIC) Studies with non Hispanic CRIC participants. STUDY DESIGN: Cross-sectional analysis. SETTING & PARTICIPANTS: Participants were aged 21-74 years with CKD using age-based estimated glomerular filtration rate (eGFR) at enrollment into the CRIC/H-CRIC Studies. H-CRIC included Hispanics recruited at the University of Illinois in 2005-2008, whereas CRIC included Hispanics and non-Hispanics recruited at 7 clinical centers in 2003-2007. FACTOR: Race/ethnicity. OUTCOMES: Blood pressure, angiotensin-converting enzyme (ACE)-inhibitor/angiotensin receptor blocker (ARB) use, and CKD-associated complications. MEASUREMENTS: Demographic characteristics, laboratory data, blood pressure, and medications were assessed using standard techniques and protocols. RESULTS: Of H-CRIC/CRIC participants, 497 were Hispanic, 1,650 were non-Hispanic black, and 1,638 were non-Hispanic white. Low income and educational attainment were nearly twice as prevalent in Hispanics compared with non-Hispanics (P < 0.01). Hispanics had self-reported diabetes (67%) more frequently than non-Hispanic blacks (51%) and whites (40%; P < 0.01). Blood pressure >130/80 mm Hg was more common in Hispanics (62%) than blacks (57%) and whites (35%; P < 0.05), and abnormalities in hematologic, metabolic, and bone metabolism parameters were more prevalent in Hispanics (P < 0.05), even after stratifying by entry eGFR. Hispanics had the lowest use of ACE inhibitors/ARBs among the high-risk subgroups, including participants with diabetes, proteinuria, and blood pressure >130/80 mm Hg. Mean eGFR was lower in Hispanics (39.6 mL/min/1.73 m(2)) than in blacks (43.7 mL/min/1.73 m(2)) and whites (46.2 mL/min/1.73 m(2)), whereas median proteinuria was higher in Hispanics (protein excretion, 0.72 g/d) than in blacks (0.24 g/d) and whites (0.12 g/d; P < 0.01). LIMITATIONS: Generalizability; observed associations limited by residual bias and confounding. CONCLUSIONS: Hispanics with CKD in the CRIC/H-CRIC Studies are disproportionately burdened with lower socioeconomic status, more frequent diabetes mellitus, less ACE-inhibitor/ARB use, worse blood pressure control, and more severe CKD and associated complications than their non-Hispanic counterparts. PMID- 21705127 TI - IgG4-related tubulointerstitial nephritis with membranous nephropathy. AB - We describe a 67-year-old woman who presented with significant proteinuria and hematuria. Kidney biopsy showed immunoglobulin G4 (IgG4)-related tubulointerstitial nephritis (TIN) with concurrent membranous nephropathy. IgG4 related TIN is a recently described entity that presents with progressive decreased kidney function and is characterized by a plasma cell-rich infiltrate that is positive for IgG4. It is associated with patchy, often well-localized, tubular atrophy and interstitial fibrosis. Workup for circulating anti phospholipase A(2) receptor antibodies was negative, suggesting that the membranous nephropathy was not "primary" and may be linked to the IgG4-related disease. The presence of significant proteinuria and hematuria in the setting of IgG4-related TIN should raise suspicion of a glomerular disease. It is important to correctly diagnose IgG4-related TIN and concurrent membranous nephropathy because the lesion responds well to steroid therapy. PMID- 21705128 TI - From diagnosis to social diagnosis. AB - In the past two decades, research on the sociology of diagnosis has attained considerable influence within medical sociology. Analyzing the process and factors that contribute to making a diagnosis amidst uncertainty and contestation, as well as the diagnostic encounter itself, are topics rich for sociological investigation. This paper provides a reformulation of the sociology of diagnosis by proposing the concept of 'social diagnosis' which helps us recognize the interplay between larger social structures and individual or community illness manifestations. By outlining a conceptual frame, exploring how social scientists, medical professionals and laypeople contribute to social diagnosis, and providing a case study of how the North American Mohawk Akwesasne reservation dealt with rising obesity prevalence to further illustrate the social diagnosis idea, we embark on developing a cohesive and updated framework for a sociology of diagnosis. This approach is useful not just for sociological research, but has direct implications for the fields of medicine and public health. Approaching diagnosis from this integrated perspective potentially provides a broader context for practitioners and researchers to understand extra medical factors, which in turn has consequences for patient care and health outcomes. PMID- 21705129 TI - Making sure. A comparative micro-analysis of diagnostic instruments in medical practice. AB - This article conceptualises diagnosis as ongoing practical judgement in medical care. Based on pragmatist and phenomenological considerations of tools in use, it uses a comparative approach to analyse similarities and differences in the use of diagnostic technologies. In the first part of the paper, a historical perspective on the innovation of the stethoscope is used to highlight the transformations in diagnostic practices occasioned by novel diagnostic instruments. In the second part of the paper, ethnographic accounts of contemporary anaesthesia are presented in order to sketch out the manifold variations of using diagnostic instruments in daily practice. Both cases are analysed on a micro-analytical level, emphasising the interrelations of bodies, tools and knowledge in concrete situations. The analysis shows how diagnostic instruments become embodied in the perceptual habits of physicians and how diagnosing becomes an ongoing activity in the course of managing an illness trajectory. PMID- 21705130 TI - The impact of mediodorsal thalamic lesions on olfactory attention and flavor perception. AB - Olfactory attention may be important in generating odor-induced tastes - an arguably universal form of synesthesia - by ensuring that the taste concurrent is captured by the nose and olfaction, not by the mouth and gustation (oral capture). To examine the role of olfactory attention in generating odor-induced tastes and oral capture we tested a small sample (n=4) of participants with likely impairments in olfactory attention - individuals with mediodorsal thalamic nucleus (MDNT) lesions. These participants were compared to two sets of controls on tests of olfactory attention, oral capture, odor and flavor perception, and control tasks. MDNT participants demonstrated impaired olfactory attention and enhanced oral capture. Greater oral capture was associated with greater olfactory attentional impairment. These findings imply that olfactory attention may be important in attributing odor-induced tastes to the olfactory modality. However, unlike for visual binding and for the neurodevelopmental synesthesias, where attention may be necessary to demonstrate both phenomena, olfactory attention deficits did not impair flavor binding or the experience of odor-induced tastes. PMID- 21705131 TI - Multidetector CT findings of skeletal chest injuries secondary to cardiopulmonary resuscitation. AB - INTRODUCTION: Rib and sternal fractures are frequent complications of cardiopulmonary resuscitation (CPR) in adults. This is the first study to evaluate the MDCT findings of chest injuries secondary to CPR, by comparing with the findings of radiography. METHODS: For 40 patients who underwent MDCT after CPR for a non-traumatic cause of cardiac arrest, we evaluated the MDCT findings of the CPR associated traumatic chest injuries and compared the diagnostic performance of chest radiography and MDCT for the evaluation of chest injuries. RESULTS: MDCT revealed that 26 patients (65%) had rib fractures and 12 patients (30%) had sternal fractures. However, radiography detected only 10 patients who had rib fractures. In 25 of the 26 cases, multiple ribs were fractured (ranging up to 13 rib fractures), and the rib fractures were bilateral in 18 of these cases. The majority of rib fractures were located in the anterior part of the thoracic cage. Six of the patients had fracture-related complications (pneumothorax=1, subclavian vein injury=1, chest wall hematoma=4). The sternal fractures predominantly occurred in the middle and lower third of the sternal body (five each for the middle and lower third of the sternal body). CONCLUSION: Rib and sternal fractures are frequent complications in patients who underwent CPR. MDCT is useful for the evaluation of chest injuries secondary to CPR as compared with that of radiography and also for the evaluation of the fracture related complications. PMID- 21705132 TI - Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms. AB - AIM: Mild therapeutic hypothermia (32-34 degrees C) improves neurological recovery and reduces the risk of death in comatose survivors of cardiac arrest when the initial rhythm is ventricular fibrillation or pulseless ventricular tachycardia. The aim of the presented study was to investigate the effect of mild therapeutic hypothermia (32-34 degrees C for 24h) on neurological outcome and mortality in patients who had been successfully resuscitated from non-ventricular fibrillation cardiac arrest. METHODS: In this retrospective cohort study we included cardiac arrest survivors of 18 years of age or older suffering a witnessed out-of-hospital cardiac arrest with asystole or pulseless electric activity as the first documented rhythm. Data were collected from 1992 to 2009. Main outcome measures were neurological outcome within six month and mortality after six months. RESULTS: Three hundred and seventy-four patients were analysed. Hypothermia was induced in 135 patients. Patients who were treated with mild therapeutic hypothermia were more likely to have good neurological outcomes in comparison to patients who were not treated with hypothermia with an odds ratio of 1.84 (95% confidence interval: 1.08-3.13). In addition, the rate of mortality was significantly lower in the hypothermia group (odds ratio: 0.56; 95% confidence interval: 0.34-0.93). CONCLUSION: Treatment with mild therapeutic hypothermia at a temperature of 32-34 degrees C for 24h is associated with improved neurological outcome and a reduced risk of death following out-of hospital cardiac arrest with non-shockable rhythms. PMID- 21705134 TI - Association of clinical benign prostate hyperplasia with prostate cancer incidence and mortality revisited: a nationwide cohort study of 3,009,258 men. AB - BACKGROUND: Although benign prostate hyperplasia (BPH) and prostate cancer (PCa) share features such as hormone-dependent growth and response to treatment with antiandrogen therapy, BPH is generally not considered a premalignant lesion. OBJECTIVE: To determine whether clinical BPH is associated with an increased risk of PCa incidence and mortality. DESIGN, SETTING, AND PARTICIPANTS: Using designs with individual participant data from five national registries, we studied the entire Danish male population from 1980 through 2006, a total of 3,009,258 Danish men. We collected PCa diagnoses (n=53,315), information on PCa mortality (n=25,459), and ascertained clinical BPH (not histologically proven BPH) through hospitalization (n=187,591) and/or surgery (n=77,698) from 1980 to 2006 and the use of alpha-adrenergic receptor antagonists (n=143,365) and/or the use of 5alpha reductase inhibitors (5-ARIs) (n=47,465) from 1995 to 2006. MEASUREMENTS: PCa incidence and mortality was assessed for each category of clinical BPH using Kaplan-Meier plots of cumulative incidence and Cox proportional hazard ratios (HRs) adjusted for potential confounders. RESULTS AND LIMITATIONS: For the entire cohort studies, multivariate-adjusted HRs for PCa incidence were 2.22 (95% confidence interval, 2.13-2.31) in men hospitalized and 3.26 (3.03-3.50) in men operated on for clinical BPH versus general population controls. Corresponding HRs for PCa mortality were 2.00 (1.91-2.08) for hospitalization and 7.85 (7.40 8.32) for surgery. For age-matched cohort studies, corresponding HRs for PCa incidence were 3.04 (2.96-3.13) for hospitalization, 2.60 (2.47-2.73) for surgery, 4.49 (4.33-4.65) for alpha-adrenergic receptor antagonist use, and 2.54 (2.40-2.68) for 5-ARI use. Each category of clinical BPH has limitations, but limitations differ between the categories and therefore are unlikely to explain the results. CONCLUSIONS: In Danish men followed for up to 27 yr, clinical BPH was associated with a two- to three-fold increased risk of PCa incidence and with a two- to eight-fold increased risk of PCa mortality. These data should not be used to infer causality. PMID- 21705135 TI - RGS19 stimulates cell proliferation by deregulating cell cycle control and enhancing Akt signaling. AB - RGS19 is a regulator of G protein signaling which is upregulated in ovarian cancers and its overexpression promotes cell proliferation in several mammalian cell types. Here we showed that cyclin D1/3 and Cdk6 were upregulated in HEK293 cells overexpressing RGS19, while INK4A and INK4B were reduced. Moreover, RGS19 augmented serum-stimulated PTEN/PDK/Akt and Rb phosphorylations in 293/RGS19 and Caco2/RGS19 cells. These changes were reversed upon the knockdown of RGS19. Consistent with an elevated Akt activity, increased levels of phosphorylated Bad and c-Raf and a diminished expression of TSC2 were detected, thus demonstrating that RGS19 can deregulate cell proliferation via multiple pathways. PMID- 21705136 TI - Utilization of recycled glass derived from cathode ray tube glass as fine aggregate in cement mortar. AB - Rapid advances in the electronic industry led to an excessive amount of early disposal of older electronic devices such as computer monitors and old televisions (TV) before the end of their useful life. The management of cathode ray tubes (CRT), which have been a key component in computer monitors and TV sets, has become a major environmental problem worldwide. Therefore, there is a pressing need to develop sustainable alternative methods to manage hazardous CRT glass waste. This study assesses the feasibility of utilizing CRT glass as a substitute for natural aggregates in cement mortar. The CRT glass investigated was an acid-washed funnel glass of dismantled CRT from computer monitors and old TV sets. The mechanical properties of mortar mixes containing 0%, 25%, 50%, 75% and 100% of CRT glass were investigated. The potential of the alkali-silica reaction (ASR) and leachability of lead were also evaluated. The results confirmed that the properties of the mortar mixes prepared with CRT glass was similar to that of the control mortar using sand as fine aggregate, and displayed innocuous behaviour in the ASR expansion test. Incorporating CRT glass in cement mortar successfully prevented the leaching of lead. We conclude that it is feasible to utilize CRT glass in cement mortar production. PMID- 21705137 TI - Perchlorate removal in Fe0/H2O systems: Impact of oxygen availability and UV radiation. AB - In this study, the removal of perchlorate (0.016mM) using Fe(0)-only (325 mesh, 10g L(-1)) and Fe(0) (10g L(-1)) with UV (254nm) reactions were investigated under oxic and anoxic conditions (nitrogen purging). Under anoxic conditions, only 2% and 5.6% of perchlorate was removed in Fe(0)-only and Fe(0)/UV reactions, respectively, in a 12h period. However, under oxic conditions, perchlorate was removed completely in the Fe(0)-only reaction, and reduced by 40% in the Fe(0)/UV reaction, within 9h. The pseudo-first-order rate constant (k(1)) was 1.63*10( 3)h(-1) in Fe(0)-only and 4.94*10(-3)h(-1) in Fe(0)/UV reaction under anoxic conditions. Under oxic conditions, k(1) was 776.9*10(-3)h(-1) in Fe(0)-only reaction and 35.1*10(-3)h(-1) in the Fe(0)/UV reaction, respectively. The chlorine in perchlorate was recovered as chloride ion in Fe(0)-only and Fe(0)/UV reactions, but lower recovery of chloride under oxic conditions might due to the adsorption/co-precipitation of chloride ion with the iron oxides. The removal of perchlorate in Fe(0)/UV reaction under oxic conditions increased in the presence of methanol (73%, 9h), a radical scavenger, indicating that OH radical can inhibit the removal of perchlorate. The removal of perchlorate by Fe(0)-only reaction under oxic condition was highest at neutral pH. Application of the Langmuir-Hinshelwood model indicated that removal of perchlorate was accelerated by adsorption/co-precipitation reactions onto iron oxides and subsequent removal of perchlorate during further oxidation of Fe(0). The results imply that oxic conditions are essential for more efficient removal of perchlorate in Fe(0)/H(2)O system. PMID- 21705138 TI - Use of pH-sensitive polymer hydrogels in lead removal from aqueous solution. AB - Three gamma crosslinked polymeric hydrogels were synthesized and evaluated as lead ion sorbents. A crosslinked poly(acrylic acid) hydrogel was compared with two 4-vinylpiridine-grafted poly(acrylic acid) hydrogels (26.74 and 48.1% 4 vinylpiridine). The retention properties for Pb(II) from aqueous solutions of these three polymers were investigated by batch equilibrium procedure. The effects of pH, contact time and Pb(II) concentration were evaluated. The optimal pH range for all polymers was 4-6. The lightly grafted polymer (PAAc-g-4VP at 26.74%) exhibited a Pb(II) removal close to 80% at 5h and above 90% at 24h. The maximum Pb(II) removal was 117.9mg g(-1) of polymer and followed the Freundlich adsorption model. XPS characterization indicates that the carboxyl groups are involved in the Pb(II) removal. PMID- 21705139 TI - Efficiency modeling of solidification/stabilization of multi-metal contaminated industrial soil using cement and additives. AB - In a laboratory study, formulations of 15% (w/w) of ordinary Portland cement (OPC), calcium aluminate cement (CAC) and pozzolanic cement (PC) and additives: plasticizers cementol delta ekstra (PCDE) and cementol antikorodin (PCA), polypropylene fibers (PPF), polyoxyethylene-sorbitan monooleate (Tween 80) and aqueous acrylic polymer dispersion (Akrimal) were used for solidification/stabilization (S/S) of soils from an industrial brownfield contaminated with up to 157, 32,175, 44,074, 7614, 253 and 7085mg kg(-1) of Cd, Pb, Zn, Cu, Ni and As, respectively. Soils formed solid monoliths with all cementitious formulations tested, with a maximum mechanical strength of 12N mm( 2) achieved after S/S with CAC+PCA. To assess the S/S efficiency of the used formulations for multi-element contaminated soils, we propose an empirical model in which data on equilibrium leaching of toxic elements into deionized water and TCLP (toxicity characteristic leaching procedure) solution and the mass transfer of elements from soil monoliths were weighed against the relative potential hazard of the particular toxic element. Based on the model calculation, the most efficient S/S formulation was CAC+Akrimal, which reduced soil leachability of Cd, Pb, Zn, Cu, Ni and As into deionized water below the limit of quantification and into TCLP solution by up to 55, 185, 8750, 214, 4.7 and 1.2-times, respectively; and the mass transfer of elements from soil monoliths by up to 740, 746, 104,000, 4.7, 343 and 181-times, respectively. PMID- 21705140 TI - A review of diseases associated with household air pollution due to the use of biomass fuels. AB - Nearly one third of the world's population use biomass fuels such as coal, wood, animal dung, and crop residues as their primary source of domestic energy. Due to their incomplete combustion, a multitude of pollutants associated with high levels of indoor air pollution (IAP) are released which include suspended particulate matter (SPM), carbon monoxide, formaldehyde, nitrogen dioxide, polycyclic aromatic hydrocarbons (PAH), etc. There is a line of evidence that exposure to those pollutants can lead to increased risk of diseases including respiratory infections (e.g., pneumonia, tuberculosis and chronic obstructive pulmonary disease (COPD), lung cancer, and asthma), low birth weight, cataracts, and cardiovascular events. It is one of the major global public health threats that require greater efforts for prevention through research and policy-making. This review summarizes the available information on potential health risks associated with biomass fuel use. PMID- 21705141 TI - Promotional effects of carbon nanotubes on V2O5/TiO2 for NOX removal. AB - A series of V(2)O(5)/TiO(2)-carbon nanotube (CNT) catalysts were synthesized by sol-gel method, and their activities for NO(X) removal were compared. A catalytic promotional effect was observed by adding CNTs to V(2)O(5)/TiO(2). The catalyst V(2)O(5)/TiO(2)-CNTs (10wt.%) showed an NO(X) removal efficiency of 89% at 300 degrees C under a GHSV of 22,500h(-1). Based on X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, NH(3) temperature-programmed desorption, temperature-programmed reduction, Brunauer Emmett-Teller surface area measurements, differential scanning calorimetry, and thermogravimetric analysis, the increased acidity and reducibility, which could promote NH(3) adsorption and oxidation of NO to NO(2), respectively, contributed to this promotion. PMID- 21705142 TI - Application of a generic bow-tie based risk analysis framework on risk management of sea ports and offshore terminals. AB - Ports and offshore terminals are critical infrastructure resources and play key roles in the transportation of goods and people. With more than 80 percent of international trade by volume being carried out by sea, ports and offshore terminals are vital for seaborne trade and international commerce. Furthermore in today's uncertain and complex environment there is a need to analyse the participated risk factors in order to prioritise protective measures in these critically logistics infrastructures. As a result of this study is carried out to support the risk assessment phase of the proposed Risk Management (RM) framework used for the purpose of sea ports and offshore terminals operations and management (PTOM). This has been fulfilled by integration of a generic bow-tie based risk analysis framework into the risk assessment phase as a backbone of the phase. For this reason Fault Tree Analysis (FTA) and Event Tree Analysis (ETA) are used to analyse the risk factors associated within the PTOM. This process will eventually help the port professionals and port risk managers to investigate the identified risk factors more in detail. In order to deal with vagueness of the data Fuzzy Set Theory (FST) and possibility approach are used to overcome the disadvantages of the conventional probability based approaches. PMID- 21705144 TI - Non chemical control of helminths in ruminants: adapting solutions for changing worms in a changing world. AB - Infections with gastrointestinal nematodes (GIN) remain a major threat for ruminant production, health and welfare associated with outdoor breeding. The control of these helminth parasites has relied on the strategic or tactical use of chemical anthelmintic (AH) drugs. However, the expanding development and diffusion of anthelmintic resistance in nematode populations imposes the need to explore and validate novel solutions (or to re-discover old knowledge) for a more sustainable control of GIN. The different solutions refer to three main principles of action. The first one is to limit the contact between the hosts and the infective larvae in the field through grazing management methods. The latter were described since the 1970s and, at present, they benefit from innovations based on computer models. Several biological control agents have also been studied in the last three decades as potential tools to reduce the infective larvae in the field. The second principle aims at improving the host response against GIN infections relying on the genetic selection between or within breeds of sheep or goats, crossbreeding of resistant and susceptible breeds and/or the manipulation of nutrition. These approaches may benefit from a better understanding of the potential underlying mechanisms, in particular in regard of the host immune response against the worms. The third principle is the control of GIN based on non-conventional AH materials (plant or mineral compounds). Worldwide studies show that non conventional AH materials can eliminate worms and/or negatively affect the parasite's biology. The recent developments and pros and cons concerning these various options are discussed. Last, some results are presented which illustrate how the integration of these different solutions can be efficient and applicable in different systems of production and/or epidemiological conditions. The integration of different control tools seems to be a pre-requisite for the sustainable management of GIN infections. This new era of GIN management requires a new paradigm: to achieve enough control to reduce the negative impact of GIN infections enabling an optimum level of production, health and welfare. PMID- 21705143 TI - Activation of spinal extracellular signal-regulated kinases (ERK) 1/2 is associated with the development of visceral hyperalgesia of the bladder. AB - Activation of extracellular signal-regulated kinases (ERK) 1/2 in dorsal horn neurons is important for the development of somatic hypersensitivity and spinal central sensitization after peripheral inflammation. However, data regarding the roles of spinal ERK1/2 in the development of visceral hyperalgesia are sparse. Here we studied the activation of ERK1/2 in the lumbosacral spinal cord after innocuous and noxious distention of the inflamed (cyclophosphamide-treated) and noninflamed urinary bladder in mice. We also correlated the spinal ERK1/2 activation to distention-evoked bladder nociception as quantified by the abdominal visceromotor response (VMR). Cyclophosphamide treatment (bladder inflammation) evoked increased bladder hyperalgesia and allodynia to bladder distention, as evident from an upward and leftward shift of the VMR stimulus response curve compared with that of noninflamed mice. Development of bladder hyperalgesia was associated with robust enhancement of ERK1/2 activation in the dorsal horn and deeper laminae bilaterally in the L6-S1 spinal cord. Functional blockade of spinal ERK1/2 activity via intrathecal administration of the upstream MEK inhibitor U0126 attenuated distention-evoked bladder nociception and caused a significant downward shift of the VMR stimulus-response curve. In summary, we have provided functional and immunohistochemical evidence that activation of lumbosacral spinal ERK1/2 is associated with the development of primary visceral (bladder) hyperalgesia. Our results suggest that aberrant processing of visceral nociceptive information at the level of the lumbosacral spinal cord via activation of ERK1/2 signaling may contribute to chronic bladder pain in the context of inflammation. PMID- 21705145 TI - An intensive search for promising fungal biological control agents of ticks, particularly Rhipicephalus microplus. AB - Entomopathogenic fungi have been investigated worldwide as promising biological control agents of the cattle tick Rhipicephalus microplus. The current study evaluates the virulence of several fungal isolates to R. microplus larva in the laboratory as part of an effort to identify isolates with promise for effective biocontrol of R. microplus in the field. Sixty fungal isolates, encompassing 5 Beauveria spp. and 1 Engyodontium albus (=Beauveria alba), were included in this study. In addition to bioassays, the isolates were characterized morphologically and investigated as to their potential for conidial mass production. These findings were correlated with previous reports on the same fungal isolates of their natural UV-B tolerance (Fernandes et al., 2007), thermotolerance and cold activity (Fernandes et al., 2008), and genotypes (Fernandes et al., 2009). R. microplus larvae obtained from artificially infested calves were less susceptible to Beauveria bassiana infection than ticks acquired from naturally infested cattle from a different location. Isolates CG 464, CG 500 and CG 206 were among the most virulent Beauveria isolates tested in this study. All fungal isolates presented morphological features consistent with their species descriptions. Of the 53 B. bassiana isolates, five (CG 481, CG 484, CG 206, CG 235 and CG 487) had characteristics that qualified them as promising candidates for biological control agents of R. microplus, viz., mean LC(50) between 10(7) and 10(8)conidiaml(-1); produced 5000 conidia or more on 60mm(2) surface area of PDAY medium; and, in comparison to untreated (control) conidia, had the best conidial tolerances to UV-B (7.04 kJ m(-2)) and heat (45 degrees C, 2h) of 50% or higher, and conidial cold (5 degrees C, 15d) activity (mycelial growth) higher than 60%. The current study of 60 Beauveria spp. isolates, therefore, singles out a few (five) with high potential for controlling ticks under field conditions. PMID- 21705146 TI - Morphological and molecular data on the dermal microfilariae of a species of Cercopithifilaria from a dog in Sicily. AB - Dermal microfilariae found in a dog from Sicily, Italy, were characterized morphologically and genetically and differentiated from those of all the other blood microfilariae commonly found in dogs. In particular, the microfilariae were short (mean length of 186.7 MUm), presented a body flattened dorso-ventrally and a rounded head, bearing a tiny cephalic hook. The genetic identity of microfilariae herein studied was also assessed by molecular amplification, sequencing and analyzing of multiple ribosomal ITS-2 and mitochondrial (cox1 and 12S) target genes. Both morphologic and genetic characterization as well as the molecular phylogenetic history inferred using sequences of a barcoding dataset were concordant in supporting the identification of Cercopithifilaria at the genus level. Surprisingly, microfilariae here examined were well distinct from Cercopithifilaria grassii (Noe, 1907), from northern Italy, and resembled those of a species described in Brazil, Cercopithifilaria bainae Almeida & Vicente, 1984. This paper provides evidence for the existence of a Cercopithifilaria species infesting a dog from Sicily and also presents a PCR protocol on skin samples as a tool for further epidemiological studies, which could provide evidence on the aetiology and the natural history of this filarial species. PMID- 21705147 TI - Efficacy of dinotefuran-pyriproxyfen, dinotefuran-pyriproxyfen-permethrin and fipronil-(S)-methoprene topical spot-on formulations to control flea populations in naturally infested pets and private residences in Tampa, FL. AB - Thirteen cats and 7 dogs living in 14 homes were treated topically with either a dinotefuran (22%, w/w)/pyriproxyfen (3.00%, w/w) (DP) or dinotefuran (4.95%, w/w)/pyriproxyfen (0.44%, w/w)/permethrin (36.08%, w/w) (DPP) topical spot-on, respectively. Twenty cats and 7 dogs living in 16 homes were treated topically with either a fipronil (9.8%, w/w)/(S)-methoprene (11.8%, w/w) or fipronil (9.8%, w/w)/(S)-methoprene (8.8%, w/w) topical spot-on (FM), respectively. All products were applied according to label directions by study investigators on day 0 and again between days 28 and 30. Flea populations on pets were assessed using visual area counts and premise flea infestations were assessed using intermittent-light flea traps on days 0, 7, 14, 21, 28-30, 40-45, and 54-60. A single application of the DP-DPP and FM formations reduced flea populations by 87.35% and 88.44%, respectively within 7 days. Following two monthly applications of either the DP DPP or FM formulations, pet flea burdens were reduced by 95.24% and 95.47%, respectively. Flea numbers in the indoor-premises were also markedly reduced by days 54-60, with 98.05% and 96.15% reductions in intermittent-light flea trap counts in the DP-DPP or FM treatment groups, respectively. PMID- 21705148 TI - Cortisol and anxiety response to a relaxing intervention on pregnant women awaiting amniocentesis. AB - BACKGROUND: Stress and anxiety during pregnancy have been associated with premature and low birth weight babies, presumably through fetus over exposion to glucocorticoids. Antenatal stress also seems to have long-term effects upon infant development and adult health. However, medication for stress may carry risks to the expectant mother, therefore the efficacy of non-pharmacological interventions should be investigated. METHODS: Pregnant women (n=154) awaiting amniocentesis, were randomly assigned in the morning and the afternoon to three groups for 30 min: (1) listening to relaxing music, (2) sitting and reading magazines, and (3) sitting in the waiting-room. Before and after that period, they completed the Spielberger's State and Trait anxiety inventory and provided blood samples for cortisol. The groups were then compared regarding change in cortisol levels and anxiety. RESULTS: Maternal cortisol and state anxiety were correlated (r=0.25, p=0.04) in the afternoon, but not in the morning. The larger decreases in cortisol occurred in the music group (-61.8 nmol/L, ANOVA: p=0.01), followed by magazine, being differences among groups more pronounced in the morning. Women in the music group also exhibited the greater decreases in state anxiety (p<0.001). Younger mothers with less gestational age were on average the most anxious, and also the ones with greater decreases in cortisol and anxiety levels after relaxation. CONCLUSION: A relaxing intervention as short as 30 min, especially listening to music, decreases plasma cortisol and self-reported state anxiety score. Pregnant women might benefit from the routine practice of relaxation in the imminence of clinical stressful events. PMID- 21705149 TI - Is fatigue related to suppression of hypothalamic-pituitary-adrenal axis activity by bile acids in chronic liver disease? PMID- 21705150 TI - Linear correlation between patient survival and decreased percentage of tumor [(18)F]fluorodeoxyglucose uptake for late-course accelerated hyperfractionated radiotherapy for esophageal cancer. AB - PURPOSE: The aims of this trial were to study whether a decreased percentage of tumor fluorodeoxyglucose (FDG) uptake (%DeltaSUVmax) correlated with overall survival and local control times for patients with esophageal cancer and which patients would benefit from a late-course accelerated hyperfractionated (LCHF) radiation scheme. METHODS AND MATERIALS: A total of 50 eligible patients with squamous esophageal cancer received positron-emission tomography examinations three times and were treated with the LCHF radiation scheme, with a dose of 68.4 Gy/41 fractions in 6.5 weeks. A %DeltaSUVmax value was calculated, and patients were stratified as highly radiosensitive (HR), moderately radiosensitive (MR), and low radiosensitivity (LR) according to %DeltaSUVmax values in the conventional fraction (CF) scheme. Then, a linear correlation was calculated between patients' survival time and %DeltaSUVmax. Local control and overall survival rates were compared after stratification. RESULTS: In the MR subgroup, there was no linear correlation between %DeltaSUVmax and the CF and LCHF schemes (correlation coefficient, R < 0.4; p > 0.05). In the other subgroups (HR and LR), %DeltaSUVmax values between the CF and LCHF schemes were correlated. Also, in the HR and LR subgroups, %DeltaSUVmax after radiation correlated with overall survival or local control rates (correlation coefficient, R >0.5, and p < 0.05). Three-year local control rates in the HR, MR, and LR subgroups were 100%, 81.5%, and 0%, respectively (p < 0.001). Also, 3-year overall survival rates were 92.4%, 58.8%, and 0% for HR, MR, and LR subgroups, respectively (p < 0.001). CONCLUSIONS: Postradiation %DeltaSUVmax was positively correlated with survival time for patients' with esophageal cancer. Patients who benefited from LCHF schedules were those with a decrease of 30% to 60% in tumor FDG uptake after the completion of CF radiation. PMID- 21705151 TI - Dosimetric benefits of intensity-modulated radiotherapy combined with the deep inspiration breath-hold technique in patients with mediastinal Hodgkin's lymphoma. AB - PURPOSE: To assess the additional benefits of using the deep-inspiration breath hold (DIBH) technique with intensity-modulated radiotherapy (IMRT) in terms of the protection of organs at risk for patients with mediastinal Hodgkin's disease. METHODS AND MATERIALS: Patients with early-stage Hodgkin's lymphoma with mediastinal involvement were entered into the study. Two simulation computed tomography scans were performed for each patient: one using the free-breathing (FB) technique and the other using the DIBH technique with a dedicated spirometer. The clinical target volume, planning target volume (PTV), and organs at risk were determined on both computed tomography scans according to the guidelines of the European Organization for Research and Treatment of Cancer. In both cases, 30 Gy in 15 fractions was prescribed. The dosimetric parameters retrieved for the statistical analysis were PTV coverage, mean heart dose, mean coronary artery dose, mean lung dose, and lung V20. RESULTS: There were no significant differences in PTV coverage between the two techniques (FB vs. DIBH). The mean doses delivered to the coronary arteries, heart, and lungs were significantly reduced by 15% to 20% using DIBH compared with FB, and the lung V20 was reduced by almost one third. The dose reduction to organs at risk was greater for masses in the upper part of the mediastinum. IMRT with DIBH was partially implemented in 1 patient. This combination will be extended to other patients in the near future. CONCLUSIONS: Radiation exposure of the coronary arteries, heart, and lungs in patients with mediastinal Hodgkin's lymphoma was greatly reduced using DIBH with IMRT. The greatest benefit was obtained for tumors in the upper part of the mediastinum. The possibility of a wider use in clinical practice is currently under investigation in our department. PMID- 21705152 TI - Artery-vein-artery venous flap for simultaneous soft-tissue repair and radial artery reconstruction: case report. AB - We present a case of partial amputation of the forearm resulting in soft-tissue and radial artery defects that were simultaneously repaired using a large artery vein-artery venous flap. The flap measured 4 * 11 cm, and we attribute its complete survival and long-term durability to the artery-vein-artery configuration. PMID- 21705153 TI - Pyarthrosis of the small joints of the hand resulting in arthrodesis or amputation. AB - PURPOSE: A septic joint is a cartilage-threatening emergency requiring prompt treatment. The purpose of this study was to examine outcomes of septic arthritis of the metacarpophalangeal and interphalangeal joints. METHODS: We performed a retrospective review of patients diagnosed with joint infection between 1976 and 2008. The end point included the number of arthrodeses and amputations performed. RESULTS: Septic joints were identified in 110 patients. All patients had incision and irrigation and debridement (I and D) of the joint. The infection was successfully treated in 83 of 110 patients. The majority of septic joints (73 of 83 patients) treated successfully with I and D had only a penetrating joint injury. Forty-eight of these patients required more than one I and D to eradicate the infection. The remaining 27 of 110 patients required either arthrodesis (13 patients) or amputation (14 patients) despite I and D. Among the 13 patients requiring arthrodesis, postoperative infection (7 patients) accounted for the majority of septic joints. Of the 14 patients requiring amputation, penetrating joint injury accounted for the majority of septic joints. Overall, those patients requiring more than 3 I and D procedures were at higher risk of arthrodesis or amputation. Increasing comorbidities correlated with worsening outcomes. CONCLUSIONS: Pyarthrosis can often be treated successfully with 1 or more I and D procedures. Despite multiple I and D procedures, 27 patients required either arthrodesis or amputation. The time to diagnosis and treatment, the number of I and D procedures, patient comorbidities, and postoperative infection following non-joint surgery are major factors influencing outcome. PMID- 21705154 TI - Current and future national costs to medicare for the treatment of distal radius fracture in the elderly. AB - PURPOSE: Distal radius fractures (DRFs) are the second most common fracture experienced by elderly individuals. In 2005, 16% of DRFs in the Medicare population were being treated with internal fixation, up from 3% in 1997. This shift in treatment strategy can have substantial financial impact on Medicare and the health care system in general. The specific aims of this project were to quantify the current and future Medicare expenditures attributable to DRF and to compare Medicare payments for the 4 treatment options for elderly DRF. METHODS: We analyzed the 100% 2007 Medicare dataset for annual DRF-attributable spending. Payments were obtained for claims that were identified as attributable to DRF by International Classification of Diseases, 9th Revision, Clinical Modification codes for DRF in conjunction with a Current Procedural Technology code for relevant treatment or service. We projected annual payments based on increasing internal fixation treatment. All payments are reported in 2007 U.S. dollars. RESULTS: In 2007, Medicare made $170 million in DRF-attributable payments. If the usage of internal fixation were to reach 50%, DRF-attributable payments could be nearly $240 million. The mean attributable payment made for each patient in 2007 was $1,983. Most of this is due to facility and staffing cost for the treatment procedure. CONCLUSIONS: This analysis provides an accurate quantification of Medicare DRF-attributable expenditure. Use of 100% Medicare data allows for the summation of actual patient experience rather than modeling or estimation. The burden of DRF is going to grow as the U.S. population ages and as internal fixation becomes more widely used. The Medicare payment data can help in allocating resources nationally to address the increasing disease burden of DRF. PMID- 21705155 TI - Arthroscopic debridement of the humeral capitellum for osteochondritis dissecans: radiographic and clinical outcomes. AB - PURPOSE: Although arthroscopic debridement of the humeral capitellum is an accepted procedure for osteochondritis dissecans, some patients develop radial head enlargement or osteoarthritic lesions after the procedure. The aim of this study was to investigate the radiographic and clinical outcomes of arthroscopic debridement and consider its indications. METHODS: We retrospectively evaluated 106 patients who had arthroscopic debridement between 1997 and 2007. Surgery was performed after closure of the capitellar physis. We categorized the patients into 4 groups by lesion size and by whether the proximal radial physis was open or closed. The average patient age at surgery was 15 years (range, 12-18 y), and the average follow-up period was 13 months (range, 8-46 mo). RESULTS: In patients with large lesions and open proximal radial physes, radiographic and clinical outcomes were poor. Three of 4 patients developed early osteoarthritic lesions of the radiohumeral joint, secondary to radial head enlargement. Radial head resection was required in 2 of 3 patients. Conversely, osteoarthritic lesions did not occur, and we observed noteworthy improvement in elbow pain routinely after the procedure in the other 3 groups. For range of motion, clinically important changes were not observed. Overall, postoperative elbow pain was absent in 89 patients. Mild pain was present in 15 patients and moderate or severe pain in 2 patients. A total of 90 patients returned to sports at pre-injury levels. Time of return to sports varied from 1 month to 5 months (mean, 2.4 mo). CONCLUSIONS: Arthroscopic debridement of the capitellum can provide excellent short-term results for the treatment of osteochondritis dissecans. However, it is contraindicated in cases with large lesions when the proximal radial physis remains open. PMID- 21705156 TI - Volar retinacular ganglions. PMID- 21705157 TI - Comparison of autologous blood, corticosteroid, and saline injection in the treatment of lateral epicondylitis: a prospective, randomized, controlled multicenter study. AB - PURPOSE: We compared saline, corticosteroid, and autologous blood injections for lateral epicondylitis in a prospective, blinded, randomized, controlled trial. The null hypothesis was that patient-rated outcomes after autologous blood injection would not be superior to corticosteroid and saline injections. METHODS: Patients with clinically diagnosed lateral epicondylitis of less than 6 months' duration were randomized into 1 of 3 groups to receive a 3-mL injection of saline and lidocaine, corticosteroid and lidocaine, or autologous blood and lidocaine. Of 34 subjects who enrolled, 28 completed follow-up. A total of 10 were randomized to the saline group, 9 to the autologous blood group, and 9 to the steroid group. Every participant had 3 mL blood drawn, and the injection syringe was foil-covered to prevent the subject from knowing the contents. The primary outcome measure was the Disabilities of the Arm, Shoulder, and Hand (DASH) score. Patients completed a pain visual analog scale, DASH, and the Patient-Rated Forearm Evaluation before injection and at 2 weeks, 2 months, and 6 months after injection. We performed statistical analysis using repeated measures of analyses of variance. RESULTS: There were no significant differences in DASH scores among the 3 groups at 2- and 6-month follow-up points, with the mean scores for saline at 20 and 10, respectively, compared with 28 and 20 for autologous blood and 28 and 13 for steroid injections. Secondary measures showed similar findings, with outcomes scores showing improvement in all 3 groups. CONCLUSIONS: In this prospective, randomized, controlled trial, autologous blood, corticosteroid, and saline injection provide no advantage over placebo saline injections in the treatment of lateral epicondylitis. Patients within each injection group demonstrated improved outcome scores over a 6-month period. PMID- 21705158 TI - Flexor tendon rupture after collagenase injection for Dupuytren contracture: case report. AB - Rupture of both flexor tendons after collagenase injection for Dupuytren contracture is a rare and problematic complication. We performed a 2-stage tendon reconstruction to treat this problem, with an acceptable result. PMID- 21705159 TI - Prevalence, characteristics, and predictors of police training initiatives by US SEPs: building an evidence base for structural interventions. AB - BACKGROUND: Community-based prevention initiatives such as syringe exchange programs (SEPs) are proven to curb injection-related HIV transmission. Policing targeting injection drug users (IDUs) can interfere with SEP functioning. Efforts to maximize the public health benefit of SEPs have included police trainings designed to reduce such interference. METHODS: We surveyed US SEP managers to assess prevalence, content, and correlates of SEP police trainings. Multivariate analyses were utilized to identify predictors of training participation. RESULTS: Of 107 SEPs (57% of all US programs), 20% reported participating in trainings during the previous year. Covered topics included the public health rationale behind SEPs (71%), police occupational health (67%), needle stick injury (62%), SEPs' legal status (57%), and harm reduction philosophy (67%). On average, trainings were seen as moderately effective, but only four programs reported conducting any formal evaluation. In multivariate modeling, training participation was independently associated with state law authorizing syringe possession by clients (aOR=3.71, 95%CI=1.04-13.23), higher frequency of client arrest (aOR=2.07, 95%CI=1.0-4.7), and systematic monitoring of adverse client police encounters (aOR=4.02, 95%CI=1.14-14.17). Assistance with police trainings was identified by 72% of respondents as the key to improving police relations. CONCLUSION: At a time when collaboration with police may become requisite for SEPs to receive federal funding, most program managers in the US perceive police trainings as a key to improved SEP-police relations. Robust evaluation is needed to better understand the impact of these trainings on law enforcement practices, SEP operations, and community health. Such research will inform technical assistance, policy design, and resource allocation. PMID- 21705160 TI - Fecal microbiota of calves in the clinical setting: effect of penicillin treatment. AB - The effect of parenteral penicillin treatment on the intestinal microbiota was determined by monitoring the phenotypic antimicrobial resistance among Escherichia coli in 19 calves (15 calves received treatment and four calves were healthy controls) and by examining changes in the fecal microbial community structure using molecular fingerprinting techniques in a subset of eight calves (five treated calves and three control calves). After five days of penicillin treatment an increased resistance to multiple unrelated antimicrobial agents, including non-beta-lactams, was seen in E. coli from treated calves, and this was not seen in the controls. Automated ribosomal intergenic spacer analysis (ARISA) and terminal restriction fragment length polymorphism (TRFLP) revealed that penicillin treatment causes a significant variation in the microbial structure within an individual calf. The study shows that parenteral administration of penicillin has an impact on the composition of the fecal microbiota in calves, and on the antimicrobial resistance pattern of their fecal E. coli. PMID- 21705161 TI - Preconception risk factors and SGA babies: Papilloma virus, omega 3 and fat soluble vitamin deficiencies. AB - BACKGROUND: Small for gestational date (SGA) babies have a poor 'whole of life' prognosis and major factors affecting SGA may be present prior to conception. AIMS: To discover whether lifestyle risk factors can be identified in women planning a pregnancy. STUDY DESIGN: Prospective study of women who were planning a pregnancy, who agreed to answer a detailed 250 question questionnaire prior to commencing to try to conceive, to being monitored, and within 7days of a positive pregnancy test having a vaginal ultrasound scan and answering further questions about the events since the last menstrual period. Details of all outcomes were recorded. SUBJECTS: 585 couples completed the study. OUTCOME MEASURES: The relationships between birth weights and questionnaire data was analysed using SPSS and parametric statistical analysis. RESULTS AND CONCLUSIONS: 401 women (67.9% of all participants) had live births. Eleven babies (2.7%) were less than the 3rd percentile in weight and a further 22 babies (5.4%) were between the 3rd and 10th weight percentiles. Mothers of SGA babies had a lower than average education, diets that were low in meat, fish, dairy foods and nuts or seeds and were more likely to conceive in the winter. Mothers of SGA babies were significantly more likely to have had a recent abnormal Pap smear test. Air travel in the month of conception was a risk factor in having a baby less than 10th percentile. CONCLUSION: The quality of lifestyle prior to conception is critical: prenatal counselling needs to be undertaken prior to conception. PMID- 21705162 TI - Factors related to functional independence in females with Parkinson's disease: a systematic review. AB - Males and females may exhibit diverse expressions of Parkinson's disease (PD) as a result of biological and social differences. In general, a higher incidence of PD is found among males (RR=1.5) compared to females. However, rigidity, postural instability and levodopa-induced dyskinesia are more prevalent in females with PD. These fluctuations affect motor performance and impact functional ability. This systematic review suggests that there is minimal research literature with respect to females living with PD. Specifically, the influence of physical ability in females with PD is underemphasized, considering its contribution to functional daily living and quality of life. Three intervention and nine functional assessment studies met inclusion criteria (n=302; mean age=65.5+/-8.3 years, 44% female). Reports suggest that females with PD have different gait patterns compared to 'healthy' age-matched females and males with PD. Females with PD experience increased freezing of gait as compared to males with PD. Dynamic balance was reduced in females compared to males with PD. Differences in cardiorespiratory fitness compared to healthy age-matched females was inconclusive. Studies were rated to be of moderate quality (20+/-5.4/32) and future studies should focus on improving sex-matched recruitment, randomized group allocation, and blinding of evaluators to ensure unbiased results. Regardless, the specific impact of PD on females warrants further investigation. PMID- 21705163 TI - Regularization of bending and crossing white matter fibers in MRI Q-ball fields. AB - In diffusion magnetic resonance imaging with high-angular-resolution diffusion imaging, a set of techniques has become available that allows better acquisition and representation of multidirectional diffusion profiles, e.g., in voxels with crossing, branching and kissing fibers. The poor spatial resolution and low signal-to-noise ratio of the data, particularly when acquired under clinical conditions, prevent tractography algorithms from reliably reconstructing complex white matter structures. With cone-beam regularization, an intervoxel smoothing approach has been described, which, in this article, is refined and adapted to fibers with subvoxel bending. By introducing the concept of asymmetric orientation distribution functions (aODFs), we are able to sharpen diffusion profiles of bending fibers and estimate subvoxel curvature. We also propose a deterministic fiber-tracking algorithm that exploits the enhanced resolution of aODFs. The approach is evaluated quantitatively and compared with state-of-the art noise-suppression techniques in a study with a biological diffusion phantom. Moreover, we present results from an in vivo study in which we demonstrate the method's ability to optimize tractography of bending fiber pathways of optic radiation. PMID- 21705164 TI - Magnetic resonance imaging on CO(2) miscible and immiscible displacement in oil saturated glass beads pack. AB - In this study, the displacement processes were observed as gaseous or supercritical CO(2) was injected into n-decane-saturated glass beads packs using a 400-MHz magnetic resonance imaging (MRI) system. Two-dimensional images of oil distribution in the vertical median section were obtained using a spin-echo pulse sequence. Gas channeling and viscous fingering appeared obviously in immiscible gaseous CO(2) displacement. A piston-like displacement front was detected in miscible supercritical CO(2) displacement that provided high sweep efficiency. MRI images were processed with image intensity analysis methods to obtain the saturation profiles. Final oil residual saturations and displacement coefficients were also estimated using this imaging intensity analysis. It was proved that miscible displacement can enhance the efficiency of CO(2) displacement notably. Finally, a special coreflood analysis method was applied to estimate the effects of capillary, viscosity and buoyancy based on the obtained saturation data. PMID- 21705165 TI - Modified INOvent for delivery of inhaled nitric oxide during cardiac MRI. AB - BACKGROUND: The aim of this study was to assess the feasibility of delivering NO through a modified system to allow clearance of the magnetic field and thus compatibility with cardiac magnetic resonance (CMR). Nitric oxide (NO) is an inhalational, selective pulmonary vasodilator with a wide range of applications in a variety of disease states, including diseases that affect the right ventricle. Accurate assessment of dynamic changes in right ventricular function necessitates CMR; however, delivery of NO is only possible using equipment that is not magnetic resonance imaging (MRI) compatible (INOvent delivery system, Ohmeda, Inc., Madison, WI, USA). METHODS: The INOvent delivery system was modified by using 35 ft. of standard oxygen tubing to allow NO delivery through an electrical conduit and into the MRI suite. The concentrations of oxygen (O(2)), nitrogen dioxide (a harmful byproduct, NO(2)) and NO were measured in triplicate using the built-in electrochemical analyzer on the INOvent. After confirmation of safety, the system was used to administer drug to a patient x, and dynamic MRI measurements were performed. RESULTS: When the standard INOvent was set to administer 40 ppm of NO, the mean/standard deviation of gas delivered was as follows: NO: 42/0 ppm; NO(2): 0.3/0.1 ppm; and O(2): 93/0 ppm. In comparison, the gas delivery of the modified INOvent was follows: NO: 41/0 ppm; NO(2): 0.5/0 ppm; and O(2): 93.7/0.6 ppm. During administration to an index patient with severe pulmonic insufficiency (PI), a measurable reduction in PI was observed by CMR. CONCLUSIONS: Nitric oxide can be administered through 35 ft. of standard oxygen tubing without significantly affecting dose delivery. This technique has potential application in patients with right-sided structural heart disease for determination of dynamic physiological changes. PMID- 21705166 TI - Three-dimensional fluid-suppressed T2-prep flow-independent peripheral angiography using balanced SSFP. AB - Accurate depiction of the vessels of the lower leg, foot or hand benefits from suppression of bright MR signal from lipid (such as bone marrow) and long-T1 fluid (such as synovial fluid and edema). Signal independence of blood flow velocities, good arterial/muscle contrast and arterial/venous separation are also desirable. The high SNR, short scan times and flow properties of balanced steady state free precession (SSFP) make it an excellent candidate for flow-independent angiography. In this work, a new magnetization-prepared 3D SSFP sequence for flow independent peripheral angiography is presented. The technique combines a number of component techniques (phase-sensitive fat detection, inversion recovery, T2 preparation and square-spiral phase-encode ordering) to achieve high-contrast peripheral angiograms at only a modest scan time penalty over simple 3D SSFP. The technique is described in detail, a parameter optimization performed and preliminary results presented achieving high contrast and 1-mm isotropic resolution in a normal foot. PMID- 21705169 TI - Identification, synthesis and quantification of process-related impurities in auraptene. AB - Impurities in chemically synthesized auraptene, an active pharmaceutical ingredient (API), were detected by a gradient reverse-phase high-performance liquid chromatography (RP-HPLC) method. Molecular weights and major product ions of these chemical compounds were determined by liquid chromatography/Triple Quadrupole (LC-MS/MS) analysis. Structural assignments were presumed as umbelliferone (Imp-I), (E)-6,7-dihydroxy-3,7-dimethyl-2-octene-umbelliferone (Imp II), (E)-6,7-epoxy-3,7-dimethyl-2-octene-umbelliferone (Imp-III) and 4 methylauraptene (Imp-IV). The impurities were authentically synthesized, confirmed by nuclear magnetic resonance spectroscopy (NMR) and infrared spectroscopy (IR), and subsequently used as reference samples in routing HPLC system suitability testing for method specificity and detectability. Method specificity was further verified by forced degradation studies. The developed method was validated for characterization of impurities in synthesized auraptene according to the guidelines of the International Conference on Harmonization (ICH) in our laboratory. PMID- 21705168 TI - Development of a 0.014-in., anti-solenoid loop MR imaging guidewire for intravascular 3.0-T MR imaging. AB - PURPOSE: This study aimed to develop a 0.014-in., anti-solenoid loop (ASL) magnetic resonance imaging guidewire (MRIG) for intravascular 3.0-T MR imaging. MATERIALS AND METHODS: We first designed the ASL MRIG, which was made of a coaxial cable with its extended inner conductor and outer conductor connected to two micro-anti-solenoids. We then evaluated in vitro the functionality of the ASL MRIG by imaging a "vessel" in a phantom and achieving signal-to-noise ratio (SNR) and SNR contour map of the new 0.014-in. ASL MRIG. Subsequently, we validated in vivo the feasibility of using the ASL MRIG to generate intravenous 3.0-T MR images of parallel iliofemoral arteries of near-human-sized living pigs. RESULTS: In vitro evaluation showed that the 0.014-in. ASL MRIG functioned well as a receiver coil with the 3.0-T MR scanner, clearly displaying the vessel wall with even distribution of MR signals and SNR contours from the ASL MRIG. Of the in vivo studies, the new ASL MRIG enabled us to successfully generate intravenous 3.0-T MR imaging of the iliofemoral arteries. CONCLUSION: This study confirms that it is possible to build such small-looped MRIG at 0.014 in. for intravascular 3.0-T MR imaging. PMID- 21705167 TI - Targeted radiofrequency field mapping using 3D reduced field-of-view-catalyzed double-angle method. AB - PURPOSE: The aim of this study was to develop a targeted volumetric radiofrequency field (B(1)(+)) mapping technique to provide region-of-interest B(1)(+) information. MATERIALS AND METHODS: Targeted B(1)(+) maps were acquired using three-dimensional (3D) reduced field-of-view (FOV) inner-volume turbo spin echo-catalyzed double-angle method (DAM). Targeted B(1)(+) maps were compared with full-FOV B(1)(+) maps acquired using 3D catalyzed DAM in a phantom and in the brain of a healthy volunteer. In addition, targeted volumetric abdomeninal B(1)(+) mapping was demonstrated in the abdomen of another healthy volunteer. RESULTS: The targeted reduced-FOV images demonstrated no aliasing artifacts in all experiments. Close match between targeted B(1)(+) map and reference full-FOV B(1)(+) map in the same region was observed, with percentage root-mean-squared error <0.4% in the phantom and <0.8% in the healthy volunteer brain. The abdominal B(1)(+) maps showed small B(1)(+) variation in the kidneys and liver from the healthy volunteer. CONCLUSION: The proposed 3D reduced-FOV catalyzed DAM provides a rapid, simple and accurate method for targeted volumetric B(1)(+) mapping and can be easily implemented for applications related to radiofrequency field mapping in small targeted regions. PMID- 21705170 TI - Relationship between improvements in heart failure patient disease specific knowledge and clinical events as part of a randomized controlled trial. AB - OBJECTIVE: To examine the changes in performance on heart failure knowledge assessments administered before and after discharge education. METHODS: We conducted a randomized controlled trial comparing the effects of a 1-h, one-on one teaching session with a nurse educator to the standard discharge process in patients with systolic heart failure. Patients completed a 30 point heart failure knowledge questionnaire (HFKQ) prior to and 3 months after the education intervention. RESULTS: Patients randomized to the nurse education intervention (n=113) demonstrated significantly higher total HFKQ score increases compared to patients receiving the standard discharge process (n=114) (median, IQR 1, 0 to 4 vs 0, -2 to 2, p=0.007). Patients experiencing death or rehospitalization in the subsequent 6 months were found to have significantly lower HFKQ scores (10, 7 to 12 vs 11, 8 to 13, p=0.002) compared to patients without a clinical event. CONCLUSION: Heart failure nurse education at the time of hospital discharge results in improved patient knowledge and reduced risk of readmission. PRACTICE IMPLICATIONS: Health care personnel should encourage education sessions for heart failure patients. Resources possibly need to be allocated for nurse led education sessions in heart failure patients as it improves outcomes and knowledge. PMID- 21705171 TI - The effect of drill trajectory on proximity to the posterior interosseous nerve during cortical button distal biceps repair. AB - PURPOSE: The aim of this study was to evaluate the effect that different drill trajectories across the radius have on the proximity of the drill tip to the posterior interosseous nerve (PIN). METHODS: In 10 cadaveric specimens, we drilled from the bicipital tuberosity across the radius using 4 different trajectories: (1) aiming across the radius at 90 degrees to the longitudinal axis of the radius, (2) distally at 45 degrees , (3) ulnarly, and (4) radially. We measured the distance between the tip of the drill as it exited the dorsal cortex of the radius and the PIN. RESULTS: Aiming 90 degrees across the radius and aiming ulnarly across the radius resulted in a distance of 11.2 +/- 3.2 mm (95% confidence interval [CI], 8.9 to 13.5 mm) and 16.0 +/- 3.8 mm (95% CI, 13.3 to 18.7 mm), respectively, between the drill tip and the PIN. Aiming the drill 45 degrees distally and aiming radially resulted in a distance of only 2.0 +/- 2.2 mm (95% CI, 0.5 to 3.6 mm) and 4.2 +/- 2.2 mm (95% CI, 2.6 to 5.8 mm), respectively. The differences were found to be statistically significant. CONCLUSIONS: On the basis of the results of this anatomic study, when using the cortical button distal biceps repair technique, we recommend drilling across the radius at 90 degrees to its longitudinal axis and aiming from 0 degrees to 30 degrees ulnarly, with the patient's forearm in full supination. This provides an increased margin of safety to prevent injury to the PIN compared with drilling radially or distally. CLINICAL RELEVANCE: By avoiding distal and radial drilling, the risks of PIN injury should be minimized during distal biceps tendon repair. PMID- 21705172 TI - Evaluation of tumor necrosis factor alpha blockade on early tendon-to-bone healing in a rat rotator cuff repair model. AB - PURPOSE: The purpose was to determine whether systemic tumor necrosis factor alpha (TNF-alpha) blockade can improve rotator cuff healing in a rat model. METHODS: One hundred twenty Lewis rats underwent unilateral detachment and repair of the supraspinatus. Rats were randomized into 2 groups. The experimental group received injections of pegylated soluble tumor necrosis factor receptor type I (3.0 mg/kg every other day for 3 doses). The control group received saline solution on the same dosing schedule. At 2, 4, and 8 weeks, 20 animals in each group were killed (4 for histologic assessment and 16 for biomechanical testing). Outcomes included qualitative histologic assessment to determine new fibrocartilage formation and collagen fiber organization. Immunohistochemical staining was performed to localize TNF-alpha, ED1 and ED2 macrophages, and tartrate-resistant acidic phosphatase. Biomechanical testing was performed to determine the ultimate load to failure, stiffness, cross-sectional area, and ultimate stress to failure. RESULTS: Qualitative assessments of histology showed that the experimental group had more cartilage formation at 4 weeks but not at 2 or 8 weeks. There was less TNF-alpha staining in the experimental group at 4 and 8 weeks, and there were fewer ED1 macrophages at 4 weeks compared with controls. The ultimate load to failure was greater in the experimental group compared with controls at 2 weeks (13.3 +/- 2.6 N v 11.2 +/- 2.7 N, P = .05) and at 4 weeks (21.7 +/- 4.6 N v 18.5 +/- 2.1 N, P = .04). The experimental group also had a higher stiffness at 2 weeks (7.2 +/- 2.3 N/mm v 5.8 +/- 1.4 N/mm, P = .04) and at 4 weeks (10.5 +/- 2.7 N/mm v 8.4 +/- 1.7 N/mm, P = .01). There were no differences in any biomechanical variable at 8 weeks. CONCLUSIONS: TNF-alpha blockade can improve the biomechanical strength of tendon-bone healing in a rat rotator cuff model at early time points, which corresponded with modest qualitative improvements in histology. However, these differences were not maintained at 8 weeks. CLINICAL RELEVANCE: TNF-alpha blockade may influence rotator cuff tendon healing. PMID- 21705174 TI - Effect of tunnel position and graft size in single-bundle anterior cruciate ligament reconstruction: an evaluation of time-zero knee stability. AB - PURPOSE: To determine whether (1) increased graft size with anatomic anterior cruciate ligament reconstruction (ACLR) would confer proportionally increased time-zero biomechanical stability and (2) larger grafts would compensate for the inferior time-zero biomechanical kinematics of nonanatomic, single-bundle ACLR. METHODS: Ten cadaveric knees were allocated for single-bundle ACLR in an anatomic, center-center or nonanatomic, posterolateral-to-anteromedial footprint position with hamstring autograft. Medial arthrotomy defined the native anterior cruciate ligament (ACL) tibial and femoral footprints. ACLR was performed with a 6-mm semitendinosus graft in 6-mm tunnels and repeated with a 9-mm semitendinosus and gracilis graft in 9-mm tunnels for each knee. Lachman and instrumented pivot shift examinations assessed knee stability in the ACL-intact, ACL-deficient, and ACLR conditions. Medial and lateral meniscectomies after ACL transection created reproducible pivot shifts. Significance was defined as P < .05. RESULTS: ACLR in the center-center or posterolateral-to-anteromedial position significantly reduced anterior tibial translation compared with the ACL- and meniscus-deficient conditions (P < .001). Larger graft size, however, did not significantly improve time-zero biomechanical stability compared with a smaller graft in the same position for either reconstruction (P = .41 to .74). A center-center ACLR controlled tibial translation significantly better than a nonanatomic graft position regardless of graft size (P < .001). A smaller graft in the anatomic position controlled tibial translation significantly better than a larger graft in a nonanatomic position (P < .001). CONCLUSIONS: This study showed that increasing graft size did not improve the time-zero biomechanical stability of the knee after ACLR. Increased graft size did not compensate for the biomechanical instability documented with the nonanatomic tunnel position. Restoration of native footprint anatomy in ACLR is of paramount importance regardless of graft size and source. CLINICAL RELEVANCE: A larger graft size does not ameliorate the inferior time-zero biomechanics associated with nonanatomic tunnel preparation during single-bundle ACLR. PMID- 21705173 TI - Novel drug OMS103HP reduces pain and improves joint motion and function for 90 days after arthroscopic meniscectomy. AB - PURPOSE: This phase 2 study compared OMS103HP (Omeros, Seattle, WA) with control (lactated Ringer's) irrigation solution in patients undergoing arthroscopic partial meniscectomy. METHODS: This was a prospective, multicenter, double-blind, randomized, vehicle-controlled, parallel-group study. Safety and postoperative pain, range of motion, and self-reported function were evaluated for 90 days. Statistical results were based on univariate analysis of variance and repeated measures analyses. RESULTS: Mean visual analog scale (VAS) pain scores within 24 hours after discharge from the recovery room showed more pain in the control group beginning at 2 hours and peaking at 8 hours. Univariate analysis of variance of mean VAS scores over the 24-hour period did not meet statistical significance. Repeated-measures analysis yielded a statistically significant difference (P = .004) for time-by-treatment interaction, showing a clear drug benefit over time based on VAS scores. There were statistically significant differences at day 7 between the groups in passive flexion without pain (P = .022). The proportion of patients achieving flexion of 95 degrees or greater, 110 degrees , and 125 degrees was greater for the OMS103HP group. The Knee Injury and Osteoarthritis Outcome Score (KOOS) showed statistically significant differences (P <= .05) between the OMS103HP and control groups for 4 of 5 outcomes (symptoms, pain, sport and recreation, and knee-based quality of life but not activities of daily living). All scores showed a treatment effect through day 90. The overall incidence of adverse events and abnormal laboratory values for the OMS103HP and control groups was similar. Serious adverse events occurred in 1 control patient. CONCLUSIONS: In this study of patients with meniscal tears who underwent simple debridement, the use of OMS103HP resulted in reduced acute postoperative pain (measured by VAS over the first 24 hours postoperatively), reduced pain during recovery (measured by the KOOS pain subscale, which measures both background levels of pain and exacerbations caused by movements or activities), improved postoperative knee motion, and improved functional outcomes as assessed with the KOOS Knee Survey. Clinical benefits of OMS103HP were consistent and sustained throughout 90 days of postoperative follow-up. LEVEL OF EVIDENCE: Level I, prospective, randomized, controlled trial. PMID- 21705175 TI - [Pseudoxanthoma elasticum and obstetric epidural analgesia: report of a case]. AB - Pseudoxanthoma elasticum is a rare inherited disorder of the elastic tissue characterised by multisystem manifestations. Skin, eyes, gastro-intestinal system and cardiovascular system are the major affected systems. We describe the anaesthetic management of a parturient affected by this disease. PMID- 21705176 TI - [Airway management in obstetrics]. AB - OBJECTIVE: Reviewing problems related to the airway management in obstetrics, taking into account the recent evolutions of the anaesthetic practices in obstetrics. DATA SOURCES: A review of the literature in English and French was performed in the Pumed database in April 2010. The first research used the following MeshTerms: "Anesthesia, Obstetrical" [Mesh] AND "Intubation, Intratracheal" [Mesh]. Complementary research used alone or in combination the following keywords: difficult tracheal intubation; failed tracheal intubation; airway; prediction of difficult tracheal intubation; maternal mortality; maternal morbidity; liability; aspiration pneumonia and obstetrical anesthesia. STUDY SELECTION: All the publications were retained excluding the correspondence. DATA EXTRACTION: Data analysis for the airway management in obstetrics, the prediction of difficult intubation, the prevention of pulmonary inhalation of gastric fluid, but also on maternal morbi-mortality in link with general anesthesia in obstetrics. DATA SYNTHESIS: Airway management in obstetrics remains a true challenge for various reasons. The physiological and anatomical modifications related to pregnancy are responsible for a faster hypoxemia, a reduction of the diameter of the pharyngolaryngal tract, as well as an increase of the risk of inhalation of gastric contents after 16 weeks of amenorrhea. The emergency or extreme emergency context and the presence of diseases like obesity or preeclampsia raise the risks of difficulties with airway management. The logical evolution of the practices, with the considerable rise of the regional anesthesia/analgesia limits the training and the maintenance of competences for intratracheal intubation in obstetrics. The training per simulation appears particularly interesting on the subject and this approach needs to be developed. The literature indicates that the incidence of difficult intubation is of one per 30. The impossible intubation is one per 280 in obstetrics, eight times greater than in the general population. No criterion of difficult intubation is sufficiently predictive alone. In obstetrics as in other contexts, the association of several criteria will permit to anticipate a difficult intubation. There is a worsening of the Mallampati during the pregnancy and during labour. To limit the risk of a difficult management of the airway in obstetrics, it will be paramount and capital, in addition to give priority to the regional anaesthesia/analgesia each time possible, to perform a careful and repeated evaluation of the predictive criteria of difficult intubation or ventilation. The inhalation of gastric fluid will systematically be prevented. The adapted material and algorithms for difficult intubation must be available in the labour wards. In case of a difficult intubation during an emergency caesarean section, the SFAR algorithms must be applied. In case of a "cannot intubate can ventilate situation", the possibility of carrying on the Caesarean maintaining the Sellick manoeuvre should be considered. The place of the laryngoscopy assisted by videolaryngoscope in this context clearly remains to be defined. Even if in the literature some cases of successful intubation through these devices suggest an interest, there is a clear deviance between the guidelines and the practices concerning general anaesthesia performed at the end of the labour. Indeed they should be systematically performed with rapid sequence induction and tracheal intubation. A reflexion on this theme is necessary in order to grant the practices to the recommendations. PMID- 21705177 TI - [The Pulsiocath catheter and magnetic resonance imaging]. PMID- 21705178 TI - [Prediction of fluid responsiveness in hypotensive children hospitalized in intensive care unit]. PMID- 21705179 TI - [Two cases of chronic pain after regional anaesthesia]. AB - We are reporting two cases of chronic neuropathic pain after traumatism during regional anaesthesia (RA). Nerve injury is a rare complication of RA and it is the neurogical deficit, which is the most often quoted in medical literature. However, in both cases the neuropathic pain was the single departure point. The reunion of the clinical element, which incorporates possible traumatism during regional anaesthesia, characteristics of pain and unusual painful localization of surgery, should have allowed a more early diagnostic and treatment. In both cases, persistent neuropathic pain incapacitates the patient several years after the traumatism. PMID- 21705180 TI - [Endotracheal tube cuff and nitrous oxide: bench evaluation and assessment of clinical practice]. AB - OBJECTIVE: To evaluate the risk of over-inflation of endotracheal tube cuffs (ETC) when used with nitrous oxide (N(2)O); to assess the rate of under and over inflation of ETC when they are inflated without a manometer; to survey anesthesiologists about how they prevent these risks. METHODS: Nine types of endotracheal tube were studied on bench using various N(2)O concentrations; airway pressure levels and two sizes of trachea. Then, the rate and magnitude of over and under inflation pressure of ETC was assessed in our clinical practice. Finally, a national survey assessed how anesthesiologists prevented misuse of endotracheal tube with N(2)O. RESULTS: Pressure in ETC rose sharply using N(2)O, up to more than 40 cmH(2)O in six over nine tube types. Only two tube types (Mallinckrodt Hi-Lo Brandt and Lanz) were immune regarding N(2)O. Pratice study showed that ETC over inflation (>30 cmH(2)O) and under inflation (<20 cmH(2)O) was observed in 50 and 31 % of patients, respectively when cuff was inflated without a manometer. In France, a minority of anesthesiologists inflated ETC with a manometer (41 %) because in 61 % of theatres only manometers were available. CONCLUSION: There are risks induced by the use of N(2)O with tracheal tubes. This study provides data to sensitize users to these risks. PMID- 21705181 TI - [Management of hypotension during spinal anaesthesia for elective caesarean section: a survey of practice in Lorraine region]. AB - OBJECTIVE: The aim of the survey was to describe current practice in management of hypotension during spinal anaesthesia for elective caesarean section in Lorraine. STUDY DESIGN: Cross-sectional study by a mail survey. METHODS: A 20 item postal questionnaire was sent to all anaesthetists working in public or private hospital with a maternity unit in Lorraine. RESULTS: The response rate was 65%. Fifty-one percent of the respondents did not have a written procedure for the management of spinal-induced hypotension. Fluid preloading with or without vasopressor was the most common practice. Colloids were used by 20% of the respondents. For prevention of hypotension, 37% used ephedrine, 28% used phenylephrine mostly in association with ephedrine and 9% based their choice on heart rate. Twenty-six percent did not administer any vasopressor to prevent hypotension. First choice vasopressor for treatment of hypotension was ephedrine. Anaesthetists in academic practice were more likely to use coloading and phenylephrine administration, but none of them used colloids for pre- or coloading. CONCLUSION: Management of hypotension during spinal anaesthesia for elective caesarean section was significantly influenced by the type of practice. PMID- 21705182 TI - Apolipoprotein E genotype as a most significant predictor of lipid response at lipid-lowering therapy: mechanistic and clinical studies. AB - APOE alleles and apolipoprotein E isoforms control plasma cholesterol level on population level. Among three E2, E3, E4 alleles, E4 allele is associated with the increase in cholesterol level, risk of atherosclerosis and Alzheimer disease, while E2 allele is associated with the decrease in cholesterol level and risk of atherosclerosis. The increase in plasma triglyceride is an independent risk factor of atherosclerosis and triglyceride-high density lipoprotein coupling determines the efficiency of reverse cholesterol transport. The impairment of this coupling specifically at hypertriglyceridemia may be followed by specific lipoprotein markers. The influence of major lipid-lowering drugs on lipoprotein metabolism and association of apoE isoforms with the efficiency of therapy by statins and fibrates are summarized both at isolated and combined increase in plasma triglyceride and cholesterol. APOE polymorphism seems to be a single genetic variant with a confirmed stratification both at candidate gene and at wide genome analyses. PMID- 21705183 TI - Action of retinoic acid receptor on EGFR gene transactivation and breast cancer cell proliferation: Interplay with the estrogen receptor. AB - In the present report, we investigated the action of retinoic acid (RA) on the transactivation of the epidermal growth factor receptor (EGFR) gene promoter. In a previous study, we showed that the estrogen receptor (ER) alpha activated by 17beta-estradiol (E2) increased EGFR expression by enhancing the binding of the transcription factor Sp1 to the EGFR minimal promoter in HeLa cells. Here, we demonstrate that ligand-activated RA receptor (RAR) alpha inhibited EGFR transactivation by competing with Sp1 for binding to the same promoter fragment in the same cell model. When RARalpha and ERalpha were coexpressed, the inhibitory effect of RA on transactivation of the EGFR promoter counteracted the enhancement induced by E2-activated ERalpha and became more pronounced in the presence of ligand-free ERalpha. In the MCF7 breast cancer cell line, which endogenously expresses RARalpha and ERalpha, RA exerted anti-proliferative effects in the presence of ligand-free ERalpha. Moreover, interplay between the pathways mediated by the two receptors was observed, as RA counteracted E2 induced cell proliferation. Our results suggest that the interference with the activity of Sp1 on the EGFR promoter could be related to the observed RA-mediated growth suppression of breast cancer cells. PMID- 21705184 TI - Ophthalmological complications in hepatitis C virus infection: side effect of interferon therapy or a direct role of HCV? AB - Several clinical studies have demonstrated that retinopathy and ophthalmic complications are features that appear mostly as side effects in HCV patients undergoing interferon (IFN) therapy. Here we underline that HCV itself is also able to modulate genes involved in ocular pathologies. Presently an in vitro model of ocular tissue derived cells infected with HCV is missing. The establishment of such in vitro models would be helpful to better understand the mechanisms through which HCV induces optical pathologies in order to specifically target the causes of ocular disease. PMID- 21705185 TI - Reduced expression of PHD2 prolyl hydroxylase gene in primary advanced uterine cervical carcinoma. AB - Decreased PHD2 expression in human carcinomas has been considered a critical factor in supporting tumor angiogenesis and growth. We studied the levels of PHD2 transcript and protein in advanced cervical cancer specimens (n=27) and normal uterine cervical tissue samples (n=27). Real-time quantitative PCR and Western blotting analysis showed significantly lower levels of PHD2 transcript (P=0.0088) and protein (P=0.0095) in cancerous tissues as compared to corresponding normal tissue. Using DNA sequencing analysis, we also found an accumulation of mutations in promoter regions of PHD2 in advanced cervical cancer specimens. Moreover, computer analysis of these mutations showed a loss of binding sites for many transcription factors. Our results suggest PHD2 as a possible target in anti angiogenic therapies in advanced uterine cervical carcinoma. PMID- 21705186 TI - [Pericarditis revealing a dermatomyositis]. PMID- 21705187 TI - Activation of polymorphonuclear leukocytes and increased plasma vasoconstrictors in vasospastic and nonvasospastic angina. AB - BACKGROUND: The cause of coronary vasoconstriction in patients with angina at rest, nonsignificant coronary stenosis, and endothelial dysfunction remains unknown. Our objective was to investigate the association between enhanced coronary vasoconstriction and increased circulating levels of vasoconstrictor agents. METHODS: Plasma levels of big endothelin-1, serotonin, and superoxide produced by polymorphonuclear leukocytes were measured in 38 patients with stable angina at rest without significant coronary artery stenosis-23 with nonvasospastic angina and 15 with vasospastic angina-and were compared with 10 patients with stable coronary disease and 20 age-matched controls. RESULTS: Patients with angina at rest showed higher big endothelin-1 (1.28 vs 0.72 fmol/mL, P < 0.001), serotonin (18.0 vs 9.1 ng/mL, P = 0.002), and superoxide produced by polymorphonuclear leukocytes (177 vs 67 nmol/10 * E8 * minutes, P = 0.001) than did controls. Serotonin and superoxide produced by polymorphonuclear leukocytes were also higher than in coronary disease patients (5.4 ng/mL, P = 0.001, and 97 nmol/10 x E8 x minutes, P = 0.005), and big endothelin-1 levels tended to be higher (0.99 fmol/mL, P = 0.073). Moreover, there were no significant differences in these 3 parameters between patients with vasospastic and nonvasospastic angina, and among the latter, between patients with a positive and those with a negative exercise stress test. CONCLUSION: Systemic plasma levels of agents with the potential to produce coronary vasoconstriction are increased in patients with stable vasospastic or nonvasospastic angina and, hence, may contribute to their angina, increased coronary tone, and impaired vasodilatory capacity. Furthermore, they may establish a mechanistic link between the 2 conditions. PMID- 21705188 TI - Venous distensibility as a key factor in the success of arteriovenous fistulas at the wrist. AB - BACKGROUND: The diameter of veins in the superficial forearm has been shown to correlate with risk for nonmaturation of newly created arteriovenous fistulas (AVFs). However, reported cut-off diameters are inconsistent. The purpose of our study was to assess the optimal diameter and distensibility of the radiocephalic vein at the wrist using the tourniquet method. METHODS: We selected 50 consecutive patients who received AVFs between June 2007 and July 2009. All patients underwent venography before surgery. Approximately 30 minutes after the first venography, the upper arm cuff was inflated to stop superficial venous return. After 1 minute, a second venography was performed, after which the diameters of the distended radiocephalic veins were measured. We used these data to determine the optimal size and distensibility of the radiocephalic vein for a successful AVF at the wrist. RESULTS: Participants consisted of 38 men and 12 women. We found no significant correlation between diabetes or hypertension and success of AVFs. We found that radiocephalic veins with diameters >3.25 mm after the tourniquet maneuver had a fourfold higher success rate compared with that of smaller veins, but this difference was not statistically significant (p = 0.09). We also found that the procedure success rate was significantly higher with radiocephalic veins whose diameters increased by >0.35 mm during venography (odds ratio = 7.422). CONCLUSION: For AVFs, it is important to use radiocephalic veins with a diameter of >=3.25 mm after the tourniquet maneuver. In addition, AVF outcomes at the wrist are significantly better using radiocephalic veins that show an increase of >0.35 mm on venography. PMID- 21705189 TI - Processed electroencephalogram response of patients undergoing carotid endarterectomy: a pilot study. AB - BACKGROUND: A risk during carotid endarterectomy (CEA) is cerebral ischemia as a result of clamping of the carotid artery. The Cerebral State Monitor is one of several electroencephalogram monitors that reflects level of consciousness of patients during anesthesia. The monitor reports level of consciousness with the empirical parameter Cerebral State Index (CSI) on a 0-100 scale. In this patient controlled prospective pilot study, we compared the CSI measured from the surgical and control hemispheres of patients undergoing CEA surgery to determine whether the parameter is affected by presumed changes in cerebral blood flow. METHODS: Fifteen consenting CEA patients entered this institutionally approved study. We connected a separate Cerebral State Monitor to the left and right sides of the patient's head and recorded CSI intraoperatively. We compared the control side data with the surgical-side data. RESULTS: Clamping caused the surgical-side CSI to drop below the control-side CSI. Shunt activation caused the CSI to rise above the control. The greatest difference between the surgical-side CSI and control-side CSI occurred at the completion of the CEA procedure. These observed trends were not statistically significant in this pilot project. CONCLUSION: Our preliminary results suggest that the CSI, and perhaps other similar indexes, may indicate changes in cerebral blood flow acutely during CEA. Our findings lend promise to a new use for these types of electroencephalogram monitors, which are prevalent in operating rooms today. PMID- 21705190 TI - Incidence and risk factors for 30-day postdischarge mortality in patients with vascular disease undergoing major lower extremity amputation. AB - BACKGROUND: Our goal was to analyze the incidence and risk factors for 30-day postdischarge mortality in patients with vascular disease undergoing major lower extremity amputation. METHODS: We queried the American College of Surgeons National Surgery Quality Improvement Program data set from the years 2005 to 2009 for amputations with vascular disease diagnosis codes. We analyzed in-hospital mortality and postdischarge mortality by year of the study and relative to length of hospital stay. Patients with American Society of Anesthesiologists physical status classification level 5, do-not-resuscitate status, disseminated cancer, and emergent operations were excluded to highlight risk among patients more likely to survive. We compared risk factors for each mortality group using separate multivariate logistic regressions. RESULTS: Our query resulted in 6,188 patients with mean age of 67 +/- 14 years; of these, 39.1% were female. Thirty day mortality was 7.6%; 4.2% in-hospital mortality and 3.4% postdischarge mortality. After postoperative day 14, the majority of deaths were after discharge and the daily death risk was almost constant until postoperative day 30 at around 2.1 per 1000 survivors. The postdischarge death rates were consistent across the 5 years of the study (chi(2): p = 0.59), despite the fact that median hospital length of stay decreased from 12 to 9 days (Kruskal-Wallis: p < 0.001). Preoperative risk factors for postdischarge death included age, functional status, lower serum albumin, serum creatinine level of >1.2 mg/dL, dialysis, serum bilirubin level of >1.0 mg/dL, black race (protective), systemic inflammatory response syndrome, steroid use for chronic condition, impaired sensorium, alcohol abuse, recent weight loss, and dyspnea. CONCLUSIONS: Patients with vascular disease undergoing major amputation are at high risk for postdischarge mortality. This risk is not associated with recent decrease in hospital stay. Systemic comorbid risk factors were identified, thus highlighting the need for adequate medical management of these patients in the 30 days after the operation. Coordination of postdischarge care to ensure management of systemic illness could potentially improve outcomes. PMID- 21705191 TI - Surgical treatment of deep brachial artery aneurysm. AB - Deep brachial artery aneurysms are extremely rare. The purpose of this article is to report a case of deep brachial artery aneurysm that was successfully treated by open surgery. A 76-year-old man presented with complaints of an asymptomatic pulsatile mass in the left axilla. A computed tomography angiography revealed a deep brachial artery aneurysm. The aneurysm was resected surgically, then the axillary artery was repaired, and the distal end of the deep brachial artery was ligated without vascular reconstruction. The patient had a good recovery with no complications, and the arterial pulses of the left upper extremity were normal. PMID- 21705192 TI - The validity of psychiatric diagnoses: the case of 'specific' developmental disorders. AB - We tested whether developmental coordination disorder (DCD) and mixed receptive expressive language disorder (RELD) are valid diagnoses by assessing whether they are separated from each other, from other childhood disorders, and from normality by natural boundaries termed zones of rarity. Standardized measures of intelligence, language, motor skills, social cognition, and executive functioning were administered to children with DCD (n = 22), RELD (n = 30), autistic disorder (n = 30), mental retardation (n = 24), attention deficit/hyperactivity disorder (n = 53) and to a representative sample of children (n = 449). Discriminant function scores were used to test whether there were zones of rarity between the DCD, RELD, and other groups. DCD and RELD were reliably distinguishable only from the mental retardation group. Cluster and latent class analyses both resulted in only two clusters or classes being identified, one consisting mainly of typical children and the other of children with a disorder. Fifty percent of children in the DCD group and 20% in the RELD group were clustered with typical children. There was no evidence of zones of rarity between disorders. Rather, with the exception of mental retardation, the results imply there are no natural boundaries between disorders or between disorders and normality. PMID- 21705193 TI - Unmet health care needs in children with cerebral palsy: a cross-sectional study. AB - Children with potentially severe health conditions such as cerebral palsy (CP) are at risk for unmet health care needs. We sought to determine whether children with CP had significantly greater unmet health care needs than children with other special health care needs (SHCN), and whether conditions associated with CP increased the odds of unmet health care needs. We analyzed data from the National Survey of Children with Special Health Care Needs, 2005-2006, using multivariate logistic regression to calculate the adjusted odds of children with CP having one or more unmet health care needs compared to children with other SHCN. We also determined the association of CP-related conditions with unmet health care needs in children with CP. After weighting to national averages, our sample represented 178,536 children with CP (1.9%), and 9,236,794 with children with other SHCN (98.1%). Although having CP increased the odds that children had unmet health care needs (OR = 1.46, 95% CI [1.07-1.99]), the presence of a "severe" health condition weakened the association. Gastrointestinal problems and emotional problems increased the odds that children with CP would have unmet health care needs above that of children without the associated conditions (p <= .01). Children with CP are similar to children with other SHCN and may benefit from collaborative programs targeting severe chronic conditions. However, children with CP and associated conditions have increased odds of unmet health care needs in comparison to children without those problems. PMID- 21705194 TI - A new hypothesis for fluidification of vocal-fold mucus: scintigraphic study. AB - OBJECTIVE: Our aim was to establish a new hypothesis for the fluidification of the mucus of the vocal folds, by using a scintigraphic method to analyze the relationship of the saliva from the oral and pharyngeal cavities to the mucosa of the laryngeal vestibule. STUDY DESIGN: We theorized that the saliva that is adsorbed on the oral and pharyngeal mucosa enters the larynx and is also adsorbed on its mucosa, as a natural layer, fluidizing the mucus of the vestibule wall. METHOD: A saline solution of sodium pertechnetate (Na(99m)TcO(4)) with radioactivity of 1.0 mCi was sprayed in the oral cavity of seven healthy volunteers, who were instructed to chew a piece of apple for as long as possible without swallowing. The migration of the radioactive saliva was recorded by a gamma-chamber apparatus. RESULTS: We observed radioactivity in the laryngeal mucosa in six of the seven volunteers, who developed no complaints and no respiratory-defense reactions. The results for frequency were statistically significant (Mann-Whitney test, P=0.05). CONCLUSION: The results indicate that an increased volume of saliva enters the larynx and is adsorbed in its mucosa, producing mucus fluidification. This supports our alternative hypothesis to the unlikely concept that hydration by water ingestion is the factor responsible for reduction of the mucus viscosity of the vocal folds. PMID- 21705195 TI - Limbic response to psychosocial stress in schizotypy: a functional magnetic resonance imaging study. AB - Psychological stress causes dopamine release in the striatum and is thought to play a role in susceptibility to psychotic illness. Previous work suggests that an elevated dopaminergic response to stress may index vulnerability to psychosis in certain individuals. With functional magnetic resonance imaging, we measured stress-induced changes in brain activity in healthy individuals at elevated risk of developing psychosis. Participants were 15 controls and 25 psychometric schizotypes: 12 with positive symptom schizotypy (perceptual aberrations) and 13 with negative symptom schizotypy (physical anhedonia), as determined by questionnaires (Chapman et al., 1976; Chapman and Chapman, 1978). In the scanner, participants performed the Montreal Imaging Stress Task and a matched sensory motor control task. Measures of self-reported stress and salivary cortisol levels were taken throughout the experiment. All three groups showed significant increases in self-reported stress and significant fMRI signal change in the striatal, limbic and cortical regions. However, the Physical Anhedonia group showed greater stress-induced striatal and limbic deactivation than the other two groups. Deactivation in the striatum was significantly correlated with Physical Anhedonia score across all subjects. Our findings suggest the presence of abnormalities in striatal response to stress in negative symptom schizotypy. PMID- 21705196 TI - Magnetic resonance spectroscopy of limbic structures displays metabolite differences in young unaffected relatives of schizophrenia probands. AB - Imaging studies of schizophrenia patients showed fronto-temporal brain volume deficits, while magnetic resonance spectroscopy (MRS) studies of patients and unaffected biological relatives have found a decrement of the neuronal marker N acetyl-aspartate (NAA) in the hippocampus and frontal lobes, and increased choline-containing phospholipids. Using a 3T MR scanner, we determined the metabolite profile within limbic regions (anterior cingulate cortex (ACC) and left hippocampus) of 36 unaffected, adolescent/young adult relatives of schizophrenia probands (first-degree=16, second-degree=20) and 25 healthy controls with no family history of schizophrenia. Significant main effects of group were found on NAA/Cho ratios for both the left hippocampus (F = 6.11, p <= 0.02) and ACC (F = 4.89, p <= 0.03) as well as for the left hippocampus Cho/Cr ratio (F = 5.55, p <= 0.02). Compared to age and sex matched healthy controls without a family history of schizophrenia, first-degree relatives of probands had greater MRS metabolite deviations than second-degree relatives. Greater familial proximity to the schizophrenia proband (or higher schizophrenia susceptibility) among biological relatives was associated with stepwise lowering of NAA/Cho and elevations in Cho/Cr ratios. The observed limbic metabolite changes among young, nonpsychotic biological relatives are likely related to shared genetic vulnerability factors, and may assist in the early identification of schizophrenia for primary and secondary prevention. PMID- 21705197 TI - Differential effects of paced and unpaced responding on delayed serial order recall in schizophrenia. AB - Working memory for temporal order is a component of working memory that is especially dependent on striatal systems, but has not been extensively studied in schizophrenia. This study was designed to characterize serial order reproduction by adapting a spatial serial order task developed for nonhuman primate studies, while controlling for working memory load and whether responses were initiated freely (unpaced) or in an externally paced format. Clinically stable schizophrenia patients (n=27) and psychiatrically healthy individuals (n=25) were comparable on demographic variables and performance on standardized tests of immediate serial order recall (Digit Span, Spatial Span). No group differences were observed for serial order recall when read sequence reproduction was unpaced. However, schizophrenia patients exhibited significant impairments when responding was paced, regardless of sequence length or retention delay. Intact performance by schizophrenia patients during the unpaced condition indicates that prefrontal storage and striatal output systems are sufficiently intact to learn novel response sequences and hold them in working memory to perform serial order tasks. However, retention for newly learned response sequences was disrupted in schizophrenia patients by paced responding, when read-out of each element in the response sequence was externally controlled. The disruption of memory for serial order in paced read-out condition indicates a deficit in frontostriatal interaction characterized by an inability to update working memory stores and deconstruct 'chunked' information. PMID- 21705198 TI - Spread of imipenem-resistant Acinetobacter baumannii of European clone II in Western China. AB - The aim of this study was to investigate the distribution of resistance genes and the clonal relationship amongst imipenem-resistant Acinetobacter baumannii isolates from ten hospitals in Western China as well as to compare the molecular epidemiological data with those of isolates from two hospitals in Hangzhou and Beijing. Genes encoding OXA carbapenemases, metallo-beta-lactamases, AmpC cephalosporinase and carbapenem resistance-associated outer membrane protein (CarO) were screened using polymerase chain reaction (PCR) and sequencing. PCR mapping was performed to determine whether insertion sequence ISAba1 elements preceded OXA carbapenemases and AmpC cephalosporinase. International clonal lineages were identified by sequence type multiplex PCR. Multilocus sequence typing (MLST) was performed to determine the sequence types (STs), and then eBURST algorithm was applied to assign clonal complexes (CCs). In this study, dissemination of acquired ISAba1 preceding the bla(OXA-23-like) gene was the predominant enzymatic resistance mechanism amongst 272 imipenem-resistant isolates. Five isolates harboured the carO gene disrupted by insertion of ISAba1 and three isolates lacked carO. All of the 36 representative isolates belonged to European clone II. Ten STs, including three novel types, were identified. These STs were clustered into CC92 and two distinct singletons. These observations suggest that imipenem-resistant A. baumannii of European clone II, which carries acquired ISAba1 preceding the bla(OXA-23-like) gene and belongs to CC92, has spread within Western China. PMID- 21705199 TI - Rate of readmission and mortality risks of schizophrenia patients who were discharged against medical advice. AB - PURPOSE: To compare the readmission and the mortality rates of schizophrenia patients who were discharged against medical advice (AMA) and patients who were discharged by physician recommendation. METHODS: The records (1984-2005) of all consecutive admissions (n=12,937) of schizophrenia patients (n=8,052) were reviewed. Out of this group, 673 (8.3%) refused to remain in the hospital and signed a hospital form for discharge AMA. Their records were analyzed for rates of re-hospitalization and mortality at study closure. The records of AMA patients were compared to those of patients with regular discharge (n=1345). RESULTS: AMA patients were younger at admission (P<0.001), comprised more males (P<0.01), more were single (P<0.0001), and had a shorter duration of illness than the controls (P<0.05). A total of 49.9% of AMA events occurred within the first 2 weeks of hospitalization. The readmission rate was significantly higher for AMA patients than for the controls (P<0.001). The mortality rate as a result of suicide (P<0.0001) and accidents (P<0.05) was higher for AMA patients compared to controls. CONCLUSION: The schizophrenia patients discharged AMA have a higher readmission rate and a higher mortality rate due to suicide and accidents compared to non-AMA discharged patients. Patients with AMA discharge warrant special community surveillance to improve outcome. PMID- 21705200 TI - Association of treatment delay, migration and urbanicity in psychosis. AB - BACKGROUND: Several factors may contribute to duration of untreated psychosis (DUP): patient-delay, referral-delay and treatment-delay caused by mental health care services (MHS-delay). In order to find the most effective interventions to reduce DUP, it is important to know what factors in these pathways to care contribute to DUP. AIM: To examine the relationship of the constituents of treatment delay, migration status and urbanicity. METHOD: In first episode psychotic patients (n=182) from rural, urban and highly urbanized areas, DUP, migration status and pathways to care were determined. RESULTS: Mean DUP was 53.6 weeks (median 8.9, SD=116.8). Patient-delay was significantly longer for patients from highly urbanized areas and for first generation immigrants. MHS-delay was longer for patients who were treated already by MHS for other diagnoses. CONCLUSIONS: Specific interventions are needed focusing on patients living in highly urbanized areas and first generation immigrants in order to shorten patient delay. MHS should improve early detection of psychosis in patients already in treatment for other diagnosis. PMID- 21705201 TI - Analysis of the contribution of sedimentation to bacterial mass transport in a parallel plate flow chamber: part II: use of fluorescence imaging. AB - Using a new phase-contrast microscopy-based method of analysis, sedimentation has recently been demonstrated to be the major mass transport mechanism of bacteria towards substratum surfaces in a parallel plate flow chamber (J. Li, H.J. Busscher, W. Norde, J. Sjollema, Colloid Surf. B. 84 (2011) 76). Here we describe a novel method for enumerating adhesion of fluorescent bacteria in a parallel plate flow chamber that allows direct imaging of the bacterial distribution along the length of the flow chamber, as caused by sedimentation. Imaging of fluorescence was done using macroscopic bio-optical imaging of the entire flow chamber, including top and bottom plates as well as of the flowing suspension in between. An algorithm is forwarded that allows to separate the fluorescence arising from the suspension and bottom plate and at the same time determines the single cell fluorescence from which the bacterial distribution over the entire bottom plate can be visualized. Enumeration of the numbers of bacteria adhering to the center of the glass bottom plate for a fluorescent Staphylococcus aureus strain was found to coincide with enumerations using phase-contrast microscopy. Moreover, due to the use of macroscopic bio-optical imaging, it was found that the number of adhering staphylococci increases linearly with distance from the inlet of the flow chamber, which could be explained from a simplified mass balance of convection, sedimentation and blocking near the bottom plate of the flow chamber. PMID- 21705202 TI - Versatile bio-ink for covalent immobilization of chimeric avidin on sol-gel substrates. AB - A bio-ink for covalent deposition of thermostable, high affinity biotin-binding chimeric avidin onto sol-gel substrates was developed. The bio-ink was prepared from heterobifunctional crosslinker 6-maleimidohexanoic acid N-hydroxysuccinimide which was first reacted either with 3-aminopropyltriethoxysilane or 3 aminopropyldimethylethoxysilane to form silane linkers 6-maleimide-N-(3 (triethoxysilyl)propyl)hexanamide or -(ethoxydimethylsilyl)propyl)-hexanamide. C terminal cysteine genetically engineered to chimeric avidin was reacted with the maleimide group of silane linker in methanol/PBS solution to form a suspension, which was printed on sol-gel modified PMMA film. Different concentrations of chimeric avidin and ratios between silane linkers were tested to find the best properties for the bio-ink to enable gravure or inkjet printing. Bio-ink prepared from 3-aminopropyltriethoxysilane was found to provide the highest amount of active immobilized chimeric avidin. The developed bio-ink was shown to be valuable for automated fabrication of avidin-functionalized polymer films. PMID- 21705203 TI - [Mohs micrographic surgery in two children with dermatofibrosarcoma protuberans]. AB - Dermatofibrosarcoma protuberans is a rare low-grade malignant tumor. The pseudopodia structure of the tumor requires 3-5 cm surgical margins. Mohs micrographic surgery (MMC) can reduce these margins to 1.3 cm while controlling all the histological excision margins. Children seem to be a good indication for this technique because it reduces the amount of skin removed. We report 2 cases of pediatric DFS treated with CMM to illustrate the usefulness of this technique in pediatrics. Two girls, aged 12 and 13 years, had a dermatofibrosarcoma located on the breast and sternum, respectively. CMM was proposed. One operative session was needed with direct closure in a second phase. MMS is a useful surgical technique for childhood tumors. If dermatofibrosarcoma is a very good indication in children, other skin tumors could benefit from this approach. PMID- 21705204 TI - Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation. AB - Mitochondrial outer membrane proteins have been found to be ubiquitinated and degraded by the proteasome. This process shares at least one component of the ERAD pathway of ER membrane protein degradation, the AAA ATPase cdc48/p97/VCP, thought to extract integral membrane proteins from the lipid bilayer and chaperone them to the proteasome. Proteasomal degradation of the outer mitochondrial membrane (OMM) protein Mcl1 regulates apoptosis whereas Parkin mediated ubiquitination and degradation of Mitofusins can inhibit mitochondrial fusion and promote mitophagy. The breadth of OMM ubiquitin/proteasome substrates and the physiological relevance of their turnover are only beginning to be understood. PMID- 21705205 TI - A high proportion of users of low-threshold facilities with needle exchange programmes in Switzerland are currently on methadone treatment: implications for new approaches in harm reduction and care. AB - BACKGROUND: Increasingly, patients receiving methadone treatment are found in low threshold facilities (LTF), which provide needle exchange programmes in Switzerland. This paper identifies the characteristics of LTF attendees receiving methadone treatment (MT) compared with other LTF attendees (non-MT). METHODS: A national cross-sectional survey was conducted in 2006 over five consecutive days in all LTF (n=25). Attendees were given an anonymous questionnaire, collecting information on socio-demographic indicators, drug consumption, injection, methadone treatment, and self-reported HIV and HCV status. Univariate analysis and logistic regression were performed to compare MT to non-MT. The response rate was 66% (n=1128). RESULTS: MT comprised 57.6% of the sample. In multivariate analysis, factors associated with being on MT were older age (OR: 1.38), being female (OR: 1.60), having one's own accommodation (OR: 1.56), receiving public assistance (OR: 2.29), lifetime injecting (OR: 2.26), HIV-positive status (OR: 2.00), and having consumed cocaine during the past month (OR: 1.37); MT were less likely to have consumed heroin in the past month (OR: 0.76, not significant) and visited LTF less often on a daily basis (OR: 0.59). The number of injections during the past week was not associated with MT. CONCLUSIONS: More LTF attendees were in the MT group, bringing to light an underappreciated LTF clientele with specific needs. The MT group consumption profile may reflect therapeutic failure or deficits in treatment quality and it is necessary to acknowledge this and to strengthen the awareness of LTF personnel about potential needs of MT attendees to meet their therapeutic goals. PMID- 21705206 TI - Metal speciation in landfill leachates with a focus on the influence of organic matter. AB - This study characterises the heavy-metal content in leachates collected from eight landfills in France. In order to identify heavy metal occurrence in the different size fractions of leachates, a cascade filtration protocol was applied directly in the field, under a nitrogen gas atmosphere to avoid metal oxidation. The results of analyses performed on the leachates suggest that most of the metals are concentrated in the <30 kDa fraction, while lead, copper and cadmium show an association with larger particles. Initial speciation calculations, without considering metal association with organic matter, suggest that leachate concentrations in lead, copper, nickel and zinc are super-saturated with respect to sulphur phases. Speciation calculations that account for metal complexation with organic matter, considered as fulvic acids based on C1(s) NEXAFS spectroscopy, show that this mechanism is not sufficient to explain such deviation from equilibrium conditions. It is therefore hypothesized that the deviation results also from the influence of biological activity on the kinetics of mineral phase precipitation and dissolution, thus providing a dynamic system. The results of chemical analyses of sampled fluids are compared with speciation calculations and some implications for the assessment of metal mobility and natural attenuation in a context of landfill risk assessment are discussed. PMID- 21705207 TI - Discussion on the methodology for determining food waste in household waste composition studies. AB - Food waste has become an increasingly discussed topic in recent years. However, there is little authoritative data on food waste quantities and composition and systematic and comparable data are missing. Household waste composition analyses, which are often carried out routinely at regular or irregular intervals, provide an opportunity for obtaining data about food waste at both local and regional levels. The results of prior waste composition studies are not really comparable due to the different classifications, definitions and methods used; in addition, these are mostly insufficiently described and not reproducible by a third party. The aim of this paper is to discuss a methodology for determining the proportion of food waste in household waste composition studies, by analysing specific problems and possible solutions. For that purpose, findings from the literature are analysed and the approach and results of a composition analysis of residual waste of a stratified sample (urban, rural area) are presented. The study suggests that in order to avoid a significant loss of information, waste should not be sieved before sorting and packed food waste should be classified into the relevant food waste category together with its packaging. The case study showed that the overall influence of the proportion of food packaging included in the food waste category, which amounted to only 8%, did not significantly influence the results and can therefore be disregarded. PMID- 21705209 TI - Polyhydroxyalkanoates as a source of chemicals, polymers, and biofuels. AB - Microbial polyhydroxyalkanoates (PHA) are a family of structurally diverse polyesters produced by many bacteria. Deleting key steps from the beta-oxidation cycle in Pseudomonas putida makes it possible to achieve precise substrate based design of PHA homopolymers, copolymers, and block polymers, allowing the study of structure-property relationship in a clear way. The PHA homopolymer synthesis also allows the microbial or chemical production of pure monomers of PHA in a convenient way without separating the mixed monomers. After used as bioplastics, PHA can be methyl esterified to become biofuels, which further extends the PHA application value. The microbial production of PHA with diverse structures is entering a new developing phase. PMID- 21705208 TI - Supercritical water oxidation of landfill leachate. AB - In this paper, ammonia as an important ingredient in landfill leachate was mainly studied. Based on Peng-Robinson formulations and Gibbs free energy minimization method, the estimation of equilibrium composition and thermodynamic analysis for supercritical water oxidation of ammonia (SCWO) was made. As equilibrium is reached, ammonia could be totally oxidized in SCW. N(2) is the main product, and the formation of NO(2) and NO could be neglected. The investigation on SCWO of landfill leachate was conducted in a batch reactor at temperature of 380-500 degrees C, reaction time of 50-300s and pressure of 25 MPa. The effect of reaction parameters such as oxidant equivalent ratio, reaction time and temperature were investigated. The results showed that COD and NH(3) conversion improved as temperature, reaction time and oxygen excess increased. Compared to organics, NH(3) is a refractory compound in supercritical water. The conversion of COD and NH(3) were higher in the presence of MnO(2) than that without catalyst. The interaction between reaction temperature and time was analyzed by using response surface method (RSM) and the results showed that its influence on the NH(3) conversion was relatively insignificant in the case without catalyst. A global power-law rate expression was regressed from experimental data to estimate the reaction rate of NH(3). The activation energy with and without catalyst for NH(3) oxidation were 107.07 +/- 8.57 kJ/mol and 83.22 +/- 15.62 kJ/mol, respectively. PMID- 21705210 TI - The role of helical tomotherapy in the treatment of bone plasmacytoma. AB - We evaluated the early clinical outcome of patients with solitary bone plasmacytoma (SP) or a solitary lesion of multiple myeloma (MM) treated with helical tomotherapy (HT) compared with 3D conformal radiotherapy (3D-CRT), in terms of target coverage and exposure of critical organs. Ten patients with SP and 3 patients with a solitary lesion of MM underwent radiation therapy (RT) delivered by HT, to a dose of 40 Gy in 20 fractions. Treatment planning was then performed with 3D-CRT and the dosimetric parameters of both techniques were compared. Patients were also assessed for response to treatment and acute toxicities. With a median follow-up of 13 months, 78% of patients with pain before RT had resolution of their symptoms. Coverage of target lesion was adequate with both techniques in 12 of 13 patients. Target coverage was significantly lower for HT (V(95%) = 98.55% vs. 97.15%; p = 0.04, for 3D-CRT and HT, respectively). Target overdoses were also lower with HT (V(105%) = 2.01% vs. 0.19%; p= 0.16), although nonsignificant. Finally, there were no significant differences in organs-at-risk irradiation between both techniques. The early treatment tolerance was excellent, with no toxicity higher than grade I. RT of SP and MM with a solitary lesion can be safely delivered with HT, with no major acute side effects and good symptomatic control. Finally, HT provides a dosimetry similar to that of 3D-CRT in terms of organs-at-risk sparing and target volume coverage. PMID- 21705211 TI - Intensity-modulated radiosurgery with rapidarc for multiple brain metastases and comparison with static approach. AB - Rotational RapidArc (RA) and static intensity-modulated radiosurgery (IMRS) have been used for brain radiosurgery. This study compares the 2 techniques from beam delivery parameters and dosimetry aspects for multiple brain metastases. Twelve patients with 2-12 brain lesions treated with IMRS were replanned using RA. For each patient, an optimal 2-arc RA plan from several trials was chosen for comparison with IMRS. Homogeneity, conformity, and gradient indexes have been calculated. The mean dose to normal brain and maximal dose to other critical organs were evaluated. It was found that monitor unit (MU) reduction by RA is more pronounced for cases with larger number of brain lesions. The MU-ratio of RA and IMRS is reduced from 104% to 39% when lesions increase from 2 to 12. The dose homogeneities are comparable in both techniques and the conformity and gradient indexes and critical organ doses are higher in RA. Treatment time is greatly reduced by RA in intracranial radiosurgery, because RA uses fewer MUs, fewer beams, and fewer couch angles. PMID- 21705212 TI - Studying sensorimotor integration in insects. AB - Sensorimotor integration is a field rich in theory backed by a large body of psychophysical evidence. Relating the underlying neural circuitry to these theories has, however, been more challenging. With a wide array of complex behaviors coordinated by their small brains, insects provide powerful model systems to study key features of sensorimotor integration at a mechanistic level. Insect neural circuits perform both hard-wired and learned sensorimotor transformations. They modulate their neural processing based on both internal variables, such as the animal's behavioral state, and external ones, such as the time of day. Here we present some studies using insect model systems that have produced insights, at the level of individual neurons, about sensorimotor integration and the various ways in which it can be modified by context. PMID- 21705213 TI - Adaptive vocal behavior drives perception by echolocation in bats. AB - Echolocation operates through adaptive sensorimotor systems that collectively enable the bat to localize and track sonar objects as it flies. The features of sonar signals used by a bat to probe its surroundings determine the information available to its acoustic imaging system. In turn, the bat's perception of a complex scene guides its active adjustments in the features of subsequent sonar vocalizations. Here, we propose that the bat's active vocal-motor behaviors play directly into its representation of a dynamic auditory scene. PMID- 21705214 TI - The effect of the introduction of exogenous strain Acidithiobacillus thiooxidans A01 on functional gene expression, structure and function of indigenous consortium during pyrite bioleaching. AB - Acidithiobacillus thiooxidans A01 was added to a consortium of bioleaching bacteria including Acidithiobacilluscaldus, Leptospirillumferriphilum, Acidithiobacillus ferrooxidans, Sulfobacillus thermosulfidooxidans, Acidiphilium spp., and Ferroplasma thermophilum cultured in modified 9 K medium containing 0.5% (w/v) pyrite, and 10.7% increase of bioleaching rate was observed. Changes in community structure and gene expression were monitored with real-time PCR and functional gene arrays (FGAs). Real-time PCR showed that addition of At. thiooxidans caused increased numbers of all consortium members except At. caldus, and At. caldus, L. ferriphilum, and F. thermophilum remained dominant in this community. FGAs results showed that after addition of At. thiooxidans, most genes involved in iron, sulfur, carbon, and nitrogen metabolisms, metal resistance, electron transport, and extracellular polymeric substances of L. ferriphilum, F. thermophilum, and Acidiphilium spp., were up-regulated while most of these genes were down-regulated at 70-78 h in At. caldus and up-regulated in At. ferrooxidans, then down-regulated at 82-86 h. PMID- 21705215 TI - Dynamic fouling behaviors of submerged nonwoven bioreactor for filtration of activated sludge with different SRT. AB - The flux variations and resistances accumulated during filtration of activated sludge with sludge retention time (SRT) of 15, 30, and 60 days were analyzed to investigate the dynamic fouling behavior in a submerged nonwoven bioreactor. Different SRT values varied sludge condition and particle size distribution in the supernatants, which caused dissimilar fouling characteristics. Short-term fouling of the nonwoven bioreactor during filtration of activated sludge with SRT of 15 days was fully reversible, and the resistance percentages of solutes, colloids, and suspended solids were 6%, 27%, and 67%, respectively. On the other hand, significant increases of colloid resistance, such as with the filtration of activated sludge with SRT of 30 and 60 days, were related to the occurrence of irreversible fouling. The phenomenon of pore blocking by particles or colloids with size analogous to the pore of nonwoven fabric was a decisive factor leading to irreversible fouling in the large-pore materials. PMID- 21705216 TI - A high throughput method and culture medium for rapid screening of phosphate accumulating microorganisms. AB - A novel PA Medium (PAM) for efficient screening of phosphate-accumulating organisms (PAOs) was developed taking Serratia marcescens NBRI1213 as model organism. The defined National Botanical Research Institute's growth medium (NBRI) supplemented with 0.1% maltose, designed for quantitative estimation of phosphate accumulation was designated as PAM. Our work suggested usage of PAM for efficient qualitative screening and as a microbiological medium for preferential selection of PAOs on Petri-plates. For qualitative screening of PAOs, Toluidine blue-O dye (TBO) was supplemented in PAM, designated as PAM-TBO. Qualitative analysis of phosphate accumulated by various groups correlated well with grouping based upon quantitative analysis of PAOs, effect of carbon, nitrogen, salts, and phosphate accumulation-defective transposon mutants. For significantly increasing sample throughput, efficiency of screening PAOs was further enhanced by adaptation of PAM-TBO assay to microtiter plate based method. It is envisaged that usage of this medium will be salutary for quick screening of PAOs from environment. PMID- 21705217 TI - Discovery of pyrrolo[2,1-f][1,2,4]triazine C6-ketones as potent, orally active p38alpha MAP kinase inhibitors. AB - Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38alpha have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation. PMID- 21705219 TI - Discovery of imidazo[1,2-b]pyridazines as IKKbeta inhibitors. Part 3: exploration of effective compounds in arthritis models. AB - We have discovered imidazo[1,2-b]pyridazine derivatives that show suppressive activity of inflammation in arthritis models. We optimized the substructures of imidazo[1,2-b]pyridazine derivatives to combine potent IKKbeta inhibitory activity, TNFalpha inhibitory activity in vivo and excellent pharmacokinetics. The compound we have acquired, which had both potent activities and good pharmacokinetic profiles based on improved physicochemical properties, demonstrated efficacy on collagen-induced arthritis models in mice and rats. PMID- 21705218 TI - Synthesis and evaluation of 1-cyclopropyl-2-thioalkyl-8-methoxy fluoroquinolones. AB - Novel fluoroquinolone derivatives substituted with a 2-thioalkyl moiety, with and without a concomitant 3-carboxylate group, were synthesized to evaluate the effect of C-2 thioalkyl substituents on gyrase binding and inhibition. The presence of a 2-thioalkyl group universally decreased activity as compared to parent fluoroquinolones. However, with derivatives of moxifloxacin the presence of either a 2-thioalkyl group or a 3-carboxylate moiety increased activity over the 2,3-unsubstituted derivative. Energy minimization of structures provides an explanation for relative activities of fluoroquinolones having a C-2 thio moiety. PMID- 21705220 TI - Antiplasmodial and cytotoxicity evaluation of 3-functionalized 2-azetidinone derivatives. AB - 3-Azido-, 3-amino- and 3-(1,2,3-triazol-1-yl)-beta-lactams were synthesized and evaluated for their antiplasmodial activity against four strains of Plasmodium falciparum and KB cells for their cytotoxicity profiles. The presence of a cyclohexyl substituent at N-1 and a phenyl group on the triazole ring markedly improved the activity profiles of triazole-tethered beta-lactam exhibiting IC(50) values of 1.13, 1.21 and 1.00 MUM against 3D7, K1 and W2 strains respectively. PMID- 21705221 TI - Fly meets yeast: checking the correct orientation of cell division. AB - Cell division is generally thought to be a process that produces an exact copy of the mother cell by precisely replicating its genomic DNA, doubling organelles, and segregating them into two cells. Many cell types from bacteria to human cells divide asymmetrically, however, to generate daughter cells with distinct characteristics. Such asymmetric divisions are fundamental to the lifespan of a cell, to embryonic development, and to stem cell homeostasis. Asymmetric division requires coordination of cellular asymmetry and the cell division machinery. Accumulating evidence suggests that the basic molecular mechanisms that govern this process are conserved from yeast to humans. In this review we highlight similarities in the mechanisms of asymmetric cell division in yeast and Drosophila male germline stem cells (GSCs) in the hope of extracting common themes underlying several systems. PMID- 21705223 TI - Phenylimino-10H-anthracen-9-ones as novel antimicrotubule agents-synthesis, antiproliferative activity and inhibition of tubulin polymerization. AB - A novel series of phenylimino-10H-anthracen-9-ones and 9-(phenylhydrazone)-9,10 anthracenediones were synthesized and evaluated for interaction with tubulin and for cytotoxicity against a panel of human tumor cell lines. The 10-(3-hydroxy-4 methoxy-phenylimino)-10H-anthracen-9-one 15h and its dichloro analog 16b were identified as potent inhibitors of tumor cell growth (16b, IC(50) K562 0.11 MUM), including multidrug resistant phenotypes. Compound 15h had excellent activity as an inhibitor of tubulin polymerization. Concentration-dependent cell cycle analyzes by flow cytometry confirmed that KB/HeLa cells treated by 15h and 16b were arrested in the G2/M phases of the cell cycle. In competition experiments, 15h strongly displaced radiolabeled colchicine from its binding site on tubulin, showing IC(50) values similar to that of colchicine. The results obtained demonstrate that the antiproliferative activity is related to the inhibition of tubulin polymerization. PMID- 21705224 TI - Porpoisamides A and B, two novel epimeric cyclic depsipeptides from a Florida Keys collection of Lyngbya sp. AB - NMR-guided fractionation of a non-polar extract of a Florida Keys collection of Lyngbya sp. resulted in the isolation of two novel epimeric cyclic depsipeptides, porpoisamides A (1) and B (2). The planar structures of these compounds were determined using NMR spectroscopic techniques. The absolute configurations of amino and hydroxy acid subunits were assigned by enantioselective HPLC analysis. These compounds showed weak cytotoxicity towards HCT-116 colorectal carcinoma and U2OS osteosarcoma cells. The porpoisamides are a unique pair of cyclic depsipeptides that are epimeric at C-2 of the beta-amino acid, 3-amino-2 methyloctanoic acid. PMID- 21705222 TI - Norovirus-host interaction: multi-selections by human histo-blood group antigens. AB - The discovery of human histo-blood group antigens (HBGAs) as receptors or ligands of noroviruses (NoVs) raises a question about the potential role of host factors in the evolution and diversity of NoVs. Recent structural analysis of selected strains in the two major genogroups of human NoVs (GI and GII) demonstrated highly conserved HBGA binding interfaces within the two groups but not between them, indicating convergent evolution of GI and GII NoVs. GI and GII NoVs are probably introduced to humans from different non-human hosts with the HBGAs as a common niche. Each genogroup has further diverged into multiple sub-lineages (genotypes) through selections by the polymorphic HBGAs of the hosts. An elucidation of such pathogen-host interaction, including determination of the phenotypes of NoV-HBGAs interaction for each genotype, is important in understanding the epidemiology, classification and disease control and prevention of NoVs. A model of this multi-selection of NoVs by HBGAs is proposed. PMID- 21705225 TI - Convolutamines I and J, antitrypanosomal alkaloids from the bryozoan Amathia tortusa. AB - Mass-directed isolation of the CH(2)Cl(2)/CH(3)OH extract from the marine bryozoan Amathia tortusa resulted in the purification of two new brominated alkaloids, convolutamines I (1) and J (2). The structures of 1 and 2 were determined following spectroscopic data analysis. Both compounds were isolated during a drug discovery program aimed at identifying new antitrypanosomal leads from a prefractionated natural product library. Compounds 1 and 2 were shown to be active toward the parasite Trypanosoma brucei brucei with IC(50) values of 1.1 and 13.7 MUM, respectively. Preliminary toxicity profiling was also performed on both 1 and 2 using the human embryonic kidney cell line, HEK293. Compound 1 was shown to exhibit cytotoxicity against HEK293 with an IC(50) of 22.0 MUM whilst 2 was inactive at 41.0 MUM. PMID- 21705226 TI - Expression of root glutamate dehydrogenase genes in tobacco plants subjected to boron deprivation. AB - Recently it has been reported that boron (B) deficiency increases the expression of Nicotiana tabacum asparagine synthetase (AS) gene in roots, and that AS might play a main role as a detoxifying mechanism to convert ammonium into asparagine. Interestingly, glutamate dehydrogenase (GDH) genes, Ntgdh-NAD;A1 and Ntgdh NAD;B2, were up-regulated when tobacco roots were subjected to B deprivation for 8 and 24 h. In addition, aminating and deaminating GDH (EC 1.4.1.2) activities were higher in B-deficient than in B-sufficient plants after 24 h of B deficiency. Ammonium concentrations were kept sufficiently low and with similar values in B-deficient roots when compared to control. Glucose and fructose contents decreased after 24 h of B deprivation. This drop in hexoses, which was corroborated by metabolomic analysis, correlated with higher GDH gene expression. Furthermore, metabolomic profiling showed that concentrations of several organic acids, phenolics, and amino acids increased after 24 h of B deficiency. Our results suggest that GDH enzyme plays an important role in metabolic acclimation of tobacco roots to B deprivation. A putative model to explain these results is proposed and discussed. PMID- 21705227 TI - Fluorescence detection of hyaluronidase. AB - We labeled hyaluronan (HA) with two fluorophores, fluorescein amine and rhodamine B amine. These two fluorophores are suitable for a fluorescence (Foerster) resonance energy transfer (FRET) which results in a fluorescein quenching and an enhanced rhodamine emission. Such labeled HA (HA-FRET) is a potential sensor for HA degradation. We studied fluorescence properties of HA-FRET in the absence and presence of hyaluronidase enzyme (HA-ase). The time-resolved fluorescence measurements indicate more than 50% of FRET in the absence of HA-ase. In the presence of HA-ase FRET decreases with time, and relative fluorescence intensities of fluorescein and rhodamine shifts to fluorescein indicating a release of FRET. The kinetics of the digestion process of HA by HA-ase depends on the concentration of the enzyme. We demonstrate that simultaneous measurements of green and red emission of HA-FRET can be used in ratio metric detection of the HA ase presence and activity. This in turn, can be utilized for the construction of a robust but reliable HA-ase sensing device. PMID- 21705228 TI - Spectral properties of the Cu-hyperaccumulating moss Scopelophilacataractae. AB - To determine the characteristics of a Cu-hyperaccumulating moss Scopelophilacataractae and the influence of Cu on its structure and on chlorophyll (Chl), we measured reflectance and fluorescence (FL) spectra of S.cataractae samples with different Cu concentrations before and after wetting and the absorption spectra of Chl extracted from these samples. We found relationships between the spectral properties and Cu concentration. These relationships can be explained as follows. The higher the Cu concentration is, the lower is the plasticity of the cell wall, and the smaller is the increase in illuminated area due to the opening of the leaves after wetting. This results in a smaller increase in absorption and smaller decrease in reabsorption of the FL by Chl itself, and accordingly, a smaller increase in the FL band of Chl after wetting. Moreover, we found that the Chl concentration in S.cataractae is much higher than that in other common mosses and is correlated with an increase in the FL band of Chl after wetting. The remarkable increase in FL seen in S.cataractae and the slight increase in FL observed in other common mosses after wetting can be explained based on these findings. PMID- 21705230 TI - Listening to action-related sentences impairs postural control. AB - According to the mirror neurons data there exist areas in the premotor cortex that are activated both during action perception and action execution. It was hypothesized that posture maintenance would be impaired by simultaneous action perception in concordance with cognitive dissonance theory. A test was conducted during which 23 neurologically normal humans were to maintain their posture erect on the forceplate and to listen to the action-related sentences. Tests of differences and Friedman analysis of variance proved that listening to sentences that describe different actions and movements in the first and the third person impairs postural control in comparison with listening to sentences that describe objects of nature and everyday life. PMID- 21705231 TI - Backpack load affects lower limb muscle activity patterns of female hikers during prolonged load carriage. AB - This study investigated the effect of prolonged load carriage on lower limb muscle activity displayed by female recreational hikers. Electromyography (EMG) signals from vastus lateralis (VL), biceps femoris (BF), semitendinosus (ST), tibialis anterior (TA) and gastrocnemius (GM) were recorded for fifteen female hikers carrying four loads (0%, 20%, 30% and 40% body weight (BW)) over 8 km. Muscle burst duration, muscle burst onset relative to initial contact and integrated EMG signals (iEMG) were calculated to evaluate muscle activity, whereas the shift in mean power frequency (MPF) was used to evaluate muscle fatigue. Increased walking distance significantly decreased the MPF of TA; decreased the iEMG for VL, ST and GM; and shortened VL muscle burst duration. Furthermore, carrying 20-40% BW loads significantly increased VL and GM iEMG and increased BF muscle burst duration, whereas a 40% BW load caused a later VL muscle burst onset. The differences observed in muscle activity with increased load mass seem to be adjustments aimed at maintaining balance and attenuating the increased loads placed on the lower limbs during gait. Based on the changes in muscle activity, a backpack load limit of 30% BW may reduce the risk of lower limb injury for female hikers during prolonged walking. PMID- 21705229 TI - Translational studies in hematopoietic cell transplantation: treatment of hematologic malignancies as a stepping stone to tolerance induction. AB - Allogeneic hematopoietic cell transplantation (HCT) has most commonly been used to treat hematologic malignancies, where it is often the only potentially curative option available. The success of HCT has been limited by transplant associated toxicities related to the conditioning regimens used and to the common immunologic consequence of donor T cell recognition of recipient alloantigens, graft-vs-host disease (GVHD). The frequency and severity of GVHD observed when extensive HLA barriers are transgressed has essentially precluded the routine use of extensively HLA-mismatched HCT. Allogeneic HCT also has potential as an approach to organ allograft tolerance induction, but this potential has not been previously realized because of the toxicity associated with traditional conditioning. In this paper we review two approaches to HCT involving reduced intensity conditioning regimens that have been associated with improvements in safety in patients with hematologic malignancies, even in the HLA-mismatched transplant setting. These strategies have been applied in the first successful pilot studies for the induction of organ allograft tolerance in humans. Thus, we summarize an example of vertical translational research between animal models and humans and horizontal translation between two separate goals that culminated in the use of HCT to achieve allograft tolerance in humans. PMID- 21705232 TI - Prevalence of abnormal ankle-brachial index among individuals with low or intermediate Framingham Risk Scores. AB - PURPOSE: To determine the prevalence of an abnormal ankle-brachial index (ABI) among subjects not considered to be at high risk for cardiovascular disease (CVD) based on the Framingham Risk Score (FRS). MATERIALS AND METHODS: Data from the Population-Based Examinations to Determine Ankle-brachiaL index (PEDAL) Study (2007-2009), a cross-sectional study at 23 U.S. sites, in conjunction with Legs for Life, a national ABI screening program, were analyzed. This study includes data from 822 participants (average age 64.3 years +/- 11.6, 69.7% women, 89.7% non-Hispanic white) without known CVD or diabetes, who were screened for peripheral artery disease (PAD) with an ABI and for whom all FRS variables were available. Participants' 10-year coronary heart disease (CHD) risk was estimated from the FRS, and three risk categories were defined: low (< 10%), intermediate (10%-19%), and high (>= 20%). ABI < 0.90 or > 1.4 in either leg was considered abnormal. RESULTS: The prevalence of abnormal ABI was 14.2% (95%confidence interval [CI] 11.9%-16.8%). According to the FRS, 463 (56.3%) participants were at low risk, 212 (25.8%) were at intermediate risk, and 147 (17.9%) were at high risk. Among participants with a low FRS (n = 463; without CVD or diabetes or both) and an intermediate FRS (n = 212; without CVD or diabetes or both), 12.3% and 12.2% had an abnormal ABI. CONCLUSIONS: The prevalence of abnormal ABI, a CHD equivalent, is high among individuals not identified as high risk by conventional Framingham-based risk assessment. PMID- 21705233 TI - Early and one-year stroke case fatality in Sao Paulo, Brazil: applying the World Health Organization's stroke STEPS. AB - Case fatality rate is considered a main determinant of stroke mortality trends. We applied the World Health Organization's Stroke STEPS to identify case fatality rates in a community hospital in Brazil. We evaluated all patients with first ever stroke seeking acute care at the hospital's emergency ward between April 2006 and December 2008 to verify early and late case fatality according to stroke subtype. We used years of formal education as a surrogate for socioeconomic status. Of 430 first-ever stroke events, 365 (84.9%) were ischemic and 65 (15.1%) were intracerebral hemorrhage. After 1 year, we adjudicated 108 deaths (86 ischemic; 22 hemorrhagic). Age-adjusted case fatality rates for ischemic stroke and intracerebral hemorrhage were 6.0% v 19.8% at 10 days, 10.6% v 22.1% at 28 days, 17.6% v 29.1% at 6 months, and 21.0% v 31.5% at 1 year. Illiteracy or no formal education was a predictor of death at 6 months (odds ratio [OR], 4.31; 95% confidence interval [CI] 1.34-13.91) and 1 year (OR, 4.21; 95% CI, 1.45-12.28) in patients with ischemic stroke, as well as at 6 months (OR, 3.19; 95% CI, 1.17 8.70) and 1 year (OR, 3.30; 95% CI, 1.30-8.45) for all stroke patients. Other variables, including previous cardiovascular risk factors and acute medical care, did not change this association to a statistically significant degree. In conclusion, case fatality, particularly up to 6 months, was higher in hemorrhagic stroke, and lack of formal education was associated with increased stroke mortality. PMID- 21705234 TI - Overestimation of self-reported activities of daily living in vascular dementia patients with a right hemisphere lesion. AB - BACKGROUND: Several studies have analyzed the perception of activities of daily living (ADL) in stroke patients based on the discrepancy between scores given by the patients and their caregivers, and the results have been controversial. OBJECTIVE: The aim was to evaluate the discrepancy between self-rating of ADL in vascular dementia (VaD) patients and evaluation by caregivers. We hypothesized that patients with right hemisphere damage (RHD) would overrate themselves on the Barthel Index (BI) compared to those with left hemisphere damage (LHD). METHODS: Sixty VaD patients, including 30 each with damage to the left and right hemispheres, were studied. The BI was used to evaluate ADL. The self-rating BI score was based on an interview of the subjects. The difference between these score was used as a measure of overrating. RESULTS: The mean BI score for LHD patients was higher than that for RHD patients. Although there was no significant difference in the self-rated BI scores between the 2 groups, the difference between self-rated BI and BI was significantly larger in RHD patients: 6 patients had damage to the right insular cortex. Additional analysis for 7 RHD and 7 LHD patients by matching the BI and Mini-Mental State Examination scores disclosed that the difference remained larger in the RHD patients. CONCLUSIONS: RHD patients had a higher self-rating for their ADL scores compared to the rating given by caregivers. It is possible that the patients overrated their capability because they were unable to imagine risks such as a fall because of right insular damage. PMID- 21705235 TI - Anesthesia preparation time is not affected by the experience level of the resident involved during his/her first month of adult cardiac surgery. AB - OBJECTIVE: This study was designed to answer the question of whether the experience level of the resident on his/her first month of adult cardiothoracic anesthesiology has an impact on operating room efficiency in a large academic medical center. Traditionally, the resident's 1st month of cardiac anesthesia had been reserved for the clinical anesthesia (CA)-2 year of training. This study analyzed the impact on operating room efficiency of moving the 1st month of cardiac anesthesia into the CA-1 year. The authors hypothesized that there would be no difference in anesthesia preparation times (defined as the interval between "in-room" and "anesthesia-ready" times) between CA-1 and CA-2 residents on their 1st month of cardiac anesthesia. DESIGN: This study was retrospective and used an electronic anesthesia information management system database. SETTING: This study was conducted on care provided at a single 450-bed academic medical center. PARTICIPANTS: This study included 12 residents in their 1st month of cardiac anesthesia. INTERVENTIONS: The anesthesia preparation time (defined as the interval between "in-room" and "anesthesia-ready" times) was measured for cases involving residents on their first month of cardiac anesthesia. MEASUREMENTS AND MAIN RESULTS: Anesthesia preparation times for 6 CA-1 resident months and 6 CA-2 resident months (100 adult cardiac procedures in total) were analyzed (49 for the CA-1 residents and 51 for the CA-2s). There were no differences in preparation time between CA-1 and CA-2 residents as a group (p = 0.8169). The CA-1 residents had an unadjusted mean (+/-standard error) of 51.1 +/- 3.18 minutes, whereas the CA-2 residents' unadjusted mean was 50.2 +/- 2.41 minutes. Adjusting for case mix (valves v coronary artery bypass graft surgery), the CA-1 mean was 49.1 +/- 5.22 minutes, whereas the CA-2 mean was 49.1 +/- 4.54 minutes. CONCLUSIONS: These findings suggest that operating room efficiency as measured by the anesthesia preparation time may not be affected by the level of the resident on his/her 1st month of adult cardiac anesthesia. PMID- 21705236 TI - Acute pain management for video-assisted thoracoscopic surgery: an update. PMID- 21705237 TI - Principles of glenoid component design and strategies for managing glenoid bone loss in revision shoulder arthroplasty in the absence of infection and rotator cuff tear. PMID- 21705238 TI - Radius morphology and its effects on rotation with contoured and noncontoured plating of the proximal radius. AB - BACKGROUND: The radius has a sagittal bow and a coronal bow. Fractures are often treated with volar anterior plating. However, the sagittal bow is often overlooked when plating. This study looks at radial morphology and the effect of plating the proximal radius with straight plates and then contoured plates bowed in the sagittal plane. We report our findings and their effect on forearm rotation. MATERIALS AND METHODS: Morphology was investigated in 14 radii. Attention was paid to the proximal shaft of the radius and its sagittal bow; from this, 6-, 7-, and 8-hole plates were contoured to fit this bow. A simple transverse fracture was then made at the apex of this bow in 23 cadaver arms. Supination and pronation were compared when plating with a straight plate and a contoured plate. Ten cadavers underwent ulna plating at the same level. The effect on rotation of fractures plated in the distal-third shaft was also measured. RESULTS: A significant reduction in rotation was found when a proximal radius fracture was plated with a straight plate compared with a contoured plate: 10.8 degrees , 12.8 degrees , and 21.7 degrees for 6-, 7-, and 8-hole plates, respectively (P < .05). Forearm rotation was decreased further when a longer plate was used. Ulna or distal shaft plating did not reduce rotation. CONCLUSION: This study has shown a significant sagittal bow of the proximal shaft of the radius. Plating this with contoured plates in the sagittal plane improves rotation when compared with straight plates. Additional ulna plating is not a source of reduced forearm rotation. PMID- 21705240 TI - Letters to the editor. PMID- 21705241 TI - Trabecular quality and cellular characteristics of normal, diabetic, and charcot bone. AB - Charcot neuroarthropathy (CN) is a disabling and devastating condition that affects many neuropathic diabetic patients. It can lead to foot deformity, ulceration, and lower extremity amputation. The pathogenesis of CN is not clear, but 1 possible predisposing factor is increased bone turnover and increased osteoclastic activity. Although the affect of diabetes on bone is not entirely clear, studies have shown increased bone fragility in diabetics with neuropathy. The purpose of the present study was to compare the bone quality histologic findings and trabecular histomorphometry, including the cellular characteristics, between normal subjects (N = 7), diabetics without CN (N = 8), and diabetics with CN (N = 8). Histologically, the bone in diabetics with CN displayed an inflammatory, myxoid infiltrate. We also observed a statistically significant decrease in the number of trabeculae in bone in diabetics with CN compared with normal controls (p < .02). However, the difference between the trabeculae in diabetics with CN and diabetics without CN was not statistically significant (p > .05). Histologically, the CN bone appeared to be infiltrated with inflammatory myxoid tissue and had a disorganized trabecular pattern compared with diabetic bone without CN and normal bone. The trabeculae in patients with CN appeared to have poor quality characteristics compared with that of the other groups. The findings from the present study might indicate that diabetes mellitus bone is fragile, and the decrease in the cellular component might impair the reparative process in those with CN foot. PMID- 21705242 TI - Effect of repetitive loading on the mechanical properties of synthetic hernia repair materials. AB - BACKGROUND: Hernia repair materials undergo repeated loading while in the body, and the impact on mechanical properties is unknown. It was hypothesized that exposure to repetitive loading would lead to decreased tensile strength and increased strain, and that these differences would become more pronounced with greater loading and unloading sequences. STUDY DESIGN: Polypropylene, expanded polytetrafluoroethylene, composite barrier, and partially absorbable meshes were evaluated. Twenty specimens (7.5 * 7.5 cm) were prepared from each material. Five specimens were subjected to ball burst testing to determine baseline biomechanical properties. Cycles of 10, 100, and 1,000 loading sequences were also performed (n = 5 each). RESULTS: BardMesh (CR Bard/Davol), Dualmesh (WL Gore), and Prolene (Ethicon) exhibited significantly reduced tensile strength; BardMesh, Proceed (Ethicon), Prolene, ProLite (Atrium Medical), ProLite Ultra (Atrium Medical), and Ultrapro (Ethicon) exhibited significantly increased strain after exposure to 1,000 cycles compared with their baseline properties. BardMesh and Prolene demonstrated both reduced tensile strength and increased strain values after 1,000 cycles, suggesting that repetitive loading has the greatest effects on these materials. In addition, BardMesh and Prolene exhibited progressively worsening effects as the number of cycles was increased. CONCLUSIONS: Deterioration of the tensile strength of the mesh or an increase in the ability of the mesh material to stretch (ie, increased strain values) could potentially lead to hernia recurrence or a poor functional result. However, the results of this study should not be interpreted to mean that hernia repair materials will fail in the body after only 10, 100, or 1,000 cycles. The conditions used in this study were more extreme than most physiologic scenarios and were intended as a pilot investigation into how the mechanical properties of hernia repair materials are affected by in vitro cyclic testing. PMID- 21705243 TI - Gap coronoidotomy for management of coronoid process hyperplasia of the mandible. AB - Patients with coronoid process hyperplasia of the mandibular area are rare. The treatment of this disease is to increase the patient's mouth opening by surgery. There are various, but controversial, methods to treat it. We present a modified (gap) coronoidotomy procedure in detail and compare it with other conventional methods to treat coronoid process hyperplasia. PMID- 21705245 TI - Effective end-to-end repair of inferior alveolar nerve defect by using nerve sliding technique. AB - OBJECTIVE: The aim of this study was to introduce a new inferior alveolar nerve (IAN) defect repair method that does not require a nerve graft. STUDY DESIGN: The IAN was isolated after removal of a buccal cortical window. The scarred area or neuroma caused by the dental implant was excised with fresh cut ends and an epineural margin. If the excised gap was too wide for direct closure, the incisive nerve was intentionally transected 5 mm anterior to the mental foramen to obtain sufficient posterior mobilization of the distal stump of the IAN. The nerve ends were then approximated directly by sliding the distal nerve end to the proximal cut end. After completing the nerve repair by using four 10-0 nylon epineural sutures, the cortical window was repositioned with a microplate and screws. RESULTS: Using this technique, 3 nerve repairs without a nerve graft were successfully achieved for gaps ~10 mm in size. CONCLUSIONS: The great advantage of this technique is that a moderate nerve defect can be anastomosed without a nerve graft when direct closure of the nerve segment is impossible without tension. PMID- 21705246 TI - Is adherence to pain self-management strategies associated with improved pain, depression and disability in those with disabling chronic pain? AB - There is generally good evidence that pain management interventions that include self-management strategies can substantially reduce disability and improve psychological well-being in patients with chronic pain. Reductions in unhelpful responses, especially catastrophising and fear-avoidance beliefs, have been established as key contributors to these gains. In contrast, there is surprisingly little evidence that adherence to self-management strategies contributes to achieving these outcomes. Difficulties in defining and measuring the use of pain self-management strategies have been obstacles for this research. Using a pragmatic way of assessing the practice of specific strategies this study investigated their ability to account for changes in pain, disability and depressive symptoms after a 3-week cognitive-behavioural pain management program. The post-treatment outcomes on these dimensions were found to be statistically and, for many, clinically significant. Consistent with previous research, reductions in catastrophising and fear-avoidance beliefs, and increased pain self efficacy beliefs, were also associated with these gains. But the key new finding was that there was a clear gradient between adherence to specific self-management strategies and reductions in pain, disability and depressive symptoms. Furthermore, adherence to the self-management strategies was predictive of better outcomes even after controlling for the moderating effects of initial catastrophising, fear-avoidance and pain self-efficacy beliefs. PMID- 21705247 TI - The influence of maternal vulnerability and parenting stress on chronic pain in adolescents in a general population sample: the TRAILS study. AB - Investigating possible psychosocial predictors of unexplained chronic pain in adolescents is crucial in understanding its development and prevention. A general population sample of adolescents (n = 2230) from the TRAILS cohort study was investigated longitudinally to assess the influence of maternal vulnerability, in terms of anxiety, depression and stress, and parenting stress at age 10-12 years, on the presence of chronic pain at age 12-15 years. Of these adolescents, 269 (12.9%) reported experiencing chronic pain, of which 77% reported severe chronic pain and 22% reported multiple chronic pain. Maternal anxiety, maternal stress and higher levels of parenting stress were related to chronic pain at a later age. Subgroup analyses showed similar results for adolescents with severe chronic pain. Mediation analyses indicated that parenting stress mediates the effect between maternal anxiety, or stress, and chronic pain. The findings suggest that interventions to diminish maternal feelings of anxiety and stress, while in turn adjusting maternal behaviour, may prevent the development of chronic pain in adolescence. PMID- 21705250 TI - ImatraNMR: novel software for batch integration and analysis of quantitative NMR spectra. AB - Quantitative NMR spectroscopy is a useful and important tool for analysis of various mixtures. Recently, in addition of traditional quantitative 1D (1)H and (13)C NMR methods, a variety of pulse sequences aimed for quantitative or semiquantitative analysis have been developed. To obtain actual usable results from quantitative spectra, they must be processed and analyzed with suitable software. Currently, there are many processing packages available from spectrometer manufacturers and third party developers, and most of them are capable of analyzing and integration of quantitative spectra. However, they are mainly aimed for processing single or few spectra, and are slow and difficult to use when large numbers of spectra and signals are being analyzed, even when using pre-saved integration areas or custom scripting features. In this article, we present a novel software, ImatraNMR, designed for batch analysis of quantitative spectra. In addition to capability of analyzing large number of spectra, it provides results in text and CSV formats, allowing further data-analysis using spreadsheet programs or general analysis programs, such as Matlab. The software is written with Java, and thus it should run in any platform capable of providing Java Runtime Environment version 1.6 or newer, however, currently it has only been tested with Windows and Linux (Ubuntu 10.04). The software is free for non commercial use, and is provided with source code upon request. PMID- 21705251 TI - Selective inner retinal dysfunction in growth hormone transgenic mice. AB - OBJECTIVE: The discovery of locally produced growth hormone (GH) and its receptor in the retina of rodents raises the possibility that GH might modulate retinal function. To test this hypothesis, we determined the retinal electroretinogram (ERG) of bovine GH (bGH) transgenic mice. DESIGN: ERGs were recorded from 11 wild type (WT) and 9 bGH mice, at 2 months of age in response to a series of light flashes at increasing intensity. Three ERG components were assessed for their amplitude and timing: a-wave, b-wave and oscillatory potentials (OPs). OPs were isolated with a 75-300 Hz digital filter. Retina layer sizes, nuclei number and vascularization were assessed by respectively staining cross sections with DAPI and Bandeiraea simplicifolia. RESULTS: OPs were selectively affected in the bGH mouse compared to WT. When OP amplitude values were normalized to the a-wave amplitude (to account for inter-animal variability in WT and bGH groups), OP2, OP3, and OP4 showed amplitude reductions (of 65%, 72%, and 68%, respectively) in the bGH mouse compared to the WT. This was accompanied by a prolongation of the implicit time for the peak of OP3 (28.1 vs 31.1 ms, WT vs bGH) and OP4 (37.8 vs 41.6 ms), while the implicit time of a- and b-waves were unaffected. Fast Fourier transform analysis revealed that the OPs' dominant frequency was significantly reduced (P<0.05) in the bGH mice (100 Hz) compared to WT (108Hz). There was no significant change in retinal histology except for a significant increase in the axial length of the eye in bGH mice. CONCLUSIONS: Mice expressing bGH display a selective inner retinal defect as demonstrated using ERG recordings. The specific OP defect observed in these mice is similar to the ERG results obtained in patients with diabetic retinopathy and in related animal models. PMID- 21705252 TI - [Development of Candida parapsilosis candidemia during caspofungin therapy]. PMID- 21705253 TI - The future of microbicides. AB - There is an urgent need to develop vaginal microbicides to empower women to better control their own sexual life and to protect themselves against HIV and other sexually transmitted infections (STIs). Prevention of STIs with its 330 million cases a year would have a great global health impact. Because of their anatomy, women are up to 8 times more susceptible than men to STIs including HIV. Women who can't negotiate condom use with their male partners have no means of protecting themselves from these infections. In the last few years, especially after the recent failures of several microbicides in Phase III trials, there was increasing pressure from those favoring the use of a more targeted approach to introduce marketed antiretroviral drugs (ARVs) into microbicides. This Pre Exposure Prophylaxis (PrEP) concept which targets only HIV using specific ARVs contrasts with the primary approach of broad spectrum microbicides which aimed at offering universal protection against several sexually transmitted pathogens. However, before using ARVs as PrEP for HIV prevention, there are still many important issues to consider. In this article, we compare both strategies, while reviewing the last 15 years of microbicide research and its future. PMID- 21705254 TI - Scoliosis secondary to a rib haemangioma. PMID- 21705255 TI - Ultrasound-assisted synthesis of aromatic 1,2-diketones from oximinoketones under neutral conditions in aqueous media. AB - We report a convenient, neutral, and facile methodology for the synthesis of aromatic 1,2-diketones from the corresponding oximinoketones in the presence of I2/SDS/water system under ultrasound-assisted conditions. Furthermore, a series of compounds were synthesized and characterized by melting point, IR, NMR, MS, and elemental analysis. Utilization of easy reaction conditions, very high to excellent yields, and short reaction times makes this manipulation potentially very useful. PMID- 21705256 TI - Acoustic emission spectra and sonochemical activity in a 36 kHz sonoreactor. AB - During ultrasound-induced cavitation in liquids, acoustic emissions at fundamental and harmonic frequencies can be detected. The effect of acoustic emissions at harmonic frequencies on the sonochemical and sonophysical activities has not been explored, especially in large-scale sonoreactors. In this study, the acoustic emissions in the range, 0-250 kHz in a 36 kHz sonoreactor with varying liquid heights were studied and compared with the sonochemical activities. The acoustic pressures at both fundamental and harmonics decreased drastically as the liquid height was increased due to the attenuation of sound energy. It was observed that the increase in input power resulted in only an increase in the acoustic emissions at derivative frequencies such as, harmonics and subharmonics. The sonochemical activity, evaluated in terms of sonochemiluminescence and H2O2 yield, was not significantly enhanced at higher input power levels. This suggests that at higher power levels, the "extra" acoustic energy is not effectively used to generate primary cavitation activity; rather it is converted to generate acoustic emissions at harmonic and subharmonic frequencies. This is an important observation for the design of energy efficiency large-scale sonochemical reactors. PMID- 21705257 TI - The effect of motion patterns on edge-loading of metal-on-metal hip resurfacing. AB - The occurrence of pseudotumours (soft tissue masses relating to the hip joint) following metal-on-metal hip resurfacing arthroplasty (MoMHRA) has been associated with high serum metal ion levels and consequently higher than normal bearing wear. We investigated the relationship between serum metal ion levels and contact stress on the acetabular component of MoMHRA patients for two functional activities; gait and stair descent. Four subjects with MoMHRA, who had their serum metal ion levels measured, underwent motion analysis followed by CT scanning. Their motion capture data was combined with published hip contact forces and finite element models representing 14% (peak force) and 60% (end of stance) of the gait cycle and 52% (peak force) of stair descent activity were created. The inclination angle of the acetabular component was increased by 10 degrees in 1 degrees intervals and the contact stresses were determined at each interval for each subject. When the inclination angle was altered in such a way as to cause the hip contact force to pass through the edge of the acetabular component edge-loading occurred. Edge-loading increased the contact stress by at least 50%; the maximum increase was 108%. Patients with low serum metal ion levels showed no increase in contact stress at peak force during gait or stair descent. Patients with high serum metal ion levels exhibited edge-loading with an increase to the inclination angle of their acetabular components. The increase in inclination angle that induced edge-loading for these subjects was less than the inter-subject variability in the angle of published hip contact forces. The results of this study suggest that high serum metal ion levels are the result of inclination angle influenced edge-loading but that edge-loading cannot be attributed to inclination angle alone and that an individual's activity patterns can reduce or even override the influence of a steep acetabular component and prevent edge-loading. PMID- 21705258 TI - Impulse control disorders in Chinese Parkinson's disease patients: the effect of ergot derived dopamine agonist. AB - OBJECTIVE: We studied the prevalence and related risk factors of impulse control disorders in Chinese Parkinson's disease patients. METHOD: We screened all non demented Parkinson's disease patients attending our Parkinson's disease clinic from August 2009 to March 2010. The clinical characteristics of patients with impulse control disorders and those without were compared. RESULTS: Of the 213 PD subjects screened, 15 (7.0%) with impulse control disorders were identified. Fourteen of these subjects were on both a dopamine agonist and Levodopa, and one was on Levodopa alone. Of the fourteen subjects on both a dopamine agonist and Levodopa, eleven were on bromocriptine and Levodopa; 10.5% of the subjects exposed to bromocriptine had impulse control disorder. Upon multivariate analysis, dose of dopamine agonist used, young age at onset of Parkinson's disease and a history of anxiety or depression were independent predictors for developing impulse control disorders. CONCLUSIONS: 7% of our Chinese PD subjects had impulse control disorders. When young Parkinson's disease patients with a history of anxiety or depression are treated with high dose of DA, they are at risk of developing impulse control disorders. PMID- 21705259 TI - Levodopa ameliorated anorectal constipation in de novo Parkinson's disease: The QL-GAT study. AB - BACKGROUND: Gastrointestinal tract (GIT) dysfunction is common in Parkinson's disease (PD) patients. However, it remains unclear whether levodopa affects GIT function in PD. OBJECTIVE: To perform an open study of levodopa's effects on anorectal constipation in de novo PD patients by the quantitative lower gastrointestinal autonomic test (QL-GAT). METHODS: Nineteen unselected de novo PD patients (10 men, 9 women; mean age, 66 years; mean duration of the disease, 2.2 years) were recruited for the study. Eighteen of the patients reported constipation. These patients were treated with 200/20 mg b.i.d. of levodopa/carbidopa for 3 months. Pre- and post-treatment, objective parameters in the QL-GAT that comprised the colonic transit time (CTT) and rectoanal videomanometry were obtained. RESULTS: Levodopa was well tolerated by all patients. There was a trend toward subjective improvements in bowel frequency and difficulty defecating. Levodopa did not significantly change CTT of the total colon or any segment of the colon. During rectal filling, levodopa significantly lessened the first sensation (p < 0.05). It also tended to augment the amplitude of spontaneous phasic rectal contraction (not statistically significant). During defecation, levodopa significantly lessened the amplitude in paradoxical sphincter contraction upon defecation (PSD) (p < 0.01). It also tended to augment the amplitude of rectal contraction and lessen the amplitude of abdominal strain (not statistically significant). Overall, levodopa significantly lessened post defecation residuals (p < 0.05). CONCLUSIONS: The QL-GAT in the present study showed for the first time that levodopa augmented rectal contraction, lessened PSD, and thereby ameliorated anorectal constipation in de novo PD patients. PMID- 21705260 TI - Effects of passive correction of scapular position on pain, proprioception, and range of motion in neck-pain patients with bilateral scapular downward-rotation syndrome. AB - The effects of passive correction of scapular position (PCSPT) on pain, proprioception, and range of motion (ROM) were investigated in neck-pain patients with bilateral scapular downward-rotation (SDR). Fifteen neck-pain patients with bilateral SDR were recruited from a workplace based work-conditioning center. The intensity of pain felt was quantified using a visual analogue scale. Kinematic data for ROM and joint-position error (JPE) were analyzed using a 3-dimensional motion-analysis system. Differences in pain, JPE, and ROM with and without PCSPT were assessed using a paired t-test. PCSPT significantly decreased JPE and neck pain during active neck rotation and significantly increased neck-rotation ROM (p < 0.05). These findings suggest that PCSPT results in decreased neck pain and improved neck-rotation ROM and proprioception during active neck rotation in neck pain patients with bilateral SDR. PMID- 21705261 TI - Pain neurophysiology education for the management of individuals with chronic low back pain: systematic review and meta-analysis. AB - Pain neurophysiology education (PNE) is a form of education for patients with chronic low back pain (CLBP). The purpose of this systematic review was to investigate the evidence for PNE in the management of pateints with CLBP. A literature search of MEDLINE, CINAHL and AMED was performed from 1996(01) 2010(09). RCT appraisal and synthesis was assessed using the Cochrane Back Review Group (CBRG) guidelines. The main outcome measures were pain, physical-function, psychological-function, and social-function. Two moderate quality RCTs (n=122) were included in the final review. According to the CBRG criteria there was very low quality evidence that PNE is beneficial for pain, physical-function, psychological-function, and social-function. Meta-analysis found PNE produced statistically significant but clinically small improvements in short-term pain of 5mm (0, 10.0mm) [mean difference (95%CI)] on the 100mm VAS. This review was limited by the small number of studies (n=2) that met the inclusion criteria and by the fact that both studies were produced by the same group that published the PNE manual. These factors contributed to the relatively low grading of the evidence. There is a need for more studies investigating PNE by different research groups to support early promising findings. Until then firm clinical recommendations cannot be made. PMID- 21705262 TI - (12)C/(13)C fractionations in plant primary metabolism. AB - Natural (13)C abundance is now an unavoidable tool to study ecosystem and plant carbon economies. A growing number of studies take advantage of isotopic fractionation between carbon pools or (13)C abundance in respiratory CO(2) to examine the carbon source of respiration, plant biomass production or organic matter sequestration in soils. (12)C/(13)C isotope effects associated with plant metabolism are thus essential to understand natural isotopic signals. However, isotope effects of enzymes do not influence metabolites separately, but combine to yield a (12)C/(13)C isotopologue redistribution orchestrated by metabolic flux patterns. In this review, we summarise key metabolic isotope effects and integrate them into the corpus of plant primary carbon metabolism. PMID- 21705263 TI - Prostate biopsy tracking with deformation estimation. AB - Transrectal biopsies under 2D ultrasound (US) control are the current clinical standard for prostate cancer diagnosis. The isoechogenic nature of prostate carcinoma makes it necessary to sample the gland systematically, resulting in a low sensitivity. Also, it is difficult for the clinician to follow the sampling protocol accurately under 2D US control and the exact anatomical location of the biopsy cores is unknown after the intervention. Tracking systems for prostate biopsies make it possible to generate biopsy distribution maps for intra- and post-interventional quality control and 3D visualisation of histological results for diagnosis and treatment planning. They can also guide the clinician toward non-ultrasound targets. In this paper, a volume-swept 3D US based tracking system for fast and accurate estimation of prostate tissue motion is proposed. The entirely image-based system solves the patient motion problem with an a priori model of rectal probe kinematics. Prostate deformations are estimated with elastic registration to maximize accuracy. The system is robust with only 17 registration failures out of 786 (2%) biopsy volumes acquired from 47 patients during biopsy sessions. Accuracy was evaluated to 0.76+/-0.52 mm using manually segmented fiducials on 687 registered volumes stemming from 40 patients. A clinical protocol for assisted biopsy acquisition was designed and implemented as a biopsy assistance system, which allows to overcome the draw-backs of the standard biopsy procedure. PMID- 21705264 TI - Max-flow segmentation of the left ventricle by recovering subject-specific distributions via a bound of the Bhattacharyya measure. AB - This study investigates fast detection of the left ventricle (LV) endo- and epicardium boundaries in a cardiac magnetic resonance (MR) sequence following the optimization of two original discrete cost functions, each containing global intensity and geometry constraints based on the Bhattacharyya similarity. The cost functions and the corresponding max-flow optimization built upon an original bound of the Bhattacharyya measure yield competitive results in nearly real-time. Within each frame, the algorithm seeks the LV cavity and myocardium regions consistent with subject-specific model distributions learned from the first frame in the sequence. Based on global rather than pixel-wise information, the proposed formulation relaxes the need of a large training set and optimization with respect to geometric transformations. Different from related active contour methods, it does not require a large number of iterative updates of the segmentation and the corresponding computationally onerous kernel density estimates (KDEs). The algorithm requires very few iterations and KDEs to converge. Furthermore, the proposed bound can be used for several other applications and, therefore, can lead to segmentation algorithms which share the flexibility of active contours and computational advantages of max-flow optimization. Quantitative evaluations over 2280 images acquired from 20 subjects demonstrated that the results correlate well with independent manual segmentations by an expert. Moreover, comparisons with a related recent active contour method showed that the proposed framework brings significant improvements in regard to accuracy and computational efficiency. PMID- 21705265 TI - A preliminary spectroscopic investigation on the molecular interaction of metal diphenylthiocarbazone complex with cellulose biopolymer and its application. AB - Biopolymer adsorbents are versatile in their application for removal of heavy metals. The present work is focused towards the preliminary study of the interaction of diphenylthiocarbazone (DTZ) complex of chromium(VI) in acidic medium with cellulose biopolymer. Chromium-DTZ complex could be quantitatively adsorbed on a cellulose column in the pH range 1.0-2.5 and the effect of various experimental parameters such as stability of the column and the complex, column breakthrough volume, and interfering ions have been studied in detail. The probable mechanism of adsorption of complex on the cellulose biopolymer was corroborated using Fourier transform infra-red spectroscopy (FT-IR), scanning electron microscopy (SEM), energy dispersive X-ray (EDX) and solid state 13C nuclear magnetic resonance techniques (CP-MAS). The pores formed due to the hydrogen bond between the cellulose layers and then the ensuing occupation of the complex between these layers and on the surface of the biopolymer layer through electrostatic attractive force and Pi interaction of aromatic ring with cellulose are expected to play a vital role in the interaction. The cellulose column could be regenerated using environmentally benign polyethylene glycol-400 (PEG-400) in acidic medium. The cellulose biosorbent has been successfully tested to study the removal of chromium as its dithizone complex from synthetic and real waste water samples. PMID- 21705266 TI - Nephelauxetic effect of low phonon antimony oxide glass in absorption and photoluminescence of rare-earth ions. AB - An antimony oxide based monolithic glass with very high Sb2O3 content (70 mol%) in the system K2O-B2O3-Sb2O3 (KBS) has been prepared for the first time. Its phonon energy (602 cm(-1)), evaluated by infrared reflection spectroscopy, is found to be very close to that of fluoride glasses (500-600 cm(-1)). After doping with different rare-earth ions, their UV-vis absorption and photoluminescence properties have been explored, compared with those observed in other hosts and justified with quantitative calculation of nephelauxetic parameter and covalent bonding characteristics. It is been proposed that tunable laser or new color visible light sources may be obtained by controlling these fundamental properties of the glass host. The results also suggest that KBS glass may be used as hosts in the place of fluoride glasses. The Judd-Ofelt parameters, Omegat=2,4,6 for Nd3+, Ho3+, and Er3+ doped in KBS glass have been evaluated and compared with other glasses. It is established that Omegat=2 value follow a direct relationship with covalent character of the hosts which not only supports the above calculation but also provides a generalized evidence for the sensitivity of this parameter to their bonding characteristics. PMID- 21705267 TI - Synthesis, spectral characterization, solution equilibria, in vitro antibacterial and cytotoxic activities of Cu(II), Ni(II), Mn(II), Co(II) and Zn(II) complexes with Schiff base derived from 5-bromosalicylaldehyde and 2-aminomethylthiophene. AB - Schiff base namely 2-aminomethylthiophenyl-4-bromosalicylaldehyde (ATS)(4-bromo-2 (thiophen-2-yl-imino)methylphenol) and its metal complexes have been synthesized and characterized by elemental analyses, IR, 1H NMR, solid reflectance, magnetic moment, molar conductance, mass spectra, ESR and thermal analysis (TGA). The analytical data of the complexes show the formation of 1:2 [M:L] ratio of the formula [ML2], where M represents Ni(II), Zn(II) and Cu(II) ions, while L represents the deprotonated Schiff base. IR spectra show that ATS is coordinated to the metal ions in a bidentate manner through azomethine-N and phenolic-oxygen groups. The ligand and their metal chelates have been screened for their antimicrobial activities using the disc diffusion method against the selected bacteria. A cytotoxicity of the compounds against colon (HCT116) and larynx (HEP2) cancer cells have been studied. Protonation constants of (ATS) ligand and stability constants of its Cu2+, Co2+, Mn2+, Zn2+ and Ni2+ complexes were determined by potentiometric titration method in 50% (v/v) DMSO-water solution at ionic strength of 0.1 M NaNO3. PMID- 21705268 TI - WU and KI polyomavirus infections in pediatric hematology/oncology patients with acute respiratory tract illness. AB - BACKGROUND: WU and KI polyomaviruses (PyV) were discovered in 2007 in respiratory tract samples in adults and children. Other polyomaviruses (BKPyV and JCPyV) have been associated with illness in immunocompromised patients, and some studies suggest a higher prevalence of WUPyV and KIPyV in this population. OBJECTIVE: To determine whether a higher prevalence or viral load for WUPyV and KIPyV exists in immunocompromised children compared with immunocompetent children. STUDY DESIGN: We measured the prevalence and viral load of WU and KI PyV by quantitative real time PCR of viral DNA in respiratory tract specimens from pediatric hematology/oncology patients and immunocompetent controls with acute respiratory illnesses. RESULTS: The prevalence of WUPyV in the immunocompromised population was 5/161 (3%) versus 14/295 (5%) in the control population (P=0.5), and 9/161 (5.6%) versus 7/295 (2.3%) respectively for KIPyV (P=0.13). The mean viral load (in copies per cell or mL of sample) for KIPyV, was higher in the immunocompromised group compared to the control group (P=0.019), but was not statistically different for WUPyV. A higher prevalence was seen in the hematopoietic stem cell transplant recipients compared with other immunocompromised patients (6/26 versus 3/43, P=0.054). Viral persistence was demonstrated only in 1/25 (4%) of sequential samples for KIPyV, and no persistence was seen for WUPyV. CONCLUSIONS: A higher prevalence of WUPyV or KIPyV in the immunocompromised population compared with the immunocompetent group was not demonstrated. Higher viral loads for KIPyV in the immunocompromised group may suggest an increased pathogenic potential in this population. PMID- 21705269 TI - Automated artifact removal as preprocessing refines neonatal seizure detection. AB - OBJECTIVE: The description and evaluation of algorithms using Independent Component Analysis (ICA) for automatic removal of ECG, pulsation and respiration artifacts in neonatal EEG before automated seizure detection. METHODS: The developed algorithms decompose the EEG using ICA into its underlying sources. The artifact source was identified using the simultaneously recorded polygraphy signals after preprocessing. The EEG was reconstructed without the corrupting source, leading to a clean EEG. The impact of the artifact removal was measured by comparing the performance of a previously developed seizure detector before and after the artifact removal in 13 selected patients (9 having artifact contaminated and 4 having artifact-free EEGs). RESULTS: A significant decrease in false alarms (p=0.01) was found while the Good Detection Rate (GDR) for seizures was not altered (p=0.50). CONCLUSIONS: The techniques reduced the number of false positive detections without lowering sensitivity and are beneficial in long term EEG seizure monitoring in the presence of disturbing biological artifacts. SIGNIFICANCE: The proposed algorithms improve neonatal seizure monitoring. PMID- 21705270 TI - Decremental responses to repetitive nerve stimulation (RNS) in motor neuron disease. AB - OBJECTIVE: To clarify the features of decremental responses following repetitive nerve stimulation in patients with motor neuron diseases (MNDs), in comparison with myasthenia gravis (MG). METHODS: The subjects consisted of 48 MND, 39 generalized MG and 19 ocular MG patients. Six muscles, both proximal and distal muscles, were tested. RESULTS: Significant decrements (>5%) in at least one muscle were observed in 83% of the MND patients, and 74% and 47% of the generalized MG and ocular MG patients, respectively. Decrements were more frequently observed in the proximal muscles both in MND and MG patients (deltoid 76% and 62%, and trapezius 71% and 51% for MND and generalized MG, respectively), suggesting lower safety factors in neuromuscular transmission in those muscles. Decrements in the nasalis were rare in MND (8%) in comparison with generalized MG (54%). CONCLUSIONS: Decremental responses were frequently observed in MND patients. There were small differences between MND and MG regarding the distribution and other features of decrements, such as the degree of the U-shape or the responses to different stimulus frequencies and to brief exercise. SIGNIFICANCE: These results imply that the underlying mechanism regulating the decrements is common to MND and MG. PMID- 21705271 TI - Emulsion culture: a miniaturized library screening system based on micro-droplets in an emulsified medium. AB - A typical library screen in directed evolution primarily requires physical separation of the clones on agar plates followed by detection of clones with improved properties; using this method only limited numbers of clones relative to the number of potential variations can be assessed. In particular, screening for a secretory enzyme is difficult to perform at high clone density, because of diffusion of the signal or unfavorable utilization of the reaction product by neighboring clones. In this study, we have developed a novel method of enrichment culture: "Emulsion Culture", i.e., segregated replication of clones in an emulsified culture medium. Clones expressing enzyme-variants are separately distributed to small (up to 50 MUm in diameter), segregated compartments composed of a droplet of medium to form several tens of millions of microcolonies in a milliliter of medium, which allows a miniaturized, in-bulk screening of clones. We applied this culture method to yeast clones expressing secretory beta galactosidase to analyze the enrichment factor achieved. A high-density screen for a signal peptide sequence that maximizes extracellular production of the enzyme was also performed to demonstrate the practicability of this culture method. In addition, micro-channel emulsification was tested as a method of forming uniformly-sized compartments in the emulsion. PMID- 21705272 TI - Targeting peripheral afferent nerve terminals for cough and dyspnea. AB - Chronic unproductive coughing and dyspnea are symptoms that severely diminish the quality of life in a substantial proportion of the population. There are presently few if any drugs that effectively treat these symptoms. Rational drug targets for cough and dyspnea have emerged over the recent years based on developments in our understanding of the innervation of the respiratory tract. These drug targets can be subcategorized into those that target the vagal afferent nerve endings, and those that target neural activity within the CNS. This review focuses on targets presumed to be in the peripheral terminals of afferent nerves within the airways. Conceptually, the activity of peripheral afferent nerves involved with unwanted urge-to-cough or dyspnea sensations can be inhibited by limiting the intensity of the stimulus, inhibiting the amplitude of the stimulus-induced generator potential, or inhibiting the transduction between the generator potential and action potential discharge and conduction. These mechanisms reveal many therapeutic strategies for anti-tussive and anti-dyspnea drug development with peripheral sites of action. PMID- 21705273 TI - Long-term safety and efficacy of rotigotine transdermal patch for moderate-to severe idiopathic restless legs syndrome: a 5-year open-label extension study. AB - BACKGROUND: Safety and efficacy of non-ergot dopamine agonists for the treatment of idiopathic restless legs syndrome have been shown in short-term trials. We did a prospective open-label extension of a 6-week, double-blind randomised trial to assess the safety, tolerability, and efficacy of rotigotine transdermal patch for up to 5 years in patients with restless legs syndrome. METHODS: Patients (aged 18 75 years) with moderate-to-severe idiopathic restless legs syndrome were treated with once-daily rotigotine transdermal patch in 33 centres in Austria, Germany, and Spain between July 31, 2003, and April 15, 2009. The dose was titrated in weekly increments (up to 4 weeks) from 0.5 mg/24 h to a maximum of 4 mg/24 h, and was followed by up to 5 years of maintenance at the optimum dose. Primary safety outcomes included occurrence of adverse events and dropouts. Efficacy assessments were secondary and included the International Restless Legs Syndrome study group severity rating scale (IRLS). Augmentation of symptoms was assessed by means of standard diagnostic criteria and was confirmed by an international expert panel. All patients who received at least one dose of study drug were included in assessments. This study is registered with ClinicalTrials.gov, number NCT00498186. FINDINGS: 295 patients entered the open-label study, of whom 126 (43%) completed 5 years of follow-up. 169 (57%) patients discontinued treatment, 89 (30%) because of adverse events and 31 (11%) because of lack of efficacy. 70 patients (24%) discontinued during year 1 of maintenance. The most common adverse events were application site reactions, which occurred in 37% (106/290) of patients in year 1, 17% (38/220) of patients in year 2, 14% (27/191) of patients in year 3, and in less than 6% of patients during year 4 (8/159) and year 5 (8/147). 56 patients (19%) discontinued because of application site reactions. Mean rotigotine dose was 2.43 mg/24 h (SD 1.21) after initial titration and 3.09 mg/24 h (1.07) at the end of maintenance. Of 89 patients who discontinued because of adverse events, 28 (31%) were on 4 mg/24 h rotigotine. Mean IRLS score of patients entering the open-label study was 27.8 (SD 5.9) at baseline of the double-blind trial. In patients who completed the maintenance period, mean IRLS score was reduced from a baseline score of 27.7 (SD 6.0) by a mean of 18.7 points (SD 9.5) to a score of 9.0 (SD 9.2) at the end of maintenance. 39% (48/123) of patients who completed the trial were classified as symptom free according to the IRLS. Clinically significant augmentation was recorded in 39 patients (13%), of whom 15 (5%) were receiving a dose of rotigotine within the range approved by the European Medicines Agency (EMA; 1-3 mg/24 h) and 24 (8%) were receiving 4 mg/24 h rotigotine. INTERPRETATION: Rotigotine transdermal patch is generally well tolerated after 1 year and provides sustained efficacy for patients with moderate to-severe restless legs syndrome at a stable dose for up to 5 years. Thus, rotigotine transdermal patch is an appropriate long-term treatment option for moderate-to-severe restless legs syndrome, a disorder that often requires lifelong treatment. FUNDING: UCB BioSciences, on behalf of Schwarz Pharma, Ireland. PMID- 21705274 TI - Another dopamine agonist for treatment of restless legs syndrome. PMID- 21705275 TI - Balanitis xerotica obliterans in children and its incidence under the age of 5 years. AB - OBJECTIVE: To analyse the incidence of BXO among paediatric circumcisions for preputial pathology, in particular in children under the age of 5 years. METHODS: Retrospective review revealed 1769 paediatric circumcisions performed between 1997 and 2008 at our institution. Data were collected on patient's age, date when sample received by pathology department and histological findings for all the foreskin samples received and examined during the study period. Epidemiological data were obtained from the Office for National Statistics, UK. RESULTS: A total of 346 foreskin samples were received and BXO was found in 182 (52.6%). There were 31 children under the age of 5 years circumcised for preputial pathology. BXO was reported in 6 (19.3%) and chronic inflammation in 16 (51.6%) of these patients. The foreskin was reported normal in 2 (6.5%) and the remaining 7 (22.6%) patients had preputial cysts or other pathology. Epidemiological population data analysis revealed the incidence of BXO per year to be 3.01 cases/1000 boys under 15 years of age and 0.322 cases/1000 boys under 5 years. CONCLUSION: The incidence of BXO in boys noted in our study is higher than previously reported. BXO can result in significant complications and should be considered in children even under 5 years. PMID- 21705277 TI - Efficacy and safety of Hizentra((r)) in patients with primary immunodeficiency after a dose-equivalent switch from intravenous or subcutaneous replacement therapy. AB - A prospective, open-label, multicenter, single-arm, Phase III study evaluated the efficacy and safety of Hizentra((r)), a 20% human IgG for subcutaneous administration, in 51 primary immunodeficiency patients over 40 weeks. Patients previously on intravenous or subcutaneous IgG were switched to weekly subcutaneous infusions of Hizentra((r)) at doses equivalent to their previous treatment. IgG levels achieved with Hizentra((r)) were similar to pre-study levels with subcutaneous, and higher by 17.7% than pre-study levels with intravenous IgG. No serious bacterial infections were reported in the efficacy period. The rate of all infections was 5.18/year/patient, the rates of days missed from work/school, and days spent in hospital were 8.00/year/patient and 3.48/year/patient, respectively. Local reactions (rate 0.060/infusion) were mostly mild (87.3%). No serious, Hizentra((r))-related adverse events were reported. Individual median infusion durations ranged between 1.14 and 1.27 h. Hizentra((r)) maintained or improved serum IgG levels without dose increases and effectively protected patients against infections. PMID- 21705276 TI - Assessment of dietary intakes of Filipino-Americans: implications for food frequency questionnaire design. AB - OBJECTIVE: The purpose of this study was to describe food consumption practices of Filipino-American adults, to describe how they respond to a food frequency questionnaire (FFQ) as a function of acculturation and sex, and to suggest modifications to the FFQ to improve dietary assessment among Filipino-Americans. METHODS: Twenty-one Filipino-American women and 14 Filipino-American men (aged 30 60 years) who varied on acculturation level were recruited from the general community of San Diego, California. Participants completed a focus group and rated the Fred Hutchinson Food Frequency Questionnaire. RESULTS: The most commonly eaten food items among Filipino-Americans were white rice, fish or meat, vegetables, and fruit. Most (76%) participants reported that the Fred Hutchinson Food Frequency Questionnaire lacked commonly eaten Filipino-American food. CONCLUSIONS AND IMPLICATIONS: Commonly consumed food, such as adobo, lumpia, and pansit, might be added to a revised FFQ; doing so may improve recall and face validity among Filipino-Americans. PMID- 21705278 TI - Myths, misconceptions, and misunderstandings about epilepsy in a Nigerian rural community: implications for community health interventions. AB - Face-to-face interviews were conducted with 365 persons without epilepsy. Seventy four (12%) attributed epilepsy to brain disorder, witchcraft (81.4%), destiny (49.8%), heredity (27.8%), and demonic possession (26.8%). Beliefs about modes of spread included saliva (28.8%), sharing utensils (19.5%), and making fun of a person with epilepsy (12.1%). Traditional medicine was the first preferred treatment option in 80.5% of participants; treatment approaches included herbal preparations (67.7%), spiritual exorcism (33.7%), special cultural diets (29.3%), charms (26.2%), and sacrificial offerings (24.1%). Reasons for preferring traditional treatment included the health facility being too far (86.1%), health personnel not being readily available (83%), and epileptic drugs not being readily available (79.6%). Incorrect local perceptions and cultural beliefs about epilepsy and inadequacies of the modern health care systems in developing countries might jointly contribute to the treatment gap. Local health staff, if appropriately strengthened, could take on additional tasks and bridge the treatment gap. Collaboration between modern and traditional health care systems may also improve treatment accessibility. PMID- 21705279 TI - Psychosocial issues for children with epilepsy. AB - Epilepsy is a pervasive disorder that consists not only of seizures, but of behavioral, academic, and social difficulties. Epilepsy has an impact on the entire family and may have a significant effect on the interrelationships between child and parent. Epilepsy also has a potentially deleterious effect on academic functioning that may be the result of central nervous system dysfunction, seizures, antiepileptic drugs, or child and family response to illness. Early assessment for psychosocial problems and appropriate interventions can be beneficial for the child and family. Particular attention should be paid to periods of transition such as the move from adolescence to adulthood. PMID- 21705280 TI - Developmental outcome after a single episode of status epilepticus. AB - Consequences of status epilepticus (SE) on psychomotor development and the specific impact of the convulsive event on emerging executive functions remain controversial. Infants treated for a single episode of SE, those treated for a single febrile seizure, and healthy infants were tested with respect to motor development, language, personal, and social skills and self-regulation. The children were divided into two age groups to investigate the impact of the convulsive event at different windows of brain maturation. We found that infants who had had SE were inferior to healthy controls on the development scales. Age differentiated SE impact on visuomotor development versus sociolinguistic development. Children who had been treated for SE had significantly more difficulties delaying a response to an attractive stimulus in one of the long delay conditions. A single episode of SE can interfere with psychomotor and cognitive development in children without previous developmental delay, and it seems that the functions that are emerging at the time of insult are most vulnerable. PMID- 21705281 TI - Randomized phase IIIb trial evaluating the continuation of bevacizumab beyond disease progression in patients with advanced non-squamous non-small-cell lung cancer after first-line treatment with bevacizumab plus platinum-based chemotherapy: treatment rationale and protocol dynamics of the AvaALL (MO22097) trial. AB - We present the treatment rationale and study design of the AvaALL (MO22097; ClinicalTrials: NCT01351415) trial, a multicenter, open-label, randomized, two arm, phase IIIb study. Patients with advanced non-squamous non-small-cell lung cancer (NSCLC) whose disease has progressed after four to six cycles of first line treatment with bevacizumab plus a platinum-based doublet and a minimum of two cycles of bevacizumab (monotherapy) maintenance treatment will be randomized in a 1:1 ratio to one of two study arms. Patients treated on arm A will receive bevacizumab 7.5 or 15 mg/kg intravenously (I.V.) on day 1, every 21 days plus, investigator's choice of agents indicated for use in second-line (limited to pemetrexed, docetaxel, or erlotinib) and subsequent lines of treatment. Patients treated on arm B, will receive investigator's choice of agents alone indicated for use in second-line and subsequent lines of treatment, but no further bevacizumab treatment. The primary endpoint of this study is overall survival (OS). Secondary endpoints include the 6-month, 12-month, and 18-month OS rates, progression-free survival, and time to progression at second and third progressive disease (PD), response rate, disease control rates, and duration of response at second and third PD. Additionally, efficacy in the subgroup of patients with adenocarcinoma, and the safety of bevacizumab treatment across multiple lines of treatment will be assessed. Exploratory objectives include assessment of the quality of life through multiple lines of treatment, comparison of the efficacy between Asian and non-Asian patients, and correlation of biomarkers with efficacy outcomes, disease response, and adverse events. PMID- 21705282 TI - Prevention of postoperative seroma-related morbidity by quilting of latissimus dorsi flap donor site: a systematic review. AB - OBJECTIVE: To systematically analyze the effectiveness of quilting of latissimus dorsi (LD) flap donor site in the prevention of seroma and related morbidities. METHODS: All published studies comparing the effectiveness of quilting versus no quilting of LD flap donor site in the prevention of seroma and related morbidities in patients undergoing breast reconstruction were analysed systemically. RESULTS: Five comparative studies on quilting versus no-quilting encompassing 440 patients were suitable for statistical analysis. There was no heterogeneity among trials. Therefore, in the fixed-effects model, quilting was effective in terms of reducing the incidence of donor-site seroma formation, reducing the average volume of the seroma, and reducing the total volume of drained seroma. In addition, quilting did not increase the risk of postoperative complications. Combined quilting and fibrin glue was also effective in reducing the average volume of the seroma and total drained volume of the seroma. Combination of quilting and glue did not influence the incidence of seroma formation at LD flap donor site and overall operative complications. CONCLUSION: Quilting of the LD flap donor site is helpful in reducing the incidence of seroma formation, reducing seroma volume, and reducing total drained seroma volume. Combined quilting and fibrin glue further enhances its effectiveness. Quilting with or without fibrin glue may be considered an option in patients undergoing LD flap breast reconstruction to control seroma-related morbidity. However, a major multicenter randomized controlled trial is required to achieve stronger and reliable evidence before recommending it as a routine procedure. PMID- 21705283 TI - Reliability of a computer-based system for measuring visual performance skills. AB - BACKGROUND: Athletes have demonstrated better visual abilities than nonathletes. A vision assessment for an athlete should include methods to evaluate the quality of visual performance skills in the most appropriate, accurate, and repeatable manner. This study determines the reliability of the visual performance measures assessed with a computer-based system, known as the Nike Sensory Station. METHODS: One hundred twenty-five subjects (56 men, 69 women), age 18 to 30, completed Phase I of the study. Subjects attended 2 sessions, separated by at least 1 week, in which identical protocols were followed. Subjects completed the following assessments: Visual Clarity, Contrast Sensitivity, Depth Perception, Near-Far Quickness, Target Capture, Perception Span, Eye-Hand Coordination, Go/No Go, and Reaction Time. An additional 36 subjects (20 men, 16 women), age 22 to 35, completed Phase II of the study involving modifications to the equipment, instructions, and protocols from Phase I. RESULTS: Results show no significant change in performance over time on assessments of Visual Clarity, Contrast Sensitivity, Depth Perception, Target Capture, Perception Span, and Reaction Time. Performance did improve over time for Near-Far Quickness, Eye-Hand Coordination, and Go/No Go. CONCLUSIONS: The results of this study show that many of the Nike Sensory Station assessments show repeatability and no learning effect over time. The measures that did improve across sessions show an expected learning effect caused by the motor response characteristics being measured. PMID- 21705284 TI - ACR/ABR clinical statement on credentialing and privileging of radiologists for diagnostic nuclear medicine, including multimodality hybrid imaging. AB - Processes for credentialing physicians and criteria for delineating their practice-specific clinical privileges vary widely across the United States. The ACR and the ABR have jointly developed this resource document to define the requisite credentials for board-certified radiologists to be privileged to practice the full gamut of diagnostic nuclear medicine, including multimodality hybrid imaging. Through its initial certification of radiologists and maintenance of certification programs for practicing certificate holders, the ABR assesses the competence and ensures excellence of its professional diplomates for clinical practice. On the basis of their education, training, and clinical work experience, board-certified radiologists are imminently qualified to supervise, interpret, and report all diagnostic nuclear medicine studies, including radionuclide cardiovascular imaging, and uniquely so for all radionuclide-based, multimodality hybrid examinations. Optimum patient care is best served by an imaging physician with training and expertise in applying, interpreting, and correlating a broad spectrum of these diagnostic technologies. PMID- 21705285 TI - Sex hormones and bariatric surgery in men. AB - The aim of this article is to review the available literature on the effect of weight loss after bariatric surgery on sex hormone levels and sexual quality of life in obese men, discuss the underlying physiology, and compare the effects of surgical and nonsurgical weight loss on sex hormone levels. Clinical trials investigating sex hormone levels in obese men after surgical and nonsurgical weight loss were identified in a Medline search. The results were synthesized, tabulated, and interpreted. Total testosterone and free testosterone are usually decreased in obese men, but were increased by both surgical and nonsurgical weight loss. The improvement in total testosterone after bariatric surgery was found to be greater than with nonsurgical weight loss in most studies. The changes were less clear on estradiol, gonadotropins, and adrenal androgens after both methods of weight loss and require further study. Improvement of sexual quality of life was more consistent with bariatric surgery. Thus, bariatric surgery is the most effective treatment of obesity-related male hypogonadism. This finding might motivate obese men with hypogonadism to opt for surgical weight loss. PMID- 21705286 TI - Circulating tumor cells as a predictive biomarker in patients with hormone sensitive prostate cancer. AB - Little information exists regarding the utility circulating tumor cell (CTC) enumeration in hormone sensitive prostate cancer. We enumerated CTC in 33 consecutive patients undergoing androgren deprivation therapy (ADT) at our institution. Multivariate analysis revealed baseline CTC as the only independent predictor of progression to CRPC. These data suggest that baseline CTC may identify those unlikely to benefit from ADT. INTRODUCTION: Circulating tumor cell (CTC) enumeration by using the Cellsearch platform has established prognostic and predictive value in patients with metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding the clinical utility of CTC enumeration in metastatic hormone-sensitive prostate cancer (mHSPC). The goal of this study was to prospectively determine the relative clinical utility of CTCs in mHSPC. PATIENTS AND METHODS: We analyzed serial CTC in conjunction with other classic biomarkers in 33 consecutive patients treated at the Nevada Cancer Institute with HSPC initiating androgen deprivation therapy and correlated these patients with prognostic prostate-specific antigen (PSA) endpoints and onset of CRPC. RESULTS: Initial CTC correlated positively with lactate dehydrogenase and alkaline phosphatase, and were unrelated to PSA and testosterone. In univariate analysis, baseline CTC, alkaline phosphatase, lactate dehydrogenase, testosterone, and follow-up CTC were individual predictors of progression to CRPC. In a multivariate Cox regression, only baseline CTC retained independent predictive value. Threshold analysis revealed the cutpoint that optimized specificity and sensitivity of the test to be 3 cells per 7.5 mL whole blood. Baseline CTC also correlated well with PSA nadir benchmarks. CONCLUSIONS: Initial CTC values predict the duration and magnitude of response to hormonal therapy. CTC enumeration may identify patients at risk of progression to CRPC before initiation of androgen deprivation therapy. PMID- 21705287 TI - Quantitation of paclitaxel and its two major metabolites using a liquid chromatography-electrospray ionization tandem mass spectrometry. AB - A sensitive and selective liquid chromatographic-tandem mass spectrometric (LC MS/MS) method for the determination of paclitaxel (Taxol) and its two major metabolites in human plasma has been developed. Samples were prepared after liquid-liquid extraction and analyzed on a C(18) column interfaced with a Q-Trap tandem mass spectrometer. Positive electrospray ionization was employed as the ionization source. The mobile phase consisted of acetonitrile-water (0.05% formic acid) (65:35) at the flow rate of 0.25 mL/min. The analytes and internal standard docetaxel were both detected by use of multiple reaction monitoring mode. The method was linear in the concentration range of 0.5-500.0 ng/mL for paclitaxel, 6alpha-hydroxypaclitaxel and p-3'-hydroxypaclitaxel, respectively. The lower limit of quantification (LLOQ) was 0.5 ng/mL for paclitaxel, 6alpha hydroxypaclitaxel and p-3'-hydroxypaclitaxel, respectively. The intra- and inter day relative standard deviation across three validation runs over the entire concentration range was less than 8.18%. The accuracy determined at three concentrations was within +/-10.8% in terms of relative error. The total run time was 7.0 min. This assay offers advantages in terms of expediency, and suitability for the analysis of paclitaxel and its metabolites in various biological fluids. PMID- 21705288 TI - Coping with "bad body image days": strategies from first-year young adult college women. AB - The purpose of this qualitative study was to understand how college women cope with body image concerns, a topic which has rarely been studied. Semi-structured interviews with first-year female college students (N=30) revealed common strategies used for body image coping as well as their perceived effectiveness. While exercise was most frequently cited, other coping strategies included healthy eating, appearance changing, talking to friends or family, religion/spirituality, spending time alone, getting out and doing something, and self-acceptance. One of the emerging themes was participation in a cycle of eating as a result of body image concerns, and then feeling bad about themselves for eating. Participants identified that women in this cycle either adopt a self defeatist attitude, believing they can do nothing about their appearance, or engage in self-improvement strategies, including goal setting. Far more women reported coping strategies that reflected avoidance or appearance fixing motives rather than acceptance. PMID- 21705289 TI - Use of shear wave sonoelastography in capsular contracture before and after secondary surgery: report of two cases. AB - We present two cases of patients undergoing secondary surgery due to Baker III and IV contracture, with detailed sonoelastography evaluation before and after the surgery. It is probably the first case where the use of sonoelastography has enabled plane colour-coded analysis of regions with different stiffness (Young moduli, kPa). The obtained results have been compared with applanation tonometry. PMID- 21705290 TI - Quality of life after severe hand injury. AB - This study explores the quality of life in 118 patients following severe and major hand injury with a Hand Injury Severity Score >50. Each patient answered five different validated outcome measures (DASH (Disability of the Arm, Shoulder, and Hand), FLZ(M) ('Fragen zur Lebenszufriedenheit'), HADS (Hospital Anxiety and Depression Score), BDDE-SR (Body Dysmorphic Disorder Examination-Self Report) and FBeK ('Fragebogen zur Beurteilung des eigenen Korpers'), which were incorporated into a single questionnaire. Each of these questionnaires covered one or more of the established quality-of-life domains. Patients with pain and pressure sensations were significantly less satisfied in life, showed lower levels of health satisfaction, had higher levels of anxiety and depression and showed higher body dysmorphic disorder levels (all p < 0.001). General life satisfaction in this hand-injury study group is highly dependent on the patients' satisfaction with their health and appearance as well as self-confidence. The quality-of-life outcomes improve with time, and despite evidence of continued impairment in the injured hand, the majority of patients had a normal quality of life. PMID- 21705291 TI - Treatment options for head and neck lymphoedema after tumour resection and radiotherapy. PMID- 21705292 TI - Importance of the suprasternal notch to nipple distance (SSN:N) for vascular complications of the nipple areola complex (NAC) in the superior pedicle vertical mammaplasty: a retrospective analysis. AB - BACKGROUND: The superior pedicle, frequently used with vertical mammaplasty, bears some risk for vascular complications of the nipple areola complex (NAC) particularly in large breasts. The suprasternal notch to nipple distance (SSN:N), geometrically associated with the longitudinal axis of the breast and length of the superior pedicle, might be an indicative parameter to assess these complications. Importance of the SSN:N for vascular complication of the NAC was focussed upon in this study. MATERIAL AND METHODS: Arterial and venous complications of 104 patients following the superior pedicle vertical mammaplasty were retrospectively evaluated both sided (n=208 breasts), according to the preoperatively measured SSN:N. Binary logistic regression (p<=0.05) was used for statistical evaluation. RESULTS: Probability of vascular compromise of the NAC is influenced by the SSN:N within the context of the superior pedicle vertical mammaplasty. An SSN:N>30 cm (n=112 breasts) is subject to venous (p=0.002) as well as arterial (p=0.232) complications of the NAC, both of which may result in partial necrosis of the tissue (p=0.029). CONCLUSION: The SSN:N measurement can be helpful to identify patients at risk for vascular complications of the superiorly stalked NAC. Modifications of the superior pedicle or other pedicles potentially providing enhanced vascular impact might be considered with an SSN:N beyond 30 cm to reduce vasculature-related complications of the NAC. PMID- 21705293 TI - Intraneural ganglion in the digital nerve of the thumb: a case report. AB - Intraneural ganglion cysts of the peripheral nerve in the upper extremity are uncommon and usually originate within the epineurium of the peripheral nerve. The current report discusses a 57-year-old woman with a neuropathic nodular mass on the thenar area of the left hand. Magnetic resonance images showed a lobulated, homogeneous mass of high signal intensity on T2-weighted images and low signal intensity with peripheral enhancement on T1-weighted images. Excisional biopsy and histopathologic examination confirmed an intraneural ganglion cyst of the digital nerve of the thumb. A successful result was obtained by surgical treatment, and there was no recurrence of abnormal sensation and paraesthesia during the 3-year follow-up period. PMID- 21705294 TI - The impact of pioglitazone on ADMA and oxidative stress markers in patients with type 2 diabetes. AB - AIMS: To determine whether pioglitazone 30 mg daily reduces levels of ADMA in adult patients with diabetes, and whether there is improvement in markers of oxidative stress. METHODS: Prospective randomized cross-over placebo-controlled study of 36 adults age 40-75 years with type 2 diabetes recruited from a single academic health center. Intervention was for 12 weeks, followed by a 4-week wash out period, followed by a second 12-week cross-over treatment period. The main outcome was comparison of the change in ADMA levels in the two treatment periods. Secondary outcomes included change in NOx and F2-isoprostanes. RESULTS: Thirty six patients were enrolled in the study, 31 completed the protocol; the study enrollment met the sample size required to detect a change of 18% in levels. There were no differences in ADMA, NOx and F2-isoprostanes levels in the two treatment periods. Non-study medication changes or changes in dose were infrequent, and a statin was added during the study period in only one patient. CONCLUSIONS: Despite previous animal data that showed an effect of pioglitazone on ADMA, the current study in human patients did not demonstrate any differences in ADMA, NOx, or F2-isoprostane levels. The results do not favor that pioglitazone has a significant impact on ADMA levels in human patients with diabetes. PMID- 21705295 TI - Long-term clinical evaluation of implant over denture. AB - PURPOSE: The use of implants to treat edentulous jaws has become a well established and accepted contemporary clinical method. The aim of this study was to analyze information about the implants used, patients, denture modality, and complications after denture insertion in partially and fully edentulous patients with implant overdentures placed. METHODS: A survey was performed about patients rehabilitated using implant dentures at the Tsurumi University Dental Hospital during 8 years. A total of 201 implants were placed: 112 in the maxilla and 89 in the mandible. Descriptive statistics were used for each patient, such as the implant positions and numbers, retainer designs, denture modalities, implant survival rate and prosthetic complications. RESULTS: The positions of implant placement were: incisor (44%); canine (26%); premolar (18%); and molar (12%). Approximately 70% of the retainers were bar attachments and magnet attachments. The majority of the prostheses were metal-based dentures (84%) compared to only 10 acrylic dentures (16%). Fully edentulous, fourteen (12 maxillary, 2 mandibular) of 171 implants failed. Partially edentulous, three (3 maxillary, 0 mandibular) of 30 implants failed. The denture complications observed during maintenance were denture fracture, retainer breakage and artificial tooth fracture. CONCLUSION: Although the mandibular implant dentures placed were exceedingly reliable for rehabilitation with a high survival rate, the maxillary implant dentures exhibited a low survival rate and more frequent complications. Significantly higher implant failures and prosthetic complications were observed in the initial period after placement than in the following years. PMID- 21705296 TI - Accuracy of palpating the long head of the biceps tendon: an ultrasonographic study. AB - OBJECTIVE: To determine the accuracy of palpating the long head of the biceps tendon (LHBT) within the intertubercular groove with the use of ultrasonographic localization as a gold standard. DESIGN: Prospective, single-blinded pilot study. SETTING: Sports medicine clinic at a tertiary care academic institution. PARTICIPANTS: Twenty-five male and female asymptomatic volunteers ages 24-41 years (mean, 30.9 +/- 4.3 years) with body mass indices of 19.3 to 36.3 kg/m(2) (23.84 +/- 4.8 kg/m(2)). METHODS: Three examiners of differing experience (a sports medicine board-certified staff physician, a sports medicine fellow, and a physical medicine and rehabilitation resident) identified the LHBT location in the intertubercular groove via palpation on a subject in the supine position and marked its location by taping an 18-gauge Tuohy needle to the skin overlying the groove. The examiner order was randomized. A fourth examiner who was blinded to the palpation order assessed the previous examiner's palpation accuracy by comparing the needle position to the sonographically determined tendon position. MAIN OUTCOME MEASURES: Needle placement in relation to the intertubercular groove was graded as being within the groove, medial to the groove, or lateral to the groove. In the latter 2 cases, the distance from the needle to the closest groove edge was recorded. RESULTS: Overall accuracy rate was 5.3% (4/75), ranging from 0% (0/25) for the resident to 12% (3/25) for the fellow (P <= .007 for interexaminer differences). All missed palpations were localized medial to the intertubercular groove by an average of 1.4 +/- 0.5 cm (range, 0.3 for the fellow to 3.5 cm for the resident). CONCLUSION: Based on the current methodology, clinicians have a tendency to localize the intertubercular groove medial to its actual location. Consequently, clinicians should exercise caution when relying on clinical palpation to either diagnose a biceps tendon disorder or perform a bicipital tendon sheath injection. When clinically indicated, sonographic guidance can be used to accurately identify the LBHT within the intertubercular groove. PMID- 21705297 TI - Peat bog wildfire smoke exposure in rural North Carolina is associated with cardiopulmonary emergency department visits assessed through syndromic surveillance. AB - BACKGROUND: In June 2008, burning peat deposits produced haze and air pollution far in excess of National Ambient Air Quality Standards, encroaching on rural communities of eastern North Carolina. Although the association of mortality and morbidity with exposure to urban air pollution is well established, the health effects associated with exposure to wildfire emissions are less well understood. OBJECTIVE: We investigated the effects of exposure on cardiorespiratory outcomes in the population affected by the fire. METHODS: We performed a population-based study using emergency department (ED) visits reported through the syndromic surveillance program NC DETECT (North Carolina Disease Event Tracking and Epidemiologic Collection Tool). We used aerosol optical depth measured by a satellite to determine a high-exposure window and distinguish counties most impacted by the dense smoke plume from surrounding referent counties. Poisson log linear regression with a 5-day distributed lag was used to estimate changes in the cumulative relative risk (RR). RESULTS: In the exposed counties, significant increases in cumulative RR for asthma [1.65 (95% confidence interval, 1.25-2.1)], chronic obstructive pulmonary disease [1.73 (1.06-2.83)], and pneumonia and acute bronchitis [1.59 (1.07-2.34)] were observed. ED visits associated with cardiopulmonary symptoms [1.23 (1.06-1.43)] and heart failure [1.37 (1.01-1.85)] were also significantly increased. CONCLUSIONS: Satellite data and syndromic surveillance were combined to assess the health impacts of wildfire smoke in rural counties with sparse air-quality monitoring. This is the first study to demonstrate both respiratory and cardiac effects after brief exposure to peat wildfire smoke. PMID- 21705298 TI - Oxidative and antioxidative effects of desflurane and sevoflurane on rat tissue in vivo. AB - General anaesthetics are often used in patients who are under oxidative stress due to a critical illness or surgical trauma. Some anaesthetics may worsen oxidative stress and some may act as antioxidants. The aim of this study was to evaluate liver, brain, kidney, and lung tissue oxidative stress in rats exposed to desflurane and sevoflurane and in unexposed rats. The animals were divided in three groups: control (received only air); sevoflurane (8 %), and desflurane (4 %). After four hours of exposure, we evaluated the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), Cu, and Zn. Exposure to either of the anaesthetics significantly increased lung MDA levels compared to control (Mann-Whitney U test; P<0.05), probably because it is the tissue directly exposed to anaesthetic gases. Oxidative stress and antioxidant activity in other tissues varied between the desflurane and sevoflurane groups. Our results suggest that anaesthesiologist should not only be aware of the oxidative or antioxidative potential of anaesthetics they use, but should also base their choices on organs which are the most affected by their oxidative action. PMID- 21705299 TI - Protective role of selenium against over-expression of cancer-related apoptotic genes induced by o-cresol in rats. AB - Cresols are monomethyl derivatives of phenol frequently used as solvents and intermediates in the production of disinfectants, fragrances, pesticides, dyes, and explosives, which is probably why they are widely distributed in the environment. General population may be exposed to cresols mainly through inhalation of contaminated air. In this study we evaluated the toxicological effects of o-cresol on differential gene expression profile of rat liver and prostate. Experiments were conducted on 80 male rats, 60 of which were exposed to o-cresol (1.5 g kg-1, 5 g kg-1, or 15 g kg-1) through feed for 8 weeks. Three groups of rats were supplemented with 0.1 mg kg-1 selenium (Se, in the form of, sodium selenite) in addition to o-cresol to evaluate its effectiveness against o cresol toxicity. Control group received neither o-cresol nor Se, while one group received Se alone. Survival was similar between the exposed and control animals. Rats exposed to 15 g kg-1 of o-cresol showed a 16 % loss in body weight by the end of the study, which may have been related to o-cresol making feed unpalatable at this concentration. Liver and prostate tissue samples were collected at the end of the treatment. mRNA analysis revealed that apoptotic genes (CYP3A, COX-2, PPARgamma, BAX, BCL2, AKT-1, and PKCalpha) related to cancer were up-regulated in liver and prostate tissues isolated from groups exposed to 5 g kg-1 and 15 g kg 1o-cresol in comparison to control. Changes in gene expression profile were prevented when rats were supplemented with Se. The exact mechanisms underlying its protective effect remain to be clarified by future studies. PMID- 21705300 TI - Nifedipine lowers cocaine-induced brain and liver enzyme activity and cocaine urinary excretion in rats. AB - The aim of this study was to see how nifedipine counters the effects of cocaine on hepatic and brain enzymatic activity in rats and whether it affects urinary excretion of cocaine. Male Wistar rats were divided in four groups of six: control, nifedipine group (5 mg kg-1i.p. a day for five days); cocaine group (15 mg kg-1i.p. a day for five days), and the nifedipine+cocaine group. Twenty-four hours after the last administration, we measured neuronal nitric oxide synthase (nNOS) activity in the brain and cytochrome P450 quantity, ethylmorphine-N demethylase, and anilinehydroxylase activity in the liver. Urine samples were collected 24 h after the last cocaine and cocaine+nifedipine administration. Urinary cocaine concentration was determined using the GC/MS method.Cocaine administration increased brain nNOS activity by 55 % (p<0.05) in respect to control, which indicates the development of tolerance and dependence. In the combination group, nifedipine decreased the nNOS activity in respect to the cocaine-only group.In the liver, cocaine significantly decreased and nifedipine significantly increased cytochrome P450, ethylmorphine-N-demethylase, and anilinehydroxylase in respect to control. In combination, nifedipine successfully countered cocaine effects on these enzymes.Urine cocaine excretion in the cocaine+nifedipine group significantly dropped (by 35 %) compared to the cocaine only group.Our results have confirmed the effects of nifedipine against cocaine tolerance and development of dependence, most likely due to metabolic interactions between them. PMID- 21705301 TI - Genotoxic effects of green tea extract on human laryngeal carcinoma cells in vitro. AB - Green tea (Camellia sinensis) contains several bioactive compounds which protect the cell and prevent tumour development. Phytochemicals in green tea extract (mostly flavonoids) scavenge free radicals, but also induce pro-oxidative reactions in the cell. In this study, we evaluated the potential cytotoxic and prooxidative effects of green tea extract and its two main flavonoid constituents epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) on human laryngeal carcinoma cell line (HEp2) and its cross-resistant cell line CK2. The aim was to see if the extract and its two flavonoids could increase the sensitivity of the cisplatin-resistant cell line CK2 in comparison to the parental cell line. The results show that EGCG and green tea extract increased the DNA damage in the CK2 cell line during short exposure. The cytotoxicity of EGCG and ECG increased with the time of incubation. Green tea extract induced lipid peroxidation in the CK2 cell line. The pro-oxidant effect of green tea was determined at concentrations higher than those found in traditionally prepared green tea infusions. PMID- 21705302 TI - Low lead exposure during foetal and early postnatal life impairs passive avoidance learning in adulthood in rats. AB - This follow-up study investigated the effects of low-level lead exposure during prenatal and early postnatal period on learning and memory in rats immediately after exposure has ceased at weaning and later in their adulthood. Male Wistar derived rats were exposed to lead (as 0.2 % lead acetate solution) through their mothers during pregnancy and lactation until they were weaned. Mothers of control rats were given tap water during pregnancy and lactation. All pups were weaned on tap water at 21 days of age and were followed up until 120 days old. Low-level lead exposure did not affect their body weight at any time during the experiment. Blood lead in the exposed rats was significantly higher on postnatal day 22 and dropped to control values by day 120. Passive avoidance test showed impaired memory retention in the exposed rats on postnatal days 25 and 120. This suggests that exposure to low-lead levels during foetal and early postnatal development of brain tissue can cause memory impairment that lasts into adulthood. PMID- 21705303 TI - The effects of hyaluronic acid, calcium hydroxide, and dentin adhesive on rat odontoblasts and fibroblasts. AB - The aim of this study was to investigate the effects and efficiency of pulp capping preparations based on hyaluronic acid, calcium hydroxide, and dentin adhesive on the pulp tissue of Sprague-Dawley rats. The rats were killed and extracted teeth sectioned transversely through the pulp. The slices were placed in a RPMI 1640 cell culture medium supplemented with 10 % foetal calf serum. During 14 days of cultivation cultures were treated with preparations that contained hyaluronic acid (Gengigel Prof(r)), and calcium hydroxide (ApexCal(r)), or with dentin adhesive (Excite(r)). Cellularity and viability of fibroblasts and odontoblasts was analysed using a haemocytometer. Hyaluronic acid proved most efficient and the least toxic for direct pulp capping. Even though calcium hydroxide and dentin adhesive demonstrated a higher degree of cytotoxicity, their effects were still acceptable in terms of biocompatibility. PMID- 21705304 TI - Work ability assessment in a patient with Wilson's disease. AB - Wilson's disease (WD) is a rare, progressive autosomal recessive disorder characterised by impaired transport and excessive accumulation of copper in the liver, brain, and other tissues. The disease is diagnosed based on clinical manifestations and screening tests results. Work ability assessment of patients with WD is based on the analysis of liver, kidney, neurological, and cognitive impairments, and takes into account patient's level of education.This article presents a case with a 48-year-old male patient, who was admitted for work ability assessment due to polymorphic symptoms. The patient had been working as a salesman for 28 years. A detailed interview and examination by occupational health and other medical specialists revealed that the patient had been suffering from Wilson's disease from the age of 13, and had now developed hepatic manifestations (compensated liver cirrhosis with portal hypertension), neurological manifestations (dystonia, dysarthria, muscle weakness, vertigo), and psychiatric manifestations (depression, insomnia, cognitive impairment) of the disease, including problems partially caused by long-lasting treatment with copper chelating agents (neurological and haematological manifestations). There were no ocular manifestations of Wilson's disease (Kayser-Fleischer rings or sunflower cataract).The patient was assessed as having drastically diminished general work ability, dominantly due to neurological and psychiatric impairments caused by Wilson's disease. PMID- 21705305 TI - Determination of artificial sweeteners in beverages and special nutritional products using high performance liquid chromatography. AB - This paper presents two high performance liquid chromatographic (HPLC) methods used for the separation and determination of artificial sweeteners aspartame, acesulphame K, sodium saccharin, and sodium cyclamate in beverages and special nutritional products (special food intended for specific population groups). All four compounds are soluble in aqueous solutions and can easily be separated and determined by HPLC with a diode array detector (DAD). The first method involved separation of aspartame, acesulphame K, and sodium saccharin on a C18 column with an isocratic elution of phosphate buffer and acetonitrile as mobile phase. The second method was used to separate sodium cyclamate on a C18 column with methanol and water as mobile phase. Under optimum conditions, both methods showed good analytical performance, such as linearity, precision, and recovery. The methods were successfully applied for the analysis of real samples of soft drinks and special nutritional products. PMID- 21705306 TI - [Cholinesterases: structure, role, and inhibition]. AB - Enzymes acetylcholinesterase (AChE; E.C. 3.1.1.7) and butyrylcholinesterase (BChE; E.C. 3.1.1.8) have intensively been investigated in biomedicine and toxicology due to important role in organisms. Even if structurally homologous, they differ in catalytic activity, specificity, for substrates, and selectivity in binding to many ligands. This paper compiles the results of research on cholinesterases and their interactions with ligands and inhibitors, and identifies amino acids of active sites involved in these interactions. PMID- 21705307 TI - [Biomonitoring of human exposure to triazine herbicides]. AB - Triazine herbicides are very common and only 0.1 % reach the target pests, while the rest moves into other environmental compartments. Their fate in the environment depends on their movement through the air, water, and soil and on the rate of their degradation or transformation. Triazine compounds may be transformed by water, microorganisms, and sunlight. Widespread use and persistence of triazine herbicides in soil has resulted in contamination of surface, drinking, and even rain water with parent compounds and degradation products, posing a risk to the general population.The metabolism and effects of triazine herbicides have been studied in experimental animals and in experiments in vitro. There are only a few studies of their metabolism and excretion in humans. Agricultural and manufacturing workers are exposed to triazines during application and production. Human exposure is monitored by determining parent compounds and their metabolites in urine. Due to the low concentrations of urinary metabolites in occupationally exposed persons, very sensitive analytical methods are required. This paper describes the structure and properties of symmetric triazine herbicides, their metabolism, and effects in humans and animals and the levels of these compounds in the urine of occupationally exposed persons. PMID- 21705315 TI - Similarities and discrepancies in homozygous factor VII defects due to mutations in the region of residues Met298 to Cys310 (exon 8) in the catalytic domain of factor VII. AB - Patients with the Arg304Gln mutation in factor VII Padua (FVII Padua) show discrepant activity levels that depend on the thromboplastin used in the assay system. This report investigates the possibility that residues close to Arg304 (exon 8) show the same discrepant behavior. All available homozygous patients with a mutation in a 13-residue region (preceding and following Arg304) have been evaluated. Only the Arg304Trp mutation showed a discrepancy similar to that shown by the Arg304Gln mutation. Other homozygotes failed to show differences, despite their all being positive for cross-reacting material. Another FVII amino acid residue involved in tissue factor binding and activation is Arg79 (exon 4). No comparison could be carried out because no homozygotes for deficiency in this region have ever been described. The relationship between these 2 residues involved in tissue factor binding and activation has not yet been completely clarified; however, Arg residues 79 and 304 are the only 2 residues definitely shown thus far to be involved in this important function. PMID- 21705316 TI - Direct and indirect effects of rotavirus vaccination upon childhood hospitalizations in 3 US Counties, 2006-2009. AB - BACKGROUND: Routine rotavirus vaccination of US infants began in 2006. We conducted active, population-based surveillance for rotavirus gastroenteritis hospitalizations in 3 US counties to assess vaccine impact. METHODS: Children <36 months old hospitalized with diarrhea and/or vomiting were enrolled from January through June each year during the period 2006-2009 and tested for rotavirus. Age stratified rates of hospitalization for rotavirus infection were compared with corresponding vaccination coverage among a control group of children with acute respiratory illness. To assess direct and indirect benefits, vaccination coverage rates in the control group were multiplied by vaccine effectiveness estimates to calculate expected reductions in the rate of hospitalization for rotavirus infection. Rotavirus serotypes were compared across years. RESULTS: Compared with 2006, a significant reduction in rates of hospitalization for rotavirus infection (P < .001) was observed in 2008 among all age groups. There was an 87% reduction in the 6-11-month-old age group (coverage, 77%), a 96% reduction in the 12-23 months-old age group (coverage, 46%), and a 92% reduction in the 24-35-month-old age group (coverage, 1%), which exceeded reductions expected on the basis of coverage and vaccine effectiveness estimates. Age-specific rate reductions were nearly equivalent to those expected on the basis of age-specific vaccine coverage in 2009. Predominant strains varied annually: G1P[8] (91%) in 2006; G1P[8] (45%) and G12P[8] (36%) in 2007; G1P[8] (89%) in 2008; and G3P[8] (43%), G2P[4] (34%), and G9P[8] (27%) in 2009. CONCLUSIONS: Rotavirus vaccination has dramatically decreased rates of hospitalization for rotavirus infection among children in these US counties. In 2008, reductions were prominent among both vaccine-eligible age groups and older, largely unvaccinated children; the latter likely resulted from indirect protection. Although rates among age groups eligible for vaccination remained low in 2009, indirect benefits disappeared. PMID- 21705318 TI - A red-shifted antenna protein associated with photosystem II in Physcomitrella patens. AB - Antenna systems of plants and green algae are made up of pigment-protein complexes belonging to the light-harvesting complex (LHC) multigene family. LHCs increase the light-harvesting cross-section of photosystems I and II and catalyze photoprotective reactions that prevent light-induced damage in an oxygenic environment. The genome of the moss Physcomitrella patens contains two genes encoding LHCb9, a new antenna protein that bears an overall sequence similarity to photosystem II antenna proteins but carries a specific motif typical of photosystem I antenna proteins. This consists of the presence of an asparagine residue as a ligand for Chl 603 (A5) chromophore rather than a histidine, the common ligand in all other LHCbs. Asparagine as a Chl 603 (A5) ligand generates red-shifted spectral forms associated with photosystem I rather than with photosystem II, suggesting that in P. patens, the energy landscape of photosystem II might be different with respect to that of most green algae and plants. In this work, we show that the in vitro refolded LHCb9-pigment complexes carry a red shifted fluorescence emission peak, different from all other known photosystem II antenna proteins. By using a specific antibody, we localized LHCb9 within PSII supercomplexes in the thylakoid membranes. This is the first report of red shifted spectral forms in a PSII antenna system, suggesting that this biophysical feature might have a special role either in optimization of light use efficiency or in photoprotection in the specific environmental conditions experienced by this moss. PMID- 21705317 TI - Encephalopathy caused by ablation of very long acyl chain ceramide synthesis may be largely due to reduced galactosylceramide levels. AB - Sphingolipids (SLs) act as signaling molecules and as structural components in both neuronal cells and myelin. We now characterize the biochemical, histological, and behavioral abnormalities in the brain of a mouse lacking very long acyl (C22-C24) chain SLs. This mouse, which is defective in the ability to synthesize C22-C24-SLs due to ablation of ceramide synthase 2, has reduced levels of galactosylceramide (GalCer), a major component of myelin, and in particular reduced levels of non-hydroxy-C22-C24-GalCer and 2-hydroxy-C22-C24- GalCer. Noteworthy brain lesions develop with a time course consistent with a vital role for C22-C24-GalCer in myelin stability. Myelin degeneration and detachment was observed as was abnormal motor behavior originating from a subcortical region. Additional abnormalities included bilateral and symmetrical vacuolization and gliosis in specific brain areas, which corresponded to some extent to the pattern of ceramide synthase 2 expression, with astrogliosis considerably more pronounced than microglial activation. Unexpectedly, unidentified storage materials were detected in lysosomes of astrocytes, reminiscent of the accumulation that occurs in lysosomal storage disorders. Together, our data demonstrate a key role in the brain for SLs containing very long acyl chains and in particular GalCer with a reduction in their levels leading to distinctive morphological abnormalities in defined brain regions. PMID- 21705319 TI - Thr-1989 phosphorylation is a marker of active ataxia telangiectasia-mutated and Rad3-related (ATR) kinase. AB - The DNA damage response kinases ataxia telangiectasia-mutated (ATM), DNA dependent protein kinase (DNA-PK), and ataxia telangiectasia-mutated and Rad3 related (ATR) signal through multiple pathways to promote genome maintenance. These related kinases share similar methods of regulation, including recruitment to specific nucleic acid structures and association with protein activators. ATM and DNA-PK also are regulated via phosphorylation, which provides a convenient biomarker for their activity. Whether phosphorylation regulates ATR is unknown. Here we identify ATR Thr-1989 as a DNA damage-regulated phosphorylation site. Selective inhibition of ATR prevents Thr-1989 phosphorylation, and phosphorylation requires ATR activation. Cells engineered to express only a non phosphorylatable T1989A mutant exhibit a modest ATR functional defect. Our results suggest that, like ATM and DNA-PK, phosphorylation regulates ATR, and phospho-peptide specific antibodies to Thr-1989 provide a proximal marker of ATR activation. PMID- 21705320 TI - Roles of phosphorylation-dependent and -independent mechanisms in the regulation of histamine H2 receptor by G protein-coupled receptor kinase 2. AB - It is widely assumed that G protein-coupled receptor kinase 2 (GRK2)-mediated specific inhibition of G protein-coupled receptors (GPCRs) response involves GRK mediated receptor phosphorylation followed by beta-arrestin binding and subsequent uncoupling from the heterotrimeric G protein. It has recently become evident that GRK2-mediated GPCRs regulation also involves phosphorylation independent mechanisms. In the present study we investigated whether the histamine H2 receptor (H2R), a Galpha(s)-coupled GPCR known to be desensitized by GRK2, needs to be phosphorylated for its desensitization and/or internalization and resensitization. For this purpose we evaluated the effect of the phosphorylating-deficient GRK2K220R mutant on H2R signaling in U937, COS7, and HEK293T cells. We found that although this mutant functioned as dominant negative concerning receptor internalization and resensitization, it desensitized H2R signaling in the same degree as the GRK2 wild type. To identify the domains responsible for the kinase-independent receptor desensitization, we co transfected the receptor with constructions encoding the GRK2 RGS-homology domain (RH) and the RH or the kinase domain fused to the pleckstrin-homology domain. Results demonstrated that the RH domain of GRK2 was sufficient to desensitize the H2R. Moreover, disruption of RGS functions by the use of GRK2D110A/K220R double mutant, although coimmunoprecipitating with the H2R, reversed GRK2K220R-mediated H2R desensitization. Overall, these results indicate that GRK2 induces desensitization of H2R through a phosphorylation-independent and RGS-dependent mechanism and extends the GRK2 RH domain-mediated regulation of GPCRs beyond Galpha(q)-coupled receptors. On the other hand, GRK2 kinase activity proved to be necessary for receptor internalization and the resulting resensitization. PMID- 21705321 TI - Oligomerization of MDC1 protein is important for proper DNA damage response. AB - Mediator of DNA damage checkpoint 1 (MDC1) plays an important role in the DNA damage response (DDR). MDC1 functions as a mediator protein and binds multiple proteins involved in different aspects of the DDR. However, little is know about the organization of MDC1 complexes. Here we show that ataxia telangiectasia, mutated (ATM) phosphorylates MDC1 at Thr-98 following DNA damage, which promotes its oligomerization. Oligomerization of MDC1 is important for the accumulation of MDC1 complex at the sites of DNA damage. Mutation of Thr-98 (T98A) would abolish its oligomerization and result in a defect in DNA damage checkpoint activation and increased sensitivity to irradiation. Taken together, these results suggest that the oligomerization of MDC1 plays an important role in DDR and help understand the formation of proteins complexes at the sites of DNA damage. PMID- 21705322 TI - Matrix Gla protein metabolism in vascular smooth muscle and role in uremic vascular calcification. AB - Matrix Gla protein (MGP) is an inhibitor of vascular calcification but its mechanism of action and pathogenic role are unclear. This was examined in cultured rat aortas and in a model of vascular calcification in rats with renal failure. Both carboxylated (GlaMGP) and uncarboxylated (GluMGP) forms were present in aorta and disappeared during culture with warfarin. MGP was also released into the medium and removed by ultracentrifugation, and similarly affected by warfarin. In a high-phosphate medium, warfarin increased aortic calcification but only in the absence of pyrophosphate, another endogenous inhibitor of vascular calcification. Although GlaMGP binds and inactivates bone morphogenic protein (BMP)-2, a proposed mediator of vascular calcification through up-regulation of the osteogenic transcription factor runx2, neither warfarin, BMP-2, nor the BMP-2 antagonist noggin altered runx2 mRNA content in aortas, and noggin did not prevent warfarin-induced calcification. Aortic content of MGP mRNA was increased 5-fold in renal failure but did not differ between calcified and noncalcified aortas. Immunoblots showed increased GlaMGP in noncalcified (5-fold) and calcified (20-fold) aortas from rats with renal failure, with similar increases in GluMGP. We conclude that rat aortic smooth muscle produces both GlaMGP and GluMGP in tissue-bound and soluble, presumably vesicular, forms. MGP inhibits calcification independent of BMP-2-driven osteogenesis and only in the absence of pyrophosphate, consistent with direct inhibition of hydroxyapatite formation. Synthesis of MGP is increased in renal failure and deficiency of GlaMGP is not a primary cause of medial calcification in this condition. PMID- 21705323 TI - Studies on human DNA polymerase epsilon and GINS complex and their role in DNA replication. AB - In eukaryotic cells, DNA replication is carried out by the coordinated action of three DNA polymerases (Pols), Pol alpha, delta, and epsilon. In this report, we describe the reconstitution of the human four-subunit Pol epsilon and characterization of its catalytic properties in comparison with Pol alpha and Pol delta. Human Pol epsilon holoenzyme is a monomeric complex containing stoichiometric subunit levels of p261/Pol 2, p59, p17, and p12. We show that the Pol epsilon p261 N-terminal catalytic domain is solely responsible for its ability to catalyze DNA synthesis. Importantly, human Pol (hPol) epsilon was found more processive than hPol delta in supporting proliferating cell nuclear antigen-dependent elongation of DNA chains, which is in keeping with proposed roles for hPol epsilon and hPol delta in the replication of leading and lagging strands, respectively. Furthermore, GINS, a component of the replicative helicase complex that is composed of Sld5, Psf1, Psf2, and Psf3, was shown to interact weakly with all three replicative DNA Pols (alpha, delta, and epsilon) and to markedly stimulate the activities of Pol alpha and Pol epsilon. In vivo studies indicated that siRNA-targeted depletion of hPol delta and/or hPol epsilon reduced cell cycle progression and the rate of fork progression. Under the conditions used, we noted that depletion of Pol epsilon had a more pronounced inhibitory effect on cellular DNA replication than depletion of Pol delta. We suggest that reduction in the level of Pol delta may be less deleterious because of its collision-and-release role in lagging strand synthesis. PMID- 21705324 TI - Aurora-A phosphorylates Augmin complex component Hice1 protein at an N-terminal serine/threonine cluster to modulate its microtubule binding activity during spindle assembly. AB - Proper assembly of mitotic spindles requires Hice1, a spindle-associated protein. Hice1 possesses direct microtubule binding activity at its N-terminal region and contributes to intraspindle microtubule nucleation as a subunit of the Augmin complex. However, whether microtubule binding activity of Hice1 is modulated by mitotic regulators remains unexplored. Here, we found that Aurora-A kinase, a major mitotic kinase, specifically binds to and phosphorylates Hice1. We identified four serine/threonine clusters on Hice1 that can be phosphorylated by Aurora-A in vitro. Of the four clusters, the Ser/Thr-17-21 cluster was the most critical for bipolar spindle assembly, whereas other phospho-deficient point mutants had a minimal effect on spindle assembly. Immunostaining with a phospho Ser-19/20 phospho-specific antibody revealed that phosphorylated Hice1 primarily localizes to spindle poles during prophase to metaphase but gradually diminishes after anaphase. Consistently, the phospho-mimic 17-21E mutant reduced microtubule binding activity in vitro and diminished localization to spindles in vivo. Furthermore, expression of the 17-21E mutant led to decreased association of Fam29a, an Augmin component, with spindles. On the other hand, expression of the phospho-deficient 17-21A mutant permitted intraspindle nucleation but delayed the separation of early mitotic spindle poles and the timely mitotic progression. Taken together, these results suggest that Aurora-A modulates the microtubule binding activity of Hice1 in a spatiotemporal manner for proper bipolar spindle assembly. PMID- 21705325 TI - Increased structural flexibility at the active site of a fluorophore-conjugated beta-lactamase distinctively impacts its binding toward diverse cephalosporin antibiotics. AB - The Omega-loop at the active site of beta-lactamases exerts significant impact on the kinetics and substrate profile of these enzymes by forming part of the substrate binding site and posing as steric hindrance toward bulky substrates. Mutating certain residues on the Omega-loop has been a general strategy for molecular evolution of beta-lactamases to expand their hydrolytic activity toward extended-spectrum antibiotics through a mechanism believed to involve enhanced structural flexibility of the Omega-loop. Yet no structural information is available that demonstrates such flexibility or its relation to substrate profile and enzyme kinetics. Here we report an engineered beta-lactamase that contains an environment-sensitive fluorophore conjugated near its active site to probe the structural dynamics of the Omega-loop and to detect the binding of diverse substrates. Our results show that this engineered beta-lactamase has improved binding kinetics and positive fluorescence signal toward oxyimino-cephalosporins, but shows little such effect to non-oxyimino-cephalosporins. Structural studies reveal that the Omega-loop adopts a less stabilized structure, and readily undergoes conformational change to accommodate the binding of bulky oxyimino cephalosporins while no such change is observed for non-oxyimino-cephalosporins. Mutational studies further confirm that this substrate-induced structural change is directly responsible for the positive fluorescence signal specific to oxyimino cephalosporins. Our data provide mechanistic evidence to support the long standing model that the evolutionary strategy of mutating the Omega-loop leads to increased structural flexibility of this region, which in turn facilitates the binding of extended spectrum beta-lactam antibiotics. The oxyimino-cephalosporin specific fluorescence profile of our engineered beta-lactamase also demonstrates the possibility of designing substrate-selective biosensing systems. PMID- 21705326 TI - The beta subunit loop that couples catalysis and rotation in ATP synthase has a critical length. AB - ATP synthase uses a unique rotational mechanism to convert chemical energy into mechanical energy and back into chemical energy. The helix-turn-helix structure in the C-terminal domain of the beta subunit containing the conserved DELSEED motif, termed "DELSEED-loop," was suggested to be involved in coupling between catalysis and rotation. If this is indeed the role of the loop, it must have a critical length, the minimum length required to sustain its function. Here, the critical length of the DELSEED-loop was determined by functional analysis of mutants of Bacillus PS3 ATP synthase that had 7-14 amino acids within the loop deleted. A 10 residue deletion lost the ability to catalyze ATP synthesis, but was still an active ATPase. Deletion of 14 residues abolished any enzymatic activity. Modeling indicated that in both deletion mutants the DELSEED-loop was shortened by ~10 A; fluorescence resonance energy transfer experiments confirmed the modeling results. This appears to define the minimum length for DELSEED-loop required for coupling of catalysis and rotation. In addition, we could demonstrate that the loss of high-affinity binding to the catalytic site(s) that had been observed previously in two deletion mutants with 3-4 residues removed was not due to the loss of negative charged residues of the DELSEED motif in these mutants. An AALSAAA mutant in which all negative charges of the DELSEED motif were removed showed a normal pattern for MgATP binding to the catalytic sites, with a clearly present high-affinity site. PMID- 21705327 TI - Thioredoxin regulates adipogenesis through thioredoxin-interacting protein (Txnip) protein stability. AB - Txnip (thioredoxin-interacting protein) is a critical mediator of metabolism and adipogenesis in vivo. The mechanisms of action of Txnip are believed to operate at least in part by inhibiting the redox signaling functions of thioredoxin. We tested here whether Txnip suppressed adipogenesis by inhibiting thioredoxin and discovered a reversal of roles; Txnip inhibits adipogenesis directly, and thioredoxin binding regulates Txnip by enhancing Txnip protein stability. Unlike Txnip, a Txnip mutant that cannot bind thioredoxin (C247S) did not prevent adipocyte differentiation, but was degraded more quickly by proteasomal targeting. Finding that endogenous Txnip protein is also rapidly degraded at the onset of adipogenesis suggested that Txnip degradation is required for adipocyte differentiation. Thioredoxin overexpression stabilized Txnip protein levels to inhibit adipogenesis, and adipogenic stimulants such as insulin promoted Txnip thioredoxin dissociation to the more labile free Txnip state. As an alpha arrestin protein, Txnip has two C-terminal tail PPXY motifs that mediate E3 ubiquitin ligase binding and Txnip protein stability. Mutating the PPXY motifs prevented Txnip degradation, even when thioredoxin binding was lost, and restored the ability of C247S Txnip to inhibit adipogenesis. These studies present a novel reconsideration of Txnip-thioredoxin signaling by showing that thioredoxin regulates the intrinsic function of Txnip as an inhibitor of adipogenesis through protein stabilization. PMID- 21705328 TI - Dual function of protein kinase C (PKC) in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced manganese superoxide dismutase (MnSOD) expression: activation of CREB and FOXO3a by PKC-alpha phosphorylation and by PKC-mediated inactivation of Akt, respectively. AB - 12-O-tetradecanoylphorbol-13-acetate (TPA) has been shown to induce transcriptional activation of human manganese superoxide dismutase (MnSOD) mRNA in human lung carcinoma cells, A549, mediated by a protein kinase C (PKC) dependent activation of cAMP-responsive element-binding protein (CREB)-1/ATF-1 like factors. In this study, we showed that MnSOD protein expression was elevated in response to TPA or TNF-alpha, but not to hydrogen peroxide treatment. TPA induced generation of reactive oxygen species (ROS) was blocked by pretreatment of the PKC inhibitor BIM and NADPH oxidase inhibitor DPI. Small interfering RNA (siRNA) experiments indicated that knocking down the NADPH oxidase components e.g. Rac1, p22(phox), p67(phox), and NOXO1 in A549 cells impaired TPA-induced MnSOD expression. To identify the PKC isozyme involved, we used a sod2 gene response reporter plasmid, pSODLUC-3340-I2E-C, capable of sensing the effect of TNF-alpha and TPA, to monitor the effects of PKC isozyme-specific inhibitors and siRNA-induced knockdown of specific PKC isozyme. Our data indicate that TPA induced MnSOD expression was independent of p53 and most likely mediated by PKC alpha-, and -epsilon-dependent signaling pathways. Furthermore, siRNA-induced knock-down of CREB and Forkhead box class O (FOXO) 3a led to a reduction in TPA induced MnSOD gene expression. Together, our results revealed that TPA up regulates, in part, two PKC-dependent transcriptional pathways to induce MnSOD expression. One pathway involves PKC-alpha catalyzed phosphorylation of CREB and the other involves a PKC-mediated the PP2A catalyzed dephosphorylation of Akt at Ser(473) which in turn leads to FOXO3a Ser(253) dephosphorylation and its activation. PMID- 21705329 TI - Prostate-derived sterile 20-like kinases (PSKs/TAOKs) are activated in mitosis and contribute to mitotic cell rounding and spindle positioning. AB - Prostate-derived sterile 20-like kinases (PSKs) 1-alpha, 1-beta, and 2 are members of the germinal-center kinase-like sterile 20 family of kinases. Previous work has shown that PSK 1-alpha binds and stabilizes microtubules whereas PSK2 destabilizes microtubules. Here, we have investigated the activation and autophosphorylation of endogenous PSKs and show that their catalytic activity increases as cells accumulate in G(2)/M and declines as cells exit mitosis. PSKs are stimulated in synchronous HeLa cells as they progress through mitosis, and these proteins are activated catalytically during each stage of mitosis. During prophase and metaphase activated PSKs are located in the cytoplasm and at the spindle poles, and during telophase and cytokinesis stimulated PSKs are present in trans-Golgi compartments. In addition, small interfering RNA (siRNA) knockdown of PSK1-alpha/beta or PSK2 expression inhibits mitotic cell rounding as well as spindle positioning and centralization. These results show that PSK catalytic activity increases during mitosis and suggest that these proteins can contribute functionally to mitotic cell rounding and spindle centralization during cell division. PMID- 21705330 TI - Pulmonary biocompatibility assessment of inhaled single-wall and multiwall carbon nanotubes in BALB/c mice. AB - With the widespread application of carbon nanotubes (CNTs) in diverse commercial processes, scientists are now concerned about the potential health risk of occupational exposures. In this study, CNT-induced pulmonary toxicity was investigated by exposing BALB/c mice to aerosolized single-wall (SW) CNT and multiwall (MW) CNT (5 MUg/g of mice) for 7 consecutive days in a nose-only exposure system. Microscopic studies showed that inhaled CNTs were homogeneously distributed in the mouse lung. The total number of bronchoalveolar lavage polymorphonuclear leukocytes recovered from the mice exposed to SWCNT and MWCNT (1.2 * 10(6) +/- 0.52 and 9.87 * 10(5) +/- 1.45; respectively) was significantly greater than control mice (5.46 * 10(5) +/- 0.78). Rapid development of pulmonary fibrosis in mice that inhaled CNT was also confirmed by significant increases in the collagen level. The lactate dehydrogenase levels were increased nearly 2- and 2.4-fold in mice that inhaled SWCNT and MWCNT, respectively, as compared with control mice. In addition, exposure of CNTs to mice showed a significant (p < 0.05) reduction of antioxidants (glutathione, superoxide dismutase, and catalase) and induction of oxidants (myloperoxidase, oxidative stress, and lipid peroxidation) compared with control. Apoptosis-related proteins such as caspase-3 and -8 activities were also significantly increased in mice that inhaled CNT than in control mice. Together, this study shows that inhaled CNTs induce inflammation, fibrosis, alteration of oxidant and antioxidant levels, and induction of apoptosis-related proteins in the lung tissues to trigger cell death. PMID- 21705331 TI - Leukemia inhibitory factor (LIF)-dependent, pluripotent stem cells established from inner cell mass of porcine embryos. AB - The pig is important for agriculture and as an animal model in human and veterinary medicine, yet despite over 20 years of effort, there has been a failure to generate pluripotent stem cells analogous to those derived from mouse embryos. Here we report the production of leukemia inhibitory factor-dependent, so-called naive type, pluripotent stem cells from the inner cell mass of porcine blastocysts by up-regulating expression of KLF4 and POU5F1. The alkaline phosphatase-positive colonies resulting from reprogramming resemble mouse embryonic stem cells in colony morphology, cell cycle interval, transcriptome profile, and expression of pluripotent markers, such as POU5F1, SOX2, and surface marker SSEA1. They are dependent on leukemia inhibitory factor signaling for maintenance of pluripotency, can be cultured over extended passage, and have the ability to form teratomas. These cells derived from the inner cell mass of pig blastocysts are clearly distinct from the FGF2-dependent "primed" induced pluripotent stem cells described recently from porcine mesenchymal cells. The data are consistent with the hypothesis that the up-regulation of KLF4, as well as POU5F1, is required to create and stabilize the naive pluripotent state and may explain why the derivation of embryonic stem cells from pigs and other ungulates has proved so difficult. PMID- 21705332 TI - Altered Toll-like receptor 2-mediated endotoxin tolerance is related to diminished interferon beta production. AB - Induction of endotoxin tolerance leads to a reduced inflammatory response after repeated challenge by LPS and is important for resolution of inflammation and prevention of tissue damage. Enterobacterial LPS is recognized by the TLR4 signaling complex, whereas LPS of some non-enterobacterial organisms is capable of signaling independently of TLR4 utilizing TLR2-mediated signal transduction instead. In this study we report that Porphyromonas gingivalis LPS, a TLR2 agonist, fails to induce a fully endotoxin tolerant state in a human monocytic cell line (THP-1) and mouse bone marrow-derived macrophages. In contrast to significantly decreased production of human IL-8 and TNF-alpha and, in mice, keratinocyte-derived cytokine (KC), macrophage inflammatory protein-2 (MIP-2), and TNF-alpha after repeated challenge with Escherichia coli LPS, cells repeatedly exposed to P. gingivalis LPS responded by producing less TNF-alpha but sustained elevated secretion of IL-8, KC, and MIP-2. Furthermore, in endotoxin tolerant cells, production of IL-8 is controlled at the signaling level and correlates well with NF-kappaB activation, whereas TNF-alpha expression is blocked at the gene transcription level. Interferon beta plays an important role in attenuation of chemokine expression in endotoxin-tolerized cells as shown in interferon regulatory factor-3 knock-out mice. In addition, human gingival fibroblasts, commonly known not to display LPS tolerance, were found to be tolerant to repeated challenge by LPS if pretreated with interferon beta. The data suggest that the inability of the LPS-TLR2 complex to induce full endotoxin tolerance in monocytes/macrophages is related to diminished production of interferon beta and may partly explain the involvement of these LPS isoforms in the pathogenesis of chronic inflammatory diseases. PMID- 21705333 TI - Severe neurologic impairment in mice with targeted disruption of the electrogenic sodium bicarbonate cotransporter NBCe2 (Slc4a5 gene). AB - The choroid plexus lining the four ventricles in the brain is where the majority of cerebrospinal fluid (CSF) is produced. The secretory function of the choroid plexus is mediated by specific transport systems that allow the directional flux of nutrients and ions into the CSF and the removal of toxins. Normal CSF dynamics and chemistry ensure that the environment for neural function is optimal. Here, we report that targeted disruption of the Slc4a5 gene encoding the electrogenic sodium bicarbonate cotransporter NBCe2 results in significant remodeling of choroid plexus epithelial cells, including abnormal mitochondrial distribution, cytoskeletal protein expression, and ion transporter polarity. These changes are accompanied by very significant abnormalities in intracerebral ventricle volume, intracranial pressure, and CSF electrolyte levels. The Slc4a5(-/-) mice are significantly more resistant to induction of seizure behavior than wild-type controls. In the retina of Slc4a5(-/-) mice, loss of photoreceptors, ganglion cells, and retinal detachment results in visual impairment assessed by abnormal electroretinogram waveforms. Our findings are the first demonstration of the fundamental importance of NBCe2 in the biology of the nervous system. PMID- 21705334 TI - Conserved tyrosine in the first transmembrane segment of solute:sodium symporters is involved in Na+-coupled substrate co-transport. AB - Solute:sodium symporters (SSSs) transport vital molecules across the plasma membrane of all living organisms. vSGLT, the Na(+)/galactose transporter of Vibrio parahemeolyticus, is the only SSS for which high resolution structural information is available, revealing a LeuT-like fold and a Na(+)-binding site analogous to the Na2 site of LeuT. Whereas the core transmembrane segments (TMs) of SSSs share high structural similarity with other transporters of LeuT-like fold, TM1 does not correspond to any TM in those structural homologs and was only resolved for the backbone atoms in the initial vSGLT structure (Protein Data Bank code 3DH4). To assess the role of TM1 in Na(+)-coupled substrate symport by the SSSs, here we have studied the role of a conserved residue in TM1 by computational modeling in conjunction with radiotracer transport and binding studies. Based on our sequence alignment and much topological data for homologous PutP, the Na(+)/proline transporter, we have simulated a series of vSGLT models with shifted TM1 residue assignments. We show that in two converged vSGLT models that retained the original TM1 backbone conformation, a conserved residue, Tyr 19, is associated with the Na(+) binding interaction network. In silico and in vitro mutagenesis of homologous Tyr-14 in PutP revealed the involvement of this conserved residue in Na(+)-dependent substrate binding and transport. Thus, our combined computational and experimental data provide the first clues about the importance of a conserved residue in TM1, a unique TM in the proteins with LeuT like fold, in the Na(+)-coupled symport mechanism of SSSs. PMID- 21705335 TI - The LptD chaperone LptE is not directly involved in lipopolysaccharide transport in Neisseria meningitidis. AB - The biosynthesis of lipopolysaccharide (LPS) in gram-negative bacteria is well understood, in contrast to the transport to its destination, the outer leaflet of the outer membrane. In Escherichia coli, synthesis and transport of LPS are essential processes. Neisseria meningitidis, conversely, can survive without LPS and tolerates inactivation of genes involved in LPS synthesis and transport. Here, we analyzed whether the LptA, LptB, LptC, LptE, LptF, and LptG proteins, recently implicated in LPS transport in E. coli, function similarly in N. meningitidis. None of the analyzed proteins was essential in N. meningitidis, consistent with their expected roles in LPS transport and additionally demonstrating that they are not required for an essential process such as phospholipid transport. As expected, the absence of most of the Lpt proteins resulted in a severe defect in LPS transport. However, the absence of LptE did not disturb transport of LPS to the cell surface. LptE was found to be associated with LptD, and its absence affected total levels of LptD, suggesting a chaperone like role for LptE in LptD biogenesis. The absence of a direct role of LptE in LPS transport was substantiated by bioinformatic analyses showing a low conservation of LptE in LPS-producing bacteria. Apparently, the role of LptE in N. meningitidis deviates from that in E. coli, suggesting that the Lpt system does not function in a completely conserved manner in all gram-negative bacteria. PMID- 21705336 TI - Impaired spermatogenesis and fertility in mice carrying a mutation in the Spink2 gene expressed predominantly in testes. AB - Spermatogenesis is a complex process involving an intrinsic genetic program composed of germ cell-specific and -predominant genes. In this study, we investigated the mouse Spink2 (serine protease inhibitor Kazal-type 2) gene, which belongs to the SPINK family of proteins characterized by the presence of a Kazal-type serine protease inhibitor-pancreatic secretory trypsin inhibitor domain. We showed that recombinant mouse SPINK2 has trypsin-inhibitory activity. Distribution analyses revealed that Spink2 is transcribed strongly in the testis and weakly in the epididymis, but is not detected in other mouse tissues. Expression of Spink2 is specific to germ cells in the testis and is first evident at the pachytene spermatocyte stage. Immunoblot analyses demonstrated that SPINK2 protein is present in male germ cells at all developmental stages, including in testicular spermatogenic cells, testicular sperm, and mature sperm. To elucidate the functional role of SPINK2 in vivo, we generated mutant mice with diminished levels of SPINK2 using a gene trap mutagenesis approach. Mutant male mice exhibit significantly impaired fertility; further phenotypic analyses revealed that testicular integrity is disrupted, resulting in a reduction in sperm number. Moreover, we found that testes from mutant mice exhibit abnormal spermatogenesis and germ cell apoptosis accompanied by elevated serine protease activity. Our studies thus provide the first demonstration that SPINK2 is required for maintaining normal spermatogenesis and potentially regulates serine protease mediated apoptosis in male germ cells. PMID- 21705337 TI - Polymerase I and transcript release factor (PTRF)/cavin-1 is a novel regulator of stress-induced premature senescence. AB - According to the "free radical theory" of aging, premature senescence induced by oxidative stress contributes to organismal aging. Polymerase I and transcript release factor (PTRF)/cavin-1 is a structural protein component of caveolae, invaginations of the plasma membrane involved in signal transduction. We show that oxidative stress up-regulates PTRF/cavin-1 protein expression and promotes the interaction between PTRF/cavin-1 and caveolin-1, another structural protein component of caveolae. Consistent with these data, the number of caveolae is dramatically increased in cells subjected to oxidative stress. We demonstrate that down-regulation of PTRF/cavin-1 by shRNA significantly inhibits oxidative stress-induced premature senescence. Mechanistically, we found that PTRF/cavin-1 expression is necessary for the oxidant-induced sequestration of Mdm2, a negative regulator of p53, into caveolar membranes, away from p53, and activation of the p53/p21(Waf1/Cip1) pathway. Expression of a mutant form of PTRF/cavin-1, which fails to localize to caveolar membranes after oxidative stress, inhibits oxidative stress-induced activation of p53 and induction of premature senescence. Thus, PTRF/cavin-1 is a novel regulator of oxidative stress-induced premature senescence by acting as a link between free radicals and activation of the p53/p21(Waf1/Cip1) pathway. PMID- 21705338 TI - Compensating stereochemical changes allow murein tripeptide to be accommodated in a conventional peptide-binding protein. AB - The oligopeptide permease (Opp) of Escherichia coli is an ATP-binding cassette transporter that uses the substrate-binding protein (SBP) OppA to bind peptides and deliver them to the membrane components (OppBCDF) for transport. OppA binds conventional peptides 2-5 residues in length regardless of their sequence, but does not facilitate transport of the cell wall component murein tripeptide (Mtp, L-Ala-gamma-D-Glu-meso-Dap), which contains a D-amino acid and a gamma-peptide linkage. Instead, MppA, a homologous substrate-binding protein, forms a functional transporter with OppBCDF for uptake of this unusual tripeptide. Here we have purified MppA and demonstrated biochemically that it binds Mtp with high affinity (K(D) ~ 250 nM). The crystal structure of MppA in complex with Mtp has revealed that Mtp is bound in a relatively extended conformation with its three carboxylates projecting from one side of the molecule and its two amino groups projecting from the opposite face. Specificity for Mtp is conferred by charge charge and dipole-charge interactions with ionic and polar residues of MppA. Comparison of the structure of MppA-Mtp with structures of conventional tripeptides bound to OppA, reveals that the peptide ligands superimpose remarkably closely given the profound differences in their structures. Strikingly, the effect of the D-stereochemistry, which projects the side chain of the D-Glu residue at position 2 in the direction of the main chain in a conventional tripeptide, is compensated by the formation of a gamma-linkage to the amino group of diaminopimelic acid, mimicking the peptide bond between residues 2 and 3 of a conventional tripeptide. PMID- 21705339 TI - Filamin A protein interacts with human immunodeficiency virus type 1 Gag protein and contributes to productive particle assembly. AB - HIV-1 Gag precursor directs virus particle assembly and release. In a search for Gag-interacting proteins that are involved in late stages of the HIV-1 replication cycle, we performed yeast two-hybrid screening against a human cDNA library and identified the non-muscle actin filament cross-linking protein filamin A as a novel Gag binding partner. The 280-kDa filamin A regulates cortical actin network dynamics and participates in the anchoring of membrane proteins to the actin cytoskeleton. Recent studies have shown that filamin A facilitates HIV-1 cell-to-cell transmission by binding to HIV receptors and coreceptors and regulating their clustering on the target cell surface. Here we report a novel role for filamin A in HIV-1 Gag intracellular trafficking. We demonstrate that filamin A interacts with the capsid domain of HIV-1 Gag and that this interaction is involved in particle release in a productive manner. Disruption of this interaction eliminated Gag localization at the plasma membrane and induced Gag accumulation within internal compartments. Moreover, blocking clathrin-dependent endocytic pathways did not relieve the restriction to particle release induced by filamin A depletion. These results suggest that filamin A is involved in the distinct step of the Gag trafficking pathway. The discovery of the Gag-filamin A interaction may provide a new therapeutic target for the treatment of HIV infection. PMID- 21705341 TI - Definitive alkene identification needed for in vitro studies with ole (olefin biosynthesis) proteins. PMID- 21705340 TI - Constitutive NF-kappaB activation confers interleukin 6 (IL6) independence and resistance to dexamethasone and Janus kinase inhibitor INCB018424 in murine plasmacytoma cells. AB - Myeloma cells are dependent on IL6 for their survival and proliferation during the early stages of disease, and independence from IL6 is associated with disease progression. The role of the NF-kappaB pathway in the IL6-independent growth of myeloma cells has not been studied. Because human herpesvirus 8-encoded K13 selectively activates the NF-kappaB pathway, we have used it as a molecular tool to examine the ability of the NF-kappaB pathway to confer IL6 independence on murine plasmacytomas. We demonstrated that ectopic expression of K13, but not its NF-kappaB-defective mutant or a structural homolog, protected plasmacytomas against IL6 withdrawal-induced apoptosis and resulted in emergence of IL6 independent clones that could proliferate long-term in vitro in the absence of IL6 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice. These IL6-independent clones were dependent on NF-kappaB activity for their survival and proliferation but were resistant to dexamethasone and INCB018424, a selective Janus kinase 1/2 inhibitor. Ectopic expression of human T cell leukemia virus 1-encoded Tax protein, which resembles K13 in inducing constitutive NF-kappaB activation, similarly protected plasmacytoma cells against IL6 withdrawal-induced apoptosis. Although K13 is known to up-regulate IL6 gene expression, its protective effect was not due to induction of endogenous IL6 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon IL6 withdrawal. Collectively, these results demonstrate that NF-kappaB activation cannot only promote the emergence of IL6 independence during myeloma progression but can also confer resistance to dexamethasone and INCB018424. PMID- 21705343 TI - Molecular cloning of a Pinguiochrysis pyriformis oleate-specific microsomal Delta12-fatty acid desaturase and functional analysis in yeasts and thraustochytrids. AB - We isolated a putative desaturase gene from a marine alga, Pinguiochrysis pyriformis MBIC 10872, which is capable of accumulating eicosapentaenoic acid (C20:5(Delta5,8,11,14,17)). The gene possessed an open reading frame of 1,314 bp encoding a putative 437 amino acid residues showing high sequence identity (37 48%) with fungal and nematode Delta12-fatty acid desaturases. Yeast cells transformed with the gene converted endogenous oleic acid (C18:1(Delta9)) to linoleic acid (C18:2(Delta9,12)). However, no double bonds were introduced into other endogenous fatty acids or exogenously added fatty acids. Flag-tagged enzyme was recovered in the micosome fraction when expressed in yeast cells. To express the gene in thraustochytrids, a construct driven by the thraustochytrid-derived ubiquitin promoter was used. Interestingly, exogenously added oleic acid was converted to linoleic acid in the gene transformants but not mock transformants of Aurantiochytrium limacinum mh0186. These results clearly indicate that the gene encodes a microsomal Delta12-fatty acid desaturase and was expressed functionally in not only yeasts but also thraustochytrids. This is the first report describing the heterozygous expression of a fatty acid desaturase in thraustochytrids, and could facilitate a genetic approach towards fatty acid synthesis in thraustochytrids which are expected to be an alternative source of polyunsaturated fatty acids. PMID- 21705344 TI - Position-dependent effect of a neural-restrictive silencer-like element present in the promoter downstream of the SCG10-like protein gene. AB - Neural-restrictive silencer (NRS) has been well characterized in SCG10 and many other neuron-specific genes; it is, however, unknown whether the promoters of the SCLIP and RB3 genes (two other SCG10 family members) share basal transcriptional mechanisms with SCG10 or not. To explore how NRS-mediated neural-specific gene transcription has evolved, we determined the genomic and promoter structures of the SCLIP gene, and found that the gene retained an NRS-like element that functioned as a negative regulator in non-neuronal cells. However, unlike the NRS in the SCG10 gene, this NRS(SCLIP) was located downstream of the transcription start site, and showed a position-dependent repressing activity. Further gel shift and NRS factor (NRSF) co-transfection experiments revealed that NRS(SCLIP) was bound and regulated by NRSF. Such an element was not found in the gene promoter of RB3, suggesting that the NRS-NRSF regulatory system evolved once SCLIP had diverged from RB3 or stathmin. PMID- 21705345 TI - Intergroup differences in the sharing of emotive states: neural evidence of an empathy gap. AB - Empathy facilitates prosocial behavior and social understanding. Here, however, we suggest that the most basic mechanism of empathy--the intuitive sharing of other's emotional and motivational states--is limited to those we like. Measuring electroencephalographic (EEG) alpha oscillations as people observed ingroup vs outgroup members, we found that participants showed similar activation patterns when feeling sad as when they observed ingroup members feeling sad. In contrast, participants did not show these same activation patterns when observing outgroup members and even less so the more they were prejudiced. These findings provide evidence from brain activity for an ingroup bias in empathy: empathy may be restricted to close others and, without active effort, may not extend to outgroups, potentially making them likely targets for prejudice and discrimination. PMID- 21705346 TI - Leptospira interrogans encodes an ROK family glucokinase involved in a cryptic glucose utilization pathway. AB - Although Leptospira interrogans is unable to utilize glucose as its carbon/energy source, the LA_1437 gene of L. interrogans serovar Lai potentially encodes a group III glucokinase (GLK). The L. interrogans GLK (LiGLK) heterogeneously expressed in Escherichia coli was purified and proved to be a homodimeric enzyme with its specific activity of 12.3 +/- 0.6 U/mg x protein determined under an improved assay condition (pH 9.0, 50 degrees C), 7.5-fold higher than that assayed under the previously used condition (pH 7.3, 25 degrees C). The improved sensitivity allowed us to detect this enzymatic activity of (5.0 +/- 0.6) * 10(-3) U/mg x protein in the crude extract of L. interrogans serovar Lai cultured in standard Ellinghausen-McCullough-Johnson-Harris medium. The k(cat) and K(m) values for d-glucose and ATP were similar to those of other group III GLKs, although the K(m) value for ATP was slightly higher. Site-directed mutagenesis analysis targeting the conserved amino acid residues in the potential ATP-binding motif hinted that a proper array of Gly residues in the motif might be important for maintaining the conformation that was essential for its function. Gene expression profiling and quantitative proteomic data mining provided preliminary evidence for the absence of efficient systems involved in glucose transport and glycolysis that might account for the failure of glucose utilization in L. interrogans. PMID- 21705347 TI - Next generation sequencing--implications for clinical practice. AB - BACKGROUND: Genetic testing in inherited disease has traditionally relied upon recognition of the presenting clinical syndrome and targeted analysis of genes known to be linked to that syndrome. Consequently, many patients with genetic syndromes remain without a specific diagnosis. AREAS OF AGREEMENT: New 'next generation' sequencing (NGS) techniques permit simultaneous sequencing of enormous amounts of DNA. A slew of research publications have recently demonstrated the tremendous power of these technologies in increasing understanding of human genetic disease. AREAS OF CONTROVERSY: These approaches are likely to be increasingly employed in routine diagnostic practice, but the scale of the genetic information yielded about individuals means that caution must be exercised to avoid net harm in this setting. AREAS TIMELY FOR DEVELOPING RESEARCH: Use of NGS in a research setting will increasingly have a major but indirect beneficial impact on clinical practice. However, important technical, ethical and social challenges need to be addressed through informed professional and public dialogue before it finds its mature niche as a direct tool in the clinical diagnostic armoury. PMID- 21705348 TI - Another angiogenesis-independent role for VEGF: SDF1-dependent cardiac repair via cardiac stem cells. PMID- 21705349 TI - A Brugada syndrome mutation (p.S216L) and its modulation by p.H558R polymorphism: standard and dynamic characterization. AB - AIMS: The Na(+) channel mutation (p.S216L), previously associated with type 3 long-QT syndrome (LQT3) phenotype, and a common polymorphism (p.H558R) were detected in a patient with an intermittent Brugada syndrome (BS) ECG pattern. The study was aimed to assess the p.S216L electrical phenotype, its modulation by p.H558R, and to identify abnormalities compatible with a mixed BS-LQT3 phenotype. METHODS AND RESULTS: The mutation was expressed alone (S216L channels), or in combination with the polymorphism (S216L-H558R channels), in a mammalian cell line (TSA201). Functional analysis included standard voltage clamp and dynamic clamp with endo- and epicardial action potential waveforms. Expression of S216L channels was associated with a 60% reduction in maximum Na(+) current (I(Na)) density, attributable to protein misfolding (rescued by mexiletine pretreatment) and moderate slowing of inactivation. I(Na) density partially recovered in S216L H558R channels, but I(Na) inactivation and its recovery were further delayed. The persistent component of I(Na) (I(NaL)) was unchanged. Under dynamic clamp conditions, I(Na) decreased in S216L channels and displayed a 'resurgent' component during late repolarization. In S216L-H558R channels, I(Na) density partially recovered and did not display a resurgent component. I(Na) changes during dynamic clamp were interpreted by numerical modelling. CONCLUSION: The BS pattern of p.S216L might result from a decrease in I(Na) density, which masked gating abnormalities that might otherwise result in a LQT phenotype. The p.H558R polymorphism decreased p.S216L expressivity, partly by lessening p.S216L effects and partly through the induction of further gating abnormalities suitable to blunt p.S216L effects during repolarization. PMID- 21705350 TI - Prevalence and impact of abnormal ROTEM(R) assays in severe blunt trauma: results of the 'Diagnosis and Treatment of Trauma-Induced Coagulopathy (DIA-TRE-TIC) study'. AB - BACKGROUND: ROTEM((r))/TEG((r)) (rotational thromboelastometry) assays appear to be useful for the treatment of bleeding trauma patients. However, data on the prevalence and impact of abnormal ROTEM((r)) assays are scarce. METHODS: This is a prospective cohort study of blunt trauma patients (Injury Severity Score >=15 or Glasgow Coma Score <=14) admitted to Innsbruck Medical University Hospital between July 2005 and July 2008. Standard coagulation tests, antithrombin (AT), prothrombin fragments (F1+2), thrombin-antithrombin complex (TAT), and ROTEM((r)) assays were measured after admission. Data on 334 patients remained for final analysis. RESULTS: ROTEM((r)) parameters correlated with standard coagulation tests (all Spearman r>0.5), and significant differences in mortality were detected for defined ROTEM((r)) thresholds [FIBTEM 7 mm (21% vs 9%, P=0.006), EXTEM MCF (maximum clot firmness) 45 mm (25.4% vs 9.4%, P=0.001)]. EXTEM MCF was independently associated with early mortality [odds ratio (OR) 0.94, 95% confidence interval (CI) 0.9-0.99] and MCF FIBTEM with need for red blood cell transfusion (OR 0.92, 95% CI 0.87-0.98). In polytrauma patients with or without head injury (n=274), the prevalence of low fibrinogen concentrations, impaired fibrin polymerization, and reduced clot firmness was 26%, 30%, and 22%, respectively, and thus higher than the prolonged international normalized ratio (14%). Hyperfibrinolysis increased fatality rates and occurred as frequently in isolated brain injury (n=60) as in polytrauma (n=274) (5%, 95% CI 1.04-13.92 vs 7.3%, 95% CI 4.52-11.05). All patients showed elevated F1+2 and TAT and low AT levels, indicating increased thrombin formation. CONCLUSIONS: Our data enlarge the body of evidence showing that ROTEM((r)) assays are useful in trauma patients. Treatment concepts should focus on maintaining fibrin polymerization and treating hyperfibrinolysis. PMID- 21705351 TI - Complete atrioventricular block in a patient with intracardiac metastases from malignant melanoma. PMID- 21705352 TI - Triple heart image: one heart beats as three. PMID- 21705353 TI - Left and right ventricular function in aortic stenosis patients 8 weeks post transcatheter aortic valve implantation or surgical aortic valve replacement. AB - AIMS: Knowledge of longitudinal left and right ventricular (LV and RV) function after transcatheter aortic valve implantation (TAVI) is scarce. We hypothesized that the longitudinal systolic biventricular function in aortic stenosis (AS) patients is affected differently by TAVI and surgical aortic valve replacement (SAVR). METHODS AND RESULTS: Thirty-three AS patients (all-TAVI group, age 81 +/- 9 years, 18 female), with EuroSCORE 18 +/- 9%, were accepted for TAVI. Seventeen of these patients were matched (by gender, age, and LV function) to 17 patients undergoing SAVR. Conventional echocardiographic parameters, systolic atrioventricular plane displacement (AVPD) at standard sites and peak systolic velocity (PSV) by pulsed tissue Doppler at basal RV free wall, LV lateral wall, and septum were studied before and 8 weeks after the procedure. Procedural success was 100%, and 30-day mortality 9%. In all TAVI patients, AVPD(lateral), PSV(lateral), AVPD(septal), and PSV(septal) increased (P< 0.001, 0.003, 0.006 and 0.002). When studying the matched patients postoperatively, both the SAVR and TAVI patients had increased PSV(lateral) and AVPD(lateral) (SAVR: P=0.03 and P=0.04, TAVI: P=0.04 and P=0.01). The PSV(RV) increased in the all-TAVI group (P=0.007), while the AVPD(RV) was unchanged. SAVR patients had decreased AVPD(RV) (P=0.001) and PSV(RV) (P=0.004), while the matched TAVI patients had unchanged RV function parameters. CONCLUSION: An improvement in regional longitudinal LV function in the septal and lateral wall could be seen after TAVI. Among the matched patients, both the TAVI and SAVR patients seemed to improve LV function in the lateral wall. RV systolic function increased in TAVI patients, but was impaired in the matched SAVR group at the 8-week follow-up. PMID- 21705354 TI - Mirror-image Gerbode defect? PMID- 21705355 TI - Shamrock aorta: unruptured sinus of Valsalva aneurysms in a patient with a prosthetic heart valve. PMID- 21705356 TI - Sudden cardiac death in Ebstein's malformation due to a cardiac haemangioma. PMID- 21705357 TI - The management of myocarditis. AB - Despite considerable advances in our understanding of myocarditis pathogenesis, the clinical management of myocarditis has changed relatively little in the last few years. This review aims to help bridge the widening gap between recent mechanistic insights, which are largely derived from animal models, and their potential impact on disease burden. We illustrate the pathogenetic mechanisms that are prime targets for novel therapeutic interventions. Pathway and pathogen specific molecular diagnostic tests have expanded the role for endomyocardial biopsy. State of the art cardiac magnetic resonance imaging can now provide non invasive tissue characterization and localize inflammatory infiltrates but imaging techniques are misleading if infectious agents are involved. We emphasize the gaps in our current clinical knowledge, particularly with respect to aetiology-based therapy, and suggest opportunities for high impact, translational investigations. PMID- 21705358 TI - Blood pressure, lipids and glucose in type 2 diabetes: how low should we go? Re discovering personalized care. AB - Epidemiological studies have clearly shown a direct relationship between the levels of blood pressure, glycaemia and LDL-cholesterol, and the complications of diabetes. Although 'lower should be better', the results of recent clinical trials examining the benefits of normalizing risk factor levels have been counter intuitive and, at times, disturbing, and have called into question this notion. This review focuses on patients with type 2 diabetes who make up 90% of patients with diabetes. It aims to provide a clear summary and interpretation of recent trials to help clinicians to set targets for cardiovascular risk factors in individual patients. It highlights areas of agreement and disagreement between current guidelines. Recent data indicate that some patient subgroups might respond differently to aggressive risk factor management. Our challenge is how to identify these patients and deliver truly personalized diabetes care that maximizes benefit, and minimizes harm. Guidelines and position statements stress the value of setting personalized targets. We explore what this means, and how this might be achieved in practice by outlining some solutions to issues that currently limit the delivery of personalized care. We call for further research assessing the overall clinical impact of cardiovascular risk factor intervention by finding appropriate ways of combining data on mortality, complications, side effects, quality of life, and cost-effectiveness. PMID- 21705359 TI - Nutrition in cardiovascular disease: salt in hypertension and heart failure. AB - There is much evidence for a causal relationship between salt intake and blood pressure (BP). The current salt intake in many countries is between 9 and 12 g/day. A reduction in salt intake to the recommended level of 5-6 g/day lowers BP in both hypertensive and normotensive individuals. A further reduction to 3-4 g/day has a much greater effect. Prospective studies and outcome trials have demonstrated that a lower salt intake is associated with a decreased risk of cardiovascular disease. Increasing evidence also suggests that a high salt intake is directly related to left ventricular hypertrophy (LVH) independent of BP. Both raised BP and LVH are important risk factors for heart failure. It is therefore possible that a lower salt intake could prevent the development of heart failure. In patients who already have heart failure, a high salt intake aggravates the retention of salt and water, thereby exacerbating heart failure symptoms and progression of the disease. A lower salt intake plays an important role in the management of heart failure. Despite this, currently there is no clear evidence on how far salt intake should be reduced in heart failure. Our personal view is that these patients should reduce their salt intake to <5 g/day, i.e. the maximum intake recommended by the World Health Organisation for all adults. If salt intake is successfully reduced, there may well be a need for a reduction in diuretic dosage. PMID- 21705360 TI - When status hurts: dimensions of women's status and domestic abuse in rural Northern India. AB - This study is a multiple logistic regression analysis of the relationship between dimensions of women's status and domestic abuse in rural Uttar Pradesh, India, using the 1998-1999 National Family Health Survey (NFHS-2). Findings indicate that the effects of a woman's status on her likelihood of experiencing abuse depend on the social realm within which status operates. Specifically, more "public" dimensions of status are associated with a greater probability of abuse, while "domestic" dimensions are protective. The findings are interpreted in terms of transitioning gender norms in Uttar Pradesh and provide clarity to the literature on the complex relationship between status and abuse. PMID- 21705361 TI - The importance of resources and information in the lives of battered mothers. AB - An increasing body of research has documented the overlap between intimate partner violence and child abuse. To date, very little research has explored mothers' perspectives on how child protection services (CPS) actually investigates and intervenes in families where intimate partner violence (IPV) as well as child abuse or neglect have occurred. The current research explores the complex role of information and resources in child protection investigations and interventions. In-person interviews were conducted with 19 mothers who had been battered and who had been involved with CPS because of the violence. Mothers reported difficulties in sharing information with and receiving information from CPS workers, but some also reported benefiting from information they received. Moreover, for a handful of women, the CPS intervention was a source of emotional strength. Implications for improving CPS interventions when IPV is occurring are discussed. PMID- 21705363 TI - Similarities between the genetic environments of blaCTX-M-15 in Escherichia coli from clinical and food samples from Spain and overseas travellers. PMID- 21705362 TI - Structure-function relationships of CarO, the carbapenem resistance-associated outer membrane protein of Acinetobacter baumannii. AB - OBJECTIVES: In the context of the increasing worldwide occurrence of imipenem resistant Acinetobacter baumannii strains, we investigated a possible porin mediated mechanism relating to the carbapenem resistance-associated outer membrane protein, CarO. The aim of this study was to determine whether this porin may be a diffusion pathway for carbapenems in A. baumannii. METHODS: By analysing and comparing the sequences of CarO with protein databanks, we identified two major groups of sequences that we named CarOa and CarOb. We overproduced in Escherichia coli, extracted, purified by affinity chromatography and refolded in Triton X-100 rCarO from both groups. Their functional properties were investigated and compared by reconstitution in planar lipid bilayers. RESULTS: This functional study showed that rCarOa and rCarOb exhibit identical single channel conductances (i.e. 20 pS in 1 M KCl) and similar poor cationic selectivity. Both channels were not specific towards meropenem and glutamic acid and poorly specific towards arginine, but they presented a marked specificity towards imipenem. From the calculated binding constants, we highlight that the CarOb channel was twice as specific as the CarOa channel for this antibiotic. Moreover, the CarOa channel could facilitate ornithine diffusion when the CarOb channel would not. CONCLUSIONS: We provide here the first evidence that CarO channels possess an imipenem (but not meropenem) binding site, and that their specificities depend on their primary structure. Any decrease in CarO expression would thus reduce the susceptibility of A. baumannii to this antibiotic. PMID- 21705364 TI - The Strategies WDK: a graphical search interface and web development kit for functional genomics databases. AB - Web sites associated with the Eukaryotic Pathogen Bioinformatics Resource Center (EuPathDB.org) have recently introduced a graphical user interface, the Strategies WDK, intended to make advanced searching and set and interval operations easy and accessible to all users. With a design guided by usability studies, the system helps motivate researchers to perform dynamic computational experiments and explore relationships across data sets. For example, PlasmoDB users seeking novel therapeutic targets may wish to locate putative enzymes that distinguish pathogens from their hosts, and that are expressed during appropriate developmental stages. When a researcher runs one of the approximately 100 searches available on the site, the search is presented as a first step in a strategy. The strategy is extended by running additional searches, which are combined with set operators (union, intersect or minus), or genomic interval operators (overlap, contains). A graphical display uses Venn diagrams to make the strategy's flow obvious. The interface facilitates interactive adjustment of the component searches with changes propagating forward through the strategy. Users may save their strategies, creating protocols that can be shared with colleagues. The strategy system has now been deployed on all EuPathDB databases, and successfully deployed by other projects. The Strategies WDK uses a configurable MVC architecture that is compatible with most genomics and biological warehouse databases, and is available for download at code.google.com/p/strategies-wdk. Database URL: www.eupathdb.org. PMID- 21705365 TI - Optimal per cent by weight of elements in diagnostic quality radiation shielding materials. AB - By increasing the usage of radiation in all aspects of lives, the human body is becoming more exposed to ionising radiation. The purpose of this study is to find the optimal radiation shielding materials to protect humans from the radiation hazards of radiation. Some elements and compounds such as Ag, Bi, Pb, W, BaSO(4) were chosen on the basis of their attenuation coefficients and other characteristics to produce optimised radiation shielding compounds. Multi objective non-dominated sorting genetic algorithm-II was used to optimise the weight fraction of the elements in compounds based on the dose equivalent rate, shield weight and cost. Consequently, sets of suitable compounds were obtained depending on various applications for energy 0.06 and 0.15 MeV. In addition, optimised lead free compounds were obtained. The results presented in a series of graphs should enable radiation shield designers to choose an appropriate combination according to their requirements. PMID- 21705366 TI - Important neuronal toxicity of microtubule-bound Tau in vivo in Drosophila. AB - The microtubule-associated protein Tau is found in large amount in axons of neurons and is involved in human neurodegenerative diseases called tauopathies, which include Alzheimer's disease. In these diseases, the Tau protein is abnormally hyperphosphorylated and one therapeutic strategy currently under consideration consists in inhibiting Tau phosphorylation. However, the consequences of an excess of hypophosphorylated Tau onto neuronal physiology have not been investigated in vivo. Here we studied how important is Tau phosphorylation for axonal transport and neurohormone release in vivo, using the Drosophila model. Surprisingly, our results demonstrate a stronger toxicity of hypophosphorylated Tau for neuronal function, when compared with normal or pseudophosphorylated Tau. This reveals a potential limit of the current therapeutic strategy aimed at inhibiting Tau phosphorylation. PMID- 21705367 TI - The neuroecology of chemical defenses. AB - Chemicals are a frequent means whereby organisms defend themselves against predators, competitors, parasites, microbes, and other potentially harmful organisms. Much progress has been made in understanding how a phylogenetic diversity of organisms living in a variety of environments uses chemical defenses. Chief among these advances is determining the molecular identity of defensive chemicals and the roles they play in shaping interactions between individuals. Some progress has been made in deciphering the molecular, cellular, and systems level mechanisms underlying these interactions, as well as how these interactions can lead to structuring of communities and even ecosystems. The neuroecological approach unifies practices and principles from these diverse disciplines and at all scales as it attempts to explain in a single conceptual framework the abundances of organisms and the distributions of species within natural habitats. This article explores the neuroecology of chemical defenses with a focus on aquatic organisms and environments. We review the concept of molecules of keystone significance, including examples of how saxitoxin and tetrodotoxin can shape the organization and dynamics of marine and riparian communities, respectively. We also describe the current status and future directions of a topic of interest to our research group-the use of ink by marine molluscs, especially sea hares, in their defense. We describe a diversity of molecules and mechanisms mediating the protective effects of sea hares' ink, including use as chemical defenses against predators and as alarm cues toward conspecifics, and postulate that some defensive molecules may function as molecules of keystone significance. Finally, we propose future directions for studying the neuroecology of the chemical defenses of sea hares and their molluscan relatives, the cephalopods. PMID- 21705368 TI - Evolution of muscle activity patterns driving motions of the jaw and hyoid during chewing in Gnathostomes. AB - Although chewing has been suggested to be a basal gnathostome trait retained in most major vertebrate lineages, it has not been studied broadly and comparatively across vertebrates. To redress this imbalance, we recorded EMG from muscles powering anteroposterior movement of the hyoid, and dorsoventral movement of the mandibular jaw during chewing. We compared muscle activity patterns (MAP) during chewing in jawed vertebrate taxa belonging to unrelated groups of basal bony fishes and artiodactyl mammals. Our aim was to outline the evolution of coordination in MAP. Comparisons of activity in muscles of the jaw and hyoid that power chewing in closely related artiodactyls using cross-correlation analyses identified reorganizations of jaw and hyoid MAP between herbivores and omnivores. EMG data from basal bony fishes revealed a tighter coordination of jaw and hyoid MAP during chewing than seen in artiodactyls. Across this broad phylogenetic range, there have been major structural reorganizations, including a reduction of the bony hyoid suspension, which is robust in fishes, to the acquisition in a mammalian ancestor of a muscle sling suspending the hyoid. These changes appear to be reflected in a shift in chewing MAP that occurred in an unidentified anamniote stem-lineage. This shift matches observations that, when compared with fishes, the pattern of hyoid motion in tetrapods is reversed and also time shifted relative to the pattern of jaw movement. PMID- 21705369 TI - The antibody-mediated targeted delivery of interleukin-10 inhibits endometriosis in a syngeneic mouse model. AB - BACKGROUND: Endometriosis is still a highly underdiagnosed disease, and the current medical and surgical treatment of endometriosis is associated with a high recurrence rate. This study investigates the use of derivatives of the human antibody F8, specific to the alternatively spliced extra-domain A of fibronectin (Fn), for the imaging and treatment of endometriosis. METHODS: Immunohistochemistry and immunofluorescence was used to evaluate antigen expression in endometriotic tissue of human endometriosis and of a syngeneic mouse model of the disease. The in vivo targeting performance of a fluorescent derivative of the F8 antibody was assessed by imaging mice with endometriosis using a near-infrared fluorescence imager, 24 h following i.v. injection of the antibody conjugate. Furthermore, the mouse model was used for therapy experiments using two recombinant F8-based immunocytokines [F8-interleukin-10 (IL10) and F8 IL2] or saline for the treatment groups. RESULTS: A very strong vascular expression of splice isoforms of Fn and of tenascin-C was observed in human endometriotic lesions by immunohistochemistry and immunofluorescence techniques. After i.v. administration, a selective accumulation of the F8 antibody in endometriotic lesions could be observed in a syngeneic mouse model. These targeting data were used as a basis for therapy experiments with a pro inflammatory (F8-IL2) and an anti-inflammatory (F8-IL10) cytokine fusion protein of the F8 antibody. The average lesion size in the F8-IL10 treatment group was clearly reduced compared with the saline control group and with the F8-IL2 group, for which no therapeutic effects were observed. CONCLUSIONS: The F8 antibody targets endometriotic lesions in vivo in a mouse model of endometriosis and may be used for the non-invasive imaging of the disease and for the pharmacodelivery of anti-inflammatory cytokines, such as IL10. PMID- 21705370 TI - In vitro development of secondary follicles from cryopreserved rhesus macaque ovarian tissue after slow-rate freeze or vitrification. AB - BACKGROUND: Ovarian tissue cryopreservation is the only option for preserving fertility in prepubertal girls and cancer patients requiring immediate treatment. Following ovarian tissue cryopreservation, fertility can be restored after tissue transplant or in vitro follicle maturation. METHODS: Macaque (n= 4) ovarian cortex was cryopreserved using slow-rate freezing (slow freezing) or vitrification. Tissues were fixed for histology or phosphohistone H3 (PPH3) analysis, cultured with bromodeoxyuridine (BrdU) or used for three-dimensional secondary follicle culture. Follicular diameter and steroid hormones were measured weekly. RESULTS: Slow freezing induced frequent cryo-injuries while vitrification consistently maintained morphology of the stroma and secondary follicles. PPH3 was similar in fresh and vitrified, but sparse in slow-frozen tissues. BrdU uptake appeared diminished following both methods compared with that in fresh follicles. In vitro follicle survival and growth were greater in fresh than in cryopreserved follicles. Antrum formation appeared similar after vitrification compared with the fresh, but was reduced following slow freezing. Steroid production was delayed or diminished following both methods compared with fresh samples. CONCLUSIONS: Secondary follicle morphology was improved after vitrification relative to slow freezing. Following vitrification, stroma was consistently more compact with intact cells typical to that of fresh tissue. BrdU uptake demonstrated follicle viability post-thaw/warming. For the first time, although not to the extent of fresh follicles, macaque follicles from cryopreserved tissue can survive, grow, form an antrum and produce steroid hormones, indicating some functional preservation. The combination of successful ovarian tissue cryopreservation with in vitro maturation of follicles will offer a major advancement to the field of fertility preservation. PMID- 21705371 TI - Pathophysiological approach to bowel dysfunction after segmental colorectal resection for deep endometriosis infiltrating the rectum: a preliminary study. AB - BACKGROUND: Colorectal segmental resection is performed worldwide in a majority of women presenting with symptomatic deep endometriosis infiltrating the rectum. The aim of the present study was to investigate the pathophysiological mechanisms involved in post-operative digestive dysfunction. METHODS: We selected patients managed by colorectal resection for rectal endometriosis, who had developed post operative severe constipation and whose follow up was superior to 24 months. To assess the mechanisms involved in the pathogenesis of this complaint, we performed a step-by-step work up including: low digestive tract endoscopy, colonic transit time measurement and when appropriate anorectal manometry, electromyography and defecographic evaluation. RESULTS: Five out of 25 (20%) patients, whose age ranged from 27 to 41 years, were investigated for severe post operative terminal constipation. Four different mechanisms responsible for terminal constipation were identified: tight stenosis of the colorectal anastomosis, post-operative neurological sequelae, colonic intussusception through the colorectal anastomosis and transit constipation that developed post surgery. CONCLUSIONS: Post-operative constipation is a frequent complaint in women managed by colorectal resection for rectal endometriosis. A multidisciplinary approach is mandatory as pathophysiologic mechanisms may vary and prove difficult to understand. The risk of post-operative bowel dysfunction following colorectal endometriosis must be taken into account whenever this technique is proposed in young women presenting with a benign disease such as deep endometriosis. PMID- 21705372 TI - Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: methodological problems. PMID- 21705374 TI - Predicting emergency department admissions. AB - OBJECTIVE: To develop and validate models to predict emergency department (ED) presentations and hospital admissions for time and day of the year. METHODS: Initial model development and validation was based on 5 years of historical data from two dissimilar hospitals, followed by subsequent validation on 27 hospitals representing 95% of the ED presentations across the state. Forecast accuracy was assessed using the mean average percentage error (MAPE) between forecasts and observed data. The study also determined a daily sample size threshold for forecasting subgroups within the data. RESULTS: Presentations to the ED and subsequent admissions to hospital beds are not random and can be predicted. Forecast accuracy worsened as the forecast time intervals became smaller: when forecasting monthly admissions, the best MAPE was approximately 2%, for daily admissions, 11%; for 4-hourly admissions, 38%; and for hourly admissions, 50%. Presentations were more easily forecast than admissions (daily MAPE ~7%). When validating accuracy at additional hospitals, forecasts for urban facilities were generally more accurate than regional forecasts (accuracy is related to sample size). Subgroups within the data with more than 10 admissions or presentations per day had forecast errors statistically similar to the entire dataset. The study also included a software implementation of the models, resulting in a data dashboard for bed managers. CONCLUSIONS: Valid ED prediction tools can be generated from access to de-identified historic data, which may be used to assist elective surgery scheduling and bed management. The paper provides forecasting performance levels to guide similar studies. PMID- 21705375 TI - Sensitive troponin assays. AB - Sensitive troponin assays have been developed to meet the diagnostic goals set by the universal definition of myocardial infarction (MI). The analytical advantages of sensitive troponin assays include improved analytical imprecision at concentrations below the 99th percentile and the ability to define a reference distribution fully. Clinically, the improved sensitivity translates into the ability to diagnosis MI earlier, possibly within 3 h from admission and the ability to use the rate of change of troponin (Delta troponin) for diagnosis. Very sensitive assays may, in appropriately selected populations (perhaps with the addition of Delta troponin), allow diagnosis on hospital admission or within 1-2 h of admission. An elevated troponin level occurring in patients without suspected acute coronary syndromes has, in all studies to date in which outcome has been examined, been shown to indicate an adverse prognosis whatever the underlying clinical diagnosis. Failure of elevation means a good prognosis allowing early, safe hospital discharge, whereas a raised value requires investigation and should help prevent clinically significant pathology being overlooked. Sensitive troponins do present a challenge to the laboratory and the clinician. For the laboratory, the diagnosis of MI requires a change in troponin value. For the clinician, the challenge is to shift from a simplistic yes/no diagnosis of MI based on a single troponin value to a diagnosis that utilises early troponin changes as part of the clinical picture, and to relate the new class of detectable troponin elevation in patients with ischaemic myocardial disease to existing clinical guidelines and trial evidence. PMID- 21705376 TI - Quantitative expression study of four cytokeratins and p63 in squamous cell carcinoma of the tongue: suitability for sentinel node navigation surgery using one-step nucleic acid amplification. AB - AIMS: Sentinel node navigation surgery (SNNS) is currently considered to provide better staging of regional metastasis. For rapid and accurate sentinel lymph node analysis, one-step nucleic acid amplification using cytokeratin 19 (CK19) has been applied, particularly in breast cancer. On the other hand, additional quantitative reverse transcription PCR targets containing cytokeratins have been reported recently in head and neck cancer. In this report, CK19 and p63 were immunohistochemically examined in primary tumours for use as molecular markers and were compared with cytokeratin 903 (CK903), cytokeratin 8/18 (CK8/18) and cytokeratin (AE1/AE3), which are used in diagnostic immunohistochemistry for head and neck squamous cell carcinoma. METHODS: The study reviewed 17 patients with T1/T2, N0 (UICC) oral squamous cell carcinoma of the tongue who were treated surgically at Kyorin University Hospital between 2002 and 2009. The intensity and proportion of tumour cells stained for CK19, CK903, p63, CK8/18 and AE1/AE3 were evaluated. RESULTS: CK19 and CK8/18 staining in cytoplasm was patchy among carcinoma cells, indicating weak expression. Staining proportion for p63, CK903 and AE1/AE3 was greater than for CK19 and CK8/18, although staining intensity for CK903 was weaker than for p63 and AE1/AE3. The difference in total score between CK19 and CK8/18 staining and p63, CK903 and AE1/AE3 staining was statistically significant (p<0.001). p63 and AE1/AE3 may be better markers than CK903, CK19 and CK8/18. CONCLUSIONS: This suggests that p63 is of clinical utility in SNNS and that CK19 is unsuitable for early tongue carcinoma. Further studies are needed before clinical application of these markers. PMID- 21705377 TI - Differential selection processes in opportunistic chlamydia screening. PMID- 21705378 TI - Older partner selection, sexual risk behaviour and unrecognised HIV infection among black and Latino men who have sex with men. AB - OBJECTIVES: The authors examine whether young black and Latino men who have sex with men (MSM) who have older sex partners are more likely than those who do not have older sex partners to have unrecognised HIV infection. The authors examine whether the association stems from (1) increased sexual risk behaviour with male partners of any age, (2) heightened risk of being exposed to HIV infection by older partners or (3) a combination of these two factors. METHODS: The analytical sample consisted of 723 black and Latino MSM, aged 18-35 years, who were HIV negative or of unknown serostatus at study entry. Participants completed a self-administered questionnaire and were tested for HIV infection. Men who reported having a male sex partner who was at least 4 years older than themselves were compared with those who did not. Outcomes included unprotected receptive anal intercourse (URAI) with male partners of any age (past 3 months) and having unrecognised HIV infection. RESULTS: Men with older partners reported a higher prevalence of URAI (AOR = 1.50, 95% CI 1.02 to 2.21). A second model found that men with older partners had increased odds of having unrecognised HIV infection (AOR = 2.51, 95% CI 1.18 to 5.34) after controlling for the number of URAI partners of any age, which remained an independent predictor. CONCLUSIONS: Young black and Latino MSM who had older male sex partners were at increased risk of having unrecognised HIV infection. This heightened risk was associated with sexual risk behaviour with partners of any age as well as possible increased exposure to HIV infection from older partners. PMID- 21705380 TI - The biochemical basis of life history adaptation: molecular and enzymological causes of NADP(+)-isocitrate dehydrogenase activity differences between morphs of Gryllus firmus that differ in lipid biosynthesis and life history. AB - Although whole-organism aspects of life-history physiology are well studied and molecular information (e.g., transcript abundance) on life-history variation is accumulating rapidly, much less information is available on the biochemical (enzymological) basis of life-history adaptation. The present study investigated the biochemical and molecular causes of specific activity differences of the lipogenic enzyme, NADP(+)-isocitrate dehydrogenase, between genetic lines of the wing-polymorphic cricket, Gryllus firmus, which differ in lipid biosynthesis and life history. With one exception, variation among 21 Nadp(+)-Idh genomic sequences, which spanned the entire coding sequence of the gene, was restricted to a few synonymous substitutions within and among replicate flight-capable or flightless lines. No NADP(+)-IDH electromorph variation was observed among individuals within or among lines as determined by polyacrylamide gel electrophoresis. Nor did any NADP(+)-IDH kinetic or stability parameter, such as K(M) for substrate or cofactor, k(cat), or thermal denaturation, differ between flight-capable and flightless lines. By contrast, line differences in NADP(+)-IDH specific activity strongly covaried with transcript abundance and enzyme protein concentration. These results demonstrate that NADP(+)-IDH-specific activity differences between artificially selected lines of G. firmus are due primarily, if not exclusively, to genetic variation in regulators of NADP(+)-IDH gene expression, with no observed contribution from altered catalytic efficiency of the enzyme due to changes in amino acid sequence or posttranslational modification. Kinetic analyses indicate that in vitro differences in enzyme specific activity between flight-capable and flightless lines likely occur in vivo. This study constitutes the most comprehensive analysis to date of the biochemical and molecular causes of naturally occurring genetic variation in enzyme activity that covaries strongly with life history. PMID- 21705379 TI - Purifying selection can obscure the ancient age of viral lineages. AB - Statistical methods for molecular dating of viral origins have been used extensively to infer the time of most common recent ancestor for many rapidly evolving pathogens. However, there are a number of cases, in which epidemiological, historical, or genomic evidence suggests much older viral origins than those obtained via molecular dating. We demonstrate how pervasive purifying selection can mask the ancient origins of recently sampled pathogens, in part due to the inability of nucleotide-based substitution models to properly account for complex patterns of spatial and temporal variability in selective pressures. We use codon-based substitution models to infer the length of branches in viral phylogenies; these models produce estimates that are often considerably longer than those obtained with traditional nucleotide-based substitution models. Correcting the apparent underestimation of branch lengths suggests substantially older origins for measles, Ebola, and avian influenza viruses. This work helps to reconcile some of the inconsistencies between molecular dating and other types of evidence concerning the age of viral lineages. PMID- 21705381 TI - On the origins of Mendelian disease genes in man: the impact of gene duplication. AB - Over 3,000 human diseases are known to be linked to heritable genetic variation, mapping to over 1,700 unique genes. Dating of the evolutionary age of these disease-associated genes has suggested that they have a tendency to be ancient, specifically coming into existence with early metazoa. The approach taken by past studies, however, assumes that the age of a disease is the same as the age of its common ancestor, ignoring the fundamental contribution of duplication events in the evolution of new genes and function. Here, we date both the common ancestor and the duplication history of known human disease-associated genes. We find that the majority of disease genes (80%) are genes that have been duplicated in their evolutionary history. Periods for which there are more disease-associated genes, for example, at the origins of bony vertebrates, are explained by the emergence of more genes at that time, and the majority of these are duplicates inferred to have arisen by whole-genome duplication. These relationships are similar for different disease types and the disease-associated gene's cellular function. This indicates that the emergence of duplication-associated diseases has been ongoing and approximately constant (relative to the retention of duplicate genes) throughout the evolution of life. This continued until approximately 390 Ma from which time relatively fewer novel genes came into existence on the human lineage, let alone disease genes. For single-copy genes associated with disease, we find that the numbers of disease genes decreases with recency. For the majority of duplicates, the disease-associated mutation is associated with just one of the duplicate copies. A universal explanation for heritable disease is, thus, that it is merely a by-product of the evolutionary process; the evolution of new genes (de novo or by duplication) results in the potential for new diseases to emerge. PMID- 21705382 TI - Characterization of unique signature sequences in the divergent maternal protein Bcl2l10. AB - Insertions or deletions (indels) of amino acids residues have been recognized as an important source of genetic and structural divergence between paralogous Bcl-2 family members. However, these signature sequences have not so far been extensively investigated amongst orthologous Bcl-2 family proteins. Bcl2l10 is an antiapoptotic member of the Bcl-2 family that has evolved rapidly throughout the vertebrate lineage and which shows conserved abundant expression in eggs and oocytes. In this paper, we have unraveled two major sites of divergence between human Bcl2l10 and its vertebrate homologs. The first one provides length variation at the N-terminus (before the BH4 domain) and the second one is located between the predicted alpha5-alpha6 pore-forming helices, providing an unprecedented case in the superfamily of helix-bundled pore-forming proteins. These two particular indels were studied phylogenetically and through biochemical and cell biological techniques, including truncation and site-directed mutagenesis. While deletion of the N-terminal extension had no significant functional impact in HeLa cells, our results suggest that the human Bcl2l10 protein evolved a calcium-binding motif in its alpha5-alpha6 interhelical region by acquiring critical negatively charged residues. Considering the reliance of female eggs on calcium-dependent proteins and calcium-regulated processes and the exceptional longevity of oocytes in the primate lineage, we propose that this microstructural variation may be an adaptive feature associated with high maternal expression of this Bcl-2 family member. PMID- 21705383 TI - Exogenously-sourced ethylene increases stomatal conductance, photosynthesis, and growth under optimal and deficient nitrogen fertilization in mustard. AB - In order to ascertain the stomatal and photosynthetic responses of mustard to ethylene under varying N availability, photosynthetic characteristics of mustard grown with optimal (80 mg N kg(-1) soil) or low (40 mg N kg(-1) soil) N were studied after the application of an ethylene-releasing compound, ethephon (2 chloroethyl phosphonic acid) at 40 days after sowing (DAS). The availability of N influenced ethylene evolution and affected stomatal conductance and photosynthesis. The effect of ethylene was smaller under deficient N where plants contained higher glucose (Glc) sensitivity, despite high ethylene evolution even in the absence of ethephon, potentially because the plants were less sensitive to ethylene per se. Ethephon application at each level of N increased ethylene and decreased Glc sensitivity, which increased photosynthesis via its effect on the photosynthetic machinery and effects on stomatal conductance. Plants grown with sufficient-N and treated with 200 MUl l(-1) ethephon exhibited optimal ethylene, the greatest stomatal conductance and photosynthesis, and growth. These plants made maximum use of available N and exhibited the highest nitrogen-use efficiency (NUE). PMID- 21705384 TI - The interplay between light and jasmonate signalling during defence and development. AB - During their evolution, plants have acquired diverse capabilities to sense their environment and modify their growth and development as required. The versatile utilization of solar radiation for photosynthesis as well as a signal to coordinate developmental responses to the environment is an excellent example of such a capability. Specific light quality inputs are converted to developmental outputs mainly through hormonal signalling pathways. Accordingly, extensive interactions between light and the signalling pathways of every known plant hormone have been uncovered in recent years. One such interaction that has received recent attention and forms the focus of this review occurs between light and the signalling pathway of the jasmonate hormone with roles in regulating plant defence and development. Here the recent research that revealed new mechanistic insights into how plants might integrate light and jasmonate signals to modify their growth and development, especially when defending themselves from either pests, pathogens, or encroaching neighbours, is discussed. PMID- 21705386 TI - Wheat floret survival as related to pre-anthesis spike growth. AB - Further improvements to wheat yield potential will be essential to meet future food demand. As yield is related to the number of fertile florets and grains, an understanding of the basis of their generation is instrumental to raising yield. Based on (i) a strong positive association between the number of fertile florets or grains and spike dry weight at anthesis; and (ii) the finding that floret death occurs when spikes grow at maximum rate, it was always assumed that floret survival depends on the growth of the spike. However, this assumption was recently questioned, suggesting that assimilates diverted to the spike do not determine the number of florets and grains and that the onset of floret death may instead be a developmental process that is not associated with spike growth. In this study, the relationships between the fate of floret primordia and spike growth from six independent experiments that included different growing conditions (greenhouse/field experiments, growing seasons, photoperiod/shading treatments during the floret primordia phase) and diverse cultivar types (winter/spring, semi-dwarf/standard-height, photoperiod sensitive/insensitive) were re-analysed together. Onset of floret death was associated with the beginning of spike growth at the maximum rate in c. 80% of the cases analysed; and the rate of floret death (the main determinant of floret survival) showed a negative quantitative relationship with spike weight at anthesis. As floret death and survival were shown to be linked to pre-anthesis spike growth, the strategy of focusing on traits associated with pre-anthesis spike growth when breeding to increase wheat yield potential further is valuable. PMID- 21705385 TI - Evidence for the involvement of the Arabidopsis SEC24A in male transmission. AB - Eukaryotic cells use COPII-coated carriers for endoplasmic reticulum (ER)-to Golgi protein transport. Selective cargo capture into ER-derived carriers is largely driven by the SEC24 component of the COPII coat. The Arabidopsis genome encodes three AtSEC24 genes with overlapping expression profiles but it is yet to be established whether the AtSEC24 proteins have overlapping roles in plant growth and development. Taking advantage of Arabidopsis thaliana as a model plant system for studying gene function in vivo, through reciprocal crosses, pollen characterization, and complementation tests, evidence is provided for a role for AtSEC24A in the male gametophyte. It is established that an AtSEC24A loss-of function mutation is tolerated in the female gametophyte but that it causes defects in pollen leading to failure of male transmission of the AtSEC24A mutation. These data provide a characterization of plant SEC24 family in planta showing incompletely overlapping functions of the AtSEC24 isoforms. The results also attribute a novel role to SEC24 proteins in a multicellular model system, specifically in male fertility. PMID- 21705387 TI - Is the 6 kDa tobacco etch viral protein a bona fide ERES marker? AB - The claim that the 6 kDa viral protein (VP) of Tobacco Etch Virus is a marker for ER exit sites (ERES) has been investigated. When transiently expressed as a CFP tagged fusion construct in tobacco mesophyll protoplasts, this integral membrane protein co-localizes with both the COPII coat protein YFP-SEC24 and the Golgi marker Man1-RFP. However, when over-expressed the VP locates to larger spherical structures which co-localize with neither ER nor Golgi markers. Nevertheless, deletion of the COPII interactive N-terminal D(X)E motif causes it to be broadly distributed throughout the ER, supporting the notion that this protein could be an ERES marker. Curiously, whereas brefeldin A (BFA) caused a typical Golgi-stack response (redistribution into the ER) of the VP in leaf epidermal cells, in protoplasts it resulted in the formation of structures identical to those formed by over-expression. However, anomalous results were obtained with protoplasts: when co-expressed with the non-cycling cis-Golgi marker Man1-RFP, a BFA-induced redistribution of the VP-CFP signal into the ER was observed, but, in the presence of the cycling Golgi marker ERD2-YFP, this did not occur. High resolution images of side-on views of Golgi stacks in epidermal cells showed that the 6 kDa VP-CFP signal overlapped considerably more with YFP-SEC24 than with Man1-RFP, indicating that the VP is proportionately more associated with ERES. However, based on a consideration of the structure of its cytoplasmic tail, the scenario that the VP collects at ERES and is transported to the cis-Golgi before being recycled back to the ER, is supported. PMID- 21705388 TI - Identification and validation of rice reference proteins for western blotting. AB - Studies of rice protein expression have increased considerably with the development of rice functional genomics. In order to obtain reliable expression results in western blotting, information on appropriate reference proteins is necessary for data normalization. To date, no published study has identified and systematically validated reference proteins suitable for the investigation of rice protein expression. In this study, nine candidate proteins were selected and their specific antibodies were obtained through immunization of rabbits with either recombinant proteins expressed in Escherichia coli or synthesized peptides. Western blotting was carried out to detect the expression of target proteins in a set of 10 rice samples representing different rice tissues/organs at different developmental stages. The expression stability of the proteins was analysed using geNorm and Microcal Origin 6.0 software. The results indicated that heat shock protein (HSP) and elongation factor 1-alpha (eEF-1alpha) were the most constantly expressed among all rice proteins tested throughout all developmental stages, while the proteins encoded by conventional internal reference genes fluctuated in amount. Comparison among the profiling of translation and transcription [expressed sequence tags (EST) and massively parallel signature sequencing (MPSS)] revealed that a correlation existed. Based on the standard curves derived from the antigen-antibody reaction, the concentrations of HSP and eEF-1alpha proteins in rice leaves were ~0.12%. Under the present experimental conditions, the lower limits of detection for HSP and eEF-1alpha proteins in rice were 0.24 ng and 0.06 ng, respectively. In conclusion, the reference proteins selected in this study, and the corresponding antibodies, can be used in qualitative and quantitative analysis of rice proteins. PMID- 21705389 TI - Comparative study of the active cadmium efflux systems operating at the plasma membrane and tonoplast of cucumber root cells. AB - The strategies developed by plants to avoid the toxicity of cadmium (Cd) and other heavy metals involve active sequestration of metals into the apoplast and vacuoles. The protein systems excluding heavy metals from the cell cytosol localize to the plasma membrane and tonoplast and are energized either by ATP or by the electrochemical gradient generated by H(+)-ATPase or by V-ATPase and pyrophosphatase (PPase), respectively. In this work, a comparative study on the contribution of both the plasma membrane and tonoplast in the active detoxification of plant cells after treatment with Cd was performed. The studies using plants treated and untreated with Cd reveal that both, H(+)-coupled and MgATP-driven efflux of Cd across plasma membranes and tonoplast is markedly stimulated in the presence of Cd in the environment. Previous studies on plasma membrane localized H(+)-coupled Cd efflux together with the present data demonstrating tonoplast H(+)/Cd(2+) antiport activity suggest that H(+)-coupled secondary transport of Cd displays a lower affinity for Cd when compared with Cd primary pumps driven by MgATP. In addition, it is shown that MgATP-energized Cd efflux across both membranes is significantly enhanced by cysteine, dithiothreitol, and glutathione. These results suggest that Cd is excluded from the cytosol through an energy-dependent system as a free ion as well as a complexed form. Although both membranes contribute in the active exclusion of ionized and complexed Cd from the cytosol, the overall calculation of Cd accumulation in the everted plasma membranes and vacuolar vesicles suggests that the tonoplast and vacuole have a major function in Cd efflux from the cytosol in the roots of cucumber subjected to Cd stress. PMID- 21705390 TI - CRFs form protein-protein interactions with each other and with members of the cytokinin signalling pathway in Arabidopsis via the CRF domain. AB - Cytokinin is a plant hormone essential for growth and development. The elucidation of its signalling pathway as a variant of the bacterial two-component signalling system (TCS) has led to a better understanding of how this hormone is involved in general plant processes. A set of cytokinin-regulated transcription factors known as cytokinin response factors (CRFs) have been described as a potential branch emanating from the TCS, yet little is known about how CRFs actually interact with each other and with members of the TCS pathway. Here the interactions of CRF proteins (CRF1-CRF8) using the yeast two-hybrid system and bimolecular fluorescence complementation in planta assays are described. It was found that CRFs are readily able to form both homo- and heterodimers with each other. The first analysis of CRF versus TCS pathway protein interactions is also provided, which indicates that CRFs (CRF1-CRF8) are able specifically to interact directly with most of the Arabidopsis histidine-phosphotransfer proteins (AHP1 AHP5) further solidifying their link to the cytokinin signalling pathway. In addition, the region of CRF proteins involved in these interactions was mapped and it was determined that the clade-specific CRF domain alone is sufficient for these interactions. This is the first described function for the CRF domain in plants. PMID- 21705391 TI - Molecular and genetic characterization of the gene family encoding the voltage dependent anion channel in Arabidopsis. AB - The voltage-dependent anion channel (VDAC), a major outer mitochondrial membrane protein, is thought to play an important role in energy production and apoptotic cell death in mammalian systems. However, the function of VDACs in plants is largely unknown. In order to determine the individual function of plant VDACs, molecular and genetic analysis was performed on four VDAC genes, VDAC1-VDAC4, found in Arabidopsis thaliana. VDAC1 and VDAC3 possess the eukaryotic mitochondrial porin signature (MPS) in their C-termini, while VDAC2 and VDAC4 do not. Localization analysis of VDAC-green fluorescent protein (GFP) fusions and their chimeric or mutated derivatives revealed that the MPS sequence is important for mitochondrial localization. Through the functional analysis of vdac knockout mutants due to T-DNA insertion, VDAC2 and VDAC4 which are expressed in the whole plant body are important for various physiological functions such as leaf development, the steady state of the mitochondrial membrane potential, and pollen development. Moreover, it was demonstrated that VDAC1 is not only necessary for normal growth but also important for disease resistance through regulation of hydrogen peroxide generation. PMID- 21705392 TI - Where, when and why brain activation differs for bilinguals and monolinguals during picture naming and reading aloud. AB - Using functional magnetic resonance imaging, we found that when bilinguals named pictures or read words aloud, in their native or nonnative language, activation was higher relative to monolinguals in 5 left hemisphere regions: dorsal precentral gyrus, pars triangularis, pars opercularis, superior temporal gyrus, and planum temporale. We further demonstrate that these areas are sensitive to increasing demands on speech production in monolinguals. This suggests that the advantage of being bilingual comes at the expense of increased work in brain areas that support monolingual word processing. By comparing the effect of bilingualism across a range of tasks, we argue that activation is higher in bilinguals compared with monolinguals because word retrieval is more demanding; articulation of each word is less rehearsed; and speech output needs careful monitoring to avoid errors when competition for word selection occurs between, as well as within, language. PMID- 21705393 TI - Theta-burst stimulation over human frontal cortex distorts perceptual stability across eye movements. AB - We perceive a stable outside world despite the constant changes of visual input induced by our eye movements. Internal monitoring of a corollary discharge associated with oculomotor commands may help to anticipate the perceptual consequences of impending eye movements. The primate frontal eye fields have repeatedly been presumed to participate in the maintenance of perceptual stability across eye movements. However, a direct link between integrity of frontal oculomotor areas and perceptual stability is missing so far. Here, we show that transcranial magnetic stimulation (TMS) over the right human frontal cortex impairs the integration of visual space across eye movements. We asked 9 healthy subjects to report the direction of transsaccadic stimulus displacements and applied TMS before the actual experiment in a novel offline stimulation protocol, continuous theta-burst stimulation (cTBS). A systematic perceptual distortion was observed after stimulation over the right frontal cortex that was best explained by an internal underestimation of executed eye movement amplitudes. cTBS apparently disturbed an internal prediction process for contraversive saccades, while the metrics of associated oculomotor actions remained unchanged. Our findings suggest an important role of the frontal cortex in the internal monitoring of oculomotor actions for the perceptual integration of space across eye movements. PMID- 21705394 TI - Predicting functional cortical ROIs via DTI-derived fiber shape models. AB - Studying structural and functional connectivities of human cerebral cortex has drawn significant interest and effort recently. A fundamental and challenging problem arises when attempting to measure the structural and/or functional connectivities of specific cortical networks: how to identify and localize the best possible regions of interests (ROIs) on the cortex? In our view, the major challenges come from uncertainties in ROI boundary definition, the remarkable structural and functional variability across individuals and high nonlinearities within and around ROIs. In this paper, we present a novel ROI prediction framework that localizes ROIs in individual brains based on their learned fiber shape models from multimodal task-based functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data. In the training stage, shape models of white matter fibers are learnt from those emanating from the functional ROIs, which are activated brain regions detected from task-based fMRI data. In the prediction stage, functional ROIs are predicted in individual brains based only on DTI data. Our experiment results show that the average ROI prediction error is around 3.94 mm, in comparison with benchmark data provided by working memory and visual task-based fMRI. Our work demonstrated that fiber bundle shape models derived from DTI data are good predictors of functional cortical ROIs. PMID- 21705395 TI - A selective estrogen receptor alpha agonist ameliorates hepatic steatosis in the male aromatase knockout mouse. AB - Male aromatase knockout mice (ArKO; an estrogen-deficient model) present with male-specific hepatic steatosis that is reversible upon 17beta-estradiol replacement. This study aims to elucidate which estrogen receptor (ER) subtype, ERalpha or ERbeta, is involved in the regulation of triglyceride (TG) homeostasis in the liver. Nine-month-old male ArKO mice were treated with vehicle, ERalpha- or ERbeta-specific agonists via s.c. injection, daily for 6 weeks. Male ArKO mice treated with ERalpha agonist had normal liver histology and TG contents compared with vehicle-treated ArKO; omental (gonadal) and infra-renal (visceral) fat pad weights were normalized to those of vehicle-treated wild-type (WT). In contrast, ERbeta agonist treatment did not result in the similar reversal of these ArKO phenotypes. In vehicle-treated ArKO mice, hepatic transcript expression of fatty acid synthase (Fasn) and stearoyl-coenzyme A desaturase 1 (key enzymes in de novo FA synthesis) were significantly elevated compared with vehicle-treated WT, but only Fasn expression was lowered to WT level after ERalpha agonist treatment. There were no significant changes in the transcript levels of carnitine palmitoyl transferase 1 (required for transfer of FA residues into the mitochondria for beta-oxidation) and sterol regulatory element-binding factor 1c (the upstream regulator of de novo FA synthesis). We also confirmed by RT-PCR that only ERalpha is expressed in the mouse liver. There were no changes in hepatic androgen receptor transcript level across all treatment groups. Our data suggest that estrogens act via ERalpha to regulate TG homeostasis in the ArKO liver. Since the liver, adipose tissue and arcuate nucleus express mainly ERalpha, estrogens could regulate hepatic functions via peripheral and central pathways. PMID- 21705396 TI - Acupuncture and the relaxation response for treating gastrointestinal symptoms in HIV patients on highly active antiretroviral therapy. AB - OBJECTIVES: To examine the effect of acupuncture and the relaxation response (RR) for treating gastrointestinal (GI) symptoms in HIV patients who are using highly active antiretroviral therapy (HAART). METHODS: The authors conducted a 4-arm 2*2 double-blind randomised controlled trial in an acupuncture clinic in the USA. Sham acupuncture and health education were used as the control conditions of real acupuncture and RR elicitation, respectively. Enrolled patients were randomised to real acupuncture+RR (AR), sham acupuncture+RR (SR), real acupuncture+health education (AE) or sham acupuncture+health education (SE) study arm. Participants listened to CDs with RR-eliciting instructions or health education while receiving acupuncture intervention. Interventions were provided twice weekly for 4 weeks and once weekly for another 4 weeks. Participants used daily diaries to record GI symptom severity ratings (0-10). The authors estimated the intervention effect as the changes in symptom rating per intervention session increase using a mixed-effects regression model. RESULTS: A total of 130 people with HIV/AIDS who were on HAART and had persistent GI symptoms were enrolled and 115 started the study intervention. The AR group had greater intervention effects for loose stools symptoms than the other three groups (beta=-0.149, -0.151 and -0.144, p value=0.013, 0.013 and 0.018 comparing AR to AE, SR and SE, respectively). The AR group also had significant intervention effects on reducing nausea symptoms when the intervention was given twice per week (beta=-0.218, p=0.001). CONCLUSIONS: Our trial provided preliminary data demonstrating the potential synergistic effects of acupuncture and RR for treating GI symptoms in HIV patients on HAART. PMID- 21705397 TI - Compliance with return-to-play regulations following concussion in Australian schoolboy and community rugby union players. AB - BACKGROUND: There is a risk of concussion when playing rugby union. Appropriate management of concussion includes compliance with the return-to-play regulations of the sports body for reducing the likelihood of premature return-to-play by injured players. PURPOSE: To describe the proportion of rugby union players who comply with the sports body's regulations on returning to play postconcussion. STUDY DESIGN: Prospective cohort study. METHODS: 1958 community rugby union players (aged 15-48 years) in Sydney (Australia) were recruited from schoolboy, grade and suburban competitions and followed over >=1 playing seasons. Club doctors/physiotherapists/coaches or trained injury recorders who attended the game reported players who sustained a concussion. Concussed players were followed up over a 3-month period and the dates when they returned to play (including either a game or training session) were recorded, as well as any return-to-play advice they received. RESULTS: 187 players sustained >=1 concussion throughout the follow-up. The median number of days before players returned to play (competition game play or training) following concussion was 3 (range 1-84). Most players (78%) did not receive return-to-play advice postconcussion, and of those who received correct advice, all failed to comply with the 3-week stand-down regulation. CONCLUSIONS: The paucity of return-to-play advice received by community rugby union players postconcussion and the high level of non-compliance with return-to-play regulations highlight the need for better dissemination and implementation of the return-to-play regulations and improved understanding of the underlying causes of why players do not adhere to return-to-play practices. PMID- 21705398 TI - Repudiation of the 'magic bullet' approach to health improvement: a call to empower people to get moving and take charge. PMID- 21705399 TI - CBT stress management reduces recurrent CAD events after myocardial infarction. PMID- 21705400 TI - Carrying one or two reduced-function CYP2C19 alleles is associated with an increased risk of major adverse cardiovascular events in people undergoing percutaneous coronary intervention and treated with clopidogrel. PMID- 21705401 TI - Behavioural therapy is more effective than delayed treatment for persistent postprostatectomy incontinence. PMID- 21705402 TI - Epinephrine for acute bronchiolitis, but not steroids alone, reduces hospital admissions. PMID- 21705403 TI - A raised metabolic rate slows pulmonary O(2) uptake kinetics on transition to moderate-intensity exercise in humans independently of work rate. AB - During exercise below the lactate threshold (LT), the rate of adjustment (tau) of pulmonary VO(2) uptake (tau) is slowed when initiated from a raised work rate. Whether this is consequent to the intrinsic properties of newly recruited muscle fibres, slowed circulatory dynamics or the effects of a raised metabolism is not clear. We aimed to determine the influence of these factors on tauV(O(2)) using combined in vivo and in silico approaches. Fifteen healthy men performed repeated 6 min bouts on a cycle ergometer with work rates residing between 20 W and 90% LT, consisting of the following: (1) two step increments in work rate (S1 and S2), one followed immediately by the other, equally bisecting 20 W to 90% LT; (2) two 20 W to 90% LT bouts separated by 30 s at 20 W to raise muscle oxygenation and pretransition metabolism (R1 and R2); and (3) two 20 W to 90% LT bouts separated by 12 min at 20 W allowing full recovery (F1 and F2). Pulmonary O(2) uptake was measured breath by breath by mass spectrometry and turbinometry, and quadriceps oxygenation using near-infrared spectroscopy. The influence of circulatory dynamics on the coupling of muscle and tauV(O(2)) lung was assessed by computer simulations. The tauV(O(2)) in R2 (32 +/- 9 s) was not different (P > 0.05) from S2 (30 +/- 10 s), but both were greater (P < 0.05) than S1 (20 +/- 10 s) and the F control bouts (26 +/- 10 s). The slowed V(O(2)) kinetics in R2 occurred despite muscle oxygenation being raised throughout, and could not be explained by slowed circulatory dynamics (tauV(O(2)) predicted by simulations: S1 = R2 < S2). These data therefore suggest that the dynamics of muscle O(2) consumption are slowed when exercise is initiated from a less favourable energetic state. PMID- 21705404 TI - Cutaneous vascular and core temperature responses to sustained cold exposure in hypoxia. AB - We tested the effect of hypoxia on cutaneous vascular regulation and defense of core temperature during cold exposure. Twelve subjects had two microdialysis fibres placed in the ventral forearm and were immersed to the sternum in a bathtub on parallel study days (normoxia and poikilocapnic hypoxia with an arterial O(2) saturation of 80%). One fibre served as the control (1 mM propranolol) and the other received 5 mM yohimbine (plus 1 mM propranolol) to block adrenergic receptors. Skin blood flow was assessed at each site (laser Doppler flowmetry), divided by mean arterial pressure to calculate cutaneous vascular conductance (CVC), and scaled to baseline. Cold exposure was first induced by a progressive reduction in water temperature from 36 to 23 degrees C over 30 min to assess cutaneous vascular regulation, then by clamping the water temperature at 10 degrees C for 45 min to test defense of core temperature. During normoxia, cold stress reduced CVC in control (-44 +/- 4%) and yohimbine sites (-13 +/- 7%; both P < 0.05 versus precooling). Hypoxia caused vasodilatation prior to cooling but resulted in greater reductions in CVC in control (-67 +/- 7%) and yohimbine sites (-35 +/- 11%) during cooling (both P < 0.05 versus precooling; both P < 0.05 versus normoxia). Core cooling rate during the second phase of cold exposure was unaffected by hypoxia (-1.81 +/- 0.23 degrees C h(-1) in normoxia versus -1.97 +/- 0.33 degrees C h(-1) in hypoxia; P > 0.05). We conclude that hypoxia increases cutaneous (non-noradrenergic) vasoconstriction during prolonged cold exposure, while core cooling rate is not consistently affected. PMID- 21705405 TI - GO-function: deriving biologically relevant functions from statistically significant functions. AB - In high-throughput studies of diseases, terms enriched with disease-related genes based on Gene Ontology (GO) are routinely found. However, most current algorithms used to find significant GO terms cannot handle the redundancy that results from the dependencies of GO terms. Simply based on some numerical considerations, current algorithms developed for reducing this redundancy may produce results that do not account for biologically interesting cases. In this article, we present several rules used to design a tool called GO-function for extracting biologically relevant terms from statistically significant GO terms for a disease. Using one gene expression profile for colorectal cancer, we compared GO function with four algorithms designed to treat redundancy. Then, we validated results obtained in this data set by GO-function using another data set for colorectal cancer. Our analysis showed that GO-function can identify disease related terms that are more statistically and biologically meaningful than those found by the other four algorithms. PMID- 21705407 TI - Clinical management of stuttering in children and adults. PMID- 21705408 TI - French guidelines are withdrawn after court finds potential bias among authors. PMID- 21705406 TI - Relative effectiveness of clinic and home blood pressure monitoring compared with ambulatory blood pressure monitoring in diagnosis of hypertension: systematic review. AB - OBJECTIVE: To determine the relative accuracy of clinic measurements and home blood pressure monitoring compared with ambulatory blood pressure monitoring as a reference standard for the diagnosis of hypertension. DESIGN: Systematic review with meta-analysis with hierarchical summary receiver operating characteristic models. Methodological quality was appraised, including evidence of validation of blood pressure measurement equipment. DATA SOURCES: Medline (from 1966), Embase (from 1980), Cochrane Database of Systematic Reviews, DARE, Medion, ARIF, and TRIP up to May 2010. Eligibility criteria for selecting studies Eligible studies examined diagnosis of hypertension in adults of all ages using home and/or clinic blood pressure measurement compared with those made using ambulatory monitoring that clearly defined thresholds to diagnose hypertension. RESULTS: The 20 eligible studies used various thresholds for the diagnosis of hypertension, and only seven studies (clinic) and three studies (home) could be directly compared with ambulatory monitoring. Compared with ambulatory monitoring thresholds of 135/85 mm Hg, clinic measurements over 140/90 mm Hg had mean sensitivity and specificity of 74.6% (95% confidence interval 60.7% to 84.8%) and 74.6% (47.9% to 90.4%), respectively, whereas home measurements over 135/85 mm Hg had mean sensitivity and specificity of 85.7% (78.0% to 91.0%) and 62.4% (48.0% to 75.0%). CONCLUSIONS: Neither clinic nor home measurement had sufficient sensitivity or specificity to be recommended as a single diagnostic test. If ambulatory monitoring is taken as the reference standard, then treatment decisions based on clinic or home blood pressure alone might result in substantial overdiagnosis. Ambulatory monitoring before the start of lifelong drug treatment might lead to more appropriate targeting of treatment, particularly around the diagnostic threshold. PMID- 21705412 TI - Contrasting physical activity patterns in children and adolescents living in differing environments in the U.K. AB - AIMS: There is evidence for lower physical activity (PA) in rural adults; it is important to evaluate how the environment influences the PA of children and adolescents. METHODS: We compared the PA of 6485 English 10-15.9 year olds according to two systems for classifying the immediate environment. System one compared urban and rural areas. System two compared urban, town and fringe, and rural areas. Analyses were carried out separately for children (<13 years) and adolescents (>13 years). RESULTS: Rural children were more active than those from urban areas (OR 1.38, 95% CI 1.15-1.66) as were adolescents (OR 1.30, 95% CI 1.11 1.51). Using trilateral division, children were more active if they lived in town and fringe (OR 1.32, 95% CI 1.03-1.67) or rural (OR 1.45, 95% CI 1.14-1.84) areas compared with urban areas. Adolescents from town and fringe areas were more active than urban dwellers (OR 1.50, 95% CI 1.24-1.81). Rural adolescents' PA did not differ from urban dwellers'. CONCLUSIONS: Rural environments support PA in children but not that of adolescents. Town and fringe areas with mixed elements of rural and urban land use appear to facilitate and sustain PA in both children and adolescents. PMID- 21705410 TI - The association between variants on chromosome 9p21 and inflammatory biomarkers in ethnically diverse women with coronary heart disease: a pilot study. AB - BACKGROUND: The most consistently replicated genetic variants associated with coronary heart disease (CHD) in populations of European descent have been found on chromosome 9p21. Yet there is little known about these associations in ethnic groups of African ancestry. These disease-associated variants are located in a genomic region of unknown function. The purpose of this exploratory study was to examine the allelic frequencies and haplotype structure of single nucleotide polymorphisms (SNPs) for Black and White women with CHD. The authors also sought to explore the relationship between these genetic variants and biomarkers of inflammation. METHODS: Using polymerase chain reaction amplification, the authors genotyped 8 SNPs in a 58-kilobase region of chromosome 9p21 in a cohort of women with CHD (n = 91). The authors examined the interethnic relationship between the SNPs and four inflammatory biomarkers (C-reactive protein, intercellular adhesion molecule-1, interleukin-6, and tumor necrosis factor-alpha) using analysis of variance (ANOVA). RESULTS: We found considerable interethnic allelic and haplotype diversity across the 9p21 locus, with only two SNPs in perfect linkage disequilibrium (LD) in both races. A pair of high- and low-risk haplotypes was most common in White women, while about 41% of Blacks carried the risk alleles for three of the eight SNPs the authors examined. The interethnic associations between the SNP genotypes and inflammatory markers were divergent in both direction and magnitude. CONCLUSIONS: Our results lend support for the importance of ancestry-specific allelic context when examining variants on chromosome 9p21. Additional work is needed to elucidate the genetic contribution to inflammatory biomarkers for diverse racial groups. PMID- 21705413 TI - Psychosocial correlates of condom use consistency among Isixhosa-speaking women living with HIV in the Western Cape Province of South Africa. AB - Many HIV-positive South African women continue to have unprotected sex. The aim of this cross-sectional study was to assess correlates of condom use consistency among Xhosa-speaking HIV-positive women in South Africa. One hundred and twenty women were recruited from five primary care clinics and completed a questionnaire. Regression analyses indicated that assertive negotiation and self efficacy for condom use were proximal correlates of condom use consistency. Mediation analyses showed that self-efficacy for assertive negotiation is a distal correlate of condom use consistency.We propose a framework of correlates of condom use consistency to inform future intervention development. PMID- 21705414 TI - How to successfully implement extended producer responsibility: considerations from an economic point of view. AB - This paper investigates the concept of extended producer responsibility (EPR) from an economic point of view. Particular importance will be placed on the concept of 'economic feasibility' of an EPR policy, which should guide decision making in this context. Moreover, the importance of the core EPR principle of 'integrating signals throughout the product chain' into the incentive structure will be demonstrated with experiences from Germany. These examples refer to sales packaging consumption, refillable drinks packages and waste electrical and electronic equipment collection. As a general conclusion, the interaction between economic principles and technological development needs to be observed carefully when designing incentive-compatible EPR policies. PMID- 21705415 TI - Prediction of leucine-rich nuclear export signal containing proteins with NESsential. AB - The classical nuclear export signal (NES), also known as the leucine-rich NES, is a protein localization signal often involved in important processes such as signal transduction and cell cycle regulation. Although 15 years has passed since its discovery, limited structural information and high sequence diversity have hampered understanding of the NES. Several consensus sequences have been proposed to describe it, but they suffer from poor predictive power. On the other hand, the NetNES server provides the only computational method currently available. Although these two methods have been widely used to attempt to find the correct NES position within potential NES-containing proteins, their performance has not yet been evaluated on the basic task of identifying NES-containing proteins. We propose a new predictor, NESsential, which uses sequence derived meta-features, such as predicted disorder and solvent accessibility, in addition to primary sequence. We demonstrate that it can identify promising NES-containing candidate proteins (albeit at low coverage), but other methods cannot. We also quantitatively demonstrate that predicted disorder is a useful feature for prediction and investigate the different features of (predicted) ordered versus disordered NES's. Finally, we list 70 recently discovered NES-containing proteins, doubling the number available to the community. PMID- 21705416 TI - TIRAP Ser180Leu polymorphism is associated with Behcet's disease. AB - OBJECTIVES: The initiating cause of Behcet's disease (BD) is unknown, but an aberrant response to infection has been suggested. In this study, single nucleotide polymorphisms in Toll-like receptors (TLRs) and associated molecules that have a sentinel function at mucosal surfaces were analysed in patients with BD. METHODS: TLR expression was determined by immunohistochemistry in buccal mucosal tissue from patients with BD, in tissue from patients with lichen planus (LP) or pyogenic granuloma (PG) as disease controls, or from healthy individuals. Using SSP-PCR we analysed SNP in CD14, TLR2, TLR4 and TIRAP (TIR domain containing adaptor protein) in patients with BD from different geographical regions. RESULTS: TLR expression was increased in buccal lesions from patients with BD compared with healthy controls; however, a similar increase was seen in lesion tissue from patients with LP or PG, suggesting that this was a generalized inflammatory response as opposed to a BD-specific response. SNP analysis showed no association between CD14, TLR2 or TLR4 polymorphisms. However, TIRAP 180Leu was significantly associated with BD in UK, but not Middle Eastern, patients. CONCLUSION: TLR expression showed no difference in tissue from patients with BD compared with either disease or healthy controls. Likewise, SNPs in TLR genes were no different from healthy controls. The association with the increased function variant of TIRAP suggests that encounter with a pathogen at mucosal sites will lead to increased cytokine production and tissue damage with persistence of mucosal lesions. PMID- 21705417 TI - Brain. Editorial. PMID- 21705418 TI - Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis. AB - Mitochondrial content within axons increases following demyelination in the central nervous system, presumably as a response to the changes in energy needs of axons imposed by redistribution of sodium channels. Myelin sheaths can be restored in demyelinated axons and remyelination in some multiple sclerosis lesions is extensive, while in others it is incomplete or absent. The effects of remyelination on axonal mitochondrial content in multiple sclerosis, particularly whether remyelination completely reverses the mitochondrial changes that follow demyelination, are currently unknown. In this study, we analysed axonal mitochondria within demyelinated, remyelinated and myelinated axons in post mortem tissue from patients with multiple sclerosis and controls, as well as in experimental models of demyelination and remyelination, in vivo and in vitro. Immunofluorescent labelling of mitochondria (porin, a voltage-dependent anion channel expressed on all mitochondria) and axons (neurofilament), and ultrastructural imaging showed that in both multiple sclerosis and experimental demyelination, mitochondrial content within remyelinated axons was significantly less than in acutely and chronically demyelinated axons but more numerous than in myelinated axons. The greater mitochondrial content within remyelinated, compared with myelinated, axons was due to an increase in density of porin elements whereas increase in size accounted for the change observed in demyelinated axons. The increase in mitochondrial content in remyelinated axons was associated with an increase in mitochondrial respiratory chain complex IV activity. In vitro studies showed a significant increase in the number of stationary mitochondria in remyelinated compared with myelinated and demyelinated axons. The number of mobile mitochondria in remyelinated axons did not significantly differ from myelinated axons, although significantly greater than in demyelinated axons. Our neuropathological data and findings in experimental demyelination and remyelination in vivo and in vitro are consistent with a partial amelioration of the supposed increase in energy demand of demyelinated axons by remyelination. PMID- 21705419 TI - Neuronal expression of TATA box-binding protein containing expanded polyglutamine in knock-in mice reduces chaperone protein response by impairing the function of nuclear factor-Y transcription factor. AB - The polyglutamine diseases consist of nine neurodegenerative disorders including spinocerebellar ataxia type 17 that is caused by a polyglutamine tract expansion in the TATA box-binding protein. In all polyglutamine diseases, polyglutamine expanded proteins are ubiquitously expressed throughout the body but cause selective neurodegeneration. Understanding the specific effects of polyglutamine expanded proteins, when expressed at the endogenous levels, in neurons is important for unravelling the pathogenesis of polyglutamine diseases. However, addressing this important issue using mouse models that either overly or ubiquitously express mutant polyglutamine proteins in the brain and body has proved difficult. To investigate the pathogenesis of spinocerebellar ataxia 17, we generated a conditional knock-in mouse model that expresses one copy of the mutant TATA box-binding protein gene, which encodes a 105-glutamine repeat, selectively in neuronal cells at the endogenous level. Neuronal expression of mutant TATA box-binding protein causes age-dependent neurological symptoms in mice and the degeneration of cerebellar Purkinje cells. Mutant TATA box-binding protein binds more tightly to the transcription factor nuclear factor-Y, inhibits its association with the chaperone protein promoter, as well as the promoter activity and reduces the expression of the chaperones Hsp70, Hsp25 and HspA5, and their response to stress. These findings demonstrate how mutant TATA box-binding protein at the endogenous level affects neuronal function, with important implications for the pathogenesis and treatment of polyglutamine diseases. PMID- 21705420 TI - Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4. AB - Charcot-Marie-Tooth disease is a genetically heterogeneous group of motor and sensory neuropathies associated with mutations in more than 30 genes. Charcot Marie-Tooth disease type 4J (OMIM 611228) is a recessive, potentially severe form of the disease caused by mutations of the lipid phosphatase FIG4. We provide a more complete view of the features of this disorder by describing 11 previously unreported patients with Charcot-Marie-Tooth disease type 4J. Three patients were identified from a small cohort selected for screening because of their early onset disease and progressive proximal as well as distal weakness. Eight patients were identified by large-scale exon sequencing of an unselected group of 4000 patients with Charcot-Marie-Tooth disease. In addition, 34 new FIG4 variants were detected. Ten of the new CMT4J cases have the compound heterozygous genotype FIG4(I41T/null) described in the original four families, while one has the novel genotype FIG4(L17P/nul)(l). The population frequency of the I41T allele was found to be 0.001 by genotyping 5769 Northern European controls. Thirty four new variants of FIG4 were identified. The severity of Charcot-Marie-Tooth disease type 4J ranges from mild clinical signs to severe disability requiring the use of a wheelchair. Both mild and severe forms have been seen in patients with the same genotype. The results demonstrate that Charcot-Marie-Tooth disease type 4J is characterized by highly variable onset and severity, proximal as well as distal and asymmetric muscle weakness, electromyography demonstrating denervation in proximal and distal muscles, and frequent progression to severe amyotrophy. FIG4 mutations should be considered in Charcot-Marie-Tooth patients with these characteristics, especially if found in combination with sporadic or recessive inheritance, childhood onset and a phase of rapid progression. PMID- 21705421 TI - Deletion mutation of sodium channel Na(V)1.7 in inherited erythromelalgia: enhanced slow inactivation modulates dorsal root ganglion neuron hyperexcitability. AB - Gain-of-function missense mutations of voltage-gated sodium channel Na(V)1.7 have been linked to the painful disorder inherited erythromelalgia. These mutations hyperpolarize activation, slow deactivation and enhance currents evoked by slow ramp stimuli (ramp currents). A correlation has recently been suggested between the age of onset of inherited erythromelalgia and the extent of hyperpolarizing shifts in mutant Na(V)1.7 channel activation; mutations causing large activation shifts have been linked to early age of onset inherited erythromelalgia, while mutations causing small activation shifts have been linked to age of onset within the second decade of life. Here, we report a family with inherited erythromelalgia with an in-frame deletion of a single residue--leucine 955 (Del L955) in DII/S6. The proband did not show symptoms until the age of 15 years, and her affected mother only experienced mild symptoms during adolescence, which disappeared at the age of 38 years. Del-L955 shows no effect on Na(V)1.7 current density and fast inactivation, but causes an approximately -24 mV shift in activation, together with increases in amplitude of persistent currents and ramp currents. The mutation also produces an approximately -40 mV shift in slow inactivation, which reduces channel availability. Comparison of the effects of the Del-L955 mutation on dorsal root ganglion neuron hyperexcitability with those produced by another inherited erythromelalgia mutation (L858F) that does not enhance slow inactivation suggests that a delayed age of onset and milder symptoms in association with a large shift of channel activation, enhanced persistent and enhanced ramp currents may be related to the approximately -40 mV shift in slow inactivation for Del-L955, the largest shift thus far demonstrated in mutant Na(V)1.7 channels. Our results suggest that despite the pivotal role of activation shift in inherited erythromelalgia development, slow inactivation may regulate clinical phenotype by altering channel availability. PMID- 21705422 TI - Similar amyloid-beta burden in posterior cortical atrophy and Alzheimer's disease. AB - While the clinical presentation of posterior cortical atrophy is clearly distinct from typical Alzheimer's disease, neuropathological studies have suggested that most patients with posterior cortical atrophy have Alzheimer's disease with an atypical visual presentation. We analysed in vivo pathophysiological markers of Alzheimer's disease such as cerebrospinal fluid biomarkers and positron emission tomography imaging with 11C-labelled Pittsburgh compound-B in posterior cortical atrophy to determine whether biochemical profile and fibrillar amyloid-beta burden topography are associated with the clinical presentation. Nine patients with posterior cortical atrophy and nine with typical Alzheimer's disease individually matched for age, duration and severity of the disease and 10 cognitively normal age-matched controls were included. 11C-labelled Pittsburgh compound-B images were analysed both using volumes of interest and on a voxel wise basis using statistical parametric mapping, taking into account the individual regional cortical atrophy. Cerebrospinal fluid biomarkers did not differ between posterior cortical atrophy and patients with Alzheimer's disease. Compared with normal controls, both posterior cortical atrophy and Alzheimer's disease groups showed increased 11C-labelled Pittsburgh compound-B uptake. No significant difference was found in regional or global 11C-labelled Pittsburgh compound-B binding between posterior cortical atrophy and Alzheimer's disease groups with both volumes of interest and voxel-wise basis using statistical parametric mapping methods. Our findings demonstrate that cerebrospinal fluid biomarkers and positron emission tomography imaging with 11C-labelled Pittsburgh compound-B may be useful in identifying an atypical visual form of Alzheimer's disease. The similar topography of fibrillar amyloid-beta deposition between typical Alzheimer's disease and posterior cortical atrophy groups suggests that, although amyloid-beta accumulation plays a critical role in the pathogenesis of Alzheimer's disease, other factors such as neurofibrillary tangles may contribute to the different clinical features observed in posterior cortical atrophy. PMID- 21705425 TI - Shaping reversibility? Long-term deep brain stimulation in dystonia: the relationship between effects on electrophysiology and clinical symptoms. AB - Long-term results show that benefits from chronic deep brain stimulation in dystonia are maintained for many years. Despite this, the neurophysiological long term consequences of treatment and their relationship to clinical effects are not well understood. Previous studies have shown that transcranial magnetic stimulation measures of abnormal long-term potentiation-like plasticity (paired associative stimulation) and GABAa-ergic inhibition (short-interval intracortical inhibition), which are seen in dystonia, normalize after several months of deep brain stimulation. In the present study, we examine the same measures in a homogenous group of 10 DYT1 gene-positive patients after long-term deep brain stimulation treatment for at least 4.5 years. Recordings were made 'on' deep brain stimulation and after stopping deep brain stimulation for 2 days. The results show that: (i) on average, prior to discontinuing deep brain stimulation, the paired associative stimulation response was almost absent and short-interval intracortical inhibition was reduced compared with normal. This pattern differs from that in both healthy volunteers and from the typical pattern of enhanced plasticity and reduced inhibition seen in deep brain stimulation-naive dystonia. It is similar to that seen in untreated Parkinson's disease and may relate to thus far unexplained clinical phenomena like parkinsonian symptoms that have sometimes been observed in patients treated with deep brain stimulation. (ii) Overall, there was no change in average physiological or clinical status when deep brain stimulation was turned off for 2 days, suggesting that deep brain stimulation had produced long-term neural reorganization in the motor system. (iii) However, there was considerable variation between patients. Those who had higher levels of plasticity when deep brain stimulation was 'on', had the best retention of clinical benefit when deep brain stimulation was stopped and vice versa. This may indicate that better plasticity is required for longer term retention of normal movement when deep brain stimulation is off. (iv) Patients with the highest plasticity 'on' deep brain stimulation were those who had been receiving stimulation with the least current drain. This suggests that it might be possible to 'shape' deep brain stimulation of an individual patient to maximize beneficial neurophysiological patterns that have an impact on clinical status. The results are relevant for understanding long-term consequences and management of deep brain stimulation in dystonia. PMID- 21705424 TI - A block to pre-prepared movement in gait freezing, relieved by pedunculopontine nucleus stimulation. AB - Gait freezing and postural instability are disabling features of Parkinsonian disorders, treatable with pedunculopontine nucleus stimulation. Both features are considered deficits of proximal and axial musculature, innervated predominantly by reticulospinal pathways and tend to manifest when gait and posture require adjustment. Adjustments to gait and posture are amenable to pre-preparation and rapid triggered release. Experimentally, such accelerated release can be elicited by loud auditory stimuli--a phenomenon known as 'StartReact'. We observed StartReact in healthy and Parkinsonian controls. However, StartReact was absent in Parkinsonian patients with severe gait freezing and postural instability. Pedunculopontine nucleus stimulation restored StartReact proximally and proximal reaction times to loud stimuli correlated with gait and postural disturbance. These findings suggest a relative block to triggered, pre-prepared movement in gait freezing and postural instability, relieved by pedunculopontine nucleus stimulation. PMID- 21705423 TI - Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. AB - Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3 thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2 methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl 1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2 methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. PMID- 21705426 TI - Cigarette smoking is associated with reduced microstructural integrity of cerebral white matter. AB - Cigarette smoking doubles the risk of dementia and Alzheimer's disease. Various pathophysiological pathways have been proposed to cause such a cognitive decline, but the exact mechanisms remain unclear. Smoking may affect the microstructural integrity of cerebral white matter. Diffusion tensor imaging is known to be sensitive for microstructural changes in cerebral white matter. We therefore cross-sectionally studied the relation between smoking behaviour (never, former, current) and diffusion tensor imaging parameters in both normal-appearing white matter and white matter lesions as well as the relation between smoking behaviour and cognitive performance. A structured questionnaire was used to ascertain the amount and duration of smoking in 503 subjects with small-vessel disease, aged between 50 and 85 years. Cognitive function was assessed with a neuropsychological test battery. All subjects underwent 1.5 Tesla magnetic resonance imaging. Using diffusion tensor imaging, fractional anisotropy and mean diffusivity were calculated in both normal-appearing white matter and white matter lesions. A history of smoking was associated with significant higher values of mean diffusivity in normal-appearing white matter and white matter lesions (P-trend for smoking status = 0.02) and with poorer cognitive functioning compared with those who never smoked. Associations with smoking and loss of structural integrity appeared to be strongest in normal-appearing white matter. Furthermore, the duration of smoking cessation was positively related to lower values of mean diffusivity and higher values of fractional anisotropy in normal appearing white matter [beta = -0.004 (95% confidence interval -0.007 to 0.000; P = 0.03) and beta = 0.019 (95% confidence interval 0.001-0.038; P = 0.04)]. Fractional anisotropy and mean diffusivity values in normal-appearing white matter of subjects who had quit smoking for >20 years were comparable with subjects who had never smoked. These data suggest that smoking affects the microstructural integrity of cerebral white matter and support previous data that smoking is associated with impaired cognition. Importantly, they suggest that quitting smoking may reverse the impaired structural integrity. PMID- 21705427 TI - Progesterone is neuroprotective following cerebral ischaemia in reproductively ageing female mice. AB - Gender differences in both vulnerability to stroke and outcome following cerebral ischaemia have frequently been observed and attributed to the action of steroid hormones. Progesterone is a candidate neuroprotective factor for stroke; however, studies are lacking which: (i) study those groups representing high risk i.e. postmenopausal females; (ii) administer progesterone solely post-ischaemia; and (iii) combine histopathological and functional assessments. Postmenopausal females, along with males, represent the group at highest risk of cerebral stroke and can be modelled using aged or ovariectomized animals. In the current study, we aimed to determine the neuroprotective effects of progesterone administration following cerebral ischaemia in aged and ovariectomized mice. Following transient middle cerebral artery occlusion, progesterone was administered at 1, 6 and 24 h post-ischaemia to aged and ovariectomized female mice. At 48 h post-ischaemia, progesterone significantly reduced the lesion volume (P < 0.05) but had no effect on neurological outcome in aged female mice. Whereas in ovariectomized mice, at 48 h post-ischaemia, progesterone treatment had no effect on the amount of lesion volume present but did significantly improve neurological outcome. In a further study of ovariectomized mice, allowed to survive for 7 days post-ischaemia, progesterone treatment significantly improved motor outcome as assessed using both the rotarod and grid test. In fact, by 7 days post-ischaemia, progesterone treated ovariectomized mice did not differ significantly in performance compared with shams, whereas vehicle-treated ovariectomized mice displayed a significant functional impairment following ischaemia. The current study has demonstrated that progesterone has different neuroprotective effects whether it is administered to aged or ovariectomized female mice and emphasizes the need to combine histopathological and functional outcomes within the same study. In addition, as progesterone-only treatment may not improve all outcomes in all groups, therapies that combine progesterone with other neuroprotective candidates should be investigated to maximize benefit following stroke. PMID- 21705428 TI - The histone acetyltransferase p300 promotes intrinsic axonal regeneration. AB - Axonal regeneration and related functional recovery following axonal injury in the adult central nervous system are extremely limited, due to a lack of neuronal intrinsic competence and the presence of extrinsic inhibitory signals. As opposed to what occurs during nervous system development, a weak proregenerative gene expression programme contributes to the limited intrinsic capacity of adult injured central nervous system axons to regenerate. Here we show, in an optic nerve crush model of axonal injury, that adenoviral (cytomegalovirus promoter) overexpression of the acetyltransferase p300, which is regulated during retinal ganglion cell maturation and repressed in the adult, can promote axonal regeneration of the optic nerve beyond 0.5 mm. p300 acetylates histone H3 and the proregenerative transcription factors p53 and CCAAT-enhancer binding proteins in retinal ganglia cells. In addition, it directly occupies and acetylates the promoters of the growth-associated protein-43, coronin 1 b and Sprr1a and drives the gene expression programme of several regeneration-associated genes. On the contrary, overall increase in cellular acetylation using the histone deacetylase inhibitor trichostatin A, enhances retinal ganglion cell survival but not axonal regeneration after optic nerve crush. Therefore, p300 targets both the epigenome and transcription to unlock a post-injury silent gene expression programme that would support axonal regeneration. PMID- 21705429 TI - Transneuronal retrograde degeneration of retinal ganglion cells and optic tract in hemianopic monkeys and humans. AB - Transneuronal retrograde degeneration of retinal ganglion cells after removal of primary visual cortex (area V1) is well established by quantitative neurohistological analysis of the ganglion cell layer in monkeys, but remains controversial in human patients. Therefore, we first histologically examined retinal degeneration in sectioned archived retinae of 26 macaque monkeys with unilateral V1 ablation and post-surgical survival times ranging from 3 months to 14.3 years. In addition, the cross-sectional area of the optic tract was measured in archived coronal histological sections of the brain of every hemianopic monkey and in sections from 10 control monkeys with non-visual bilateral cortical lesions. The ratios of nasal and temporal retinal ganglion cell counts in the contralesional eye and ipsi/contralateral optic tract areas were calculated and compared. They show that the decline was initially more pronounced for the optic tract, slackened after 3 years post-lesion and was steeper for the ganglion cells thereafter. Nevertheless, both measures were highly correlated. Second, we calculated ratios from structural magnetic resonance images to see whether the optic tracts of four human hemianopes would show similar evidence of transneuronal degeneration of their ipsilesional optic tract. The results were consistent with extensive and time-dependent degeneration of the retinal ganglion cell layer. The measures of the optic tracts provide evidence for comparable transneuronal retinal ganglion cell degeneration in both primate species and show that structural magnetic resonance image can both reveal and assess it. PMID- 21705430 TI - Activities of human RRP6 and structure of the human RRP6 catalytic domain. AB - The eukaryotic RNA exosome is a highly conserved multi-subunit complex that catalyzes degradation and processing of coding and noncoding RNA. A noncatalytic nine-subunit exosome core interacts with Rrp44 and Rrp6, two subunits that possess processive and distributive 3'-to-5' exoribonuclease activity, respectively. While both Rrp6 and Rrp44 are responsible for RNA processing in budding yeast, Rrp6 may play a more prominent role in processing, as it has been demonstrated to be inhibited by stable RNA secondary structure in vitro and because the null allele in budding yeast leads to the buildup of specific structured RNA substrates. Human RRP6, otherwise known as PM/SCL-100 or EXOSC10, shares sequence similarity to budding yeast Rrp6 and is proposed to catalyze 3' to-5' exoribonuclease activity on a variety of nuclear transcripts including ribosomal RNA subunits, RNA that has been poly-adenylated by TRAMP, as well as other nuclear RNA transcripts destined for processing and/or destruction. To characterize human RRP6, we expressed the full-length enzyme as well as truncation mutants that retain catalytic activity, compared their activities to analogous constructs for Saccharomyces cerevisiae Rrp6, and determined the X-ray structure of a human construct containing the exoribonuclease and HRDC domains that retains catalytic activity. Structural data show that the human active site is more exposed when compared to the yeast structure, and biochemical data suggest that this feature may play a role in the ability of human RRP6 to productively engage and degrade structured RNA substrates more effectively than the analogous budding yeast enzyme. PMID- 21705431 TI - Major role for mRNA binding and restructuring in sRNA recruitment by Hfq. AB - Bacterial small RNAs (sRNAs) modulate gene expression by base-pairing with target mRNAs. Many sRNAs require the Sm-like RNA binding protein Hfq as a cofactor. Well characterized interactions between DsrA sRNA and the rpoS mRNA leader were used to understand how Hfq stimulates sRNA pairing with target mRNAs. DsrA annealing stimulates expression of rpoS by disrupting a secondary structure in the rpoS leader, which otherwise prevents translation. Both RNAs bind Hfq with similar affinity but interact with opposite faces of the Hfq hexamer. Using mutations that block interactions between two of the three components, we demonstrate that Hfq binding to a functionally critical (AAN)(4) motif in rpoS mRNA rescues DsrA binding to a hyperstable rpoS mutant. We also show that Hfq cannot stably bridge the RNAs. Persistent ternary complexes only form when the two RNAs are complementary. Thus, Hfq mainly acts by binding and restructuring the rpoS mRNA. However, Hfq binding to DsrA is needed for maximum annealing in vitro, indicating that transient interactions with both RNAs contribute to the regulatory mechanism. PMID- 21705434 TI - Confidence interval estimation for the Bland-Altman limits of agreement with multiple observations per individual. AB - The limits of agreement (LoA) method proposed by Bland and Altman has become a standard for assessing agreement between different methods measuring the same quantity. Virtually, all method comparison studies have reported only point estimates of LoA due largely to the lack of simple confidence interval procedures. In this article, we address confidence interval estimation for LoA when multiple measurements per individual are available. Separate procedures are proposed for situations when the underlying true value of the measured quantity is assumed changing and when it is perceived as stable. A fixed number of replicates per individual is not needed for the procedures to work. As shown by the worked examples, the construction of these confidence intervals requires only quantiles from the standard normal and chi-square distributions. Simulation results show the proposed procedures perform well. A SAS macro implementing the methods is available on the publisher's website. PMID- 21705432 TI - Localization of mRNAs coding for mitochondrial proteins in the yeast Saccharomyces cerevisiae. AB - Targeted mRNA localization is a likely determinant of localized protein synthesis. To investigate whether mRNAs encoding mitochondrial proteins (mMPs) localize to mitochondria and, thus, might confer localized protein synthesis and import, we visualized endogenously expressed mMPs in vivo for the first time. We determined the localization of 24 yeast mMPs encoding proteins of the mitochondrial matrix, outer and inner membrane, and intermembrane space and found that many mMPs colocalize with mitochondria in vivo. This supports earlier cell fractionation and microarray-based studies that proposed mMP association with the mitochondrial fraction. Interestingly, a number of mMPs showed a dependency on the mitochondrial Puf3 RNA-binding protein, as well as nonessential proteins of the translocase of the outer membrane (TOM) complex import machinery, for normal colocalization with mitochondria. We examined the specific determinants of ATP2 and OXA1 mRNA localization and found a mutual dependency on the 3' UTR, Puf3, Tom7, and Tom70, but not Tom20, for localization. Tom6 may facilitate the localization of specific mRNAs as OXA1, but not ATP2, mRNA was mislocalized in tom6Delta cells. Interestingly, a substantial fraction of OXA1 and ATP2 RNA granules colocalized with the endoplasmic reticulum (ER) and a deletion in MDM10, which mediates mitochondria-ER tethering, resulted in a significant loss of OXA1 mRNA localization with ER. Finally, neither ATP2 nor OXA1 mRNA targeting was affected by a block in translation initiation, indicating that translation may not be essential for mRNA anchoring. Thus, endogenously expressed mRNAs are targeted to the mitochondria in vivo, and multiple factors contribute to mMP localization. PMID- 21705433 TI - Cognitive motivations of free riding and cooperation and impaired strategic decision making in schizophrenia during a public goods game. AB - Schizophrenia is generally characterized by various positive and negative symptoms that are accompanied by significant social dysfunction. Various researchers investigated the functional impairments in schizophrenia including impaired theory of mind (TOM), poor integration of affective and cognitive information, and malfunctioning of adaptive and strategic learning process. However, most of the studies were limited to simplified cognitive tests or computerized choice games that exclude real social interaction. The aim of the current study was to investigate human strategies based on the incentives and particularly the cognitive and emotional motivations of free riding. We examined the decision patterns of 41 healthy subjects (HSs) and 37 schizophrenia patients (SZ) during the public goods game (PGG), one of the games simulating human cooperation and free riding in group interactions. Strategic decision processes during the iterative binary PGG were assessed in terms of cognitive understanding, loss sensitivity, and TOM. We found that greed and loss sensitivity both motivated free-riding behavior in the HS, but that they were more vulnerable to greedy incentives than to possible loss. More significantly, the SZ clearly displayed a lower prevalence of free riding and distinct decision patterns from HS. Nonstrategic and unexpectedly low free ridings in the SZ likely arise from poor integration of cognitive and affective information. We suggest that loss sensitivity and TOM as well as cognitive understanding are involved in regulation of the free riding and cooperative behavior. PMID- 21705435 TI - On weighting approaches for missing data. AB - We review the class of inverse probability weighting (IPW) approaches for the analysis of missing data under various missing data patterns and mechanisms. The IPW methods rely on the intuitive idea of creating a pseudo-population of weighted copies of the complete cases to remove selection bias introduced by the missing data. However, different weighting approaches are required depending on the missing data pattern and mechanism. We begin with a uniform missing data pattern (i.e. a scalar missing indicator indicating whether or not the full data is observed) to motivate the approach. We then generalise to more complex settings. Our goal is to provide a conceptual overview of existing IPW approaches and illustrate the connections and differences among these approaches. PMID- 21705436 TI - Robust non-parametric tests for complex-repeated measures problems in ophthalmology. AB - The NonParametric Combination methodology (NPC) of dependent permutation tests allows the experimenter to face many complex multivariate testing problems and represents a convincing and powerful alternative to standard parametric methods. The main advantage of this approach lies in its flexibility in handling any type of variable (categorical and quantitative, with or without missing values) while at the same time taking dependencies among those variables into account without the need of modelling them. NPC methodology enables to deal with repeated measures, paired data, restricted alternative hypotheses, missing data (completely at random or not), high-dimensional and small sample size data. Hence, NPC methodology can offer a significant contribution to successful research in biomedical studies with several endpoints, since it provides reasonably efficient solutions and clear interpretations of inferential results. Pesarin F. Multivariate permutation tests: with application in biostatistics. Chichester-New York: John Wiley &Sons, 2001; Pesarin F, Salmaso L. Permutation tests for complex data: theory, applications and software. Chichester, UK: John Wiley &Sons, 2010. We focus on non-parametric permutation solutions to two real case studies in ophthalmology, concerning complex-repeated measures problems. For each data set, different analyses are presented, thus highlighting characteristic aspects of the data structure itself. Our goal is to present different solutions to multivariate complex case studies, guiding researchers/readers to choose, from various possible interpretations of a problem, the one that has the highest flexibility and statistical power under a set of less stringent assumptions. MATLAB code has been implemented to carry out the analyses. PMID- 21705437 TI - Assessing non-inferiority with time-to-event data via the method of non parametric covariance. AB - Non-parametric methods have been well recognised as useful tools for time-to event (survival) data analysis because they provide valid statistical inference with few assumptions. Tangen and Koch have proposed the use of the method of non parametric covariance for time-to-event data in a traditional superiority setting. In this article, we extended their method to assess non-inferiority of two treatments. To evaluate this non-parametric method versus the classical semi parametric Cox proportional hazards regression model, simulations in terms of the Type 1 error rate and power were performed and compared. The results showed that the two methods were generally comparable regarding the Type 1 error rate when adjustment for the covariates correlated with the survival time was made. In the non-inferiority setting, the covariate-adjusted non-parametric analysis was shown to always increase power. However, this was not necessarily the case for the adjusted Cox model where results were inconsistent to those seen in the superiority setting. For illustration, an application of the proposed non parametric method to a trial involving pemetrexed, a recently approved drug for first-line treatment of non-small cell lung cancer, is included. PMID- 21705438 TI - Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discovery. AB - Large observational data sets are a great asset to better understand the effects of medicines in clinical practice and, ultimately, improve patient care. For an empirical pattern in observational data to be of practical relevance, it should represent a substantial deviation from the null model. For the purpose of identifying such deviations, statistical significance tests are inadequate, as they do not on their own distinguish the magnitude of an effect from its data support. The observed-to-expected (OE) ratio on the other hand directly measures strength of association and is an intuitive basis to identify a range of patterns related to event rates, including pairwise associations, higher order interactions and temporal associations between events over time. It is sensitive to random fluctuations for rare events with low expected counts but statistical shrinkage can protect against spurious associations. Shrinkage OE ratios provide a simple but powerful framework for large-scale pattern discovery. In this article, we outline a range of patterns that are naturally viewed in terms of OE ratios and propose a straightforward and effective statistical shrinkage transformation that can be applied to any such ratio. The proposed approach retains emphasis on the practical relevance and transparency of highlighted patterns, while protecting against spurious associations. PMID- 21705439 TI - High-throughput mapping of the promoters of the mouse olfactory receptor genes reveals a new type of mammalian promoter and provides insight into olfactory receptor gene regulation. AB - The olfactory receptor (OR) genes are the largest mammalian gene family and are expressed in a monogenic and monoallelic fashion in olfactory neurons. Using a high-throughput approach, we mapped the transcription start sites of 1085 of the 1400 murine OR genes and performed computational analysis that revealed potential transcription factor binding sites shared by the majority of these promoters. Our analysis produced a hierarchical model for OR promoter recognition in which unusually high AT content, a unique epigenetic signature, and a stereotypically positioned O/E site distinguish OR promoters from the rest of the murine promoters. Our computations revealed an intriguing correlation between promoter AT content and evolutionary plasticity, as the most AT-rich promoters regulate rapidly evolving gene families. Within the AT-rich promoter category the position of the TATA-box does not correlate with the transcription start site. Instead, a spike in GC composition might define the exact location of the TSS, introducing the concept of "genomic contrast" in transcriptional regulation. Finally, our experiments show that genomic neighborhood rather than promoter sequence correlates with the probability of different OR genes to be expressed in the same olfactory cell. PMID- 21705440 TI - Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation. AB - Although targeting the Ras/Raf/MEK pathway remains a promising anticancer strategy, mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitors in clinical development are likely to be limited in their ability to produce durable clinical responses due to the emergence of acquired drug resistance. To identify potential mechanisms of such resistance, we established MEK inhibitor-resistant clones of human HT-29 colon cancer cells (HT 29R cells) that harbor the B-RafV600E mutation. HT-29R cells were specifically resistant to MEK inhibition in vitro and in vivo, with drug-induced elevation of MEK/ERK and their downstream targets primarily accountable for drug resistance. We identified MEK1(F129L) mutation as a molecular mechanism responsible for MEK/ERK pathway activation. In an isogenic cell system that extended these findings into other cancer cell lines, the MEK1(F129L) mutant exhibited higher intrinsic kinase activity than wild-type MEK1 [MEK1(WT)], leading to potent activation of ERK and downstream targets. The MEK1(F129L) mutation also strengthened binding to c-Raf, suggesting an underlying mechanism of higher intrinsic kinase activity. Notably, the combined use of Raf and MEK inhibitors overcame the observed drug resistance and exhibited greater synergy in HT-29R cells than the drug-sensitive HT-29 parental cells. Overall, our findings suggested that mutations in MEK1 can lead to acquired resistance in patients treated with MEK inhibitors and that a combined inhibition of Raf and MEK may be potentially useful as a strategy to bypass or prevent drug resistance in the clinic. PMID- 21705441 TI - Leuconostoc miyukkimchii sp. nov., isolated from brown algae (Undaria pinnatifida) kimchi. AB - A Gram-staining-positive, non-motile and non-spore-forming lactic acid bacterium, designated strain M2(T), was isolated from fermented brown algae (Undaria pinnatifida) kimchi in South Korea. Cells of the isolate were facultatively anaerobic ovoids and showed catalase- and oxidase-negative reactions. Growth of strain M2(T) was observed at 4-35 degrees C and at pH 5.0-9.0. The G+C content of the genomic DNA was 42.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain M2(T) belonged to the genus Leuconostoc and was most closely related to Leuconostoc inhae IH003(T), Leuconostoc kimchii IH25(T), Leuconostoc gasicomitatum LMG 18811(T), Leuconostoc gelidum DSM 5578(T), Leuconostoc palmae TMW2.694(T) and Leuconostoc holzapfelii BFE 7000(T) with 98.9 %, 98.8 %, 98.8 %, 98.7 %, 98.5 % and 98.2 % sequence similarity, respectively. DNA-DNA hybridization values between strain M2(T) and Leuconostoc inhae KACC 12281(T), Leuconostoc kimchii IH25(T), Leuconostoc gelidum KACC 12256(T), Leuconostoc gasicomitatum KACC 13854(T), Leuconostoc palmae DSM 21144(T) and Leuconostoc holzapfelii DSM 21478(T) were 13.8+/-3.2 %, 14.3+/-3.4 %, 9.9+/-1.0 %, 13.2+/-0.8 %, 22.4+/-4.9 % and 16.2+/-4.6 %, respectively, which allowed differentiation of strain M2(T) from the closely related species of the genus Leuconostoc. On the basis of phenotypic and molecular properties, strain M2(T) represents a novel species in the genus Leuconostoc, for which the name Leuconostoc miyukkimchii sp. nov. is proposed. The type strain is M2(T) ( = KACC 15353(T) = JCM 17445(T)). PMID- 21705442 TI - Phaeospirillum tilakii sp. nov., a phototrophic alphaproteobacterium isolated from aquatic sediments. AB - Two strains (JA492(T) and JA590) of spiral-shaped, anaerobic, Gram-stain negative, motile, purple non-sulfur bacteria were isolated from aquatic sediments from a bird sanctuary and a stream, respectively, and were characterized by a polyphasic taxonomic approach. Bacteriochlorophyll a and carotenoids (rhodopin, lycopene, hydroxylycopene glucoside and dihydroxylycopene diglucoside) were present as photosynthetic pigments. Intracellular photosynthetic membranes were of the stacked type. The major fatty acids were C(18 : 1)omega7c, C(16 : 0) and summed feature 3 (C(16 : 1)omega6c and/or C(16 : 1)omega7c) in both strains. Ubiquinones and menaquinones were present as major quinone components. The genomic DNA G+C contents of strains JA492(T) and JA590 were 63.8 and 61.5 mol%, respectively. Both strains were closely related (mean DNA-DNA hybridization >70 %). Phylogenetic analysis showed that the strains clustered with species of the genus Phaeospirillum of the family Rhodospirillaceae, class Alphaproteobacteria. Based on 16S rRNA gene sequence analysis, both strains showed highest sequence similarity with Phaeospirillum oryzae JA317(T) (97.2-97.4 %), Phaeospirillum molischianum DSM 120(T) (96.5-96.7 %), Phaeospirillum fulvum DSM 113(T) (96.7 96.9 %) and Phaeospirillum chandramohanii JA145(T) (96.5-96.7 %). DNA-DNA relatedness between strain JA492(T) and its closest relative in the genus Phaeospirillum was less than 42 %. It is evident from phenotypic, chemotaxonomic and molecular genetic data that strain JA492(T) represents a novel species of the genus Phaeospirillum, for which the name Phaeospirillum tilakii sp. nov. is proposed; the type strain is JA492(T) ( = NBRC 107650(T) = KCTC 15012(T)). PMID- 21705443 TI - Kribbella amoyensis sp. nov., isolated from rhizosphere soil of a pharmaceutical plant, Typhonium giganteum Engl. AB - An actinomycete, designated XMU 198(T), was isolated from the rhizosphere soil of a pharmaceutical plant, Typhonium giganteum Engl., collected in Xiamen City, China. 16S rRNA gene sequence analysis showed that the isolate exhibited highest sequence similarities with Kribbella flavida KACC 20148(T), K. karoonensis Q41(T) and K. alba YIM 31975(T) (98.7, 98.4 and 98.2 %, respectively). The chemotaxonomic characteristics further supported the assignment of strain XMU 198(T) to the genus Kribbella: ll-diaminopimelic acid in the cell-wall peptidoglycan; glucose and galactose with minor amounts of ribose as the whole cell sugars; polar lipids comprising phosphatidylglycerol, diphosphatidylglycerol, phosphatidylcholine, phosphatidylinositol and unidentified phospholipids; a fatty acid profile characterized by the predominance of iso-C(16 : 0), iso-C(14 : 0) and anteiso-C(15 : 0); and MK 9(H(4)) as the main menaquinone. Gyrase subunit B gene (gyrB) sequence analysis showed that the genetic distances between strain XMU 198(T) and all other members of the genus Kribbella were greater than 0.014, the value used as the threshold for species delineation within this genus. A wide range of genotypic and phenotypic characteristics, as well as DNA-DNA relatedness between strain XMU 198(T) and K. flavida DSM 17836(T) (41.18 %), K. karoonensis Q41(T) (38.02 %) and K. alba DSM 15500(T) (50.58 %), distinguished the isolate from its closest phylogenetic neighbours. On the basis of the above data, a novel species of the genus Kribbella, Kribbella amoyensis sp. nov., is proposed. The type strain is XMU 198(T) ( = DSM 24683(T) = NBRC 107914(T)). PMID- 21705444 TI - Geofilum rubicundum gen. nov., sp. nov., isolated from deep subseafloor sediment. AB - A novel, facultatively anaerobic bacterium (strain JAM-BA0501(T)) was isolated from a deep subseafloor sediment sample at a depth of 247 m below seafloor off the Shimokita Peninsula of Japan in the north-western Pacific Ocean (Site C9001, 1180 m water depth). Cells of strain JAM-BA0501(T) were gram-negative, filamentous, non-spore-forming and motile on solid medium by gliding. Phylogenetic analysis based on the 16S rRNA gene sequence of strain JAM-BA0501(T) indicated a distant relationship to strains representing genera within the order Bacteroidales, such as Alkaliflexus imshenetskii Z-7010(T) (91.1 % similarity), Marinilabilia salmonicolor ATCC 19041(T) (86.2 %) and Anaerophaga thermohalophila Fru22(T) (89.3 %). The new isolate produced isoprenoid quinones with menaquinone MK-7 as the major component, and the predominant fatty acids were iso-C(15 : 0) and anteiso-C(15 : 0). The DNA G+C content of the isolate was 42.9 mol%. Based on its taxonomic distinctiveness, strain JAM-BA0501(T) is considered to represent a novel species of a new genus within the family Marinilabiliaceae, for which the name Geofilum rubicundum gen. nov., sp. nov. is proposed. The type strain of Geofilum rubicundum is JAM-BA0501(T) ( = JCM 15548(T) = NCIMB 14482(T)). PMID- 21705445 TI - Flavivirga jejuensis gen. nov., sp. nov., and Flavivirga amylovorans sp. nov., new members of the family Flavobacteriaceae isolated from seawater, and emended descriptions of the genera Psychroserpens and Lacinutrix. AB - Two yellow, rod-shaped, gram-reaction-negative, strictly aerobic bacterial strains, designated JC2682(T) and JC2681(T), were isolated from a seawater sample of Jeju Island, Korea. The isolates required sea salts for growth and showed gliding motility. Phylogenetic analyses based on 16S rRNA gene sequences revealed that strains JC2682(T) and JC2681(T) shared 96.9 % similarity and formed a robust monophyletic group within the radiation encompassing the family Flavobacteriaceae. This distinct clade, which had varying branch positions depending on the tree-making algorithm used, represents a new genus within the family Flavobacteriaceae. The predominant isoprenoid quinone (menaquinone 6, MK 6) and DNA G+C content (27-33 mol%) were consistent with its assignment to the family Flavobacteriaceae, but the polar lipid profile, fatty acid composition and overall phenotypic traits demonstrated that the test strains were not closely affiliated to any recognized genera. Based on data from the present polyphasic taxonomic study, strains JC2682(T) and JC2681(T) are considered to represent two novel species of a new genus in the family Flavobacteriaceae, for which the names Flavivirga jejuensis gen. nov., sp. nov. and Flavivirga amylovorans sp. nov. are proposed, respectively. The type strain of Flavivirga jejuensis is JC2682(T) ( = KACC 14158(T) = JCM 17113(T)). The type strain of Flavivirga amylovorans is JC2681(T) ( = KACC 14157(T) = JCM 17112(T)). Amended descriptions of the genera Psychroserpens and Lacinutrix are provided. PMID- 21705447 TI - Actinomadura sediminis sp. nov., a marine actinomycete isolated from mangrove sediment. AB - In this study, the taxonomic position of an actinobacterium, strain YIM M 10931(T), which was isolated from a mangrove sediment sample collected in Dugong Creek, Little Andaman, India, was determined by a polyphasic approach. This gram positive, aerobic strain produced branched substrate mycelium and aerial hyphae, which differentiated into short, hooked or spiral spore chains. The organism contained meso-diaminopimelic acid as the diagnostic diamino acid in the cell wall peptidoglycan. The whole cell sugars consisted of mannose, ribose, glucose, galactose and madurose. The cellular fatty acid profile mainly consisted of iso C(16 : 0), 10-methyl C(18 : 0) and C(16 : 0). The quinone system was predominantly composed of MK-9(H(8)) (45.5 %) and MK-9(H(6)) (39 %). The phospholipids detected were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol mannoside, phosphatidylinositol and two unknown phospholipids. The organism showed a combination of morphological and chemotaxonomic properties typical of members of the genus Actinomadura. Moreover, phylogenetic analysis based on a 16S rRNA gene sequence generated from the strain identified its closest relatives as Actinomadura cremea DSM 43676(T) (98.4 % sequence similarity), Actinomadura rifamycini DSM 43936(T) (97.4 %) and Actinomadura apis IM17-1(T) (96.9 %). It was obvious from the resulting phylogenetic trees that strain YIM M 10931(T) belongs to a distinct subclade within the evolutionary radiation of the genus Actinomadura. DNA-DNA hybridizations of strain YIM M 10931(T) with A. cremea DSM 43676(T) and A. rifamycini DSM 43936(T) were performed and further confirmed that the isolate represents a separate genomic species. Based on the phenotypic and genotypic characteristics presented, it is proposed that strain YIM M 10931(T) represents a novel species within the genus Actinomadura, for which the name Actinomadura sediminis sp. nov. is proposed; the type strain is YIM M 10931(T) ( = CCTCC AA 2010009(T) = DSM 45500(T)). PMID- 21705446 TI - Neptuniibacter halophilus sp. nov., isolated from a salt pan, and emended description of the genus Neptuniibacter. AB - A bacterial strain designated antisso-13(T) was isolated from a salt pan in southern Taiwan and characterized using a polyphasic taxonomic approach. Strain antisso-13(T) was gram-negative, aerobic, creamy white in colour, rod-shaped and motile by single monopolar flagellum. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain antisso-13(T) belonged to the genus Neptuniibacter and its closest neighbour was Neptuniibacter caesariensis MED92(T), with 96.7 % sequence similarity. Phylogenetic analyses based on rpoB and recA gene sequences and deduced amino acid sequences also revealed that the novel strain and N. caesariensis MED92(T) formed a distinct phylogenetic cluster. Strain antisso-13(T) exhibited optimal growth at 25-30 degrees C, with 2.0-4.0 % NaCl and at pH 7.0. Cellular fatty acids were C(16 : 1)omega7c (39.8 %), C(18 : 1)omega7c (29.4 %), C(16 : 0) (15.5 %), C(10 : 0) 3-OH (7.5 %), anteiso-C(11 : 0) (1.8 %), C(18 : 0) (1.8 %), C(11 : 0) 2-OH (1.6 %), iso-C(10 : 0) (1.2 %) and C(14 : 0) (1.1 %). The major respiratory quinone was ubiquinone Q-8. The polar lipid profile consisted of a mixture of phosphatidylglycerol, phosphatidylethanolamine and several uncharacterized polar lipids and the DNA G+C content was 54.2 mol%. The results of physiological and biochemical tests allowed clear phenotypic differentiation of this isolate from previously described members of the genus Neptuniibacter. It is evident from the genotypic and phenotypic data that strain antisso-13(T) should be classified as a representative of a novel species in the genus Neptuniibacter. The name proposed for this taxon is Neptuniibacter halophilus sp. nov.; the type strain is antisso 13(T) ( = LMG 25378(T) = BCRC 80079(T)). An emended description of the genus Neptuniibacter is provided. PMID- 21705448 TI - Chitinivorax tropicus gen. nov., sp. nov., a chitinolytic bacterium isolated from a freshwater lake. AB - A facultatively anaerobic, chitinolytic bacterium, strain KL-9(T), was isolated from a freshwater lake in Taiwan and characterized by using a polyphasic taxonomic approach. Cells of strain KL-9(T) were gram-negative, rod-shaped, motile by means of a single polar flagellum and non-spore-forming. Growth occurred at 15-40 degrees C (optimum, 30-37 degrees C), at pH 7.0-9.0 (optimum, pH 8.0) and with 0-1.0 % NaCl (optimum, 0 %). The predominant fatty acids were summed feature 3 (comprising C(16 : 1)omega7c and/or C(16 : 1)omega6c) and C(16 : 0). The major isoprenoid quinone was Q-8. The DNA G+C content of strain KL-9(T) was 64.6 mol%. The polar lipid profile consisted of a mixture of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidyldimethylethanolamine and several uncharacterized phospholipids and aminolipids. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain KL-9(T) formed a distinct lineage with respect to closely related genera within the class Betaproteobacteria, being most closely related to members of the genera Leeia, Chitinimonas, Silvimonas and Andreprevotia. Levels of 16S rRNA gene sequence similarity with respect to the type strains of type species of these genera were below 91 %. On the basis of genotypic and phenotypic data, strain KL 9(T) is thus considered to represent a novel species of a new genus within the class Betaproteobacteria, for which the name Chitinivorax tropicus gen. nov., sp. nov. is proposed. The type strain of Chitinivorax tropicus is KL-9(T) ( = BCRC 80168(T) = LMG 25530(T)). PMID- 21705449 TI - Bacillus kochii sp. nov., isolated from foods and a pharmaceuticals manufacturing site. AB - Three Gram-staining-positive, strictly aerobic, motile, catalase-positive, endospore-forming rods, designated WCC 4582(T), WCC 4581 and WCC 4583, were isolated from two different food sources and a pharmaceuticals production site. The three isolates were highly similar in their 16S rRNA gene sequences (100 % similarity) and groEL sequences (99.2-100 % similarity), Fourier-transform infrared spectroscopic fingerprints and other features tested. The isolates were most closely related to Bacillus horneckiae; the isolates and the type strain of B. horneckiae shared 97.6 % and 89.6 % 16S rRNA gene and groEL sequence similarities, respectively. The organisms grew optimally at 30 degrees C, at pH 7 and in the presence of 0.5 % (w/v) NaCl. The cell-wall peptidoglycan of WCC 4582(T) contained meso-diaminopimelic acid (A1gamma) and the genomic DNA G+C content was 36.4 mol%. DNA-DNA relatedness between strain WCC 4582(T) and B. horneckiae NRRL B-59162(T) was 17 %. The three isolates are considered to represent a novel species of the genus Bacillus, for which the name Bacillus kochii sp. nov. is proposed. The type strain is WCC 4582(T) ( = DSM 23667(T) = CCUG 59877(T) = LMG 25855(T)). PMID- 21705450 TI - Induction of HLA-DP4-restricted anti-survivin Th1 and Th2 responses using an artificial antigen-presenting cell. AB - PURPOSE: In previous cancer vaccine clinical trials targeting survivin, induction of specific CD8(+) T-cell responses did not consistently lead to clinical responses. Considering the critical role of CD4(+) T-cell help in generating antitumor immunity, integration of anti-survivin CD4(+) T-cell responses may enhance the efficacy of anti-survivin cancer immunotherapy. Human leukocyte antigen (HLA)-DP4 is emerging as an attractive MHC target allele of CD4(+) T cell mediated immunotherapy, because it is one of the most frequent HLA alleles in many ethnic groups. In this article, we aimed to elucidate DP4-restricted CD4(+) T-cell responses against survivin in cancer patients. EXPERIMENTAL DESIGN: We generated a human cell-based artificial antigen-presenting cell (aAPC) expressing HLA-DP4, CD80, and CD83 and induced DP4-restricted antigen-specific CD4(+) T cells. The number, phenotype, effector function, and in vitro longevity of generated CD4(+) T cells were determined. RESULTS: We first determined previously unknown DP4-restricted CD4(+) T-cell epitopes derived from cytomegalovirus pp65, to which sustained Th1-biased recall responses were induced in vitro by using DP4 aAPC. In contrast, DP4-aAPC induced in vitro both Th1 and Th2 long-lived anti survivin CD4(+) T cells from cancer patients. Both survivin-specific Th1 and Th2 cells were able to recognize survivin-expressing tumors in a DP4-restricted manner. Neither survivin-specific interleukin 10 secreting Tr1 cells nor Th17 cells were induced by DP4-aAPC. CONCLUSIONS: DP4-restricted anti-survivin Th1 and Th2 immunity with sufficient functional avidity can be induced from cancer patients. The development of strategies to concurrently induce both CD4(+) and CD8(+) T-cell responses against survivin is warranted for optimal anti-survivin cancer immunotherapy. PMID- 21705452 TI - TLX1-induced T-cell acute lymphoblastic leukemia. AB - The TLX1 transcription factor oncogene is frequently activated by chromosomal translocations in T-cell acute lymphoblastic leukemia (T-ALL) and defines a distinct molecular group of tumors characterized by differentiation arrest at the early cortical stage of thymocyte differentiation and excellent response to therapy. Recent developments from the analysis of genomic data on TLX1-specific transcriptional targets and analysis of the molecular mechanisms of TLX1 transformation in human- and mouse-induced leukemias have shown novel insight into the activity of this transcription factor oncogene. Aberrant expression of TLX1 in T-cell progenitors disrupts normal T-cell development and triggers the development of aneuploidy during T-cell transformation. Importantly, the disruption of the mitotic checkpoint in TLX1-induced tumors may be linked not only to the acquisition of secondary genetic alterations in T-ALL but also to increased sensitivity of these tumors to chemotherapy with drugs targeting the formation of the mitotic spindle. PMID- 21705451 TI - Potential prostate cancer drug target: bioactivation of androstanediol by conversion to dihydrotestosterone. AB - High-affinity binding of dihydrotestosterone (DHT) to the androgen receptor (AR) initiates androgen-dependent gene activation, required for normal male sex development in utero, and contributes to prostate cancer development and progression in men. Under normal physiologic conditions, DHT is synthesized predominantly by 5alpha-reduction of testosterone, the major circulating androgen produced by the testis. During androgen deprivation therapy, intratumoral androgen production is sufficient for AR activation and prostate cancer growth, even though circulating testicular androgen levels are low. Recent studies indicate that the metabolism of 5alpha-androstane-3alpha, 17beta-diol by 17beta hydroxysteroid dehydrogenase 6 in benign prostate and prostate cancer cells is a major biosynthetic pathway for intratumoral synthesis of DHT, which binds AR and initiates transactivation to promote prostate cancer growth during androgen deprivation therapy. Drugs that target the so-called backdoor pathway of DHT synthesis provide an opportunity to enhance clinical response to luteinizing hormone-releasing hormone (LHRH) agonists or antagonists, AR antagonists, and inhibitors of 5alpha-reductase enzymes (finasteride or dutasteride), and other steroid metabolism enzyme inhibitors (ketoconazole or the recently available abiraterone acetate). PMID- 21705453 TI - Resveratrol selectively induces DNA Damage, independent of Smad4 expression, in its efficacy against human head and neck squamous cell carcinoma. AB - PURPOSE: Alterations in Smad4 signaling and its loss cause genomic instability and head and neck squamous cell carcinoma (HNSCC), suggesting that agents that target both Smad4-dependent and -independent pathways could control HNSCC. EXPERIMENTAL DESIGN: Resveratrol efficacy was evaluated against the HNSCC cells FaDu, Cal27, Det562, and Cal27-Smad4 for viability, DNA damage, cell-cycle progression, and apoptosis, as well as gamma-H2AX expression, and focus formation (gamma-H2AX and Brca1). Resveratrol efficacy was also examined in nude mice for FaDu xenograft growth. Xenografts were analyzed for gamma-H2AX and cleaved caspase-3. RESULTS: Resveratrol (5-50 MUmol/L) suppressed viability and induced DNA damage in FaDu and Cal27 cells but not in normal human epidermal keratinocytes and human foreskin fibroblasts, showing its selectivity toward HNSCC cells; however, Det562 cells were resistant to resveratrol even at 100 MUmol/L. Cal27 cells stably transfected with Smad4 showed similar resveratrol effects as parental Cal27, indicating that a lack of resveratrol effect in Det562 cells was independent of Smad4 status in these cells. Furthermore, resveratrol caused S-phase arrest and apoptotic death of FaDu and Cal27 cells together with induction of Brca1 and gamma-H2AX foci. Resveratrol (50 mg/kg body weight) treatment also inhibited FaDu tumor growth in nude mice, and gamma-H2AX and cleaved caspase-3 were strongly increased in xenografts from resveratrol-treated mice compared with controls. CONCLUSION: Our findings for the first time showed antiproliferative, DNA damaging, and apoptotic effects of resveratrol in HNSCC cells independent of Smad4 status, both in vitro and in vivo, suggesting that more studies are needed to establish its potential usefulness against HNSCC. PMID- 21705454 TI - Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients. AB - PURPOSE: Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy. EXPERIMENTAL DESIGN: We conducted genome-wide association studies (GWAS) to identify single-nucleotide polymorphisms (SNP) associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMap lymphoblastoid cell lines (LCL) and replicated them in additional LCLs. SNPs passing both stages of the cell-based study were tested for association with progression-free survival (PFS) in patients. Phase 1 validation was based on 377 ovarian cancer patients receiving at least four cycles of carboplatin and paclitaxel from the Australian Ovarian Cancer Study (AOCS). Positive associations were then assessed in phase 2 validation analysis of 1,326 patients from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. RESULTS: In the initial GWAS, 342 SNPs were associated with carboplatin-induced cytotoxicity, of which 18 unique SNPs were retained after assessing their association with gene expression. One SNP (rs1649942) was replicated in an independent LCL set (Bonferroni adjusted P < 0.05). It was found to be significantly associated with decreased PFS in phase 1 AOCS patients (P(per-allele) = 2 * 10(-2)), with a stronger effect in the subset of women with optimally debulked tumors (P(per-allele) = 4 * 10(-3)). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumors (P(per-allele) = 9 * 10(-3)). However, this SNP was not significant in phase 2 validation analysis with patients from numerous cohorts. CONCLUSION: This study shows the potential of cell-based, genome-wide approaches to identify germline predictors of treatment outcome and highlights the need for extensive validation in patients to assess their clinical effect. PMID- 21705456 TI - Guidelines for the management of oesophageal and gastric cancer. PMID- 21705455 TI - The two faces of interferon-gamma in cancer. AB - Interferon-gamma is a cytokine whose biological activity is conventionally associated with cytostatic/cytotoxic and antitumor mechanisms during cell mediated adaptive immune response. It has been used clinically to treat a variety of malignancies, albeit with mixed results and side effects that can be severe. Despite ample evidence implicating a role for IFN-gamma in tumor immune surveillance, a steady flow of reports has suggested that it may also have protumorigenic effects under certain circumstances. We propose that, in fact, IFN gamma treatment is a double-edged sword whose anti- and protumorigenic activities are dependent on the cellular, microenvironmental, and/or molecular context. As such, inhibition of the IFN-gamma/IFN-gamma receptor pathway may prove to be a viable new therapeutic target for a subset of malignancies. PMID- 21705457 TI - Towards spoken clinical-question answering: evaluating and adapting automatic speech-recognition systems for spoken clinical questions. AB - OBJECTIVE: To evaluate existing automatic speech-recognition (ASR) systems to measure their performance in interpreting spoken clinical questions and to adapt one ASR system to improve its performance on this task. DESIGN AND MEASUREMENTS: The authors evaluated two well-known ASR systems on spoken clinical questions: Nuance Dragon (both generic and medical versions: Nuance Gen and Nuance Med) and the SRI Decipher (the generic version SRI Gen). The authors also explored language model adaptation using more than 4000 clinical questions to improve the SRI system's performance, and profile training to improve the performance of the Nuance Med system. The authors reported the results with the NIST standard word error rate (WER) and further analyzed error patterns at the semantic level. RESULTS: Nuance Gen and Med systems resulted in a WER of 68.1% and 67.4% respectively. The SRI Gen system performed better, attaining a WER of 41.5%. After domain adaptation with a language model, the performance of the SRI system improved 36% to a final WER of 26.7%. CONCLUSION: Without modification, two well known ASR systems do not perform well in interpreting spoken clinical questions. With a simple domain adaptation, one of the ASR systems improved significantly on the clinical question task, indicating the importance of developing domain/genre specific ASR systems. PMID- 21705458 TI - A framework for assessing patient crossover and health information exchange value. AB - OBJECTIVE: To evaluate the benefit of a health information exchange (HIE) between hospitals, we examine the rate of crossover among neurosurgical inpatients treated at Emory University Hospital (EUH) and Grady Memorial Hospital (GMH) in Atlanta, Georgia. To inform decisions regarding investment in HIE, we develop a methodology analyzing crossover behavior for application to larger more general patient populations. DESIGN: Using neurosurgery inpatient visit data from EUH and GMH, unique patients who visited both hospitals were identified through classification by name and age at time of visit. The frequency of flow patterns, including time between visits, and the statistical significance of crossover rates for patients with particular diagnoses were determined. MEASUREMENTS: The time between visits, flow patterns, and proportion of patients exhibiting crossover behavior were calculated for the total population studied as well as subpopulations. RESULTS: 5.25% of patients having multiple visits over the study period visited the neurosurgical departments at both hospitals. 77% of crossover patients visited the level 1 trauma center (GMH) before visiting EUH. LIMITATIONS: The true patient crossover may be under-estimated because the study population only consists of neurosurgical inpatients at EUH and GMH. CONCLUSION: We demonstrate that detailed analysis of crossover behavior provides a deeper understanding of the potential value of HIE. PMID- 21705459 TI - In response to: Electronic health records in small physician practices: availability, use, and perceived benefits. PMID- 21705461 TI - Usefulness influences visual appearance in motion transparency depth rivalry. AB - Two sets of dots moving in opposite directions are usually seen as two transparent surfaces. Deciding which surface is in front of the other is bistable and observers exhibit strong biases to see one particular motion direction in front. Surprisingly, biases are dependent on stimulus orientation in a persistent, idiosyncratic, and irrelevant manner. We investigated here whether this preferred direction is arbitrarily fixed or can instead be updated from the context. Observers performed two tasks alternately. One task was to report the surface seen in front in a transparent motion stimulus. The other task was a visual search for a slow dot. Unknown to the observers, we systematically paired the target dot with one surface direction in an attempt to make that surface appear preferentially in front. This manipulation was sufficient to change the observer's preferred direction for the surface seen in front. Attentional explanations did not account for the results. Observers modified their idiosyncratic preference in motion transparency depth rivalry only because it was useful to perform well in an auxiliary task. PMID- 21705460 TI - Targeted advertising, promotion, and price for menthol cigarettes in California high school neighborhoods. AB - OBJECTIVES: To describe advertising, promotions, and pack prices for the leading brands of menthol and nonmenthol cigarettes near California high schools and to examine their associations with school and neighborhood demographics. METHODS: In stores (n = 407) within walking distance (0.8 km [1/2 mile]) of California high schools (n = 91), trained observers counted ads for menthol and nonmenthol cigarettes and collected data about promotions and prices for Newport and Marlboro, the leading brand in each category. Multilevel modeling examined the proportion of all cigarette advertising for any menthol brand, the proportion of stores with sales promotions, and the lowest advertised pack price in relation to store types and school/neighborhood demographics. RESULTS: For each 10 percentage point increase in the proportion of Black students, the proportion of menthol advertising increased by 5.9 percentage points (e.g., from an average of 25.7% 31.6%), the odds of a Newport promotion were 50% higher (95% CI = 1.01, 2.22), and the cost of Newport was 12 cents lower (95% CI = -0.18, -0.06). By comparison, the odds of a promotion and the price for Marlboro, the leading brand of nonmenthol cigarettes, were unrelated to any school or neighborhood demographics. CONCLUSIONS: In high school neighborhoods, targeted advertising exposes Blacks to more promotions and lower prices for the leading brand of menthol cigarettes. This evidence contradicts the manufacturer's claims that the availability of its promotions is not based on race/ethnicity. It also highlights the need for tobacco control policies that would limit disparities in exposure to retail marketing for cigarettes. PMID- 21705462 TI - Mortality among Swedish chimney sweeps (1952-2006): an extended cohort study. AB - OBJECTIVES: We extended a cohort study of Swedish chimney sweeps and prolonged follow-up in order to increase power and study those first employed after 1950 when oil began to replace wood as a main fuel for heating in Sweden. METHODS: Male Swedish chimney sweeps who were members of the national trade union in 1981 2006 were identified (n=1087) and included to a previous cohort of those employed in 1918-1980 (n=5287). All employment histories were updated, and the total extended cohort (n=6374) was linked to the registers of Causes of Death and Total Population and followed for mortality from 1952 through 2006. Standardised mortality ratios (SMRs) were estimated using the Swedish male population as reference. RESULTS: 1841 observed deaths resulted in an SMR for all causes of deaths of 1.29 (95% CI 1.24 to 1.36). Mortality was significantly increased for all malignant tumours, oesophageal cancer, bowel cancer, liver cancer, lung cancer, alcoholism, ischaemic heart disease, non-malignant respiratory diseases, liver cirrhosis, external causes and suicides. The lung cancer SMR remained increased, although attenuated, after adjustment for group-level smoking data, SMR of 1.52 (95% CI 1.26 to 1.89). Duration of employment showed no consistent evidence of dose-response associations. Alcohol-related deaths (liver cirrhosis and alcoholism) were not increased among those employed >30 years. Mortality among those employed after 1950 was similar to that of the entire cohort. CONCLUSIONS: Chimney sweeps are exposed to high levels of toxic substances in the occupation, but excess alcohol and smoking habits were also observed, and the results must be interpreted cautiously. However, group-level data on tobacco smoking indicated that the lung cancer excess only to some extent could be explained by smoking habits, and the increased mortality from oesophageal cancer and ischaemic heart disease among chimney sweeps employed >30 years is less likely to be caused by excess alcohol habits. PMID- 21705463 TI - Urinary biomarkers of exposure to glycol ethers and chlorinated solvents during pregnancy: determinants of exposure and comparison with indirect methods of exposure assessment. AB - OBJECTIVES: To describe urine levels of metabolites of glycol ethers and chlorinated solvents in a sample of pregnant women from the general population, to study their occupational and non-occupational determinants and to compare them with the results of indirect assessment methods of solvent exposure. METHODS: A sample of 451 pregnant women was randomly selected from a general population cohort. At inclusion, the women in this sample completed a self-administered questionnaire about their social and medical characteristics, occupation and exposure to different products at work and in non-occupational activities. Occupational exposure to solvents was assessed from the woman's self-report and from a job-exposure matrix. Eight alkoxycarboxylic acids and trichloroacetic acid and trichloroethanol were measured with chromatography in urine samples collected at inclusion. Associations between metabolite levels and job titles, exposure to products used at work, and solvent exposure were studied. RESULTS: The different glycol ether metabolites were detected in 5.3%-96.4% of the urine samples, trichloroacetic acid in 6.4% and trichloroethanol in 5.5%. Nurses had butoxyacetic acid and phenoxyacetic acid in their urine most often, whereas methoxyethoxyacetic acid was the most frequent among nursing aides. Among cleaners, ethoxyacetic acid and ethoxyethoxyacetic acid were the most frequent. The occupation of hairdresser was associated with urinary excretion of ethoxyacetic acid, ethoxyethoxyacetic acid, butoxyacetic acid and phenoxyacetic acid. Among the women classified as exposed to solvents, the agents identified most often were ethoxyacetic acid, ethoxy-ethoxyacetic acid, butoxyacetic acid, phenoxyacetic acid, trichloroacetic acid and trichloroethanol. Ethoxyethoxyacetic acid was the only metabolite associated with non-occupational exposure. CONCLUSIONS: Metabolites of glycol ethers and chlorinated solvents were present at low levels in the urine of pregnant women. Most metabolites were associated with occupational exposure. PMID- 21705464 TI - Sensorimotor skills and focal dystonia are linked to putaminal grey-matter volume in pianists. AB - BACKGROUND: Focal hand dystonia has been associated with morphometric changes and distorted somatotopic representations in the putamen. OBJECTIVE: The authors used voxel-based morphometry (VBM) to identify regions in the putamen where grey matter volume is associated with musician's dystonia (MD) or the skill level of piano playing in professional pianists. METHODS: In 11 pianists with MD affecting the right hand and 12 healthy pianists without dystonia, the authors performed high-resolution T1-weighted MRI of the brain. The authors also measured the temporal variability of key strokes during scale playing with the right hand to characterise the individual skill level of piano playing. Statistical comparisons of the normalised and smoothed grey-matter maps were performed to test for dystonia and performance-related structural changes in the putamen. RESULTS: During scale playing, the timing of consecutive key strokes was more variable in MD patients than in non-dystonic pianists. Regional grey-matter volume in the middle part of left and right putamen increased with timing variability during piano playing in pianists with and without MD. Between-group comparisons revealed that MD patients had a larger grey-matter volume in the right middle putamen compared with healthy musicians. CONCLUSION: In highly trained pianists with and without MD, the volume of the associative motor territory in the middle putamen reflects both the skill level of piano playing and the presence of dystonia. While a smaller volume is associated with better timing skills, a relative expansion is correlated with the presence of focal task-specific hand dystonia. PMID- 21705465 TI - Updating the international research agenda for sport injury prevention. PMID- 21705466 TI - Emergency department coding of bicycle and pedestrian injuries during the transition from ICD-9 to ICD-10. AB - BACKGROUND: The international classification of diseases version 10 (ICD-10) uses alphanumeric expanded codes and external cause of injury codes (E-codes). OBJECTIVE: To examine the reliability and validity of emergency department (ED) coders in applying E-codes in ICD-9 and -10. METHODS: Bicycle and pedestrian injuries were identified from the ED information system from one period before and two periods after transition from ICD-9 to -10 coding. Overall, 180 randomly selected bicycle and pedestrian injury charts were reviewed as the reference standard (RS). Original E-codes assigned by ED coders (ICD-9 in 2001 and ICD-10 in 2004 and 2007) were compared with charts (validity) and also to ICD-9 and -10 codes assigned from RS chart review, to each case by an independent (IND) coder (reliability). Sensitivity, specificity, simple, and chance-corrected agreements (kappa statistics) were calculated. RESULTS: Sensitivity of E-coding bicycle injuries by the IND coder in comparison with the RS ranged from 95.1% (95% CI 86.3 to 99.0) to 100% (95% CI 94.0 to 100.0) for both ICD-9 and -10. Sensitivity of ED coders in E-coding bicycle injuries ranged from 90.2% (95% CI 79.8 to 96.3) to 96.7% (95% CI 88.5 to 99.6). The sensitivity estimates for the IND coder ranged from 25.0% (95% CI 14.7 to 37.9) to 45.0% (95% CI 32.1 to 58.4) for pedestrian injuries for both ICD-9 and -10. CONCLUSION: Bicycle injuries are coded in a reliable and valid manner; however, pedestrian injuries are often miscoded as falls. These results have important implications for injury surveillance research. PMID- 21705467 TI - Lanthanum carbonate, like sevelamer-HCl, retards the progression of vascular calcification and atherosclerosis in uremic apolipoprotein E-deficient mice. AB - BACKGROUND: Atherosclerosis and vascular calcification (VC) progression in chronic kidney disease is favored by disturbances of mineral metabolism. We compared the effect of phosphate binder lanthanum (La) carbonate with sevelamer HCl on atherosclerosis, VC and bone structure and function in mice with chronic renal failure (CRF). METHODS: Apolipoprotein E-deficient (apoE(-/-)) mice were randomized to one non-CRF and three CRF groups, fed with standard diet (one non CRF and one CRF) or diet supplemented with either 3% lanthanum carbonate (La3%) or 3% sevelamer-HCl (Sev3%). RESULTS: Both La3% and Sev3% supplemented CRF mice displayed a decrease of serum phosphorus, calcification at both intimal and medial aortic sites and atherosclerosis. This was associated with a reduction of plaque Type I collagen expression by both binders and of positive nitrotyrosine staining in response to sevelamer-HCl only. Increased mineral apposition and bone formation rates in unsupplemented CRF mice were reduced by Sev3% but not by La3%. CONCLUSIONS: The beneficial effects of La carbonate and sevelamer-HCl on the progression of VC and atherosclerosis in CRF mice could be mainly due to a decrease in phosphate retention and likewise a reduction of arterial Type I collagen expression. The effect of La carbonate differed from that of sevelamer HCl in that it did not appear to exert its vascular effects via changes in oxidative stress or bone remodeling in the present model. PMID- 21705468 TI - Tobacco: an equal-opportunity killer? PMID- 21705469 TI - Identification of Fyn as the binding partner for the WASP N-terminal domain in T cells. AB - Wiskott-Aldrich syndrome protein (WASP) plays important roles in TCR signaling. In transgenic (Tg) mice, over-expression of the WASP N-terminal region (exons 1 5) including the enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) homology 1 (EVH1) domain and anti-WASP-EVH1 single-chain variable fragment (scFv) intracellular expressed antibodies (intrabodies) impairs IL-2 production in activated T cells. However, it largely remains unknown that how this domain transduces TCR signaling. Here, we demonstrate for the first time that the WASP N terminal domain specifically associates with the Fyn SH3 domain; the interaction was uncovered by screening a lambdagt11 cDNA expression library obtained from the mouse T-cell line KKF. The interaction between Fyn and WASP was inhibited by over expression of the WASP N-terminal domain and anti-WASP-EVH1 scFv intrabodies in gene-transfected NIH3T3 cells and T cells derived from these Tg mice. WASP interacting protein binding to the EVH1 domain of WASP was also inhibited in these Tg mice T cells. Furthermore, tyrosine phosphorylation of WASP and nuclear translocation of nuclear factor of activated T cells following TCR stimulation was severely inhibited by over-expression of the WASP N-terminal domain. These observations strongly suggest that the WASP N-terminal domain plays a pivotal role in the TCR signaling cascade by binding to Fyn. PMID- 21705470 TI - Proinflammatory role of angiotensin II in a rat nephrosis model induced by adriamycin. AB - INTRODUCTION: Nephrotic syndrome induced by adriamycin (ADR) is an experimental model of glomerulosclerosis in humans. The AT(1) receptor for angiotensin II (Ang II) is involved in the renal expression of the nuclear factor-kappa B (NF-KappaB) during this nephrosis. NF-KappaB is a transcription factor for proinflammatory effects of Ang II; however, there is no information about the role of this receptor in the renal proinflammatory events in ADR nephrosis. MATERIALS AND METHODS: To determine the role of Ang II in ADR nephrosis, Sprague-Dawley rats were treated with ADR (6 mg/kg iv). One ADR group received oral losartan treatment (15 mg/kg gavage) 3 days before ADR injection and then daily for 4 weeks, and the other group water. Animals were sacrificed at week 4 and renal macrophage infiltration, ICAM-1, superoxide anion (O(2(-))) and Ang II expressions were analysed by indirect immunofluorescence and histochemical techniques. RESULTS: ADR rats showed increased expression of ICAM-1, Ang II, O(2( )) and macrophage infiltration, events that were diminished by losartan treatment. Ang II expression remained unaltered after antagonist treatment. Proteinuria was reduced after 3 weeks of treatment. CONCLUSIONS: These data suggest that Ang II plays a role in the inflammatory events during ADR-induced nephrosis, probably mediated by AT(1) receptors. PMID- 21705471 TI - Viruses with more than 1,000 genes: Mamavirus, a new Acanthamoeba polyphaga mimivirus strain, and reannotation of Mimivirus genes. AB - The genome sequence of the Mamavirus, a new Acanthamoeba polyphaga mimivirus strain, is reported. With 1,191,693 nt in length and 1,023 predicted protein coding genes, the Mamavirus has the largest genome among the known viruses. The genomes of the Mamavirus and the previously described Mimivirus are highly similar in both the protein-coding genes and the intergenic regions. However, the Mamavirus contains an extra 5'-terminal segment that encompasses primarily disrupted duplicates of genes present elsewhere in the genome. The Mamavirus also has several unique genes including a small regulatory polyA polymerase subunit that is shared with poxviruses. Detailed analysis of the protein sequences of the two Mimiviruses led to a substantial amendment of the functional annotation of the viral genomes. PMID- 21705474 TI - Restricted interests and anxiety in children with autism. AB - A preoccupation with restricted interests (RI) is a core symptom of autism spectrum disorders (ASD). Engagement in RI is commonly observed in this population and impacts social, adaptive, and emotional functioning. The presence of anxiety disorders and overlap in symptom expression with RI, such as obsessive compulsive disorder (OCD), in children with ASD suggests a possible link between anxiety and the RI manifestation. RI play a multidimensional role in ASD and have been described as being expressed in multiple forms, such as fact collection or the enactment of RI through play. However, there is little research exploring in more detail the possible relationship between RI expression and anxiety. To explore the association between RI expression and anxiety, the current study examined the association between the various modes of RI expression and anxiety disorder symptoms in 68 elementary-aged children diagnosed with high-functioning ASD. Findings indicated that symbolic enactment of RI in the form of play, rather than information collection or time engaged in RI, was significantly linked with the increased presence and severity of anxiety symptoms. The conceptualization of RI as possible maladaptive coping responses to negative emotional experiences is discussed. PMID- 21705472 TI - Long conserved fragments upstream of Mammalian polyadenylation sites. AB - Polyadenylation is a cotranscriptional nuclear RNA processing event involving endonucleolytic cleavage of the nascent, emerging pre-messenger RNA (pre-mRNA) from the RNA polymerase, immediately followed by the polymerization of adenine ribonucleotides, called the poly(A) tail, to the cleaved 3' end of the polyadenylation site (PAS). This apparently simple molecular processing step has been discovered to be connected to transcription and splicing therefore increasing its potential for regulation of gene expression. Here, through a bioinformatic analysis of cis-PAS-regulatory elements in mammals that includes taking advantage of multiple evolutionary time scales, we find unexpected selection pressure much further upstream, up to 200 nt, from the PAS than previously thought. Strikingly, close to 3,000 long (30-500 nt) noncoding conserved fragments (CFs) were discovered in the PAS flanking region of three remotely related mammalian species, human, mouse, and cow. When an even more remote transitional mammal, platypus, was included, still over a thousand CFs were found in the proximity of the PAS. Even though the biological function of these CFs remains unknown, their considerable sizes makes them unlikely to serve as protein recognition sites, which are typically <=15 nt. By harnessing genome wide DNaseI hypersensitivity data, we have discovered that the presence of CFs correlates with chromatin accessibility. Our study is important in highlighting novel experimental targets, which may provide new understanding about the regulatory aspects of polyadenylation. PMID- 21705473 TI - Characterizing the influence of effective population size on the rate of adaptation: Gillespie's Darwin domain. AB - Characterizing the role of effective population size in dictating the rate of adaptive evolution remains a major challenge in evolutionary biology. Depending on the underlying distribution of fitness effects of new mutations, populations of different sizes may differ vastly in their rate of adaptation. Here, we collect polymorphism data at over 100 loci for two closely related Drosophila species with different current effective population sizes (N(e)), Drosophila miranda and D. pseudoobscura, to evaluate the prevalence of adaptive evolution versus genetic drift in molecular evolution. Utilizing these large and consistently sampled data sets, we obtain greatly improved estimates of the demographic histories of both species. Specifically, although current N(e) differs between these species, their ancestral sizes were much more similar. We find that statistical approaches capturing recent adaptive evolution (using patterns of polymorphisms) detect higher rates of adaptive evolution in the larger D. pseudoobscura population. In contrast, methods aimed at detecting selection over longer time periods (i.e., those relying on divergence data) estimate more similar rates of adaptation between the two species. Thus, our results suggest an important role of effective population size in dictating rates of adaptation and highlight how complicated population histories--as is probably the case for most species--can effect rates of adaptation. Additionally, we also show how different methodologies to detect positive selection can reveal information about different timescales of adaptive evolution. PMID- 21705475 TI - Attentional status of faces for people with autism spectrum disorder. AB - In recent years there has been a growing interest in the role of attention in the processing of social stimuli in individuals with autism spectrum disorders (ASD). Research has demonstrated that, for typical adults, faces have a special status in attention and are processed in an automatic and mandatory fashion even when participants attempt to ignore them. Under conditions of high load in a selective attention task, when irrelevant stimuli are usually not processed, typical adults continue to process distractor faces. Although there is evidence of a lack of attentional bias towards faces in ASD, there has been no direct test of whether faces are processed automatically using the distractor-face paradigm. In the present study 16 typical adults and 16 adults with ASD performed selective attention tasks with face and musical instrument distractors. The results indicated that even when the load of the central task was high, typical adults continued to be distracted by irrelevant face stimuli, whereas individuals with ASD were able to ignore them. In the equivalent non-social task, distractors had no effect at high load for either group. The results suggest that faces are processed in an automatic and mandatory fashion in typical adults but not in adults with ASD. PMID- 21705476 TI - Characterization and crystallization of mouse aldehyde oxidase 3: from mouse liver to Escherichia coli heterologous protein expression. AB - Aldehyde oxidase (AOX) is characterized by a broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide and N methylphthalazinium, or aldehydes, such as benzaldehyde, retinal, and vanillin. In the past decade, AOX has been recognized increasingly to play an important role in the metabolism of drugs through its complex cofactor content, tissue distribution, and substrate recognition. In humans, only one AOX gene (AOX1) is present, but in mouse and other mammals different AOX homologs were identified. The multiple AOX isoforms are expressed tissue-specifically in different organisms, and it is believed that they recognize distinct substrates and carry out different physiological tasks. AOX is a dimer with a molecular mass of approximately 300 kDa, and each subunit of the homodimeric enzyme contains four different cofactors: the molybdenum cofactor, two distinct [2Fe-2S] clusters, and one FAD. We purified the AOX homolog from mouse liver (mAOX3) and established a system for the heterologous expression of mAOX3 in Escherichia coli. The purified enzymes were compared. Both proteins show the same characteristics and catalytic properties, with the difference that the recombinant protein was expressed and purified in a 30% active form, whereas the native protein is 100% active. Spectroscopic characterization showed that FeSII is not assembled completely in mAOX3. In addition, both proteins were crystallized. The best crystals were from native mAOX3 and diffracted beyond 2.9 A. The crystals belong to space group P1, and two dimers are present in the unit cell. PMID- 21705477 TI - The recurrent cervical swelling syndrome. AB - The objective of this study is to report an overlooked cause of cervical swelling linked to a thoracic duct (TD) intraluminal obstruction. Four consecutive patients underwent supraclavicular fossa echo-colour-Doppler assessment (ECD) because of recurrent spontaneous cervical swelling. In all patients, during the swelling period we documented a TD dilation with hyperechogenic content, resulting undetectable during asymptomatic periods; ECD also allowed an effective differential diagnosis with TD cysts, obstructive malignancy or other causes of cervical swelling. In conclusion, ECD is to be considered an effective tool in cervical swelling and TD anomalies investigation. PMID- 21705478 TI - In vitro effect of calcium dobesilate on oxidative/inflammatory stress in human varicose veins. AB - AIM: To determine whether calcium dobesilate can act in chronic venous insufficiency by similar antioxidant, anti-inflammatory mechanisms as in diabetic retinopathy. METHODS: Calcium dobesilate was tested in vitro for its protective action against oxidative/inflammatory stress in human varicose veins. Varicose greater saphenous veins were obtained from 14 patients (11 men, 3 women) aged 53 65 years. Oxidative stress was induced exogenously in the vein segments, with the phenazine methosulphate (PMS)/NADH couple. Total antioxidant status (TAS) and malondialdehyde (MDA) contents were used as markers of oxidative stress. RESULTS: Calcium dobesilate significantly prevented oxidative disturbances in the micromolar range. PMS/NADH-dependent TAS decrease was fully prevented with IC(50) = 11.4 +/- 2.3 umol/L (n = 6 veins), whereas MDA increase was fully prevented with IC(50) = (102 +/- -3) umol/L (n = 6 veins). Calcium dobesilate acted quali- and quantitatively like rutin, the reference compound. Comparison with pharmacokinetic data suggests that calcium dobesilate can act at therapeutic concentrations. CONCLUSION: Calcium dobesilate protected human varicose veins against oxidative stress in vitro at levels that correspond to therapeutic concentrations. Further studies are required to investigate whether a similar action is found in varicose veins from patients orally treated with calcium dobesilate. PMID- 21705479 TI - Can foam sclerotherapy be used to safely treat bilateral varicose veins? AB - OBJECTIVE: We assessed the use of ultrasound guided foam sclerotherapy (UGFS) to treat bilateral varicose veins either as synchronous or interval procedures. We specifically assessed total foam volume usage and its influence on early outcome and complications. METHODS: We reviewed our prospectively compiled computerised database of patients with bilateral varicose veins who have undergone UGFS. Duplex findings, foam volumes used and clinical outcome were assessed. RESULTS: One hundred and twelve patients had undergone UGFS for bilateral varicose veins. Sixty-one had bilateral UGFS (122 legs) and 51 had interval UGFS (102 legs). Seventy-eight percent bilateral and 60% interval procedures were for single trunk disease. Median foam volumes per treatment episode were: 17.5 mls bilateral, and 10 mls interval FS. At two weeks 81% of legs had complete occlusion after bilateral UGFS compared to 70% after interval UGFS. One patient in the bilateral UGFS developed transient visual disturbance. There was no systemic complications in the interval UGFS. CONCLUSIONS: Bilateral foam sclerotherapy treatment did not adversly affect vein occlusion rates and there was no significant difference in complication rates between the two groups. Bilateral UGFS can be safely performed in selected patient presenting with bilateral varicose veins. PMID- 21705480 TI - Superficial vein ablation for the treatment of primary chronic venous ulcers. AB - OBJECTIVE: This retrospective study was undertaken to review our experience with ablation of superficial veins with significant reflux, using VNUS ClosureFAST RF (radiofrequency) or laser 980 nm, in patients with primary chronic venous ulcers, and also determine its effects in ulcer healing and ulcer recurrence. METHOD: Included were 25 limbs (18 patients with chronic primary venous ulcers (clinical, aetiological, anatomical and pathological elements [CEAP] classification C6), who underwent endovenous ablation with RF for the axial veins or laser for the perforating veins during a two-year period. RESULTS: Of the 18 patients, there were eight men and 10 women. The median age of the group was 68 (range 37-89) years. The number of ablations done in each leg with an ulcer varied from one to eight, with a median of three. During a follow-up period of 6-12 months, one patient failed ulcer healing despite sequential ablations of refluxing veins. There was one case that developed recurrence of a small ulcer after six months and was successfully treated with a perforator ablation. CONCLUSION: Endovenous ablation of incompetent superficial veins improves the healing of chronic primary venous ulcers and decreases the recurrence rates. PMID- 21705481 TI - Epigenetic regulation of cellular adhesion in cancer. AB - Epigenetics describes the development and maintenance of stable heritable gene expression patterns, which allow cells to show different phenotypes despite of a commonly shared genetic code. The increasing knowledge in this field during the last decades reveals its importance for many physiological processes like differentiation, embryogenesis and parental imprinting, but also for some diseases such as cancer. Recent data have shown that the complexity of carcinogenesis can no longer be explained solely on the basis of genetic changes, but epigenomic alterations such as changes of the DNA methylation pattern and/or post-translational histone modifications and changes of microRNA expression need to be equally considered. Such epigenetic alterations may cause permanent changes in gene expression patterns and may therefore essentially contribute to some of the known phenotypic characteristics of cancer cells like the loss of growth control, altered intercellular communication and enhanced motility. The two latter may essentially be associated with the downregulation of cellular adhesion molecules, which may therefore be relevant in the context of cancer invasiveness and prognosis. The targeted modification of the epigenome may therefore open new horizons within the increasingly important field of epigenetic therapeutics particularly in view of the regulation of cellular adhesion with particular attention to tumor cell invasion and metastasis. PMID- 21705482 TI - Muscarinic receptor subtype-3 gene ablation and scopolamine butylbromide treatment attenuate small intestinal neoplasia in Apcmin/+ mice. AB - M3 subtype muscarinic receptors (CHRM3) are over-expressed in colon cancer. In this study, we used Apc(min/+) mice to identify the role of Chrm3 expression in a genetic model of intestinal neoplasia, explored the role of Chrm3 in intestinal mucosal development and determined the translational potential of inhibiting muscarinic receptor activation. We generated Chrm3-deficient Apc(min/+) mice and compared intestinal morphology and tumor number in 12-week-old Apc(min/+)Chrm3(-/ ) and Apc(min/+)Chrm3(+/+) control mice. Compared with Apc(min/+)Chrm3(+/+) mice, Apc(min/+)Chrm3(-/-) mice showed a 70 and 81% reduction in tumor number and volume, respectively (P < 0.01). In adenomas, beta-catenin nuclear staining was reduced in Apc(min/+)Chrm3(-/-) compared with Apc(min/+)Chrm3(+/+) mice (P < 0.02). Whereas Apc gene mutation increased the number of crypt and Paneth cells and decreased villus goblet cells, these changes were absent in Apc(min/+)Chrm3( /-) mice. To determine whether pharmacological inhibition of muscarinic receptor activation attenuates intestinal neoplasia, we treated 6-week-old Apc(min/+) mice with scopolamine butylbromide, a non-subtype-selective muscarinic receptor antagonist. After 8 weeks of continuous treatment, scopolamine butylbromide treated mice showed a 22% reduction in tumor number (P = 0.027) and a 36% reduction in tumor volume (P = 0.004) as compared with control mice. Compared with Chrm3 gene ablation, the muscarinic antagonist was less efficacious, most probably due to shorter duration of treatment and incomplete blockade of muscarinic receptors. Overall, these findings indicate that interplay of Chrm3 and beta-catenin signaling is important for intestinal mucosal differentiation and neoplasia and provide a proof-of-concept that pharmacological inhibition of muscarinic receptor activation can attenuate intestinal neoplasia in vivo. PMID- 21705483 TI - Multi-institutional prostate cancer study of genetic susceptibility in populations of African descent. AB - Prostate cancer disparities have been reported in men of African descent who show the highest incidence, mortality, compared with other ethnic groups. Few studies have explored the genetic and environmental factors for prostate cancer in men of African ancestry. The glutathione-S-transferases family conjugates carcinogens before their excretion and is expressed in prostate tissue. This study addressed the role of GSTM1 and GSTT1 deletions on prostate cancer risk in populations of African descent. This multi-institutional case-control study gathered data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database, the African-Caribbean Cancer Consortium (AC3) and Men of African Descent and Carcinoma of the Prostate Consortium (MADCaP). The analysis included 10 studies (1715 cases and 2363 controls), five in African-Americans, three in African Caribbean and two in African men. Both the GSTM1 and the GSTT1 deletions showed significant inverse associations with prostate cancer [odds ratio (OR): 0.90, 95% confidence interval (CI) 0.83-0.97 and OR 0.88, 95% CI: 0.82-0.96, respectively]. The association was restricted to Caribbean and African populations. A significant positive association was observed between GSTM1 deletion and prostate cancer in smokers in African-American studies (OR: 1.28, 95% CI: 1.01-1.56), whereas a reduced risk was observed in never-smokers (OR: 0.66, 95% CI: 0.46 0.95). The risk of prostate cancer increased across quartiles of pack-years among subjects carrying the deletion of GSTM1 but not among subjects carrying a functional GSTM1. Gene-environment interaction between smoking and GSTM1 may be involved in the etiology of prostate cancer in populations of African descent. PMID- 21705484 TI - Iron deficiency in community-dwelling US adults with self-reported heart failure in the National Health and Nutrition Examination Survey III: prevalence and associations with anemia and inflammation. AB - BACKGROUND: Iron deficiency has been proposed as a potential therapeutic target in heart failure, but its prevalence and association with anemia and clinical outcomes in community-dwelling adults with heart failure have not been well characterized. METHODS AND RESULTS: Using data from the Third National Health and Nutrition Examination Survey, we evaluated the associations between iron deficiency, hemoglobin, C-reactive protein (CRP), and all-cause and cardiovascular mortality in 574 adults with self-reported heart failure. Iron deficiency was defined in both absolute and functional terms as a ferritin level <100 MUg/L or between 100 and 299 MUg/L if the transferrin saturation was <20%. Iron deficiency was present in 61.3% of participants and was associated with reduced mean hemoglobin (13.6 versus 14.2 g/dL, P=0.007) and increased mean CRP (0.95 versus 0.63 mg/dL, P=0.04). Over a median of 6.7 years of follow-up, there were 300 all-cause deaths, 193 of which were from cardiovascular causes. In age- and sex-adjusted Cox proportional hazards models, hemoglobin, CRP, and transferrin saturation but not iron deficiency were significantly associated with all-cause and cardiovascular mortality. In multivariate models, hemoglobin remained an independent predictor of cardiovascular mortality, whereas CRP remained an independent predictor of both all-cause and cardiovascular mortality. CONCLUSIONS: Iron deficiency is common in heart failure and is associated with decreased hemoglobin and increased CRP. In multivariate analysis, hemoglobin was associated with cardiovascular mortality while CRP was associated with both all cause and cardiovascular mortality. Iron deficiency was not associated with all cause or cardiovascular mortality in this cohort. PMID- 21705485 TI - Drug and device effects on peak oxygen consumption, 6-minute walk distance, and natriuretic peptides as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction. AB - BACKGROUND: Although peak oxygen consumption (peak VO(2)), 6-minute walk distance (6MW), and natriuretic peptides (BNP and NT-proBNP) are predictors of mortality in heart failure (HF) patients, it is not known whether therapy-induced changes in these measures can predict therapeutic effect on mortality. The objective of this analysis is to quantitatively assess the relationship between therapeutic effects on commonly proposed short-term markers in HF trials and therapeutic effects on long-term outcome in patients with HF and left ventricular dysfunction. METHODS AND RESULTS: We identified drug or device therapies for which there exists at least 1 randomized, controlled trial (RCT) assessing mortality over at least 6 months in at least 500 patients. For each of these therapies, we identified RCTs assessing the short-term changes in VO(2), 6MW, BNP, and NT-proBNP (few of the mortality RCTs assessed the short-term changes in markers). For each intervention, we calculated the odds ratio for mortality (using random effect meta-analysis when necessary), as well as the trial level average drug- or device-induced change in the markers. We assessed the correlation between the odds ratio for death with the placebo-corrected change in the functional parameter or biomarker across the interventions. We identified mortality RCTs of 27 distinct therapies (n=73 267 patients) with a median follow up of 19 months, that directed the search for RCTs of the effect of those interventions on the functional markers and biomarkers. There were 54 peak VO(2) trials (n=4646 patients), 34 6MW trials (n=6995 patients), 15 BNP trials (n=7233), and 6 NT-proBNP trials (n=1946) included in this analysis. There was no significant correlation between the average therapy-induced placebo-corrected change in peak VO(2) and the odds ratio for mortality (r=0.158, P=0.26). Increased drug or device-induced average change in 6MW was correlated with increased odds ratio for mortality (r=0.373, P=0.036). There was no significant correlation between the average therapy-induced, placebo-corrected change in the natriuretic peptides and the odds ratio for mortality (BNP: r=-0.065, P=0.82, NT proBNP: r=-0.667, P=0.15). There was no apparent relation between change in the functional parameter or biomarker and categorical effect on mortality. CONCLUSIONS: This analysis, limited to trial level data from different therapeutic eras, suggests that drug- or device-induced effects on peak VO(2), 6MW, and natriuretic peptides found in short-term trials do not predict the corresponding average long-term therapeutic effects on mortality for patients with HF and left ventricular dysfunction. PMID- 21705486 TI - Colocalization and regulated physical association of presynaptic serotonin transporters with A3 adenosine receptors. AB - Activation of A3 adenosine receptors (A3ARs) rapidly enhances the activity of antidepressant-sensitive serotonin (5-HT) transporters (SERTs) in vitro, ex vivo, and in vivo. A3AR agonist stimulation of SERT activity is lost in A3AR knockout mice. A3AR-stimulated SERT activity is mediated by protein kinase G1 (PKGI)- and p38 mitogen-activated protein kinase (MAPK)-linked pathways that support, respectively, enhanced SERT surface expression and catalytic activation. The mechanisms by which A3ARs target SERTs among other potential effectors is unknown. Here we present evidence that A3ARs are coexpressed with SERT in midbrain serotonergic neurons and form a physical complex in A3AR/hSERT cotransfected cells. Treatment of A3AR/SERT-cotransfected Chinese hamster ovary cells with the A3AR agonist N6-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine (1 MUM, 10 min), conditions previously reported to increase SERT surface expression and 5-HT uptake activity, enhanced the abundance of A3AR/SERT complexes in a PKGI dependent manner. Cotransfection of SERT with L90V-A3AR, a hyperfunctional coding variant identified in subjects with autism spectrum disorder, resulted in a prolonged recovery of receptor/transporter complexes after A3AR activation. Because PKGI and nitric-oxide synthetase are required for A3AR stimulation of SERT activity, and proteins PKGI and NOS both form complexes with SERT, our findings suggest a mechanism by which signaling pathways coordinating A3AR signaling to SERT can be spatially restricted and regulated, as well as compromised by neuropsychiatric disorders. PMID- 21705487 TI - Stiffness and heterogeneity of the pulmonary endothelial glycocalyx measured by atomic force microscopy. AB - The mechanical properties of endothelial glycocalyx were studied using atomic force microscopy with a silica bead (diameter ~18 MUm) serving as an indenter. Even at indentations of several hundred nanometers, the bead exerted very low compressive pressures on the bovine lung microvascular endothelial cell (BLMVEC) glycocalyx and allowed for an averaging of stiffness in the bead-cell contact area. The elastic modulus of BLMVEC glycocalyx was determined as a pointwise function of the indentation depth before and after enzymatic degradation of specific glycocalyx components. The modulus-indentation depth profiles showed the cells becoming progressively stiffer with increased indentation. Three different enzymes were used: heparinases III and I and hyaluronidase. The main effects of heparinase III and hyaluronidase enzymes were that the elastic modulus in the cell junction regions increased more rapidly with the indentation than in BLMVEC controls, and that the effective thickness of glycocalyx was reduced. Cytochalasin D abolished the modulus increase with the indentation. The confocal profiling of heparan sulfate and hyaluronan with atomic force microscopy indentation data demonstrated marked heterogeneity of the glycocalyx composition between cell junctions and nuclear regions. PMID- 21705488 TI - The birth certificate as an efficient means of identifying children conceived with the help of infertility treatment. AB - Recent work suggests that infertility treatment is associated with adverse child health outcomes. In exploring various methods of assembling a cohort of children conceived by infertility treatment, the authors conducted a validation study of the assisted reproductive technology and infertility drug use check boxes on the Massachusetts birth certificate. Using 2001 and 2002 data, the authors conducted telephone interviews with 399 women whose child's birth certificate had at least one of the boxes checked along with 185 women who were over age 42 years or who delivered twins or higher order multiples to compare the check box information with maternal report. Among the 579 women with available information, the birth certificate was fully concordant with respect to infertility treatment status for 271 (47%) women, partially concordant for 248 (43%) women, and discordant for 60 (10%) women. Agreement between the birth certificate and maternal report was good for singletons (weighted kappa = 0.66) but was found to be very poor among twins and higher order multiples (weighted kappa = 0.05). The authors concluded that birth certificates are an efficient means of locating children conceived with the help of infertility treatment but that they are not appropriate for identifying type of treatment. PMID- 21705489 TI - Mitochondrial evidence for panmixia despite perceived barriers to gene flow in a widely distributed waterbird. AB - We examined the mitochondrial genetic structure of American white pelicans (Pelecanus erythrorhynchos) to: 1) verify or refute whether American white pelicans are panmictic and 2) understand if any lack of genetic structure is the result of contemporary processes or historical phenomena. Sequence analysis of mitochondrial DNA control region haplotypes of 367 individuals from 19 colonies located across their North American range revealed a lack of population genetic or phylogeographic structure. This lack of structure was unexpected because: 1) Major geographic barriers such as the North American Continental Divide are thought to limit dispersal; 2) Differences in migratory behavior are expected to promote population differentiation; and 3) Many widespread North American migratory bird species show historic patterns of differentiation resulting from having inhabited multiple glacial refugia. Further, high haplotype diversity and many rare haplotypes are maintained across the species' distribution, despite frequent local extinctions and recolonizations that are expected to decrease diversity. Our findings suggest that American white pelicans have a high effective population size and low natal philopatry. We suggest that the rangewide panmixia we observed in American white pelicans is due to high historical and contemporary gene flow, enabled by high mobility and a lack of effective physical or behavioral barriers. PMID- 21705490 TI - Paralog-specific primers for the amplification of nuclear Loci in tetraploid barbels (barbus: cypriniformes). AB - Thirty paralog-specific primers were developed, following an intron-primed exon crossing strategy, for S7 and growth hormone genes in Barbus (subgenera Barbus and Luciobarbus). We found that paralog-specific amplification requires the use of only one paralog-specific primer, allowing their simultaneous use with universal exon-primed intron-crossing primers of broad taxonomic applicability. This hybrid annealing strategy guarantees both specificity and generality of amplification reactions and represents a step forward in the amplification of duplicated nuclear loci in polyploid organisms and members of multigene families. Assays of several representative taxa identified high levels of segregating single nucleotide polymorphisms (SNPs) and nucleotide diversity within each of these subgenera. Additionally, several insertions-deletions (indels) that are diagnostic across species are found in intronic regions. Therefore, these primers provide a reliable source of valuable nuclear SNP and indel data for population and species level studies of barbels, such as applied conservation and basic evolutionary studies. PMID- 21705491 TI - De novo discovery and multiplexed amplification of microsatellite markers for black alder (Alnus glutinosa) and related species using SSR-enriched shotgun pyrosequencing. AB - Recent developments in sequencing technologies and bioinformatics analyses provide an unprecedented opportunity for cost and time effective high quality microsatellite marker discovery in nonmodel organisms for which no genomic information is available. Here, we use shotgun pyrosequencing of a microsatellite enriched library to develop, for the first time, microsatellite markers for Alnus glutinosa, a keystone tree species of European riparian woodland communities. From a total of 17 855 short sequences, we identified 590 perfect microsatellites from which 392 had designed primers. A subset of 48 loci were tested for amplification, 12 of which were polymorphic in A. glutinosa. These 12 loci were successfully coamplified in a single multiplex polymerase chain reaction experiment and validated for population genetics applications. In addition, 10 and 8 of these microsatellites were found to be transferable to the related A. incana and A. cordata species. The developed multiplex of 12 microsatellite markers therefore provides new opportunities for experimental evolutionary and forest genetics research in Alnus. PMID- 21705492 TI - Retraction. Jiang S, Alberich-Jorda M, Zagozdzon R, Parmar K, Fu Y, Mauch P, Banu N, Makriyannis A, Tenen DG, Avraham S, Groopman JE, Avraham HK. Cannabinoid receptor 2 and its agonists mediate hematopoiesis and hematopoietic stem and progenitor cell mobilization. Blood. 2011;117(3):827-838. PMID- 21705493 TI - Intravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentration. AB - This is the first study to investigate the efficacy of intravenous iron in treating fatigue in nonanemic patients with low serum ferritin concentration. In a randomized, double-blinded, placebo-controlled study, 90 premenopausal women presenting with fatigue, serum ferritin <= 50 ng/mL, and hemoglobin >= 120 g/L were randomized to receive either 800 mg of intravenous iron (III)-hydroxide sucrose or intravenous placebo. Fatigue and serum iron status were assessed at baseline and after 6 and 12 weeks. Median fatigue at baseline was 4.5 (on a 0-10 scale). Fatigue decreased during the initial 6 weeks by 1.1 in the iron group compared with 0.7 in the placebo group (P = .07). Efficacy of iron was bound to depleted iron stores: In patients with baseline serum ferritin <= 15 ng/mL, fatigue decreased by 1.8 in the iron group compared with 0.4 in the placebo group (P = .005), and 82% of iron-treated compared with 47% of placebo-treated patients reported improved fatigue (P = .03). Drug-associated adverse events were observed in 21% of iron-treated patients and in 7% of placebo-treated patients (P = .05); none of these events was serious. Intravenous administration of iron improved fatigue in iron-deficient, nonanemic women with a good safety and tolerability profile. The efficacy of intravenous iron was bound to a serum ferritin concentration <= 15 ng/mL. This study was registered at the International Standard Randomized Controlled Trial Number Register (www.isrctn.org) as ISRCTN78430425. PMID- 21705494 TI - GABP transcription factor is required for myeloid differentiation, in part, through its control of Gfi-1 expression. AB - GABP is an ets transcription factor that regulates genes that are required for myeloid differentiation. The tetrameric GABP complex includes GABPalpha, which binds DNA via its ets domain, and GABPbeta, which contains the transcription activation domain. To examine the role of GABP in myeloid differentiation, we generated mice in which Gabpa can be conditionally deleted in hematopoietic tissues. Gabpa knockout mice rapidly lost myeloid cells, and residual myeloid cells were dysplastic and immunophenotypically abnormal. Bone marrow transplantation demonstrated that Gabpalpha null cells could not contribute to the myeloid compartment because of cell intrinsic defects. Disruption of Gabpa was associated with a marked reduction in myeloid progenitor cells, and Gabpalpha null myeloid cells express reduced levels of the transcriptional repressor, Gfi 1. Gabp bound and activated the Gfi1 promoter, and transduction of Gabpa knockout bone marrow with Gfi1 partially rescued defects in myeloid colony formation and myeloid differentiation. We conclude that Gabp is required for myeloid differentiation due, in part, to its regulation of the tran-scriptional repressor Gfi-1. PMID- 21705495 TI - HTLV-1 bZIP factor enhances TGF-beta signaling through p300 coactivator. AB - Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is etiologically associated with adult T-cell leukemia. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the provirus, is involved in both regulation of viral gene transcription and T-cell proliferation. We showed in this report that HBZ interacted with Smad2/3, and enhanced transforming growth factor-beta (TGF-beta)/Smad transcriptional responses in a p300-dependent manner. The N-terminal LXXLL motif of HBZ was responsible for HBZ-mediated TGF-beta signaling activation. In a serial immunoprecipitation assay, HBZ, Smad3, and p300 formed a ternary complex, and the association between Smad3 and p300 was markedly enhanced in the presence of HBZ. In addition, HBZ could overcome the repression of the TGF-beta response by Tax. Finally, HBZ expression resulted in enhanced transcription of Pdgfb, Sox4, Ctgf, Foxp3, Runx1, and Tsc22d1 genes and suppression of the Id2 gene; such effects were similar to those by TGF-beta. In particular, HBZ induced Foxp3 expression in naive T cells through Smad3-dependent TGF-beta signaling. Our results suggest that HBZ, by enhancing TGF-beta signaling and Foxp3 expression, enables HTLV-1 to convert infected T cells into regulatory T cells, which is thought to be a critical strategy for virus persistence. PMID- 21705496 TI - Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions. AB - Hyperhomocysteinemia (HHcy) increases permeability of the blood-brain barrier, but the mechanisms are undetermined. Homocysteine (Hcy) is an agonist of the neuronal N-methyl-D-aspartate receptor (NMDAr). We tested the hypothesis that HHcy disrupts the blood-brain barrier by an NMDAr-dependent mechanism in endothelium. In brain microvascular endothelial cells, there was no change in expression of the adherens junction protein VE-cadherin with Hcy treatment, but there was a significant decrease in the amount of beta-catenin at the membrane. Moreover, Hcy caused nuclear translocation of beta-catenin and attachment to the promoter for the tight junction protein claudin-5, with concomitant reduction in claudin-5 expression. Using a murine model of HHcy (cbs(+/-)), treatment for 2 weeks with an NMDAr antagonist (memantine) rescued cerebrovascular expression of claudin-5 and blood-brain barrier permeability to both exogenous sodium fluorescein and endogenous IgG. Memantine had no effect on these parameters in wild-type littermates. The same results were obtained using an in vitro model with brain microvascular endothelial cells. These data provide the first evidence that the NMDAr is required for Hcy-mediated increases in blood-brain barrier permeability. Modulating cerebral microvascular NMDAr activity may present a novel therapeutic target in diseases associated with opening of the blood-brain barrier in HHcy, such as stroke and dementia. PMID- 21705498 TI - Thrombophilia and outcomes of assisted reproduction technologies: a systematic review and meta-analysis. AB - Thrombophilia has been associated with pregnancy complications and recurrent miscarriage. The aim of this systematic review was to evaluate the controversial association between thrombophilia and failures of assisted reproduction technology (ART). A systematic search of the literature for studies reporting on thrombophilia in women undergoing ART up to April 2011 yielded 33 studies (23 evaluating anti-phospholipid antibodies, 5 inherited thrombophilia, and 5 both) involving 6092 patients. Overall, methodologic quality of the studies was poor. Combined results from case-control studies showed that factor V Leiden was significantly more prevalent among women with ART failure compared with fertile parous women or those achieving pregnancy after ART (odds ratio = 3.08; 95% confidence interval, 1.77-5.36). The prothrombin mutation, methylenetetrahydrofolate reductase mutation, deficiency of protein S, protein C, or anti-thrombin were all not associated with ART failure. Women with ART failure tested more frequently positive for anti-phospholipids antibodies (odds ratio = 3.33; 95% confidence interval, 1.77-6.26) with evidence of high degree of between study heterogeneity (I(2) = 75%; P < .00001). Prospective cohort studies did not show significant associations between thrombophilia and ART outcomes. Although case-control studies suggest that women experiencing ART failures are more frequently positive for factor V Leiden and anti-phospholipid antibodies, the evidence is inconclusive and not supported by cohort studies. PMID- 21705497 TI - Maintenance and break of immune tolerance against human factor VIII in a new transgenic hemophilic mouse model. AB - Replacement of the missing factor VIII (FVIII) is the current standard of care for patients with hemophilia A. However, the short half-life of FVIII makes frequent treatment necessary. Current efforts focus on the development of longer acting FVIII concentrates by introducing chemical and genetic modifications to the protein. Any modification of the FVIII protein, however, risks increasing its immunogenic potential to induce neutralizing antibodies (FVIII inhibitors), and this is one of the major complications in current therapy. It would be highly desirable to identify candidates with a high risk for increased immunogenicity before entering clinical development to minimize the risk of exposing patients to such altered FVIII proteins. In the present study, we describe a transgenic mouse line that expresses a human F8 cDNA. This mouse is immunologically tolerant to therapeutic doses of native human FVIII but is able to mount an antibody response when challenged with a modified FVIII protein that possesses altered immunogenic properties. In this situation, immunologic tolerance breaks down and antibodies develop that recognize both the modified and the native human FVIII. The applicability of this new model for preclinical immunogenicity assessment of new FVIII molecules and its potential use for basic research are discussed. PMID- 21705499 TI - Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. AB - Systemic iron requirements are met predominantly through the recycling of iron from senescent erythrocytes by macrophages, a process in which the iron exporter ferroportin (Fpn1) is considered to be essential. Yet the role of Fpn1 in macrophage iron recycling and whether it influences innate immune responses are poorly understood in vivo. We inactivated Fpn1 in macrophages by crossing Fpn1 floxed animals with macrophage-targeted LysM-Cre or F4/80-Cre transgenic mice. Macrophage Fpn1 deletion mice were overtly normal; however, they displayed a mild anemia and iron accumulation in splenic, hepatic, and bone marrow macrophages when fed a standard diet. Iron loading was exacerbated after the administration of iron dextran or phenylhydrazine. When Fpn1(LysM/LysM) mice were challenged with an iron-deficient diet, they developed a more severe anemia and strikingly higher splenic iron levels than control mice, indicating significantly impaired iron mobilization from macrophages. Because immune responses can be altered by modulating iron status, we also examined the expression of proinflammatory cytokines. We found that expression levels of TNF-alpha and IL-6 were significantly enhanced in Fpn1(LysM/LysM) macrophages lacking Fpn1. These studies demonstrate that Fpn1 plays important roles in macrophage iron release in vivo and in modulating innate immune responses. PMID- 21705502 TI - Pet travel: absolute harmonisation 'not a scientifically sound position'. PMID- 21705503 TI - Welsh Government to review evidence base for TB eradication programme. PMID- 21705500 TI - Clearance of circulating activated platelets in polycythemia vera and essential thrombocythemia. AB - Essential thrombocythemia (ET) and polycythemia vera (PV) are characterized by persistent platelet activation. The mechanisms involved in their clearance are poorly characterized. In the present study, we report that leukocytes were actively involved in platelet disposal in 51 patients with ET and 30 with PV, but not in 70 age- and sex-matched controls. The fraction of circulating neutrophils and monocytes that had phagocytosed platelets, as assessed by flow cytometry, was significantly higher in patients with PV or ET, independently of hydroxyurea treatment, than in controls. Platelet phagocytosis by circulating leukocytes was confirmed by confocal and electron microscopy. The lack of effect of hydroxyurea, which disrupts the P-selectin/P-selectin glycoprotein ligand 1 (PSGL-1) interaction, suggests a P-selectin-independent mechanism. This hypothesis was confirmed in an ad hoc animal model based on the in vivo injection of activated platelets from P-selectin(+/+) and P-selectin(-/-) mice. P-selectin expression was associated with an earlier and effective clearance of platelets by neutrophils. A second delayed, P-selectin-independent phase actively involved monocytes. Our results suggest that phagocytic clearance of platelets by leukocytes occurs in PV and ET, possibly involving P-selectin-dependent and independent pathways, thus representing a novel mechanism to remove activated platelets from the circulation. PMID- 21705501 TI - Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3. AB - Imatinib-resistant tyrosine kinase (TK) fusions involving FGFR1, JAK2, or FLT3 are rare but recurrent in patients with eosinophilia-associated neoplasms. We report here 2 male patients with ETV6-FLT3(+) myeloid/lymphoid neoplasms with eosinophilia who were treated with the multitargeted TK inhibitors sunitinib and sorafenib. Patient 1 achieved rapid complete hematologic response and complete cytogenetic response after 3 months of taking sunitinib. A secondary blast phase caused by clonal evolution was diagnosed after 6 months. He achieved a second complete hematologic response after taking sorafenib but relapsed 2 months later. An N841K point mutation within the TK domain of FLT3, previously reported in acute myeloid leukemia and potentially conferring resistance to sorafenib, was subsequently identified. Patient 2 was heavily pretreated according to the initial diagnosis of T-lymphoblastic lymphoma and died in sunitinib-induced pancytopenia. This report highlights the importance of a careful diagnostic workup for eosinophilia-associated neoplasms to evaluate the possibility of TK inhibitor therapy. PMID- 21705504 TI - Defra seeks views on modifying the animal welfare inspection regime. PMID- 21705505 TI - Relaxation of BSE controls 'acceptable', says FSA. PMID- 21705506 TI - Talks continue on sheep EID. PMID- 21705508 TI - Peer support brings benefits for students. PMID- 21705509 TI - Towards better understanding and treatment of gill disease in salmonids. PMID- 21705510 TI - Home Office consultation on changes to the Animals (Scientific Procedures) Act. PMID- 21705511 TI - Newcastle disease: a continuing threat to UK poultry. PMID- 21705512 TI - Food security and veterinary services in developing countries. PMID- 21705513 TI - Testing for suspected bovine psoroptic mange in Scotland. PMID- 21705514 TI - Where have all the young men gone? PMID- 21705515 TI - The development and evaluation of a measure assessing school nurses' perceived barriers to addressing pediatric obesity. AB - School nurses represent an important resource for addressing pediatric obesity and weight-related health. However, school nurses perceive numerous barriers that prevent them from addressing the weight-related health of students. The current study developed and tested a new, comprehensive measure of nurses' perceptions of 10 types of barriers to addressing pediatric weight in a nationally representative sample of 214 school nurses. The measure was developed in the context of Bronfenbrenner's (1979) ecological systems theory and includes subscales assessing nurses' perceptions of skills-based, job-related, and societal barriers. Confirmatory factor analyses (CFAs) provided evidence for the validity of the measure, including the three barrier subscales. In addition, the subscales demonstrated adequate internal consistencies. Results indicate that school nurses perceive barriers to addressing weight-related health on multiple ecological levels, which may inform intervention or continuing education efforts. Future pediatric weight programs that involve school nurses might consider using the measure to assess nurses' perceptions of barriers. PMID- 21705516 TI - In-depth quantitative cardiac proteomics combining electron transfer dissociation and the metalloendopeptidase Lys-N with the SILAC mouse. AB - In quantitative proteomics stable isotope labeling has progressed from cultured cells toward the total incorporation of labeled atoms or amino acids into whole multicellular organisms. For instance, the recently introduced (13)C(6)-lysine labeled SILAC mouse allows accurate comparison of protein expression directly in tissue. In this model, only lysine, but not arginine, residues are isotope labeled, as the latter may cause complications to the quantification by in vivo conversion of arginine to proline. The sole labeling of lysines discourages the use of trypsin, as not all peptides will be quantifiable. Therefore, in the initial work Lys-C was used for digestion. Here, we demonstrate that the lysine directed protease metalloendopeptidase Lys-N is an excellent alternative. As lysine directed peptides generally yield longer and higher charged peptides, alongside the more traditional collision induced dissociation we also implemented electron transfer dissociation in a quantitative stable isotope labeling with amino acid in cell culture workflow for the first time. The utility of these two complementary approaches is highlighted by investigating the differences in protein expression between the left and right ventricle of a mouse heart. Using Lys-N and electron transfer dissociation yielded coverage to a depth of 3749 proteins, which is similar as earlier investigations into the murine heart proteome. In addition, this strategy yields quantitative information on ~ 2000 proteins with a median coverage of four peptides per protein in a single strong cation exchange-liquid chromatography-MS experiment, revealing that the left and right ventricle proteomes are very similar qualitatively as well as quantitatively. PMID- 21705517 TI - Learning words in space and time: probing the mechanisms behind the suspicious coincidence effect. AB - A major debate in the study of word learning centers on the extension of categories to new items. The rational approach assumes that learners make structured inferences about category membership, whereas the mechanistic approach emphasizes the attentional and memory processes that form the basis of generalization behaviors. Recent support for the rational view comes from observations of the suspicious-coincidence effect: People generalize category membership narrowly when presented with three subordinate-level exemplars that share the same label and generalize category membership broadly when presented with one exemplar. Across three experiments, we examined the mechanistic basis of this effect. Results showed that the presentation of multiple subordinate-level exemplars led to narrow generalization only when the exemplars were presented simultaneously, even when the number of exemplars was increased from three to six. These data demonstrate that the suspicious-coincidence effect is firmly grounded in the general cognitive processes of attention, memory, and visual comparison. PMID- 21705518 TI - Culturally divergent responses to mortality salience. AB - Two experiments compared the effects of death thoughts, or mortality salience, on European and Asian Americans. Research on terror management theory has demonstrated that in Western cultural groups, individuals typically employ self protective strategies in the face of death-related thoughts. Given fundamental East-West differences in self-construal (i.e., the independent vs. interdependent self), we predicted that members of Eastern cultural groups would affirm other people, rather than defend and affirm the self, after encountering conditions of mortality salience. We primed European Americans and Asian Americans with either a death or a control prime and examined the effect of this manipulation on attitudes about a person who violates cultural norms (Study 1) and on attributions about the plight of an innocent victim (Study 2). Mortality salience promoted culturally divergent responses, leading European Americans to defend the self and Asian Americans to defend other people. PMID- 21705519 TI - Power and choice: their dynamic interplay in quenching the thirst for personal control. AB - Power and choice represent two fundamental forces that govern human behavior. Scholars have largely treated power as an interpersonal construct involving control over other individuals, whereas choice has largely been treated as an intrapersonal construct that concerns the ability to select a preferred course of action. Although these constructs have historically been studied separately, we propose that they share a common foundation--that both are rooted in an individual's sense of personal control. Because of this common underlying basis, we hypothesized that power and choice are substitutable; that is, we predicted that the absence of one would increase the desire for the other, which, when acquired, would serve to satisfy the broader need for control. We also predicted that choice and power would exhibit a threshold effect, such that once one source of control had been provided (e.g., power), the addition of the other (e.g., choice) would yield diminishing returns. Six experiments provide evidence supporting these predictions. PMID- 21705520 TI - Spurious also? Name-similarity effects (implicit egotism) in employment decisions. PMID- 21705521 TI - A functional role for the motor system in language understanding: evidence from theta-burst transcranial magnetic stimulation. AB - Does language comprehension depend, in part, on neural systems for action? In previous studies, motor areas of the brain were activated when people read or listened to action verbs, but it remains unclear whether such activation is functionally relevant for comprehension. In the experiments reported here, we used off-line theta-burst transcranial magnetic stimulation to investigate whether a causal relationship exists between activity in premotor cortex and action-language understanding. Right-handed participants completed a lexical decision task, in which they read verbs describing manual actions typically performed with the dominant hand (e.g., "to throw," "to write") and verbs describing nonmanual actions (e.g., "to earn," "to wander"). Responses to manual action verbs (but not to nonmanual-action verbs) were faster after stimulation of the hand area in left premotor cortex than after stimulation of the hand area in right premotor cortex. These results suggest that premotor cortex has a functional role in action-language understanding. PMID- 21705522 TI - Diversity and antibiotic resistance patterns of Sphingomonadaceae isolates from drinking water. AB - Sphingomonadaceae (n = 86) were isolated from a drinking water treatment plant (n = 6), tap water (n = 55), cup fillers for dental chairs (n = 21), and a water demineralization filter (n = 4). The bacterial isolates were identified based on analysis of the 16S rRNA gene sequence, and intraspecies variation was assessed on the basis of atpD gene sequence analysis. The isolates were identified as members of the genera Sphingomonas (n = 27), Sphingobium (n = 28), Novosphingobium (n = 12), Sphingopyxis (n = 7), and Blastomonas (n = 12). The patterns of susceptibility to five classes of antibiotics were analyzed and compared for the different sites of isolation and taxonomic groups. Colistin resistance was observed to be intrinsic (92%). The highest antibiotic resistance prevalence values were observed in members of the genera Sphingomonas and Sphingobium and for beta-lactams, ciprofloxacin, and cotrimoxazole. In tap water and in water from dental chairs, antibiotic resistance was more prevalent than in the other samples, mainly due to the predominance of isolates of the genera Sphingomonas and Sphingobium. These two genera presented distinct patterns of association with antibiotic resistance, suggesting different paths of resistance development. Antibiotic resistance patterns were often related to the species rather than to the site or strain, suggesting the importance of vertical resistance transmission in these bacteria. This is the first study demonstrating that members of the family Sphingomonadaceae are potential reservoirs of antibiotic resistance in drinking water. PMID- 21705523 TI - Effects of orally administered Bdellovibrio bacteriovorus on the well-being and Salmonella colonization of young chicks. AB - Bdellovibrio bacteriovorus is a bacterium which preys upon and kills Gram negative bacteria, including the zoonotic pathogens Escherichia coli and Salmonella. Bdellovibrio has potential as a biocontrol agent, but no reports of it being tested in living animals have been published, and no data on whether Bdellovibrio might spread between animals are available. In this study, we tried to fill this knowledge gap, using B. bacteriovorus HD100 doses in poultry with a normal gut microbiota or predosed with a colonizing Salmonella strain. In both cases, Bdellovibrio was dosed orally along with antacids. After dosing non Salmonella-infected birds with Bdellovibrio, we measured the health and well being of the birds and any changes in their gut pathology and culturable microbiota, finding that although a Bdellovibrio dose at 2 days of age altered the overall diversity of the natural gut microbiota in 28-day-old birds, there were no adverse effects on their growth and well-being. Drinking water and fecal matter from the pens in which the birds were housed as groups showed no contamination by Bdellovibrio after dosing. Predatory Bdellovibrio orally administered to birds that had been predosed with a gut-colonizing Salmonella enterica serovar Enteritidis phage type 4 strain (an important zoonotic pathogen) significantly reduced Salmonella numbers in bird gut cecal contents and reduced abnormal cecal morphology, indicating reduced cecal inflammation, compared to the ceca of the untreated controls or a nonpredatory DeltapilA strain, suggesting that these effects were due to predatory action. This work is a first step to applying Bdellovibrio therapeutically for other animal, and possibly human, infections. PMID- 21705524 TI - Identification of Xanthomonas fragariae, Xanthomonas axonopodis pv. phaseoli, and Xanthomonas fuscans subsp. fuscans with novel markers and using a dot blot platform coupled with automatic data analysis. AB - Phytosanitary regulations and the provision of plant health certificates still rely mainly on long and laborious culture-based methods of diagnosis, which are frequently inconclusive. DNA-based methods of detection can circumvent many of the limitations of currently used screening methods, allowing a fast and accurate monitoring of samples. The genus Xanthomonas includes 13 phytopathogenic quarantine organisms for which improved methods of diagnosis are needed. In this work, we propose 21 new Xanthomonas-specific molecular markers, within loci coding for Xanthomonas-specific protein domains, useful for DNA-based methods of identification of xanthomonads. The specificity of these markers was assessed by a dot blot hybridization array using 23 non-Xanthomonas species, mostly soil dwelling and/or phytopathogens for the same host plants. In addition, the validation of these markers on 15 Xanthomonas spp. suggested species-specific hybridization patterns, which allowed discrimination among the different Xanthomonas species. Having in mind that DNA-based methods of diagnosis are particularly hampered for unsequenced species, namely, Xanthomonas fragariae, Xanthomonas axonopodis pv. phaseoli, and Xanthomonas fuscans subsp. fuscans, for which comparative genomics tools to search for DNA signatures are not yet applicable, emphasis was given to the selection of informative markers able to identify X. fragariae, X. axonopodis pv. phaseoli, and X. fuscans subsp. fuscans strains. In order to avoid inconsistencies due to operator-dependent interpretation of dot blot data, an image-processing algorithm was developed to analyze automatically the dot blot patterns. Ultimately, the proposed markers and the dot blot platform, coupled with automatic data analyses, have the potential to foster a thorough monitoring of phytopathogenic xanthomonads. PMID- 21705525 TI - Comparing nonsynergy gamma models and interaction models to predict growth of emetic Bacillus cereus for combinations of pH and water activity values. AB - This research aims to test the absence (gamma hypothesis) or occurrence of synergy between two growth-limiting factors, i.e., pH and water activity (a(w)), using a systematic approach for model selection. In this approach, preset criteria were used to evaluate the performance of models. Such a systematic approach is required to be confident in the correctness of the individual components of the combined (synergy) models. With Bacillus cereus F4810/72 as the test organism, estimated growth boundaries for the a(w)-lowering solutes NaCl, KCl, and glucose were 1.13 M, 1.13 M, and 1.68 M, respectively. The accompanying a(w) values were 0.954, 0.956, and 0.961, respectively, indicating that equal a(w) values result in similar effects on growth. Out of the 12 models evaluated using the preset criteria, the model of J. H. T. Luong (Biotechnol. Bioeng. 27:280-285, 1985) was the best model to describe the effect of a(w) on growth. This a(w) model and the previously selected pH model were combined into a gamma model and into two synergy models. None of the three models was able to describe the combined pH and a(w) conditions sufficiently well to satisfy the preset criteria. The best matches between predicted and experimental data were obtained with the gamma model, followed by the synergy model of Y. Le Marc et al. (Int. J. Food Microbiol. 73:219-237, 2002). No combination of models that was able to predict the impact of both individual and combined hurdles correctly could be found. Consequently, in this case we could not prove the existence of synergy nor falsify the gamma hypothesis. PMID- 21705526 TI - Role of the five RNA helicases in the adaptive response of Bacillus cereus ATCC 14579 cells to temperature, pH, and oxidative stresses. AB - In this study, growth rates and lag times of the five RNA helicase-deleted mutants of Bacillus cereus ATCC 14579 were compared to those of the wild-type strain under thermal, oxidative, and pH stresses. Deletion of cshD and cshE had no impact under any of the tested conditions. Deletion of cshA, cshB, and cshC abolished growth at 12 degrees C, confirming previous results. In addition, we found that each RNA helicase had a role in a specific temperature range: deletion of cshA reduced growth at all the tested temperatures up to 45 degrees C, deletion of cshB had impact below 30 degrees C and over 37 degrees C, and deletion of cshC led mainly to a cold-sensitive phenotype. Under oxidative conditions, deletion of cshB and cshC reduced growth rate and increased lag time, while deletion of cshA increased lag time only with H(2)O(2) and reduced growth rate at a high diamide concentration. Growth of the DeltacshA strain was affected at a basic pH independently of the temperature, while these conditions had a limited effect on DeltacshB and DeltacshC strain growth. The RNA helicases CshA, CshB, and CshC could participate in a general adaptation pathway to stressful conditions, with a stronger impact at low temperature and a wider role of CshA. PMID- 21705527 TI - Cofermentation of cellobiose and galactose by an engineered Saccharomyces cerevisiae strain. AB - We demonstrate improved ethanol yield and productivity through cofermentation of cellobiose and galactose by an engineered Saccharomyces cerevisiae strain expressing genes coding for cellodextrin transporter (cdt-1) and intracellular beta-glucosidase (gh1-1) from Neurospora crassa. Simultaneous fermentation of cellobiose and galactose can be applied to producing biofuels from hydrolysates of marine plant biomass. PMID- 21705528 TI - Roles of two Shewanella oneidensis MR-1 extracellular endonucleases. AB - The dissimilatory iron-reducing bacterium Shewanella oneidensis MR-1 is capable of using extracellular DNA (eDNA) as the sole source of carbon, phosphorus, and nitrogen. In addition, we recently demonstrated that S. oneidensis MR-1 requires eDNA as a structural component during all stages of biofilm formation. In this study, we characterize the roles of two Shewanella extracellular endonucleases, ExeS and ExeM. While ExeS is likely secreted into the medium, ExeM is predicted to remain associated with the cell envelope. Both exeM and exeS are highly expressed under phosphate-limited conditions. Mutants lacking exeS and/or exeM exhibit decreased eDNA degradation; however, the capability of S. oneidensis MR-1 to use DNA as the sole source of phosphorus is only affected in mutants lacking exeM. Neither of the two endonucleases alleviates toxic effects of increased eDNA concentrations. The deletion of exeM and/or exeS significantly affects biofilm formation of S. oneidensis MR-1 under static conditions, and expression of exeM and exeS drastically increases during static biofilm formation. Under hydrodynamic conditions, a deletion of exeM leads to altered biofilms that consist of densely packed structures which are covered by a thick layer of eDNA. Based on these results, we hypothesize that a major role of ExeS and, in particular, ExeM of S. oneidensis MR-1, is to degrade eDNA as a matrix component during biofilm formation to improve nutrient supply and to enable detachment. PMID- 21705530 TI - Adherent-invasive Escherichia coli phenotype displayed by intestinal pathogenic E. coli strains from cats, dogs, and swine. AB - The adherent-invasive Escherichia coli (AIEC) pathotype, which has been associated with Crohn's disease, shows similar traits to human and animal extraintestinal pathogenic E. coli (ExPEC) with respect to their phylogenetic origin and virulence gene profiles. Here, we demonstrate that animal ExPEC strains generally do not share the AIEC phenotype. In contrast, this phenotype is very frequent among animal intestinal pathogenic E. coli (InPEC) strains, particularly of feline and canine origin, that genetically resemble ExPEC. These results strengthen the particular identity and disease specificity of the AIEC pathotype and the putative role animals might play in the transmission of AIEC like strains to humans. PMID- 21705529 TI - Changes in bacterial diversity associated with epithelial tissue in the beef cow rumen during the transition to a high-grain diet. AB - Our understanding of the ruminal epithelial tissue-associated bacterial (defined as epimural bacteria in this study) community is limited. In this study, we aimed to determine whether diet influences the diversity of the epimural bacterial community in the bovine rumen. Twenty-four beef heifers were randomly assigned to either a rapid grain adaptation (RGA) treatment (n = 18) in which the heifers were allowed to adapt from a diet containing 97% hay to a diet containing 8% hay over 29 days or to the control group (n = 6), which was fed 97% hay. Rumen papillae were collected when the heifers were fed 97%, 25%, and 8% hay diets. PCR denaturing gradient gel electrophoresis (DGGE) and quantitative real-time PCR analysis were used to characterize rumen epimural bacterial diversity and to estimate the total epimural bacterial population (copy numbers of the 16S rRNA gene). The epimural bacterial diversity from RGA heifers changed (P = 0.01) in response to the rapid dietary transition, whereas it was not affected in control heifers. A total of 88 PCR-DGGE bands were detected, and 44 were identified from phyla including Firmicutes, Bacteroidetes, and Proteobacteria. The bacteria Treponema sp., Ruminobacter sp., and Lachnospiraceae sp. were detected only when heifers were fed 25% and 8% hay diets, suggesting the presence of these bacteria is the result of adaptation to the high-grain diets. In addition, the total estimated population of rumen epimural bacteria was positively correlated with molar proportions of acetate, isobutyrate, and isovalerate, suggesting that they may play a role in volatile fatty acid metabolism in the rumen. PMID- 21705531 TI - Potential pathogenicity and host range of extended-spectrum beta-lactamase producing Escherichia coli isolates from healthy poultry. AB - Thirty of 33 epidemiologically unrelated extended-spectrum beta-lactamase (ESBL) producing Escherichia coli isolates from healthy poultry lacked the virulence genes commonly associated with human-pathogenic strains. The main zoonotic risk is associated with the broad host range of avian E. coli belonging to sequence type complex 10 and of IncN and IncI1 plasmids carrying bla(CTX-M) or bla(SHV). PMID- 21705532 TI - Molecular tracking, through processing, of Campylobacter strains colonizing broiler flocks. AB - Many of the poultry flocks produced in the United Kingdom are colonized with Campylobacter, and the intensive nature of poultry processing usually results in contaminated carcasses. In this study, a previously reported molecular oligonucleotide probe method was used to track a specific flock-colonizing strain(s) on broiler carcasses during processing in two United Kingdom commercial poultry processing plants. Five Campylobacter-positive flocks were sampled at four points along the processing line, postbleed, postpluck, prechill, and postchill, and two Campylobacter-negative flocks processed immediately after positive flocks were sampled prechill. flaA was sequenced from Campylobacter strains isolated from these flocks, and strain-specific probes were synthesized. Skin and cecal samples were plated onto selective agar to give individual colonies, which were transferred onto membranes. These were then hybridized with the strain- and genus-specific probes. For all the 5 positive flocks, there was a significant reduction in campylobacters postbleed compared to postpluck but no subsequent fall on sampling pre- and postchill, and the strain(s) predominating on the carcasses throughout processing came from the flock being processed. This indicates that strains from the abattoir environment were not a significant cause of carcass contamination in flocks with well-established campylobacter colonization. However, negative flocks that were preceded by positive flocks were contaminated by strains that did not generally originate from the predominating strains recovered from the ceca of the previous positive flocks. This suggests that the abattoir environment has a significant role in the contamination of carcasses from negative but not fully colonized flocks. PMID- 21705533 TI - Evidence of an American origin for symbiosis-related genes in Rhizobium lusitanum. AB - Randomly amplified polymorphic DNA (RAPD) analysis was used to investigate the diversity of 179 bean isolates recovered from six field sites in the Arcos de Valdevez region of northwestern Portugal. The isolates were divided into 6 groups based on the fingerprint patterns that were obtained. Representatives for each group were selected for sequence analysis of 4 chromosomal DNA regions. Five of the groups were placed within Rhizobium lusitanum, and the other group was placed within R. tropici type IIA. Therefore, the collection of Portuguese bean isolates was shown to include the two species R. lusitanum and R. tropici. In plant tests, the strains P1-7, P1-1, P1-2, and P1-16 of R. lusitanum nodulated and formed nitrogen-fixing symbioses both with Phaseolus vulgaris and Leucaena leucocephala. A methyltransferase-encoding nodS gene identical with the R. tropici locus that confers wide host range was detected in the strain P1-7 as well as 24 others identified as R. lusitanum. A methyltransferase-encoding nodS gene also was detected in the remaining isolates of R. lusitanum, but in this case the locus was that identified with the narrow-host-range R. etli. Representatives of isolates with the nodS of R. etli formed effective nitrogen-fixing symbioses with P. vulgaris and did not nodulate L. leucocephala. From sequence data of nodS, the R. lusitanum genes for symbiosis were placed within those of either R. tropici or R. etli. These results would support the suggestion that R. lusitanum was the recipient of the genes for symbiosis with beans from both R. tropici and R. etli. PMID- 21705534 TI - Selection of fecal enterococci exhibiting tcrB-mediated copper resistance in pigs fed diets supplemented with copper. AB - Copper, as copper sulfate, is increasingly used as an alternative to in-feed antibiotics for growth promotion in weaned piglets. Acquired copper resistance, conferred by a plasmid-borne, transferable copper resistance (tcrB) gene, has been reported in Enterococcus faecium and E. faecalis. A longitudinal field study was undertaken to determine the relationship between copper supplementation and the prevalence of tcrB-positive enterococci in piglets. The study was done with weaned piglets, housed in 10 pens with 6 piglets per pen, fed diets supplemented with a normal (16.5 ppm; control) or an elevated (125 ppm) level of copper. Fecal samples were randomly collected from three piglets per pen on days 0, 14, 28, and 42 and plated on M-Enterococcus agar, and three enterococcal isolates were obtained from each sample. The overall prevalence of tcrB-positive enterococci was 21.1% (38/180) in piglets fed elevated copper and 2.8% (5/180) in the control. Among the 43 tcrB-positive isolates, 35 were E. faecium and 8 were E. faecalis. The mean MICs of copper for tcrB-negative and tcrB-positive enterococci were 6.2 and 22.2 mM, respectively. The restriction digestion of the genomic DNA of E. faecium or E. faecalis with S1 nuclease yielded a band of ~194-kbp size to which both tcrB and the erm(B) gene probes hybridized. A conjugation assay demonstrated cotransfer of tcrB and erm(B) genes between E. faecium and E. faecalis strains. The higher prevalence of tcrB-positive enterococci in piglets fed elevated copper compared to that in piglets fed normal copper suggests that supplementation of copper in swine diets selected for resistance. PMID- 21705535 TI - Bovine Bacillus anthracis in Cameroon. AB - Bovine Bacillus anthracis isolates from Cameroon were genetically characterized. They showed a strong homogeneity, and they belong, together with strains from Chad, to cluster Abeta, which appears to be predominant in western Africa. However, one strain that belongs to a newly defined clade (D) and cluster (D1) is penicillin resistant and shows certain phenotypes typical of Bacillus cereus. PMID- 21705536 TI - Introduced Siberian chipmunks (Tamias sibiricus barberi) harbor more-diverse Borrelia burgdorferi sensu lato genospecies than native bank voles (Myodes glareolus). AB - Little attention has been given in scientific literature to how introduced species may act as a new host for native infectious agents and modify the epidemiology of a disease. In this study, we investigated whether an introduced species, the Siberian chipmunk (Tamias sibiricus barberi), was a potentially new reservoir host for Borrelia burgdorferi sensu lato, the causative agent of Lyme disease. First, we ascertained whether chipmunks were infected by all of the B. burgdorferi sensu lato genospecies associated with rodents and available in their source of infection, questing nymphs. Second, we determined whether the prevalence and diversity of B. burgdorferi sensu lato in chipmunks were similar to those of a native reservoir rodent, the bank vole (Myodes glareolus). Our research took place between 2006 and 2008 in a suburban French forest, where we trapped 335 chipmunks and 671 voles and collected 743 nymphs of ticks that were questing for hosts by dragging on the vegetation. We assayed for B. burgdorferi sensu lato with ear biopsy specimens taken from the rodents and in nymphs using PCR and restriction fragment length polymorphism (RFLP). Chipmunks were infected by the three Borrelia genospecies that were present in questing nymphs and that infect rodents (B. burgdorferi sensu stricto, B. afzelii, and B. garinii). In contrast, voles hosted only B. afzelii. Furthermore, chipmunks were more infected (35%) than voles (16%). These results may be explained by the higher exposure of chipmunks, because they harbor more ticks, or by their higher tolerance of other B. burgdorferi sensu lato genospecies than of B. afzelii. If chipmunks are competent reservoir hosts for B. burgdorferi sensu lato, they may spill back B. burgdorferi sensu lato to native communities and eventually may increase the risk of Lyme disease transmission to humans. PMID- 21705537 TI - Isolation and characterization of Methanothermobacter crinale sp. nov., a novel hydrogenotrophic methanogen from the Shengli oil field. AB - Syntrophic acetate oxidation coupled with hydrogenotrophic methanogenesis is an alternative methanogenic pathway in certain thermophilic anaerobic environments such as high-temperature oil reservoirs and thermophilic biogas reactors. In these environments, the dominant thermophilic methanogens were generally related to uncultured organisms of the genus Methanothermobacter. Here we isolated two representative strains, Tm2(T) and HMD, from the oil sands and oil production water in the Shengli oil field in the People's Republic of China. The type strain, Tm2(T), was nonmotile and stained Gram positive. The cells were straight to slightly curved rods (0.3 MUm in width and 2.2 to 5.9 MUm in length), but some of them possessed a coccal shape connecting with the rods at the ends. Strain Tm2(T) grew with H(2)-CO(2), but acetate is required. Optimum growth of strain Tm2(T) occurred in the presence of 0.025 g/liter NaCl at pH 6.9 and a temperature of 65 degrees C. The G+C content of the genomic DNA was 40.1 mol% +/- 1.3 mol% (by the thermal denaturation method) or 41.1 mol% (by high-performance liquid chromatography). Analysis of the 16S rRNA gene sequence indicated that Tm2(T) was most closely related to Methanothermobacter thermautotrophicus DeltaH(T) and Methanothermobacter wolfeii VKM B-1829(T) (both with a sequence similarity of 96.4%). Based on these phenotypic and phylogenic characteristics, a novel species was proposed and named Methanothermobacter crinale sp. nov. The type strain is Tm2(T) (ACCC 00699(T) = JCM 17393(T)). PMID- 21705538 TI - Development of a 16S rRNA gene primer and PCR-restriction fragment length polymorphism method for rapid detection of members of the genus Megasphaera and species-level identification. AB - The genus Megasphaera is relevant to the environment, human health and food, and renewable energy for the future. In this study, a primer set was designed for PCR restriction fragment length polymorphism (RFLP) analyses to detect and identify the members of Megasphaera. Direct detection and identification were achieved for environmental samples and isolates. PMID- 21705539 TI - Complex expression of the cellulolytic transcriptome of Saccharophagus degradans. AB - Saccharophagus degradans is an aerobic marine bacterium that can degrade cellulose by the induced expression of an unusual cellulolytic system composed of multiple endoglucanases and glucosidases. To understand the regulation of the cellulolytic system, transcript levels for the genes predicted to contribute to the cellulolytic system were monitored by quantitative real-time PCR (qRT-PCR) during the transition to growth on cellulose. Four glucanases of the cellulolytic system exhibited basal expression during growth on glucose. All but one of the predicted cellulolytic system genes were induced strongly during growth on Avicel, with three patterns of expression observed. One group showed increased expression (up to 6-fold) within 4 h of the nutritional shift, with the relative expression remaining constant over the next 22 h. A second group of genes was strongly induced between 4 and 10 h after nutritional transfer, with relative expression declining thereafter. The third group of genes was slowly induced and was expressed maximally after 24 h. Cellodextrins and cellobiose, products of the predicted basally expressed endoglucanases, stimulated expression of representative cellulase genes. A model is proposed by which the activity of basally expressed endoglucanases releases cellodextrins from Avicel that are then perceived and transduced to initiate transcription of each of the regulated cellulolytic system genes forming an expression pattern. PMID- 21705540 TI - Concentration and diversity of noroviruses detected in Luxembourg wastewaters in 2008-2009. AB - Noroviruses (NoV) in 78 wastewater samples from Luxembourg were quantified, cloned, and sequenced in 2008-2009. The concentrations of NoV genogroup II and the relative occurrences of certain genotypes changed significantly during the winter season. NoV genogroup I was frequently detected by real-time reverse transcription-PCR (RT-PCR), albeit at 30-fold lower concentrations than for genogroup II, hampering attempts to assess overall genetic diversity by the cloning/sequencing approach. PMID- 21705541 TI - Differences in the rumen methanogen populations of lactating Jersey and Holstein dairy cows under the same diet regimen. AB - In the dairy cattle industry, Holstein and Jersey are the breeds most commonly used for production. They differ in performance by various traits, such as body size, milk production, and milk composition. With increased concerns about the impact of agriculture on climate change, potential differences in other traits, such as methane emission, also need to be characterized further. Since methane is produced in the rumen by methanogenic archaea, we investigated whether the population structure of methanogen communities would differ between Holsteins and Jerseys. Breed-specific rumen methanogen 16S rRNA gene clone libraries were constructed from pooled PCR products obtained from lactating Holstein and Jersey cows, generating 180 and 185 clones, respectively. The combined 365 sequences were assigned to 55 species-level operational taxonomic units (OTUs). Twenty OTUs, representing 85% of the combined library sequences, were common to both breeds, while 23 OTUs (36 sequences) were found only in the Holstein library and 12 OTUs (18 sequences) were found only in the Jersey library, highlighting increased diversity in the Holstein library. Other differences included the observation that sequences with species-like sequence identity to Methanobrevibacter millerae were represented more highly in the Jersey breed, while Methanosphaera-related sequences and novel uncultured methanogen clones were more frequent in the Holstein library. In contrast, OTU sequences with species-level sequence identity to Methanobrevibacter ruminantium were represented similarly in both libraries. Since the sampled animals were from a single herd consisting of two breeds which were fed the same diet and maintained under the same environmental conditions, the differences we observed may be due to differences in host breed genetics. PMID- 21705542 TI - Detection of new Francisella-like tick endosymbionts in Hyalomma spp. and Rhipicephalus spp. (Acari: Ixodidae) from Bulgaria. AB - We report on the identification of two new Francisella-like endosymbionts (FLEs) found in three different tick species from Bulgaria. The FLEs were characterized by 16S rRNA and tul4 gene sequencing and seem to lack the molecular marker RD1. These two new taxa seem to be facultative secondary endosymbionts of ticks. PMID- 21705543 TI - Generation of targeted deletions in the genome of Rhodothermus marinus. AB - The aim of this work was to develop an approach for chromosomal engineering of the thermophile Rhodothermus marinus. A selection strategy for R. marinus had previously been developed; this strategy was based on complementing a restriction negative trpB strain with the R. marinus trpB gene. The current work identified an additional selective marker, purA, which encodes adenylosuccinate synthase and confers adenine prototrophy. In a two-step procedure, the available Trp(+) selection was used during the deletion of purA from the R. marinus chromosome. The alternative Ade(+) selection was in turn used while deleting the endogenous trpB gene. Since both deletions are unmarked, the purA and trpB markers may be reused. Through the double deletant SB-62 (DeltatrpB DeltapurA), the difficulties that are associated with spontaneous revertants and unintended chromosomal integration of marker-containing molecules are circumvented. The selection efficiency in R. marinus strain SB-62 (DeltatrpB DeltapurA) was demonstrated by targeting putative carotenoid biosynthesis genes, crtBI, using a linear molecule containing a marked deletion with 717 and 810 bp of 5' and 3' homologous sequences, respectively. The resulting Trp(+) transformants were colorless rather than orange-red. The correct replacement of an internal crtBI fragment with the trpB marker was confirmed by Southern hybridization analysis of the transformants. Thus, it appears that target genes in the R. marinus chromosome can be readily replaced with linear molecules in a single step by double crossover recombination. PMID- 21705544 TI - Population genetic structure of clinical and environmental isolates of Blastomyces dermatitidis, based on 27 polymorphic microsatellite markers. AB - Blastomyces dermatitidis, a thermally dimorphic fungus, is the etiologic agent of North American blastomycosis. Clinical presentation is varied, ranging from silent infections to fulminant respiratory disease and dissemination to skin and other sites. Exploration of the population genetic structure of B. dermatitidis would improve our knowledge regarding variation in virulence phenotypes, geographic distribution, and difference in host specificity. The objective of this study was to develop and test a panel of microsatellite markers to delineate the population genetic structure within a group of clinical and environmental isolates of B. dermatitidis. We developed 27 microsatellite markers and genotyped B. dermatitidis isolates from various hosts and environmental sources (n=112). Assembly of a neighbor-joining tree of allele-sharing distance revealed two genetically distinct groups, separated by a deep node. Bayesian admixture analysis showed that two populations were statistically supported. Principal coordinate analysis also reinforced support for two genetic groups, with the primary axis explaining 61.41% of the genetic variability. Group 1 isolates average 1.8 alleles/locus, whereas group 2 isolates are highly polymorphic, averaging 8.2 alleles/locus. In this data set, alleles at three loci are unshared between the two groups and appear diagnostic. The mating type of individual isolates was determined by PCR. Both mating type-specific genes, the HMG and alpha-box domains, were represented in each of the genetic groups, with slightly more isolates having the HMG allele. One interpretation of this study is that the species currently designated B. dermatitidis includes a cryptic subspecies or perhaps a separate species. PMID- 21705545 TI - Biochemical and mutational studies of the Bacillus cereus CECT 5050T formamidase support the existence of a C-E-E-K tetrad in several members of the nitrilase superfamily. AB - Formamidases (EC 3.5.1.49) are poorly characterized proteins. In spite of this scarce knowledge, ammonia has been described as playing a central role in the pathogenesis of human pathogens such as Helicobacter pylori, for which formamidase has been shown to participate in the nitrogen metabolic pathway. Sequence analysis has revealed that at least two different groups of formamidases are classified as EC 3.5.1.49: on the one hand, the derivatives of the FmdA-AmdA superfamily, which are the best studied to date, and on the other hand, the derivatives of Helicobacter pylori AmiF. Here we present the cloning, purification, and characterization of a recombinant formamidase from Bacillus cereus CECT 5050T (BceAmiF), the second member of the AmiF subfamily to be characterized, showing new features of the enzyme further supporting its relationship with aliphatic amidases. We also present homology modeling-based mutational studies confirming the importance of the Glu140 and Tyr191 residues in the enzymatic activities of the AmiF family. Moreover, we can conclude that a second glutamate residue is critical in several members of the nitrilase superfamily, meaning that what has consistently been identified as a C-E-K triad is in fact a C-E-E-K tetrad. PMID- 21705546 TI - Antimicrobial resistance and virulence determinants in European Salmonella genomic island 1-positive Salmonella enterica isolates from different origins. AB - Salmonella genomic island 1 (SGI1) contains a multidrug resistance region conferring the ampicillin-chloramphenicol-streptomycin-sulfamethoxazole tetracycline resistance phenotype encoded by bla(PSE-1), floR, aadA2, sul1, and tet(G). Its increasing spread via interbacterial transfer and the emergence of new variants are important public health concerns. We investigated the molecular properties of SGI1-carrying Salmonella enterica serovars selected from a European strain collection. A total of 38 strains belonging to S. enterica serovar Agona, S. enterica serovar Albany, S. enterica serovar Derby, S. enterica serovar Kentucky, S. enterica serovar Newport, S. enterica serovar Paratyphi B dT+, and S. enterica serovar Typhimurium, isolated between 2002 and 2006 in eight European countries from humans, animals, and food, were subjected to antimicrobial susceptibility testing, molecular typing methods (XbaI pulsed-field gel electrophoresis [PFGE], plasmid analysis, and multilocus variable-number tandem repeat analysis [MLVA]), as well as detection of resistance and virulence determinants (PCR/sequencing and DNA microarray analysis). Typing experiments revealed wide heterogeneity inside the strain collection and even within serovars. PFGE analysis distinguished a total of 26 different patterns. In contrast, the characterization of the phenotypic and genotypic antimicrobial resistance revealed serovar-specific features. Apart from the classical SGI1 organization found in 61% of the strains, seven different variants were identified with antimicrobial resistance properties associated with SGI1-A (S. Derby), SGI1-C (S. Derby), SGI1-F (S. Albany), SGI1-L (S. Newport), SGI1-K (S. Kentucky), SGI1-M (S. Typhimurium), and, eventually, a novel variant similar to SGI1-C with additional gentamicin resistance encoded by aadB. Only minor serovar specific differences among virulence patterns were detected. In conclusion, the SGI1 carriers exhibited pathogenetic backgrounds comparable to the ones published for susceptible isolates. However, because of their multidrug resistance, they may be more relevant in clinical settings. PMID- 21705547 TI - Role of rpoS in the development of cell envelope resilience and pressure resistance in stationary-phase Escherichia coli. AB - This work investigated the role of rpoS in the development of increased cell envelope resilience and enhanced pressure resistance in stationary-phase cells of Escherichia coli. Loss of both colony-forming ability and membrane integrity, measured as uptake of propidium iodide (PI), occurred at lower pressures in E. coli BW3709 (rpoS) than in the parental strain (BW2952). The rpoS mutant also released much higher concentrations of protein under pressure than the parent. We propose that RpoS-regulated functions are responsible for the increase in membrane resilience as cells enter stationary phase and that this plays a major role in the development of pressure resistance. Strains from the Keio collection with mutations in two RpoS-regulated genes, cfa (cyclopropane fatty acyl phospholipid synthase) and osmB (outer membrane lipoprotein), were significantly more pressure sensitive and took up more PI than the parent strain, with cfa having the greatest effect. Mutations in the bolA morphogene and other RpoS regulated lipoprotein genes (osmC, osmE, osmY, and ybaY) had no effect on pressure resistance. The cytoplasmic membranes of the rpoS mutant failed to reseal after pressure treatment, and strains with mutations in osmB and nlpI (new lipoprotein) were also somewhat impaired in the ability to reseal their membranes. The cfa mutant, though pressure sensitive, was unaffected in membrane resealing, implying that the initial transient permeabilization event is critical for loss of viability rather than the failure to reseal. The enhanced pressure sensitivity of polA, recA, and xthA mutants suggested that DNA may be a target of oxidative stress in pressure-treated cells. PMID- 21705548 TI - Repression of the antifungal activity of Pseudomonas sp. strain DF41 by the stringent response. AB - The stringent response (SR) enables bacteria to adapt to nutrient limitation through production of the nucleotides guanosine tetraphosphate and guanosine pentaphosphate, collectively known as (p)ppGpp. Two enzymes are responsible for the intracellular pools of (p)ppGpp: RelA acts as a synthetase, while SpoT can function as either a synthetase or a hydrolase. We investigated how the SR affects the ability of the biological control agent Pseudomonas sp. strain DF41 to inhibit the fungal pathogen Sclerotinia sclerotiorum (Lib.) de Bary. Strain DF41 relA and relA spoT mutants were generated and found to exhibit increased antifungal activity. Strain DF41 produces a lipopeptide (LP) molecule that is essential for Sclerotinia biocontrol. LP production and protease activity were both elevated in the relA and relA spoT mutants. Addition of relA but not spoT in trans restored the mutant phenotype to that of the parent. Next, we investigated whether an association exists between the SR and known regulators of biocontrol, including the Gac system and RpoS. A gacS mutant of strain DF41 produced less (p)ppGpp and exhibited a 1.7-fold decrease in relA expression compared to the wild type, suggesting that relA forms part of the Gac regulon. We discovered that rpoS transcription was reduced significantly in the SR mutants. Furthermore, rpoS provided in trans restored protease activity to wild-type levels but did not attenuate antifungal activity. Finally, relA expression was decreased in the mutants, indicating that the SR is required for maximum expression of relA. PMID- 21705549 TI - Spatial and temporal analysis of the microbial community in the tailings of a Pb Zn mine generating acidic drainage. AB - Analysis of spatial and temporal variations in the microbial community in the abandoned tailings impoundment of a Pb-Zn mine revealed distinct microbial populations associated with the different oxidation stages of the tailings. Although Acidithiobacillus ferrooxidans and Leptospirillum spp. were consistently present in the acidic tailings, acidophilic archaea, mostly Ferroplasma acidiphilum, were predominant in the oxidized zones and the oxidation front, indicating their importance to generation of acid mine drainage. PMID- 21705550 TI - Life, death, and in-between: meanings and methods in microbiology. AB - Determination of microbial viability by the plate count method is routine in microbiology laboratories worldwide. However, limitations of the technique, particularly with respect to environmental microorganisms, are widely recognized. Many alternatives based upon viability staining have been proposed, and these are often combined with techniques such as image analysis and flow cytometry. The plethora of choices, however, adds to confusion when selecting a method. Commercial staining kits aim to simplify the performance of microbial viability determination but often still need adaptation to the specific organism of interest and/or the instruments available to the researcher. This review explores the meaning of microbial viability and offers guidance in the selection and interpretation of viability testing methods. PMID- 21705551 TI - Short- and long-term adaptation to ethanol stress and its cross-protective consequences in Lactobacillus plantarum. AB - This paper describes the molecular responses of Lactobacillus plantarum WCFS1 toward ethanol exposure. Global transcriptome profiling using DNA microarrays demonstrated adaptation of the microorganism to the presence of 8% ethanol over short (10-min and 30-min) and long (24-h) time intervals. A total of 57 genes were differentially expressed at all time points. Expression levels of an additional 859 and 873 genes were modulated after 30 min and 24 h of exposure to the solvent, respectively. Ethanol exposure led to induced expression of genes involved in citrate metabolism and cell envelope architecture, as well as canonical stress response pathways controlled by the central stress regulators HrcA and CtsR. Correspondingly, cells grown for 24 h in medium containing 8% ethanol exhibited higher levels of citrate consumption and modified cell membrane fatty acid composition and showed invaginating septa compared with cells grown in liquid medium without ethanol. In addition, these physiological changes resulted in cross-protection against high temperatures but not against several other stresses tested. To evaluate the role of HrcA and CtsR in ethanol tolerance, ctsR and hrcA gene deletion mutants were constructed. The growth rate of the L. plantarum DeltactsR::cat strain was impaired in de Man-Rogosa-Sharpe (MRS) medium containing 8% ethanol, whereas growth of the L. plantarum DeltahrcA::cat and DeltactsR DeltahrcA::cat mutants was indistinguishable from that of wild-type cells. Overall, these results suggest that the induction of CtsR class III stress responses provides cross-protection against heat stress. PMID- 21705553 TI - Scheuermann's kyphosis; current controversies. AB - This review of the literature presents the current understanding of Scheuermann's kyphosis and investigates the controversies concerning conservative and surgical treatment. There is considerable debate regarding the pathogenesis, natural history and treatment of this condition. A benign prognosis with settling of symptoms and stabilisation of the deformity at skeletal maturity is expected in most patients. Observation and programmes of exercise are appropriate for mild, flexible, non-progressive deformities. Bracing is indicated for a moderate deformity which spans several levels and retains flexibility in motivated patients who have significant remaining spinal growth. The loss of some correction after the completion of bracing with recurrent anterior vertebral wedging has been reported in approximately one-third of patients. Surgical correction with instrumented spinal fusion is indicated for a severe kyphosis which carries a risk of progression beyond the end of growth causing cosmetic deformity, back pain and neurological complications. There is no consensus on the effectiveness of different techniques and types of instrumentation. Techniques include posterior-only and combined anteroposterior spinal fusion with or without posterior osteotomies across the apex of the deformity. Current instrumented techniques include hybrid and all-pedicle screw constructs. PMID- 21705552 TI - Randomized, double-blinded clinical trial for human norovirus inactivation in oysters by high hydrostatic pressure processing. AB - Contamination of oysters with human noroviruses (HuNoV) constitutes a human health risk and may lead to severe economic losses in the shellfish industry. There is a need to identify a technology that can inactivate HuNoV in oysters. In this study, we conducted a randomized, double-blinded clinical trial to assess the effect of high hydrostatic pressure processing (HPP) on Norwalk virus (HuNoV genogroup I.1) inactivation in virus-seeded oysters ingested by subjects. Forty four healthy, positive-secretor adults were divided into three study phases. Subjects in each phase were randomized into control and intervention groups. Subjects received Norwalk virus (8FIIb, 1.0 * 10(4) genomic equivalent copies) in artificially seeded oysters with or without HPP treatment (400 MPa at 25 degrees C, 600 MPa at 6 degrees C, or 400 MPa at 6 degrees C for 5 min). HPP at 600 MPa, but not 400 MPa (at 6 degrees or 25 degrees C), completely inactivated HuNoV in seeded oysters and resulted in no HuNoV infection among these subjects, as determined by reverse transcription-PCR detection of HuNoV RNA in subjects' stool or vomitus samples. Interestingly, a white blood cell (granulocyte) shift was identified in 92% of the infected subjects and was significantly associated with infection (P = 0.0014). In summary, these data suggest that HPP is effective at inactivating HuNoV in contaminated whole oysters and suggest a potential intervention to inactivate infectious HuNoV in oysters for the commercial shellfish industry. PMID- 21705554 TI - The Edinburgh Orthopaedic Trauma Unit and the International Trauma Symposium. AB - This brief annotation summarises the particular contributions made by the annual Edinburgh International Trauma Symposium in various areas of research into aspects of orthopaedic trauma and the management of acutely injured patients, during the 25 years since its establishment. PMID- 21705555 TI - Patient-reported outcomes in the Swedish Hip Arthroplasty Register: results of a nationwide prospective observational study. AB - We present the development and results of a nationwide, prospective, observational follow-up programme including patient-reported outcome measures (PROMs) for the Swedish Hip Arthroplasty Register. The programme started in 2002 and has gradually expanded to include all units performing total hip replacement in Sweden. The self-administered PROMs protocol comprises the EQ-5D instrument, the Charnley class categorisation and visual analogue scales for pain and satisfaction. These current analyses include 34 960 total hip replacements with complete pre- and one-year post-operative questionnaires. Patients eligible for total hip replacement generally report low health-related quality of life and suffer from pain. One year post-operatively the mean EQ-5D index increased to above the level of an age- and gender-matched population, with a considerable reduction of pain (p < 0.001). Females, younger patients and those with Charnley category C reported a lower EQ-5D index pre-operatively than males, older patients and Charnley category A or B, respectively (all p < 0.001). In a multivariable regression analysis Charnley category C, male gender and higher age were associated with less improvement in health-related quality of life (p < 0.001). Nationwide implementation of a PROMs programme requires a structured organisation and effective data capture. Patients' response rates to the Registry are good. The continuous collection of PROMs permits local and national improvement work and allows for further health-economic evaluation. PMID- 21705556 TI - Lower rates of dislocation with increased femoral head size after primary total hip replacement: a five-year analysis of NHS patients in England. AB - Increased femoral head size may reduce dislocation rates following total hip replacement. The National Joint Registry for England and Wales has highlighted a statistically significant increase in the use of femoral heads >= 36 mm in diameter from 5% in 2005 to 26% in 2009, together with an increase in the use of the posterior approach. The aim of this study was to determine whether rates of dislocation have fallen over the same period. National data for England for 247 546 procedures were analysed in order to determine trends in the rate of dislocation at three, six, 12 and 18 months after operation during this time. The 18-month revision rates were also examined. Between 2005 and 2009 there were significant decreases in cumulative dislocations at three months (1.12% to 0.86%), six months (1.25% to 0.96%) and 12 months (1.42% to 1.11%) (all p < 0.001), and at 18 months (1.56% to 1.31%) for the period 2005 to 2008 (p < 0.001). The 18-month revision rates did not significantly change during the study period (1.26% to 1.39%, odds ratio 1.10 (95% confidence interval 0.98 to 1.24), p = 0.118). There was no evidence of changes in the coding of dislocations during this time. These data have revealed a significant reduction in dislocations associated with the use of large femoral head sizes, with no change in the 18 month revision rate. PMID- 21705557 TI - Why large-head metal-on-metal hip replacements are painful: the anatomical basis of psoas impingement on the femoral head-neck junction. AB - Large-head metal-on-metal total hip replacement has a failure rate of almost 8% at five years, three times the revision rate of conventional hip replacement. Unexplained pain remains a feature of this type of arthroplasty. All designs of the femoral component of large-head metal-on-metal total hip replacements share a unique characteristic: a subtended angle of 120 degrees defining the proportion of a sphere that the head represents. Using MRI, we measured the contact area of the iliopsoas tendon on the femoral head in sagittal reconstruction of 20 hips of patients with symptomatic femoroacetabular impingement. We also measured the articular extent of the femoral head on 40 normal hips and ten with cam-type deformities. Finally, we performed virtual hip resurfacing on normal and cam-type hips, avoiding overhang of the metal rim inferomedially. The articular surface of the femoral head has a subtended angle of 120 degrees anteriorly and posteriorly, but only 100 degrees medially. Virtual surgery in a normally shaped femoral head showed a 20 degrees skirt of metal protruding medially where iliopsoas articulates. The excessive extent of the large-diameter femoral components may cause iliopsoas impingement independently of the acetabular component. This may be the cause of postoperative pain with these implants. PMID- 21705558 TI - Soft-tissue changes in hip abductor muscles and tendons after total hip replacement: comparison between the direct anterior and the transgluteal approaches. AB - The direct anterior approach in total hip replacement anatomically offers the chance to minimise soft-tissue trauma because an intermuscular and internervous plane is explored. This motivated us to abandon our previously used transgluteal approach and to adopt the direct anterior approach for total hip replacement. Using MRI, we performed a retrospective comparative study of the direct anterior approach with the transgluteal approach. There were 25 patients in each group. At one year post-operatively all the patients underwent MRI of their replaced hips. A radiologist graded the changes in the soft-tissue signals in the abductor muscles. The groups were similar in terms of age, gender, body mass index, complexity of the reconstruction and absence of symptoms. Detachment of the abductor insertion, partial tears and tendonitis of gluteus medius and minimus, the presence of peri-trochanteric bursal fluid and fatty atrophy of gluteus medius and minimus were significantly less pronounced and less frequent when the direct anterior approach was used. There was no significant difference in the findings regarding tensor fascia lata between the two approaches. We conclude that use of the direct anterior approach results in a better soft-tissue response as assessed by MRI after total hip replacement. However, the impact on outcome needs to be evaluated further. PMID- 21705559 TI - Arthroscopy of the hip in patients following joint replacement. AB - Arthroscopy of the native hip is an established diagnostic and therapeutic procedure. Its application in the symptomatic replaced hip is still being explored. We describe the use of arthroscopy of the hip in 24 symptomatic patients following total hip replacement, resurfacing arthroplasty of the hip and partial resurfacing (study group), and compared it with arthroscopy of the native hip in 24 patients (control group). A diagnosis was made or confirmed at arthroscopy in 23 of the study group and a therapeutic arthroscopic intervention resulted in relief of symptoms in ten of these. In a further seven patients it led to revision hip replacement. In contrast, arthroscopy in the control group was diagnostic in all 24 patients and the resulting arthroscopic therapeutic intervention provided symptomatic relief in 21. The mean operative time in the study group (59.7 minutes (35 to 93)) was less than in the control group (71 minutes (40 to 100), p = 0.04) but the arthroscopic approach was more difficult in the arthroplasty group. We suggest that arthroscopy has a role in the management of patients with a symptomatic arthroplasty when other investigations have failed to provide a diagnosis. PMID- 21705560 TI - High tibial osteotomy with a dynamic axial fixator: precision in achieving alignment. AB - We report the outcome of 32 patients (37 knees) who underwent hemicallostasis with a dynamic external fixator for osteoarthritis of the medial compartment of the knee. There were 16 men (19 knees) and 16 women (18 knees) with a mean age at operation of 54.6 years (27 to 72). The aim was to achieve a valgus overcorrection of 2 degrees to 8 degrees or mechanical axis at 62.5% (+/- 12.5%). At a mean follow-up of 62.8 months (51 to 81) there was no change in the mean range of movement, and no statistically significant difference in the Insall Salvati index or tibial slope (p = 0.11 and p = 0.15, respectively). The mean hip knee-ankle angle changed from 190.6 (183 degrees to 197 degrees ) to 176.0 degrees (171 degrees to 181 degrees ), with a mean final position of the mechanical axis of 58.5% (35.1% to 71.2%). The desired alignment was attained in 31 of 37 (84%) knees. There were 21 excellent, 13 good, two fair and one poor result according to the Oxford knee score with no correlation between age and final score. This score was at its best at one year with a statistically significant deterioration at two years (p = 0.001) followed by a small but not statistically significant deterioration until the final follow-up (p = 0.17). All the knees with Ahlback grade 1 osteoarthritis had excellent or good results. Complications included pin tract infections involving 16.4% of all pins used, delayed union in two, knee stiffness in four, fracture of the lateral cortex in one and ring sequestrum in one. In conclusion, hemicallostasis provides precision in attaining the desired alignment without interfering with tibial slope or patellar height, and is relatively free of serious complications. PMID- 21705561 TI - A brief report on managing infected nonunion of a high tibial osteotomy in two stages: a case series involving seven knees. AB - The management of nonunion following high tibial osteotomy by total knee replacement (TKR) has been reported previously. We have extended the treatment to embrace cases with an infected high tibial osteotomy by performing an initial debridement with a period of antibiotic treatment followed by TKR. We have reviewed the results of seven knees in six patients with a mean follow-up of 40.5 months (20 to 57) after the staged TKR. At the latest follow-up, all the pseudarthroses had healed and there had been no recurrence of infection. The mean Hospital for Special Surgery knee score improved from 51.2 (35 to 73) to a mean of 91.7 (84 to 98) at final review. Management of nonunion following high tibial osteotomy with a TKR can be extended to infected cases when treated in two stages with a debridement and antibiotic therapy prior to TKR. PMID- 21705562 TI - Bicruciate-stabilised total knee replacements produce more normal sagittal plane kinematics than posterior-stabilised designs. AB - Bicruciate-stabilised total knee replacement (TKR) aims to restore normal kinematics by replicating the function of both cruciate ligaments. We performed a prospective, randomised controlled trial in which bicruciate- and posterior stabilised TKRs were implanted in 13 and 15 osteo-arthritic knees, respectively. The mean age of the bicruciate-stabilised group was 63.9 years (SD 10.00) and that of the posterior-stabilised group 63.2 years (SD 6.7). A control group comprised 14 normal subjects with a mean age of 67.9 years (SD 7.9). The patellar tendon angle (PTA) was measured one week pre-operatively and at seven weeks post operatively during knee extension, flexion and step-up exercises. At near full extension during step-up, the bicruciate-stabilised TKR produced a higher mean PTA than the posterior-stabilised TKR, indicating that the bicruciate design at least partially restored the kinematic role of the anterior cruciate ligament. The bicruciate-stabilised TKR largely restored the pre-operative kinematics, whereas the posterior-stabilised TKR resulted in a consistently lower PTA at all activities. The PTA in the pre-operative knees was higher than in the control group during the step-up and at near full knee extension. Overall, both groups generated a more normal PTA than that seen in previous studies in high knee flexion. This suggested that both designs of TKR were more effective at replicating the kinematic role of the posterior cruciate ligament than those used in previous studies. PMID- 21705563 TI - Does cyclical loading affect the elution of antibiotics from articulating cement knee spacers? AB - Two-stage revision surgery for infected total knee replacement offers the highest rate of success for the elimination of infection. The use of articulating antibiotic-laden cement spacers during the first stage to eradicate infection also allows protection of the soft tissues against excessive scarring and stiffness. We have investigated the effect of cyclical loading of cement spacers on the elution of antibiotics. Femoral and tibial spacers containing vancomycin at a constant concentration and tobramycin of varying concentrations were studied in vitro. The specimens were immersed and loaded cyclically to 250 N, with a flexion excursion of 45 degrees , for 35 000 cycles. The buffered solution was sampled at set intervals and the antibiotic concentration was established so that the elution could be calculated. Unloaded samples were used as a control group for statistical comparison. The elution of tobramycin increased proportionately with its concentration in cement and was significantly higher at all sampling times from five minutes to 1680 minutes in loaded components compared with the control group (p = 0.021 and p = 0.003, respectively). A similar trend was observed with elution of vancomycin, but this failed to reach statistical significance at five, 1320 and 1560 minutes (p = 0.0508, p = 0.067 and p = 0.347, respectively). However, cyclically loaded and control components showed an increased elution of vancomycin with increasing tobramycin concentration in the specimens, despite all components having the same vancomycin concentration. The concentration of tobramycin influences both tobramycin and vancomycin elution from bone cement. Cyclical loading of the cement spacers enhanced the elution of vancomycin and tobramycin. PMID- 21705564 TI - Risk factors for symptomatic deep-vein thrombosis in patients after total ankle replacement who received routine chemical thromboprophylaxis. AB - The aim of this study was to identify the incidence of post-operative symptomatic deep-vein thrombosis (DVT), as well as the risk factors for and location of DVT, in 665 patients (701 ankles) who underwent primary total ankle replacement. All patients received low-molecular-weight heparin prophylaxis. A total of 26 patients (3.9%, 26 ankles) had a symptomatic DVT, diagnosed by experienced radiologists using colour Doppler ultrasound. Most thrombi (22 patients, 84.6%) were localised distally in the operated limb. Using a logistic multiple regression model we identified obesity, a previous venous thromboembolic event and the absence of full post-operative weight-bearing as independent risk factors for developing a symptomatic DVT. The incidence of symptomatic DVT after total ankle replacement and use of low-molecular-weight heparin is comparable with that in patients undergoing total knee or hip replacement. PMID- 21705565 TI - Immobilisation of the knee and ankle and its impact on drivers' braking times: a driving simulator study. AB - The purpose of this study was to investigate the effects of right leg restriction at the knee, ankle or both, on a driver's braking times. Previous studies have not investigated the effects of knee restriction on braking performance. A total of 23 healthy drivers performed a series of emergency braking tests in a driving simulator in either an above-knee plaster cast, a below-knee cast, or in a knee brace with an increasing range of restriction. The study showed that total braking reaction time was significantly longer when wearing an above-knee plaster cast, a below-knee plaster cast or a knee brace fixed at 0 degrees , compared with braking normally (p < 0.001). Increases in the time taken to move the foot from the accelerator to the brake accounted for some of the increase in the total braking reaction time. Unexpectedly, thinking time also increased with the level of restriction (p < 0.001). The increase in braking time with an above-knee plaster cast in this study would increase the stopping distance at 30 miles per hour by almost 3 m. These results suggest that all patients wearing any lower limb plaster cast or knee brace are significantly impaired in their ability to perform an emergency stop. We suggest changes to the legislation to prevent patients from driving with lower-limb plaster casts or knee braces. PMID- 21705566 TI - Percutaneous screw fixation without bone grafting for established scaphoid nonunion with substantial bone loss. AB - Ununited fractures of the scaphoid with extensive bone resorption are usually treated by bone grafting and internal fixation, using either an open or a minimally invasive technique. We studied the feasibility of percutaneous fixation without bone grafting in a consecutive series of 27 patients with established nonunion of an undisplaced fracture of the scaphoid and extensive local resorption of bone. They were treated by a single surgeon with rigid fixation alone, using a headless cannulated screw inserted through a volar percutaneous technique. Clinical examination, standard radiographs and CT confirmed that the fracture had united in all patients at a mean of 11.6 weeks (8 to 16), and that their functional scores had improved. We concluded that extensive resorption at the fracture site is not an absolute indication for bone grafting, and that percutaneous fixation alone will eventually produce healing of ununited undisplaced fractures of the scaphoid regardless of the size of the gap. PMID- 21705567 TI - The biomechanical performance of locking plate fixation with intramedullary fibular strut graft augmentation in the treatment of unstable fractures of the proximal humerus. AB - We evaluated the biomechanical properties of two different methods of fixation for unstable fractures of the proximal humerus. Biomechanical testing of the two groups, locking plate alone (LP), and locking plate with a fibular strut graft (LPSG), was performed using seven pairs of human cadaveric humeri. Cyclical loads between 10 N and 80 N at 5 Hz were applied for 1,000,000 cycles. Immediately after cycling, an increasing axial load was applied at a rate of displacement of 5 mm/min. The displacement of the construct, maximum failure load, stiffness and mode of failure were compared. The displacement was significantly less in the LPSG group than in the LP group (p = 0.031). All maximum failure loads and measures of stiffness in the LPSG group were significantly higher than those in the LP group (p = 0.024 and p = 0.035, respectively). In the LP group, varus collapse and plate bending were seen. In the LPSG group, the humeral head cut out and the fibular strut grafts fractured. No broken plates or screws were seen in either group. We conclude that strut graft augmentation significantly increases both the maximum failure load and the initial stiffness of this construct compared with a locking plate alone. PMID- 21705568 TI - Comparing normal and torn rotator cuff tendons using dynamic shear analysis. AB - This study reports the application of a novel method for quantitatively determining differences in the mechanical properties of healthy and torn rotator cuff tissues. In order to overcome problems of stress risers at the grip-tendon interface that can obscure mechanical measurements of small tendons, we conducted our investigation using dynamic shear analysis. Rotator cuff tendon specimens were obtained from 100 patients during shoulder surgery. They included 82 differently sized tears and 18 matched controls. We subjected biopsy samples of 3 mm in diameter to oscillatory deformation under compression using dynamic shear analysis. The storage modulus (G') was calculated as an indicator of mechanical integrity. Normal tendons had a significantly higher storage modulus than torn tendons, indicating that torn tendons are mechanically weaker than normal tendons (p = 0.003). Normal tendons had a significantly higher mean shear modulus than tendons with massive tears (p < 0.01). Dynamic shear analysis allows the determination of shear mechanical properties of small tissue specimens obtained intra-operatively that could not be studied by conventional methods of tensile testing. These methods could be employed to investigate other musculoskeletal tissues. This pilot study provides some insight into mechanisms that might contribute to the failure of repair surgery, and with future application could help direct the most appropriate treatment for specific rotator cuff tears. PMID- 21705569 TI - Metal ion levels in patients with a lumbar metal-on-metal total disc replacement: should we be concerned? AB - The purpose of this study was to evaluate whether concerns about the release of metal ions in metal-on-metal total hip replacements (THR) should be extended to patients with metal-bearing total disc replacements (TDR). Cobalt and chromium levels in whole blood and serum were measured in ten patients with a single-level TDR after a mean follow-up of 34.5 months (13 to 61) using inductively-coupled plasma mass spectrometry. These metal ion levels were compared with pre-operative control levels in 81 patients and with metal ion levels 12 months after metal-on metal THR (n = 21) and resurfacing hip replacement (n = 36). Flexion-extension radiographs were used to verify movement of the TDR. Cobalt levels in whole blood and serum were significantly lower in the TDR group than in either the THR (p = 0.007) or the resurfacing group (p < 0.001). Both chromium levels were also significantly lower after TDR versus hip resurfacing (p < 0.001), whereas compared with THR this difference was only significant for serum levels (p = 0.008). All metal ion levels in the THR and resurfacing groups were significantly higher than in the control group (p < 0.001). In the TDR group only cobalt in whole blood appeared to be significantly higher (p < 0.001). The median range of movement of the TDR was 15.5 degrees (10 degrees to 22 degrees ). These results suggest that there is minimal cause for concern about high metal ion concentrations after TDR, as the levels appear to be only moderately elevated. However, spinal surgeons using a metal-on-metal TDR should still be aware of concerns expressed in the hip replacement literature about toxicity from elevated metal ion levels, and inform their patients appropriately. PMID- 21705570 TI - The presacral retroperitoneal approach for axial lumbar interbody fusion: a prospective study of clinical outcomes, complications and fusion rates at a follow-up of two years in 26 patients. AB - The presacral retroperitoneal approach for axial lumbar interbody fusion (presacral ALIF) is not widely reported, particularly with regard to the mid-term outcome. This prospective study describes the clinical outcomes, complications and rates of fusion at a follow-up of two years for 26 patients who underwent this minimally invasive technique along with further stabilisation using pedicle screws. The fusion was single-level at the L5-S1 spinal segment in 17 patients and two-level at L4-5 and L5-S1 in the other nine. The visual analogue scale for pain and Oswestry Disability Index scores were recorded pre-operatively and during the 24-month study period. The evaluation of fusion was by thin-cut CT scans at six and 12 months, and flexion-extension plain radiographs at six, 12 and 24 months. Significant reductions in pain and disability occurred as early as three weeks postoperatively and were maintained. Fusion was achieved in 22 of 24 patients (92%) at 12 months and in 23 patients (96%) at 24 months. One patient (4%) with a pseudarthrosis underwent successful revision by augmentation of the posterolateral fusion mass through a standard open midline approach. There were no severe adverse events associated with presacral ALIF, which in this series demonstrated clinical outcomes and fusion rates comparable with those of reports of other methods of interbody fusion. PMID- 21705571 TI - The Andersson lesion in ankylosing spondylitis: distinguishing between the inflammatory and traumatic subtypes. AB - A number of causes have been advanced to explain the destructive discovertebral (Andersson) lesions that occur in ankylosing spondylitis, and various treatments have been proposed, depending on the presumed cause. The purpose of this study was to identify the causes of these lesions by defining their clinical and radiological characteristics. We retrospectively reviewed 622 patients with ankylosing spondylitis. In all, 33 patients (5.3%) had these lesions, affecting 100 spinal segments. Inflammatory lesions were found in 91 segments of 24 patients (3.9%) and traumatic lesions in nine segments of nine patients (1.4%). The inflammatory lesions were associated with recent-onset disease; a low modified Stoke ankylosing spondylitis spine score (mSASSS) due to incomplete bony ankylosis between vertebral bodies; multiple lesions; inflammatory changes on MRI; reversal of the inflammatory changes and central bony ankylosis at follow up; and a good response to anti-inflammatory drugs. Traumatic lesions were associated with prolonged disease duration; a high mSASSS due to complete bony ankylosis between vertebral bodies; a previous history of trauma; single lesions; nonunion of fractures of the posterior column; acute kyphoscoliotic deformity with the lesion at the apex; instability, and the need for operative treatment due to that instability. It is essential to distinguish between inflammatory and traumatic Andersson lesions, as the former respond to medical treatment whereas the latter require surgery. PMID- 21705572 TI - Is a fracture of the transverse process of L5 a predictor of pelvic fracture instability? AB - In the management of a pelvic fracture prompt recognition of an unstable fracture pattern is important in reducing mortality and morbidity. It is believed that a fracture of the transverse process of L5 is a predictor of pelvic fracture instability. However, there is little evidence in the literature to support this view. The aim of this study was to determine whether a fracture of the transverse process of L5 is a reliable predictor of pelvic fracture instability. We reviewed our hospital trauma database and identified 80 patients who sustained a pelvic fracture between 2006 and 2010. There were 32 women and 48 men with a mean age of 40 years (10 to 96). Most patients were injured in a road traffic accident or as a result of a fall from a height. A total of 41 patients (51%) had associated injuries. The pelvic fractures were categorised according to the Burgess and Young classification. There were 45 stable and 35 unstable fractures. An associated fracture of the transverse process of L5 was present in 17 patients; 14 (40%) of whom had an unstable fracture pattern. The odds ratio for an unstable fracture of the pelvis in the presence of a fracture of the transverse process of L5 was 9.3 and the relative risk was 2.5. A fracture of the transverse process of L5 in the presence of a pelvic fracture is associated with an increased risk of instability of the pelvic fracture. Its presence should alert the attending staff to this possibility. PMID- 21705573 TI - The surgical treatment of anterior column and anterior wall acetabular fractures: short- to medium-term outcome. AB - Isolated fractures of the anterior column and anterior wall are a relatively rare subgroup of acetabular fractures. We report our experience of 30 consecutive cases treated over ten years. Open reduction and internal fixation through an ilioinguinal approach was performed for most of these cases (76.7%) and percutaneous techniques were used for the remainder. At a mean follow-up of four years (2 to 6), 26 were available for review. The radiological and functional outcomes were good or excellent in 23 of 30 patients (76.7%) and 22 of 26 patients (84.6%) according to Matta's radiological criteria and the modified Merle d'Aubigne score, respectively. Complications of minor to moderate severity were seen in six of the 30 cases (20%) and none of the patients underwent secondary surgery or replacement of the hip. PMID- 21705574 TI - Long-term results of conservative treatment of Sanders type 4 fractures of the calcaneum: a series of 64 cases. AB - A high rate of complications is associated with open reduction and internal fixation of Sanders type 4 fractures of the calcaneum. We assessed the long-term outcome of 83 Sanders type 4 comminuted intra-articular fractures of the calcaneum in 64 patients who underwent non-operative treatment between 1999 and 2005. Each fracture was treated by closed reduction and immobilisation in a long leg cast. Patients were reviewed every three months in the first year, and every six months thereafter. At each visit, the involved ankles were assessed by the American Orthopaedic Foot and Ankle Society (AOFAS) criteria. The degree of fracture healing and the presence of osteoarthritis were assessed. At a mean follow-up of 51 months (24 to 70) the mean AOFAS score was 72 (52 to 92). Osteoarthritis was scored radiologically using Graves' classification and was evident in the subtalar joints of 75 ankles (90%) on x-ray and in all ankles on CT scans, of which 20 were grade 0 or 1, 39 grade 2, and 24 grade 3. A non operative approach to treating these fractures may be simpler, less expensive, easier to administer with fewer complications, and may be better tolerated than surgery, by many patients. PMID- 21705575 TI - The final diagnosis in patients with a suspected primary malignancy of bone. AB - We investigated the eventual diagnosis in patients referred to a tertiary centre with a possible diagnosis of a primary bone malignancy. We reviewed our database from between 1986 and 2010, during which time 5922 patients referred with a suspicious bone lesion had a confirmed diagnosis. This included bone sarcoma in 2205 patients (37%), benign bone tumour in 1309 (22%), orthopaedic conditions in 992 (17%), metastatic disease in 533 (9%), infection in 289 (5%) and haematological disease in 303 (5%). There was a similar frequency of all diagnoses at different ages except for metastatic disease. Only 0.6% of patients (17 of 2913) under the age of 35 years had metastatic disease compared with 17.1% (516 of 3009) of those over 35 years (p < 0.0001). Of the 17 patients under 35 years with metastatic disease, only four presented with an isolated lesion, had no past history of cancer and were systematically well. Patients under the age of 35 years should have suitable focal imaging (plain radiography, CT or MRI) and simple systemic studies (blood tests and chest radiography). Reduction of the time to biopsy can be achieved by avoiding an unnecessary investigation for a primary tumour to rule out metastatic disease. PMID- 21705577 TI - Tibial hemimelia with separate soft-tissue cover of the tibia and fibula. AB - We report a variant of tibial hemimelia in a six-year-old boy that did not comply with recognised classification systems. The femur and knee were normal, but the fibula was displaced proximally and there was severe diastasis of the proximal and distal tibiofibular joints to the extent that a grossly deformed foot articulated with the fibula and there was separate soft-tissue cover for the distal tibia and fibula. Although it would have been preferable to create a one bone leg, amputate the foot and use the fibula as the stump for a below-knee prosthesis, local circumstances resulted in the choice of a disarticulation through the knee. This was undertaken without complications, and six months post operatively the child was walking comfortably with a prosthesis. PMID- 21705576 TI - The management of the orthopaedic sequelae of meningococcal septicaemia: patients treated to skeletal maturity. AB - Septicaemia resulting from meningococcal infection is a devastating illness affecting children. Those who survive can develop late orthopaedic sequelae from growth plate arrests, with resultant complex deformities. Our aim in this study was to review the case histories of a series of patients with late orthopaedic sequelae, all treated by the senior author (CFB). We also describe a treatment strategy to address the multiple deformities that may occur in these patients. Between 1997 and 2009, ten patients (seven girls and three boys) were treated for late orthopaedic sequelae following meningococcal septicaemia. All had involvement of the lower limbs, and one also had involvement of the upper limbs. Each patient had a median of three operations (one to nine). Methods of treatment included a combination of angular deformity correction, limb lengthening and epiphysiodesis. All patients were skeletally mature at the final follow-up. One patient with bilateral below-knee amputations had satisfactory correction of her right amputation stump deformity, and has complete ablation of both her proximal tibial growth plates. In eight patients length discrepancy in the lower limb was corrected to within 1 cm, with normalisation of the mechanical axis of the lower limb. Meningococcal septicaemia can lead to late orthopaedic sequelae due to growth plate arrests. Central growth plate arrests lead to limb-length discrepancy and the need for lengthening procedures, and peripheral growth plate arrests lead to angular deformities requiring corrective osteotomies and ablation of the damaged physis. In addition, limb amputations may be necessary and there may be altered growth of the stump requiring further surgery. Long-term follow-up of these patients is essential to recognise and treat any recurrence of deformity. PMID- 21705578 TI - Neuritis ossificans of the tibial, common peroneal and lateral sural cutaneous nerves. AB - We describe a 23-year-old woman with neuritis ossificans involving the tibial, common peroneal and lateral sural nerves. She presented with chronic debilitating posterior knee pain. An MRI scan showed masses in these nerves, biopsy of which revealed a histological diagnosis of neuritis ossificans. Treatment with OxyContin and Neurotin for two years resulted in resolution of symptoms. Follow up MRI demonstrated a resolution of two of the three masses. There was a persistent area of ossification without associated oedema in the common peroneal nerve. Neuritis ossificans has the histological appearance of myositis ossificans and follows a similar clinical course. The success of conservative treatment in this case suggests that the potential complications of surgical excision can be avoided. PMID- 21705579 TI - Exceptionally aggressive pigmented villonodular synovitis of the hip unresponsive to radiotherapy. AB - Pigmented villonodular synovitis (PVNS) is a rare benign neoplastic proliferation of synovial tissue which is typically localised and usually responds well to surgery and/or radiotherapy. We present a case of unusually aggressive of PVNS of the hip in a 73-year-old woman. PMID- 21705581 TI - Divergent DNA methylation patterns associated with abiotic stress in Hevea brasiliensis. AB - Cytosine methylation is a fundamental epigenetic mechanism for gene-expression regulation and development in plants. Here, we report for the first time the identification of DNA methylation patterns and their putative relationship with abiotic stress in the tree crop Hevea brasiliensis (source of 99% of natural rubber in the world). Regulatory sequences of four major genes involved in the mevalonate pathway (rubber biosynthesis pathway) and one general defense-related gene of three high-yielding popular rubber clones grown at two different agroclimatic conditions were analyzed for the presence of methylation. We found several significant variations in the methylation pattern at core DNA binding motifs within all the five genes. Several consistent clone-specific and location specific methylation patterns were identified. The differences in methylation pattern observed at certain pivotal cis-regulatory sites indicate the direct impact of stress on the genome and support the hypothesis of site-specific stress induced DNA methylation. It is assumed that some of the methylation patterns observed may be involved in the stress-responsive mechanism in plants by which they adapt to extreme conditions. The study also provide clues towards the existence of highly divergent phenotypic characters among Hevea clones despite their very similar genetic make-up. Altogether, the observations from this study prove beyond doubt that there exist epigenetic variations in Hevea and environmental factors play a significant role in the induction of site-specific epigenetic mutations in its genome. PMID- 21705582 TI - Genome analysis of a Mycoplasma hyorhinis strain derived from a primary human melanoma cell line. AB - The complete genome of Mycoplasma hyorhinis strain MCLD has been sequenced and annotated. This genome differs by the inversion of a 14.4-kb and a 3.7-kb fragment and the deletion of a 9.9-kb fragment from M. hyorhinis strain HUB-1, isolated from swine respiratory tract. The genome revealed 778 coding sequences (CDSs), with a limited number of vlp genes encoding variable surface lipoproteins. PMID- 21705583 TI - Draft genome sequence of Paenibacillus elgii B69, a strain with broad antimicrobial activity. AB - Here, we report the draft genome sequence of Paenibacillus elgii B69, which was isolated from soil and has broad-spectrum antimicrobial activity. As far as we know, the P. elgii genome is the largest of the Paenibacillus genus for which genome sequences are available. Multiple sets of genes related to antibiotic biosynthetic pathways have been found in the genome. PMID- 21705584 TI - Genome sequence of the thermophilic strain Bacillus coagulans 2-6, an efficient producer of high-optical-purity L-lactic acid. AB - Bacillus coagulans 2-6 is an efficient producer of lactic acid. The genome of B. coagulans 2-6 has the smallest genome among the members of the genus Bacillus known to date. The frameshift mutation at the start of the d-lactate dehydrogenase sequence might be responsible for the production of high-optical purity l-lactic acid. PMID- 21705585 TI - Genome sequences of eight morphologically diverse Alphaproteobacteria. AB - The Alphaproteobacteria comprise morphologically diverse bacteria, including many species of stalked bacteria. Here we announce the genome sequences of eight alphaproteobacteria, including the first genome sequences of species belonging to the genera Asticcacaulis, Hirschia, Hyphomicrobium, and Rhodomicrobium. PMID- 21705586 TI - Genome sequences of the biotechnologically important Bacillus megaterium strains QM B1551 and DSM319. AB - Bacillus megaterium is deep-rooted in the Bacillus phylogeny, making it an evolutionarily key species and of particular importance in understanding genome evolution, dynamics, and plasticity in the bacilli. B. megaterium is a commercially available, nonpathogenic host for the biotechnological production of several substances, including vitamin B(12), penicillin acylase, and amylases. Here, we report the analysis of the first complete genome sequences of two important B. megaterium strains, the plasmidless strain DSM319 and QM B1551, which harbors seven indigenous plasmids. The 5.1-Mbp chromosome carries approximately 5,300 genes, while QM B1551 plasmids represent a combined 417 kb and 523 genes, one of the largest plasmid arrays sequenced in a single bacterial strain. We have documented extensive gene transfer between the plasmids and the chromosome. Each strain carries roughly 300 strain-specific chromosomal genes that account for differences in their experimentally confirmed phenotypes. B. megaterium is able to synthesize vitamin B(12) through an oxygen-independent adenosylcobalamin pathway, which together with other key energetic and metabolic pathways has now been fully reconstructed. Other novel genes include a second ftsZ gene, which may be responsible for the large cell size of members of this species, as well as genes for gas vesicles, a second beta-galactosidase gene, and most but not all of the genes needed for genetic competence. Comprehensive analyses of the global Bacillus gene pool showed that only an asymmetric region around the origin of replication was syntenic across the genus. This appears to be a characteristic feature of the Bacillus spp. genome architecture and may be key to their sporulating lifestyle. PMID- 21705588 TI - Genome sequence of Salinisphaera shabanensis, a gammaproteobacterium from the harsh, variable environment of the brine-seawater interface of the Shaban Deep in the Red Sea. AB - We present the genome of Salinisphaera shabanensis, isolated from a brine seawater interface and representing a new order within the Gammaproteobacteria. Its adaptations to physicochemical and nutrient availability fluctuations include six genes encoding heavy metal-translocating P-type ATPases and multiple genes involved in iron uptake, siderophore production, and poly-beta-hydroxybutyrate synthesis. PMID- 21705587 TI - Complete genome sequence of the marine cellulose- and xylan-degrading bacterium Glaciecola sp. strain 4H-3-7+YE-5. AB - Glaciecola sp. strain 4H-3-7+YE-5 was isolated from subseafloor sediments at Suruga Bay in Japan and is capable of efficiently hydrolyzing cellulose and xylan. The complete genome sequence of Glaciecola sp. 4H-3-7+YE-5 revealed several genes encoding putatively novel glycoside hydrolases, offering a high potential for plant biomass degradation. PMID- 21705589 TI - The Fsr quorum-sensing system of Enterococcus faecalis modulates surface display of the collagen-binding MSCRAMM Ace through regulation of gelE. AB - Ace, a known virulence factor and the first identified microbial surface component recognizing adhesive matrix molecule (MSCRAMM) of Enterococcus faecalisis associated with host cell adherence and endocarditis. The Fsr quorum sensing system of E. faecalis, a two-component signal transduction system, has also been repeatedly linked to virulence in E. faecalis, due in part to the transcriptional induction of an extracellular metalloprotease, gelatinase (GelE). In this study, we discovered that disruption of the Fsr pathway significantly increased the levels of Ace on the cell surface in the latter phases of growth. Furthermore, we observed that, in addition to fsrB mutants, other strains identified as deficient in GelE activity also demonstrated a similar phenotype. Additional experiments demonstrated the GelE-dependent cleavage of Ace from the surface of E. faecalis, confirming that GelE specifically reduces Ace cell surface display. In addition, disruption of the Fsr system or GelE expression significantly improved the ability of E. faecalis to adhere to collagen, which is consistent with higher levels of Ace on the E. faecalis surface. These results demonstrate that the display of Ace is mediated by quorum sensing through the action of GelE, providing insight into the complicated world of Gram-positive pathogen adhesion and colonization. PMID- 21705590 TI - Annotated genome sequence of Lactobacillus pentosus MP-10, which has probiotic potential, from naturally fermented Alorena green table olives. AB - Lactobacillus pentosus MP-10 was isolated from brines of naturally fermented Alorena green table olives. MP-10 has potential probiotic traits, including inhibition of human pathogenic bacteria, survival at low pH (1.5), and bile salt tolerance (3%). Here, we report for the first time the annotated genome sequence of L. pentosus. PMID- 21705591 TI - Draft genome sequences of two Pseudomonas aeruginosa clinical isolates with different antibiotic susceptibilities. AB - Pseudomonas aeruginosa is a primary cause of opportunistic infections. We have sequenced and annotated the genomes of two P. aeruginosa clinical isolates evidencing different antibiotic susceptibilities. Registered differences in the composition of their accessory genomes may provide clues on P. aeruginosa strategies to thrive in different environments like infection loci. PMID- 21705592 TI - Quorum sensing and silencing in Vibrio parahaemolyticus. AB - The quorum regulatory cascade is poorly characterized in Vibrio parahaemolyticus, in part because swarming and virulence factors--the hallmarks of the organism- are repressed by this scheme of gene control, and quorum sensing seems to be silenced in many isolates. In these studies, we examine a swarming-proficient, virulent strain and identify an altered-function allele of the quorum regulator luxO that is demonstrated to produce a constitutively active mimic of LuxO~P. We find that LuxO* affects the expression of three small regulatory RNAs (Qrrs) and the activity of a translational fusion in opaR, the output regulator. Tests for epistasis showed that luxO* is dominant over luxO and that opaR is dominant over luxO. Thus, information flow through the central elements of the V. parahaemolyticus quorum pathway is proven for the first time. Quorum-sensing output was explored using microarray profiling: the OpaR regulon encompasses ~5.2% of the genome. OpaR represses the surface-sensing and type III secretion system 1 (T3SS1) regulons. One novel discovery is that OpaR strongly and oppositely regulates two type VI secretion systems (T6SS). New functional consequences of OpaR control were demonstrated: OpaR increases the cellular cyclic di-GMP (c-di-GMP) level, positively controls chitin-induced DNA competency, and profoundly blocks cytotoxicity toward host cells. In expanding the previously known quorum effects beyond the induction of the capsule and the repression of swarming to elucidate the global scope of genes in the OpaR regulon, this study yields many clues to distinguishing traits of this Vibrio species; it underscores the profoundly divergent survival strategies of the quorum On/Off phase variants. PMID- 21705593 TI - Genome sequence of Halorhabdus tiamatea, the first archaeon isolated from a deep sea anoxic brine lake. AB - We present the draft genome of Halorhabdus tiamatea, the first member of the Archaea ever isolated from a deep-sea anoxic brine. Genome comparison with Halorhabdus utahensis revealed some striking differences, including a marked increase in genes associated with transmembrane transport and putative genes for a trehalose synthase and a lactate dehydrogenase. PMID- 21705594 TI - Complete genome sequence of the obligate piezophilic hyperthermophilic archaeon Pyrococcus yayanosii CH1. AB - Pyrococcus yayanosii CH1 is the first obligate piezophilic hyperthermophilic archaeon isolated from the deep-sea hydrothermal site Ashadze on the mid-Atlantic ridge at a depth of 4,100 m. This organism grows within a temperature range of 80 to 108 degrees C and a hydrostatic pressure range of 20 to 120 MPa, with optima at 98 degrees C and 52 MPa, respectively. Here, we report the complete genome sequence (1,716,817 bp, with a G+C content of 51.6%) of the type strain P. yayanosii CH1(T) (= JCM 16557). This genomic information reveals a systematic view of the piezoadaptation strategy and evolution scenario of metabolic pathways in Thermococcales. PMID- 21705595 TI - Counteractive balancing of transcriptome expression involving CodY and CovRS in Streptococcus pyogenes. AB - Streptococcus pyogenes (group A streptococcus [GAS]) responds to environmental changes in a manner that results in an adaptive regulation of the transcriptome. The objective of the present study was to understand how two global transcriptional regulators, CodY and CovRS, coordinate the transcriptional network in S. pyogenes. Results from expression microarray data and quantitative reverse transcription-PCR (qRT-PCR) showed that the global regulator CodY controls the expression of about 250 genes, or about 17% of the genome of strain NZ131. Additionally, the codY gene was shown to be negatively autoregulated, with its protein binding directly to the promoter region with a CodY binding site. In further studies, the influence of codY, covRS, and codY-covRS mutations on gene expression was analyzed in growth phase-dependent conditions using C medium, reported to mimic nutritional abundance and famine conditions similar to those found during host GAS infection. Additional biological experiments of several virulence phenotypes, including pilin production, biofilm formation, and NAD glycohydrolase activity, demonstrated the role that both CodY and CovRS play in their regulation. Correlation analysis of the overall data revealed that, in exponentially growing cells, CodY and CovRS act in opposite directions, with CodY stimulating and CovRS repressing a substantial fraction of the core genome, including many virulence factors. This is the first report of counteractive balancing of transcriptome expression by global transcription regulators and provides important insight into how GAS modulates gene expression by integrating important extracellular and intracellular information. PMID- 21705597 TI - An essential tyrosine phosphatase homolog regulates cell separation, outer membrane integrity, and morphology in Caulobacter crescentus. AB - Although reversible phosphorylation on tyrosine residues regulates the activity of many eukaryotic proteins, there are few examples of this type of regulation in bacteria. We have identified the first essential tyrosine phosphatase homolog in a bacterium, Caulobacter crescentus CtpA. ctpA mutants with altered active-site residues are nonviable, and depletion of CtpA yields chains of cells with blebbed outer membranes, linked by unresolved peptidoglycan. CtpA overexpression reduces cell curvature in a manner similar to deleting the intermediate filament protein crescentin, but it does not disrupt crescentin localization or membrane attachment. Although it has no obvious signal sequence or transmembrane-spanning domains, CtpA associates with the Caulobacter inner membrane. Immunolocalization experiments suggest that CtpA accumulates at the division site during the last quarter of the cell cycle. We propose that CtpA dephosphorylates one or more proteins involved in peptidoglycan biosynthesis or remodeling, which in turn affect cell separation, cell envelope integrity, and vibrioid morphology. PMID- 21705598 TI - Draft genome of the psychrotolerant acidophile Acidithiobacillus ferrivorans SS3. AB - Acidithiobacillus ferrivorans SS3 is a psychrotolerant acidophile capable of growth in the range of 5 degrees to 30 degrees C (optimum, ~25 degrees C). It gains energy from the oxidation of ferrous iron and inorganic sulfur compounds and obtains organic carbon from carbon dioxide. Here, we present the draft genome sequence of A. ferrivorans SS3 that will permit investigation of genes involved in growth in acidic environments at low temperatures. PMID- 21705596 TI - CsrA and TnaB coregulate tryptophanase activity to promote exotoxin-induced killing of Caenorhabditis elegans by enteropathogenic Escherichia coli. AB - Enteropathogenic Escherichia coli(EPEC) requires the tnaA-encoded enzyme tryptophanase and its substrate tryptophan to synthesize diffusible exotoxins that kill the nematode Caenorhabditis elegans. Here, we demonstrate that the RNA binding protein CsrA and the tryptophan permease TnaB coregulate tryptophanase activity, through mutually exclusive pathways, to stimulate toxin-mediated paralysis and killing of C. elegans. PMID- 21705599 TI - Genome sequence of Haloplasma contractile, an unusual contractile bacterium from a deep-sea anoxic brine lake. AB - We present the draft genome of Haloplasma contractile, isolated from a deep-sea brine and representing a new order between Firmicutes and Mollicutes. Its complex morphology with contractile protrusions might be strongly influenced by the presence of seven MreB/Mbl homologs, which appears to be the highest copy number ever reported. PMID- 21705600 TI - Bacteriophage infection in rod-shaped gram-positive bacteria: evidence for a preferential polar route for phage SPP1 entry in Bacillus subtilis. AB - Entry into the host bacterial cell is one of the least understood steps in the life cycle of bacteriophages. The different envelopes of Gram-negative and Gram positive bacteria, with a fluid outer membrane and exposing a thick peptidoglycan wall to the environment respectively, impose distinct challenges for bacteriophage binding and (re)distribution on the bacterial surface. Here, infection of the Gram-positive rod-shaped bacterium Bacillus subtilis by bacteriophage SPP1 was monitored in space and time. We found that SPP1 reversible adsorption occurs preferentially at the cell poles. This initial binding facilitates irreversible adsorption to the SPP1 phage receptor protein YueB, which is encoded by a putative type VII secretion system gene cluster. YueB was found to concentrate at the cell poles and to display a punctate peripheral distribution along the sidewalls of B. subtilis cells. The kinetics of SPP1 DNA entry and replication were visualized during infection. Most of the infecting phages DNA entered and initiated replication near the cell poles. Altogether, our results reveal that the preferentially polar topology of SPP1 receptors on the surface of the host cell determines the site of phage DNA entry and subsequent replication, which occurs in discrete foci. PMID- 21705601 TI - Complete genome sequence of the Crohn's disease-associated adherent-invasive Escherichia coli strain HM605. AB - Adherent-invasive Escherichia coli strains are increasingly being associated with intestinal pathologies. Here we present the genome sequence of E. coli HM605, a strain isolated from colonic biopsy specimens of a patient with Crohn's disease. PMID- 21705602 TI - Complete genome sequence of Propionibacterium acnes type IB strain 6609. AB - Propionibacterium acnes is an anaerobic Gram-positive bacterium that forms part of the normal human cutaneous microbiota and is thought to play a central role in acne vulgaris, a chronic inflammatory disease of the pilosebaceous unit (I. Kurokawa et al., Exp. Dermatol. 18:821-832, 2009). Here we present the whole genome sequence of P. acnes type IB strain 6609, which was recovered from a skin sample from a woman with no recorded acne history and is thus considered a nonpathogenic strain (I. Nagy, Microbes Infect. 8:2195-2205, 2006). PMID- 21705603 TI - Genome sequence of Helicobacter bizzozeronii strain CIII-1, an isolate from human gastric mucosa. AB - The canine-adapted Helicobacter bizzozeronii is the only nonpylori Helicobacter species isolated from human gastric biopsy tissue. Here we present the genome sequence of strain CIII-1, isolated from a 45-year-old female patient with severe gastric symptoms. This is the first genome sequence of nonpylori gastric Helicobacter isolated from human gastritis. PMID- 21705604 TI - Genome sequence of Streptomyces sp. strain Tu6071. AB - Streptomyces sp. Tu6071 is a soil-dwelling bacterium which has a highly active isoprenoid biosynthesis. Isoprenoids are important precursors for biopharmaceutical molecules such as antibiotics or anticancer agents, e.g., landomycin. Streptomyces sp. Tu6071 produces the industrially important terpene glycosides phenalinolactones, which have antibacterial activity against several Gram-positive bacteria. The availability of the genome sequence of Streptomyces sp. Tu6071 allows for understanding the biosynthesis of these pharmaceutical molecules and will facilitate rational genome modification to improve industrial use. PMID- 21705606 TI - Complete genome sequence of the polycyclic aromatic hydrocarbon-degrading bacterium Alteromonas sp. strain SN2. AB - Alteromonas sp. strain SN2, able to metabolize polycyclic aromatic hydrocarbons, was isolated from a crude oil-contaminated sea-tidal flat. Here we report the complete 4.97-Mb genome sequence and annotation of strain SN2. These will advance the understanding of strain SN2's adaptation to the sea-tidal flat ecosystem and its pollutant metabolic versatility. PMID- 21705607 TI - Complete genome sequence of Lactobacillus kefiranofaciens ZW3. AB - Lactobacillus kefiranofaciens ZW3 was isolated in Tibet, China, from kefir grain, a traditional dairy product that is known to provide many health benefits to humans. Here, we present the genome features of L. kefiranofaciens ZW3 and the identification of a gene cluster related to the synthesis of exopolysaccharide, an important constituent of the Tibetan kefir. PMID- 21705605 TI - Whole-genome shotgun sequencing of an Indian-origin Lactobacillus helveticus strain, MTCC 5463, with probiotic potential. AB - Lactobacillus helveticus MTCC 5463 was isolated from a vaginal swab from a healthy adult female. The strain exhibited potential probiotic properties, with their beneficial role in the gastrointestinal tract and their ability to reduce cholesterol and stimulate immunity. We sequenced the whole genome and compared it with the published genome sequence of Lactobacillus helveticus DPC4571. PMID- 21705608 TI - The Bradyrhizobium japonicum frcB gene encodes a diheme ferric reductase. AB - Iron utilization by bacteria in aerobic environments involves uptake as a ferric chelate from the environment, followed by reduction to the ferrous form. Ferric iron reduction is poorly understood in most bacterial species. Here, we identified Bradyrhizobium japonicum frcB (bll3557) as a gene adjacent to, and coregulated with, the pyoR gene (blr3555) encoding the outer membrane receptor for transport of a ferric pyoverdine. FrcB is a membrane-bound, diheme protein, characteristic of eukaryotic ferric reductases. Heme was essential for FrcB stability, as were conserved histidine residues in the protein that likely coordinate the heme moieties. Expression of the frcB gene in Escherichia coli conferred ferric reductase activity on those cells. Furthermore, reduced heme in purified FrcB was oxidized by ferric iron in vitro. B. japonicum cells showed inducible ferric reductase activity in iron-limited cells that was diminished in an frcB mutant. Steady-state levels of frcB mRNA were strongly induced under iron limiting conditions, but transcript levels were low and unresponsive to iron in an irr mutant lacking the global iron response transcriptional regulator Irr. Thus, Irr positively controls the frcB gene. FrcB belongs to a family of previously uncharacterized proteins found in many proteobacteria and some cyanobacteria. This suggests that membrane-bound, heme-containing ferric reductase proteins are not confined to eukaryotes but may be common in bacteria. PMID- 21705610 TI - Genome of the cyanobacterium Microcoleus vaginatus FGP-2, a photosynthetic ecosystem engineer of arid land soil biocrusts worldwide. AB - The filamentous cyanobacterium Microcoleus vaginatusis found in arid land soils worldwide. The genome of M. vaginatus strain FGP-2 allows exploration of genes involved in photosynthesis, desiccation tolerance, alkane production, and other features contributing to this organism's ability to function as a major component of biological soil crusts in arid lands. PMID- 21705611 TI - Complete genome sequences of four mammalian isolates of Chlamydophila psittaci. AB - Chlamydia psittaci is an obligate intracellular zoonotic pathogen primarily of birds, but it is also known to infect a variety of mammalian species. Here we report the genomes of four strains isolated from sheep (C19/98), pigs (01DC11), cattle (02DC15), and humans (08DC60). PMID- 21705612 TI - Complete genome sequence of the bacterium Porphyromonas gingivalis TDC60, which causes periodontal disease. AB - Porphyromonas gingivalis is a black-pigmented asaccharolytic anaerobe and a major causative agent of periodontitis. Here, we report the complete genome sequence of P. gingivalis strain TDC60, which was recently isolated from a severe periodontal lesion in a Japanese patient. PMID- 21705609 TI - Genome sequence of Leuconostoc pseudomesenteroides KCTC 3652. AB - We announce the genome sequence of one of the most prevalent lactic acid bacteria present during the manufacturing process of cane juice, the type strain Leuconostoc pseudomesenteroides KCTC 3652 (3,244,985 bp, with a G+C content of 38.3%), which consists of 1,160 large contigs (>100 bp in size). All of the contigs were assembled by the Newbler Assembler 2.3 software program (454 Life Sciences). PMID- 21705613 TI - Aggravation by paroxetine, a selective serotonin reuptake inhibitor, of antral lesions generated by nonsteroidal anti-inflammatory drugs in rats. AB - Recent clinical studies have suggested a risk of adverse gastric reactions from the concomitant use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) with nonsteroidal anti-inflammatory drugs (NSAIDs). We examined the adverse effects of SSRIs on antral lesions produced by indomethacin in rats. Rats fasted for 24 h were refed for 1 h, then administered indomethacin (30 mg/kg s.c.) 1 h after the refeeding and killed 6 h later. Paroxetine (1-10 mg/kg) was given orally 30 min before indomethacin. Indomethacin caused antral lesions in refed rats. Paroxetine dose-dependently aggravated these lesions, despite provoking no damage by itself. Similar results were obtained when other NSAIDs such as diclofenac, flurbiprofen, and loxoprofen were coadministered with paroxetine or when indomethacin was coadministered with other antidepressants such as fluvoxamine and milnacipran, but not imipramine or maprotiline. Exogenous 5-HT also worsened the indomethacin-induced antral damage, whereas the aggravating effect of paroxetine was attenuated by ondansetron, a selective 5-HT(3) antagonist, but not antagonists for other 5-HT receptor subtypes. Indomethacin plus paroxetine had no effect on gastric secretion but significantly decreased mucosal superoxide dismutase (SOD) activity as well as GSH content. The antral damage induced by indomethacin plus paroxetine was significantly prevented by antisecretory (acid or pepsin) agents and mucosal protective agents as well as SOD and allopurinol. These results suggest that SSRIs aggravate NSAID-induced antral lesions, probably via the activation of 5HT(3) receptors, and the mechanism of aggravation may involve the corrosive action of acid/pepsin as well as an impaired antioxidative system. PMID- 21705614 TI - Luteolin, a novel natural inhibitor of tumor progression locus 2 serine/threonine kinase, inhibits tumor necrosis factor-alpha-induced cyclooxygenase-2 expression in JB6 mouse epidermis cells. AB - Targeting tumor necrosis factor (TNF)-alpha-mediated signal pathways may be a promising strategy for developing chemopreventive agents, because TNF-alpha mediated cyclooxygenase (COX)-2 expression plays a key role in inflammation and carcinogenesis. Luteolin [2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-chromenone] exerts anticarcinogenic effects, although little is known about the underlying molecular mechanisms and specific targets of this compound. In the present study, we found that luteolin inhibited TNF-alpha-induced COX-2 expression by down regulating the transactivation of nuclear factor-kappaB and activator protein-1. Furthermore, luteolin inhibited TNF-alpha-induced phosphorylation of mitogen activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/ERK/p90(RSK), mitogen-activated protein kinase kinase 4/c-Jun N-terminal kinase/c-Jun, and Akt/p70(S6K). However, it had no effect on the phosphorylation of p38. These effects of luteolin on TNF-alpha-mediated signaling pathways and COX-2 expression are similar to those achieved by blocking tumor progression locus 2 serine/threonine kinase (TPL2) using pharmacologic inhibitors and small interfering RNAs. Luteolin inhibited TPL2 activity in vitro and in TPL2 immunoprecipitation kinase assays by binding directly in an ATP-competitive manner. Overall, these results indicate that luteolin exerts potent chemopreventive activities, which primarily target TPL2. PMID- 21705615 TI - Uncoupling protein 2 negatively regulates mitochondrial reactive oxygen species generation and induces phosphatase-mediated anti-inflammatory response in experimental visceral leishmaniasis. AB - To reside and multiply successfully within the host macrophages, Leishmania parasites impair the generation of reactive oxygen species (ROS), which are a major host defense mechanism against any invading pathogen. Mitochondrial uncoupling proteins are associated with mitochondrial ROS generation, which is the major contributor of total cellular ROS generation. In the present study we have demonstrated that Leishmania donovani infection is associated with strong upregulation of uncoupling protein 2 (UCP2), a negative regulator of mitochondrial ROS generation located at the inner membrane of mitochondria. Functional knockdown of macrophage UCP2 by small interfering RNA-mediated silencing was associated with increased mitochondrial ROS generation, lower parasite survival, and induction of marked proinflammatory cytokine response. Induction of proinflammatory cytokine response in UCP2 knocked-down cells was a direct consequence of p38 and ERK1/2 MAPK activation, which resulted from ROS mediated inhibition of protein tyrosine phosphatases (PTPs). Administration of ROS quencher, N-acetyl-l-cysteine, abrogated PTP inhibition in UCP2 knocked-down infected cells, implying a role of ROS in inactivating PTP. Short hairpin RNA mediated in vivo silencing of UCP2 resulted in decreased Src homology 2 domain containing tyrosine phosphatase 1 and PTP-1B activity and host-protective proinflammatory cytokine response resulting in effective parasite clearance. To our knowledge, this study, for the first time, reveals the induction of host UCP2 expression during Leishmania infection to downregulate mitochondrial ROS generation, thereby possibly preventing ROS-mediated PTP inactivation to suppress macrophage defense mechanisms. PMID- 21705616 TI - IFN-alpha confers resistance of systemic lupus erythematosus nephritis to therapy in NZB/W F1 mice. AB - The critical role of IFN-alpha in the pathogenesis of human systemic lupus erythematosus has been highlighted in recent years. Exposure of young lupus-prone NZB/W F1 mice to IFN-alpha in vivo leads to an accelerated lupus phenotype that is dependent on T cells and is associated with elevated serum levels of BAFF, IL 6, and TNF-alpha, increased splenic expression of IL-6 and IL-21, formation of large germinal centers, and the generation of large numbers of short-lived plasma cells that produce IgG2a and IgG3 autoantibodies. In this study, we show that both IgG2a and IgG3 autoantibodies are pathogenic in IFN-alpha-accelerated lupus, and their production can be dissociated by using low-dose CTLA4-Ig. Only high dose CTLA4-Ig attenuates both IgG2a and IgG3 autoantibody production and significantly delays death from lupus nephritis. In contrast, BAFF/APRIL blockade has no effect on germinal centers or the production of IgG anti-dsDNA Abs but, if given at the time of IFN-alpha challenge, delays the progression of lupus by attenuating systemic and renal inflammation. Temporary remission of nephritis induced by combination therapy with cyclophosphamide, anti-CD40L Ab, and CTLA4-Ig is associated with the abrogation of germinal centers and depletion of short lived plasma cells, but relapse occurs more rapidly than in conventional NZB/W F1 mice. This study demonstrates that IFN-alpha renders NZB/W F1 relatively resistant to therapeutic intervention and suggests that the IFN signature should be considered when randomizing patients into groups and analyzing the results of human clinical trials in systemic lupus erythematosus. PMID- 21705617 TI - RGS10 restricts upregulation by chemokines of T cell adhesion mediated by alpha4beta1 and alphaLbeta2 integrins. AB - Chemokines rapidly and transiently upregulate alpha4beta1 and alphaLbeta2 integrin-mediated adhesion during T lymphocyte extravasation by activating Galpha dependent inside-out signaling. To limit and terminate Galpha-mediated signaling, cells can use several mechanisms, including the action of regulator of G protein signaling (RGS) proteins, which accelerate the GTPase activity of Galpha subunits. Using human T cells silenced for or overexpressing RGS10, we show in this article that RGS10 functions as an inhibitor of Galpha(i)-dependent, chemokine-upregulated T cell adhesion mediated by alpha4beta1 and alphaLbeta2. Shear stress-dependent detachment and cell spreading analyses revealed that RGS10 action mainly targets the adhesion strengthening and spreading phases of alpha4beta1-mediated cell attachment. Associated with these observations, chemokine-stimulated Vav1-Rac1 activation was longer sustained and of higher intensity in RGS10-silenced T cells, or inhibited in cells overexpressing RGS10. Of importance, expression of constitutively activated Rac1 forms in cells overexpressing RGS10 led to the rescue of CXCL12-stimulated adhesion to VCAM-1 to levels similar to those in control transfectants. Instead, adhesion under flow conditions, soluble binding experiment, flow cytometry, and biochemical analyses revealed that the earlier chemokine-triggered integrin activation step was mostly independent of RGS10 actions. The data strongly suggest that RGS10 opposes activation by chemokines of the Vav1-Rac1 pathway in T cells, leading to repression of adhesion strengthening mediated by alpha4beta1. In addition to control chemokine-upregulated T cell attachment, RGS10 also limited adhesion independent cell chemotaxis and activation of cdc42. These results identify RGS10 as a key molecule that contributes to the termination of Galpha-dependent signaling during chemokine-activated alpha4beta1- and alphaLbeta2-dependent T cell adhesion. PMID- 21705618 TI - GM-CSF production by glioblastoma cells has a functional role in eosinophil survival, activation, and growth factor production for enhanced tumor cell proliferation. AB - Medicinal interventions of limited efficacy are currently available for the treatment of glioblastoma multiforme (GBM), the most common and lethal primary brain tumor in adults. The eosinophil is a pivotal immune cell in the pathobiology of atopic disease that is also found to accumulate in certain tumor tissues. Inverse associations between atopy and GBM risk suggest that the eosinophil may play a functional role in certain tumor immune responses. To assess the potential interactions between eosinophils and GBM, we cultured human primary blood eosinophils with two separate human GBM-derived cell lines (A172, U87-MG) or conditioned media generated in the presence or absence of TNF-alpha. Results demonstrated differential eosinophil adhesion and increased survival in response to coculture with GBM cell lines. Eosinophil responses to GBM cell line conditioned media included increased survival, activation, CD11b expression, and S100A9 release. Addition of GM-CSF neutralizing Abs to GBM cell cultures or conditioned media reduced eosinophil adhesion, survival, and activation, linking tumor cell-derived GM-CSF to the functions of eosinophils in the tumor microenvironment. Dexamethasone, which has been reported to inhibit eosinophil recruitment and shrink GBM lesions on contrast-enhanced scans, reduced the production of tumor cell-derived GM-CSF. Furthermore, culture of GBM cells in eosinophil-conditioned media increased tumor cell viability, and generation of eosinophil-conditioned media in the presence of GM-CSF enhanced the effect. These data support the idea of a paracrine loop between GM-CSF-producing tumors and eosinophil-derived growth factors in tumor promotion/progression. PMID- 21705619 TI - Repetitive immunization breaks tolerance to type XVII collagen and leads to bullous pemphigoid in mice. AB - Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease of the elderly associated with considerable morbidity and mortality. As unspecific immunosuppressants are still the mainstay of BP therapy, several animal models, based on the passive transfer of autoantibodies or immune cells, have been developed to obtain a better understanding of the pathogenesis of BP and evaluate novel therapeutic interventions. We describe in this study an experimental model inducing BP by immunization of immunocompetent mice with a recombinant form of the immunodominant 15th noncollagenous domain of murine BP180 (type XVII collagen). The homologous noncollagenous 16A domain of human BP180 has previously been identified as an immunodominant region in human BP. Immunization of female SJL/J mice with the murine peptide led to clinical disease within 14 wk in 56% of mice. In contrast, none of the other strains developed blisters despite the presence of autoantibodies. The clinical disease manifested for at least 8 wk without further manipulation. This novel immunization-induced model reflects key immunopathological characteristics of human BP, including binding of complement fixing autoantibodies along the dermal-epidermal junction, elevated total IgE serum levels, and infiltration of skin lesions with eosinophilic granulocytes. The use of immunocompetent mice and the induction of sustained clinical disease not requiring additional interventions make this immunization-induced mouse model most suitable to further explore the pathogenesis of BP and novel therapeutic interventions for this and other autoantibody-mediated diseases. PMID- 21705620 TI - Th2 responses to helminth parasites can be therapeutically enhanced by, but are not dependent upon, GITR-GITR ligand costimulation in vivo. AB - The immune suppression that characterizes human helminth infections can hinder the development of protective immunity or help to reduce pathogenic inflammation. Signaling through the T cell costimulator glucocorticoid-induced TNFR-related protein (GITR) counteracts immune downregulation by augmenting effector T cell responses and abrogating suppression by Foxp3(+) regulatory T cells. Thus, superphysiological Ab-mediated GITR costimulation represents a novel therapy for promoting protective immunity toward parasitic helminths, whereas blocking physiological GITR-GITR ligand (GITRL) interactions may provide a mechanism for dampening pathogenic Th2 inflammation. We investigated the superphysiological and physiological roles of the GITR-GITRL pathway in the development of protective and pathogenic Th2 responses in murine infection models of filariasis (Litomosoides sigmodontis) and schistosomiasis (Schistosoma mansoni). Providing superphysiological GITR costimulation using an agonistic anti-GITR mAb over the first 12 d of L. sigmodontis infection initially increased the quantity of Th2 cells, as well as their ability to produce Th2 cytokines. However, as infection progressed, the Th2 responses reverted to normal infection levels, and parasite killing remained unaffected. Despite the Th2-promoting role of superphysiological GITR costimulation, Ab-mediated blockade of the GITR-GITRL pathway did not affect Th2 cell priming or maintenance during L. sigmodontis infection. Blockade of GITR GITRL interactions during the acute egg phase of S. mansoni infection resulted in reduced Th2 responses, but this effect was confined to the spleen and did not lead to changes in liver pathology. Thus, although superphysiological GITR costimulation can therapeutically enhance Th2 responses, physiological GITR-GITRL interactions are not required for the development of Th2-mediated resistance or pathology in murine models of filariasis and schistosomiasis. PMID- 21705622 TI - Overexpression of Ste20-related proline/alanine-rich kinase exacerbates experimental colitis in mice. AB - Inflammatory bowel disease, mainly Crohn's disease and ulcerative colitis, are characterized by epithelial barrier disruption and altered immune regulation. Colonic Ste20-like proline/alanine-rich kinase (SPAK) plays a role in intestinal inflammation, but its underlying mechanisms need to be defined. Both SPAK transfected Caco2-BBE cells and villin-SPAK transgenic (TG) FVB/6 mice exhibited loss of intestinal barrier function. Further studies demonstrated that SPAK significantly increased paracellular intestinal permeability to FITC-dextran. In vivo studies using the mouse models of colitis induced by dextran sulfate sodium (DSS) and trinitrobenzene sulfonic acid showed that TG FVB/6 mice were more susceptible to DSS and trinitrobenzene sulfonic acid treatment than wild-type FVB/6 mice, as demonstrated by clinical and histological characteristics and enzymatic activities. Consistent with this notion, we found that SPAK increased intestinal epithelial permeability, which likely facilitated the production of inflammatory cytokines in vitro and in vivo, aggravated bacterial translocation in TG mice under DSS treatment, and consequently established a context favorable for the triggering of intestinal inflammation cascades. In conclusion, overexpression of SPAK inhibits maintenance of intestinal mucosal innate immune homeostasis, which makes regulation of SPAK important to attenuate pathological responses in inflammatory bowel disease. PMID- 21705621 TI - A TCR transgenic mouse reactive with multiple systemic dimorphic fungi. AB - Dimorphic fungi collectively account for 5-10 million new infections annually worldwide. Ongoing efforts seek to clarify mechanisms of cellular resistance to these agents and develop vaccines. A major limitation in studying the development of protective T cells in this group of organisms is the lack of tools to detect, enumerate, and characterize fungus-specific T cells during vaccination and infection. We generated a TCR transgenic mouse (Bd 1807) whose CD4(+) T cells respond to a native epitope in Blastomyces dermatitidis and also in Histoplasma capsulatum. In this study, we characterize the mouse, reveal its applications, and extend our analysis showing that 1807 cells also respond to the related dimorphic fungi Coccidioides posadasii and Paracoccidioides lutzii. On adoptive transfer into vaccinated wild-type mice, 1807 cells become activated, proliferate, and expand in the draining lymph nodes, and they differentiate into T1 effectors after trafficking to the lung upon lethal experimental challenge. Bd 1807 cells confer vaccine-induced resistance against B. dermatitidis, H. capsulatum, and C. posadasii. Transfer of naive 1807 cells at serial intervals postvaccination uncovered the prolonged duration of fungal Ag presentation. Using 1807 cells, we also found that the administration of vaccine only once induced a maximal pool of effector/memory CD4(+) cells and protective immunity by 4 wk after vaccination. The autologous adoptive transfer system described in this study reveals novel features of antifungal immunity and offers a powerful approach to study the differentiation of Ag-specific T cells responsive to multiple dimorphic fungi and the development of CD4(+) T cell memory needed to protect against fungal infection. PMID- 21705623 TI - ML1419c peptide immunization induces Mycobacterium leprae-specific HLA-A*0201 restricted CTL in vivo with potential to kill live mycobacteria. AB - MHC class I-restricted CD8(+) T cells play an important role in protective immunity against mycobacteria. Previously, we showed that p113-121, derived from Mycobacterium leprae protein ML1419c, induced significant IFN-gamma production by CD8(+) T cells in 90% of paucibacillary leprosy patients and in 80% of multibacillary patients' contacts, demonstrating induction of M. leprae-specific CD8(+) T cell immunity. In this work, we studied the in vivo role and functional profile of ML1419c p113-121-induced T cells in HLA-A*0201 transgenic mice. Immunization with 9mer or 30mer covering the p113-121 sequence combined with TLR9 agonist CpG induced HLA-A*0201-restricted, M. leprae-specific CD8(+) T cells as visualized by p113-121/HLA-A*0201 tetramers. Most CD8(+) T cells produced IFN gamma, but distinct IFN-gamma(+)/TNF-alpha(+) populations were detected simultaneously with significant secretion of CXCL10/IFN-gamma-induced protein 10, CXCL9/MIG, and VEGF. Strikingly, peptide immunization also induced high ML1419c specific IgG levels, strongly suggesting that peptide-specific CD8(+) T cells provide help to B cells in vivo, as CD4(+) T cells were undetectable. An additional important characteristic of p113-121-specific CD8(+) T cells was their capacity for in vivo killing of p113-121-labeled, HLA-A*0201(+) splenocytes. The cytotoxic function of p113-121/HLA-A*0201-specific CD8(+) T cells extended into direct killing of splenocytes infected with live Mycobacterium smegmatis expressing ML1419c: both 9mer and 30mer induced CD8(+) T cells that reduced the number of ML1419c-expressing mycobacteria by 95%, whereas no reduction occurred using wild-type M. smegmatis. These data, combined with previous observations in Brazilian cohorts, show that ML1419c p113-121 induces potent CD8(+) T cells that provide protective immunity against M. leprae and B cell help for induction of specific IgG, suggesting its potential use in diagnostics and as a subunit (vaccine) for M. leprae infection. PMID- 21705624 TI - Autoimmune disease risk variant of IFIH1 is associated with increased sensitivity to IFN-alpha and serologic autoimmunity in lupus patients. AB - Increased IFN-alpha signaling is a heritable risk factor for systemic lupus erythematosus (SLE). IFN induced with helicase C domain 1 (IFIH1) is a cytoplasmic dsRNA sensor that activates IFN-alpha pathway signaling. We studied the impact of the autoimmune-disease-associated IFIH1 rs1990760 (A946T) single nucleotide polymorphism upon IFN-alpha signaling in SLE patients in vivo. We studied 563 SLE patients (278 African-American, 179 European-American, and 106 Hispanic-American). Logistic regression models were used to detect genetic associations with autoantibody traits, and multiple linear regression was used to analyze IFN-alpha-induced gene expression in PBMCs in the context of serum IFN alpha in the same blood sample. We found that the rs1990760 T allele was associated with anti-dsDNA Abs across all of the studied ancestral backgrounds (meta-analysis odds ratio = 1.34, p = 0.026). This allele also was associated with lower serum IFN-alpha levels in subjects who had anti-dsDNA Abs (p = 0.0026). When we studied simultaneous serum and PBMC samples from SLE patients, we found that the IFIH1 rs1990760 T allele was associated with increased IFN induced gene expression in PBMCs in response to a given amount of serum IFN-alpha in anti-dsDNA-positive patients. This effect was independent of the STAT4 genotype, which modulates sensitivity to IFN-alpha in a similar way. Thus, the IFIH1 rs1990760 T allele was associated with dsDNA Abs, and in patients with anti dsDNA Abs this risk allele increased sensitivity to IFN-alpha signaling. These studies suggest a role for the IFIH1 risk allele in SLE in vivo. PMID- 21705625 TI - Antigen localization controls T cell-mediated tumor immunity. AB - Effective antitumor immunotherapy requires the identification of suitable target Ags. Interestingly, many of the tumor Ags used in clinical trials are present in preparations of secreted tumor vesicles (exosomes). In this study, we compared T cell responses elicited by murine MCA101 fibrosarcoma tumors expressing a model Ag at different localizations within the tumor cell in association with secreted vesicles (exosomes), as a nonsecreted cell-associated protein, or as secreted soluble protein. Remarkably, we demonstrated that only the tumor-secreting vesicle-bound Ag elicited a strong Ag-specific CD8(+) T cell response, CD4(+) T cell help, Ag-specific Abs, and a decrease in the percentage of immunosuppressive regulatory T cells in the tumor. Moreover, in a therapeutic tumor model of cryoablation, only in tumors secreting vesicle-bound Ag could Ag-specific CD8(+) T cells still be detected up to 16 d after therapy. We concluded that the localization of an Ag within the tumor codetermines whether a robust immunostimulatory response is elicited. In vivo, vesicle-bound Ag clearly skews toward a more immunogenic phenotype, whereas soluble or cell-associated Ag expression cannot prevent or even delay outgrowth and results in tumor tolerance. This may explain why particular immunotherapies based on these vesicle-bound tumor Ags are potentially successful. Therefore, we conclude that this study may have significant implications in the discovery of new tumor Ags suitable for immunotherapy and that their location should be taken into account to ensure a strong antitumor immune response. PMID- 21705626 TI - Stromal cell-derived factor-1 signaling via the CXCR4-TCR heterodimer requires phospholipase C-beta3 and phospholipase C-gamma1 for distinct cellular responses. AB - The CXCR4 chemokine receptor is a G protein-coupled receptor that signals in T lymphocytes by forming a heterodimer with the TCR. CXCR4 and TCR functions are consequently highly cross regulated, affecting T cell immune activation, cytokine secretion, and T cell migration. The CXCR4-TCR heterodimer stimulates T cell migration and activation of the ERK MAPK and downstream AP-1-dependent cytokine transcription in response to stromal cell-derived factor-1 (SDF-1), the sole chemokine ligand of CXCR4. These responses require Gi-type G proteins as well as TCR ITAM domains and the ZAP70 tyrosine kinase, thus indicating that the CXCR4 TCR heterodimer signals to integrate G protein-coupled receptor-associated and TCR-associated signaling molecules in response to SDF-1. Yet, the phospholipase C (PLC) isozymes responsible for coupling the CXCR4-TCR heterodimer to distinct downstream cellular responses are incompletely characterized. In this study, we demonstrate that PLC activity is required for SDF-1 to induce ERK activation, migration, and CXCR4 endocytosis in human T cells. SDF-1 signaling via the CXCR4 TCR heterodimer uses PLC-beta3 to activate the Ras-ERK pathway and increase intracellular calcium ion concentrations, whereas PLC-gamma1 is dispensable for these outcomes. In contrast, PLC-gamma1, but not PLC-beta3, is required for SDF-1 mediated migration via a mechanism independent of LAT. These results increase understanding of the signaling mechanisms employed by the CXCR4-TCR heterodimer, characterize new roles for PLC-beta3 and PLC-gamma1 in T cells, and suggest that multiple PLCs may also be activated downstream of other chemokine receptors to distinctly regulate migration versus other signaling functions. PMID- 21705628 TI - Is endothelial-independent vascular reactivity compromised in obese subjects with metabolic syndrome? PMID- 21705627 TI - Subclinical vascular disease burden and risk for death and cardiovascular events in older community dwellers. AB - BACKGROUND: Individual measures and previous composite measures of subclinical vascular disease defined high risk for cardiovascular events, but did not detect low and modest risk. A different approach might better describe the spectrum from low to high risk. Methods and Results. In the Cardiovascular Health Study, 3,252 participants without history of clinical cardiovascular disease (M +/- SD 74.3 years +/- 5.1, 63% women, 17% African Americans) had noninvasive vascular assessments in 1992-1993. We assigned a score of 0, 1, or 2 (no, mild, or severe abnormalities) to ankle-arm index, electrocardiogram, and common carotid intima media thickness, based on clinical cutoffs. A summary index (range 0-6, absent to severe disease) summed individual scores. Abdominal aortic ultrasound and brain magnetic resonance imaging were collected in a subsample. Mortality and incident cardiovascular events were identified through June 2008. Event and death rates increased across index grades. Comparing grades 1 to 5+ with absent disease, and adjusting for demographics, hazard ratios for cardiovascular events within 8 years ranged from 1.1 (95% confidence interval 0.8-1.6) to 4.7 (3.4-6.9) and, for mortality, from 1.5 (1.0-2.3) to 5.0 (3.3-7.7) (p for trend across grades <.001 for both outcomes). Adjustment for cardiovascular risk factors did not substantially change the associations. The index improved mortality risk classification over demographics and risk factors in participants who did not die during the follow-up. Including in the index the aortic ultrasound and the brain magnetic resonance imaging further improved risk classification. CONCLUSIONS: Older adults with minimal subclinical vascular disease had low cardiovascular events risk and mortality. This approach might more fully account for vascular burden. PMID- 21705630 TI - Intestinal growth and morphology is associated with the increase in heat shock protein 70 expression in weaning piglets through supplementation with glutamine. AB - The objectives of this study were to determine the effects of oral Gln supplementation on growth performance, intestinal morphology, and expression of heat shock protein (Hsp) 70 in weaning piglets. A total of 65 piglets after weaning at 21 d of age (d 0) were used in this experiment. Five piglets were randomly selected and euthanized initially at d 0 to determine baseline values for the expression of Hsp70 in the small intestine. The remaining piglets were randomly assigned to 1 of 2 treatments and received 0 or 1 g of oral Gln/kg of BW every 12 h. After piglets were humanely killed at d 3, 7, and 14 postweaning, the duodenum, jejunum, and ileum of piglets were sampled to evaluate intestinal morphology and the expression and localization of Hsp70. The results indicated that oral Gln supplementation increased plasma concentrations of Gln compared with those in control piglets (P < 0.05). Average daily gain and ADFI were greater in piglets orally supplemented with Gln than in control piglets during the whole period (P < 0.05). The incidence of diarrhea in piglets orally supplemented with Gln was 24% less than (P = 0.064) that in control piglets at 8 to 14 d after weaning. The weights of the jejunum and ileum were greater in piglets orally supplemented with Gln compared with those of control piglets relative to BW on d 14 postweaning (P < 0.05). The villus height and the villus height:crypt depth ratio in the jejunum and the ileum were greater in piglets receiving oral Gln on d 14 postweaning (P < 0.05) than in control piglets. These results indicate that Gln supplementation can influence the intestinal morphology of weaned piglets. The expression of hsp70 mRNA and Hsp70 proteins in the duodenum and jejunum was greater in piglets supplemented with Gln than in control piglets (P < 0.05). However, Gln supplementation had no effect on the expression of hsp70 mRNA and Hsp70 proteins in the ileum. Moreover, the localization of Hsp70 in the cytoplasm indicated that Hsp70 has a cytoprotective role in epithelial cell function and structure. These results indicate that Gln supplementation may be beneficial for intestinal health and development and may thus mitigate diarrhea and improve growth performance. The protective mechanisms of Gln in the intestine may be associated with the increase in Hsp70 expression. PMID- 21705631 TI - Analyzing the effect of different approaches of penalized relationship in multistage selection schemes. AB - The aim of this study was to extend optimum contribution selection to more realistic breeding schemes with multistage selection. It seems that if the last selection stage accounts for the relationship of the selected animals, then previous selection stages also account for this relationship. An extreme example was considered here: the preselection of dairy bulls that enter a progeny testing scheme. First the penalty on the average relationship in selection step 1 is assumed the same as in step 2. Thereafter, situations with different penalties on the average relationship in the 2 selection steps were analyzed. The simulation started with the generation of prior EBV, which were sampled from a truncated normal distribution. Possible candidates for further progeny testing were selected and progeny test EBV were simulated, where the progeny test was based on 100 daughters per young bull. In situations with greater accuracy of prior EBV, high trait heritability and prior EBV were available for 2,000 bulls; the results were similar for both approaches, independent of family size. However, in a situation with low accuracy of prior EBV and low trait heritability it could be observed that with increasing penalty on the average relationship, correction for relationship in stage 1 yielded in a similar genetic level compared with selecting only for high prior EBV. If the number of bulls with prior EBV increased from 2,000 to 4,000, an increasing penalty on an average relationship gave an improved genetic level. A further improvement of the results with respect to genetic level and average relationship could be observed by increasing the penalty on an average relationship in selection step 1 above that in selection step 2. Overall, this study showed that it is beneficial to use a penalty on an average relationship already for the selection of bulls that enter the progeny test. In case optimum contribution was applied with a constraint on the average relationship in stage 2, this constraint may be translated into a penalty on the average relationship, and the current results suggested that the optimal penalty in selection stage 1 should be twice that of stage 2. PMID- 21705632 TI - An increased feed intake during early pregnancy improves sow body weight recovery and increases litter size in young sows. AB - This study evaluated the effect of feeding level and protein content in feed in first- and second-parity sows during the first month of gestation on sow BW recovery, farrowing rate, and litter size during the first month of gestation. From d 3 to 32 after the first insemination, sows were fed either 2.5 kg/d of a standard gestation diet (control, n = 49), 3.25 kg/d (+30%) of a standard gestation diet (plus feed, n = 47), or 2.5 kg/d of a gestation diet with 30% greater ileal digestible AA (plus protein, n = 49). Feed intake during the experimental period was 29% greater for sows in the plus feed group compared with those in the control and plus protein groups (93 vs. 72 kg, P < 0.05). Sows in the plus feed group gained 10 kg more BW during the experimental period compared with those in the control and plus protein groups (24.2 +/- 1.2 vs. 15.5 +/- 1.2 and 16.9 +/- 1.2 kg, respectively, P < 0.001). Backfat gain and loin muscle depth gain were not affected by treatment (P = 0.56 and P = 0.37, respectively). Farrowing rate was smaller, although not significantly, for sows in the plus feed group compared with those in the control and plus protein groups (76.6% vs. 89.8 and 89.8%, respectively, P = 0.16). Litter size, however, was larger for sows in the plus feed group (15.2 +/- 0.5 total born) compared with those in the control and plus protein groups (13.2 +/- 0.4 and 13.6 +/- 0.4 total born, respectively, P = 0.006). Piglet birth weight was not different among treatments (P = 0.65). For both first- and second-parity sows, the plus feed treatment showed similar effects on BW gain, farrowing rate, and litter size. In conclusion, an increased feed intake (+30%) during the first month of gestation improved sow BW recovery and increased litter size, but did not significantly affect farrowing rate in the subsequent parity. Feeding a 30% greater level of ileal digestible AA during the same period did not improve sow recovery or reproductive performance in the subsequent parity. PMID- 21705633 TI - Toward an ideal animal model to trace donor cell fates after stem cell therapy: production of stably labeled multipotent mesenchymal stem cells from bone marrow of transgenic pigs harboring enhanced green fluorescence protein gene. AB - The discovery of postnatal mesenchymal stem cells (MSC) with their general multipotentiality has fueled much interest in the development of cell-based therapies. Proper identification of transplanted MSC is crucial for evaluating donor cell distribution, differentiation, and migration. Lack of an efficient marker of transplanted MSC has precluded our understanding of MSC-related regenerative studies, especially in large animal models such as pigs. In the present study, we produced transgenic pigs harboring an enhanced green fluorescent protein (EGFP) gene. The pigs provide a reliable and reproducible source for obtaining stable EGFP-labeled MSC, which is very useful for donor cell tracking after transplantation. The undifferentiated EGFP-tagged MSC expressed a greater quantity of EGFP while maintaining MSC multipotentiality. These cells exhibited homogeneous surface epitopes and possessed classic trilineage differentiation potential into osteogenic, adipogenic, and chondrogenic lineages, with robust EGFP expression maintained in all differentiated progeny. Injection of donor MSC can dramatically increase the thickness of infarcted myocardium and improve cardiac function in mice. Moreover, the MSC, with their strong EGFP expression, can be easily distinguished from the background autofluorescence in myocardial infarcts. We demonstrated an efficient, effective, and easy way to identify MSC after long-term culture and transplantation. With the transgenic model, we were able to obtain stem or progenitor cells in earlier passages compared with the transfection of traceable markers into established MSC. Because the integration site of the transgene was the same for all cells, we lessened the potential for positional effects and the heterogeneity of the stem cells. The EGFP-transgenic pigs may serve as useful biomedical and agricultural models of somatic stem cell biology. PMID- 21705634 TI - Perspectives for feed-efficient animal production. AB - Modern animal breeding programs are largely based on biotechnological procedures, including AI and embryo transfer technology. Recent breakthroughs in reproductive technologies, such as somatic cell nuclear transfer and in vitro embryo production, and their combination with the emerging molecular genetic tools, will further advance progress and provide new opportunities for livestock breeding. This is urgently needed in light of the global challenges such as the ever increasing human population, the limited resources of arable land, and the urgent environmental problems associated with farm animal production. Here, we focus on genomic breeding strategies and transgenic approaches for making farm animals more feed efficient. Based on studies in the mouse and rat model, we have identified a panel of genes that are critically involved in the regulation of feed uptake and that could contribute toward future breeding of farm animals with reduced environmental impact. We anticipate that genetically modified animals will play a significant role in shaping the future of feed-efficient and thus sustainable animal production, but will develop more slowly than the biomedical applications because of the complexity of the regulation of feed intake and metabolism. PMID- 21705635 TI - Genetic parameter estimates among scale activity score and farrowing disposition with reproductive traits in swine. AB - The primary objective of this study was to determine if certain behavior traits were genetically correlated with reproduction. If 1 or both of the behavior traits were found to be correlated, a secondary objective was to determine if the behavior traits could be useful in selecting for more productive females. A scale activity score taken at 5 mo of age and a farrowing disposition score taken at farrowing were selected as the behavioral traits. Scale activity score ranged from 1 to 5 and farrowing disposition ranged from 1 to 3. Reproductive traits included age at puberty, number born alive, number born dead, litter birth weight, average piglet birth weight, number weaned, litter weaning weight, average weaning weight, wean-to-estrus interval, ovulation rate including gilts, and postweaning ovulation rate. Genetic correlations between scale activity score and reproduction ranged from -0.79 to 0.61. Three of the correlations, number born alive (P < 0.01), average piglet birth weight (P < 0.001), and wean-to estrus interval (P = 0.014), were statistically significant but included both favorable and antagonistic correlations. In contrast, all but 1 of the farrowing disposition correlations was favorable and ranged from -0.66 to 0.67. Although only the correlation with litter birth weight was significant (P = 0.018), the consistent favorable direction of all farrowing disposition correlations, except average weaning weight, shows a potential for inclusion of farrowing disposition into a selection program. PMID- 21705636 TI - Effect of linseed oil and fish oil alone or as an equal mixture on ruminal fatty acid metabolism in growing steers fed maize silage-based diets. AB - Because of the potential benefits to human health, there is interest in increasing 18:3n-3, 20:5n-3, 22:6n-6, and cis-9,trans-11 CLA in ruminant foods. Four Aberdeen Angus steers (406 +/- 8.2 kg of BW) fitted with ruminal and duodenal cannulas were used in a 4 * 4 Latin square experiment with 21-d periods to examine the potential of fish oil (FO) and linseed oil (LO) in the diet to increase ruminal outflow of trans-11 18:1 and total n-3 PUFA in growing cattle. Treatments consisted of a control diet (60:40; forage:concentrate ratio, on a DM basis, respectively) based on maize silage, or the same basal ration containing 30 g/kg of DM of FO, LO, or a mixture (1:1, wt/wt) of FO and LO (LFO). Diets were offered as total mixed rations and fed at a rate of 85 g of DM/(kg of BW(0.75)/d). Oils had no effect (P = 0.52) on DMI. Linseed oil had no effect (P > 0.05) on ruminal pH or VFA concentrations, whereas FO shifted rumen fermentation toward propionate at the expense of acetate. Compared with the control, LO increased (P < 0.05) 18:0, cis 18:1 (Delta9, 12-15), trans 18:1 (Delta4-9, 11 16), trans 18:2, geometric isomers of 9,11, 11,13, and 13,15 CLA, trans-8,cis-10 CLA, trans-10,trans-12 CLA, trans-12,trans-14 CLA, and 18:3n-3 flow at the duodenum. Inclusion of FO in the diet resulted in greater (P < 0.05) flows of cis 9 16:1, trans 16:1 (Delta6-13), cis 18:1 (Delta9, 11, and 13), trans 18:1 (Delta6 15), trans 18:2, 20:5n-3, 22:5n-3, and 22:6n-3, and decreased (P < 0.001) 18:0 at the duodenum relative to the control. For most fatty acids at the duodenum, responses to LFO were intermediate of FO and LO. However, LFO resulted in greater (P = 0.04) flows of total trans 18:1 than LO and increased (P < 0.01) trans-6 16:1 and trans-12 18:1 at the duodenum compared with FO or LO. Biohydrogenation of cis-9 18:1 and 18:2n-6 in the rumen was independent of treatment, but both FO and LO increased (P < 0.001) the extent of 18:3n-3 biohydrogenation compared with the control. Ruminal 18:3n-3 biohydrogenation was greater (P < 0.001) for LO and LFO than FO, whereas biohydrogenation of 20:5n-3 and 22:6n-3 in the rumen was marginally less (P = 0.05) for LFO than FO. In conclusion, LO and FO at 30 g/kg of DM altered the biohydrogenation of unsaturated fatty acids in the rumen, causing an increase in the flow of specific intermediates at the duodenum, but the potential of these oils fed alone or as a mixture to increase n-3 PUFA at the duodenum in cattle appears limited. PMID- 21705637 TI - Vitamin E and polyunsaturated fatty acids in bovine muscle and the oxidative stability of beef from cattle receiving grass or concentrate-based rations. AB - The present study was designed to assess the balance between antioxidant and prooxidant components and the oxidative stability of beef from cattle fed exclusively grazed pasture (PAS) or a barley-based concentrate offered indoors (CONC) for 11 mo, or fed grass silage indoors for a 5-mo winter period, followed for the remaining 6-mo summer period by grazed pasture (SiP) or by grazed pasture plus concentrate at 50% of the dietary DM (SiPC). Muscle prooxidant and antioxidant components were determined by measuring fatty acids and alpha tocopherol concentration of LM, respectively. Lipid oxidation and color stability were monitored in ground LM, packaged in a high-oxygen modified atmosphere, over 11 d of refrigerated storage. Vitamin E concentration decreased (P < 0.0005) with an increasing proportion of concentrate in the diet (2.59, 2.45, 1.76, and 1.15 MUg/g for PAS, SiP, SiPC, and CONC, respectively). A greater proportion of PUFA was found in LM from cattle in the PAS, SiP, and SiPC groups compared with animals in the CONC group (9.62, 11.04, 8.96, and 6.94%, respectively; P < 0.0005). A greater concentration of highly peroxidizable PUFA was found in LM from heifers in the PAS, SiP, and SiPC groups compared with those in the CONC group (0.84, 0.85, 0.87, and 0.65 mg/g of muscle, respectively; P = 0.02). Dietary treatment affected lipid oxidation (P < 0.0005), with greater 2 thiobarbituric acid reactive substance values in beef from heifers in the SiPC group than in beef from those in the PAS, SiP, and CONC groups. Dietary treatment affected myoglobin oxidation (P = 0.002) during storage, with greater metmyoglobin accumulation in beef from animals receiving concentrate (CONC and SiPC treatments) than in beef from cattle in the PAS and SiP groups. Consequently, feeding concentrate impaired meat color stability over the storage duration, with greater H* (hue angle) values (P < 0.0005) in meat from heifers in the SiPC and CONC groups compared with meat from those in the PAS and SiP groups. The results of the present study confirm a positive effect of grass-based feeding systems on meat color stability compared with concentrate-based dietary strategies. It appears that vitamin E in muscle alone does not explain the resistance of meat to oxidative deterioration because a clear interaction with highly peroxidizable PUFA exists. PMID- 21705638 TI - Effect of grazing and dietary protein on eating quality of Podolian beef. AB - Twenty-four young Podolian bulls were used to evaluate the effect of rearing system (extensive vs. intensive) in relation to postmortem aging (11 and 18 d) on the eating quality of the meat, with the diet of outdoor animals adjusted to the protein content of the indoor system (15% CP) or to the minimum protein content required for satisfactory growth (12% CP). At 415 +/- 9.35 (SE) d of age, with a mean BW of 337.5 +/- 16.51 (SE) kg, animals were allotted to 3 groups for the finishing period (172 d): 1) indoor group receiving a diet at 15% CP; 2) grazing animals receiving a diet at 15% CP of DM; and 3) grazing animals receiving a diet at 12% CP of DM. Longissimus dorsi lumborum muscle sampled from the right half and divided longitudinally into 2 sections was aged in vacuum packaging at 4 degrees C until 11 and 18 d postmortem, respectively. Rearing system did not affect (P > 0.05) color, Warner-Bratzler shear force, texture profile, water holding capacity, and most of the sensory attributes of the beef steaks. However, sensory tenderness was less in the meat from outdoor animals receiving a diet with 15% CP than in meat from outdoor animals receiving a diet with 12% CP or from the indoor group (P < 0.05). Meat aged 18 d showed decreased Warner-Bratzler shear force (P < 0.001), hardness (P < 0.001), cohesiveness (P < 0.05), springiness (P < 0.05), gumminess (P < 0.01), chewiness (P < 0.01), and thawing loss (P < 0.01) compared with meat aged for 11 d. Prolonging the aging time up to 18 d significantly increased b* (yellowness; P < 0.05), cooking losses (P < 0.001), and the intensity of all the texture sensory attributes, namely, juiciness and fatness (P < 0.05), chewiness, tenderness, and flavor (P < 0.01). Significant correlations were found between instrumental and sensory variables (range of r = -0.55 to -0.85, P < 0.05 to 0.001). Overall, in the present study, the rearing system did not markedly affect meat sensory and physical properties. Thus, we conclude that an outdoor system, even with reduced protein supplementation, may represent a valid farming system for local breeds in Mediterranean areas characterized by poor-quality pastures. However, an extended aging period is suggested to improve the main factor limiting the quality of this product, namely, reduced tenderness. PMID- 21705639 TI - Development and application of a crossbreeding simulation model for goat production systems in tropical regions. AB - A deterministic simulation model was developed to estimate biological production efficiency and to evaluate goat crossbreeding systems under tropical conditions. The model involves 5 production systems: pure indigenous, first filial generations (F1), backcross (BC), composite breeds of F1 (CMP(F1)), and BC (CMP(BC)). The model first simulates growth, reproduction, lactation, and energy intakes of a doe and a kid on a 1-d time step at the individual level and thereafter the outputs are integrated into the herd dynamics program. The ability of the model to simulate individual performances was tested under a base situation. The simulation results represented daily BW changes, ME requirements, and milk yield and the estimates were within the range of published data. Two conventional goat production scenarios (an intensive milk production scenario and an integrated goat and oil palm production scenario) in Malaysia were examined. The simulation results of the intensive milk production scenario showed the greater production efficiency of the CMP(BC) and CMP(F1) systems and decreased production efficiency of the F1 and BC systems. The results of the integrated goat and oil palm production scenario showed that the production efficiency and stocking rate were greater for the indigenous goats than for the crossbreeding systems. PMID- 21705640 TI - The COP1 ortholog PPS regulates the juvenile-adult and vegetative-reproductive phase changes in rice. AB - Because plant reproductive development occurs only in adult plants, the juvenile to-adult phase change is an indispensable part of the plant life cycle. We identified two allelic mutants, peter pan syndrome-1 (pps-1) and pps-2, that prolong the juvenile phase in rice (Oryza sativa) and showed that rice PPS is an ortholog of Arabidopsis thaliana CONSTITUTIVE PHOTOMORPHOGENIC1. The pps-1 mutant exhibits delayed expression of miR156 and miR172 and the suppression of GA biosynthetic genes, reducing the GA(3) content in this mutant. In spite of its prolonged juvenile phase, the pps-1 mutant flowers early, and this is associated with derepression of RAP1B expression in pps-1 plants independently of the Hd1 Hd3a/RFT1 photoperiodic pathway. PPS is strongly expressed in the fourth and fifth leaves, suggesting that it regulates the onset of the adult phase downstream of MORI1 and upstream of miR156 and miR172. Its ability to regulate the vegetative phase change and the time of flowering suggests that rice PPS acquired novel functions during the evolution of rice/monocots. PMID- 21705641 TI - How to make a C4 plant: insight from comparative transcriptome analysis. PMID- 21705642 TI - Defective pollen wall is required for anther and microspore development in rice and encodes a fatty acyl carrier protein reductase. AB - Aliphatic alcohols naturally exist in many organisms as important cellular components; however, their roles in extracellular polymer biosynthesis are poorly defined. We report here the isolation and characterization of a rice (Oryza sativa) male-sterile mutant, defective pollen wall (dpw), which displays defective anther development and degenerated pollen grains with an irregular exine. Chemical analysis revealed that dpw anthers had a dramatic reduction in cutin monomers and an altered composition of cuticular wax, as well as soluble fatty acids and alcohols. Using map-based cloning, we identified the DPW gene, which is expressed in both tapetal cells and microspores during anther development. Biochemical analysis of the recombinant DPW enzyme shows that it is a novel fatty acid reductase that produces 1-hexadecanol and exhibits >270-fold higher specificity for palmiltoyl-acyl carrier protein than for C16:0 CoA substrates. DPW was predominantly targeted to plastids mediated by its N-terminal transit peptide. Moreover, we demonstrate that the monocot DPW from rice complements the dicot Arabidopsis thaliana male sterile2 (ms2) mutant and is the probable ortholog of MS2. These data suggest that DPWs participate in a conserved step in primary fatty alcohol synthesis for anther cuticle and pollen sporopollenin biosynthesis in monocots and dicots. PMID- 21705643 TI - Transcription factor-dependent chromatin remodeling at heat shock and copper responsive promoters in Chlamydomonas reinhardtii. AB - How transcription factors affect chromatin structure to regulate gene expression in response to changes in environmental conditions is poorly understood in the green lineage. To shed light on this issue, we used chromatin immunoprecipitation and formaldehyde-assisted isolation of regulatory elements to investigate the chromatin structure at target genes of HSF1 and CRR1, key transcriptional regulators of the heat shock and copper starvation responses, respectively, in the unicellular green alga Chlamydomonas reinhardtii. Generally, we detected lower nucleosome occupancy, higher levels of histone H3/4 acetylation, and lower levels of histone H3 Lys 4 (H3K4) monomethylation at promoter regions of active genes compared with inactive promoters and transcribed and intergenic regions. Specifically, we find that activated HSF1 and CRR1 transcription factors mediate the acetylation of histones H3/4, nucleosome eviction, remodeling of the H3K4 mono- and dimethylation marks, and transcription initiation/elongation. By this, HSF1 and CRR1 quite individually remodel and activate target promoters that may be inactive and embedded into closed chromatin (HSP22F/CYC6) or weakly active and embedded into partially opened (CPX1) or completely opened chromatin (HSP70A/CRD1). We also observed HSF1-independent histone H3/4 deacetylation at the RBCS2 promoter after heat shock, suggesting interplay of specific and presumably more generally acting factors to adapt gene expression to the new requirements of a changing environment. PMID- 21705644 TI - Evolution of C4 photosynthesis in the genus Flaveria: how many and which genes does it take to make C4? AB - Selective pressure exerted by a massive decline in atmospheric CO(2) levels 55 to 40 million years ago promoted the evolution of a novel, highly efficient mode of photosynthetic carbon assimilation known as C(4) photosynthesis. C(4) species have concurrently evolved multiple times in a broad range of plant families, and this multiple and parallel evolution of the complex C(4) trait indicates a common underlying evolutionary mechanism that might be elucidated by comparative analyses of related C(3) and C(4) species. Here, we use mRNA-Seq analysis of five species within the genus Flaveria, ranging from C(3) to C(3)-C(4) intermediate to C(4) species, to quantify the differences in the transcriptomes of closely related plant species with varying degrees of C(4)-associated characteristics. Single gene analysis defines the C(4) cycle enzymes and transporters more precisely and provides new candidates for yet unknown functions as well as identifies C(4) associated pathways. Molecular evidence for a photorespiratory CO(2) pump prior to the establishment of the C(4) cycle-based CO(2) pump is provided. Cluster analysis defines the upper limit of C(4)-related gene expression changes in mature leaves of Flaveria as 3582 alterations. PMID- 21705645 TI - Generation of mature murine monocytes from heterogeneous bone marrow and description of their properties. AB - Monocytes are involved in a wide range of physiological and pathological processes, many of which are studied in mouse models. Current protocols to isolate murine monocytes are few and result in unsatisfactory cell yield and purity. Here, we describe a novel approach to efficiently differentiate large numbers of mature inflammatory monocytes from heterogeneous bone marrow cell suspensions. Bone marrow cell suspensions were isolated by flushing femurs and tibias from Balb/c and C57Bl/6 mice, supplemented with macrophage colony stimulating factor (M-CSF), and were cultured on ultra-low attachment surfaces to inhibit adherence-mediated maturation. Cells were harvested at indicated time points, underwent time-line analysis of the differentiation processes, and were subsequently extensively phenotyped to verify their monocytotic properties. In order to confirm downstream compatibility, we tested for typical monocyte behavior. Our protocol yielded 24 +/- 6 * 10(6) differentiated cells per donor mouse, 10-fold higher than yields obtained using previously described peripheral blood isolation methods. Differentiated cells consisted of approximately 47% +/- 12% monocytes, the rest being mature macrophages. We increased monocyte purity to 86% +/- 6% by depleting adherent macrophages. Our findings indicate that bone marrow-derived monocytes (BMDMs) are an attractive tool to study, for example, the innate and adaptive immune system, atherosclerosis, and cellular migration during infection. Moreover, BMDM transplantation could be used to test novel, therapeutic in vivo approaches in mice disease models. PMID- 21705646 TI - Chronic low-frequency stimulation transforms cat masticatory muscle fibers into jaw-slow fibers. AB - Cat masticatory muscle during regeneration expresses masticatory-specific myofibrillar proteins upon innervation by a fast muscle nerve but acquires the jaw-slow phenotype when innervated by a slow muscle nerve. Here, we test the hypothesis that chronic low-frequency stimulation simulating impulses from the slow nerve can result in masticatory-to-slow fiber-type transformation. In six cats, the temporalis muscle was continuously stimulated directly at 10 Hz for up to 12 weeks using a stimulator affixed to the skull. Stimulated muscles were analyzed by immunohistochemistry using, among others, monoclonal antibodies against masticatory-specific myosin heavy chain (MyHC), myosin binding protein-C, and tropomyosins. Under the electrodes, stimulation induced muscle regeneration, which generated slow fibers. Deep to the electrodes, at two to three weeks, two distinct populations of masticatory fibers began to express slow MyHC: 1) evenly distributed fibers that completely suppressed masticatory-specific proteins but transiently co-expressed fetal MyHCs, and 2) incompletely transformed fibers that express slow and masticatory but not fetal MyHCs. SDS-PAGE confirmed de novo expression of slow MyHC and beta-tropomyosin in the stimulated muscles. We conclude that chronic low-frequency stimulation induces masticatory-to-slow fiber type conversion. The two populations of transforming masticatory fibers may differ in their mode of activation or lineage of their myogenic cells. PMID- 21705648 TI - Arthroscopic management of chronic patellar tendinopathy. AB - BACKGROUND: In patients with patellar tendinopathy in whom nonoperative management is unsuccessful, surgery is an option to return to high levels of physical activity. Although open surgery is traditionally advocated, an arthroscopic approach may be safe and effective. PURPOSE: This study was undertaken to analyze medium- and long-term outcome of 64 patients undergoing arthroscopic surgery for the management of patellar tendinopathy after failing nonoperative treatment. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 64 patients (73 knees), 27 of whom were professional athletes, with patellar tendinopathy refractory to nonoperative management underwent arthroscopic debridement of the adipose tissue of the Hoffa's body posterior to the patellar tendon, debridement of abnormal patellar tendon, and excision of the lower pole of the patella. Preoperative and postoperative evaluation was undertaken using the International Knee Documentation Committee (IKDC), Lysholm knee scale, and Victorian Institute of Sport Assessment-Patella (VISA-P) scores for all patients at 1 and 3 years. No patients were lost to follow-up. Forty three and 29 patients were similarly assessed at 5 and 10 years, respectively, after surgery. Return to sports and rehabilitation was also assessed. RESULTS: The IKDC, Lysholm, and VISA-P scores all significantly improved at 1 and 3 years' follow-up. The average preoperative IKDC score of 51.6 improved to 86.4 at both the 1- and 3-year stage. The average preoperative Lysholm score of 52.3 improved to 94.7 at 1-year follow-up and was 95.5 at 3-year follow-up. The average preoperative VISA-P score of 35.3 improved to 69.8 at the 1-year stage and was 70.7 at the 3-year follow-up. These scores remained significantly better for the patients assessed at 5 and 10 years' follow-up. There were no postoperative complications. Nineteen of the 27 professional athletes returned to sports at the same level. Seven patients developed pain after sports within 3 years after the operation, a failure rate of 7 of 73 knees (9.6%). All patients were able to return to sports by 3 months. CONCLUSION: Arthroscopic surgery for patients with patellar tendinopathy, refractory to nonoperative management, appears to provide significant improvements in symptoms and function, with improvements maintained for at least 3 years. These results suggest that some patients may not be able to achieve their presymptom sporting level; or if they do, they may participate in sports with some degree of residual symptoms. Limited data show that these improvements are maintained for up to 10 years. Early return to sports may also be achieved. PMID- 21705647 TI - Expression of focal adhesion proteins in the developing rat kidney. AB - Focal adhesions play a critical role as centers that transduce signals by cell matrix interactions and regulate fundamental processes such as proliferation, migration, and differentiation. Focal adhesion kinase (FAK), paxillin, integrin linked kinase (ILK), and hydrogen peroxide-inducible clone-5 (Hic-5) are major proteins that contribute to these events. In this study, we investigated the expression of focal adhesion proteins in the developing rat kidney. Western blotting analysis revealed that the protein levels of FAK, p-FAK(397), paxillin, p-paxillin(118), and Hic-5 were high in embryonic kidneys, while ILK expression persisted from the embryonic to the mature stage. Immunohistochemistry revealed that FAK, p-FAK(397), paxillin, and p-paxillin(118) were strongly expressed in condensed mesenchymal cells and the ureteric bud. They were detected in elongating tubules and immature glomerular cells in the nephrogenic zone. Hic-5 was predominantly expressed in mesenchymal cells as well as immature glomerular endothelial and mesangial cells, suggesting that Hic-5 might be involved in mesenchymal cell development. ILK expression was similar to that of FAK in the developmental stages. Interestingly, ILK was strongly expressed in podocytes in mature glomeruli. ILK might play a role in epithelial cell differentiation as well as kidney growth and morphogenesis. In conclusion, the temporospatially regulated expression of focal adhesion proteins during kidney development might play a role in morphogenesis and cell differentiation. PMID- 21705649 TI - Are meniscus and cartilage injuries related to time to anterior cruciate ligament reconstruction? AB - BACKGROUND: Functional instability after anterior cruciate ligament injury can be successfully treated with ligament reconstruction. However, the associated meniscus and cartilage lesions often cannot be repaired and may have long-term detrimental effects on knee function. PURPOSE: The authors used the large database within the Kaiser Permanente Anterior Cruciate Ligament Reconstruction Registry to evaluate time to surgery, age, and gender as risk factors for meniscus and cartilage injury and associations with meniscus repair rates in patients. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A retrospective review of the Kaiser Permanente Anterior Cruciate Ligament Reconstruction Registry was performed. The associations between time to surgery, age, and gender with meniscus and cartilage lesions and meniscus repair were analyzed using binary logistic regression modeling to calculate odds ratios (ORs) while adjusting for potential confounding variables. RESULTS: A total of 1252 patients met the inclusion criteria. The risk of medial meniscus injury increased only with time to surgery (6-12 months: OR = 1.81, 95% confidence internal [CI] 1.29-2.54, P = .001; and >12 months: OR = 2.19, 95% CI 1.58-3.02, P < .001). The risk of lateral meniscus injury decreased only with female gender (OR = 0.65, 95% CI 0.51-0.83, P = .001). The risk of cartilage injury increased with age (OR = 1.05 per year, 95% CI 1.04-1.07, P < .001) and time to surgery >12 months (OR = 1.57, 95% CI 1.12-2.20, P = .009), but decreased with female gender (OR = 0.71, 95% CI 0.54-0.92, P = .009). Medial meniscus repairs relative to medial meniscus injury decreased with increasing time to surgery (3-6 months: OR = 0.61, 95% CI 0.37-1.00, P = .050; and >12 months: OR = 0.41, 95% CI 0.25-0.67, P < .001) and increasing age (OR = 0.96 per year, 95% CI 0.94-0.98, P < .001). CONCLUSION: Increased risk of medial meniscus injury and decreased repair rate were strongly associated with increasing time to surgery. Increased risk of cartilage injury was associated with increasing age, increasing time to surgery, and male gender. PMID- 21705650 TI - Chronic tears of the reflected head of the rectus femoris: results of operative treatment. AB - BACKGROUND: While the majority of quadriceps muscle strains can be managed nonoperatively, rare cases remain symptomatic despite nonoperative treatment. PURPOSE: The purpose of this study is to report on results of surgical treatment of a limited number of cases of persistently symptomatic tears of the reflected head of the rectus femoris. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The records of 5 patients with chronic tears of the rectus femoris treated with excision of the reflected head were reviewed. A telephone interview regarding return to sport and current limitations was completed if patients were available for further follow-up. RESULTS: A review of 5 cases of surgical treatment of chronic tears of the reflected head of the rectus was completed. Patients included 1 woman and 4 men with an average age of 21 years (range, 18-24 years). Three patients played football (2 kickers) and 2 played soccer at a collegiate level. All 5 reported a significant decrease in pain during sport and activities of daily living and were able to return to collegiate athletics. Two patients had a late recurrence of pain with kicking that resolved with nonoperative treatment, 1 had residual thigh pain with intense play, 1 had no pain but noted decreased kicking accuracy, and 1 patient returned to play without symptoms. CONCLUSION: Strain injuries to the reflected head of the rectus femoris can benefit from delayed excision in rare cases that fail nonoperative management. High-level kicking athletes are likely to experience significant reduction in pain, but may have some residual or recurrent symptoms that limit competitive level of play postoperatively. PMID- 21705651 TI - Absence of Nkx2-3 homeodomain transcription factor induces the formation of LYVE 1-positive endothelial cysts without lymphatic commitment in the spleen. AB - In contrast to peripheral lymph nodes possessing lymphatic and blood vasculature, the spleen in both humans and rodents is largely devoid of functioning lymphatic capillaries. Here it is reported that in mice lacking homeodomain transcription factor Nkx2-3, the spleen contains an extensive network of lymphocyte-filled sacs lined by cells expressing LYVE-1 antigen, a marker associated with lymphatic endothelium cells (LECs). Real-time quantitative PCR analyses of Nkx2-3 mutant spleen revealed a substantial increase of LYVE-1 and podoplanin mRNA levels, without the parallel increase of mRNA for VEGFR-3 (vascular endothelial growth factor receptor Type 3) and Prox1 (Prospero homeobobox protein 1), two markers specific for LECs. Although these structures express VEGFR-2/flk-1, they lack Prox1 protein, indicating their non-LEC endothelial origin. The LYVE-1(+) structures are bordered with ER-TR7(+) fibroblastic reticular cells with small clusters of macrophages expressing MARCO and sialoadhesin. Short-term cell tracing studies using labeled lymphocytes indicate that these LYVE-1(+) cysts are largely excluded from the systemic circulation. Cells expressing LYVE-1 glycoprotein as putative precursors for such structures are detectable in the spleen of late-stage embryos, and the formation of LYVE-1(+) structures is independent from the activity of lymphotoxin beta-receptor. Thus the splenic vascular defects in Nkx2-3 deficiency include the generation of LYVE-1(+) cysts, comprised of endothelial cells without being committed along the LEC lineage. PMID- 21705652 TI - A critical threshold of rehabilitation involving brain-derived neurotrophic factor is required for poststroke recovery. AB - BACKGROUND: Enriched rehabilitation (ER; environmental enrichment plus skilled reaching) improves recovery after middle cerebral artery occlusion (MCAo) in rats. Fundamental issues such as whether ER is effective in other models, optimal rehabilitation intensity, and underlying recovery mechanisms have not been fully assessed. OBJECTIVE: The authors tested whether the efficacy of ER varies with ischemia model and assessed the importance of rehabilitation intensity and brain derived neurotrophic factor (BDNF) in recovery. METHODS: Rats in experiment 1 received 8 weeks of ER or remained in standard housing. Functional outcome was assessed with the staircase and cylinder tasks. Surprisingly, ER provided no functional benefit in any model. In this experiment, ER was delivered during the light phase, whereas other studies delivered ER in the dark phase of the light cycle. It was hypothesized that in the light, rats engaged in less rehabilitation or alternatively that BDNF was lower. Experiment 2 tested these hypotheses. Following MCAo, rats received ER in either the light or dark phase of the light cycle. Functional outcome was assessed and BDNF levels were measured in the motor cortex and hippocampus. RESULTS: Recovery was accompanied by increased BDNF. This occurred only in rats that received ER in the dark and these animals reached more than those in the light condition. CONCLUSIONS: Data suggest that there is a critical threshold of rehabilitation, below which recovery will not occur, and that BDNF mediates functional recovery. The use of intensive rehabilitation therapies for stroke patients is strongly supported. PMID- 21705653 TI - CESA5 is required for the synthesis of cellulose with a role in structuring the adherent mucilage of Arabidopsis seeds. AB - Imbibed Arabidopsis (Arabidopsis thaliana) seeds are encapsulated by mucilage that is formed of hydrated polysaccharides released from seed coat epidermal cells. The mucilage is structured with water-soluble and adherent layers, with cellulose present uniquely in an inner domain of the latter. Using a reverse genetic approach to identify the cellulose synthases (CESAs) that produce mucilage cellulose, cesa5 mutants were shown to be required for the correct formation of these layers. Expression of CESA5 in the seed coat was specific to epidermal cells and coincided with the accumulation of mucilage polysaccharides in their apoplast. Analysis of sugar composition showed that although total sugar composition or amounts were unchanged, their partition between layers was different in the mutant, with redistribution from adherent to water-soluble mucilage. The macromolecular characteristics of the water-soluble mucilage were also modified. In accordance with a role for CESA5 in mucilage cellulose synthesis, crystalline cellulose contents were reduced in mutant seeds and birefringent microfibrils were absent from adherent mucilage. Although the mucilage-modified5 mutant showed similar defects to cesa5 in the distribution of sugar components between water-soluble and adherent mucilage, labeling of residual adherent mucilage indicated that cesa5 contained less cellulose and less pectin methyl esterification. Together, the results demonstrate that CESA5 plays a major and essential role in cellulose production in seed mucilage, which is critical for the establishment of mucilage structured in layers and domains. PMID- 21705654 TI - B73-Mo17 near-isogenic lines demonstrate dispersed structural variation in maize. AB - Recombinant inbred lines developed from the maize (Zea mays ssp. mays) inbreds B73 and Mo17 have been widely used to discover quantitative trait loci controlling a wide variety of phenotypic traits and as a resource to produce high resolution genetic maps. These two parents were used to produce a set of near isogenic lines (NILs) with small regions of introgression into both backgrounds. A novel array-based genotyping platform was used to score genotypes of over 7,000 loci in 100 NILs with B73 as the recurrent parent and 50 NILs with Mo17 as the recurrent parent. This population contains introgressions that cover the majority of the maize genome. The set of NILs displayed an excess of residual heterozygosity relative to the amount expected based on their pedigrees, and this excess residual heterozygosity is enriched in the low-recombination regions near the centromeres. The genotyping platform provided the ability to survey copy number variants that exist in more copies in Mo17 than in B73. The majority of these Mo17-specific duplications are located in unlinked positions throughout the genome. The utility of this population for the discovery and validation of quantitative trait loci was assessed through analysis of plant height variation. PMID- 21705655 TI - Structure and expression profile of the phosphate Pht1 transporter gene family in mycorrhizal Populus trichocarpa. AB - Gene networks involved in inorganic phosphate (Pi) acquisition and homeostasis in woody perennial species able to form mycorrhizal symbioses are poorly known. Here, we describe the features of the 12 genes coding for Pi transporters of the Pht1 family in poplar (Populus trichocarpa). Individual Pht1 transporters play distinct roles in acquiring and translocating Pi in different tissues of mycorrhizal and nonmycorrhizal poplar during different growth conditions and developmental stages. Pi starvation triggered the up-regulation of most members of the Pht1 family, especially PtPT9 and PtPT11. PtPT9 and PtPT12 showed a striking up-regulation in ectomycorrhizas and endomycorrhizas, whereas PtPT1 and PtPT11 were strongly down-regulated. PtPT10 transcripts were highly abundant in arbuscular mycorrhiza (AM) roots only. PtPT8 and PtPT10 are phylogenetically associated to the AM-inducible Pht1 subfamily I. The analysis of promoter sequences revealed conserved motifs similar to other AM-inducible orthologs in PtPT10 only. To gain more insight into gene regulatory mechanisms governing the AM symbiosis in woody plant species, the activation of the poplar PtPT10 promoter was investigated and detected in AM of potato (Solanum tuberosum) roots. These results indicated that the regulation of AM-inducible Pi transporter genes is conserved between perennial woody and herbaceous plant species. Moreover, poplar has developed an alternative Pi uptake pathway distinct from AM plants, allowing ectomycorrhizal poplar to recruit PtPT9 and PtPT12 to cope with limiting Pi concentrations in forest soils. PMID- 21705656 TI - The function of mammalian Polo-like kinase 1 in microtubule nucleation. PMID- 21705657 TI - Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and beta-cell apoptosis. AB - Type 1 diabetes (T1D) is a complex disease characterized by the loss of insulin secreting beta-cells. Although the disease has a strong genetic component, and several loci are known to increase T1D susceptibility risk, only few causal genes have currently been identified. To identify disease-causing genes in T1D, we performed an in silico "phenome-interactome analysis" on a genome-wide linkage scan dataset. This method prioritizes candidates according to their physical interactions at the protein level with other proteins involved in diabetes. A total of 11 genes were predicted to be likely disease genes in T1D, including the INS gene. An unexpected top-scoring candidate gene was huntingtin-interacting protein (HIP)-14/ZDHHC17. Immunohistochemical analysis of pancreatic sections demonstrated that HIP14 is almost exclusively expressed in insulin-positive cells in islets of Langerhans. RNAi knockdown experiments established that HIP14 is an antiapoptotic protein required for beta-cell survival and glucose-stimulated insulin secretion. Proinflammatory cytokines (IL-1beta and IFN-gamma) that mediate beta-cell dysfunction in T1D down-regulated HIP14 expression in insulin secreting INS-1 cells and in isolated rat and human islets. Overexpression of HIP14 was associated with a decrease in IL-1beta-induced NF-kappaB activity and protection against IL-1beta-mediated apoptosis. Our study demonstrates that the current network biology approach is a valid method to identify genes of importance for T1D and may therefore embody the basis for more rational and targeted therapeutic approaches. PMID- 21705658 TI - Mechanism of von Willebrand factor scissile bond cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). AB - The platelet-tethering function of von Willebrand factor (VWF) is proteolytically regulated by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which cleaves the Tyr1605-Met1606 (P1-P1') bond in the VWF A2 domain. To date, most of the functional interactions between ADAMTS13 and VWF that have been characterized involve VWF residues that are C terminal to the scissile bond. We now demonstrate that the substrate P3 position in VWF, Leu1603, is a critical determinant of VWF proteolysis. When VWF Leu1603 was substituted with Ser, Ala, Asn, or Lys in a short VWF substrate, VWF115, proteolysis was either greatly reduced or ablated (up to 400-fold reduction in k(cat)/K(m)). As Leu1603 must interact with residues proximate to the Zn(2+) ion coordinated in the active center of ADAMTS13, we sought the corresponding S3 interacting residues. Substitution of 10 candidate residues in the metalloprotease domain of ADAMTS13 identified two spatially separated clusters centered on Leu198 or Val195 (acting with Leu232 and Leu274, or with Leu151, respectively), as possible subsites interacting with VWF. These experimental findings using the short VWF115 substrate were replicated using full-length VWF. It is hypothesized that VWF Leu1603 interacts with ADAMTS13 Leu198/Leu232/Leu274 and that Val195/Leu151 may form part of a S1 subsite. The recognition of VWF Leu1603 by ADAMTS13, in conjunction with previously reported remote exosites C terminal of the cleavage site, suggests a mechanism whereby the VWF P1-P1' scissile bond is brought into position over the active site for cleavage. Together with recently characterized remote exosite interactions, these findings provide a general framework for understanding the ADAMTS family substrate interactions. PMID- 21705659 TI - In vitro system capable of differentiating fast Ca2+-triggered content mixing from lipid exchange for mechanistic studies of neurotransmitter release. AB - Understanding the molecular principles of synaptic vesicle fusion is a long sought goal. It requires the development of a synthetic system that allows manipulations and observations not possible in vivo. Here, we report an in vitro system with reconstituted synaptic proteins that meets the long-sought goal to produce fast content release in the millisecond time regime upon Ca(2+) triggering. Our system simultaneously monitors both content and lipid exchange, and it starts from stable interacting pairs of donor and acceptor vesicles, mimicking the readily releasable pool of synaptic vesicles prior to an action potential. It differentiates between single-vesicle interaction, hemifusion, and complete fusion, the latter mimicking quantized neurotransmitter release upon exocytosis of synaptic vesicles. Prior to Ca(2+) injection, the system is in a state in which spontaneous fusion events between donor and acceptor vesicles are rare. Upon Ca(2+) injection, a rapid burst of complete fusion events emerges, followed by a biphasic decay. The present study focuses on neuronal SNAREs, the Ca(2+) sensor synaptotagmin 1, and the modulator complexin. However, other synaptic proteins could be added and their function examined. Ca(2+) triggering is cooperative, requiring the presence of synaptotagmin, whereas SNAREs alone do not produce a fast fusion burst. Manipulations of the system mimic effects observed in vivo. These results also show that neuronal SNAREs alone do not efficiently produce complete fusion, that the combination of SNAREs with synaptotagmin lowers the activation barriers to full fusion, and that complexin enhances this kinetic control. PMID- 21705660 TI - Direct visualization of myosin-binding protein C bridging myosin and actin filaments in intact muscle. AB - Myosin-binding protein C (MyBP-C) is a thick filament protein playing an essential role in muscle contraction, and MyBP-C mutations cause heart and skeletal muscle disease in millions worldwide. Despite its discovery 40 y ago, the mechanism of MyBP-C function remains unknown. In vitro studies suggest that MyBP-C could regulate contraction in a unique way--by bridging thick and thin filaments--but there has been no evidence for this in vivo. Here we use electron tomography of exceptionally well preserved muscle to demonstrate that MyBP-C does indeed bind to actin in intact muscle. This binding implies a physical mechanism for communicating the relative sliding between thick and thin filaments that does not involve myosin and which could modulate the contractile process. PMID- 21705662 TI - Confined glassy dynamics at grain boundaries in colloidal crystals. AB - Grain boundary (GB) microstructure and dynamics dictate the macroscopic properties of polycrystalline materials. Although GBs have been investigated extensively in conventional materials, it is only recently that molecular dynamics simulations have shown that GBs exhibit features similar to those of glass-forming liquids. However, current simulation techniques to probe GBs are limited to temperatures and driving forces much higher than those typically encountered in atomic experiments. Further, the short spatial and temporal scales in atomic systems preclude direct experimental access to GB dynamics. Here, we have used confocal microscopy to investigate the dynamics of high misorientation angle GBs in a three-dimensional colloidal polycrystal, with single-particle resolution, in the zero-driving force limit. We show quantitatively that glassy behavior is inherent to GBs as exemplified by the slowing down of particle dynamics due to transient cages formed by their nearest neighbors, non-Gaussian probability distribution of particle displacements and string-like cooperative rearrangements of particles. Remarkably, geometric confinement of the GB region by adjacent crystallites decreases with the misorientation angle and results in an increase in the size of cooperatively rearranging regions and hence the fragility of the glassy GBs. PMID- 21705661 TI - Five phosphonate operon gene products as components of a multi-subunit complex of the carbon-phosphorus lyase pathway. AB - Organophosphonate utilization by Escherichia coli requires the 14 cistrons of the phnCDEFGHIJKLMNOP operon, of which the carbon-phosphorus lyase has been postulated to consist of the seven polypeptides specified by phnG to phnM. A 5,660-bp DNA fragment encompassing phnGHIJKLM is cloned, followed by expression in E. coli and purification of Phn-polypeptides. PhnG, PhnH, PhnI, PhnJ, and PhnK copurify as a protein complex by ion-exchange, size-exclusion, and affinity chromatography. The five polypeptides also comigrate in native-PAGE. Cross linking of the purified protein complex reveals a close proximity of PhnG, PhnI, PhnJ, and PhnK, as these subunits disappear concomitant with the formation of large cross-linked protein complexes. Two molecular forms are identified, a major form of molecular mass of approximately 260 kDa, a minor form of approximately 640 kDa. The stoichiometry of the protein complex is suggested to be PhnG(4)H(2)I(2)J(2)K. Deletion of individual phn genes reveals that a strain harboring plasmid-borne phnGHIJ produces a protein complex consisting of PhnG, PhnH, PhnI, and PhnJ, whereas a strain harboring plasmid-borne phnGIJK produces a protein complex consisting of PhnG and PhnI. We conclude that phnGHIJK specify a soluble multisubunit protein complex essential for organophosphonate utilization. PMID- 21705663 TI - The prognostic impact of duration of anemia during chemotherapy in advanced epithelial ovarian cancer. AB - OBJECTIVE: To propose a measure of anemia to be used as a prognostic factor for progression-free survival and overall survival in advanced epithelial ovarian cancer patients. PATIENTS AND METHODS: Seventy-six patients with International Federation of Gynecology and Obstetrics stage III and stage IV epithelial ovarian cancer who had received at least six courses of platinum- and taxane-based systemic chemotherapy and achieved clinical or pathologic complete response were included. A novel prognostic factor based on the duration of anemia was proposed and the impact of anemia on progression-free and overall survival times was analyzed by a log-rank test and a Cox proportional hazards model. RESULTS: We introduce a binary variable, Hb1020, that takes a value of 1 if the duration of a hemoglobin (Hb) level <10 g/dL is >=20% of the total duration of chemotherapy. We propose Hb1020 as a potential prognostic factor for epithelial ovarian cancer. The 5-year progression-free survival rates were 48.4% in the Hb1020 = 0 group (duration of Hb <10 g/dL <20% of total duration) and 17.7% in the Hb1020 = 1 group (p = .026). The 5-year overall survival rates were 64.6% and 45.0%, respectively (p = .015). CONCLUSIONS: Hb1020, based on the duration of anemia, is a potential prognostic factor for epithelial ovarian cancer. Using Hb1020, we will be able to administer highly optimized treatment for anemia to improve patient survival. Further independent studies are needed to confirm its prognostic role. PMID- 21705664 TI - Current targeted therapies in breast cancer: clinical applications in the elderly woman. AB - The incidence of breast cancer is two to three times higher in women aged >=65 years than in the whole population, whereas their mortality rate is threefold to fourfold higher. Targeted therapies allow significantly longer disease-free survival times. Nevertheless, in an elderly population, these treatments need to be prescribed with caution. This paper reviews the treatments of breast cancer in the elderly, and the issues of targeted therapies and their toxicities. Patients with human epidermal growth factor receptor (HER)-2(+) breast cancer benefit from trastuzumab; although cardiotoxic effects are observed in <5% of patients when given alone, they affect ~25% of patients when combined with anthracyclines. Bevacizumab leads to a longer progression-free survival time and lower risk for progression in patients with metastatic breast cancer when added to paclitaxel or docetaxel. Although generally well tolerated, it is associated with a higher risk for arterial thromboembolism and hypertension. Lapatinib is approved for the treatment of advanced or metastatic breast cancer in patients not responding to trastuzumab, combined with capecitabine chemotherapy. The most frequent side effects concern the gastrointestinal system and dermatologic symptoms. The life expectancy of breast cancer patients should be taken into account to determine the appropriateness of treatments. The quality of life of elderly cancer patients must be assessed with an appropriate tool. Older patients exhibit greater vulnerability, suggesting identification and exclusion of patients at high cardiac risk. Future recommendations for the treatment of elderly women with breast cancer should include a multidisciplinary approach and a global geriatric assessment before treatment with anti-HER-2 therapy or bevacizumab. PMID- 21705665 TI - TOP2A amplification in the absence of that of HER-2/neu: toward individualization of chemotherapeutic practice in breast cancer. AB - PRIMARY OBJECTIVE: To investigate the relationship between human epidermal growth factor receptor (HER)-2/neu and the gene encoding topoisomerase IIalpha (TOP2A) in breast cancer, while elucidating their association with clinicopathological variables. METHODS: Real-time quantitative polymerase chain reaction (RQ-PCR) was performed on a 96-patient study group to assess gene amplification, and levels were determined using the comparative cycle threshold approach and Taqman assays. An immunohistochemistry (IHC) microarray (n = 76) was then employed to check for correlation between gene amplification and protein expression levels. RESULTS: Amplification levels of TOP2A did not differ significantly according to HER-2/neu status by either RQ-PCR or IHC microarray. Of the HER-2/neu(-) patients, 29.1% demonstrated levels of TOP2A above the third quartile, whereas 22.9% of the HER 2/neu(+) patients had values in the first quartile (log TOP2A <0.62), thereby indicating low-level amplification. Of the 60 patients characterized as HER 2/neu(-) using IHC and fluorescence in situ hybridization (FISH), 22.9% were classified as TOP2A(+) on the IHC microarray. Of the 14 patients deemed HER 2/neu(+) using IHC and FISH, meanwhile, the majority (n = 10) were classified as TOP2A(+). CONCLUSIONS: Our results indicate that amplification of TOP2A in breast cancer is not confined to those who are concomitantly HER-2/neu(+), and suggest that a significant proportion of HER-2/neu(-) patients exhibit high levels of TOP2A. PMID- 21705666 TI - Occupancy of both sites on the thyrotropin (TSH) receptor dimer is necessary for phosphoinositide signaling. AB - The thyroid-stimulating hormone (TSH) receptor signals via G(s) to produce cAMP and via G(q/11) to produce inositol-1,4,5-trisphosphate, which is degraded to inositol monophosphate (IP1; phosphoinositide signaling). The potency of TSH for cAMP signaling is higher than for phosphoinositide signaling, and it was suggested that there are "spare receptors" for cAMP signaling. In a human embryonic kidney macrophage scavenger receptor-expressing (HEK-EM) 293 model system, there are no spare receptors, but the cells still exhibited 100-fold differences in potencies. Dose responses for TSH-stimulated dissociation of prebound (125)I-TSH (negative cooperativity; EC(50)=70 mU/ml), which requires TSH binding to both sites of the TSH receptor (TSHR) homodimer, and TSH-stimulated IP1 production (EC(50)=50 mU/ml) were indistinguishable. Fluorescence resonance energy transfer (FRET) using tagged receptors showed that TSHR formed homodimers and heterodimers with two binding-deficient mutant TSHRs, L252P and C41S. When L252P or C41S was expressed with TSHR, that is, when TSHR/L252P or TSHR/C41S heterodimers could only bind one TSH, TSH-stimulated IP1 production was decreased relative to cAMP production. The slopes of linear regression analyses comparing fold stimulation by TSH of IP1 vs. cAMP production were 0.044 +/- 0.0047, 0.0043 +/- 0.0041, and 0.0059 +/- 0.0014 for cells expressing TSHR alone, TSHR and L252P, or TSHR and C41S, respectively. We suggest that TSHR coupling to phosphoinositide signaling is dependent on binding 2 molecules of TSH to TSHR homodimer, causing a conformational change allowing coupling to G(q/11). PMID- 21705667 TI - Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis. AB - Inactivation of glycogen synthase kinase (GSK)-3 has been implicated in cancer progression. Previously, we showed an abundance of inactive GSK-3 in the human chronic myeloid leukemia (CML) cell line. CML is a hematopoietic malignancy caused by an oncogenic Bcr-Abl tyrosine kinase. In Bcr-Abl signaling, the role of GSK-3 is not well defined. Here, we report that enforced expression of constitutively active GSK-3 reduced proliferation and increased Bcr-Abl inhibition-induced apoptosis by nearly 1-fold. Bcr-Abl inhibition activated GSK-3 and GSK-3-dependent apoptosis. Inactivation of GSK-3 by Bcr-Abl activity is, therefore, confirmed. To reactivate GSK-3, we used glucosylceramide synthase (GCS) inhibitor PDMP to accumulate endogenous ceramide, a tumor-suppressor sphingolipid and a potent GSK-3 activator. We found that either PDMP or silence of GCS increased Bcr-Abl inhibition-induced GSK-3 activation and apoptosis. Furthermore, PDMP sensitized the most clinical problematic drug-resistant CML T315I mutant to Bcr-Abl inhibitor GNF-2-, imatinib-, or nilotinib-induced apoptosis by >5-fold. Combining PDMP and GNF-2 eliminated transplanted-CML-T315I mutants in vivo and dose dependently sensitized primary cells from CML T315I patients to GNF-2-induced proliferation inhibition and apoptosis. The synergistic efficacy was Bcr-Abl restricted and correlated to increased intracellular ceramide levels and acted through GSK-3-mediated apoptosis. This study suggests a feasible novel anti-CML strategy by accumulating endogenous ceramide to reactivate GSK-3 and abrogate drug resistance. PMID- 21705668 TI - The transcriptional regulator megakaryoblastic leukemia-1 mediates serum response factor-independent activation of tenascin-C transcription by mechanical stress. AB - The extracellular matrix protein tenascin-C (TNC) is up-regulated in processes influenced by mechanical stress, such as inflammation, tissue remodeling, wound healing, and tumorigenesis. Cyclic strain-induced TNC expression depends on RhoA actin signaling, the pathway that regulates transcriptional activity of serum response factor (SRF) by its coactivator megakaryoblastic leukemia-1 (MKL1). Therefore, we tested whether MKL1 controls TNC transcription. We demonstrate that overexpression of MKL1 strongly induces TNC expression in mouse NIH3T3 fibroblasts and normal HC11 and transformed 4T1 mammary epithelial cells. Part of the induction was dependant on SRF and a newly identified atypical CArG box in the TNC promoter. Another part was independent of SRF but required the SAP domain of MKL1. An MKL1 mutant incapable of binding to SRF still strongly induced TNC, while induction of the SRF target c-fos was abolished. Cyclic strain failed to induce TNC in MKL1-deficient but not in SRF-deficient fibroblasts, and strain induced TNC expression strongly depended on the SAP domain of MKL1. Promoter reporter and chromatin immunoprecipitation experiments unraveled a SAP-dependent, SRF-independent interaction of MKL1 with the proximal promoter region of TNC, attributing for the first time a functional role to the SAP domain of MKL1 in regulating gene expression. PMID- 21705669 TI - Glucocorticoid dose determines osteocyte cell fate. AB - In response to cellular insult, several pathways can be activated, including necrosis, apoptosis, and autophagy. Because glucocorticoids (GCs) have been shown to induce both osteocyte apoptosis and autophagy, we sought to determine whether osteocyte cell fate in the presence of GCs was dose dependent by performing in vivo and in vitro studies. Male Swiss-Webster mice were treated with slow-release prednisolone pellets at 1.4, 2.8, and 5.6 mg/kg/d for 28 d. An osteocyte cell line, MLO-Y4 cells, was treated with various doses of dexamethasone. We found that GC treatments dose dependently decreased activation of antioxidant-, autophagy-, and antiapoptosis-focused RT-PCR gene pathways in mouse cortical bone. The activation of antioxidant genes was correlated with autophagy gene expression after the GC treatments. The presence of osteocyte autophagy, as detected by immunostaining for LC3, increased ~50% at the distal femur cortical bone region but not at trabecular bone region at the 1.4 and 2.8 mg/kg/d GC dose levels. The number of apoptotic osteocytes was increased at the cortical bone region by ~40% initially observed at the 2.8 mg/kg/d dose level. In addition, the presence of the osteocyte autophagy was associated with an increased protein level of cathepsin K in vitro after the GC treatments. In summary, we found that GC treatment dose-dependently decreased antioxidant gene expression, with lower GC doses activating autophagy, whereas a higher dose increased apoptosis. These data suggest that autophagy may provide a mechanism for osteocytes to survive the stress after GC exposure and provide further insight into how GCs alter bone cell fate. PMID- 21705670 TI - Endothelial cells downregulate apolipoprotein D expression in mural cells through paracrine secretion and Notch signaling. AB - Endothelial and mural cell interactions are vitally important for proper formation and function of blood vessels. These two cell types communicate to regulate multiple aspects of vessel function. In studying genes regulated by this interaction, we identified apolipoprotein D (APOD) as one gene that is downregulated in mural cells by coculture with endothelial cells. APOD is a secreted glycoprotein that has been implicated in governing stress response, lipid metabolism, and aging. Moreover, APOD is known to regulate smooth muscle cells and is found in abundance within atherosclerotic lesions. Our data show that the regulation of APOD in mural cells is bimodal. Paracrine secretion by endothelial cells causes partial downregulation of APOD expression. Additionally, cell contact-dependent Notch signaling plays a role. NOTCH3 on mural cells promotes the downregulation of APOD, possibly through interaction with the JAGGED 1 ligand on endothelial cells. Our results show that NOTCH3 contributes to the downregulation of APOD and by itself is sufficient to attenuate APOD transcript expression. In examining the consequence of decreased APOD expression in mural cells, we show that APOD negatively regulates cell adhesion. APOD attenuates adhesion by reducing focal contacts; however, it has no effect on stress fiber formation. These data reveal a novel mechanism in which endothelial cells control neighboring mural cells through the downregulation of APOD, which, in turn, influences mural cell function by modulating adhesion. PMID- 21705671 TI - Temperature effects on morphological integrity and Ca2+ signaling in freshly isolated murine feed artery endothelial cell tubes. AB - To study Ca(2+) signaling in the endothelium of murine feed arteries, we determined the in vitro stability of endothelial cell (EC) tubes freshly isolated from abdominal muscle feed arteries of male and female C57BL/6 mice (5-9 mo, 25 35 g). We tested the hypothesis that intracellular Ca(2+) concentration ([Ca(2+)](i)) responses to muscarinic receptor activation would increase with temperature. Intact EC tubes (length: 1-2 mm, width: 65-80 MUm) were isolated using gentle enzymatic digestion with trituration to remove smooth muscle cells. A freshly isolated EC tube was secured in a chamber and superfused at 24 (room temperature), 32, or 37 degrees C. Using fura-2 dye, [Ca(2+)](i) was monitored (ratio of fluorescence at 340- to 380-nm wavelength) at rest and in response to bolus doses of ACh (20 nmol to 200 MUmol). The morphological integrity of EC tubes was preserved at 24 and 32 degrees C. Based on the Ca(2+) K(d) values we determined for fura-2 (174 nM at 24 degrees C and 146 nM at 32 degrees C), resting [Ca(2+)](i) remained stable for 180 min at both 24 and 32 degrees C (27 +/- 4 and 34 +/- 2 nM, respectively), with peak responses to ACh (20 MUmol) increasing from ~220 nM at 24 degrees C to ~500 nM at 32 degrees C (P < 0.05). There was no difference in responses to ACh between EC tubes from male versus female mice. When EC tubes were maintained at 37 degrees C (typical in vivo temperature), resting [Ca(2+)](i) increased by ~30% within 15 min, and gaps formed between individual ECs as they retracted and extruded dye, precluding further study. We conclude that EC tubes enable Ca(2+) signaling to be evaluated in the freshly isolated endothelium of murine feed arteries. While Ca(2+) responses are enhanced by approximately twofold at 32 versus 24 degrees C, the instability of EC tubes at 37 degrees C precludes their study at typical body temperature. PMID- 21705672 TI - Discovery of shear- and side-specific mRNAs and miRNAs in human aortic valvular endothelial cells. AB - The role of endothelial cells (ECs) in aortic valve (AV) disease remains relatively unknown; however, disease preferentially occurs in the fibrosa. We hypothesized oscillatory shear (OS) present on the fibrosa stimulates ECs to modify mRNAs and microRNAs (miRNAs) inducing disease. Our goal was to identify mRNAs and miRNAs differentially regulated by OS and laminar shear (LS) in human AVECs (HAVECs) from the fibrosa (fHAVECs) and ventricularis (vHAVECs). HAVECs expressed EC markers as well as some smooth muscle cell markers and functionally aligned with the flow. HAVECs were exposed to OS and LS for 24 h, and total RNA was analyzed by mRNA and miRNA microarrays. We found over 700 and 300 mRNAs down- and upregulated, respectively, by OS; however, there was no side dependency. mRNA microarray results were validated for 26 of 28 tested genes. Ingenuity Pathway Analysis revealed thrombospondin 1 (Thbs1) and NF-kappaB inhibitor-alpha (Nfkbia) as highly connected, shear-sensitive genes. miRNA array analysis yielded 30 shear sensitive miRNAs and 3 side-specific miRNAs. miRNA validation confirmed 4 of 17 shear-sensitive miRNAs and 1 of 3 side-dependent miRNAs. Using miRWalk and several filtering steps, we identified shear-sensitive mRNAs potentially targeted by shear-sensitive miRNAs. These genes and signaling pathways could act as therapeutic targets of AV disease. PMID- 21705673 TI - PKCalpha mediates acetylcholine-induced activation of TRPV4-dependent calcium influx in endothelial cells. AB - Transient receptor potential vanilloid channel 4 (TRPV4) is a polymodally activated nonselective cationic channel implicated in the regulation of vasodilation and hypertension. We and others have recently shown that cyclic stretch and shear stress activate TRPV4-mediated calcium influx in endothelial cells (EC). In addition to the mechanical forces, acetylcholine (ACh) was shown to activate TRPV4-mediated calcium influx in endothelial cells, which is important for nitric oxide-dependent vasodilation. However, the molecular mechanism through which ACh activates TRPV4 is not known. Here, we show that ACh induced calcium influx and endothelial nitric oxide synthase (eNOS) phosphorylation but not calcium release from intracellular stores is inhibited by a specific TRPV4 antagonist, AB-159908. Importantly, activation of store-operated calcium influx was not altered in the TRPV4 null EC, suggesting that TRPV4 dependent calcium influx is mediated through a receptor-operated pathway. Furthermore, we found that ACh treatment activated protein kinase C (PKC) alpha, and inhibition of PKCalpha activity by the specific inhibitor Go-6976, or expression of a kinase-dead mutant of PKCalpha but not PKCepsilon or downregulation of PKCalpha expression by chronic 12-O-tetradecanoylphorbol-13 acetate treatment, completely abolished ACh-induced calcium influx. Finally, we found that ACh-induced vasodilation was inhibited by the PKCalpha inhibitor Go 6976 in small mesenteric arteries from wild-type mice, but not in TRPV4 null mice. Taken together, these findings demonstrate, for the first time, that a specific isoform of PKC, PKCalpha, mediates agonist-induced receptor-mediated TRPV4 activation in endothelial cells. PMID- 21705674 TI - Endothelin-mediated in vivo pressor responses following TRPV1 activation. AB - Transient receptor potential vanilliod 1 (TRPV1) channels have recently been postulated to play a role in the vascular complications/consequences associated with diabetes despite the fact that the mechanisms through which TRPV1 regulates vascular function are not fully known. Accordingly, our goal was to define the mechanisms by which TRPV1 channels modulate vascular function and contribute to vascular dysfunction in diabetes. We subjected mice lacking TRPV1 [TRPV1((-/-))], db/db, and control C57BLKS/J mice to in vivo infusion of the TRPV1 agonist capsaicin or the alpha-adrenergic agonist phenylephrine (PE) to examine the integrated circulatory actions of TRPV1. Capsaicin (1, 10, 20, and 100 MUg/kg) dose dependently increased MAP in control mice (5.7 +/- 1.6, 11.7 +/- 2.1, 25.4 +/- 3.4, and 51.6 +/- 3.9%), which was attenuated in db/db mice (3.4 +/- 2.1, 3.9 +/- 2.1, 7.0 +/- 3.3, and 17.9 +/- 6.2%). TRPV1((-/-)) mice exhibited no changes in MAP in response to capsaicin, suggesting the actions of this agonist are specific to TRPV1 activation. Immunoblot analysis revealed decreased aortic TRPV1 protein expression in db/db compared with control mice. Capsaicin-induced responses were recorded following inhibition of endothelin A and B receptors (ET(A) /ET(B)). Inhibition of ET(A) receptors abolished the capsaicin-mediated increases in MAP. Combined antagonism of ET(A) and ET(B) receptors did not further inhibit the capsaicin response. Cultured endothelial cell exposure to capsaicin increased endothelin production as shown by an endothelin ELISA assay, which was attenuated by inhibition of TRPV1 or endothelin-converting enzyme. TRPV1 channels contribute to the regulation of vascular reactivity and MAP via production of endothelin and subsequent activation of vascular ET(A) receptors. Impairment of TRPV1 channel function may contribute to vascular dysfunction in diabetes. PMID- 21705675 TI - Cardiac pressure overload hypertrophy is differentially regulated by beta adrenergic receptor subtypes. AB - In isolated myocytes, hypertrophy induced by norepinephrine is mediated via alpha(1)-adrenergic receptors (ARs) and not beta-ARs. However, mice with deletions of both major cardiac alpha(1)-ARs still develop hypertrophy in response to pressure overload. Our purpose was to better define the role of beta AR subtypes in regulating cardiac hypertrophy in vivo, important given the widespread clinical use of beta-AR antagonists and the likelihood that patients treated with these agents could develop conditions of further afterload stress. Mice with deletions of beta(1), beta(2), or both beta(1)- and beta(2)-ARs were subjected to transverse aortic constriction (TAC). After 3 wk, beta(1)(-/-) showed a 21% increase in heart to body weight vs. sham controls, similar to wild type, whereas beta(2)(-/-) developed exaggerated (49% increase) hypertrophy. Only when both beta-ARs were ablated (beta(1)beta(2)(-/-)) was hypertrophy totally abolished. Cardiac function was preserved in all genotypes. Several known inhibitors of cardiac hypertrophy (FK506 binding protein 5, thioredoxin interacting protein, and S100A9) were upregulated in beta(1)beta(2)(-/-) compared with the other genotypes, whereas transforming growth factor-beta(2), a positive mediator of hypertrophy was upregulated in all genotypes except the beta(1)beta(2)(-/-). In contrast to recent reports suggesting that angiogenesis plays a critical role in regulating cardiac hypertrophy-induced heart failure, we found no evidence that angiogenesis or its regulators (VEGF, Hif1alpha, and p53) play a role in compensated cardiac hypertrophy. Pressure overload hypertrophy in vivo is dependent on a coordination of signaling through both beta(1)- and beta(2)-ARs, mediated through several key cardiac remodeling pathways. Angiogenesis is not a prerequisite for compensated cardiac hypertrophy. PMID- 21705676 TI - In vivo assessment of neurocardiovascular regulation in the mouse: principles, progress, and prospects. AB - A growing body of evidence indicates that a number of common complex diseases, including hypertension, heart failure, and obesity, are characterized by alterations in central neurocardiovascular regulation. However, our understanding of how changes within the central nervous system contribute to the development and progression of these and other diseases remains unclear. As with many areas of cardiovascular research, the mouse has emerged as a key species for investigations of neuroregulatory processes because of its amenability to highly specific genetic manipulations. In parallel with the development of increasingly sophisticated murine models has come the miniaturization and advancement in methodologies for in vivo assessment of neurocardiovascular end points in the mouse. The following brief review will focus on a number of key direct and indirect experimental approaches currently in use, including measurement of arterial blood pressure, assessment of cardiovascular autonomic control, and evaluation of arterial baroreflex function. The advantages and limitations of each methodology are highlighted to allow for a critical evaluation by the reader when considering these approaches. PMID- 21705677 TI - Activation of Pak1/Akt/eNOS signaling following sphingosine-1-phosphate release as part of a mechanism protecting cardiomyocytes against ischemic cell injury. AB - We investigated whether plasma long-chain sphingoid base (LCSB) concentrations are altered by transient cardiac ischemia during percutaneous coronary intervention (PCI) in humans and examined the signaling through the sphingosine-1 phosphate (S1P) cascade as a mechanism underlying the S1P cardioprotective effect in cardiac myocytes. Venous samples were collected from either the coronary sinus (n = 7) or femoral vein (n = 24) of 31 patients at 1 and 5 min and 12 h, following induction of transient myocardial ischemia during elective PCI. Coronary sinus levels of LCSB were increased by 1,072% at 1 min and 941% at 5 min (n = 7), while peripheral blood levels of LCSB were increased by 579% at 1 min, 617% at 5 min, and 436% at 12 h (n = 24). In cultured cardiac myocytes, S1P, sphingosine (SPH), and FTY720, a sphingolipid drug candidate, showed protective effects against CoCl induced hypoxia/ischemic cell injury by reducing lactate dehydrogenase activity. Twenty-five nanomolars of FTY720 significantly increased phospho-Pak1 and phospho-Akt levels by 56 and 65.6% in cells treated with this drug for 15 min. Further experiments demonstrated that FTY720 triggered nitric oxide release from cardiac myocytes is through pertussis toxin-sensitive phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase signaling. In ex vivo hearts, ischemic preconditioning was cardioprotective in wild-type control mice (Pak1(f/f)), but this protection appeared to be ineffective in cardiomyocyte-specific Pak1 knockout (Pak1(cko)) hearts. The present study provides the first direct evidence of the behavior of plasma sphingolipids following transient cardiac ischemia with dramatic and early increases in LCSB in humans. We also demonstrated that S1P, SPH, and FTY720 have protective effects against hypoxic/ischemic cell injury, likely a Pak1/Akt1 signaling cascade and nitric oxide release. Further study on a mouse model of cardiac specific deletion of Pak1 demonstrates a crucial role of Pak1 in cardiac protection against ischemia/reperfusion injury. PMID- 21705678 TI - Chronic renal failure alters endothelial function in cerebral circulation in mice. AB - We examined structure, composition, and endothelial function in cerebral arterioles after 4 wk of chronic renal failure (CRF) in a well-defined murine model (C57BL/6J and apolipoprotein E knockout female mice). We also determined quantitative expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (on serine 1177 and threonine 495), and caveolin-1; quantitative expression of markers of vascular inflammation or oxidative stress [Rock-1, Rock-2, VCAM-1, and peroxisome proliferator-activated receptor-gamma (PPARgamma)]; and the plasma concentration of L-arginine and asymmetric dimethylarginine (ADMA). Our hypothesis was that endothelial function would be impaired in cerebral arterioles during CRF following either a decrease in NO production (through alteration of eNOS expression or regulation) or an increase in NO degradation (due to oxidative stress or vascular inflammation). Endothelium dependent relaxation was impaired during CRF, but endothelium-independent relaxation was not. CRF had no effect on cerebral arteriolar structure and composition. Quantitative expressions of eNOS, eNOS phosphorylated on serine 1177, caveolin-1, Rock-1, Rock-2, and VCAM-1 were similar in CRF and non-CRF mice. In contrast, quantitative expression of PPARgamma (which exercises a protective role on blood vessels) was significantly lower in CRF mice, whereas quantitative expression of eNOS phosphorylated on the threonine 495 (the inactive form of eNOS) was significantly higher. Lastly, the plasma concentration of ADMA (a uremic toxin and an endogenous inhibitor of eNOS) was elevated and plasma concentration of L-arginine was low in CRF. In conclusion, endothelial function is impaired in a mouse model of early stage CRF. These alterations may be related (at least in part) to a decrease in NO production. PMID- 21705679 TI - Risk factor modification and projections of absolute breast cancer risk. AB - BACKGROUND: Although modifiable risk factors have been included in previous models that estimate or project breast cancer risk, there remains a need to estimate the effects of changes in modifiable risk factors on the absolute risk of breast cancer. METHODS: Using data from a case-control study of women in Italy (2569 case patients and 2588 control subjects studied from June 1, 1991, to April 1, 1994) and incidence and mortality data from the Florence Registries, we developed a model to predict the absolute risk of breast cancer that included five non-modifiable risk factors (reproductive characteristics, education, occupational activity, family history, and biopsy history) and three modifiable risk factors (alcohol consumption, leisure physical activity, and body mass index). The model was validated using independent data, and the percent risk reduction was calculated in high-risk subgroups identified by use of the Lorenz curve. RESULTS: The model was reasonably well calibrated (ratio of expected to observed cancers = 1.10, 95% confidence interval [CI] = 0.96 to 1.26), but the discriminatory accuracy was modest. The absolute risk reduction from exposure modifications was nearly proportional to the risk before modifying the risk factors and increased with age and risk projection time span. Mean 20-year reductions in absolute risk among women aged 65 years were 1.6% (95% CI = 0.9% to 2.3%) in the entire population, 3.2% (95% CI = 1.8% to 4.8%) among women with a positive family history of breast cancer, and 4.1% (95% CI = 2.5% to 6.8%) among women who accounted for the highest 10% of the total population risk, as determined from the Lorenz curve. CONCLUSIONS: These data give perspective on the potential reductions in absolute breast cancer risk from preventative strategies based on lifestyle changes. Our methods are also useful for calculating sample sizes required for trials to test lifestyle interventions. PMID- 21705680 TI - The numbers game: the risky business of projecting risk. PMID- 21705681 TI - Endosomal localization of the serum resistance-associated protein in African trypanosomes confers human infectivity. AB - Trypanosoma brucei rhodesiense is the causative agent of human African sleeping sickness. While the closely related subspecies T. brucei brucei is highly susceptible to lysis by a subclass of human high-density lipoproteins (HDL) called trypanosome lytic factor (TLF), T. brucei rhodesiense is resistant and therefore able to establish acute and fatal infections in humans. This resistance is due to expression of the serum resistance-associated (SRA) gene, a member of the variant surface glycoprotein (VSG) gene family. Although much has been done to establish the role of SRA in human serum resistance, the specific molecular mechanism of SRA-mediated resistance remains a mystery. Thus, we report the trafficking and steady-state localization of SRA in order to provide more insight into the mechanism of SRA-mediated resistance. We show that SRA traffics to the flagellar pocket of bloodstream-form T. brucei organisms, where it localizes transiently before being endocytosed to its steady-state localization in endosomes, and we demonstrate that the critical point of colocalization between SRA and TLF occurs intracellularly. PMID- 21705682 TI - Characterization of a dominant cone degeneration in a green fluorescent protein reporter mouse with disruption of Loci associated with human dominant retinal dystrophy. AB - PURPOSE. To characterize anatomically and functionally the retinal degeneration observed in a transgenic mouse line (OPN1LW-EGFP) expressing enhanced green fluorescent protein (EGFP) in a subpopulation of cone photoreceptors, and to map the location of the transgenic insertion. METHODS. An anatomic comparison of cone survival was carried out between wild type (WT) and transgenic mice at three postnatal time points (P80, P140, and P245). Retinal function was assessed at P245 by ERG and included an ultraviolet flicker stimulus to isolate S-cone function. Chromosomal mapping by FISH and high-resolution mapping on DNA fibers (Fiber-FISH) were performed to identify the location of the transgenic insertion. RESULTS. GFP expression was largely absent in S-cones. Cone numbers were significantly reduced in OPN1LW-EGFP mice at all time points compared to WT, with cone loss independent of GFP expression. Anatomic loss correlated with a functional deficit in dark- and light-adapted ERG responses, including a reduction in UV-flicker response, confirming the degeneration of S-cones. The phenotype of heterozygote mice was slightly less severe than in homozygotes, consistent with a dominantly inherited cone dystrophy. The transgenic insertion mapped to a specific region on chromosome 10 orthologous with loci for progressive bifocal chorioretinal atrophy and North Carolina macular dystrophy on human chromosome 6. CONCLUSIONS. Cone loss is global in OPN1LW-EGFP mice and is independent of GFP expression. The mechanism underlying the degeneration remains elusive; however, disruption of loci associated with dominantly inherited retinal degenerations in humans makes this mouse of great interest. PMID- 21705683 TI - Morphologic and confocal investigation on Salzmann nodular degeneration of the cornea. AB - PURPOSE: To investigate the ultrastructure of advanced Salzmann nodular degeneration (SND) and to correlate it to confocal in vivo findings. METHODS: The corneal degenerative nodules from four patients with SND were examined with confocal microscopy and then removed and processed for light microscopy (LM) and transmission electron microscopy (TEM). RESULTS: The confocal examination revealed elongated basal epithelial cells and activated keratocytes in the anterior stroma near the nodules. Occasional subbasal nerves and tortuous stromal nerve bundles were observed. With LM and TEM, five zones were described: one internodular and four pertaining the nodule, each characterized by peculiar aspects of the epithelium and stroma. As also confirmed by the morphometry, in the zones corresponding to the nodules, the epithelium was lower and with fewer cell layers than the peripheral zones. Over the nodules, the basement membrane was discontinuous or absent and the Bowman's layer, when present, had a granular filamentous appearance. The nodular stroma was formed by many activated keratocytes and irregular lamellae. Subbasal nerves were always isolated and had degenerative changes in the center of the nodule. CONCLUSIONS: This work illustrates the confocal microscopic findings associated with LM and TEM observations in patients with advanced SND. Our data revealed milder changes of the epithelium together with more pronounced changes of the basement membrane and Bowman's layer, which are aspects of increased keratocyte activity and an altered nerve pattern. All of these structures seem to contribute to the characteristic corneal disorganization of SND. PMID- 21705684 TI - Diagnostic accuracy of OCT with a normative database to detect diffuse retinal nerve fiber layer atrophy: Diffuse Atrophy Imaging Study. AB - PURPOSE: To investigate the diagnostic accuracy of Stratus optical coherence tomography (OCT) with its internal normative database to detect diffuse retinal nerve fiber layer (RNFL) atrophy in glaucoma subjects. METHODS: One hundred two eyes of 102 glaucoma patients with diffuse RNFL atrophy and 102 healthy eyes of 102 age-matched subjects were enrolled in the Diffuse Atrophy Imaging Study. Two experienced observers graded RNFL photographs of diffuse RNFL atrophy eyes using a four-level grading system. The diagnostic performances for detecting diffuse RNFL atrophy were examined according to visual field results and RNFL photograph grading. RESULTS: Using a criterion of abnormal at the <5% level, the overall sensitivity of the Stratus OCT parameters ranged from 61.5% to 84.5%, and the overall specificity ranged from 90.2% to 99.0%. For mild, moderate, and severe diffuse RNFL atrophy, the superior quadrant had a sensitivity of 41.0%, 83.3%, and 100.0%, respectively, and the inferior quadrant had a sensitivity of 35.0%, 88.5%, and 100.0%, respectively. The highest likelihood ratios were obtained at the 11 and 12 o'clock sectors for superior RNFL and the 6 and 7 o'clock sectors for inferior RNFL. CONCLUSIONS: OCT with a normative database can detect diffuse RNFL atrophy with moderate sensitivity and high specificity. Because the sensitivity of Stratus OCT is closely related to the degree of diffuse RNFL atrophy and the visual field results, OCT with an internal normative database should be evaluated with prudence, especially in the early stage of glaucoma with diffuse RNFL atrophy. PMID- 21705686 TI - Diurnal variation of retina thickness measured with time domain and spectral domain optical coherence tomography in healthy subjects. AB - PURPOSE. To investigate diurnal variations in macular thickness and total macular volume using time domain optical coherence tomography (TD-OCT) and spectral domain OCT (SD-OCT) in healthy subjects. METHODS. Data were derived from 52 eyes of 52 healthy subjects. Macular thickness, macular volume was measured by using TD-OCT and SD-OCT at 8 AM and 6 PM. RESULTS. Comparing TD-OCT measurements, retinal thickness was significantly greater in the afternoon than in the morning in 3 of 9 grid subfields: central macular thickness (CMT) (194 vs. 190 MUm; P = 0.006), superior inner area (276 vs. 273 MUm; P = 0.010), and temporal inner area (261 vs. 258 MUm; P = 0.006). In SD-OCT measurements, CMT, pericentral macular thickness, and macular volume did not differ significantly between the morning and the afternoon. Comparing the absolute variation in the parameters measured by the two devices, central macular thickness and temporal inner area thickness differed significantly (P = 0.015, P = 0.029), whereas other area thicknesses and macular volumes did not. Comparing the relative variation of the two devices, CMT and temporal inner area thickness differed significantly (P = 0.014, P = 0.027), whereas other area thicknesses and macular volume showed no significant difference. The moduli of variations for CMT, macular volume, and pericentral macular thickness were significantly lower using SD-OCT than using TD-OCT. CONCLUSIONS. The diurnal variation of the TD-OCT measurements was likely due to the limited repeatability of the device rather than to tissue variation. Diurnal variation was not found using SD-OCT, which has better repeatability. PMID- 21705685 TI - Hyperoxia therapy of pre-proliferative ischemic retinopathy in a mouse model. AB - PURPOSE: To investigate the therapeutic use and mechanisms of action of normobaric hyperoxia to promote revascularization and to prevent neovascularization in a mouse model of oxygen-induced ischemic retinopathy. METHODS: Hyperoxia treatment (HT, 40%-75% oxygen) was initiated on postnatal day (P) 14 during the pre-proliferative phase of ischemic retinopathy. Immunohistochemistry, ELISA, and quantitative PCR were used to assess effects on retinal vascular repair and pathologic angiogenesis in relation to glial cell injury, VEGF protein, and mRNA levels of key mediators of pathologic angiogenesis. Effects of intravitreal injections of VEGF and the VEGF inhibitor VEGFR1/Fc fusion protein were also studied. RESULTS: Administration of HT during the ischemic pre-proliferative phase of retinopathy effectively accelerated the process of revascularization while preventing the development of vitreous neovascularization. HT enhanced the formation of specialized endothelial tip cells at the edges of the repairing capillary networks and blocked the overexpression of several molecular mediators of angiogenesis, inflammation, and extracellular proteolysis. HT markedly reduced the reactive expression of GFAP in Muller cells and improved the morphology of astrocytes in the avascular region of the retina. Exogenous VEGF administered into the vitreous on P14 was not sufficient to cause vitreous neovascularization in the HT mice. Injection of the VEGF antagonist VEGFR1/Fc blocked both pathologic and physiological angiogenesis and did not rescue astrocytes. CONCLUSIONS: HT may be clinically useful to facilitate vascular repair while blocking neovascularization in the pre proliferative stage of ischemic retinopathy by correcting a broad range of biochemical and cellular abnormalities. PMID- 21705687 TI - Dietary omega-3 fatty acids and the risk for age-related maculopathy: the Alienor Study. AB - PURPOSE: Previous studies have suggested a lower risk for age-related maculopathy (ARM) in subjects with high dietary intake of long-chain omega-3 polyunsaturated fatty acids (PUFA). The authors report the associations of ARM with past dietary intakes in French elderly subjects. METHODS: The Alienor Study is a population based epidemiologic study on nutrition and age-related eye diseases performed in residents of Bordeaux 73 years of age and older. Six hundred sixty-six subjects (1289 eyes) with complete data were included in the analyses. ARM was classified from retinal photographs taken in 2006 to 2008 in five exclusive stages: late neovascular ARM (n = 21 subjects, 29 eyes); late atrophic ARM (n = 19 subjects, 33 eyes); large soft indistinct drusen and/or reticular drusen and/or large distinct drusen with pigment abnormalities (early ARM2, n = 67 subjects, 100 eyes); large soft distinct drusen alone or pigment abnormalities alone (early ARM1, n = 119 subjects, 163 eyes); and no ARM (n = 440 subjects, 964 eyes). Dietary intakes were estimated from a 24-hour dietary recall performed by dieticians (2001-2002). Associations were estimated using logistic Generalized Estimating Equation. RESULTS: After multivariate adjustment, subjects with high intake of long-chain omega-3 PUFA showed a decreased risk for early ARM1 (odds ratio [OR], 0.83; 95% confidence interval [95% CI], 0.71-0.98; P = 0.03) and late neovascular ARM (OR, 0.26; 95% CI, 0.08-0.83; P = 0.02). Associations with late atrophic ARM were in the same direction but did not reach statistical significance (OR, 0.74; 95% CI, 0.52-1.06; P = 0.10). Overall, high intakes of long-chain omega-3 PUFA were associated with reduced risk for late ARM (OR, 0.59; 95% CI, 0.39-0.88; P = 0.01). CONCLUSIONS: These results confirm a decreased risk for ARM in subjects with high intake of long-chain omega-3 PUFA. PMID- 21705688 TI - Simultaneous cell death and upregulation of poly(ADP-ribose) polymerase-1 expression in early postnatal mouse retina. AB - PURPOSE: Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme that transfers ADP-ribose units (PAR polymer) to nuclear proteins and has been implicated in caspase-independent cell death in different models of retinal degeneration. The involvement of PARP-1 in cell death occurring during normal postnatal development of the mouse retina was investigated. In addition, the expression of apoptosis inducing factor (AIF), a caspase-independent cell death mediator, was explored because PARP-1 activation has been related to the translocation of a 57-kDa form of AIF into the cell nucleus. METHODS: Cell death was determined in retinas of developing mice by both ELISA and TUNEL. PARP-1, PAR, and AIF were analyzed by immunocytochemistry and immunoblotting. Quantification of PARP-1 mRNA levels was also performed by real-time PCR. RESULTS: PARP-1 upregulation and PAR polymer formation, indicative of PARP-1 activity, were observed during the first postnatal week simultaneously with the presence of abundant dying cells, some of which were not associated with active caspase-3. PARP-1 was downregulated and PARP-1 activity progressively declined in the retina during subsequent postnatal development, coinciding with the decrease in cell death. Truncated AIF (57 kDa) was present in the retina during the first postnatal week, gradually decreasing thereafter, and had a nuclear localization in some cells, which also showed strong PAR polymer nuclear staining. CONCLUSIONS: These results show that a caspase-independent cell death pathway exists during the normal development of the mouse retina and suggest that PARP-1 participates in this cell death pathway by mediating AIF translocation to the cell nucleus. PMID- 21705689 TI - Ocular hypotensive effect of oral palmitoyl-ethanolamide: a clinical trial. AB - PURPOSE: To investigate the effect of oral palmitoyl-ethanolamide (PEA) on intraocular pressure (IOP) in primary open angle glaucoma (POAG) and ocular hypertension (OH). METHODS: In a prospective, randomized, double-blind, crossover clinical trial, 42 patients with POAG or OH who were treated with timolol 0.5% and whose IOP was between 19 and 24 mm Hg received oral PEA (300-mg tablets twice a day) or placebo (PEA vehicle tablets twice a day) for 2 months (period 1), and, after a 2-month washout, received the other treatment for 1 month (period 2). IOP, best-corrected visual acuity, and visual field parameters were considered. RESULTS: After PEA treatment (mean baseline IOP, 21.6 +/- 1.7 mm Hg), IOP was reduced by 3.2 +/- 1.3 mm Hg at 1 month and by 3.5 +/- 1.2 mm Hg (15.9% +/- 5.1%) at 2 months (ANOVA, P < 0.001; both Tukey-Kramer, P < 0.01 vs. baseline); after placebo (mean baseline IOP, 21.5 +/- 1.5 mm Hg), IOP was reduced by 0.4 +/- 1.2 mm Hg at 1 month and by 0.3 +/- 1.3 mm Hg at 2 months (t-test at both time points, P < 0.001 vs. PEA). No statistically significant vital signs, visual field, visual acuity changes, or adverse events were detected in either group. CONCLUSIONS: Systemic administration of PEA reduces IOP in patients with glaucoma and ocular hypertension. PEA could be a valuable tool for the treatment of glaucoma (http://www.umin.ac.jp/ctr/index/htm number, UMIN000002833). PMID- 21705690 TI - Optical coherence tomography of the swollen optic nerve head: deformation of the peripapillary retinal pigment epithelium layer in papilledema. AB - PURPOSE. To examine the biomechanical deformation of load bearing structures of the optic nerve head (ONH) resulting from raised intracranial pressure, using high definition optical coherence tomography (HD-OCT). The authors postulate that elevated intracranial pressure induces forces in the retrolaminar subarachnoid space that can deform ONH structures, particularly the peripapillary Bruch's membrane (BM) and RPE layers. METHODS. The authors compared HD-OCT optic nerve and peripapillary retinal nerve fiber layer (RNFL) findings in eyes with papilledema caused by raised intracranial pressure to findings in eyes with optic disc swelling caused by optic neuritis and nonarteritic anterior ischemic optic neuropathy (NAION), conditions without intracranial hypertension. The authors measured average thickness of the RNFL and the angle of the RPE/BM at the temporal and nasal borders of the neural canal opening. The angle was measured as positive with inward (toward the vitreous) angulation and as negative with outward angulation. RESULTS. Of 30 eyes with papilledema, 20 eyes (67%) had positive RPE/BM rim angles. One of eight optic neuritis (12%) eyes and 1 of 12 NAION (8%) eyes had positive angulation. In five eyes with papilledema, RNFL thickening increased, three of which developed positive RPE/BM angles. On follow up, 22 papilledema eyes had a reduction of RNFL swelling, and 17 of these eyes had less positive RPE/BM angulation. CONCLUSIONS. In papilledema, the RPE/BM is commonly deflected inward, in contrast to eyes with NAION or optic neuritis. The RPE/BM angulation is presumed to be caused by elevated pressure in the subarachnoid space, does not correlate with the amount of RNFL swelling, and resolves as papilledema subsides. PMID- 21705691 TI - Effort-reward imbalance at work and recurrent coronary heart disease events: a 4 year prospective study of post-myocardial infarction patients. AB - OBJECTIVE: Prospective studies have shown that effort-reward imbalance (ERI) at work is associated with the incidence of a first coronary heart disease (CHD) event. However, it is unknown whether ERI at work increases the risk of recurrent CHD events. The objective of this study was to determine whether ERI at work and its components (effort and reward) increase the risk of recurrent CHD in post myocardial infarction (post-MI) workers. METHODS: We carried out a prospective cohort study of 669 men and 69 women who returned to work after a first MI. ERI at work was assessed by telephone interview using validated scales of reward and psychological demands. The outcome was a composite of fatal CHD, nonfatal MI, and unstable angina. CHD risk factors were documented in medical files and by interview. The participants were followed up for a mean period of 4.0 years (1998 2005). RESULTS: During the follow-up, 96 CHD events were documented. High ERI and low reward were associated with recurrent CHD (respective adjusted hazard ratios [HRs] = 1.75, 95% confidence interval [CI] = 0.99-3.08, and HR = 1.77, 95% CI = 1.16-2.71). There was a gender interaction showing stronger effects among women (respective adjusted HRs for high ERI and low reward: HR = 3.95, 95% CI = 0.93 16.79, and HR = 9.53, 95% CI = 1.15-78.68). CONCLUSIONS: Post-MI workers holding jobs that involved ERI or low reward had increased risk of recurrent CHD. PMID- 21705692 TI - Effort-reward imbalance at work and psychological distress: a validation study of post-myocardial infarction patients. AB - OBJECTIVES: To examine whether the psychometric properties of the effort-reward imbalance (ERI) at work scales could be replicated with post-myocardial infarction (post-MI) patients and to measure the criterion validity through its association with psychological distress. METHODS: A cross-sectional survey was conducted among 814 patients (739 men and 75 women) who had returned to work after their first MI and who were followed up by telephone at an average of 2.2 years after their baseline interview (1998-2000). The psychological demands scale of the Karasek Job Content Questionnaire was used to measure effort. Reward was measured with nine items from the original reward scale by Siegrist plus two proxy items. Exploratory and confirmatory factor analyses were used to test the theoretical structure of ERI. Using log-binomial regression models, we evaluated the association between ERI scales and psychological distress measured with the 14-item Psychiatric Symptom Index. RESULTS: ERI scales and subscales demonstrated adequate internal consistencies. Exploratory factor analysis using oblique (promax) rotation yielded a three-factor solution with items representative of extrinsic effort (Factor 1) and reward subscales (Factors 2 and 3). Confirmatory factor analysis demonstrated a good fit with the data. The internal consistencies and discriminant validities of the ERI scales were satisfactory. Furthermore, effort, reward, and ERI ratio were significantly associated with psychological distress (adjusted prevalence ratio [PR] = 1.71, 95% confidence interval [CI] = 1.26-2.31; PR = 1.63, 95% CI = 1.16-2.29; and PR = 1.70, 95% CI = 1.17-2.47, respectively). CONCLUSIONS: The psychometric properties of the ERI scales were generally reproduced among post-MI patients. The associations with psychological distress supported the criterion validity of the ERI scales in this population. PMID- 21705711 TI - Perfluoroalkyl sulfonates cause alkyl chain length-dependent hepatic steatosis and hypolipidemia mainly by impairing lipoprotein production in APOE*3-Leiden CETP mice. AB - Perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) are stable perfluoroalkyl sulfonate (PFAS) surfactants, and PFHxS and PFOS are frequently detected in human biomonitoring studies. Some epidemiological studies have shown modest positive correlations of serum PFOS with non-high-density lipoprotein (HDL)-cholesterol (C). This study investigated the mechanism underlying the effect of PFAS surfactants on lipoprotein metabolism. APOE*3-Leiden.CETP mice were fed a Western-type diet with PFBS, PFHxS, or PFOS (30, 6, and 3 mg/kg/day, respectively) for 4-6 weeks. Whereas PFBS modestly reduced only plasma triglycerides (TG), PFHxS and PFOS markedly reduced TG, non-HDL-C, and HDL-C. The decrease in very low-density lipoprotein (VLDL) was caused by enhanced lipoprotein lipase-mediated VLDL-TG clearance and by decreased production of VLDL-TG and VLDL-apolipoprotein B. Reduced HDL production, related to decreased apolipoprotein AI synthesis, resulted in decreased HDL. PFHxS and PFOS increased liver weight and hepatic TG content. Hepatic gene expression profiling data indicated that these effects were the combined result of peroxisome proliferator-activated receptor alpha and pregnane X receptor activation. In conclusion, the potency of PFAS to affect lipoprotein metabolism increased with increasing alkyl chain length. PFHxS and PFOS reduce plasma TG and total cholesterol mainly by impairing lipoprotein production, implying that the reported positive correlations of serum PFOS and non-HDL-C are associative rather than causal. PMID- 21705712 TI - Extrapolating the acute behavioral effects of toluene from 1- to 24-h exposures in rats: roles of dose metric and metabolic and behavioral tolerance. AB - Recent research on the acute effects of volatile organic compounds suggests that extrapolation from short (~1 h) to long durations (up to 4 h) may be improved by using estimates of brain toluene concentration (Br[Tol]) instead of cumulative inhaled dose (C * t) as a metric of dose. This study compared predictions of these two dose metrics on the acute behavioral effects of inhaled toluene in rats during exposures up to 24 h in duration. We first evaluated estimates of Br[Tol] with a physiologically based toxicokinetic (PBTK) model for rats intermittently performing an operant task while inhaling toluene for up to 24 h. Exposure longer than 6 h induced P450-mediated metabolism of toluene. Adjusting the corresponding parameters of the PBTK model improved agreement between estimated and observed values of Br[Tol] in the 24-h exposure scenario. Rats were trained to perform a visual signal detection task and were then tested while inhaling toluene (0, 1125, and 1450 ppm for 24 h and 1660 ppm for 21 h). Tests occurred at times yielding equivalent C * t products but different estimates of Br[Tol], and also at 1 and 6 h afterexposure. Effects of toluene were better predicted by Br[Tol] than by C * t. However, even using Br[Tol] as the dose metric (after accounting for metabolic induction), acute dose-effect functions during 24-h exposures were shifted to the right relative to 1-h exposures, indicating that a dynamic behavioral tolerance also developed during prolonged exposure to toluene. PMID- 21705713 TI - Gender-specific interplay of signaling through beta-catenin and CAR in the regulation of xenobiotic-induced hepatocyte proliferation. AB - Aberrant signaling through the Wnt/beta-catenin pathway is a critical determinant in human and rodent liver carcinogenesis and generally accepted to be a potent driver of proliferation. Xenobiotic agonists of the constitutive androstane receptor (CAR) induce massive acute hyperplasia of mouse liver and facilitate the outgrowth of hepatocellular carcinomas with activated beta-catenin. In the present study, the interplay of beta-catenin-dependent and CAR-dependent signaling in the liver and its effect on hepatocyte proliferation were analyzed in transgenic mice with hepatocyte-specific knockout of Ctnnb1 (encoding beta catenin) following treatment with two CAR agonists, 1,4-bis[2-(3,5 dichloropyridyloxy)]-benzene (TCPOBOP) and phenobarbital. Hepatocyte-specific knockout of beta-catenin inhibited CAR agonists-induced hepatocyte proliferation in male mice. By contrast, the proliferative effect of CAR agonists was strongly augmented in female beta-catenin knockout animals. This was due to prolonged proliferation of the knockout hepatocytes. CAR-mediated hepatocyte proliferation was, at least in part, dependent on estrogen signaling and was associated with enhanced expression of FoxM1 and elevated activity of the PDK1/p90RSK pathway. In conclusion, our study shows that gender-specific factors determine whether beta catenin signaling plays a pro- or an antiproliferative role in the regulation of mouse hepatocyte proliferation induced by CAR agonists. PMID- 21705714 TI - A validated hybrid computational fluid dynamics-physiologically based pharmacokinetic model for respiratory tract vapor absorption in the human and rat and its application to inhalation dosimetry of diacetyl. AB - Diacetyl vapor is associated with bronchiolar injury in man but primarily large airway injury in the rat. The goal of this study was to develop a physiologically based pharmacokinetic model for inspired vapor dosimetry and to apply the model to diacetyl. The respiratory tract was modeled as a series of airways: nose, trachea, main bronchi, large bronchi, small bronchi, bronchioles, and alveoli with tissue dimensions obtained from the literature. Airborne vapor was allowed to absorb (or desorb) from tissues based on mass transfer coefficients. Transfer of vapor within tissues was based on molecular diffusivity with direct reaction with tissue substrates and/or metabolism being allowed in each tissue compartment. In vitro studies were performed to provide measures of diacetyl metabolism kinetics and direct reaction rates allowing for the development of a model with no unassigned variables. Respiratory tract uptake of halothane, acetone, ethanol and diacetyl was measured in male F344 rat to obtain data for model validation. The human model was validated against published values for inspired vapor uptake. For both the human and rat models, a close concordance of model estimates with experimental measurements was observed, validating the model. The model estimates that limited amounts of inspired diacetyl penetrate to the bronchioles of the rat (<2%), whereas in the lightly exercising human, 24% penetration to the bronchioles is estimated. Bronchiolar tissue concentrations of diacetyl in the human are estimated to exceed those in the rat by 40-fold. These inhalation dosimetric differences may contribute to the human-rat differences in diacetyl-induced airway injury. PMID- 21705715 TI - The synthetic gestagen levonorgestrel impairs metamorphosis in Xenopus laevis by disruption of the thyroid system. AB - Synthetic gestagens, including levonorgestrel (LNG), are active compounds in contraceptives, and several studies report their occurrence in surface waters. However, information about endocrine-disrupting effects in nontarget organisms is scarce. The present study investigated effects of LNG exposure on thyroid hormone dependent metamorphosis of Xenopus laevis. Premetamorphic X. laevis tadpoles at Nieuwkoop and Faber (NF) stage 48 were exposed in a flow-through culture system to four LNG concentrations (10(-11), 10(-10), 10(-9), and 10(-8)M) over the period of metamorphosis. At NF 58 and 66, tadpoles were examined sex specifically. Developmental time and organismal responses were recorded and correlated with molecular and histopathological endpoints. Exposure to 10(-8)M LNG caused an inhibition of metamorphosis resulting in developmental arrest at early climax stages as giant tadpoles or tailed frogs. In brain-pituitary tissue of NF 58 tadpoles, gene expression of thyroid-stimulating hormone (beta-subunit; TSHbeta), TH receptor beta (TRbeta), and deiodinase type 3 (D3) was not changed. Instead, prolactin (PRL) messenger RNA (mRNA) was significantly increased by 10( 9)M LNG in females and by 10(-8)M LNG in both sexes. In NF 66 tadpoles, mRNA levels of TSHbeta mRNA were significantly increased in the 10(-9) and 10(-8)M LNG treatment groups indicating a hypothyroid state. No changes of TRbeta, D3, and PRL gene expression were detected. Histopathological evaluation of thyroid gland sections revealed no typical sign of hypothyroidism but rather an inactivated appearance of the thyroid. In conclusion, our data demonstrate for the first time a completely new aspect of thyroid system disruption caused by synthetic gestagens in developing amphibians. PMID- 21705716 TI - Twenty-four hour human urine and serum profiles of bisphenol a during high dietary exposure. AB - By virtue of its binding to steroid hormone receptors, bisphenol A (BPA, the unconjugated bioactive monomer) is hypothesized to be estrogenic when present in sufficient quantities in the body, raising concerns that widespread exposure to BPA may impact human health. To better understand the internal exposure of adult humans to BPA and the relationship between the serum and urinary pharmacokinetics of BPA, a clinical exposure study was conducted. Blood and urine samples were collected approximately hourly over a 24-h period from 20 adult volunteers who ingested 100% of one of three specified meals comprising standard grocery store food items for breakfast, lunch, and dinner. The volunteers' average consumption of BPA, estimated from the urinary excretion of total BPA ((TOT)BPA = conjugated BPA + BPA), was 0.27 MUg/kg body weight (range, 0.03-0.86), 21% greater than the 95th percentile of aggregate exposure in the adult U.S. population. A serum time course of (TOT)BPA was observable only in individuals with exposures 1.3-3.9 times higher than the 95th percentile of aggregate U.S. exposure. The (TOT)BPA urine concentration T(max) was 2.75 h (range, 0.75-5.75 h) post-meal, lagging the serum concentration T(max) by ~1 h. Serum (TOT)BPA area under the curve per unit BPA exposure was between 21.5 and 79.0 nM*h*kg/MUg BPA. Serum (TOT)BPA concentrations ranged from less than or equal to limit of detection (LOD, 1.3 nM) to 5.7 nM and were, on average, 42 times lower than urine concentrations. During these high dietary exposures, (TOT)BPA concentrations in serum were undetectable in 83% of the 320 samples collected and BPA concentrations were determined to be less than or equal to LOD in all samples. PMID- 21705718 TI - How to compose a manuscript review for the Journal of Ultrasound in Medicine. PMID- 21705717 TI - Differences in tissue distribution of HBCD alpha and gamma between adult and developing mice. AB - Hexabromocyclododecane (HBCD) is a mixture of three stereoisomers alpha (alpha), beta (beta), and gamma (gamma). gamma-HBCD dominates the mixture (~70%), and despite alpha-HBCD's minor contribution to global HBCD production and usage (~10%), it is the dominant congener found in most biotic samples worldwide. Evidence of toxicity and lack of stereoisomer studies drives the importance of understanding HBCD toxicokinetics in potentially susceptible populations. The majority of public health concern has focused on hazardous effects resulting from exposure of infants and young children to HBCD due to reports on adverse developmental effects in rodent studies, in combination with human exposure estimates suggesting that nursing infants and young children have the highest exposure to HBCD. This study was designed to investigate differences in the disposition of both gamma-HBCD and alpha-HBCD in infantile mice reported to be susceptible to the HBCD commercial mixture. The tissue distribution of alpha [(14)C]HBCD- and gamma-[(14)C]HBCD-derived radioactivity was monitored in C57BL/6 mice following a single oral dose of either compound (3 mg/kg) after direct gavage at postnatal day 10. Mice were held up to 7 days in shoebox cages after which pups were sacrificed, tissue collected, and internal dosimetry was measured. Developing mice exposed to alpha-HBCD had an overall higher body burden than gamma-HBCD at every time point measured; at 4 days postexposure, they retained 22% of the alpha-HBCD administered dose, whereas pups exposed to gamma HBCD retained 10%. Total body burden in infantile mice after exposure to gamma HBCD was increased 10-fold as compared with adults. Similarly, after exposure to alpha-HBCD, infantile mice contained 2.5-fold higher levels than adult. These differences lead to higher concentrations of the HBCD diastereomers at target tissues during critical windows of development. The results indicate that the toxicokinetics of the two HBCD diastereomers differ between developing and adult mice; whereas distribution patterns are similar, concentrations of each HBCD diastereomer's-derived radioactivity are higher in the pup's liver, fat, kidney, brain, blood, muscle, and lungs than in the adult's. This study suggests that developmental stage may be a risk factor for the harmful effects of alpha-HBCD and gamma-HBCD, when developing animals may be more sensitive to effects and have increased body burden. PMID- 21705719 TI - Fracture status in men assessed by quantitative ultrasound measurements at the calcaneus. AB - OBJECTIVES: The aim of the study was to assess fracture status in men by quantitative ultrasound measurements at the calcaneus. The diagnostic accuracy of quantitative ultrasound measurements was evaluated at baseline and follow-up. METHODS: We observed 165 men (baseline age +/- SD, 59.84 +/- 10.6 years) recruited from an outpatient osteoporosis clinic. The mean follow-up duration was approximately 101.3 +/- 35 months. There was no difference in either age or body mass index at baseline between the patients with a fracture history (n = 30) and the others (n = 135). The following fractures were identified at baseline: ankle, 15; wrist, 10; rib, 9; foot, 5; and hip, 1. The speed of sound (meters per second), broadband ultrasound attenuation (decibels per megahertz), and stiffness index (percent) were measured with a quantitative ultrasound device. The date of fracture occurrence at follow-up was defined as the final point. RESULTS: In the patients with a fracture history, the ultrasound variables were significantly lower than those in the rest of the group (P < .05). During the follow-up period, fractures occurred in 21 patients (wrist, 11; ankle, 5; rib, 3; hip, 1; and humerus, 1), and the ultrasound outcomes were nonsignificantly lower in the fractured men. The risk of fracture was estimated by the Cox regression analysis. A prior fracture was the only factor that significantly (4 times) increased the risk of a subsequent fracture (hazard ratio, 4.21; 95% confidence interval, 1.81 9.86; P < .001). CONCLUSIONS: Calcaneus ultrasound measurements can distinguish between patients with fractures and those without. In follow-up, ultrasound measurements did not indicate an increased fracture risk; a prior osteoporotic fracture was the major prognostic factor. PMID- 21705720 TI - Quantitative ultrasound measurement of the calcaneus in Southeast Asian children with thalassemia: comparison with dual-energy X-ray absorptiometry. AB - OBJECTIVES: The purpose of this study was to test the hypothesis that quantitative ultrasound properties of the calcaneus in Southeast Asian children treated for thalassemia have different characteristics than those of their healthy counterparts and thereby can be used for assessing the risk of osteoporosis. METHODS: Broadband ultrasound attenuation and the speed of sound were measured from groups of thalassemic and healthy children and compared with bone mineral density (BMD) estimated from dual-energy X-ray absorptiometry to determine intergroup and intragroup dependencies of the measurements and variations with differences in sex and anthropometric characteristics. RESULTS: Broadband ultrasound attenuation and speed of sound measurements were found to be independent of sex but dependent on age in the thalassemic children. Consistently, broadband ultrasound attenuation had lower values and the speed of sound had higher values compared with those of the healthy children in each age group. Broadband ultrasound attenuation correlated well with the speed of sound and also with age, weight, and height, but the speed of sound did not show an association with these parameters. Broadband ultrasound attenuation correlated moderately with BMD in the lumbar spine and whole body, but the corresponding association was much weaker for the speed of sound. In the thalassemic children, both broadband ultrasound attenuation and BMD increased with age as they grew older but not fast enough compared with the healthy children, and the risk of osteoporosis was greater at older ages. CONCLUSIONS: Calcaneal quantitative ultrasound may be used as a diagnostic screening tool for assessing the bone status in thalassemic Southeast Asian children and for deciding whether further dual-energy X-ray absorptiometry is needed, particularly in those who are at a greater risk for osteoporosis as identified by low body weight and height. PMID- 21705721 TI - Sonographic measurement of thyroid volumes in healthy Chinese infants aged 0 to 12 months. AB - OBJECTIVES: The purposes of this study were to determine thyroid volumes in healthy Chinese infants aged 0 to 12 months and to provide reference data for normal thyroid growth. METHODS: A total of 408 healthy infants (229 male and 179 female) were enrolled in the study. The length, breadth, and depth of the thyroid gland were measured with sonography. The volume of each lobe was calculated by the correct ellipsoid formula (volume = length * breadth * depth * 0.479). RESULTS: All of the infants' thyroids showed a normal uniform echo texture on sonography. The thyroid volume increased with age (r = 0.519; P < .001). Moreover, positive associations were noted between thyroid volume and height and weight (r = 0.517; P < . 001; r = 0.499; P < .001, respectively). No significant differences based on sex were found (t = 1.784; P = .075). CONCLUSIONS: The thyroid volumes in these healthy Chinese infants varied from those reported in the published literature on healthy European infants. It is important to establish local reference ranges for thyroid volumes in healthy infants. PMID- 21705722 TI - Variables influencing the accuracy of 2-dimensional and real-time 3-dimensional echocardiography for assessment of small volumes, areas, and distances: an in vitro study using static tissue-mimicking phantoms. AB - OBJECTIVES: The aim of this study was to assess the validity, accuracy, and reproducibility of real-time 3-dimensional (3D) echocardiography for small distances, areas, and volumes. METHODS: Real-time 3D echocardiography using matrix technology was performed in small calibrated tissue-mimicking phantoms and compared with 2-dimensional (2D) echocardiography. In a systematic variation of variables on data acquisition and analysis including different 3D workstations (manual disk summation versus semiautomatic border detection), the relative contributions of sources of errors were determined. The clinical relevance of the in vitro findings was assessed in 5 neonates and infants. RESULTS: Distance calculation was valid (mean relative error +/- SD, -0.15% +/- 1.2%). Underestimation of areas and volumes was significant for both 2D and 3D echocardiography (area: 2D, -7.0% +/- 2.9%; 3D, -6.0% +/- 2.8%; volume: 2D, 13.1% +/- 4.5%; 3D, -6.7% +/- 2.5%; P < .05). Adjustment of compression and gain on data acquisition (difference of the means: 2D, 11.6%; 3D, 17.9%), gain on postprocessing (3D, 3.4%), and the border detection algorithm on analysis (2D, 4.8%; 3D, 16.6%) had a highly significant effect on volume and area calculations (P < .001). In vivo, compression and gain on acquisition (3D, 19.1%) and the 3D workstation on analysis (3D, 22.2%) had a highly significant impact on left ventricular volumetry (P < .001). CONCLUSIONS: Real-time 3D echocardiography is a reliable method for calculation of small distances, areas, and volumes comparable with the size of the neonatal and infant heart. Variables influencing boundary identification during image acquisition and analysis have a significant impact on 2D and 3D area and volume calculations. Standardized protocols are mandatory to avoid these sources of error in both clinical practice and research. PMID- 21705723 TI - Varicocele and epididymitis in Behcet disease. AB - OBJECTIVE: Behcet disease is a systemic disease with protean manifestations. Vasculitis is a hallmark of the disease and may involve arteries, veins, and capillaries. Varicocele is dilatation of the pampiniform plexus veins. We aimed to investigate the incidence of varicocele in patients with Behcet disease. METHODS: The study included 47 male patients with Behcet disease and 31 healthy control participants. All underwent a clinical evaluation including a medical history and systemic and scrotal examinations. Subsequently, 2 investigators blinded to the clinical data performed sonographic examinations and measured pampiniform plexus vein diameters. RESULTS: The mean age of the patients +/- SD was 23.4 +/- 3.2 years; disease durations ranged from 3 to 120 months (46 +/- 31 months). Scrotal pain or a palpable mass was detected by clinical examination in 24 patients with Behcet disease (51.1%) and 5 healthy participants (16.1%; P = .002). By color Doppler examination, left varicocele was diagnosed in 26 patients with Behcet disease (55.3%) and 9 healthy participants (29%; P = .02). All patients with right varicocele also had left varicocele; that condition was detected in 10.6% (5 patients) of the Behcet disease group and 6.4% (2 patients) of the control group (P > .05). Eight patients with Behcet disease (17%) had epididymitis, whereas none of the healthy participants did (P = .019, Fisher exact test). Genital ulcers and erythema nodosum lesions were more common among patients with varicocele (P = .034 and .058, respectively). There were no differences in smoking, epididymitis, arthritis, uveitis, or other clinical parameters for distinguishing varicocele in patients with Behcet disease. CONCLUSIONS: The incidence of varicocele was increased in Behcet disease. Whether varicocele confers fertility problems in patients with Behcet disease and the underlying mechanism for a possible association are yet to be determined. PMID- 21705724 TI - Inter-reader differences in common carotid artery intima-media thickness: implications for cardiovascular risk assessment and vascular age determination. AB - OBJECTIVES: Far wall common carotid artery intima-media thickness, a surrogate measure of atherosclerosis, requires the tracing of two carotid wall interfaces on ultrasound images: the lumen-intima and media-adventitia. Vascular age is derived from intima-media thickness measurements. We studied how tracing the wall interfaces affects intima-media thickness measurements and estimates of vascular age. METHODS: Five readers made far-wall common carotid intima-media thickness measurements on 26 carotid artery images. Each reader traced lines at the lumen intima and media-adventitia interfaces. An observer, blinded to reader identity and intima-media thickness values, reviewed the images and estimated the relative location of these lines compared to his judgment of the interface location: +1 for 1 pixel above the interface, 0 at the interface, and -1 if below. The significance of differences was evaluated by analysis of variance. RESULTS: Mean intima-media thickness measurements ranged between 0.57 and 0.78 mm and showed significant differences between readers (P < .009). Differences in carotid intima media thickness measurements made by the readers were significantly associated with the location of the media-adventitia interfaces (P < .0001) but not the lumen-intima interfaces (P = .07). The intima-media thickness differences corresponded to mean differences in estimated vascular age ranging from 14 to 21 years. CONCLUSIONS: Inter-reader differences in common carotid intima-media thickness measurements are mostly seen for the media-adventitia wall interface and are detectable by an experienced observer. These inter-reader differences affect the use of intima-media thickness measurements for cardiovascular risk evaluation, can cause substantial errors in vascular age estimates, and might be correctable by performing replicate readings of standard image sets. PMID- 21705725 TI - A triple-targeted ultrasound contrast agent provides improved localization to tumor vasculature. AB - OBJECTIVES: Actively targeting ultrasound contrast agents to tumor vasculature improves contrast-enhanced sonography of tumor angiogenesis. This report summarizes an evaluation of multitargeted microbubbles, comparing single-, dual-, and triple-targeted motifs. METHODS: Microbubbles were avidin-biotin linked to antibodies against mouse alpha(V)beta(3)-integrin, P-selectin, and vascular endothelial growth factor receptor 2. These receptors are constitutively overexpressed in tumor vasculature. Binding comparisons between targeted microbubble groups were evaluated on mouse SVR angiosarcoma endothelial cells. Levels of the targeted receptors were characterized with flow cytometry. Targeted microbubble groups were administered to human MDA-MB-231 breast cancer tumor bearing mice (n = 3) followed by contrast-enhanced sonography in a microbubble sensitive harmonic imaging mode implemented on an ultrasound scanner equipped with a linear array transducer (5 MHz transmit and 10 MHz receive) to evaluate differences in microbubble accumulation in the tumor vasculature. RESULTS: In vitro analysis showed a 50% increase (P < .001) in triple-targeted microbubble binding over dual-targeted microbubble groups in mouse SVR cells. Mice bearing MDA-MB-231 tumors showed a 40% increase in tumor image intensity after dosing with triple-targeted microbubbles compared with single- and dual-targeted microbubbles (P = .006). Histologic staining confirmed the presence of alpha(V)beta(3)-integrin, P-selectin, and vascular endothelial growth factor receptor 2 in the tumors. CONCLUSIONS: Microbubble accumulation in the tumor vasculature was improved using a triple-targeted microbubble approach. PMID- 21705726 TI - Ultrasound contrast agents affect the angiogenic response. AB - OBJECTIVES: The interaction of ultrasound contrast agents (UCAs) and ultrasound (US) provides a way to spatially and temporally target tissues. Recently, UCAs have been used therapeutically to induce localized angiogenesis. Ultrasound contrast agents, however, have been documented to induce negative bioeffects. To further understand the balance of risks and benefits of UCAs and to examine the mechanism of US-UCA-induced angiogenesis, this study explored the role of UCAs, in particular Definity (Lantheus Medical Imaging, Inc, North Billerica, MA), in producing an angiogenic response. METHODS: The gracilis muscles of Sprague Dawley rats were exposed to 1-MHz US. The rats were euthanized the same day or allowed to recover for 3 or 6 days post exposure (DPE). Ultrasound peak rarefactional pressures (P(r)s) of 0.25, 0.83, 1.4, and 2.0 MPa were used while rats were infused with either saline or Definity. Assessments for angiogenesis included capillary density, inflammation, and vascular endothelial growth factor (VEGF), both acutely (0 DPE) and at 3 and 6 DPE. RESULTS: The results of this study suggest that the angiogenic response is dependent on infusion media, P(r), and DPE. While capillary density did not reach significance, VEGF expression was significant for infusion media, P(r), and DPE with inflammation co-occurrence (P < .05). CONCLUSIONS: These results suggest that the angiogenic response is elicited by a mechanical effect of US-UCA stimulation of VEGF that is potentially optimized when collapse occurs. PMID- 21705727 TI - Stage IA ovarian cancers: comparison of sonographic findings and histopathologic types between patients with normal and elevated serum cancer antigen 125 levels. AB - OBJECTIVES: The purpose of this study was to compare sonographic findings and histopathologic types of stage IA ovarian cancers between groups with normal and elevated cancer antigen 125 (CA-125) levels. METHODS: Between 2000 and 2009, 146 stage IA ovarian cancers were treated surgically (85 invasive and 61 borderline, 73 self-referred with tumor-related symptoms, 20 self-referred with nonspecific symptoms, 52 identified through screening, and 1 other). Of these, 87 cases (60%) had normal serum CA-125 levels (<35 U/mL). Their pre-operative sonographic findings and histopathologic types were compared to those of cases with elevated CA-125 levels. RESULTS: Statistically significant differences were found between the proportions of patients with elevated CA-125 levels in groups having tumors with maximal diameters of less than 20 cm and at least 20 cm (P = .03) and groups having tumors with less than 50% and 50% to 80% solid components (P = .02). In the group with normal CA-125 levels, we found predominantly mucinous adenocarcinoma in multilocular cysts with less than 50% solid components (25 cases), and clear cell adenocarcinoma in unilocular cysts with less than 50% solid components (12 cases), whereas in the group with elevated CA-125 levels, mucinous adenocarcinoma in multilocular cysts with less than 50% solid components (19 cases) and endometrioid adenocarcinoma in solid tumors (>=80% solid components) were predominant (5 cases). CONCLUSIONS: Stage IA ovarian cancers with normal CA-125 levels tend to be smaller, have less solid components, and have a slightly different distribution of histopathologic types than cancers with elevated CA-125 levels. PMID- 21705728 TI - Gray scale and power Doppler study of biopsy-proven Kikuchi disease. AB - OBJECTIVES: Kikuchi disease is a benign, self-limiting cause of cervical lymphadenopathy. It can show sonographic features similar to those of other common causes of lymphadenopathy. The purpose of this study was to characterize the sonographic features of Kikuchi disease that can contribute in differentiating between Kikuchi disease and other diseases causing cervical lymphadenopathy. METHODS: Sonographic findings of 175 patients with biopsy-proven Kikuchi disease were retrospectively reviewed. The mean age of the patients was 27.3 years, and the female to male ratio was 3.5:1. All patients had undergone sonographically guided core biopsy. Pathologic findings were classified into proliferative (n = 57), necrotizing (n = 109), and xanthomatous (n = 9) types. On gray scale sonography, lymph nodes were assessed by their size, shape (shortest/longest axis ratio), location, echogenicity, presence of conglomeration, gross necrosis, calcification, echogenic nodal hilum, and increased perinodal echogenicity. The vascular pattern was assessed on power Doppler imaging. RESULTS: The mean maximum diameter of the lymph nodes was 1.6 cm. Forty-four percent of them (77 of 175) were oval (shortest/longest axis ratio, 0.5-0.7) and 48% (84 of 175) were elongated (shortest/longest axis ratio, <0.5). Most were located in levels II and V. Seventeen lymph nodes showed gross necrosis, and none showed calcification. One hundred fifty-two lymph nodes (86.8%) had an echogenic hilum, and 76% (133 of 175) showed increased perinodal echogenicity. Increased perinodal echogenicity was seen in 93.5% of the necrotizing type (102 of 109) and 43.8% of the proliferative type (25 of 57); the difference between the two types was statistically significant (P = .001). Normal (n = 161), displaced (n = 13), and absent (n = 1) hilar vascularity was seen on power Doppler studies. CONCLUSIONS: Sonographic findings of Kikuchi disease can contribute to the differentiation between Kikuchi disease and other causes of cervical lymphadenopathy. PMID- 21705729 TI - Comparison of sonography and computed tomography as imaging tools for assessment of airway structures. AB - OBJECTIVES: The aim of this study was to compare airway anatomic parameters as measured by sonography and computed tomography (CT). METHODS: Fifteen adult patients underwent CT followed by sonography of the anterior neck under standard conditions. A radiologist and an anesthesiologist with experience in airway imaging examined the scans and performed measurements of specific airway parameters: distance to the posterior surface of the tongue, thickness of the submental region, hyomental distance, depth of the epiglottis from skin (above and below the hyoid bone), thyrohyoid distance, depth of the arytenoid cartilage from skin, and fat pad thickness at the thyroid cartilage. After performing the measurements, they compared the images by the two modalities for descriptions of the structures. Means and SDs were calculated for the measurements, and a paired t test was performed to determine statistically significant differences in the measurements by sonography and CT. RESULTS: The means of all parameters were closely related except hyomental distance (sonography, 5.23 +/- 0.58 cm; CT, 3.50 +/- 0.42 cm). The paired t test showed that the mean values for depth of the epiglottis below the hyoid (3.89 versus 4.17 cm; P = .31), thyrohyoid distance (1.03 versus 1.02 cm; P = .95), and depth of the arytenoid cartilage (2.90 versus 2.66 cm; P = .21) were not significantly different as measured by sonography and CT, respectively. CONCLUSIONS: The study shows that sonography can reliably image all of the structures visualized by CT, and in general, infrahyoid parameters agree well between the two modalities, as opposed to suprahyoid parameters, which may be affected by unintentional head extension. PMID- 21705730 TI - Reproducibility of shear wave velocity measurements by acoustic radiation force impulse imaging of the liver: a study in healthy volunteers. AB - OBJECTIVES: The purposes of this study were to investigate interobserver reproducibility using acoustic radiation force impulse imaging and to develop an acoustic radiation force impulse scoring system. METHODS: Fifty healthy volunteers with normal liver function test values were selected for the study. Shear wave velocity measurements, expressed in meters per second, were taken in a deep portion of liver segment 6. Two observers with different levels of experience performed the measurements independently and blindly. RESULTS: All of the measurements taken by the 2 observers were valid, even in volunteers with a body mass index of greater than 28 kg/m(2). The results point to very good interobserver reproducibility of shear wave velocity measurements, with an intraclass coefficient correlation of 0.86 (P < .001). CONCLUSIONS: The results of this study show that shear wave velocity measurements using the acoustic radiation force impulse technique and a standardized protocol are accurate and reproducible. PMID- 21705731 TI - Ultrasound biosafety during pregnancy: what do operators know in the developing world?: national survey findings from pakistan. AB - OBJECTIVES: The purpose of this study was to evaluate the knowledge and attitudes of ultrasound users toward safety aspects during routine obstetric examinations. METHODS: A self-administered questionnaire was given to all registered participants of the 10th Annual International Radiological Conference in Karachi, Pakistan. RESULTS: A total of 306 participants completed the questionnaire (response rate, 70%), including 170 consultant radiologists (55%), 90 radiology residents (30%), 31 sonographers (10%), and 15 others (5%). The mean sonography experience of the end users +/- SD was 5.1 +/- 5 years. Around half of the participants (45.5%) reported that there should be limitations on the use of ultrasound during low-risk pregnancy. Overall, safety knowledge was inadequate among the participants. However, those who were concerned about limitations on the use of ultrasound during pregnancy were 2.5 times more likely to be familiar with the mechanical index (P < .001) and 1.8 times more likely to be familiar with the thermal index (P < .001). CONCLUSIONS: Increased training for professionals on safety issues of ultrasound procedures during pregnancy is needed. Furthermore, the concept of the absolute safety of ultrasound procedures without knowledge of safety parameters such as the mechanical and thermal indices needs to be changed, and more clarity is required when defining parameters under which the procedures can be safely performed. PMID- 21705732 TI - Observed prevalence of congenital heart defects from a surveillance study in China. AB - OBJECTIVES: The purpose of this study was to estimate the prevalence of major and minor congenital heart defects among fetuses and neonates using sonography in a general population of 4 areas surrounding Shanghai, China. METHODS: Pregnant women were recruited between April 2004 and December 2005 in Jiaxing City, Suzhou City, Changshu County, and Haining County. All participants could have 3 sonographic examinations performed by specially trained physicians regardless of medical indication: a fetal sonographic screen and fetal echocardiography between 20 and 28 weeks' gestation and neonatal echocardiography. Diagnoses of congenital heart defects were made on the basis of review of all available scans by an international group of experts in pediatric cardiology. Prevalence rates were calculated per 1000 births. RESULTS: Among 4006 scanned fetuses and neonates, there were 75 congenital heart defects, including 12 major defects. The observed prevalence for all congenital heart defects was 18.7 (95% confidence interval, 14.8-23.5) per 1000 births, and the prevalence for major defects was 3.0 (95% confidence interval, 1.6-5.2) per 1000 births. The most common defects were ventricular septal defects (n = 47 [62.7%]), atrial septal defects (n = 14 [18.7%]), tetralogy of Fallot (n = 4 [5.3%]), and hypoplastic left heart syndrome (n = 3 [4.0%]). CONCLUSIONS: The prevalence of all congenital heart defects in the 4 areas of China studied was higher than that reported in other countries, with ventricular septal defects being the most frequent defects. Our data likely reflect a better estimate of the total prevalence of congenital heart defects in China than reported previously. PMID- 21705733 TI - Cervical length changes from the first to second trimester of pregnancy, and prediction of preterm birth by first-trimester sonographic cervical measurement. AB - OBJECTIVES: The purpose of this study was to examine the evolution of cervical length from the first to second trimester of pregnancy and the value of first trimester cervical measurement in the prediction of preterm delivery. METHODS: We conducted a longitudinal prospective study. Cervical length was measured by transvaginal sonography at 11 to 14 weeks (Cx1), 16 to 19 weeks (Cx2), and 20 to 24 weeks (Cx3). RESULTS: Eight hundred singleton pregnancies were studied. The median cervical lengths were 33 mm for Cx1 and 31 mm for Cx2 and Cx3. Significant independent predictors for cervical length were maternal weight, height, and history of cervical surgery for Cx1, maternal height, history of cervical surgery, and history of preterm delivery for Cx2, and history of cervical surgery, history of first-trimester miscarriage, and history of spontaneous preterm delivery for Cx3. Mean cervical length shortening was 2.36 mm between Cx1 and Cx3. In the subgroups of women with previous cervical surgery and history of previous preterm birth, cervical shortening was significantly more prominent. The median Cx1 was significantly shorter in the women who subsequently delivered preterm; Cx1 predicted preterm delivery before 34 weeks (odds ratio, 0.746; 95% confidence interval, 0.649-0.869) and preterm delivery before 32 weeks (odds ratio, 0.734; 95% confidence interval, 0.637-0.912). CONCLUSIONS: Cervical length in the first trimester depends on maternal characteristics and a history of cervical surgery. The cervix exhibits minimal changes from 11 to 24 weeks for most women, although the shortening is more prominent in women with a history of cervical surgery or preterm delivery. First-trimester cervical length measurement can predict preterm delivery. PMID- 21705734 TI - Collaborative study on 3-dimensional sonography for the prenatal diagnosis of central nervous system defects. AB - OBJECTIVES: Prenatal diagnosis of central nervous system (CNS) anomalies by 2 dimensional sonography is challenging because of difficulties in obtaining complete visualization of the fetal brain during routine examinations, which is necessary for identification of its axial, coronal, and sagittal planes. Three dimensional (3D) sonography has been introduced as a tool for studying the fetal CNS because of its ability to facilitate examinations of the fetal brain. The objective of this study was to determine inter-center agreement in diagnosing CNS defects by review of 3D volume data sets. METHODS: This study included 11 centers with expertise in 3D fetal neurosonography. A total of 217 fetuses with and without confirmed CNS defects were scanned after 18 weeks' gestation, and their volume data sets were uploaded onto a centralized file transfer protocol server and later analyzed by all of the centers. Intercenter agreement was determined using a kappa statistic for multiple raters. RESULTS: All volumes were made anonymous and sent to the centers for blinded analysis with the exception of the data sets they had themselves previously uploaded. For identification of fetuses with CNS defects, the sensitivity, specificity, positive and negative predictive values, and false-positive and -negative rates were 93.3%, 96.5%, 96.5%, 93.3%, 3.5%, and 6.7%, respectively. No differences were found in the efficacy of the diagnostic indices according to either the route of acquisition (transabdominal or trans-vaginal) or the gestational age at diagnosis (18-24 or >24 weeks). Intercenter agreement was excellent (kappa = 0.92; 95% confidence interval, 0.88 0.97). CONCLUSIONS: Among centers with technical expertise, remote review of 3D sonographic volumes of the fetal CNS resulted in an accurate and reliable method for diagnosis of fetal brain malformations. PMID- 21705735 TI - Diagnosis of fetal limb abnormalities before 15 weeks: cause for concern. AB - OBJECTIVES: The purposes of this study were (1) to identify cases of limb abnormalities identified before 15 weeks and correlate with outcomes and (2) to assess first-trimester nuchal translucency examinations to determine how frequently the upper and lower limbs were identified. METHODS: A retrospective review was conducted of sonographic studies up to 15 weeks' gestational age from 2003 to 2010 at our high-risk fetal center. Data were collected regarding fetal gestational age, limb abnormalities, associated anatomic abnormalities, pregnancy outcomes, karyotypes, autopsy results, and the utility of transabdominal sonography, transvaginal sonography, and 3-dimensional sonography. A retrospective analysis of 100 consecutive first-trimester examinations was also conducted to assess the sensitivity of transabdominal sonography in visualization of limb buds. RESULTS: A total of 15 cases were identified with a mean gestational age of 12 weeks 6 days. Club hand was the most common abnormality seen (8 cases), followed by absence of long bones (5 cases), a missing limb (5 cases), club foot (5 cases), shortening of long bones (2 cases), abnormal hands (2 cases), clenched hands (2 cases), and overlapping digits (1 case). Trisomy 18 was present in 9 cases. Transabdominal sonography allowed for detection of all limb buds in 100 consecutive nuchal translucency examinations and 9 of 15 cases of limb abnormalities. Four of the cases resulted in fetal death, and the remaining 11 cases were terminated. CONCLUSIONS: Fetal limb abnormalities can be detected on sonography before 15 weeks' gestational age and are often associated with serious congenital conditions, especially trisomy 18. Transabdominal sonography alone can show most of these abnormalities, although transvaginal and 3-dimensional sonography can provide additional information. Targeted evaluation of fetal limbs during sonography before 15 weeks should be considered in high risk populations. PMID- 21705736 TI - Fetal polydactyly: a study of 24 cases ascertained by prenatal sonography. AB - Records of 24 pregnancies with fetal polydactyly were reviewed for the type of polydactyly, family history, associated sonographic findings, genetic testing, and postnatal/postmortem examination findings. The importance of fetal polydactyly can be mainly elucidated by the family history and absent or associated anomalies on a specialized malformation scan. Fetal karyotyping diagnoses frequent chromosomal anomalies in about half of cases with additional malformations, and array comparative genomic hybridization may be a future means of detecting cryptic chromosomal aberrations. Syndromic disorders of monogenic origin demand a careful interdisciplinary clinical assessment for establishing a clinical diagnosis and prognosis for the outcome of the child. PMID- 21705737 TI - Bilateral tardus-parvus waveforms in a patient with aortic coarctation. PMID- 21705738 TI - Transcranial sonography of basal ganglia calcifications in Fahr disease. PMID- 21705739 TI - Sonographic findings of parosteal lipoma of the radius causing posterior interosseous nerve compression with radiographic and magnetic resonance imaging correlation. PMID- 21705740 TI - The impact of depression on dual tasking among patients with high fall risk. AB - Depression predicts fall risk among older adults, and this relationship may be partially explained by depression-associated executive dysfunction, relevant to navigating demanding environments. This pilot study examined timed stepping accuracy under simple and complex dual-task conditions, using an instrumented walkway based on the Trail Making Test. Participants were balance-impaired older adults, either with (n = 8; major depressive disorder [MDD]) or without (n = 8; nondepressed [ND]) MDD. After accounting for comfortable gait speed and age, the MDD group was significantly slower than the ND group on the walkway with the highest cognitive demand and demonstrated greater dual-task cost, both of which were correlated with performance on traditional measures of executive functioning. No group differences were observed on the walkway with the least cognitive demand. Balance-impaired older adults with MDD demonstrate increased stepping accuracy time under cognitively demanding conditions, reflecting executive dysfunction and an additional contribution to increased fall risk. PMID- 21705741 TI - From the editors. BOR launches the "World of reproductive biology". PMID- 21705744 TI - Subchronic oral toxicity study of furan in B6C3F1 Mice. AB - Furan is a heterocyclic organic compound formed during heat treatment for processing and preservation of various types of food. Rodent studies have previously shown that furan is a hepatocarcinogen. Those studies were conducted over a high dose range, which induced tumors at nearly 100% incidence at all doses. This ninety-day gavage study in mice was conducted to extend the dose to a lower range (0.0, 0.03, 0.12, 0.5, 2.0, and 8.0 mg/kg body weight [bw] per day) to identify a no-observed adverse effect level for hepatotoxicity and to characterize non-neoplastic effects, including those affecting clinical biochemistry, hematology, tissue morphology, and histopathology. The liver was the primary target organ with dose-dependent toxicity. Liver weights were increased at the 8.0 mg/kg bw dose in females only. Levels of the serum enzyme alanine transaminase, representative of liver damage, were increased three-fold at the highest dose. Histological changes in the liver were observed at 2.0 and 8.0 mg/kg bw in both sexes. Although clinical parameters were also altered for the kidney, these differences were not accompanied by histological changes. Based on these clinical biochemical and histological changes, a no-observed adverse effect level of 0.12 mg/kg bw per day of furan in mice is suggested. PMID- 21705745 TI - Effect of environmental contaminants on Beta cell function. AB - There is an increasing concern that chemicals in the environment are contributing to the global rise in the prevalence of type 2 diabetes (T2D). However, there is limited evidence for direct effects of these chemicals on beta cell function. Therefore, the goals of this study were (1) to test the hypothesis that environmental contaminants can directly affect beta cell function and (2) examine mechanistic pathways by which these contaminants could affect beta cell function. Using mouse beta TC-6 cells, we examined the acute effects of 6 substances (benzo[a]pyrene, bisphenol A [BPA], propylparaben, methylparaben, perfluorooctanoic acid, and perfluorooctyl sulfone) on insulin secretion. Only BPA treatment directly affected insulin secretion. Furthermore, chronic exposure to BPA altered the expression of key proteins in the cellular and endoplasmic reticulum stress response. These data suggest that long-term BPA exposure may be detrimental to beta cell function and ultimately be an important contributor to the etiology of T2D. PMID- 21705746 TI - Imputation of missing genotypes from sparse to high density using long-range phasing. AB - Related individuals share potentially long chromosome segments that trace to a common ancestor. We describe a phasing algorithm (ChromoPhase) that utilizes this characteristic of finite populations to phase large sections of a chromosome. In addition to phasing, our method imputes missing genotypes in individuals genotyped at lower marker density when more densely genotyped relatives are available. ChromoPhase uses a pedigree to collect an individual's (the proband) surrogate parents and offspring and uses genotypic similarity to identify its genomic surrogates. The algorithm then cycles through the relatives and genomic surrogates one at a time to find shared chromosome segments. Once a segment has been identified, any missing information in the proband is filled in with information from the relative. We tested ChromoPhase in a simulated population consisting of 400 individuals at a marker density of 1500/M, which is approximately equivalent to a 50K bovine single nucleotide polymorphism chip. In simulated data, 99.9% loci were correctly phased and, when imputing from 100 to 1500 markers, more than 87% of missing genotypes were correctly imputed. Performance increased when the number of generations available in the pedigree increased, but was reduced when the sparse genotype contained fewer loci. However, in simulated data, ChromoPhase correctly imputed at least 12% more genotypes than fastPHASE, depending on sparse marker density. We also tested the algorithm in a real Holstein cattle data set to impute 50K genotypes in animals with a sparse 3K genotype. In these data 92% of genotypes were correctly imputed in animals with a genotyped sire. We evaluated the accuracy of genomic predictions with the dense, sparse, and imputed simulated data sets and show that the reduction in genomic evaluation accuracy is modest even with imperfectly imputed genotype data. Our results demonstrate that imputation of missing genotypes, and potentially full genome sequence, using long-range phasing is feasible. PMID- 21705747 TI - Genetic drift widens the expected cline but narrows the expected cline width. AB - Random genetic drift shifts clines in space, alters their width, and distorts their shape. Such random fluctuations complicate inferences from cline width and position. Notably, the effect of genetic drift on the expected shape of the cline is opposite to the naive (but quite common) misinterpretation of classic results on the expected cline. While random drift on average broadens the overall cline in expected allele frequency, it narrows the width of any particular cline. The opposing effects arise because locally, drift drives alleles to fixation--but fluctuations in position widen the expected cline. The effect of genetic drift can be predicted from standardized variance in allele frequencies, averaged across the habitat: . A cline maintained by spatially varying selection (step change) is expected to be narrower by a factor of ?1- relative to the cline in the absence of drift. The expected cline is broader by the inverse of this factor. In a tension zone maintained by underdominance, the expected cline width is narrower by about 1- relative to the width in the absence of drift. Individual clines can differ substantially from the expectation, and we give quantitative predictions for the variance in cline position and width. The predictions apply to clines in almost one-dimensional circumstances such as hybrid zones in rivers, deep valleys, or along a coast line and give a guide to what patterns to expect in two dimensions. PMID- 21705748 TI - Hitchhiking effect of a beneficial mutation spreading in a subdivided population. AB - A central problem in population genetics is to detect and analyze positive natural selection by which beneficial mutations are driven to fixation. The hitchhiking effect of a rapidly spreading beneficial mutation, which results in local removal of standing genetic variation, allows such an analysis using DNA sequence polymorphism. However, the current mathematical theory that predicts the pattern of genetic hitchhiking relies on the assumption that a beneficial mutation increases to a high frequency in a single random-mating population, which is certainly violated in reality. Individuals in natural populations are distributed over a geographic space. The spread of a beneficial allele can be delayed by limited migration of individuals over the space and its hitchhiking effect can also be affected. To study this effect of geographic structure on genetic hitchhiking, we analyze a simple model of directional selection in a subdivided population. In contrast to previous studies on hitchhiking in subdivided populations, we mainly investigate the range of sufficiently high migration rates that would homogenize genetic variation at neutral loci. We provide a heuristic mathematical analysis that describes how the genealogical structure at a neutral locus linked to the locus under selection is expected to change in a population divided into two demes. Our results indicate that the overall strength of genetic hitchhiking--the degree to which expected heterozygosity decreases--is diminished by population subdivision, mainly because opportunity for the breakdown of hitchhiking by recombination increases as the spread of the beneficial mutation across demes is delayed when migration rate is much smaller than the strength of selection. Furthermore, the amount of genetic variation after a selective sweep is expected to be unequal over demes: a greater reduction in expected heterozygosity occurs in the subpopulation from which the beneficial mutation originates than in its neighboring subpopulations. This raises a possibility of detecting a "hidden" geographic structure of population by carefully analyzing the pattern of a selective sweep. PMID- 21705749 TI - Sex-specific incompatibility generates locus-specific rates of introgression between species. AB - Disruption of interactions among ensembles of epistatic loci has been shown to contribute to reproductive isolation among various animal and plant species. Under the Bateson-Dobzhansky-Muller model, such interspecific incompatibility arises as a by-product of genetic divergence in each species, and the Orr-Turelli model indicates that the number of loci involved in incompatible interactions may "snowball" over time. We address the combined effect of multiple incompatibility loci on the rate of introgression at neutral marker loci across the genome. Our analysis extends previous work by accommodating sex specificity: differences between the sexes in the expression of incompatibility, in rates of crossing over between neutral markers and incompatibility loci, and in transmission of markers or incompatibility factors. We show that the evolutionary process at neutral markers in a genome subject to incompatibility selection is well approximated by a purely neutral process with migration rates appropriately scaled to reflect the influence of selection targeted to incompatibility factors. We confirm that in the absence of sex specificity and functional epistasis among incompatibility factors, the barrier to introgression induced by multiple incompatibility factors corresponds to the product of the barriers induced by the factors individually. A new finding is that barriers to introgression due to sex-specific incompatibility depart in general from multiplicativity. Our partitioning of variation in relative reproductive rate suggests that such departures derive from associations between sex and incompatibility and between sex and neutral markers. Concordant sex-specific incompatibility (for example, greater impairment of male hybrids or longer map lengths in females) induces lower barriers (higher rates of introgression) than expected under multiplicativity, and discordant sex-specific incompatibility induces higher barriers. PMID- 21705750 TI - Quantification of inbreeding due to distant ancestors and its detection using dense single nucleotide polymorphism data. AB - Inbreeding depression, which refers to reduced fitness among offspring of related parents, has traditionally been studied using pedigrees. In practice, pedigree information is difficult to obtain, potentially unreliable, and rarely assessed for inbreeding arising from common ancestors who lived more than a few generations ago. Recently, there has been excitement about using SNP data to estimate inbreeding (F) arising from distant common ancestors in apparently "outbred" populations. Statistical power to detect inbreeding depression using SNP data depends on the actual variation in inbreeding in a population, the accuracy of detecting that with marker data, the effect size, and the sample size. No one has yet investigated what variation in F is expected in SNP data as a function of population size, and it is unclear which estimate of F is optimal for detecting inbreeding depression. In the present study, we use theory, simulated genetic data, and real genetic data to find the optimal estimate of F, to quantify the likely variation in F in populations of various sizes, and to estimate the power to detect inbreeding depression. We find that F estimated from runs of homozygosity (Froh), which reflects shared ancestry of genetic haplotypes, retains variation in even large populations (e.g., SD=0.5% when Ne=10,000) and is likely to be the most powerful method of detecting inbreeding effects from among several alternative estimates of F. However, large samples (e.g., 12,000-65,000) will be required to detect inbreeding depression for likely effect sizes, and so studies using Froh to date have probably been underpowered. PMID- 21705751 TI - ELAV-mediated 3'-end processing of ewg transcripts is evolutionarily conserved despite sequence degeneration of the ELAV-binding site. AB - Regulation of alternative mRNA processing by ELAV (embryonic lethal abnormal visual system)/Hu proteins is mediated by binding to AU-rich elements of low complexity. Since such sequences diverge very rapidly during evolution, it has not been clear if ELAV regulation is maintained over extended phylogenetic distances. The transcription factor Erect wing (Ewg) is a major target of ELAV in Drosophila melanogaster and coordinates metabolic gene expression with regulation of synaptic plasticity. Here, we demonstrate evolutionary conservation of ELAV regulation of ewg despite massive degeneration of its binding site and of associated elements in the regulated intronic 3'-end processing site in distantly related Drosophila virilis. In this species, the RNA-binding part of ELAV protein is identical to D. melanogaster. ELAV expression as well as expression and regulation of ewg are also conserved. Using in vitro binding assays and in vivo transgene analysis, we demonstrate, however, that the ELAV-binding site of D. virilis is fully functional in regulating alternative splicing of ewg intron 6 in D. melanogaster. Known features of the ELAV-binding site, such as the requirement of multiple poly(U) motifs spread over an extended binding site of ~150 nt and a higher affinity to the 3' part of the binding site, are conserved. We further show that the 135-bp ELAV-binding site from D. melanogaster is sufficient for ELAV recruitment in vivo. Hence, our data suggest that ELAV/Hu protein-regulated alternative RNA processing is more conserved than anticipated from the alignment of degenerate low-complexity sequences. PMID- 21705752 TI - A flexible estimating equations approach for mapping function-valued traits. AB - In genetic studies, many interesting traits, including growth curves and skeletal shape, have temporal or spatial structure. They are better treated as curves or function-valued traits. Identification of genetic loci contributing to such traits is facilitated by specialized methods that explicitly address the function valued nature of the data. Current methods for mapping function-valued traits are mostly likelihood-based, requiring specification of the distribution and error structure. However, such specification is difficult or impractical in many scenarios. We propose a general functional regression approach based on estimating equations that is robust to misspecification of the covariance structure. Estimation is based on a two-step least-squares algorithm, which is fast and applicable even when the number of time points exceeds the number of samples. It is also flexible due to a general linear functional model; changing the number of covariates does not necessitate a new set of formulas and programs. In addition, many meaningful extensions are straightforward. For example, we can accommodate incomplete genotype data, and the algorithm can be trivially parallelized. The framework is an attractive alternative to likelihood-based methods when the covariance structure of the data is not known. It provides a good compromise between model simplicity, statistical efficiency, and computational speed. We illustrate our method and its advantages using circadian mouse behavioral data. PMID- 21705753 TI - Functional dissection of the neural substrates for sexual behaviors in Drosophila melanogaster. AB - The male-specific Fruitless proteins (FruM) act to establish the potential for male courtship behavior in Drosophila melanogaster and are expressed in small groups of neurons throughout the nervous system. We screened ~1000 GAL4 lines, using assays for general courtship, male-male interactions, and male fertility to determine the phenotypes resulting from the GAL4-driven inhibition of FruM expression in subsets of these neurons. A battery of secondary assays showed that the phenotypic classes of GAL4 lines could be divided into subgroups on the basis of additional neurobiological and behavioral criteria. For example, in some lines, restoration of FruM expression in cholinergic neurons restores fertility or reduces male-male courtship. Persistent chains of males courting each other in some lines results from males courting both sexes indiscriminately, whereas in other lines this phenotype results from apparent habituation deficits. Inhibition of ectopic FruM expression in females, in populations of neurons where FruM is necessary for male fertility, can rescue female infertility. To identify the neurons responsible for some of the observed behavioral alterations, we determined the overlap between the identified GAL4 lines and endogenous FruM expression in lines with fertility defects. The GAL4 lines causing fertility defects generally had widespread overlap with FruM expression in many regions of the nervous system, suggesting likely redundant FruM-expressing neuronal pathways capable of conferring male fertility. From associations between the screened behaviors, we propose a functional model for courtship initiation. PMID- 21705754 TI - Ectopic gene expression and organogenesis in Arabidopsis mutants missing BRU1 required for genome maintenance. AB - Chromatin reconstitution after DNA replication and repair is essential for the inheritance of epigenetic information, but mechanisms underlying such a process are still poorly understood. Previously, we proposed that Arabidopsis BRU1 functions to ensure the chromatin reconstitution. Loss-of-function mutants of BRU1 are hypersensitive to genotoxic stresses and cause release of transcriptional gene silencing of heterochromatic genes. In this study, we show that BRU1 also plays roles in gene regulation in euchromatic regions. bru1 mutations caused sporadic ectopic expression of genes, including those that encode master regulators of developmental programs such as stem cell maintenance and embryogenesis. bru1 mutants exhibited adventitious organogenesis, probably due to the misexpression of such developmental regulators. The key regulatory genes misregulated in bru1 alleles were often targets of PcG SET-domain proteins, although the overlap between the bru1-misregulated and PcG SET-domain-regulated genes was limited at a genome-wide level. Surprisingly, a considerable fraction of the genes activated in bru1 were located in several subchromosomal regions ranging from 174 to 944 kb in size. Our results suggest that BRU1 has a function related to the stability of subchromosomal gene regulation in the euchromatic regions, in addition to the maintenance of chromatin states coupled with heritable epigenetic marks. PMID- 21705755 TI - A survey for novel imprinted genes in the mouse placenta by mRNA-seq. AB - Many questions about the regulation, functional specialization, computational prediction, and evolution of genomic imprinting would be better addressed by having an exhaustive genome-wide catalog of genes that display parent-of-origin differential expression. As a first-pass scan for novel imprinted genes, we performed mRNA-seq experiments on embryonic day 17.5 (E17.5) mouse placenta cDNA samples from reciprocal cross F1 progeny of AKR and PWD mouse strains and quantified the allele-specific expression and the degree of parent-of-origin allelic imbalance. We confirmed the imprinting status of 23 known imprinted genes in the placenta and found that 12 genes reported previously to be imprinted in other tissues are also imprinted in mouse placenta. Through a well-replicated design using an orthogonal allelic-expression technology, we verified 5 novel imprinted genes that were not previously known to be imprinted in mouse (Pde10, Phf17, Phactr2, Zfp64, and Htra3). Our data suggest that most of the strongly imprinted genes have already been identified, at least in the placenta, and that evidence supports perhaps 100 additional weakly imprinted genes. Despite previous appearance that the placenta tends to display an excess of maternally expressed imprinted genes, with the addition of our validated set of placenta-imprinted genes, this maternal bias has disappeared. PMID- 21705756 TI - Pathways of resistance to thymineless death in Escherichia coli and the function of UvrD. AB - Thymineless death (TLD) is the rapid loss of viability in bacterial, yeast, and human cells starved of thymine. TLD is the mode of action of common anticancer drugs and some antibiotics. TLD in Escherichia coli is accompanied by blocked replication and chromosomal DNA loss and recent work identified activities of recombination protein RecA and the SOS DNA-damage response as causes of TLD. Here, we examine the basis of hypersensitivity to thymine deprivation (hyper-TLD) in mutants that lack the UvrD helicase, which opposes RecA action and participates in some DNA repair mechanisms, RecBCD exonuclease, which degrades double-stranded linear DNA and works with RecA in double-strand-break repair and SOS induction, and RuvABC Holliday-junction resolvase. We report that hyper-TLD in uvrD cells is partly RecA dependent and cannot be attributed to accumulation of intermediates in mismatch repair or nucleotide-excision repair. These data imply that both its known role in opposing RecA and an additional as-yet-unknown function of UvrD promote TLD resistance. The hyper-TLD of ruvABC cells requires RecA but not RecQ or RecJ. The hyper-TLD of recB cells requires neither RecA nor RecQ, implying that neither recombination nor SOS induction causes hyper-TLD in recB cells, and RecQ is not the sole source of double-strand ends (DSEs) during TLD, as previously proposed; models are suggested. These results define pathways by which cells resist TLD and suggest strategies for combating TLD resistance during chemotherapies. PMID- 21705757 TI - Effect of growth under selection on appearance of chromosomal mutations in Salmonella enterica. AB - Populations adapt physiologically using regulatory mechanisms and genetically by means of mutations that improve growth. During growth under selection, genetic adaptation can be rapid. In several genetic systems, the speed of adaptation has been attributed to cellular mechanisms that increase mutation rates in response to growth limitation. An alternative possibility is that growth limitation serves only as a selective agent but acts on small-effect mutations that are common under all growth conditions. The genetic systems that initially suggested stress induced mutagenesis have been analyzed without regard for multistep adaptation and some include features that make such analysis difficult. To test the selection-only model, a simpler system is examined, whose behavior was originally attributed to stress-induced mutagenesis (Yang et al. 2001, 2006). A population with a silent chromosomal lac operon gives rise to Lac+ revertant colonies that accumulate over 6 days under selection. Each colony contains a mixture of singly and doubly mutant cells. Evidence is provided that the colonies are initiated by pre-existing single mutants with a weak Lac+ phenotype. Under selection, these cells initiate slow-growing clones, in which a second mutation arises and improves growth of the resulting double mutant. The system shows no evidence of general mutagenesis during selection. Selection alone may explain rapid adaptation in this and other systems that give the appearance of mutagenesis. PMID- 21705759 TI - The joint effects of background selection and genetic recombination on local gene genealogies. AB - Background selection, the effects of the continual removal of deleterious mutations by natural selection on variability at linked sites, is potentially a major determinant of DNA sequence variability. However, the joint effects of background selection and genetic recombination on the shape of the neutral gene genealogy have proved hard to study analytically. The only existing formula concerns the mean coalescent time for a pair of alleles, making it difficult to assess the importance of background selection from genome-wide data on sequence polymorphism. Here we develop a structured coalescent model of background selection with recombination and implement it in a computer program that efficiently generates neutral gene genealogies for an arbitrary sample size. We check the validity of the structured coalescent model against forward-in-time simulations and show that it accurately captures the effects of background selection. The model produces more accurate predictions of the mean coalescent time than the existing formula and supports the conclusion that the effect of background selection is greater in the interior of a deleterious region than at its boundaries. The level of linkage disequilibrium between sites is elevated by background selection, to an extent that is well summarized by a change in effective population size. The structured coalescent model is readily extendable to more realistic situations and should prove useful for analyzing genome-wide polymorphism data. PMID- 21705758 TI - Novel rank-based approaches for discovery and replication in genome-wide association studies. AB - In recent years, genome-wide association studies (GWAS) have uncovered a large number of susceptibility variants. Nevertheless, GWAS findings provide only tentative evidence of association, and replication studies are required to establish their validity. Due to this uncertainty, researchers often focus on top ranking SNPs, instead of considering strict significance thresholds to guide replication efforts. The number of SNPs for replication is often determined ad hoc. We show how the rank-based approach can be used for sample size allocation in GWAS as well as for deciding on a number of SNPs for replication. The basis of this approach is the "ranking probability": chances that at least j true associations will rank among top u SNPs, when SNPs are sorted by P-value. By employing simple but accurate approximations for ranking probabilities, we accommodate linkage disequilibrium (LD) and evaluate consequences of ignoring LD. Further, we relate ranking probabilities to the proportion of false discoveries among top u SNPs. A study-specific proportion can be estimated from P-values, and its expected value can be predicted for study design applications. PMID- 21705760 TI - Loss of Drosophila melanogaster p21-activated kinase 3 suppresses defects in synapse structure and function caused by spastin mutations. AB - Microtubules are dynamic structures that must elongate, disassemble, and be cleaved into smaller pieces for proper neuronal development and function. The AAA ATPase Spastin severs microtubules along their lengths and is thought to regulate the balance between long, stable filaments and shorter fragments that seed extension or are transported. In both Drosophila and humans, loss of Spastin function results in reduction of synaptic connections and disabling motor defects. To gain insight into how spastin is regulated, we screened the Drosophila melanogaster genome for deletions that modify a spastin overexpression phenotype, eye size reduction. One suppressor region deleted p21-activated kinase 3 (pak3), which encodes a member of the Pak family of actin-regulatory enzymes, but whose in vivo function is unknown. We show that pak3 mutants have only mild synaptic defects at the larval neuromuscular junction, but exhibit a potent genetic interaction with spastin mutations. Aberrant bouton morphology, microtubule distribution, and synaptic transmission caused by spastin loss of function are all restored to wild type when pak3 is simultaneously reduced. Neuronal overexpression of pak3 induces actin-rich thin projections, suggesting that it functions in vivo to promote filopodia during presynaptic terminal arborization. pak3 therefore regulates synapse development in vivo, and when mutated, suppresses the synaptic defects that result from spastin loss. PMID- 21705763 TI - Association between maternal intimate partner violence victimization and childhood immunization in India. AB - Empirical evidence regarding the relationship between use of child health services and maternal intimate partner violence (IPV) exposure is sparse. The present study examined the relationship between maternal IPV and childhood immunization status in India using the nationally representative NFHS-3 (n = 6947). Exposure was past year IPV and the outcome was full immunization. IPV victimization was associated with decreased likelihood of being fully immunized after controlling for a range of socio-demographic variables. We also found that differences in measurement of the immunization status (self-report vs. health card) had different implications for the observed association; women reporting IPV and not having the vaccination card were most vulnerable to lack of immunization of their children. Findings suggest the need for increased programmatic efforts to prevent both the prevalence of IPV as well as the multiple MCH consequences of such violence. PMID- 21705761 TI - CLAVATA signaling pathway receptors of Arabidopsis regulate cell proliferation in fruit organ formation as well as in meristems. AB - The CLAVATA1 (CLV1), CLV2, and CORYNE (CRN) receptors in Arabidopsis thaliana maintain cell proliferation in shoot apical meristems by restricting expression of the transcription factor WUSCHEL (WUS). Previously characterized receptor mutants generate extra fruit and floral organs that are proposed to arise from enlarged floral meristems (FMs). We identified new alleles in clv1, clv2, and crn and found that most mutants produce only extra fruit organs and generate FMs of similar dimensions as wild type. Characterization of gynoecium development in receptor mutants revealed increased cell proliferation and ectopic fruit organ initiation after FM termination. These regions of increased cell division also display expanded expression of the cell proliferation-promoting transcription factor SHOOTMERISTEMLESS (STM), similar to the expansion of WUS expression in the shoot apical meristems of strong clv1 mutants. We also examined genetic interactions between the ERECTA (ER) and BARELY ANY MERISTEM 1 (BAM1) receptor like kinases and CLV pathway receptors. Our results suggest a model in which CLV1/BAM1 and CLV2/CRN complexes act in separate, parallel pathways in shoot meristems, while the CLV1, CLV2, and CRN receptors function together in a linear pathway during fruit development. These results demonstrate the importance of regulating cell proliferation in plants that undergo organogenesis throughout their life cycle. PMID- 21705762 TI - Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure. AB - The emerging paradigm for Na(+) current in heart failure (HF) is that its transient component (I(NaT)) responsible for the action potential (AP) upstroke is decreased, whereas the late component (I(NaL)) involved in AP plateau is augmented. Here we tested whether Na(v)beta(1)- and Na(v)beta(2)-subunits can modulate I(NaL) parameters in normal and failing ventricular cardiomyocytes (VCMs). Chronic HF was produced in nine dogs by multiple sequential coronary artery microembolizations, and six dogs served as a control. I(Na) and APs were measured by the whole cell and perforated patch-clamp in freshly isolated and cultured VCMs, respectively. I(NaL) was augmented with slower decay in HF VCMs compared with normal heart VCMs, and these properties remained unchanged within 5 days of culture. Post-transcriptional silencing SCN1B and SCN2B were achieved by virally delivered short interfering RNA (siRNA) specific to Na(v)beta(1) and Na(v)beta(2). The delivery and efficiency of siRNA were evaluated by green fluorescent protein expression, by the real-time RT-PCR, and Western blots, respectively. Five days after infection, the levels of mRNA and protein for Na(v)beta(1) and Na(v)beta(2) were reduced by >80%, but mRNA and protein of Na(v)1.5, as well as I(NaT), remained unchanged in HF VCMs. Na(v)beta(1)-siRNA reduced I(NaL) density and accelerated I(NaL) two-exponential decay, whereas Na(v)beta(2)-siRNA produced an opposite effect in VCMs from both normal and failing hearts. Physiological importance of the discovered I(NaL) modulation to affect AP shape and duration was illustrated both experimentally and by numerical simulations of a VCM excitation-contraction coupling model. We conclude that in myocytes of normal and failing dog hearts Na(v)beta(1) and Na(v)beta(2) exhibit oppositely directed modulation of I(NaL). PMID- 21705764 TI - Feasibility and effectiveness of early initiation of combination antiretroviral therapy in HIV-infected infants in a government clinic of Kwazulu-Natal, South Africa. AB - A recent randomized trial showed dramatic improvement in survival of HIV-infected infants receiving early combination antiretroviral therapy (cART). However, few data are available for resource-limited settings. Therefore we conducted a chart review of HIV-infected infants initiated on cART between 2005 and 2008. Of 129 treated infants, 94 completed 6 months, 62 completed 12 months, and 39 completed 18 months of cART. Median age at initiation of cART was 8.6 months (range 2.1 11.9) and 77.2% had advanced disease. Undetectable VL was found in 78.8% of children who reached 18 months of treatment. CD4% increased from a median of 15.4% at baseline to 33.1% at 18 months. Weight for age Z-score increased from a mean +/- SD of -2.7 +/- 1.97 to 0.02 +/- 1.10 at 18 months. Findings show favourable response to cART in HIV-infected infants outside a research environment, despite initial advanced disease. Efforts should be made to initiate cART as early as possible. PMID- 21705765 TI - Home care practices for newborns in rural southern Nepal during the first 2 weeks of life. AB - The provision of essential newborn care through integrated packages is essential to improving survival. We analyzed data on newborn care practices collected among infants who participated in a community-based trial in rural Nepal. Analysis focused on feeding, hygienic, skin/cord care and thermal care practices. Data were analyzed for 23,356 and 22,766 newborns on Days 1 and 14, respectively. About 56.6% of the babies were breastfed within 24 h and 80.4% received pre lacteal feeds within the first 2 weeks of life. Only 13.3% of the caretakers always washed their hands before caring for their infant. Massage with mustard oil was near universal, 82.2% of the babies slept in a warmed room and skin-to skin contact was rare (4.5%). Many of these commonly practiced behaviors are detrimental to the health and survival of newborns. Key areas to be addressed when designing a community-endorsed care package were identified. PMID- 21705767 TI - Brain tumour and infiltrations dosimetry of boron neutron capture therapy combined with 252Cf brachytherapy. AB - This article presents a dosimetric investigation of boron neutron capture therapy (BNCT) combined with (252)Cf brachytherapy for brain tumour control. The study was conducted through computational simulation in MCNP5 code, using a precise and discrete voxel model of a human head, in which a hypothetical brain tumour was incorporated. A boron concentration ratio of 1:5 for healthy-tissue: tumour was considered. Absorbed and biologically weighted dose rates and neutron fluency in the voxel model were evaluated. The absorbed dose rate results were exported to SISCODES software, which generates the isodose surfaces on the brain. Analyses were performed to clarify the relevance of boron concentrations in occult infiltrations far from the target tumour, with boron concentration ratios of 1:1 up to 1:50 for healthy-tissue:infiltrations and healthy-tissue:tumour. The average biologically weighted dose rates at tumour area exceed up to 40 times the surrounding healthy tissue dose rates. In addition, the biologically weighted dose rates from boron have the main contribution at the infiltrations, especially far from primary tumour. In conclusion, BNCT combined with (252)Cf brachytherapy is an alternative technique for brain tumour treatment because it intensifies dose deposition at the tumour and at infiltrations, sparing healthy brain tissue. PMID- 21705766 TI - Positional orthology: putting genomic evolutionary relationships into context. AB - Orthology is a powerful refinement of homology that allows us to describe more precisely the evolution of genomes and understand the function of the genes they contain. However, because orthology is not concerned with genomic position, it is limited in its ability to describe genes that are likely to have equivalent roles in different genomes. Because of this limitation, the concept of 'positional orthology' has emerged, which describes the relation between orthologous genes that retain their ancestral genomic positions. In this review, we formally define this concept, for which we introduce the shorter term 'toporthology', with respect to the evolutionary events experienced by a gene's ancestors. Through a discussion of recent studies on the role of genomic context in gene evolution, we show that the distinction between orthology and toporthology is biologically significant. We then review a number of orthology prediction methods that take genomic context into account and thus that may be used to infer the important relation of toporthology. PMID- 21705768 TI - Characterization of the multiple CRISPR loci on Streptomyces linear plasmid pSHK1. AB - The complete nucleotide sequence including the novel telomere sequence of Streptomyces linear plasmid pSHK1 consists of 187,263-bp, 158 genes, in which 51 genes resemble those of the linear plasmid SCP1 of Streptomyces coelicolor A3(2), and 20 genes encode transposases. Strikingly, the repetitive CRISPRs (clustered regularly interspaced short palindromic repeats) and cas (CRISPR-associated) genes were found, including a cluster of eight cas genes, in the order cas2B cas1B-cas3B-cas5-cas4-cas2A-cas1A-cas3A, bracketed by a pair of divergent CRISPRs, and five other dispersed CRISPRs. The cas2B-cas1B-cas3B-cas5 or cas4 cas2A-cas1A genes were co-transcribed. Protein-protein interactions between Cas5 and Cas1A, 2A, 2B, 3B were detected by yeast two-hybrids, indicating a critical role of Cas5 for the formation of protein complexes. By polymerase chain reaction and Southern hybridization, 12 cas4 genes including three on linear plasmids were found among 75 newly isolated Streptomyces strains. The paired-CRISPRs and bracketed cas were also conserved in several other Streptomyces or actinomycete species. However, unlike other bacteria, the CRISPRs-cas in pSHK1 could not provide immunity against introduction of phage PhiC31 and plasmid containing the particular spacers in Streptomyces. PMID- 21705769 TI - Socio-economic position predicts grip strength and its decline between 79 and 87 years: the Lothian Birth Cohort 1921. PMID- 21705771 TI - Educational disparities in quality of diabetes care in a universal health insurance system: evidence from the 2005 Korea National Health and Nutrition Examination Survey. AB - OBJECTIVE: To investigate educational disparities in the care process and health outcomes among patients with diabetes in the context of South Korea's universal health insurance system. DESIGN: Bivariate and multiple regression analyses of data from a cross-sectional health survey. SETTING: A nationally representative and population-based survey, the 2005 Korea National Health and Nutrition Examination Survey. PARTICIPANTS: Respondents aged 40 or older who self-reported prior diagnosis with diabetes (n= 1418). MAIN OUTCOME MEASURES: Seven measures of the care process and health outcomes, namely (i) receiving medical treatment for diabetes, (ii) ever received diabetes education, (iii) received dilated eye examination in the past year, (iv) received microalbuminuria test in the past year, (v) having activity limitation due to diabetes, (vi) poor self-rated health and (vii) self-rated health on a visual analog scale. RESULTS: Except for receiving medical care for diabetes, overall process quality was low, with only 25% having ever received diabetes education, 39% having received a dilated eye examination in the past year and 51% having received a microalbuminuria test in the past year. Lower education level was associated with both poorer care processes and poorer health outcomes, whereas lower income level was only associated with poorer health outcomes. CONCLUSION: While South Korea's universal health insurance system may have succeeded in substantially reducing financial barriers related to diabetes care, the quality of diabetes care is low overall and varies by education level. System-level quality improvement efforts are required to address the weaknesses of the health system, thereby mitigating educational disparities in diabetes care quality. PMID- 21705772 TI - Adherence to clinical practice guidelines and outcomes in diabetic patients. AB - OBJECTIVE: To examine the level of adherence to clinical practice guidelines and its relationship to outcomes in patients with diabetes. DESIGN: Retrospective cohort study. SETTING: A tertiary teaching hospital in Korea. PARTICIPANTS: Patients aged >=18 years with diabetes (n = 4994) who visited the study hospital once or more during 2004. MAIN OUTCOME MEASURES: The outcomes were mortality from the database of the Statistics Korea and end-stage renal disease (ESRD) incidence from ESRD registry in the Korean Society of Nephrology until December 2009. RESULTS: Testing rates for blood pressure, eye examination, HbA1c, renal function and lipid profiles were 93.9, 32.8, 84.9, 33.5 and 45.9%, respectively. The percentage of patients achieving each treatment goal was 27.8% for blood pressure, 44.2% for HbA1c and 49.4% for low-density lipoprotein (LDL) cholesterol. There were 11.7% patients with composite outcome (death and/or ESRD). Male gender, level of HbA1c (<7%), presence of HbA1c data, checking eye examination, presence of data on urine albumin-to-creatinine ratio (UACR) and having anti-platelet medication were associated with better outcome. CONCLUSIONS: The adherence to recommendations was unsatisfactory, especially in checking eye examination, testing UACR and LDL cholesterol, and achieving a target goal for each parameter. Guideline adherence was positively related to better prognosis. Active strategies to apply the guidelines to clinical practice should be developed to improve patient outcomes. PMID- 21705773 TI - Characterization and identification of essential residues of the glycoside hydrolase family 64 laminaripentaose-producing-beta-1, 3-glucanase. AB - Laminaripentaose-producing beta-1,3-glucanase (LPHase) from Streptomyces matensis DIC-108 uniquely catalyzes the hydrolysis of beta-1,3-glucan to release laminaripentaose as the predominant product. For studying this novel enzyme, the gene of LPHase was reconstructed with polymerase chain reaction and over expressed in Escherichia coli. The recombinant wild-type enzyme and various mutants were further purified to >90% homogeneity on an ion-exchange chromatograph. The catalysis of the recombinant LPHase is confirmed to follow a one-step single-displacement mechanism with (1)H-NMR spectrometry. To determine the amino-acid residues essential for the catalysis, more than ten residues, including five highly conserved residues--Asp(143), Glu(154), Asp(170), Asp(376) and Asp(377), were mutated. Among the mutants, E154Q, E154G, D174N and D174G significantly lost catalytic activity. Further investigation with chemical rescue using sodium azide on E154G and D174G confirmed that Glu(154) functions as the general acid whereas Asp(170) serves as the general base in a catalytic turnover. This work is the first report that provides direct information for the identification of the essential residues of GH-64 through kinetic examination. PMID- 21705770 TI - The prevalence of congenital uterine anomalies in unselected and high-risk populations: a systematic review. AB - BACKGROUND: The prevalence of congenital uterine anomalies in high-risk women is unclear, as several different diagnostic approaches have been applied to different groups of patients. This review aims to evaluate the prevalence of such anomalies in unselected populations and in women with infertility, including those undergoing IVF treatment, women with a history of miscarriage, women with infertility and recurrent miscarriage combined, and women with a history of preterm delivery. METHODS: Searches of MEDLINE, EMBASE, Web of Science and the Cochrane register were performed. Study selection and data extraction were conducted independently by two reviewers. Studies were grouped into those that used 'optimal' and 'suboptimal' tests for uterine anomalies. Meta-analyses were performed to establish the prevalence of uterine anomalies and their subtypes within the various populations. RESULTS: We identified 94 observational studies comprising 89 861 women. The prevalence of uterine anomalies diagnosed by optimal tests was 5.5% [95% confidence interval (CI), 3.5-8.5] in the unselected population, 8.0% (95% CI, 5.3-12) in infertile women, 13.3% (95% CI, 8.9-20.0) in those with a history of miscarriage and 24.5% (95% CI, 18.3-32.8) in those with miscarriage and infertility. Arcuate uterus is most common in the unselected population (3.9%; 95% CI, 2.1-7.1), and its prevalence is not increased in high risk groups. In contrast, septate uterus is the most common anomaly in high-risk populations. CONCLUSIONS: Women with a history of miscarriage or miscarriage and infertility have higher prevalence of congenital uterine anomalies compared with the unselected population. PMID- 21705774 TI - Apparent heterogeneity in the pIII-peptide fusion protein in single-phage clones isolated from peptide libraries. AB - Ligand homogeneity is an important issue in affinity chromatography. Using phages expressing peptides on the pIII protein, a heterogeneity in the binding of monoclonal phages was observed during affinity chromatography on supermacroporous cryogels. Fractions with different apparent binding affinities could be separated by stepwise elution. When these different fractions were re-applied, the respective differences in affinity were retained. However, when phage fractions with different apparent affinities were first amplified, an offspring was generated with again variable affinities. As the sequence of the peptide insert was the same, the heterogeneity must be ascribed to differences in avidity and although no direct evidence could be generated, we hypothesize that this is possibly due to phages displaying different numbers of the same peptide as a consequence of either proteolytic or packaging events during the amplification step in Escherichia coli. PMID- 21705776 TI - Republished review: Ocular manifestations of the antiphospholipid syndrome. AB - Antiphospholipid syndrome (APS) is an autoimmune disease characterised by a heterogenous group of antibodies directed against negatively charged phospholipids including antiphospholipid antibodies (aPL), anticardiolipin antibodies (aCL) and beta-2 glycoprotein I (abeta-2-GP1). The major features of this disorder include arterial and venous thrombosis and recurrent fetal loss. The vasculature of the eye is frequently involved and may be the presenting manifestation. A diagnosis of APS should be considered in a young patients without traditional thromboembolic risk factors presenting with ocular vaso occlusive disease. Management of these patients involves a team-approach with a haematologist/oncologist or rheumatologist to manage the coagulation status of these patients to prevent further systemic vascular occlusions. PMID- 21705775 TI - Republished review: Gene therapy for ocular diseases. AB - The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future. PMID- 21705777 TI - Three kinds of reflection. PMID- 21705778 TI - Fatigue and depression predict physician visits and work disability in women with primary Sjogren's syndrome: results from a cohort study. AB - OBJECTIVES: Patients with primary SS (pSS) are frequently suffering from multiple enduring disorders that raise the risk of work disability and require treatment by various health-care specialists. We aimed at determining predictors of physician visits and work disability in pSS patients. METHODS: Physician visits within the past 6 months, employment status and sick leave were compared among 176 female pSS patients and 115 age-matched controls. Dryness, pain, fatigue and depression were assessed by rating scales of the EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI), the Profile of Fatigue and Discomfort (PROFAD) and Patient Health Questionnaire depression measurements (PHQ-9). Factors associated with an increased number of physician visits and inability to work were determined by multivariate logistic regression analysis. RESULTS: Patients and controls were comparable in age and education, but differed significantly in the prevalence of depression (38.1 vs 7.9%, P < 0.001), the number of physician visits [17.0 (10.0) vs 6.5 (4.5); P < 0.001] and gainful employment (<=64 years: 52.8 vs 77.1% P < 0.001). Multivariate regression analyses revealed that depression (PHQ-9) and/or fatigue, particularly lack of stamina, but not dryness, were significantly associated with physician visits and working status in pSS patients. Patients with high ratings for the statement 'I have had difficulties to keep going, was easily worn out or lacking in energy' had a highly increased risk of not being gainfully employed (adjusted OR 4.1; 95% CI 1.5, 11.2; P < 0.001). CONCLUSION: In pSS, lack of stamina and/or depression cause a higher level of individual and societal burden than dry eyes and mouth. Fatigue and depression deserve more recognition as treatment targets in pSS. PMID- 21705779 TI - Autoregulatory circuit of human rpL3 expression requires hnRNP H1, NPM and KHSRP. AB - Alternative pre-mRNA splicing (AS) is a major mechanism that allows proteomic variability in eukaryotic cells. However, many AS events result in mRNAs containing a premature termination codon, which are degraded by nonsense-mediated mRNA decay (NMD) pathway. We have previously demonstrated that human rpL3 autoregulates its expression through the association of AS with NMD. In fact, overexpression of rpL3 promotes downregulation of canonical splicing and upregulation of alternative splicing that produces an NMD-targeted mRNA isoform. The result of these events is a decreased production of rpL3. We have also identified heterogeneous nuclear ribonucleoprotein (hnRNP) H1 as a splicing factor involved in the regulation of rpL3 alternative splicing and identified its regulatory cis-elements within intron 3 transcript. Here, we report that NPM and KHSRP are two newly identified proteins involved in the regulation of rpL3 gene expression via AS-NMD. We demonstrate that hnRNP H1, KHSRP and NPM can be found associated, and present also in ribonucleoproteins (RNPs) including rpL3 and intron 3 RNA in vivo, and describe protein-protein and RNA-protein interactions. Moreover, our data provide an insight on the crucial role of hnRNP H1 in the regulation of the alternative splicing of the rpL3 gene. PMID- 21705780 TI - Unique translation initiation of mRNAs-containing TISU element. AB - Translation Initiator of Short 5' UTR (TISU) is a unique regulatory element of both transcription and translation initiation. It is present in a sizable number of genes with basic cellular functions and a very short untranslated region (5' UTR). Here, we investigated translation initiation from short 5' UTR mRNAs with AUG in various contexts. Reducing 5' UTR length to the minimal functional size increases leaky scanning from weak and strong initiators but hardly affects translation initiation and ribosomal binding directed by TISU. Ribosome interaction with TISU mRNA is cap dependent and involves AUG downstream nucleotides that compensate for the absent 5' UTR contacts. Interestingly, eIF1 inhibits cap-proximal AUG selection within weak or strong contexts but not within TISU. Furthermore, TISU-directed translation is unaffected by inhibition of the RNA helicase eIF4A. Thus, TISU directs efficient cap-dependent translation initiation without scanning, a mechanism that would be advantageous when intracellular levels of eIF1 and eIF4A fluctuate. PMID- 21705781 TI - Spontaneous spinal epidural hematoma. PMID- 21705782 TI - A huge diaphragmatic schwannoma mimicking diaphragm palsy. PMID- 21705783 TI - Mortality predictors in hospitalized elderly patients. AB - AIM: To find out which of the two predictors, Charlson co-morbidity index or vitamin B12, better estimates the risk of in-hospital mortality in seriously ill patients. METHOD: Electronic hospital records of 1509 elderly patients aged 65 and older were retrospectively surveyed. RESULTS: Albumin, age and elevated vitamin B12 levels were significantly associated with increased in-hospital mortality. Charlson co-morbidity index was not significantly associated with death. The highest mortality (24.3%) was found in the group of patients who were concomitantly in the lowest albumin quartile and the highest vitamin B12 levels quartile. In this group, mortality increased significantly with age. By elasticity calculation, vitamin B12 capability to predict mortality was higher by ~ 3 times than that of Charlson co-morbidity index. CONCLUSION: In view of the fact that vitamin B12 levels have been found to predict mortality, they should be measured in geriatric practice, in addition to albumin levels, as a practical and reliable tool for identifying high risk elderly hospitalized patients. Probably, a combination of two or more available and inexpensive routinely taken tests can give a better estimation of mortality than some complicated tools, like Charlson co-morbidity index. PMID- 21705784 TI - Does hypokalaemia cause nephropathy? An observational study of renal function in patients with Bartter or Gitelman syndrome. AB - BACKGROUND: Hypokalaemic nephropathy has been described in patients with chronic potassium depletion; it is a condition in which proximal tubular vacuolization and interstitial fibrosis occur, resulting in a decline in glomerular filtration rate (GFR) and, in some cases, renal failure. It has been described in patients with chronic diarrhoea, eating disorders, laxative abuse and primary hyperaldosteronism; also occasionally in Bartter syndrome (BS), in which severe hypokalaemia accompanies significant renal sodium and water losses, though rarely in Gitelman syndrome (GS), in which there is equally severe hypokalaemia, but only modest sodium losses. AIM: We hypothesized that hypokalaemic nephropathy may not be due to potassium depletion per se, but persistently elevated circulating levels of aldosterone, possibly with superimposed episodes of renal hypoperfusion. DESIGN AND METHODS: We searched UK and European data sets to retrospectively compare serum and urinary parameters in patients with GS and BS. RESULTS: The patients with GS often had lower serum potassium concentrations than patients with BS, but the BS patients had significantly higher serum creatinine concentrations and lower estimated GFRs (eGFR). BS patients had significantly higher fractional excretions of sodium compared with GS patients, as well as higher plasma renin activities and serum aldosterone levels. CONCLUSION: These findings show that in genetically confirmed cases of BS and GS, the degree of hypokalaemia (as an index of chronic potassium depletion) does not correlate with GFR, and that on-going sodium and water losses, and consequent secondary hyperaldosteronism, may play a more important role in the aetiology of hypokalaemic nephropathy. PMID- 21705785 TI - Tracking of blood pressure from childhood to adolescence in a Greek cohort. AB - BACKGROUND: Studies have reported tracking of blood pressure (BP) from childhood to adulthood but with inconsistent results mainly due to methodological and ethnic differences. We aimed to examine BP tracking during a 7-year period in a Greek cohort. METHODS: This is a longitudinal school-based study conducted during 1990-96 in Athens, Greece. Children underwent BP and anthropometric measurements on two to three visits annually (averaged to annual values) for 7 years. RESULTS: A total of 166 children with complete yearly follow-up data for the examined period were included (mean baseline age 9 +/- 1.7 years, range: 5-12 years, 89 boys). At baseline, the prevalence of pre- and hypertension was 22.9 and 24.1% respectively and at the end of the follow-up 24.1% (P = NS vs. baseline) and 13.3% (P = 0.02 vs. baseline) respectively. Systolic/diastolic BP tracking correlation coefficients between 1990 and 1996 were 0.38 (P < 0.001)/0.20 (P = 0.06) for boys and 0.30 (P = 0.007)/0.22 (P = 0.06) for girls. Among children with baseline BP >=90th centile (systolic and/or diastolic), 44% remained in the same BP range after 7 years. In stepwise multiple regression analysis, baseline systolic BP, male gender, baseline body mass index (BMI) and change in BMI from baseline to the end of the follow-up (DeltaBMI) were significant predictors of systolic BP levels at the end of the follow-up. Baseline diastolic BP, baseline BMI and DeltaBMI were significant predictors of diastolic BP at the end of the follow-up. CONCLUSIONS: These data suggest that the risk of developing high BP during adolescence can be predicted by BP and BMI at childhood. PMID- 21705786 TI - Body mass index and health-related quality of life in adults: a population based study in five cities of China. AB - BACKGROUND: To investigate the relationship between obesity and health-related quality of life (HRQL) in a randomly selected Chinese sample. METHODS: A total of 3600 residents aged 18-80 years were sampled in five cities of China using a randomized stratified multiple-stage sampling method to receive the interview, with a self-completed questionnaire to collect demographic information, and the Mandarin version of Short Form 36 Health Survey questionnaire (SF-36) to assess HRQL, followed by height and weight measurements for calculating body mass index (BMI). Cross-sectional association between BMI and HRQL was analysed. RESULTS: Among the 3207 participants (mean age 42 years) suitable for analysis, BMI differed by age and gender. Based on the international or the Asian BMI categories, in women, meaningful impairments were seen between obese and normal weight participants in four physical health scales, and only one scale of the four mental health scales--vitality scale was affected by obesity; in men, impairments by obesity were not found in all of the eight SF-36 scales, and better HRQL in two mental health scales were observed in obese participants compared to normal weight ones; after adjusting related variables, several physical but not mental health scales were found impaired by obesity. CONCLUSION: Obesity impaired physical but not mental health, and the impairments varied between genders. Public health agencies and government should emphasize the impairments of obesity on physical health. PMID- 21705787 TI - Pontine tegmental cap dysplasia: the neurotologic perspective. AB - OBJECTIVES: Pontine tegmental cap dysplasia (PTCD) is a rare congenital malformation. Clinical and imaging findings in 3 patients and the authors' experience with bilateral cochlear implantation in 1 patient are described. STUDY DESIGN: Retrospective review. SETTING: Two tertiary medical centers. SUBJECTS AND METHODS: Three patients were evaluated by an otolaryngologist and underwent magnetic resonance imaging (MRI) of the temporal bones and brain. High-resolution computed tomography (CT) scanning of the temporal bones was performed in 2 patients. Imaging findings of the brain, the presence and course of resolvable cranial nerves, the membranous labyrinth, and internal auditory canals were reviewed. Clinical data were reviewed. RESULTS: All patients demonstrated typical brain characteristics of PTCD. Mild, bilateral cochlear dysplasia was noted in 2, and all had a normal vestibular labyrinth. The cochleovestibular nerves were universally absent bilaterally. The facial nerves were subjectively deficient bilaterally in 1 patient, unilaterally in the second patient, and normal in the third. An accessory canal for the seventh cranial nerve, referred to as a duplicated internal auditory canal, was present in all patients. Auditory brainstem response testing revealed profound bilateral sensorineural hearing loss in all of the patients; none suffered facial weakness. A single patient underwent bilateral cochlear implantation with only minimal response. CONCLUSION: The authors report 3 cases of PTCD with emphasis on imaging of the seventh and eighth cranial nerves and clinical neurotologic findings. All patients manifested duplicated internal auditory canals, a previously unreported finding in PTCD. Bilateral profound sensorineural hearing loss is due to absence of the cochleovestibular nerve. Prognosis for cochlear implantation is poor. PMID- 21705788 TI - Tinnitus with temporomandibular joint disorders: a specific entity of tinnitus patients? AB - OBJECTIVE: Tinnitus is frequently associated with temporomandibular joint (TMJ) dysfunction. However, the nature of the relationship is not fully understood. Here the authors compared 30 patients with a confirmed diagnosis of temporomandibular joint dysfunction and tinnitus to a group of 61 patients with tinnitus but without any subjective complaints of TMJ dysfunction with respect to clinical and demographic characteristics. STUDY DESIGN: Case-control study. SETTING: Tertiary referral center. SUBJECTS: Tinnitus patients with and without TMJ dysfunction presenting at the Department of Prosthetic Dentistry and th: Tinnitus Clinic at the University of Regensburg. RESULTS: Tinnitus patients with TMJ disorder had better hearing function (P < .0005), lower age (P = .001), and lower age at tinnitus onset (P = .002) and were more frequently female (P = .003). Their subjectively perceived tinnitus loudness was lower (P = .01), and more of them could modulate their tinnitus by jaw or neck movements (P = .001). CONCLUSION: Classical risk factors for tinnitus (age, male gender, hearing loss) are less relevant in tinnitus patients with TMJ disorder, suggesting a causal role of TMJ pathology in the generation and maintenance of tinnitus. Based on this finding, treatment of TMJ disorder may represent a causally oriented treatment strategy for tinnitus. PMID- 21705789 TI - Genetic polymorphisms of ADH1C and CYP2E1 and risk of oral squamous cell carcinoma. AB - OBJECTIVE: Several studies have suggested that the metabolism of alcohol is modulated by the polymorphisms in genes encoding ethanol-metabolizing enzymes, including alcohol dehydrogenase 1C, ADH1C, and cytochrome P450-dependent monooxygenase, CYP2E1. Genetic polymorphisms of ethanol-metabolizing enzymes may affect individual susceptibility to oral cancer. The purpose of this study was to investigate the associations between ADH1C and CYP2E1 gene polymorphisms with oral squamous cell carcinoma in an ethnically homogeneous Caucasian population. DESIGN: Case-control study. SETTING: Serbian national general hospital. SUBJECTS AND METHODS: The study was conducted on 123 oral cancer patients and a control group of 177 individuals of the Caucasian race and the same ethnicity, matched in age and gender, without previous cancer history. The control group consisted of 120 population-based and 57 hospital-based controls of heavy-drinking individuals. Genetic polymorphisms of ADH1C SspI, ADH1C HaeIII, CYP2E1 RsaI, and CYP2E1 Ins were determined by the polymerase chain reaction and restriction fragment length polymorphisms. RESULTS: After adjustment by potential confounders, the significant increase of oral cancer risk, independent of alcohol drinking, was observed in individuals with the variant ADH1C SspI*2/*2 genotype (odds ratio, 3.029; P = .014) and in combined ADH1C SspI*1/*2 and ADH1C SspI*2/*2 genotypes (odds ratio, 2.605; P = .002), compared to the ADH1C*1/1* wild type. The association of other polymorphisms under study was not observed. CONCLUSION: This study suggested that the ADH1C SspI polymorphism could play a significant role in the etiology of oral cancer, whereas ADH1C HaeIII, CYP2E1 RsaI, and CYP2E1 Ins could have minor influence. PMID- 21705790 TI - During stopover, migrating blackcaps adjust behavior and intake of food depending on the content of protein in their diets. AB - During migration, birds undergo alternating periods of fasting and re-feeding that are associated with dynamic changes in body mass (m(b)) and in organ size, including that of the digestive tract. After arrival at a migratory stopover site, following a long flight, a bird must restore the tissues of its digestive tract before it can refuel. In the present study we examined how the availability of dietary protein influences refueling of migrating blackcaps (Sylvia atricapilla) during a migratory stopover. We tested the following predictions in blackcaps deprived of food and water for 1-2 days to induce stopover behavior: (1) birds provided with a low-protein diet will gain m(b), lean mass and fat mass, and increase in pectoral muscle size slower than do birds fed a high protein diet; (2) since stopover time is shorter in spring, birds will gain m(b) and build up fat tissue and lean tissue faster than in autumn; and (3) if low dietary protein limits a bird's ability to gain m(b) and fat reserves, then birds that do not obtain enough protein will initiate migratory restlessness (Zugunruhe) earlier than will birds with adequate dietary protein. These predictions were tested by providing captured migrating blackcaps with semisynthetic isocaloric diets differing only in their protein content. Each day, we measured m(b), and food intake; also lean mass and fat mass were measured using dual energy X-ray absorptiometry. In addition, we monitored nocturnal activity with a video recording system. In both spring and autumn, birds fed diets containing either 3 or 20% protein increased in m(b), lean mass and fat mass at similar rates during the experiment. However, the group receiving 3% protein ate more than did the group receiving 20% protein. In support of our predictions, m(b), lean mass, fat mass, and intake of food all were higher in spring than in autumn. We also found that in spring all birds had higher levels of migratory restlessness, but birds fed 3% protein were less active at night than were birds fed 20% protein, possibly an adaptation conserving energy and protein. We conclude that protein requirements of migrating blackcaps during stopover are lower than expected, and that birds can compensate for low dietary protein by behavioral responses, i.e. hyperphagia and decreased migratory restlessness, that ensure rapid refueling. PMID- 21705792 TI - Heterothermy in Afrotropical mammals and birds: a review. AB - Recent years have seen a rapid increase in the number of Afrotropical endotherms known to avoid mismatches between energy supply and demand by using daily torpor and/or hibernation. Among mammals, heterothermy has been reported in 40 species in six orders, namely Macroscelidea, Afrosoricida, Rodentia, Eulipotyphla, Primates and Chiroptera. These species span a range in body mass of 7-770 g, with minimum heterothermic body temperatures ranging from 1-27 degrees C and bout length varying from 1 h to 70 days. Daily torpor is the most common form of heterothermy, with true hibernation being observed in only seven species, Graphiurus murinus, Graphiurus ocularis, Atelerix frontalis, Cheirogaleus medius, Cheirogaleus major, Microcebus murinus and Microcebus griseorufus. The traditional distinction between daily torpor and hibernation is blurred in some species, with free-ranging individuals exhibiting bouts of > 24 h and body temperatures < 16 degrees C, but none of the classical behaviours associated with hibernation. Several species bask in the sun during rewarming. Among birds, heterothermy has been reported in 16 species in seven orders, and is more pronounced in phylogenetically older taxa. Both in mammals and birds, patterns of heterothermy can vary dramatically among species occurring at a particular site, and even among individuals of a single species. For instance, patterns of heterothermy among cheirogalid primates in western Madagascar vary from daily torpor to uninterrupted hibernation for up to seven months. Other examples of variation among closely-related species involve small owls, elephant shrews and vespertilionid bats. There may also be variation in terms of the ecological correlates of torpor within a species, as is the case in the Freckled Nightjar Caprimulgus tristigma. PMID- 21705791 TI - Effects of ethanol on food consumption and skin temperature in the Egyptian fruit bat (Rousettus aegyptiacus). AB - Since mammalian frugivores generally choose to eat ripe fruit in which ethanol concentration ([EtOH]) increases as the fruit ripens, we asked whether ethanol acts as an appetitive stimulant in the Egyptian fruit bat, Rousettus aegyptiacus, and also studied the effects of ethanol on their skin temperature (T(s)). We hypothesized that the responses of fruit bats to dietary ethanol are concentration dependent and tested the predictions that the bats' response is positive, i.e., they eat more when [EtOH] in the food is in the range found in naturally ripe fruit, while it negatively affects them at higher concentrations. We also tested the prediction that in winter, even when availability of fruit is low and thermoregulatory costs are high, ingestion of ethanol by fruit bats is low because assimilated ethanol reduces shivering thermogenesis and peripheral vasodilation; these, alone or together, are detrimental to the maintenance of body temperature (T(b)). In summer, captive bats offered food containing 0.1% ethanol significantly increased consumption over food with no ethanol; they did not change consumption when food contained 0.01, 0.3, or 0.5% ethanol; but significantly decreased consumption at higher levels of ethanol [EtOH], i.e., 1 and 2%. In winter, captive bats ate significantly less when their food contained 0.1% ethanol than when it contained 0, 0.3, or 0.5%. During summer, freshly caught bats ate significantly more ethanol-containing food than freshly caught bats in winter. Skin temperature (T(s)) in Egyptian fruit bats decreased significantly at an ambient temperature (T(a)) of 12 degrees C (winter conditions) after gavage with liquid food containing 1% ethanol. The effect was clearly temperature-dependent, since ethanol did not have the same effect on bats gavaged with food containing 1% or no ethanol at a T(a) of 25 degrees C (summer conditions). In conclusion, ethanol may act as an appetitive stimulant for Egyptian fruit bats at low concentrations, but only in summer. Bats are deterred by food containing [EtOH] corresponding to that in overripe, unpalatable fruit (1 and 2%). Furthermore, during winter, Egyptian fruit bats are deterred by ethanol rich fruit, possibly due to the potential thermoregulatory consequences of ethanol consumption. PMID- 21705793 TI - The physiology and ontogeny of daily oral behaviors. AB - In the masticatory system, activities of muscles are the main source of force. The daily activity of the jaw muscle is a measure of the total daily loading of the tissues involved. This article gives an overview on the recent assessments of the physiology and ontogeny of the daily use of the jaw muscles. Variations in the characteristics of daily activity could be linked to differences in the types of fibers composing the muscles as well as to the properties of the underlying bone, although these relationships are not absolute. Experimental decrease of the hardness of foods eaten by rats and rabbits showed a significant decrease in the number of daily bursts of feeding. These reductions in daily muscular activity were accompanied by higher mineralization of bone and by a transition toward "faster" fiber types in the muscles. It was revealed in rabbits that the characteristics of the daily activities of muscles (total duration of activity, number and lengths of bursts) were not altered during the transition from suckling to chewing and remained largely unaffected during further postnatal development. These results suggest that, despite large anatomical and functional changes, the average daily load on the jaw muscles by the masticatory system appears to be established before chewing develops and remains largely unchanged all the way through development. Whenever the daily muscular activity changes, this seems to have a significant effect on the properties of the tissues involved. PMID- 21705794 TI - Integrator networks: illuminating the black box linking genotype and phenotype. AB - Emerging concepts in developmental biology, such as facilitated variation and dynamical patterning modules, address a major shortcoming of the Modern Synthesis in Biology: how genotypic variation is transduced into functional yet diverse phenotypic variation. Still, we lack a theory to explain how variation at the cellular and tissue level is coordinated into variation at the whole-organism level, especially as priority of cellular and tissue functions change over an individual's lifetime and are influenced by environmental variation. Here, we propose that interactions among a limited subset of physiological factors that we call, integrators, regulate most phenotypic variation at the organismal level. Integrators are unique among physiological factors in that they have the propensity to coordinate the expression of conserved gene modules of most types of tissues because they participate as nodes in a hierarchical network. In other words, integrator networks impose physiological epistasis, meaning that whole organism phenotypic responses will be influenced by previous experiences, current environmental conditions, and fitness priorities as encoded by individual integrators. Below, we provide examples of how integrator networks are responsible for both profound and irreversible phenotypic changes (i.e., metamorphosis, sexual differentiation) as well as subtler, transient (e.g., pelage color, seasonal fluctuations in lymphoid and reproductive tissues) variation. The goal of this article is not to describe completely how integrator networks function, but to stimulate discussion about the role of physiology in linking genetic to phenotypic variation. To generate useful data sets for understanding integrator networks and to inform whole-organism physiology generally, we describe several useful tools including vector-field editing, response-surface regression, and experiments of life-table responses. We then close by highlighting some implications of integrator networks for conservation and biomedicine. PMID- 21705795 TI - Incorporating population-level variation in thermal performance into predictions of geographic range shifts. AB - Determining how species' geographic ranges are governed by current climates and how they will respond to rapid climatic change poses a major biological challenge. Geographic ranges are often spatially fragmented and composed of genetically differentiated populations that are locally adapted to different thermal regimes. Tradeoffs between different aspects of thermal performance, such as between tolerance to high temperature and tolerance to low temperature or between maximal performance and breadth of performance, suggest that the performance of a given population will be a subset of that of the species. Therefore, species-level projections of distribution might overestimate the species' ability to persist at any given location. However, current approaches to modeling distributions often do not consider variation among populations. Here, we estimated genetically-based differences in thermal performance curves for growth among 12 populations of the scarlet monkeyflower, Mimulus cardinalis, a perennial herb of western North America. We inferred the maximum relative growth rate (RGR(max)), temperature optimum (T(opt)), and temperature breadth (T(breadth)) for each population. We used these data to test for tradeoffs in thermal performance, generate mechanistic population-level projections of distribution under current and future climates, and examine how variation in aspects of thermal performance influences forecasts of range shifts. Populations differed significantly in RGR(max) and had variable, but overlapping, estimates of T(opt) and T(breadth). T(opt) declined with latitude and increased with temperature of origin, consistent with tradeoffs between performances at low temperatures versus those at high temperatures. Further, T(breadth) was negatively related to RGR(max), as expected for a specialist-generalist tradeoff. Parameters of the thermal performance curve influenced properties of projected distributions. For both current and future climates, T(opt) was negatively related to latitudinal position, while T(breadth) was positively related to projected range size. The magnitude and direction of range shifts also varied with T(opt) and T(breadth), but sometimes in unexpected ways. For example, the fraction of habitat remaining suitable increased with T(opt) but decreased with T(breadth). Northern limits of all populations were projected to shift north, but the magnitude of shift decreased with T(opt) and increased with T(breadth). Median latitude was projected to shift north for populations with high T(breadth) and low T(opt), but south for populations with low T(breadth) and high T(opt). Distributions inferred by integrating population-level projections did not differ from a species-level projection that ignored variation among populations. However, the species-level approach masked the potential array of divergent responses by populations that might lead to genotypic sorting within the species' range. Thermal performance tradeoffs among populations within the species' range had important, but sometimes counterintuitive, effects on projected responses to climatic change. PMID- 21705799 TI - Environmentally cued hatching across taxa: embryos respond to risk and opportunity. AB - Most animals begin life in eggs, protected and constrained by a capsule, shell, or other barrier. As embryos develop, their needs and abilities change, altering the costs and benefits of encapsulation, and the risks and opportunities of the outside world. When the cost/benefit ratio is better outside the egg, animals should hatch. Adaptive timing of hatching evolves in this context. However, many environmental variables affect the optimal timing of hatching so there is often no consistent best time. Across a broad range of animals, from flatworms and snails to frogs and birds, embryos hatch at different times or at different developmental stages in response to changing risks or opportunities. Embryos respond to many types of cues, assessed via different sensory modalities. Some responses appear simple. Others are surprisingly complex and sophisticated. Parents also manipulate the timing of hatching. The number and breadth of examples of cued hatching suggest that, in the absence of specific information, we should not assume that hatching timing is fixed. Our challenge now is to integrate information on the timing of hatching across taxa to better understand the diversity of patterns and how they are structured in relation to different types of environmental and developmental variation. As starting points for comparative studies, I: (1) suggest a framework based on heterokairy-individual, plastic variation in the rate, timing, or sequence of developmental events and processes-to describe patterns and mechanisms of variation in the timing of hatching; (2) briefly review the distribution of environmentally cued hatching across the three major clades of Bilateria, highlighting the diverse environmental factors and mechanisms involved; and (3) discuss factors that shape the diversity of plastic and fixed timing of hatching, drawing on evolutionary theory on phenotypic plasticity which directs our attention to fitness trade offs, environmental heterogeneity, and predictive cues. Combining mechanistic and evolutionary perspectives is necessary because development changes organismal interactions with the environment. Integrative and comparative studies of the timing of hatching will improve our understanding of embryos as both evolving and developing organisms. PMID- 21705796 TI - Mouse knockout of the cholesterogenic cytochrome P450 lanosterol 14alpha demethylase (Cyp51) resembles Antley-Bixler syndrome. AB - Antley-Bixler syndrome (ABS) represents a group of heterogeneous disorders characterized by skeletal, cardiac, and urogenital abnormalities that have frequently been associated with mutations in fibroblast growth factor receptor 2 or cytochrome P450 reductase genes. In some ABS patients, reduced activity of the cholesterogenic cytochrome P450 CYP51A1, an ortholog of the mouse CYP51, and accumulation of lanosterol and 24,25-dihydrolanosterol has been reported, but the role of CYP51A1 in the ABS etiology has remained obscure. To test whether Cyp51 could be involved in generating an ABS-like phenotype, a mouse knock-out model was developed that exhibited several prenatal ABS-like features leading to lethality at embryonic day 15. Cyp51(-/-) mice had no functional Cyp51 mRNA and no immunodetectable CYP51 protein. The two CYP51 enzyme substrates (lanosterol and 24,25-dihydrolanosterol) were markedly accumulated. Cholesterol precursors downstream of the CYP51 enzymatic step were not detected, indicating that the targeting in this study blocked de novo cholesterol synthesis. This was reflected in the up-regulation of 10 cholesterol synthesis genes, with the exception of 7 dehydrocholesterol reductase. Lethality was ascribed to heart failure due to hypoplasia, ventricle septum, and epicardial and vasculogenesis defects, suggesting that Cyp51 deficiency was involved in heart development and coronary vessel formation. As the most likely downstream molecular mechanisms, alterations were identified in the sonic hedgehog and retinoic acid signaling pathways. Cyp51 knock-out mice provide evidence that Cyp51 is essential for embryogenesis and present a potential animal model for studying ABS syndrome in humans. PMID- 21705800 TI - Roles of environmental cues for embryonic incubation and hatching in mudskippers. AB - Reproduction on mudflats requires that eggs are protected from different environmental challenges during development and hatch when environmental conditions are favorable for survival of juveniles. Mudskippers are air breathing, amphibious gobies of the subfamily Oxudercinae, and one of a few vertebrates that reside on mudflats. They excavate burrows in mudflats and deposit eggs in them. However, these burrows are filled with extremely hypoxic water, in which eggs could not survive. To secure embryonic development within their burrows, the burrow-guarding parental fish (a male or mating pair) store fresh air in an egg chamber, located near the bottom or at mid-depth in a burrow, by transporting mouthfuls of air during each low tide. The Japanese mudskipper, Periophthalmus modestus, is the best-studied species regarding reproductive strategies. The air-supplying behavior appears to be predominantly governed by the oxygen levels within egg chambers, but also by some other factor that is possibly related to the tidal cycle. When embryonic development is complete, the burrow-guarding male P. modestus removes the air from the egg chamber and releases the air outside the burrow on a nocturnal rising tide. Consequently, the tide floods the egg chamber and induces hatching. Because P. modestus eggs only have a 5-6 day window for hatching competence, the male's initial selection of the position for the burrow in the intertidal zone and the timing of spawning relative to the tidal cycle are both important factors in hatching success. This is particularly crucial for those burrows in higher intertidal zones, which may be reached only by spring high tides. Not much is known for other mudskippers, but it is likely that they also employ similar reproductive strategies. The objective of this review is to summarize available information on reproductive strategies of mudskippers, and to discuss future directions to better elucidate mechanisms and adaptive significance for the reproduction of mudskippers. Further comparative studies with both mudskippers and other oxudercine gobies dwelling mudflats could shed new light on how vertebrates solved problems of reproduction when they expanded habitats to environments in an air-water interface. PMID- 21705797 TI - Cholesterol- and sphingolipid-rich microdomains are essential for microtubule based membrane protrusions induced by Clostridium difficile transferase (CDT). AB - Clostridium difficile toxin (CDT) is a binary actin-ADP-ribosylating toxin that causes depolymerization of the actin cytoskeleton and formation of microtubule based membrane protrusions, which are suggested to be involved in enhanced bacterial adhesion and colonization of hypervirulent C. difficile strains. Here, we studied the involvement of membrane lipid components of human colon adenocarcinoma (Caco-2) cells in formation of membrane protrusions. Depletion of cholesterol by methyl-beta-cyclodextrin inhibited protrusion formation in a concentration-dependent manner but had no major effect on the toxin-catalyzed modification of actin in target cells. Repletion of cholesterol reconstituted formation of protrusions and increased velocity and total amount of protrusion formation. Methyl-beta-cyclodextrin had no effect on the CDT-induced changes in the dynamics of microtubules. Formation of membrane protrusions was also inhibited by the cholesterol-binding polyene antibiotic nystatin. Degradation or inhibition of synthesis of sphingolipids by sphingomyelinase and myriocin, respectively, blocked CDT-induced protrusion formation. Benzyl alcohol, which increases membrane fluidity, prevented protrusion formation. CDT-induced membrane protrusions were stained by flotillin-2 and by the fluorescent-labeled lipid raft marker cholera toxin subunit B, which selectively interacts with GM1 ganglioside mainly located in lipid microdomains. The data suggest that formation and especially the initiation of CDT-induced microtubule-based membrane protrusions depend on cholesterol- and sphingolipid-rich lipid microdomains. PMID- 21705801 TI - Bioinspirations: cell-inspired small-scale systems for enabling studies in experimental biomechanics. AB - Biomechanical forces govern the behaviors of organisms and their environment and examining these behaviors to understand the underlying phenomena is an important challenge. One experimental approach for probing these interactions between organisms and their biomechanical environment uses biologically-inspired, artificial surrogates that reproduce organic mechanical systems. For the case of complex, multicellular organisms, robot surrogates have been particularly effective, such as in the analysis of the fins of fish and insects' wings. This biologically-inspired approach is also exciting when examining cell-scale responses as multicellular organisms' behavior is directly influenced by the integrated interactions of smaller-scale components (i.e., cells). In this review, we introduce the burgeoning field of engineering of artificial cells, which focuses on developing cell-scale entities replicating cellular behaviors. We describe both a bottom-up approach to constructing artificial cells, using molecular components to directly assemble artificial cells, as well as a top-down approach, in which living cells are encapsulated in a single entity whose behavior is determined by its constituent members. In particular, we discuss the potential role of these artificial cells as implantable controllers, designed to alter the mechanical behavior of a host organism. Eventually, artificial cells designed to function as small-scale controllers may help alter organisms' phenotypes. PMID- 21705802 TI - Atomic structure of bacteriophage Sf6 tail needle knob. AB - Podoviridae are double-stranded DNA bacteriophages that use short, non contractile tails to adsorb to the host cell surface. Within the tail apparatus of P22-like phages, a dedicated fiber known as the "tail needle" likely functions as a cell envelope-penetrating device to promote ejection of viral DNA inside the host. In Sf6, a P22-like phage that infects Shigella flexneri, the tail needle presents a C-terminal globular knob. This knob, absent in phage P22 but shared in other members of the P22-like genus, represents the outermost exposed tip of the virion that contacts the host cell surface. Here, we report a crystal structure of the Sf6 tail needle knob determined at 1.0 A resolution. The structure reveals a trimeric globular domain of the TNF fold structurally superimposable with that of the tail-less phage PRD1 spike protein P5 and the adenovirus knob, domains that in both viruses function in receptor binding. However, P22-like phages are not known to utilize a protein receptor and are thought to directly penetrate the host surface. At 1.0 A resolution, we identified three equivalents of l-glutamic acid (l-Glu) bound to each subunit interface. Although intimately bound to the protein, l-Glu does not increase the structural stability of the trimer nor it affects its ability to self-trimerize in vitro. In analogy to P22 gp26, we suggest the tail needle of phage Sf6 is ejected through the bacterial cell envelope during infection and its C-terminal knob is threaded through peptidoglycan pores formed by glycan strands. PMID- 21705803 TI - Cell entry of avian reovirus follows a caveolin-1-mediated and dynamin-2 dependent endocytic pathway that requires activation of p38 mitogen-activated protein kinase (MAPK) and Src signaling pathways as well as microtubules and small GTPase Rab5 protein. AB - Very little is known about the mechanism of cell entry of avian reovirus (ARV). The aim of this study was to explore the mechanism of ARV entry and subsequent infection. Cholesterol mainly affected the early steps of the ARV life cycle, because the presence of cholesterol before and during viral adsorption greatly blocked ARV infectivity. Although we have demonstrated that ARV facilitating p38 MAPK is beneficial for virus replication, its mechanism remains unknown. Here, we show that ARV-induced phosphorylation of caveolin-1 (Tyr(14)), dynamin-2 expression, and Rac1 activation through activation of p38 MAPK and Src in the early stage of the virus life cycle is beneficial for virus entry and productive infection. The strong inhibition by dynasore, a specific inhibitor of dynamin-2, and depletion of endogenous caveolin-1 or dynamin-2 by siRNAs as well as the caveolin-1 colocalization study implicate caveolin-1-mediated and dynamin-2 dependent endocytosis as a significant avenue of ARV entry. By means of pharmacological inhibitors, dominant negative mutants, and siRNA of various cellular proteins and signaling molecules, phosphorylation of caveolin-1, dynamin 2 expression, and Rac1 activation were suppressed, suggesting that by orchestrating p38 MAPK, Src, and Rac1 signaling cascade in the target cells, ARV creates an appropriate intracellular environment facilitating virus entry and productive infection. Furthermore, disruption of microtubules, Rab5, or endosome acidification all inhibited ARV infection, suggesting that microtubules and small GTPase Rab5, which regulate transport to early endosome, are crucial for survival of ARV and that exposure of the virus to acidic pH is required for productive infection. PMID- 21705804 TI - Molecular basis of actin nucleation factor cooperativity: crystal structure of the Spir-1 kinase non-catalytic C-lobe domain (KIND)*formin-2 formin SPIR interaction motif (FSI) complex. AB - The distinct actin nucleation factors of the Spir and formin subgroup families cooperate in actin nucleation. The Spir/formin cooperativity has been identified to direct two essential steps in mammalian oocyte maturation, the asymmetric spindle positioning and polar body extrusion during meiosis. Understanding the nature and regulation of the Spir/Fmn cooperation is an important requirement to comprehend mammalian reproduction. Recently we dissected the structural elements of the Spir and Fmn family proteins, which physically link the two actin nucleation factors. The trans-regulatory interaction is mediated by the Spir kinase non-catalytic C-lobe domain (KIND) and the C-terminal formin Spir interaction motif (FSI). The interaction inhibits formin nucleation activity and enhances the Spir activity. To get insights into the molecular mechanism of the Spir/Fmn interaction, we determined the crystal structure of the KIND domain alone and in complex with the C-terminal Fmn-2 FSI peptide. Together they confirm the proposed structural homology of the KIND domain to the protein kinase fold and reveal the basis of the Spir/formin interaction. The complex structure showed a large interface with conserved and positively charged residues of the Fmn FSI peptide mediating major contacts to an acidic groove on the surface of KIND. Protein interaction studies verified the electrostatic nature of the interaction. The data presented here provide the molecular basis of the Spir/formin interaction and give a first structural view into the mechanisms of actin nucleation factor cooperativity. PMID- 21705805 TI - PG12, a phospholipid analog with potent antimalarial activity, inhibits Plasmodium falciparum CTP:phosphocholine cytidylyltransferase activity. AB - In the human malaria parasite Plasmodium falciparum, the synthesis of the major and essential membrane phospholipid, phosphatidylcholine, occurs via the CDP choline and the serine decarboxylase phosphoethanolamine methylation (SDPM) pathways, which are fueled by host choline, serine, and fatty acids. Both pathways share the final two steps catalyzed by two essential enzymes, P. falciparum CTP:phosphocholine cytidylyltransferase (PfCCT) and choline-phosphate transferase (PfCEPT). We identified a novel class of phospholipid mimetics, which inhibit the growth of P. falciparum as well as Leishmania and Trypanosoma species. Metabolic analyses showed that one of these compounds, PG12, specifically blocks phosphatidylcholine biosynthesis from both the CDP-choline and SDPM pathways via inhibition of PfCCT. In vitro studies using recombinant PfCCT showed a dose-dependent inhibition of the enzyme by PG12. The potent antimalarial of this compound, its low cytotoxicity profile, and its established mode of action make it an excellent lead to advance for further drug development and efficacy in vivo. PMID- 21705807 TI - Bury the bill. PMID- 21705808 TI - WIBL: Workbench for Integrative Biological Learning. AB - The construction of integrated datasets from potentially hundreds of sources with bespoke formats, and their subsequent visualization and analysis, is a recurring challenge in systems biology. We present WIBL, a visualization and model development environment initially geared towards logic-based modelling of biological systems using integrated datasets. WIBL combines data integration, visualisation and modelling in a single portal-based workbench providing a comprehensive solution for interdisciplinary systems biology projects. PMID- 21705806 TI - An ABCA1-independent pathway for recycling a poorly lipidated 8.1 nm apolipoprotein E particle from glia. AB - Lipid transport in the brain is coordinated by glial-derived lipoproteins that contain apolipoprotein E (apoE) as their primary protein. Here we show that apoE is secreted from wild-type (WT) primary murine mixed glia as nascent lipoprotein subspecies ranging from 7.5 to 17 nm in diameter. Negative-staining electron microscropy (EM) revealed rouleaux, suggesting a discoidal structure. Potassium bromide (KBr) density gradient ultracentrifugation showed that all subspecies, except an 8.1 nm particle, were lipidated. Glia lacking the cholesterol transporter ABCA1 secreted only 8.1 nm particles, which were poorly lipidated and nondiscoidal but could accept lipids to form the full repertoire of WT apoE particles. Receptor-associated-protein (RAP)-mediated inhibition of apoE receptor function blocked appearance of the 8.1 nm species, suggesting that this particle may arise through apoE recycling. Selective deletion of the LDL receptor (LDLR) reduced the level of 8.1 nm particle production by approximately 90%, suggesting that apoE is preferentially recycled through the LDLR. Finally, apoA-I stimulated secretion of 8.1 nm particles in a dose-dependent manner. These results suggest that nascent glial apoE lipoproteins are secreted through multiple pathways and that a greater understanding of these mechanisms may be relevant to several neurological disorders. PMID- 21705809 TI - Tunneling nanotubes mediate rescue of prematurely senescent endothelial cells by endothelial progenitors: exchange of lysosomal pool. AB - Although therapeutic effect of adoptive transfer of endothelial progenitor cells (EPC) has been well-substantiated, the actual engraftment is relatively low compared to a robust functional improvement of vasculopathy. Cellular mechanisms governing this action remain elusive. A recently discovered cell-cell communication via tunneling nanotube (TNT) formation is capable of transferring mitochondria and lysosomes between the cells - "organellar diakinesis". Based on the previous demonstration of lysosomal dysfunction in endothelial cells exposed to AGE-modified collagen I, we inquired whether TNT mechanism may be involved in EPC-mediated repair of stressed endothelial cells. Here we demonstrate that EPC selectively and multiplicatively establish TNT communication with stressed endothelia. The guidance cues for the selectivity are provided by exofacially exposed phosphatidylserine moieties. Lysosomal transfer is associated with the preservation of lysosomal pH gradient, functionally reconstituting lysosomal pool of stressed cells and improving endothelial cell viability, reducing premature senescence and apoptosis. In vivo, adoptive transfer of EPC to streptozotocin diabetic mice results in a TNT-dependent reduction of senescent endothelial cells and correction of endothelium-dependent vasorelaxation. Collectively, these data establish a selective multiplicative effect of TNT between EPC and stressed endothelia, reconstitution of the lysosomal pool, and improved viability and function of stressed endothelia. PMID- 21705811 TI - Editorial. The imperfection of genitourinary tract. PMID- 21705812 TI - Prostate cancer: to screen or not to screen. AB - This paper evaluates the use of prostate-specific antigen (PSA) as a screening tool for prostate cancer. A current and contentious issue in both public and medical spheres, we are still lacking clear evidence and guidelines. Here, the Wilson and Jungner screening criteria are used as a framework to suggest that PSA testing is not yet a proven tool for population screening. Additionally, the conflicting results of two recent randomised controlled trials are compared. The European Randomised trial of Screening for Prostate Cancer (ERSPC) found that PSA screening reduced prostate cancer-related deaths by 20% (adjusted p=0.04). Meanwhile the North American Prostate, Lung, Colon and Ovarian cancer trial (PLCO) found no significant impact of screening on mortality. The reasons for these differing outcomes are discussed in greater detail under the categories of methodology, study size, screening interval, cause of death and tumour demographics. The authors of this article conclude that PSA screening, at best, has a moderate impact on prostate cancer mortality. PSA-screening does, however, pose a high risk of over-diagnosis and over-treatment with its associated morbidity. Furthermore, economic and quality of life evaluations are lacking at present. Data are awaited from the UK Department of Health - funded ProtecT study,as well as longer-term outcomes of the ERSPC. PMID- 21705813 TI - Prostate cancer: to screen or not to screen. Editorial Comment. PMID- 21705815 TI - Clinical-pathological differences and smoking habit depending on gender in a cohort of patients with transitional cell carcinoma of the bladder: retrospective study. AB - OBJECTIVES: The increased incidence of transitional cell carcinoma (TCC) of the bladder in men is known, generally attributed to greater exposure to the effect carcinogenic products. Although it has been reported that cancer-specific outcome can be particularly adverse in women due to socioeconomic or biological factors, clinical-pathological differences of TCC at the time of diagnosis have not been sufficiently studied. The aim of this study is to analyze whether there are gender-related differences in grade and tumor stage in primary bladder TCC. METHODS: All consecutive primary bladder TCC diagnoses made in our institution between 1990 and 2009 have been included. We retrospectively analyzed age, smoking, symptoms at presentation, tumor grade (WHO 1973), tumor size and number, and TNM stage, comparing men and women. Statistical analysis was conducted using the Mann-Whitney U test as non-parametric test and Chi-squared test to compare frequencies. RESULTS: We analyzed 1196 patients (992 males and 204 females) with a 5:1 ratio. We found significant differences in age (69 years vs. 73 years), smoking (46.5% vs. 11.2%)and muscle-invasive stage (12.1% vs. 18.1%). Correcting by tobacco consumption, never-smoker women have larger and more aggressive tumors with a frequency of muscle-invasive disease three times higher than male never smokers and equaling to male current-smokers. CONCLUSION: TCC of the bladder is more frequent in males than females. In this series, women are older at the time of diagnosis and most often affected by muscle-invasive disease particularly in never-smokers. We need studies to analyze the potential impact of passive smoking to justify these results. PMID- 21705814 TI - Saturation biopsies for prostate cancer detection: effectiveness, safety and predictive factors. AB - OBJECTIVES: To determine the effectiveness and safety of saturation biopsies for prostate cancer detection of and to identify predictive variables for cancer. METHODS: We conducted a retrospective transversal study in which we analyzed 144 saturation biopsies (January '06 - July '09). INCLUSION CRITERIA: at least two sets of biopsies without evidence of malignancy and Prostate Specific Antigen (PSA)levels >10 ng/ml or PSA kinetics suggestive of malignancy (rate >0.75 ng/ml/year)and patients with atypia in a previous biopsy.The variables analyzed were: age, abnormal digital rectal examination (DRE), total PSA, free/total PSA ratio, prostate volume, PSA density, previous histopathology, number of cylinders obtained and complications. Statistical analysis was performed using the Chi square test, Student's t-test and logistic regression. RESULTS: Mean age was 66 years (SD +/- 6.4), mean total PSA 14.4 ng/ml (SD +/- 12.6), mean free/total PSA ratio 0.09 (SD +/- 0.09), mean prostate volume 61.6 cc (SD +/- 27.4), mean PSA density 0.27 (SD +/- 0.26) and mean number of cylinders obtained 30.45 (SD +/- 3.8). We diagnosed 32% of the patients with prostatic adenocarcinoma. We observed PSA density was higher in the prostate cancer group, 0.39 (SD +/- 0.36), compared to 0.21 (SD +/- 0.18) in patients without cancer (p=0.003). Adenocarcinoma was found in 58% of the biopsies in patients with suspicious DRE, compared to 28% with normal DRE (p=0.009). Mean prostate volume in the prostate cancer group was 52.5 (SD +/- 24.7)compared to 66.0 (SD +/- 27.7)in the group without cancer (p=0.006). In the multivariate analysis, the PSA density (p=0.02; 95% CI 1.36 - 37.36) was the only variable that independently predicted the presence of adenocarcinoma. No statistically significant differences were found in either univariate or multivariate analysis for the remaining variables analyzed. The incidence of complications was similar to that described in the literature for other series. CONCLUSIONS: Saturation biopsy is safe and effective for detection of prostate cancer. PSA density was the only factor that was shown to be independent predictive variable for tumor diagnosis. PMID- 21705816 TI - Evaluation of PSA testing by general practitioners: regional study in the autonomic Community of Valencia. AB - OBJECTIVES: The aim of the study is to compare the use of PSA testing among general practitioners (GPs). METHODS: The number of PSA tests ordered by general practitioners in the years 2008-2009 was examined in a cross-sectional study of nine health districts of Spain. The percentage of PSA ordered to men younger than 50 (PSA<50/PSAtotal) and 40 years (PSA<40/PSAtotal) was calculated. The percentage of men over 50 years who were attended was also calculated and this data was compared with the number of PSA ordered to this population. For two of the departments, these data were also compared between GPs and urologists. RESULTS: PSA testing in 2009 is higher than 2008 in seven health districts. PSA testing in men younger than 50 years was increased along the period of the study and in men younger than 40 years remained steady. The differences between the values of the indicators for urologists and GPs are significant. CONCLUSIONS: The number of PSA tests and the percentage performed to men younger 50 years has been increasing and the variability is high. These data are suggestive for interventions focused on PSA testing and prostate cancer screening in primary care settings. PMID- 21705817 TI - The candidate for renal transplantation work up: medical, urological and oncological evaluation. AB - Renal transplantation prolongs life, reduces morbidity, improves quality of life, and enables social rehabilitation of patients with end stage renal disease (ESRD). Kidney transplantation is a surgical procedure with inherent risks due to anesthesia and the surgical procedure itself. In ESRD patients medical background and comorbidities are crucial at the time of considering a renal transplant candidate because they can determine the procedure success OBJECTIVES: To update and review, according to recent literature, the evaluation of renal transplant candidates. METHODS: We performed a retrospective review of medical literature published in Medline/Pubmed about the most important facts of medical, urological and oncological evaluation of ESRD patients candidates to renal transplant. RESULTS: Pretransplant medical evaluation aims to diagnose, treat, and optimize any preexisting disease, and how these can interfere with patient and graft survival. It is important to consider age, cardiovascular disease, presence of diabetes mellitus, coagulation disorders, obesity, gastrointestinal diseases, ESRD situation and associated complications, active infection and non compliance with treatment and follow up. Urological requirements for successful renal transplantation are the absence of urinary infections, a compliant and continent reservoir, and a reliable method of achieving complete bladder evacuation. Certain urological diseases may not be obvious in the anuric patient. Pretransplant urological evaluation aims to diagnose, treat, and optimize any preexisting urological disease that can jeopardize transplant evolution. Cancer is a frequent and recognized complication of organ transplantation. The need of continuous immunosuppressive therapy may lead to immunosuppression-related side effects and direct oncogenic effects. Pre-existing malignancies should be extensively evaluated before proceeding to transplantation. Appropriate screening for malignancies is recommended in ESRD patients during routine pretransplant evaluation. CONCLUSION: This review highlights the importance of performing a comprehensive medical, urological and oncological assessment before transplantation. We will go through these mayor aspects of the evaluation of ESRD patients, how these might affect renal transplantation, which complementary test should be performed, and what are the latest recommendations for those situations. Careful pre-operative work-up of every transplant candidate is mandatory to improve post-transplant organ and patient survival. The workup should be tailored according to patients ' specific conditions, by a multidisciplinary approach before proceeding to transplantation. PMID- 21705818 TI - Retrocaval ureter in children. Case report and bibliographic review. AB - OBJECTIVE: Retrocaval ureter is a rare disease which is due to a abnormal development of the inferior cava vein. It usually presents with ureteral obstruction, and surgery is needed for symptomatic cases. METHOD: We present a case of retrocaval ureter and a revision of the literature. RESULTS: A 9 year-old boy who had consulted for macroscopic hematuria. The intravenous urography (IVU) suggested the diagnosis of retrocaval right ureter, which is confirmed by magnetic resonance imaging (MR). Make us resection of the retrocaval segment and relocation of the ureter anterior to the inferior vena cava. Follow-up IVU showed good resolution of hydronephrosis. CONCLUSIONS: Retrocaval ureter is a rare disease, with easy diagnostic and effective treatment. Other associated anomalies could be associated. PMID- 21705819 TI - Bladder hernia. AB - OBJECTIVE: To report a new case of bladder hernia. We reviewed the clinical features, diagnosis and treatment of this disease. METHODS: Case report of a patient diagnosed with bladder hernia. RESULTS: We expose the clinical picture and the most common form of diagnosis and the more effective treatment. CONCLUSIONS: Bladder hernia is rare disorder that is diagnosed clinically and whose treatment is surgical, with very good results. PMID- 21705820 TI - 46,XX T testicular disorder of sex development. Case report. AB - OBJECTIVE: We present a case of X-Y translocation with male phenotype (46,XX testicular disorder of sex development) and review the literature. METHODS: Disorders of sex development with mismatch of genetic, gonadal and phenotypic sex are quite rare, and some are due to genetic or chromosomal abnormalities. The karyotype was investigated by a cytogenetic study of peripheral blood (phytohemagglutinin-timulated lymphocyte culture over 72 hours). G-banding analysis of 25 metaphases showed a 46,XX chromosome constitution (46 chromosomes with XX sexual composition). Fluorescence in situ hybridization (FISH) analysis with probes for X centromeres and the sex-determining region of the Y chromosome (SRY) (testis-determining factor gene) showed two X chromosomes. The analysis also showed the SRY signal in the telomeric region of the short arm of one of the chromosomes. RESULTS: In recent years, a number of other genes involved in disorders of sex development in animals and humans have also been identified. Genetic defects in the peptide hormone receptors, members of the steroid receptor superfamily, and other transcription factors, as well as any of a series of enzymes and cofactors involved in steroid biosynthesis can cause abnormal determination and differentiation. CONCLUSIONS: Although chromosomal abnormalities are rarely present in patients with apparently normal external genitalia, they should be considered in urology consultations by adolescents and adults, particularly in the investigation of gynecomastia or infertility. PMID- 21705821 TI - Prostatic nephrogenic adenoma. Case report. AB - OBJECTIVE: We present a case of prostatic urethra nephrogenic adenoma as an incidental finding following transurethral resection of the prostate. METHOD/RESULT: It is an incidental diagnosis of nephrogenic adenoma of prostatic urethra in a 50-year-old male operated for benign prostatic hyperplasia by means of transurethral resection. CONCLUSIONS: Nephrogenic adenoma is an infrequent and benign lesion of the urinary tract, associated with a previous history of trauma or irritation on the urothelium. Predisposing factors include infections, calculi, surgery, trauma and kidney transplantation. PMID- 21705822 TI - Hepatic cyst displacing the kidney. PMID- 21705823 TI - Inguinal-scrotal bladder hernia associated with pelvic kidney. PMID- 21705824 TI - Bilateral renal vascular trauma in a 32 year old male. PMID- 21705825 TI - A case study: Te in ZnSe and Mn-doped ZnSe quantum dots. AB - Photoluminescence (PL) behavior of ZnSe(1-y)Te(y) quantum dots is investigated by varying Te concentration as well as size. The striking effect of quantum confinement is the observation of isoelectronic center-related emission at room temperature in lieu of near-band-edge emission that dominates the optical scenario. ZnSe(0.99)Te(0.01) quantum dots were also doped by Mn(2+) ions. The Mn(2+) ion-related d-d transition is drastically suppressed by Te isoelectronic centers. Incorporation of Mn(2+) at substitutional sites in ZnSe(0.99)Te(0.01) quantum dots is also confirmed by the electron paramagnetic resonance measurements. Effect of Te isoelectronic impurity on the emission behavior is more pronounced than that of Mn(2+) ions. A subtle blueshift in the orange d-d transition is a sign of a decrease in crystal field strength. PL and photoluminescence excitation measurements on Zn(1-x)Se(0.99)Te(0.01)Mn(x) quantum dots indicate that the transition probability from the lowest unoccupied molecular orbital to Te levels is substantially larger than that to Mn(2+) d-d levels. PMID- 21705826 TI - Freestanding films of crosslinked gold nanoparticles prepared via layer-by-layer spin-coating. AB - A new, extremely efficient method for the fabrication of films comprised of gold nanoparticles (GNPs) crosslinked by organic dithiols is presented in this paper. The method is based on layer-by-layer spin-coating of both components, GNPs and crosslinker, and enables the deposition of films several tens of nanometers in thickness within a few minutes. X-ray diffraction and conductance measurements reveal the proper adjustment concentration of the crosslinker solution of the critical is in order to prevent the destabilization and coalescence of particles. UV/vis spectroscopy, atomic force microscopy, and conductivity measurements indicate that films prepared via layer-by-layer spin-coating are of comparable quality to coatings prepared via laborious layer-by-layer self-assembly using immersion baths. Because spin-coated films are not bound chemically to the substrate, they can be lifted-off by alkaline underetching and transferred onto 3d-electrodes to produce electrically addressable, freely suspended films. Comparative measurements of the sheet resistances indicate that the transfer process does not compromise the film quality. PMID- 21705827 TI - Nonlinear membrane model for large amplitude vibration of single layer graphene sheets. AB - The nonlinear vibrational properties of single layer graphene sheets (SLGSs) are investigated using a membrane model. The nonlinear equation of motion is considered for the SLGSs by including the effects of stretching due to large amplitudes. The equation of motion is numerically solved utilizing the finite difference method for SLGSs with different initial and boundary conditions, sizes and pretensions. It is concluded that the nonlinear fundamental frequency of SLGSs increases by increasing the pretension and initial velocity. In addition, it is observed that an increase in the pretension weakens the effects of the initial velocity on the fundamental frequency, such that the fundamental frequency approximately becomes independent of the initial velocity. This is an important feature of the vibrating systems consisting of SLGSs which are used in the nano-electromechanical systems (NEMS), where resonators with a specific fundamental frequency and independent of the initial velocity are of interest. PMID- 21705828 TI - Growth of axial SiGe heterostructures in nanowires using pulsed laser deposition. AB - Axial heterojunctions between pure silicon and pure germanium in nanowires have been realized combining pulsed laser deposition, chemical vapor deposition and electron beam evaporation in a vapor-liquid-solid nanowire growth experiment using gold nanoparticles as catalyst for the 1D wire growth. Energy dispersive x ray mappings and line scans show a compositional transition from pure silicon to pure germanium and vice versa with exponential and thus comparably sharp transition slopes. Based on these results not only Si-Ge heterojunctions seem to be possible using the vapor-liquid-solid growth process but also heterojunctions in optoelectronic III-V compounds such as InGaAs/GaAs or group III nitride compounds such as InGaN/GaN as well as axial p-n junctions in Si nanowires. PMID- 21705829 TI - Electrically conductive hexagonally ordered nanoporous membranes produced by ion beam induced carbonization of block-copolymer precursors. AB - Highly ordered carbonized nanoporous membranes are produced by ion-beam treatment of self-assembled block copolymer precursor films. The membranes are electrically conductive, as verified by scanning tunnelling microscopy (STM) measurements. The carbonization degree is investigated by means of Raman and infrared (IR) spectroscopy, and the morphology of the films via transmission electron microscopy (TEM). Domains of perfect hexagonal order of the pores are visualized via digital interference of a TEM image of a membrane with computer-generated triangular lattices, producing specific moire fringes. This novel material could be interesting for applications in nano-catalysis, micro-electronics, and as the grid for STM and TEM imaging of free-standing nano-objects. PMID- 21705830 TI - A novel strategy to produce highly stable and transparent aqueous 'nanosolutions' of water-insoluble drug molecules. AB - A surprisingly large proportion of new drug candidates emerging from drug discovery programmes are water-insoluble and, as a result, have poor oral bioavailability. To overcome insolubility, the drug particles are usually dispersed in a medium during product formation, but large particles that are formed may affect product performance and safety. Many techniques have been used to produce nanodispersions-dispersions with nanometre-scale dimensions-that have properties similar to solutions. However, making nanodispersions requires complex processing, and it is difficult to achieve stability over long periods. In this paper, we report a generic method for preparing drug nanoparticles with a combination of antisolvent precipitation in the presence of water-soluble matrices and spray-drying. The spray-dried powder composites (solid dispersion) are microspherical, highly stable and thus form transparent nanodispersions or so called 'nanosolutions' of water-insoluble drug when simply added to water. Aqueous nanodispersions of silybin (a kind of water-insoluble drug for liver protection) with an average size of 25 nm produced with this approach display a 10 times faster dissolution rate than that of raw drug. This has great potential to offer a novel solution for innovative drugs of the future. PMID- 21705831 TI - Exchange interactions, spin waves, and Curie temperature in zincblende half metallic sp-electron ferromagnets: the case of CaZ (Z = N, P, As, Sb). AB - Using first-principle calculations in conjunction with the frozen-magnon technique we have calculated the exchange interactions and spin-wave dispersions in the series of the zincblende half-metallic II-V (CaZ, Z = N, P, As, Sb) ferromagnets. The calculated exchange constants are used to estimate the Curie temperature within the random phase approximation. The large Stoner gap in these alloys gives rise to well-defined undamped spin waves throughout the Brillouin zone. Moreover we show that the spin-wave stiffness constants for the considered systems are among the largest available for local moment ferromagnets. The predicted Curie temperature of half-metallic CaN is noticeably higher than the room temperature with respect to the other compounds, and thus we propose CaN as a promising candidate for future applications in spintronic devices. PMID- 21705832 TI - Vibrational properties of vitreous GeSe2 with the Becke-Lee-Yang-Parr density functional. AB - The vibrational properties of vitreous GeSe(2) are studied within the Becke-Lee Yang-Parr (BLYP) generalized gradient approximation to density functional theory. For this purpose, we consider two models. The first one is derived from a chemically ordered network, previously generated through classical molecular dynamics. The second one is generated through first-principles molecular dynamics simulations based on the BLYP functional and shows a larger variety of structural motifs. We describe the structural and electronic properties of our models, including bond lengths, first-neighbor coordinations, and the electronic density of states. The vibrational properties are addressed through the vibrational density of states, the infrared spectrum, and the Raman spectrum. For the chemically ordered model, the vibrational properties obtained with the BLYP functional are of comparable quality with respect to previous results obtained with the Perdew-Wang (PW) functional. However, a global consideration of our results indicates that the BLYP functional yields an overall improved description for the vibrational properties of vitreous GeSe(2). The BLYP dielectric constants are closer to experimental values. Furthermore, we found that the Raman spectrum of the model generated through first-principles molecular dynamics within the BLYP scheme is largely improved with respect to an analogous model generated within the PW scheme. PMID- 21705833 TI - Strong immune responses induced by a DNA vaccine containing HPV16 truncated E7 C terminal linked to HSP70 gene. AB - BACKGROUND: Vaccines capable of controlling tumor virus based infections are found difficult to develop due to the consistence latent infection in the host. DNA vaccines are attractive tools for the development of HPV vaccines and inducing antigen-specific immunity owing to the stability, simplicity of delivery, safety and cost effectiveness. However, there is a need to increase their potency by procedures such as using HSP70 gene as an adjuvant. OBJECTIVE: To evaluate a DNA vaccine containing HPV16 truncated E7 C-terminal cytotoxic T lymphocyte epitopes linked to HSP70 gene (HSP70-tE7) in an animal model. METHODS: Mice were immunized with the plasmid DNA after pre-treatment with cardiotoxin. The splenocytes of immunized mice were then tested for CTL activity by detecting the apoptosis and necrosis in target cells, cytokine production by ELISA, CD4 and CD8 frequencies by flow cytometry, and lymphocyte stimulation by MTT assay. RESULTS: The recombinant expression vector was able to elicit immune responses close to that of full length E7 complete gene. Although the use of a small part of a target antigen can induce immune responses equivalent to the full length antigen, it fails to elicit statistically significant stronger immune responses when fused with HSP70 compared to the complete E7 gene alone. CONCLUSION: The potent immunogenicity of HPV16 E7 was preserved in the HSP70-tE7 vaccine and may represent a target of choice for the therapeutic vaccination strategies. However, to improve the immunogenicity polytope DNA vaccines which elicit multiple effector and memory CTL responses should be considered in future studies of DNA based cancer vaccines. PMID- 21705834 TI - Effect of LIGHT adjuvant on kinetics of T-cell responses induced by HSV-1 DNA immunization. AB - BACKGROUND: Studies on efficacy of various vaccines that prevent or reduce the primary and recurrent HSV-1 infection have demonstrated the importance of cellular immunity for protection against the infection. We previously used DNA vaccination to induce cellular immunity against HSV-1 infection in mice. OBJECTIVE: The aim of our study was to evaluate the effect of LIGHT; a member of TNF super family, on the kinetic of CTL response induced by HSV-1 glycoprotein B based DNA vaccine. METHODS: Using a granzyme B ELISA for detection and analysis of CD8+ T cells, CTL activity was determined in the spleen of BALB/c mice at various time points after primary and booster dose of vaccination. The kinetics of CTL response to primary and secondary HSV-1 infection and DNA vaccination were compared to those induced by DNA vaccination in combination with LIGHT adjuvant in the present study. RESULTS: In primary and secondary immunization, the CTL activity in the HSV injected group peaked 7 days and 12 hours post immunization, respectively. After 5 days, LIGHT could neither accelerate the CTL response compared to DNA vaccination alone nor could enhance the CTL activity in the primary and the first peak of memory response, the amount of granzyme B induced by the LIGHT containing vaccine was significantly higher than that induced by the vaccine without the adjuvant. CONCLUSION: Although LIGHT enhances the cellular response in the booster dose of vaccination, it does not accelerate the CTL response. PMID- 21705835 TI - HLA-B27 association with uveitis in an Asian Indian population. AB - BACKGROUND: Uveitis refers to diseases characterized by intraocular inflammation of the uveal tract. Anterior uveitis is a common ocular disease characterized by inflammation of the iris and the ciliary body. OBJECTIVES: To establish the frequency of HLA-B27-positive uveitis in Asian Indian population, study their clinical profile and compare it with other reports in literature. METHODS: We retrospectively reviewed medical data of 89 patients of uveitis referred for HLA B27 typing with predominantly ocular symptoms during the period from April 2006 October 2010. All patients were tested for complete blood count, erythrocyte sedimentation rate, infectious diseases serology, HLA-B27 typing, and prepared radiographs of the sacroiliac joints and lumbar spine if required. RESULTS: The HLA-B27 positive rate was 56.2% among patients and 3% for control samples. Most of the patients were in the age group of 41-50 years with a male predominance. CONCLUSIONS: HLA-B27 was seen to be associated with acute anterior uveitis in Asian Indian males and the test is important for confirmation of diagnosis, prognostication and also for planning the treatment. PMID- 21705836 TI - Stromal cell derived factor-1 genetic variation at locus 801 in patients with myasthenia gravis. AB - BACKGROUND: Myasthenia gravis (MG) is the most common disorder of neuromuscular junction in which autoantibodies develop against nicotinic acetylcholine receptor for unknown reasons. The association of immunomodulator genes with different autoimmune disease has been studied in recent years. OBJECTIVE: The aim of this study was to investigate correlation between a genetic variation in Stromal Cell Derived Factor-1 (SDF1) and susceptibility to MG in an Iranian population. METHODS: Genotyping of SDF1 at position 801 G/A was performed by Polymerase Chain Reaction-Restriction Length Polymorphism (PCR-RFLP) in 87 patients with confirmed myasthenia gravis and 261 normal control subjects. RESULTS: No statistically significant differences were observed in the frequencies of genotypes and alleles between patients and controls (p>0.05). Furthermore, no significant differences in the genotype distribution were found between the cases with different stages (p>0.05). CONCLUSION: Our data suggest that the SDF1 gene polymorphism at position 801 G/A is not associated with myasthenia gravis. PMID- 21705837 TI - Immunomodulatory activity of the aqueous extract of seeds of Abrus precatorius Linn (Jequirity) in mice. AB - BACKGROUND: Various compounds of plant origin have been widely investigated since ancient times for their possible immunomodulatory properties as well as for the treatment of a wide range of diseases. OBJECTIVE: To study the immunomodulatory functions of the aqueous extract of the seeds of Abrus precatorius commonly known as Indian liquorice (Fabaceae), a medicinal plant native to central India. METHODS: Swiss albino mice were intraperitoneally treated with three doses (0.75, 1.25 and 2.5 ug/kg b.w.) of extract for 7 days. Relative organ weight, delayed type hypersensitivity (DTH) response, haemagglutination titre (HT) and Phagocytic index (PI) were studied in various groups of animals. RESULTS: The results showed no significant difference in relative organ weight of spleen, liver, thymus and kidney in various groups of animals. Treatment of rats with increasing concentrations of the extract decreased the footpad thickness indicating a dose related inhibitory effect of the extract on delayed type hypersensitivity. In the HT test, the plant extract showed a suppressive effect at all doses, and these changes were significant as the dose increased. Phagocytic index was also increased in a dose dependent manner. CONCLUSION: The reduction of antibody titre, delayed type hypersensitivity response and the increase in phagocytic index indicates that Abrus precatorius has an inhibitory effect on the immune functions in mice. PMID- 21705838 TI - Clinical, histopathological and immunofluorescent findings of IgA nephropathy. AB - BACKGROUND: IgA nephropathy, a prevalent disease in Asia, is considered the main cause of end stage renal disease among primary glomerular disease. OBJECTIVE: To determine the frequency of different clinical, histopathological and immunofluorescent characteristics of IgA nephropathy. METHODS: Renal biopsies of 376 patients were received for immunofluorescent and for histopathological studies. Biopsies were stained with fluorescene isothyocyanate (FITC) labeled antibodies against IgG, IgA, IgM, C3, C4 and fibrinogen for fluorescent microscopy. For histopathological examination, the specimens were stained with hematoxylin and eosin, periodic acid schiff and methanamine silver stains for light microscopy. RESULTS: IgA nephropathy was diagnosed in 39 cases (10.4%) with a mean age 31.5 years and a male to female ratio of 2.8:1. The disease was observed in 11(29.7%) patients aged 21-30 years, followed by 8 patients (21.6%) aged 11-20 years group. Nephrotic range proteinuria was the most common laboratory finding which was detected in 11 patients (37%). Mesangioproliferative glomerulonephritis was the most common histopathological finding which was found in 7 patients (35%). IgA with other immunoglobulins and complements were deposited in 28 specimens (71.8%) as detected by immunofluorescence. CONCLUSION: IgA nephropathy is common in young people and one third of it results in end stage renal disease. We suggest that Immunofluorescent assay can be considered for the conclusive diagnosis of IgA nephropathy in young patients presenting with proteinuria/hematuria. PMID- 21705839 TI - Down-regulation of CD14 transcripts in human glioblastoma cell line U87 MG. AB - BACKGROUND: Pattern recognition receptors (PRRs) are the main sensors of pathogen and danger signals in innate immunity of which Toll Like Receptors (TLRs) are the most studied ones. The contribution of PRRs in cerebral inflammation induced by microbial infection, tissue damage and cancer has not extensively been addressed so far. Glioma is the most common tumor of the central nervous system and glioblastomas are the most common and most malignant primary brain tumors. OBJECTIVE: The objectives of the present study were to investigate the expression of several PRRs including TLR2, TLR4, MyD88 and CD14 transcripts in human glioblastoma cell line U87 MG and compare their expression level with peripheral blood mononuclear cells (PBMC) obtained from healthy individuals. METHODS: Touchdown PCR (TD-PCR) and Real-time quantitative PCR (qPCR) were applied to detect and quantify the expression level of TLR2, TLR4, MyD88 and CD14 transcript in U87 MG cell line and (PBMC) of healthy individuals. RESULTS: According to our results, human glioblastoma cell line U87 MG expresses TLR2, TLR4, MyD88 and CD14 transcripts in TD-PCR. Moreover, the quantification of the expression of these genes revealed a highly significant down-regulation of CD14 and a slight up regulation of TLR2 transcripts as compared to PBMC of healthy individuals. CONCLUSION: The lower expression level of CD14 in human glioblastoma cell line, might have a potential implication for CD14 mediated cerebral pathology. PMID- 21705840 TI - Profiles of MMP-2 expression in Jurkat, Molt-4 and U937 cells. AB - BACKGROUND: Leukemia is a malignant proliferative disorder of the hematopoietic cells. The important role of angiogenesis in leukemia has been reported by several studies. Matrix metalloproteinases (MMPs) are a large group of endopeptidases which degredate the extracellular matrix and play an important role in angiogenesis. OBJECTIVE: The present study was conducted to evaluate the patterns of MMP-2 activity in three leukemic cell lines. METHODS: Human leukemic monocyte (U937) and T cells (Molt-4 and Jurkat) were cultured in complete RPMI 1640 medium. The cells were then seeded at a density of 106 cells/ml and were incubated with different concentrations of phorbol myristate acetate (PMA) (1-25 ng/ml) or phytoheamagglutinin (PHA) (2-10 ug/ml) for 24 hours. The MMP-2 activity in cell-conditioned media was then evaluated by gelatin zymography. Statistical comparisons between groups were made by analysis of variance (ANOVA). RESULTS: PHA/PMA significantly and dose-dependently increased MMP-2 activity in U937 cells after 24 hours of incubation compared with untreated control cells. Moreover, PHA/PMA significantly induced MMP-2 activity in Molt-4 and Jurkat cells after 24 hours of incubation in a dose-dependent manner compared with untreated control cells. CONCLUSION: We conclude that human leukemic Jurkat, U937 and Molt-4 cells could potentially display MMP-2 activity with different degrees. Thus, these cell lines could provide an appropriate system to study the mechanisms regulating MMPs production in leukemia patients. PMID- 21705841 TI - Berberine ameliorates hyperglycemia in alloxan-induced diabetic C57BL/6 mice through activation of Akt signaling pathway. AB - Recently, it is implicated that the abnormality of Akt signaling pathway is involved in the diabetic pathology. Previous studies have demonstrated that berberine could decrease blood glucose by elevating liver glycogen synthesis. However, the underlying mechanism is still unclear. In the present study, we investigated the effects of berberine on fasting blood glucose, liver glycogen, Akt, Glycogen synthase kinase-3, glucokinase and insulin receptor substrate (IRS) in alloxan-induced diabetic mice, exploring its possible hypoglycemic mechanism. We found that in alloxan-induced diabetic mice, the high blood glucose was significantly lowered by berberine treatment. Liver glycogen content, the expression and activity of glucokinase and the phosphorylated Akt and IRS were all significantly reduced in diabetic mice whereas berberine blocked these changes. Berberine also depressed the increasing of phosphorylated GSK-3beta in diabetic mice. Collectively, Berberine upregulates the activity of Akt possibly via insulin signaling pathway, eventually lowering high blood glucose in alloxan induced diabetic mice. PMID- 21705843 TI - Anti-neuroinflammatory activity of Kamebakaurin from Isodon japonicus via inhibition of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase pathway in activated microglial cells. AB - Compelling evidence supports the notion that the majority of neurodegenerative diseases are associated with microglia-mediated neuroinflammation. Therefore, quelling of microglial activation may lead to neuronal cell survival. The present study investigated the effects of Kamebakaurin (KMBK), a kaurane diterpene isolated from Isodon japonicus HARA (Labiatae), on the production of pro inflammatory mediators in lipopolysaccharide (LPS)-stimulated cytotoxicity in rat primary microglial cultures and the BV-2 cell line. KMBK significantly inhibited the LPS-induced production of nitric oxide (NO) in a concentration-dependent fashion in activated microglial cells. The mRNA and protein levels of inducible nitric oxide synthase (iNOS) and cyclooxycenase-2 (COX-2) were also decreased dose-dependently. Furthermore KMBK inhibited the JNK and p38 mitogen-activated protein kinases (MAPKs) in LPS-stimulated BV-2 microglial cells. Considering the results obtained, the present study authenticated the potential benefits of KMBK as a therapeutic target in ameliorating microglia-mediated neuroinflammatory diseases. PMID- 21705842 TI - Dietary intake of vitamin B(6) and risk of breast cancer in Taiwanese women. AB - BACKGROUND: B vitamins, including vitamin B(6), are coenzymes that are important for DNA integrity and stability. Deficiencies in B vitamins may promote tumor carcinogenesis. METHODS: We examined the association of dietary vitamin B(6) intake with overall breast cancer risk and breast cancers stratified by hormone receptor status. This case-control study included 391 breast cancer cases and 782 control subjects enrolled at the Tri-Service General Hospital in Taipei, Taiwan. Energy-adjusted intake of vitamin B(6) was derived from a food frequency questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. RESULTS: As compared with women in the lowest tertile, the multivariate-adjusted ORs for breast cancer among women in the second and highest tertiles of vitamin B(6) intake were 0.78 (95% CI, 0.64 2.52) and 0.64 (0.26-0.92), respectively. In addition, higher vitamin B(6) intake was associated with a significantly lower risk of developing ER-negative breast tumors. CONCLUSIONS: Our findings suggest that higher intake of vitamin B(6) is associated with a reduction in breast cancer risk, particularly ER-negative tumors. PMID- 21705844 TI - Asperlin from the marine-derived fungus Aspergillus sp. SF-5044 exerts anti inflammatory effects through heme oxygenase-1 expression in murine macrophages. AB - Asperlin is a fungal metabolite isolated from Aspergillus sp. SF-5044. In the present study, we isolated asperlin from the marine-derived fungus Aspergillus sp. SF-5044 and demonstrated that it inhibited inducible nitric oxide synthase (iNOS) expression, reduced iNOS-derived NO, suppressed cyclooxygenase (COX)-2 expression, and reduced COX-derived prostaglandin (PG) E2 production in lipopolysaccharide (LPS)-stimulated RAW264.7 and murine peritoneal macrophages. Similarly, asperlin reduced the production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. In addition, asperlin inhibited the phosphorylation and degradation of IkappaB-alpha, as well as the nuclear translocation of p65 caused by the stimulation of LPS in RAW264.7 macrophages. Furthermore, asperlin induced heme oxygenase (HO)-1 expression through nuclear translocation of nuclear factor E2-related factor 2 and increased HO activity in RAW264.7 macrophages. The effects of asperlin on the LPS-induced expression of iNOS and COX-2 and production of NO, PGE2, TNF-alpha, and IL-1beta were partially reversed by a HO-1 inhibitor, tin protoporphyrin. These findings suggest that asperlin-induced HO-1 expression plays a role in the anti-inflammatory effects of asperlin in macrophages. PMID- 21705846 TI - Patient-side assay of lipase activity correlating with pancreatic lipase immunoreactivity in the dog. AB - Pancreatitis is a common exocrine pancreatic disease in dogs, and the pancreatic lipase immunoreactivity (PLI) test is used for diagnosis. Enzyme catalytic assay is thought to have low specificity, but a lipase activity assay with increased specificity has been developed in human clinical chemistry. We measured serum lipase activity of 65 client-owned dogs using the newly developed FUJI DRI-CHEM slide and compared the results with their PLI concentrations. The results showed a good correlation (r = 0.91), and the normal and pancreatitis dogs identified based on the PLI values were correctly separated based on lipase activity. The present study suggests that FUJI DRI-CHEM lipase activity would be helpful for diagnosis of pacreatitis in dogs and, in particular, that it can be used as a patient-side assay and contributes to immediate treatment. PMID- 21705847 TI - Relationship between diarrhea and peripheral leukocyte population in neonatal Japanese black calves. AB - Neonatal Japanese Black (JB) calves show a high incidence of diarrhea. The objective of this study was to analyze the immune cell populations of neonatal JB calves in detail and examine its correlation with the incidence of diarrhea immediately after birth. Understanding the immune cell populations is helpful in clinics in order to determine the condition of the immune system for prevention of diseases. Blood samples were obtained from JB calves on the day of birth. The peripheral leukocyte populations were analyzed separately for calves that had diarrhea within 2 weeks after birth (diarrhea group; n = 26) and for calves without diarrhea (control group; n = 74). The numbers of the peripheral blood CD3(+)TcR1-N12(+) and CD8(+) T cells were significantly lower in the diarrhea group compared with the control group. These findings suggest that the congenital lower peripheral gammadelta and CD8(+) T cells results in a high risk of diarrhea in neonatal JB calves. PMID- 21705848 TI - Abdominal aortic chondrosarcoma in a dog. AB - A 14-year-old, mixed breed dog was presented with acute pain and paresis of the hindlimbs. Ultrasonography revealed an intraluminal mass and an abrupt halt of blood flow signal in the distal abdominal aorta. The mass had homogeneous hyperechoic echotexture compared with blood flow. Although clinical presentation suggested a thromboembolism and pituitary dependent hyperadrenocorticism was suspected as a predisposing cause based on adrenal function tests and ultrasonography, an aortic chondrosarcoma originating from the distal abdominal aorta was diagnosed with histologic examination. Primary aortic sarcoma is extremely rare, and extraskeletal chondrosarcoma is only reported in 2 cases previously. Aortic neoplasm should be included in differential diagnosis when an intraluminal aortic mass is observed on ultrasonography and acute paresis of hindlimbs is shown. PMID- 21705849 TI - Tonsillectomy and steroid pulse therapy for IgA nephropathy. AB - IgA nephropathy (IgAN) is the common cause of primary glomerulonephritis worldwide. The clinical course of IgAN is extremely variable and ranges from asymptomatic microscopic hematuria to rapidly progressive renal failure. The pathogenetic mechanisms of IgAN are still unclear, but a hypothesis consisting of two pathways has been proposed. The first pathway is continuous antigenic stimulation of the innate immune system by the tonsillar mucosa via the mucosa bone marrow axis. In the second pathway, the anomalous stimulated immune response in the bone marrow results in the production of aberrantly glycosylated IgA1 and its subsequent deposition within the mesangial area. Based on the hypothesis, tonsillectomy plus steroid pulse therapy were introduced. A recent meta-analysis showed that tonsillectomy with or without steroid pulse therapy resulted in clinical remission with favorable long-term efficacy in IgAN patients. Tonsillectomy plus steroid pulse therapy now seems to be an effective treatment for IgAN patients with hematuria and minimal proteinuria, and it is more effective in patients with less severe histological findings. The efficacy of the combination therapy depends on the duration of the IgAN. Randomized, controlled trials are needed to examine the efficacy of tonsillectomy plus steroid pulse therapy in different clinical stages of IgAN. PMID- 21705850 TI - Absolute humidity as a deterministic factor affecting seasonal influenza epidemics in Japan. AB - Influenza epidemics occur periodically during the winter season in temperate areas. Characteristic features of winter include low temperature and low humidity. Humidity is expressed in two different ways: absolute humidity (AH) defined as absolute amount of water in the air, and relative humidity (RH) defined as the relative proportion of water in the air in comparison to the maximum water vapor. There have been many arguments for RH as a determinant factor for influenza epidemics. On the other hand, we have been putting emphasis on AH on the basis of our epidemiological observations. In this context, a recent experimental and theoretical study by other investigators has shown that AH correlates with influenza survival, transmission, and seasonality. Accordingly, we collected meteorological and influenza epidemiological data from 46 prefectures in temperate Japan for 1991-1995 and 1999-2009, and analyzed 2,392 sets of weekly compiled data for each season year by using multiple linear regression analysis, in which the numbers of influenza cases were regarded as a function of AH and RH. We found that the standardized partial regression coefficient for AH was consistently stronger than that for RH with statistical significance. In addition, AH increased and decreased significantly at the time of the epidemic onset and subsidence in seven and twelve out of fourteen influenza seasons, respectively, whereas RH did so in none and two out of fourteen influenza seasons. Thus, we have substantiated our quarter-century-old assertion that AH strongly correlates with the onset and subsidence of influenza epidemics. PMID- 21705855 TI - Non-invasive detection of a palifermin-mediated adaptive response following chemotherapy-induced damage to the distal small intestine of rats. AB - INTRODUCTION: Pre-clinical studies have indicated that palifermin may be an effective treatment modality for intestinal mucositis, a debilitating complication of cancer chemotherapy. We determined whether palifermin was protective in rats with experimentally induced intestinal mucositis and the applicability of the sucrose breath test (SBT) to monitor palifermin for its efficacy as an anti-mucositis agent. RESULTS: SBT values and sucrase activity were reduced in all 5-FU-treated groups compared with untreated controls (p < 0.05). At 72 h post 5-FU, sucrase activity was higher in rats treated with palifermin compared with 5-FU controls (p < 0.05). Jejunal and ileal villus heights were lower in all 5-FU groups compared with saline controls. METHODS: Dark agouti rats (n = 10) were subcutaneously injected with palifermin or vehicle for 3 d after which they were injected with 5-fluorouracil (5-FU) and sacrificed after 72 h. The in vivo SBT and in vitro sucrase assay were used to evaluate small intestinal function and damage. Intestinal disease severity was determined by histological assessment of villus height and crypt depth. CONCLUSION: The SBT can monitor the ability of palifermin to modify the functional capacity of the small intestine in rats with intestinal mucositis. Further studies are indicated to investigate the prophylactic potential of palifermin against intestinal mucositis. PMID- 21705856 TI - Toxin on a stick: modular CDI toxin delivery systems play roles in bacterial competition. AB - Contact-dependent growth inhibition (CDI) is the first contact-dependent competition system identified in bacteria. CDI is mediated by the CdiA/CdiB two partner secretion system, and the BamA outer membrane protein serves as the CDI receptor on target cells. A small immunity protein, CdiI, is required to protect inhibitor cells from their own CDI system. Recent results from our group show that CDI systems are present in a number of important gram-negative plant and animal pathogens. The C-terminal region of CdiA (CdiA-CT) is polymorphic and contains growth inhibitory activity. The CdiA-CT from uropathogenic Esherichia coli 536 is a tRNase whereas a CdiA-CT from Dickeya dadantii 3937 has DNase activity. Accordingly, these bacteria contain distinct CdiI proteins, which specifically bind and inactivate cognate CdiA-CT. Remarkably, CdiA-CTs are modular: one CdiA "stick" can deliver different CdiA-CT toxins. We discuss these findings as well as results showing that CDI plays an important role in intra strain bacterial competition in the natural world. A detailed mechanistic understanding of CDI could facilitate development of probiotics and antimicrobials that target specific pathogens. PMID- 21705857 TI - The effect of L-DOPA on Cryptococcus neoformans growth and gene expression. AB - Cryptococcus neoformans is unusual among melanotic fungi in that it requires an exogenous supply of precursor to synthesize melanin. C. neoformans melanizes during mammalian infection in a process that presumably uses host-supplied compounds such as catecholamines. L-3,4-dihydroxyphenylalanine (L-DOPA) is a natural catecholamine that is frequently used to induce melanization in C. neoformans and L-DOPA-melanized cryptococci manifest resistance to radiation, phagocytosis, detergents and heavy metals. Given that C. neoformans needs exogenous substrate for melanization one question in the field is the extent to which melanin-associated phenotypes reflect the presence of melanin or metabolic changes in response to substrates. In this study we analyze the response of C. neoformans to L-DOPA with respect to melanization, gene expression and metabolic incorporation. Increasing the concentration of L-DOPA promotes melanin formation up to concentrations > 1 mM, after which toxicity is apparent as manifested by reduced growth. The timing of C. neoformans cells to melanization is affected by growth phase and cell density. Remarkably, growth of C. neoformans in the presence of L-DOPA results in the induction of relatively few genes, most of which could be related to stress metabolism. We interpret these results to suggest that the biological effects associated with melanization after growth in L-DOPA are largely due to the presence of the pigment. This in turn provides strong support for the view that melanin contributes to virulence directly through its presence in the cell wall. PMID- 21705859 TI - Prevalence of influenza vaccination among nurses and ancillary workers in Italy: systematic review and meta analysis. AB - INTRODUCTION: Italian Ministry of Health, recommends vaccination for seasonal influenza to all healthcare workers (HCW), particularly to nurses who have an important interaction with patients. The aim of this study is to conduct a systematic review in order to estimate the pooled prevalence of influenza vaccinations among nurses and ancillary workers in Italy and analyse the enhancing and hindering factors. RESULTS: The review was performed using 15 articles, six containing the prevalence of vaccination for nurses and ancillary workers, while the others qualitative analysis. In all the selected articles the score calculation has been carried out by using a protocol for observational studies. The nurses and ancillary workers pooled proportion of influenza vaccination was respectively 13.47% (95%CI 9.58-17.90%) and 12.52% (95%CI 9.97 15.31%). DISCUSSION: The Italian mean of influenza vaccination prevalence appear low if compared to other European countries, ranging from 15% to 29% in Countries such as UK, Germany, France. This situation of weakness should be seen as an opportunity to improve the vaccination rate for seasonal influenza significantly This should be done by intervening on the category which affirms caring less. In fact, this category has a priority to receive vaccination, due to their numbers and closer contact to patients. METHODS: Research was conducted using medical database Scopus, PubMed, the search engine Google Scholar and ISI web of knowledge, and was concluded February 1st 2011. PMID- 21705858 TI - Chromatin modifying protein 1A (Chmp1A) of the endosomal sorting complex required for transport (ESCRT)-III family activates ataxia telangiectasia mutated (ATM) for PanC-1 cell growth inhibition. AB - Chromatin modifying protein 1A (Chmp1A) is a member of the Endosormal sorting complex required for transport (ESCRT)-III family whose over-expression induces growth inhibition, chromatin condensation, and p53 phosphorylation. p53 is a substrate for Ataxia telangiectasia mutated (ATM), which can be activated upon chromatin condensation. Thus, we propose that Chmp1A regulates ATM, and the nuclear localization signal (NLS) is required for ATM activation. Our data demonstrated that over-expression of full-length Chmp1A induced an increase in active, phosphorylated ATM in the nucleus, where they co-localized. It also induced an increase in phospho-p53 in the nucleus, and in vitro ATM kinase and p53 reporter activities. The intensity of phospho-p53 closely followed that of ectopically induced full-length Chmp1A, suggesting a tight correlation between Chmp1A over-expression and p53 phosphorylation. On the other hand, Chmp1A depletion (reported to promote cell growth) had minor effects on phospho-ATM and p53 expression compared to control, which had very little expression of these proteins. NLS-deleted cells showed uniform cytoplasmic-Chmp1A expression and acted like shRNA-expressing cells (cell growth promotion and minimal effect on ATM), demonstrating the significance of NLS on ATM activation and growth inhibition. C-deleted Chmp1A, detected in the cytoplasm at the enlarged vesicles, increased phospho-ATM and p53, and inhibited growth; yet it had no effect on in vitro ATM kinase or p53 reporter activities, suggesting that the C-domain is not required for ATM activation. Finally, ATM inactivation considerably reduced Chmp1A mediated growth inhibition and phosphorylation of p53, showing that Chmp1A regulates tumor growth partly through ATM signaling. PMID- 21705860 TI - Ease of conversion from venovenous extracorporeal membrane oxygenation to cardiopulmonary bypass and venoarterial extracorporeal membrane oxygenation with a bicaval dual lumen catheter. AB - Extracorporeal circulatory support revolutionized the field of cardiothoracic surgery, initially in the form of cardiopulmonary bypass (CPB) and then in its modified form, extracorporeal membrane oxygenation (ECMO). Although initial cannulation techniques involved open intrathoracic approaches, the increased prevalence of reoperative sternotomies and the emergence of minimally invasive surgery encouraged the development of peripheral cannulation methods and configurations. The Avalon Elite Bicaval Dual Lumen catheter (Avalon Laboratories, LLC, CA) can be placed in the right internal jugular vein to provide venovenous (VV) ECMO. However, some patients on VV ECMO then develop compromised cardiac performance. We describe two ways in which the Avalon Elite was used, first for complete venous drainage through a single peripheral site for CPB and in the other to convert a patient on VV ECMO to axillary artery venoarterial (VA) ECMO. PMID- 21705861 TI - Advancing physical activity theory: a review and future directions. AB - As behavioral physical activity (PA) research matures, the adaptation and augmentation of theories with PA-specific concepts are required to improve explanatory power and to justify the uniqueness of the discipline. This review details the advances of three prominent theories applied to understand PA. We conclude by presenting a framework for researchers to test whether a particular behavioral theory holds use in the PA domain. PMID- 21705862 TI - Impact of circulating dehydroepiandrosterone on androgen formation in women. PMID- 21705864 TI - The impact of weight and fat mass loss and increased physical activity on physical function in overweight, postmenopausal women: results from the Women on the Move Through Activity and Nutrition study. AB - OBJECTIVE: The aim of this study was to determine whether changes in leisure time physical activity (LTPA) and body composition reflect concomitant changes in 400 meter walk time. METHODS: Data were collected at the baseline and 48-month visits in the Women on the Move Through Activity and Nutrition study. At baseline, participants (n = 508) were randomized to the lifestyle intervention or health education group. The lifestyle intervention focused on weight (7%-10%) and waist circumference reduction through healthy lifestyle behavior change. Change in walk time over 48 months was the primary outcome. Secondary measures included change in LTPA and body composition measures including, body weight, body mass index, waist circumference, and dual-energy x-ray absorptiometry--derived fat and lean mass. RESULTS: Increased LTPA and reductions in body weight, body mass index, waist circumference, and fat mass were associated with decreased walk time from baseline to 48 months (P < 0.01). After stratification by group, LTPA was no longer significantly related to walk time in the health education group. CONCLUSIONS: Increased LTPA and weight loss resulted in improved physical function, as measured by the 400-meter walk, in a group of overweight, postmenopausal women. These findings support the use of the 400-meter walk to evaluate progress in physical activity or weight loss programs. PMID- 21705865 TI - Is high homocysteine level a risk factor for cognitive decline in elderly? A systematic review, meta-analysis, and meta-regression. AB - OBJECTIVE: [corrected] High homocysteine (Hct) has been causatively linked to Alzheimer disease (AD) and vascular dementia (VaD) in old age, but research methodologies and outcome measures are heterogeneous. It remains unclear whether the findings can be generalized across studies. METHODS: Random-effects meta analyses were conducted on studies examining the relationship between Hct level and risk of developing dementia/cognitive decline between comparison groups. Meta regression identified patient- and trial-related factors, which may contribute to heterogeneity. RESULTS: Seventeen relevant studies (6,122 participants; 13 cross sectional and fourprospective studies) were included. Compared with controls, Hct was significantly elevated in AD (pooled standardized mean difference [SMD]: 0.59; 95% confidence interval [CI]: 0.38-0.80; significant heterogeneity: tau = 0.105) and VaD (pooled SMD: 1.30; 95% CI: 0.75-1.84; significant heterogeneity: tau = 0.378). Meta-regression identified mean age as significant moderator for AD versus controls and mean age and mean folate levels as significant moderators for VaD versus controls. Hct was significantly higher in VaD relative to AD (pooled SMD: 0.48; 95% CI: 0.23-0.73; moderately significant heterogeneity: tau = 0.076); proportion of men and mean folate levels were significant moderators. High-Hct level was not associated with risk of developing dementia in prospective studies (pooled odds ratio: 1.34; 95% CI: 0.94-1.91, nonsignificant heterogeneity: tau = 0.048). CONCLUSION: Individuals with AD and VaD have higher Hct levels than controls; however, a causal relationship between high-Hct level and risk of developing dementia is not supported. More prospective studies and randomized controlled trials are required to test the therapeutic benefits of lowering Hct levels. PMID- 21705866 TI - Head and neck squamous cell carcinomas. PMID- 21705868 TI - Health care utilization in frontotemporal lobar degeneration. AB - The aim of this study was to find out how patients with frontotemporal lobar degeneration are cared for, to which extent family caregivers utilize professional support, and which medical treatment patients receive. Using a standardized interview, information was obtained from the caregivers of 124 patients with frontotemporal lobar degeneration on patient survival, sociodemographic characteristics, living arrangements, health care situation including formal and informal support, and pharmacological and nonpharmacological treatment. At the time of the interview, 72 patients were still alive, whereas 52 patients had already died before the interview. Fifty-seven percent of the patients lived at home. At the time of the interview/before death, respectively, 43% of the patients had been institutionalized into a nursing home on average 6.4 years after the onset of first symptoms. The mortality risk for patients who were admitted to a nursing home was 5 times higher than for those who were cared for at home. Fifty-one percent of the patients were treated with antidepressants, 23% with antipsychotics, and 34% with cholinesterase inhibitors or memantine. Forty percent of the patients received nonpharmacological treatment. PMID- 21705869 TI - Assessing the diagnostic accuracy of pulse pressure variations for the prediction of fluid responsiveness: a "gray zone" approach. AB - BACKGROUND: Respiratory arterial pulse pressure variations (PPV) are the best predictors of fluid responsiveness in mechanically ventilated patients during general anesthesia. However, previous studies were performed in a small number of patients and determined a single cutoff point to make clinical discrimination. The authors sought to test the predictive value of PPV in a large, multicenter study and to express it using a gray zone approach. METHODS: The authors studied 413 patients during general anesthesia and mechanical ventilation in four centers. PPV, central venous pressure, and cardiac output were recorded before and after volume expansion (VE). Response to VE was defined as more than 15% increase in cardiac output after VE. The following approaches were used to determine the gray zones: resampled and two-graph receiver operator characteristic curves. The impact of changes in the benefit-risk balance of VE on the gray zone was also evaluated. RESULTS: The authors observed 209 responders (51%) and 204 nonresponders (49%) to VE. The area under receiver operating characteristic curve was 0.89 (95% CI: 0.86-0.92) for PPV, compared with 0.57 (95% CI: 0.54-0.59) for central venous pressure (P < 10). The gray zone approach identified a range of PPV values (between 9% and 13%) for which fluid responsiveness could not be predicted reliably. These PPV values were seen in 98 (24%) patients. Changes in the cost ratio of VE moderately affected the gray zone limits. CONCLUSION: Despite a strong predictive value, PPV may be inconclusive (between 9% and 13%) in approximately 25% of patients during general anesthesia. PMID- 21705870 TI - Performance of anesthetic depth indexes in rabbits under propofol anesthesia: prediction probabilities and concentration-effect relations. AB - BACKGROUND: The permutation entropy, the approximate entropy, and the index of consciousness are some of the most recently studied electroencephalogram-derived indexes. In this work, a thorough comparison of these indexes was performed using propofol anesthesia in a rabbit model. METHODS: Six rabbits were anesthetized with three propofol infusion rates: 70, 100, and 130 mg . kg-1 . h-1, each maintained for 30 min, in a random order for each animal. Data recording was performed in the awake animals 20, 25, and 30 min after each infusion rate was begun in the recovered animals and consisted of electroencephalogram recordings, evaluation of depth of anesthesia according to a clinical scale, and arterial blood samples for plasma propofol determination. Median and spectral edge frequencies were analyzed for single-scale permutation entropy and composite multiscale permutation entropy, approximate entropy, index of consciousness, and the spectral parameters. The spectral parameters and single-scale and multiscale permutation entropies were corrected for the presence of burst suppression. Performance of the indexes was compared by prediction probability and pharmacodynamic analysis. RESULTS: The single-scale and composite multiscale permutation entropies with a burst suppression correction showed better prediction probabilities than did the other electroencephalogram-derived parameters but not better than the electromyographic activity. CONCLUSION: Single scale and multiscale permutation entropies may be promising measures of propofol anesthetic depth when corrected for burst suppression. Additional studies should investigate the information measured by electromyography algorithms from commercial monitors of anesthetic depth. The rabbit may be a promising animal model for electroencephalographic studies because it provides a good-quality signal. PMID- 21705871 TI - Meningitis after invasive treatment of the trigeminal ganglion: two case reports and a review of the literature. AB - OBJECTIVES: The objective of this case is to report the rare complication of a meningitis after an invasive treatment of the trigeminal ganglion. METHODS: In this case report, two cases of meningitis due to oral streptococci are reported and a review of literature is presented. RESULTS AND DISCUSSION: This complication should be recognized as early as possible to prevent deterioration of the situation. Meningitis must be suspected when a patient reports headache and fever within days after an invasive treatment of the trigeminal ganglion. PMID- 21705872 TI - Neurophysiological characterization of persistent postthoracotomy pain. AB - OBJECTIVES: The postthoracotomy pain syndrome (PTPS) has a prevalence of 30% to 40%. Although intraoperative nerve damage during thoracotomy has been demonstrated, it has not been clearly linked to PTPS and detailed quantitative sensory characterization data have so far not been presented, comparing PTPS and pain-free patients. METHODS: Neurophysiological characterization was performed in 17 patients with PTPS and 24 pain-free postthoracotomy patients using a detailed quantitative sensory testing protocol and psychometric questionnaires. RESULTS: Pain and pain-free patients had increased thresholds to tactile detection (P=0.001 and P=0.01) and cool detection (P<0.001 and P<0.01) on the operated side versus the contralateral side. Pain patients also had increased thresholds for warmth detection (P<0.001) and heat pain (P<0.01) on the operated side. The PTPS patients demonstrated increased side-to-side differences for warmth detection (P<0.01), heat pain (P<0.05), and cool detection (P<0.05) thresholds compared with pain-free patients. Pain patients also more frequently experienced cool hyperesthesia (8 of 17 vs. 1 of 24, P<0.01), but no differences were found for pressure pain, temporal summation, or sensory mapping to cool (200 cm vs. 76 cm, P=0.18). Hospital Anxiety and Depression Scale scores were higher for PTPS than for pain-free patients (P<0.01). DISCUSSION: Neurophysiological assessments indicate nerve injury to be common in pain and pain-free patients after thoracotomy. The combination of increased thresholds together with hyperesthesia, suggests consequences of nerve injury to be more pronounced in PTPS patients. PMID- 21705873 TI - Effectiveness of a multidimensional physical therapy program on pain, pressure hypersensitivity, and trigger points in breast cancer survivors: a randomized controlled clinical trial. AB - OBJECTIVE: To evaluate the effects of an 8-week multidimensional physical therapy program, including strengthening exercises and recovery massage, on neck and shoulder pain, pressure hypersensitivity, and the presence of active trigger points (TrPs) in breast cancer survivors. METHODS: In this randomized controlled clinical trial, 44 breast cancer survivors were randomly assigned into 2 groups: CUIDATE group who received a multidimensional physical therapy program; or CONTROL group who received usual care treatment for breast cancer. CUIDATE program consisted of 24 hours of individual physical training (aerobic, mobility, stretching, and strengthening exercises) and 12 hours of physical therapy recovery (stretching, massage) interventions (3 times/wk, 90 min). Outcomes included neck and shoulder pain (visual analog scale, 0 to 100), pressure pain thresholds over the C5-C6 zygapophyseal joints, deltoid muscles, second metacarpal and tibialis anterior muscles, and the presence of active TrPs in shoulder muscles. Outcomes were assessed at baseline and after the 8-week program by a blinded assessor. RESULTS: The CUIDATE group showed an estimated improvement for neck pain of -56 mm [95% confidence interval (CI), -71--40, P<0.001; effect size 2.72, 1.94 to 3.44] and for shoulder/axillary of -56 mm (95% CI, -74--38, P<0.001; effect size 2.45, 1.66 to 3.23). Improvements were also noted for pressure pain thresholds levels: C5-C6 zygapophyseal joints (between-group differences 101 kPa, 95% CI, 60-143; effect size 1.68, 1.00 to 2.35; 92 kPa 55 to 129; d: 1.98, 1.18 to 2.77), deltoid muscles (98 kPa, 45 to 149; d: 1.34, 0.62 to 2.04; 75 kPa 18 to 132; d: 1.12, 0.27 to 1.96), second metacarpal (93 kPa, 45 to 134; d: 1.30, 0.63 to 1.86; 99 kPa 59 to 139; d: 1.60, 0.96 to 2.24), and tibialis anterior muscles (71 kPa, 40 to 144; d: 1.16, 0.65 to 2.34; 118 kPa 57 to 178; d: 1.17, 0.56 to 1.77). Finally, patients within the CUIDATE program showed a greater reduction of active muscle TrPs compared with the CONTROL group (P<0.01). CONCLUSIONS: An 8-week multidimensional program including strengthening exercises, and massage as major components was effective for improving neck and shoulder pain and reducing widespread pressure hyperalgesia in breast cancer survivors compared with usual care treatment. PMID- 21705874 TI - Cancer patient attitudes toward analgesic usage and pain intervention. AB - OBJECTIVES: Although pain is commonly experienced by cancer patients, many receive inadequate pain management. Little data exist quantifying analgesic usage among oncology patients. This study evaluates perceived causes of pain and investigates reasons why oncology patients fail to receive optimal pain management. METHODS: An institutional review board-approved questionnaire assessing pain control and analgesic usage was posted on OncoLink. Between November 2005 and July 2008, 1107 patients responded. Respondents were female (73%), white (74%), educated beyond high school (64%), and had surgery (69%), chemotherapy (64%), and radiation (47%). Most had breast (30%), gastrointestinal (12%), gynecologic (11%), and lung (8%) malignancies. RESULTS: Sixty-seven percent of respondents reported pain, with 48% reporting pain directly from their cancer and 47% reporting pain from their cancer treatment. Among patients in pain, 25% did not use analgesics. Analgesic usage was significantly less in men (44% vs. 52%, P=0.023), minorities (42% vs. 53%, P=0.001), and patients with lower education levels (45% vs. 53%, P=0.013). Usage varied by cancer diagnosis and was higher among patients who received chemotherapy (56% vs. 40%, P<0.001) and radiation (53% vs. 47%, P=0.058). Reasons for not taking analgesics included: health care provider not recommending medications (85%), fearing addiction/dependence (80%), and inability to pay (76%). Many patients reporting pain, not taking analgesics, pursued alternative therapies (94%). DISCUSSION: Most cancer patients perceive pain from their disease or treatment, regardless of therapy received. Many, however, did not use analgesics due to concerns of addiction, cost, or lack of health care provider endorsement. Providers should regularly discuss pain symptoms and management with cancer patients. PMID- 21705875 TI - Sensitivity of single-domain versus multiple-domain outcome measures to identify responders in chronic low-back pain: pooled analysis of 2 placebo-controlled trials of etoricoxib. AB - OBJECTIVES: A composite responder index for chronic low-back pain (CLBP) has recently been proposed to evaluate the efficacy of CLBP treatments in clinical trials. We compared the responsiveness of this composite measure with a number of single-item responder definitions. METHODS: We pooled data from 2 placebo controlled studies of etoricoxib in CLBP to evaluate 5 response criteria: 30% pain intensity (PI) reduction; 50% PI reduction; 20 mm absolute reduction (100 mm PI visual analog scale); patient global assessment of response to therapy (PGART); and the composite criteria of 30% reduction in PI+30% improvement in PGART of disease status+no worsening in function. We used bootstrap analysis and logistic regression to assess the ability to differentiate etoricoxib and placebo, and the kappa coefficient to assess agreement among the responder criteria. RESULTS: The criterion of a 20 mm improvement in PI resulted in the greatest proportion (71.5%) of patients being classified as responders and all criteria separated etoricoxib from placebo (P<=0.0001). PGART had the highest discriminant ability (odds ratio 5.90), and was significantly (P<0.05) more discriminant than the 20 mm and >=30% improvements and the composite criteria. After adjusting for all other measures, only PGART continued to show a significant treatment effect for etoricoxib versus placebo (P=0.0003). Kappa values contrasting the composite criteria and the single-item measures ranged from 0.59 to 0.85. DISCUSSION: These findings do not support the superiority of a composite index over single-item ratings of PI and PGART ratings, but do suggest that PGART ratings may be more responsive to treatment, perhaps because they measure something in addition to change in PI. PMID- 21705876 TI - Assessment of chronic pain after thoracotomy: a 1-year prevalence study. AB - OBJECTIVES: The primary goal of this study was to investigate the incidence of chronic pain 1 year after a thoracotomy. Secondary goals were to determine which interventions and patient characteristics were associated with reports of chronic pain, to identify risk factors, to clarify the neuropathic component, and to determine the impact of chronic pain on daily life. METHODS: All 86 patients, who had undergone a posterolateral thoracotomy at our institution between October 2007 and March 2008, received a questionnaire 1 year after the surgical procedure and were contacted by phone 1 week later. RESULTS: Sixty-five patients responded. Prevalence of chronic pain was 48%; among them 8 patients had neuropathic pain (12% of the whole group). Current, average, and maximal pain scale scores were 1.1+/-1.2, 1.3+/-1.3, and 3.4+/-1.7 (visual analog scale), respectively. Patients with chronic pain were about 10 years younger (P=0.07) and had a significantly less severe American Society of Anesthesiologists (ASA) score (29% grade I versus 17%, P=0.04). With regard to risk factors, age and ASA score were negatively correlated with chronic pain whereas number of drains was positively correlated to it. In most patients with pain (84%), activities of daily life were affected. DISCUSSION: Chronic pain is common after thoracotomy and its neuropathic component is infrequent. As age, ASA scores, number of drains, and situations relating to daily life seem to play a role in pain occurrence, a multifaceted approach against the onset of chronic pain is advisable. PMID- 21705877 TI - Usefulness of double vital staining with 1% fluorescein and 1% lissamine green in patients with dry eye syndrome. AB - PURPOSE: To determine the relative staining characteristics of the nasal and temporal conjunctiva as compared with other measures of dry eye and evaluate the qualitative clinical impression of the utility of the double vital staining with fluorescein and lissamine green. METHODS: Ocular surface staining was performed with a mixture of 1% fluorescein and 1% lissamine green in 50 patients with dry eye (12 patients with Sjogren syndrome and 38 patients with non-Sjogren syndrome). Ocular surface disease index (OSDI), tear breakup time (BUT), and Schirmer test were evaluated. Digital photographs were taken after vital staining on the ocular surface, and the grade of staining in various areas was assessed. Correlation among the degrees of staining, OSDI, and ocular surface parameters was analyzed. RESULTS: The nasal conjunctiva evidenced greater staining compared with the temporal conjunctiva and cornea (P = 0.04). Staining of the nasal conjunctiva showed significant correlation with OSDI (P < 0.01) and BUT (P = 0.03). Staining of the temporal conjunctiva correlated significantly with OSDI (P = 0.01), and staining of the cornea correlated with BUT (P = 0.02). CONCLUSIONS: Double vital staining with 1% fluorescein and 1% lissamine green correlates with symptoms and some ocular surface parameters in patients with dry eye and helps to identify ocular surface changes easily. It may be a useful method for the diagnosis of dry eye and the assessment of the therapeutic effect in patients with dry eye syndrome. PMID- 21705878 TI - Boston keratoprosthesis for keratopathy in eyes with retained silicone oil: a new indication. AB - PURPOSE: To analyze the visual outcome of Boston keratoprosthesis for keratopathy in silicone oil-filled eyes. METHODS: Retrospective chart review of patients with silicone oil-induced keratopathy undergoing Boston keratoprosthesis between January 2008 and June 2010 was performed. Patients received Boston keratoprosthesis as the primary procedure or after a failed penetrating keratoplasty because of silicone oil-induced keratopathy after assessing possible visual potential. Silicone oil had to be retained in all eyes because of persistent ocular hypotony. RESULTS: Of the 8 eyes that underwent surgery, anatomic retention and visual improvement were noted in 7 eyes (87.5%). The visual acuity improved to 20/200 or better in 6 eyes (66.67%). Repeated corneal melt necessitated the removal of the prosthesis with corneal transplant in 1 eye. Membranectomy was performed twice for retroprosthetic membrane in 1 eye. CONCLUSIONS: Boston keratoprosthesis seems to be a viable option for visual rehabilitation in postvitrectomized eyes with a decrease in vision due to retained silicone oil-induced keratopathy. PMID- 21705879 TI - Pediatric ocular surface infections: a 5-year review of demographics, clinical features, risk factors, microbiological results, and treatment. AB - PURPOSE: To evaluate the clinical and microbiological profiles of pediatric patients with ocular surface infections requiring corneal or conjunctival scraping for diagnosis. METHODS: The medical records of 138 consecutive patients aged 18 years or younger who had undergone corneal or conjunctival scraping over a 5-year-period in a tertiary ophthalmic center were reviewed. Demographics, clinical features, risk factors, microbiological results, and treatment were recorded. RESULTS: Ocular surface infections were classified into 4 groups: infectious keratitis (group 1); blepharokeratoconjunctivitis (group 2); conjunctivitis (group 3); and congenital nasolacrimal duct obstruction or dacryocystitis (group 4). The groups had different mean ages of presentation, with group 4 presenting the youngest at 2 years and group 1 presenting the oldest at 14 years. Contact lens wear and blepharitis were the major risk factors. The positive culture rate was 60.9%, of which 65.5% were Gram-positive organisms. Coagulase-negative staphylococci were the most common organisms (23.2%), followed by Pseudomonas aeruginosa (9.4%) and Staphylococcus aureus (8.0%). Microbial yield was highest in group 1 (86%) and lowest in group 3 (38.6%). There were 9 orthokeratology-related infectious keratitis cases (18%) and 9 chlamydial ophthalmia neonatorum cases isolated. CONCLUSIONS: With increasing contact lens wear in the pediatric and adolescent populations and the common occurrence of blepharokeratoconjunctivitis and staphylococcal ocular surface infections, parents and children should be highly vigilant with eyelid hygiene and contact lens practice. PMID- 21705880 TI - Pregnancy-induced progression of keratoconus. AB - PURPOSE: To report eyes with keratoconus that progressed during pregnancy. METHODS: Seven eyes of 4 patients with progression of keratoconus during pregnancy were included in this study. The mean age of patients and the mean follow-up duration were 29.3 years and 39 months, respectively. Progressive keratoconus was documented with changes in refraction, corneal topography, and rigid gas-permeable lens fitting pattern. Patients with accompanying systemic and ocular diseases associated with keratoconus, uncontrolled atopic disease, and eye rubbing were excluded. RESULTS: Mean increase in spherical equivalent refraction and simulated keratometry values were 1.4 +/- 1.1 and 1.1 +/- 0.8 diopters, respectively. In eyes wearing rigid gas-permeable lenses, increase in corneal apical touch and decrease in the base curve radius of the best-fitting contact lens were observed. CONCLUSIONS: Hormonal changes during pregnancy may affect corneal biomechanics negatively, and pregnancy may be a previously unrecognized risk factor for progression of keratoconus. To our knowledge, this is the first study showing pregnancy-induced keratoconus progression in patients with no accompanying disease. PMID- 21705881 TI - Optimal amount of calories for critically ill patients: depends on how you slice the cake! AB - OBJECTIVE: The optimal amount of calories required by critically ill patients continues to be controversial. The objective of this study is to examine the relationship between the amount of calories administered and mortality. DESIGN: Prospective, multi-institutional audit. SETTING: Three hundred fifty-two intensive care units from 33 countries. PATIENTS: A total of 7,872 mechanically ventilated, critically ill patients who remained in the intensive care unit for at least 96 hrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated the association between the amount of calories received and 60-day hospital mortality using various sample restriction and statistical adjustment techniques and demonstrate the influence of the analytic approach on the results. In the initial unadjusted analysis, we observe a significant association between increased caloric intake and increased mortality (odds ratio 1.28; 95% confidence interval 1.12-1.48 for patients receiving more than two-thirds of their caloric prescription vs. those receiving less than one-third of their prescription). Excluding days after permanent progression to oral intake attenuated the estimates of harm (unadjusted analysis: odds ratio 1.04; 95% confidence interval 0.90-1.20). Restricting the analysis to patients with at least 4 days in the intensive care unit before progression to oral intake and excluding days of observation after progression to oral intake resulted in a significant benefit to increased caloric intake (unadjusted odds ratio 0.73; 95% confidence interval 0.63-0.85). When further adjusting for both evaluable days and other important covariates, patients who received more than two-thirds of their caloric prescription are much less likely to die than those receiving less than one-third of their prescription (odds ratio 0.67; 95% confidence interval 0.56-0.79; p < .0001). When treated as a continuous variable, the overall association between the percent of the caloric prescription received and mortality is highly statistically significant with increasing calories associated with decreasing mortality (p < .0001). CONCLUSIONS: The estimated association between the amount of calories and mortality is significantly influenced by the statistical methodology used. The most appropriate available analyses suggest that attempting to meet caloric targets may be associated with improved clinical outcomes in critically ill patients. PMID- 21705882 TI - Pulmonary vascular reserve during experimental pulmonary embolism: effects of a soluble guanylate cyclase stimulator, BAY 41-8543. AB - OBJECTIVES: Pulmonary embolism causes pulmonary hypertension by mechanical obstruction and vasoconstriction. Therapeutic potential of pharmacologic dilation of unblocked vessels has received limited attention. We tested pulmonary vasodilator reserve using a soluble guanylate cyclase stimulator, BAY 41-8543. DESIGN: Controlled animal study. SETTING: Medical center research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Pulmonary embolism was induced by infusing 25-MUm plastic microspheres in the right jugular vein, producing mild or moderate pulmonary hypertension. Control animals with no pulmonary embolism received suspension medium for microspheres. MEASUREMENTS AND MAIN RESULTS: Mild pulmonary embolism increased right ventricular peak systolic pressure (from 28 to 38 mm Hg) and decreased cardiac output (from 46 to 34 mL/min) with no change in mean arterial pressure. Infusion of BAY 41-8543 (50-200 MUg/kg) decreased right ventricular peak systolic pressure. Five hrs moderate pulmonary embolism increased right ventricular peak systolic pressure (from 28 to 47 mm Hg) and decreased cardiac output (from 48 to 27 mL/min), causing right ventricular peak systolic pressure/cardiac output to increase from 0.6 control with no pulmonary embolism to 1.8 mm Hg/mL/min in 5-hr moderate pulmonary embolism + solvent for BAY 41-8543. Treatment of 5-hr moderate pulmonary embolism with BAY 41-8543 (50 MUg/kg) caused a 2.2-fold increase in cardiac output (59 mL/min) with a 46% reduction in right ventricular peak systolic pressure (38 mm Hg), suggesting significant pulmonary vasodilation. Moderate pulmonary embolism decreased arterial sO2 (from 83% to 71%) and increased lactate (from 0.5 to 2.3 mmol/L). Treatment with BAY 41-8543 normalized sO2 and lactate. Hemolysis occurred during moderate experimental pulmonary embolism (60-fold increase in plasma hemoglobin). Treatment with BAY 41-8543 reduced free plasma hemoglobin content by 80%. CONCLUSIONS: In the setting of moderate impervious pulmonary embolism, treatment with a guanylate cyclase stimulator normalized pulmonary hemodynamics, reduced hemolysis, and improved oxygenation. These data support the hypothesis that pharmacologic dilation of nonobstructed pulmonary vasculature can effectively treat acute pulmonary hypertension from pulmonary embolism. PMID- 21705883 TI - Diaphragm dysfunction assessed by ultrasonography: influence on weaning from mechanical ventilation. AB - OBJECTIVE: To determine the prevalence of diaphragmatic dysfunction diagnosed by M-mode ultrasonography (vertical excursion <10 mm or paradoxic movements) in medical intensive care unit patients and to assess the influence of diaphragmatic dysfunction on weaning outcome. DESIGN: Prospective, observational study. SETTING: Twenty-eight-bed medical intensive care unit in a university-affiliated hospital. PATIENTS: Eighty-eight consecutive patients in the medical intensive care unit who required mechanical ventilation over 48 hrs and met the criteria for a spontaneous breathing trial were assessed. Patients with a history of diaphragmatic or neuromuscular disease or evidence of pneumothorax or pneumomediastinum were excluded. INTERVENTIONS: During spontaneous breathing trial, each hemidiaphragm was evaluated by M-mode ultrasonography using the liver and spleen as windows with the patient supine. Rapid shallow breathing index was simultaneously calculated at the bedside. MEASUREMENTS AND MAIN RESULTS: The prevalence of ultrasonographic diaphragmatic dysfunction among the eligible 82 patients was 29% (n = 24). Patients with diaphragmatic dysfunction had longer weaning time (401 [range, 226-612] hrs vs. 90 [range, 24-309] hrs, p < .01) and total ventilation time (576 [range, 374-850] hrs vs. 203 [range, 109-408] hrs, p < .01) than patients without diaphragmatic dysfunction. Patients with diaphragmatic dysfunction also had higher rates of primary (20 of 24 vs. 34 of 58, p < .01) and secondary (ten of 20 vs. ten of 46, p = .01) weaning failures than patients without diaphragmatic dysfunction. The area under the receiver operating characteristics curve of ultrasonographic criteria in predicting weaning failure was similar to that of rapid shallow breathing index. CONCLUSIONS: Using M-mode ultrasonography, diaphragmatic dysfunction was found in a substantial number of medical intensive care unit patients without histories of diaphragmatic disease. Patients with such diaphragmatic dysfunction showed frequent early and delayed weaning failures. Ultrasonography of the diaphragm may be useful in identifying patients at high risk of difficulty weaning. PMID- 21705884 TI - Evaluation of new acute kidney injury biomarkers in a mixed intensive care unit. AB - OBJECTIVE: Biomarkers for detection of acute kidney injury and prediction of mortality will be useful to improve the outcomes of critically ill patients. Although several promising acute kidney injury biomarkers have been reported, evaluation in heterogeneous disease-oriented populations is necessary to confirm their reliability before their translation to clinical use. This study was undertaken to evaluate the reliability of new acute kidney injury biomarkers including urinary L-type fatty acid-binding protein with heterogeneous intensive care unit populations. DESIGN: Prospective observational cohort study. SETTING: Single-center study, 15-bed medical-surgical mixed intensive care unit at a university hospital. PATIENTS: Three hundred thirty-nine adult critically ill patients who had been admitted to the intensive care unit were studied prospectively. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Five urinary biomarkers (L-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, interleukin-18, N-acetyl-beta-D-glucosaminidase, and albumin) were measured at intensive care unit admission. By the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) criteria, 131 patients (39%) were diagnosed as acute kidney injury. Urinary L-type fatty acid-binding protein detected acute kidney injury better than the other biomarkers did (the area under the receiver operating characteristic curves for L-type fatty acid-binding protein 0.75, neutrophil gelatinase-associated lipocalin 0.70, interleukin-18 0.69, N-acetyl beta-D-glucosaminidase 0.62, albumin 0.69). Urinary L-type fatty acid-binding protein predicted later-onset acute kidney injury after intensive care unit admission with the highest area under the receiver operating characteristic curve value of 0.70. Furthermore, L-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, and interleukin-18 were able to predict 14-day mortality with higher area under the receiver operating characteristic curves than acute kidney injury detection (area under the receiver operating characteristic curve for L-type fatty acid-binding protein 0.90, neutrophil gelatinase-associated lipocalin 0.83, interleukin-18 0.83). The combination of L type fatty acid-binding protein and neutrophil gelatinase-associated lipocalin improved mortality prediction (area under the receiver operating characteristic curve 0.93). CONCLUSION: This prospective observational study with a cohort of heterogeneous patients treated in a mixed intensive care unit revealed that new acute kidney injury biomarkers have a significantly and moderately predictive use for acute kidney injury diagnosis and that urinary L-type fatty acid-binding protein and neutrophil gelatinase-associated lipocalin can serve as new biomarkers of mortality prediction in critical care. PMID- 21705885 TI - Validation of a gene expression-based subclassification strategy for pediatric septic shock. AB - OBJECTIVE: Septic shock heterogeneity has important implications for clinical trial implementation and patient management. We previously addressed this heterogeneity by identifying three putative subclasses of children with septic shock based exclusively on a 100-gene expression signature. Here we attempted to prospectively validate the existence of these gene expression-based subclasses in a validation cohort. DESIGN: Prospective observational study involving microarray based bioinformatics. SETTING: Multiple pediatric intensive care units in the United States. PATIENTS: Separate derivation (n = 98) and validation (n = 82) cohorts of children with septic shock. INTERVENTIONS: None other than standard care. MEASUREMENTS AND MAIN RESULTS: Gene expression mosaics of the 100 class defining genes were generated for 82 individual patients in the validation cohort. Using computer-based image analysis, patients were classified into one of three subclasses ("A," "B," or "C") based on color and pattern similarity relative to reference mosaics generated from the original derivation cohort. After subclassification, the clinical database was mined for phenotyping. Subclass A patients had higher illness severity relative to subclasses B and C as measured by maximal organ failure, fewer intensive care unit-free days, and a higher Pediatric Risk of Mortality score. Patients in subclass A were characterized by repression of genes corresponding to adaptive immunity and glucocorticoid receptor signaling. Separate subclass assignments were conducted by 21 individual clinicians using visual inspection. The consensus classification of the clinicians had modest agreement with the computer algorithm. CONCLUSIONS: We have validated the existence of subclasses of children with septic shock based on a biologically relevant, 100-gene expression signature. The subclasses have relevant clinical differences. PMID- 21705886 TI - Efficacy of ventilator waveforms observation in detecting patient-ventilator asynchrony. AB - OBJECTIVES: The value of visual inspection of ventilator waveforms in detecting patient-ventilator asynchronies in the intensive care unit has never been systematically evaluated. This study aims to assess intensive care unit physicians' ability to identify patient-ventilator asynchronies through ventilator waveforms. DESIGN: Prospective observational study. SETTING: Intensive care unit of a University Hospital. PATIENTS: Twenty-four patients receiving mechanical ventilation for acute respiratory failure. INTERVENTION: Forty-three 5 min reports displaying flow-time and airway pressure-time tracings were evaluated by 10 expert and 10 nonexpert, i.e., residents, intensive care unit physicians. The asynchronies identified by experts and nonexperts were compared with those ascertained by three independent examiners who evaluated the same reports displaying, additionally, tracings of diaphragm electrical activity. MEASUREMENTS AND MAIN RESULTS: Data were examined according to both breath-by-breath analysis and overall report analysis. Sensitivity, specificity, and positive and negative predictive values were determined. Sensitivity and positive predictive value were very low with breath-by-breath analysis (22% and 32%, respectively) and fairly increased with report analysis (55% and 44%, respectively). Conversely, specificity and negative predictive value were high with breath-by-breath analysis (91% and 86%, respectively) and slightly lower with report analysis (76% and 82%, respectively). Sensitivity was significantly higher for experts than for nonexperts for breath-by-breath analysis (28% vs. 16%, p < .05), but not for report analysis (63% vs. 46%, p = .15). The prevalence of asynchronies increased at higher ventilator assistance and tidal volumes (p < .001 for both), whereas it decreased at higher respiratory rates and diaphragm electrical activity (p < .001 for both). At higher prevalence, sensitivity decreased significantly (p < .001). CONCLUSIONS: The ability of intensive care unit physicians to recognize patient ventilator asynchronies was overall quite low and decreased at higher prevalence; expertise significantly increased sensitivity for breath-by-breath analysis, whereas it only produced a trend toward improvement for report analysis. PMID- 21705887 TI - Inflammatory biomarkers and prediction for intensive care unit admission in severe community-acquired pneumonia. AB - OBJECTIVE: Increased inflammatory response is related to severity and outcome in community-acquired pneumonia, but the role of inflammatory biomarkers in deciding intensive care unit admission is unknown. We assessed the relationship between inflammatory response, prediction for intensive care unit admission, delayed intensive care unit admission, and outcome in patients with community-acquired pneumonia. DESIGN: Prospective clinical study. SETTING: Intensive care units of two university hospitals. PATIENTS: We included 627 ward and 58 intensive care unit patients with community-acquired pneumonia, 36 with direct and 22 with delayed intensive care unit admission. INTERVENTIONS: Serum levels of C-reactive protein, procalcitonin, tumor necrosis factor-alpha, interleukin-1, interleukin 6, interleukin-8, and interleukin-10 at admission. MEASUREMENTS AND MAIN RESULTS: We assessed the prediction for intensive care unit admission of biomarkers and the Infectious Diseases Society of America/American Thoracic Society guidelines minor criteria for severe community-acquired pneumonia. Procalcitonin (p=.001), C reactive protein (p=.005), tumor necrosis factor-alpha (p=.042), and interleukin 6 (p=.003) levels were higher in intensive care unit-admitted patients; however, the Infectious Diseases Society of America/American Thoracic Society guidelines minor severity criteria predicted better intensive care unit admission (odds ratio, 12.03; 95% confidence interval, 5.13-28.20; p<.001). No patient with severe community-acquired pneumonia by three or more minor severity criteria and procalcitonin levels below the optimal cutoff (0.35 ng/mL) needed intensive care unit admission compared with 14 (23%) with levels above the cutoff (p=.032). In patients initially admitted to wards, procalcitonin (p=.012) and C-reactive protein (p=.039) were higher in those 22 patients subsequently transferred to the intensive care unit after adjusting for age, comorbidities, and Pneumonia Severity Index risk class. Despite initially admitted to wards, 14 (64%) patients with delayed intensive care unit admission had already criteria for severe community-acquired pneumonia at admission compared with 73 (12%) ward patients (p<.001). CONCLUSION: Inflammatory biomarkers identified patients needing intensive care unit admission, including those with delayed intensive care unit admission. Patients with severe community-acquired pneumonia by minor criteria and low levels of procalcitonin may be safely admitted to wards. Correctly applying the Infectious Diseases Society of America/American Thoracic Society guidelines would reduce substantially delayed intensive care unit admission. PMID- 21705888 TI - Increased blood glucose variability during therapeutic hypothermia and outcome after cardiac arrest. AB - OBJECTIVE: Hypothermia impairs blood glucose homeostasis and insulin sensitivity. However, the impact of therapeutic hypothermia on blood glucose levels and insulin requirements is unknown. We analyzed blood glucose variability during therapeutic hypothermia in patients with coma after cardiac arrest and examined its impact on outcome. DESIGN: Prospective observational study. SETTING: Two university hospital medical/surgical intensive care units. PATIENTS: Comatose cardiac arrest patients treated with therapeutic hypothermia (33 degrees C, 24 hrs). INTERVENTIONS: Insulin therapy (blood glucose target 6-8 mmol/L [110-150 mg/dL]), according to a written algorithm, with nurse-driven adjustment of insulin dose. MEASUREMENTS AND MAIN RESULTS: Two-hundred and twenty patients (median age 61 yrs, median time to return of spontaneous circulation 20 min) were studied. Two time periods, comparable in duration, were categorized: therapeutic hypothermia (stable maintenance phase) and normothermia (after rewarming). Blood glucose variability was defined as the difference between maximum and minimum blood glucose concentration during each time period. Mean blood glucose (8.3+/ 2.3 vs. 7.1+/-1.3 mmol/L), blood glucose variability (5.7+/-3.9 vs. 3.7+/-3.6 mmol/L), and insulin dose (2+/-2 vs. 1+/-1 U/h) were higher during therapeutic hypothermia compared to normothermia (all p<.001). Higher mean blood glucose (7.9+/-1.8 mmol/L in survivors vs. 8.7+/-2.6 mmol/L in nonsurvivors, p=.02) and increased blood glucose variability (4.9+/-3.5 vs. 6.5+/-4.1 mmol/L, p=.003) during therapeutic hypothermia were associated with mortality. After adjusting for time to return of spontaneous circulation, initial arrest rhythm, and cardiac arrest etiology, increased blood glucose variability during therapeutic hypothermia, but not mean blood glucose level, was an independent predictor of inhospital mortality (odds ratio for death 1.10 [confidence interval 1.02-1.19], p=.016). CONCLUSIONS: Mild therapeutic hypothermia is associated with higher blood glucose levels, increased blood glucose variability, and greater insulin requirements compared to the postrewarming normothermic phase. Increased blood glucose variability during therapeutic hypothermia is a predictor of inhospital mortality after cardiac arrest, independent of injury severity and mean blood glucose levels. PMID- 21705889 TI - Comparison of airway pressure release ventilation to conventional mechanical ventilation in the early management of smoke inhalation injury in swine. AB - OBJECTIVE: The role of airway pressure release ventilation in the management of early smoke inhalation injury has not been studied. We compared the effects of airway pressure release ventilation and conventional mechanical ventilation on oxygenation in a porcine model of acute respiratory distress syndrome induced by wood smoke inhalation. DESIGN: Prospective animal study. SETTING: Government laboratory animal intensive care unit. PATIENTS: Thirty-three Yorkshire pigs. INTERVENTIONS: Smoke inhalation injury. MEASUREMENTS AND MAIN RESULTS: Anesthetized female Yorkshire pigs (n = 33) inhaled room-temperature pine-bark smoke. Before injury, the pigs were randomized to receive conventional mechanical ventilation (n = 15) or airway pressure release ventilation (n = 12) for 48 hrs after smoke inhalation. As acute respiratory distress syndrome developed (PaO2/Fio2 ratio <200), plateau pressures were limited to <35 cm H2O. Six uninjured pigs received conventional mechanical ventilation for 48 hrs and served as time controls. Changes in PaO2/Fio2 ratio, tidal volume, respiratory rate, mean airway pressure, plateau pressure, and hemodynamic variables were recorded. Survival was assessed using Kaplan-Meier analysis. PaO2/Fio2 ratio was lower in airway pressure release ventilation vs. conventional mechanical ventilation pigs at 12, 18, and 24 hrs (p < .05) but not at 48 hrs. Tidal volumes were lower in conventional mechanical ventilation animals between 30 and 48 hrs post injury (p < .05). Respiratory rates were lower in airway pressure release ventilation at 24, 42, and 48 hrs (p < .05). Mean airway pressures were higher in airway pressure release ventilation animals between 6 and 48 hrs (p < .05). There was no difference in plateau pressures, hemodynamic variables, or survival between conventional mechanical ventilation and airway pressure release ventilation pigs. CONCLUSIONS: In this model of acute respiratory distress syndrome caused by severe smoke inhalation in swine, airway pressure release ventilation-treated animals developed acute respiratory distress syndrome faster than conventional mechanical ventilation-treated animals, showing a lower PaO2/Fio2 ratio at 12, 18, and 24 hrs after injury. At other time points, PaO2/Fio2 ratio was not different between conventional mechanical ventilation and airway pressure release ventilation. PMID- 21705890 TI - The Accreditation Council for Graduate Medical Education resident duty hour new standards: history, changes, and impact on staffing of intensive care units. AB - OBJECTIVES: The Accreditation Council for Graduate Medical Education recently released new standards for supervision and duty hours for residency programs. These new standards, which will affect over 100,000 residents, take effect in July 2011. In response to these new guidelines, the Society of Critical Care Medicine convened a task force to develop a white paper on the impact of changes in resident duty hours on the critical care workforce and staffing of intensive care units. PARTICIPANTS: A multidisciplinary group of professionals with expertise in critical care education and clinical practice. DATA SOURCES AND SYNTHESIS: Relevant medical literature was accessed through a systematic MEDLINE search and by requesting references from all task force members. Material published by the Accreditation Council for Graduate Medical Education and other specialty organizations was also reviewed. Collaboratively and iteratively, the task force corresponded by electronic mail and held several conference calls to finalize this report. MAIN RESULTS: The new rules mandate that all first-year residents work no more than 16 hrs continuously, preserving the 80-hr limit on the resident workweek and 10-hr period between duty periods. More senior trainees may work a maximum of 24 hrs continuously, with an additional 4 hrs permitted for handoffs. Strategic napping is strongly suggested for trainees working longer shifts. CONCLUSIONS: Compliance with the new Accreditation Council for Graduate Medical Education duty-hour standards will compel workflow restructuring in intensive care units, which depend on residents to provide a substantial portion of care. Potential solutions include expanded utilization of nurse practitioners and physician assistants, telemedicine, offering critical care training positions to emergency medicine residents, and partnerships with hospitalists. Additional research will be necessary to evaluate the impact of the new standards on patient safety, continuity of care, resident learning, and staffing in the intensive care unit. PMID- 21705891 TI - Cholecystokinin octapeptide induces hypothermia and improves outcomes in a rat model of cardiopulmonary resuscitation. AB - OBJECTIVES: To investigate the effects of cholecystokinin octapeptide on thermoregulation, postresuscitation myocardial function, neurologic outcome, and duration of survival in a rat model of cardiopulmonary resuscitation. DESIGN: : Prospective, randomized, placebo-controlled experimental study. SETTING: University-affiliated animal research laboratory. SUBJECTS: Ten male Sprague Dawley rats. INTERVENTIONS: Ventricular fibrillation was induced and untreated for 6 mins. Defibrillation was attempted after 8 mins of cardiopulmonary resuscitation. Animal temperature was adjusted to 37.0 degrees C with the aid of a heating lamp. At 30 mins after resuscitation, animals were randomized to receive an intravenous injection of either cholecystokinin octapeptide (200 MUg/kg in 0.3 mL saline) or vehicle placebo (0.3 mL saline). The ambient temperature settings and that of the distance of the heating lamp from the animal remained the same in both groups throughout the entire experiment. MEASUREMENTS AND MAIN RESULTS: Body temperature, hemodynamic measurements, and postresuscitation myocardial function, including cardiac output, left ventricular ejection fraction, and myocardial performance index, were measured together with neurologic deficit scores and duration of survival. RESULTS: After injection of cholecystokinin octapeptide, blood temperature decreased progressively from 37.0 degrees C to 34.8 degrees C 5 hrs after resuscitation and returned to 37.0 degrees C at 9 hrs after injection. In the control group, blood temperature was sustained at 37.0 degrees C +/- 0.2 degrees C during the same period of observation. Myocardial and neurologic function and duration of survival were significantly better in the cholecystokinin octapeptide-treated animals when compared to the control group. CONCLUSIONS: : In a rat model of cardiopulmonary resuscitation, cholecystokinin octapeptide induced mild hypothermia, attenuated postresuscitation myocardial dysfunction, and improved neurologic outcome and duration of survival. PMID- 21705892 TI - Antibiotic exposure and resistance development in Pseudomonas aeruginosa and Enterobacter species in intensive care units. AB - OBJECTIVES: We quantified the association between antibiotic exposure and acquisition of antibiotic resistance in Pseudomonas aeruginosa and Enterobacter species in intensive care unit patients. DESIGN: Prospective cohort study. SETTING AND PATIENTS: In 1,201 patients, respiratory tract colonization was determined through regular screening on admission, twice weekly, and on discharge. Primary outcome was the acquisition of antibiotic resistance in previous antibiotic sensitive P. aeruginosa and Enterobacter species, with acquisition attributable to cross-transmission excluded based on genotyping and epidemiologic linkage. Cox regression analysis, adjusted for covariates, was performed to calculate hazard ratios of patients exposed to antibiotics compared to patients not exposed to antibiotics. MEASUREMENTS AND MAIN RESULTS: In total, 194 and 171 patients were colonized with P. aeruginosa and Enterobacter species, respectively. Two or more cultures per episode were available for 126 and 108 patients. For P. aeruginosa, ceftazidime exposure was associated with 6.3 acquired antibiotic resistance events per 100 days of exposure, whereas incidence rates were lower for ciprofloxacin, meropenem, and piperacillin-tazobactam. In multivariate analysis, meropenem, ciprofloxacin, and ceftazidime were significantly associated with risk of resistance development in P. aeruginosa (adjusted hazard ratio, 11.1; 95% confidence interval, 2.4-51.5 for meropenem; adjusted hazard ratio, 4.1; 95% confidence interval, 1.1-16.2 for ciprofloxacin; adjusted hazard ratio, 2.5; 95% confidence interval, 1.1-5.5 for ceftazidime). For Enterobacter, ceftriaxone and ciprofloxacin exposure were associated with most antibiotic resistance acquisitions. No significant associations were found in multivariate analysis. CONCLUSIONS: Meropenem exposure is associated with the highest risk of resistance development in P. aeruginosa. Increasing carbapenem use attributable to emergence of Gram-negative bacteria producing extended spectrum beta-lactamases will enhance antibiotic resistance in P. aeruginosa. PMID- 21705893 TI - Delayed neurological recovery after decompressive craniectomy for severe nonpenetrating traumatic brain injury. AB - OBJECTIVE: This study aimed to assess the incidence and factors associated with delayed neurologic recovery after decompressive craniectomy for severe nonpenetrating traumatic brain injury. DESIGN: Retrospective cohort study. SETTING: Two major neurotrauma centers in Western Australia. PATIENTS: One hundred and four adult neurotrauma patients who had had a decompressive craniectomy and remained moderately disabled or worse at 6-month follow-up. MEASUREMENTS AND MAIN RESULTS: Glasgow Outcome Scale scores at 6, 12, and 18 months were used to assess the neurologic recovery of the patients, and logistic regression was used to identify the factors associated with delayed neurologic recovery between 6 and 18 months after surgery. Among a total of 176 patients who required decompressive craniectomy between 2004 and 2010, 104 (59%) had moderate to severe disability 6 months after surgery. Fifty of these patients (48%, 95% confidence interval: 39-58) had >= 1 grade of improvement in Glasgow Outcome Scale score between 6 and 18 months after surgery. Of the 59 patients who had an unfavorable outcome (severe disability or vegetative state) 6 months after surgery, 15 patients (25%, 95% confidence interval: 16-38) improved and had attained a favorable outcome (moderate disability or near normal neurologic function) by the 18-month follow-up. An absence of nonevacuated intracerebral hematoma (>1 cm in diameter) (odds ratio 6.67, 95% confidence interval: 1.12 33.3; p = .038) and a higher admission Glasgow Coma Scale (odds ratio per point increment 1.44, 95% confidence interval: 1.07-1.96; p = .018) were the only two factors significantly associated with a higher chance of delayed neurologic improvement from unfavorable to favorable neurologic outcome between 6 and 18 months after surgery. CONCLUSIONS: Delayed neurologic recovery after decompressive craniectomy for severe nonpenetrating traumatic brain injury was very common; absence of nonevacuated intracerebral hematoma and a high admission Glasgow Coma Scale were associated with a higher chance of delayed neurologic recovery after decompressive craniectomy. PMID- 21705894 TI - The impact of daily evaluation and spontaneous breathing test on the duration of pediatric mechanical ventilation: a randomized controlled trial. AB - OBJECTIVES: To assess whether the combination of daily evaluation and use of a spontaneous breathing test could shorten the duration of mechanical ventilation as compared with weaning based on our standard of care. Secondary outcome measures included extubation failure rate and the need for noninvasive ventilation. DESIGN: A prospective, randomized controlled trial. SETTING: Two pediatric intensive care units at university hospitals in Brazil. PATIENTS: The trial involved children between 28 days and 15 yrs of age who were receiving mechanical ventilation for at least 24 hrs. INTERVENTIONS: Patients were randomly assigned to one of two weaning protocols. In the test group, the children underwent a daily evaluation to check readiness for weaning with a spontaneous breathing test with 10 cm H2O pressure support and a positive end-expiratory pressure of 5 cm H2O for 2 hrs. The spontaneous breathing test was repeated the next day for children who failed it. In the control group, weaning was performed according to standard care procedures. MEASUREMENTS AND MAIN RESULTS: A total of 294 eligible children were randomized, with 155 to the test group and 139 to the control group. The time to extubation was shorter in the test group, where the median mechanical ventilation duration was 3.5 days (95% confidence interval, 3.0 to 4.0) as compared to 4.7 days (95% confidence interval, 4.1 to 5.3) in the control group (p = .0127). This significant reduction in the mechanical ventilation duration for the intervention group was not associated with increased rates of extubation failure or noninvasive ventilation. It represents a 30% reduction in the risk of remaining on mechanical ventilation (hazard ratio: 0.70). CONCLUSIONS: A daily evaluation to check readiness for weaning combined with a spontaneous breathing test reduced the mechanical ventilation duration for children on mechanical ventilation for >24 hrs, without increasing the extubation failure rate or the need for noninvasive ventilation. PMID- 21705895 TI - Femoral venous catheter: a misleading cause of gas in the liver. AB - OBJECTIVES: The presence of a femoral venous catheter could be associated with gas presence in the hepatic veins. This entity should be recognized to avoid a misdiagnosis of gas presence in the portal veins or in the biliary tract. Objectives are to assess: 1) the incidence of gas presence in the hepatic veins in intensive care unit patients explored by abdominal computed tomography scan; 2) the rate of gas presence in the liver in intensive care unit patients with a catheter inserted in the femoral vein; and 3) the specific imaging features. DESIGN: A retrospective study in a medical intensive care unit in a teaching hospital in France. MEASUREMENTS: All consecutive abdominal computed tomography scans performed in intensive care unit patients between 2008 and 2010 were retrospectively reviewed independently by an intensivist and a radiologist. Presence of gas in the liver was noticed and its location was specified using multiplanar reconstruction. MAIN RESULTS: We analyzed 235 computed tomography scans (performed in 207 patients). Gas was identified in the liver on 10.2% of computed tomography scans. Gas was located in the hepatic veins in 12 cases (50%), in the biliary tract in ten cases (41.7%), and in the portal veins in two cases (8.3%). All patients with gas in the hepatic veins had a femoral venous catheter. Characteristics of gas location within the hepatic veins on computed tomography scan axial views were not different from those of gas located in the biliary tract or in the portal venous system. Gas was present in the hepatic veins in 12 of 83 (14.5%) of the computed tomography scans with a femoral venous catheter and was associated with gas presence in other vessels of the inferior vena cava system in five of 12 (41.7%) cases. CONCLUSIONS: Gas located in the hepatic veins related to femoral venous catheter is a frequent cause of gas in the liver in intensive care unit patients. This imaging feature could be misleading. Multiplanar reconstruction should be performed to differentiate this aspect from those of gas in the biliary tract or in the portal venous system. PMID- 21705896 TI - Incidence of treated cardiac arrest in hospitalized patients in the United States. AB - OBJECTIVE: The incidence and incidence over time of cardiac arrest in hospitalized patients is unknown. We sought to estimate the event rate and temporal trends of adult inhospital cardiac arrest treated with a resuscitation response. DESIGN: Three approaches were used to estimate the inhospital cardiac arrest event rate. First approach: calculate the inhospital cardiac arrest event rate at hospitals (n = 433) in the Get With The Guidelines-Resuscitation registry, years 2003-2007, and multiply this by U.S. annual bed days. Second approach: use the Get With The Guidelines-Resuscitation inhospital cardiac arrest event rate to develop a regression model (including hospital demographic, geographic, and organizational factors), and use the model coefficients to calculate predicted event rates for acute care hospitals (n = 5445) responding to the American Hospital Association survey. Third approach: classify acute care hospitals into groups based on academic, urban, and bed size characteristics, and determine the average event rate for Get With The Guidelines-Resuscitation hospitals in each group, and use weighted averages to calculate the national inhospital cardiac arrest rate. Annual event rates were calculated to estimate temporal trends. SETTING: Get With The Guidelines-Resuscitation registry. PATIENTS: Adult inhospital cardiac arrest with a resuscitation response. MEASUREMENTS AND MAIN RESULTS: The mean adult treated inhospital cardiac arrest event rate at Get With The Guidelines-Resuscitation hospitals was 0.92/1000 bed days (interquartile range 0.58 to 1.2/1000). In hospitals (n = 150) contributing data for all years of the study period, the event rate increased from 2003 to 2007. With 2.09 million annual U.S. bed days, we estimated 192,000 inhospital cardiac arrests throughout the United States annually. Based on the regression model, extrapolating Get With The Guidelines-Resuscitation hospitals to hospitals participating in the American Hospital Association survey projected 211,000 annual inhospital cardiac arrests. Using weighted averages projected 209,000 annual U.S. inhospital cardiac arrests. CONCLUSIONS: There are approximately 200,000 treated cardiac arrests among U.S. hospitalized patients annually, and this rate may be increasing. This is important for understanding the burden of inhospital cardiac arrest and developing strategies to improve care for hospitalized patients. PMID- 21705897 TI - The biochemical effects of restricting chloride-rich fluids in intensive care. AB - OBJECTIVE: To determine the biochemical effects of restricting the use of chloride-rich intravenous fluids in critically ill patients. DESIGN: Prospective, open-label, before-and-after study. SETTING: University-affiliated intensive care unit. PATIENTS: A cohort of 828 consecutive patients admitted over 6 months from February 2008 and cohort of 816 consecutive patients admitted over 6 months from February 2009. INTERVENTIONS: We collected biochemical and fluid use data during standard practice without clinician awareness. After a 6-month period of education and preparation, we restricted the use of chloride-rich fluids (0.9% saline [Baxter, Sydney, Australia], Gelofusine [BBraun, Melsungen, Germany], and Albumex 4 [CSL Bioplasma, Melbourne, Australia]) in the intensive care unit and made them available only on specific intensive care unit specialist prescription. MEASUREMENTS AND MAIN RESULTS: Saline prescription decreased from 2411 L in the control group to 52 L in the intervention group (p < .001), Gelofusine from 538 to 0 L (p < .001), and Albumex 4 from 269 to 80 L (p < .001). As expected, Hartmann's lactated solution prescription increased from 469 to 3205 L (p < .001), Plasma-Lyte from 65 to 160 L (p < .05), and chloride-poor Albumex 20 from 87 to 268 L (p < .001). After intervention, the incidence of severe metabolic acidosis (standard base excess <-5 mEq/L) decreased from 9.1% to 6.0% (p < .001) and severe acidemia (pH <7.3) from 6.0% to 4.9% (p < .001). However, the intervention also led to significantly greater incidence of severe metabolic alkalosis (standard base excess >5 mEq/L) and alkalemia (pH >7.5) with an increase from 25.4% to 32.8% and 10.5% to 14.7%, respectively (p < .001). The time-weighted mean chloride level decreased from 104.9 +/- 4.9 to 102.5 +/- 4.6 mmol/L (p < .001), whereas the time-weighted mean standard base excess increased from 0.5 +/- 4.5 to 1.8 +/- 4.7 mmol/L (p < .001), mean bicarbonate from 25.3 +/- 4.0 to 26.4 +/- 4.1 mmol/L (p < .001) and mean pH from 7.40 +/- 0.06 to 7.42 +/- 0.06 (p < .001). Overall fluid costs decreased from $15,077 (U.S.) to $3,915. CONCLUSIONS: In a tertiary intensive care unit in Australia, restricting the use of chloride-rich fluids significantly affected electrolyte and acid-base status. The choice of fluids significantly modulates acid-base status in critically ill patients. PMID- 21705898 TI - Characteristics of out-of-hospital shock care. AB - OBJECTIVE: Regionalization of care is a potential strategy for the management of shock. There are no data describing the regional distribution of patients with out-of-hospital shock. We sought to describe the incidence, demographic, clinical, and regional characteristics of patients with traumatic and nontraumatic medical shock treated by out-of-hospital emergency medical services. DESIGN: Descriptive study using Pennsylvania statewide emergency medical services patient care data. SETTING: Commonwealth of Pennsylvania, 2006-2008. PATIENTS: Adult (age >= 18 yrs) noncardiac arrest patients with shock, defined as initial systolic blood pressure <= 80 mm Hg. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared patient characteristics, demographics, emergency medical services treatment, and regional differences between traumatic and nontraumatic medical shock. Of 3,327,306 adult nonarrest patients, 42,941 (1.29%; 95% confidence interval, 1.28% to 1.30%) had shock in the field, including 39,424 with medical shock and 3,517 with traumatic shock. Patients with medical shock were more likely to be older, female, and treated by rural emergency medical services agencies and experienced longer transport times. County-level annual shock rates varied for medical (median, 99; interquartile range, 44-273; range, 5 1634) and traumatic (median, seven; interquartile range, 3-18; range, 0-300) cases. Per-capita shock rates varied for medical (median, 105 per 100,000 population; interquartile range, 83-128; range, 37-263) and traumatic (median, seven per 100,000 population; interquartile range, 5-10; range, 0-39) cases. The correlation between county-level total annual medical and traumatic shock rates was strong (rho = .80). CONCLUSIONS: While sharing similar regional distributions, key differences exist between emergency medical services patients with traumatic and nontraumatic shock. These differences identify opportunities for and barriers to regionalizing emergency medical services care of patients with shock. PMID- 21705899 TI - Encephalopathy in acute liver failure resulting from acetaminophen intoxication: new observations with potential therapy. AB - OBJECTIVE: Hyperammonemia is a major contributing factor to the encephalopathy associated with liver disease. It is now generally accepted that hyperammonemia leads to toxic levels of glutamine in astrocytes. However, the mechanism by which excessive glutamine is toxic to astrocytes is controversial. Nevertheless, there is strong evidence that glutamine-induced osmotic swelling, especially in acute liver failure, is a contributing factor: the osmotic gliopathy theory. The object of the current communication is to present evidence for the osmotic gliopathy theory in a hyperammonemic patient who overdosed on acetaminophen. DESIGN: Case report. SETTING: Johns Hopkins Hospital. PATIENT: A 22-yr-old woman who, 36 hrs before admission, ingested 15 g acetaminophen was admitted to the Johns Hopkins Hospital. She was treated with N-acetylcysteine. Physical examination was unremarkable; her mental status was within normal limits and remained so until approximately 72 hrs after ingestion when she became confused, irritable, and agitated. INTERVENTIONS: She was intubated, ventilated, and placed on lactulose. Shortly thereafter, she was noncommunicative, unresponsive to painful stimuli, and exhibited decerebrate posturing. A clinical diagnosis of cerebral edema and increased intracranial pressure was made. She improved very slowly until 180 hrs after ingestion when she moved all extremities. She woke up shortly thereafter. MEASUREMENTS AND MAIN RESULTS: Despite the fact that hyperammonemia is a major contributing factor to the encephalopathy observed in acute liver failure, the patient's plasma ammonia peaked when she exhibited no obvious neurologic deficit. Thereafter, her plasma ammonia decreased precipitously in parallel with a worsening neurologic status. She was deeply encephalopathic during a period when her liver function and plasma ammonia had normalized. Plasma glutamine levels in this patient were high but began to normalize several hours after plasma ammonia had returned to normal. The patient only started to recover as her plasma glutamine began to return to normal. CONCLUSIONS: We suggest that the biochemical data are consistent with the osmotic gliopathy theory--high plasma ammonia leads to high plasma glutamine--an indicator of excess glutamine in astrocytes (the site of brain glutamine synthesis). This excess glutamine leads to osmotic stress in these cells. The lag in recovery of brain function presumably reflects time taken for the astrocyte glutamine concentration to return to normal. We hypothesize that an inhibitor of brain glutamine synthesis may be an effective treatment modality for acute liver failure. PMID- 21705900 TI - N-acetylcysteine is effective for prevention but not for treatment of folic acid induced acute kidney injury in mice. AB - OBJECTIVES: There is controversy regarding the benefits of N-acetylcysteine in acute kidney injury. This study was to compare three commonly used regimens and explore which regimen is best for the protection of acute kidney injury. DESIGN: Prospective experimental study. SETTING: University research laboratory. INTERVENTIONS: Acute kidney injury was induced with folic acid intraperitoneal injection in mice. Mice in pretreatment were treated with a subcutaneous injection of N-acetylcysteine before the folic acid injection. Mice in posttreatment were treated with N-acetylcysteine after folic acid. Mice in pre- + posttreatment were treated with N-acetylcysteine before folic acid and after folic acid. Placebo mice received vehicle only using the pre- + posttreatment protocol. Fourteen healthy animals were given N-acetylcysteine to evaluate for toxicity and the other 24 mice subjected to folic acid were killed for kidney histology and analysis for oxidative injury. The same studies were also carried out in milder acute kidney injury (lower folic acid) model. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of creatinine, cystatin C, and reduced glutathione were measured. Survival time was assessed up to 7 days. The survival rates in N acetylcysteine pretreatment mice were significantly better (73.33% vs. 46.67%, p < .04) and acute kidney injury was significantly less compared with placebo. However, mice with posttreatment exhibited significantly worse survival and more severe acute kidney injury. Histologic findings were consistent with functional parameters. Glutathione levels decreased less in N-acetylcysteine pretreatment but also increased beginning on day 2 compared with placebo (11.5 vs. 8.1 MUg/mL, p < .05). Glutathione levels did not increase in N-acetylcysteine posttreatment. However, three different N-acetylcysteine interventions neither significantly improved nor worsened renal function in the milder acute kidney injury model. CONCLUSION: N-acetylcysteine pretreatment was effective in reducing the incidence and severity of acute kidney injury as well as in increasing survival. However, N acetylcysteine posttreatment worsened folic acid toxicity. Only pretreatment was effective in increasing glutathione. These data may help explain the variation from clinical studies of N-acetylcysteine use. PMID- 21705901 TI - Intensive care unit renal support therapy volume is not associated with patient outcome. AB - OBJECTIVE: Evidence suggests that patients requiring high-risk procedures benefit from care at institutions providing a large volume of these procedures. Our objective was to determine whether there is a volume-outcome relationship among intensive care unit patients receiving renal support therapy in two different healthcare systems (France and the United States). DESIGN: Retrospective cohort study. SETTING: Two multicenter intensive care unit databases: CUB-Rea (France) and Project IMPACT (United States). PATIENTS: All nonsurgical adults requiring renal support therapy from 1997 to 2007 were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed association of annual renal support therapy volume with intensive care unit and hospital mortality using multivariable modeling, accounting for clustering and adjusting for age, comorbidities, admitting diagnosis, illness severity, pre-intensive care unit length of stay, admission source, and hospital and intensive care unit characteristics. Our final cohorts were 9,449 patients treated in 32 intensive care units in CUB-Rea and 3,498 patients treated in 76 intensive care units in Project IMPACT. Patient demographics did not differ between cohorts. Renal support therapy delivery varied widely across intensive care units (3-129 patients per year in CUB-Rea, 1-66 in Project IMPACT). Overall intensive care unit and hospital mortality rates were 45% and 49% in CUB-Rea and 34% and 47% in Project IMPACT. After adjustment for patient, intensive care unit, and hospital characteristics, there was no association between renal support therapy volume and intensive care unit or hospital mortality whether we treated volume as a continuous measure or quartiles. Higher renal support therapy volume was associated with shorter length of stay only in CUB-Rea. CONCLUSIONS: There is a large variation in annual renal support therapy volume across intensive care units in France and the United States but no association of higher volumes with improved outcomes. PMID- 21705902 TI - Metabolic effects of albumin therapy in acute lung injury measured by proton nuclear magnetic resonance spectroscopy of plasma: a pilot study. AB - OBJECTIVE: Improved means to monitor and guide interventions could be useful in the intensive care unit. Metabolomic analysis with bioinformatics is used to understand mechanisms and identify biomarkers of disease development and progression. This pilot study evaluated plasma proton nuclear magnetic resonance spectroscopy as a means to monitor metabolism following albumin administration in acute lung injury patients. DESIGN: This study was conducted on plasma samples from six albumin-treated and six saline-treated patients from a larger double blind trial. The albumin group was administered 25 g of 25% human albumin in 0.9% saline every 8 hrs for a total of nine doses over 72 hrs. A 0.9% concentration of saline was used as a placebo. Blood samples were collected immediately before, 1 hr after, and 4 hrs after the albumin/saline administration for the first, fourth, and seventh doses (first dose of each day for 3 days). Samples were analyzed by proton nuclear magnetic resonance spectroscopy, and spectra were analyzed by principal component analysis and biostatistical methods. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After 1 day of albumin therapy, changes in small molecules, including amino acids and plasma lipids, were evident with principal component analysis. Differences remained 3 days after the last albumin administration. Analysis of data along with spectra from healthy controls showed that spectra for patients receiving albumin had a trajectory toward the spectra observed for healthy individuals while those of the placebo controls did not. CONCLUSION: The data suggest that metabolic changes detected by proton nuclear magnetic resonance spectroscopy and the bioinformatics tool may be a useful approach to clinical research, especially in acute lung injury. PMID- 21705903 TI - Saddle pulmonary embolism: is it as bad as it looks? A community hospital experience. AB - BACKGROUND: Saddle pulmonary embolism represents a large clot and a risk for sudden hemodynamic collapse. However, the clinical presentation and outcomes vary widely. On the basis of the findings of right heart dysfunction on echocardiograms, computed tomography angiography, or cardiac enzyme elevation, some argue for the use of thrombolytics or catheter thrombectomy even for hemodynamically stable patients. OBJECTIVE: To investigate the outcomes and management of patients with saddle pulmonary embolism, including radiographic appearance (estimate of clot burden) and echocardiographic features. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: This study is a retrospective evaluation of all patients with computed tomography angiography positive for pulmonary embolism from June 1, 2004, to February 28, 2009. Two radiologists selected those with saddle pulmonary embolism and evaluated the clot burden score. The clinical information, echocardiography, treatments, and outcomes of these patients were extracted via chart review. Saddle pulmonary embolism was found in 37 of 680 patients (5.4%, 95% confidence interval 4% to 7%) with documented pulmonary embolism on computed tomography angiography. For patients with saddle pulmonary embolism, the median age was 60 yrs and 41% were males. Major comorbidities were neurologic (24%), recent surgery (24%), and malignancy (22%). Transient hypotension occurred in 14% and persistent shock in 8%. One patient required mechanical ventilation. Echocardiography was performed in 27 patients (73%). Right ventricle enlargement and dysfunction were found in 78% and elevated pulmonary artery systolic pressure in 67%. Computed tomography angiography demonstrated a high median pulmonary artery clot burden score of 31 points. The median right ventricle to left ventricle diameter ratio was 1.39. Inferior vena cava filters were placed in 46%. Unfractionated heparin was administered in 33 (87%) and thrombolytics in four (11%). The median hospital length of stay was 9 days. Two of 37 saddle pulmonary embolism patients (5.4%) died in the hospital (95% confidence interval 0.7% to 18%). CONCLUSIONS: Most patients with saddle pulmonary embolism found on computed tomography angiography responded to the standard management for pulmonary embolism with unfractionated heparin. Although ominous in appearance, most patients with saddle pulmonary embolism are hemodynamically stable and do not require thrombolytic therapy or other interventions. PMID- 21705904 TI - Cerebral blood flow and cerebrovascular autoregulation in a swine model of pediatric cardiac arrest and hypothermia. AB - OBJECTIVE: Knowledge remains limited regarding cerebral blood flow autoregulation after cardiac arrest and during postresuscitation hypothermia. We determined the relationship of cerebral blood flow to cerebral perfusion pressure in a swine model of pediatric hypoxic-asphyxic cardiac arrest during normothermia and hypothermia and tested novel measures of autoregulation derived from near infrared spectroscopy. DESIGN: Prospective, balanced animal study. SETTING: Basic physiology laboratory at an academic institution. SUBJECTS: Eighty-four neonatal swine. INTERVENTIONS: Piglets underwent hypoxic-asphyxic cardiac arrest or sham surgery and recovered for 2 hrs with normothermia followed by 4 hrs of either moderate hypothermia or normothermia. In half of the groups, blood pressure was slowly decreased through inflation of a balloon catheter in the inferior vena cava to identify the lower limit of cerebral autoregulation at 6 hrs postresuscitation. In the remaining groups, blood pressure was gradually increased by inflation of a balloon catheter in the aorta to determine the autoregulatory response to hypertension. Measures of autoregulation obtained from standard laser-Doppler flowmetry and indices derived from near-infrared spectroscopy were compared. MEASUREMENTS AND MAIN RESULTS: Laser-Doppler flux was lower in postarrest animals compared to sham-operated controls during the 2-hr normothermic period after resuscitation. During the subsequent 4-hr recovery, hypothermia decreased laser-Doppler flux in both the sham surgery and postarrest groups. Autoregulation was intact during hypertension in all groups. With arterial hypotension, postarrest, hypothermic piglets had a significant decrease in the perfusion pressure lower limit of autoregulation compared to postarrest, normothermic piglets. The near-infrared spectroscopy-derived measures of autoregulation accurately detected loss of autoregulation during hypotension. CONCLUSIONS: In a pediatric model of cardiac arrest and resuscitation, delayed induction of hypothermia decreased cerebral perfusion and decreased the lower limit of autoregulation. Metrics derived from noninvasive near-infrared spectroscopy accurately identified the lower limit of autoregulation during normothermia and hypothermia in piglets resuscitated from arrest. PMID- 21705905 TI - Risk factors for positive admission surveillance cultures for methicillin resistant Staphylococcus aureus and vancomycin-resistant enterococci in a neurocritical care unit. AB - OBJECTIVE: Hospitals are under increasing pressure to perform active surveillance cultures for methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. This study aimed to identify patients at low and high risk for positive admission surveillance cultures for methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus in a neurocritical care unit using readily ascertainable historical factors. DESIGN: Before/after study with nested case/control study. SETTING: Neurocritical care unit of an academic hospital. PATIENTS: During the intervention period (July 2007 to June 2008), after implementation of an admission surveillance culture screening program for methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, 2,059 patients were admitted to the neurocritical care unit for a total of 5,957 patient days. INTERVENTIONS: Cases had positive methicillin resistant Staphylococcus aureus or vancomycin-resistant Enterococcus admission surveillance cultures within 48 hrs of hospital admission. Controls had negative cultures. MEASUREMENTS AND MAIN RESULTS: Admission surveillance cultures grew methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus in 35 of 823 (4.3%) and 19 of 766 (2.5%) patients, respectively. Factors significantly associated with both methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus colonization were intravenous antibiotics and hospitalization in the past year, immunocompromised health status, intravenous drug use, long-term hemodialysis, and known prior carrier status. Transfer from an outside hospital and residence in a long-term care facility in the past year were associated with vancomycin-resistant Enterococcus colonization. Classification and regression tree analysis was used to identify variables that best predicted positive methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus surveillance cultures. A classification and regression tree model with six of these variables yielded an overall cross-validated predictive accuracy of 87.12% to detect methicillin resistant Staphylococcus aureus colonization. For vancomycin-resistant Enterococcus, a four-variable classification and regression tree model (intravenous antibiotics, hospitalization and long-term patient care in the past year, and not being "admitted same day of procedure") optimized the predictive accuracy (94.91%). There were no cases of vancomycin-resistant Enterococcus colonization in patients admitted same day of procedure. CONCLUSIONS: Colonization with methicillin-resistant Staphylococcus aureus and vancomycin resistant Enterococcus in neurocritical care patients can be predicted with a high predictive accuracy using decision trees that include four to six readily attainable risk factors. In our setting, in the absence of these risk factors and in patients admitted from home for neurosurgical procedures, routine admission surveillance cultures to the intensive care unit may not be cost-effective. PMID- 21705907 TI - Non-anaesthesiologists should not be allowed to administer propofol for procedural sedation: a Consensus Statement of 21 European National Societies of Anaesthesia. AB - Propofol, which is the most commonly used drug for induction of general anaesthesia, has also become a popular drug for procedural sedation. Because its use may be associated with serious and potentially fatal side-effects, the manufacturers of propofol restrict its use solely to personnel trained in general anaesthesia. In spite of this warning, the use of propofol for procedural sedation by non-anaesthesiologists is rapidly expanding in many countries. Recently, the US Food and Drugs Administration (FDA) denied a petition from gastroenterologists seeking the removal of this particular restriction. This unequivocal ruling of the FDA received strong support from the American Society of Anesthesiologists (ASA). At about the same time, the European Society of Anaesthesiology (ESA), together with various European gastroenterology societies, published new guidelines entitled 'Non-anaesthesiologist Administration of Propofol for Gastrointestinal Endoscopy' (NAAP). Following publication of the NAAP guidelines, many reservations have been expressed by ESA member societies and individuals, dealing with professional, political, procedural and safety oriented concerns. Out of concern for patient safety, and in order to officially and publicly dissociate themselves from the NAAP guidelines, 21 national societies of anaesthesiology in Europe, all of whom are ESA members, have signed a Consensus Statement confirming that due to its significant well known risks, propofol should be administered only by those trained in the administration of general anaesthesia. PMID- 21705908 TI - Nutritional epidemiological studies in cancer prevention: what went wrong, and how to move forwards. AB - It has been almost 30 years since Doll and Peto suggested that most of the differences in cancer rates could be attributed to the environment and behavioral factors including diet. Since then epidemiological studies have reported that individuals consuming large amounts of fruits and vegetables have a reduced risk of cancer. From this evidence, large randomized trials of long duration were designed to test the hypothesis that some micronutrients contained in plant foods decrease cancer risk. Despite the promising experimental and epidemiological data, most randomized controlled trials failed to confirm a protective role for single or combined elements in cancer prevention. The results from randomized trials of micronutrients for cancer prevention have been mixed. Some trials did not demonstrate chemopreventive efficacy for their primary endpoints but showed statistically significant reductions in secondary outcomes, whereas others showed unexpected harmful effects. On the basis of these findings and reflections of what went wrong it is important to find alternative approaches to move forwards in cancer prevention. Clearly, the evidence is not encouraging for further preventive trials on cancer in healthy populations. However, if we identify high risk individuals using models that include genetic polymorphisms, or in the future, MicroRNA profiles, prevention trials could be designed to target only these groups. PMID- 21705906 TI - The association between blood pressure and incident Alzheimer disease: a systematic review and meta-analysis. AB - BACKGROUND: Many epidemiologic studies have considered the association between blood pressure (BP) and Alzheimer disease, yet the relationship remains poorly understood. METHODS: In parallel with work on the AlzRisk online database (www.alzrisk.org), we conducted a systematic review to identify all epidemiologic studies meeting prespecified criteria reporting on the association between hypertension, systolic BP, or diastolic BP and incident Alzheimer disease. When possible, we computed summary measures using random-effects models and explored potential heterogeneity related to age at BP assessment. RESULTS: Eighteen studies reporting on 19 populations met the eligibility criteria. We computed summary relative risks (RR(Sigma)) for 3 measures of BP: hypertension (RR(Sigma) = 0.97 [95% confidence interval = 0.80-1.16]); a 10-mm Hg increase in systolic BP (RR(Sigma) = 0.95 [0.91-1.00]); and a 10-mm Hg increase in diastolic BP (RR(Sigma) = 0.94 [0.85-1.04]). We were unable to compute summary estimates for the association between categories of systolic or diastolic BP and Alzheimer disease; however, there did not appear to be a consistent pattern across studies. After stratifying on age at BP assessment, we found a suggestion of an inverse association between late-life hypertension and Alzheimer disease and a suggestion of an adverse association between midlife diastolic hypertension and Alzheimer disease. CONCLUSIONS: Based on existing epidemiologic research, we cannot determine whether there is a causal association between BP and Alzheimer disease. Selection bias and reverse causation may account for the suggested inverse association between late-life hypertension on Alzheimer disease, but, given the expected direction of these biases, they are less likely to account for the suggestion that midlife hypertension increases risk. We advocate continuing systematic review; the AlzRisk database entry on this topic (www.alzrisk.org), which was completed in parallel with this work, will be updated as new studies are published. PMID- 21705909 TI - Carboplatin dosing in ovarian cancer: problems and pitfalls. AB - OBJECTIVE: Carboplatin is one of the most effective chemotherapeutic drugs for the treatment of ovarian cancer. It has simple pharmacokinetics and a predictable toxicity profile. The dose can be calculated effectively based on a patient's renal function as defined by the glomerular filtration rate (GFR). The measurement of the GFR is best done using radioisotopes, but this is expensive and not widely available, so many centers use equations to estimate GFR based on serum creatinine and other easily measured data. Recent changes in the measurement of serum creatinine, and a move toward isotope dilution mass spectrometry standardized values, have highlighted the difficulty in safely and effectively calculating doses of carboplatin in patients with ovarian cancer. METHODS: We have evaluated the currently available evidence for the most common methods of estimating and measuring GFR. We explored the problems and pitfalls with using each of these methods or equations and examined the effects of small changes in clinical parameters and the effect on carboplatin dose. RESULTS: Previous studies evaluating carboplatin's toxicity and efficacy used various different methods of GFR estimation and older methods of creatinine measurement. These may not translate to use with newer laboratory methods and may result in higher delivered doses than anticipated. CONCLUSIONS: The lack of consistency in carboplatin dosing, and changing creatinine values are a cause for concern if patient toxicity is a possible outcome. The need for new studies using new standard methods that can be widely used are urgently required to provide clarity in this area. PMID- 21705910 TI - How to improve training in bowel surgery for gynecological oncologists-experience from a single center in the United kingdom. AB - INTRODUCTION: There is now a growing realization of the lack of experience of gynecological oncology trainees in gastrointestinal surgery. Advanced fellowship programs in gastrointestinal surgery have been suggested as a potential solution to this problem. PATIENTS AND METHODS: We present data relating to gastrointestinal procedures performed by the gynecological oncology trainee during a fellowship program over a 3-year period in a single gynecological oncology center in the United Kingdom. RESULTS: Over a 36-month period, 369 cases of invasive ovarian cancer were diagnosed in our institute, of which 278 (75.3%) were stage III/IV disease. Bowel surgery was performed in 86 patients (30.9%) with stage III/IV ovarian cancer. A total of 121 gastrointestinal procedures were performed during the study period, as some patients had more than one procedure. We present the procedures the gynecological oncology fellow performed and assisted during this period. DISCUSSION: To improve competencies in performing bowel surgery among gynecological oncology trainees, we suggest sustained exposure in bowel surgery over the entire duration of the training program. PMID- 21705911 TI - Re:"parametrial involvement in FIGO stage IB1 cervical carcinoma". PMID- 21705912 TI - Sex hormones, insulin resistance, and diabetes mellitus among men with or at risk for HIV infection. AB - OBJECTIVE: To examine the relationship of free testosterone (FT) and sex hormone binding globulin (SHBG) with insulin resistance and diabetes mellitus (DM) in HIV disease. DESIGN: Cross-sectional analysis from 322 HIV-uninfected and 534 HIV infected men in the Multicenter AIDS Cohort Study. METHODS: : The main outcomes were DM and homeostasis model assessment-insulin resistance (HOMA-IR). DM was defined as fasting serum glucose >=126 or self-reported DM and use of DM medications. HOMA-IR was calculated from fasting serum glucose and fasting insulin. RESULTS: Compared with HIV-uninfected men in our sample, HIV-infected men were younger, with lower body mass index, and more often black. HIV-infected men had lower FT (P < 0.001) and higher SHBG (P < 0.0001). The adjusted odds ratio for DM was 1.98 (95% confidence interval: 1.04 to 3.78); mean adjusted log HOMA-IR was 0.21 units higher in HIV-infected men (P < 0.0001). Log SHBG, but not log FT, was associated with DM (odds ratio = 0.44, 95% confidence interval: 0.25 to 0.80) in both groups. Log FT and log SHBG were inversely related to insulin resistance (P < 0.05 for both) independent of HIV. CONCLUSIONS: Compared with HIV uninfected men, HIV-infected men had lower FT, higher SHBG, and more insulin resistance and DM. Lower FT and lower SHBG were associated with insulin resistance regardless of HIV serostatus. This suggests that sex hormones play a role in the pathogenesis of glucose abnormalities among HIV-infected men. PMID- 21705914 TI - Cardiopulmonary exercise testing and SF-36 in patients with atrial septal defect type secundum. AB - PURPOSE: Although exercise capacity is impaired, atrial septal defect (ASD) patients report satisfactory exercise tolerance. This study aimed at (1) evaluating cardiopulmonary exercise testing (CPX) and (2) evaluating the impact of exercise capacity on perceived health status using a self-reported health questionnaire (SF-36) in patients with open and closed ASD. METHODS: Seventeen patients (mean age 37 +/- 17, 9 males) with open ASD and 24 (mean age 37 +/- 14, 6 male) with closed ASD were included. All underwent CPX and completed a SF-36 questionnaire. Age- and gender-matched controls were selected for comparison of CPX variables and SF-36 was compared with results from a general population. RESULTS: Patients with open ASD had lower peak oxygen uptake (VO(2)) (27.9 +/- 9.7 vs 38.5 +/- 9.5 mL . kg(-1) . min(-1). P = .009) and higher VE/VCO(2) slope (31.0 +/- 7.7 vs 24.1 +/- 4.8; P = .004) than controls. Patients with closed ASD had lower peak VO(2) (26.2 +/- 8.4 vs 34.8 +/- 9.7 mL . kg(-1) . min(-1). P = .014) and peak heart rate (163 +/- 25 vs 178 +/- 16 bpm; P = .035) than controls. Perceived health-status was lower in patients with open ASD than the general population. Peak VO(2) correlated significantly with physical functioning, emotional functioning, and bodily pain in open ASD and with physical functioning, bodily pain, role limitation, vitality, and mental health in closed ASD patients. CONCLUSION: Patients with open and closed ASD had decreased peak VO(2). Patients with open ASD had lower ventilatory efficiency. Closed ASD patients had chronotropic incompetence because of beta-blockers. SF-36 was reduced in patients with open ASD but not closed ASD. Reduced exercise capacity affected several domains of perceived health-status in ASD patients. PMID- 21705913 TI - Cardiac output, blood pressure variability, and cognitive decline in geriatric cardiac patients. AB - OBJECTIVE: To prospectively investigate whether baseline findings on specific cardiovascular indices are predictive of subsequent rate of decline in Attention Executive-Psychomotor function in a cohort of ambulatory older adults with cardiovascular diseases (CVDs). METHODS: One hundred seventy-two older adults with CVD were administered a neuropsychological battery of executive functions tests at study entry, and at 12 and 36 months thereafter. At study entry, they also underwent vascular assessments including cardiac output, ejection fraction, blood pressure (BP), brachial artery reactivity, and carotid intima media thickness. Random coefficient regressions were used to investigate the effect of these cardiac indices on rate of decline in Attention-Executive-Psychomotor function. RESULTS: Cardiac output, systolic BP variability, and diastolic BP variability predicted decline in Attention-Executive-Psychomotor function. Specifically, lower cardiac output, reduced variability in systolic BP, and increased variability in diastolic BP were associated with a faster rate of decline in Attention-Executive-Psychomotor function. Mean resting systolic and diastolic blood pressure did not predict decline in Attention-Executive Psychomotor function. CONCLUSIONS: Decline in frontal-subcortical cognitive functions among patients with CVDs appears to be mediated by systemic hypoperfusion and variability in blood pressure. The precise nature of these relationships, especially with regard to blood pressure variability, is complex and demands continued investigation. PMID- 21705915 TI - Cardiac rehabilitation participation in underserved populations. Minorities, low socioeconomic, and rural residents. AB - Cardiac rehabilitation (CR) services in the United States are underutilized and participation is particularly low for racial and ethnic minorities, low socioeconomic status patients, and rural residents. Reduced participation may not only indicate a failure in transitional cardiac care during the in hospital referral process but also could be due to barriers attributed to patients, providers, employers, or medical systems. In-depth analysis of this problem is impeded by difficulties with the identification of underserved groups in clinical settings. Disparities in CR participation certainly contribute to poor medical outcomes in these populations that stand to benefit greatly from lifestyle modifications. It is critical that CR providers survey their communities for underserved populations and coordinate creative efforts aimed at overcoming barriers to participation. Moreover, it is likely that referral to, and participation in, CR will soon be considered a quality indicator, providing further incentive for programs to optimize CR utilization among all eligible patients. PMID- 21705916 TI - Spinal epidural lipomatosis: a common imaging feature in Scheuermann disease. AB - STUDY DESIGN: Retrospective study. OBJECTIVES: To find out if spinal epidural lipomatosis (SEL) occurs more commonly among patients with Scheuermann disease than in the general population. SUMMARY AND BACKGROUND: On the basis of our own radiologic and operative observation, SEL seems to occur frequently in patients with Scheuermann disease. METHODS: Magnetic resonance imaging of 87 individuals (72% male, average age 19+/-6 y) from 2 centers (29 consecutive patients with Scheuermann disease and 58 controls) were retrospectively evaluated by 2 neuroradiologists. Spinal epidural fat (EF) at seventh thoracic vertebra (EF7), maximum EF (EFmax), dural sac diameter at T7 and at the level of maximum EF (DS7 and DSmax) were measured. EF ratios at T7 (EFR7) and at maximum EF (EFRmax) were calculated as EF/DS. Body mass index (BMI) for study population and kyphosis severity for the patients were recorded. Mann-Whitney, Spearman correlation, and chi tests were performed dependent on the variable in question. RESULTS: EF7, DS7, EFmax, EFR7, and EFRmax was significantly higher among patients with Scheuermann disease (EFmax 5.7+/-2.4 mm) than among controls (EFmax 3.8+/-1.1 mm), P<0.001. Twelve patients with Scheuermann disease (41%) fulfilled our proposed criteria for the diagnosis of SEL (EFmax>6 mm+EFRmax>0.51) compared with 2 (3%) among controls (P<0.001). Patients with Scheuermann disease exhibited higher BMI than controls (24.9+/-5 kg/m vs. 22.9+/-4 kg/m, P=0.138). Logistic regression showed that the occurrence of SEL among patients with Scheuermann disease was independent of BMI (P=0.880). The degree of kyphosis in patients with Scheuermann's disease (62+/-20 degrees ) was correlated to the amount of the EF. CONCLUSIONS: As SEL occurs more frequently among patients with Scheuermann disease, spine magnetic resonance imaging should be routinely performed to screen each of these patients to avoid impending neurological injury during surgery, especially in those exhibiting SEL. PMID- 21705917 TI - Loss of correction in the treatment of thoracolumbar kyphosis secondary to ankylosing spondylitis: a comparison between Smith-Petersen osteotomies and pedicle subtraction osteotomy. AB - STUDY DESIGN: Retrospective comparison of database patients. OBJECTIVE: To evaluate the difference of loss of correction between Smith-Petersen osteotomies (SPOs) and pedicle subtraction osteotomy (PSO) in patients with thoracolumbar kyphosis secondary to ankylosing spondylitis (AS). SUMMARY OF BACKGROUND DATA: SPOs and PSO are reported to be the 2 major techniques for correction of thoracolumbar kyphosis resulting from AS. Previous studies have tried to compare the indication, technical aspects, correction obtained, and complication rates between the aforementioned 2 techniques. However, reports addressing a comparison of loss of correction between SPOs and PSO are limited. MATERIALS AND METHODS: On the basis of the types of osteotomies, 50 patients were divided into 2 groups: (1) SPOs group (n=19) including 16 male and 3 female patients, with an age range from 21 to 40 years (mean 27 y). The preoperative global kyphosis (GK) ranged from 41 to 99 degrees (average 64.6+/-25.6 degrees); (2) PSO group (n=31) consisted of 26 male and 5 female patients, with an age range from 22 to 54 years (mean 36 y). The preoperative GK was 50 to 96 degrees (average 73.7+/-23.6 degrees). Radiographic parameters including sagittal vertical axis, T12-S1 lordosis, GK, and angle of fusion levels were measured. RESULTS: Both groups showed similar preoperative and postoperative thoracic kyphosis, lumbar lordosis, and sagittal vertical axis. The average GK was corrected to 25.5 degrees and 31.4 degrees in SPOs group and PSO group, respectively. All cases were followed for a minimum of 2 years. At the last follow-up, mean loss of correction in the fusion levels were 6.1 degrees in SPOs group and 1.3 degrees in PSO group, respectively. The difference was statistically significant (P=0.034). Loss of correction of >5 degrees occurred in 4 cases (21.1%) in SPOs group, and 5 cases (16.1%) in PSO group. CONCLUSIONS: Both SPOs and PSO showed similar effect in correcting the thoracolumbar kyphosis secondary to AS. However, patients treated with the SPOs technique showed higher risk in loss of correction in the instrumented region. PMID- 21705918 TI - Kyphoplasty versus vertebroplasty: restoration of vertebral body height and correction of kyphotic deformity with special attention to the shape of the fractured vertebrae. AB - STUDY DESIGN: Retrospective comparative analysis. OBJECTIVE: We analyzed kyphosis correction, vertebral height restoration, and bone cement leakage in patients treated by vertebroplasty (VP) and kyphoplasty (KP) to compare the effectiveness of VP and KP for the treatment of osteoporotic vertebral compression fractures. SUMMARY OF BACKGROUND DATA: Superior results have been reported for the use of KP for kyphotic deformity correction and collapsed vertebral height restoration. However, there are no previous comparative reports comparing the efficacy of KP versus VP according to the shapes of fractured vertebrae. METHODS: A total of 103 patients underwent either VP (n=58) or KP (n=45) for treatment of osteoporotic vertebral compression fracture between October 2006 and September 2009. We organized the patients into 6 groups according to treatment method and fracture type: VP (wedge-shaped), VP (V-shaped), VP (flat-shaped), KP (wedge-shaped), KP (V-shaped), and KP (flat-shaped). Comparisons were performed for kyphosis correction, vertebral height restoration, and cement leakage between VP and KP groups. RESULTS: KP was more effective than VP, especially for middle column height restoration and bone cement leakage prevention, for all fracture types (P value <0.05). In addition, KP was more effective in anterior height restoration and kyphosis correction in both flat and wedge-shape fractures (P value <0.05). However, posterior column vertebral height was not restored in either the KP group or the VP group. The clinical outcomes did not differ between the 2 groups (P value >0.05). CONCLUSIONS: KP has a significant advantage over VP in terms of kyphosis correction, vertebral height restoration, and cement leakage prevention. KP has an obvious advantage in terms of middle vertebral height restoration and cement leakage prevention, especially for V-shape compression fractures. PMID- 21705919 TI - Cervical endplate and facet arthrosis: an anatomic study of cadaveric specimens. AB - STUDY DESIGN: An anatomic, epidemiologic study of cervical endplate and facet arthrosis in cadaveric spines. OBJECTIVE: To determine the prevalence of cervical endplate and facet arthrosis and the relationship between these 2 entities in a large population sample. SUMMARY OF BACKGROUND DATA: Cervical endplate and facet arthrosis are common radiographic findings, which have both been linked to pain. However, the prevalence and relationship between cervical endplate and facet arthrosis has not been clearly defined. METHODS: The cervical vertebrae from 234 cadaveric spines were examined by a single investigator for evidence of endplate and facet arthrosis. Arthrosis at each endplate and facet was graded on a continuum from 0 to IV. Race, age at death, and sex of each specimen were also recorded. Stepwise multiple linear regression was used to analyze any association between race, age, sex, endplate arthrosis, and facet arthrosis. Factors with P values <0.05 remained in the analysis. Two-tailed t tests for matched samples were used to analyze any difference between mean endplate and facet arthrosis severity scores among patients within the same decades of life. RESULTS: Concurrent cervical endplate and facet arthrosis was present in 77% of the study population. Stepwise multiple linear regression revealed significant (P<0.01) associations between endplate and facet arthrosis and between age and facet arthrosis. Race and sex did not correlate with facet arthrosis. In addition, patients in age groups 30 to 39, 40 to 49, 50 to 59, 60 to 69, 70 to 79, and 80 to 89 demonstrated more severe (P<0.01) endplate arthrosis in comparison with facet arthrosis. CONCLUSIONS: Concurrent cervical endplate and facet arthrosis is a common condition. Cervical endplate arthrosis and advancing age are associated with cervical facet arthrosis independent of race and sex. Cervical endplate arthrosis precedes facet arthrosis. PMID- 21705920 TI - Lessons from the field: the essential elements for point-of-care transformation. AB - BACKGROUND: The challenges facing healthcare in the 21st century frequently seem intractable and insurmountable. Systemic problems impair the quality and continuity of care and caregivers' quality of life. For over 25 years, the Clinical Practice Model Resource Center (CPMRC) in Grand Rapids, MI, has focused on transforming healthcare at the point of care to achieve its mission to co create and sustain the best places to work and to receive care. CONCEPTUAL FRAMEWORK: The extent of the vision to transform practice at the point of care calls for a shift from the common quick fix change mindset to a Professional Practice Framework mindset that guides the actions steps to achieve greater clinical integration and standardize, sustainable transformation in a complex healthcare system. METHODS: An overview of the Clinical Practice Model (CPM) Framework's conceptual underpinnings and the importance of the use of a Framework to guide transformation work across an International Consortium of hospitals are summarized. The lessons learned come from shared learning within a growing volunteer interdisciplinary, international consortium of over 276 rural, community, and university clinical settings. RESULTS: The Consortium's collective work has resulted in clinical, financial, and operational outcomes related to healthy work cultures, evidence-based practice, interdisciplinary, integrated documentation, and partnership councils. The cycle of organizational transformation ensures support for the professional processes, scope of practice, service across lifeline and continuum, integration and interoperability, evidence based tools, interdisciplinary practice, and research-based and updated information. CONCLUSIONS: The power of organizational change flowing from a Framework is evident in replicable interventions and sustainable outcomes. PMID- 21705921 TI - Effect of functional stabilization training on lower limb biomechanics in women. AB - PURPOSE: This study aimed to verify the effects of functional stabilization training on lower limb kinematics, functional performance, and eccentric hip and knee torques. METHODS: Twenty-eight women were divided into a training group (TG; n = 14), which carried out the functional stabilization training during 8 wk, and a control group (CG; n = 14), which carried out no physical training. The kinematic assessment of the lower limb was performed during a single-leg squat, and the functional performance was evaluated by way of the single-leg triple hop and the timed 6-m single-leg hop tests. The eccentric hip abductor, adductor, lateral rotator, medial rotator, and the knee flexor and extensor torques were measured using an isokinetic dynamometer. RESULTS: After 8 wk, the TG significantly reduced the values for knee abduction (from -6.86 degrees to 1.49 degrees ), pelvis depression (from -10.21 degrees to -7.86 degrees ) and femur adduction (from 7.08 degrees to 5.19 degrees ) as well as increasing the excursion of femur lateral rotation (from -0.55 degrees to -3.67 degrees ). Similarly, the TG significantly increased the values of single-leg triple hop (from 3.52 to 3.92 m) and significantly decreased the values of timed 6-m single leg hop tests (from 2.43 to 2.14 s). Finally, the TG significantly increased the eccentric hip abductor (from 1.31 to 1.45 N . m . kg(-1)), hip lateral rotator (from 0.75 to 0.91 N . m . kg(-1)), hip medial rotator (from 1.45 to 1.66 N . m . kg(-1)), knee flexor (from 1.43 to 1.55 N . m . kg(-1)), and knee extensor (from 3.46 to 4.40 N . m . kg(-1)) torques. CONCLUSIONS: Strengthening of the hip abductor and lateral rotator muscles associated with functional training improves dynamic lower limb alignment and increases the strength and functional performance. PMID- 21705922 TI - Tribute to Ralph W. Hale: Executive Vice President of the American College of Obstetricians and Gynecologists, 1993-2011. PMID- 21705923 TI - 2010 Pitkin Award and 2010 Kaminetzky Prize Paper. PMID- 21705925 TI - Comparative Performance of the 2009 International Federation of Gynecology and Obstetrics' Staging System for Uterine Corpus Cancer. PMID- 21705924 TI - Medical Methods for Mid-Trimester Termination of Pregnancy. PMID- 21705926 TI - Optimal Interval for Ultrasound Surveillance in Monochorionic Twin Gestations. PMID- 21705927 TI - Bipolar Radiofrequency Compared With Thermal Balloon Endometrial Ablation in the Office: A Randomized Controlled Trial. PMID- 21705928 TI - Neonatal Outcomes After Demonstrated Fetal Lung Maturity Before 39 Weeks of Gestation. PMID- 21705929 TI - Pregnancy-Related Mortality in the United States, 1998 to 2005. PMID- 21705932 TI - Committee Opinion No. 488: Pharmacogenetics. PMID- 21705931 TI - Abstracts and Summaries of Online Material in the May 2011 Issue. PMID- 21705933 TI - Committee Opinion No. 489: Hepatitis B, Hepatitis C, and Human Immunodeficiency Virus Infections in Obstetrician-Gynecologists. PMID- 21705934 TI - Committee Opinion No. 490: Partnering With Patients to Improve Safety. PMID- 21705935 TI - Committee Opinion No. 491: Health Literacy. PMID- 21705937 TI - Committee Opinion No. 493: Cultural Sensitivity and Awareness in the Delivery of Health Care. PMID- 21705936 TI - Committee Opinion No. 492: Effective Patient-Physician Communication. PMID- 21705938 TI - Objective visual assessment of antiangiogenic treatment for wet age-related macular degeneration. AB - PURPOSE: To assess cortical responses in patients undergoing antiangiogenic treatment for wet age-related macular degeneration (AMD) using functional magnetic resonance imaging (fMRI) as an objective, fixation-independent measure of topographic visual function. METHODS: A patient with bilateral neovascular AMD was scanned using fMRI before and at regular intervals while undergoing treatment with intravitreal antiangiogenic injections (ranibizumab). Blood oxygenation level-dependent signals were measured in the brain while the patient viewed a stimulus consisting of a full-field flickering (6 Hz) white light alternating with a uniform gray background (18 s on and 18 s off). Topographic distribution and magnitude of activation in visual cortex were compared longitudinally throughout the treatment period (<1 year) and with control patients not currently undergoing treatment. Clinical behavioral tests were also administered, including visual acuity, microperimetry, and reading skills. RESULTS: The area of visual cortex activated increased significantly after the first treatment to include more posterior cortex that normally receives inputs from lesioned parts of the retina. Subsequent treatments yielded no significant further increase in activation area. Behavioral measures all generally showed an improvement with treatment but did not always parallel one another. The untreated control patient showed a consistent lack of significant response in the cortex representing retinal lesions. CONCLUSIONS: Retinal treatments may not only improve vision but also result in a concomitant improvement in fixation stability. Current clinical behavioral measures (e.g., acuity and perimetry) are largely dependent on fixation stability and therefore cannot separate improvements of visual function from fixation improvements. fMRI, which provides an objective and sensitive measure of visual function independent of fixation, reveals a significant increase in visual cortical responses in patients with wet AMD after treatment with antiangiogenic injections. Despite recent evidence that visual cortex degenerates subsequent to retinal lesions, our results indicate that it can remain responsive as its inputs are restored. PMID- 21705939 TI - Age-related changes in tear menisci imaged by optical coherence tomography. AB - PURPOSE: To determine age-related changes of tear menisci in healthy subjects and to compare tear variables between age-matched normals and dry eye subjects. METHODS: Anterior segment optical coherence tomography was used to measure upper and lower tear menisci in healthy subjects (n = 197, 8-83 years) and in age matched dry eye patients (n = 38, 19-72 years). Measured tear variables included the height and area of the tear meniscus. Tear meniscus volumes were calculated based on the cross-sectional areas of the tear menisci and the eyelid lengths. The age-related decrease rates of the tear menisci were also calculated. RESULTS: There were significant negative correlations between age and all tear meniscus dimensions (r ranged from -0.649 to -0.753; p < 0.05) in the healthy group. The rate of decrease for the total tear meniscus volume in healthy subjects was 1.0% per year. Compared with age-matched healthy subjects, the height, cross-sectional area, and volume of the upper and lower tear menisci in dry eye subjects were significantly smaller (p < 0.05). CONCLUSIONS: Tear menisci decreased with age in the healthy group. The variables in age-matched dry eye subjects were significantly lower than those in the healthy group. PMID- 21705940 TI - Topography of cone dark adaptation deficits in age-related maculopathy. AB - PURPOSE: Despite widespread agreement that dark adaptation is abnormal in age related maculopathy (ARM), the optimal retinal location for detection of this deficit is unclear. We quantified the diagnostic potential of cone dark adaptation as a function of retinal eccentricity and compared this with the diagnostic potential of the time to the rod-cone-break (RCB). METHODS: Cone dark adaptation was monitored after an 80% cone photopigment bleach in 10 subjects with ARM and 10 age-matched controls, using four achromatic annuli (0.5, 2, 7, and 12 degrees radius) centered on the fovea. Threshold recovery data were modeled and the time constant of cone recovery (tau), final cone threshold, and time to RCB were determined. Diagnostic potential was evaluated by constructing receiver operating characteristic curves for these parameters. RESULTS: Cone tau was significantly longer for the ARM group at 2, 7, and 12 degrees . The greatest difference between groups was observed at 12 degrees from fixation. At this location, the mean tau was 3.49 (+/-2.02) min and 0.64 (+/-0.38) min for ARM and control subjects, respectively (p = 0.002), and time to RCB was 17.68 (+/-5.37) min and 9.05 (+/-2.11) min for ARM and control subjects, respectively (p = 0.001). Correspondingly, receiver operating characteristic curves showed that the diagnostic potential of dark adaptometry is greatest for stimuli presented 12 degrees from fixation; for cone tau, the area under the curve = 0.99 +/- 0.02 and for time to RCB, area under the curve = 0.96 +/- 0.04. CONCLUSIONS: This study has shown cone-mediated dark adaptation to be significantly impaired in ARM. Our results provide compelling evidence in support of the diagnostic potential of cone dark adaptation and the use of annular stimuli at 12 degrees . The observation that cone tau is highly diagnostic at this eccentricity is significant clinically because this parameter may be quantified within a few minutes. PMID- 21705941 TI - Evaluation of tear stability after surgery for conjunctivochalasis. AB - PURPOSE: To evaluate the efficacy of surgical treatment for conjunctivochalasis using the Tear Film Stability Analysis System. METHODS: Fifteen eyes of 15 patients (74.5 +/- 4.8 years; 14 females and 1 male) who had surgical reconstruction of the tear meniscus for conjunctivochalasis underwent evaluation with a symptom questionnaire, Schirmer I test, fluorescein tear film break-up time (FBUT), and break-up time index (BUI) measurement by Tear Film Stability Analysis System examinations that were performed preoperatively and 3 months after the surgery. Changes of these tear parameters were statistically analyzed using the paired t test. RESULTS: After the surgery, the mean FBUT and BUI values significantly improved from 5.7 +/- 3.2 s and 42.8 +/- 18.7, respectively, to 8.4 +/- 2.5 s and 60.7 +/- 16.5, respectively (FBUT, p = 0.0438; BUI, p = 0.0036). The mean Schirmer test value showed no significant changes before and after surgery (p = 0.9064). Fourteen eyes (93.3%) had improvement of ocular symptoms after surgery. One eye (6.7%) with no improvement of ocular symptoms, FBUT, and BUI after surgery appeared to have aqueous tear deficiency. CONCLUSIONS: Surgical treatment for conjunctivochalasis was associated with improvement of tear stability and clinical dry eye symptoms. PMID- 21705942 TI - Endoscopic ultrasound identifies synchronous pancreas cystic lesions not seen on initial cross-sectional imaging. AB - OBJECTIVES: A retrospective review conducted to determine the utility of endoscopic ultrasound (EUS) examination of the pancreas after initial pancreatic cyst detection with cross-sectional imaging. METHODS: A retrospective review of 145 patients referred for EUS for evaluation of pancreas cystic lesions. Initial cross-sectional imaging reports were reviewed and compared to subsequent EUS findings. Findings evaluated included cyst size, number, multifocality, presence in different surgical fields, cyst wall nodularity, main pancreatic duct (PD) dilation, communication with PD, and features suggestive of serous cystadenoma. RESULTS: Compared to computed tomographic scan, EUS more frequently identified pancreatic cystic lesion multifocality (47% vs 13%, P < 0.0001) and their presence in different surgical fields (33.3% vs 4.2%, P < 0.0001). Compared to magnetic resonance imaging, EUS was superior in identifying multifocality (58% vs 34%, P = 0.0002) and the presence of cysts in different surgical fields (42% vs. 26%, P = 0.021). Malignancy was suspected or confirmed in 3 patients by EUS fine needle aspiration cytology, not suspected by cross-sectional imaging. Endoscopic ultrasound identified unappreciated features of serous cystadenomas in 10 patients. CONCLUSION: Endoscopic ultrasound identified synchronous pancreatic cystic lesions unappreciated by initial cross-sectional imaging, with undetected cysts frequently outside of typical resection margins. In addition, EUS identified the presence of unappreciated high- or low-risk characteristics in a small percentage of patients. PMID- 21705943 TI - Comparison of pancreatic head resection with segmental duodenectomy and pylorus preserving pancreatoduodenectomy for benign and low-grade malignant neoplasms of the pancreatic head. AB - OBJECTIVE: The aim of this study was to investigate the clinical benefits of pancreatic head resection with segmental duodenectomy (PHRSD) with a particular emphasis on the long-term outcome. METHODS: A retrospective analysis of PHRSD (77 patients) and pylorus-preserving pancreatoduodenectomy (PPPD; 55 patients) was performed for benign and low-grade malignant neoplasms of the pancreatic head. The zintraoperative and postoperative courses and long-term nutritional statuses were compared. RESULTS: The mean operative time and blood loss were significantly less in the PHRSD group than in the PPPD group (351 vs 395 minutes, P = 0.005; and 474 vs 732 mL, P < 0.0001, respectively). Fewer overall postoperative complications occurred in the PHRSD group than in the PPPD group (33.8% vs 52.7%, respectively, P = 0.03). Postoperative weight loss and changes in the serum total protein and albumin levels were significantly milder in the PHRSD group than in the PPPD group (P = 0.04, P = 0.04, and P = 0.046, respectively). The overall recurrence-free survival rates in patients with noninvasive intraductal papillary mucinous neoplasms were equivalent in both groups. CONCLUSIONS: The present results suggest that PHRSD fulfills the operative safety, long-term nutritional status, and curative goals and could be the best option for patients with benign or low-grade malignant pancreatic lesions. PMID- 21705944 TI - The predominant distribution of vesicular monoamine transporter 2 in the alpha cells and delta cells, not beta cells, in rat islets. PMID- 21705945 TI - A modified 13C-mixed triglyceride breath test detects moderate pancreatic exocrine insufficiency. AB - OBJECTIVES: The noninvasive 13C-mixed triglyceride breath test (13C-MTG-T) has been shown to diagnose severe pancreatic exocrine insufficiency reliably. We hypothesized that sensitivity of the test could be increased by strict limitation of physical activity, correction for gastric emptying velocity, and/or increased lipid dose. METHODS: In 10 healthy volunteers and 9 patients with suspected pancreatic disease, a secretin test, a modified 13C-MTG-T (250 mg 13C-MTG, 26 g fat, breath samples over 8 hours), and a 13C-octanoic acid gastric emptying test were performed. Subjects remained strictly seated during breath testing. RESULTS: Intravenously administered secretin 1 U/kg.h stimulated outputs of all enzymes significantly. Mean basal and stimulated enzyme outputs were similar in patients and healthy controls; however, compared with normal values, 5 patients and 1 control had moderately decreased lipase output. Cumulative 4-, 6-, and 8-hour 13C exhalation was significantly lower in patients than in controls. Sensitivity of 13C-MTG-T (6-h cumulative 13C exhalation <27% of dose) for detection of decreased lipase output was 100%; specificity was 92%. Gastric emptying parameters were similar in patients and controls, and correction for these did not improve accuracy of 13C-MTG-T. CONCLUSIONS: The modified 13C-MTG-T detects moderate pancreatic exocrine insufficiency. PMID- 21705946 TI - Timing of endoscopy after extracorporeal shock wave lithotripsy for chronic pancreatitis. AB - OBJECTIVES: Extracorporeal shock wave lithotripsy (ESWL) and endoscopic retrograde cholangiopancreatography (ERCP) are used to clear main pancreatic duct (MPD) stones and alleviate pain in patients with chronic pancreatitis. The goal of this study was to determine if delayed ERCP after disintegration of MPD stones with ESWL improves the successful clearance of the MPD. METHODS: Adult patients with chronic pancreatitis who underwent ESWL for stone disintegration were identified from an ESWL database at a single tertiary referral center. The complete clearance of stones from the MPD with ERCP performed less than 2 days after ESWL was compared to complete clearance from ERCP more than 2 days after ESWL. RESULTS: Nineteen patients underwent ERCP less than 2 days after ESWL, and 3 (16%) of the 19 achieved MPD clearance. Eleven patients underwent ERCP more than 2 days after ESWL, and 9 (82%) of 11 patients achieved MPD clearance (P = 0.001). In total, 19 of 30 ERCPs were performed less than 2 days after ESWL, and 84% failed to clear the MPD (P = 0.001). CONCLUSIONS: The timing of ERCP after ESWL may be important to successfully clear stones from the MPD. This study shows that ERCP performed less than 2 days after ESWL may be more likely to fail, possibly owing to ESWL-induced edema. Delaying ERCP after ESWL may allow tissue recovery after ESWL. PMID- 21705947 TI - Prognostic implications of lymph node metastases in carcinoma of the body and tail of the pancreas. AB - OBJECTIVE: The current classification of pancreatic cancer is based only on anatomic location of metastatic lymph nodes (LNs). On the other hand, the number of metastatic LNs has been used in staging of colorectal, esophageal, and gastric cancers. The aim of this study was to assess the prognostic impact of the number or ratio of the metastatic LNs in pancreatic body and tail carcinoma. METHODS: Eighty-five patients with pancreatic body and tail adenocarcinoma who underwent pancreatectomy were included. Location, number, ratio of metastatic LNs, and the survival of patients were analyzed. RESULTS: Forty patients with LN metastasis had poor prognosis (P = 0.007). The prognoses of patients with 5 or more metastatic LNs were poorer than those with less than 5 metastatic LNs (P = 0.046), and patients with a metastatic LN ratio of 0.2 or more had the worst prognosis. Multivariate analysis revealed that 5 or more metastatic LNs and metastatic LN ratio of 0.2 or more were independent prognostic factors for survival (P = 0.0015 and P = 0.014, respectively). CONCLUSION: These results indicate that the number and the ratio of metastatic LNs can be used to predict poor patient survival and as a staging strategy. PMID- 21705948 TI - Gastric emptying in patients with autoimmune pancreatitis. AB - OBJECTIVES: Autoimmune pancreatitis (AIP) and its extrapancreatic lesions seem to be clinical manifestations of organs involved in IgG4-related systemic disease. To clarify whether the stomach is a target organ, gastric function was evaluated in patients with AIP. METHODS: In 6 patients with AIP, gastric emptying was assessed by Carbon 13 (13C) acetate breath test before and after steroid therapy. Based on 4-hour breath samples, the half 13CO2 excretion time (T(1/2)) and the time of maximal excretion (T(max)) were calculated as gastric emptying parameters. Data of 20 healthy volunteers were used as controls. The number of IgG4-positive plasma cells in gastrofiberscopic biopsy specimens was counted before and after steroid therapy. RESULTS: Both T(1/2) and T(max) in patients with AIP decreased significantly after steroid therapy (T(1/2): 1.89 +/- 0.21 hours vs 1.69 +/- 0.15 hours, P = 0.046; and T(max): 1.1 +/- 0.2 hours vs 0.96 +/ 0.2 hours, P = 0.027), and became similar to those of the controls (T(1/2): 1.69 +/- 0.32 hours and T(max): 0.98 +/- 0.2 hour). The number of IgG4-positive plasma cells infiltrating the gastric mucosa decreased after steroid therapy. CONCLUSIONS: Gastric emptying was impaired in patients with AIP and improved to the reference range after steroid therapy. The stomach may be a target organ of IgG4-related systemic disease. PMID- 21705949 TI - Serotonin-producing enterochromaffin cell tumors of the pancreas: clinicopathologic study of 15 cases and comparison with intestinal enterochromaffin cell tumors. AB - OBJECTIVES: Serotonin-producing tumors of the pancreas are rare endocrine neoplasms composed of enterochromaffin (EC) cells that have been mainly described in the literature as case reports. This study analyzes the clinicopathologic features of a series of pancreatic EC cell neoplasms and their similarities to and differences from intestinal EC cell tumors. METHODS: The morphological, immunohistochemical, ultrastructural, and fluorescent in situ hybridization features of 15 pancreatic and 20 intestinal serotonin-producing neoplasms were compared. In addition, we reviewed the literature on pancreatic serotonin producing tumors to better understand the clinicopathologic features of this rare tumor type. RESULTS: The lack of substance P and acidic fibroblast growth factor immunoreactivity; the low immunohistochemical expression of CDX2, vesicular monoamine transporter 1, connective tissue growth factor, and prostatic acid phosphatase; the lack of S100-positive sustentacular cells; the strong expression of vesicular monoamine transporter 2; and peculiar ultrastructural features characterize pancreatic EC cell tumors and differentiate them from intestinal ones, although both categories show similar chromosome 18 cytogenetic alterations. The review of the literature indicates that pancreatic functioning tumors associated with the carcinoid syndrome arise in younger patients and are larger, more frequently malignant, and more aggressive neoplasms than pancreatic nonfunctioning ones. CONCLUSIONS: Pancreatic EC cell tumors show several different morphological features compared with related intestinal tumors despite similar cytogenetic alterations on chromosome 18. PMID- 21705950 TI - Fluorescence in situ hybridization and K-ras analyses improve diagnostic yield of endoscopic ultrasound-guided fine-needle aspiration of solid pancreatic masses. AB - OBJECTIVES: Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is the main diagnostic modality for pancreatic mass lesions. However, cytology is often indeterminate, leading to repeat FNAs and delay in care. Here, we evaluate whether combining routine cytology with fluorescence in situ hybridization (FISH) and K-ras/p53 analyses improves diagnostic yield of pancreatic EUS-FNA. METHODS: Fifty EUS-FNAs of pancreatic masses in 46 patients were retrospectively analyzed. Mean follow-up was 68 months. Thirteen initial cytologic samples (26%) were benign, 23 malignant (46%), and 14 atypical (28%). We performed FISH for p16, p53, LPL, c-Myc, MALT1, topoisomerase 2/human epidermal growth factor receptor 2, and EGFR, as well as K-ras/p53 mutational analyses. RESULTS: On final diagnosis, 11 (79%) of atypical FNAs were malignant, and 3 benign (21%). Fluorescence in situ hybridization was negative in all benign and all atypical samples with final benign diagnosis. Fluorescence in situ hybridization plus K-ras analysis correctly identified 60% of atypical FNAs with final malignant diagnosis. Combination of routine cytology with positive FISH and K-ras analyses yielded 87.9% sensitivity, 93.8% specificity, 96.7% positive predictive value, 78.9% negative predictive value, and 89.8% accuracy. CONCLUSIONS: Combining routine cytology with FISH and K-ras analyses improves diagnostic yield of EUS-FNA of solid pancreatic masses. We propose to include these ancillary tests in the workup of atypical cytology from pancreatic EUS-FNA. PMID- 21705951 TI - Are biochemical markers of neuroendocrine tumors coreleased with insulin following local calcium stimulation in patients with insulinomas? AB - OBJECTIVES: The objective was to test whether chromogranin A (CgA), neuron specific enolase (NSE), and pancreatic polypeptide (PP) are released from the pancreas during the selective arterial calcium stimulation and hepatic venous sampling test (ASVS) in patients with insulinomas. METHODS: We determined CgA, NSE, PP, insulin, C-peptide, and proinsulin in blood samples obtained during the ASVS test in 19 patients with insulinomas. Levels following calcium injection into the arteries supplying the tumor were compared with levels following calcium stimulation of arteries supplying healthy pancreatic tissue. RESULTS: After calcium injection into the artery supplying the insulinoma, a significant 8-fold increase in insulin (range, 2.3-117; P < 0.001), a 3.8-fold increase in C-peptide (1.7-32.4; P < 0.001), and a 1.9-fold increase in proinsulin (0.7-5.3, P < 0.001) were detectable whereas NSE and CgA did not increase. No significant increases in insulin, C-peptide, proinsulin, CgA, and NSE concentrations were found after calcium injection into control arteries. Pancreatic polypeptide increased 1.5 fold (0.8-4.5; P = 0.017) after calcium injection into the tumor artery and 2.4 fold (0.8-7.9; P = 0.016) after injection into the control artery. CONCLUSIONS: Insulin, C-peptide, and proinsulin are released by insulinoma cells in response to arterial calcium stimulation, whereas CgA and NSE are not released. Also from our study it seems that PP may be released by healthy islet cells after calcium stimulation. PMID- 21705952 TI - Endocrine pancreatic function changes after acute pancreatitis. AB - OBJECTIVE: This study aimed to investigate the impairment of pancreatic endocrine function and the associated risk factors after acute pancreatitis (AP). METHODS: Fifty-nine patients were subjected to tests of pancreatic function after an attack of pancreatitis. The mean time after the event was 3.5 years. Pancreatic endocrine function was evaluated by fasting blood glucose (FBG), glycosylated hemoglobin, fasting blood insulin, and C-peptide. Homeostasis model assessment was used to evaluate insulin resistance and islet beta-cell function. Pancreatic exocrine function was evaluated by fecal elastase 1. Factors that could influence endocrine function were also investigated. RESULTS: Nineteen patients (32%) were found to have elevated FBG, whereas 5 (8%) had abnormal glycosylated hemoglobin levels. The levels of FBG, fasting blood insulin, and C-peptide were higher in patients than in controls (P < 0.01). The islet beta-cell function of patients was lower than that of controls (P < 0.01), whereas insulin resistance index was higher among patients (P < 0.01). Obesity, hyperlipidemia, and diabetes-related symptoms were found to be associated with endocrine insufficiency. Pancreatic exocrine functional impairment was found at the same time. CONCLUSIONS: Endocrine functional impairment with insulin resistance was found in patients after AP. Obesity, hyperlipidemia, and diabetes-related symptoms increased the likelihood of developing functional impairment after AP. PMID- 21705953 TI - Improved quantification of islet transplants by magnetic resonance imaging with Resovist. AB - OBJECTIVES: We aimed to develop an accurate and reproducible method to quantify transplanted islets and monitor their functional status in vivo. To support this aim, we investigated the cytotoxic effect of Resovist on islet function and survival. METHODS: The average pixel number for a single Resovist-labeled islet was measured. To determine Resovist cytotoxicity, DNA fragmentation, adenosine diphosphate-adenosine triphosphate ratio, ion channel activity, and in vivo islet function were evaluated. To quantitatively monitor the fate of islet transplant, we transplanted Resovist-labeled islets into syngeneic C57BL/6 mice for magnetic resonance imaging analysis. RESULTS: The average pixel volume for a medium-sized islet (100-150 MUm in diameter) was determined from the contrast signal void of magnetic resonance image. Toxicological analysis showed that Resovist did not affect islet at concentrations up to 40 times the labeling dose. In the quantitative analysis, the number of contrast spots did not correlated with the number of transplanted islets, whereas our newly adopted measure showed a significant correlation. CONCLUSIONS: Islet transplant survival may be safely and accurately monitored using magnetic resonance imaging with the Resovist. We found in this study that pixel number may correlate more closely than the number of contrast spots with the number of islets transplanted. PMID- 21705954 TI - Perfusion computed tomography findings of autoimmune pancreatitis. AB - OBJECTIVES: The aim of this study was to clarify the pancreatic blood perfusion in patients with autoimmune pancreatitis (AIP) and the changes after steroid treatment. METHODS: Perfusion computed tomography was performed in 11 patients with AIP and 12 control subjects. Pancreatic volumetric blood flow (F(V)), volume of distribution (V(D)), and blood transit time tau were determined from a single compartment kinetic model. Nine patients with AIP were reexamined by perfusion computed tomography after corticosteroid administration. RESULTS: The pancreatic F(V) values of the 11 patients with AIP (82.7/min) were significantly lower than those of control subjects (163.5/min, P = 0.0006). On the other hand, the pancreatic V(D) and tau values were not significantly different between AIP and normal. After steroid treatment, the F(V) values of 9 reexamined patients with AIP (76.2/min) were significantly elevated (109.8/min, P = 0.0391). However, the changes of the values after the treatment differed in degree among individuals. The values of 4 patients were dramatically elevated to greater than 100/min, whereas those of 4 other patients did not improve well. The value of the remaining patient whose initial F(V) value was normal (168.09/min) did not change after the treatment. CONCLUSIONS: Pancreatic volumetric perfusion was attenuated in AIP patients. The perfusion was improved after the steroid treatment. PMID- 21705955 TI - Cyclooxygenase-2 polymorphisms and pancreatic cancer susceptibility. AB - OBJECTIVES: DNA sequence variants in the cyclooxygenase-2 (COX-2) gene may lead to altered COX-2 production and/or activity, resulting in interindividual differences in susceptibility to pancreatic cancer. To test this hypothesis, we investigated the relationship between polymorphisms in the COX-2 gene and the risk of pancreatic cancer in a European population. METHODS: The COX-2 genotypes for 7 single-nucleotide polymorphisms (rs2745557, rs5277, rs2066826, rs4648261, rs4648262, rs2206593, and rs5275) were determined in 162 pancreatic cancer patients and 170 control subjects without cancer who were matched for age and sex. Data analysis was by conditional logistic regression analysis, adjusting for age, sex, and smoking. RESULTS: Two haplotypes (GGAGGGT and GCGGGGT for rs2745557, rs5277, rs2066826, rs4648261, rs4648262, rs2206593, rs5275, respectively) were more frequent among the patients compared with control subjects (P < 0.024), although no individually statistically significant associations for the 7 single-nucleotide polymorphisms studied were detected. CONCLUSIONS: Our findings suggest the individual polymorphisms we studied in the COX-2 gene are not associated with risk of pancreatic cancer. However, the finding of a modest association with 2 haplotypes might be consistent with a small effect, which could be also seen at the genotype level had more samples been available. PMID- 21705956 TI - Transition from neonatal intensive care unit to special care nurseries: experiences of parents and nurses. AB - OBJECTIVES: To explore parents' and nurses' experiences with the transition of infants from the neonatal intensive care unit to a special care nursery. DESIGN: Qualitative explorative study in two phases. SETTING: Level IIID neonatal intensive care unit in a university hospital and special care nurseries (level II) in five community hospitals in the Netherlands. PARTICIPANTS: Twenty-one pairs of parents and 18 critical care nurses. METHODS AND MAIN RESULTS: Semistructured interviews were used. Thematic analysis and comparison of themes across participants were performed. Trust was a central theme for parents. Three subthemes, related to the chronological stages of transition, were identified: gaining trust; betrayal of trust; and rebuilding confidence. Trust was associated with five other themes: professional attitude; information management; coordination of transfer; different environments; and parent participation. Although nurses at an early stage repeatedly mentioned a possible transition to community hospitals, the actual announcement took many parents by surprise. Parents felt excluded during the actual transfer and most questioned its necessity. In the special care nursery, parents found it difficult to adjust to new routines and to gain trust in new caregivers, but eventually their worries dissolved. In contrast to neonatal intensive care unit nurses, special care nursery nurses quite understood the impact of transition on parents. CONCLUSIONS: Both parents and nurses considered present transitional arrangements to be inadequate. Nurses should provide more effective discharge planning and transitional care. A positive labeling of the transition as a first step to home discharge for the newborn seems appropriate. Parents need to be better-informed and should be involved in the planning process. PMID- 21705958 TI - The Groningen LCPUFA study: No effect of short-term postnatal long-chain polyunsaturated fatty acids in healthy term infants on cardiovascular and anthropometric development at 9 years. AB - Conflicting evidence exists on the effect of long-chain polyunsaturated fatty acid (LCPUFA) formula supplementation on cardiovascular health in term infants. It is known that LCPUFA supplementation does not affect infant growth, but long term outcome data are not available. The current study investigates whether 2 mo LCPUFA formula supplementation affects cardiovascular and anthropometric development at 9 y. A prospective, double-blind, randomized trial was performed in healthy term infants: a standard formula control group (CF, n = 169) and a LCPUFA-supplemented group [LF, n = 145; 0.45% (by wt) AA and 0.30% (by wt) docosahexaenoic acid (DHA)]. A breastfed group (BF; n = 159) served as reference. At the age of 9 y, systolic and diastolic blood pressure, heart rate, head circumference, weight, and height were measured. Univariate and multivariate analyses were performed; 63 to 79% of children were assessed. None of the cardiovascular or anthropometric measurements differed between the formula groups. Breastfed children had a marginally lower heart rate than formula-fed children, in particular compared with children fed control formula. Blood pressure and parameters of growth including BMI of breast and formula-fed children did not differ. In conclusion, the study suggests that short-term LCPUFA supplementation does not influence cardiovascular and anthropometric development at 9 y. PMID- 21705960 TI - Cerebral oxygenation during the first days of life in preterm and term neonates: differences between different brain regions. AB - Near-infrared spectroscopy is a noninvasive method for monitoring brain oxygenation. The aim of the study was to investigate differences between cerebral oxygenation in different brain regions in newborns. In a prospective study, we monitored simultaneously left and right frontoparietal and temporo-occipital regional cerebral oxygen saturation (rScO2) and cerebral fractional tissue extraction (cFTOE: (arterial oxygen saturation (SaO2) - rScO2)/SaO2) using near infrared spectroscopy. A 2-h measurement was performed on d 1, 3, and 7. We included 10 very preterm (GA <32 wk), 10 preterm (GA: 32-37 wk), and 10 term (GA >=37 wk) neonates. Limits of agreement for difference of the measurements between different places were determined using the Bland-Altman method. In all subgroups, the rScO2 and cFTOE values at different regions were not different. Limits of agreement were between +/-14 and +/-18% for all subgroups. Left-to-right differences were small between different postnatal and GAs. A decrease and increase over time for rScO2 and cFTOE values was detected for all four brain regions, most pronounced for infants with GA <32 wk. Cerebral oxygenation in stable preterm and term neonates seems not to differ between different regions of the brain during the early neonatal period. However, variability of individual measurements was quite high as indicated by large limits of agreement. PMID- 21705959 TI - Long-chain polyunsaturated fatty acid supplementation in infancy reduces heart rate and positively affects distribution of attention. AB - A double-blind, randomized, controlled, parallel-group prospective trial was conducted to determine whether a dose-response existed for four different levels of docosahexaenoic acid (DHA) supplementation on the cognitive performance of infants. A total of 122 term infants were fed one of four different formulas varying in their DHA composition (0.00, 0.32, 0.64, and 0.96% of total fatty acids as DHA) from birth to 12 mo. The three DHA-supplemented formulas also contained 0.64% of total fatty acids as arachidonic acid (ARA, 20:4n-6). Infants were tested at 4, 6, and 9 mo of age on a visual habituation protocol that yielded both behavioral and psychophysiological indices of attention. Infants in all DHA+ARA-supplemented conditions had lower heart rates than those in the unsupplemented condition; there was no dose-response for this effect. The distribution of time that infants spent in different phases of attention (a cognitive index derived from the convergence of behavioral and cardiac responses) varied as a function of dosage. Infants supplemented at the two lower DHA doses spent proportionately more time engaged in active stimulus processing than infants fed the unsupplemented formula, whereas infants fed the highest dose were intermediate and did not differ from any other group. PMID- 21705961 TI - Hemodynamic changes in the breast and frontal cortex of mothers during breastfeeding. AB - The objective of this study was to confirm physiological reactions in the breast and brain in mothers during breastfeeding and collect basic objective data, aiming at effective support for breastfeeding. Ten healthy women who were exclusively breastfeeding their babies participated in this study. Changes in the concentration of oxygenated Hb (oxyHb) and deoxygenated Hb in the breasts and frontal cortex of these women during breastfeeding lactation were measured using double-channel near-infrared spectroscopy (NIRS). Changes were measured in three conditions: (1) in both breasts; (2) the ipsilateral breast and frontal cortex; and (3) the contralateral breast and frontal cortex. OxyHb and total Hb (totalHb) levels in the bilateral breasts decreased significantly after the onset of breastfeeding in comparison with prebreastfeeding levels. These two values repeatedly increased and decreased thereafter. In the frontal cortex, regardless of which breast was involved, oxyHb and totalHb levels increased significantly in comparison with prebreastfeeding levels. Similar hemodynamic changes occurred simultaneously in the bilateral breasts during breastfeeding regardless of the feeding or nonfeeding side. Hemodynamic changes were also noted in the frontal cortex, but the reactions in the breast and prefrontal cortex were different and not synchronous, confirming that the physiological circulatory dynamics during breastfeeding vary among organs. PMID- 21705962 TI - Elastase inhibitory activity of airway alpha1-antitrypsin is protected by treatment with a catalytic antioxidant in a baboon model of severe bronchopulmonary dysplasia. AB - Recent studies in animal models of bronchopulmonary dysplasia (BPD) suggest that antioxidant treatments may be beneficial for the disease. However, the mechanisms by which these drugs improve the course of BPD are not completely known. Alpha1 antitrypsin (alpha1-AT) is one of the major serine protease inhibitors in human plasma that has antielastase and antiapoptotic activities. Both activities of alpha1-AT are dependent on its reactive site loop (RSL), which is highly susceptible to oxidative inactivation. In this study, we investigated the elastase inhibitory activity of alpha1-AT in two different baboon models of BPD, the "new BPD" and the "severe BPD" models, and determined the effect of treatment with a catalytic antioxidant, Mn(III) meso-tetrakis(N-ethylpyridinium-2 yl)porphyrin (MnTE-2-PyP), on the elastase inhibitory activity of alpha1-AT in the severe BPD model. Our results demonstrate the presence of sufficient elastase inhibitory activity of the airway alpha1-AT in the new but not in the severe BPD model. Treatment of severe BPD group baboons with the catalytic antioxidant MnTE 2-PyP resulted in augmentation of the elastase inhibitory activity of alpha1-AT. These findings suggest that prevention of the oxidative inactivation of alpha1-AT may be one of the mechanisms by which antioxidant therapy improves the pulmonary outcomes in animal models of severe BPD. PMID- 21705963 TI - Spot the red herring: breastfeeding, fruitpuree, and infant autonomic functioning the generation R study. AB - Several studies have suggested that breastfeeding is related to infant autonomic functioning. The authors investigated whether this is a causal relation. In all, 444 mothers reported breastfeeding practices 2 mo postpartum. Infant autonomic functioning was assessed by heart rate variability at age 14 mo, after discontinuation of breastfeeding. The dose-dependent association between breastfeeding and infant autonomic functioning was tested with linear regression models adjusted for multiple confounders. The authors investigated the relation of fruitpuree consumption with infant autonomic functioning. Fruitpuree consumption has similar socioeconomic epiphenomena but is not related via the same causal mechanism to autonomic regulation as breastfeeding. Nonbreastfed infants had high sympathetic modulation [7.87 log (ms)/SD, 95% CI: 7.71-8.02], partially breastfed infants had intermediate sympathetic modulation [7.75 log (ms)/SD, 95% CI: 7.51-7.82], sympathetic modulation of exclusively breastfed infants was low [7.63 log (ms)/SD, 95% CI: 7.50-7.77]. However, this association could be explained by socioeconomic confounders. Furthermore, fruitpuree consumption was similarly associated with reduced infant sympathetic modulation. The association between breastfeeding practices and infant sympathetic modulation was accounted for by socioeconomic and environmental factors. We found a similar association between fruitpuree consumption and autonomic functioning, further suggesting that the association between breastfeeding and infant autonomic functioning is noncausal. PMID- 21705964 TI - Correction of gliadin transport within enterocytes through celiac disease serum. AB - Celiac disease (CD) is caused by loss of tolerance toward gluten and related cereal products. The delivery of gliadin peptides (GP) to HLA-DR-positive late endosomes (LE) of enterocytes is required for antigen presentation and tolerance generation. We hypothesized that anti-gliadin antibodies in CD serum modify gliadin transport into LE within enterocytes. CD and control duodenal biopsies were incubated with digests of gluten as well as with serum of CD patients. Lissamin-labeled GP AA31-43 and AA56-68 were endocytozed by Caco-2 cells with serum of CD- or control patients. Colocalization of gliadin with the LE marker LAMP-2 and cathepsin D was determined and quantified on immunofluorescence and immunoelectron microscopical level. Up to 13% of internalized gliadin was located in LE of CD biopsies incubated with CD serum compared with less than 4% in CD biopsies without CD serum as well as in control biopsies. In Caco-2 cells, the colocalization coefficient of GP AA31-43 and LE was 0.82 with CD serum, 0.42 with control serum, and 0.48 with culture medium. Incubation with CD serum can direct GP AA31-43 into LE of enterocytes which is required for antigen presentation. PMID- 21705965 TI - Regulation of ocular adrenoceptor genes expression by 5-MCA-NAT: implications for glaucoma treatment. AB - We have demonstrated that 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT), reduces intraocular pressure (IOP) in rabbits. In addition, we have reported a link between hypotensive effect of 5-MCA-NAT and sympathetic nervous system. Moreover, it is known that aqueous humour production is controlled by the activation of adrenoceptors (ADRs) present in the ocular ciliary epithelium. Thus, the aim of this study is to investigate if the hypotensive effect of 5-MCA NAT is due to a regulation of ciliary ADR genes expression. To confirm this we followed the effect of 5-MCA-NAT on rabbit IOP for 144 consecutive hours. A sustained IOP reduction for up to 72 h (P<0.01) was seen. In addition, changes in ADRB2 and ADRA2A mRNA were measured in cultured rabbit nonpigmented ciliary epithelial cells. After 5-MCA-NAT treatment, a significant downregulation of ADRB2 and upregulation of ADRA2A was observed. These results provide the regulation of ADRs mRNA by 5-MCA-NAT. PMID- 21705966 TI - Evaluating the impact of simulation on translational patient outcomes. AB - INTRODUCTION: A long and rich research legacy shows that under the right conditions, simulation-based medical education (SBME) is a powerful intervention to increase medical learner competence. SBME translational science demonstrates that results achieved in the educational laboratory (T1) transfer to improved downstream patient care practices (T2) and improved patient and public health (T3). METHOD: This is a qualitative synthesis of SBME translational science research (TSR) that employs a critical review approach to literature aggregation. RESULTS: Evidence from SBME and health services research programs that are thematic, sustained, and cumulative shows that measured outcomes can be achieved at T1, T2, and T3 levels. There is also evidence that SBME TSR can yield a favorable return on financial investment and contributes to long-term retention of acquired clinical skills. The review identifies best practices in SBME TSR, presents challenges and critical gaps in the field, and sets forth a TSR agenda for SBME. CONCLUSIONS: Rigorous SBME TSR can contribute to better patient care and improved patient safety. Consensus conference outcomes and recommendations should be presented and used judiciously. PMID- 21705967 TI - Research regarding methods of assessing learning outcomes. AB - As the use of simulation-based assessment expands for healthcare workers, there is a growing need for research to quantify the psychometric properties of the associated process and outcome measures. PMID- 21705968 TI - The accuracy of clinical assessments as a measure for teamwork effectiveness. AB - INTRODUCTION: Team training in healthcare is usually evaluated by observers who either score trainees' behaviors, social skills, and cognitive skills during simulation or measure changes in the clinical state of a mannequin. Both methods have shortcomings that limit their usefulness. We propose Brunswik's probabilistic functionalism and the Accuracy Score (AS), a measure emerging from judgment analysis, as elements of a complementary approach that could increase the objectivity of team training evaluation. We report an initial investigation. METHOD: Three groups of neonatal clinicians participated in a resuscitation experiment involving three different training interventions. During the experiment, at various phases, the participants were required to assign an Apgar score to a mannequin. ANALYSIS: The AS was used to test how accurately the clinicians assigned Apgar scores to the mannequin across different levels of task demand, training content, and training delivery method. RESULTS: The AS was lower when task demand increased (P < 0.01). The AS was higher after teamwork training than after clinical training (P < 0.05) and better after hands-on teamwork training than after lecture-based teamwork training (P < 0.05). CONCLUSIONS: Because it is simple and objective, the AS may complement existing measures for team training evaluation. Future studies are required in which the AS is tested with a larger number of trainees, in longitudinal experiments, across different training areas, and is compared with previously validated team performance measures. PMID- 21705970 TI - Coronary calcifications detected by computed tomography are not markers of cardiac allograft vasculopathy. AB - BACKGROUND: Cardiac allograft vasculopathy (CAV) still limits survival after heart transplantation. Currently available noninvasive tests are of inferior value to detect CAV, and thus invasive coronary angiography (ICA) is frequently performed. Cardiac dual-source computed tomography calcium scoring (DSCTCS) offers the possibility to detect coronary calcifications, which might serve as a noninvasive marker of CAV. This study sought to evaluate its clinical feasibility. METHODS: One hundred sixty-one patients (130 men; 31 women; mean age: 50.5+/-12.1 years) underwent DSCTCS 1+/-2 days before annual routine ICA. Mean posttransplant time was 73.7+/-49.6 months. The results of DSCTCS were compared with ICA. RESULTS: In 100 patients (85 men; 15 women; mean age: 51.5+/ 12.3 years), coronary calcifications were detected, and in 61 patients (45 men; 16 women; mean age: 49.0+/-11.7 years), coronary calcifications were excluded. ICA excluded CAV in 82 patients (63 men; 19 women; mean age: 48.6+/-11.9 years). In 79 patients (67 men; 12 women; mean age: 52.5+/-12.2 years), CAV was detected of whom 11 patients needed stent implantation. No statistically significant difference of DSCTCS in patients without (17.2+/-29.5; range: 0-190) and with CAV (33.4+/-66.8; range: 0-385) was observed (P=0.133). Moreover, 4 of 11 (36.4%) severely diseased patients had a calcium score of zero. Sensitivity, specificity, negative predictive value, and positive predictive value for CAV detection (calcium score threshold >0) was calculated as 72.2%, 47.6%, 47.7%, and 57.0%, respectively. Diagnostic accuracy was 59.6%. CONCLUSION: DSCTCS is not a valuable noninvasive modality for CAV detection and thus not recommended in clinical practice. Moreover, we hypothesize that it represents preexisting or de novo traditional coronary atherosclerosis than CAV. PMID- 21705969 TI - Clinical outcome of treatments for spinal dural arteriovenous fistulas: results of multivariate analysis and review of the literature. AB - STUDY DESIGN: This study was a case series study using a prospective single institute database for the treatment of spinal dural arteriovenous fistulas (SDAVFs). OBJECTIVE: To evaluate clinical factors that influence the neurological outcomes of treatment for SDAVFs, which were obtained from the analysis of 21 patients treated in our institution, and to provide management recommendations based on the review of former major clinical studies including our own reported over the past 2 decades. SUMMARY OF BACKGROUND DATA: Since 1977, when Kendall and Logue described the etiology of SDAVFs as hyperpressure of intrathecal veins due to an abnormal shunting from the arteries, treatment strategies have improved dramatically along with developments in neuroimaging, endovascular techniques and materials, and microsurgery based on the underlying pathophysiological process. However, therapeutic guidelines remain controversial. METHODS: Patients treated for SDAVFs from 2000 to 2008 were eligible. Age, sex, level of shunting, initial symptom, duration of symptom, the treatment method, and clinical symptoms before and 6 months after treatment were investigated. RESULTS: There were a total of 30 patients (18 male and 12 female), with a mean age of 59 years; 21 of them underwent treatment for the first time. We conducted a univariate analysis using a logistic regression model, on age, sex, the level of SDAVFs, duration of symptoms, symptom (sensory or paralysis), and gait function and micturition before treatment, and the intervention method were set as variables to investigate the risk factors for motor deficit 6 months after the treatment. Only gait function before treatment was correlated with the motor deficit 6 months after treatment (odds ratio = 10.0; 95% confidence interval = 1.28-78.11, P = 0.03).From these results, intervention at an early stage would be the key to a preferable outcome of the treatment for SDAVFs. CONCLUSION: The clinical status before treatment significantly influenced the clinical outcome after the treatment. PMID- 21705971 TI - Both darbepoetin alfa and carbamylated erythropoietin prevent kidney graft dysfunction due to ischemia/reperfusion in rats. AB - BACKGROUND: Ischemia/reperfusion (I/R) injury is an important cause of renal graft dysfunction. Increases in cold and warm ischemia times lead to a higher risk of early posttransplant complications including delayed graft function and acute rejection. Moreover, prolonged cold ischemia is a predictor of long-term graft loss in kidney transplant patients. METHODS: Darbepoetin alfa (DA) and carbamylated nonerythropoietic derivative of erythropoietin (CEPO) protective effects were evaluated in a model of I/R injury after kidney transplantation in both syngeneic and allogeneic combinations. The effects of wortmannin (phosphorylated Akt [p-Akt] inhibitor) administration were also investigated. Serum creatinine was evaluated at 16, 24, 48 hr and at 4 and 7 days posttransplant. Animals were killed 24 hr or 7 days after transplant and kidneys were processed for histological analysis, immunohistochemistry assessment of erythropoietin receptor (EPOR) and beta-common chain receptor expression, granulocyte infiltration, nitrotyrosine staining, p-Akt expression, peritubular capillary (PTC) density, apoptosis, antioxidant, and antiapoptotic gene expression. RESULTS: DA and CEPO significantly reduced serum creatinine, tubular injury, tubular nitrotyrosine staining, and prevented I/R-induced tubular apoptosis, but only when given both to the donor and to the recipient. DA and CEPO cytoprotection was associated with prevention of I/R-induced drop of p-Akt expression in tubuli, and almost complete preservation of capillary density in the tubulointerstitium of the graft. CEPO was more effective than DA in reducing tubular oxidative stress and preserving PTCs. CONCLUSION: DA and CEPO when given both to the donor and to the recipient, prevented renal graft dysfunction, tubular oxidative stress, and apoptosis after I/R injury in kidney transplantation. Their cytoprotection was mediated by tubular p-Akt activation and PTC density preservation. PMID- 21705972 TI - Study of the extraction process and in vivo inhibitory effect of ganoderma triterpenes in oral mucosa cancer. AB - The aim of the reported study was to optimize the extraction process for ganoderma triterpenes and to investigate the in vivo inhibitory effect of ganoderma triterpenes on the genesis and progression of oral cancer. Single factor and orthogonal methods were used to investigate the effects of extraction solvent, solvent amount, extraction time, extraction temperature, and number of extractions, on the extraction rate for ganoderma triterpenes. A golden hamster model with cheek pouch dynamic canceration was established to receive oral treatment of ganoderma triterpenes water solution. Animals were continuously monitored, oral tissue samples were collected for histopathologic examination, and changes in the expression of VEGF (vascular endothelial growth factor) and Caspase-3 were detected by immunohistochemical methods. Optimization of the experimental conditions allowed the identification of the optimal extraction conditions: 90% ethanol as the extraction solvent, a solvent amount by the liquid material ratio of 35 mL/g, extraction time of 2 h and extraction temperature of 80 degrees C. Under these conditions, the average extraction rate of ganoderma triterpenes was 1.09%. Tests in golden hamsters showed that compared with the model group during the same period, animals in the treatment group had better conditions, constantly larger number of normal cases shown by histopathologic results (P < 0.01), and consistently smaller numbers of cases with paraplasm (P < 0.05). Immunohistochemical results showed that compared with the model group, the treatment group had significantly lower (P < 0.05) rates of positive VEGF expression in the normal state, simple epithelial hyperplasia, epithelial dysplasia or squamous cell carcinoma disease stages. Caspase-3 expression showed a tendency toward a gradual increase with the worsening of disease severity in each group. Compared with the model group, the treatment group had significantly lower (P < 0.05) rates of positive Caspase-3 in the normal state, simple epithelial hyperplasia, epithelial dysplasia or squamous cell carcinoma disease grades. Using the optimized extraction process, ganoderma triterpenes could be extracted with high efficiency, and the results of animal tests showed inhibitory effects of ganoderma triterpenes on oral mucosa cancer. PMID- 21705973 TI - Generation and detection of levuglandins and isolevuglandins in vitro and in vivo. AB - Levuglandins (LGs) and isolevuglandins (isoLGs), formed by rearrangement of endoperoxide intermediates generated through the cyclooxygenase and free radical induced oxidation of polyunsaturated fatty acids (PUFAs), are extraordinarily reactive, forming covalent adducts incorporating protein lysyl epsilon-amino groups. Because they accumulate, these adducts provide a dosimeter of oxidative injury. This review provides an updated and comprehensive overview of the generation of LG/isoLG in vitro and in vivo and the detection methods for the adducts of LG/isoLG and biological molecules in vivo. PMID- 21705974 TI - Neuroprotective effects of vanillyl alcohol in Gastrodia elata Blume through suppression of oxidative stress and anti-apoptotic activity in toxin-induced dopaminergic MN9D cells. AB - Gastrodia elata Blume (GE) has long been used in oriental countries as a traditional herbal medicine to relieve symptoms associated with neurological ailments such as vertigo, general paralysis and epilepsy. In this study, we have investigated the effects of GE extracts and its major bioactive components on 1 methyl-4-phenylpyridinium (MPP+)-treated MN9D dopaminergic cells, a classic in vitro model for Parkinson's disease (PD). We found that vanillyl alcohol effectively inhibited the cytotoxicity and improved cell viability in MPP+ induced MN9D dopaminergic cells. The underlying mechanisms of vanillyl alcohol action were also studied. Vanillyl alcohol attenuated the elevation of reactive oxygen species (ROS) levels, decreased in the Bax/Bcl-2 ratio and poly (ADP ribose) polymerase proteolysis. These results indicate that vanillyl alcohol protected dopaminergic MN9D cells against MPP+-induced apoptosis by relieving oxidative stress and modulating the apoptotic process and is therefore a potential candidate for treatment of neurodegenerative diseases such as Parkinson's disease. PMID- 21705975 TI - Disturbances of biomarkers of iron and oxidant-antioxidant homeostasis in patients with beta-thalassemia intermedia. AB - BACKGROUND: Disturbances of oxidative stress and antioxidant status have been reported in patients with Beta-ThM and in a limited number of patients with ThI. OBJECTIVES: To I) study relevant biomarkers of iron metabolism, oxidative stress and antioxidant status, in untransfused patients with ThI and II) evaluate the relation of changes in biomarkers to the clinicalhematological phenotype and genotype. DESIGN: Biomarkers of iron metabolism (ferritin, NTBI, sTfR), of oxidant activity (MDA, GSSG, GSSC/GSHT, NO) and of antioxidant enzymes (GR, GPx, SOD) and Vitamins (E, C, A) were estimated and analyzed in 20 controls and 33 patients with ThI, sub-classified into mild (17) and severe (16) types. All but five were untransfused. RESULTS: Clinical phenotypes of mild and severe ThI were related to distinct genotypes, 11 for mild and 14 for severe. The three iron biomarkers were significantly increased in both ThI types compared to controls and in severe compared to mild types. The ferritin levels (total iron load) had a highly significant positive correlation with age (p<0.001) and sTfR. Biomarkers with oxidant activity were also significantly increased in ThI patients compared to controls; significantly higher levels for MDA, NTBI, and GSSG/GSHT were found in severe ThI. The activity of antioxidant enzymes GR, GP and SOD, was significantly significantly reduced in patients, especially in the severe type. Vitamin C was mildly reduced in both types of ThI. CONCLUSIONS: Activity of relevant biomarkers of iron and oxidant-antioxidant homeostasis was significantly increased in untransfused patients with ThI. These changes coincide with the severity of clinical phenotype, genotype and bone marrow erythroid activity evaluated by sTfR levels. PMID- 21705976 TI - Pathophysiology of beta thalassaemia. AB - In beta thalassemia, unbalanced alpha globin chain synthesis results in severely rheologically compromised erythrocytes with premature destruction in the peripheral circulation and ineffective erythropoiesis within the bone marrow and in extramedullary sites. In nontransfused beta thalassemia patients, erythropoiesis,anemia and hypoxia down-regulate hepcidin, the master regulator of iron homeostasis. Hepcidin deficiency in turn allows excessive duodenal iron absorption and development of systemic iron overload. In regularly transfused patients iron overload is mostly due to red cell breakdown. When the iron binding capacity of transferrin is saturated, iron can appear in the serum in a free form, called Non-Transferrin-Bound Iron, a powerful catalyst for the formation of free radicals, capable of causing oxidative stress and damage to mitochondria, lysosomes, lipid membranes, proteins, and DNA. Apart from the iron overload related complications, other pathological conditions such as bone disease, gallstones and thromboembolic events occur in a relevant proportion of subjects with thalassemia. PMID- 21705977 TI - The multifactorial origin of growth failure in thalassaemia. AB - Growth failure in thalassaemia major (TM) has been recognised for many years, and has persisted despite major therapeutic advances. The child with TM has a particular growth pattern, which is relatively normal until age 9-10 years; after this age a slowing down of growth velocity and reduced or absent pubertal growth spurt are observed. The pathogenesis of growth failure is multifactorial. The fundamental problem is the free iron and hemosiderosis-induced damage of the endocrine glands. Additional factors may contribute to the aetiology of growth delay including chronic anaemia and hypoxia, chronic liver disease, zinc and folic acid and nutritional deficiencies, intensive use of chelating agents, emotional factors, endocrinopathies (hypogonadism, delayed puberty, hypothyroidism, disturbed calcium homeostasis and bone disease) and last but not least dysregulation of the GH-IGF-1 axis.Three phases of growth disturbances according to age of presentation are well recognised, and have different aetiologies: in the first phase growth disturbance is mainly due to hypoxia, anaemia, ineffective erythropoiesis and nutritional factors. During late childhood (second phase), growth retardation is mainly due to iron overload affecting GH-IGF-1 axis and other potential endocrine complications. Although appropriate iron chelation therapy can improve growth and development, TM children and adolescents treated intensively with desferrioxamine remain short as well, showing body disproportion between the upper and lower body segment. After the age of 10-11 years (third phase), delayed or arrested puberty is an important contributing factor to growth failure in adolescent thalassaemics, who do not exhibit a normal growth spurt. During the last decades therapeutic progress and bone marrow transplantation resulted in a prolonged life expectancy in TM patients. Growth retardation, however, continues to be a significant challenge in these individuals, often affecting their social adjustment and quality of life. PMID- 21705978 TI - Age related IGF-I changes and IGF-I generation in thalassemia major. AB - We measured serum concentrations of insulin like growth factor-I (IGF-I) in 20 thalassemic males with short stature (height SDS <-2) and/or slow growth velocity (GV <-1 SD) throughout their childhood and adolescence, compared these data with normal reference data validated in our lab, and evaluated their growth hormone secretion in response to clonidine and glucagon stimulation. We also performed IGF-I generation test on 26 patients with beta thalassemia major (BTM) before and after blood transfusion to evaluate the effect of increased hemoglobin (Hb) on IGF-I and its response to GH. We obtained the following results. 1) No statistical difference in age, HSDS, target height SDS or bone age was observed between BTM patients with growth hormone deficiency (GHD) compared to those with normal GH secretion (GHS). 2) The age-related levels in serum total IGF-I in thalassemic males were significantly decreased from early childhood to 18 years of age compared to normal subjects. Thalassemic males with GHD did not show any significant peak of IGF-I levels until 18 years of age, whereas thalassemic males with normal GH response to provocation (GHS) achieved a significant peak level of IGF-I that was attenuated and late compared to normal males. The basal serum IGF I concentrations at different ages did not differ between the GHD and GHS groups until the age of 12 years. After 12 years of age, IGF-I levels were significantly higher in thalassemic children with GHS. A significant increase in the circulating basal IGF-I concentrations from 53 +/-35 ug/l to 82.6 +/- 39 ug/L was achieved with increasing Hb concentration after blood transfusion. The serum total IGF-I levels increased significantly with the administration of human growth hormone (hGH) for 4 days, both before and after blood transfusion. The peak IGF-I response to GH injections did not differ before compared to after blood transfusion. The percent increment of IGF-I levels generated after GH injections was higher in thalassemic children with GHD as compared to those with GHS both before and after blood transfusion. In conclusion, our results showed that agerelated serum IGF-I concentrations were significantly lower in short thalassemic patients, with and without GHD, during childhood and adolescence, compared to normal standards. Correction of anemia significantly increased serum concentration of IGF-I but does not affect the increase of IGF-I in response to GH stimulation. PMID- 21705979 TI - GH deficiency in adult B-thalassemia major patients and its relationship with IGF 1 production. AB - Endocrine complications in Beta-thalassemia represent a prominent cause of morbidity. Above all, dysfunction of GH-IGF-1 axis is of a major concern because of its pathogenic role on cardiac and bone disease, frequently described in this clinical setting. The aim of this paper is to analyze GH-IGF-1 axis in a cohort of 25 adult patients affected by Beta-thalassemia. We found that GH deficiency was present in only 8% of our patients if diagnosis was based on GH peak below 9MUg/L to two GH provocative tests instead of only one, and was mainly related to iron overload. On the contrary, IGF-1 production was impaired in a higher percentage of patients (72%), without significant correlation with iron burden. Of note, patients with hepatitis C virus infection showed lower IGF-1 concentrations than uninfected subjects despite a normal GH reserve, suggesting that partial GH insensitivity at the post-receptor level may play a key role in IGF-1 deficiency described in thalassemic patients. PMID- 21705980 TI - Growth hormone and adrenal response to intramuscular glucagon test and its relationship to IGF-1 production and left ventricular ejection fraction in adult B-thalassemia major patients. AB - In patients with b-thalassemia major (TM), the anterior pituitary gland is particularly sensitive to free radical stresses. It has been reported that the GH deficiency (GHD) may be secondary to either pituitary or hypothalamic dysfunction. The duration of the disease, the patient's age and the severity of iron overload are the most important factors responsible for the defect of growth hormone (GH) secretion. Recent reports have documented a frequency of severe growth hormone deficiency in 13%-32% of patients with b-thalassemia major. All of these patients underwent GH-releasing hormone (GH-RH) plus arginine (ARG) testing. We undertook the present study to evaluate the GH and adrenal response during glucagon stimulation test (GST) in patients with TM because the GH-RH plus ARG test in patients with hypothalamic GHD may be misleading. Thirty-three adult TM patients were recruited (mean age 36.6 years). Fifty four percent were included in the severe GHD group (GH peak below 3mg/l). The IGF-1 level in TM patients was consistently low (60.3 +/- 35.3 mg/l) and 86.6% of patients with a normal GH response to GST had a low IGF-1 level. These findings are also indicative of a relative resistance to GH. In eight out of 18 TM patients (44.4%), the GHD was associated with hypogonadotropic hypogonadism. A positive correlation was found between GH peak after GST and IGF-1 level (r = 0.8, p: 0.003) and a negative correlation between the age of female TM patients and GH peak (r = 0.711, p: 0.007). All patients but one had no evidence of cardiac iron overload (mean T2* 30.4 +/- 8.2 ms; range 14-44 ms). The mean LVEF (%) in TM patients was no different when compared to healthy controls. However, three patients with severe GHD and normal T2*were found to have reduced LVEF.One patient (4%) had a peak cortisol response to GST compatible to adrenal insufficiency. Nausea, headache and?or hypoglycemia occurred in 3 patients (12%) during GST. In conclusion, our study demonstrates that the presence of GHD is frequent in adult TM patients. According to the international guidelines for medical practice, we believe that before considering hormone replacement therapy, a second test to confirm the diagnosis of GHD and adrenal insufficiency is required. PMID- 21705981 TI - Adrenal function in thalassemia major adolescents. AB - BACKGROUND: Several studies reported a significant prevalence of adrenal insufficiency, ranging from 18-45%, in patients with thalassemia. Evidence for dissociation of cortisol and adrenal androgen secretion in patients with beta thalassemia was previously reported. AIM: We measured adrenal androgen response along with cortisol to the standard (250 mg) dose ACTH test. METHODS: Forty five beta-thalassemia major (TM) patients were enrolled. Their ages ranged between 12 and 20 years (14.9 +/- 2.2 years). All patients underwent the 250 mg cosyntropin test in the morning before blood transfusion. Blood samples for total cortisol, dehdroepiandrosterone (DHEA) and androstendione (A) measurements were collected before and 60 min after IV injection of 250 mg cosyntropin. Adrenal insufficiency was observed in 7 of 45 (15.5%) patients. Adrenal androgen levels decreased significantly with advancing Tanner stage. No difference was noted between patients with and without adrenal insufficiency regarding anthropometric and laboratory parameters. CONCLUSION: Adrenal insufficiency is not a rare complication in thalassemia. Adrenal androgen production declines with advancing puberty in thalassemic adolescents and might explain the poor development of pubic and axillary hair observed in this condition. PMID- 21705982 TI - Bone disease in thalassaemia major: recent advances in pathogenesis and clinical aspects. AB - Bone is a dynamic organ, constantly changing metabolically and being remodelled through the balanced activity of osteoclast and osteoblast on trabecular surfaces. Osteoporosis represents a continuum, in which multiple pathogenic mechanisms converge to cause loss of bone mass and deterioration of microarchitecture of skeletal structure. In thalassaemia major (TM), progressive 'aging' of bone starts in early childhood, through the gradual development of an imbalance between augmented osteoclastic resorption and insufficient osteoblastic bone formation. Chronic anemia, iron toxicity and endocrine complications, via a complex mechanism, lead to alterations in the RANK/RANKL/OPG system in favor of increased osteoclastic activity and enhanced osteoblastic dysfunction. Hypogonadotrophic hypogonadism and delayed puberty are the most common endocrine complications in patients with TM; they also contribute to osteopenia and osteoporosis, which is present in more than 50% of patients. There are gender differences not only in the prevalence but also in the severity of the osteoporosis syndrome. The anabolic effects of GH and IGF-1 on bone formation are important for the acquisition of bone mass, mainly during childhood and puberty. In TM, GH secretory dysfunction is common and contributes to osteopenia and osteoporosis, along with other endocrinopathies such as hypoparathyroidism and vitamin D deficiency, hypothyroidism and diabetes. Prevention is with no doubt the first step in the management of osteoporosis in TM, with the final goal of preventing bone loss and fractures. The management of patients with TM should start as early as birth in order to minimize the disease complications. Induction of puberty at a proper age with estrogens in girls and testosterone in boys and later treatment of hypogonadism with HRT are vital steps in the prevention of bone disease in TM. Biphosphonates, the well known medication for osteoporosis, have been tried in the treatment of TM-osteoporosis with promising outcomes. Since the origin of bone disease in TM is multifactorial and some of the underlying pathogenic mechanisms are still unclear, further research in this field is needed, which will allow the design of optimal therapeutic measures. PMID- 21705983 TI - beta-thalassemia and thyroid failure: is there a role for thyroid autoimmunity? AB - Autoimmunity is not believed to be involved in tissue damage of Beta-Thalassemia (Beta-Thal), although nonspecific triggering of autoimmunity by iron overload has been suggested. We recently re-evaluated thyroid function and autoimmunity in 132 Beta-Thal patients born and living in Sardinia Island, where a high prevalence of both Beta-Thal and autoimmune disease is well documented and in 1002 age and sex matched euthyroid individuals from the general population. The prevalence of primary hypothyroidism in Beta-Thal patients was 28.7% (38/132), without significant difference between males (M) and females (F). Hypothyroidism was associated with smaller and hypoechoic glands, while no difference in the prevalence of anti-thyroid antibodies (ATA) was found between Beta-Thal patients with or without thyroid failure. Interestingly, the prevalence of ATA in Beta Thal women (9.2%) was significantly lower than that found in age-matched euthyroid women (20.0%). Our study confirms that thyroid autoimmunity has no role in the pathogenesis of hypothyroidism in b-Thal. Moreover, the lower ATA prevalence in Beta-Thal women suggests that iron overload may inhibit rather then trigger thyroid autoimmunity. PMID- 21705984 TI - Abnormal seminal parameters in patients with thalassemia intermedia and low serum folate levels. AB - Seminal parameters were evaluated in 16 fully mature patients with thalassemia intermedia. Their ages ranged from 19 to 54 years (mean age 27 yrs) and serum ferritin levels varied from 205 to 3400 ng/ml. Eleven patients (68.7 %) had normal seminal parameters, 1 (1.6 %) had oligospermia, 3 (18.7 %) had asthenospermia and 1 (1.6 %) had oligoasthenospermia. A significant positive correlation was observed between the serum ferritin and ALT and serum ferritin and ?-GT (r: 0.636, p: 0.007; r: 0.497, p: 0.048, respectively), ALT and ?-GT (r: 0.749, p: 0.001) and total sperm concentration and serum folate (r: 0.572, p: 0.02). Despite some limitations, our study has useful clinical implications for the treatment of patients with thalassemia intermedia. PMID- 21705985 TI - Papillary thyroid cancer in thalassaemia. AB - Thyroid cancer is the most frequent endocrine neoplasm in the general population. Its incidence is 5-10/100,000 per year, with an annual death rate of 0.2 1.2/100,000 in men and 0.4-2.8/100,000 in women. In thalassaemia patients the frequency of this disease is unknown. In this paper we describe five cases of papillary thyroid cancer in thalassaemia patients followed at the Day Hospital for Thalassaemia and Haemoglobinopathies, in Ferrara, Italy. We consider the possible key role of iron as a carcinogenic agent and we also discuss the practical implications of our clinical observations. PMID- 21705986 TI - Acquired central hypothyroidism in a male thalassaemic patient with severe iron overload. AB - Acquired central hypothyroidism (CH) is a rare form of hypothyroidism that results from a variety of conditions affecting the hypothalamus and the pituitary gland. This pathology remains difficult to diagnose in patients with chronic disease. The Authors describe a 21-year-old patient with thalassaemia (TM) who was referred for the evaluation of short stature and hypogonadism, and was found to have CH.This case report stresses the importance of following thyroid function in TM patients and underlines the criteria for diagnosis and treatment. PMID- 21705987 TI - Adrenal incidentaloma in thalassemia: a case report and literature review. AB - In the last 30 years the development and widespread use of modern imaging techniques has caused a 20-time increase in the diagnosis of adrenal incidentaloma (AI). Among AIs myelolipoma (ML) is reported with a frequency up to 10%. In the literature 8 patients with adrenal masses in thalassaemia or chronic haemolytic anaemia have been reported: five cases were shown to have extramedullary haematopoiesis (EH) and 3 ML. We describe here a case of an adult male affected by beta thalassaemia intermedia and large bilateral lipomatous adrenal masses. The patient was referred to our ward at the age of 55 and underwent hormonal testing, MRI, and SPECT/CT scans. Adrenal masses were hormonally inactive, and fat-containing on MRI and CT scans. SPECT/CT examination with 99mTccolloid demonstrated the presence of marrow tissue. ML and EH are the only two tumours with marrow tissue among lipomatous adrenal masses. In our patient a brown nodular mass was resected and histologically classified as ML. In benign adrenal masses, radiological follow-up is indicated; in case of large bilateral masses adrenal function tests are suggested periodically in order to detect possible adrenal hypofunction. PMID- 21705988 TI - Diffuse intracerebral calcification in a beta-thalassaemia major patient with hypoparathyroidism: a case report. AB - Beta-thalassemia major is a complex medical problem found worldwide. Endocrinopathies are some of the most frequent dysfunctions found in these patients. Iron overload in different organs is responsible for multiple endocrine complications particularly in the absence of adequate chelation therapy. One of the most prevalent endocrine complications of thalassemia major is hypoparathyroidism. It can cause cerebral calcifications in the basal ganglia but seldom outside of the extrapyramidal system. There are few studies about intracerebral calcification due to hypoparathyroidism in patients with thalassemia major. We report the case of a 14 year-old girl who came to our Center with the chief complaint of a generalized tonic-clonic seizure. The patient was known to have beta-thalassemia major since she was 9 months old. Computerized tomographic scan of the brain was done which showed diffuse intracranial calcifications in deep white matter, posterior fossa, basal ganglia and both thalami. Laboratory and neuroimaging assessments revealed the diagnosis of hypoparathyroidism. We strongly recommend periodic assessment and tight control of serum calcium level in all patients with betathalassemia major. Prompt treatment with oral calcium supplements and an active form of vitamin D can prevent hypoparathyroidism and its neurologic complications. Comprehensive evaluation and treatment of other endocrinopathies in accordance with hypoparathyroidism is suggested. PMID- 21705989 TI - Generalized tonic-clonic seizures in a thalassemic patient with hypoparathyroidism and brain calcinosis. AB - Acquired hypoparathyroidism (HPT) is a not uncommon complication in patients with b-thalassemia major. The insufficient production of parathyroid hormone is mainly due to iron overload in parathyroid glands. We report a 22-year-old female thalassemic patient referred to our Unit for hypogonadism. During the previous two years she had presented with tonic-clonic seizures. After the second episode the patient was treated with phenytoin and valproate. Laboratory investigations were compatible with a diagnosis of HPT. A computed tomography scan of the head showed diffuse cerebral calcifications in the basal ganglia, frontal subcortical white matter, lentiform nucleus and cerebellum. After treatment with oral calcium supplementation and calcitriol she did not experience any further seizures. In addition, we present a brief review of the literature and report the Authors' recommendations. PMID- 21705990 TI - Case report: thalassemia intermedia patient with hypertension non-responsive to combined medical treatment. AB - Pheochromocytoma is a rare disease in the general population and, to the best of our knowledge, only one case has been reported so far in patients with hemoglobinopathies. We describe the occurrence of pheochromocytoma in a patient with thalassemia intermedia associated with Gilbert's disease and Crigler- Najjar Type 2 syndrome. PMID- 21705991 TI - Paraplegia in a thalassaemic patient with short stature. AB - Extramedullary hematopoiesis (EMH) is a normal compensatory reaction that occurs in almost all chronic hemolytic anemia, especially in transfusion independent thalassemia intermedia, and can involve many organs or tissues, including the epidural space leading to spinal cord compression syndrome. We present a case of EMH in a 29 year old woman with thalassemia major, regularly transfused since the time of diagnosis (age 21 months), who presented with sudden muscle weakness, difficulty walking and maintaining the upright position. Magnetic Resonance Imaging (MRI) of the thoracic spine showed spinal cord compression secondary to extramedullary hematopoiesis in the spinal canal, leading to early therapy. The neurosurgical treatment (decompressive laminectomy D3-D6) in our patient brought a significant and rapid recovery. The next two MRI of the spine (after 6 and 18 months) were both negative for recurrence. PMID- 21705992 TI - Absence of teratogenicity of deferasirox treatment during pregnancy in a thalassaemic patient. AB - A 34 year-old female thalassaemia major patient regularly followed in our Thalassaemia Centre was diagnosed at 16 years of age with primary amenorrhea. The endocrine investigations were compatible with hypogonadotropic hypogonadism. Puberty was induced with oral oestrogens and progesterone, followed by transdermal hormone replacement therapy. She had initiated regular blood transfusions at 8 months of age and iron chelation therapy with desferioxamine at the age of 2 years, and in 2006 she was switched to treatment with the oral iron chelator deferasirox (DFX). In November 2009, the patient reported a temporary interruption of transdermal hormone replacement therapy during the previous July and August, and complained of the absence of menstrual flow since then. We suspected a pregnancy that was confirmed by pelvic ultrasound (presence of a fetus of 20 weeks' gestational age) and positive plasma b-hCG levels (14000 mIU/ ml). DFX was immediately discontinued and the patient was managed jointly with an obstetrician expert in haemoglobin disorders. In March 2010 she delivered via caesarean section, at 38 weeks of gestation, a male neonate with a weight of 3.300 Kg with no complications or malformations. The main messages from this patient are that: (i) the hypogonadotropic hypogonadism, secondary to iron overload, may be reversible, (ii) transdermal hormone replacement therapy and regular iron chelation therapy may have had a synergistic action on the activation of hypothalamic-pituitary-gonadal axis, (iii) the deferasirox treatment during pregnancy may be harmless for the fetus at the usually recommended therapeutic doses, (iv) periodic patient education is needed in order to fully explain the aim and the effects of sex steroid hormone replacement therapy given transdermally. The Authors discuss the current knowledge on iron chelation therapy during pregnancy. PMID- 21705993 TI - Chemotherapy-induced cardiotoxicity: role of the conventional echocardiography and the tissue Doppler. AB - AIM: The cardiotoxicity of anticancer drugs is an emerging problem and only an identification of the early signs of cardiotoxicity by conventional echocardiography and not (tissue Doppler imaging, TDI), will limit and contain the long-term cardiotoxicity effects. The aim of this study was to identify, through conventional echocardiography and TDI, parameters to use as early "signs" of cardiotoxicity. METHODS: A prospective study was performed using patients with breast cancer (72 women, median age 57 +/- 12) treated with anticancer drugs (adjuvant chemotherapy). All patients underwent a careful cardiological evaluation before starting treatment (T0) and during follow-up at 3 months (T1), 6 months (T2) and 1 year (T3). Electrocardiography and echocardiography were performed in all patients in these times. Echocardiography evaluation considered the following parameters: systolic and diastolic diameters and volumes, LVEF, MAPSE, TAPSE, E/A TDI (Em, Am, Sm, IVCT, IVRT, ET, TEI index). On the basis of chemotherapy treatment, patients were divided into 5 groups: A=FEC (fluorouracil, epirubicin, cyclophosphamide), B=FEC+trastuzumab, C=trastuzumab, D=FEC+taxotere, E=FEC+taxolo+trastuzumab. RESULTS: A significant reduction in the echo parameters of TDI was observed. TDI appears to offer important advantages over traditional techniques in revealing the presence of early signs of cardiotoxicity. CONCLUSION: The TDI should be utilized to complement conventional echocardiography in the assessment of cardiotoxicity. PMID- 21705994 TI - Changing the coronary bifurcation angles after stenting procedures: the relevance to the technique and unfavorable outcome (Three-dimensional analysis). AB - AIM: Percutaneous transluminal balloon co-ronary angioplasty (PTCA) of coronary bifurcations is associated with a low success rate, higher rate of complications and need for revascularazation. We sought to analyze: 1) the change in 3D measurement of angles following stenting of coronary bifurcations; and 2) if changes in these angles might predict unfavourable outcomes. METHODS: Coronary angiograms of 102 patients with bifurcation lesions were analyzed with 3D software (CardiOp-B) before and after stenting. The change in angle between the proximal main artery and side branch (BA), and between the distal main artery and side branch (BS) were measured. A change of >= 5 degrees after stenting was considered significant. The results were compared with clinical follow-up. RESULTS: Bifurcation lesions included 66 left anterior descending/first diagonal (LAD/D1) lesions, 15 left main stem (LMS) lesions, 19 atrioventricular circumflex/obtuse marginal (AVCx/OM) lesions, and 2 coronary artery (RCA) crux lesions. BA and BS measured 138.3 degrees +/- 17.2 degrees and 64.3 degrees +/ 20.6 degrees respectively. Stent deployment altered BA and BS significantly in 80-90% of cases. Furthermore, BS correlated positively with the magnitude of change in BS after stenting. BA was unaffected by the complexity of the stenting procedure, whereas BS increased significantly in complex versus simple stenting strategies (P<0.05). Procedure related complications occurred in 15.6% of patients. The incidence of in-hospital complications was lower when BA was increased (P<0.05). The one year incidence of the composite of in-hospital complications and late complications was also significantly lower when BA was increased by >= 5 degrees (P=0.027). A decrease of BA was associated with 80% more complications compared to cases where BA was increased. No correlation was found between the change of BS and procedural or late complications. CONCLUSION: 3D measurements of coronary bifurcation angles prior to stenting can predict changes in bifurcation geometry after stenting. A decrease in BA after stenting is a strong predictor for less favourable outcomes of coronary bifurcation stenting procedures. PMID- 21705995 TI - Routine stress testing after percutaneous coronary interventions. AB - Percutaneous coronary intervention (PCI) is the most frequently performed cardiovascular procedure. Many physicians caring for post-PCI patients have routinely subjected patients to periodic stress testing. In the recent years, due to widespread use of drug eluting stents the combined rates of major adverse cardiac events (MACE) and in-stent restenosis (ISR) dropped <10% in the initial 12 months post-PCI, with only half of these patients bearing symptoms. This has translated into reduced pre-test probability of post-PCI ischemia. Consequently, the beneficial effect of this practice came into question. Moreover, in addition to its financial implications, routine post-PCI stress testing may carry potential harm: medication or exercise induced arrhythmia, infarction and/or death, patient irradiation exposure, false-positive tests resulting in excessive invasive testing or interventions, and the illusion of "wellness" in the face of a somewhat unpredictable disease. This review addresses the role stress testing post-PCI: it is concluded that routine stress testing in clinically stable asymptomatic post-PCI patients should be discouraged. Selective utilization of stress testing in patients with exceptionally high risk of ISR or MACE can be utilized to answer important clinical questions or guide and refine clinical care. PMID- 21705996 TI - Echocardiography: future developments. What is diastole and how to assess it? Impaired left ventricular systolic function. AB - Epidemiologic data show that diastolic heart failure is responsible for 38% to 54% of all heart failure cases. Left ventricular diastolic function can be characterized invasively in the catheter laboratory and non-invasively by echocardiography. Although echocardiography does not directly measure hemodynamic parameters, it is the most practical routine clinical approach for the evaluation of left ventricular diastolic function with given clinical and experimental evidence supporting its use as well as its safety, versatility, and portability. A set of echocardiographic paramters suitable for the description of diastolic function has been investigated or is still under investigation. Two guideline papers exist with regard to the assessment of diastolic function, diastolic dysfunction and diastolic heart failure. Mitral inflow pattern, isovolumetric relaxation time, flow propagation velocity, tissue Doppler imaging and pulmonary vein flow pattern are central parameters established for the assessment of diastolic function, estimation of left atrial pressure and left ventricular enddiastolic pressure. Furthermore, calculated parameters, e.g. like E/E', E/Vp, AR-A, for a more accurate determination of diastolic dysfunction have been evaluated. With respect to recent guidelines and recommendations, this review summarizes the physiology and pathophysiology of diastole, current echocardiographic methods and calculated echocardiographic parameters for the assessment of left ventricular diastolic function and dysfunction. In addition, an overview of the current state of research with regard to the echocardiographic assessment of left ventricular diastolic function will be given. PMID- 21705997 TI - Imaging and modern assessment of the right ventricle. AB - The right ventricular function is difficult to assess owing to its complex morphology, structure and function. The right ventricle (RV) comprises three compartments, the inlet, the apex, and the outlet contracting with a peristaltic motion from the inflow to the outflow chamber and is tightly linked to left ventricular (LV) function through the pulmonary circulation, the interventricular septum and the myocardium inside the pericardial envelop. The relation of RV function to symptom occurrence, exercise capacity and prognosis in a wide variety of cardiac diseases emphasizes the usefulness of its routine assessment. The evaluation of the RV is largely carried out by echocardiography in daily clinical practice despite important limitations inherent to two-dimensional imaging. Multiple views and numerous parameters allow clinicians to integrate the RV function in the clinical decision-making process. Recent modalities of echocardiography such as myocardial deformation and three-dimensional imaging or exercise echocardiography are promising tools for the assessment of the RV. Cardiac magnetic resonance imaging provides the unique opportunity to image the RV in motion and in three dimensions without the limitation of echogenicity. Therefore, cardiac magnetic resonance imaging is taking a growing place in the assessment of the RV in a wide variety of cardio-pulmonary diseases as pulmonary hypertension, ischemia, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, heart failure or congenital heart diseases. Integrating the complex interplay between both ventricles and the pulmonary circulation, this review will discuss the latest results of standard and novel techniques allowing the assessment of RV function by echocardiography and cardiac magnetic resonance imaging, and will provide to the clinicians, facing therapeutic challenges, a comprehensive overview of right heart function. PMID- 21705998 TI - Echocardiographic assessment of pressure volume relations in heart failure and valvular heart disease: using imaging to understand physiology. AB - Pressure volume (PV) based analysis, using classic hemodynamic principles, has served as a basis for our understanding of cardiac physiology and disease states for decades. However, PV analysis has been restricted to primarily the basic research setting and for preclinical testing and has not be widely applied in part because of the invasive nature of the procedure and the expertise required to obtain adequate data using the conductance catheter. Development of single beat methodologies that rely on echocardiographic measurements of ventricular volume and Doppler and peripheral estimates of ventricular pressure and timing of the cardiac cycle has enabled broader application of PV analysis. This review explores the physiologic background, basic methodology, and recent and potential future applications of noninvasive PV analysis. PMID- 21705999 TI - Optimal role of rest and stress echocardiography in cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) is an effective treatment for patients with advanced heart failure (HF), depressed left ventricular (LV) function and wide QRS complex. CRT improves symptoms, exercise capacity, LV function and reduces HF hospitalization and mortality rates. However, in parallel with the impressive results for CRT in several large trials, a consistent percentage of patients do not respond to CRT when the traditional patient selection criteria are applied. The prevalence of non-responders is about 30% when clinical end points are considered but it is much higher (>= 45%) if echocardiographic end points are used. Reduction of the number of non-responders is currently one of the main challenges in the field of CRT. Response to CRT has been related to the presence of cardiac dyssynchrony prior to implantation. LV dyssynchrony can be evaluated using different echocardiographic methods. When LV dyssynchrony is added to traditional patient selection criteria, the prevalence of non-responders decreases considerably. However, the value of LV dyssynchrony to predict response to CRT has shown some limitations and is possibly not sufficient. CRT response is clearly modulated by several factors. Regional and global myocardial viability are key pieces of the puzzle as well as the presence and severity of mitral regurgitation (MR). Echocardiography thus plays an important role in the care of HF patients treated with cardiac resynchronization therapy and is useful to assess acute and long-term beneficial effects of CRT. Numerous recent published reports have used echocardiographic techniques to potentially help patient selection for CRT prior to implantation and to optimize device settings afterwards. These topics are discussed in this review. PMID- 21706000 TI - Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. AB - Elucidating how and to what extent CpG islands (CGIs) are methylated in germ cells is essential to understand genomic imprinting and epigenetic reprogramming. Here we present, to our knowledge, the first integrated epigenomic analysis of mammalian oocytes, identifying over a thousand CGIs methylated in mature oocytes. We show that these CGIs depend on DNMT3A and DNMT3L but are not distinct at the sequence level, including in CpG periodicity. They are preferentially located within active transcription units and are relatively depleted in H3K4me3, supporting a general transcription-dependent mechanism of methylation. Very few methylated CGIs are fully protected from post-fertilization reprogramming but, notably, the majority show incomplete demethylation in embryonic day (E) 3.5 blastocysts. Our study shows that CGI methylation in gametes is not entirely related to genomic imprinting but is a strong factor in determining methylation status in preimplantation embryos, suggesting a need to reassess mechanisms of post-fertilization demethylation. PMID- 21706001 TI - Increased methylation variation in epigenetic domains across cancer types. AB - Tumor heterogeneity is a major barrier to effective cancer diagnosis and treatment. We recently identified cancer-specific differentially DNA-methylated regions (cDMRs) in colon cancer, which also distinguish normal tissue types from each other, suggesting that these cDMRs might be generalized across cancer types. Here we show stochastic methylation variation of the same cDMRs, distinguishing cancer from normal tissue, in colon, lung, breast, thyroid and Wilms' tumors, with intermediate variation in adenomas. Whole-genome bisulfite sequencing shows these variable cDMRs are related to loss of sharply delimited methylation boundaries at CpG islands. Furthermore, we find hypomethylation of discrete blocks encompassing half the genome, with extreme gene expression variability. Genes associated with the cDMRs and large blocks are involved in mitosis and matrix remodeling, respectively. We suggest a model for cancer involving loss of epigenetic stability of well-defined genomic domains that underlies increased methylation variability in cancer that may contribute to tumor heterogeneity. PMID- 21706002 TI - De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. AB - Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous. PMID- 21706004 TI - Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. AB - There is emerging evidence that people with successfully treated HIV infection age prematurely, leading to progressive multi-organ disease, but the reasons for this are not known. Here we show that patients treated with commonly used nucleoside analog anti-retroviral drugs progressively accumulate somatic mitochondrial DNA (mtDNA) mutations, mirroring those seen much later in life caused by normal aging. Ultra-deep re-sequencing by synthesis, combined with single-cell analyses, suggests that the increase in somatic mutation is not caused by increased mutagenesis but might instead be caused by accelerated mtDNA turnover. This leads to the clonal expansion of preexisting age-related somatic mtDNA mutations and a biochemical defect that can affect up to 10% of cells. These observations add weight to the role of somatic mtDNA mutations in the aging process and raise the specter of progressive iatrogenic mitochondrial genetic disease emerging over the next decade. PMID- 21706005 TI - Distinct microRNA signatures in human lymphocyte subsets and enforcement of the naive state in CD4+ T cells by the microRNA miR-125b. AB - MicroRNAs are small noncoding RNAs that regulate gene expression post transcriptionally. Here we applied microRNA profiling to 17 human lymphocyte subsets to identify microRNA signatures that were distinct among various subsets and different from those of mouse lymphocytes. One of the signature microRNAs of naive CD4+ T cells, miR-125b, regulated the expression of genes encoding molecules involved in T cell differentiation, including IFNG, IL2RB, IL10RA and PRDM1. The expression of synthetic miR-125b and lentiviral vectors encoding the precursor to miR-125b in naive lymphocytes inhibited differentiation to effector cells. Our data provide an 'atlas' of microRNA expression in human lymphocytes, define subset-specific signatures and their target genes and indicate that the naive state of T cells is enforced by microRNA. PMID- 21706006 TI - The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo. AB - The migration of neutrophils into inflamed tissues is a fundamental component of innate immunity. A decisive step in this process is the polarized migration of blood neutrophils through endothelial cells (ECs) lining the venular lumen (transendothelial migration (TEM)) in a luminal-to-abluminal direction. By real time confocal imaging, we found that neutrophils had disrupted polarized TEM ('hesitant' and 'reverse') in vivo. We noted these events in inflammation after ischemia-reperfusion injury, characterized by lower expression of junctional adhesion molecule C (JAM-C) at EC junctions, and they were enhanced by blockade or genetic deletion of JAM-C in ECs. Our results identify JAM-C as a key regulator of polarized neutrophil TEM in vivo and suggest that reverse TEM of neutrophils can contribute to the dissemination of systemic inflammation. PMID- 21706007 TI - The structural basis of modularity in ECF-type ABC transporters. AB - Energy coupling factor (ECF) transporters are used for the uptake of vitamins in Prokarya. They consist of an integral membrane protein that confers substrate specificity (the S-component) and an energizing module that is related to ATP binding cassette (ABC) transporters. S-components for different substrates often do not share detectable sequence similarity but interact with the same energizing module. Here we present the crystal structure of the thiamine-specific S component ThiT from Lactococcus lactis at 2.0 A. Extensive protein-substrate interactions explain its high binding affinity for thiamine (K(d) ~10(-10) M). ThiT has a fold similar to that of the riboflavin-specific S-component RibU, with which it shares only 14% sequence identity. Two alanines in a conserved motif (AxxxA) located on the membrane-embedded surface of the S-components mediate the interaction with the energizing module. Based on these findings, we propose a general transport mechanism for ECF transporters. PMID- 21706003 TI - Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. AB - Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ~2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 * 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 * 10(-11)) and one near SPRY2 (P = 3 * 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance. PMID- 21706008 TI - Chfr and RNF8 synergistically regulate ATM activation. AB - Protein ubiquitination is a crucial component of the DNA damage response. To study the mechanism of the DNA damage-induced ubiquitination pathway, we analyzed the impact of the loss of two E3 ubiquitin ligases, RNF8 and Chfr. Notably, DNA damage-induced activation of ATM kinase is suppressed in cells deficient in both RNF8 and Chfr (double-knockout, or DKO), and DKO mice develop thymic lymphomas that are nearly diploid but harbor clonal chromosome translocations. Moreover, DKO mice and cells are hypersensitive to ionizing radiation. We present evidence that RNF8 and Chfr synergistically regulate histone ubiquitination to control histone H4 Lys16 acetylation through MRG15-dependent acetyltransferase complexes. Through these complexes, RNF8 and Chfr affect chromatin relaxation and modulate ATM activation and DNA damage response pathways. Collectively, our findings demonstrate that two chromatin-remodeling factors, RNF8 and Chfr, function together to activate ATM and maintain genomic stability in vivo. PMID- 21706009 TI - Electrically tunable spin injector free from the impedance mismatch problem. AB - Injection of spin currents into solids is crucial for exploring spin physics and spintronics. There has been significant progress in recent years in spin injection into high-resistivity materials, for example, semiconductors and organic materials, which uses tunnel barriers to circumvent the impedance mismatch problem; the impedance mismatch between ferromagnetic metals and high resistivity materials drastically limits the spin-injection efficiency. However, because of this problem, there is no route for spin injection into these materials through low-resistivity interfaces, that is, Ohmic contacts, even though this promises an easy and versatile pathway for spin injection without the need for growing high-quality tunnel barriers. Here we show experimental evidence that spin pumping enables spin injection free from this condition; room temperature spin injection into GaAs from Ni(81)Fe(19) through an Ohmic contact is demonstrated through dynamical spin exchange. Furthermore, we demonstrate that this exchange can be controlled electrically by applying a bias voltage across a Ni(81)Fe(19)/GaAs interface, enabling electric tuning of the spin-pumping efficiency. PMID- 21706010 TI - Hybrid elastic solids. AB - Metamaterials can exhibit electromagnetic and elastic characteristics beyond those found in nature. In this work, we present a design of elastic metamaterial that exhibits multiple resonances in its building blocks. Band structure calculations show two negative dispersion bands, of which one supports only compressional waves and thereby blurs the distinction between a fluid and a solid over a finite frequency regime, whereas the other displays 'super anisotropy' in which compressional waves and shear waves can propagate only along different directions. Such unusual characteristics, well explained by the effective medium theory, have no comparable analogue in conventional solids and may lead to novel applications. PMID- 21706011 TI - In situ nanocompression testing of irradiated copper. AB - Increasing demand for energy and reduction of carbon dioxide emissions has revived interest in nuclear energy. Designing materials for radiation environments necessitates a fundamental understanding of how radiation-induced defects alter mechanical properties. Ion beams create radiation damage efficiently without material activation, but their limited penetration depth requires small-scale testing. However, strength measurements of nanoscale irradiated specimens have not been previously performed. Here we show that yield strengths approaching macroscopic values are measured from irradiated ~400 nm diameter copper specimens. Quantitative in situ nanocompression testing in a transmission electron microscope reveals that the strength of larger samples is controlled by dislocation-irradiation defect interactions, yielding size independent strengths. Below ~400 nm, size-dependent strength results from dislocation source limitation. This transition length-scale should be universal, but depends on material and irradiation conditions. We conclude that for irradiated copper, and presumably related materials, nanoscale in situ testing can determine bulk-like yield strengths and simultaneously identify deformation mechanisms. PMID- 21706012 TI - Short-term plasticity and long-term potentiation mimicked in single inorganic synapses. AB - Memory is believed to occur in the human brain as a result of two types of synaptic plasticity: short-term plasticity (STP) and long-term potentiation (LTP; refs 1-4). In neuromorphic engineering, emulation of known neural behaviour has proven to be difficult to implement in software because of the highly complex interconnected nature of thought processes. Here we report the discovery of a Ag(2)S inorganic synapse, which emulates the synaptic functions of both STP and LTP characteristics through the use of input pulse repetition time. The structure known as an atomic switch, operating at critical voltages, stores information as STP with a spontaneous decay of conductance level in response to intermittent input stimuli, whereas frequent stimulation results in a transition to LTP. The Ag(2)S inorganic synapse has interesting characteristics with analogies to an individual biological synapse, and achieves dynamic memorization in a single device without the need of external preprogramming. A psychological model related to the process of memorizing and forgetting is also demonstrated using the inorganic synapses. Our Ag(2)S element indicates a breakthrough in mimicking synaptic behaviour essential for the further creation of artificial neural systems that emulate characteristics of human memory. PMID- 21706013 TI - Large-scale automated synthesis of human functional neuroimaging data. AB - The rapid growth of the literature on neuroimaging in humans has led to major advances in our understanding of human brain function but has also made it increasingly difficult to aggregate and synthesize neuroimaging findings. Here we describe and validate an automated brain-mapping framework that uses text-mining, meta-analysis and machine-learning techniques to generate a large database of mappings between neural and cognitive states. We show that our approach can be used to automatically conduct large-scale, high-quality neuroimaging meta analyses, address long-standing inferential problems in the neuroimaging literature and support accurate 'decoding' of broad cognitive states from brain activity in both entire studies and individual human subjects. Collectively, our results have validated a powerful and generative framework for synthesizing human neuroimaging data on an unprecedented scale. PMID- 21706014 TI - A public genome-scale lentiviral expression library of human ORFs. AB - Functional characterization of the human genome requires tools for systematically modulating gene expression in both loss-of-function and gain-of-function experiments. We describe the production of a sequence-confirmed, clonal collection of over 16,100 human open-reading frames (ORFs) encoded in a versatile Gateway vector system. Using this ORFeome resource, we created a genome-scale expression collection in a lentiviral vector, thereby enabling both targeted experiments and high-throughput screens in diverse cell types. PMID- 21706015 TI - Direct measurement of DNA affinity landscapes on a high-throughput sequencing instrument. AB - Several methods for characterizing DNA-protein interactions are available, but none have demonstrated both high throughput and quantitative measurement of affinity. Here we describe 'high-throughput sequencing'-'fluorescent ligand interaction profiling' (HiTS-FLIP), a technique for measuring quantitative protein-DNA binding affinity at unprecedented depth. In this approach, the optics built into a high-throughput sequencer are used to visualize in vitro binding of a protein to sequenced DNA in a flow cell. Application of HiTS-FLIP to the protein Gcn4 (Gcn4p), the master regulator of the yeast amino acid starvation response, yielded ~440 million binding measurements, enabling determination of dissociation constants for all 12-mer sequences having submicromolar affinity. These data revealed a complex interdependency between motif positions, allowed improved discrimination of in vivo Gcn4p binding sites and regulatory targets relative to previous methods and showed that sets of genes with different promoter affinities to Gcn4p have distinct functions and expression kinetics. Broad application of this approach should increase understanding of the interactions that drive transcription. PMID- 21706016 TI - Selected reaction monitoring mass spectrometry reveals the dynamics of signaling through the GRB2 adaptor. AB - Signaling pathways are commonly organized through inducible protein-protein interactions, mediated by adaptor proteins that link activated receptors to cytoplasmic effectors. However, we have little quantitative data regarding the kinetics with which such networks assemble and dissolve to generate specific cellular responses. To address this deficiency, we designed a mass spectrometry method, affinity purification-selected reaction monitoring (AP-SRM), which we used to comprehensively and quantitatively investigate changes in protein interactions with GRB2, an adaptor protein that participates in a remarkably diverse set of protein complexes involved in multiple aspects of cellular function. Our data reliably define context-specific and time-dependent networks that form around GRB2 after stimulation, and reveal core and growth factor selective complexes comprising 90 proteins identified as interacting with GRB2 in HEK293T cells. Capturing a key hub protein and dissecting its interactions by SRM should be equally applicable to quantifying signaling dynamics for a range of hubs in protein interaction networks. PMID- 21706017 TI - Songbirds possess the spontaneous ability to discriminate syntactic rules. AB - Whether the computational systems in language perception involve specific abilities in humans is debated. The vocalizations of songbirds share many features with human speech, but whether songbirds possess a similar computational ability to process auditory information as humans is unknown. We analyzed their spontaneous discrimination of auditory stimuli and found that the Bengalese finch (Lonchura striata var. domestica) can use the syntactical information processing of syllables to discriminate songs). These finches were also able to acquire artificial grammatical rules from synthesized syllable strings and to discriminate novel auditory information according to them. We found that a specific brain region was involved in such discrimination and that this ability was acquired postnatally through the encounter with various conspecific songs. Our results indicate that passerine songbirds spontaneously acquire the ability to process hierarchical structures, an ability that was previously supposed to be specific to humans. PMID- 21706019 TI - Preventing interference between different memory tasks. AB - When learned in quick succession, declarative and motor skill tasks interfere with one another and subsequent recall is impaired. Depending on the order of the tasks, we were able to prevent memory interference in humans by applying transcranial magnetic stimulation to either the dorsolateral prefrontal or the primary motor cortex, and neither memory was impaired. Our observations suggest that distinct mechanisms support the communication between different types of memory processing. PMID- 21706018 TI - Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. AB - Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of brain injuries of the newborn that cause cerebral palsy and cognitive disabilities, as well as multiple sclerosis in adults. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults. Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting beta-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination. The small molecule inhibitor XAV939, which targets the enzymatic activity of tankyrase, acted to stabilize Axin2 levels in OLPs from brain and spinal cord and accelerated their differentiation and myelination after hypoxic and demyelinating injury. Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process. PMID- 21706020 TI - In vivo evidence that retinal bipolar cells generate spikes modulated by light. AB - Retinal bipolar cells have been assumed to generate purely graded responses to light. To test this idea we imaged the presynaptic calcium transient in live zebrafish. We found that ON, OFF, transient and sustained bipolar cells are all capable of generating fast 'all-or-none' calcium transients modulated by visual stimulation. PMID- 21706021 TI - Regulation of behavioral plasticity by systemic temperature signaling in Caenorhabditis elegans. AB - Animals cope with environmental changes by altering behavioral strategy. Environmental information is generally received by sensory neurons in the neural circuit that generates behavior. However, although environmental temperature inevitably influences an animal's entire body, the mechanism of systemic temperature perception remains largely unknown. We show here that systemic temperature signaling induces a change in a memory-based behavior in C. elegans. During behavioral conditioning, non-neuronal cells as well as neuronal cells respond to cultivation temperature through a heat-shock transcription factor that drives newly identified gene expression dynamics. This systemic temperature signaling regulates thermosensory neurons non-cell-autonomously through the estrogen signaling pathway, producing thermotactic behavior. We provide a link between systemic environmental recognition and behavioral plasticity in the nervous system. PMID- 21706022 TI - Rab35 GTPase and OCRL phosphatase remodel lipids and F-actin for successful cytokinesis. AB - Abscission is the least understood step of cytokinesis. It consists of the final cut of the intercellular bridge connecting the sister cells at the end of mitosis, and is thought to involve membrane trafficking as well as lipid and cytoskeleton remodelling. We previously identified the Rab35 GTPase as a regulator of a fast recycling endocytic pathway that is essential for post furrowing cytokinesis stages. Here, we report that the phosphatidylinositol-4,5 bisphosphate (PtdIns(4,5)P2) 5-phosphatase OCRL, which is mutated in Lowe syndrome patients, is an effector of the Rab35 GTPase in cytokinesis abscission. GTP-bound (active) Rab35 directly interacts with OCRL and controls its localization at the intercellular bridge. Depletion of Rab35 or OCRL inhibits cytokinesis abscission and is associated with local abnormal PtdIns(4,5)P2 and F actin accumulation in the intercellular bridge. These division defects are also found in cell lines derived from Lowe patients and can be corrected by the addition of low doses of F-actin depolymerization drugs. Our data demonstrate that PtdIns(4,5)P2 hydrolysis is important for normal cytokinesis abscission to locally remodel the F-actin cytoskeleton in the intercellular bridge. They also reveal an unexpected role for the phosphatase OCRL in cell division and shed new light on the pleiotropic phenotypes associated with Lowe disease. PMID- 21706023 TI - Variegated gene expression caused by cell-specific long-range DNA interactions. AB - Mammalian genomes contain numerous regulatory DNA sites with unknown target genes. We used mice with an extra beta-globin locus control region (LCR) to investigate how a regulator searches the genome for target genes. We find that the LCR samples a restricted nuclear subvolume, wherein it preferentially contacts genes controlled by shared transcription factors. No contacted gene is detectably upregulated except for endogenous beta-globin genes located on another chromosome. This demonstrates genetically that mammalian trans activation is possible, but suggests that it will be rare. Trans activation occurs not pan cellularly, but in 'jackpot' cells enriched for the interchromosomal interaction. Therefore, cell-specific long-range DNA contacts can cause variegated expression. PMID- 21706024 TI - Exchange-coupled magnetic nanoparticles for efficient heat induction. AB - The conversion of electromagnetic energy into heat by nanoparticles has the potential to be a powerful, non-invasive technique for biotechnology applications such as drug release, disease treatment and remote control of single cell functions, but poor conversion efficiencies have hindered practical applications so far. In this Letter, we demonstrate a significant increase in the efficiency of magnetic thermal induction by nanoparticles. We take advantage of the exchange coupling between a magnetically hard core and magnetically soft shell to tune the magnetic properties of the nanoparticle and maximize the specific loss power, which is a gauge of the conversion efficiency. The optimized core-shell magnetic nanoparticles have specific loss power values that are an order of magnitude larger than conventional iron-oxide nanoparticles. We also perform an antitumour study in mice, and find that the therapeutic efficacy of these nanoparticles is superior to that of a common anticancer drug. PMID- 21706025 TI - Detecting single viruses and nanoparticles using whispering gallery microlasers. AB - There is a strong demand for portable systems that can detect and characterize individual pathogens and other nanoscale objects without the use of labels, for applications in human health, homeland security, environmental monitoring and diagnostics. However, most nanoscale objects of interest have low polarizabilities due to their small size and low refractive index contrast with the surrounding medium. This leads to weak light-matter interactions, and thus makes the label-free detection of single nanoparticles very difficult. Micro- and nano-photonic devices have emerged as highly sensitive platforms for such applications, because the combination of high quality factor Q and small mode volume V leads to significantly enhanced light-matter interactions. For example, whispering gallery mode microresonators have been used to detect and characterize single influenza virions and polystyrene nanoparticles with a radius of 30 nm (ref. 12) by measuring in the transmission spectrum either the resonance shift or mode splitting induced by the nanoscale objects. Increasing Q leads to a narrower resonance linewidth, which makes it possible to resolve smaller changes in the transmission spectrum, and thus leads to improved performance. Here, we report a whispering gallery mode microlaser-based real-time and label-free detection method that can detect individual 15-nm-radius polystyrene nanoparticles, 10-nm gold nanoparticles and influenza A virions in air, and 30 nm polystyrene nanoparticles in water. Our approach relies on measuring changes in the beat note that is produced when an ultra-narrow emission line from a whispering gallery mode microlaser is split into two modes by a nanoscale object, and these two modes then interfere. The ultimate detection limit is set by the laser linewidth, which can be made much narrower than the resonance linewidth of any passive resonator. This means that microlaser sensors have the potential to detect objects that are too small to be detected by passive resonator sensors. PMID- 21706026 TI - Bi- and trilayer graphene solutions. AB - Bilayer and trilayer graphene with controlled stacking is emerging as one of the most promising candidates for post-silicon nanoelectronics. However, it is not yet possible to produce large quantities of bilayer or trilayer graphene with controlled stacking, as is required for many applications. Here, we demonstrate a solution-phase technique for the production of large-area, bilayer or trilayer graphene from graphite, with controlled stacking. The ionic compounds iodine chloride (ICl) or iodine bromide (IBr) intercalate the graphite starting material at every second or third layer, creating second- or third-stage controlled graphite intercolation compounds, respectively. The resulting solution dispersions are specifically enriched with bilayer or trilayer graphene, respectively. Because the process requires only mild sonication, it produces graphene flakes with areas as large as 50 um(2). Moreover, the electronic properties of the flakes are superior to those achieved with other solution-based methods; for example, unannealed samples have resistivities as low as ~1 kOmega and hole mobilities as high as ~400 cm(2) V(-1) s(-1). The solution-based process is expected to allow high-throughput production, functionalization, and the transfer of samples to arbitrary substrates. PMID- 21706027 TI - A pharmacological approach to first aid treatment for snakebite. AB - Snake venom toxins first transit the lymphatic system before entering the bloodstream. Ointment containing a nitric oxide donor, which impedes the intrinsic lymphatic pump, prolonged lymph transit time in rats and humans and also increased rat survival time after injection of venom. This pharmacological approach should give snakebite victims more time to obtain medical care and antivenom treatment. PMID- 21706028 TI - Low levels of SIV infection in sooty mangabey central memory CD4+ T cells are associated with limited CCR5 expression. AB - Naturally simian immunodeficiency virus (SIV)-infected sooty mangabeys do not progress to AIDS despite high-level virus replication. We previously showed that the fraction of CD4(+)CCR5(+) T cells is lower in sooty mangabeys compared to humans and macaques. Here we found that, after in vitro stimulation, sooty mangabey CD4(+) T cells fail to upregulate CCR5 and that this phenomenon is more pronounced in CD4(+) central memory T cells (T(CM) cells). CD4(+) T cell activation was similarly uncoupled from CCR5 expression in sooty mangabeys in vivo during acute SIV infection and the homeostatic proliferation that follows antibody-mediated CD4(+) T cell depletion. Sooty mangabey CD4(+) T(CM) cells that express low amounts of CCR5 showed reduced susceptibility to SIV infection both in vivo and in vitro when compared to CD4(+) T(CM) cells of rhesus macaques. These data suggest that low CCR5 expression on sooty mangabey CD4(+) T cells favors the preservation of CD4(+) T cell homeostasis and promotes an AIDS-free status by protecting CD4(+) T(CM) cells from direct virus infection. PMID- 21706029 TI - Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. AB - We report that breast cancer cells that infiltrate the lungs support their own metastasis-initiating ability by expressing tenascin C (TNC). We find that the expression of TNC, an extracellular matrix protein of stem cell niches, is associated with the aggressiveness of pulmonary metastasis. Cancer cell-derived TNC promotes the survival and outgrowth of pulmonary micrometastases. TNC enhances the expression of stem cell signaling components, musashi homolog 1 (MSI1) and leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). MSI1 is a positive regulator of NOTCH signaling, whereas LGR5 is a target gene of the WNT pathway. TNC modulation of stem cell signaling occurs without affecting the expression of transcriptional enforcers of the stem cell phenotype and pluripotency, namely nanog homeobox (NANOG), POU class 5 homeobox 1 (POU5F1), also known as OCT4, and SRY-box 2 (SOX2). TNC protects MSI1-dependent NOTCH signaling from inhibition by signal transducer and activator of transcription 5 (STAT5), and selectively enhances the expression of LGR5 as a WNT target gene. Cancer cell-derived TNC remains essential for metastasis outgrowth until the tumor stroma takes over as a source of TNC. These findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix component of the metastatic niche. PMID- 21706030 TI - Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. AB - Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. Cyclin-dependent kinase 1 (Cdk1) phosphorylates BRCA1, and this is essential for efficient formation of BRCA1 foci. Here we show that depletion or inhibition of Cdk1 compromises the ability of cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA-wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize nontransformed cells or tissues to inhibition of PARP. Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers. PMID- 21706031 TI - Functional mapping of single spines in cortical neurons in vivo. AB - The individual functional properties and spatial arrangement of afferent synaptic inputs on dendrites have a critical role in the processing of information by neurons in the mammalian brain. Although recent work has identified visually evoked local dendritic calcium signals in the rodent visual cortex, sensory evoked signalling on the level of dendritic spines, corresponding to individual afferent excitatory synapses, remains unexplored. Here we used a new variant of high-resolution two-photon imaging to detect sensory-evoked calcium transients in single dendritic spines of mouse cortical neurons in vivo. Calcium signals evoked by sound stimulation required the activation of NMDA (N-methyl-D-aspartate) receptors. Active spines are widely distributed on basal and apical dendrites and pure-tone stimulation at different frequencies revealed both narrowly and widely tuned spines. Notably, spines tuned for different frequencies were highly interspersed on the same dendrites: even neighbouring spines were mostly tuned to different frequencies. Thus, our results demonstrate that NMDA-receptor-dependent single-spine synaptic inputs to the same dendrite are highly heterogeneous. Furthermore, our study opens the way for in vivo mapping of functionally defined afferent sensory inputs with single-synapse resolution. PMID- 21706032 TI - In vivo genome editing restores haemostasis in a mouse model of haemophilia. AB - Editing of the human genome to correct disease-causing mutations is a promising approach for the treatment of genetic disorders. Genome editing improves on simple gene-replacement strategies by effecting in situ correction of a mutant gene, thus restoring normal gene function under the control of endogenous regulatory elements and reducing risks associated with random insertion into the genome. Gene-specific targeting has historically been limited to mouse embryonic stem cells. The development of zinc finger nucleases (ZFNs) has permitted efficient genome editing in transformed and primary cells that were previously thought to be intractable to such genetic manipulation. In vitro, ZFNs have been shown to promote efficient genome editing via homology-directed repair by inducing a site-specific double-strand break (DSB) at a target locus, but it is unclear whether ZFNs can induce DSBs and stimulate genome editing at a clinically meaningful level in vivo. Here we show that ZFNs are able to induce DSBs efficiently when delivered directly to mouse liver and that, when co-delivered with an appropriately designed gene-targeting vector, they can stimulate gene replacement through both homology-directed and homology-independent targeted gene insertion at the ZFN-specified locus. The level of gene targeting achieved was sufficient to correct the prolonged clotting times in a mouse model of haemophilia B, and remained persistent after induced liver regeneration. Thus, ZFN-driven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease. PMID- 21706034 TI - An iron-dependent and transferrin-mediated cellular uptake pathway for plutonium. AB - Plutonium is a toxic synthetic element with no natural biological function, but it is strongly retained by humans when ingested. Using small-angle X-ray scattering, receptor binding assays and synchrotron X-ray fluorescence microscopy, we find that rat adrenal gland (PC12) cells can acquire plutonium in vitro through the major iron acquisition pathway--receptor-mediated endocytosis of the iron transport protein serum transferrin; however, only one form of the plutonium-transferrin complex is active. Low-resolution solution models of plutonium-loaded transferrins derived from small-angle scattering show that only transferrin with plutonium bound in the protein's C-terminal lobe (C-lobe) and iron bound in the N-terminal lobe (N-lobe) (Pu(C)Fe(N)Tf) adopts the proper conformation for recognition by the transferrin receptor protein. Although the metal-binding site in each lobe contains the same donors in the same configuration and both lobes are similar, the differences between transferrin's two lobes act to restrict, but not eliminate, cellular Pu uptake. PMID- 21706033 TI - Discovery of selective bioactive small molecules by targeting an RNA dynamic ensemble. AB - Current approaches used to identify protein-binding small molecules are not suited for identifying small molecules that can bind emerging RNA drug targets. By docking small molecules onto an RNA dynamic ensemble constructed by combining NMR spectroscopy and computational molecular dynamics, we virtually screened small molecules that target the entire structure landscape of the transactivation response element (TAR) from HIV type 1 (HIV-1). We quantitatively predict binding energies for small molecules that bind different RNA conformations and report the de novo discovery of six compounds that bind TAR with high affinity and inhibit its interaction with a Tat peptide in vitro (K(i) values of 710 nM-169 MUM). One compound binds HIV-1 TAR with marked selectivity and inhibits Tat-mediated activation of the HIV-1 long terminal repeat by 81% in T-cell lines and HIV replication in an HIV-1 indicator cell line (IC(50) ~23.1 MUM). PMID- 21706036 TI - Intervening during infancy to prevent pediatric obesity. PMID- 21706037 TI - Bypass of metabolic diseases with surgery. PMID- 21706038 TI - Younger patients have poorer biochemical outcome after radical prostatectomy in high-risk prostate cancer. AB - The aim of this study was to investigate the prognostic significance of patient age with respect to tumour aggressiveness in men who underwent radical prostatectomy (RP) for prostate cancer. In this study, we reviewed the records of 743 patients who received RP without neoadjuvant or adjuvant therapy at our institution and were followed up for >2 years postoperatively. For our analyses, the patients were divided into two groups according to age: younger (<60 years) and older (>=60 years). Through uni- and multivariate analyses, associations of various clinicopathological parameters, including biochemical recurrence-free survival, with patient age, were evaluated among all patients, and the patients were stratified according to their D'Amico risk classification. Among all subjects, younger (n=126) and older (n=617) patients showed no significant differences regarding pathological parameters and biochemical recurrence-free survival (P=0.288). For the high-risk group (n=206), younger patients had a lower rate of biochemical recurrence-free survival following surgery than older patients (P=0.017), despite the fact that no significant differences were observed regarding various known prognostic parameters between the two age groups. In addition, multivariate analysis revealed that age was an independent predictor of biochemical recurrence-free survival among the high-risk group (P=0.003). Our results showed that relatively younger patients have a comparable biochemical outcome compared with their older counterparts following RP performed for prostate cancer. However, among patients with high-risk disease, younger patients have a worse biochemical outcome following RP compared with older patients. PMID- 21706040 TI - Preliminary study of letrozole use for improving spermatogenesis in non obstructive azoospermia patients with normal serum FSH. AB - We investigated whether letrozole (2.5 mg day(-1)) improves sperm count in non obstructive azoospermia (NOA) patients. Four men were included in this study, and they had folliculo-stimulating hormone and other hormone levels within the normal range and no varicoceles or chromosomal aberrations. These four patients were administered letrozole for 3 months. Sperm count, testicular volume, gonadotropin, testosterone (T) and estradiol (E2) blood levels were assessed before, during and 1 week after the suspension of treatment. All patients showed spermatozoa in their ejaculate, increased gonadotropin and T levels and lower E2 levels (P<0.05 in all cases), when letrozole was administered. This suggests that letrozole treatment might improve sperm count in an NOA sub-population; however, more studies, including the proper controls, are needed to confirm its efficacy. PMID- 21706039 TI - The effect of environmental contaminants on testicular function. AB - Male reproductive health has deteriorated considerably in the last few decades. Nutritional, socioeconomic, lifestyle and environmental factors (among others) have been attributed to compromising male reproductive health. In recent years, a large volume of evidence has accumulated that suggests that the trend of decreasing male fertility (in terms of sperm count, quality and other changes in male reproductive health) might be due to exposure to environmental toxicants. These environmental contaminants can mimic natural oestrogens and target testicular spermatogenesis, steroidogenesis, and the function of both Sertoli and Leydig cells. Most environmental toxicants have been shown to induce reactive oxygen species, thereby causing a state of oxidative stress in various compartments of the testes. However, the molecular mechanism(s) of action of the environmental toxicants on the testis have yet to be elucidated. This review discusses the effects of some of the more commonly used environmental contaminants on testicular function through the induction of oxidative stress and apoptosis. PMID- 21706041 TI - Interleukin-17A is involved in development of spontaneous pulmonary emphysema caused by Toll-like receptor 4 mutation. AB - AIM: To explore the pathogenic role of Th17 cells and interleukin-17A (IL-17A) associated signaling pathways in spontaneous pulmonary emphysema induced by a Toll-like receptor 4 mutant (TLR4(mut)). METHODS: Lungs were obtained from wild type (WT) or TLR4mut mice that were treated with or without recombinant mouse IL 17A (1 MUg.kg(-1).d(-1), ip) from the age of 3 weeks to 3 months. Pulmonary emphysema was determined using histology, immunochemistry, and biochemical analysis. T cell polarization was determined with flow cytometry, the levels of cytokines were measured using ELISA, and the levels of IL-17A-associated signaling molecules were detected using Western blot. RESULTS: Compared to WT mice, 3 month-old TLR4(mut) mice were characterized by significantly reduced infiltration of Th17 cells into lungs (2.49%+/-1.13 % nus 5.26%+/-1.39%), and significantly reduced expression levels of IL-17A (3.66+/-0.99 pg/MUg nus 10.67+/ 1.65 pg/MUg), IL-23 (12.43+/-1.28 pg/MUg nus 28.71+/-2.57 pg/MUg) and IL-6 (51.82+/-5.45 pg/MUg nus 92.73+/-10.91 pg/MUg) in bronchoalveolar lavage fluid. In addition, p38 MAPK phosphorylation and AP-1 expression were decreased to 27%+/ 9% and 51%+/-8%, respectively, of that in WT mice. Treatment of TLR4(mut) mice with IL-17A increased the infiltration of Th17 cells into lungs and expression levels of IL-17A, IL-6, and IL-23 in bronchoalveolar lavage fluid, attenuated MDA and apoptosis, and improved emphysema accompanied with increased phosphorylation of p38 MAPK and expression of AP-1. CONCLUSION: Th17 cells, in particular the cytokine IL-17A, play a crucial role in the pathogenesis of TLR4(mut)-induced spontaneous pulmonary emphysema. Both of them are potential targets for therapeutic strategies for pulmonary emphysema. PMID- 21706042 TI - Tyrosine sulfation in N-terminal domain of human C5a receptor is necessary for binding of chemotaxis inhibitory protein of Staphylococcus aureus. AB - AIM: Staphylococcus aureus evades host defense through releasing several virulence proteins, such as chemotaxis inhibitory protein of staphylococcus aureus (CHIPS). It has been shown that extracellular N terminus of C5a receptor (C5aR) forms the binding domain for CHIPS, and tyrosine sulfation is emerging as a key factor in determining protein-protein interaction. The aim of this study was to evaluate the role of tyrosine sulfation of N-terminal of C5aR in its binding with CHIPS. METHODS: Expression plasmids encoding C5aR and its mutants were prepared using PCR and site-directed mutagenesis and were used to transfect HEK 293T cells using calcium phosphate. Recombinant CHIPS protein was purified. Western blotting was used to examine the binding efficiency of CHIPS to C5aR or its mutants. RESULTS: CHIPS exclusively binds to C5aR, but not to C5L2 or C3aR. A nonspecific sulfation inhibitor, sodium chlorate (50 nmol/L), diminishes the binding ability of C5aR with CHIPS. Blocking sulfation by mutation of tyrosine to phenylalanine at positions 11 and 14 of C5aR N terminus, which blocked sulfation, completely abrogates CHIPS binding. When tyrosine 14 alone was mutated to phenylalanine, the binding efficiency of recombinant CHIPS was substantially decreased. CONCLUSION: The results demonstrate a structural basis of C5aR-CHIPS association, in which tyrosine sulfation of N-terminal C5aR plays an important role. Our data may have potential significance in development of novel drugs for therapeutic intervention. PMID- 21706043 TI - Polymorphisms of VEGFA gene and susceptibility to hemorrhage risk of brain arteriovenous malformations in a Chinese population. AB - AIM: To evaluate the influence of the vascular endothelial growth factor A (VEGFA) polymorphisms on risk of presentation with intracerebral hemorrhage (ICH). METHODS: Nine selected VEGFA single-nucleotide polymorphisms (SNPs) were genotyped in 311 patients with brain arteriovenous malformations (BAVM) in a Chinese population. Associations between individual SNPs/haplotypes and the hemorrhage risk of BAVMs were evaluated using logistic regression analysis. RESULTS: In the single-locus analysis, rs1547651 was associated with increased risk of ICH (adjusted OR=2.11, 95% CI=1.01-4.42 compared with the AA genotype). In particular, an increased risk for ICH was associated with this variant in female patients (adjusted OR=3.21, and 95% CI=0.99-10.36). Haplotype-based analyses revealed that haplotype 'GC' in block 1 and haplotype 'ACC' in block 2 were associated with a 30%-38% reduction in the risk of ICH in patients with BAVMs compared to the most common haplotype (P(sim)=0.033 and P(sim)=0.005, respectively). The protective effect of haplotype 'ACC' in block 2 was more evident in male patients and subjects with BAVMs of a size >=3 cm (adjusted OR=0.57, 95% CI=0.34-0.97 and adjusted OR=0.57, 95% CI=0.31-0.86, respectively). CONCLUSION: The results suggest that VEGFA gene variants may contribute to ICH risk of BAVM. PMID- 21706044 TI - HMBOX1 negatively regulates NK cell functions by suppressing the NKG2D/DAP10 signaling pathway. AB - HMBOX1 is a new member of the homeobox family. Homeobox members have been reported to participate in embryonic development and systemic metabolism, but the function of HMBOX1 remains unclear, especially in the hematopoietic system. Here, we show that HMBOX1 is expressed at a high level in primary human NK cells but is expressed at much lower levels in NK cell lines. Overexpression of HMBOX1 significantly inhibited NK cell activities, including natural cytotoxicity against tumor cells, the level of CD107a (a marker protein for degranulation) and the production of cytolytic proteins (perforin and granzymes). More interestingly, HMBOX1 negatively regulated the expression of NKG2D and the activation of the NKG2D/DAP10 signaling pathway in NK cells. This effect was reversed by knocking down HMBOX1. Taken together, these findings demonstrate that HMBOX1 may act as a negative regulator of NK cell functions via suppressing the NKG2D/DAP10 signaling pathway. PMID- 21706045 TI - Methylation-mediated repression of microRNA-143 enhances MLL-AF4 oncogene expression. AB - Fusion proteins containing the amino terminus of mixed lineage leukemia (MLL) are common in acute lymphoblastic leukemia (ALL) due to translocations. The MLL-AF4 fusion protein is generated by the translocation t(4;11)(q21;q23), and t(4;11) positive ALL patients (MLL-AF4 ALL), have a notoriously poorer prognosis compared with patients with other MLL-associated leukemias. The detailed role of this fusion protein in leukemogenesis is not well understood. MicroRNAs (miRNAs) targeting the AF4 3' untranslated regions may modulate MLL-AF4 fusion protein levels, raising the question of whether regulation of these miRNAs are involved in the progression of MLL-AF4 ALL. In this study, we show that miR-143 was identified as a regulator of MLL-AF4 expression in MLL-AF4 ALL samples. Restoration of miR-143 in MLL-AF4-positive RS4;11 and MV4-11 cells induced apoptosis, negatively contributing to leukemia cell growth by reducing MLL-AF4 fusion protein levels. Furthermore, miR-143 was epigenetically repressed by promoter hypermethylation in MLL-AF4-positive primary blasts and cell lines, but not in normal bone marrow cells and MLL-AF4-negative primary blasts, which was directly associated with expression of the MLL-AF4 oncogene. This is the first study to show that miR-143 functions as a tumor suppressor in MLL-AF4 B-cell ALL. These data reveal the therapeutic promise of upregulating miR-143 expression for MLL-AF4 B-cell ALL. PMID- 21706046 TI - MMP-9 from sublethally irradiated tumor promotes Lewis lung carcinoma cell invasiveness and pulmonary metastasis. AB - Matrix metalloproteinases (MMPs) associate with tumor progression and metastasis. We sought to investigate the role of MMP-9 from sublethally irradiated tumor in accelerated pulmonary metastasis of Lewis lung carcinoma (LLC-LM) and the corresponding anti-metastasis strategies in C57BL/6 mice. We used Matrigel-coated Boyden chamber assays and chicken chorioallantoic membrane assays to evaluate the invasion capability of irradiated LLC-LM cells (7.5 Gy), reverse transcription polymerase chain reaction and the western blot assay to investigate the expression of MMPs by irradiated cells, and small interfering RNA duplexes to inhibit MMP-9 expression. LLC-LM cells differing in MMP-2 or -9 expression were subcutaneously injected into right thighs and the resulting tumors were irradiated (10 Gy * 5) to induce pulmonary metastasis. Radiation significantly enhanced MMP-9 at both the transcriptional and translational levels. MMP-9 siRNA significantly inhibited in vitro radiation-enhanced invasiveness. The number of radiation-accelerated pulmonary metastases was significantly reduced by MMP-9 knockdown and MMP-2/9 knockdown. Reverse transcription-polymerase chain reaction of LLC-LM cells in the blood and lung tissue revealed MMP-9 involvement in radiation-enhanced intravasation. Either higher-dose irradiation (30 Gy * 2) or pretreatment with prototypical MMP-9 inhibitor, zoledronic acid, significantly reduced the number of pulmonary metastases. The viability of irradiated tumor was seen on both positron emission tomography and magnetic resonance imaging, and tumor/serum MMP-9 levels suggested the association of local control of primary tumor and inhibition of time-dependent MMP-9 activities. Our results demonstrate that MMP-9 is crucially involved in radiation-enhanced LLC-LM cell invasiveness in vitro and in pulmonary metastasis from inadequately irradiated primary tumor in vivo. PMID- 21706048 TI - MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis. AB - As invading breast carcinoma cells breach their underlying basement membrane, they become confronted with a dense three-dimensional reactive stroma dominated by type I collagen. To develop metastatic capabilities, invading tumor cells must acquire the capacity to negotiate this novel microenvironment. Collagen influences the fate of epithelial cells by inducing apoptosis. However, the mechanisms used by invading tumor cells to evade collagen-induced apoptosis remain to be defined. We demonstrate that membrane type-1 matrix metalloproteinase (MT1-MMP/MMP-14) confers breast cancer cells with the ability to escape apoptosis when embedded in a collagen gel and after orthotopic implantation in vivo. In the absence of MMP-14-dependent proteolysis, type I collagen triggers apoptosis by inducing the expression of the pro-apoptotic Bcl-2 interacting killer in luminal-like breast cancer cells. These findings reveal a new mechanism whereby MMP-14 activity promotes tumor progression by circumventing apoptosis. PMID- 21706047 TI - Eya2 is required to mediate the pro-metastatic functions of Six1 via the induction of TGF-beta signaling, epithelial-mesenchymal transition, and cancer stem cell properties. AB - Six1 is a critical regulator of embryonic development that requires interaction with the Eya family of proteins (Eya1-4) to activate the transcription of genes involved in neurogenesis, myogenesis and nephrogenesis. Although expression of Six1 and Eya family members is predominantly observed in development, their overexpression is observed in numerous cancers. Importantly, both Six1 and Eya have independently been shown to mediate breast cancer metastasis, but whether they functionally interact during tumor progression has not been explored. Herein, we demonstrate that knockdown of Eya2 in MCF7 mammary carcinoma cells reverses the ability of Six1 to induce transforming growth factor-beta signaling, as well as to induce characteristics associated with epithelial-mesenchymal transition and cancer stem cells, suggesting that Six1 is dependent on Eya2 to mediate numerous pro-metastatic characteristics. The importance of the Six1-Eya interaction in human breast cancer is underscored by the finding that high levels of Six1 correlate with shortened time to relapse and metastasis as well as decreased survival only when co-expressed with high levels of Eya2. Overall, these data implicate Eya2 as a necessary co-factor for many of the metastasis promoting functions of Six1, suggesting that targeting the Six1-Eya interaction may inhibit breast cancer progression. As Six1 and Eya2 are not highly expressed in most adult tissues, the Six1-Eya interaction may be a valuable future therapeutic target whose inhibition would be expected to impair breast cancer progression while conferring limited side effects. PMID- 21706049 TI - Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion. AB - LKB1 is a tumor susceptibility gene for the Peutz-Jeghers cancer syndrome and is a target for mutational inactivation in sporadic human malignancies. LKB1 encodes a serine/threonine kinase that has critical roles in cell growth, polarity and metabolism. A novel and important function of LKB1 is its ability to regulate the phosphorylation of CREB-regulated transcription co-activators (CRTCs) whose aberrant activation is linked with oncogenic activities. However, the roles and mechanisms of LKB1 and CRTC in the pathogenesis of esophageal cancer have not been previously investigated. In this study, we observed altered LKB1-CRTC signaling in a subset of human esophageal cancer cell lines and patient samples. LKB1 negatively regulates esophageal cancer cell migration and invasion in vitro. Mechanistically, we determined that CRTC signaling becomes activated because of LKB1 loss, which results in the transcriptional activation of specific downstream targets including LYPD3, a critical mediator for LKB1 loss-of-function. Our data indicate that de-regulated LKB1-CRTC signaling might represent a crucial mechanism for esophageal cancer progression. PMID- 21706050 TI - miR-130a targets MET and induces TRAIL-sensitivity in NSCLC by downregulating miR 221 and 222. AB - Non-small cell lung cancer (NSCLC) accounts for ~80% of all lung cancers. Although some advances in lung cancer therapy have been made, patient survival is still quite poor. Two microRNAs, miR-221 and miR-222, upregulated by the MET proto-oncogene, have been already described to enhance cell survival and to induce TNF-related apoptosis-inducing ligand (TRAIL) resistance in NSCLC cell lines, through the downregulation of p27(kip1), PTEN and TIMP3. Here, we further investigated this pathway and showed that miR-130a, expressed at low level in lung cancer cell lines, by targeting MET was able to reduce TRAIL resistance in NSCLC cells through the c-Jun-mediated downregulation of miR-221 and miR-222. Moreover, we found that miR-130a reduced migratory capacity of NSCLC. A better understanding of MET-miR-221 and 222 axis regulation in drug resistance is the key in developing new strategies in NSCLC therapy. PMID- 21706051 TI - RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor alpha. AB - Transcription factor RUNX3 is inactivated in a number of malignancies, including breast cancer, and is suggested to function as a tumor suppressor. How RUNX3 functions as a tumor suppressor in breast cancer remains undefined. Here, we show that about 20% of female Runx3(+/-) mice spontaneously developed ductal carcinoma at an average age of 14.5 months. Additionally, RUNX3 inhibits the estrogen dependent proliferation and transformation potential of ERalpha-positive MCF-7 breast cancer cells in liquid culture and in soft agar and suppresses the tumorigenicity of MCF-7 cells in severe combined immunodeficiency mice. Furthermore, RUNX3 inhibits ERalpha-dependent transactivation by reducing the stability of ERalpha. Consistent with its ability to regulate the levels of ERalpha, expression of RUNX3 inversely correlates with the expression of ERalpha in breast cancer cell lines, human breast cancer tissues and Runx3(+/-) mouse mammary tumors. By destabilizing ERalpha, RUNX3 acts as a novel tumor suppressor in breast cancer. PMID- 21706053 TI - Semaphorin 5A and plexin-B3 regulate human glioma cell motility and morphology through Rac1 and the actin cytoskeleton. AB - Semaphorins are implicated in glioma progression, although little is known about the underlying mechanisms. We have reported plexin-B3 expression in human gliomas, which upon stimulation by Sema5A causes significant inhibition of cell migration and invasion. The concomitant inactivation of Rac1 is of mechanistic importance because forced expression of constitutively active Rac1 abolishes these inhibitory effects. Furthermore, Sema5A induces prominent cell collapse and ramification of processes reminiscent of astrocytic morphology, which temporally associate with extensive disassembly of actin stress fibers and disruption of focal adhesions, followed by accumulation of actin patches in protrusions. Mechanistically, Sema5A induces transient protein kinase C (PKC) phosphorylation of fascin-1, which can reduce its actin-binding/bundling activities and temporally parallels its translocation from cell body to extending processes. PKC inhibition or fascin-1 knockdown is sufficient to abrogate Sema5A-induced morphological differentiation, whereas the process is hastened by forced expression of fascin-1. Intriguingly, Sema5A induces re-expression of glial fibrillary acidic protein (GFAP), which when silenced restricts differentiation of glioma cells to bipolar instead of multipolar morphology. Therefore, we hypothesize complementary functions of fascin-1 and GFAP in the early and late phases of Sema5A-induced astrocytic differentiation of gliomas, respectively. In summary, Sema5A and plexin-B3 impede motility but promote differentiation of human gliomas. These effects are plausibly compromised in high-grade human astrocytomas in which Sema5A expression is markedly reduced, hence leading to infiltrative and anaplastic characteristics. This is evident by increased invasiveness of glioma cells when endogenous Sema5A is silenced. Therefore, Sema5A and plexin-B3 represent potential novel targets in counteracting glioma progression. PMID- 21706052 TI - NF-kappaB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699. AB - The stress-inducible transcription factor, nuclear factor (NF)-kappaB induces genes involved in proliferation and apoptosis. Aberrant NF-kappaB activity is common in cancer and contributes to therapeutic-resistance. Poly(ADP-ribose) polymerase-1 (PARP-1) is activated during DNA strand break repair and is a known transcriptional co-regulator. Here, we investigated the role of PARP-1 function during NF-kappaB activation using p65 small interfering RNA (siRNA), PARP siRNA or the potent PARP-1 inhibitor, AG-014699. Survival and apoptosis assays showed that NF-kappaB p65(-/-) cells were more sensitive to ionizing radiation (IR) than p65(+/+) cells. Co-incubation with p65 siRNA, PARP siRNA or AG-014699 radio sensitized p65(+/+), but not p65(-/-) cells, demonstrating that PARP-1 mediates its effects on survival via NF-kappaB. Single-strand break (SSB) repair kinetics, and the effect SSB repair inhibition by AG-014699 were similar in p65(+/+) and p65(-/-) cells. As preventing SSB repair did not radio-sensitize p65(-/-) cells, we conclude that radio-sensitization by AG-014699 is due to downstream inhibition of NF-kappaB activation, and independent of SSB repair inhibition. PARP-1 catalytic activity was essential for IR-induced p65 DNA binding and NF-kappaB dependent gene transcription, whereas for tumor necrosis factor (TNF)-alpha treated cells, PARP-1 protein alone was sufficient. We hypothesize that this stimulus-dependent differential is mediated via stimulation of the poly(ADP ribose) polymer, which was induced following IR, not TNF-alpha. Targeting DNA damage-activated NF-kappaB using AG-014699 may therefore overcome toxicity observed with classical NF-kappaB inhibitors without compromising other vital inflammatory functions. These data highlight the potential of PARP-1 inhibitors to overcome NF-kappaB-mediated therapeutic resistance and widens the spectrum of cancers in which these agents may be utilized. PMID- 21706054 TI - Identification and angiogenic role of the novel tumor endothelial marker CLEC14A. AB - Tumor endothelial markers (TEMs) that are highly expressed in human tumor vasculature compared with vasculature in normal tissue hold clear therapeutic potential. We report that the C-type lectin CLEC14A is a novel TEM. Immunohistochemical and immunofluorescence staining of tissue arrays has shown that CLEC14A is strongly expressed in tumor vasculature when compared with vessels in normal tissue. CLEC14A overexpression in tumor vessels was seen in a wide range of solid tumor types. Functional studies showed that CLEC14A induces filopodia and facilitates endothelial migration, tube formation and vascular development in zebrafish that is, CLEC14A regulates pro-angiogenic phenotypes. CLEC14A antisera inhibited cell migration and tube formation, suggesting that anti-CLEC14A antibodies may have anti-angiogenic activity. Finally, in endothelial cultures, expression of CLEC14A increased at low shear stress, and we hypothesize that low shear stress due to poor blood flow in the disorganized tumor vasculature induces expression of CLEC14A on tumor vessels and pro angiogenic phenotypes. PMID- 21706055 TI - The clathrin-binding domain of CALM-AF10 alters the phenotype of myeloid neoplasms in mice. AB - The PICALM (CALM) gene, whose product is involved in clathrin-mediated endocytosis, has been identified in two recurring chromosomal translocations, involving either MLL or MLLT10 (AF10). We developed a mouse model of CALM-AF10(+) leukemia to examine the hypothesis that disruption of endocytosis contributes to leukemogenesis. Exclusion of the C-terminal portion of CALM from the fusion protein, which is required for optimal binding to clathrin, resulted in the development of a myeloproliferative disease, whereas inclusion of this domain led to the development of acute myeloid leukemia and changes in gene expression of several cancer-related genes, notably Pim1 and Crebbp. Nonetheless, the development of leukemia could not be attributed directly to interference with endocytosis or consequential changes in proliferation and signaling. In leukemia cells, full-length CALM-AF10 localized to the nucleus with no consistent effect on growth factor endocyctosis, and suppressed histone H3 lysine 79 methylation regardless of the presence of clathrin. Using fluorescence resonance energy transfer analysis, we show that CALM-AF10 has a propensity to homo-oligomerize, raising the possibility that the function of endocytic proteins involved in chimeric fusions may be to provide dimerization properties, a recognized mechanism for unleashing oncogenic properties of chimeric transcription factors, rather than disrupting the internalization of growth factor receptors. PMID- 21706057 TI - Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation. AB - Ras is one of the most frequently activated oncogenes in cancer. Two mitogen activated protein kinases (MAPKs) are important for ras transformation: extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase 2 (JNK2). Here we present a downstream signal amplification cascade that is critical for ras transformation in murine embryonic fibroblasts. This cascade is coordinated by ERK and JNK2 MAPKs, whose Ras-mediated activation leads to the enhanced levels of three oncogenic transcription factors, namely, c-Myc, activating transcription factor 2 (ATF2) and ATF3, all of which are essential for ras transformation. Previous studies show that ERK-mediated serine 62 phosphorylation protects c-Myc from proteasomal degradation. ERK is, however, not alone sufficient to stabilize c-Myc but requires the cooperation of cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncogene that counteracts protein phosphatase 2A-mediated dephosphorylation of c-Myc. Here we show that JNK2 regulates Cip2a transcription via ATF2. ATF2 and c-Myc cooperate to activate the transcription of ATF3. Remarkably, not only ectopic JNK2, but also ectopic ATF2, CIP2A, c-Myc and ATF3 are sufficient to rescue the defective ras transformation of JNK2-deficient cells. Thus, these data identify the key signal converging point of JNK2 and ERK pathways and underline the central role of CIP2A in ras transformation. PMID- 21706056 TI - Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells. AB - Ezrin is a multifunctional protein that connects the actin cytoskeleton to the extracellular matrix through transmembrane proteins. High ezrin expression is associated with lung metastasis and poor survival in cancer. We screened small molecule libraries for compounds that directly interact with ezrin protein using surface plasmon resonance to identify lead compounds. The secondary functional assays used for lead compound selection included ezrin phosphorylation as measured by immunoprecipitation and in vitro kinase assays, actin binding, chemotaxis, invasion into an endothelial cell monolayer, zebrafish and Xenopus embryonic development, mouse lung organ culture and an in vivo lung metastasis model. Two molecules, NSC305787 and NSC668394, that directly bind to ezrin with low micromolar affinity were selected based on inhibition of ezrin function in multiple assays. They inhibited ezrin phosphorylation, ezrin-actin interaction and ezrin-mediated motility of osteosarcoma (OS) cells in culture. NSC305787 mimicked the ezrin morpholino phenotype, and NSC668394 caused a unique developmental defect consistent with reduced cell motility in zebrafish. Following tail vein injection of OS cells into mice, both molecules inhibited lung metastasis of ezrin-sensitive cells, but not ezrin-resistant cells. The small molecule inhibitors NSC305787 and NSC668394 demonstrate a novel targeted therapy that directly inhibits ezrin protein as an approach to prevent tumor metastasis. PMID- 21706058 TI - Epigenetic repression of E-cadherin expression by hepatitis B virus x antigen in liver cancer. AB - Loss of E-cadherin is associated with acquisition of metastatic capacity. Numerous studies suggest that histone deacetylation and/or hypermethylation of CpG islands in E-cadherin gene (CDH1) are major mechanisms responsible for E cadherin silencing in different tumors and cancer cell lines. The hepatitis B virus (HBV)-encoded X antigen, HBx, contributes importantly to the development of hepatocellular carcinoma using multiple mechanisms. Experiments were designed to test if in addition to CDH1 hypermethylation HBx promotes epigenetic modulation of E-cadherin transcriptional activity through histone deacetylation and miR-373. The relationships between HBx, E-cadherin, mSin3A, Snail-1 and miR-373 were evaluated in HBx expressing (HepG2X) and control (HepG2CAT) cells by western blotting, immunoprecipitation (IP), chromatin IP as well as by immunohistochemical staining of liver and tumor tissue sections from HBV-infected patients. In HepG2X cells, decreased levels of E-cadherin and elevated levels of mSin3A and Snail-1 were detected. Reciprocal IP with anti-HBx and anti-mSin3A demonstrated mutual binding. Furthermore, HBx-mSin3A colocalization was detected by immunofluorescent staining. HBx downregulated E-cadherin expression by the recruitment of the mSin3A/histone deacetylase complex to the Snail-binding sites in human CDH1. Histone deacetylation inhibition by Trichostatin-A treatment restored E-cadherin expression. Mir-373, a positive regulator of E-cadherin expression, was downregulated by HBx in HepG2X cells and tissue sections from HBV infected patients. Thus, histone deacetylation of CDH1 and downregulation of miR 373, together with the previously demonstrated hypermethylation of CDH1 by HBx, may be important for the understanding of HBV-related carcinogenesis. PMID- 21706060 TI - Validating a gene expression signature proposed to differentiate liposarcomas that use different telomere maintenance mechanisms. PMID- 21706059 TI - A tumor-suppressing function in the epithelial adhesion protein Trask. AB - Trask/CDCP1 is a transmembrane glycoprotein widely expressed in epithelial tissues whose functions are just beginning to be understood, but include a role as an anti-adhesive effector of Src kinases. Early studies looking at RNA transcript levels seemed to suggest overexpression in some cancers, but immunostaining studies are now providing more accurate analyses of its expression. In an immuno-histochemical survey of human cancer specimens, we find that Trask expression is retained, reduced or sometimes lost in some tumors compared with their normal epithelial tissue counterparts. A survey of human cancer cell lines also show a similar wide variation in the expression of Trask, including some cell types with the loss of Trask expression, and additional cell types that have lost the physiological detachment-induced phosphorylation of Trask. Three experimental models were established to interrogate the role of Trask in tumor progression, including two gain-of-function models with tet inducible expression of Trask in tumor cells lacking Trask expression, and one loss-of-function model to suppress Trask expression in tumor cells with abundant Trask expression. The induction of Trask expression and phosphorylation in MCF-7 cells and in 3T3v-src cells was associated with a reduction in tumor metastases while the shRNA-induced knockdown of Trask in L3.6pl cancer cells was associated with increased tumor metastases. The results from these three models are consistent with a tumor-suppressing role for Trask. These data identify Trask as one of several potential candidates for functionally relevant tumor suppressors on the 3p21.3 region of the genome frequently lost in human cancers. PMID- 21706062 TI - Environmental conditions are important for establishing and evaluating pre clinical models of GVHD. PMID- 21706061 TI - Regulation of NF-kappaB activity by competition between RelA acetylation and ubiquitination. AB - The nuclear factor (NF)-kappaB transcription factor has essential roles in inflammation and oncogenesis. Its ubiquitous RelA subunit is regulated by several post-translational modifications, including phosphorylation, ubiquitination and acetylation. Ubiquitination promotes the termination of RelA-dependent transcription, but its regulation is incompletely understood. Through mass spectrometry analysis of ubiquitinated RelA, we identified seven lysines that were attached to degradative and non-degradative forms of polyubiquitin. Interestingly, lysines targeted for acetylation were among the residues identified as ubiquitin acceptor sites. Mutation of these particular sites resulted in decreased polyubiquitination. Acetylation and ubiquitination were found to inhibit each other, consistent with their use of overlapping sites. Reconstitution of rela(-/-) fibroblasts with wild-type and mutant forms of RelA revealed that modifications at these residues can have activating and inhibitory functions depending on the target gene context. Altogether, this study elucidates that ubiquitination and acetylation can modulate each other and regulate nuclear NF-kappaB function in a gene-specific manner. PMID- 21706063 TI - Donor cell leukaemia after allogeneic haematopoietic SCT followed by prolonged thalidomide maintenance for multiple myeloma. PMID- 21706064 TI - Endoscopic diagnosis of acute intestinal GVHD following allogeneic hematopoietic SCT: a retrospective analysis in 175 patients. AB - Diagnosis of acute intestinal GVHD (aGVHD) following allogeneic hematopoietic cell transplantation is based on clinical symptoms and histological lesions. This retrospective analysis aimed to validate the 'Freiburg Criteria' for the endoscopic grading of intestinal aGVHD. Grade 1: no clear-cut criteria; grade 2: spotted erythema; grade 3: aphthous lesions; and grade 4: confluent defects, ulcers, denudation of the mucosa. Having excluded patients with infectious diarrhea, we evaluated 175 consecutive patients between January 2001 and June 2009. Setting a cutoff between grade 1 (no change in therapy) and grade 2 (intensification of immunosuppression), macroscopy had a sensitivity of 89.2% (95% confidence interval (CI): 80.4-94.9%), a specificity of 79.4% (95% CI: 69.6 87.1%), a positive-predictive value of 79.6% (95% CI: 70.0-87.2%) and a negative predictive value of 89.0% (95% CI: 80.2-94.9%). In all, 20% of patients with aGVHD in the lower gastrointestinal tract (GIT) had lesions only in the terminal ileum. In all patients with aGVHD >=2 of the upper GIT, typical lesions were also found in the lower GIT. Ileo-colonoscopy showed the highest diagnostic yield for aGVHD. In conclusion, the 'Freiburg Criteria' for macroscopic diagnosis of intestinal aGVHD provide high accuracy for identifying aGVHD >=2. PMID- 21706066 TI - Transplantation: alemtuzumab induction is safe for renal transplant recipients. PMID- 21706065 TI - Transplantation: Kidney-paired donation: do transplantations need to be performed simultaneously? PMID- 21706067 TI - Dialysis: Infection increases the risk of cardiovascular events in the elderly. PMID- 21706068 TI - Transplantation: Urinary NGAL levels in potential deceased kidney donors may be useful in determining donor suitability. PMID- 21706069 TI - Meta Analysis of Functional Neuroimaging Data via Bayesian Spatial Point Processes. AB - As the discipline of functional neuroimaging grows there is an increasing interest in meta analysis of brain imaging studies. A typical neuroimaging meta analysis collects peak activation coordinates (foci) from several studies and identifies areas of consistent activation. Most imaging meta analysis methods only produce null hypothesis inferences and do not provide an interpretable fitted model. To overcome these limitations, we propose a Bayesian spatial hierarchical model using a marked independent cluster process. We model the foci as offspring of a latent study center process, and the study centers are in turn offspring of a latent population center process. The posterior intensity function of the population center process provides inference on the location of population centers, as well as the inter-study variability of foci about the population centers. We illustrate our model with a meta analysis consisting of 437 studies from 164 publications, show how two subpopulations of studies can be compared and assess our model via sensitivity analyses and simulation studies. Supplemental materials are available online. PMID- 21706070 TI - A novel alkaline protease from wild edible mushroom Termitomyces albuminosus. AB - A protease with a molecular mass of 30 kDa and the N-terminal sequence of GLQTNAPWGLARSS, was isolated from fresh fruiting bodies of the wild edible mushroom Termitomyces albuminosus. The purification protocol included ion exchange chromatography on DEAE-cellulose, Q-Sepharose, SP-Sepharose and FPLC-gel filtration on Superdex 75. The protein was unadsorbed on DEAE-cellulose and Q Sepharose, but adsorbed on SP-Sepharose. The optimal pH and temperature of the purified enzyme were 10.6 and 60 degrees C, respectively. The enzyme was stable in the presence of 2 % (v/v) Tween 80 and 4 M urea. More than 80 % of the enzyme activity was retained in 2 % (v/v) Triton X 100, 54 % in 10 mM EDTA and 31 % in 2 % (w/v) SDS. The enzyme was strongly inhibited by phenylmethylsulfonyl fluoride (PMSF), but not inhibited by dithiothreitol (DTT), pepstatin or lima bean trypsin inhibitor suggesting that it was a serine protease but not a trypsin-like one. The protease was inhibited by Hg(2+), Cu(2+), and Fe(3+) ions. The K(m) and V(max) values of the purified enzyme for casein were 8.26 mg ? ml(-1) and 0.668 mg ? ml(-1) ? min(-1), respectively. PMID- 21706071 TI - High ionic conductivity P(VDF-TrFE)/PEO blended polymer electrolytes for solid electrochromic devices. AB - Solid polymer electrolytes with excellent ionic conductivity (above 10(-4) S cm( 1)), which result in high optical modulation for solid electrochromic (EC) devices are presented. The combination of a polar host matrix poly(vinylidene fluoride-trifluoroethylene) P(VDF-TrFE) and a solid plasticized of a low molecular weight poly(ethylene oxide) (PEO) (M(w)<= 20,000) blended polymer electrolyte serves to enhance both the dissolution of lithium salt and the ionic transport. Calorimetric measurement shows a reduced crystallization due to a better intermixing of the polymers with small molecular weight PEO. Vibrational spectroscopy identifies the presence of free ions and ion pairs in the electrolytes with PEO of M(w)<= 8000. The ionic dissolution is improved using PEO as a plasticizer when compared to liquid propylene carbonate, evidently shown in the transference number analysis. Ionic transport follows the Arrhenius equation with a low activation energy (0.16-0.2 eV), leading to high ionic conductivities. Solid electrochromic devices fabricated with the blended P(VDF-TrFE)/PEO electrolytes and polyaniline show good spectroelectrochemical performance in the visible (300-800 nm) and near-infrared (0.9-2.4 MUm) regions with a modulation up to 60% and fast switching speed of below 20 seconds. The successful introduction of the solid polymer electrolytes with its best harnessed qualities helps to expedite the application of various electrochemical devices. PMID- 21706073 TI - Comparison of molecular conductance between planar and twisted 4-phenylpyridines by means of two-dimensional phase separation of tetraphenylporphyrin templates at a liquid-HOPG interface. AB - Tetraphenylporphyrin (TPP) rhodium chlorides coordinated by planar and twisted 4 phenylpyridine derivatives were synthesized. An STM image was taken by a 2-D phase separation technique and the conductance was evaluated. Difference in apparent height between these phenylpyridines reflects the conductance ratio of ligands. PMID- 21706072 TI - HYDRAmers: design, synthesis and characterization of different generation novel Hydra-like dendrons based on multifunctionalized adamantane. AB - In this communication we present a new synthetic strategy to different generation Hydra-like dendrons based on tetrafunctionalized adamantane as a building block. The novel dendrons, which we termed HYDRAmers, possess at the periphery and at the central core orthogonal protections that can be exploited for conjugation of targeting ligands, drugs and/or imaging probes. PMID- 21706074 TI - Highly enhanced electrochemiluminescence based on synergetic catalysis effect of enzyme and Pd nanoparticles for ultrasensitive immunoassay. AB - An immunosensor based on the electrochemiluminescence (ECL) of luminol was proposed by coupling enzymatic reaction to in situ generate coreactant with Pd nanoparticles as catalyst for the ECL reaction, which was successfully applied for the ultrasensitive detection of alpha-1-fetoprotein with a low detection limit of 33 fg mL(-1). PMID- 21706075 TI - More electron rich than cyclopentadienyl: 1,2-diaza-3,5-diborolyl as a ligand in ferrocene and ruthenocene analogs. AB - Ruthenium and iron sandwich complexes incorporating cyclopentadienyl analogs with CB(2)N(2)(-) skeletons were characterized. Electrochemical measurements supported by computational studies revealed that in combination with larger metal ions such as Ru the CB(2)N(2)(-) ligand can be more electron-rich than its organic counterpart. PMID- 21706076 TI - Heteroepitaxial growth of ZnO branches selectively on TiO2 nanorod tips with improved light harvesting performance. AB - A seeded heteroepitaxial growth of ZnO nanorods selectively on TiO(2) nanorod tips was achieved by restricting crystal growth on highly hydrophobic TiO(2) nanorod film surfaces. Intriguing light harvesting performance and efficient charge transport efficiency has been found, which suggest potential applications in photovoltaics and optoelectronics. PMID- 21706077 TI - Taming functionality: easy-to-handle chiral phosphiranes. AB - Enantiopure chiral phosphiranes possessing a binaphthyl backbone demonstrate remarkable thermal stability, are highly resistant to air-oxidation and are effective ligands in catalytic asymmetric hydrosilylations. PMID- 21706078 TI - Palladium-catalyzed Sonogashira reactions of aryl amines with alkynes via in situ formation of arenediazonium salts. AB - A general and convenient palladium-catalyzed Sonogashira reaction of in situ generated arenediazonium salts has been developed and various internal arylalkynes are produced in good yields under mild conditions. PMID- 21706079 TI - A small molecule that induces assembly of a four way DNA junction at low temperature. AB - Small molecules that induce the formation of higher order DNA structures have potential therapeutic and nanotechnology applications. Screening of a click library has identified the first compound to induce the formation of a Holliday junction structure at room temperature without the need for a high temperature annealing step. PMID- 21706080 TI - Visible light-induced charge storage, on-demand release and self photorechargeability of WO3 film. AB - Tungsten oxide (WO(3)) electrodes subjected to a positive bias are self photorecharged with alkali cations in the electrolyte during visible light illumination. Upon photoexcitation, part of the photogenerated charges generated by WO(3) is stabilized by the cations and stored in situ within the WO(3) framework. This light-induced storage of charges is subsequently utilized in dark conditions in an on-demand manner and is able to be recharged in the successive illumination cycles. The amount of charges stored is shown to be dependent on the cation ionic radii and the presence of these intercalated cations is verified by X-ray diffraction (XRD) and inductively coupled plasma mass spectroscopy (ICP MS). This self-photorecharge and on-demand charge-release phenomena demonstrate the ability of WO(3) to supply photoexcited charges under dark condition in a photoelectrochemical reaction with greater flexibility. PMID- 21706081 TI - Synthesis, structural characterization and luminescent properties of a series of Cu(I) complexes based on polyphosphine ligands. AB - A series of Cu(I) complexes with a [Cu(NN)(PP)](+) moiety, [Cu(phen)(pba)](BF(4)) (1a), [Cu(2)(phen)(2)(pbaa)](BF(4))(2) (2a), [Cu(2)(phen)(2)(pnaa)](BF(4))(2) (3a), [Cu(2)(phen)(2)(pbbaa)](BF(4))(2) (4a), [Cu(dmp)(pba)](BF(4)) (1b), [Cu(2)(dmp)(2)(pbaa)](BF(4))(2) (2b), [Cu(2)(dmp)(2)(pnaa)](BF(4))(2) (3b) and [Cu(2)(dmp)(2)(pbbaa)](BF(4))(2) (4b) (phen = 1,10-phenanthroline, dmp = 2,9 dimethyl-1,10-phenanthroline, pba = N,N bis((diphenylphosphino)methyl)benzenamine, pbaa = N,N,N',N' tetrakis((diphenylphosphino)methyl)benzene-1,4-diamine, pnaa = N,N,N',N' tetrakis((diphenylphosphino)methyl)naphthalene-1,5-diamine and pbbaa = N,N,N',N' tetrakis((diphenylphosphino)methyl)biphenyl-4,4'-diamine), were rationally designed and synthesized. These complexes were characterized by (1)H and (31)P NMR, electrospray mass spectrometry, elemental analysis and X-ray crystal structure analysis. Introduction of different central arene spacers (phenyl, naphthyl, biphenyl) into ligands, resulting in the size variation of these complexes, aims to tune the photophysical properties of the complexes. Each Cu(I) ion in these complexes adopts a distorted tetrahedral geometry constructed by the chelating diimine and phosphine groups. Intermolecular C-H...pi and/or pi...pi interactions are involved in the solid states. The dmp-containing complex exhibits better emission relative to the corresponding phen complex due to the steric encumbrance of bulky alkyl groups. Furthermore, for complexes with identical diimine but different phosphine ligands, the tendency of increased emission lifetime as well as blue-shifted emission in the solid state follows with the decrease in size of complexes. Intermolecular C-H...pi interactions have an influence on the final solid state photophysical properties through vibrationally relaxed non-radiative energy transfer in the excited state. Smaller sized complexes show better photophysical properties due to less vibrationally relaxed behavior related to flexible C-H...pi bonds. Nevertheless, the tendency for increased quantum yield and emission lifetime, as well as blue-shifted emission in dilute solution goes with the increase in size of complexes. The central arene ring (phenyl, naphthyl or biphenyl) has an influence on the final photophysical properties. The larger the pi-conjugated extension of central arene ring is, the better the photophysical properties of complex are. The rigid and large-sized complex 3b, with a high quantum yield and long lifetime, is the best luminophore among these complexes. PMID- 21706082 TI - New iron(II) alpha-iminopyridine complexes and their catalytic activity in the oxidation of activated methylene groups and secondary alcohols to ketones. AB - A set of iron(II) complexes of the general formula [Fe(OTf)(2)L(2)] was synthesized in 32 to 78% isolated yields, where L represents a bidentate alpha iminopyridine ligand. Four of the iron complexes were characterized structurally, revealing a rich coordination chemistry, because the coordination geometry of the iron complexes strongly depends on the substitution pattern exhibited by the ligands L. The catalytic activity of the new complexes was demonstrated in the oxidation of cyclohexane, activated methylene groups and secondary alcohols to the corresponding ketones utilizing H(2)O(2) and t-BuOOH as the oxidants. The oxidation of activated methylene groups and secondary alcohols to the corresponding ketones with t-BuOOH gave isolated yields between 22 and 91% (4 h, room temperature, 3% catalyst load). The influence of the structure of the ligand on the activity of the corresponding metal complex is also reported. Furthermore, UV-vis experiments were performed which provided evidence for the formation of an [Fe-O-O-t-Bu] intermediate. PMID- 21706083 TI - Tuning the spin-transition properties of pyrene-decorated 2,6 bispyrazolylpyridine based Fe(II) complexes. AB - Two 2,6-bispyrazolylpyridine ligands (bpp) were functionalized with pyrene moieties through linkers of different lengths. In the ligand 2,6-di(1H-pyrazol-1 yl)-4-(pyren-1-yl)pyridine (L1) the pyrene group is directly connected to the bpp moiety via a C-C single bond, while in the ligand 4-(2,6-di(1H-pyrazol-1 yl)pyridin-4-yl)benzyl-4-(pyren-1-yl)butanoate (L2) it is separated by a benzyl ester group involving a flexible butanoic chain. Subsequent complexation of Fe(II) salts revealed dramatic the influence of the nature of the pyrene substitution on the spin-transition behaviour of the resulting complexes. Thus, compound [Fe(L1)(2)](ClO(4))(2) (1) is blocked in its high spin state due to constraints caused by a strong intermolecular pi-pi stacking in its structure. On the other hand, the flexible chain of ligand L2 in compounds [Fe(L2)(2)](ClO(4))(2) (2) and [Fe(L2)(2)](BF(4))(2).CH(3)CN.H(2)O (3) prevents structural constraints allowing for reversible spin transitions. Temperature dependent studies of the photophysical properties of compound 3 do not reveal any obvious correlation between the fluorescence of the pyrene group and the spin state of the spin transition core. PMID- 21706084 TI - Facile synthesis and platinum complexes of 4',5,5''-trisubstituted-2,2':6',2'' terpyridines. AB - The synthesis of trisubstituted 4',5,5'' terpyridines is described. The strategy begins with synthesis of 2-acetyl-5-bromopyridine (3) from 2,5-dibromopyridine, substitution of the bromine in 3 using a variety of metal-catalyzed reactions and then formation of the terpyridine using the Krohnke reaction. The complexes have been prepared by reaction of [Pt(PhCN)(2)Cl(2)] with the appropriate silver salt followed by addition of the terpyridyl ligand. The crystal structure of two complexes have been determined via X-ray diffraction and the MLCT (metal-to ligand charge-transfer) emissions determined by UV/Vis spectroscopy. PMID- 21706085 TI - Synthesis and characterisation of luminescent rhenium tricarbonyl complexes with axially coordinated 1,2,3-triazole ligands. AB - A series of 1-alkyl-4-aryl-1,2,3-triazoles (1-methyl-4-phenyl-1,2,3-triazole (1a); 1-propyl-4-phenyl-1,2,3-triazole (1b); 1-benzyl-4-phenyl-1,2,3-triazole (1c); 1-propyl-4-p-tolyl-1,2,3-triazole (1d)) have been prepared through a one pot procedure involving in situ generation of the alkyl azide from a halide precursor followed by copper catalysed alkyne/azide cycloaddition (CuAAC) with the appropriate aryl alkyne. Cationic Re(I) complexes [Re(bpy)(CO)(3)(1a-d)]PF(6) (2a-d) were then prepared by stirring [Re(bpy)(CO)(3)Cl] with AgPF(6) in dichloromethane in the presence of ligands 1a-d. X-ray crystal structures were obtained for 2a and 2b. In the solid state, 2a adopts a highly distorted geometry, which is not seen for 2b, in which the plane of the triazole ligand tilts by 13 degrees with respect to the Re-N bond as a result of a pi-stacking interaction between the Ph substituent and one of the rings of the bpy ligand. This pi-stacking interaction also results in severe twisting of the bpy ligand. Infrared spectra of 2a-d exhibit nu(CO) bands at ~2035 and ~1926 cm(-1) suggesting that these ligands are marginally better donors than pyridine (nu(CO) = 2037, 1932 cm(-1)). The complexes are luminescent in aerated dichloromethane at room temperature with emission maxima at 542 to 552 nm comparable to that of the pyridine analogue (549 nm) and blue shifted relative to the parent chloride complex. Long luminescent lifetimes are observed for the triazole complexes (475 to 513 ns) in aerated dichloromethane solutions at room temperature. PMID- 21706086 TI - Adduct formation of Thimerosal with human and rat hemoglobin: a study using liquid chromatography coupled to electrospray time-of-flight mass spectrometry (LC/ESI-TOF-MS). AB - Thimerosal (THI) is used as a preservative in many vaccines throughout the world. Ethylmercury (EtHg(+)), released from THI in aqueous media, has a high affinity to thiol functions of proteins. In blood, hemoglobin is a likely target protein because of its high abundance and its several free thiol functions. In comparison to hemoglobin of human origin, hemoglobin of rats exhibits almost twice as many free thiol groups, which might lead to different binding behavior and therefore a limited comparability between the situation in man and in rats, which are frequently used as models for mercury species toxicity investigations. Thus, the adduct formation of EtHg(+) with hemoglobin of humans and rats was compared under simulated physiological conditions by using gradient reversed-phase liquid chromatography (LC) with electrospray time-of-flight mass spectrometry (ESI-TOF MS) detection. The binding stoichiometry correlated with the number of free thiols in the alpha- and beta-chain of hemoglobin. The use of rats to verify the safety of additives in vaccines like Thimerosal is therefore doubtful and should be reevaluated. PMID- 21706087 TI - Direct alkylation of indoles and amines by tert-enamides: facile access to pharmaceutically active 2-oxo-1-pyrrolidine analogues. AB - Direct alkylation of indoles and amines by tertiary enamides for the synthesis of pharmaceutically active 2-oxo-1-pyrrolidine analogues was described. With only a 0.5 mol% catalyst loading, molecular iodine was demonstrated to be efficiently enough to promote the reaction under neat condition. Only Markovnikov addition product was obtained indicating that the reactions proceeded with excellent regioselectivity. PMID- 21706089 TI - Acylation of Grignard reagents mediated by N-methylpyrrolidone: a remarkable selectivity for the synthesis of ketones. AB - An efficient user-friendly method of acylation of Grignard reagents to selectively synthesize ketones is presented, which is assisted by simple amides such as NMP, or DMF. The present chemoselective method tolerates a variety of functional groups such as ketone, ester, nitrile and other functional groups. PMID- 21706088 TI - Synthetic studies on the solanacol ABC ring system by cation-initiated cascade cyclization: implications for strigolactone biosynthesis. AB - We report a new method for constructing the ABC ring system of strigolactones, in a single step from a simple linear precursor by acid-catalyzed double cyclization. The reaction proceeds with a high degree of stereochemical control, which can be qualitatively rationalized using DFT calculations. Our concise synthetic approach offers a new model for thinking about the (as yet) unknown chemistry that is employed in the biosynthetic pathways leading to this class of plant hormones. PMID- 21706090 TI - Selective electrochemical fluorination of organic molecules and macromolecules in ionic liquids. AB - This article provides an outline of recent studies on selective electrochemical fluorination in ionic liquid fluoride salts toward green sustainable chemistry. First, a brief historical background of electrochemical fluorination in organic solvents is provided, and some particular problems and unique solvent effects associated with this technique are briefly mentioned. Second, recent progress in selective fluorination and fluorodesulfurization of organic molecules and macromolecules in ionic liquids using direct and indirect electrolysis with recyclable mediators is reviewed. PMID- 21706091 TI - Fluidic shear-assisted formation of actuating multilamellar lipid tubes using microfabricated nozzle array device. AB - Molecular self-assemblies exhibiting automatic motions have received much attention as potential artificial models of living organisms. We have developed a microfluidic picolitre nozzle-array device to form multilamellar lipid tubes (MLTs) under fluidic shear stress, which transformed into different two patterns (yarn-balls and double-helixes) and also exhibited unique self-actuation behaviors. PMID- 21706092 TI - Immobilization of folic acid on Eu3+-doped nanoporous silica spheres. AB - Folic acid (FA) was immobilized on Eu(3+)-doped nanoporous silica spheres (Eu:NPSs) through mediation of the 3-aminopropyltriethoxysilane adlayer. The ordered nanopores of Eu:NPS were preserved by the immobilization. The FA immobilized Eu:NPSs showed the characteristic photoluminescence peak due to interactions between the FA molecules and Eu(3+) ions, and highly dispersed stability in phosphate buffered saline. PMID- 21706093 TI - Direct detection of fatty acid ethyl esters using low temperature plasma (LTP) ambient ionization mass spectrometry for rapid bacterial differentiation. AB - Low temperature plasma mass spectrometry (LTP-MS) was employed to detect fatty acid ethyl esters (FAEE) from bacterial samples directly. Positive ion mode FAEE mass spectrometric profiles of sixteen different bacterial samples were obtained without extraction or other sample preparation. In the range m/z 200-300, LTP mass spectra show highly reproducible and characteristic patterns. To identify the FAEE's associated with the characteristic peaks, accurate masses were recorded in the full scan mode using an LTQ/Orbitrap instrument, and tandem mass spectrometry was performed. Data were examined by principal component analysis (PCA) to determine the degree of differentiation possible amongst different bacterial species. Gram-positive and gram-negative bacteria are readily distinguished, and 11 out of 13 Salmonella strains show distinctive patterns. Growth media effects are observed but do not interfere with species recognition based on the PCA results. PMID- 21706094 TI - Human carbonic anhydrase II as a host for piano-stool complexes bearing a sulfonamide anchor. AB - d(6)-piano-stool complexes bearing an arylsulfonamide anchor display sub micromolar affinity towards human Carbonic Anhydrase II (hCA II). The 1.3 A resolution X-ray crystal structure of [(eta(6)-C(6)Me(6))Ru(bispy 3)Cl](+)? hCA II highlights the nature of the host-guest interactions. PMID- 21706095 TI - Bis(imidate)palladium(II) complexes with labile ligands. Mimics of classical precursors? AB - A novel synthetic route to prepare palladium(II) precursor analogous of classical [Pd(Cl)(2)(solvent)(2)] has been developed. Just stirring Pd(3)(AcO)(6) in dimethyl sulfide at room temperature, in the stoichiometric presence of protic imidate ligands, resulted in the precipitation of the desired complexes [Pd(imidate)(2)(SMe(2))(2)] (imidate = succinimidate (succ) 1, phthalimidate (phthal) 2, maleimidate (mal) 3, saccharinate (sac) 4 or glutarimidate (glut) 5). The new complexes are very soluble in common solvents and have been fully characterized, including an X-ray diffraction analysis of 2. Analogous reactions with succinimide in acetonitrile or dimethylsulfoxide produced [Pd(succinimidate)(2)(solvent)(2)] (6 and 7, respectively) as off-white powders. Thermal decomposition of 6 produces a new species 6* with bridging imidate ligands that can be formulated as a trimer similar to Pd(3)(AcO)(6). The usefulness of 1-5 as precursors has been tested by reactions against monodentated neutral donor ligands, PPh(3) (a compounds), or pyridine (py, b compounds), to produce ten new derivatives of the general formula trans-[Pd(imidate)(2)(L)(2)]. The single-crystal structures of compounds 2a, 3a, 4a, 4a', 5a and 4b have also been established, allowing an interesting molecular and supramolecular structural discussion. A cis-conformation was induced when the bidentate chelate ligand 1,2 bis(diphenylphosphino)benzene (dppb, c compounds) was made to react with 1-5. Structural characterization by X-ray diffraction of complex 2c confirmed the proposed formula. Catalytic activity in Suzuki-Miyaura cross-coupling of aryl bromides and benzyl bromides with aryl boronic acids has been tested. PMID- 21706096 TI - Zinc complexes of Ttz(R,Me) with O and S donors reveal differences between Tp and Ttz ligands: acid stability and binding to H or an additional metal (Ttz(R,Me) = tris(3-R-5-methyl-1,2,4-triazolyl)borate; R = Ph, tBu). AB - Alkylzinc complexes, (Ttz(R,Me))ZnR' (R = tBu, Ph; R' = Me, Et), show interesting reactivity with acids, bases and water. With acids (e.g. fluorinated alcohols, phenols, thiophenol, acetylacetone, acetic acid, HCl and triflic acid) zinc complexes of the conjugate base (CB), (Ttz(R,Me))ZnCB, are generated. Thus the B N bonds in Ttz ligands are acid stable. (Ttz(R,Me))ZnCB complexes were characterized by (1)H, (13)C-NMR, IR, MS, elemental analysis, and, in most cases, single crystal X-ray diffraction. The four coordinate crystal structures included (Ttz(R,Me))Zn(CB) [where R = Ph, CB (conjugate base) = OCH(2)CF(3) (2), OPh (6), SPh (8), p-OC(6)H(4)(NO(2)) (10); R = tBu, CB = OCH(CF(3))(2) (3), OPh (5), SPh (7)*, p-OC(6)H(4)(NO(2)) (9) (* indicates a rearranged Ttz ligand)]. The use of bidentate ligands resulted in structures [(Ttz(Ph,Me))Zn(CB) (CB = acac (12), OAc (14))] in which the coordination geometries are five, and intermediate between four and five, respectively. Interestingly, three forms of (Ttz(Ph,Me))Zn(p OC(6)H(4)(NO(2))) (10) were analyzed crystallographically including a Zn coordinated water molecule in 10(H(2)O), a coordination polymer in 10(CP), and a p-nitrophenol molecule hydrogen bonded to a triazole ring in 10(Nit). Ttz ligands are flexible since they are capable of providing kappa(3) or kappa(2) metal binding and intermolecular interactions with either a metal center or H through the four position nitrogen (e.g. in 10(CP) and HTtz(tBu,Me).H(2)O, respectively). Preliminary kinetic studies on the protonolysis of LZnEt (L = Ttz(tBu,Me), Tp(tBu,Me)) with p-nitrophenol in toluene at 95 degrees C show that these reactions are zero order in acid and first order in the LZnEt. PMID- 21706097 TI - Recognition of d-fructose based on tetra-boronic functionalized viologen in aqueous solution. AB - A highly selective and sensitive switch for d-fructose is formed by 8 hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) fluorescent dye and the tetra-boronic acid viologen receptor ToBV. The sensing system can not only recognize d-fructose among seven natural d-monosaccharides but also may distinguish the enantiomer of d/l-fructose. The research rationale and results will offer a new strategy for the development of saccharides recognition. PMID- 21706098 TI - Transformations of the natural cytokinin N6-isopentenyladenine in aqueous acidic media: structural aspects. AB - N6-Isopentenyladenine (L1) was subjected to variously acidic media in 0.1 M, 1 M and 2 M HCl. In dependence on the acidity of the medium, the formation of three main acid hydrolysis products, involving the N6-isopentenyladeninium (HL1) (1), 7,8,9,10-tetrahydro-7,7-dimethyl-3H-pyrimido[2,1-i]purin-6-ium (HL2) (2) or 5 amino-4-(4,4-dimethyl-3,4,5,6-tetrahydropyrimidin-2-yl)-imidazolium (H(2)L3) (3 5) cations, were determined and characterized by multinuclear solution-state NMR spectroscopy and in the solid state by single crystal X-ray analysis. The coordination abilities of these transformation products have been also investigated. The compounds of the compositions [Zn(HL1)Cl(3)].H(2)O (1), [Zn(3)(HL2)(2)Cl(8)] (2), (H(2)L3)[CuCl(4)] (4) and (H(2)L3)[ZnCl(4)] (5) have been prepared in dependence on the acidity of the medium used by the reactions of L1 with ZnCl(2).1.5H(2)O or CuCl(2).2H(2)O. Based on the NMR spectroscopic and X ray crystallographic results, the mechanism of transformation of L1 in the acidic medium, involving the protonation, cyclization and ring fission, has been suggested. PMID- 21706099 TI - Nanoparticle-coated PDMS elastomers for enhancement of Raman scattering. AB - A simple but efficient method for highly sensitive Raman detection, covering a thin polydimethylsiloxane elastomer, pre-coated with a layer of Au or Ag nanoparticles, onto the detected substrate, is proposed. Moreover, this nanoparticle-coated PDMS elastomer can be used for chemical imaging with high sensitivity. PMID- 21706100 TI - Enhanced light harvesting in mesoporous TiO2/P3HT hybrid solar cells using a porphyrin dye. AB - We report panchromatic light harvesting in hybrid TiO(2)/P3HT photovoltaic devices using a porphyrin dye that complements the light absorption of P3HT. The high short circuit photocurrent (12.1 mA cm(-2)) obtained is found to be due, in part, to Forster resonance energy transfer from the P3HT to the dye. PMID- 21706101 TI - Aryne reaction with trifluoromethyl ketones in three modes: C-C bond cleavage, [2+2] cycloaddition and O-arylation. AB - Trifluoromethyl ketones were found to be coupled with arynes in three modes depending upon their substitution patterns, namely C-C bond cleavage, [2+2] cycloaddition and O-arylation. PMID- 21706102 TI - Functional mesoporous carbon nanotubes and their integration in situ with metal nanocrystals for enhanced electrochemical performances. AB - Functional mesoporous carbon nanotubes (MCNTs) and their integration in situ with Pt nanocrystals (Pt/MCNTs) have been designed and successfully developed via a facile route, which exhibited enhanced performances in energy storage and conversion applications. PMID- 21706103 TI - The chemistry of the p-block elements with thioether, selenoether and telluroether ligands. AB - The synthesis and structures of acyclic and macrocyclic thio-, seleno- and telluro-ether complexes of the metallic and metalloid elements of Groups 13-16 reported since 2000 are described. The diverse structures range from discrete monomers through to infinite 1-, 2- or 3-D polymers. The coordination chemistry in this area is quite different to familiar d-block chemistry and the underlying factors are explored. PMID- 21706104 TI - Synthesis and characterization of dithienylbenzobis(thiadiazole)-based low band gap polymers for organic electronics. AB - New donor-acceptor alternating conjugated polymers were synthesized and characterized. Among them, PCPBBT exhibited a band-gap of 1.01 eV and ambipolar characteristics with MU(h) = 7.1 * 10(-4) cm(2) V(-1) s(-1) and MU(e) = 3.3 * 10( 3) cm(2) V(-1) s(-1). PMID- 21706105 TI - Recognition of thymine in DNA bulges by a Zn(II) macrocyclic complex. AB - A Zn(II) macrocyclic complex with appended quinoline is a bifunctional recognition agent that uses both the Zn(II) center and the pendent aromatic group to bind to thymine in bulges with good selectivity over DNA containing G, C or A bulges. Spectroscopic studies show that the stem containing the bulge stays largely intact in a DNA hairpin with the Zn(II) complex bound to the thymine bulge. PMID- 21706106 TI - A highly selective and sensitive on-off sensor for silver ions and cysteine by light scattering technique of DNA-functionalized gold nanoparticles. AB - DNA-functionalized gold nanoparticles are shown to act as a light-scattering switch. Ag(+) ion turns on the switch through the DNA-Au NPs conjugates based on the formation of cytosine-Ag(+)-cytosine base pairs, whereas cysteine turns off the light-scattering signal because it competitively binds to Ag(+). PMID- 21706107 TI - Dynamic self-assembly of molecular capsules via solvent polarity controlled reversible binding of nitrate anions with C3 symmetric tripodal receptors. AB - A series of N-bridgehead tripodal receptors bearing amide functionality is reported which displays reversible binding of nitrate anions via solvent polarity controlled molecular capsule formation through a dynamic self-assembly process. PMID- 21706108 TI - A generalized supramolecular strategy for self-sorted assembly between donor and acceptor gelators. AB - An effective supramolecular strategy for self-sorting between naphthalene-diimide (NDI) acceptor and dialkoxy-naphthalene (DAN) donor organogelators is reported. The concept is based on mismatch in the placement of the two amide functionalities in the donor and acceptor chromophores so that self-sorting ensured maximum effect of H-bonding. PMID- 21706109 TI - Metallomics in Japan. PMID- 21706110 TI - Photochromic and photophysical properties of new benzo- and naphtho[1,3]oxazine switches. AB - A new set of photochromic hindered benzo- and naphtho[1,3]oxazines with fast switching speed between the closed and open form were synthesised. Laser excitation of these uncoloured molecules (with ~10 ns FWHM pulses) leads to the cleavage of the C-O bond and opening of the oxazine ring in less than 20 ns, generating a thermally unstable coloured zwitterionic species that reverts in few nanoseconds to the initial oxazine closed form. For these derivatives a detailed spectroscopic and photophysical study was undertaken involving measurements of absorption and phosphorescence spectra, phosphorescence quantum yields (phi(Ph)), phosphorescence lifetimes (tau(Ph)), triplet energies (E(T)), singlet oxygen (phi(Delta)) and ring opening photoreaction (phi) quantum yields, reisomerization kinetics and the zwitterionic form lifetime. A remarkable solvent effect on the lifetime of the photogenerated species was observed. PMID- 21706111 TI - Ground and excited state properties of photoactive platinum(IV) diazido complexes: theoretical considerations. AB - Recently synthesized by the group of Sadler, the platinum(IV) diazido complexes [Pt(N(3))(2)(OH)(2)(L')(L'')] (L' and L'' are N-donor ligands) have potential to be used as photoactivatable metallodrugs in cancer chemotherapy. In the present study optimized structures and UV-Vis electronic spectra of trans,trans,trans- and cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] (1t and 1c, respectively) as well as cis,trans,cis-[Pt(N(3))(2)(OH)(2)(L)(2)] (L = NH(3), NH(2)CH(3), NF(3), PH(3), PF(3), H(2)O, CO, OH(-), CN(-), py, imid; 2c-11c) and cis,trans [Pt(N(3))(2)(OH)(2)(bpy)] (12c) complexes were predicted using density functional theory (DFT). The ground state electronic structures of all complexes were analyzed with the help of the natural bond orbital analysis (NBO). The electronic spectra of 1c and 1t were computed using time-dependent density functional theory (TDDFT) with five different density functionals and the ab initio CASSCF/CASPT2 method (for the five lowest energy transitions). The best agreement with available experiments was found in the case of the long-range corrected omegaB97X functional. The electronic transitions were characterized by the analysis of the natural transition orbitals (NTO). The low-lying excited singlet states of 1t and 1c have significant azide-to-platinum(IV) charge-transfer character (LMCT). Geometry optimization of the three lowest singlet excited states performed using TDDFT results in the simultaneous dissociation of two azide ligands with the formation of the azidyl radicals N(3) and photoreduction of Pt(IV) to Pt(II). Variation of the ligand L does not strongly affect the nature and the relative energies of the low-lying states. It is shown that the replacement of the OH(-) groups in 1c by OPh(-) ligands results in the red shift of the intense N(3)(-) >Pt LMCT band and the appearance of transitions with significant intensity in the visible region of the spectrum. The dissociative nature of the low-lying unoccupied orbitals remains unaffected. These theoretical results may suggest new experimental routes for the improvement of the photochemical activity of Pt(IV) diazido complexes. PMID- 21706112 TI - Highly effective chiral phosphorus amidite-olefin ligands for palladium-catalyzed asymmetric allylic substitutions. AB - This paper describes the development of a type of novel P-olefin hybrid ligand by the incorporation of terminal olefins onto phosphorus amidite ligands for palladium-catalyzed asymmetric allylic alkylations of indoles and substitutions with amines to give the desired products in 70-97% yield with 91-98% ee. PMID- 21706113 TI - Detection of viral nucleoprotein binding to anti-influenza aptamers via SERS. AB - A highly sensitive surface-enhanced Raman (SERS)-based method for detection of influenza viral nucleoproteins is described. The intrinsic SERS spectrum of the aptamer-nucleoprotein complex provides direct evidence of binding between a polyvalent anti-influenza aptamer and the nucleoproteins of three influenza strains. PMID- 21706114 TI - Gapped ferromagnetic graphene nanoribbons. AB - We theoretically design a graphene-based all-organic ferromagnetic semiconductor by terminating zigzag graphene nanoribbons (ZGNRs) with organic magnets. A large spin-split gap with a 100% spin polarized density of states near the Fermi energy is obtained, which is of potential application in spin transistors. The interactions among electron, spin and lattice degrees of freedom are studied using the first-principles calculations including non-collinear spin orientations. All of the calculations consistently demonstrate that although no d electrons existing, the antiferromagnetic pi-pi exchange together with the strong electron-lattice interactions between organic magnets and ZGNRs make the ground state ferromagnetic. PMID- 21706115 TI - Controlled growth and catalytic activity of gold monolayer protected clusters in presence of borohydride salts. AB - In the presence of large excesses of borohydride salts, gold monolayer protected clusters can be grown to larger sizes simply by controlling the amount of reducing agent added to smaller clusters. In addition, gold monolayer clusters can be used as catalysts for reduction reactions by sodium borohydride; results suggest such catalysts have sterically constrained active sites. PMID- 21706116 TI - Rapid (~10 min) synthesis of single-crystalline, nanorice TiO2 mesoparticles with a high photovoltaic efficiency of above 8%. AB - A novel rapid (~10 min) microwave-hydrothermal synthesis is demonstrated for nanorice TiO(2) mesoparticles as an anode of a dye-sensitized solar cell with an excellent photovoltaic efficiency of above 8%. PMID- 21706117 TI - Synthesis and metallic probe induced conductance of Au tipped ultranarrow PbS rods. AB - Au tipped ultranarrow PbS nanorods are synthesized. DFT electronic structure calculations and transport studies show that Au probes modify the nature and energies of PbS nanorod orbitals creating efficient electron conduction channels for enhanced conductance even at low applied bias. PMID- 21706118 TI - Zinc-zinc bonded decamethyldizincocene Zn2(eta(5)-C5Me5)2 as catalyst for the inter- and intramolecular hydroamination reaction. AB - The Zn-Zn bonded compound [(eta(5)-Cp*)(2)Zn(2)] was investigated as catalyst for the inter- and intramolecular hydroamination reaction. High reaction rates under mild conditions were observed. This is the first application of a Zn-Zn bonded compound as catalyst. PMID- 21706119 TI - A bright, slow cryogenic molecular beam source for free radicals. AB - We demonstrate and characterize a cryogenic buffer gas-cooled molecular beam source capable of producing bright beams of free radicals and refractory species. Details of the beam properties (brightness, forward velocity distribution, transverse velocity spread, rotational and vibrational temperatures) are measured under varying conditions for the molecular species SrF. Under typical conditions we produce a beam of brightness 1.2 * 10(11) molecules/sr/pulse in the X(2)Sigma(+)(v = 0, N(rot) = 0) state, with 140(m/s) forward velocity and a rotational temperature of ~ 1 K. This source compares favorably to other methods for producing beams of free radicals and refractory species for many types of experiments. We provide details of construction that may be helpful for others attempting to use this method. PMID- 21706120 TI - Influence of monovalent ion size on colloidal forces probed by Monte Carlo simulations. AB - The present work studies the role of ionic size in the interactions between the electrical double layers of colloids immersed into electrolyte solutions of monovalent ions. Such interactions are studied by means of Monte Carlo (MC) simulations and the classical Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. Despite the omission of the steric effects and some other features of real electrolyte solutions, DLVO theory is known to work qualitatively well for 1:1 electrolyte solutions. However, this affirmation is based on previous tests where an ionic diameter around 0.4 nm was taken for all ionic species. In contrast, some experimental studies suggest that larger hydrated ions should be considered and even specified for each type of ion. In this work, the importance of ionic size is analyzed by applying the primitive model of electrolyte to the intermediate region between a pair of equally charged infinite planar surfaces. The double layer interactions were calculated from the ionic densities at the distance of closest approach to the charged surfaces, this method constitutes an alternative to the traditional calculations at the midplane. Our MC simulations predict the existence of negative net pressures for monovalent electrolytes in the case of zero charge density. In addition, MC simulations reveal some disagreements with theoretical predictions for ionic diameters larger than 0.4 nm. These discrepancies can become significant if surface charge density is large enough due to the restructuration of the double layer. The physical mechanisms for these deviations are also discussed. PMID- 21706121 TI - Design, synthesis and evaluation of nitric oxide releasing derivatives of 3-n butylphthalide as antiplatelet and antithrombotic agents. AB - Novel nitric oxide (NO) releasing derivatives (7a-7l) of 3-n-butylphthalide (NBP) were designed and synthesized. Compound 7e inhibited the adenosine diphosphate (ADP), thrombin (TH) and arachidonic acid (AA)-induced in vitro platelet aggregation, superior to NBP and aspirin, released moderate levels of NO, and improved aqueous solubility relative to NBP. Furthermore, 7e exhibited greater antithrombotic activity than NBP and aspirin in rats, and protected against collagen and adrenaline-induced thrombosis in mice. Therefore, NO-releasing NBP derivatives possessed potent antiplatelet aggregation and antithrombotic activity. Our findings may aid in the design of new therapeutic agents for the treatment of thrombosis-related ischemic stroke. PMID- 21706122 TI - Personal, biomechanical, and psychosocial risk factors for rotator cuff syndrome in a working population. AB - OBJECTIVE: Rotator cuff syndrome (RCS) is a major health problem among workers. The aim of the study was to examine the risk factors for RCS among workers exposed to various levels of shoulder constraints. METHODS: From 3710 workers, representative of a French region's working population, trained occupational physicians diagnosed a total of 142 cases of RCS among men and 132 among women between 2002-2005. Diagnoses were established by standardized physical examination while personal factors and work exposure were assessed by self administered questionnaires. Statistical associations between RCS and personal and work-related factors were analyzed for each gender using logistic regression modeling. RESULTS: The personal risk factors for RCS were age [odds ratio (OR) for 1-year increment 1.07, 95% confidence interval (95% CI) 1.05-1.09, among men and 1.08, 95% CI 1.06-1.10, among women] and diabetes mellitus (OR 2.9, 95% CI 1.0-8.6, among women). The work-related risk factors were (i) sustained or repeated arm abduction (>= 2 hours/day) >90 degrees among men (OR 2.3, 95% CI 1.3 3.9) and >60 degrees among women (OR 1.8, 95% CI 1.0-3.2) or both conditions among men (OR 2.0, 95% CI 1.1-3.7) and women (OR 3.6, 95% CI 1.8-7.3); (ii) high repetitiveness of the task (>= 4 hours/day) among men (OR 1.6, 95% CI 1.0-2.4) and women (OR 1.7, 95% CI 1.1-2.5); (iii) high perceived physical demand among men (OR 2.0, 95% CI 1.3-3.1); (iv) high psychological demand among men (OR 1.7, 95% CI 1.2-2.5); and (v) low decision authority among women (OR 1.5, 95% CI 1.0 2.3). CONCLUSION: Personal (ie, age) and work-related physical (ie, arm abduction) and psychosocial factors were associated with RCS for both genders in this working population. PMID- 21706124 TI - Perceptions and attitudes of Japanese gynecologic cancer patients to Kampo (Japanese herbal) medicines. AB - BACKGROUND: Kampo (Japanese herbal) medicine is the complementary and alternative medicine that is most frequently used by Japanese doctors. We studied the perceptions and attitudes of Japanese gynecologic cancer patients to Kampo medicines and analyzed the characteristics of the backgrounds of Kampo users. METHODS: A total of 476 patients with gynecologic cancer completed a self reported questionnaire on Kampo medicine. State anxiety and trait anxiety were also assessed using the State-Trait Anxiety Inventory. RESULTS: It was confirmed that 22.9% of the women had used Kampo medicine. Kampo users were more likely to have had chemotherapy and were more likely to have experienced uncomfortable side effects of cancer treatment. Kampo users were more likely to believe that 'Kampo offers relief of symptoms,' 'fewer side effects than Western-style medicine,' and 'is not less effective than Western-style medicine' than nonusers. Kampo users expressed a stronger attitude of 'I want to take Kampo medicine.' Multiple risk ratio regression analysis revealed that chemotherapy (RR, 1.82; 95% CI, 1.14 2.91), lower state anxiety (RR, 0.76; 95% CI, 0.58-1.00), and higher trait anxiety (RR, 1.46; 95% CI, 1.11-1.92) were independently associated with Kampo use. CONCLUSIONS: This study showed that slightly less than one-fourth of Japanese gynecologic cancer patients take Kampo medicine. Kampo users made more favorable comments on Kampo medicine than nonusers. Our findings suggest that the psychological characteristics of individual patients is one of the factors that can influence the usage of Kampo. PMID- 21706123 TI - Outcome, clinical prognostic factors and genetic predictors of adverse reactions of intermittent combination chemotherapy with docetaxel, estramustine phosphate and carboplatin for castration-resistant prostate cancer. AB - OBJECTIVES: Docetaxel-based chemotherapy is effective in patients with castration resistant prostate cancer (CRPC). This phase II study assessed the outcome and predictive factors for prognosis and toxicity following intermittent chemotherapy with docetaxel, estramustine phosphate, and carboplatin (DEC) in patients with CRPC. METHODS: Thirty-five patients were treated with a DEC regimen that consisted of a 28-day cycle of drugs as follows: docetaxel (60 mg/m(2) on day 1), carboplatin (AUC 5 on day 1) and estramustine phosphate (560 mg daily). Treatment was continued intermittently. The end point was to test the effect of DEC on the response rate and overall survival (OS). Statistical correlations between the outcomes and predictive factors, including clinical parameters and 8 single nucleotide polymorphisms (SNPs) related to drug metabolism, were assessed. RESULTS: Prostate-specific antigen levels decreased by more than 30% in 65.7% of the patients. The median OS following DEC was 17.8 months, and the median total time of chemotherapy holiday was 7.7 months (range 1.7-35.8). On multivariate analysis, serum lactate dehydrogenase (LDH) was an independent prognostic factor for OS (p = 0.007). On SNP analysis, patients carrying the TT genotype of the ABCB1 C3435T polymorphism showed a significantly more severe leukocytopenia during the first cycle of DEC therapy compared to patients with the CC + CT genotype (p = 0.036). CONCLUSION: Combination chemotherapy with DEC has a potential effect on CRPC with acceptable toxicity. Serum LDH may be a promising predictor of prognosis, and the ABCB1 C3435T polymorphism may be a genetic predictor of the severity of leukocytopenia in patients with CRPC treated with DEC. PMID- 21706125 TI - Ileal perforation induced by acute radiation injury under gefitinib treatment. AB - Enteritis is one of the side effects of radiotherapy to the abdominal cavity. Radiation enteritis involves damage to mucous membranes in the acute phase and to stromal tissues in the late phase. Perforation of the intestine tends to occur in the late phase, and rarely in the acute phase. However, we describe here a case of intestinal perforation occurring in the acute phase after irradiation in a patient who received gefitinib treatment. Gefitinib, one of the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), is widely used to treat non-small cell lung cancer (NSCLC) patients, but is simultaneously known to inhibit wound healing. We suspect that gefitinib may affect regeneration of the small intestinal mucosa injured by irradiation. A 76-year-old woman had NSCLC with metastases to the 5th lumbar, sacral, and right iliac bones. To control the pain from bone metastasis, anterior-posterior opposing portal irradiation (total 35 Gy) was started, and was completed over 22 days. On day 25 after starting radiotherapy, the patient began to take gefitinib. On day 35, she presented with acute peritonitis, and an emergency laparotomy was performed. The terminal ileum was affected by radiation enteritis and there were two pin-hole perforations. In the surgical specimen, no cancerous lesions were detected, and immunohistochemical staining of phosphorylated EGFR (pEGFR) was negative. pEGFR has an important role in mucous membrane repair after irradiation. Intestinal perforation in the acute phase of radiation enteritis may be associated with impaired mucosal repair mechanisms due to the use of an EGFR-TKI such as gefitinib, as evidenced by the absence of pEGFR. PMID- 21706127 TI - Factors associated with quality of life in older adults in the United States. AB - PURPOSE: According to the World Health Organization, quality of life (QOL) includes physical and mental health, emotional well-being, and social functioning. Using an adaptation of Andersen's behavioral model, we examined the associations between the three dimensions of QOL and needs and health behaviors in a nationally representative sample of adults 65 years and older. METHODS: A representative sample from the 2005-2006 National Health and Nutrition Examination Survey (NHANES) was used. NHANES over-samples persons 60 years and older, African Americans, and Hispanics. Frequencies and distribution patterns were assessed, followed by bivariate and multiple regression analyses. RESULTS: These older adults reported high levels of QOL. However, associations between needs and health behaviors and QOL varied across dimensions. Activities of daily living (ADL) were associated with all three dimensions. Depression was associated with two dimensions and memory problems with one dimension. Physical activity was linked to social functioning, and health care utilization was linked to emotional well-being. CONCLUSIONS: The differences in associations with different dimensions of QOL confirm that this is a multidimensional concept. Since depression, memory problems, and ADL function were all associated with some dimension of QOL, future interventions to improve QOL in older adults should include screening and treatment for these problems. PMID- 21706128 TI - Individual interviews and focus groups in patients with rheumatoid arthritis: a comparison of two qualitative methods. AB - PURPOSE: To compare two different approaches to performing focus groups and individual interviews, an open approach, and an approach based on the International Classification of Functioning, Disability and Health (ICF). METHODS: Patients with rheumatoid arthritis attended focus groups (n = 49) and individual interviews (n = 21). Time, number of concepts, ICF categories identified, and sample size for reaching saturation of data were compared. Descriptive statistics, Chi-square tests, and independent t tests were performed. RESULTS: With an overall time of 183 h, focus groups were more time consuming than individual interviews (t = 9.782; P < 0.001). In the open approach, 188 categories in the focus groups and 102 categories in the interviews were identified compared to the 231 and 110 respective categories identified in the ICF-based approach. Saturation of data was reached after performing five focus groups and nine individual interviews in the open approach and five focus groups and 12 individual interviews in the ICF-based approach. CONCLUSION: The method chosen should depend on the objective of the study, issues related to the health condition, and the study's participants. We recommend performing focus groups if the objective of the study is to comprehensively explore the patient perspective. PMID- 21706129 TI - Production of classical swine fever virus envelope glycoprotein E2 as recombinant polyhedra in baculovirus-infected silkworm larvae. AB - Although, classical swine fever virus (CSFV) envelope glycoprotein E2 subunit vaccine has been developed using the baculovirus expression system, the expression of viral antigens in baculovirus-infected insect cells is often ineffective. Therefore, an alternative strategy to the traditional baculovirus expression system is needed that is more productive and effective. Here, we report a novel strategy for the large-scale production of a CSFV E2 in the larvae of a baculovirus-infected silkworm, Bombyx mori. We constructed a recombinant B. mori nucleopolyhedrovirus (BmNPV) that expressed recombinant polyhedra together with the N-terminal 179 amino acids of CSFV E2 (E2DeltaC). BmNPV-E2DeltaC infected silkworm larvae expressed native polyhedrin and approximately 44-kDa fusion protein that was detected using both anti-polyhedrin and anti-CSFV E2 antibodies. Electron and confocal microscopy both demonstrated that the recombinant polyhedra contained both the fusion protein and native polyhedrin were morphologically normal and contained CSFV E2DeltaC. The CSFV E2DeltaC antigen produced in BmNPV-E2DeltaC-infected silkworm larvae reached 0.68 mg/ml of hemolymph and 0.53 mg/larva at 6-days post-infection. Six-week-old female BALB/c mice that were immunized with the E2DeltaC protein purified from solubilized recombinant polyhedra elicited CSFV E2 antibodies, which indicated that the CSFV E2DeltaC protein from recombinant polyhedra was immunogenic. The virus neutralization test showed that the serum from mice that were treated with E2DeltaC protein from recombinant polyhedra contained significant levels of virus neutralization activity. These results demonstrate that this strategy can be used for the large-scale production of CSFV E2 antigen. PMID- 21706130 TI - Perinatal stroke: a case-based review. AB - Neonatal stroke is a diverse clinical entity. Terminology and aetiology described in the literature are very varied. While numerous risk factors are cited, only few case-control studies have investigated them in a systematic fashion. This equipoise extends to the investigational and management profile of perinatal stroke too. Controversy persists about the suitability of detailed haematological thrombophilia workup in the neonatal period. This case-based review details the variable clinical presentation in term and preterm neonates, discusses the current literature, ascertains the respective roles of various imaging modalities, explores relevant new neuroprotective interventions and proposes a systematic approach to clinical and neuroimaging workup. Long-term follow-up is important as many infants suffer neuro-disability, which might need early intervention strategies. PMID- 21706131 TI - Minimal disease detection in peripheral blood and bone marrow from patients with non-metastatic neuroblastoma. AB - PURPOSE: In non-metastatic neuroblastoma (NB), the identification of the cases that require more intensive treatment is still difficult. Minimal disease (MD) and minimal residual disease (MRD) detection in outcome prediction seems to be important in advanced neuroblastoma, but there are not many studies focused on patients with non-metastatic disease. The aim of this study was to determine whether the presence of MD detected at diagnosis could be associated with bad prognosis. PROCEDURES: Quantitative reverse transcriptase-polymerase chain reaction QRT-PCR was performed on peripheral blood (PB) and bone marrow (BM) samples from patients with non-metastatic NB at diagnosis for tyrosine hydroxylase (TH) and doublecortin (DCX) mRNAs detection. RESULTS: The frequencies of detecting MD in our series of 102 patients with non-metastatic NB were as follows: 6.2% (5/81) PB samples and 10.6% (10/94) BM samples. Overall survival was similar for patients who expressed or not the MD biomarkers at diagnosis. However, patients with MD detected in PB showed lower EFS than patients with negative PB (P = 0.038). CONCLUSIONS: Minimal disease detection in PB seems to be useful for predicting relapse probabilities in patients with non-metastatic NB. The stages 1 and 2 patients with neuroblastoma showed high survival rates, and MD was detected in a small number of patients probably being non-contributory for predicting patient outcome. For stage 3 patients with NB, MD detection by QRT-PCR in PB at diagnosis could be useful for predicting outcome and for early and sensitive detection of relapsing disease. PMID- 21706132 TI - Cancer stroma proteome expression profile of superficial bladder transitional cell carcinoma and biomarker discovery. AB - PURPOSE: To globally characterize the stroma expression profile of superficial bladder transitional cell carcinoma and to discuss the cancer biology as well as biomarker discovery from stromal cells. METHODS: Laser capture microdissection was used to harvest purified bladder cancer stromal cells and normal stromal cells from 4 paired samples. Next, two-dimensional liquid chromatography-tandem mass spectrometry was used to identify the proteome expression profile. The differential proteins were further analyzed using bioinformatics tools and compared with the published literature. RESULTS: A total of 606/601 proteins commonly appeared in 4 paired samples. Six hundred and thirty-seven proteins were differentially expressed between cancer and normal stroma. Among them, 321/316 proteins specific expressed in cancer/normal stromal cells. Differential proteins were compared with the entire list of the international protein index (IPI). 36/49 GO terms exhibited as enriched and 25/14 exhibited as depleted in biological process; 39/40 GO terms exhibited as enriched and 9/4 exhibited as depleted in cellular component, respectively. Significantly altered pathways between cancer/normal stroma mainly include focal adhesion, EHEC, oxidative phosphorylation, glycolysis/gluconeogenesis, TCA cycle. Finally, descriptive statistics show the data that PI <= 8 have normal distribution and the proteins with extremes of PI and MW have the same probability to be a biomarker. CONCLUSIONS: The present study identified the proteome expression profile of bladder cancer stromal cells and normal stromal cells. Furthermore, our results confirm proteins origin from stroma play important role in cancer biology and highlight a novel view of cancer and stress the importance of including factors related to the cancer stroma into biomarker discovery. PMID- 21706133 TI - A single episode of maternal deprivation impairs the motivation for cocaine in adolescent mice. AB - RATIONALE: Early-life adverse events, like maternal deprivation (MD), have been associated with the later development of mood and anxiety disorders. Scarce data are available describing behavioural and endocrine alterations in maternally deprived (DEP) animals during the periadolescent period. We hypothesize that a single episode of MD early in life would alter reward function and lead to a long lasting behavioural and neuroendocrine changes during adolescence. OBJECTIVES: Our aim was to evaluate the effects of a single episode of MD in CD1 adolescent mice (postnatal day 35) on a range of tests for anxiety- and depression-related behaviours (open field, elevated plus maze and tail suspension test). We further assess whether these effects could affect cocaine self-administration behaviour. In order to correlate behavioural and neuroendocrine responses to stress, brain derived neurotrophic factor (BDNF) levels were assessed in brain structures related to emotional and cognitive processes. RESULTS: During the cocaine self administration, the time required for achieving the acquisition criteria was significantly increased and the breaking point values in progressive schedule were significantly reduced in DEP adolescent mice, suggesting impairment in rewarding functions. The behavioural tests also confirm an increase in anxiety- and depression-related behaviours in DEP adolescent mice. The results on BDNF level indicated a decrease in response to MD in amygdala and hippocampus, confirming the behavioural data. CONCLUSIONS: Our findings demonstrated for the first time that a single episode of early MD can impair the motivation for cocaine consumption in adolescent mice and can be associated with anxiety- and depressive-like behaviour. PMID- 21706135 TI - Retracted article: Selective activation of the metabotropic glutamate receptor subtype 7 "mGluR7" attenuates acquisition, expression, and reinstatement of ethanol place preference. PMID- 21706134 TI - Genetic propensities to increase ethanol intake in response to stress: studies with selectively bred swim test susceptible (SUS), alcohol-preferring (P), and non-preferring (NP) lines of rats. AB - RATIONALE: Swim test susceptible (SUS) rats selectively bred for reduced struggling in the forced swim test (FST) following stress show high voluntary ethanol intake like alcohol-preferring (P) rats selectively bred for ethanol preference. It is unknown whether stress enhances drinking in SUS rats or FST behavior in P and non-preferring (NP) rats. OBJECTIVES: The aim of this study was to assess the response to stress in male SUS, Sprague-Dawley (SD), P, and NP rats on 10% ethanol drinking and FST behavior. METHODS: In experiment 1, SUS and SD rats had limited access to ethanol and water following white noise, rehousing, and forced swim stress. In experiment 2, P and NP rats received footshock, white noise, restraint, or no stress prior to the FST. Rats then had continuous access to ethanol and water, and the effects of weekly exposures to stress were measured. RESULTS: SUS rats drank more ethanol (M = 2.98 g/kg) than SD rats (M = 1.26 g/kg) at baseline. Stress produced sustained increases (~33% of baseline) in ethanol intake in SUS rats. NP rats spent twice as much time immobile as P rats in the FST. Stress did not alter FST behavior in P or NP rats. Only footshock produced an increase (~29%) in ethanol intake in P rats. CONCLUSIONS: Selection for stress-induced depressive-like behavior in SUS rats is associated with enhanced stress-induced ethanol drinking. However, the selection for alcohol preference is not associated with stress-induced depressive-like behavior but is associated with footshock stress-induced ethanol drinking. In these experiments, relationships among stress, depressive-like behavior, and alcohol preference were not symmetrical. PMID- 21706136 TI - Chemokine upregulation in response to anal sphincter and pudendal nerve injury: potential signals for stem cell homing. AB - PURPOSE: Stromal derived factor-1 (SDF-1) and monocyte chemotactic protein-3 (MCP 3) are signals forcing the migration of bone marrow-derived stem cells to ischemic tissue. This study investigates SDF-1 and MCP-3 expression following direct injury to the anal sphincter and pudendal nerve and to determine if these same mechanisms have any role. METHODS: Chemokine expression was studied after anal sphincter injury in female rats after either a sphincterotomy (n = 15), pudendal nerve crush (PNC; n = 15), sham pudendal nerve crush (n = 15), or acted as unmanipulated controls (n = 5). Analysis was done at 1 h and 10 and 21 days after injury. RESULTS: After injury, SDF-1 expression increased 40.2 +/- 6.42 (P = 0.01) at 1 h and 28.2 +/- 2.37 (P = 0.01) at 10 days, respectively, compared to controls. Likewise, MCP-3 expression increased 40.8 +/- 8.17 (P = 0.02) at the same intervals compared to controls. After PNC, SDF-1 expression increased 46.4 +/- 6.01 (P = 0.02) and 50.6 +/- 10.11 (P = 0.01), and MCP-3 expression increased 46.3 +/- 7.76 (P = 0.03) and 190.8 +/- 22.15 (P = 0.01), respectively, at the same time intervals compared to controls. However, when PNC was compared to sham injured, a significant increase was seen in SDF-1 and MCP-3 at 10 days. At 21 days, PNC compared to sham injured was significantly low in expression for both SDF-1 and MCP-3 (P < 0.05). CONCLUSIONS: Direct anal sphincter injury results in higher levels of SDF-1 and MCP-3 expression soon after injury, whereas denervation via pudendal nerve crush results in greater SDF-1 and MCP-3 expression 10 days after injury. Chemokine overexpression suggests the potential for cell-based therapeutic strategies. PMID- 21706137 TI - Association between OCTN1/2 gene polymorphisms (1672C-T, 207G-C) and susceptibility of Crohn's disease: a meta-analysis. AB - PURPOSE: Although a number of genetic studies have attempted to link organic cation transporter 1/2 (OCTN1/2) polymorphisms to susceptibility of Crohn's disease (CD), the results were often inconsistent. The present study aimed at investigating the associations. METHODS: The PubMed, EBSCO, and BIOSIS databases were searched to identify eligible studies which were published in English before April 2011. The association was assessed by odds ratio (OR) with 95% confidence intervals (CI). RESULTS: A total of 15 case-control studies, containing 4,489 cases/5,351 controls for OCTN1 and 4,474 cases/5,377 controls for OCTN2 were included. Overall, significant associations were found between OCTN1/2 polymorphisms and susceptibility of Crohn's disease for all genetic models. In the subgroup analyses, significant associations were found in the Caucasian population for OCTN1 (TT vs. CC: OR = 1.425, 95% CI 1.247-1.628; TT vs. CT: OR = 1.299, 95% CI 1.149-1.468; dominant model: OR = 1.344, 95% CI 1.197-1.508; and recessive model: OR = 1.179, 95% CI 1.066-1.305) and for OCTN2 (CC vs. GG: OR = 1.309, 95% CI 1.078-1.588; CC vs. CG: OR = 1.200, 95% CI 1.002-1.438; dominant model (OR = 1.231, 95% CI 1.036-1.462; recessive model: OR = 1.148, 95% CI 1.031 1.279). Significant associations were not found in the East Asian population. CONCLUSIONS: This meta-analysis suggests that OCTN1/2 polymorphisms were associated with susceptibility of CD in the Caucasian population but not in the East Asian population. PMID- 21706138 TI - Perioperative quality of care is modulated by process management with clinical pathways for fast-track surgery of the colon. AB - PURPOSE: Clinical pathways (CPs) are increasingly used to improve quality of care. However, evidence if such improvements are also feasible in fast-track colorectal surgery is lacking. This study evaluates effects of a CP for fast track colonic resections with respect to process and outcome quality. METHODS: We compared 78 consecutive patients undergoing colonic resections in 2008 and being treated with a CP (CP group) with 133 consecutive patients treated without CP between 2006 and 2007 (pre-CP group). Indicators for process quality were epidural catheter placement, postoperative mobilisation, resumption of solid diet, Foley catheter removal and length of stay. Outcome quality was measured through morbidity, mortality, re-operations and readmissions. RESULTS: In the CP group, patients received epidural analgesia significantly more often (87.2% vs. 75.2%; p =0.04), were mobilized (38.9% vs. 20.6% on the day of surgery; p = 0.03) and resumed a solid diet earlier (60.5% vs. 49.6% on day 1; p = 0.002). Foley catheter removal and length of stay did not differ between the groups. There were no significant differences regarding morbidity (28.2% vs. 32.3%), mortality (1.2% vs. 2.3%), re-operations (6.4% vs. 9.0%) and readmissions (2.6% vs. 3.8%). CONCLUSIONS: After CP implementation for fast-track surgery of the colon, several indicators of process quality improved while others such as length of stay remained unaltered. There were no significant changes in outcome parameters. CPs are a viable instrument to improve specific aspects of perioperative process management, but their selective benefits have to be critically weighed against the infrastructural and personal efforts required for design and implementation. PMID- 21706140 TI - Acute kidney injury in a patient with psychological eating disorder. PMID- 21706139 TI - ABA signaling in stomatal guard cells: lessons from Commelina and Vicia. AB - Abscisic acid (ABA) signaling mechanisms have been studied in a broad variety of plant species using complementary analyses, taking advantage of different methodologies suitable for each plant species. Early studies on ABA biosynthesis using Solanum lycopersicum mutants suggested an importance of ABA synthesis in stomatal closure. To understand ABA signaling in guard cells, cellular, biochemical and electrophysiological studies in Vicia faba and Commelina communis have been conducted, providing fundamental knowledge that was further reconfirmed by molecular genetic studies of Arabidopsis. In this article, examples of stomatal studies in several plants and prospects in ABA research are discussed. PMID- 21706141 TI - Deeply dissecting stemness: making sense to non-coding RNAs in stem cells. AB - Adult stem cells are an important source for the regeneration of damaged body parts. Unlike fish and amphibians, the regeneration capacity of human tissues is rather limited. Therefore, one might ask for reasons that led to the loss of regenerative capacity during evolution. Although intensive efforts have been made, we still cannot answer this question definitively. Recent advances in so called "-omics" (e.g. transcriptomics, proteomics) technologies allowed researchers to obtain detailed views of both mRNA and protein expression levels at different time points during regeneration and tissue repair. It is now possible to make a series of snap shots to characterize stem cell activities at various stages. Recent findings have revealed an enormous plasticity of different cell types reaffirming the landscape model of cell differentiation. Apparently, differentiation of stem cells into a certain lineage is not a fixed process but rather a delicate balance, in which different signaling pathways are involved. To understand this balance, it is utmost importance to profile and catalog changes that occur during the differentiation process of stem cells both at mRNA and protein levels. In this review, we survey the impact of expression profiling on stem cell research with a particular emphasis on non-coding RNAs. PMID- 21706142 TI - The role of chemokines in mesenchymal stem cell homing to myocardium. AB - A growing body of preclinical evidence suggests that mesenchymal stem cells (MSCs) are effective for the structural and functional recovery of the infracted heart. Accordingly, clinical trials are underway to determine the benefit of MSC based therapies. While systemic administration of MSCs is an attractive strategy, and is the route currently used for the administration of MSCs in clinical studies for myocardial infarction, the majority of infused cells do not appear to localize to infracted myocardium in animal studies. Recently, important progress has been made in identifying chemokine receptors critical for the migration and homing of MSCs. Here, we review recent literature regarding mechanisms of MSC homing and recruitment to the ischemic myocardium, and discuss potential influences of low engraftment rates of systemically administered MSCs to the infracted heart tissue on the effects of MSC-based therapies on myocardial infarction. PMID- 21706143 TI - Are circulating gonadotropin isoforms naturally occurring biased agonists? Basic and therapeutic implications. AB - The gonadotropins, luteinizing hormone, human chorionic gonadotropin and follicle stimulating hormone, are key regulators of reproduction. As a result of this function, they have been the focus of research for many years. Isolated or recombinant proteins have been successfully used therapeutically for the treatment of infertility; and, in the case of compounds that block gonadotropin activity, for their potential utility in contraception. Until recently, selective small molecules modulating gonadotropin receptor activity have proven difficult to identify. The gonadotropins are glycoproteins that are released into the plasma as differently glycosylated isoforms and bind to specific G protein coupled receptors. The degree of glycosylation on the gonadotropins has been shown to be important for the biological activities of these hormones and is differentially regulated depending on the steroidal status. Recent data from the study of glycosylated variants of LH, hCG and FSH have revealed that these isoforms have distinct signaling properties that allow for gonadotropin pleiotropic signals to be transduced effectively at the level of the receptor. Thus, glycosylated variants of the gonadotropins behave as biased agonists. Recently, newly developed, small molecule, synthetic allosteric compounds have been identified that are capable of mimicking this biased signaling. This opens the door to development of orally available, drug-like therapies for reproductive disorders that offer similar pleiotropic richness as that offered by the complex, endogenous hormones. PMID- 21706144 TI - The impact of signet-ring cell carcinoma histology on bladder cancer outcome. AB - BACKGROUND: Signet-ring cell carcinoma (SRCC) of the urinary bladder is a rare entity. No previous studies have directly compared the cancer-specific survival of patients with SRCC to patients with urothelial carcinoma (UC) of the urinary bladder. MATERIALS AND METHODS: Patients with diagnosis of urinary bladder SRCC and UC were identified in the Surveillance, epidemiology, and end results program (SEER) (2001-2004). Demographic of patients and clinical characteristics at diagnosis were compared. Differences in cancer-specific survival were compared using univariate and multivariate analysis. RESULTS: A total of 103 patients with SRCC and 14,648 patients with UC were indentified. Patients with SRCC were younger (P < 0.001), more commonly presented with higher-grade histology (P < 0.001) and advanced stage disease (P < 0.001), in comparison with patients with UC. The 3-year cancer-specific survival rate was 67.0% for patients with UC and 33.2% for SRCC. On multivariate analysis, there was an increased mortality risk in patients with SRCC versus UC (HR 1.49, 95% CI 1.11-2.00, P < 0.01). CONCLUSIONS: Even after adjusting for demographic, surgical, and pathological factors, cancer-specific survival rate was significantly worse in patients with SRCC compared to UC. Further research into the biology of this rare tumor is required to explain these results. PMID- 21706146 TI - Right ventricular volume analysis by angiography in right ventricular cardiomyopathy. AB - Imaging of the right ventricle (RV) for the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is commonly performed by echocardiography or magnetic resonance imaging (MRI). Angiography is an alternative modality, particularly when MRI cannot be performed. We hypothesized that RV volume and ejection fraction computed by angiography would correlate with these quantities as computed by MRI. RV volumes and ejection fraction were computed for subjects enrolled in the North American ARVC/D Registry, with both RV angiography and MRI studies. Angiography was performed in the 30 degrees right anterior oblique (RAO) and 60 degrees left anterior oblique (LAO) views. Angiographic volumes were computed by RAO view and two-view (RAO and LAO) formulae. 17 subjects were analyzed (11 men and 6 women), with 15 subjects classified as affected, and two as unaffected by modified Task Force criteria. The correlation coefficient of MRI to the two-view angiographic analysis was 0.72 (P = 0.003) for end-diastolic volume and 0.68 (P = 0.005) for ejection fraction. Angiographically derived volumes were larger than MRI derived volume (P = 0.009) and with the slope in a linear relationship equal to 0.8 for end diastolic volume, and 0.9 for RV ejection fraction (P < 0.001), computed by the two view formula. End-diastolic volumes and ejection fractions of the RV obtained by dual view angiography correlate with these quantities by MRI. RV end-diastolic volumes are larger by RV angiography in comparison with MRI. PMID- 21706145 TI - Romiplostim for the treatment of chronic immune thrombocytopenia in adult Japanese patients: a double-blind, randomized Phase III clinical trial. AB - The efficacy and safety of romiplostim, a thrombopoietin-mimetic peptibody, were evaluated in a double-blind, placebo-controlled, randomized trial of Japanese patients with chronic immune thrombocytopenia (ITP). Thirty-four ITP patients received romiplostim (n = 22) or placebo (n = 12) for 12 weeks, with a starting romiplostim dose of 3 MUg/kg weekly. The primary end point was the number of weeks with platelet response, defined as a platelet count >=50 * 10(9)/L (not including the 4 weeks after rescue medication administration). Patients received a median of 4 (range 1-19) prior ITP therapies including splenectomy in 44%. On study, 68% also received concomitant ITP therapy. Weekly responses occurred for a median of 11 weeks with romiplostim as compared to 0 weeks with placebo (p < 0.0001). Most romiplostim-treated patients (95%) achieved platelet responses; two showed extended responses after the treatment period. The use of rescue medication was required in 9% of romiplostim-treated patients as compared with 17% of placebo-treated patients. Both treatment groups had similar incidences of adverse events (91% romiplostim, 92% placebo). Adverse events that occurred more frequently (>10%) in romiplostim-treated patients included nasopharyngitis, headache, peripheral edema, back pain, and extremity pain. In conclusion, romiplostim significantly increased and maintained platelet counts and was well tolerated in Japanese patients with ITP. PMID- 21706147 TI - Very small calcifications are detected and scored in the coronary arteries from small voxel MDCT images using a new automated/calibrated scoring method with statistical and patient specific plaque definitions. AB - A negative (zero) Agatston coronary calcium score (CCS) by current methods confers a very low risk for hard coronary events during the next years. However, controversy remains on how to use a negative score since some hard events still occur. We report on a new method with improved detection sensitivity for very small calcifications with the potential to more confidently rule out early atherosclerotic disease. Seventy-eight (78) patients with negative Agatston scores by conventional methods with 2.5 mm slices were selected from routine GE 64 MDCT scans. Each scan was reconstructed a second time from the same data to create 0.625 mm isotropic voxels. The 2.5 mm images were manually scored by the usual Agatston method using the GE SmartScoreTM software. Both the 2.5 and 0.625 mm image sets were scored with a new automated and calibrated method (N-vivoTM, Image Analysis). The software automatically computes dual scoring thresholds that are statistically defined and specific for each patient, scanner, and scan. The images were hybrid calibrated by simultaneous scanned phantoms in combination with in vivo blood/muscle references. The output reported the calibrated mass scores along with the number of plaques using 18 pt, 3-D connectivity criteria. A CCS Test phantom with known CaHA microspheres was used to validate the method. Twenty-three percent (18 of 78) of the patients with negative Agatston scores by the conventional method scored positive for coronary calcifications by the N-vivo method. The number of small plaques scored per patient varied from 1 to 4. One patient with a single small calcification suffered a hard coronary event during the CT scan. All of the detected plaques were located in the proximal heart. The conventional CCS method misclassified 23% of these patients as having negative coronary calcium scores. The N-vivo automated scoring method with small voxel CT images increased the detection sensitivity of small calcifications with no increase in radiation dose. Detection of small coronary calcified plaques occult to conventional scoring methods may increase the negative predictive power of calcium scoring and may improve plaque composition analysis. PMID- 21706149 TI - Biweekly cetuximab plus irinotecan as second-line chemotherapy for patients with irinotecan-refractory and KRAS wild-type metastatic colorectal cancer according to epidermal growth factor receptor expression status. AB - BACKGROUND: Cetuximab plus irinotecan has been shown to be effective in metastatic colorectal cancer (mCRC) patients with wild-type (WT) KRAS and positive EGFR expressions (EGFR+). Retrospective analysis revealed that the efficacy of cetuximab was similar in mCRC patients negative (EGFR-) and positive for EGFR. However, the efficacy of cetuximab has not been assessed prospectively in EGFR- mCRC patients. METHODS: This was a prospective, multicenter phase II study assessed the efficacy and safety of biweekly cetuximab (500 mg/m(2)) and irinotecan (150-180 mg/m(2)) in patients with histologically proven adenocarcinoma with WT-KRAS and measurable lesion(s), either EGFR + or EGFR-, determined immunohistochemically, who failed first-line irinotecan-containing chemotherapy. The primary endpoint was response rate (RR), and the secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). RESULTS: Forty patients were enrolled; 20 EGFR + and 20 EGFR-; their baseline characteristics were balanced. The overall RR was 45% (18/40, 95% CI 29.6-60.4), 55% (11/20) in EGFR + and 35% (7/20) in EGFR- patients. Median PFS was 7.1 months (95% CI 4.8-9.4), 8.3 months in EGFR + and 4.9 months in EGFR- patients. Median OS was 18.5 months (95% CI 15.2-21.8), 17.2 months in EGFR + and 18.5 months in EGFR- patients. Grade 3 or 4 toxicities included neutropenia in 5 patients (12.5%) and febrile neutropenia/skin rash/asthenia in 2 (5%). CONCLUSIONS: Biweekly cetuximab plus irinotecan as second-line treatment showed significant anti-tumor activity in patients with irinotecan-refractory mCRC and WT-KRAS regardless of EGFR expression status. PMID- 21706150 TI - Dexamethasone for adult community-acquired bacterial meningitis: 20 years of experience in daily practice. AB - The aim of the study was to assess adjunctive intravenous dexamethasone in adult community-acquired bacterial meningitis (BM) in daily practice. Analysis of consecutive patients (1990-2009) with acute community-acquired bacterial meningitis in a single centre in Zagreb, Croatia, N = 304. Adjusted relative risks [RR, dexamethasone vs. no dexamethasone (control)] of Glasgow Outcome Scale (GOS) = 1 (death) and GOS = 5 (full recovery) at discharge/end of specific treatment were estimated considering demographics; co-morbidity; BM pathogenesis and on-admission characteristics, and cerebrospinal fluid (CSF) inflammation markers; causative agent and antibiotic use. Two hundred forty (79%) patients had proven BM (43.1% Streptococcus pneumoniae, any other agent <= 8.2%). No independent effects of dexamethasone on GOS = 1 or GOS = 5 were observed in the entire cohort (dexamethasone n = 119, control n = 185; RR = 1.06, 95% CI 0.77 1.45 and RR = 0.99, CI 0.83-1.20, respectively), microbiologically proven disease (dexamethasone n = 104, control n = 136; RR = 0.97, CI 0.69-1.38 and RR = 1.03, CI 0.82-1.28), pneumococcal disease (dexamethasone n = 71, control n = 60; RR = 0.95, CI 0.53-1.70 and RR = 0.82, CI 0.57-1.18), and also in other BM, subgroups based on consciousness disturbance, CSF markers, prior use of antibiotics and timing of appropriate antibiotic treatment. CSF markers did not predict the outcomes. CONCLUSIONS: Our experience does not substantiate the reported benefits of adjunctive dexamethasone in adult BM. Socio-economic and methodological factors do not seem to explain this discrepancy. Empirical use of dexamethasone in this setting appears controversial. PMID- 21706148 TI - Modes of Abeta toxicity in Alzheimer's disease. AB - Alzheimer's disease (AD) is reaching epidemic proportions, yet a cure is not yet available. While the genetic causes of the rare familial inherited forms of AD are understood, the causes of the sporadic forms of the disease are not. Histopathologically, these two forms of AD are indistinguishable: they are characterized by amyloid-beta (Abeta) peptide-containing amyloid plaques and tau containing neurofibrillary tangles. In this review we compare AD to frontotemporal dementia (FTD), a subset of which is characterized by tau deposition in the absence of overt plaques. A host of transgenic animal AD models have been established through the expression of human proteins with pathogenic mutations previously identified in familial AD and FTD. Determining how these mutant proteins cause disease in vivo should contribute to an understanding of the causes of the more frequent sporadic forms. We discuss the insight transgenic animal models have provided into Abeta and tau toxicity, also with regards to mitochondrial function and the crucial role tau plays in mediating Abeta toxicity. We also discuss the role of miRNAs in mediating the toxic effects of the Abeta peptide. PMID- 21706151 TI - A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease with motor neuron degeneration. Riluzole is the only available treatment. Two-thirds of ALS patients present with growth hormone (GH) deficiency. The aim of this study is to determine if add-on of GH to riluzole, with an individually regulated dose based on Insulin-like growth factor 1 (IGF-I) production, was able to reduce neuronal loss in the motor cortex, reduce mortality, and improve motor function of ALS patients. Patients with definite/probable ALS, in treatment with riluzole, aged 40-85 years, and with disease duration <=3 years were enrolled. The study was randomized, placebo controlled, and double blind. Before treatment, patients were tested with a GH releasing hormone (GHRH) + arginine test. The initial dose of GH was 2 IU s.c. every other day, and was progressively increased to a maximum of 8 IU. Primary endpoint was N-acetylaspartate/(creatine + choline) (NAA/Cre + Cho) ratio in motor cortex assessed by magnetic resonance spectroscopy performed at months 0, 6, and 12. Secondary endpoints were mortality and ALS functional rating scale revised (ALSFRS-R). The NAA/(Cre + Cho) ratio decreased in all patients who completed the trial. No significant difference was noted between treated and placebo group. At baseline, although IGF-I levels were within the normal range, 73% of patients had GH deficiency, being severe in half of them. Compared with bulbar onset, spinal-onset patients showed more depressed GH response to the GHRH + arginine stimulation test (10.4 +/- 7.0 versus 15.5 +/- 8.1 ng/mL; p < 0.05). Insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] increased from 2.1 +/- 1.0 at baseline to 4.6 +/- 1.9 at 12 months (p < 0.001). Insulin-like growth factor (IGF) binding protein 3 (IGFBP-3) decreased from 8,435 +/- 4,477 ng/mL at baseline to 3,250 +/- 1,780 ng/mL at 12 months (p < 0.001). The results show that GH exerted no effect on cerebral NAA or clinical progression assessed by ALSFRS-R. Two-thirds of ALS patients had GH deficit, with higher levels in the bulbar-onset group. During follow-up, patients showed progressive increase in HOMA-IR and decrease in IGFBP-3 levels. PMID- 21706152 TI - Progress in Alzheimer's disease. AB - After more than one century from Alois Alzheimer and Gaetano Perusini's first report, progress has been made in understanding the pathogenic steps of Alzheimer's disease (AD), as well as in its early diagnosis. This review discusses recent findings leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological markers. In addition, treatment options will be discussed, with emphasis on new disease-modifying compounds and future trial design suitable to test these drugs in an early phase of the disease. PMID- 21706153 TI - Primary internal fixation and soft-tissue reconstruction in the treatment for an open Lisfranc fracture-dislocation. AB - The importance of anatomical reduction for improved outcome has been recognised in the management of Lisfranc injuries. Operative fixation is indicated in case of dislocation or unstable ligamentous injury, because discongruity of the Lisfranc joint can lead to deleterious functional outcome. Screws are the recommended method of fixation of the medial en middle column, and K-wires are used for stabilisation of the unstable lateral column. Primary arthrodesis can provide advantages in pure ligamentous injury. In the management of complex open Lisfranc fractures, external fixation with K-wires can be used, but often results in a high percentage of arc deformities and functional limitations. In recent years, there is a progressive change from external to internal fixation in primary stabilisation of open fractures. This case report describes the treatment for a grade III open Lisfranc fracture-dislocation by use of primary internal fixation and soft-tissue reconstruction. PMID- 21706154 TI - Volume slicing of cone-beam computed tomography images for navigation of percutaneous scaphoid fixation. AB - PURPOSE: Percutaneous scaphoid fixation (PSF) is growing in popularity as a treatment option for non-displaced fractures. Success of this procedure demands high-precision screw placement, which can be difficult to achieve with standard 2D imaging. This study aimed to develop and test a system for computer-assisted navigation using volume slicing of 3D cone-beam computed tomography (CBCT). METHODS: The navigated technique involved a distinctive workflow in which a 3D CBCT imager was calibrated preoperatively, circumventing the need for intraoperative patient-based registration. Intraoperatively, a 3D CBCT image was acquired for both preoperative planning and direct navigation using volume rendered slices. An in vitro study was conducted to compare the navigated approach to two conventional fluoroscopic methods for volar PSF. The surgical goal was to insert a guide wire to maximize both length and central placement. RESULTS: There was no significant difference in the mean central placement of guide wire, although the variance in central placement was significantly lower using VS navigation (P < 0.01). The lengths of the drill paths were significantly longer for the VS-navigated group compared with one 2D group (P < 0.1). Each navigated trial required only one drilling attempt and resulted in less radiation exposure than conventional C-arm (P < 0.01). CONCLUSIONS: Volume-sliced navigation achieved a more repeatable and reliable central pin placement, with fewer drilling attempts than conventional 2D techniques. Volume-sliced navigation had a higher number of drill paths within the optimal zone maximizing both length of the path and depth from the surface. PMID- 21706155 TI - Multiple primary malignancies: analysis of 23 patients with at least three tumors. AB - BACKGROUND: There is scarcity of reports addressing patients with three or more malignancies. The aim of this study is to present a detailed analysis of patients presenting with at least three primary malignant tumors. PATIENTS AND METHODS: Records of cancer patients presenting to King Hussein Cancer Center (Amman, Jordan) between June 2006 and March 2011 were retrospectively reviewed. Patients harboring multiple primary tumors were included for detailed analysis. Data relating to epidemiological features, pathological characteristics, and disease outcomes were extracted. RESULTS: Out of 14,040 cases, 319 patients (2.3%) harbored two or more while 23 patients (0.16%) harbored three or more primary malignant tumors. This study included 17 males and six females between 4 and 78 years of age (median, 52 years) at the time of diagnosis of the first malignancy. The most prevalent tumor was colorectal adenocarcinoma found in nine, followed by lymphoma in seven, and prostate adenocarcinoma in six patients. The most common tumor combinations were colorectum-non-melanoma skin, colorectum-kidney, and non melanoma skin-kidney all found in four patients, respectively. At a median follow up of 96 months from the time of diagnosis of the first primary (range, 2-337 months) and 8 months from the time of diagnosis of the last primary (range, 1-48 months), 13 were alive with no evidence of disease, six were alive with residual disease, three were dead due to disease, and one patient was alive with unknown disease status. CONCLUSIONS: The possibility of multiple primary malignancies should always be considered during the treatment and follow-up of cancer patients. This case series could prove helpful to clinicians faced with similar, however, exceedingly rare scenarios. Due to the realistic potential for long-term survival, we recommend aggressive treatment of these patients. PMID- 21706156 TI - MDM2 SNP309 and TP53 R72P associated with severe and febrile neutropenia in breast cancer patients treated with 5-FU/epirubicin/cyclophosphamide. AB - The aim of this study was to investigate the association of two genetic polymorphisms, MDM2 SNP309 and TP53 R72P, with incidence of neutropenia in breast cancer patients treated with 5-FU/epirubicin/cyclophosphamide (FEC). Primary breast cancer patients (n = 216) treated with adjuvant FEC (60, 75 or 100 mg/m(2)) were included in this study. The association of genotypes of MDM2 SNP309 and TP53 R72P, determined by TaqMan SNP Genotyping Assays, with febrile neutropenia (FN) was investigated. In the patients treated with FEC100, G/G genotype for MDM2 SNP309 (G/G genotype( MDM2 )) was significantly (P < 0.01) associated with a lower incidence (5.3 vs. 39.2%) of severe neutropenia (<100/mm(3)) than with T/T + T/G genotypes( MDM2 ), and C/C genotype for TP53 R72P (C/C genotype( TP53 )) was significantly (P = 0.03) associated with a higher incidence (58.3 vs. 27.3%) of FN than with G/G + G/C genotypes( TP53 ). The combination of C/C genotype( TP53 ) and T/T + T/G genotype( MDM2 ) showed the highest risk for developing severe neutropenia (83.3%) and FN (62.5%) than any other combinations. In the patients treated with FEC60 or FEC75, there was no significant association of MDM2 SNP309 and TP53 R72P with severe neutropenia and FN. MDM2 SNP309 and TP53 R72P are significantly associated with severe neutropenia and FN, respectively, in breast cancer patients treated with FEC100, and especially their combination may be a useful predictor of severe neutropenia and FN. PMID- 21706157 TI - NQO1 expression correlates inversely with NFkappaB activation in human breast cancer. AB - NQO1 participates in cellular defense against oxidative stress and regulates apoptosis via p53- and NFkappaB-mediated pathways. We have previously found that homozygous missense variant NQO1*2 (rs1800566) predicts poor survival among breast cancer patients, particularly after anthracycline-based adjuvant chemotherapy. Here, we investigated NQO1 and NFkappaB protein expression and global gene expression profiles in breast tumors with correlation to tumor characteristics and survival after adjuvant chemotherapy. We used immunohistochemical analysis of tissue microarrays to study NQO1 and NFkappaB expression in two series of tumors: 1000 breast tumors unselected for treatment and 113 from a clinical trial comparing chemotherapy regimens after anthracycline treatment in advanced breast cancer. We used gene expression arrays to define genes co-expressed with NQO1 and NFkappaB. NQO1 and nuclear NFkappaB were expressed in 83% and 11% of breast tumors, and correlated inversely (P = 0.012). NQO1 protein expression was associated with estrogen receptor (ER) expression (P = 0.011), whereas 34.5% of NFkappaB-nuclear/activated tumors were ER negative (P = 0.001). NQO1 protein expression and NFkappaB activation showed only trends, but no statistical significance for patient survival or outcome after anthracycline treatment. Gene expression analysis highlighted 193 genes that significantly correlated with both NQO1 and NFkappaB in opposite directions, consistent with the expression patterns of the two proteins. Inverse correlation was found with genes related to oxidation/reduction, lipid biosynthesis and steroid metabolism, immune response, lymphocyte activation, Jak-STAT signaling and apoptosis. The inverse relationship between NQO1 protein expression and NFkappaB activation, underlined also by inverse patterns of association with ER and gene expression profiles of tumors, suggests that NQO1-NFkappaB interaction in breast cancer is different from several other tissue types, possibly due to estrogen receptor signaling in breast cancer. Neither NQO1 nor NFkappaB protein expression appear as significant prognostic or predictive markers in breast cancer. PMID- 21706158 TI - High risk of unilateral recurrent laryngeal nerve paralysis after esophagectomy using cervical anastomosis. AB - The goal of this study was to estimate the incidence of temporary and permanent unilateral recurrent laryngeal nerve paralysis (URLNP) after esophagectomies with cervical anastomosis and to determine the impact of surgical technique, tumor type, tumor localization and age on the incidence of URLNP. From March 2002 to November 2009, 84 patients underwent a laryngoscopical evaluation before and after esophagectomy with cervical anastomosis prospectively. If the postoperative URLNP recovered within 6 months, the paresis was classified as transient; if not, it was defined as permanent. The results indicate that the overall incidence of postoperative URLNP was 50% (42/84). Twenty-four of the 84 patients (28.6%) showed a transient URLNP. A permanent URLNP was observed in 9 of the 84 patients (10.7%). The remaining 9 of the 84 patients (10.7%) were categorized as paresis with unknown clinical outcome due to missing follow-up. There were significantly more postoperative URLNPs in the group operated by transthoracic esophagectomy than by transhiatal esophagectomy (p < 0.001). Multifocal tumors and those localized suprabifurcational showed a higher incidence of postoperative URLNP than unifocal lesions with infrabifurcational localization (p = 0.046). Histological type of tumor and patients' age had no impact on URLNP. The high incidence of URLNP in our study underlines the high risk of URLNP after esophagectomy with cervical anastomosis, and consequently the importance of routine laryngoscopic pre- and postoperative evaluation of the vocal fold motility. PMID- 21706159 TI - Management of total laryngectomy patients over time: from the consultation announcing the diagnosis to long term follow-up. AB - Throat cancer has always struck people's imagination. This type of cancer affects some of the patient's most essential physiological functions: speaking, swallowing and breathing. At advanced stages, radical surgery is disabling. The impact of a mutilated larynx corresponds to a very real trauma that is both individual and social. Our aim is to define how a total laryngectomy (TL) is represented by both the surgeon and the patient. The history of TL makes it possible to understand the changes that were needed for the key players in the subject to impose or accept this operation. Without doubt, the implementation of the "cancer plan" in the early 2000s was a major turning point in the management of patients with neoplasia. Increased awareness among the elite, encouraged by the mobilisation of patients and their families, is the explanation for the new role played by TL in 2008. The progress made in medical and surgical techniques, modifications to the patient-carer relationship and the appearance of the concept of Quality of Life are all themes that have changed the approach to this operation and the management of patients undergoing a TL. PMID- 21706160 TI - Transcriptome profiling and molecular marker discovery in red pepper, Capsicum annuum L. TF68. AB - Transcriptome from high throughput sequencing-by-synthesis is a good resource of molecular markers. In this study, we present utility of massively parallel sequencing by synthesis for profiling the transcriptome of red pepper (Capsicum annuum L. TF68) using 454 GS-FLX pyrosequencing. Through the generation of approximately 30.63 megabases (Mb) of expressed sequence tag (EST) data with the average length of 375 base pairs (bp), 9,818 contigs and 23,712 singletons were obtained by raw reads assembly. Using BLAST alignment against NCBI non-redundant and a UniProt protein database, 30% of the tentative consensus sequences were assigned to specific function annotation, while 24% returned alignments of unknown function, leaving up to 46% with no alignment. Functional classification using FunCat revealed that sequences with putative known function were distributed cross 18 categories. All unigenes have an approximately equal distribution on chromosomes by aligning with tomato (Solanum lycopersicum) pseudomolecules. Furthermore, 1,536 high quality single nucleotide discrepancies were discovered using the Bukang mature fruit cDNA collection (dbEST ID: 23667) as a reference. Moreover, 758 simple sequence repeat (SSR) motif loci were mined from 614 contigs, from which 572 primer sets were designed. The SSR motifs corresponded to di- and tri- nucleotide motifs (27.03 and 61.92%, respectively). These molecular markers may be of great value for application in linkage mapping and association mapping research. PMID- 21706161 TI - Molecular characterization, recombinant expression in Escherichia coli and biological activity of (S)-Tetrahydroberberine oxidase from Corydalis saxicola Bunt. AB - (S)-Tetrahydroberberine [(S)-THB] oxidase is the last enzyme of benzylisoquinoline alkaloids pathway which catalyzes the dehydrogenation of four hydrogen atoms of (S)-THB to produce berberine, the final step of berberine biosynthesis. A (S)-THB gene, designated as Cs(S)-THBO (Genbank accession No. HQ393909), was cloned from a Corydalis saxicola cDNA library by rapid amplification of cDNA ends. The full-length of cDNA of Cs(S)-THBO was 1127 bp with an open reading frame of 699 bp that predicted to encode a 232-amino acid polypeptide, with a predicted molecular mass of 25.20 kDa. Cs(S)-THBO was the first (S)-THBO gene found in C. saxicola. Real-time quantitative PCR analysis indicated that Cs(S)-THBO was constitutively expressed in roots, stems, leaves and flowers of C. saxicola, and with the highest expression level in roots. The results of treatment experiment for plant defense responses revealed that expression of Cs(S)-THBO had a prominent diversity. Recombinant Cs(S)-THBO protein expressed in Escherichia coli strain BL21 (DE3) was active. The results of feeding experiment and HPLC-DAD-ESI-MS(n) analysis showed that Cs(S)-THBO had the function of catalyzing (S)-tetrahydroberberine to berberine. PMID- 21706162 TI - Modulatory effect of resveratrol on SIRT1, SIRT3, SIRT4, PGC1alpha and NAMPT gene expression profiles in wild-type adult zebrafish liver. AB - Sirtuins (SIRTs) are NAD(+)-dependent deacetylases that catalyze the hydrolysis of acetyl-lysine residues. They play an important role in many physiological and pathophysiological processes, such as the regulation of lifespan and the prevention of metabolic diseases. In this study, we analyzed the effect of resveratrol on the gene expression levels of SIRT1, SIRT3, SIRT4, PGC1alpha, and NAMPT, as well as its effect on NAD(+) and NADH levels, in the liver of non stressed or non impaired wild-type zebrafish. Semiquantative RT-PCR assays showed that resveratrol did not change the mRNA levels of SIRT1 and PGC1alpha but decreased the expression levels of the SIRT3, SIRT4, and NAMPT genes. The decrease in NAMPT mRNA levels was accompanied by an increase in NADH levels, thereby decreasing the NAD(+)/H ratio. Taken together, our results suggest that resveratrol plays a modulatory role in the transcription of the NAMPT, SIRT3, and SIRT4 genes. Zebrafish is an interesting tool that can be used to understand the mechanisms of SIRTs and NAMPT metabolism and to help develop therapeutic compounds. However, further investigations using healthy experimental animals are required to study the modulation of the SIRT and NAMPT genes by resveratrol before it is used as a nutraceutical compound in healthy humans. PMID- 21706163 TI - The effects of NOS3 Glu298Asp variant on colorectal cancer risk and progression in Turkish population. AB - Endothelial nitric oxide synthase (eNOS), coded by the gene NOS3, may play an important role in uncontrollable cellular growth in several cancer types. Our study was performed to test the association between Glu298Asp polymorphisms in the NOS3 gene and colorectal cancer risk and progression. In this study, NOS3 Glu298Asp polymorphism was genotyped in 84 patients with colorectal cancer and 99 healthy subjects using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. There were significant differences in the distribution of NOS3 genotypes and frequencies of the alleles between colorectal cancer patients and controls (P = 0.016, P = 0.006, respectively). The increased frequency of NOS3 Glu298Asp homozygotes genotypes in patients who had advanced tumour stage was statistically significant (P = 0.042). Our findings have suggested that NOS3 Glu298Asp polymorphism might be associated with the risk and progression of colorectal cancer in Turkish population. PMID- 21706164 TI - Characterization and subcellular localization of geranylgeranyl diphosphate synthase from Catharanthus roseus. AB - The enzyme geranylgeranyl diphosphate synthase (GGPS: EC 2.5.1.1, EC 2.5.1.10, EC 2.5.1.29) catalyses the formation of geranylgeranyl diphosphate (GGPP) from isopentenyl diphosphate and dimethylallyl diphosphate via three successive condensation reactions. A full-length nucleotide sequence of GGPS (named CrGGPS) was cloned from the medicinal plant Catharanthus roseus. The deduced polypeptide has 383 amino acids with a calculated mass of 41.6 kDa and possesses prenyltransferase signatures characteristic of plant type II GGPS. The enzyme was characterized by functional complementation in carotenoid accumulating strains of Escherichia coli. When cultures of Catharanthus cell lines were treated with methyljasmonate, no specific increase in transcript levels were observed. In plants, GGPS are encoded by a small multigene family and the isoforms have been shown to be localized in three different subcellular compartments: chloroplast, endoplasmic reticulum and mitochondria. We investigated the subcellular distribution of CrGGPS through transient transformations of C. roseus cells with a yellow fluorescent protein-fused construct. Our results clearly indicate that CrGGPS is located to plastids within stroma and stromules. PMID- 21706165 TI - The association between adiponectin (+45T/G) and adiponectin receptor-2 (+795G/A) single nucleotide polymorphisms with cirrhosis in Iranian population. AB - Adiponectin which possesses anti-inflammatory and insulin-sensitizing properties is elevated in blood circulation of liver cirrhosis patients. The genetic variations in the adiponectin gene can affect the circulating adiponectin level and stimulation of adiponectin receptor that may affect the activity of adiponectin. We investigated the effect of adiponectin single nucleotide polymorphisms (SNP) 45 T/G and adiponectin receptor-2 gene SNP 795G/A in cirrhotic Iranian population. A total of 97 cirrhotic patients and 128 healthy controls from Iranian population were genotyped for the adiponectin and adiponectin receptor 2 gene (+45T>G and 795G/A) by polymerase chain reaction restriction fragment length polymorphism. G frequency was 21.1% versus 12.89% (P = 0.001) for SNP45, and G frequency was 75.8% versus 76.2% (P = 0.526) for SNP795G/A in the patients and control group, respectively. Based on our findings, the expression of the G allele at SNP45 is higher in the patient group compared with healthy subjects, suggesting that it may affect liver injury through changes in the plasma adiponectin level. PMID- 21706166 TI - Heavy metal resistance in Cupriavidus metallidurans CH34 is governed by an intricate transcriptional network. AB - The soil bacterium Cupriavidus metallidurans CH34 contains a high number of heavy metal resistance genes making it an interesting model organism to study microbial responses to heavy metals. In this study the transcriptional response of strain CH34 was measured when challenged to sub-lethal concentrations of various essential or toxic metals. Based on the global transcriptional responses for each challenge and the overlap in upregulated genes between different metal responses, the sixteen metals were clustered in three groups. In addition, the transcriptional response of already known metal resistance genes was assessed, and new metal response gene clusters were identified. The majority of the studied metal response loci showed similar expression profiles when cells were exposed to different metals, suggesting complex interplay at transcriptional level between the different metal responses. The pronounced redundancy of these metal resistant regions-as illustrated by the large number of paralogous genes-combined with the phylogenetic distribution of these metal response regions within either evolutionary related or other metal resistant bacteria, provides important insights on the recent evolutionary forces shaping this naturally soil-dwelling bacterium into a highly metal-resistant strain well adapted to harsh and anthropogenic environments. PMID- 21706167 TI - Novel human BTB/POZ domain-containing zinc finger protein ZBTB1 inhibits transcriptional activities of CRE. AB - BTB/POZ protein family plays a key role in many biological processes by regulating the transcriptional activities of some downstream genes. Here, we characterized the member of C(2)H(2) type zinc finger gene, Zinc finger and BTB domain containing 1 (ZBTB1). The complete sequence of ZBTB1 cDNA contains a 2142 bp open reading frame (ORF) and encodes a 713 amino acid protein with an N terminal BTB/POZ domain that is similar to the same domain of other known transcription regulators and eight classical zinc finger C(2)H(2) motifs in the C terminus. Subcellular localization analysis demonstrated that ZBTB1 was localized to the nucleus, forming dot-like structures. Transcriptional activity assays showed that ZBTB1 was a transcription repressor and overexpression of ZBTB1 in the COS7 cells reduced the transcriptional activities of cAMP response element (CRE). Further studies showed that the BTB domain and ZNF motifs of ZBTB1 may both be involved in this suppression. These results suggest that ZBTB1 protein may act as a transcription repressor in the activation of CREB and cAMP-mediated signal transduction pathways to mediate cellular functions. PMID- 21706168 TI - A novel cutaneous vasculitis syndrome induced by levamisole-contaminated cocaine. AB - In order to describe the clinical and serologic features of a cutaneous vasculitis due to cocaine contaminated with the adulterant levamisole, we report four new cases of this syndrome along with 12 previously reported cases identified through a PubMed Literature search (1964 to March 2011). Of the 16 patients described, the average age was 43, with a female predominance (81% of patients). Over half of patients had involvement of the earlobes, and the rash frequently affected the extremities in a "retiform" pattern. Leukopenia or neutropenia was reported in 56% of patients. Ninety-three percent were anti neutrophil cytoplasmic antibody positive, and 63% tested positive for anti phospholipid antibodies. The predominant pattern seen on histopathological examination of the skin was small vessel vasculitis and/or a thrombotic vasculopathy. Treatment in these patients varied widely, with several patients showing improvement or resolution of the rash without specific therapy following cessation of illicit drug use. This new cutaneous vasculitis syndrome can be recognized by its characteristic rash and skin pathology, together with leukopenia and autoantibody production. Certain clinical features can be attributed to the adulterant levamisole, though cocaine as well may play a role in its pathogenesis. PMID- 21706169 TI - Isolation and characterization of four novel Gram-positive bacteria associated with the rhizosphere of two endemorelict plants capable of degrading a broad range of aromatic substrates. AB - Four new Gram-positive, phenol-degrading strains were isolated from the rhizospheres of endemorelict plants Ramonda serbica and Ramonda nathaliae known to exude high amounts of phenolics in the soil. Isolates were designated Bacillus sp. PS1, Bacillus sp. PS11, Streptomyces sp. PS12, and Streptomyces sp. PN1 based on 16S rDNA sequence and biochemical analysis. In addition to their ability to tolerate and utilize high amounts of phenol of either up to 800 or up to 1,400 mg l(-1) without apparent inhibition in growth, all four strains were also able to degrade a broad range of aromatic substrates including benzene, toluene, ethylbenzene, xylenes, styrene, halogenated benzenes, and naphthalene. Isolates were able to grow in pure culture and in defined mixed culture on phenol and on the mixture of BTEX (benzene, toluene, ethylbenzene, and xylenes) compounds as a sole source of carbon and energy. Pure culture of Bacillus sp. PS11 yielded 1.5 fold higher biomass amounts in comparison to mixed culture, under all conditions. Strains successfully degraded phenol in the soil model system (2 g kg(-1)) within 6 days. Activities of phenol hydroxylase, catechol 1,2-dioxygenase, and catechol 2,3-dioxygenase were detected and analyzed from the crude cell extract of the isolates. While all four strains use ortho degradation pathway, enzyme indicative of meta degradation pathway (catechol 2,3-dioxygenase) was also detected in Bacillus sp. PS11 and Streptomyces sp. PN1. Phenol degradation activities were induced 2 h after supplementation by phenol, but not by catechol. Catechol slightly inhibited activity of catechol 2,3-dioxygenase in strains PS11 and PN1. PMID- 21706170 TI - Manipulation of heterogeneity product in 4'-demethylepipodophyllotoxin biotransformation process by using yeast extract as nitrogen source. AB - Manipulation of product heterogeneity was attempted by using yeast extract as nitrogen source in Alternaria alternata S-f6 transformation process of 4' demethylepipodophyllotoxin. When the nitrogen source of NaNO(3) was replaced by yeast extract, the heterogeneity of biotransformation products was significantly varied from a single product (i.e., 4'-demethylpodophyllotoxone) to four podophyllum derivates. According to the kinetics of 4'-demethylepipodophyllotoxin biotransformation process by A. alternata S-f6, the starting substrate of 4' demethylepipodophyllotoxin was preferentially transformed to produce 4' demethylpodophyllotoxone (1) with an oxidation reaction. By the further comparison of products configuration, 4beta-caprinoyl-4' demethylepipodophyllotoxin (3) was produced from 4'-demethylpodophyllotoxone (1) instead of 4'-demethylisopicropodophyllone (2), which might be produced from 4' demethylpodophyllotoxone (1) with the isomerization of lactone. Finally, 4' demethylisopicropodophyllone (2) was hydrolyzed to produce 3alpha-hydroxymethyl (6, 7)-dioxol-4-one-naphthalene (4). This work shows new information on the 4' demethylepipodophyllotoxin biotransformation process by A. alternata S-f6 and provides a foundation for further studies on the structural diversification of a bioactive natural lead compound. PMID- 21706172 TI - Improving ethanol fermentation performance of Saccharomyces cerevisiae in very high-gravity fermentation through chemical mutagenesis and meiotic recombination. AB - Genome shuffling is an efficient way to improve complex phenotypes under the control of multiple genes. For the improvement of strain's performance in very high-gravity (VHG) fermentation, we developed a new method of genome shuffling. A diploid ste2/ste2 strain was subjected to EMS (ethyl methanesulfonate) mutagenesis followed by meiotic recombination-mediated genome shuffling. The resulting haploid progenies were intrapopulation sterile and therefore haploid recombinant cells with improved phenotypes were directly selected under selection condition. In VHG fermentation, strain WS1D and WS5D obtained by this approach exhibited remarkably enhanced tolerance to ethanol and osmolarity, increased metabolic rate, and 15.12% and 15.59% increased ethanol yield compared to the starting strain W303D, respectively. These results verified the feasibility of the strain improvement strategy and suggested that it is a powerful and high throughput method for development of Saccharomyces cerevisiae strains with desired phenotypes that is complex and cannot be addressed with rational approaches. PMID- 21706171 TI - Ammonia-oxidizing archaea and ammonia-oxidizing bacteria in six full-scale wastewater treatment bioreactors. AB - In this study, dideoxy sequencing and 454 high-throughput sequencing were used to analyze diversities of the ammonia monooxygenase (amoA) genes and the 16S rRNA genes of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) in six municipal wastewater treatment plants. The results showed that AOB amoA genes were quite diverse in different wastewater treatment plants while the 16S rRNA genes were relatively conserved. Based on the observed complexity of amoA and 16S rRNA genes, most of the AOB can be assigned to the Nitrosomonas genus, with Nitrosomonas ureae, Nitrosomonas oligotropha, Nitrosomonas marina, and Nitrosomonas aestuarii being the four most dominant species. From the sequences of the AOA amoA genes, most AOA observed in this study belong to the CGI.1b group, i.e., the soil lineage. The AOB amoA and 16S rRNA genes were quantified by quantitative PCR and 454 high-throughput pyrosequencing, respectively. Although the results from the two approaches show some disconcordance, they both indicated that the abundance of AOB in activated sludge was very low. PMID- 21706173 TI - Biotechnological conversion of glycerol to 2-amino-1,3-propanediol (serinol) in recombinant Escherichia coli. AB - Microbial conversion is an important technology for the refinement of renewable resources. Here, we describe the biotechnological conversion of glycerol to 2 amino-1,3-propanediol (serinol), a relevant intermediate in several chemical syntheses processes. Either the dihydroxyacetone phosphate aminotransferase/dihydrorhizobitoxine synthase (RtxA) of Bradyrhizobium elkanii USD94 or only the N-terminal domain (RtxA513) comprising the first reaction, respectively, was expressed in recombinant Escherichia coli. Serinol contents of up to 3.3 g/l were achieved in batch cultures. We could further clarify that glutamic acid is the preferred cosubstrate for the transamination of dihydroxyacetone phosphate to serinolphosphate, which is the essential step in serinol synthesis. An in vivo detoxification of serinol employing wax ester synthase/acyl-CoA:diacyl-glycerol acyl transferase from Acinetobacter baylyi ADP1 was not accomplished. This study paves the way for biotechnological production of serinol from glycerol derived from the biodiesel industry. PMID- 21706174 TI - Use of glucosamine and chondroitin and lung cancer risk in the VITamins And Lifestyle (VITAL) cohort. AB - OBJECTIVE: Inflammation plays an important role in lung carcinogenesis. Epidemiologic studies have reported inverse associations of non-steroidal anti inflammatory drug (NSAID) use and lung cancer risk. Previously, we found that ever use of glucosamine and chondroitin, which have anti-inflammatory properties, were inversely associated with lung cancer risk. After an additional year of follow-up, we further examined the association including frequency/duration of use, interaction with factors associated with inflammation, and lung cancer histology. METHODS: Participants were members of the VITamins And Lifestyle cohort. Adults, aged 50-76 years, who were residents of western Washington State, completed a baseline questionnaire in 2000-2002 (n = 76,904). Participants were queried on their use of glucosamine and chondroitin, over the 10 years prior to baseline, and categorized as nonuser, low use < 4 days/week or < 3 years, or high use >= 4 days/week and >= 3 years. Lung cancer cases (n = 808) were ascertained through linkage to the Surveillance, Epidemiology, and End Results cancer registry. RESULTS: High 10-year use of glucosamine [hazard ratio (HR), 0.77; 95% CI: 0.56-1.07; p trend = 0.04] but not chondroitin was associated with a reduction in lung cancer risk. The association with glucosamine was limited to adenocarcinoma (HR, 0.49; 95% CI: 0.27-0.90; p trend <0.01) and was not modified by NSAID use or smoking status. CONCLUSIONS: Our results for glucosamine use are similar to the prior human studies of NSAID use and lung cancer, both in magnitude and the limitation of the association to adenocarcinoma. Unlike NSAIDs, glucosamine has no known adverse effects. Although confirmatory studies are needed, glucosamine is an attractive candidate for lung cancer chemoprevention. PMID- 21706175 TI - Heterogeneity in age-related white matter changes. AB - White matter changes occur endemically in routine magnetic resonance imaging (MRI) scans of elderly persons. MRI appearance and histopathological correlates of white matter changes are heterogeneous. Smooth periventricular hyperintensities, including caps around the ventricular horns, periventricular lining and halos are likely to be of non-vascular origin. They relate to a disruption of the ependymal lining with subependymal widening of the extracellular space and have to be differentiated from subcortical and deep white matter abnormalities. For the latter a distinction needs to be made between punctate, early confluent and confluent types. Although punctate white matter lesions often represent widened perivascular spaces without substantial ischemic tissue damage, early confluent and confluent lesions correspond to incomplete ischemic destruction. Punctate abnormalities on MRI show a low tendency for progression, while early confluent and confluent changes progress rapidly. The causative and modifying pathways involved in the occurrence of sporadic age related white matter changes are still incompletely understood, but recent microarray and genome-wide association approaches increased the notion of pathways that might be considered as targets for therapeutic intervention. The majority of differentially regulated transcripts in white matter lesions encode genes associated with immune function, cell cycle, proteolysis, and ion transport. Genome-wide association studies identified six SNPs mapping to a locus on chromosome 17q25 to be related to white matter lesion load in the general population. We also report first and preliminary data that demonstrate apolipoprotein E (ApoE) immunoreactivity in white matter lesions and support epidemiological findings indicating that ApoE is another factor possibly related to white matter lesion occurrence. Further insights come from modern MRI techniques, such as diffusion tensor and magnetization transfer imaging, as they provide tools for the characterization of normal-appearing brain tissue beyond what can be expected from standard MRI scans. There is a need for additional pre- and postmortem studies in humans, including these new imaging techniques. PMID- 21706176 TI - Cell stress induces TDP-43 pathological changes associated with ERK1/2 dysfunction: implications in ALS. AB - TDP-43 has been implicated in the pathogenesis of amyotrophic lateral sclerosis and other neurodegenerative diseases. Here we demonstrate, using neuronal and spinal cord organotypic culture models, that chronic excitotoxicity, oxidative stress, proteasome dysfunction and endoplasmic reticulum stress mechanistically induce mislocalization, phosphorylation and aggregation of TDP-43. This is compatible with a lack of function of this protein in the nucleus, specially in motor neurons. The relationship between cell stress and pathological changes of TDP-43 also includes a dysfunction in the survival pathway mediated by mitogen activated protein kinase/extracellular signal-regulated kinases (ERK1/2). Thus, under stress conditions, neurons and other spinal cord cells showed cytosolic aggregates containing ERK1/2. Moreover, aggregates of abnormal phosphorylated ERK1/2 were also found in the spinal cord in amyotrophic lateral sclerosis (ALS), specifically in motor neurons with abnormal immunoreactive aggregates of phosphorylated TDP-43. These results demonstrate that cellular stressors are key factors in neurodegeneration associated with TDP-43 and disclose the identity of ERK1/2 as novel players in the pathogenesis of ALS. PMID- 21706177 TI - Evaluation of gastrointestinal pathology and treatment in children with suspected biliary dyskinesia. AB - AIM: Decreased gallbladder ejection fraction (GBEF) was reported in patients who had abdominal pain and gastrointestinal (GI) diseases. The study aims were to review pathology of GI tract in children with acalculous biliary-type abdominal pain and to evaluate the pain improvement after a 2-week trial of proton pump inhibitor (PPI) and laparoscopic cholecystectomy (LC). METHODS: Children below 18 years of age with a history of biliary-type abdominal pain by ROME III criteria were evaluated. All underwent an upper endoscopy and their histologic findings of the proximal GI tract were reviewed. Responses to a 2-week trial of PPI and LC were analyzed. RESULTS: Sixteen were identified with biliary-type abdominal pain with GBEF <35%. Endoscopic and histologic evidence of reflux esophagitis was observed in 11 children those of gastritis in 3 children. A GI pathology of these children is mostly acid-related and four of ten children experienced a complete response to PPIs and did not require LC. Nine children had LC; four had complete and four had partial pain improvement. CONCLUSION: A trial of PPIs may be cost effective prior to considering LC in these patients since four of ten children experienced a complete response to PPIs without the requirement of LC, compared with four of nine children who improved completely. PMID- 21706178 TI - Transvaginal mesh for prolapse repair: what is all the controversy about? AB - The use of synthetic mesh for the management of pelvic organ prolapse has been embroiled in a contentious debate over the past decade, with only more partisanship among physicians strictly against its use versus those pelvic surgeons who believe it to be a useful tool in their armamentarium. At the heart of the controversy lies the concern, by its detractors, for complications related to mesh use outweighing the as yet not rigorously tested benefit of augmenting repairs with mesh. This article discusses, in detail, the current literature supporting the use of mesh in the management of pelvic organ prolapse repair. The rising concern for complications, both simple and complex, will be addressed. This review aims to narrow the divide between physicians and to address their discordant beliefs by objectively reporting the most up-to-date data on biologic and synthetic mesh use in pelvic organ prolapse repair. PMID- 21706179 TI - The natural course of radiographic progression in ankylosing spondylitis: differences between genders and appearance of characteristic radiographic features. AB - Our study set out to analyze the radiographic progression of ankylosing spondylitis (AS) patients based on gender differences. A total of 146 AS patients were retrospectively blindly analyzed in at least 2 time points within 6 years using the modified Stokes AS Spine Score. The mean follow-up time was 3.8 +/- 1.7 years, and 114 patients (78%) were male. The overall progression was similar between genders. Females showed higher progression in the cervical spine, and males in the lumbar spine. More females showed new cervical syndesmophytes, and more males showed new lumbar syndesmophytes. More females showed slow radiographic progression, and more males showed fast radiographic progression, while moderate progression was similar for both genders. Dorsal syndesmophytes showed no impact in the prediction of future progression. Female AS patients showed more cervical structural lesions, but male patients overall showed more rapid progress, leading us to conclude that dorsal vertebral edges do not add in depiction of radiographic deterioration in AS patients. PMID- 21706180 TI - Epithelial-mesenchymal transition induced by senescent fibroblasts. AB - Depending on the cell type and tissue environment, epithelial and mesenchymal cell phenotypes are not static and can be highly dynamic. Epithelial-mesenchymal transitions (EMTs) and reverse EMTs provide flexibility during embryogenesis. While EMTs are a critical normal process during development and wound healing, properties of the EMT have been implicated in human pathology, particularly cancer metastasis. A normal undamaged epithelium does not typically exhibit features of an EMT. However, particularly under the influence of the surrounding microenvironment, cancer cells may reactivate developmental phenotypes out of context in the adult. This reactivation, such as the EMT, can facilitate tumor cell invasion and metastasis, and therefore is a major mechanism of tumor progression. Conversely, cellular senescence, which is associated with aging, is a process by which cells enter a state of permanent cell cycle arrest, thereby constituting a potent tumor suppressive mechanism. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into pro-inflammatory cells having the ability to promote tumor progression, in part by inducing an EMT in nearby epithelial cells. Here, we summarize the potential impacts of SASP factors, particularly interleukins, on tissue microenvironments and their ability to stimulate tumor progression through induction of an EMT. PMID- 21706181 TI - Transformation of tobacco and Arabidopsis plants with Stellaria media genes encoding novel hevein-like peptides increases their resistance to fungal pathogens. AB - Two novel antifungal hevein-like peptides, SmAMP1.1a and SmAMP2.2a, were previously isolated from seeds of Stellaria media. It has been established that these peptides accumulate in this weed as a result of proteolysis of two propeptides, pro-SmAMP1 and pro-SmAMP2. The primary structure of these propeptides is unique; in addition to having a signal peptide and negatively charged C-terminus, each of these structures consists of two hevein-like peptides of different length separated by a space rather than a single peptide. In this work, we demonstrated that the expression of the pro-SmAMP1 and pro-SmAMP2 genes was tissue-specific and increased substantially under exposure to fungal infection. To elucidate whether S. media has any advantages in defending against phytopathogens due to its unusual structure of pro-SmAMP1 and pro-SmAMP2, on the basis of the pro-SmAMP1 gene, we created three genetic constructs. Arabidopsis and tobacco plants were subsequently transformed with these constructs. Transgenic plants bearing the full-length pro-SmAMP1 gene exhibited the best resistance to the phytopathogens Bipolaris sorokiniana and Thielaviopsis basicola. The resistance of S. media plants to phytopathogenic fungi was likely due to the fungal-inducible expression of pro-SmAMP1 and pro-SmAMP2 genes, and due to the specific features of the primary structure of the corresponding propeptides. As a result of the processing of these propeptides, two different antimicrobial peptides were released simultaneously. Based on our results, we conclude that the genes for antimicrobial peptides from S. media may be promising genetic tools for the improvement of plant resistance to fungal diseases. PMID- 21706182 TI - Biobanking and deceased persons. AB - Early biomedical research focused primarily on the study of specific diseases or sets of diseases within small groups of living research participants. Accordingly, the first ethical frameworks governing biomedical research addressed short-term, limited-scope research involving living research participants. Due to recent interest in longitudinal population studies and biobanking, research is increasingly long term. This shift raises several ethical and legal issues concerning the impact of a participant's death on research. This paper offers an overview of these issues in the context of longitudinal biobanking genetic research. Our first part outlines the legal and ethical frameworks that govern the effect of the participants' death on consent. This will be followed by an analysis of the legal and ethical frameworks that govern the secondary use of deceased participants' data and samples and the return of deceased participants' individual research results to biological family members. In our second part, we will review the current literature and discuss the above mentioned issues using the bioethics "principlism" theory before concluding. PMID- 21706183 TI - Genomic databases access agreements: legal validity and possible sanctions. AB - Large-scale, public genomic databases have greatly improved the capacity of researchers to do genomic research. In order to ensure that the scientific community uses data from these public resources properly, data access agreements have been developed to complement already existing legal and ethical norms. Sanctions to address cases of data misuse constitute an essential part of this compliance framework meant to protect stakeholders in genomic research. Yet very little research and community debate has been done on this most important topic. This paper presents a review of different sanctions that could be invoked in cases of non-compliance from data users. They have been identified through comprehensive research and analysis of over 450 documents (journal articles, policy, guidelines, access policies, etc.) related to this topic. Given the considerable impact on users of even the milder sanctions considered in our paper, it is essential that stakeholders strive to achieve the highest degree of standardization and transparency when designing controlled-access agreements. It is only fair, after all, that users be able to expect that the border between acceptable and unacceptable conduct is clearly delineated and predictable in controlled-access policies. This suggests the importance for researchers to undertake additional empirical studies on the clarity and accessibility of existing database access agreements and related policies in the near future. PMID- 21706185 TI - Mutations in the NRG1 gene are associated with Hirschsprung disease. AB - Hirschsprung disease (HSCR, congenital colon aganglionosis) is a relatively common complex genetic condition caused by abnormal development of the enteric nervous system (ENS). Through a recent genome-wide association study conducted on Chinese HSCR patients, we identified a new HSCR contributing locus, neuregulin 1 (NRG1; 8p12), a gene known to be involved in the development of the ENS. As genes in which disease-associated common variants are found are to be considered as candidates for the search of deleterious rare variants (RVs) in the coding sequences, we sequenced the NRG1 exons of 358 sporadic HSCR patients and 333 controls. We identified a total of 13 different heterozygous RVs including 8 non synonymous (A28G, E134K, V266L, H347Y, P356L, V486M, A511T, P608A) and 3 synonymous amino acid substitutions (P24P, T169T, L483L), a frameshift (E239fsX10), and a c.503-4insT insertion. Functional analysis of the most conserved non-synonymous substitutions, H347Y and P356L, showed uneven intracellular distribution and aberrant expression of the mutant proteins. Except for T169T and V486M, all variants were exclusive to HSCR patients. Overall, there was a statistically significant over-representation of NRG1 RVs in HSCR patients (p = 0.008). We show here that not only common, but also rare variants of the NRG1 gene contribute to HSCR. This strengthens the role of NRG1. PMID- 21706184 TI - Realizing the promise of population biobanks: a new model for translation. AB - The promise of science lies in expectations of its benefits to societies and is matched by expectations of the realisation of the significant public investment in that science. In this paper, we undertake a methodological analysis of the science of biobanking and a sociological analysis of translational research in relation to biobanking. Part of global and local endeavours to translate raw biomedical evidence into practice, biobanks aim to provide a platform for generating new scientific knowledge to inform development of new policies, systems and interventions to enhance the public's health. Effectively translating scientific knowledge into routine practice, however, involves more than good science. Although biobanks undoubtedly provide a fundamental resource for both clinical and public health practice, their potentiating ontology--that their outputs are perpetually a promise of scientific knowledge generation--renders translation rather less straightforward than drug discovery and treatment implementation. Biobanking science, therefore, provides a perfect counterpoint against which to test the bounds of translational research. We argue that translational research is a contextual and cumulative process: one that is necessarily dynamic and interactive and involves multiple actors. We propose a new multidimensional model of translational research which enables us to imagine a new paradigm: one that takes us from bench to bedside to backyard and beyond, that is, attentive to the social and political context of translational science, and is cognisant of all the players in that process be they researchers, health professionals, policy makers, industry representatives, members of the public or research participants, amongst others. PMID- 21706188 TI - Hip fracture management, before and beyond surgery and medication: a synthesis of the evidence. AB - INTRODUCTION: The geriatrician and orthopedic surgeon's roles are well defined in hip fracture management, yet other health-care providers contribute significantly toward care, as well as maximizing rehabilitation potential and decreasing readmissions. We examine evidence concerning pre-hospital care, pain management, multidisciplinary rehabilitation and secondary prevention strategies. METHODS: Cochrane reviews and randomized controlled trials were identified through PubMed to synthesize current evidence in the role of multidisciplinary management of the patient with a hip fracture from injury to secondary prevention. The well recognized roles of the geriatrician, anesthetist and orthopedic surgeon were not evaluated for the purpose of this review. RESULTS: Transport of patients with a hip fracture can be eased through non-pharmaceutical simple, inexpensive techniques. Nerve blockade appears effective and easily administered in the emergency department. In-hospital multidisciplinary rehabilitation programs are effective in both earlier discharge and reducing falls, morbidity and mortality. Fall prevention programs are effective in nursing home patients, but not community dwellers. Osteoporosis prevention is primarily a medical endeavor; however, exercise and education may contribute to increased bone mineral density, compliance and better results of treatment. CONCLUSION: Multidisciplinary medical management of patients with hip fractures is being improved within the hospital environment resulting in earlier discharge with decreased morbidity. There is evidence to show the benefits to patients with hip fractures from peripheral modalities within the hospital; however unless resident in a facility, multidisciplinary management is not clearly of benefit. PMID- 21706187 TI - See-and-treat approaches to cervical cancer prevention for HIV-infected women. AB - Cervical cancer remains the second commonest cancer among women worldwide, and more than 85% of the global burden of this disease occurs in the developing world. HIV-infected women have a higher likelihood of developing persistent high risk human papillomavirus (HPV) infection, precancer, and invasive cervical cancer than seronegative women. Although highly effective primary and secondary prevention strategies are currently available, they remain inaccessible to the vast majority of women. Because of their simplicity and affordability, see-and treat cervical cancer screening modalities have the potential to substantially improve women's access to cancer prevention, as well as to create much needed infrastructure for future molecular-based cervical screening and HPV vaccination programs. Additional data addressing the effectiveness of see-and-treat approaches for HIV-infected women are urgently needed. Studies informing best practice guidelines on when to start, when to stop, and how frequently to screen HIV-infected women within the see-and-treat paradigm would be of great value. PMID- 21706189 TI - Can cardiac surgery cause hypopituitarism? AB - Apoplexy of pituitary adenomas with subsequent hypopituitarism is a rare but well recognized complication following cardiac surgery. The nature of cardiac on-pump surgery provides a risk of damage to the pituitary because the vascular supply of the pituitary is not included in the cerebral autoregulation. Thus, pituitary tissue may exhibit an increased susceptibility to hypoperfusion, ischemia or intraoperative embolism. After on-pump procedures, patients often present with physical and psychosocial impairments which resemble symptoms of hypopituitarism. Therefore, we analyzed whether on-pump cardiac surgery may cause pituitary dysfunction also in the absence of pre-existing pituitary disease. Twenty-five patients were examined 3-12 months after on-pump cardiac surgery. Basal hormone levels for all four anterior pituitary hormone axes were measured and a short synacthen test and a growth hormone releasing hormone plus arginine (GHRH-ARG) test were performed. Quality of life (QoL), depression, subjective distress for a specific life event, sleep quality and fatigue were assessed by means of self rating questionnaires. Hormonal alterations were only slight and no signs of anterior hypopituitarism were found except for an insufficient growth hormone rise in two overweight patients in the GHRH-ARG-test. Psychosocial impairment was pronounced, including symptoms of moderate to severe depression in 9, reduced mental QoL in 8, dysfunctional coping in 6 and pronounced sleep disturbances in 16 patients. Hormone levels did not correlate with psychosocial impairment. On pump cardiac surgery did not cause relevant hypopituitarism in our sample of patients and does not serve to explain the psychosocial symptoms of these patients. PMID- 21706190 TI - Blood lipids and stroke: what more can we do besides reducing low-density lipoprotein cholesterol? AB - Statin therapy has became the most important advance in stroke prevention since the introduction of aspirin and blood pressure-lowering therapies. Other lipid modifying drugs have been less successful in reducing the incidence of stroke, but because of evidence for the use of triglyceride-lowering drugs and treatments that raise concentrations of high-density lipoprotein (HDL) cholesterol, further investigations are needed, particularly in patients with an atherogenic dyslipidemia profile (high triglycerides and low HDL cholesterol levels). Furthermore, beyond reducing low-density lipoprotein cholesterol and possibly improving other lipids fractions in patients who are at high risk of stroke, the present review shoes that lipid-modifying drugs might have neuroprotective effects that should also be further explored. PMID- 21706191 TI - Perfusion defect size predicts engraftment but not early retention of intra myocardially injected cardiosphere-derived cells after acute myocardial infarction. AB - Therapeutic cell retention and engraftment are critical for myocardial regeneration. Underlying mechanisms, including the role of tissue perfusion, are not well understood. In Wistar Kyoto rats, syngeneic cardiosphere-derived cells (CDCs) were injected intramyocardially, after experimental myocardial infarction. CDCs were labeled with [(18)F]-FDG (n = 7), for quantification of 1-h retention, or with sodium-iodide-symporter gene (NIS; n = 8), for detection of 24-h engraftment by reporter imaging. Perfusion was imaged simultaneously. Infarct size was 37 +/- 9 and 38 +/- 9% of LV in FDG and NIS groups. Cell signal was located in the infarct border zone in all animals. No significant relationship was observed between infarct size and 1-h CDC retention (r = -0.65; P = 0.11). However, infarct size correlated significantly with 24-h engraftment (r = 0.75; P = 0.03). Residual perfusion at the injection site was not related to cell retention/engraftment. Larger infarcts are associated with improved CDC engraftment. This observation encourages further investigation of microenvironmental conditions after ischemic damage and their role in therapeutic cell survival. PMID- 21706192 TI - Warfarin anticoagulation: a survey of patients' knowledge of their treatment. AB - INTRODUCTION: Warfarin is used for the treatment of thromboembolic disease. It requires careful and sustained monitoring due to its narrow therapeutic index and potentially life-threatening complications. Patient education and knowledge is, therefore, vital. AIMS: To assess, in a specialised anticoagulation clinic, the extent of patients' knowledge of their warfarin treatment. METHODS: Ethical approval was obtained. All patients, aged over 18 years, attending our anticoagulation clinic during our study period were asked to participate. RESULTS: We enrolled 181 patients, 47.9% of respondents were unaware of any potential drug interactions, 57.7% of patients were unaware of any potential side effects, 20% of patients had experienced side effects, 10.9% of patients had been hospitalised due to side effects, 58% of which were due to Haemorrhage and 79% of patients kept a personal record of their INR. CONCLUSIONS: Patients' understanding of warfarin treatment was poor, despite their high level of compliance. PMID- 21706193 TI - Needs of low-income african american cancer survivors: multifaceted and practical. AB - This study aimed to identify the needs of low-income, African American cancer survivors in an urban setting. Data were collected from semi-structured interviews conducted with cancer survivors (n = 12), caregivers (n = 10), professionals (n = 10), and surveys from town hall meetings (n = 80). The major needs identified, across all groups, included a diverse array of practical needs including transportation, financial and job assistance, childcare, self-care assistance, more education and lifestyle information when diagnosed as well as after diagnosis, better post treatment plan, and more need for social support. They identified the ideal resource center as being located within the survivor's neighborhood and would provide a range of medically specific support as well as recreational services. Being of limited economic means has a host of implications for those diagnosed with cancer and for their family members. Participants suggested that needs for cancer survivors have to take into account a complexity of factors including culture, family, and especially economic implications. PMID- 21706194 TI - Quality of life among immigrant Latina breast cancer survivors: realities of culture and enhancing cancer care. AB - Breast cancer is the most common cancer among Latinas. This study examined social, cultural, and health care system factors that impact the quality of life and survivorship experiences of Latina immigrant breast cancer survivors. We interviewed Latina breast cancer survivors (n = 19) and, based on the interview findings, conducted two focus groups (n = 9). Research staff translated transcripts from Spanish into English. Two trained raters reviewed the content and identified themes. Thematic content analysis was used to categorize and organize data. Participants were largely monolingual in Spanish, predominantly from Central and South America and most (68%) had lived in the U.S. for ten or more years. All women were diagnosed and treated in the U.S. and were an average of 3.1 years from diagnosis. Women's survivorship experiences appeared to be shaped by cultural beliefs and experiences as immigrants such as secrecy/shame about a breast cancer diagnosis, feelings of isolation, importance of family support (familism), challenges with developing social relationships in the U.S. (less personalismo), and, for some, their partner's difficulty with showing emotional support (machismo). Navigating the U.S. medical system and language barriers were additional challenges in the participants' health care interactions. Latina breast cancer survivors adhere to certain cultural values and face unique issues as immigrants, potentially influencing overall quality of life and doctor-patient communication. Efforts to improve Latina immigrant breast cancer survivors' quality of life could include increased assessment of psychosocial functioning and referral to social support services, culturally sensitive navigation programs, and consistent use of appropriately trained interpreters. PMID- 21706195 TI - Perioperative care of a child with transposition of the great arteries. AB - OPINION STATEMENT: Because a minority of patients with D-transposition of the great arteries are diagnosed in utero by ultrasound, most present after delivery with cyanosis. In the absence of apparent lung disease, cyanotic neonates suspected of having a cardiac lesion should be immediately transferred to an intensive care unit at a pediatric tertiary care center for monitoring, resuscitation, and to define the cardiac anatomy and physiology. A prostaglandin E-1 infusion is usually initiated to maintain ductal patency and promote intra cardiac mixing. In the past, balloon atrial septostomy (BAS) was routinely performed to enlarge the atrial septal defect and improve intra-cardiac mixing while the infants awaited surgery. Recent literature has reported an increase risk of stroke in neonates who undergo BAS, although more recent studies refute this. Our current practice is to perform BAS in neonates who have both echocardiographic evidence of a restrictive atrial septum and hypoxia or instability that is unresponsive to other interventions. The occasional patient who does not respond to initial management may have elevated pulmonary vascular resistance and may stabilize with pulmonary vasodilators, such as inhaled nitric oxide. Rarely, a child does not respond to interventional and pharmacologic resuscitation and requires mechanical support pre-operatively with extracorporeal membrane oxygenation (ECMO). In our experience, ECMO has been a successful bridge to corrective surgery with excellent outcomes. After pre-operative stabilization, arterial switch procedure is typically performed in the first week of life with very favorable early results. PMID- 21706197 TI - Is the effect of a posterior cruciate ligament resection in total knee arthroplasty predictable? AB - PURPOSE: It is broadly supposed that in total knee arthroplasty, the flexion/extension gap ratio is increased after resection of the posterior cruciate ligament (PCL). However, studies are rare and results are inconsistent. Therefore, this study was conducted to determine whether PCL release regularly increases the flexion gap. METHODS: Data from 50 consecutive posterior stabilised knee prostheses were analysed retrospectively. Using imageless computer navigation, the joint-gap width was measured over the entire range of motion before and after PCL release. RESULTS: PCL release had no effect on the extension gap, but it increased the flexion gap significantly. An increase of >3 mm occurred in 36% of patients and of >5 mm in 12%. No clinically relevant effect (<2 mm) was found in 44% of patients. CONCLUSION: PCL release increased the flexion/extension gap ratio on average, but the individual effect could not be predicted. Therefore, we recommend PCL release before the femoral resections are performed, as this step mainly determines the ratio between extension and flexion gap. PMID- 21706196 TI - Archaeal amoA genes outnumber bacterial amoA genes in municipal wastewater treatment plants in Bangkok. AB - The contribution of ammonia-oxidizing archaea (AOA) to nitrogen removal in wastewater treatment plants (WWTPs) remains unknown. This study investigated the abundance of archaeal (AOA) and bacterial (ammonia-oxidizing bacteria (AOB)) amoA genes in eight of Bangkok's municipal WWTPs. AOA amoA genes (3.28 * 10(7) +/- 1.74 * 10(7)-2.23 * 10(11) +/- 1.92 * 10(11) copies l(-1) sludge) outnumbered AOB amoA genes in most of the WWTPs even though the plants' treatment processes, influent and effluent characteristics, removal efficiencies, and operation varied. An estimation of the ammonia-oxidizing activity of AOA and AOB suggests that AOA involved in autotrophic ammonia oxidation in the WWTPs. Statistical analysis shows that the numbers of AOA amoA genes correlated negatively to the ammonium levels in effluent wastewater, while no correlation was found between the AOA amoA gene numbers and the oxygen concentrations in aeration tanks. An analysis of the AOB sequences shows that AOB found in the WWTPs limited to only two AOB clusters which exhibit high or moderate affinity to ammonia. In contrast to AOB, AOA sequences of various clusters were retrieved, and they were previously recovered from a variety of environments, such as thermal and marine environments. PMID- 21706198 TI - Remote magnetic versus manual catheter navigation for circumferential pulmonary vein ablation in patients with atrial fibrillation. AB - BACKGROUND: Only limited data exist on the clinical utility of remote magnetic navigation (RMN) for pulmonary vein (PV) ablation. Aim of this prospective study was to evaluate the safety and efficacy of RMN for PV isolation as compared to the manual (CON) approach. METHODS AND RESULTS: A total of 161 consecutive patients undergoing circumferential PV isolation were included. Open-irrigated 3.5 mm ablation catheters under the guidance of a mapping system were used. The catheter was navigated with the Stereotaxis Niobe II system in the RMN group (n = 107) and guided manually in the CON group (n = 54). Electrical isolation of all PVs was achieved in 90% of the patients in the RMN group and in 87% in the CON group (p = 0.6). All subjects were followed every 3 months by 7d Holter-ECG. At 12 months of follow-up, 53.5% (RMN) and 55.5% (CON) of the patients were free of any left atrial tachycardia/atrial fibrillation (AF) episode (p = 0.57). Free of symptomatic AF recurrence were 66.3% (RMN) and 62.1% (CON) of the subjects (p = 0.80). Use of RMN was associated with longer procedure duration (p < 0.0001), ablation times (p < 0.0001), and RF current application duration (p < 0.05). In contrast, fluoroscopy time was lower in the RMN group (p < 0.0001). Major complications occurred in 6 of 161 procedures (3.7%), with no significant difference between groups (p = 0.75). CONCLUSION: RMN-guided PV ablation provides comparable acute and long-term success rates as compared to manual navigation. Procedural complication rates are similar. The use of RMN is associated with markedly reduced fluoroscopy time, but prolonged ablation and procedure duration. PMID- 21706199 TI - Repair for active infective atrioventricular valve endocarditis: 23-year single center experience. AB - OBJECTIVES: We retrospectively compared early and long-term results of mitral (MV) and tricuspid valve (TV) repair in patients with isolated active infective atrioventricular valve (AV) endocarditis over a period of 23 years. METHODS: Between April 1986 and December 2009, a total of 1,409 patients with active infective endocarditis (AIE) were operated upon. Of these, 106 (7.2%) patients (n = 69 men, age 2-84 years) underwent repair of AVE (MV n = 68, TV n = 38). Repair techniques included vegetectomy and leaflet resection, annular plication and annuloplasty, and pericardial patch leaflet and annular reconstruction without any artificial device. Perioperative characteristics, probability of survival, freedom from recurrence and reoperation, and predictors for early mortality were analyzed. Follow-up (0-23 years) was completed in 95% with a total of 667 patient years. RESULTS: The 30-day, 1-, 5- and 10-year survival rate for MV repair was 89.7 +/- 0.4, 82.2 +/- 4.6, 72.6 +/- 5.5 and 56.5 +/- 7.3% and for TV repair 94.7 +/- 3.7, 88.7 +/- 5.3, 69.4 +/- 8.8 and 64.5 +/- 9.5%, respectively (ns). Three patients (2.8%) had to undergo reoperation due to early failure of reconstruction (n = 2 MV, n = 1 TV). Freedom from valve-related reoperation at 1 and 10 years was 88.4 +/- 4.1 and 75.4 +/- 7.4% for the MV repair and 97.4 +/- 2.6 and 93.94 +/- 4.2% for the TV repair group (ns). Endocarditis reoccurred early in 2 MV repair patients (1.9%). Freedom from reoperation due to reinfection at 1 and 10 years after MV repair was 96.6 +/- 2.3 and 91.6 +/- 5.4% and after TV repair 100 and 83.3 +/- 9.5%. CONCLUSIONS: Repair for AV endocarditis yields excellent results. It is associated with low operative mortality and provides satisfactory early and long-term survival and favorable freedom from recurrent endocarditis and repeat operation. It should be considered as the primary surgical option in these patients, and AV replacement should be performed only in cases of severe AV destruction that renders repair techniques impossible. PMID- 21706200 TI - Dyadic adjustment, family coping, body image, quality of life and psychological morbidity in patients with psoriasis and their partners. AB - BACKGROUND: Psoriasis is an incurable and chronic disease that includes unpredictable periods of remission and relapse requiring long-term therapy. PURPOSE: This paper focuses on the relationship among family coping, psychological morbidity, body image, dyadic adjustment and quality of life in psoriatic patients and their partners. METHOD: One hundred and one patients with psoriasis and 78 partners comprised the sample. They were regular users of the Dermatology Service of a Central Northern hospital in Portugal and a private dermatology clinic. Patients with psoriasis were assessed on anxiety, depression, body image, quality of life, dyadic adjustment and family coping. Partners were assessed on the same measures except body image and quality of life. RESULTS: A positive relationship among dyadic adjustment, psychological morbidity and family coping in patients and their partners was found. Also, patients with lower levels of quality of life had partners with higher levels of depressive and anxious symptoms. Better dyadic adjustment predicted family coping in the psoriatic patient. High levels of dyadic adjustment in patients and low partners' trait anxiety predicted better dyadic adjustment in partners. CONCLUSION: The results highlight the importance of incorporating family variables in psychological interventions in psoriasis' care, particularly family coping and dyadic adjustment as well as the need for psychological intervention to focus both on patients and partners. PMID- 21706201 TI - Effect of the pH and temperature on the biosorption of lead(II) and cadmium(II) by sodium-modified stalk sponge of Zea mays. AB - OBJECTIVE: The present work was carried out to investigate the effects of temperature, initial pH, initial concentration, and contact time on the biosorption of lead (Pb) and cadmium (Cd) by modified stalk sponge of Zea mays using a batch technique. METHODS: The biomass was chemically modified with a 0.1 M NaCl solution. The lead and cadmium sorption process was evaluated at 20 degrees C, 30 degrees C, 40 degrees C, and 50 degrees C. RESULTS: The results showed that the modified stalk sponge of Z. mays had a good capacity for biosorption of Pb(II) and Cd(II). The kinetic behavior was described by the pseudo-second-order model for both metallic species. The experimental isotherms obtained at different temperatures were fit with Langmuir and Freundlich models. Thermodynamic parameters DeltaH(0) and DeltaS(0) were calculated using the van't Hoff equation, and the results show that Pb(II) and Cd(II) sorption by modified stalk sponge of Z. mays is an exothermic and spontaneous process. PMID- 21706203 TI - Age should not be a barrier to performing capsule endoscopy in the elderly with anaemia. PMID- 21706202 TI - Cameron ulcers: you will find only what you seek. PMID- 21706204 TI - Is it worthwhile to perform capsule endoscopy for asymptomatic patients with positive immunochemical faecal occult blood test? AB - BACKGROUND: The immunochemical faecal occult blood test (IFOBT) is widely performed for colorectal cancer screening, but the usefulness of IFOBT in the detection of disorders of the small intestine is unknown. The objective of this study was to investigate what proportion of IFOBT-positive subjects with negative colonoscopy and oesophagogastroduodenoscopy has pathologies of the small intestine detected by capsule endoscopy (CE). METHODS: Between October 2008 and June 2010, asymptomatic IFOBT-positive patients with negative total colonoscopy and oesophagogastroduodenoscopy underwent CE. CE findings were classified into three categories: P0 (no abnormalities, or findings without potential for bleeding), P1 (findings with uncertain potential for bleeding), P2 and (findings with high potential for bleeding). RESULTS: Fifty-three patients (37 males, 16 females; 52.1 +/- 13.0 years) were included. There were no cases with P2, 19 cases with P1, and 34 cases with P0 (there were no abnormalities in 25 of 34 cases). As a result, lesions in the small intestine were detected in 28 cases. Additional examination was considered necessary for five patients after CE, but no abnormality was detected, and therapeutic intervention was not undertaken in any case. Caecal completion rate was 92.5%. CONCLUSIONS: No significant pathologies of the small intestine were detected in asymptomatic IFOBT-positive cases with negative colonoscopy and oesophagogastroduodenoscopy. CE is of limited use in asymptomatic patients with positive IFOBT. PMID- 21706205 TI - Natural Orifice Translumenal Endoscopic Surgery (NOTES): patients' perceptions and attitudes. AB - BACKGROUND: Natural orifice translumenal endoscopic surgery (NOTES) has generated a surge of enthusiasm among researchers by virtue of its challenge to the dogma and potential benefits. However, no data is available in the medical literature about NOTES' acceptance by patients in Asia. The aim of the study is to survey patients' perceptions and attitudes towards NOTES. METHODS: It is a questionnaire based multi-center study on inpatient subjects with various gastrointestinal disorders from 14 hospitals in 12 cities of China. Procedural details with the benefits and risks of NOTES, laparoscopic surgery, and conventional surgery were explained to all registered candidates. They were required to choose and cite reasons for adopting one of the above three surgical techniques as the preferred mode of treatment. The reasons for selection of the surgical treatment were: safety, efficacy, cost, postoperative pain, abdominal wounds, and scarring. RESULTS: There were 1,797 cases, including 976 (54.3%) males and 821 females (45.7%). Based on their comprehension of the procedure, 802 (44.6%) patients opted for NOTES, 757 (42.1%) for laparoscopic surgery, and 238 (13.2%) for conventional surgery. NOTES was mainly selected by the young and educated persons, especially females and by those with past exposure to laparoscopy or conventional surgery. The choice of treatment was significantly correlated with age (P=0.0021), education (P=0.0209), past medical history (laparoscopy, P=0.0134; open surgery, P<0.0001), and department of admission (P=0.0173). The preference for NOTES was based on safety (37.3%), cost (17.6%), elimination of postoperative scars (16.1%), abdominal wounds (16.0%), and efficacy (13.1%). CONCLUSIONS: The vast majority of patients prefer mini-invasive surgery to conventional surgery. The potential recipients of NOTES are educated and younger age groups. However, a few consider NOTES as a safe and effective intervention at present. PMID- 21706206 TI - Tumor marker levels before and after curative treatment of hepatocellular carcinoma as predictors of patient survival. AB - BACKGROUND: alpha-fetoprotein (AFP) is used as a marker for hepatocellular carcinoma (HCC), which is influenced by hepatitis. Protein-induced vitamin K absence or antagonist II (PIVKA-II) is a sensitive diagnostic marker. Changes in these markers after treatment may reflect curability and predict outcome. METHODS: We conducted an analysis of prognosis in 470 HCC patients who received curative treatments, and examined the relationship between changes in AFP and PIVKA-II levels after 1 month of treatment in 156 patients. Subjects were divided into three groups according to changes in both levels: (1) normal (L) group before treatment, (2) normalization (N) or (3) decreased but still above normal level or unchanged (ANU) group after treatment. RESULTS: High AFP and PIVKA-II levels were significantly associated with poor tumor-free and overall survival. The presence of large size and advanced stage were significantly associated with prevalence of DU group. Overall survival in the AFP-L group was significantly better than that of other groups and overall survival in PIVKA-II-L and N groups were significantly better than that of the PIVKA-II-ANU groups. The combination of changes in the AFP- ANU and PIVKA-II- ANU groups showed the worst tumor-free and overall survivals. Multivariate analysis identified high pre-treatment levels of AFP and PIVKA-II and combination of AFP- ANU and PIVKA-II- ANU as significant determinants of poor tumor-free and overall survival, particularly in patients who underwent hepatectomy. CONCLUSION: We conclude that high levels of AFP or PIVKA-II after treatment for HCC did not sufficiently reflect curative efficacy of treatment and reflected a poor predictor of prognosis in HCC patients. PMID- 21706207 TI - Prediction of sustained virological response to combination therapy with pegylated interferon alfa and ribavirin in patients with genotype 3 chronic hepatitis C. AB - BACKGROUND: Sustained virological response (SVR) rates in patients with hepatitis C are heterogeneous and are influenced by a wide range of host and viral factors. AIM: To evaluate the efficacy of combination therapy with pegylated interferon alfa (PEG-IFN-alpha) and ribavirin (RBV), and document the SVR rates taking into consideration various predictive factors in patients with chronic hepatitis C (CHC) genotype 3. METHODS: Ninety-seven treatment-naive patients with CHC genotype 3 (mean age 41.46+/-11.51 years, M:F ratio 79:18), who received a combination of PEG-IFN (alpha-2a or alpha-2b) and RBV were retrospectively analyzed (2006-2008) for the early virological response (EVR) at 12 weeks, end of treatment response (ETR), and SVR at 6 months. RESULTS: Eighty-four (86.6%) patients achieved EVR and 81 (83.5%) achieved ETR, while SVR was achieved in 65 (67.0%) patients. Of the 84 patients who achieved EVR, 77 (91.7%) achieved ETR and 61 (72.6%) achieved SVR at 6 months. Age and body mass index (BMI) were found to be important predictors (*P<0.05) of SVR. CHC patients with a history of alcohol intake showed decreased SVR (52%) (*P=0.035) as compared to nonalcoholics (80%). Cirrhotic versus noncirrhotic patients showed no difference in SVR (54.5% vs. 70.7%) (P=0.157). Serum alanine aminotransferase (ALT) (P=0.169) and hepatitis C virus (HCV) RNA levels (P=0.42) also did not have an influence on the SVR. CONCLUSION: Combination therapy with PEG-IFN-alpha and RBV demonstrated good tolerability in CHC genotype 3 infection. Age, BMI, and alcohol consumption play an important role in determining treatment outcome. PMID- 21706208 TI - Influence of specific immunotherapy on the activity of human T lymphocyte Kv1.3 voltage-gated potassium channels in insect venom allergic patients. AB - Kv1.3 channels play an important role in T lymphocytes function. CD4(+) and CD4(+)CD25(+) T cells are two broad categories of T cells that are critically involved in the immunoresponse to allergens and that are also a major target for allergen immunotherapy. The aim of the study was to evaluate the effects of venom immunotherapy (VIT) on the activity of Kv1.3. channels on noncultured subsets: CD4(+) and CD4(+)CD25(+) T cells of insect venom allergic patients. Eleven patients with allergic reactions to bee or wasp venoms participated in the study. The patients were provided VIT according to the ultrarush protocol. CD4(+) and CD4(+)CD25(+) T cells were isolated from peripheral blood mononuclear cells of VIT-treated patients by an immunomagnetic method. We used the whole-cell patch clamp technique to investigate the whole potassium chord conductance (gK) of Kv1.3. channels in CD4(+) and CD4(+)CD25(+) T cells of venom-sensitive patients before and during the course of VIT. The conductance of Kv1.3. channels on CD4(+)CD25(+) T cells decreased during the course of VIT. On day 0 it was 0.054 +/- 0.07 [nS], and on day 70 it was 0.008 +/- 0.09 [nS] (P = 0.03). The observed decrease of the gK of the Kv1.3 channels in the subpopulation of activated T cells may contribute to T cell tolerance and functional unresponsiveness of these cells to allergen in the early stages of VIT. PMID- 21706209 TI - Uterus didelphys, hemihydrocolpos and empty ipsilateral lumbar fossa in a newborn girl: involuted dysplastic kidney rather than renal agenesis. AB - We report a case of Herlyn-Werner-Wunderlich syndrome diagnosed in the neonatal period. US revealed the classic association of a uterus didelphys with blind hemivagina and no ipsilateral kidney. The diagnosis was established by postnatal US and confirmed by MRI. Differential diagnoses are discussed. A trans-hymeneal resection of the vaginal septum was performed at 1 month of age. Intra operative endoscopy revealed no left hemitrigone but showed an atretic orifice in the ipsilateral blind hemivagina, probably corresponding to the insertion of an ectopic ureter. Follow-up was unremarkable. PMID- 21706210 TI - [Extramammary Paget disease: successful therapy with imiquimod 5% cream]. AB - A 90-year-old woman presented with an extensive primary form of extramammary Paget disease localized in the anogenital region. An associated carcinoma could be excluded. Due to the age of the patient, the location and extent of the tumor as well as existing comorbidities, neither a surgical nor a radio-oncological treatment were advisable. A local treatment with imiquimod 5% cream applied 3 times weekly for 2 * 3 weeks led to a clinically and histopathologically complete remission. As also shown by other authors, imiquimod appears to be a treatment option for the primary form of extramammary Paget disease. PMID- 21706211 TI - [Treatment-refractory anti-laminin 332 mucous membrane pemphigoid. Remission following adjuvant immunoadsorption and rituximab]. AB - Mucous membrane pemphigoid (MMP) is clinically characterized by predominant involvement of mucous membranes which in case of conjunctival lesions can lead to blindness. In MMP, autoantibodies are directed against different proteins of the dermal-epidermal junction; in 25% of cases, laminin 332 is the target. Anti laminin 332 MMP with ocular involvement is particularly difficult to treat. A 46 year-old Caucasian man with anti-laminin 332 pemphigoid and extensive oral and nasal erosions as well as severe conjunctival involvement did not respond to intravenous dexamethasone-cyclophosphamide pulses combined with oral cyclophosphamide. After initiation of a therapeutic regimen originally established for the treatment of pemphigus, including immunoapheresis and rituximab in combination with intravenous dexamethasone-cyclophosphamide pulses and oral mycophenolate mofetil, lesions cleared within 4 months and circulating autoantibody levels became undetectable 3 months later. This is the first report of the successful use of adjuvant immunoapheresis and rituximab in previously treatment-refractory anti-laminin 332 MMP. PMID- 21706212 TI - Multiple plans and memory performance: results of a randomized controlled trial targeting fruit and vegetable intake. AB - To test whether forming and memorizing more action plans has larger effects than generating fewer plans. In a randomized controlled trial with five intervention groups and one control group, 478 participants were asked to form one, two, three, four, or five action plans, or to complete questionnaires only (control group). One week later, behavior change was measured and participants of the intervention groups completed a free recall task. Outcome measures are daily intake of fruit and vegetables as well as recall of plans. Fruit and vegetable intake increased with higher numbers of plans, and was significantly larger in groups that formed four (d = 0.36) or five plans (d = 0.48) as compared to controls. The sum of recalled plans reflected the number of generated plans, but was unrelated to behavior change. Generating multiple plans benefits behavior change, but to be implemented they need not be recalled. PMID- 21706213 TI - Forgive to live: forgiveness, health, and longevity. AB - This study examined multiple types of forgiveness as predictors of mortality and potential psychosocial, spiritual, and health mechanisms of the effects of forgiveness on longevity. Data from a nationally representative sample of United States adults ages 66 and older assessed forgiveness, health, religiousness/spirituality, and socio-demographics (N = 1,232). God's unconditional forgiveness and conditional forgiveness of others initially emerged as statistically significant predictors of mortality risk. However, only conditional forgiveness of others remained a significant predictor of mortality after controlling for religious, socio-demographic, and health behavior variables. Mediators of the association between conditional forgiveness of others and mortality were examined, and a statistically significant indirect effect was identified involving physical health. These findings suggest that conditional forgiveness of others is associated with risk for all-cause mortality, and that the mortality risk of conditional forgiveness may be conferred by its influences on physical health. PMID- 21706214 TI - Single-center clinical comparison of two reinforced ureteral access sheaths for retrograde ureteroscopic treatment of urinary lithiasis. AB - BACKGROUND: Ureteral access sheaths (UAS) are used to facilitate ureteroscopic procedures. Difficulties in use, including sheath distortion, buckling, and difficulty in placement, have been reported. However, few clinical comparisons have been performed. We present the first large-scale comparison of the Applied ForteXE((r)) and ACMI-Gyrus Uropass((r)) UAS. METHODS: We retrospectively compared patients who underwent ureteroscopy for urolithiasis with one of two types of UAS: Applied Forte XE((r)) or ACMI-Gyrus Uropass((r)). Demographics, operative parameters, and outcomes were assessed. Statistical analysis was performed. RESULTS: In 125 (64.4%) male and 69 (35.6%) female patients, 194 UAS were used. One hundred and thirteen (58.2%) Applied Forte XE((r)) and 81 (41.8%) ACMI-Gyrus Uropass((r)) were utilized. Success rates for sheath deployment were as follows: overall = 186/194 (95.8%); Applied Forte XE((r)) = 107/113 (94.7%); and ACMI-Gyrus Uropass((r)) = 79/81 (97.5%) (P = 0.472). Of the 194 patients 131 (67.5%) had a pre-existing stent. Sheath deployment failures occurred in 7 men and 1 woman, of which 4/8 (50%) had no pre-existing stent. Limitations of deployed sheaths occurred at low frequency in both Applied Forte XE 17/107 (15.9%) and ACMI-Gyrus 6/79 (7.6%), with no significant difference observed (P = 0.120). Limitations in use was high in men (P = 0.019). At a mean follow-up of 41 months, no ureteral strictures were noted. CONCLUSIONS: No significant differences were seen in overall success rates for both sheaths. Both sheaths had high deployment success rates and a similar low frequency of sheath-related limitations. We noted increased limitations in the use of deployed sheaths in men. Successful sheath use may depend on both the sheath itself and patient/operative parameters. PMID- 21706215 TI - New advanced glycation end-products inhibitors from Dichrostachys cinerea Wight & Arn. AB - Free radical scavenging and advanced glycation end-product (AGE) inhibitory potential were evaluated in the crude methanol extract of Dichrostachys cinerea. Bioassay-guided isolation led to the identification of four flavan-3-ols, namely (-)-mesquitol (1), oritin (2), (-)-festidinol (3) and (-)-epicatechin (4). Analysis of structure-activity relationships revealed that the presence of 7,8 dihydroxyl groups in the A-ring of flavan-3-ols in conjunction with 3',4' dihydroxyls in the B-ring (1) is an important criterion for displaying potent AGE inhibitory activity along with free radical scavenging properties. (-)-Mesquitol (1), oritin (2), and (-)-festidinol (3) were found to be new natural AGE inhibitors. (-)-Mesquitol (1) displayed the most potent AGE inhibitory activity. Results suggest that (-)-mesquitol (1) may serve as an important natural organic lead compound for future development of antiglycating agents along with potent antioxidant activity. PMID- 21706216 TI - Discussion paper: what happened to the 'bio' in the bio-psycho-social model of low back pain? AB - PURPOSE: Over 20 years ago the term non-specific low back pain became popular to convey the limitations of our knowledge of the pathological source of most people's low back pain. Knowledge of underlying pathology has advanced little since then, despite limited improvements in outcomes for patients with low back pain. METHODS: This paper discusses potential misunderstandings related to diagnostic studies in the field of low back pain and argues that future diagnostic studies should include and investigate pathological sources of low back pain. RESULTS: Six potential misunderstandings are discussed. (1) Until diagnosis is shown to improve outcomes it is not worth investigating; (2) without a gold standard it is not possible to investigate diagnosis of low back pain; (3) the presence of pathology in some people without low back pain means it is not important; (4) dismissal of the ability to diagnose low back pain in clinical guidelines is supported by the same level of evidence as recommendations for therapy; (5) suggesting use of a diagnostic test in research is misinterpreted as endorsing its use in current clinical practice; (6) we seem to have forgotten the 'bio' in biopsychosocial low back pain. CONCLUSIONS: We believe the misunderstandings presented in this paper partly explain the lack of investigation into pathology as an important component of the low back pain experience. A better understanding of the biological component of low back pain in relation, and in addition, to psychosocial factors is important for a more rational approach to management of low back pain. PMID- 21706217 TI - In vitro biocompatibility of modified potassium fluorrichterite and potassium fluorrichterite-fluorapatite glass-ceramics. AB - Potassium fluorrichterite (KNaCaMg(5)Si(8)O(22)F(2)) glass-ceramics were modified by either increasing the concentration of calcium in the glass (GC5), or by the addition of P(2)O(5) to produce potassium fluorrichterite-fluorapatite (GP2). The solubility of the stoichiometric composition (GST), GC5 and GP2 were measured using the standard test described in ISO 6872:1995 (Dental Ceramics). Ion release profiles were determined for Si, Ca, Mg, Na, K and P using inductively coupled plasma mass spectrometry and fluoride ion (F(-)) concentration was measured using an ion-selective electrode. The cytotoxicity of all compositions was assessed using cultured rat osteosarcoma cells (ROS, 17/2.8). Cell response was qualitatively assessed using scanning electron microscopy (SEM) and quantitatively using the Alamar blue assay. GST was the least soluble and also released the lowest concentration of ions following immersion in water. Of the modified compositions, GC5 demonstrated intermediate solubility but the greatest ion release while GP2 exhibited the highest solubility. This was most likely due to GC5 having the greatest proportion of residual glass following crystallisation. The mass loss exhibited by GP2 may have been due in part to the partial disintegration of the surface of specimens during solubility testing. SEM demonstrated that all compositions supported the growth of healthy ROS cells on their surfaces, and this data was further supported by the quantitative Alamar blue assay. PMID- 21706218 TI - Reactive calcium-phosphate-containing poly(ester-co-ether) methacrylate bone adhesives: setting, degradation and drug release considerations. AB - This study has investigated novel bone adhesives consisting of fluid photo polymerizable poly(lactide-co-propylene glycol-co-lactide)dimethacrylate (PGLA DMA) mixed with systematically varying fillers of beta-tricalcium phosphate (beta TCP) and monocalcium phosphate monohydrate (MCPM), for the delivery of an antibacterial drug chlorhexidine (CHX). All formulations were found to polymerize fully within 200 s after exposure to blue light. In addition, water sorption by the polymerized materials catalyzed varying filler conversion to dicalcium phosphate (DCP) (i.e. brushite and monetite). With greater DCP levels, faster degradation was observed. Moreover, increase in total filler content enhanced CHX release, associated with higher antibacterial activity. These findings thus suggest that such rapid-setting and degradable adhesives with controllable drug delivery property could have potential clinical value as bone adhesives with antibacterial activity. PMID- 21706219 TI - Improved interaction of osteoblast-like cells with apatite-nanodiamond coatings depends on fibronectin. AB - New apatite (AP)/nanodiamond (ND) coating has been developed to improve physical and biological properties of stainless steel (SS) versus single AP coating. Homogeneously electrodeposited AP-ND layer demonstrates increased mechanical strength, interlayer cohesion and ductility. In the absence of serum, osteoblast like MG63 cells attach well but poorly spread on both AP and AP-ND substrata. Pre adsorption with serum or fibronectin (FN) improves the cellular interaction-an effect that is better pronounced on the AP-ND coating. In single protein adsorption study fluorescein isothiocyanate-labeled FN (FITC-FN) shows enhanced deposition on the AP-ND layer consistent with the significantly improved cell adhesion, spreading and focal adhesions formation (in comparison to SS and AP), particularly at low FN adsorption concentrations (1 MUg/ml). Higher FN concentrations (20 MUg/ml) abolish this difference suggesting that the promoted cellular interaction of serum (where FN is low) is caused by the greater affinity for FN. Moreover, it is found that MG63 cells tend to rearrange both adsorbed and secreted FN on the AP-ND layer suggesting facilitated FN matrix formation. PMID- 21706220 TI - Epidural anesthesia with intravenous dexmedetomidine sedation in the successful anesthetic management of MRI-guided focused ultrasound ablation of early prostatic cancer. AB - We report on five patients who underwent MRI-guided focused ultrasound ablation of prostatic cancer under epidural anesthesia with intravenous dexmedetomidine sedation. This pioneering procedure requires an immobile therapeutic field with adequate sedation and analgesia provided to the patients. Duration of the procedure is longer compared to diagnostic MRI scans. In combination with epidural anesthesia, dexmedetomidine was used to provide moderate levels of sedation without causing respiratory depression or hemodynamic instability, and was useful in preventing shivering. The pharmacological properties of dexmedetomidine contribute to make this technique safe and effective. PMID- 21706221 TI - Symptomatic response to divalproex in subtypes of conduct disorder. AB - To investigate response to Divalproex sodium (DVPX) with respect to Reactive/Affective/Defensive/Impulsive (RADI) and Proactive/Instrumental/Premeditated (PIP) aggression among adolescent males with conduct disorder (CD), using results from a randomized, double-blind, placebo controlled trial. It was hypothesized that DVPX response among participants with RADI aggression would be greater than among those with PIP aggression. Fifty eight ethnically diverse males with severe CD were assigned to High Distress (HDCD) or Low Distress (LDCD) Conduct Disorder, corresponding with RADI and PIP aggression, respectively. Following a 1-week washout, all subjects were randomized to a high dose (up to 1,500 mg/day) or low dose (up to 250 mg/day) of DVPX. Baseline and endpoint assessments included Clinical Global Impression (CGI), Achenbach Self Report (YSR), and Weinberger Adjustment Inventory (WAI-62). Response to DVPX was significantly higher in the HDCD group (64%) than in the LDCD group (22%) in the high-dose treatment group (p = 0.03). Mean weekly WAI-62 distress scores declined significantly among the HDCD subjects than among LDCD subjects in the high-dose group. These results support the utility of mood stabilizing agents such as DVPX in treating patients with disorders characterized by the RADI pattern of aggression, including those with severe CD. PMID- 21706222 TI - Probability Steiner trees and maximum parsimony in phylogenetic analysis. AB - The phylogenetic tree (PT) problem has been studied by a number of researchers as an application of the Steiner tree problem, a well-known network optimisation problem. Of all the methods developed for phylogenies the maximum parsimony (MP) method is a simple and commonly used method because it relies on directly observable changes in the input nucleotide or amino acid sequences. In this paper we show that the non-uniqueness of the evolutionary pathways in the MP method leads us to consider a new model of PTs. In this so-called probability representation model, for each site a node in a PT is modelled by a probability distribution of nucleotide or amino acid states, and hence the PT at a given site is a probability Steiner tree, i.e. a Steiner tree in a high-dimensional vector space. In spite of the generality of the probability representation model, in this paper we restrict our study to constructing probability phylogenetic trees (PPT) using the parsimony criterion, as well as discussing and comparing our approach with the classical MP method. We show that for a given input set although the optimal topology as well as the total tree length of the PPT is the same as the PT constructed by the classical MP method, the inferred ancestral states and branch lengths are different and the results given by our method provide a plausible alternative to the classical ones. PMID- 21706223 TI - Long-term mortality associated with community-onset bloodstream infection. AB - PURPOSE: Although bloodstream infection is widely recognized as an important cause of acute morbidity and mortality, long-term mortality outcomes are less well defined. The objective of this study was to define the early (<=28 days) and late (>28 days) mortality and assess determinants of late death following community-onset bloodstream infection. METHODS: All adult residents of the Calgary Zone who had community-onset bloodstream infections during the period 1 January 2003 and 31 December 2007 were included. The mortality outcome was assessed through to 31 December 2008. RESULTS: A total of 4,553 cases were identified, of which 2,105 (46%) were healthcare-associated and 2,448 (54%) were community-acquired. The 28-day, 90-day, and 365-day all-cause case-fatality rates were 561/4,553 (12%), 780/4,553 (17%), and 1,131 (25%), respectively. Within the first 28 days, the median time to death was 4 (interquartile range [IQR] 1-12) days, with 158 (28%) and 212 (38%) of early (<=28-day) deaths occurring by days 1 and 2, respectively. Among survivors to 28 days (n = 3,992), 570 (14%) suffered late 1-year mortality (i.e., death occurred between 29 and 365 days postinception). The most common causes of death in this cohort as listed by the vital statistics data were malignancy in 220 (39%), cardiovascular in 135 (24%), and infection-related in 37 (7%). Older age, higher Charlson score, prolonged initial admission duration, and healthcare-associated and polymicrobial infections were independently associated with late 1-year mortality. CONCLUSIONS: Community-onset bloodstream infection is associated with major early and late mortality. PMID- 21706224 TI - Yokenella regensburgei in an immunocompromised host: a case report and review of the literature. AB - Yokenella regensburgei belongs to the Enterobacteriaceae and shares some biochemical characteristics with Hafnia alvei. A few case reports have suggested that it is an opportunistic pathogen, but there is no strong evidence to support its clinical importance. Until recently, it was difficult to accurately differentiate between Y. regensburgei and H. alvei by use of routine identification techniques. Here, we present a case of soft tissue infection and bacteremia caused by Y. regensburgei, which was successfully treated by intravenous administration of ceftriaxone for three weeks, and review the previous literature. PMID- 21706225 TI - Favorable outcome after life-threatening meningococcal disease complicating influenza A(H1N1) infection. AB - PURPOSE: Neurological complications of influenza A(H1N1) have been reported in several patients since the onset of the pandemic in 2009. However, meningococcal disease complicating influenza A(H1N1) has not been reported. PATIENTS: Two patients were admitted to an intensive care unit (ICU) for altered mental status, fever, and rapidly spreading petechial purpura. They were diagnosed with meningococcal meningitis and/or meningococcemia and influenza A(H1N1) co infection. CONCLUSIONS: Meningococcal disease presenting as meningitis and/or meningococcemia is among the potential complications of influenza A(H1N1) infection. Physicians should be aware of this co-infection, as it must be detected and treated promptly with antibiotics in addition to supportive care. PMID- 21706226 TI - Extended-spectrum beta-lactamase-producing Gram-negative pathogens in community acquired urinary tract infections: an increasing challenge for antimicrobial therapy. AB - BACKGROUND: Extended-spectrum beta-lactamases (ESBLs) are an increasing challenge in the treatment of urinary tract infections (UTIs), and also in the community. We aimed to investigate the characteristics of patients with UTIs due to ESBL producing Escherichia coli and to assess the risk factors for ESBLs in community acquired isolates. METHODS: We performed a retrospective study from January 1, 2007 to December 31, 2009 at a tertiary care teaching hospital in Switzerland, comparing patients with community-acquired versus healthcare-associated UTIs due to ESBL-producing E. coli. Additionally, we investigated the antimicrobial susceptibility of these isolates. RESULTS: A total of 123 patients were studied, of whom 79 (64%) had community-acquired and 44 (36%) had healthcare-associated UTIs. Community-acquired isolates were associated with acute uncomplicated UTIs (odds ratio [OR] 6.62, 95% confidence interval [CI] 1.83-36.5, P < 0.001). Risk factors were recurrent UTI (OR 3.04, 95% CI 1.14-9.14, P = 0.022) and female sex (OR 2.46, 95% CI 1.01-6.08). Community-acquired ESBL-producing E. coli urinary isolates showed high resistance rates to most of the currently used oral antimicrobial agents, including beta-lactam antibiotics (amoxicillin-clavulanic acid, 69.6% resistance), quinolones (ciprofloxacin, 84.8% resistance; norfloxacin, 83.9% resistance), and trimethoprim-sulfamethoxazole (75.9% resistance), except for nitrofurantoin (15% resistance) and fosfomycin (0% resistance). CONCLUSION: UTI due to ESBL-producing E. coli are emerging, and also in a country with low antibiotic use. Because of increasing antibiotic resistance rates of E. coli to current standard therapy and because of the resistance patterns of ESBL-producing E. coli, guidelines for the management of UTIs must be revised. Fosfomycin or nitrofurantoin are recommended for the first-line empirical oral treatment of community-acquired uncomplicated UTIs. PMID- 21706227 TI - Differences in outpatient antibiotic prescription in Italy's Lombardy region. AB - OBJECTIVES: We assessed the antibiotic patterns of use and geographical distribution of prevalence and consumption by age in 15 Local Health Units (LHUs) of Italy's Lombardy region. METHODS: A retrospective analysis of reimbursement data for the community-dwelling population in 2005 was performed. Prescriptions reimbursed by the National Health System and consumption as defined daily doses (DDD) per 1,000 inhabitants per day (DID) were analyzed. A logistic regression was performed to evaluate the association between antibiotic drug prescription and age, gender, and LHU of residence of the population. RESULTS: During 2005, a total of 3,120,851 people (34% of the population) received at least one antibiotic drug prescription. The highest prescription prevalence was observed in the 0-17 and 80 or more years age ranges (41.6 and 41.9%, respectively). Large differences were found in the prevalence rates between different LHUs (ranging from 28.7% in Milan to 39.4% in Brescia) and in DID (ranging from 12.6 DID in Sondrio to 18.9 DID in Brescia). The age and residence of the population were the main determinants of drug exposure. In particular, patients aged <18 years (odds ratio [OR] = 1.73; 95% confidence interval [CI] 1.73, 1.74), aged 65 years or older (OR = 1.64; 95% CI 1.63, 1.65), and those that live in Brescia (OR = 1.66; 95% CI 1.65, 1.66) had a statistically significant higher risk of antibiotic drug exposure. CONCLUSIONS: The observed intra-regional differences underline the need for a careful monitoring with the aim to reduce antibiotic resistance and improve the rational use of drugs. PMID- 21706228 TI - Metabolites of polycyclic aromatic hydrocarbons (PAHs) in bile as biomarkers of pollution in European eel (Anguilla anguilla) from German rivers. AB - In the light of the alarming decline of the European eel (Anguilla anguilla L.) population, there is an urgent need to define ecological indicators for eel habitat quality. Due to an increasing shortage of glass eels available for local stock enhancement, the decision of whether restocking is a valuable management tool to increase high-quality silver eel escapement to the sea needs to be evaluated. Organic contaminants, such as polycyclic aromatic hydrocarbons (PAHs), are among the major threats to fish in their habitat. Therefore, the aim of the investigation presented here was to examine metabolites of PAHs in eel bile as one possible marker for habitat quality. In total, 170 yellow eels were collected in the rivers Rhine, Ems, Weser, Elbe, Havel, Schlei, Eider, Trave, Warnow, Peene, Uecker, and Oder in 2009. PAH metabolites in eel bile were analyzed using high-performance liquid chromatography with fluorescence detection. Metabolites of pyrene and phenanthrene were investigated. Concentrations of PAH metabolites in eel bile varied significantly between several rivers, with the highest mean concentrations of 1-hydroxypyrene and 1-hydroxyphenanthrene in eel bile from the river Trave (2421 and 632 ng/ml). Moreover, huge differences in the ratio of 1 hydroxypyrene to 1-hydroxyphenanthrene, with the highest mean value in eel bile from the river Ems (7.43) and the lowest mean value in eel bile from the river Uecker (0.70), indicate different sources of PAH contamination. A comparative analysis of PAH-metabolite contamination of eels in different river systems is seen as a first step toward a classification of freshwater habitats for restocking purposes. PMID- 21706229 TI - Histological study of organogenesis in Cucumis melo L. after genetic transformation: why is it difficult to obtain transgenic plants? AB - Melon (Cucumis melo L.) is widely considered as a recalcitrant species for genetic transformation. In this study, we developed different regeneration and transformation protocols and we examined the regeneration process at different steps by histological studies. The highest regeneration rate (1.13 +/- 0.02 plants per explant) was obtained using cotyledon explants of the 'Vedrantais' genotype on Murashige and Skoog (MS) medium supplemented with 0.2 mg/l 6 benzylaminopurine (BAP) and 0.2 mg/l dimethylallylaminopurine (2-iP). Agrobacterium tumefaciens-mediated transformations with the uidA reporter gene were realized on cotyledon explants cultivated in these conditions: 70-90% of explants expressed a transient GUS activity during the early stages of regeneration, however, only few transgenic plants were obtained (1.8-4.5% of stable transformation with the GV2260pBI101 strain). These results revealed a low capacity of melon GUS-positive cells to regenerate transgenic plants. To evaluate the influence of the Agrobacterium infection on plant regeneration, histological analyses were conducted on explants 2, 7, 15, and 28 days after co-culture with the GV2260pBI101 strain. Genetic transformation occurred in epidermal and sub epidermal cells and reached the meristematic structures expressing a high level of GUS activity during 14 days of culture; but after this period, most of the meristematic structures showed premature cell vacuolization and disorganization. This disruption of the GUS-positive meristematic areas could be responsible of the difficulties encountered to regenerate melon plants after genetic transformation. PMID- 21706231 TI - Gap junction permeability between tenocytes within tendon fascicles is suppressed by tensile loading. AB - Gap junction communication is an essential component in the mechanosensitive response of tenocytes. However, little is known about direct mechanoregulation of gap junction turnover and permeability. The present study tests the hypothesis that mechanical loading alters gap junction communication between tenocyte within tendon fascicles. Viable tenocytes within rat tail tendon fasicles were labelled with calcein-AM and subjected to a fluorescent loss induced by photobleaching (FLIP) protocol. A designated target cell within a row of tenocytes was continuously photobleached at 100% laser power whilst recording the fluorescent intensity of neighbouring cells. A mathematical compartment model was developed to estimate the intercellular communication between tenocytes based upon the experimental FLIP data. This produced a permeability parameter, k, which quantifies the degree of functioning gap functions between cells as confirmed by the complete inhibition of FLIP by the inhibitor 18alpha-glycyrrhentic acid. The application of 1N static tensile load for 10 min had no effect on gap junction communication. However, when loading was increased to 1 h, there was a statistically significant reduction in gap junction permeability. This coincided with suppression of connexin 43 protein expression in loaded samples as determined by confocal immunofluorescence. However, there was an upregulation of connexin 43 mRNA. These findings demonstrate that tenocytes remodel their gap junctions in response to alterations in mechanical loading with a complex mechanosensitive mechanism of breakdown and remodelling. This is therefore the first study to show that tenocyte gap junctions are not only important in transmitting mechanically activated signals but that mechanical loading directly regulates gap junction permeability. PMID- 21706230 TI - Expression profiles of precursor and mature microRNAs under dehydration and high salinity shock in Populus euphratica. AB - MicroRNAs (miRNAs) are small non-coding RNAs that play vital roles in plant abiotic stress responses via cleavage or translational inhibition of their target mRNAs. Populus euphratica is a typical stress-resistant sessile organism that grows in desert areas. Here, we identified sequences of 12 miRNA precursors from 11 families and 13 mature miRNAs from 12 families by PCR amplification in P. euphratica. To detect expression differences in mature miRNAs and their precursors under dehydration and high salinity shock in P. euphratica, we examined 14 miRNA precursors from 13 miRNA families and 17 mature miRNAs from 17 miRNA families using the SYBR Green RT-PCR assay. This is the first report of expression profiles for both precursor and mature miRNAs in P. euphratica. By profiling both the mature miRNAs and the precursors under abiotic stress shock, it was possible to identify miRNA whose processing is regulated during stress shock environments. A majority of the genes predicted to be targets for plant miRNAs are involved in development, stress resistance and metabolic processes. We have cloned and experimentally identified in vivo five of the predicted target genes and quantified the five target mRNAs from the same RNA sample simultaneously. Based on this study, we propose some regulatory pathways that illustrate the important role that miRNAs play in response to abiotic stress shock in P. euphratica. PMID- 21706232 TI - Rapid synthesis of new block copolyurethanes derived from L-leucine cyclodipeptide in reusable molten ammonium salts: novel and efficient green media for the synthesis of new hydrolysable and biodegradable copolyurethanes. AB - This study concerns the synthesis of novel multi block polyurethane (PU) copolymers containing cyclodipeptide, taking the advantage of ionic liquids (ILs) under microwave irradiation. For this, L-leucine anhydride cyclodipeptide (LACP) was prepared and then a new class of poly(ether-urethane-urea)s (PEUUs) was synthesized in molten ammonium type ILs. ILs were used as reaction media and PUs were prepared via two-step polymerization method. In the first step, 4,4' methylene-bis-(4-phenylisocyanate) (MDI) was reacted with LACP to produce isocyanate-terminated oligo(imide-urea) as hard segment (NCO-OIU). Chain extension of the aforementioned pre-polymer with polyethyleneglycol (PEG) of molecular weights of 1000 (PEG-1000) was the second step to furnish a series of new PEUUs. These multiblock copolymers are thermally stable, soluble in amide type solvents, hydrolysable and biodegradable. PEUUs prepared in ILs under microwave irradiation showed more phase separation and crystallinity than PEUUs prepared under conventional method. The protocol presented here has the merits of environmentally benign, simple operation, convenient work-up, short reaction time and good yields without using volatile organic solvents, and catalysts. Ammonium type reaction media were air and water stable, and relatively cheap, which makes them suitable for application. The results demonstrate that they can be easily separated into water and reused without losing activity. Reusability of tetrabutylammonium bromide as reaction media makes the method a cost effective and environmentally benign method under microwave irradiation. Thus, we could prepare environmentally friendly polymers via environmentally benign method. PMID- 21706233 TI - Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence. AB - PURPOSE: Epigenetic silencing of the DNA mismatch repair genes has been poorly described in colorectal carcinomas showing the classic adenoma-carcinoma pathway of carcinogenesis. The aim of this study was to investigate the methylation status of MutL homolog 1 (hMLH1), MutS homolog 2 (hMSH2), and O-6-methylguanine DNA methyltransferase (MGMT) in a series of colorectal carcinomas that contain both adenomas and carcinomas. METHODS: Promoter methylation of hMLH1, hMSH2, and MGMT was evaluated in normal mucosa, adenoma, and carcinoma samples from 112 colorectal cancer patients. Methylation was assessed by bisulfite modification and methylation-specific PCR. Expression of the gene products was also examined by immunohistochemistry. RESULTS: Of the 112 adenomas, methylation was detected for hMLH1 (2, 1.8%), hMSH2 (9, 8.0%), and MGMT (38, 33.9%). In the carcinoma samples, methylation was seen in hMLH1 (2, 1.8%), hMSH2 (15, 13.4%), and MGMT (53, 47.3%). In normal mucosa, hMSH2 (6, 5.4%) and MGMT (12, 10.7%) were methylated, whereas hMLH1 was not. Immunohistochemical analysis revealed abnormal hMLH1 (14, 12.5%), hMSH2 (11, 9.8%), and MGMT (53, 47.3%) expression with a significant correlation between aberrant MGMT methylation and a loss of MGMT expression. CONCLUSIONS: These data suggest that CpG island methylation in hMSH2 and MGMT, but not hMLH1, is closely related to carcinogenesis in colorectal carcinomas presenting with a conventional adenoma-carcinoma sequence. Therefore, the detection of hMSH2 and MGMT methylation may have clinical significance in the evaluation of colon cancer patients and in tumor-specific management of the disease. PMID- 21706235 TI - Direct analysis of dried blood spots coupled with mass spectrometry: concepts and biomedical applications. AB - Because of the emergence of dried blood spots (DBS) as an attractive alternative to conventional venous plasma sampling in many pharmaceutical companies and clinical laboratories, different analytical approaches have been developed to enable automated handling of DBS samples without any pretreatment. Associated with selective and sensitive MS-MS detection, these procedures give good results in the rapid identification and quantification of drugs (generally less than 3 min total run time), which is desirable because of the high throughput requirements of analytical laboratories. The objective of this review is to describe the analytical concepts of current direct DBS techniques and to present their advantages and disadvantages, with particular focus on automation capacity and commercial availability. Finally, an overview of the different biomedical applications in which these concepts could be of major interest will be presented. PMID- 21706234 TI - Protective effects of walnut extract against amyloid beta peptide-induced cell death and oxidative stress in PC12 cells. AB - Amyloid beta-protein (Abeta) is the major component of senile plaques and cerebrovascular amyloid deposits in individuals with Alzheimer's disease. Abeta is known to increase free radical production in neuronal cells, leading to oxidative stress and cell death. Recently, considerable attention has been focused on dietary antioxidants that are able to scavenge reactive oxygen species (ROS), thereby offering protection against oxidative stress. Walnuts are rich in components that have anti-oxidant and anti-inflammatory properties. The inhibition of in vitro fibrillization of synthetic Abeta, and solubilization of preformed fibrillar Abeta by walnut extract was previously reported. The present study was designed to investigate whether walnut extract can protect against Abeta-induced oxidative damage and cytotoxicity. The effect of walnut extract on Abeta-induced cellular damage, ROS generation and apoptosis in PC12 pheochromocytoma cells was studied. Walnut extract reduced Abeta-mediated cell death assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) reduction, and release of lactate dehydrogenase (membrane damage), DNA damage (apoptosis) and generation of ROS in a concentration-dependent manner. These results suggest that walnut extract can counteract Abeta-induced oxidative stress and associated cell death. PMID- 21706236 TI - Plasma membrane proteomic analysis of human osteosarcoma and osteoblastic cells: revealing NDRG1 as a marker for osteosarcoma. AB - Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. To identify new biomarkers for early diagnosis of OS and novel therapeutic candidates, we carried out a plasma membrane proteomic study based on two-dimensional electrophoresis (2DE). The OS cell line MG-63 and the human osteoblastic cell line hFOB1.19 were adopted as the comparison model. We extracted plasma membrane by aqueous two-phase partition extraction. The proteins were separated through 2DE. We analyzed the differentially expressed proteins by Imagemaster software and then identified them by liquid chromatography-tandem mass spectrometry, and the location and function of differential proteins were searched through the Gene Ontology database. In total, 220 protein spots were separated by 2DE. Seven proteins with more than 2.0-folds of difference were successfully identified from 13 gel spots, with 6 up-regulated and 1 down regulated. Gene Ontology analysis of the differentially expressed proteins indicated that these proteins were involved in seven kinds of functions including binding, structural, cell motility, receptor activity, electron carrier activity, NADH dehydrogenase (ubiquinone) activity, and transcription repressor activity. The up-regulation of NDRG1 was verified in osteosarcoma through Western blotting and by immunohistochemistry in paraffin-embedded tissues. The plasma membrane proteins identified in this study may provide new insights into osteosarcoma cancer biology and potential diagnostic and therapeutic biomarkers. PMID- 21706237 TI - Quantitative expression analysis of apoptotic/antiapoptotic genes and association with immunolocalization of BAX and BCL-2 in peripheral and central giant cell lesions of the jaws. AB - Central giant cell lesion (CGCL) and peripheral giant cell lesion (PGCL) of the jaws are characterized by multinucleated osteoclast-like giant cells in a background of mononuclear cells. While mononuclear cells retain proliferative activity in both lesions, giant cells are Ki-67 negative. This observation raised the theory that giant cells are formed by cytoplasmic fusion of mononuclear cells, and also that these lesions are of reactive nature. As the giant cells are not proliferating in CGCL and PGCL, apoptosis of such cells should be investigated. We investigated the transcription of BAX and BCL-2 mRNAs in six fresh samples of CGCL and six fresh samples of PGCL by qRT-PCR (quantitative reverse transcription PCR) and used immunohistochemistry to demonstrate the localization of these proteins, as well as caspase 3 active in six paraffin embedded samples of CGCL and nine paraffin-embedded samples of PGCL. While both groups showed increased expression of BAX and BCL-2 mRNA, PGCL showed a higher apoptotic index (ratio BAX/BCL-2) than CGCL. The three proteins investigated were expressed almost exclusively in the cytoplasm of giant cells. To further confirm apoptotic activity, we performed TUNEL analysis in the same samples of the immunohistochemistry and found a higher positivity in the giant cells of PGCL compared to the giant cells of CGCL. Our results show increased expression of apoptotic-related genes in both PGCL and CGCL and that the giant cells are probably the main source of these events. Also, it raises a hypothesis that differences in the apoptotic activity might be associated with the different clinical behavior of CGCL and PGCL. PMID- 21706238 TI - Does the 'hikikomori' syndrome of social withdrawal exist outside Japan? A preliminary international investigation. AB - PURPOSE: To explore whether the 'hikikomori' syndrome (social withdrawal) described in Japan exists in other countries, and if so, how patients with the syndrome are diagnosed and treated. METHODS: Two hikikomori case vignettes were sent to psychiatrists in Australia, Bangladesh, India, Iran, Japan, Korea, Taiwan, Thailand and the USA. Participants rated the syndrome's prevalence in their country, etiology, diagnosis, suicide risk, and treatment. RESULTS: Out of 247 responses to the questionnaire (123 from Japan and 124 from other countries), 239 were enrolled in the analysis. Respondents' felt the hikikomori syndrome is seen in all countries examined and especially in urban areas. Biopsychosocial, cultural, and environmental factors were all listed as probable causes of hikikomori, and differences among countries were not significant. Japanese psychiatrists suggested treatment in outpatient wards and some did not think that psychiatric treatment is necessary. Psychiatrists in other countries opted for more active treatment such as hospitalization. CONCLUSIONS: Patients with the hikikomori syndrome are perceived as occurring across a variety of cultures by psychiatrists in multiple countries. Our results provide a rational basis for study of the existence and epidemiology of hikikomori in clinical or community populations in international settings. PMID- 21706239 TI - Benign tertian malaria: how benign is it today? PMID- 21706240 TI - Rectal involvement in neutropenic enterocolitis. AB - Neutropenic enterocolitis is a common gastrointestinal complication in children undergoing chemotherapy for a variety of malignancies. It usually involves ileum and caecum, and involvement of rectum has rarely been reported. The authors report neutropenic enterocolitis in a child undergoing chemotherapy for acute lymphoblastic lymphoma which presented with ileus along with a mass like lesion in the rectum. PMID- 21706241 TI - Trend of morbidity related to pandemic Influenza A (H1N1) infection in a tertiary care teaching institution in south India. PMID- 21706242 TI - Juvenile Graves' disease with opthalmopathy, lymphadenopathy, accelerated growth and congestive cardiac failure. AB - Graves' disease in childhood is a rare clinical entity. The authors report a case of Graves' disease in a 3-year-old child, who had opththalmopathy, accelerated growth, cervical lymphadenopathy, hepatosplenomegaly and congestive cardiac failure; and responded well to treatment. PMID- 21706243 TI - Isolated bilateral severe fetal hydrothorax: complete resolution following a single postnatal thoracocentesis. AB - Isolated pleural effusion is a rare condition in a fetus or neonate with high mortality. When there are no other findings of hydrops fetalis or documented etiology such as inflammatory, iatrogenic or cardiac problems exist, isolated pleural effusion is considered. Timely diagnosis and management not only avoids mortality but also results in excellent prognosis. For fetal hydrothorax, intrauterine management is usually recommended. For those who present late, postnatal management includes intubation, thoracocentesis, ventilation and supportive care. The authors present isolated bilateral severe hydrothorax in a preterm neonate that resulted in severe respiratory compromise at birth. A single postnatal thoracocentesis resulted in complete resolution. No definite etiology for hydrothorax could be established. He had normal growth and development during his follow up till 1 year of age. PMID- 21706244 TI - Association between peak serum bilirubin and neurodevelopmental outcomes in term babies with hyperbilirubinemia. AB - OBJECTIVE: To find the association between neonatal Peak serum bilirubin (PSB) levels and the neurodevelopmental outcomes at 6 months in term infants with neonatal hyperbilirubinemia. METHODS: Term neonates who developed jaundice with atleast one PSB value of above 15 mg/dl within first wk of life were included. Babies with any condition affecting the neurodevelopment, like prematurity, convulsions or asphyxia were excluded from the study. This prospective cohort study included 66 term babies out of the 6548 newborns delivered during the study period. RESULTS: The incidence of abnormal developmental quotient gradually increased with increase in the level of PSB. Based on univariate analysis, a PSB >= 22 mg/dl (the cut off obtained based on Receiver operating characteristic curve), Rh incompatibility and occurrence of jaundice within 2 days of life were found to be significant risk factors for abnormal developmental quotient. These three risk factors were also independently associated with abnormal development by multivariate logistic regression analysis. CONCLUSIONS: PSB level of >= 22 mg/dl, Rh incompatibility and occurrence of jaundice within 2 days of life are independent predictors of abnormal development in babies with neonatal jaundice. PMID- 21706245 TI - Comparison of acetaminophen and ketoprofen in febrile children: a single dose randomized clinical trial. AB - OBJECTIVE: To compare ketoprofen with acetaminophen in febrile children in terms of proportion of achieved temperatures below 37.8 degrees C and time of temperature reduction. METHODS: 316 patients (6 months-12 years) with fever were randomly assigned to receive a single dose of acetaminophen or ketoprofen orally. Tympanic temperature was measured at the time of antipyretic administration and at 15, 30, 60, 120,180, 240 min thereafter. RESULTS: A higher proportion of patients in the ketoprofen group achieved a temperature below 37.8 degrees C during the 4 h follow up (95% CI, 3.03-12.99, p < 0.001). Treatment with ketoprofen was more likely to achieve temperature below 37.8 degrees C compared to acetaminophen with odds ratio 6.25. (95% CI, 3.03-12.99, p < 0.001). Ketoprofen was superior at temperatures >=39 degrees C (p < 0.001). Ketoprofen group showed significantly lower mean temperatures at times 15 min (95% CI, 0.95 3.36; P < 0.001), 30 min (95% CI, 3.87-6.59; P < 0.001), 60 min (95% CI, 6.99 10.14; P < 0.001), 120 min (95% CI, 1.66-5.49; P < 0.001), 180 min (95% CI, 0.47 5.73; p < 0.05), and 240 min (95% CI, 3.87-6.59; p < 0.05). The mean temperature reductions at times 15, 30 and 60 min were larger in ketoprofen group (p < 0.001). Ketoprofen was superior to acetaminophen for less time with fever in the first 4 h (p < 0.001). CONCLUSIONS: It seems reasonable to use ketoprofen first in need of rapid fever reduction. PMID- 21706246 TI - Diagnostic value of interferon- gamma release assays (QuantiFERON-TB Gold(r) In Tube) in childhood tuberculosis. AB - OBJECTIVE: To evaluate the efficacy and diagnostic potential of interferon- gamma release assays QuantiFERON-TB Gold(r) In Tube (QFT-TB-IT) for the detection of gamma interferon against the antigen ESAT-6, CFP-10, TB 7.7(p4) of Mycobacterium tuberculosis and compare the reactivity with other methods (smear, culture and IS6110 targeting PCR). METHODS: The study was carried out on children with pulmonary and extra pulmonary tuberculosis along with matching and PPD+ controls (82 cases, 48 matching controls and 20 PPD+ controls). RESULTS: QFT-TB-IT showed a significantly higher sensitivity (51.2%) as compared with LJ medium culture method (11.0%; p < 0.001), BacT/Alert 3D system (12.1%; p < 0.001), ZN staining (19.5%; p < 0.001) and PCR (45.1%; p < 0.05). Specificity of QFT-TB-IT was 48.0%. CONCLUSIONS: Less specificity of this assay may be due to high endemicity of tuberculosis. However, further studies are recommended. PMID- 21706247 TI - Repair and reconstruction of a resected tumor defect using a composite of tissue flap-nanotherapeutic-silk fibroin and chitosan scaffold. AB - A multifaceted strategy using a composite of anti-cancer nanotherapeutic and natural biomaterials silk fibroin (SF) and chitosan (CS) blend scaffolds was investigated for the treatment of a tissue defect post-tumor resection by providing local release of the therapeutic and filling of the defect site with the regenerative bioscaffolds. The scaffold-emodin nanoparticle composites were fabricated and characterized for drug entrapment and release, mechanical strength, and efficacy against GILM2 breast cancer cells in vitro and in vivo in a rat tumor model. Emodin nanoparticles were embedded in SF and SFCS scaffolds and the amount of emodin entrapment was a function of the scaffold composition and emodin loading concentration. In vitro, there was a burst release of emodin from all scaffolds during the first 2 days though it was detected even after 24 days. Increase in emodin concentration in the scaffolds decreased the overall elastic modulus and ultimate tensile strength of the scaffolds. After 6 weeks of in vivo implantation, the cell density (p < 0.05) and percent degradation (p < 0.01) within the remodeled no emodin SFCS scaffold was significantly higher than the emodin loaded SFCS scaffolds, although there was no significant difference in the amount of collagen deposition in the regenerated SFCS scaffold. The presence and release of emodin from the SFCS scaffolds inhibited the integration of SFCS into the adjacent tumor due to the formation of an interfacial barrier of connective tissue that was lacking in emodin-free SFCS scaffolds. While no significant difference in tumor size was observed between the in vivo tested groups, tumors treated with emodin loaded SFCS scaffolds had decreased presence and size and similar regeneration of new tissue as compared to no emodin SFCS scaffolds. PMID- 21706248 TI - Protein side-chain resonance assignment and NOE assignment using RDC-defined backbones without TOCSY data. AB - One bottleneck in NMR structure determination lies in the laborious and time consuming process of side-chain resonance and NOE assignments. Compared to the well-studied backbone resonance assignment problem, automated side-chain resonance and NOE assignments are relatively less explored. Most NOE assignment algorithms require nearly complete side-chain resonance assignments from a series of through-bond experiments such as HCCH-TOCSY or HCCCONH. Unfortunately, these TOCSY experiments perform poorly on large proteins. To overcome this deficiency, we present a novel algorithm, called NASCA: (NOE Assignment and Side-Chain Assignment), to automate both side-chain resonance and NOE assignments and to perform high-resolution protein structure determination in the absence of any explicit through-bond experiment to facilitate side-chain resonance assignment, such as HCCH-TOCSY. After casting the assignment problem into a Markov Random Field (MRF), NASCA: extends and applies combinatorial protein design algorithms to compute optimal assignments that best interpret the NMR data. The MRF captures the contact map information of the protein derived from NOESY spectra, exploits the backbone structural information determined by RDCs, and considers all possible side-chain rotamers. The complexity of the combinatorial search is reduced by using a dead-end elimination (DEE) algorithm, which prunes side-chain resonance assignments that are provably not part of the optimal solution. Then an A* search algorithm is employed to find a set of optimal side-chain resonance assignments that best fit the NMR data. These side-chain resonance assignments are then used to resolve the NOE assignment ambiguity and compute high-resolution protein structures. Tests on five proteins show that NASCA: assigns resonances for more than 90% of side-chain protons, and achieves about 80% correct assignments. The final structures computed using the NOE distance restraints assigned by NASCA: have backbone RMSD 0.8-1.5 A from the reference structures determined by traditional NMR approaches. PMID- 21706249 TI - The Broad Autism Phenotype Questionnaire: mothers versus fathers of children with an autism spectrum disorder. AB - Parents of individuals with autism were examined using the Broad Autism Phenotype Questionnaire (BAPQ; Hurley et al. in J Autism Dev Disord 37:1679-1690, 2007) assessing BAP-related personality and language characteristics. The BAPQ was administered to parents as a self-report and as an informant (spouse)-based measure. Results indicated the same pattern of differences for the informant and best-estimate (average between self-report and informant scores) reports. Fathers were rated as more "aloof" than mothers, whereas mothers were rated as more "rigid" than fathers. Fathers described their wives as less "aloof" and more "rigid" compared to the mothers' self-descriptions. Correlational analyses revealed no significant associations among parent/child characteristics and parents' BAPQ scores. Results are discussed in reference to sex differences in BAP-related characteristics in parents of children with autism. PMID- 21706250 TI - Spatiotemporal trends of mercury in walleye and largemouth bass from the Laurentian Great Lakes region. AB - The risk of mercury (Hg) exposure to humans and wildlife from fish consumption has driven extensive mercury analysis throughout the Great Lakes Region since the 1970s. This study compiled fish-Hg data from multiple sources in the region and assessed spatiotemporal trends of Hg concentrations in two representative top predator fish species. Walleye (Sander vitreus) and largemouth bass (Micropterus salmoides) were chosen for the trend analysis because they had more Hg records (63,872) than other fish species that had been sampled from waters throughout the region. Waterbody types were inland lakes (70%), the Great Lakes, impoundments, and rivers. The compiled datasets were analyzed with a mixed effects statistical model having random effects of station, year, and fish length; and fixed effects of year, tissue type, fish length, habitat, and season. The results showed a generally declining temporal trend in fish-Hg for the region (1970-2009), with spatial trends of increasing Hg concentration from south to north and from west to east across the region. Nonlinearity was evident in the general downward trends of Ontario walleye, with a shift to an upward trend beginning in the 1990s. Only ongoing monitoring can reveal if this upward shift is an oscillation in a long-term decline, a statistical anomaly, or a sustained declining temporal trend in regional fish-Hg concentrations. PMID- 21706251 TI - The impact of caspase-12 on susceptibility to candidemia. AB - Candida is one of the leading causes of sepsis, and an effective host immune response to Candida critically depends on the cytokines IL-1beta and IL-18, which need caspase-1 cleavage to become bioactive. Caspase-12 has been suggested to inhibit caspase-1 activation and has been implicated as a susceptibility factor for bacterial sepsis. In populations of African descent, CASPASE-12 is either functional or non-functional. Here, we have assessed the frequencies of both CASPASE-12 alleles in an African-American Candida sepsis patients cohort compared to uninfected patients with similar predisposing factors. African-American Candida sepsis patients (n = 93) and non-infected African-American patients (n = 88) were genotyped for the CASPASE-12 genotype. Serum cytokine concentrations of IL-6, IL-8, and IFNgamma were measured in the serum of infected patients. Statistical comparisons were performed in order to assess the effect of the CASPASE-12 genotype on susceptibility to candidemia and on serum cytokine concentrations. Our findings demonstrate that CASPASE-12 does not influence the susceptibility to Candida sepsis, nor has any effect on the serum cytokine concentrations in Candida sepsis patients during the course of infection. Although the functional CASPASE-12 allele has been suggested to increase susceptibility to bacterial sepsis, this could not be confirmed in our larger cohort of fungal sepsis patients. PMID- 21706252 TI - Improvement of L-valine production at high temperature in Brevibacterium flavum by overexpressing ilvEBNrC genes. AB - Brevibacterium flavum ATCC14067 was engineered for L: -valine production by overexpression of different ilv genes; the ilvEBN(r)C genes from B. flavum NV128 provided the best candidate for L: -valine production. In traditional fermentation, L: -valine production reached 30.08 +/- 0.92 g/L at 31 degrees C in 72 h with a low conversion efficiency of 0.129 g/g. To further improve the L: valine production and conversion efficiency based on the optimum temperatures of L: -valine biosynthesis enzymes (above 35 degrees C) and the thermotolerance of B. flavum, the fermentation temperature was increased to 34, 37, and 40 degrees C. As a result, higher metabolic rate and L: -valine biosynthesis enzymes activity were obtained at high temperature, and the maximum L: -valine production, conversion efficiency, and specific L: -valine production rate reached 38.08 +/- 1.32 g/L, 0.241 g/g, and 0.133 g g(-1) h(-1), respectively, at 37 degrees C in 48 h fermentation. The strategy for enhancing L: -valine production by overexpression of key enzymes in thermotolerant strains may provide an alternative approach to enhance branched-chain amino acids production with other strains. PMID- 21706253 TI - Tyrosine phosphorylation turns alkaline transition into a biologically relevant process and makes human cytochrome c behave as an anti-apoptotic switch. AB - Cytochrome c (Cc) is a key protein in cell life (respiration) and cell death (apoptosis). On the one hand, it serves as a mitochondrial redox carrier, transferring electrons between the membrane-embedded complexes III and IV. On the other hand, it acts as a cytoplasmic apoptosis-triggering agent, forming the apoptosome with apoptosis protease-activating factor-1 (Apaf-1) and activating the caspase cascade. The two functions of cytochrome c are finely tuned by the phosphorylation of tyrosines and, in particular, those located at positions 48 and 97. However, the specific cytochrome c-phosphorylating kinase is still unknown. To study the structural and functional changes induced by tyrosine phosphorylation in cytochrome c, we studied the two phosphomimetic mutants Y48E and Y97E, in which each tyrosine residue is replaced by glutamate. Such substitutions alter both the physicochemical features and the function of each mutant compared with the native protein. Y97E is significantly less stable than the WT species, whereas Y48E not only exhibits lower values for the alkaline transition pK (a) and the midpoint redox potential, but it also impairs Apaf-1 mediated caspase activation. Altogether, these findings suggest that the specific phosphorylation of Tyr48 makes cytochrome c act as an anti-apoptotic switch. PMID- 21706255 TI - The determinants of neighborhood satisfaction: racial proxy revisited. AB - Understanding the factors that drive individuals' residential preferences is a critical issue in the study of racial segregation. An important debate within this field is whether individuals-especially whites-prefer to live in predominantly white neighborhoods because they wish to avoid the social problems that may be more likely to occur in predominantly black neighborhoods (i.e., the racial proxy hypothesis) or because of racial factors that go beyond these social class-related characteristics. Through a multilevel analysis of data from the 2004-2005 Chicago Area Study and several administrative sources, we assess the extent to which the racial proxy hypothesis describes neighborhood satisfaction among whites, African Americans, and Latinos living across a broad range of neighborhood contexts. The racial proxy perspective applies weakly to whites' satisfaction: whites report less satisfaction in neighborhoods with more minority residents, and only some of their dissatisfaction can be attributed to local social characteristics. The racial proxy hypothesis applies more strongly to blacks' and Latinos' satisfaction. In some cases, especially for Latinos, higher levels of satisfaction in integrated neighborhoods can largely be attributed to the fact that these places have better socioeconomic conditions and fewer social problems than predominantly minority communities. At the same time, effects of racial/ethnic composition persist in unique and somewhat divergent ways for blacks and Latinos, supporting the assertion that racial composition matters, above and beyond its relation to social class. Taken together, these findings suggest that individuals balance both socioeconomic and race-related concerns in their residential preferences. PMID- 21706254 TI - Nuclear targeting with cell-specific multifunctional tricarbonyl M(I) (M is Re, (99m)Tc) complexes: synthesis, characterization, and cell studies. AB - Auger-emitting radionuclides such as (99m)Tc have been the focus of recent studies aiming at finding more selective therapeutic approaches. To explore the potential usefulness of (99m)Tc as an Auger emitter, we have synthesized and biologically evaluated novel multifunctional structures comprising (1) a pyrazolyl-diamine framework bearing a set of donor atoms to stabilize the [M(CO)(3)](+) (M is Re, (99m)Tc) core; (2) a DNA intercalating moiety of the acridine orange type to ensure close proximity of the radionuclide to DNA and to follow the internalization and subcellular trafficking of the compounds by confocal fluorescence microscopy; and (3) a bombesin (BBN) analogue of the type X BBN[7-14] (where X is SGS, GGG) to provide specificity towards cells expressing the gastrin releasing peptide receptor (GRPr). Of the evaluated (99m)Tc complexes, Tc ( 3 ) containing the GGG-BBN[7-14] peptide showed the highest cellular internalization in GRPr-positive PC3 human prostate tumor cells, presenting a remarkably high nuclear uptake in the same cell line. Live-cell confocal imaging microscopy studies with the congener Re complex, Re ( 3 ), showed a considerable accumulation of fluorescence in the nucleus, with kinetics of uptake similar to that exhibited by Tc ( 3 ). Together, these data show that the acridine orange intercalator and the metal fragment are colocalized in the nucleus, which indicates that they remain connected despite the lysosomal degradation of Tc ( 3 )/Re ( 3 ). These compounds are the first examples of (99m)Tc bioconjugates that combine specific cell targeting with nuclear internalization, a crucial issue to explore use of (99m)Tc in Auger therapy. PMID- 21706256 TI - Responsive survey design, demographic data collection, and models of demographic behavior. AB - To address declining response rates and rising data-collection costs, survey methodologists have devised new techniques for using process data ("paradata") to address nonresponse by altering the survey design dynamically during data collection. We investigate the substantive consequences of responsive survey design-tools that use paradata to improve the representative qualities of surveys and control costs. By improving representation of reluctant respondents, responsive design can change our understanding of the topic being studied. Using the National Survey of Family Growth Cycle 6, we illustrate how responsive survey design can shape both demographic estimates and models of demographic behaviors based on survey data. By juxtaposing measures from regular and responsive data collection phases, we document how special efforts to interview reluctant respondents may affect demographic estimates. Results demonstrate the potential of responsive survey design to change the quality of demographic research based on survey data. PMID- 21706257 TI - Jewish physicians' beliefs and practices regarding religion/spirituality in the clinical encounter. AB - We used data from a 2003 survey of US physicians to examine differences between Jewish and other religiously affiliated physicians on 4-D of physicians' beliefs and practices regarding religion and spirituality (R/S) in the clinical encounter. On each dimension, Jewish physicians ascribed less importance to the effect of R/S on health and a lesser role for physicians in addressing R/S issues. These effects were partially mediated by lower levels of religiosity among Jewish physicians and by differences in demographic and practice-level characteristics. The study provides a salient example of how religious affiliation can be an important independent predictor of physicians' clinically relevant beliefs and practices. PMID- 21706258 TI - Rho-kinase inhibition attenuates calcium-induced contraction in beta-escin but not Triton X-100 permeabilized rabbit femoral artery. AB - K+-depolarization (KCl) of smooth muscle has long been known to cause Ca2+ dependent contraction, but only recently has this G protein-coupled receptor (GPCR)-independent stimulus been associated with rhoA kinase (ROCK)-dependent myosin light chain (MLC) phosphatase inhibition and Ca2+ sensitization. This study examined effects of ROCK inhibition on the concentration-response curves (CRCs) generated in femoral artery by incrementally adding increasing concentrations of KCl to intact tissues, and Ca2+ to tissues permeabilized with Triton X-100, beta-escin and alpha-toxin. For a comparison, tissue responses were assessed also in the presence of protein kinase C (PKC) and MLC kinase inhibition. The ROCK inhibitor H-1152 induced a strong concentration-dependent inhibition of a KCl CRC. A relatively low GF-109203X concentration (1 MUM) sufficient to inhibit conventional PKC isotypes also inhibited the KCl CRC but did not affect the maximum tension. ROCK inhibitors had no effect on the Ca2+ CRC induced in Triton X-100 or alpha-toxin permeabilized tissues, but depressed the maximum contraction induced in beta-escin permeabilized tissue. GF-109203X at 1 MUM depressed the maximum Ca2+-dependent contraction induced in alpha-toxin permeabilized tissue and had no effect on the Ca2+ CRC induced in Triton X-100 permeabilized tissue. The MLC kinase inhibitor wortmannin (1 MUM) strongly depression the Ca2+ CRCs in tissues permeabilized with Triton X-100, alpha-toxin and beta-escin. H-1152 inhibited contractions induced by a single exposure to a submaximum [Ca2+] (pCa 6) in both rabbit and mouse femoral arteries. These data indicate that beta-escin permeabilized muscle preserves GPCR-independent, Ca2+- and ROCK-dependent, Ca2+ sensitization. PMID- 21706259 TI - Pubertal timing fluctuations across middle school: implications for girls' psychological health. AB - The relative nature of pubertal timing has received little attention in research linking early pubertal development with psychological adjustment. The current study examines the dynamic association between pubertal timing and internalizing symptoms among an urban, ethnically diverse sample of girls (n=1,167; 50% Latina, 30% Black/African American, 11% Asian, 9% White). By relying on six waves of data, we detected substantial within-person variability in pubertal timing, which in turn related to fluctuations in depressive symptoms, global self-worth, and social anxiety in multilevel analyses. Within-person changes in the direction of more advanced development compared to peers consistently predicted more depressive symptoms; however, more advanced development was related to lower self worth only at the beginning of middle school. By the end of middle school, less advanced development predicted social anxiety. Results challenge the notion that pubertal timing is a stable individual characteristic, with implications for studying the psychosocial correlates of pubertal development across multiple years. PMID- 21706260 TI - Racial and ethnic disparities in obesity during the transition to adulthood: the contingent and nonlinear impact of neighborhood disadvantage. AB - Neighborhood disadvantage in early adolescence may help explain racial and ethnic disparities in obesity during the transition to adulthood; however the processes may work differently for males and females and for minority groups compared to Whites. The present study examines the relationship between neighborhood disadvantage and young adult obesity and the extent to which it contributes to racial/ethnic disparities among males and females. Data are from waves I and III of The National Longitudinal Study of Adolescent Health (Add Health), a nationally representative sample of adolescents administered between 1994 and 2002. The final sample of 5,759 adolescents was 54% female, 63% White, 21% African American, 16% Hispanic, and 14 years of age, on average, at wave I. Using hierarchical logit models and controlling for prior obesity status, findings indicate that, for females, adolescent neighborhood disadvantage partially explains racial/ethnic disparities in young adult obesity. Further, neighborhood disadvantage increases the odds of becoming obese for adolescent females in a curvilinear form, and this relationship significantly varies between Whites and Hispanics. Neighborhood disadvantage does not increase the risk of obesity for males, regardless of race/ethnicity. Implications for obesity prevention are discussed. PMID- 21706261 TI - The influence of loss aversion on mountain bikers' behavioral intentions. AB - Public involvement in management decision making has received increased attention from researchers in recent years. These studies, however, have rarely considered differences in behavior resulting from gains and losses, despite ample evidence that individuals' behavior is not the same across situations. Individuals are often more sensitive to losses than gains, which research suggests is related to ownership (real or perceived) of the item lost. We present evidence from a within subjects quasi-experimental design to test whether mountain bikers' reported intentions differ between gain based and loss based conditions. These data were analyzed using a multi-step repeated measures analysis of variance and repeated measures analysis of covariance. The results suggest that losses are more powerful than gains in motivating public engagement in management decision making. Further, the type of action was also shown to influence behavioral intentions. Additional analyses provide support to the claim that, centrality, used as a proximate measure of ownership, moderates the contextual effects on behavioral intentions. Thus, loss aversion, moderated by ownership, is a plausible explanation of stakeholder involvement. PMID- 21706262 TI - Systemic sclerosis complicated by arrhythmogenic right ventricular dysplasia that was misinterpreted as pulmonary arterial hypertension. AB - A 58-year old Japanese woman who had been diagnosed with and managed for systemic sclerosis (SSc) with pulmonary arterial hypertension died suddenly. However, the autopsy revealed marked right ventricular dilatation, and the myocardium had been replaced by fatty tissue. These findings were consistent with arrhythmogenic right ventricular dysplasia (ARVD). A literature search identified nine cases of SSc with ARVD in Japan, including this case; this number is significantly higher than the value estimated from the prevalences of ARVD and SSc in Japan, suggesting an association between these two rare diseases. PMID- 21706263 TI - Etanercept in combination with conventional disease-modifying antirheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis patients intolerant to methotrexate. AB - Although etanercept (ETN) is effective when used in monotherapy for the treatment of rheumatoid arthritis (RA), ETN/methotrexate (MTX) combination therapy is more efficacious. However, some patients show MTX intolerance; these patients may develop adverse events (AEs) or have risk factors for AEs. There is limited published information regarding the efficacy of combination therapy involving ETN and disease-modifying antirheumatic drugs other than MTX. Therefore, we evaluated the effects of combination therapy with ETN and salazosulfapyridine (SASP) and/or bucillamine (Bc), a D: -penicillamine analogue, in MTX-intolerant RA patients. Indices of RA activity, including disease activity score in 28 joints (DAS28), were retrospectively analyzed over a 48-week period in 66 patients treated with ETN. Treatment efficacy was compared in the following 4 major treatment groups: ETN monotherapy, ETN + MTX, ETN + SASP, and ETN + SASP + Bc. Although intergroup differences in the percent change of DAS were not statistically significant, ETN + SASP + Bc seemed to be more effective than ETN monotherapy, and the efficacy of ETN + SASP + Bc was comparable to that of ETN + MTX according to the European League Against Rheumatism (EULAR) improvement ratings. These results suggest that ETN + SASP + Bc combination therapy may be a viable option for RA treatment in patients in whom MTX cannot be used. PMID- 21706264 TI - Investigation of zinc, copper, lead and cadmium accumulation in the tissues of Sander lucioperca (L., 1758) living in Hirfanli Dam Lake, Turkey. AB - This study, some metals (zinc, copper, lead and cadmium) were analyzed in liver, muscle and gills of Sander lucioperca (Linnaeus, 1758) caught from the Hirfanli Dam Lake in December 2007. The highest concentrations were found in liver (zinc:32.5 MUg/g, lead:10.73 MUg/g, copper:5.85 MUg/g, cadmium:0.76 MUg/g) of Sander lucioperca. It was seen that the accumulation of zinc, lead and cadmium primarily took place in liver followed by muscles and gills. It was observed that copper is mainly accumulated in liver followed by gill and mucsles. PMID- 21706266 TI - Effect of sugars on the molecular motion of freeze-dried protein formulations reflected by NMR relaxation times. AB - PURPOSE: To relate NMR relaxation times to instability-related molecular motions of freeze-dried protein formulations and to examine the effect of sugars on these motions. METHODS: Rotating-frame spin-lattice relaxation time (T(1rho)) was determined for both protein and sugar carbons in freeze-dried lysozyme-sugar (trehalose, sucrose and isomaltose) formulations using solid-state (13)C NMR. RESULTS: The temperature dependence of T(1rho) for the lysozyme carbonyl carbons in lysozyme with and without sugars was describable with a model that includes two different types of molecular motion with different correlation times (tau(c)) for the carbon with each tau(c) showing Arrhenius temperature dependence. Both relaxation modes have much smaller relaxation time constant (tau(c)) and temperature coefficient (Ea) than structural relaxation and may be classified as beta-relaxation and gamma-relaxation. The tau(c) and Ea for gamma-relaxation were not affected by sugars, but those for beta-relaxation were increased by sucrose, changed little by trehalose, and decreased by isomaltose, suggesting that the beta-mobility of the lysozyme carbonyl carbons is decreased by sucrose and increased by isomaltose. CONCLUSION: T(1rho) determined for the lysozyme carbonyl carbons can reflect the effect of sugars on molecular mobility in lysozyme. However, interpretation of relaxation time data is complex and may demand data over an extended temperature range. PMID- 21706265 TI - Rehabilitation--emerging technologies, innovative therapies, and future objectives. AB - Stroke is the leading cause of long-term disability. The goal of stroke rehabilitation is to improve recovery in the years after a stroke and to decrease long-term disability. This article, titled "Rehabilitation--Emerging Technologies, Innovative Therapies, and Future Objectives" gives evidence-based information on the type of rehabilitation approaches that are effective to improve functional mobility and to address cognitive impairments. We review the importance of taking a translational approach to neurorehabilitation, considering the interaction of motor and cognitive systems, skilled learned purposeful limb movement, and spatial navigation ability. Known biologic mechanisms of neurorecovery are targeted in relation to technology implemented by members of the multidisciplinary team. Results from proof-of-concept, within subjects, and randomized controlled trials are presented, and the implications for optimal stroke rehabilitation strategies are discussed. Developing clinical practices are highlighted and future research directions are proposed with goals to provide insight on what the next steps are for this burgeoning discipline. PMID- 21706267 TI - Effect of cryogrinding on chemical stability of the sparingly water-soluble drug furosemide. AB - PURPOSE: To investigate the effect of cryogrinding on chemical stability of the diuretic agent furosemide and its mixtures with selected excipients. METHODS: Furosemide was ground at liquid nitrogen temperature for 30, 60, 120 and 180 min. Mixtures of furosemide-PVP and furosemide-inulin (1:1) were milled under cryogenic conditions. Materials were analyzed by XRD, UPLC, MS and NMR. RESULTS: Upon increasing the milling time, a significant build-up of an unidentified impurity 1, probably the main degradation product, was noticed. Cogrinding of furosemide with PVP and inulin worsened chemical stabilization of the pharmaceutical. The main degradation product formed upon cryomilling was subsequently identified as 4-chloro-5-sulfamoylanthranilic acid (CSA). Based on some theoretical considerations involving specific milling conditions, the milling intensity and an expected specific milling dose have been calculated. Results indicate that cryogenic grinding is capable to initiate mechanically induced decomposition of furosemide. CONCLUSIONS: Cryogenic grinding can activate and accelerate not only structural changes (solid state amorphization) but also chemical decomposition of pharmaceuticals. A cryogenic milling device should be considered as a chemical reactor, where under favourable conditions chemical reactions could be mechanically initiated. PMID- 21706268 TI - The patient-doctor relationship and online social networks: results of a national survey. AB - BACKGROUND: The use of online social networks (OSNs) among physicians and physicians-in-training, the extent of patient-doctor interactions within OSNs, and attitudes among these groups toward use of OSNs is not well described. OBJECTIVE: To quantify the use of OSNs, patient interactions within OSNs, and attitudes toward OSNs among medical students (MS), resident physicians (RP), and practicing physicians (PP) in the United States. DESIGN/SETTING: A random, stratified mail survey was sent to 1004 MS, 1004 RP, and 1004 PP between February and May 2010. MEASUREMENTS: Percentage of respondents reporting OSN use, the nature and frequency of use; percentage of respondents reporting friend requests by patients or patients' family members, frequency of these requests, and whether or not they were accepted; attitudes toward physician use of OSNs and online patient interactions. RESULTS: The overall response rate was 16.0% (19.8% MS, 14.3% RP, 14.1% PP). 93.5% of MS, 79.4% of RP, and 41.6% of PP reported usage of OSNs. PP were more likely to report having visited the profile of a patient or patient's family member (MS 2.3%, RP 3.9%, PP 15.5%), and were more likely to have received friend requests from patients or their family members (MS 1.2%, RP 7.8%, PP 34.5%). A majority did not think it ethically acceptable to interact with patients within OSNs for either social (68.3%) or patient-care (68.0%) reasons. Almost half of respondents (48.7%) were pessimistic about the potential for OSNs to improve patient-doctor communication, and a majority (79%) expressed concerns about maintaining patient confidentiality. CONCLUSION: Personal OSN use among physicians and physicians-in-training mirrors that of the general population. Patient-doctor interactions take place within OSNs, and are more typically initiated by patients than by physicians or physicians-in-training. A majority of respondents view these online interactions as ethically problematic. PMID- 21706270 TI - Formulation and stability testing of itraconazole crystalline nanoparticles. AB - Itraconazole (ITZ) crystalline nanoparticles were prepared using relatively simple, low-cost sonoprecipitation technique, in which both the solvent and antisolvent were organic in nature. The effect of stabilizer type (hydroxypropyl methylcellulose, hydroxypropyl cellulose, Inutec SP1(r), and pluronic F127), drying method (oven and freeze drying) and matrix former used (Avicel PH101, and Aerosil(r)200) on the dissolution performance as a key characteristic of nanocrystals was evaluated. In 10 min, all of the prepared nanocrystals showed 3.77-8.59 times improvement in percent drug dissolved compared to pure ITZ. Concerning the effect of stabilizer type, the following rank order can be given: pluronic F127 >= hydroxypropyl cellulose >= hydroxypropyl methylcellulose (HPMC) > inutec SP1. Freeze-dried ITZ nanocrystals containing Avicel PH 101 showed better dissolution rate compared to other nanocrystals. The chemical structure of itraconazole nanocrystals was not changed as revealed by Fourier transform infrared. Stability study of selected nanocrystals (F5, F7, and F8) revealed physical and chemical stability of F7 and F8, while a decrease in dissolution rate of F5 was observed (although being chemically stable) when stored under high relative humidity conditions. Although inutec is less potent than pluronic F127 and HPMC regarding their effect on dissolution rate enhancement, it is equipotent to pluronic F127 in preserving the rapid drug dissolution. PMID- 21706269 TI - Significance of heparanase-1 and vascular endothelial growth factor in adrenocortical carcinoma angiogenesis: potential for therapy. AB - The purpose of this study was to determine the correlation between human adrenocortical carcinoma (ACC) and the proteins involved in tumor angiogenesis, and to evaluate the angiogenic status of ACC. The expression of heparanase-1 (HPA 1), vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor-2 (VEGFR-2) as well as microvessel density (MVD) were measured in a series of tissue samples from 44 human sporadic adrenocortical tumors by immunohistochemistry. These specimens were classified as adenomas (n = 20) and carcinomas (n = 24) according to the histological criteria defined by Weiss. A total of 22 of 24 (91.67%) malignant cases showed positive staining for HPA-1 and 3 of 20 (15%) benign cases showed positive, the difference of HPA-1 expression between ACA and ACC was statistically significant (P < 0.001). Similarly, VEGF staining was seen in 70.83% (17/24) of the malignant cases versus 25% (5/20) of the benign, the difference of VEGF expression among two groups was statistically significant (P = 0.002). VEGFR-2 expressed highly in the ACC group (79.17%, 19/24) and lowly in the benign group (25%, 5/20), the two groups had extremely significant difference (P < 0.001). Malignant cases showed higher MVD compared to benign tumors (84.70 +/- 12.44 vs. 21.05 +/- 8.07, P < 0.001). HPA-1 and VEGF expression were positively correlated with MVD in all specimens (r_s = 0.812, P = 0.001; r_s = 0.834, P < 0.001). In conclusion, these results suggest that angiogenesis of human ACC maybe mediated by these proteins and they could represent selective targets for the molecularly targeted treatments of ACC. PMID- 21706271 TI - Primary cardiac lymphoma detected by 18F-FDG PET scan: a case report. PMID- 21706272 TI - The art of communicating: The Nuclear Cardiology Report. PMID- 21706273 TI - Quantification of edema reduction using differential quantitative T2 (DQT2) relaxometry mapping in recurrent glioblastoma treated with bevacizumab. AB - The purpose of the current study was to quantify the reduction in T2 signal abnormality accompanying administration of the anti-angiogenic drug bevacizumab in recurrent glioblastoma (GBM) patients using a voxel-wise differential quantitative T2 (DQT2) mapping technique. Twenty-six patients with recurrent GBM treated with bevacizumab were scanned before and 4-6 weeks after treatment on a 1.5T clinical MR scanner. Quantitative T2 maps were created from proton density and T2-weighted images acquired using a standard multi-echo fast-spin echo sequence. T2 maps after treatment were co-registered with T2 maps prior to treatment in the same patient, and then voxel-wise subtraction was performed to create DQT2 maps for each patient. Results suggest DQT2 maps allow visualization and quantification of voxel-wise T2 changes resulting from anti-VEGF therapy. Results demonstrated a significant decrease in T2 within pre-treatment T2 abnormal regions (mean reduction = 49.4 ms at 1.5T) following anti-VEGF treatment (Wilcoxon signed rank test, P < 0.0001). An elevated residual, post-treatment, median T2 was predictive of both progression-free (Log-rank, P = 0.0074) and overall survival (Log-rank, P = 0.0393). PMID- 21706274 TI - Stereotactic LINAC radiosurgery for incompletely resected or recurrent atypical and anaplastic meningiomas. AB - BACKGROUND: The optimal management of subtotally resected or recurrent malignant meningiomas remains controversial. We evaluated the efficacy of linear accelerator (LINAC) radiosurgery for atypical and anaplastic meningiomas after incomplete resection or treatment of recurrences. METHODS: Between August 1990 and December 2003, 16 patients with 28 meningiomas WHO II and III were treated by stereotactic LINAC radiosurgery at our institution. The median radiological follow-up was 60.3 months, respectively (range: 7.2-173.9 months). Fourteen tumors in nine patients were classified as WHO II and 14 tumors in seven patients as WHO III. The median surface dose was 14 Gy (range: 10-15 Gy) with a median tumor volume of 4.8 ml (range: 0.51-51.4 ml). RESULTS: Clinical condition improved in four patients, remained unchanged in nine and deteriorated in one. Tumor shrinkage was seen in eight of 28 meningiomas and a stable disease in 12. Eight of 28 meningiomas showed local tumor progression. The overall tumor control rate (TCR) was 84%, 70%, 70% after 3, 5, 10 years. According to grading the corresponding TCR after 3, 5, 10 years was 91%, 81%, 81% for grade II and 77%, 60%, 60% for grade III meningiomas. Overall progression-free survival (PFS) was 74%, 67%, 58% after 3, 5, 10 years. According to grading the PFS after 3, 5, 10 years was 88%, 75%, 75% for grade II meningiomas and 57%, 57%, 43% for grade III meningiomas. CONCLUSION: Our results show the efficacy and safety of LINAC radiosurgery for incompletely resected or recurrent malignant meningiomas with a relatively high local tumor control and low morbidity. PMID- 21706275 TI - Jejunal subserosal hematoma in an 11-year-old boy. AB - INTRODUCTION: Intramural hematoma may be subserosal, intramuscular, or submucosal or may involve the entire thickness of the bowel wall. Subserosal hematoma of the jejunum in children is uncommon. DISCUSSION: We report a case of an 11-year-old boy with a jejunal subserosal hematoma presenting with duodenojejunal obstruction. Emergency laparotomy was performed and subserous hematoma involving the 7-cm long bowel was found. Serosal incision was done for evacuation of blood and clots. The patient had an uneventful postoperative course. The clinical picture and radiological findings were presented and discussed. PMID- 21706276 TI - Gender-related differences in repopulation and early tumor response to preoperative radiotherapy in rectal cancer patients. AB - PURPOSE: Inhibition of tumor proliferation rate based on bromodeoxyuridine labelling index (BrdUrdLI), S-phase fraction (SPF) and MIB-1 labelling index (MIB 1 LI) as an early rectal cancer response to preoperative radiotherapy (RT). METHODS AND MATERIALS: A total of 122 patients qualified either for short RT (5 Gy/fraction/5 days) and surgery about 1 week after RT (schedule I) or for short RT and a 4-week interval before surgery (schedule II). Tumor samples were taken twice from each patient: before RT and at the time of surgery. In each sample, the BrdUrdLI, SPF and MIB-1 were calculated. Early tumor response was assessed by a biologist, a pathologist and surgeons. RESULTS: Fifty-six patients were treated according to schedule I and 66 patients according to schedule II. Mean BrdUrdLI, SPF and MIB-1 LI before RT were 8.8%, 21.0% and 53.3%, respectively, and these values did not differ between the two compared groups. After RT, tumors showed statistically significant growth inhibition based on all assessed biological markers. As pretreatment assessed parameter was not predictive for early clinical and pathologic tumor response, prognostic role of the relative value (RV), that is, the ratio of assessed parameter after RT to before RT for each of the assessed markers, was considered. The ratios were calculated separately for fast and slowly proliferating tumors and separately for male and female patients. Fast proliferating tumors were more responsive. Differences with regard to sex were visible only in slowly proliferating tumors. Accelerated cell repopulation (4.8 28%/day) was noticed in female slowly proliferating tumors about 4 weeks after RT. Only for relative MIB-1 LI it was possible to show significant correlation with pathological tumor regression. Lack of such correlation for BrdUrdLI and SPF might reflect accelerated repopulation, particularly in slowly proliferating female tumors. CONCLUSIONS: Accelerated repopulation was noticed in slowly proliferating tumors in females about 4 weeks after RT. PMID- 21706277 TI - Anti genotoxic effect of Mosinone-A on 7, 12-dimethyl benz[a] anthracene induced genotoxicity in male golden Syrian hamsters. AB - The present study was aimed to evaluate the antigenotoxic effect of Mosinone-A on 7,12-dimethylbenz[a]anthracene induced genotoxicity. The frequency of micronucleated polychromatic erythrocytes [MnPCEs], chromosomal aberrations [CA], DNA damage (comet assay) as cytogenetic markers and the status of lipid peroxidation byproducts, antioxidants and phase II detoxification agents were used as biochemical markers to assess the antigenotoxic effect of Mosinone-A on DMBA induced genotoxicity. A single intraperitoneal injection of DMBA (30 mg/kg b.wt) to golden Syrian hamsters, resulted in marked elevation in the frequency of MnPCEs, aberrations in the chromosomal structure were found in bone marrow and DNA damage (comet assay) was found in blood cells and altered level of lipid peroxidation, antioxidants, and phase II detoxification agents. Oral pretreatment of Mosinone-A (2 mg/kg b.wt) for 5 days to DMBA treated animals significantly reduced the frequency of MnPCEs, chromosomal abnormalities such as chromosomal break, gap, minute, fragment, DNA damage and reversed the status of biochemical variables. Our results thus demonstrated the antigenotoxic effect of Mosinone-A on DMBA induced genotoxicity in male golden Syrian hamsters. PMID- 21706278 TI - Imprinting and expression analysis of a non-coding RNA gene in the mouse Dlk1 Dio3 domain. AB - The Dlk1-Dio3 imprinted domain not only is implicated growth and development of the embryo and placenta, but also affects adult metabolism and brain function. In this study, we identified the imprinting status of a mouse non-coding RNA gene, B830012L14Rik, mapped to the Dlk1-Dio3 domain by the polymorphism- and sequencing based approach. Imprinting analysis showed that the gene was expressed maternally at E15.5, E18.5 and postnatal day 1 mice. Two transcripts of approximately 1.9 and 3.5 kb were detected by northern blot. Furthermore, we examined the spatiotemporal expression patterns of the gene during the mouse development. In situ hybridization analysis showed that B830012L14Rik was mainly expressed in forebrain, pituitary, cartilage primordium of spinal column, lung and liver at E13.5 and E15.5. The results of real-time quantitative RT-PCR showed that the B830012L14Rik expression in brain, heart, lung and liver was higher at E15.5 than at E12.5 and E18.5. Furthermore, the gene expression increased progressively in brain from E12.5 to E15.5 whereas decreased from E15.5 to E19.5. This study may provide further insights into the imprinting, genomic features and expression regulation of the Dlk1-Dio3 imprinted cluster. PMID- 21706279 TI - Different combination schedules of gemcitabine with endostar affect antitumor efficacy. AB - PURPOSE: Antiangiogenic drugs inhibit tumor growth by decreasing blood supply and causing transient "normalization" of the tumor vasculature, thereby improving the delivery of systemic chemotherapy. A higher dose of antiangiogenic drugs may lead to a more marked decrease in intratumoral blood flow but may concomitantly cause a decrease in delivery of chemotherapeutic agents. The purpose of this study was to define an optimal schedule for the combination of gemcitabine with a recombinant endostatin, endostar. METHODS: We evaluated the antitumor effects with different schedules of gemcitabine combined with or without endostar. The changes of vascular endothelial growth factor (VEGF) levels in tumor extracts and sera after gemcitabine treatment were examined. Endostar was also assessed for its abilities to inhibit the increase in VEGF levels. Apoptotic cells and microvessel density within tumor tissue were also examined. RESULTS: Endostar administered simultaneously with or following gemcitabine improved the inhibition of tumor growth, compared with gemcitabine alone. VEGF levels decreased immediately after gemcitabine treatment, but increased in the following several days. Endostar administered simultaneously with or following gemcitabine could inhibit the increase in VEGF levels, thereby cause a decreased vessel density and an increased apoptosis in tumor tissue. CONCLUSIONS: Our finding suggested that endostar given simultaneously with or following gemcitabine might be optimal to enhance the antitumor effect. PMID- 21706280 TI - Internal structures of agar-gelatin co-hydrogels by light scattering, small-angle neutron scattering and rheology. AB - Internal structures of agar-gelatin co-hydrogels were investigated as a function of their volumetric mixing ratio, [Formula: see text] , 1.0 and 2.0 using dynamic light scattering (DLS), small-angle neutron scattering (SANS) and rheology. The degree of non-ergodicity ( X = 0.2 +/- 0.02) , which was extracted as a heterodyne contribution from the measured dynamic structure factor data remained less than that of homogeneous solutions where ergodicity is expected (X = 10. The static structure factor, I(q) , results obtained from SANS were interpreted in the Guinier regime (low-q , which implied the existence of ~ 250 nm long rod-like structures (double-helix bundles), and the power law (intermediate-q regions) yielded I (q) ~ q(-alpha) with alpha = 2.3 , 1.8 and 1.6 for r = 0.5 , 1.0 and 2.0. This is indicative of the presence of Gaussian chains at low r , while at r = 2 there was a propensity of rod-shaped structures. The gel strength and transition temperatures measured from frequency sweep and temperature ramp studies were suggestive of the presence of a stronger association between the two biopolymer networks at higher r . The results indicate that the internal structures of agar-gelatin co-hydrogels were highly dependent on the volumetric mixing ratio. PMID- 21706281 TI - Synaptic vesicles studied by dynamic light scattering. AB - The size polydispersity distribution of synaptic vesicles (SVs) is characterized under quasi-physiological conditions by dynamic light scattering (DLS). Highly purified fractions of SVs obtained from rat brain still contain a small amount of larger contaminant structures, which can be quantified by DLS and further reduced by asymmetric-flow field-flow (AFFF) fractionation. The intensity autocorrelation functions g (2)(tau) recorded from these samples are analyzed by a constrained regularization method as well as by an alternative direct modeling approach. The results are in quantitative agreement with the polydispersity obtained from cryogenic electron microscopy of vitrified SVs. Next, different vesicle fusion assays based on samples composed of SVs and small unilamellar proteoliposomes with the fusion proteins syntaxin 1 and SNAP-25A are characterized by DLS. The size increase of the proteoliposomes due to SNARE-dependent fusion with SVs is quantified by DLS under quasi-physiological conditions. PMID- 21706282 TI - Dynamical behavior of molecular motor assemblies in the rigid and crossbridge models. AB - We present a detailed analysis of the dynamical instabilities appearing in two kinetic theories for the collective behavior of molecular motors: the rigid two state model and the two-state crossbridge (or power-stroke) model with continuous binding sites. We calculate force-velocity relations, discuss their stability, plot a diagram that summarizes the oscillation regimes, identify the location of the Hopf bifurcation with a memory effect, discuss the oscillation frequency and make a link with single-molecule experiments. We show that the instabilities present in these models naturally translate into non-linearities in force displacement relations, and at linear order give forces that are similar to the delayed stretch activation observed in oscillating muscles. We also find that instabilities can appear for both apparent load-decelerated and load-accelerated detachment rates in a 3-state crossbridge model. PMID- 21706283 TI - Activation of MAPK/c-Fos induced responses in oral epithelial cells is specific to Candida albicans and Candida dubliniensis hyphae. AB - Oral epithelial cells detect the human pathogenic fungus Candida albicans via NF kappaB and a bi-phasic mitogen-activated protein kinase (MAPK) signaling response. However, discrimination between C. albicans yeast and hyphal forms is mediated only by the MAPK pathway, which constitutes activation of the MAPK phosphatase MKP1 and the c-Fos transcription factor and is targeted against the hyphal form. Given that C. albicans is not the only Candida species capable of filamentation or causing mucosal infections, we sought to determine whether this MAPK/MKP1/c-Fos mediated response mechanism was activated by other pathogenic Candida species, including C. dubliniensis, C. tropicalis, C. parapsilosis, C. glabrata and C. krusei. Although all Candida species activated the NF-kappaB signaling pathway, only C. albicans and C. dubliniensis were capable of inducing MKP1 and c-Fos activation, which directly correlated with hypha formation. However, only C. albicans strongly induced cytokine production (G-CSF, GM-CSF, IL 6 and IL-1alpha) and cell damage. Candida dubliniensis, C. tropicalis and C. parapsilosis were also capable of inducing IL-1alpha and this correlated with mild cell damage and was dependent upon fungal burdens. Our data demonstrate that activation of the MAPK/MKP1/c-Fos pathway in oral epithelial cells is specific to C. dubliniensis and C. albicans hyphae. PMID- 21706284 TI - Effectiveness of high-dose progestin and long-term outcomes in young women with early-stage, well-differentiated endometrioid adenocarcinoma of uterine endometrium. AB - PURPOSE: We assessed the effectiveness of high-dose progestins as a conservative treatment in young women with endometrial adenocarcinoma. METHODS: We retrospectively reviewed the hospital data of patients with endometrial cancer that were managed conservatively. Of those women with grade 1 endometrioid endometrial adenocarcinoma, we included those who were younger than 40 years and in whom the disease was clinically confined to the endometrium. A complete response was defined pathologically as the absence of tissue with adenocarcinoma or hyperplasia. RESULTS: Fourteen patients were included. Their mean age was 30.0 +/- 4.8 years and the mean follow-up period was 47.3 +/- 29.7 months. Twelve patients received 30-500 mg/day medroxyprogesterone acetate and two received 160 or 240 mg/day megestrol acetate. The median duration of treatment was 6 months (range 3-15 months) and 13 (93%) patients showed a complete response. Endometrial pathology reappeared in four patients (4/13, 31%) including two relapses, three of whom developed after the patients gave birth. Six patients used a combined oral contraceptive or a progestin-releasing intrauterine device as a maintenance therapy and experienced no recurrence. Four women (4/7, 57%) conceived successfully seven times with assisted-reproductive technology. No adverse effects of the progestins or tumor-related death were noted. CONCLUSIONS: High dose progestin therapy can be an effective conservative treatment in young patients with well-differentiated early-stage endometrial cancer. If patients wish to preserve their fertility even after they have completed childbearing, maintenance therapy with a cyclic oral contraceptive or a progestin-releasing intrauterine device may be an option to prevent recurrence. PMID- 21706285 TI - Effect of the simultaneous administration of glucocorticoids and IL-15 on human NK cell phenotype, proliferation and function. AB - We have previously reported a synergistic effect between hydrocortisone (HC) and IL-15 on promoting natural killer (NK) cell expansion and function. In the present study, we extend our findings to methylprednisolone (MeP) and dexamethasone (Dex), thus ascribing to glucocorticoids (GCs) a general feature as positive regulators of IL-15-mediated effects on NK cells. We demonstrate that each GC when combined with IL-15 in cultures of peripheral blood (PB)-derived CD56(+) cells induces increased expansion of CD56(+)CD3(-) cells displaying high cytolytic activity, IFN-gamma production potential and activating receptor expression, including NKp30, NKp44, NKp46, 2B4, NKG2D and DNAM-1. Furthermore, GCs protected NK cells from IL-15-induced cell death. The combination of IL-15 with GCs favored the expansion of a relatively more immature CD16(low/neg) NK cell population, with high expression of NKG2A and CD94, and significantly lower expression of KIR (CD158a and CD158b) and CD57, compared to IL-15 alone. IL-15 expanded NK cells, in the presence or absence of GCs, did not express CD62L, CXCR1 or CCR7. However, the presence of GCs significantly increased the density of CXCR3 and induced strong CXCR4 expression on the surface of NK cells. Our data indicate that IL-15/GC-expanded NK cells, apart from their increased proliferation rate, retain their functional integrity and exhibit a migratory potential rendering them useful for adoptive transfer in NK cell-based cancer immunotherapy. PMID- 21706286 TI - Rapid real-time PCR assay for culture and tissue identification of Geomyces destructans: the etiologic agent of bat geomycosis (white nose syndrome). AB - Geomyces destructans is the etiologic agent of bat geomycosis, commonly referred to as white nose syndrome (WNS). This infection has caused severe morbidity and mortality in little brown bats (Myotis lucifugus) and has also spread to other bat species with significant decline in the populations. Currently, G. destructans infection is identified by culture, ITS-PCR, and histopathology. We hypothesized that a real-time PCR assay would considerably improve detection of G. destructans in bats. The 100 bp sequence of the Alpha-L-Rhamnosidase gene was validated as a target for real-time PCR. The assay sensitivity was determined from serial dilution of DNA extracted from G. destructans conidia (5 * 10(-1)-5 * 10(7)), and the specificity was tested using DNA from 30 closely and distantly related fungi and 5 common bacterial pathogens. The real-time PCR assay was highly sensitive with detection limit of two G. destructans conidia per reaction at 40 PCR cycles. The assay was also highly specific as none of the other fungal or bacterial DNA cross-reacted in the real-time PCR assay. One hundred and forty seven bat tissue samples, suspected of infection with G. destructans, were used to compare the real-time PCR assay to other methods employed for the detection of G. destructans. Real-time PCR was highly sensitive with 80 of 147 (55%) samples testing positive for G. destructans DNA. In comparison, histopathology examination revealed 64/147 (44%) positive samples. The internal transcribed spacer (ITS)-PCR yielded positive amplicon for G. destructans from 37 tissue samples (25%). The least sensitive assay was the fungal culture with only 17 tissue samples (12%) yielding G. destructans in culture. The data suggested that the real-time PCR assay is highly promising for rapid, sensitive, and specific identification of G. destructans. Further trials and inter-laboratory comparisons of this novel assay are recommended to improve the diagnosis of bat geomycosis. PMID- 21706287 TI - Heart rate recovery in obstructive sleep apnea: scientific toy or clinical tool? PMID- 21706288 TI - C-reactive protein and heart rate recovery in middle-aged men with severe obstructive sleep apnea. AB - OBJECTIVE: The study aimed to evaluate whether the inflammatory marker "high sensitivity C-reactive protein (hsCRP)" level was associated with impaired heart rate recovery at 1 min after exercise termination (HRR-1) in middle-aged patients with severe obstructive sleep apnea (OSA). METHODS: Thirty middle-aged male patients (40-64 years old) with severe OSA (apnea-hypopnea index [AHI] >= 30 h( 1)) and 30 subjects without OSA (AHI < 5 h(-1)), matched with age and body mass index (BMI), were recruited. All subjects underwent an overnight polysomnography and completed a symptom-limited maximal exercise test. Cardiopulmonary parameters included peak oxygen consumption (VO(2peak)) and heart rate response during and immediately after exercise. Fasting blood samples were drawn for hsCRP analysis. RESULT: Patients with severe OSA had significantly higher hsCRP levels (0.18 vs. 0.07 mg/dl, P < 0.01), lower reduced HRR-1, peak heart rate, and VO(2peak) values than those in the controls. The hsCRP levels significantly correlated with HRR-1 in the OSA group (r = -0.69, P < 0.01) after adjustment for VO(2peak) (r = -0.66, P < 0.01). Furthermore, stepwise multiple regression analysis showed that HRR-1 and AHI were significant predictors of hsCRP levels in all participants (adjusted R(2) = 0.53, P < 0.01). CONCLUSIONS: Blunted HRR was shown in middle-aged men with severe OSA, and it was associated with high hsCRP levels significantly. PMID- 21706289 TI - Do patients at risk of sleep apnea have an increased risk of cardio-respiratory complications during endoscopy procedures? AB - BACKGROUND: Patients with sleep apnea (OSA) have an increased risk of perioperative complications. AIM: The purpose of this study is to assess whether OSA increases the risk of cardio-respiratory complications in patients undergoing endoscopic procedures with conscious sedation. METHODS: A prospective study over a 7-month period was performed. All patients undergoing upper, lower, or combined endoscopy were asked to fill in the Berlin questionnaire. The questionnaire was scored, and patients were classified as high or low risk for sleep apnea based on the suggested scoring criteria. Patients who had previously undergone a sleep study were excluded. Demographics and co-morbidities were identified from the electronic medical record. Procedure type, amount of sedation, and minor and major complications were identified from the endoscopy flow sheet. The minor complications were defined as hypertension, hypotension, bradycardia, tachycardia, hypoxemia, and bradypnea (respiratory rate <8 breaths/min). Major complications included chest pain, arrhythmia, altered mental status, respiratory distress, and a minor complication that required a significant intervention, such as use of a reversal agent, atropine, up-titration of oxygen for hypoxemia, or prolonged observation. RESULTS: Procedures were performed in 904 patients: colonoscopies, 68.0%; upper endoscopies, 22.8%; and combined procedures, 9.2%. Five hundred fifty-three patients were identified as low risk (61.2%), and 351 were identified as high risk (38.8%). The mean age was 59.5 +/- 10.5 years, mean body mass index was 28.9 +/- 6.6, mean neck circumference was 16.2 +/- 6.3 in., and 91.4% were males. The median Charlson co-morbidity index was 1 (25-75% percentage range 0-2). All patients received midazolam and fentanyl during endoscopy. The median and 25-75% range for midazolam and fentanyl dosages were 5 mg, 4-6 mg and 100 MUg, 75-125 MUg, respectively. Minor complications were observed in 10.56% of low-risk patients and 10.63% of high-risk patients (p = not significant (NS); odds ratio, 1.01; 95% confidence interval 0.65-1.56). Major complications were observed in 3.25% of low-risk patients and 1.9% of high-risk patients (p = ns; odds ratio, 0.6; 95% confidence interval 0.26-1.46). CONCLUSION: For patients undergoing endoscopy procedures under conscious sedation, the presence of OSA does not clearly increase the risk of cardiopulmonary complications. PMID- 21706290 TI - Genetic determinants of platelet response to clopidogrel. AB - Antiplatelet agents are the mainstay treatment in the prevention and management of atherothrombotic complications. However, a substantial interpatient variability in response to clopidogrel has been reported. Furthermore, patients with coronary artery disease and lesser platelet inhibition in response to clopidogrel are at increased risk for cardiovascular events. Clopidogrel after absorption requires two-step oxidation by the hepatic cytochrome P450 to generate its active metabolite. Polymorphisms of genes encoding the cytochrome enzymes and P-glycoprotein involved in clopidogrel absorption are regarded as major determinants of the interindividual variability in the clopidogrel-induced platelet inhibition. In our review we discuss the prevalence and clinical significance of various alleles of the genes: CYP2C19 and ABCB1 in the setting of coronary artery disease. Allele CYP2C19*2 is associated with excess of ischaemic events including myocardial infarction and stent thrombosis. On the other hand, CYP2C19*17 allele poses a serious threat of bleeding. Data concerning the prognostic value of genetic variant 3435C->T of ABCB1 remain inconclusive. PMID- 21706291 TI - Experimental study of primary repair of colonic leakage with a degradable stent in a porcine model. AB - BACKGROUND: Anastomotic leakage is a major complication of colon resection. Fecal diversion is necessary in most patients and restoration of intestinal continuity has to be performed several months later. It carries a long treatment time and a considerable financial cost. We have developed a method of primary repair of colonic leakage with a degradable stent. METHODS: Thirty pigs were included in this study. Colonic anastomotic leakage model was made successfully by open procedure in 15 pigs and primary repair with a degradable stent was performed 3 days later. Conventional colonic anastomosis was performed in the other 15 pigs without making leakage. Pigs of each group were sacrificed at schedule to evaluate the healing of anastomosis and observe the occurrence of complications. RESULTS: No re-leakage occurred after primary repair, and no anastomotic stricture, peritoneal abscess, or colonic necrosis occurred in either group. No significant difference in bursting pressure or hydroxyproline content was found between the two groups. CONCLUSIONS: Primary repair of colonic leakage with a degradable stent is a feasible method in this porcine model. PMID- 21706292 TI - The ommatidia of Arca noae: a three-tier structure with a central light-guiding element for the receptor cell. AB - The compound eyes of ark clams appear to function as an optical system to trigger shell closure against predators. We have analyzed the structure of the ommatidia of Arca noae by thin section electron microscopy and serial sectioning, Concanavalin A-gold labeling and acid phosphatase cytochemistry. Our results demonstrate that the ommatidia are a three-tier structure composed of a central single receptor cell, surrounded and covered by proximal pigment cells followed by rows of distal pigment cells. The receptor cells of Arca noae have no lens and the disks of their receptive segment are derived from sensory cilia. The distal mitochondrial segment in the cytoplasm between the nucleus and the receptive segment is surrounded by a mass of Concanavalin A-reactive glycogen particles. Although both, proximal and distal pigment cells have numerous microvilli, only those of the proximal pigment cells form a well-aligned brush border. The microvilli of the latter are ~9-11 MUm long and have a diameter of ~70-80 nm. Numerous microlamellar bodies cover them. The microlamellar bodies are stored in acid phosphatase-negative secretory granules of the pigment granule-free apical cytoplasm of proximal pigment cells before their secretion. Observation of living compound eyes indicated that the apex of proximal pigment cells transmitted significantly more light than the surrounding distal pigment cells. Hence, the regular geometry of the brush border seems to be a light-guiding structure for receptor cells similar to an optical fiber. PMID- 21706293 TI - Effects of carbaryl and 1-naphthol on soil population of cyanobacteria and microalgae and select cultures of diazotrophic cyanobacteria. AB - Carbaryl application to soil collected from a rice fallow field was relatively less toxic to viable estimates of cyanobacteria and microalgae under nonflooded conditions than under flooded conditions. Application of 1-naphthol, the hydrolysis product of carbaryl, to soil under both the regimes increased the population of both cyanobacteria and microalgae. Soil application of carbaryl and 1-naphthol in combination, up to 1.0 kg ha(-1), was nontoxic to the viable population. The toxicity exerted by carbaryl and 1-naphthol towards growth, measured in terms of chlorophyll a, and nitrogenase activity was more pronounced in Anabaena spp. than in Nostoc spp. PMID- 21706295 TI - Developing a measure of prenatal case management dosage. AB - Recently, federal funding was designated through the Patient Protection and Affordable Care Act giving states the opportunity to expand their prenatal case management programs (PCM) through home visitation. Studies evaluating the effect of PCM on birth outcomes have shown little or no positive results. One suggested reason for these findings is a lack of attention in the assessment of dosage. The objective of this study is to demonstrate the use of measuring PCM dosage when assessing pregnancy outcomes. A birth cohort (N = 4,582) encompassing Medicaid insured Iowa residents enrolled in PCM who gave birth to a singleton from October 2005 to December 2006 was constructed from linked Iowa birth, Medicaid Claims, and Women's Health Information Systems datasets. Data was used to create a dosage measure capturing the duration of enrollment, amount of time spent with a case manager, and breadth of interventions. Bivariate analysis and logistic regression were used to assess the relationship between PCM dosage and the birth outcomes. Dosage was significantly associated with LBW (X (2) = 31.1, P < 0.001) and PTB (X (2) = 56.2, P < 0.001). After adjustment for potential confounders, the likelihood of LBW and PTB were aOR: 0.47 (95% CI: 0.36-0.63) and aOR: 0.60 (95% CI: 0.44-0.82) for women with medium dosage (compared to low dosage), respectively. For women with high PCM dosage the likelihood of LBW and PTB was aOR 0.40 (95% CI: 0.31-0.51) and aOR = 0.62 (95% CI: 0.48-0.81), respectively. This study showed that PCM dosage was significantly associated with lower odds of an adverse pregnancy outcome occurring. PMID- 21706296 TI - Effects of the regulatory ligands calcium and GTP on the thermal stability of tissue transglutaminase. AB - Tissue transglutaminase undergoes thermal inactivation with first-order kinetics at moderate temperatures, in a process which is affected in opposite way by the regulatory ligands calcium and GTP, which stabilize different conformations. We have explored the processes of inactivation and of unfolding of transglutaminase and the effects of ligands thereon, combining approaches of differential scanning calorimetry (DSC) and of thermal analysis coupled to fluorescence spectroscopy and small angle scattering. At low temperature (38-45 degrees C), calcium promotes and GTP protects from inactivation, which occurs without detectable disruption of the protein structure but only local perturbations at the active site. Only at higher temperatures (52-56 degrees C), the protein structure undergoes major rearrangements with alterations in the interactions between the N and C-terminal domain pairs. Experiments by DSC and fluorescence spectroscopy clearly indicate reinforced and weakened interactions of the domains in the presence of GTP and of calcium, and different patterns of unfolding. Small angle scattering experiments confirm different pathways of unfolding, with attainment of limiting values of gyration radius of 52, 60 and 90 A in the absence of ligands and in the presence of GTP and calcium. Data by X-rays scattering indicate that ligands influence retention of a relatively compact structure in the protein even after denaturation at 70 degrees C. These results suggest that the complex regulation of the enzyme by ligands involves both short- and long range effects which might be relevant for understanding the turnover of the protein in vivo. PMID- 21706294 TI - Nonrenal and renal activity of systemic lupus erythematosus: a comparison of two anti-C1q and five anti-dsDNA assays and complement C3 and C4. AB - Associations of different assays for antibodies to C1q (anti-C1q) and to dsDNA (anti-dsDNA) and of complements C3 and C4 with disease activity in patients with systemic lupus erythematosus (SLE) were studied. The clinical manifestations of 223 SLE patients were recorded, and the disease activity was assessed by the SLEDAI score. Anti-C1q were determined by two enzyme-linked immunosorbent assays (ELISA) and anti-dsDNA by a radioimmunoassay (RIA), a Crithidia immunofluorescence (IF) assay and three ELISA assays using human telomere DNA, plasmid DNA circles, or calf thymus DNA as antigens, respectively. Complement C3 and C4 were determined by nephelometry. Control sera were obtained from 98 blood donors. In patients with SLE, the prevalence of anti-C1q was 17-18% and that of anti-dsDNA was 36-69%. Anti-C1q, anti-dsDNA, and complement C3 and C4 correlated well with the overall activity of SLE (r = 0.323-0.351, 0.353-0.566, and -0.372 0.444, respectively; P < 0.001). Sensitivity, specificity, positive predictive value, and negative predictive value for active lupus nephritis among SLE patients were 40-44, 92, 29, and 91-92% for anti-C1q and 48-68, 29-66, 11-16, and 86-91% for anti-dsDNA, respectively. Patients with active nephritis had higher levels of anti-C1q and lower levels of C3 and C4 than patients with inactive nephritis (P = 0.003-0.018). The corresponding associations of anti-dsDNA were somewhat weaker (P = 0.023-0.198). Hematological parameters reflecting disease activity correlated clearly better with anti-dsDNA and complement C3 and C4 than with anti-C1q. Anti-C1q is inferior to anti-dsDNA as a diagnostic test in SLE and in the evaluation of overall clinical activity of the disease. Anti-C1q together with complement C3 and C4 may offer useful additional information to monitor lupus nephritis activity. There are no practical differences between different assays for anti-C1q and anti-dsDNA. PMID- 21706297 TI - Predictive models for worsening prognosis in potential candidates for active surveillance of presumed low-risk prostate cancer. AB - PURPOSE: Low-risk prostate cancer patients clinically eligible for active surveillance can also be managed surgically. We evaluated the pathologic outcomes for this cohort that was treated by radical prostatectomy and devised nomograms to predict patients at risk of upgrading and/or upstaging. MATERIALS AND METHODS: Seven hundred and fifty patients treated by radical prostatectomy from Jan 2005 to the present fulfilled conventional active surveillance criteria and formed the study cohort. Preoperative data on standard clinicopathologic parameters were available. The radical prostatectomy specimens were graded and staged, and any upgrading to Gleason sum >6 or upstaging to >=pT3 ('worsening prognosis') were noted. Multivariable logistic regression models were used to develop predictive nomograms. RESULTS: Of the 750 patients, 303 (40.4%) patients were either upgraded or upstaged. Multivariable analysis found that preoperative PSA, number of positive cores, and prostate volume were significantly predictive of worsening prognosis and formed the nomogram criteria. CONCLUSIONS: Of patients deemed eligible for active surveillance based on conventional criteria, 40.4% have worse prognostic factors after radical prostatectomy. Current active surveillance criteria may be too relaxed, and the use of nomograms which we have devised, may aid in counseling primary prostate cancer patients considering active surveillance as their therapy of choice. PMID- 21706298 TI - Analysis of the enhancer-blocking function of the TBS element from Petunia hybrida in transgenic Arabidopsis thaliana and Nicotiana tabacum. AB - Transcriptional enhancers possess the ability to override the tissue-specificity and efficiency of nearby promoters, which is of concern when generating transgenic constructs bearing multiple cassettes. One means of preventing these inappropriate interactions is through the use of enhancer-blocking insulators. The 2-kb transformation booster sequence (TBS) from Petunia hybrida has been shown previously to exhibit this function when inserted between an enhancer and promoter in transgenic Arabidopsis thaliana. In this study, we attempted to further characterize the ability of this fragment to impede enhancer-promoter interference through an analysis of transgenic Arabidopsis and Nicotiana tabacum lines bearing various permutations of the TBS element between the cauliflower mosaic virus (CaMV) 35S enhancer and an assortment of tissue-specific promoters fused to the beta-glucuronidase (GUS) reporter gene. The full-length TBS fragment was found to function in both orientations, although to a significantly lesser degree in the reverse orientation, and was operational in both plant species tested. While multiple deletion fragments were found to exhibit activity, it appeared that several regions of the TBS were required for maximal enhancer blocking function. Furthermore, we found that this element exhibited promoter like activity, which has implications in terms of possible mechanisms behind its ability to impede enhancer-promoter communication in plants. PMID- 21706299 TI - Learning a stick-balancing task involves task-specific coupling between posture and hand displacements. AB - Theories of motor learning argue that the acquisition of novel motor skills requires a task-specific organization of sensory and motor subsystems. We examined task-specific coupling between motor subsystems as subjects learned a novel stick-balancing task. We focused on learning-induced changes in finger movements and body sway and investigated the effect of practice on their coupling. Eight subjects practiced balancing a cylindrical wooden stick for 30 min a day during a 20 day learning period. Finger movements and center of pressure trajectories were recorded in every fifth practice session (4 in total) using a ten camera VICON motion capture system interfaced with two force platforms. Motor learning was quantified using average balancing trial lengths, which increased with practice and confirmed that subjects learned the task. Nonlinear time series and phase space reconstruction methods were subsequently used to investigate changes in the spatiotemporal properties of finger movements, body sway and their progressive coupling. Systematic increases in subsystem coupling were observed despite reduced autocorrelation and differences in the temporal properties of center of pressure and finger trajectories. The average duration of these coupled trajectories increased systematically across the learning period. In short, the abrupt transition between coupled and decoupled subsystem dynamics suggested that stick balancing is regulated by a hierarchical control mechanism that switches from collective to independent control of the finger and center of pressure. In addition to traditional measures of motor performance, dynamical analyses revealed changes in motor subsystem organization that occurred when subjects learned a novel stick-balancing task. PMID- 21706300 TI - Transcranial direct current stimulation's effect on novice versus experienced learning. AB - Transcranial direct current stimulation (TDCS) is a non-invasive form of brain stimulation applied via a weak electrical current passed between electrodes on the scalp. In recent studies, TDCS has been shown to improve learning when applied to the prefrontal cortex (e.g., Kincses et al. in Neuropsychologia 42:113 117, 2003; Clark et al. Neuroimage in 2010). The present study examined the effects of TDCS delivered at the beginning of training (novice) or after an hour of training (experienced) on participants' ability to detect cues indicative of covert threats. Participants completed two 1-h training sessions. During the first 30 min of each training session, either 0.1 mA or 2.0 mA of anodal TDCS was delivered to the participant. The anode was positioned near F8, and the cathode was placed on the upper left arm. Testing trials immediately followed training. Accuracy in classification of images containing and not-containing threat stimuli during the testing sessions indicated: (1) that mastery of threat detection significantly increased with training, (2) that anodal TDCS at 2 mA significantly enhanced learning, and (3) TDCS was significantly more effective in enhancing test performance when applied in novice learners than in experienced learners. The enhanced performance following training with TDCS persisted into the second session when TDCS was delivered early in training. PMID- 21706301 TI - Spatial dependency of action simulation. AB - In this study, we investigated the spatial dependency of action simulation. From previous research in the field of single-cell recordings, grasping studies and from crossmodal extinction tasks, it is known that our surrounding space can be divided into a peripersonal space and extrapersonal space. These two spaces are functionally different at both the behavioral and neuronal level. The peripersonal space can be seen as an action space which is limited to the area in which we can grasp objects without moving the object or ourselves. The extrapersonal space is the space beyond the peripersonal space. Objects situated within peripersonal space are mapped onto an egocentric reference frame. This mapping is thought to be accomplished by action simulation. To provide direct evidence of the embodied nature of this simulated motor act, we performed two experiments, in which we used two mental rotation tasks, one with stimuli of hands and one with stimuli of graspable objects. Stimuli were presented in both peri- and extrapersonal space. The results showed increased reaction times for biomechanically difficult to adopt postures compared to more easy to adopt postures for both hand and graspable object stimuli. Importantly, this difference was only present for stimuli presented in peripersonal space but not for the stimuli presented in extrapersonal space. These results extend previous behavioral findings on the functional distinction between peripersonal- and extrapersonal space by providing direct evidence for the spatial dependency of the use of action simulation. Furthermore, these results strengthen the hypothesis that objects situated within the peripersonal space are mapped onto an egocentric reference frame by action simulation. PMID- 21706302 TI - Prostate multimodality image registration based on B-splines and quadrature local energy. AB - PURPOSE: Needle biopsy of the prostate is guided by Transrectal Ultrasound (TRUS) imaging. The TRUS images do not provide proper spatial localization of malignant tissues due to the poor sensitivity of TRUS to visualize early malignancy. Magnetic Resonance Imaging (MRI) has been shown to be sensitive for the detection of early stage malignancy, and therefore, a novel 2D deformable registration method that overlays pre-biopsy MRI onto TRUS images has been proposed. METHOD: The registration method involves B-spline deformations with Normalized Mutual Information (NMI) as the similarity measure computed from the texture images obtained from the amplitude responses of the directional quadrature filter pairs. Registration accuracy of the proposed method is evaluated by computing the Dice Similarity coefficient (DSC) and 95% Hausdorff Distance (HD) values for 20 patients prostate mid-gland slices and Target Registration Error (TRE) for 18 patients only where homologous structures are visible in both the TRUS and transformed MR images. RESULTS: The proposed method and B-splines using NMI computed from intensities provide average TRE values of 2.64 +/- 1.37 and 4.43 +/ 2.77 mm respectively. Our method shows statistically significant improvement in TRE when compared with B-spline using NMI computed from intensities with Student's t test p = 0.02. The proposed method shows 1.18 times improvement over thin-plate splines registration with average TRE of 3.11 +/- 2.18 mm. The mean DSC and the mean 95% HD values obtained with the proposed method of B-spline with NMI computed from texture are 0.943 +/- 0.039 and 4.75 +/- 2.40 mm respectively. CONCLUSIONS: The texture energy computed from the quadrature filter pairs provides better registration accuracy for multimodal images than raw intensities. Low TRE values of the proposed registration method add to the feasibility of it being used during TRUS-guided biopsy. PMID- 21706303 TI - Respiratory distress: an unrecognized non-motor phenomenon in patients with parkinsonism. AB - Although respiratory abnormalities are associated with parkinsonism, patients rarely complain of dyspnea. This study describes ten patients with parkinsonism and symptoms of dyspnea and respiratory distress that were unexplained by a pulmonary or cardiac abnormality or a psychological problem. Suggested underlying mechanisms are a central pathology affecting respiratory rhythm generation at the brainstem or lack of coordination of the respiratory muscles causing involuntary movements of the diaphragm. Dyspnea and respiratory distress should be included among the non-motor symptoms of parkinsonism. PMID- 21706304 TI - Arthroscopic repair of type II superior labrum anterior posterior (SLAP) lesions in patients over the age of 45 years: a prospective study. AB - BACKGROUND: Superior labrum anterior posterior (SLAP) lesions are a well-defined cause of shoulder pain and disability and may occur in conjunction with rotator cuff tears. This study was designed to prospectively evaluate the minimum 2 year results of arthroscopic repair of type II SLAP lesions in patients over the age of 45 years with and without rotator cuff tears. PATIENTS AND METHODS: Thirty five patients with symptomatic type II SLAP lesions were enrolled in the study. All patients underwent arthroscopic SLAP repair and simultaneous repairs were carried out in 17 of these patients who had concomitant full-thickness rotator cuff tears. Patients were grouped into two with regard to the presence of rotator cuff tears. The outcome was assessed by University of California at Los Angeles (UCLA) score and clinical examination (forward flexion/internal rotation/external rotation). RESULTS: At an average follow-up of 2.5 years, both groups displayed significant improvements in UCLA score (31.2 vs. 11.8; p < 0.01) and range of motion. Compared with the group that had SLAP and concomitant rotator cuff tears, patients in isolated SLAP group had significantly better scores in function (9.4 vs. 8.6; p = 0.045) and patient satisfaction (4.9 vs. 4.5; p = 0.039). No significant difference was found between two groups with respect to range of motion. CONCLUSIONS: The arthroscopic repair of symptomatic type II SLAP lesions yields favorable outcomes in patients over 45 years of age and the presence of accompanying rotator cuff tears has a negative effect on the results. PMID- 21706305 TI - Anatomical structures at risk with the proud retrograde femoral nail. AB - BACKGROUND: Post-operative knee pain is common following retrograde nailing, with its etiology often multifactorial although a well-established cause is nail protrusion from the intercondylar notch. The aim of this study was to assess the structures at risk if the nail is left proud of the femoral articular surface. METHODS: A retrograde femoral nail (Synthes Distal Femoral Nail) was inserted into the distal femur of 15 cadaveric lower limbs using the standard technique. The nail was left 10 mm proud of the articular surface and locked in this position. The knee was then put through a full range of movement while recording the intra-articular structures that came into contact with the distal end of the nail as well as the position of the knee when this occurred. This was repeated with the nail 5 mm proud. RESULTS: With the nail 10 mm proud, it impinged on the anterior horn of the medial meniscus in 14 cases and the anterior horn of the medial meniscus as well as the tibial insertion of the ACL in one case at 15 degrees of flexion. At 70 degrees of flexion the nail came into contact with the distal margin of the patellar articular surface in the midline in all 15 cases. With the nail 5 mm proud, it impinged on the anterior horn of the medial meniscus in seven cases and the tibial insertion of the ACL as well as the anterior horn of the medial meniscus in eight cases as the knee was brought into full extension. In flexion the distal margin of the patellar articular surface in the midline came into contact with the nail at 70 degrees of flexion in all 15 cases. CONCLUSION: Correct positioning of a retrograde femoral nail is of paramount importance to avoid further iatrogenic injury to intra-articular structures. PMID- 21706306 TI - Disc space distraction is a potent risk factor for adjacent disc disease after PLIF. AB - We reported that excessive disc space distraction caused by insertion of large cages during posterior lumbar interbody fusion (PLIF) combined with pedicle screws (PS) induces adjacent segment disease (ASD). Spinous process plate (SPP) is known to allow cage subsidence when used in PLIF, since they cannot share vertical loads. We therefore hypothesize that the incidence of ASD after PLIF with SPP should be lower than that after PLIF with PS due to this loss of disc space distraction. MATERIALS AND METHODS: Radiographic ASD is defined as development of spondylolisthesis > 3 mm, decrease in disc height > 3 mm, or intervertebral angle at flexion lesser than -5 degrees . Symptomatic ASD is defined by a decrease of >= 4 points in Japanese Orthopedic Association score. One hundred and thirty patients with L4 spondylolisthesis were treated with either PLIF with SPP (n = 45) or PLIF with PS (n = 85) and followed up for a minimum of 2 years (mean, 39.0 months). RESULTS: L4-5 disc space distraction in the SPP group was significantly smaller (0.4 mm) as compared to the PS group (1.8 mm). The incidence of clinical ASD in the SPP group (2%, 1/45) was also significantly less than that in the PS group (15%, 13/85). Multivariate analysis showed that disc space distraction was the most significant risk factor. CONCLUSIONS: Among various risk factors for ASD after PLIF, the excessive distraction of disc space proved to be a potent risk factor for ASD. PMID- 21706307 TI - Assessing preferences for improved smoking cessation medications: a discrete choice experiment. AB - BACKGROUND: The use of smoking cessation medications can considerably enhance the long-term abstinence rate at a reasonable cost, but only a small proportion of quitters seek medical assistance. The objective of this study was to evaluate the factors that influence the decision to use such treatments and the willingness-to pay of smokers for improved cessation drugs. METHOD: A discrete choice experiment was conducted amongst smokers in the French-speaking part of Switzerland. Choice sets consisted of two hypothetical medications described via five attributes (price, efficacy, possibility of minor side effects, attenuation of weight gain and availability) and an opt-out option. Various discrete choice models were estimated to analyse both the factors that influence treatment choice and those that influence the overall propensity to use a smoking cessation medication. RESULTS: Our results indicate that smokers are willing to pay for higher efficacy, less-frequent side effects and prevention of weight gain. Whether the drug is available over-the-counter or on medical prescription is of secondary importance. In addition, we show that there are several individual-specific factors influencing the decision to use such medications, including education level. Results also indicate substantial preference heterogeneity. CONCLUSION: This study shows that there is a potential demand for improved cessation medications. Broader usage could be reached through lower out-of-pocket price and greater efficacy. Secondary aspects such as side effects and weight gain should also be taken into consideration. PMID- 21706310 TI - Sexual satisfaction among men living with HIV in Europe. AB - This study determined risk factors for decreased sexual satisfaction among men living with HIV (MLHIV). Self-administered questionnaires were distributed consecutively to all MLHIV attending 17 European HIV treatment centres. The sample included 1,017 MLHIV, among whom 79.2% self-identified as homosexual or bisexual. Sexual satisfaction was measured for five domains of sexual functioning and 33.2% reported low satisfaction in at least one domain. Decreased sexual satisfaction was associated with psychosocial factors, i.e. depression (OR 2.77, P < 0.001), anxiety (OR 1.77, P < 0.001), stress (OR 2.27, P < 0.001) and social factors, such as low partner support (OR 2.28, P < 0.001) and experiences of HIV related discrimination (OR 1.69, P < 0.001). Discussing satisfaction with sexuality should be integrated in regular HIV care, considering patients' personal and relationship-related resources next to medical treatment if indicated. PMID- 21706309 TI - Melanization of a meristematic mutant of Fonsecaea monophora increases tolerance to stress factors while no effects on antifungal susceptibility. AB - Melanin is a complex polymer, which is widely distributed in nature, and is known as an important virulence factor in opportunistic and pathogenic fungi. In this study, three melanin mutants of Fonsecaea monophora from a case of chromoblastomycosis were generated from a parent strain that lacked hyphal morphology but was meristematic instead. Two albino mutants, one of which (CBS 125187) produced secreted melanin and another (CBS 125149) lacked melanin, grew faster than a mutant with cell-wall-associated and secreted melanin (CBS 125188) and than the meristematic parent strain (CBS 122845) (P < 0.05). The albino strains were also more sensitive to low pH, high UV radiation, and oxidative stress (P < 0.05). However, susceptibility testing against eight antifungal agents showed no statistical difference (P > 0.05). The discovery of three melanin mutants of a single meristematic mutant provided an alternative way to study the role of cell-wall-associated and secreted melanins in the pathogenesis of black fungi. PMID- 21706311 TI - Developing a programme for medication reconciliation at the time of admission into hospital. AB - The aim of this article is to describe the methods used to develop the medication reconciliation programme implemented in a tertiary care hospital, and to discuss the main problems encountered and lessons learned during the process. A quasi experimental study was carried out, analysing discrepancies between routine medication and drugs prescribed in the hospital, before and after an electronic reconciliation tool was introduced at admission. This tool was integrated into the computerized provider order entry system. The implementation of the electronic reconciliation tool has shown a reduction of the rate of discrepancies, decreasing from 7.24% (CI 95% 6.0-8.5) before the intervention to 4.18% (CI 95% 3.2-5.1) afterwards. Projects like this are costly, but this study has made it possible to detect numerous areas where interventions could be useful and proved the importance of a medication reconciliation programme. PMID- 21706312 TI - Neurophysiological preconditions of syntax acquisition. AB - Although the neural network for language processing in the adult brain is well specified, the neural underpinning of language acquisition is still underdetermined. Here, we define the milestones of syntax acquisition and discuss the possible neurophysiological preconditions thereof. Early language learning seems to be based on the bilateral temporal cortices. Subsequent syntax acquisition apparently primarily recruits a neural network involving the left frontal cortex and the temporal cortex connected by a ventrally located fiber system. The late developing ability to comprehend syntactically complex sentences appears to require a neural network that connects Broca's area to the left posterior temporal cortex via a dorsally located fiber pathway. Thus, acquisition of syntax requires the maturation of fiber bundles connecting the classical language-relevant brain regions. PMID- 21706314 TI - Effect of physiological levels of phytoestrogens on mouse oocyte maturation in vitro. AB - Phytoestrogens are a group of naturally occurring compounds that have weak estrogenic activity. Genistein and daidzein are major phytoestrogens produced by soybeans. It has been reported previously that at high concentration, some phytoestrogens inhibit cell cycle progression of mouse germinal vesicle (GV) oocytes, but the environmentally relevant level is much lower. Here we show the effects of low concentrations of the isoflavones genistein, daidzein and the daidzein metabolite, equol, on mouse oocyte maturation. GV oocytes denuded of cumulus cells were cultured in TaM medium containing low levels (5 MUM) of genistein, daidzein. or equol. In all cases, the oocytes underwent normal GV break down, first polar body extrusion and became arrested at metaphase II (mII). As judged by fluorescence microscopy, the treated mII oocytes exhibited normal distributions of actin microfilaments, cortical granules and metaphase spindle formation with condensed metaphase chromatin. Moreover, mRNA expression levels of the cytostatic factors Emi2 and Mos were similar to those of their respective controls. These data suggest that exposure of maturing GV oocytes to environmental levels of genistein, daidzein or equol in vitro do not cause negative effects on maturation to produce mII oocytes. PMID- 21706313 TI - Creatine kinase MM TaqI and methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms influence exercise-induced C-reactive protein levels. AB - Physical training induces beneficial adaptations, but exhausting exercise increases reactive oxygen species, which can cause muscular injuries with consequent inflammatory processes, implying jeopardized performance and possibly overtraining. Acute strenuous exercise almost certainly exceeds the benefits of physical activity; it can compromise performance and may contribute to increased future risk of cardiovascular disease (CVD) in athletes. Polymorphisms in the muscle-type creatine kinase (CK-MM) gene may influence performance and adaptation to training, while many potentially significant genetic variants are reported as risk factors for CVD. Therefore, we investigated the influence of polymorphisms in CK-MM TaqI and NcoI, methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and C-reactive protein (CRP G1059C) genes on exercise-induced damage and inflammation markers. Blood samples were taken immediately after a race (of at least 4 km) that took place outdoors on flat tracks, and were submitted to genotyping and biochemical evaluation of aspartate aminotransferase (AST), CK, CRP and high-sensitivity CRP (hs-CRP). CK-MM TaqI polymorphism significantly influenced results of AST, CK and hs-CRP, and an association between MTHFR C677T and A1298C with CRP level was found, although these levels did not exceed reference values. The results indicate that these polymorphisms can indirectly influence performance, contribute to higher susceptibility to exercise-induced inflammation or protection against it, and perhaps affect future risks of CVD in athletes. PMID- 21706315 TI - Sequence analysis of S1 genes of infectious bronchitis virus isolated in Thailand during 2008-2009: identification of natural recombination in the field isolates. AB - During 2008-2009, fifteen field infectious bronchitis viruses (IBVs) were isolated from commercial chicken farms in Thailand. After sequencing of the complete S1 gene, phylogenetic analysis was performed and this found that the Thai IBV isolates were divided into three distinct groups, unique to Thailand (group I), QX-like IBV (group II), and Massachusetts type (group III). This finding indicated that the recent Thai IBVs evolved separately and that at least three groups of viruses are circulating in Thailand. The recombination analysis of the S1 gene demonstrated that the 5'-terminus of the group I was similar to isolate THA001 which was unique to Thailand, isolated in 1998 whereas the 3' terminus was similar to the group II. Moreover, the analysis of the S1 gene of the group II showed that the 5'-terminus was similar to QXIBV, isolated in China whereas the remaining region at the 3'-terminus was similar to the Chinese strain JX/99/01. The results indicated that the recombination events occurred in the S1 gene between the field strains. Based on these facts, the field IBV in Thailand has undergone genetic recombination. PMID- 21706316 TI - Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor. AB - PURPOSE: Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. METHODS: Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. RESULTS: In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. CONCLUSIONS: Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary. PMID- 21706317 TI - The plasma and cerebrospinal fluid pharmacokinetics of the platinum analog satraplatin after intravenous administration in non-human primates. AB - BACKGROUND: Satraplatin is an orally bioavailable platinum analog with preclinical activity in cisplatin resistant models and clinical activity in adults with refractory cancers. The cerebrospinal fluid (CSF) penetration of cisplatin and carboplatin in non-human primates (NHP) is limited (3.7 and 2.6%, respectively). We evaluated the plasma and CSF pharmacokinetics (PK) of satraplatin after an intravenous (IV) dose in NHP. METHODS: Satraplatin (120 mg/m(2)) was administered as 1 h IV infusion in DMSO (5%) and normal saline to 5 NHP. Serial blood and CSF samples were obtained over 48 h. Plasma ultrafiltrate (UF) was immediately prepared by centrifugation. Platinum was quantified in plasma UF and CSF using a validated atomic absorption spectroscopy assay with lower limit of quantification (LLQ) of 0.025 MUM in UF and 0.006 MUM after concentration in CSF. Pharmacokinetic parameters were estimated using non compartmental analyses. CSF penetration was calculated from the CSF AUC(0-48h) : plasma UF AUC(0-48h). RESULTS: Satraplatin was well tolerated. Median (range) PK parameters in plasma UF were: maximum concentration (C (max)) 8.3 MUM (5.7-10.6), area under the curve (AUC(0-48h)) 29.2 MUM h (22.6-33.2), clearance 0.36 l/h/kg (0.31-0.37), and t (1/2) 18.8 h (13.4-25). Satraplatin was detected in the CSF of all NHP. Median (range) PK parameters in CSF were: C (max) 0.07 MUM (0.02-0.12), AUC(0-48h) 1.2 MUM h (0.49-2.43). The median (range) CSF penetration of satraplatin was 4.3% (2.2-7.4). CONCLUSIONS: Satraplatin penetration into CSF is similar to that of carboplatin and cisplatin, despite its greater lipophilicity. The development of a phase I trial of satraplatin for refractory childhood solid tumors including brain tumors is in progress. PMID- 21706318 TI - Functional endoscopic sinus surgery in children: predictive factors of outcome. AB - The main objective of this study is to assess the results of functional endoscopic sinus surgery in children and to determine which factors independently influence the postoperative results. It is a prospective study by Mansoura University Hospital. 87 patients with different applications of pediatric endoscopic sinus surgery (PESS) chronic rhinosinusitis (CRS) with nasal allergy (45 patients), CRS without nasal allergy (36 patients) and CRS with polypsis (6 patients) from 2005 to 2010 were included. All children underwent endoscopic sinus surgery. All patients were clinically, radiologically and endoscopically monitored. In this study, the overall success rate was 87.69%, the success rate for CRS with nasal allergy was 87.5%, the success rate for CRS without nasal allergy was 85.7% and the success rate for CRS with polyposis was 93%. Regarding the patients' age, it could affect the surgical score value (X(2) = 9.446 and P* = 0.009). There was significant relation between type of the preoperative disease extent, adenoidectomy, second look operation and postoperative improvement. There was no significant relation between type of the preoperative disease or previous surgery and postoperative improvement. In conclusion, postoperative improvement was significantly correlated with extent of preoperative disease, adenoidectomy and second look operation and not significantly correlated with type of the preoperative disease or previous surgery. The results of PESS are influenced by age group, a younger age group is associated with more adhesions and recurrences and an older age group is associated with blood loss and higher surgical score. All these variables are contributing in the outcome of PESS. PMID- 21706319 TI - Return to theatre in secondary post-tonsillectomy haemorrhage: a comparison of coblation and dissection techniques. AB - The aim of this study is to examine the incidence of return to theatre (RTT) for post-operative haemorrhage following coblation and dissection tonsillectomy and to investigate those that required RTT more than 10 days post-surgery. Retrospective review of post-tonsillectomy haemorrhages requiring RTT from April 2005 to March 2009 was conducted. Of 2,541 tonsillectomies performed, 81% were by coblation and 19% by dissection methods. The overall RTT rate was 1.7%. No difference was found in the overall RTT rates for primary and secondary haemorrhage between the two techniques. However, the overall RTT rates for primary and secondary haemorrhage were higher in adults than children (P = 0.0456 and P = 0.0215, respectively). RTT for secondary haemorrhage during the first ten post-operative days occurred in both coblation and dissection tonsillectomy with no significant difference. After the first post-operative week, late secondary bleeding requiring RTT occurred only in the coblation group (P = 0.0676). Four patients required blood transfusion; all were in the coblation group, three of which were required during RTT in the late secondary haemorrhage (after 10 days). The post-operative RTT rates for coblation tonsillectomy did not reveal a change of trend over the 4-year study period. Our RTT rate for secondary haemorrhage is higher than earlier published results. A learning curve could not be identified in RTT for coblation tonsillectomy haemorrhage. Late secondary haemorrhages requiring surgical intervention have only been identified in cases performed by coblation and could potentially be life threatening as 33% (3/9) required blood transfusion. This phenomenon may be explained by a particular physiological healing process associated with coblation. PMID- 21706320 TI - Efficiency of laser treatment in patients with hereditary hemorrhagic telangiectasia. AB - Earlier studies have shown the effect of laser treatment on epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT). At the present time, only very few prospective trials have been performed, and many studies are based on patients' subjective assessment of the severity of epistaxis. This prospective study measures the objective effect of laser treatment in HHT patients with mild to moderate epistaxis. We introduce an objective measure to assess the severity of epistaxis: the bleeding time (BT). Before and after treatment, the quality of life, as measured by the patient, was assessed and compared to normative data. In 30 patients, we measured the BT before laser treatment 1.5 and 6.5 months after treatment. The Short form 36 (SF-36), a validated health questionnaire, was completed before and 6.5 months after treatment. Compared to preoperative value, BT was significantly reduced 1.5 and 6.5 months after laser treatment (p < 0.05) in both cases. No significant difference in quality of life, before and after treatment, was found. The quality of life of the HHT patients was reduced in five out of eight dimensions when compared with the Danish background population. Laser treatment reduces epistaxis in HHT patients with mild to moderate epistaxis for at least 6 months; this group of patients have reduced quality of life compared to the background population. PMID- 21706321 TI - Nose- and sinus-related quality of life and GERD. AB - Though some data indicate an association between gastroesophageal reflux disease (GERD) and upper airway inflammatory disease, a connection between GERD and chronic rhinosinusitis (CRS) is a matter of controversy in today's medicine. The aim of this study was to examine whether patients with GERD have a different nose and sinus-related quality of life compared to a control group. A total of 77 patients with GERD diagnosed by gastroscopy were evaluated according to their nose- and sinus-related quality of life. It was scored using the Sino-Nasal Outcome Test-20 (SNOT-20). Total SNOT-20 score was compared with a control group consisting of 480 teachers. The average total SNOT-20 score in patients with GERD was 22.1, and in the control group 9.4 (p < 0.005). In the patient group, the median was 17.0 and standard deviation 18.4 corresponding to 5.0 and 11.5 in the controls. The 95% confidence interval in the patient group was (18.0, 26.3), and (8.3, 10.4) in the control group. Patients with GERD have a reduced nose- and sinus-related quality of life compared to a control group based on the fact that they have a significantly higher total SNOT-20 score than the controls. Accordingly, this study indicates that there is a causal relationship between GERD and CRS. PMID- 21706322 TI - 'Valve-stabilised' rhinospirometry can predict the benefit of septal surgery: a pre- and post-operative correlation study. AB - Septoplasty is a procedure often associated with high levels of patient dissatisfaction post-operatively. This study examined whether rhinospirometry and a modified 'valve-stabilised' technique could pre-operatively predict the outcome of septal surgery and therefore have a role as an objective tool for selection of patients suffering from nasal obstruction due to septal deformity for the procedure of septoplasty. A prospective study was performed of patients attending Singleton Hospital, Swansea, for surgical treatment of nasal obstruction due to septal deformity. Participants were asked to undertake decongested visual analogue scoring (VAS) and rhinospirometric assessment of their nasal obstruction in both normal 'resting' and 'valve-stabilised' nasal positioning. These investigations were undertaken on the day of surgery and 6 weeks post operatively. Results were converted into nasal partition ratio scores and were assessed statistically for difference, correlation and accuracy. A total of 29 individual participants were included in the study. Septal surgery produced a statistically significant improvement in nasal airflow symmetry in the normal 'resting' nasal position using rhinospirometry (Wilcoxon ranked p > 0.5). This difference was not seen between evaluations in 'valve-stabilised' position (Wilcoxon p < 0.001). No statistical difference was evident between pre-operative 'valve-stabilised' testing and post-operative 'resting position'. The finding was also apparent on VAS nasal assessment. Correlation studies showed a strong relationship between pre-operative 'valve-stabilised' and post-operative 'resting' rhinospirometry results (Spearman's rho = 0. 586, p < 0.002). The strength of this relationship between VAS assessments was less pronounced (Spearman's rho = 0.386 p = 0.07). 'Valve-stabilised' rhinospirometry and VAS appear to be useful pre-operatively to predict the outcome of septal surgery, in terms of airflow symmetry, for nasal obstruction due to septal deformity, with pre-operative 'valve-stabilised' results correlating well with the post-operative standard 'resting' outcomes. Valve-stabilised rhinospirometry may have a role in pre-operatively predicting of likely post-operative patient satisfaction, although further studies are required in this area. PMID- 21706323 TI - Unbalanced oxidative status in idiopathic sudden sensorineural hearing loss. AB - An impaired cochlear perfusion seems to be an important etiopathogenetic event in idiopathic sudden sensorineural hearing loss (ISSNHL). Recently, oxidative stress has been proposed as risk factors of microvascular damage. This observational study aimed to evaluate the possible role of oxidative stress in ISSNHL. In thirty-nine ISSNHL patients and seventy healthy subjects serum reactive oxygen species concentrations (ROS) and total antioxidant capacity (TAC) were measured by spectrophotometric methods on F.R.E.E. analyzer (Diacron International, Italy). Moreover, a global oxidative stress index (Oxidative-INDEX), reflecting both oxidative and antioxidant counterparts, was also calculated. 25/39 patients showed oxidative stress due to ROS levels significantly higher than controls (348.2 +/- 84.8 vs. 306.75 +/- 46.7 UCarr; p = 0.001). The Oxidative-INDEX was significantly higher in patients than in controls (0.75 +/- 2.4 vs. -0.0007 +/- 1.28 AU, p = 0.03). As oxidative stress is a key determinant in endothelial dysfunction, our findings could suggest vascular impairment involvement in ISSNHL etiopathogenesis. PMID- 21706325 TI - TRAIL and guardian angel of genome integrity: ATM boards TRAIL blazer. AB - Prostate cancer is a multifaceted progressive multistep disorder that arises because of accumulation of genetic and epigenetic abnormalities, which escort to the transformation of normal cells into malignant derivatives. Despite tremendous strides have been made in the understanding of prostate cancer biology, yet approaches towards cancer-targeted therapy still face confrontations in standardization. This review brings to attention, the regulators in complex genetic backgrounds to enlighten our understanding of transformation and metastasis in human systems. Recent evidence gives a clue that prostate cancer may be linked to deregulated DNA damage repair processes, as various combinations of targeted deletions in genes controlling cell-cycle checkpoints; apoptosis and DNA repair result in prostate cancer progression and aggressiveness. An insight of the orchestration between DNA damage-based molecular responses and TRAIL provides an understanding of the mechanisms that cause apoptosis and may provide rationale for the development of novel therapeutic strategies. PMID- 21706324 TI - Experience with combination of cisplatin plus gemcitabine chemotherapy and intensity-modulated radiotherapy for locoregionally advanced nasopharyngeal carcinoma. AB - The purpose of this study was to evaluate the efficacy and toxicity of cisplatin plus gemcitabine chemotherapy and intensity-modulated radiation therapy (IMRT) for locoregionally advanced nasopharyngeal carcinoma (NPC). A total of 54 patients (stage IIB: 6, stage III: 24, stage IVA-B: 24) with locoregionally advanced NPC were treated with cisplatin 25 mg/m(2) intravenously on days 1-3, and gemcitabine 1,000 mg/m(2) of 30-min intravenous infusion on days 1 and 8, every 3 weeks for two cycles as neoadjuvant chemotherapy. Two cycles of the same regimen were administered as adjuvant chemotherapy 28 days after the end of radiotherapy. The prescription doses were 66-70.4 Gy to the gross tumor volume (GTV), 66 Gy to positive neck nodes, 60 Gy to the high-risk clinical target volume and 54 Gy to the low-risk clinical target volume. The overall response rate to neoadjuvant chemotherapy was 88.6%. Toxicity was mainly grade 1/2 myelosuppression. All patients completed IMRT. The median follow-up duration was 30 months (range, 12-60 months). The 3-year locoregional control, metastasis-free rate and overall survival were 94.9%, 86.2% and 87.7%, respectively. Severe late toxicities included grade 3 trismus in one patient, grade 3 hearing impairment in one patient and cranial nerve XII palsy in one patient. No grade 4 late toxicities were observed. A combination of cisplatin plus gemcitabine chemotherapy and intensity-modulated radiotherapy for locoregionally advanced NPC is well-tolerated, convenient, effective and warrants further studies. PMID- 21706326 TI - Primary cardiac pheochromocytoma with multiple endocrine neoplasia. AB - PURPOSE: Cardiac pheochromocytoma with multiple endocrine neoplasia syndrome (MENS) is rare. We present a rare case of concurrent cardiac pheochromocytoma and pituitary adenoma, a rare variant of the MEN syndromes and a review of the literature with special emphasis on diagnosis and treatment. METHODS: Different from the single MENS type I or type II, Variant MENS' symptoms and signs are so nontypical that it is easy to make a misdiagnosis or missed diagnosis. One patient with variant MENS was treated surgically and relevant case data were collected. RESULTS: The perioperative course was uneventful. At 24-month follow up, catecholamine levels returned to normal and no symptoms of pheochromocytoma was found. CONCLUSIONS: Cardiac pheochromocytoma with Multiple Endocrine Neoplasia can be treated by operation with good prognosis. Surgical removal to provide relief or effective control of symptoms is the treatment of choice. PMID- 21706328 TI - Phase-resolved real-time breath analysis during exercise by means of smart processing of PTR-MS data. AB - Separation of inspiratory, mixed expired and alveolar air is indispensable for reliable analysis of VOC breath biomarkers. Time resolution of direct mass spectrometers often is not sufficient to reliably resolve the phases of a breathing cycle. To realise fast on-line breath monitoring by means of direct MS utilising low-fragmentation soft ionisation, a data processing algorithm was developed to identify inspiratory and alveolar phases from MS data without any additional equipment. To test the algorithm selected breath biomarkers (acetone, isoprene, acetaldehyde and hexanal) were determined by means of quadrupole proton transfer reaction mass spectrometry (PTR-MS) in seven healthy volunteers during exercise on a stationary bicycle. The results were compared to an off-line reference method consisting of controlled alveolar breath sampling in Tedlar(r) bags, preconcentration by solid-phase micro extraction (SPME), separation and identification by GC-MS. Based on the data processing method, quantitative attribution of biomarkers to inspiratory, alveolar and mixed expiratory phases was possible at any time during the experiment, even under respiratory rates up to 60/min. Alveolar concentrations of the breath markers, measured by PTR-MS ranged from 130 to 2,600 ppb (acetone), 10 to 540 ppb (isoprene), 2 to 31 ppb (acetaldehyde), whereas the concentrations of hexanal were always below the limit of detection (LOD) of 3 ppb. There was good correlation between on-line PTR-MS and SPME-GC-MS measurements during phases with stable physiological parameters but results diverged during rapid changes of heart rate and minute ventilation. This clearly demonstrates the benefits of breath-resolved MS for fast on-line monitoring of exhaled VOCs. PMID- 21706329 TI - Oluwatosin O. Dada wins ABC best paper award. Interview by Andrea Pfeifer. PMID- 21706330 TI - Cellular markers of neuroinflammation and neurogenesis after ischemic brain injury in the long-term survival rat model. AB - MRI was employed to follow the neurodegenerative foci and the localization of inflammatory cells by magnetically labeled CD4+ or CD8+ lymphocytes in the ischemia/reperfusion long-lived rats (9 and 13 months after 10 min of cardiac arrest). MRI of ischemic rats showed: (1) blood-brain barrier (BBB) leakage in the area of the dorsal hippocampus and brainstem-hindbrain level in basal cerebellum, (2) unlike anti-CD8 magnetic antibodies anti-CD4 ultra small paramagnetic iron oxide particles (USPIO) antibodies revealed hypointense areas in the brainstem-interbrain region and caudoputamen not found in animals that were not injected with USPIO antibodies, and (3) dilation in the retrosplenial area. Immunocytochemistry revealed microglial activation in the hippocampus and striatum, with indications of activation in thalamic lateral dorsal nuclei and the subventricular zone. In the CA1 and CA3 regions, it was noted that OX42- and ED1-positive granules appear in neuronal somata. Immunostaining of lymphocytes with TCR confirmed the T-cell presence in ischemic brain parenchyma of the hippocampus and striatum. The above observations thus point to a persistent dysfunction of BBB that in long-term may still lead to infiltration of T cells that are predominantly of helper (CD4+) type. Such inflammatory processes are backed by microglial activity even up to 1 year after ischemia/reperfusion. Moreover, in these animals an augmented expression of neurogenesis markers and neuroblast migration was also revealed in the subventricular zone. Thus, a balance of degenerative processes and inflammatory surveillance with neurogenesis could determine the long-term outcome of global ischemia survival or the previously proposed formation of amyloid plaques and Alzheimer's-type dementia. PMID- 21706331 TI - Effects of prescribed fire, supplemental feeding, and mammalian predator exclusion on hispid cotton rat populations. AB - Predation and food resources can strongly affect small mammal population dynamics directly by altering vital rates or indirectly by influencing behaviors. Fire may also strongly influence population dynamics of species inhabiting fire-adapted habitats because fire can alter food and cover availability. We used capture-mark recapture and radio-telemetry studies to experimentally examine how supplemental feeding, mammalian predator exclusion, and prescribed fire affected survival, abundance, and reproduction of hispid cotton rats (Sigmodon hispidus) in southwestern Georgia, USA. Prescribed fire reduced survival, abundance, and rates of transitions to reproductive states. Food supplementation increased survival, transitions to reproductive states, and abundance, but was not sufficient to prevent post-fire declines in any of these parameters. Mammalian predator exclusion did not strongly affect any of the considered parameters. Our results show that fire strongly influenced cotton rat populations in our study site, primarily by reducing cover and increasing predation risk from non-mammalian predators. PMID- 21706332 TI - Boulders increase resistance to clear-cut logging but not subsequent recolonization rates of boreal bryophytes. AB - The extent to which a plant assemblage might recolonize a disturbed system is in general related to the availability of propagule sources and sites with appropriate conditions for establishment. Both these factors might be sensitive to aspects of spatial heterogeneity. Microtopographic variation may enhance initial resistance by reducing the impact of the disturbance and facilitating establishment of incoming propagules by providing shaded "safe-sites". This study explores the influence of microtopographic heterogeneity (caused by variation in surface boulder cover) on the recolonization of closed-canopy forest floor bryophytes using a chronosequence of 75 spruce-dominated forests in south-central Sweden (2-163 years after clear-cutting). We found that high boulder cover did increase survival and subsequent persistence in young forests at both investigated scales (i.e. 1,000 and 100 m(2)), although this pattern became less evident on the smaller spatial scale. Species accumulation in boulder-poor subplots was not different when surrounded by boulder-rich compared with boulder poor subplots suggesting short-distance recolonization from boulder-created refugia to be of little importance during recolonization. To conclude, it seems that boulders increase initial resistance to clear-cutting for this bryophyte guild, but that the subsequent recolonization process is more likely to depend on external propagule sources and factors affecting establishment such as the microclimate in the developing stand. PMID- 21706334 TI - Strangulated perforated hiatus hernia due to pyloric stenosis. AB - The first patient with strangulated hiatus hernia due to pyloric stenosis is reported. A 70-year-old male patient presented as an emergency with severe left sided chest pain, tachycardia, tachypnea, dysphagia, and nausea but no vomiting. The diagnosis of strangulated hiatus hernia due to pyloric stenosis was suspected, because a CT scan done 24 h following a barium meal showed much retained barium in both infra- and supradiaphragmatic parts of the stomach. Recognition of this condition is important since absence of pneumoperitoneum should not delay the diagnosis. In this complication, the perforation is likely to be at the hiatus, not the fundus as occurs in other causes of strangulation. A gastric drainage procedure should be an essential part of treatment. PMID- 21706333 TI - Quaternary record of aridity and mean annual precipitation based on delta15N in ratite and dromornithid eggshells from Lake Eyre, Australia. AB - The cause(s) of the late Pleistocene megafauna extinction on the Australian continent remains largely unresolved. Unraveling climatic forcing mechanisms from direct or indirect human agents of ecosystem alteration has proven to be extremely difficult in Australia due to the lack of (1) well-dated vertebrate fossils and (2) paleo-environmental and -ecological records spanning the past approximately 100 ka when regional climatic conditions are known to have significantly varied. We have examined the nitrogen isotope composition (delta(15)N) of modern emu (Dromaius novaehollandiae) eggshells collected along a precipitation gradient in Australia, along with modern climatological data and dietary delta(15)N values. We then used modern patterns to interpret an approximately 130-ka record of delta(15)N values in extant Dromaius and extinct Genyornis newtoni eggshells from Lake Eyre to obtain a novel mean annual precipitation (MAP) record for central Australia spanning the extinction interval. Our data also provide the first detailed information on the trophic ecology and environmental preferences of two closely related taxa, one extant and one extinct. Dromaius eggshell delta(15)N values show a significant shift to higher values during the Last Glacial Maximum and Holocene, which we interpret to indicate more frequent arid conditions (<200 mm MAP), relative to delta(15)N from samples just prior to the megafauna extinction. Genyornis eggshells had delta(15)N values reflecting wetter nesting conditions overall relative to those of coeval Dromaius, perhaps indicating that Genyornis was more reliant on mesic conditions. Lastly, the Dromaius eggshell record shows a significant decrease in delta(13)C values prior to the extinction, whereas the Genyornis record does not. Neither species showed a concomitant change in delta(15)N prior to the extinction, which suggests that a significant change in vegetation surrounding Lake Eyre occurred prior to an increase in local aridity. PMID- 21706335 TI - Pollen vacuoles and their significance. AB - Vacuoles of several types can be observed in pollen throughout its development. Their physiological significance reflects the complexity of the biological process leading to functional pollen grains. Vacuolisation always occurs during pollen development but when ripe pollen is shed the extensive translucent vacuoles present in the vegetative parts in previous stages are absent. Vacuole functions vary according to developmental stage but in ripe pollen they are mainly storage sites for reserves. Vacuoles cause pollen to increase in size by water accumulation and therefore confer some degree of resistance to water stress. Modalities of vacuolisation occur in pollen in the same manner as in other tissues. In most cases, autophagic vacuoles degrade organelles, as in the microspore after meiosis, and can be regarded as cytoplasm clean-up following the transition from the diploid sporophytic to the haploid gametophytic state. This also occurs in the generative cell but not in sperm cells. Finally, vacuoles have a function when microspores are used for pollen embryogenesis in biotechnology being targets for stress induction and afterwards contributing to cytoplasmic rearrangement in competent microspores. PMID- 21706336 TI - Characterization of chromoplasts and carotenoids of red- and yellow-fleshed papaya (Carica papaya L.). AB - Chromoplast morphology and ultrastructure of red- and yellow-fleshed papaya (Carica papaya L.) were investigated by light and transmission electron microscopy. Carotenoid analyses by LC-MS revealed striking similarity of nutritionally relevant carotenoid profiles in both the red and yellow varieties. However, while yellow fruits contained only trace amounts of lycopene, the latter was found to be predominant in red papaya (51% of total carotenoids). Comparison of the pigment-loaded chromoplast ultrastructures disclosed tubular plastids to be abundant in yellow papaya, whereas larger crystalloid substructures characterized most frequent red papaya chromoplasts. Exclusively existent in red papaya, such crystalloid structures were associated with lycopene accumulation. Non-globular carotenoid deposition was derived from simple solubility calculations based on carotenoid and lipid contents of the differently colored fruit pulps. Since the physical state of carotenoid deposition may be decisive regarding their bioavailability, chromoplasts from lycopene-rich tomato fruit (Lycopersicon esculentum L.) were also assessed and compared to red papaya. Besides interesting analogies, various distinctions were ascertained resulting in the prediction of enhanced lycopene bioavailability from red papaya. In addition, the developmental pathway of red papaya chromoplasts was investigated during fruit ripening and carotenogenesis. In the early maturation stage of white fleshed papaya, undifferentiated proplastids and globular plastids were predominant, corresponding to incipient carotenoid biosynthesis. Since intermediate plastids, e.g., amyloplasts or chloroplasts, were absent, chromoplasts are likely to emerge directly from proplastids. PMID- 21706337 TI - Development of the Casparian strip is delayed by blue light in pea stems. AB - To understand the regulatory mechanisms involved in tissue development by light, the kinetics of regulation of Casparian strip (CS) development in garden pea stems was studied. We found that short-term irradiation with white light delayed the development of the CS and used this delay to assess the quantitative effect of light on CS development. We examined the effect of the duration and fluence rates of white light treatment on CS development and observed a significant relationship between fluence and the delay in CS development indicating that the Bunsen-Roscoe law of reciprocity holds for this response. The effect of white light irradiation was not inhibited in the presence of a photosynthetic inhibitor, DCMU, or a carotenoid biosynthesis inhibitor, Norflurazon, indicating that the delay in CS development by light is a photomorphogenetic response rather than a subsidiary effect mediated by photosynthetic activity. An action spectrum for the response displayed a major peak in the blue-light region, suggesting a dominant role for blue-light receptors. A minor peak in the red-light region also suggested the possible involvement of phytochromes. Although phytochromes are known to contribute to blue-light responses, phytochrome-deficient mutants showed a normal delay of CS development in response to blue light, indicating that the response is not mediated by phytochrome and suggesting a role for one or more specific blue-light receptors. PMID- 21706338 TI - Influence of ascorbic acid on the activity of the investigational anticancer drug KP1019. AB - Ascorbic acid has been previously discussed to have antitumor potential through its interaction with transition metal ions such as iron and copper. Furthermore, ascorbic acid may act as a reducing agent for Ru(III) compounds such as indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019), an investigational anticancer drug which is supposed to be activated by reduction, prior to binding to cellular target proteins. Therefore, we investigated the influence of ascorbic acid on the activity of this antitumor metal complex in cell culture studies. We show that co-incubation of equicytotoxic, constant amounts of KP1019 with high concentrations of ascorbic acid (50-700 MUM) increases cytotoxicity of the ruthenium anticancer drug in the human colon carcinoma cell line SW480, human cervical carcinoma KB-3-1 cells, and the multidrug-resistant subline KBC-1, whereas addition of low concentrations (2.7-50 MUM) has a strong chemoprotective effect in the human colon carcinoma cell line SW480, but not in multidrug-resistant KBC-1 cells. Although cellular uptake of KP1019 is not altered, ascorbic acid induce stronger interaction of the ruthenium compound with DNA both in SW480 cells and under cell-free conditions with plasmid DNA. Even if DNA interactions probably play a subordinate role in vivo given the extensive protein binding of the compound, our data exemplify that ascorbic acid enhances the reactivity of KP1019 with biomolecules. Moreover, we demonstrate that the levels of KP1019-generated reactive oxygen species are markedly decreased by co-incubation with ascorbic acid. Conclusively, our results indicate that application of high doses of ascorbic acid might increase the anticancer effects of KP1019. PMID- 21706339 TI - Neoplastic disorders of prostate glands in the light of synchrotron radiation and multivariate statistical analysis. AB - The prostate gland is the most common site of neoplastic disorders in men. The pathogenesis of inflammatory cells, prostatic intraepithelial neoplasia (PIN) lesions, and prostate cancer is still under investigation. Inflammatory cells by producing free radicals are considered as major and universal contributors to cancerogenesis. PIN is regarded as a precursor lesion to prostate cancer or a marker signaling the vulnerability of the epithelium to neoplastic transformation [1]. Differentiation markers that are frequently changed in early invasive carcinoma are also changed in PIN lesions. In this study, prostate tissue samples obtained during surgical operation and classified as various disease states (inflammation, PIN lesions, and cancer) were examined. The samples were measured by means of microbeam synchrotron-radiation-induced X-ray emission (micro-SRIXE). Special attention was paid to examine the relationship between the earlier mentioned disorders and changes in relative concentrations of S, K, Ca, Fe, Cu, and Zn. Applying the image-processing program ImageJ enabled us to select the areas of interest from two-dimensional maps of various prostate samples according to the histopathologist's evaluation. Detailed analysis of micro-SRIXE spectra based on multivariate methods shows significant differences between elemental concentrations in inflammatory cells, PIN lesions, and cancerous tissues, which confirms that this method can be used to distinguish various pathological states in prostate tissues. Information obtained in this way may provide better understanding of the biochemistry of unhealthy prostate tissues, thus opening the way to find new medicines/treatments to prevent or slow down some harmful intracellular processes. PMID- 21706340 TI - A unique genome-wide association analysis in extended Utah high-risk pedigrees identifies a novel melanoma risk variant on chromosome arm 10q. AB - Only two genome-wide association (GWA) screens have been published for melanoma (Nat Genet 47:920-925, 2009; Nat Genet 40:838-840, 2008). Using a unique approach, we performed a genome-wide association study in 156 related melanoma cases from 34 high-risk Utah pedigrees. Genome-wide association analysis was performed on nearly 500,000 markers; we compared cases to 2,150 genotypically matched samples from Illumina's iControls database. We performed genome-wide association with EMMAX software, which is designed to account for population structure, including relatedness between cases. Three SNPs exceeded a genome-wide significance threshold of p < 5 * 10(-8) on chromosome arm 10q25.1 (rs17119434, rs17119461, and rs17119490), where the most extreme p value was 7.21 * 10(-12). This study represents a new and unique approach to predisposition gene identification; and it is the first genome-wide association study performed in related cases in high-risk pedigrees. Our approach illustrates an example of using high-risk pedigrees for the identification of new melanoma predisposition variants. PMID- 21706342 TI - Personalized medicine: new genomics, old lessons. AB - Personalized medicine uses traditional, as well as emerging concepts of the genetic and environmental basis of disease to individualize prevention, diagnosis and treatment. Personalized genomics plays a vital, but not exclusive role in this evolving model of personalized medicine. The distinctions between genetic and genomic medicine are more quantitative than qualitative. Personalized genomics builds on principles established by the integration of genetics into medical practice. Principles shared by genetic and genomic aspects of medicine, include the use of variants as markers for diagnosis, prognosis, prevention, as well as targets for treatment, the use of clinically validated variants that may not be functionally characterized, the segregation of these variants in non Mendelian as well as Mendelian patterns, the role of gene--environment interactions, the dependence on evidence for clinical utility, the critical translational role of behavioral science, and common ethical considerations. During the current period of transition from investigation to practice, consumers should be protected from harms of premature translation of research findings, while encouraging the innovative and cost-effective application of those genomic discoveries that improve personalized medical care. PMID- 21706343 TI - Closure of population biobanks and direct-to-consumer genetic testing companies. AB - Genetic research gained new momentum with the completion of the Human Genome Project in 2003. Formerly centered on the investigation of single-gene disorders, genetic research is increasingly targeting common complex diseases and in doing so is studying the whole genome, the environment and its impact on genomic variation. Consequently, biobanking initiatives have emerged around the world as a tool to sustain such progress. Whether they are small scale or longitudinal, public or private, commercial or non-commercial, biobanks should consider the possibility of closure. Interestingly, while raising important ethical issues, this topic has hardly been explored in the literature. Indeed, ethical issues associated with sale, insolvency, end of funding, or transfer of materials to other entities (which are all issues either related to or possible consequences of closure) are seldom the subject of discussion. In an attempt to fill this gap, this paper will discuss-using population and direct-to-consumer (DTC) genetic testing companies' biobanks as case studies-(1) international and national normative documents addressing the issue of closure and (2) the internal policies of population biobanks and DTC genetic testing companies. The analysis will inform the debate on biobank closure and elucidate the underlying ethical issues, which include, but are not limited to informed consent, storage and privacy. PMID- 21706344 TI - Pregnancy concomitant with metastatic adult granulosa cell tumor. AB - INTRODUCTION: Metastatic adult granulosa cell tumor of the ovary is rarely encountered with pregnancy. CASE REPORT AND RESULTS: Primigravida (26 years) presented at 20 weeks of gestation with acute abdomen and clinical evidence of supraclavicular lymphadenopathy and ascites. She was diagnosed of adult granulosa cell tumor (AGCT) of the right ovary following right salpingoophrectomy done 1 month prior to conception. Fine needle aspiration cytology of supraclavicular lymph node, revealed it to be a metastatic AGCT. Chemotherapy was given antepartum and she delivered a healthy preterm baby at 30 weeks. Subsequently, she had optimal debulking surgery following 6 cycles of cisplatin-based chemotherapy. Baby at 10 months of age was with normal milestones. CONCLUSIONS: The case is an unusual presentation of metastatic adult granulosa cell tumor at child bearing age. Although rapidly progressing, successful prolongation of pregnancy till 30 weeks of gestation was possible with the judicious use of chemotherapy. Fetal and maternal outcomes were favorable. PMID- 21706341 TI - Molecular genetic studies of gene identification for sarcopenia. AB - Sarcopenia, which is characterized by a progressive decrease of skeletal muscle mass and function with aging, is closely related to several common diseases (such as cardiovascular and airway diseases) and functional impairment/disability. Strong genetic determination has been reported for muscle mass and muscle strength, two most commonly recognized and studied risk phenotypes for sarcopenia, with heritability ranging from 30 to 85% for muscle strength and 45 90% for muscle mass. Sarcopenia has been the subject of increasing genetic research over the past decade. This review is designed to comprehensively summarize the most important and representative molecular genetic studies designed to identify genetic factors associated with sarcopenia. We have methodically reviewed whole-genome linkage studies in humans, quantitative trait loci mapping in animal models, candidate gene association studies, newly reported genome-wide association studies, DNA microarrays and microRNA studies of sarcopenia or related skeletal muscle phenotypes. The major results of each study are tabulated for easy comparison and reference. The findings of representative studies are discussed with respect to their influence on our present understanding of the genetics of sarcopenia. This is a comprehensive review of molecular genetic studies of gene identification for sarcopenia, and an overarching theme for this review is that the currently accumulating results are tentative and occasionally inconsistent and should be interpreted with caution pending further investigation. Consequently, this overview should enhance recognition of the need to validate/replicate the genetic variants underlying sarcopenia in large human cohorts and animal. We believe that further progress in understanding the genetic etiology of sarcopenia will provide valuable insights into important fundamental biological mechanisms underlying muscle physiology that will ultimately lead to improved ability to recognize individuals at risk for developing sarcopenia and our ability to treat this debilitating condition. PMID- 21706345 TI - Effects of intravaginal estriol and pelvic floor rehabilitation on urogenital aging in postmenopausal women. AB - PURPOSE: To assess the effects of the combination of pelvic floor rehabilitation and intravaginal estriol administration on stress urinary incontinence (SUI), urogenital atrophy and recurrent urinary tract infections in postmenopausal women. METHODS: Two-hundred-six postmenopausal women with urogenital aging symptoms were enrolled in this prospective randomized controlled study. Patients were randomly divided into two groups and each group consisted of 103 women. Subjects in the treatment group received intravaginal estriol ovules, such as 1 ovule (1 mg) once daily for 2 weeks and then 2 ovules once weekly for a total of 6 months as maintenance therapy plus pelvic floor rehabilitation. Subjects in the control group received only intravaginal estriol in a similar regimen. We evaluated urogenital symptomatology, urine cultures, colposcopic findings, urethral cytologic findings, urethral pressure profiles and urethrocystometry before, as well as after 6 months of treatment. RESULTS: After therapy, the symptoms and signs of urogenital atrophy significantly improved in both groups. 61/83 (73.49%) of the treated patients, and only 10/103 (9.71%) of the control patients referred a subjective improvement of their incontinence. In the patients treated by combination therapy with estriol plus pelvic floor rehabilitation, we observed significant improvements of colposcopic findings, and there were statistically significant increases in mean maximum urethral pressure (MUP), in mean urethral closure pressure (MUCP), as well as in the abdominal pressure transmission ratio to the proximal urethra (PTR). CONCLUSIONS: Our results showed that combination therapy with estriol plus pelvic floor rehabilitation was effective and should be considered as a first-line treatment for symptoms of urogenital aging in postmenopausal women. PMID- 21706346 TI - Glomerulonephritis with crescents among adult Saudi patients outcome and its predictors. AB - The aim of this study is to investigate the clinical and pathological features and outcome of glomerulonephritis with crescents among adult patients. This is a retrospective study of all cases of crescentic GN seen over a 9-year period (2001 2010). Histological features were assessed, and renal function at baseline and end of follow-up period was recorded. Results among different etiological groups at baseline and end of follow-up period were compared. The mean age in the whole group was 35.6 years (16.2), with the lowest mean in the lupus nephritis (LN) group [27.7 years (9.9)] and the highest in the pauciimmune glomerulonephritis (PIGN) group (P = 0.001). There were 72 cases enrolled in the study. LN accounted for 49.3% of the cases, PIGN for 26.5%, other immune complex glomerulonephritis (ICGN) for 19% and post-infectious GN accounted for 6.3% The majority (85.7%) of the patients had renal impairment at presentation (mean serum creatinine levels were 247 (85) MUmol/l, 412 (75) MUmol/l and 230 (141) MUmol/l in LN, PICN and ICGN, respectively (P = 0.05). Women accounted for 85.3, 76.5 and 36.2% of the patients in LN, PICN and ICGN, respectively (P = 0.025). By the end of the follow up period of 26 (22.9) months, 25.8% of the patients were requiring dialysis (16.70% in the LN group, 50% in PIGN and 25% in ICGN (P = 0.05) and 21.7% had nephrotic range proteinuria (16.7, 1 and 33.3%, respectively (P = 0.4). Using logistic multivariate analysis, the only independent factors found to predict need for dialysis of prognosis were percent of sclerosed glomeruli (P = 0.05) and presence of ATN (P = 0.028). Baseline proteinuria or SCr, gender and number of glomeruli with crescents, on the other hand, did not impact prognosis. Using linear regression multivariate analysis, SCr, protein excretion and activity score at biopsy did not influence change in SCr or final SCr during the follow-up period. Using ANOVA to compare the groups of LN, PIGN and ICGN), we found significant differences only in gender between LN and ICGN (P = 0.035), in percent glomerular global sclerosis (between LN and PIGN (P = 0.007) and between LN and ICGN (P = 0.012) and in age (between LN and PIGN (P = 0.006). Almost half of our patients with CrGN were due to LN which is higher than that reported by others where PIGN was the more prevalent etiology. Patients with PICN were older and had worse prognosis. This could be explained by the higher number of globally sclerosed glomeruli in the PIGN group. PMID- 21706347 TI - Cell growth arrest and apoptosis induced by Oct4 or Nanog knockdown in mouse embryonic stem cells: a possible role of Trp53. AB - It has been clear that both Oct4 and Nanog play essential roles in maintaining embryonic stem cells (ESCs) undifferentiation. However, the roles of Oct4 and Nanog in ESCs growth and apoptosis have been much less explored. In this study, we systematically examined the effects of Oct4 or Nanog knockdown on mouse ESCs (mESCs) growth and apoptosis as well as potential mechanisms. Our results show that Oct4 or Nanog knockdown induces growth arrest and apoptosis in mESCs, indicating that the two genes also play important roles in mESCs survival and growth. Moreover, upregulation in Trp53 and its downstream genes expression was detected in Oct4 or Nanog knockdown mESCs, suggesting a possible role of Trp53 in Oct4 or Nanog knockdown induced mESCs growth arrest and apoptosis. PMID- 21706348 TI - The association between the PTPN22 C1858T polymorphism and rheumatoid arthritis: a meta-analysis update. AB - The aim of this study was to determine whether the protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. A meta-analysis was conducted on the PTPN22 C1858T polymorphism involving eighteen studies, which in total contained 20344 RA patients and 21828 controls. Meta-analysis revealed an association between the PTPN22 C1858T polymorphism T allele and RA in all subjects (odds ratio [OR] = 1.637, 95% confidence interval [CI] = 1.514-1.770, P < 0.001). After stratification by ethnicity, analysis indicated that the PTPN22 C1858T polymorphism T allele was significantly associated with RA in Europeans and Non-Europeans (OR = 1.587, 95% CI = 1.486-1.696, P < 0.001; OR = 1.748, 95% CI = 1.274-2.398, P < 0.001). Meta-analysis of the CT + TT genotype showed the same result patterns as that shown by the PTPN22 C1858T polymorphism T allele. Furthermore, a direct comparison between rheumatoid factor (RF)-positive and negative subjects revealed a significant association with the T allele in RA patients with RF, but not in subjects without RF. In conclusion, this meta analysis confirms that the PTPN22 C1858T polymorphism is associated with RA susceptibility in different ethnic groups, especially in Europeans, and the PTPN22 C1858T polymorphism T allele is significantly more prevalent in RF positive patents than in RF-negative patients. PMID- 21706349 TI - Characterization, and expression profile of a phenylalanine ammonia lyase gene from Jatropha curcas L. AB - A PAL gene designated as JcPAL1 was cloned from J. curcas L. The full-length is 2336 bp in size with one intron and two exons, encoding a polypeptide of 713 amino acids. Its 5'-upstream region is rich in putative cis-elements including not only PAL typical TATA box, L-box and transcriptional initiation site (TIS) but also light responding motifs. Expression pattern analysis indicated that JcPAL1 were expressed in all tissues, most highly in flowers. When Treated with ABA, GA3, high and low temperature, expression of JcPAL1 were induced. Recombinant JcPAL1 has a pH optimum at 8.7 and a temperature optimum at 60 degrees C in 100 mM Tris-HCl buffer. The Km and Kcat values are 0.125 mM and 1.73 S(-1) for L: -phenylalanine, and 1.312 mM and 0.109 S(-1) for L: -tyrosine, respectively. These findings suggested that JcPAL1 might involve in the J. curcas responding to various stresses and L: -Phe should be its true physiological substrate. This study is essential prior to uncover whether and how the PAL initiated phenylpropanoid metabolic networks functioning in the defense responses of J. curcas. PMID- 21706350 TI - Differentially expressed three non-coding alternate exons at 5' UTR of regulatory type I beta subunit gene of mouse. AB - Prkar1b gene encodes regulatory type I, beta subunit (RIbeta) of cAMP dependent protein kinase A in mouse. Among the various isoforms of regulatory and catalytic subunits that comprise mammalian PKA, RIbeta subunit is considered to be one of the important subunits for neuronal functions. This is involved in multiple forms of synaptic plasticity, and influences memory and learning by maintaining hippocampal long-term potentiation (LTP). Deficient expression of this gene has been implicated in autoimmune disease systemic lupus erythematosus (SLE). We have identified two novel non-coding exons of the Prkar1b gene (designated as exon 1A and exon 1B), which are spliced to the canonical exon 2 and constitute the 5' untranslated region giving rise to three alternative transcript isoforms. We have also confirmed the expression of the previously known first exon (designated as exon 1C) with known transcript published earlier. The transcripts containing exons 1A, 1B and 1C are differentially regulated during the development and tissue types. In silico study of more than 20 kb nucleotide sequence upstream of known translational initiation codon revealed three distinct promoter regions named as PA, PB, and PC upstream of the exon 1A, exon 1B and exon 1C respectively. PB is non-CpG related promoter but PA and PC are CpG related promoters, however all three promoters are TATA less. Further analysis showed that these promoters possess potential signature sequences for common as well as different transcription factors suggesting complex regulation of Prkar1b gene. PMID- 21706351 TI - Transcript expression profiling of stress responsive genes in response to short term salt or PEG stress in sugarcane leaves. AB - Semi-quantitative RT-PCR based transcript expression of stress responsive genes was studied in leaves of sugarcane plants exposed to short-term (up to 24 h) salt (NaCl, 200 mM) or polyethylene glycol-PEG 8000 (20% w/v) stress. Transient increase in expression of NHX (sodium proton antiporter), SUT1 (sucrose transporter1), PDH (proline dhydrogenase) and CAT2 (catalase2) was observed in response to 2-4 h PEG stress. However, salt stress imposed repression of NHX, PDH and CAT2 at these time points. The transcript level of the delta (1)-pyrolline-5 carboxylate synthetase (P5CS) increased slightly in salt treatment while in response to the PEG stress, the gene expression increased at 4 h treatment but then decreased considerably by 80% at 24 h. The results thus indicated differential regulation of these stress responsive genes in response to salt or PEG stress in sugarcane. Further, the transcript expression data was compared with that available for the Arabidopsis homologs at Arabidopsis eFP Browser and Genevestigator V3 tools. Understanding transcript gene expression patterns of the stress responsive genes may provide insights into complex regulatory network of stress tolerance. PMID- 21706352 TI - Initial analysis of the hemocyanin subunit type 1 (Hc1 gene) from Locusta migratoria manilensis. AB - Hemocyanins are copper-containing (Cu(+)) proteins that transport oxygen in many arthropods hemolymph. We characterized Hc1 gene from the grasshopper species Locusta migratoria manilensis. In particular, we cloned and sequenced the corresponding cDNAs and studied their expression at different developmental stages. The cDNA of Hc1 gene (GenBank accession no.:HQ213937) is 2271 bp in length and the open reading frame is 2016 bp, which encodes a 672 amino acids protein with a calculated molecular mass of 77.9 kD and the isoelectric point of 6.06. Sequence alignment analysis result showed that this gene shares 94.7% identity with Schistocerca americana EHP. In addition, analysis of quantitative RT-PCR indicated that, LmiHc1 was expressed in the embyro (24, 39, 62, 86, 144, and 193 h after hatch), nymphs (1st instar, 2nd instar, 3rd instar, 4th instar and 5th instar) and in adult. These results showed that Hc1 plays an important role in grasshopper, which may be related to an enhanced oxygen supply. Phylogenetic analysis of insecta based on Hc1 are basically consistent with the morphology. PMID- 21706353 TI - Proteomic identification of erythrocyte membrane protein deficiency in hereditary spherocytosis. AB - Hereditary spherocytosis (HS) is the most common congenital hemolytic anemia in Caucasians, with an estimated prevalence ranging from 1:2000 to 1:5000. The molecular defect in one of the erythrocytes (RBC) membrane proteins underlying HS like; spectrin-alpha, spectrin-beta, ankyrin, band 3 and protein 4.2 that lead to membrane destabilization and vesiculation, may change the RBCs into denser and more rigid cells (spherocytes), which are removed by the spleen, leading to the development of hemolytic anemia. It is classified as mild, moderate and severe, according to the degree of the hemolytic anemia and the associated symptoms. Two dimensional gel electrophoresis (2-DE) is potentially valuable method for studying heritable disorders as HS that involve membrane proteins. This separation technique of proteins based upon two biophysically unrelated parameters; molecular weight and charge, is a good option in clinical proteomics in terms of ability to separate complex mixtures, display post-translational modifications and changes after phosphorylation. In this study, we have used contemporary methods with some modifications for the solubilisation, separation and identification of erythrocyte membrane proteins in normal and in HS RBCs. Spectrin alpha and beta chain, ankyrin and band 3 proteins expression differences were found with PDQuest software 8.0.1. and peptide mass fingerprinting (PMF) analysis performed for identification of proteins in this study. PMID- 21706354 TI - Vitellogenin induction and reproductive status in wild Chilean flounder Paralichthys adspersus (Steindachner, 1867) as biomarkers of endocrine disruption along the marine coast of the South Pacific. AB - This study evaluated the condition factor, gonadosomatic, and hepatosomatic indexes, occurrence of plasmatic vitellogenin (Vg), and frequency of spermatogenic maturity stages in male Chilean flounders, Paralichthys adspersus, caught at three different coastal sites off the Bio-Bio region, central Chile, during 1 year. The Vg was detected by polyacrylamide gel electrophoresis with sodium dodecyl sulfate and Western blot analyses using an antibody against Chilean flounder Vg. The spermatogenic maturity stages were analyzed by histological gonadic diagnostic. The prevalence of plasmatic Vg induction in male fish differed significantly among sites. The flounders sampled from the Itata area were the most affected. Evaluations of biometric data, plasmatic Vg induction, and spermatogenic maturity stages of the flounder showed the following: (1) lower gonadosomatic index, (2) greater hepatosomatic index, (3) greater prevalence of plasmatic Vg, and (4) delayed development of the gonad. The results suggest that estrogenic endocrine-disruption compounds are introduced into the marine environment, negatively affecting the fish studied. The relevance of this report is discussed in relation to estrogenic compounds introduced by industrial and municipal wastewater effluents in the areas studied. PMID- 21706356 TI - How frequently do allegations of scientific misconduct occur in ecology and evolution, and what happens afterwards? AB - Scientific misconduct obstructs the advance of knowledge in science. Its impact in some disciplines is still poorly known, as is the frequency in which it is detected. Here, I examine how frequently editors of ecology and evolution journals detect scientist misconduct. On average, editors managed 0.114 allegations of misconduct per year. Editors considered 6 of 14 allegations (42.9%) to be true, but only in 2 cases were the authors declared guilty, the remaining being dropped for lack of proof. The annual rate of allegations that were probably warranted was 0.053, although the rate of demonstrated misconduct was 0.018, while the rate of false or erroneous allegations was 0.024. Considering that several cases of misconduct are probably not reported, these findings suggest that editors detect less than one-third of all fraudulent papers. PMID- 21706355 TI - Cytotoxic effect of eugenol on the expression of molecular markers related to the osteogenic differentiation of human dental pulp cells. AB - The cytotoxic effect of eugenol on the expression of molecular markers related to the osteogenic differentiation of human dental pulp cells such as collagen synthesis and the expression of two osteogenesis-related genes, alkaline phosphatase (ALP) and bone sialoprotein (BSP), was studied using human dental pulp cells (D824 cells). Cellular growth and survival were decreased by treatment of cells with eugenol in a concentration-dependent manner. The incorporation rate of [(3)H] proline into the acid-insoluble fraction and the synthesis of type I-V collagens were also reduced by treatment of cells with eugenol in a concentration dependent fashion. The mRNA expression of ALP was scarcely affected in cells exposed to eugenol, whereas the mRNA and protein expression of BSP was down regulated depending on the concentrations of eugenol. The results suggest that because collagen synthesis and BSP expression play a critical role in hard tissue formation, eugenol used for endodontic treatment may give rise to cytotoxic effects to the normal function of stem cells reported to exist in human dental pulp tissue and periodontal ligament. PMID- 21706357 TI - Ethics as a beneficial Trojan horse in a technological society. AB - This article explores the transformation of ethics in a globalizing technological society. After describing some basic features of this society, particularly the primacy it gives to a special type of technical rationality, three specific influences on traditional ethics are examined: (1) a change concerning the notion of value, (2) the decreasing relevance of the concept of axiological hierarchy, and (3) the new internal architecture of ethics as a net of values. These three characteristics suggest a new pragmatic understanding of ethics. From a pragmatic perspective, the process of introducing ethical values into contemporary society can be regarded as a beneficial Trojan horse, a metaphor that will be developed further. PMID- 21706358 TI - Safety of concurrent bevacizumab therapy and anticoagulation in glioma patients. AB - Venous thromboembolic events (VTE) are common in glioma patients and are typically treated with anticoagulant medications. The anti-angiogenic agent bevacizumab (BVZ) increases the risks of both VTE and hemorrhagic complications. Little is known about the hemorrhagic risk of anticoagulation in glioma patients receiving BVZ. We reviewed medical records from 282 BVZ-treated patients at our center and identified 64 who received concurrent anticoagulant therapy. The risk and severity of hemorrhagic complications were assessed. Fisher's exact test was used to compare the risk of hemorrhage between subjects who received and did not receive anticoagulants. Forty-seven patients (73%) had glioblastoma, 15 (23%) anaplastic glioma, and 2 (3%) other tumors. Thirteen (20%) and 51 (80%) patients received warfarin and low-molecular-weight heparin, respectively. The indication for anticoagulation was deep venous thrombosis in 37 patients (58%), pulmonary embolism in 22 (34%), and both in 5 (8%). Thirteen patients (20%) experienced hemorrhage, of which four hemorrhages (6%) were serious (grade >= 3): one patient had grade 5 intracerebral hemorrhage (ICH), one grade 4 ICH, one grade 3 epistaxis, and one grade 3 gastrointestinal hemorrhage. ICH was seen in seven patients (11%), of which five (8%) were grade 1. Among 218 patients who did not receive anticoagulants, there were two (1%) serious hemorrhages (both grade 4 ICH). Both the serious hemorrhage rate and overall ICH rate were higher in patients who received anticoagulants (P = 0.03 and 0.02, respectively). Anticoagulant use during BVZ therapy may increase the risk of hemorrhage in glioma patients, although it is generally well tolerated. PMID- 21706359 TI - Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. AB - Approximately one-third of patients with advanced, HER2-positive breast cancer develop brain metastases. A significant proportion of women experience central nervous system (CNS) progression after standard radiation therapy. The optimal treatment in the refractory setting is undefined. This study evaluated the toxicity and efficacy of lapatinib in combination with chemotherapy among patients with HER2-positive, progressive brain metastases. Patients with HER2 positive breast cancer with progressive brain metastases after trastuzumab and cranial radiotherapy were included. The primary endpoint was CNS objective response, defined as a >= 50% volumetric reduction of CNS lesion(s) in the absence of new or progressive CNS or non-CNS lesions, or increasing steroid requirements. The study was closed early after 22 of a planned 110 patients were enrolled due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm. The objective response rate (ORR) in the lapatinib plus capecitabine arm was 38% (exact 95% confidence interval [CI] 13.9-68.4). No responses were observed in the lapatinib plus topotecan arm. Although the study was stopped prior to full enrollment, some promising indications of CNS activity were noted for lapatinib plus capecitabine. The combination of lapatinib plus topotecan was not active and was associated with excess toxicity. PMID- 21706360 TI - Intervertebral disc changes with angulation, compression and reduced mobility simulating altered mechanical environment in scoliosis. AB - PURPOSE: The intervertebral discs become wedged and narrowed in scoliosis, and this may result from altered biomechanical environment. The effects of four permutations of disc compression, angulation and reduced mobility were studied to identify possible causes of progressive disc deformity in scoliosis. The purpose of this study was to document morphological and biomechanical changes in four different models of altered mechanical environment in intervertebral discs of growing rats and in a sham and control groups. METHODS: External rings were attached by percutaneous pins transfixing adjacent caudal vertebrae of 5-week-old Sprague-Dawley rats. Four experimental Groups of animals underwent permutations of the imposed mechanical conditions (A) 15 degrees disc angulation, (B) angulation with 0.1 MPa compression, (C) 0.1 MPa compression and (R) reduced mobility (N = 20 per group), and they were compared with a sham group (N = 12) and control group (N = 8) (total of 6 groups of animals). The altered mechanical conditions were applied for 5 weeks. Intervertebral disc space was measured from micro-CT images at weeks 1 and 5. Post euthanasia, lateral bending stiffness of experimental and within-animal control discs was measured in a mechanical testing jig and collagen crimp was measured from histological sections. RESULTS: After 5 weeks, micro-CT images showed disc space loss averaging 35, 53, 56 and 35% of the adjacent disc values in the four intervention groups. Lateral bending stiffness was 4.2 times that of within-animal controls in Group B and 2.3 times in Group R. The minimum stiffness occurred at an angle close to the in vivo value, indicating that angulated discs had adapted to the imposed deformity, this is also supported by measurements of collagen crimping at concave and convex sides of the disc annuli. CONCLUSION: Loss of disc space was present in all of the instrumented discs. Thus, reduced mobility, that was common to all interventions, may be a major source of the observed disc changes and may be a factor in disc deformity in scoliosis. Clinically, it is possible that rigid bracing for control of scoliosis progression may have secondary harmful effects by reducing spinal mobility. PMID- 21706361 TI - Surgery improves pain, function and quality of life in patients with spinal metastases: a prospective study on 118 patients. AB - PURPOSE: There are few prospective studies on surgical outcomes and survival in patients with metastatic disease to the spine. The magnitude and duration of effect of surgery on pain relief and quality of life remains uncertain. Therefore, the aim of this clinical study was to prospectively evaluate clinical, functional, quality of life and survival outcomes after palliative surgery for vertebral metastases. METHODS: 118 consecutive patients who underwent spinal surgery for symptomatic vertebral metastases were prospectively followed up for 12 months or until death. Clinical data and data from the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire were obtained pre- and post-operatively and at regular follow-up intervals. RESULTS: Surgery was effective in achieving rapid improvement in axial and radicular pain, neurological deficit, sphincteric dysfunction and ambulatory status, with a complication rate of 26% and a 12 month mortality rate of 48%. Almost 50% of patients had complete resolution of back pain, radiculopathy and neurological deficit. Of the patients who were non-ambulant and incontinent, over 50% regained ambulatory ability and recovered urinary continence. The overall incidence of wound infection or breakdown was 6.8% and the local recurrence rate was 8.5%. There was a highly significant improvement in physical, role, cognitive and emotional functioning and global health status post-operatively. Greatest improvement in pain, function and overall quality of life occurred in the early post-operative period and was maintained until death or during the 12 month prospective follow-up period. CONCLUSION: The potential for immediate and prolonged improvement in pain, function and quality of life in patients with symptomatic vertebral metastases should be considered during the decision-making process when selecting and counselling patients for surgery. PMID- 21706362 TI - Dyadic goal appraisal during treatment for infertility: how do different perspectives relate to partners' adjustment? AB - BACKGROUND: Infertility often is a dyadic stressor that constitutes blockage of a major life goal. PURPOSE: This study's primary aims were to examine heterosexual partners' goal appraisals during treatment for infertility and to test whether the direct effects of and interactions between partners' goal-related perceptions were associated with each partner's adjustment. METHOD: Women (n = 37) receiving fertility treatment and their male partners (n = 37) completed measures of goal appraisal and psychological adjustment. RESULTS: Partners did not differ on ratings of the importance of the goal of parenthood, but women indicated lower perceived chance of becoming pregnant and higher perceived goal blockage than their partners. Goal appraisals were moderately correlated between partners and uncorrelated with the number of treatment procedures undergone by the couple. Women reported greater depressive symptoms, more infertility-specific thought intrusion, and lower positive states of mind than their partners. Women's appraisal of greater likelihood of becoming pregnant was psychologically protective, but greater perceived likelihood of becoming pregnant reported by their partners was associated with women's negative psychological adjustment. CONCLUSION: Examining the associations between couples' goal appraisals and psychological adjustment may aid in developing targeted interventions to promote psychological adjustment to infertility. The small sample may have prevented identifying interactions between partners' goal assessment measures. PMID- 21706363 TI - Feasibility of referral of patients with elevated blood pressure from the Emergency Department. AB - Recent studies suggest that patients' elevated blood pressure (BP) readings in the Emergency Department (ED) may be due to hypertension (HTN) rather than pain and anxiety. Identifying BP patterns suggestive of HTN in the ED presents an opportunity for referral. The purpose of this prospective cohort study was to assess the feasibility of referral of ED patients with elevated BP readings suggestive of HTN. Adults with elevated BP suggestive of HTN and no history of HTN were tracked as to referral status using an actively monitored ED referral system. Patients referred to a community clinic network were tracked regarding clinic visits, subsequent BP, and diagnosis of HTN. Of 662 patients with elevated BP in the ED at triage, 197 (29.8%) had a pattern of blood pressure readings that were suggestive of HTN. Of these, 63 (32.0%) were referred to in-network clinics, 5 (2.5%) were referred out of network, and 129 (65.5%) were not referred. Of the 63 referred to network clinics, 17 (27.0%) kept their appointments and of those, 5 (29.4%) were diagnosed with HTN. Elevated BP was not mentioned in any ED physician referral notes as a reason for referral and the number of appointments kept among patients who were referred was low. Referral to outpatient clinics based on BP levels suggestive of HTN may not be feasible despite active referral systems. PMID- 21706365 TI - Transplantation of neural stem cells overexpressing cardiotrophin-1 inhibits sprouting of hippocampal mossy fiber in a rat model of status epilepticus. AB - In this study, we studied the effects of hippocampal transplantation of neural stem cells (NSCs) overexpressing cardiotrophin 1 (CT1) on hippocampal mossy fiber sprouting (MFS) in a rat model of status epilepticus (SE). SE rats (lithium pilocarpine model) were randomized into four study groups (18 rats per group): CT1-NSCs group, NSCs group, SE control group, and normal control group. Six rats were randomly chosen from each group at 1, 4, and 8 weeks after transplantation. MFS in hippocampal dentate gyrus was scored (Timm staining) at these time points. The MFS scores were as follows: CT1-NSCs 0.77 +/- 0.04, 2.48 +/- 0.89, and 2.39 +/- 0.82 (1, 4, and 8 weeks after transplantation, respectively); NSCs 1.12 +/- 0.62, 3.17 +/- 0.64, and 3.88 +/- 0.51; SE control 1.32 +/- 0.35, 3.28 +/- 0.75, and 4.32 +/- 1.55; and normal control 0.37 +/- 0.06, 0.34 +/- 0.07, and 0.43 +/- 0.04. Compared to SE control group and NSCs group, the scores of MFS in CT1-NSCs group were significantly lower (P < 0.05). In conclusion, transplantation with NSCs overexpressing CT1 inhibits hippocampal MFS and facilitates reduction of recurrent seizures. PMID- 21706366 TI - Individual management of recurrent intracranial aneurysms: the Wuxi experience. AB - Recurrent intracranial aneurysms can occur after either surgical clipping or endovascular therapy. In this article, we present a consecutive series of 18 patients who underwent individual treatment for recurrent aneurysms after primary coil embolization or surgical clipping. During an 8-year period between May 1997 and December 2005, 18 patients underwent individual treatment for recurrent aneurysms. Clinical data and imaging studies of the patients were analyzed retrospectively. Out of the 18 patients, 13 had recurrent aneurysms located in the anterior circulation, and 5 had aneurysms of the posterior circulation. Treatment consisted of coiling in 16 patients and clipping in two patients. Of the 18 patients, 15 achieved a good or excellent recovery, two were paralyzed, and one died post-treatment. Both the surgical clipping and endovascular embolization for the treatment of recurrent intracranial aneurysms can achieve very good radiological results with low mortality rates. One of the key points for the successful treatment of this kind of lesions is the proper, individual, and interdisciplinary patient selection. PMID- 21706367 TI - Elevated content of osteopontin in plasma and tumor tissues of patients with laryngeal and hypopharyngeal carcinoma associated with metastasis and prognosis. AB - The aim of this study was to evaluate the usefulness of osteopontin (OPN) expression level in plasma and tumor tissues of patients with laryngeal and hypopharyngeal squamous-cell carcinoma for predicting metastasis and survival of this tumor. The OPN expression in tumor tissues was detected by immunohistochemical staining in a tissue microarray of laryngeal and hypopharyngeal carcinomas, and the OPN level in plasma was measured by ELISA. The expression levels of OPN in plasma and tumor tissues were associated with clinicopathological features and survival of laryngeal and hypopharyngeal carcinomas. Results showed that the OPN expression quantitation either in tissues or plasma was significantly correlated with differentiation and lymphatic metastasis of the laryngeal and hypopharyngeal carcinoma. Elevated OPN level of plasma and tissues was significantly associated with poor survival. In conclusion, elevated OPN level in plasma and tumor tissues was significantly associated with metastasis and survival of laryngeal and hypopharyngeal carcinomas. Elevated OPN level in plasma and tumor tissues may become a useful indicator of prognosis for laryngeal and hypopharyngeal cancers. PMID- 21706368 TI - Neoadjuvant concurrent chemoradiotherapy with capecitabine and oxaliplatin in patients with locally advanced esophegeal cancer. AB - Evaluation of the feasibility and efficacy of neoadjuvant concurrent chemoradiotherapy (CRT) with capecitabine and oxaliplatin in patients with locally advanced esophageal cancer. Forty-two patients were eligible for the study. The chemotherapy during CRT consisted of two cycles of intravenous oxaliplatin of 120 mg/m(2) on day 1 and oral capecitabine 825 mg/m(2) twice daily on days 1-14 at 3-week intervals. The radiotherapy (1.8 Gy/fraction/day to a total dose of 45 Gy) was delivered to the primary tumor site and regional lymph node. All patients completed the planned treatment. Overall clinical response rate was 54.8% with complete response in 16.7% while pathological response rate was 38%. Anemia was the commonest hematologic toxicity (52.3%) with grade 3 in 4.7%, and esophagitis was the commonest non-hematologic toxicity 59.5% with grade 3 and 4 in 9.5%. No treatment-related death was observed. After a median follow up duration of 19 months, the 2-year survival rate was 42%, median survival time was 20 months (95%CI: 13.802-26.198), while 2-year progression-free survival (PFS) rate was 32.5% with median PFS time of 15 months (95%CI: 10.042-19.958). Neoadjuvant concurrent CRT with capecitabine and oxaliplatin was found to be well tolerated and effective in patients with locally advanced esophageal cancer; however, these results should be further evaluated in a phase III study. PMID- 21706371 TI - Abandonment of newborn infants: a Danish forensic medical survey 1997-2008. AB - Concealment of pregnancy and newborn infant abandonment are closely associated with neonaticide, the killing of an infant within the first 24 h of life or less than 28-30 days depending on the jurisdiction. Abandonment of newborn infants occurs throughout the world and often the outcome for the infant is death. Together with neonaticide it is felt to be one of the least preventable crimes. In this retrospective study we present all forensically known Danish cases of abandoned newborn infant corpses, covering the period from 1997 to 2008. Eleven newborn infant corpses were found; we registered characteristics of the newborn infants and the circumstances of the cases based on autopsy reports. One further newborn infant was included, dating back to 1992, as it was found to be connected with one of the later cases. The mean age of the women who abandoned their newborn infants was 22 years, and five of the autopsied newborn infants were probably alive when abandoned. In two cases the newborn infants were half siblings and abandoned by the same mother. The time span from abandonment to when the newborn infant was found ranged from hours to 7 years. Two-thirds of the newborn infants were girls (66.6%). The most common means of disposal was in a plastic bag (~60%); only one newborn infant was wearing clothes when found. Causes of death were usually given as asphyxia, brain injury or simply undetermined. Two-thirds of the newborn infants showed signs of violence. None of the newborn infants had congenital malformations. PMID- 21706373 TI - Diffuse infiltrative syphilitic retinitis in an HIV-positive patient. PMID- 21706372 TI - Flexible bacterial strains that oxidize arsenite in anoxic or aerobic conditions and utilize hydrogen or acetate as alternative electron donors. AB - Arsenic is a carcinogenic compound widely distributed in the groundwater around the world. The fate of arsenic in groundwater depends on the activity of microorganisms either by oxidizing arsenite (As(III)), or by reducing arsenate (As(V)). Because of the higher toxicity and mobility of As(III) compared to As(V), microbial-catalyzed oxidation of As(III) to As(V) can lower the environmental impact of arsenic. Although aerobic As(III)-oxidizing bacteria are well known, anoxic oxidation of As(III) with nitrate as electron acceptor has also been shown to occur. In this study, three As(III)-oxidizing bacterial strains, Azoarcus sp. strain EC1-pb1, Azoarcus sp. strain EC3-pb1 and Diaphorobacter sp. strain MC-pb1, have been characterized. Each strain was tested for its ability to oxidize As(III) with four different electron acceptors, nitrate, nitrite, chlorate and oxygen. Complete As(III) oxidation was achieved with both nitrate and oxygen, demonstrating the novel ability of these bacterial strains to oxidize As(III) in either anoxic or aerobic conditions. Nitrate was only reduced to nitrite. Different electron donors were used to study their suitability in supporting nitrate reduction. Hydrogen and acetate were readily utilized by all the cultures. The flexibility of these As(III)-oxidizing bacteria to use oxygen and nitrate to oxidize As(III) as well as organic and inorganic substrates as alternative electron donors explains their presence in non-arsenic contaminated environments. The findings suggest that at least some As(III) oxidizing bacteria are flexible with respect to electron-acceptors and electron donors and that they are potentially widespread in low arsenic concentration environments. PMID- 21706374 TI - Ceruloplasmin protects against rotenone-induced oxidative stress and neurotoxicity. AB - To clarify the neuroprotective property of ceruloplasmin and the pathogenesis of aceruloplasminemia, we generated ceruloplasmin-deficient (CP-/-) mice on the C57BL/10 genetic background and further treated them with a mitochondrial complex I inhibitor, rotenone. There was no iron accumulation in the brains of CP-/- mice at least up to 60 weeks of age. Without rotenone treatment, CP-/- mice showed slight motor dysfunction compared with CP+/+ mice, but there were no detectable differences in the levels of oxidative stress markers between these two groups. A low dose of rotenone did not affect the mitochondrial complex I activity in our mice, however, it caused a significant change in motor behavior, neuropathology, or the levels of oxidative stress markers in CP-/- mice, but not in CP+/+ mice. Our data support that ceruloplasmin protects against rotenone-induced oxidative stress and neurotoxicity, probably through its antioxidant properties independently of its function of iron metabolism. PMID- 21706376 TI - Plasma ceruloplasmin ferroxidase activity correlates with the nigral sonographic area in Parkinson's disease patients: a pilot study. AB - Increased area of the substantia nigra (SN) associated to iron deposition has been proposed as a specific marker for Parkinson's disease (PD). Echogenicity, assessed by transcranial sonography (TCS), has been used to measure such an iron deposition. On the other hand, ferroxidase activity is known to play a role in brain iron metabolism and thus could be involved in increased SN echogenicity of PD patients. The present study was conducted to search for a possible correlation between both markers: TCS of SN and plasma ferroxidase activity. Twenty-one PD patients and 13 healthy volunteers (HV) were included. Mean SN sonographic areas were 0.31 cm2 for PD patients and 0.12 cm2 for HV (P < 0.001), while plasma ferroxidase activity was reduced in PD patients (P < 0.001). Interestingly, plasma ferroxidase activity was inversely correlated with the SN size by TCS (R2 = 0.31), suggesting a relationship between the two markers. PMID- 21706375 TI - Expression of cholinergic, insulin, vitamin D receptors and GLUT 3 in the brainstem of streptozotocin induced diabetic rats: effect of treatment with vitamin D3. AB - Complications arising from diabetes mellitus include cognitive deficits, neurophysiological and structural changes in the brain. The current study investigated the expression of cholinergic, insulin, Vitamin D receptor and GLUT 3 in the brainstem of streptozotocin-induced diabetic rats. Radioreceptor binding assays and gene expression were done in the brainstem of male Wistar rats. Our results showed that B(max) of total muscarinic, muscarinic M3 receptors was increased and muscarinic M1 receptor was decreased in diabetic rats compared to control. A significant increase in gene expression of muscarinic M3, alpha7 nicotinic acetylcholine, insulin, Vitamin D3 receptors, acetylcholine esterase, choline acetyl transferase and GLUT 3 were observed in the brainstem of diabetic rats. Immunohistochemistry studies of muscarinic M1, M3 and alpha7 nicotinic acetylcholine receptors confirmed the gene expression at protein level. Vitamin D3 and insulin treatment reversed diabetes-induced alterations to near control. This study provides an evidence that diabetes can alter the expression of cholinergic, insulin, Vitamin D receptors and GLUT 3 in brainstem. We found that Vitamin D3 treatment could modulate the Vitamin D receptors and plays a pivotal role in maintaining the glucose transport and expressional level of cholinergic receptors in the brainstem of diabetic rats. Thus, our results suggest a therapeutic role of Vitamin D3 in managing neurological disorders associated with diabetes. PMID- 21706377 TI - Modeling of the neurovascular coupling in epileptic discharges. AB - Despite the interest in simultaneous EEG-fMRI studies of epileptic spikes, the link between epileptic discharges and their corresponding hemodynamic responses is poorly understood. In this context, biophysical models are promising tools for investigating the mechanisms underlying observed signals. Here, we apply a metabolic-hemodynamic model to simulated epileptic discharges, in part generated by a neural mass model. We analyze the effect of features specific to epileptic neuronal activity on the blood oxygen level dependent (BOLD) response, focusing on the issues of linearity in neurovascular coupling and on the origin of negative BOLD signals. We found both sub- and supra-linearity in simulated BOLD signals, depending on whether one observes the early or the late part of the BOLD response. The size of these non-linear effects is determined by the spike frequency, as well as by the amplitude of the excitatory activity. Our results additionally indicate a minor deviation from linearity at the neuronal level. According to a phase space analysis, the possibility to obtain a negative BOLD response to an epileptic spike depends on the existence of a long and strong excitatory undershoot. Moreover, we strongly suggest that a combined EEG-fMRI modeling approach should include spatial assumptions. The present study is a step towards an increased understanding of the link between epileptic spikes and their BOLD responses, aiming to improve the interpretation of simultaneous EEG-fMRI recordings in epilepsy. PMID- 21706379 TI - Biodiversity conservation, ecosystem services and livelihoods in tropical landscapes: towards a common agenda. AB - Trade-offs between ecosystem conservation and agricultural production can more easily be addressed by shifting the view from the plot scale to the scale of the landscape and integrating biodiversity friendly land use systems into development strategies. The provision of ecosystem services such as watershed protection and carbon sequestration by natural and complex agro-ecosystems can play an important role in making such integrated landscape approaches viable. This special issue brings together papers that were presented at a symposium on agroforestry and landscape scale conservation at the Second World Agroforestry Congress in Nairobi in August 2009. It is divided into two sections focusing on: (1) the biological mechanisms and implications of landscape scale conservation strategies as influenced by land use, especially agroforestry; and (2) the economic drivers and public policies that determine to a large extent the success of agroforestry based landscape conservation strategies. The contributions provide evidence both for the potential and limitations of agroforestry in landscape scale conservation and development strategies and highlight the importance of economic incentives and policies to promote integrated landscape solutions. This introductory paper summarizes and discusses the contributions and concludes with policy recommendations and research needs. PMID- 21706378 TI - Semiparametric estimation of treatment effect with time-lagged response in the presence of informative censoring. AB - In many randomized clinical trials, the primary response variable, for example, the survival time, is not observed directly after the patients enroll in the study but rather observed after some period of time (lag time). It is often the case that such a response variable is missing for some patients due to censoring that occurs when the study ends before the patient's response is observed or when the patients drop out of the study. It is often assumed that censoring occurs at random which is referred to as noninformative censoring; however, in many cases such an assumption may not be reasonable. If the missing data are not analyzed properly, the estimator or test for the treatment effect may be biased. In this paper, we use semiparametric theory to derive a class of consistent and asymptotically normal estimators for the treatment effect parameter which are applicable when the response variable is right censored. The baseline auxiliary covariates and post-treatment auxiliary covariates, which may be time-dependent, are also considered in our semiparametric model. These auxiliary covariates are used to derive estimators that both account for informative censoring and are more efficient then the estimators which do not consider the auxiliary covariates. PMID- 21706380 TI - Outreach programs, peer pressure, and common sense: what motivates homeowners to mitigate wildfire risk? AB - In recent years, altered forest conditions, climate change, and the increasing numbers of homes built in fire prone areas has meant that wildfires are affecting more people. An important part of minimizing the potential negative impacts of wildfire is engaging homeowners in mitigating the fire hazard on their land. It is therefore important to understand what makes homeowners more or less willing to take action. The research presented here comes from a study that interviewed a total of 198 homeowners in six communities in the western United States about the activities they had undertaken to mitigate their fire risk, the factors that contributed to their decisions, and their future intentions. The current paper reports on findings from the first half of the longitudinal study, after 3 years we will return to interview the current homeowner on the same properties to assess maintenance actions and facilitating and limiting factors. Overall we found a body of individuals who understand the fire risk, are taking numerous mitigation actions, and think that these actions have reduced their risk. These homeowners typically did not expect the government to do it for them: they wanted information about what to do and, in some cases, assistance with the work, but saw taking care of their property primarily as their responsibility. Responses also show that key information sources and motivating factors vary by location and that it is not inherently necessary to have relationships between community members to create defensible space. PMID- 21706381 TI - Perceptions of ranchers about medusahead (Taeniatherum caput-medusae (L.) Nevski) management on sagebrush steppe rangelands. AB - Medusahead (Taeniatherum caput-medusae (L.) Nevski) is an exotic annual grass invading rangelands in the western United States. Medusahead is a serious management concern because it decreases biodiversity, reduces livestock forage production, and degrades the ecological function of rangelands. Despite the obvious importance of ranchers as partners in preventing and managing medusahead in rangelands, little is known about their perceptions and behaviors concerning medusahead management. We present the results of a survey of ranchers operating on sagebrush steppe rangeland in a three-county area in southeast Oregon encompassing over 7.2 million ha. The primary objective of this research was to determine if the presence of medusahead on a ranch influenced its operator's perceptions and behaviors concerning invasive plant control and prevention. Ranchers operating on medusahead-infested rangeland were more likely to indicate increased awareness and concern about medusahead and the potential for its continued expansion. Ranchers operating on rangeland invaded by medusahead were also more likely to indicate use of measures to prevent the spread of medusahead and other invasive plants on rangeland, interest in educational opportunities concerning invasive annual grass management, and plans for controlling invasive annual grasses in the future. This study revealed an alarming trend in which individuals are less likely to implement important prevention measures and participate in education opportunities to improve their knowledge of invasive plants until they directly experience the negative consequences of invasion. Information campaigns on invasive plants and their impacts may rectify this problem; however, appropriate delivery methods are critical for success. Web- or computer-based invasive plant information and tools were largely unpopular among ranchers, whereas traditional forms of information delivery including brochures/pamphlets and face-to-face interaction were preferred. However, in the future web- or computer-based information may become more popular as ranchers become more familiar with them. PMID- 21706382 TI - Psychosocial factors and health as determinants of quality of life in community dwelling older adults. AB - PURPOSE: It is important to understand the determinants of differences in quality of life in old age and to include a wide range of possible predictors. The present study investigated the determinants of quality of life in two groups of older adults for whom there was an unusually informative set of possible predictor variables. METHOD: Participants were members of the Lothian Birth Cohorts of 1921 (n = 550) or 1936 (n = 1,091). Four facets of quality of life (QoL) and general QoL were measured using the WHOQOL-BREF. Possible determinants included personality traits, measured with the International Personality Item Pool (IPIP) scales; childhood and old age general cognitive ability, measured with the Moray House Test; minor psychological symptoms, measured with the Hospital Anxiety and Depression Scale (HADS); physical health, assessed by grip strength and cardiovascular disease history; and sociodemographic factors, assessed by interview. RESULTS: Linear regression analyses revealed that HADS depression had the greatest influence on quality of life. Personality traits, most notably Emotional Stability, also predicted quality of life to varying degrees, along with factors reflecting current life circumstances. There were differences between the two cohorts in the variables which predicted quality of life. There were different, conceptually relevant, contributions to the different QoL facets. CONCLUSIONS: Personality traits and minor depressive symptoms have an important influence on self-reported quality of life in old age. Quality of life may be influenced more by current than past circumstances, and this relationship may change with age. PMID- 21706383 TI - Burn-induced apoptosis of cardiomyocytes is survivin dependent and regulated by PI3K/Akt, p38 MAPK and ERK pathways. AB - Survivin belongs to the family of genes known as inhibitors of apoptosis, and although it has been implicated in the prevention of cancer, its potential role in burn-induced cardiac injury is unknown. In this study, we investigated the effects of survivin blockade on burn-induced cardiac apoptosis. Using a standardized Sprague-Dawley rat model of third-degree burn injury over 40% of total body surface area, apoptosis was measured in vivo followed by in vitro assessment of burn serum-stimulated cardiomyocytes. Based on the Western blot analyses, real-time PCR, ELISA, and TUNEL, apoptosis and caspase activation both in vivo and in vitro were significantly increased after severe burn injury, while survivin expression was increased (up to 2.90-fold) during the early stage of burn injury and was almost completely abolished 8 h after the burn. Survivin deficient cardiomyocytes, as well as hearts from rats treated with the survivin inhibitor YM155, exhibited increased caspase-3 protein and mRNA expression and apoptosis ratio at different times after the burn. Furthermore, inhibition of ERK, phosphoinositol 3-kinase contributed the burn serum-induced increase in apoptosis and caspase-3 protein expression, and decreased survivin expression, whereas burn serum-induced increase in apoptosis was attenuated by P38 mitogen activated protein kinase inhibition. These data identify survivin as a critical anti-apoptotic regulator of cardiomyocytes after burn injury. ERK, P38 MAPK and PI3K were found to be upstream regulators of survivin. PMID- 21706384 TI - Isomerization of vaccenic acid to cis and trans C18:1 isomers during biohydrogenation by rumen microbes. AB - In ruminants, cis and trans C18:1 isomers are intermediates of fatty acid transformations in the rumen and their relative amounts shape the nutritional quality of ruminant products. However, their exact synthetic pathways are unclear and their proportions change with the forage:concentrate ratio in ruminant diets. This study traced the metabolism of vaccenic acid, the main trans C18:1 isomer found in the rumen, through the incubation of labeled vaccenic acid with mixed ruminal microbes adapted to different diets. [1-(13)C]trans-11 C18:1 was added to in vitro cultures with ruminal fluids of sheep fed either a forage or a concentrate diet. (13)C enrichment in fatty acids was analyzed by gas chromatography-mass spectrometry after 0, 5 and 24 h of incubation. (13)C enrichment was found in stearic acid and in all cis and trans C18:1 isomers. Amounts of (13)C found in fatty acids showed that 95% of vaccenic acid was saturated to stearic acid after 5 h of incubation with the concentrate diet, against 78% with the forage diet. We conclude that most vaccenic acid is saturated to stearic acid, but some is isomerized to all cis and trans C18:1 isomers, with probably more isomerization in sheep fed a forage diet. PMID- 21706385 TI - Life events and depressive symptoms in African American adolescents: do ecological domains and timing of life events matter? AB - Considerable research has documented associations between adverse life events and internalizing symptoms in adolescents, but much of this research has focused on the number of events experienced, with less attention to the ecological context or timing of events. This study examined life events in three ecological domains relevant to adolescents (i.e., family, peers, themselves) as predictors of the course of depressive symptoms among a community epidemiologically defined sample of 419 (47.2% females) urban African American adolescents. Given that youth depressive symptoms change over time, grade level was examined as a moderator. For males, the strength of associations between life events happening to participants, family life events, and peer life events and depressive symptoms did not change from grades 6-9. For females, the strength of the association between peer life events and depressive symptoms did not change over time, but the strength of associations between life events happening to participants and family life events and females' depressive symptoms decreased over time. Implications of the findings and directions for future research are discussed. PMID- 21706387 TI - Recurrent infections in a rheumatoid arthritis patient with a primary immunodeficiency, treated with conventional and biologic disease-modifying anti rheumatic drugs. AB - A 64-year-old woman with longstanding rheumatoid arthritis suffered from recurrent severe infections after treatment with both synthetic and biologic disease-modifying anti-rheumatic drugs (DMARDs). She was found to have mannose binding lectin (MBL) deficiency. MBL deficiency is associated with increased risk of infections, in particular in individuals treated with immunomodulating drugs. Patients with a history of recurrent infections in childhood, and severe infections after treatment with synthetic or biologic DMARDs, should be tested for MBL deficiency. PMID- 21706388 TI - Altered HepG2 cell models using etomoxir versus tert-butylhydroperoxide. AB - Energetic failure which occurs in both ischemia/reperfusion and acute drug induced hepatotoxicity is frequently associated with oxidative stress. This study displays the setting of a new cell culture model for hepatic energetic failure, i.e., HepG2 models modified by etomoxir [ETO] addition [0.1 mM to 1 mM] and compares the cell impact versus tert-butylhydroperoxide [TBOOH; 0.2 mM], an oxidative stress inducer. As it was observed with Minimum Essential Medium (MEM) without any interfering agent, decreasing temperature drastically lowered adenosine triphosphate (ATP) levels, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) viability test, and protein content, compared to 37 degrees C (p=0.02, p<0.001 and p<0.001, respectively), but to a larger extent in the presence of ETO or TBOOH. The alteration was generally highly dependent on the ETO concentration, time, and temperature. At 37 degrees C 24 h after (T24h), regarding ETO concentration, R2 correlation ratio was 0.65 (p<0.001), 0.70 (p<0.001), and 0.89 (p<0.001) for ATP levels, protein content, and viability, respectively. The lowest ETO concentration producing a significant effect was 0.25 mM. Concerning time dependency (i.e., T24h versus after 5 h (T5h)), at 37 degrees C with ETO, ATP level continued to significantly decrease between T5h and T24h. In a similar way, at 37 degrees C, the MTT viability test decrease was accelerated only between T5h and T24h for ETO concentrations higher than 0.5 mM (p=0.016 and p=0.0001 for 0.75 and 1 mM, respectively). On the contrary, with TBOOH, comparing T24h versus T5h, cellular indicators were improved but generally remained lower than MEM without any interfering agent at T24h, suggesting that TBOOH action was time limited probably in relation with its oxidation in cell medium. This study confirms the interest of altered ETO cell model to screen agents (or formulation) prone to prevent or treat energetic depletion in relation with oxidative stress. PMID- 21706389 TI - Non-human primate models of alcohol-related phenotypes: the influence of genetic and environmental factors. AB - Because of their complex social structures, behaviors, and genetic similarities to humans, nonhuman primates are useful for studying how genetic factors influence alcohol consumption. The neurobiological systems that influence addiction vulnerability may do so by acting on alcohol response, reward pathways, behavioral dyscontrol, and vulnerability to stress and anxiety. Rhesus macaques show individual differences in alcohol response and temperament, and such differences are influenced by genetic variants that are similar functionally to those present in humans. Genes at which variation moderates these phenotypes include those encoding monoamine oxidase A (MAOA-LPR), the serotonin transporter (HTTLPR), corticotropin releasing hormone (CRH-248C/T and -2232 C/G), Neuropeptide Y (NPY-1002 T/G), and the MU-opioid receptor (OPRM1 C77G). These provide opportunities for modeling how genetic and environmental factors (i.e., stress, individual's sex, or alcohol exposure) interact to influence alcohol consumption. Studies in primates may also reveal selective factors have driven maintenance or fixation of alleles that increase risk for alcohol use disorders in modern humans. PMID- 21706386 TI - SOD1 and TDP-43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments. AB - Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no cure. Breakthroughs in understanding ALS pathogenesis came with the discovery of dominant mutations in the superoxide dismutase 1 gene (SOD1) and other genes, including the gene encoding transactivating response element DNA binding protein 43 (TDP-43). This has led to the creation of animal models to further our understanding of the disease and identify a number of ALS-causing mechanisms, including mitochondrial dysfunction, protein misfolding and aggregation, oxidative damage, neuronal excitotoxicity, non-cell autonomous effects and neuroinflammation, axonal transport defects, neurotrophin depletion, effects from extracellular mutant SOD1, and aberrant RNA processing. Here we summarise the SOD1 and TDP-43 animal models created to date, report on recent findings supporting the potential mechanisms of ALS pathogenesis, and correlate this understanding with current developments in the clinic. PMID- 21706406 TI - Genotoxicity in Atlantic killifish (Fundulus heteroclitus) from a PAH contaminated Superfund site on the Elizabeth River, Virginia. AB - The Atlantic Wood Industries Superfund site (AWI) on the Elizabeth River in Portsmouth, VA is heavily contaminated with polycyclic aromatic hydrocarbons (PAHs) from a wood treatment facility. Atlantic killifish, or mummichog (Fundulus heteroclitus), at this Superfund site are exposed to very high concentrations of several carcinogens. In this study, we measured PAH concentrations in both fish tissues and sediments. Concurrently, we assessed different aspects of genotoxicity in the killifish exposed in situ. Both sediment and tissue PAH levels were significantly higher in AWI samples, relative to a reference site, but the chemistry profile was different between sediments and tissues. Killifish at AWI exhibited higher levels of DNA damage compared to reference fish, as measured via the flow cytometric method (FCM), and the damage was consistent with sediment PAH concentrations. Covalent binding of benzo[a]pyrene (BaP) metabolites to DNA, as measured via LC-MS/MS adduct detection methods, were also elevated and could be partially responsible for the DNA damage. Using similar LC-MS/MS methods, we found no evidence that oxidative DNA adducts had a role in observed genotoxicity. PMID- 21706407 TI - The role of CYP1A inhibition in the embryotoxic interactions between hypoxia and polycyclic aromatic hydrocarbons (PAHs) and PAH mixtures in zebrafish (Danio rerio). AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants with elevated concentrations in waters that may also experience hypoxia. Previous research has shown interactions between hypoxia and some PAHs (fluoranthene, alpha-naphthoflavone) but no interaction with others (benzo[a]pyrene (BaP), beta naphthoflavone). Here we examine how hypoxia (7.4% oxygen, ~35% of normoxia) affects the embryotoxicity of PAHs that act through different mechanisms and the role that CYP1A inhibition may play in these interactions. About 500 MUg/l BaP and 1-200 MUg/l benzo[k]fluoranthene (BkF) interacted synergistically with hypoxia to induce pericardial edema in developing zebrafish (Danio rerio). Hypoxia protected from the embryotoxicity of pyrene (PY) and had no effect on the toxicity of polychlorinated biphenyl-126. Despite previous reports of other CYP1A inhibitors interacting with hypoxia, up to 2,000 MUg/l dibenzothiophene, 2 aminoanthracene (AA), and carbazole (CB) all failed to induce embryotoxicity under normoxic or hypoxic conditions. The toxicity of PAH mixtures--including binary mixtures of BaP/AA and BaP/CB and two environmentally relevant, complex mixtures--were exacerbated severely by hypoxia to induce or worsen pericardial edema and cause mortality. The interactions between hypoxia and BkF and PY were closely mimicked by morpholino knockdown of CYP1A, indicating a potential role for metabolism of these compounds in their toxicity. Our results indicate that various PAHs may exhibit synergistic, antagonistic or additive toxicity with hypoxia. The enhanced toxicity of environmental mixtures of PAHs under hypoxia suggests that risk assessments that do not take into account potential interactions with hypoxia may underestimate the threat of PAHs to fish in contaminated sites. PMID- 21706408 TI - Differential service utilization associated with trauma-informed integrated treatment for women with co-occurring disorders. AB - Women with co-occurring mental health and substance use disorders and trauma histories vary greatly in symptom severity and use of support services. This study estimated differential effects of an integrated treatment intervention (IT) across sub-groups of women in this population on services utilization outcomes. Data from a national study were used to cluster participants by symptoms and service utilization, and then estimate the effect of IT versus usual care on 12 month service utilization for each sub-group. The intervention effect varied significantly across groups, in particular indicating relative increases in residential treatment utilization associated with IT among women with predominating trauma and substance abuse symptoms. Understanding how IT influences service utilization for different groups of women in this population with complex needs is an important step toward achieving an optimal balance between need for treatment and service utilization, which can ultimately improve outcomes and conserve resources. PMID- 21706409 TI - Distinct actions of intermittent and sustained beta-adrenoceptor stimulation on cardiac remodeling. AB - Heart disease is associated with increased sympathetic nerve activity and elevated levels of circulating catecholamines, resulting in chronic stimulation of the beta-adrenergic receptors (beta-AR) and consequent pathological cardiac remodeling. Experimentally, chronic administration of the beta-AR agonist isoproterenol (ISO) has been most commonly used to model beta-AR-induced cardiac remodeling. However, it remains unclear whether beta-AR-mediated cardiac remodeling and dysfunction differs between sustained versus pulsatile (intermittent) exposure to a beta-agonist. Here, we compare the effects of intermittent versus sustained administration of ISO on cardiac remodeling and function in mice. Animals were administered 5 mg (kg d)(-1) ISO for 2 weeks either by daily subcutaneous injection, or continuous infusion via an implanted osmotic minipump. Cardiac function and remodeling were determined by echocardiography, micromanometry and histology. Moreover, Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were utilized to define the proteins and genes involved. Both sustained and intermittent administration of ISO resulted in a similar degree of cardiac hypertrophy (16% and 19%, respectively). However, mice receiving ISO by daily injection developed more severe ventricular systolic and diastolic dysfunction and myocardial fibrosis compared with mice receiving ISO via the osmotic minipump. The disparity in results between the delivery methods is suggested to be due, at least in part, to increased expression of fibrogenic factors, including connective tissue growth factor (CTGF) and NADPH oxidase (NOX4), in mice receiving intermittent application of ISO. In summary, compared with sustained exposure to a beta-AR agonist, intermittent beta-AR stimulation leads to more severe cardiac dysfunction and fibrosis. These findings not only further our understanding of beta-AR function in the setting of cardiac pathophysiology, but also highlight that significant differences can result dependent upon the mode of experimental beta-AR stimulation in inducing cardiomyopathy. PMID- 21706410 TI - Viral proteomics: the emerging cutting-edge of virus research. AB - Viruses replicate and proliferate in host cells while continuously adjusting to and modulating the host environment. They encode a wide spectrum of multifunctional proteins, which interplay with and modify proteins in host cells. Viral genomes were chronologically the first to be sequenced. However, the corresponding viral proteomes, the alterations of host proteomes upon viral infection, and the dynamic nature of proteins, such as post-translational modifications, enzymatic cleavage, and activation or destruction by proteolysis, remain largely unknown. Emerging high-throughput techniques, in particular quantitative or semi-quantitative mass spectrometry-based proteomics analysis of viral and cellular proteomes, have been applied to define viruses and their interactions with their hosts. Here, we review the major areas of viral proteomics, including virion proteomics, structural proteomics, viral protein interactomics, and changes to the host cell proteome upon viral infection. PMID- 21706411 TI - Crystal structure of histidine-containing phosphocarrier protein from Thermoanaerobacter tengcongensis MB4 and the implications for thermostability. AB - Protein thermostability is an inherent characteristic of proteins from thermophilic microorganisms, and therefore enables these organisms to survive at extreme temperatures. Although it is well-known that thermostable proteins are critical for the growth of thermophilic organisms, the structural basis of protein thermostability is not yet fully understood. The histidine-containing phosphocarrier (HPr) protein, a phosphate shuttle protein in the phosphoenolpyruvate-dependent sugar transport system (PTS) of bacterial species, is an ideal model for investigating protein thermostability with respect to its small size and deficiency in disulphide bonds or cofactors. In this study, the HPr protein from Thermoanaerobacter tengcongensis (TtHPr) is cloned and purified. Crystal structure with good quality has been determined at 2.3 A resolution, which provides a firm foundation for exploring the thermostable mechanism. However, it shows that the crystal structure is conserved and no clue can be obtained from this single structure. Furthermore, detailed comparison of sequence and structure with the homologs from meso- or thermophilic bacteria shows no obvious rule for thermostability, but the extra salt-bridge existing only in thermophilic bacteria might be a better explanation for thermostability of HPr. Thus, mutations are performed to interrupt the salt-bridge in HPrs in thermophilic bacteria. Using site-directed mutations and the circular dichroism method, thermostability is evaluated, and the mutational variations are shown to have a faster denaturing rate than for wild-type viruses, indicating that mutations cause instability in the HPrs. Understanding the higher-temperature resistance of thermophilic and hyperthermophilic proteins is essential to studies on protein folding and stability, and is critical in engineering efficient enzymes that can work at a high temperature. PMID- 21706413 TI - Copper ions influence the toxicity of beta-amyloid(1-42) in a concentration dependent manner in a Caenorhabditis elegans model of Alzheimer's disease. AB - beta-amyloid (Abeta) and copper play important roles in the pathogenesis of Alzheimer's disease (AD). However, the behavioral correlativity and molecular mechanisms of Abeta and copper toxicity have been investigated less often. In the present study, we investigated the interaction and toxicity of Abeta1-42 and copper in the Abeta1-42 transgenic Caenorhabditis elegans worm model CL2006. Our data show that the paralysis behavior of CL2006 worms significantly deteriorated after exposure to 10(-3) mol L(-1) copper ions. However, the paralysis behavior was dramatically attenuated with exposure to 10(-4) mol L(-1) copper ions. The exogenous copper treatment also partially changed the homeostatic balance of zinc, manganese, and iron. Our data suggest that the accumulation of reactive oxygen species (ROS) was responsible for the paralysis induced by Abeta and copper in CL2006. The ROS generation induced by Abeta and copper appear to be through sod-1, prdx-2, skn-1, hsp-60 and hsp-16.2 genes. PMID- 21706412 TI - Expression, characterization, and antimicrobial ability of T4 lysozyme from methylotrophic yeast Hansenula polymorpha A16. AB - Lysozyme is an enzyme that is essential for protection against bacterial infections. In this study, a T4 lysozyme gene was cloned into the yeast expression vector pPIC9K under the control of the Pichia pastoris glyceraldehyde 3-phosphate dehydrogenase promoter (pGAP). A Hansenula polymorpha-derived ribosomal DNA (rDNA)-targeting element was inserted into the expression vector and was critical for stable DNA integration into the H. polymorpha chromosome. Recombinant T4 lysozyme was successfully expressed in the yeast H. polymorpha A16; 0.49 g L(-1) secreted recombinant T4 lysozyme was obtained 72 h after incubation in culture broth that had an initial pH of 6.0. Recombinant T4 lysozyme showed lytic activity against the cell walls of the gram positive bacteria, Micrococcus lysodeikticus, and the gram negative bacteria Xanthomonas campestris pv. malvacearum and Xanthomonas oryzae pv. oryzae. The zone of inhibition assay was used to evaluate antimicrobial activity. Mass spectrometry showed the N-terminal sequence of recombinant T4 lysozyme was identical to that of the native enzyme. SDS-PAGE indicated that the molecular mass of recombinant T4 lysozyme was 18.7 kD which corresponds to a monomer of the native enzyme. SDS PAGE without 0.2 mol L(-1) dithiothreitol treatment detected two bands (15 and 31 kD) suggesting that some recombinant T4 lysozyme formed inter- and intra molecular disulfide bonds which resulted in loss of enzyme activity. PMID- 21706414 TI - Alteration of encephalomyocarditis virus pathogenicity due to a mutation at position 100 of VP1. AB - Encephalomyocarditis virus (EMCV) infection leads to many diseases including encephalitis, myocarditis and diabetes in its natural host, the mouse. In this study, we generated four cDNA clones with a point mutation at position 100 of VP1. The amino acids isoleucine, alanine, serine and proline were substituted with threonine in the four different clones of EMCV strain BJC3 by site-specific mutagenesis, and viable viruses were rescued. Although all mutants and wild-type viruses display different plaque morphologies, they replicate comparably in BHK 21 cells. The pathogenicity of the mutated viruses was systematically analyzed to investigate the importance of this amino acid in the viral pathogenicity and disease phenotype of EMCV infection in mice. The results showed that the isoleucine- (T1100I) and proline-mutated viruses (T1100P) exhibited a reduced mortality, lower cerebral virus loads and alleviated brain damage while the viruses with serine (T1100S) and alanine (T1100A) substitutions displayed similar properties as the wild-type virus. These findings indicate that the amino acid at position 100 of VP1 is important for EMCV in vivo infection, and its mutation alters the pathogenicity of viral infection in mice. PMID- 21706415 TI - Complexity and characteristic frequency studies in ECG signals of mice based on multiple scale factors. AB - Existing methods of physiological signal analysis based on nonlinear dynamic theories only examine the complexity difference of the signals under a single sampling frequency. We developed a technique to measure the multifractal characteristic parameter intimately associated with physiological activities through a frequency scale factor. This parameter is highly sensitive to physiological and pathological status. Mice received various drugs to imitate different physiological and pathological conditions, and the distributions of mass exponent spectrum curvature with scale factors from the electrocardiogram (ECG) signals of healthy and drug injected mice were determined. Next, we determined the characteristic frequency scope in which the signal was of the highest complexity and most sensitive to impaired cardiac function, and examined the relationships between heart rate, heartbeat dynamic complexity, and sensitive frequency scope of the ECG signal. We found that all animals exhibited a scale factor range in which the absolute magnitudes of ECG mass exponent spectrum curvature achieve the maximum, and this range (or frequency scope) is not changed with calculated data points or maximal coarse-grained scale factor. Further, the heart rate of mice was not necessarily associated with the nonlinear complexity of cardiac dynamics, but closely related to the most sensitive ECG frequency scope determined by characterization of this complex dynamic features for certain heartbeat conditions. Finally, we found that the health status of the hearts of mice was directly related to the heartbeat dynamic complexity, both of which were positively correlated within the scale factor around the extremum region of the multifractal parameter. With increasing heart rate, the sensitive frequency scope increased to a relatively high location. In conclusion, these data provide important theoretical and practical data for the early diagnosis of cardiac disorders. PMID- 21706416 TI - A novel strategy to derive iPS cells from porcine fibroblasts. AB - Induced pluripotent stem (iPS) cell technology demonstrates that somatic cells can be reprogrammed to a pluripotent state by over-expressing four reprogramming factors. This technology has created an interest in deriving iPS cells from domesticated animals such as pigs, sheep and cattle. Moloney murine leukemia retrovirus vectors have been widely used to generate and study mouse iPS cells. However, this retrovirus system infects only mouse and rat cells, which limits its use in establishing iPS cells from other mammals. In our study, we demonstrate a novel retrovirus strategy to efficiently generate porcine iPS cells from embryonic fibroblasts. We transfected four human reprogramming factors (Oct4, Sox2, Klf4 and Myc) into fibroblasts in one step by using a VSV-G envelope coated pantropic retrovirus that was easily packaged by GP2-293 cells. We established six embryonic stem (ES)-like cell lines in human ES cell medium supplemented with bFGF. Colonies showed a similar morphology to human ES cells with a high nuclei-cytoplasm ratio and phase-bright flat colonies. Porcine iPS cells could form embryoid bodies in vitro and differentiate into the three germ layers in vivo by forming teratomas in immunodeficient mice. PMID- 21706417 TI - Cross-talk between NMDA and GABA(A) receptors in cultured neurons of the rat inferior colliculus. AB - Neuronal ion channels of different types often do not function independently but will inhibit or potentiate the activity of other types of channels, a process called cross-talk. The N-methyl-D-aspartate receptor (NMDA receptor) and the gamma-aminobutyric acid type A receptor (GABA(A) receptor) are important excitatory and inhibitory receptors in the central nervous system, respectively. Currently, cross-talk between the NMDA receptor and the GABA(A) receptor, particularly in the central auditory system, is not well understood. In the present study, we investigated functional interactions between the NMDA receptor and the GABA(A) receptor using whole-cell patch-clamp techniques in cultured neurons from the inferior colliculus, which is an important nucleus in the central auditory system. We found that the currents induced by aspartate at 100 MUmol L(-1) were suppressed by the pre-perfusion of GABA at 100 MUmol L(-1), indicating cross-inhibition of NMDA receptors by activation of GABA(A) receptors. Moreover, we found that the currents induced by GABA at 100 MUmol L(-1) (I (GABA)) were not suppressed by the pre-perfusion of 100 MUmol L(-1) aspartate, but those induced by GABA at 3 MUmol L(-1) were suppressed, indicating concentration-dependent cross-inhibition of GABA(A) receptors by activation of NMDA receptors. In addition, inhibition of IGABA by aspartate was not affected by blockade of voltage-dependent Ca(2+) channels with CdCl(2) in a solution that contained Ca(2+), however, CdCl(2) effectively attenuated the inhibition of I (GABA) by aspartate when it was perfused in a solution that contained Ba(2+) instead of Ca(2+) or a solution that contained Ca(2+) and 10 mmol L(-1) BAPTA, a membrane-permeable Ca(2+) chelator, suggesting that this inhibition is mediated by Ca(2+) influx through NMDA receptors, rather than voltage-dependent Ca(2+) channels. Finally, KN-62, a potent inhibitor of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), reduced the inhibition of I (GABA) by aspartate, indicating the involvement of CaMKII in this cross-inhibition. Our study demonstrates a functional interaction between NMDA and GABA(A) receptors in the inferior colliculus of rats. The presence of cross-talk between these receptors suggests that the mechanisms underlying information processing in the central auditory system may be more complex than previously believed. PMID- 21706418 TI - Effects of cutting frequency and height on alkaloid production in endophyte infected drunken horse grass (Achnatherum inebrians). AB - An evaluation was performed on the influence of mowing height (2.5, 5.0 or 7.5 cm) and mowing frequency (weekly or fortnightly) on levels of ergot alkaloids (ergine and ergonovine) formed in drunken horse grass, Achnatherum inebrians, grown under greenhouse conditions. Samples were taken monthly and alkaloids were extracted and analyzed by reverse-phase HPLC. Alkaloid levels increased more or less linearly with plant age over the first four months following establishment. Levels were higher in samples cut fortnightly compared to those cut weekly, and were higher when plants were cut at a mowing height of 7.5 cm vs. 2.5 cm. In most cases, the highest alkaloid levels observed were almost three times those of the lowest. If plant protection applications are developed for the endophytic fungus, Neotyphodium gansuense, it will be necessary to be aware of the potential role of plant husbandry practices (e.g., defoliation frequency and intensity) for reducing or enhancing levels of plant alkaloids. Similar husbandry factors may affect alkaloid levels in other Neotyphodium-grass associations, which would be interesting for further study. PMID- 21706419 TI - Fertilization regimes affect the soil biological characteristics of a sudangrass and ryegrass rotation system. AB - The sudangrass (Sorghum sudanense) and ryegrass (Lolium multiflorum L.) rotation is an intensive and new cropping system in Central China. Nutrient management practices in this rotation system may influence soil fertility, the important aspects of which are soil biological properties and quality. As sensitive soil biological properties and quality indicators, soil microbial community activity, microbial biomass, enzyme activities, soil organic matter (SOM) and total N resulting from different fertilization regimes in this rotation system were studied through a four-year field experiment from April 2005 to May 2009. Treatments included control (CK), fertilizer phosphorus and potassium (PK), fertilizer nitrogen and potassium (NK), fertilizer nitrogen and phosphorus (NP) and a fertilizer nitrogen, phosphorus and potassium combination (NPK). Soil microbial community activities in the NK, NP and NPK treatments were significantly lower than those in the CK and PK treatments after the sudangrass and ryegrass trial. The highest microbial biomass C, microbial biomass N, SOM, total N, sucrase and urease activities were found in the NPK treatment, and these soil quality indicators were significantly higher in the NK, NP and NPK treatments than in the PK and CK treatments. Soil microbial biomass and enzyme activities were positively associated with SOM in the sudangrass and ryegrass rotation system, indicating that fertilization regimes, especially N application, reduced microbial community activity in the soil. Proper fertilization regimes will increase microbial biomass, enzyme activity and SOM and improve soil fertility. PMID- 21706420 TI - Neural basis for successful encoding and retrieval of prospective memory. AB - Prospective memory (PM) refers to memory for future intentions. Difference due to memory (Dm effect) is the difference in neural activity related to stimuli that were subsequently remembered or forgotten. Using event-related potentials (ERPs), the present study investigated the Dm effect for PM using a subsequent task switching paradigm. The results showed that a Dm effect of ERP P150 was more positive-going for later PM hit trials than for later PM forgotten trials during 100-200 ms. This Dm effect may reflect the process for the production of future intention or the process for attention. Consistent with previously reported Dm effects of other types of memory, we found that the fbN2 (250-280 ms) and late positivity component (400-700 ms) were stronger in later PM hit trials than in forgotten trials. The fbN2 was evoked by Chinese characters. The late positivity component was related to the precise encoding process. In conclusion, because of the early P150, PM encoding appears to be somewhat different from previously identified Dm effects. However, further research is needed. Our findings reveal that Dm effects of PM share similar characteristics with known Dm effects of other types of episodic memory after the very early stage of neural processing. PMID- 21706446 TI - Pomegranate sensitizes Tamoxifen action in ER-alpha positive breast cancer cells. AB - It is estimated that one in eight women will be affected with cancer during their lives, which means over 1 million women worldwide will be diagnosed with breast cancer in the year of 2011. Roughly, 70% of breast cancer will be estrogen receptor-alpha (ER-alpha) positive. The presence of ER-alpha is associated with better prognosis and is able to determine if tumors will respond to the estrogen blocking/ER-antagonist drug Tamoxifen (TAM). However, a significant fraction of ER-positive tumors respond with minimal or no response to TAM. It is unclear why some breast cancer cells resist TAM and how to make these cells respond. Early evidence suggests Pomegranate fruit extracts (PFEs) exhibit an anticancer effect against some cancers. The objective of the study was to determine whether PFEs may able to enhance/sensitize the TAM's effect in ER-positive MCF-7 breast cancer cells. To test the hypothesis, we determined the effect of PFEs on sensitive and TAM-resistant-MCF-7 cell viability and cell death in the presence or absence of TAM under estrogenic or non-estrogenic culture environment. The present studies demonstrated that PFEs enhance the TAM action in both sensitive and TAM-resistant MCF-7 cells through the inhibition of cell viability (regular or estrogen induced) by inducing cell-death machinery. Collectively, the results showed for the first time that pomegranate combined with TAM may represent a novel and a powerful approach to enhance and sensitize TAM action. PMID- 21706447 TI - HpSumf1 is involved in the activation of sulfatases responsible for regulation of skeletogenesis during sea urchin development. AB - Sulfatases such as arylsulfatase and heparan sulfate 6-O-endosulfatase play important roles in morphogenesis during sea urchin development. For the activation of these sulfatases, Calpha-formylglycine formation by sulfatase modifying factor (Sumf) is required. In this study, to clarify the regulatory mechanisms for the activation of sulfatases during sea urchin development, we examined the expression and function of the Hemicentrotus pulcherrimus homologs of Sumf1 and Sumf2 (HpSumf1 and HpSumf2, respectively). Expression of HpSumf1 but not HpSumf2 mRNA was dynamically changed during early development. Functional analyses of recombinant HpSumf1 and HpSumf2 using HEK293T cells expressing mouse arylsulfatase A (ArsA) indicated that HpSumf1 and HpSumf2 were both able to activate mammalian ArsA. Knockdown of HpSumf1 using morpholino antisense oligonucleotides caused abnormal spicule formation in the sea urchin embryo. Injection of HpSumf2 mRNA had no effect on skeletogenesis, while injection of HpSumf1 mRNA induced severe supernumerary spicule formation. Taken together, these findings suggest that HpSumf1 is involved in the activation of sulfatases required for control of skeletogenesis. PMID- 21706448 TI - Manifestation of atypical hemolytic uremic syndrome caused by novel mutations in MCP. AB - Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Mutations in genes encoding regulators of the alternative complement pathway (CFH, MCP, C3, CFI, CFB, THBD, and CFHR1-5) are connected with this disease. Polymorphisms (SNPs) in these genes might also influence the manifestation of aHUS. We have analyzed the genes of CFH, CFI, MCP, and C3 in a cohort of 10 unrelated Czech patients with clinically diagnosed familial aHUS. Surprisingly, 4 patients had mutations only in MCP, without mutations in any of the other genes that cause aHUS. Mutations, as yet unpublished, were widely distributed over the gene (SCR2 domain, signal peptide, and cytoplasmic region). The phenotype of the patients and their close relatives (14 individuals) was also investigated. Functional examination of MCP was also provided and proved lower expression on granulocytes in all mutations. Severity of disease varied, but onset was never earlier than 5 years of age. Penetrance of disease was 50% among carriers. We found that the severity and recurrence of the disease within families varied and might also be dependent on SNPs. Mutations in the MCP gene seems to be a common etiology of aHUS in Czech patients. PMID- 21706449 TI - Improvement of measles immunity among migrant populations: lessons learned from a prevalence study in a Swiss prison. AB - BACKGROUND: Measles persists worldwide despite the implementation of general vaccination campaigns. The environmental and demographic characteristics in many prisons increase the risk of measles epidemics. A large proportion of inmates come from countries where immunisation coverage is low. We aimed to estimate the susceptibility to measles among prisoners in order to implement preventative measures. METHODS: Serology screening for measles was carried out among 116 inmates in Switzerland's largest pre-trial prison. Socio-demographic characteristics were collected through a structured questionnaire. Risk factors for lack of measles immunity were examined. RESULTS: A total of 7 out of 116 (6%) inmates were not immune to measles. All 37 inmates from sub-Saharan Africa were immune. Considering only people native from regions other than sub-Saharan Africa, 7 of 40 inmates born after 1981 were susceptible (18.5%), whereas none of the 39 inmates born in 1981 or before were susceptible (p = 0.006). CONCLUSION: Susceptibility to measles was fairly low in this prison population composed mainly of migrants. Living in sub-Saharan Africa during childhood, and birth before 1982 were protective factors associated with the presence of immunity against measles. The heterogeneity of vaccination campaigns in the various regions of the world, particularly in terms of the timing of their introduction and scale of diffusion, explains epidemiological variability. Targeted vaccination in accordance to origin and age would offer excellent herd immunity and would substantially reduce risks of outbreaks as well as costs. PMID- 21706450 TI - Population based age stratified morbidities of premature infants in Switzerland. AB - OBJECTIVE: To provide population-based, gestational age (GA) stratified incidence of mortality and morbidities. METHODS: Population-based prospective observational study of infants born between 23 0/7 and 31 6/7 weeks GA in the years 2000-2004 in all Swiss neonatal intensive care units. Outcomes measured were: mortality, severe intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC), moderate/severe bronchopulmonary dysplasia (BPD) and free of major complications. RESULTS: Mortality was 19% of 3083 infants. Mortality (95% CI) decreased from 95% (88%, 99%) at 23 weeks to 3% (2%, 5%) at 31 weeks. Short-term survival free of major complications was 66% (65%, 68%) overall and increased from 2%(0%, 9%) to 89% (87%, 92%). Rate of IVH was 8% (7%, 9%), PVL 2% (2%, 3%), NEC 3% (3%, 4%) and BPD 11% (10%, 12%). Males had more IVH than females (9% vs. 6%). Antenatal steroids were associated with lower mortality (11% vs. 18%) and IVH (5% vs. 12%). Odds of free of major complications (OR, 95%CI) were positive for female gender 1.2 (1.0, 1.5), steroids 1.3 (1.1, 1.5), multiple gestation 1.3 (1.0, 1.6), not small for gestational age 2.7 (2.0, 3.5), and each additional week of GA 1.6 (1.5, 1.7). CONCLUSION: Mortality and incidence of morbidities known to influence outcome show a weekly decline with increasing gestational age, except for PVL. Gestational age stratified data are a key component for prenatal counselling. PMID- 21706451 TI - Knowledge of oral drug treatment in immunocompromised patients on hospital discharge. AB - PRINCIPLES: Several studies have shown that patients' inappropriate knowledge about their medication is associated with non-adherence. The aim of this study was to assess immunocompromised inpatient knowledge of their oral drug treatment on discharge. METHODS: We conducted a single-centre, prospective, cross-sectional study from July to November 2008 in the Immunology unit of a university-based hospital. Knowledge of all oral prescribed medication was assessed before discharge of immunocompromised inpatients using a self-administered questionnaire, assessing drug name, dosage, indication and administration guidelines. Prescribed drugs were classified as treatments for chronic disease, or as adjuvant treatments which were differentiated regarding their link with the chronic disease. RESULTS: Over four months, 17 transplant recipients and 38 HIV infected patients were included. Overall, 57% of the 497 prescribed drugs were adequately known. The proportions of drugs adequately known were 79%, 91%, 81% and 62% respectively for the drug name, dosage, indication and administration guideline components. Drugs for the treatment of chronic disease were more adequately known than adjuvant treatments. Older age and a low educational level were significantly associated with poor knowledge of drugs. CONCLUSIONS: Immunocompromised patients demonstrated moderate to good knowledge of oral drugs on discharge. Adjuvant treatments were less well known than drugs for the treatment of chronic disease. Some recommendations for interventions aimed at utilising the skills of clinical pharmacists are needed. Efforts which encourage patients to be active participants in their own treatment could improve therapeutic adherence and reduce potential complications. PMID- 21706452 TI - Targeted therapy in breast cancer: what's new? AB - Breast cancer is the most commonly diagnosed malignancy and one of the major causes of death among women. Breast cancer is also one of the most investigated diseases but whose biological features are still not well understood, several effective treating strategies having been explored in dealing with different types of advanced breast cancer, such as endocrine therapy and molecular targeted therapy. Trastuzumab is the first approved targeted anti-cancer agent to show an attractive response rate and outcomes in treating HER-2 positive metastatic breast cancer patients. However, primary or acquired trastuzumab resistance usually occurs some time into the use of trastuzumab and leads to treatment resistance or tumour progression. The promising results with trastuzumab targeted therapy encouraged further investigations in this area exploring several novel targeted agents aiming to overcome the resistance drawback of trastuzumab. In this review we discuss the major newly developed targeted agents in breast cancer treatment, including the novel anti-HER-2 monoclonal antibody pertuzumab or ertumaxomab, small molecular tyrosine inhibitor lapatinib, selective PARP1 inhibitor olaparib, mTOR inhibitor rapamycin analogues, and sheddase inhibitors. Many of these novel targeted drugs or molecules showed additional or complementary effects to trastuzumab therapy that need further and wider investigation. PMID- 21706453 TI - Treatment algorithm for moderate to severe ulcerative colitis. AB - The care for a patient with ulcerative colitis (UC) remains challenging despite the fact that morbidity and mortality rates have been considerably reduced during the last 30 years. The traditional management with intravenous corticosteroids was modified by the introduction of ciclosporin and infliximab. In this review, we focus on the treatment of patients with moderate to severe UC. Four typical clinical scenarios are defined and discussed in detail. The treatment recommendations are based on current literature, published guidelines and reviews, and were discussed at a consensus meeting of Swiss experts in the field. Comprehensive treatment algorithms were developed, aimed for daily clinical practice. PMID- 21706454 TI - What can be done with expired pharmaceuticals? A review of literature as it pertains to special operations force?s medics. AB - Over the past decade, increasing evidence suggests that pharmaceuticals may continue to be potent beyond their date of expiration. Despite this evidence, we have not yet experienced a change in United States federal policy that would recommend usage of expired pharmaceuticals. While the scientific community and federal regulators continue to study the matter, the medical community is often guilty of misunderstanding the nuances of the issue. As a result, many healthcare professionals misinform their peers and their patients on either the appropriateness or inappropriateness of taking expired medications. Even though both the American Medical Association (AMA) and the Food and Drug Administration (FDA) do not recommend the dosing of expired pharmaceuticals at this time, discussion of the issue is warranted in order to understand the potential behind some expired drugs and to encourage further research. This discussion is particularly relevant to the Special Operations medical community, since Special Operations Force's (SOF) medics frequently encounter expired medication overseas. Given their unique skill set and working environment, the SOF medic should be familiar with the potential applications of expired medications, including their drawbacks. PMID- 21706455 TI - Guidelines for implementing medical operations in the Counterinsurgency (COIN) fight: a framework for engagement. AB - Several articles have been published over the last decade that describe the current role of medical operations (variously known as MEDCAPS- Medical Civic Action Programs, CMEs- Co-Operative Medical Engagements, etc.) in COIN and stability operations. Many of these articles focus on the experiences of healthcare and support personnel and their observations of inappropriately used U.S. Military healthcare resources. These medical assets were often used to provide fragmented and direct patient care to local populations. These operations were conducted in a non-sustainable fashion.2 Most importantly, poorly organized efforts damage COIN efforts and alienate local populations. Effective medical operations must be nested within the larger realm of overall COIN actions. In this paper, a fundamental framework is presented to align medical operations within COIN missions. PMID- 21706456 TI - Medical rules of engagement negative patients: the dilemma of forward surgical teams in counterinsurgency operations. AB - By definition, Forward Surgical Teams (FSTs) are located far forward in the battlespace to allow for emergent treatment of life and limb threatening trauma sustained by United States and coalition forces as well as those injured according to the medical rules of engagement (MROE). While official doctrine dictates that MROE negative patients are not entitled to care by American military medical assets, experience has shown that some FSTs do not always adhere to that doctrine during counterinsurgency (COIN) operations. Medical civic action programs (MEDCAPS) have been used in modern COIN conflicts in an attempt to gain favor with and influence the host nations? local population. However, the results have frequently been counterproductive to the intended mission. The FST, by doctrine, is not equipped to take part in traditional MEDCAPS. The focus of this paper is to explore the potential role of the FST in COIN operations. Possible roles for the FST in COIN include improving the host nation medical capabilities through education and training. Further, surgery can be a useful commodity to gain positive influence with or to trade for intelligence from key local national leaders. PMID- 21706457 TI - Advanced airway management in combat casualties by medics at the point of injury: a sub-group analysis of the reach study. AB - background: Optimal airway management protocols for the prehospital battlefield setting have not been defined. Airway management strategies in this environment must take into account the injury patterns, the environment and training requirements of military prehospital providers. METHODS: This is a post-hoc, sub group analysis of the Registry of Emergency Airways Arriving at Combat Hospitals or REACH database. This study examines only those patients who had advanced airways placed for trauma by an enlisted military medic at the point of injury. results: Twenty (100%) of the patients had a traumatic injury, 19 (95%) were male, and 13 (65%) had a gun shot wounds (GSWs) as the mechanism of injury. The majority, 12 (60%) patients had an esophageal-tracheal airway device placed. Of the remaining patients, four (20%) underwent endotracheal intubation, three (15%) had a surgical cricothyroidotomy performed, and one (5%) had a Laryngeal Mask Airway (LMA) placed. Seventeen (85%) of the twenty patients were dead on arrival or died shortly after arrival at the Combat Support Hospital (CSH). All of the patients that died had a Glasgow Coma Scale (GCS) of three upon arrival. The Glasgow Coma Scale provides a score in the range 3-15; patients with scores of 3 8 are usually said to be in a coma. Three patients in this group survived to transfer from the CSH. Two of the transfers were lost to follow up, one with a GSW to the head and GCS of three, the other with a GCS of five from injuries sustained in an explosion. The third patient had a surgical cricothyroidotomy (SC) performed in the field for an expanding neck hematoma and recovered fully following surgery. conclusions: Casualties that tolerate invasive airway management without sedation in the context of trauma prognosticates a very high mortality. Airway management algorithms for military providers should reflect the casualties encountered on the battlefield not patients in cardiac arrest which predominate in the civilian EMS airway management practice. Further data are needed to understand the injuries encountered on the battlefield and to develop airway management solutions that optimize outcomes of patients with battlefield trauma. PMID- 21706458 TI - A comparison of direct versus indirect laryngoscopic visualization during endotracheal intubation of lightly embalmed cadavers utilizing the GlideScope(r), Storz Medi Pack Mobile Imaging SystemTM and the New Storz CMACTM videolaryngoscope. AB - BACKGROUND: Studies indicate that the skills needed to use video laryngoscope systems are easily learned by healthcare providers. This study compared several video laryngoscopic (VL) systems and a direct laryngoscope (DL) view when used by medical residents practicing intubation on cadavers. The video devices used included the Storz Medi Pack Mobile Imaging SystemTM, the Storz CMAC(r) VL System and the GlideScope(r). METHODS: After Institutional Review Board (IRB) approval, University of Nebraska Medical Center, Department of Emergency Medicine (UNMC EM) residents were recruited and given a brief pre-study informational period. The cadavers were lightly embalmed. The study subjects were asked to perform intubations on two cadavers using both DL and VL while using the three different VL systems. Procedural data was recorded for each attempt and pre and post experience perceptions were collected. RESULTS: N=14. All subjects reported their varied previous intubation experience. The average airway score using DL: for the Storz VL was 1.54 (SD = 0.576) and for the C-MAC was 1.46 (SD = 0.637). Success in intubation of the standard airway using DL was 93% versus a 100% success rate when intubating with indirect VL visualization. CONCLUSION: Based on our data, we believe that the incorporation of VL into cadaver airway management training provided an improved learning environment for the study residents. In our study, the resident subjects were 93% successful with DL intubation even though 50% had less than 30 intubations. As well, there was a 100% success rate when intubating with indirect VL visualization. In conclusion, the researchers believe this cadaver model incorporated with VL is a powerful tool which may help improve the overall learning curve for orotracheal intubation. PMID- 21706459 TI - Interest survey and guide to medical school admissions for SOF medics. AB - The University of North Carolina at Chapel Hill and the Special Warfare Training Group, Airborne (SWTG)(A) at Fort Bragg, NC began a bilateral partnership in 2009 to enhance medical training, care and innovation in austere environments. As a result of this partnership, instructors from the Joint Special Operations Training Center have been completing month-long rotations in the North Carolina Jaycee Burn Center and University of North Carolina Hospitals. This rotation has been successful and prompted us to assess the interest of Special Operation Forces (SOF) medics is in pursuing careers in healthcare, especially medical school. We surveyed the Special Forces Medical Sergeant (SFMS) listserve on Army Knowledge Online (AKO) to collect these data. This article will review SFMS survey responses and offer information on how to negotiate medical school admissions. PMID- 21706460 TI - Adaptations to a new physical training program in the combat controller training pipeline. AB - OBJECTIVES: The United States Air Force combat controller (CCT) training pipeline is extremely arduous and historically has a high attrition rate of 70 to 80%. The primary objective of this study was to evaluate the impact of incorporating a 711 Human Performance Wing (HPW) / Biobehavior, Bioassessment, and Biosurveillance Branch (RHPF)-developed physical fitness-training program into the combat controller (CCT) 5-level training physical fitness program. METHODS: One-hundred nine CCT trainees were tested and trained during their initial eight weeks at the 720th Special Tactics Training Squadron (STTS) at Hurlburt Field. Modifications to their physical training program were principally aimed at reducing overtraining and overuse injury, educating trainees and cadre on how to train smarter, and transitioning from traditional to "functional" PT. A battery of physiological measurements and a psychological test were administered prior to and immediately after trainees undertook an 8-week modified physical fitness training program designed to reduce overtraining and injury and improve performance. We performed multiple physical tests for cardiovascular endurance (VO2max and running economy), "anaerobic" capacity (Wingate power and loaded running tests), body composition (skinfolds), power (Wingate and vertical jump), and reaction time (Makoto eye-hand test). We used the Mental Toughness Questionnaire 48 (MTQ-48) for the psychological test. RESULTS: We observed several significant improvements in physical and physiological performance over the eight weeks of training. Body composition improved by 16.2% (p < 0.05). VO2max, time-to-exhaustion, and ventilatory threshold were all significantly higher after implementation of the new program than before it. We observed strong trends towards improvement in work accomplished during loaded running (p = 0.07) and in average power per body mass during lower body Wingate (p = 0.08). Other measures of lower body power did not change significantly over the training period, but did show mild trends towards improvement. Upper body average and peak power per kilogram of body mass both improved significantly by 5.8% and 8.1%, respectively. Reaction time was significantly better posttraining as demonstrated by a 7% improvement during the reactive test. Reactive accuracy also improved significantly with the post test accuracy percentage jumping from 61% to 76%. Furthermore, overuse injuries, a major source of attrition fell by a dramatic 67%. CONCLUSIONS: The modifications resulted in significant improvement in trainees? graduation rate. In the eight classes prior to implementation of these changes, average CCT graduating class size was nine trainees. For the eight classes following the changes, average CCT graduating class rose to 16.5 trainees, an increase of 83%. Due to its success, STTS leadership expanded the modifications from the eight weeks prior to CDS to include the entire second year of the pipeline. PMID- 21706461 TI - Military static line parachuting injuries seen by the airborne battalion provider. AB - Military static line parachuting exposes jumpers to a variety of novel methods of injury. Providers assigned to Airborne units need to develop and maintain a high index of suspicion when dealing with jump-related injuries. Understanding the incident rate and the mechanism of injury can help a provider better identify injuries based on the history of the incidence and develop that index of suspicion. Injuries can happen at almost any point during the jump process and each step has both common and unique injuries associated with it. In addition to identifying, managing, and treating the injuries involved, providing information on estimated time until return to duty can be beneficial for the commander. In the end, a provider's best tools for managing Airborne-related injuries are an understanding of Airborne operations, quality orthopedic skills, and a high index of suspicion. PMID- 21706462 TI - Case report: Acute Intermittent Porphyria in a 21 year-old active duty male. AB - Acute Intermittent Porphyria (AIP) is one of a group of rare metabolic disorders arising from reduced activity of any of the enzymes in the heme biosynthetic pathway. The porphyrias can be very difficult for the practitioner to understand. There are several types of porphyrias, which have been known by various different names and are classified from different perspectives1 based on where the defective synthesis site is, or what the clinical manifestations are. Since practitioners rarely encounter this disease process, it is commonly not considered in the differential diagnoses. AIP can be confused with other causes of acute abdominal disorders such as appendicitis with peritonitis or nephrolithiasis. Patients with AIP typically give a history of constipation, fatigue, irritability, and insomnia that precede their acute attack. Symptoms occur intermittently in some patients with acute attacks lasting for several days or longer and were usually followed by complete recovery. This case report deals with an initial presentation of AIP in an otherwise healthy 21-year-old active duty male Soldier. Clinical presentation, diagnosis and treatment are discussed as is a brief historical anecdote. PMID- 21706463 TI - Experimental infection of pigs with group A rotavirus and enterotoxigenic Escherichia coli in India: gross, histopathological and immunopathological study. AB - The authors describe a detailed study conducted in Assam, India, of gross, histopathological and immunopathological alterations in pigs experimentally infected with rotavirus and enterotoxigenic Escherichia coli (ETEC) expressing K88 pili. A total of 30 Caesarean derived piglets were infected experimentally with rotavirus alone or in combination with ETEC to study the gross and histopathological alterations and the distribution pattern of different B- and T cell subsets in the gut. Villus atrophy, especially in the jejunum and ileum, was the consistent lesion in piglets infected with rotavirus, while in piglets simultaneously infected with rotavirus and ETEC, severe necrosis of the intestinal villi was observed. Ultrastructural studies revealed similar pathological alterations in the ileum of the infected piglets. A morphometric study of the intestinal villi and crypts showed a reduction in the ratio between the average villus height and crypt depth (VH:CD ratio) in the group infected with rotavirus (5.95+/-0.33) and those infected with rotavirus and ETEC (7.90+/ 0.16). A higher (p<0.01) reduction in the VH:CD ratio was observed in the jejunum (8.83+/-0.79) and ileum (8.46+/-0.78) compared that in the duodenum (10.03+/ 0.50) of the infected pigs. Piglets infected with rotavirus and sacrificed on day 6 post infection revealed the presence of lymphocytes containing cytoplasmic IgA+ (cIgA+) cells in the villus lamina propria and intra-epithelial CD8+ T cells in the villus epithelia. Rotavirus infection of young piglets in association with ETEC was more severe than rotavirus infection alone. Such infection resulted in marked clinico-pathological and immunological alterations in the infected piglets. PMID- 21706464 TI - One Health or...some health? AB - In essence, the One Health concept represents a visionary paradigm shift for health and health care (for humans and animals) by promoting interdisciplinary communications and by co-equal and respectful collaborations for more expeditious public health (infectious diseases) and comparative biomedical investigations, research and discoveries. This is intended to be all-inclusive among the scientific disciplines of human medicine, veterinary medicine and all other related scientific health disciplines. This reprinted Opinion piece, 'One Health...or some health?' highlights a potentially serious disconnect within the One Health movement viz. the trend towards excluding the One Health comparative medicine research and clinical advances resulting from the utilisation of One Health principles. The view that including this critical aspect of One Health endeavours may unduly detract from international public health considerations is short-sighted and deleterious to the promotion of health in its broadest sense. PMID- 21706465 TI - The need for veterinary nursing in Nigeria. AB - Traditionally, nursing care has been identified as an integral part of human medicine but is not well recognised in veterinary medicine as practised in Nigeria. In caring for human beings, a nurse is expected to have the fundamental understanding of disease aetiology, manifestations, diagnosis, management, rehabilitation, prevention and control. This is equally applicable to the care of animals. The role of veterinary nursing in veterinary medicine is significant considering the multitude of issues involved in the care of animals. The keeping of domestic animals is becoming popular and consequently the spread of infectious diseases from animals to human beings is on the increase. It is vital for human beings and animals to coexist in a healthy environment. The authors examine the importance of nursing care in veterinary medicine, the current situation in Nigeria, the role of veterinary nurses, the inter-professional approach to veterinary medicine, preparedness for the emergence of infectious diseases and career opportunities for veterinary nurses. This premise falls within the context of the 'One Health' concept. PMID- 21706466 TI - An in vitro monocyte culture method and establishment of a human monocytic cell line (K63). AB - A novel method of monocyte culture in vitro was developed. The fraction of monocytes was obtained by density centrifugation of heparinised human venous blood samples. Monocytes were suspended in a modified Rosewell Park Memorial Institute medium (RPMI)-1640 (mRPMI) supplemented with 10% non-inactivated autologous serum added to the feeder cells. An avian cell line was used for feeder cells. Only those monocytes that settled on feeder cells grew rapidly at 37 degrees C-38 degrees C into a formation of clumped masses within two to three days. The cell mass was harvested and subcultures were made without feeder cells. A stable cell line (K63) was established from subcultures using a limited dilution method and cell cloning in microplates. K63 cells were adapted for later growth in the mRPMI medium supplemented with 10% foetal calf serum. The cells were well maintained at over 50th passage levels. This method proved to be applicable for monocyte cultures of animals as well. PMID- 21706467 TI - Detection of fowl poxvirus integrated with reticuloendotheliosis virus sequences from an outbreak in backyard chickens in India. AB - Fowl poxvirus (FPV) infection was observed in unvaccinated backyard chickens. A total of 15 birds were affected in a flock of 37. Pock lesions were observed on the comb, eyelids, beak and wattles. The birds appeared sick with roughened feathers and stunted growth. No mortality was recorded. DNA was isolated from scabs and polymerase chain reaction (PCR) was performed to amplify the 4b core protein gene of FPV, the envelope (env) gene of reticuloendotheliosis virus (REV) and the region of FPV flanking REV 5' long terminal repeat (LTR). Correct-size PCR products of 578 bp, 807 bp and 370 bp, respectively, were observed in agarose gel electrophoresis. Sequence analysis of these products suggests that the virus was an FPV with a genome containing an integrated near full-length REV provirus. Given the fact that REV has been associated with immunosuppression, its presence in the genome of FPV appears to play an important role in the pathogenesis of fowl pox and presumably prolongs persistence of FPV in bird populations. In the present case, fowl pox has been observed to have persisted for about three years in fowl that were reared in backyard systems in villages. PMID- 21706469 TI - Characterisation of Staphylococcus aureus strains isolated from food for human consumption. AB - An investigation was conducted to evaluate Staphylococcus aureus contamination in various types of food of animal origin. Of the 350 samples examined, 14.0% were found to be contaminated with S. aureus. Prevalence rates varied according to type, namely: 19.3% for fresh meat products, 13.3% for fresh cheeses, 3.6% for bakery products and 7.7% for deli products. The isolated S. aureus strains then underwent 16S rDNA polymerase chain reaction (PCR) followed by reverse latex agglutination tests to identify enterotoxigenic strains. The results were compared with data obtained by subjecting the same strains to tests for the genes coding for the S. aureus enterotoxins (SEs) sea, seb, sec, sed, see, seg, seh, sei and toxic shock syndrome toxin 1 (TSST 1). Reversed passive latex agglutination (RPLA) testing revealed that 16.3% of strains (8/49) produced enterotoxins, while on PCR, 48.97% (24/49) were found to carry one or more genes for the production of SEs, and were therefore potentially enterotoxigenic. PMID- 21706471 TI - Contaminated commercial dehydrated food as source of multiple Salmonella serotypes outbreak in a municipal kennel in Tuscany. AB - The authors describe a large outbreak of canine salmonellosis in a municipal kennel in Tuscany. During the outbreak, 174 samples of 'diarrhetic' and 'normal' faeces and two batches of commercial dehydrated dog food were cultured for pathogenic bacteria. The results of 25, out of a total of 41 dogs (60.9%) revealed at least one faecal sample as being positive for Salmonella; incidence per sampling ranged from 12.5% to 34%. Nine of 10 samples of dehydrated food were positive. Ten totally different serotypes were isolated from dry food and faeces: the results of the pulsed-field gel electrophoresis referred to similarity between the Salmonella Montevideo, Muenster and Worthington isolates recovered from both the food and canine faecal samples. PMID- 21706473 TI - Quality of surface fresh waters needing protection or improvement in order to be support fish life: 12 years of monitoring pursuant to European Union Directive 78/659/EEC. AB - To implement European Union Directive 78/659/EEC concerning the quality of fresh waters that require protection or improvement in order to support fish life, the Abruzzo Regional Council commissioned the Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise 'G. Caporale' (by Regional Law No. 50 of 10 August 1994, to conduct a census of the surface freshwaters in the region, and to classify them. The authors describe the freshwater classifications obtained through monitoring campaigns conducted over a period of twelve years (1996 to 2008). The results indicate slight improvements in the quality of the water over time in terms of contamination by chemicals for which they were monitored; however, 14 stretches do not comply with the requirements of the European Union Directive. PMID- 21706474 TI - OCT2, SSX and SAGE1 reveal the phenotypic heterogeneity of spermatocytic seminoma reflecting distinct subpopulations of spermatogonia. AB - Spermatocytic seminoma (SS) is a rare testicular neoplasm that occurs predominantly in older men. In this study, we aimed to shed light on the histogenesis of SS by investigating the developmental expression of protein markers that identify distinct subpopulations of human spermatogonia in the normal adult testis. We analysed the expression pattern of OCT2, SSX2-4, and SAGE1 in 36 SS cases and four intratubular SS (ISS) as well as a series of normal testis samples throughout development. We describe for the first time two different types of SS characterized by OCT2 or SSX2-4 immunoexpression. These findings are consistent with the mutually exclusive antigenic profile of these markers during different stages of testicular development and in the normal adult testis. OCT2 was expressed predominantly in A(dark) spermatogonia, SSX2-4 was present in A(pale) and B spermatogonia and leptotene spermatocytes, whilst SAGE1 was exclusively present in a subset of post-pubertal germ cells, most likely B spermatogonia. The presence of OCT2 and SSX2-4 in distinct subsets of germ cells implies that these markers represent germ cells at different maturation stages. Analysis of SAGE1 and SSX2-4 in ISS showed spatial differences suggesting ongoing maturation of germ cells during progression of SS tumourigenesis. We conclude that the expression pattern of OCT2, SSX2-4, and SAGE1 supports the origin of SS from spermatogonia and provides new evidence for heterogeneity of this tumour, potentially linked either to the cellular origin of SS or to partial differentiation during tumour progression, including a hitherto unknown OCT2 positive variant of the tumour likely derived from A(dark) spermatogonia. PMID- 21706475 TI - Incidence, nature and impact of error in surgery. AB - BACKGROUND: Adverse events occur in 3.8-17 per cent of hospital admissions. The purpose of this study was to analyse the incidence of medical errors and assess the feasibility of an error registry for quality improvement programmes. METHODS: Errors were recorded prospectively in a complication registry between 1 June 2005 and 31 December 2007. Events were coded according to the Trauma Registry of the American College of Surgeons; the nature of events was recorded and the severity graded using the 1992 Clavien system. Recorded events were discussed by the medical staff on a daily basis and, if by consensus judged to be errors, were saved to the registry database. RESULTS: Of 12,121 patients admitted to the surgical ward during the study interval, 2033 (16.8 per cent) had a complication and 735 (6.1 per cent) had an error documented in the registry. Of 873 recorded errors, 607 (69.5 per cent) were of little or no consequence (Clavien grade I) and 220 (25.2 per cent) required therapeutic intervention (Clavien grade IIa and IIb). Errors leading to permanent injury (Clavien grade III) occurred in 41 instances (4.7 per cent) and five patients (0.6 per cent) died (Clavien grade IV). CONCLUSION: This study shows that errors are common in surgery, and that near misses are more frequent than errors with serious consequences. It is hypothesized that registration of near misses might prevent errors with serious consequences and thus improve quality of care. PMID- 21706476 TI - Importance of specimen length during temporal artery biopsy. AB - BACKGROUND: Variations in surgical technique of temporal artery biopsy (TAB) performed for diagnosis of giant cell arteritis (GCA) may contribute to high false-negative rates. This was a retrospective analysis of a large database that explored potential associations between specimen length and diagnostic sensitivity of TAB. METHODS: Histopathological reports and medical records of patients who underwent TAB in six hospitals between 2004 and 2009 were reviewed. RESULTS: A total of 966 biopsies were analysed. The median postfixation specimen length was 1 (range 0.1-8.5) cm and 207 biopsies (21.4 per cent) were positive for GCA. Significant variation in prebiopsy erythrocyte sedimentation rate (ESR), arterial specimen length and positive results was noted amongst hospitals. Multivariable analysis revealed that patient age, ESR value and specimen length were independent predictors of GCA. Positive biopsies had significantly longer median specimen length compared with negative biopsies: 1.2 (range 0.3-8.5) versus 1.0 (0.2-8.0) cm respectively (P = 0.001). Receiver operating characteristic (ROC) analysis identified postfixation specimen length of at least 0.7 cm as the cut-off length with highest positive predictive value for a positive biopsy (area under ROC curve 0.574). Biopsies with specimen length of 0.7 cm or more had a significantly higher rate of positive results than smaller specimens (24.8 versus 12.9 per cent respectively; odds ratio 2.17, P = 0.001). CONCLUSION: Specimen length and ESR were independent prognostic factors of a positive TAB result. A uniform referral practice and standard specimen length of approximately 1 cm could help eliminate discrepancies in the results of TAB. PMID- 21706477 TI - Ribosomal protein RPL41 induces rapid degradation of ATF4, a transcription factor critical for tumour cell survival in stress. AB - By activating protective pathways, tumour cells are not only capable of survival in stress, but often associated with increased aggressiveness and metastasis. Activating transcription factor 4 (ATF4) is a major coordinator of tumour cell survival in stress and is commonly overexpressed in tumours. Numerous studies suggested that the ATF4 is a potential therapeutic target for cancer. In this report, we describe that a small ribosomal peptide, RPL41, induced rapid ATF4 degradation. By immunofluorescence staining, RPL41 induced ATF4 relocation from nuclei to cytoplasm, where ATF4 co-stained with a proteasome marker; the RPL41 induced ATF4 relocation and degradation were blocked by the proteasome inhibitor MG132. An in vivo phosphorylation study showed that RPL41 induced ATF4 phosphorylation and serine 219 of ATF4 was essential for RPL41-induced ATF4 degradation. Cells with RPL41 knockdown had significantly increased ATF4, suggesting that RPL41 could play a physiological role in regulating the cellular ATF4 level. RPL41 was capable of inducing tumour cell death and cell cycle arrest; at low dose, RPL41 sensitized tumour cells A549 to the DNA damage agent cisplatin. These studies suggest that RPL41, a small peptide that is chemically synthesizable and capable of self-cell penetration, may have potential as an anti ATF4 agent for cancer therapy. PMID- 21706478 TI - MicroRNAs in colorectal cancer metastasis. AB - Metastatic disease is the major cause of death in colorectal cancer (CRC) patients. The metastatic process is highly inefficient and comprises multiple sequential steps. While many genetic factors relevant in this process have already been identified, the epigenetic factors underlying each step still remain obscure. MicroRNAs (miRNAs) are key regulators in tumourigenesis, but their role in the development of cancer metastasis is poorly investigated. The majority of miRNAs involved in the metastatic process have been identified in breast cancer cell lines, and in CRC less data are available. We review the role of miRNAs in the metastatic pathway of CRC, including escape of apoptosis, epithelial mesenchymal transition (EMT), angiogenesis, and invasion. Better understanding of the complex role of miRNAs in the development of CRC metastases may provide new insights that could be of therapeutic consequence. PMID- 21706480 TI - Deregulated miR-155 promotes Fas-mediated apoptosis in human intervertebral disc degeneration by targeting FADD and caspase-3. AB - The role of apoptosis in the pathogenesis of intervertebral disc degeneration (IDD) remains enigmatic. Accumulating evidence has shown that the apoptotic machinery is regulated by miRNAs. We hypothesized that miRNAs might contribute to apoptosis in IDD. We have found that 29 miRNAs were differentially expressed and miR-155 was down-regulated in degenerative nucleus pulposus (NP). The deregulation of miR-155 was further verified using real-time PCR (0.56 fold, p < 0.05). Bioinformatics target prediction identified FADD and caspase-3 as putative targets of miR-155. Furthermore, miR-155 inhibited FADD and caspase-3 expression by directly targeting their 3'-UTRs, which was abolished by mutation of the miR 155 binding sites. In vitro up-regulation of miR-155 in human NP cells by transfection with lentiviral pre-miR-155 resulted in repression of FADD and caspase-3; whereas knockdown of miR-155 with lentiviral antigomiR-155 led to over expression of FADD and caspase-3. Also, Fas-mediated apoptosis was increased when antagonizing miR-155 and decreased when using pre-miR-155 in human NP cells. In addition, we presented direct evidence of NP cells undergoing apoptosis in IDD tissues using transmission electron microscopy analysis. Moreover, a combination of in situ hybridization (ISH) and immunohistochemistry (IHC) revealed that miR 155 expressed in the cytoplasm of human NP cells with reverse correlation with FADD and caspase-3. In summary, this is the first study addressing the underlying mechanisms of IDD in terms of apoptosis and miRNAs. Furthermore, caspase-3 is identified as a novel target of miR-155. Our results suggest that deregulated miR 155 promotes Fas-mediated apoptosis in human IDD by targeting FADD and caspase-3, implicating an aetiological and therapeutic role of miR-155 in IDD. PMID- 21706479 TI - PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1 deficient non-small cell lung cancer. AB - Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11-19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours. PMID- 21706481 TI - Osteoclast formation and function in pigmented villonodular synovitis. AB - Pigmented villonodular synovitis (PVNS) is a synovial tumour-like lesion that frequently causes osteolysis. PVNS contains numerous macrophages and osteoclast like giant cells. In this study, we have analysed the cytochemical and functional characteristics of mononuclear and multinucleated cells in PVNS and determined the cellular and humoral mechanisms underlying giant cell formation and resorption in PVNS. Giant cells and CD14(+) and CD14(-) mononuclear cell populations were isolated from PVNS synovial tissue and cultured alone or in the presence and absence of the osteoclastogenic factors, RANKL and M-CSF. Osteoclast formation and activity was assessed by expression of TRAP and evidence of lacunar resorption. Giant cells in PVNS expressed an osteoclast-phenotype (CD51(+) , TRAP(+) , CD14(-) , HLA-DR(-) ) and were formed only in cultures of mononuclear cells that expressed the macrophage marker CD14. Osteoclast formation required RANKL and occurred in both the presence and absence of exogenous M-CSF. CD14(-) cells in PVNS expressed RANKL. Lacunar resorption by PVNS-derived giant cells was abolished by the addition of the bisphosphonate, zoledronate. Our findings indicate that osteoclasts form by a RANKL-dependent mechanism from CD14(+) mononuclear phagocytes in PVNS. Osteoclast formation occurred even in the absence of exogenous M-CSF, a finding which is in keeping with over-expression of M-CSF playing a pathogenic role in this condition. Anti-osteoclast resorptive treatment may be useful to control osteolysis in PVNS. PMID- 21706482 TI - Cystogenic potential of CD133+ progenitor cells of human polycystic kidneys. AB - In autosomal dominant polycystic kidney disease, cysts arise focally and disrupt normal renal tissue leading to renal failure. In the present study, we show that cyst-lining cells express the stem cell marker CD133. CD133+ progenitor cells isolated from polycystic kidney, carrying mutations of PKD genes, showed a dedifferentiated phenotype similar to CD133+ progenitor cells from normal kidney. However, these cells were more proliferative and presented a defective epithelial differentiation phenotype with respect to normal renal CD133+ cells as they were not able to express all tubular epithelial cell markers when cultured in epithelial differentiation medium. Polycystic CD133+ cells, in contrast to normal renal CD133+ cells, formed cysts in vitro in a three-dimensional culture system and in vivo when injected subcutaneously within Matrigel in SCID mice. Rapamycin treatment reduced in vitro proliferation of polycystic CD133+ cells and decreased cystogenesis both in vitro and in vivo. The in vitro epithelial differentiation was only partially improved by rapamycin. These results indicate that polycystic CD133+ cells retain a dedifferentiated phenotype and the ability to generate cysts. PMID- 21706487 TI - Effects of RANKL on the thymic medulla. AB - The thymic medulla provides a microenvironment where medullary thymic epithelial cells (mTECs) contribute to the establishment of self-tolerance by the deletion of self-reactive T cells and the generation of regulatory T cells. The progression of thymocyte development critically regulates the optimum formation of the thymic medulla, as discussed in this article. Of note, it was recently identified that RANKL produced by positively selected thymocytes plays a major role in the thymocyte-mediated medulla formation. Indeed, transgenic expression of soluble RANKL increased the number of mTECs and enlarged the thymic medulla in mice. The effects of RANKL on the thymic medulla may be useful for the engineering of self-tolerance in T cells. PMID- 21706488 TI - Damage-associated molecular patterns (DAMPs) and mesenchymal stem cells: a matter of attraction and excitement. AB - Necrotic cell death is a typical feature of solid tumors leading to the release of necrotic products, also known as damage-associated molecular patterns (DAMPs), that enhance angiogenesis and prime the immune response. Among the DAMPs, particular attention has been focused on the DNA-binding molecule high-mobility group box 1 (HMGB-1) that can act as a chemoattractant and activator of granulocytes. Here, we discuss an article in this issue of the European Journal of Immunology that demonstrates that DAMPs promote both proliferation and trafficking of mesenchymal stem cells (MSCs), identifying HMGB-1 as a key factor in the regulation of these processes. Moreover, the study shows that DAMPs interfere with the expression of the immunosuppressive molecule indoleamine-2,3 dioxygenase in MSCs, and that the biological activity of HMGB-1 toward MSCs is abolished when HMGB-1 is oxidized. Based on the data from this, and other studies, we depict a model in which DAMPs released from necrotic tumor cells attract and stimulate local proliferation of MSCs that differentiate into tumor associated fibroblasts promoting tumor growth and angiogenesis. Importantly, the hypoxic conditions of the tumor microenvironment may protect DAMPs from oxidation and thereby preserve their functionality. PMID- 21706492 TI - Bioanalysis 2011. PMID- 21706489 TI - Influence of whole arm loss of chromosome 16q on gene expression patterns in oestrogen receptor-positive, invasive breast cancer. AB - A whole chromosome arm loss of 16q belongs to the most frequent and earliest chromosomal alterations in invasive and in situ breast cancers of all common subtypes. Besides E-cadherin, several putative tumour suppressor genes residing on 16q in breast cancer have been investigated. However, the significance of these findings has remained unclear. Thus, other mechanisms leading to gene loss of function (eg haploinsufficiency, or distortion of multiple regulative subnetworks) remain to be tested as a hypothesis. To define the effect on gene expression of whole-arm loss of chromosome 16q in invasive breast cancer, we performed global gene expression analysis on a series of 18 genetically extensively characterized invasive ductal breast carcinomas and verified the results by quantitative real-time PCR (qRT-PCR). The distribution of the differential genes across the genome and their expression status was studied. A second approach by qRT-PCR in an independent series of 30 breast carcinomas helped to narrow down the observed effect. Whole-arm chromosome 16q losses, irrespective of other chromosomal changes, are associated with decreased expression of a number of candidate genes located on 16q (eg CDA08, CGI-128, SNTB2, NQO1, SF3B3, KIAA0174, ATBF1, GABARAPL2, KARS, GCSH, MBTPS1 and ZDHHC7) in breast carcinomas with a low degree of genetic instability. qRT-PCR provided evidence to suggest that the expression of these genes was reduced in a gene dosage-dependent manner. The differential expression of the candidate genes according to the chromosomal 16q-status vanished in genetically advanced breast cancer cases and changed ER status. These results corroborate previous reports about the importance of whole-arm loss of chromosome 16q in breast carcinogenesis and give evidence for the first time that haploinsufficiency, in the sense of a gene dosage effect, might be an important contributing factor in the early steps of breast carcinogenesis. PMID- 21706493 TI - Mammalian plasma membrane proteins as potential biomarkers and drug targets. AB - Defining the plasma membrane proteome is crucial to understand the role of plasma membrane in fundamental biological processes. Change in membrane proteins is one of the first events that take place under pathological conditions, making plasma membrane proteins a likely source of potential disease biomarkers with prognostic or diagnostic potential. Membrane proteins are also potential targets for monoclonal antibodies and other drugs that block receptors or inhibit enzymes essential to the disease progress. Despite several advanced methods recently developed for the analysis of hydrophobic proteins and proteins with posttranslational modifications, integral membrane proteins are still under represented in plasma membrane proteome. Recent advances in proteomic investigation of plasma membrane proteins, defining their roles as diagnostic and prognostic disease biomarkers and as target molecules in disease treatment, are presented. PMID- 21706494 TI - The application of magnetic bead hybridization for the recovery and STR amplification of degraded and inhibited forensic DNA. AB - A common problem in the analysis of forensic DNA evidence is the presence of environmentally degraded and inhibited DNA. Such samples produce a variety of interpretational problems such as allele imbalance, allele dropout and sequence specific inhibition. In an attempt to develop methods to enhance the recovery of this type of evidence, magnetic bead hybridization has been applied to extract and preconcentrate DNA sequences containing short tandem repeat (STR) alleles of interest. In this work, genomic DNA was fragmented by heating, and sequences associated with STR alleles were selectively hybridized to allele-specific biotinylated probes. Each particular biotinylated probe-DNA complex was bound to streptavidin-coated magnetic beads using enabling enrichment of target DNA sequences. Experiments conducted using degraded DNA samples, as well as samples containing a large concentration of inhibitory substances, showed good specificity and recovery of missing alleles. Based on the favorable results obtained with these specific probes, this method should prove useful as a tool to improve the recovery of alleles from degraded and inhibited DNA samples. PMID- 21706495 TI - Identification of tyrosine nitration in UCH-L1 and GAPDH. AB - Protein tyrosine nitration is a post-translational modification commonly used as a marker of cellular oxidative stress associated with numerous pathophysiological conditions. We focused on ubiquitin carboxyl terminal hydrolase-L1 (UCH-L1) and glyceraldehyde-3-phosphate (GAPDH) which are high-abundant brain proteins that have been identified to be highly susceptible to oxidative modification. Both UCH L1 and GAPDH have been linked to the pathogenesis of Alzheimer's and Parkinson's disease, however specific nitration sites have not been elucidated. Identification of specific nitration sites and quantitation of endogenous nitrated proteins are important in correlating this modification to disease pathology. In this study, purified UCH-L1 and GAPDH were nitrated in vitro with peroxynitrite and the presence of nitrated proteins was confirmed by anti-3 nitrotyrosine Western blots. Data-dependent LC-MS/MS analysis identified several distinct tyrosine nitration sites in UCH-L1 (Tyr-80) and GAPDH (Tyr-47, Tyr-92, and Tyr-312). Subsequent validation with synthetic peptides was conducted for selected nitropeptides. An LC-MS/MS method was developed for semi-quantitative determination of the synthetic nitropeptides: KGQEVSPKVY(*) (UCH-L1) and mFQY(*) DSTHGKF (GAPDH). The nitropeptides were detectable in the mid-attomole range and the peak area response was linear over three orders of magnitude. Targeted analysis of endogenous UCH-L1 and GAPDH nitration was then conducted in an in vivo second-hand smoke rat model to evaluate the utility of this approach. PMID- 21706496 TI - Setup for human sera MALDI profiling: the case of rhEPO treatment. AB - The implementation of high-throughput technologies based on qualitative and quantitative methodologies for the characterization of complex protein mixtures is increasingly required in clinical laboratories. MALDI profiling is a robust and sensitive technology although the serum high dynamic range imposes a major limitation hampering the identification of less abundant species decreasing the quality of MALDI profiling. A setup to improve these parameters has been performed for recombinant human erythropoietin (rhEPO) monitoring in serum, analyzing the effects of two commercially available columns (MARS Hu7 and Hu14) for immunodepletion, and two matrices (alpha-cyano-4-hydroxycinnamic acid and 2',4'-dihydroxyacetophenone) for peak quality improvement. The immunodepletion capability of both columns was determined by 2-D DIGE, which precisely revealed the efficacy of Hu14 in protein removal and the serum dynamic range decrement. In addition, the type of matrix, the sample dilution, and the efficacy of optimized parameters were used for serum profiling of ten healthy subjects before and after rhEPO treatment. The principal component analysis indicates that a combination of Hu14 column and 2',4'-dihydroxyacetophenone matrix increases data quality allowing the discrimination between treated and untreated samples, making serum MALDI profiling suitable for clinical monitoring of rhEPO. PMID- 21706497 TI - Chiral selectivity of guanosine media in capillary electrophoresis. AB - Gels formed by self-association of monomeric guanosine compounds join numerous other agents such as cyclodextrins, crown ethers, chiral surfactants, antibiotics, proteins, and polysaccharides for chiral separations. Guanosine gels (G-gels) are self-assembled networks of hydrogen-bonded tetrads formed by guanosine nucleotides and their derivatives. The tetrads stack upon themselves to form columnar, helical aggregates that are stabilized by pi-pi interactions and centrally located cations. Previous work showed the effectiveness of G-gels formed by guanosine-5'-monophophate for separation of the enantiomers of the cationic drug propranolol using capillary electrophoresis. Subsequently, it was found that not all chiral compounds could be resolved into their enantiomers, leading us to investigate in this work the structural features that appear to be correlated to enantiomerically selective interactions of chiral compounds with G gels. For those compounds (anionic 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate and zwitterionic tryptophan) for which enantiomeric resolution was achieved, the effects of experimental conditions and G-gel composition were examined. For other compounds with no net charge (hydrobenzoin and zwitterionic amino acids and derivatives), the migration times were used as an indicator of the extent of interaction with the G-gel run buffer. It was found that the extent of interaction alone does not determine the chiral selectivity of the G-gel, indicating that the mechanism of chiral separation involves particular structural characteristics of the chiral compounds. PMID- 21706498 TI - Determination of sphingosine kinase 2 activity using fluorescent sphingosine by capillary electrophoresis. AB - The study of sphingosine and sphingosine-1-phosphate is now widespread due to their immense role as intra- and extracellular messenger molecules. The balance and interplay of these ceramide metabolites is dependent on the activities of kinase and phosphatase enzymes. Sphingosine and sphingosine-1-phosphate are found in very minute quantities in cells; thus, they require highly sensitive techniques for quantitative analysis. In this study, we developed a quantitative assay for the determination of sphingosine kinase 2 (SphK2) activity both in vitro and with cell lysates, using CE-LIF. Sphingosine fluorescein was used as the substrate. The K(M) of SphK2 for sphingosine fluorescein was 2.8 +/- 0.8 MUM with a V(max) of 2490 +/- 520 MUM/min and a k(cat) of 1920 +/- 402/s. The inhibition of SphK2 was also investigated using four different inhibitors for which 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole inhibitor was the most potent for the in vitro inhibition of SphK2 while N,N-dimethylsphingosine (DMS) did not inhibit but rather increased SphK2 activity. The fluorescence-based approach for the determination of the enzymatic activity of SphK2 proves to be useful for the quantitative determination of SphK2 activity in vitro and in cell lysates, and could be extended to single-cell analysis or applied in drug screening. PMID- 21706499 TI - Transient isotachophoresis in on-line solid phase extraction capillary electrophoresis time-of-flight-mass spectrometry for peptide analysis in human plasma. AB - In this study, we evaluated the combination of transient isotachophoresis with on line solid-phase extraction capillary electrophoresis time-of-flight mass spectrometry (SPE-tITP-CE-TOF-MS) to improve sensitivity of peptide analysis, using several opioid peptides as model compounds. First, standard solutions were analyzed in order to establish the tITP-CE methodology using UV and TOF-MS detection. The volume and composition of the leading and terminating electrolytes (i.e. LE and TE) for an efficient tITP were investigated to obtain optimum detection sensitivity and electrophoretic separation. In the best cases, LODs in tITP-CE-TOF-MS were tenfold better than those obtained in CE-TOF-MS (i.e. 5 versus 50 ng/mL). Afterwards, the tITP-CE-TOF-MS methodology was adapted to perform SPE-tITP-CE-TOF-MS. Repeatability, linearity and LODs were investigated and compared to the values obtained by SPE-CE-TOF-MS. Furthermore, human plasma samples fortified with the opioid peptides were analyzed in order to show the potential of SPE-tITP-CE-TOF-MS for peptide analysis in biological fluids. The LODs attained in standard solutions and plasma samples for some of the studied peptides (i.e. 0.01 and 0.1 ng/mL, respectively) were tenfold better than those obtained in SPE-CE-TOF-MS, proving the enhanced sensitivity that could be achieved when both on-line preconcentration approaches were combined together. PMID- 21706500 TI - A method for quantitative analysis of an anticancer drug in human plasma with CE ESI-TOF-MS. AB - In this study, the extraction recoveries of an anticancer drug (Imatinib) from human plasma using a common liquid-liquid extraction (LLE) method and a new strong cation exchange (SCX) solid-phase extraction (SPE) column was investigated. The extracts were analyzed with CE coupled on-line to electrospray ionization (ESI) time-of-flight mass spectrometry (TOF-MS) using a monoquaternarized piperazine compound (M7C4I) for capillary coatings. Clean extracts with high and reproducible extraction recoveries ranging between 85 and 91% with % RSD values of 2.5% (n = 3) were obtained using the SCX-SPE columns. This can be compared with the recoveries obtained with the LLE method ranging between 30 and 35%. The CE-ESI-TOF-MS analysis was performed in <10 min with peak efficiencies up to 4.7 * 105 plates/m and an average % RSD for the repeatability of the migration times of the analytes of 1.9% (n = 3) using acidic buffer and adding 5% ACN to the sample. The calibration curves were linear over the range of 0-1500 ng/mL with correlation coefficient (R2 >= 0.997 and % RSD values of 0.5% (n=3). The intra-day and inter-day assay variations were lower than 8%. The presented CE-ESI-TOF-MS method with the use of SCX-SPE columns yielded rapid, efficient and high extraction recoveries together with high sensitivity (LOD 5 ng/mL), selectivity and good linearity. Accordingly, the method can readily be used for accurate determination and therapeutic monitoring of the Imatinib blood levels for more effective patient treatment. In addition, it can be applied for the extraction, quantification and clinical assessments of metabolites of Imatinib and other basic pharmaceutical drug molecules in biological fluids or pharmaceutical dosage forms. PMID- 21706501 TI - Targeted ultrasound examination and DNA testing for Noonan syndrome, in fetuses with increased nuchal translucency and normal karyotype. AB - OBJECTIVE: To define sonographic criteria that may improve the prenatal diagnosis of Noonan syndrome by targeted DNA testing. METHODS: We searched our Fetal Medicine Unit records for all cases with a final diagnosis of Noonan syndrome. A literature review was undertaken to identify the sonographic features of Noonan syndrome fetuses. Information was pooled to define the most common features. RESULTS: In our database, we identified three cases of Noonan syndrome. The diagnosis was suspected prenatally in two of them. Thirty-nine cases were identified in the literature. In the presented cases we show that suspicion of Noonan syndrome should arise when, after an increased nuchal translucency, ultrasound investigation in the second trimester shows a persistant nuchal fold (NF) or cystic hygroma in combination with at least one of the following features: hydrops fetalis, pleural effusion, cardiac anomalies, polyhydramnios or specific facial abnormalities. CONCLUSION: Prenatal ultrasound findings in Noonan syndrome can be subtle and aspecific, but when specific characteristics are present additional targeted DNA analysis is indicated. PMID- 21706502 TI - First trimester sonographic features of anorectal atresia: report of two cases. PMID- 21706503 TI - Genetic screening in a university clinic: impact of primary language. AB - OBJECTIVE: To contrast Spanish-speaking (S) with English-speaking (E) obstetric patients regarding utilization of genetic screening, motivation for undergoing/declining screening, pregnancy-related anxiety, knowledge about genetic conditions, and printed information as an adjunct to counseling. METHOD: Paper surveys were given to patients (n = 121) in an academic OB/GYN clinic or placed in charts (n = 271) over a 4-week period. Comparisons were evaluated with Chi-square and Fisher's exact tests. RESULTS: Completed surveys were returned from 245 gravidas (response rate 63%, S 48%, and E 67%). Uptake of genetic screening was similar between the groups (S 69% vs. E 57%, p = 0.13). No significant differences were noted in patients' motivation regarding screening, source of screening information, or self-assessed pregnancy-related anxiety. Familiarity of genetic disorders other than Down syndrome differed between the S and E groups (p < 0.003). Perceived positive utility of printed information differed significantly when groups were analyzed by language (S 85% vs. E 47%, p < 0.001) and by uptake of screening(screened 62% vs. not screened 44%, p = 0.006). CONCLUSION: A majority of study participants (n = 147, 60%) chose genetic screening; uptake and motivation were similar across language groups. Familiarity with genetic conditions was deficient and screening terminology confusing regardless of primary language. The perceived positive utility of printed information (S > E) highlights the importance of clear and early counseling. PMID- 21706504 TI - Preventing mucopolysaccharidosis type II (Hunter syndrome): PGD and establishing a Hunter (46, XX) stem cell line. AB - OBJECTIVES: Preimplantation genetic diagnosis (PGD) enables the identification of affected embryos prior to implantation. We present for the first time three families in which either the oocytes or embryos obtained from female carriers of mutations in the iduronate-2-sulfatase (IDS) gene underwent PGD for mucopolysaccharidosis type II (Hunter syndrome). Furthermore, we report the first ever derivation of a Hunter's syndrome (46, XX) human stem cell line from embryos (HESC) carrying the IDS and oculocutaneus albinism type 2 mutations. METHODS: Combined polar body (PB) 1 and 2 or a single cell of a six- to eight-cell embryo (blastomere) was used for genetic analysis by multiplex polymerase chain reaction assay using six microsatellite polymorphic markers flanking the gene and mutation. RESULTS: One couple underwent four PB-PGD cycles, with birth of a healthy girl; the second couple with one PB-PGD cycle had healthy twins; the third couple underwent seven cycles of double PGD for Hunter and Albinism syndrome with birth of healthy twins. One novel Hunter 46, XX HESC line was established displaying typical characteristics of HESC cells. CONCLUSIONS: PGD is a reliable method to prevent pregnancy of children affected with Hunter syndrome. In addition, derived HESC can be further utilized for drug testing and better understanding of the pathogenesis of this syndrome. PMID- 21706505 TI - Congenital diaphragmatic hernia as prenatal presentation of Apert syndrome. PMID- 21706506 TI - Effect of cord puncture site in cordocentesis at mid-pregnancy on pregnancy outcomes. AB - OBJECTIVES: To compare the procedure and pregnancy outcomes of pregnancies undergoing cordocentesis between a group of cord insertion puncture and that of free loop puncture. MATERIALS AND METHODS: Pregnancies undergoing cordocenteses meeting the following inclusion criteria were recruited: (1) singleton pregnancies at gestational ages of 18-22 weeks; (2) no fetal abnormalities; (3) the procedures performed by experienced operators; and (4) the procedures of no placenta penetration. The recruited cases were classified into two groups: a group of cordocenteses with puncture site at placental cord insertion (Group 1) and those with puncture site at cord free loop (Group 2). The primary outcomes to be compared were rates of fetal loss, newborns with low birth weight and preterm birth. The secondary outcomes included a rate of successful procedures, umbilical cord bleeding, fetal bradycardia, maternal blood contamination, and duration of the procedure time. RESULTS: Of 6147 cordocenteses recruited, 2214 met inclusion criteria. The mean duration to complete the procedure in Group 1 was significantly shorter than that in Group 2 (4.5 +/- 5.4 vs. 6.7 +/- 8.5 min, Student's t-test; p = 0.001). The mean birth weight and gestational age at delivery were comparable between the two groups. No significant differences between the two groups were seen in rates of fetal loss, low birth weight, preterm birth, successful procedures, umbilical cord bleeding, or fetal bradycardia. However, the rate of maternal blood contamination was significantly higher in the group of puncture at the cord insertion site. CONCLUSION: Of cordocenteses performed based on accessibility and quality of visualization, cord insertion puncture may cause more maternal blood contamination but free loop puncture may be associated with more difficult procedures, while the safety was comparable. PMID- 21706507 TI - Ultrasound detection rate of single umbilical artery in the first trimester of pregnancy. AB - OBJECTIVE: To determine accuracy of first trimester detection of single umbilical artery (SUA). METHODS: The number of vessels in the umbilical cord was examined in a prospective cohort of 779 singleton, low-risk, unselected pregnancies, in the first (11-13 weeks) and second (17-24 weeks) trimesters, using both power and color Doppler and after delivery, by placental histopathologic exam. Concordance between first and second trimester findings to postnatal diagnoses was compared by calculating kappa coefficients. RESULTS: There was medium concordance between the findings in the first trimester and the postnatal diagnoses (kappa = 0.52) and high concordance (kappa = 0.89) for the second trimester scan. Sensitivity, specificity, positive and negative predictive values for the findings in the first trimester were 57.1, 98.9, 50.0 and 99.2% and for the second trimester were 86.6, 99.9, 92.9 and 99.7%. CONCLUSION: Sensitivity and positive predictive value of first trimester scan to identify an isolated SUA in a prospective unselected population was poor. Diagnosis of isolated SUA as well as a definitive judgment about the presence of associated anomalies would still require a scan in the second trimester. PMID- 21706509 TI - The role of three-dimensional imaging reconstruction to measure the corpus callosum: comparison with direct mid-sagittal views. AB - OBJECTIVES: To determine the accuracy of measuring the corpus callosum (CC) length in reconstructed mid-sagittal views obtained by 3D multiplanar manipulations or volume contrast imaging in the C-plane (VCI-C) in comparison to measurements obtained by direct mid-sagittal view. METHODS: Forty-six normal fetuses were examined by 2D and 3D ultrasound between 23 and 32 weeks of gestation. Direct mid-sagittal views were obtained by either the transabdominal or/and the transvaginal approach. 3D reconstructed mid-sagittal views were obtained by either 3D multiplanar manipulations or VCI-C. The CC length was measured in direct mid-sagittal views and in 3D reconstructed mid-sagittal views. RESULTS: One hundred and thirty ultrasound examinations were performed. In 118 cases (91%) it was possible to obtain both a direct and a 3D reconstructed mid sagittal view. Measurements of the CC length in direct mid-sagittal views correlated significantly with the measurements in reconstructed mid-sagittal views when the region underneath the comma-shaped echogenic structure was measured, but correlated poorly when this echogenic structure was included. CONCLUSIONS: Reconstructed mid-sagittal views obtained by 3D multiplanar manipulations or by VCI-C are valid approaches for measuring CC length. In these views the CC should be measured as the region underneath the comma-shaped echogenic structure. PMID- 21706508 TI - Refining the critical region for congenital diaphragmatic hernia on chromosome 15q26 from the study of four fetuses. PMID- 21706510 TI - Prenatal brain imaging in congenital toxoplasmosis. AB - OBJECTIVE: To describe brain imaging findings and outcomes in fetuses with confirmed congenital toxoplasmosis (CTX). METHODS: Physicians from Prenatal Diagnosis Units in ten Latin American countries were contacted and asked to provide data on fetuses with ultrasound findings suggestive of intrauterine infection and a positive diagnosis of CTX. The imaging studies were reviewed, and findings were described and tabulated. RESULTS: Intracranial findings suggestive of CTX were identified in eight patients at a median gestational age of 31.5 weeks (range, 24.4-34 weeks). Ventriculomegaly was found in seven patients [severe (3), mild (4)]. Multiple echogenic nodular foci consistent with calcifications were found in seven patients [brain parenchyma (7), periventricular zone (3) and caudothalamic zone (3)]. Diffuse periventricular echogenicity or cysts were seen in three and callosal dysgenesis in one. All six survivors have choroidoretinitis and intracranial calcifications, four suffer from developmental delay and three of these four children also suffer from seizures and blindness. Postnatal hydrocephaly was found in five children. CONCLUSIONS: Ventriculomegaly associated with multiple echo-dense nodules is characteristic of severe fetal toxoplasmosis and carries a poor prognosis. When the ventricles have normal size or are only mildly dilated, the nodules restricted to the parenchyma development may be normal. PMID- 21706511 TI - Holoprosencephaly at prenatal diagnosis: analysis of 28 cases regarding etiopathogenic diagnoses. AB - OBJECTIVE: To assess the likelihood of finding an etiopathogenic cause in an ultrasonographic prenatal diagnosis of holoprosencephaly. MATERIALS AND METHODS: From January 1996 to June 2010, 13 883 prenatal diagnoses through chorionic villus sampling or amniocentesis were made. Every fetus with holoprosencephaly at ultrasound was evaluated. Gestational age, additional ultrasound findings, and fetal karyotype were recorded. Molecular diagnosis and parental karyotype were studied, if relevant. RESULTS: Twenty-eight fetuses were diagnosed with holoprosencephaly (0.20%). All cases had additional ultrasound findings (100%). A definitive etiology was found in 23 cases (82.14%): karyotype was abnormal in 19 (67.9%) and normal in 8 (28.5%) cases. In the normal karyotype group, although molecular testing was performed in a few cases, one mutation of gene SIX 3 was diagnosed, one diagnosis of dysgnathia complex was made, and two fetuses presented Smith-Lemli-Opitz syndrome. No etiopathogenic diagnosis was made in five fetuses. CONCLUSIONS: Our results showed that a definitive etiology can be established in most cases of prenatal holoprosencephaly. Chromosomal anomalies were the most frequent finding. However, in euploid fetuses, molecular diagnosis is worthwhile, as different genes with different inheritance patterns may be responsible for this malformation. Thorough evaluation proved beneficial for assessing more accurate prognosis and recurrence risks. PMID- 21706512 TI - The transvaginal probe as a uterine manipulator: a new technique to simplify transabdominal chorionic villus sampling in cases with difficult access to the trophoblast. AB - OBJECTIVES: To evaluate the efficacy of using the transvaginal probe to manipulate the uterus and change the position of the trophoblast, and to simplify access to the chorionic villus under difficult conditions. METHODS: One thousand five hundred and thirty-nine procedures were performed in our centre in 1524 pregnant women from September 2006 to September 2009. In 90 of these, a difficult access to the trophoblast was observed and uterine manipulation under continuous ultrasound guidance with a double needle technique, was applied to obtain the sample. Of these, 86 samples were taken from singleton pregnancies and 4 from two bichorionic twin pregnancies RESULTS: One thousand five hundred and thirty-nine transabdominal chorionic villus sampling (TA-CVS) procedures were conducted on 1524 pregnant women. As many as 1449 were performed without manipulation with the transvaginal probe and in 90 cases the manipulation was carried out. In 89 cases, access to the trophoblast was difficult and the uterus was manipulated, which enabled an adequate TA-CVS to be performed with a single aspiration. In one case, TA-CVS was not performed due to significant pelvic pain in a patient with a fixed, retroflexed uterus and a previous history of endometriosis. CONCLUSIONS: Uterine manipulation with the transvaginal probe may be a useful solution in cases where TA-CVS is limited by difficult access to the trophoblast. PMID- 21706513 TI - First-trimester stepwise sequential prenatal screening for Down syndrome using NT and maternal age. PMID- 21706514 TI - Detection rate of quadruple-marker screening determined by clinical follow-up and registry data in the statewide California program, July 2007 to February 2009. AB - OBJECTIVE: To evaluate the efficiency of California's quadruple-marker screening program and construct receiver-operating characteristic (ROC) curves. METHODS: This study included the screening records of 552 941 women during July 2007 to February 2009. The screen-positive women received clinical follow-up services at state-approved centers. We used the California Chromosome Defect Registry which includes clinical, laboratory, and demographic data from the prenatal diagnostic centers, cytogenetic laboratories, hospitals, and prenatal care providers. Risk calculations, screen-positive rates (SPRs), detection rates (DRs) for chromosomal abnormalities, and 95% confidence intervals (95% CIs) were determined. ROC curves comparing the quadruple-marker to triple-marker screening were constructed. RESULTS: The DR and SPR for trisomy 21 (N = 827) during the quadruple-marker time period were 75.7% (95% CI 72.8-78.6%) and 3.75% (95% CI 3.70-3.80%) compared with 77.4% (95% CI 75.0-79.7%) and 5.4% during the triple-marker phase. The DRs were 78.2% (95% CI 75.0-81.4%) with ultrasound dating and 66.9% (95% CI 59.7-74.0%) for last-menstrual-period-dated pregnancies. For trisomy 18, triploidy, and trisomy 13, the DRs were 84.3, 95.7, and 43.5%, respectively. CONCLUSIONS: The DR for trisomy 21 in California's statewide quadruple-marker screening is very similar to the Program's previously reported DR using triple-marker screening. However, this was achieved at a lower SPR, demonstrating improved screening performance. PMID- 21706515 TI - Effects of melamine on pregnant dams and embryo-fetal development in rats. AB - There are worldwide concerns regarding the potential adverse effect of melamine. This study investigated the potential effects of melamine on pregnant dams and embryo-fetal development in Sprague-Dawley rats following maternal exposure on gestational days (GD) 6-20. Melamine was administered to pregnant rats by gavage at doses of 0, 200, 400 and 800 mg kg-1 per day (n = 8-10 for each group). All dams were subjected to a Caesarean section on GD 21 and their fetuses were examined for morphological abnormalities. With administration of melamine at 800 mg kg-1 per day, maternal toxicity manifested as increased incidences of clinical signs and death, lower body weight gain and food intake, and increases in heart, adrenal gland and kidney weights. Histopathological examinations revealed an increase in incidences of congestion, tubular necrosis/degeneration, crystals, casts, inflammatory cells in tubules, tubular dilation and tubular hyaline droplets in the maternal kidneys, while fetal kidneys (one fetus/litter) did not show any histopathological changes. Developmental toxic effects included a decrease in fetal weight, an increase in the incidence of skeletal variations and a delay in fetal ossification. No treatment-related maternal or developmental effects were observed at doses <= 400 mg kg-1 per day. These results show that 15 day repeated oral dosing of melamine is embryo-/fetotoxic at a maternotoxic dose, but not teratogenic in rats. The no-observed-adverse-effect level of melamine for pregnant dams and embryo-fetal development is considered to be 400 mg kg-1 per day. PMID- 21706516 TI - Commentary on 'Multivariate meta-analysis: potential and promise'. PMID- 21706517 TI - Mock jury research: where do we go from here? AB - This paper reviews the four types of validity that make up Cook and Campbell's traditional approach for social science research in general and psychological research in particular: internal validity, statistical conclusion validity, external validity, and construct validity. The most important generalizability threat to the validity of jury research is not likely a selection main effect (i.e., the effect of relying solely on undergraduate mock jurors) but is more likely the interaction of sample with construct validity factors. Researchers who try to capture the trial process with experimental paradigms may find that undergraduate mock jurors react differently to those efforts than do more representative community samples. We illustrate these issues with the seven papers that make up this volume, and conclude by endorsing Diamond's call for a two-stage research process in which findings with samples of convenience gradually add more realistic trial processes and representative samples to confirm the initial findings and increase the research program's credibility. PMID- 21706522 TI - From diagnosis to treatment and beyond. PMID- 21706525 TI - Share, don't hoard: The importance of information exchange in 21st century health criminal justice partnerships. PMID- 21706518 TI - Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. AB - The need, safety, and effectiveness of vitamin D supplementation during pregnancy remain controversial. In this randomized, controlled trial, women with a singleton pregnancy at 12 to 16 weeks' gestation received 400, 2000, or 4000 IU of vitamin D(3) per day until delivery. The primary outcome was maternal/neonatal circulating 25-hydroxyvitamin D [25(OH)D] concentration at delivery, with secondary outcomes of a 25(OH)D concentration of 80 nmol/L or greater achieved and the 25(OH)D concentration required to achieve maximal 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] production. Of the 494 women enrolled, 350 women continued until delivery: Mean 25(OH)D concentrations by group at delivery and 1 month before delivery were significantly different (p < 0.0001), and the percent who achieved sufficiency was significantly different by group, greatest in 4000-IU group (p < 0.0001). The relative risk (RR) for achieving a concentration of 80 nmol/L or greater within 1 month of delivery was significantly different between the 2000- and the 400-IU groups (RR = 1.52, 95% CI 1.24-1.86), the 4000- and the 400-IU groups (RR = 1.60, 95% CI 1.32-1.95) but not between the 4000- and. 2000 IU groups (RR = 1.06, 95% CI 0.93-1.19). Circulating 25(OH)D had a direct influence on circulating 1,25(OH)(2)D(3) concentrations throughout pregnancy (p < 0.0001), with maximal production of 1,25(OH)(2)D(3) in all strata in the 4000-IU group. There were no differences between groups on any safety measure. Not a single adverse event was attributed to vitamin D supplementation or circulating 25(OH)D levels. It is concluded that vitamin D supplementation of 4000 IU/d for pregnant women is safe and most effective in achieving sufficiency in all women and their neonates regardless of race, whereas the current estimated average requirement is comparatively ineffective at achieving adequate circulating 25(OH)D concentrations, especially in African Americans. PMID- 21706526 TI - Learning motivational interviewing in a real-life setting: a randomised controlled trial in the Swedish Prison Service. AB - BACKGROUND: Motivational interviewing (MI) is a client-centred, directive counselling style for helping people to explore and resolve ambivalence about behaviour change and shown to decrease drug and alcohol use. A five-session semi structured MI intervention [Beteende, Samtal, Forandring (BSF; Behaviour, Counselling, Change)] was implemented in Swedish prisons. AIMS: To examine whether, in a real-life implementation of semi-structured MI, staff receiving ongoing MI training, based on audio-recorded feedback in peer groups (BSF+), possess greater MI skill compared with staff receiving workshop-only MI training (BSF), and staff conducting usual prison planning interviews (UPI). METHODS: Prisoners were randomised to one of the three interventions. The fi rst sessions between staff and prisoner with complete data were assessed with the Motivational Interviewing Treatment Integrity Code 3.0. RESULTS: Content analysis of 45 staff: prisoner sessions revealed that counsellors in the BSF+ group were significantly more competent in MI than those in the UPI group, but there was no difference in MI competency between the BSF and UPI groups. Overall, staff were rated as not having achieved beginning proficiency. CONCLUSIONS: Our findings suggest that staff delivering motivational interviewing programmes for substance-misusing prisoners in Sweden are not being given sufficient training for the task. Previous literature has suggested that staff need more than a basic 3- to 5-day workshop training, but our findings suggest that they may need longer-term continuing supervision and support than previously recognised. PMID- 21706527 TI - Social climate along the pathway of care in women's secure mental health service: variation with level of security, patient motivation, therapeutic alliance and level of disturbance. AB - BACKGROUND: Social climate has been measured in a variety of therapeutic settings, but there is little information about it in secure mental health services, or how it may vary along a gender specific care pathway. AIM: To assess social climate in women's secure wards and its variation by level of security and ward type, therapeutic alliance, patient motivation, treatment engagement and disturbed behaviour. METHOD: Three-quarters (80, 76%) of staff and nearly all (65, 92%) of patients in the two medium-security wards and two low-security wards that comprised the unit completed the Essen Climate Evaluation Schema (EssenCES) and the California Psychotherapy Alliance Scale (CALPAS); patients also completed the Patient Motivation Inventory (PMI). Pre-assessment levels of disturbed behaviour and treatment engagement were recorded. RESULTS: Social climate varied according to ward type and level of security. EssenCES ratings indicative of positive social climate were associated with lower levels of security; such ratings were also associated with lower behavioural disturbance and with higher levels of motivation, treatment engagement and therapeutic alliance. CONCLUSION: This serial cross-sectional survey indicated that use of the EssenCES alone might be a good practical measure of treatment progress/responsivity. A longitudinal study would be an important next step in establishing the extent to which it would be useful in this regard. PMID- 21706528 TI - The prevalence of mental disorders in Spanish prisons. AB - BACKGROUND: The prevalence of mental disorders among prisoners has been researched in a few countries worldwide but never previously in Spain. AIM: Our aim was to estimate the lifetime and last month prevalence of mental disorders in a Spanish prison population. METHODS: This is a descriptive, cross-sectional, epidemiological study of 707 male prisoners. Sociodemographic, clinical and offending data were collected by interviewers. Offending data were confirmed using penitentiary records. Mental disorders were assessed with the clinical version of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition Axis I Disorders, and personality disorders were assessed through the Spanish version of the International Personality Disorders Examination. RESULTS: The lifetime prevalence of mental disorder was 84.4%. Substance use disorder (abuse and dependence) was the most frequent disorder (76.2%) followed by anxiety disorder (45.3%), mood disorder (41%) and psychotic disorder (10.7%). The period (last month) prevalence of any mental disorder was 41.2%. Anxiety disorder was the most prevalent (23.3%) followed by substance use disorder (abuse and dependence; 17.5%), mood disorder (14.9%) and psychotic disorder (4.2%). CONCLUSION: Although period prevalence figures, which are those generally provided in research into rates of mental disorder among prisoners, are useful for planning improvements to services within prisons, the fact that almost all of these men had a lifetime prevalence of at least one mental disorder suggests a much wider need for improving services, including community services, for this group. PMID- 21706530 TI - Many reasons to celebrate! PMID- 21706529 TI - Macromol. Rapid commun. 1/2009. PMID- 21706531 TI - Regioregular Poly(3-hexylthiophene) in a Novel Conducting Amphiphilic Block Copolymer. AB - Regioregular poly(3-hexylthiophene) has been successfully incorporated into a novel amphiphilic block copolymer. The amphiphilic nature of poly(3 hexylthiophene)-block-poly(acrylic acid) has been investigated using spectroscopic methods and has yielded solvatochromic behavior in several solvents of varying polarity. Evidence suggests that a supramolecular, long range ordering of block copolymer occurs in polar solvents, resulting in the formation of aggregates. Despite relatively large amounts of non-conductive blocks, the poly(3 hexylthiophene) diblock copolymer yields a high conductivity of 1 S . cm(-1) , and atomic force microscopy shows the formation of a highly organized nanofibrilar morphology in the solid state. PMID- 21706532 TI - Polyethylene nanocomposite heat-sealants with a versatile peelable character. AB - A novel heat-sealing performance is achieved by polyethylene (PE) nanocomposites reinforced by ethylene vinyl acetate (EVA) and montmorillonite (MMT). Appropriate nanocomposite design leads to hermetic seals with a general peelable/easy-open character across the broadest possible sealing temperature range. Observations of the fracture seal surfaces by infrared spectroscopy and electron microscopy reveal that this behavior originates from a synergistic effect of the EVA copolymer and the montmorillonite clay nanofiller. Namely, the combination of EVA copolymers and MMT nanofillers provides sufficiently favorable interactions for nanocomposite formation and mechanical robustness, but weak enough interfacial adhesion to promote a general cohesive failure of the sealant at the EVA/MMT interfaces. PMID- 21706533 TI - Successive chain-growth condensation polymerization for the synthesis of well defined diblock copolymers of aromatic polyamide and aromatic polyether. AB - Well-defined diblock condensation copolymers composed of an aromatic polyamide and an aromatic polyether have been synthesized by means of successive chain growth condensation polymerizations. Polymerization of a polyamide monomer with an orthogonally difunctional initiator is accompanied with side reactions. On the other hand, polymerization with a monofunctional initiator afforded well-defined polyamide, which has been converted into a macroinitiator by introduction of a terminal 4-fluorobenzophenone unit. Well-defined diblock copolymers are obtained by polymerization of a polyether monomer in the presence of this macroinitiator. PMID- 21706534 TI - Unprecedented Route to Ordered Polyaniline: Direct Synthesis of Highly Crystalline Fibrillar Films with Strong pi-pi Stacking Alignment. AB - Films of polyaniline (PANI) featuring about 80% crystallinity and characterised with strong pi-pi stacking alignment parallel to the film surface have been obtained directly after the original synthesis upon simple drying of the aqueous PANI suspension. A strong anisotropy in the growth of the nano-sized crystals produced during the synthesis results in the formation of micrometer-length fibrils perpendicular to the film surface in the course of water evaporation. The regular intercalation of water molecules between the PANI chains seems to be crucial for their ordering throughout the synthesis and film formation. PMID- 21706535 TI - Facile Access to an Efficient Solid-Supported Click Catalyst System Based on Poly(ethyleneimine). AB - A novel heterogeneous copper(I) catalyst system, which is based on readily available poly(ethyleneimine), has been used as a recyclable catalyst for Cu(I) catalyzed "click" 1,3 dipolar cycloaddition reactions of azides and alkynes in organic media. Branched poly(ethyleneimine) was first methylated and then cross linked with 1,9-dibromononane. Subsequently, after the immobilization of Cu(I)Br, this system was applied for heterogeneous copper catalyzed click chemistry of a few model reagents and polymeric compounds. PMID- 21706536 TI - Silyl-Terminated Ethylene-co-Norbornene Copolymers by Organotitanium-Based Catalysts. AB - Ethylene (E) and norbornene (N) were copolymerized in the presence of PhSiH(3) as chain-transfer agent with [Ti(eta(5) :eta(1) -C(5) Me(4) SiMe(2) NBu(t) )(eta(1) Me)(2) ] precatalyst combined with [Ph(3) C][B(C(6) F(5) )(4) ]. The silane was introduced at chain-ends of E-co-N copolymers with concomitant reinitiation of the growing polymer chain. The concentrations of the silane and polymer molecular weight are inversely correlated. The characteristic signals of ?SiH(2) Ph chain ends were observed by (1) H NMR. The Si heteroatom is predominantly adjacent to ethylene units in E-co-N copolymers with high N content. PMID- 21706537 TI - Low bandgap polymers by copolymerization of thiophene with benzothiadiazole. AB - Three low bandgap copolymers of thiophene and benzothiadiazole with electron donating and electron-withdrawing substituents, P1, P2, and P3, have been synthesized by Pd-catalyzed Stille-coupling. Electronic energy levels of the polymers are estimated by cyclic voltammetry. The polymer films show a broad absorption band in the wavelength range from 300 to 750 nm. Among the polymers, the polymer that contains the 5,6-dinitrobenzothiadiazole unit, P3, possesses the smallest bandgap of 1.55 eV calculated from its absorption band-edge at ~800 nm. With the increase of the electron-withdrawing ability of the substituents on the benzothiadiazole unit, the energy bandgap of the polymers decreased in the order P1 > P2 > P3. The results indicate that stronger electron-withdrawing substituents on the acceptor unit can effectively decrease the bandgap of the polymers. PMID- 21706538 TI - Large deformable multiwalled carbon nanotube core-shell structure on polystyrene beads. AB - Multiwalled carbon nanotube (MWCNT)-coated polystyrene (PS) beads have been prepared by dispersion polymerization followed by a layer-by-layer self-assembly method. The concentration of carboxylic acid groups on the MWCNTs increased from 1.81 * 10(21) to 3.43 * 10(22) COO(-) per g as the treatment time was increased from 3 to 9 h. The sulfonated polystyrene (SPS) beads changed from being negatively charged to positively charged when the cationic polyelectrolyte was self-assembled on their surface. The surface morphology of the adsorbed polyelectrolyte was smooth without any aggregation and the thickness of the polyelectrolyte coating on the SPS beads was ~0.6 um. The electrical conductivity and resistance of the MWCNT-coated SPS beads were measured to be 4.0 * 10(-2) S . cm(-1) and 12.8 Omega at a volume fraction of 91%, respectively. PMID- 21706539 TI - Vapor-based polymer gradients. AB - Chemical vapor deposition (CVD) co-polymerization was used to fabricate polymer coatings, which comprise of reactive surface composition gradients. Two functionalized derivatives of [2.2]paracyclophane were fed into a two-source CVD system at a 180 degrees angle, then copolymerized and deposited as a polymer gradient. Infrared and X-ray photoelectron spectroscopy (XPS) confirmed the compositional changes within the bulk polymer and at the surface. By manipulating process parameters, gradients of tailored compositional slope can be deposited on a wide range of substrates. We also were able to selectively immobilize fluorescence-labeled ligands onto the reactive polymer gradients, making CVD based gradient surfaces a flexible platform for fabricating biomolecular substrates. PMID- 21706540 TI - Synthesis of Crosslinked Sulfonated Poly(phenylene sulfide sulfone nitrile) for Direct Methanol Fuel Cell Applications. AB - With a view towards direct methanol fuel cell applications, novel sulfonated poly(phenylene sulfide sulfone nitrile) (sPPSSfN) has been prepared and subsequently crosslinked by a Friedel-Craft reaction using 4,4'-oxybis(benzoic acid) as a crosslinker to achieve lower water swelling and lower methanol permeability. The dimensional change of SPPSSfN40 is 43.7% in 90 degrees C liquid water but that of the crosslinked membrane, XsPPSSfN40, is 23.3% while maintaining proton conductivity at 0.22 S . cm(-1) . These results show that the Friedel-Craft crosslinking of the novel sPPSSfN membrane effectively reduces water uptake and the degree of swelling while improving the dimensional stability and maintaining high proton conductivity. PMID- 21706542 TI - Macromol. Rapid commun. 11/2009. PMID- 21706541 TI - Author Guidelines 2009 (as of November 5, 2008). PMID- 21706543 TI - Propylene Polymerization Performance of Isolated and Aggregated Ti Species Studied Using a Well-Designed TiCl(3) /MgCl(2) Ziegler-Natta Model Catalyst. AB - In propylene polymerization with MgCl(2) -supported Ziegler-Natta catalysts, it is known that the reduction of TiCl(4) with alkylaluminum generates Ti(3+) active species, and at the same time, leads to the growth of TiCl(x) aggregates. In this study, the aggregation states of the Ti species were controlled by altering the Ti content in a TiCl(3) /MgCl(2) model catalyst prepared from a TiCl(3) . 3C(5) H(5) N complex. It is discovered that all the Ti species become isolated mononuclear with a highly aspecific feature below 0.1 wt.-% of the Ti content, and that the isolated aspecific Ti species are more efficiently converted into highly isospecific ones by the addition of donors than active sites in aggregated Ti species. PMID- 21706544 TI - Spontaneous self-assembly of a mono-component polyimide bearing terminal hydrogen bonding sites in a single solvent. AB - A unique example of macromolecular self-assembly, where a mono-component homopolyimide bearing carboxy end-groups spontaneously forms nanopartilces with novel dimple-like morphology in a single good solvent, is presented. The self assembly process is dramatically affected by the solution concentration and the temperature. It is proposed that such an unexpected self-assembly behavior is a synergistic result of the self-complementary hydrogen bonding between carboxy end groups and the propensity to parallel packing of polyimide chains through aromatic interactions. PMID- 21706545 TI - Supramolecular Network Based on the Self-Assembly of gamma-Cyclodextrin with Poly(ethylene glycol) and its Shape Memory Effect. AB - A novel supramolecular network has been prepared based on the formation of inclusion complexes between gamma-cyclodextrin and poly(ethylene glycol), in which the PEG chains are interlocked by gamma-CD rings. This PEG/gamma-CD network exhibits good shape memory behavior because of the crosslinked structure. The crosslinked PEG/gamma-CD inclusion complexes and PEG crystallites account for the fixing phase and reversible phase, respectively. The characteristics of the materials have been investigated by (1) H NMR spectroscopy, XRD, DSC, DMA, viscosity tests, and swelling measurements. PMID- 21706546 TI - Switching the Solubility of PMMA Bearing Attached Cyclodextrin-Moieties by Supramolecular Interactions with Ionic Liquids. AB - Methacrylate-modified beta-cyclodextrin (beta-CD) and methyl methacrylate (MMA) have been radically copolymerized to obtain hydrophobic CD copolymers. The water insoluble copolymers are able to form highly stable inclusion complexes with anions of ionic liquids. Surprisingly, the inclusion of the anions in the CD cavity results in a significant change of thermal and solution properties. Furthermore, it can be shown that the structure of the ionic liquid anions influences the coil structure of the copolymers. The obtained results could be proven by means of microcalorimetry, differential scanning calorimetry, and dynamic light scattering. PMID- 21706547 TI - Precipitation Polymerization in Ethanol and Ethanol/Water to Prepare Uniform Microspheres of Poly(TMPTA-styrene). AB - The precipitation polymerization of styrene-trihydroxymethyl propane triacrylate has been carried out using ethanol and an ethanol/water mixture as the solvent. Uniform microspheres with high monomer conversion are achieved within 4 h, a much shorter polymerization time than that reported for the precipitation polymerization of divinyl benzene-styrene in acetonitrile. The results clearly demonstrate that use of water as a co-solvent is indeed very effective to promote the polymerization to high conversion and to obtain uniform microspheres. With no water under the otherwise same experimental conditions, only about 57% of monomer conversion is obtained; while the monomer conversion is remarkably increased to 96% when 12 vol.-% of water is used. PMID- 21706548 TI - Precision sulfonic Acid ester copolymers. AB - Linear ethylene copolymers containing sulfonic acid ethyl esters precisely spaced on every 21st carbon have been synthesized using metathesis polycondensation chemistry. These precision structures with one directly attached and one aromatic spaced sulfonic acid ester are synthesized with the goal of tailoring layered higher order morphologies in contrast to conventional clustered ionic polyolefins. Primary structural characterization confirms the precision polymer structures. Additional secondary microstructural analysis by DSC shows a recoverable endothermic melt transition of polyethylene-like lamellae crystallites of the directly attached ester while completely amorphous behavior is observed when the ester is spaced away from the backbone with an aromatic group. PMID- 21706549 TI - Water Soluble Star-block Copolypeptides: Towards Biodegradable Nanocarriers for Versatile and Simultaneous Encapsulation. AB - The synthesis of water soluble star-block copolypeptides and their encapsulation properties are described. The star-block copolypeptides, obtained by ring-opening polymerization of amino acid N-carboxyanhydrides, consist of a PEI core, a hydrophobic polyphenylalanine or polyleucine inner shell, and a negatively charged polyglutamate outer shell. The encapsulation study showed that these water soluble, amphiphilic star-block copolypeptides could simultaneously encapsulate versatile compounds ranging from hydrophobic to anionic and cationic hydrophilic guest molecules. PMID- 21706550 TI - Alkylthio-substituted polythiophene: absorption and photovoltaic properties. AB - Two polythiophene derivatives with electron-donating alkylthio side chains, poly[(3-hexylthio)thiophene] (P3HST) and poly[(3-hexylthio)thiophene-alt thiophene] (P3HST-co-Th) have been synthesized and characterized. Both P3HST and P3HST-co-Th show broader absorption peaks than poly(3-hexylthiophene). Meanwhile, the alkylthio side chains decrease the HOMO energy level of the polymers, which benefits the higher open circuit voltage of the polymer solar cells (PSCs) based on the polymer as donor. PSCs have been fabricated with the polymers as donor and [6,6]-phenyl C61 butyric acid methyl ester as acceptor (1: 1, w/w). The devices based on P3HST and P3HST-co-Th show an open circuit voltage of 0.63 V, and a power conversion efficiency of 0.34% and 0.5%, respectively, under the illumination of AM1.5, 80 mW . cm(-2) . PMID- 21706551 TI - Kinetics of core-shell nanoparticle formation by two-dimensional nuclear magnetic resonance. AB - We have studied the kinetics of polymeric nanoparticle formation for poly(styrene block-4-vinylpyridine) [P(S-b-4-VPy)], chains in a non-selective solvent using 1,4-dibromobutane (DBB) as a cross-linker by means of different nuclear magnetic resonance (NMR) spectroscopy techniques. The kinetic process was followed using (1) H, (13) C, and 2-D Heteronuclear Single Quantum Correlation (HSQC) NMR experiments. The kinetic data obtained from 2-D HSQC and (1) H NMR experiments were in good agreement between them, proving the reliability of the 2-D HSQC NMR technique for the in situ study of the kinetics of core-shell nanoparticle formation. A value of 1.5 * 10(-5) s(-1) was determined for the apparent kinetic constant of the P(S-b-4-VPy)-DBB core-shell nanoparticle formation process. PMID- 21706552 TI - Decorating polypyrrole nanotubes with au nanoparticles by an in situ reduction process. AB - Au nanoparticle-decorated polypyrrole nanotubes (defined as PPy/Au nanocomposites) are prepared by an in situ reduction process. Polypyrrole (PPy) nanotubes are prepared by a self-degraded template method, and Au nanoparticles are deposited in situ by the reduction of HAuCl(4) . The size and uniformity of the Au nanoparticles that decorate the PPy nanotubes can be controlled by adjusting the experimental conditions, such as the stabilizers used and the reaction temperature. The morphologies and optical properties of the nanocomposites have been characterized by scanning electron microscopy, transmission electron microscopy, UV-vis, and FT-IR spectroscopy. Conductivity measurements show that the conductivities of the nanocomposites decrease with a decrease of temperature, and the conductivity-temperature relationship obeys the quasi-one dimensional variable range hopping model. PMID- 21706553 TI - Synthesis and Aggregation Behavior of Multi-Responsive Double Hydrophilic ABC Miktoarm Star Terpolymer. AB - We report the first example of the synthesis and the "schizophrenic" micellization behavior of a multi-responsive double hydrophilic ABC miktoarm star terpolymer. A well-defined miktoarm star terpolymer consisting of poly(ethylene glycol), poly(2-(diethylamino)ethyl methacrylate), and poly(N isopropylacrylamide) arms, PEG(-b-PDEA)-b-PNIPAM, was synthesized via the combination of atom transfer radical polymerization (ATRP) and click reaction. Containing pH-responsive PDEA and thermo-responsive PNIPAM arms, this novel type of miktoarm star terpolymer molecularly dissolves in aqueous solution at acidic pH and room temperature, but supramolecularly self-assembles into PDEA-core micelles at alkaline pH and room temperature, and PNIPAM-core micelles at acidic pH and elevated temperatures. Most importantly, both types of micellar aggregates possess well-solvated hybrid coronas. PMID- 21706555 TI - Macromol. Rapid commun. 12/2009. PMID- 21706554 TI - Synthesis of block copolymers with a pentasilane core. AB - We report a new method for the synthesis of block copolymers with a pentasilane core by the polymerization of alkyl methacrylate monomers using the pentasilyl dianion as an initiator. The polymerization proceeded with living features and yielded the corresponding block copolymers with controlled molecular weights. The amphiphilic block copolymer was obtained by the polymer reaction, and it formed sphere-like aggregates in MeOH/H(2) O solution. PMID- 21706556 TI - Some issues related to polyaniline micro-/nanostructures. AB - This feature article reviews the authors' work combined with highlighted specific aspects of polyaniline (PANI) macro/nanostructures, focusing on such issues as the following. 1) The new development of a hard-template method. 2) Evaluation of a template-free method in universality, controllability, and simplicity as well as the self-assembly mechanism. 3) Multi-functionality based on a template-free method associated with other approaches. 4) Cooperation effect of a micelle soft template and molecular interactions as a new tool to complex 3D microstructures assembled from 2D or 1D nanostructures. 5) Electrical and transport properties of a single PANI nanotube, as measured by a four-probe method. 6) Sensors guided by reversible switching wettability through a doping/de-doping process. An outlook is also briefly given. PMID- 21706557 TI - Well-Organized CdS/C(60) in Block Copolymer Micellar Cores. AB - CdS nanoparticles of 4.5 nm diameter were synthesized in poly(2-vinylpyridine) micellar cores which were obtained by solvating a polystyrene-block-poly(2 vinylpyridine) block copolymer in polystyrene-selective toluene. Then, a C(60) toluene solution was dispersed into the CdS micelle solution with stirring. This led to the well-defined organization of two different nanoparticles; specifically: a CdS NP decorated by several/dozens of C(60) molecules, because C(60) molecules were strongly coordinated with pyridine molecules in the micellar cores by charge-transfer complexation C 60delta--P2VP(delta+) . A harmoniously organized CdS/C(60) micellar structure was clearly verified by transmission electron microscopy. Fluorescent quenching of CdS nanoparticles, which was strongly affected by neighboring C(60) molecules, was observed. PMID- 21706558 TI - Unusual photopolymerization behavior of amino Acid-derived polydiacetylene supramolecules. AB - UV-irradiation of aqueous suspensions of amino acid-derived amphiphilic diacetylene supramolecules promotes a process that involves initial formation of species that absorb at 640 nm followed by the generation of polymers that have longer wavelength (686 nm) absorbance. The initially formed intermediate polydiacetylenes display substantial colorimetric reversibility while the long wavelength absorbing polymers show irreversible thermochromism during heating and cooling cycles. The long wavelength absorbing polydiacetylenes, formed from amino acid-derived amphiphilic diacetylene supramolecules, are suggested to have more planer backbone structures that allow more efficient overlap of the conjugated p orbitals. PMID- 21706559 TI - Rigid crosslinked polyacrylamide monoliths with well-defined macropores synthesized by living polymerization. AB - Rigid crosslinked polyacrylamide monoliths with well-defined macropores have been successfully fabricated by organotellurium-mediated living radical polymerization (TERP) accompanied by spinodal decomposition. The TERP forms homogeneous networks derived from N,N-methylenebis(acrylamide) (BIS), in which spinodal decomposition is induced to form macropores. Macropore diameter can be controlled from submicrons to a few microns, and also the obtained networks contain mesopores in the macroporous skeletons, which are collapsed by evaporative drying. They are promising materials with hydrophilic polyacrylamide surfaces and have enough strength to preserve the macropores from the surface tension arising in the repetitive swelling and drying that may occur in many applications. PMID- 21706560 TI - Electric field-aided formation combined with a nanoimprinting technique for replicating a plant leaf. AB - The surface of the taro plant leaf was replicated using a nanoimprinting technique (NIT) supplemented with an electric field. This field-aided nanoimprinting method (FA-NIT) consists of two steps: applying an electric field to a liquid polymer under the plant leaves and the curing process of the polymer with the applied electric field. An appropriate electric field was needed to induce the electrokinetic phenomena of a liquid polymer to obtain a good replicated surface. The roughness fabricated by the FA-NIT was about 45% higher than the one prepared by NIT. The FA-NIT method is a good supplementary technique to improve the quality of NIT. PMID- 21706561 TI - Regioregulated Syntheses of Poly(aminopyridine)s by Pd-catalyzed Amination Reaction. AB - Regioregulated poly(aminopyridine)s were synthesized by a Pd-catalyzed C?N coupling reaction. The polymerization using Pd(0) and a bulky monodentate phosphine ligand distinctively produced the para-linked and meta-linked poly(aminopyridine)s, without the need for a protection process. The regioregularity of the polymer was confirmed by (1) H NMR spectroscopy. Model reactions were studied to evaluate the possibility of crosslinkage in the polymer. A large difference in reactivity was observed between 5-amino-2 bromopyridine and 2-amino-5-bromopyridine, which should have afforded same product. Density functional theory (DFT) calculations indicated that electron densities of the Br-bound carbon atom and the pyridine-nitrogen atom determine the reactivity of the monomers. PMID- 21706562 TI - Synthesis and Self-Assembly of pH-Responsive Amphiphilic Poly(dimethylaminoethyl methacrylate)-block-Poly(pentafluorostyrene) Block Copolymer in Aqueous Solution. AB - We report the synthesis of a novel pH-responsive amphiphilic block copolymer poly(dimethylaminoethyl methacrylate)-block-poly(pentafluorostyrene) (PDMAEMA-b PPFS) using RAFT-mediated living radical polymerization. Copolymer micelle formation, in aqueous solution, was investigated using fluorescence spectroscopy, static and dynamic light scattering (SLS and DLS), and transmission electron microscopy (TEM). DLS and SLS measurements revealed that the diblock copolymers form spherical micelles with large aggregation numbers, N(agg) ~ 30 where the dense PPFS core is surrounded by dangling PDMAEMA chains as the micelle corona. The hydrodynamic radii, R(h) of these micelles is large, at pH 2-5 as the protonated PDMAEMA segments swell the micelle corona. Above pH 5, the PDMAEMA segments are gradually deprotonated, resulting in a lower osmotic pressure and enhanced hydrophobicity within the micelle, thus decreasing the R(h) . However, the radius of gyration, R(g) remains independent of pH as the dense PPFS cores predominate. PMID- 21706563 TI - Facile Access to Hydroxy-Functional Core-Shell Microspheres via Grafting of Ethylene Oxide by Anionic Ring-Opening Polymerization. AB - We present a facile access route to hydroxy-functional narrow disperse microspheres of well-defined grafting density (GD). Ethylene oxide has been grafted from highly crosslinked poly(divinyl benzene) microspheres by anionic ring-opening polymerization using sec-butyllithium as activator together with the phosphazene base t-BuP(4) . Initially, core microspheres have been prepared by precipitation polymerization utilizing divinyl benzene (DVB, 80 wt.-%). The grafting of poly(ethylene oxide) (PEO) from the surface resulted in the formation of functional core-shell microspheres with hydroxy-terminal end groups. The number average particle diameter of the grafted microspheres was 3.6 um and the particle weight increased by 5.7%. The microspheres were characterized by SEM, FT IR spectroscopy, elemental analysis, and fluorescence microscopy. The surface GD (determined via two methods) was 1.65 +/- 0.06 and 2.09 +/- 0.08 chains . nm(-2) , respectively. PMID- 21706564 TI - Synthesis, characterization and self-assembly of novel amphiphilic block copolymers with a polyhedral oligomeric silsesquioxanes moiety attached at the junction of the two blocks. AB - A novel well-defined amphiphilic block copolymer, with the polyhedral oligomeric silsesquioxane (POSS) moiety at the junction of the two blocks of polystyrene and poly(ethylene oxide) (PEO), was designed and synthesized. First, a macroinitiator containing a POSS moiety and a PEO chain was prepared and then atom transfer radical polymerization of styrene was carried out in the presence of the macroinitiator in bulk. The polymerization results show that the process bears the characteristics of controlled/living free radical polymerizations. The structure and molecular weight of the polymers were characterized by GPC, (1) H NMR, and FT-IR spectroscopy. The self-assembly behaviors of the polymers was investigated by TEM and SEM. It was observed that the polymers can self-assemble into vesicles in aqueous solution. PMID- 21706565 TI - Fabrication of Aligned Polyaniline Nanofiber Array via a Facile Wet Chemical Process. AB - In this work, we demonstrate for the first time a template free approach to synthesize aligned polyaniline nanofiber (PN) array on a passivated gold (Au) substrate via a facile wet chemical process. The Au surface was first modified using 4-aminothiophenol (4-ATP) to afford the surface functionality, followed subsequently by an oxidation polymerization of aniline (AN) monomer in an aqueous medium using ammonium persulfate as the oxidant and tartaric acid as the doping agent. The results show that a vertically aligned PANI nanofiber array with individual fiber diameters of ca. 100 nm, heights of ca. 600 nm and a packing density of ca. 40 pieces.um(-2) , was synthesized. PMID- 21706566 TI - Macromol. Rapid commun. 13/2009. PMID- 21706567 TI - Macromol. Rapid commun. 13/2009. PMID- 21706568 TI - Polymer brushes by nitroxide-mediated polymerization. AB - This review article describes the preparation of polymer brushes by nitroxide mediated radical polymerization using either the 'grafting to' or the 'grafting from' approach. The use of TEMPO as a classical initiator is intensively described. More sophisticated nitroxides are also included in the discussion. Brush formation on flat surfaces such as wafers and also on particles is reported. Finally, some applications of polymer brushes are presented. PMID- 21706569 TI - All-conjugated, rod-rod block copolymers-generation and self-assembly properties. AB - Based on their rigid-rod structure all-conjugated, rod-rod block copolymers show a preferred tendency to self-assemble into low-curvature vesicular or lamellar nanostructures independent from their specific chemical structure and composition. This unique and attractive behaviour is clearly illustrated in a few examples of such all-conjugated block copolymers. The resulting nanostructured heteromaterials may find applications in electronic devices or artificial membranes. PMID- 21706570 TI - Solvent influence on propagation kinetics in radical polymerizations studied by pulsed laser initiated polymerizations. AB - The influence of the reaction medium (organic solvents, water, ionic liquids, supercritical CO(2) ) on the propagation rate in radical polymerizations has very different causes, e.g., hindered rotational modes, hydrogen bonding or electron pair donor/acceptor interactions. Depending on the origin of the solvent influence propagation rate coefficients, k(p) , may be enhanced by up to an order of magnitude associated with changes in the pre-exponential or the activation energy of k(p) . In contrast, non-specific interactions, size and steric effects lead to rather small changes in the vicinity of the radical chain end and are reflected by modest variations in k(p) . PMID- 21706571 TI - UV-Responsive Behavior of Azopyridine-Containing Diblock Copolymeric Vesicles: Photoinduced Fusion, Disintegration and Rearrangement. AB - A novel amphiphilic diblock copolymer composed of a hydrophilic poly(ethylene oxide) and a hydrophobic polymethacrylate with photochromic azopyridine moieties in the side groups was synthesized by atom transfer radical polymerization. The copolymeric vesicles showed photoinduced circular process including fusion, damage and defect formation, disruption, disintegration and rearrangement in H(2) O/THF during the irradiation of UV light. The process of photoresponsive cycle can be inhibited at any moment by visible light. PMID- 21706572 TI - Synthesis and properties of oligophenylene-layered polymers. AB - We report syntheses of phenylene-, biphenylene-, and terphenylene-layered polymers with a xanthene scaffold by the modified Suzuki-Miyaura coupling reaction. Their optical properties were studied in detail. The polymer end-capped by nitrobenzene units, which act as fluorescence quenchers, exhibited the photo excited energy transfer from the layered oligophenylenes to the terminal units. PMID- 21706573 TI - A novel approach for incorporation of mono-functional bioactive phenols into polyanhydrides. AB - Antiseptics based on phenol and phenolic derivatives were chemically incorporated into polyanhydrides as pendant groups via ester linkages. Polyanhydrides with antiseptic loadings of 46-58 wt.-% were obtained with molecular weights ranging from 9 400-23 000. In general, polymers with the bulkier antiseptics were more difficult to polymerize and yielded lower molecular weights. All polyanhydrides were amorphous with glass transition temperatures ranging from 27-58 degrees C. Polymers were deemed noncytotoxic after culturing L929 mouse fibroblast cells in media containing the polymers at two concentrations (0.10 and 0.01 mg . mL(-1) ) over three days. In summary, mono-functional bioactives can be chemically incorporated into noncytotoxic polyanhydrides. PMID- 21706574 TI - Gold nanoparticle-hybridized "nano-sponge" polymer coatings to enhance the reliability and sensitivity of biosensors. AB - We have created a new functional biosensor coating composed of polyelectrolyte multilayers containing gold nanoparticles. This gold-hybridized polyelectrolyte multilayer film possesses a stable nanoporous structure under physiological conditions. Antibody molecules were successfully conjugated onto the gold nanoparticles within the film. This functional coating successfully extinguished false signals from non-specific binding of proteins and cells and also provided highly enhanced detection sensitivity. Furthermore, the drastic differences in protein and cellular adhesion properties between a chip coated with the nanoporous PEM film and a bare chip demonstrate that morphological control of biological interactions on chip surfaces is possible. PMID- 21706575 TI - In situ Synthesis of Metal Nanoparticle Embedded Free Standing Multifunctional PDMS Films. AB - We demonstrate a simple one-step method for synthesizing noble metal nanoparticle embedded free standing polydimethylsiloxane (PDMS) composite films. The process involves preparing a homogenous mixture of metal salt (silver, gold and platinum), silicone elastomer and the curing agent (hardener) followed by curing. During the curing process, the hardener crosslinks the elastomer and simultaneously reduces the metal salt to form nanoparticles. This in situ method avoids the use of any external reducing agent/stabilizing agent and leads to a uniform distribution of nanoparticles in the PDMS matrix. The films were characterized using UV-Vis spectroscopy, transmission electron microscopy and X ray photoemission spectroscopy. The nanoparticle-PDMS films have a higher Young's modulus than pure PDMS films and also show enhanced antibacterial properties. The metal nanoparticle-PDMS films could be used for a number of applications such as for catalysis, optical and biomedical devices and gas separation membranes. PMID- 21706576 TI - Influence of crystal thickness and topological constraints on chain diffusion in linear polyethylene. AB - (13) C solid-state exchange NMR is applied to study the influence of morphology on chain diffusion between crystalline and noncrystalline regions in ultrahigh molecular weight linear polyethylene (PE). Lamellar-doubling reduces the exchange rate by a factor of two indicating that the chain diffusion coefficient is largely independent of the lamellar thickness. This is discussed in terms of molecular processes in the crystallites leading to chain diffusion, confirming that the role of defects is minor compared to helical jumps of extended stems. Hindrance of the chain diffusion resulting from chain entanglements was only observed after the chains diffuse over long distances. Moreover, the role of the interphase between the noncrystalline and the crystalline regions on chain diffusion is discussed. PMID- 21706577 TI - Oligomerization of electron-deficient vinyl monomers through an ate-complex mechanism: a new role for b(c(6) f(5) )(3) lewis Acid. AB - The Lewis acid B(C(6) F(5) )(3) in combination with hydrosilanes exhibits remarkable activity in the oligomerization of sulfone- and phosphonate-based monomers. This process opens new routes to high-tech silicone-based materials, i.e., thermoplastic elastomers and heat-resistant polysiloxanes. PMID- 21706578 TI - Macromol. Rapid commun. 2/2009. PMID- 21706579 TI - Design of Heterocomplementary H-Bonding RAFT Agents - Towards the Generation of Supramolecular Star Polymers. AB - Supramolecular poly(vinyl acetate) PVAc 3-arms stars were successfully generated by Reversible Addition-Fragmentation chain Transfer (RAFT)-polymerized chains bearing hydrogen-bonding heterocomplementary associating units. Chain Transfer Agents (CTA) bearing thymine- and diaminopyridine-based units were first synthesized and proved to mediate efficiently the polymerization of VAc. The binding ability of the chains in solution was then demonstrated by (1) H NMR and GPC measurements, proving the formation of the supramolecular stars. PMID- 21706580 TI - Fluorescence Investigations of Oxygen-Doped Simple Amine Compared with Fluorescent PAMAM Dendrimer. AB - Blue emission of oxygen-doped tertiary amine (triethylamine), a key unit of fluorescent poly(amido amine) dendrimer, was demonstrated. It was found that the fluorescence intensity could be further enhanced if the tertiary amines locate densely in the dendrimer interior as the branching sites. Moreover, a solvatochromic phenol blue, instead of oxygen, is able to induce the blue fluorescence of the tertiary amino-branching sites based on a guaranteed host guest complexation of phenol blue molecules and dendrimer interior. PMID- 21706581 TI - Microwave-Sensitive Foamable Poly(ionic liquids) Bearing tert-Butyl Ester Groups: Influence of Counterions on the Ester Pyrolysis. AB - Several poly(ionic liquids) have been synthesized based on poly(1-vinyl-3-tert butoxycarbonylmethylene imidazolium) salts with different counterions to investigate the tert-butyl ester pyrolysis of these compounds. It is found that the counterions strongly influence the temperature of the pyrolysis. The pyrolysis temperature shifts to higher or lower temperatures depending on the nature of the counterions. The use of microwave irradiation was employed to accelerate the gas release because of the high dipolar interaction of amorphous salts with microwaves. The result of these reactions is the formation of organic foams that could be of industrial interest. PMID- 21706582 TI - Organized shells on clay nanotubes for controlled release of macromolecules. AB - The use of tubular halloysite clay as a nanotemplate for layer-by-layer (LbL) shell assembly and its utilization for controlled release of drug macromolecules are studied. The LbL nanoshell allowed additional control for the sustained release of drug loaded halloysite tubes. The number of polymeric layers in the shell and molecular weight of the assembled polymers influences the drug release rate. Three bilayer shells of chitosan and gelatin of 15 nm thicknesses gave the best encapsulation and retardation in the release rate of dexamethasone. An encapsulation of the macromolecules inside the lumen of the biocompatible clay nanotubes coupled with the polyelectrolyte shell formation provides a novel formulation for the controlled release of bioactive agents. PMID- 21706583 TI - Synthesis of amphiphilic supramolecular miktoarm star copolymers by molecular recognition. AB - Synthesis of novel amphiphilic supramolecular miktoarm star copolymers has been achieved through complementary molecular recognition and interactions between carboxy groups and amino groups. Polystyrenes carrying two and one carboxy groups at the middle of the polymer chain are used as precursors to react with poly(ethylene oxide) (PEO) end-capped with a primary amine functionality (-NH(2) ) or a quaternary ammonium hydroxide functionality (-N(+) (CH(2) CH(3) )(3) OH(-) ). The result suggests that the basicity of the amine plays a key role in the molecular recognition procedure. The efficiency of ionic bond formation can be enhanced from 40% up to 97% by using PEO-N(+) (CH(2) CH(3) )(3) OH(-) instead of PEO-NH(2) . The obtained supramolecular polymers can be dissociated in dilute acid solution at room temperature. PMID- 21706584 TI - Functionalization of macroporous organic polymer monolith based on succinimide ester reactivity for chiral capillary chromatography: a cyclodextrin click approach. AB - Macroporous cross-linked organic polymer based on N-acryloxysuccinimide (NAS) and ethylene dimethacrylate (EDMA) was prepared inside 75 um id fused silica capillary as a functionalizable monolithic stationary phase for chromatographic applications. Succinimide groups on the monolith surface provide reactive sites able to react readily through standard electrophile-nucleophile chemistry. Propargylamine was used to prepare alkyne functionalized poly(NAS-co-EDMA). Onto this azido-reactive polymer surface was grafted beta-cyclodextrin (CD) via a triazole ring utilizing the copper(I)-catalyzed 1,3-dipolar cyclo-addition reaction. Chemical characterization was performed in situ after each synthetic step by means of Raman spectroscopy. Good enantioseparations of flavanone enantiomers, chosen as test chiral compound, were achieved under reversed phase conditions by both capillary electrochromatography and nano-liquid chromatography (nano-LC) techniques. These results demonstrate the potentiality and usefulness of click chemistry in the preparation of beta-CD containing chiral organic polymer monolith. PMID- 21706585 TI - Water Storage in Thin Films Maintaining the Total Film Thickness as Probed with in situ Neutron Reflectivity. AB - We investigate a new type of thin film material which allows for water storage without an increase in film thickness, whereas typically water storage in polymers and polymer films is accompanied with a strong swelling of the film, i.e., a strong increase in the film thickness. So these films will avoid problems related to strains which are caused by swelling. The basic key for the preparation of such thin films is the installation of a glassy network by the use of an asymmetric diblock copolymer polystyrene-block-poly(N-isopropylacrylamide) [P(S-b-NIPAM)] with a long PS and short PNIPAM block in combination with a solvent which is more equal in interaction with both the blocks as compared to water. With in situ neutron reflectivity the water storage and removal are probed. The total film thickness increases only by 2.5% by allowing for a total water storage of 17.4%. Thus the material can be used for coatings to reduce humidity in nano-applications, which might suffer from changes in the water content of the surrounding environment. PMID- 21706586 TI - Catalytic Polymerizations of Hydrophobic, Substituted, Acetylene Monomers in an Aqueous Medium by Using a Monomer/Hydroxypropyl-beta-cyclodextrin Inclusion Complex. AB - Ten hydrophobic, substituted, acetylene monomers were examined as to their abilities to form an inclusion complex with hydroxypropyl-beta-cyclodextrin (HPCD). Only the monomers with suitable substitutents were found to form the monomer/HPCD complex, which was identified by NMR, FTIR, and UV-vis spectroscopy. Polymerizations of the monomers were successfully carried out in aqueous solution by using the prepared monomer/HPCD inclusion complex and by using a water-soluble Rh-based catalyst, [Rh(cod)(2) BF(4) ] or [Rh(nbd)(H(2) O)OTs]. Such polymerizations provided high-yield (>90%) polymers with a cis content of approximately 100%. The as-prepared polymers could take an ordered helical conformation, just like their counterparts obtained in organic solvents. PMID- 21706587 TI - Cross-Linking and Degradation Properties of Plasma Enhanced Chemical Vapor Deposited Poly(2-hydroxyethyl methacrylate). AB - Plasma Enhanced Chemical Vapor Deposition (PECVD) of poly-2-hydroxyethyl methacrylate (pHEMA) biocompatible, biodegradable polymer films were produced alone and cross-linked with ethylene glycol diacrylate (EGDA). Degree of cross linking was controlled via manipulation of the EGDA flow rate, which influenced the amount of swelling and the extent of degradation of the films in an aqueous solution over time. Noncross-linked pHEMA films swelled 10% more than cross linked films after 24 h of incubation in an aqueous environment. Increasing degree of film cross-linking decreased degradation over time. Thus, PECVD pHEMA films with variable cross-linking properties enable tuning of gel formation and degradation properties, making these films useful in a variety of biologically significant applications. PMID- 21706588 TI - Co-Continuous Polymeric Nanostructures via Simple Melt Mixing of PS/PMMA. AB - Blends of polystyrene/poly(methyl methacrylate) (PS/PMMA) (30/70) prepared by simple melt mixing form a droplet (PS) in-matrix (PMMA) morphology. It is found that addition of a carefully designed copolymer PS-b-P(S-ran-MMA) (SSM) compatibilizer could convert the morphology into a co-continuous system. Indeed, the continuity of the dispersed PS phase increased with an increase in PS-b-P(S ran-MMA) content, and a fully co-continuous morphology (continuity = 100%) was obtained at 20% SSM fraction with a characteristic size of 100 nm. PMID- 21706589 TI - Macromol. Rapid commun. 3/2009. PMID- 21706590 TI - Fluorescence-amplifying assay for irradiated DNA lesions using water-soluble conjugated polymers. AB - A new platform has been developed for DNA lesion detection using a cationic conjugated polymer (CCP). DNA that contains two adjacent thymine bases is irradiated with ultraviolet light to allow for the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone dimers. The DNA lesions block the primer extension, and the base labeled with fluorescein cannot be incorporated into the DNA strand. Addition of the CCP leads to inefficient fluorescence resonance energy transfer (FRET) from CCP to fluorescein. For the case without DNA lesions, successful primer extension allows for efficient FRET between them. In view of the FRET signal changes, the DNA lesions can be detected. This new protocol offers a convenient detection for DNA lesions in aqueous solution without any isolation and washing steps. PMID- 21706591 TI - Preparation of monodisperse polylactide microspheres by dispersion polymerization using a polymeric stabilizer with hydroxy groups. AB - Monodisperse poly(D,L-lactide) (PDLLA) microspheres have been prepared by dispersion polymerization of D,L-lactide with a synthetic polymeric stabilizer. The polymerization is carried out in xylene/heptane (1:2, v/v) at 368 K for 3 h with poly[(dodecyl methacrylate)-co-(2-hydroxyethyl methacrylate)] (P(DMA-co HEMA)). P(DMA-co-HEMA) has hydroxy groups as an initiation group for pseudoanionic dispersion polymerization. The particle diameter and the coefficient of variation concerning the diameter distribution of the obtained PDLLA microspheres are 3.9 um and 4.3%, respectively. In addition, from the results of dynamic light scattering measurements, it is found that P(DMA-co-HEMA) and the PDLLA-grafted copolymer form a micellar structure in solution. PMID- 21706592 TI - Modular Synthesis of Thermosensitive P(NIPAAm-co-HEMA)/beta-CD Based Hydrogels via Click Chemistry. AB - Two kinds of representative polymers, poly(N-isopropylacrylamide) (PNIPAAm) and beta-cyclodextrin (beta-CD) were selected and modified with azide and alkyne fucntional groups, respectively. When the solutions of these two modified polymers were mixed together, a cross-linking reaction, a type of Huisgen's 1,3 dipolar azide-alkyne cycloaddition, occurred in the presence of Cu(I) catalyst. The strategy described here provides several advantages for the hydrogel formation including mild reaction conditions and controllable gelation rate. The resulted hydrogels were studied in terms of scanning electric microscopy (SEM), equilibrium swelling ratio and swelling/shrinking kinetics. The data obtained demonstrated the hydrogels had a porous structure as well as favorable thermosensitivity. PMID- 21706593 TI - Synthesis and Ring Opening Polymerization of a New Functional Lactone, alpha-Iodo epsilon-caprolactone: A Novel Route to Functionalized Aliphatic Polyesters. AB - A new functional lactone, alpha-iodo-epsilon-caprolactone (alphaIepsilonCL), was synthesized from epsilon-caprolactone by anionic activation using a non nucleophilic strong base (lithium diisopropylamide) followed by an electrophilic substitution with iodine chloride. Ring-opening (co)polymerizations of the resulting monomer with epsilon-caprolactone were carried out using tin 2 ethylhexanoate as a catalyst in toluene at 100 degrees C. Homopolymerization of alphaIepsilonCL was achieved, and poly(alphaIepsilonCL) was fully characterized by SEC, (1) H NMR and elemental analysis. Random copolymerizations of alphaIepsilonCL with epsilonCL were controlled with experimental molecular weights close to the theoretical values, narrow molecular weight distributions and a good agreement between experimental and theoretical molar compositions of alphaIepsilonCL. PMID- 21706594 TI - A New Disubstituted Polyacetylene for the Detection of alpha-Amino Acids. AB - New imidazole-functionalized disubstituted polyacetylene was synthesized by utilizing the postfunctional strategy. In addition, its ability to sense copper ions and alpha-amino acids by fluorescence quenching has been studied. The quenching of the fluorescence of the imidazole-functionalized disubstituted polyacetylene was observed at a very low level of Cu(2+) (7.0 * 10(-7) mol . L( 1) ). The fluorescent intensity decreased rapidly upon the increase of the concentration of the added solution of Cu(2+) . It was expected that the addition of alpha-amino acids to the solution of the polyacetylene/Cu(2+) complex could turn on the fluorescence of the polyacetylene, if alpha-amino acids could remove the copper ions from the complex. Glycine, was used for testing: upon the addition of glycine the quenched fluorescence of P1 turned on immediately. The detection limit was as low as 6.0 * 10(-5) mol . L(-1) . PMID- 21706595 TI - In situ Synthesis of Magnetic Iron Oxide Nanoparticles in Thermally Responsive Alginate-Poly(N-isopropylacrylamide) Semi-Interpenetrating Polymer Networks. AB - A novel semi-interpenetrating polymer network based on alginate and poly(N isopropylacrylamide) (PNiPAAm) has been synthesized that shows response to temperature and magnetic fields. Highly homogeneous porous hydrogels are obtained by copolymerizing N-isopropylacrylamide and bis-acrylamide in the presence of an aqueous alginate solution. The synthesis of magnetic iron oxides by in-situ oxidation of iron cations coordinated to the alginate network results in a hydrogel with an enhanced deswelling rate with respect to pure PNiPAAm. PMID- 21706596 TI - Polyaniline fan-like architectures of rectangular sub-microtubes synthesized in dilute inorganic Acid solution. AB - Rectangular-tube-based fan-like polyaniline has been readily fabricated by the oxidation polymerization of low-concentration aniline in dilute HCl aqueous solution for the first time. Different from the conventional polymerization that proceeds in concentrated acidic solution (to produce nanofibers), this synthesis was conducted in dilute inorganic acid solution at room temperature and created polyaniline hierarchical fan-like architectures. The morphological evolution of the product has been followed with respect to the reaction time, based on which conceivable interpretations of the formation of rectangular tubes and their assembly into fan-like architectures are given. Other inorganic acids (HNO(3) , H(2) SO(4) , and H(3) PO(4) ) with low concentrations have been used to replace HCl in the reaction system to validate the adaptability of this approach in this report. PMID- 21706597 TI - Encapsulation of a single metal nanoparticle with tunable size in a monodisperse polymer microcapsule. AB - A versatile approach to fabricate monodisperse poly[styrene-co-(divinyl benzene)] (PS-co-DVB) microcapsules that contain a single gold nanoparticle (AuNP) has been demonstrated. Using the PS-co-DVB microcapsule as a microreactor, aqueous HAuCl(4) and NaBH(4) solutions are subsequently infiltrated. The size of the resulting AuNP inside of the PS-co-DVB microcapsules is easily tunable by controlling the repeated infiltration cycles of aqueous HAuCl(4) and NaBH(4) . PS co-DVB microcapsules that contain a single silver and palladium nanoparticle are also obtained by following a similar protocol. PMID- 21706598 TI - Orientation of syndiotactic polystyrene crystallized in cylindrical nanopores. AB - Syndiotactic polystyrene (sPS) nanorods with different diameters have been prepared by using anodic aluminum oxide templates, and the orientation of the sPS crystals in the nanorods has been investigated by FT-IR spectroscopy. It is found that the c axis of the beta' crystals preferentially oriented perpendicular to the axis of the nanorod, and the degree of orientation is lower as the diameter of the nanorod decreases. This unexpected result is attributed to nuclei formed at the surface of the nanopores and their subsequent growth, in addition to the preferential growth compatible with the pore direction by the nuclei formed in the bulk film and in the nanorods. PMID- 21706600 TI - Macromol. Rapid commun. 4-5/2009. PMID- 21706599 TI - Click polyester: synthesis of polyesters containing triazole units in the main chain by click chemistry and improved thermal property. AB - A "click" polymerization of dialkynes that contain an ester linkages and diazides to has been performed to synthesize various polyesters, termed "click polyesters" with a high $?overline M _{?rm n}$ of 1.0 * 10(4) to 7.0 * 10(4) in an excellent yield. This polymerization accompanied a formation of 1,4-disubstituted triazoles in the polyester main chain by a Cu(I) catalyst. The triazole ring formation in the polyester main chain leads to improved thermal properties and enhancement of the even-odd effect of methylene chain length of the produced click polyesters. This report is the first report of the application of click chemistry to synthesize a series of polyesters under mild conditions. PMID- 21706601 TI - Happy Birthday, MRC - Off to New Horizons. PMID- 21706602 TI - Porous polymers: enabling solutions for energy applications. AB - A new generation of porous polymers was made for various energy-related applications, e.g., as fuel cell membranes, as electrode materials for batteries, for gas storage, partly from renewable resources. This review intends to catch this emerging field by reporting on a variety of different approaches to make high performing polymers porous. This includes template techniques, polymers with inherent microporosity, polymer frameworks by ionothermal polymerization, and the polymerization of carbon from appropriate precursors and by hydrothermal polymerization. In this process, we try to not only identify the current status of the field, but also point to open question and tasks to identify the potentially relevant progress. PMID- 21706603 TI - Recent developments in lipase-catalyzed synthesis of polyesters. AB - Polyester synthesis by lipase catalyst involves two major polymerization modes: i) ring-opening polymerization of lactones, and, ii) polycondensation. Ring opening polymerization includes the finding of lipase catalyst; scope of reactions; polymerization mechanism; ring-opening polymerization reactivity of lactones; enantio-, chemo- and regio-selective polymerizations; and, chemoenzymatic polymerizations. Polycondensation includes polymerizations involving condensation reactions between carboxylic acid and alcohol functional groups to form an ester bond. In most cases, a carboxylic acid group is activated as an ester form, such as a vinyl ester. Many recently developed polymerizations demonstrate lipase catalysis specific to enzymatic polymerization and appear very useful. Also, since lipase-catalyzed polyester synthesis provides a good opportunity for conducting "green polymer chemistry", the importance of this is described. PMID- 21706604 TI - Self-Assembled Block Copolymer Aggregates: From Micelles to Vesicles and their Biological Applications. AB - The ability of amphiphilic block copolymers to self-assemble in selective solvents has been widely studied in academia and utilized for various commercial products. The self-assembled polymer vesicle is at the forefront of this nanotechnological revolution with seemingly endless possible uses, ranging from biomedical to nanometer-scale enzymatic reactors. This review is focused on the inherent advantages in using polymer vesicles over their small molecule lipid counterparts and the potential applications in biology for both drug delivery and synthetic cellular reactors. PMID- 21706605 TI - Self-assembly and dynamics of polypeptides. AB - This work highlights the results of recent efforts to understand the hierarchical self-assembly and dynamics of polypeptides with the aid of different NMR techniques, X-ray scattering, and dielectric spectroscopy. The concerted application of these techniques sheds light on the origin of the glass transition, the persistence of the alpha-helical peptide secondary motif, and the effects of topology and packing on the type and persistence of secondary structures. With respect to the freezing of the dynamics at the liquid-to-glass temperature it was found that the origin of this effect is a network of defected hydrogen bonds. The presence of defected hydrogen-bonded regions reduces the persistence length of alpha-helices. Block copolypeptides provide means to manipulate both the type and persistence of peptide secondary structures. PMID- 21706606 TI - Polymers and Sulfur: what are Organic Polysulfides Good For? Preparative Strategies and Biological Applications. AB - Sulfur(II)-containing polymers (polysulfides) combine flexible synthetic and processing techniques with a unique responsiveness to oxidants. Here, the polysulfide oxidative sensitivity is put into the biological context of the development of new anti-inflammatory therapies - the development of new anti inflammatory methodologies, adopted interactions and the minimisation of foreign body reactions - through the review of 50 years of research on polysulfide synthetic methodologies. Attention is paid to the identification of the most flexible and robust preparative techniques. PMID- 21706607 TI - Functionalized Graphenes and Thermoplastic Nanocomposites Based upon Expanded Graphite Oxide. AB - Exfoliation of expanded GO represents an attractive route to functionalized graphenes as versatile 2D carbon nanomaterials and components of a wide variety of polymer nanocomposites. Thermally reduced graphite oxides (TrGO) with specific surface areas of 600 to 950 m(2) . g(-1) were obtained by oxidation of graphite followed by thermal expansion at 600 degrees C. Thermal post treatment at 700 degrees C and 1 000 degrees C increased carbon content (81 to 97 wt.-%) and lowered resistivity (1 600 to 50 Omega . cm). During melt extrusion with PC, iPP, SAN and PA6, exfoliation afforded uniformly dispersed graphenes with aspect ratio > 200. In comparison to conventional 0D and 1D carbon nanoparticles, TrGO afforded nanocomposites with improved stiffness and lower percolation threshold. Recent progress and new strategies in development of functionalized graphenes and graphene-based nanocomposites are highlighted. PMID- 21706608 TI - Quartz crystal microbalance studies on conformational change of polymer chains at interface. AB - The conformation of polymers at interface profoundly influences the interfacial properties. Quartz crystal microbalance with dissipation (QCM-D) is a newly developed technique to detect polymer behavior at interface in real time. In this article, we mainly review our QCM-D studies. Our focus is on temperature induced collapse and swelling of tethered polymer chains, pancake-to-brush transition and mushroom-to-brush of polymer chains. PMID- 21706609 TI - Hierarchical Assembly of Collagen-Like Peptides in vitro Provides Structural Causes of Osteogenesis Imperfecta. AB - Collagen type I peptides, representative of native to disease states for the bone disease, Osteogenesis imperfecta, were studied with regard to self-assembly into triple helices and liquid crystalline mesophases. The purpose of the study was to establish insight into collagen mutations in terms of propagation of single chain defects up the scale of materials hierarchy, toward solid state fibril assemblies formed from collagen. Studies carried out in vitro demonstrated the value of this approach in establishing in vitro disease models, as the degree of collagen disruption could be recapitulated by the point mutations to show major impact on macroscopic features. Fourier transform infrared spectroscopy, circular dichroism, atomic force microscopy and optical ellipsometry were used to assess the structural and morphological changes at the various length scales post assembly. The results demonstrated that glycine to alanine to aspartic acid single substitutions in the collagen peptides progressively disrupted normal assembly, reflected in lower thermal stability, loss of triple helical structure and loss of mesophase formation. This approach can provide a basis upon which to study collagen biomaterial templates for controlled hydroxyapatite formation and changes in cell signaling related to bone remodeling, related to the severity of the disease. PMID- 21706610 TI - Monte-carlo method for simulations of ring polymers in the melt. AB - A detailed analysis of the efficiency of a Monte-Carlo (MC) method employing non local moves for simple lattice ring polymers is presented. While the introduction of kink-translocation moves for linear chains results in the expected speedup by a factor of the order of the number of sites, this is significantly reduced for a melt of rings. PMID- 21706611 TI - Effect of added homopolymer on the hexagonal phase formed by cylindrical block copolymer micelles in a selective solvent. AB - The effect of addition of A homopolymer chains to HEX phases formed by cylindrical micelles obtained by dissolving an AB diblock copolymers in an A selective solvent was investigated. The following general trends were observed: (i) order-order transitions from HEX -> Gyroid (G) -> Lamellae (LAM); (ii) the inter-cylinder spacing of the HEX phase increased; (iii) when the homopolymer molecular weight and concentration was high, macrophase separation of the system occurred. The A homopolymer chains do not mix significantly with the A domain of the diblock due to excluded volume interactions, causing the corona chain brush to contract. As a result, order-order transitions that reduce the interfacial curvature are observed. PMID- 21706612 TI - Understanding and Optimizing the SMX Static Mixer. AB - Using the Mapping Method different designs of SMX motionless mixers are analyzed and optimized. The three design parameters that constitute a specific SMX design are: The number of cross-bars over the width of channel, N(x) , the number of parallel cross-bars per element, N(p) , and the angle between opposite cross-bars theta. Optimizing N(x) , somewhat surprisingly reveals that in the standard design with N(p) = 3, N(x) = 6 is the optimum using both energy efficiency as well as compactness as criteria. Increasing N(x) results in under-stretching and decreasing N(x) leads to over-stretching of the interface. Increasing N(p) makes interfacial stretching more effective by co-operating vortices. Comparing realized to optimal stretching, we find the optimum series for all possible SMX(n) designs to obey the universal design rule N(p) = (2/3) N(x) -1, for N(x) = 3, 6, 9, 12, .... PMID- 21706613 TI - Thin Film Instabilities in Blends under Cylindrical Confinement. AB - Rayleigh instabilities in bilayers of poly(methyl methacrylate) (PMMA) and polystyrene (PS) confined within the cylindrical nanoporous anodic aluminum oxide (AAO) membranes were investigated. The bilayered nanotubes were thermally annealed to induce phase separation and instabilities in the confined films. For short annealing times, the nanotubes were transformed into nanorods with periodic encapsulated air pockets. With longer annealing times, the air-pockets coalesced to form columns of air. Small air inclusions encased in periodic domains of PS were, in turn, incorporated within PMMA nanorods. Selectively removing the PMMA by exposure to UV radiation and washing with acetic acid, left PS nanospheres with an air inclusion. Gold nanoparticles having PS ligands were also incorporated within the PS phase, generating novel composite morphologies. PMID- 21706614 TI - Simultaneous deconvolution of the bivariate distribution of molecular weight and chemical composition of polyolefins made with ziegler-natta catalysts. AB - Polyolefins made with Ziegler-Natta catalysts have non-uniform distributions of molecular weight (MWD) and chemical composition (CCD). The MWD is usually measured by high-temperature gel permeation chromatography (GPC) and the CCD by either temperature rising elution fractionation (TREF) or crystallization analysis fractionation (CRYSTAF). A mathematical model is needed to quantify the information provided by these analytical techniques and to relate it to the presence of multiple site types on Ziegler-Natta catalysts. We developed a robust computer algorithm to deconvolute the MWD and CCD of polyolefins simultaneously using Flory's most probable distribution and the cumulative CCD component of Stockmayer's distribution, which includes the soluble fraction commonly present in linear low-density polyethylene (LLDPE) resins and have applied this procedure for the first time to several industrial LLDPE resins. The deconvolution results are reproducible and consistent with theoretical expectations. PMID- 21706616 TI - Macromol. Rapid commun. 6/2009. PMID- 21706615 TI - Investigation of Oxygen Permeation through Composites of PMMA and Surface Modified ZnO Nanoparticles. AB - Oxygen permeabilities of nanocomposite films consisting of poly(methyl methacrylate) (PMMA) and different amounts of spherical zinc oxide (ZnO) nanoparticles were determined to investigate the barrier effect of this material with respect to particle content. A method was applied which is based on quenching of an excited phosphorescent dye by oxygen. Possible effects of the nanoparticles on the response of the dye molecules were investigated and were ruled out. PMID- 21706617 TI - pH Responsive Polymeric Brush Nanostructures: Preparation and Characterization by Scanning Probe Oxidation and Surface Initiated Polymerization. AB - pH-responsive PHEMA-based polymeric nanostructures were grown in a controlled manner by ATRP-based surface-initiated polymerization. Initiator nanopatterns were obtained on silicon wafers covered with OTS resists made by AFM scanning probe oxidation lithography. AFM images confirmed isolated grafting of stimuli responsive hedge and dot brush structures exhibiting dimensions corresponding to a few tens of chains. PMID- 21706618 TI - Nanofibrilar polyaniline: direct route to carbon nanotube water dispersions of high concentration. AB - Water dispersible nanofibrilar polyaniline (NF-PANI) provides a novel and direct route towards carbon nanotube water dispersions of high concentration. Carrying out the chemical synthesis of NF-PANI in the presence of carbon nanotubes (CNTs) results in an entirely nanostructured nanofibrilar polyaniline/carbon nanotube (NF-PANI/CNT) composite material that contains well segregated CNTs partially coated by NF-PANI. This new approach is simple, fast, and inexpensive, and enables the direct preparation of stable and homogeneous dispersions of the composites in water at concentrations up to 10 mg . mL(-1) , even for the highest CNT loadings of 50 wt.-% without the participation of surfactants or stabilizers. PMID- 21706619 TI - Selective Localization and Migration of Multiwalled Carbon Nanotubes in Blends of Polycarbonate and Poly(styrene-acrylonitrile). AB - Multiwalled carbon nanotubes (MWNTs) have been introduced into blends of polycarbonate (PC) and poly(styrene-acrylonitrile) (SAN) by melt mixing in a microcompounder. Co-continuous blends are prepared by either pre-compounding low amounts of nanotubes into PC or SAN or by mixing all three components together. Interestingly, in all blends, regardless of the way of introducing the nanotubes, the MWNTs were exclusively located within the PC phase, which resulted in much lower electrical resistivities as compared to PC or SAN composites with the same MWNT content. The migration of MWNTs from the SAN phase into the PC phase during common mixing is explained by interfacial effects. PMID- 21706620 TI - The Peculiar Response of DNA Hydrogel Fibers to a Salt and pH Stimulus. AB - DNA hydrogels which are composed of an entangled network without a crosslinker are synthesized and examined in regards to their sensitivity to salt and pH changes. The DNA hydrogel fibers only exhibited a marked response - that is a fast and large change in length - under biological conditions ([Na(+) ] = 0.15 M at pH = 7) and are therefore suitable materials for bio-inspired devices. PMID- 21706621 TI - Fabrication of compositional-gradient biodegradable polymeric films showing self bending deformation. AB - A compositional graded film of poly(epsilon-caprolactone) (PCL) with 4,4' thiodiphenol (TDP), in the film thickness direction, was fabricated by self diffusing of TDP in the PCL melt. We found out the self-bending deformation of the gradient film, which bent into a rolled-up shape by itself. The initial shape of the film was flat when the sample was quenched from the melt. Upon the fast crystallization of PCL, the gradient film bent to the side with low TDP content. Then, after PCL crystallized the film bent to the opposite direction, that is, to the side with high TDP content. This bending to the TDP rich region was induced by not only the crystallization of PCL but also mass transfer due to the diffusion of TDP from TDP rich region to poor region. PMID- 21706622 TI - A Facile Strategy for the Preparation of Azide Polymers via Room Temperature RAFT Polymerization by Redox Initiation. AB - A new vinyl aryl azide monomer, 4-azidophenyl methacrylate (APM), has been synthesized and characterized by (1) H NMR and FT-IR spectroscopy. The thermal stability of APM has been investigated by temperature-dependent FT-IR spectroscopy and (1) H NMR, and the monomer has been demonstrated to be quite stable at ambient temperature. Reversible addition-fragmentation chain transfer (RAFT) homopolymerization and copolymerizations of APM with methyl acrylate, methyl methacrylate, and styrene have been carried out at room temperature using a redox initiator, benzoyl peroxide (BPO)/N,N-dimethylaniline (DMA). The results show that the polymerizations bear all the characteristics of controlled/living free-radical polymerizations. Moreover, the cycloaddition of azido group to carbon-carbon double bond can be avoided in the polymerization process at room temperature. PMID- 21706623 TI - Polyphosphazene Microcapsules Fabricated through Covalent Assembly. AB - Hollow polyphosphazene microcapsules have been fabricated by the covalent layer by-layer assembly of polydichlorophosphazene (PDCP) and hexamethylenediamine (HDA) on aminosilanized silica particles, followed by core removal in a HF/NH(4) F solution. The hollow and intact microcapsules in both wet and dry states have been characterized by transmission electron microscopy and confocal laser scanning microscopy. The chemical structure of the microcapsules has been verified by FT-IR spectroscopy. The microcapsules could be hydrolytically degraded in a phosphate buffer at biological pH. PMID- 21706624 TI - Composite polyamide 6/polypyrrole conductive nanofibers. AB - Conductive Polyamide 6 (PA-6) nanofibers were prepared by making a conductive polypyrrole coating obtained by a polymerization of pyrrole molecules directly on the fiber surface. A solution of PA-6 added with ferric chloride in formic acid has been electrospun and the fibers obtained showed an average diameter of 260 nm with a smooth surface. The fibers have been then exposed to pyrrole vapours and a compact coating of polypyrrole was formed on the fiber surface. The growth of the coating was monitored by measuring the increment of the fiber diameter and by FT IR spectroscopy. The same technique was used to study the interaction between the ferric chloride and the polyamide chains. The polypyrrole coating on the fibers turned out to be conductive with a pure resistive characteristic and the stability of the conductivity was evaluated in air at room temperature. PMID- 21706625 TI - Pyrene-functionalised, alternating copolyimide for sensing nitroaromatic compounds. AB - A novel, pyrene-functionalised copolymer has been synthesised in a single step via imidisation of poly(maleic anhydride-alt-1-octadecene) with 1 pyrenemethylamine, and its potential for the detection of volatile nitro aromatic compounds (NACs) evaluated. The new copolymer forms complexes in solution with NACs such as 2,5-dinitrobenzonitrile, as shown by (1) H NMR, UV-vis and fluorescence spectroscopy. Moreover, thin films of this copolymer, cast from THF solution, undergo almost instantaneous fluorescence quenching when exposed to the vapour of 2,5-dinitrobenzonitrile (a model for TNT) at ambient temperatures and pressures. PMID- 21706626 TI - Shell cross-linked micelles as cationic templates for the preparation of silica coated nanoparticles: strategies for controlling the mean particle diameter. AB - The mean diameter of poly[2-(dimethylamino)ethyl methacrylate]-block-poly[2 (diisopropylamino)ethyl methacrylate] (PDMA-PDPA) diblock copolymer micelles can be easily adjusted from 27-155 nm (as measured by DLS) by either selective quaternisation of the PDMA block or by adding PDPA homopolymer prior to micellisation; these self-assembled nanostructures can be shell crosslinked with 1,2-bis-(2-iodoethoxy)ethane and subsequently used as templates for the preparation of silica-coated nanoparticles and, ultimately, hollow silica nanoparticles. PMID- 21706627 TI - Phase Behavior of a Weakly Interacting Polystyrene and Poly(n-hexyl methacrylate) System: Evidence for the Coexistence of UCST and LCST. AB - The phase behavior of a weakly interacting binary system composed of deuterated polystyrene (dPS) and poly(n-hexyl methacrylate) (PnHMA) was investigated by the turbidity measurement for the binary blend, and by small angle X-ray scattering (SAXS) and depolarized light scattering for the block copolymers. For the binary dPS/PnHMA blend, a new phase diagram involving both the upper critical solution transition (UCST) and lower critical solution transition (LCST) was observed by the delicate control of molecular weights between dPS and PnHMA. Whereas for the block copolymers such as dPS-block-PnHMA and PS-block-PnHMA, an order-to-disorder transition (ODT) on heating was observed within the experimental temperature range depending on the molecular weight. This coexistence of both a UCST and LCST in the dPS/PnHMA blend consequently represents the experimental evidence that the corresponding (d)PS-b-PnHMAs possess not only ODT, but also lower disorder-to order transition (LDOT) character driven by a compressibility difference, although the latter is hindered by thermal degradation. PMID- 21706628 TI - Amphiphilic patchy composite colloids. AB - A new approach to fabricate patchy silica/polymeric gel composite colloids with amphiphilic performance is reported. The amphiphilic performance is rendered by selectively modifying the silica framework with a silane that contains an oleophilic alkyl chain. The patchy composite colloids are dispersible in both water and oil, and may be used as a solid particle surfactant. The modified silica framework can also assist other functional materials to disperse in a desired media. The corresponding silica/carbon composite colloids become amphiphilic after a sequential activation of carbon and modification of silica, and meanwhile possess as good electron conductivity as the as-prepared silica/carbon composite colloids. PMID- 21706629 TI - Macromol. Rapid commun. 7/2009. PMID- 21706630 TI - Efficient usage of thiocarbonates for both the production and the biofunctionalization of polymers. AB - End group modification of polymers prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization was accomplished by conversion of trithiocarbonate into reactive functions able to conjugate easily with biomolecules or bioactive functionality. Polymers were prepared by RAFT, and subsequent aminolysis led to sulfhydryl-terminated polymers that reacted in situ with an excess of dithiopyridyl disulfide to yield pyridyl disulfide-terminated macromolecules or in the presence of ene to yield functional polymers. In the first route, the pyridyl disulfide end groups allowed coupling with oligonucleotide and peptide. The second approach exploited thiol-ene chemistry to couple polymers and model compounds such as carbohydrate and biotin with high yield. PMID- 21706631 TI - Amplified Fluorescence Turn-On Assay for Mercury(II) Detection and Quantification based on Conjugated Polymer and Silica Nanoparticles. AB - An amplified fluorescence turn-on assay for mercury(II) detection and quantification was developed. This method makes use of specific thymine/mercury(II)/thymine coordination to capture Fl-labeled DNA onto NP surface. Addition of a cationic conjugated polymer leads to an amplified Fl signal in solution. A sigmoidal Hg(2+) working curve is obtained at fixed [NP] with a detection limit of 0.1 * 10(-6) M. However, by reducing [Hg(2+) ] and [NP] simultaneously, while maintaining [Hg(2+) ]:[DNA duplex] = 3:1, a linear calibration curve is observed with a detection limit of 5 * 10(-9) M. The CCP assisted mercury(II) assay shows potential applications in environmental mercury detection and for industrial process control. PMID- 21706632 TI - Enhanced One- and Two-Photon Excitation Emission of a Porphyrin Photosensitizer by FRET from a Conjugated Polyelectrolyte. PMID- 21706633 TI - Tough photonic crystals fabricated by photo-crosslinkage of latex spheres. AB - A general method to enhance the mechanical properties and solvent resistance of photonic crystals (PCs) has been demonstrated. This is carried out by the crosslinkage of latex spheres via photopolymerization of acrylamide (AAm) infiltrated among them. The crosslinked PAAm enhances the interaction among latex spheres of the PCs film, and contributes to the improvement of mechanical strength and solvent resistance. The result provides a simple approach to make tough PCs films by photo-crosslinkage, and can be extended to a wide variety of materials, will be of great importance for the practical application of PCs. PMID- 21706634 TI - Order-Order Transition of C -> sdG -> sL -> S in ABC Triblock Copolymer Thin Film Induced by Solvent Vapor. AB - The morphology transition of polystyrene-block-poly(butadiene)-block-poly(2 vinylpyridine) (SBV) triblock thin film induced in benzene vapor showing weak selectivity for PS is investigated. The order-order transitions (OOT) in the sequence of core-shell cylinders (C), sphere in 'diblock gyroid' (sdG), sphere in lamella (sL) and sphere (S) are observed. The projection along (111) direction in Gyroid phase (sdG(111)) is found to epitaxially grow from C(001) in the film. Instead of sdG(111), sdG(110)(0.1875) develops to the phase of sL. Consequently, the film experiences the transition sequence of sdG(111) -> sdG(211) -> sdG(110)(0.25) -> sdG(110)(0.1875) between C and sL. The mechanism is analyzed from the total surface area of the blocks. PMID- 21706635 TI - Vesicles Formed by Oligostyrene-block-Oligoaniline-block-Oligostyrene Triblock Oligomer. AB - Novel pi-conjugated coil-rod-coil triblock oligomers containing optoelectronic active oligoaniline segments were synthesized. The block oligomer can self assemble into diverse aggregating morphologies including spherical micelles and thin-layer vesicles in THF, which is found associated with the removing of the protecting groups of oligoaniline segments. A possible mechanism was proposed to explain the self-assembly behavior changes in which chain conformation variation of the aniline segments initiated from deprotection of the nitrogen atoms is pointed to be the key factor that dominates the transition process. PMID- 21706636 TI - Catalytic Chain Transfer (co-)Polymerization: Unprecedented Polyisoprene CCG and a New Concept to Tune the Composition of a Statistical Copolymer. AB - Borohydrido-halflanthanidocene/dialkylmagnesium combinations are found to be powerful catalytic systems for the chain transfer polymerization of isoprene and its copolymerization with styrene. A behavior close to a lanthanide catalyzed polyisoprene chain growth on magnesium is reported. Transmetalation is further shown to occur in the course of the statistical copolymerization of isoprene and styrene. For the same monomer feed, the amount of styrene inserted in the copolymer can be increased by a factor 3 using 10 equiv. dialkylmagnesium versus 1 in the range of our experimental conditions. Chain transfer in the course of a metal catalyzed statistical copolymerization may thus be viewed as a new and original way for the control of the composition of a copolymer. PMID- 21706637 TI - New Strategy Targeting Well-Defined Polymethylene-block-Polystyrene Copolymers: The Combination of Living Polymerization of Ylides and Atom Transfer Radical Polymerization. AB - Well-defined polymethylene-block-polystyrene (PM-b-PS) diblock copolymers were synthesized via a combination of living polymerization of ylides and atom transfer radical polymerization (ATRP) of styrene. A series of hydroxyl terminated polymethylenes (PM-OHs) with different molecular weight and narrow molecular weight distribution were prepared using living polymerization of ylides following efficient oxidation in a quantitive functionality. Then, the macroinitiators (PM-MIs ($?overline M _{?rm n}$ = 1 900-15 000; PDI = 1.12-1.23)) transformed from PM-OHs in ~ 100% conversion initiated ATRPs of styrene to construct PM-b-PS copolymers. The GPC traces indicated the successful extension of PS segment ($?overline M _{?rm n}$ of PM-b-PS = 5 000-41 800; PDI = 1.08 1.23). Such copolymers were characterized by (1) H NMR and DSC. PMID- 21706638 TI - Electrospinning of collagen nanofiber scaffolds from benign solvents. AB - Nanofiber scaffolds of collagen have been fabricated via electrospinning using benign solvent systems as a replacement for 1,1,1,3,3,3 hexafluoro-2-propanol. Simple binary mixtures of phosphate-buffered saline and ethanol have been found to be highly effective for electrospinning. FTIR spectra suggest that the triple helical structure of collagen was conserved after dissolution and electrospinning. Crosslinking of the electrospun collagen scaffolds was achieved with standard methods. PMID- 21706639 TI - A Highly Active Iron-Based Catalyst System for the AGET ATRP of Styrene. AB - The atom transfer radical polymerization of styrene using activators generated by electron transfer (AGET ATRP) has been carried out in bulk in a limited amount of air at 110 degrees C, using 1,3,5-(2'-bromo-2'-methylpropionato)benzene (BMPB) as an initiator and FeCl(3) . 6H(2) O/tris(3,6-dioxaheptyl) amine (TDA 1)/ascorbic acid (VC) as a novel Fe(III) -mediated catalyst system. The results of the polymerizations demonstrate the features of 'living'/controlled free radical polymerization, such as the number-average molecular weights being close to their corresponding theoretical values and increasing linearly with monomer conversion, and narrow molecular weight distributions ($?overline M _{?rm w} /?overline M _{?rm n}$ = 1.18-1.26). The end functionality of the obtained polymers was confirmed by (1) H and (13) C NMR spectra as well as a chain extension reaction. PMID- 21706640 TI - Preparation of Polar Ethylene-Norbornene Copolymers by Metallocene Terpolymerization with Triisobutylaluminium-Protected But-3-en-1-ol. AB - But-3-en-1-ol has been pre-protected by triisobutylaluminium and terpolymerized with ethylene and norbornene by rac-[Et(Ind)(2) ]ZrCl(2) /MAO catalysts. The strong polarity of diisobutyl(but-3-en-1-oxy)aluminum causes a slight reduction in the catalyst activity and yields a small fraction of crystallinity. The but-3 en-1-ol content in the terpolymer is as high as 3.2% and can be readily adjusted by varying the reaction conditions. When the norbornene/ethylene ratio is over 10, the norbornene incorporation efficiency is not affected by the polar monomer and is close to that of the copolymerization. Similar to the ethylene/norbornene copolymers, the thermal properties of the obtained terpolymers are mainly determined by their norbornene contents. PMID- 21706641 TI - Macromol. Rapid commun. 8/2009. PMID- 21706642 TI - Toward main chain metallo-terpyridyl supramolecular polymers: "the metal does the trick". AB - Metallo-supramolecular chemistry offers possibilities for the construction of stimuli-responsive polymeric materials where the environment can have a large impact on the reversibility and strength of interactions between the individual components. The potential of manipulating the strength of the intermolecular non covalent bonds can result in impressive modifications of the metallo supramolecular structure and, subsequently, produces changes in the properties of the designed material. The present feature article provides an overview on recent developments in the field of metallo-polymerization of chelating terpyridyl and analogues ligands. Synthetic strategies are described followed by a discussion regarding the characterization and the application of the reviewed metallo supramolecular structures, mainly based on terpyridines. PMID- 21706643 TI - Nanocomposites of Size-Tunable ZnO-Nanoparticles and Amphiphilic Hyperbranched Polymers. AB - Highly dispersed ZnO nanoparticles with variable particle sizes were successfully prepared within an amphiphilic hyperbranched polyetherpolyol matrix via decomposition of an organometallic precursor in the presence of air leading to stable nanocomposites. The high degree of stabilization during and after the synthesis by the polymer permits control over the nanoparticle size and therefore, due to the quantum-size-effect, the particle properties. Furthermore, these polymer-inorganic nanocomposites can easily be dispersed in apolar solvents to yield highly transparent, stable solutions. PMID- 21706644 TI - Copolymers of Intrinsic Microporosity Based on 2,2',3,3'-Tetrahydroxy-1,1' dinaphthyl. AB - A series of new copolymers with high molecular weight and low polydispersity, prepared from tetrahydroxydinaphthyl, tetrahydroxyspirobisindane, and tetrafluoroterephthalonitrile monomers, prevent efficient space packing of the stiff polymer chains and consequently show intrinsic microporosity. One copolymer, DNPIM-33, has an excellent combination of properties with good film forming characteristics and gas transport performance, and exhibits higher selectivity than the corresponding spirobisindane-based homopolymer PIM-1 for gas pairs, such as O(2) /N(2) , with a corresponding small decrease in permeability. This work demonstrates that significant improvements in properties may be obtained through development of copolymers with intrinsic microporosity (CoPIMs) that extends the spectrum of high-molecular-weight ladder structures of poly(dibenzodioxane)s. PMID- 21706645 TI - Design of Experiment (DoE) as a Tool for the Optimization of Source Conditions in SEC-ESI-MS of Functional Synthetic Polymers Synthesized via ATRP. AB - Design of experiment (DoE) is applied to establish the optimum ionization conditions for analyzing synthetic polymers via coupled size exclusion chromatography electrospray ionization mass spectrometry (SEC-ESI-MS) yielding maximum ionization efficiency. The ion source conditions were optimized with regard to the ionization efficiency, the amount of fragmentation, as well as the formation of salt adducts. A D-optimal experimental design was employed for this purpose and the recorded data were evaluated by a quadratic response surface model, accounting for possible interactions between the individual source settings. It was established that the ionization efficiency can be improved by up to one order of magnitude without compromising the softness of the ionization process and that optimal ionization conditions are found at similar source settings regardless of the charge state. The present optimization exercise therefore provides a hands-on guide for the use of experimental design to determine optimum ionization conditions during the SEC-ESI-MS of functional polymers. PMID- 21706646 TI - Ultra-fast fabrication of colloidal photonic crystals by spray coating. AB - An ultra-fast fabrication of large-scale colloidal PCs via spray coating was demonstrated. The latex spheres with hydrophobic core and hydrophilic shell were designed, and the latex shell with abundant COOH groups resulted in strong hydrogen bonding interaction among latex spheres, which boosted latex arrangement during the spray procedure. The resultant samples with area of 7 * 12 cm(2) were easily fabricated within 1 min on different substrates. This ultra-fast fabrication procedure would be of great importance for the practical application of PCs for optic devices and functional coatings. PMID- 21706647 TI - A Template-Free Method toward Urchin-Like Polyaniline Microspheres. AB - Urchin-like PANI microspheres with an average diameter of 5-10 um have been successfully prepared. Their surfaces consist of highly oriented nanofibers of ~30 nm diameter and 1 um length. The solvent composition plays an important role in the formation process of urchin-like PANI microspheres. The structure of the products has been characterized by FT-IR, UV-vis, and XRD. To investigate the self-assembly of urchin-like PANI microspheres, the effect of polymerization time on the morphology of the products has been studied. The morphological evolution process indicates that the urchin-like microspheres originate from the self assembly of nanoplates, which then grow into urchin-like microstructures with nanofibers on the surface. PMID- 21706648 TI - Synthesis of Folic Acid Functionalized PLLA-b-PPEGMA Nanoparticles for Cancer Cell Targeting. AB - Poly(L-lactic acid)-block-poly(poly(ethylene glycol) monomethacrylate) (PLLA-b PPEGMA) has been prepared by the ring-opening polymerization of lactide with a double-headed initiator, 2-hydroxyethyl 2'-methyl-2'-bromopropionate (HMBP), followed by atom transfer radical polymerization (ATRP) of poly(ethylene glycol) monomethacrylate (PEGMA). PLLA-b-PPEGMA nanoparticles with encapsulated Fe(3) O(4) are prepared by a solvent evaporation/extraction technique, and then further functionalized with folic acid, a cancer targeting ligand. Our results show that such functionalized PLLA-b-PPEGMA nanoparticles have good potential as carriers for targeted drug delivery in cancer treatment. PMID- 21706649 TI - Phase biaxility in smectic-a side-chain liquid crystalline elastomers. AB - (2) H NMR investigations on the biaxial phase behavior of smectic-A liquid crystalline side-chain elastomers are presented. Biaxiality parameters were determined by measuring the quadrupolar splitting of two spin probes, namely benzene-d(6) and hexamethylbenzene-d(18) , at various angles between the principal director and the external magnetic field: while for a uniaxial sample the angular dependence can be described by the second Legendre polynomial, an additional asymmetric term needs to be included to fit the data of the two investigated biaxial systems. Two elastomers synthesized from mesogens that differ in the molecular geometry in order to study the molecular origin of biaxiality were compared. Biaxiality is observed for both elastomers when approaching the glass transition, suggesting that the network dynamics dominate the formation of the biaxial phase. PMID- 21706650 TI - Multifunctional Poly(N-vinylcarbazole)-Based Block Copolymers and their Nanofabrication and Photosensitizing Properties. AB - The synthesis of poly(N-vinylcarbazole)-based block copolymers functionalized with rhenium diimine complexes or pendant terpyridine ligands is reported. The copolymers are synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization, and they exhibit interesting morphological properties as a result of the phase separation between different blocks. The rhenium complex polymer block may function as a photosensitizer, while the terpyridine-containing polymer block can be used as the template for nanofabrication by selective deposition of zinc complexes. PMID- 21706651 TI - Comparison of covalently and noncovalently functionalized carbon nanotubes in epoxy. AB - Carbon nanotubes typically require the use of a dispersing or stabilizing agent to prevent significant aggregation during incorporation into a polymer matrix. These additives must be strongly associated, either covalently or physically, to achieve their purpose. In this study, multi-walled carbon nanotubes (MWNTs) were dispersed into an epoxy matrix using polyethylenimine (PEI) as a dispersant that was either covalently attached to the nanotubes or physically mixed to result in only noncovalent interaction. Epoxy composites containing covalently modified MWNTs exhibited greater storage modulus and reduced electrical conductivity. PMID- 21706652 TI - A Micellar Complex of a Conjugated Polyelectrolyte for Efficient FRET to Dye Labeled DNA. AB - A polymer-surfactant micellar complex has been studied as a fluorescence resonance energy transfer (FRET) donor to fluorescein-labeled DNA (ssDNA-Fl). In water, the molar absorptivity and fluorescence quantum efficiency of cationic poly(fluorene-co-phenylene) (c-PFP) are substantially increased in the presence of non-ionic surfactants. A TEM microscopic study shows the formation of a nanowire micellar complex of c-PFP and the surfactants. About a 400% enhancement of the FRET signal is measured in c-PFP/ssDNA-Fl with Brij 30, relative to that without surfactants. The signal amplification is successfully modulated using different types of non-ionic surfactants which perturb the complexation, fine structure of the complex (i.e., donor-acceptor separation), and the resulting energy transfer process. PMID- 21706654 TI - Macromol. Rapid commun. 9-10/2009. PMID- 21706653 TI - Macromol. Rapid commun. 9-10/2009. PMID- 21706655 TI - From the past to the future. PMID- 21706656 TI - Suzuki Polycondensation: Polyarylenes a la Carte. AB - This review draws a rather comprehensive picture of how Suzuki polycondensation was discovered in 1989 and how it was subsequently developed into the most powerful polymerization method for polyarylenes during the last 20 years. It combines insights into synthetic issues with classes of polymers prepared and touches upon aspects of this method's technological importance. Because a significant part of the developmental work was carried out in industry, the present review makes reference to an unusually large number of patents. PMID- 21706657 TI - Recent advances in solid-state MAS NMR methodology for probing structure and dynamics in polymeric and supramolecular systems. AB - This article reviews recent applications of novel (1) H, (2) H, (13) C, (15) N and (17) O solid-state MAS NMR methods that provide new insight into the structural and dynamic processes that determine the bulk properties of polymeric and supramolecular materials. The review highlights methods that exploit the sensitivity to structure and dynamics of the NMR chemical shift and quadrupolar coupling as well as the through-space dipolar coupling and through-bond J coupling. In particular, it is shown that solid-state NMR exhibits marked sensitivity to key intra- and intermolecular hydrogen-bonding and pi-pi interactions, allowing, for example, the very accurate determination of internuclear distances as well as the probing of dynamics over a very wide range of timescales. PMID- 21706658 TI - Organic/Organic' heterojunctions: organic light emitting diodes and organic photovoltaic devices. AB - Heterojunctions created from thin films of two dissimilar organic semiconductor materials [organic/organic' (O/O') heterojunctions] are an essential component of organic light emitting diode displays and lighting systems (OLEDs, PLEDs) and small molecule or polymer-based organic photovoltaic (solar cell) technologies (OPVs). O/O' heterojunctions are the site for exciton formation in OLEDs, and the site for exciton dissociation and photocurrent production in OPVs. Frontier orbital energy offsets in O/O' heterojunctions establish the excess free energy controlling rates of charge recombination and formation of emissive states in OLEDs and PLEDs. These energy offsets also establish the excess free energy which controls charge separation and the short-circuit photocurrent (J(SC) ) in OPVs, and set the upper limit for the open-circuit photopotential (V(OC) ). We review here how these frontier orbital energy offsets are determined using photoemission spectroscopies, how these energies change as a function of molecular environment, and the influence of interface dipoles on these frontier orbital energies. Recent examples of heterojunctions based on small molecule materials are shown, emphasizing those heterojunctions which are of interest for photovoltaic applications. These include heterojunctions of perylenebisimide dyes with trivalent metal phthalocyanines, and heterojunctions of titanyl phthalocyanine with C(60) , and with pentacene. Organic solar cells comprised of donor/acceptor pairs of each of these last three materials confirm that the V(OC) scales with the energy offsets between the HOMO of the donor and LUMO of the acceptor ($E_{{?rm HOMO}^{?rm D} } - E_{{?rm LUMO}^{?rm A} }$). PMID- 21706659 TI - Polymer brushes for surface tuning. AB - Mixed polymer brushes as functional ultra thin films for surface functionalization have an enormous potential to create a variety of smart, switchable, and multifunctional surfaces and thin films. It is shown how computer simulations can contribute to a better understanding of the switching behavior of brushes. Furthermore, it is described how polymer brushes can be used to create surfaces with switchable ultrahydrophobicity and wettability gradients, as well as functional layers for the immobilization of nanoparticles. Applications of these versatile and multifunctional brush coatings are envisioned in many areas including fluid control, microfluidics, and thin film sensors. PMID- 21706660 TI - Toy amphiphiles on the computer: What can we learn from generic models? AB - Generic coarse-grained models are designed such that they are (i) simple and (ii) computationally efficient. A priori, they do not aim at representing particular materials, but classes of materials, hence they can offer insight into universal properties of these classes. Here we review generic models for amphiphilic molecules and discuss applications in studies of self-assembling nanostructures and the local structure of bilayer membranes, i.e., their phases and their interactions with nanosized inclusions. Special attention is given to the comparison of simulations with elastic continuum models, which are, in some sense, generic models on a higher coarse-graining level. In many cases, it is possible to bridge quantitatively between generic particle models and continuum models, hence multiscale modeling works on principle. On the other side, generic simulations can help to interpret experiments by providing information that is not accessible otherwise. PMID- 21706661 TI - Mesoscopic membrane physics: concepts, simulations, and selected applications. AB - The window of a few tens to a few hundred nanometers in length scale is a booming field in lipid membrane research, owing largely to two reasons. First, many exciting biophysical and cell biological processes take place within it. Second, experimental techniques manage to zoom in on this sub-optical scale, while computer simulations zoom out to system sizes previously unattainable, and both will be meeting soon. This paper reviews a selection of questions and concepts in this field and demonstrates that they can often be favorably addressed with highly simplified simulation models. Among the topics discussed are membrane adhesion to substrates, mixed lipid bilayers, lipid curvature coupling, pore formation by antimicrobial peptides, composition-driven protein aggregation, and curvature driven vesiculation. PMID- 21706662 TI - Poly(aryleneethynylene)s. AB - Poly(aryleneethynylene)s (PAE) are easily synthesized, chemically stable, and color-responsive towards their surroundings. These superbly chromic polymers are attractive as active transducers in sensors and advanced organic electronic devices. PAEs are generally fluorescent with emission maxima ranging from 420-600 nm, and can be either water- or organo-soluble. PAEs from linear building blocks are rigid rod molecules and display a host of supramolecular arrangements in solution and in the solid state. The poly(para-phenyleneethynylene)s (PPE) are lyotropic or thermotropic smectic liquid crystalline. In the solid state, PPEs display lamellar supramolecular structures that lead to distinct stranded nanoscale morphologies. The spectroscopy and the optical properties of the PAEs and in particular of the PPEs are dominated by their conformation, which is influenced by solid-state packing, solvent, temperature and other factors. The presence of twisted and planar forms and their interconversion leads to attractive structure/property relationships; PAEs are of use as ingredients for advanced supramolecular materials. PMID- 21706663 TI - Supramolecular Structures Generated by Spherical Polyelectrolyte Brushes and their Application in Catalysis. AB - We survey recent studies on composite particles made from spherical polyelectrolyte brushes (SPB) and catalytically active nanoparticles or enzymes. SPB consist of a solid core (diameter: ca. 100 nm) onto which long chains of anionic or cationic polyelectrolyte (PE) are densely grafted ("PE brush"). Immersed in water the PE layer affixed to the colloidal core will swell due to the enormous osmotic pressure of the confined counterions ("osmotic brush"). This confinement of the counterions can be used to generate metal nanoparticles on the surface of the SPB. Moreover, enzymes can be immobilized within the PE layer. In both cases, the resulting composite particles are stable against coagulation and can be easily handled and filtered off. The catalytic activity of both systems is largely preserved in case of the enzymes, in case of the metal nanoparticles it is even enhanced. Thus, the SPB present an excellent carrier system for applications in catalysis. PMID- 21706664 TI - Fluorene-Based Copolymers Containing Dinaphtho-s-indacene as New Building Blocks for High-Efficiency and Color-Stable Blue LEDs. AB - By incorporating a new building block, 7,7,15,15-tetraoctyldinaphtho-s-indacene (NSI), into the backbone of poly(9,9-dioctylfluorene) (PFO), a novel series of blue light-emitting copolymers (PFO-NSI) have been developed. The insertion of the NSI unit into the PFO backbone leads to the increase of local effective conjugation length, to form low-energy fluorene-NSI-fluorene (FNF) segments that serve as exciton trapping sites, to which the energy transfers from the high energy PFO segments. This causes these copolymers to show red-shifted emissions compared with PFO, with a high efficiency and good color stability and purity. The best device performance with a luminance efficiency of 3.43 cd . A(-1) , a maximum brightness of 6 539 cd . m(-2) , and CIE coordinates of (0.152, 0.164) was achieved. PMID- 21706665 TI - Segmental Mobility in the Non-crystalline Regions of Semicrystalline Polymers and its Implications on Melting. AB - Detailed knowledge on chain mobility in polymers is of fundamental interest in order to understand their mechanical properties. As a specific example, the melting behavior of semicrystalline polyethylene can be studied by thermal analysis and NMR spectroscopy. In ultra high molecular weight polyethylene (UHMW PE) crystallised via different routes, i.e., directly during polymerisation, from solution, or from the melt, and melted under different protocols, different melting processes involving detachment of stems from the crystals and cluster melting can be distinguished. Melting by the consecutive detachment of chain stems from the crystal substrate ultimately results in a melt state where chain dynamics for entanglement formation are much more restricted. PMID- 21706666 TI - Polytriarylamines with on-chain crystal violet moieties. AB - A novel polytriarylamine (PTAA)-type alternating copolymer with on-chain crystal violet moieties has been generated which shows the expected strong dependence of its UV-Vis absorption spectrum from the pH value of the surrounding medium. Starting from the colorless leucocrystal violet form subsequent protonation/water elimination (by trifluoroacetic acid) leads to the formation of a blue colored, cationic copolymer with on-chain crystal violet units that displays a characteristic Vis absorption band peaking at 627 nm. Further protonation leads to the generation of the corresponding dicationic species which is accompanied by a red shift of the long wavelength absorption maximum to 713 nm. The novel pH sensitive polytriarylamine derivatives will be investigated as potential p-type semiconductors for OFET (gas) sensors. PMID- 21706667 TI - Nonfouling Polypeptide Brushes via Surface-initiated Polymerization of N(epsilon) -oligo(ethylene glycol)succinate-L-lysine N-carboxyanhydride. AB - This contribution describes the preparation of nonfouling polypeptide brushes via surface-initiated ring-opening polymerization of oligo(ethylene glycol) modified L-lysine N-carboxyanhydrides. Circular dichroism experiments indicated that these surface-anchored polypeptide chains assume an alpha-helical conformation, which does not change between pH 4 and 9. Furthermore, nonspecific adsorption of fluorescent labeled bovine serum albumin and fibrinogen on glass slides modified with these brushes was greatly reduced compared to unmodified glass substrates. PMID- 21706668 TI - Similarities in the structural organization of major and minor ampullate spider silk. AB - Minor and major ampullate spider silks are studied under varying mechanical stress by static and time-resolved FT-IR spectroscopy. This enables one to trace the external mechanical excitation on a microscopic level and to determine for the different moieties the time dependence of the molecular order parameters and corresponding band shifts. It is concluded that the hierarchical nanostructure of both types of silk is similar, being composed of highly oriented nanocrystals, which are interconnected by amorphous chains that obey the worm-like chain model and have a Gaussian distribution of pre-strain. By that it is possible to describe the mechanical properties of both silks by two adjustable parameters only, the center and width of the distribution. For major ampullate silk, the observed variability is small in pronounced contrast to the findings for minor ampullate. PMID- 21706669 TI - Patterned hydrogel layers produced by electrochemically triggered polymerization. AB - We report on a lithographic mode of electrochemically triggered free radical polymerization. The polymerization is initiated by the reduction of an electrochemically active initiator. Hydrogel patterns can be written by employing a small insulated counter electrode. The investigations show that the "pen" actually is a small oxygen bubble between the counter electrode and the sample surface. The spot size corresponds to the size of the bubble produced between the counter electrode and the substrate. The gas/liquid interface traps the growing chains and guides the growth of a gel layer at the bubble surface. Since bubbles can be created and controlled in many different ways, this mechanism constitutes an easy route for the formation of structured, surface-bound polymer layers. PMID- 21706670 TI - Interfacial excess free energies of solid-liquid interfaces by molecular dynamics simulation and thermodynamic integration. AB - A method to compute the interfacial excess free energy of systems where a liquid phase is interacting with a solid phase is presented. The calculations are carried out by means of molecular dynamics simulations. The algorithm is based on a thermodynamic integration scheme that reversibly turns a flexible atomistically detailed solid surface that interacts with a liquid phase into a flat surface and allows the calculation of the variation in Gibbs free energy. The approach is probed by applying it to a model system of Lennard-Jones particles and comparing to previous calculations on similar systems. PMID- 21706671 TI - Optical waveguide spectroscopy for the investigation of protein-functionalized hydrogel films. AB - This article reports the implementation of optical waveguide spectroscopy (OWS) for the quantitative time-resolved observation of changes in the swelling behavior and mass density of protein-functionalized hydrogel films. In the experiment, a thin film of an N-isopropylacrylamide (NIPAAm)-based polymer that supported optical waveguide modes is attached to a metallic sensor surface. IgG molecules are in situ immobilized in this gel by using novel coupling chemistry with a charge-attraction scheme based on a tetrafluorophenol sulfonate active ester. The anti-fouling properties of the functionalized hydrogel network and the kinetics of the affinity binding of protein molecules in the gel are investigated. PMID- 21706673 TI - The nature and extent of body image concerns among surgically treated patients with head and neck cancer. AB - BACKGROUND: The purpose of this study was to describe body image concerns for surgically treated patients with head and neck cancer and evaluate the relationship between body image concerns and quality of life outcomes. METHODS: Data were obtained from 280 patients undergoing surgical treatment for head and neck cancer. We used a cross-sectional design and obtained data from individuals at different time points relative to initiation of surgical treatment. Participants completed the Body Image Scale, the Functional Assessment of Cancer Therapy Scale-Head and Neck Version, and a survey designed for this study to evaluate disease-specific body image issues, satisfaction with care regarding body image issues, and interest in psychosocial intervention. RESULTS: Body image concerns were prevalent in the majority of participants with 75% acknowledging concerns or embarrassment about one or more types of bodily changes at some point during treatment. Significant associations were found between body image concerns and all major domains of quality of life. Age, gender, cancer type, time since surgery, and body image variables were significantly associated with psychosocial outcomes. A clear subset of participants expressed dissatisfaction with care received about body image issues and/or indicated they would have liked additional resources to help them cope with body image changes. CONCLUSIONS: These data provide useful information to document wide-ranging body image difficulties for this population and provide important targets for the development of relevant psychosocial interventions. PMID- 21706672 TI - Pandemic influenza: certain uncertainties. AB - For at least five centuries, major epidemics and pandemics of influenza have occurred unexpectedly and at irregular intervals. Despite the modern notion that pandemic influenza is a distinct phenomenon obeying such constant (if incompletely understood) rules such as dramatic genetic change, cyclicity, "wave" patterning, virus replacement, and predictable epidemic behavior, much evidence suggests the opposite. Although there is much that we know about pandemic influenza, there appears to be much more that we do not know. Pandemics arise as a result of various genetic mechanisms, have no predictable patterns of mortality among different age groups, and vary greatly in how and when they arise and recur. Some are followed by new pandemics, whereas others fade gradually or abruptly into long-term endemicity. Human influenza pandemics have been caused by viruses that evolved singly or in co-circulation with other pandemic virus descendants and often have involved significant transmission between, or establishment of, viral reservoirs within other animal hosts. In recent decades, pandemic influenza has continued to produce numerous unanticipated events that expose fundamental gaps in scientific knowledge. Influenza pandemics appear to be not a single phenomenon but a heterogeneous collection of viral evolutionary events whose similarities are overshadowed by important differences, the determinants of which remain poorly understood. These uncertainties make it difficult to predict influenza pandemics and, therefore, to adequately plan to prevent them. PMID- 21706674 TI - Mass spectrometry characterization for chemoenzymatic glycoprotein synthesis. AB - The current project describes the chemoenzymatic modification of bovine ribonuclease B (RNase B) to contain a single glycosylation site with a known glycan. A reactive disaccharide oxazoline derivative was synthesized and stereospecifically added to deglycosylated RNase B through endo-beta-N acetylglucosaminidase M catalyzed chemoenzymatic transglycosylation. Oxazoline formation conditions were optimized using mass spectrometry, and the product verified based on its collision-induced dissociation (CID) mass spectrum. Enzymatic removal of native glycans as well as formation of the desired homogeneous product was also monitored using mass spectrometry. LC-MS(n) using four sequential rounds of CID was used to verify that the original glycosylation site had been reorganized to contain the new glycan. The techniques described herein are not limited to this analyte or glycan and should be amenable to the synthesis of numerous homogeneous glycoconjugates with judicious choice of enzyme/substrate combinations. The combined use of chemoenzymatic synthesis and mass spectrometry-based characterization shows promise for the development of homogeneous glycoprotein reference materials. A well-defined glycoprotein standard containing a single glycan of known composition, linkage and stereochemistry would be of great value for the comparison and evaluation of glycoprotein analysis techniques. PMID- 21706676 TI - Azidoacetone as a complexing agent of transition metals Ni2+/Co2+ promoted dissociation of the C-C bond in azidoacetone. AB - The relevance of metal interactions with azides has led us to the study of the complexation of some transition metals, nickel and cobalt, by azidoacetone by means of electrospray ionization mass spectrometry (ESI-MS). Complexes were obtained from solutions of NiCl(2) and CoCl(2) , in methanol/water. Nickel was electrosprayed with other counter ion, bromide (Br), as well as other solvent (ethanol/water). For nickel and cobalt, the complexes detected were single positively charged, with various stoichiometries, some resulted from the fragmentation of the ligand, the loss of N(2) being quite common. The most abundant species were [Ni(II)Az(2)X](+) where X = Cl, Br and Az = azidoacetone. Some of the complexes showed solvation with the solvent components. Metal reduction was observed in complexes where a radical was lost, resulting from the homolytic cleavage of a metal coordination bond. Collision-induced dissociation (CID) experiments followed by tandem mass spectrometry (MS-MS) analysis were not absolutely conclusive about the coordination site. However, terminal ions of the fragmentation routes were explained by a gas-phase mechanism proposed where a C-C bond was activated and the metal inserted subsequently. Density functional theory calculations provided structures for some complexes. In [Ni(II)Az(2)X](+) species, one azidoacetone ligand is monodentate and the dominant binding location is the alkylated nitrogen and not the carbonyl group. The other azidoacetone ligand is bidentate showing coordination through alkylated nitrogen and the carbonyl group. These are also the preferential binding sites for the most stable isomer of [Ni(II)AzX](+) species. PMID- 21706675 TI - Electrospray ionization ion-trap multiple-stage mass spectrometry of Quillaja saponins. AB - Fifteen identified C-18 fatty acyl-containing saponin structures from Quillaja saponaria Molina have been investigated by electrospray ionization ion-trap multiple-stage mass spectrometry (ESI-IT-MS(n)) in positive ion mode. Their MS(1) MS(3) spectra were analyzed and ions corresponding to useful fragments, important for the structural identification of Quillaja saponins, were recognized. A few key fragments could describe the structural variations in the C-3 and the C-28 oligosaccharides of the Quillaja saponins. A flowchart involving a stepwise procedure based on key fragments from the MS(1)-MS(3) spectra of these saponins, together with key fragments from these saponins and 13 previously investigated saponins, was constructed for the identification of structural elements in Quillaja saponins. Peak intensity ratios in MS(3) spectra were found to be correlated to structural features of the investigated saponins and is therefore of value for the identification of regioisomers. PMID- 21706677 TI - Simultaneous and high-throughput quantitation of urinary tetranor PGDM and tetranor PGEM by online SPE-LC-MS/MS as inflammatory biomarkers. AB - Quantitation of urinary tetranor PGDM or tetranor PGEM (tPGDM and tPGEM) in the past was performed separately using off-line SPE LC-MS/MS methods. The manual SPE procedure is generally time-consuming and cost-ineffective. In addition, simultaneous quantitation of tPGDM and tPGEM is favorable yet very challenging because of the similar chemical structures and identical MRM transitions. This work describes the development and validation of a high-throughput online SPE-LC MS/MS method, allowing simultaneous and high-throughput measurement of tPGDM and tPGEM in human urine. The reportable range of the assay was 0.2-40 ng/ml for tPGDM and 0.5-100 ng/ml for tPGEM. Intra- and inter-assay precision and accuracy determined using quality control samples were all within acceptable ranges (% CV and % Bias < 15%). Tetranor PGDM was stable under all tested conditions while tPGEM was stable at 4 degrees C and after three F/T cycles but not stable at room temperature for 24 h (recovery below 80%). The assay was applied to measure urinary tPGDM and tPGEM among healthy volunteers, smokers and COPD patients. Significantly higher urinary levels of both tPGDM and tPGEM were observed in COPD patients than those of non-smoking healthy volunteers. These results demonstrated that the high-throughput online SPE-LC-MS/MS assay provides sensitive, reproducible and accurate measurement of urinary tPGDM and tPGEM as biomarkers for assessing inflammatory diseases such as COPD. PMID- 21706678 TI - How the ASBMB recommended curriculum has influenced one sole biochemist. PMID- 21706679 TI - Caring for students: A teacher's view. AB - The asymmetry in power relations that exist between physicians and patients also exist between teachers and students. Thus, the dimensions of student care are analogous to those of patient care. The interactions between teachers and students are analyzed using the framework of the principles of beneficence (non maleficence), autonomy, and justice, which have been generally applied to physician-patient interactions. PMID- 21706680 TI - Teaching molecular biology to undergraduate biology students: An illustration of protein expression and purification*. AB - Practical classes on protein expression and purification were given to undergraduate biology students enrolled in the elective course "Introduction to Genetic Engineering." The heterologous expression of the green fluorescent protein (GFP)* of Aequorea victoria is an interesting system for didactic purposes because it can be viewed easily during experiments. The students were provided with basic information about the molecular features and applications of the GFP in molecular biology, the available heterologous expression systems, and the theoretical and experimental details of GFP expression in Escherichia coli and its purification. E. coli BL21-competent cells were transformed with the pET28a expression vector containing the GFP gene fused to a histidine (His) tag. During the induction of a transformed clone by isopropylthiogalactoside, a time course for GFP expression was analyzed by SDS-PAGE, and the expression was also visualized by the increasing green fluorescence of the bacterial culture. After cellular disruption, protein purification was illustrated by affinity chromatography of the His-tagged protein in a nickel column. Eluted fractions containing imidazole in increasing concentrations were analyzed visually and also by SDS-PAGE, demonstrating the role of imidazole in protein recovery by competition with nonspecific proteins and the His-tagged protein. The results obtained and the experimental factors involved in protein expression, solubilization, and folding were discussed following the laboratory experiments. These practical classes allowed several current approaches to molecular biology to be demonstrated rapidly and helped underscore some of the topics taught during the course. PMID- 21706681 TI - A curriculum skills matrix for development and assessment of undergraduate biochemistry and molecular biology laboratory programs. AB - We have designed a skills matrix to be used for developing and assessing undergraduate biochemistry and molecular biology laboratory curricula. We prepared the skills matrix for the Project Kaleidoscope Summer Institute workshop in Snowbird, Utah (July 2001) to help current and developing undergraduate biochemistry and molecular biology program designers to determine which laboratory techniques, skills, and theories to include in a 4-year plan. The skills matrix can be used to evaluate and assess the types of laboratory skills as well as the level at which they are taught in biochemistry and molecular biology curricula. The matrix can foster better communication between faculty in chemistry, biology, math, and physics as they share curricular information. As an example of utility of the skills matrix, we used it to survey several commonly used biochemistry laboratory manuals to evaluate the skills covered in each text. PMID- 21706682 TI - Contribution of each complex of the mitochondrial respiratory chain in the generation of the proton-motive force*. AB - A new parameter is presented for considering the contribution from each complex of the mitochondrial respiratory chain to the creation of the electrochemical gradient. This parameter is the proton gradient generated in each complex per pair of electrons transported (DeltaH(+) /2e(-) ) and may be calculated as the sum of the electrons taken up from the N-side and the electrons released at the P side. The DeltaH(+) /2e(-) values take into account all the electrons taken up and released in each complex and differentiate between the contribution from protons that are translocated from the N-side to the P-side and the contribution of scalar protons. Using these values, the P/O ratios for the oxidation of NADH and succinate are predicted to be 2.5 and 1.5, respectively. PMID- 21706683 TI - Supplementing introductory biology with on-line curriculum*. AB - We developed web-based modules addressing fundamental concepts of introductory biology delivered through the LON-CAPA course management system. These modules were designed and used to supplement large, lecture-based introductory biology classes. Incorporating educational principles and the strength of web-based instructional technology, choices were made about knowledge presentation, representation, and construction (W. A. Nelson, D. B. Palumbo (1992) J. Educ. Media Hypermedia 1, 287-299). Knowledge presentation focused on big and connecting ideas. Knowledge representation provided students the opportunity to interact with concepts in several ways using multiple representations. For knowledge construction, we facilitated students' active and meaningful interactions with content using interwoven high-level questions. Students' extended responses to a questionnaire indicated that these modules influenced the students learning in meaningful ways. (For access to demonstration modules, go to demo.lon-capa.org/cgi-bin/signon.pl?hhmi.). PMID- 21706684 TI - Adapting a biochemistry course to distance education. AB - Internet-based distance education seems to be an attractive alternative to offer courses dealing with specific topics that are not conveniently explored in undergraduate courses. This is a good way to provide access to the recent and updated discoveries in this research area and to reach people who could not take the classes in the traditional mode. Using the communication advantages available via the Internet, we adapted the course "Biochemistry of Nutrition," first offered as a summer course to be entirely carried out at distance. The adaptation explored the use of online tools such as E-mail communication among students and teachers, computer conferencing in small groups to discuss specific subjects, and texts and software downloads to be used as main references. Graduate students had their first real experience as teachers, which proved to be very productive for both the development of the Internet version of the course and their integration with undergraduate students. PMID- 21706685 TI - A spectroscopic-based laboratory experiment for protein conformational studies*. AB - This article describes a practical experiment for teaching basic spectroscopic techniques to introduce the topic of protein conformational change to students in the field of molecular biology, biochemistry, or structural biology. The spectroscopic methods employed in the experiment are absorbance, for protein concentration measurements, and fluorescence and circular dichroism, for probing protein conformational changes. PMID- 21706686 TI - A simple method for detecting genetically modified maize in common food products. AB - A commercially available leaf DNA extraction and amplification kit has been adapted for the detection of genetically modified material in common food products containing maize. Amplification using published primer pairs specific for the Bacillus thuringiensis delta-endotoxin and maize invertase genes results in a 226-bp invertase PCR product in all samples (an internal positive control) plus a 184-bp product in samples that are genetically modified with the endotoxin gene. The ease and rapidity of DNA extraction and PCR make this exercise especially suitable for advanced-placement high school or lower division college biology students. PMID- 21706687 TI - Using cytochome c to monitor electron transport and inhibition in beef heart submitochondrial particles*. AB - We present a two-part undergraduate laboratory exercise. In the first part, electron transport in bovine heart submitochondrial particles causing reduction of cytochrome c is monitored at 550 nm. Redox-active dyes have historically been used in most previous undergraduate laboratory exercises of this sort but do not demonstrate respiratory inhibition by antimycin A and rotenone. By using cytochrome c instead of redox-active dyes, it is possible to observe inhibition of electron transport in the presence of the aforementioned respiratory inhibitors. In the second part, students are asked to design a soluble redox chain between NADH and cytochrome c using catalytic amounts of redox-active dyes. The students are also responsible for designing the assays and control. The entire experiment can be performed in 3 h with single-beam spectrophotometers that are currently used in most undergraduate teaching laboratories. This exercise is suitable for large undergraduate classes of over 200 students and can be performed either by a single student or a student pair. PMID- 21706688 TI - The zymogen-enteropeptidase system: A practical approach to study the regulation of enzyme activity by proteolytic cleavage*. AB - The present research describes an efficient procedure to obtain high levels of trypsinogen and chymotrypsinogen by using a simple, rapid, and easily reproducible method. The extraction process and the time-course of activation of zymogens can be carried out in a single laboratory period, without sophisticated equipment. The main objective was to prepare a laboratory class that would stimulate student interest in enzyme regulation, exploring the fact that the catalytic activity of some enzymes is regulated by different mechanisms. The regulation of proteolytic enzymes requires the synthesis of an inactive zymogen and its being irreversibly "switched on" by specific proteolytic cleavage. PMID- 21706689 TI - Problem-based learning and undergraduate research. PMID- 21706690 TI - The expression of ovomucoid gene*. AB - Terms to be familiar with before you start to solve the test: gene expression, isolation of RNA, Northern blotting, hybridization, autoradiography, pre-mRNA splicing, exons and introns, poly(A) tail, and triplet code. PMID- 21706691 TI - International benchmarking of biotech research and research training centers lessons and perspectives: Results from a european-united states comparative study characterizing the centers and their performance. PMID- 21706692 TI - Commentary: Getting help to mark multiple choice questions. PMID- 21706693 TI - Response to G. R. Parslow "listen to the message" [biochemistry and molecular biology education 31, 269 (2003)]. PMID- 21706694 TI - Websites of note. PMID- 21706696 TI - Alcohol metabolism (sung to the tune of amazing grace). PMID- 21706697 TI - Facilitating student understanding of buffering by an integration of mathematics and chemical concepts. AB - We describe a simple undergraduate exercise involving the titration of a weak acid by a strong base using a pH meter and a micropipette. Students then use their data and carry out graphical analyses with a spreadsheet. The analyses involve using mathematical concepts such as first-derivative and semi-log plots and provide an opportunity for collaboration between biochemistry and mathematics instructors. By focusing on titration data, rather than the titration process, and using a variety of graphical transformations, we believe that students achieve a deeper understanding of the concept of buffering. PMID- 21706698 TI - Innovative tools for scientific and technological education in italian secondary schools. AB - This paper describes the project "Biotech a Scuola" ("Biotech at School"), financed by the Italian Ministry of Education within the SeT program (Special Project for Scientific-Technological Education). The project involved the University of Siena, five senior and junior secondary schools in the Siena area, and a private company. Twenty-three teachers from diverse fields and 318 students from 15 classes were involved. The aim of the project was to improve scientific technological teaching by providing schools with the support and materials necessary to understand some fundamental aspects of biotechnology. With this project we propose a model of close cooperation among various educational sectors with the goal of teaching junior and senior high school students some of the theory and practice of modern biotechnology. PMID- 21706699 TI - Adjusting a biochemistry course for physical education majors: A case study. AB - The purpose of this study was to investigate and analyze the events responsible for curricular characteristics that lead to positive outcomes in university teaching using a biochemistry course taught to physical education students as a model. The research was carried out as a case study, supported by questionnaires, classroom observation, document analysis, and interviews. The overall analyses of obtained data were validated by means of triangulation protocols, which proved the following reasons for the course achievements: 1) teaching staff deeply committed to the course; 2) contents adaptation to students' careers; 3) gradual adjustment of the teaching strategies and evaluation tools; 4) valorization of formative evaluation; and 5) providing a suitable affective milieu. PMID- 21706700 TI - Shopping in analogia. PMID- 21706701 TI - An introduction to mass spectrometry applications in biological research. AB - Mass spectrometry involves the measurement of the mass-to-charge ratio of ions. It has become an essential analytical tool in biological research and can be used to characterize a wide variety of biomolecules such as sugars, proteins, and oligonucleotides. In this review, a brief history of mass spectrometry is discussed, and the basic principles of the technology are introduced. A summary of some current applications is provided, as are examples of recently published research. The current methods used to identify, quantify, and characterize proteins and peptides are then reviewed. The range of applications of mass spectrometry is considerable and only promises to grow as the technology continues to improve. PMID- 21706702 TI - Outcomes of a research-driven laboratory and literature course designed to enhance undergraduate contributions to original research. AB - This work describes outcomes of a research-driven advanced microbiology laboratory and literature research course intended to enhance undergraduate preparation for and contributions to original research. The laboratory section was designed to teach fundamental biochemistry and molecular biology techniques in the context of an original research project. Site-directed mutants of a gene of interest were constructed, and the effects of mutations on the resulting enzymes were analyzed. Students were also introduced to the literature surrounding their project, electronic literature databases, and preparation of computer-generated slides for oral presentations. Student progress was evaluated through a laboratory report written as scientific manuscript, an oral presentation, a 10-page written review, and an essay examination. In the semester following the laboratory course, four of the 14 undergraduates joined the host laboratory to continue their projects as individual undergraduate researchers. Quantifiable outcomes of the course and subsequent undergraduate research included i) production of eight new site-directed mutants and preliminary characterization of the corresponding enzymes, ii) training of four individual undergraduate researchers prior to joining the laboratory, iii) publication of a manuscript with results from two undergraduate researchers, and iv) presentation of two posters with undergraduate co-authors at a national meeting. This research driven approach may be applicable to enhance undergraduate contributions to other original research projects that have defined goals achievable within the timeframe of a single semester. PMID- 21706703 TI - An hypothesis-driven, molecular phylogenetics exercise for college biology students. AB - This hypothesis-driven laboratory exercise teaches how DNA evidence can be used to investigate an organism's evolutionary history while providing practical modeling of the fundamental processes of gene transcription and translation. We used an inquiry-based approach to construct a laboratory around a nontrivial, open-ended evolutionary question about the relationship of five species of Drosophila. In the course of answering this question, students at the early college biology level learn how the information in DNA can be extracted and used by both the cell and scientists. This dual proximate-ultimate approach introduces students to the techniques of PCR, DNA sequencing, and phylogenetic sequence analysis while simultaneously providing a concrete pen-and-paper model of the cellular processes of transcription and translation. The laboratory has been successfully employed over 3 years with first-year college students and has proven its versatility by being easily adapted to a "dry lab" form with advanced high school students. PMID- 21706704 TI - Sex determination using PCR. AB - PCR has revolutionized many aspects of biochemistry and molecular biology research. In the following exercise, students learn PCR by isolating their own DNA, amplifying specific segments of the X and Y chromosomes, and estimating the sizes of the PCR products using agarose gel electrophoresis. Based on the pattern of PCR products, students can distinguish between male and female samples and determine the gender of an unknown DNA donor. The exercise is presented for upper division undergraduate majors in microbiology, biochemistry, and molecular biology, but can be adapted to different academic levels and disciplines. The use of student samples in the exercise can enhance learning of these techniques by making PCR and agarose gel electrophoresis directly relevant to the students. PMID- 21706705 TI - Commentary: Constructivist pedagogy. PMID- 21706706 TI - Protein transport into the rough endoplasmic reticulum. AB - Terms to be familiar with before you start to solve the test: in vitro protein synthesis, endoplasmic reticulum, [(35) S]methionine labeling, ribosomes, aminoacyl-tRNA synthase, microsomes, signal recognition particle (SRP),1 The abbreviations used are: SRP, signal recognition particle; NEM, N-ethylmaleimide; MCQ, multiple-choice question. SRP receptor, protease, detergent, SDS-PAGE, autoradiography, protein glycosylation, peptidyl transferase, protein kinases, signal peptide, signal peptidase. PMID- 21706708 TI - Commentary: Twenty years of computers in biochemical education: Orwell denied. PMID- 21706707 TI - The minds' eye: Biomedical visualization: The most powerful tool in science. PMID- 21706709 TI - Websites of note. PMID- 21706711 TI - Purine and pyrimidine metabolism, designed by Donald Nicholson: Commentary. PMID- 21706712 TI - Implementing the recommended curriculum in biochemistry and molecular biology at a regional comprehensive university through a biology/chemistry double major: The minnesota state university moorhead experience*. AB - Minnesota State University Moorhead (MSUM) is a regional comprehensive university that is part of the Minnesota State Colleges and Universities (MnSCU) system. The current student population consists of ~7,600 full- and part-time students who are enrolled in one of 135 majors that lead to baccalaureate degrees. MSUM is committed to excellence in science teaching and research for undergraduates. It is an institutional member of the Council on Undergraduate Research and has three faculty members participating in Project Kaleidoscope (PKAL) Faculty for the 21st Century. Fourteen years ago, MSUM renewed its effort to have faculty participate in active research. All science faculty members hired since that time have been required to establish research programs. The primary purpose for the faculty engaging in ongoing research projects is to involve undergraduates in a meaningful research experience, thus training these students to become scientists. PMID- 21706713 TI - A response to BIO 2010: Transforming undergraduate education for future research biologists, from the perspective of the biochemistry and molecular biology major program at Kenyon College. AB - The National Research Council completed a major study of undergraduate biology education, BIO 2010-Transforming Undergraduate Education For Future Research Biologists (BIO 2010), funded by the Howard Hughes Medical Institute and the National Institutes of Health. The BIO 2010 report recommends that biology pedagogy should use an interdisciplinary approach incorporating a strong basis in mathematics and physical sciences. Many of the aims of BIO 2010 can be met by an interdisciplinary major program such as that of Biochemistry and Molecular Biology at Kenyon College. The Kenyon program effectively encourages students to connect biology with chemistry and mathematics and to develop a sound basis for research in the biological sciences. A continuing challenge is to balance the needs for depth of physical and mathematical understanding and breadth of diversity in biology. PMID- 21706714 TI - Virtual bioinformatics distance learning suite*. AB - Distance learning as a computer-aided concept allows students to take courses from anywhere at any time. In bioinformatics, computers are needed to collect, store, process, and analyze massive amounts of biological and biomedical data. We have applied the concept of distance learning in virtual bioinformatics to provide university course material over the Internet. Currently, we provide two fully computer-based courses, "Introduction to Bioinformatics" and "Bioinformatics in Functional Genomics." Here we will discuss the application of distance learning in bioinformatics training and our experiences gained during the 3 years that we have run the courses, with about 400 students from a number of universities. The courses are available at bioinf.uta.fi. PMID- 21706715 TI - Oxidation-reduction calculations in the biochemistry course. AB - Redox calculations have the potential to reinforce important concepts in bioenergetics. The intermediacy of the NAD(+) /NADH couple in the oxidation of food by oxygen, for example, can be brought out by such calculations. In practice, students have great difficulty and, even when adept at the calculations, frequently do not understand their significance. The causes of this problem are identified with 1) the context in which redox calculations are presented and 2) the confusion over the formalism of the redox potential, particularly the meaning of the sign that refers to direction of current flow but is frequently confused with thermodynamic sign. A method is described for teaching redox calculations that is straight-forward and simple for students to perform but, at the same time, brings out the key concepts. The primacy of the free energy is emphasized and the method is used to reinforce an understanding of respiration. PMID- 21706716 TI - The use of item analysis for improvement of biochemical teaching. AB - Item analysis was used to find out which biochemical explanations need to be improved in biochemical teaching, not which items are to be discarded, improved, or reusable in biochemical examinations. The analysis revealed the basic facts of which "less able" students had more misunderstanding than "able" students. Identifying these basic facts helps biochemistry teachers to improve their teaching. PMID- 21706717 TI - An interactive introduction to protein structure. AB - To improve student understanding of protein structure and the significance of noncovalent interactions in protein structure and function, students are assigned a project to write a paper complemented with computer-generated images. The assignment provides an opportunity for students to select a protein structure that is of interest and detail three to five noncovalent interactions important for protein structure and/or function. The assignment is designed to provide a hands-on learning experience for students in a moderately large introductory biochemistry class. PMID- 21706718 TI - Gene amplification by PCR and subcloning into a GFP-fusion plasmid expression vector as a molecular biology laboratory course*. AB - A novel experimental sequence for the advanced undergraduate laboratory course has been developed at Earlham College. Utilizing recent improvements in molecular techniques for a time-sensitive environment, undergraduates were able to create a chimera of a selected gene and green fluorescent protein (GFP) in a bacterial expression plasmid over the course of a single semester in a weekly 3-h laboratory period. Students designed PCR primers for amplification of the selected gene using computational DNA sequence analysis tools. During the experimental portion of the course, students amplified and ligated the target DNA into a commercially available GFP expression vector. Following transformation of the ligation product, plasmids were harvested from the resulting bacterial colonies and were analyzed by restriction digestion to confirm the creation of the chimeric GFP-DNA. This course gave students valuable experience with commonly used molecular techniques in an authentic research project. In addition, students gained experience with experimental design and execution. The techniques presented here are flexible and can be generalized for use with almost any DNA sequence and expression vector. This series also serves as an example of how faculty can adapt their ongoing research projects to the undergraduate laboratory. PMID- 21706719 TI - Formation and detoxification of reactive oxygen species. AB - A model of reactive oxygen species metabolism is proposed as a laboratory exercise for students. The superoxide ion in this model is generated during the reaction of oxidation of xanthine, catalyzed by xanthine oxidase. The effect of catalase, superoxide dismutase, and allopurinol on superoxide ion generation and removal in this system is also determined, using cytochrome c as a probe. PMID- 21706720 TI - The ribosomal RNA is a useful marker to visualize rhizobia interacting with legume plants. AB - Symbiosis between rhizobia and leguminous plants leads to the formation of nitrogen-fixing root nodules. In the present article, we recommend the use of the ribosomal RNA (rRNA) isolated from legume nodules in an experimental class with the purpose of introducing students to the structure of eukaryotic and prokaryotic ribosomes and of demonstrating rhizobia colonization and nodule occupancy. We consider that this activity might help students previously trained in molecular biology handling to experience a richer way of learning some concepts and methodology in molecular plant-microbe interactions. PMID- 21706721 TI - Characterization of the CCR5 chemokine receptor gene. AB - The life cycle of retroviruses is an essential topic of modern cell biology instruction. Furthermore, the process of HIV viral entry into the cell is a question of great interest in basic and clinical biology. This paper describes how students can easily recover their own DNA, amplify a portion of the CCR5 chemokine receptor gene, characterize wild-type and mutant genotypes, and provide a timely backdrop for learning the many molecular facets of the HIV virus. This exercise can easily lead to current and ongoing discussions of the relevance of mutant alleles in the CCR5 co-receptor and possible HIV tolerance. Student laboratory reports often discussed the potential importance of structure to the function of CCR5 protein within the context of HIV infection and resistance. Discussions of structure linked to function are key components of student assessment. PMID- 21706722 TI - Biochemistry and academic abstinence. PMID- 21706723 TI - cAMP Regulation of the lactose operon. AB - Terms to be familiar with before you start to solve the test: lactose operon, adenylate cyclase, cAMP, catabolite activator protein (CAP), expression plasmid, lac operator, lac repressor, lactose, glucose, promoter, cis- and trans-acting factors. PMID- 21706724 TI - Commentary: Communicating science. PMID- 21706725 TI - Lucenz simulator: A tool for the teaching of enzyme kinetics. AB - A program has been developed that will produce simulated enzyme kinetic data suitable for inclusion in problem sets for undergraduates. Mechanisms simulated include one- and two-substrate reactions and various types of inhibition. The effects of variation of pH and temperature may be modeled, as may the effects of random errors on the experimental procedure. The graphical output is suitable for use in lecture demonstrations. PMID- 21706726 TI - Websites of note. PMID- 21706728 TI - The microarray revolution: Perspectives from educators. AB - In recent years, microarray analysis has become a key experimental tool, enabling the analysis of genome-wide patterns of gene expression. This review approaches the microarray revolution with a focus upon four topics: 1) the early development of this technology and its application to cancer diagnostics; 2) a primer of microarray research, designed to guide the beginner; 3) a highlight of the Genome Consortium for Active Teaching (GCAT), a worldwide consortium of faculty who are integrating microarrays into the undergraduate teaching laboratory; and 4) the use of microarrays in the biotechnology industry with a look forward to future applications. A central theme within this review is the profound relevance of new, bioinformatics-based, technologies to undergraduate students within the biosciences. PMID- 21706729 TI - Slow-binding inhibition: A theoretical and practical course for students. AB - Tyrosinase (EC 1.14.18.1) catalyzes the oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) to 2,3,5,6-tetrahydro-5,6-dioxo-1H-indole-2-carboxylate (dopachrome), according to the classical Michaelis-Menten kinetic mechanism. The enzyme is strongly but slowly inhibited by alpha-amino-beta-[N-(3-hydroxy-4-pyridone)] propionic acid (L-mimosine), a toxic plant amino acid. Easily available reagents and simple spectrophotometric detection of the product make the experimental characterization and kinetic analysis of tyrosinase action convenient and interesting for teaching purposes. In the present article, we present a theoretical and practical guide to the kinetic analysis of slow-binding inhibition. The effect of L-mimosine on tyrosinase is established by progress curve measurements, carried out on a conventional spectrophotometer equipped with a rapid kinetic accessory. In the analysis, we recommend a classical linearization approach but we also took advantage of a more reliable nonlinear regression method to avoid subjective bias. A multistep procedure starts by careful inspection of the curves to discriminate between candidate mechanisms. Next, the evaluation of initial and steady-state velocities provides information on the enzyme catalytic and Michaelis-Menten constants, as well as the corresponding inhibition constants. Subsequently, an appropriate mathematical derivation enables estimation of the isomerization rate constants characteristic for a slow-binding inhibitor. To conclude, we suggest simultaneous multivariable regression, using all the progress curve data, to cross-check the proposed reaction mechanism and evaluated kinetic constants. PMID- 21706730 TI - Bioinformatics in undergraduate education: Practical examples. AB - Bioinformatics has emerged as an important research tool in recent years. The ability to mine large databases for relevant information has become increasingly central to many different aspects of biochemistry and molecular biology. It is important that undergraduates be introduced to the available information and methodologies. We present a problem-based approach for incorporation of bioinformatics into existing courses. Examples of exercises are presented along with resources available on the World-Wide Web. PMID- 21706731 TI - An introductory bioinformatics exercise to reinforce gene structure and expression and analyze the relationship between gene and protein sequences. AB - We have developed an introductory bioinformatics exercise for sophomore biology and biochemistry students that reinforces the understanding of the structure of a gene and the principles and events involved in its expression. In addition, the activity illustrates the severe effect mutations in a gene sequence can have on the protein product. Students search GenBank for the wild-type nucleotide sequence of the Caenorhabditis elegans unc-22 gene, the amino acid sequence of its gene product, and the nucleotide sequence of the transposon Tc5. The nucleotide sequences are manipulated using two programs in the Lasergene(r) software package from DNASTAR(r). The first program, EditSeq(r), enables students to experience the meticulous process required to precisely locate and remove intron sequences from the wild-type unc-22 allele to generate a cDNA sequence. The unc-22(r466) allele is generated by inserting the sequence of the transposon Tc5 into the appropriate location of the third exon in unc-22. The open reading frames of both cDNAs are located and then translated. MegAlign(r), the second program, aligns the wild-type sequence of the UNC-22 protein and the wild-type and mutant protein sequences that were constructed. The degree of sequence similarity between the aligned proteins allows students to verify their success in processing the gene, as well as to visualize the truncated protein product from the Tc5 mutant allele. Student feedback and possible modifications to the exercise as well as supplemental exercises are also discussed. PMID- 21706732 TI - An enzymatic clinical chemistry laboratory experiment incorporating an introduction to mathematical method comparison techniques. AB - An enzymatic laboratory experiment based on the analysis of serum is described that is suitable for students of clinical chemistry. The experiment incorporates an introduction to mathematical method-comparison techniques in which three different clinical glucose analysis methods are compared using linear regression and Bland-Altman difference plots. The experiment may also be undertaken using simple glucose solutions by general biochemistry students. PMID- 21706733 TI - A colorimetric process to visualize erythrocyte exovesicles aggregates*. AB - A biochemistry laboratory class protocol is described in order to create an opportunity for students to apply by doing the theoretical concepts underlying biomolecules and vesicles properties, together with the principles of centrifugation and colorimetric methodologies. Through simple procedures the students will i) observe the segregation of the vesicles suspensions into two separate phases (phtalate esters gradient and vesicle aggregates); ii) visualize the vesicle aggregates by protein, enzyme, and phospholipids coloration processes; and iii) discuss and explain the visualized colors by proper biochemical reactions. The aims, objectives, methodology of teaching/learning, and assessment for this laboratory class are indicated. PMID- 21706734 TI - Agarose gel electrophoresis system in the classroom: Detection of DNA strand breaks through the alteration of plasmid topology. AB - Good quality scientific teaching depends on the ability of researchers to translate laboratory experiments into high school and undergraduate classes, bridging the advanced and basic science with common knowledge. A fast-growing field in biomedical sciences is oxidative stress, which has been associated to several diseases, including cancer and neurodegenerative disorders. We suggest herein a simple methodology for exploring DNA damage as an introductory pathway to these themes. The potential of natural or artificial products to induce DNA strand breaks can be easily tested in supercoiled plasmids incubated with selected products followed by agarose gel electrophoresis. This is designed to detect single and double strand breaks caused by reactive oxygen species generated by the products being tested. The altered topology of the damaged plasmid migrates slowly in the gel, creating a new band. We further introduce the quantitation of supercoiled DNA forms using densitometry of the gel with a digital camera; the values can then be used to estimate the number of breaks per genome using Poisson distribution. The system is inexpensive, rapid, and does not need high-cost equipment and supplies and can be performed in high schools and undergraduate classes with a minimal structure. PMID- 21706735 TI - Immunoassay for visualization of protein-protein interactions on Ni nitrilotriacetate support: Example of a laboratory exercise with recombinant heterotrimeric Galpha(i2) beta(1gamma2) Tagged by Hexahistidine from sf9 Cells. AB - We have developed an in vitro assay for following the interaction between the alpha(i2) subunit and beta(1gamma2) dimer from sf9 cells. This method is suitable for education purposes because it is easy, reliable, nonexpensive, can be applied for a big class of 20 students, and avoid the commonly used kinetic approach, which does not allow visualization of protein-protein interaction. PMID- 21706736 TI - Dealing with doubt. PMID- 21706737 TI - Thermodynamic properties of peptide folding. AB - Inter- and intramolecular forces and thermodynamics are concepts usually presented early within introductory biochemistry and have relevance to many topics throughout the remainder of the course. For this reason, it is important to have a good foundation in these concepts so they can be applied to many systems. To this end, a group problem has been developed that allows students to analyze thermodynamic data and, using their knowledge of inter- and intramolecular forces, gain an understanding of the elements involved in the thermodynamic stability and folding of a peptide. PMID- 21706738 TI - An in-gel enzyme assay*. AB - Terms to be familiar with before you start to solve the test: signal transduction, growth factor signalling, nerve growth factor (NGF), epidermal growth factor (EGF), mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases (ERKs), MAPK/ERK kinase (MEK), SDS-PAGE, [gamma-(32) P]ATP, autoradiography, caspases, protein kinases, phosphatidylinositol 3-kinase (PI3K), gene induction, alternative splicing. PMID- 21706739 TI - Biotechnology: What it is, what it is not, and the challenges in reaching a national or global consensus. PMID- 21706740 TI - Commentary: Tabula Rasa (Latin): A clean slate on which anything can be written. PMID- 21706741 TI - Websites of note. PMID- 21706743 TI - Glutamine metabolism: Role in acid-base balance*. AB - The intent of this review is to provide a broad overview of the interorgan metabolism of glutamine and to discuss in more detail its role in acid-base balance. Muscle, adipose tissue, and the lungs are the primary sites of glutamine synthesis and release. During normal acid-base balance, the small intestine and the liver are the major sites of glutamine utilization. The periportal hepatocytes catabolize glutamine and convert ammonium and bicarbonate ions to urea. In contrast, the perivenous hepatocytes are capable of synthesizing glutamine. During metabolic acidosis, the kidney becomes the major site of glutamine extraction and catabolism. This process generates ammonium ions that are excreted in the urine to facilitate the excretion of acids and bicarbonate ions that are transported to the blood to partially compensate the acidosis. The increased renal extraction of glutamine is balanced by an increased release from muscle and liver and by a decreased utilization in the intestine. During chronic acidosis, this adaptation is sustained, in part, by increased renal expression of genes that encode various transport proteins and key enzymes of glutamine metabolism. The increased levels of phosphoenolpyruvate carboxykinase result from increased transcription, while the increase in glutaminase and glutamate dehydrogenase activities result from stabilization of their respective mRNAs. Where feasible, this review draws upon data obtained from studies in humans. Studies conducted in model animals are discussed where available data from humans is either lacking or not firmly established. Because there are quantitative differences in tissue utilization and synthesis of glutamine in different mammals, the review will focus more on common principles than on quantification. PMID- 21706744 TI - Neuroglobin and cytoglobin: Two new entries in the hemoglobin superfamily*. AB - Neuroglobin (Ngb) and cytoglobin (Cygb) are two newly discovered intracellular members of the vertebrate hemoglobin (Hb) family. Ngb, predominantly expressed in nerve cells, is of ancient evolutionary origin and is homologous to nerve-globins of invertebrates. Cygb, present in many different tissues, shares common ancestry with myoglobin (Mb) and can be traced to early vertebrate evolution. Ngb and Cygb display the classical three-on-three alpha-helical globin fold and are endowed with a hexa-coordinate heme Fe atom, in both their ferrous and ferric forms, having the heme distal HisE7 residue as the endogenous sixth ligand. Reversible intramolecular hexa- to penta-coordination of the heme Fe atom modulates Ngb and Cygb ligand-binding properties. In Ngb and Cygb, ligand migration to/from the heme distal site may be assisted by protein/matrix tunnel cavity systems. The physiological roles of Ngb and Cygb are poorly understood. Ngb may protect neuronal cells from hypoxic-ischemic insults, may act as oxidative stress responsive sensor protein, and may sustain NO/O(2) scavenging and/or reactive oxygen species (ROS) detoxification. Cygb, located in the cytoplasm of fibroblasts, chondroblasts, osteoblasts, and hepatic stellate cells, has been hypothesized to be involved in collagen synthesis. In neurons, Cygb, located in both cytoplasm and nucleus, may provide O(2) for enzymatic reactions, and may be involved in a ROS (NO)-signaling pathway(s). Here, we review current knowledge on Ngb and Cygb in terms of their structure, function, and evolutionary links to the well-known human HbA and Mb. PMID- 21706745 TI - Calculation of theoretical yields in metabolic networks*. AB - Nature has created elaborate networks of reactions to convert substrates into the building blocks of living cells as well as a myriad of natural products. The biosynthetic pathways responsible for each metabolite produced have a certain material and energetic "cost" associated with them. The theoretical calculation of these costs aid in analyzing metabolic pathways and engineering metabolic changes in cells. Depending on the complexity and structure of the metabolic system under consideration, different approaches need to be taken for the calculations. In this article, a systematic method to calculate theoretical yields is described for simple linear and cyclic pathways. A published error in the theoretical cost calculations for photorespiration is corrected (J. N. Siedow and D.A. Day (2000) Biochemistry and Molecular Biology of Plants, American Society of Plant Physiologists, Rockville, MD, pp. 676-726). A matrix-vector formulation of the stoichiometric pathways is presented for more complex systems. PMID- 21706746 TI - An introductory undergraduate course covering animal cell culture techniques. AB - Animal cell culture is a core laboratory technique in many molecular biology, developmental biology, and biotechnology laboratories. Cell culture is a relatively old technique that has been sparingly taught at the undergraduate level. The traditional methodology for acquiring cell culture training has been through trial and error, instruction when undertaking the first graduate student position, or instruction when hired for a specific industrial cell culture position. However, cell culture is an important candidate course for any biotechnology-related training program because it is a technique that must be performed by investigators before they perform many molecular procedures, and vertebrate cell culture is becoming increasingly important for biomanufacturing of therapeutic proteins. Therefore, a cell culture techniques course is an important offering for undergraduate students who aspire to graduate training, and also undergraduate students who will seek employment with biotechnology companies immediately after graduation. Recently, a cell culture techniques course was developed and delivered to students at North Carolina State University as a component of an undergraduate Biotechnology minor curricula. Currently, the instructors at North Carolina State University are seeking to provide students with the necessary technical and critical reasoning skills to successfully perform animal cell culture. PMID- 21706747 TI - The human side of science education: Using McGregor's theory Y as a framework for improving student motivation*. AB - Student motivation is correlated with learning. Douglas McGregor's Theory X and Theory Y as a basis for understanding and improving motivation in the business world can be directly applied to the science classroom. Teachers with a Theory Y perspective (students naturally want to learn) provide increased motivation for students and promote more active learning than Theory X-style teachers who do not view students as active learners. Many teachers are not aware of their Theory X/Theory Y orientation and how this bias may be impacting their interaction with students. This article explores the benefits of moving from a Theory X to a more Theory Y style of teaching. PMID- 21706748 TI - Student-designed enzyme-linked metabolite assay kits. AB - The extensive use of commercial kits in molecular biology and biochemistry has prompted us to design a series of practical sessions to help students become familiar with the uses and limitations of pre-packaged assay systems. To facilitate an understanding of these assay systems and to promote reflection on their appropriate use, students manufacture their own kit for one of four enzyme linked metabolite assays. To do this they must investigate the role of each of the components in the assay, optimize the conditions where possible, check for cross reactivity, and then work this assay up for a few related "real" samples. Students make up all the buffers, the standard solution, instructions, and even the packaging. The kit is checked for accuracy by the producers, "marketed" to other students, and evaluated by their peers. By going through this process, students learn the benefits and pitfalls of commercial kits as well as reinforcing the basic principles of metabolite measurement and gaining experience with assay design, troubleshooting, and problem solving. PMID- 21706749 TI - The effect of carbon source and fluoride concentrations in the streptococcus mutans biofilm formation*. AB - The main objective of this class experiment is to show the influence of carbon source and of different fluoride concentrations on the biofilm formation by the bacterium Streptococcus mutans. The observation of different biofilm morphology as a function of carbon source and fluoride concentration allows an interesting discussion regarding the metabolic pathways that lead to cavity development, about the role of fluoride on this disease prevention, and also on the importance of biofilm formation to the cariogenic potential of this bacterium, one of the main responsible for this multifatorial disease appearance. On addition to that, the low execution cost and the simple technical apparatus makes this experiment easy to perform. PMID- 21706750 TI - A phytase enzyme-based biochemistry practical particularly suited to students undertaking courses in biotechnology and environmental science. AB - Courses in introductory biochemistry invariably encompass basic principles of enzymology, with reinforcement of lecture-based material in appropriate laboratory practicals. Students undertaking practical classes are more enthusiastic, and generally display improved performance, when the specific experiments undertaken show direct relevance to their core degree area. Herein is described an enzyme-based practical of particular relevance to students undertaking primary degrees in biotechnology, environmental science, nutrition, as well as animal and veterinary science. The practical entails assay of phytase, an enzyme that is now routinely included in monogastric animal feed in order to ameliorate the negative nutritional and environmental consequences of its substrate, dietary phytic acid. The practical is technically straightforward, requiring relatively basic laboratory equipment and reagents that are both easily obtained and relatively inexpensive. To be an effective digestive supplement, the enzyme must display a combination of physicochemical properties, which provide sufficient scope for an interesting and multifaceted post-laboratory discussion. PMID- 21706751 TI - Simple protocol for secondary school hands-on activity: Electrophoresis of pre stained nucleic acids on agar-agar borate gels. AB - An extremely simple, inexpensive, and safe method is presented, which emulates nucleic acids isolation and electrophoretic analysis as performed in a research environment, in the context of a secondary school hands-on activity. The protocol is amenable to an interdisciplinary approach, taking into consideration the electrical and chemical parameters of the electrophoretic system. Furthermore, the laboratory is framed in a more comprehensive pedagogical setting, which addresses the methodological aspects of a pivotal scientific enterprise such as the Human Genome Project. In this setting, the hands-on activity is complemented with animations, paper models, and discussions. Additionally, our results indicate that the use of borate buffer and agar-agar gels suits many of the experiments included in college-level laboratory activities, which currently make use of more expensive agarose gels and TBE or TAE buffers. PMID- 21706752 TI - Ethical conduct in the laboratory: Looking the other way. PMID- 21706753 TI - Electrophoretic behavior of hemoglobin variants. AB - Terms to be familiar with before you start to solve the test: hemoglobins, erythrocytes, reticulocytes, amino acids, alpha and beta globin chains, electrophoresis, isoelectric point, sickle cell anemia. PMID- 21706754 TI - European doctorate in biotechnology: Added value for european academia and industry. AB - It has long been recognized that educational programs and degrees are not equivalent across Europe. Add to this the fact that Europe consists of many different cultures and languages, then it is not surprising that the free circulation of scientists and their job market in the European Union is severely restricted. This is one of several debated causes for the crisis in European biotechnology, which is in danger of succumbing to the competition of North America, Japan, and some of the developing countries. The Universities (even those tradition-ridden), the European University Association, and the European Commission are aware of the danger and plans are in preparation for sweeping organizational and cultural changes. The problem is how long will it take and how long can we afford to wait? A number of biotechnologists and scientists from several institutions and many countries decided, instead of waiting, to make a preliminary move in the right direction. With the help of the European Commission and using European Molecular Biology Organization, European Federation of Biotechnology, and the European University Rectors as references, the European Association for Higher Education in Biotechnology was founded in 1995 by representatives of universities and research institutes. It awards the additional title of European Doctor to PhD graduates showing excellence in biotechnology and/or related Life Science subjects and who are willing to fulfil a program of studies that is both international and interdisciplinary. The present article reports on the first 9 years of this adventure. PMID- 21706755 TI - Commentary: BLOGs. PMID- 21706756 TI - Websites of note. PMID- 21706758 TI - Introductory course based on a single problem: Learning nucleic acid biochemistry from AIDS research. AB - In departure from the standard approach of using several problems to cover specific topics in a class, I use a single problem to cover the contents of the entire semester-equivalent biochemistry classes. I have developed a problem-based service-learning (PBSL) problem on HIV/AIDS to cover nucleic acid concepts that are typically taught in the second semester of a biochemistry class. Use of research articles on a specific topic allows developing problems such as one discussed here. The implementation of this problem is similar to teaching literature-based courses but is tailored to undergraduate work. Details of designing and setting up this problem, along with the pros and cons of this approach, are discussed here. PMID- 21706759 TI - Tagging and purifying proteins to teach molecular biology and advanced biochemistry. AB - Two distinct courses, "Molecular Biology" taught by the Biology Department and "Advanced Biochemistry" taught by the Chemistry Department, complement each other and, when taught in a coordinated and integrated way, can enhance student learning and understanding of complex material. "Molecular Biology" is a comprehensive lecture-based course with a 3-h laboratory once a week, while "Advanced Biochemistry" is a completely laboratory-based course with lecture fully integrated around independent student projects. Both courses emphasize and utilize cutting-edge technology. Teaching across departmental boundaries allows students access to faculty expertise and techniques rarely used at the undergraduate level, namely the tagging of proteins and their use in protein purification. PMID- 21706760 TI - A biochemistry and molecular biology course for secondary school teachers*. AB - This article describes a course for reinforcing the knowledge of biochemistry in secondary school science teachers. The Department of Biochemistry and Molecular Biology of the University of Barcelona designed a course to bring these teachers up to date with this discipline. In addition to updating their knowledge of biochemistry and molecular biology, this course aims to provide teachers with a set of relevant laboratory practices that can be applied in their practical lessons. PMID- 21706761 TI - Diphenyl carbazide restores electron transport in isolated, illuminated chloroplasts after electron transport from water has been eliminated by mild heat treatment. AB - Freshly isolated, illuminated chloroplasts oxidize water and transfer the resulting electrons through the photosynthetic electron transport chains in their thylakoid membranes to the artificial electron acceptor, dichlorophenol indophenol (DCPIP). As a consequence, DCPIP is reduced and the decline in absorbance over time can be used to measure the rate of electron transfer. When gently heated, chloroplasts lose the capacity to oxidize water and the transfer of electrons to DCPIP is eliminated. Electron transport through chloroplasts to DCPIP is restored in the presence of the artificial electron donor diphenylcarbazide (DPC). If students gain experience with the DCPIP photoreduction assay and are given information on normal chloroplast function, they should be able to predict the behavior of heat-treated chloroplasts in a variety of experimental conditions. A number of such predictions are outlined and tested. The experiments can all be conducted with a limited repertoire of equipment and easily prepared solutions. Consequently, this work is well suited to an investigative study in which each student group, in consultation with instructors, can make and test its own prediction. The ways in which changing different variables can affect the quality of the experimental results is emphasized. Additional studies, on measurements of rates of oxygen evolution and emitted chlorophyll fluorescence, are briefly described to support the inferences that heat-treated chloroplasts do not oxidize water and that the vectorial transfer of electrons through them to DCPIP is identical to that in untreated chloroplasts. PMID- 21706762 TI - A rapid PCR-RFLP method for monitoring genetic variation among commercial mushroom species*. AB - We report the development of a simplified procedure for restriction fragment length polymorphism (RFLP) analysis of mushrooms. We have adapted standard molecular techniques to be amenable to an undergraduate laboratory setting in order to allow students to explore basic questions about fungal diversity and relatedness among mushroom species. The streamlined protocols allowed students to practice important molecular techniques within the context of self-designed investigative projects. This laboratory experience provided opportunities for students to practice strategies for examining molecular diversity among species. PMID- 21706763 TI - Solving an ethical issue involved in experimentation with animals in a brazilian teaching laboratory*. AB - Changes are occurring within Brazilian institutes of higher education; currently several universities are reviewing their course offerings and teaching approaches to determine if they meet the needs of today's undergraduate students. When changes are made to the curriculum of experimental courses, there should be an understood guarantee that all efforts to avoid ethical and biosafety issues have been diligently considered. Ethical considerations lead us to create an alternative experimental session to be conducted that eliminated the use of rats, the conventional in vivo model employed for learning metabolism of glycogen in our university. To avoid possible biosafety issues, we prepared an alternative sample to simulate human urine, which we called guarurine. Using our new method, it is possible to verify positive results imitating a diabetic and starving people samples for detection of glucose and ketone. The alternative tool described herein is not only particularly suited to bypass the ethics of using animals for teaching, but also permits the discussion of significant aspects of pathological and physiological situations such as diabetics and starvation in a simple, safe, and interesting way. PMID- 21706764 TI - From gene to protein: Prostatic acid phosphatase: Structure and expression of gene and protein*. AB - A set of classes for medical students is designed to reinforce an understanding of the basic laboratory methods of molecular biology and protein biochemistry in the context of a clinically important problem, prostate gland pathology. Students examine the gene coding for prostatic acid phosphatase and they assay expression of the gene in different lines of prostate cancer cell cultures (LNCaP and PC-3). The three-dimensional structure of the expressed protein is also investigated, in relation to its catalytic function. Students are encouraged to collect data for their experiments and to perform laboratory exercises on their own. The theory and practice should stimulate the students' discussion of various fields of biochemistry and molecular biology. PMID- 21706765 TI - Math literacy. PMID- 21706767 TI - Websites of note. PMID- 21706766 TI - Estrogen regulation of the expression of a cytochrome P450 isoenzyme*. AB - Terms to be familiar with before you start to solve the test: cytochrome P450 enzymes, xenobiotics, estrogens, steroid receptors, gene induction, SDS, chromatin, immunoprecipitation, immunoglobulin G (IgG), agarose gel electrophoresis, promoter, transcription factors, enhancer, histones, nonhistone proteins, PCR, Taq polymerase, primers, oligonucleotides, radioactive labeling, nondenaturing PAGE. PMID- 21706768 TI - Software review: BioROM 2005. PMID- 21706774 TI - A comparative study of induced pluripotent stem cells generated from frozen, stocked bone marrow- and adipose tissue-derived mesenchymal stem cells. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) and adipose tissue-derived mesenchymal stem cells (AMSCs) have been used clinically for tissue regeneration; however, their proliferation/differentiation potentials are limited. Recently, induced pluripotent stem cells (iPSCs), known to have nearly unlimited potential to proliferate and differentiate into cells of all three germ layers, have gained wide interest in regenerative medicine. Here, we generated iPSCs from frozen stocked AMSCs and BMSCs and examined their biological characteristics by comparative analyses. Although the iPSCs were more challenging to generate from the BMSCs than the AMSCs, both iPSC populations expressed pluripotent markers, such as stage-specific embryonic antigen (SSEA)-3, SSEA-4, tumour-related antigens (TRAs) TRA-1-60 and TRA-1-81, OCT3/4 and NANOG. Furthermore, both cell populations differentiated well into three germ layer-derived cells, both in vitro and in vivo. These results indicate that iPSCs derived from frozen AMSCs/BMSCs exhibit equally acceptable iPSC characteristics and have potential in clinical applications as an alternative source of autogenous stem cells. PMID- 21706775 TI - Cell encapsulation and cryostorage in PVA-gelatin cryogels: incorporation of carboxylated epsilon-poly-L-lysine as cryoprotectant. AB - It is desirable to produce cryopreservable cell-laden tissue-engineering scaffolds whose final properties can be adjusted during the thawing process immediately prior to use. Polyvinyl alcohol (PVA)-based solutions provide platforms in which cryoprotected cell suspensions can be turned into a ready-to use, cell-laden scaffold by a process of cryogelation. In this study, such a PVA system, with DMSO as the cryoprotectant, was successfully developed. Vascular smooth muscle cell (vSMC)-encapsulated cryogels were investigated under conditions of cyclic strain and in co-culture with vascular endothelial cells to mimic the environment these cells experience in vivo in a vascular tissue engineering setting. In view of the cytotoxicity DMSO imposes with respect to the production procedure, carboxylated poly-L-lysine (COOH-PLL) was substituted as a non-cytotoxic cryoprotectant to allow longer, slower thawing periods to generate more stable cryogels. Encapsulated vSMC with DMSO as a cryoprotectant responded to 10% cyclic strain with increased alignment and proliferation. Cells were stored frozen for 1 month without loss of viability compared to immediate thawing. SMC-encapsulated cryogels also successfully supported functional endothelial cell co-culture. Substitution of COOH-PLL in place of DMSO resulted in a significant increase in cell viability in encapsulated cryogels for a range of thawing periods. We conclude that incorporation of COOH-PLL during cryogelation preserved cell functionality while retaining fundamental cryogel physical properties, thereby making it a promising platform for tissue engineering scaffolds, particularly for vascular tissue engineering, or cell preservation within microgels. PMID- 21706776 TI - An analysis of bone regeneration at a segmental bone defect by controlled release of bone morphogenetic protein 2 from a biodegradable sponge composed of gelatin and beta-tricalcium phosphate. AB - To treat large bone defects is a clinically challenging problem and utilizing tissue engineering technology is an attractive approach for overcoming such a problem. Previously, a biodegradable sponge incorporating bone morphogenic protein-2 (BMP-2), which can control the release of BMP-2 for a prolonged time in an in vivo environment, was reported. In addition, a biodegradable sponge composed of gelatin and beta-tricalcium phosphate (betaTCP), gelatin-betaTCP sponge to develop a more ideal scaffold for enhancing bone regeneration was also created and previously reported. The purpose of this study was to investigate the effectiveness of the gelatin-betaTCP sponge for the promotion of bone regeneration in a critical-sized bone defect site in vivo. Apparent bone regeneration was induced by the gelatin sponge incorporating BMP-2 and the gelatin-betaTCP sponge with BMP-2 incorporation. In contrast, no apparent bone formation was induced by either the gelatin sponge only or the gelatin-betaTCP sponge without BMP-2. To investigate the quality of the regenerated bone, we conducted a biomechanical evaluation with a three-point bending test. We found no significant difference between the gelatin sponge incorporating BMP-2 and the gelatin-betaTCP sponge incorporating BMP-2 groups. Incorporation of betaTCP into the gelatin sponge was expected to enhance biomechanical strength during the initial bone regeneration. However, our observations showed that the gelatin betaTCP sponge did not significantly improve the quality of regenerated bone from the viewpoint of biomechanical assessment, even though it did not impair the effectiveness of the promotion of bone regeneration by BMP-2 in the bone defect. PMID- 21706777 TI - Flat and tubular membrane systems for the reconstruction of hippocampal neuronal network. AB - The selection of appropriate biomaterials that promote cellular adhesion and growth is particularly important for the in vitro reconstruction of neuronal network. This study focused on the development of new polymeric membranes in flat and tubular (hollow-fibre) configurations as novel biomaterials for neuronal outgrowth. Two membrane systems constituted by modified polyetheretherketone (PEEK-WC) and polyacrylonitrile (PAN) membranes were developed and used for the culture of hamster hippocampal neurons. We demonstrated that all investigated membranes supported the adhesion and growth of hippocampal neurons enhancing neuronal differentiation and neurite alignment. The differences in cell behaviours between cells cultured on flat and hollow-fibre (HF) membranes were highlighted by the quantitative analysis of neuronal marker fluorescence intensity, morphometric analysis, RT-PCR analysis and also by metabolic activity measurements. In particular, the PAN HF membranes showed ideal growth culture conditions, guaranteeing adequate levels of metabolic features. Primary hippocampal cells cultured on PAN HF membranes were able to recreate in vitro a 3D neural tissue-like structure that, mimicking the hippocampal tissue, could be used as a tool for the study of natural and pathological neurobiological events. PMID- 21706779 TI - Abdominal aortic aneurysms: triple A, double trouble. PMID- 21706780 TI - Is sex exercise? And is it hard on the heart? PMID- 21706778 TI - Manipulation of miRNA activity accelerates osteogenic differentiation of hMSCs in engineered 3D scaffolds. AB - Cell-based tissue engineering strategies have shown tremendous promise for the repair of bone mass deficiencies, but the efficient and appropriate induction of stem cells down osteogenic pathways remains a significant roadblock to the effective implementation of cell-based therapies. When grown in culture, human Mesenchymal Stromal/Stem Cells (hMSCs) remain multipotent, requiring specific exogenous signals to induce osteogenic differentiation. hMSCs used in transplantations, therefore, must be presented with local signals, often provided by the host's own tissues, to be directed down bone-related lineages. This process is relatively inefficient and remains difficult to control. In an effort to enhance osteogenesis, hMSCs were transfected with specific miRNA mimics and inhibitors that had originally identified for their ability to increase Alkaline Phosphatase (ALP) activity. Transfection with miRNA reagents had the effect of sensitizing hMSCs to soluble osteogenic factors, resulting in a rapid and robust induction of bone-related markers, including ALP activity and calcium deposition. Synthetic 3D tissue constructs prepared with miRNA-transfected hMSCs demonstrated similar responses to soluble osteogenic signals, suggesting that controlling miRNA activity in hMSCs can be an effective tool for enhancing the induction of osteogenesis for tissue engineering purposes. PMID- 21706781 TI - Cholesterol and prostate cancer. PMID- 21706782 TI - On call. Compared to the problems your readers ask about, my issue may seem silly. But I hope you'll give me some advice, since it really is very annoying. I'm troubled by excessive sweating. PMID- 21706783 TI - Towards kidney allocation on basis of HLA-DR compatibility. AB - In the past years immunosuppressive regiments were mainly directed against T cell reactivity. Recently, alloreactivity by B cells and HLA antibodies have received more attention often triggered by the proposal of Terasaki on the "humoral theory of transplantation". Alloantibodies are not only a relevant factor before transplantation, but are also a cause of allograft dysfunction after transplantation. In the present report we advocate the possibility to reduce the effect of these detrimental, donor specific antibodies in organ transplantation. We propose to introduce fully HLA-DR compatibility in renal transplantation to increase the possibility of the patient to receive an adequately matched organ leading to an increased graft survival. This procedure is associated with a lower degree of allosensitization towards the donor HLA antigens and in case of graft failure, a higher chance to be retransplanted. This step can be seen as the first in a series of possibilities to diminish allosensitization without the need of additional immunosuppressive treatments. PMID- 21706784 TI - [Prerequisites for pertinent clinical examination facing a child with abdominal pain]. AB - A high-quality initial clinical examination is the best way to start a pertinent diagnostic process. It is important to keep out of ones mind a previous diagnosis. Questioning and physical examination are of same value. Questioning must be done in an usual language without suggesting answers; nevertheless it is recommended to cross questions in order to be sure of the patient's history. Physical examination uses as well eyes, ears and nose, as fingers. The whole body, and not only the belly, must be checked. The self-control of a well-trained practitioner results in a high level of confidence from both child and parents, and is the main key to succeed in clinical examination. PMID- 21706785 TI - [Mobile phone based wireless microscopy imaging technology]. AB - This article proposes a new device named "Wireless Cellscope" that combining mobile phone and optical microscope together. The established wireless microscope platform consists of mobile phone, network monitor, miniaturized microscope or high resolution microscope etc. A series of conceptual experiments were performed on microscopic observation of ordinary objects and mice tumor tissue slices. It was demonstrated that, the new method could acquire microscopy images via a wireless way, which is spatially independent. With small size and low cost, the device thus developed has rather wide applicability in non-disturbing investigation of cell/tissue culture and long distance observation of dangerous biological sample etc. PMID- 21706786 TI - [Fluorescent signal detection of chromatographic chip by algorithms of pyramid connection and Gaussian mixture model]. AB - We proposed a new algorithm for automatic identification of fluorescent signal. Based on the features of chromatographic chips, mathematic morphology in RGB color space was used to filter and enhance the images, pyramid connection was used to segment the areas of fluorescent signal, and then the method of Gaussian Mixture Model was used to detect the fluorescent signal. Finally we calculated the average fluorescent intensity in obtained fluorescent areas. Our results show that the algorithm has a good efficacy to segment the fluorescent areas, can detect the fluorescent signal quickly and accurately, and finally realize the quantitative detection of fluorescent signal in chromatographic chip. PMID- 21706787 TI - [A technique for the vein extraction from the susceptibility weighted imaging of the brain]. AB - This paper studies the vein extraction technique based on the susceptibility weighted imaging (SWI) and introduced an improved self-adaptive threshold method based on the vessel enhancing diffusion. The approach employs the combination indicator of the local gray character, the global gray character and the tubular information of the vein. It first applies the vessel enhancing diffusion filter to enhance the continuity of the vein, increases the detection rate of tiny vein and suppresses the nucleus areas. And then it uses the improved self-adaptive threshold method to extract the vein. The results demonstrate that this approach can solve the problem above and extract the vein from the SWI image accurately. PMID- 21706788 TI - [Hydrodynamics analysis of waveform of capacity model inspiratory phase]. AB - PURPOSE: To make the capacity model of SMART new-type multi-functional ventilator achieve the capability that the flow can be stable and adjusted accurately. METHODS: To analysis the problems in the course of development with fluid mechanics principle, find the deficiencies of original design and improve it. RESULTS: The inspiratory phase waveform of IPPV. SIMV,etc, breathing pattern presented square wave, achieved the goal of adjustable flow. CONCLUSIONS: Using the fluid mechanics principle guiding the design of ventilator gas circuit can get twice the result with half the effort. PMID- 21706789 TI - [The measurement method and effective evaluation for the respiration monitoring of patient]. AB - This article introduces a method of thoracic impedance, evaluation indexes and evaluation method for the respiration monitoring, including the methods basing on lab testing and clinical database testing, it will provide a reference for improving the efficiency of respiration monitoring. PMID- 21706790 TI - [Calculation of parameters and accurate control with real-time compensator in drive system of pulsatile blood pump]. AB - This article introduces a new method using the servo motor which is controlled by ARM microcontroller to provide power for a pulsatile blood pump to beat. This method is featured with straightforward structure, accurate control, excellent timeliness, stable performance and small noise. And it can adjust the rate of beat, the rate of flow and the compression ratio according to actual demand. PMID- 21706791 TI - [Research in the performance of the HA ceramic scaffold added with bioglass]. AB - Selecting appropriate bone repair materials has been an issue in the area of research and development as well as clinical applications. The main concerns are the mechanical strength of the material as well as the biocompatibility of the material. Ca/P(calcium phosphate) ceramic belongs to the group of bioactive ceramic. It has become the central focus of alternative artificial bone research. However, the mechanical strength of Ca/P ceramic has limited its further development. Adding bioglass to Ca/P ceramic has not only increased its mechanical strength, but also improved its bioactivity. PMID- 21706792 TI - [A design of refractometer based on blur circle]. AB - OBJECTIVE: Design a convenient and stable eye refractometer based on the theory of blur circle. METHODS: Analyze the retinal blur circle in both Emsly reduced eye model and Liou & Brennan 1997 eye model by ZEMAX. Design the coefficients including PD (pupil diameter) and NO' (length between node point and fovea) with the purpose of improving the accuracy. At last, compare the clinical optometry data from this refractor with the data obtained from optometry hospital in Wenzhou. RESULTS: The blur circle diameters are nearly the same in both reduced eye model and the Liou & Brennan 1997 eye model. With the PD = 4 mm and NO' = 20 mm, the refractor shows a fine accuracy in optometry. The paired t test shows that the myopia group and the astigmatism axial direction group have no statistical difference between the data from the blur circle refractor and the hospital (P > 0.05), while the astigmatism degree group has the result of P = 0.41 which may be caused by the poor cooperation of pediatric patients. 80% of the astigmatism degree data differ from the data from the hospital in less than 0.75D. CONCLUSION: The blur circle refractor, with the features of convenience and fine accuracy, is promised to be a new style of refractometer in the future. PMID- 21706793 TI - [Design of an adjustable simulated lung]. AB - We designed an adjustable simulated lung for clinical use. Depending on the feature of adjustable resistance and compliance, the device could simulate various pathological changes of lung, such as obstructive diseases and restrictive diseases. Thru simulating various pathological conditions with the device, the clinicians could learn how to manipulate a mechanical ventilator. In addition, the device has a leakage equipment for simulating leakage of respiratory circuit, depending on which the clinicians could learn more about ventilators. PMID- 21706794 TI - [Design of absorbable Bondi of dura]. AB - A sort of absorbable Bondi of dura, whose main body is glue capsule, to compensate the deficiency of previous craniotomy, which easily causes delayed epidural hematoma. This device will help conglutinate dura to skull plate tightly, to stop bleeding and other purposes. PMID- 21706795 TI - [Design and analysis of the optimization of the hospital exam planning and scheduling model]. AB - OBJECTIVE: Improve the electronic application appointment and scheduling methods in hospital to optimize patients appointment and improve utilization of hospital inspection equipment. METHOD: Analyze the workflow of existing electronic application and put forward the improvement scheme. RESULT: Developed a set of efficient appointment scheduling system, thus optimize the workflow of hospital exam. CONCLUSION: This system not only optimizes the patient's examination time, but also improves the utilization of hospital inspection equipment. PMID- 21706796 TI - [Hospital integrated maintenance management system design and application]. AB - According to hospital medical equipment, information equipment and water, electricity and other equipment maintenance procedures, this paper planned and developed a comprehensive maintenance management system for hospitals. The system implements equipment maintenance, maintenance applications, maintenance registration, preventive maintenance, data quantitative analysis and other functions. PMID- 21706797 TI - [Research progress in electromagnetic tracking method]. AB - Electromagnetic tracking is a method to track the position and space attitude of objects utilizing electromagnetic field. In this paper, the main methods during the development of Electromagnetic tracking are summarized and classified according to the magnetic field generation method, the number of magnetic sources and sensors used, the configuration and geometry of them. Tracking algorithm and calibration methods are also discussed. The critical issues during the development of electromagnetic tracking are analyzed, with the hope of helping the further research and application of electromagnetic tracking. PMID- 21706798 TI - [Ten years review of the development and administration of Shanghai IVD reagents]. AB - This article reviews the development and administration of Shanghai IVDs (In Vitro Diagnostics) manufactures by analyzing the administration and history of the regulation of IVDs in ten years. It is to find out the problems in the administration of IVDs manufactures and products, and to make suggestions for improvements. PMID- 21706799 TI - [Perspectives on the development of quality management system for medical devices in China from the GMP aspects]. AB - The full implementation of GMP for medical devices, which is an important step to improve quality management system of medical devices production, will have a positive impact on the quality management system of medical device. It will improve and promote the development of quality management system for medical device, by updating the idea and rebuilding the frame and optimizing the contents. PMID- 21706800 TI - [The meaning of the conception of scientific examination to create "Drug Testing in China" brand]. AB - Through the analysis of the current drug testing market, this paper discussion the meeting of creating "Drug Testing in China" brand on the concept of scientific testing. PMID- 21706801 TI - [Determination of the content of zotarolimus on the drug eluting stents by HPLC]. AB - OBJECT: To establish a method for the content determination of zotarolimus on the drug eluting stents. METHODS: HPLC analysis was carried out with Zorbax Eclipse C8 column (4.6 x 75 mm 3.5 microm)and MPA acetate buffer solution: acetonitrile (51:49), MPB acetate buffer solution: acetonitrile (5:95) as the mobile phase. The detection wavelength was 278 nm. RESULT: There was a good linear relationship between the concentration of zotarolimus and the areas in the range of 5 microg/ml-75 microg/ml (r = 0.99986). The average recovery was 101.58% with RSD 0.68% (n = 6). CONCLUSION: The method is simple, accurate and reproducible. It can be used as the quality test for zotarolimus on the drug eluting stents. PMID- 21706802 TI - [Meet the challenge of the implementation of the EMC standard for medical electrical equipment]. AB - This paper reveals the EMC quality situation of China's medical electrical equipment and the existing security risks in order to arouse the concerns of the government supervision departments, technical inspection units, the production enterprises and the users. It also serves as a reference when formulating related policies and measures. PMID- 21706803 TI - [Comparison of domestic and international standards for orthopedic implants]. AB - A great deal of comparisons on domestic standards for Orthopedic implants with ISO and ASTM standards have been presented, and some conclusions have been drawn: Domestic standards for orthopedic implants coincide with ISO and ASTM standards in the items of materials, geometry and classification. There are much bigger differences in some key performances of implants such as assembly, fatigue, wear and tear and so on. Some constructive ways have been suggested. PMID- 21706804 TI - [Development of automatic atomization network]. AB - This article develops a system of intelligent atomization which can shorten the time for the preparation of the clinical atomization and avoid mistakes. The system will enable patients enjoy the treatment right after swiping their ID cards. PMID- 21706805 TI - [Internal fixation treatment of multiple rib fractures with absorbable rib connecting-pins under epidural anesthesia]. AB - OBJECTIVE: To study the indications, methods and experience of absorbable rib connecting-pins fixation in the treatment of multiple rib fractures. METHOD: 52 cases with multiple rib fractures were performed internal fixation with absorbable rib-connecting-pins under epidural anesthesia. RESULTS: All cases were followed up for 1 to 12 months, with an average of 5 months. All fractures were achieved healing in 3 to 6 months after the operation and were not found chest wall deformity. CONCLUSIONS: Absorbable rib-connecting-pins fixation is a simple and effective method and worthies recommending to perform operation for the appropriate cases with multiple rib fractures. PMID- 21706806 TI - [Development and application of the transparent combined dilation conductor]. AB - According to the clinical needs of treatment for the carpal tunnel syndrome, a transparent combined dilation conductor was developed for the endoscopic carpal tunnel release. There are kinds of characters for this conductor: good photo permeability, facility to operation, easy to use, no toxic effect, low system cost etc. PMID- 21706807 TI - [Development and application of emergency medical information management system]. AB - OBJECTIVE: To meet the needs of clinical practice of rescuing critical illness and develop the information management system of the emergency medicine. METHODS: Microsoft Visual FoxPro, which is one of Microsoft's visual programming tool, is used to develop computer-aided system included the information management system of the emergency medicine. RESULTS: The system mainly consists of the module of statistic analysis, the module of quality control of emergency rescue, the module of flow path of emergency rescue, the module of nursing care in emergency rescue, and the module of rescue training. It can realize the system management of emergency medicine and,process and analyze the emergency statistical data. CONCLUSIONS: This system is practical. It can optimize emergency clinical pathway, and meet the needs of clinical rescue. PMID- 21706808 TI - [Practice and experience about construction of pharmacy automation at general hospital]. AB - This paper introduce how to combining the whole package automatic dispensing machine with intelligent storage cabinets at outpatient pharmacy. Furthermore, this paper introduce how to integrated this system with hospital information systems which can provide references for the construction of automatic hospital pharmacy in our country. PMID- 21706809 TI - [Alcohol medicine and Hiromasa Ishii in Japan and the world]. PMID- 21706810 TI - [Research achievement of Dr. Hiromasa Ishii at Keio University]. PMID- 21706811 TI - [The contributions of Dr. Ishii to the international scientific society of ISBRA]. PMID- 21706812 TI - [Inheritance from Dr. Ishii: Future of gastroenterology related with alcohol consumption]. PMID- 21706813 TI - [Life, and water, alcohol and nutrition]. PMID- 21706814 TI - [Effect of ethanol on nerve dependent vasorelaxation and vasoconstriction]. AB - Vascular tone is controlled by endothelium and nerves innervating blood vessels. Endothelium releases various substances such as PGI2 (Prostacyclin), NO (nitric oxide), TXA2 (thromboxane A2) and ET-1 (endothelin-1). It is well documented that ethanol affects vascular responses mediated by these substances. On the other hand, peripheral vascular tone is also regulated not only by sympathetic adrenergic nerves but also by nonadrenergic noncholinergic (NANC) nerves. NANC nerves include NO nerves and sensory nerves which release calcitonin gene-related peptide (CGRP) and nerve-mediated hyperpolarizing factor (NDHF). However, effect of ethanol on nerve-mediated vascular responses remains poorly understood. Therefore, this review summarizes the effect of ethanol on the sympathetic adrenergic nerve-mediated vasoconstriction and the sensory nerve-mediated vasorelaxation. PMID- 21706816 TI - [Anti-platelet aggregation activity observed in the first distillation fraction of Honkaku-Shochu]. PMID- 21706815 TI - [Evaluation of the relapse prevention guidance for drug-dependent inmates: the intervention using self-teach workbook and group therapy in a "private finance initiative" prison--the first report]. AB - BACKGROUND: In Japan, methamphetamine (MAP) abuse has been a serious problem for 60 years, and many of MAP abusers have been incarcerated in prisons as a violator of the Stimulant Control Law in Japan. AIMS: The purpose of the present study is to evaluate effectiveness of the relapse prevention guidance for drug-dependent inmates using a self-teaching workbook for drug-abusing adolescents and group therapy, conducted in the Harima Rehabilitation Program Center, one of the new prisons which the Ministry of Justice founded cooperating private enterprises as a "Private Finance Initiative" project. METHODS: We provided for 89 male drug dependent inmates, incarcerated in the Harima Rehabilitation Program Center, with the relapse prevention guidance consisting of a self-teaching workbook and group therapy, and implement pre-and post-evaluations by the Self-efficacy Scale for Drug Dependence (SES) and the Stages of Change Readiness and Treatment Eagerness Scale, 8th version for Drug Dependence (SOCRATES-8D). RESULTS: After a waiting term, the participants were provided with a self-teaching program, subsequently with a group program. At the point of completing the waiting term, no significant changes were observed in the SES and SOCRATES-8D scores. However, at the point of completing the self-teaching program, the SES scores significantly fell, while the total SOCRATES-8D score and the scores of the two subscales, the "Recognition" and "Ambivalence," significantly rose. Further, at the point of completing the group program, the total scores of the SES and SOCRATES-8D, and the score of the two SOCRATES-8D subscales, the "Recognition" and "Taking Steps," significantly rose. CONCLUSION: The relapse prevention guidance consisting of a self-teaching workbook and group therapy, conducted in the Harima Rehabilitation Program Center, were supposed to bring same internal changes as the "Stage of Changes" model, proposed by Prochaska and DiClemente, to drug-dependent inmates. PMID- 21706817 TI - [Goodness of compound patterns based on symmetry groups]. AB - This study examined the ordinal agreement and order conservation hypotheses of Imai (1986), which predict that a pattern is considered good if it is invariant for more transformations. Undergraduates (N = 144) made goodness ratings for 21 dot compound patterns. The patterns consisted of 8-dot and 13-dot figures with solid and/or open circles. Both the figures and the patterns were invariant under the transformations of rotation and reflection, forming cyclic (C1, C2, C4) or dihedral (D1, D2, D4) groups. The results showed no significant differences among the four combinations of solid and open circles. When the 13-dot C1 figure was overlapped with the 8-dot figures, the C1 compound patterns were rated the poorest. The goodness ratings of the Cn and Dn patterns were the increasing functions of the number of transformations, which supports the ordinal agreement hypothesis. When alternated with the 8-dot D4 figure, the 8-dot C1 figure superimposed with the 13-dot figures reduced the goodness ratings of the C1 patterns, but the order of the ratings was conserved, which supports the order conservation hypothesis. PMID- 21706818 TI - [The effect of humor coping with interpersonal stress on the relationship between cynical hostility, conscious defensiveness, and depression]. AB - This study examined the effect of humor coping with interpersonal stress on the relationship between cynical hostility, conscious defensiveness, and depression. University students (N = 375; 214 men and 161 women) participated in a questionnaire survey. The results of hierarchical multiple regression analyses by sex showed that humor coping with interpersonal stress alleviated the detrimental influence of cynical hostility on depression only for men with low conscious defensiveness. For women, humor coping with interpersonal stress played a role in alleviating depression independently of hostility and conscious defensiveness. These findings suggest that there are differences between men and women in the role of humor coping with interpersonal stress in affecting depression. Methodological limitations of the present study are discussed, along with possible improvements for future studies. PMID- 21706819 TI - [Asymmetric switch cost: an investigation using lateralized readiness potentials]. AB - Switching to a dominant task incurs larger costs than switching to a non-dominant task. This study investigated whether this cost asymmetry derives from the inhibition of the dominant task rule that occurred during the previous trial. Participants were presented with a five-letter array consisting of (left) and (right), and asked to respond to the central target letter after being informed about the task rule with a pre-cue. The rule was switched between dominant (left hand to, right-hand to) and non-dominant tasks (right-hand to, left-hand to) every two trials. Reaction times revealed the asymmetrical switch cost and the effect of target-flanker congruency. Stimulus-locked lateralized readiness potentials showed that the dominant task rule was inhibited during the non dominant task, whereas this inhibition was not carried over to the dominant task trial. PMID- 21706820 TI - [Inferring the meaning of a novel adjective by Japanese preschoolers]. AB - This study examined how Japanese preschoolers infer the meaning of a novel adjective and noun. The participants, 41 three-year-olds and 44 four-year-olds, were introduced to a novel adjective or a novel noun in association with a familiar object. They were then shown five test objects and asked to choose all the objects to which they could apply the novel word. The results indicated that although both three- and four-year-olds tried to extend adjectives using a different principle from nouns, only four-year-olds successfully extended a novel adjective based on the sameness of property. Three-year-olds seem to have trouble extracting a common property across objects especially when those objects belong to different basic-level categories. PMID- 21706821 TI - [An improved method using k-means to determine the optimal number of clusters, considering the relations between several variables]. AB - In this article, we propose a non-hierarchical clustering method that can consider the relations between several variables and determine the optimal number of clusters. By utilizing the Mahalanobis distance instead of the Euclidean distance, which is calculated in k-means, we could consider the relations between several variables and obtain better groupings. Assuming that the data are samples from a mixture normal distribution, we could also calculate Akaike's information criterion (AIC) and the Bayesian information criterion (BIC) to determine the number of clusters. We used simulation and real data examples to confirm the usefulness of the proposed method. This method allows determination of the optimal number of clusters, considering the relations between several variables. PMID- 21706822 TI - [Using the Implicit Association Test (IAT) to measure implicit shyness]. AB - Previous research has shown that implicitly measured shyness predicted spontaneous shy behavior in social situations, while explicit self-ratings of shyness predicted controlled shy behavior (Asendorpf, Banse, & Mucke, 2002). The present study examined whether these same results would be replicated in Japan. In Study 1, college students (N=47) completed a shyness Implicit Association Test (IAT for shyness) and explicit self-ratings of shyness. In Study 2, friends (N=69) of the Study 1 participants rated those participants on various personality scales. Covariance structure analysis, revealed that only implicit self-concept measured by the shyness IAT predicted other-rated high interpersonal tension (spontaneous shy behavior). Also, only explicit self-concept predicted other-rated low praise seeking (controlled shy behavior). The results of this study are similar to the findings of the previous research. PMID- 21706823 TI - [False memories based on indirect associations of gender stereotypes of occupations]. AB - This study examined whether false memories, as revealed by the Deese-Roediger McDermott (DRM) paradigm, can arise from indirect stereotype associations, as proposed by Lenton, Blair, and Hastie (2001). We found significant indications of stereotype-evoked false memories. The participants in our experiment reported that they were unaware of the gender theme of the studied list, suggesting that the false memories were due to implicit associative processes. Although we could not replicate an increase in the false recognition of stereotypically gender congruent occupations, we detected a gender-congruent effect partially by the analyses of the "Remember" responses and the participants' egalitarian attitudes against the gender role. Moreover, analyses of the "Know" responses indicated that participants' attitudes toward gender roles potentially moderate the degree that they form occupational gender stereotypes. Implications of the results for basic/applied research on the interactions between stereotype and memory are discussed. PMID- 21706824 TI - [Discrimination thresholds for recognizing facial emotions: mostly higher among the elderly]. AB - Elderly people have lower ability for recognizing facial emotions than younger people. Previous studies showed that older adults had difficulty in recognizing anger, sadness and fear, but there were no consistent results for happiness, surprise and disgust. Most of these studies used a small number of stimuli, and tabulated the number of correct responses for facial expressions. These characteristics of the task might be the source of the discrepancy in the findings. The present study used a task which measures participants' discrimination thresholds for six basic emotions using psychophysical measurement methods. The results showed that the thresholds for elderly participants (74.8 +/ 6.5 yrs) were significantly higher than for younger participants (20.1 +/- 1.6 yrs) for sadness, surprise, anger, disgust and fear. There was no significant difference for happiness. Since the task that we developed was sufficiently sensitive, it is a useful tool for assessing individuals' ability to perceive emotion. PMID- 21706825 TI - [New trends in research on personality traits: contributions to economics and epidemiology]. AB - Research has shown that personality traits have strong predictive validity for economic variables (e.g., income, work attainment) and epidemiological variables (e.g., longevity, physical health), as well as for psychological variables such as problem behaviors, and mental disorders. Importantly, personality traits are predictive even after controlling for socioeconomic status and cognitive abilities. The authors believe that current personality research in Japan almost completely overlooks this perspective. In this article, the authors review these new trends in personality psychological research. They propose a model for research involving A (accurate assessments), B (big samples), C (controlling for covariates and confounders), D (developmental trajectories), and E (economic and epidemiological variables). They outline three future directions to embody personality psychology for prediction, prevention, public wealth, and population health. PMID- 21706826 TI - [Future neuroprotective strategies in the post-thrombolysis era--neurovascular unit protection and vascular endothelial protection]. AB - From an appearance of recombinant tissue plasminogen activator (rt-PA) in the clinical therapy on 2005 in Japan, the therapeutic strategy of ischemic stroke therapy is now changing dramatically. Many experimental data from animal stroke and clinical trials of neuroprotective agents failed to clinical useful therapeutic strategy. A free radical scavenger, edaravone is the first clinical drug for neuroprotection in the world which has been used in almost all ischemic stroke patients in Japan from 2001. Now, it is especially useful in thrombolytic therapy with rtPA, whereas we still need the newly more effective neuroprotective drugs which can be applied to many ischemic stroke patients. Therefore, we review and describe the future neuroprotective strategies in the post-thrombolysis era. PMID- 21706827 TI - [Ischemic stroke and heparin-induced thrombocytopenia]. AB - Immune-mediated heparin-induced thrombocytopenia (HIT) is a rare but serious side effect of heparin therapy which presents various thromboembolic events associated with high mortality and morbidity. There have been few reports about the prevalence of HIT in acute ischemic stroke, which our retrospective study and a multi-center prospective cohort study respectively estimated as 0.5% and 1.7% of unfractionated heparin-treated acute ischemic stroke patients. Once the onset of HIT is suspected, its therapy should be started immediately because treatment delay of HIT will bring a poor outcome. Stroke physicians should be aware of HIT, as heparin use will become increased more than ever in clinical practice with the development of new intravascular treatment techniques. PMID- 21706828 TI - [The development and validation of a new comprehensive self-completing questionnaire for symptoms in Parkinson's disease (MASAC-PD 31)]. AB - BACKGROUND: Patients with Parkinson's disease (PD) suffer from various symptoms. In order to identify untreated symptoms within the limited time of a clinical interview, we developed a new self-completing questionnaire (MASAC-PD 31). The questionnaire consists of two parts (5 domains, 31 items); Part I intended at rating the motor symptoms and activities of daily living (ADL) during both "on" and "off" periods, and Part II aimed at screening and assessing mainly the non motor symptoms, such as sleep-related difficulties, autonomic symptoms, cognition, mood and others. The purpose of this study was to evaluate the validity, reliability, and clinical usefulness of the questionnaire. SUBJECTS AND METHODS: Based on the number of valid answers in a pilot trial, MASAC-PD 31 was refined by improving the expression and layout. Of the initially enrolled 107 patients attending three hospitals, 102 patients were included in the final analysis. Correlations of the scores on the MASAC-PD 31 with other clinical scales were evaluated. A second trial consisting of 57 participants was conducted a month later to assess the test-retest reproducibility of the questionnaire. RESULTS: The average time needed to complete MASAC-PD 31 was 17 min (range: 3-90 min). Each of the domains in Part I showed high internal consistency (Cronbach's alpha: 0.663 for "on" motor) and strong correlations with preexisting indices (Spearman's correlation coefficient: 0.547, 0.544, and 0.571 for "on" motor against "on" UPDRS, PDQ-39, and Schwab & England ADL scale, respectively). The questions in the Part II domains also showed strong correlations with preexisting scales. Most of the items showed high reproducibility (weighted kappa coefficient) and consistency. CONCLUSION: This new comprehensive questionnaire was shown to be valid and reliable for assessing the motor disability in patients with PD. Moreover, it may be useful in clinical management for identifying clinically unrecognized symptoms, especially non-motor problems. PMID- 21706829 TI - [A case of inflammatory myopathy with widely skin rash following use of supplements containing Spirulina]. AB - A 49-year old woman noticed her skin rash several days after taking supplements containing Spirulina, a planktonic blue-green alga. Her skin rash was spreading over large parts of her body, even after stop ingestion two months later. Five months later, she developed muscle weakness of neck flexor and left proximal upper extremity. On admission, creatine kinase (CK) was elevated to 1,268 IU/ml in the serum. A muscle specimen revealed many necrotizing muscle fibers and the infiltration of mononuclear cells in the peri- and endomysium including a lot of eosinophils. Immunohistochemical staining showed the infiltration of CD4 positive cells in the peri- and endomysium and that of CD20 positive B cells in the perivascular regions. She was diagnosed as having inflammatory myopathy with widely skin rash. Therapy with administration of prednisolone and cyclophosphamide followed by methyl-prednisolone pulse improved her clinical symptoms. There is a similar report describing a case of dermatomyositis after ingestion of Spirulina, which is known to have immune-stimulating property such as accelerating tumor necrosis factor (TNF)-alpha production. Also, TNF-alpha single nucleotide polymorphisms (TNF-308A) was demonstrated to have strong association with onset of myositis in Caucasians. The use of Spirulina could result in inflammatory myopathy under some specific conditions. PMID- 21706830 TI - [A case of chronic inflammatory demyelinating polyradiculoneuropathy concomitant with acquired von Willebrand syndrome]. AB - We report a case of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) concomitant with acquired von Willebrand syndrome. A 33-year-old man developed motor and sensory polyneuropathy with electrophysiological conduction slowing. At this time, M-protein was absent He was diagnosed with CIDP and received intravenous immunoglobulin and subsequent oral corticosteroids, which resulted in almost complete remission for over 10 years. At the age of 44, he presented with chronic anemia. Laboratory tests and colonoscopy revealed that he had acquired von Willebrand syndrome with monoclonal gammopathy of undetermined significance (IgG lambda type) and colon cancer. Bleeding symptoms were.resolved with intravenous immunoglobulin, but not with supplementation of factor VIII. Shortly after successful excision of the cancer, CIDP and acquired von Willebrand syndrome simultaneously recurred. Intravenous immunoglobulin produced rapid improvement of both neurological and hematological abnormalities. Concurring CIDP and acquired von Willebrand syndrome in the present case may indicate that the conditions have a partly common immunological background including monoclonal gammopathy and a potential common autoantibody-mediated mechanism. Alternatively, dysfunction of von Willebrand factor may increase blood-nerve barrier permeability, inducing the recurrence of CIDP. PMID- 21706831 TI - [Convulsive syncope associated with transient hemodynamic ischemia in the basal ganglia]. AB - The pathophysiology of convulsive movements in patients with convulsive syncope remains unclear. Here, we report a patient with convulsive syncope whose convulsive movements seemed to be associated with transient hemodynamic ischemia in the basal ganglia. A 74-year-old man had 1-year history of orthostatic hypotension and transient clonic jerks in the limbs and trunk, predominantly in the right upper limb. His convulsive movements were evoked approximately 1 minute after sitting up or standing up from the supine position and lasted for several tens of seconds. He felt mild faint while the convulsive movements lasted, but he was oriented and could follow simple commands. He was diagnosed as pure autonomic failure. Video-electroencephalogram (EEG) recorded generalized slows without any epileptiform discharges when the symptoms appeared. Single-photon emission computed tomography (SPECT) was performed using split-dose method to evaluate the change in blood flow when the convulsive movements appeared. During symptoms, a significant decrease in blood flow was revealed in the anterior part of the left basal ganglia, bilateral frontal areas, and right cerebellar hemisphere. An alteration in the functional balance between the basal ganglia and the cerebral cortices may play a role in the generation of convulsive movements in patients with convulsive syncope. PMID- 21706832 TI - [Beneficial effects of rituximab in a case of anti-myelin antibody-associated neuropathy]. AB - We report here in a 61-year-old woman in whom sensory disturbance predominantly affecting the distal portion of the limbs progressed over the course of 1 year. Blood tests showed IgM monoclonal gammopathy as well as the presence of anti myelin-associated glycoprotein (MAG) antibody. Nerve conduction studies revealed significant prolongation of distal latency, and sural nerve biopsy showed IgM deposition on the myelin sheath. She was diagnosed as suffering anti-MAG neuropathy. High-dose intravenous immunoglobulin therapy proved to be ineffective and her symptoms progressed. Therefore, rituximab was administered and the sensory disturbance improved. Although no detailed studies on rituximab therapy for anti-MAG neuropathy have been reported in Japan, the present findings suggest that rituximab may be more effective than immunoglobulin therapy and other conventional therapies that have been used for autoimmune neuropathies. PMID- 21706833 TI - [Utilization and imitation behavior following right parietotemporal lesions]. AB - A 65 year-old man showed bilateral, but more marked on the right, instinctive grasp reaction, utilization and imitation behavior after a right parietotemporal lobe infarction. Attention disturbance, left unilateral spatial neglect, and constructional disturbance were also observed. Fluid attenuated inversion recovery (FLAIR) MRI revealed high intensity lesions over the right parietotemporal cortex and white matter. Magnetic resonance angiography showed occlusion of the right internal carotid artery, and ultrasonography revealed left moderate internal carotid artery stenosis. Utilization and imitation behavior is usually attributed to a frontal lesion, rarely to a basal ganglionic or thalamic lesion, but not to a parietotemporal lesion. In this patient, the utilization and imitation behavior was thought to be attributed to right frontal lobe dysfunction without apparent MRI abnormalities, supposedly because of the right internal carotid artery occlusion in addition to the right parietal lobe infarction, both of which are thought to suppress the executive center in the left parietal lobe. PMID- 21706835 TI - [Evidence-based medicine for intermittent exotropia]. PMID- 21706834 TI - [A patient with prosopagnosia which developed after an infarction in the left occipital lobe in addition to an old infarction in the right occipital lobe]. AB - A 66-year-old, right-handed male, was admitted to our hospital with difficulty in recognizing faces and colors. He had suffered a stroke in the right occipital region three years earlier that had induced left homonymous hemianopsia, but not prosopagnosia. A neurological examination revealed prosopagnosia, color agnosia, constructional apraxia, and topographical disorientation, but not either hemineglect or dressing apraxia. The patient was unable to distinguish faces of familiar persons such as his family and friends, as well as those of unfamiliar persons such as doctors and nurses. Brain MRI demonstrated an old infarction in the right medial occipital lobe and a new hemorrhagic infarction in the left medial occipital lobe, including the fusiform and lingual gyrus. It is unclear whether a purely right medial occipital lesion can be responsible for prosopagnosia, or whether bilateral medial occipital lesions are necessary for this occurrence. The current case indicated that bilateral medial occipital lesions play an important role in inducing porsopagnosia. PMID- 21706836 TI - [Anderson criteria in early glaucomatous visual field defects with the SITA Standard]. AB - PURPOSE: We evaluated the positive rate of the Anderson criteria of suspected early glaucomatous visual field defects (GVFDs). SUBJECTS AND METHODS: Ninety-six eyes of 96 patients, who had suspected primary open-angle glaucoma with apparent glaucomatous optic disc changes and who had more than -6.0 dB of mean deviation (MD) with Swedish Interactive Thresholding Algorithm Standard (SITA-S) Central 30 2 program in the Humphrey Field Analyzer, were selected. We applied the Anderson criteria and calculated the positive rates for these criteria and for three elements pattern deviation probability plots (PD plots), glaucoma hemifield test (GHT), pattern standard deviation (PSD). RESULTS: The positive rate of the Anderson criteria was 78.1% and the PD plots (77.1%) were significantly higher rate than the GHT (62.5%) or the PSD (63.5%). The positive rate of the Anderson criteria was 100% in the MD of less than -3.0 dB and was 65.6% even in the MD of more than -3 dB (p < 0.0001). On the other hand, 57.9% of the eyes with an MD between -2 dB and -1 dB showed positive in all elements. At more than -1.0 dB of MD, the PD plots (50.0%) were significantly higher than the PSD (18.8%) or the GHT (21.9%) (PSD: p = 0.0085, GHT : p = 0.0190). CONCLUSION: Using the SITA-S, the Anderson criteria showed a high positive rate in eyes with suspected early GVFDs. PMID- 21706837 TI - [Surgical results of unilateral recession-resection for intermittent exotropia in children: multicenter study in Japan]. AB - PURPOSE: To survey the surgical results of unilateral recession-resection surgery for intermittent exotropia of children through a multicenter study in Japan. SUBJECTS AND METHODS: A retrospective study was performed at 6 Japanese hospitals. A total of 377 patients who underwent the first surgery of unilateral recession-resection, at the ages of 4 to 12 years with a follow-up of more than 3 years were included. Those who had amblyopia or vertical deviation were excluded. Ocular deviations before and after surgery, type of exotropia, the age at surgery and the size of the surgical operations were studied. The change in deviation by surgery (surgical effect; PD/mm) and final deviation between 15PD exodeviation and 10 PD esodeviation was categorized as a cure. Factors affecting to the cure were statistically evaluated. RESULTS: The average age at surgery was 6.7 years, the average of preoperative deviation was 31.6 PD and the average size of surgery (recession + resection) was 11.1 mm. The surgical effect and the preoperative deviation were positively related. Two hundred and sixty cases among the 377 cases (69.0%) were determined as being cured. Preoperative deviation of less than 30 PD (p = 0.02) and one-week postoperative esodeviation (p < 0.001) were significantly related to the cure. CONCLUSIONS: The distribution of surgical age and preoperative deviation of intermittent extropia of children were elucidated. Preoperative deviation under 30PD and esodeviation (overcorrection) at one-week postoperative time were significantly related to the cure. PMID- 21706838 TI - [Corneal astigmatism before cataract surgery]. AB - PURPOSE: To investigate the distribution of corneal astigmatism, and the relationship of astigmatism to the patients' age in a large number of pre cataract surgery patients. MATERIALS AND METHOD: We retrospectively examined 12428 eyes of 7187 patients (5396 eyes of men, 7032 eyes of women) who underwent cataract surgery at Kitasato University Hospital from April, 2002 to September, 2009. The mean patients' age at the time of surgery was 69.9 +/- 12.1 years. We determined corneal astigmatism using an Auto Refract Keratometer ARK-700A, a RKT 7700 (Nidek), a RK-F1 (Canon) and a Retinomax K-plus2(Righton). We carried out these measurements at least three times for each patient, and the average values were used for analysis. RESULTS: The mean corneal astigmatism was 1.02 +/- 0.81 D (0 to 14.75 D). The percentage of 1 D or less of corneal astigmatism was 63.6%, that of more than 1 D and 1.5 D or less was 20.9%, that of more than 1.5 D and 2 D or less was 7.4%, that of more than 2 D and 2.5 D or less was 3.8% and that of more than 2.5 D and 3 D or less was 1.8%. Neither significant laterality nor age difference in corneal astigmatism were found. The prevalence of with-the-rule astigmatism (WTR) was common in young population, whereas the prevalence of against-the-rule astigmatism(ATR) increased in the older population, whereas the prevalence of oblique astigmatism remains unchanged. CONCLUSIONS: Approximately two thirds of the preoperative patients had 1 D or less corneal astigmatism, and the remaining one third had over 1 D corneal astigmatism. The frequency of WTR was greater at a younger age, and that of ATR, at an older age. PMID- 21706839 TI - [Review of clinical features of circumscribed choroidal hemangioma in 28 cases]. AB - PURPOSE: To review the clinical features and management of circumscribed choroidal hemangioma. METHODS: Twenty eight cases of circumscribed choroidal hemangioma diagnosed at Tokyo Medical University Hospital from 1991 through 2008 were reviewed. We retrospectively studied the frequency of the individual tumors, gender, age, size of tumors, presence of serous detachment and hyperopia, management and outcome. RESULTS: Sixteen patients were men and 12 cases were women. The average age was 55 years. The average basal diameter of the tumors was 3.3 optic disc. Serous retinal detachment was observed in 19 cases (70%). Seventeen eyes agreed with the definition of hyperopia, 10 cases (59%) developed hyperopia. Thirteen cases (46%) were observed without any treatment, 10 cases(36%) were treated with transpupillary thermotherapy (TTT) and 5 cases (18%) were treated with dye laser. Thirteen cases (46%) showed improvement, 13 cases (46%) remained constant and 2 cases (7%) showed deterioration. CONCLUSION: Circumscribed choroidal hemangioma is a relatively rare clinical entity. The management should be tailored to the individual patients including the tumor size presence of serous detachement and visual acuity. PMID- 21706841 TI - [Nontypeable Haemophilus influenzae (NTHi) epidemiology]. AB - While most systemic pediatric Haemophilus influenzae infections are caused by the type b strain (Hib), nontypeable H. influenzae: (NTHi) has been considered a respiratory tract pathogen common in local infection such as acute otitis media, acute pneumonia, secondary chronic respiratory disease and other otorhinolaryngologic infections. Recent findings show, however, that NTHi also causes invasive infections such as meningitis, bacteremia, and lower respiratory tract infections such as pneumonia. A review of NTHi epidemiology from the 1990s onward shows that NTHi causes significant morbidity in pediatric acute otitis media, sinusitis, conjunctivitis and lower respiratory diseases such as pneumonia in Japan. This summary also reviews the worldwide influence of Streptococcus pneumoniae and Hib vaccines on causative pathogens, and several studies about increasing incidence of invasive infections due to NTHi. This review also touches on the emergence of treatment- and drug-resistant H. influenzae, which are now major public health challenges. As a cause of bacterial pediatric infection, NTHi is an important target for prevention. PMID- 21706840 TI - [Case of Heerfordt's syndrome presenting polyneuropathy]. AB - BACKGROUND: Acute presentation of sarcoidosis with the combination of uveitis, parotid gland enlargement, facial nerve palsy, and fever is called Heerfordt's syndrome. Clinically recognizable involvement of the nervous system occurs in < 10% of patients with sarcoidosis, and polyneuropathy in 24% with neurosarcoidosis. CASE: A 28-year-old woman diagnosed with Guillain-Barre syndrome was admitted and treated for a month in the Department of Neurology, Mie University hospital. Her visual acuity decreased 2 weeks after discharge. She was admitted to the Department of Ophthalmology, Mie University Hospital. She presented typical optic sarcoidosis. As she had uveitis, facial nerve palsy, parotid gland enlargement and fever in the clinical course, we diagnosed her condition as Heerfordt's syndrome. CONCLUSION: On rare occasions a Heerfordt's syndrome patient may present with Guillain-Barre-like symptoms. PMID- 21706842 TI - [Phylogenetic analysis of rabies viruses isolated from animals in Tokyo in the 1950s]. AB - Molecular epidemiological analysis of 96 rabies viruses isolated from animals in Tokyo in the 1950s involves Japanese fixed virus, Komatsugawa, Takamen, and Nishigahara strains. Strains isolated in Tokyo were divided into Tokyo 1 and Tokyo 2, and grouped into a worldwide distribution cluster differing from Takamen and Nishigahara. Tokyo 1 was grouped into the same cluster as viruses isolated from United States west coast dogs in the 1930s and 1940s. Tokyo 2 was grouped into the same cluster as the Komatsugawa strain, also known as a cluster of viruses from the Khabarovsk raccoon dog, and the Lake Baikal stepped fox in Russia. These findings suggest that 1950s Tokyo rabies viruses were related to those in Russia and the USA. PMID- 21706843 TI - [Efficacy of inactivating viruses by photocatalytically reacting nonwoven titanium dioxide fabric]. AB - Titanium dioxide (TiO2) photocatalysis causes oxidative destruction dependent on electrons excited by < or = 400 nm ultraviolet (UV) rays. Many studies have covered the destruction of organics and bacteria and bacteriophage inactivation by photocatalysis. We studied the inactivation by new nonwoven siliconized titanium dioxide fabric of the feline calicivirus F9 (FCV-F9), human adenovirus GB (HAdv3-GB), and influenza A and B virus (A/New Caledonia, B/Shandong, and 5 clinical strains). We spotted 10 microL of viral suspensions containing infectious 5 log10 50% tissue culture doses (TCID50) onto 1 cm2 pieces of TiO2 coated nonwoven control fabric treated or not treated with UV light (lambda(max), 365 nm, 1,100-1,300 microW/cm2). We then measured the virus titers of 50 microL of viral suspension recovered from these fabrics. FCV-F9 and HAdv3-GB infectivity titers were reduced by over 3.5 log10 TCID50 after 30 min of irradiation, but influenza viral titer was reduced to where it was undetectable even without UV irradiation. Comparing individual viral titer reduction due to nonwoven fabric contact without UV irradiation exposure, showed that FCV-F9 and HAdv3-GB titer infectivity was not reduced. In contrast, influenza A and B titer infectivity was reduced to 2 log10 TCID50 after 5 min of contact with the nonwoven fabric and to 3 log10 TCID50 after 30 min of contact. Titers of 6 of 7 influenza A and B strains were reduced by over 4 log10 TCID50 within 30 min. Siliconized TiO2 coated nonwoven fabric thus efficiently inactivated FCV-F9 and HAdV-GB and absorbed influenza viruses. PMID- 21706844 TI - [Phases 3 and 4 immunization immunogenicity with combined measles-rubella vaccine]. AB - A two-phase combined measles-rubella vaccine (MR) immunization schedule was introduced for age 1 and prior to primary school entry in Japan in April 2006. Further immunization was also introduced for 13 (Phase 3) and 18-year-old (Phase 4) cohorts for the 5-year period from April 2008 to March 2013. We surveyed Phases 3 and 4 MR immunization immunogenicity and safety. From August 2007 to December 2009, we conducted 3 Phase 3 and 15 Phase 4 immunizations. We then took paired serum samples (pre- and 4-6 weeks post-immunization), and measured measles antibody titers using hemagglutination inhibition (HI) and neutralizing test (NT), and rubella antibody titers using HI. Pre-positive measles HI antibody titer (> or = 8) was 72% (13/18) and pre-positive measles NT antibody titer (> or = 2) was 100% (18/18). Post-positive measles HI and NT antibody titers were 94% (17/18) and 100% (18/18). Mean post-immunization measles HI and NT antibody titers were significantly higher than pre-titers, with four-fold or greater increases seen in 9 (50%) and 6 (33%) subjects. Pre-positive rubella HI antibody titer (> or = 8) was 94% (17/18), and post-positive rubella HI antibody titer 100% (18/18). Mean post-immunization rubella HI antibody titer was significantly higher than pre-titer, with four-fold or greater increases seen in 8 subjects (44%). Paired HI antibody titers were measured in pre- and post-Phase 1 immunization for measles in 3 subjects and for rubella in 2 subjects. Those with post-Phase 1 measles HI antibody titers of 32, 64, and 128 yielded titers of 16, 8, and < 8 pre-Phase 3 or Phase 4 immunization, showing antibody reduction or seronegative conversion. Those with post-Phase 1 rubella HI antibody titers of 128 and 256 yielded titers of 64 and 32 in pre-Phase 4 immunization, showing antibody reduction. Seroconversion or four-fold or greater increases in titer were seen post-immunization in 60% (3/5) of these subjects. A clinical reaction survey of all subjects 4 weeks post-immunization, showed only 1 case of mild fever and no local or systemic adverse reactions such as generalized urticaria or anaphylaxis. In conclusion, Phases 3 and 4 MR immunogenicity was satisfactory. PMID- 21706845 TI - [Field epidemiology investigation on measles outbreak started from a junior high school at Kita Ibaraki City]. AB - We studied measles outbreak in Ibaraki Prefecture in spring 2002 as members of Field Epidemiology Training Program Japan (FETPJ). Of 84 cases diagnosed by not laboratory test but clinically, 67 (79.8%) were junior high school students, 9 (10.7%) were other students, and 8 (9.5%) were ordinary adult and infant citizens. Of the 84, 46 (54.8%) had been vaccinated. Most did not show typical Koplik spots. The city in which the school was located promoted vaccinations for infants and children aged 7.5 years old to grade 1 in High school. Questionnaire given to junior high students were detected 86 cases, of whom 57 (66.3%) were male. Overall, 4 peaks of clusters were observed in an epidemic curve, among which graduates' farewell parties and graduation ceremonies were the most common opportunities for measles virus exposure. The overall vaccination rate at school was 82.2%, vaccine efficacy extremely low at 72.5%, and vaccine failure high at 15.2%. Symptoms among those vaccinated were significantly milder than those not vaccinated. Immunity of those vaccinated as infants may have been decreased due to scarcity of measles cases in the last 10 years. In such situations--much less in typical measles among susceptible non affected and non vaccinated subjects- atypical or mild measles may be difficult to diagnose. These findings may keep clarify the need to introduce two-dose measles immunization in Japan. PMID- 21706846 TI - [Study of measles history, vaccination, antibody status, and vaccination effectiveress for school teachers]. AB - To determine an efficient measles vaccination program for school teachers, we studied knowledge about measles history, immunization, and immunity status among 269 school teachers in Ichihara City in 2009. We found that (1) many are uncertain about disease and immunization history, with neither history related to the immunity status of neutralizing antibody titer (NT), (2) particle agglutination (PA) and enzyme immunoassay (EIA) testing have replaced NT in commercial laboratories, but persons having antibodies fewer than 8-fold of the NT titer as a sensitivity desigration for measles, and 11 false-positive immunity results are indicated in PA testing (cutoff: 256-fold) and 140 false-positive sensitivity results in EIA testing (cutoff: 16.0 EIA), and (3) sensitivity cases are 7.1% in the naturally infected generation born before 1977 and 23.7% in the vaccinated generation born after 1978. Given "herd" immunity, we concluded that all vaccinated-generation persons should be administered additional vaccination regardless of sensitivity due to history, immunization, and PA or EIA antibody testing. PMID- 21706847 TI - [A case of primary human immunodeficiency virus infection with severe rhabdomyolysis without acute renal failure]. AB - Subjects with primary human immunodeficiency virus (HIV) infection often have acute retroviral syndrome. Some develop rhabdomyolysis, which can lead to acute renal failure. A 21-year-old man admitted for consciousness disturbance was initially considered to have aseptic meningitis associated with primary HIV infection. On hospitalization day 3, he developed severe rhabdomyolysis with elevated serum creatine kinase (CK) of 218,100 IU/L with serum creatinine normal at 0.9 mg/dL. Following massive extracellular fluid infusion and urinary alkalinization, serum CK decreased smoothly, without renal failure. Severe rhabdomyolysis was concomitant with systemic inflammatory response syndrome (SIRS) only on admission day. Acute renal failure in those with rhabdomyolysis may be influenced by renal possibly due to SIRS and tubular damage from reactive oxygen species, rather than by tubular obstruction by myoglobin casts, although this depends on the extent of myolysis. Acute renal failure is prevented in those with primary HIV infection developing rhabdomyolysis, based on renal blood flow control, if condition causing SIRS do not become a complication. PMID- 21706848 TI - [A case of corpus callosum splenium encephalopathy and 2009 influenza A/H1N1]. AB - Encephalopathy with reversible lesion of the corpus callosum splenium has a favorable prognosis, but that in 2009 influenza A/H1N1 is unknown. We report a case of clinically mild encephalopathy with a reversible lesion of the corpus callosum splenium in which 2009 influenza A/H1N1 virus was confirmed by laboratory tests. A 15-year-old Japanese girl seen at the emergency unit for loss of consciousness 18 hours after fever onset had been diagnosed with influenza A, and administered zanamivir. Diffusion-weighted magnetic resonance imaging (MRI) indicated lesions of the corpus callosum splenium, and electroencephalography showed slow basic activity, suggesting influenza A related to encephalopathy. She required intensive care with ventilation for two days. Her consciousness had become normal by day 6 after onset, and MRI findings improved on day 7. She recovered without adverse sequelae. PMID- 21706849 TI - [Peritonitis due to post-myomectomy Mycoplasma hominis infection]. AB - A 36-year-old woman undergoing a myomectomy developed postoperative surgical saite peritonitis and hematoma. Eight days postoperatively, she developed a 38 degrees C-plus fever and accumulated ascites, with fever unchanged despite antimicrobial beta-lactams therapy. Following transvaginal ascitic drainage, her fever disappeared. Recurrent 38 degrees C fever and inflammation were cured by clindamycin of 1.2 g/day. M. hominis detected from ascites drainage was considered the primary causative organism. Nongenito-urinary M. hominis infection is often difficult to detect, as in our case. Gram staining, for example, is not useful in ascertaining small organisms such as Mycoplasma spp. having no cell walls to stain. M. hominis grows slowly, requiring over three days to form colonies on blood agar plates, requiring time to identify pathogens. We report case showing the importance of suspecting M. hominis of causing gynecological surgical-site infection. When common bacterial pathogen cultures remain negative and when empiric beta-lactam antibiotic treatment is ineffective, M. hominis should be suspected. In conclusion, M. hominis should be considered a causative following myomectomy resection. PMID- 21706850 TI - [A case of Salmonella-infected thoracoabdominal aortic aneurysm making final diagnosis difficult]. AB - We report a case of thoracoabdominal aortic aneurysm (TAAA) due to Salmonella Enteritidis making final diagnosis difficult. A 63-year-old man with a history of diabetes mellitus, hypertension, and cerebral infarction was seen elsewhere for a 40 degrees C fever, vomiting, and shaking on day 1 after onset. He was diagnosed with Salmonella bacteremia and hospitalized by us for intensive care. Computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound imaging did not, however, show critical findings of aneurysm, endocarditis, or osteomyelitis, and laboratory testing suggest significant inflammatory symptoms. He did not respond to antibiotics, but had an intermittent low fever during the first hospitalization. On day 48 after onset during the second hospitalization, abdominal CT showed an aneurysm -3 cm in diameter in the thoracoabdominal aorta above the renal artery- small enough to have been missed in earlier diagnosis. Surgery and TAAA graft replacement were done on day 64. Bacterial culture of the graft showed no Salmonella growth due to long-term in vivo antibiotic exposure. He recovered without significant complications, with oral ciprofloxacin antibiotic therapy continued to the present. This case indicates the importance of an early diagnosis through continuous blood culture and imaging for Salmonella sp blood stream infection. PMID- 21706851 TI - [A case of repeated upper gastrointestinal bleeding secondary to Legionella pneumonia]. AB - A 70-year-old woman admitted for nausea and diarrhea was diagnosed with Legionella pneumonia based on chest X-ray and urinary antigen testing. Despite severe complications, she recovered thanks to ciprofloxacin administration. On hospital day 8, she went into hypovolemic shock necessitating emergency gastrointestinal (GI) fiberscopy, which showed active lower gastric bleeding. The exposed artery was clipped endoscopically and proton pump inhibitor was started. At hospital day 16, the woman's active GI bleeding recurred, requiring further endoscopic clipping. On hospital day 20, oozing occurred in the middle gastric body. To prevent recurrent bleeding, extensive gastrectomy was done on hospital day 28. Legionella pneumonia is common pneumonia, as are GI symptoms in Legionella pneumonia, but GI bleeding is rare. Only cases of GI bleeding secondary to Legionella pneumonia have been reported in Japan, in addition to our case, and four of the 5 died after GI bleeding, indicating the dismal prognosis. The relationship between Legionella pneumonia and GI bleeding, although uncertain and rare, requires especially close observation. PMID- 21706852 TI - [Two cases of anti-NMDA receptor encephalitis]. AB - Anti-NMDA receptor encephalitis, reported by Dalmau et al., is a paraneoplastic encephalitis frequently associated with ovarian teratoma. After the manifestation of schizophrenia-like psychotic symptoms in the initial stage, serious neurological symptoms such as convulsions and central hypoventilation develop. We report two cases of 17-year-old girls with anti-NMDA receptor encephalitis who exhibited different clinical courses. Case 1 showed a typical course of anti-NMDA receptor encephalitis associated with sustained consciousness disturbance requiring long-term artificial respiration. Case 2 underwent surgery for an ovarian teratoma in the early stages of the disorder, did not show convulsions or central hypoventilation, and recovered without any sequelae. Early resection of the ovarian teratoma and the immune suppression therapy may have contributed to the rapid recovery and favorable outcome in case 2. Psychiatrists are the first to see a majority of patients with anti-NMDA receptor encephalitis because of psychiatric symptoms and behavioral changes observed in the initial stage. For successful treatment, psychiatrists need to cooperate with neurologists and gynecologists early in the course of this disorder. Psychiatrists' knowledge of the symptoms and clinical course of this form of encephalitis is essential for early detection and adequate treatment, which may be life-saving and contribute to good functional outcomes. PMID- 21706853 TI - [Treatment of offenders with mental disorders: focusing on prison psychiatry]. AB - Forensic mental health services exist in a nebulous space at the intersection of two different systems-criminal justice and mental health-and the entanglement of these systems poses intricate problems for psychiatrists. This article discusses the present circumstances of forensic mental health services in Japan, focusing on trends in prison psychiatry. In the traditional Japanese system, offenders with mental disorders were treated within general psychiatry as involuntarily admitted patients, or within the prison system as mentally ill inmates. As a consequence of recent legal reform, however, this situation has radically changed. The Medical Treatment and Supervision Act of 2005 aimed to provide intensive psychiatric treatment to offenders with mental disorders, attaching great importance to their reintegration into society. Under the new system, a person who commits a serious criminal offense in a state of insanity or diminished capacity shall be referred by the public prosecutor to the district court; following a treatment order of the court, the person shall be treated in psychiatric facilities established by the law. While the new system is expected to play a role in the context of specialist forensic psychiatry, its distinction from general psychiatry remains unclear. For example, persons who commit serious crimes, such as assault, in an acute psychotic state are occasionally admitted to general psychiatric hospitals, even if they meet the criteria for a treatment order under the Medical Treatment and Supervision Act. The relationship between prison psychiatry and specialist forensic psychiatry is still more problematic. Compared to the intensive, rehabilitation-oriented care provided under the Medical Treatment and Supervision Act, mental health services in penal institutions have a number of disadvantages, and it is unlikely that mentally ill prisoners have benefited from the recent progress in forensic psychiatry. Statistics show that the number of sentenced prisoners with mental disorders has steadily increased during the last decade. Although a majority of these individuals are substance abusers, the number of patients with schizophrenia who are unable to serve a sentence due to severe illness is not insignificant. Although patients are sometimes transferred to medical prisons, a substantial number of inmates with mental disorders remain in general prisons, most of which lack adequate medical staff. Accordingly, the growing number of mentally ill inmates is imposing a heavy burden on the penal administration system. Provisions of the Mental Health and Welfare Act pertaining to general psychiatry are not applicable to patients in penal institutions. The Psychiatric Review Board established in each prefecture does not intervene in the management of these facilities. As a result, legal safeguards against the violation of patients' rights are not sufficiently guaranteed in penal institutions. There are no legal provisions for transferring patients with severe mental disorders from prisons to psychiatric hospitals. Once sentenced to imprisonment, offenders with mental disorders are treated almost exclusively within the prison system. This situation is particularly serious in the case of patients with long-term sentences. In addition, the continued availability of psychiatric care after discharge from prison, which is crucial for preventing relapse of illness and recidivism, is not assured. When a mentally ill inmate is discharged, the head of the institution is required to report the discharge to the prefectural governor, in accordance with the Mental Health and Welfare Act. Recently, although the number of such reports has sharply increased, in actuality many of the persons reported are not admitted to hospitals because they do not meet the criteria for involuntary admission, and the provisions of the Medical Treatment and Supervision Act do not apply to them. In conclusion, more attention should be paid to the reform of prison psychiatry. Coordination of the separate functions of general psychiatry, specialist forensic psychiatry, and prison psychiatry is also important. PMID- 21706854 TI - [A call for immediate abolishment of the Medical Treatment and Supervision Act]. AB - The author demonstrates that Japan's Medical Treatment and Supervision Act of 2005 is meaningless and harmful from the perspective of psychiatric treatment, and worthless in terms of enhancing public safety. He goes on to propose a step by-step process for reforming both the practice of psychiatry in general and that branch of the justice system that deals with defendants who have psychiatric disorders. The author suggests that the cost of reforms can be offset by abolishing the law in question and reducing the number of psychiatric hospital beds, and argues that it is possible to immediately halve the number of those beds. The author emphasizes that, while it is possible to immediately abolish the law, there will be anxiety associated with the progression of reforms. PMID- 21706855 TI - [Toward further reform of mental health care and welfare]. AB - The Committee for Investigating the Future of Mental Health Care and Welfare, launched in 2008 by the Ministry of Health, Labour and Welfare, issued its final report in September 2009. The 2009 report was an expert-driven interim review of implementation of the 10-year plan proposed in the 2004 "Vision for Reforming Mental Health Care and Welfare," which marked its midpoint in 2009, and was conducted in order to identify priority issues in the final five years of the plan. The report recognizes that "mental illness significantly impairs quality of life and causes great socioeconomic loss"; that "health care and welfare assistance systems that support the ability of people with mental disorders to live in the community are inadequate"; and that "large numbers of patients with schizophrenia remain institutionalized over the long term. The report notes that this is due to previous policies that promoted institutionalized care, with regard to which concerned parties, including government entities, have expressed regret." The new approach described in the report can be summarized as (1) promoting the basic principle of moving from institutionalized care toward community-based care, based on the vision for reform noted above; (2) creating a society where patients who have mental disorders can receive high-quality health care, and depending on the patients' symptoms and wishes where they can receive appropriate health care and welfare services while continuing to live independently and securely in the community; and (3) speeding up the process of reform in mental health care and welfare. The core focus of reform is expressed in four fundamental principles: (1) restructuring mental health care (restructuring and improving the healthcare system by upgrading community centered healthcare, shifting the focus of hospital care to the acute stage, and similar efforts) ; (2) improving the quality of mental health care (improving the quality of health care provided to each individual patient, whether it involves pharmacological or psychosocial therapy, and also improving the quality of health care by promoting staff development) ; (3) strengthening community living support systems (developing welfare services that support the ability of persons with disabilities to live in the community, improving care management, improving emergency and community health services, securing places of residence, etc.) ; and (4) prioritizing increased awareness and understanding of psychiatric illness (promoting an accurate understanding of mental disorders so that patients can obtain help at an early stage, and so that people with mental disorders can live as fully-participating members of the community). The committee also reviewed the targets stated in the vision for reform, and established a new maximum limit of 150,000 patients institutionalized with schizophrenia (the number was 196,000 in 2005). By 2011, the committee will also set a concrete target for the number of patients institutionalized with dementia. Preserving the 2004 goals expressed under the vision for reform, the mean target ratio of patients remaining hospitalized in psychiatric wards less than one year, for all prefectures, was set at 24% or less, while the target discharge rate for patients hospitalized for one year or longer, for each prefecture, was fixed at a minimum of 29%. PMID- 21706856 TI - [Clinical evaluation of rapid identification of bacteria from positive-testing blood culture bottles by internal transcribed spacer PCR]. AB - Delays in diagnosis and initiation of treatment of severe infections such as sepsis greatly influence patient prognosis. Our laboratory introduced rapid identification of bacterial species by PCR for positive blood culture samples as a routine laboratory test since April 2008. We extracted DNA directly from positive blood culture bottles and amplified the internal transcribed spacer (ITS) region of pathogenic microorganisms by PCR in order to identify bacterial species from electrophoretic patterns of PCR products. Of 167 strains from 167 samples excluding three samples with polymicrobial organisms, 144 strains (86.2%) were correctly identified at species level and 17 strains (10.2%) at genus level. The time required between DNA extraction and bacterial identification was about one and one-half hours. In patients with MRSA sepsis, the time of initiation of treatments such as administration of anti-MRSA drugs and intravascular catheter removal has clearly become earlier with the introduction of ITS-PCR, resulting decreased mortality from 35.0% to 16.0%. Rapid identification of pathogens directly from blood culture bottles by ITS-PCR seems to be useful for appropriate treatment of severe infectious diseases. PMID- 21706857 TI - [Usefulness of survivin/glyceraldehyde-3-phosphate dehydrogenase ratio in urine exfoliated cells for the detection of bladder tumor]. AB - OBJECTIVE: Survivin is one of the apoptosis inhibitor proteins and is rarely expressed in adult normal tissues. However, survivin expression has been detected in various tumors. In this study, we evaluated the usefulness of urinary survivin/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) ratio as a marker for bladder tumor. PATIENTS AND METHODS: Urine samples were obtained from 72 patients with bladder tumor, 36 with urinary tract inflammation as controls. Survivin and GAPDH mRNA expression was measured by quantitative real-time PCR assay in urine cells. The GAPDH housekeeping gene was used for normalization of survivin expression. We also analyzed survivin protein levels using urine samples and recombinant protein by western blotting. RESULTS: High expression of survivin was confirmed on the protein level using urine samples of bladder tumor by western blotting. Survivin/GAPDH mRNA ratios of bladder tumor quantified by real-time PCR was significantly higher than those of controls (p=0.001). In pathological stage of bladder tumor, survivin/ GAPDH mRNA ratio of pTis was significantly high compared with pTa and pT1 (p < 0.001, p=0.001, respectively). Grade3 tumors expressed high level of survivin/GAPDH mRNA ratio compared with Grade 1 and Grade 2 tumors (p=0.03). The sensitivity, the specificity and AUC(area under the curve) of survivin/ GAPDH mRNA ratio was 83.3%, 86.1% and 0.898, respectively. CONCLUSION: Measuring survivin/GAPDH mRNA ratio in urine is non-invasive and high sensitive examination. Therefore, survivin/GAPDH mRNA ratio is useful marker for the detection of bladder tumor, especially to detect carcinoma in situ. PMID- 21706859 TI - [New parameters "average flow" and "acceleration wave": comparison with current parameters in the flow volume curve]. AB - AIM: The flow volume curve is an essential test method for diagnosis and treatment of the respiratory diseases. However, this curve depends on patient's continuous effort toward optimal expiration and it has been reported that differences in this effort may possibly result in error in flow speed. To overcome the potential error, we devised the "average flow" and the "acceleration wave" that comprehends the overall data of the expiration flow speed, and have done comparative analysis with the current parameters. METHODS: The average flow is derived by taking the integration from the beginning of the expiration to the end, and divides the integrated value by the number of data counts. Additionally, the acceleration wave is derived by taking the second degree derivative of the flow volume curve. RESULTS: The average flow showed strong correlation among healthy male and healthy female V50, obstructive index and criteria for COPD severity patients. Also, we were able to obtain the maximum acceleration from the acceleration wave. Significantly, this value showed strong correlation with the COPD patient's peak flow and average flow/peak flow. CONCLUSIONS: If the ratio of the average flow and the peak flow is below a fixed criterion, it is an obstructive lung disease, if it is above, it is possible to detect restrictive lung disease. Since the maximum acceleration rate of the acceleration wave is derived by the start of the expiration nearly up to 100 ml, it is especially possible to detect minute changes of the flow speed in large respiratory tract. PMID- 21706858 TI - [Effects of anticoagulants and storage temperature on immature platelet fraction % (IPF%) values in stored samples measured by the automated hematology analyzer, XE-5000--utility of CTAD-anticoagulation and room temperature storage]. AB - Measurement of reticulated platelet percentage (RP%) is thought to be a useful marker for differential diagnosis and analysis of platelet kinetics in patients with thrombocytopenic disorders. Two methods are used to detect RP; flow cytometric method and immature platelet fraction (IPF) method using automated hematology analyzers. Although IPF% measured by the automated hematology analyzers is simple and convenient, we already reported that IPF% values were highly fluctuated in stored whole blood sample with EDTA-2K at 4 degrees C day by day. In this study we investigated the stability of IPF% in blood samples obtained from 11 patients with chronic immune thrombocytopenic purpura (ITP) and 19 healthy volunteers using the automated hematology analyzer, XE-5000 (Sysmex) under various storage conditions. EDTA-2K, 3.13% sodium citrate, acid-citrate dextrose solution (ACD), citrate-theophylline-adenosine-dipyridamole solution (CTAD), or sodium fluoride was used as an anticoagulant. When blood samples obtained from healthy subjects were stored at 4 degrees C, IPF% values markedly increased in a time-dependent manner by any anticoagulant examined. On the other hand, there was no significant or only slight difference in IPF% values at room temperature (RT) storage except sodium fluoride. However, in patients with ITP the elevated IPF% values fluctuated widely in EDTA-2K, sodium citrate and ACD anticoagulated samples even at RT storage. In contrast, IPF% values in CTAD samples stored at RT were highly stable in all patients with ITP up to 4 day storage. These results suggest that the measurement of IPF% by XE-5000 provides quite stable data up to 4 day-storage in ITP patients as well as healthy subjects under CTAD-anticoagulation and RT storage conditions. PMID- 21706861 TI - [How to utilize JSML2009 guideline of laboratory examination]. AB - As a resident, I am rotating various departments. I am called for to acquire knowledge, skills, and attitudes for primary care. Although I mainly perform medical examinations and treatments of inpatients, I also have some opportunities to treat outpatients who come to an emergency room. There we see various patients, from whose medical background we know nothing, to who are coming to our hospital regularly for years and have huge medical records. We need to choose suitable examinations and to interpret examination results. In the process, I utilize JSML2009 guideline of laboratory examination. Through my cases, I describe how to utilize the guideline. PMID- 21706860 TI - [A case of Desulfovibrio desulfuricans cultured from blood in Japan]. AB - We report a case of Desulfovibrio desulfuricans bacteremia in a 60-year-old-man. In our case, anaerobic blood culture bottle turned out positive after five days' incubation. Gram stain showed the presence of slightly-curved Gram negative rod. Suspecting Campylobacter and Helicobacter, we added microaerobic culture while tentatively reporting Campylobacter to the physician. We then added anaerobic culturing with Brucella HK (RS) Agar because microaerobic culture proved the absence of microaerophile. We found small colonies on the third day, then we started anaerobic culture and eventually identified Desulfovibrio desulfuricans. We believe this is the first report of Desulfovibrio desulfuricans cultured from blood in Japan. In case Gram stain shows the presence of spiral bacterium, it is recommended to observe closely considering Desulfovibrio. PMID- 21706862 TI - [Importance of JSLM2009 guideline and a message regarding the next set of guideline]. AB - The Japanese Society of Laboratory Medicine has established the JSLM2009 guideline. This guideline is very useful for performing laboratory examinations precisely. However, further improvements in this guideline are desirable for the future. I think that JSLM2009 guideline has the following advantages and disadvantages for clinicians. ADVANTAGES: (1) JSLM 2009 guideline has referred to many guidelines from other medical societies in order to maintain comparability among guidelines. (2) Many figures have been to help clinician understand the strategy of laboratory medicine. (3) There are also many recommendations indicating when clinicians should consult an expert. (4) JSLM2009 guideline indicates whether or not each laboratory examination is covered by Japanese health insurance. DISADVANTAGES: (1) There are some ambiguities that may lead to mistakes. (2) Descriptions of the sensitivity and specificity of laboratory medicine are insufficient. (3) The evidence level supporting various aspects of laboratory medicine has not been described. (4) There are certain areas that are based on insufficient evidence. In this context, I consider that the next set of guideline should be based on evidence that adequately supports laboratory medicine, while maintaining the current advantages of JSLM2009 guideline. PMID- 21706863 TI - [How to use JSLM2009 guideline on the bedside teaching and learning in teaching hospitals]. AB - It is tremendously important to learn standard practice for residents especially of postgraduate year 1 and 2 grades. In teaching hospitals, residential training is usually "on the job" and management of patients is highly individualized. Thus, residents are always aware of how far their practice stands away from principles. To confirm principles of daily practice easily, JSLM2009 Guideline is an important tool in residential training. Attending physicians and supervisors should educate their residents about "clinical pearls" in addition to principles. PMID- 21706864 TI - [Clinical laboratory guidelines beneficial for Japanese people]. AB - Recently, people are suffering from information overload, especially in the field of health care. Since 2007, we have been performing the duties of a nonprofit organization (NPO), the Standard Clinical Information Center. The purpose of this NPO is to make available standard clinical information based on various clinical guidelines, including JSLM2009, to the public. In 2005, we launched our website, in which easy-to-learn information on common clinical laboratory tests was presented. Through our actions, we have found that there are some problems with JSLM2009, as follows. The principal benefit of guidelines should be to improve the quality of care received by patients. However, JSLM2009 is too complicated to apply to daily clinical practice. The contents are too numerous and redundant. It resembles a textbook. The guideline refers to many other clinical guidelines. However, in those guidelines, evidence about what to recommend is often lacking, misleading, or misinterpreted. These problems should be overcome in the near future. PMID- 21706865 TI - [Survey for the guideline JSLM 2009 users]. AB - The guideline committee in the Japanese Society of Laboratory Medicine sent approximate 3,400 books of the guideline JSLM 2009 to the institutions related to our society and the survey was performed to obtain useful opinions from the users and to reflect them to the next version. Forty seven answers (1.4%) were recovered by the end of April 2010. In the overall impressions, 13 users evaluated the guideline JSLM 2009 as excellent, 29 as fair, 3 as average and 2 as the other. The numbers of the users evaluating the most useful section were 24 for the "approaches by laboratory test results" section, 19 for the "symptom" session, 22 for the "disease" session and 28 for the "evaluation of the laboratory test results" section. The opinions were mostly supportive, but some constructive opinions were also obtained such that the foci of some parts were obscure, that the description should have been more conclusive, that their contents were incomplete, that this guideline was rather the textbook than the guideline, and that the committee should provide this guideline in the DVD format including movies, figures or animations. From the survey, it was suggested that the guideline users were more interested in the contents specific to laboratory tests than in the symptoms or the diseases. The committee should reflect these opinions to the next version. PMID- 21706866 TI - [Towards better understanding of hematolymphoid malignancies--based on the WHO 2008 classification: summary]. AB - The revised WHO classification of tumors of hematopoietic and lymphoid tissues (4th edition) was published in 2008. A number of information from molecular biology was introduced, new patterns of classification were proposed, and specific molecular diagnostics and molecular-targeting therapy were introduced in a part of these diseases. In this symposium, four remarkable points of the WHO 2008 classification (myeloproliferative neoplasms and JAK2 mutation, approaches to hypereosinophilic syndromes, morphology of myelodysplastic syndromes, and varied classification of lymphoid malignancies) were presented by the expert speakers, and the better understanding of the revised classification is warranted. PMID- 21706867 TI - [Knowledge management system for laboratory work and clinical decision support]. AB - This paper discusses a knowledge management system for clinical laboratories. In the clinical laboratory of Toranomon Hospital, we receive about 20 questions relevant to laboratory tests per day from medical doctors or co-medical staff. These questions mostly involve the essence to appropriately accomplish laboratory tests. We have to answer them carefully and suitably because an incorrect answer may cause a medical accident. Up to now, no method has been in place to achieve a rapid response and standardized answers. For this reason, the laboratory staff have responded to various questions based on their individual knowledge. We began to develop a knowledge management system to promote the knowledge of staff working for the laboratory. This system is a type of knowledge base for assisting the work, such as inquiry management, laboratory consultation, process management, and clinical support. It consists of several functions: guiding laboratory test information, managing inquiries from medical staff, reporting results of patient consultation, distributing laboratory staffs notes, and recording guidelines for laboratory medicine. The laboratory test information guide has 2,000 records of medical test information registered in the database with flexible retrieval. The inquiry management tool provides a methos to record all questions, answer easily, and retrieve cases. It helps staff to respond appropriately in a short period of time. The consulting report system treats patients' claims regarding medical tests. The laboratory staffs notes enter a file management system so they can be accessed to aid in clinical support. Knowledge sharing using this function can achieve the transition from individual to organizational learning. Storing guidelines for laboratory medicine will support EBM. Finally, it is expected that this system will support intellectual activity concerning laboratory work and contribute to the practice of knowledge management for clinical work support. PMID- 21706868 TI - [Development of a clinical decision support system using clinical laboratory test data]. AB - OBJECTIVES: An alert system in a hospital information system (HIS) would be helpful for physicians to prescribe medication appropriately. In this study we developed an alert system that extracts target problems from the raw data and verifies whether contraindicated medication is prescribed. METHODS: This system scrutinizes data handled in the HIS. It picks up data needed to ascertain problems and data on medication entered. If patient data indicate impaired renal function, or the dosage is over prescribed according to a patient's renal function, the system sends an alert message. The system also determines whether a patient has liver diseases, renal diseases or diabetes mellitus based on clinical laboratory and prescription data, and checks whether a patient is prescribed medication that is contraindicated to his/her problem. When a physician selects patients from an inpatient or an outpatient list, the system presents alerts concerning these patients. RESULTS: We counted the number of alerts for inpatients. The frequency of alerts for overdose due to patients' renal function and contraindication for patients with liver disease were more frequent than alerts for other reasons. Of patients with renal dysfunction who were prescribed contraindicated medication, 24% had their medication discontinued before the alert system was put into operation. In contrast, that rate significantly increased to 54% after the alert system was initiated. CONCLUSION: We developed an alert system that extracts target problems and verifies whether inappropriate medication is prescribed. The alerts generated by this system were effectively contributed to discontinuing contraindicated medication. PMID- 21706869 TI - [Necessity of clinical decision support system created by medical staff]. AB - To support patient safety, we have established a new system that collates medical facility clinical records, examination results and orders, and implementation information comprehensively in real time, checks for consistency and validity, and sends warnings to the appropriate people at the appropriate time. Because our system actually corrects inaccurate operation information, it is different from most existing facilities for patient safety in that it reconstructs information independently from the HIS (Hospital Information System). We were permitted to send warning messages not only to the doctor who entered the orders, but also to the chief of medical staff and team members. For the warning method, we tried screen flashes and chimes, mobile phone messages, and high quality interactive voice responses. We also investigated the degree of message usefulness. Therein, by not relying on "authenticity" and "readability," but by exhaustively collecting and appropriately revising in alignment with the use of information, we have created an original system that collects accurate information. This original system was established by medical staff members. The appropriate revisions mentioned herein are items which meticulously reflect the medical professional's comments and selected operation and signify why a "Clinical Decision Support System created by medical staff" is necessary. PMID- 21706870 TI - [Molecular mechanism and physiological roles of mitochondrial fusion and fission]. PMID- 21706871 TI - [Microtubule cytoskeleton determines plant shape]. PMID- 21706872 TI - [Genetic dissection of cardiac morphogenesis in zebrafish]. PMID- 21706873 TI - [Novel transcriptional regulation of human StAR gene]. PMID- 21706874 TI - [Elucidation of the function based on the whole structure of rat liver vault, the largest ribonucleo-protein particle]. PMID- 21706875 TI - [Molecular evidence for synaptic tagging hypothesis]. PMID- 21706876 TI - [Exploring the neural circuits for sound and gravity senses in the fruit fly]. PMID- 21706877 TI - [Regulation of Rab-GEF cascade in yeast secretory pathway]. PMID- 21706878 TI - [In vivo optical imaging of cancer]. PMID- 21706879 TI - [In vivo cell biology of cortical neuronal migration and morphological changes]. PMID- 21706880 TI - [New trends in shotgun proteomics]. PMID- 21706881 TI - [The twenty-third reports of the study on Yusho--PCBS and dioxin-related compounds. Forward]. PMID- 21706882 TI - [Effects of dioxin-related compounds on bone metabolism]. PMID- 21706883 TI - [An epidemiologic examination on the prevalence of the periodontal diseases and oral pigmentation in Yusho patients in 2010]. AB - An epidemiologic examination was carried out to reveal the prevalence of the periodontal diseases and oral pigmentation in patients with Yusho in 2010. The results obtained were as follows. 1) Yusho patients complained of tooth pain and periodontal diseases such as gingival swelling, but not of oral pigmentation. 2) 104 patients out of 117 patients with Yusho, who were measured periodontal pocket depth according to Ramfjord' methods, had at least one tooth with periodontal pocket deeper than 3 mm. Similarly, 314 teeth out of a total 551 examined teeth showed a periodontal pocket with more than 3 mm in depth. However, it was determined that 57 teeth had a periodontal pocket deeper than 4 mm. 3) Oral pigmentation was observed in 63 patients out of 122 patients with Yusho. In this study, gingival pigmentation was most predominant among oral pigmentation. The prevalence of oral pigmentation in male patients seemed to be somewhat higher than that in female patients. In addition, the prevalence of oral pigmentation tended to be higher in patients under seventy years old than patients beyond the age of seventy. These results indicated that PCB-related compounds may be responsible for the higher prevalence of both periodontal diseases and oral pigmentation. PMID- 21706884 TI - [Impaired mitogen-induced lymphocyte transformation in patients with Yusho]. AB - To investigate chronic immune effects of polychlorinated biphenyl (PCB) and polychlorinated dibenzofuran (PCDF), in vitro lymphocyte transformation in response to phytohemagglutinin (PHA) and concanavalin A (Con A) was studied in 139 patients with Yusho and 61 controls. PHA-induced lymphocyte transformation was significantly lower in patients with Yusho than in controls. PHA-induced lymphocyte transformation was inversely correlated with the concentrations of PCB and 2,3,4,7, 8-pentachlorodibenzofuran (PeCDF) in the blood. Con A-induced lymphocyte transformation showed similar inverse correlations with the concentrations of PCB and 2,3,4,7, 8-PeCDF. We conclude that impairment of mitogen-induced lymphocyte transformation in patients with Yusho may be associated with PCB and 2,3,4,7,8-PeCDF in the blood. PMID- 21706885 TI - [The temporal change rate of 2,3,4,7,8-PCDF level among examinees of annual health checkups of Yusho]. AB - BACKGROUND: Yusho is an incidence of food poisoning caused by rice bran oil in 1968. Its main causal agent is considered as 2,3,4,7,8-penta-chlorodibenzofuran (PeCDF). The patients have been suffered by the various symptoms, and their blood concentration of PeCDF is still higher than the general population. OBJECTIVES: The purpose of this study is to estimate the change rate of PeCDF concentration among the examinees of annual health examination of Yusho patients. RESULTS AND CONCLUSIONS: PeCDF concentration of 118 men and 140 women who received the health examination four times or more from 2001 to 2008 was statistically analyzed. The estimated annual change rate of the PeCDF concentration was low; 1.43% reduction and 1.03% increase were observed, respectively, for men and women who have low PeCDF concentration, and 3.6% and 3.7% reductions, respectively, for men and women who have high concentration of PeCDF. The reduction rate was associated with age and smoking habit in men, and drinking habit in women. PMID- 21706886 TI - [Relationship between half-lives of blood dioxins and possible metabolic mechanism]. AB - Blood levels of dioxins in Yusho patients have been measured for 10 years. The purposes of this study were to determine the half-lives of dioxins on the basis of the data obtained from Yusho patients and to compare the half-lives of the compounds. Linear regression analysis was performed using the binary logarithmic value of each dioxin level as the dependent variable and the year of measurement as the independent variable. The linear coefficient obtained from this linear regression analysis was the reciprocal number of the half-life. The relationship between the blood dioxin levels estimated in 2004 and the reciprocal number of half-life was evaluated. Of the studied dioxins, the concentrations of some compounds were strongly correlated with that of 2,3,4,7,8-PeCDF. For 2 such compounds, the correlation coefficient of the reciprocal numbers of half-life were greater than the correlation coefficient of the logarithmic values of the estimated concentrations. Of these 2 compounds, the concentration of 3,3,4,4,5,5 HxCB was at least 50 times less than that of the 2,3,4,7, 8-PeCDF in rice oil: however, their current concentrations are equivalent. Patients with high levels of 2,3,4,7,8-PeCDF also showed high levels of 3,3,4,4,5,5-HxCB. Yusho patients may have a disease-specific mechanism to supply 3,3,4,4,5,5-HxCB. PMID- 21706887 TI - [Prevalence of atopic dermatitis and serum IgE of Yusho patients born before 1967]. AB - Dioxins may have an impact on the human immunological system, which would increase the risk to develop allergic diseases, such as atopic dermatitis. In order to determine the lifetime prevalence of atopic dermatitis in Yusho patients, a questionnaire-based survey was conducted in 2008. One thousand and seventy-one out of 1430 certified yusho patients who were born before Yusho accident answered the questionnaires, and the prevalence of atopic dermatitis in Yusho patients was 5.5%. We also measured serum IgE in 515 Yusho patients who attended annual medical check-ups from 2007 to 2009 and in 172 control subjects. Serum levels of IgE in Yusho patients were 250.7 +/- 663.4 IU/ml, whereas those in control subjects were 265.0 +/- 602.0 IU/ml. There was no significant difference in serum levels of IgE between Yusho patients and control subjects. In addition, no significant correlation was observed between serum levels of IgE and blood levels of dioxins in Yusho patients. PMID- 21706888 TI - [Chemokine profile of Yusho patients]. AB - Dioxins may have an impact on the human immunological system, which would increase the risk to develop allergic diseases, such as atopic dermatitis. In the present study, we measured serum levels of Th1- and Th2-favored chemokines in 233 Yusho patients who attended annual medical check-ups from 20.06 to 2009 and in 97 control subjects. Serum levels of CCL5, CCL17, and CCL27 in Yusho patients were significantly lower than those in control subjects. In addition, serum levels of some chemokines have weak correlations with blood levels of dioxins in either Yusho patients or control subjects. PMID- 21706889 TI - [Time serial changes in the concentrations of the etiological agents of fetal Yusho--PCDDs and PCDFs]. AB - We determined polychlorinated dibenzofurans (PCDFs) and polychlorinated dibenzo-p dioxins (PCDDs) in 6 preserved umbilical cords of fetal Yusho patients and in 11 preserved umbilical cords of Yusho suspected persons who were born to mothers with Yusho from 1970 to 2002, which were Yusho group. As a control, we also analyzed PCDFs and PCDDs in 15 preserved umbilical cords of babies who were born to healthy mothers, which was healthy group, in the same period of time. As a result, 2,3,4,7,8-pentachlorodibenzofuran and 1,2,3,4,7,8-hexachlorodibenzofuran, true causal agents of fetal Yusho, were only determined in the umbilical cords of fetal Yusho patients, except for one umbilical cords of Yusho suspected persons. Decreasing rate in concentrations of PCDFs and PCDDs seemed to greater in Yusho group than in healthy group during this period of time. Therefore, we considered due to high exposure to PCDFs some drug metabolizing enzymes such as aryl hydrocarbon hydroxylase were induced and the excretion of PCDFs and PCDDs were enhanced from the bodies of Yusho group. In order to clarify this hypothesis, further more detail researches are required. PMID- 21706890 TI - [Time serial changes in the concentrations of the related agents to fetal Yusho- dioxin-like PCBs and PCBs]. AB - We determined dioxin-like polychlorinated biphenyls (PCBs) and PCBs in 6 preserved umbilical cords of fetal Yusho patients and in 11 preserved umbilical cords of Yusho suspected persons who were born to mothers with Yusho from 1970 to 2002, which were Yusho group. As a control, we also analyzed dioxin-like PCBs and PCBs in 15 preserved umbilical cords of babies who were born to healthy mothers, which was healthy group, in the same period of time. As a result, concentrations of three dioxin-like PCBs, that is, #156, #157 and #189 which were 6 to 20 times higher in fetal Yusho patients than in healthy babies were still 4 to 6 times greater in Yusho group than in healthy group about 20 years after the outbreak of Yusho, but could not recognize this characteristic anymore about 30 years after the outbreak. Decreasing rate in concentrations of dioxin-like PCBs and PCBs seemed to higher in Yusho group than in healthy group during this period of time. Therefore, we considered due to heavy exposure to PCDFs some drug metabolizing enzymes such as aryl hydrocarbon hydroxylase were induced and excretion of the related agents to fetal Yusho were enhanced from the bodies of Yusho group. In order to clarify this hypothesis, further more detail studies are needed. PMID- 21706891 TI - [Promotive excretion of causative agents of Yusho by fermented brown rice with Aspergillus oryze in Yusho patients]. AB - Forty two years have passed since the outbreak of Kanemi rice oil poisoning, namely, Yusho in the western Japan. However, even now the Yusho patients have been still suffering from several objective and subjective symptoms. In order to improve or, if possible, to cure such symptoms, the most important therapeutic treatment is considered to actively excrete the causative agents, that is, polychlorinated dibenzofurans (PCDFs) from the bodies of the patients and to reduce their body burdens. In rats, chlorophyll and dietary fiber have been shown to promote the fecal excretion of PCDFs and polychlorinated dibenzo-p-dioxins (PCDDs) and to reduce their levels in rats. In this study, we have examined whether such kinds of effect are also observed by fermented brown rice with Aspergillus oryzae (FBRA) containing 5% spirulina, which is so-called spirulina HI * GENKI, the health food and relatively rich with chlorophyll and dietary fiber, in eighteen Yusho patients. They were divided into two groups, namely group A, ten patients (3 males and 7 females) with the mean age of 67.7 years old and group B, eight patients (4 males and 4 females) with the mean age of 64.1 years old. Among the patients of group A, three patients were especially highly contaminated with PCDFs and we classified them into group A (High). Respective mean concentrations of PCDFs in the blood just before initiating this study were as follows; group A : 145 pg/g lipid, group A (High) : 371 pg/g lipid and group B : 52.1 pg/g lipid. Contamination levels of PCDFs, PCDDs and dioxin-like polychlorinated biphenyls (PCBs) in group A (High) were 1.7 to 2.6 times higher than those in group A and 2.4 to 7.1 times higher than those in group B. Accordingly, concentrations of dioxins (PCDFs + PCDDs + dioxin-like PCBs) in the blood of groups A, A (High) and B were, respectively, 194, 458 and 85 pg-TEQ/g lipid. Concentrations of PCBs were also the highest in group A (High) : 1399 ng/g lipid, in group A : 748 ng/g lipid and the lowest in group B : 456 ng/g lipid. Groups A and A (High) took around 7.0 g of spirulina HI * GENKI after each meal and three times a day for the first one year and for the second one year, they did not take spirulina HI * GENKI anymore. Group B took spirulina HI * GENKI with the same manner as the group A only for the second one year. The concentrations of PCDFs, PCDDs, dioxin-like PCBs and PCBs in the blood were also measured at the end of the first and second year, respectively. Assuming the body fat is also contaminated with these compounds at their concentrations on lipid weight basis in the blood and the content of body fat is 20% of 60 kg body weight, we computed the average amounts in their net excretion from the body of the patients due to spirulina HI * GENKI in the three groups. As a result, in group A (High), 341 ng TEQ/patient of dioxins was excreted from the body, which was 3.4 times greater than that in group A and 12 times higher than that in group B. Therefore, promotive excretions of causative agents of Yusho were the most effective in group A (High) and we consider spirulina HI * GENKI is more effective from the therapeutic point of view in more highly contaminated Yusho patients. PMID- 21706893 TI - [Blood PCB concentrations and their tendencies examined in Fukuoka 2007-2010 annual inspections for Yusho]. AB - We performed PCB congener specific analysis using HRGC/HRMS and determined their concentrations and blood chromatogram classifications in 275 individual blood samples collected during annual Yusho examinations between 2007 and 2010. When both blood total PCB concentrations and blood chromatogram classifications were compared among eleven Yusho patients undergoing examinations between 2007 and 2010, the longitudinal concentrations and classifications in the respective individuals hardly changed over these years. In a subset of persons suspected of Yusho, it was found that the mean total blood concentrations of three index congeners, that is, 2, 3', 4, 4', 5-pentaCB (PCB118), 2, 2', 4, 4', 5, 5'-hexaCB (PCB153), 2, 3, 3', 4, 4', 5-hexaCB (PCB156) and mean blood total PCB concentrations gradually decreased between 2007 and 2010. Mean concentration of PCB118 in blood from persons suspected of Yusho was calculated as 0.035 ng/g in the 2010 examination, which was 36% lower than the mean value of 0.054 ng/g in the 2007 examination: the concentration of PCB118 showed the highest degree of decrease among the three index congeners. Among persons suspected of Yusho, occupational rates of persons with blood PCB concentrations below one ppb in the entire population increased from approx. 50% in 2007 to approx. 70% in 2010. The lowest concentration of PCB156 in blood of persons suspected of Yusho in 2010 was 0.43 pg/g, which was almost equivalent to the limit of the determination value on HRGC/HRMS, S/N = 10. PMID- 21706892 TI - [Differences in the bone mineral density in patients with Kanemi Yusho treated before and after the age of 18 years]. AB - This study examined patients with Kanemi Yusho. The patients' height, weight, and bone mineral density were measured. The density of the distal end of the radius was measured using dual energy X-ray absorptiometry and the calcaneum was measured with ultrasound. We also measured urine levels of cross-linked N telopeptides of type I collagen, serum tartrate-resistant acid phosphatase 5b, serum bone-specific alkaline phosphatase, serum Ca, serum P and blood PCB level. The patient group that took PCBs when they were 0 to 18 years old (such patients were 42 to 60 years old at the time of the study) showed no correlation between the bone density of the radius and calcaneum in spite of treatment received when they were over 18 years of age (> 60 years of age at the time of the study). The bone mineral density in Kanemi Yusho was not different from the control group. The levels of only serum bone-specific alkaline phosphatase were correlated with the bone mineral density of the radius and calcaneum in patients treated when they were over 18 years of age (currently over 60 years old). PCBs might have had an effect on bone density and bone metabolism. PMID- 21706894 TI - [The difference between male and female dioxin concentrations in the blood of Yusho patients]. AB - In 1968, the contamination of cooking oil by heat-degraded polychlorinated biphenyls (PCBs) caused a case of mass poisoning, the so-called Yusho incident. The cause of Yusho disease is thought to be ingested toxic substances, including not only PCBs but polychlorinated dibenzofuran (PCDFs) in Kanemi rice oil. Extensive studies have been performed since 1995 by the Yusho study group involving follow-up surveys of human blood concentrations of the casual compounds in Yusho patients as well as clinical trials of the acceleration of the excretion of these compounds in Yusho patients. We have previously measured dioxin concentrations in the blood of 649 Yusho patients in annual medical examinations from 2001 to 2009. We determined that the concentrations of 2,3,4,7,8-PeCDF 1,2,3,4,7,8-HxCDF 1,2,3,6,7,8-HxCDF, and 3,3',4,4',5,5'-HxCB (#169) in the blood of Yusho patients were more than twice as high levels to as those of normal controls. In this study, we compared the concentrations of 2,3,4,7,8-PeCDF, 1,2,3,4,7,8-HxCDF, 1,2,3,6,7,8-HxCDF, and 3,3',4,4',5,5'-HxCB (#169) in the blood of male Yusho patients with those of female Yusho patients. As a result, it was found that the mean concentrations of 2,3,4,7,8-PeCDF 1,2,3,4, 7,8-HxCDF 1,2,3,6,7,8-HxCDF, and 3,3',4,4',5,5'-HxCB (#169) in female Yusho patients were 2.9, 3.7, 2.4, and 1.3 times higher, respectively, than those of male Yusho patients. PMID- 21706895 TI - [The rapid analysis of polychlorinated quaterphenyls in blood using different diameter capillary column with the high-resolution gas chromatograph high resolution mass spectrometer]. AB - The polychlorinated quaterphenyl (PCQ) concentrations in blood are important discriminative parameters in yusho patient. In this study, a rapid analytical method for PCQ using different diameter capillary column (rapid-Rtx65TG) with high-resolution gas chromatograph high-resolution mass spectrometer (HRGC/HRMS) instead of the gas chromatograph electron capture detector (ECD/GC) was developed. Using different diameter capillary columns, the analysis time of the HRGC/HRMS was drastically shortened, and the detection sensitivity was improved. In the rapid-Rtx65TG column, a small-bore capillary column (length 1m, I.D. 0.1mm) was connected with the inlet side of the GC, and behind that column, a large-bore capillary column (length 15mm, I.D. 0.53mm) for octadecachloroquaterphenyl (ODCQ) analysis was connected. In the HRGC/HRMS measurement of ODCQ by the rapid-Rtx65TG column, the minimum limit of detection for the apparatus was 0.4 pg, and the minimum limit of determination for the blood was 0.008 ppb. On ECD/GC in the conventional method and HRGC/HRMS in this study, the PCQ concentration in blood including yusho patients and yusho suspected persons was almost equivalent. PMID- 21706897 TI - [In vivo metabolism of 2,2',3,4,4',5'-hexachlorobiphenyl (CB138) in guinea pigs]. AB - Our preceding studies reported using animal liver microsomes that 2, 2', 3, 4, 4', 5'-hexachlorobiphenyl (hexaCB) (CB138), a worldwide and persistent organohalogen pollutant, was metabolized to two major hydroxy (OH)-metabolites, 3'-OH-CB138 (M-3) and 2'-OH-2, 3, 3', 4, 4', 5'-hexaCB (M-4), and two dechlorinated OH-metabolites (M-1 and M-2) in guinea pigs at much faster rate than in rats and hamsters. In this study, the distribution of four CB138 metabolites to the serum and liver 4 days after exposure and their fecal excretion were studied in guinea pigs administered with CB138 intraperitoneally. 3'-OH-CB138 (M-3) was a major metabolite in the liver, serum and feces. M-1 was observed as a minor metabolite in guinea pig feces. In contrast, trace amount of M-2 was present in guinea pig serum. However, 2'-OH-2, 3, 4, 3', 4', 5'-hexaCB (M 4) which was a major metabolite in the in vitro system using guinea pig liver microsomes was not found in all tissues and feces tested in this study. On the other hand, the exact chemical structures of M-1 and M-2 were determined to be 6' OH-2, 3, 3', 4, 4'-pentaCB and 4'-OH-2, 2', 3, 4, 5'-pentaCB, respectively, by comparison of the retention time and mass fragmentation of the synthetic authentic samples in GC-MS. From these results, it is suggested that the metabolism of CB138 in guinea pigs may proceed by three pathways, a direct hydroxylation at 3'-position, and also the formation of 2',3'- or 3', 4'-epoxide and subsequent dechlorination and that three metabolites show the different mode of distribution and excretion. PMID- 21706896 TI - [The effect of maternal exposure to dioxin on fetal steroidogenesis in the steroidogenic organs]. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposed to pregnant or lactational mother impairs the reproduction and development of the pups. The defect is a serious problem, because it is caused by TCDD at much lower doses than that needed for acute toxicity in the mother. However, the toxic mechanism underlying the defect remains to be obscure. We have previously revealed that maternal exposure to TCDD (1 microg/kg) causes a reduction in luteinizing hormone in the fetal pituitary, leading to the reduced expression of testicular steroidogenic proteins such as steroidogenic acute-regulatory protein (StAR) and cytochrome P450 (CYP) 17. In addition, we have provided evidence that such a reduction imprints defects in sexual behaviors at adulthood. In this study, we investigated TCDD effect on fetal steroidogenesis in the extra-gonadal tissues. Even when pregnant Wistar rats at gestational day (GD) 15 were orally treated with TCDD (0.25, 1 or 3 microg/kg), neither expression of StAR nor CYP17 mRNA was affected in the adrenal gland, placenta and hypothalamus of male fetuses (GD20). However, TCDD induced placental StAR (3 microg/kg) and adrenal CYP17 mRNAs (0.25 microg/kg) in female fetuses. Therefore, our study suggests that while TCDD gives damage to male fetal steroidogenesis in a testis-specific manner, the dioxin enhances the steroidogenesis of the fetal adrenal gland and placenta in females. Thus, the mechanism whereby TCDD exerts its endocrine-disrupting properties is considered to differ, at least partially, between male and female fetuses. PMID- 21706898 TI - [Intestinal intussusceptions in adults]. AB - BACKGROUND: Intestinal intussusception occur when a portion of the gastrointestinal tract invaginates into the part of the tract that precedes into the peristaltic direction. AIMS: To determine clinical presentation, diagnostic methods and outcome of the intestinal intussusception and to compare our results to previous data. METHODS: A retrospective study of 20 patients with mean age of 40 years admitted between 1982 and 1999 and underwent surgery for intestinal intussusceptions. RESULTS: Our patients were 10 males and 10 females. The clinical findings were essentially abdominal pain (90%). Preoperative diagnosis of intestinal intussusceptions was established in 30% of cases. Intussusceptions were ileo-ileal (n=10), ileo-colic (n=7) and colo-colic (n=3). 12 patients had tumors. For all intussusceptions involving the colon, all patients underwent resection while intussusceptions located on the small bowel were treated by reduction then resection or simple reduction then fixation. The mortality rate was 5%. CONCLUSION: Intestinal intussusception in adults is uncommon in comparison with children. Correct diagnosis is often established during surgery. Resection is recommended because of the frequent malignancy. PMID- 21706899 TI - The first kitchen: Eleanor Roosevelt's austerity drive. PMID- 21706900 TI - Linzer torte. PMID- 21706901 TI - Down under: the hidden allure of root vegetables. PMID- 21706902 TI - Burger queen: April Bloomfield's gastropub revolution. PMID- 21706903 TI - Borscht. PMID- 21706904 TI - Maintenance of certification: the profession's response to physician quality. PMID- 21706906 TI - Nature's spoils: the underground food movement ferments revolution. PMID- 21706907 TI - Turbot. PMID- 21706905 TI - Family physician participation in maintenance of certification. AB - PURPOSE: The American Board of Family Medicine has completed the 7-year transition of all of its diplomates into Maintenance of Certification (MOC). Participation in this voluntary process must be broad-based and balanced for MOC to have any practical national impact on health care. This study explores family physicians' geographic, demographic, and practice characteristics associated with the variations in MOC participation to examine whether MOC has potential as a viable mechanism for dissemination of information or for altering practice. METHODS: To investigate characteristics associated with differential participation in MOC by family physicians, we performed a cross-sectional comparison of all active family physicians using descriptive and multinomial logistic regression analyses. RESULTS: Eighty-five percent of active family physicians in this study (n = 70,323) have current board certification. Ninety one percent of all active board-certified family physicians eligible for MOC are participating in MOC. Physicians who work in poorer neighborhoods (odds ratio [OR] = 1.105; 95% confidence interval [CI], 1.038-1.176), who are US-born or foreign-born international medical graduates (OR = 1.221; 95% CI, 1.124-1.326; OR = 1.444; 95% CI, 1.238-1.684, respectively), or who are solo practitioners (OR = 1.460; 95% CI, 1.345-1.585) are more likely to have missed initial MOC requirements than those from a large, undifferentiated reference group of certified family physicians. When age is held constant, female physicians are less likely to miss initial MOC requirements (OR = 0.849; 95% CI, 0.794-0.908). Physicians practicing in rural areas were found to be performing similarly in meeting initial MOC requirements to those in urban areas (OR = 0.966; 95% CI, 0.919-1.015, not significant). CONCLUSION: Large numbers of family physicians are participating in MOC. The significant association between practicing in underserved areas and lapsed board certification, however, warrants more research examining causes of differential participation. The penetrance of MOC engagement shows that MOC has the potential to convey substantial practice-relevant medical information to physicians. Thus, it offers a potential channel through which to improve health care knowledge and medical practice. PMID- 21706908 TI - Christmas pudding. PMID- 21706909 TI - Soil-transmitted helminthiases: estimates of the number of children needing preventive chemotherapy and number treated, 2009. PMID- 21706910 TI - Monthly report on dracunculiasis cases, January-April 2011. PMID- 21706911 TI - Performance of acute flaccid paralysis (AFP) surveillance and incidence of poliomyelitis, 2011. PMID- 21706912 TI - [The use of cardio-vascular technologies in radical treatment of recurrent disseminated renal cancer]. PMID- 21706913 TI - [To the 140th anniversary of birth of P.A. Gertsen]. PMID- 21706914 TI - How to make your doctor listen. PMID- 21706915 TI - Helicobacter pylori: association with gall bladder disorders in Pakistan. AB - Helicobacter species colonise the biliary tract and therefore this study explores the relationship between of Helicobacter pylori and cholecystitis. Bile and gall bladder tissue samples were obtained from 144 patients who underwent cholecystectomy. Of these, 89 had chronic cholecystitis with cholelithiasis, 44 had gall bladder carcinoma and 11 had gall bladder polyps. Histopathology examination included special staining and immunohistochemistry (IHC), while Helicobacter species (H. pylori, H. bilis and H. hepaticus) were detected by the polymerase chain reaction (PCR). Sequencing and BLAST query of PCR products was undertaken and samples were considered to contain H. pylori if both PCR and IHC were positive. Immunohistochemistry for H. pylori was positive in 22 (25%) cases compared to five (9%) in the control group (P=0.02). Testing (PCR) for 16S rDNA was positive in 23 (26%) cases compared to six (11%) controls (P=0.03). Negative PCR results were obtained for H. bilis and H. hepaticus. Twenty-four (89%) were positive by both 16S rDNA PCR and IHC for H. pylori (P<0.001). Both PCR for 16S rDNA and IHC were positive in 21 (24%) cases compared to five (9%) controls (P=0.03). Sequencing of 16S rRNA and glmM PCR products were consistent with H. pylori. In conclusion, H. pylori DNA was demonstrated in cases of chronic cholecystitis and gall bladder carcinoma associated with cholelithiasis, but this association requires further study. PMID- 21706916 TI - Prevalence of clustered regulatory interspaced short palindromic repeat (CRISPR) like sequences in mitis-group streptococci. AB - Clustered regulatory interspaced short palindromic repeats (CRISPRs) have been discovered in many bacteria and archaea. Many CRISPR-like sequences have been identified in an increasing number of studies on the function of CRISPRs. One CRISPR-like sequence of approximately 240 base pairs has been found to be highly conserved within 11 genome sequences of Streptococcus pneumoniae. A specific CRISPR-like polymerase chain reaction (PCR) assay was designed with the novel primers CRISPR 5F (forward primer) 5'-CTA ATY TCA TAA CCA TAR GAA TC-3' and CRISPR 3R (reverse primer) 5'-GAT AAR ATC CTY TAA WCT TCT AG-3' to detect the presence of this CRISPR-like sequence in pneumococci, as well as in viridans group streptococci (VGS). This study investigates the prevalence of this CRISPR like sequence in S. pneumoniae and 12 viridans-group streptococcal species and shows its existence to be shared by the majority of S. pneumoniae and, to a lesser extent, S. mitis. This CRISPR-like sequence was also found in S. australis and it is highly conserved among these strains, suggesting possible biological functional differences from true CRISPR because this CRISPR-like sequence has relatively few repeat numbers, and adjacent homology of CRISPR-associated (cas) genes was absent. The sharing of this CRISPR-like sequence between pneumococci, the mitis group and other VGS, as well as its high sequence homology, may suggest close evolutionary emergence of this sequence between these species. PMID- 21706917 TI - Multidrug resistance-associated biomarkers PGP, GST-pi, Topo-II and LRP as prognostic factors in primary ovarian carcinoma. AB - This study aims to investigate the expression of P-glycoprotein (PGP), glutathione S-transferase pi (GST-pi), DNA topoisomerase II (Topo-II) and lung resistance-related protein (LRP) in ovarian carcinoma, thus providing better chemotherapy choice and post-operative prognosis for ovarian carcinoma patients. A total of 80 primary ovarian carcinoma, 16 benign ovarian epithelial neoplasm, and 12 normal ovarian tissue samples were collected. Immunohistochemistry was used to detect the expression of PGP, GST-pi, Topo-II and LRP, and the results were analysed by correlation with clinicopathological parameters. Positive expression rates of PGP, GST-pi, Topo-II and LRP in patients with ovarian carcinoma (57.5%, 58.8%, 76.3% and 73.8%, respectively) were all higher than those found in normal and benign tissue (P<0.05). In clinical stages I/II vs. III/IV, the expression rates of PGP, GST-pi, Topo-II and LRP were 40.7% vs. 66% (P<0.05), 40.7% vs. 67.9% (P<0.05), 66.7% vs. 81.1% (P>0.05) and 55.6% vs. 83.0% (P<0.05), respectively. Carcinoma differentiation ranged from well to poor, and expression levels of each marker were as follows: PGP, 57.9%, 62.1% and 53.1% (P>0.05); GST-pi, 36.8%, 55.2% and 75.0% (P<0.05); Topo-II, 52.6%, 79.3% and 87.5% (P<0.05); and LRP, 84.2%, 69.0% and 71.9% (P>0.05). Ovarian carcinoma patients with PGP-, GST-pi-, Topo-II- and LRP-positive expression had a shorter median survival time than those who were negative for these markers (PGP: 36 months vs. 48 months [P=0.0017]; GST-pi: 36 months vs. 41 months [P=0.0103]; Topo II: 37 months vs. 39 months [P=0.3811]; LRP: 37 months vs. 55 months [P=0.002]). COX regression analysis demonstrated that the clinical stage of the tumour, and the expression of PGP, GST-pi or LRP, may influence patient survival time after surgery. The relative death risk for patients with clinical stage III/IV tumours increased 9.46-fold compared to those with stage I/II tumours. The relative death risk in the PGP-, GST-pi- and LRP-positive groups increased by 2.049-, 2.452- or 2.609-fold, respectively, compared with the corresponding negative groups. PGP, GST-pi, Topo-II and LRP are all expressed in primary ovarian carcinoma, indicating the presence of multidrug resistance in this disease. Combined evaluation of PGP, GST-pi, Topo-II and LRP expression may enable better chemotherapeutic choice and provide an accurate prognosis for ovarian carcinoma patients. PMID- 21706918 TI - Cryptosporidium and other enteric parasitic infections in HIV-seropositive individuals with and without diarrhoea in Osogbo, Nigeria. AB - The primary objective of this cross-sectional study is to correlate the presence of Cryptosporidium and other gastrointestinal parasites with the presence of diarrhoea in human immunodeficiency virus (HIV)-infected patients. Stool samples from 96 HIV-seropositive cases were examined for non-opportunistic parasites using the direct and formol-ether concentration methods, while the modified Ziehl Neelsen technique was used to detect Cryptosporidium spp. The overall prevalence of Cryptosporidium spp. was 54.2%. Other intestinal parasites detected included Ascaris lumbricoides (59.4%), hookworm (5.2%), Entamoeba histolytica (3.1%), Strongyloides stercoralis (1%) and Taenia spp. (1%). Infection inmales was more common (68.2%) than in females (55.4%) but the difference was not statistically significant. Therewas a significant association between Cryptosporidium infection and CD4+ count (P=0.0001), with the highest parasite prevalence (90%) observed among patients who had the lowest CD4+ count (<200 cells/mm3). Forty-five (86.5%) patients with Cryptosporidium infection presented with diarrhoea and the difference between those with and without diarrhoea was statistically significant (P=0.0001). There was a statistically significant difference (P=0.0001) among the age groups, with the 41-50 group showing the highest prevalence (84.6%) of infection. Co-infection was observed in 13.5% of the patients. As no drug is currently available for the treatment of cryptosporidiosis, emphasis should be placed on educating HIV-infected individuals about prevention. PMID- 21706919 TI - Biomedical scientist training officers' evaluation of integrated (co-terminus) Applied Biomedical Science BSc programmes: a multicentre study. AB - The introduction of the Institute of Biomedical Science (IBMS) portfolio for pre registration training in 2003 allowed universities to develop integrated (co terminus) biomedical science BSc programmes. Students undertake structured placements within clinical pathology laboratories as part of their degree. The clinical training and professional development of students is undertaken by training officers (TOs), who are experienced Health Professions Council (HPC) registered biomedical scientists and usually also members of the IBMS. This study aims to evaluate TOs' perceptions of these integrated degrees as a means of delivering pre-registration training for biomedical scientists. A questionnaire to collect quantitative data and be completed anonymously was sent to TOs, via staff at participating universities. Items considered TOs' perceptions in four categories: how well students fitted into the laboratory team, their professional and scientific development, the impact of delivering integrated degrees on service delivery, and the commitment to training students. Surveys took place in 2007, 2008 and 2009 and involved TOs taking students from 10, 14 and 17 universities each year, respectively. The response rates to the survey were 60% in 2007, 34% in 2008 and 12% in 2009. Participants were representative in terms of age, gender and pathology discipline and had a broad range of experience with students. The overall mean score for TOs perceptions was 3.38 in 2007 which increased significantly to 3.99 in 2009 (Kruskall Wallis test chi2 = 21.13, P<0.01). Mean scores in three of the four categories were positive in 2007, although the impact on service delivery was perceived negatively. In all areas, means were significantly greater in 2009. The results indicate that TOs view the integrated degrees favourably and are happy with the scientific and professional development of students. Although designing training sessions suitable for undergraduates took extra work initially, TOs are committed to delivering the training. PMID- 21706920 TI - Evaluation of 25-hydroxyvitamin D quantification using a commercial HPLC kit method. PMID- 21706921 TI - Effect of swab type on the analytical sensitivity of five point-of-care tests for group A streptococci. PMID- 21706922 TI - Comparison of the identification of Acinetobacter spp. with API20NE and 16S rRNA gene sequencing techniques. PMID- 21706923 TI - Optimising pre-analytical performance of interferon-gamma release assays for TB exposure. PMID- 21706924 TI - Chromosome microarray analysis in a clinical environment: new perspective and new challenge. AB - The analysis of the human genome has largely been undertaken in a research environment, but recent developments in technology and associated workflow have allowed diagnostic laboratories to interrogate DNA at significantly improved levels of resolution. Principally, whole genome-based analysis of copy number changes using microarrays has led to this method replacing conventional karyotyping as a routine diagnostic workhorse. The resolution offered by microarrays is an improvement of at least an order of magnitude compared to karyotyping, but it comes at a cost in terms of the time spent in data interpretation. Overall, however, the die has been cast and cytogeneticists need to become familiar with the tools use by molecular geneticists and bioinformaticists. The following review provides a brief background to array technology, but uses a series of case studies to illustrate the usefulness and challenges of interpreting array data. PMID- 21706925 TI - The Armed Forces Research Institute of Medical Sciences: five decades of collaborative medical research. AB - The Armed Forces Research Institute of Medical Sciences (AFRIMS) is a 50-year-old joint institute of the US and Royal Thai Army Medical Departments located in Bangkok, Thailand. Investigators from the Institute have carried out research in Thailand and the region, in collaboration with many partners, focused on a large number of tropical infectious diseases. In celebration of the 50th anniversary, this paper summarizes highlights of this research, focusing on malaria, Japanese encephalitis, dengue, diarrhea and HIV. In addition, research done in support of the medical problems of refugees and of the health of Thai peace-keeping forces are summarized. The research carried out by AFRIMS and added to the scientific literature has contributed significantly to advancement in multiple areas of tropical infectious disease. PMID- 21706926 TI - Knowledge, attitudes and practices regarding malaria control in an endemic area of southern Iran. AB - Iran is in the malaria pre-elimination stage. In this situation community based strategies are important for malaria control. In order to intensify elimination activities we need to have a better understanding of the knowledge, attitudes and practices (KAP) of malaria prevention in the community. We carried out a KAP study in one malaria endemic district in southern Iran in 2009 using a structured questionnaire. Five villages with indigenous malaria cases during the previous year and a high potential for anopheline mosquito breeding were selected. All the households in each village were visited and the head of the household or other responsible adult was interviewed. Data were analyzed using SPSS 11.5. A total of 494 respondents from the five villages participated. More than 33% of people in the study area were living in sheds with poor facilities. The illiteracy level of the studied population was high (44.2%) and significantly affected the knowledge and practices of the respondents about malaria control (p<0.05). Descriptive analysis showed significant differences between sex, job and history of malaria infection of the respondents and their knowledge and practices about malaria control (p<0.05). Knowledge of the respondents about the route of transmission in malaria was good; 72.1% knew mosquitoes were the vector. Most people knew at least one symptom of the disease. The practices of respondents were 59.5% for bednet use and 9.3% for screening windows. The knowledge, attitudes and practices of respondents in this survey about malaria control were good in some cases, but in general needed to be improved with educational programs. PMID- 21706927 TI - Glucantime efficacy in the treatment of zoonotic cutaneous leishmaniasis. AB - Pentavalent antimony (SbV) compounds are still considered the first line of treatment for all forms of leishmaniasis. There have been reports of drug resistance and unresponsiveness to treatment with these drugs. We investigated the clinical response to treatment of cutaneous leishmaniasis with glucantime, the drug of choice for all forms of leishmaniasis in Iran. All individuals suspected of cutaneous leishmaniasis from October 2007 to March 2008 were included in the study if met specific criteria. After laboratory diagnosis and parasite identification by PCR, 43 patients agreed to participate and complete the protocol for treatment. Meglumine antimoniate (glucantime) was given at a dose of 20 mg/kg/day for 20 days (two 10-day periods) according to a World Health Organization (WHO) recommended protocol. Response to treatment was evaluated 6 weeks after initiation of treatment. Fifteen patients (34.9%) were clinically unresponsive to glucantime treatment while the remaining 28 patients (65.1%) responded to treatment. There were no statistically significant differences by occupation, gender, chronicity of the disease before starting treatment, number of lesions, or age between the glucantime sensitive and resistant patients. Our study showed a significant level of unresponsiveness to glucantime among patients with cutaneous leishmaniasis caused by Leishmania major in Iran. These findings highlight the need for new treatment regimens. PMID- 21706928 TI - Biliary Fasciola gigantica case report from Turkey. AB - We present a case of Fasciola gigantica-induced biliary obstruction and cholestasis diagnosed and treated via endoscopy and trichlorobendazole treatment. This is the first case of Fasciola gigantica treated via endoscopic biliary extraction during ERCP and drug treatment reported from Turkey. PMID- 21706929 TI - Soil-transmitted helminthiasis in rural south-west China: prevalence, intensity and risk factor analysis. AB - Only few studies in rural China have explored the epidemiology of intestinal helminth infections and identified risk factors for transmission. The study was carried out in Simao and Mengla counties, where single fecal samples were collected from 317 school-aged children and from 94 inhabitants of a single village. Fecal specimens were examined with the Kato-Katz thick smear method and examined for helminth eggs. Data regarding socio-demographic and behavioral risk factors were collected using questionnaires. In Simao County the overall soil transmitted helminthes (STH) prevalence was 40.2% (2.7, 5.4 and 35.7% for ascariasis, trichuriasis and hookworm infection, respectively). The STH infection rates were significantly higher in Mengla County, with an overall prevalence of 68.3% (19.0, 34.6 and 47.3% for ascariasis, trichuriasis and hookworm infection, respectively). Females were less likely to be infected with Trichuris trichiura (OR 0.29; 95% CI 0.15-0.56) and with hookworms (OR 0.55; 95% CI 0.33-0.93) than males. Hookworm infections were more prevalent among those 12 years of age or older (OR 2.9; 95% CI 1.2-7.1). Children of mothers with educational attainment of secondary school or higher had a protective effect against T. trichiura (OR 0.18; 95% CI 0.06-0.54) and hookworm (OR 0.21; 95% CI 0.09-0.51) infections. In the village survey, hookworm was the most prevalent species (62.8%) with infection seen in those 50 years of age and older. Based on recommended intervention strategies by the World Health Organization, Simao County should opt for school-based deworming once each year, while Mengla County should implement a similar strategy biannually, but should include the elderly population. PMID- 21706930 TI - Epidemiology of soil-transmitted helminthiases in Malaysia. AB - We reviewed the epidemiology of STH in Malaysia from the 1970s to 2009. High prevalence rates persist among the rural Aborigines, estate workers and in urban slums and squatter areas. Trichuris trichiura is the most prevalent helminth in Malaysia ranging from 2.1% to 98.2%. Ascaris lumbricoides follows closely with a prevalence rate of 4.6-86.7%, while hookworm is the least prevalent (0-37.0%). A countrywide control program with special emphasis on school-based intervention is highly recommended among aboriginal people. PMID- 21706931 TI - First report of Ctenocephalides felis felis on the Asiatic Golden Cat, Catopuma temminckii in Thailand. AB - The cat flea, Ctenocephalidesfelisfelis (Siphonaptera: Pulicidae) has been reported to parasitize many species of wild and domestic animals and could serve as a vector of zoonotic pathogens. This is the first report of the presence of cat fleas on the Asiatic Golden Cat, Catopuma temminckii (Carnivora: Felidae), quarantined in Khao Pratabchang Wildlife and Breeding Center, Ratchaburi Province, Thailand. The findings of this report may be helpful in evaluating the potential risks associated with increased contact between wild and domestic animals and humans in this region. PMID- 21706932 TI - Antioxidative systems defense against oxidative stress induced by blood meal in Aedes aegypti. AB - The release of iron from hemoglobin via the digestion of a blood meal in female mosquitoes can potentially induce oxidative damage and even death. These mosquitoes need an effective antioxidant to prevent this. We carried out this study to determine the antioxidant activities of ferritin, glutathione peroxidase (GPx), glutathione S-transferase (GST) and catalase, and glutathione (GSH). These enzymes had their greatest activity among 4 day old virgin female mosquitoes. Using a single blood feed model, groups of female mosquitoes were tested at 4, 7 and 20 days post-emergence. They were allowed to feed on a hamster for 1 hour. The engorged mosquitoes were collected at 48 and 72 hours after their blood meal. There were no changes in GSH, GPx, GST or catalase levels, but ferritin levels increased markedly (about 2-3 fold) by 48 hours post blood-feed in all mosquito age groups. On repeated blood-feed experiments, mosquitoes aged 4 days were blood fed, once every 3 days and were collected 48 hours after their most recent blood meal. A significant decrease in GSH and GPx activity and a further increase in ferritin, were detected. Ferritin levels were 0.19+/-0.03 and 0.14+/-0.02 ng/microg protein in the repeat and single blood-feed groups, respectively. These results suggest ferritin is an inducible, sensitive defense system protecting against oxidative stress caused by iron derived from blood meals in Aedes aegypti mosquitoes. PMID- 21706933 TI - Dusk to dawn activity patterns of anopheline mosquitoes in West Timor and Java, Indonesia. AB - Malaria is a serious health issue in Indonesia. We investigated the dusk to dawn anopheline mosquito activity patterns, host-seeking and resting locations in coastal plain, hilly and highland areas in West Timor and Java. Adult mosquitoes were captured landing on humans or resting in houses or animal barns. Data analyzed were: mosquito night-time activities; period of peak activity; night time activity in specific periods of time and for mosquito resting locations. Eleven species were recorded; data were sparse for some species therefore detailed analyses were performed for four species only. In Java Anopheles vagus was common, with a bimodal pattern of high activity. In West Timor, its activity peaked around midnight. Other species with peak activity around the middle of the night were An. barbirostris and An. subpictus. Most species showed no biting and resting preference for indoors or outdoors, although An. barbirostris preferred indoors in West Timor, but outdoors in Java. An. aconitus and An. annularis preferred resting in human dwellings; An. subpictus and An. vagus preferred resting in animal barns. An. barbirostris preferred resting in human dwellings in West Timor and in animal barns in Java. The information is useful for planning the mosquito control aspect of malaria management. For example, where mosquito species have peak activity at night indoors, bednets and indoor residual spraying should reduce malaria risk, but where mosquitoes are most active outdoors, other options may be more effective. PMID- 21706934 TI - Use of dengue NS1 antigen for early diagnosis of dengue virus infection. AB - Accurate and timely diagnosis of dengue virus is important for early detection of dengue virus infection. In this study, the usefulness of the dengue NS1 antigen test was evaluated as a routine, rapid diagnostic test for dengue virus infection. A total of 208 sera from patients suspected of having dengue virus infection were collected and tested for dengue antibody, dengue genome and dengue NS1 antigen. Dengue antibody test, dengue PCR test and dengue antigen test were able to detect dengue virus infection from Days 1 to 8 in 72.8, 52.8 and 44.0% of samples, respectively. Of the 208 sera tested, 69.2% (144/208) of the acute sera were positive for dengue virus infection based on IgM antibody, IgG antibody, NS1 antigen and PCR tests. Thirty-two point two percent of the samples (67/208) were found positive for dengue NS1 antigen, 38.5% (80/208) were PCR positive, 40.9% (85/208) were IgM positive and 36.1% (75/208) were IgG positive for dengue virus. The results reveal the detection rate of dengue virus infection was similar for PCR and dengue antibody (65.9%) and for NS1 antigen and dengue antibody (62.0%) combinations. Therefore, the dengue NS1 antigen test can be used to complement the current antibody test used in peripheral laboratories. Thus, the combination of the NS1 antigen and antibody tests could increase the diagnostic efficiency for early diagnosis of dengue infection. PMID- 21706935 TI - Evaluation of rapid immunochromatographic NS1 test, anti-dengue IgM test, semi nested PCR and IgM ELISA for detection of dengue virus. AB - Dengue virus (DENV) causes various clinical symptoms of differing severity based on time of infections. The existing laboratory methods, semi-nested PCR and Dengue IgM ELISA, still have limitations for diagnosis. A commercially available rapid immunochromatographic dengue NS1 antigen and IgM antibody tests in comparison with semi-nested PCR and IgM ELISA for confirmation of DENV infection were evaluated. In total, 237 single acute serum specimens and 50 paired sera of dengue patients were examined using the rapid dengue NS1 antigen test, IgM antibody test, semi-nested PCR and Dengue IgM ELISA. The NS1 and IgM rapid tests showed sensitivity of 70.6%, and 75.6%, respectively, and specificity of 73.4% and 97.1%, respectively. The combination of NS1 and IgM tests enhanced diagnosis. Thus rapid dengue NS1 antigen and IgM antibody tests are highly appropriate for diagnosis of dengue infection as it is rapid, easily applicable, sensitive and highly specific. PMID- 21706936 TI - Heavy proteinuria following dengue hemorrhagic fever. AB - We report a case of nephrotic range proteinuria with 24-hour urine protein level of 335.7 mg/kg/day which developed following dengue hemorrhagic fever. Due to prolonged hypoalbuminemia from renal loss, right pleural effusion persisted and required pleuracentesis. The patient did not have classical nephrotic syndrome. The proteinuria improved without specific treatment. A renal biopsy was not performed due to self-resolution of the proteinuria and azotemia. Heavy proteinuria is not a typical characteristic of dengue virus infection, therefore the pathophysiology of this nephropathy has not been well described to date. PMID- 21706937 TI - Human avian influenza in Indonesia: are they really clustered? AB - Understanding the epidemiology of human H5N1 cases in Indonesia is important. The question of whether cases are clustered or not is unclear. An increase in clustered cases suggests greater transmissibility. In the present study, 107 confirmed and 302 suspected human H5N1 cases in Indonesia during 2005-2007 were analyzed for spatial and temporal distribution. Most confirmed cases (97.2%) occurred on two main islands (Java and Sumatera). There were no patterns of disease occurrence over time. There were also no correlations between occurrence patterns in humans and poultry. Statistical analysis showed confirmed cases were clustered within an area on Java island covered by 8 districts along the border of three neighboring provinces (Jakarta, West Java, and Banten). This study shows human H5N1 cases in Indonesia were clustered at two sites where there was a high rate of infection among poultry. These findings are important since they highlight areas of high risk for possible human H5N1 infection in Indonesia, thus, preventive measures may be taken. PMID- 21706938 TI - Poultry raising systems and highly pathogenic avian influenza outbreaks in Thailand: the situation, associations, and impacts. AB - Highly pathogenic avian influenza (HPAI), caused by the virus strain H5N1, currently occurs worldwide with the greatest burden in Southeast Asia where the disease was first reported. In Thailand where the disease was first confirmed in January 2004, the virus had been persistent as a major threat to the poultry industry and human health over the past several years. It was generally hypothesized that the main reason for the disease to circulate in Thailand was the existence of traditional backyard chickens and free-range ducks raising systems. Consequently, this study reviewed the structure of poultry raising systems, the recent outbreaks of HPAI H5N1, the disease association to the backyard and free-grazing poultry production, and consequences of the outbreaks in Thailand. Although the major outbreaks in the country had declined, the sustaining disease surveillance and prevention are still strongly recommended. PMID- 21706939 TI - Hepatitis B and hepatitis C virus in Thai blood donors. AB - Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major causes of transfusion-transmitted infection (TTI). In Thailand, the prevalence of HBV infection in new blood donors has decreased gradually from 7.1% in 1988 to 2.6% in 2009. This drastic decline in HBV prevalence is mostly the result of an effective expanded program on immunization (EPI) against HBV; the current coverage rate with HBV vaccine in newborns is more than 98% nation-wide. The prevalence of HCV infection, has decreased at a slower rate due to lack of HCV vaccination. The use of healthy volunteer blood donors and nucleic acid amplification technology (NAT) has also contributed to the steady decrease in rates of HBV and HCV infections. We summarize the current status of the EPI program for preventing HBV and the current strategy of HBV and HCV screening in new blood donors. PMID- 21706940 TI - HIV trends and related risk factors among men having sex with men in mainland China: findings from a systematic literature review. AB - The purpose of this study was to assess trends in the HIV epidemic and risk factors for HIV infection among men having sex with men (MSM) in mainland China. A literature review was conducted. Data from studies regarding HIV prevalence, syphilis infection and risk behavior, were pooled into three chronological stages. The independent correlates of HIV infection were gathered in order to guide the development of future interventions. HIV prevalences were 2.5% (95%CI 1.8-3.7), 1.8% (95%CI 1.1-2.9) and 3.3% (95%CI 2.0-5.3) before 2004, during 2004 to 2005 and 2006 to 2007, respectively. About two-thirds of MSM had multiple male sex partners during the previous six months (P6M), and more than one third of MSM engaged in unprotected anal intercourse (UAI) during last sex. Only UAI among commercial sex workers declined significantly. More than one quarter of MSM had female partners in P6M and the proportion having multiple female partners declined. The rates of unprotected vaginal sex had a downward trend. The prevalence of injecting drug use was low and remained the same. The number of lifetime male sexual partners and the frequency of anal sex in P6M were independently associated with HIV infection; UAI was correlated to the number of male partners, buying sex from males, being part of a mobile population, prior HIV testing and having a prior sexually transmitted disease (STD). We conclude intervention programs targeting UAI and multiple partners are urgently needed to control the HIV epidemic among MSM in mainland China. PMID- 21706941 TI - Is the bed capture enzyme immunoassay useful for surveillance in concentrated epidemics? The case of female sex workers in Indonesia. AB - Although the BED capture enzyme immunoassay (BED-CEIA) tends to over-estimate HIV incidence in general population epidemics, its limitations may be less relevant to some sub-populations in concentrated epidemics. This study assesses the plausibility of BED-CEIA estimates for female sex workers (FSWs) in Indonesia. Data were derived from a cross-sectional anonymous linked behavioral and biological surveillance survey. Independent samples of 2,917 direct and indirect FSWs, were gathered from seven and five cities, respectively, via three-stage time-location sampling. Participants provided behavioral information, venous blood and vaginal swabs. Specimens testing positive for HIV were subjected to BED CEIA to identify recent infections. The median duration of sex work was 12 months. The estimated HIV prevalence was 8.2% and the incidence was 4.1 per 100 person years, slightly lower than an Asian Epidemic Model (AEM) estimate. HIV incidence was higher among: direct FSWs (p<0.001), those reporting genital ulcers in the past year (p<0.001), those with active syphilis (p=0.017), and those not receiving periodic presumptive treatment for STIs during the previous 6 months (p=0.045). Low general population HIV prevalence, short durations of sex work and low ART coverage of those eligible for treatment make it unlikely that HIV incidence estimates for FSWs in Indonesia are distorted by long-standing infections and viral suppression. External consistency with model-based estimates and internal consistency in regard to known risk factors for HIV infection add to the plausibility of the estimates. Pending advances in methods for estimating HIV incidence, it may be premature to summarily dismiss the BED-CEIA in concentrated HIV epidemics. PMID- 21706942 TI - Renal impairment in HIV-1 infected patients receiving antiretroviral regimens including tenofovir in a resource-limited setting. AB - A retrospective cohort study was conducted among HIV-1 infected patients taking tenofovir as part of an anti-HIV drug regimen in a resource-limited setting in Thailand. One hundred thirty patients with a mean_SD age of 39.7+/-7.4 years, of whom 55% were male, were included in the study. Fifty-eight (45%), 48 (37%), and 24 (18%) patients concurrently received nevirapine-based, efavirenz-based, and protease inhibitor (PI)-based regimens, respectively. The median (IQR) value for serum creatinine was 0.8 (0.6-0.9) mg/dl, for eGFR was 103 (96-120) ml/min/1.73 m2 and for CD4 was 302 (194-511) cells/mm3 at the time of tenofovir initiation. At 3-6 months, the median (IQR) eGFR was 100 (88-117) ml/min/1.73 m2 (p=0.002, compared to baseline). The proportions of patients with an estimated glomerular filtration rate (eGFR)<30 ml/min/1.73 m2 at baseline and 3-6 months were 0% and 2%, respectively (p<0.001). At 6-months follow-up, 2 patients (1.4%) were diagnosed with acute renal failure at 3 weeks and 9 weeks after tenofovir use, respectively. Both patients received a boosted PI in the regimen. Overall, the incidence of acute renal failure was 0.26 per 100 person-months. Renal function progressed to irreversible renal failure in one patient. In summary, tenofovir associated renal impairment is not uncommon in a real-life practice. This report highlights the potentially irreversible adverse effect of this agent, particularly in patients with vulnerable kidneys and concomitant use of tenofovir and boosted PI. PMID- 21706943 TI - Hepatotoxicity in patients co-infected with tuberculosis and HIV-1 while receiving non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy and rifampicin-containing anti-tuberculosis regimen. AB - To evaluate the rate of and risk factors for hepatotoxicity in tuberculosis (TB) and human immunodeficiency virus type 1 (HIV-1) co-infected patients while receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) and a rifampicin (RMP)-containing anti-TB regimen. We analyzed data from the N2R study which was an open label, randomized, comparative trial comparing treatment outcomes between 71 TB/HIV-1 co-infected patients receiving efavirenz (EFV)-based and nevirapine (NVP)-based ART; all of whom were receiving RMP-containing anti-TB treatment. Demographic data, liver function test, CD4 cell count, plasma HIV-1 RNA, hepatitis B surface antigen and anti-hepatitis C virus antibody were collected before initiating ART (week 0). Liver enzymes and total bilirubin levels were monitored at 6 weeks, 12 weeks and 24 weeks after ART initiation. All patients were followed until TB therapy was completed. Of 142 patients, 8 patients were excluded. Among the remaining 134 patients, the mean+/-SD age was 36.8+/-8.6 years and 67.2% were male. Severe hepatotoxicity (grade 3 or 4) developed in 4 patients (2.9%); 3 patients (4.6%) in the NVP group and 1 patient (1.4%) in the EFV group. Severe hyperbilirubinemia (grade 3 or 4) occurred in 7 patients (5.2%); 5 patients (7.7%) in the NVP group and 2 patients (2.9%) in the EFV group. Grade 1 or 2 hepatotoxicity occurred in 34 patients (31.4%). Hepatitis C virus co-infection (adjusted OR 3.03; 95%CI 1.26 7.29) was an independent risk factor associated with grade 1-4 hepatotoxicity (p=0.013). Monitoring of hepatotoxicity should be considered in TB/HIV-1 co infected patients who are infected with HCV and receiving NVP. PMID- 21706944 TI - Drug susceptibility of Mycobacterium tuberculosis in patients with AIDS at a tertiary care hospital in northern India. AB - The study was done to determine the anti-tuberculosis drug resistance patterns of Mycobacterium tuberculosis (MTB) in AIDS patients. Fifty antiretroviral drug naive new AIDS patients with clinical evidence of pulmonary tuberculosis and no previous history of tuberculosis were recruited. Baseline CD4 counts and plasma viral loads (PVL) were measured by flow cytometry and RT-PCR, respectively. Sputum samples were obtained from each patient and subjected to Ziehl-Neelsen staining and cultured on Lowenstein-Jensen medium and using the BACTEC 460 system (B460). Antimicrobial susceptibilities were tested in all isolates using the B460 gystem. The occurrence of MTB was found to be more common with a PVL>4 log10 copies/ml (odds ratio: 4.6). Of 15 MTB isolates, 8 (53.3%) had single drug resistance, 4 (26.7%) had multidrug resistance (MDR) and 1 (6.7%) had resistance to three drugs (non-MDR). Two isolates (13.3%) were sensitive to all the four drugs. Resistance to first line anti-tuberculosis drugs was found to be higher among AIDS patients with MTB. PMID- 21706945 TI - Improvement of district hospital service system to increase treatment adherence among tuberculosis patients in Pakistan. AB - Adherence to medication regimen is essential for tuberculosis (TB) treatment success. We carried out quasi-experimental, single group intervention study at Rawalpindi District Hospital to improve TB patient treatment adherence using a Chronic Care Model (CCM). Ninety-nine newly diagnosed TB patients at the TB Clinic, Rawalpindi District Hospital, during February-March 2009, were included in the study. A set of four quality indicators were determined based on current scientific evidence: quality of service system, patient satisfaction, treatment adherence and cure rate. Care quality changes over time were analyzed by paired t test. Significant improvements in service quality were seen post-intervention. Overall, the hospital service system quality improved to "good" (from 1.0% to 28.3%), and patient satisfaction increased to "good" (10.2% to 54.1%). Treatment adherence increased (from 23.2% to 56.1%). The quarterly cure rate increased notably (5.3% to 17.2%). The overall mean scores for hospital service system quality, patient satisfaction, and TB patient treatment adherence, improved significantly 6 month post-intervention (p<0.001). PMID- 21706946 TI - Cutaneous miliary tuberculosis in a renal transplant patient: a case report and literature review. AB - The incidence of tuberculosis in renal transplant recipients is higher than in the general population. However, the incidence of cutaneous miliary tuberculosis in these patients is very rare. We report a 56-year-old renal transplant Thai man admitted to the hospital with prolong fever, dry cough and multiple small erythematous papules on his extremities. A chest X-ray revealed diffuse miliary infiltration. Mycobacterium tuberculosis DNA was demonstrated in bronchoalveolar lavage fluid by polymerase chain reaction. Histopathology of a skin biopsy showed poorly formed noncaseating granulomatous inflammation in the lower dermis and was positive for many acid-fast bacilli. Miliary tuberculosis of the lung and skin were diagnosed. The respiratory symptom and the skin lesions improved after treatment with anti-tuberculous drugs. PMID- 21706947 TI - Seroprevalence of Leptospira borgpetersenii serovar javanica infection among dairy cattle, rats and humans in the Cauvery river valley of southern India. AB - Leptospirosis is a major problem of dairy farms in Tamilnadu, India, resulting in abortions, stillbirths and infertility. Serologic and genetic analyses of samples from cattle, humans and rodents were performed in order to estimate infection prevalence and identify leptospiral species. Five hundred and fifteen sera and 76 urine samples were collected from dairy cattle on 25 farms including a farm that practiced rat control. Sera and kidney samples were also collected from field rats (Rattus norvegicus) in the vicinity of these farms. In addition, sera were collected from farm workers. Serum antibody was measured by the microscopic agglutination test. Leptospires isolated from blood, kidney, and urine were characterized as to serovar. Genomospecies were predicted using random amplified polymorphic DNA (RAPD) profiling. SecY gene sequencing was performed as a tool for tracing of source. Seroprevalence of 87.%, 51.% and 76.5% for cattle, rats and humans, respectively, was observed on endemic farms. Prevalences on a non endemic farm were lower. Antibodies to Autumnalis, Javanica, Icterohaemorrhagiae and Pomona predominated in both cattle and rats. Thirteen isolates from rat kidneys were identified as serogroup Javanica, serovar Javanica. RAPD comparisons and secY gene sequencing identified these isolates as Leptospira borgpetersenii. These results altogether indicated that L. borgpetersenii was the dominant species in these areas with serovar Javanica apparently derived from rats which provided an important source of infection in cattle resulting a high incidence of infertility, abortion and.still-birth in the Cauvery river valley, Tiruchirappalli, Tamilnadu. PMID- 21706948 TI - Bartonella seroprevalence in rural Thailand. AB - We estimated the prevalence of anti-Bartonella antibodies among febrile and non febrile patients presenting to community hospitals in rural Thailand from February 2002 through March 2003. Single serum specimens were tested for IgG titers to four Bartonella species, B. henselae, B. quintana, B. elizabethae and B. vinsonii subsp vinsonii using an indirect immunofluorescent assay. A titer 21:256 was considered positive. Forty-two febrile patients (9.9%) and 19 non febrile patients (19%) had positive serology titers to at least one Bartonella species. Age-standardized Bartonella seroprevalence differed significantly between febrile (10%) and non-febrile patients (18%, p=0.047), but did not differ by gender. Among all 521 patients, IgG titers 21:256 to B. henselae were found in 20 participants (3.8%), while 17 (3.3%) had seropositivity to B. quintana, 51 (9.8%) to B. elizabethae, and 19 (3.6%) to B. vinsonii subsp vinsonii. These results suggest exposure to Bartonella species is more common in rural Thailand than previously suspected. PMID- 21706949 TI - Risk factors and clinical outcomes of multidrug-resistant Acinetobacter baumannii bacteremia at a university hospital in Thailand. AB - Multidrug-resistant (MDR) Acinetobacter baumannii has become a major cause of hospital-acquired infection worldwide. There are few papers regarding this particular subject. Our aim was to assess the incidence of bacteremia due to MDR Acinetobacter baumannii, factors associated with the infection, and clinical outcomes. We studied 49 cases of A. baumannii bacteremia in adult patients admitted to a university hospital in Northeast Thailand between 2005 and 2007. The incidence of MDR A. baumannii bacteremia was 3.6 episodes per 10,000 hospital admissions. Significantly independent factors associated with MDR A. baumannii bacteremia were previous: 1) ICU admission [odds ratio (OR) 10.01; 95% confidence interval (CI) 1.39-72.20]; 2) use of beta-lactam/beta-lactamase inhibitor antibiotics (OR 8.06; 95%CI 1.39-46.64); and 3) use of a carbapenem antibiotics (OR 11.40; 95%CI 1.44-89.98). The overall mortality rate was significantly higher in the MDR group than in the susceptible group (91.7% vs 48%, respectively) (p=0.001). The significantly independent factors related to mortality were: 1) APACHE II score (OR 1.25; 95%CI 1.03-1.52) and 2) secondary bacteremia (OR 14.86; 95%CI 1.37-161.90). This study revealed the significantly independent factors associated with MDR A. baumannii bacteremia were prior ICU admission and prior use of broad spectrum antibiotics. This infection has a high mortality rate. Emphasis needs to be on prevention, strict application of infection control and appropriate use of antibiotics. PMID- 21706950 TI - Antimicrobial activity of Gynostemma pentaphyllum extracts against fungi producing aflatoxin and fumonisin and bacteria causing diarrheal disease. AB - Gynostemma pentaphyllum was investigated to determine its antimicrobial activities against human.and animal pathogens that produce aflatoxin, fumonisin, and diarrheal disease. The fungi were Aspergillusflavus, Aspergillus parasiticus and Fusarium verticillioides. The bacteria were Vibrio, Salmonella, Shigella, Escherichia coli and Staphylococcus aureus. G. pentaphyllum was extracted by five different methods. The obtained extracts were designated Extracts A, B, C, D and E. The results of the antifungal assay against A.flavus andA. parasiticus showed Extracts A and B at 10,000 ppm inhibited growth at 8-28%. Extracts A and B at 10,000 ppm also showed activity against F. verticillioides at 41-43%. Extract A, B and C were able to inhibit the tested strains better than the Extracts D and E. The MIC values of the extracts against gram-negative bacteria ranged from or=2 types) bacterial growth. All 4th version notes had mixed bacterial growth: gram-positive bacilli (79%), coagulase-negative staphylococci (75%), Staphylococcus aureus (38%), Klebsiella spp (21%), Pseudomonas spp (19%), Escherichia coli (9%), viridans group streptococci (VGS) (8%), and non-hemolytic streptococci (4%). Seventy-six percent of the newer 5th version notes had mixed bacterial growth: gram-positive bacilli (68%), coagulase-negative staphylococci (64%), S. aureus (13%), Klebsiella spp (9%), Pseudomonas spp (5%), E. coli (2%) and VGS (2%). These results indicate the Saudi one Riyal paper note is commonly contaminated with bacteria, and may act as a vehicle for the transmission of potentially pathogenic bacteria. The more the bill had been handled the greater the contamination was. PMID- 21706952 TI - Knowledge of sexual and reproductive health among adolescents attending school in Kelantan, Malaysia. AB - The objectives of this study were to describe the knowledge of sexual and reproductive health among adolescents attending school and to compare the levels of knowledge between males and females and between older and younger groups of adolescents. Across-sectional study was conducted among 1,034 secondary school students using a self administered validated questionnaire. The items with the fewest correct responses included: whether one can get pregnant after a single act of sexual intercourse (30.4%), whether sexual intercourse causes sexually transmitted diseases (STDs) (12.4%) and whether washing the vagina after sexual intercourse prevents pregnancy (17.0%). Their main source of sexual information was friends (64.4%). An independent t-test revealed the mean knowledge score was significantly higher among females than males on items assessing whether the genitalia may be touched freely by family members, females having attained menarche may become pregnant if having sex, whether pregnancy will occur if there is penetration of the penis into the vagina, whether premarital sexual intercourse causes pregnancy and if there is a relationship between abandoned babies and premarital pregnancies. The mean knowledge score assessing whether pregnancy can be prevented using condoms was higher among males than females. The mean knowledge scores were significantly higher among form four and form five students than forms one, two and three students. Lack of knowledge regarding important aspects of sexual and reproductive health warrant the need to strengthen sexual and reproductive health education. PMID- 21706953 TI - Effectiveness of a model of risky sexual behavior prevention among adolescent boys in Thailand. AB - The objectives of this study were to identify predictable factors affecting risky sexual behavior and to evaluate the effectiveness of a risky sexual behavior prevention program among boys one and two months after the program. The Information-Motivation-Behavioral skills (IMB) model program was carried out among 74 adolescent boys aged 10-13 years and 74 of their parents in Phitsanulok Province, Thailand. Repeated analysis was employed to analyze the program's effectiveness. After the program, mean scores for comfort in talking about sex, self-efficacy, and skills in condom use increased significantly (p<0.05), and mean scores regarding knowledge about sexually transmitted infections and skills in decision making decreased significantly (p<0.05) compared to baseline. Boys participating in this program improved their condom use skills and comfort talking about sex at two months follow-up (t=3.82, p<0.001; t=3.10, p=0.003, respectively). These results provided evidence for applicability of a prevailing theory-based intervention within the local cultural context. PMID- 21706954 TI - Evaluation of knowledge about protection against Crimean-Congo hemorrhagic fever. AB - This study was conducted in order to evaluate individuals' knowledge about protection against Crimean Congo hemorrhagic fever (CCHF). This descriptive study was carried out among 478 persons, to whom a Family Health Center located within boundaries of Erzurum Metropolitan Municipality, provides health service. A questionnaire form developed by the researchers was used for collecting data. Seventy-one point eight percent of individuals who participated in the study stated they had knowledge about CCHF, 25.9% stated that region was risky in terms of being bitten by ticks, 61.3% stated they could recognize ticks and 56.1% stated that not all tick bites cause the disease. Seventy-seven point eight percent stated CCHF is a virulent disease, 33.1% stated it can be transmitted from human to human and 30.3% stated it can be transmitted from animals to humans. In terms of protection from tick bites, 45, 15.3 and 11.3% of individuals stated wearing clothes to cover the whole body, carefully inspecting the body, and not touching ticks with bare hands, respectively, were good methods. Ninety two point one percent stated it is necessary to go to a healthcare organization immediately in case of tick bite, whereas 18% of individuals stated it is necessary to remove the tick with tweezers or forceps. The results of this study show most individuals are not well informed about methods for protecting against CCHF, for removing ticks and what precautions to take to protect against tick bites. PMID- 21706955 TI - Mental health assessment tool for older thai adults: development and psychometric testing. AB - The purpose of this study was to develop and test the psychometric properties of the Mental Health Assessment Tool for Older Thai Adults (MHAT-T), a 32-item self report questionnaire. Development of the MHAT-T was based on an exploratory sequential mixed methods design, where the results of the first method (qualitative) were used to develop the mental health assessment tool for older Thai adults. The initial questionnaire was composed of 100 items and carried out among 1,266 older Thai adults (aged 60 years and over), including Buddhists, Muslims, and Catholics in the northeastern, northern, central, and southern Thailand, and the Bangkok Metropolitan Area. The exploratory factor analysis, with an acceptable factor structure model, yielded 32 items aligned with five factors: family attachment, mental quality, community dignity and support, mental status, mental capacity. The preliminary psychometric properties demonstrated the internal consistency of the MHAT-T was at a high range of 0.76 to 0.87 and acceptable for a new instrument. The MHAT-T had an excellent content validity index score of 0.99. Test-retest reliability at two weeks was fair (0.54 to 1.00, p>0.001). A score of 92 of 106 points was classified as normal mental health. The MHAT-T served adequately as a newly captured construct and should be offered as a tool for assessing mental health among older Thai adults in the community. PMID- 21706956 TI - Increasing the national budget for medical care. Foreward. PMID- 21706957 TI - Seeking ways to revitalize the healthcare system--the role of national and local governments, the public, and individuals in the healthcare industry. PMID- 21706959 TI - The global trend in international accreditation of hospitals and the Kameda experience. PMID- 21706958 TI - Considering Japanese healthcare from an economist's perspective. PMID- 21706960 TI - Healthcare for the uninsured--is there a perfect storm brewing? PMID- 21706961 TI - Current status and issues of medical care and the long-term care insurance system for the old-old elderly in Japan. PMID- 21706962 TI - A case of laughter therapy that helped improve advanced gastric cancer. AB - We have reported the case of a patient diagnosed as having advanced gastric cancer at the age of 88 years old. An endoscopy revealed a type-2 gastric cancer of 25 x 30 mm in the lesser curvature of the middle stomach body and an IIa gastric cancer with T2 SS and cardiac accessory lesions. Both the type-2 and IIa lesions were defined as tub1 with surrounding atrophic gastritis and entero epithelium metaplastic carcinoma. Considering the patient's age and her desire not to receive cancer treatment, we prescribed laughter therapy as recommended by the Society for Healing Environment. The program was implemented in a laughter inducing environment and consisted of five stages: (1) Making the patient feel safe, (2) Relaxing the patient, (3) Increasing the effectiveness, (4) Improving her condition and (5) Increasing her joy of living. One year and seven months later, an endoscopy of the lesser curvature of the middle stomach body indicated that the lesions clearly improved with a morphological reduction into IIa + IIc masses. A tissue biopsy revealed that nucleus abnormality clearly improved from the initial diagnosis, with no irregularity in size. The suspected lesion was localized to a limited area near the stomach wall. Although partial gastric adenocarcinoma was suspected, the cancers turned into gastric adenoma, atrophic gastritis, and enteroepithelium metaplastic carcinoma. Now, five years after the initial diagnosis, she maintains a good condition. Laughter, one of our casual behaviors, has the effect of reducing the stress experienced by the human body. Laughter is expected to become alternative medicine in the future, and we hope to see more reports and evidence on soothing therapies using laughter. PMID- 21706963 TI - Consideration of grand design for the care environment in hospitals--smell, lighting and sound. AB - We investigated grand designs for the care environment in hospitals, focusing on smell, lighting and sound, based on a database of observed domestic general hospitals (12 institutions), consisting of 1235 photographs and descriptive data. As a result, we identified four areas that should be incorporated into grand designs for this type of care environment: [1] The smell environment with (1) the exclusion of "odors", and (2) regulation of "fragrances"; [2] the lighting environment with lighting that successfully incorporates nature; [3] the sound environment that incorporates (1) pleasant sounds, and (2) the exclusion of excess noise; and [4] a natural environment and a healing space where individuals can feel at ease. The most important challenges in reform of the care environment are an emphasis on an approach that employs the senses, and the necessity of raising the awareness of healthcare providers in relation to this type of environment. Although current hospital care environments are being improved through the independent efforts of hospitals themselves, we anticipate that the future will bring about a care environment in which more attention is paid to air quality, lighting and sound, when assessing, hospital function. PMID- 21706964 TI - The prevalence of pandemic (H1N1) 2009 in a suburb of Osaka city--based on reports on the temporary closing of classes. AB - An outbreak of pandemic (H1N1) 2009 occurred in May 2009 in Osaka and Kobe, Japan. We studied the prevalence of this strain of influenza in Yao City. According to the study, the frequency of temporary class closure did not vary significantly among the first to sixth grades of elementary schools; however, there was a markedly lower frequency of temporary closures among junior high school third-year classes. PMID- 21706965 TI - Health inequalities: is Japan a paradox? PMID- 21706966 TI - Do not cut consultants. PMID- 21706967 TI - Report highlights confusion about role of support workers. PMID- 21706968 TI - RCN alarmed by lack of nurse involvement in new GP consortia. PMID- 21706969 TI - DH wants safeguarding to be a local council legal responsibility. PMID- 21706970 TI - 'Indistinct' nurse consultant role is disappearing from view. PMID- 21706971 TI - My guide to clinical leadership: be yourself, listen and engage. PMID- 21706972 TI - Audit says older people who fall are denied proper care. PMID- 21706973 TI - Learning curve. AB - Midwives can find it difficult to broach the subject of eating disorders in antenatal clinics, yet they are as important to tackle as obesity. PMID- 21706974 TI - The right combination. AB - A community gynaecological service in the West Midlands combines GP and nursing skills to bring care closer to patients' homes. PMID- 21706975 TI - Putting it all together. AB - With an extensive career in cancer care, Catherine Gillespie is able to pull nursing and policy together. PMID- 21706976 TI - Improving the nursing care of patients with mesothelioma. AB - This article describes the establishment and work of the national Mesothelioma Nurse Action Team, a nursing initiative aimed at improving the care and support of people affected by mesothelioma in the UK. The incidence of mesothelioma is increasing and survival is poor, with more patients in the UK dying from mesothelioma than from malignant melanoma or cervical cancer. PMID- 21706977 TI - Traditional and complementary approaches to child health. AB - AIM: To explore primary care nurses' reported behaviour in consultations and their knowledge, beliefs and attitudes in relation to traditional and complementary approaches (TCA) for children. METHOD: Semi-structured, face-to face interviews were carried out with 15 nurses (practice nurses, nurse practitioners and health visitors) in north west London. Qualitative data were analysed using framework analysis. FINDINGS: Health visitors had greater knowledge and understanding of TCA than practice nurses or nurse practitioners, often informed by patients and personal experience. Health visitors reported that they discussed TCA with families using a culturally competent and family-centred approach to explain the advantages and disadvantages of TCA. This is probably made possible by their ongoing, close relationship with parents in the home environment and their focus on child health. Other primary care nurses were reluctant to engage with patients on TCA because of concerns about liability, lack of information and practice and policy constraints. CONCLUSION: Practice nurses and nurse practitioners may be able to improve their holistic and patient centred practice by learning from health visitors' experience, particularly cultural differences and safety issues. Nurses and their professional bodies may need to explore how this can be achieved given the time-limited and focused nature of practice-based consultations. PMID- 21706978 TI - Polypharmacy in older adults. AB - This article explores the issue of polypharmacy in older adults. The physiological changes in organ function in older people and the effect of this on pharmacokinetics and pharmacodynamics are discussed. The risks of adverse drug reactions and adverse drug interactions linked to polypharmacy are explored. Strategies to achieve optimal prescribing in older people are considered. PMID- 21706980 TI - Quick fix or citable source? PMID- 21706979 TI - Improving quality of life. PMID- 21706981 TI - Making big decisions. PMID- 21706982 TI - I'll meet you half way. PMID- 21706983 TI - The continuing challenge of preventing pressure ulcers. PMID- 21706984 TI - Preventing pressure ulcers in hospitals: A systematic review of nurse-focused quality improvement interventions. AB - BACKGROUND: A systematic review of the literature on nurse-focused interventions conducted in the hospital setting informs the evidence base for implementation of pressure ulcer (PU) prevention programs. Despite the availability of published guidelines, there is little evidence about which interventions can be successfully integrated into routine care through quality improvement (QI). The two previous literature syntheses on PU prevention have included articles from multiple settings but have not focused specifically on QI. METHODS: A search of six electronic databases for publications from January 1990 to September 2009 was conducted. Trial registries and bibliographies of retrieved studies and reviews, and Internet sites of funding agencies were also searched. Using standardized forms, two independent reviewers screened publications for eligibility into the sample; data were abstracted and study quality was assessed for those that passed screening. FINDINGS: Thirty-nine studies met the inclusion criteria. Most of them used a before-and-after study design in a single site. Intervention strategies included PU-specific changes in combination with educational and/or QI strategies. Most studies reported patient outcome measures, while fewer reported nursing process of care measures. For nearly all the studies, the authors concluded that the intervention had a positive effect. The pooled risk difference for developing PUs was -.07 (95% confidence interval [CI]: -0.0976, -0.0418) comparing the pre- and postintervention status. CONCLUSION: Future research can build the evidence base for implementation through an increased emphasis on understanding the mechanisms by which improved outcomes are achieved and describing the conditions under which specific intervention strategies are likely to succeed or fail. PMID- 21706985 TI - Identifying gaps, barriers, and solutions in implementing pressure ulcer prevention programs. AB - BACKGROUND: Patients continue to suffer from pressure ulcers (PUs), despite implementation of evidence-based pressure ulcer (PU) prevention protocols. In 2009, Joint Commission Resources (JCR) and Hill-Rom created the Nurse Safety Scholar-in-Residence (nurse scholar) program to foster the professional development of expert nurse clinicians to become translators of evidence into practice. The first nurse scholar activity has focused on PU prevention. Four hospitals with established PU programs participated in the PU prevention implementation project. PU PREVENTION IMPLEMENTATION PROJECT: Each hospital's team completed an inventory of PU prevention program components and provided copies of accompanying documentation, along with prevalence and incidence data. Site visits to the four participating hospitals were arranged to provide opportunities for more in-depth analysis and support. Following the initial site visit, the project team at each hospital developed action plans for the top three barriers to PU program implementation. A series of conference calls was held between the site visits. YEAR 1 PROJECT RESULTS: Pressure Ulcer Program Gaps and Recommendations. The four hospitals shared common gaps in terms of limitations in staff education and training; lack of physician involvement; limited involvement of unlicensed nursing staff; lack of plan for communicating at-risk status; and limited quality improvement evaluations of bedside practices. Detailed recommendations were identified for addressing each of these gaps. these CONCLUSIONS: Recommendations for eliminating gaps have been implemented by the participating teams to drive improvement and to reduce hospital-acquired PU rates. The nurse scholars will continue to study implementation of best practices for PU prevention. PMID- 21706986 TI - Multipayer patient-centered medical home implementation guided by the chronic care model. AB - BACKGROUND: A unique statewide multipayer ini Pennsylvania was undertaken to implement the Patient-Centered Medical Home (PCMH) guided by the Chronic Care Model (CCM) with diabetes as an initial target disease. This project represents the first broad-scale CCM implementation with payment reform across a diverse range of practice organizations and one of the largest PCMH multipayer initiatives. METHODS: Practices implemented the CCM and PCMH through regional Breakthrough Series learning collaboratives, supported by Improving Performance in Practice (IPIP) practice coaches, with required monthly quality reporting enhanced by multipayer infrastructure payments. Some 105 practices, representing 382 primary care providers, were engaged in the four regional collaboratives. The practices from the Southeast region of Pennsylvania focused on diabetes patients (n = 10,016). RESULTS: During the first intervention year (May 2008-May 2009), all practices achieved at least Level 1 National Committee for Quality Assurance (NCQA) Physician Practice Connections Patient-Centered Medical Home (PPC-PCMH) recognition. There was significant improvement in the percentage of patients who had evidence-based complications screening and who were on therapies to reduce morbidity and mortality (statins, angiotensin-converting enzyme inhibitors). In addition, there were small but statistically significant improvements in key clinical parameters for blood pressure and cholesterol levels, with the greatest absolute improvement in the highest-risk patients. CONCLUSIONS: Transforming primary care delivery through implementation of the PCMH and CCM supported by multipayer infrastructure payments holds significant promise to improve diabetes care. PMID- 21706987 TI - A systematic review of failures in handoff communication during intrahospital transfers. AB - BACKGROUND: Handoffs serve a critical function in ensuring patient care continuity during transitions of care. Studies to date have predominantly focused on intershift handoffs, with relatively little attention given to intrahospital transfers. A systematic literature review was conducted to characterize the nature of handoff failures during intrahospital transfers and to examine factors affecting handoff communication and the effectiveness of current interventions. METHODS: Primary studies investigating handoff communication between care providers during intrahospital transfers were sought in the English-language literature between 1980 and February 2011. Data for study design, population characteristics, sample size, setting, intervention specifics, and relevant outcome measures were extracted. DATA SYNTHESIS: Study results were summarized by the impact of communication breakdown during intrahospital transfer of patients, and the current deficiencies in the process. Results of interventions were summarized by their effect on the quality of handoff communication and patient safety. FINDINGS: The initial search identified 516 individual articles, 24 of which satisfied the inclusion criteria. Some 19 were primary studies on handoff practices and deficiencies, and the remaining 5 were interventional studies. The studies were categorized according to the clinical settings involved in the intrahospital patient transfers. CONCLUSIONS: There is consistent evidence on the perceived impact of communication breakdown on patient safety during intrahospital transfers. Exposure of handoffs at patient transfers presents challenges that are not experienced in intershift handoffs. The distinct needs of the specific clinical settings involved in the intrahospital patient transfer must be considered when deciding on suitable interventions. PMID- 21706988 TI - A survey of the use of time-out protocols in emergency medicine. AB - BACKGROUND: Time-outs, as one of the elements of the Joint Commission Universal Protocol for Preventing Wrong Site, Wrong Procedure, and Wrong Person Surgery has been in effect since July 1, 2004. Time-outs are required by The Joint Commission for all hospital procedures regardless of location, including emergency departments (EDs). Attitudes about ED time-outs were assessed for a sample of senior emergency physicians serving in leadership roles for a national professional society. METHODS: A survey questionnaire was administered to members of the American College of Emergency Physicians (ACEP) Council at the October 2009 ACEP Council meeting on the use of time-outs in the ED. A total of 225 (72%) of the 331 councilors present filled out the survey. RESULTS: Twenty-nine (13%) of respondents were unaware of a formal time-out policy in their ED, 79 (35%) reported that ED time-outs were warranted, and 5 (2%) reported they knew of an instance where a time-out may have prevented an error. Chest tubes (167 respondents [74%]) and the use of sedation (142 respondents [63%]) were most commonly identified as ED procedures that necessitated a time-out. Episodes of any wrong-site error in their EDs were reported by 16 (7%) of the respondents. Wrong patient (9 respondents [4%]) and wrong procedure (2 respondents [1%]) errors were less common. CONCLUSIONS: Although the time-out requirement has been in effect since 2004, more than 1 in 10 of ED physicians in this sample ofED physician leaders were unaware of it. According to the respondents, medical errors preventable by time-outs were rare; however, time-outs may be useful for certain procedures, particularly when there is a risk of wrong-site, wrong patient, or wrong-procedure medical errors. PMID- 21706989 TI - A moment in history and a time for celebration: the performance of nursing and midwifery in Excellence in Research for Australia. PMID- 21706990 TI - National regulation in Australia: a time for standardisation in roles and titles. AB - BACKGROUND: The past few years has seen a growth in the number of new nursing roles and position titles in many countries, including Australia. The Australian situation is unique due to the lack of professional engagement and debate in determining the purpose of some of these new positions. Often these new roles have been poorly defined, and there is no national consistency in nomenclature. The recent move to a national nursing registration system provides an opportunity for change. METHOD: Discursive paper. RESULTS: New roles arise for a number of reasons, including a change in function or title for a preexisting role or in response to the establishment a completely new position. However, the lack of a co-ordinated approach to introduction of new roles may lead to role proliferation (the rapid increase or spread of new positions and position titles), role blurring (where the boundaries of different positions become less distinct) and role confusion (where both nurses and health system clients experience a lack of clarity regarding the precise scope of roles). CONCLUSION: Professional nursing practice is defined by the impact on patient outcomes, not by position titles. As such, the potential positive impact of a new role on patient outcomes should be the primary consideration when considering its introduction. National regulation of the profession provides an opportunity for the profession to debate and determine some consistency in position titles, responsibilities and areas of specialty practice. PMID- 21706991 TI - The role of nurses and midwives in the governance of local health networks. AB - Current health reforms in Australia will establish local health networks of public hospitals each with a governing body. The establishment of these governing bodies, particularly in states like NSW where these entities do not currently exist within the public hospital system, provides opportunities for nurses, midwives and other clinicians to seek appointment to them. The policy and discussion papers on the establishment of the local health networks promise that local clinicians will be appointed to these governing bodies. Debate within the nursing and midwifery profession seems focused on the management of nursing and midwifery services within the new local health networks and not on the role of nurses and midwives on governing bodies. Nurses and midwives undoubtedly have a role to play on these governing councils, however there are a range of issues that should be considered on the role that nurses, midwives (and other clinicians) will play when appointed to the governing councils to ensure that they can appropriately undertake the role of a council member. The role of governance differs from that of management and clinicians who aspire to appointment of these governing bodies should be aware of the difference in these roles. PMID- 21706992 TI - Sustaining and growing the rural nursing and midwifery workforce: understanding the issues and isolating directions for the future. AB - Nurses and midwives represent the largest group of health professionals in the Australian health care system. In rural environments nurses and midwives make up a greater proportion of the health workforce than in urban settings, which makes their role in service provision even more significant. The role and scope of these nurses and midwives' practice is by necessity more generalist than specialist, which results in disciplinary strengths and weaknesses. As generalist health professionals they work in diverse settings such as public hospitals, multi-purpose services, community health, aged care and in non-government and private for profit and no-profit organisations including general practices. Their scope of practice covers prevention, intervention and rehabilitation and is lifespan inclusive. Rural nurses and midwives are older than their metropolitan based counterparts, work part-time and traditionally have limited access to professional development often due to ineffective locum relief programs. Workplace inflexibility, access to acceptable housing and partner employment are factors cited as inhibitors to growing this workforces. The future of the rural nursing and midwifery workforce will only be secured if Government invests to a greater degree in both education and training and the development of a nationally agreed remuneration scale that allows for part-time work. PMID- 21706993 TI - An exploration of the role and scope of the clinical nurse consultant (CNC) in a metropolitan health service. AB - INTRODUCTION: Clinical nurse consultants have been a part of the nursing workforce for some time however a lack of clarity regarding this role has led to significant variations in health service expectations, workloads and scope for the Clinical nurse consultants working within this metropolitan health service. AIM: The aim of this study was to explore the role of the CNC as it is perceived by them, in the context of this health service. METHOD: A qualitative approach was used for this study. Following ethics approval a single audio-taped focus group was undertaken to gather data. Guiding questions were used to elicit responses from the group, moderated by the co-investigators. The focus group was transcribed verbatim. Each researcher independently analysed the narrative data, using coding and clustering the data to develop primary and sub-themes. RESULTS: Whilst each participant experiences their role individually, there were four themes derived from comments expressed by the participants: 'Diversity and conflict', 'Leaders but powerless', 'Support systems' and 'The portfolio holder role'. CONCLUSION: The role of the Clinical nurse consultant is complex and diverse. The variability in the role suggests that organisational consensus of the role, scope and purpose of the CNC position has not been actualised, resulting in a lack of support systems, and an underutilisation of the Clinical nurse consultants as leaders, where they can challenge existing practice and guide future directions in care delivery. PMID- 21706994 TI - Maintaining oral health during pregnancy: perceptions of midwives in Southwest Sydney. AB - Current evidence highlights the importance of maintaining good oral health during pregnancy, unfortunately, many women in Australia do not access dental services at this time. Compounding the situation is the lack of importance placed on the value of good maternal oral health by prenatal care providers. These constraints highlight the potential value of having preventive oral health advice and referral to an appropriate care pathway during the prenatal period. Midwives are in an excellent position to offer such a service, although the specific aspects of the role have not been clearly defined in Australia. As a preliminary step to the development of an oral health service program, initiated by midwives, this study assesses the midwives' perceptions of such an approach. Data were collected for this qualitative study via a focus group with 15 midwives. Thematic analyses of the data showed that despite the high prevalence of poor oral health in the area, most midwives were unaware of its possible ill-effects on maternal and child health. Midwives were also reluctant to discuss oral health with pregnant women because of a lack of appropriate referral pathways to the Public Dental Services. Midwives were receptive to the idea of establishing this new service but highlighted barriers such as the time involved, the competencies required and the need for referral pathways. The findings suggest that a midwifery-initiated oral health service has potential although issues such as training, time constraints and referral pathways must be addressed. PMID- 21706995 TI - Women with breast cancers' preferences for surveillance follow-up. AB - BOCKGROUND: On completion of treatment people with breast cancer are offered surveillance at a hospital clinic and/or in primary care. It is unclear whom patients prefer to consult about their problems following cancer treatment. METHOD: Patients being followed up by a hospital nurse were surveyed at their follow-up appointment and three months later. The survey included demographic information, symptom profile, and the Patient Enablement Index (PEI). A subsequent survey of the patients' general practitioners (GPs)s confirmed which patients had consulted their GP prior to the nurse appointment. Three months after their appointment patients completed the PEI and were surveyed about their preference of practitioner for problems following treatment. RESULTS: 101 patients responded to the first survey and 60 patients to the follow-up survey. In 68% of cases women reported that they did not consult their GP about breast cancer related symptoms prior to their appointment at the clinic, choosing instead to present to a Breast Care Nurse (BCN). In the survey patients preferred their GP if they needed a physical examination (p = 0.007) or referral to a specialist (p <0.001). Older patients were more likely to choose a BCN if they wanted a mammogram and a GP if they wanted a physical exam or emotional support. The PEI scores after follow-up with the BCNs were equivalent to those reported following GP consultations. CONCLUSION: Patients prefer their GP overall, but we observed that the majority of women did not consult their GP when they had scheduled appointments with a BCN at a hospital clinic. PMID- 21706996 TI - Qualitative content analysis of suicidal ideation in Korean college students. AB - The suicide rate for ages 15-24 increased recently in South Korea. The purpose of this study was to understand the suicidal ideation using the qualitative content analysis in South Korean college students. The data were collected with non structured open questions in 134 college students and were analyzed with qualitative content analysis. The collected materials were classified 2 categories, 6 themes, and 21 theme clusters. Two categories are emerged: (1) facilitators of suicidal ideation, and (2) inhibitors of suicidal ideation. This study identified that the facilitators of suicidal ideation are physical, psychological and societal concerns, and suggested that the inhibitors of suicidal ideation are influenced by religious and cultural context. These results presented that Buddhism and Confucianism had influence on reasons to not attempting suicide behavior as the inhibitor of suicidal ideation. In conclusion, cultural context should be considered to develop strategies for the suicide prevention in South Korean college student. PMID- 21706997 TI - The theory-practice gap and skill acquisition: an issue for nursing education. AB - Matching textbook descriptions of clinical situations with the reality of practice is an ongoing problem faced by members of the nursing profession and is commonly referred to as the "theory-practice gap". This ubiquitous gap is inevitably encountered by all nurses at various times; yet it is widely agreed that it is student nurses--given their novice, rule governed status--who find themselves in the midst of the theory-practice void. This paper will discuss the nature of the theory-practice gap and skill acquisition, in relation to a personal experience of mine as an undergraduate nursing student, and its significance in relation to student anxiety levels, nurse education (specifically the roles of the classroom teacher and clinical educators), teaching methods and the responsibility of the student to become accountable for their own education. I intend to communicate how my personal situation was dealt with and evaluate that experience in relation to current nursing literature. Ultimately, this discussion will demonstrate the value of reflection underpinning the development of competency in nursing and its role in bridging the theory-practice gap. PMID- 21706998 TI - Fixes for failing organs. PMID- 21706999 TI - A network of networks. PMID- 21707000 TI - In his own words. PMID- 21707001 TI - A shave, a haircut--and a kidney? PMID- 21707002 TI - The matchmaker. PMID- 21707004 TI - The case for collegiality. PMID- 21707003 TI - Learning from experience. PMID- 21707005 TI - Physicians generate jobs in Minnesota. PMID- 21707006 TI - Ed Ratner, M.D. PMID- 21707008 TI - Minnesota firsts: a timeline of transplant milestones. PMID- 21707007 TI - The new transplant patient. PMID- 21707009 TI - The first and last days of medicine. PMID- 21707010 TI - Stem cell research in Minnesota: here today, gone tomorrow? PMID- 21707011 TI - Special treatment--the story of Medicare's ESRD entitlement. PMID- 21707012 TI - Bundled payment for ESRD--including ESAs in Medicare's dialysis package. PMID- 21707013 TI - Hand transplantation. AB - The first successful hand transplant was performed in 1998, opening up a new possibility for patients who have suffered mutilating hand injuries. Since then, more than 60 such procedures have been performed throughout the world. This article describes the evolution of hand transplantation, outcomes of patients listed in the International Registry of Hand and Composite Tissue Transplantation, and ethical issues involved in hand transplantation. It also describes the hand transplantation program at Mayo Clinic, which was established in 2010. PMID- 21707014 TI - Regenerative medicine: a reality of stem cell technology. AB - Regenerative medicine aims to restore homeostasis through a broad spectrum of strategies ranging from transplantation of donor organs to augmentation of innate healing processes. Its first clinical application emerged five decades ago when bone marrow-derived stem cells were used to replace defective progenitor cells. Since then, a variety of technological advances have expanded its scope. Most recently, the advent of natural or bioengineered stem cell products for tissue repair has inspired hope that the toughest obstacles in transplant medicine--the shortage of organs and organ rejection--might be overcome.This article describes the evolution of regenerative medicine and some of the ways it is being used in research and clinical practice. PMID- 21707015 TI - The ACO dilemma: should we or shouldn't we? PMID- 21707016 TI - Central retinal vein occlusion after intense exercise: response to intravitreal bevacizumab. AB - A 40-year-old male athlete developed a central retinal vein occlusion after intense exercise and secondary dehydration. A comprehensive systemic evaluation was within the normal range. After a series of 11 intravitreal injections of bevacizumab over a 24-month period, spectral-domain optical coherence tomography showed resolution of macular edema with a 55-letter gain in visual acuity. PMID- 21707017 TI - The effect of corneal anterior surface eccentricity on astigmatism after cataract surgery. AB - BACKGROUND AND OBJECTIVE: To evaluate the effect of cornea eccentricity on induced astigmatism after cataract surgery. PATIENTS AND METHODS: The study included 125 eyes of 87 patients. Preoperative corneal astigmatism, pachymetry, and eccentricity were measured. During cataract surgery, the location of the main incision (2.8-mm clear corneal) was selected to be either superior, superior nasal, superior-temporal, nasal, or temporal to decrease the preexisting corneal astigmatism. Aspheric intraocular lenses were implanted. Keratometry and manifest refraction were recorded 6 months after surgery. Astigmatism was calculated using vector subtraction software. RESULTS: Three parameters significantly affected postoperative astigmatism: preoperative amount of corneal astigmatism, eccentricity of anterior cornea, and location of the main incision. The mean surgically induced astigmatism (SIA) was calculated to be: superior = 0.82 diopters (D), superior-nasal = 0.50 D, superior-temporal = 0.63 D, temporal = 0.45 D, and nasal = 0.55 D. Superior incision induced the greatest SIA and temporal incision induced the smallest SIA. The eccentricity of anterior cornea showed significantly positive correlation with the amount of SIA (P < .001). The preoperative corneal cylinder power showed significantly positive correlation with the amount of SIA (P < .001). CONCLUSION: Postoperative astigmatism was affected by various factors in cataract surgery. The greatest postoperative astigmatism is expected in corneas with high anterior eccentricity, high preoperative corneal astigmatism, and superior location of the main incision. PMID- 21707018 TI - Engaging learners across generations: the progressive professional development approach. PMID- 21707019 TI - Evaluating an activity: beyond the "form". AB - Activity evaluation has often focused on the "evaluation form." Other strategies for activity evaluation open the door to focus on knowledge gained and application of learning in practice. The outcome of the learning activity can then be more accurately determined. PMID- 21707020 TI - A multifaceted approach to improve the care of hospitalized older adults. AB - This column discusses a multifaceted approach to improve the care of hospitalized older adults. PMID- 21707021 TI - Focusing on nurses' strengths. AB - Research has demonstrated the importance of an engaged work force. Nurses are engaged when they work in jobs that actualize their strengths. PMID- 21707023 TI - The Revised Bloom's Taxonomy: implications for educating nurses. AB - One of the essential goals for continuing education in nursing is to enhance nurses' ability to improve patient care outcomes. Toward this goal, learners need to transfer learned knowledge to actual practice. Achieving effective transfer requires knowledge of thinking paradigms in relation to specific subject content. Educators can facilitate knowledge transfer by developing instructional designs that incorporate subject content and cognitive processes related to the use of the subject content. However, it is difficult to develop such instructional designs. The Revised Bloom's Taxonomy provides a framework for meeting this educational need. In this article, the authors establish the relevance of the Revised Bloom's Taxonomy to continuing education and describe how to use the taxonomy to plan an educational session with an emphasis on promoting knowledge transfer. PMID- 21707024 TI - A high quantum efficiency preserving approach to ligand exchange on lead sulfide quantum dots and interdot resonant energy transfer. AB - We present a new approach to ligand exchange on lead sulfide (PbS) quantum dots (QDs) in which the QDs are reacted with preformed Pb cation-ligand exchange units designed to promote reactions that replace surface Pb and oleate groups on the as grown QDs. This process introduces negligible surface defects as the high quantum efficiency (~55%) of the as-grown QDs is maintained. Infrared spectroscopy and electron microscopy are used to confirm the replacement of ligands and time resolved photoluminescence to demonstrate the expected inverse sixth power dependence of the nonradiative resonant energy transfer rate on inter-QD spacing. PMID- 21707025 TI - Synthesis of a pladienolide B analogue with the fully functionalized core structure. AB - Starting from (R)-(-)-linalool (6), terminus differentiation and chain extension via aldol type reactions led to ketophosphonate 16 (C1-C8 building block). In a Horner-Wadsworth-Emmons reaction, 16 reacted with aldehyde 22, which contained the vicinal anti-Me-OH pattern and a vinyl iodide function, to provide the C1-C13 part of pladienolide B. After Shiina macrolactonization, reduction of the enone 26 gave the core structure 27. A Stille cross-coupling of vinyl iodide 27 with tributylphenylstannane eventually furnished analogue 30. PMID- 21707026 TI - Silver triflate-catalyzed cyclopropenation of internal alkynes with donor /acceptor-substituted diazo compounds. AB - Silver triflate was found to be an efficient catalyst for the cyclopropenation of internal alkynes using donor-/acceptor-substituted diazo compounds as carbenoid precursors. Highly substituted cyclopropenes, which cannot be synthesized directly via rhodium(II)-catalyzed carbenoid chemistry, can now be readily accessed. PMID- 21707027 TI - Robust control of microdomain orientation in thin films of block copolymers by zone casting. AB - Block copolymers with chemically immiscible segments exhibit a variety of microphase-separated nanostructures on the scale of 10-100 nm. Controlling the orientation of these microphase separated nanostructures is vital in many applications such as lithography, membranes, data storage, and so forth. Typical strategies involve the use of external fields or patterned substrates. Here, we report a robust zone casting technique to achieve highly ordered thin films of block copolymers on centimeter-scale substrates. The robustness of this technique is its powerful control on diverse morphologies and exceptional tolerance on versatility of block copolymer chemistry as well as allowance of a wide spectrum of substrates. We demonstrate that perpendicular orientations with respect to the surface are achieved for block copolymers with both lamellar and cylindrical morphologies by controlling solution casting rate, temperatures, and block copolymer chemical structures. Thin films of both noncrystalline and crystalline block copolymers exhibit excellent orientational order and lateral order. However, the lateral order in the thin films of crystalline block copolymers shows dependence on casting temperature and melting temperature of the crystalline segment. Remarkably, all the ordering is independent of the substrates on which the block copolymer films are cast. PMID- 21707028 TI - A highly selective redox, chromogenic, and fluorescent chemosensor for Hg2+ in aqueous solution based on ferrocene-glycine bioconjugates. AB - The synthesis, electrochemical, optical, and metal-cation-sensing properties of ferrocene-glycine conjugates C(30)H(38)O(8)N(8)Fe (2) and C(20)H(24)O(4)N(4)Fe (3) have been documented. Both compounds 2 and 3 behave as very selective redox (DeltaE(1/2) = 217 mV for 2 and DeltaE(1/2) = 160 mV for 3), chromogenic, and fluorescent chemosensors for Hg(2+) cations in an aqueous environment. The considerable changes in their absorption spectra are accompanied by the appearance of a new low-energy peak at 630 nm (2, epsilon = 1600 M(-1) cm(-1); 3, epsilon = 822 M(-1) cm(-1)). This is also accompanied by a strong color change from yellow to purple, which allows a prospective for the "naked eye" detection of Hg(2+) cations. These chemosensors present immense brightness and fluorescence enhancement (chelation-enhanced fluorescence = 91 for 2 and 42 for 3) following Hg(2+) coordination within the limit of detection for Hg(2+) at 7.5 parts per billion. PMID- 21707029 TI - Specialisation of the venom gland proteome in predatory cone snails reveals functional diversification of the conotoxin biosynthetic pathway. AB - Conotoxins, venom peptides from marine cone snails, diversify rapidly as speciation occurs. It has been suggested that each species can synthesize between 1000 and 1900 different toxins with little to no interspecies overlap. Conotoxins exhibit an unprecedented degree of post-translational modifications, the most common one being the formation of disulfide bonds. Despite the great diversity of structurally complex peptides, little is known about the glandular proteins responsible for their biosynthesis and maturation. Here, proteomic interrogations on the Conus venom gland led to the identification of novel glandular proteins of potential importance for toxin synthesis and secretion. A total of 161 and 157 proteins and protein isoforms were identified in the venom glands of Conus novaehollandiae and Conus victoriae, respectively. Interspecies differences in the venom gland proteomes were apparent. A large proportion of the proteins identified function in protein/peptide translation, folding, and protection events. Most intriguingly, however, we demonstrate the presence of a multitude of isoforms of protein disulfide isomerase (PDI), the enzyme catalyzing the formation and isomerization of the native disulfide bond. Investigating whether different PDI isoforms interact with distinct toxin families will greatly advance our knowledge on the generation of cone snail toxins and disulfide-rich peptides in general. PMID- 21707030 TI - Up-regulated desaturase and elongase gene expression promoted accumulation of polyunsaturated fatty acid (PUFA) but not long-chain PUFA in Lates calcarifer, a tropical euryhaline fish, fed a stearidonic acid- and gamma-linoleic acid enriched diet. AB - The limited activity of Delta6 fatty acid desaturase (FAD6) on alpha-linolenic (ALA, 18:3n-3) and linoleic (LA, 18:2n-6) acids in marine fish alters the long chain (>=C(20)) polyunsaturated fatty acid (LC-PUFA) concentration in fish muscle and liver when vegetable oils replace fish oil (FO) in aquafeeds. Echium oil (EO), rich in stearidonic acid (SDA, 18:4n-3) and gamma-linoleic acid (GLA, 18:3n 6), may enhance the biosynthesis of n-3 and n-6 LC-PUFA by bypassing the rate limiting FAD6 step. Nutritional and environmental modulation of the mechanisms in LC-PUFA biosynthesis was examined in barramundi, Lates calcarifer , a tropical euryhaline fish. Juveniles were maintained in either freshwater or seawater and fed different dietary LC-PUFA precursors present in EO or rapeseed oil (RO) and compared with FO. After 8 weeks, growth of fish fed EO was slower compared to the FO and RO treatments. Irrespective of salinity, expression of the FAD6 and elongase was up-regulated in fish fed EO and RO diets, but did not lead to significant accumulation of LC-PUFA in the neutral lipid of fish tissues as occurred in the FO treatment. However, significant concentrations of eicosapentaenoic acid (EPA, 20:5n-3) and arachidonic acid (ARA, 20:4n-6), but not docosahexaenoic acid (DHA, 22:6n-3), appeared in liver and, to a lesser extent, in muscle of fish fed EO with marked increases in the phospholipid fraction. Fish in the EO treatment had higher EPA and ARA in their liver phospholipids than fish fed FO. Endogenous conversion of dietary precursors into neutral lipid LC-PUFA appears to be limited by factors other than the initial rate-limiting step. In contrast, phospholipid LC-PUFA had higher biosynthesis, or selective retention, in barramundi fed EO rather than RO. PMID- 21707031 TI - Phlorhizin protects against erythrocyte cell membrane scrambling. AB - Phlorhizin interferes with glucose transport. Glucose depletion triggers suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling. Eryptosis is further triggered by oxidative stress. The present study explored whether phlorhizin influences eryptosis following glucose depletion or oxidative stress. Cell membrane scrambling was estimated from annexin binding, cell volume from forward scatter (FSC), and cytosolic Ca(2+) concentration from Fluo-3 fluorescence. Phlorhizin (10-100 MUM) added alone did not modify scrambling, FSC, or Fluo-3 fluorescence. Glucose depletion (48 h) significantly increased Fluo-3 fluorescence, decreased FSC, and increased annexin binding, effects in part significantly blunted by phlorhizin (annexin binding >= 10 MUM, FSC >= 50 MUM). Oxidative stress (30 min 0.3 mM tert-butylhydroperoxide) again significantly increased Fluo-3 fluorescence and triggered annexin binding, effects again in part significantly blunted by phlorhizin (Fluo-3 fluorescence >= 50 MUM, annexin-binding >= 10 MUM). Phlorhizin did not blunt the cell shrinkage induced by oxidative stress. The present observations disclose a novel effect of phlorhizin, that is, an influence on suicidal erythrocyte death following energy depletion and oxidative stress. PMID- 21707032 TI - Potential health implication of in vitro human low-density lipoprotein-vitamin E oxidation modulation by polyphenols derived from Cote d'Ivoire's oil palm species. AB - Antioxidant activities of polyphenolic compounds extracted (PPEs) from ripe fruits of oil palms are investigated by studying their in vitro effects on human low-density lipoprotein (LDL) oxidation. Four oil palm species ( Elaeis guineensis ) are issued from the National Centre of Agronomic Research of Cote d'Ivoire, of which two are parental varieties (HP1 and HP2), while the other two are crossing varieties (HP3 and HP4). The main identified compounds were rutin (HP3 and HP4) and caffeic and chlorogenic (5-caffeoyl quinic) acids (HP1, HP3, and HP4). The highest total phenolic content was found for HP4, while it was significantly lower for HP2. Antioxidative effects were monitored by Cu(2+)- or 2,2'-azobis(2-amidinopropane) hydrochloride (AAPH)-induced generation of conjugated dienes (lag time and oxidation rate). The highest PPE specific antioxidant activity (SAA) values were obtained with crossing varieties (HP3 and HP4) in the copper-oxidation assay. In the AAPH-oxidation assay, SAA values were comparable for all four varieties. PPEs were effective at preventing LDL-vitamin E depletion in vitro. They could exert direct beneficial antioxidant effects on vitamin E and other antioxidants contained in food and beverages in vivo, within the gastrointestinal (GI) tract. These data could also be of particular importance for a healthier nutrition or the management of chronic diseases by a polyphenol-rich diet. PMID- 21707033 TI - Ordered complex structures formed by paramagnetic particles via self-assembly under an ac/dc combined magnetic field. AB - We apply ac and dc magnetic fields simultaneously in orthogonal directions to each other to a solution, in which paramagnetic microparticles are dispersed, and show that complex secondary structures composed of oscillating chain clusters, that is, long linear clusters interconnected by T-, L-, and criss-cross junctions, are self-assembled. Disklike clusters are formed at some junctions and the number of disklike clusters increases as the frequency of the ac magnetic field increases. We finally show that the angle between long linear clusters can be altered by changing the ratio of the intensities of the ac and dc magnetic fields. PMID- 21707034 TI - Influence of the degree of ionization and molecular mass of weak polyelectrolytes on charging and stability behavior of oppositely charged colloidal particles. AB - Positively charged amidine latex particles are studied in the presence of poly(acrylic acid) (PAA) with different molecular masses under neutral and acidic conditions by electrophoresis and time-resolved dynamic light scattering. Under neutral conditions, where PAA is highly charged, the system is governed by the charge reversal induced by the quantitatively adsorbing polyelectrolyte and attractive patch-charge interactions. Under acidic conditions, where PAA is more weakly charged, the following two effects come into play. First, the lateral structure of the adsorbed layers becomes more homogeneous, which weakens the attractive patch-charge interactions. Second, polyelectrolyte adsorption is no longer quantitative and partitioning into the solution phase is observed, especially for PAA of low molecular mass. PMID- 21707035 TI - Evaluating nanoparticle sensor design for intracellular pH measurements. AB - Particle-based nanosensors have over the past decade been designed for optical fluorescent-based ratiometric measurements of pH in living cells. However, quantitative and time-resolved intracellular measurements of pH in endosomes and lysosomes using particle nanosensors are challenging, and there is a need to improve measurement methodology. In the present paper, we have successfully carried out time-resolved pH measurements in endosomes and lyosomes in living cells using nanoparticle sensors and show the importance of sensor choice for successful quantification. We have studied two nanoparticle-based sensor systems that are internalized by endocytosis and elucidated important factors in nanosensor design that should be considered in future development of new sensors. From our experiments it is clear that it is highly important to use sensors that have a broad measurement range, as erroneous quantification of pH is an unfortunate result when measuring pH too close to the limit of the sensitive range of the sensors. Triple-labeled nanosensors with a pH measurement range of 3.2-7.0, which was synthesized by adding two pH-sensitive fluorophores with different pK(a) to each sensor, seem to be a solution to some of the earlier problems found when measuring pH in the endosome-lysosome pathway. PMID- 21707036 TI - Metal ion coordination with an asymmetric fan-shaped dendrimer at the air-water interface. AB - Metal coordination to monolayers of 4-{10-[4-(3,5-bis-benzyloxy)-phenyl] anthracen-9-yl}-benzoic acid ([G1-An]-CO(2)H, G1) and 4-(10-{4-[3,5-bis-(3,5-bis benzyloxy)-benzyloxy]-phenyl}-anthracen-9-yl)-benzoic acid ([G2-An]-CO(2)H, G2) at the air-water interface and to Langmuir-Blodgett (LB) films was investigated using surface pressure-area isotherms, ultraviolet-visible (UV-vis) spectroscopy, atomic force microscopy (AFM), and X-ray reflectivity (XRR). Surface pressure area isotherms show that G1 and G2 have different limiting areas according to the type of subphase. The limiting area of G1 and G2 increased more with Al(3+) than with Eu(3+) in the subphase. This result indicates that the hydrophilic core group is anchored to ions in the water via bidentate chelates with the carboxylate oxygen atoms of G1 and G2. Circular domains and aggregates were observed for the LB film. The different behavior of Eu(3+) and Al(3+) complexes is originated from the intrinsic nature of the ion, i.e., coordination number. PMID- 21707037 TI - Role of hydrogen in chemical vapor deposition growth of large single-crystal graphene. AB - We show that graphene chemical vapor deposition growth on copper foil using methane as a carbon source is strongly affected by hydrogen, which appears to serve a dual role: an activator of the surface bound carbon that is necessary for monolayer growth and an etching reagent that controls the size and morphology of the graphene domains. The resulting growth rate for a fixed methane partial pressure has a maximum at hydrogen partial pressures 200-400 times that of methane. The morphology and size of the graphene domains, as well as the number of layers, change with hydrogen pressure from irregularly shaped incomplete bilayers to well-defined perfect single layer hexagons. Raman spectra suggest the zigzag termination in the hexagons as more stable than the armchair edges. PMID- 21707038 TI - The effects of confinement inside carbon nanotubes on catalysis. AB - The unique tubular morphology of carbon nanotubes (CNTs) has triggered wide research interest. These structures can be used as nanoreactors and to create novel composites through the encapsulation of guest materials in their well defined channels. The rigid nanotubes restrict the size of the encapsulated materials down to the nanometer and even the sub-nanometer scale. In addition, interactions may develop between the encapsulated molecules and nanomaterials and the CNT surfaces. The curvature of CNT walls causes the pi electron density of the graphene layers to shift from the concave inner to the convex outer surface, which results in an electric potential difference. As a result, the molecules and nanomaterials on the exterior walls of CNTs likely display different properties and chemical reactivities from those confined within CNTs. Catalysis that utilizes the interior surface of CNTs was only explored recently. An increasing number of studies have demonstrated that confining metal or metal oxide nanoparticles inside CNTs often leads to a different catalytic activity with respect to the same metals deposited on the CNT exterior surface. Furthermore, this inside and outside activity difference varies based on the metals used and the reactions catalyzed. In this Account, we describe the efforts toward understanding the fundamental effects of confining metal nanoparticles inside the CNT channels. This research may provide a novel approach to modulate their catalytic performance and promote rational design of catalysts. To achieve this, we have developed strategies for homogeneous dispersion of nanoparticles inside nanotubes. Because researchers have previously demonstrated the insertion of nanoparticles within larger nanotubes, we focused specifically on multiwalled carbon nanotubes (MWCNTs) with an inner diameter (i.d.) smaller than 10 nm and double-walled carbon nanotubes (DWCNTs) with 1.0-1.5 nm i.d. The results show that CNTs with well-defined morphology and unique electronic structure of CNTs provide an intriguing confinement environment for catalysis. PMID- 21707039 TI - Facile construction of manganese oxide doped carbon nanotube catalysts with high activity for oxygen reduction reaction and investigations into the origin of their activity enhancement. AB - MnOx-doped carbon nanotube (MnOx-CNTs) catalysts for the oxygen reduction reaction (ORR) were fabricated using a simple electrochemical deposition method. MnOx-CNTs (0.85 wt % MnOx) could exhibit an improved electrocatalytic activity, long-term stability and excellent resistance to crossover-effect compared to Pt/C catalysts. High-resolution transmission electron microscopy (HRTEM) and X-ray diffraction analysis confirm that the MnOx in the MnOx-CNTs exists in an amorphous state. Moreover, compared to the catalytic performances of MnOx on other substrates, the MnOx-CNTs exhibit a high ORR activity. X-ray photoelectron spectroscopy results suggest that the electron transfer, from the CNTs to the Mn ions occurs and the high positive charge is generated on the MnOx-CNT surface. This is believed to be origin of the catalytic activity observed in the ORR using MnOx-CNTs. PMID- 21707040 TI - Aqueous-mixed ionic liquid system: phase transitions and synthesis of gold nanocrystals. AB - Micelle-vesicle-micelle (MVM) transitions are observed in the aqueous-mixed ionic liquid (1-butyl-3-methylimidazolium octyl sulfate and 3-methyl-1-octylimidazolium chloride) system. The surface activity of mixed ILs, phase behavior, and solution structures in the system have been thoroughly characterized using conductometry, tensiometry, fluorimetry, dynamic light scattering (DLS), viscometry, turbidity, atomic force microscopy (AFM), transmission electron microscopy (TEM), and (1)H NMR techniques. Synergetic interactions between the two ILs in monolayers at the air/water interface and in micelles/vesicles have been determined using the regular solution approach, and the origins of spontaneous vesicle formation in this novel system are discussed. Using a photoreduction method, the formation of stable gold nanoparticles (GNPs) and microscale nanosheets of different shapes and sizes in the micellar and vesicle solutions has been reported. The studies show the potential of a mixed IL system in constructing stable micelles/supramolecular assemblies, such as bilayer vesicles, which are effective in the preparation of the desired nanomaterials. PMID- 21707041 TI - Tissue morphing control on dynamic gradient surfaces. AB - In this report, we develop smart surfaces for the spatial and temporal control of mammalian cell behavior. We integrate a bioactive surface strategy with a photo electroactive surface strategy to generate dynamic ligand surface gradients for controlling cell adhesion, tissue shape morphing, and cell tissue migration. PMID- 21707042 TI - Stress-sensing nanomaterial calibrated with photostimulated luminescence emission. AB - Calibration of high spatial resolution stress-sensing alumina-epoxy nanomaterials is presented. The piezospectroscopic property of luminescent chromium-doped alumina nanoparticles embedded as "nano-sensors" in epoxy-based materials is the basis for the stress sensing capabilities. The stress-optical properties are determined as piezopectroscopic coefficients in compression experiments for nanomaterials containing varying volume fractions of alumina nanoparticles. An increasing stress-sensitivity was demonstrated with higher volume fractions. Thermal variations were shown to have negligible effects on the stress sensing property. The development of this material sensing system will enable quantitative measurement and non-invasive monitoring of stress distributions within a polymer system applied as adhesives or as coatings on a substrate under loading conditions. PMID- 21707043 TI - Encapsulation of active cytoskeletal protein networks in cell-sized liposomes. AB - We demonstrate that cytoskeletal actin-myosin networks can be encapsulated with high efficiency in giant liposomes by hydration of lipids in an agarose hydrogel. The liposomes have cell-sized diameters of 10-20 MUm and a uniform actin content. We show by measurements of membrane fluorescence intensity and bending rigidity that the majority of liposomes are unilamellar. We further demonstrate that the actin network can be specifically anchored to the membrane by biotin-streptavidin linkages. These protein-filled liposomes are useful model systems for quantitative studies of the physical mechanisms by which the cytoskeleton actively controls cell shape and mechanics. In a broader context, this new preparation method should be widely applicable to encapsulation of proteins and polymers, for instance, to create polymer-reinforced liposomes for drug delivery. PMID- 21707044 TI - SANS and UV-vis spectroscopy studies of resultant structure from lysozyme adsorption on silica nanoparticles. AB - The interaction of lysozyme protein (M.W. 14.7 kD) with two sizes of silica nanoparticles (16 and 25 nm) has been examined in aqueous solution using UV-vis spectroscopy and small-angle neutron scattering (SANS). The measurements were performed on fixed concentration (1 wt %) of nanoparticles and varying concentration of protein in the range 0 to 2 wt %. The adsorption isotherm as obtained using UV-vis spectroscopy suggests strong interaction of the two components and shows an exponential behavior. The saturation values of adsorption are found to be around 90 and 270 protein molecules per particle for 16 and 25 nm sized nanoparticles, respectively. The adsorption of protein on nanoparticles leads to the aggregation of particles and these structures have been studied by SANS. The aggregates are characterized by fractal structure coexisting with unaggregated particles at low protein concentrations and free proteins at higher protein concentrations. Further, contrast variation SANS measurements have been carried out to differentiate the adsorbed and free protein in these systems. PMID- 21707045 TI - Verdazyl radicals as substrates for organic synthesis: a synthesis of 3-methyl-5 aryl-1,3,4-oxadiazolones. AB - The synthesis of oxadiazolones under hydrolytic conditions is described for a series of 3-methyl-5-aryl-1,3,4-oxadiazolone compounds. The unique starting materials for the hydrolysis reaction are obtained from efficient 1,3-dipolar cycloaddition reactions of styrene and azomethine imine dipoles derived from verdazyl radicals via a disproportionation reaction. A proposed mechanism for the formation of these biologically relevant oxadiazolones includes an opening of the tetrazinone ring followed by a 5-exo-trig ring closure. In support of the mechanism, in one case the ring-opened intermediate was isolated and subsequently treated with acid to give the relevant oxadiazolone. PMID- 21707046 TI - Isolation and biological evaluation of jatrophane diterpenoids from Euphorbia dendroides. AB - From the Montenegrin spurge Euphorbia dendroides, seven new diterpenoids [jatrophanes (1-6) and a tigliane (7)] were isolated and their structures elucidated by spectroscopic techniques. The biological activity of the new compounds was studied against four human cancer cell lines. The most effective jatrophane-type compound (2) and its structurally closely related derivative (1) were evaluated for their interactions with paclitaxel and doxorubicin using a multi-drug-resistant cancer cell line. Both compounds exerted a strong reversal potential resulting from inhibition of P-glycoprotein transport. PMID- 21707047 TI - Atomic-resolution structure of an N5 flavin adduct in D-arginine dehydrogenase. AB - D-Arginine dehydrogenase (DADH) catalyzes the flavin-dependent oxidative deamination of D-arginine and other D-amino acids to the corresponding imino acids. The 1.07 A atomic-resolution structure of DADH crystallized with D-leucine unexpectedly revealed a covalent N(5) flavin adduct, instead of the expected iminoleucine product in the active site. This acyl adduct has been successfully reproduced by photoreduction of DADH in the presence of 4-methyl-2-oxopentanoic acid (ketoleucine). The iminoleucine may be released readily because of weak interactions in the binding site, in contrast to iminoarginine, converted to ketoleucine, which reacts with activated FAD to form the covalently linked acyl adduct. PMID- 21707048 TI - Turn-on aptameric system for simple and selective detection of protein via base stacking-dependent DNA hybridization event. AB - Base stacking is employed in an entirely new type of sensing platform for the simple and robust detection of protein. Only in the presence of protein, the aptamer DNA can hybridize stably with the capture DNA to form a stem-loop structure due to the enhancement of base stacking. This leads to a strong chemiluminescence emission for simple protein detection. With the use of a platelet-derived growth factor as a model, a fM detection limit was obtained with a dynamic range that spanned 4 orders of magnitude. Upon modification, the approach presented herein was also extended to detect other types of targets including Hg(2+) ion and adenosine and also other types of labels such as fluorescence nanogold. We believe such advancements will represent a significant step toward improved diagnostics and more personalized medical treatment and environmental monitoring. PMID- 21707049 TI - Visualizing diastereomeric interactions of chiral amine-chiral copper salen adducts by EPR spectroscopy and DFT. AB - Single enantiomers of R/S-methylbenzylamine (MBA) were found to selectively form adducts with two chiral Cu-salen complexes, [Cu(II)(1)] (H(2)1 = N,N'-bis(3,5 ditert-butylsalicylidene)-1,2-diaminocyclohexane) and [Cu(II)(2)] (H(2)2 = N,N' bis-salicylidene-1,2-cyclohexanediamino). The axial g/A spin Hamiltonian parameters of the Cu-MBA adducts were typical of 5-coordinate species. Enantiomer discrimination in the MBA binding was directly evidenced by W-band CW EPR, revealing an 86 +/- 5% preference for formation of the R,R-[Cu(1)] + S-MBA adducts compared to R,R-[Cu(1)] + R-MBA; this was reduced to a 57 +/- 5% preference for R,R-[Cu(2)] + S-MBA following removal of the tert-butyl groups. The structure of these diastereomeric adducts was further probed by different hyperfine techniques (ENDOR and HYSCORE), although no structural differences were detected between these adducts using these techniques. The diastereomeric adducts were found to possess lower symmetry, as evidenced by rhombic g tensors and inequivalent H(imine) couplings. This was caused by the selective binding mode of MBA onto one side of the chiral Cu(II) complex. DFT calculations were performed on the R,R-[Cu(1)] + S-MBA and R,R-[Cu(1)] + R-MBA adducts. A distinct difference in orientation and binding mode of the MBA was identified in both adducts, confirming the experimental results. The preferred heterochiral R,R-[Cu(1)] + S MBA adduct was found to be 5 kJ mol(-1) lower in energy compared to the homochiral adduct. A delicate balance of steric repulsion between the alpha proton (attached to the asymmetric carbon atom) of MBA and the methine proton (attached to the asymmetric carbon atom) of [Cu(1)] was crucial in the stereoselective binding. PMID- 21707050 TI - Effect of the F610A mutation on substrate extrusion in the AcrB transporter: explanation and rationale by molecular dynamics simulations. AB - The tripartite efflux pump AcrAB-TolC is responsible for the intrinsic and acquired multidrug resistance in Escherichia coli. Its active part, the homotrimeric transporter AcrB, is in charge of the selective binding of substrates and energy transduction. The mutation F610A has been shown to significantly reduce the minimum inhibitory concentration of doxorubicin and many other substrates, although F610 does not appear to interact strongly with them. Biochemical study of transport kinetics in AcrB is not yet possible, except for some beta-lactams, and other techniques should supply this important information. Therefore, in this work, we assess the impact of the F610A mutation on the functionality of AcrB by means of computational techniques, using doxorubicin as substrate. We found that the compound slides deeply inside the binding pocket after mutation, increasing the strength of the interaction. During subsequent conformational alterations of the transporter, doxorubicin was either not extruded from the binding site or displaced along a direction other than the one associated with extrusion. Our study indicates how subtle interactions determine the functionality of multidrug transporters, since decreased transport might not be simplistically correlated to decreased substrate binding affinity. PMID- 21707051 TI - Thermal decomposition of methyl 2-azidopropionate studied by UV photoelectron spectroscopy and matrix isolation IR spectroscopy: heterocyclic intermediate vs imine formation. AB - Methyl 2-azidopropionate (N(3)CH(3)CHCOOCH(3), M2AP) has been synthesized and characterized by different spectroscopic methods, and the thermal decomposition of this molecule has been investigated by matrix isolation infrared (IR) spectroscopy and ultraviolet photoelectron spectroscopy (UVPES). Computational methods have been employed in the spectral simulation of both UVPES and matrix IR spectra and in the rationalization of the thermal decomposition results. M2AP presents a HOMO vertical ionization energy (VIE) of 9.60 +/- 0.03 eV and contributions from all four lowest-energy conformations of this molecule are detected in the gas phase. Its thermal decomposition starts at ca. 400 degrees C and is complete at ca. 650 degrees C, yielding N(2), CO, CO(2), CH(3)CN, and CH(3)OH as the final decomposition products. Methyl formate (MF) and CH(4) are also found during the pyrolysis process. Analysis of the potential energy surface of the decomposition of M2AP indicates that M2AP decomposes preferentially into the corresponding imine (M2IP), through a 1,2-H shift synchronous with the N(2) elimination (Type 1 mechanism), requiring an activation energy of 160.8 kJ/mol. The imine further decomposes via two competitive routes: one accounting for CO, CH(3)OH, and CH(3)CN (DeltaE(G3) = 260.2 kJ/mol) and another leading to CO(2), CH(4), and CH(3)CN (DeltaE(G3) = 268.6 kJ/mol). A heterocyclic intermediate (Type 2 mechanism)-4-Me-5-oxazolidone-can also be formed from M2AP via H transfer from the remote O-CH(3) group, together with the N(2) elimination (DeltaE(G3) = 260.2 kJ/mol). Finally, a third pathway which accounts for the formation of MF through an M2AP isomer is envisioned. PMID- 21707052 TI - Anisotropic swelling and fracture of silicon nanowires during lithiation. AB - We report direct observation of an unexpected anisotropic swelling of Si nanowires during lithiation against either a solid electrolyte with a lithium counter-electrode or a liquid electrolyte with a LiCoO(2) counter-electrode. Such anisotropic expansion is attributed to the interfacial processes of accommodating large volumetric strains at the lithiation reaction front that depend sensitively on the crystallographic orientation. This anisotropic swelling results in lithiated Si nanowires with a remarkable dumbbell-shaped cross section, which develops due to plastic flow and an ensuing necking instability that is induced by the tensile hoop stress buildup in the lithiated shell. The plasticity-driven morphological instabilities often lead to fracture in lithiated nanowires, now captured in video. These results provide important insight into the battery degradation mechanisms. PMID- 21707053 TI - Probabilistic multicompartmental model for interpreting DGT kinetics in sediments. AB - Extensive research has been performed on the use of the DIFS (DGT-Induced Fluxes in Soils and Sediments) model to interpret diffusive gradients in thin-film, or DGT, measurements in soils and sediments. The current report identifies some areas where the DIFS model has been shown to yield poor results and proposes a model to address weaknesses. In particular, two major flaws in the current approaches are considered: (i) many studies of accumulation kinetics in DGT exhibit multiple kinetic stages and (ii) several combinations of the two fitted DIFS parameters can yield identical results, leaving the question of how to select the 'best' combination. Previously, problem (i) has been addressed by separating the experimental data sets into distinct time segments. To overcome these problems, a model considering two types of particulate binding sites is proposed, instead of the DIFS model which assumed one single particulate pool. A probabilistic approach is proposed to fit experimental data and to determine the range of possible physical parameters using Probability Distribution Functions (PDFs), as opposed to single values without any indication of their uncertainty. The new probabilistic model, called DGT-PROFS, was tested on three different formulated sediments which mainly differ in the presence or absence of iron oxides. It was shown that a good fit can be obtained for the complete set of data (instead of DIFS-2D) and that a range of uncertainty values for each modeling parameter can be obtained. The interpretation of parameter PDFs allows one to distinguish between a variety of geochemical behaviors, providing useful information on metal dynamics in sediments. PMID- 21707054 TI - Cold adaptation of tropomyosin. AB - The conformational stability of unphosphorylated and phosphorylated alpha,alpha striated tropomyosins from rabbit and shark (95% identical sequences) has been investigated. Three additional core positions are occupied by atypical amino acids in the protein from shark: Thr179(d), Ser190(a), and Ser211(a). These changes are thought to have further destabilized most, if not all, of the carboxyl-terminal half of the molecule. Heat-induced unfolding of shark tropomyosin (2 mg/mL, 0.1 M salt, pH 7) as monitored by far-UV circular dichroism is biphasic [T(m1) ~ 33 degrees C (main), and T(m2) ~ 54 degrees C] and takes place over a wider temperature span than that of the mammalian protein. The relationship between ellipticity (and excess heat) and temperature is insensitive to the presence in either tropomyosin of covalently bound phosphate. At ~10 mg/mL, the minor endotherm of shark tropomyosin is shifted to ~60 degrees C and T(m2) - T(m1) is increased to 25 degrees C; otherwise, the results of calorimetry are in agreement with those of circular dichroism. Analyses of cyanogen bromide fragments by far-UV circular dichroism and intact protein by near-UV circular dichroism (T(m) ~ 32 degrees C) show that the most stable sizable portion of shark tropomyosin is located within the amino-terminal half of the molecule. These findings illuminate those regions in tropomyosin where flexibility is critical and show that substitutions predicted to be unfavorable in one temperature regime are desirable in another. PMID- 21707055 TI - The dioxygenase-encoding olsD gene from Burkholderia cenocepacia causes the hydroxylation of the amide-linked fatty acyl moiety of ornithine-containing membrane lipids. AB - Burkholderia cenocepacia is an important opportunistic pathogen, and one of the most striking features of the Burkholderia genus is the collection of polar lipids present in its membrane, including phosphatidylethanolamine (PE) and ornithine-containing lipids (OLs), as well as the 2-hydroxylated derivatives of PE and OLs (2-OH-PE and 2-OH-OLs, respectively), which differ from the standard versions by virtue of the presence of a hydroxyl group at C2 (2-OH) of an esterified fatty acyl residue. Similarly, a lipid A-esterified myristoyl group from Salmonella typhimurium can have a 2-hydroxy modification that is due to the LpxO enzyme. We thus postulated that 2-hydroxylation of 2-OH-OLs might be catalyzed by a novel dioxygenase homologue of LpxO. In B. cenocepacia, we have now identified two open reading frames (BCAM1214 and BCAM2401) homologous to LpxO from S. typhimurium. The introduction of bcam2401 (designated olsD) into Sinorhizobium meliloti leads to the formation of one new lipid and in B. cenocepacia of two new lipids. Surprisingly, the lipid modifications on OLs due to OlsD occur on the amide-linked fatty acyl chain. This is the first report of a hydroxyl modification of OLs on the amide-linked fatty acyl moiety. Formation of hydroxylated OLs occurs only when the biosynthesis pathway for nonmodified standard OLs is intact. The hydroxyl modification of OLs on the amide-linked fatty acyl moiety occurs only under acid stress conditions. An assay has been developed for the OlsD dioxygenase, and an initial characterization of the enzyme is presented. PMID- 21707056 TI - Processing of arsenopyritic gold concentrates by partial bio-oxidation followed by bioreduction. AB - Gold is commonly liberated from sulfide minerals by chemical and biological oxidation. Although these technologies are successful, they are costly and produce acidic waste streams. Removal of mineral-sulfur to overcome the mineralogical barrier could also be done by bioreduction, producing hydrogen sulfide (H(2)S). To make the sulfur within these minerals available for bioreduction, the use of partial bio-oxidation as a pretreatment to oxidize the sulfides to elemental sulfur was investigated in gas lift loop reactor experiments. Experiments at 35 degrees C using a refractory concentrate showed that at pH 2 arsenopyrite is preferentially partially oxidized over pyrite and that elemental sulfur can be subsequently converted into H(2)S at pH 5 via bioreduction using H(2) gas. A single partial bio-oxidation/bioreduction treatment increased the gold recovery of the concentrate from 6% to 39%. As elemental sulfur seems to inhibit further oxidation by covering the mineral surface, several treatments may be required to reach a gold recovery >90%. Depending on the number of treatments this method could be an interesting alternative to bio-oxidation. PMID- 21707057 TI - Structure and mechanism of the trans-acting acyltransferase from the disorazole synthase. AB - The 1.51 A resolution X-ray crystal structure of the trans-acyltransferase (AT) from the "AT-less" disorazole synthase (DSZS) and that of its acetate complex at 1.35 A resolution are reported. Separately, comprehensive alanine-scanning mutagenesis of one of its acyl carrier protein substrates (ACP1 from DSZS) led to the identification of a conserved Asp45 residue on the ACP, which contributes to the substrate specificity of this unusual enzyme. Together, these experimental findings were used to derive a model for the selective association of the DSZS AT and its ACP substrate. With a goal of structurally characterizing the AT-ACP interface, a strategy was developed for covalently cross-linking the active site Ser -> Cys mutant of the DSZS AT to its ACP substrate and for purifying the resulting AT-ACP complex to homogeneity. The S86C DSZS AT mutant was found to be functional, albeit with a transacylation efficiency 200-fold lower than that of its wild-type counterpart. Our findings provide new insights as well as new opportunities for high-resolution analysis of an important protein-protein interface in polyketide synthases. PMID- 21707058 TI - A simple analytical method for dhurrin content evaluation in cyanogenic plants for their utilization in fodder and biofumigation. AB - Cyanogenic plants have some potential as biocidal green manure crops in limiting several soilborne pests and pathogens. Sorghum (Sorghum bicolor (L.) Moench) and Sudangrass (Sorghum bicolor subsp. sudanense (P.) Stapf), in fact, contain the cyanogenic glucoside p-hydroxy-(S)-mandelonitrile-beta-D-glucoside (dhurrin) as a substrate of its secondary defensive system able to release hydrogen cyanide following tissue lesions due to biotic or abiotic factors. Given that dhurrin content is correlated with the biofumigant efficacy of the plants, a high dhurrin content could be a positive character for utilization of sorghum and Sudangrass as biocidal green manure plants. For chemical characterization of the available germplasm, a simple, safe, and accurate method is necessary. In this paper, a new method for dhurrin analysis, based on methanol extraction and high-performance liquid chromatography, is reported and discussed. The feasibility of this analytical procedure was tested by evaluating dhurrin level in roots and stems during cultivation of four different sorghum and Sudangrass varieties in agronomic trials performed in 2008 in the Po valley (Italy). The dhurrin content ranged from 0.16 +/- 0.04 to 7.14 +/- 0.32 mg g(-1) on dried matter (DM) in stems and from 1.38 +/- 0.02 to 6.57 +/- 0.09 mg g(-1) on DM in roots, showing statistical differences among the tested germplasms that could be linked to the efficacy of their utilization as biofumigant plants. The method also opens new perspectives for the characterization of sorgum plants as fodder, for which the presence of dhurrin is considered to be negative for its well-known toxicity. PMID- 21707059 TI - Bioluminescence is produced from a trapped firefly luciferase conformation predicted by the domain alternation mechanism. AB - According to the domain alternation mechanism and crystal structure evidence, the acyl-CoA synthetases, one of three subgroups of a superfamily of adenylating enzymes, catalyze adenylate- and thioester-forming half-reactions in two different conformations. The enzymes accomplish this by presenting two active sites through an ~140 degrees rotation of the C-domain. The second half-reaction catalyzed by another subgroup, the beetle luciferases, is a mechanistically dissimilar oxidative process that produces bioluminescence. We have demonstrated that a firefly luciferase variant containing cysteine residues at positions 108 and 447 can be intramolecularly cross-linked by 1,2-bis(maleimido)ethane, trapping the enzyme in a C-domain-rotated conformation previously undocumented in the available luciferase crystal structures. The cross-linked luciferase cannot adenylate luciferin but is nearly fully capable of bioluminescence with synthetic luciferyl adenylate because it retains the ability to carry out the oxidative half-reaction. The cross-linked luciferase is apparently trapped in a conformation similar to those adopted by acyl-CoA synthetases as they convert acyl adenylates into the corresponding CoA thioesters. PMID- 21707060 TI - An M2L4 molecular capsule with an anthracene shell: encapsulation of large guests up to 1 nm. AB - A new M(2)L(4) molecular capsule with an aromatic shell was prepared using two Pd(II) ions and four bisanthracene ligands. The self-assembled capsule possesses a cavity with a diameter of ~1 nm that can encapsulate medium-sized spherical and planar molecules as well as a very large molecule (C(60)) in quantitative yields. The encapsulated guests are fully segregated and shielded from the external environment by the large anthracene panels. PMID- 21707061 TI - N3-dye-induced visible laser anatase-to-rutile phase transition on mesoporous TiO2 films. AB - Titanium dioxide has been extensively used in photocatalysis and dye-sensitized solar cells, where control of the anatase-to-rutile phase transformation may allow the realization of more efficient devices exploiting the synergic effects at anatase/rutile interfaces. Thus, a systematic study showing the proof of concept of a dye-induced morphological transition and an anatase-to-rutile transition based on visible laser (532 nm) and nano/micro patterning of mesoporous anatase (Degussa P25 TiO(2)) films is described for the first time using a confocal Raman microscope. At low laser intensities, only the bleaching of the adsorbed N3 dye was observed. However, high enough temperatures to promote melting/densification processes and create a deep hole at the focus and an extensive phase transformation in the surrounding material were achieved using 1s laser pulses of 25-41 mW/cm(2), in resonance with the MLCT band. The dye was shown to play a key role, being responsible for the absorption and efficient conversion of the laser light into heat. As a matter of fact, the dye is photothermally decomposed to amorphous carbon or to gaseous species (CO(x), NO(x), and H(2)O) under a N(2) or O(2) atmosphere, respectively. PMID- 21707062 TI - Water-medium and solvent-free organic reactions over a bifunctional catalyst with Au nanoparticles covalently bonded to HS/SO3H functionalized periodic mesoporous organosilica. AB - An operationally simple approach for the preparation of a new class of bifunctional Au nanoparticle-acid catalysts has been developed. In situ reduction of Au(3+) with HS-functionalized periodic mesoporous organosilicas (PMOs) creates robust, fine Au nanoparticles and concomitantly produces a sulfonic acid moiety strongly bonded to PMOs. Characterizations of the nanostructures reveal that Au nanoparticles are formed with uniformed, narrow size distribution around 1-2 nm, which is very critical for essential catalytic activities. Moreover, the Au nanoparticles are mainly attached onto the pore surface rather than onto the outer surface with ordered mesoporous channels, allowing for maximal exposure to reaction substrates while minimizing Au nanoparticle leaching. Their higher S(BET), V(P), and D(P) than either the Au-HS-PMO(Et) or the Au/SO(3)H-PMO(Et) render the catalyst with comparably even higher catalytic efficiency than its homogeneous counterparts. Furthermore, the unique amphiphilic compartment of the Au-HS/SO(3)H-PMO(Et) nanostructures enables organic reactions to proceed efficiently in a pure aqueous solution without using any organic solvents or even without water. As demonstrated experimentally, remarkably, the unique bifunctional Au-HS/SO(3)H-PMO(Et) catalyst displays higher efficiencies in promoting water-medium alkyne hydration, intramolecular hydroamination, styrene oxidation, and three-component coupling reactions and even the solvent-free alkyne hydration process than its homogeneous catalysts. The robust catalyst can be easily recycled and used repetitively at least 10 times without loss of catalytic efficiency. These features render the catalyst particularly attractive in the practice of organic synthesis in an environmentally friendly manner. PMID- 21707063 TI - Nanostructured Ti(0.7)Mo(0.3)O2 support enhances electron transfer to Pt: high performance catalyst for oxygen reduction reaction. AB - The slow rate of the oxygen reduction reaction (ORR) and the instability of Pt based catalysts are two of the most important issues that must be solved in order to make proton exchange membrane fuel cells (PEMFCs) a reality. Additionally, the serious carbon corrosion on the cathode side is a critical problem with respect to the durability of catalyst that limits its wide application. Here, we present a new approach by exploring robust noncarbon Ti(0.7)Mo(0.3)O(2) used as a novel functionalized cocatalytic support for Pt. This approach is based on the novel nanostructure Ti(0.7)Mo(0.3)O(2) support with "electronic transfer mechanism" from Ti(0.7)Mo(0.3)O(2) to Pt that can modify the surface electronic structure of Pt, owing to a shift in the d-band center of the surface Pt atoms. Furthermore, another benefit of Ti(0.7)Mo(0.3)O(2) is the extremely high stability of Pt/Ti(0.7)Mo(0.3)O(2) during potential cycling, which is attributable to the strong metal/support interaction (SMSI) between Pt and Ti(0.7)Mo(0.3)O(2). This also enhances the inherent structural and chemical stability and the corrosion resistance of the TiO(2)-based oxide in acidic and oxidative environments. We also demonstrate that the ORR current densities generated using cocatalytic Pt/Ti(0.7)Mo(0.3)O(2) are respectively ~7- and 2.6-fold higher than those of commercial Pt/C and PtCo/C catalysts with the same Pt loading. This new approach opens a reliable path to the discovery advanced concept in designing new catalysts that can replace the traditional catalytic structure and motivate further research in the field. PMID- 21707064 TI - Excited electronic states, transition probabilities, and radiative lifetimes of CAs: a theoretical contribution and challenge to experimentalists. AB - High-level CASSCF/MRCI calculations with a quintuple-zeta quality basis set are reported by characterizing for the first time a manifold of electronic states of the CAs radical yet to be investigated experimentally. Along with the potential energy curves and the associated spectroscopic constants, the dipole moment functions for selected electronic states as well as the transition dipole moment functions for the most relevant electronic transitions are also presented. Estimates of radiative transition probabilities and lifetimes complement this investigation, which also assesses the effect of spin-orbit interaction on the A (2)Pi state. Whenever pertinent, comparisons of similarities and differences with the isovalent CN and CP radicals are made. PMID- 21707066 TI - About the barriers to reaction of CCl4 with HFeOH and FeCl2. AB - The reactions of zerovalent iron with water and carbon tetrachloride are of interest for environmental remediation of contaminated water and soil. Atom dropping experiments have shown that the reactions of iron atoms with water and CCl(4) may produce HFeOH and FeCl(2), respectively, but these compounds are themselves unreactive toward CCl(4) at the low temperatures under which the atom dropping experiments were performed. We report a modeling study of these reactions using density functional theory, ab initio Hartree-Fock and couple cluster theory, and principles of Marcus-Hush theory to characterize the underlying intrinsic barriers and rationalize the experimental results. Electron correlated CCSD(T) calculations (at B3LYP/TZVP optimized structures) show that the transition state for Cl atom transfer from CCl(4) to HFeOH arises from crossing of electronic states in which the configuration of Fe changes from a quintet high spin state in the Fe(II) reactant to a sextet high spin state in the Fe(III) products. The crossing point is 23.8 kcal/mol above a long-range precursor complex that is 2.1 kcal/mol more stable than the separated reactants. The electronic structure changes in these Cl atom transfer reactions involve unpairing of d electrons in Fe(II) and their recoupling with Cl-C sigma bond electrons. These processes can be conveniently described by invoking the self exchange reactions HFeOH/HFeClOH, FeCl(2)/FeCl(3), and CCl(4)/(*)CCl(3) for which we determined the energy barriers to be 15.5, 13.1, 18.6 kcal/mol, respectively. For the cross reaction FeCl(2)/CCl(4), we estimated a barrier of 16.6 kcal/mol relative to the separated reactants and 21.1 kcal/mol from the precursor complex. The magnitudes of the reaction barriers are consistent with reports of the absence of products in the atom-dropping experiments. PMID- 21707065 TI - Highly anisotropic stability and folding kinetics of a single coiled coil protein under mechanical tension. AB - Coiled coils are one of the most abundant protein structural motifs and widely mediate protein interactions and force transduction or sensation. They are thus model systems for protein engineering and folding studies, particularly the GCN4 coiled coil. Major single-molecule methods have also been applied to this protein and revealed its folding kinetics at various spatiotemporal scales. Nevertheless, the folding energy and the kinetics of a single GCN4 coiled coil domain have not been well determined at a single-molecule level. Here we used high-resolution optical tweezers to characterize the folding and unfolding reactions of a single GCN4 coiled coil domain and their dependence on the pulling direction. In one axial and two transverse pulling directions, we observed reversible, two-state transitions of the coiled coil in real time. The transitions equilibrate at pulling forces ranging from 6 to 12 pN, showing different stabilities of the coiled coil in regard to pulling direction. Furthermore, the transition rates vary with both the magnitude and the direction of the pulling force by greater than 1000 folds, indicating a highly anisotropic and topology-dependent energy landscape for protein transitions under mechanical tension. We developed a new analytical theory to extract energy and kinetics of the protein transition at zero force. The derived folding energy does not depend on the pulling direction and is consistent with the measurement in bulk, which further confirms the applicability of the single-molecule manipulation approach for energy measurement. The highly anisotropic thermodynamics of proteins under tension should play important roles in their biological functions. PMID- 21707067 TI - Tunable dielectric properties of transition metal dichalcogenides. AB - Since discovery of graphene, layered materials have drawn considerable attention because of their possible exfoliation into single and multilayer 2D sheets. Because of strong surface effects, the properties of these materials vary drastically with the number of layers in a sheet. We have performed first principles density functional based calculations to evaluate the electron energy loss spectrum (EELS) of bulk, monolayer, and bilayer configurations of several transition metal dichalcogenides, which include semiconducting as well as metallic compounds. Our investigation shows that the peaks in the EELS spectra move toward larger wavelengths (red shift) with the decrease in number of layers. The pi plasmon peak shifts slightly by 0.5-1.0 eV, while a significant shift of around 5.5-13.0 eV is obtained for pi + sigma plasmon, when exfoliated from bulk to single-layer. This underscores the importance of the interlayer coupling on the loss spectra and the dielectric properties. Our results are found to be in very good agreement with the recent measurements performed by Coleman et al. (Science2011, 331, 568). PMID- 21707068 TI - A facile Cu(I)/TF-BiphamPhos-catalyzed asymmetric approach to unnatural alpha amino acid derivatives containing gem-bisphosphonates. AB - A novel catalytic asymmetric Michael addition of azomethine ylide with beta substituted alkylidene bisphosphates was realized in the presence of a chiral copper(I)/TF-BiphamPhos complex. The present system provides a unique and facile access to enantioenriched unnatural alpha-amino acid derivatives containing gem bisphosphonates (gem-BPs) in high yields with excellent diastereoselectivities and enantioselectivities. Subsequent transformations lead to the expedient preparation of biologically active unnatural alpha-amino acid derivatives containing BPs and bisphosphonic acids without loss of diastereo- and enantiomeric excess. PMID- 21707069 TI - Poly(aniline) nanowires in sol-gel coated ITO: a pH-responsive substrate for planar supported lipid bilayers. AB - Facilitated ion transport across an artificial lipid bilayer coupled to a solid substrate is a function common to several types of bioelectronic devices based on supported membranes, including biomimetic fuel cells and ion channel biosensors. Described here is fabrication of a pH-sensitive transducer composed of a porous sol-gel layer derivatized with poly(aniline) (PANI) nanowires grown from an underlying planar indium-tin oxide (ITO) electrode. The upper sol-gel surface is hydrophilic, smooth, and compatible with deposition of a planar supported lipid bilayer (PSLB) formed via vesicle fusion. Conducting tip AFM was used to show that the PANI wires are connected to the ITO, which convert this electrode into a potentiometric pH sensor. The response to changes in the pH of the buffer contacting the PANI nanowire/sol-gel/ITO electrode is blocked by the very low ion permeability of the overlying fluid PSLB. The feasibility of using this assembly to monitor facilitated proton transport across the PSLB was demonstrated by doping the membrane with lipophilic ionophores that respond to a transmembrane pH gradient, which produced an apparent proton permeability several orders of magnitude greater than values measured for undoped lipid bilayers. PMID- 21707072 TI - A new paradigm for anion trapping in high capacity and selectivity: crystal-to crystal transformation of cationic materials. AB - We describe a new methodology to the selective trapping of priority pollutants that occur inherently as oxo-anions (e.g., perchlorate, chromate, arsenate, pertechnetate, etc.) or organic anions (e.g., salicylate, pharmaceuticals, and their metabolites, which are often chlorinated into potentially more harmful compounds). The typical approach to trapping anions is exchange into cationic hosts such as resins or layered double hydroxides. Both capacity and selectivity are limited by the equilibrium of the process and moreover are often subject to interference, e.g. by carbonate that is always present in water from atmospheric CO(2). Our approach takes advantage of the metastability of our cationically charged materials to instead trap by recrystallization to a new structure. Exceptionally high adsorption capacities for permanganate and perrhenate--studied as models for pertechnetate--were found for a Ag(I)-based cationic extended framework. The exchange capacity reached 292 and 602 mg/g, respectively, over five times the exchange capacity compared to conventional layered double hydroxides. Our cationic material can also selectively trap these and other toxic oxo-anions when nontoxic anions (e.g., nitrate, carbonate) were present in an over 100-fold excess concentration. PMID- 21707071 TI - Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. AB - We have investigated the transcriptomic and/or proteomic patterns of 71 solute carrier (SLC) and organic solute (OST) transporters, 34 ATP-binding cassette (ABC) transporters, and 51 metabolizing enzymes in human brain microvessels. We used quantitative RT-PCR and LC-MS/MS to examine isolated brain microvessels and cortex biopsies from 12 patients with epilepsia or glioma. SLC2A1/GLUT1, SLC1A3/EAAT1, and SLC1A2/EAAT2 were the main SLC proteins whereas ABCG2/BCRP, ABCB1/MDR1, ABCA2 and ABCA8 were the main ABC quantified in isolated brain microvessels; ABCG2/BCRP was 1.6-fold more expressed than ABCB1/MDR1, and ABCC4/MRP4 was 10 times less abundant than ABCB1/MDR1. CYP1B1 and CYP2U1 were the only quantifiable CYPs. Finally, GSTP1, COMT, GSTM3, GSTO1 and GSTM2 proteins were the main phase II enzymes quantified; UGTs and NATs were not detected. Our extensive investigation of gene and protein patterns of transporters and metabolizing enzymes provides new molecular information for understanding drug entry and metabolism in the human blood-brain barrier. PMID- 21707073 TI - Sulfonated poly(arylene ether sulfone ketone) multiblock copolymers with highly sulfonated blocks. Long-term fuel cell operation and post-test analyses. AB - The stability of poly(arylene ether sulfone ketone) (SPESK) multiblock copolymer membranes having highly sulfonated hydrophilic blocks was tested in an operating fuel cell. The electrochemical properties and drain water were monitored during the test, followed by post-test analyses of the membrane. During a 2000-h fuel cell operation test at 80 degrees C and 53% RH (relative humidity) and with a constant current density (0.2 A cm(-2)), the cell voltage showed minor losses, with slight increases in the resistance. In the drain water, anions such as formate, acetate, and sulfate were observed. Post-test analyses of the chemical structure by NMR and IR spectra revealed that the sulfonated fluorenyl group with ether linkage was the most likely to have degraded during the long-term operation, producing these small molecules. The minor oxidative degradation only slightly affected the proton conductivity, water uptake, and phase-separated morphology. PMID- 21707070 TI - Genetically modified mesenchymal stem cells for improved islet transplantation. AB - The use of adult stem cells for therapeutic purposes has met with great success in recent years. Among several types of adult stem cells, mesenchymal stem cells (MSCs) derived from bone marrow (BM) and other sources have gained popularity for basic research and clinical applications because of their therapeutic potential in treating a variety of diseases. Because of their tissue regeneration potential and immune modulation effect, MSCs were recently used as cell-based therapy to promote revascularization, increase pancreatic beta-cell proliferation, and avoid allograft rejection in islet transplantation. Taking advantage of the recent progress in gene therapy, genetically modified MSCs can further enhance and expand the therapeutic benefit of primary MSCs while retaining their stem-cell like properties. This review aims to gain a thorough understanding of the current obstacles to successful islet transplantation and discusses the potential role of primary MSCs before or after genetic modification in islet transplantation. PMID- 21707074 TI - Theoretical investigation into the structural, thermochemical, and electronic properties of the decathio[10]circulene. AB - For the first time, a theoretical study has been performed on the prototypical decathio[10]circulene (C(20)S(10)) species, which is an analogue of the novel octathio[8]circulene "Sulflower" molecule (C(16)S(8)). Examinations of the singlet and triplet states of C(20)S(10) were made at the B3LYP/6-311G(d) level. Local minima of C(2) and C(s) symmetry were found for the lowest singlet and triplet states, respectively. The stability of C(20)S(10) was assessed by calculating the DeltaH degrees (f) of C(16)S(8) and C(20)S(10) and the DeltaH(o) for their decomposition into C(2)S units. Frontier molecular orbital plots show that structural adjacent steric factors along with the twist and strain orientations of C(20)S(10) do not disturb the aromatic pi-delocalizing effects. In fact, C(20)S(10) maintains the same p(z) HOMO character as C(16)S(8). These similarities are further verified by density-of-states characterization. Calculated infrared spectra of C(16)S(8) and C(20)S(10) show broad similarities. Molecular electrostatic potential results reveal that eight of the peripheral sulfur atoms are the most electronegative atoms in the molecule, while the interior ten-membered ring exhibits virtually no electronegativity. PMID- 21707075 TI - Precise isomerization polymerization of alkenylcyclohexanes: stereoregular polymers containing six-membered rings along the polymer chain. AB - Pd and Ni diimine complexes catalyze the isomerization polymerization of alkenylcyclohexanes to afford polymers composed of alternating trans-cyclohexane 1,4-diyl rings and oligomethylene spacers with high selectivity. The melting points of the polymers vary from 130 to 226 degrees C depending on length of the oligomethylene spacer. PMID- 21707076 TI - Thiolated mucoadhesive and PEGylated nonmucoadhesive organosilica nanoparticles from 3-mercaptopropyltrimethoxysilane. AB - A novel approach has been developed to synthesize thiolated sub-100 nm organosilica nanoparticles from 3-mercaptopropyltrimethoxysilane (MPTS) through its self-condensation in dimethylsulfoxide in contact with atmospheric oxygen. The formation of MPTS nanoparticles proceeds through the condensation of methoxysilane groups and simultaneous disulfide bridging caused by partial oxidation of thiol groups. These nanoparticles showed excellent colloidal stability in dilute aqueous dispersions but underwent further self-assembly into chains and necklaces at higher concentrations. They exhibited very good ability to adhere to ocular mucosal surfaces, which can find applications in drug delivery. The thiolated nanoparticles could also be easily modified through PEGylation resulting in a loss of their mucoadhesive properties. PMID- 21707077 TI - From fragment screening to in vivo efficacy: optimization of a series of 2 aminoquinolines as potent inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). AB - Using fragment-based screening of a focused fragment library, 2-aminoquinoline 1 was identified as an initial hit for BACE1. Further SAR development was supported by X-ray structures of BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery of potent compounds. These strategies enabled us to integrate the C-3 side chain on 2-aminoquinoline 1 extending deep into the P2' binding pocket of BACE1 and enhancing the ligand's potency. We were able to improve the BACE1 potency to subnanomolar range, over 10(6)-fold more potent than the initial hit (900 MUM). Further elaboration of the physical properties of the lead compounds to those more consistent with good blood-brain barrier permeability led to inhibitors with greatly improved cellular activity and permeability. Compound 59 showed an IC(50) value of 11 nM on BACE1 and cellular activity of 80 nM. This compound was advanced into rat pharmacokinetic and pharmacodynamic studies and demonstrated significant reduction of Abeta levels in cerebrospinal fluid (CSF). PMID- 21707078 TI - Potent, metabolically stable benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR inhibitors for polycystic kidney disease. AB - We previously reported the discovery of pyrimido-pyrrolo-quinoxalinedione (PPQ) inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and showed their efficacy in an organ culture model of polycystic kidney disease (PKD) (J. Med. Chem. 2009, 52, 6447-6455). Here, we report related benzopyrimido-pyrrolo-oxazinedione (BPO) CFTR inhibitors. To establish structure-activity relationships and select lead compound(s) with improved potency, metabolic stability, and aqueous solubility compared to the most potent prior compound 8 (PPQ-102, IC(50) ~ 90 nM), we synthesized 16 PPQ analogues and 11 BPO analogues. The analogues were efficiently synthesized in 5-6 steps and 11-61% overall yield. Modification of 8 by bromine substitution at the 5-position of the furan ring, replacement of the secondary amine with an ether bridge, and carboxylation, gave 6-(5-bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11 phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido [4',5':3,4]pyrrolo [1,2 d][1,4]oxazine-2-carboxylic acid 42 (BPO-27), which fully inhibited CFTR with IC(50) ~ 8 nM and, compared to 8, had >10-fold greater metabolic stability and much greater polarity/aqueous solubility. In an embryonic kidney culture model of PKD, 42 prevented cyst growth with IC(50) ~ 100 nM. Benzopyrimido-pyrrolo oxazinediones such as 42 are potential development candidates for antisecretory therapy of PKD. PMID- 21707079 TI - The crystal structure of Streptococcus pyogenes uridine phosphorylase reveals a distinct subfamily of nucleoside phosphorylases. AB - Uridine phosphorylase (UP), a key enzyme in the pyrimidine salvage pathway, catalyzes the reversible phosphorolysis of uridine or 2'-deoxyuridine to uracil and ribose 1-phosphate or 2'-deoxyribose 1-phosphate. This enzyme belongs to the nucleoside phosphorylase I superfamily whose members show diverse specificity for nucleoside substrates. Phylogenetic analysis shows Streptococcus pyogenes uridine phosphorylase (SpUP) is found in a distinct branch of the pyrimidine subfamily of nucleoside phosphorylases. To further characterize SpUP, we determined the crystal structure in complex with the products, ribose 1-phosphate and uracil, at 1.8 A resolution. Like Escherichia coli UP (EcUP), the biological unit of SpUP is a hexamer with an alpha/beta monomeric fold. A novel feature of the active site is the presence of His169, which structurally aligns with Arg168 of the EcUP structure. A second active site residue, Lys162, is not present in previously determined UP structures and interacts with O2 of uracil. Biochemical studies of wild-type SpUP showed that its substrate specificity is similar to that of EcUP, while EcUP is ~7-fold more efficient than SpUP. Biochemical studies of SpUP mutants showed that mutations of His169 reduced activity, while mutation of Lys162 abolished all activity, suggesting that the negative charge in the transition state resides mostly on uracil O2. This is in contrast to EcUP for which transition state stabilization occurs mostly at O4. PMID- 21707081 TI - CO-induced embedding of Pt adatoms in a partially reduced FeO(x) film on Pt(111). AB - The reduction of a single-layer FeO film grown on Pt(111) by CO at elevated pressures and temperatures has been studied through an interplay of scanning tunneling microscopy, ambient-pressure X-ray photoelectron spectroscopy, and density functional theory calculations. Exposure of the FeO thin film to CO at pressures between 1 and 30 Torr and temperatures between 500 and 530 K leads to formation of a honeycomb-structured Fe(3)O(2) film with hollow sites occupied by single Pt atoms extracted from the substrate surface. The formation of these adatoms is driven by an increase in CO adsorption energy. In addition, the structure incorporates undercoordinated Fe centers, which are proposed to have substantial effects on the catalytic properties of the surface. PMID- 21707080 TI - Determination of alachlor and its metabolite 2,6-diethylaniline in microbial culture medium using online microdialysis enriched-sampling coupled to high performance liquid chromatography. AB - In this study, a simple and novel microdialysis sampling technique incorporating hollow fiber liquid phase microextraction (HF-LPME) coupled online to high performance liquid chromatography (HPLC) for the one-step sample pretreatment and direct determination of alachlor (2-chloro-2',6'-diethyl-N (methoxymethyl)acetanilide) and its metabolite 2,6-diethylaniline (2,6-DEA) in microbial culture medium has been developed. A reversed-phase C-18 column was utilized to separate alachlor and 2,6-DEA from other species using an acetonitrile/water mixture (1:1) containing 0.1 M phosphate buffer solution at pH 7.0 as the mobile phase. Detection was carried out with a UV detector operated at 210 nm. Parameters that influenced the enrichment efficiency of online HF-LPME sampling, including the length of the hollow fiber, the perfusion solvent and its flow rate, the pH, and the salt added in sample solution, as well as chromatographic conditions were thoroughly optimized. Under optimal conditions, excellent enrichment efficiency was achieved by the microdialysis of a sample solution (pH 7.0) using hexane as perfusate at the flow rate of 4 MUL/min. Detection limits were 72 and 14 ng/mL for alachlor and 2,6-DEA, respectively. The enrichment factors were 403 and 386 (RSD < 5%) for alachlor and 2,6-DEA, respectively, when extraction was performed by using a 40 cm regenerated cellulose hollow fiber and hexane as perfusion solvent at the flow rate of 0.1 MUL/min. The proposed method provides a sensitive, flexible, fast, and eco friendly procedure to enrich and determine alachlor and its metabolite (2,6-DEA) in microbial culture medium. PMID- 21707082 TI - High-order multiblock copolymers via iterative Cu(0)-mediated radical polymerizations (SET-LRP): toward biological precision. AB - We report a new approach for the facile synthesis of high-order multiblock copolymers comprising very short blocks. The approach entails sequential addition of different monomers via an iterative single electron transfer-living radical polymerization technique, allowing nearly perfect control of the copolymer microstructure. It is possible to synthesize high-order multiblock copolymers with unprecedented control, i.e., A-B-C-D-E-etc., without any need for purification between iterative 24 h block formation steps. To illustrate this concept, we report the synthesis of model P(MA-b-MA...) homopolymer and P(MA-b nBuA-b-EA-b-2EHA-b-EA-b-nBuA) copolymer in extremely high yield. Finally, the halide end-group can be modified via "click chemistry", including thiol-bromide click chemistry, sodium methanethiosulfonate nucleophilic substitution, and atom transfer radical nitroxide coupling reaction, to yield functional, structurally complex macromolecules. PMID- 21707083 TI - The 2010 Philip S. Portoghese Medicinal Chemistry Lectureship: addressing the "core issue" in the design of estrogen receptor ligands. PMID- 21707085 TI - Subamolide E from Cinnamomum subavenium induces sub-G1 cell-cycle arrest and caspase-dependent apoptosis and reduces the migration ability of human melanoma cells. AB - The aim of this work was to investigate the anticancer cytotoxic effects of natural compound subamolide E on the human skin cancer melanoma A375.S2 cells. Subamolide E was isolated from Cinnamomum subavenium and demonstrated cytotoxicities in the cell-growth assay at concentration ranges from 0 to 100 MUM at 24 h. Propidium iodide staining and flow cytometry analyses were used to evaluate cell-cycle distribution and found that subamolide E caused DNA damage in the sub-G1 phase with a dose-dependent manner after 24 h of treatment. According to the western blot result, subamolide-E-treated cells with the increase of caspase-dependent apoptotic proteins induced related pathway mechanisms. Subamolide E also showed antimigratory activities of A375.S2 cells on the wound healing assay. Finally, subamolide E demonstrated minor cytotoxicities to normal human skin cells (keratinocytes, melanocytes, and fibroblasts); therefore, it is a potential chemotherapeutic agent against skin melanoma. PMID- 21707084 TI - Delivery of a peptide radiopharmaceutical to brain with an IgG-avidin fusion protein. AB - The genetic engineering, host cell expression, purity, identity, and in vivo brain drug targeting properties are described for a new IgG-fusion protein, designated the cTfRMAb-AV fusion protein. Avidin (AV) is fused to the carboxyl terminus of the heavy chain of the genetically engineered chimeric monoclonal antibody (mAb) against the mouse transferrin receptor (TfR). The TfRMAb binds the endogenous TfR on the blood-brain barrier (BBB), which triggers transport into brain from blood. The cTfRMAb-AV fusion protein is produced in stably transfected Chinese hamster ovary cells, which are grown in serum free medium under conditions of biotin starvation. Following affinity purification, the purity and identity of the cTfRMAb-AV fusion protein were verified by electrophoresis and Western blotting. The affinity of the cTfRMAb for the murine TfR is high, K(I) = 4.6 +/- 0.5 nM, despite fusion of avidin to the antibody heavy chain. The model peptide radiopharmaceutical used in this study is the Abeta(1-40) amyloid peptide of Alzheimer's disease (AD), which in a brain-penetrating form could be used to image the amyloid plaque in brain in AD. The BBB transport and brain uptake of the [(125)I]-Abeta(1-40) peptide was measured in mice injected intravenously (IV) with the peptide either free or conjugated to the cTfRMAb-AV fusion protein. The brain uptake of the free Abeta(1-40) peptide was very low, 0.1% of injected dose (ID)/gram brain following i.v. injection, and is comparable to the brain uptake of a brain blood volume marker. However, the brain uptake of the Abeta(1-40) peptide was high, 2.1 +/- 0.2% ID/gram brain, following attachment of the biotinylated peptide to the cTfRMAb-AV fusion protein. Capillary depletion analysis showed the peptide penetrated the brain parenchyma from blood. The cTfRMAb-AV fusion protein is a new drug delivery system that can target to mouse brain monobiotinylated peptide or antisense radiopharmaceuticals. PMID- 21707086 TI - Luminescence of lanthanide-dimethyl sulfoxide compound solutions. AB - Dimethyl sulfoxide (DMSO) has the ability to penetrate living tissues without causing significant damage. Of foremost importance to our understanding of the possible functions of DMSO in biological systems is its ability to replace some of the water molecules associated with the cellular constituents or to affect the structure of the omnipresent water. Luminescence probes have been widely used for biological studies such as labeling, imaging, and detection. Luminescence probes formed in DMSO may find new applications. Here luminescence compounds formed by refluxing lanthanide nitrates of Ce, La, Tb, Yb, Nd, Gd, and Eu in DMSO are reported and their luminescence properties investigated. On the basis of their luminescence spectral properties, the compounds can be classified into four classes. For compounds I with Yb, Ce, and La, the excitation and emission spectra are very broad and their excitation or emission peaks are shifted to longer wavelengths when the monitored emission or excitation wavelength is longer. For compounds II with Gd and Nd, both the excitation and emission spectra are very broad but their emission wavelengths change little at different excitation wavelengths. For Tb-DMSO as compound III, both the typical emissions from the f-f transitions of Tb(3+) and a broad emission at 445 nm are observed. At low reaction temperatures, the f-f emissions are dominant, while at high reaction temperatures such as 180 degrees C, the broad emission at 445 nm is dominant. For compound IV, Eu-DMSO, the dominant emissions are from the f-f transitions of Eu(3+) and only a weak broad emission is observed, which is likely from the d-f transition of Eu(2+) rather than from metal-to-ligand charge transfer states. PMID- 21707087 TI - Theoretical study of 1,2-hydride shift associated with the isomerization of glyceraldehyde to dihydroxy acetone by Lewis acid active site models. AB - The isomerization of glyceraldehyde to dihydroxy acetone catalyzed by the active site of Sn-beta zeolite is investigated using the B3LYP density functional and MP2 levels of theory. Structural studies were aimed to understanding the binding modes of glyceraldehyde with the active site, and the detailed free energy landscape was computed for the isomerization process. The rate-limiting step for the isomerization is the 1,2-hydride shift, which is enhanced by the active participation of the hydroxyl group in the hydrolyzed Sn-beta active site analogues to the one seen in the xylose isomerase. On the basis of the assessment of the activation barriers for isomerization by the Sn, Zr, Ti, and Si zeolite models, the activity of the catalysts are in the order of Sn > Zr > Ti > Si in aqueous dielectric media. PMID- 21707089 TI - Design and production of a chimeric resilin-, elastin-, and collagen-like engineered polypeptide. AB - Protein-inspired biomaterials have gained great interest as an alternative to synthetic polymers, in particular, for their potential use as biomedical devices. The potential inspiring models are mainly proteins able to confer mechanical properties to tissues and organs, such as elasticity (elastin, resilin, spider silk) and strength (collagen, silk). The proper combination of repetitive sequences, each of them derived from different proteins, represents a useful tool for obtaining biomaterials with tailored mechanical properties and biological functions. In this report we describe the design, the production, and the preliminary characterization of a chimeric polypeptide, based on sequences derived from the highly resilient proteins resilin and elastin and from collagen like sequences. The results show that the obtained chimeric recombinant material exhibits promising self-assembling properties. Young's modulus of the fibers was determined by AFM image analysis and lies in the range of 0.1-3 MPa in agreement with the expectations for elastin-like and resilin-like materials. PMID- 21707088 TI - Gd complexes of macrocyclic diethylenetriaminepentaacetic acid (DTPA) biphenyl 2,2'-bisamides as strong blood-pool magnetic resonance imaging contrast agents. AB - We report the synthesis of macrocyclic DTPA conjugates of 2,2'-diaminobiphenyl and their Gd complexes of the type [Gd(L)(H(2)O)].xH(2)O (2a,b; L = 1a,b) for use as new MRI blood-pool contrast agents (MRI BPCAs). Pharmacokinetic inertness of 2 compares well with those of analogous Gd-DTPA MRI CAs currently in use. The present system also shows very high stability in human serum. The R(1) relaxivity reaches 10.9 mM(-1) s(-1), which is approximately 3 times as high as that of structurally related Gd-DOTA (R(1) = 3.7 mM(-1) s(-1)). The R(1) relaxivity in HSA goes up to 37.2 mM(-1) s(-1), which is almost twice as high as that of MS 325, a leading BPCA, demonstrating a strong blood pool effect. The in vivo MR images of mice obtained with 2b are coherent, showing strong signal enhancement in heart, abdominal aorta, and small vessels. Even the brain tumor is vividly enhanced for an extended period of time. The structural uniqueness of 2 is that it is neutral in charge and thus makes no resort to electrostatic interaction, supposedly one of the essential factors for the blood-pool effect. PMID- 21707090 TI - Reversible and selective sensing of aniline vapor by perylene-bridged bis(cyclodextrins) assembly. AB - Detecting volatile amines is a significant topic in quality control of food and medical diagnosis. Selectively sensing a given gaseous amine from other analogues, however, still remains a formidable challenge in solid-state fluorescence sensing because of the lack of specialized binding sites. Herein, we demonstrate a new supramolecular strategy for selectively sensing aniline based on the aggregation of perylene-cyclodextrin conjugate 1. Compared with our previous results based on perylene-bridged bis(permethyl-beta-cyclodextrins), the present system achieves a pronounced improvement of both selectivity and reversibility. The sensory material was constructed from the pi-stacking aggregate of 1 embedded in poly(vinylidene fluoride) membrane, which ensures benign solid-state fluorescence with potential amplification mechanism as well as convenient preparation and practical operation. Grafting cyclodextrin receptors endows the sensory material with desired selectivity as a result of diverse binding abilities. Especially, the thermodynamically reversible host-guest inclusion leads to the excellent sensing reversibility. The present research opens the way to build new n-type fluorescence sensory materials for detecting volatile amines instantly with compelling selectivity, sensitivity, and reversibility. PMID- 21707091 TI - Effect of temperature and salinity on phosphate sorption on marine sediments. AB - Our previous studies on the phosphate sorption on sediments in Florida Bay at 25 degrees C in salinity 36 seawater revealed that the sorption capacity varies considerably within the bay but can be attributed to the content of sedimentary P and Fe. It is known that both temperature and salinity influence the sorption process and their natural variations are the greatest in estuaries. To provide useful sorption parameters for modeling phosphate cycle in Florida Bay, a systematic study was carried out to quantify the effects of salinity and temperature on phosphate sorption on sediments. For a given sample, the zero equilibrium phosphate concentration and the distribution coefficient were measured over a range of salinity (2-72) and temperature (15-35 degrees C) conditions. Such a suite of experiments with combinations of different temperature and salinity were performed for 14 selected stations that cover a range of sediment characteristics and geographic locations of the bay. Phosphate sorption was found to increase with increasing temperature or decreasing salinity and their effects depended upon sediment's exchangeable P content. This study provided the first estimate of the phosphate sorption parameters as a function of salinity and temperature in marine sediments. Incorporation of these parameters in water quality models will enable them to predict the effect of increasing freshwater input, as proposed by the Comprehensive Everglades Restoration Plan, on the seasonal cycle of phosphate in Florida Bay. PMID- 21707092 TI - Alternative spiroketalization methods toward purpuromycin: a hemiketal conjugate addition strategy and use of an electron-rich isocoumarin precursor. AB - Two methods are presented that were designed to circumvent the persistent problem of benzofuran formation and instead yield a spiroketal of the rubromycin family type. First, using an alternative disconnection, a hemiketal conjugate addition to a naphthaquinone electrophile was investigated. Synthesis of the requisite electrophile provided insight into the selective oxidation and functionalization of the naphthalene portion. Second, the electronic features of the isocoumarin ring system were adjusted, and the corresponding reactivity further supports the hypothesis that electron-rich isocoumarins are capable of spiroketalization. Robust, flexible syntheses from simple precursors were developed that allowed multiple reduced isocoumarins to be generated. Combined, the data presented herein give insight into the sensitivities of this family and illuminate other potential methods of spiroketalization. In addition, the convergent assembly of substrates containing different naphthaquinone and isocoumarin subunits highlights the utility of our 1,3-dipolar cycloaddition approach to generate analogs of these structures for SAR, as well as chemical reactivity studies. PMID- 21707093 TI - High-pressure gas hydrates of argon: compositions and equations of state. AB - Volume changes corresponding to transitions between different phases of high pressure argon gas hydrates were studied with a piston-cylinder apparatus at room temperature. Combination of these data with the data taken from the literature allowed us to obtain self-consistent set of data concerning the equations of state and compositions of the high-pressure hydrates of argon. PMID- 21707095 TI - Three-dimensional Fe speciation of an inclusion cloud within an ultradeep diamond by confocal MU-X-ray absorption near edge structure: evidence for late stage overprint. AB - A stream of 1-20 MUm sized mineral inclusions having the negative crystal shape of its host within an "ultra-deep" diamond from Rio Soriso (Juina area, Mato Grosso State, Brazil) has been studied with confocal MU-X-ray absorption near edge structure (MUXANES) at the Fe K and Mn K edges. This technique allows the three-dimensional nondestructive speciation of the Fe and Mn containing minerals within the inclusion cloud. The observed Fe-rich inclusions were identified to be ferropericlase (Fe,Mg)O, hematite and a mixture of these two minerals. Confocal MU-X-ray fluorescence (MUXRF) further showed that Ca-rich inclusions were present as well, which are spatially separated from or in close contact with the Fe-rich inclusions. The inclusions are aligned along a plane, which most likely represents a primary growth zone. In the close vicinity of the inclusions, carbon coated planar features are visible. The three-dimensional distribution indicates a likely fluid overprint along an open crack. Our results imply that an imposed negative diamond shape of an inclusion alone does not exclude epigenetic formation or intense late stage overprint. PMID- 21707094 TI - Copper redox cycling in the prion protein depends critically on binding mode. AB - The prion protein (PrP) takes up 4-6 equiv of copper in its extended N-terminal domain, composed of the octarepeat (OR) segment (human sequence residues 60-91) and two mononuclear binding sites (at His96 and His111; also referred to as the non-OR region). The OR segment responds to specific copper concentrations by transitioning from a multi-His mode at low copper levels to a single-His, amide nitrogen mode at high levels (Chattopadhyay et al. J. Am. Chem. Soc. 2005, 127, 12647-12656). The specific function of PrP in healthy tissue is unclear, but numerous reports link copper uptake to a neuroprotective role that regulates cellular stress (Stevens, et al. PLoS Pathog.2009, 5 (4), e1000390). A current working hypothesis is that the high occupancy binding mode quenches copper's inherent redox cycling, thus, protecting against the production of reactive oxygen species from unregulated Fenton type reactions. Here, we directly test this hypothesis by performing detailed pH-dependent electrochemical measurements on both low and high occupancy copper binding modes. In contrast to the current belief, we find that the low occupancy mode completely quenches redox cycling, but high occupancy leads to the gentle production of hydrogen peroxide through a catalytic reduction of oxygen facilitated by the complex. These electrochemical findings are supported by independent kinetic measurements that probe for ascorbate usage and also peroxide production. Hydrogen peroxide production is also observed from a segment corresponding to the non-OR region. Collectively, these results overturn the current working hypothesis and suggest, instead, that the redox cycling of copper bound to PrP in the high occupancy mode is not quenched, but is regulated. The observed production of hydrogen peroxide suggests a mechanism that could explain PrP's putative role in cellular signaling. PMID- 21707096 TI - Temperature dependence of ion and water diffusion in crown ether loaded Nafion matrix. AB - Temperature dependence study of the self-diffusion coefficient of Cs(+) ion in dibenzo-18-crown-6 (DB18C6) modified Nafion-117 (Cs-Naf-CR) was carried out in the temperature range of 50-65 degrees C. Temperature dependence of water diffusion in Cs-Naf-CR was also studied to understand the mechanism of cation and water transport in the membrane. Because of the very slow kinetics of isotopic exchange, self-diffusion measurement of Na(+) in Na-Naf-CR was carried out only at 60 degrees C. The result indicates that self-diffusion behavior is governed by the nature of the cation in which the crown ether was loaded in the membrane matrix. The activation energy of diffusion for Cs(+) ion and water in Cs-Naf-CR was found to be much higher than that in the pure Cs(+) form of Nafion (Cs-Naf). Water uptake of the membrane was also found to have reduced compared to Cs/Na Naf. The results point to the binding of the ions by DB18C6 and the destruction of the water channels in the crown ether loaded membrane. The differential scanning calorimetry (DSC) data supports these observations. PMID- 21707097 TI - Oleate-induced beta cell dysfunction and apoptosis: a proteomic approach to glucolipotoxicity by an unsaturated fatty acid. AB - High levels of fatty acids contribute to loss of functional beta cell mass in type 2 diabetes, in particular in combination with high glucose levels. The aim of this study was to elucidate the role of the unsaturated free fatty acid oleate in glucolipotoxicity and to unravel the molecular pathways involved. INS-1E cells were exposed to 0.5 mM oleate, combined or not with 25 mM glucose, for 24 h. Protein profiling of INS-1E cells was done by 2D-DIGE, covering pH ranges 4-7 and 6-9 (n = 4). Identification of differentially expressed proteins (P < 0.05) was based on MALDI-TOF analysis using Peptide Mass Fingerprint (PMF) and fragmentation (MS/MS) of the most intense peaks of PMF and proteomic results were confirmed by functional assays. Oleate impaired glucose-stimulated insulin secretion and decreased insulin content. 2D-DIGE analysis revealed 53 and 54 differentially expressed proteins for oleate and the combination of oleate and high glucose, respectively. Exposure to oleate down-regulated chaperones, hampered insulin processing and ubiquitin-related proteasomal degradation, and induced perturbations in vesicle transport and budding. In combination with high glucose, shunting of excess amounts of glucose toward reactive oxygen species production worsened beta cell death. The present findings provide new insights in oleate-induced beta cell dysfunction and identify target proteins for preservation of functional beta cell mass in type 2 diabetes. PMID- 21707098 TI - Nanosize-induced hydrogen storage and capacity control in a non-hydride-forming element: rhodium. AB - We report the first example of nanosize-induced hydrogen storage in a metal that does not absorb hydrogen in its bulk form. Rhodium particles with diameters of <10 nm were found to exhibit hydrogen-storage capability, while bulk Rh does not absorb hydrogen. Hydrogen storage was confirmed by in situ powder X-ray diffraction, solid-state (2)H NMR, and hydrogen pressure-composition isotherm measurements. The hydrogen absorption capacity could be tuned by controlling the particle size. PMID- 21707099 TI - Energetic, entropic, and volumetric effects in nonaqueous associated solutions. AB - On the basis of a simple two-state association model (TSAM), a comprehensive study of thermodynamic response functions for nonaqueous associated solutions is presented. The excess isobaric heat capacities C(p)(E)(T) and excess thermal expansivities V(p)(E) = (?V(E)/?T)(p) for a number of alcohol-alkane, amine alkane, alcohol-ether, and alcohol-alcohol mixtures have been experimentally determined at atmospheric pressure within 278.15-338.15 K for C(p)(E) and 283.15 333.15 K for V(p)(E)(T). A rich variety (in some cases unreported) of temperature dependences for C(p)(E)(T) but also for V(p)(E)(T) curves has been observed. This thermodynamic information has been rationalized with the TSAM, which is found to qualitatively account for all observations. Specifically, the model provides a detailed dissection of the energetic and entropic effects of association that are reflected on C(p)(E)(T), and of the volumetric effects that are echoed on V(p)(E)(T). The latter, almost unexplored to date, are found to be opposite to what is currently being conjectured for "low-temperature water", and they stimulate further experimental studies on aqueous solutions of nonelectrolytes. PMID- 21707100 TI - Modeling of isomeric structure of diphenyl urethane by FT-IR spectroscopy during synthesis from phenylisocyanate and phenol as an inverse kinetic problem. AB - Isomeric structure of diphenyl urethane during synthesis from phenylisocyanate and phenol has been investigated by modeling the reaction extent as an inverse kinetic problem, using FT-IR difference spectroscopy, to obtain structural information on the formation of the isomeric structure. The aim of this study was to determine the primary algebraic structures (an inverse problem), which describe the chemical reaction system in terms of spectroscopic observables. Moreover, a conventional description of the evolution of chemical species and of the change of moles of the observable species, as a function of time, was explored, defined in terms of the extent of reaction xi and the reaction stoichiometries nu, based on the Jouguet-de Donder equation, for an invariant system in batch experiments. Two processes for diphenyl urethane with hydrogen bonding and their free form were identified. Experimental input for the identification is a matrix of in situ spectroscopic data A (FT-IR/ATR spectra measured during the reaction process) and a matrix of initial moles (N(0)). Subsequently, (1) the number of observable reactions present, (2) the change of moles and their extent of reactions xi, (3) the reaction stoichiometries v, (4) the concentration of all observable species (C), and finally (5) the kinetic rate constants were determined. Meaningful extraction of such algebraic system information (an inverse algebraic problem) is a mandatory prerequisite for the subsequent detailed kinetic modeling (an inverse kinetic problem). This research opens up the possibility of modeling the extent of the reaction and performing a kinetic analysis of the hydrogen bonding in an organic system. Important information could be extracted, for understanding of different functions and interactions of hydrogen bonding in a supramolecular system. PMID- 21707101 TI - Extending carbon chain length of 1-butanol pathway for 1-hexanol synthesis from glucose by engineered Escherichia coli. AB - An Escherichia coli strain was engineered to synthesize 1-hexanol from glucose by extending the coenzyme A (CoA)-dependent 1-butanol synthesis reaction sequence catalyzed by exogenous enzymes. The C4-acyl-CoA intermediates were first synthesized via acetyl-CoA acetyltransferase (AtoB), 3-hydroxybutyryl-CoA dehydrogenase (Hbd), crotonase (Crt), and trans-enoyl-CoA reductase (Ter) from various organisms. The butyryl-CoA synthesized was further extended to hexanoyl CoA via beta-ketothiolase (BktB), Hbd, Crt, and Ter. Finally, hexanoyl-CoA was reduced to yield 1-hexanol by aldehyde/alcohol dehydrogenase (AdhE2). Enzyme activities for the C6 intermediates were confirmed by assays using HPLC and GC. 1 Hexanol was secreted to the fermentation medium under anaerobic conditions. Furthermore, co-expressing formate dehydrogenase (Fdh) from Candida boidinii increased the 1-hexanol titer. This demonstration of 1-hexanol production by extending the 1-butanol pathway provides the possibility to produce other medium chain length alcohols using the same strategy. PMID- 21707102 TI - beta-Cyclodextrin-based polycationic amphiphilic "click" clusters: effect of structural modifications in their DNA complexing and delivery properties. AB - Monodisperse facial amphiphiles consisting of a beta-cyclodextrin (betaCD) platform exposing a multivalent display of cationic groups at the primary rim and bearing hydrophobic chains at the secondary oxygens have been prepared by implementing two very robust "click" methodologies, namely cuprous cation catalyzed azide-alkyne cycloaddition (CuAAC) and thiourea-forming reaction. Most interestingly, the use of solid-supported Cu(I) catalysts was found to be very well suited for multiple CuAAC while facilitating purification of the C(7) symmetric macromolecular triazole adducts. The strategy is compatible with molecular diversity-oriented approaches, which has been exploited to generate a small library of click polycationic amphiphilic CDs (paCDs) for assessing the influence of structural modifications in the ability to complex, compact, and protect pDNA and the efficiency of the resulting paCD:pDNA nanocomplexes (CDplexes) to deliver DNA into cells and promote transfection. The results indicate that fine-tuning the hydrophilic/hydrophobic balance is critical to achieve optimal self-assembling properties and stability of the resulting CDplexes in saline- and serum-containing media. Triazole-type paCDs were, in general, less efficient in promoting gene transfection than thiourea-type derivatives. Nevertheless, the current body of results support that the "dual click" approach implying sequential CuAAC and thiourea-forming reactions represents a versatile strategy to optimize the gene delivery capabilities of cyclodextrin-based facial amphiphiles. PMID- 21707103 TI - Total synthesis of (+)-mupirocin H from D-glucose. AB - Enantioselective total synthesis of mupirocin H is accomplished starting from D glucose featuring strategic application of D-glucose derived chirality, diastereoselective Still-Barrish hydroboration, and further elaboration of carbon chain to furnish a phenyltetrazolyl sulfone intermediate, which on coupling with (2S,3S)-2-methyl-3-(triisopropylsilyloxy)butanal under Julia-Kocienski olefination conditions gave an advanced E-olefinic intermediate selectively. The E-olefin was transformed to the 4-hydroxynitrile, a prefinal substrate, which on acid-catalyzed oxidative lactonization furnished the target molecule mupirocin H in 19 steps from known compound 6 (longest linear sequence) with an overall yield of 4.96%. PMID- 21707104 TI - Virtual issue on plasmonics. PMID- 21707106 TI - Alternative spiroketalization methods toward purpuromycin: a diketone approach to prevent benzofuran formation. AB - The central portion of purpuromycin has been assembled via a classical spiroketalization reaction. Key to promoting this reaction mode versus benzofuran formation was the oxidation state of the spiroketal core. With a higher oxidation state, even the electron-deficient isocoumarin found in purpuromycin could be employed directly in the spiroketalization. The two halves of the spiroketalization precursor were joined via a nitrile oxide/styrene 1,3-dipolar cycloaddition. A very mild selenium dioxide oxidation was used to introduce the required oxidation state of the spiroketal core. PMID- 21707107 TI - Differential expression of odorant-binding proteins in the mandibular glands of the honey bee according to caste and age. AB - Odorant-binding proteins (OBPs) and chemosensory proteins (CSPs) mediate both perception and release of chemical stimuli in insects. The genome of the honey bee contains 21 genes encoding OBPs and 6 encoding CSPs. Using a proteomic approach, we have investigated the expression of OBPs and CSPs in the mandibular glands of adult honey bees in relation to caste and age. OBP13 is mostly expressed in young individuals and in virgin queens, while OBP21 is abundant in older bees and is prevalent in mated queens. OBP14, which had been found in larvae, is produced in hive workers' glands. Quite unexpectedly, the mandibular glands of drones also contain OBPs, mainly OBP18 and OBP21. We have expressed three of the most represented OBPs and studied their binding properties. OBP13 binds with good specificity oleic acid and some structurally related compounds, OBP14 is better tuned to monoterpenoid structures, while OBP21 binds the main components of queen mandibular pheromone as well as farnesol, a compound used as a trail pheromone in the honey bee and other hymenopterans. The high expression of different OBPs in the mandibular glands suggests that such proteins could be involved in solubilization and release of semiochemicals. PMID- 21707108 TI - Synthesis of amidic alginate derivatives and their application in microencapsulation of lambda-cyhalothrin. AB - 1-Octyl amine was covalently coupled to sodium alginate(NaAlg) in an aqueous phase reaction via acidamide functions using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC-HCl) as a coupling reagent to provide octyl grafted amphiphilic alginate-amide derivative(OAAD) for subsequent use in lambda cyhalothrin (LCH) microcapsule application. The structure of OAAD was confirmed by FT-IR and (1)H NMR spectroscopies. The new alginate-amide derivative was used for fabricating microcapsule that can effectively encapsulate LCH by emulsification-gelation technique. The microcapsules were characterized by optical microscopy (OM), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and laser particle size analysis. The encapsulation efficiency and drug release behavior of LCH from the microcapsules were investigated. Results showed that the microcapsules were in spherical form with diameter mostly in the range of 0.5-10 MUm and possessed a structure with LCH as core and OAAD as shell. The encapsulation efficiency and the release performance of the microcapsules were influenced by DS of OAAD and amount of CaCl(2). The mechanism of LCH release was found to vary from anomalous to Fickian to quasi Fickian transport with the DS of OAAD varied from 10.8 to 30.3 and the CaCl(2)/emulsion ratios varied from 0.09 to 0.03%. PMID- 21707109 TI - Slow release and delivery of antisense oligonucleotide drug by self-assembled peptide amphiphile nanofibers. AB - Antisense oligonucleotides provide a promising therapeutic approach for several disorders including cancer. Chemical stability, controlled release, and intracellular delivery are crucial factors determining their efficacy. Gels composed of nanofibrous peptide network have been previously suggested as carriers for controlled delivery of drugs to improve stability and to provide controlled release, but have not been used for oligonucleotide delivery. In this work, a self-assembled peptide nanofibrous system is formed by mixing a cationic peptide amphiphile (PA) with Bcl-2 antisense oligodeoxynucleotide (ODN), G3139, through electrostatic interactions. The self-assembly of PA-ODN gel was characterized by circular dichroism, rheology, atomic force microscopy (AFM) and scanning electron microscopy (SEM). AFM and SEM images revealed establishment of the nanofibrous PA-ODN network. Due to the electrostatic interactions between PA and ODN, ODN release can be controlled by changing PA and ODN concentrations in the PA-ODN gel. Cellular delivery of the ODN by PA-ODN nanofiber complex was observed by using fluorescently labeled ODN molecule. Cells incubated with PA-ODN complex had enhanced cellular uptake compared to cells incubated with naked ODN. Furthermore, Bcl-2 mRNA amounts were lower in MCF-7 human breast cancer cells in the presence of PA-ODN complex compared to naked ODN and mismatch ODN evidenced by quantitative RT-PCR studies. These results suggest that PA molecules can control ODN release, enhance cellular uptake and present a novel efficient approach for gene therapy studies and oligonucleotide based drug delivery. PMID- 21707110 TI - Electric field driven changes of a gramicidin containing lipid bilayer supported on a Au(111) surface. AB - Langmuir-Blodgett and Langmuir-Schaeffer methods were employed to deposit a mixed bilayer consisting of 90% of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 10% of gramicidin (GD), a short 15 residue ion channel forming peptide, onto a Au(111) electrode surface. This architecture allowed us to investigate the effect of the electrostatic potential applied to the electrode on the orientation and conformation of DMPC molecules in the bilayer containing the ion channel. The charge density data were determined from chronocoulometry experiments. The electric field and the potential across the membrane were determined through the use of charge density curves. The magnitudes of potentials across the gold supported biomimetic membrane were comparable to the transmembrane potential acting on a natural membrane. The information regarding the orientation and conformation of DMPC and GD molecules in the bilayer was obtained from photon polarization modulation infrared reflection absorption spectroscopy (PMIRRAS) measurements. The results show that the bilayer is adsorbed, in direct contact with the metal surface, when the potential across the interface is more positive than -0.4 V and is lifted from the gold surface when the potential across the interface is more negative than -0.4 V. This change in the state of the bilayer has a significant impact on the orientation and conformation of the phospholipid and gramicidin molecules. The potential induced changes in the membrane containing peptide were compared to the changes in the structure of the pure DMPC bilayer determined in earlier studies. PMID- 21707112 TI - Identification of toxifying and detoxifying moieties for mutagenicity prediction by priority assessment. AB - The search for structural subunits that affect compound toxicity cannot be manually performed on large databases. In addition, the a priori definition of important groups is impossible. Structural diversity requires the analysis of the complete data space and the selection of the details there present. A single substructure cannot be considered sufficient when assigning compound toxicity. In contrast, if we consider all the substructures in the database as the elements of a complete collection and if we can build a working hierarchy, the identification of the best feasible result using the available data is possible. If the database includes several significant examples, the results will be valuable. The use of a fragment-based description of a mutagenicity database together with the realization of a general hierarchy allows for the identification of the moieties that control the toxifying/detoxifying action of each compound. PMID- 21707111 TI - Crystallographic and kinetic evidence of allostery in a trypsin-like protease. AB - Protein allostery is based on the existence of multiple conformations in equilibrium linked to distinct functional properties. Although evidence of allosteric transitions is relatively easy to identify by functional studies, structural detection of a pre-existing equilibrium between alternative conformations remains challenging even for textbook examples of allosteric proteins. Kinetic studies show that the trypsin-like protease thrombin exists in equilibrium between two conformations where the active site is either collapsed (E*) or accessible to substrate (E). However, structural demonstration that the two conformations exist in the same enzyme construct free of ligands has remained elusive. Here we report the crystal structure of the thrombin mutant N143P in the E form, which complements the recently reported structure in the E* form, and both the E and E* forms of the thrombin mutant Y225P. The side chain of W215 moves 10.9 A between the two forms, causing a displacement of 6.6 A of the entire 215-217 segment into the active site that in turn opens or closes access to the primary specificity pocket. Rapid kinetic measurements of p-aminobenzamidine binding to the active site confirm the existence of the E*-E equilibrium in solution for wild-type and the mutants N143P and Y225P. These findings provide unequivocal proof of the allosteric nature of thrombin and lend strong support to the recent proposal that the E*-E equilibrium is a key property of the trypsin fold. PMID- 21707113 TI - Clean coupling of unfunctionalized porphyrins at surfaces to give highly oriented organometallic oligomers. AB - The direct coupling of complex, functional organic molecules at a surface is one of the outstanding challenges in the road map to future molecular devices. Equally demanding is to meet this challenge without recourse to additional functionalization of the molecular building blocks and via clean surface reactions that leave no surface contamination. Here, we demonstrate the directional coupling of unfunctionalized porphyrin molecules--large aromatic multifunctional building blocks--on a single crystal copper surface, which generates highly oriented one-dimensional organometallic macromolecular nanostructures (wires) in a reaction which generates gaseous hydrogen as the only byproduct. In situ scanning tunneling microscopy and temperature programmed desorption, supported by theoretical modeling, reveal that the process is driven by C-H bond scission and the incorporation of copper atoms in between the organic components to form a very stable organocopper oligomer comprising organometallic edge-to-edge porphyrin-Cu-porphyrin connections on the surface that are unprecedented in solution chemistry. The hydrogen generated during the reaction leaves the surface and, therefore, produces no surface contamination. A remarkable feature of the wires is their stability at high temperatures (up to 670 K) and their preference for 1D growth along a prescribed crystallographic direction of the surface. The on-surface formation of directional organometallic wires that link highly functional porphyrin cores via direct C-Cu-C bonds in a single-step synthesis is a new development in surface-based molecular systems and provides a versatile approach to create functional organic nanostructures at surfaces. PMID- 21707114 TI - Indium(III)-catalyzed asymmetric hetero-Diels-Alder reaction of Brassard-type diene with aliphatic aldehydes. AB - A highly diastereo- and enantioselective hetero-Diels-Alder (HDA) reaction of a Brassard-type diene with aliphatic aldehydes has been developed. The chiral N,N' dioxide L2/In(OTf)(3) complex was efficient toward the obtention of the corresponding beta-methoxy-gamma-methyl alpha,beta-unsaturated delta-lactones in good yields (up to 86%) as well as dr and ee values (up to 97:3 cis/trans and 94% ee). In addition, the product 4a could be easily transformed into the methyl protected epi-prelactone B by hydrogenation. PMID- 21707115 TI - Bambus[n]urils: a new family of macrocyclic anion receptors. AB - A recently discovered anion receptor is jointed by three related macrocycles differing in the number of glycoluril units and type of substitution. The synthesis is carried out in nonpolar solvents compared to aqueous media used in the case of the original macrocycle. The size of macrocycle is controlled by a template. A hexameric macrocycle with benzyl substitution binds halide anions with an affinity exceeding 10(9) M(-1) while a tetrameric analog does not bind any of the investigated anions. PMID- 21707116 TI - Ratiometric fluorescent sensor for silver ion and its resultant complex for iodide anion in aqueous solution. AB - In aqueous solution, sensor DQAg can selectively detect Ag(+) based on inhibition of the resonance, demonstrating a large hypsochromic shift of 84 nm and remarkable changes in the ratio (F(481 nm)/F(565 nm)) of the emission intensity (R/R(0) up to 26-fold). Furthermore, the resultant Ag-DQAg also displays a ratiometric and highly selective response to iodide anion over other anions due to the liberation of DQAg from the complex by precipitating AgI. PMID- 21707117 TI - Thermomorphic polyethylene-supported olefin metathesis catalysts. AB - The preparation of polyethylene-oligomer (PE(olig))-supported N-heterocyclic carbene ligands (NHCs) and their Ru complexes is described. These complexes are structurally analogous to their low molecular weight counterparts and can serve as thermomorphic, recoverable/recyclable ring-closing metathesis (RCM) catalysts. Because of the insolubility of PE(olig)-supported species at 25 degrees C, such complexes can perform homogeneous RCM reactions at 65 degrees C and, upon cooling, precipitate as solids. This allows for their quantitative separation from solutions of products. PMID- 21707118 TI - A remarkably simple protocol for the N-formylation of amino acid esters and primary amines. AB - A simple, convenient, and wide scope protocol for the N-formylation of amino acid esters and primary amines has been developed utilizing only imidazole in warm DMF. PMID- 21707119 TI - Synthesis of enantiopure substituted piperidines via an aziridinium ring expansion. AB - Herein we report a novel methodology for the asymmetric synthesis of 3 substituted piperidines from readily available chiral building blocks. This method, which features a novel irreversible dihydropyrole-tetrahydropyridine ring expansion, allows the introduction of a large variety of substituents at the 3 position and permits substitution at the 2- and 6-position giving mono-, di-, or trisubstituted piperidines with high diastereocontrol. PMID- 21707121 TI - In vivo-in vitro and XANES spectroscopy assessments of lead bioavailability in contaminated periurban soils. AB - Lead (Pb) bioaccessibility was assessed using 2 in vitro methods in 12 Pb contaminated soils and compared to relative Pb bioavailability using an in vivo mouse model. In vitro Pb bioaccessibility, determined using the intestinal phase of the Solubility Bioaccessibility Research Consortium (SBRC) assay, strongly correlated with in vivo relative Pb bioavailability (R(2) = 0.88) following adjustment of Pb dissolution in the intestinal phase with the solubility of Pb acetate at pH 6.5 (i.e., relative Pb bioaccessibility). A strong correlation (R(2) = 0.78) was also observed for the relative bioaccessibility leaching procedure (RBALP), although the method overpredicted in vivo relative Pb bioavailability for soils where values were <40%. Statistical analysis of fit results from X-ray absorption near-edge structure (XANES) data for selected soils (n = 3) showed that Pb was strongly associated with Fe oxyhydroxide minerals or the soil organic fraction prior to in vitro analysis. XANES analysis of Pb speciation during the in vitro procedure demonstrated that Pb associated with Fe minerals and the organic fraction was predominantly solubilized in the gastric phase. However, during the intestinal phase of the in vitro procedure, Pb was strongly associated with formation of ferrihydrite which precipitated due to the pH (6.5) of the SBRC intestinal phase. Soils where Fe dissolution was limited had markedly higher concentrations of Pb in solution and hence exhibited greater relative bioavailability in the mouse model. This data suggests that coexistence of Fe in the intestinal phase plays an important role in reducing Pb bioaccessibility and relative bioavailability. PMID- 21707122 TI - Use of industrial byproducts as alumina sources for the synthesis of calcium sulfoaluminate cements. AB - Calcium sulfoaluminate (CSA) cements show some desirable environmentally friendly features that include the possibility of using several industrial byproducts as raw materials in their manufacturing process. Alumina powder, from the secondary aluminum manufacture, and anodization mud, from the production process of anodized aluminum, have proved to be suitable as partial or total substitutes for an expensive natural material like bauxite. CSA clinker generating raw mixtures, containing limestone, natural gypsum, bauxite, and/or one of the alumina-rich byproducts, were heated 2 h in a laboratory electric oven at temperatures ranging from 1150 to 1300 degrees C. Conversion of reactants into 4CaO.3Al(2)O(3).SO(3) (the key component of CSA cements), evaluated using X-ray diffraction (XRD) analysis, increased with an increase of both burning temperature and byproduct concentration. When examined through differential thermogravimetric and XRD analyses, a synthetic CSA clinker (made from the raw mixture incorporating alumina powder as a total replacement of bauxite) mixed with 20% gypsum showed a hydration behavior almost similar to that of an industrial CSA cement containing the same amount of gypsum. PMID- 21707123 TI - Attentional bias toward threat in contamination fear: overt components and behavioral correlates. AB - Recent research suggests that an attentional bias toward threat may play a causal role in obsessive-compulsive disorder (OCD) with contamination concerns. However, the attentional components involved in this bias, as well as its behavioral correlates, remain unclear. In the present study, eye movements were recorded in individuals high and low in contamination fear (HCF, LCF, respectively) during 30 s exposures to stimulus arrays containing contamination threat, general threat, pleasant, and neutral images. HCF individuals oriented gaze toward contamination threat more often than LCF individuals in initial fixations, and this bias mediated group differences in responding to a behavioral challenge in a public restroom. No group differences were found in the maintenance of gaze on contamination threat, both in terms of initial gaze encounters, as well as gaze duration over time. However, the HCF group made shorter fixations on contamination threat relative to other image types. The implications of these findings for further delineating the nature and function of attentional biases in contamination-based OCD are discussed. PMID- 21707124 TI - Mind the gap: assessing impairment among children affected by proposed revisions to the diagnostic criteria for oppositional defiant disorder. AB - The Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5) workgroup for disruptive behavior disorders is considering adopting a frequency threshold for symptoms of oppositional defiant disorder (ODD). In the present study, the impact of substituting the term "often" with a specific age-based frequency on impairment and prognosis among preschool children was tested in a longitudinal design. Mutually exclusive groups were created to identify children who met criteria for ODD based on a symptom threshold of "often," as in Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM-4), and those that met criteria for ODD based on a threshold of "1-2 times per day," which approximated the proposal for DSM-5. Comparisons of these groups to each other and to nondiagnosed peers determined the impact of changing the symptom threshold on impairment and prognosis. Close to one-third of children who met DSM 4 criteria for ODD did not meet criteria under the alternative diagnosis; African American children were overrepresented in this group. Preschoolers who met DSM-4, but not the alternative criteria, had higher rates of ODD, conduct disorder (CD), and were more impaired than their nondiagnosed peers at baseline and follow-up. Preschoolers meeting DSM-4 criteria were less impaired than children meeting the alternative ODD criteria at baseline according to parent, but not according to teacher report. No differences could be detected between those meeting DSM-4 and those meeting the alternative criteria in rate of ODD, CD, or impairment at follow-up. Among clinically referred preschool children, changing the symptom threshold for ODD could result in a sizable group of children who would no longer meet diagnostic criteria, despite demonstrating significant morbidity concurrently and prospectively. PMID- 21707120 TI - Quantum mechanical investigations of organocatalysis: mechanisms, reactivities, and selectivities. PMID- 21707125 TI - Predeployment, deployment, and postdeployment risk factors for posttraumatic stress symptomatology in female and male OEF/OIF veterans. AB - [Correction Notice: An erratum for this article was reported in Vol 120(4) of Journal of Abnormal Psychology (see record 2011-19996-001). In the article there was an error in the affiliation bylines for Rani Elwy and Susan Eisen. Their affiliations should have been listed as Edith Nourse Rogers Memorial Veterans Hospital and Department of Health Policy and Management, Boston University School of Public Health.] Prior research on risk factors for posttraumatic stress symptomatology (PTSS) in war-exposed Veterans has revealed both direct and indirect mechanisms of risk that span predeployment, deployment, and postdeployment timeframes. The aims of the present study were to identify the mechanisms through which previously documented risk factors contribute to PTSS in a national sample of 579 female and male Veterans deployed to Afghanistan for Operation Enduring Freedom (OEF) or to Iraq for Operation Iraqi Freedom (OIF), as well as to examine the extent to which results mirror associations observed among Vietnam Veterans (King, King, Foy, Keane, & Fairbank, 1999). Consistent with conservation of resources (COR) theory (Hobfoll, 1989, 2001), findings indicated that PTSS is accounted for by multiple chains of risk, many originating in predeployment experiences that place Veterans at risk for additional stress exposure, and foretell difficulty accessing resources in the face of subsequent stressors. Importantly, the majority of previously documented mechanisms were replicated in this study, suggesting key pathways through which risk factors may contribute to PTSS across different Veteran populations. Results also revealed a number of novel risk mechanisms for OEF/OIF female Veterans, particularly with respect to the role of deployment family relationships in risk for PTSS. PMID- 21707126 TI - Latent class analysis of eating disorders: relationship to mortality. AB - The current diagnostic nomenclature for eating disorders has shortcomings. Empirical attempts to identify a new nomenclature have found numerous latent structures, but validation of this work has been largely cross-sectional, and nothing is known yet about the relationship of derived latent classes to mortality. This study examined latent diagnostic structure in 1,885 participants seeking outpatient eating disorder treatment over an 18-year period. Eating disorder symptoms were used as indicators, and the main validator was mortality as assessed using computerized linkage to the National Death Index. Six latent classes were derived; three of the six had significantly elevated standardized mortality ratios. It appeared that the latent class structure yielded better delineation of mortality risk than the existing classifications in the Diagnostic and Statistical Manual of Mental Disorders. These results provide support for an alternative, empirically derived diagnostic structure. PMID- 21707127 TI - Expectancies regarding the interaction between smoking and substance use in alcohol-dependent smokers in early recovery. AB - The purpose of this study was to investigate expectancies regarding the interaction between cigarette smoking and use of alcohol among alcohol-dependent smokers in early recovery, using the Nicotine and Other Substances Interaction Expectancies Questionnaire (NOSIE). Participants were 162 veterans, 97% male, with a mean age of 50 years, enrolled in a clinical trial aimed at determining the efficacy of an intensive smoking cessation intervention versus usual care. At baseline, participants were assessed on measures of smoking behavior, abstinence thoughts about alcohol and tobacco use, symptoms of depression, and smoking substance use interaction expectancies. In addition, biologically verified abstinence from tobacco and alcohol was assessed at 26 weeks. Participants reported that they expected smoking to have less of an impact on substance use than substance use has on smoking (p < .001). Severity of depressive symptoms was significantly associated with the expectancy that smoking provides a way of coping with the urge to use other substances (p < .01). The expectation that smoking increases substance urges/use was predictive of prospectively measured and biologically verified abstinence from smoking at 26 weeks (p < .03). The results add to our knowledge of smoking-substance use interaction expectancies among alcohol-dependent smokers in early recovery and will inform the development of more effective counseling interventions for concurrent alcohol and tobacco use disorders. PMID- 21707128 TI - Understanding the dorsal and ventral systems of the human cerebral cortex: beyond dichotomies. AB - Traditionally, characterizations of the macrolevel functional organization of the human cerebral cortex have focused on the left and right cerebral hemispheres. However, the idea of left brain versus right brain functions has been shown to be an oversimplification. We argue here that a top-bottom divide, rather than a left right divide, is a more fruitful way to organize human cortical brain functions. However, current characterizations of the functions of the dorsal (top) and ventral (bottom) systems have rested on dichotomies, namely where versus what and how versus what. We propose that characterizing information-processing systems leads to a better macrolevel organization of cortical function; specifically, we hypothesize that the dorsal system is driven by expectations and processes sequences, relations, and movement, whereas the ventral system categorizes stimuli in parallel, focuses on individual events, and processes object properties (such as shape in vision and pitch in audition). To test this hypothesis, we reviewed over 100 relevant studies in the human neuroimaging and neuropsychological literatures and coded them relative to 11 variables, some of which characterized our hypothesis and some of which characterized the previous dichotomies. The results of forward stepwise logistic regressions supported our characterization of the 2 systems and showed that this model predicted the empirical findings better than either the traditional dichotomies or a left-right difference. PMID- 21707129 TI - Why do lie-catchers fail? A lens model meta-analysis of human lie judgments. AB - Decades of research has shown that people are poor at detecting lies. Two explanations for this finding have been proposed. First, it has been suggested that lie detection is inaccurate because people rely on invalid cues when judging deception. Second, it has been suggested that lack of valid cues to deception limits accuracy. A series of 4 meta-analyses tested these hypotheses with the framework of Brunswik's (1952) lens model. Meta-Analysis 1 investigated perceived cues to deception by correlating 66 behavioral cues in 153 samples with deception judgments. People strongly associate deception with impressions of incompetence (r = .59) and ambivalence (r = .49). Contrary to self-reports, eye contact is only weakly correlated with deception judgments (r = -.15). Cues to perceived deception were then compared with cues to actual deception. The results show a substantial covariation between the 2 sets of cues (r = .59 in Meta-Analysis 2, r = .72 in Meta-Analysis 3). Finally, in Meta-Analysis 4, a lens model analysis revealed a very strong matching between behaviorally based predictions of deception and behaviorally based predictions of perceived deception. In conclusion, contrary to previous assumptions, people rarely rely on the wrong cues. Instead, limitations in lie detection accuracy are mainly attributable to weaknesses in behavioral cues to deception. The results suggest that intuitive notions about deception are more accurate than explicit knowledge and that lie detection is more readily improved by increasing behavioral differences between liars and truth tellers than by informing lie-catchers of valid cues to deception. PMID- 21707130 TI - Noise effects on human performance: a meta-analytic synthesis. AB - Noise is a pervasive and influential source of stress. Whether through the acute effects of impulse noise or the chronic influence of prolonged exposure, the challenge of noise confronts many who must accomplish vital performance duties in its presence. Although noise has diffuse effects, which are shared in common with many other chronic forms of stress, it also exerts its own specific influences on various forms of cognitive and motor response. We present a quantitative evaluation of these influences so that their harmful effects can be mitigated, their beneficial effects exploited, and any residual effects incorporated and synthesized into selection, training, and design strategies to facilitate human performance capacities. Predictions of single and joint moderator effects were made on the basis of major theories of noise and performance, specifically those explanations based on arousal, masking, or cognitive-resource mechanisms. These predictions were tested through moderator analyses of effects as a function of task type, performance measure, noise type and schedule, and the intensity and duration of exposure. Observed outcome effects (797 effect sizes derived from 242 studies) varied as a function of each of these moderators. Collective findings identified continuous versus intermittent noise, noise type, and type of task as the major distinguishing characteristics that moderated response. Mixed evidence was obtained for the traditional arousal and masking explanations for noise effects. The overall pattern of findings was most consistent with the maximal adaptability theory, a mental-resource-based explanation of stress and performance variation. PMID- 21707131 TI - A misleading review of response bias: comment on McGrath, Mitchell, Kim, and Hough (2010). AB - In the May 2010 issue of Psychological Bulletin, R. E. McGrath, M. Mitchell, B. H. Kim, and L. Hough published an article entitled "Evidence for Response Bias as a Source of Error Variance in Applied Assessment" (pp. 450-470). They argued that response bias indicators used in a variety of settings typically have insufficient data to support such use in everyday clinical practice. Furthermore, they claimed that despite 100 years of research into the use of response bias indicators, "a sufficient justification for [their] use... in applied settings remains elusive" (p. 450). We disagree with McGrath et al.'s conclusions. In fact, we assert that the relevant and voluminous literature that has addressed the issues of response bias substantiates validity of these indicators. In addition, we believe that response bias measures should be used in clinical and research settings on a regular basis. Finally, the empirical evidence for the use of response bias measures is strongest in clinical neuropsychology. We argue that McGrath et al.'s erroneous perspective on response bias measures is a result of 3 errors in their research methodology: (a) inclusion criteria for relevant studies that are too narrow; (b) errors in interpreting results of the empirical research they did include; (c) evidence of a confirmatory bias in selectively citing the literature, as evidence of moderation appears to have been overlooked. Finally, their acknowledging experts in the field who might have highlighted these errors prior to publication may have prevented critiques during the review process. PMID- 21707133 TI - A controlled evaluation of the distress criterion for binge eating disorder. AB - OBJECTIVE: Research has examined various aspects of the validity of the research criteria for binge eating disorder (BED) but has yet to evaluate the utility of Criterion C, "marked distress about binge eating." This study examined the significance of the marked distress criterion for BED using 2 complementary comparison groups. METHOD: A total of 1,075 community volunteers completed a battery of self-report instruments as part of an Internet study. Analyses compared body mass index (BMI), eating-disorder psychopathology, and depressive levels in 4 groups: 97 participants with BED except for the distress criterion (BED-ND), 221 participants with BED including the distress criterion (BED), 79 participants with bulimia nervosa (BN), and 489 obese participants without binge eating or purging (NBPO). Parallel analyses compared these study groups using the broadened frequency criterion (i.e., once weekly for binge/purge behaviors) proposed for the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the 4th edition (DSM-IV) twice-weekly frequency criterion. RESULTS: The BED group had significantly greater eating-disorder psychopathology and depressive levels than the BED-ND group. The BED group, but not the BED-ND group, had significantly greater eating-disorder psychopathology than the NBPO comparison group. The BN group had significantly greater eating-disorder psychopathology and depressive levels than all 3 other groups. The group differences in eating-disorder psychopathology existed even after controlling for depression levels, BMI, and demographic variables, although some differences between the BN and BED groups were attenuated when controlling for depression levels. CONCLUSIONS: These findings provide support for the validity of the "marked distress" criterion for the diagnosis of BED. PMID- 21707134 TI - Predictors of response to an attention modification program in generalized social phobia. AB - OBJECTIVE: At least 3 randomized, placebo-controlled, double-blind studies have supported the efficacy of computerized attention modification programs (AMPs) in reducing symptoms of anxiety in patients diagnosed with an anxiety disorder. In this study we examined patient characteristics that predicted response to AMP in a large sample of individuals diagnosed with generalized social phobia. METHOD: The sample comprised 112 individuals seeking treatment for generalized social phobia who completed a randomized clinical trial comparing AMP (n = 55) with a placebo condition (i.e., attention control condition; n = 57). We examined the following domains of baseline predictors of treatment response: (a) demographic characteristics (gender, age, ethnicity, years of education); (b) clinical characteristics (Axis I comorbidity, trait anxiety, depression); and (c) cognitive disturbance factors (attentional bias for social threat, social interpretation bias). RESULTS: Results revealed that ethnicity predicted treatment response across both conditions: Participants who self-identified as non-Caucasian displayed better overall response than did Caucasians. The only prescriptive variable to emerge was attentional bias for social threat at preassessment. Participants in the AMP group who exhibited larger attentional bias scores displayed significantly greater reductions in clinician-rated social anxiety symptoms than did their counterparts in the attention control condition. CONCLUSIONS: These results suggest that AMP may be targeted to individuals most likely to benefit from these programs. PMID- 21707135 TI - Hazardous drinking and military community functioning: identifying mediating risk factors. AB - OBJECTIVE: Hazardous drinking is a serious societal concern in military populations. Efforts to reduce hazardous drinking among military personnel have been limited in effectiveness. There is a need for a deeper understanding of how community-based prevention models apply to hazardous drinking in the military. Community-wide prevention efforts may be most effective in targeting community functioning (e.g., support from formal agencies, community cohesion) that impacts hazardous drinking via other proximal risk factors. The goal of the current study is to inform community-wide prevention efforts by testing a model of community functioning and mediating risk factors of hazardous drinking among active duty U.S. Air Force personnel. METHOD: A large, representative survey sample of U.S. Air Force active duty members (N = 52,780) was collected at 82 bases worldwide. Hazardous drinking was assessed with the widely used Alcohol Use Disorders Identification Test (Saunders, Aasland, Babor, de la Fuente, & Grant, 1993). A variety of individual, family, and community measures were also assessed. Structural equation modeling was used to test a hypothesized model of community functioning, mediating risk factors and hazardous drinking. RESULTS: Depressive symptoms, perceived financial stress, and satisfaction with the U.S. Air Force were identified as significant mediators of the link between community functioning and hazardous drinking for men and women. Relationship satisfaction was also identified as a mediator for men. CONCLUSIONS: These results provide a framework for further community prevention research and suggest that prevention efforts geared at increasing aspects of community functioning (e.g., the U.S. Air Force Community Capacity model) may indirectly lead to reductions in hazardous drinking through other proximal risk factors. PMID- 21707136 TI - An effectiveness trial of a selected dissonance-based eating disorder prevention program for female high school students: Long-term effects. AB - OBJECTIVE: Efficacy trials found that a dissonance-based eating disorder prevention program in which female high school and college students with body image concerns critique the thin ideal reduced eating disorder risk factors, eating disorder symptoms, and future eating disorder onset. The present effectiveness trial tested whether this program produces effects through long term follow-up when high school clinicians recruit students and deliver the intervention under real-world conditions. METHOD: Female high school students with body image concerns (N = 306; M age = 15.7 years, SD = 1.1) were randomized to the dissonance intervention or an educational brochure control condition and completed assessments through 3-year follow-up. RESULTS: Dissonance participants showed significantly greater decreases in body dissatisfaction at 2-year follow up and eating disorder symptoms at 3-year follow-up than controls; effects on other risk factors, risk for eating disorder onset, and other outcomes (e.g., body mass) were marginal or nonsignificant. CONCLUSIONS: Although it was encouraging that some key effects persisted over long-term follow-up, effects were on average smaller in this effectiveness trial than previous efficacy trials, which could be due to (a) facilitator selection, training, and supervision; (b) the lower risk status of participants; or (c) the use of a control condition that produces some effects. PMID- 21707137 TI - Family group cognitive-behavioral preventive intervention for families of depressed parents: 18- and 24-month outcomes. AB - OBJECTIVE: In a long-term follow-up of a randomized controlled trial (Compas et al., 2009) to examine the effects at 18- and 24-month follow-ups of a family group cognitive-behavioral (FGCB) preventive intervention for mental health outcomes for children and parents from families (N = 111) of parents with a history of major depressive disorder (MDD). METHOD: Parents with a history of MDD and their 9- to 15-year-old children were randomly assigned to a FGCB intervention or a written information comparison condition. Children's internalizing, externalizing, anxiety/depression, and depressive symptoms; episodes of MDD and other psychiatric diagnoses; and parents' depressive symptoms and episodes of MDD were assessed at 18 and 24 months after randomization. RESULTS: Children in the FGCB condition were significantly lower in self-reports of anxiety/depression and internalizing symptoms at 18 months and were significantly lower in self-reports of externalizing symptoms at 18 and 24 months. Rates of MDD were significantly lower for children in the FGCB intervention over the 24-month follow-up (odds ratio = 2.91). Marginal effects were found for parents' symptoms of depression at 18 and 24 months but not for episodes of MDD. CONCLUSIONS: Support was found for a FGCB preventive intervention for children of parents with a history of MDD significantly reducing children's episodes of MDD over a period of 2 years. Significant effects for the FGCB intervention were also found on internalizing and externalizing symptoms, with stronger effects at 18- than at 24-month follow-up. PMID- 21707138 TI - A quantitative method for the analysis of nomothetic relationships between idiographic structures: dynamic patterns create attractor states for sustained posttreatment change. AB - OBJECTIVE: The present article aimed to demonstrate that the establishment of dynamic patterns during the course of psychotherapy can create attractor states for continued adaptive change following the conclusion of treatment. METHOD: This study is a secondary analysis of T. D. Borkovec and E. Costello (1993). Of the 55 participants in the original study, 33 were retained for the present analysis due to the homogeneity of psychotherapy outcome among these participants. Of these 33, the majority were White (88%) and female (70%), and the average age was 35.44 years (SD = 14.46). Participants participated in 12 weeks of either cognitive behavioral therapy or applied relaxation. Daily diary entries from the treatment period were subjected to time series analyses in order to determine the degree of order versus disorder present within individual dynamic systems. These idiographic data were then aggregated for nomothetic analysis of treatment outcome via linear mixed effect models. RESULTS: Spectral power due to daily to intradaily oscillations in thrice-daily diary data significantly moderated reliable change over posttreatment follow-up such that lesser power predicted increases in reliable change over the 1-year follow-up period. Additionally, residual variance for dynamic factor models significantly moderated the slope for change over the follow-up period, such that lesser variance--and thus greater order in dynamic systems--predicted increases in reliable change. CONCLUSIONS: The degree of order in dynamic systems established during therapy acted as an adaptive attractor state, promoting continued positive gains 1 year after the conclusion of therapy. The present study represents an important innovation in the study of dynamic systems in psychotherapy. PMID- 21707139 TI - Strain differences in zebrafish (Danio rerio) social roles and their impact on group task performance. AB - "Key" individuals in a social group are those that are centrally connected and thus serve as a hub for information flow across the group. From this position, they have the potential to have a powerful influence on group dynamics and performance. Here, we use metrics from social network theory to identify Key individuals in groups of 3-4 zebrafish (Danio rerio), and to measure the impact of removing those individuals from the group. We compared the results for two genetically distinct strains of zebrafish and found that although their social dynamics were superficially similar, one strain (Scientific Hatcheries, SH) responded to social perturbation, whereas the other (Parganas North, PN) did not. For both strains, groups that retained their Key fish performed better on a simple group foraging-learning task than did those from which the Key fish had been removed. However, the SH strain learned the task more quickly than did the PN strain, perhaps in part because of sex differences in task performance or because of strain differences in the reaction to experimental disturbance. We also confirm the utility of measures of social dynamics and social role that can be estimated reliably from very short observation sessions and by relatively untrained observers. These results set the stage for future research into the genetic mechanisms underlying social roles and group learning in vertebrates. PMID- 21707140 TI - Flexible route selection by pigeons (Columba livia) on a computerized multi-goal navigation task with and without an "obstacle". AB - The ability to select efficient routes while reaching several locations, in situations addressed as the "traveling salesperson problem (TSP)", seems to play an important role in the lives of nonhuman species as well as humans. One of our previous studies with pigeons (Columba livia) used different variations of computerized navigation tasks to move a target to one or more goals, and showed that the birds consistently exhibited tendencies to visit the nearest goal first (Miyata & Fujita, 2010). Is this inflexible tendency consistent across all situations, or is it abandoned if it leads to a nonefficient strategy? The present study compared pigeons' route selection strategies in two-goal navigation tasks with and without having an L-shaped line as an obstacle barrier between the starting location of the target and the nearer goal. The pigeons frequently started by visiting the nearer goal in trials with no obstacles, whereas in trials having obstacles the birds often visited the farther goal first. For the detour trials with obstacles, the birds started from visiting the farther goal significantly more often than chance, even though disparity between the two traveling sequences was relatively small. The data demonstrated a case in which a tendency to visit the nearest goal was flexibly abandoned when the route required a detour behavior. Detailed analyses of the movement paths further suggest that the pigeons made decisions to choose a farther goal during the initial few steps, although a past history of reinforcement to avoid the barrier might have guided the birds' behavior. PMID- 21707141 TI - Young infants' generalization of emotional expressions: effects of familiarity. AB - From birth, infants are exposed to a wealth of emotional information in their interactions. Much research has been done to investigate the development of emotion perception, and factors influencing that development. The current study investigates the role of familiarity on 3.5-month-old infants' generalization of emotional expressions. Infants were assigned to one of two habituation sequences: in one sequence, infants were visually habituated to parental expressions of happy or sad. At test, infants viewed either a continuation of the habituation sequence, their mother depicting a novel expression, an unfamiliar female depicting the habituated expression, or an unfamiliar female depicting a novel expression. In the second sequence, a new sample of infants was matched to the infants in the first sequence. These infants viewed the same habituation and test sequences, but the actors were unfamiliar to them. Only those infants who viewed their own mothers and fathers during the habituation sequence increased looking. They dishabituated looking to maternal novel expressions, the unfamiliar female's novel expression, and the unfamiliar female depicting the habituated expression, especially when sad parental expressions were followed by an expression change to happy or to a change in person. Infants are guided in their recognition of emotional expressions by the familiarity of their parents, before generalizing to others. PMID- 21707142 TI - But what about the Empress of Racnoss? The allocation of attention to spiders and Doctor Who in a visual search task is predicted by fear and expertise. AB - If there is a spider in the room, then the spider phobic in your group is most likely to point it out to you. This phenomenon is believed to arise because our attentional systems are hardwired to attend to threat in our environment, and, to a spider phobic, spiders are threatening. However, an alternative explanation is simply that attention is quickly drawn to the stimulus of most personal relevance in the environment. Our research examined whether positive stimuli with no biological or evolutionary relevance could be allocated preferential attention. We compared attention to pictures of spiders with pictures from the TV program Doctor Who, for people who varied in both their love of Doctor Who and their fear of spiders. We found a double dissociation: interference from spider and Doctor Who-related images in a visual search task was predicted by spider fear and Doctor Who expertise, respectively. As such, allocation of attention reflected the personal relevance of the images rather than their threat content. The attentional system believed to have a causal role in anxiety disorders is therefore likely to be a general system that responds not to threat but to stimulus relevance; hence, nonevolutionary images, such as those from Doctor Who, captured attention as quickly as fear-relevant spider images. Where this leaves the Empress of Racnoss, we are unsure. PMID- 21707143 TI - Threat of bodily harm has opposing effects on cognition. AB - Several theoretical frameworks have suggested that anxiety/stress impairs cognitive performance. A competing prediction is made by attentional narrowing models that predict that stress decreases the processing of task-irrelevant items, thus benefiting performance when task-irrelevant information interferes with behavior. Critically, previous studies have not evaluated these competing frameworks when potent emotional manipulations are involved. Here, we used threat of bodily harm preceding a color-word Stroop task to test these claims. We found a basic effect of threat consisting of a slowing down of performance during neutral Stroop trials. Furthermore, both facilitation and interference scores were affected by threat of shock in a way that was consistent with a reduced distractor effect. Taken together, we interpret our findings in terms of two opposing effects of stress on cognitive performance. Although partly consistent with the attentional narrowing hypothesis, both resource models and cognitive breadth models require revision in order to account for the results. PMID- 21707144 TI - It's a bittersweet symphony: simultaneously mixed emotional responses to music with conflicting cues. AB - Some evidence indicates that emotional reactions to music can be organized along a bipolar valence dimension ranging from pleasant states (e.g., happiness) to unpleasant states (e.g., sadness), but songs can contain some cues that elicit happiness (e.g., fast tempos) and others that elicit sadness (e.g., minor modes). Some models of emotion contend that valence is a basic building block of emotional experience, which implies that songs with conflicting cues cannot make people feel happy and sad at the same time. Other models contend that positivity and negativity are separable in experience, which implies that music with conflicting cues might elicit simultaneously mixed emotions of happiness and sadness. Hunter, Schellenberg, and Schimmack (2008) tested these possibilities by having subjects report their happiness and sadness after listening to music with conflicting cues (e.g., fast songs in minor modes) and consistent cues (e.g., fast songs in major modes). Results indicated that music with conflicting cues elicited mixed emotions, but it remains unclear whether subjects simultaneously felt happy and sad or merely vacillated between happiness and sadness. To examine these possibilities, we had subjects press one button whenever they felt happy and another button whenever they felt sad as they listened to songs with conflicting and consistent cues. Results revealed that subjects spent more time simultaneously pressing both buttons during songs with conflicting, as opposed to consistent, cues. These findings indicate that songs with conflicting cues can simultaneously elicit happiness and sadness and that positivity and negativity are separable in experience. PMID- 21707145 TI - Emotions in memories of success and failure: a cultural perspective. AB - Americans and Chinese tend to behave differently in response to success and failure: Americans tend to persist on a task after success, whereas Chinese tend to persist after failure. This study examined whether cultural differences in emotional reactions to success and failure account for these differences. American and Chinese students recalled personal success and failure events, evaluated the primary emotion evoked by the event, and responded to measures of concerns, appraisals, and willingness to try the same task again. Americans were more likely than Chinese to report that their success enhanced their self-esteem. Chinese were more likely than Americans to estimate that their success would make others jealous and enhance others' respect for their family. Chinese, compared to Americans, viewed failures as more tolerable, as less problematic for their goals, and as less damaging to their self-esteem. Culture moderated the relations between these components of emotion and willingness to try the task again. In short, culturally framed emotional reactions to success and failure result in different patterns of anticipated self-regulation. PMID- 21707146 TI - Fear detection and visual awareness in perceiving bodily expressions. AB - Many research reports have concluded that emotional information can be processed without observers being aware of it. The case for perception without awareness has almost always been made with the use of facial expressions. In view of the similarities between facial and bodily expressions for rapid perception and communication of emotional signals, we conjectured that perception of bodily expressions may also not necessarily require visual awareness. Our study investigates the role of visual awareness in the perception of bodily expressions using a backward masking technique in combination with confidence ratings on a trial-by-trial basis. Participants had to detect in three separate experiments masked fearful, angry and happy bodily expressions among masked neutral bodily actions as distractors and subsequently the participants had to indicate their confidence. The onset between target and mask (Stimulus Onset Asynchrony, SOA) varied from -50 to +133 ms. Sensitivity measurements (d-prime) as well as the confidence of the participants showed that the bodies could be detected reliably in all SOA conditions. In an important finding, a lack of covariance was observed between the objective and subjective measurements when the participants had to detect fearful bodily expressions, yet this was not the case when participants had to detect happy or angry bodily expressions. PMID- 21707147 TI - Psychosocial resources, threat, and the perception of distance and height: support for the resources and perception model. AB - Threatening things are often perceptually exaggerated, such that they appear higher, closer, of greater duration, or more intense than they actually are. According to the Resources and Perception Model (RPM) psychosocial resources can prevent this exaggeration, leading to more accurate perception. Two studies tested RPM. Study 1 showed that the perceived closeness of a threatening object (a live tarantula) but not an innocuous object (a cat toy) was moderated by induced self-worth. Further, the more self-worth that participants experienced, the less close the tarantula appeared to them. Study 2 showed that greater levels of self-esteem reduced perceived height, but only among participants prevented from holding a protective handrail while looking down. Together, these studies confirm that resources moderate the physical perception of both distance and height, that resources moderate perception of threats but not nonthreats, that different resources have similar moderating effects, and that psychosocial resources can supplant physical resources. PMID- 21707148 TI - Sad mood promotes self-initiated mental contrasting of future and reality. AB - Self-regulation by mentally contrasting a positive future with negative reality leads people to differentiate in their goal commitments: They commit to goals when expectations of success are high and let go when expectations of success are low. On the contrary, when indulging in the positive future or dwelling on negative reality, people fail to consider expectations of success and do not form selective goal commitments (Oettingen, Pak, & Schnetter, 2001). Whereas prior research has examined the effects of experimentally induced mental contrasting, we address sad mood as a contextual influence promoting self-initiated mental contrasting. Across various mood inductions, sad moods--which are associated with problem solving strategies--facilitated self-initiated mental contrasting more than neutral moods (Studies 1, 5) or happy moods (Studies 2, 3, 4, 6). Importantly, mood did not affect the relation between mental contrasting and selective formation of goal commitment (Studies 5, 6). The results suggest that sad moods aid in self-regulation by making people self-initiate goal commitments that are sensitive to their expectations of success. PMID- 21707149 TI - Effects of intranasal oxytocin on 'compassion focused imagery'. AB - This study explored the effects of oxytocin on Compassion Focused Imagery (CFI), that is, imagining another "mind" being deeply compassionate to oneself, and the interaction of these effects with self-criticism and feeling socially safe with others. Forty-four healthy participants (29 men and 15 women) completed self report measures of self-criticism, attachment style, and social safeness before taking part in a double-blind randomized placebo controlled study. They attended two imagery sessions, receiving oxytocin in one and a placebo in the other. Positive affect was measured before and after each imagery session, and "imagery experience" was assessed after each session. Overall, oxytocin increased the ease of imagining compassionate qualities but there were important individual differences in how CFI was experienced. Participants higher in self-criticism, lower in self-reassurance, social safeness, and attachment security had less positive experiences of CFI under oxytocin than placebo, indicating that the effects of oxytocin on affiliation may depend on attachment and self-evaluative styles. PMID- 21707150 TI - The automaticity of emotional face-context integration. AB - Recent studies have demonstrated that context can dramatically influence the recognition of basic facial expressions, yet the nature of this phenomenon is largely unknown. In the present paper we begin to characterize the underlying process of face-context integration. Specifically, we examine whether it is a relatively controlled or automatic process. In Experiment 1 participants were motivated and instructed to avoid using the context while categorizing contextualized facial expression, or they were led to believe that the context was irrelevant. Nevertheless, they were unable to disregard the context, which exerted a strong effect on their emotion recognition. In Experiment 2, participants categorized contextualized facial expressions while engaged in a concurrent working memory task. Despite the load, the context exerted a strong influence on their recognition of facial expressions. These results suggest that facial expressions and their body contexts are integrated in an unintentional, uncontrollable, and relatively effortless manner. PMID- 21707151 TI - Delighted and distracted: positive affect increases priming for irrelevant information. AB - Emotional states are known to influence how people process relevant information. Here, we address the impact of emotional state on irrelevant information. In this experiment, participants were randomly assigned to a neutral or positive mood induction, and then completed a task that involved viewing a sequence of overlapping pictures and words. They were instructed to attend to the pictures and ignore the distracting words. Following a filled interval, implicit memory for the distracting words was tested using a word fragment completion task. Individuals in the positive mood group showed increased implicit memory for previously irrelevant information compared to those in the neutral mood group. These findings are consistent with the view that positive mood broadens attention to include encoding of irrelevant information in the environment, and this can impact subsequent performance. PMID- 21707152 TI - Is expressive suppression always associated with poorer psychological functioning? A cross-cultural comparison between European Americans and Hong Kong Chinese. AB - The habitual use of expressive suppression as an emotion regulation strategy has been consistently linked to adverse outcomes in a number of domains, including psychological functioning. The present study aimed to uncover whether the suppression-health relationship is dependent on cultural context, given differing cultural norms surrounding the value of suppressing emotional displays. We hypothesized that the negative associations between suppression and psychological functioning seen in European Americans would not be seen among members of East Asian cultures, in which emotional restraint is relatively encouraged over emotional expression. To test this hypothesis, we asked 71 European American students and 100 Chinese students from Hong Kong to report on their use of expressive suppression, life satisfaction, and depressed mood. A moderation analysis revealed that expressive suppression was associated with adverse psychological functioning for European Americans, but not for Chinese participants. These findings highlight the importance of context in understanding the suppression-health relationship. PMID- 21707153 TI - I didn't mean to hurt you! Unconscious origins of experienced self-agency over others' emotions. AB - Our conscious experiences of self-agency tell us that we cause and change other people's emotions during social interactions, even without awareness of what we did. How do such experiences of being the cause of an outcome, such as the emotions of others, emerge? Previous authorship ascription research suggests that unconsciously primed knowledge about emotions produces a sense of self-agency upon seeing the primed emotions expressed in another agent. Taking into account the crucial role of valence and the nature of one's own actions in understanding others' behaviors, we predicted that preactivated knowledge linked to a particular emotion, in terms of action or valence, increases experienced self agency upon seeing the emotion in another agent. In four experiments, participants interacted with another agent and observed this agent's neutral expressions change into emotional expressions. Results showed that various kinds of subliminal primes enhance experienced self-agency over the observed emotions. Our findings support the idea that the unconscious authorship ascription process is less rigid when outcomes are socially meaningful. PMID- 21707154 TI - The art and science of guessing. AB - This research examined how one affectively reacts to others' guesses at a value one cares about, such as one's income. Conventional wisdom suggests that people will feel happier upon receiving more favorable guesses (e.g., higher income) than less favorable guesses. We found the opposite pattern. We propose a model to explain the effect and identify its boundaries and report experimental evidence for the model. This research enriches existing literature on self-enhancement and yields practical implications for how to approach guessing in interpersonal communications. PMID- 21707155 TI - Men appear more lateralized when noticing emotion in male faces. AB - Empirical tests of the "right hemisphere dominance" versus "valence" theories of emotion processing are confounded by known sex differences in lateralization. Moreover, information about the sex of the person posing an emotion might be processed differently by men and women because of an adaptive male bias to notice expressions of threat and vigilance in other male faces. The purpose of this study was to investigate whether sex of poser and emotion displayed influenced lateralization in men and women by analyzing "laterality quotient" scores on a test which depicts vertically split chimeric faces, formed with one half showing a neutral expression and the other half showing an emotional expression. We found that men (N = 50) were significantly more lateralized for emotions indicative of vigilance and threat (happy, sad, angry, and surprised) in male faces relative to female faces and compared to women (N = 44). These data indicate that sex differences in functional cerebral lateralization for facial emotion may be specific to the emotion presented and the sex of face presenting it. PMID- 21707156 TI - The impact of task-irrelevant emotional stimuli on attention in three domains. AB - Whether task-irrelevant emotional stimuli facilitate or disrupt attention performance may depend on a range of factors, such as emotion type, task difficulty, and stimulus duration. Few studies, however, have systematically examined the influence of these factors on attention performance. Sixty-three adults, scoring within a normative range for mood and anxiety symptoms, completed either an easy or difficult version of an attention task measuring three aspects of attention performance: alerting, orienting, and executive attention. Results showed that in the easy task only, threatening versus nonthreatening task irrelevant emotional faces facilitated orienting regardless of stimulus duration. These effects were no longer significant during the difficult condition. When the easy and difficult conditions were examined together, duration effects emerged such that stimuli of longer durations lead to greater interference, although effects were nonlinear. Findings illustrate that threat-relevant emotional stimuli facilitate attention during tasks with low cognitive load, but underscore the importance of considering a range of task parameters. Results are discussed in the context of adaptive and maladaptive emotion-attention interactions. PMID- 21707157 TI - Screaming, yelling, whining, and crying: categorical and intensity differences in vocal expressions of anger and sadness in children's tantrums. AB - Young children's temper tantrums offer a unique window into the expression and regulation of strong emotions. Previous work, largely based on parental report, suggests that two emotions, anger and sadness, have different behavioral manifestations and different time courses within tantrums. Individual motor and vocal behaviors, reported by parents, have been interpreted as representing different levels of intensity within each emotion category. The present study used high-fidelity audio recordings to capture the acoustic features of children's vocalizations during tantrums. Results indicated that perceptually categorized screaming, yelling, crying, whining, and fussing each have distinct acoustic features. Screaming and yelling form a group with similar acoustic features while crying, whining, and fussing form a second acoustically related group. Within these groups, screaming may reflect a higher intensity of anger than yelling while fussing, whining, and crying may reflect an increasing intensity of sadness. PMID- 21707158 TI - Who am I to judge? Self-disgust predicts less punishment of severe transgressions. AB - Although recent research has shown that experimentally induced disgust and the personality trait of disgust sensitivity is associated with more severe moral decisions, no study to date has examined how disgust, experienced specifically toward the self, influences morally relevant decisions. Participants (n = 109) in the present study completed a measure of self-disgust, disgust sensitivity, and depressive symptoms and then evaluated nonoffenses, moderate offenses, and severe offenses with regard to level of disgust and punishment deserved. The results showed that self-disgust significantly predicted more disgust and punishment ratings of nonoffenses when controlling for individual differences in both depressive symptoms and disgust sensitivity. In contrast, self-disgust significantly predicted less disgust and punishment ratings of severe offenses when controlling for individual differences in depressive symptoms and disgust sensitivity. The implications of these findings for further conceptualizing how the heterogeneous construct of disgust operates in the moral domain are discussed. PMID- 21707159 TI - Look before you regulate: differential perceptual strategies underlying expressive suppression and cognitive reappraisal. AB - Successful emotion regulation is important for maintaining psychological well being. Although it is known that emotion regulation strategies, such as cognitive reappraisal and expressive suppression, may have divergent consequences for emotional responses, the cognitive processes underlying these differences remain unclear. Here we used eye-tracking to investigate the role of attentional deployment in emotion regulation success. We hypothesized that differences in the deployment of attention to emotional areas of complex visual scenes may be a contributing factor to the differential effects of these two strategies on emotional experience. Eye-movements, pupil size, and self-reported negative emotional experience were measured while healthy young adult participants viewed negative IAPS images and regulated their emotional responses using either cognitive reappraisal or expressive suppression. Consistent with prior work, reappraisers reported feeling significantly less negative than suppressers when regulating emotion as compared to a baseline condition. Across both groups, participants looked away from emotional areas during emotion regulation, an effect that was more pronounced for suppressers. Critically, irrespective of emotion regulation strategy, participants who looked toward emotional areas of a complex visual scene were more likely to experience emotion regulation success. Taken together, these results demonstrate that attentional deployment varies across emotion regulation strategies and that successful emotion regulation depends on the extent to which people look toward emotional content in complex visual scenes. PMID- 21707160 TI - Gratitude when it is needed most: social functions of gratitude in women with metastatic breast cancer. AB - Theory and evidence suggest that everyday positive emotions may be potent factors in resilience during periods of chronic stress, yet the body of evidence is scant. Even less research focuses on the adaptive functions of specific positive emotions in this critical context. In the current research, 54 women with metastatic breast cancer provided information about their emotional responses to benefits received to test hypotheses regarding the social functions of gratitude. One set of analyses provide support for the hypothesized role of ego transcendence in feeling gratitude upon receipt of a benefit from another person. As predicted, in a second set of analyses, grateful responding to received benefits predicted an increase in perceived social support over three months only for women low in ambivalence over emotional expression. These findings add to evidence regarding the social causes and consequences of gratitude, supporting a view of gratitude as an other-focused positive emotion that functions to promote high-quality relationships. Discussion focuses on the chronically stressful context as an important testing ground for theory on gratitude and other positive emotions. PMID- 21707161 TI - Disgusting smells cause decreased liking of gay men. AB - An induction of disgust can lead to more negative attitudes toward an entire social group: Participants who were exposed to a noxious ambient odor reported less warmth toward gay men. This effect of disgust was equally strong for political liberals and conservatives, and was specific to attitudes toward gay men-there was only a weak effect of disgust on people's warmth toward lesbians, and no consistent effect on attitudes toward African Americans, the elderly, or a range of political issues. PMID- 21707162 TI - A 12-Point Circumplex Structure of Core Affect. AB - Core Affect is a state accessible to consciousness as a single simple feeling (feeling good or bad, energized or enervated) that can vary from moment to moment and that is the heart of, but not the whole of, mood and emotion. In four correlational studies (Ns = 535, 190, 234, 395), a 12-Point Affect Circumplex (12 PAC) model of Core Affect was developed that is finer grained than previously available and that integrates major dimensional models of mood and emotion. Self report scales in three response formats were cross-validated for Core Affect felt during current and remembered moments. A technique that places any external variable into the 12-PAC showed that 29 of 38 personality scales and 30 of 30 mood scales are significantly related to Core Affect, but not in a way that revealed its basic dimensions. PMID- 21707163 TI - Affect bursts: dynamic patterns of facial expression. AB - Affect bursts consist of spontaneous and short emotional expressions in which facial, vocal, and gestural components are highly synchronized. Although the vocal characteristics have been examined in several recent studies, the facial modality remains largely unexplored. This study investigated the facial correlates of affect bursts that expressed five different emotions: anger, fear, sadness, joy, and relief. Detailed analysis of 59 facial actions with the Facial Action Coding System revealed a reasonable degree of emotion differentiation for individual action units (AUs). However, less convergence was shown for specific AU combinations for a limited number of prototypes. Moreover, expression of facial actions peaked in a cumulative-sequential fashion with significant differences in their sequential appearance between emotions. When testing for the classification of facial expressions within a dimensional approach, facial actions differed significantly as a function of the valence and arousal level of the five emotions, thereby allowing further distinction between joy and relief. The findings cast doubt on the existence of fixed patterns of facial responses for each emotion, resulting in unique facial prototypes. Rather, the results suggest that each emotion can be portrayed by several different expressions that share multiple facial actions. PMID- 21707164 TI - Attentional bias to emotional stimuli is altered during moderate- but not high intensity exercise. AB - Little is known regarding how attention to emotional stimuli is affected during simultaneously performed exercise. Attentional biases to emotional face stimuli were assessed in 34 college students (17 women) using the dot-probe task during counterbalanced conditions of moderate- (heart rate at 45% peak oxygen consumption) and high-intensity exercise (heart rate at 80% peak oxygen consumption) compared with seated rest. The dot-probe task consisted of 1 emotional face (pleasant or unpleasant) paired with a neutral face for 1,000 ms; 256 trials (128 trials for each valence) were presented during each condition. Each condition lasted approximately 10 min. Participants were instructed to perform each trial of the dot-probe task as quickly and accurately as possible during the exercise and rest conditions. During moderate-intensity exercise, participants exhibited significantly greater attentional bias scores to pleasant compared with unpleasant faces (p < .01), whereas attentional bias scores to emotional faces did not differ at rest or during high-intensity exercise (p > .05). In addition, the attentional bias to unpleasant faces was significantly reduced during moderate-intensity exercise compared with that during rest (p < .05). These results provide behavioral evidence that during exercise at a moderate intensity, there is a shift in attention allocation toward pleasant emotional stimuli and away from unpleasant emotional stimuli. Future work is needed to determine whether acute exercise may be an effective treatment approach to reduce negative bias or enhance positive bias in individuals diagnosed with mood or anxiety disorders, or whether attentional bias during exercise predicts adherence to exercise. PMID- 21707165 TI - Emotional response to musical repetition. AB - Two experiments examined the effects of repetition on listeners' emotional response to music. Listeners heard recordings of orchestral music that contained a large section repeated twice. The music had a symmetric phrase structure (same length phrases) in Experiment 1 and an asymmetric phrase structure (different length phrases) in Experiment 2, hypothesized to alter the predictability of sensitivity to musical repetition. Continuous measures of arousal and valence were compared across music that contained identical repetition, variation (related), or contrasting (unrelated) structure. Listeners' emotional arousal ratings differed most for contrasting music, moderately for variations, and least for repeating musical segments. A computational model for the detection of repeated musical segments was applied to the listeners' emotional responses. The model detected the locations of phrase boundaries from the emotional responses better than from performed tempo or physical intensity in both experiments. These findings indicate the importance of repetition in listeners' emotional response to music and in the perceptual segmentation of musical structure. PMID- 21707166 TI - Choke or thrive? The relation between salivary cortisol and math performance depends on individual differences in working memory and math-anxiety. AB - In the current study, we explored how a person's physiological arousal relates to their performance in a challenging math situation as a function of individual differences in working memory (WM) capacity and math-anxiety. Participants completed demanding math problems before and after which salivary cortisol, an index of arousal, was measured. The performance of lower WM individuals did not depend on cortisol concentration or math-anxiety. For higher WM individuals high in math-anxiety, the higher their concentration of salivary cortisol following the math task, the worse their performance. In contrast, for higher WM individuals lower in math-anxiety, the higher their salivary cortisol concentrations, the better their performance. For individuals who have the capacity to perform at a high-level (higher WMs), whether physiological arousal will lead an individual to choke or thrive depends on math-anxiety. PMID- 21707167 TI - Valence resolution of ambiguous facial expressions using an emotional oddball task. AB - Previous research suggests that neural and behavioral responses to surprised faces are modulated by explicit contexts (e.g., "He just found $500"). Here, we examined the effect of implicit contexts (i.e., valence of other frequently presented faces) on both valence ratings and ability to detect surprised faces (i.e., the infrequent target). In Experiment 1, we demonstrate that participants interpret surprised faces more positively when they are presented within a context of happy faces, as compared to a context of angry faces. In Experiments 2 and 3, we used the oddball paradigm to evaluate the effects of clearly valenced facial expressions (i.e., happy and angry) on default valence interpretations of surprised faces. We offer evidence that the default interpretation of surprise is negative, as participants were faster to detect surprised faces when presented within a happy context (Exp. 2). Finally, we kept the valence of the contexts constant (i.e., surprised faces) and showed that participants were faster to detect happy than angry faces (Exp. 3). Together, these experiments demonstrate the utility of the oddball paradigm to explore the default valence interpretation of presented facial expressions, particularly the ambiguously valenced facial expression of surprise. PMID- 21707168 TI - Flexible emotional responsiveness in trait resilience. AB - Field studies and laboratory experiments have documented that a key component of resilience is emotional flexibility--the ability to respond flexibly to changing emotional circumstances. In the present study we tested the hypotheses that resilient people exhibit emotional flexibility: (a) in response to frequently changing emotional stimuli and (b) across multiple modalities of emotional responding. As participants viewed a series of emotional pictures, we assessed their self-reported affect, facial muscle activity, and startle reflexes. Higher trait resilience predicted more divergent affective and facial responses (corrugator and zygomatic) to positive versus negative pictures. Thus, compared with their low-resilient counterparts, resilient people appear to be able to more flexibly match their emotional responses to the frequently changing emotional stimuli. Moreover, whereas high-trait-resilient participants exhibited divergent startle responses to positive versus negative pictures regardless of the valence of the preceding trial, low-trait-resilient participants did not exhibit divergent startle responses when the preceding picture was negative. High-trait resilient individuals, therefore, appear to be better able than are their low resilient counterparts to either switch or maintain their emotional responses depending on whether the emotional context changes. The present findings broaden our understanding of the mechanisms underlying resilience by demonstrating that resilient people are able to flexibly change their affective and physiological responses to match the demands of frequently changing environmental circumstances. PMID- 21707169 TI - When dynamic, the head and face alone can express pride. AB - Prior research suggested that pride is recognized only when a head and facial expression (e.g., tilted head with a slight smile) is combined with a postural expression (e.g., expanded body and arm gestures). However, these studies used static photographs. In the present research, participants labeled the emotion conveyed by four dynamic cues to pride, presented as video clips: head and face alone, body posture alone, voice alone, and an expression in which head and face, body posture, and voice were presented simultaneously. Participants attributed pride to the head and face alone, even when postural or vocal information was absent. Pride can be conveyed without body posture or voice. PMID- 21707170 TI - Forgiveness and relationship satisfaction: mediating mechanisms. AB - Although the ability to forgive transgressions has been linked to overall relationship satisfaction, the mechanisms that mediate this association have not been established. We propose that the tendency to forgive a romantic partner increases relationship satisfaction via increased relational effort and decreased negative conflict. In two studies, we used structural equations modeling to examine these variables as potential mechanisms that drive this association. In Study 1 (N = 523) and Study 2 (N = 446) we found that these variables significantly mediated the association between forgiveness and relationship satisfaction. The findings were robust when examined concurrently and longitudinally, across multiple measures of forgiveness, and when accounting for baseline relationship satisfaction and interpersonal commitment. These two mechanisms parallel theorized positive and negative dimensions of forgiveness and the motivational transformation that is said to underlie forgiveness. Theoretical implications and implications for intervention are discussed. PMID- 21707171 TI - A meta-analytic review of internalizing, externalizing, and academic adjustment among children of deployed military service members. AB - Parental deployment during military conflicts has the potential to impact child adjustment. As increased numbers of military Service members have children, it is critical to understand the association between military deployment and child adjustment. In order to resolve inconsistencies in the existing literature, we performed a meta-analytic review of 16 studies that report associations of military deployment with internalizing, externalizing, and academic adjustment among children. Results indicate a small association between deployment and poorer adjustment. This association varied across several features of the studies. Age moderation was such that the associations are strongest in middle childhood and weakest during adolescence. The method that adjustment was assessed also moderated this association, such that maladjustment was evident primarily with parents' reports. Study design also moderated associations, such that comparisons to civilian controls indicated associations with maladjustment, whereas comparisons to nondeployed military and prepost comparisons did not. These findings summarize the existing quantitative literature to indicate that parental deployment has a negligible association with child maladjustment and provide a foundation for future research. PMID- 21707172 TI - Military youth and the deployment cycle: emotional health consequences and recommendations for intervention. AB - The United States military force includes over 2.2 million volunteer service members. Three out of five service members who are deployed or are preparing for deployment have spouses and/or children. Stressors associated with the deployment cycle can lead to depression, anxiety, and behavior problems in children, as well as psychological distress in the military spouse. Further, the emotional and behavioral health of family members can affect the psychological functioning of the military service member during the deployment and reintegration periods. Despite widespread acknowledgment of the need for emotional and behavioral health services for youth from military families, many professionals in a position to serve them struggle with how to best respond and select appropriate interventions. The purpose of this paper is to provide an empirically based and theoretically informed review to guide service provision and the development of evidence based treatments for military youth in particular. This review includes an overview of stressors associated with the deployment cycle, emotional and behavioral health consequences of deployment on youth and their caretaking parent, and existing preventative and treatment services for youth from military families. It concludes with treatment recommendations for older children and adolescents experiencing emotional and behavioral health symptoms associated with the deployment cycle. PMID- 21707173 TI - Military fathers' perspectives on involvement. AB - Military fathers endure repeated separations from their children. In this qualitative study we describe military fathers' range of involvement with their children, paying special attention to the implications of deployment separation and reintegration. We discuss father involvement using three overlapping major domains of functioning: cognitive, affective, and behavioral. Additionally, we consider how types of father involvement differ vis-a-vis child age. Data were gathered via focus groups conducted with 71 fathers at 14 U.S. military installations. Descriptions of involvement were rich and varied. Involvement with children was a major concern for fathers, despite or perhaps because of the challenges of military careers. We discuss factors that help explain variations in involvement and offer insights about the conceptualization of father involvement for occupations requiring prolonged absences from home. PMID- 21707174 TI - Longitudinal motivational predictors of dietary self-care and diabetes control in adults with newly diagnosed type 2 diabetes mellitus. AB - OBJECTIVE: This prospective study examined relationships between constructs from social-cognitive theory (Bandura, 1986) and self-determination theory (Deci & Ryan, 1985; Deci & Ryan, 1991) and the diabetes outcomes of dietary self-care and diabetes control. METHOD: Longitudinal data were collected from 237 people newly diagnosed with Type 2 diabetes who filled in questionnaires on dietary self-care, and motivational factors derived from social-cognitive theory and self determination theory. Blood samples were taken to assess diabetes control (HbA1c). Repeated measurements were taken every 3-4 months for a total of five time points over 18 months. Predictor measures included autonomy support, autonomous and controlled motivation, amotivation, dietary self-efficacy, positive and negative outcome expectancies for dietary self-care and self evaluation. Age, sex, BMI, and diabetes knowledge were included as control measures. RESULTS: Using Generalized Estimating Equations (GEE) analyses two models were tested: a standard model reflecting longitudinal associations between absolute values of predicted and outcome variables; and a change model examining motivational predictors of changes over time in diabetes outcomes of dietary self care and diabetes control (HbA1c). Dietary self-care was longitudinally associated with self-efficacy, self-evaluation (the strongest predictor) autonomy support and autonomous motivation, but not with controlled motivation or outcome expectancies. Changes in dietary self-care were predicted by changes in self efficacy, self-evaluation, and controlled motivation but not by changes in autonomous motivation or autonomy support. Negative outcome expectancies regarding diet were longitudinally associated with HbA1c, and changes in negative outcome expectancies predicted changes in HbA1c. However, there were indications that dietary self-care predicted changes in HbA1c. CONCLUSIONS: The results indicate that autonomy support, self-efficacy and, in particular, self-evaluation are key targets for interventions to improve dietary self-care. PMID- 21707175 TI - The effect of lexical frequency on spoken word recognition in young and older listeners. AB - When identifying spoken words, older listeners may have difficulty resolving lexical competition or may place a greater weight on factors like lexical frequency. To obtain information about age differences in the time course of spoken word recognition, young and older adults' eye movements were monitored as they followed spoken instructions to click on objects displayed on a computer screen. Older listeners were more likely than younger listeners to fixate high frequency displayed phonological competitors. However, degradation of auditory quality in younger listeners does not reproduce this result. These data are most consistent with an increased role for lexical frequency with age. PMID- 21707176 TI - Working memory training and transfer in older adults. AB - There has been a great deal of interest, both privately and commercially, in using working memory training exercises to improve general cognitive function. However, many of the laboratory findings for older adults, a group in which this training is of utmost interest, are discouraging due to the lack of transfer to other tasks and skills. Importantly, improvements in everyday functioning remain largely unexamined in relation to WM training. We trained working memory in older adults using a task that encourages transfer in young adults (Chein & Morrison, 2010). We tested transfer to measures of working memory (e.g., Reading Span), everyday cognitive functioning [the Test of Everyday Attention (TEA) and the California Verbal Learning Test (CVLT)], and other tasks of interest. Relative to controls, trained participants showed transfer improvements in Reading Span and the number of repetitions on the CVLT. Training group participants were also significantly more likely to self-report improvements in everyday attention. Our findings support the use of ecological tasks as a measure of transfer in an older adult population. PMID- 21707177 TI - Positive affect, meaning in life, and future time perspective: an application of socioemotional selectivity theory. AB - Four studies tested the prediction that positive affect (PA) would relate more strongly to meaning in life (MIL) as a function of perceived time limitations. In Study 1 (N = 360), adults completed measures of PA and MIL. As predicted, PA related more strongly to MIL for older, compared to younger, participants. In Studies 2 and 3, adults (N = 514) indicated their current position in their life span, and rated their MIL. PA, whether naturally occurring (Study 2) or induced (Study 3), was a stronger predictor of MIL for individuals who perceived themselves as having a limited amount of time left to live. Finally, in Study 4 (N = 98) students completed a measure of PA, MIL, and future time perspective (FTP). Results showed that PA was more strongly linked to MIL for those who believed they had fewer opportunities left to pursue their goals. Overall, these findings suggest that the experience of PA becomes increasingly associated with the experience of MIL as the perception of future time becomes limited. The contribution of age related processes to judgments of well-being are discussed. PMID- 21707178 TI - The effects of attention on age-related relational memory deficits: evidence from a novel attentional manipulation. AB - Healthy aging is often accompanied by episodic memory decline. Prior studies have consistently demonstrated that older adults show disproportionate deficits in relational memory (RM) relative to item memory (IM). Despite rich evidence of an age-related RM deficit, the source of this deficit remains unspecified. One of the most widely investigated factors of age-related RM impairment is a reduction in attentional resources. However, no prior studies have demonstrated that reduced attentional resources are the critical source of age-related RM deficits. Here, we used qualitatively different attention tasks and tested whether reduced attention for relational processing underlies the RM deficit observed in aging. In Experiment 1, we imposed either item-detection or relation-detection attention tasks on young adults during episodic memory encoding and found that only the concurrent attention task that involves relational processing disproportionately impaired RM performance in young adults. Moreover, by ruling out the possible confound of task difficulty on the disproportionate RM impairment, we further demonstrated that reduced relational attention is a key factor for the age related RM deficit. In Experiment 2, we replicated the results from Experiment 1 by using different materials of stimuli and found that the effect of relational attention on RM is material general. The results of Experiment 2 also showed that reducing attentional resources for relational processing in young adults strikingly equated their RM performance to that of older adults. Thus, this study documents the first evidence that reduced attentional resources for relational processing are a critical factor for the relational memory impairment observed in aging. PMID- 21707179 TI - Personality traits prospectively predict verbal fluency in a lifespan sample. AB - In a community-dwelling sample (N = 4,790; age range 14-94), we examined whether personality traits prospectively predicted performance on a verbal fluency task. Open, extraverted, and emotionally stable participants had better verbal fluency. At the facet level, dispositionally happy and self-disciplined participants retrieved more words; those prone to anxiety and depression and those who were deliberative retrieved fewer words. Education moderated the association between conscientiousness and fluency such that participants with lower education performed better on the fluency task if they were also conscientious. Age was not a moderator at the domain level, indicating that the personality-fluency associations were consistent across the life span. A disposition toward emotional vulnerability and being less open, less happy, and undisciplined may be detrimental to cognitive performance. PMID- 21707180 TI - Problem-solving variability in older spouses: how is it linked to problem-, person-, and couple-characteristics? AB - Problem-solving does not take place in isolation and often involves social others such as spouses. Using repeated daily life assessments from 98 older spouses (M age = 72 years; M marriage length = 42 years), the present study examined theoretical notions from social-contextual models of coping regarding (a) the origins of problem-solving variability and (b) associations between problem solving and specific problem-, person-, and couple- characteristics. Multilevel models indicate that the lion's share of variability in everyday problem-solving is located at the level of the problem situation. Importantly, participants reported more proactive emotion regulation and collaborative problem-solving for social than nonsocial problems. We also found person-specific consistencies in problem-solving. That is, older spouses high in Neuroticism reported more problems across the study period as well as less instrumental problem-solving and more passive emotion regulation than older spouses low in Neuroticism. Contrary to expectations, relationship satisfaction was unrelated to problem-solving in the present sample. Results are in line with the stress and coping literature in demonstrating that everyday problem-solving is a dynamic process that has to be viewed in the broader context in which it occurs. Our findings also complement previous laboratory-based work on everyday problem-solving by underscoring the benefits of examining everyday problem-solving as it unfolds in spouses' own environment. PMID- 21707181 TI - The relationship of fear of falling and balance confidence with balance and dual tasking performance. AB - According to traditional conceptualizations of the relationship between fear of falling and falls in older adults, fear of falling is considered to be predictive of falls because it leads to activity avoidance which, in turn, leads to de conditioning that increases fall risk. The recent literature has begun to challenge such conceptualizations. Specifically, it has been argued that fear of falling and anxiety, in and of themselves, have a direct negative effect on balance. In this study we manipulated anxiety level by asking older research participants to walk either on the floor (low anxiety condition) or an elevated platform (high anxiety condition). Half the time participants carried a tray (dual tasking) and half the time they did not. Manipulation checks (involving heart rate, galvanic skin response, and self-reported anxiety measurement) confirmed that the experimental manipulation was successful in affecting anxiety level. The results demonstrate that the experimental manipulation (platform vs. floor) affected balance parameters and dual tasking performance with the platform condition resulting in a less stable gait. In addition, increased task demand (i.e., dual tasking) also had a negative effect on balance performance. Finally, the results demonstrate that the paper and pencil measures of fear can also predict balance performance (although the variance accounted for is small) even after controlling for medical risk factors for falling. Implications for models of fear of falling are discussed. PMID- 21707182 TI - Age and motivation predict gaze behavior for facial expressions. AB - This study investigated age-related differences between younger (M = 25.52 years) and older (M = 70.51 years) adults in avoidance motivation and the influence of avoidance motivation on gaze preferences for happy, neutral, and angry faces. In line with the hypothesis of reduced negativity effect later in life, older adults avoided angry faces and (to a lesser degree) preferred happy faces more than younger adults did. This effect cannot be explained by age-related changes in dispositional motivation. Irrespective of age, avoidance motivation predicted gaze behavior towards emotional faces. The study demonstrates the importance of interindividual differences beyond young adulthood. PMID- 21707183 TI - Mind-wandering in younger and older adults: converging evidence from the Sustained Attention to Response Task and reading for comprehension. AB - One mechanism that has been hypothesized to contribute to older adults' changes in cognitive performance is goal neglect or impairment in maintaining task set across time. Mind-wandering and task-unrelated thought may underlie these potential age-related changes. The present study investigated age-related changes in mind-wandering in three different versions of the Sustained Attention to Response Task (SART), along with self-reported mind-wandering during a reading for comprehension task. In the SART, both younger and older adults produced similar levels of faster reaction times before No-Go errors of commission, whereas, older adults produced disproportionate post-error slowing. Subjective self-reports of mind-wandering recorded during the SART and the reading task indicated that older adults were less likely to report mind-wandering than younger adults. Discussion focuses on cognitive and motivational mechanisms that may account for older adults' relatively low levels of reported mind-wandering. PMID- 21707185 TI - Cognitive and developmental influences in visual-motor integration skills in young children. AB - Measures of visual-motor integration skills continue to be widely used in psychological assessments with children. However, the construct validity of many visual-motor integration measures remains unclear. In this study, we investigated the relative contributions of maturation and cognitive skills to the development of visual-motor integration skills in young children (N = 856). We used a block regression analysis to determine the contribution of maturation, as indicated by age, followed by broad cognitive factors (Study 1) and subsequently by individual subtests in verbal and nonverbal domains subsumed under each factor (Study 2) in explaining score variance of the Bender Visual-Motor Gestalt Test (2nd ed.; BG II; Brannigan & Decker, 2003) Copy and Recall scores in children between the ages of 4 and 7 years. Results confirm that maturation accounted for a large proportion of variance in both BG-II Copy and Recall performance, above which Stanford-Binet Intelligence Scale (5th ed.; SB-5; Roid, 2003) Quantitative Reasoning and Fluid Reasoning factors significantly contributed to visual-motor integration performance for the Copy phase, and SB-5 Quantitative Reasoning and Visual-Spatial factors accounted for a significant amount of variance for the Recall phase. Additionally, nonverbal domains were more related to visual-motor performance than verbal domains. Results from this study are interpreted to suggest nonverbal reasoning and visual-spatial attention are important contributing factors to visual-motor integration, as measured by the BG-II. Developmental implications of visual-motor integration skills, nonverbal problem solving, and mathematical competence are discussed. PMID- 21707184 TI - Distress and recurrence of intrusive thoughts in younger and older adults. AB - The current study incorporated a life span perspective into existing theories of intrusive thoughts to examine age-related differences in the difficulty controlling intrusive thoughts, the distress following intrusive thought recurrences, and the meanings assigned to these recurrences. Younger (N = 51) and older (N = 49) community adults were randomly assigned to suppress (i.e., keep out of mind) or monitor an intrusive thought. Participants rated their positive and negative affect throughout engagement with the intrusive thought, and they also rated the meanings they gave to recurrences of their everyday intrusive thoughts. The results demonstrated that older adults tended to perceive greater difficulty with controlling the intrusive thought than younger adults despite the fact that they did not differ in the actual recurrence of the intrusive thought. With regard to distress, older adults experienced steadier levels of positive affect than younger adults throughout engagement with the intrusive thought. However, older adults also reported greater residual negative affect after engaging with the intrusive thought than younger adults. Finally, older and younger adults appeared to assign meanings to recurrences of intrusive thoughts in line with age-relevant concerns. Specifically, older adults were prone to interpret the recurrence of intrusive thoughts as a sign of cognitive decline, but they were less likely than younger adults to see intrusive thoughts as a sign of moral failure. Together, these results highlight a range of potential risk and protective factors in older adults for experiencing emotion dysregulation after intrusive thoughts. PMID- 21707186 TI - An abbreviated tool for assessing feminine norm conformity: psychometric properties of the Conformity to Feminine Norms Inventory-45. AB - The Conformity to Feminine Norms Inventory-45 (CFNI-45; Parent & Moradi, 2010) is an important tool for assessing level of conformity to feminine gender norms and for investigating the implications of such norms for women's functioning. The authors of the present study assessed the factor structure, measurement invariance, reliability, and validity of the CFNI-45 with data from 520 college women (55% White). Confirmatory factor analyses with data from this sample suggested acceptable fit for the posited 9-factor structure. Furthermore, analyses of measurement invariance indicated similar structural properties with members of socioculturally dominant (i.e., White) and nondominant (i.e., women of color) racial/ethnic status groups. Also, subscales of the CFNI-45 demonstrated acceptable internal consistency reliability coefficients, and correlations with convergent and discriminant validity indicators supported the validity of subscales scores. Overall, results offered support for the CFNI-45 as a multidimensional measure of women's conformity to feminine norms. The CFNI-45 can be used in research to facilitate evaluation of the theorized roles of conformity to feminine norms in women's mental health, vocational behavior, interpersonal relationships, and other domains. The CFNI-45 can be used in clinical practice to assess and attend to clients' conformity to feminine norms as is called for in the American Psychological Association's (2007) Guidelines for Psychological Practice with Girls and Women. PMID- 21707187 TI - Toward a hierarchical model of criminal thinking: evidence from item response theory and confirmatory factor analysis. AB - Item response theory (IRT) methods were applied to items from the 80-item Psychological Inventory of Criminal Thinking Styles (PICTS; G. D. Walters, 1995) to determine how well they measure the latent trait of criminal thinking in a group of 2,872 male medium security prison inmates. Preliminary analyses revealed that the 64 PICTS thinking style items, 32 PICTS proactive criminal thinking items, and 24 PICTS reactive criminal thinking items were sufficiently unidimensional to meet the local independence requirements of IRT. The PICTS was fitted to a 2-parameter logistic-graded response IRT model, the results of which showed that the 8 items measuring denial of harm (Sentimentality) displayed weak discrimination (a < 0.5), whereas most of the proactive and reactive items displayed moderate to good discrimination (a > 1.0). Information function analysis revealed that all 3 components of a hierarchical model of criminal thinking--PICTS total scale, PICTS proactive factor, and PICTS reactive factor- displayed greater precision at higher rather than lower levels of the trait dimension. The study findings indicate that items from the PICTS Sentimentality scale do a poor job of measuring general criminal thinking, whereas items from the other 7 PICTS thinking style scales provide their most precise estimates at the upper end of the trait dimension. PMID- 21707188 TI - Extension of the simulated drinking game procedure to multiple drinking games. AB - The present study extended the Simulated Drinking Game Procedure (SDGP) to obtain information about different types of drinking games. Phase I participants (N = 545) completed online screening questionnaires assessing substance use and drinking game participation. Participants who met the selection criteria for Phase II (N = 92) participated in laboratory sessions that consisted of three different periods of drinking game play. Sixty-two percent (N = 57) of the sample was female. Data from these sessions was used to estimate the peak Blood Alcohol Concentration (BAC) a participant would achieve if they consumed alcohol while participating in the SDGP. Total consumption and estimated BAC varied as a function of game type. The total consumption and estimated BAC obtained while playing Beer Pong and Memory varied significantly as a function of group. Total ounces consumed while playing Three Man varied significantly as a function of group; however, the variation in estimated BAC obtained while playing Three Man was not significant. Results indicated that estimated BACs were higher for female participants across game type. Previous experience playing the three drinking games had no impact on total drink consumption or estimated BAC obtained while participating in the SDGP. The present study demonstrated that the SDGP can be used to generate estimates of how much alcohol is consumed and the associated obtained BAC during multiple types of drinking games. In order to fully examine whether previous experience factors in to overall alcohol consumption and BAC, future research should extend the SDGP to incorporate laboratory administration of alcohol during drinking game participation. PMID- 21707190 TI - Discounting of hypothetical and potentially real outcomes in nicotine-dependent and nondependent samples. AB - Discounting is a behavioral phenomenon in which the value of an outcome diminishes as a function of its increased delay or decreased probability and is related to substance abuse research because of its theoretical ties with behavioral models of impulsive choice. Research to date suggests that hypothetical outcomes used in discounting research yield data that are indistinguishable from those using potentially real outcomes. However, the extant literature focuses primarily on delay discounting in non-drug-using humans and has not examined whether hypothetical outcomes yield disproportionate numbers of nonsystematic response patterns. In two experiments, we compared hypothetical and potentially real monetary outcomes in delay and probability discounting tasks in terms of rates of discounting and the frequency of nonsystematic response patterns. In Experiment 1, 61 adults reported no smoking, binge drinking, or illicit drug use in the past year. Experiment 2 included a community sample of nicotine-dependent adults (N = 36). In both experiments, discounting for hypothetical and potentially real outcomes yielded similar data, replicating and extending a growing literature pointing to the empirical equivalence of these outcomes. These findings are relevant to research on discounting that is frequently used in the study of substance use and other impulse-control behaviors. PMID- 21707189 TI - Amount of earnings during prize contingency management treatment is associated with posttreatment abstinence outcomes. AB - Contingency management (CM) treatments that provide patients with the opportunity to earn chances of winning prizes of varying magnitudes are becoming increasingly popular. In the CM literature, magnitude of reinforcement is linked with effect sizes, such that CM treatments that provide larger magnitude reinforcement are more efficacious than those that provide lower magnitude reinforcement. With prize CM, even when magnitudes of overall expected prize earnings are constant, some patients win more prizes than others. Thus, patients who win larger overall amounts of prizes during treatment may have better outcomes than those who win fewer prizes. This study evaluated the impact of overall amounts of prizes won on long-term abstinence outcomes. The dollar amount of prizes won during prize CM treatments was determined from 78 cocaine-abusing methadone-maintenance patients who were randomized to prize CM treatments in three clinical trials. Abstinence three months following the end of the CM intervention was the primary dependent variable. The dollar amount of prizes won during CM treatment was a significant predictor of submission of cocaine-negative urine samples and self-reports of cocaine abstinence at the follow-up evaluation, even after controlling for other variables associated with long-term abstinence, such as pretreatment urinalysis results and longest duration of abstinence achieved during treatment. These results suggest that magnitudes of earnings during prize CM may impact outcomes and call for further experimentation of parameters related to the efficacy of prize CM. PMID- 21707191 TI - Risk-taking and alcohol use disorders symptomatology in a sample of problem drinkers. AB - The relationship between risk-taking behavior and alcohol use disorder (AUD) symptoms is poorly understood. This study employed a modified version of a behavioral measure of risk-taking, the Balloon Analogue Risk Task (BART), to examine its relationship to alcohol use and related symptoms in a community sample of individuals with or at risk for AUD. A total of 158 (71.9% male) participants completed a testing battery that included the BART, a structured diagnostic interview for AUD, and measures of alcohol use and related problems. Estimates of IQ and working memory were assessed as covariates. Results indicated that the relationship between risk-taking propensity, as assessed by the BART, and alcohol problems was significant and negative. Individuals with higher symptom count made fewer pumps per trial on the BART, indicating less risk taking. It is important to note that this relationship was attenuated when controlling for estimated IQ and working memory span. Further examination demonstrated that IQ and age mediated the relationship between risk-taking propensity and symptom count. The main negative relationship observed between risk-taking on the BART and alcohol use and AUD symptomatology in this sample stands in contrast to the positive relationships observed in adolescent and nonclinical samples. Together, these findings highlight the need to consider development and the course of addiction to fully elucidate the effects of risky decision making on AUD liability. Furthermore, our results demonstrate the importance of inclusion of neurocognitive covariates (IQ), as well as demographic variables (age) when using this task. PMID- 21707192 TI - Reinforcement magnitude modulation of rate dependent effects in pigeons and rats. AB - Response rate can influence the behavioral effects of many drugs. Reinforcement magnitude may also influence drug effects. Further, reinforcement magnitude can influence rate-dependent effects. For example, in an earlier report, we showed that rate-dependent effects of two antidepressants depended on reinforcement magnitude. The ability of reinforcement magnitude to interact with rate dependency has not been well characterized. It is not known whether our previous results are specific to antidepressants or generalize to other drug classes. Here, we further examine rate-magnitude interactions by studying effects of two stimulants (d-amphetamine [0.32-5.6 mg/kg] and cocaine [0.32-10 mg/kg]) and two sedatives (chlordiazepoxide [1.78-32 mg/kg] and pentobarbital [1.0-17.8 mg/kg]) in pigeons responding under a 3-component multiple fixed-interval (FI) 300-s schedule maintained by 2-, 4-, or 8-s of food access. We also examine the effects of d-amphetamine [0.32-3.2 mg/kg] and pentobarbital [1.8-10 mg/kg] in rats responding under a similar multiple FI300-s schedule maintained by 2- or 10- food pellet (45 mg) delivery. In pigeons, cocaine and, to a lesser extent, chlordiazepoxide exerted rate-dependent effects that were diminished by increasing durations of food access. The relationship was less apparent for pentobarbital, and not present for d-amphetamine. In rats, rate-dependent effects of pentobarbital and d-amphetamine were not modulated by reinforcement magnitude. In conclusion, some drugs appear to exert rate-dependent effect which are diminished when reinforcement magnitude is relatively high. Subsequent analysis of the rate-dependency data suggest the effects of reinforcement magnitude may be due to a diminution of drug-induced increases in low-rate behavior that occurs early in the fixed-interval. PMID- 21707193 TI - Naloxone and rimonabant reduce the reinforcing properties of exercise in rats. AB - Naloxone and rimonabant block neurotransmitter action of some drugs of abuse (such as ethanol, opiates, and nicotine), and thereby reduce drug seeking and self-administration by suppressing the drugs' reinforcing properties. The present study represents an attempt to elucidate whether these drugs may also reduce rewarding properties of other events, in this case, activity-based reinforcement. In Experiment 1, 10 obese and 10 lean Zucker rats pressed a locked door under a progressive ratio schedule of reinforcement that, when unlocked, provided access to a running wheel for 2-min intervals. After baseline breakpoints were established, doses of naloxone (0.3-10 mg/kg) were administered prior to experimental sessions. Obese rats exhibited lower baseline breakpoints for wheel activity, lower response rates, and fewer revolutions compared to lean rats. Naloxone decreased revolutions and response rates for lean and obese rats, but did not reduce breakpoints. In Experiment 2, five Long-Evans rats pressed a door to unlock a wheel for 20 s of wheel activity. Doses of rimonabant (1-10 mg/kg) were administered before some experimental sessions. The highest dose of rimonabant suppressed breakpoints and response rates, but did not affect revolutions. These data suggest that both drugs reduce the reinforcing properties of wheel running, but do so in different manners: naloxone may suppress wheel based activity (consummatory behavior), but not seeking (appetitive behavior), and rimonabant does the converse. The data also support the role of endocannabinoids in the reinforcing properties of exercise, an implication that is important in terms of CB1 antagonists as a type of pharmacotherapy. PMID- 21707194 TI - Repulsed by violence: disgust sensitivity buffers trait, behavioral, and daily aggression. AB - Many models of aggression include negatively valenced emotions as common elicitors of aggressive behavior. Yet, the motivational direction of these emotions is not taken into account. The current work explored whether sensitivity to a negative emotion associated with behavioral avoidance-disgust-will predict lower levels of aggression. Five studies tested the hypothesis that disgust sensitivity predicts less aggression. In Study 1 (N = 92), disgust sensitivity predicted less trait physical and verbal aggression. In Study 2 (N = 268), participants high in disgust sensitivity were less likely to behave aggressively towards a stranger on a reaction-time task. In Study 3 (N = 51), disgust sensitivity was associated with less intimate partner violence inclinations. Study 4 (N = 247) replicated this effect longitudinally. In Study 5 (N = 166), each domain of disgust (i.e., moral, sexual, and pathogen disgust) had a buffering effect on daily aggression when daily experiences activated those specific domains. These results highlight the usefulness of considering the motivational direction of an emotion when examining its influence on aggression. PMID- 21707195 TI - Held in contempt: the psychological, interpersonal, and performance consequences of contempt in a work context. AB - Guided by a social function of emotions perspective, the authors examined a model of the psychological, interpersonal, and performance consequences of contempt in a series of 3 experiments that tested the outcomes of being a recipient of contempt in the work domain. In these experiments, participants engaged in a business strategy simulation with a virtual partner-a computer programmed to give contemptuous and other types of feedback. In Study 1, which examined the task performance and interpersonal outcomes of contempt, recipients of contempt had significantly better task performance but also significantly more interpersonal aggressiveness toward their virtual partners compared with recipients of failure, angry, or neutral feedback. Study 2 examined 3 psychological outcomes mediating the contempt-task performance/aggression relationship: self-esteem, returned feelings of contempt, and activation levels. Lowered levels of implicit self esteem and greater levels of activation significantly mediated the relationship between receiving contempt and task performance, whereas the contempt-aggression relationship was mediated by lowered implicit self-esteem and increased feelings of returned contempt. Study 3 examined status as a moderator of these relationships. Low-status recipients had significantly better task performance than did equal-status recipients, who performed significantly better than did the high-status recipients of contempt. In addition, low-status recipients displayed significantly lower levels of aggression in response to contempt than did equal status and high-status recipients. PMID- 21707196 TI - Listening, not watching: situational familiarity and the ability to detect deception. AB - In 4 experiments, the authors investigated the influence of situational familiarity with the judgmental context on the process of lie detection. They predicted that high familiarity with a situation leads to a more pronounced use of content cues when making judgments of veracity. Therefore, they expected higher classification accuracy of truths and lies under high familiarity. Under low situational familiarity, they expected that people achieve lower accuracy rates because they use more nonverbal cues for their veracity judgments. In all 4 experiments, participants with high situational familiarity achieved higher accuracy rates in classifying both truthful and deceptive messages than participants with low situational familiarity. Moreover, mediational analyses demonstrated that higher classification accuracy in the high-familiarity condition was associated with more use of verbal content cues and less use of nonverbal cues. PMID- 21707197 TI - Personality development across the life span: longitudinal analyses with a national sample from Germany. AB - Longitudinal data from a national sample of Germans (N = 20,434) were used to evaluate stability and change in the Big Five personality traits. Participants completed a brief measure of personality twice, 4 years apart. Structural equation modeling techniques were used to establish measurement invariance over time and across age groups. Substantive questions about differential (or rank order) and mean-level stability and change were then evaluated. Results showed that differential stability was relatively strong among all age groups but that it increased among young adults, peaked in later life, and then declined among the oldest old. Patterns of mean-level change showed that Extraversion and Openness declined over the life span, whereas Agreeableness increased. Mean levels of Conscientiousness increased among young adults and then decreased among older adults. Trajectories for Neuroticism were relatively flat, with slight increases during middle age and a slight decline in late life. PMID- 21707198 TI - When and why do ideal partner preferences affect the process of initiating and maintaining romantic relationships? AB - Three studies explored how the traits that people ideally desire in a romantic partner, or ideal partner preferences, intersect with the process of romantic relationship initiation and maintenance. Two attraction experiments in the laboratory found that, when participants evaluated a potential romantic partner's written profile, they expressed more romantic interest in a partner whose traits were manipulated to match (vs. mismatch) their idiosyncratic ideals. However, after a live interaction with the partner, the match vs. mismatch manipulation was no longer associated with romantic interest. This pattern appeared to have emerged because participants reinterpreted the meaning of the traits as they applied to the partner, a context effect predicted by classic models of person perception (S. E. Asch, 1946). Finally, a longitudinal study of middle-aged adults demonstrated that participants evaluated a current romantic partner (but not a partner who was merely desired) more positively to the extent that the partner matched their overall pattern of ideals across several traits; the match in level of ideals (i.e., high vs. low ratings) was not relevant to participants' evaluations. In general, the match between ideals and a partner's traits may predict relational outcomes when participants are learning about a partner in the abstract and when they are actually in a relationship with the partner, but not when considering potential dating partners they have met in person. PMID- 21707199 TI - Patterns of stability in adult attachment: an empirical test of two models of continuity and change. AB - One of the core assumptions of attachment theory is that attachment representations are stable over time. Unfortunately, the data on attachment stability have been ambiguous, and as a result, alternative theoretical perspectives have evolved to explain them. The objective of the present research was to evaluate alternative models of stability by studying adults in 2 intensive longitudinal investigations. Specifically, we assessed attachment representations in 1 sample (N = 203) daily over a 30-day period and in the other sample (N = 388) weekly over a year. Analyses show that the patterns of stability that exist in adult attachment are most consistent with a prototype model--a model assuming that there is a stable factor underlying temporary variations in attachment. Moreover, although the Big Five personality traits exhibited a pattern of stability that was similar to that of attachment, they did not account for the stability observed in attachment. PMID- 21707200 TI - Stages of change and physical activity among individuals with severe mental illness. AB - OBJECTIVE: To apply the constructs of the transtheoretical model (TTM) of change to understand physical activity among individuals with severe mental illness. METHOD: Predictions of stages of change of physical activity and self-reported physical activity were investigated among 92 adults with severe mental illness, using cognitive and behavioral processes of change, self-efficacy, and perceived pros and cons of exercise as predictors. RESULTS: Separate logistic regression analyses for adjacent pairs of stages indicated that 33% of the variance was accounted for when predicting preparation versus action/maintenance stages, with behavioral processes making a significant unique contribution to prediction. A multiple-regression analysis was conducted to examine prediction of self-reported physical activity on the basis of all of the TTM measures, and the full model accounted for nearly 27% of the variance. CONCLUSION: Results suggest that TTM constructs hold promise in understanding physical activity of people with severe mental illness with significant implications for clinical practice and future research. PMID- 21707201 TI - The role of contextual associations in producing the partial reinforcement acquisition deficit. AB - Three conditioned suppression experiments with rats as subjects assessed the contributions of the conditioned stimulus (CS)-context and context-unconditioned stimulus (US) associations to the degraded stimulus control by the CS that is observed following partial reinforcement relative to continuous reinforcement training. In Experiment 1, posttraining associative deflation (i.e., extinction) of the training context after partial reinforcement restored responding to a level comparable to the one produced by continuous reinforcement. In Experiment 2, posttraining associative inflation of the context (achieved by administering unsignaled outcome presentations in the context) enhanced the detrimental effect of partial reinforcement. Experiment 3 found that the training context must be an effective competitor to produce the partial reinforcement acquisition deficit. When the context was down-modulated, the target regained behavioral control thereby demonstrating higher-order retrospective revaluation. The results are discussed in terms of retrospective revaluation, and are used to contrast the predictions of a performance-focused model with those of an acquisition-focused model. PMID- 21707202 TI - Effects of response bias and judgment framing on operator use of an automated aid in a target detection task. AB - Automated diagnostic aids prone to false alarms often produce poorer human performance in signal detection tasks than equally reliable miss-prone aids. However, it is not yet clear whether this is attributable to differences in the perceptual salience of the automated aids' misses and false alarms or is the result of inherent differences in operators' cognitive responses to different forms of automation error. The present experiments therefore examined the effects of automation false alarms and misses on human performance under conditions in which the different forms of error were matched in their perceptual characteristics. Young adult participants performed a simulated baggage x-ray screening task while assisted by an automated diagnostic aid. Judgments from the aid were rendered as text messages presented at the onset of each trial, and every trial was followed by a second text message providing response feedback. Thus, misses and false alarms from the aid were matched for their perceptual salience. Experiment 1 found that even under these conditions, false alarms from the aid produced poorer human performance and engendered lower automation use than misses from the aid. Experiment 2, however, found that the asymmetry between misses and false alarms was reduced when the aid's false alarms were framed as neutral messages rather than explicit misjudgments. Results suggest that automation false alarms and misses differ in their inherent cognitive salience and imply that changes in diagnosis framing may allow designers to encourage better use of imperfectly reliable automated aids. PMID- 21707203 TI - Partitioning default effects: why people choose not to choose. AB - Default options exert an influence in areas as varied as retirement program design, organ donation policy, and consumer choice. Past research has offered potential reasons why no-action defaults matter: (a) effort, (b) implied endorsement, and (c) reference dependence. The first two of these explanations have been experimentally demonstrated, but the latter has received far less attention. In three experiments we produce default effects and demonstrate that reference dependence can play a major role in their effectiveness. We find that the queries formulated by defaults can produce differences in constructed preferences and further that manipulating queries can also mitigate default effects. The experimental context involves two environmentally consequential alternatives: cheap, inefficient incandescent light bulbs, and expensive, efficient compact fluorescent bulbs. Within this context we also measure the impact of each potential rationale for a default effect. PMID- 21707204 TI - Optimizing schedules of retrieval practice for durable and efficient learning: how much is enough? AB - The literature on testing effects is vast but supports surprisingly few prescriptive conclusions for how to schedule practice to achieve both durable and efficient learning. Key limitations are that few studies have examined the effects of initial learning criterion or the effects of relearning, and no prior research has examined the combined effects of these 2 factors. Across 3 experiments, 533 students learned conceptual material via retrieval practice with restudy. Items were practiced until they were correctly recalled from 1 to 4 times during an initial learning session and were then practiced again to 1 correct recall in 1-5 subsequent relearning sessions (across experiments, more than 100,000 short-answer recall responses were collected and hand-scored). Durability was measured by cued recall and rate of relearning 1-4 months after practice, and efficiency was measured by total practice trials across sessions. A consistent qualitative pattern emerged: The effects of initial learning criterion and relearning were subadditive, such that the effects of initial learning criterion were strong prior to relearning but then diminished as relearning increased. Relearning had pronounced effects on long-term retention with a relatively minimal cost in terms of additional practice trials. On the basis of the overall patterns of durability and efficiency, our prescriptive conclusion for students is to practice recalling concepts to an initial criterion of 3 correct recalls and then to relearn them 3 times at widely spaced intervals. PMID- 21707205 TI - Dynamic adaptation to history of trial difficulty explains the effect of congruency proportion on masked priming. AB - In reaction time research, there has been an increasing appreciation that response-initiation processes are sensitive to recent experience and, in particular, the difficulty of previous trials. From this perspective, the authors propose an explanation for a perplexing property of masked priming: Although primes are not consciously identified, facilitation of target processing by a related prime is magnified in a block containing a high proportion of related primes and a low proportion of unrelated primes relative to a block containing the opposite mix (Bodner & Masson, 2001). In the present study, this phenomenon is explored with a parity (even/odd) decision task in which a prime (e.g., 2) precedes a target that can be either congruent (e.g., 4) or incongruent (e.g., 3). It is shown that the effect of congruence proportion with masked primes cannot be explained in terms of the blockwise prime-target contingency. Specifically, with masked primes, there is no congruency disadvantage in a block containing a high proportion of incongruent primes, but there is a congruency advantage when the block contains an equal proportion of congruent and incongruent primes. In qualitative contrast, visible primes are sensitive to the blockwise prime-target contingency. The authors explain the relatedness proportion effect found with masked primes in terms of a model according to which response-initiation processes adapt to the statistical structure of the environment, specifically the difficulty of recent trials. This account is supported with an analysis at the level of individual trials using the linear mixed effects model. PMID- 21707206 TI - Washing away your (good or bad) luck: physical cleansing affects risk-taking behavior. AB - Many superstitious practices entail the belief that good or bad luck can be "washed away." Consistent with this belief, participants who recalled (Experiment 1) or experienced (Experiment 2) an episode of bad luck were more willing to take risk after having as opposed to not having washed their hands, whereas participants who recalled or experienced an episode of good luck were less willing to take risk after having as opposed to not having washed their hands. Thus, the psychological effects of physical cleansings extend beyond the domain of moral judgment and are independent of people's motivation: incidental washing not only removes undesirable traces of the past (such as bad luck) but also desirable ones (such as good luck), which people would rather preserve. PMID- 21707208 TI - Recollection-based prospective metamemory judgments are more accurate than those based on confidence: judgments of remembering and knowing (JORKS). AB - Five experiments were conducted to examine whether the nature of the information that is monitored during prospective metamemory judgments affected the relative accuracy of those judgments. We compared item-by-item judgments of learning (JOLs), which involved participants determining how confident they were that they would remember studied items, with judgments of remembering and knowing (JORKs), which involved participants determining whether studied items would later be accompanied by contextual details (i.e., remembering) or would not (i.e., knowing). JORKs were more accurate than JOLs when remember-know or confidence judgments were made at test and when cued recall was the outcome measure, but not for yes-no recognition. We conclude that the accuracy of metamemory judgments depends on the nature of the information monitored during study and test and that metamemory monitoring can be improved if participants are asked to base their judgments on contextual details rather than on confidence. These data support the contention that metamemory decisions can be based on qualitatively distinct cues, rather than an overall memory strength signal. PMID- 21707209 TI - Curved saccade trajectories reveal conflicting predictions in associative learning. AB - We report how the trajectories of saccadic eye movements are affected by memory interference acquired during associative learning. Human participants learned to perform saccadic choice responses based on the presentation of arbitrary central cues A, B, AC, BC, AX, BY, X, and Y that were trained to predict the appearance of a peripheral target stimulus at 1 of 3 possible locations, right (R), mid (M), or left (L), in the upper hemifield. We analyzed as measures of associative learning the frequency, latency, and curvature of saccades elicited by the cues and directed at the trained locations in anticipation of the targets. Participants were trained on two concurrent discrimination problems A+R, AC+R, AX+M, X+M and B+L, BC+L, BY+M, Y+M. From a connectionist perspective, cues were predicted to acquire associative links connecting the cues to the trained outcomes in memory. Model simulations based on the learning rule of the Rescorla and Wagner (1972) model revealed that for some cues, the prediction of the correct target location was challenged by the interfering prediction of an incorrect location. We observed that saccades directed at the correct location in anticipation of the target curved away from the location that was predicted by the interfering association. Furthermore, changes in curvature during training corresponded to predicted changes in associative memory. We propose that this curvature was caused by the inhibition of the incorrect prediction, as previously has been suggested with the concept of distractor inhibition (Sheliga, Riggio, & Rizzolatti, 1994; Tipper, Howard, & Houghton, 2000). The paradigm provides a new method to examine memory interference during associative learning. PMID- 21707207 TI - Effects of aging and IQ on item and associative memory. AB - The effects of aging and IQ on performance were examined in 4 memory tasks: item recognition, associative recognition, cued recall, and free recall. For item and associative recognition, accuracy and the response time (RT) distributions for correct and error responses were explained by Ratcliff's (1978) diffusion model at the level of individual participants. The values of the components of processing identified by the model for the recognition tasks, as well as accuracy for cued and free recall, were compared across levels of IQ (ranging from 85 to 140) and age (college age, 60-74 years old, and 75-90 years old). IQ had large effects on drift rate in recognition and recall performance, except for the oldest participants with some measures near floor. Drift rates in the recognition tasks, accuracy in recall, and IQ all correlated strongly. However, there was a small decline in drift rates for item recognition and a large decline for associative recognition and cued recall accuracy (70%). In contrast, there were large effects of age on boundary separation and nondecision time (which correlated across tasks) but small effects of IQ. The implications of these results for single- and dual-process models of item recognition are discussed, and it is concluded that models that deal with both RTs and accuracy are subject to many more constraints than are models that deal with only one of these measures. Overall, the results of the study show a complicated but interpretable pattern of interactions that present important targets for modeling. PMID- 21707210 TI - In search of on-line locality effects in sentence comprehension. AB - Many comprehension theories assert that increasing the distance between elements participating in a linguistic relation (e.g., a verb and a noun phrase argument) increases the difficulty of establishing that relation during on-line comprehension. Such locality effects are expected to increase reading times and are thought to reveal properties and limitations of the short-term memory system that supports comprehension. Despite their theoretical importance and putative ubiquity, however, evidence for on-line locality effects is quite narrow linguistically and methodologically: It is restricted almost exclusively to self paced reading of complex structures involving a particular class of syntactic relation. We present 4 experiments (2 self-paced reading and 2 eyetracking experiments) that demonstrate locality effects in the course of establishing subject-verb dependencies; locality effects are seen even in materials that can be read quickly and easily. These locality effects are observable in the earliest possible eye-movement measures and are of much shorter duration than previously reported effects. To account for the observed empirical patterns, we outline a processing model of the adaptive control of button pressing and eye movements. This model makes progress toward the goal of eliminating linking assumptions between memory constructs and empirical measures in favor of explicit theories of the coordinated control of motor responses and parsing. PMID- 21707211 TI - Thinking can cause forgetting: memory dynamics in creative problem solving. AB - Research on retrieval-induced forgetting has shown that retrieval can cause the forgetting of related or competing items in memory (Anderson, Bjork, & Bjork, 1994). In the present research, we examined whether an analogous phenomenon occurs in the context of creative problem solving. Using the Remote Associates Test (RAT; Mednick, 1962), we found that attempting to generate a novel common associate to 3 cue words caused the forgetting of other strong associates related to those cue words. This problem-solving-induced forgetting effect occurred even when participants failed to generate a viable solution, increased in magnitude when participants spent additional time problem solving, and was positively correlated with problem-solving success on a separate set of RAT problems. These results implicate a role for forgetting in overcoming fixation in creative problem solving. PMID- 21707212 TI - Cultural differences in strategic behavior: a study in computational estimation. AB - Imbo and LeFevre (2009) observed that Asians (responding in their 2nd language) selected strategies less adaptively than did non-Asians (responding in their 1st language). In the present research, we tested whether adaptive strategy selection is (a) really more resource demanding for Asians than for non-Asians or (b) more resource demanding for participants answering in a nonpreferred language. Three groups of participants were tested on a computational estimation task (e.g., 42 * 57 ~ ?) in no-load and load conditions: 40 Belgian-educated adults who answered in their first language (Dutch), 40 Chinese-educated adults who answered in their first language (Chinese), and 40 Chinese-educated adults who answered in their second language (English). Although the Chinese were faster and more accurate than the Belgians, they selected strategies less adaptively. That is, the Chinese were less likely to choose the strategy that produced the best estimate; this was especially so when their working memory was loaded. Further, we also observed that the Chinese who answered in English were slower than the Chinese who answered in Chinese; this difference was larger for difficult strategies and under working memory load. These results are interpreted in terms of the encoding complex model, whereas the explanation for the adaptivity results is based on cultural differences in educational history. PMID- 21707213 TI - Fast similarities: efficiency advantages of similarity-focused comparisons. AB - People constantly have to make efficient use of their limited cognitive resources. Recently, T. Mussweiler and K. Epstude (2009) demonstrated that comparative thinking simplifies information processing and increases the efficiency of judgment. However, there are different types of comparative thinking. While comparing 2 entities, people may focus on either similarities or dissimilarities between target and standard. The authors propose that these 2 comparative thinking styles differ in their efficiency. Specifically, the authors hypothesize that comparisons with a focus on similarities lead to more focused information processing and faster judgments than comparisons with a dissimilarity focus. In line with these hypotheses, the authors demonstrate that participants are indeed faster at judging the similarity of 2 stimuli (Study 1) and that they search for less target information in a comparative judgment task (Study 2) if they focus on similarities rather than dissimilarities. Focusing on similarities thus appears to be the more efficient comparative thinking style. PMID- 21707214 TI - The influence of levels of processing on recall from working memory and delayed recall tasks. AB - Recent research in working memory has highlighted the similarities involved in retrieval from complex span tasks and episodic memory tasks, suggesting that these tasks are influenced by similar memory processes. In the present article, the authors manipulated the level of processing engaged when studying to-be remembered words during a reading span task (Experiment 1) and an operation span task (Experiment 2) in order to assess the role of retrieval from secondary memory during complex span tasks. Immediate recall from both span tasks was greater for items studied under deep processing instructions compared with items studied under shallow processing instructions regardless of trial length. Recall was better for deep than for shallow levels of processing on delayed recall tests as well. These data are consistent with the primary-secondary memory framework, which suggests that to-be-remembered items are displaced from primary memory (i.e., the focus of attention) during the processing phases of complex span tasks and therefore must be retrieved from secondary memory. PMID- 21707215 TI - Neurobiological and memory models of risky decision making in adolescents versus young adults. AB - Predictions of fuzzy-trace theory and neurobiological approaches are examined regarding risk taking in a classic decision-making task--the framing task--as well as in the context of real-life risk taking. We report the 1st study of framing effects in adolescents versus adults, varying risk and reward, and relate choices to individual differences, sexual behavior, and behavioral intentions. As predicted by fuzzy-trace theory, adolescents modulated risk taking according to risk and reward. Adults showed standard framing, reflecting greater emphasis on gist-based (qualitative) reasoning, but adolescents displayed reverse framing when potential gains for risk taking were high, reflecting greater emphasis on verbatim-based (quantitative) reasoning. Reverse framing signals a different way of thinking compared with standard framing (reverse framing also differs from simply choosing the risky option). Measures of verbatim- and gist-based reasoning about risk, sensation seeking, behavioral activation, and inhibition were used to extract dimensions of risk proneness: Sensation seeking increased and then decreased, whereas inhibition increased from early adolescence to young adulthood, predicted by neurobiological theories. Two additional dimensions, verbatim- and gist-based reasoning about risk, loaded separately and predicted unique variance in risk taking. Importantly, framing responses predicted real life risk taking. Reasoning was the most consistent predictor of real-life risk taking: (a) Intentions to have sex, sexual behavior, and number of partners decreased when gist-based reasoning was triggered by retrieval cues in questions about perceived risk, whereas (b) intentions to have sex and number of partners increased when verbatim-based reasoning was triggered by different retrieval cues in questions about perceived risk. PMID- 21707216 TI - How modality specific is the iambic-trochaic law? Evidence from vision. AB - The iambic-trochaic law has been proposed to account for the grouping of auditory stimuli: Sequences of sounds that differ only in duration are grouped as iambs (i.e., the most prominent element marks the end of a sequence of sounds), and sequences that differ only in pitch or intensity are grouped as trochees (i.e., the most prominent element marks the beginning of a sequence). In 3 experiments, comprising a familiarization and a test phase, we investigated whether a similar grouping principle is also present in the visual modality. During familiarization, sequences of visual stimuli were repeatedly presented to participants, who were asked to memorize their order of presentation. In the test phase, participants were better at remembering fragments of the familiarization sequences that were consistent with the iambic-trochaic law. Thus, they were better at remembering fragments that had the element with longer duration in final position (iambs) and fragments that had the element with either higher temporal frequency or higher intensity in initial position (trochees), as compared with fragments that were inconsistent with the iambic-trochaic law or that never occurred during familiarization. PMID- 21707217 TI - Semantic information activated during retrieval contributes to later retention: Support for the mediator effectiveness hypothesis of the testing effect. AB - Previous research has proposed that tests enhance retention more than do restudy opportunities because they promote the effectiveness of mediating information- that is, a word or concept that links a cue to a target (Pyc & Rawson, 2010). Although testing has been shown to promote retention of mediating information that participants were asked to generate, it is unknown what type of mediators are spontaneously activated during testing and how these contribute to later retention. In the current study, participants learned cue-target pairs through testing (e.g., Mother: _____) or restudying (e.g., Mother: Child) and were later tested on these items in addition to a never-before-presented item that was strongly associated with the cue (e.g., Father)--that is, the semantic mediator. Compared with participants who learned the items through restudying, those who learned the items through testing exhibited higher false alarm rates to semantic mediators on a final recognition test (Experiment 1) and were also more likely to recall the correct target from the semantic mediator on a final cued recall test (Experiment 2). These results support the mediator effectiveness hypothesis and demonstrate that semantically related information may be 1 type of natural mediator that is activated during testing. PMID- 21707218 TI - To be or not to be...included in an event file: integration and retrieval of distractors in stimulus-response episodes is influenced by perceptual grouping. AB - The binding of stimulus and response features into stimulus-response (S-R) episodes or "event files" is a basic process for the efficient control of behavior. However, relevant information is usually accompanied by information that is irrelevant for the selection of action. Recent studies showed that even irrelevant information is bound into event files. In this study, we investigated the boundary conditions of distractor-response binding and subsequent distractor based response retrieval processes. In particular, we tested whether the inclusion of distractor information into S-R episodes is modulated by whether the distractor and target stimulus are perceived as belonging to the same object or as belonging to different objects. We argue that distracting information is only bound into S-R episodes if it is perceived as belonging to the same object as the relevant information, whereas no binding occurs when the distracting information is perceived as belonging to a separate object. In 6 experiments, we found evidence for the modulation of distractor-response bindings according to perceptual grouping principles. PMID- 21707219 TI - Memory activation and the availability of explanations in sequential diagnostic reasoning. AB - In the field of diagnostic reasoning, it has been argued that memory activation can provide the reasoner with a subset of possible explanations from memory that are highly adaptive for the task at hand. However, few studies have experimentally tested this assumption. Even less empirical and theoretical work has investigated how newly incoming observations affect the availability of explanations in memory over time. In this article we present the results of 2 experiments in which we address these questions. While participants diagnosed sequentially presented medical symptoms, the availability of potential explanations in memory was measured with an implicit probe reaction time task. The results of the experiments were used to test 4 quantitative cognitive models. The models share the general assumption that observations can activate and inhibit explanations in memory. They vary with respect to how newly incoming observations affect the availability of explanations over time. The data of both experiments were predicted best by a model in which all observations in working memory have the same potential to activate explanations from long-term memory and in which these observations do not decay. The results illustrate the power of memory activation processes and show where additional deliberate reasoning strategies might come into play. PMID- 21707220 TI - The shielding function of task sets and its relaxation during task switching. AB - The goal of the presented experiments was to investigate the dynamic interplay of task shielding and its relaxation during task switching. Task shielding refers to the finding that single task sets in terms of 2-choice categorization rules help shielding against distraction from irrelevant stimulus attributes. During task switching, this shielding should temporarily be relaxed to prevent the perseveration of the previous task, on the downside making the system more vulnerable toward the intrusion of irrelevant information. Participants had to switch between a digit and a letter categorization task. An irrelevant stimulus feature (Experiment 1: color, Experiment 2: font) varied randomly, orthogonal to the task. The presence or absence of an interaction of the irrelevant feature (switch vs. repetition) and the response (switch vs. repetition) was taken as evidence for the absence or presence of task shielding, respectively. Replicating previous results, irrelevant feature and response did not interact on task repetitions, indicating successful shielding. On task switches, however, the irrelevant feature interacted with the response, supporting the assumption that task shielding is temporarily relaxed during task switching. PMID- 21707221 TI - Upper age limits for accessing pediatric oncology centers in Italy: a barrier preventing adolescents with cancer from entering national cooperative AIEOP trials. AB - A limited proportion of adolescents with cancer currently receives treatment at pediatric oncology centers and this factor is considered one of the possible explanations for the lack of improvement in survival trends observed over the years in this age group. The adoption of inflexible upper age limits for admitting patients to pediatric units may help to explain this situation. This paper reports the results of a national survey on adolescents' access to, and age limits adopted by, Italian pediatric oncology centers, briefly discussing possible actions to bridge the gap in adolescents' access to care. The analysis showed a great variability in the upper age limits adopted at Italian pediatric oncology centers; in many cases age limits are set at 16, 15, or even 14 years. As major finding, a correlation was documented between age limits and number of adolescents treated in the pediatric centers. In principle, this finding should suggest that increasing the upper age limit may result in an increase of the access of adolescents in pediatric oncology centers. PMID- 21707222 TI - Immunosuppressive therapy without hematopoietic growth factor exposure in pediatric acquired aplastic anemia. AB - Immunosuppressive therapy (IST) is recommended for children with acquired aplastic anemia (AA) who lack a human leukocyte antigen (HLA)-matched sibling donor for hematopoietic cell transplantation (HCT). Hematopoietic growth factors have often been included in IST supportive care, but prolonged exposure may increase the risk of secondary clonal evolution. The authors evaluated response, survival, and the incidence of clonal evolution following cyclosporine-based IST without hematopoietic growth factor exposure in a population-based pediatric cohort, identified retrospectively. Forty-five patients with a median age of 7.3 years (range 1.2-17.0 years) were included. Partial (PR) and complete (CR) response was achieved in 82% and 64%, at a median of 55 days (range 11-414 days) and 7.6 months (range 2.8-82.2 months), respectively. Patients with associated seronegative hepatitis had an increased likelihood of PR and CR on multivariate analyses (PR: hazard ratio [HR] 3.15, 95% confidence interval [CI] 1.40, 7.11; CR: HR 2.99, 95% CI 1.35, 6.62), whereas older children were less likely to achieve IST response than children younger than 5 years at diagnosis. Five- and 10-year overall survival was 96% +/- 4% and 90% +/- 7%, respectively, and 5-year failure-free survival was 63% +/- 8%. There was no infection-related mortality, although 16.4% of patients had at least 1 episode of documented bacteremia. The 5 year cumulative incidence of relapse was 12.9% and of clonal evolution was 3.2%. The authors conclude that children with AA who receive IST without hematopoietic growth factor support have excellent response and survival outcomes and a low incidence of clonal evolution. PMID- 21707223 TI - Detection of early cardiac dysfunction in patients with beta-thalassemia major and thalassemia trait by tissue doppler echocardiography. AB - Cardiac complications are the leading cause of death in beta-thalassemia major (TM) patients. The aim of this study was to investigate the impact of iron overload on ventricular functions using conventional and tissue Doppler imaging (TDI) in patients with TM and compare them with children with thalassemia trait (TT) and healthy controls. This prospective study includes 3 groups: group 1: 29 patients with beta-TM; group 2: 28 patients with TT; group 3: 29 healthy controls. Peak late relaxation velocity determined by conventional echocardiography for the right ventricle was significantly higher and the E/A ratio for the right ventricle and left ventricle were significantly lower in TM patients than the other groups (P < .05). Peak late relaxation velocity determined by TDI for the left ventricle, interventricular septum, and right ventricle were significantly higher in TM patients than the TT subjects and controls (P < .001). The E/A ratio determined by TDI for the left ventricle, interventricular septum, and right ventricle were significantly lower in group 1 than the other 2 groups (P < .001). There was a negative correlation between the ferritin level and E/A ratio for the left ventricle, interventricular septum, and right ventricle using TDI (P < .05). Conventional echocardiographic techniques have failed to distinguish ventricular functions of asymptomatic patients with TM from the subjects with TT and from normal controls when global functions were examined. The present study indicates that TDI should be used for screening of TM and TT subjects' cardiac functions. PMID- 21707224 TI - Resolution of pulmonary hypertension with low-molecular-weight heparin, steroid, and prostacyclin analogue therapy: could it be early-phase pulmonary veno occlusive disease? AB - Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. The authors present a case of neuroblastoma with progressive dyspnea, hypoxemia, and pulmonary hypertension. A computed tomography scan of the chest revealed septal thickening and diffuse micronodules. The patient was diagnosed as PVOD and was successfully treated with low-molecular-weight heparin (LMWH) and corticosteroid. PMID- 21707225 TI - Recombinant human erythropoietin beta: the effect of weekly dosing on anemia, quality of life, and long-term outcomes in pediatric cancer patients. AB - Anemia, which is a common problem in cancer patients, has a negative effect on survival by decreasing the efficacy of chemotherapy and particularly of radiotherapy, as well as impairing the quality of life (QoL) of patients. Recombinant human erythropoietin (rHuEPO) decreases a patient's need for transfusions and increases their QoL. The aim of this study was to evaluate the effect of weekly single-dose EPO treatment on transfusion rates, QoL, and hemoglobin (Hb) levels. In addition, patients were followed up for a long period to assess the impact of EPO treatment on survival. The study was conducted from December 2001 to December 2002 in patients with newly diagnosed lymphoma or solid tumors using a prospective and controlled design. EPO-beta was given as a single dose of 450 U/kg once a week for 12 weeks. The study and control groups included 16 patients each. Hb levels measured in the study group at the 4th, 8th, and 12th weeks were significantly higher than the values recorded before the start of chemotherapy. In the control group, Hb levels post chemotherapy were significantly lower than values recorded prior to treatment. The increased Hb levels in the study group were significant at the 8th and 12th weeks of treatment compared to levels measured prior to treatment. In the control group, Hb levels at the 4th and 8th weeks were significantly lower than pretreatment levels. When the percent increase of Hb levels of the study and control groups with respect to treatment week was compared, the difference was statistically significant at the 4th, 8th, and 12th weeks. Although the increase on the performance scale within each group during treatment was significant in both the study and control groups, the increase was more marked in the study group. The percent increase on the performance scale with respect to week of treatment was higher in the study group than in the control group. In EPO treatment group, side effects were seen in 38% of patients, with 19% being local pain in the injection area, 13% local hyperemia, and 6% headache. The mean follow-up period of the study and control group was 7.03 +/- 0.41 (6.0-7.41) and 7.46 +/- 0.45 (6.58-7.83) years, respectively; no statistically significant difference existed between these figures. Overall survival at the end of 7 years of follow-up was 68.8% and 81.3% for the study and control groups, respectively. The use of EPO-beta in lymphoma and solid tumor patients on a once-weekly regimen (450 U/kg) was determined to be effective in increasing Hb levels, decreasing transfusion rates, and improving QoL. This regimen was safe, did not cause serious side effects, and can be recommended because of its high patient compliance and tolerability. An effect of EPO on prognosis was not evident. We could not have an explanation on the effect of EPO treatment on prognosis, as there were low number of patients and advanced staged patients died earlier. Therefore, a larger number of patients are needed to clarify the effect of EPO treatment on prognosis. PMID- 21707226 TI - Protective effects of hominis placenta hydrolysates on radiation enteropathy in mice. AB - The aim of this study was to investigate whether the hominis placenta hydrolysates (HPhs) have a protective effect against radiation-induced enteropathies. HPh (1-10 mg kg-1, i.p.) was treated to C57BL/6 mice, once daily for 5 days. Mice were irradiated (10 Gy) 1 h after the last injection. Cell damage was investigated at 24 and 72 h by haematoxylin-eosin staining, and the apoptotic index was determined at 24 h by deoxynucleotidyl transferase-mediated dUTP nick end labelling staining. The results showed that the HPh alleviated radiation-induced damage of crypts and suppressed apoptosis dose dependently. In conclusion, hominis placenta might be a beneficial agent against radiation induced intestinal complications. PMID- 21707227 TI - Comparative analysis of the oil and supercritical CO(2) extract of Schinus molle L. growing in Yemen. AB - In this study, we report the preliminary data on the chemical composition of Yemeni Schinus molle L. volatile oil obtained by supercritical extraction with carbon dioxide (40 degrees C and 90 bar), SFE, and by hydrodistillation (HD). The composition of the volatile oil has been analysed by GC and GC-MS. The content of the major constituents in the oils from leaves varied in the following ranges: germacrene D 3.7% in SFE and 16.7% in HD; beta-caryophyllene 19.1% in SFE and 13.5% in HD. The amount of monoterpenes constituted 4%, in all the analysed samples, while the number of sesquiterpenes was 44% in supercritical and 67% in HD oil. Some compounds were not identified by GC-MS and it will require further analysis using other analytical techniques. PMID- 21707228 TI - Comparative study of volatile oil compositions of two Plectranthus species from northern India. AB - The leaf and inflorescence essential oils of Plectranthus rugosus Wall. (syn. Rabdosia rugosa Wall.) and Plectranthus incanus L. (syn. Plectranthus mollis L.), which grow wild in Uttarakhand, India, were analysed and compared by capillary gas chromatography and gas chromatography-mass spectrometry. The analysis led to the identification of 43 constituents, forming 89.5-93.6% of the total oil compositions. Both leaf and inflorescence oil of P. rugosus were dominated by sesquiterpene hydrocarbons (71.8%, 71.7%) represented by beta-caryophyllene (36.2%, 29.8%), germacrene D (25.2%, 28.2%) and alpha-humulene (6.6%, 8.6%) as the major constituents. Conversely, the leaf and inflorescence oil of P. incanus were dominated by monoterpenoids (74.4%, 65.8%) with piperitenone oxide (44.2%, 38.5%), piperitone (8.6%, 12.2%) and terpinolene (14.5%, 10.2%) as major constituents. Piperitenone oxide, piperitone, cis- and trans-piperitols and trans piperitol acetate were the marker constituents in P. incanus, which were not noted in the essential oil of P. rugosus. PMID- 21707229 TI - Characterisation of protease activity in extracellular products secreted by Giardia duodenalis trophozoites treated with propolis. AB - Results from our laboratory revealed propolis activity on Giardia trophozoites proliferation. Since therapeutic agents can inhibit the activity of proteases related to relevant biologic and physiologic processes of parasites, this study was undertaken to characterise the proteolytic activity of excretory/secretory products (ESP) of trophozoites treated with propolis. ESP was obtained from culture supernatants of trophozoites exposed to 250 and 500 ug mL(-1) of propolis. ESP were tested in sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the protein profiles and the protease activity was assayed in gelatin-containing gels. Synthetic inhibitors were used to characterise the protease classes. Treated and non-treated ESP showed a similar protein and hydrolysis pattern. A simple pattern of protein composed by five evident bands of approximately 167, 132, 79, 61 and 51 kDa was found, and the zymograms comprised hydrolysis zones distributed from >170 to 23 kDa. No inhibition was seen on protease activity of propolis-treated trophozoites, whose hydrolysis pattern was similar to control. One may conclude that both ESP degraded gelatin and the activity was predominantly due to cysteine proteases. Although propolis had no effect on the proteolytic activity, further studies could identify the active constituents responsible for propolis antigiardial activity and their mechanisms of action. PMID- 21707230 TI - The use of spray-drying to enhance celecoxib solubility. AB - The present research investigates the enhancement of the dissolution rate of celecoxib by using spray-drying to prepare a solid dispersion with various polymers, namely Kollicoat IR(r) (Kollicoat), polyvinyl alcohol (PVA) 22000, or polyethylene glycol 6000 (PEG). The investigated drug-to-polymer mass ratios were 1:1, 1:2, and 1:4 by weight. Hydroalcoholic or methylene chloride solvent systems were used. The obtained yields ranged from 65% to 78%, whereas the entrapment efficiencies were between 68% and 82%. The results revealed an increase in the dissolution rate of the prepared particles up to 200% within 20 min. The prepared particles were investigated using differential scanning calorimetry, scanning electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. The increased dissolution rate was attributed to hydrogen bond formation between celecoxib and each polymer together with the reduced size of the formed particles offering a greater overall surface area. It was concluded that spray-drying may be considered a successful one-step technique to improve the dissolution rate of celecoxib when using Kollicoat, PVA, or PEG as the carrier polymer. PMID- 21707231 TI - Composition of fatty oils from semen ziziphi spinosae and its cardiotonic effect on isolated toad hearts. AB - In this study, the composition of fatty oil from Semen Ziziphi Spinosae and its cardiotonic activity on the heart isolated from a toad were studied. Oil-in-water (O/W) emulsions of fatty oil were prepared by the perfusion method. The fatty oil had a positive inotropic effect on isolated rat hearts at a concentration between 5 * 10(-3) and 2 * 10(-2) mL/10 mL, and the effect was in positive correlation with the concentration of calcium ions. In addition, this effect was inhibited by 2 mg/mL nifedipine, suggesting that the cardiotonic mechanism could be responsible for accelerating the inflow of calcium ions. Gas chromatography-mass spectrometry analysis showed that the main constituents of the fatty oil were 9 octadecenoic acid (43.32%), 9,12-octadecadienoic acid (42.57%), hexadecanoic acid (4.76%), 9-eicosenoic acid (2.95%), stearic acid (2.41%) and arachidic acid (0.81%). This preliminary study revealed that the fatty oil of Semen Ziziphi Spinosae exhibited remarkable cardiotonic activity in the tested models, and it is necessary to further reveal the effective substances of the fatty oil. PMID- 21707232 TI - Long-term time course of affective lability after subthalamic deep brain stimulation electrode implantation. AB - The mechanism and time course of emotional side effects of subthalamic deep brain stimulation in Parkinson's disease are a matter for discussion. We report a 53 month follow-up of a patient with affective lability. Postoperative lesion plus bilateral stimulation strongly influenced mood in the first week in terms of laughing behavior, while voltage changes had only minor long-term impact up to 37 months on negative emotion, possibly caused by the right electrode stimulating the subthalamic nucleus and adjacent fiber tracts involving the internal capsule. Thus we conclude that affective lability can occur with different temporal dynamics of microlesion, and early and chronic stimulation. PMID- 21707233 TI - Antioxidant capacity and total phenolic contents of oregano (Origanum vulgare), lavender (Lavandula angustifolia) and lemon balm (Melissa officinalis) from Romania. AB - The study reported here presents a comparative screening of three medicinal plants including oregano (Origanum vulgare L.), lavender (Lavandula angustifolia) and lemon balm (Melissa officinalis) having the same geographical origin, the Southeast region of Romania, and growing in the same natural conditions. The contents of total phenolics and total flavonoids for the extracts of these were determined. Furthermore, the total antioxidant capacity was also evaluated. It was found that Origanum vulgare and Melissa officinalis extracts present the most effective antioxidant capacity in scavenging DPPH radicals, while Lavandula angustifolia is less active. High performance liquid chromatography-mass spectrometry analysis was used to identify the components of extracts. Major phenolic acids identified in the analysed species were ferulic, rosmarinic, p coumaric and caffeic, while predominant flavonoids were quercetin, apigenin kaempherol, which were present as glucosides. PMID- 21707234 TI - Antitumor activity and antioxidant role of a novel water-soluble carboxymethyl chitosan-based copolymer. AB - In this study, a natural polymer, chitosan (CS) has been converted through modified procedures to produce a water-soluble nontoxic form that has been evaluated as a novel potential antitumor drug. CS was carboxymethylated and then further modified in mild aqueous medium via graft copolymerization using a new simple and reproducible method. The synthesized new derivative of carboxymethylated CS (DCMC) was fully characterized by numerous techniques including Fourier transform infrared spectroscopy (FT-IR), elemental analyzer (EA), scanning electron microscopy (SEM), two-dimensional wide-angle X-ray scattering (2D-WAXS), and differential scanning calorimetry (DSC). The anticancer activity of the DCMC was investigated using mice bearing Ehrlich ascites tumor cells (EAC) at different doses dissolved in isotonic saline. It has been found that treatment with DCMC significantly inhibited tumor growth in a dose-dependent manner. To better understand the molecular mechanism explaining the DCMC effect on cancer cells, we tested the response of EAC cells in vivo to DCMC using flow cytometry cell cycle analysis. The cell cycle analysis revealed a G2/M phase accumulation as well as a significant increase in sub-G1 phase cells after treatment with DCMC. This indicates an induction of apoptosis in EAC cells associated with a highly significant decrease in tumor volume. In general, our results indicated that the DCMC is a regulator of tumor cell growth and differentiation not only by causing G2/M cell cycle arrest but also inducing their apoptotic death. Moreover, the estimated hematological profile such as hemoglobin, RBCs, as well as WBCs counts revealed normal levels in mice treated with DCMC, indicating the possibility of using the DCMC in cancer chemotherapy without causing anemia like other drugs. Biochemical assays also revealed that treatment with DCMC has led to an augmentation of the antioxidant defense system without affecting lipid peroxidation in EAC-bearing mice. PMID- 21707235 TI - The relationship between HbA1c level, symptoms and self-rated health in type 2 diabetic patients. AB - OBJECTIVE: Improving glycaemic control is generally supposed to reduce symptoms experienced by type 2 diabetic patients, but the relationships between glycated haemoglobin (HbA(1c)), diabetes-related symptoms, and self-rated health (SRH) are unclarified. This study explored the relationships between these aspects of diabetes control. DESIGN: A cross-sectional study one year after diagnosis of type 2 diabetes. SUBJECTS: A population-based sample of 606 type 2 diabetic patients, median age 65.6 years at diagnosis, regularly reviewed in primary care. MAIN OUTCOME MEASURES: The relationships between HbA(1c), diabetes-related symptoms, and SRH. RESULTS: The patients' median HbA(1c) was 7.8 (reference interval: 5.4-7.4 % at the time of the study). 270 (45.2%) reported diabetes related symptoms within the past 14 days. SRH was associated with symptom score (gamma = 0.30, p < 0.001) and HbA(1c) (gamma = 0.17, p = 0.038) after correction for covariates. The relation between HbA(1c) and symptom score was explained by SRH together with other confounders, e.g. hypertension (gamma = 0.02, p = 0.40). The relation between the symptom fatigue and SRH was not explained by symptom score and significantly modified the direct association between symptom score and SRH. CONCLUSIONS: Symptom relief may not occur even when HbA(1c) level is at its lowest average level in the natural history of diabetes, and symptoms and SRH are closely linked. Monitoring symptoms in the clinical encounter to extend information on disease severity, as measured e.g. by HbA(1c), may help general practitioners and patients to understand the possible impact of treatments and of disease manifestations in order to obtain optimum disease control. PMID- 21707236 TI - Ecology of medical care in a publicly funded health care system: a registry study in Sweden. AB - OBJECTIVE: To explore the influence of sociodemographic factors on access to appointments with physicians in primary, secondary, and tertiary health care in a publicly funded health care system. DESIGN: A population-based registry study. SETTING: Different health care settings in Vasternorrland county, Sweden. SUBJECTS: All residents in the county at the end of 2006. MAIN OUTCOME MEASURES: The number of people per 1000 residents who had at least one appointment with a physician in an average month in different health care settings. RESULTS: A total of 87 people had appointments with a physician in primary health care, 44 in outpatient clinics at a regional hospital, 20 in an emergency department, 14 in home care, and two in a university hospital outpatient clinic. Twelve were hospitalized at a regional hospital and <1 at the university hospital. Being young or elderly, female, divorced, widowed, and having a contractor as usual source of care were all independently associated with higher odds of receiving primary care. CONCLUSIONS: The physician's office in primary care is the setting that has the potential to affect the largest number of people. The extent of the use of health care was independently influenced by all sociodemographic characteristics studied, which highlights the importance of individual factors in future resource allocation. Regarding availability the ecology model provides superior information as compared with the absolute number of physicians' appointments. The prerequisites in Sweden of high-quality registries and unique personal identification numbers encourage future research on the ecology model to optimize accessibility of health care. PMID- 21707237 TI - Fourth ventricle meningiomas: a rare entity. AB - Fourth ventricle meningiomas (FVMs) are rare, often misdiagnosed, lesions. To the best of our knowledge, 47 cases have been reported in the literature: we describe our series of three cases treated at our Institution, focusing on some diagnostic tips and intraoperative features of these tumours. Our three patients have a history of headache. Gait disturbances, vomiting and/or diplopia complicated the clinical picture before the referral at our Department. The operations were uneventful, and the patients fully recovered from neurological symptoms. They are free of recurrence at a median follow-up of 19 years. FVMs are rare lesions, which are difficult to differentiate preoperatively from the much more common ependymomas. A preoperative distinction would be extremely advantageous: indeed, although both tumours share similar radiological and clinical patterns, they clearly differ as to surgical difficulty and outcome. In fact, meningiomas are comparatively easier to remove, granting better clinical results. PMID- 21707238 TI - Antibiotic resistant infections with antibiotic-impregnated Bactiseal catheters for ventriculoperitoneal shunts. AB - BACKGROUND: Shunts remain the commonest means by which hydrocephalus is treated. Despite the changes in valve and catheter technology, shunt infection and blockage are still a cause of great headache for the patient as well as the neurosurgeon. Antibiotic-laced catheters were proposed as a means by which to reduce shunt colonization and infection. METHODS: We present our experience of 52 months of Bactiseal catheters in all consecutive patients who underwent a ventriculoperitoneal (VP) shunt from July 2004 to November 2008, under the care of one neurosurgeon. This was a prospective study with outcome measures of infection, blockage, intra and postoperative complications and revision surgery. RESULTS: One hundred and twenty-five patients underwent VP shunting with Bactiseal catheters, with a combination of NSC, Strata and Burr Hole valves. The age range of the patients was from 1 week premature to 64-years old. Forty-two of the patients were paediatric. The aetiology for hydrocephalus included posterior fossa tumoursto intra-ventricular haemorrhage, post-meningitic hydrocephalus and aqueduct stenosis. The overall complication rate was 12%. The following complications occurred: blockage in two cases; haemorrhage and blockage in two cases; CSF leak in one case; infection in four cases; other in three cases (peritoneal adhesions, wound erosion and postoperative peritonitis). There were four infections in total (3.2%). All of these occurred within six months of implantation. All infections were caused by rifampicin resistant Staphylococcus epidermidis. CONCLUSION: In an era of increasing methicillin-resistant Staphylococcus aureus (MRSA) resistance and 'superbugs', is the use of antibiotic laced catheters adding to the pool of resistant bacteria which may be harder to treat? Vigilance is required, as rare and resistant staphylococci strains occasionally can emerge as causative agents for VP shunt infections, in both adults and children, and their treatment can be difficult. PMID- 21707239 TI - Clipping of distal superior cerebellar artery aneurysm with preservation of the parent vessel: a case report. AB - A 29-year-old male presented with subarachnoid haemorrhage and a diagnosis of a ruptured distal superior cerebellar artery (SCA) aneurysm. The distal SCA harboured perforators to the brainstem; electrophysiological changes during temporary clipping proved the need for surgical clipping over endovascular occlusion. Successful clipping without distal occlusion was performed. PMID- 21707240 TI - A case of intracerebral metastasis in osteosarcoma without active pulmonary metastasis. AB - Intracerebral metastasis in osteosarcoma is extremely rare. A 14-year-old girl who had previously been operated upon for osteosarcoma of the femur presented with seizures and left hemiparesis. A right parietal lesion with calcification and brain oedema was found. After resection of the mass, pathology revealed an osteosarcoma metastasis. PMID- 21707241 TI - Differential expression of a novel voltage gated potassium channel--Kv 1.5 in astrocytomas and its impact on prognosis in glioblastoma. AB - INTRODUCTION: Ion channels are subjects of intense research, due to their easy access and potential for being drug targets. Kv1.5 is a voltage gated potassium channel, earlier thought to be cardiac specific. Recent studies have revealed that K(+) channels play an important role in apoptosis, glial cell proliferation and biology of various cancers. No study has so far been performed to assess their expression in astrocytomas and correlate its impact on the clinical behaviour of gliomas. METHODS: Sixty samples of astrocytoma which included 9 diffuse astrocytoma (DA) grade II, 11 anaplastic astrocytoma (AA) grade III and 40 glioblastoma (GBM), along with normal brain tissue (cerebral cortex; n = 5) were analysed for their Kv1.5 protein expression. Immunohistochemical expression of Kv1.5 in various grades was assessed semi quantitatively. The patients with GBM (n = 40) were treated with uniform protocol and their survival was documented. RESULTS: The mean expression of Kv1.5 in DA, AA and GBM was 22.2 +/- 9.71%, 11.81 +/- 12.3% and 10.37 +/- 11.05%, respectively, the difference being statistically significant (p = 0.004). The mean expression in low grade astrocytoma (WHO II) was significantly higher than higher grades (22.2% and 10.7%; p = 0.005). On analysing the influence of Kv1.5 expression on survival of GBM patients, we noted that increasing Kv1.5 labelling index (LI) correlated with a favourable prognosis, albeit not being significant (p = 0.310; HR = 0.901). CONCLUSIONS: Kv1.5 expression occurs more in DA, when compared to high grade astrocytoma. GBM patients with higher Kv1.5 expression had better survival, though not reaching statistical significance. PMID- 21707242 TI - The true value of C-reactive protein measurement in neurosurgical patients. PMID- 21707243 TI - Endovascular treatment of AVM-associated aneurysm of anterior inferior cerebellar artery through persistent primitive hypoglossal artery. AB - We present a patient with the combination of persistent primitive hypoglossal artery and the origin of left common carotid artery from the brachiocephalic trunk, who had subarachnoid haemorrhage caused by a ruptured aneurysm. The aneurysm was on distal anterior inferior cerebellar artery which was a feeder to cerebellar arterio-venous malformation. PMID- 21707244 TI - Rodent under the hat. AB - This report describes a case of neglected scalp basal cell carcinoma (BCC) resulting in total destruction of soft tissue and underlying cranium, with remarkably preserved dura and no parenchymal involvement. A 57-year-old woman presented with a 2-week history of lethargy. On removal of her hat, a large round ulcer was revealed. It transpired that the patient noticed a pruritic scalp lesion 9 months ago. As the lesion and wound enlarged, she was too embarrassed to inform her family and hid it under a hat at all time. She never experienced meningitic symptoms. Biopsy confirmed BCC. Subsequently, she underwent two free latissimus dorsi flap reconstructions to cover the wound and palliative radiotherapy. She responded well to treatment. This case provides a rare opportunity to observe the natural history of scalp BCC. The reasons for the rarity of this mode of presentation and the low incidence of intracranial infection are discussed. PMID- 21707245 TI - Tumour-infiltrating T-cell subpopulations in glioblastomas. AB - This study was designed to determine the incidence and prognostic value of various populations of tumour-infiltrating T cells in glioblastomas. We also evaluated the difference in T-cell populations after conventional treatment. Sixty-seven patients with glioblastomas underwent surgery between 2003 and April 2009. Immunohistochemical staining was performed for CD3, CD4, CD8 and FoxP3, and the average number and percentage of positive cells were calculated. In eight patients, the average number of subpopulations was compared between the specimens obtained during the first and second operations. Age, gender, Karnofsky performance status, Radiation Therapy Oncology Group-recursive partitioning analysis (RTOG-RPA) classes, extent of removal, treatment modality, O-6 methylguanine-DNA methyltransferase (MGMT) methylation status and immunopositivity for CD4, CD8 and FoxP3 were analyzed as prognostic factors. There was an average of 12.8 +/- 1.8 CD31 T cells, 1.5 +/- 0.5 CD41 T cells, 6.8 +/- 1.3 CD81 T cells and 0.6 +/- 0.2 FoxP3 cells. The percentage of positive T cell subpopulations was 89.6%, 22.4%, 77.6% and 34.3% for CD3, CD4, CD8 and FoxP3, respectively. In eight patients, there was no difference in the subpopulations between the first and second operations. The median progression free survival was 7.0 months (95% CI, 5.2-8.9 months) and the overall survival was 14.8 months (95% CI, 11-18.7 months). Univariate analysis showed a statistically significant difference in progression-free survival for CD8 (p = 0.02) and overall survival for RTOG-RPA classes (p = 0.003), the extent of removal (p = 0.01) and MGMT promoter methylation status (p = 0.005). Based on multivariate analysis, RTOG-RPA classes were significantly associated with longer overall survival. The intratumoural immune response occurred frequently in glioblastomas and there was a consistent response, even after conventional treatment. There was a statistically significant difference in progression-free survival for CD81 T cells in immunologically privileged central nervous system. PMID- 21707246 TI - Levels of endotoxin in 390 Swedish homes: determinants and the risk for respiratory symptoms in children. AB - Endotoxins are microbiological agents which ubiquitously exist in an indoor environment, and are believed to be causal agents for a number of diseases. This study investigated the indoor levels and determinants of endotoxins and their impact on asthma and allergy diseases among Swedish pre-school children. House dust samples from 390 homes of 198 case children with asthma and allergy and 202 healthy control children were collected in the Dampness Building and Health (DBH) study. House dust endotoxin levels in the child's bedroom and living rooms ranged from 479-188,000 EU/g dust and from 138-942,000 EU/g dust, respectively. Pet keeping and agricultural activities were significantly associated with the higher endotoxin concentration levels in indoor dust. Endotoxins in theindoor environment did not associate to asthma and allergy diseases in the children. However, we found an association between endotoxins and the presence of disease symptoms in the sub-group of families without indoor pets. PMID- 21707247 TI - A recent paper by Abouhossein et al. (2010) investigates the long-sharing mechanism of loads between the disc, ligaments and facet joints of the human lumbar spine. PMID- 21707248 TI - Anti-biofilm potential of a glycolipid surfactant produced by a tropical marine strain of Serratia marcescens. AB - A tropical marine bacterium isolated from the hard coral, Symphyllia sp. was identified as Serratia marcescens on the basis of morphological, biochemical and 16S rDNA analysis. The bacterium showed antimicrobial activity towards the pathogens Candida albicans and Pseudomonas aeruginosa and the marine biofouling bacterium Bacillus pumilus. S. marcescens displayed biosurfactant activity as evidenced by drop collapse, blood hemolysis and surface tension reduction (52.0 27 mN m(-1)). The active compound was purified by solvent extraction and silicic acid chromatography. Characterization was by thin layer chromatography, gas chromatography mass spectroscopy (GC-MS), Fourier transform infrared (FTIR) spectroscopy and (1)H as well as (13)C nuclear magnetic resonance (NMR) analysis. The surfactant was found to be a glycolipid composed of glucose and palmitic acid. The glycolipid prevented adhesion of C. albicans BH, P. aeruginosa PAO1 and B. pumilus TiO1. The glycolipid also disrupted preformed biofilms of these cultures in microtitre plates. Confocal laser scanning microscopy and electron microscopy confirmed the effective removal of biofilms from glass surfaces. The glycolipid derived from S. marcescens could thus serve as a potential anti biofilm agent. PMID- 21707249 TI - Flavonoids from Lupinus texensis and their free radical scavenging activity. AB - Seventeen flavonoids including one new compound were isolated from Texas bluebonnet (Lupinus texensis), the state flower of Texas. Their structures were determined by extensive nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry analyses. High-performance liquid chromatography analytic method for simultaneous determination of the 17 compounds was established and validated. Eleven isolated flavonoids were first evaluated for their free radical scavenging activity using alpha,alpha-diphenyl-beta picrylhydrazyl scavenging assay and they showed activity with EC(50) 48.6-172.5 ug mL(-1). PMID- 21707250 TI - Topical anti-inflammatory constituents of lipophilic leaf fractions of Alchornea floribunda and Alchornea cordifolia. AB - The leaves of Alchornea floribunda and Alchornea cordifolia are used traditionally as topical anti-inflammatory agents. In this study, two highly lipophilic fractions AFLF and ACLF isolated from A. floribunda and A. cordifolia leaves respectively were investigated for topical anti-inflammatory effects using xylene-induced mice ear oedema as a model of inflammation. AFLF and ACLF at 5 mg per ear showed significant (p < 0.01) topical anti-inflammatory effect with oedema inhibitions of 64.0% and 79.0% at 2 h, respectively. When compared to indomethacin (5 mg per ear), these fractions showed significantly (p < 0.05) higher topical anti-inflammatory effect. Gas chromatography-mass spectrometry analysis revealed that AFLF is composed mainly of long chain saturated and unsaturated hydrocarbons (18.78%) and their oxygenated derivatives (1.89%); while ACLF is rich in volatile oils eugenol (21.26%) and cadinol (4.76%), and other constituents like, nanocosaine (36.86%) and steroid derivatives, ethyl iso allocholate (4.59%) and 3-acetoxy-7,8-epoxylanostan-1-ol (15.86%). Analysis of the volatile oil (ACV) extracted from the fresh leaves of A. cordifolia revealed the presence of high concentrations of eugenol (41.7%), cadinol (2.46%), Caryophylene (1.04%), Linalool (30.59%) and (E)-alpha-bergamotene (4.54%). These compounds could be contributing to the topical anti-inflammatory effects of A. floribunda and A. cordifolia leaf extracts. PMID- 21707251 TI - Antihyperglycaemic effects of ethanol extracts of Carica papaya and Pandanus amaryfollius leaf in streptozotocin-induced diabetic mice. AB - Diabetes mellitus is a global disease that is increasing in an alarming rate. The present study was undertaken to study the antidiabetic effect of the ethanol extracts of Carica papaya and Pandanus amaryfollius on streptozotocin-induced diabetic mice. The results of the present study indicated that there was no significant difference in the body weight of the treated groups when compared to diabetic control. Whereas, there was significant (P < 0.05) decrease in the blood glucose level of the plant-treated groups compared to the diabetic control. Histologically the pancreas of the treated groups indicated significant regeneration of the beta-cells when compared to the diabetic control. The liver tissues of the treated group indicated a reduction in fatty changes and pyknotic nucleus. The kidney tissues of the treated groups indicated significant recovery in the cuboidal tissue. The results from the phytochemical screening indicated the presence of flavonoids, alkaloids, saponin and tannin in C. papaya and P. amaryfollius. The antidiabetic effect of C. papaya and P. amaryfollius observed in the present study may be due to the presence of these phytochemicals. PMID- 21707252 TI - Long-term adherence to a physical activity intervention: the role of telephone assisted vs. self-administered coping plans and strategy use. AB - OBJECTIVE: This study investigated the role of coping plans and the use of selection, optimisation and compensation (SOC) strategies within an experimental evaluation of a 26-week physical exercise intervention. METHODS: Older women (N=86, M (age)=73.7 years) were randomly assigned to a telephone-assisted or a self-administered coping planning intervention after 6 weeks' participation in an exercise programme. The number of different coping plans formulated, exercise specific SOC strategy use and their interaction were used to predict objectively measured long-term adherence to the intervention. RESULTS: The number of coping plans formulated (beta=0.28) and goal-pursuit strategies reported (sum score of optimisation and compensation strategies, beta=0.39) predicted adherence to the exercise programme over 20 weeks. The predictive strength of coping plans increased with decreasing numbers of goal-pursuit strategies (beta=-0.21). Women supported via telephone reported significantly more coping plans than did women in the self-administered coping planning group, F(1,80)=9.47, p=0.003. CONCLUSION: Coping plans have a buffering effect on adherence levels when use of SOC strategies is low. Older women's adherence to physical activities may be improved if they are given direct support in generating coping plans involving strategies of selection, optimisation and compensation. PMID- 21707253 TI - Terpenoid composition and antifungal activity of three commercially important essential oils against Aspergillus flavus and Aspergillus niger. AB - Hydro-distilled essential oils extracted from three commercially important aromatic plants were analysed by capillary gas chromatography-flame ionization detector and gas chromatography/quadrupole mass spectrometry and subjected to antifungal activity. Fifteen compounds, which accounted for 97.8% of Acorus calamus root oil composition have been identified. Besides the major constituent (Z)-asarone (81.1-92.4%), (Z)-methyl isoeugenol (1.8-2.1%), (Z)-isoelemicin (1.2 1.3%), (E)-asarone (1.0-2.6%), (E)-methyl isoeugenol (0.2-0.4%), (Z)-beta-ocimene (0.2-0.4%), elemicin (0.2-0.3%), linalool (0.1-0.9%) and kessane (t-0.2%) were identified. Monoterpenes constituted the main fraction of Origanum vulgare essential oil attaining 90.5% of the total oil composition. p-Cymene (10.3%) was the major component of the monoterpene hydrocarbon fraction while thymol (53.2%) and carvacrol (3.9%) were the most abundant oxygenated monoterpenes among the 33 identified constituents. Cinnamomum tamala leaf oil contained (E)-cinnamaldehyde as the principal component. Quantitative variations in (Z)-cinnamaldehyde (5.8 7.1%), linalool (6.4-8.5%) and (E)-cinnamyl acetate (4.7-5.2%) were significant. The antifungal activity of the hydro-distilled essential oils of A. calamus, O. vulgare and C. tamala were evaluated against Aspergillus flavus and Aspergillus niger. Disc diffusion method was used for the determination of the inhibitory effect. O. vulgare essential oil exhibited the highest activity. Moreover, all three essential oils inhibit the growth of A. flavus and A. niger. PMID- 21707254 TI - Chemical compounds from Phoenician juniper berries (Juniperus phoenicea). AB - Natural chemical compounds are a widely researched topic worldwide because of their potential activity against cerebrovascular diseases. Chemicals from Juniperus phoenicea berries are reported in this study. Lipids (11%) from seeds are mainly unsaturated (86%). Minerals are also quantified like Na (63.8 mg per 100 g DW) or K (373.9 mg per 100 g DW). Total reduced sugars are ca 192.6 mg g( 1) DW. Polyphenols and flavonoids from berries are highly present with an average of 1764 +/- 174.3 mg gallic acid per 100 g DW and 890 +/- 47.6 mg rutin per 100 g DW, respectively. Mean free radical scavenging activities, determined by DPPH and ABTS, are 1337 +/- 126.2 mM TEAC per 100 g DW and 1105.7 +/- 95.9 mM TEAC per 100 g DW, respectively. All findings improve the possible presence of biologically active fractions in phytocomplex that could be used as such and/or extracted for the formulation of supplements and/or ingredients for the pharmaceutical industry. PMID- 21707255 TI - Elegaphenone and 7-epi-clusianone, the major cytotoxic constituents of Hypericum elegans. AB - Two cytotoxic constituents, namely elegaphenone and 7-epi-clusianone, were isolated from the aerial parts of Hypericum elegans Stepan ex Willd. Elegaphenone was identified as (E)-(2-(3,7-dimethylocta-2,6-dienyloxy)-4,6 dihydroxyphenyl)(phenyl)methanone by means of spectral evidence. Both compounds showed prominent cytotoxicity on HD-MY-Z, K-562 and KE-37 tumour cell lines. The IC(50) values for elegaphenone were 15.9 (HD-MY-Z), 13.9 (K-562) and 16.9 (KE-37) umol while those of 7-epi-clusianone were 9.8 (HD-MY-Z), 11.8 (K-562) and 13.6 (KE-37) umol. The established oligonucleosomal deoxyribonucleic acid (DNA) fragmentation of genomic DNA following short-term (6 h) or long-term (24 h) exposure to the tested compounds clearly indicates that the induction of apoptotic cell death is an important component for their cytotoxic mode of action. PMID- 21707256 TI - Recovery of phenolic compounds from grape seeds: effect of extraction time and solid-liquid ratio. AB - The aim of this research was to study the recovery of phenolic compounds from grape seeds, by-products from winemaking industries, using ethanolic solid-liquid extraction. For such a purpose, the combined effects of the extraction time (9, 19 and 29 h) and the solid-liquid ratio (0.10, 0.20 and 0.30 gdw mL(-1)), were investigated (where dw = dry waste). Results demonstrated that Pinot Noir seeds had high levels of both total polyphenols (73.66 mg(Gallic Acid Equivalent) gdw( 1)) and flavonoids (30.90 mg(Catechin Equivalent) gdw(-1)), being the optimum extraction time 19 h approximately. The main phenolic compounds analysed with high performance liquid chromatography were catechin and quercetin with a maximum extraction yield obtained at 29 h (362.23 and 339.35 mg/100 gdw, respectively). Concentration of the polyphenols and their antiradical powers are demonstrated to have a significant linear correlation. PMID- 21707257 TI - Seasonal variation in essential oil yield and composition from Thymus vulgaris L. during different growth stages in the south of Jordan. AB - The effect of plant space and time of harvesting on yield and quality of Thymus vulgaris was evaluated in Jordan. Thyme was cultivated in rows of 50 cm apart with inter-row spacing of 15, 30 or 45 cm and was grown at various development stages. Plants were harvested during different growth stages including vegetation, beginning of blooming, full blooming and fruit maturation. Results indicated that oil yields of thyme were affected by growth stage and inter-row spacing. The maximum oil yields was obtained by harvesting at the early growth stage, which was found superior to oil yield corresponding to the later stages of collection. With 45 cm inter-row spacing, the maximum oil yield was recorded when the samples were collected at growth stage. Indicated results showed that the chemical composition during various growth stages was characterised by high percentage of carvacrol and its corresponding monoterpenic hydrocarbon precursors rho-cymene and gamma-terpinene, and ether 1,4-cineol. PMID- 21707258 TI - Is preschool executive function causally related to academic achievement? AB - The primary objective of this study was to reevaluate the well-established result that preschoolers' performance on executive function tasks are positively associated with their performance on academic achievement tests. The current study replicated the previously established concurrent associations between children's performance on EF tasks and academic achievement tests. Specifically, children's performance on measures of inhibitory and motor control were positively associated with their performance on tests of reading, writing, and mathematics achievement (rs = .2-.5); moreover, although diminished in magnitude, most of these associations held up even after including an earlier measure of academic achievement as a covariate (rs = .1-.3). However, the application of an alternative analytic method, fixed effects analysis, a method that capitalizes on repeated measures data to control for all time stable measured and unmeasured covariates, rendered the apparent positive associations between executive function and academic achievement nonsignificant (rs = .0-.1). Taken together, these results suggest that the well-replicated association between executive function abilities and academic achievement may be spurious. Results are discussed with respect to the importance of utilizing analytic methods and research designs that facilitate strong causal inferences between executive function and academic achievement in early childhood, as well as the limitations of making curriculum development recommendations and/or public policy decisions based on studies that have failed to do so. PMID- 21707259 TI - When family looks strange and strangers look normal: a case of impaired face perception and recognition after stroke. AB - We describe a patient (JS) with impaired recognition and distorted visual perception of faces after an ischemic stroke. Strikingly, JS reports that the faces of family members look distorted, while faces of other people look normal. After neurological and neuropsychological examination, we assessed response accuracy, response times, and skin conductance responses on a face recognition task in which photographs of close family members, celebrities and unfamiliar people were presented. JS' performance was compared to the performance of three healthy control participants. Results indicate that three aspects of face perception appear to be impaired in JS. First, she has impaired recognition of basic emotional expressions. Second, JS has poor recognition of familiar faces in general, but recognition of close family members is disproportionally impaired compared to faces of celebrities. Third, JS perceives faces of family members as distorted. In this paper we consider whether these impairments can be interpreted in terms of previously described disorders of face perception and recent models for face perception. PMID- 21707260 TI - The rate of compliance to seat belt usage among automobile drivers on three categories of roads in Nigeria: an observational survey. AB - Injuries to head, chest and abdomen are a major cause of death for unrestrained vehicle occupants, particularly the drivers. The use of seat belts therefore plays a significant role in reducing the severity of injuries. The study examined the compliance rate of seat belt use on different road hierarchies in Abeokuta (Nigeria) using an observatory method. Findings indicated that there was 54%, 37.3% and 13.6% compliance rate on three categories of roads studied. Also, females complied more with the use of seat belts on each of the roads with compliance rates at 43.3%, 47.2% and 50% compared with males who had 32.6%, 38.6% and 39.6% seat belt compliance rates. Chi-square analysis showed significant variations in the use of seat belt on the roads (p < 0.05). The paper suggests increased awareness and enforcement of traffic laws among others in order to ensure sustainable use of seat belts among motorists in Nigeria. PMID- 21707261 TI - Discrepancy in unilateral spatial neglect between daily living and neuropsychological test situations: a single case study. AB - We report results of our investigation of the case of a 34-year-old woman (YJ) who showed persistent left unilateral spatial neglect (USN) in daily living, frequently hitting obstacles or bumping into the wall, although her visuospatial ability was mostly preserved in paper and pencil neuropsychological tests. In order to clarify this apparent discrepancy, her eye fixation pattern was monitored in testing situations and in natural daily activities using an eye camera. The results showed that when taking the standard tests YJ tended to shift her fixation point to the left edge of the testing frame to overcome over searching tendency to the right as left hemianopics without left USN would do. However in natural situations, this compensatory leftward fixation was not found. This may be due to the lack of adequate frames of reference in the natural environment. Our findings suggest limitation of laboratory neuropsychologicial testing to fully appreciate the scope of a patient's disability in natural settings. PMID- 21707262 TI - Differential predictability of four dimensions of affect intensity. AB - Individual differences in affect intensity are typically assessed with the Affect Intensity Measure (AIM). Previous factor analyses suggest that the AIM is comprised of four weakly correlated factors: Positive Affectivity, Negative Reactivity, Negative Intensity and Positive Intensity or Serenity. However, little data exist to show whether its four factors relate to other measures differently enough to preclude use of the total scale score. The present study replicated the four-factor solution and found that subscales derived from the four factors correlated differently with criterion variables that assess personality domains, affective dispositions, and cognitive patterns that are associated with emotional reactions. The results show that use of the total AIM score can obscure relationships between specific features of affect intensity and other variables and suggest that researchers should examine the individual AIM subscales. PMID- 21707263 TI - Intra-operative localisation of spinal level using pre-operative CT-guided placement of a flexible hook-wire marker. AB - Confident intra-operative localisation of thoracic spinal pathology remains challenging. Several strategies are routinely employed, including intra-operative fluoroscopy and pre-operative image-guided skin marking. These techniques are limited both by potential inaccuracy and inconvenience. Here we present a novel, efficient and accurate technique for intra-operative localisation of thoracic spinal pathology using pre-operative CT-guided placement of a flexible hook-wire marker. PMID- 21707264 TI - Latina adolescents' perceptions of their male partners' influences on childbearing: findings from a qualitative study in California. AB - Teenage births among Latina women living in the USA remain higher than any other racial/ethnic group. This study explored the role that male partners play in the occurrence of pregnancy and their influence on teenage mothers' future plans in a sample of women pregnant with their first child. Qualitative analysis revealed that partners played a significant role in the use of contraception, timing and desire for pregnancy and young women's post-pregnancy plans for education, work and childrearing. Men's older age, concerns about contraceptive use and fertility, reluctance to use condoms, and readiness for parenthood put their partners at increased risk for pregnancy. More acculturated men were supportive of young women's educational goals in many cases, whereas less acculturated males subscribed to more rigid gender roles which required that their partners remain at home after the birth of their child. These findings have important implications for programmes that seek to reduce teenage pregnancy in the US Latino population. PMID- 21707265 TI - Assessment of PCDD/F, PCB, OCP and BPA dietary exposure of non-breast-fed European infants. AB - The aim of this study is to obtain data on the exposure of non-breast-fed infants to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F), polychlorinated biphenyls (PCB), organochlorine pesticides (OCP), and bisphenol A (BPA) and its chlorinated derivatives through consumption of commercial infant foods with largest shares of the market in 22 European Union countries. The E-Screen bioassay was employed to assess the oestrogenicity of the baby foods and the ethoxyresorufin-O-deethylase (EROD) induction was measured to determine the levels of PCDD/F and PCB. Consequently, the highest total effective xenoestrogen burden (TEXB) of 73.60 pM Eeq g(-1) was found in the soy-based formula and the EROD bioassay was always below the limit of quantification (LOQ) (3.5 pg g(-1)). Overall, the estimated dietary exposure to BPA via commercial baby foods was lower than the tolerable daily intake (TDI) of 50 ug kg(-1) body weight (bw). Furthermore, the findings indicated that the dietary exposure of 0-9-month-old infants through the products investigated here does not exceed the maximum TDI of 4 pg WHO-TEQ (toxic equivalents) kg(-1) bw. However, exposure to more than 2 pg WHO-TEQ kg(-1) bw day(-1) might occur for 0-4-month-old infants consuming 'starting' hypoallergenic formula. Moreover, analysis of OCP indicated that the dietary exposure of non-breast-fed infants was not harmful. Considering the importance of early development and the vulnerability of infants and children, it is essential to determine their dietary exposure to contaminants in order to decide which efforts of risk reduction should receive highest priority. PMID- 21707266 TI - Visualized voices: a case study of audio-visual synesthesia. AB - We report a single case study of a synesthete (PS) who has complex visual experiences from sounds, including human voices. Different vowel sounds from different speakers and modified to be of different pitch (f0) were presented to PS and controls who were asked to draw an (abstract) visual image of the sound noting colors, sizes, and locations. PS tended to be more consistent over time than controls. For both PS and controls, the pitch of the vowel influenced the choice of luminance (higher pitch being lighter) and vertical position (higher pitch being higher in space). However, the gender of the speaker influenced the size of the 'image' independently of pitch (vowels from males being larger). PMID- 21707267 TI - Simultaneous determination of five aluminum lake dyes in chewing gum by HPLC with photodiode array detection. AB - A simple and rapid method has been developed and validated for the determination of five food aluminum lake dyes (Tartrazine Al lake, Sunset Yellow Al lake, Ponceau 4R Al lake, Allura Red Al lake and Brilliant Blue Al lake) in chewing gum. The dye portions of the target aluminum lakes were simultaneous extracted with 0.25 M NaOH and cleaned up by liquid-liquid extraction with dichloromethane, followed by further purification using Oasis WAX solid-phase extraction (SPE) cartridges. Analytes were separated by HPLC using an Inertsil (r) ODS-3 column coupled to a photodiode array detector. The amounts of the aluminum lake dyes were finally quantified and indicated as their dye portions using corresponding calibration curves over ranges of 0.5 to 50 ug ml(-1), with correlation coefficients >0.9999. Recoveries of the dye parts in aluminum lake dyes (spiked at levels of 1, 5, 25 ug g(-1)) ranged from 72.5 to 116.4%, with relative standard deviations between 0.9 and 6.5%. Limits of detection and limits of quantification for all analytes were 0.15 and 0.50 ug g(-1), respectively. This method was successfully applied in real samples of chewing gum. PMID- 21707268 TI - Comparative study of low- versus high-resolution liquid chromatography-mass spectrometric strategies for measuring perfluorinated contaminants in fish. AB - Perfluorinated compounds (PFCs) are usually monitored by high-performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) on triple quadrupole instruments. Although not yet widely implemented in the field, high resolution mass spectrometry (HRMS) today appears as a valuable alternative for these halogenated chemicals due to their significant mass defect. Indeed, this second approach offers a way to cope with particular matrix effects caused by co eluting and isobaric interferences affecting the measurement of some PFCs in fish. The present study compares three different LC-MS-related instruments and various signal acquisition modes, from low-resolution full-scan and selected ion monitoring (SIM) mode on a triple quadrupole (QqQ) instrument to high-resolution full-scan or product ion-scan mode on orbital trap (LTQ-Orbitrap) or quadrupole time-of-flight (Q-TOF) devices. Performances are compared for seven model compounds belonging to seven PFCs subclasses: perfluoralkylsulfonate, perfluoroalkylcarboxylate, perfluoroalkylsulfinate, perfluoroalkyl-sulfonamide, fluorotelomer saturated acid, fluorotelomer unsaturated acid and perfluoroalkylphosphonic acid. Low-resolution MS/MS was found to be unsurprisingly reliable for extended multi-residue monitoring. However, the high stability of PFCs leads to a relatively poor and non-specific fragmentation pathway in MS/MS. In addition, biliary acid-interfering compounds (e.g. taurochenodeoxycholic acid), which where encountered in the present case in fish samples but that may be present in other biological samples, were found particularly disturbing in low-resolution MS/MS. Indeed, these interferences presented the same retention time and diagnostic signals as PFOS, leading to a possible overestimation of the PFOS quantification in LC-MS/MS. On the other hand, high-resolution MS and MS/MS (LTQ-Orbitrap and Q-TOF) provided better results in terms of signal specificity and sensitivity. For instance, the estimated limits of detection (LOD) reached for PFOS on QqQ, Q-TOF and LTQ Orbitrap instruments were 3.8, 0.7 and 0.5 pg injected, respectively. PMID- 21707269 TI - Haemorrhagic shearing lesions associated with diffuse axonal injury: application of T2 star-weighted angiography sequence in the detection and clinical correlation. AB - PURPOSE: To assess the diagnostic value of T2 star-weighted angiography (SWAN) sequence for diffuse axonal injury (DAI) by virtue of correlation analysis between the number, volume and regional distribution of haemorrhagic lesions determined with SWAN sequence and clinical variables. METHODS: Twenty-eight DAI patients were included in our study and were divided into subgroups in compliance with dichotomized clinical variables separately. Global and regional number, volume and distribution of haemorrhagic lesions were compared between groups by non-parametric Mann-Whitney U test (two tailed) and independent samples t test. Spearman's rank correlation analysis was performed to compare the dichotomized clinical variables with the global and regional number and volume of lesions. RESULTS: Patients with lower Glasgow Coma Scale (GCS) score (<=8, n = 16) or prolonged coma (>4 days, n = 15) or abnormal pupillary light reflex (PLR, n = 15) had a greater global number (p <= 0.01) and apparent volume (p <= 0.01) of haemorrhagic lesions. In our study, haemorrhage extent in most brain regions, such as frontal white matter (FW), parietotemporaloccipital white matter (PTOW), corpus callosum (CC), thalamus (THAL), brain stem (BS), were greater in the lower GCS group, in the prolonged coma group and in the abnormal PLR group (p <= 0.05). Significant correlations were found between haemorrhage extent in global range and the dichotomized clinical variables (p <= 0.01). Correlations were also found between haemorrhage extent in most regions, such as FW, PTOW, CC, THAL and BS, and the dichotomized clinical variables (p <= 0.05). The number of involved regions was much more higher in the lower GCS group and the prolonged coma group (p < 0.0001). CONCLUSION: More accurate and objective assessment of injury can be obtained in DAI patients via SWAN sequence. PMID- 21707271 TI - Influencing and adjusting in daily emotional situations: a comparison of European and Asian American action styles. AB - Emotions are for action, but action styles in emotional episodes may vary across cultural contexts. Based on culturally different models of agency, we expected that those who engage in European-American contexts will use more influence in emotional situations, while those who engage in East-Asian contexts will use more adjustment. European-American (N=60) and Asian-American (N=44) college students reported their action style during emotional episodes four times a day during a week. Asian Americans adjusted more than European Americans, whereas both used influence to a similar extent. These cultural differences in action style varied across types of emotion experienced. Moreover, influencing was associated with life satisfaction for European Americans, but not for Asian Americans. PMID- 21707270 TI - Determination of atrazine and degradation products in Luxembourgish drinking water: origin and fate of potential endocrine-disrupting pesticides. AB - Several pesticides have been hypothesized to act as endocrine-disrupting compounds, exhibiting hormonal activity and perturbing normal physiological functions. Among these, especially s-triazine herbicides have received increased attention. Despite being banned in many countries, including the European Union, atrazine is still the world's most widely used herbicide. Despite its discontinued use, considerable concentrations of atrazine and its degradation products, mainly desethylatrazine (DEA) and deisopropylatrazine (DIA), are still found in the environment, including drinking water sources. The aim of this investigation was to study concentrations of especially s-triazine herbicides and major degradation products in drinking water, including spring water, tap water and bottled water in Luxembourg. Spring water (2007/2008/2009, n = 69/69/69), tap water (2008/2009, n = 19/26), and bottled water (2007/2008/2009, n = 5/13/7) were sampled at locations in Luxembourg and investigated for pesticides by LC-ESI MS/MS. Atrazine was the predominant triazine, detectable in many spring water locations, tap and bottled water, ranging (mean) from 0-57 (9), 0-44 (4), and 0-4 (1) ng l(-1), respectively. DEA and DIA in spring water ranged (mean) from 0-120 (19) and 0-27 (3) ng l(-1), with higher concentrations from agricultural areas and low molar ratios of DEA:atrazine <0.5 and high ratios of atrazine:nitrate suggesting point-source contamination. Levels (mean) of DEA and DIA in tap water were 0-62 (14) and 0-6 (<1) ng l(-1) and in bottled water 0-11 (2) and 0-7 (2) ng l(-1). Simazine and other triazines were detected in traces (<5 ng l(-1)). Thus, the conducted monitoring suggested the presence of low concentrations of s triazines in raw and finished water, presumably partly due to non-agricultural contamination, with concentrations being below thresholds advocated by the European Union Directive 98/83/EC. PMID- 21707272 TI - Nephron-sparing surgery versus radical nephrectomy for kidney tumors: benefits and limitations. PMID- 21707273 TI - The potential of virus-based gene therapies for treatment of metastatic kidney cancer. PMID- 21707274 TI - Personalizing prophylactic surgery in cancer: current practice and future perspectives from new genome-wide association studies. PMID- 21707275 TI - Breast cancer, obesity and hormonal imbalance: a worrisome trend. PMID- 21707277 TI - Sorafenib for the management of advanced renal cell carcinoma. AB - The approval of sorafenib (Nexavar((r))) launched a new era of targeted therapy for advanced renal cell carcinoma (RCC). Sorafenib was the first oral multikinase inhibitor available for use in RCC, demonstrating a significant clinical benefit for patients living with this disease in the Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET). As other targeted agents have emerged and expanded options for patients with RCC, understanding the optimal role of targeted therapies in different treatment settings has become more important. This article reviews the expansive clinical evidence supporting the use of sorafenib in RCC, including analyses across a variety of subpopulations, and examines the impact of sorafenib on clinical practice and its future role in RCC. PMID- 21707278 TI - Breast care in 2011 and beyond: state of policy, state of science. AB - The National Consortium of Breast Centers (NCoBC) is an interdisciplinary group of medical and allied health professionals, advocates and administrators championing the cause of collaborative care as it relates to breast health and breast cancer. The annual meeting was held in Las Vegas (NV, USA) between 13 and 16 March 2011, and because we are not wholly identified as a breast cancer society, our research and programs are varied. To the best of our ability we represent the diversity of our membership on the planning committee and we are proud of the conference that has just taken place. While ours is not a forum for the presentation of new research, it is the forum used to impart important knowledge from the past year to the most diverse group that meets around the topic of breast care. Important highlights from our meeting will be discussed in the following article. PMID- 21707279 TI - Defining the role of the immune system in cancer treatment: highlights from the Immunochemotherapy Conference. AB - The Immunochemotherapy: Correcting Immune Escape in Cancer meeting was co organized by George Prendergast (Lankenau Institute for Medical Research, PA, USA), Guido Kroemer (Gustave Roussy Cancer Institute, Paris, France) and Laurence Zitvogel (Gustave Roussy Cancer Institute) in partnership with Abcam. It brought together investigators with a diverse background in immunology, oncology and cancer biology, and offered a forum for discussion of a new vision that acknowledges the role of the host immune system not only in cancer development and progression, but also as a major determinant of response to treatment. An important implication of this vision is that synergy between conventional cytocidal modalities and immune response modifiers is not only possible, but holds the promise to revolutionize cancer treatment. The emerging evidence that was presented in support of this new concept will be summarized in this article. PMID- 21707280 TI - 5th Canadian Melanoma Conference: research frontiers. AB - The prospects for the treatment of metastatic melanoma are improving. Whereas previous scientific meetings dedicated to the treatment of metastatic melanoma patients were overshadowed by our inability to improve overall survival or lengthen the time to progression, the results presented at the most recent meetings are hopeful. The 5th Canadian Melanoma Conference held on 24-27 February in Banff (AB, Canada) was nothing short of optimistic. This year's meeting was divided into three themes: basic science and pathology, dermatology and surgery, and immunology and systemic treatment. In addition, dermoscopy case studies were presented, and Hoffmann la Roche sponsored a symposium on the evaluation of treatment for advanced melanoma. It underscored the importance of early detection and patient stratification, based upon the molecular profile of the tumor, in order to optimize the response to targeted therapy. PMID- 21707281 TI - Molecular signatures that predict nodal metastasis in bladder cancer: does the primary tumor tell tales? AB - Evaluation of: Smith SC, Baras AS, Dancik G et al. A 20-gene model for molecular nodal staging of bladder cancer: development and prospective assessment. Lancet Oncol. 12, 137-143 (2011). Accurate identification of nodal status in patients with bladder cancer is important in determining their prognosis and administration of perioperative chemotherapy. In this article, we review the study by Smith and colleagues, documenting the identification of a 20-gene model that can predict nodal stage in patients with bladder cancer based on the profiles of their primary tumors. The gene-expression model generated in this study was able to identify node-positive disease based on tumor tissues obtained from patients in a Phase III bladder cancer trial cohort. The model was able to predict nodal status independent of standard clinicopathologic prognostic criteria. This study adds the agnostic profiling dimension to prior investigations that have attempted to define molecular signatures that predict nodal metastasis in bladder cancer patients based on the primary tumors' gene expression profiles. PMID- 21707282 TI - Discussion on the influence of HER2 status on the clinical outcome of bladder cancer continues. AB - Evaluation of: Bolenz C, Shariat SF, Karakiewicz PI et al. Human epidermal growth factor receptor 2 expression status provides independent prognostic information in patients with urothelial carcinoma of the urinary bladder. BJUI 106, 1216-1222 (2010). The article under evaluation by Bolenz et al. reports on an association between human EGF receptor 2 (HER2) overexpression and aggressive urothelial carcinoma of the urinary bladder: more lymphovascular invasion, higher risk of recurrence and higher disease-specific mortality. These results add to the controversy regarding HER2 status and clinical outcome that is currently known. First, a consensus for the best technique and cut-off is needed. Only then can the relationship between HER2 overexpression and clinical outcome be investigated without current limitations. Although there are already trials ongoing on targeted therapy in bladder cancer, this should be viewed with caution, as patient selection is based on inconsistent definitions of HER2 overexpression. Selection of patients who might benefit from targeted therapy can only be carried out after consensus has been reached. PMID- 21707283 TI - The role of tissue microarray in the era of target-based agents. AB - Tissue microarray (TMA) technologies have been developed over the last years, mainly to identify biomarkers useful for the correct identification and characterization of tumors. Moreover, TMA has been implemented in retrospective studies in order to identify predictive biomarkers of response to a given therapy and/or to find potential new targets for biological therapy. We analyzed the fields of application of TMA technology and the design of TMA varying according to the objectives to be studied. In this article, the reader will learn how to design TMAs in order to cover the objectives of clinical trials based upon the use of target-based agents. The main limits and advantages of TMA and the results achieved in cancer diagnosis will be also described. Tissue microarray technology should be systematically applied to define critical markers, in retrospective studies and in the screening of most human tumors in order to find new possible molecular targets and to molecularly define the diagnosis of the neoplastic diseases. TMAs have substantially improved the field of translational studies, even in the design and follow-up of studies based upon the use of target-based agents in cancer therapy. PMID- 21707284 TI - Quality of reporting in randomized controlled trials conducted in China on the treatment of cancer pain. AB - BACKGROUND: Research in China has been rapidly gaining momentum, but as yet there is no systematic evaluation of quality of reporting in randomized controlled trials (RCTs) on the treatment of cancer pain conducted in China. Therefore, an assessment in this field is an imperative issue. METHODS: A PubMed search of reports published between 1994 and 2009 followed by an examination and critical appraisal of reporting in RCTs on the treatment of cancer pain was conducted in China. All reports had been examined to describe their general characteristics and evaluate the quality of their reporting. Quality of reporting was assessed against a subset of criteria adapted from the Consolidated Standards of Reporting Trials (CONSORT) statement. RESULTS: A total of 46 RCTs were included in full text. The frequency of RCTs was found to increase over time: from one (2.2%) in 1994-1997 to 28 (60.9%) in 2006-2009. There were fewer papers published in this field in foreign journals, as funding sources and opportunities for collaborative research with foreigners are still limited. Visual analogue scales were the main method of cancer pain evaluation (19 reports; 41.4%). Only 12 studies (26.1%) are deemed to have authentic randomization and 36 papers (78.3%) provided no information about blinding of either participants or investigators. In 22 papers (47.8%), there was no information about the length of time for which participants were followed. Only 15 (32.6%) of the included trials reported approval by an ethics committee and 17 (37.0%) adequately discussed informed consent. CONCLUSION: The quality of reporting in RCTs on the treatment of cancer pain conducted in China needs to be improved. Three critical steps should be strictly conducted including randomization, blinding and follow-up. Reporting of RCTs in this field conducted in China should meet and keep up with the standards of CONSORT statement. PMID- 21707285 TI - Current status of ablative techniques for small renal masses. AB - The past few decades have witnessed a steady increase in the number of newly diagnosed small renal masses. Although historically managed by surgical resection, many of these small renal masses are now noted to be amenable to less invasive treatment modalities including thermal ablation or active surveillance. Contemporary series suggest that renal thermal ablation (including cryoablation or radiofrequency ablation), when selectively employed, can maintain oncologic efficacy comparable to extirpation while minimizing complications and treatment morbidity. Therefore, as the incidence of small renal masses in elderly comorbid patients rises, it is likely we will see ablative techniques assume a greater role in management. PMID- 21707286 TI - Tumor enucleation: a safe treatment alternative for renal cell carcinoma. AB - The treatment of renal cell carcinoma has evolved tremendously over the years. Initially the entire kidney was removed along with the renal tumor despite the size or extent of the mass. Early attempts to remove tumors with a normal surrounding parenchymal margin showed equivalent oncologic results in small renal masses. Attempts to preserve more renal parenchyma in patients with compromised renal function led to the enucleation of renal masses by blunt dissection following the natural plane between the peritumor pseudocapsule and the renal parenchyma. Enucleation of renal tumors has been especially useful for renal preservation in patients with preoperative renal insufficiency, solitary kidneys, multiple renal lesions and hereditary renal cell carcinoma syndromes. Comparable long-term progression and cancer-specific survival has been shown with tumor enucleation and standard partial nephrectomy. However, there has been considerable controversy regarding the safety of renal tumor enucleation due to histopathologic findings of pseudocapsule tumor invasion. Current data suggest that tumor enucleation is a safe alternative for small renal masses that are locally confined on preoperative imaging, easily delineated intraoperatively and do not appear to grossly invade beyond the pseudocapsule. PMID- 21707287 TI - Allogeneic stem cell transplantation for renal cell carcinoma. AB - Allogeneic hematopoietic stem cell transplantation from a compatible donor has been utilized as adoptive immunotherapy in metastatic, cytokine-refractory renal cell carcinoma (RCC). Since the year 2000, several investigators have established that RCC is susceptible to a graft-versus-tumor effect: they reported that patients with renal cancer may have partial or complete disease responses, in the 20-40% range, after allogeneic transplantation following a reduced-intensity regimen. However, transplant-related mortality is still high in the 10-20% range, and responses are rarely durable. Experimental evidence suggests that donor derived T cells and natural killer cells are the main mediators of the graft versus-RCC effect upon allogeneic hematopoietic stem-cell transplantation. Isolation of CD8(+) cytotoxic T lymphocyte clones recognizing several target antigens of graft-versus-RCC effect (minor histocompatibility antigens on RCC cells; a peptide epitope derived from human endogenous retrovirus type E; the tumor-associated antigen encoded by the Wilms' tumor 1 gene) has increased our knowledge of the disease and has opened up the possibility of antigen-specific adoptive cell therapy. The introduction in the clinic of molecularly targeted agents that interfere with neoangiogenesis, both monoclonal antibodies and small tyrosine-kinase inhibitor molecules (e.g., sunitinib, sorafenib and bevacizumab), has decreased the use of allogeneic transplantation. Although not curative, novel targeted agents may be combined with allogeneic transplantation or with adoptive cell therapy in order to maximize the chances of cure. PMID- 21707288 TI - Systemic therapy for sarcomatoid renal cell carcinoma. AB - Renal cell carcinoma (RCC) is the most common malignant neoplasm of the kidney, and sarcomatoid RCC is an aggressive and lethal variant. Sarcomatoid features can be seen in all types of RCC and do not constitute a separate histologic type. No cellular or genetic biomarker for the sarcomatoid variant has yet been discovered. Most systemic therapies developed for metastatic RCC are less effective in sarcomatoid RCC, although some of the cytotoxic drugs may actually be more effective for sarcomatoid RCC because of its rapid rate of proliferation. Several ongoing prospective clinical trials are investigating new drug combinations for this disease. PMID- 21707289 TI - Predictive factors of response to treatment in patients with metastatic renal cell carcinoma: new evidence. AB - Renal cell carcinoma represents approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. Many agents that target angiogenesis (e.g., sunitinib, sorafenib, bevacizumab and pazopanib) and mTOR-targeted therapy (e.g., temsirolimus and everolimus) have been approved as first-line agents. The choice of the most suitable treatment for advanced renal cell carcinoma depends on the definition of risk. In this article, we reviewed the scientific literature identifying predictive factors on the activity/efficacy of a specific therapy. PMID- 21707290 TI - Management of advanced bladder cancer in patients with impaired renal function. AB - Advanced transitional-cell carcinoma of the bladder is the most common cancer of the urinary tract, with a high mortality rate. Cisplatin-based chemotherapy has demonstrated prolonged survival of these patients and is considered the standard of care. Nevertheless, 40-50% of patients have impaired renal function that precludes the use of cisplatin. The non-nephrotoxic platinum analogue, carboplatin, has emerged as the most popular alternative in this setting, used mainly in doublets. However, it has not shown similar efficacy to cisplatin. In this article, platinum-based or platinum-free regimens, monotherapies or combination therapies are discussed as treatment options for this population. Their efficacy and toxicity are also being analyzed. The study of newer targeted therapies in the treatment of bladder cancer is also discussed, as are future perspectives and a five-year view in the treatment of the disease in patients with renal impairment. PMID- 21707291 TI - Improving selection of appropriate urinary diversion following radical cystectomy for bladder cancer. AB - Radical cystectomy represents the gold-standard of treatment for invasive bladder cancer. Following cystectomy, various options for urinary diversion may be offered to patients. This article represents an overview of the history of urinary diversion, explains the current selection criteria used at one of the most experienced bladder cancer centers worldwide, and provides an update on the current understanding of continence mechanisms. Furthermore, we review the current literature on quality of life for patients with different forms of urinary diversion. Excellent functional results can be achieved with continent forms of urinary diversion. It is important to consider the relative and absolute contraindications when choosing any form of urinary diversion. Proper patient selection and thorough standardized preoperative counseling is critical in achieving optimal results. PMID- 21707292 TI - Efficacy of combined intravesical immunotherapy and chemotherapy for non-muscle invasive bladder cancer. AB - Intravesical immunotherapy using attenuated bacillus Calmette-Guerin (BCG) strains and intravesical chemotherapy are the modalities most commonly used to treat intermediate- or high-risk patients with non-muscle invasive bladder cancer. BCG has been shown to decrease recurrence rates by up to 67% compared with tumor resection alone, but intensive BCG maintenance regimens are poorly tolerated in a large proportion of patients. Intravesical chemotherapy also decreases the risk of recurrence for these patients, but has diminished efficacy compared with BCG. If BCG dose reduction can be achieved with combined intravesical immunotherapy and chemotherapy, this regimen may improve compliance and thus optimize treatment for these patients by limiting side effects from BCG monotherapy, while at the same time improving oncologic efficacy via the separate anti-tumor mechanisms of these agents. The authors discuss the most recent data regarding combining these agents in an alternating or sequential regimen. PMID- 21707293 TI - Potential of histone deacetylase inhibitors for bladder cancer treatment. AB - Bladder cancer incidence increases with age, presumably reflecting a cumulative exposure to carcinogens and ever-increasing life expectancy. While aberrant protein expression due to DNA mutations is an essential step during oncogenesis, one recent interest has been the role of epigenetic changes in regulating bladder tumor development. Because aberrant histone acetylation has been linked to malignant diseases in several cases, histone deacetylase inhibitors have great potential as new anticancer drugs owing to their ability to modulate transcription and induce differentiation and apoptosis. We herein review the current knowledge on epigenetic issues in bladder cancer, particularly regarding histone acetylation, and discuss its implications for understanding the molecular basis and treatment of this disease. PMID- 21707296 TI - The role of nanofibrous structure in osteogenic differentiation of human mesenchymal stem cells with serial passage. AB - Using scaffolds with autologous stem cells is a golden strategy for the treatment of bone defects. In this strategy, human mesenchymal stem cells (hMSCs) have often been isolated and expanded in vitro on a plastic surface to obtain a sufficient cell number before seeding on a suitable scaffold. MATERIALS & METHODS: Investigating the influence of serial passages (from passage two to passage eight) on the abilities of proliferation and osteogenic differentiation of hMSCs on 24-well tissue culture polystyrene plates and poly L-lactic acid electrospun nanofibrous scaffolds was performed to determine how prolonged culture affected these cellular abilities and how the nanofibrous scaffolds supported the osteogenic differentiation potential of hMSCs. RESULTS & CONCLUSION: Serial passage caused adverse changes in hMSCs characteristics, which were indicated by the decline in both proliferation and osteogenic differentiation abilities. Interestingly, the poly L-lactic acid nanofibrous scaffolds showed a significant support in recovering the osteogenic abilities of hMSCs, which had been severely affected by prolonged culture. PMID- 21707297 TI - Chitosan/PLGA particles for controlled release of alpha-tocopherol in the GI tract via oral administration. AB - AIM: The physiochemical properties, controlled release characteristics, stability and cellular uptake of chitosan (Chi)/poly(D,L-lactide-co-glycolide) (PGLA) and PLGA particles with entrapped alpha-tocopherol were investigated to understand the behavior of these nanoparticles in the GI tract. MATERIALS & METHODS: Chi/PLGA and PLGA particles stabilized by lecithin were synthesized and fully characterized for oral gastrointestinal delivery via transmission electron microscopy, dynamic light scattering, high-performance liquid chromatography and fluorescence microscopy. RESULTS: Particle stability was pH- and system dependent. In vitro release profiles showed a higher percentage of drug released in the intestinal domain by Chi/PLGA as opposed to the PLGA nanoparticles. Fluorescent counterparts of these particles were confirmed to associate with the surface of the intestinal villi, and penetrate deep in the endothelial lining of rabbit intestinal explants, indicating uptake. CONCLUSION: In vitro and ex vivo results showed that PLGA and Chi/PLGA nanoparticles were efficiently taken up by the GI tract and could be optimized to deliver alpha-tocopherol to the intestine and improve its bioavailability. PMID- 21707298 TI - Targeting nevirapine delivery across human brain microvascular endothelial cells using transferrin-grafted poly(lactide-co-glycolide) nanoparticles. AB - AIMS: Poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) were grafted with transferrin (Tf) to enhance the transport of nevirapine (NVP) across human brain microvascular endothelial cells (HBMECs). METHODS: NVP-loaded PLGA NPs with surface-grafting Tf (Tf/NVP-PLGA NPs) were incubated with HBMECs and immunochemical staining characterized Tf receptors (TfRs). RESULTS: The polydispersity index of Tf/NVP-PLGA NPs was lower than 0.008. The entrapment efficiency of NVP and loading efficiency of Tf was 20-75% and 15-80%, respectively. Tf slightly retarded the release of NVP from PLGA. Dioctadecyldimethylammonium bromide (DODAB)-stabilized Tf/NVP-PLGA NPs reduced the viability of HBMECs to 70-75%. The secretion of TNF-alpha was inhibited by Tf and stimulated by DODAB. The permeability of NVP across HBMECs reached maxima at 67% DODAB and 0.1-0.2% Tf. An increase in the concentration of Tf enhanced the uptake of Tf/NVP-PLGA NPs via a TfR-mediated mechanism. CONCLUSION: Tf/NVP-PLGA NPs are efficacious carriers in targeting delivery across HBMECs for viral therapy. PMID- 21707299 TI - Silica microcapsules from diatoms as new carrier for delivery of therapeutics. AB - AIM: This study explores the use of natural silica-based porous material from diatoms, known as diatomaceous earth, as a drug carrier of therapeutics for implant- and oral-delivery applications. MATERIALS & METHODS: To prove this concept, two drugs models were used and investigated: a hydrophobic (indomethacin) and hydrophilic (gentamicin). RESULTS & DISCUSSION: Results show the effectiveness of diatom microcapsules for drug-delivery application, showing 14-22 wt% drug loading capacity and sustained drug release over 2 weeks. Two steps in the drug release from diatom structures were observed: the first, rapid release (over 6 h is attributed to the surface deposited drug) and the second, slow and sustained release over 2 weeks with zero order kinetics. CONCLUSION: These results confirm that natural material based on diatom silica can be successfully applied as a drug carrier for both oral and implant drug-delivery applications, offering considerable potential to replace existing synthetic nanomaterials. PMID- 21707300 TI - The cool, the bad, the ugly, and the powerful: identity struggles in schoolboy peer culture. AB - Drawing upon a one-year-long ethnography of boys' constructions of their gender and sexual identities in one South African high school, this paper seeks to empirically explore and theorise how 58 grade 10 and grade 11 working-class boys create and seek out spaces among their male peers from which to cultivate their masculinities through heterosexual discourses, including being 'at risk' of getting AIDS. In this study, boys' daily struggles of trying to straddle the divide between hypersexual versus homosexual/effeminate versions of masculinity both subverted and reinforced hegemonic gender/sexual relations in the school context. Being caught up in this restrictive grip of heteronormativity meant that there were few spaces in male peer culture to resist hegemonic masculinity. The 'responsible male/controlled' position is indicative of one such space in which boys attempted to resist forms of hyper-sexuality. While this position cannot really be viewed as progressive, it nevertheless allowed boys to re-position themselves as moral agents through an assertion of control over their sexuality. Given the presence of these identity struggles, this paper, in general, suggests that interventions with boys need to cautiously explore these tensions/contradictions in identity making as opportunities to cultivate more gender sensitive and less violent discourses on masculinity. PMID- 21707301 TI - Delayed resolution of extensive T2-weighted intramedullary signal changes after oblique corpectomy for cervical spondylotic myelopathy. AB - We report two cases of cervical spondylotic myelopathy (CSM) with extensive T2 weighted intramedullary changes noted on preoperative imaging extending far beyond the level of compression. A delayed resolution 2 years after cervical oblique corpectomy was noted in both cases. This short report cautions against diagnosing this unusual magnetic resonance imaging (MRI) finding as an intramedullary tumour, demyelination or an inflammatory process. PMID- 21707302 TI - Abdominal wall endometrioma in a patient with lumbo-peritoneal shunt: case report. AB - Lumbo-peritoneal shunt as one of the modalities for management of benign intracranial hypertension is prone to complications. We are reporting a rare complication of lumbo-peritoneal shunt insertion in which our patient had developed a painful swelling on the scar site. Surgical exploration confirmed diagnosis of abdominal wall endometriosis. Abdominal wall swelling with variation in size and tenderness during menstrual cycle in female patients with shunt, especially lumbo-peritoneal shunt, should raise the suspicion of endometriosis. PMID- 21707303 TI - Combined analysis of levels of serum B-cell activating factor and a proliferation inducing ligand as predictor of disease progression in patients with chronic lymphocytic leukemia. AB - B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are regulators of normal B-cell development and survival. We investigated their role in chronic lymphocyticleukemia (CLL) by relating serum protein levels and CLL cell mRNA expression with clinical factors and disease progression. In patients with CLL, BAFF serum levels were significantly lower than in controls (0.64 ng/mL vs. 0.77 ng/mL, p = 0.014), and APRIL serum levels were significantly higher (4.10 ng/mL vs. 1.84 ng/mL, p = 0.041). CLL cells expressed BAFF and APRIL mRNA at lower levels than normal B-cells. Low BAFF serum levels were significantly correlated with a high blood lymphocyte count and advanced clinical stage, whereas APRIL levels were correlated with CD38 expression. In a multivariate analysis, the combined analysis of BAFF and APRIL serum levels emerged as an independent predictor of disease progression. PMID- 21707304 TI - Long-term clinical improvement of progressive multifocal leukoencephalopathy associated with prominent inflammatory response and follicular lymphoma. PMID- 21707305 TI - Antimicrobial drug discovery. PMID- 21707306 TI - How antibacterials really work: impact on drug discovery. PMID- 21707307 TI - Are nonlethal targets useful for developing novel antimicrobials? PMID- 21707309 TI - Relationship between pharmacodynamic indices and killing patterns in vitro. AB - Antimicrobial agents are conventionally categorized in three classes based on their pharmacokinetic/pharmacodynamic properties, based on their exposure response relationship in vivo with either area under the concentration-time curve, C(max) or T>MIC. Alternatively, they are often categorized as 'concentration dependent' and 'concentration independent' (or time dependent), based on their in vitro kill kinetics. However, both of these classifications are arbitrary at best. Various classes of drugs display different modes of action and in reality there is a whole spectrum of pharmacokinetic/pharmacodynamic characteristics. Whereas the relationship between in vitro kill kinetics and in vivo exposure response relationships has been demonstrated in the past, methods were cumbersome and the results of such studies were not always easy to grasp. In the study, Tam and Nikolaou develop a framework by defining the average kill rate D during a dosing interval based on in vitro kill kinetics and correlate that with dosing regimen design as well as dose. They show, in an easy-to-grasp manner, what these correlations entail and the impact of killing characteristics on pharmacodynamic behavior in vivo. They conclude that their framework could be used in drug development to predict efficacy in vivo and the effect of changing doses and dosing regimens can be used as a tool in decision support. PMID- 21707310 TI - Tuberculosis drugs: new candidates and how to find more. AB - The recent years have witnessed significant progress in the development of new drug candidates for the treatment of TB. While many of these are now in clinical trials, continued research is needed in order to sustain the drug discovery pipeline and meet the increasing needs of TB patients. These include shortening treatment, killing drug-resistant strains, and finding medications compatible with antiretroviral and diabetes therapy. Nowadays, TB drug discovery benefits from high-throughput screening methods, availability of conditional expression systems, and biophysical and biochemical techniques that enable target-based rational drug design. This article reviews the current state of TB drug development and discusses possible approaches to finding new leads. PMID- 21707311 TI - Road to clinical efficacy: challenges and novel strategies for antimicrobial peptide development. AB - Since the discovery of magainins, cecropins and defensins 30 years ago, antimicrobial peptides (AMPs) have been hailed as a potential solution to the dearth of novel antibiotic development. AMPs have shown robust activity against a wide variety of pathogens, including drug-resistant bacteria. Unlike small molecule antibiotics, however, AMPs have failed to translate this success to the clinic. Only the polymyxins, gramicidins, nisin and daptomycin are currently approved for medical use; the latter is the only example to have been developed in the last several decades. Nonetheless, researchers continue to isolate, modify and develop novel AMPs for therapeutic applications. Efforts have focused on increasing stability, reducing cytotoxicity, improving antimicrobial activity and incorporating AMPs in novel formulations, including nanoscale particles. As peptide synthesis and recombinant production methodologies improve, and more relevant bioassays become available, it becomes increasingly likely that AMPs will break the regulatory barrier and enter the marketplace as valuable antimicrobial weapons in the next 10 years. PMID- 21707312 TI - Therapeutic options for infections with Enterobacteriaceae producing carbapenem hydrolyzing enzymes. AB - Enterobacteriaceae that produce serine carbapenemases or metallo-beta-lactamases, such as KPC, OXA-48, VIM or NDM, respectively, are spreading mostly as nosocomial pathogens worldwide. Such strains are typically resistant to most if not all available antimicrobials. Specific relevant clinical data are scarce to guide the determination of the most appropriate treatment options. Data on antimicrobial susceptibility, resistance development, synergy, pharmacokinetic and pharmacodynamic parameters of the candidate regimens, as well as the experience from the treatment of infections with nonfermenting Gram-negative pathogens, can aid in this regard. Colistin and tigecycline are most likely to be active in vitro against Enterobacteriaceae producing carbapenem-hydrolyzing beta lactamases, but resistance development is of concern. Individual members of the aminoglycoside class can also be active in vitro, while carbapenems or aztreonam (specifically for metallo-beta-lactamase producers) can have low minimum inhibitory concentrations. Current data do not reliably support the use of these agents as monotherapy for systemic infections. Several expanded-spectrum cephalosporins, such as ceftazidime, may be active against OXA-48 type producers. Fosfomycin might be useful as a last-resort option as part of combination regimens. Combination antimicrobial therapy with agents exhibiting synergy might also be of benefit, until novel effective agents could become clinically available. PMID- 21707313 TI - Antimicrobials for bacterial bioterrorism agents. AB - The limitations of current antimicrobials for highly virulent pathogens considered as potential bioterrorism agents drives the requirement for new antimicrobials that are suitable for use in populations in the event of a deliberate release. Strategies targeting bacterial virulence offer the potential for new countermeasures to combat bacterial bioterrorism agents, including those active against a broad spectrum of pathogens. Although early in the development of antivirulence approaches, inhibitors of bacterial type III secretion systems and cell division mechanisms show promise for the future. PMID- 21707314 TI - Development of novel drugs for human African trypanosomiasis. AB - Human African trypanosomiasis (HAT) or 'sleeping sickness' is a neglected tropical disease caused by the parasite Trypanosoma brucei. Novel models for funding pharmaceutical development against HAT are beginning to yield results. The Drugs for Neglected Diseases initiative (DNDi) rediscovered a nitroimidazole, fexinidazole, which is currently in Phase I clinical trials. Novel benzoxaboroles, discovered by Anacor, Scynexis and DNDi, have good pharmacokinetic properties in plasma and in the brain and are curative in a murine model of stage two HAT with brain infection. The Consortium for Parasitic Drug Development (CPDD) has identified a series of dicationic compounds that can cure a monkey model of stage two HAT. With other screening programs yielding hits, the pipeline for new HAT drugs might finally begin to fill. PMID- 21707315 TI - Target identification and validation of novel antimalarials. AB - It has been recognized that new antimalarials with a novel mode of action are critical to combat the continued emergence and dissemination of drug-resistant parasites that threaten the efficacy of current malaria treatments. Thus, recent high-throughput screening campaigns have been initiated using asexual intraerythrocytic stage cell-based assays of Plasmodium falciparum. These have led to the unprecedented identification of over 10,000 new antimalarial compounds. Inherently, novel compounds identified by cell-based assays will have poorly defined modes of action. While some of these compounds may have recognizable targets, the majority of cell-based hits are comprised of unique chemical scaffolds usually lacking cross-resistance with known drugs. It is likely that these novel antimalarial scaffolds will reveal new targets. A challenge for the community will be to assign these small molecules to their targets. In this article, we review methodologies to assist in the determination of a compound's mode of action. PMID- 21707317 TI - DNA barcoding unveils a high rate of mislabeling in a commercial freshwater catfish from Brazil. AB - BACKGROUND AND AIMS: Molecular markers have contributed to species authentication by flagging mislabeling and the misidentification of commercial landings. Such tools are of great value since the market substitution of fish of lower value for highly commercialized species is expected to become more pronounced due to a shortage of natural stocks. MATERIALS AND METHODS: Here we report on the molecular identification 4results from processed fish products (i.e. fillets) and whole fishes sold in Brazilian markets under the common name surubim (Pseudoplatystoma spp.). RESULTS: DNA barcoding revealed the incorrect labeling of around 80% of all samples analyzed, with mislabeling being more pronounced within fillets rather than whole fish. CONCLUSION: To our knowledge, this is the first report correlating the rate of fraud with processed fish products. The establishment of an official list of acceptable common names for freshwater fish and seafood is urgently needed in Brazil for further trade regulations to take place. PMID- 21707318 TI - DNA barcoding reveals hidden diversity in the Neotropical freshwater fish Piabina argentea (Characiformes: Characidae) from the Upper Parana Basin of Brazil. AB - BACKGROUND AND AIMS: We analyzed a small and wide geographically distributed Neotropical freshwater fish, the Piabina argentea from the Upper Parana Basin, to check the hypothesis that this species is composed of more than one biological unit, since it has a limited dispersion, through the DNA barcode technique. MATERIALS AND METHODS: Partial mitochondrial COI and CytB gene sequences were obtained for 58 specimens drawn from 13 localities. RESULTS: Phylogenetic analysis revealed six major clusters of P. argentea. Kimura-two-parameter (K2P) genetic divergences among these six P. argentea clusters ranged from 2 to 5.6% and from 2.3 to 5.4% for COI and CytB genes, respectively, and these values were on average approximately nine times greater than intra-cluster K2P divergences. The fixation index (F(ST)) among clusters showed very high values and the haplotype network analysis displayed seven unconnected units. CONCLUSION: These results reinforce the hypothesis that the widely distributed P. argentea species concept as currently conceived actually represents more than one species (possibly six). These results demonstrate the efficacy of DNA barcoding for the discovery of hidden diversity in Neotropical freshwater fishes, and we conclude that barcoding is a useful tool for alpha taxonomy. PMID- 21707319 TI - Complete mitochondrial genome of a new vole Proedromys liangshanensis (Rodentia: Cricetidae) and phylogenetic analysis with related species: are there implications for the validity of the genus Proedromys? AB - AIM. The complete mitochondrial genome sequence of a newly discovered vole, Proedromys liangshanensis (Rodentia: Cricetidae: Arvicolinae), was determined. RESULTS. The mitogenome of P. liangshanensis is 16,296 bp in length. As with most other mammals, it contains the same gene order and an identical number of genes or regions, including 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and one putative control region. The A+T content of the control region is 58.2%, the lowest proportion detected so far in Myomorpha. To confirm the phylogenetic position of P. liangshanensis, we carried out phylogenetic analyses based on complete mitochondrial genomic data using Bayesian, maximum parsimony, and maximum likelihood methods. CONCLUSION. All results revealed that P. liangshanenis is sister to Microtus. Although the results do not bear light on the validity of the genus Proedromys, based on the morphological characters, we suggest that Proedromys is an independent genus of equal rank to the genus Microtus. PMID- 21707320 TI - Mito-communications. PMID- 21707321 TI - The mitochondrial genome of Polylabris halichoeres (Monogenea: Microcotylidae). AB - This study presents the complete mitochondrial (mt) genome of Polylabris halichoeres, which is the largest mt genome sequenced of monogeneans so far and the second complete sequence after Microcotyle sebastis from the Microcotylidae. It is basically similar to that of M. sebastis, with the exception of a high level of gene rearrangement located between trnC and trnL((UUR)), a translocation of trnM and trnH, as well as a highly repetitive region (HRR) in the large non coding region (NCR). We also find a series of trnI pseudogenes (PsiI) and one unknown short open reading frame (ORF) in the large NCR. Although the ORF cannot be unambiguously regarded as an atp8 gene, we cannot rule out the possibility that it has other functional importance, but it need further study in the future. PMID- 21707322 TI - An exophytic brain stem glioblastoma in an elderly presenting as a cerebellopontine angle syndrome. AB - Exophytic brain stem gliomas are rare and are generally seen in paediatric population. These are usually low grade gliomas. We report a case of brainstem glioblastoma in an elderly patient presenting as a cerebellopontine mass. PMID- 21707323 TI - Niosomes as a potential drug delivery system for increasing the efficacy and safety of nystatin. AB - Nonionic surfactant (NIS) vesicles (niosomes) formed from self-assembly of hydrated synthetic NIS monomers are capable of entrapping a variety of drugs and have been evaluated as an alternative to liposomes. Nystatin (NYS) is a polyene antifungal drug that has been used in the treatment of cutaneous, vaginal and oral fungal infections since the 1950s. The aim of this work is to encapsulate NYS in niosomes to obtain a safe and effective formula administered parenterally for neutropenic patients. NYS niosomes were prepared by the thin-film hydration method using Span 60 or Span 40 and cholesterol (CHOL). Stearylamine and dicetyl phosphate were added as the positive and negative charge-inducing agents (CIA), respectively. Two molar ratios were used, namely NIS/CHOL/CIA (1:1:0.1 and 2:1:0.25). Neutral and positively charged niosomes gave the highest encapsulation efficiencies. NYS niosomes were characterized using transmission electron microscopy, differential scanning calorimetry and dynamic light scattering. The release of neutral and negatively charged NYS niosomes was estimated, and it showed a slow sustained release profile. A 25-kGy gamma-irradiation dose was sufficient to sterilize the investigated vesicles. NYS niosomes exerted less nephrotoxicity and hepatotoxicity in vivo, showed higher level of drug in vital organs and revealed pronounced efficacy in elimination of the fungal burden in experimental animals infected with Candida albicans compared with those treated with free NYS. Niosomal encapsulation thus provided means for parenteral administration of NYS, reducing its toxicity and making it a more active antifungal agent. PMID- 21707324 TI - Occupational accidents in the Finnish local government sector: utilisation of national statistics. AB - Occupational accidents in the Finnish local government sector in 2004 are analysed by gender, age and occupation class in order to identify particular risk groups. The accident data are compared with data concerning the number of employees, using frequency distributions and accident incidence rates. The possibilities of providing occupation class-specific accident incidence rates are also discussed. According to the results, commuting accidents are more common and severe in the local government sector than in general in Finland. In the local public sector occupational accidents more often involved women than men. Compared to other age groups and occupational classes, occupational accidents are more common in the age band of 45-54 and in the occupational class of medical and nursing work. However, compared to the employees' data, men and younger employees had an increased workplace accident risk, while women and older employees had an increased risk of commuting accidents. The highest accident incidence rate was in farming and animal husbandry work. Currently, the calculation of occupation class specific accident incidence rates is difficult. Improving the consistency of the occupation classifications used in the various data sources would facilitate more reliable calculation of rates. PMID- 21707325 TI - Preformulation evaluation of AZD1305, an oxabispidine intended for oral and intravenous treatment. AB - AIM: AZD1305 is a novel, water-soluble investigational antiarrhythmic agent for restoration and maintenance of sinus rhythm in atrial fibrillation patients. The present studies were performed to evaluate the possibility for further development of the compound. METHODS: A set of technical approaches were used, including X-ray powder diffractometry, differential scanning calorimetry, thermogravimetrical analysis, dynamic vapor sorption, scanning electron microscopy, salt screen, and liquid chromatography. RESULTS: AZD1305 is a crystalline oxabispidine and its neutral form is a base with a pK(a) of 9.9. The substance degrades with higher temperature and lower pH. The free base of the solid substance is stable at 25 degrees C (closed container), 40 degrees C/75% relative humidity (open container), and at 50 degrees C (closed container) for at least 3 months. The free base of AZD1305 is polymorphic with two known forms. Both forms are non-hygroscopic ansolvates with melting points of approximately 90 degrees C. No salt was found with overall improved properties. The substance had a strong odor, which was reduced by increased particle size. CONCLUSIONS: The free base of AZD1305 seemed to be the most suitable agent for product development even though it has a fairly low melting point and occurred as two different crystal forms. Form B was the most stable thermodynamically in the temperature interval of interest. PMID- 21707326 TI - Dynamic changes of myocardial oxygen consumption at pacing increased heart rate - the first observation by the continuous measurement of systemic oxygen consumption. AB - OBJECTIVES: To assess dynamic changes in myocardial oxygen consumption (myoVO(2)) during atrial pacing increased heart rate by continuous measurement of systemic oxygen consumption (sysVO(2)). METHODS: Six mechanically ventilated pigs were atrially paced to increase heart rate from baseline 98 +/- 9 to 120-140-160-180 bpm for 10 minutes at each stage, with 10 minute intervals without pacing between stages. sysVO(2) was continuously measured with a respiratory mass spectrometer. Left anterior descending coronary arterial flow, aorta and coronary sinus blood gases were measured to calculate index of whole heart myoVO(2). RESULTS: sysVO(2) peaked at the initiation of pacing in the first two to three minutes, followed by a decrease and subsequent stabilization. As heart rate increased, sysVO(2) increased by 0.08 +/- 0.06 ml/kg/min, 0.14 +/- 0.05 ml/kg/min and 0.17 +/- 0.10 ml/kg/min, representing a 1.2 +/- 0.9%, 2.1 +/- 0.7% and 3.0 +/- 1.8% increase of sysVO(2) respectively; myoVO(2) increased by 0.16 +/- 0.12 to 0.31 +/- 0.14 to 0.36 +/- 0.24 ml/100 g/min, representing a 11 +/- 9%, 21 +/- 9% and 26 +/- 12% increase of myoVO(2), respectively. The absolute and relative increases in sysVO(2) were significantly correlated with the increases in myoVO(2). CONCLUSIONS: On-line continuous sysVO(2) monitoring by respiratory mass spectrometry allows non-invasive assessments of dynamic changes in myoVO(2) in vivo. The mechanism for the peaked increase in sysVO(2) at the initiation of pacing remains to be explored. PMID- 21707328 TI - The International Index of Erectile Function: a methodological critique and suggestions for improvement. AB - The International Index of Erectile Function is a well-worded and psychometrically valid self-report questionnaire widely used as the standard for the evaluation of male sexual function. However, some conceptual and statistical problems arise when using the measure with men who are not sexually active. These problems are illustrated using 2 empirical examples, and the authors provide recommended solutions to further strengthen the efficacy and validity of this measure. PMID- 21707327 TI - Testosterone gel replacement improves sexual function in depressed men taking serotonergic antidepressants: a randomized, placebo-controlled clinical trial. AB - Testosterone replacement is the most effective treatment for sexual dysfunction in hypogonadal men. Comorbid depression and antidepressant side effects may reduce its influence. The authors conducted a 6-week, double-blind, placebo controlled clinical trial of testosterone gel versus placebo gel in men with major depressive disorder who were currently taking a serotonergic antidepressant and exhibited low or low-normal testosterone level. A total of 100 men were enrolled at 2 study sites (Boston, Massachusetts, USA, and Tel Aviv, Israel). The effects of testosterone augmentation on sexual functioning were determined using domain scores on the International Index of Erectile Function (IIEF). Complete pre- and posttrial IIEF data were available for 63 subjects. Men randomized to testosterone (n = 31) and placebo (n = 32) were similar in age, baseline testosterone levels, and baseline IIEF scores. At study termination, men randomized to placebo showed virtually no change from baseline in mean (95% CI) IIEF score (-0.7 [-6.5, 5.2]), whereas those receiving testosterone exhibited a substantial increase (15.8 [8.5, 23.1]). The estimated mean difference between groups was 16.8 [7.5, 26.1]; p = .001 by linear regression with adjustment for age and study site. There were also significant between-group differences in each of the 5 IIEF subscales, as well as on the single question involving ejaculatory ability (p <= .03 in all cases). Effect sizes in these comparisons remained little changed, and generally remained statistically significant, when we further adjusted for change in depression scores on the Montgomery Asberg Depression Rating Scale. It is notable that the subgroup of men with the highest baseline testosterone levels showed virtually the same improvement as those with lower levels, suggesting that the observed improvement was unlikely to be due simply to correction of hypogonadism alone. In depressed men with low or low-normal testosterone levels who continued to take serotonergic antidepressants, treatment with exogenous testosterone was associated with a significant improvement in sexual function, particularly including ejaculatory ability. PMID- 21707329 TI - Students' experiences and perceived benefits of a sex education curriculum: a qualitative analysis. AB - A qualitative evaluation explored the experiences and perceived benefits of students who participated in an abstinence-plus sex education program at enrollment and conclusion. The sample included 1130 inner-city high school students, 73.7% of whom were Hispanic. Thematic analysis was used to identify main themes in responses made by students to 3 open-ended questions. The most common preparticipation request was for information about sexually transmitted infections. At program conclusion, the most common response theme involved the quality of course delivery. Students indicated that they appreciated the facilitators who allowed open conversations. The implications of these findings to sex education programs are discussed. PMID- 21707330 TI - Partner attachment as a predictor of long-term response to treatment with couples therapy. AB - Vulnerability factors such as insecure attachment may have a lasting effect on the outcome of couples therapy, even long after discharge from treatment. Given that attachment has never been examined as an outcome predictor for couples therapy in the long term, the authors studied its effect on outcome during and after couples therapy. This prospective study included 71 inpatients participating in group couples therapy who the authors measured at baseline, immediately posttreatment at 2 months, and at 8 and 20 months, regarding two outcomes: problem-solving capacity (using the Interactional Problem Solving Questionnaire) and psychopathology (using the 90-item Symptom Check List). At baseline, the authors measured partner attachment (using the Experiences in Close Relationships Questionnaire). Mixed model analyses showed that attachment-related dysfunctional working models of self and others predicted less improvement in psychopathology (p = .04) and problem-solving capacity (p = .01), respectively. Special attention to insecure attachment in couples therapy may therefore prove valuable in terms of outcome in the long run. PMID- 21707331 TI - Heterosexual anal intercourse: increasing prevalence, and association with sexual dysfunction, bisexual behavior, and venereal disease history. AB - Representative samples of the Czech population were surveyed with regard to sexual behavior in 1993, 1998, 2003, and 2008 (N = 7,720). Lifetime prevalence of Heterosexual Anal Intercourse increased from 1993 to 2008 (16.6% to 19.7% among women, 15.7% to 25.3% among men). Anal intercourse was associated with lifetime number of sex partners, current masturbation, and histories (prevalence of which increased from 1993 to 2008) of homosexual sex, prostitution, venereal disease (adjusted for number of sex partners), and women's sexual dysfunction. The authors discuss the possible reasons for the increasing prevalence and the associations. Multivariate predictors of ever having a sexual dysfunction or a venereal disease are also presented. PMID- 21707332 TI - Social relationships and activities among married psychiatric inpatients with sexual difficulties. AB - This study examined the social relationships and activities of married adults with sexual difficulties receiving inpatient psychiatric care in Ontario, Canada. The authors conducted secondary analysis of population-level data on 11,982 married inpatients who were assessed with the Resident Assessment Instrument Mental Health. The authors used descriptive statistics, chi-square analyses, and multivariate logistic regression techniques. Results indicated that 10.7% experienced sexual difficulties, which were related to higher likelihood of dysfunctional social relationships and to lower likelihood of social contact, especially among married women. These findings suggest that assessment of sexual function should be seen as part of comprehensive psychiatric care to support recovery. PMID- 21707336 TI - Potential risks of "risk" language in breastfeeding advocacy. AB - In this article the authors analyze the use of "risks of formula language" versus "benefits of breastfeeding language" in breastfeeding advocacy texts. Feeding intentionality and 434 adult respondents' assessments of advocacy texts were examined at a mid-western university in the fall of 2009. No significant difference was observed between those who read text phrased in terms of "risks of formula feeding" and those who read text describing "benefits of breastfeeding" in feeding intentionality. Results supported the expectation that respondents would less favorably assess texts using risk language-respondents rated risk texts as less trustworthy, accurate, and helpful compared to benefit text. Texts were also varied in "medical" and "breastfeeding advocacy group" affiliations. Analyses revealed that texts including the medical logo were rated significantly more favorably compared to breastfeeding advocacy logo and no logo conditions. Findings suggest that use of risk language may not be an advantageous health promotion strategy, but may be counter-productive to the goals of breastfeeding advocates. PMID- 21707337 TI - The relation of psychological stress to pregnancy outcome among women undergoing in-vitro fertilization and intracytoplasmic sperm injection. AB - A considerable literature has been accumulated regarding the relation of psychological factors to in-vitro fertilization outcome. However, study findings have been inconsistent, and the association between psychological stress and in vitro fertilization outcomes is still unclear. The aim of the authors in this study was to examine the relation of infertility-related stress, anxiety, and depressive symptoms to in-vitro fertilization outcome. The sample consisted of 160 women with fertility problems undergoing fertility treatment in a public hospital in Athens, Greece between November 2008 and July 2009. The relation of infertility-related stress, anxiety, and depressive symptoms to in-vitro fertilization outcome was assessed by using hierarchical, sequential logistic regression, while controlling for the effects of relevant biomedical factors. After the embryo transfer, 41 women (26%) had a positive pregnancy outcome. Logistic regression analyses revealed that, controlling for biomedical factors (age, number of oocytes retrieved, and embryos transferred) infertility-specific stress (OR = 0.964, p = .011) and nonspecific anxiety (OR = 0.889, p = .006) were negatively associated with a positive pregnancy outcome after IVF. Psychological stress was negatively associated with in-vitro fertilization outcome, after controlling for biomedical variables. Fertility treatment protocols should consider including counselling interventions to potentially mitigate adverse effects of stress. PMID- 21707338 TI - Attitudes toward menstruation, menstrual-related symptoms, and premenstrual syndrome among adolescent girls: a rural school-based survey. AB - Folk culture surrounding menstrual-related matters has considerable implications for symptom expression and treatment-seeking behavior. A cross-sectional survey of 1,295 rural adolescent girls aged 13 to 19 years was conducted between February 4 and April 16, 2009 to examine these associations. With a higher score indicating a more positive attitude toward menstruation, the mean attitude score was 3.84 (SD +/- 1.62) out of a maximum of six. No significant association was observed between the severity of menstrual symptoms and attitudes. Most (63.1%) of the participants identified themselves as having premenstrual symptoms, and 61.1% viewed premenstrual symptoms as a normal part of menstrual cycle. Participants with a higher severity of symptoms in the premenstrual (OR 1.05, 95% CI 1.01-1.10) and menstrual phase (OR 1.04, 95% CI 1.01-1.07), were more likely to consult a physician for premenstrual symptoms, and having a divorced/separated parents was associated with a reduced odds of consulting a physician compared to those having parents that were married (OR 0.19, 95% CI 0.05-0.83). The findings imply the need for education to help adolescent girls manage menstrual symptoms and increase awareness of the benefit of treating them. Given that menstrual related information was widely available from mothers, family, and social culture are potentially important in shaping good menstrual attitudes. PMID- 21707339 TI - Determinants of tubal ligation in Puebla, Mexico. AB - Tubal ligation provides an effective and reliable method by which women can choose to limit the number of children they will bear. However, because of the irreversibility of the procedure and other potential disadvantages, it is important to understand factors associated with women's choice of this method of birth control. Between May 1999 and August 2000, data were collected from 755 women aged 40 to 60 years from a cross-section of neighborhoods of varying socio economic make-up in Puebla, Mexico, finding a tubal ligation rate of 42.2%. Multiple logistic regression models were utilized to examine demographic, socio economic, and reproductive history characteristics in relation to women's choice of tubal ligation. Regression analyses were repeated with participants grouped by age to determine how the timing of availability of tubal ligation related to the decision to undergo the procedure. The results of this study suggest that younger age, more education, use of some forms of birth control, and increased parity were associated with women's decisions to undergo tubal ligation. The statistically significant difference of greater tubal ligation and lower hysterectomy rates across age groups reflect increased access to tubal ligation in Mexico from the early 1970s, supporting the idea that women's choice of tubal ligation was related to access. PMID- 21707340 TI - Feeling the blues of infertility in a South Asian context: psychological well being and associated factors among Sri Lankan women with primary infertility. AB - Primary infertility may have a considerable impact on the psychological well being of women. In the present study, the authors investigated the psychological well-being and its correlates among Sri Lankan women with primary infertility. A total of 177 women with primary infertility were compared with 177 fertile women matched for age and duration of marriage to identify differences in the psychological well-being between the two groups. They were recruited from a prevalence survey conducted in the district of Colombo, Sri Lanka from August 2005 to February 2006. The General Health Questionnaire-30 (GHQ-30) and Mental Health sub-components of the Short Form-36 (SF-36) were used to measure psychological well-being. In addition, infertile women with and without psychological distress were compared to identify the social, marital, treatment, and demographic factors independently associated with psychological distress. A significantly higher proportion of women with primary infertility (66.1%; 95% CI 58.6-73.0%) had psychological distress as compared to fertile women (18.6 %; 95% CI 13.2-25.2%; P < 0.001). After adjustment for confounding factors, infertile women who were psychologically distressed were significantly less educated (OR = 55.3; 95% CI 15.2-201.0), had poor marital communication (OR = 3.5; 95% CI 1.3 9.8), had a higher priority for having children (OR = 4.2; 95% CI 1.3-13.8), and had been previously (OR = 39.1; 95% CI 8.3-185.4) or currently (OR = 11.0; 95% CI 3.0-40.6) investigated/treated for infertility when compared with infertile women without distress. Women with primary infertility reported more distress as compared to fertile women. Psychological distress among infertile women was associated with poorer education, being previously/currently investigated/treated, placing higher importance on having children, and having poor marital communication. The need for psychological intervention targeting infertile women in clinics and community settings is highlighted. PMID- 21707341 TI - Measuring physical activity and sedentary behaviors in women with young children: a systematic review. AB - Current evidence indicates that women with young children are less active than women without children. In this review the authors investigated the methods of measuring physical activity employed in studies of women with young children (aged 1-5 years) and the associated challenges in measurement. Articles from databases (MEDLINE, OVID, CINAHL, Google Scholar) and manual searches were limited to English peer-reviewed journals published from 1990 to 2010. Studies that included measurement of physical activity in samples of women with young children were selected. Measurement properties were extracted, and original reliability and validity articles were reviewed for physical activity measurement tools used by 15 samples. The evidence base was dominated by self-report measurement tools, many of which assessed leisure-time physical activity only. Use of motion sensors to assess physical activity in this population was limited. It is likely that much of the habitual physical activity performed by women with young children has not been captured by self-report measures. Further investigation should be undertaken using tools that capture adequately all health enhancing physical activity among women with young children. PMID- 21707342 TI - Human genome. Introduction. PMID- 21707343 TI - Human genome and the african personality: implications for social work. AB - The integration of the human genome with the African personality should be viewed as an interdependent whole. The African personality, for purposes of this article, comprises Black experiences, Negritude, and an Africa-centered axiology and epistemology. The outcome results in a spiritual focused collective consciousness. Anthropologically, historically (and with the Human Genome Project), genetically Africa has proven to be the source of all human life. Human kind wherever they exist on the planet using the African personality must be viewed as interconnected. Although racism and its progeny discrimination preexist the human genome project (HGP), the human genome provides an evidence-based rationale for the end to all policy and subsequent practice based on race and racism. Policy must be based on evidence to be competent practice. It would be remiss if not irresponsible of social work and the other behavioral scientist concerned with intervention and prevention behaviors to not infuse the findings of the HCPs. The African personality is a concept that provides a wholistic way to evaluate human behavior from an African worldview. PMID- 21707344 TI - The human genome project: an historical perspective for social workers. AB - Having mapped the human genome, the Human Genome Project maintains that certain genes can be linked to specific diseases and certain forms of human behavior. This breakthrough, it is hoped, will lead to the effective treatment, even the elimination of serious, debilitating illnesses for all groups of people. However, because the project conjures up memories of eugenics, the project raises concerns about its potential for identifying and linking diseases and social conditions (e.g., criminal behavior) to certain groups. This article places the Human Genome Project in historical context in terms of its resemblance to the eugenics movement in America and a period in social work history when the profession embraced eugenics and was guided by the movement's premises in its response to poor people. PMID- 21707345 TI - Cultural competency, human genomics, and the elimination of health disparities. AB - It is unclear what impact human genomics research will have on the nation's efforts to close the gap in health disparities between and among racial/ethnic and disadvantaged groups. The literature suggests that understanding socio economic and cultural factors are important for understanding the complex issues offer by genetic explanations of racial/ethnic differences. While this research will lead to tremendous improvements in health status of the overall population, its impact on reducing health disparities is likely to be minimal. Establishment of culturally competent systems of care, in contrast, offers great promise for reducing and eliminating health disparities. PMID- 21707346 TI - Human genomics: challenges for African Americans and policy implications for direct social work practice. AB - Recent advancements in the scientific study of the human genome may benefit African Americans through increased knowledge of the causes and cures for diseases that disproportionately affect them. Other potential benefits are far reaching and include legal and socioeconomic importance for the African American community. Although these benefits have tremendous appeal, advancements in genomic science pose significant social issues for African Americans. Disparities in access, insensitive and discriminatory programming, a lack of appreciation of environmental factors, and misuse of genetic databases are among the challenges for African Americans. This article identifies the major benefits and challenges of human genomics cited in literature from various disciplines and discusses policy implications for direct social work practice. The author explains the importance of social work involvement in shaping genetic policies and outlines traditional roles social workers may play in establishing ethnic-sensitive public policies and agency practices to protect the interests of African Americans who interface with the rapidly expanding field of human genomics. PMID- 21707347 TI - African Americans and genetic research, risk versus benefit: implications for the profession of social work. AB - The Human Genome Project was a 13-year study with great potential for improving the health of the current generation and extending the life of future generations. Genetic research, though showing potential for good, may also result in societal problems. This article considers the implications of future genetic research for African Americans and other vulnerable groups with a retrospective view of medical research and the African Americans' experience. In light of the growing health disparity between Whites and Blacks, this article argues for minority participation in clinical trials and other studies. It addresses the role of social workers as genetic counselors and encourages, especially social workers of color, involvement in the field of genetics as advocates, teachers, and as members of research teams. PMID- 21707348 TI - An education model for integrating genetics and genomics into social work practice. AB - Findings from the Human Genome Project (HGP) suggest that tremendous opportunities exist for increased life expectancies and improved quality of life. The findings also raise enormous concerns about ethical, legal, and psychosocial implications, particularly for underrepresented and vulnerable populations. This article proposes an education model that focuses on genetically informed, ethical practice that will help social worker practitioners and educators play a more effective role as they confront the many implications of genetic and genomic research in the 21st century. PMID- 21707349 TI - Human genome project and sickle cell disease. AB - Sickle cell disease is one of the most common genetic blood disorders in the United States that affects 1 in every 375 African Americans. Sickle cell disease is an inherited condition caused by abnormal hemoglobin in the red blood cells. The Human Genome Project has provided valuable insight and extensive research advances in the understanding of the human genome and sickle cell disease. Significant progress in genetic knowledge has led to an increase in the ability for researchers to map and sequence genes for diagnosis, treatment, and prevention of sickle cell disease and other chronic illnesses. This article explores some of the recent knowledge and advances about sickle cell disease and the Human Genome Project. PMID- 21707350 TI - The confluence of human genomics, environment, and determinants of health-related quality of life among African American hemodialysis patients. AB - The intersection of human genome sequencing, environmental factors that lend to further understanding of the etiology of complex diseases, and components that constitute the health-related quality of life for African American hemodialysis patients are explored in this article. There are many renal diseases that have genetic components. Even though genetic polymorphisms and allelic variations can explain some of the etiology and disparities in disease susceptibility for African Americans, the role of the environment must also be considered. For African American hemodialysis patients, the environmental influences of religiosity and social support, along with genetic factors, affect their health related quality of life. A study of 176 African American hemodialysis patients revealed that religiosity and social support had a significant impact on patient's health-related quality of life. Implications of the study mandate that social and behavioral researchers, who tend to focus on environmental issues, be given more freedom and latitude, along with genetic researchers, in designing and implementing studies involving genomic sequencing and the influence on health disparities among persons of African descent. PMID- 21707351 TI - Balancing environmental and genetic factors for alcoholism in the black community: implications for social work practice. AB - This article discusses the importance and relevance of balancing environmental and genetic factors for understanding alcoholism in the Black community. Studies are reviewed and myths dispelled to highlight the need for addressing the historical complexities and current challenges of alcoholism for Blacks. Suggestions for practice, research, and policy at the genetic and environmental levels are offered. PMID- 21707352 TI - Effects of neurofibromatosis type 1 on children's development. AB - In-depth study of the human genome holds the potential to provide needed focus on genetic disorders that affect hundreds of thousands of children and significantly affect their development. Neurofibromatosis Type-1 (NF-1) is one of the most common genetic disorders that affect neurological, cognitive, social, and physical development. NF-1 affects all racial groups and both genders equally. NF 1 occurs in about 1 in 2,500 to 3,300 individuals in the population. The incidence rate at birth is about 0.0004 births in the United States and is growing in prevalence. Children with NF-1 experience a range of psychomotor and cognitive impairments that affect the quality of their social lives and their learning and academic achievements. Interventions to address the psychosocial and educational needs of children with NF-1 include a range of social and academic support services, which are most effective when they are comprehensive, involve a multidisciplinary team of educational and health experts, and include a focus on supporting and empowering family members to be effective caregivers. Efforts to address the needs of children with NF-1 and to provide adequate support to their families have significant policy implications for local, state, and federal officials. PMID- 21707353 TI - Autism and the African American community. AB - It is estimated that autism spectrum disorders (ASD) affect 1 in 500 live births per year. However, due to varying techniques for diagnosis and treatment, the disability remains the subject of debate. African Americans tend to suffer disproportionate rates of disability and disease when compared to other racial and ethnic groups due to access to preventative and curative care. However, evidence demonstrates that although rates of diagnosis for autism occur at the same rates in all racial groups, diagnosis in African American children occurs later than in White children. As a result, African American children may require longer and more intensive intervention. This article examines the etiology of autism, diagnosis, and treatment strategies and its impact on African American families. A case method approach is utilized to describe the impact of autism on an African American family. Implications for future research and professional practice and policy are discussed. Understanding autism is important as it relates to the human genome. PMID- 21707354 TI - Diagnostic and possible therapeutic application of a monoclonal antibody (14G8) directed against botulinum type C neurotoxin. AB - A monoclonal antibody, designated 14G8, detected Clostridium botulinum type C neurotoxin in immunoassays requiring native confirmation of the analyte. 14G8 bound to the light chain of the type C neurotoxin, which is conserved between strains of C. botulinum type C and C/d mosaic neurotoxins. 14G8 did not react to any other serotypes of C. botulinum neurotoxins. In mouse phrenic nerve hemidiaphragm assays, 14G8, when combined with a second antibody (5D9-H9-A9, which reacts to epitopes on the carboxy terminus of the heavy chain), was able to protect the mouse myoneural junction from intoxication with C. botulinum type C neurotoxin. When used individually, both 14G8 and 5D9-H9-G9 antibodies slowed the loss of twitch tension in the mouse phrenic nerve-hemidiaphragm assays, but did not completely protect the phrenic nerve from paralysis. In in vivo mouse botulinum neurotoxin type C challenge studies, the combination of 14G8 and 5D9-H9 A9 significantly increased mean time-to-death and survival when compared to toxin controls and mice receiving only one of the monoclonal antibodies. These results suggest that the 14G8 monoclonal antibody could have useful therapeutic applications. PMID- 21707355 TI - Functional identification of a non-fusion TRAIL extracellular protein and preparation of its polyclonal antibody. AB - Human tumor necrosis factor related apoptosis inducing ligand (TRAIL) can selectively induce apoptosis in a variety of transformed cells and is currently being developed as a cancer therapeutic drug. Here we expressed the TRAIL protein including extracellular (114-281aa) without any tag protein named TRAIL-NT, and prepared anti-TRAIL polyclonal antibodies (Poly-Ab). The human TRAIL extracellular gene was amplified from PBMC and cloned into pGEM-T-Easy vector for sequence analysis. The expression vector pET-28a/TRAIL was constructed using the DNA recombinant method, and the recombinant protein without any tag protein was expressed in Escherichia coli BL21(DE3). The TRAIL-NT protein was purified by cation ion-exchange column and identified by SDS-PAGE and Western blot analysis. The proliferation inhibition activity of TRAIL-NT was detected by the MTT method, Wright-Giemsa staining assay, and FACS. The polyclonal antibody of TRAIL-NT was obtained after the BALB/C mice were immunized with purificated TRAIL-NT protein. Results showed that the target protein expressed in E. coli BL21(DE3) has the same molecular weight as that expected and could be recognized by anti-TRIAL Poly Ab. The TRAIL-NT protein could also inhibit proliferation and induced apoptosis of Jurkat cells but no cytotoxicity to human liver cells and PBMC was observed. This preliminary research laid a solid foundation for further research on its biological activity and application in anti-tumor therapy. PMID- 21707356 TI - Screening for inhibitors of plant protease D1 using novel monoclonal antibodies directed against its carboxyl terminal. AB - Carboxyl terminal processing protease of D1 protein (CtpA) catalyzes carboxyl terminal processing of D1 protein, which is predicted to be an excellent target for a general broad-spectrum herbicide. In this study, the CtpA gene from spinach cDNA was cloned and overexpressed and the recombinant CtpA fusion protein (rCtpA) was used as antigen to immunize BALB/c mice for the production of monoclonal antibody (MAb). Western blot and ELISA results indicated that both rCtpA and the PDZ domain protein of CtpA had specific binding abilities to MAbs, while the specificity and sensitivity of rCtpA were much higher than that of the PDZ domain. These results suggest that parts of the antigen determinant of CtpA were located in the PDZ domain. The MAbs and related results obtained in this study proved the feasibility of high-throughput screening of lead compounds for protease as inhibitors and mechanism analysis of CtpA enzyme. PMID- 21707357 TI - Green fluorescent-conjugated anti-CEA single chain antibody for the detection of CEA-positive cancer cells. AB - According to World Health Organization (WHO), cancer is a leading cause of death worldwide, accounting for 7.4 million deaths (around 13% of all deaths) in 2004. Monoclonal/recombinant antibodies, which specifically target clinical biomarkers of disease, have increasingly been applied as powerful tools in cancer imaging and therapy, a fact that is highlighted by some nine FDA-approved monoclonal antibodies (MAbs) or their immunoconjugates (as of December 2008) for use in cancer treatment. In this study, five monoclonal antibodies (MAbs) were generated and characterized against carcinoembryonic antigen (CEA), which is widely used clinically as both a blood and tissue tumor marker of epithelial malignancy. Variable domains (VH and VL) of one the stable MAbs with highest affinity were PCR-amplified and assembled as single-chain antibody fragment (scFv). Following the cloning and expression of scFv antibody fragments in Escherichia coli, the functional binding and specificity of the recombinant antibody were confirmed by ELISA. To develop a direct in vitro detection of CEA-positive cancer cells, scFv DNA was genetically fused to enhanced green fluorescent protein (EGFP) gene and expressed in bacteria. The chimeric fluorescent protein is able to specifically detect CEA-positive cell lines; no cross-reactivity was observed with a negative control cell line. This strategy will likely allow the establishment of a rapid, single-step detection assay of CEA, which is considered to be one of the best predictors of malignancy among all other tumor markers. PMID- 21707358 TI - Domain recognition of the ING1 tumor suppressor by a panel of monoclonal antibodies. AB - The inhibitor of growth (ING) family of proteins play key roles in cell cycle arrest, apoptosis, cell aging, and the DNA damage response. To date, several domains including the plant homeodomain (PHD), lamin interacting domain (LID), and nuclear localization sequence (NLS) have been identified in the ING family of proteins that contribute to their function. To better understand the functional attributes of the ING proteins, we have developed and further characterized a panel of monoclonal IgGs that we call CAbs 1-9 based on their recognition sites, strength of binding affinity, and their specificity for ING1. All of the nine CAbs recognize the C-terminal half of the p33(ING1b) protein, which is fully conserved among all ING1 isoforms, being encoded by a common exon. Two of the nine CAbs bind a fragment that includes the PHD, which is the most conserved domain among ING family proteins (ING1-5), and one CAb cross-reacts with all ING family proteins that are encoded by different genes. Five of the nine CAbs recognized a fragment of ING1, which includes the NLS. Another two, CAb3 and CAb9, show affinity against an inter-domain sequence between the LID and the NLS. The sequence between the LID and NLS is less conserved among the ING proteins and, as expected, CAbs 3 and 9 were completely specific for ING1. Understanding the domains recognized by the different CAbs should further the functional analysis of the ING proteins that are known to participate in a wide variety of protein complexes, both in the cytoplasm and in the nucleus where they bind epigenetic histone marks via their PHD regions and lamin A via their LID domains. PMID- 21707359 TI - Purification of human prostatic-specific antigen (hPSA) from seminal plasma by immunoaffinity chromatography using a monoclonal antibody anti total PSA. AB - Human prostate-specific antigen (hPSA) is found in serum and semen in a variety of forms, is form-free and complex, and has clinical importance to prostate cancer diagnosis. Here, a simple procedure is described for the efficient purification of hPSA from seminal plasma. The semen was clarified by centrifugation, and the isolation of PSA was carried out by immunoaffinity chromatography using the monoclonal antibody anti total PSA CB-PSA.4. The recuperation of PSA from seminal plasma by this procedure was 66.4%, and a purification factor of 65.8 was reached. The specificity activity obtained was 0.79 mg PSA/mg protein, and the preparation appeared homogeneous by SDS-PAGE and immunoelectrophoresis. A molecular weight of preparation was 30.46 kDa by SDS PAGE, similar to the commercial PSA. These results indicate that immunoaffinity purification of PSA by means of this monoclonal antibody is a simple one-step procedure for the production of biologically active, highly purified human PSA. PMID- 21707360 TI - A single-chain antibody fragment against human thyroglobulin: construction and evaluation of immunoreactivity. AB - Smaller recombinant antibody fragments are at the forefront of in vivo diagnosis and therapy. These units possess better distribution and faster clearance than larger molecules. Among these, single chain antibody fragments (scFv) are emerging as credible alternatives. These proteins are shown to have same specificities and affinities for their antigens as the parental monoclonal antibody (MAb). We have attempted to produce scFv against human thyroglobulin (H Tg) using anti-Tg secreting hybridoma cells and PCR-based cloning approach. Hybridoma secreting anti-Tg MAb B10IV was established. cDNA was prepared from hybridoma cells. The V(H) and V(L) genes were amplified and cloned. The gene sequences were submitted to Genebank database (accession nos. AJ508533 and AM072962, respectively.) V(L) and V(H) genes were then linked together with a linker peptide and successfully cloned in pET28a and expressed as His-tag fusion protein in expression host BL21 (DE3). The scFv protein from IPTG-induced cells was purified under native conditions by immobilized metal affinity chromatography on a Ni-NTA agarose column. The yield expressed in Escherichia coli was approximately 8 mg/L. ScFv could be labeled with (125)I and its immunoreactivity evaluated in radioassays. Although scFv demonstrated specific binding to H-Tg, the immunoreactivity was low (10.3%) compared to the parental MAb B10IV, which showed immunoreactivity of 37.27%. Inhibition radioassays exhibited that scFv and MAb interact with the same epitope on the target antigen, indicating its specificity. PMID- 21707361 TI - Characterization of a monoclonal antibody specific for novel Bcr/Abl out-of-frame fusion proteins. AB - The new tumor-specific antigens Bcr/Abl-OOF, identified in Philadelphia chromosome (Ph)-positive leukemia cells, are derived from an alternative splicing event involving BCR exons 1, 13, or 14 and ABL exons 4 and 5. The COOH-terminus of these transcription products contain an amino acid portion derived from an out of-frame (OOF) reading of the ABL gene; these variants are expressed in Ph positive chronic myelogenous leukemia (CML) and acute lymphocytic leukemia patients. Previously, we confirmed the presence of out-of-frame peptide-specific T cells in the peripheral blood of CML patients with the ability to lyse primary autologous CML cells. We also demonstrated that the out-of-frame Abl portion was immunogenic in HLA-A2.1 transgenic mice. Here we describe the production and characterization of monoclonal antibody 1D8G8, a new tool for localization and functional studies of the tumor antigen Bcr/Abl-OOF. This antibody recognizes the out-of-frame protein portion of the native full-length Bcr/Abl-OOF protein expressed in cells transiently transfected, as demonstrated by immunoprecipitation and immunofluorescence, and binds to a specific epitope of this antigen presented in association with HLA-A2.1 molecules at the surface of these cells, as demonstrated by flow cytometry. Thus this MAb could be useful to better understand how this new protein presents in Ph-positive cells beside the canonical Bcr/Abl fusion proteins. PMID- 21707362 TI - Domain-specific monoclonal antibodies produced against human PGRN. AB - Progranulin (PGRN) encodes a 68.5-kDa secreted growth factor that is composed of seven and a half tandem repeats of a 12-cysteine granulin motif. PGRN is expressed in many tissues and has a role in mediating development, wound repair, inflammation, and tumorigenesis. Mutations leading to a loss of function in PGRN are the most common cause of familial frontotemporal lobar degeneration with TDP 43-positive inclusions (FTLD-TDP). In this study, we established hybridoma cell lines producing antibodies against human PGRN. Murine monoclonal antibodies (MAbs) against human PGRN were generated by using purified eukaryotic recombinant PGRN-6His fusion protein as immunogen. A panel of seven monoclonal antibodies was obtained after the preliminary screening by indirect enzyme-linked immunosorbent assay (ELISA), the data of which was confirmed by Western blot analysis and immunocytochemistry. By using constructs expressing a series of C- and N-terminal truncations, and single domains of PGRN, the particular domains recognized by MAbs were also identified. Domain-specific anti-PGRN MAbs will be an essential tool for investigating the role of PGRN in normal physiological or pathological conditions. PMID- 21707363 TI - One-step monoclonal antibody based enzyme-linked immunosorbent assay for direct determination of cortisol in serum. AB - Monoclonal antibodies to cortisol have obvious potential advantages as starting materials for assay systems to detect their levels in body fluids. This is very important for monitoring pituitary gland and adrenal functions. To develop a one step competitive heterogeneous enzyme-linked immunosorbent assay (ELISA), a monoclonal anti-cortisol antibody was generated using a reasonably designed haptenic derivative. Cortisol-3-O-carboxymethyloxime was coupled to carrier protein bovine serum albumin (BSA) to enhance its immunogenicity. Spleen cells were prepared from a BALB/c mouse, which had repeatedly been immunized with a conjugate of cortisol-3-O-carboxymethyloxime-bovine serum albumin (cortisol-3-O CMO-BSA), to be fused with SP2/0 myeloma cells. After one fusion experiment, four hybridoma clones secreting a practical antibody were established. One of the resulting monoclonal antibodies, 2C9D11B5, showed an affinity constant (Ka) of 1.4 * 10(10) M(-1) for cortisol and provided a practical calibration curve (limit of detection [LOD], 0.26 ng per assay) in this ELISA system employing cortisol-21 hemisuccinate-horseradish peroxidase (cortisol-21-HS-HRP) as a tracer. Cross reactivities with related C-21 steroids were acceptably low: 11-deoxycortisol (3.5%), cortisone (0.47%), corticosterone (<0.01%), progesterone (<0.01%), 17 hydroxyprogesterone (1.2%), 6-hydroxycortisol (7.6%), and tetrahydrocortisol (<0.01%). The intra-assay and inter-assay coefficient of variations (CVs) ranged from 4.3% to 9.2% and 3.8% to 10.4 %, respectively. The analytical recoveries were 92.3% to 116.3%. Serum cortisol levels of healthy volunteers were determined after chilled acetone, stripped to be 292.76 +/- 201.38 ng/mL (n=5), which are in the reference range. PMID- 21707364 TI - A novel monoclonal antibody specific to mouse IL-17. AB - IL-17 is secreted by T helper (Th) 17 cells, and might play important roles in host defense against extracellular bacterial infection and fungal infection and contribute to the pathogenesis of various autoimmune inflammatory diseases. Here we have, for the first time, generated the monoclonal antibody against the rat IL 17 protein, which is secreted by T helper (Th) 17 cells. Enzyme-linked immunosorbent assay (ELISA) and Western immunoblotting were used to screen the hybridomas. As a result, one MAb named Y11 (IgG1) was characterized, which was effective in detecting the recombinant and the cellular protein. Then the MAb was used to detect the expression of IL-17 in rat intestine graft tissues by immunohistochemical analysis. Thus, Y11 could be considered a useful tool for studies of IL-17 expression and function. PMID- 21707365 TI - Differentiating pestes des petits ruminants and rinderpest viruses by a novel monoclonal antibody. AB - Peste des petits ruminant (PPR) is an acute, febrile, viral disease of small ruminants with great economic importance. PPR and rinderpest (RP) viruses are antigenically related and need to be differentiated serologically. The use of monoclonal antibodies (MAbs) in ELISA for specific diagnostics and separation of PPR and RPV is important. For this purpose, six Balb/c mice were immunized with inactivated antigen from the Nijeria strain. Fusion cloning was performed 3 months later by directly using cloning plates, selecting the hybridoma colonies at an early stage with an inverted microscope, and transferring the colonies into 96-well plates with a micropipette. From 300 wells, nearly 56 hybridoma clones were found, from which, after testing in ELISA, 11 with higher titer were selected. Among these, only two clones were placed for limiting dilution (1H1, 6A12). Only one clone (6A12L1F12) had no cross-reactivity with RP, reacted with the N protein, and was of IgG2 isotype. PMID- 21707366 TI - Two novel monoclonal antibodies produced against human CD83 molecule. AB - CD83, a maturation marker for human and mouse dendritic cells (DCs), plays a critical role in CD4(+) T cell development as well as peripheral immune regulation. Here, two novel mouse anti-human CD83 monoclonal antibodies (MAbs) were prepared and their immunological characteristics were determined. Among the two MAbs, 8B4 binds to a linear epitope whereas 1E11 recognizes a conformational epitope. Cross-linking of 8B4 but not 1E11 with CD83-Ig augments the fusion protein mediated inhibition of peripheral blood mononuclear cells (PBMCs). Thus the two MAbs may be good candidates for immunoassaying and functional exploration of CD83 molecule. PMID- 21707367 TI - Generation of rat monoclonal antibody specific for mouse importin alpha8. AB - The transport of proteins in and out of the nucleus plays important roles in major cellular processes, such as signal transduction and regulation of cell cycle. Proteins that contain a nuclear localization signal (NLS) are recognized by an importin alpha/beta heterodimer and targeted to the nucleus. Here, we report the generation of a rat monoclonal antibody (MAb) that recognizes a novel importin alpha family member, importin alpha8, which is expressed during oocyte maturation and early embryonic development. Immunoblot and immunolocalization analyses showed that this MAb was specific for mouse importin alpha8 and not other importin alpha family members. These data suggest that this MAb is useful for analyzing molecular functions of importin alpha8. PMID- 21707368 TI - Generation and characterization of a monoclonal antibody against importin alpha7/NPI-2. AB - Many nuclear proteins are transported into the nucleus via the importin alpha/beta-mediated pathway. Importin alpha comprises a multigene family. In this study, we generated and characterized a rat monoclonal antibody (MAb) 3F8 to importin alpha7. The antibody was generated by the hybridization of mouse myeloma cells with lymph node cells from an immunized rat. The MAb 3F8 specifically recognized importin alpha7 among importin alpha isoforms as evidenced by immunoblotting analysis. Furthermore, MAb 3F8 detected exogenous importin alpha7 in COS-7 cells by immunofluorescence. This MAb will be useful in the analysis of the isoform-specific function of importin alpha7. PMID- 21707379 TI - Major constituents and antimicrobial activity of Korean herb Acorus calamus. AB - The constituents and antimicrobial activity of the essential oil from Acorus calamus were analysed. Methyl isoeugenol and cyclohexanone were identified as the major constituents of the essential oil. The essential oil was tested for antimicrobial activity against bacteria and yeast, and has shown strong antibiotic activities against most of the tested microbes, except Escherichia coli. The hexane extract has shown a similar pattern of antimicrobial activity as the essential oil. Methyl isoeugenol, the most abundant constituent in the essential oil, has also shown similar antimicrobial activity, except against Bacillus subtilis. The essential oil as well as the hexane extract and methyl isoeugenol have shown antimicrobial activity against Propionibacterium acne, which is known to be involved in acne vulgaris. PMID- 21707380 TI - A new carotenoid glycoside from Rehmannia glutinosa. AB - A new carotenoid glycoside, namely neo-rehmannioside (1), together with five known compounds, 6-O-seco-hydroxyaeginetoyl ajugol (2), oxyrehmaionoside B (3), ajugol (4), geniposidic acid (5) and geniposide (6) was isolated from the 95% ethanol extract of dry roots of Rehmannia glutinosa. The structure of the new compound (1) was determined based on MS, IR, 1-D and 2-D NMR spectral data. PMID- 21707383 TI - Reputation and precedent in the bevacizumab decision. PMID- 21707384 TI - Changing end points in breast-cancer drug approval--the Avastin story. PMID- 21707385 TI - The planet paparazzi: Earth through the lens of interplanetary spacecraft. PMID- 21707386 TI - Habitable zone limits for dry planets. AB - Most discussion of habitable planets has focused on Earth-like planets with globally abundant liquid water. For an "aqua planet" like Earth, the surface freezes if far from its sun, and the water vapor greenhouse effect runs away if too close. Here we show that "land planets" (desert worlds with limited surface water) have wider habitable zones than aqua planets. For planets at the inner edge of the habitable zone, a land planet has two advantages over an aqua planet: (i) the tropics can emit longwave radiation at rates above the traditional runaway limit because the air is unsaturated and (ii) the dry air creates a dry stratosphere that limits hydrogen escape. At the outer limits of the habitable zone, the land planet better resists global freezing because there is less water for clouds, snow, and ice. Here we describe a series of numerical experiments using a simple three-dimensional global climate model for Earth-sized planets. Other things (CO(2), rotation rate, surface pressure) unchanged, we found that liquid water remains stable at the poles of a low-obliquity land planet until net insolation exceeds 415 W/m(2) (170% that of modern Earth), compared to 330 W/m(2) (135%) for the aqua planet. At the outer limits, we found that a low-obliquity land planet freezes at 77%, while the aqua planet freezes at 90%. High-obliquity land and aqua planets freeze at 58% and 72%, respectively, with the poles offering the last refuge. We show that it is possible that, as the Sun brightens, an aqua planet like Earth can lose most of its hydrogen and become a land planet without first passing through a sterilizing runaway greenhouse. It is possible that Venus was a habitable land planet as recently as 1 billion years ago. PMID- 21707387 TI - FeS/S/FeS(2) redox system and its oxidoreductase-like chemistry in the iron sulfur world. AB - The iron-sulfur world (ISW) theory is an intriguing prediction regarding the origin of life on early Earth. It hypothesizes that life arose as a geochemical process from inorganic starting materials on the surface of sulfide minerals in the vicinity of deep-sea hot springs. During the last two decades, many experimental studies have been carried out on this topic, and some interesting results have been achieved. Among them, however, the processes of carbon/nitrogen fixation and biomolecular assembly on the mineral surface have received an inordinate amount of attention. To the present, an abiotic model for the oxidation-reduction of intermediates participating in metabolic pathways has been ignored. We examined the oxidation-reduction effect of a prebiotic FeS/S/FeS(2) redox system on the interconversion between several pairs of alpha-hydroxy acids and alpha-keto acids (i.e., lactate/pyruvate, malate/oxaloacetate, and glycolate/glyoxylate). We found that, in the absence of FeS, elemental sulfur (S) oxidized alpha-hydroxy acids to form corresponding keto acids only at a temperature higher than its melting point (113 degrees C); in the presence of FeS, such reactions occurred more efficiently through a coupled reaction mechanism, even at a temperature below the phase transition point of S. On the other hand, FeS was shown to have the capacity to reversibly reduce the keto acids. Such an oxidoreductase-like chemistry of the FeS/S/FeS(2) redox system suggests that it can determine the redox homeostasis of metabolic intermediates in the early evolutionary phase of life. The results provide a possible pathway for the development of primordial redox biochemistry in the iron-sulfur world. Key Words: Iron-sulfur world-FeS/S/FeS(2) redox system-Oxidoreductase-like chemistry. Astrobiology 11, 471-476. PMID- 21707388 TI - Survival of Bacillus subtilis endospores on ultraviolet-irradiated rover wheels and Mars regolith under simulated Martian conditions. AB - Endospores of Bacillus subtilis HA101 were applied to a simulated Mars Exploration Rover (MER) wheel and exposed to Mars-normal UV irradiation for 1, 3, or 6 h. The experiment was designed to simulate a contaminated rover wheel sitting on its landing platform before rolling off onto the martian terrain, as was encountered during the Spirit and Opportunity missions. When exposed to 1 h of Mars UV, a reduction of 81% of viable endospores was observed compared to the non-UV irradiated controls. When exposed for 3 or 6 h, reductions of 94.6% and 96.6%, respectively, were observed compared to controls. In a second experiment, the contaminated rover wheel was rolled over a bed of heat-sterilized Mars analog soil; then the analog soil was exposed to full martian conditions of UV irradiation, low pressure (6.9 mbar), low temperature (-10 degrees C), and an anaerobic CO(2) martian atmosphere for 24 h to determine whether endospores of B. subtilis on the contaminated rover wheel could be transferred to the surface of the analog soil and survive martian conditions. The experiment simulated conditions in which a rover wheel might come into contact with martian regolith immediately after landing, such as is designed for the upcoming Mars Science Laboratory (MSL) rover. The contaminated rover wheel transferred viable endospores of B. subtilis to the Mars analog soil, as demonstrated by 31.7% of samples showing positive growth. However, when contaminated soil samples were exposed to full martian conditions for 24 h, only 16.7% of samples exhibited positive growth-a 50% reduction in the number of soil samples positive for the transferred viable endospores. PMID- 21707389 TI - Legally public but privately practiced: segregating the lactating body. AB - Contemporary discourses position the "ideal mother" as a breastfeeding one; however, most mothers are faced with an economic imperative to return to work shortly after delivery, complicating their ability to continue breastfeeding. Some organizations have begun to provide lactation rooms for breastfeeding employees. Adopting a Foucauldian lens, I explore the ways in which a lactation room functions as what Foucault might have termed a heterotopian space, blurring the boundaries of public and private spheres. I combine rhetorical analysis of a lactation room, journal entries, media coverage, and my own experiences to answer recent appeals from scholars to address the role of space in communication research. I argue that the well-intended vision of the lactation room may be appreciated by some, but the composition of the room (e.g., single-occupancy design, discreet location) undercuts its necessity. PMID- 21707390 TI - Entertainment-education in the context of humor: effects on safer sex intentions and risk perceptions. AB - Past research has examined the effects of entertainment narratives on story related behaviors, but most has focused primarily on dramatic genres rather than comedy. The present study examines how the presence or absence of pregnancy related humor influences viewers' counterarguing, perceived severity, and intentions to engage in unprotected sexual behavior. Results were consistent with expectations in that related humor reduced counterarguing while also trivializing the severity of the consequences of sexual behavior. When the pregnancy storyline was presented in its original humorous context, viewers reported greater intentions to engage in unprotected sex than when pregnancy was presented in a more serious tone. Model testing clarified this finding by revealing the underlying mechanisms. Practical and theoretical implications are discussed. PMID- 21707391 TI - Assessing the influence of patient participation in primary care medical interviews on recall of treatment recommendations. AB - This study examined the relationship between patient participation and recall of treatment recommendations among a sample of 96 patients at two primary care medical clinics. Using multilevel modeling analysis, the results of this study indicated a significant positive correlation (t(81)= 8.84, p < .0001) between patients' participation and their ability to recall treatment recommendations discussed with their physicians. The results presented here suggest that patients who take a more active role in medical interviews may have an increased ability to recall important information discussed during these interactions. This is of utmost importance because the ability to recall treatment recommendations is an important predictor of health outcomes. PMID- 21707392 TI - Computational medicinal chemistry: part III. PMID- 21707393 TI - Pharmacophores for medicinal chemists: a personal view. PMID- 21707395 TI - Ask the experts: focus on computational chemistry. PMID- 21707396 TI - ClickMD: an intuitive web-oriented molecular dynamics platform. AB - BACKGROUND: Molecular dynamics (MD) simulations are broadly used to reproduce protein motions at an atomic level of detail. Running MD simulations is generally considered an expert-driven task. DISCUSSION: ClickMD provides an integrated web oriented platform for processing and analyzing the time-dependent behavior of a biomolecular system in an MD workflow. ClickMD is freely available online and can be easily integrated into the drug-design process, in particular in combination with molecular docking simulations. CONCLUSION: ClickMD has the potential to reduce the shuffling among various software applications and to facilitate the seamless processing of the MD trajectories. PMID- 21707397 TI - Structure-based quantitative structure--activity relationship modeling of estrogen receptor beta-ligands. AB - BACKGROUND: A variety of chemotypes have been studied as estrogen receptor (ER) beta-selective ligands for potential drugs against various indications, including neurodegenerative diseases. Their structure--activity relationship data and the x ray structures of the ERbeta ligand-binding domain bound with different ligands have become available. Thus, it is vitally important for future development of ERbeta-selective ligands that robust quantitative structure-activity relationship (QSAR) models be built. METHODS/RESULTS: We employed a newly developed structure- based QSAR method (structure-based pharmacophore keys QSAR) that utilizes both the structure--activity relationship data and the 3D structural information of ERbeta, as well as a robust QSAR workflow to analyze 37 ligands. Four sets of QSAR models were obtained, among which approximately 30 models afforded high (>0.60) training-r(2) and test set-R(2) statistics. CONCLUSION: We have obtained an ensemble of predictive models of ERbeta ligands that will be useful in the future discovery of novel ERbeta-selective molecules. PMID- 21707398 TI - In silico design and search for acetylcholinesterase inhibitors in Alzheimer's disease with a suitable pharmacokinetic profile and low toxicity. AB - Alzheimer's disease is a complex neurodegenerative disorder of the central nervous system, characterized by amyloid-beta deposits, tau-protein aggregation, oxidative stress and reduced levels of acetylcholine in the brain. One pharmacological approach is to restore acetylcholine level by inhibiting acetylcholinesterase (AChE) with reversible inhibitors, such as galanthamine, thus helping to improve the cognitive symptoms of the disease. In order to design new galanthamine derivatives and search for novel, potential inhibitors with improved interactions, as well as a suitable pharmacokinetic profile and low toxicity, several molecular modeling techniques were applied. These techniques included the investigation of AChE-drug complexes (1QT1 and 1ACJ Protein Data Bank codes), ligand-binding sites calculation within the active site of the enzyme, pharmacophore perception of galanthamine derivatives, virtual screening, toxicophorical analysis and estimation of pharmacokinetics properties. A total of four galanthamine derivatives having a N-alkyl-phenyl chain were designed, since the tertiary amine substituents could reach the peripheral anionic site that is not occupied by galanthamine. In addition, 12 drug-like compounds from the Ilibdiverse database were selected by virtual screening as novel, hypothetical AChE inhibitors. The toxicophorical analysis revealed that only four proposed inhibitors have chemical groups able to develop mutagenicity and chromosome damage. The remaining compounds showed only mild or none toxicophorical alerts. At least three screened compounds presented theoric parameters consistent with good oral bioavailability. The designed molecules have the potential to become new lead compounds that might guide the design of drugs with optimized pharmacodynamic and pharmacokinetic properties in order to improve the treatment of Alzheimer's disease by creating new pharmacotherapeutic options. PMID- 21707399 TI - Computational tools for polypharmacology and repurposing. AB - Most drugs act on a multitude of targets rather than on one single target. Polypharmacology, an upcoming branch of pharmaceutical science, deals with the recognition of these off-target activities of small chemical compounds. Due to the high amount of data to be processed, application of computational methods is indispensable in this area. This review summarizes the most important in silico approaches for polypharmacology. The described methods comprise network pharmacology, machine learning techniques and chemogenomic approaches. The use of these methods for drug repurposing as a branch of drug discovery and development is discussed. Furthermore, a broad range of prospective applications is summarized to give the reader an overview of possibilities and limitations of the described techniques. PMID- 21707400 TI - Electron-density descriptors as predictors in quantitative structure- activity/property relationships and drug design. AB - The use of electron density-based molecular descriptors in drug research, particularly in quantitative structure--activity relationships/quantitative structure--property relationships studies, is reviewed. The exposition starts by a discussion of molecular similarity and transferability in terms of the underlying electron density, which leads to a qualitative introduction to the quantum theory of atoms in molecules (QTAIM). The starting point of QTAIM is the topological analysis of the molecular electron-density distributions to extract atomic and bond properties that characterize every atom and bond in the molecule. These atomic and bond properties have considerable potential as bases for the construction of robust quantitative structure--activity/property relationships models as shown by selected examples in this review. QTAIM is applicable to the electron density calculated from quantum-chemical calculations and/or that obtained from ultra-high resolution x-ray diffraction experiments followed by nonspherical refinement. Atomic and bond properties are introduced followed by examples of application of each of these two families of descriptors. The review ends with a study whereby the molecular electrostatic potential, uniquely determined by the density, is used in conjunction with atomic properties to elucidate the reasons for the biological similarity of bioisosteres. PMID- 21707401 TI - Chemodiversity and molecular plasticity: recognition processes as explored by property spaces. AB - In the last few years, a need to account for molecular flexibility in drug-design methodologies has emerged, even if the dynamic behavior of molecular properties is seldom made explicit. For a flexible molecule, it is indeed possible to compute different values for a given conformation-dependent property and the ensemble of such values defines a property space that can be used to describe its molecular variability; a most representative case is the lipophilicity space. In this review, a number of applications of lipophilicity space and other property spaces are presented, showing that this concept can be fruitfully exploited: to investigate the constraints exerted by media of different levels of structural organization, to examine processes of molecular recognition and binding at an atomic level, to derive informative descriptors to be included in quantitative structure--activity relationships and to analyze protein simulations extracting the relevant information. Much molecular information is neglected in the descriptors used by medicinal chemists, while the concept of property space can fill this gap by accounting for the often-disregarded dynamic behavior of both small ligands and biomacromolecules. Property space also introduces some innovative concepts such as molecular sensitivity and plasticity, which appear best suited to explore the ability of a molecule to adapt itself to the environment variously modulating its property and conformational profiles. Globally, such concepts can enhance our understanding of biological phenomena providing fruitful descriptors in drug-design and pharmaceutical sciences. PMID- 21707402 TI - Drug discovery and the use of computational approaches for infectious diseases. AB - For centuries infectious diseases were the scourge of humanity, overcome only by the discovery of vaccination and penicillin. With an armamentarium of effective antibiotics, vaccines and drugs at hand, infectious diseases for many years were considered to be negligible. With the onset of the AIDS pandemic, the return of tuberculosis and influenza (e.g., swine influenza) this notion has changed in recent years. Drug discovery for infectious diseases, therefore, is again gaining increasing interest. This article discusses the drug-discovery process in this area and introduces major computational approaches used to identify suitable drug targets and to discover and optimize chemical lead compounds towards drug candidates using examples from antiparasitic drug discovery. PMID- 21707403 TI - Allosteric inhibition of the hepatitis C virus NS5B polymerase: in silico strategies for drug discovery and development. AB - Chronic infection by hepatitis C virus (HCV) often leads to severe liver disease including cirrhosis, hepatocellular carcinoma and liver failure. Despite it being more than 20 years since the identification of HCV, the current standard of care for treating the infection is based on aspecific therapy often associated with severe side effects and low-sustained virological response. Research is ongoing to develop new and better medications, including a broad range of allosteric NS5B polymerase inhibitors. This article reviews traditional computational methodologies and more recently developed in silico strategies aimed at identifying and optimizing non-nucleoside inhibitors targeting allosteric sites of HCV NS5B polymerase. The drug-discovery approaches reviewed could provide take home lessons for general computer-aided research projects. PMID- 21707406 TI - Effects of emotional tone and visual complexity on processing health information in prescription drug advertising. AB - This experiment explored how the emotional tone and visual complexity of direct to-consumer (DTC) drug advertisements affect the encoding and storage of specific risk and benefit statements about each of the drugs in question. Results are interpreted under the limited capacity model of motivated mediated message processing framework. Findings suggest that DTC drug ads should be pleasantly toned and high in visual complexity in order to maximize encoding and storage of risk and benefit information. PMID- 21707404 TI - Software and resources for computational medicinal chemistry. AB - Computer-aided drug design plays a vital role in drug discovery and development and has become an indispensable tool in the pharmaceutical industry. Computational medicinal chemists can take advantage of all kinds of software and resources in the computer-aided drug design field for the purposes of discovering and optimizing biologically active compounds. This article reviews software and other resources related to computer-aided drug design approaches, putting particular emphasis on structure-based drug design, ligand-based drug design, chemical databases and chemoinformatics tools. PMID- 21707407 TI - Older lesbian sexuality: identity, sexual behavior, and the impact of aging. AB - In response to the very limited and mostly outdated literature on older lesbian sexuality, this exploratory study examined older lesbian sexual identity, romantic relationships, the impact of aging, and experiences of discrimination within these contexts. Utilizing an online survey that recruited via numerous online lesbian communities and snowball sampling, 456 lesbians over the age of 50 responded to closed, Likert scale, and open-ended questions that provided a preliminary understanding of older lesbian sexuality. The results indicated that older lesbians have experienced fluidity in past romantic and sexual relationships, as well as in erotic fantasies, despite strong identification with being lesbian. The findings also indicate a decreased focus on sexuality in the context of relationships, with more focus on stability and continuity. Future research is needed that provides greater specificity and detail about older lesbian conceptions of sexual behavior and sexual identity labels, as well as specific sexual behaviors. PMID- 21707408 TI - Short-term positive and negative consequences of sex based on daily reports among college students. AB - Because sexual behavior may be associated with a broader range of outcomes than physical consequences like sexually transmitted infections and pregnancy, it is important to understand consequences of sex that may influence mental and social well-being in emerging adulthood. This article describes the short-term intrapersonal and interpersonal consequences reported by college students on days they engage in vaginal sex and what factors predict experiencing particular consequences. Data are from first-year college students who reported vaginal sex on at least one of 28 sampled days (mean age = 18.5 years; 53% female; 30% Hispanic/Latino [HL]; of non-HL participants, 30% were African American, 22% were Asian American, 35% were European American, and 12% were multiracial; N = 209 people and N = 679 person days). Participants reported positive consequences more frequently than negative consequences. Non-use of contraception and sex with a non-dating partner were associated with greater odds of reporting negative consequences. These findings have implications for messages about casual sex and use of contraception in sex education and sexual health programming. PMID- 21707409 TI - Effectiveness of a mass media campaign in promoting HIV testing information seeking among African American women. AB - "Take Charge. Take the Test." (TCTT), a media campaign promoting HIV testing among African American women, was piloted in Cleveland and Philadelphia from October 2006 to October 2007. This study assesses TCTT's effectiveness in promoting HIV testing information seeking among target audiences in each pilot city. The authors analyzed data on telephone hotlines promoted by the campaign and the www.hivtest.org Web site to examine trends in hotline calls and testing location searches before, during, and after the campaign. Cleveland hotline data were available from October 1, 2005, through February 28, 2008, for a total of 29 months (N = 126 weeks). Philadelphia hotline data were available from May 1, 2006, through February 28, 2008, for a total of 22 months (N = 96 weeks). The authors assessed the relation between market-level measures of the campaign's advertising activities and trends in hotline call volume and testing location searches. They found a significant relation between measures of TCTT advertising and hotline calls. Specifically, they found that increases in advertising gross ratings points were associated with increases in call volume, controlling for caller demographics and geographic location. The campaign had similar effects on HIV testing location searches. Overall, it appears the campaign generated significant increases in HIV information seeking. Results are consistent with other studies that have evaluated the effects of media campaigns on similar forms of information seeking. This study illustrates useful methods for evaluating campaign effects on information seeking with data on media implementation, hotline calls, and zip code-based searches for testing locations. PMID- 21707410 TI - The picture of mental health/illness in the printed media in three Central European countries. AB - Even in the era of the Internet, printed media are still among the most frequently identified sources of mental health information. Many studies have shown that this information is frequently negative and contributes to stigmatization of people with mental illness. This international comparative study describes the content of media messages about mental health/illness in terms of stigma in three Central European countries. The study sample comprised all articles pertaining to the topic of mental health/illness (N = 450) identified during five week-long periods in 2007 chosen from the six most widely read newspapers and magazines in each country. The authors used content analysis methods to achieve quantitative and qualitative objectives. More than half of all articles contained negative statements reflecting stigma toward persons with mental illness. Substance abuse disorders are the most frequent mental conditions covered in all three countries (22%), and psychotic disorders are the most stigmatized. Countries significantly differ in length of articles, in the association of aggressive behavior with persons with mental illness, and in the use of a sensationalized style of writing. Coverage of mental health/illness issues differs to some extent across countries but is generally of poor quality. On the basis of the authors' findings, practical recommendations for journalists can be tailored specifically for each country. PMID- 21707411 TI - Structural and functional measures of inner retinal integrity following visual acuity improvement in a patient with hereditary motor and sensory neuropathy type VI. AB - PURPOSE: To report measures of inner retinal integrity following improvement in visual acuity and visual fields in a patient with hereditary motor and sensory neuropathy type VI (HMSN VI). CASE REPORT: The patient is a Caucasian male with HMSN VI (type 2A Charcot-Marie-Tooth disease and associated optic atrophy) and a c.1090C->T (p.R364W) mutation in the mitofusin 2 (MFN2) gene. The patient's best corrected visual acuity improved from 20/200 (OD) and 20/400 (OS) at the initial visit to 20/25 in each eye when tested 7 years later. The visual field defects in both eyes that were present at the initial visit were absent at the follow-up visit. The structural integrity of the inner retina was assessed by an evaluation of retinal nerve fiber layer thickness (RNFLT) using optical coherence tomography (OCT), and the functional integrity was assessed by the amplitude of the photopic negative response (PhNR) of the electroretinogram (ERG). At the follow-up visit, the patient's RNFLT was less than the 5th percentile for control subjects in the superior and inferior quadrants OD and in one sector of the temporal quadrant OS, but was within normal limits elsewhere. The PhNR amplitude of each eye was below the lower limit of the normal range. CONCLUSION: The abnormally low PhNR amplitudes and abnormally thin RNFL in certain quadrants of the retina following improvement of visual acuity and visual fields to near-normal values illustrates the potential usefulness of assessing the structure and function of the inner retina in HMSN VI patients. PMID- 21707412 TI - Glutaredoxin s12: unique properties for redox signaling. AB - AIMS: Cysteines (Cys) made acidic by the protein environment are generally sensitive to pro-oxidant molecules. Glutathionylation is a post-translational modification that can occur by spontaneous reaction of reduced glutathione (GSH) with oxidized Cys as sulfenic acids (-SOH). The reverse reaction (deglutathionylation) is strongly stimulated by glutaredoxins (Grx) and requires a reductant, often GSH. RESULTS: Here, we show that chloroplast GrxS12 from poplar efficiently reacts with glutathionylated substrates in a GSH-dependent ping pong mechanism. The pK(a) of GrxS12 catalytic Cys is very low (3.9) and makes GrxS12 itself sensitive to oxidation by H(2)O(2) and to direct glutathionylation by nitrosoglutathione. Glutathionylated-GrxS12 (GrxS12-SSG) is temporarily inactive until it is deglutathionylated by GSH. The equilibrium between GrxS12 and glutathione (E(m(GrxS12-SSG))= -315 mV, pH 7.0) is characterized by K(ox) values of 310 at pH 7.0, as in darkened chloroplasts, and 69 at pH 7.9, as in illuminated chloroplasts. INNOVATION: Based on thermodynamic data, GrxS12-SSG is predicted to accumulate in vivo under conditions of mild oxidation of the GSH pool that may occur under stress. Moreover, GrxS12-SSG is predicted to be more stable in chloroplasts in the dark than in the light. CONCLUSION: These peculiar catalytic and thermodynamic properties could allow GrxS12 to act as a stress-related redox sensor, thus allowing glutathione to play a signaling role through glutathionylation of GrxS12 target proteins. PMID- 21707413 TI - Effect of ethanolic extract of Rubia peregrina L. (Rubiaceae) on monoamine mediated behaviour. AB - In the traditional system of medicine in Sardinia, Rubia peregrina (RP) is reported as an aphrodisiac herb. Since aphrodisiacs may also have dopaminergic activity, and there can be a reciprocal relationship between dopaminergic and serotonergic functions in the central nervous system, the aim here was to study the effect of the ethanolic extract of the aerial parts of R. peregrina on monoamine-mediated behaviour. The RP (100 and 200 mg kg(-1) intraperitoneally) significantly inhibited haloperidol (1 mg kg(-1) i.p.) induced catalepsy in mice (p < 0.01, dopamine-mediated response) lithium sulphate induced head twitches in rats (serotonin-mediated response) and was without effect on clonidine-induced hypothermia in rats (noradrenaline-mediated response). The study concludes that R. peregrina improves the dopaminergic function, diminishes the serotonin mediated function and is devoid of any effect on the noradrenergic function. The study suggests that we should carry out further experiments to investigate the psychopharmacological profile of R. peregrina. PMID- 21707414 TI - Spinal cord ischemia and atherosclerosis: a review of the literature. AB - INTRODUCTION: A paucity of literature exists regarding spinal cord ischemia and atherosclerosis. Therefore, the present study aimed to review this literature in hopes of better understanding this pathology. METHODS: Various search engines and databases were accessed using the following terms "atherosclerosis and spinal cord ischemia", "atherosclerosis and vascular myelopathy", "spinal cord ischemia" and "arteriosclerosis of spinal arteries". RESULTS: Twenty publications were found to be relevant to the present review. However, very few studies were identified that dealt specifically with atherosclerosis and spinal cord ischemia. The more valid cross-sectional studies indicated that local atherosclerosis in the spinal arterial network is minimal in comparison with the rest of the body. The anterior spinal artery appears to be one of the few arteries affected by atherosclerotic plaque formation. A greater propensity to affect the lower cervical spinal cord and a correlation with advancing age appears to exist. Systemic atherosclerosis may or may not have an effect on ischemia of the spinal cord. CONCLUSIONS: Much of the current literature regarding atherosclerosis and spinal cord ischemia is vague and conflicting. Future studies aimed at, for example, imaging of the spinal cord in patients with ischemic-like symptoms are warranted. PMID- 21707415 TI - Outcomes assessment of role-play scenarios for teaching responsible conduct of research. AB - We describe the summative assessment of role-play scenarios that we previously developed to teach central topics in the responsible conduct of research (RCR) to graduate students in science and engineering. Interviews with role-play participants, with participants in a case discussion training session, and with untrained students suggested that role-playing might promote a deeper appreciation of RCR by shifting the focus away from wanting to simply "know the rules." We also present the results of a think-aloud case analysis study and describe the development of a behaviorally-anchored rating scale (BARS) to assess participants' case analysis performance. PMID- 21707416 TI - How to build a scientific publishing career based on hundreds of letters-to-the editor: "The Art of Loss". AB - Letters-to-the-editor represent an important characteristic of scientific interchange especially because the initial peer-review may not fulfill the qualitative control of a manuscript. On the other hand, it is well known that such publications are accepted easier than regular ones and may be a gateway for authors without outstanding scientific merits to input their names in high impact factor journals. A letter-to-the-editor (intended as a commentary to one of our works) allowed us to discover a very peculiar and unexpected fact for the medical literature, worthy to be shared with the worldwide scientific community. PMID- 21707418 TI - Informed consent of very sick subjects in Nigeria. AB - This article highlights a number of ethical challenges I face in obtaining informed consent from very sick subjects with suspected pulmonary tuberculosis (TB). Some of the subjects with TB have an associated human immunodeficiency virus (HIV) infection. From my experience in administering informed consent and health surveys, I found the subjects to be generally mentally stable but physically exhausted. Many of the very sick subjects cough excessively and cannot tolerate a 45-minute conversation with the study staff in order for them to administer consent and conduct a survey after the routine clinical evaluation. In this situation, the administration of a qualitative consent that preserves the subject's right and autonomy becomes a challenge. PMID- 21707417 TI - Who cares about consent requirements for sourcing human embryonic stem cells? Are errors in the past really errors of the past? AB - Through an Access to Information Act request, we have obtained the consent forms used by the providers of every human embryonic stem cell (hESC) line approved for use by the Canadian Institutes of Health Research (CIHR), and examined them to verify whether or not they meet the consent requirements established by Canadian law and regulations. Our findings show that at least seven out of ten consent forms studied did not satisfy these minimum requirements. We then outline various options for responding to this situation in terms of: (i) remedial measures for dealing with executive problems with regulatory oversight procedures; and (ii) remedial measures for dealing with the impugned lines. PMID- 21707419 TI - Survival of infectious prions in water. AB - The objective of this study was to evaluate the fate of infectious prions in water. Known concentrations of infectious prions were added to deionized water, tap water, and wastewater. Samples were incubated at 25 degrees C, 37 degrees C, and 50 degrees C for 1 to 8 weeks. The standard scrapie cell assay (SSCA) which includes the ELISPOT (Enzyme Linked Immuno-Spot) reaction was performed to determine prion infectivity and quantity as a function of time. A reduction of infectious prions was observed at 25 degrees C, 37 degrees C, and 50 degrees C ranging between 0.5-log10 and 1.4-log10 in one week. Results suggest that organic matter was instrumental in protecting infectious prions, allowing them to remain infectious for a longer period of time. Thus, our data effectively show a quantifiable reduction of infectious prions in water and identifies some of the components that may influence infectivity. PMID- 21707421 TI - Micronucleus frequencies in lymphocytes and reticulocytes in a pesticide-exposed population in Portugal. AB - A wide range of chemical products known to be acutely toxic is currently used in the agricultural sector, including numerous pesticides with different compositions. Nevertheless, the effects in human health as result of chronic exposure to low levels are not yet completely understood. The methodology for determination of micronuclei (MN) in lymphocytes (CBMN) is well established, and accumulating data demonstrated a correlation to enhanced risk of cancer development. However, analysis of MN in reticulocytes (MN-RET) in humans is a recent tool on human biomonitoring. The aim of this study was to examine the influence of pesticide exposure on MN-RET and CBMN frequencies. In total, 177 individuals were studied (93 controls and 84 exposed). All individuals included in the exposed group were exposed regularly to various chemicals. Both MN-RET and CBMN were significantly higher in the exposed subjects compared to controls. The CBMN frequencies were quantitatively higher in females than males, especially within the exposed group. Smoking habits exerted no marked influence on the frequency of the biomarkers studied. A significant and positive correlation was found between both indicators. Within the exposed group, data showed that there was a significant correlation between MN-RET and recent exposure (exposure in the previous 10 d) that is not found when considering CBMN. It is conceivable that due to the short life span of reticulocytes, MN-RET were found to be more reliable to characterize recent genetic damage as opposed to CBMN. PMID- 21707422 TI - Evaluation of genotoxicity in gills and hemolymph of clam Ruditapes decussatus fed with the toxic dinoflagellate Prorocentrum lima. AB - Diarrheic shellfish poisoning (DSP) is a gastrointestinal (GIT) disease that appears a few hours after ingesting okadaic acid (OA)-contaminated mollusks; okadaic acid is present in dinoflagellates of the genera Dinophysis and Prorocentrum. Toxic manifestations occur all year round at a higher or lesser intensity, and as a consequence, extractive production factories need to be closed during these periods which affects the economy of aquaculture industries. Although the concentration of harmful algae is usually found at high levels in clam digestive gland, bivalve mortality was not increased. In this study, the genotoxic effects produced by OA in clam Ruditapes decussatus were determined using the comet assay. In vitro (exposing hemocytes to different concentrations of OA) and in vivo (feeding clams with toxic dinoflagellate Prorocentrum lima) experiments were conducted in order to determine the genotoxic effects of OA on bivalve cells. Hemocytes and gill cells were analyzed by in vivo and in vitro approaches. While the in vitro study showed a rapid effect of OA on hemocytes, data obtained in the in vivo experiment reflected contradictory results dependent upon the concentration of OA and cell type evaluated. An increase in DNA damage was observed at the lower concentration and only in gill tissue. The results obtained may contribute to a better understanding of the mechanisms underlying genotoxic effects induced by OA on bivalves. PMID- 21707423 TI - Evaluation of okadaic acid-induced genotoxicity in human cells using the micronucleus test and gammaH2AX analysis. AB - Marine algal blooms have become a public health concern due to increasing frequency in the environment and severity of exposure consequences. Human intoxications produced by phycotoxins occur globally through consumption of marine fish products containing bioaccumulated toxins. Okadaic acid (OA) is the main representative of diarrheic shellfish poisoning (DSP) toxin. OA was found to inhibit protein phosphatases and to produce oxidative damage, as well as to disturb different cellular functions including cell cycle, gene expression, and DNA repair mechanisms. The aim of this study was to determine whether OA induced genotoxicity by using a micronucleus (MN) test and gammaH2AX analysis, and to elucidate the underlying mechanisms. Human peripheral blood leukocytes, neuroblastoma cells (SHSY5Y), and hepatoma cells (HepG2) were treated with a range of OA concentrations in the presence and absence of S9 fraction. MN induction was observed in leukocytes at all concentrations tested, and in SHSY5Y and HepG2 cells only at the highest concentration (1000 nM). In contrast, gammaH2AX analysis was only positive for HepG2 cells. Taking together these data, in addition to the comet assay results obtained in a previous study in this issue, OA was found to exert a either a clastogenic or aneugenic effect dependent upon the cell types examined. PMID- 21707424 TI - Chemical exposure and occupational symptoms among Portuguese hairdressers. AB - Hairdressing is predominantly a female activity, in which several chemicals are handled, some of which are known to be allergenic and potentially carcinogenic. Several epidemiological studies showed an association between occupational exposure to chemicals in hairdressing salons and skin and respiratory-tract conditions. The aim of this study were to characterize the occupational exposure to total volatile organic compounds (VOC) and ammonia (NH3) in 50 Portuguese hairdressers' salons and to analyze the prevalence of respiratory and skin symptoms in 134 hairdressing professionals. Data indicated that internal sources of total VOC are mainly due to indoor sources, with average concentrations (1.4 mg/m3) above the Portuguese reference levels (0.6 mg/m3). Of the hairdressers' salons studied, 4% had a mean NH3 concentration higher than Portuguese (20 ppm) and American Conference of Industrial Hygienists (ACGIH) (25 ppm) reference levels. Hand dermatitis was the occupational symptom most reported by hairdressers (50%), followed by eye irritation (43%). The results of this study suggest that hairdressers' occupational activities are linked with higher risk of developing hand and wrist/arm dermatitis and symptoms in the upper respiratory tract. The proper use of disposable gloves, hands, wrists, and arms skin monitoring, and the frequent use of moisturizers in the workplace are effective measures to prevent the occurrence of dermatitis in these professionals. Displacement ventilation and/or local exhaust with adequate air exchange rate are recommended particularly in technical areas where hairdressing chemicals are mixed. PMID- 21707425 TI - Omic approaches in environmental issues. AB - Biomonitoring requires the application of batteries of different biomarkers, as environmental contaminants induce multiple responses in organisms that are not necessarily correlated. Omic technologies were proposed as an alternative to conventional biomarkers since these techniques quantitatively monitor many biological molecules in a high-throughput manner and thus provide a general appraisal of biological responses altered by exposure to contaminants. As the studies using omic technologies increase, it is becoming clear that any single omic approach may not be sufficient to characterize the complexity of ecosystems. This work aims to provide a preliminary working scheme for the use of combined transcriptomic and proteomic methodologies in environmental biomonitoring. There are difficulties in working with nonmodel organisms as bioindicators when combining several omic approaches. As a whole, our results with heterologous microarrays in M. spretus and suppressive subtractive hybridization (SSH) in P. clarkii indicated that animals sustaining a heavy pollution burden exhibited an enhanced immune response and/or cell apoptosis. The proteomic studies, although preliminary, provide a holistic insight regarding the manner by which pollution shifts protein intensity in two-dimensional gel electrophoresis (2-DE), completing the transcriptomic approach. In our study, the sediment element concentration was in agreement with the intensity of protein expression changes in C. maenas crabs. In conclusion, omics are useful technologies in addressing environmental issues and the determination of contamination threats. PMID- 21707426 TI - Comparison between two bivalve species as tools for the assessment of pollution levels in an estuarian environment. AB - Estuaries are semi-enclosed marine areas with water short residence times. Estuary ecosystems show a higher susceptibility to contamination, as historically these sites are linked to urban and industrial development. Polycyclic aromatic hydrocarbons (PAH) are ubiquitous contaminants present in high quantities in these marine environments. Chemical analyses of sediments provides information regarding PAH pollution levels but not a direct measure of the toxicological effects attributed to these contaminants. Samples of sediments and of two bivalve species, Cerastoderma edule and Mytilus galloprovincialis, were collected from two locations (Corcubion and A Concha) in an estuary from northwestern Spain. The PAH levels in sediment and bivalve species and possible sources were determined. A moderate level and a low level of pyrogenic PAH contamination were observed in Corcubion and in A Concha, respectively. Genotoxic damage was evaluated in gills and hemocytes from mussels and cockles by means of the comet assay. DNA damage measured as DNAt values showed a reliable relationship with pollution load levels of the two sampling sites. The higher sensitivity of C. edule compared to M. galloprovincialis enables one to recommend including another species coupled with mussels for biomonitoring estuarine environments. PMID- 21707427 TI - Chromium-induced genotoxicity and interference in human lymphoblastoid cell (TK6) repair processes. AB - Two model chromium (Cr) compounds, one hexavalent (sodium chromate) and one trivalent (chromium chloride), were investigated in a human lymphoblastoid cell line (TK6) to increase our knowledge regarding Cr-induced genotoxicity mechanisms. Both selected compounds were genotoxic using the comet assay, although the percentage of DNA in tail obtained after treatment with Cr(VI) was significantly higher than that obtained with Cr(III), at the higher concentrations tested. To determine the nature of the induced damage, enzymes recognizing oxidized bases were used. Treatments with formamidopyrimidine (FPG) and endonuclease III (EndoIII) displayed a greater degree of DNA damage, indicating that the induction of oxidized bases accounts for an important proportion of the damage induced by Cr compounds. In addition, the kinetic repair studies showed that generated DNA damage is removed in approximately 8 h, with the damage induced by Cr(III) being removed/repaired more rapidly than damage produced by Cr(VI). To detect Cr interferences with the repair process, a post treatment was applied after exposure to 2 Gy gamma radiation. Post-treatment significantly delayed the repair kinetics of DNA damage induced by radiation. This interference effect induced by Cr(VI) was more pronounced. In conclusion, evidence indicates that a high proportion of the Cr-induced DNA damage is correlated with oxidative damage, and that both Cr compounds interfere with repair mechanisms involved in repair of DNA damage induced by gamma radiation. PMID- 21707428 TI - Occupational exposure to formaldehyde: genotoxic risk evaluation by comet assay and micronucleus test using human peripheral lymphocytes. AB - Formaldehyde (FA) is a world high-production compound with numerous applications ranging from production of resins to medicines. Due to its sensitizing properties, irritating effects and potential cancer hazard FA is of great environmental health concern. Numerous studies in humans and experimental animals demonstrated that inhaled FA produced toxicity, genotoxicity, and cancer at distal sites. IARC, based on sufficient data, reclassified FA as a human carcinogen. The highest level of human exposure to this aldehyde occurs in occupational settings, namely, in pathology and anatomy laboratories, where FA is commonly used as a fixative and tissue preservative. Several studies consistently showed that the levels of airborne FA in anatomy laboratories exceeded recommended exposure criteria. In order to assess the genotoxic effects of chronic occupational exposure to FA, a group of pathology/anatomy workers was assessed using a micronucleus (MN) test and comet assay. The level of exposure to FA was also determined and the time-weighted average (TWA) of exposure was calculated for each subject. The TWA mean value for FA exposed workers was 0.43 +/- 0.06 ppm, exceeding national and international recommended limit levels of 0.3 ppm. Both MN frequency and comet assay parameters were significantly higher in exposed subjects. Data obtained confirm a correlation between genetic damage and occupational exposure to FA. These data, along with recent implications of human carcinogenicity, point out the need for close monitoring of occupational exposure to FA. Implementation of security and hygiene measures as well as good practices campaigns may be crucial to decrease risk. PMID- 21707429 TI - Role of citrus juices and distinctive components in the modulation of degenerative processes: genotoxicity, antigenotoxicity, cytotoxicity, and longevity in Drosophila. AB - It is well established that breakfast beverages contain high quantities of Citrus juices. The purpose of the present study was to assess the nutraceutical value of orange and lemon juices as well as two of their active compounds: hesperidin and limonene. Indicator assays were performed at three levels to evaluate different biological health promoter activities: (i) determination of the safety and DNA damage protecting ability against free radicals by using the somatic mutation and recombination test (SMART) in Drosophila melanogaster, (ii) study of the modulating role for life span in Drosophila melanogaster, and (iii) measurement of the cytotoxic activity against the human tumor cell line HL60. The highest concentrations assayed for lemon juice and limonene (50% v/v and 0.73 mM, respectively) showed genotoxic activity as evidenced from SMART. Orange and lemon juices as well as hesperidin and limonene exhibit antigenotoxic activity against hydrogen peroxide used as an oxidative genotoxin. Life-span experiments revealed that the lower concentrations of orange juice, hesperidin, and limonene exerted a positive influence on the life span of Drosophila. Finally all substances showed cytotoxic activity, with hesperidin being least active. Taking into account the safety, antigenotoxicity, longevity, and cytotoxicity data obtained in the different assays, orange juice may be a candidate as a nutraceutical food as it (1) is not genotoxic, (2) is able to protect DNA against free radicals, and (3) inhibits growth of tumor cells. PMID- 21707430 TI - Monitoring follow up of two areas affected by the Prestige oil four years after the spillage. AB - The sinking of the oil tanker Prestige in November 2002 resulted in the spill of more than 63,000 tonnes of crude oil, and polluted more than 1,000 km of coastline, especially affecting Galicia (northwestern Spain). Four years after the accident, a new biological monitoring study was undertaken of two Galician areas intensely affected by the spill, Lira and Ancoradoiro, previously evaluated in the months following the accident ( Laffon et al. 2006 ). The mussel Mytilus galloprovincialis was employed as bioindicator organism to determine both polycyclic aromatic hydrocarbons (PAH) levels and genotoxic effects. PAH were determined chromatographically in seawater samples and mussel tissues collected from November 2006 to January 2008. The results obtained showed that PAH pollution was still present in these areas, but bioaccumulation of these compounds in mussels was low, compared to reference mussels, and lower than in our previous study. DNA damage assessment was also performed in gills and hemolymph cells by means of the alkaline comet assay. DNA damage levels were higher in mussels from the exposed areas than in reference mussels. DNA damage decreased after a 7-d recovery period in the laboratory, but prolonging the recovery period up to 14 d did not contribute to less DNA damage in gill cells. Hemolymph cells were more sensitive than gill cells to the induction of DNA damage. PMID- 21707431 TI - Geno- and immunotoxic effects on populations living near a mine: a case study of Panasqueira mine in Portugal. AB - Mining industry is a vital economic sector for many countries but it is also one of the most hazardous activities, both occupationally and environmentally. Existing studies point to several adverse effects on communities' health living near mines, effects such as mesothelioma and respiratory illnesses. Results achieved in a geochemical sampling campaign undertaken in the vicinity of Sao Francisco de Assis village showed an anomalous distribution of some heavy metals in soils and waters. To evaluate the effects of mining activities on human health produced by these conditions, a group of 28 individuals from Sao Francisco de Assis village was examined for some biological endpoints. A nonexposed group (30 individuals) with the same demographic characteristics without exposure to genotoxic compounds was also studied and data obtained from both groups compared. Results of the T-cell receptor mutation assay and micronucleus (MN) test showed significant increases in the frequencies of both mutations and MN in exposed subjects compared to controls. Data obtained in the analysis of the different lymphocyte subsets demonstrated significant decreases in percentages of CD3+ and CD4+ cells, and a significant increase in percentage of CD16/56+ cells, in exposed individuals. The results of the present study indicate an elevated risk of human environmental contamination resulting from mining activities, emphasizing the need to implement preventive measures, remediation, and rehabilitation plans. This would lead to a reduction in cancer risk not only for this particular population but for all populations exposed under similar conditions. PMID- 21707432 TI - Construction and validation of a dose-response curve using the comet assay to determine human radiosensitivity to ionizing radiation. AB - Individual radiosensitivity is an individual characteristic associated with an increased reaction to ionizing radiation. The purpose of our work is to establish a dose-response curve useful to classify individuals as radiosensitive or radioresistant. Thus, a dose-response curve was constructed by measuring in vitro responses to increasing doses (0 to 8 Gy) of gamma radiation in the comet assay. The obtained curve fit well with a linear equation in the range of 0 to 8 Gy. The overall dose-response curve was constructed for percent DNA in tail, as a measure of the genetic damage induced by irradiation. To probe the goodness of the constructed curve, a validation study was carried out with whole blood from two donors in a blind study. Results show that, for the two applied doses (2 and 6 Gy), the obtained values fit well inside the interval of confidence of the curve. In conclusion, our results demonstrate the usefulness of the comet assay in determining individual responses to defined doses of gamma radiation. The standard dose-response curve constructed may be used to detect individuals departing from reference values. PMID- 21707433 TI - Assays to determine DNA repair ability. AB - DNA repair is crucial to the integrity of the human genome since mammalian cells are continuously exposed to different chemical and physical genotoxic agents. To counteract the lesions induced by these agents, organisms have developed a number of highly conserved repair mechanisms involving numerous protein complexes grouped in several different repair pathways. The importance of studying the individual capacity to repair DNA damage lies in the observation that deficient repair mechanisms of the genome have been linked to the presence of large number of diseases and cancer, and alterations in these mechanisms may also alter the susceptibility of individuals exposed to a particular mutagen. This review focused on the current knowledge of different assays developed to evaluate DNA repair capacity (DRC). These assays, which are grouped into five major categories, have been successfully applied in (1) in vitro studies, (2) epidemiological studies in patients with cancer or other different pathologies, and (3) environmentally or occupationally exposed populations. Nevertheless, some of the limitations include high interlaboratory variability and difficulty to implement the assays on a large scale. The selection of an adequate DRC assay needs to be made on the basis of the objective raised for its application and taking into account a number of determining factors, namely, (1) speed and cost, (2) type of DNA repair to be evaluated, and (3) sample availability. PMID- 21707434 TI - Clinical relevance of thyroglobulin doubling time in the management of patients with differentiated thyroid cancer. PMID- 21707435 TI - Publication of industry-sponsored medical research: guidelines from the Consortium of Laboratory Medicine Journal Editors. PMID- 21707436 TI - The Roche Elecsys and Siemens-Centaur thyroglobulin autoantibody assays show comparable clinical performance to the recently unavailable Beckman-Coulter access thyroglobulin autoantibody assay in identifying samples with potentially false-low thyroglobulin measurements due to thyroglobulin autoantibody interference. PMID- 21707439 TI - Progress and outlook of inorganic nanoparticles for delivery of nucleic acid sequences related to orthopedic pathologies: a review. AB - The anticipated growth in the aging population will drastically increase medical needs of society; of which, one of the largest components will undoubtedly be from orthopedic-related pathologies. There are several proposed solutions being investigated to cost-effectively prepare for the future--pharmaceuticals, implant devices, cell and gene therapies, or some combination thereof. Gene therapy is one of the more promising possibilities because it seeks to correct the root of the problem, thereby minimizing treatment duration and cost. Currently, viral vectors have shown the highest efficacies, but immunological concerns remain. Nonviral methods show reduced immune responses but are regarded as less efficient. The nonviral paradigms consist of mechanical and chemical approaches. While organic-based materials have been used more frequently in particle-based methods, inorganic materials capable of delivery have distinct advantages, especially advantageous in orthopedic applications. The inorganic gene therapy field is highly interdisciplinary in nature, and requires assimilation of knowledge across the broad fields of cell biology, biochemistry, molecular genetics, materials science, and clinical medicine. This review provides an overview of the role each area plays in orthopedic gene therapy as well as possible future directions for the field. PMID- 21707438 TI - Transforming growth factor-beta 3 stimulates cartilage matrix elaboration by human marrow-derived stromal cells encapsulated in photocrosslinked carboxymethylcellulose hydrogels: potential for nucleus pulposus replacement. AB - Degeneration of the nucleus pulposus (NP) has been implicated as a major cause of low back pain. Tissue engineering strategies using marrow-derived stromal cells (MSCs) have been used to develop cartilaginous tissue constructs, which may serve as viable NP replacements. Supplementation with growth factors, such as transforming growth factor-beta 3 (TGF-beta3), has been shown to enhance the differentiation of MSCs and promote functional tissue development of such constructs. A potential candidate material that may be useful as a scaffold for NP tissue engineering is carboxymethylcellulose (CMC), a biocompatible, cost effective derivative of cellulose. Photocrosslinked CMC hydrogels have been shown to support NP cell viability and promote phenotypic matrix deposition capable of maintaining mechanical properties when cultured in serum-free, chemically defined medium (CDM) supplemented with TGF-beta3. However, MSCs have not been characterized using this hydrogel system. In this study, human MSCs (hMSCs) were encapsulated in photocrosslinked CMC hydrogels and cultured in CDM with and without TGF-beta3 to determine the effect of the growth factor on the differentiation of hMSCs toward an NP-like phenotype. Constructs were evaluated for matrix elaboration and functional properties consistent with native NP tissue. CDM supplemented with TGF-beta3 resulted in significantly higher glycosaminoglycan content (762.69+/-220.79 ng/mg wet weight) and type II collagen (COL II) content (6.25+/-1.64 ng/mg wet weight) at day 21 compared with untreated samples. Immunohistochemical analyses revealed uniform, pericellular, and interterritorial staining for chondroitin sulfate proteoglycan and COL II in growth factor-supplemented constructs compared with faint, strictly pericellular staining in untreated constructs at 21 days. Consistent with matrix deposition, mechanical properties of hydrogels treated with TGF-beta3 increased over time and exhibited the highest peak stress in stress-relaxation (sigma(pk)=1.489+/-0.389 kPa) at day 21 among all groups. Taken together, these results demonstrate that hMSCs encapsulated in photocrosslinked CMC hydrogels supplemented with TGF-beta3 are capable of elaborating functional extracellular matrix consistent with the NP phenotype. Such MSC-laden hydrogels may have application in NP replacement therapies. PMID- 21707440 TI - Biomarkers of endothelial dysfunction: can they help us deciphering systemic inflammation and sepsis? AB - The endothelial integrity, as mechanical barrier against microorganisms and as natural "anticoagulant", is crucial for physiologic organ function. Systemic activation of the endothelium upon inflammation, sepsis, and septic shock is always ending in blood-tissue barrier disruption. With increasing dysfunction, uncontrolled clotting activation, capillary microthrombi formation, tissue edema, local hypoxia, and ischemia are initiated. This in turn enhances a vicious circle leading to multiple organ failure and death. Therefore, biomarkers reflecting this special compartment may help in the early detection of systemic inflammation and its complications. This review provides an overview of the most important endothelial biomarkers and their possible use in sepsis. PMID- 21707441 TI - Biomarkers of kidney injury. AB - CONTEXT: Acute kidney injury (AKI) represents a common serious clinical problem. Up to date mortality due to AKI, especially in intensive care units, has not been changed significantly over the past 50 years. This is partly due to a delay in initiating renal protective and appropriate therapeutic measures since until now there are no reliable early-detecting biomarkers. The gold standard, serum creatinine, displays poor specificity and sensitivity with regard to recognition of the early period of AKI. OBJECTIVE: Our objective was to review established markers versus novel urine and serum biomarkers of AKI in humans, which have progressed to clinical phase with regard to their diagnostic and prognostic value. MATERIALS AND METHODS: A review was performed on the basis of literature search of renal failure, acute kidney injury, and biomarkers in Pubmed. RESULTS: Next to established biomarkers as creatinine and cystatin C, other molecules such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), monocyte chemotactic peptide (MCP-1), Netrin-1, and interleukin (IL)-18 are available and represent promising new markers that, however, need to be further evaluated in the clinical setting for suitability. DISCUSSION: In clinical settings with incipient AKI, not only the development and the implementation of more sensitive biomarkers are required for earlier treatment initiation in order to attenuate the severity of kidney injury, but also equally important remains the substantial improvement and application of refined and prophylactic therapeutic options in these situations. CONCLUSION: Adequately powered clinical trials testing a row of biomarkers are warranted before they may qualify for full adoption in clinical practice. PMID- 21707442 TI - Novel biomarkers in human terminal heart failure and under mechanical circulatory support. AB - This review summarizes recent findings on novel biochemical plasma biomarkers in terminal heart failure patients, which might predict an advanced mortality risk or even recovery. Moreover, we discussed the regulation of these heart failure related biomarkers under mechanical circulatory support. PMID- 21707443 TI - Monitoring tolerance and rejection in organ transplant recipients. AB - To avoid toxic side effects caused by permanent immunosuppressive treatment, research in transplantation focuses on new treatment strategies inducing tolerance or allowing drug weaning. Implementing drug minimization into clinical routine can be only safely achieved when guided by biomarkers reflecting the individual immune reactivity. We review recently described biomarkers and assays allowing identification of patients suitable for drug weaning or at risk of rejection. However, the majority of described biomarkers and assays have not been validated in prospective clinical trials. Thus, collaborative efforts are needed to design and perform prospective multicenter trials to validate the identified biomarkers across different laboratories. PMID- 21707444 TI - Analysis of V/Q-matching--a safety "biomarker" in pulmonary drug development? AB - Ventilation (V')/perfusion (Q') mismatch (VQM) is the single most important reason for gas-exchange abnormalities in pulmonary diseases. Pharmacological approaches can further aggravated VQM and its assessment is important to avoid hypoxemia. A theoretical framework for VQM, its relevance in clinical trials, and a stepwise evaluation approach is outlined. This assessment should entail stratification of patients- and mechanisms-at-risk for VQM. Also, its boundary conditions (e.g. cardiac output, perfusion pressure, hemoglobin concentration, changes in ventilation) need to be taken into consideration. Ultimately, VQM assessment requires invasive approaches. VQM evaluation is an important safety "biomarker" to avoid negative study outcome due to gas-exchange abnormalities. PMID- 21707445 TI - Choice of angiotensin receptor blocker in moderate hypertension. A UK-based cost benefit comparison of olmesartan- and candesartan-based regimens. AB - INTRODUCTION: Selection of antihypertensive therapy hinges on an appropriate combination of efficacy, tolerability and compatibility with co-morbidities. Within a given class of antihypertensives, the choice of agent is often driven by cost, with the cheapest appropriate agent being chosen. Amongst the angiotensin receptor blockers (ARBs), this choice will often be losartan, as it is available in generic form. However, as the blood pressure lowering efficacy of losartan is modest, some patients will require an alternative ARB. In the UK this choice is often candesartan, although the agent with greatest BP lowering efficacy is olmesartan. The objective of this study was to use a cost-benefit model to compare the costs associated with target achievement using each of these two agents, in order to guide optimum use of prescribing budgets. METHOD: A probabilistic cost-benefit model was constructed for a cohort of patients with moderate hypertension, based on a standardised titration and maintenance algorithm using either olmesartan or candesartan, combined with thiazide and calcium channel blocker where required. Direct treatment costs were recorded, along with the proportion of patients achieving pre-defined treatment targets at each treatment level. Results were expressed as mean treatment cost per patient reaching target. RESULTS: Based on the current QoF target of 150 mmHg systolic, 94.3% of patients on the olmesartan-based regimen reached target of 150 mmHg, compared with 89.0% of those on the candesartan-based regimen. 86% of olmesartan patients reached target on <3 drugs, compared with 74% of candesartan patients. The mean 12-month cost per patient reaching target was L171.36 for olmesartan versus L189.91 for candesartan. Ongoing annual maintenance costs for patients at target were L169.97 and L182.64, respectively. Similar results were obtained when considering alternative treatment targets LIMITATIONS: The study only compared two ARBs - candesartan and olmesartan and the results relate to prescribing costs only and do not include other healthcare costs. Additionally, the chosen outcome was blood pressure target achievement, rather than clinical endpoints. Given the stated objectives of the model, we do not believe these issues will have introduced bias in the direction of either comparator CONCLUSION: Although olmesartan has an apparently higher acquisition cost than candesartan, its superior BP lowering efficacy means that the overall cost per patient treated to target is actually lower. This result could have significant implications for making savings within primary care prescribing budgets in the UK. PMID- 21707447 TI - Impact of bariatric surgery on pulmonary function and nitric oxide in asthmatic and non-asthmatic obese patients. AB - BACKGROUND: Asthma is an important co-morbidity of obesity. This study evaluated the impact of bariatric surgery on respiratory function in obese patients and compared the outcomes in asthmatic and non-asthmatic subjects. METHODS: The study was observational and prospective and included subjects on waiting list for bariatric surgery. Pulmonary function, symptoms, and exhaled nitric oxide were assessed before surgery and 1 year after. RESULTS: Twenty-nine severe obese subjects (age range: 25-66 years) with a mean body mass index of 44.8 +/- 4.7 kg/m(2) were included. Fourteen of them had also intermittent to moderate asthma. In the whole population, the body mass index decreased from 44.8 +/- 4.7 to 41.1 +/- 3.9 kg/m(2) (p = .0001) and the forced vital capacity increased from 3.05 +/- 0.83 to 3.50 +/- 0.81 L (p = .043). No change was seen in forced expiratory volume and oxygen saturation. These results remained valid also analyzing asthmatics and non-asthmatics separately. Concerning nitric oxide, the decrease at 1 year was significantly different between the two populations, since in asthma patients exhaled nitric oxide decreased by 4.86 ppb after bariatric surgery and increased by 0.27 ppb in non-asthmatics (p = .04). CONCLUSIONS: Bariatric surgery significantly reduces the intake of inhaled corticosteroids and the levels of exhaled nitric oxide, thus bronchial inflammation, in asthmatics. PMID- 21707448 TI - Family-centred care: a critical perspective. PMID- 21707449 TI - Sport-related concussion and occupational therapy: expanding the scope of practice. PMID- 21707450 TI - Effects of barley beta-glucan-enriched flour fractions on the glycaemic index of bread. AB - The aim of this research was to evaluate beta-glucan-enriched flours, obtained from barleys with either normal or waxy starch, for their effects on the glycaemic index (GI) and the quality of bread. Rheological results confirmed that when barley flour was included in the dough the overall quality of bread slightly worsened. However, positive consequences on glycaemia were obtained with the normal starch barley: the GI of all-wheat bread (82.8 +/- 7.2) was significantly reduced (57.2 +/- 7.9) when 40% of wheat flour was substituted with beta-glucan enriched barley flour (6.0% +/- 0.1 beta-glucan in the final flour blend). In contrast, this positive effect was significantly reduced (GI: 70.1 +/- 9.1) when 40% of wheat flour was substituted with the beta-glucan-enriched flour of a waxy barley (CDC Alamo; 6.6 +/- 0.2 beta-glucan in the final flour blend), suggesting that the ability of beta-glucans to lower the GI was affected by the barley starch-type. PMID- 21707451 TI - Effect of fish oil supplementation in pregnancy on the fatty acid composition of erythrocyte phospholipids and breast milk lipids. AB - To investigate the effect of n-3 polyunsaturated fatty acid (PUFA) supplementation on the fatty acid composition of erythrocyte phospholipids and breast milk lipids, pregnant Brazilian women in the 30th week of gestation were randomized to supplement their usual diet with 2 g/day of fish oil (FO group) or primrose oil (PO group, control) capsules for 15 days. Erythrocyte phospholipids from FO group had proportionally higher docosahexaenoicacid and eicosapentaenoic acid levels and furthermore, the ratio of n-6/n-3 PUFA was significantly lower in the breast milk lipids compared with the control group. Assessment of plasma anti oxLDL autoantibodies and thiobarbituric acid-reactive substance concentration demonstrated that both groups had the same levels and they were unaltered by supplementations. PMID- 21707452 TI - Privacy and data management in the era of massively parallel next-generation sequencing. PMID- 21707453 TI - Application of 3D hydrogel microarrays in molecular diagnostics: advantages and limitations. PMID- 21707454 TI - Ovarian cancer screening and peritoneal carcinomatosis: standards, 'omics' and miRNAs for personalized management. PMID- 21707455 TI - Bad breath: can analysis of exhaled breath help sniff out cancer ? PMID- 21707456 TI - Isolation of rare circulating tumor cells in cancer patients: technical aspects and clinical implications. AB - Circulating tumor cells (CTCs) may be detected in the blood of patients with epithelial tumors using different analytical approaches. The relative number of CTCs is low and they include a heterogeneous population of cells with diverse biological and molecular characteristics, often different from those of the respective primary tumor. Until recently, they have been difficult to detect and, even though discordant results have been reported when different methods of detection were used, they may provide prognostic and predictive information. Several antibody- or molecular-based CTC detection methods have been developed, offering hope for individualized risk assessment by utilizing CTCs as biomarkers of disease progression and drug response. Pilot studies have also shown that by utilizing methods that permit, besides enumeration, a molecular characterization of CTCs, one could better identify high-risk patients, predict response to targeted therapies, analyze gene expression profiles (in order to identify new potential drug targets) and increase our knowledge of the metastatic process. In this article we review the techniques currently utilized for isolation and characterization of CTCs and we discuss their potential utility in clinical oncology focusing on the future perspectives in this field. PMID- 21707457 TI - Early diagnosis of sepsis using serum biomarkers. AB - Sepsis, an innate immunological response of systemic inflammation to infection, is a growing problem worldwide with a relatively high mortality rate. Immediate treatment is required, necessitating quick, early and accurate diagnosis. Rapid molecular-based tests have been developed to address this need, but still suffer some disadvantages. The most commonly studied biomarkers of sepsis are reviewed for their current uses and diagnostic accuracies, including C-reactive protein, procalcitonin, serum amyloid A, mannan and IFN-gamma-inducible protein 10, as well as other potentially useful biomarkers. A singular ideal biomarker has not yet been identified; an alternative approach is to shift research focus to determine the diagnostic relevancy of multiple biomarkers when used in concert. Challenges facing biomarker research, including lack of methodology standardization and assays with better detection limits, are discussed. The ongoing efforts in the development of a multiplex point-of-care testing kit, enabling quick and reliable detection of serum biomarkers, may have great potential for early diagnosis of sepsis. PMID- 21707458 TI - Potential of breath and skin analysis for monitoring blood glucose concentration in diabetes. AB - The ability to monitor blood glucose noninvasively has long been a goal of those with diabetes, due to the pain and inconvenience of current blood glucose monitoring devices. This article investigates the potential for monitoring compounds in breath and emitted through skin for inferring blood glucose concentration. Potential markers and an assessment of their suitability for noninvasive monitoring are discussed. The varying technologies developed for monitoring volatile organic compounds in breath and from the skin of diabetics and their suitability for development as a hand-held device is reviewed. The potential exists for the use of breath and skin monitoring as an alternative to blood glucose, but it may take years to collect sufficient clinical data for robust correlations to be possible. PMID- 21707459 TI - Microfluidic devices for diagnostic applications. AB - Microfluidic systems have become an attractive platform for diagnostic applications. The technology not only allows drastically decreased assay volumes (down to picoliters), but also accelerates sample processing and readout. In this article we give an overview of the different kinds of systems, ranging from non- or minimally instrumented point-of-care devices for the detection of pathogens to fully-instrumented cutting-edge technologies such as next-generation sequencing and droplet-based microfluidics. We expect that microfluidic systems will have a major impact on future diagnostic (e.g., disposable devices) and therapeutic approaches (e.g., personalized medicine). Here we summarize current trends and critically review the limitations. PMID- 21707460 TI - Oligonucleotide microarrays in constitutional genetic diagnosis. AB - Oligonucleotide microarrays such as comparative genomic hybridization arrays and SNP microarrays enable the identification of genomic imbalances - also termed copy-number variants - with increasing resolution. This article will focus on the most significant applications of high-throughput oligonucleotide microarrays, both in genetic diagnosis and research. In genetic diagnosis, the method is becoming a standard tool for investigating patients with unexplained developmental delay/intellectual disability, autism spectrum disorders and/or with multiple congenital anomalies. Oligonucleotide microarray have also been recently applied to the detection of genomic imbalances in prenatal diagnosis either to characterize a chromosomal rearrangement that has previously been identified by standard prenatal karyotyping or to detect a cryptic genomic imbalance in a fetus with ultrasound abnormalities and a normal standard prenatal karyotype. In research, oligonucleotide microarrays have been used for a wide range of applications, such as the identification of new genes responsible for monogenic disorders and the association of a copy-number variant as a predisposing factor to a common disease. Despite its widespread use, the interpretation of results is not always straightforward. We will discuss several unexpected results and ethical issues raised by these new methods. PMID- 21707461 TI - Biosensors based on combined optical and electrochemical transduction for molecular diagnostics. AB - Electrochemical and optical biosensors exist to monitor different fluids containing analytes of interest. Until today, these have been developed separately. Owing to the creation of new transducer configurations such as indium tin-coated glass fiber optics, these methods can now be used separately, in parallel and it is hoped that one day they will be able to be used simultaneously; thus, using the same probe to measure a single analyte using two different methods (electrochemical and optical) or two different analytes with either of the aforementioned methods sitting on the same probe. This article will highlight the importance, as well as the usefulness, of combining measurement methodologies in improving sensor response and sensitivity. PMID- 21707463 TI - Bridging the gap between the immune and glutamate hypotheses of schizophrenia and major depression: Potential role of glial NMDA receptor modulators and impaired blood-brain barrier integrity. AB - OBJECTIVES: Previous studies have suggested that the pathogenesis of schizophrenia and major depression involves an altered peripheral immune system. It is not clear, however, whether such changes are associated with corresponding neuroinflammatory responses and disturbances of neurotransmission. METHODS: This paper reviews the current state of knowledge about the involvement of immune alterations in schizophrenia and major depression and a possible link to disturbances of glutamatergic transmission. RESULTS: Inflammatory endogenous modulators of the NMDA receptor, the kynurenine pathway metabolites, are potential candidates for such a link. Studies of the blood and cerebrospinal fluid have suggested a schizophrenia-related upregulation of the NMDA receptor antagonist kynurenic acid in astrocytes, analogous to the ketamine psychosis model. Conversely, it has been proposed that there is depression-related microglial synthesis of the NMDA receptor agonist quinolinic acid, which is consistent with the observation that ketamine has therapeutic effects in major depression. Few publications have studied NMDA receptor modulating kynurenines in the brain, however. CONCLUSIONS: Future research on the cerebral cell-type specific distribution of kynurenine metabolites and their brain-regional concentration imbalances will be required to connect peripheral immune changes, the hypotheses of blood-brain barrier dysfunction and glial pathology with concepts of altered neurotransmission in schizophrenia and major depression. PMID- 21707464 TI - A brief questionnaire on metacognition: psychometric properties. AB - OBJECTIVES: Existing questionnaires on personal views of one's own cognitive functioning are either unduly long, restrict their focus on memory, and/or capture complaints rather than the general status quo. A brief 9-item questionnaire was developed, assessing metacognition with two subscales covering metamemory and metaconcentration. METHODS: The questionnaire was tested in a sample of healthy women (n = 228) aged 70-93 years, during two face-to-face interviews with an interval of 6 months. RESULTS: Subscales were confirmed to have factorial validity. While objective cognitive test performance did not predict self-reported everyday functioning, metamemory and metaconcentration accounted for a substantial amount of its variance. The newly developed instrument was shown to be predominantly characterized by latent trait variance components. CONCLUSION: The presented questionnaire is advantageous for the assessment of metacognition as it is brief and easily applicable. Since metacognition is highly relevant for sustained independence in old age, the questionnaire is suitable to capture important determining factors in research on aging phenomena and processes. PMID- 21707465 TI - Fewer intrusions after an attentional bias modification training for perceptual reminders of analogue trauma. AB - The present experimental analogue study used computerised attention training to investigate the role of attention bias in the prediction of intrusive memories. After exposure to a trauma film, participants in a training group (n=22) were presented with a variant of the exogenic cueing task (ECT) in which visual film reminders (i.e., stills from the trauma film) were always presented during invalid and neutral control stimuli always during valid trials. The purpose of this cue-location contingency was reinforcing the direction of attention away from film reminders. Control participants (n=23) performed a similar training without such a contingency. Post-training processing bias was assessed with a single target Rapid Serial Visual Presentation (RSVP) task, in which trauma-film reminders served as task-irrelevant distracters appearing shortly before a neutral target. The frequency of film-related intrusions was recorded in a take home diary and at a follow-up session three days after film viewing. Participants who underwent attention training reported fewer film-related intrusions and showed less interference by visual film distracters than controls. Implications for research on attention bias after real-life trauma are discussed. PMID- 21707466 TI - IMP-type metallo-beta-lactamases in Gram-negative bacilli: distribution, phylogeny, and association with integrons. AB - Twenty-nine IMP-type beta-lactamases (IMPs) have been identified in at least 26 species of clinically important Gram-negative bacilli from more than 24 countries/regions. Most of bla(IMP) genes are harbored by class 1 integrons that are usually embedded in transposons and/or plasmids, footnoting their horizontal transfer and worldwide distribution. bla(IMP) genes usually co-exist with other resistance genes, such as aacA, catB, and bla(OXA), resulting in multi-drug resistance. Compared to other gene cassettes, 76.3% of the bla(IMP) gene cassettes are located adjacent to Pc promoter of the class 1 integrons, indicating that the bla(IMP) genes are readily expressed in most of bacterial hosts. PMID- 21707467 TI - Streptomyces nucleases. AB - Streptomyces nucleases are widely distributed and multifunctional enzymes acting on both DNA and RNA. They occur extra as well as intracellularly and can be classified under sugar specific and sugar non-specific nucleases. Nucleases play different roles like analytical, biological, and nutritional. They are also used in programmed cell death. Although more than 20 nucleases are reported to date, very little information is available regarding their structure-function relationship, active site based sequence homology, and the probable mechanism of action. This review describes the history, occurrence, localization, production, purification, properties, and applications of Streptomyces nucleases. PMID- 21707468 TI - Factors influencing the uptake of memory compensations: a qualitative analysis. AB - In 1996, Wilson and Watson stated that it is not always easy to persuade people with memory impairments to use memory strategies, despite the value of using them. To date, there has been no in-depth exploration of what motivates people to use memory compensations from the perspective of the individual with an acquired brain injury. In this study eight people attending an out-patient brain injury rehabilitation service were interviewed. Transcripts were analysed using interpretative phenomenological analysis. Four master themes emerged from the analysis: emotional barriers that need to be overcome before memory compensations are used; factors that may have a reverse effect on motivation, such as the strategy being an unpleasant reminder that one is different; beliefs about memory, such as it is better to use your own memory rather than relying on memory aids otherwise it will become lazy; and the final master theme "It's not in my nature", i.e., it does not fit with the person's lifestyle. The results show that motivation for strategy use depends on complex processes that include social, emotional and practical factors. This study demonstrates the importance of adhering to a biopsychosocial approach within rehabilitation. PMID- 21707469 TI - Behavioral couples therapy for substance abusers: where do we go from here? AB - Behavioral couples therapy (BCT) is an evidence-based family treatment for substance abuse. The results of numerous investigations over the past 30 years indicate that participation in this treatment by married or cohabiting substance abusing patients, compared with more traditional individual-based interventions, results in greater reductions in substance use, higher levels of relationship satisfaction, greater reductions in partner violence, and more favorable cost outcomes. This review examines the rationale for using BCT, the empirical literature supporting its use, methods used as part of this intervention, and future research directions. PMID- 21707470 TI - New toxics, new poverty: a social understanding of the freebase cocaine/Paco in Buenos Aires, Argentina. AB - Included within the field of research on changes in drug use patterns and vulnerability are conditions of emergency related to economic crisis, wars, and political conflict. This study addresses the complex connections between the rapid propagation of freebase cocaine (FBC)-locally known as "pasta base" or "Paco" in Argentina and the normalization of the consequences of Argentina's 2001 2002 political-economic crisis. On the basis of the results of an ethnographic study carried out in three neighborhoods of the Greater Buenos Aires area between 2001 and 2005, this article aims to analyze how changes in the material and social living conditions are interrelated with the high toxicity of FBC/Paco and engender the emerging compulsion of its consumption and deterioration to the bodies, subjectivities, and social activities of active drug users from these shantytowns. By analyzing the changes in transactions directly or indirectly involving drugs-specifically those ranging from cocaine to FBC/Paco-we can argue how structural poverty, "new poverty," is not only associated with the expansion of FBC/Paco but is also shaped by its use, modes of consumption, associated health problems, and sufferings. PMID- 21707471 TI - Apolipoprotein A5-12238 T>C gene polymorphism and risk factors for metabolic syndrome in the Guo Shan Yao and the Han populations. PMID- 21707472 TI - Is there any impact of cognitive remediation on an ecological test in schizophrenia? AB - INTRODUCTION: Cognitive deficits are commonly reported in schizophrenia and have a significant impact on the daily life of patients and on their social and work inclusion. Cognitive remediation therapies (CRT) may enhance the capabilities of schizophrenia patients. Although social and work integration is the ultimate goal of CRT, previous studies have failed to carry out a detailed assessment of the effects on everyday life. METHODS: Fifty-nine schizophrenia patients were randomised into two groups (remediation or usual treatment) to test the effects of a new remediation programme, which included both rehearsal and strategy learning, on cognitive functions. An ecological test was used to evaluate its transfer to daily living skills. RESULTS: Cognitive improvements are revealed in CRT patients, mainly in memory and executive functions. Patients showing some deficiencies to perform the ecological test had better scores after the CRT. Moreover, they significantly improve their social activity scores. CONCLUSIONS: CRT would facilitate mental load monitoring by enhancing or reallocating cognitive resources, facilitating the patient's organisation and autonomy. The rehearsal learning approach improves the ability to carry out automatic operations that are less demanding in terms of cognitive resources, thereby increasing the resources available for acquisition and efficient use of strategies provided during the strategy learning approach. PMID- 21707473 TI - The quality of life and psychological status of mothers of hospitalized pediatric oncology patients. AB - This study compares the quality of life (QoL) and psychological status of mothers of children with cancer with those of mothers of children without cancer. One hundred hospitalized children and their mothers, as primary caregivers, were included in this study. Fifty mothers with healthy children were enrolled as the control group. A children and mother query form was used to obtain demographical data. The disease histories were extracted from patient records. QoL was measured with the Medical Outcomes Study 36-item Short Form Survey (SF-36) and the State Trait Anxiety Inventory (STAI) in order to assess the psychological symptoms of the mothers in the study and in the control groups. The mean age of the caregivers was 35.93 +/- 8.27 years, whereas the mean age of the mothers in the control group was 39.72 +/- 6.88 years. The general health, vitality, social functioning, and mental health scores from the SF-36 and the STAI-trait scores were significantly poorer among the mothers of children with cancer as compared with the scores of the mothers of children without cancer (P < .05). Significant negative correlations were found between the age of the children, the age at diagnosis, and the SF-36 subscores for physical functioning, physical role, and pain (P < .05). The mothers of children with cancer, who require hospital care, have poorer QoL and psychological health than the mothers of healthy children. These results suggest that the current system for treating cancer in Turkish children should also include close monitoring of the care-giving mothers' QoL and psychological health. PMID- 21707475 TI - Plasminogen activation-based thrombolysis for ischaemic stroke: the diversity of targets may demand new approaches. AB - The plasminogen activating enzyme system has been exploited and harnessed for therapeutic, mainly thrombolytic benefit for many years. While plasminogen activator-based thrombolysis turned out to be a resounding success, it has become apparent that the "plasminogen activating system" per se is not only designed to simply remove fibrin and some other matrix proteins. Indeed, the plasminogen activators and the plasminogen activator inhibitors have important effects on cell signalling through both proteolytic and non-proteolytic means and can promote unwanted side effects, particularly in the brain. Tissue type plasminogen activator (t-PA) was heralded as a fibrin-selective plasminogen activator and subjected to clinical development in the early 1980's initially for the treatment of patients with myocardial infarction. t-PA was given FDA approval in the mid 1990's for use in ischaemic stroke patients, but it could only be administered within a short 3h window post- stroke as later use was associated with an increased risk of intracerebral haemorrhage. Hence only a small percentage of these patients were eligible for thrombolysis to restore blood flow to the brain. Since t-PA-mediated plasmin generation is not only impacting on the cerebral blood clot, extending the therapeutic time window for thrombolysis is not a simple task. The ultimate success will depend on how well the future generation of thrombolytic agents promote efficacious removal of a fibrin clot without promoting collateral damage particularly in the brain. PMID- 21707474 TI - Effects of altered plasminogen activator inhibitor-1 expression on cardiovascular disease. AB - Plasminogen Activator Inhibitor-1 (PAI-1) is a multifunctional protein with the ability to not only regulate fibrinolysis through inhibition of plasminogen activation, but also cell signaling events which have direct downstream effects on cell function. Elevated plasma levels of this protein have been shown to have profound effects on the development and progression of cardiovascular diseases. However, results from a number of studies, especially those using PAI-1 deficient mouse models, have demonstrated that its function is ambiguous, with evidence of both preventing and enhancing various disease states. A number of lifestyle changes and pharmacological reagents have been identified that can regulate PAI-1 levels or function. Those reagents that target function are focused on its ability to regulate plasmin formation, and have been studied in in vivo models of thrombosis. Further investigations involving regulation of cell function could potentially resolve paradoxical issues associated with the function of this protein in regulating cardiovascular disease. PMID- 21707476 TI - Regulation of cell migration and invasion by specific modules of uPA: mechanistic insights and specific inhibitors. AB - Urokinase (uPA) is a 411 residues serine protease originally identified for its ability to activate plasminogen and generate plasmin, a broad-spectrum matrix- and fibrin-degrading enzyme. Later, this protease has been shown to possess also a clear-cut ability to stimulate cell migration and survival in a catalytic independent manner. This activity turned out to be exerted through the growth factor-like domain (GFD-like, residues 1-49) of the protease binding to a GPIanchored membrane receptor (uPAR), in complex with transmembrane receptors such as integrins, the epidermal growth factor and the formyl-peptide receptors. Direct binding of uPA to integrins through its kringle (residues 50-131) and connecting peptide (residues 132-158) regions results in enhanced migration. The dual function of uPA in promoting migration while reducing the physical resistance of extracellular matrix underlies its crucial role in the invasion of malignant tumours. Consolidated evidence emerging from animal models and clinical studies shows that the overexpression of uPA is a causal determinant to tumour metastasis and is associated to a poor prognosis. Therefore, pinpointing the molecular interactions and identifying novel agents to interfere with the diverse activities of uPA is a goal of basic and applied research. In this review, we discuss the general theme of cell migration and invasion. A description of the uPA structure-function relationship and the functional effects of isolated domains is presented. Current information on molecular agonistic as well as antagonistic compounds, including the compounds which have reached clinical trials, is provided. PMID- 21707477 TI - uPAR as anti-cancer target: evaluation of biomarker potential, histological localization, and antibody-based therapy. AB - Degradation of proteins in the extracellular matrix is crucial for the multistep process of cancer invasion and metastasis. Compelling evidence has demonstrated the urokinase receptor (uPAR) and its cognate ligand, the urokinase plasminogen activator (uPA), to play critical roles in the concerted action of several proteolytic systems in generation of a high proteolytic potential required for tissue remodeling processes. uPAR is additionally cleaved by uPA on the cell surface, liberating domain I, resulting in abrogated pericellular proteolysis. The expression of both uPAR and uPA is significantly up-regulated during cancer progression and is primarily confined to the tumor-associated stromal compartment. Furthermore, both uPAR and uPA have proven to be prognostic markers in several types of cancer; high levels indicating poor survival. The cleaved forms of uPAR are also prognostic markers, and a potential diagnostic and predictive impact of the different uPAR forms has been reported. Hence, pericellular proteolysis seems to be a suitable target for anti-cancer therapy and numerous approaches have been pursued. Targeting of this process may be achieved by preventing the binding of uPA to uPAR on the cell surface and/or by direct inhibition of the catalytic activity of uPA. Both strategies have been pursued and inhibition of these functions has shown effect in xenogenic cancer models. Pericellular proteolysis has also been inhibited in vivo in mouse models of wound healing and hepatic fibrinolysis using mouse monoclonal antibodies (mAbs) against mouse uPA or uPAR. These reagents will target uPA and uPAR in both stromal cells and cancer cells, and their therapeutic potential can now be assessed in syngenic mouse cancer models. PMID- 21707478 TI - Structural basis for therapeutic intervention of uPA/uPAR system. AB - Urokinase-type plasminogen activator (uPA) is one of the two physiological serine proteases responsible for the activation of plasminongen to plasmin. uPA activity is regulated by its inhibitors (PAI-1 and PAI-2) and its receptor (uPAR), and an expanding list of their interacting proteins. In addition to plasminogen activation, this system also plays important roles in the regulation of many cellular processes including cell proliferation, adhesion and migration. It is beyond reasonable doubt that this enzyme system plays a central role in tumor biology and represents a high potential target for therapeutic intervention of tumor growth and metastasis. During the past fifteen years, crystal structures of uPA and its inhibitors have facilitated the development of uPA inhibitors. Many crystal structures of proteins in the uPA/uPAR system have also been reported recently, especially a series of structures of uPAR and its complexes with vitronectin and uPA, facilitating the development and evaluation of uPAR inhibitors. Recent progress on uPA inhibitors will be summarized in this article. The unique structural features and the druggable potentials of these new structures will also be discussed. PMID- 21707479 TI - Rational targeting of the urokinase receptor (uPAR): development of antagonists and non-invasive imaging probes. AB - In the last two decades, the urokinase-type plasminogen activator receptor (uPAR) has been implicated in a number of human pathologies such as cancer, bacterial infections, and paroxysmal nocturnal hemoglobinuria. The primary function of this glycolipid-anchored receptor is to focalize uPA-mediated plasminogen activation at the cell surface, which is accomplished by its high-affinity interaction with the growth factor-like domain of uPA. Detailed insights into the molecular basis underlying the interactions between uPAR and its two bona fide ligands, uPA and vitronectin, have been obtained recently by X-ray crystallography and surface plasmon resonance studies. Importantly, these structural studies also define possible druggable target sites in uPAR for small molecules and provide guidelines for the development of reporter groups applicable for non-invasive molecular imaging of uPAR expression in vivo by positron emission tomography. In this review, we will discuss recent advances in our perception of the structure function relationships of uPAR ligation and how these may assist translational research in preclinical intervention studies of uPAR function. PMID- 21707480 TI - The plasminogen activation system in pathology: use in prognosis and therapy. PMID- 21707481 TI - Ceramide-based therapeutics for the treatment of cancer. AB - The bioactive sphingolipid, ceramide, has garnered major interest as a principle regulator of cellular stress, proliferation, senescence, and death. Of particular interest to cancer biologists and clinical oncologist, dysregulated ceramide metabolism has been documented in both solid and non-solid malignancies. Moreover, most anticancer chemotherapeutics stimulate ceramide accumulation through increased ceramide synthesis or through the inhibition of ceramide catabolism. In fact, neutralization of ceramide via glycosylation or phosphorylation in malignant cells has been linked to multidrug chemoresistance. New therapeutic strategies to overcome chemoresistance focus on increasing endogenous ceramide levels by stimulating ceramide synthesis, by inhibiting ceramide neutralization, or by the direct delivery of exogenous ceramide. This review will discuss new therapeutic strategies designed specifically to modulate ceramide metabolism, as well as nanoscale delivery systems engineered to selectively deliver ceramide to cancerous cells and tissues. PMID- 21707482 TI - Ceramide transfer protein and cancer. AB - Sphingolipids are important structural components of membranes, and play an equally important role in basic cellular processes as second messengers. Recently, sphingolipids are receiving increasing attention in cancer research. Ceramide is the central molecule that regulates sphingolipid metabolism forming the basic structural backbone of sphingolipids and the precursor of all complex sphingolipids. It is been proposed to be an important regulator of tumor cell death following exposure to stress stimuli. The increase or decrease of ceramide levels leading to change in sensitivity of cancer cells to stress stimuli provides support for a central role of ceramide signaling in cell death. In this review, we have focused on ceramide transfer protein (CERT) as a major regulator of ceramide flux in the cell. PMID- 21707483 TI - Sphingolipid metabolism and drug resistance in hematological malignancies. AB - Drug resistance represents a serious barrier to the successful treatment of hematological malignancies. In leukemias, resistance mechanisms that involve membrane-resident proteins belonging to the ABC (ATP-binding cassette) transporter protein family are of particular interest, wherein enhanced expression is often associated with poor prognosis and frequent in relapsed or refractory disease. These proteins reduce the intracellular concentration of antitumor agents, greatly diminishing clinical efficacy. Research in this area has been directed at the design of agents, "pump antagonists", to overcome the effluxing capacity of drug transporters; however, this direction has had limited clinical success. An allied function of ABC transporters like P-glycoprotein (P gp) is glycolipid trafficking, an area that has not been explored from a therapeutic standpoint. In this capacity, it turns out that glycolipid synthesis can be attenuated by pump antagonists; this is perhaps an adventitious property of P-gp. Recent research in the area of lipid metabolism, specifically ceramide and glycolipids, has provided insight into the function of glycosphingolipids in multidrug resistance and in the action of chemotherapy. This review is intended to bring together those aspects of glycosphingolipid metabolism that might be leveraged to enhance the therapeutic performance of ceramide and to discuss how ABC transporters like P-gp might be targeted to potentiate and magnify ceramide driven proapoptotic cascades. PMID- 21707484 TI - The gut-to-breast connection - interdependence of sterols and sphingolipids in multidrug resistance and breast cancer therapy. AB - Almost all classes of bioactive lipids such as cholesterol and cholesterol derivatives, phospholipids and lysophospholipids, eicosanoids, and sphingolipids are critically involved in tumorigenesis. However, a systematic analysis of the distinct tumorigenic functions of lipids is rare. As a general principle, lipids either act directly by binding to receptors and other cell signaling proteins in growth control, or indirectly by regulating membrane organization such as the formation of membrane microdomains (lipid rafts) that modulate receptor or other membrane protein function. Lipid rafts are known to be formed by cholesterol and the sphingolipids or ceramide derivatives sphingomyelin and glucosylceramide (cholesterol-sphingomyelin-glucosylceramide or CSG rafts). In this review, we discuss the interconnection of sphingolipids with cholesterol and its derivatives in breast cancer drug resistance. Bile acids are cholesterol derivatives that are first synthesized in the liver (primary bile acids) and then metabolized by intestinal bacteria giving rise to secondary bile acids. They activate farnesoid X receptor (FXR), which inhibits cholesterol conversion to primary bile acids and induces the expression of drug resistance proteins. We introduce a novel model by which bile acid-mediated activation of FXR may promote the formation of CSG lipid rafts that trans-activate drug resistance proteins in breast cancer. Since breast cancer stem cells express high levels of drug resistance proteins, our model predicts that serum bile acids promote breast cancer stem cell survival and metastasis. Our model also predicts that FXR antagonists in combination with sphingolipid biosynthesis inhibitors may be promising candidates for novel drugs in lipid therapy of breast cancer. PMID- 21707485 TI - Sphingolipid metabolism and leukemia: a potential for novel therapeutic approaches. AB - Since the discovery and initial characterizations of sphingolipids (SLs) in 1884, extensive research has established that these molecules not only are structural components of eukaryotic membranes but they are also critical bioactive lipids involved in fundamental cellular processes such as proliferation, differentiation, apoptosis, inflammation, migration, and autophagy. Altered SL metabolism has been observed in many pathological conditions including hematological malignancies. Thus, targeting the SL pathway to induce lipid changes to counteract specific pathologies is currently being pursued as a promising, novel therapeutic intervention. In this review, we discuss the general characteristics of the SL pathway, illustrating those features relevant to the understanding of the role of SLs in leukemia, and we address novel SL-targeting therapeutic approaches. PMID- 21707486 TI - Hypoxia-inducible factors and sphingosine 1-phosphate signaling. AB - Hypoxia, defined as reduced tissue oxygen concentration, is a characteristic of solid tumors and is an indicator of unfavorable diagnosis in patients. At the cellular level, the adaptation to hypoxia is under the control of two related transcription factors, HIF-1alpha and HIF-2alpha (Hypoxia-Inducible Factor), which activate expression of genes promoting angiogenesis, metastasis, increased tumor growth and resistance to treatments. A role for HIF-1alpha and HIF-2alpha is also emerging in hematologic malignancies such as lymphoma and l eukemia. Recent studies have identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway - which elicits various cellular processes including cell proliferation, cell survival or angiogenesis - as a new regulator of HIF-1alpha or HIF-2alpha activity. This review will consider how targeting the SphK1/S1P signaling could represent an attractive strategy for therapeutic intervention in cancer. PMID- 21707487 TI - Regulation of autophagy by sphingolipids. AB - Autophagy is an evolutionary conserved process by which cells recycle intracellular materials to maintain homeostasis in different cellular contexts. Under basal conditions it prevents accumulation of damaged proteins and organelles; during starvation, autophagy provides cells with sufficient nutrients to survive. Sphingolipids are a family of bioactive molecules modulating vital cellular functions such as apoptosis, cell cycle arrest or proliferation. Besides these functions, some sphingolipids like ceramide, sphingosine- 1-phosphate or gangliosides have been described to promote autophagy in several cancer cell lines. Current evidence supports the notion that induction of autophagic cell death can halt tumorigenesis. Of interest, some chemotherapeutic agents used for the treatment of hematological malignancies trigger the production of endogenous sphingolipids with pro-autophagic effects. In this review we describe the regulation and functions of the sphingolipid-induced autophagy and the tight relationship with the cancer cell response to current chemotherapeutic regimens. PMID- 21707488 TI - Ceramidases in hematological malignancies: senseless or neglected target? AB - Ceramidases are ubiquitous amidohydrolases that catalyze the cleavage of ceramides into sphingosine and fatty acids. This reaction exerts a cytoprotective role in physiological conditions, while altered ceramidase activities favour a number of human diseases. Among these diseases, several reports point to important roles of ceramidases, mainly the acid ceramidase, in the initiation and progression of cancer, and the response of tumors to radio- or chemotherapy. Multiple reports confirm the interest of acid ceramidase inhibitors as anticancer drugs, either alone or in combination with other therapies. Sphingolipid metabolism plays a role in hematological malignancies and appears as an interesting target for therapeutic intervention. Although the use of ceramidase inhibitors in chemotherapy of hematologic cancers has not been widely investigated, a number of indirect evidence suggest that inhibition of specific ceramidases could potentiate the effect of drugs in clinical use to treat hematologic malignancies and may afford strategies to combat relapses. The arsenal of ceramidase inhibitors so far available is wide and hopefully, upcoming research will assess the feasibility of this approach. PMID- 21707489 TI - S1P regulation of macrophage functions in the context of cancer. AB - The sphingolipid sphingosine-1-phosphate (S1P) is an important regulator of immune cell functions in vivo. Besides recruiting lymphocytes to blood and lymph, it may promote immune cell survival and proliferation, but also interferes with their activation. Hereby, S1P may act as an intracellular second messenger or cofactor or, upon being secreted from cells, may bind to and activate a family of specific G-protein-coupled receptors (S1PR1-5). Extracellular versus intracellular S1P hereby might trigger synergistic/identical or fundamentally distinct responses. Furthermore, engagement of different S1PRs is connected to different functional outcome. This complexity is exemplified by the influence of S1P on the inflammatory potential of macrophages, shaping their role in inflammatory pathologies such as atherosclerosis and cancer. Here, we summarize the recent progress in understanding the impact of S1P signaling in macrophage biology, discuss its impact in solid as well as 'wet' tumors and elaborate potential options to interfere with S1P signaling in the context of cancer. PMID- 21707491 TI - Regulation of sphingosine kinase in hematological malignancies and other cancers. AB - The sphingolipids ceramide, sphingosine and sphingosine 1-phosphate have emerged as important signaling molecules that regulate a number of important cellular processes. Sphingosine 1-phosphate enhances cell survival and proliferation, and also regulates angiogenesis, cell invasion, and differentiation via both its cell surface G protein-coupled receptors and recently identified intracellular effectors. In contrast, ceramide and sphingosine elicit growth arrest and apoptosis through direct modulation of a number of intracellular targets. The cellular balance of these sphingolipids contributes to the determination of cell fate, and it is now clear that disruption in this 'sphingolipid rheostat' contributes to the development, progression and chemotherapeutic resistance of both hematological malignancies and solid tumors. The sphingosine kinases are central regulators of this pathway since they not only increase sphingosine 1 phosphate and assist in reduction of ceramide and sphingosine, but are also regulated at multiple levels by external stimuli. Thus, targeting the regulation of the sphingosine kinases may be a viable therapeutic strategy for a diverse array of cancers. Here, we describe the current knowledge of sphingosine kinase regulation, effects of current and potential chemotherapeutic agents on this system, and discuss the implications of this for the treatment of hematological malignancies and other cancers. PMID- 21707490 TI - Targeting sphingosine-1-phosphate receptors in cancer. AB - Sphingosine 1-phosphate (S1P) is a bioactive lipid with diverse biological functions, including cell proliferation, differentiation, angiogenesis, chemotaxis, and migration. Many of the activities of S1P are mediated through five closely related G-protein-coupled receptors of the sphingosine-1-phosphate receptor family (S1PR) which play a crucial role in sphingolipid metabolism. Each of these receptors appears to be tissue specific and to have demonstrated roles in the regulation of cell proliferation and survival in various cancer types. Further analysis of the function that S1PRs serve in hematological malignancies offers a great potential for the discovery of novel and selective therapeutic agents targeting these receptors. This review focuses on the characterization of S1PRs and their roles in cancer development in various signaling pathways mediated through specific G coupled protein. In particular, pharmacological agents targeting these S1PRs will be discussed and their potential will be examined. PMID- 21707492 TI - Targeting sphingosine-1-phosphate in hematologic malignancies. AB - Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that regulates several processes important for hematologic cancer progression. S1P is generated by two sphingosine kinases, SphK1 and SphK2, and is exported outside the cell, where it activates specific cell surface S1P G-protein coupled receptors in autocrine/paracrine manner, coined "inside-out signaling". In this review, we highlight the importance of SphK1 and inside-out signaling by S1P in hematologic malignancy. We also summarize the results of studies targeting the SphK1/S1P/S1P receptor axis and the effects of the S1P receptor modulator, FTY720, in hematologic malignancy. PMID- 21707494 TI - The rationale of targeting neutrophils with dapsone during glioblastoma treatment. AB - Data from past research is presented showing that neutrophils are active participants in new vessel formation in normal physiology, in proliferating human endometrium, in non-cancer pathologies as in the pannus of rheumatoid arthritis, and in various cancers, among them glioblastoma. These data show that interleukin 8 (IL-8) is a major chemokine attracting neutrophil infiltrates in these states. Since the old anti-Hansen's disease drug dapsone inhibits neutrophil migration along an IL-8 gradient towards increasing concentrations, and is used therapeutically for this attribute to good effect in dermatitis herpetiformis, bullous pemphigoid and rheumatoid arthritis, we suggest dapsone may deprive glioblastoma of neutrophil-mediated growth promoting effects. We review past research showing that vascular endothelial growth factor, VEGF, is carried predominantly intracellularly within neutrophils--only 2% of circulating VEGF is found free in serum. Based on the available evidence summarized by the authors, dapsone has a strong theoretical potential to become a useful anti-VEGF, anti angiogenic agent in glioblastoma treatment. PMID- 21707495 TI - Erlotinib in glioblastoma: lost in translation? AB - Glioblastoma represents the most common primary brain tumor in adults. Despite improvements of multimodal therapy, the prognosis of this disease remains unfavorable. Thus, great efforts have been made to identify therapeutic agents directed against those specific molecular targets whose presence was shown to be associated with worse clinical outcomes. The epidermal growth factor receptor (HER1/EGFR) has been identified as one such target, and different compounds were developed to inhibit HER1/EGFR and/ or its mutant form, EGFRvIII. However, clinical trials did not confirm the initial enthusiasm conveyed by promising results from experimental studies. Therefore, a therapeutic approach directed at inhibiting solely HER1/EGFR does not seem to translate into a clinical benefit. This review discusses the current therapeutic situation in the setting of glioblastoma while putting the spotlight on erlotinib, a HER1/EGFR-targeted small molecule tyrosine kinase inhibitor. PMID- 21707496 TI - Clinical development of experimental virus-mediated gene therapy for malignant glioma. AB - Advances in medical and surgical treatments in the last decades have resulted in quantum leaps in the overall survival of patients with many types of malignant disease, while survival of patients with malignant gliomas (WHO histological grades 3 and 4) has been only moderately improved. Maximum surgical resection, external fractionated radiotherapy, and oral chemotherapy during and after irradiation currently represent the pillars of malignant glioma therapy. Novel and experimental modalities aimed at a more selective and more effective treatment are however being increasingly developed and tested in clinical studies. Improved understanding of the fundamental mechanisms of glioma growth, resistance, and recurrence has resulted in the introduction of biologically and molecularly targeted therapies such as virus-mediated gene therapy, often in combination with spatially defined delivery methods specifically designed to be used in the local environment of the brain, such as convection-enhanced delivery. This review summarizes the key findings of the most important phase I and II clinical studies employing gene therapy with naturally occurring or genetically modified non-replicating or conditionally replicating (oncolytic) viruses, such as retrovirus, adenovirus, herpes-simplex-virus, Newcastle disease virus, or reovirus, in patients with primary or recurrent malignant gliomas. In addition, the two phase III gene therapy studies carried out to date in glioma patients and employing retrovirus or adenovirus vectors are presented in detail and critically discussed. Areas of necessary improvements and possible future developments of viruses and delivery methods are outlined. PMID- 21707493 TI - Sphingolipid signaling and hematopoietic malignancies: to the rheostat and beyond. AB - Sphingosine-1-phosphate (S1P) is a bioactive lipid with diverse functions including the promotion of cell survival, proliferation and migration, as well as the regulation of angiogenesis, inflammation, immunity, vascular permeability and nuclear mechanisms that control gene transcription. S1P is derived from metabolism of ceramide, which itself has diverse and generally growth-inhibitory effects through its impact on downstream targets involved in regulation of apoptosis, senescence and cell cycle progression. Regulation of ceramide, S1P and the biochemical steps that modulate the balance and interconversion of these two lipids are major determinants of cell fate, a concept referred to as the "sphingolipid rheostat." There is abundant evidence that the sphingolipid rheostat plays a role in the origination, progression and drug resistance patterns of hematopoietic malignancies. The pathway has also been exploited to circumvent the problem of chemotherapy resistance in leukemia and lymphoma. Given the broad effects of sphingolipids, targeting multiple steps in the metabolic pathway may provide possible therapeutic avenues. However, new observations have revealed that sphingolipid signaling effects are more complex than previously recognized, requiring a revision of the sphingolipid rheostat model. Here, we summarize recent insights regarding the sphingolipid metabolic pathway and its role in hematopoietic malignancies. PMID- 21707498 TI - Targeting betaIII-tubulin in glioblastoma multiforme: from cell biology and histopathology to cancer therapeutics. AB - Glioblastoma multiforme (GBM) is the most common, aggressive, and chemorefractory brain tumor in human adults. Notwithstanding significant discoveries in the elucidation of pathways of molecular signaling and genetics of GBM during the past 20 years there has been no breakthrough in the pharmacological treatment of this high-grade malignancy. We, and others, have previously demonstrated increased expression of betaIII-tubulin in GBM asserting a link between aberrant expression of this beta-tubulin isotype and a disruption of microtubule dynamics associated either with malignant tumor development de novo, or with progression and malignant transformation of a low-grade glioma into GBM. This article reviews betaIII-tubulin as a promising target in the experimental treatment of GBM and examines the potential use of epothilones, a new family of anticancer agents shown to be active in betaIII-tubulin-expressing tumor cells, as well as the "double hit" therapeutic concept of tumor cell sensitization to tubulin binding agents (TBAs) by betaIII-tubulin silencing. The latest progress regarding the function and potential role of betaIII-tubulin in aggressive tumor behavior, cancer stem cells, tumor cell hypoxia, and resistance to taxane-related compounds, is also critically appraised. PMID- 21707497 TI - Targeted toxins for glioblastoma multiforme: pre-clinical studies and clinical implementation. AB - Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. GBM is very aggressive due to its poor cellular differentiation and invasiveness, which makes complete surgical resection virtually impossible. Therefore, GBM's invasive nature as well as its intrinsic resistance to current treatment modalities makes it a unique therapeutic challenge. Extensive examination of human GBM specimens has uncovered that these tumors overexpress a variety of receptors that are virtually absent in the surrounding non-neoplastic brain. Human GBMs overexpress receptors for cytokines, growth factors, ephrins, urokinase-type plasminogen activator (uPA), and transferrin, which can be targeted with high specificity by linking their ligands with highly cytotoxic molecules, such as Diptheria toxin and Pseudomonas exotoxin A. We review the preclinical development and clinical translation of targeted toxins for GBM. In view of the clinical experience, we conclude that although these are very promising therapeutic modalities for GBM patients, efforts should be focused on improving the delivery systems utilized in order to achieve better distribution of the immuno-toxins in the tumor/resection cavity. Delivery of targeted toxins using viral vectors would also benefit enormously from improved strategies for local delivery. PMID- 21707499 TI - Angiogenesis in glioblastoma multiforme: navigating the maze. AB - Blood vessel formation is a fundamental process that occurs during both normal and pathologic periods of tissue growth. In aggressive malignancies such as glioblastoma multiforme (GBM), vascularization is often excessive and facilitates tumor progression. In an attempt to maintain tumors in a state of quiescence, multiple anti-angiogenic agents have been developed. Although several angiogenesis inhibitors have produced enhanced clinical benefits in GBM, many of these pharmacologic agents result in transitory initial response phases followed by evasive tumor resistance. Thus, a significant need exists for the discovery of novel and effective anti-angiogenic therapies. The development of new molecular targeted therapeutic strategies is often complicated by the complexity of angiogenic signal transduction. Due to the labyrinthine nature of these signaling pathways, increased production of other angiogenic factors may compensate for the inhibition of key vascular targets like vascular endothelial growth factor (VEGF). Such compensatory mechanisms facilitate vascularization and allow tumor growth to proceed even in the presence of anti-angiogenic agents. This review presents the challenges of targeting the intricate vascular network of GBM and discusses the clinical implications for recent advancements in targeted anti angiogenic drug therapy. PMID- 21707500 TI - Therapeutic strategies to target multiple kinases in glioblastoma. AB - Glioblastoma (GBM), the most common primary brain tumor in adults, is one of the most aggressive human cancers associated with high mortality. Standard treatments following diagnosis include surgical resection, radiotherapy and adjunctive chemotherapy. However, almost all patients develop disease progression following this multimodal therapy. Recent understanding in genomic and molecular abnormalities in GBM has shifted the treatment paradigm towards using molecularly targeted agents. One of the most prominent targets in cancer treatment is kinases, which can be commonly targeted by small molecule inhibitors or monoclonal antibodies. Despite the initial enthusiasm in exploring kinase inhibitors for GBM, first-generation kinase inhibitors that selectively disrupt single kinases have failed to demonstrate clinical benefit in most patients with GBM. Mechanisms of resistance may include genetic heterogeneity with cross-talk and coactivation of multiple signaling pathways, upregulation of alternative signaling cascades, limited drug delivery and existence of highly-resistant cellular subpopulations such as cancer stem cells. One strategy to circumvent this challenge is to target multiple kinases by multitargeted kinase inhibitors or combinations of single targeted kinase inhibitors, both of which have been evaluated in clinical trials for GBM. PMID- 21707501 TI - Nucleic acid-based therapeutics for glioblastoma. AB - Nucleic acid based therapeutics offer the possibility of tailor-made treatment of malignant diseases. For recurrent glioblastoma multiforme (GBM), the most aggressive type of brain tumor, no accepted treatment exists, making therapeutically active nucleic acids a viable option. In this review, current preclinical and clinical studies harnessing the potential of antitumoral nucleic acids for GBM treatment will be considered. These include gene therapy to over express antitumoral gene products, RNA interference to knock down components that promote tumor progression, and the tumor-targeted delivery of antitumoral double stranded RNA. Vectors applied in GBM for the delivery of nucleic acids will be discussed. These include non-replicating and replicating (oncolytic) viruses, as well as non-viral delivery vectors based on polycations or cationic lipids. PMID- 21707502 TI - Natural products: promising resources for cancer drug discovery. AB - Natural products are important sources of anti-cancer lead molecules. Many successful anti-cancer drugs are natural products or their analogues. Many more are under clinical trials. The present review focuses on chemopreventive and anti cancer activities of polar and non-polar extracts, semi purified fractions and pure molecules from terrestrial plants of India reported between 2005 and 2010 emphasizing possible mechanisms of action of pure molecules. PMID- 21707503 TI - Targeting cancer using fragment based drug discovery. AB - Over the past decade, fragment-based drug discovery has developed significantly and has gained increasing popularity in the pharmaceutical industry as a powerful alternative and complement to traditional high-throughput screening approaches for hit identification. Fragment-based methods are capable of rapidly identifying starting points for structure-based drug design from relatively small libraries of low molecular weight compounds. The main constraints are the need for sensitive methods that can reliably detect the typically weak interactions between fragments and the target protein, and strategies for transforming fragments into higher molecular weight drug candidates. This approach has recently been validated as series of compounds from various programs have entered clinical trials. PMID- 21707505 TI - Atypical GTPases as drug targets. AB - The Ras GTPases are the founding members of large Ras superfamily, which constitutes more than 150 of these important class of enzymes. These GTPases function as GDP-GTP-regulated binary switches that control many fundamental cellular processes. There are a number of GTPases that have been identified recently, which do not confine to this prototype termed as "atypical GTPases" but have proved to play a remarkable role in vital cellular functions. In this review, we provide an overview of the crucial physiological functions mediated by RGK and Centaurin class of multi domain atypical GTPases. Moreover, the recently available atypical GTPase structures of the two families, regulation, physiological functions and their critical roles in various diseases will be discussed. In summary, this review will highlight the emerging atypical GTPase family which allows us to understand novel regulatory mechanisms and thus providing new avenues for drug discovery programs. PMID- 21707504 TI - Selective activation of intracellular signalling pathways in dendritic cells for cancer immunotherapy. AB - One of the major challenges in achieving effective anti-cancer immunotherapy is to counteract immunological tolerance. Most tumor-associated antigens (TAAs) are sensed as self. Hence, naturally occurring tolerance towards them has to be overcome. Fortunately, there is increasing evidence that anti-tumor immune responses occur and play a crucial role in the success of well-established anti neoplastic therapies such as radiotherapy and chemotherapy. In fact, their effectiveness relies on signalling by pattern recognition receptors such as Toll like receptors (TLRs). TLR signal transduction involves activation of a few well known pathways, of which nuclear factor kappaB (NF-kappaB) and mitogen activated protein kinases (MAPKs) are possibly the best characterized. Therefore, constitutive activation of these pathways in immune cells can potentially enhance anti-tumor immunity, especially when targeted to professional antigen presenting cells (APCs) such as dendritic cells (DCs). Several strategies have been devised to test this hypothesis, including constitutive activation of TLRs, NF-kappaB and MAPKs (extracellular-signal regulated kinase (ERK), p38 and c-Jun kinase 1 (JNK1)). Activation of these pathways in mouse and human DCs has differential effects in immunogenicity and in many cases, enhanced antitumor immunity in pre clinical models, establishing the basis for future clinical applications. PMID- 21707506 TI - Impact of oncogenic protein tyrosine phosphatases in cancer. AB - Protein tyrosine phosphatases (PTPs) constitute a large family of enzymes that can exert both positive and negative effects on signaling pathways. They play dominant roles in setting the levels of intracellular phosphorylation downstream of many receptors including receptor tyrosine kinases and G protein-coupled receptors. As observed with kinases, deregulation of PTP activity can also contribute to cancer. This review will examine a broad array of PTP family members that positively affect oncogenesis in human cancer tissues. We will describe the PTP family, their biological significance in oncology, and how recent progress is being made to more effectively target specific PTPs. Finally, we will discuss the therapeutic implications of targeting these oncogenic PTPs in cancer. PMID- 21707507 TI - Coordinated expression of Pax-5 and FAK1 in metastasis. AB - The Pax-5 gene encodes a B-cell-specific activator protein (BSAP) that plays a key role in B lymphocyte differentiation and embryogenesis. The deregulation of this transcription factor is also linked to B cell malignancies and recently to other cancers. More specifically, the downstream effects of Pax-5 promote cell cell interactions and mediate the activation of adhesion genes which result in an epithelial phenotypic behavior of human carcinoma cells. To gain a better understanding of Pax-5-mediated gene regulation, we studied available gene expression data in depth and identified several Pax-5 downstream targets. Among these, we found that Pax-5 activity is consistently inversely correlated with the expression of Focal Adhesion Kinase 1 (FAK1). FAK1 is known to enhance migration of cancer cells and promote metastatic dissemination to distant sites. Further analysis looking at genome wide profiling of Pax-5 DNAbinding points to both direct and indirect regulation of FAK1 expression by Pax-5 and its downstream targets. These findings suggest a key role for Pax-5 in phenotypic transitioning during metastasis through the regulation of FAK1 activity. PMID- 21707508 TI - Cell contact/adhesion proteins Lgl and DFak56: tumorigenic and whole-organism vital effects studied in Drosophila. AB - Drosophila modeling can be effectively used for comprehensive and refined analysis of tumorigenesis, including the discovery of therapeutic anti-cancer drugs and their testing [1]. The Drosophila lgl gene was the first animal tumor suppressor found and the first tumor-associated gene encoding cytoplasmic protein. We compared the gene ontology of two cancer associated cytoplasmic proteins, Lgl and DFak56 (ortholog of human focal adhesion kinase, FAK). On the molecular level, both Lgl and FAK are involved in protein binding and the formation of macromolecular complexes mediated by phosphorylation in specific sites. On the cellular level, Lgl and FAK participate in cytoskeletal structure/dynamics, cell/ESM and cell to cell adhesion, and cell/tissue polarity. The biological processes of both genes comprise protein transport, cell signaling, cell motility and proliferation. Surprisingly, we found that diverse lgl*- null variants are widespread in lgl*-/lgl+ haplozygotic state in distant populations. To address this paradox, we found that under permanent thermal stress the developmental viability and the life span of lgl*-/lgl+ heterozygotes increased compared to the control flies. The stress-protective haplo-adaptive effect was maternally mediated and sex-specific, as males are more sensitive. The exposure of virgin haplozygotic females with one functional lgl allele to pulse thermal stress at successive stages of oogenesis showed that the germ line - early oocyte stage appeared most sensitive. Pulse heating of this stage in the parental females with one lgl dose resulted in a transgenerational haplo-adaptive effect on the viability and life span of the next generation animals. These data are important for a comprehensive knowledge of cancer-associated gene effects and evaluation of the aftermath of cancer therapy. PMID- 21707509 TI - FAK and WNT signaling: the meeting of two pathways in cancer and development. AB - Recent studies connect the FAK and Wnt/beta-catenin signaling pathways, both which promote cancer when aberrantly activated in mammalian cells. Over stimulation of either Wnt/beta-catenin or FAK activities was independently shown to promote numerous types of human cancers, including colon, breast, prostate and ovary. Observations in different model systems suggest a complex and dynamic cross-talk between these two pathways. During early vertebrate development, FAK protein is required for the proper regulation of Wnt/beta- catenin signaling that controls pattern formation in the developing nervous system. In Xenopus laevis embryos, FAK protein depletion eliminated Wnt3a gene expression in the neural plate. In mouse osteoclast cells, mechanical stimulation through FAK activation stabilized beta-catenin protein to promote its nuclear translocation. In contrast, in the mouse intestine, FAK activity was induced downstream of Wnt to promote intestinal regeneration and was also essential for tumorigenesis in an APC deletion model of colorectal cancer. Adding to this complexity, in human cell lines, FAK induced a context-dependent modulation of Wnt signaling to activate target-gene expression. Other diseases are also associated with FAK and Wnt pathway over-activation. Increased FAK and Wnt pathway activities were independently implicated in idiopathic pulmonary fibrosis (IPF), a lung disease of unknown etiology. Revealing the FAK-Wnt connection in IPF could provide a better understanding of disease pathology. There appear to be multiple interactions between the Wnt/beta-catenin and FAK signaling pathways in different cell types and organisms. Mutual FAK-Wnt pathway regulation could be a general phenomenon, having many still undetermined roles in either normal physiological or disease processes. PMID- 21707510 TI - A novel small molecule inhibitor of FAK and IGF-1R protein interactions decreases growth of human esophageal carcinoma. AB - INTRODUCTION: Esophageal cancer remains an aggressive disease with poor survival rates. FAK and IGF-1R are two important tyrosine kinases important for cell survival signaling and found to be upregulated in esophageal cancer. Our hypothesis is that a novel small molecule compound that disrupts FAK and IGF-1R protein-protein interactions (PPIs) would decrease the growth of human esophageal cancer. METHODS: The compound INT2-31 (NSC344553) was identified from a virtual high throughput screen to bind to FAK and disrupt PPIs. The in vitro effects of this compound, +/- 5-FU chemotherapy, on cell signaling, viability and apoptosis in human esophageal cancer cells (KYSE 70, 140) and a direct esophageal cancer xenograft was evaluated. RESULTS: INT2-31 caused a disruption of PPIs between FAK and IGF-1R starting at a concentration of 1MUM. It also caused a dose dependent inhibition of cell viability and induction of apoptosis at low micromolar doses. These effects were associated with decreased AKT and ERK1/ERK2 phosphorylation. INT2-31 treatment, when administered via IP injection, at 50mg/kg, resulted in an in vivo decrease in tumor growth in a direct xenograft. Furthermore, treatment with 5-FU chemotherapy combined with INT2-31 resulted in a synergistic increase in apoptosis and decrease in tumor growth compared to 5-FU or INT2-31 alone. CONCLUSIONS: A novel compound that disrupts the PPIs of FAK and IGF-1R results in decreased tumor proliferation and increased apoptosis. These effects appear to be mediated through downregulation of p-AKT and p-ERK. This compound deserves further study as a novel treatment strategy in patients with esophageal cancer. PMID- 21707511 TI - Ceramide and apoptosis: exploring the enigmatic connections between sphingolipid metabolism and programmed cell death. AB - Programmed cell death, or apoptosis, is a complex process whereby eukaryotic cells react to physiologic or pathophysiologic stimuli by undergoing genetically programmed suicide. Programmed cell death involves many well-characterized signaling pathways including permeabilization of the mitochondrial outer membrane and activation of caspases. Other pathways, such as pro-apoptotic lipid signaling, are less understood despite many years of study. The sphingolipid ceramide has received considerable attention as a key regulator of programmed cell death, yet the mechanisms of its up-regulation and ability to control cell fate remain ill-defined. In this review, we will examine the connections between sphingolipid metabolism and programmed cell death with a focus on the role of de novo sphingolipid synthesis and sphingosine salvage in producing pro-apoptotic ceramide. We will also highlight the evidence supporting an increasingly complex role for ceramide in regulating apoptosis and provide a framework in which to ask new questions about the functions of this enigmatic lipid. PMID- 21707512 TI - Current prospective of aldose reductase inhibition in the therapy of allergic airway inflammation in asthma. AB - The prevalence of asthma and costs of its care have been continuously increasing, but novel therapeutic options to treat this inflammatory disease have not been brought to the US market. Current therapies such as inhaled steroids, long-acting beta-agonist bronchodilators, antihistamines and immunomodulators may control the symptoms of allergic asthma but fail to modify the underlying disease. Excessive use of steroids and other immunosuppresents alter the patient's quality of life, produce undesirable toxicities, and increase the risk of other pathologies such as diabetes. Hence novel therapeutic options to manage asthma are desirable. In the present review, we have discussed the role of the polyol pathway enzyme aldose reductase (AR) in the amplification of allergic airway inflammation. Recent studies have indicated that AR inhibition prevents the NF-kappaB-dependent generation of pro-inflammatory cytokines and chemokines in mouse models of allergic airway inflammation indicating the potential use of AR inhibition as a novel tool to control allergic responses. Since orally available AR inhibitors have already undergone phase III clinical trials for diabetic neuropathy and appear to have a manageable side effects profile, they could be readily developed as potential new drugs for the treatment of asthma and related complications. PMID- 21707513 TI - Bimolecular fluorescence complementation: illuminating cellular protein interactions. AB - Many cellular processes depend on the establishment of selective stable or transient interactions between proteins. Therefore, the ability to identify and characterize these contacts in physiologically relevant environments is crucial to understanding the networks of contacts that allow the transmission and integration of biological information in living cells. Protein-fragment complementation assays (PCA) have emerged as approaches that report on the proximity of two given proteins in the cell at a given location and time. In particular, bimolecular fluorescence complementation (BIFC) allows noninvasive imaging of protein binding in living cells at high spatial resolution and without the requirement for exogenous substrates. In the present review, we discuss PCA and BIFC fundamentals, the implementation of BIFC assays and selected applications of BIFC in drug discovery, developmental studies or neurological disorders. PMID- 21707514 TI - Alpha fetoprotein is more than a hepatocellular cancer biomarker: from spontaneous immune response in cancer patients to the development of an AFP-based cancer vaccine. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, with a poor prognosis and limited therapeutic options. Due to its overexpression in the majority of HCCs, alpha-fetoprotein (AFP) represents one of the most useful markers for hepatocarcinomas and for monitoring patients' response to therapy. Although it was earlier reported that AFP has immunosuppressive properties, it has been recently demonstrated that AFP induces spontaneous T and B cells responses in HCC patients. The characterization of AFP-immunogenic epitopes gives the opportunity to design AFP-based cancer vaccines for human HCC. The activity of AFP-based vaccines has been investigated in HCC mouse models in order to develop novel strategies to treat patients with HCC. This review will discuss the rationale for using the AFP-based vaccination strategy and recent results corroborating the usefulness of AFP vaccines as a potential tool for cancer therapy. PMID- 21707516 TI - Senescent phenotype of trabecular meshwork cells displays biomarkers in primary open-angle glaucoma. AB - Glaucoma is a major cause of irreversible blindness, affecting more than 70 million individuals worldwide. Elevated intraocular pressure (IOP) is a major risk factor in the development of glaucoma and in the progression of glaucomatous damage. High IOP usually occurs as a result of an increase in aqueous humor outflow resistance in trabecular meshwork (TM). Primary open angle glaucoma (POAG) is characterized by quantifiable parameters including the IOP, the aqueous outflow facility, and geometric measurements of the optic disc and visual defects. Morphological and biochemical analyses of the TM of POAG patients revealed loss of cells, increased accumulation of extracellular matrix (ECM), changes in the cytoskeleton, cellular senescence and the process of subclinical inflammation. Various biochemical and molecular biology biomarkers of TM cells senescence are considered in the article. Oxidative stress is becoming an important factor more likely to be involved in the pathogenesis of POAG. Treatment of TM cells with oxidative stress induced POAG-typical changes like ECM accumulation, cell death, disarrangement of the cytoskeleton, advanced senescence and the release of inflammatory markers. Oxidative stress is able to induce characteristic glaucomatous TM changes and these oxidative stress-induced TM changes can be minimized by the use of antioxidants, such as carnosine-related analogues and IOP-lowering substances. There is evidence demonstrating that carnosine related analogues may have antioxidative capacities, can prevent cellular senescence and the attrition of telomeres during the action of oxidative stress. Prevention of oxidative stress exposure to the TM with N-acetylcarnosine ophthalmic prodrug of carnosine and oral formulation of non-hydrolized carnosine may help to reduce the progression of POAG. The previous work has demonstrated that carnosine is able to reach the TM directly via the transcorneal and systemic pathways of administration with N-acetylcarnosine ophthalmic prodrug and oral formulation of non-hydrolized carnosine. We suggest in this article that dual therapy with N-acetylcarnosine lubricant eye drops, oral formulation of non hydrolized carnosine combined with anti-glaucoma adrenergic drug may become the first-line therapy in glaucoma due to their efficiency in reducing IOP, prevention and reversal of oxidative stress-induced damages in TM and the low rate of severe side effects during combined treatment. PMID- 21707515 TI - Resistance to chemotherapy and molecularly targeted therapies: rationale for combination therapy in malignant melanoma. AB - Metastatic melanoma is one of the most intractable tumors, with all current regimens showing limited survival impact. Failure of most agents is attributed to development of therapy resistance. Accumulated evidence points to the apoptotic defect of melanoma cells and the surge of survival signals stimulated by cytotoxic drugs, as a way that tumors circumvent cytotoxic chemotherapy. An overview of inhibitors developed against these growth/survival factors, which are potential partners to be combined with systemic chemotherapy, will be discussed. The escape mechanism from molecular inhibitors also suggests a "vertical" or "horizontal" combination of molecularly targeted therapies. A better understanding of the interactions between simultaneously used regimens and of the rationale for combination therapy will provide new insights to improve survival and quality of life in patients with advanced melanoma. PMID- 21707518 TI - Roles of metalloproteases in metastatic niche. AB - Metalloproteinases (MMPs) are a cluster of at least 23 enzymes belonging to the more wide family of endopeptidases called Metzincins, whose structure is characterized by the presence of a zinc ion at the catalytic site. Although the general view of MMPs as physiologic scissors involved in extracellular matrix (ECM) degradation and tissue remodeling is still valid, additional functions have recently emerged, including the ability to cleave non ECM molecules such as growth factors, cytokines and chemokines from their membrane-anchored proforms. These functions are utilized by tumor cells and are fundamental in the determination of tumor progression and invasion. The effect of MMPs activity in cancer progression has been traditionally associated with the acquisition by tumor cells of an invasive phenotype, an indispensable requisite for the metastatic spreading of cancer cells. In addition to the traditional view, a new role for MMPs in creating a favourable microenvironment has been proposed, so that MMPs are not only involved in cell invasion, but also in signaling pathways that control cell growth, inflammation, or angiogenesis. Finally, recent evidence suggest a role of MMPs in the so called "pre-metastatic niche" that is the hypothesis of an early distant modification of the premetastatic site by primary cancer cells. This new hypothesis is changing our traditional view about MMPs and provides important insights into the effective time window for the therapeutic use of MMP inhibitors. In this review we provide the main available data about the ability of MMPs in creating a suitable microenvironment for tumor growth in metastatic sites and we indicate the implication of these data on the potential use of MMP inhibitors in the metastatic therapy. PMID- 21707517 TI - Prostacyclin receptor regulation--from transcription to trafficking. AB - The prostacyclin receptor (IP--International Union of Pharmacology nomenclature) is a member of the seven transmembrane G-protein coupled receptor (GPCR) superfamily. Recent concerns with selective and non-selective COX-1/COX-2 inhibition have exposed an important cardioprotective role for IP in preventing atherothrombosis. Receptor dysfunction (genetic variants) or reduced signaling (COX-2 inhibition) in high cardiovascular risk patients leads to increased cardiovascular events. These clinical observations have also been confirmed genetically by mouse knockout studies. Thus, receptor regulation is paramount in ensuring correct function in the prevention of atherothrombosis. This review summarizes recent literature on how this important receptor is regulated, from transcription to transport (to and from the membrane surface). These regulatory processes are critical in ensuring that IP receptors are adequately expressed and functional on the cell surface. PMID- 21707519 TI - Improved prediction of protein ligand-binding sites using random forests. AB - This article describes a novel method for predicting ligand-binding sites of proteins. This method uses only 8 structural properties as input vector to train 9 random forest classifiers which are combined to predict binding residues. These predicted binding residues are then clustered into some predicted ligand-binding sites. According to our measurement criterion, this method achieved a success rate of 0.914 in the bound state dataset and 0.800 in the unbound state dataset, which are better than three other methods: Q-SiteFinder, SCREEN and Morita's method. It indicates that the proposed method here is successful for predicting ligand-binding sites. PMID- 21707520 TI - Alternative nucleophilic residues in intein catalysis of protein splicing. AB - Protein-splicing inteins are widespread in nature and have found many applications in protein research and engineering. The mechanism of protein splicing typically requires a nucleophilic amino acid residue at both position 1 (first residue of intein) and position +1 (first residue after intein), however it was not clear whether or how the three different nucleophilic residues (Cys, Ser, and Thr) would work differently at these two positions. To use intein in a target protein of interest, one needs to choose an intein insertion site to have a nucleophilic residue at position +1, therefore it is desirable to know what nucleophilic residue(s) are preferred by different inteins. In this study we began with a statistical analysis of known inteins, which showed an unequal distribution of the three nucleophilic residues at positions 1 and +1, and then subjected six different mini-inteins to site-directed mutagenesis to systematically test the functionality of the three nucleophilic residues at the two positions. At position 1, most natural inteins had Cys and none had Thr. When the Cys at position 1 of the six inteins was mutated to Ser and Thr, the splicing activity was abolished in all except one case. At position +1, Cys and Ser were nearly equally abundant in natural inteins, and they were found to be functionally interchangeable in the six inteins of this study. When the two positions were studied as 1/+1 combination, the Cys/Ser combination was abundant in natural inteins, whereas the Ser/Cys combination was conspicuously absent. Similarly, all of the six inteins of this study spliced with the Cys/Ser combination, whereas none spliced with the Ser/Cys combination. These findings have interesting implications on the mechanism of splicing and the selection of intein insertion sites, and they also produced two rare mini-inteins that could splice with Thr at position +1. PMID- 21707521 TI - Plasmin: its role in the extracellular processing of progalanin in tumor tissue. AB - Galanin is a neuropeptide that is widely distributed in the central and peripheral nervous systems. In a previous study, we showed that a small cell lung carcinoma (SCLC) cell line, SBC-3A, released progalanin but not galanin, and that progalanin was then converted to galanin(1-20), the active form. Because the galanin(1-20) had undergone hydrolysis at Arg and Lys residues, the protease concerned was surmised to have a trypsin-like activity. The present study was performed to identify the trypsin-like protease which had previously been found to activate progalanin in this tumor tissue. The protease was isolated using chromatography and electrophoresis, and identified in tumor extracts from SBC-3A tumor-bearing mice; the major protease was found to be plasmin. We next confirmed that extracellular processing of progalanin occurs in SCLC tumor tissue (tumors produced by the implantation of SBC-3A cells into mice), and in two types of breast tumor tissue (obtained by implantation into mice of BT-549 and MDA-MB-436 cells). In cell culture, processed forms of progalanin were undetectable in SBC 3A, BT-549 or MDA-MB-436 cells. Conversely, gel filtration chromatography analysis of tumor extracts from SBC-3A, BT-549 and MDA-MB-436-bearing mice, revealed that galanin-like immunoreactivity (galanin-LI) in these tumor extracts was due to the presence of progalanin (14 kDa) and galanin(1-20) (2 kDa). Moreover, trypsin-like protease activity was elevated, and plasmin was expressed abundantly in SBC-3A, BT-549 and MDA-MB-436 tumors in mice. In addition, tranexamic acid, a plasmin inhibitor, inhibited progalanin conversion to galanin(1-20). The present study revealed that plasmin was present in tumor tissue, and that it was responsible for processing progalanin to galanin(1-20) in the extracellular environment. PMID- 21707522 TI - Prevention of aggregation and autocatalysis for sustaining biological activity of recombinant BoNT/A-LC upon long-term storage. AB - Protein aggregation during expression, purification, storage, or transfer into requisite assay buffers hampers the use of proteins for in vitro studies. The formation of these aggregates represents a major obstacle in the study of biological activity and also restricts the spectrum of protein products being available for the biomedical applications. The catalytic light chain of botulinum neurotoxin type A undergoes autocatalysis and aggregation after purification upon long-term storage and freeze-thawing. In present study the conditions for the high level expression and purification of biologically active light chain protein of botulinum neurotoxin were optimized from a synthetic gene. Several co-solvents were screened in order to prevent autocatalysis and aggregation of rBoNT/A-LC. The effect of the co-solvents is studied on endopeptidase activity during long term storage of the recombinant protein. The purified rBoNT/A-LC was also evaluated for its immunogenicity. PMID- 21707523 TI - A new lectin from the tuberous rhizome of Kaempferia rotunda: isolation, characterization, antibacterial and antiproliferative activities. AB - A lectin (designated as KRL) was purified from the extracts of Kaempferia rotunda Linn. tuberous rhizome by glucose-sepharose affinity chromatography. KRL was determined to be a 29.0 +/- 1.0 kDa polypeptide by SDS-PAGE under both reducing and non-reducing conditions. KRL was a divalent ion dependent glycoprotein with 4% neutral sugar which agglutinated different groups of human blood cells. Methyl alpha-D-mannopyranoside, D-mannose and methyl-alpha-D-glucopyranoside were the most potent inhibitors. N-terminal sequence of KRL showed similarity to some mannose/ glucose specific lectins but the main differences with their molecular masses and sugar content. KRL lost its activity markedly in the presence of denaturants and exhibited high agglutination activity from pH 6.0 to 8.2 and temperature 30 to 60 degrees C. The lectin showed toxicity against brine shrimp nauplii with the LC50 value of 18 +/- 6 ug/ml and strong agglutination activity against seven pathogenic bacteria. KRL inhibited the growth of six bacteria partially and did not show antifungal activity. In addition, antiproliferative activity against Ehrlich ascites carcinoma (EAC) cells showed 51% and 67% inhibition in vivo in mice administered 1.25 mg/kg/day and 2.5 mg/kg/day of KRL respectively by injection for five days. PMID- 21707524 TI - A catalytically inactive Lys49 PLA2 isoform from Bothrops jararacussu venom that stimulates insulin secretion in pancreatic beta cells. AB - A new secretory phospholipase A2 (sPLA2) isoform from Bothrops jararacussu venom (BjVIII) has been characterized by causing platelet aggregation, an absent activity in BthTx-I, Prtx-I and PrTx-II sPLA2s. According to our results, BjVIII also enhances insulin release by the pancreatic beta cells. The complete amino acid sequence of the new isoform was determined by Edman degradation and de novo peptide sequencing. These analyses showed a G35K amino acid modification for BjVIII in comparison with BthTx-I, PrTx-I and Prtx-II, a structural difference that has been related to the conflicting biological activities among BjVIII and other Lys49 sPLA2s. The whole set of evidences collected in this work indicates that, besides the C-terminal region and B-wing of PLA2, the calcium binding loop in BjVIII should be considered as an important region, involved in the pharmacological effects of Lys49-sPLA2 isoforms from the Bothrops genus. PMID- 21707525 TI - Thermodynamic and kinetic destabilization of triosephosphate isomerase resulting from the mutation of conserved and non-conserved cysteines. AB - Several variants of Saccharomyces cerevisiae triosephosphate isomerase (yTIM) were studied to determine how mutations of conserved and non-conserved Cys residues affect the enzyme. Wild-type yTIM has two buried free cysteines: Cys 41 (non-conserved) and the invariant Cys 126. Single-site mutants, containing substitutions of these cysteines with Ala, Val, or Ser (the three most conservative changes for a buried Cys, according to substitution matrices), were examined for stability and enzymatic activity. Neither of the Cys residues was found to be essential for enzyme catalysis. Determination of the global stability of the mutants indicated that, regardless of which Cys was substituted, individual Cys->Ala and Cys->Val mutations, as well as the C41S substitution, all decrease the unfolding free energy of the dimeric protein by less than 23 kJ mol( 1) (at 37 degrees C, pH 7.4), as compared to the wild-type enzyme. In contrast, a substantially larger destabilization (37 kJ mol(-1)) was found in the C126S mutant. These results suggest that, with the exception of C126S, all of these mutations can be regarded as neutral (i.e., mutations that do not impair the reproductive success of the organism). Accordingly, Cys 126 has remained invariant across evolution because its neutral substitutions by Ala or Val would require a highly unlikely, concerted double mutation at any of the Cys codons. Furthermore, detrimental effects to a cell expressing the C126S TIM mutant more likely arise from the high unfolding rate of this enzyme. PMID- 21707526 TI - Bioengineering RNA silencing across the life kingdoms. AB - RNA silencing negatively regulates gene expression at transcriptional and posttranscriptional levels, guided by small RNA molecules. It modulates core regulatory pathways across the eukaryotes, such as developmental processes or stress responses. The widespread existence of this phenomenon and the key pathways regulated have led to the development of a new technology based on the modification of gene expression, which has been applied successfully in different areas such as medicine or agriculture. Here we review the most important patents related to RNA silencing across the life kingdoms, including biotechnological applications into medicine, crop science and bioengineering. PMID- 21707527 TI - Heterotrophic cultivation of microalgae for production of biodiesel. AB - High cell density cultivation of microalgae via heterotrophic growth mechanism could effectively address the issues of low productivity and operational constraints presently affecting the solar driven biodiesel production. This paper reviews the progress made so far in the development of commercial-scale heterotrophic microalgae cultivation processes. The review also discusses on patentable concepts and innovations disclosed in the past four years with regards to new approaches to microalgal cultivation technique, improvisation on the process flow designs to economically produced biodiesel and genetic manipulation to confer desirable traits leading to much valued high lipid-bearing microalgae strains. PMID- 21707528 TI - Pre-clinical and clinical aspects of peptide-based vaccine against human solid tumors. AB - Peptides deriving from tumor-associated antigens and recognized by patient T cells have been firstly defined in the early 90's, and then used as vaccine in animal models and in cancer patients. Early trials showed a variable, often even high frequency of patients developing peptide-specific T-cell mediated immune response usually accompanied by a lower frequency of clinical response. Modified, long peptides could be synthesized with a higher in vitro binding to the corresponding HLA allele that only seldom translated into a clear improvement in the tumor response. However, we show here that more recent studies of multipeptide-based vaccines resulted in a higher and more robust T cell response causing also a more effective clinical response particularly in melanoma and prostate cancer patients. In this article, we also used some of the recent patents describing different inventions related to pre-clinical and clinical aspects of peptide based vaccines against human solid tumors. PMID- 21707529 TI - Antineoplastic potential of medicinal plants. AB - Cancer is one of the most dreaded diseases worldwide and the incidence is on the rise in both developing and developed countries. It is treated by chemotherapy, radiotherapy and surgery. In spite of advances in treatment strategies, cancer still remains a major cause of death. Research is on for development of better drugs which are more effective and simultaneously cause fewer side effects. Plants have been used for the treatment of various ailments of man and animals since ages. They are being screened extensively to explore the possibility of development of economically viable anticancer drugs. Natural products of plant origin currently constitute a considerable proportion of commercially available antineoplastic drugs. This review gives an insight into commercially available anticancer drugs of plant origin and also patents granted to plant derived components, extracts and polyherbal formulations possessing anticancer activity. The exhaustive work reviewed here on antineoplastic activity of various plants both in vitro and experimental models throughout the world will help design further research in this field. PMID- 21707530 TI - The emerging role of sunitinib in the treatment of advanced epithelial thyroid cancer: our experience and review of literature. AB - Tyrosine kinase receptors have been shown to play an important role in epithelial thyroid tumor growth and angiogenesis. Thyroid cancers commonly present oncogene mutations involved in MAPK kinase pathway like BRAF and RET; they are also frequently dependent on VEGF stimuli. Preliminary clinical experiences suggest a promising role of sunitinib (a tyrosine kinase inhibitor) for the treatment of advanced thyroid cancers. This review deals with the available data on the effect of sunitinib in the treatment of metastatic, radioiodine refractory thyroid cancers. We also report our experience with the off-label use of sunitinib in such patients. PMID- 21707531 TI - The use of erythropoietin and its derivatives to treat spinal cord injury. AB - Spinal Cord Injury (SCI) is a complex process which leads to destruction of neuronal tissue and also vascular structure. After SCI many potentially toxic substances are activated and released into the injury site causing secondary degeneration. Erythropoietin (EPO) is a possible therapeutic strategy to treat SCI. Over the last decade attention has been focused on the molecular mechanisms underlying its neuroprotective effects. A major concern expressed by clinicians is that besides its protective effects, EPO also demonstrates hematopoietic activity and increases the risk for thrombosis after the administration of multiple doses of this glycoprotein. Recently, tissue protective functions of EPO have been separated from its hematopoietic actions leading to the development of EPO derivatives and mimetics. Neuroscientists are focusing on recombinant human EPO (rhEPO) and its non-erythropoietic derivatives, investigating their anti apoptotic potential and anti-inflammatory function as well as their role in restoring vascular integrity. Carbamylated erythropoietin (CEPO) and asialo erythropoietin (AsialoEPO) are structural derivatives of EPO that have no effect on erythrocyte mass whereas they retained its neuroprotective effects. In this review article, we provide a short overview of the animal studies on rhEPO and its derivatives in experimental models of SCI. Both the efficacy and the safety profile of EPO-structural and functional variants are still to be demonstrated in patients. Further clinical studies should reveal whether derivatives and variants of erythropoietin provide any benefits over the use of rhEPO in the treatment of spinal cord injury observed in the experimental studies. PMID- 21707532 TI - Farnesoid X receptor agonist for the treatment of liver and metabolic disorders: focus on 6-ethyl-CDCA. AB - 6-ethyl-chedeoxycholic acid (6E-CDCA) is a farnesoid X receptor (FXR) ligand endowed with agonistic activity under development for treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) and liver-related metabolic disorders including non-alcoholic fatty liver disease (NAFLD) and non alcoholic steatohepatitis (NASH). FXR is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps of bile acid uptake, metabolism and excretion. 6E-CDCA has been investigated in preclinical models of cholestasis, liver fibrosis and diet-induced atherosclerosis. In a phase II clinical trial in patients with PBC, 6E-CDCA met the primary endpoint of a reduction in alkaline phosphatase levels but safety data indicated that the drug exacerbated pruritus, one of the main symptoms of PBC, suggesting that 6E-CDCA or FXR are mediators of pruritus in humans. Treatment of patients with diabetes and liver steatosis resulted in amelioration of insulin sensitivity despite a reduction a slight reduction in HDL and increased levels of LDL were observed. These side effects on bile acids and lipid metabolism were all predicted by pre clinical studies, suggesting that potent FXR ligands hold promise but potential side effects might limit their development. PMID- 21707533 TI - Effects of galantamine in Alzheimer's disease: double-blind withdrawal studies evaluating sustained versus interrupted treatment. AB - To evaluate the effects of galantamine withdrawal, and compare this with uninterrupted therapy, two 6-week double-blind withdrawal studies (Studies 1 and 2) were performed. These enrolled individuals who had completed one of two 3- or 5-month randomized clinical trials (parent trials) involving patients with mild to moderate Alzheimer's disease (AD). In Study 1 (GAL-USA-11; n'723), patients continuously treated with galantamine 16 mg/day exhibited a mean (+/- standard error [SE]) improvement in 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale score of 1.8 (+/- 0.46) points at Week 6 compared with the parent trial baseline, (p < 0.001 vs placebo; observed cases analysis). Over the same period, patients switched from galantamine to placebo and those who had received continuous placebo, exhibited mean (+/- SE) deteriorations of 0.7 (+/- 0.49) and 1.2 (+/- 0.49) points, respectively. Similar trends were apparent in Study 2 (GAL-USA-5; n=118). In Study 1, subgroup analyses demonstrated cognitive benefits with continuing galantamine treatment and deterioration associated with galantamine withdrawal in patients with advanced moderate AD (baseline Mini Mental State Examination score <=14) and in individuals deemed non-responsive in terms of Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus) evaluation at the end of the parent trial (CIBIC-plus score > 4). No safety issues were identified. In patients with mild to moderate AD who have exhibited cognitive benefits from up to 5 months' galantamine treatment, continuing therapy reinforces previously achieved benefit, whereas in patients in whom galantamine is discontinued, although no safety concerns arise, the natural progression of AD is apparent. PMID- 21707534 TI - Igf-I signaling in response to hyperglycemia and the development of diabetic complications. AB - IGF-I is structurally related to proinsulin and when administered to human subjects it enhances insulin sensitivity. However because of its growth promoting properties and its relationship to growth hormone, it has been proposed as a etiologic factor in the development of diabetic complications. This review discusses recently published data regarding the ability of hyperglycemia to sensitize cells that are capable of dedifferentiating to the growth promoting effects of IGF-I. Under normoglycemic conditions vascular smooth muscle and endothelial cells are cystostatic and stimulation of the IGF-I receptor activates the adaptor protein IRS-1 which leads to PI-3 kinase pathway activation. Following exposure to hyperglycemia these cell types undergo a signaling switch whereby an entirely different mechanism is utilized to activate both the PI-3 kinase and the MAP pathways. This leads to increased cell proliferation and migration. This molecular mechanism involves the coordinate regulation of signaling molecules and scaffolding proteins. Activation of this alternative signaling mechanism is directly linked to the stimulation of pathophysiologic processes that are involved in the pathogenesis of both diabetic retinopathy and atherosclerosis. Inhibition of activation of these intermediates has been shown to attenuate glucose induced pathophysiologic changes and results in the inhibition of both atherosclerotic lesion progression and diabetic retinopathy. In summary, hyperglycemia induces a signaling switch in vascular endothelial and smooth muscle cells that results in enhanced sensitivity to the growth promoting effects of IGF-I. This may be an important variable for determining the progression of atherosclerosis in poorly controlled diabetes and in the development of retinopathy. PMID- 21707535 TI - Optimized native gel systems for separation of thylakoid protein complexes: novel super- and mega-complexes. AB - Gel-based analysis of thylakoid membrane protein complexes represents a valuable tool to monitor the dynamics of the photosynthetic machinery. Native-PAGE preserves the components and often also the conformation of the protein complexes, thus enabling the analysis of their subunit composition. Nevertheless, the literature and practical experimentation in the field sometimes raise confusion owing to a great variety of native-PAGE and thylakoid-solubilization systems. In the present paper, we describe optimized methods for separation of higher plant thylakoid membrane protein complexes by native-PAGE addressing particularly: (i) the use of detergent; (ii) the use of solubilization buffer; and (iii) the gel electrophoresis method. Special attention is paid to separation of high-molecular-mass thylakoid membrane super- and mega-complexes from Arabidopsis thaliana leaves. Several novel super- and mega-complexes including PS (photosystem) I, PSII and LHCs (light-harvesting complexes) in various combinations are reported. PMID- 21707536 TI - Dock/Nck facilitates PTP61F/PTP1B regulation of insulin signalling. AB - PTP1B (protein tyrosine phosphatase 1B) is a negative regulator of IR (insulin receptor) activation and glucose homoeostasis, but the precise molecular mechanisms governing PTP1B substrate selectivity and the regulation of insulin signalling remain unclear. In the present study we have taken advantage of Drosophila as a model organism to establish the role of the SH3 (Src homology 3)/SH2 adaptor protein Dock (Dreadlocks) and its mammalian counterpart Nck in IR regulation by PTPs. We demonstrate that the PTP1B orthologue PTP61F dephosphorylates the Drosophila IR in S2 cells in vitro and attenuates IR-induced eye overgrowth in vivo. Our studies indicate that Dock forms a stable complex with PTP61F and that Dock/PTP61F associate with the IR in response to insulin. We report that Dock is required for effective IR dephosphorylation and inactivation by PTP61F in vitro and in vivo. Furthermore, we demonstrate that Nck interacts with PTP1B and that the Nck/PTP1B complex inducibly associates with the IR for the attenuation of IR activation in mammalian cells. Our studies reveal for the first time that the adaptor protein Dock/Nck attenuates insulin signalling by recruiting PTP61F/PTP1B to its substrate, the IR. PMID- 21707537 TI - A new HLA-C*07 variant allele, C*07:108, identified by sequence-based typing. AB - The new HLA-C*07:108 differs from C*07:01:01 by two transversions in exon 3. PMID- 21707538 TI - One amino acid change located in the conserved region of the alpha 1 domain specifies the novel HLA-C*07:147 allele. AB - The novel HLA-C allele HLA-C*07:147 contains one nucleotide substitution in exon 2 leading to an amino acid change in the alpha 1 domain from phenylalanine to leucine. PMID- 21707539 TI - A novel HLA allele derived from a likely DRB1/DRB3 gene conversion event: HLA DRB3*01:15. AB - A novel HLA allele, DRB3*01:15, was likely derived via cis-gene conversion. PMID- 21707540 TI - A novel HLA-DQB1*03:02 variant designated DQB1*03:02:05. AB - The new DQB1*03:02:05 differs from DQB1*03:02:01 by two nucleotide exchanges in exon 2. PMID- 21707541 TI - Sequencing of a single HLA-B genotype including two rare alleles allows the detection of a new allele, B*44:130. AB - The novel HLA-B*44:130 allele was found in a Spanish donor. B*44:130 differs from B*44:40 by four nucleotide changes at codons 11, 12 and 24, producing three amino acid replacements, 11A>S, 12M>V and 24T>S. PMID- 21707542 TI - Characterization of the genomic full-length sequence of C*04:03 and C*04:06 in Chinese Han individuals. AB - The genomic full-length sequences of C*04:03 and C*04:06 were first identified by cloning and sequencing. PMID- 21707543 TI - Identification of a novel HLA-B*13:41 allele in a Chinese bone marrow donor. AB - Nucleotide sequence of HLA-B*13:41 allele was different from that of B*13:02:01 at position 538 C>T and 539 T>G, resulting in an amino acid from Leu to Trp at codon 156. PMID- 21707544 TI - Identification of a novel HLA-B allele, B*35:01:25, by sequence-based typing in a Korean individual. AB - The new allele B*35:01:25 showed a single nucleotide substitution compared with B*35:01:01 at codon 238 (GAT/GAC). PMID- 21707545 TI - A novel HLA-B*48 allele, B*48:01:03, identified by sequence-based typing. AB - A new allele HLA-B*48:01:03 showed one nucleotide difference with B*48:01:01 at codon 269 (CCC->CCT). PMID- 21707546 TI - Sequence-based HLA high-resolution typing of a bone marrow donor/recipient pair shows the novel HLA allele DQB1*06:43. AB - The novel HLA-DQB1*06:43 allele differs from HLA-DQB1*06:01:01 in one nucleotide substitution at codon 73 in exon 2. PMID- 21707547 TI - Identification of a new HLA-DRB1* 14 allele, DRB1*14:99, by HLA typing of an Asian individual. AB - We report the new HLA-DRB1*14:99 allele differing from DRB1*14:01:01 by one nucleotide in exon 2. PMID- 21707548 TI - Efficacy and safety of perioperative pregabalin for post-operative pain: a meta analysis of randomized-controlled trials. AB - We calculated in a meta-analysis the effect size for the reduction of post operative pain and post-operative analgesic drugs, which can be obtained by the perioperative administration of pregabalin. Three end-points of efficacy were analysed: early (6 h-7 days) post-operative pain at rest (17 studies) and during movement (seven studies), and the amount of analgesic drugs in the studies that obtained identical results for pain at rest (12 studies). Reported adverse effects were also analysed. The daily dose of pregabalin ranged from 50 to 750 mg/day. The duration of treatment in patients assessed for pain ranged from a single administration to 2 weeks. Pregabalin administration reduced the amount of post-operative analgesic drugs (30.8% of non-overlapping values - odds ratio=0.43). There was no effect with 150, and 300 or 600 mg/day provided identical results. Pregabalin increased the risk of dizziness or light-headedness and of visual disturbances, and decreased the occurrence of post-operative nausea and vomiting (PONV) in patients who did not receive anti-PONV prophylaxis. The administration of pregabalin during a short perioperative period provides additional analgesia in the short term, but at the cost of additional adverse effects. The lowest effective dose was 225-300 mg/day. PMID- 21707549 TI - Unlocking the locked in; a need for team approach in rehabilitation of survivors with locked-in syndrome. AB - OBJECTIVES: A stroke that affects the medulla oblongata and/or pons can result in tetra pareses and paralysis of the lower cranial nerves while other parts of the brain remain intact, thus locking the person in. The incidence and prevalence is not known. The aim of this article is to communicate the need for and benefits of a comprehensive rehabilitation and a standardized way of approaching the locked in person. MATERIAL AND METHODS: To illustrate the rehabilitation process, we present four cases to highlight the needs of the person and what is required of the team. RESULTS: Communication at arrival: three persons communicated through eye movement, one by weak voice. At follow-up (1-6 years later): computer assisted communication was used by two persons, a letter board by one and 'ordinary communication' by one. CONCLUSIONS: There is a need for follow-up not only to re-assess skills and needs partly owing to new technologies but also to see whether the person needs more assistance to adapt to the alternative means of communication or whether the carers of the person need extra information about communication. We conclude that the low incidence of the syndrome necessitates a skilled team in which different professionals can together assess the person. This probably requires some centralization. PMID- 21707550 TI - Myelin glycosphingolipid immunoreactivity and CSF levels in multiple sclerosis. AB - OBJECTIVES: Patients with multiple sclerosis were reported to harbour antibodies not only against proteins and glycoproteins but also against glycolipids, including sulfatide and galactosylceramide (GalCer), the two major glycosphingolipids of myelin. However, previous results were inconsistent concerning glycosphingolipid levels, antibody type, dominance of serum or Cerebrospinal fluid compartments and relationship to the multiple sclerosis (MS) course. RESULTS: We hereby report that the cerebrospinal fluid levels of sulfatide were increased in patients with MS (n = 46) compared with controls (n = 50, P < 0.001). In addition, patients had higher serum IgM anti-glycosphingolipid titres than controls (P = 0.03 for sulfatide, <0.001 for GalCer), while the anti glycosphingolipid IgM antibodies in the cerebrospinal fluid were essentially normal. However, in seven of 46 patients cerebrospinal fluid IgG antibodies against GalCer (P = 0.004) could be detected, which was not found in any of the control individuals, and this finding might mirror the occurrence of more specific B-cell clones behind the blood-brain barrier. CONCLUSIONS: The IgM immunoreactivity in serum did not show any relationship to the type of course or severity of MS, arguing against a phenomenon secondary to myelin damage. Thus, the IgM antibody findings are compatible with an early antigen challenge or autoimmunity associated with natural antibodies. PMID- 21707551 TI - Clinical heterogeneity in Parkinson's disease revisited: a latent profile analysis. AB - OBJECTIVE: The heterogeneity of Parkinson's disease (PD) is increasingly recognized, and several attempts have been made to subclassify subjects on clinical or cognitive features. We explored the utility of latent profile analysis (LPA) as a means of classifying patients with PD on clinical features and test validity of these subclasses against neuropsychological data. METHODS: LPA utilizing clinical variables while controlling for age was applied to a cohort of 71 outpatients with PD. The resultant subgroups were validated via comparison to 30 control subjects on neuropsychological tests of executive, memory, and visuospatial functions. RESULTS: The LPA resulted in a three-class solution identifying a 'younger onset, mild motor impairment group', a 'moderate motor impairment group', and an 'old onset, fast progression group'. The groups were distinguishable on cognitive variables with the 'younger onset mild motor impairment subgroup' displaying deficits pertaining verbal acquisition, visuospatial construction, and set maintenance. The 'moderate motor impairment group' exhibited widespread cognitive impairment, and the 'old onset, fast disease progression group' had extensive cognitive impairment but outperformed the former group on verbal acquisition and visuospatial function. CONCLUSION: LPA holds promise in PD research as it uncovered three PD subtypes distinguished by motor symptoms and disease progression and validated by cognitive variables. PMID- 21707552 TI - Effects of the abrupt switch from solution to modified-release granule formulation of valproate. AB - BACKGROUND: A new modified-release (MR) granule formulation of valproate (VPA) has been recently developed for the treatment of children with epilepsy. It consists of tasteless microspheres that can be sprinkled on soft foods and easily swallowed. There are no data on the effectiveness of this formulation in pediatric age. AIM OF THE STUDY: To evaluate the effects of the abrupt switch from solution to VPA MR granules in children undergoing chronic treatment. METHODS: We enrolled children receiving VPA solution as sole or adjunctive therapy and switched them to MR granules at identical dosages. VPA blood level, treatment efficacy (clinical and EEG data), tolerability (adverse reactions), palatability, ease of administration, and compliance were evaluated before switching (T0) and after 4 weeks (T1). RESULTS: Out of 112 enrolled children, 108 (96.4%) completed the evaluation. We observed no significant differences between the patients at T0 and T1 in VPA blood levels, treatment efficacy, tolerability, and compliance. MR granules were judged more palatable (P < 0.05) and easier to administer (P < 0.05) than solution by children and parents. At 6-month follow up, all patients continued to use MR granules. CONCLUSION: Modified-release granule formulation of VPA may be a reliable alternative to solution for its convenience of use. PMID- 21707553 TI - Learning curve and pitfalls of a laparoscopic score to describe peritoneal carcinosis in advanced ovarian cancer. AB - OBJECTIVE: To prospectively estimate the agreement between a fellow in training in gynecologic oncology and a senior surgeon performing a laparoscopic score to describe peritoneal carcinosis diffusion in patients with advanced ovarian cancer. DESIGN: Single-institutional non-inferiority trial. SETTING: University hospital tertiary care center. POPULATION: Ninety consecutive patients with primary advanced ovarian cancer. METHODS: The patients underwent staging laparoscopy by a fellow in gynecologic oncology and a senior surgeon, sequentially and blindly. Single laparoscopic parameters (omental cake, peritoneal and diaphragmatic carcinosis, mesenteric retraction, bowel stomach infiltration, superficial liver metastasis) and a comprehensive laparoscopic score (PIV) were assessed in each procedure and registered. MAIN OUTCOME MEASURES: No differences in the score discriminating performance for predicting optimal cytoreduction were observed between fellows' and seniors' evaluations. RESULTS: The median number of staging laparoscopies performed by each fellow was 30 (range 28-32). The median score was 6 (0-10) for the fellows and 6 (0-14) for senior surgeons (p=ns). Results were superimposable in 57 of 90 patients (63.3%). Dividing the study period into two blocks, cases 1-45 and cases 46-90, differences were equally distributed over time (16.6 vs. 20%; p=0.9). The area under the curve of the receiver operating characteristic (ROC) curves for the score of fellows and seniors was 0.86 and 0.89, respectively (p=ns). CONCLUSIONS: The laparoscopic assessment of peritoneal cancer diffusion according to a laparoscopic score can reliably be carried out by a fellow in gynecologic oncology after 12 months' experience without significant differences from a senior surgeon's assessment. PMID- 21707554 TI - Evaluation of the discrepancy between pH and lactate in combined fetal scalp blood sampling. AB - OBJECTIVE: To evaluate the rate of discrepancy between pH and lactate values in fetal blood sampling (FBS). To evaluate differences in obstetric management in response to combined tests (pH and lactate) and single tests (pH or lactate). DESIGN: Descriptive study. SETTING: Uppsala University Hospital, Sweden. POPULATION: Labors monitored by FBS during one year (n=241). METHODS: Discrepancy in the combined tests was defined as a test having one abnormal and one normal value. Abnormal pH was defined as 7.24 or lower and abnormal lactate as 4.2 or higher. The results were categorized according to whether the test was normal or abnormal and according to whether it was a combined or single analysis. MAIN OUTCOME MEASURES: Discrepancy between pH and lactate values in combined tests. Frequency of operative delivery for fetal distress (ODFD). Time interval from the last FBS to ODFD. RESULTS: In the combined tests with abnormality, a discrepancy between pH and lactate values occurred in 55%. The mean time interval from the last FBS to ODFD was longer in combined tests with one abnormal compared with two abnormal test results, 75 vs. 37 minutes (p<0.05). Operative delivery for fetal distress was performed less often after combined tests than after single tests: 41/62 (66%) vs. 19/20 (95%) (p<0.05). CONCLUSION: In the combined test, discrepancies were common and occurred in half of the samples with an abnormality. Obstetric management was influenced by the discrepancy between test results with respect to ODFD rates and the time interval from the last FBS to delivery. PMID- 21707555 TI - Medication prescribed to people with personality disorder: the influence of patient factors and treatment setting. AB - OBJECTIVE: To examine the extent of use and clinical rationale for the prescribing of psychotropic drugs for people with personality disorder (PD) who are in contact with mental health services. METHOD: Clinical records of 278 patients with a primary diagnosis of PD were examined. RESULTS: Just over 80% (N = 225) of patients were being prescribed psychotropic medication. One in five was prescribed three or more drugs. People with comorbid mental disorders were more likely to receive psychotropic medication. Half those prescribed antidepressants had no record of depression in their records. While drug treatments were mostly prescribed for depressive and psychotic symptoms, they were also used to try to manage behavioural problems such as self-harm or given in response to patient requests for treatment. People receiving specialist PD services (OR = 0.35, 95% CI = 0.13-0.95) or other specialist services (OR = 0.24, 95% CI = 0.10-0.60) were less likely to be prescribed drug treatments. CONCLUSION: Drug treatments are widely used for people with PD despite the relatively weak evidence base. Both the type of personality problem and the context in which treatment is delivered appear to have an impact on whether drug treatments are prescribed. PMID- 21707557 TI - Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study. AB - OBJECTIVES: To determine whether the use of medications with possible and definite anticholinergic activity increases the risk of cognitive impairment and mortality in older people and whether risk is cumulative. DESIGN: A 2-year longitudinal study of participants enrolled in the Medical Research Council Cognitive Function and Ageing Study between 1991 and 1993. SETTING: Community dwelling and institutionalized participants. PARTICIPANTS: Thirteen thousand four participants aged 65 and older. MEASUREMENTS: Baseline use of possible or definite anticholinergics determined according to the Anticholinergic Cognitive Burden Scale and cognition determined using the Mini-Mental State Examination (MMSE). The main outcome measure was decline in the MMSE score at 2 years. RESULTS: At baseline, 47% of the population used a medication with possible anticholinergic properties, and 4% used a drug with definite anticholinergic properties. After adjusting for age, sex, educational level, social class, number of nonanticholinergic medications, number of comorbid health conditions, and cognitive performance at baseline, use of medication with definite anticholinergic effects was associated with a 0.33-point greater decline in MMSE score (95% confidence interval (CI)=0.03-0.64, P=.03) than not taking anticholinergics, whereas the use of possible anticholinergics at baseline was not associated with further decline (0.02, 95% CI=-0.14-0.11, P=.79). Two-year mortality was greater for those taking definite (OR=1.68; 95% CI=1.30-2.16; P<.001) and possible (OR=1.56; 95% CI=1.36-1.79; P<.001) anticholinergics. CONCLUSION: The use of medications with anticholinergic activity increases the cumulative risk of cognitive impairment and mortality. PMID- 21707558 TI - Test-retest reliability of the oxygen uptake efficiency slope in surgical patients. AB - The oxygen uptake efficiency slope is a measure of cardiopulmonary fitness, that can be obtained from a sub-maximal cardiopulmonary exercise test. It has been evaluated in medical patients but its reliability in surgical populations remains uncertain. We conducted a test-retest study with the aim of establishing the reliability of the oxygen uptake efficiency slope in relation to that of the anaerobic threshold and peak oxygen uptake, in general surgical patients. Twenty six patients over 60 years old completed two symptom-limited, incremental cycle ergometry tests within 7 days. The mean (SD) anaerobic threshold was 13.0 (3.0) mlO(2) .kg(-1) .min(-1) . There were no significant differences between mean test and retest values of anaerobic threshold (p = 0.50), peak oxygen uptake (p = 0.76) or oxygen uptake efficiency slope (p = 0.42). Reliability coefficients (95% CI) for the anaerobic threshold, oxygen uptake efficiency slope and peak oxygen uptake were 66.7% (45.3-87.9%), 89.0% (81.0-96.9%) and 91.7% (85.7-97.8%), respectively. The oxygen uptake efficiency slope was determined easily in all patients and found to have excellent reliability. Its clinical utility in determining pre-operative fitness warrants further evaluation. PMID- 21707559 TI - Comparison of the manoeuvrability and ease of use of the Ambu aScope and Olympus re-usable fibrescope in a manikin. AB - In this study, we compared the manoeuvrability and ease of use of the single-use Ambu aScope and Olympus re-usable fibrescope in a manikin set to simulate difficult fibrescope placement. A total of 75 anaesthetists took part in this randomised crossover non-inferiority study. We recorded the time to task completion, tip surface collision count and participants' impression of ease of use. For the Ambu aScope and Olympus fibrescope, the mean (SD) first attempt time to task completion was 63 (31) s and 53 (23) s, respectively (95% CI of the difference 3-17 s), p = 0.008. This rejected the null hypothesis of a difference of > 30 s. The mean (SD) number of tip surface collisions was 2.7 (1.9) and 2.5 (1.8), respectively, (95% CI of the difference -0.4 to 0.7) p = 0.56. However, the participants found the Olympus easier to use (p < 0.001). Mean (SD) visual analogue scores for the perceived ease of use (0 mm = extremely difficult and 100 mm = extremely easy) were 65 (18) mm and 77 (14) mm for the Ambu aScope and Olympus scopes, respectively. This study found that the single-use Ambu aScope is as easy to manoeuvre as the Olympus re-usable fibrescope. This single-use device appears to be an acceptable alternative to the re-usable fibrescope. PMID- 21707560 TI - Addition of clonidine to a continuous patient-controlled epidural infusion of low concentration levobupivacaine plus sufentanil in primiparous women during labour. AB - We studied the potentiation of analgesia for labour by the addition of clonidine to epidural low-concentration levobupivacaine with sufentanil in a randomised, double-blinded study. We enrolled primiparous women who were in spontaneous labour. The study solutions, made of 100 ml levobupivacaine 0.0625% plus sufentanil 0.45 MUg.ml(-1) and either 150 MUg clonidine or no clonidine, were used for induction of analgesia, and for its maintenance with self-administered boluses and a continuous background infusion. The need for additional epidural boluses during labour was lower and analgesia and maternal satisfaction were better in the clonidine (n = 57) than in the control group (n = 58). Blood pressure was lower and the rate of instrumental delivery higher in the clonidine group. Clonidine (1.36 MUg.ml(-1)) added to the epidural solution of low concentration levobupivacaine improves the quality of analgesia. The relevance of the haemodynamic effects should be explored in larger validation studies. PMID- 21707561 TI - Evaluation of systolic murmurs using transthoracic echocardiography by anaesthetic trainees. AB - Focused transthoracic echocardiography by anaesthetists in the peri-operative period has recently been described; the data suggest that the specific skills required can be obtained by non cardiology physicians with limited training. Aortic stenosis is known to increase significantly the peri-operative risk in non cardiac surgery. This study aimed to assess the ability of echocardiography naive trainee anaesthetists to recognise and assess the severity of aortic stenosis after a set amount of training. Five trainees underwent 2 h of didactic and hands on teaching in evaluation of the aortic valve, after which they scanned 20 patients each. Their results were compared with those obtained by an experienced cardiac anaesthetist with echocardiography training and qualifications. There was 100% concordance between trainees and the consultant for assessment of clinically significant aortic stenosis, with no cases of misdiagnosis. There was also 90 100% agreement (kappa statistic 0.8-1) between the consultant and each trainee's assessment of clinically significant aortic stenosis based on a peak aortic velocity > 3 m.sec(-1). Anaesthesia trainees can be successfully and rapidly trained to recognise and estimate the severity of aortic stenosis. PMID- 21707562 TI - The Difficult Airway Society 'ADEPT' guidance on selecting airway devices: the basis of a strategy for equipment evaluation. AB - Faced with the concern that an increasing number of airway management devices were being introduced into clinical practice with little or no prior evidence of their clinical efficacy or safety, the Difficult Airway Society formed a working party (Airway Device Evaluation Project Team) to establish a process by which the airway management community within the profession could itself lead a process of formal device/equipment evaluation. Although there are several national and international regulations governing which products can come on to the market and be legitimately sold, there has hitherto been no formal professional guidance relating to how products should be selected (i.e. purchased). The Airway Device Evaluation Project Team's first task was to formulate such advice, emphasising evidence-based principles. Team discussions led to a definition of the minimum level of evidence needed to make a pragmatic decision about the purchase or selection of an airway device. The Team concluded that this definition should form the basis of a professional standard, guiding those with responsibility for selecting airway devices. We describe how widespread adoption of this professional standard can act as a driver to create an infrastructure in which the required evidence can be obtained. Essential elements are that: (i) the Difficult Airway Society facilitates a coherent national network of research active units; and (ii) individual anaesthetists in hospital trusts play a more active role in local purchasing decisions, applying the relevant evidence and communicating their purchasing decisions to the Difficult Airway Society. PMID- 21707563 TI - The effect of transoesophageal echocardiography probe insertion on tracheal cuff pressure. AB - Increased tracheal cuff pressure during mechanical ventilation is associated with reduced mucosal blood flow and ischaemia, as well as postoperative sore throat. We assessed the potential effects of transoesophageal echocardiography probe insertion on the tracheal cuff pressure in patients undergoing cardiac surgery. Using a manometer, the cuff pressure of a high-volume, low-pressure tracheal tube (inner diameter 7.0 mm for women and 7.5 mm for men) was adjusted to 25-30 cm H(2)O before blind insertion of a transoesophageal echocardiography probe. The pressure changes were then recorded for 1 min. After probe insertion, the mean (SD) intra-cuff pressure increased from 27.7 (1.5) to 36.2 (6.4) cm H(2)O (p < 0.001) and was > 35 cm H(2)0 in 17/38 patients (45%). Our results suggest that transoesophageal echocardiography probe insertion may increase the tracheal cuff pressure more than that is generally recommended and therefore the latter should be routinely monitored under such circumstances. PMID- 21707564 TI - A double-blind randomised comparison of intravenous patient-controlled remifentanil with intramuscular pethidine for labour analgesia. AB - In a prospective, double-blind, randomised controlled trial, we compared the efficacy of patient-controlled analgesia using remifentanil (25-30 MUg per bolus) with intramuscular pethidine (50-75 mg) for labour analgesia in 69 parturients. Parturients receiving patient-controlled analgesia reported less pain than those receiving intramuscular pethidine throughout the study period (p < 0.001), with maximal reduction in visual analogue pain score at 2 h after commencement of analgesia (mean (SD) 20 (17) in the patient-controlled analgesia group and 36 (22) in the intramuscular pethidine group. The median (95% CI) time to the first request for rescue analgesics was significantly longer with patient-controlled analgesia (8.0 (6.8-9.2) h) compared with intramuscular pethidine (4.9 (3.8-5.4) h, p < 0.001). Maternal satisfaction scores were also higher with remifentanil compared with intramuscular pethidine (p= 0.001). There was no report of sedation, aponea or oxygen desaturation in either group, and Apgar scores were similar between groups. We conclude that patient-controlled analgesia with remifentanil provides better labour analgesia and maternal satisfaction than intramuscular pethidine. At this dose, maternal and fetal side effects were uncommon. PMID- 21707565 TI - Echocardiography in intensive care--where we are heading? PMID- 21707566 TI - Safe sedation? PMID- 21707567 TI - Strengthening the evidence base for airway equipment: time to be more 'ADEPT'? PMID- 21707569 TI - Survival in cancer patients hospitalized for psoriasis: a commentary. PMID- 21707570 TI - Measure the extent of hand eczema rather than its severity? PMID- 21707571 TI - The sun's vitamin against sun allergy. PMID- 21707572 TI - In praise of small studies. PMID- 21707573 TI - Efficacious and safe management of moderate to severe scalp seborrhoeic dermatitis using clobetasol propionate shampoo 0.05% combined with ketoconazole shampoo 2%: a randomized, controlled study. AB - BACKGROUND: Topical antifungals and corticosteroids are the mainstay of treatment for seborrhoeic dermatitis. The short-contact clobetasol propionate 0.05% shampoo (CP) is an efficacious and safe once-daily treatment for scalp psoriasis. OBJECTIVES: To evaluate the efficacy and safety of CP alone and combined with ketoconazole shampoo 2% (KC) in the treatment of moderate to severe scalp seborrhoeic dermatitis. METHODS: This randomized and investigator-blinded study consisted of three phases, each lasting 4 weeks. During the treatment phase, subjects were randomized to receive KC twice weekly (K2), CP twice weekly (C2), CP twice weekly alternating with KC twice weekly (C2 + K2) or CP four times weekly alternating with KC twice weekly (C4+K2). All subjects received KC once weekly during the maintenance phase and were untreated during the follow-up phase. RESULTS: At the end of the treatment phase, all three CP-containing regimens were significantly more efficacious than K2 in decreasing the overall disease severity (P < 0.05). Both combination regimens were also significantly more efficacious than K2 in decreasing each individual sign of the disease (P < 0.05). While the C2 and C4 + K2 groups experienced slight worsening during the maintenance phase, the efficacy of C2 + K2 was sustained and remained the highest among all groups. All regimens were well tolerated without inducing any skin atrophy. Similarly low incidences of telangiectasia, burning and adverse events were observed among the four groups. CONCLUSIONS: The combination therapy of twice-weekly CP alternating with twice-weekly KC provided significantly greater efficacy than KC alone and a sustained effect in the treatment of moderate to severe scalp seborrhoeic dermatitis. PMID- 21707574 TI - Lenalidomide downregulates the cell survival factor, interferon regulatory factor 4, providing a potential mechanistic link for predicting response. AB - Overexpression of the transcription factor interferon regulatory factor-4 (IRF4), which is common in multiple myeloma (MM), is associated with poor prognosis. Patients with higher IRF4 expression have significantly poorer overall survival than those with low IRF4 expression. Lenalidomide is an IMiD immunomodulatory compound that has both tumouricidal and immunomodulatory activity in MM. This study showed that lenalidomide downregulated IRF4 levels in MM cell lines and bone marrow samples within 8 h of drug exposure. This was associated with a decrease in MYC levels, as well as an initial G1 cell cycle arrest, decreased cell proliferation, and cell death by day 5 of treatment. In eight MM cell lines, high IRF4 levels correlated with increased lenalidomide sensitivity. The clinical significance of this observation was investigated in 154 patients with MM. Among MM patients with high levels of IRF4 expression, treatment with lenalidomide led to a significantly longer overall survival than other therapies in a retrospective analysis. These data confirm the central role of IRF4 in MM pathogenesis; indicate that this is an important mechanism by which lenalidomide exerts its antitumour effects; and may provide a mechanistic biomarker to predict response to lenalidomide. PMID- 21707575 TI - Severe acquired anaemia in Africa: new concepts. AB - Severe anaemia is common in Africa. It has a high mortality and particularly affects young children and pregnant women. Recent research provides new insights into the mechanisms and causes of severe acquired anaemia and overturns accepted dogma. Deficiencies of vitamin B12 and vitamin A, but not of iron or folic acid, are associated with severe anaemia. Bacterial infections and, in very young children, hookworm infections are also common in severe anaemia. Irrespective of the aetiology, the mechanism causing severe anaemia is often red cell production failure. Severe anaemia in Africa is therefore a complex multi-factorial syndrome, which, even in an individual patient, is unlikely to be amenable to a single intervention. Policies and practices concerning anaemia diagnosis, treatment and prevention need to be substantially revised if we are to make a significant impact on the huge burden of severe anaemia in Africa. PMID- 21707576 TI - Palliative care: what approaches are suitable in developing countries? AB - The enormous burden of life-threatening illnesses, including cancer, human immunodeficiency virus infection, and others, such as sickle cell disease, associated with physical and psychosocial suffering explains the illustrious need for palliative care in developing countries. Despite the demonstrated need, current provision of palliative care in Africa is at best limited, and at worst non-existent. Access to essential pain medicines, particularly oral morphine, for control of pain is extremely limited and far below the global mean. There is a general lack of government policies that recognize palliative care as an essential component of health care and there is inadequate training for both health care professionals and the general public about palliative care. A public health strategy, as recommended by the World Health Organization (WHO), offers the best approach for translating knowledge and skills into evidence-based, cost effective interventions that can reach everyone in need of palliative care in developing countries. PMID- 21707577 TI - Haemophilia: provision of factors and novel therapies: World Federation of Hemophilia goals and achievements. AB - For nearly 50 years, the goal of the World Federation of Hemophilia (WFH) has been to achieve 'Treatment for All' patients with inherited bleeding disorders, regardless of where they live. With proper diagnosis, management and care, people with bleeding disorders can live perfectly healthy lives. Without treatment, the reality is that many will die young or, if they survive, suffer joint damage that leaves them with permanent disabilities. Only about 25% of the estimated 400 000 people with haemophilia worldwide receive adequate treatment. The percentage is far lower for those with von Willebrand Disease (VWD) and the rarer bleeding disorders. The achievements of the WFH to close the gap in care for people with bleeding disorders are measureable over time by using three key indicators; the difference in the estimated and actual number of people known with bleeding disorders, the amount of treatment products needed versus that available, and the number of people born with bleeding disorders and the number who reach adulthood. There are five essential elements to achieve a sustainable national care programme: ensuring accurate laboratory diagnosis, achieving government support, improving the care delivery system, increasing the availability of treatment products, and building a strong national patient organization. PMID- 21707578 TI - Chelation treatment in sickle-cell-anaemia: much ado about nothing? AB - Blood transfusions may prevent and treat serious complications related to sickle cell disease (SCD) when performed according to specific guidelines. However, blood transfusion requirements in SCD inevitably lead to increased body iron burden. An adequate chelation treatment may prevent complications and reduce morbidity and mortality. This review evaluates the effectiveness, safety and costs of chelation treatment. The included trials were examined according to the recommendations of the American College of Cardiology (ACC) and the American Heart Association (AHA). Overall, 14 trials and a total of 502 patients with SCD were included in this review. Deferoxamine alone (s.c. or i.v.), deferiprone alone or versus deferoxamine, deferasirox versus deferoxamine and combined treatment with deferoxamine plus deferiprone were included and evaluated in the analysis. Only two randomized clinical trials have been reported. The results of this analysis suggest that use of chelation treatment in SCD to date has been based on little efficacy and safety evidence, although it is widely recommended and practised. The cost/benefit ratio has not been fully explored. Further research with larger randomized clinical trials needs to be performed. PMID- 21707579 TI - Lymphomas in sub-Saharan Africa--what can we learn and how can we help in improving diagnosis, managing patients and fostering translational research? AB - Approximately 30 000 cases of non-Hodgkin lymphoma (NHL) occur in the equatorial belt of Africa each year. Apart from the fact that Burkitt lymphoma (BL) is very common among children and adolescents in Africa and that an epidemic of human immunodeficiency virus (HIV) infection is currently ongoing in this part of the world, very little is known about lymphomas in Africa. This review provides information regarding the current infrastructure for diagnostics in sub-Saharan Africa. The results on the diagnostic accuracy and on the distribution of different lymphoma subsets in sub-Saharan Africa were based on a review undertaken by a team of lymphoma experts on 159 fine needle aspirate samples and 467 histological samples during their visit to selected sub-Saharan African centres is presented. Among children (<18 years of age), BL accounted for 82% of all NHL, and among adults, diffuse large B-cell lymphoma accounted for 55% of all NHLs. Among adults, various lymphomas other than BL, including T-cell lymphomas, were encountered. The review also discusses the current strategies of the International Network of Cancer Treatment and Research on improving the diagnostic standards and management of lymphoma patients and in acquiring reliable clinical and pathology data in sub-Saharan Africa for fostering high quality translational research. PMID- 21707580 TI - Genetic strategies for the treatment of sickle cell anaemia. AB - Sickle cell anaemia is a severe inherited blood disorder for which there is presently no curative therapy other than allogeneic haematopoietic stem cell (HSC) transplantation. This therapeutic option, however, is not available to most patients because of the lack of a matched related donor. Different genetic strategies aiming to treat the anaemia and prevent sickling are under investigation. They include strategies to transfer a regulated globin gene in autologous HSCs-the most developed approach, which is about to undergo clinical evaluation-, and strategies to either restore endogenous HBG expression, repair or eliminate HBB(S) mutant transcripts, or correct the sickle mutation in HSCs or induced pluripotent stem cells. Their common ultimate goals are to afford therapeutic levels of HbA or HbF in the erythroid progeny of autologous HSCs (sufficient to prevent pathological sickling) and engraft the genetically modified HSCs with minimal short-term toxicity (primarily caused by the conditioning regimen) and long-term toxicity (primarily caused by genotoxicity). We discuss here the status of application of these technologies, outlining recent advances and the hurdles that lay ahead. PMID- 21707581 TI - The differential effect of lenalidomide monotherapy in patients with relapsed or refractory transformed non-Hodgkin lymphoma of distinct histological origin. AB - Transformed lymphoma (TL) represents a heterogeneous group of lymphomas with an aggressive course and poor prognosis. We assessed the clinical benefit of single agent lenalidomide based on histological origin, including transformed follicular lymphoma (tFL) and transformed chronic lymphocytic leukaemia/small lymphocytic lymphoma (tCLL/SLL). Our analysis included 33 patients with TL. Patients received lenalidomide at a median dose of 25 mg/d. The overall response rate (ORR) was 46%, with a median response duration of 12.8 months after a median follow-up of 5.6 months. Median progression-free survival was 5.4 months. Among patients with tFL, ORR was 57%, with a median response duration of 12.8 months. None of the patients with tCLL/SLL responded to lenalidomide monotherapy. The most common grade 3/4 adverse events were reversible myelosuppression. Our results suggest that the original lymphoma histology (i.e. FL) in TL patients may potentially be associated with response to salvage lenalidomide monotherapy. PMID- 21707582 TI - Epigenetic silencing of MIR203 in multiple myeloma. AB - Epigenetic inactivation of tumour suppressor microRNAs has been implicated in carcinogenesis. We studied the promoter methylation of MIR203 in eight normal marrow controls, eight multiple myeloma (MM) cell lines, 20 monoclonal gammopathy of undetermined significance (MGUS), 123 diagnostic MM and 19 relapsed MM samples by methylation-specific polymerase chain reaction. Promoter of MIR203 was unmethylated in normal controls but homozygously methylated in 25% MM cell lines. Treatment with 5-Aza-2'-deoxycytidine led to promoter demethylation and MIR203 re expression. Cyclic AMP responsive element binding protein 1 (CREB1) mRNA was predicted as a MIR203 direct target. Luciferase activity was reduced in constructs carrying wild-type CREB1 3'UTR upon MIR203 expression but not in those carrying mutant CREB1 3'UTR. Moreover, restoration of MIR203 led to downregulation of CREB1 protein and inhibition of myeloma cell proliferation. In primary samples, MIR203 methylation occurred in 25.0% MGUS, 23.6% diagnostic MM, and 21.1% relapsed MM samples. In conclusion, MIR203 methylation is disease specific with reversible gene silencing in MM. MIR203 is a tumour suppressor microRNA inhibiting cellular proliferation by targeting CREB1 mRNA in MM. Comparable occurrence of MIR203 methylation in MGUS and MM at diagnosis or relapse suggested that MIR203 methylation may be an early event in myelomagenesis instead of being acquired during disease progression. PMID- 21707583 TI - Intermediate dose of imatinib in combination with chemotherapy followed by allogeneic stem cell transplantation improves early outcome in paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL): results of the Spanish Cooperative Group SHOP studies ALL-94, ALL-99 and ALL-2005. AB - Philadelphia-chromosome acute lymphoblastic leukaemia (Ph+ ALL) is a subgroup of ALL with very high risk of treatment failure. We report here the results of the Sociedad Espanola de Hematologia y Oncologia Pediatricas (SEHOP/SHOP) in paediatric Ph+ ALL treated with intermediate-dose imatinib concurrent with intensive chemotherapy. The toxicities and outcome of these patients were compared with historical controls not receiving imatinib. Patients with Ph+ ALL aged 1-18years were enrolled in three consecutive ALL/SHOP trials (SHOP-94/SHOP 99/SHOP-2005). In the SHOP-2005 trial, imatinib (260mg/m(2) per day) was given on day-15 of induction. Allogeneic haematopoietic stem-cell transplantation (HSCT) from a matched related or unrelated donor was scheduled in first complete remission (CR1). Forty-three patients were evaluable (22 boys, median age 6.8years, range, 1.2-15). Sixteen received imatinib whereas 27 received similar chemotherapy without imatinib. Seventeen of 27 and 15 of 16 patients in the non imatinib and imatinib cohort, respectively, underwent HSCT in CR1. With a median follow-up of 109 and 39months for the non-imatinib and imatinib cohorts, the 3 year event-free survival (EFS) was 29.6% and 78.7%, respectively (P=0.01). These results show that, compared to historical controls, intermediate dose of imatinib given concomitantly with chemotherapy and followed by allogeneic HSCT markedly improved early EFS in paediatric Ph+ ALL. PMID- 21707584 TI - Reduced-intensity conditioning haematopoietic cell transplantation for haemophagocytic lymphohistiocytosis: an important step forward. AB - Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunodeficiency characterized by severe systemic hyper-inflammatory responses to infectious or other triggers of the immune system. In many patients, the underlying cause of HLH is a genetic defect leading to defective CD8(+) T cell and natural killer cell granule-mediated cytotoxicity. The treatment of HLH consists principally of immune suppression followed by allogeneic haematopoietic cell transplantation (HCT) to cure the underlying defect and prevent relapse of HLH. Initial treatment regimens consist of steroids coupled with either etoposide or antithymocyte globulin, +/- ciclosporin. Complete responses are observed in only 50-75% of patients and even after a complete response, relapse and death still occur. The only definitive, long-term cure for patients with genetic forms of HLH is allogeneic HCT. Unfortunately, allogeneic HCT for patients with HLH is often complicated by critical illness, extensive organ involvement, active infections, or refractory HLH. For these reasons, patients are unusually prone to developing transplant-related toxicities and complications. In recent years, great strides have been made with regard to the care and transplantation of patients with HLH. Here we review the current state of the treatment of patients with HLH with allogeneic HCT, highlighting the important steps forward that have been made with reduced-intensity conditioning. PMID- 21707586 TI - Comment from the Editor-in-Chief on correspondence in this issue on immuno techniques. PMID- 21707585 TI - Biweekly rituximab, cyclophosphamide, vincristine, non-pegylated liposome encapsulated doxorubicin and prednisone (R-COMP-14) in elderly patients with poor risk diffuse large B-cell lymphoma and moderate to high 'life threat' impact cardiopathy. AB - This Phase II study assessed feasibility and efficacy of a biweekly R-COMP-14 regimen (rituximab, cyclophosphamide, non-pegylated liposome-encapsulated doxorubicin, vincristine and prednisone) in untreated elderly patients with poor risk diffuse large B-cell lymphoma (DLBCL) and moderate to high 'life threat' impact NIA/NCI cardiac comorbidity. A total of 208 courses were delivered, with close cardiac monitoring, to 41 patients (median age: 73years, range: 62-82; 37% >75years) at a median interval of 15.6 (range, 13-29) days; 67% completed all six scheduled courses. Response rate was 73%, with 68% complete responses (CR); 4 year disease-free survival (DFS) and time to treatment failure (TTF) were 72% and 49%, respectively. Failures were due to early death (n=3), therapy discontinuations (no-response n=2; toxicity n=6), relapse (n=6) and death in CR (n=3). Incidence of cardiac grade 3-5 adverse events was 7/41 (17%; 95% confidence interval: 8-31%). Time to progression and overall survival at 4-years were 77% and 67%, respectively. The Age-adjusted Charlson Comorbidity Index (aaCCI) correlated with failures (P=0.007) with patients scoring <=7 having a longer TTF (66% vs. 29%; P=0.009). R-COMP-14 is feasible and ensures a substantial DFS to poor-risk DLBCL patients who would have been denied anthracycline-based treatment due to cardiac morbidity. The aaCCI predicted both treatment discontinuation rate and TTF. PMID- 21707587 TI - Knockout controls and the specificity of cannabinoid CB2 receptor antibodies. PMID- 21707589 TI - 'Altered' mesenteric artery SK(Ca) : functional implications? PMID- 21707591 TI - Protective pathways against colitis mediated by appendicitis and appendectomy. AB - Appendicitis followed by appendectomy (AA) at a young age protects against inflammatory bowel disease (IBD). Using a novel murine appendicitis model, we showed that AA protected against subsequent experimental colitis. To delineate genes/pathways involved in this protection, AA was performed and samples harvested from the most distal colon. RNA was extracted from four individual colonic samples per group (AA group and double-laparotomy control group) and each sample microarray analysed followed by gene-set enrichment analysis (GSEA). The gene-expression study was validated by quantitative reverse transcription polymerase chain reaction (RT-PCR) of 14 selected genes across the immunological spectrum. Distal colonic expression of 266 gene-sets was up-regulated significantly in AA group samples (false discovery rates < 1%; P-value < 0.001). Time-course RT-PCR experiments involving the 14 genes displayed down-regulation over 28 days. The IBD-associated genes tnfsf10, SLC22A5, C3, ccr5, irgm, ptger4 and ccl20 were modulated in AA mice 3 days after surgery. Many key immunological and cellular function-associated gene-sets involved in the protective effect of AA in experimental colitis were identified. The down-regulation of 14 selected genes over 28 days after surgery indicates activation, repression or de repression of these genes leading to downstream AA-conferred anti-colitis protection. Further analysis of these genes, profiles and biological pathways may assist in developing better therapeutic strategies in the management of intractable IBD. PMID- 21707592 TI - Loss of balance between T helper type 17 and regulatory T cells in chronic human immunodeficiency virus infection. AB - The aim of this study is to characterize the changes of CD4(+) CD25(high) forkhead box P3 (FoxP3(+) ) regulatory T cells (T(reg) ), interleukin (IL)-17 secreting T helper type 17 (Th17) cell frequencies and the balance of these two subsets in a cohort of chronic human immunodeficiency virus type 1 (HIV-1) infected patients in China. A total of 115 untreated chronic HIV-infected individuals and 32 healthy donors were recruited in this study. Peripheral blood mononuclear cells were isolated from ethylenediamine tetracetic acid (EDTA) anti coagulated fresh whole blood and stained to characterize the frequencies of T(reg) and Th17. Of a total 115 patients, 42 individuals including 10 elite controllers were followed-up for more than 1 year, and changes of T(reg) and Th17 frequencies were analysed over time. The continuous loss of Th17 cells was accompanied by a concomitant rise in the frequency of T(reg) cells, resulting in a loss of Th17/T(reg) balance during the progressive HIV infection. Meanwhile, the T(reg) levels, Th17 levels and Th17/T(reg) ratios of the elite controller group were comparable to those of the HIV-1 negative controls in the follow-up study. Additionally, we demonstrated that loss of balance between Th17 and T(reg) is associated with an earlier CD4 T cell decline during the course of HIV infection. Our results indicate that a loss of immune-balance of Th17 to T(reg) during HIV-1 disease progression and the persistence of such an immune-balance in the elite controllers may have a critical role in HIV-1 infection and further shed new light into understanding the pathogenesis of HIV-1. PMID- 21707593 TI - Mannose-binding lectin deficiency linked to cytomegalovirus (CMV) reactivation and survival in lung transplantation. AB - Despite the use of immunosuppressives mainly influencing T and B cell responses, the prevalence of the bronchiolitis obliterans syndrome (BOS) after lung transplantation is high. Mannose-binding lectin (MBL) is a pattern recognition molecule of complement and an important component of the innate immunity. MBL is associated with rejection, infection and survival in other solid organ transplantations. In this study the relation between functional MBL levels and cytomegalovirus (CMV) reactivations and the development of BOS and survival after lung transplantation was investigated. MBL levels were measured in 85 patients before and in 57 of these patients after lung transplantation. The relation of MBL on survival, CMV reactivation and the development of BOS were investigated with Kaplan-Meier (log-rank) survival analysis. MBL levels decreased on average by 20% (P < 0.001) after transplantation and eventually returned to pretransplant levels. Fourteen of the 85 patients had deficient pretransplant MBL levels and these patients had a tendency towards a better survival compared to those with normal MBL levels (P = 0.08). Although no correlation was found between MBL deficiency and the development of BOS, more CMV reactivations occurred in recipients with deficient versus normal levels of MBL (P = 0.03). Our results suggest that MBL deficiency is associated with CMV reactivations and a longer overall survival, but not with the development of BOS. PMID- 21707594 TI - Management of inherited thrombophilia: guide for genetics professionals. AB - Venous thromboembolism (VTE) is a common source of morbidity and mortality in developed countries. Heritable risk factors for VTE (thrombophilias) can be identified in 30-50% of affected patients. Factor V Leiden, prothrombin 20210G>A, and deficiencies of antithrombin, protein C and protein S increase the risk of a first VTE. However, an individual's thrombotic risk is determined by a complex interplay of genetic, acquired and circumstantial risk factors. At least 50% of VTE events in thrombophilic individuals are provoked by predisposing factors such as immobility, surgery, trauma, cancer, hormonal therapy and pregnancy. Non modifiable risk factors such as advancing age and family history also increase thrombotic risk. An evidence-based risk factor evaluation is an essential step in VTE prevention. This review will educate genetics professionals about inherited and acquired risk factors for VTE and discuss recommendations for management of asymptomatic individuals with thrombophilia. PMID- 21707595 TI - Central motor conduction studies and diagnostic magnetic resonance imaging in children with severe primary and secondary dystonia. AB - AIM: Dystonia in childhood has many causes. Imaging may suggest corticospinal tract dysfunction with or without coexistent basal ganglia damage. There are very few published neurophysiological studies on children with dystonia; one previous study has focused on primary dystonia. We investigated central motor conduction in 62 children (34 males, 28 females; age range 3-19y, mean age 10y 8mo, SD 4y 8mo) with severe dystonia to evaluate corticospinal tract integrity before consideration for deep brain stimulation. METHOD: Distal motor and F-wave latencies were measured in the ulnar and/or posterior tibial nerves. Transcranial magnetic stimulation was applied over the motor cortex and motor-evoked potentials were recorded in the activated abductor digiti minimi and/or abductor hallucis muscles. Central motor conduction time (CMCT) was calculated using the F wave method. RESULTS: CMCT was normal in 50 out of 62 patients; 12 patients showed prolonged CMCT to upper and/or lower limbs. Most children with severe primary and secondary dystonia had normal CMCT, indicating corticospinal tract integrity despite abnormal imaging in 42 out of 50 patients. Abnormal CMCT was found in two out of 12 patients with normal imaging. INTERPRETATION: This study provides new CMCT data for children with severe primary and secondary dystonia. Over 50% of children with evidence of periventricular white-matter damage from magnetic resonance imaging had normal CMCT, challenging traditional pathophysiological models. This is consistent with recent diffusion tensor imaging in children with periventricular white-matter damage, showing disruption of sensory connections rather than corticospinal tract damage. CMCT helps refine our understanding of imaging changes in complex motor disorders of childhood. PMID- 21707596 TI - Developing and validating the Communication Function Classification System for individuals with cerebral palsy. AB - AIM: The purpose of this study was to create and validate the Communication Function Classification System (CFCS) for children with cerebral palsy (CP), for use by a wide variety of individuals who are interested in CP. This paper reports the content validity, interrater reliability, and test-retest reliability of the CFCS for children with CP. METHOD: An 11-member development team created comprehensive descriptions of the CFCS levels, and four nominal groups comprising 27 participants critiqued these levels. Within a Delphi survey, 112 participants commented on the clarity and usefulness of the CFCS. Interrater reliability was completed by 61 professionals and 68 parents/relatives who classified 69 children with CP aged 2 to 18 years. Test-retest reliability was completed by 48 professionals who allowed at least 2 weeks between classifications. The participants who assessed the CFCS were all relevant stakeholders: adults with CP, parents of children with CP, educators, occupational therapists, physical therapists, physicians, and speech-language pathologists. RESULTS: The interrater reliability of the CFCS was 0.66 between two professionals and 0.49 between a parent and a professional. Professional interrater reliability improved to 0.77 for classification of children older than 4 years. The test-retest reliability was 0.82. INTERPRETATION: The CFCS demonstrates content validity and shows very good test-retest reliability, good professional interrater reliability, and moderate parent-professional interrater reliability. Combining the CFCS with the Gross Motor Function Classification System and the Manual Ability Classification System contributes to a functional performance view of daily life for individuals with CP, in accordance with the World Health Organization's International Classification of Functioning, Disability and Health. PMID- 21707597 TI - Transcranial magnetic stimulation: a path from pyramidal to extrapyramidal syndrome? PMID- 21707598 TI - Controlled study of the effects of continuous intrathecal baclofen infusion in non-ambulant children with cerebral palsy. AB - AIM: To measure changes in children with severe spastic cerebral palsy (CP) after continuous intrathecal baclofen (ITB) infusion over 18 months and to compare the results with those of a comparison group awaiting treatment. METHOD: Thirty-eight children with severe spastic CP considered suitable for ITB were assessed when first seen, just before insertion of an intrathecal pump, and 9 months and 18 months later. Eighteen children waited around 9 months for a pump (group 1: nine males, nine females; mean age 9y 11mo [SD 3y 7mo], nine in Gross Motor Function Classification System [GMFCS] level IV, nine in level V). This baseline period was used as a control for comparison with the first and second 9-month periods after the pump for the remaining 20 children (group 2: 11 males, nine females; mean age 10y 2mo [SD 3y 1mo], nine in GMFCS level IV, 11 in level V). The main outcome measure was the Pediatric Evaluation of Disability Inventory (PEDI); other assessments were of function, ease of care, quality of life, and costs of new equipment. RESULTS: No significant change was found in the PEDI between group 1 while awaiting treatment and group 2 in the two periods afterwards, nor in the Lifestyle Assessment Questionnaire or the cost of new equipment. Significant changes were found in group 2 in the first 9 months according to the modified Ashworth score (difference between mean values for groups -1.7, standard error 0.58; p=0.008), Penn Spasm score (-1.3, 0.37; p=0.001), mean joint range of movement (8.3 degrees , 2.8; p=0.005), and Caregiver Questionnaire (-19.7, 5.1; p=0.01), and in the second 9 months for the Modified Ashworth Scale score (-0.62, 0.12; p=0.001). INTERPRETATION: ITB in children with severe spastic CP over the first 18 months improves their quality of life in terms of comfort and ease of care. It has less effect on function, participation in society, or the overall cost of new equipment. PMID- 21707599 TI - Parenting stress and children with cerebral palsy: a European cross-sectional survey. AB - AIM: The aim of this study was to describe stress in the parents of children with cerebral palsy and investigate associations with very high stress. METHOD: A cross-sectional survey was conducted of parents of 818 children aged 8 to 12 years from nine regions in Europe. Families were eligible to participate if they were living in one of the specified geographic areas. Parental stress was captured using the Parenting Stress Index Short Form, which has 36 items and takes 10 minutes to complete. Parents rate items on a 5-point Likert scale, with higher scores indicating higher stress. The Short Form yields scores on three subscales and a Total Stress score. A trained research associate administered the questionnaire in the child's home and visits lasted 90 to 120 minutes. All data collected were reported by parents unless otherwise stated. RESULTS: The Total Stress score on the Parenting Stress Index was dichotomized into scores of less than 99 or 99 or more, the latter indicating 'very high' stress. Most respondents were mothers (94%), and 26% reported very high stress levels. The parents of children with communication impairment had higher odds for very high stress (odds ratio [OR] 1.9; 95% confidence interval [CI] 1.2-3.0) than those whose child had no such impairment; the parents of children with moderate or severe pain had higher odds for very high stress (OR 1.7 [95% CI 1.1-2.4] and 2.5 [95% CI 1.5 4.3] respectively) than those whose child had no pain; and the parents of children with an intellectual impairment had higher odds for very high stress (OR 1.8; 95% CI 1.2-2.9) than those whose child had none. There was no association between very high stress and motor impairment. The subscales 'parent-child dysfunctional interaction' and 'difficult child' contributed most to the Total Stress score. INTERPRETATION: Parents of children with communication difficulties, intellectual impairment, or pain are at very high risk of stress. The final model explained 12% of the observed variation in very high stress. PMID- 21707600 TI - Evaluating experimental treatment of leukodystrophies. PMID- 21707601 TI - Oral and non-oral sensorimotor interventions enhance oral feeding performance in preterm infants. AB - AIM: The aim of this study was to determine whether oral, tactile/kinaesthetic (T/K), or combined (oral+T/K) interventions enhance oral feeding performance and whether combined interventions have an additive/synergistic effect. METHOD: Seventy-five preterm infants (mean gestational age 29 wk; standard error of the mean [SEM] 0.3 wk; mean birthweight 1340.3g; SEM 52.5 g; 49 males and 26 females) were randomly assigned to one of three intervention groups or a control group. The oral group received sensorimotor input to the oral structures, the T/K group received sensorimotor input to the trunk and limbs, and the combined group received both. The outcomes were time from introduction of nipple feeding to independent oral feeding (d), proficiency (intake in the first 5 min, %), volume transfer (%), rate of transfer (mL/min), volume loss (%), and length of hospital stay (d). RESULTS: Infants in the three intervention groups achieved independent oral feeding 9-10 days earlier than those in the control group (p<0.001; effect size 1.9-2.1). Proficiency (p <= 0.002; effect size 0.7-1.4) at the time of one to two and three to five oral feedings per day, volume transfer (p <= 0.001; effect size 0.8-1.1) at one to two, three to five, and six to eight oral feedings per day, and overall rate of transfer (p <= 0.018; effect size 0.8-1.1) were greater, and overall volume losses were less (p <= 0.007; effect size 0.9-1.1), than in the control group (p <= 0.042). The combined group attained independent oral feeding at a significantly younger postmenstrual age than controls (p=0.020) and had clinically greater proficiency than the T/K group (p=0.020; effect size 0.7) and oral group (p=0.109; effect size 0.5). Length of hospital stay was not significantly different between groups (p=0.792; effect size 0.02-0.3). INTERPRETATION: Oral and T/K interventions accelerated the transition from introduction to independent oral feeding and enhanced oral feeding skills. T/K has beneficial effects beyond the specific targeted system. The combined sensorimotor intervention led to an additive/synergistic effect for proficiency, further benefiting this population. PMID- 21707602 TI - The role of birthweight discordance in the intellectual and motor outcome for triplets at early school age. AB - AIM: We assessed motor and intellectual outcome in triplets at school age and investigated the predictive value of perinatal and demographic factors. METHODS: Seventy-one live-born newborn infants (24 triplet pregnancies) were prospectively enrolled at birth. At the age of 6 years, 58 children (31 males, 27 females; mean gestational age 31.2 wks [SD 2.2 wks]; mean birthweight 1622 g [SD 440 g]) returned for a neurodevelopmental examination. A comparison group for triplets born before 32 gestational weeks comprising 26 gestational age-, birthweight-, and sex-matched singletons was also recruited (mean gestational age 30.1 wk [SD 1.5 wk]; mean birthweight 1142 g [SD 210 g]; 12 males, 14 females). The Zurich Neuromotor Assessment was used to examine motor performance, and intellectual abilities were assessed with the Kaufman Assessment Battery for Children (K-ABC). RESULTS: Motor performance and movement quality in these individuals was significantly reduced compared with the test norms for all motor tasks (p<0.001) other than static balance. The mean values on the Mental Processing Composite (95.3, SD 8.4) and the Achievement Scale (90.1, SD 13.8) of the K-ABC were also lower than those in the test reference (p<0.05 and p<0.01 respectively). Triplets born at less than 32 weeks' gestation showed poorer pure motor and adaptive gross motor performance (both p<0.05) than, but similar intellectual performance to, the gestational age-, birthweight- and sex-matched singletons. Poor outcome was predicted by low socio-economic status and by intertriplet birthweight discordance (both p<0.01). INTERPRETATION: Triplets were at an increased risk of mild motor and intellectual impairments. This finding is important for tailoring therapeutic interventions for these children and for parental counselling. Very preterm triplets showed similar outcomes to the singleton comparison children, except that they had poorer motor performance. Low socio-economic status was a major risk factor for impaired intellectual development. In addition, birthweight discordance may also be considered a predictor for poor long-term motor and intellectual outcome in triplets. PMID- 21707603 TI - The effects of continuous intrathecal baclofen infusion in non-ambulant children with cerebral palsy. PMID- 21707604 TI - The natural course of gross motor deterioration in metachromatic leukodystrophy. AB - AIM: Motor deterioration is a key feature in metachromatic leukodystrophy (MLD). The lack of data about its natural course impedes evaluation of therapeutic interventions. This study aimed to provide data about motor decline in MLD. METHOD: Fifty-nine patients (27 males, 32 females) with MLD (21 with late infantile MLD and 38 with juvenile MLD) were recruited within a nationwide survey (the German LEUKONET). Median (range) age at onset was 17 months (9-27) for the group with late-infantile MLD and 6 years 2 months (2y 11mo-14y) for the group with juvenile MLD. Gross motor function was assessed using the Gross Motor Function Classification for MLD. RESULTS: In late-infantile MLD, all patients showed loss of all gross motor function until 3 years 4 months of age. Patients with juvenile MLD showed a more variable and significantly longer motor decline (p<0.001). For a patient with the juvenile form showing first gait disturbances, the probability of remaining stable for more than 1 year was 84%, and 51% for more than 2 years. Having lost independent walking, subsequent motor decline was as steep as in the late-infantile form (median 5 mo, interquartile range 3-22). INTERPRETATION: The course of motor disease was more variable in juvenile MLD with respect to onset and dynamics. However, the motor decline after the loss of independent walking was similarly steep in both forms. These data can serve as a reference for clinical studies that are topics of current research and allow definition of inclusion/exclusion criteria. PMID- 21707605 TI - Status epilepticus in a neonate treated with pyridoxine because of a familial recurrence risk for antiquitin deficiency: pyridoxine toxicity? AB - Pyridoxine-dependent epilepsy (PDE) is a treatable inborn error of metabolism with autosomal recessive inheritance. Antenatal and postnatal prophylactic administration of pyridoxine has been recommended to improve the developmental outcome in possible future pregnancies. We report on a male offspring of a second pregnancy at risk for PDE. While on prophylactic treatment with oral pyridoxine, the newborn developed encephalopathy and status epilepticus at age 14 days. Seizures did not respond to parenteral pyridoxine and additional treatment with folinic acid. After treatment was changed to pyridoxal 5'-phosphate, the infant's condition improved. Antiquitin deficiency was excluded by biochemical and molecular genetic testing, and cofactor treatment was stopped on day 26. He has since remained seizure-free with normal psychomotor development. In healthy newborns, high-dose treatment with pyridoxine may result in increased rather than decreased neuroexcitability. Postnatal prophylactic pyridoxine treatment of fetuses and neonates at risk for PDE should be limited to the shortest possible time, by either prenatal diagnosis or immediate postnatal biochemical and genetic testing. PMID- 21707606 TI - How do we use the assessment of general movements in clinical practice? PMID- 21707607 TI - Developing the Communication Function Classification System for individuals with cerebral palsy. PMID- 21707608 TI - Parent stress and children with cerebral palsy. PMID- 21707609 TI - The influence of age on timing of single-event multilevel surgery: are adolescents with cerebral palsy comparable to a younger cohort? PMID- 21707610 TI - Birthweight discordance does not necessarily equal growth restriction. PMID- 21707611 TI - Profiling the expression of interleukin (IL)-28 and IL-28 receptor alpha in systemic lupus erythematosus patients. AB - BACKGROUND: Interleukin (IL)-28 is an interferon-lambda-family member involved in immunity against viral infection and tumour. We here determined the expression profiles of IL-28 and IL-28 receptor alpha (IL-28RA) in patients with systemic lupus erythematosus (SLE) to evaluate the possibility that IL-28 is linked to the pathogenesis of SLE. MATERIALS AND METHODS: The serum IL-28 protein levels were determined by ELISA, and the IL-28 and IL-28RA transcript levels in peripheral blood mononuclear cells (PBMCs) and peripheral blood T cells were determined by RT-PCR. The levels in patients with SLE with the active disease activity were statistically compared with those in normal controls. RESULTS: IL-28 protein in sera and IL-28 transcripts in PBMCs and unactivated T cells were detectable only in some individuals, and IL-28 transcripts in T cells were induced by cell activation with anti-CD2, anti-CD3 and anti-CD28 antibodies. However, compared with normal controls, patients with SLE more frequently had detectable IL-28 protein in serum and had the higher IL-28 transcript levels in activated CD4(+) T cells, but not activated CD8(+) T cells. Two IL-28RA transcripts isoforms were detected in PBMCs and T cells, and their levels in patients with SLE were comparable with those in normal controls. CONCLUSIONS: The expression of IL-28, a T-cell autocrine factor, is dysregulated in patients with SLE, supporting the possibility that IL-28 may contribute to some of the SLE pathogenesis. PMID- 21707612 TI - Comparison of different bile acid-phospholipid conjugates in acute hepatitis. AB - INTRODUCTION: The bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a promising novel compound with profound hepatoprotective functions in vitro and in vivo. Because of high costs of LPE synthesis from hydrolysis of phosphatidylethanolamide (PE), costs for UDCA LPE synthesis for in vivo and human use can become quite high. In this study, we evaluated whether ursodeoxycholyl phosphatidylethanolamide (udca-pe), which is more cost-effective, could replace udca-lpe in terms of protection from hepatocellular injury. MATERIALS AND METHODS: Anti-apoptotic and anti inflammatory properties of UDCA-PE and UDCA-LPE were compared in TNFalpha/cyclohexamide (CHX)-treated HepG2 cells as well as in a mouse model of d galactosamine/lipopolysaccharide (Gal/LPS)-induced acute liver injury. RESULTS: Ursodeoxycholyl lysophosphatidylethanolamide inhibited TNFalpha/CHX-induced apoptosis in HepG2 cells in a dose-dependent manner and markedly ameliorated Gal/LPS-mediated fulminant hepatitis in mice. In contrast, UDCA-PE showed weaker hepatoprotective functions at low concentrations, and protection was lost at higher dosage. Analysis of hepatic gene expression showed that both conjugates significantly reduced Gal/LPS-mediated expression of chemoattractants, such as monocyte chemotactic protein 1 (MCP1) and RANTES. These inhibitory effects by UDCA-PE were transient while those by UDCA-LPE were sustained in attenuating expression of inflammatory MCP1 and RANTES expression. CONCLUSIONS: Our data underline the superiority of UDCA-LPE compared to UDCA-PE in ameliorating acute liver inflammation. This indicates the significance of the lyso-functional group of bile acid conjugate for optimal hepatoprotection and reduction in inflammation in vivo. PMID- 21707614 TI - Dissolved oxygen as an indicator of bioavailable dissolved organic carbon in groundwater. AB - Concentrations of dissolved oxygen (DO) plotted vs. dissolved organic carbon (DOC) in groundwater samples taken from a coastal plain aquifer of South Carolina (SC) showed a statistically significant hyperbolic relationship. In contrast, DO DOC plots of groundwater samples taken from the eastern San Joaquin Valley of California (CA) showed a random scatter. It was hypothesized that differences in the bioavailability of naturally occurring DOC might contribute to these observations. This hypothesis was examined by comparing nine different biochemical indicators of DOC bioavailability in groundwater sampled from these two systems. Concentrations of DOC, total hydrolysable neutral sugars (THNS), total hydrolysable amino acids (THAA), mole% glycine of THAA, initial bacterial cell counts, bacterial growth rates, and carbon dioxide production/consumption were greater in SC samples relative to CA samples. In contrast, the mole% glucose of THNS and the aromaticity (SUVA(254)) of DOC was greater in CA samples. Each of these indicator parameters were observed to change with depth in the SC system in a manner consistent with active biodegradation. These results are uniformly consistent with the hypothesis that the bioavailability of DOC is greater in SC relative to CA groundwater samples. This, in turn, suggests that the presence/absence of a hyperbolic DO-DOC relationship may be a qualitative indicator of relative DOC bioavailability in groundwater systems. PMID- 21707613 TI - Active tissue factor and activated factor XI in patients with acute ischemic cerebrovascular events. AB - BACKGROUND: Elevated factor (F)XI and tissue factor (TF) have been reported to occur in patients with acute ischemic stroke (AIS). We sought to investigate whether circulating activated FXI (FXIa) and TF on admission can predict clinical outcomes in patients with acute cerebrovascular events. MATERIALS AND METHODS: In the observational study, we evaluated 205 consecutive patients aged 70 years or less within the first 72 h of acute event, including 140 with AIS and 65 with transient ischemic attack (TIA). Plasma TF and FXIa activity were determined on admission in clotting assays by measuring the response to inhibitory monoclonal antibodies. RESULTS: Active TF and FXIa activity were detected in 58 (28.9%) and 132 (64.4%) patients on admission, respectively. Active TF was detected in 45 of the 136 AIS patients with available TF levels (33.1%) and 13 of the 65 patients with acute TIA (20%; 0.05). Corresponding values for FXIa were 99 of the 140 (70.7%) and 33 of the 65 (50.8%; P= 0.006), respectively. Patients with detectable TF were more frequently women and hypertensive, while subjects with detectable FXIa had more often diabetes and higher levels of fibrinogen, C reactive protein and interleukin-6 (all P < 0.05). Patients with detectable FXIa but not TF had higher National Institutes of Health Stroke Scale score, higher modified Rankin scale score and lower Barthel Index at discharge (all P < 0.05). CONCLUSIONS: Circulating active TF and FXIa occur frequently in acute cerebrovascular ischemic events. Active FXIa in plasma might be useful as a novel risk marker of worse functional outcomes in patients with acute cerebrovascular events. PMID- 21707615 TI - Irrigation effects in the northern lake states: Wisconsin central sands revisited. AB - Irrigated agriculture has expanded greatly in the water-rich U.S. northern lake states during the past half century. Source water there is usually obtained from glacial aquifers strongly connected to surface waters, so irrigation has a potential to locally decrease base flows in streams and water levels in aquifers, lakes, and wetlands. During the nascent phase of the irrigation expansion, water availability was explored in works of some fame in the Wisconsin central sands by Weeks et al. (1965) on the Little Plover River and Weeks and Stangland (1971) on "headwater area" streams and lakes. Four decades later, and after irrigation has grown to a dominant landscape presence, we revisited irrigation effects on central sands hydrology. Irrigation effects have been substantial, on average decreasing base flows by a third or more in many stream headwaters and diminishing water levels by more than a meter in places. This explains why some surface waters have become flow and stage impaired, sometimes to the point of drying, with attendant losses of aquatic ecosystems. Irrigation exerts its effects by increasing evapotranspiration by an estimated 45 to 142 mm/year compared with pre-irrigated land cover. We conclude that irrigation water availability in the northern lake states and other regions with strong groundwater-surface water connections is tied to concerns for surface water health, requiring a focus on managing the upper few meters of aquifers on which surface waters depend rather than the depletability of an aquifer. PMID- 21707616 TI - Continuous maximum flow segmentation method for nanoparticle interaction analysis. AB - In recent years, tomographic three-dimensional reconstruction approaches using electrons rather than X-rays have become popular. Such images produced with a transmission electron microscope make it possible to image nanometre-scale materials in three-dimensional. However, they are also noisy, limited in contrast and most often have a very poor resolution along the axis of the electron beam. The analysis of images stemming from such modalities, whether fully or semiautomated, is therefore more complicated. In particular, segmentation of objects is difficult. In this paper, we propose to use the continuous maximum flow segmentation method based on a globally optimal minimal surface model. The use of this fully automated segmentation and filtering procedure is illustrated on two different nanoparticle samples and provide comparisons with other classical segmentation methods. The main objectives are the measurement of the attraction rate of polystyrene beads to silica nanoparticle (for the first sample) and interaction of silica nanoparticles with large unilamellar liposomes (for the second sample). We also illustrate how precise measurements such as contact angles can be performed. PMID- 21707617 TI - Dopamine D1 receptor signaling system regulates ryanodine receptor expression after intermittent exposure to methamphetamine in primary cultures of midbrain and cerebral cortical neurons. AB - Regulatory mechanisms of ryanodine receptor (RyR) expression are not well known, although methamphetamine (METH) has been reported to up-regulate RyRs in mouse brain. This study investigate regulatory mechanisms of RyR expression by dopaminergic system using the midbrain and cerebral cortical neurons in primary culture intermittently exposed to METH and dopamine receptor (DR) agonists (1 h/day, for 3 days). Intermittent METH (10 MUM) exposure enhanced RyR-1 and -2 proteins and their mRNA, but not RyR-3 expression in the both types of the neurons. These METH-induced increases of RyR proteins and their mRNA were dose dependently blocked by SCH23390 (a selective D(1) DR antagonist), but not a D(2)DR antagonist sulpiride, suggesting a regulatory role of D(1)DRs in RyR expression by METH in these neurons. In cerebral cortical neurons, intermittent SKF82958 (a selective D(1)DR agonist) exposure increased RyR-1 and -2 proteins and their mRNA, whereas quinpirole (a selective D(2)DR agonist) showed no effects. KT5720, a protein kinase A inhibitor, dose-dependently attenuated the METH-stimulated RyR-1 and -2 expressions in cerebral cortical neurons. METH significantly increased phosphorylation of cAMP-response element-binding protein, which was completely suppressed by SCH23390. These results indicate that RyR-1 and -2 expressions are regulated by D(1)DRs via the signal transduction linked to D(1)DRs. PMID- 21707618 TI - Spartin recruits PKC-zeta via the PKC-zeta-interacting proteins ZIP1 and ZIP3 to lipid droplets. AB - Protein kinase C-zeta interacting proteins (ZIP1-3) recruit the enzymatic activity of the atypical protein kinase C isoforms PKC-lambda/iota or PKC-zeta to target proteins. In this study, we searched for binding partners of ZIP3 in the CNS and identified spartin, a multifunctional protein that is mutated in spastic paraplegia type 20. In transfected cells, spartin was present on the surface of lipid droplets (LD), whereas ZIP proteins appeared in intracellular speckles. In the presence of spartin, ZIP1 and ZIP3 were translocated to spartin-positive LD. This translocation was mediated by amino acids 196-393 of spartin that interacted with an N-terminal region of ZIP proteins. Furthermore, ZIP proteins interacted simultaneously with spartin and PKC-zeta, resulting in an enrichment of PKC-zeta on spartin/ZIP-labelled LD. Without spartin, neither ZIP proteins nor PKC-zeta were detected on LD. Interestingly, the presence of the spartin/ZIP/PKC-zeta complex increased LD size. This effect was most pronounced upon incorporation of the ZIP3 isoform into the trimer. Finally, we co-localized spartin, ZIP proteins and PKC-zeta in axon terminals of neurons in the mammalian retina. In summary, we describe spartin as new binding partner of the ZIP/PKC-zeta dimer that recruits PKC-zeta to LD and show that the expressed ZIP isoform regulates LD size. PMID- 21707619 TI - Comparative analysis of peanut NBS-LRR gene clusters suggests evolutionary innovation among duplicated domains and erosion of gene microsynteny. AB - * Plant genomes contain numerous disease resistance genes (R genes) that play roles in defense against pathogens. Scarcity of genetic polymorphism makes peanut (Arachis hypogaea) especially vulnerable to a wide variety of pathogens. * Here, we isolated and characterized peanut bacterial artificial chromosomes (BACs) containing a high density of R genes. Analysis of two genomic regions identified several TIR-NBS-LRR (Toll-interleukin-1 receptor, nucleotide-binding site, leucine-rich repeat) resistance gene analogs or gene fragments. We reconstructed their evolutionary history characterized by tandem duplications, possibly facilitated by transposon activities. We found evidence of both intergenic and intragenic gene conversions and unequal crossing-over, which may be driving forces underlying the functional evolution of resistance. * Analysis of the sequence mutations, protein secondary structure and three-dimensional structures, all suggest that LRR domains are the primary contributor to the evolution of resistance genes. The central part of LRR regions, assumed to serve as the active core, may play a key role in the resistance function by having higher rates of duplication and DNA conversion than neighboring regions. The assumed active core is characterized by significantly enriched leucine residue composition, accumulation of positively selected sites, and shorter beta sheets. * Homologous resistance gene analog (RGA)-containing regions in peanut, soybean, Medicago, Arabidopsis and grape have only limited gene synteny and microcollinearity. PMID- 21707620 TI - BcSpl1, a cerato-platanin family protein, contributes to Botrytis cinerea virulence and elicits the hypersensitive response in the host. AB - Proteins belonging to the cerato-platanin family are small proteins with phytotoxic activity. A member of this family, BcSpl1, is one of the most abundant proteins in the Botrytis cinerea secretome. Expression analysis of the bcspl1 gene revealed that the transcript is present in every condition studied, showing the highest level in planta at the late stages of infection. Expression of a second cerato-platanin gene found in the B. cinerea genome, bcspl2, was not detected in any condition. Two bcspl1 knock-out mutants were generated and both showed reduced virulence in a variety of hosts. * bcspl1 was expressed in Pichia pastoris and the recombinant protein was able to cause a fast and strong necrosis when infiltrated in tomato, tobacco and Arabidopsis leaves, in a dose-dependent manner. The BcSpl1-treated plant tissues showed symptoms of the hypersensitive response such as induction of reactive oxygen species, electrolyte leakage, cytoplasm shrinkage, and cell autofluorescence, as well as the induction of defense genes considered to be markers of the hypersensitive response. The Arabidopsis bak1 mutation partially prevented the induction of necrosis in this plant by BcSpl1. Two different BcSpl1-derived 40-amino acids peptides were also active in inducing necrosis. PMID- 21707621 TI - Sequencing crop genomes: approaches and applications. AB - Many challenges face plant scientists, in particular those working on crop production, such as a projected increase in population, decrease in water and arable land, changes in weather patterns and predictability. Advances in genome sequencing and resequencing can and should play a role in our response to meeting these challenges. However, several barriers prevent rapid and effective deployment of these tools to a wide variety of crops. Because of the complexity of crop genomes, de novo sequencing with next-generation sequencing technologies is a process fraught with difficulties that then create roadblocks to the utilization of these genome sequences for crop improvement. Collecting rapid and accurate phenotypes in crop plants is a hindrance to integrating genomics with crop improvement, and advances in informatics are needed to put these tools in the hands of the scientists on the ground. PMID- 21707622 TI - Auxin promotes the transition from chloronema to caulonema in moss protonema by positively regulating PpRSL1and PpRSL2 in Physcomitrella patens. AB - Protonemata are multicellular filamentous networks that develop following the germination of a haploid moss spore and comprise two different cell types - chloronema and caulonema. The ROOT HAIR DEFECTIVE SIX-LIKE1 (PpRSL1) and PpRSL2 basic helix-loop-helix transcription factors and auxin promote the development of caulonema in Physcomitrella patens but the mechanism by which these regulators interact during development is unknown. We characterized the role of auxin in regulating the function of PpRSL1 and PpRSL2 in the chloronema-to-caulonema transition during protonema development. Here, we showed that a gradient of cell identity developed along protonemal filaments; cells were chloronemal in proximal regions near the site of spore germination becoming progressively more caulonemal distally as filaments elongated. Auxin controlled this transition by positively regulating the expression of PpRSL1 and PpRSL2 genes. Auxin did not induce caulonemal development in Pprsl1 Pprsl2 double mutants that lack PpRSL1 and PpRSL2 gene activity while constitutive co-expression of PpRSL1 and PpRSL2 in the absence of auxin was sufficient to program constitutive caulonema development. Together, these data indicate that auxin positively regulates PpRSL1 and PpRSL2 whose expression is sufficient to promote caulonema differentiation in moss protonema. PMID- 21707623 TI - Evaluation of an electrostatic toxicity model for predicting Ni(2+) toxicity to barley root elongation in hydroponic cultures and in soils. AB - Assessing environmental risks of metal contamination in soils is a complex task because the biologically effective concentrations of metals in soils vary widely with soil properties. The factors influencing the toxic effect of nickel (Ni) on root growth of barley (Hordeum vulgare) were re-evaluated using published data from both soil and hydroponic cultures. The electrical potential (psi(0) (o) ) and ion activities ({I(z) }(0) (o) ) at the outer surfaces of root-cell plasma membranes (PMs) were computed as the basis of the re-evaluation. The reanalyses demonstrated that root growth was related to: the Ni(2+) activity at the PM surface, ({Ni(2+) }(0) (o) ); calcium (Ca) deficiency (related to {Ca(2+) }(0) (o) ); osmotic effects; and modification of intrinsic Ni(2+) toxicity by magnesium (Mg(2+) ; this appeared to exert an intrinsic (specific) ameliorating effect on intrinsic Ni(2+) toxicity). Electrostatic toxicity models (ETM) were developed to relate root growth to these factors (R(2) > 0.751). Based on the ETM developed in soil culture and a Ni(2+) solid-solution partitioning model, critical metal concentrations in soils linked to a biological effect were well predicted for 16 European soils with a wide range of properties, indicating the potential utility of ETM in risk assessment of metals in terrestrial ecosystems. PMID- 21707624 TI - Patricia Barry: in memorium. PMID- 21707625 TI - Clinical manifestations of aggressive acts by schizophrenic inpatients: a prospective study. AB - PURPOSE: The purpose of this study was to explore the clinical manifestations of aggressive acts by schizophrenic patients during hospitalization. DESIGN AND METHODS: This prospective study followed 107 schizophrenic patients admitted to an acute psychiatric ward in Taiwan. The Chinese version of the Violence Scale was used to count and rate aggressive acts. The categories of the trend of aggressive acts were analyzed. FINDINGS: The highest incidence rate of aggressive acts (58.9%) occurred during the initial week of hospitalization and decreased through the fourth week (16.9%). Most were disturbing but not severe. The incidence and decrease patterns of aggressive acts were found. PRACTICE IMPLICATIONS: Aggressive acts can be prevented and managed. PMID- 21707626 TI - The effects of the Gatekeeper Suicide-Awareness Program for nursing personnel. AB - PURPOSE: This study evaluates whether a short training program can improve nurses' abilities to recognize and effectively respond to patients exhibiting suicidal behavior. DESIGN AND METHODS: The study is a randomized controlled trial. Ninety-eight nurses in the experimental group attended the regular monthly continuing education class and a 90-min Gatekeeper Suicide-Awareness Program. Ninety-seven nurses in the control group only attended the regular monthly continuing education class. Before and after the different educational interventions, all the nurses were asked to complete a questionnaire to link demographic data and to access their awareness of suicide warning signs and their responses if encountering a potentially suicidal individual. FINDINGS: Nurses who participated in the Gatekeeper Suicide-Awareness Program were much more aware of suicide warning signs and more willing to refer patients for professional counseling. PRACTICE IMPLICATIONS: We suggest that nursing personnel's continuing education include a training program for suicide prevention. PMID- 21707627 TI - Socio-demographic and clinical profiles of paranoid and nonparanoid schizophrenia: a prospective, multicenter study in China. AB - PURPOSE: This study aimed to explore the socio-demographic and clinical characteristics of paranoid and nonparanoid subtypes of schizophrenia. DESIGN AND METHODS: In a multicenter, randomized, controlled, longitudinal study, 374 clinically stable schizophrenia patients were interviewed at entry with standardized assessment instruments and followed for 12-26 months. FINDINGS: In the multivariate analysis, male sex, married marital status, urban abode, and more frequent relapse over the study period were independently associated with paranoid schizophrenia. PRACTICE IMPLICATIONS: The socio-demographic and clinical characteristics of Chinese patients with the paranoid subtype of schizophrenia are different from those of their Caucasian counterparts who are more likely to be women and have a better outcome. PMID- 21707628 TI - Support Our Staff--a unique program to help deal with patient assault. AB - PURPOSE: The program "Support Our Staff" was developed to provide assaulted staff with the most current information and coping strategies. CONCLUSIONS: Participants reported being helped by the program and felt better prepared to cope with future assaults. However, victims felt blamed for the disruption caused by the assault and resented the lack of support from management. PRACTICE IMPLICATIONS: Management needs to take responsibility for their role in violence within the institution, allowing staff to escape the isolation and guilt. Reporting must be encouraged and staff asked to contribute to the development of efficient programs, thus leading to a sense of empowerment. PMID- 21707629 TI - Are you survey ready? Online evaluation of a multidrug-resistant organisms educational program in a behavioral health hospital. AB - PURPOSE: The Joint Commission established a new safety goal mandating staff education in evidence-based infection prevention due to multidrug-resistant organisms (MDROs). This pilot study assessed the effectiveness of the MDRO educational module in our behavioral health hospital. DESIGN AND METHODS: An online survey was administered to a convenience sample (N= 44) consisting of employees hired within the previous 8 months. FINDINGS: Results identified knowledge gaps between and among disciplines that guided subsequent improvements to our MDRO educational module. PRACTICE IMPLICATIONS: Online surveys are an effective way to evaluate knowledge gaps and may be useful in other educational activities within nursing. PMID- 21707630 TI - Photography as a method of data collection: helping people with long-term mental illness to convey their life world. AB - PURPOSE: The purpose of this article is to describe a method to help patients with long-term mental illness describe their life situations--their "life worlds" -through photography. CONCLUSIONS: Photographs and interviews are useful for data collection. The positive effect of this method is allowing informants who have long-term mental illnesses to express their perceptions. PRACTICE IMPLICATIONS: Nurses can use photography in conjunction with interviews to ascertain the life worlds of their patients. PMID- 21707631 TI - A relationship-based model for psychiatric nursing practice. AB - PURPOSE: This article synthesizes research and theory in information processing, infant development, attachment theory, and trauma, and proposes a treatment framework for psychiatric nursing practice. CONCLUSIONS: The primacy of the nurse -patient relationship is central to healing, and elements of the psychotherapeutic relationship are delineated. PRACTICE IMPLICATIONS: This model has the potential to serve as a practice framework for psychiatric nursing, for all levels of psychiatric nursing practice. PMID- 21707632 TI - Biological perspectives. Antipsychotics and the "fast-off" theory. PMID- 21707634 TI - Photocatalytic activity and related surface properties of transparent ZnO films prepared by a low-temperature aqueous route. AB - Transparent ZnO were prepared using solutions with various trisodium citrate concentrations by a spin-spray method at 90 degrees C. The morphological and structural characteristics, as well as photocatalytic activity of the resulting ZnO films were examined with respect to the added trisodium citrate concentration. Photocatalytic activities of the ZnO films were evaluated from photodecomposition of methylene blue (MB) in aqueous solution. With increasing citrate concentrations, the ZnO films came to have higher transmittances in visible region but lower MB decomposition rate. Both high transmittance and high photocatalytic activity were achieved in the ZnO film prepared in the citrate concentration of 0.5 mm. The possible mechanism for the difference in photocatalytic activity by the samples prepared with the various concentrations of citrate was discussed from the viewpoint of film texture, crystal orientation and surface chemical state. PMID- 21707633 TI - UVA, UVB and UVC induce differential response signaling pathways converged on the eIF2alpha phosphorylation. AB - It is clear that solar UV irradiation is a crucial environmental factor resulting in skin diseases partially through activation of cell signaling toward altered gene expression and reprogrammed protein translation. Such a key translational control mechanism is executed by the eukaryotic initiation factor 2alpha subunit (eIF2alpha) and the downstream events provoked by phosphorylation of eIF2alpha at Ser(51) are clearly understood, but the upstream signaling mechanisms on the eIF2alpha-Ser(51) phosphorylation responses to different types of UV irradiations, namely UVA, UVB and UVC, are still not well elucidated. Herein, our evidence reveals that UVA, UVB and UVC all induce a dose- and time-dependent phosphorylation of eIF2alpha-Ser(51) through distinct signaling mechanisms. UVA induced eIF2alpha phosphorylation occurs through MAPKs, including ERKs, JNKs and p38 kinase, and phosphatidylinositol (PI)-3 kinase. By contrast, UVB-induced eIF2alpha phosphorylation is through JNKs and p38 kinase, but not ERKs or PI-3 kinase, whereas UVC-stimulated response to eIF2alpha phosphorylation is via JNKs alone. Furthermore, we have revealed that ATM is involved in induction of the intracellular responses to UVA and UVB, rather than UVC. These findings demonstrate that wavelength-specific UV irradiations activate differential response signaling pathways converged on the eIF2alpha phosphorylation. Importantly, we also show evidence that a direct eIF2alpha kinase PKR is activated though phosphorylation by either RSK1 or MSK1, two downstream kinases of MAPKs/PI-3 kinase-mediated signaling pathways. PMID- 21707635 TI - Feasibility of light-emitting diode uses for annular reactor inner-coated with TiO2 or nitrogen-doped TiO2 for control of dimethyl sulfide. AB - Limited environmental pollutants have only been investigated for the feasibility of light-emitting diodes (LED) uses in photocatalytic decomposition (PD). The present study investigated the applicability of LEDs for annular photocatalytic reactors by comparing PD efficiencies of dimethyl sulfide (DMS), which has not been investigated with any LED-PD system, between photocatalytic systems utilizing conventional and various LED lamps with different wavelengths. A conventional 8 W UV/TiO(2) system exhibited a higher DMS PD efficiency as compared with UV-LED/TiO(2) system. Similarly, a conventional 8 W visible-lamp/N enhanced TiO(2) (NET) system exhibited a higher PD efficiency as compared with six visible-LED/NET systems. However, the ratios of PD efficiency to the electric power consumption were rather high for the photocatalytic systems using UV- or visible-LED lamps, except for two LED lamps (yellow- and red-LED lamps), compared to the photocatalytic systems using conventional lamps. For the photocatalytic systems using LEDs, lower flow rates and input concentrations and shorter hydraulic diameters exhibited higher DMS PD efficiencies. An Fourier transformation infrared analysis suggested no significant absorption of byproducts on the catalyst surface. Consequently, it was suggested that LEDs can still be energy-efficiently utilized as alternative light sources for the PD of DMS, under the operational conditions used in this study. PMID- 21707636 TI - Proteome analysis of maize seeds: the effect of artificial ageing. AB - Previous understanding of the mechanism of seed ageing is largely based on observations on imbibed seeds rather than dry seeds. The present research was conducted to investigate whether seed ageing has effects on the dry seeds through proteome analysis. Maize (Zea mays cv. Dabaitou) seeds were artificially aged at 50 degrees C (13.58% moisture content) for 5 or 13 days, and the total protein was extracted from embryos of the dry seeds. Two-dimensional electrophoresis was performed and the differentially expressed proteins were identified by matrix assisted laser desorption ionization-time of flight mass spectrometry. A total of 40 proteins were identified, in which 16 proteins were upregulated, indicating that artificial ageing affected the proteome of the dry seeds. Proteomic studies revealed that the signal transduction and transcription were disturbed by artificial ageing, which might lead to reduced protection against ageing. Artificial ageing also increased proteases and broke down stored proteins, impaired metabolism and energy supply, and ultimately resulted in seed deterioration. Proteins involved in metabolism and energy were the largest downregulated protein group, with regard to glycolysis, tricarboxylic acid cycle, the electron transport chain and oxidative phosphorylation. The downregulation of these proteins, together with reduction in the specific activity of glucose-6 phosphate dehydrogenase, and the content of glucose 6-phosphate, pyruvic acid and ATP in aged seeds, suggested the important roles of the mobilization of stored carbohydrates and energy supply in seed ageing and seed vigor. The present work provides new information about the proteomic changes during seed ageing and provides a possible mechanism for seed deterioration. PMID- 21707637 TI - The family of maize D-type cyclins: genomic organization, phylogeny and expression patterns. AB - Cyclin proteins, associated to cyclin-dependent kinases (CDKs), play fundamental roles in cell cycle control as they constitute a very important driving force to allow cell cycle progression. D-type cyclins (CycDs) are important both for interpreting external mitogenic signals and in the control of the G1 phase. The maize (Zea mays) genome appears to contain at least 17 different CycD genes, and they fall into the subgroups previously described for other plants. Maize CycDs have been named according to identity percentages of the corresponding orthologs in rice and Arabidopsis. In silico analysis confirmed the presence of characteristic cyclin domains in each maize CycD gene and showed that their genomic organization is similar to their orthologs in rice and Arabidopsis. The expression of maize CycD genes was followed in seeds, during germination in the presence/absence of exogenously added hormones, and also in different plantlet tissues (mesocotyl, root tips and first leaf). Most cyclins were expressed in germinating seeds and at least in one of the plantlet tissues tested; almost all of the detected cyclins show an accumulating pattern of mRNA along germination (0 24 h) and higher levels in root tissue. Interestingly, some cyclins show high levels in non-proliferating tissues as leaf. Addition of auxins or cytokinins does not seem to importantly modify transcript levels; on the other hand, addition of abscisic acid repressed the expression of several cyclins. The role of each CycD during germination and plant growth and its interaction with other cell cycle proteins becomes a topic of the highest interest. PMID- 21707639 TI - Ambivalent sexism: a tool for understanding and improving gender relations in organizations. AB - This study tested predictions regarding ambivalent sexism, previously studied cross-culturally, here "within-culturally", between groups from different organizational settings. Based on three samples (334 adults in general, 744 industrial employees, and 189 high school students), completing a Swedish version of the Ambivalent Sexism Inventory (ASI), the results revealed that men scored higher on hostile and benevolent sexism than women, and high school students scored higher than both adult samples on both forms of sexism. The results generally confirmed the predictions; the gender gap in benevolent sexism decreased as a function of increasing levels of general sexism and the correlation between hostile and benevolent sexism decreased with higher levels of general sexism. In fact, the groups scoring highest on general sexism displayed significant negative correlations indicating a polarized ideology of women among these groups. Implications, both theoretical and practical, derived from these results are discussed. PMID- 21707638 TI - Investigation of a His-rich arabinogalactan-protein for micronutrient biofortification of cereal grain. AB - The micronutrient content of most cereal grains is low and responsible for malnutrition deficiencies in millions of people who rely on grains as their primary food source. Any strategy that can increase the micronutrient content of grain will have significant benefits to world health. We identified a gene from barley encoding a cell wall protein with multiple histidine (His)-rich motifs interspersed with short arabinogalactan-protein (AGP) domains and have called it Hordeum vulgare His-rich AGP (HvHRA1). Sequence analysis shows that His-rich AGPs are rare in plants and that the number of His-rich and AGP domains differ between cereals and dicots. The barley and wheat encoded proteins have more than 13 His rich domains, whereas the putative rice orthologue has only 5 His-rich regions. His-rich motifs are well-established metal-binding motifs; therefore, we developed transgenic (Tx) rice plants that constitutively overexpress barley HvHRA1. There was no significant effect on plant growth or grain yield in Tx plants. Purification of AGPs from wild-type and Tx plants showed that only Tx plants contained detectable levels of a His-rich AGP. Calcein assay shows that the AGP fraction from Tx plants had increased binding affinity for Cu(2+) . Micronutrient analysis of brown and white rice showed that the grain nutrient yield for Fe, Zn and Cu was higher in two Tx lines compared to their respective nulls, although the differences were not statistically significant. This approach highlights the potential of the plant apoplast (cell wall) for storage of key nutrients through overexpression of genes for metal-binding proteins. PMID- 21707644 TI - Latent change score modeling of psychophysiological data: an empirical instantiation using electrodermal responding. AB - We examined latent change score (LCS) modeling as an approach to the analysis of children's skin conductance level (SCL) throughout a stressful task-a simulated interadult argument-as it relates to externalizing and internalizing symptoms. LCS is an extension of traditional multilevel modeling (MLM), which allows estimation of proportional growth terms. Children (age 6-12 years; N=150) were from two-parent families. Mothers reported on children's internalizing and externalizing symptoms. Results indicated that the LCS models outperformed the traditional MLM. The use of LCS yielded important novel information regarding profile and pattern of responding for various children and is likely to advance understanding of relations between children's physiological responses and psychopathology symptoms. PMID- 21707645 TI - European Academy of Allergy and Clinical Immunology task force report on 'dose response relationship in allergen-specific immunotherapy'. AB - BACKGROUND: For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen products for SIT are being increasingly required to conform to regulatory requirements for human medicines, which include the need to demonstrate dose-dependent effects. METHODS: This report, produced by a Task Force of the EAACI Immunotherapy Interest Group, evaluates the currently available data on dose-response relationships in SIT and aims to provide recommendations for the design of future studies. RESULTS: Fifteen dose-ranging studies fulfilled the inclusion criteria and twelve reported a dose-response relationship for clinical efficacy. Several studies also reported a dose-response relationship for immunological and safety endpoints. Due to the use of different reference materials and methodologies for the determination of allergen content, variations in study design, and choice of endpoints, no comparisons could be made between studies and, as a consequence, no general dosing recommendations can be made. CONCLUSION: Despite recently introduced guidelines on the standardization of allergen preparations and study design, the Task Force identified a need for universally accepted standards for the measurement of allergen content in SIT preparations, dosing protocols, and selection of clinical endpoints to enable dose-response effects to be compared across studies. PMID- 21707646 TI - Spatial variation in photosynthetic CO(2) carbon and oxygen isotope discrimination along leaves of the monocot triticale (Triticum * Secale) relates to mesophyll conductance and the Peclet effect. AB - Carbon and oxygen isotope discrimination of CO(2) during photosynthesis (Delta(13)C(obs) and Delta(18)O(obs)) were measured along a monocot leaf, triticale (Triticum * Secale). Both Delta(13)C(obs) and Delta(18)O(obs) increased towards the leaf tip. While this was expected for Delta(18)O(obs) , because of progressive enrichment of leaf water associated with the Peclet effect, the result was surprising for Delta(13) C(obs). To explore parameters determining this pattern, we measured activities of key photosynthetic enzymes [ribulose bis phosphate carboxylase-oxygenase (Rubisco), phosphoenolpyruvate carboxylase (PEPC) and carbonic anhydrase) as well as maximum carboxylation and electron transport rates (V(cmax) and J(max)) along the leaf. Patterns in leaf internal anatomy along the leaf were also quantified. Mesophyll conductance (g(m)) is known to have a strong influence on Delta(13)C(obs) , so we used three commonly used estimation methods to quantify variation in g(m) along the leaf. Variation in Delta(13)C(obs) was correlated with g(m) and chloroplast surface area facing the intercellular air space, but unrelated to photosynthetic enzyme activity. The observed variation could cause errors at higher scales if the appropriate portion of a leaf is not chosen for leaf-level measurements and model parameterization. Our study shows that one-third of the way from the base of the leaf represents the most appropriate portion to enclose in the leaf chamber. PMID- 21707647 TI - Changes in light intensity reveal a major role for carbon balance in Arabidopsis responses to high temperature. AB - High temperature (HT) is a major limiting factor for plant productivity. Because some responses to HT, notably hyponasty, resemble those encountered in low light (LL), we hypothesized that plant responses to HT are under the control of carbon balance. We analysed the interactive effects of HT and irradiance level on hyponasty and a set of traits related to plant growth in natural accessions of Arabidopsis thaliana and mutants affected in heat dissipation through transpiration (NCED6-OE, ost2) and starch metabolism (pgm). HT induced hyponasty, reduced plant growth and modified leaf structure. LL worsened the effects of HT, while increasing light restored trait values close to levels observed at control temperature. Leaf temperature per se did not play a major role in the observed responses. By contrast, a major role of carbon balance was supported by hyponastic growth of pgm, as well as morphological, physiological (photosynthesis, sugar and starch contents) and transcriptional data. Carbon balance could be a common sensor of HT and LL, leading to responses specific of the shade avoidance syndrome. Hyponasty and associated changes in plant traits could be key traits conditioning plant performance under competition for light, particularly in warm environments. PMID- 21707648 TI - Mycorrhizal symbiosis stimulates endoreduplication in angiosperms. AB - Symbiotic and parasitic relationships can alter the degree of endoreduplication in plant cells, and a limited number of studies have documented this occurrence in root cells colonized by arbuscular mycorrhizal (AM) fungi. However, this phenomenon has not been tested in a wide range of plant species, including species that are non-endopolyploid and those that do not associate with AM fungi. We grew 37 species belonging to 16 plant families, with a range of genome sizes and a range in the degree of endopolyploidy. The endoreduplication index (EI) was compared between plants that were inoculated with Glomus irregulare and plants that were not inoculated. Of the species colonized with AM fungi, 22 of the 25 species had a significant increase in endopolyploid root nuclei over non mycorrhizal plants, including species that do not normally exhibit endopolyploidy. Changes in the EI were strongly correlated (R(2) = 0.619) with the proportion of root length colonized by arbuscules. No change was detected in the EI for the 12 non-mycorrhizal species. This work indicates that colonization by symbiotic fungi involves a mechanism to increase nuclear DNA content in roots across many angiosperm groups and is likely linked to increased metabolism and protein production. PMID- 21707649 TI - Hydrogen peroxide modulates the dynamic microtubule cytoskeleton during the defence responses to Verticillium dahliae toxins in Arabidopsis. AB - The molecular mechanisms of signal transduction of plants in response to infection by Verticillium dahliae (VD) are not well understood. We previously showed that NO may act as an upstream signalling molecule to trigger the depolymerization of cortical microtubules in Arabidopsis. In the present study, we used the wild-type, and atrbohD and atrbohF mutants of Arabidopsis to explore the mechanisms of action of H(2)O(2) signals and the dynamic microtubule cytoskeleton in defence responses. We demonstrated that H(2)O(2) may also act as an upstream signalling molecule to regulate cortical microtubule depolymerization. The depolymerization of the cortical microtubules played a functional role in the signalling pathway to mediate the expression of defence genes. The results indicate that H(2)O(2) modulates the dynamic microtubule cytoskeleton to trigger the expression of defence genes against V. dahliae toxins (VD-toxins) in Arabidopsis. PMID- 21707650 TI - Water supply and not nitrate concentration determines primary root growth in Arabidopsis. AB - Understanding how root system architecture (RSA) adapts to changing nitrogen and water availability is important for improving acquisition. A sand rhizotron system was developed to study RSA in a porous substrate under tightly regulated nutrient supply. The RSA of Arabidopsis seedlings under differing nitrate (NO3-) and water supplies in agar and sand was described. The hydraulic conductivity of the root environment was manipulated by using altered sand particle size and matric potentials. Ion-selective microelectrodes were used to quantify NO3- at the surface of growing primary roots in sands of different particle sizes. Differences in RSA were observed between seedlings grown on agar and sand, and the influence of NO3- (0.1-10.0 mm) and water on RSA was determined. Primary root length (PRL) was a function of water flux and independent of NO3-. The percentage of roots with laterals correlated with water flux, whereas NO3- supply was important for basal root (BR) growth. In agar and sand, the NO3- activities at the root surface were higher than those supplied in the nutrient solution. The sand rhizotron system is a useful tool for the study of RSA, providing a porous growth environment that can be used to simulate the effects of hydraulic conductivity on growth. PMID- 21707651 TI - Are gas exchange responses to resource limitation and defoliation linked to source:sink relationships? AB - Productivity of trees can be affected by limitations in resources such as water and nutrients, and herbivory. However, there is little understanding of their interactive effects on carbon uptake and growth. We hypothesized that: (1) in the absence of defoliation, photosynthetic rate and leaf respiration would be governed by limiting resource(s) and their impact on sink limitation; (2) photosynthetic responses to defoliation would be a consequence of changing source:sink relationships and increased availability of limiting resources; and (3) photosynthesis and leaf respiration would be adjusted in response to limiting resources and defoliation so that growth could be maintained. We tested these hypotheses by examining how leaf photosynthetic processes, respiration, carbohydrate concentrations and growth rates of Eucalyptus globulus were influenced by high or low water and nitrogen (N) availability, and/or defoliation. Photosynthesis of saplings grown with low water was primarily sink limited, whereas photosynthetic responses of saplings grown with low N were suggestive of source limitation. Defoliation resulted in source limitation. Net photosynthetic responses to defoliation were linked to the degree of resource availability, with the largest responses measured in treatments where saplings were ultimately source rather than sink limited. There was good evidence of acclimation to stress, enabling higher rates of C uptake than might otherwise have occurred. PMID- 21707652 TI - Impact of irradiance on the C allocation in the coastal marine diatom Skeletonema marinoi Sarno and Zingone. AB - Elemental stoichiometry and organic composition were investigated in an Adriatic strain of Skeletonema marinoi, cultured at 25 [low light (LL)] and 250 [high light (HL)]umol photon m-2 s-1. Inorganic carbon acquisition, fixation and allocation, and silicic acid and orthophosphate uptake were also studied. The C:P ratio was below the Redfield ratio, especially at LL. In HL cells, N quota was halved, C quota was similar, silica quota was lower, growth rate and long-term net primary productivity were almost doubled, relative to LL cells. The HL:LL cell quota ratios were 6 for lipid, 0.5 for protein and 0.4 for carbohydrate. Phosphoenolpyruvate carboxylase (PEPc) and glutamine synthetase (GS) activities were unaffected by the growth irradiance; phosphoenolpyruvate carboxykinase (PEPck) was 2.5-fold more active in LL cells. This suggests that in S. marinoi, C4 photosynthesis is unlikely, PEPc is anaplerotic and PEPck may be involved in the conversion of lipid C to carbohydrates, especially in LL cells. Because about 50% of the cost for the production of an HL cell is caused by lipid biosynthesis, we propose that the preferential allocation of C to lipid at HL takes advantage of the relatively high volume-based energy content of lipids, in an organism that reduces its size at each vegetative cell division. PMID- 21707653 TI - Phloem unloading follows an extensive apoplasmic pathway in cucumber (Cucumis sativus L.) fruit from anthesis to marketable maturing stage. AB - The phloem unloading pathway remains unclear in fruits of Cucurbitaceae, a classical stachyose-transporting species with bicollateral phloem. Using a combination of electron microscopy, transport of phloem-mobile symplasmic tracer carboxyfluorescein, assays of acid invertase and sucrose transporter, and [(14)C]sugar uptake, the phloem unloading pathway was studied in cucumber (Cucumis sativus) fruit from anthesis to the marketable maturing stage. Structural investigations showed that the sieve element-companion cell (SE-CC) complex of the vascular bundles feeding fruit flesh is apparently symplasmically restricted. Imaging of carboxyfluorescein unloading showed that the dye remained confined to the phloem strands of the vascular bundles in the whole fruit throughout the stages examined. A 37 kDa acid invertase was located predominantly in the cell walls of SE-CC complexes and parenchyma cells. Studies of [(14)C]sugar uptake suggested that energy-driven transporters may be functional in sugar trans-membrane transport within symplasmically restricted SE-CC complex, which was further confirmed by the existence of a functional plasma membrane sucrose transporter (CsSUT4) in cucumber fruit. These data provide a clear evidence for an apoplasmic phloem unloading pathway in cucumber fruit. A presumption that putative raffinose or stachyose transporters may be involved in soluble sugars unloading was discussed. PMID- 21707654 TI - Crosstalk between abiotic ultraviolet-B stress and biotic (flg22) stress signalling in Arabidopsis prevents flavonol accumulation in favor of pathogen defence compound production. AB - Plants respond to both abiotic and biotic stresses with alterations in the expression of genes required to produce protective metabolites. Sometimes plants can be challenged with different stresses simultaneously and as they cannot evade from this situation, priorities have to be set to deal with the most urgent threat. The abiotic stress ultraviolet-B (UV-B) light induces the production of UV-protective flavonols in Arabidopsis Col-0 cell suspension cultures and this accumulation is attenuated by concurrent application of the bacterial elicitor flg22 (simulating biotic stress). This inhibition correlates with strong suppression of the flavonol biosynthesis genes. In parallel, flg22 induces the production of defence-related compounds, such as the phytoalexins, camalexin and scopoletin, as well as lignin, a structural barrier thought to restrict pathogen spread. This correlated positively with flg22-mediated expression of enzymes for lignin, scopoletin and camalexin production. As flavonols, lignin and scopoletin are all derived from phenylalanine, it appears that the plant focuses the metabolism on production of scopoletin and lignin at the expense of flavonol production. Furthermore, it appears that this crosstalk involves antagonistic regulation of two opposing MYB transcription factors, the positive regulator of the flavonol pathway MYB12 (UV-B-induced and flg22-suppressed) and the negative regulator MYB4 (UV-B- and flg22-induced). PMID- 21707655 TI - Nutritional benefit from leaf litter utilization in the pitcher plant Nepenthes ampullaria. AB - The pitcher plant Nepenthes ampullaria has an unusual growth pattern, which differs markedly from other species in the carnivorous genus Nepenthes. Its pitchers have a reflexed lid and sit above the soil surface in a tighly packed 'carpet'. They contain a significant amount of plant-derived materials, suggesting that this species is partially herbivorous. We tested the hypothesis that the plant benefits from leaf litter utilization by increased photosynthetic efficiency sensu stricto cost/benefit model. Stable nitrogen isotope abundance indicated that N. ampullaria derived around 41.7 +/- 5.5% of lamina and 54.8 +/- 7.0% of pitcher nitrogen from leaf litter. The concentrations of nitrogen and assimilation pigments, and the rate of net photosynthesis (A(N)), increased in the lamina as a result of feeding, but did not increase in the trap. However, maximal (F(v) /F(m)) and effective photochemical quantum yield of photosystem II (Phi(PSII)) were unaffected. Our data indicate that N. ampullaria benefits from leaf litter utilization and our study provides the first experimental evidence that the unique nitrogen sequestration strategy of N. ampullaria provides benefits in term of photosynthesis and growth. PMID- 21707656 TI - Differential response of young and adult leaves to herbicide 2,4 dichlorophenoxyacetic acid in pea plants: role of reactive oxygen species. AB - In this work the differential response of adult and young leaves from pea (Pisum sativum L.) plants to the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) (23 mm) applied by foliar spraying was investigated. The concentration of 2,4-D (23 mm) and the time of treatment (72 h) were previously optimized in order to visualize its toxic effects on pea plants. Under these conditions, the herbicide induced severe disturbances in mesophyll cells structure and proliferation of vascular tissue in young leaves and increased acyl-CoA oxidase (ACX), xanthine oxidase (XOD) and lipoxygenase (LOX) activities in young leaves, and only ACX and LOX in adult leaves. This situation produced reactive oxygen species (ROS) over accumulation favoured by the absence of significant changes in the enzymatic antioxidants, giving rise to oxidative damages to proteins and membrane lipids. An increase of ethylene took place in both young and adult leaves and the induction of genes encoding the stress proteins, PRP4A and HSP 71,2, was observed mainly in young leaves. These results suggest that ROS overproduction is a key factor in the effect of high concentrations of 2,4-D, and ROS can trigger a differential response in young and adult leaves, either epinasty development in young leaves or senescence processes in adult tissues. PMID- 21707657 TI - Physiological impact of mitochondrial alternative oxidase on photosynthesis and growth in Arabidopsis thaliana. AB - The mitochondrial alternative oxidase (AOX) has been suggested to have a beneficial role in illuminated leaves, but its function has not yet been fully elucidated. In this study, we investigated the effects of a knockout of the AOX1a gene on photosynthesis and growth under several light conditions in Arabidopsis thaliana. The AOX-deficient aox1a mutant showed a lowered operating efficiency of photosystem II and an enhanced activity of cyclic electron transport around photosystem I (CET-PSI) at high irradiance. To further address the physiological association of AOX with CET-PSI, we crossed aox1a with the pgr5 mutant, which is impaired in CET-PSI activity. In the pgr5 mutant background, AOX deficiency did not affect the apparent photosynthetic efficiency, indicating that the direct contribution of AOX to photosynthesis is not so large compared with CET-PSI. Nevertheless, the growth of the aox1a pgr5 double mutant was significantly impaired depending on the light intensity under growth conditions. The possibility of a synergistic function of AOX with CET-PSI in supporting plant growth is discussed. PMID- 21707658 TI - Producing parasitic helminth reference and draft genomes at the Wellcome Trust Sanger Institute. AB - The Wellcome Trust Sanger Institute (WTSI) is producing de novo reference quality genomes for parasitic helminth species from platyhelminth tapeworms (cestodes), flukes (trematodes) and roundworms (nematodes) primarily using second-generation (Illumina and 454) sequencing technologies. The reference genomes will be followed with draft coverage from a number of related strains or species. Comparing species- or strain-specific differences will help to unravel the genomic basis for differences in the organism's biology and ultimately contribute towards identifying potential novel targets for vaccine therapies. Second generation sequencing technologies are revolutionizing parasite genomics. This article reviews the impact that sequencing technologies has had on genomics and how it has shaped the parasitic helminth genome sequencing initiative at WTSI. PMID- 21707659 TI - Advancing the business creed? The framing of decisions about public sector managed care. AB - Relatively little research has clarified how executives of for-profit healthcare organisations frame their own motivations and behaviour, or how government officials frame their interactions with executives. Because managed care has provided an organisational structure for health services in many countries, we focused our study on executives and government officials who were administering public sector managed care services. Emphasising theoretically the economic versus non-economic motivations that guide economic behaviour, we extended a long term research project on public sector Medicaid managed care (MMC) in the United States. Our method involved in-depth, structured interviews with chief executive officers of managed care organisations, as well as high-ranking officials of state government. Data analysis involved iterative interpretation of interview data. We found that the rate of profit, which proved relatively low in the MMC programme, occupied a limited place in executives' self-described motivations and in state officials' descriptions of corporation-government interactions. Non economic motivations included a strong orientation toward corporate social responsibility and a creed in which market processes advanced human wellbeing. Such patterns contradict some of the given wisdom about how corporate executives and government officials construct their reality. PMID- 21707661 TI - Men's discourses of help-seeking in the context of depression. AB - Depression is an illness increasingly constructed as a gendered mood disorder and consequently diagnosed in women more than men. The diagnostic criteria used for its assessment often perpetrate and reproduce gender stereotypes. The stigma associated with mental illness and the gendered elements of depression suggest there are likely numerous discourses that position, explain, and justify help seeking practices. This qualitative study explored men's discourses of seeking help for depression. The methodological approach was informed by a social constructionist perspective of language, discourse and gender that drew on methods from discourse analysis. We conducted individual in-depth, semi structured interviews with 38 men with depression, either formally diagnosed or self reported. The analysis revealed five discursive frames that influenced the men's talk about help-seeking and depression: manly self-reliance; treatment seeking as responsible independent action; guarded vulnerability; desperation; and genuine connection. The findings are discussed within a broader context of social discourses of gender, the limitations of current help-seeking literature and the evidence for how men seek help in ways that extend traditional notions of medical treatment. PMID- 21707660 TI - Grey spaces: the wheeled fields of residential care. AB - Many individuals living in residential care use a wheelchair as their primary means of mobility. Although studies have documented challenges encountered by residents in these facilities, few have addressed the role that wheelchairs, as potential enablers and barriers to mobility and participation, play in their lives. To better understand residents' experiences, an ethnographic study was conducted drawing on Bourdieu's theoretical constructs of capital, field, and habitus. Participant observations were conducted at two facilities, and residents, family members and staff took part in in-depth individual interviews. Our analysis revealed three themes. Ready to roll detailed how residents used wheelchairs as a source of comfort and means for expanding their social space, while staff could use them as a means to move and control some residents. Squeaky wheels described how residents solicited assistance from staff and family amid having to wait to perform activities of daily living. In, out and about revealed diversity in the places residents went, spaces they shared and the social activities in which they engaged inside and outside their residential facilities. The study findings emphasise how wheelchairs constitute capital that governs many fields of practice for residents and staff and suggest how practice and policy might be adjusted. PMID- 21707662 TI - Forgetting and remembering epilepsy: collective memory and the experience of illness. AB - How do people with epilepsy relate to the long and troubling history of this disease? Drawing on two sets of interviews with people with epilepsy, one cohort from the mid-1970s and one from 2005 to 2006, this article examines how memories of what epilepsy has been shape the individual and collective identities of people living with epilepsy. We find striking similarities in how people in both interview cohorts talk about what epilepsy was in 'the Dark Ages', by which they refer to the recent past. Likewise, we find evidence of a collective identity among people with epilepsy. However, memories of epilepsy's past do not appear to serve as a basis for collective identity. Rather, these recollections are located in narratives of hope, in which people with epilepsy express confidence that the lives and life chances of people with epilepsy have improved--will continue to improve--over time. Indeed, to the extent that people with epilepsy share a temporal orientation, it is much more to a collective future than to a collective past. Our conclusions, therefore, focus on the ways that the meanings of the past are shaped not only by present events but also by anticipated futures. PMID- 21707663 TI - From personal tragedy to personal challenge: responses to stigma among sober living home residents and operators. AB - Sober living homes for people attempting to maintain abstinence from alcohol and drugs can act as a buffer against the high rates of substance misuse that are endemic to many urban environments. Sober living homes and other group homes for people with disabilities have faced persistent opposition from neighbourhood associations, which raises the question of stigma. This article describes the responses of sober living home residents and operators to the threat of stigma across a diverse set of neighbourhoods. Ten focus groups were conducted with 68 residents and operators of 35 sober living homes in Los Angeles County, California, between January 2009 and March 2010. Results showed that few residents reported experiences of blatant stigmatisation by neighbours; however, they were well aware of the stereotypes that could be ascribed to them. Despite this potential stigma, residents developed valued identities as helpers in their communities, providing advice to neighbours whose family or friends had substance use problems, and organising community service activities to improve the appearance of their neighbourhoods. With their attention to local context, sober living home residents and operators challenge the personal tragedy approach of much traditional advocacy on health-related stigma. PMID- 21707664 TI - Does reading keep you thin? Leisure activities, cultural tastes, and body weight in comparative perspective. AB - While sedentary leisure-time activities such as reading, going to movies, attending cultural events, going to sporting events, watching TV, listening to music, and socialising with friends would seem to contribute to excess weight, a perspective focusing on socioeconomic status (SES) differences in cultural tastes suggests the opposite, that some sedentary activities are associated with lower rather than higher body weight. This study aims to test theories of cultural distinction by examining relationships between leisure-time activities and body weight. Using 2007 data on 17 nations from the International Social Survey Program (ISSP), the analysis estimates relationships between the body mass index and varied leisure-time activities while controlling for SES, physical activities, and sociodemographic variables. Net of controls for SES and physical activities, participation time in cultural activities is associated with lower rather than higher body weight, particularly in high-income nations. The results suggest that both cultural activities and body weight reflect forms of distinction that separate SES-based lifestyles. PMID- 21707665 TI - HIV and identity: the experience of AIDS support group members who unexpectedly tested HIV negative in Uganda. AB - Living with HIV, for many of those infected, has meant adjusting to life with a stigmatised condition and, until recently, the threat of looming death. We explore the adjustment of a group of long-term former clients of The AIDS Support Organisation (TASO) in Uganda who, when tested for HIV during the rollout of antiretroviral therapy in 2004, were found to be HIV negative. In-depth semi structured interviews with 34 former TASO clients were conducted between 2005 and 2007. Their narratives reveal a great deal about the biographical disruption they have faced, and the biographical work that they have undertaken in both the personal and the social dimensions of their lives in order to manage their new found HIV-uninfected status. After the negative test result, as they were no longer HIV-infected, they had to leave TASO and that support was sorely missed, as was the friendship of TASO members to whom they often felt reluctant to disclose their new status. The identity 'reversal' or change was often handled privately. Compared with their transition to an HIV-positive identity, they now lacked a social dimension to their identity transformation as they managed their new identity in the face of self- and public doubt. PMID- 21707666 TI - Rejection as a call to arms: inter-racial hostility and support for political action as outcomes of race-based rejection in majority and minority groups. AB - Both majority and minority group members fear race-based rejection, and respond by disparaging the groups that they expect will reject them. It is not clear, however, how this process differs in minority and majority groups. Using large representative samples of White (N= 4,618) and Maori (N= 1,163) New Zealanders, we found that perceptions of race-based rejection predicted outgroup negativity in both groups, but in different ways and for different reasons. For White (but not Maori) New Zealanders, increased intergroup anxiety partially mediated the relationship between cognitions of rejection and outgroup negativity. Maori who expected to be rejected on the basis of their race reported increased ethnic identification and, in part through this, increased support for political action benefiting their own group. This finding supports collective-action models of social change in historically disadvantaged minority groups. PMID- 21707667 TI - The 11th world survey of cardiac pacing and implantable cardioverter defibrillators: calendar year 2009--a World Society of Arrhythmia's project. AB - A worldwide cardiac pacing and implantable cardioverter-defibrillator (ICD) survey was undertaken for calendar year 2009 and compared to a similar survey conducted in 2005. There were contributions from 61 countries: 25 from Europe, 20 from the Asia Pacific region, seven from the Middle East and Africa, and nine from the Americas. The 2009 survey involved 1,002,664 pacemakers, with 737,840 new implants and 264,824 replacements. The United States of America (USA) had the largest number of cardiac pacemaker implants (225,567) and Germany the highest new implants per million population (927). Virtually all countries showed increases in implant numbers over the 4 years between surveys. High-degree atrioventricular block and sick sinus syndrome remain the major indications for implantation of a cardiac pacemaker. There remains a high percentage of VVI(R) pacing in the developing countries, although compared to the 2005 survey, virtually all countries had increased the percentage of DDDR implants. Pacing leads were predominantly transvenous, bipolar, and active fixation. The survey also involved 328,027 ICDs, with 222,407 new implants and 105,620 replacements. Virtually all countries surveyed showed a significant rise in the use of ICDs with the largest implanter being the USA (133,262) with 434 new implants per million population. This was the largest pacing and ICD survey ever performed, because of mainly a group of loyal enthusiastic survey coordinators. It encompasses more than 80% of all the pacemakers and ICDs implanted worldwide during 2009. PMID- 21707669 TI - Persistence of antibiotic resistance in bacterial populations. AB - Unfortunately for mankind, it is very likely that the antibiotic resistance problem we have generated during the last 60 years due to the extensive use and misuse of antibiotics is here to stay for the foreseeable future. This view is based on theoretical arguments, mathematical modeling, experiments and clinical interventions, suggesting that even if we could reduce antibiotic use, resistant clones would remain persistent and only slowly (if at all) be outcompeted by their susceptible relatives. In this review, we discuss the multitude of mechanisms and processes that are involved in causing the persistence of chromosomal and plasmid-borne resistance determinants and how we might use them to our advantage to increase the likelihood of reversing the problem. Of particular interest is the recent demonstration that a very low antibiotic concentration can be enriching for resistant bacteria and the implication that antibiotic release into the environment could contribute to the selection for resistance. Several mechanisms are contributing to the stability of antibiotic resistance in bacterial populations and even if antibiotic use is reduced it is likely that most resistance mechanisms will persist for considerable times. PMID- 21707668 TI - The circadian clock of Neurospora crassa. AB - Circadian clocks organize our inner physiology with respect to the external world, providing life with the ability to anticipate and thereby better prepare for major fluctuations in its environment. Circadian systems are widely represented in nearly all major branches of life, except archaebacteria, and within the eukaryotes, the filamentous fungus Neurospora crassa has served for nearly half a century as a durable model organism for uncovering the basic circadian physiology and molecular biology. Studies using Neurospora have clarified our fundamental understanding of the clock as nested positive and negative feedback loops regulated through transcriptional and post transcriptional processes. These feedback loops are centered on a limited number of proteins that form molecular complexes, and their regulation provides a physical explanation for nearly all clock properties. This review will introduce the basics of circadian rhythms, the model filamentous fungus N. crassa, and provide an overview of the molecular components and regulation of the circadian clock. PMID- 21707671 TI - Comparison of microbial communities associated with three Atlantic ultramafic hydrothermal systems. AB - The distribution of Archaea and methanogenic, methanotrophic and sulfate-reducing communities in three Atlantic ultramafic-hosted hydrothermal systems (Rainbow, Ashadze, Lost City) was compared using 16S rRNA gene and functional gene (mcrA, pmoA and dsrA) clone libraries. The overall archaeal community was diverse and heterogeneously distributed between the hydrothermal sites and the types of samples analyzed (seawater, hydrothermal fluid, chimney and sediment). The Lost City hydrothermal field, characterized by high alkaline warm fluids (pH>11; T<95 degrees C), harbored a singular archaeal diversity mostly composed of unaffiliated Methanosarcinales. The archaeal communities associated with the recently discovered Ashadze 1 site, one of the deepest active hydrothermal fields known (4100 m depth), showed significant differences between the two different vents analyzed and were characterized by putative extreme halophiles. Sequences related to the rarely detected Nanoarchaeota phylum and Methanopyrales order were also retrieved from the Rainbow and Ashadze hydrothermal fluids. However, the methanogenic Methanococcales was the most widely distributed hyper/thermophilic archaeal group among the hot and acidic ultramafic-hosted hydrothermal system environments. Most of the lineages detected are linked to methane and hydrogen cycling, suggesting that in ultramafic-hosted hydrothermal systems, large methanogenic and methanotrophic communities could be fuelled by hydrothermal fluids highly enriched in methane and hydrogen. PMID- 21707672 TI - Genetic diversity of cyanobacteria in four eutrophic lakes. AB - Recent studies indicate genetic diversity of cyanobacteria in eutrophic lakes is not represented well by culture collections or morphology. Yet, few studies have investigated genetic richness and evenness of cyanobacteria using culture independent methods. We compared the genetic structure of cyanobacteria supported by four neighboring eutrophic lakes during the ice-free season. The partial phycobilincpcB/A genes plus intergenic spacer (PC-IGS) was used as a genetic marker.Sequences were phylogeneticallygrouped by maximum likelihood into genotypes representing sub-genera of the major taxa. Genotypes fell into genera commonly observed by microscopy in these lakes including Microcystis, Aphanizomenon, Chroococcus, Anabaena, and Cylindrospermopsis. Only three genotypes were shared among all four lakes, despite significant water flowage between lakes.A Parsimony P-test indicated lakes were significantly (p=0.01) clustered on the maximum likelihood tree. Pairwise differences using Unifrac distance were moderately or not significant. Analysis of molecular variance (AMOVA) indicated genetic variation among all genotypes (phi=0.06, p<0.001) and 94% of variability occurred within lakes rather than between lakes (6%), explaining the lack of pairwise differences between lakes. Lorenze curves of genotype abundance in each lake showed genetic structure was only moderately uneven (Gini coefficients of 0.37-0.5) indicating lakes did not support dominant genotypes. Overall, results from this study suggest diversity of cyanobacteria is shaped by heterogeneity within lakes (temporally or spatially) and relatively even population structures. PMID- 21707670 TI - Broad-specificity efflux pumps and their role in multidrug resistance of Gram negative bacteria. AB - Antibiotic resistance mechanisms reported in Gram-negative bacteria are causing a worldwide health problem. The continuous dissemination of 'multidrug-resistant' (MDR) bacteria drastically reduces the efficacy of our antibiotic 'arsenal' and consequently increases the frequency of therapeutic failure. In MDR bacteria, the overexpression of efflux pumps that expel structurally unrelated drugs contributes to the reduced susceptibility by decreasing the intracellular concentration of antibiotics. During the last decade, several clinical data have indicated an increasing involvement of efflux pumps in the emergence and dissemination of resistant Gram-negative bacteria. It is necessary to clearly define the molecular, functional and genetic bases of the efflux pump in order to understand the translocation of antibiotic molecules through the efflux transporter. The recent investigation on the efflux pump AcrB at its structural and physiological levels, including the identification of drug affinity sites and kinetic parameters for various antibiotics, may pave the way towards the rational development of an improved new generation of antibacterial agents as well as efflux inhibitors in order to efficiently combat efflux-based resistance mechanisms. PMID- 21707673 TI - Diverse communities of arbuscular mycorrhizal fungi inhabit sites with very high altitude in Tibet Plateau. AB - Diversity of arbuscular mycorrhizal fungi (AMF) is well studied in many ecosystems, but little is known about AMF in cold-dominated regions with very high altitude. Here, we examined AMF communities associated with two plant species in the Tibet Plateau. Roots and rhizosphere soils of Dracocephalum heterophyllum (pioneer species) and Astragalus polycladus (late-successional species) were sampled at five sites with altitude from 4500 to 4800 m a.s.l. A total of 21 AMF phylotypes were identified from roots and spores following cloning and sequencing of 18S rRNA gene, including eight new phylotypes and one new family-like clade. More AMF phylotypes colonized root samples of D. heterophyllum (5.4+/-0.49) than of A. polycladus (1.93+/-0.25). Vegetation coverage was the most important factor influencing AMF community composition in roots. Globally infrequent phylotype Glo-B2 in Glomus group B was the most dominant in roots, followed by globally frequent phylotype Glo-A2 related to Glomus fasciculatum/intraradices group. Our findings suggest that a diverse AMF flora is present in the Tibet Plateau, comprising both potentially habitat selective and generalist fungi. PMID- 21707674 TI - Development of bacterial community during spontaneous succession on spoil heaps after brown coal mining. AB - Changes in the abundance of bacteria and fungi and in the composition of bacterial communities during primary succession were investigated in a brown coal mine deposit area near Sokolov, the Czech Republic, using phospholipid fatty acids analysis, microarray and 16S rRNA gene sequencing. The study considered a chronosequence of sites undergoing spontaneous succession: 6-, 12-, 21- and 45 year-old and a 21-year-old site revegetated with Alnus glutinosa. During succession, organic carbon and the total nitrogen content increased while the pH and the C/N ratio decreased. Microbial biomass and bacterial diversity increased until 21 years and decreased later; bacteria dominated over fungi in the initial and late phases of succession. Bacterial community composition of the 6-year-old site with no vegetation cover largely differed from the older sites, especially by a higher content of Gammaproteobacteria, Cyanobacteria and some Alphaproteobacteria. Bacteria belonging to the genera Acidithiobacillus, Thiobacillus and related taxa, the CO(2) and N(2) fixers, dominated the community at this site. In the later phases, bacterial community development seemed to reflect more the changes in soil nutrient content and pH than vegetation with a decrease of Actinobacteria and an increase of Acidobacteria. The site revegetated with A. glutinosa resembled the 45-year-old primary succession site and exhibited an even lower pH and C/N ratio, indicating that recultivation is able to accelerate soil development. PMID- 21707675 TI - Nitrogen turnover in soil and global change. AB - Nitrogen management in soils has been considered as key to the sustainable use of terrestrial ecosystems and a protection of major ecosystem services. However, the microorganisms driving processes like nitrification, denitrification, N-fixation and mineralization are highly influenced by changing climatic conditions, intensification of agriculture and the application of new chemicals to a so far unknown extent. In this review, the current knowledge concerning the influence of selected scenarios of global change on the abundance, diversity and activity of microorganisms involved in nitrogen turnover, notably in agricultural and grassland soils, is summarized and linked to the corresponding processes. In this context, data are presented on nitrogen-cycling processes and the corresponding microbial key players during ecosystem development and changes in functional diversity patterns during shifts in land use. Furthermore, the impact of increased temperature, carbon dioxide and changes in precipitation regimes on microbial nitrogen turnover is discussed. Finally, some examples of the effects of pesticides and antibiotics after application to soil for selected processes of nitrogen transformation are also shown. PMID- 21707676 TI - Detection of respiratory viruses on air filters from aircraft. AB - AIMS: To evaluate the feasibility of identifying viruses from aircraft cabin air, we evaluated whether respiratory viruses trapped by commercial aircraft air filters can be extracted and detected using a multiplex PCR, bead-based assay. METHODS AND RESULTS: The ResPlex II assay was first tested for its ability to detect inactivated viruses applied to new filter material; all 18 applications of virus at a high concentration were detected. The ResPlex II assay was then used to test for 18 respiratory viruses on 48 used air filter samples from commercial aircraft. Three samples tested positive for viruses, and three viruses were detected: rhinovirus, influenza A and influenza B. For 33 of 48 samples, internal PCR controls performed suboptimally, suggesting sample matrix effect. CONCLUSION: In some cases, influenza and rhinovirus RNA can be detected on aircraft air filters, even more than 10 days after the filters were removed from aircraft. SIGNIFICANCE AND IMPACT OF THE STUDY: With protocol modifications to overcome PCR inhibition, air filter sampling and the ResPlex II assay could be used to characterize viruses in aircraft cabin air. Information about viruses in aircraft could support public health measures to reduce disease transmission within aircraft and between cities. PMID- 21707677 TI - Comparative sequence analysis of recA gene among Vibrio cholerae isolates from Iran with globally reported sequences. AB - AIMS: To study the genetic relatedness between V. cholerae isolates from Iran and other countries based on housekeeping gene recA sequence analysis. METHODS AND RESULTS: A 995-bp region of the recA gene from 24 V. cholerae isolates obtained from human and surface water origins in Iran over a 5-year period was sequenced and compared with the sequence data from the isolates belonging to other places. Cluster analysis of the constructed dendrogram based on recA sequence divergence for our clinical isolates showed one sequence type (ST), whereas environmental isolates revealed eight STs. Interestingly, one of our environmental isolates was intermixed with clinical isolates in the largest cluster containing the epidemic strains. Our 24 isolates plus 198 global isolates available in the GenBank showed 77 sequence types (STs) with at least one nucleotide difference. CONCLUSIONS: Our result suggested that recA sequencing is a reliable analysis method for understanding the relatedness of the local isolates with the isolates obtained elsewhere. SIGNIFICANCE AND IMPACT OF THE STUDY: Understanding the genetic relatedness between V. cholerae isolates could give insights into the health care system for better control and prevention of the cholera. PMID- 21707678 TI - Evolution of antimicrobial resistance of Acinetobacter baumannii in a university hospital. AB - AIMS: To investigate the susceptibility pattern and the molecular epidemiology of Acinetobacter baumannii isolates in two periods (1994-1996 and 2004-2007) in Londrina University Hospital. METHODS AND RESULTS: Antimicrobial susceptibility of 150 A. baumannii isolates was assessed by disc diffusion and agar dilution methods. Genetic similarity amongst the isolates was evaluated by ERIC-PCR. Resistance of A. baumannii to carbapenems increased from 2% (1994-1996) to 73% (2004-2007). Thirty-eight clones were detected. CONCLUSIONS: The results of the study suggest that the high prevalence of carbapenem resistance amongst Acinetobacter baumannii organisms in this institution is not caused by the spread of a predominant clone. SIGNIFICANCE AND IMPACT OF THE STUDY: This work reinforces the importance monitoring antimicrobial susceptibility rates. PMID- 21707679 TI - Randomised clinical trial: anti-viral activity of ANA773, an oral inducer of endogenous interferons acting via TLR7, in chronic HCV. AB - BACKGROUND: The ANA773 is an oral prodrug of a small-molecule toll-like receptor (TLR)7 agonist. Preclinical and healthy volunteer clinical studies with ANA773 have demonstrated induction of endogenous interferon-alpha (IFN-alpha) of multiple subtypes, which supports the potential utility in the treatment of chronic hepatitis C virus (HCV) infection. AIM: To examine safety, tolerability, pharmacodynamics, pharmacokinetics and anti-viral activity of ANA773. METHODS: The ANA773 was investigated in a double-blind, placebo-controlled study in 34 patients chronically infected with HCV of any genotype. Patients were treatment naive or had relapsed following previous interferon-based treatment. This dose escalation study was composed of four dose groups (800, 1200, 1600 and 2000mg). In each group, six to eight patients received ANA773 and two received placebo. Patients were dosed with ANA773 every-other-day for either 28 days (800, 1200 or 1600mg) or 10days (2000mg). RESULTS: Mild to moderate adverse events were reported, with an increase in frequency and intensity with increasing dose. No serious AEs were reported and there were no early discontinuations. There were dose-related increases in various markers of IFN-alpha response. The mean maximum change in serum HCV RNA level from baseline was -0.34, -0.29, -0.40, -0.97 and 1.26log(10) in the placebo, 800, 1200, 1600 and 2000mg cohorts, respectively. At the 2000mg dose, ANA773 significantly (P=0.037) reduced serum HCV RNA levels (range: 0.14 to -3.10log(10) ). CONCLUSION: The ANA773 was generally well tolerated and resulted in a dose-related IFN-dependent response leading to a significant decrease in serum HCV RNA levels in the 2000mg dose group. PMID- 21707680 TI - Meta-analysis: antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding - an updated Cochrane review. AB - BACKGROUND: Antibiotic prophylaxis seems to decrease the incidence of bacterial infections in patients with cirrhosis and upper gastrointestinal bleeding and is considered standard of care. However, there is no updated information regarding the effects of this intervention. AIM: To assess the benefits and harms of antibiotic prophylaxis in cirrhotic patients with gastrointestinal bleeding by performing a systematic review of randomised trials. METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE and Science Citation Index EXPANDED until June 2010. We statistically combined data calculating relative risk (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes. RESULTS: Twelve trials (1241 patients) evaluating antibiotic prophylaxis against placebo or no antibiotic prophylaxis were included. Antibiotic prophylaxis was associated with reduced mortality (RR 0.79, 95% CI 0.63-0.98), mortality from bacterial infections (RR 0.43, 95% CI 0.19 0.97), bacterial infections (RR 0.35, 95% CI 0.26-0.47), rebleeding (RR 0.53, 95% CI 0.38-0.74) and days of hospitalisation (MD -1.91, 95% CI -3.80-0.02). Trials analysing rebleeding rate and hospitalisation length are still scarce, thus, caution should be exerted when interpreting the results. CONCLUSIONS: Antibiotic prophylaxis in patients with cirrhosis and upper gastrointestinal bleeding significantly reduced bacterial infections, and reduce all-cause mortality, bacterial infection mortality, rebleeding events and hospitalisation length. Novel clinically significant outcomes were included in this meta-analysis. Some benefits are biased and the risks are not yet properly assessed, this encourages future research in this field. PMID- 21707681 TI - Multicentre comparison of the Glasgow Blatchford and Rockall Scores in the prediction of clinical end-points after upper gastrointestinal haemorrhage. AB - BACKGROUND: The Glasgow Blatchford Score (GBS) is increasingly being used to predict intervention and outcome following upper gastrointestinal haemorrhage (UGIH). AIM: To compare the GBS with both the admission and full Rockall scores in predicting specific clinical end-points following UGIH. PATIENTS AND METHODS: Data on consecutive patients presenting to four UK hospitals were collected. Admission history, clinical and laboratory data, endoscopic findings, treatment and clinical follow-up were recorded. Using ROC curves, we compared the three scores in the prediction of death, endoscopic or surgical intervention and transfusion. Results A total of 1555 patients (mean age 56.7years) presented with UGIH during the study period. Seventy-four (4.8%) died, 223 (14.3%) had endoscopic or surgical intervention and 363 (23.3%) required transfusion. The GBS was similar at predicting death compared with both the admission Rockall (area under ROC curve 0.804 vs. 0.801) and full Rockall score (AUROC 0.741 vs. 0.790). In predicting endo-surgical intervention, the GBS was superior to the admission Rockall (AUROC 0.858 vs. 0.705; P<0.00005) and similar to the full Rockall score (AUROC 0.822 vs. 0.797). The GBS was superior to both admission Rockall (AUROC 0.944 vs. 0.756; P<0.00005) and full Rockall scores (AUROC 0.935 vs. 0.792; P<0.00005) in predicting need for transfusion. CONCLUSIONS: Despite not incorporating age, the GBS is as effective as the admission and full Rockall scores in predicting death after UGIH. It is superior to both the admission and full Rockall scores in predicting need for transfusion, and superior to the admission Rockall score in predicting endoscopic or surgical intervention. PMID- 21707682 TI - Kinetics of butyrate metabolism in the normal colon and in ulcerative colitis: the effects of substrate concentration and carnitine on the beta-oxidation pathway. AB - BACKGROUND: Butyrate, a colonic metabolite of carbohydrates, is considered as the major energy source for the colonic mucosa. An impaired butyrate metabolism has been reported in ulcerative colitis (UC), however, the cause still remains unknown. AIM: In the present study, we investigated whether higher butyrate concentrations could normalise the oxidation rate in UC. Furthermore, it was investigated whether carnitine could enhance the butyrate oxidation. METHODS: Mucosal biopsies from a total of 26 UC patients and 25 controls were incubated with (14)C-labelled Na-butyrate and the produced (14)CO(2) was measured. First, the rate of oxidative metabolism was compared at three different concentrations of Na-butyrate (0.05 mm, 1 mm and 10 mm). Then, incubations of biopsies were performed with carnitine alone or combined with ATP. RESULTS: Overall, butyrate oxidation in UC was significantly lower than that in controls. The maximum rate of butyrate oxidation was achieved in UC and control subjects from 1 mm onwards. Increasing the butyrate concentration to a level to be present in the colonic lumen, i.e. 10 mm, did not increase the rate of butyrate oxidation in UC to the rate observed in controls. Addition of carnitine alone or combined with ATP caused no effects. CONCLUSIONS: Saturation of butyrate kinetics was achieved from 1 mm in UC and control subjects. The rate of butyrate metabolism was significantly impaired in active ulcerative colitis. The addition of compounds interfering with the beta-oxidation pathway had no effect on the butyrate metabolism in UC. PMID- 21707683 TI - Larval morphology of the lesser housefly, Fannia canicularis. AB - The morphology of all larval instars of Fannia canicularis (Linnaeus) (Diptera: Fanniidae) is documented using a combination of light and scanning electron microscopy. The following structures are documented for all instars: antennal complex; maxillary palpus; facial mask; cephaloskeleton; ventral organ; anterior spiracle; Keilin's organ; posterior spiracle; fleshy processes, and anal pad. Structures reported for the first time for all instars include: two pairs of lateral prominences on the prothoracic segment; additional ventrolateral prominences on the second thoracic segment, and a papilla at the base of the posterior spiracle. Other structures reported for the first time are anterior spiracles in the first instar and a serrated tip on the mouthhook in the second instar. A trichoid sensillum on the posterior spiracular plate, representing a sensory organ otherwise unknown in the Calyptratae, is described in the second and third instars. Results are discussed and compared with existing knowledge on dipteran larval morphology. PMID- 21707684 TI - Risk perception. PMID- 21707685 TI - On the local sensitivity analysis of the inoperability input-output model. AB - Natural and man-made disasters are currently a source of major concern for contemporary societies. In order to understand their economic impacts, the inoperability input-output model has recently gained recognition among scholars. In a recent paper, Percoco (2006) has proposed an extension of the model to map the technologically most important sectors through so-called fields of influence. In the present note we aim to show that this importance measure also has a clear connection with local sensitivity analysis theory. PMID- 21707686 TI - Risk perception and information processing: the development and validation of a questionnaire to assess self-reported information processing. AB - The role of information processing in understanding people's responses to risk information has recently received substantial attention. One limitation of this research concerns the unavailability of a validated questionnaire of information processing. This article presents two studies in which we describe the development and validation of the Information-Processing Questionnaire to meet that need. Study 1 describes the development and initial validation of the questionnaire. Participants were randomized to either a systematic processing or a heuristic processing condition after which they completed a manipulation check and the initial 15-item questionnaire and again two weeks later. The questionnaire was subjected to factor reliability and validity analyses on both measurement times for purposes of cross-validation of the results. A two-factor solution was observed representing a systematic processing and a heuristic processing subscale. The resulting scale showed good reliability and validity, with the systematic condition scoring significantly higher on the systematic subscale and the heuristic processing condition significantly higher on the heuristic subscale. Study 2 sought to further validate the questionnaire in a field study. Results of the second study corresponded with those of Study 1 and provided further evidence of the validity of the Information-Processing Questionnaire. The availability of this information-processing scale will be a valuable asset for future research and may provide researchers with new research opportunities. PMID- 21707687 TI - The BRAF(V600E) mutation is associated with malignant ultrasonographic features in thyroid nodules. AB - CONTEXT: Several ultrasonographic (US) features of thyroid nodules have been reported to predict malignancy. The BRAF(V600E) mutation is a useful diagnostic marker for differentiating papillary thyroid carcinoma from benign thyroid nodules, especially in BRAF(V600E) -prevalent populations such as in Korea. OBJECTIVE: To evaluate the association of BRAF(V600E) mutation with US features of thyroid nodules in predicting the malignancy of thyroid nodules in Korean patients. DESIGN: A total of 991 thyroid nodules from 823 patients in fine-needle aspiration biopsy (FNAB) specimens were investigated. The relationship between US features and the presence of BRAF(V600E) mutation by pyrosequencing method was prospectively analysed. RESULTS: The BRAF(V600E) mutation was associated with the following US features: solid composition [odds ratio (OR) 20.338; 95% confidence interval (CI): 4.952-83.532; P < 0.001], marked hypoechogenicity (OR 30.744; 95% CI: 15.951-59.255; P < 0.001), irregular margin (OR 9.889; 95% CI: 7.005-13.859; P < 0.001), taller-than-wide shape (OR 6.031; 95% CI: 4.343-8.376; P < 0.001) and the presence of microcalcifications (OR 6.664; 95% CI: 4.604-9.648; P < 0.001). The BRAF(V600E) mutation with malignant US features in FNAB enhanced the diagnostic accuracy compared with cytologic diagnosis alone (94.3%vs 69.7%). CONCLUSION: The BRAF(V600E) mutation is significantly associated with malignant US features, such as solid composition, marked hypoechogenicity, irregular margin, taller-than-wide shape and the presence of microcalcifications. The application of BRAF(V600E) mutation analysis in US-guided FNAB can improve the diagnostic accuracy of thyroid nodules. PMID- 21707688 TI - Molecular screening of the TSH receptor (TSHR) and thyroid peroxidase (TPO) genes in Korean patients with nonsyndromic congenital hypothyroidism. AB - OBJECTIVE: To investigate thyroid-stimulating hormone receptor (TSHR) and thyroid peroxidase (TPO) mutations in Korean patients with primary congenital hypothyroidism (CH). CONTEXT: Congenital hypothyroidism is a common genetic disorder in which the majority of mutations occur in the TSHR and TPO genes. DESIGN: We examined the frequencies of TSHR and TPO mutations among Korean patients with primary CH. Furthermore, we explored the relationships between imaging findings and mutation status. PATIENTS: A total of 193 paediatric patients with nonsyndromic CH were enrolled in the present study. MEASUREMENTS: Patients with decreased (99m) Tc uptake were screened for TSHR mutations using Sanger sequencing, and those with increased uptake were screened for TPO mutations. The relationships between scintigraphic and ultrasonographic findings and mutation status were analysed. RESULTS: Thirteen (16.5%) of 79 patients with decreased (99m) Tc uptake were found to harbour TSHR mutations including G132R, G245S, R450H, R519C and F525S. The R450H mutation was present in 13 (72.2%) of 18 disease alleles. Seven (10.3%) of 68 patients with increased (99m) Tc uptake harboured TPO mutations including R189Q, K439E, G493S, C808LfsX72, A863T, R875Hfs and P883S. The TSHR and TPO mutations were observed only in patients with normal to slightly enlarged thyroid glands. CONCLUSIONS: This study identified underlying TSHR and TPO mutations in Korean patients with CH and revealed a possible relationship between imaging findings and mutation status. In addition, the low rate of mutation positivity suggests significant genetic heterogeneity of CH in the Korean population. PMID- 21707689 TI - Daily urine iodine excretion while consuming a low-iodine diet in preparation for radioactive iodine therapy in a high iodine intake area. AB - OBJECTIVE: Recommended durations of low-iodine diet (LID) in preparation for radioactive iodine therapy (RAIT) vary among major guidelines and are important for patients in areas where iodine intake is high. The aim of this study was to investigate daily changes in urine iodine excretion after starting a LID. DESIGN: The daily iodine/creatinine (I/Cr) ratios and simple iodine concentration (simple I) of morning spot urine from 19 patients with differentiated thyroid carcinoma were measured for 2 weeks from the start of LID for RAIT preparation. We set the cut-off of I/Cr and simple I for poor LID preparation at >66.2 MUg/gCr and >150 MUg/l, respectively. The day when daily I/Cr or simple I became equal to or below the cut-off both by 95% CI and 90th percentile was defined as the end-point for the appropriate duration of LID for RAIT. RESULTS: On day 6 of LID, the I/Cr ratio decreased below the cut-off (<=66.2 MUg/gCr) both by 95% CI (0-60.8) and by 90th percentile (51.9). Simple I reached the cut-off (<=150 MUg/l) on day 3 by both parameters (95%CI: 2.3-90.5; 90th percentile: 126.5). The morning spot-urine I/Cr and simple I on day 7 and day 14 were significantly lower than on day 0 (P < 0.05). CONCLUSIONS: One week of a strict LID is enough to decrease the level of urine iodine excretion in preparation for RAIT even in high iodine intake areas. These results provide essential data for future outcome studies regarding LID preparation for RAIT. PMID- 21707690 TI - A concerted decline in insulin secretion and action occurs across the spectrum of fasting and postchallenge glucose concentrations. AB - AIMS/HYPOTHESIS: Individuals with impaired fasting glucose (IFG) are at increased risk of developing diabetes over the subsequent decade. However, there is uncertainty as to the mechanisms contributing to the development of diabetes. We sought to quantitate insulin secretion and action across the prediabetic range of fasting glucose. METHODS: We studied a cohort of 173 individuals with a fasting glucose concentration <7.0 mM after an overnight fast using a 75-g oral glucose tolerance test (OGTT). Insulin action (S(i)) was estimated using the oral glucose minimal model, and beta-cell responsivity indices (phi) were estimated using the oral C-peptide minimal model. The disposition index (DI) for each individual was calculated. The relationship of DI, phi and S(i) with fasting and postchallenge glucose, as well as other covariates, was explored using a generalized linear regression model. RESULTS: In this cross-sectional study, S(i) and DI were inversely related to fasting glucose concentrations. On the other hand, phi was unrelated to fasting glucose concentrations. S(i), phi and DI were all inversely related to area above basal glucose concentrations after glucose challenge. Multiple parameters including body composition and gender contributed to the variability of S(i) and DI at a given fasting or postchallenge glucose concentration. CONCLUSIONS/INTERPRETATION: Defects in insulin secretion and action interact with body composition and gender to influence postchallenge glucose concentrations. There is considerable heterogeneity of insulin secretion and action for a given fasting glucose likely because of patient subsets with isolated IFG and normal glucose tolerance. PMID- 21707691 TI - Similar superantigen gene profiles and superantigen activity in norwegian isolates of invasive and non-invasive group a streptococci. AB - Group A streptococcus (GAS) harbours several virulence factors, including M protein (coded by the emm gene) and superantigens (SAgs). SAgs are extracellular toxins that directly activate the immune system by cross-binding to the HLA class II molecule and T cell receptor (TCR), thereby causing activation of up to 30% of the T cells and subsequent massive secretion of cytokines. Forty-eight GAS strains isolated from patients at Norwegian hospitals between 1988 and 2004 were included in this study. Of these, 24 were invasive streptococcal toxic shock syndrome (STSS) or necrotizing fasciitis (NF) isolates and 24 were non-invasive pharyngitis isolates, matched for having the same T-type and year of isolation as the invasive isolates. The isolates were characterized by emm sequence typing, multilocus sequence typing (MLST) and SAg gene profiles. A correlation between T type, emm type, sequence type and SAg gene profile was revealed. No difference between invasive and non-invasive isolates regarding serotype or genotype was demonstrated. Selected invasive and non-invasive isolates with identical SAg gene profiles were analysed for SAg activity in bacterial growth culture media with and without human cell culture media added. A human T cell proliferation assay was used as measurement for SAg activity and simultaneously we also measured the cytokine content in normal human peripheral blood leucocyte cell culture media. The results revealed that invasive and non-invasive isolates did not differ significantly in SAg activity as it is present in semipurified bacterial culture medium. PMID- 21707692 TI - CD44/CD70 blockade and anti-CD154/LFA-1 treatment synergistically suppress accelerated rejection and prolong cardiac allograft survival in mice. AB - Current treatments that are efficient in controlling effector T cell responses to allografts have limited efficacy on the accelerated rejection mediated by memory T cells. Effective targeting of alloreactive memory T cells may therefore be explored to improve therapeutic approaches towards solving this problem. In this study, we investigated the synergistic effect of CD44/CD70 blockade and anti CD154/LFA-1 treatment on the accelerated rejection mediated by memory T cells. While CD44/CD70 blockade had limited effects on the alloresponses of effector T cells in vivo, it diminished the expansion of both CD4(+) and CD8(+) memory T cells in recipients adoptively transferred with donor-sensitized T cells. In combination with anti-CD154/LFA-1 treatment, CD44/CD70 blockade significantly prolonged cardiac allograft survival in adoptive transfer recipients. We demonstrated that treatment with the combination of all four antibodies (anti CD154/LFA-1/CD44/CD70) inhibited accelerated rejection by markedly suppressing the alloresponses of effector and memory T cells and reducing the number of graft infiltration lymphocytes in adoptive transfer recipients. Meanwhile, CD44/CD70 blockade and anti-CD154/LFA-1 treatment synergically enhanced regulatory T cells (Tregs) by increasing the proportion of splenic Tregs and the expression of IL-10 in these recipients. Our findings contribute to the potential design of therapies for accelerated allograft rejection. PMID- 21707693 TI - MMP activation in diagnostics of periodontitis and systemic inflammation. PMID- 21707694 TI - Evidence grade associating periodontitis to preterm birth and/or low birth weight: I. A systematic review of prospective cohort studies. AB - AIM: The aims of this systematic review (SR) were to evaluate the association between maternal periodontitis and preterm birth (PB) and/or low birth weight (LBW), and the methodological quality of prospective cohort studies conducted for such a purpose. METHODS: MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched up to and including October 2010 to identify prospective studies on the association of periodontitis with PB and/or LBW. Search was conducted by two independent reviewers. The methodological quality of the observational studies was assessed using a specially designed methodological tool. Random effects meta-analyses were conducted thoroughly. RESULTS: Search strategy identified 1680 potentially eligible articles, of which 12 prospective studies were included. One cohort study had their data reported in two articles. Of the 11 studies, 10 showed a high methodological quality and one a medium methodological quality. Nine studies (81.8%) found an association between periodontitis and PB and/or LBW. Meta-analysis showed a significant risk of preterm delivery for pregnant women with periodontitis [risk ratio (RR): 1.70 (95% confidence interval (CI): 1.03, 2.81)] and a significant risk for LBW [RR: 2.11 (95% CI: 1.05, 4.23)] or PB/LBW [RR: 3.57 (95% CI: 1.87, 6.84)], as well as a high and unexplained degree of heterogeneity between studies. CONCLUSION: Although this SR found a consistent association between periodontitis and PB and/or LBW, this finding should be treated with great caution until the sources of heterogeneity can be explained. PMID- 21707695 TI - Digital image processing versus visual assessment of chewed two-colour wax in mixing ability tests. AB - Two-colour chewing gum and wax have been widely used as test foods to evaluate the ability to mix and knead a food bolus. The mixing of the colours has been assessed by computer analysis or by visual inspection. Reports contradict each other about whether computer analysis and visual assessment could equally well discriminate between the masticatory performances of groups of participants with different dental status. This study compares the results of computer analysis of digital images of chewed two-colour wax with the results of visual assessment of these images. Sixty healthy subjects participated and chewed on red-blue wax for 5, 10, 15 and 20 chewing strokes. The subjects were divided into three groups of 20, matched for age and gender, according to their dental status: natural dentition, full dentures and maxillary denture plus implant-supported mandibular overdenture. Mixing of the chewed wax was determined by computer analysis of images of the wax and by visual assessment of the images by five examiners. Both the computer method and the observers were able to distinguish the mixing abilities of the dentate subjects from the two denture wearer groups. Computer analysis could also discriminate the mixing abilities of the two denture groups. However, observers were not able to distinguish the mixing abilities of the two denture groups after 5, 10 and 15 chewing strokes. Only after 20 chewing strokes, they could detect a significant difference in mixing ability. PMID- 21707696 TI - The shortened dental arch revisited: from evidence to recommendations by the use of the GRADE approach. AB - Clinicians must frequently decide whether or not to treat patients with loss of posterior teeth, a condition called the shortened dental arch (SDA). Although many studies have been reported, there are no clear recommendations for the management of SDA cases. In this work, therefore, an innovative system, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, was used to grade the evidence and strength of recommendations for clinical intervention. An extensive literature search for longitudinal studies was conducted on 17 November 2010 in the PubMed and LILACS electronic databases using the term shortened dental arch. A 'snowballing' strategy, for example, manual searching of the reference lists of included papers, was also conducted. Unpublished and published studies were sought in ClinicalTrials.gov and in the search engine 'Google' (Scholar) in English, French, German, Italian, Portuguese and Spanish. Finally, grey literature was searched in OpenSIGLE (System for Information on Grey Literature in Europe). Titles and abstracts of 133 articles were initially assessed. Nine studies were finally included. Although there was no difference between the effectiveness of restorative and non-restorative approaches for SDA, fixed partial dentures seem better than removable prostheses. The overall body of evidence was, however, graded as low quality. Two different clinical scenarios are used to illustrate recommendations in the management of SDA cases by the use of the GRADE system. The GRADE approach may improve transparency in a shared decision-making process, mainly under conditions in which the quality of evidence is low or unclear. PMID- 21707697 TI - Appropriateness of viscoelastic soft materials as in vitro simulators of the periodontal ligament. AB - The periodontal ligament is a viscoelastic soft tissue that connects the tooth to the alveolar bone. This tissue should be simulated in numerical as well as in laboratory models. The mechanical properties of this tissue were previously determined ex vivo and in vivo. The aim of the study was to analyse the appropriateness of impression and reline materials used in dentistry to simulate viscoelastic behaviour of the periodontal ligament. Two reline [Durabase (Reliance Dental MFG, Co.) and Soft Liner (GC Corporation)] and two impression [President Plus (Coltene) and Prestige L (Vanini Dental Industry)] materials were examined in recovery and tensile relaxation tests. Recovery: This experiment simulated in vivo test. Roots of a pair of plastic maxillary premolar teeth were covered with each test material and embedded in acryl while maintaining the contact point. A 0.1-mm stainless steel strip, inserted at the contact point and maintained for 10 s, was used to tip the teeth. After removal, the tightness of dental contact point was measured over 30 min by determining the force needed to insert a 0.05-mm metal strip. Tensile relaxation: strips were elongated to 120%, 140% and 160% of their initial length and maintained at that length for 30 min. Two-phase decay function was applied. The results showed that elastic modulus and relaxation behaviour were significantly different between materials. Elastic modulus values were in the same range of those reported in the literature. However, the recovery values and behaviour showed that impression materials, especially President, are the materials of choice for this purpose because they simulated better the in vivo test. PMID- 21707698 TI - Comparison of ambulatory and polysomnographic recording of jaw muscle activity during sleep in normal subjects. AB - Clinicians and investigators need a simple and reliable recording device to diagnose or monitor sleep bruxism (SB). The aim of this study was to compare recordings made with an ambulatory electromyographic telemetry recorder (TEL-EMG) with those made with standard sleep laboratory polysomnography with synchronised audio-visual recording (PSG-AV). Eight volunteer subjects without current history of tooth grinding spent one night in a sleep laboratory. Simultaneous bilateral masseter EMG recordings were made with a TEL-EMG and standard PSG. All types of oromotor activity and rhythmic masseter muscle activity (RMMA), typical of SB, were independently scored by two individuals. Correlation and intra-class coefficient (ICC) were estimated for scores on each system. The TEL-EMG was highly sensitive to detect RMMA (0.988), but with low positive predictive value (0.231) because of a high rate of oromotor activity detection (e.g. swallowing and scratching). Almost 72% of false-positive oromotor activity scored with the TEL-EMG occurred during the transient wake period of sleep. A non-significant correlation between recording systems was found (r = 0.49). Because of the high frequency of wake periods during sleep, ICC was low (0.47), and the removal of the influence of wake periods improved the detection reliability of the TEL-EMG (ICC = 0.88). The TEL-EMG is sensitive to detect RMMA in normal subjects. However, it obtained a high rate of false-positive detections because of the presence of frequent oromotor activities and transient wake periods of sleep. New algorithms are needed to improve the validity of TEL-EMG recordings. PMID- 21707699 TI - Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function. AB - AIM: To evaluate the influence of different stages of chronic renal insufficiency on the pharmacokinetics and safety/tolerability of the transdermally applied dopamine agonist rotigotine in an open label group comparison including 32 subjects (healthy, mild, moderate or severe impairment of renal function and patients with end-stage renal insufficiency requiring haemodialysis). METHODS All subjects received a single transdermal 10 cm2 patch (24 h patch-on period) containing 4.5 mg rotigotine (nominal drug release 2 mg 24 h-1). Main evaluations included relative bioavailability and renal elimination of rotigotine and its metabolites. RESULTS: Point estimates for the ratios between the groups with moderate to severe renal impairment and healthy subjects for the pharmacokinetic parameters AUC(0,t(last) ) and C(max) for the active substance unconjugated rotigotine were near 1:0.88 for AUC and 0.93 for C(max) for moderate renal impairment, 1.14 and 1.18 for severe renal impairment and 1.05 and 1.25 for end stage renal insufficiency requiring haemodialysis. There was no correlation of these parameters with creatinine clearance. The amount of unconjugated rotigotine excreted into urine and renal clearance decreased with increasing severity of renal insufficiency but had no observable effect on total clearance as the amounts excreted were below 1% of the administered dose. Occurrence of adverse events did not increase with the degree of renal insufficiency. CONCLUSIONS: The pharmacokinetic profiles of unconjugated rotigotine were similar in healthy subjects and subjects with impaired renal function indicating that no dose adjustments are required for transdermal rotigotine in patients with different stages of chronic renal insufficiency including patients on haemodialysis. PMID- 21707700 TI - High dose methotrexate chemotherapy: pharmacokinetics, folate and toxicity in osteosarcoma patients. AB - AIMS: To investigate the relationships between pretreatment folate concentrations, MTX pharmacokinetics and acute toxicities following high dose methotrexate (HD MTX) therapy. METHODS: MTX and its major extracellular metabolite 7-OH-MTX were measured in eight serum samples per HD MTX cycle in 65 consecutive osteosarcoma patients (288 cycles) and AUC (area under the blood concentration-time curve) was calculated. Pretreatment concentrations of folate in serum (S) and erythrocytes (ER) were determined. Hepatic, renal and haematological toxicities, assessed by routine laboratory parameters, as well as mucositis were graded according to National Cancer Institute Common Terminology Criteria for adverse events (CTCAE v.3.0). Dermatitis and pleuritis were reported as occurred or not. RESULTS: S- and ER-folate pretreatment concentrations increased significantly with increasing number of HD MTX cycles (P < 0.001). ER folate pretreatment concentrations were higher among males (median 610 nmol l-1, 95% CI 550, 680) compared with females (median 465 nmol l-1, 95% CI 430, 520, P < 0.001), but showed no correlation with MTX or 7-OH-MTX pharmacokinetics. We found correlations between alanine aminotransferase peak concentration (ALAT(max) ) and clearance of MTX (P < 0.001), gender (P < 0.001), age (P < 0.001) and 7-OH-MTX concentrations (P < 0.001), the latter being the main factor influencing ALAT(max) . CONCLUSION: Our results suggest that 7-OH-MTX is involved in the development of HD MTX hepatic toxicity and that young female patients are most affected. PMID- 21707701 TI - Short QT syndrome in infancy. Therapeutic drug monitoring of hydroquinidine in a newborn infant. PMID- 21707702 TI - Histopathological and immunophenotypic features of testicular tumour of the adrenogenital syndrome. AB - AIMS: Testicular tumour of the adrenogenital syndrome (TTAGS) is a rare neoplasm histologically resembling Leydig cell tumour (LCT). We report six cases of TTAGS and analyse histopathological and immunophenotypical features that distinguish TTAGS from LCT. METHODS AND RESULTS: Six cases of congenital adrenal hyperplasia with bilateral TTAGS were examined histologically and immunohistochemically and compared to seven cases of testicular LCT. TTAGS was characterized histologically by sheets of polygonal cells separated by dense fibrous tissue with focal lymphocyte infiltration. All cases of TTAGS lacked cytological atypia except for one, which displayed scattered large pleomorphic, nuclei with one or two prominent nucleoli and sporadic mitotic figures. Immunohistochemically, all cases of TTAGS showed diffuse and strong positivity for CD56 and negative reactivity for androgen receptor. Reactivity for synaptophysin varied from focal (five cases) or diffuse (one case). In contrast, LCT displayed focal weak to moderate or negative reactivity for CD56 and focal weak or negative reactivity for synaptophysin, but positive reactivity for androgen receptor in six of seven cases. CONCLUSIONS: In addition to clinical information, biochemical profile and histopathological findings, our results suggest that immunohistochemistry using a panel of antibodies including CD56, synaptophysin and androgen receptor is helpful in differentiating TTAGS from LCT. PMID- 21707703 TI - Inhibin bodies: a new marker for immature Sertoli cells. AB - AIMS: To provide a marker for immature and dysgenetic Sertoli cells which allows easy identification in patients in which Sertoli cell maturation does not take place properly, such as those consulting for cryptorchidism, testicular tumours and infertility. METHODS AND RESULTS: We performed immunohistochemistry against inhibin-alpha subunit and the endoplasmic reticulum marker Grp78 in normal human testes from fetal life to adulthood, and in several testicular lesions where Sertoli cell maturation is abnormal. We describe a pattern of inhibin immunostain (inhibin bodies of 2-9 MUm in diameter at the Sertoli cells cytoplasm apical pole) in immature and dysgenetic Sertoli cells that facilitates their identification. Inhibin bodies were found in tubules with either no germ cells or only spermatogonia or carcinoma in situ (CIS) and seminoma cells, but not in tubules containing more advanced germ cells. CONCLUSIONS: Our data provide a new marker of immature and dysgenetic Sertoli cells. In addition, our data suggest that inhibin bodies represent a slower transit of inhibin through the endoplasmic reticulum, as inhibin bodies were associated with Grp78. PMID- 21707704 TI - Relevance of cohort design for studying the frequency of the ERG rearrangement in prostate cancer. AB - AIMS: ERG rearrangements, mostly resulting in TMPRSS2-ERG fusions, are frequent alterations in prostate cancer (PCa), with a frequency ranging from 15% to 78%. As the reason for this variability is unknown, our aim was to investigate the ERG rearrangement frequency with a cohort design. METHODS AND RESULTS: We assessed three well-defined cohorts for ERG rearrangements, using fluorescence in situ hybridization (FISH). The first cohort comprised 119 prostatectomy specimens. The second and third cohorts included incidentally diagnosed PCa [71 cystoprostatectomy specimens, and 105 transurethral resection of the prostate (TURP) specimens]. Seventy of 119 (59%) cases of the prostatectomy cohort harboured ERG rearrangements. Regarding zonal origin, 2/11 (18%) transition zone (TZ) foci and 75/145 (52%) peripheral zone (PZ) foci harboured ERG rearrangements. Within the cystoprostatectomies, 24/71 (34%) cases harboured ERG rearrangements. Regarding zonal origin, 2/9 (22%) TZ foci and 26/86 (30%) PZ foci harboured ERG rearrangements. PCa incidentally identified by TURP harboured ERG rearrangements in 31/105 (29%) cases. CONCLUSIONS: ERG rearrangements occur in TZ PCa, although at a lower frequency than in PZ PCa. We confirmed that approximately half of all prostatectomies harbour ERG rearrangements. However, the frequency in incidentally diagnosed PCa cohorts was significantly lower, even if multifocality was considered. Consequently, zonal origin and cohort design are key for studying the clinical implications of ERG rearrangements. PMID- 21707705 TI - Expression of hedgehog pathway components in prostate carcinoma microenvironment: shifting the balance towards autocrine signalling. AB - AIMS: The hedgehog (Hh) signalling pathway has been implicated in the pathogenesis and aggressiveness of prostate cancer through epithelial-mesenchymal interactions. The aim of this study was to elucidate the cell-type partitioned expression of the Hh pathway biomarkers in the non-neoplastic and tumour microenvironments and to correlate it with the grade and stage of prostate cancer. METHODS AND RESULTS: Expression of the Hh pathway components (Shh, Smo, Ptch, Gli1) in the microenvironment of non-neoplastic peripheral zone (n = 119), hormone-naive primary prostate carcinoma (n = 141) and castrate-resistant bone marrow metastases (n = 53) was analysed using immunohistochemistry in tissue microarrays and bone marrow sections. Results showed that epithelial Shh, Smo and Ptch expression was up-regulated, whereas stromal Smo, Ptch, and Gli1 expression was down-regulated in prostate carcinomas compared to non-neoplastic peripheral zone tissue. Ptch expression was modulated further in high-grade and high-stage primary tumours and in bone marrow metastases. Hh signalling correlated with ki67 and vascular endothelial growth factor (VEGF) but not with CD31 expression. CONCLUSION: Our results highlight the importance of Hh-mediated epithelial mesenchymal interactions in the non-neoplastic prostate and imply that shifting the balance from paracrine towards autocrine signalling is important in the pathogenesis and progression of prostate carcinoma. PMID- 21707706 TI - Modified UroVysion scoring criteria increase the urothelial carcinoma detection rate in cases of equivocal urinary cytology. AB - AIMS: UroVysion((r)) is a four-target fluorescence in situ hybridization technique for the detection of urothelial carcinoma (UC) in urinary cytology. The aim of this retrospective study was to investigate the UC detection rate of a modified UroVysion test in patients with equivocal urinary cytology. The modification comprised the addition of a cytological prescreening technique and different evaluation criteria. METHODS AND RESULTS: Thin-layer slides were prepared from the residual urine samples of 82 patients with equivocal urinary cytology, prestained and prescreened to confirm the presence of atypical urothelial cells. The same slides were used for the UroVysion test, and scored according to different evaluation criteria. The results were compared with the outcomes of cystoscopic and histological findings. UroVysion detected 68% of the UCs when the manufacturer's evaluation criteria were applied. In cases of altered evaluation criteria, the sensitivity increased to 81% when at least one copy number change of a probe target was considered to be a positive test result. The specificity only decreased from 84% to 82%. CONCLUSIONS: Our data suggest that the sensitivity of the UroVysion test can be increased by the addition of a cytological pre-screening technique prior to the UroVysion test and a modification of the UroVysion evaluation criteria. PMID- 21707707 TI - Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder. AB - AIMS: Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway dysregulation has been implicated in the development of urothelial carcinoma. However, its clinical relevance has not been substantially validated in human samples. The aim of this study was to assess the expression of the pathway in a large cohort of bladder cancers using the tissue microarray technique. METHODS AND RESULTS: Immunohistochemical stains for phosphatase and tensin homologue (PTEN), phosphorylated Akt, mTOR, S6 and 4E-BP1 were performed for 887 cases, and the results were correlated with clinicopathological characteristics. The high expression of p-S6 and p-Akt corresponded significantly with high-grade and advanced-stage, while losses of PTEN and p-4E-BP1 were observed more often in high-grade and high-stage tumours. High expression of p Akt and p-S6 predicted progression and cancer-specific mortality for non-muscle invasive cancers treated by transurethral resection, and p-Akt was an independent factor in multivariate analysis. High expression of p-mTOR and p-Akt correlated with higher cumulative incidence of cancer-specific mortality for muscle-invasive cancer, and p-mTOR was an independent prognostic factor. CONCLUSIONS: We have demonstrated the impact of PI3K/Akt/mTOR alteration on the biological behaviour of bladder tumours. Proper immunohistochemical examination of the PI3K/Akt/mTOR pathway can provide useful prognostic information, and the findings may represent an additional therapeutic avenue in the treatment of bladder cancers. PMID- 21707708 TI - Clear-cell papillary renal cell carcinoma: 24 cases of a distinct low-grade renal tumour and a comparative genomic hybridization array study of seven cases. AB - AIMS: To report clinicopathological and genomic characteristics of (ccpRCC), a rare, recently characterized renal tumour entity. METHODS AND RESULTS: Twenty four renal tumours identified as ccpRCC were collected. Data from comparative genomic hybridization on microarrays (array-CGH) were obtained for seven of these. Most tumours (58%) occurred in the absence of renal disease. Mean patient age was 58.1 years. Tumours were small (mean size: 2.4 cm) and classified as pT1. Histological characteristics consisted of tubules and papillae lined by a single layer of small clear cells harbouring low-grade nuclei (Fuhrman grades 1 or 2). Architectural variations, with compact areas (41% of cases) and a micro- or macrocystic pattern (67% of cases) were observed frequently. Immunostaining demonstrated diffuse, strong expression of cytokeratin 7 and vimentin, whereas CD10, racemase, RCC antigen, translocation factor E3, TFE3 and translocation factor EB were consistently negative. In seven tumours, array-CGH detected no chromosomal imbalances. CONCLUSIONS: Clear-cell papillary renal cell carcinoma (ccpRCC) were differentiated from other renal neoplasms by a specific constellation of histopathological and immunohistochemical features, without characteristic genomic imbalances. Clinical, histopathological and genomic data suggested that these tumours have a low potential for malignancy. PMID- 21707709 TI - In situ lobular neoplasia of the breast with marked myoepithelial proliferation. AB - AIMS: To present four new cases of in situ lobular neoplasia associated with marked proliferation of myoepithelial cells. METHODS AND RESULTS: Four recently seen cases showing extensive foci of in situ lobular neoplasia, as confirmed by negative E-cadherin staining, were stained for myoepithelial cells using CD10, smooth muscle actin and cytokeratin 5/6. Invasive lobular carcinoma was also present in two cases; one case was associated with multiple foci of collagenous spherulosis, and one was associated with a radial scar. Marked myoepithelial proliferation was seen around most of the in situ lobular foci or mingled with lobular cells. CONCLUSIONS: Marked proliferation of myoepithelial cells is sometimes encountered in association with extensive in situ lobular neoplasia. It is suggested that this proliferation might have a role in maintaining the in situ status of these lesions or, alternatively, that there is a shared factor responsible for the simultaneous proliferation of certain 'lobular' cell types and myoepithelial cells. PMID- 21707710 TI - Na+/H+ exchanger regulatory factor 1 expression levels in blood and tissue predict breast tumour clinical behaviour. AB - AIMS: Several studies have demonstrated that Na(+) /H(+) exchanger regulatory factor 1 (NHERF1) protein, which is overexpressed and heterogeneously distributed in different stages of breast cancer, could be used as a tumour marker for prognosis in molecular detection strategies. We observed that tumour-infiltrated lymphocytes in the tumour tissue display a high level of NHERF1 staining, in contrast to those present in the contiguous non-involved tissue. Hypothesizing that cancer cells elicit a specific T-cell response associated with the characteristics of the solid tumour, our aim was to evaluate NHERF1 in peripheral lymphocytes from healthy donors and breast cancer patients. METHODS AND RESULTS: NHERF1 levels were analysed in 55 breast cancer patients and 40 healthy donors, and these levels were compared with clinical pathological features. NHERF1 was overexpressed in circulatory peripheral lymphocytes from patients as compared with those from healthy subjects. Furthermore, in both circulatory lymphocytes and tissues, NHERF1 was positively associated with tumour grade, Nottingham Prognostic Index and oestrogen receptor, whereas there was no association with other clinical parameters in either tissue. CONCLUSIONS: We propose that NHERF1 measurements in circulatory lymphocytes of breast cancer patients may be a valid method for the prediction of breast cancer occurrence and prognosis, and may have value in the management of cancer patients. PMID- 21707711 TI - Tissue remodelling in breast cancer: human mast cell tryptase as an initiator of myofibroblast differentiation. AB - AIMS: Cancerogenesis is characterized by increase of differentiated myofibroblasts. Mast cells (MCs) exert powerful effects on fibroblasts through a variety of mediators. We investigated alpha-smooth-muscle actin (alpha-SMA(+) ) and CD34(+) fibroblasts, density of toluidine blue-stained (MCs-TB) and tryptase immunolabelled MCs (MCs-Try) in 30 primary breast tumours. METHODS AND RESULTS: Tumour (T), peri-tumoral (PT) and non-tumoral (NT) tissue was studied by immunohistochemistry and electron microscopy. MCs-TB and MCs-Try increased gradually from NT to PT and T and the comparison between the three compartments varied significantly. Degranulated MCs were present more significantly in NT and adjacent PT than T. Transition between NT, PT and T was marked by increasing alpha-SMA(+) fibroblasts and slow disappearance of CD34(+) stromal cells. In NT, CD34(+) fibroblasts correlated with low density both of MCs-TB and intact MCs-Try (P=0.0346 and P=0.0409, respectively). In T, the few preserved CD34(+) fibroblasts were associated with low-density degranulated MCs-Try (P=0.0173). The alpha-SMA(+) fibroblasts correlated with high density of intact MCs-Try in PT, and with high density of degranulated MCs-Try in T (P=0.0289), also confirmed by ultrastructural analysis. CONCLUSIONS: This preliminary investigation suggests that during breast cancer progression the MCs may contribute to stromal remodelling and differentiation of myofibroblasts, through tryptase released in stromal microenvironment. PMID- 21707712 TI - Prognostic significance of CD8+ T lymphocytes in breast cancer depends upon both oestrogen receptor status and histological grade. AB - AIMS: Results of previous studies on the influence of tumour infiltrating lymphocytes on prognosis of women with breast cancer have been mixed. This study re-evaluates the role of tumour-infiltrating lymphocytes as a prognostic marker in women with breast cancer. METHODS AND RESULTS: Immunochemistry staining of CD8(+) T cells was performed on a tissue microarray of 1953 breast carcinomas. When all tumours were considered, no association between the lymphocyte count and patient survival was found. In univariate analysis, there was a reduced disease specific survival for women with oestrogen receptor (ER)-positive tumours with high intraepithelial lymphocyte count (P=0.004). In those with ER-negative tumours, the disease-specific survival was improved when the intraepithelial, stromal and total lymphocyte counts were high, the total lymphocyte count also being an independent prognostic marker on multivariate analysis (P=0.031). When stratified by histological grade, on univariate analysis, the previously observed inferior outcome in women with high lymphocyte count and ER-positive tumours remained significant only if tumours were also of low grade, and the superior outcome in those with ER-negative tumours remained significant if tumours were also of high grade. CONCLUSIONS: Our results raise the possibility of different immune-tumour interactions based on ER status and histological grade. PMID- 21707713 TI - High incidences of DNA ploidy abnormalities in tongue squamous cell carcinoma of young patients: an international collaborative study. AB - AIMS: This multi-centre analysis assessed the DNA content of TSCC in 37 young patients (<40 years) and 28 old patients (>50 years) and determined the correlation of DNA ploidy findings with clinicopathological data. METHODS AND RESULTS: Image cytometry was carried out using an automated cellular imaging system on Feulgen-stained histological sections to obtain high-fidelity DNA histograms. Among young patients, 37.8% were females compared to 18.7% in the older group (P=0.002). In total, 48.6% patients were non-smokers and 40.5% were non-drinkers compared to 10.7% non-smokers and non-drinkers in the older group (P<0.0001). TNM, clinical stage of disease and histological grade of differentiation did not differ between groups. Tumour aneuploidy was detected in 86.5% and tetraploidy in 24.3% young patients; this was significantly greater than in the older group where 64.3% were aneuploid (P<0.0001) and 7.2% tetraploid (P<0.0001). The mean values of DNA index (DI) and DNA heterogeneity index as well as the percentage of cells with DI exceeding 5N were higher in young patients (P<0.0001). CONCLUSIONS: Young patients with TSCC represent a distinct clinical entity. The high incidence of DNA ploidy abnormalities suggest that they may have increased genomic instability and indicates underlying genetic differences between TSCC in young and older patients. PMID- 21707714 TI - Mammalian target of rapamycin expression and laryngeal squamous cell carcinoma prognosis: novel preliminary evidence. AB - AIMS: The mammalian target of rapamycin (mTOR) has a key role in regulating cancer cell proliferation, apoptosis, cell migration, and angiogenesis. The aim of this study was to assess the relationships between mTOR and clinicopathological and prognostic parameters in laryngeal squamous cell carcinoma (SCC). METHODS AND RESULTS: Mammalian target of rapamycin expression was determined in 103 consecutive operable laryngeal SCCs. Among the mTOR positive cases, the locoregional recurrence rate was higher (P=0.048) and the disease-free survival (DFS) rate was shorter (P=0.031) in patients with mTOR expression >50.7%. In the N(0) subgroup, the disease recurrence rate was higher (P=0.034) and the DFS was shorter (P=0.009) in patients with mTOR expression >50.7%. In mTOR-positive patients, multivariate analysis showed that N stage (P=0.0001) and mTOR status (P=0.042) were independent indicators of a poor prognosis. CONCLUSIONS: mTOR appeared to be a significant predictor of DFS in univariate and multivariate models. mTOR expression in laryngeal SCC may be useful for the detection of patients at higher risk for recurrence, and N(0) patients at higher risk for early locoregional recurrence who might benefit from more aggressive therapy. The role of mTOR inhibitors in multimodality or multitarget strategies against laryngeal SCC warrants investigation. PMID- 21707715 TI - Commentary on IgG4-related sialadenitis: Mikulicz's disease, Kuttner's tumour, and eponymy. PMID- 21707716 TI - Immunohistochemical analysis of 1844 human epithelial and haematopoietic tumours and sarcomas for IDH1R132H mutation. AB - AIMS: Mutations in the isocitrate dehydrogenase 1 gene have been identified recently to play a key role in diffuse astrocytoma and oligodendroglioma as well as in acute myeloid leukaemia. In glioma, IDH1R132H is the most common mutation type, which is associated with younger patient age and longer patient survival compared to wild-type status. Sequencing analyses of carcinomas and lymphomas have detected IDH1 mutations in only a small fraction of cases. In those studies, IDH1R132H was also the most frequent mutation. The aim of the present study was to analyse a comprehensive series of human tumours for IDH1R132H mutation. METHODS AND RESULTS: A total of 1844 formalin-fixed paraffin-embedded tumours, including carcinomas, sarcomas and haematopoietic tumours were investigated immunohistochemically using a mutation-specific antibody for IDH1(R132H). Our positive control series consisted of a collection of diffuse astrocytomas and oligodendrogliomas. No IDH1R132H mutation was found in this series. CONCLUSIONS: IDH1R132H mutations occur almost exclusively in glioma and acute myeloid leukaemia. PMID- 21707717 TI - Human epidermal growth factor receptor 2 overexpression and amplification in mucinous tumours of ovary. PMID- 21707718 TI - Smoothelin in bladder and gastrointestinal tract again. PMID- 21707719 TI - Expression of p16 in post-radiotherapy cervical biopsies. PMID- 21707720 TI - Gastric pseudolipomatosis: biopsy follow-up and immunohistochemical analysis of a rare condition. PMID- 21707721 TI - Signet ring cell cancer in a patient with Russell body gastritis--a possible diagnostic pitfall. PMID- 21707722 TI - The importance of retaining post mortem tissue--'pseudomesotheliomatous' Merkel cell carcinoma of the pleura. PMID- 21707723 TI - Usefulness of Aggressive Behaviour Risk Assessment Tool for prospectively identifying violent patients in medical and surgical units. AB - AIM: The aim of this study is to evaluate the usefulness of the Aggressive Behaviour Risk Assessment Tool for prospectively identifying violent patients in medical-surgical units. BACKGROUND: Although patient violence against nurses is a serious occupational hazard, there is a lack of simple screening tools with acceptable sensitivity and specificity for identifying potentially violent patients in medical-surgical units. METHODS: A prospective cohort study involving patients admitted to six medical-surgical units at an acute care hospital was conducted from August 2009 to December 2009. Primary nurses completed the 17-item checklist within 24 hours of admission. A second identical checklist was completed by another nurse to assess the inter-rater reliability. Following a violent event or just prior to discharge, the violent event outcome section was completed to collect information about violent event, if any. A multivariate logistic regression model with backward elimination was used to select a set of parsimonious items that best predict violent behaviours. RESULTS: Fifty-six patients out of 2063 (2.7%) had one or more violent events. A parsimonious set of ten items were selected for the tool. Receiver Operating Characteristics analysis of Aggressive Behaviour Risk Assessment Tool showed that the area under the curve was 0.82 (95% Confidence Interval, 0.75-0.90). The sensitivity and specificity at the cut-off score of 1 were 70.9% and 89.3%, respectively. The Cohen's Kappa for inter-rater reliability was 0.647. CONCLUSION: The Aggressive Risk Assessment Tool is a simple, easy-to-use assessment tool with acceptable inter-rater reliability, sensitivity and specificity that may be useful for prospectively identifying violent patients in medical-surgical units. PMID- 21707724 TI - Transcultural spirituality: the spiritual journey of hospitalized patients with schizophrenia in Taiwan. AB - AIM: The aim of this study was to explore how hospitalization and the diagnosis of schizophrenia have an impact on Taiwanese patients' spiritual life. BACKGROUND: Psychiatric nurses tend to construe patients' spiritual issues as pathological problems and consequently are reluctant to address patient's spirituality, which results in spirituality being overlooked in mental illness. An individual's spiritual journey is dependent upon their cultural background and beliefs; however, the professional's preconceived ideas suppress the voice of patients with schizophrenia to share their experiences of their spiritual journey. The lack of research exploring spirituality in mental illness in Taiwan means that spiritual care is overlooked in practice. This study sets out to explore spirituality from the perspectives of patients in two mental hospitals in Taiwan. METHODS: Using a qualitative approach, 22 long-term hospitalized patients diagnosed with schizophrenia were interviewed. Several themes from the data were identified using Ritchie and Spencer's (1994) five stages analytical framework. The study was carried out from 2006 to 2008. RESULTS: Patients revealed spiritual distress as a consequence of prolonged hospitalization. They used referents consistent with traditional Chinese philosophical perspectives derived from Taoism and Confucianism to describe various features of their spiritual distress and their longing for spiritual revival, transcendence and to be accepted as normal persons. CONCLUSIONS: In this age of globalization, nurses need to be fully cognisant of the cultural aspects of patients to respond to a mental health patient's spirituality. Clinical and educational guidelines and policies could be developed for spiritual care in Taiwan. PMID- 21707725 TI - Recruitment bias and characteristics of participants with severe cerebral palsy in a cross-sectional survey. AB - AIM: This article is a report of recruitment bias in a sample of 5-25-year-old patients with severe cerebral palsy. BACKGROUND: The way in which study participants are recruited into research can be a source of bias. METHOD: A cross sectional survey of 5-25-year-old patients with severe cerebral palsy using standardized questionnaires with parents/carers was undertaken in 2007/2008. A case register was used as the sampling frame, and 260 families were approached: 178/260 (68%) responded and 82/260 families never replied (non-respondents). Among responders: 127/178 (71%) opted in to the study, but only 123/127 were assessed, and 82/178 were opted out (or refused). Multivariable logistic regression giving odds ratios was used to study the association between participant characteristics and study outcomes (responders vs. non-responders; opting in vs. opting out; assessed vs. eligible, but not assessed). RESULTS: Responders (compared with non-responders) were significantly more likely to have a family member with cerebral palsy who was male and resident in more affluent areas. Families who opted in (compared with those opting out and refusing) were more likely to have a family member with cerebral palsy and intellectual impairment and to reside in certain geographical areas. Families who were actually assessed (compared with all eligible, but not assessed) were more likely to have a family member with cerebral palsy and intellectual impairment. CONCLUSION: Several sources of bias were identified during recruitment for this study. This has implications for the interpretation and conclusions of surveys of people with disabilities and complex needs. PMID- 21707726 TI - A model to advance nursing science in trauma practice and injury outcomes research. AB - AIMS: This discussion paper reports development of a model to advance nursing science and practice in trauma care based on an analysis of the literature and expert opinion. BACKGROUND: The continuum of clinical care provided to trauma patients extends from the time of injury through to long-term recovery and final outcomes. Nurses bring a unique expertise to meet the complex physical and psychosocial needs of trauma patients and their families to influence outcomes across this entire continuum. DATA SOURCES: Literature was obtained by searching CINAHL, PubMed and OvidMedline databases for 1990-2010. Search terms included trauma, nursing, scope of practice and role, with results restricted to those published in English. Manual searches of relevant journals and websites were undertaken. DISCUSSION: Core concepts in this trauma outcomes model include environment, person/family, structured care settings, long-term outcomes and nursing interventions. The relationships between each of these concepts extend across all phases of care. Intermediate outcomes are achieved in each phase of care and influence and have congruence with long-term outcomes. Implications for policy and practice. This model is intended to provide a framework to assist trauma nurses and researchers to consider the injured person in the context of the social, economic, cultural and physical environment from which they come and the long-term goals that each person has during recovery. The entire model requires testing in research and assessment of its practical contribution to practice. CONCLUSION: Planning and integrating care across the trauma continuum and recognition of the role of the injured person's background, family and resources will lead to improved long-term outcomes. PMID- 21707727 TI - Information-seeking behaviour of nurses: where is information sought and what processes are followed? AB - AIM: This paper is a report of a study on how nurses inform their decision-making in the workplace. BACKGROUND: Despite the growing availability of research evidence, nurses have been slow to adopt it into their daily decision-making. METHOD: The study was undertaken in Ireland between 2006 and 2007 using a sequential mixed methods approach. In phase 1, the views of a quota sample of 29 nurses were explored using semi-structured interviews incorporating vignettes. Phase 2 involved the design and dissemination of a survey to a disproportionate stratified random sample of 1356 nurses. The response rate was 29%. FINDINGS: In decision-making, nurses accessed other people, especially nursing colleagues, the most frequently. Sources that provided prepackaged information such as guidelines were favoured over sources that provided access to original research. The process of information-seeking for routine and non-routine decisions was different. Nurses making routine decisions relied mostly on their experience and an assessment of the patient. In non-routine decision-making, participants experienced more uncertainty about their decisions. Accordingly, sources of information used were more varied and the information-seeking process more extensive. The study highlighted the complexities of establishing whether information used in decision-making is research based or not. CONCLUSION: Routine practices should be reviewed and updated regularly through organizational mandates, as nurses do not generally question them. Research information to inform non-routine decision-making must be easily available to nurses in their workplace, as information searches generally prioritize finding enough, rather than the best, information to make a decision. PMID- 21707728 TI - The relationship between clinical indicators, coping styles, perceived support and diabetes-related distress among adults with type 2 diabetes. AB - AIM: This article is a report of a cross-sectional study examining the degree to which clinical indicators, coping styles and perceived support from healthcare professionals and family are related to diabetes-related distress. BACKGROUND: Many people with type 2 diabetes experience high levels of distress stemming from concerns and worries associated with their disease. Diabetes-related distress has predominantly been studied in relation to diabetes management and metabolic control, and to some extent in relation to coping styles and perceived social support. To date, little is known about the relative contribution of clinical indicators, coping styles and perceptions of social support to perceived distress among people with type 2 diabetes. METHODS: A sample comprising 425 Norwegian adults, aged 30-70, with type 2 diabetes, completed questionnaires assessing coping styles, perceived social support from health professionals and family and diabetes-related distress assessed by the Problem Areas in Diabetes Scale. Demographical and clinical data were collected by self-report. Data were collected in October 2008. FINDINGS: Results from the regression analyses showed a greater variance in emotional distress accounted for by coping styles (21.3%) and perceived support (19.7%) than by clinical indicators (5.8%). CONCLUSION: FINDINGS may indicate that healthcare providers should pay more attention to non-clinical factors such as coping styles and social support, when addressing diabetes-related distress. They should also be aware that interventions based on psychosocial approaches may primarily influence distress, and not necessarily metabolic control. PMID- 21707729 TI - An ecological study of community-level correlates of suicide mortality rates in the Flemish region of Belgium, 1996-2005. AB - An ecological study of age-standardized suicide rates in Belgian communities (1996-2005) was conducted using spatial regression techniques. Community characteristics were significantly related to suicide rates. There was mixed support for the social integration perspective: single person households were associated with higher suicide rates, while religious participation was unrelated and both immigration and the presence of non-European inhabitants had a negative impact. Deprivation had a positive relation with suicide. Population density had a negative influence on suicide rates. Areas with older populations had higher suicide risks than expected. A spatial contagion effect of neighboring communities was present for men. In the conclusion, hypotheses are presented on why an aging population could be associated with higher suicide rates in the community. PMID- 21707730 TI - Variables associated with repeated suicide attempt in a criminal justice population. AB - The aim of this study was to identify factors associated with repeated suicide attempts among criminal justice clients examined for substance abuse using the Addiction Severity Index. Among suicide attempters (n=1,404), repeaters (two or more attempts, n=770) were compared to nonrepeaters. In logistic regression, repetition was associated with younger age, opioid analgesics, somatic medication, overdose, maternal psychiatric problems, delirium tremens, cognitive problems, and violent behavior. As in other settings, factors associated with repetition differed from those associated with suicide attempts in general. In this setting, substance use complications and cognitive problems were connected to repetition and should be addressed in risk assessments. PMID- 21707731 TI - RT real-time PCR-based quantification of Uromyces fabae in planta. AB - Quantification of obligate biotrophic parasites has been a long-standing problem in plant pathology. Many attempts have been made to determine how much of a pathogen is present in infected plant tissue. Methods of quantification included scoring disease symptoms, microscopic evaluation, determination of specific compounds like Ergosterol, and lately nucleic acid-based technologies. All of these methods have their drawbacks, and even real-time PCR may not be quantitative if for example the organism of interest has specific and differing numbers of nuclei in different infection structures. We applied reverse transcription (RT) real-time PCR to quantify Uromyces fabae within its host plant Vicia faba. We used three different genes, which have been shown to be constitutively expressed. Our analyses show an exponential increase of fungal material between 4 and 9 days post inoculation and thereafter reaching a steady state of around 45% of total RNA. We also used haustorium-specific genes to determine the amount of haustoria present at each time point. These analyses parallel the development of the whole fungus with the exception of the steady state level, which is only around 5% of the total RNA. This indicates that RT real-time PCR is a suitable method for quantification of obligate biotrophic parasites, and also for the differentiation of developmental stages. PMID- 21707732 TI - Genetic transformation of Veillonella parvula. AB - Veillonellae are one of the most prevalent and predominant microorganisms in both the supra- and subgingival plaques of the human oral cavity. Veillonellae's mutualistic relationships with the early, middle, and late colonizers of the oral cavity make them an important component of oral biofilm ecology. Unlike other ubiquitous early colonizers in the oral cavity, surprisingly little is known about Veillonella biology due to our lack of ability to genetically transform this group of bacteria. The objective of this study was to test the transformability of veillonellae. Using Veillonella parvula strain PK1910, we first obtained spontaneous mutations conferring streptomycin resistance. These mutations all carry a K43N substitution in the RpsL protein. Using the mutated rpsL gene as a selection marker, a variety of conditions were tested and optimized for electroporation. With the optimized protocol, we were able to introduce the first targeted mutation into the chromosome of V. parvula PK1910. Although more studies are needed to develop a robust genetic manipulation system in veillonellae, our results demonstrated, for the first time, that V. parvula is transformable, at least for strain PK1910. PMID- 21707733 TI - Tight control of mycotoxin biosynthesis gene expression in Aspergillus flavus by temperature as revealed by RNA-Seq. AB - To better understand the effect of temperature on mycotoxin biosynthesis, RNA-Seq technology was used to profile the Aspergillus flavus transcriptome under different temperature conditions. This approach allowed us to quantify transcript abundance for over 80% of fungal genes including 1153 genes that were differentially expressed at 30 and 37 degrees C. Eleven of the 55 secondary metabolite clusters were upregulated at the lower temperature, including aflatoxin biosynthesis genes, which were among the most highly upexpressed genes. On average, transcript abundance for the 30 aflatoxin biosynthesis genes was 3300 times greater at 30 degrees C as compared with 37 degrees C. The results are consistent with the view that high temperature negatively affects aflatoxin production by turning down transcription of the two key transcriptional regulators, aflR and aflS. Subtle changes in the expression levels of aflS to aflR appear to control transcription activation of the aflatoxin cluster. PMID- 21707734 TI - Acinetobacter sp. HM746599 isolated from leatherback turtle blood. AB - A newly described bacterial isolate, Acinetobacter sp. HM746599, has been obtained from leatherback sea turtle hatchling blood. The implication is that the hatchling was infected during development in the egg, which is substantiated by other studies to be reported by us in the future. The 16S rRNA gene sequence of the bacterium (GenBank accession number: HM746599) showed the greatest similarity to the identified species, Acinetobacter beijerinckii (97.6-99.78%) and Acinetobacter venetianus (99.78%). Acinetobacter sp. HM746599 are gram-negative, rod-shaped coccobacilli and are hemolytic/cytotoxic to human and sea turtle red blood cells (RBCs). Hemolysis is not the result of any detectable soluble toxin. Acinetobacter beijerinckii and A. venetianus hemolyze sheep RBCs while Acinetobacter sp. HM746599 does not, and unlike A. venetianus, the growth of Acinetobacter sp. HM746599 and A. beijerinckii is not supported by l-arginine. Many Acinetobacter species, especially hemolytic ones, are pathogenic to immunologically compromised humans and it is possible that, in addition to sea turtles, this bacterium might also be a danger to susceptible humans who handle infected hatchlings. The bacteria are available from CCUG (Culture Collection, University Gothenburg, Goteborg, Sweden) and from NRRL (Agricultural Research Service Culture Collection, Peoria, IL). PMID- 21707735 TI - Reduced invasion to human epithelial cell lines of Salmonella enterica serovar Typhi carrying S. Typhimurium sopD2. AB - Salmonella enterica serovar Typhi and Typhimurium are closely related serovars. However, S. Typhi, a human-specific pathogen, has 5% of genes as pseudogenes, far more than S. Typhimurium, which only has 1%. One of these pseudogenes corresponds to sopD2, which in S. Typhimurium encodes an effector protein involved in Salmonella-containing vacuole biogenesis in human epithelial cell lines, which is needed for full virulence of the pathogen. We investigated whether S. Typhi trans complemented with the functional sopD2 gene from S. Typhimurium (sopD2(STM) ) would reduce the invasion of human epithelial cell lines. Our results showed that the presence of sopD2(STM) in S. Typhi significantly modified the bacterial ability to alter cellular permeability and decrease the CFUs recovered after cell invasion of human epithelial cell line. These results add to mounting evidence that pseudogenes contribute to S. Typhi adaptation to humans. PMID- 21707736 TI - Manipulation of autophagy by bacteria for their own benefit. AB - Autophagy is the host innate immune system's first line of defense against microbial intruders. When the innate defense system recognizes invading bacterial pathogens and their infection processes, autophagic proteins act as cytosolic sensors that allow the autophagic pathway to be rapidly activated. However, many intracellular bacterial pathogens deploy highly evolved mechanisms to evade autophagic recognition, manipulate the autophagic pathway, and remodel the autophagosomal compartment for their own benefit. Here current topics regarding the recognition of invasive bacteria by the cytosolic innate immune system are highlighted, including autophagy and the mechanisms that enable bacteria to evade autophagy. Also highlighted are some selective examples of bacterial activities that manipulate the autophagic pathways for their own benefit. PMID- 21707737 TI - The opportunistic yeast pathogen Trichosporon asahii colonizes the skin of healthy individuals: analysis of 380 healthy individuals by age and gender using a nested polymerase chain reaction assay. AB - Deep-seated trichosporonosis is an opportunistic fungal infection with a poor prognosis and high mortality rate. The major causative agent is Trichosporon asahii; its route of infection is not clear. To elucidate whether this microorganism is part of the cutaneous microbiota, we examined skin samples from 380 healthy Japanese ranging in age from 0 to 82 years using a nested PCR assay. The colonization frequency of T. asahii increased with age up to 13-15 years in male and 30-39 years in female subjects, subsequently decreasing gradually in both sexes until senescence. Of the nine genotypes of the intergenic spacer region of the T. asahii rRNA gene, type 1 predominated (81.7%), followed by types 4 (6.7%) and 6 (5.5%). The distribution of identified genotypes was similar to that for T. asahii isolated from clinical specimens (blood and urine) of patients with deep-seated trichosporonosis and quite different from that of environmental isolates. Additionally, T. asahii DNA was detected stably from skin samples over 1 year. The opportunistic yeast pathogen T. asahii is part of the cutaneous fungal microbiota in humans. Cutaneous T. asahii may be one of the routes through which deep-seated trichosporonosis is acquired, whereas environmental T. asahii is not associated with this infection. PMID- 21707738 TI - Acidic environments induce differentiation of Proteus mirabilis into swarmer morphotypes. AB - Although swarmer morphotypes of Proteus mirabilis have long been considered to result from surfaced-induced differentiation, the present findings show that, in broth medium containing urea, acidic conditions transform some swimmer cells into elongated swarmer cells. This study has also demonstrates that P. mirabilis cells grown in acidic broth medium containing urea enhance virulence factors such as flagella production and cytotoxicity to human bladder carcinoma cell line T24, though no significant difference in urease activity under different pH conditions was found. Since there is little published data on the behavior of P. mirabilis at various hydrogen-ion concentrations, the present study may clarify aspects of cellular differentiation of P. mirabilis in patients at risk of struvite formation due to infection with urease-producing bacteria, as well as in some animals with acidic or alkaline urine. PMID- 21707739 TI - Two novel retron elements are replaced with retron-Vc95 in Vibrio cholerae. AB - Bacterial reverse transcriptase (RT) is responsible for the production of an RNA DNA complex called multicopy single-stranded DNA (msDNA). The genetic element required for the sysnthesis of msDNA is named a retron. Here, we characterize two novel retrons named retron-Vc81 and retron-Vc137 in Vibrio cholerae. Interestingly, retron-Vc81 and retron-Vc137 are replaced by retron-Vc95 at the same location on the chromosome. PMID- 21707740 TI - Virological surveillance of human influenza in Indonesia, October 2008-March 2010. AB - Despite the high prevalence of highly pathogenic H5N1 influenza A viruses in Indonesia, epidemiology information on seasonal human influenza is lacking. The present authors, therefore, conducted virologic surveillance in Surabaya, East Java from October 2008 to March 2010. Influenza viruses, including pandemic (H1N1) 2009 viruses, were isolated from 71 of 635 individuals tested. Seasonal influenza peaked in the rainy season. Compared with seasonal influenza viruses, pandemic 2009 viruses were isolated from younger patients with milder symptoms. Given the high prevalence of H5N1 infections in humans, continued influenza surveillance is essential for pandemic preparedness. PMID- 21707741 TI - Oral health-related quality of life--associations with oral health and conditions in Swedish 70-year-old individuals. AB - OBJECTIVE: The aim of this study was to evaluate oral health-related quality of life (OHRQoL) in relation to different chronic oral conditions and perception of oral health among elderly individuals. BACKGROUND: Health-related quality of life is important to assess and understand the impact of different diseases and conditions on individuals' well-being. MATERIAL AND METHODS: Randomly selected 70 year-old individuals (N = 561) were included in this analysis. They were clinically examined and answered a questionnaire. Variables used were perceived oral health, satisfaction with appearance of teeth, problems with chewing and dry mouth, burning mouth syndrome, dental anxiety and dental visiting habits. To measure the participants' perception of the impact of oral conditions on their well-being, the Oral Health Impact Profile (OHIP-14) was used. RESULTS: The OHIP 14 distribution of sum of scores showed a floor effect but revealed acceptable psychometric properties with regard to reliability and validity. Multivariable logistic regression revealed three highly predictive variables for individuals with high OHIP-14 scores: using dentures, having chewing problems and being dissatisfied with appearance of teeth. CONCLUSION: Use of dentures, having chewing problems and being dissatisfied with appearance of teeth are associated with high OHIP-14 sums, indicating strong influence on OHRQoL. PMID- 21707742 TI - Understanding the psychology of geriatric edentulous patients. AB - OBJECTIVE: This article focuses on understanding our older patients who require complete prosthodontic care. By breaking down the patient psychology to its component parts, it is easier to obtain a clear picture of this special cohort of patients. Considering the increase in number of geriatric edentulous patients, this knowledge will help the dentist serve the geriatric population better. BACKGROUND: The role of psychology and personality in complete denture treatment is well documented. The geriatric patient who needs complete dentures has a psychological aspect that needs consideration. Although significant, these aspects may sometimes be ignored or considered irrelevant. MATERIALS AND METHODS: A review of relevant literature was carried out to obtain data on the psychology and personality of geriatric, complete denture patients and their behavioural changes. The obtained data was filtered and condensed to provide a short but comprehensive look at the geriatric edentulous patient's psychology. CONCLUSION: When handling geriatric edentulous patients, the dentist must be confident of addressing and managing the psychology of these patients. A thorough understanding of the geriatric mental state thus becomes important and significant for the clinician. PMID- 21707743 TI - Edentulism and dental caries in Victorian nursing homes. AB - OBJECTIVES: The aim of this project was to investigate edentulism and dental caries in nursing home residents in Victoria, Australia. BACKGROUND: The Australian population is ageing with a growing number of people living in nursing homes. These residents are at increased risk for dental caries, have more teeth present now than at any time in the past 50 years and often have difficulty maintaining adequate oral hygiene. MATERIALS AND METHODS: Clinical dental examinations were conducted at 31 nursing homes in Melbourne and regional Victoria between May 2005 and June 2006. A total of 510 residents were examined out of 1345 eligible participants. Socio-demographic and medical history was collected via questionnaire. RESULTS: Just over half of the residents were dentate (53.9%), and dentate residents had a mean of 14.4 teeth present and 2.66 untreated decayed teeth. Residents who required total assistance with oral hygiene had more decayed teeth and fewer filled teeth than residents who did not require assistance. CONCLUSIONS: Nursing home residents in Victoria are retaining an increasing number of natural teeth and have more tooth surfaces at risk for dental caries. Untreated dental caries was a significant problem for residents, particularly for those who are dependent on others for their daily oral hygiene care. PMID- 21707744 TI - Improved growth of preterm infants receiving mother's own raw milk compared with pasteurized donor milk. AB - AIM: To determine whether growth, feeding tolerance and infectious events of preterm infants is related to the proportion of intake of mother's own raw milk (maternal milk) versus pooled pasteurized banked breast milk (donor milk). METHODS: This is a prospective observational study of 55 premature infants born less than 32 weeks of gestational age admitted to the neonatal intensive care unit at the Children's Hospital of Toulouse during two 6-month periods from 2003 to 2005. Enrolled infants were exclusively on enteral feeds with maternal milk +/ donor milk. RESULTS: Mean gestational age was 28.6 weeks (SD 1.5) and mean birth weight 1105 grams (SD 282). During the time of exclusively breast milk feeds, weight gain (g/kg/day) was correlated to the proportion of maternal milk consumed (p = 0.0048, r = 0.4). Necrotizing enterocolitis was inversely correlated to the amount of maternal milk. The amount of maternal milk did not impact on infectious events. CONCLUSION: Mother's own raw milk improves weight gain compared with donor milk in preterm infants. Lactation strategies should be sought that helps mothers to increase their milk production. PMID- 21707745 TI - Is history bunk? PMID- 21707746 TI - Problem of double pass recording using infrared light. PMID- 21707749 TI - A complex case of angulated and bifurcated lesion facilitated by excimer laser coronary angioplasty. AB - Angulated lesions have been shown to be associated with abrupt closure or periprocedural myocardial injury. In particular, when disease is present at the level of the angulated or bifurcated lesion, balloon dilatation may help in wire crossing but it may also cause branch occlusion. Several methods and devices have been described to manipulate coronary guidewires across angulated and bifurcated lesions. This case report describes a highly angulated coronary bifurcated lesion where, after the failure of multiple wires to cross the lesion toward the main branch, it was successfully crossed after excimer laser debulking, which facilitated the wire crossing into the main branch, without causing branch occlusion. PMID- 21707750 TI - The 8p11 myeloid and lymphoid neoplasm. PMID- 21707751 TI - NPM1 mutation is a stable marker for minimal residual disease monitoring in acute myeloid leukaemia patients with increased sensitivity compared to WT1 expression. AB - Mutation in the NPM1 gene occurs in 60% of acute myeloid leukaemia (AML) patients with normal karyotype. NPM1 mutation is potentially a superior minimal residual disease (MRD) marker compared to WT1 gene overexpression by being specific to the malignant clone, although experimental evidence published so far includes very limited numbers of relapsed cases. Also, the stability of the NPM1 mutation has been questioned by reports of the mutation being lost at relapse. In the present study we compared NPM1 mutation and WT1 overexpression as MRD markers in 20 cases of relapsed AML. The 20 patients experienced a total of 28 morphological relapses. Karyotypic evolution was detected in 56% of relapses. All relapses were accompanied by high levels of NPM1 mutation, along with high WT1 mRNA levels, thus demonstrating complete stability of both markers during relapse. Detectable NPM1 mutation following a period of morphological remission was accompanied by a morphological relapse in all cases. In contrast, WT1 expression was detected in 33% of the NPM1 mutation negative samples. This background WT1 expression produced by non-leukaemia cells was highly variable, both between and within patients, and limited the de facto sensitivity of the WT1 expression analysis. The present study therefore provides important experimental evidence demonstrating that NPM1 mutation is superior to WT1 overexpression as marker of MRD in NPM1-mutated AML, even in the presence of extensive karyotypic evolution. PMID- 21707752 TI - A pilot study to evaluate the success and survival rate of titanium-zirconium implants in partially edentulous patients: results after 24 months of follow-up. AB - OBJECTIVES: Implants made from a new titanium-zirconium (TiZr) alloy (Roxolid) have shown good osseointegration with no adverse effects in animal studies. This single-cohort pilot study was performed to evaluate the performance and safe use of reduced-diameter implants made from this new TiZr alloy for the first time in human subjects, in a prospective case-controlled series. METHODS: In two private specialist clinics, each of 22 patients received one 3.3 mm TiZr test implant with a Regular Neck Standard Plus design. The use of the new implant was restricted to the indications and protocol for the use of the existing 3.3 mm diameter regular-neck implant made from Grade IV titanium. The test implants were splinted to a standard Grade IV titanium Regular Neck implant with a fixed dental prosthesis. RESULTS: Twenty of 22 patients had a successful and surviving implant at the 2-year follow-up; one study implant was lost 80 days after placement due to infection spreading from an adjacent tooth and one patient did not complete the 2-year assessment. The mean change in the functional bone level 2 years after loading was -0.33 +/- 0.54 mm (-0.32 +/- 0.61 mm and -0.34 +/- 0.63 mm mesial and distal, respectively). Patients had healthy peri-implant soft tissues, as indicated by mean probing pocket depths ranging from 2.21 to 2.89 mm after 2 years. CONCLUSIONS: Within the limits of this pilot study, the performance of the new implant material was safe and reliable. The new implants meet established success and survival criteria after 2 years. PMID- 21707753 TI - Accuracy of cone beam computed tomography in assessing peri-implant bone defect regeneration: a histologically controlled study in dogs. AB - OBJECTIVE: To assess the accuracy of cone-beam computed tomography (CBCT) in terms of buccal bone-wall configuration and peri-implant bone defect regeneration after guided bone regeneration (GBR). MATERIAL AND METHODS: Titanium implants were inserted into standardized box-shaped defects in the mandible of 12 foxhounds. Defects of one side were augmented following the principle of GBR, while the other side was left untreated. Radiological evaluation was performed using CBCT and compared with histomorphometrical measurements of the respective site serving as a validation method. RESULTS: Non-augmented control sites providing a horizontal bone width (BW) of<0.5 mm revealed a significantly lower accuracy between the radiological and the histological evaluation of the buccal defect depth (1.93 +/- 1.59 mm) compared with the group providing a BW of >0.5 mm (0.7 +/- 0.7 mm) (P<0.05, Mann-Whitney U-test). In GBR-treated defects, the subgroup <0.5 mm (1.49 +/- 1.29 mm) revealed a significantly higher difference between CBCT and histology compared with >0.5 mm (0.82 +/- 1.07) (P>0.05, Mann Whitney U-test). However, a radiological discrimination between original bone, integrated and non-integrated bone substitute material was not reliable. Additionally, it was found that a minimum buccal BW of 0.5 mm was necessary for the detection of bone in radiology. CONCLUSION: The evaluation of peri-implant bone defect regeneration by means of CBCT is not accurate for sites providing a BW of <0.5 mm. Moreover, a safe assessment of the success of the GBR technique is not possible after the application of a radiopaque bone substitute material. PMID- 21707754 TI - Maxillary sinus floor elevation and grafting with deproteinized bovine bone mineral: a clinical and histomorphometric study. AB - OBJECTIVES: This study evaluated the histomorphometric and clinical outcomes of maxillary sinus floor elevation using deproteinized bovine bone mineral (DBBM). MATERIAL AND METHODS: Maxillary sinuses with a residual vertical height of <5 mm were augmented with DBBM alone before implant placement 9 months later. At the time of implant surgery, trephine samples were removed and histological and histomorphometric analyses were performed to examine the percentage of bone and residual graft using point counting and software-aided analysis. Patients were recalled for clinical and radiographic examination up to 3 years later. RESULTS: Twenty-five patient specimens were analysed. The percentages of regenerated bone and residual graft material were 19% and 40%, respectively. Software-aided analysis was comparable to point counting. Twelve patients attended for clinical follow-up. Implants placed into this regenerated bone exhibited success and survival rates of 100% after an average follow-up of 3 years. The average vertical height gained was 7.9 mm. CONCLUSIONS: The use of DBBM alone in maxillary sinus floor elevation is a predictable method to gain vertical bone height in the posterior maxilla. PMID- 21707755 TI - Skin organ culture as a model to study oxidative stress, inflammation and structural alterations associated with UVB-induced photodamage. AB - BACKGROUND: Ultraviolet (UV) irradiation is a major cause of skin damage, of long term alteration of skin metabolism, homoeostasis and physical structure. The analysis of UV-induced pathogenic processes requires in vitro models allowing biochemical studies, and appropriate for the development of novel, accurate diagnosis methods based on non-invasive procedures. OBJECTIVES: This work was aimed to reproduce the effects of UVB on whole-skin explants ex vivo and to study underlying biochemical mechanisms, especially in correlation with skin autofluorescence. METHODS: Human skin organ cultures were irradiated with UVB and subjected to enzyme assays, Western blots, solid-phase ELISA, HPLC and fluorescence measurements. RESULTS: UVB irradiation was found to enhance ROS production, to deplete the pool of low-molecular-weight antioxidants and to decrease the overall antioxidant capacity in the epidermis, in a manner dependent on xanthine-oxidase activity. Epidermal cell proliferation and mitochondrial activity were transiently stimulated. IkappaB-alpha was degraded, and the secretion of inflammatory cytokines was drastically increased. Inducible nitric oxide synthase activity was increased in non-irradiated controls, probably due to the mechanical stress of skin excision, and this phenomenon was suppressed by UVB. Autofluorescence measurements revealed alterations of dermal protein crosslinks following UVB irradiation. CONCLUSIONS: Skin organ culture proved to be an integrated model appropriate for in vitro analysis of UVB biologic effects and their correlations, and for the study of non-invasive diagnostic methods in cellular and molecular terms. PMID- 21707756 TI - Intracellular calcium response to high temperature is similar in undifferentiated and differentiated cultured human keratinocytes. AB - A series of thermo-sensitive proteins is expressed in epidermal keratinocytes, where they function as cation channels that are activated at temperatures in the range of 28-42 degrees C. Here, we examined the influence of high temperature on intracellular calcium level in undifferentiated and differentiated cultured human keratinocytes, which are considered to be representative of deeper and upper epidermal layers, respectively. We found that the percentages of responsive keratinocytes among undifferentiated and differentiated cells exposed to temperatures in the warm-hot range (30-50 degrees C) were essentially the same. In contrast, we previously demonstrated that undifferentiated keratinocytes were more sensitive than differentiated cells to low temperature (<22 degrees C). Thus, the deeper layer of the epidermis is more sensitive to cold than the upper layer, but the response to warm-hot temperatures appears to be homogeneous throughout the epidermis. PMID- 21707757 TI - Development of a 3D pigmented skin model to evaluate RNAi-induced depigmentation. AB - Because current skin whitening agents often have insufficient efficacy and side effects, we aim to develop effective and safe therapeutics using RNA interference (RNAi). We established a pigmented human-reconstructed skin model as a first step in the development of novel siRNA-based depigmenting agents. Histological characterization revealed that our model had a similar morphology as normal human skin, expressed keratinocyte differentiation as well as basement membrane markers, and showed a high degree of pigmentation. The utility of the model to study RNAi-induced depigmentation was validated by incorporation of melanocytes transfected with siRNA against tyrosinase, a key enzyme in skin pigmentation. This resulted in a strong reduction in pigmentation and inhibition of melanin transfer proving that siRNA-mediated gene silencing in melanocytes worked successfully in our model. Therefore, this self-made 3D skin model will be a useful and easy tool to validate the whitening potential of candidate genes with a presumed function in melanin synthesis or transfer. PMID- 21707758 TI - Cyclosporin A inhibits nucleotide excision repair via downregulation of the xeroderma pigmentosum group A and G proteins, which is mediated by calcineurin inhibition. AB - Cyclosporin A (CsA) inhibits nucleotide excision repair (NER) in human cells, a process that contributes to the skin cancer proneness in organ transplant patients. We investigated the mechanisms of CsA-induced NER reduction by assessing all xeroderma pigmentosum (XP) genes (XPA-XPG). Western blot analyses revealed that XPA and XPG protein expression was reduced in normal human GM00637 fibroblasts exposed to 0.1 and 0.5 MUm CsA. Interestingly, the CsA treatment reduced XPG, but not XPA, mRNA expression. Calcineurin knockdown in GM00637 fibroblasts using RNAi led to similar results suggesting that calcineurin dependent signalling is involved in XPA and XPG protein regulation. CsA-induced reduction in NER could be complemented by the overexpression of either XPA or XPG protein. Likewise, XPA-deficient fibroblasts with stable overexpression of XPA (XP2OS-pCAH19WS) did not show the inhibitory effect of CsA on NER. In contrast, XPC-deficient fibroblasts overexpressing XPC showed CsA-reduced NER. Our data indicate that the CsA-induced inhibition of NER is a result of downregulation of XPA and XPG protein in a calcineurin-dependent manner. PMID- 21707759 TI - Elevated MMP-7 levels in patients with systemic sclerosis: correlation with pulmonary involvement. AB - BACKGROUND: Fibrosis is characterized by an excessive accumulation of connective tissue because of an imbalance between synthesis and degradation of extracellular matrix proteins. Systemic sclerosis (SSc) is a prototypic chronic inflammatory disease leading to a severe fibrosis of the skin and many internal organs. QUESTIONS ADDRESSED: We investigated whether serum MMP-7 levels reflect the activity of the fibrotic reaction in systemic sclerosis. EXPERIMENTAL DESIGN: Serum samples were obtained from 123 patients with systemic sclerosis. MMP-serum levels of all patients with SSc were compared with age-matched healthy controls. RESULTS: Significantly increased median serum MMP-7 levels were found in patients with SSc when compared with controls. The median MMP-7 serum level of patients with lung fibrosis (LF) was significantly higher compared with those without LF. Accordingly, patients with dyspnea and DLCO (diffusion capacity of the lung for carbon monoxide) levels below 60% showed significantly higher median MMP-7 levels. CONCLUSIONS: Elevated MMP-7 levels are associated with an advanced stage of SSc and LF. These data suggest that in SSc MMP-7 is involved in the process of fibrotic tissue remodelling. PMID- 21707760 TI - Differential suppression of epidermal antimicrobial protein expression in atopic dermatitis and in EFAD mice by pimecrolimus compared to corticosteroids. AB - It has been suggested that the increased rate of bacterial infection in atopic dermatitis (AD) may be caused by reduced antimicrobial protein (AMP) expression. We were interested whether common treatments in AD affect antimicrobial defense. We investigated the effects of topically applied corticosteroids betamethasone valerate (BV) and triamacinolone acetonide (TA) and those of the calcineurin inhibitor pimecrolimus for 3 weeks on AMP expression in AD. BV and TA treatment in AD led to a significant reduction in AMP expression; protein expression of human beta-defensins (hBD)-2 and hBD-3, psoriasin, RNase 7 and cathelicidin LL-37 was below the level in skin of healthy controls. After pimecrolimus treatment, AMP expression was also reduced but less compared to BV and TA; the expression levels of hBD-2, psoriasin and RNase 7 still remained above the control levels. In essential fatty acid-deficient (EFAD) mice, a model of chronic skin barrier disease with inflammation, expression of the mouse beta-defensins mBD-1, mBD-3 and mBD-14 (orthologues for hBD-1, hBD-2 and hBD-3, respectively), was reduced by both treatments, again more pronounced by BV compared to pimecrolimus. In summary, we found that treatment for AD with corticosteroids in human skin and EFAD mice caused a strong reduction in AMPs; reduction was less with pimecrolimus. This result may explain the clinical observation that prolonged treatment with topical corticosteroids sometimes leads to bacterial infection. PMID- 21707761 TI - Kinetics and differential expression of the skin-related chemokines CCL27 and CCL17 in psoriasis, atopic dermatitis and allergic contact dermatitis. AB - CCL27 and CCL17 are chemokines believed to be involved in the process of establishing the inflammatory infiltrate, characteristic for the various inflammatory skin diseases. The skin-specific CCL27 binds the chemokine receptor 10 (CCR10), and CCL17 is a chemokine receptor-4 (CCR4) ligand. The purpose of our study was to characterize the expression of CCL27 and CCL17 in the inflammatory skin diseases: psoriasis, atopic dermatitis (AD) and acute allergic contact dermatitis (ACD) induced in nickel-sensitive individuals. Surprisingly, our studies revealed a markedly decreased CCL27 mRNA and protein expression in psoriatic lesions compared with non-lesional psoriatic skin. A minor CCL17 mRNA increase was measured in lesional psoriatic skin. No alterations were found in AD. In ACD, we found a pronounced (90-fold) raise in CCL17 mRNA and a 50-fold increase in CCL17 protein compared with normal skin. A kinetic ACD study of CCL17 expression showed the highest mean value 24 h after hapten application. Furthermore, we found the mRNA levels of CCR10 and CCR4 paralleling the results of their corresponding ligands. Overall, our principal findings were a distinct decrease in CCL27 in lesional psoriatic skin and a marked upregulation of CCL17 in ACD. These findings underscore the differential cutaneous T-cell recruitment in different inflammatory diseases. PMID- 21707762 TI - Study on the roles of beta-catenin in hydrogen peroxide-induced senescence in human skin fibroblasts. AB - Oxidative stress is one of the most important causes of the cellular senescence process. Previous studies showed that beta-catenin can regulate FoxO3a and this association was enhanced in cells exposed to oxidative stress. It has also been reported that beta-catenin can regulate some senescence-related proteins. We propose that beta-catenin may play a crucial role in senescence of normal human primary skin fibroblasts (NHSFs). Here, we explored the roles and mechanisms of beta-catenin on H(2)O(2)-induced senescence in NHSFs. beta-catenin expression was decreased in NHSFs after H(2)O(2) treatment. Overexpression of beta-catenin in NHSFs led to a marked delay of many senescent phenotypes induced by H(2)O(2). Furthermore, overexpression of beta-catenin in NHSFs can antagonise the alteration of reactive oxygen species accumulation and some senescence-related proteins expression induced by H(2)O(2) treatment. Our data demonstrated that beta-catenin can protect NHSFs from H(2)O(2)-induced premature senescence by alleviating oxidative stress and regulating some senescence-related molecules. PMID- 21707763 TI - Effects of topical application of aqueous solutions of hexoses on epidermal permeability barrier recovery rate after barrier disruption. AB - Previous studies have suggested that hexose molecules influence the stability of phospholipid bilayers. Therefore, the effects of topical application of all 12 stereoisomers of dextro-hexose on the epidermal barrier recovery rate after barrier disruption were evaluated. Immediately after tape stripping, 0.1 m aqueous solution of each hexose was applied on hairless mouse skin. Among the eight dextro-aldohexoses, topical application of altose, idose, mannose and talose accelerated the barrier recovery, while allose, galactose, glucose and gulose had no effect. Among the four dextro-ketohexoses, psicose, fructose, sorbose and tagatose all accelerated the barrier recovery. As the effects of hexoses on the barrier recovery rate appeared within 1 h, the mechanism is unlikely to be genomic. Instead, these hexoses may influence phase transition of the lipid bilayers of lamellar bodies and cell membrane, a crucial step in epidermal permeability barrier homeostasis. PMID- 21707764 TI - Exploring the role of a nonablative laser (1320 nm cooltouch laser) in skin photorejuvenation. AB - BACKGROUND: Nonablative laser has been used for the treatment and prevention of skin aging for many years. Although the mechanism has not been elucidated, histological evaluation showed that the dermal fibroblasts and its collagen production should be the main target for this rejuvenation. In order to determine the effects of a 1320 nm nonablative laser on the human dermal fibroblasts, the two main secretion factors, basic fibroblast growth factor (bFGF) and transforming growth factor beta1(TGF-beta1), in vitro were detected. METHODS: The human dermal fibroblasts were cultured and irradiated with a 1320 nm laser at the dose of 15, 20, and 24 J/cm(2) respectively. The number of fibroblasts was counted and the levels of bFGF and TGF-beta1 were detected by enzyme-linked immunosorbent assay at the time points of 0, 24, 48, and 72 h after irradiation. RESULTS: The results showed that both the number of fibroblasts and the secretion of bFGF increased after the irradiation at the dose of 20 and 24 J/cm(2) (P<0.05) compared with that of the control cells. The bFGF secretion in the group exposed to 20 J/cm(2) was more significant than that of 24 J/cm(2), and the peak level was 24 h after irradiation. The level of TGF-beta1 secretion decreased after irradiation in a dose-dependent manner (15 and 20 J/cm(2), both P<0.05; 24 J/cm(2), P<0.01), and reached a nadir at 24 h. CONCLUSION: Our results suggested that the 1320 nm nonablative laser accelerates the vitality of fibroblasts, promotes the secretion of bFGF, and inhibits TGF-beta1 secretion by fibroblasts. PMID- 21707765 TI - Increased urethral resistance by periurethral injection of low serum cultured adipose-derived mesenchymal stromal cells in rats. AB - OBJECTIVES: To evaluate the effects of a periurethral injection of low serum cultured adipose tissue-derived mesenchymal stromal cells (LASC) and to develop a new autologous cell therapy for stress urinary incontinence. METHODS: F344 rats were divided into three groups as based on the periurethral injection of LASC, GAX collagen or vehicle (control). At 2 and 4 weeks after injection, leak point pressure (LPP) was measured before and after transection of the pelvic nerves. For cell tracking, LASC of green fluorescent protein transgenic rats were injected into nude rats. RESULTS: At 2 weeks, both the LASC and collagen groups showed significantly higher LPP than the control group. At 4 weeks, the increase in LPP in the LASC group remained, whereas LPP in the collagen group decreased to baseline levels. In the absence of the urethral closure reflex after transection of the pelvic nerves, LPP in the LASC group was significantly higher than that in the other two groups. Histologically, the size of the urethral lumen was smaller in the LASC group than the collagen group. At 4 weeks, most of the LASC were positive for myogenic antigens including alpha-smooth muscle actin, desmin and calponin I. CONCLUSIONS: Periurethral injection of autologous LASC capable of myogenic differentiation made a greater contribution to the increase in urethral resistance than did the conventional collagen bulk injection. Thus, its use for treatment of stress urinary incontinence can be postulated. PMID- 21707766 TI - Efficacy of selective alpha1A adrenoceptor antagonist silodosin in the medical expulsive therapy for ureteral stones. AB - Recently, we reported that alpha1A adrenoceptor (AR) is the main participant in phenylephrine-induced human ureteral contraction. We therefore decided to carry out a prospective randomized study to evaluate the effects of silodosin, a selective alpha1A AR antagonist, as a medical expulsive therapy for ureteral stones. A total of 187 male patients, who were referred to our department for the management of symptomatic unilateral ureteral calculi of less than 10 mm, were randomly divided into two groups: group A (92 patients), who were instructed to drink 2 L of water daily, and group B (95 patients), who received the same instruction and were also given silodosin (8 mg/daily) for a maximum of 8 weeks. Expulsion rate, mean expulsion time and need for analgesics were examined. Overall, the mean expulsion time was 15.19 +/- 7.14 days for group A and 10.27 +/ 8.35 days for group B (P = 0.0058). In cases involving distal ureteral stones, the mean expulsion time was 13.40 +/- 5.90 and 9.29 +/- 5.91 days, respectively (P = 0.012). For stones of 1-5 mm in diameter, the mean expulsion time was 14.28 +/- 6.35 and 9.56 +/- 8.45 days, respectively (P = 0.017). For stones of 6-9 mm in diameter, the stone expulsion rate was 30.4% and 52.2% (P = 0.036), and the mean expulsion time was 21.00 +/- 9.9 and 11.33 +/- 8.31 days, respectively (P = 0.038). Herein, we report the first on silodosin in the management of ureteral lithiasis. Our findings suggest that silodosin might have potential as a medical expulsive therapy for ureteral stones. PMID- 21707767 TI - Erythroderma as a paraneoplastic cutaneous disorder in systemic anaplastic large cell lymphoma. AB - BACKGROUND: Paraneoplastic cutaneous disorders (PCDs) or dermadromes are skin conditions that have an association with internal malignancies but are not themselves malignant. We report the first two cases of systemic anaplastic large cell lymphoma (s-ALCL) accompanied by erythroderma and multiple leg ulcers as PCDs. CASE 1: A 52-year-old Japanese man presented with disseminated itchy papular erythemas which he had over his entire body for the preceding 5 years that later exacerbated to erythroderma. Multiple punched-out ulcers also developed on his lower legs. Superficial lymph nodes (LNs) were swollen, and a left axillary LN biopsy demonstrated dense CD30(+) atypical large cell (ALC) infiltration. By contrast, lymphocytes infiltrating into the erythroderma and leg ulcers were CD30(-) , and T-cell receptor beta (TCRbeta) chain gene rearrangement was negative in skin biopsy specimens. Thus, he was diagnosed with s-ALCL. Not only his s-ALCL but also his erythroderma and leg ulcers responded well to chemotherapy. CASE 2: A 71-year-old Japanese woman presented with erythroderma that persisted for approximately 20 years after mastectomy. At her initial hospital visit, she was diagnosed with s-ALCL by biopsy of swollen left inguinal LNs. Similar to Case 1, CD30(+) ALCs were negative in skin samples with normal TCRbeta chain gene rearrangement. As the erythrodermic skin lesion responded well to chemotherapy for s-ALCL, it was considered a PCD. CONCLUSION: s-ALCL development may be predicted by the precedence and concurrence of intractable paraneoplastic erythrodermic and ulcerative skin lesions, as reported in our two cases. PMID- 21707768 TI - Midfacial analysis and planning for midface augmentation with injectable filling materials: an anatomical approach. AB - BACKGROUND: Midfacial augmentation improves the appearance of patients with flat or ptotic cheek. OBJECTIVES: To develop a simple method of preoperative delineating the location of the ideal malar prominence and determining the best area to augment with injectable filling materials. METHODS: We used detailed analysis of the facial features of some Caucasian men and women as the basis for this study. RESULTS: We described a technique to locate the ideal malar prominence and proposed a classification of midfacial contour defects. CONCLUSION: This method greatly simplifies the surgeon's task of determining the area to be augmented. PMID- 21707769 TI - Clinical parameters in male genital lichen sclerosus: a case series of 329 patients. AB - BACKGROUND: The dermatological aspects of male genital lichen sclerosus (MGLSc) have not received much prominence in the literature. Sexual morbidity appears under-appreciated, the role of histology is unclear, the relative places of topical medical treatment and circumcision are not established, the prognosis for sexual function, urinary function and penis cancer is uncertain and the pathogenesis has not been specifically studied although autoimmunity (as in women) and HPV infection have been mooted. OBJECTIVE: To illuminate the above by analysing the clinical parameters of a large series of patients with MGLSc. METHODS: A total of 329 patients with a clinical diagnosis of MGLSc were identified retrospectively from a dermatology-centred multidisciplinary setting. Their clinical and histopathological features and outcomes have been abstracted from the records and analysed by simple descriptive statistics. RESULTS: The collation and analysis of clinical data derived from the largest series of men with MGLSc ever studied from a dermatological perspective has been achieved. These data allow the conclusions below to be drawn. CONCLUSIONS: MGLSc is unequivocally a disease of the uncircumcised male; the adult peak is late in the fourth decade; dyspareunia is a common presenting complaint; non-specific histology requires careful interpretation; most men are either cured by topical treatment with ultrapotent steroid (50-60%) or by circumcision (>75%); effective and definitive management appears to abrogate the risk of developing penile squamous cell carcinoma; urinary contact is implicated in the pathogenesis of MGLSc; HPV infection and autoimmunity seem unimportant. PMID- 21707770 TI - A pilot randomized controlled trial to examine the feasibility and efficacy of an educational nursing intervention to improve self-management practices in patients with mild-moderate psoriasis. AB - BACKGROUND: Large numbers of people are expected to self-manage their skin condition, but limited attention has been given to studies of self-management in psoriasis, neither clearly highlighting the challenge nor seeking to develop interventions to support its effectiveness. OBJECTIVES: 1. To test the feasibility of a new educational intervention to enable people with psoriasis to self-manage more effectively an adequately powered multi-centred trial design through piloting. METHOD: Pilot randomized controlled trial with adults (n = 64) with mild-moderate psoriasis in Primary Care in the United Kingdom. Both groups continued with usual treatment. A theory-based educational intervention was designed. The primary outcome measure was the Dermatology Life Quality Index (DLQI). Secondary measures included the Psoriasis Area and Severity Index (PASI) and qualitative feedback from participants. Assessment of the feasibility of the intervention included recruitment and acceptability to participants. RESULTS: Delivery of the intervention was feasible and positively evaluated. Recruitment strategies and the intervention need minor modification. As a pilot study there was insufficient power to detect significant score changes. Sub group analysis of participants with a PASI or DLQI of >6 indicated a modest reduction in PASI in the intervention group which demonstrates a trend that may indicate that this intervention has potential value for people with moderate psoriasis when combined with qualitative data. CONCLUSION: This study highlights the feasibility of delivering a self-efficacy based educational intervention for people with mild moderate psoriasis in primary care establishing the numbers and design required for an adequately powered multi-centred trial. PMID- 21707771 TI - Psychological distress and coping strategies in patients attending a dermatology outpatient clinic. AB - BACKGROUND: Psychological distress is frequent among dermatological patients. The development of a positive attitude toward diagnosis and treatment is thought to be critical for successful coping and mental health outcomes. OBJECTIVE: The aim of this study was to assess the coping strategies and the psychological distress, due to anxiety and depression, in an unselected sample of dermatological patients. METHODS: Self-administered questionnaires (HADS, COPE) were given to 603 dermatological patients. RESULTS: Out of 567 participants, 149 (26.2%) scored positive for Anxiety, and 52 (9.2%) scored positive for Depression. Multivariate analysis, adjusting for gender, age, socio-economic status, and disease, showed that both Anxiety and Depression are associated with a less frequent use of Positive attitude coping. CONCLUSION: Our results reinforce the notion that while planning the treatment of dermatological patients, evaluating their mental health might help to provide optimal treatment. Since coping ability was found to be important for mental health status, policy implications could include emphasis on social programs to assist individuals to manage stress, as well as psychological support. PMID- 21707772 TI - Effectiveness of topical calcineurin inhibitors as monotherapy or in combination with hydroxychloroquine in cutaneous lupus erythematosus. AB - BACKGROUND: Calcineurin inhibitors show potent anti-inflammatory effects and favorable safety profile when used in the treatment of cutaneous lupus erythematosus (CLE). OBJECTIVE: The present study investigates the change in clinical parameters of erythema, desquamation and edema, when calcineurin inhibitors are used as monotherapy or in combination with hydroxychloroquine in CLE for a period of 60 days. METHODS: 18 patients were treated with topical tacrolimus and 20 patients with topical pimecrolimus, as monotherapy or in combination with hydroxychloroquine. Clinical parameters of erythema, desquamation and edema were assessed on a scale from 0 to 3 for erythema and edema and 0 to 2 for desquamation. RESULTS: Statistically significant improvement in erythema, desquamation and edema was observed in patients on monotherapy with calcineurin inhibitor and combination treatment with hydroxychloroquine, regardless of disease type. Combination treatment resulted in improvement of edema in 100% of patients, while monotherapy did so in 75% of patients. CONCLUSIONS: Topical calcineurin inhibitors enhance the therapeutic effect of systemic agents in cutaneous lupus erythematosus, and result in improvement of the clinical parameters studied. PMID- 21707773 TI - Malignant melanomas on head/neck and foot: differences in time and latitudinal trends in Norway. AB - BACKGROUND: Cutaneous malignant melanoma (CMM) incidence continues to increase in many parts of the world. Solar ultraviolet (UV) radiation is the main environmental risk factor for CMM. Different body locations are subjected to different doses and exposure patterns of solar UV. Time and latitudinal trends of CMMs on shielded and exposed skin give valuable information about the aetiology of these cancers. In this study, we have compared the time and latitudinal trends of CMM incidence on skin areas which are chronically (head and neck) and rarely (foot) exposed to UV radiation, to gain more information about the relationship between sun doses, exposure patterns and melanomagenesis. METHODS: We have analysed epidemiological data from the Cancer Registry of Norway, for foot and head and neck CMM for two time periods: 1966-1986 and 1987-2007. RESULTS: Cutaneous malignant melanoma incidence rate on head and neck has increased with time, while incidence rates of foot CMM have remained almost constant with time in Norway. There is a large north-south gradient in incidence rates of CMM on head and neck in Norway, while there is almost no north-south gradient for CMM incidence on foot. CONCLUSIONS: Comparisons of time trends and latitudinal trends of the incidence rates of CMM on head/neck and on foot indicate that solar radiation plays a role in the induction of the former CMM but probably not for the latter. PMID- 21707774 TI - Basal cell carcinoma of the head region: therapeutical results of 350 lesions treated with Mohs micrographic surgery. AB - BACKGROUND: Basal cell carcinoma (BCC) is a non-melanocytic skin tumour with a high risk of recurrence after incomplete treatment, especially the aggressive subtypes (basosquamous, micronodular and morphea BCC). The percentage of recurrence also depends on the anatomical site of the tumour. Nose-cheek fold, paranasal fold, retroauricular fold and internal canthus are considered to be critical sites. OBJECTIVE: The aim of this study was to report on recurrence rates for BCC treated with Mohs micrographic surgery (MMS). MATERIAL AND METHODS: We retrospectively studied 350 BCCs of the head region treated with MMS. Results were analysed with chi-squared test and Fisher test and were considered significant when P value was <=0.05. RESULTS: In our study, the percentage of BCC recurrence rate after MMS was of 3.4% for primary BCC and 4.9% for recurrent BCC; these were similar to the recurrence rates reported in the literature. CONCLUSIONS: Low recurrence rate can be achieved when treated with MMS; it is the treatment of choice for many BCC of the head. Aggressive histopathological subtypes, critical head sites and recurrence after incomplete excision are the most important indications for MMS. PMID- 21707775 TI - Cold air analgesia as pain reduction during photodynamic therapy of actinic keratoses. AB - BACKGROUND: Photodynamic therapy (PDT) is an effective treatment for actinic keratoses and non-melanoma skin cancer. The main side effect of PDT is pain during the illumination. OBJECTIVES: To assess the effect of cold air as pain relief during MAL-PDT for field cancerization on different body areas. METHODS: A prospective, open, intra-individual right-left comparison study was performed in 43 patients with MAL-PDT as field cancerization. One area received cold air analgesia while the other did not. Pain was evaluated by numeric rating scale (NRS) during the illumination. The patients' received a questionnaire and recorded pain and postinflammatory symptoms on a visual analogue scale (VAS). RESULTS: We found a statistical significant difference in overall pain score at 3 and 9 minutes. The area receiving cold air during illumination had a mean NRS of 5.1 while the opposite side, not receiving cold air, had NRS of 6.1. At 9 minutes the side receiving cold air had mean NRS of 5.0, and the side without had 5.7. The pain difference on the chest was the most pronounced with a NRS of 5.2 without air and 3.5 with cold air. There was a significant difference in erythema immediately after, 1 h and 24 h after illumination. LIMITATIONS: Small, open, not blinded study. The difference in pain was small. CONCLUSION: Cold air is an effective method for moderate pain relief. It is an easy, noninvasive method that can be used on all body parts. PMID- 21707776 TI - Immunization of hamsters against Clostridium difficile infection using the Cwp84 protease as an antigen. AB - Clostridium difficile is a pathogen responsible for diarrhoea and colitis, particularly after antibiotic treatment. We evaluated the C. difficile protease Cwp84, found to be associated with the S-layer proteins, as a vaccine antigen to limit the C. difficile intestinal colonization and therefore the development of the infection in a clindamycin-treated hamster model. First, we evaluated the immune response and the animal protection against death induced by several immunization routes: rectal, intragastric and subcutaneous. Antibody production was variable according to the immunization routes. In addition, serum Cwp84 antibody titres did not always correlate with animal protection after challenge with a toxigenic C. difficile strain. The best survival rate was observed with the rectal route of immunization. Then, in a second assay, we selected this immunization route to perform a larger immunization assay including a Cwp84 immunized group and a control group. Clostridium difficile intestinal colonization and survival rate, as well as the immune response were examined. Clostridium difficile hamster challenge resulted in a 26% weaker and slower C. difficile intestinal colonization in the immunized group. Furthermore, hamster survival in the Cwp84 immunized group was 33% greater than that of the control group, with a significant statistical difference. PMID- 21707777 TI - Upregulation of progranulin by Helicobacter pylori in human gastric epithelial cells via p38MAPK and MEK1/2 signaling pathway: role in epithelial cell proliferation and migration. AB - Helicobacter pylori is a major human pathogen associated with gastric diseases such as chronic active gastritis, peptic ulcer, and gastric carcinoma. The growth factor progranulin (PGRN) is a secreted glycoprotein that functions as an important regulator of cell growth, migration, and transformation. We aimed to determine the molecular mechanisms by which H. pylori upregulates the expression of PGRN and the relationship between H. pylori infection and production of PGRN in controlling cell proliferation and migration. Levels of PGRN were examined in gastric tissues from patients and in vitro in gastric epithelial cells. Cell proliferation was measured by colony formation assay. Cell migration was monitored by wound healing migration assay. PGRN protein levels were increased in patients with gastritis and gastric cancer tissue. Infection of gastric epithelial cells with H. pylori significantly increased PGRN expression in a time dependent manner. Blockade of the p38 and MEK1/2 pathway by inhibitor inhibited H. pylori-mediated PGRN upregulation. Activation of p38 and MEK1/2 pathway by H. pylori was also identified. Knockdown of PGRN attenuated the H. pylori-induced proliferative activity and migration of cancer cells. These findings suggest that the upregulation of PGRN in H. pylori-infected gastric epithelial cells may contribute to the carcinogenic process. PMID- 21707778 TI - Deletion of the aceE gene (encoding a component of pyruvate dehydrogenase) attenuates Salmonella enterica serovar Enteritidis. AB - Salmonella enterica serovar Enteritidis (S. Enteritidis) is a major food-borne pathogen. From a transposon insertion mutant library created previously using S. Enteritidis 10/02, one of the mutants was identified to have a 50% lethal dose (LD(50) ) at least 100 times that of the parental strain in young chicks, with an attenuation in a poorly studied gene encoding a component of pyruvate dehydrogenase, namely the aceE gene. Evaluation of the in vitro virulence characteristics of the DeltaaceE?kan mutant revealed that it was less able to invade epithelial cells, less resistant to reactive oxygen intermediate, less able to survive within a chicken macrophage cell line and had a retarded growth rate compared with the parental strain. Young chicks vaccinated with 2 * 10(9) CFU of the DeltaaceE?kan mutant were protected from the subsequent challenge of the parental strain, with the mutant colonized in the liver and spleen in a shorter time than the group infected with the parental strain. In addition, compared with the parental strain, the DeltaaceE?kan mutant did not cause persistent eggshell contamination of vaccinated hens. PMID- 21707779 TI - Regulation of the IL-10/IL-12 axis in human dendritic cells with probiotic bacteria. AB - In this study, we have used monocyte-derived dendritic cells (DCs) to design a screening model for the selection of microorganisms with the ability to suppress DC-secreted IL-12p70, a critical cytokine for the induction of T-helper cell type 1 immune responses under inflammatory conditions. By the treatment of DCs with cocktails containing TLR agonists and proinflammatory cytokines, the cells increased the secretion of the Th1-promoting cytokine IL-12p70. Clinically used probiotics were tested for their IL-10- and IL-12p70-stimulating properties in immature DCs, and showed a dose-dependent change in the IL-10/IL-12p70 balance. Lactobacillus acidophilus NCFM(TM) and the probiotic mixture VSL#3 showed a strong induction of IL-12p70, whereas Lactobacillus salivarius Ls-33 and Bifidobacterium infantis 35624 preferentially induced IL-10. Escherichia coli Nissle 1917 induced both IL-10 and IL-12p70, whereas the probiotic yeast Saccharomyces boulardii induced low levels of cytokines. When combining these microorganisms with the Th1-promoting cocktails, E. coli Nissle 1917 and B. infantis 35624 were potent suppressors of IL-12p70 secretion in an IL-10 independent manner, indicating a suppressive effect on Th1-inducing antigen presenting cells. The present model, using cocktail-stimulated DCs with potent IL 12p70-stimulating capacity, may be used as an efficient tool to assess the anti inflammatory properties of microorganisms for potential clinical use. PMID- 21707780 TI - Enhancement of Bordetella parapertussis infection by Bordetella pertussis in mixed infection of the respiratory tract. AB - The epidemiological and pathogenic relationship between Bordetella pertussis and Bordetella parapertussis, the two causes of whooping cough (pertussis), is unclear. We hypothesized that B. pertussis, due to its immunosuppressive activities, might enhance B. parapertussis infection when the two species were present in a coinfection of the respiratory tract. The dynamics of this relationship were examined using the mouse intranasal inoculation model. Infection of the mouse respiratory tract by B. parapertussis was not only enhanced by the presence of B. pertussis, but B. parapertussis significantly outcompeted B. pertussis in this model. Staggered inoculation of the two organisms revealed that the advantage for B. parapertussis is established at an early stage of infection. Coadministration of PT enhanced B. parapertussis single infection, but had no effect on mixed infections. Mixed infection with a PT deficient B. pertussis strain did not enhance B. parapertussis infection. Interestingly, the depletion of airway macrophages reversed the competitive relationship between these two organisms, but the depletion of neutrophils had no effect on mixed infection or B. parapertussis infection. We conclude that B. pertussis, through the action of PT, can enhance a B. parapertussis infection, possibly by an inhibitory effect on innate immunity. PMID- 21707781 TI - Effects of a prebiotic, Immunogen(r), on feed utilization, body composition, immunity and resistance to Aeromonas hydrophila infection in the common carp Cyprinus carpio (Linnaeus) fingerlings. AB - This study evaluated the effects of a commercial prebiotic, Immunogen, on feed utilization, growth rate, immunity promotion and carcass composition of the common carp Cyprinus carpio fingerlings. The fingerlings were adopted for 2 weeks and then reared in triplicate groups in 250-l tanks (n = 15 per tank with average initial weights of 11.12 +/- 0.55 g). The fish fed on five isonitrogenous and isoenergetic experimental diets containing different levels of Immunogen (0, 0.5, 1, 1.5 and 2.5 g prebiotic/kg diet) to apparent satiation thrice a day for 8 weeks. Weight gain showed no differences among the groups fed different Immunogen levels. Both feed efficiency ratio and protein efficiency ratio significantly (p < 0.05) increased with increasing Immunogen levels from 0.5 to 1.5 g/kg diet. The highest protein content (p < 0.05) was found in the fish fed a diet containing 2.5 g/kg prebiotic. Haematological parameters and plasma total protein concentration were also significantly higher (p < 0.05) in the fingerlings fed diets containing 1.5 and 2.5 g/kg prebiotic in relation to the control. The control fish contained the highest mean of total bacterial counts. The lowest mean (p < 0.05) of total bacterial counts was observed in the fish fed the diet containing 2.5 g/kg Immunogen. The present study reveals that a dietary Immunogen supplementation from 1 to 1.5 g/kg is capable to improve the feed efficiency and growth performance of C. carpio fingerlings as well as their resistance to A. hydrophila infection. PMID- 21707782 TI - Influence of diet on calcium metabolism, tissue calcification and urinary sludge in rabbits (Oryctolagus cuniculus). AB - Rabbits absorb more calcium (Ca) from their diet than they require, and excrete surplus via urine, which therefore contains a typical 'sludge'. This makes rabbits susceptible to Ca-containing uroliths. But given the Ca content of diets of free-ranging specimens, and the limited reports of urinary sludge and Ca contents in free-ranging lagomorphs, we can suspect that rabbits are naturally adapted to high urinary Ca loads. We fed four groups of New Zealand hybrid rabbits [n = 28, age at start 5-6 weeks) pelleted diets consisting of lucerne hay only (L, Ca 2.32% dry matter (DM)], lucerne:oats 1:1 (LG, Ca 1.36%), grass hay only (G, Ca 1.04%), or grass:oats 1:1 (GG, 0.83%) for 25 weeks, with water available ad libitum. Diets were not supplemented with Ca, phosphorus, or vitamin D. Rabbits on diets LG and GG had lower food and water intakes, lower faeces and urine output, grew faster and had higher body mass at slaughter (mainly attributable to adipose tissue). Apparent Ca digestibility decreased in the order L-LG-G/GG. Rabbits on L had larger and heavier kidneys, more urinary sediment at sonography, and a higher urinary Ca content than the other groups. No animal showed signs of urolithiasis/calcinosis at X-ray, sonography, or gross pathology. Kidney/aorta histology only sporadically indicated Ca deposits, with no systematic difference between groups. Under the conditions of the experiment, dietary Ca loads in legume hay do not appear problematic for rabbits, and other factors, such as water supply and level of activity may be important contributors to urolithiasis development in veterinary patients. However, due to the lower Ca content of grass hay, the significantly lower degree of urinary sludge formation, and the significantly higher water intake related with grass hay feeding, grass hay-dominated diets are to be recommended for rabbits in which urolithiasis prevention is an issue. PMID- 21707783 TI - Toenail onychomycosis due to Trichophyton violaceum complex. (An unusual, emerging localization of this anthropophilic dermatophyle). PMID- 21707784 TI - A case of subcutaneous phaeohyphomycosis caused by Cladosporium cladosporioides and its treatment. PMID- 21707785 TI - Letter to the editor: giant angiomyxoid tumor in a renal allograft. PMID- 21707786 TI - Evaluation of reproductive tract infection during early post-partum period and its relationship with subsequent reproductive performance in high milk producing dairy cows. AB - Clinically normal Holstein-Friesian cows (n = 43) were used to establish a relationship between the evaluations of the uterine condition by vaginoscopy, Metricheck, endometrial cytology (EC) and ultrasonography (US) during post-partum period (pp), and subsequent reproductive performance. The uterine status of the selected cows was evaluated by EC, Metricheck, US and vaginoscopy on a weekly basis from the third week (W3) to the seventh week (W7) pp. The animals were bred after a voluntary waiting period of 45-60 days pp and diagnosed for pregnancy status at 45 days after breeding by US. First service conception rate (FSCR) of bred animals was 32.6% (14/43). There was no significant difference in polymorphonuclear leucocyte percentage between conceived and non-conceived cows during different weeks post-partum. First service conception rate in animals with normal vaginal discharge as detected by Metricheck was significantly low when compared to those of abnormal discharge during W3 (2.3% vs 30.3%; p < 0.001) and W4 (4.7% vs 29.7%; p < 0.01) post-partum. Using US, the number of pregnant cows having fluid in uterus (FIU) during W6 (p < 0.01) and W7 (p < 0.001) post-partum was significantly lower (2/34, 4.7% and 1/43, 2.3%, respectively) than those that had no FIU (12/43, 27.9% and 13/43, 30.3%, respectively). Using vaginoscopy, FSCR in animals having abnormal discharge was significantly (p < 0.01) low when compared to that of normal discharge (2.4% vs 30.2%) during W5 and W6 post partum. In conclusion, Metricheck during W3 and W4 and detection of FIU by US and vaginoscopy during W6 and W7 pp can be used as good predictive tools to anticipate the future reproductive performance of dairy cattle. PMID- 21707787 TI - From transcription to activation: how group A streptococcus, the flesh-eating pathogen, regulates SpeB cysteine protease production. AB - Streptococcal pyrogenic exotoxin B (SpeB) is a protease secreted by group A streptococci and known to degrade a wide range of host and GAS proteins in vitro. Although the role of SpeB in GAS infection is debated, recent evidence has conclusively demonstrated that SpeB is critical for the pathogenesis of severe invasive disease caused by GAS. Genetic inactivation of the speB gene results in significantly decreased virulence in a necrotizing fasciitis model of infection. Production of fully active SpeB by GAS is extremely complex. Following transcription and translation the SpeB protein is secreted as an inactive zymogen, which is autocatalytically processed through a series of intermediates to form an active protease. Each step from transcription to protease activation is tightly controlled and regulated by the bacterial cell reflecting the critical role played by this virulence factor in GAS infection. Here we review the molecular aspects of SpeB production by GAS from transcription to activation and the multiple layers of control involved. PMID- 21707788 TI - Role for Sit4p-dependent mitochondrial dysfunction in mediating the shortened chronological lifespan and oxidative stress sensitivity of Isc1p-deficient cells. AB - Saccharomyces cerevisiae cells lacking Isc1p, an orthologue of mammalian neutral sphingomyelinase 2, display a shortened lifespan and an increased sensitivity to oxidative stress. A lipidomic analysis revealed specific changes in sphingolipids that accompanied the premature ageing of Isc1p-deficient cells under severe calorie restriction conditions, including a decrease of dihydrosphingosine levels and an increase of dihydro-C(26) -ceramide and phyto-C(26) -ceramide levels, the latter raising the possibility of activation of ceramide-dependent protein phosphatases. Consequently, deletion of the SIT4 gene, which encodes for the catalytic subunit of type 2A ceramide-activated protein phosphatase in yeast, abolished the premature ageing and hydrogen peroxide sensitivity of isc1Delta cells. SIT4 deletion also abolished the respiratory defects and catalase A deficiency exhibited by isc1Delta mutants. These results are consistent with catabolic derepression associated with the loss of Sit4p. The overall results show that Isc1p is an upstream regulator of Sit4p and implicate Sit4p activation in mitochondrial dysfunction leading to the shortened chronological lifespan and oxidative stress sensitivity of isc1Delta mutants. PMID- 21707789 TI - The secretion ATPase ComGA is required for the binding and transport of transforming DNA. AB - Transformation requires specialized proteins to facilitate the binding and uptake of DNA. The genes of the Bacillus subtilis comG operon (comGA-G) are required for transformation and to assemble a structure, the pseudopilus, in the cell envelope. No role for the pseudopilus has been established and the functions of the individual comG genes are unknown. We show that among the comG genes, only comGA is absolutely required for DNA binding to the cell surface. ComEA, an integral membrane DNA-binding protein plays a minor role in the initial binding step, while an unidentified protein which communicates with ComGA must be directly responsible for binding to the cell. We show that the use of resistance to DNase to measure 'DNA uptake' reflects the movement of transforming DNA to a protected state in which it is not irreversibly associated with the protoplast, and presumably resides outside the cell membrane, in the periplasm or associated with the cell wall. We suggest that ComGA is needed for the acquisition of DNase resistance as well as for the binding of DNA to the cell surface. Finally, we show that the pseudopilus is required for DNA uptake and we offer a revised model for the transformation process. PMID- 21707790 TI - Neurochemical organization and experience-dependent activation of estrogen associated circuits in the songbird auditory forebrain. AB - The classic steroid hormone estradiol is rapidly produced by central auditory neurons in the songbird brain and instantaneously modulates auditory coding to enhance the neural and behavioral discrimination of acoustic signals. Although recent advances highlight novel roles for estradiol in the regulation of central auditory processing, current knowledge on the functional and neurochemical organization of estrogen-associated circuits, as well as the impact of sensory experience in these auditory forebrain networks, remains very limited. Here we show that both estrogen-producing and -sensitive neurons are highly expressed in the caudomedial nidopallium (NCM), the zebra finch analog of the mammalian auditory association cortex, but not other auditory forebrain areas. We further demonstrate that auditory experience primarily engages estrogen-producing, and to a lesser extent, estrogen-responsive neurons in NCM, that these neuronal populations moderately overlap and that acute episodes of sensory experience do not quantitatively affect these circuits. Finally, we show that whereas estrogen producing cells are neurochemically heterogeneous, estrogen-sensitive neurons are primarily glutamatergic. These findings reveal the neurochemical and functional organization of estrogen-associated circuits in the auditory forebrain, demonstrate their activation and stability in response to sensory experience in behaving animals, and highlight estrogenic circuits as fundamental components of central networks supporting sensory processing. PMID- 21707791 TI - Modulation of astroglial glutamine synthetase activity affects nociceptive behaviour and central sensitization of medullary dorsal horn nociceptive neurons in a rat model of chronic pulpitis. AB - Previous studies indicate that the astroglial glutamate-glutamine shuttle may be involved in acute pulpal inflammatory pain by influencing central sensitization induced in nociceptive neurons in the trigeminal subnucleus caudalis [the medullary dorsal horn (MDH)] by application of an inflammatory irritant to the rat tooth pulp. The aim of this study was to test if intrathecal application to the rat medulla of the astroglial glutamine synthetase inhibitor methionine sulfoximine (MSO) can influence the central sensitization of MDH nociceptive neurons and the animal's associated behaviour that are manifested in a model of chronic pulpitis pain induced by exposure of a mandibular molar pulp. This model was found to be associated with nocifensive behaviour and enhanced reflex activity evoked by mechanical stimulation of the rat's facial skin and with immunocytochemical evidence of astroglial activation in the MDH. These features were apparent for up to 28 days post-operatively. During this post-operative period, the nocifensive behaviour and enhanced reflex activity were significantly attenuated by intrathecal application of MSO (5 MUL, 10 mM) but not by vehicle application. In electrophysiological recordings of nociceptive neuronal activity in the MDH, central sensitization was also evident in pulp-exposed rats but not in intact rats and could be significantly attenuated by MSO application but not by vehicle application. These behavioural and neuronal findings suggest that the astroglial glutamate-glutamine shuttle is responsible for the maintenance of inflammation-induced nocifensive behavioural changes and the accompanying central sensitization in MDH nociceptive neurons in this chronic pulpitis pain model. PMID- 21707792 TI - Perirhinal cortex lesions uncover subsidiary systems in the rat for the detection of novel and familiar objects. AB - The present study compared the impact of perirhinal cortex lesions on tests of object recognition. Object recognition was tested directly by looking at the preferential exploration of novel objects over simultaneously presented familiar objects. Object recognition was also tested indirectly by presenting just novel objects or just familiar objects, and recording exploration levels. Rats with perirhinal cortex lesions were severely impaired at discriminating a novel object from a simultaneously presented familiar object (direct test), yet displayed normal levels of exploration to novel objects presented on their own and showed normal declines in exploration times for familiar objects that were repeatedly presented (indirect tests). This effective reduction in the exploration of familiar objects after perirhinal cortex lesions points to the sparing of some recognition mechanisms. This possibility led us to determine whether rats with perirhinal cortex lesions can overcome their preferential exploration deficits when given multiple object familiarisation trials prior to that same (familiar) object being paired with a novel object. It was found that after multiple familiarisation trials, objects could now successfully be recognised as familiar by rats with perirhinal cortex lesions, both following a 90-min delay (the longest delay tested) and when object recognition was tested in the dark after familiarisation trials in the light. These latter findings reveal: (i) the presumed recruitment of other regions to solve recognition memory problems in the absence of perirhinal cortex tissue; and (ii) that these additional recognition mechanisms require more familiarisation trials than perirhinal-based recognition mechanisms. PMID- 21707793 TI - Spatio-temporal dynamics, differentiation and viability of human neural stem cells after implantation into neonatal rat brain. AB - Neural stem cells (NSCs) have attracted major research interest due to their potential use in cell replacement therapy. In patients, human cells are the preferred choice, one source of human NSCs being the brain of fetuses. The aims of the present study were to explore the long-term differentiation, mobility and viability of NSCs derived from the human fetal striatum in response to intracerebral implantation. To investigate long-term spatio-temporal and functional dynamics of grafts in vivo by magnetic resonance imaging, these cells were labeled with superparamagnetic iron oxide (SPIO) nanoparticles prior to implantation. SPIO-labeling of human NSCs left the quantitative profile of the proliferation, cell composition and differentiation capacity of the cells in vitro unaltered. Also after transplantation, the phenotypes after long-term cell differentiation were not significantly different from naive cells. Upon transplantation, we detected a hypointensity corresponding to the striatal graft location in all animals and persisting for at least 4 months. The hypointense signal appeared visually similar both in location and in volume over time. However, quantitative volumetric analysis showed that the detectable, apparent graft volume decreased significantly from 3 to 16 weeks. Finally, the human NSCs were not proliferating after implantation, indicating lack of tumor formation. These cells are thus a promising candidate for translationally relevant investigations for stem cell-based regenerative therapies. PMID- 21707794 TI - Triiodothyronine administration ameliorates the demyelination/remyelination ratio in a non-human primate model of multiple sclerosis by correcting tissue hypothyroidism. AB - Remyelination failure is a key landmark in chronic progression of multiple sclerosis (MS), the most diffuse demyelinating disease in human, but the reasons for this are still unknown. It has been shown that thyroid hormone administration in the rodent models of acute and chronic demyelinating diseases improved their clinical course, pathology and remyelination. In the present study, we translated this therapeutic attempt to experimental allergic encephalomyelitis (EAE) in the non-human primate Callithrix Jacchus (marmoset). We report that short protocols of triiodothyronine treatment shifts the demyelination/remyelination balance toward remyelination, as assessed by morphology, immunohistochemistry and molecular biology, and improves the clinical course of the disease. We also found that severely ill animals display hypothyroidism and severe alteration of deiodinase and thyroid hormone receptor mRNAs expression in the spinal cord, which was completely corrected by thyroid hormone treatment. We therefore suggest that thyroid hormone treatment improves myelin sheath morphology in marmoset EAE, by correcting the dysfunction of thyroid hormone cellular effectors. PMID- 21707795 TI - Von Willebrand factor predicts major bleeding and mortality during oral anticoagulant treatment. AB - AIMS: Oral anticoagulation (OAC), predominantly with warfarin, is an effective treatment to prevent thromboembolic events. Serious bleeding is a frequent and feared treatment complication. In this longitudinal cohort study of OAC-treated patients, we aimed to evaluate the relationship between von Willebrand factor (VWF) levels and risk of bleeding complications, cardiovascular mortality and all cause mortality. METHODS AND RESULTS: A total of 719 patients receiving warfarin treatment were observed for a mean duration of 4.2 years. All bleeding complications causing hospitalization were registered and classified into clinically relevant bleeding (CRB) and major bleeding. Ischaemic stroke, peripheral arterial embolism, myocardial infarction, and death were also recorded. We identified 113 cases of CRB and 73 of major bleeding. In total, 161 deaths occurred during follow-up with cardiovascular disease identified as the cause of death in 110 patients. Patients in the highest tertile of VWF had a significantly increased risk of bleeding complications: hazard ratio (HR) 2.53 (95% CI 1.41-4.56) for major bleeding and HR 2.19 (95% CI 1.38-3.48) for CRB. VWF, expressed either in tertiles or as a continuous variable, showed a significant association with cardiovascular mortality (HR 1.68, 95% CI 1.40-2.01) and all-cause mortality (HR 1.77, 95% CI 1.52-2.05). In multivariate Cox regression analysis, the findings remained significant after adjusting for age, high-sensitivity C-reactive protein and creatinine. CONCLUSIONS: Patients with high levels of VWF had an increased risk of bleeding complications, cardiovascular mortality and all-cause mortality during OAC treatment. Our findings imply that the use of VWF as a risk marker for thromboembolic events is complicated by the association of VWF with bleeding complications. PMID- 21707796 TI - Red cell concentrate storage and transport temperature. AB - BACKGROUND AND OBJECTIVES: This study investigated the current U.K. guidelines for storage and transport of red cell concentrates (RCC) in saline, adenine, glucose and mannitol (SAGM). The guidelines stipulate storage at 2-6 degrees C but allow exposure to between 1-10 degrees C core temperature in a single occurrence of less than 5 h and a surface temperature of 2-10 degrees C for no more than 12 h during transportation. METHODS AND MATERIALS: Twenty RCC units in SAGM were selected on the day of blood collection (day 0) and in vitro quality was tested pre- and post-temperature deviation at 10 degrees C and up to day 42 of storage. Each group of 10 RCC units was incubated for either 12 h or for both 5 and 12 h. RESULTS: Haemolysis was below the 0.8% U.K. limit at day 42 in all units, although there was an unexpected trend towards lower haemolysis in packs incubated for 5 and 12 h rather than just 12 h alone. Supernatant potassium was significantly higher than reference data on day 35 (P < 0.05) with a maximum of 58 mmol L(-1) and day 42 (P < 0.001). All units incubated at 10 degrees C had comparable levels of adenosine triphosphate and, 2,3-diphosphoglycerate to reference data from previous studies, throughout storage. CONCLUSION: These results suggest that exposure to 10 degrees C for 12 h or for 5 and 12 h did not adversely affect in vitro red cell quality for the remainder of the components shelf life. PMID- 21707797 TI - Genetic and functional analyses describe a novel 730delG mutation in the KEL gene causing K0 phenotype in a Taiwanese blood donor. AB - AIMS/OBJECTIVES: The purpose of this study was to explore the molecular basis of the K0 phenotype of a Taiwanese blood donor found to have anti-Ku alloantibodies. BACKGROUND: With respect to Kell blood group antigens, almost all Taiwanese have the (K-, k+) phenotype. MATERIALS AND METHODS: Alloantibody identification and KEL antigen typing were performed. Enzymatic function assays were carried out to detect the Kell glycoprotein on RBCs. The KEL genes were sequenced to detect genetic variation. To determine the origin of this novel allele, family studies were conducted. RESULTS: The alloantibody was identified as anti-Ku. The donor was typed K0 . The KEL gene-sequencing data revealed that this K0 donor is a compound heterozygote with two different null alleles. He bears a novel 730delG mutation in one allele. Family studies suggested that the donor inherited the 730delG mutation from his father. The endothelin-converting activity assay indicated that his RBCs had no functional Kell glycoprotein. Other family members who had only one null allele with the 730delG mutation had the phenotype (K-, k+). CONCLUSION: For blood transfusion safety, it is important to establish an effective screening algorithm to identify rare phenotypes, such as the K0 phenotype, and to establish a database of rare blood groups. PMID- 21707798 TI - Identifying transmission routes for hepatitis B and C in recently infected blood donors in England--challenges to obtaining post-test information. PMID- 21707799 TI - Genomic clustering of cyanogenic glucoside biosynthetic genes aids their identification in Lotus japonicus and suggests the repeated evolution of this chemical defence pathway. AB - Cyanogenic glucosides are amino acid-derived defence compounds found in a large number of vascular plants. Their hydrolysis by specific beta-glucosidases following tissue damage results in the release of hydrogen cyanide. The cyanogenesis deficient1 (cyd1) mutant of Lotus japonicus carries a partial deletion of the CYP79D3 gene, which encodes a cytochrome P450 enzyme that is responsible for the first step in cyanogenic glucoside biosynthesis. The genomic region surrounding CYP79D3 contains genes encoding the CYP736A2 protein and the UDP-glycosyltransferase UGT85K3. In combination with CYP79D3, these genes encode the enzymes that constitute the entire pathway for cyanogenic glucoside biosynthesis. The biosynthetic genes for cyanogenic glucoside biosynthesis are also co-localized in cassava (Manihot esculenta) and sorghum (Sorghum bicolor), but the three gene clusters show no other similarities. Although the individual enzymes encoded by the biosynthetic genes in these three plant species are related, they are not necessarily orthologous. The independent evolution of cyanogenic glucoside biosynthesis in several higher plant lineages by the repeated recruitment of members from similar gene families, such as the CYP79s, is a likely scenario. PMID- 21707800 TI - The charophycean green algae provide insights into the early origins of plant cell walls. AB - Numerous evolutionary innovations were required to enable freshwater green algae to colonize terrestrial habitats and thereby initiate the evolution of land plants (embryophytes). These adaptations probably included changes in cell-wall composition and architecture that were to become essential for embryophyte development and radiation. However, it is not known to what extent the polymers that are characteristic of embryophyte cell walls, including pectins, hemicelluloses, glycoproteins and lignin, evolved in response to the demands of the terrestrial environment or whether they pre-existed in their algal ancestors. Here we show that members of the advanced charophycean green algae (CGA), including the Charales, Coleochaetales and Zygnematales, but not basal CGA (Klebsormidiales and Chlorokybales), have cell walls that are comparable in several respects to the primary walls of embryophytes. Moreover, we provide both chemical and immunocytochemical evidence that selected Coleochaete species have cell walls that contain small amounts of lignin or lignin-like polymers derived from radical coupling of hydroxycinnamyl alcohols. Thus, the ability to synthesize many of the components that characterize extant embryophyte walls evolved during divergence within CGA. Our study provides new insight into the evolutionary window during which the structurally complex walls of embryophytes originated, and the significance of the advanced CGA during these events. PMID- 21707801 TI - Soybean NAC transcription factors promote abiotic stress tolerance and lateral root formation in transgenic plants. AB - NAC transcription factors play important roles in plant growth, development and stress responses. Previously, we identified multiple NAC genes in soybean (Glycine max). Here, we identify the roles of two genes, GmNAC11 and GmNAC20, in stress responses and other processes. The two genes were differentially induced by multiple abiotic stresses and plant hormones, and their transcripts were abundant in roots and cotyledons. Both genes encoded proteins that localized to the nucleus and bound to the core DNA sequence CGT[G/A]. In the protoplast assay system, GmNAC11 acts as a transcriptional activator, whereas GmNAC20 functions as a mild repressor; however, the C-terminal end of GmANC20 has transcriptional activation activity. Over-expression of GmNAC20 enhances salt and freezing tolerance in transgenic Arabidopsis plants; however, GmNAC11 over-expression only improves salt tolerance. Over-expression of GmNAC20 also promotes lateral root formation. GmNAC20 may regulate stress tolerance through activation of the DREB/CBF-COR pathway, and may control lateral root development by altering auxin signaling-related genes. GmNAC11 probably regulates DREB1A and other stress related genes. The roles of the two GmNAC genes in stress tolerance were further analyzed in soybean transgenic hairy roots. These results provide a basis for genetic manipulation to improve the agronomic traits of important crops. PMID- 21707803 TI - Corn hybrids display lower metabolite variability and complex metabolite inheritance patterns. AB - We conducted a comparative analysis of the root metabolome of six parental maize inbred lines and their 14 corresponding hybrids showing fresh weight heterosis. We demonstrated that the metabolic profiles not only exhibit distinct features for each hybrid line compared with its parental lines, but also separate reciprocal hybrids. Reconstructed metabolic networks, based on robust correlations between metabolic profiles, display a higher network density in most hybrids as compared with the corresponding inbred lines. With respect to metabolite level inheritance, additive, dominant and overdominant patterns are observed with no specific overrepresentation. Despite the observed complexity of the inheritance pattern, for the majority of metabolites the variance observed in all 14 hybrids is lower compared with inbred lines. Deviations of metabolite levels from the average levels of the hybrids correlate negatively with biomass, which could be applied for developing predictors of hybrid performance based on characteristics of metabolite patterns. PMID- 21707804 TI - Interplay of MYB factors in differential cell expansion, and consequences for tomato fruit development. AB - We previously identified SlFSM1 as an early fruit-specific gene encoding a short protein harboring a non-canonical SANT/MYB-like domain. Here, we investigated the role of FSM1 during fruit development in tomato and its mode of action. By analyzing tomato plants ectopically expressing FSM1, we established that it negatively affects cell expansion, particularly of those cells with the highest potential to expand, such as those residing inner to the vascular bundles in the fruit pericarp. This function of FSM1 differs from that of the snapdragon FSM1 like gene, RAD, which through an antagonistic activity with DIV participates in establishing floral asymmetry. Revealing an additional component of the FSM1/RAD regulatory complex, we show here that FSM1 physically interacts with FSB1, a previously uncharacterized factor harboring an atypical MYB repeat. We also demonstrate that FSB1 physically interacts with the transcription factor MYBI, a homolog of DIV. Our results show that the formation of the FSB1-MYBI complex is competed by FSM1, which recognizes in FSB1 the same region as MYBI does. Taken together, these studies expose a function for the FSM1/FSB1/MYBI complex in controlling tomato cell expansion, while revealing a mechanism by which competing MYB-MYB interactions could participate in the control of gene expression. PMID- 21707802 TI - Arabidopsis thaliana alpha1,2-glucosyltransferase (ALG10) is required for efficient N-glycosylation and leaf growth. AB - Assembly of the dolichol-linked oligosaccharide precursor (Glc(3) Man(9) GlcNAc(2) ) is highly conserved among eukaryotes. In contrast to yeast and mammals, little is known about the biosynthesis of dolichol-linked oligosaccharides and the transfer to asparagine residues of nascent polypeptides in plants. To understand the biological function of these processes in plants we characterized the Arabidopsis thaliana homolog of yeast ALG10, the alpha1,2 glucosyltransferase that transfers the terminal glucose residue to the lipid linked precursor. Expression of an Arabidopsis ALG10-GFP fusion protein in Nicotiana benthamiana leaf epidermal cells revealed a reticular distribution pattern resembling endoplasmic reticulum (ER) localization. Analysis of lipid linked oligosaccharides showed that Arabidopsis ALG10 can complement the yeast Deltaalg10 mutant strain. A homozygous Arabidopsis T-DNA insertion mutant (alg10 1) accumulated mainly lipid-linked Glc(2) Man(9) GlcNAc(2) and displayed a severe protein underglycosylation defect. Phenotypic analysis of alg10-1 showed that mutant plants have altered leaf size when grown in soil. Moreover, the inactivation of ALG10 in Arabidopsis resulted in the activation of the unfolded protein response, increased salt sensitivity and suppression of the phenotype of alpha-glucosidase I-deficient plants. In summary, these data show that Arabidopsis ALG10 is an ER-resident alpha1,2-glucosyltransferase that is required for lipid-linked oligosaccharide biosynthesis and subsequently for normal leaf development and abiotic stress response. PMID- 21707805 TI - Evaluation of the psychometric properties of a modified Chinese version of the Caregiver Task Inventory--refinement and psychometric testing of the Chinese Caregiver Task Inventory: a confirmatory factor analysis. AB - AIM: To test the reliability and validity of the modified Chinese version of the Caregiver Task Inventory. BACKGROUND: The original Caregiver Task Inventory was developed in 1983 by Clark and Rakowski in the USA. It was used to measure Chinese family caregivers' needs in Hong Kong. Its failure to evaluate the psychometric properties of the instrument measuring the needs of family caregivers across cultures limited its scientific rigor. DESIGN: A quantitative study method was used to test the psychometrics of the modified Chinese version of the Caregiver Task Inventory. METHODS: A convenience sample of 114 family caregivers completed the Caregiver Task Inventory in 2005 to test different aspects of the validity and reliability and confirm items of the short form of the Chinese Caregiver Task Inventory-25. RESULTS: The content validity of the 25 items of the Chinese Caregiver Task Inventory was validated by six experts, who assessed the correlation between caregiving tasks and the five refined sub scales. The construct validity was determined by confirmatory factor analysis (CFA). The chi(2) goodness-of-fit, chi(2): df ratio, goodness-of-fit index (GFI), adjusted GFI and root mean square residual were obtained and used to assess the fit of the model. The internal consistency and stability of the Chinese Caregiver Task Inventory-25 were determined by Cronbach's method (0.93) and the internal reliability (item total correlation) for the five refined sub-scales ranged from 0.67-0.86. CFA and internal consistency analysis showed a strong degree of fit between the conceptualisation and the development of the measurement. CONCLUSIONS: The Chinese Caregiver Task Inventory-25 is a relevant and culturally appropriate research instrument to measure the needs of Chinese family caregivers. RELEVANCE TO CLINICAL PRACTICE: This study reveals that stroke nurses should assess the impacts of caregiving tasks on caregivers' physical and psychological stress levels prior to planning relevant interventions. PMID- 21707806 TI - Informal stroke caregivers' self-appraised problem-solving abilities as a predictor of well-being and perceived social support. AB - AIM: To describe the relationship between self-appraised problem-solving abilities and psychological distress, burden and perceived social support in informal, family stroke caregivers. BACKGROUND: Previous research suggests that self-appraised problem-solving abilities play a significant role in the well being of family caregivers of patients with chronic illness. However, little is known about its role in caregivers of stroke survivors. DESIGN: Prospective correlational study. METHODS: One week before discharge, 103 family caregivers of survivors of a first stroke were assessed for their perceived problem-solving abilities, social support, anxiety, depression and physical well-being. At three months postdischarge, 85 of these caregivers (83% retention) were reassessed on the same measures. In addition, their levels of burden and perceived difficulties were also measured. RESULTS: Using multiple regression, overall self-appraised problem-solving abilities and its subscale 'confidence in problem-solving' at one week before discharge were significant predictors of caregiver perceived social support (R(2) = 29%) and perceived physical well-being (R(2) = 42%) at three months postdischarge. Other relationships were non-significant. CONCLUSIONS: Caregivers' perceived social support and physical well-being were significantly predicted by confidence in problem-solving. RELEVANCE TO CLINICAL PRACTICE: This study is timely given the challenges facing health systems in Hong Kong to effectively manage chronic illness through family-centred care. The significant relationships between caregiver self-appraised problem-solving, perceived social support and well-being suggest that interventions maximising caregiver confidence in problem-solving might be valuable in supporting family caregivers of stroke survivors. Nurses working with families caring for stroke survivors both close to discharge and in the early transition stages back at home may be in an ideal position to offer this support. PMID- 21707807 TI - A systematic review of the effects of e-health on chronically ill patients. AB - AIMS AND OBJECTIVES: We aimed to investigate whether e-health is equal to or better than usual face-to-face care with regard to outcomes on health, quality of life, patient satisfaction and costs. Therefore, we systematically reviewed the literature on e-health in chronically ill patients compared with or as an addition to usual care. BACKGROUND: Interactive websites on internet are increasingly used to inform and treat patients. This type of contact between patients and health care providers, which is called e-health, is easily accessible and particularly interesting for chronically ill patients. DESIGN: A systematic review. METHODS: We searched the databases PubMed, CINAHL, the Cochrane Database of systematic reviews, DARE and CENTRAL for articles published between January 2000-July 2009. RESULTS: The search strategy yielded in total 695 possibly relevant references, which resulted in 12 RCTs after application of the in- and exclusion criteria. Most of the studies were well designed according to the Cochrane criteria for RCTs. The studies are divided into e-health vs. usual care and e-health as addition to usual care. e-Health consisted of monitoring, treatment instructions, self-management training and general information and communication between patient and caregiver. Most of the studies showed small to moderate positive effects on health outcomes. Cost-effectiveness, quality of life and patient satisfaction were rarely investigated in the included studies. CONCLUSIONS: e-Health interventions for chronically ill patients, offered instead of usual care or in addition to usual care, lead to small to moderate positive effects on primary health outcomes. However, the evidence was not fully convincing, because of the limited number of studies available and the methodological limitations. Further research is needed to confirm the cost effectiveness of e-health interventions for patients with chronic diseases. RELEVANCE TO CLINICAL PRACTICE: e-Health is a promising tool for treatment and self-management training of chronically ill patients. PMID- 21707808 TI - Adherence to a sodium-restricted diet is associated with lower symptom burden and longer cardiac event-free survival in patients with heart failure. AB - AIM: To determine whether adherence to a sodium-restricted diet affects symptom burden and cardiac event-free survival in patients with heart failure. BACKGROUND: The recommendation of an sodium-restricted diet is a standard component of HF management. Therefore, it is important to investigate whether adherence to sodium-restricted diet is actually associated with improvements in symptom burden and cardiac event-free survival. DESIGN: A prospective cohort study. METHODS: A total of 232 patients [71% male, 65 +/- 10 years, 63% New York Heart Association (NYHA) class III/IV, ejection fraction (EF) 30 +/- 9%] with HF received 24-hour urinary sodium excretion (24-hr UNa) assessments and were divided into two groups using a cut-off value of 3 g 24-hr UNa. Symptom burden, including the frequency and severity of heart failure symptoms, was assessed according to the modified Memorial Symptom Assessment Scale-Heart Failure with a higher score indicating a greater symptom burden. Cardiac event-free survival over a 12-month period was determined by reviewing medical records. RESULTS: Patients with 24-hr UNa >= 3 g exhibited greater symptom burdens (beta = 0.23, p < 0.001) in hierarchical linear regression analyses and shorter cardiac event free survival [hazard ratio = 1.81, 95% confidence interval = 1.17-2.80) than patients with 24-hr UNa < 3 g in hierarchical Cox hazards regressions, after controlling for age, gender, HF aetiology, body mass index, NYHA class, EF, and total comorbidity score. CONCLUSIONS: If sodium intake is limited to less than 3 g/day, symptom burden and clinical health outcomes can be improved in HF patients. RELEVANCE TO CLINICAL PRACTICE: Health care providers need to help patients understand the rationale for an sodium-restricted diet to prevent worsening heart failure symptoms and unnecessary cardiac events. Continuous monitoring for dietary sodium intake as well as worsening heart failure symptoms should be emphasised in patient education. PMID- 21707809 TI - Parental report of infant sleep behavior by electronic versus paper-and-pencil diaries, and their relationship to actigraphic sleep measurement. AB - Reliable, valid and cost-effective methods for the assessment of infant sleep and sleep problems are of major importance. In this study, the first aim was to assess the agreement of an electronic diary as well as a paper diary with actigraphy for measuring infant sleep patterns in a community sample. The second aim was to assess the feasibility and acceptance of, and compliance with, the electronic diary and the paper diary. Ninety parents reported infant sleep behavior in a paper diary in their home environments for a total of 6 days, 95 in an electronic diary, within two consecutive weeks while actigraphic data were obtained simultaneously. We found moderate to good agreement between electronic diaries and actigraphy (r = 0.41-0.65, P < 0.01), and paper diaries and actigraphy (r = 0.47-0.70, P < 0.01). In addition, this study also found good agreement between both diaries and also between both diaries and actigraphy for sleep percentage over 24 h (electronic diaries and actigraphy: 54.1 +/- 0.7%, 52.5 +/- 0.7%, P < 0.05; paper diaries and actigraphy: 55.1 +/- 0.5%, 52.2 +/- 0.6%, P < 0.01) and for daytime (electronic diaries and actigraphy: 27.3 +/- 0.9%, 23.5 +/- 1.2%, P < 0.01; paper diaries and actigraphy: 27.3 +/- 0.8%, 23.2 +/- 1.0%, P < 0.01), with the exception that less daytime sleep was recorded on actigraphy than on either diary. In conclusion, the electronic diary and the paper diary are valid and well-accepted methods for the assessment of infant sleep. Parents preferred the electronic diary but, conversely, they were less compliant in completing it. PMID- 21707810 TI - Alcohol consumption, problem drinking, abstention and disability pension award. The Nord-Trondelag Health Study (HUNT). AB - AIMS: To examine associations of abstention, alcohol consumption and problem drinking with subsequent disability pensioning (DP), and whether previous excessive consumption ('sick-quitting') could explain some of the increased risk for DP among abstainers. DESIGN: Prospective population-based study. SETTING AND PARTICIPANTS: Data were from two waves of the Nord-Trondelag Health Study (HUNT) linked with the national insurance database. The two main analyses included 37,729 (alcohol consumption) and 34,666 (problem drinking) participants. MEASUREMENTS: Alcohol consumption was measured by self-reported consumption, while problem drinking was assessed by the Cut down, Annoyed, Guilt, Eye-opener (CAGE) questionnaire. Information on subsequent DP, including diagnosis for which the DP was awarded, was gathered from the national insurance database. Covariates included somatic illness and symptoms, mental health, health-related behaviour, socio-economic status and social activity. FINDINGS: Those reporting the highest level of alcohol consumption were not at increased risk for DP [hazard ratio (HR) 1.12, 95% confidence interval (CI): 0.92-1.38], whereas problem drinking was a strong predictor (HR 2.79, 95% CI: 2.08-3.75) compared to their corresponding reference groups. Alcohol abstainers were also at increased risk for DP, but among them, the previous consumers (HR 1.95, 95% CI: 1.48-2.57) and previous excessive consumers (HR 1.67, 95% CI: 1.01-2.74) were at higher risk for DP than constant abstainers. CONCLUSIONS: Problem drinking is linked to subsequent requirement for a disability pension but mere alcohol consumption is not. This is partly explained by 'sick-quitting'. PMID- 21707812 TI - An evolutionary modelling approach to understanding the factors behind plant invasiveness and community susceptibility to invasion. AB - Ecologists have had limited success in understanding which introduced species may become invasive. An evolutionary model is used to investigate which traits are associated with invasiveness. Translocation experiments were simulated in which species were moved into similar but evolutionarily younger communities. The main findings were that species that had previously been the most abundant in their original communities have significantly higher rates of establishment than did species that had previously occurred at low abundance in their original community. However, if establishment did occur, previously abundant and previously low-abundant species were equally likely to become dominant and were equally likely to exclude other species from their new community. There was a suggestion that the species that were most likely to establish and exclude others were 'genetically' different. When species that had evolved in different simulations (but with identical environmental conditions) were transplanted into communities that had also evolved in different simulations of the same conditions, the outcomes were difficult to predict. Observed rates of establishment and subsequent competitive dominance were observed to be species- and community combination-specific. This evolutionary study represents a novel in silico attempt to tackle invasiveness in an experimental framework and may provide a new methodology for tackling these issues. PMID- 21707813 TI - Temnospondyli bite club: ecomorphological patterns of the most diverse group of early tetrapods. AB - Temnospondyls were a successful group of early tetrapods that lived during the Palaeozoic and Mesozoic periods. Different ecomorphotypes were present (terrestrial, amphibious and fully aquatic) with a wide range of lifestyles. Herein, we analysed several clades of temnospondyls using geometric morphometrics, Finite Element Analysis, and comparative phylogenetic analysis. Some temnospondyli clades were 'crocodilomorph' feeding analogues. The skull analysis reveals a concordance between form and feeding function, in amphibious and fully aquatic feeders. The form of terrestrial feeders could be consequences of adaptative or phylogenetical constraints. Basal temnospondyls, as edopoids, were able to leave the water and feed on land. Eryopids continued as terrestrial feeders, although some members showed a shift to increased aquatic feeding. The aquatic environment was especially occupied by archegosaurs during the Permian. After the Permo-Triassic extinction, trematosaurs and capitosaurs returned to the aquatic environment and their members were amphibious and fully aquatic feeders until their disappearance. PMID- 21707811 TI - Sertraline delays relapse in recently abstinent cocaine-dependent patients with depressive symptoms. AB - AIMS: Whether the selective serotonin re-uptake inhibitor sertraline at 200 mg/day delays relapse in recently abstinent cocaine-dependent individuals. DESIGN: The study involved a 12-week, double-blind, placebo-controlled clinical trial with 2-week residential stay followed by 10-week out-patient participation. SETTING: Veterans Affairs residential unit and out-patient treatment research program. PARTICIPANTS: Cocaine-dependent volunteers (n = 86) with depressive symptoms (Hamilton score > 15), but otherwise no major psychiatric or medical disorder or contraindication to sertraline. MEASUREMENTS: Participants were housed on a drug-free residential unit (weeks 1-2) and randomized to receive sertraline or placebo. Participants then participated on an out-patient basis during weeks 3-12 while continuing to receive study medication. Patients participated in a day substance abuse/day treatment program during weeks 1-3 and underwent weekly cognitive behavioral therapy during weeks 4-12. The primary outcome measure was thrice-weekly urine results and the secondary measure was Hamilton Depression scores. FINDINGS: Pre-hoc analyses were performed on those who participated beyond week 2. Generally, no group differences in retention or baseline characteristics occurred. Sertraline patients showed a trend towards longer time before their first cocaine-positive urine ('lapse', chi(2) = 3.67, P = 0.056), went significantly longer before having two consecutive urine samples positive for cocaine ('relapse', chi(2) = 4.03, P = 0.04) and showed significantly more days to lapse (26.1 +/- 16.7 versus 13.2 +/- 10.5; Z = 2.89, P = 0.004) and relapse (21.3 +/- 10.8 versus 32.3 +/- 14.9; Z = 2.25, P = 0.02). Depression scores decreased over time (F = 43.43, P < 0.0001), but did not differ between groups (F = 0.09, P = 0.77). CONCLUSIONS: Sertraline delays time to relapse relative to placebo in cocaine-dependent patients who initially achieve at least 2 weeks of abstinence. PMID- 21707814 TI - Crest evolution in newts: implications for reconstruction methods, sexual selection, phenotypic plasticity and the origin of novelties. AB - The dorsal crest of newts (Salamandridae) is a novel, phenotypically plastic, sexually selected trait that may evolve in association with complex courtship behaviours. We estimated a near-comprehensive, time-calibrated phylogeny for salamandrids and analysed the evolution of their crests and display behaviour. Different models give conflicting reconstructions for crest evolution, showing that likelihood can estimate incorrect ancestral states with strong statistical support. The best-fitting model suggests that crests evolved once and were lost repeatedly, supporting the hypothesis that sexually selected traits may be frequently lost. We demonstrate the correlated evolution of crests and courtship behaviour and show that species with larger numbers of crest-related traits have larger repertoires of behaviours. We also show that phenotypically plastic morphological traits can be maintained over long macroevolutionary timescales (~25-48 Myr). Finally, we use salamandrids to address how novel structures may arise, and support a model involving the expansion and subdivision of pre existing structures. PMID- 21707815 TI - Quantitative genetics of migration syndromes: a study of two barn swallow populations. AB - Migration is a complex trait although little is known about genetic correlations between traits involved in such migration syndromes. To assess the migratory responses to climate change, we need information on genetic constraints on evolutionary potential of arrival dates in migratory birds. Using two long-term data sets on barn swallows Hirundo rustica (from Spain and Denmark), we show for the first time in wild populations that spring arrival dates are phenotypically and genetically correlated with morphological and life history traits. In the Danish population, length of outermost tail feathers and wing length were negatively genetically correlated with arrival date. In the Spanish population, we found a negative genetic correlation between arrival date and time elapsed between arrival date and laying date, constraining response to selection that favours both early arrival and shorter delays. This results in a decreased rate of adaptation, not because of constraints on arrival date, but constraints on delay before breeding, that is, a trait that can be equally important in the context of climate change. PMID- 21707816 TI - Year-round resource defence and the evolution of male and female song in suboscine birds: social armaments are mutual ornaments. AB - The evolution of sexually monomorphic (i.e. mutual) ornamentation has attracted growing attention as a 'blind-spot' in evolutionary biology. The popular consensus is that female ornaments are subject to the same modes of sexual selection as males: intrasexual competition and mate choice. However, it remains unclear how these forces interact within and between sexes, or whether they fully capture selection on female traits. One possibility is that the 'armament ornament' model - which proposes that traits used primarily in male-male contests are also co-opted by females as indicators of male quality - can be extended to explain signal evolution in both sexes. We examine this idea by testing the function of acoustic signals in two species of duetting antbirds. Behavioural observations and playback experiments suggest that male and female songs function primarily as armaments in competitive interactions. Removal experiments reveal that song is also a classic ornament used by unpaired males and females to advertise for mates. These results indicate that 'armament-ornament' processes may operate in reciprocal format, potentially explaining widespread mutual ornamentation in species with elevated intrasexual competition for resources. In addition, given that songs mediate competition between species outside the breeding season, our findings suggest that processes shaping monomorphic ornaments extend beyond the traditional definitions of sexual selection and are best understood in the broader framework of social selection. PMID- 21707817 TI - Factors influencing progress toward sympatric speciation. AB - Many factors could influence progress towards sympatric speciation. Some of the potentially important ones include competition, mate choice and the degree to which alternative sympatric environments (resources) are discrete. What is not well understood is the relative importance of these different factors, as well as interactions among them. We use an individual-based numerical model to investigate the possibilities. Mate choice was modelled as the degree to which male foraging traits influence female mate choice. Competition was modelled as the degree to which individuals with different phenotypes compete for portions of the resource distribution. Discreteness of the environment was modelled as the degree of bimodality of the underlying resource distribution. We find that strong mate choice was necessary, but not sufficient, to cause sympatric speciation. In addition, sympatric speciation was most likely when the resource distribution was strongly bimodal and when competition among different phenotypes was intermediate. Even under these ideal conditions, however, sympatric speciation occurred only a fraction of the time. Sympatric speciation owing to competition on unimodal resource distributions was also possible, but much less common. In all cases, stochasticity played an important role in determining progress towards sympatric speciation, as evidenced by variation in outcomes among replicate simulations for a given set of parameter values. Overall, we conclude that the nature of competition is much less important for sympatric speciation than is the nature of mate choice and the underlying resource distribution. We argue that an increased understanding of the promoters and inhibitors of sympatric speciation is best achieved through models that simultaneously evaluate multiple potential factors. PMID- 21707818 TI - Comment on "Cannabinoid receptor and N-acyl phosphatidylethanolamine phospholipase D--evidence for altered expression in multiple sclerosis". PMID- 21707819 TI - MMP-2/MMP-9 plasma level and brain expression in cerebral amyloid angiopathy associated hemorrhagic stroke. AB - Cerebral amyloid angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly. Matrix metalloproteinases (MMPs) have been implicated in blood-brain barrier disruption and ICH pathogenesis. In this study, we determined the levels MMP-2 and MMP-9 in plasma and their brain expression in CAA-associated hemorrhagic stroke. Although MMP-2 and MMP-9 plasma levels did not differ among patients and controls, their brain expression was increased in perihematoma areas of CAA-related hemorrhagic strokes compared with contralateral areas and nonhemorrhagic brains. In addition, MMP-2 reactivity was found in beta amyloid (Abeta)-damaged vessels located far from the acute ICH and in chronic microbleeds. MMP-2 expression was associated to endothelial cells, histiocytes and reactive astrocytes, whereas MMP-9 expression was restricted to inflammatory cells. In summary, MMP-2 expression within and around Abeta-compromised vessels might contribute to the vasculature fatal fate, triggering an eventual bleeding. PMID- 21707820 TI - Post-natal corticosteroids are associated with reduced expiratory flows in children born very preterm. AB - AIM: Infants born very prematurely often received corticosteroids to minimise the risk of developing bronchopulmonary dysplasia (BPD) but their long term impact on lung function at school age is unclear. METHODS: A cross-sectional study of 105 children [mean gestation of 27 weeks] was undertaken. Lung function assessments were conducted at a mean age of 10 years according to standard criteria. Corticosteroid dose was obtained from the medical record. RESULTS: Spirometry in the BPD group was not significantly different to the non-BPD group, mean per-cent predicted (95% confidence interval) forced expiratory volume in 1 s (FEV1) 83% (79, 87) versus 86% (83, 90), FEF25%-75% 67% (60, 73) versus 75% (69, 81). Antenatal steroid treatment alone did not adversely affect airflow FEV1, 88% (84.92) versus 90% (82.97), and forced expiratory flow (FEF)25%-75%, 75% (69.81) versus 87% (70.104). Children who received post-natal corticosteroids had significantly lower flows than those who did not (FEV1 82% (78.85) vs. 88% (85.92), P = 0.006; FEF25%-75% 65% (59.71) vs. 78% (72.84), P = 0.003). Regression analysis revealed days on oxygen and days ventilated were statistically significant but weak predictors of airflow at 10 years of age. CONCLUSIONS: A diagnosis of BPD did not predict reduced spirometry in middle childhood. Children who received post-natal corticosteroids as preterm infants had reduced expiratory flows compared with those who did not. While post-natal corticosteroids may be a marker of severity of lung disease, the potential of post-natal corticosteroids to influence lung development requires further investigation. PMID- 21707821 TI - Speech concerns at 5 years and adult educational and mental health outcomes. AB - AIM: To determine if parent-reported speech concerns at 5 years predict poorer educational and mental health outcomes at 21 years independent of social context and child's receptive language, behaviour and motor concerns at 5 years. To determine if these adult outcomes are mediated by school performance at 14 years. METHODS: Information on speech concerns at 5- and 21-year outcomes was available for 3193 participants from a birth cohort of 7223 infants. At 5, child behaviour was measured using a behavioural checklist, and at 21 years, it was measured by the Young Adult Self-Report. Peabody Picture Vocabulary Test-Revised at 5 years was not available for all children. Maternal mental health and social information at 5 years and educational outcomes at 14 years and 21 years were collected prospectively by questionnaire. Potential confounding and mediating factors were analysed using logistic regression. RESULTS: Children with speech concerns were less likely to have completed secondary school (P < 0.01) or gained better overall position (OP) scores (P < 0.001). OP scores rank students in Queensland applying for tertiary entrance. There was no association with mental health outcomes. Findings were independent of maternal and social factors, and motor concerns, though attenuated by behaviour and Peabody Picture Vocabulary Test-Revised scores. In the model adjusted for these factors, any concerns predicted OP score 1-11 (odds ratio 0.58; 95% confidence interval 0.42, 0.79), though if academic functioning at 14 was included, no associations were significant. CONCLUSION: Maternal-reported speech concerns at 5 years predict poorer educational though not adult mental health outcomes. PMID- 21707822 TI - Art of persuasion: an analysis of techniques used to market foods to children. AB - AIM: Persuasive marketing techniques, such as promotional characters, influence children's food preferences and requests for foods. The aim of this research was to describe the techniques used to market unhealthy foods and beverages to children on Sydney free-to-air television. METHODS: Marketing techniques designed to appeal to children were identified from international literature and summarised into a systematic coding tool. Using this tool, the marketing techniques used in a random sample of 100 unique food advertisements, broadcasted on Sydney free-to-air television, were coded. Frequency of marketing techniques was analysed overall and for use in advertisements marketing unhealthy foods, emotionally or verbally appealing to parents, or featuring child actors. RESULTS: Advertisers' use of persuasive techniques generally did not differ by type of food advertised. Marketing techniques with greater prominence in unhealthy food advertising were palatability (54% of unhealthy food advertisements), convenience (52%), fantasy/imagination (28%), fun/happiness (17%) and cartoon characters (9%). Advertisements emotionally appealing to parents (24%) were significantly more likely to make general health or nutrition statements (38% vs. 17%), and appealed to children concurrently through fun/happiness and fantasy/imagination appeals. Children were depicted in advertisements as eating with friends or family, situated within the home and frequently snacking on less healthy foods. CONCLUSIONS: Food and beverage advertisers use a range of visual, audio and emotive techniques to appeal to children and their parents that do not discriminate by the type of food advertised. The range and complexity of these techniques complicate the restriction of their use in food advertising to children. PMID- 21707824 TI - Radiation-induced cavernous malformations of the cauda equina mimicking carcinomatous or infectious meningitis. A case report. AB - The authors present a case of multiple radiation-induced cavernous malformations of the cauda equina in a patient with a remote history of testicular cancer and extended field radiation therapy. Magnetic resonance imaging (MRI) demonstrated multiple nodular areas of enhancement coating the nerve roots of the cauda equina, mimicking an aggressive leptomeningeal process such as carcinomatous or infectious meningitis. Biopsy of one of these lesions revealed ectatic vascular channels devoid of intervening neuroglial tissue consistent with cavernous malformation. PMID- 21707825 TI - AscentTM: a novel balloon microcatheter device used as the primary coiling microcatheter of a basilar tip aneurysm. AB - Intracranial aneurysms undergoing balloon-assisted endovascular repair are particularly challenging given the concurrent use of one or more catheters in addition to the primary coiling microcatheter. Here, we describe a previously unreported novel device where a balloon catheter was used as the primary coiling microcatheter, thereby eliminated the need for additional catheters. PMID- 21707827 TI - Differences in early dynamic connectivity between visual expansion and contraction stimulations revealed by an fMRI-directed MEG approach. AB - BACKGROUND AND PURPOSE: The human visual system responds asymmetrically to visual motion stimuli in opposite directions due to the involvement of the same brain areas but different operating processes. The expansion mode is thought to invoke a vigilance mechanism, whereas the contraction mode does not. METHODS: To investigate discrepancies between these modes, we produced dynamic connectivity maps based on mutual information between visual-evoked dipole sources of magnetoencephalography, which were steered by visual activity patterns in functional magnetic resonance imaging under two motion-stimulus modes. RESULTS: In the expansion mode, information was conveyed from V1 at 50-75 ms after motion onset, fed forward to V3A and then V5. Top-down connectivity paths were evident after a latency of 100 ms. Many of these interactions occurred within 200 ms. However, in the contraction mode, information was conveyed from V3A to V5, followed by feedback, but regained from V1 after a latency of 250 ms. Although these interactions were delayed by about 250 ms, they were completed within 500 ms. CONCLUSIONS: These findings show that detect spatiotemporal differences between expansion and contraction modes can be readily detected using time-flow charts. Moreover, delay interactions could be insensitive to object motion away from the observer. PMID- 21707826 TI - Analysis of T2 intensity by magnetic resonance imaging of deep gray matter nuclei in multiple sclerosis patients: effect of immunomodulatory therapies. AB - OBJECTIVE: To investigate differences in T2 intensity of deep gray matter (dGM) structures by magnetic resonance imaging (MRI) in multiple sclerosis (MS) patients undergoing various immunomodulatory therapies. BACKGROUND: In MS, dGM T2 hypointensities by MRI are hypothesized to represent iron deposition and are known to be associated with worse disease stage as assessed by brain atrophy, cognitive and physical disability. The relation between immunotherapies and T2 intensity, however, has been not been investigated in detail. METHODS: A total of 255 MS patients were stratified into those on no treatment (NON, n= 45), and those on immunomodulatory treatments for >=6 months (ie, interferon beta [IFNbeta]n= 118, glatiramer acetate [GA]n= 41, natalizumab [NAT]n= 39, and mycophenolate mofetil [MMF]n= 12). T2 intensities of dentate nucleus (DN), substantia nigra (SN), red nucleus (RN), and globus pallidus (GP) were measured. Group differences in T2 intensities were assessed using a linear regression model with T2 intensities as outcome variable, treatment group as main independent variable, and clinical measures such as Expanded Disability Status Scale (EDSS) score, years of MS, and 25-feet walk time (T25-FW) as covariates. To compare T2 intensities before and after treatment in a subset of NAT-treated patients, we used the Wilcoxon signed-rank test. RESULTS: When adjusted for EDSS, duration of disease and T25-FW, across all deep nuclei, NAT-treated patients had significantly higher T2 intensities than untreated patients (DN p= 1.65 * 10(-5) ; SN p= 2.37 * 10(-5) ; RN p= 3.90 * 10(-6) ; GP p= 1.05 * 10(-6) ), IFNbeta treated patients (DN p= 1.65 * 10(-5) ; SN p= 2.37 * 10(-5) ; RN p= 3.90 * 10(-6) ; GP p= 1.05 * 10(-6) ), and GA-treated patients (DN p= 1.65 * 10(-5) ; SN p= 2.37 * 10(-5) ; RN p= 3.90 * 10(-6) ; GP p= 1.05 * 10(-6) ). In a subset of MS patients receiving NAT, there was a significant increase in T2 intensities in all the dGM nuclei after 24 months of treatment (DN p= 0.00021; SN p= <0.0001; RN p= 0.00015; GP p= 0.00011). CONCLUSION: Our preliminary observations suggest that long-term NAT therapy in MS patients may affect T2 intensity levels of dGM brain nuclei, hence suggesting a potential effect of NAT beyond anti-inflammatory effect. Prospective studies are warranted to provide more insights into our preliminary observations. PMID- 21707828 TI - Pilot study to determine the utility of point-of-care ultrasound in the assessment of difficult laryngoscopy. AB - OBJECTIVES: Prediction of difficult laryngoscopy in emergency care settings is challenging. The preintubation clinical screening tests may not be applied in a large number of emergency intubations due to the patient's clinical condition. The objectives of this study were 1) to determine the utility of sonographic measurements of thickness of the tongue, anterior neck soft tissue at the level of the hyoid bone, and thyrohyoid membrane in distinguishing difficult and easy laryngoscopies and 2) to examine the association between sonographic measurements (thickness of tongue and anterior neck soft tissue) and difficult airway clinical screening tests (modified Mallampati score, thyromental distance, and interincisor gap). METHODS: This was a prospective observational study at an academic medical center. Adult patients undergoing endotracheal intubation for an elective surgical procedure were included. The investigators involved in data collection were blinded to each other's assessments. Demographic variables were collected preoperatively. The clinical screening tests to predict a difficult airway were performed. The ultrasound (US) measurements of tongue and anterior neck soft tissue were obtained. The laryngoscopic view was graded using Cormack and Lehane classification by anesthesia providers on the day of surgery. To allow for comparisons between difficult airway and easy airway groups, a two-sided Student's t-test and Fisher's exact test were employed as appropriate. Spearman's rank correlation coefficients were used to examine the association between screening tests and sonographic measurements. RESULTS: The mean (+/-standard deviation [SD]) age of 51 eligible patients (32 female, 19 male) was 53.1 (+/ 13.2) years. Six of the 51 patients (12%, 95% confidence interval [CI] = 3% to 20%) were classified as having difficult laryngoscopy by anesthesia providers. The distribution of laryngoscopy grades for all subjects was 63, 25, 4, and 8% for grades 1, 2, 3, and 4, respectively. In this study, 83% of subjects with difficult airways were males. No other significant differences were noted in the demographic variables and difficult airway clinical screening tests between the two groups. The sonographic measurements of anterior neck soft tissue were greater in the difficult laryngoscopy group compared to the easy laryngoscopy group at the level of the hyoid bone (1.69, 95% CI = 1.19 to 2.19 vs. 1.37, 95% CI = 1.27 to 1.46) and thyrohyoid membrane (3.47, 95% CI = 2.88 to 4.07 vs. 2.37, 95% CI = 2.29 to 2.44). No significant correlation was found between sonographic measurements and clinical screening tests. CONCLUSIONS: This pilot study demonstrated that sonographic measurements of anterior neck soft tissue thickness at the level of hyoid bone and thyrohyoid membrane can be used to distinguish difficult and easy laryngoscopies. Clinical screening tests did not correlate with US measurements, and US was able to detect difficult laryngoscopy, indicating the limitations of the conventional screening tests for predicting difficult laryngoscopy. PMID- 21707830 TI - Successful treatment of recurrent digital mucoid cysts using a 1,444-nm neodymium doped yttrium aluminum garnet laser. PMID- 21707831 TI - Long-pulse neodymium-doped yttrium aluminum garnet laser treatment improves amiodarone-induced hyperpigmentation. PMID- 21707832 TI - A novel injection technique for horizontal neck lines correction using calcium hydroxylapatite. PMID- 21707833 TI - Performance of the On-Q pain infusion device during changes in environmental temperature. AB - BACKGROUND: The On-Q infusion device is an elastomeric device with a flow regulator that controls the flow of a local anesthetic agent through a peripheral catheter. As variations in external temperature may affect the diameter of the tubing or viscosity of the fluid, it is feasible that alterations in flow may be caused by such temperature variations. This study evaluates the performance of this device during variations in environmental temperature. METHODS: The disposable 400 ml On-Q pain ball infusion devices were filled and connected to a single, end hole infusion catheter and set to infuse at 14 ml.h(-1) . Eighteen devices were used in the study (six of each at three different temperatures). The temperatures included hot (54 degrees C), room temperature (21 degrees C), and cold (6 degrees C). The devices were allowed to flow for 24 h. The fluid delivered during each 12-h period was measured using a graduated column. RESULTS: There were significant differences in the output from the devices at the hot (54 degrees C) temperature and the cold (6 degrees C) temperature when compared to room temperature (21 degrees C). When compared to room temperature, the output decreased to 67% and 54% of the control group (room temperature) during hours 0 12 and 12-24, respectively, in a cold environment (6 degrees C). An increased external temperature resulted in a greater output from the devices. When compared to the room temperature devices, the output was 49% higher during the first 12 h and 40% higher during the second 12 h at an external temperature of 54 degrees C. CONCLUSIONS: This preliminary investigation demonstrates what may be clinically significant changes in output from the On-Q pain device based on the external temperature. These alterations in flow could result in inadequate analgesia or even potentially toxicity if these devices are used in smaller patients especially the pediatric population. PMID- 21707835 TI - Estimated glomerular filtration rate: which equation is best and how should it be used? PMID- 21707834 TI - Evaluation of multiple commercial molecular and conventional diagnostic assays for the detection of respiratory viruses in children. AB - This study compares the performance of four commercial multiplex PCR assays (Resplex II Panel v2.0, Seeplex RV15, xTAG RVP and xTAG RVP Fast) and direct fluorescent antibody (DFA) staining and viral isolation. Seven hundred and fifty nasopharyngeal swabs were tested for 17 viral agents. In each assay, the sensitivity and specificity for each target were determined against a composite reference standard. Two hundred and eighty-eight out of 750 (38.4%) specimens were positive by DFA or viral isolation, while an additional 214 (28.5%) were positive by multiplex PCR, for a total positivity rate of 66.9%. Of 502 positive specimens, one virus was detected in 420 specimens (83.7%), two in 77 (15.3%), three in four (0.8%) and four in one case (0.2%). Compared with a composite reference standard, the inter-assay accuracy of the multiplex PCR assays varied, but all were superior to conventional diagnostic methods in detecting a broad range of respiratory viral agents in children. In addition, the sensitivity of two commercial assays, Resplex II Plus PRE and Seeplex Influenza A/B Subtyping, was determined relative to the Astra influenza Screen & Type assay for detection of influenza A viruses, including seasonal influenzas and pandemic H1N1 2009 influenza A virus. Using 75 positive and 55 negative nasopharyngeal swabs for influenza A by the Astra assay, the sensitivity of Seeplex and Resplex was 95.9% and 91.8%, respectively, with a specificity of 100% for both. PMID- 21707836 TI - Autonephrectomized renal calcified mass. PMID- 21707837 TI - Giant sporadic renal angiomyolipoma with spontaneous haemorrhage. PMID- 21707838 TI - Towards better renal palliative care. PMID- 21707839 TI - Morbidity burden of end-stage kidney disease in Australia: hospital separation rates among people receiving kidney replacement therapy. AB - BACKGROUND: Mortality associated with dialysis and transplantation is well characterized. Less well described are hospital separation rates for "non-renal" diagnoses among people receiving kidney replacement therapy (KRT = haemodialysis, peritoneal dialysis and kidney transplantation). We examined these rates among Australians receiving KRT. METHODS: Observational study based on Australian National Hospital Morbidity Database, incorporating Australian public and private hospitals. Separations from this dataset were examined for 2002-7, excluding day only haemodialysis. ICD (International Classification of Disease) codes were used to identify separations for people receiving chronic KRT. Separations categorized into "renal" and "non-renal" by principal diagnosis. Separation rate, admission length and in-hospital mortality were compared with the general population. RESULTS: Overall hospital separation rate (adjusted for age and gender) was increased relative to the general population for all groups: for HD patients, relative rate (RR) was 4.49 [95% confidence interval 4.460-4.53]; for PD patients 5.52 [5.460-5.59]; for transplant recipients 4.83 [4.20-4.28] (all p < 0.001). When restricted to separations with a "non-renal" principal diagnosis, the excess remained among KRT groups: HD adjusted RR 2.20 [2.170-2.22], PD 2.00 [1.950-2.04] and transplants 2.63 [2.600-2.66], all p < 0.001). The length and in-hospital mortality for separations in each KRT group was also increased. By ICD-10 chapter, rates of separations with infectious and metabolic causes were increased in all KRT groups; separations with circulatory and respiratory causes were also increased. CONCLUSION: Among people receiving KRT in Australia, there is a substantial burden of morbidity in addition to that directly related to KRT. This is most marked for infective, endocrine and circulatory and respiratory hospitalisations. PMID- 21707840 TI - Plasma cell infiltrates and renal allograft outcomes in indigenous and non indigenous people of the Northern Territory of Australia. AB - INTRODUCTION: Plasma cell-rich rejection is a distinct histological phenomenon associated with poor renal allograft outcomes. Aboriginal and Torres Straight Islander (ATSI) transplant recipients have poorer allograft survival and higher rates of acute rejection. We sought to determine whether a higher incidence of plasma cell-rich infiltrates (PCIR) could account for poorer survival. METHODS: Renal transplant biopsies performed in recipients from the Northern Territory of Australia between 1985 and 2007 were reviewed and correlated with outcome. Biopsies were designated PCIR positive when plasma cells constituted >10% of the interstitial infiltrate. RESULTS: Four hundred and seventy-seven biopsies from 177 recipients (108 ATSI) were performed. Median graft survival was shorter for recipients with PCIR: 4.0 years (interquartile range 2.18-6.41) versus 5.4 years (2.0-9.99) (P = 0.013). ATSI recipients had higher rates of plasma cell-rich rejection (RR 1.76, 95% CI 1.43-2.17, P < 0.0001), which occurred earlier (251 vs 869 days, P = 0.03) compared with non-indigenous recipients. On multivariate analysis, PCIR did not independently influence allograft survival. There was a correlation between PCIR and panel reactive antibody peak >20% (RR 1.29, 95% CI 1.03-1.56, P = 0.025), >=5 human leukocyte antigen mismatches (RR 1.91, 1.41 2.58, p < 0.0001), increasing post-transplant infection rate (>10 infections RR 5.11, 1.69-15.5, P = 0.004), and subsequent death from septicaemia (RR 1.6, 1.17 2.18, P = 0.003). CONCLUSION: PCIR is associated with infection and markers of chronic immunological stimulation but does not independently contribute to inferior renal allograft outcomes, even in ATSI recipients. PMID- 21707841 TI - Nephrotoxicity of vancomycin in patients with methicillin-resistant Staphylococcus aureus bacteraemia. AB - AIM: Vancomycin and teicoplanin are the two most used glycopeptides for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is suspected to have more nephrotoxicity but this has not been clearly established. The aim of this study was to assess its nephrotoxicity by a consensus definition of acute kidney injury (AKI): the risk (R), injury (I), failure (F), loss and end stage renal disease (RIFLE) classification. METHODS: Patients with MRSA bacteraemia who were prescribed either vancomycin or teicoplanin between 2003 and 2008 were classified. Patients who developed AKI were classified by RIFLE criteria. Variables such as comorbidities, laboratory data and medical cost information were also obtained from the database. Outcomes determined were: (i) the rate of nephrotoxicity and mortality; and (ii) the association of nephrotoxicity with the length of hospital stay and costs. RESULTS: The study included 190 patients (vancomycin 33, teicoplanin 157). Fifteen patients on vancomycin and 27 patients on teicoplanin developed AKI (P = 0.0004). In the vancomycin group, four, eight and three patients were classified to RIFLE criteria R, I and F, respectively. In the teicoplanin group, 17, nine and one patient were classified to RIFLE criteria R, I and F, respectively. Kaplan-Meier analysis showed significant difference in time to nephrotoxicity for the vancomycin group compared to the teicoplanin group. No significant differences were found between the groups in terms of total mortality, length of hospital stay and costs. CONCLUSION: The study data suggest that vancomycin is associated with a higher likelihood of nephrotoxicity using the RIFLE classification. PMID- 21707842 TI - Detection of early lymphangiogenesis by lymphatic microvascular density and endothelial proliferation status in preneoplastic and neoplastic lesions of the uterine cervix. AB - The characteristics of lymphangiogenesis in preneoplastic and neoplastic lesions of the uterine cervix are not well known and the role of this process in tumor progression and metastasis is not well understood. The aim of the present study was to characterize the morphology and distribution of lymphatic vessels and lymphatic proliferative status and to evaluate the value of lymphatic microvascular density (LMVD) in premalignant and malignant lesions of the uterine cervix. One hundred and twenty-eight paraffin-embedded cervical specimens were immunostained with D2-40 antibody specific for lymphatic endothelial cells. Colocalization of D2-40 and Ki67 for the proliferative characterization of lymphatic vessels was obtained by performing double immunostaining. A low density of lymphatic vessels was detected in normal cervix and squamous metaplasia. Intense and particular lymphangiogenic response was found in low and high grade squamous intraepithelial lesions and microinvasive carcinoma. Lymphatic proliferation occurred early in cervical lesions, being more active in premalignant lesions and microinvasive carcinomas than in invasive lesions. Our results suggest an early initiation of an active lymphangiogenesis in cervical lesions. These findings support the hypothesis that cervical preneoplastic lesions represent a critical point in the development of the lymphatic network vasculature. Early lymphangiogenesis could explain lymph node metastasis associated with cervical invasive carcinomas at preliminary diagnosis. PMID- 21707843 TI - Retinoid receptors in human esophageal squamous cell carcinoma: retinoid X receptor as a potent prognostic factor. AB - Retinoids regulate cell proliferation and differentiation in normal and neoplastic tissue. These effects are mainly mediated by two types of nuclear retinoid receptors, retinoic acid receptors (RAR) and retinoid X receptors (RXR). RXR have been demonstrated to play important roles in esophageal carcinoma, but the expression of RXRbeta and RXRgamma has not been examined in esophagus. Therefore, we examined the immunoreactivity of all subtypes of RAR and RXR in 53 non-neoplastic esophageal epithelium and 74 esophageal squamous cell carcinoma tissues. In non-neoplastic epithelium RARbeta immunoreactivity was marked in the basal layer and weak in the suprabasal layer, but immunoreactivity of other retinoid receptors was detected in both of layers. In addition, the status of RARbeta and RXRbeta immunoreactivity inversely correlated with that of lymph node metastasis (P= 0.0477 and P= 0.0034, respectively); decreased RXRbeta immunoreactivity of carcinoma cells was positively associated with adverse clinical outcome of the patients (P= 0.0187). These findings all indicate the important roles of retinoid receptors, especially, RXR in the esophageal squamous cell carcinoma. PMID- 21707844 TI - Immunohistochemical ETS-related gene detection in a Japanese prostate cancer cohort: diagnostic use in Japanese prostate cancer patients. AB - Chromosomal rearrangements that result in high expression levels of the ETS related gene (ERG) present in approximately 50% of prostate cancer (PCa) patients, making this one of the most common oncogenic alterations in PCa. However, ERG overexpression at the protein level has not been rigorously evaluated in Japanese PCa patients. In this study, we evaluated ERG expression using antibody-based detection in 230 prostate specimens in a Japanese PCa cohort. Overall, we identified 20.1% ERG-positive PCa cases. ERG was not detected in benign glands. The specificity of ERG staining for detecting PCa was almost 100%; all of the ERG-positive samples were also diagnosed as PCa. The expression level of the ERG protein correlated with clinicopathological variables, including grade (P= 0.038), stage (P= 0.005), and metastatic status (P= 0.014). No correlation was observed with age (P= 0.196) or with preoperative prostate specific antigen level (P= 0.322). Although the frequency of ERG-positive cases in Japanese PCa patients (20.1%) was lower than that reported in a PCa cohort in Western countries (approximately 50%), our study demonstrates that the clinical utility of ERG detection at the protein level can serve as an ancillary tool for diagnosing PCa in the Japanese population. PMID- 21707845 TI - Matrix-producing carcinoma of the breast in the Chinese population: a clinicopathological study of 13 cases. AB - Matrix-producing carcinoma (MPC) of the breast is an extremely rare variant of metaplastic carcinoma. The aim of this study was to evaluate the clinicopathological features and immunohistochemical expression profile of this rare tumor in Chinese population. Thirteen cases of MPC were evaluated using morphology observation and immunohistochemistry. All tumors had invasive carcinoma with an abrupt transition to chondromyxoid matrix without an intervening spindle cell sarcomatoid component. The distribution of tumor cells was diffuse in eight cases and peripheral in five cases. Matrix distribution was diffuse or multifocal. Necrosis was present in 11 cases. An overt invasive ductal carcinoma was observed in 11 cases and the other two tumors were consistent with MPC arising in microglandular adenosis. Ten of 13 cases were triple negative (ER , PR-, Her2/neu-). Eight of 10 triple negative cases were cytokeratin 5/6, cytokeratin 14 or epidermal growth factor receptor positive, consistent with the basal-like phenotype. S-100 protein was positive in all cases. At the time of initial diagnosis, one of 13 patients had lung metastasis and axillary lymph nodes metastasis. Follow-up time ranged from 6 to 30 months. All patients remained alive. One patient developed a soft tissue metastasis 24 months after surgery. PMID- 21707846 TI - Clinicopathological characteristics of primary lung adenocarcinoma predominantly composed of goblet cells in surgically resected cases. AB - Primary lung adenocarcinomas predominantly composed of goblet cells (APGC) are relatively rare, and the clinicopathological characteristics have remained unclear. The aim of this study was to clarify the clinicopathological characteristics of APGC. We selected adenocarcinoma with a goblet cell-type component of >= 90% from 2228 cases of surgically resected primary lung adenocarcinoma. The clinicopathological characteristics of APGC (46 cases) were analyzed. APGC showed a significantly higher rate of tumor location on the left side, in the lower lobe and pathological stage I, when compared with the other types of adenocarcinoma. Furthermore, APGC displayed a lower frequency of central fibrosis, plural invasion, pulmonary metastasis, lymphatic permeation, and vascular invasion. APGC showed local recurrence in two of 46 cases (4.3%) and no incidents of distant metastasis. When compared with non-mucinous bronchioloalveolar adenocarcinomas (non-mucinous BAC) without central fibrosis, APGC without central fibrosis, corresponding to mucinous BAC, showed a significantly higher rate of tumor location on the left side and in the lower lobe. In conclusion, APGC formed a distinct subset and should be considered separately from lung adenocarcinoma based on frequent involvement of the left and lower lung and lack of central fibrosis. PMID- 21707847 TI - Duplication of the digestive organs in the retroperitoneum: a case report with reference to the importance of a standardized nomenclature and definition. AB - Duplications of the digestive organs, especially in the retroperitoneum, are rare malformations. We present the case of a 20-year-old man who had recurrent abdominal pain because of a solid and cystic mass located in the retroperitoneum, posterior to the pancreatic body. Preoperative diagnosis was difficult and a resection was performed. Histopathologically, intestinal mucosa, respiratory mucosa, aberrant pancreatic tissue, smooth muscle coat, and an external fibrous capsule were found. The mass was diagnosed as a duplication of the digestive organs. Findings in the pancreatic tissue indicated chronic pancreatitis and mild atypia in the pancreatic duct epithelium. Currently, many terms are used to describe these series of malformations, including duplication, foregut cyst, gastrointestinal duplication cyst, and enteric duplication cyst. Consequently, diagnosis and investigation can be difficult. In the atlas produced by the Armed Forces Institute of Pathology, duplication is used as a standardized diagnostic nomenclature with subclassification according to the site, but this has not been uniformly accepted. In addition, there are cases whose origins are unclear, especially in the retroperitoneum. In this report, we propose that the term duplication should be uniformly used for all cases in the digestive organs, and that they may then be distinguished according to their mechanisms. PMID- 21707849 TI - Tryptase-positive mast cells and CD8-positive T cells in human endometrial cancer. AB - In this study, we correlated the number of tryptase-reactive mast cells with the number of CD8-positive T cells in human endometrial adenocarcinoma biopsy specimens by means of immunohistochemical techniques. Results have shown that CD8 positive T cell counts correlate to tryptase-positive mast cell counts and that these parameters increase in accordance with the tumor progression of human endometrial carcinoma. These data suggest that inhibition of inflammation or manipulation of inflammatory resolution pathways may be a new therapeutic approach for the treatment of endometrial adenocarcinoma. PMID- 21707848 TI - Tumor-to-tumor metastasis: lung adenocarcinoma metastasizing to a follicular variant of papillary thyroid carcinoma. AB - Cancer-to-cancer metastasis into a thyroid neoplasm is an uncommon phenomenon with possible diagnostic difficulties. Here, we describe a case of lung adenocarcinoma metastatic into a follicular variant of papillary thyroid carcinoma (FVPTC). A 60-year-old woman with no prior history of malignant neoplasm presented with a nodule in the right lobe of the thyroid gland, some masses in the left lung were found by radiological examination. Histopathological examination of the thyroidectomy specimen demonstrated two different components of carcinoma in a single thyroid nodule; one was FVPTC and the other was high grade adenocarcinoma. Although both components shared the TTF-1+/CK7+/CK19+/CK20 /SP-A- immunoprofile, only the former was positive for thyroglobulin, and only the latter was positive for CEA. The epidermal growth factor receptor (EGFR) gene mutation at exon21 (L858R) was present only in the latter. The lung biopsy specimen showed cytological, immunohistochemical, and EGFR genotypic features similar to those of the high-grade adenocarcinoma component of the thyroid nodule. These findings resulted in a reliable diagnosis of lung adenocarcinoma metastasizing into an FVPCT and treatment with EGFR-targeted therapy. These results demonstrate that a panel of immunohistochemical staining and molecular analysis is helpful for both diagnosis and appropriate postoperative treatment for a patient with cancer-to-cancer metastasis. PMID- 21707850 TI - Mullerian adenosarcoma with sarcomatous overgrowth in the pelvic cavity extending into the inferior vena cava and the right atrium. PMID- 21707851 TI - Cutting edge technologies in respiratory research: lung function testing. AB - Pulmonary function testing is part of routine clinical practice in respiratory medicine. It is based around spirometry, which will remain the central measurement of lung function given its prognostic significance and its integral role in defining severity of airways disease. However, there is an increasing body of evidence from studies using new methods of lung function measurement which are providing new insights into pathophysiology of disease. This body of data is forming a basis for their future clinical role, once the economics of producing the relevant devices becomes attractive. The forced oscillation technique and multiple breath nitrogen washout are currently the most commonly used of the newer lung function techniques, which are refinements of long established techniques. Optical coherence tomography, optical reflection, electrical impedance and vibration response imaging have arisen by development of novel devices. The recent use of these techniques is reviewed. PMID- 21707852 TI - Chronic cough and esomeprazole: a double-blind placebo-controlled parallel study. AB - BACKGROUND AND OBJECTIVE: Gastro-oesophageal reflux has been implicated in the pathogenesis of chronic cough. Guidelines on management suggest a therapeutic trial of anti-reflux medication. Esomeprazole is a proton pump inhibitor licensed for the long-term treatment of acid reflux in adults and we compared the effects of esomeprazole and placebo on patients with chronic cough. METHODS: This was a prospective, single-centre, randomized, double-blind, placebo-controlled, parallel group study conducted over 8weeks. Fifty adult non-smokers with chronic cough and normal spirometry were randomized. Patients completed cough-related quality-of-life and symptom questionnaires and subjective scores of cough frequency and severity at the beginning and end of the study. They also kept a daily diary of symptom scores. Citric acid cough challenge and laryngoscopic examination were performed at baseline and the end of the study. The primary outcome was improvement in cough score. RESULTS: There were no differences in cough scores in the placebo and treatment arms of the study although some significant improvements were noted when compared to baseline. In the cough diary scores there was a trend towards greater improvement in the treatment arm in patients with dyspepsia. CONCLUSIONS: Esomeprazole did not have a clinically important effect greater than placebo in patients with cough. It suggests a marked placebo effect in the treatment of cough. PMID- 21707853 TI - Prevalence of anxiety and depression among chronic bronchitis patients and the associated factors. AB - BACKGROUND AND OBJECTIVE: Patients with COPD, including those with chronic bronchitis (CB), have a high risk of suffering from psychiatric disorders. Although depression has always received greater attention in these patients, most of the published studies have been of poor methodological quality. Anxiety has received less attention than depression among COPD patients. The aim of this study was to assess the prevalence of anxiety and depression among patients with CB and to identify associated factors. METHODS: This was a descriptive, epidemiological population-based study. The study was based on individual data obtained from the 2006 Spanish National Health Survey. Subjects aged 40years and over were selected for the study. Individuals with CB were identified using a specific questionnaire. Sociodemographic characteristics and health-related variables were analysed. RESULTS: Of the 20,060 subjects selected, 1320 were categorized as having CB (6.5%). The prevalence of anxiety was 15.6% among subjects with CB and 9.4% among those without the disease (P<0.01). Variables that were independently and significantly associated with anxiety among CB patients were female gender, increased age and concomitant comorbidities. The prevalence of depression was 15.9% among subjects with CB and 7.6% among those without the disease (P<0.05). Variables associated with depression among CB patients were female gender, middle age, poorer self-perception of health status, concomitant comorbidities, abstemiousness and the need for emergency room attendance in the previous year. CONCLUSIONS: Anxiety or depression is around twice as frequent among CB patients as it is among those without CB. Variables associated with anxiety or depression among CB patients included female gender and concomitant comorbidities. PMID- 21707854 TI - Antipsychotics and cognitive function. PMID- 21707855 TI - Survey in Shanghai communities: the public awareness of and attitude towards dementia. AB - OBJECTIVE: To assess the knowledge of and attitudes towards dementia among Shanghai residents. METHODS: A 10-item optional questionnaire relating to dementia was developed for the project. Questionnaires were randomly distributed to 1806 families, each family had one respondent. RESULTS: A total of 1531 questionnaires were available. Among them, 45% considered 'dementia is a normal part of ageing' and 29-41% correctly identified the symptoms of mild dementia. Of the respondents, 43% indicated that they would not be ashamed of having a demented relative, and 45% did not think that medical care benefited those with dementia. Subgroups analyses showed there was a wider agreement on the concept 'dementia is a normal part of ageing' in the elderly or the females with primary school education background than the counterpart. According to the educational level, the sequence (from the highest to the lowest) of the proportion of respondents who considered a demented relative to be shameful was as follows: middle school group (60.5%) > primary school group (41.3%) > university group (25.2%); according to age group: adult group (59.8%) > elderly group (37.3%) > youth group (30.2%). There was a higher identification rate of the symptoms of mild dementia in women than in men (P < 0.01). According to the educational level, the sequence (from the highest to the lowest) of identification rate was: university group > primary school group > middle school group; according to age group: elderly group > youth group > adult group. There was a significant difference among groups (P < 0.01). Multivariate regression results suggested that the sex, educational level and age had an influence on the concept of 'dementia is part of normal ageing'; the feeling of shame of having demented relatives was influenced by the educational level and age. CONCLUSION: Lack of correct knowledge about dementia and discrimination of dementia are highly prevalent among urban residents in Shanghai. PMID- 21707856 TI - Protein kinase C stabilizes X-linked inhibitor of apoptosis protein (XIAP) through phosphorylation at Ser(87) to suppress apoptotic cell death. AB - BACKGROUND: Multiple protein kinases have been shown to be involved in the apoptotic neuronal loss of Alzheimer's disease (AD). Although some studies support the role of protein kinase C (PKC) in amyloid precursor protein processing as well as in tau phosphorylation, a direct role for PKC in apoptotic neuronal death remains to be clarified. In the present study, we report on the possible role of PKC in cell survival during conditions of stress through phosphorylation of the X-linked inhibitor of apoptosis protein (XIAP). METHODS: Phosphorylation of XIAP at Ser87 was confirmed by western blot analysis employing phosphorylation dependent anti-XIAP antibody after incubation of recombinant XIAP with active PKC in vitro. And increased phosphorylation of XIAP at the site was also confirmed in SH-SY5Y cells treated with PKC activator, phorbol 12-myristate 13-acetate (PMA). A mutant XIAP construct in which Ser87 was substituted by Ala, was prepared, and transfected to cells. After the transfection of wild or mutant XIAP, cells viability was evaluated by counting living and dead cells treated with PMA during etoposide-induced apoptosis. RESULTS: Recombinant XIAP was phosphorylated at Ser(87) by PKC in vitro and treatment of XIAP-transfected SH SY5Y cells with a PKC activator, phorbol 12-myristate 13-acetate (PMA) induced phosphorylation of XIAP at Ser(87) . Pulse chase experiments revealed that, when phosphorylated at Ser(87) , wild-type XIAP is more stable than XIAP with a Ser87Ala substitution, which is degraded faster. Importantly, the phosphorylation of XIAP at the site by PKC significantly increased cell survival up to approximately 2.5 times under the condition of apoptosis induced by 25 ug/ml etoposide. CONCLUSION: The findings of the present study indicate a role for PKC, through phosphorylation of XIAP at Ser(87) and its stabilization, in cell survival under conditions of stress and lend strength to the idea that PKC is crucial in regulating neuronal homeostasis, which may be impaired in AD. PMID- 21707857 TI - Subjective experiences of family caregivers of patients with dementia as predictive factors of quality of life. AB - BACKGROUND: The aim of the present study was to investigate predictive factors of quality of life (QOL) in home caregivers of patients with dementia. METHODS: A total of 118 home caregivers (48 male, 70 female) were asked to complete the World Health Organization (WHO) Quality of Life 26 (WHO/QOL-26) questionnaire, the Pines Burnout Measure (BM), and the Beck Depression Inventory, second edition (BDI-II). Patient demographics and clinical data regarding cognitive impairment, neuropsychiatric symptoms, and dementia severity were obtained from medical records. RESULTS: Spearman rank correlation coefficients revealed that caregiver QOL was significantly correlated with patients' neuropsychiatric symptoms (r= 0.19; P < 0.05), as well as depressive symptoms (r=-0.59, P < 0.01) and burnout (r=-0.59, P < 0.01) in caregivers. Stepwise multiple regression analysis revealed that depressive symptoms in caregivers was the strongest predictor for caregiver QOL (R(2) = 0.37, P < 0.001) and that caregiver QOL was best predicted by the combination of depressive symptoms, burnout, and the cognitive impairment of patients (R(2) = 0.46, P < 0.05). CONCLUSION: The results of the present study demonstrate that subjective experiences of caregivers are more strongly correlated with caregiver QOL than patient-related variables and are thus powerful determinants of caregiver QOL. These findings suggest that caregiver intervention, which aims to increase QOL, may benefit from the incorporation of strategies to reduce depressive symptoms and burnout. PMID- 21707858 TI - Serum homocysteine and physical exercise in patients with Parkinson's disease. AB - BACKGROUND: Hyperhomocysteinemia is a major risk factor for cerebral and peripheral vascular diseases, as well as cortical and hippocampal injury, including an increased risk of dementia and cognitive impairment. Elevated serum homocysteine (Hcy) concentrations are common in patients with Parkinson's disease (PD) who have been treated with levodopa; however, physical exercises can help reduce Hcy concentrations. The aim of the present study was to compare serum Hcy levels in patients with PD who partook in regular physical exercises, sedentary PD patients, and healthy controls. METHODS: Sixty individuals were enrolled in the present study across three groups: (i) 17 patients who did not partake of any type of exercise; (ii) 24 PD patients who exercised regularly; and (iii) 19 healthy individuals who did not exercise regularly. All participants were evaluated by Hoehn and Yahr scale, the Unified Parkinson's Disease Rating Scale (UPDRS) and Schwab and England scale (measure daily functionality). The serum levels of Hcy were analyzed by blood samples collected of each participant. An analysis of variance and a Tukey's post hoc test were applied to compare and to verify differences between groups. Pearson's correlation and stepwise multiple regression analyses were used to consider the association between several variables. RESULTS: Mean plasma Hcy concentrations in individuals who exercised regularly were similar to those in the healthy controls and significantly lower than those in the group that did not exercise at all (P= 0.000). In addition, patients who did not exercise were receiving significantly higher doses of levodopa than those patients who exercised regularly (P= 0.001). A positive relationship between levodopa dose and Hcy concentrations (R(2) = 0.27; P= 0.03) was observed in patients who did not exercise, but not in those patients who exercised regularly (R(2) = 0.023; P= 0.15). CONCLUSIONS: The results of the present study suggest that, even with regular levodopa therapy, Hcy concentrations in PD patients who exercise regularly are significantly lower than in patients who do not exercise and are similar Hcy concentrations in healthy controls. PMID- 21707859 TI - Cell-based therapy for patients with vascular dementia. AB - The homeostasis of neuronal cells is maintained by the cerebral circulation and blood-brain barrier. Circulating bone marrow-derived immature cells, including CD34-positive (CD34+) cells, have been implicated in homeostasis of the cerebral microvasculature. Decreased levels of circulating CD34+ cells, associated with ageing and/or cardiovascular risk factors, correlate with poor clinical outcomes in patients with cerebrovascular and cardiovascular diseases. Clinical trials with local transplantation of bone marrow-derived immature cells for patients with limb ischaemia, including Buerger's disease and arteriosclerosis obliterans, have been shown to improve impaired microcirculation. In the present review, current findings about the correlation between circulating immature cells and microcirculation are reviewed, and the possibility of novel cell-based therapy in patients with vascular dementia is discussed. PMID- 21707860 TI - Low-dose aripiprazole resolved complex hallucinations in the left visual field after right occipital infarction (Charles Bonnet syndrome). AB - We reported a patient who suffered from complex visual hallucinations with left homonymous hemianopsia. Brain imaging showed an acute haemorrhage infarct at the right occipital lobe. Charles Bonnet syndrome (CBS) was suspected and aripiprazole was prescribed at 5 mg daily. After 3 weeks, the symptoms of hallucinations and anxiety were relieved. Although some CBS patients might be self-limited without discomfort, low-dose aripiprazole can be considered as a safe medication for significantly anxious patients with CBS. PMID- 21707861 TI - Creutzfeldt-Jakob disease. AB - Creutzfeldt-Jakob disease (CJD) is a progressive, degenerative, and fatal disease of the central nervous system. It is caused by abnormal accumulation of prion proteins and is characterized mainly by progressive dementia, myoclonus, and cerebellar, pyramidal, and extrapyramidal findings. Psychiatric symptoms may also accompany CJD and are often the first signs of the disease. The incidence of CJD is approximately 1 in 1 000 000. In certain cases, a diagnosis can be made by demonstrating the accumulation of pathological prion proteins. However, in many cultures brain biopsies or post-mortem evaluations are not welcomed by either the patients or their relatives. In these cases, the importance of additional diagnostic tools increases. Herein, we report on a CJD patient who first consulted a psychiatrist with early psychiatric symptoms. The patient developed neurological symptoms later and was subsequently diagnosed as sporadic CJD based on clinical and laboratory findings rather than brain biopsy. Repeated electroencephalograms (EEG) played a pivotal role in our evaluation of the patient. This case is an interesting presentation of CJD both because of the timing of the symptoms and because of the typical EEG findings that led to the diagnosis. PMID- 21707862 TI - Pet therapy in elderly patients with mental illness. AB - BACKGROUND: To evaluate the effects of pet therapy on cognitive function, mood and perceived quality of life on elderly inpatients (mean age 84.7 years; 95.2% women) affected by dementia, depression and psychosis. METHODS: Mini-Mental State Examination (MMSE) and 15-items Geriatric Depression Scale (GDS) were administered to 10 patients (pet group) and 11 controls (control group) together with a self-perceived quality-of-life questionnaire, before and after a pet therapy intervention that lasted 6 weeks. MMSE and GDS mean scores were compared between and within groups by Student's t-test. RESULTS: Both the pet group and control group improved on GDS and MMSE. Within the pet group, GDS symptoms decreased by 50% (from 5.9 to 2.7, P= 0.013), whereas mean MMSE score increased by 4.5 (P= 0.060). The between group comparison showed a positive effect of pet therapy intervention on GDS (P= 0.070). Most of the participants reported an improvement of their perceived quality of life. CONCLUSIONS: Pet therapy is efficient in improving depressive symptoms and cognitive function in residents of long-term care facilities with mental illness. PMID- 21707863 TI - Combination of pigment epithelium-derived factor with radiotherapy enhances the antitumor effects on nasopharyngeal carcinoma by downregulating vascular endothelial growth factor expression and angiogenesis. AB - Nasopharyngeal carcinoma (NPC), which has the highest incidence in South China, is mainly treated by radiotherapy. However, the survival rate remains low. Angiogenesis is closely correlated with progress of NPC. Thus, the combination of anti-angiogenesis with radiation is an attractive strategy for NPC treatment. A heterogenic xenografted human NPC nude mice model was established to investigate the effect of pigment epithelium-derived factor (PEDF), a potent anti-angiogenic factor, and the combined effect of PEDF and radiotherapy on nasopharyngeal carcinoma. Pigment epithelium- derived factor remarkably suppressed the growth of NPC by 43.52% and decreased the tumor microvessel density (MVD). Pigment epithelium-derived factor had no effects on the proliferation and apoptosis of NPC cell lines by MTT and flow cytometry assay. However, PEDF decreased vascular endothelial growth factor (VEGF) in NPC cell lines by downregulation of hypoxia inducible factor 1a, a crucial transcriptional factor for VEGF expression, as demonstrated by western blotting and immunofluorescent staining assay. Interestingly, irradiation alone could also effectively downregulate VEGF and MVD of xenografted tumor, which indicates that irradiation suppresses NPC not only by killing tumor cells but also through anti-angiogenesis. Furthermore, combined treatment of PEDF with irradiation enhanced the antitumor efficacy. The MVD and VEGF in the combined therapy were much less than in the treatment with PEDF or radiotherapy alone. Our observation demonstrated that the combination of PEDF with radiotherapy enhances the efficacy of the antitumor effect on NPC by the coordinated inhibition on angiogenesis, which implies the potential role of PEDF as an adjuvant agent for NPC treatment. PMID- 21707864 TI - EW-7203, a novel small molecule inhibitor of transforming growth factor-beta (TGF beta) type I receptor/activin receptor-like kinase-5, blocks TGF-beta1-mediated epithelial-to-mesenchymal transition in mammary epithelial cells. AB - Recently, small molecule inhibitors of transforming growth factorbeta (TGF-beta) type I receptor kinase / activin receptor-like kinase-5 (ALK5) have been developed to target TGF-beta signalling as a therapeutic strategy for combating cancer. In the present study, the authors examined a novel small molecule inhibitor of ALK5, 3-((5- ([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin 2-yl)thiazol-2-ylamino)methyl)benzonitrile (EW-7203) in breast cancer cells to determine if it has potential for cancer treatment. The inhibitory effects of EW 7203 on TGF-beta-induced Smad signalling and epithelial- to-mesenchymal transition (EMT) were investigated in mammary epithelial cells using luciferase reporter assays, immunoblotting, confocal microscopy and wound healing assays. In addition, the suppressive effects of EW-7203 on mammary cancer metastasis to the lung were examined using a Balb / c xenograft model system. The novel ALK5 inhibitor, EW-7203, inhibited the TGF-beta1-stimulated transcriptional activation of p3TP-Lux and pCA-GA12- Luc. In addition, EW-7203 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 was increased by TGF-beta1. In addition, EW-7203 inhibited TGF-beta1-induced EMT and wound healing of NMuMG cells. Furthermore, in xenografted Balb / c mice, EW-7203 inhibited metastasis to the lung from breast tumors. The novel ALK5 inhibitor, EW-7203, efficiently inhibited TGF-beta1-induced Smad signalling, EMT and breast tumor metastasis to the lung in vivo, demonstrating that EW-7203 has therapeutic potential for breast cancer metastasis to the lung. PMID- 21707865 TI - Response of subtype-specific human breast cancer-derived cells to poly(ADP ribose) polymerase and checkpoint kinase 1 inhibition. AB - When DNA damage is detected, checkpoint signal networks are activated to stop the cell cycle, and DNA repair processes begin. Inhibitory compounds targeting components of DNA damage response pathways have been identified and are being used in clinical trials, in combination with chemotherapeutic agents, to enhance cancer therapy. Inhibitors of checkpoint kinases, Chk1 and Chk2, have been shown to sensitize tumor cells to DNA damaging agents, and treatment of BRCA1/2 deficient tumor cells, as well as triple negative breast cancers, with poly(ADP ribose) polymerase (PARP) inhibitors has shown promise. But systematic studies to determine which tumor subtypes are likely to respond to these specific inhibitors have not been reported. The current study was designed to test sensitivity of specific breast cancer subtype-derived cells to two classes of these new inhibitory drugs, PARP and Chk1 inhibitors. Luminal, HER2 overexpressing, and triple negative breast cancer-derived cells were tested for sensitivity to killing by PARP inhibitors, ABT-888 and BSI-201, and Chk1 inhibitor, PF-00477736, alone or in combination with gemcitabine or carboplatin. Each of the triple negative breast cancer cell lines showed strong sensitivity to the Chk1 inhibitor, but only the BRCA1-deficient breast cancer cell lines showed sensitivity to the PARP inhibitors, suggesting that in vitro testing of cancer cell lines of specific subtypes, with panels of the different PARP and Chk1 inhibitors, will contribute to stratification of patients for clinical trials using these classes of inhibitors. PMID- 21707866 TI - Overexpression of estrogen receptor-alpha in human papillary thyroid carcinomas studied by laser- capture microdissection and molecular biology. AB - The expression pattern of estrogen receptor (ER) isoforms in normal and tumor thyroid tissues is still controversial and poor defined, therefore, a more detailed study of the distribution of these molecules is needed. Most discrepancies might be due to the methods utilized. We studied the expression of ER isoforms in human papillary thyroid carcinoma (PTC), in fine-needle aspiration biopsy-derived specimens, and in cells, using more accurate techniques, such as laser-capture microdissection, real-time quantitative PCR, and Western blot. Laser-capture microdissection allowed us to isolate homogeneous cell populations from human PTC surgical samples. Tumor, peritumor, or normal host tissue of the same sample were separately dissected and analyzed by RT-PCR and Western blot. Estrogen receptor-alpha mRNA was more expressed in cancer-microdissected cells from human PTC, as compared with microdissected cells obtained from surrounding normal host tissue (450 vs 12, P = 0.001). A similar pattern was observed with Western blot for the ER-a protein. By contrast, ER-beta mRNA expression was not detected among the microdissected tissue fractions. Fine-needle aspiration biopsy derived specimens showed a similar expression pattern to ER. Moreover, human PTC cell line BCPAP and cancer stem cells from PTC, analyzed under hypoxic conditions, showed a hypoxia-driven increase in ER-alpha expression. In conclusion, ER-alpha might have an important role in human PTC, and its overexpression can be studied in routine needle aspirate as a possible marker of malignancy. PMID- 21707868 TI - A literature review of the pathophysiology and onset of post-stroke spasticity. AB - BACKGROUND: Spasticity occurs after stroke and gives rise to substantial burden for patients and caregivers. Although it has been studied for many years, its definition continues to undergo reconsideration and revision. This partly reflects the diversity of its manifestations and that its pathophysiology, although well studied, is still debated. METHODS: A literature review was carried out to define the pathophysiology and risk factors for onset of post-stroke spasticity. RESULTS: It is clear that an acquired brain injury, including stroke, results in an imbalance of inhibitory and excitatory impulses that leads to upper motor neuron symptoms and that the location and extent of the lesions result in differing symptoms and degrees of spastic severity. The onset of spasticity is highly variable and may occur shortly or more than 1 year after stroke. The current understanding of spasticity onset is complicated by the role of contractures, which have been assumed to arise out of spasticity but may have a role in its cause. Other possibly predictive factors for the risk of post-stroke spasticity have been identified, including early arm and leg weakness, left-sided weakness, early reduction in activities of daily living, and a history of smoking. CONCLUSIONS: Further understanding of spasticity risk factors is necessary for the development and integration of early interventions and preventive measures to reduce spasticity onset and severity. PMID- 21707867 TI - Sex steroid hormones in pairs of tumor and serum from breast cancer patients and pathobiological role of androstene-3beta, 17beta-diol. AB - Estrogens play an important role in the pathobiology of breast cancer. In postmenopausal women, peripheral synthesis of estrogens from adrenal/ovarian androgens, dehydroepiandrosterone (DHEA) or androstenedione (Adione), by estrogen metabolizing enzymes is important. Besides estrone (E1) and estradiol (E2), androgen metabolites, such as androstene-3beta, 17beta-diol (Aenediol) or 5alpha androstane-3beta, 17beta-diol (Aanediol), are known to have estrogenic functions, although they have been studied much less in breast cancer. To precisely elucidate steroid metabolism in breast cancer patients and to identify the pathobiological role of estrogenic androgen metabolites, concentrations of DHEA, Adione, Aenediol, Aanediol, E1, and E2 in pairs of serum and tumor tissue from patients with primary breast cancer were measured by liquid chromatography-tandem mass spectrometry. Cell proliferation assays using Aenediol were performed for four breast cancer cell lines. Serous E2 concentration was extremely low in postmenopausal women; however, a marked increase in tumor tissue was observed in hormone receptor-positive cases. E1 concentration, in contrast, was sustained at a higher level, even in postmenopausal serum, and did not increase in tumor tissue irrespective of the hormone receptor status. Dehydroepiandrosterone was most abundant in all samples, and exhibited a similar pattern as Adione and Aenediol. 5alpha-Androstane-3beta, 17beta-diol was undetectable in most samples. Androstene-3beta, 17beta-diol proliferated estrogen receptor-apositive breast cancer cells in the absence of E2. The intratumoral increase of E2, but not E1, in hormone receptor-positive postmenopausal breast cancer tissue, as well as the proliferative role of Aenediol, was elucidated. PMID- 21707869 TI - Clinical characteristics of essential tremor in Taiwan: an exploratory comparative study. AB - BACKGROUND: There are few large-scale clinical analyses of essential tremor (ET) in Asia. We studied the detailed clinical profile with emphasizing the age of onset, tremor location, specific tremor patterns, and rate of progression (ROP) to delineate the characteristics of Taiwanese ET patients and found the difference between the Taiwanese and the Caucasians ET patients. METHODS: All ET patients fulfilled the Movement Disorders Society diagnosis criteria were investigated with a standardized assessment protocol, which including clinical evaluation, uniform severity scoring, self-reported questionnaires, accelerometry, surface electromyography, and videotaped tremor examination. RESULTS: Of 219 patients recruited from July 2008 to October 2009, 153 completed the study protocol. Their mean age was 58.9 years and 47% were women, and 33.3% had family history (FH). There was bimodal distribution in age of tremor onset in patients without but not in those with FH. Head tremor (HT) was present in 48 of 153 (31%) patients. Patients with HT showed slower tremor frequency and less ROP than those without HT. Sixty-seven (44%) patients presented with intention tremor (IT). Male gender and voice tremor were predictive factors of IT occurrence. CONCLUSIONS: Comparing with the Caucasians, Taiwanese ET patients have different patterns of onset-age distribution and lack of female predominance in ET with HT. However, patients with IT and without HT also progressed more rapid as found in the Caucasian. PMID- 21707870 TI - Approach to the treatment, characterization and diagnosis of an acquired auto antibody directed against factors prothrombin, factor X and factor IX: a case report and review of the literature. AB - Bleeding disorders secondary to acquired non-inhibitory antibodies directed against vitamin K-dependent coagulation proteins are rare. In this report, the authors describe a patient with a low grade lymphoma who presented with a fatal acquired bleeding manifestation and abnormal hemostatic studies resulting from deficiencies in both prothrombin and factor X. Patient plasma samples were collected and studied for the presence of an acquired inhibitor. Levels of plasma coagulation proteins were measured using immunoassay. Patient anti-prothrombin immunoglobulin G was isolated and binding to prothrombin, prothrombin F1.2, factors IX and X was evaluated using immunoblots and competition immunoassay. Prolongation in the prothrombin time and activated partial thromboplastin time suggested a factor deficiency in the common pathway of coagulation. Functional and antigenic levels of both prothrombin and factor X were decreased. An IgG subtype-4 antibody was isolated from patient plasma using affinity chromatography on prothrombin-sepharose. This antibody was found to bind to a common metal-ion dependent conformational epitope found on the gamma-carboxyglutamic acid (Gla) domain of prothrombin, factor X and factor IX. This report represents the first description of an acquired bleeding disorder resulting from a unique cross reactive auto-antibody against a common metal-ion-dependent antigenic structure on the Gla-domain of the vitamin K-dependent proteins. PMID- 21707871 TI - rFVIIa administered by continuous infusion during surgery in patients with severe congenital FVII deficiency. AB - The use of recombinant FVIIa (rFVIIa) to control bleed in individuals with FVII deficiency has been proven to be effective. The main problems associated with its use are that it requires frequent bolus injections to counteract its short half life and high cost. Our study aimed to evaluate whether any advantage could be gained by providing rFVIIa by continuous infusion during surgery with regard to haemostatic efficacy, safety and cost. The prospective study included 10 patients with severe FVII deficiency, who underwent 25 surgical procedures (13 major and 12 minor procedures) and were treated with rFVIIa administered by continuous infusion. Tranexamic acid was given concomitantly every 8 h. Prothrombin time, FVII:C assay and thrombin generation assay were used to monitor the treatment. The mean total dose given was 10 mg during a major surgery and 4.4 mg during a minor surgery for a mean treatment duration of 7.5 and 4.0 days respectively. This corresponds to a reduction of 70-90% in drug usage and medication cost compared with bolus injections. Except for one major perioperative bleeding, excellent haemostasis was achieved in all procedures. One patient developed a transient inhibitory activity. None of these events affected the postoperative course or prolonged the hospital stay. Our study demonstrated that continuous infusion of rFVIIa during surgery is safe, effective and highly cost effective. PMID- 21707872 TI - Primary care for tinnitus: practice and opinion among GPs in England. AB - RATIONALE, AIM AND OBJECTIVE: Effective tinnitus management starts with appropriate general practitioner (GP) triage, which in England can be guided by the Department of Health's Good Practice Guide (GPG). Despite the prevalence of the condition, there has never been a systematic survey of its management in primary care in England. We aimed to evaluate how people with tinnitus are assessed and managed in general practice, noting variation in practice across GPs and health authorities, and evaluating how closely typical practice aligns to the GPG for tinnitus. METHODS: A nine-item postal questionnaire was sent to 2000 GPs randomly selected to proportionally represent the number of primary care trusts and strategic health authorities in England. RESULTS: We received 368 responses. Responses indicated a mix of frequent and infrequent practices, for example, 90% of GPs assessed the impact of tinnitus on quality of life, but fewer examined cranial nerves (38%) or assessed for a carotid bruit (26%) during a tinnitus consultation. In the management of tinnitus, 83% routinely removed earwax, and 87% provided information-based advice. In contrast, only 4% of responders would offer antidepressant drugs or psychological therapies. Thematic analysis revealed a desire for concise training on tinnitus management. CONCLUSIONS: GP assessment and management of tinnitus represents potential inequity of service for tinnitus patients. While the GPG aims to promote equity of care, it is only referred to by a minority of clinicians and so its utility for guiding service delivery is questionable. Although some GPs highlighted little demand for tinnitus management within their practice, many others expressed an unmet need for specific and concise GP training on tinnitus management. Further work should therefore evaluate current informational resources and propose effective modes of delivering educational updates. PMID- 21707873 TI - Automating the process of critical appraisal and assessing the strength of evidence with information extraction technology. AB - BACKGROUND: Critical appraisal, one of the most crucial steps in the practice of evidence-based medicine, is expertise-dependent and time-consuming. The objective of this study was to develop and evaluate an automated text-mining system that could determine the evidence level provided by a medical article. METHODS: A text processor was designed and built to interpret the abstracts of medical literature. The system extracted information about: (1) the impact factor of the journal; (2) study design; (3) human subject involvement; (4) number of subjects; (5) P-value; and (6) confidence intervals. We used a classification tree algorithm (C4.5) to create a decision tree using supervised classification. Each article was categorized into evidence level A, B or C, and the output was compared to that determined by domain experts (the reference standard). RESULTS: We used a corpus of 3180 cardiovascular disease original research articles, of which 1108 were previously assigned evidence level A, 1705 level B and 367 level C by domain experts. The abstracts were analysed by our automated system and an evidence level was assigned. The algorithm accurately classified 85% of the articles. The agreement between computer and domain experts was substantial (kappa-value: 0.78). Cross-validation showed consistent results across repeated tests. CONCLUSION: The automated engine accurately classified the evidence level. Misclassification might have resulted from incomplete information retrieval and inaccurate data extraction. Further efforts will focus on assessing relevance and using additional study design features to refine evidence level classification. PMID- 21707874 TI - Comparison of efficiency between FLPe and Cre for recombinase-mediated cassette exchange in vitro and in adenovirus vector production. AB - Cre and FLP recombinases mediate not only specific deletions and insertions, but also the recombinase-mediated cassette exchange (RMCE) reaction, which is used in cell biotechnology including ES cells and mouse genetics. However, comparison of efficiencies for Cre and FLP in RMCE has not been made. We here examined the detailed process of RMCE with Cre and FLP in vitro using mutant loxP 2272 and three mutant FRTs (FRT G, FRT H, and FRT F3) and then quantitatively compared the RMCE reactions in vitro. Interestingly, in the in vitro reactions, the RMCE efficiency of Cre reached a plateau level of approximately 5% and did not proceed further, whereas that of FLPe reached approximately 12-13%, showing that FLPe reached a higher level of efficiency than Cre possibly when they were supplied at a very high concentration. Moreover, we quantitatively compared the production efficiency of E1-deleted adenovirus vector using the RMCE method with Cre or FLP. The results showed that FLPe was again found more efficient than Cre in RMCE reaction. Thus, although Cre is considered more active than, or similar to, FLPe, it may not be necessarily true for RMCE reaction. Possible reasons explaining these results are discussed. PMID- 21707875 TI - Reaching millennium development goal 4 - the Gambia. AB - To describe how, through a DSS in a rural area of The Gambia, it has been possible to measure substantial reductions in child mortality rates and how we investigated whether the decline paralleled the registered fall in malaria incidence in the country. METHODS: Demographic surveillance data spanning 19.5 years (1 April 1989-30 September 2008) from 42 villages around the town of Farafenni, The Gambia, were used to estimate childhood mortality rates for neonatal, infant, child (1-4 years) and under-5 age groups. Data were presented in five a priori defined time periods, and annual rates per 1000 live births were derived from Kaplan-Meier survival probabilities. RESULTS: From 1989-1992 to 2004 2008, under-5 mortality declined by 56% (95% CI: 48-63%), from 165 (95% CI: 151 181) per 1000 live births to 74 (95% CI: 65-84) per 1000 live births. In 1- to 4 year-olds, mortality during the period 2004-2008 was 69% (95% CI: 60-76%) less than in 1989-1992. The corresponding mortality decline in infants was 39% (95% CI: 23-52%); in neonates, it was 38% (95% CI: 13-66%). The derived annual under-5 mortality rates declined from 159 per 1000 live births in 1990 to 45 per 1000 live births in 2008, thus implying an attainment of MDG4 seven years in advance of the target year of 2015. CONCLUSION: Achieving MDG4 is possible in poor, rural areas of Africa through widespread deployment of relatively simple measures that improve child survival, such as immunisation and effective malaria control. PMID- 21707876 TI - Viral acute respiratory infections among infants visited in a rural hospital of southern Mozambique. AB - OBJECTIVES: To determine the epidemiology and clinical presentation of virus associated acute respiratory infections (ARI) in Mozambican infants. METHODS: A systematic selection of nasopharyngeal aspirates (n = 333), collected from infants younger than 12 months who visited Manhica District Hospital (southern Mozambique) with ARI during a 12 months respiratory syncitial virus surveillance, were tested for other common respiratory viruses. Four different polymerase chain reactions were used to diagnose rhinovirus (RV), influenza (Flu; A and B), adenovirus (ADV), human metapneumovirus (hMPV), parainfluenza (PIV; 1, 2, 3 and 4AB) and enterovirus (EV). RESULTS: At least one study virus was identified in more than half of the samples tested (185/333). Overall, 231 viruses were detected among 185 infants, listed in the order of prevalence: RV (26%), Flu (15%), ADV (14%), hMPV (7%), PIV (5%) and EV (3%). Acute respiratory infections (ARI) cases and viral episodes were seasonal and concentrate during the warm and the rainy season. Clinical features were similar among all study children regardless of the detection of virus, with the exception of ear discharge, which was more frequent among viral cases [6% (11/183) vs. 1% (2/144); P = 0.034]. Children with multiple viral infections had higher odds of severity such as nasal flaring and indrawing (OR = 2.7, P = 0.028 and OR = 3.8, P = 0.007, respectively) and higher odds of hospitalisation (OR = 4.42, P = 0.001, adjusted by age and sex). CONCLUSIONS: Viral ARI are frequent among infants visited in MHD. Strategies to prevent mild respiratory infections, and specially their complications, might alleviate health systems of source-limited settings. PMID- 21707877 TI - Can lay health workers increase the uptake of childhood immunisation? Systematic review and typology. AB - OBJECTIVES: Lay health workers (LHWs) are used in many settings to increase immunisation uptake among children. However, little is known about the effectiveness of these interventions. The objective of this review was to assess the effects of LHW interventions on childhood immunisation uptake. METHODS: We searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, British Nursing Index and Archive, AMED, POPLINE and WHOLIS, reference lists of included papers and relevant reviews, and contacted the authors of relevant papers. We selected randomised and non-randomised controlled trials, controlled before-after studies, and interrupted time series of any intervention delivered by LHWs and designed to increase childhood immunisation uptake. Two authors independently extracted data using a standard form and assessed risk of bias and evidence quality. FINDINGS: We identified twelve studies, ten of which were randomised controlled trials. Seven studies were conducted among economically disadvantaged populations in high-income countries. Five studies were from low- and middle-income countries. In ten studies, LHWs promoted childhood immunisation. In two studies, LHWs vaccinated children themselves. In most of the studies, the control group populations received no intervention or standard care. Most of the studies showed that LHWs increased immunisation coverage. However, study settings were diverse, allowing us to carry out only one meta-analysis including four studies. CONCLUSION: LHWs could make an important contribution to achieving the Millennium Development Goal for child health. However, more high quality studies are needed, particularly from LMICs. More studies are also needed to assess the effects of using LHWs to vaccinate children themselves. PMID- 21707878 TI - Political will for better health, a bottom-up process. AB - Lately, different voices in the global public health community have drawn attention to the interaction between the State and civil society in the context of reducing health inequities. A rights-based approach empowers people not only to claim their rights but also to demand accountability from the State. Lessons from history show that economic growth does not automatically have positive implications for population health. It may even be disruptive in the absence of strong stewardship and regulation by national and local public health authorities. The field research in which we have been involved over the past 20 years in the Philippines, Palestine, Cuba, and Europe confirms that organized communities and people's organizations can effectively pressure the state into action towards realizing the right to health. Class analysis, influencing power relations, and giving the State a central role have been identified as three key strategies of relevant social movements and NGOs. More interaction between academia and civil society organizations could contribute to enhance and safeguard the societal relevance of public health researches. Our own experience made us discover that social movements and public health researchers have a lot to learn from one another. PMID- 21707879 TI - Antimicrobial susceptibility of bacterial isolates from community acquired infections in Sub-Saharan Africa and Asian low and middle income countries. AB - OBJECTIVE: Antimicrobial resistance has arisen across the globe in both nosocomial and community settings as a consequence of widespread antibiotic consumption. Poor availability of laboratory diagnosis means that resistance frequently goes unrecognised and may only be detected as clinical treatment failure. In this review, we provide an overview of the reported susceptibility of common community acquired bacterial pathogens in Sub-Saharan Africa and Asia to the antibiotics that are most widely used in these areas. METHODS: We reviewed the literature for reports of the susceptibility of prevalent pathogens in the community in SSA and Asia to a range of commonly prescribed antibiotics. Inclusion criteria required that isolates were collected since 2004 and that they were obtained from either normally sterile sites or urine. The data were aggregated by region and by age group. RESULTS: Eighty-three studies were identified since 2004 which reported the antimicrobial susceptibilities of common bacterial pathogens. Different methods were used to assess in-vitro susceptibility in the different studies. The quality of testing (evidenced by resistance profiles) also varied considerably. For Streptococcus pneumoniae and Neisseria meningitidis most drugs maintained relatively high efficacy, apart from co-trimoxazole to which there were high levels of resistance in most of the pathogens surveyed. CONCLUSIONS: Compared with the enormous infectious disease burden and widespread use of antibiotics there are relatively few reliable data on antimicrobial susceptibility from tropical Asia and Africa upon which to draw firm conclusions, although it is evident that many commonly used antibiotics face considerable resistance in prevalent bacterial pathogens. This is likely to exacerbate morbidity and mortality. Investment in improved antimicrobial susceptibility testing and surveillance systems is likely to be a highly cost effective strategy and should be complemented by centralized and readily accessible information resources. PMID- 21707880 TI - High prevalence of distal sensory polyneuropathy in antiretroviral-treated and untreated people with HIV in Tanzania. AB - OBJECTIVES: To describe the prevalence of distal sensory polyneuropathy (DSP), a complication of both advanced HIV disease and of antiretroviral therapy (ART), amongst Tanzanians with HIV, on and off ART (including stavudine) with CD4 counts above and below 200 cells/MUl. METHODS: We recruited participants attending ART clinic into four groups: >6 months ART exposure and (i) CD4 < 200 cells/MUl or (ii) CD4 > 200 cells/MUl (ART/CD4 < 200 and ART/CD4 > 200, respectively); ART naive and (iii) CD4 < 200 cells/MUl or iv)CD4 > 200 cells/MUl (noART/CD4 < 200 and noART/CD4 > 200, respectively). Primary outcome was DSP, as defined by presence of at least one symptom and one sign. RESULTS: Of 326 evaluable participants, 81 (32 men, median age 38 years, median CD4 142 cells/MUl) were enrolled in the ART/CD4 < 200 group, 78 (17 men, median age 37 years, median CD4 345 cells/MUl) in ART/CD4 > 200, 81 (30 men, median age 37 years, median CD4 128 cells/MUl) in noART/CD4 < 200 and 86 (22 men, median age 33 years, median CD4 446 cells/MUl) in noART/CD4 > 200. Numbness was the most commonly reported symptom. DSP prevalence ranged from 43.2% in ART/CD4 < 200 to 20.9% in noART/CD4 > 200. DSP was more common among men (adjusted odds ratio [aOR] 1.9, 95% confidence interval [CI] 1.2-3.3) and older participants (aOR 2.7, 95% CI 1.1-6.2 for age 40 + vs. <30 years). CONCLUSION: Distal sensory polyneuropathy is common amongst those attending this clinic, even those with no ART exposure and a CD4 count above 200 cells/MUl. Stavudine and didanosine expose HIV-infected patients to an additional avoidable risk of DSP. Access to non-neurotoxic ART regimes as well as earlier HIV diagnosis and initiation of ART is needed. PMID- 21707881 TI - Detection, cellular localization and antibacterial activity of two lytic enzymes of Pediococcus acidilactici ATCC 8042. AB - AIM: In Pediococcus acidilactici ATCC 8042, two activities of peptidoglycan hydrolase (PGH) with lytic effect against Micrococcus lysodeikticus and Staphylococcus aureus have been detected. This work intends to elucidate the growth phase of maximum lytic activity, the localization and the effectiveness of the activity against pathogenic Gram-negative and Gram-positive bacteria. METHODS AND RESULTS: Cells were grown in MRS medium and collected at different growth stages, and the proteins were extracted. The highest PGH activity was found during the logarithmic growth phase in the protein fraction bound to the cell membrane. From this fraction, two distinct proteins bands (110- and 99-kDa) in SDS-PAGE were partially purified with a three-step procedure. Both bands showed lytic activity against M. lysodeikticus. Mass spectrometry analysis (LC/ESI MS/MS) indicated that the 110-kDa band corresponded to a protein of unknown function. The 99-kDa band corresponded to a N-acetylmuramidase that harboured catalytic sites with N-acetylmuramoyl-L-alanine amidase and N acetylglucosaminidase activities. Both proteins are reported in the Ped. acidilactici 7_4 genome. The fraction containing the concentrated proteins (110 and 99 kDa) inhibited the growth of several pathogenic strains as: Bacillus cereus, Listeria monocytogenes and Salmonella typhimurium. The growth of S. aureus was diminished by 3 logarithmic units as early as 0.5 h of growth, while inhibition of Escherichia coli and Ped. acidilactici was observed after 18 and 8 h, respectively (both in one logarithmic unit). The minimum inhibitory concentration against S. aureus was 10 MUg ml(-1). CONCLUSION: Pediococcus acidilactici harbours at least two lytic enzymes, one of them recognized as PGH for the first time, which exert antibacterial activity against several bacterial strains. SIGNIFICANCE AND IMPACT OF THE STUDY: Both PGH activities have a broad growth inhibition spectrum and could be used to control pathogenic bacteria. Because this activity comes from a lactic acid bacterium, it could be safely used in manufacturing processes of fermented foods. PMID- 21707882 TI - Typing of O26 enterohaemorrhagic and enteropathogenic Escherichia coli isolated from humans and cattle with IS621 multiplex PCR-based fingerprinting. AB - AIMS: This study evaluated a typing method of O26:H11 enterohaemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC) based on the variation in genomic location and copy numbers of IS621. METHODS AND RESULTS: Two multiplex PCRs, targeting either the left (5') or right (3') IS/chromosome junction of 12 IS621 insertion sites and one PCR specific of another truncated copy, were developed. Thirty-eight amplification profiles were observed amongst a collection of 69 human and bovine O26:H11 EHEC and EPEC. Seventy-one per cent of the 45 EHEC and EPEC with identical IS621 fingerprints within groups of two, three or four isolates had >85% pulsed field gel electrophoresis (PFGE) profile similarity, including four groups of epidemiologically related EHEC or EPEC, while most of the groups had <85% similarity between each others. Epidemiologically related EHEC from each of three independent outbreaks in Japan and Belgium also exhibited identical IS621 fingerprints and PFGE profiles. CONCLUSIONS: The IS621 fingerprinting and the PFGE are complementary typing assays of EHEC and EPEC; though, the former is less discriminatory. SIGNIFICANCE AND IMPACT OF THE STUDY: The IS621 printing method represents a rapid (24 h) first-line surveillance and typing assay, to compare and trace back O26:H11 EHEC and EPEC during surveys in farms, multiple human cases and outbreaks. PMID- 21707883 TI - Extension of Bacillus endospore gas dynamic heating studies to multiple species and test conditions. AB - AIMS: Shock wave-induced damage to a variety of Bacillus endospore species is studied for a wide range of postshock temperatures and test times in oxidative and non-oxidative gas environments. METHODS AND RESULTS: Bacillus atrophaeus and Bacillus subtilis endospores are nebulized into an aqueous aerosol, loaded into the Stanford aerosol shock tube (SAST) and subjected to shock waves of controlled strength. Endospores experience uniform test temperatures between 500 and 1000 K and pressures ranging from 2 to 7 atm, for either a short test time (~2.5 ms) or a relatively long test time (~45 ms). During this process, the bioaerosol is observed using in situ laser absorption and scattering diagnostics. Additionally, shock-treated samples are extracted for ex situ analysis including viability plating and flow cytometry. For short test times, results are consistent with previous studies; all endospore species begin to lose the ability to form colonies when shock-heated to temperatures above 500 K, while significant breakdown in morphology is observed for postshock temperatures above 700 K. Oxidative bath gases did not affect viability losses or morphological breakdown rates. Experiments with extended postshock test time showed increased viability loss with minimal morphological damage for shocks between 600 and 700 K. CONCLUSIONS: Genetic differences between B. subtilis and B. atrophaeus endospores do not confer noticeable gains in resistance to shock heating. Oxidative environments do not exacerbate shock-induced damage to endospores. Extended test time experiments reinforce our hypothesis that a temperature/time-dependent inactivation mechanism that does not involve morphological breakdown exists at low-to-moderate postshock temperatures. SIGNIFICANCE AND IMPACT OF THE STUDY: The methodology and experiments described in this paper extend the study of the interactions of endospores with shock/blast waves to new species and environmental conditions. PMID- 21707884 TI - Aerobic exercise improves insulin resistance and decreases body fat and serum levels of leptin in patients with hepatitis C virus. AB - AIM: Hepatitis C virus infection often complicates glucose intolerance, which can be caused by insulin resistance. Aerobic exercise can improve insulin resistance and decrease body fat in patients with diabetes. The aim of the present study is to clarify whether aerobic exercise improves insulin resistance and decreases body fat in patients with chronic hepatitis C (CH-C). METHODS: Seventeen patients with CH-C received nutrition education at entry and every two months thereafter. The following were evaluated before and after 6 months of walking at least 8000 steps/day monitored using a pedometer that started 2 months after entry: body composition, fat and muscle weight, visceral and subcutaneous fat areas (VFA and SFA, respectively), liver function tests, the Homeostatic Model of Assessment of Insulin Resistance (HOMA-IR), serum tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, adiponectin, leptin and the Short Form-36. RESULTS: Fifteen of the 17 patients completed the study protocol. Bodyweight, body mass index, fat weight, VFA, SFA, alanine aminotransferase level and HOMA-IR were significantly decreased at the end of the study (P = 0.004, =0.004, =0.008, =0.041, =0.001, =0.023 and =0.002, respectively). Serum levels of TNF-alpha, IL-6 and adiponectin did not change, whereas those of leptin significantly decreased (P = 0.002). CONCLUSION: Patients with CH-C could safely walk as aerobic exercise. Furthermore, walking improved insulin resistance and decreased body fat while lowering serum levels of leptin. PMID- 21707885 TI - High prevalence of hepatitis C virus infection in Airin district, Osaka, Japan: A hospital-based study of 1162 patients. AB - AIM: The Airin district, located in Nishinari-ku, Osaka, is known as Japan's largest slum area, and has the largest concentration of day laborers in the country. We conducted a large hospital-based study to determine the prevalence of hepatitis C virus (HCV) infection in the district. METHODS: The subjects were 1162 men (mean age, 57 +/- 9 years) admitted to the Osaka Socio-Medical Center Hospital between April 2005 and March 2008. Their case records were retrospectively reviewed. RESULTS: Anti-HCV antibodies were found in 218 (18.8%) patients; in contrast, only 24 (2.1%) patients had hepatitis B surface antigen. The prevalence of anti-HCV antibodies was 59% among the 122 patients admitted for liver diseases and 14% among the 1040 patients with other diseases. Among 927 patients with normal alanine aminotransferase levels (<=40 IU/L), 128 (13.8%) had anti-HCV antibodies. The prevalence of anti-HCV antibodies increased with age significantly (P < 0.001). At least 33 of the 218 (15%) patients with anti-HCV antibodies admitted to having a history of injection drug use. Interferon therapy was initiated in 26 patients (11 with genotype 1, 14 with genotype 2 and one unclassifiable), but only six completed their scheduled regimens. Hepatocellular carcinoma was diagnosed in 20 patients, but only seven had early-stage disease in which curative treatment, such as surgical hepatectomy or percutaneous ablation, was indicated. CONCLUSION: The prevalence of HCV infection in the Airin district is extremely higher than that in the Japanese general population. Patient education and strict action against illegal drug use are indispensable to prevent the spread of HCV infection from the district. PMID- 21707886 TI - Potential of the international scoring system for the diagnosis of Wilson disease to differentiate Japanese patients who need anti-copper treatment. AB - AIM: Patients with Wilson disease show complex clinical features. Accurate diagnosis at the initial clinical manifestation is important for patients to receive effective treatment with anti-copper agents. In this study, we assessed whether the international scoring system for the diagnosis of Wilson disease is a reliable tool for screening Japanese patients with primary copper toxicosis requiring anti-copper treatment. METHODS: Twenty-three Japanese patients suspected of Wilson disease were enrolled in this study. We performed long-range polymerase chain reaction to detect ATP7B mutations in this series. Finally, we retrospectively assessed the reliability of using a diagnostic score of 4 or more points as the cut-off for this scoring system. RESULTS: Ten patients were homozygous or compound heterozygous for ATP7B mutations including a novel mutation of 3837 bp deletion including 3 exons. The mutation would have been missed by the traditional analysis. Six patients were heterozygous for ATP7B mutations. Three of these six patients had additional diagnostic points. The other three patients were diagnosed as carriers of a mutant gene based on their low scores. One of the seven patients free from ATP7B mutation was affected by copper toxicosis. Though the score was 3 points based on increased urinary copper and copper-positive cirrhosis, anti-copper treatment promptly improved liver failure, which was likely due to idiopathic copper toxicosis. CONCLUSION: The international scoring system for diagnosis of Wilson disease is a fairly reliable tool for screening Japanese patients who need anti-copper treatment. Caution is needed for patients with possible idiopathic copper toxicosis because the maximal score is 4 points. PMID- 21707887 TI - Detection of D-3-phosphoglycerate dehydrogenase autoantibodies in patients with autoimmune hepatitis: Clinical significance evaluation. AB - AIM: D-3-phosphoglycerate dehydrogenase (3-PHGDH) was identified as a putative target of autoantibodies in autoimmune hepatitis (AIH). The aims of the present study were to detect anti-3-PHGDH in patients with AIH and other chronic liver diseases and to analyze their clinical relevance. METHODS: Human 3-PHGDH gene was cloned and expressed in Escherichia coli and used in enzyme-linked immunosorbent assays and Western blots. Serum from patients with AIH (n = 101), primary biliary cirrhosis (PBC, n = 122), chronic hepatitis C (CHC, n = 117), chronic hepatitis B (CHB, n = 112), and from patients with other autoimmune disease (n = 125) were investigated. RESULTS: The highest incidence and activity of anti-PHGDH was observed in AIH patients. Thirty-two of 40 untreated (80%) and 37 of 61 AIH patients treated with corticosteroid (60.7%) were positive. Antibody titers decreased significantly during corticosteroid treatment. 15.8% of PBC patients, 9.8% of CHB and 12.8% of CHC patients, were anti-PHGDH-positive, with less than 12% of patients positive with other autoimmune diseases via reactions with recombinant 3-PHGDH protein. CONCLUSION: Anti-PHGDH were detected in chronic liver diseases. They occur predominantly in AIH, and corticosteroid treatment seems to decrease antibody titers. Whether the antibodies are primary or secondary phenomena and whether they are related to the etiology or pathogenesis, at least in a subgroup of patients with chronic liver diseases, has still to be evaluated. PMID- 21707888 TI - Cancer preventive effect of pegylated interferon alpha-2b plus ribavirin in a real-life clinical setting in Japan: PERFECT interim analysis. AB - AIM: This study was conducted to clarify the incidence of hepatocellular carcinoma (HCC) and the factors contributing to its occurrence by following chronic hepatitis C patients who received pegylated interferon (PEG-IFN) alpha-2b plus ribavirin (RBV) combination therapy. METHODS: Patients who received PEG IFN alpha-2b and RBV combination therapy with no history of HCC or HCC within 3 months after the start of treatment were observed for the onset of HCC at 67 centers. RESULTS: Sustained virological response (SVR) was observed in 999 (53.5%) of 1865 patients eligible for analysis. During the observation period (median duration: 4 years and 3 months), HCC developed in 59 patients (3.1%). A significant difference was observed in the 5-year cumulative incidence of HCC between SVR and non-SVR patients (1.1% vs. 7.1%). Factors contributing to HCC selected in multivariate analysis were therapeutic efficacy, sex, age, alanine aminotransferase (ALT) level at 24 weeks after the end of treatment, and platelet count. Non-SVR patients with ALT improvement after the end of treatment had a significantly lower 5-year cumulative incidence of HCC than those without (3.4% vs. 11.0%). HCC developed in 10 patients who achieved SVR, and multivariate analysis indicated that ALT level at 24 weeks after the end of treatment was the only significant factor contributing to HCC. CONCLUSION: Several known risk factors for HCC contributed to HCC in patients who received PEG-IFN alpha-2b and RBV combination therapy, and ALT abnormality after the end of treatment contributes to the onset of HCC in both non-SVR and SVR patients. PMID- 21707889 TI - Mechanisms of functional specificity among plasma-membrane syntaxins in Arabidopsis. AB - Syntaxins and interacting SNARE proteins enable membrane fusion in diverse trafficking pathways. The Arabidopsis SYP1 family of plasma membrane-localized syntaxins comprises nine members, of which KNOLLE and PEN1 play specific roles in cytokinesis and innate immunity, respectively. To identify mechanisms conferring specificity of action, we examined one member of each subfamily-KNOLLE/SYP111, PEN1/SYP121 and SYP132-in regard to subcellular localization, dynamic behavior and complementation of knolle and pen1 mutants when expressed from the same promoters. Our results suggest that cytokinesis-specific syntaxin requires high level accumulation during cell-plate formation, which necessitates de novo synthesis rather than endocytosis of pre-made protein from the plasma membrane. In contrast, syntaxin in innate immunity does not need upregulation of expression but instead requires pathogen-induced and endocytosis-dependent retargeting to the infection site. This feature of PEN1 is not afforded by SYP132. Additionally, PEN1 could not substitute for KNOLLE because of SNARE domain differences, as revealed by protein chimeras. In contrast, SYP132 was able to rescue knolle as did KNOLLE-SYP132 chimeras. Unlike KNOLLE and PEN1, which appear to have evolved to perform specialized functions, SYP132 stably localized at the plasma membrane and thus might play a role in constitutive membrane fusion. PMID- 21707890 TI - A nonaggregating surfactant protein C mutant is misdirected to early endosomes and disrupts phospholipid recycling. AB - Interstitial lung disease in both children and adults has been linked to mutations in the lung-specific surfactant protein C (SFTPC) gene. Among these, the missense mutation [isoleucine to threonine at codon 73 = human surfactant protein C (hSP-C(I73T) )] accounts for ~30% of all described SFTPC mutations. We reported previously that unlike the BRICHOS misfolding SFTPC mutants, expression of hSP-C(I73T) induces lung remodeling and alveolar lipoproteinosis without a substantial Endoplasmic Reticulum (ER) stress response or ER-mediated intrinsic apoptosis. We show here that, in contrast to its wild-type counterpart that is directly routed to lysosomal-like organelles for processing, SP-C(I73T) is misdirected to the plasma membrane and subsequently internalized to the endocytic pathway via early endosomes, leading to the accumulation of abnormally processed proSP-C isoforms. Functionally, cells expressing hSP-C(I73T) demonstrated both impaired uptake and degradation of surfactant phospholipid, thus providing a molecular mechanism for the observed lipid accumulation in patients expressing hSP-C(I73T) through the disruption of normal phospholipid recycling. Our data provide evidence for a novel cellular mechanism for conformational protein associated diseases and suggest a paradigm for mistargeted proteins involved in the disruption of the endosomal/lysosomal sorting machinery. PMID- 21707891 TI - Deconstructing the mechanisms of angle closure with anterior segment optical coherence tomography. AB - BACKGROUND: To illustrate the common mechanisms of angle closure by observing the changes following a laser iridotomy and then cataract surgery with anterior segment optical coherence tomography. DESIGN: Retrospective interventional case series. PARTICIPANTS: Four patients with iridotrabecular contact. METHODS: The anterior chamber was imaged in different lighting conditions prior to and following a laser iridotomy and then cataract surgery. The images were superimposed on each other, using the interscleral spur line as a common baseline. MAIN OUTCOME MEASURES: Qualitative and quantitative analysis of the changes of the iris and the drainage angle. RESULTS: Iridotrabecular contact was seen in dark conditions in all patients. Iridotrabecular contact related to pupil block was abolished after a laser iridotomy. Persistent iridotrabecular contact following a laser iridotomy, due to a lens-induced mechanism, was abolished after cataract surgery. Iridotrabecular contact that persisted after a laser iridotomy and cataract surgery was due to a 'pure' plateau iris syndrome or peripheral anterior synechiae. These treatments lowered the height of the iris plane in the region posterior to the trabecular meshwork. CONCLUSION: Following a laser iridotomy and cataract surgery, there is posterior movement of the iris plane away from the trabecular meshwork, but iridotrabecular contact can persist due to the ciliary processes or peripheral anterior synechiae. These changes show that the risk of iridotrabecular contact depends on the height of the iris plane relative to the trabecular meshwork and the degree of physiologic pupil dilation, and that angle closure can be a multi-mechanism disease rather than a pure one. PMID- 21707892 TI - '... (D)eath, a necessary end, will come when it will come', (William Shakespeare, Julius Caesar, Act 2, Scene 2.). PMID- 21707893 TI - Palliative care, double effect and the law in Australia. AB - Care and decision-making at the end of life that promotes comfort and dignity is widely endorsed by public policy and the law. In ethical analysis of palliative care interventions that are argued potentially to hasten death, these may be deemed to be ethically permissible by the application of the doctrine of double effect, if the doctor's intention is to relieve pain and not cause death. In part because of the significance of ethics in the development of law in the medical sphere, this doctrine is also likely to be recognized as part of Australia's common law, although hitherto there have been no cases concerning palliative care brought before a court in Australia to test this. Three Australian States have, nonetheless, created legislative defences that are different from the common law with the intent of clarifying the law, promoting palliative care, and distinguishing it from euthanasia. However, these defences have the potential to provide less protection for doctors administering palliative care. In addition to requiring a doctor to have an appropriate intent, the defences insist on adherence to particular medical practice standards and perhaps require patient consent. Doctors providing end-of-life care in these States need to be aware of these legislative changes. Acting in accordance with the common law doctrine of double effect may not provide legal protection. Similar changes are likely to occur in other States and Territories as there is a trend towards enacting legislative defences that deal with the provision of palliative care. PMID- 21707894 TI - Scalp vein thrombosis mimicking giant cell arteritis relapse. AB - Scalp vein thrombosis is an unusual complication during giant cell arteritis. Revealed by headache, it can be misdiagnosed as a disease relapse. An ultrasound scan should rapidly be performed to make the diagnosis, avoiding inappropriate treatment escalation. PMID- 21707895 TI - Smooth muscle myopathy as an underrecognized manifestation of active systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with protean manifestations. We here present a case of unexplained diarrhoea and abdominal pain in a patient with SLE. Investigations revealed dilatation of stomach, small bowel and colonic wall, biliary and pancreatic ducts, renal collecting systems and ureters as well as thoracic aorta and major pulmonary arteries, as manifestations of a smooth muscle myopathy that was responsive to immunosuppressive therapy with cyclosporin A. PMID- 21707896 TI - Oncology workforce issues: the challenge of the outpatient clinic. AB - It is well-recognized that cancer prevalence is increasing and will continue to do so over the coming years. Adaptation of cancer services to this reality, however, has been slow. The oncology workforce, already short-staffed, will be overburdened if change does not occur in a timely manner. The results of this study seek to highlight the current workings of oncology outpatient clinics at this hospital, and to identify areas of deficiencies that need to be addressed. By presenting a portrait of our outpatient clinics, it is hoped that a discussion surrounding workforce issues can be actively engaged, as this is crucial in order to succeed in providing quality care for our cancer patients, and simultaneously to support and mentor our invaluable medical and allied health staff. PMID- 21707897 TI - Nutcracker syndrome. PMID- 21707898 TI - Fabry's disease cardiomyopathy. PMID- 21707899 TI - Acute obstructive suppurative cholangitis as a cause of acute kidney injury and rhabdomyolysis. PMID- 21707900 TI - Acute hepatitis B infection following blood transfusion. PMID- 21707901 TI - History of attempted suicide and the medical review of systems. PMID- 21707902 TI - A meta-analysis of crop pest and natural enemy response to landscape complexity. AB - Many studies in recent years have investigated the relationship between landscape complexity and pests, natural enemies and/or pest control. However, no quantitative synthesis of this literature beyond simple vote-count methods yet exists. We conducted a meta-analysis of 46 landscape-level studies, and found that natural enemies have a strong positive response to landscape complexity. Generalist enemies show consistent positive responses to landscape complexity across all scales measured, while specialist enemies respond more strongly to landscape complexity at smaller scales. Generalist enemy response to natural habitat also tends to occur at larger spatial scales than for specialist enemies, suggesting that land management strategies to enhance natural pest control should differ depending on whether the dominant enemies are generalists or specialists. The positive response of natural enemies does not necessarily translate into pest control, since pest abundances show no significant response to landscape complexity. Very few landscape-scale studies have estimated enemy impact on pest populations, however, limiting our understanding of the effects of landscape on pest control. We suggest focusing future research efforts on measuring population dynamics rather than static counts to better characterise the relationship between landscape complexity and pest control services from natural enemies. PMID- 21707903 TI - An interaction switch predicts the nested architecture of mutualistic networks. AB - Nested architecture is distinctive in plant-animal mutualistic networks. However, to date an integrative and quantitative explanation has been lacking. It is evident that species often switch their interactive partners in real-world mutualistic networks such as pollination and seed-dispersal networks. By incorporating an interaction switch into a novel multi-population model, we show that the nested architecture rapidly emerges from an initially random network. The model allowing interaction switches between partner species produced predictions which fit remarkably well with observations from 81 empirical networks. Thus, the nested architecture in mutualistic networks could be an intrinsic physical structure of dynamic networks and the interaction switch is likely a key ecological process that results in nestedness of real-world networks. Identifying the biological processes responsible for network structures is thus crucial for understanding the architecture of ecological networks. PMID- 21707905 TI - The bacterial second messenger c-di-GMP: mechanisms of signalling. AB - Cyclic-di-GMP (c-di-GMP) regulates many important bacterial processes. Freely diffusible intracellular c-di-GMP is determined by the action of metabolizing enzymes that allow integration of numerous input signals. c-di-GMP specifically regulates multiple cellular processes by binding to diverse target molecules. This review highlights important questions in research into the mechanisms of c di-GMP signalling and its role in bacterial physiology. PMID- 21707904 TI - In search of Brucella abortus type IV secretion substrates: screening and identification of four proteins translocated into host cells through VirB system. AB - Type IV secretion systems (T4SS) are specialized protein complexes used by many bacterial pathogens for the delivery of effector molecules that subvert varied host cellular processes. Brucella spp. are facultative intracellular pathogens capable of survival and replication inside mammalian cells. Brucella T4SS (VirB) is essential to subvert lysosome fusion and to create an organelle permissive for replication. One possible role for VirB is to translocate effector proteins that modulate host cellular functions for the biogenesis of the replicative organelle. We hypothesized that proteins with eukaryotic domains or protein-protein interaction domains, among others, would be good candidates for modulation of host cell functions. To identify these candidates, we performed an in silico screen looking for proteins with distinctive features. Translocation of 84 potential substrates was assayed using adenylate cyclase reporter. By this approach, we identified six proteins that are delivered to the eukaryotic cytoplasm upon infection of macrophage-like cells and we could determine that four of them, encoded by genes BAB1_1043, BAB1_2005, BAB1_1275 and BAB2_0123, require a functional T4SS for their delivery. We confirmed VirB-mediated translocation of one of the substrates by immunofluorescence confocal microscopy, and we found that the N-terminal 25 amino acids are required for its delivery into cells. PMID- 21707906 TI - Natural haemozoin modulates matrix metalloproteinases and induces morphological changes in human microvascular endothelium. AB - Severe malaria, including cerebral malaria (CM), is characterized by the sequestration of parasitized erythrocytes in the microvessels after cytoadherence to endothelial cells. Products of parasite origin, such as haemozoin (HZ), contribute to the pathogenesis of severe malaria by interfering with host inflammatory response. In human monocytes, HZ enhanced the levels of matrix metalloproteinase-9 (MMP-9), a protease involved in neuroinflammation. Here the effects of HZ on the regulation of MMPs by the human microvascular endothelial cell line HMEC-1 were investigated. Cells treated with natural (n)HZ appeared elongated instead of polygonal, and formed microtubule-like vessels on synthetic basement membrane. nHZ enhanced total gelatinolytic activity by inducing proMMP-9 and MMP-9 without affecting basal MMP-2. The level of the endogenous tissue inhibitor of MMP-9 (TIMP-1) was not altered by nHZ, while TIMP-2, the MMP-2 inhibitor, was enhanced. Additionally, nHZ induced MMP-1 and MMP-3, two enzymes sequentially involved in collagenolysis and proMMP-9 proteolytic activation. Lipid-free HZ did not reproduce nHZ effects. Present data suggest that the lipid moiety of HZ alters the MMP/TIMP balances and promotes the proteolytic activation of proMMP-9 in HMEC-1, thereby enhancing total gelatinolytic activity, cell activation and inflammation. These findings might help understanding the mechanisms of blood brain barrier damage during CM. PMID- 21707907 TI - Vimentin binding is critical for infection by the virulent strain of Japanese encephalitis virus. AB - Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, causes acute encephalitis with high mortality in humans. We used a pair of virulent (RP-9) and attenuated (RP-2ms) variants of JEV to pull down the cell surface molecules bound with JEV particle; their identities were revealed by LC-MS/MS analysis. One major protein bound with RP-9 and weakly with RP-2ms was identified as the intermediate filament protein vimentin. Infection of RP-9 but not that of RP-2ms was blocked by anti-vimentin antibodies and by recombinant-expressed vimentin proteins. Knockdown of vimentin expression reduced the levels of viral binding and viral production of RP-9, but not that of RP-2ms. The different vimentin dependency for JEV infection could be attributed to the major structural envelope protein, as the recombinant RP-9 with an E-E138K mutation became resistant to anti-vimentin blockage. Furthermore, RP-2ms mainly depended on cell surface glycosaminoglycans for viral binding and it became vimentin-dependent only when binding to glycosaminoglycans was blocked. Thus, we suggest that vimentin contributes to virulent JEV infection and might be a new target to intervene in this deadly infection. PMID- 21707908 TI - Civil war: is it all about disease and xenophobia? A comment on Letendre, Fincher & Thornhill. AB - Letendre, Fincher & Thornhill (2010) argue that pathogen intensity provides the ultimate explanation for why some countries are more prone to civil war than others. They argue that the economic and political factors highlighted in previous research on civil war are largely caused by underlying differences in pathogen intensity, and contend that disease proneness increases the risk of civil war through its effects on resource competition and xenophobia. They present empirical evidence that they interpret as consistent with their argument: a statistically significant correlation between pathogen intensity and civil war onset. In this comment, we raise concerns over their interpretation of the empirical evidence and their proposed causal mechanisms. We find that the data provide stronger evidence for the reverse causal relationship, namely that civil war causes disease to become more prevalent. This finding is consistent with the literatures on the public health effects of civil war as well as research on state capacity and public health. PMID- 21707909 TI - SPECT MIBI imaging for cardiac output and index in end stage renal disease. AB - To compare cardiac output (CO) and cardiac index (CI) and left ventricular ejection fraction (LVEF) in end-stage renal disease (ESRD) with a control group using gated single photon emission computed tomography (SPECT)/computed tomography (CT) imaging. Altered cardiovascular function with increased CO secondary to arterio-venous fistulas (AVF) for dialysis has been reported in patients with ESRD. Thirty-two patients (18 with AVF or graft) referred for pre renal transplant cardiac assessment using SPECT/CT were studied with 2 comparison groups, 42 normal weight (body mass index<30) and 46 obese (body mass index>30) patients. End-stage renal disease patients had overall reduced mean hemoglobin 11.6 mg/dL and elevated mean parathyroid hormone of 396 pg/mL. Gated SPECT using MIBI was performed after Bruce protocol apart from 4 renal patients who underwent cardiac stressing with adenosine. Cardiac output was calculated by product of stroke volume and resting heart rate and CI determined. Mean CI was 2.6 L/min/m(2) for renal disease group compared with 2.2 and 2.3 L/min/m(2) for the normal weight and obese groups, P=0.005 and 0.005 respectively (Wilcoxon's rank test). Cardiac output was increased for the renal group; 4.9 L/min, equal to the obese group but greater than normal weight group at 4.3 L/min. No significant difference in LVEF was seen between the 3 patient groups. No significant difference in CI or output was seen between the renal disease patients with AVF and those without fistulas. Cardiac ouput and CI, assessed using SPECT/CT, are increased in patients with ESRD. This may be independent of the presence of AVF or grafts and other factors such as anemia and hyperparathyroidism may contribute to this high output cardiac function. As LVEF is not increased for these patients, increased heart rate, may also contribute to elevated CO. PMID- 21707910 TI - CD11b+ leukocyte microparticles are associated with high-risk angiographic lesions and recurrent cardiovascular events in acute coronary syndromes. PMID- 21707911 TI - Earlier recovery of platelet function after discontinuation of treatment with ticagrelor compared with clopidogrel in patients with high antiplatelet responses. AB - BACKGROUND: The rate of recovery of platelet function after discontinuation of P2Y(12) inhibitors depends on the reversibility of the antiplatelet effect and the extent of the on-treatment response. P2Y(12) inhibition increases the bleeding risk in patients requiring surgery. OBJECTIVES: To evaluate recovery of platelet function after discontinuation of ticagrelor vs. clopidogrel in stable coronary artery disease (CAD) patients with high levels of platelet inhibition (HPI) during the ONSET/OFFSET study. METHODS: Patients received aspirin 75-100 mg per day and either ticagrelor 90 mg twice-daily or clopidogrel 75 mg daily for 6 weeks. This subanalysis included patients with HPI after the last dose of maintenance therapy, defined as: inhibition of platelet aggregation (IPA) > 75% 4 h post-dose (ADP 20 MUm, final extent); < 120 P2Y(12) reaction units 8 h post dose (VerifyNow P2Y(12) assay); or platelet reactivity index < 50% 8 h post-dose (VASP-P assay). RESULTS: IPA > 75% was observed in 39 out of 47 ticagrelor treated and 17 out of 44 clopidogrel-treated patients. The rate of offset of IPA over 4-72 h was greater with ticagrelor (IPA %/hour slope: -1.11 vs. -0.67 for clopidogrel; P < 0.0001). Mean IPA was significantly lower with ticagrelor than clopidogrel between 48 and 168 h post-dose (P < 0.01). Similar findings were observed with the other assays. The average time for IPA to decline from 30% to 10% was 50.8 h with ticagrelor vs. 110.4 h with clopidogrel. CONCLUSIONS: In patients with HPI, recovery of platelet function was more rapid after discontinuation of ticagrelor than clopidogrel leading to significantly greater platelet reactivity by 48 h after the last dose in the ticagrelor group. PMID- 21707912 TI - Lupus anticoagulant: performance of the tests as recommended by the latest ISTH guidelines. AB - OBJECTIVES: Lupus anticoagulant (LA) is clinically the most relevant among all antiphospholipid antibody tests. Recently, new guidelines for LA detection were published. The objective of this retrospective cohort study was to compare tests recommended under these guidelines with other methods used for LA detection. METHODS: The study group consisted of 336 subjects suffering from various autoimmune diseases. We used activated partial thromboplastin time (aPTT), diluted Russell viper venom time (dRVVT) and diluted prothrombin time (dPT) tests for LA detection together with a ratio between sensitive and insensitive aPTT reagent. We also tested if LA was dependent on beta(2) glycoprotein I (beta(2) GPI) using one of the recently described methods. RESULTS: All LA tests performed were associated with a history of thrombosis. The highest odds ratio (OR) for thrombosis was found for beta(2) GPI-dependent LA but sensitivity was low (OR = 8.4; specificity/sensitivity = 98%/15%). All LA tests showed a much stronger association with thrombosis than with pregnancy failure. CONCLUSIONS: LA tested by aPTT and/or dRVVT (at least one out of two tests positive), as recommended by the guidelines, was associated less strongly with a history of thrombosis (OR = 4.1) than either of these tests separately (OR = 5.0 and 4.3, respectively). With both tests positive ('double LA positivity') the association with thrombosis was stronger (OR = 6.5) compared with only one positive test. In fact, 'double LA positivity', detected by combinations of any of the tests studied, was markedly associated with a history of thrombosis. PMID- 21707913 TI - Mixed methods evaluation research for a mental health screening and referral clinical pathway. AB - RATIONALE: This study is an exemplar of mixed method evaluation research for development of a clinical pathway. AIM: To develop and evaluate an evidence based, feasible mental health screening and referral clinical pathway for Department of Veterans' Affairs-funded community nursing care of war veterans and war widows in the Australian context. METHODS: Mixed methods were applied to formulate and clinically evaluate an appropriate pathway. The pathway was applied at urban and rural sites for the nursing care of 97 war veteran and war widow clients. Evaluative data were collected from clients, their informal carers, community nurses, and general practitioners. Chart auditing and pre-post measures were undertaken. Collaboration occurred with an interdisciplinary design team. RESULTS: The final modified six-page pathway includes use of validated screening tools (Kessler Psychological Distress Scale [K10]) and Alcohol Use Disorder Identification Test, appropriate referral information, directions for support and health-promoting education, and evidence-based guidelines. IMPLICATIONS FOR PRACTICE: The clinical pathway is a useful, tested, evidence-based guide for generalist community nurses to identify and suitably respond to common mental healthcare needs of war veterans and war widows. The pathway provides outcomes acceptable to clients and their carers, nurses and doctors. CONCLUSIONS: This study provides an evaluated clinical pathway for generalist community nurses to screen for mental health difficulties, make appropriate referrals as required and to support war veteran and war widow clients. However, the study also shows how research can be used to develop and evaluate practical, evidence-based clinical pathways. PMID- 21707914 TI - Enhanced mobilization of the bone marrow-derived circulating progenitor cells by intracoronary freshly isolated bone marrow cells transplantation in patients with acute myocardial infarction. AB - Autologous bone marrow cell transplantation (BMCs-Tx) is a promising novel option for treatment of cardiovascular disease. We analysed in a randomized controlled study the influence of the intracoronary autologous freshly isolated BMCs-Tx on the mobilization of bone marrow-derived circulating progenitor cells (BM-CPCs) in patients with acute myocardial infarction (AMI). Sixty-two patients with AMI were randomized to either freshly isolated BMCs-Tx or to a control group without cell therapy. Peripheral blood (PB) concentrations of CD34/45(+) - and CD133/45(+) circulating progenitor cells were measured by flow cytometry in 42 AMI patients with cell therapy as well as in 20 AMI patients without cell therapy as a control group on days 1, 3, 5, 7, 8 and 3, 6 as well as 12 months after AMI. Global ejection fraction (EF) and the size of infarct area were determined by left ventriculography. We observed in patients with freshly isolated BMCs-Tx at 3 and 12 months follow up a significant reduction of infarct size and increase of global EF as well as infarct wall movement velocity. The mobilization of CD34/45(+) and CD133/45(+) BM-CPCs significantly increased with a peak on day 7 as compared to baseline after AMI in both groups (CD34/45(+): P < 0.001, CD133/45(+): P < 0.001). Moreover, this significant mobilization of BM-CPCs existed 3, 6 and 12 months after cell therapy compared to day 1 after AMI. In control group, there were no significant differences of CD34/45(+) and CD133/45(+) BM-CPCs mobilization between day 1 and 3, 6 and 12 months after AMI. Intracoronary transplantation of autologous freshly isolated BMCs by use of point of care system in patients with AMI may enhance and prolong the mobilization of CD34/45(+) and CD133/45(+) BM-CPCs in PB and this might increase the regenerative potency after AMI. PMID- 21707916 TI - C-peptide promotes lesion development in a mouse model of arteriosclerosis. AB - Patients with insulin resistance and early type 2 diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. Typically, these patients show elevated serum levels of the proinsulin cleavage product C-peptide and immunohistochemical data from our group revealed C-peptide deposition in early lesions of these individuals. Moreover, in vitro studies suggest that C-peptide could promote atherogenesis. This study examined whether C peptide promotes vascular inflammation and lesion development in a mouse model of arteriosclerosis. ApoE-deficient mice on a high fat diet were treated with C peptide or control injections for 12 weeks and the effect on lesion size and plaque composition was analysed. C-peptide treatment significantly increased C peptide blood levels by 4.8-fold without having an effect on glucose or insulin levels, nor on the lipid profile. In these mice, C-peptide deposition in atherosclerotic plaques was significantly increased compared with controls. Moreover, lesions of C-peptide-treated mice contained significantly more macrophages (1.6 +/- 0.3% versus 0.7 +/- 0.2% positive area; P < 0.01) and more vascular smooth muscle cells (4.8 +/- 0.6% versus 2.4 +/- 0.3% positive area; P < 0.01). Finally, lipid deposition measured by Oil-red-O staining in the aortic arch was significantly higher in the C-peptide group compared with controls. Our results demonstrate that elevated C-peptide levels promote inflammatory cell infiltration and lesion development in ApoE-deficient mice without having metabolic effects. These data obtained in a mouse model of arteriosclerosis support the hypothesis that C-peptide may have an active role in atherogenesis in patients with diabetes and insulin resistance. PMID- 21707917 TI - Alterations in the contractile phenotype of the bladder: lessons for understanding physiological and pathological remodelling of smooth muscle. AB - The contractile properties of the urinary bladder are changed by the conditions of normal development and partial bladder outlet obstruction. This change in the contractile phenotype is accompanied by changes in the regulatory cascades and filaments that regulate contractility. This review focuses on such changes during the course of normal development and in response to obstruction. Our goal is to discuss the experimental evidence that has accumulated from work in animal models and correlate these findings with the human voiding phenotype. PMID- 21707918 TI - Caveolin induces cardioprotection through epigenetic regulation. AB - Lipid rafts represent a sub-compartment of the plasma membrane that co-ordinate and regulate varieties of signalling processes, whereas caveolins are the integral membrane protein of the lipid raft. Recent evidence demonstrated the pivotal role of caveolins in cardioprotection against ischaemic injury, although their mechanism of action is not clear. However, new understanding of epigenetic modification during ischaemia reperfusion suggests additional targeted approaches that have not been explored before. To study the role of caveolin on epigenetic regulation, isolated mouse heart was prepared from wild-type (WT) and caveolin-1 knockout (Cav-1 KO) mouse and preconditioned them with four cyclic episodes of ischaemia/reperfusion followed by 30 min. global ischaemia and 120 min. reperfusion. We found that Cav-1 KO mouse abolished the acetylation of histone (H3 and H4) and increased the methylation of histone in the preconditioned heart. The increased histone methylation was significantly correlated with an increased level of histone methyltranferase G9a protein and increased the level of histone decaetylase (HDAC) activity. Cav-1 KO mouse also decreased the translocation of forkhead transcription factor (FOXO3a) to the nucleus and reduced the induction of the expression of SIRT-1 in the preconditioned heart. Cardioprotective property of Cav-1 was further confirmed by reduced ventricular function, increased cardiomyocyte apoptosis, increased expression of junas kinase (JNK) and Bax and decreased expression of phospho-adenosine monophosphate-activated protein kinase (AMPK), phospho-AKT and B cell lymphoma-2 (Bcl-2) in Cav-1 KO preconditioned heart. The results clearly indicate that Cav-1 induces cardioprotection through epigenetic regulation. PMID- 21707915 TI - Caveolins in rhabdomyosarcoma. AB - Caveolins are scaffolding proteins that play a pivotal role in numerous processes, including caveolae biogenesis, vesicular transport, cholesterol homeostasis and regulation of signal transduction. There are three different isoforms (Cav-1, -2 and -3) that form homo- and hetero-aggregates at the plasma membrane and modulate the activity of a number of intracellular binding proteins. Cav-1 and Cav-3, in particular, are respectively expressed in the reserve elements (e.g. satellite cells) and in mature myofibres of skeletal muscle and their expression interplay characterizes the switch from muscle precursors to differentiated elements. Recent findings have shown that caveolins are also expressed in rhabdomyosarcoma, a group of heterogeneous childhood soft-tissue sarcomas in which the cancer cells seem to derive from progenitors that resemble myogenic cells. In this review, we will focus on the role of caveolins in rhabdomyosarcomas and on their potential use as markers of the degree of differentiation in these paediatric tumours. Given that the function of Cav-1 as tumour conditional gene in cancer has been well-established, we will also discuss the relationship between Cav-1 and the progression of rhabdomyosarcoma. PMID- 21707919 TI - Laypeoples' preferred sources of health information on the emergency management of tooth avulsion. AB - AIM: When planning nationwide information campaigns on the emergency management of tooth avulsion, the populations' preference to different modes of information delivery should be taken into consideration. We currently lack information on that. The aim of this study was, therefore, to assess laypeoples' preferred sources of information on the emergency management of tooth avulsion. METHODOLOGY: This was a joint study undertaken by experts in media and experts in dental traumatology. Interview-assisted questionnaires were conducted on a sample of 579 adults from Kuwait. Subjects were asked to choose their three preferred sources of information on the emergency management of tooth avulsion. Subjects' responses and sociodemographic data were registered. The data were descriptively analyzed, and a chi-square test was used to assess the relation of the subjects' preferences to their registered demographics. RESULTS: The Internet, health care professionals, and TV were the three most preferred sources of information on the emergency management of tooth avulsion across all groups, regardless of the sociodemographic characteristics. Younger adults, singles and subjects with higher education significantly preferred the Internet. Older adults preferred TV. Family was a preferred source in geographic districts populated with extended families, while friends were a preferred source in geographic districts populated by expatriates. CONCLUSIONS: Younger people and those with higher education can be effectively targeted through the Internet, while it is more effective to target older people through TV. Information, on tooth avulsion management, given by health care professionals is preferred across all population segments. PMID- 21707921 TI - Applications and trends in systems biology in biochemistry. AB - Systems biology has received an ever increasing interest during the last decade. A large amount of third-party funding is spent on this topic, which involves quantitative experimentation integrated with computational modeling. Industrial companies are also starting to use this approach more and more often, especially in pharmaceutical research and biotechnology. This leads to the question of whether such interest is wisely invested and whether there are success stories to be told for basic science and/or technology/biomedicine. In this review, we focus on the application of systems biology approaches that have been employed to shed light on both biochemical functions and previously unknown mechanisms. We point out which computational and experimental methods are employed most frequently and which trends in systems biology research can be observed. Finally, we discuss some problems that we have encountered in publications in the field. PMID- 21707920 TI - Tissue reactions to subperiosteal onlays of demineralized xenogenous dentin blocks in rats. AB - OBJECTIVES: This study was undertaken to examine the influence of partial demineralization of xenogenous dentin on bone formation in an osteoconductive environment. MATERIALS AND METHODS: Sixty dentin blocks, 2-3 mm thick and 4 mm in diameter, were prepared from developing teeth of young pigs. Forty blocks were demineralized in 24% ethylenediaminetetraacetic acid (pH 7.0) for 1, 2, 6 or 12 h. Forty adult rats divided into eight groups with five rats in each group were used. A sagittal midcranial incision was made from the occipital to the frontal region. Through a subperiostal dissection, a pocket was created on each side of the skull. One demineralized block was placed on one side, and a non demineralized block was placed on the contralateral side, or the pocket was left empty as controls. Thus, eight experimental groups with five rats in each were formed. RESULTS: Resorption increased significantly with increasing degree of demineralization while bone formation increased significantly with increasing degree of demineralization, provided inflammation was compensated for. This suggests an important role for inflammation or infection control during the healing period of osteogenic implants to optimize osseous integration in an osteoconductive environment. CONCLUSION: Partial demineralization of xenogenous dentin blocks may provide a method for optimizing the integration of dentin onlays in an osteoconductive environment, thus stabilizing the implant and slowing down replacement resorption. PMID- 21707922 TI - C-Terminal extension of a plant cysteine protease modulates proteolytic activity through a partial inhibitory mechanism. AB - The amino acid sequence of ervatamin-C, a thermostable cysteine protease from a tropical plant, revealed an additional 24-amino-acid extension at its C-terminus (CT). The role of this extension peptide in zymogen activation, catalytic activity, folding and stability of the protease is reported. For this study, we expressed two recombinant forms of the protease in Escherichia coli, one retaining the CT-extension and the other with it truncated. The enzyme with the extension shows autocatalytic zymogen activation at a higher pH of 8.0, whereas deletion of the extension results in a more active form of the enzyme. This CT extension was not found to be cleaved during autocatalysis or by limited proteolysis by different external proteases. Molecular modeling and simulation studies revealed that the CT-extension blocks some of the substrate-binding unprimed subsites including the specificity-determining subsite (S2) of the enzyme and thereby partially occludes accessibility of the substrates to the active site, which also corroborates the experimental observations. The CT extension in the model structure shows tight packing with the catalytic domain of the enzyme, mediated by strong hydrophobic and H-bond interactions, thus restricting accessibility of its cleavage sites to the protease itself or to the external proteases. Kinetic stability analyses (T(50) and t(1/2) ) and refolding experiments show similar thermal stability and refolding efficiency for both forms. These data suggest that the CT-extension has an inhibitory role in the proteolytic activity of ervatamin-C but does not have a major role either in stabilizing the enzyme or in its folding mechanism. PMID- 21707923 TI - Motion of the Ca2+-pump captured. AB - Studies of ion pumps, such as ATP synthetase and Ca(2+)-ATPase, have a long history. The crystal structures of several kinds of ion pump have been resolved, and provide static pictures of mechanisms of ion transport. In this study, using fast-scanning atomic force microscopy, we have visualized conformational changes in the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) in real time at the single molecule level. The analyses of individual SERCA molecules in the presence of both ATP and free Ca(2+) revealed up-down structural changes corresponding to the Albers-Post scheme. This fluctuation was strongly affected by the ATP and Ca(2+) concentrations, and was prevented by an inhibitor, thapsigargin. Interestingly, at a physiological ATP concentrations, the up-down motion disappeared completely. These results indicate that SERCA does not transit through the shortest structure, and has a catalytic pathway different from the ordinary Albers-Post scheme under physiological conditions. PMID- 21707924 TI - The tandemly repeated domains of a beta-propeller phytase act synergistically to increase catalytic efficiency. AB - beta-Propeller phytases (BPPs) with tandemly repeated domains are abundant in nature. Previous studies have shown that the intact domain is responsible for phytate hydrolysis, but the function of the other domain is relatively unknown. In this study, a new dual-domain BPP (PhyH) from Bacillus sp. HJB17 was identified to contain an incomplete N-terminal BPP domain (PhyH-DI, residues 41 318) and a typical BPP domain (PhyH-DII, residues 319-644) at the C-terminus. Purified recombinant PhyH and PhyH-DII required Ca(2+) for phytase activity, showed activity at low temperatures (0-35 degrees C) and pH 6.0-8.0, and remained active (at 37 degrees C) after incubation at 60 degrees C and pH 6.0 12.0. Compared with PhyH-DII, PhyH is catalytically more active against phytate (catalytic constant 27.72 versus 4.17 s(-1)), which indicates the importance of PhyH-DI in phytate degradation. PhyH-DI was found to hydrolyze phytate intermediate D-Ins(1,4,5,6) P(4), and to act synergistically (a 1.2-2.5-fold increase in phosphate release) with PhyH-DII, other BPPs (PhyP and 168PhyA) and a histidine acid phosphatase. Furthermore, fusion of PhyH-DI with PhyP or 168PhyA significantly enhanced their catalytic efficiencies. This is the first report to elucidate the substrate specificity of the incomplete domain and the functional relationship of tandemly repeated domains in BPPs. We conjecture that dual-domain BPPs have succeeded evolutionarily because they can increase the amount of available phosphate by interacting together. Additionally, fusing PhyH-DI to a single-domain phytase appears to be an efficient way to improve the activity of the latter. PMID- 21707925 TI - Brain pharmacokinetics of two prolyl oligopeptidase inhibitors, JTP-4819 and KYP 2047, in the rat. AB - Prolyl oligopeptidase (PREP) inhibitors are potential drug candidates for the treatment of neurological disorders, but little is known about their ability to cross the blood-brain barrier and to reach the target site. This study characterizes brain pharmacokinetics of two potent PREP inhibitors, JTP-4819 and KYP-2047. Firstly, the in vitro permeability (P(app) ) of JTP-4819 and KYP-2047 through a bovine brain microvessel endothelial cell monolayer was assessed. Then, the in vivo brain/blood ratio was determined for the total brain and plasma concentrations and also for the unbound extracellular drug concentrations after a single dose (50 MUmol/kg i.p.). KYP-2047 had a significantly higher P(app) than JTP-4819. In vivo, KYP-2047 had higher total and unbound brain/blood ratios. KYP 2047 was equally distributed between the cortex, hippocampus and striatum. In the case of JTP-4819, the unbound brain extracellular concentrations could not be readily predicted from the unbound blood levels, probably because of its poor membrane penetration properties. KYP-2047 displayed a better ability to reach the intracellularly located brain PREP, and it inhibited this enzyme more effectively than JTP-4819 after an equimolar single dose. In conclusion, KYP-2047 showed better brain penetration characteristics than JTP-4819 both in vitro and in vivo. KYP-2047 is a brain-penetrating, potent and long-acting PREP inhibitor; thus, it represents a convenient pharmacological tool for assessing the potential of PREP as a drug target. PMID- 21707926 TI - Gepirone-ER treatment of low sexual desire associated with depression in women as measured by the DeRogatis Inventory of Sexual Function (DISF) fantasy/cognition (desire) domain--a post hoc analysis. AB - INTRODUCTION: Gepirone-extended release (ER) is effective in treating hypoactive sexual desire disorder (HSDD), as measured by the percent of females with HSDD that no longer met criteria for HSDD treatment. Another approach is to determine treatment effect on sexual desire using a recognized rating scale for sexual function. Because gepirone-ER has antidepressant and anxiolytic effects, investigation of these effects on sexual desire is appropriate. AIM: The aim of this study was to determine whether gepirone-ER has positive effects on sexual desire as measured by the DeRogatis Inventory of Sexual Function (DISF) in a post hoc analysis of 8- and 24-week studies and if this gepirone effect is independent of its antidepressant or anxiolytic activity. MAIN OUTCOME MEASURES: The main outcome measures used for this study were the Hamilton Depression Rating Scale (HAMD-25), change from baseline (CFB), and DISF CFB. METHODS: Three hundred thirty-four women selected for depressive symptoms, not sexual dysfunction, received gepirone-ER (40-80 mg/day) in a controlled study of atypical depression using the HAMD-25 to measure antidepressant efficacy and a DISF subscale (domain I) to measure sexual cognition/fantasy (desire). After treatment, a 50% reduction from baseline HAMD-25 score identified antidepressant responders. Item 12 of HAMD scale (psychic anxiety) was used to define anxiolytic response scores of 0, 1 as responders, and scores of 2, 3, and 4 as nonresponders. RESULTS: Gepirone-ER had no significant antidepressant or an anxiolytic effect in study 134006; however, DISF results demonstrate that gepirone-ER improves sexual desire in short term (P=0.043) and long term (P=0.006). Both gepirone-ER antidepressant and anxiolytic responders have statistically significant improved sexual desire. Gepirone-ER antidepressant and anxiolytic nonresponders also show statistically significant improvement. CONCLUSIONS: In depressed women, gepirone-ER has three mechanisms of action affecting sexual desire: an antidepressant effect, an anxiolytic effect, and a pro-sexual effect. Gepirone-ER improves sexual desire from the 24th to the 50th percentile according to population norms for the DISF. PMID- 21707927 TI - Impact of systemically active neurohumoral factors on the erectile response of the rat. AB - INTRODUCTION: Mean arterial pressure (MAP) and specific regulation of penile blood flow are the primary determinants of an erection. While this concept is well recognized, the differential relationship between systemically acting vasoactive factors on arterial pressure and erectile responses is not well described. AIM: The aim of this study was to determine how the modification of systemic levels of neurohumoral factors impacts on the magnitude and efficiency of the erectile response. MAIN OUTCOME MEASURES: The main outcome measures for this study are changes in MAP and intracavernosal pressure (ICP) following electrostimulation of the cavernous nerve. METHODS: Anesthetized adult, male Sprague-Dawley rats were catheterized for measuring MAP (carotid), ICP, and drug administration (vena cava). Erections were induced via cavernous nerve electrostimulation. Vasoactive drug infusions were used to produce changes in MAP levels including: hexamethonium, angiotensin II (ANGII)+/-hexamethonium, methoxamine+/-hexamethonium, losartan, MAHMA NONOate, and terbutaline. RESULTS: In general, ICP and MAP were linearly correlated regardless of treatment. Hexamethonium markedly dropped MAP and proportionately decreased the magnitude of the erectile response. ANGII or methoxamine given to hexamethonium-pretreated or untreated rats increased MAP similarly, but produced contrasting effects on erectile responses. ANGII-induced pressor responses were associated with increased erectile responses whereas all methoxamine treatments markedly decreased erectile responses. Depressor changes with losartan or terbutaline, but not MAHMA NONOate, also impacted negatively on the efficiency of the erectile responses at lower arterial pressures. CONCLUSIONS: In general, the magnitude of the erectile responses was found to be dependent upon the level of MAP, although the mechanism by which arterial pressure was changed impacted substantially on the characteristics of the relationship. The major finding was that circulation wide alpha-adrenoceptor stimulation was extremely deleterious to erectile responses whereas global stimulation of ANG II receptors was actually proerectile. Overall, the results indicate that neurohumoral specificity in systemic hemodynamic control is also critical in establishing the optimal erectile environment in rats. PMID- 21707928 TI - A randomized, double-blind, placebo-controlled, parallel study to assess the efficacy and safety of once-a-day tadalafil in men with erectile dysfunction who are naive to PDE5 inhibitors. AB - INTRODUCTION: The majority of subjects included in previous tadalafil once-a-day clinical trials were non-naive to previous phosphodiesterase 5 (PDE5) inhibitors on demand. A study on PDE5 inhibitor naive subjects was therefore warranted. AIM: To evaluate the efficacy and safety of once-a-day tadalafil in PDE5 inhibitor naive men with erectile dysfunction (ED). MAIN OUTCOMES MEASURES: Primary efficacy end points were changes from baseline to end point in the International Index of Erectile Function (IIEF) Erectile Function (EF) domain score and the per subject proportion of "yes" responses to sexual encounter profile (SEP) question 2 (SEP2) and question 3 (SEP3). METHODS: PDE5 inhibitor-naive men with ED (N=217) were randomized in a 1:2 ratio to receive placebo or tadalafil 5 mg once a day for 12 weeks. Enrollment began in January 2009 and the last subject completed in January 2010. RESULTS: At end point, least square mean change from baseline IIEF EF domain score (7.3 vs. 3.4), SEP2 (23.8% vs. 12.2%) and SEP3 (39.5% vs. 21.5%), was significantly larger for tadalafil vs. placebo (all P<0.001). The most common adverse events (AEs) in tadalafil-treated subjects were back pain, nasopharyngitis, dyspepsia, headache, and myalgia. Four subjects (2.7%) in the tadalafil group and one subject (1.4%) in the placebo group discontinued because of AEs. CONCLUSIONS: In PDE5 inhibitor-naive men, tadalafil once a day significantly improved EF compared with placebo. Safety results were consistent with previous tadalafil once-a-day clinical trials. PMID- 21707929 TI - CCL5 (RANTES) gene polymorphisms in pulmonary tuberculosis patients of south India. AB - The chemokine CCL5 is known to play an important role in the formation of granuloma during infection with Mycobacterium tuberculosis. Production of CCL5 is influenced by polymorphisms in the CCL5 gene. Hence, in the present study, we investigated whether polymorphisms in the promoter and intron regions of CCL5 gene are associated with susceptibility or resistance to pulmonary tuberculosis in south Indian population. Polymorphisms in the promoter (-403G/A and -28C/G) and intron (In1.1T/C) regions of CCL5 gene were studied in 212 pulmonary tuberculosis (PTB) patients and 213 healthy controls (HCs). Allele and genotype frequencies of CCL5 gene polymorphisms were not different between PTB patients and HCs. When the haplotype and diplotype frequencies were compared, a significantly decreased frequencies of the haplotype A-C-C [P = 0.037; Odds ratio (OR): 0.57; 95% confidence interval (CI): 0.34-0.97] and the diplotype G/A-T/C (P = 0.017; OR: 0.46; 95% CI: 0.24-0.88) were observed among PTB patients when compared with HCs. However, the significant differences observed for the haplotype and the diplotype were lost when corrected for multiple comparisons [Bonferroni correction: A-C-C P corrected (P(c) ) = 0.148 and G/A-T/C P(c) = 0.136]. Though the present results suggest that the CCL5 gene haplotype A-C-C and the diplotype G/A-T/C may be associated with resistance to PTB, further studies with increased sample size may be useful to confirm this present finding as well as to understand the role of CCL5 haplotype and diplotype on genetic susceptibility to TB. PMID- 21707930 TI - Muscle fatigue and excitation-contraction coupling responses following a session of prolonged cycling. AB - AIM: The mechanisms underlying the fatigue that occurs in human muscle following sustained activity are thought to reside in one or more of the excitation contraction coupling (E-C coupling) processes. This study investigated the association between the changes in select E-C coupling properties and the impairment in force generation that occurs with prolonged cycling. METHODS: Ten volunteers with a peak aerobic power (VO(2peak)) of 2.95 +/- 0.27 L min(-1) (mean +/- SE), exercised for 2 h at 62 +/- 1.3%. Quadriceps function was assessed and tissue properties (vastus lateralis) were measured prior to (E1-pre) and following (E1-post) exercise and on three consecutive days of recovery (R1, R2 and R3). RESULTS: While exercise failed to depress the maximal activity (V(max) ) of the Na(+) ,K(+) -ATPase (P = 0.10), reductions (P < 0.05) were found at E1 post in V(max) of sarcoplasmic reticulum Ca(2+) -ATPase (-22%), Ca(2+) -uptake ( 26%) and phase 1(-33%) and 2 (-38%) Ca(2+) -release. Both V(max) and Ca(2+) release (phase 2) recovered by R1, whereas Ca(2+) -uptake and Ca(2+) -release (phase 1) remained depressed (P < 0.05) at R1 and at R1 and R2 and possibly R3 (P < 0.06) respectively. Compared with E1-pre, fatigue was observed (P < 0.05) at 10 Hz electrical stimulation at E1-post (-56%), which persisted throughout recovery. The exercise increased (P < 0.05) overall content of the Na(+), K(+)-ATPase (R1, R2 and R3) and the isoforms beta2 (R1, R2 and R3) and beta3 (R3), but not beta1 or the alpha-isoforms (alpha1, alpha2 and alpha3). CONCLUSION: These results suggest a possible direct role for Ca(2+)-release in fatigue and demonstrate a single exercise session can induce overlapping perturbations and adaptations (particularly to the Na(+), K(+)-ATPase). PMID- 21707931 TI - Increased systolic blood pressure after mild cold and rewarming: relation to cold induced thermogenesis and age. AB - AIM: Higher winter mortality in elderly has been associated with augmented systolic blood pressure (SBP) response and with impaired defense of core temperature. Here we investigated whether the augmented SBP upon mild cold exposure remains after a rewarming period, and whether SBP changes are linked to thermoregulation. Therefore, we tested the following hypotheses: cold-induced increase in SBP (1) remains augmented after rewarming in elderly compared to young adults (2) is related to non-shivering thermogenesis (NST) upon mild cold (3) is related to vasoconstriction upon mild cold. METHODS: Blood pressure, energy expenditure (EE), skin and core temperature, skin perfusion (abdomen, forearm, both sides of hand) and % body fat were measured in 12 young adults (Y) and 12 elderly (E). Supine subjects were exposed to a thermoneutral baseline 0.5 h (T(air) = 30.1 degrees C), 1 h mild cold (T(air) = 20.7 degrees C), 1 h rewarming (T(air) = 34.8 degrees C) and 1 h baseline (T(air) = 30.5 degrees C). RESULTS: Upon mild cold only the young adults showed significant NST (Y: +2.5 +/- 0.6 W m(-2), P < 0.05). No significant age effects in vasoconstriction were observed. After rewarming per cent change in SBP (%DeltaSBP) remained significantly increased in both age groups and was augmented in elderly (Y: +5.0% +/- 1.2% vs. E: +14.7% +/- 3.1%, P < 0.05). Regression analysis revealed that %DeltaSBP significantly related to DeltaEE upon mild cold (P < 0.01, r(2) = 0.35) and in elderly also to %body fat (P < 0.02, r(2) = 0.57). CONCLUSION: Individual changes in SBP after rewarming correlate negatively to NST. Elderly did not show NST, which explains the greater SBP increase in this group. In elderly a relatively large %body fat protected against the adverse effects of mild cold. PMID- 21707932 TI - Transferring from an acute hospital and settling into a subacute facility: the experience of patients with dementia. AB - BACKGROUND: In a Melbourne metropolitan health network, patients with dementia can have difficulty settling into a subacute rehabilitation facility after transfer from the acute hospital. AIMS AND OBJECTIVES: To understand how older patients with mild to moderate dementia experienced the transfer from acute to subacute care and settling-in period. DESIGN: A descriptive design was used. Eight patients with mild to moderate dementia were recruited, one to 5 days after transfer. METHOD: A qualitative method using in-depth interviews was used. The data were analysed using content analysis. RESULTS: Four main themes were identified: 'Settling into a new environment', 'staff attitudes to people with dementia', 'loss of control' and 'family support'. CONCLUSIONS: Person-centred care that comes from the perspective of respect for the individual transcends all these issues. People with dementia require more support to settle after transfer. Family involvement can assist in facilitating a smooth transition. IMPLICATIONS FOR PRACTICE: Nurses who understand the specific needs of patients with dementia can develop ways of working with patients to ensure person-centred care. More conversations with people with dementia are needed to investigate how this can be achieved. Orientation procedures should ensure that support for people with dementia is optimized during the settling-in phase. PMID- 21707933 TI - Dance performance as a method of intervention as experienced by older persons with dementia. AB - BACKGROUND: Previous studies have shown that dance can bring out the strength and resources of persons with dementia. PURPOSE: To describe for later evaluation how older persons with dementia experience dance performances in a nursing home. DESIGN: Four dance performances, based on the recollections the older persons had of different seasons, were arranged in one nursing home. METHODS: Qualitative descriptive study, with 13 older persons with dementia, four family members, seven nurses and three practical nurse students. Data were collected and analysed using methodological triangulation. RESULTS: Older persons identified dance performance activity as a process. They had a positive attitude towards the dance performance and performers, and they had experiences of different elements of the dance performance. The older persons forgot their ailments during the performances, and the performances evoked various emotions and awoke memories. Some of them had negative experiences of dancing and dance performances. The older persons experienced a common bond with other spectators. CONCLUSION: Watching a dance performance is an active process for older persons with dementia. IMPLICATIONS FOR PRACTICE: Reminiscence about the dance performance gives the older person an opportunity to deal with the experiences evoked by the performance. PMID- 21707934 TI - Investigation of inflicted injury in a young girl reveals mild haemophilia A and Turner's syndrome. AB - A 2-year-old girl presented to casualty with a right knee effusion after apparently minor trauma. Inflicted injury was suspected and full forensic coagulation studies were performed which revealed a mild deficiency of factor VIII. Screening of the exons and intron/exon boundaries of F8 gene indicated that the child appeared to be homozygous for the missense mutation c.5123G>A (p.Arg1708His) in exon 14 of the F8 gene. This mutation has been reported to be associated with mild haemophilia A. The possibility of hemizygosity had been masked by the test kit employed but referral to the genetics service and subsequent array CGH resulted in a diagnosis of Turner syndrome. PMID- 21707935 TI - Reticulocyte and haemoglobin profiles in elite triathletes over four consecutive seasons. AB - INTRODUCTION: The World Anti-Doping Agency has implemented the Blood Passport in attempt to detect blood doping in athletes. The Blood Passport looks for uncommon changes overtime in reticulocytes percentage (Ret %), as a variable of the OFF-hr score, and haemoglobin concentration ([Hb]) reflecting potential doping violations. Few studies, however, have actually investigated the concurrent stability of Ret % and [Hb] in athletes over extended periods of time, none of which were measured in athletes who undergo strenuous and prolonged physical exercise. METHODS: Measurements of Ret % and [Hb] were assessed over the course of four competitive seasons in elite triathletes (10 males and seven female). Blood was obtained at the start of the season, precompetitive period, competitive period and at the end of the competitive period. RESULTS: Differences (P<0.001) were observed in both [Hb] and Ret % between genders and there was a high variability between subjects. Neither males nor females exhibited differences in [Hb] across all periods within one season. Within gender, analysis revealed that Ret % varied significantly (P=0.0018) between periods only in female athletes. CONCLUSION: We conclude that Ret % and [Hb] remain stable over four consecutive seasons in elite triathletes, confirming that both parameters are valid for antidoping purposes based on the Blood Passport. In addition, Ret % fluctuations within one season require further investigation in females. PMID- 21707936 TI - On-demand but not prophylactic treatment with FVIII concentrate increase thrombin activatable fibrinolysis inhibitor activation in severe haemophilia A patients. AB - INTRODUCTION: Thrombin activatable fibrinolysis inhibitor (TAFI) down-regulates fibrinolysis after activation by thrombin/thrombomodulin. We investigated the effect of treatment with FVIII concentrate on plasma levels of pro-TAFI and activated TAFI in haemophilia A patients. METHODS: Samples were collected pre and posttreatment from patients treated prophylactically or on-demand. Pro-TAFI, TAFI/TAFIi and FVIII levels were measured in all samples. RESULTS: Treatment had no effect on pro-TAFI levels. Pro-TAFI was similar in both patient groups but higher than in controls. Patients from the prophylactic treatment group had measurable FVIII levels pretreatment while in the treatment-on-demand group FVIII levels were <=0.01 IU/mL. In the prophylactic treatment group, the levels of TAFI/TAFIi were significantly lower pre- and posttreatment (4.31 +/- 3.14 and 3.48 +/- 2.65 ng/mL respectively) than in the on-demand group (13.02 +/- 3.47 and 14.87 +/- 3.47 ng/mL respectively). This difference may be due to release of tissue factor at the injury site in the on-demand group. This could induce thrombin and TAFI activation within the clot counterbalancing fibrinolysis in these patients. In the prophylactic group, no injury existed, thus there was insufficient thrombin generation within the clot to activate TAFI. CONCLUSION: These findings suggest that in patients to whom FVIII is administered on demand the fibrinolysis activity is more down regulated than in patients following a prophylactic treatment regime. PMID- 21707937 TI - Clinical course and molecular features in 21 patients with atypical chronic myeloid leukemia. PMID- 21707938 TI - Production and characterization of liquid-stored and lyophilized reconstituted human infusible platelet membranes. AB - INTRODUCTION: During recent years, the need for platelet concentrate (PC) has increased. Infusible platelet membranes (IPM) have been developed as an alternative to standard PCs, with the additional advantage of long shelf-life and increased viral safety. In this study, IPM construction and the morphological and biological features of these microvesicles were surveyed to determine their binding capacities in vitro. METHODS: Thirty-five PC units prepared by the Iranian Blood Transfusion Organization were used to produce IPM. Platelets were lysed by repeated cycles of freezing and thawing, virally inactivated with wet heat in the presence of different concentrations of sodium octanoate as a heat stabilizer, and then sonicated. IPM were separated, kept at 4 degrees C or lyophilized, and examined for binding to collagen and von Willebrand factor (VWF). RESULTS: IPM retained the binding capacity for collagen and VWF, and the extent of VWF binding was dependent on the concentration of the heat stabilizer. Additionally, a higher binding capacity was demonstrated for liquid-stored compared with lyophilized IPM. CONCLUSION: This study revealed the potential of IPM microvesicles to mimic the binding features of platelets in vitro. PMID- 21707940 TI - Themes of delusions and hallucinations in first-episode psychosis. AB - AIM: The study aims to examine the themes of delusions and hallucinations in a cohort of adolescent and young adult patients (aged 15-26 years) presenting with a first episode of psychosis. METHODS: Information was collected retrospectively from 143 randomly selected medical files, using a questionnaire. RESULTS: Over 70% of patients were found to have either delusions or hallucinations at initial presentation. Delusions of persecution, reference and second person auditory hallucinations were the most commonly reported psychotic symptoms at initial presentation. CONCLUSIONS: Anxiety in the context of developmental life events may influence the presentation of patients in this age group. This patient group may also have a less well-developed system of delusional beliefs compared with older patients with established illness. A better understanding of delusions and hallucinations in a first episode of psychosis may help early identification and engagement of these patients. PMID- 21707941 TI - Performance metrics for an academic society--the annual meeting. PMID- 21707939 TI - Strategies for effective recruitment of individuals at risk for developing psychosis. AB - AIM: Early identification of individuals in the prodrome and first episode of psychosis can lead to pre-emptive intervention and perhaps prevention of the significant functional decline that often accompanies a first psychotic episode. The development of an extensive community outreach and education campaign is essential for programmes that aim to identify and treat individuals in the early stages of psychotic illness. METHODS: Over the last decade, the Cognitive Assessment and Risk Evaluation (CARE) programme at the University of California San Diego has implemented a recruitment strategy to increase public awareness about early psychosis and establish community collaboration in San Diego county. Educational materials were distributed to community partners, local media and via the Internet. The number and pattern of referrals were then analysed to inform ongoing recruitment efforts. RESULTS: Overall, 799 referrals were telephone screened. Of the 313 who completed diagnostic interviews, 223 were enrolled including 122 in an 'At Risk' state and 101 in an early psychotic episode. The majority who met inclusion criteria were referred by outpatient mental health practitioners (46.6%), whereas 16.1% came from inpatient facilities and 16.1% were from Internet sites. Other important referral sources were the public schools, community colleges and the National Alliance on Mental Illness. CONCLUSIONS: The successful recruitment efforts of the CARE programme reflect not only the extensive educational outreach but also the emphasis on enhancing professional relationships with community partners. The Internet became an important source of information and referrals and will likely be an essential component of any public education campaign. PMID- 21707942 TI - The Atlanta Clinical and Translational Science Institute: clinical and translational science education and training partnership. PMID- 21707943 TI - Complement proteins C3 and C4 bind to collagen and elastin in the vascular wall: a potential role in vascular stiffness and atherosclerosis. AB - Circulating inflammatory mediators including complement activation products participate in the pathogenesis of cardiovascular diseases. As such, previous reports demonstrating the presence of complement proteins within atherosclerotic plaque and on the luminal surface would be anticipated. In contrast, we have recently made the unexpected observation that complement proteins also deposit along the external elastic lamina of mouse aortas in the absence of luminal deposition or plaque development. This suggests that complement activation may play a critical role in the pathogenesis of vascular stiffness and atherosclerosis through a mechanism initiated within the adventitia rather than on the endothelial surface. This hypothesis was tested in the current study by ultrastructural identification of the C3- and C4-binding targets within the adventitia of the mouse aorta. The results demonstrate extensive binding of C3 and C4 to both collagen and elastin fibers within the adventitia in both ApoE(-/ ) and C57Bl/6J control mice, as well as the presence of C3 and C4 within perivascular adipose tissue. These observations suggest a potential "outside-in" mechanism of vascular stiffness during which perivascular adipose may produce C3 and C4 that bind to collagen and elastin fibers within the adventitia through covalent thiolester bonds, leading to increased vascular stiffness. PMID- 21707944 TI - Evaluating translational research: a process marker model. AB - OBJECTIVE: We examine the concept of translational research from the perspective of evaluators charged with assessing translational efforts. One of the major tasks for evaluators involved in translational research is to help assess efforts that aim to reduce the time it takes to move research to practice and health impacts. Another is to assess efforts that are intended to increase the rate and volume of translation. METHODS: We offer an alternative to the dominant contemporary tendency to define translational research in terms of a series of discrete "phases." RESULTS: We contend that this phased approach has been confusing and that it is insufficient as a basis for evaluation. Instead, we argue for the identification of key operational and measurable markers along a generalized process pathway from research to practice. CONCLUSIONS: This model provides a foundation for the evaluation of interventions designed to improve translational research and the integration of these findings into a field of translational studies. PMID- 21707945 TI - Community conceptualizations of health: implications for transdisciplinary team science. AB - OBJECTIVE: This exploratory study set out to identify how communities in the Tufts University Clinical Translational Science Institute (CTSI) catchment area define health-related research priority areas. METHODS: Three focus groups comprising community stakeholders were conducted in three communities. Participants were representatives from community-based organizations and health centers. A systematic content analysis was performed that involved the identification, labeling, and categorization of data followed by thematic analysis. RESULTS: Participant conceptualizations of health and health priorities were not formulated in the context of specific disease conditions, such as diabetes, obesity, cardiovascular disease, or asthma. Instead, participants described contextual factors including social, environmental, economic, and political conditions that influence health and health behavior. CONCLUSIONS: Respondents in the Tufts University CTSI catchment area, like many diverse urban communities, described multiple interconnected social determinants of health and well-being. As such, they were interested in research that focuses on "upstream" areas of intervention as opposed to disease prevention at the individual level. In addition, respondents were interested in research that would catalyze community change. PMID- 21707946 TI - Effects of combination of proliferative agents and erythropoietin on left ventricular remodeling post-myocardial infarction. AB - Erythropoietin (EPO) has the potential to improve ischemic tissue by mobilizing endothelial progenitor cells and enhancing neovascularization. We hypothesized that combining EPO with human chorionic gonadotrophin (hCG) would improve post myocardial infarction (MI) effects synergistically. METHODS: After MI, five to seven animals were randomly assigned to each of the following treatments: control; hCG; EPO; hCG + EPO, and prolactin (PRL) + EPO. Follow-up echocardiograms were performed to assess cardiac structure and function. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and western blot analysis for apoptosis-related proteins, and cell proliferation by immunostaining for Ki67 and c-kit cells. RESULTS: The MI-mediated increased chamber systolic dimension (p < 0.05 in controls) was attenuated by hCG, EPO, and hCG + EPO (p < 0.05 vs. control) but not PRL + EPO. Similarly all treatment groups, except PRL + EPO, reduced MI induced increases (p < 0.05 vs. control) in ejection fraction (EF). The functional improvement in the EPO-treated groups was accompanied by increased capillary density. Apoptosis was markedly reduced in all treated groups. Significantly more cardiac c-kit(+) cells were found in the hCG + EPO group. CONCLUSION: Our findings revealed that EPO, hCG, or their combination ameliorate cardiac remodeling post-MI. Whereas EPO stimulates neovascularization only and hCG + EPO stimulates c-kit+ cell proliferation. These data suggest that combining mobilizing and proliferative agents adds to the durability and sustainability of cytokine-based therapies for remodeling post-MI. PMID- 21707947 TI - Pharmacologic correction of dominant-negative GH1 deficiency causing mutations. AB - PURPOSE: Dominant-negative growth hormone gene (GH1) mutations cause familial isolated growth hormone deficiency type II (IGHD II), which is characterized by GH deficiency, occasional multiple anterior pituitary hormone deficiencies, and anterior pituitary hypoplasia. We have previously shown that 17.5-/22-kDa GH1 transcript ratios correlate with the severity of the IGHD II phenotype. We hypothesized that different pharmaceutical agents could affect the GH1 transcript ratio by modulating alternative splicing. METHODS: We exposed peripheral blood mononuclear cells from IGHD II patients and unaffected family members to different pharmacologic agents and then determined the 17.5-/22-kDa transcript ratios by real-time PCR. RESULTS: Dexamethasone and digoxin significantly increased the 17.5-/22-kDa transcript ratio, while sodium butyrate and 5 iodotubericidin significantly decreased the ratio. CONCLUSION: Since we have previously shown that the ratio of the 17.5-/22-kDa GH1 transcripts correlates with severity of the IGHD II phenotype, our findings here suggest that selected previously unconsidered agents could possibly reduce the severity of IGHD II, while other agents could possibly exacerbate the disease phenotype. PMID- 21707948 TI - Transfection of human platelets with short interfering RNA. AB - Platelets contain mRNAs and are capable of translating mRNA into protein, and it has been previously demonstrated that platelets increase their levels of integrin beta3 overtime while in blood bank storage conditions. We are unaware of prior attempts to introduce nucleic acids into platelets. Considering the potential clinical and research utility of manipulating platelet gene expression, we tested whether small interfering RNAs (siRNAs) could be transfected into normal human platelets. Multiple conditions were tested, including lipofectamine versus electroporation, different amounts of siRNA, the effect of different buffers and the presence of plasma during transfection, and the time for optimal siRNA incorporation after transfection. Using flow cytometry to assess transfection efficiency, we found that optimal transfection was obtained using lipofectamine, washed platelets, and 400 pmoles siRNA. Cell sorting of transfected platelets suggested that the incorporated siRNA was able to knockdown the level of a targeted mRNA. This is the first ever demonstration that nucleic acids can be introduced directly into platelets, and offers proof of concept for manipulating gene expression in platelets by nonviral methods. Future technical improvements may permit improving the quality and/or lifespan of stored human platelets. PMID- 21707949 TI - Association of TCF7L2 allelic variations with gastric function, satiation, and GLP-1 levels. AB - OBJECTIVE: Genetic variation in transcription factor 7-like 2 (TCF7L2), a regulator of proglucagon processing, is reproducibly associated with type 2 diabetes. GLP-1 alters gastric function and increases satiation. HYPOTHESIS: Genetic variation in TCF7L2 is associated with satiation, gastric motor function, and GLP-1 concentrations. METHODS: In 62 adults, a single nucleotide polymorphism (SNP) of TCF7L2 (rs7903146) was genotyped and associations with gastric emptying (GE) of solids and liquids, gastric volume (GV), and satiation (maximum tolerated volume and symptoms after nutrient drink test) were explored using a dominant genetic model, with gender and BMI as covariates. In 50 of the participants, we also measured plasma GLP-1 during fasting and after ingestion of a nutrient drink. RESULTS: Presence of the T allele compared to CC genotype in rs7903146 SNP of the TCF7L2 gene was associated with reduced fasting GV (246.3 +/- 11.4 mL for CC group, compared to 215.7 +/- 11.4 mL for CT/TT group, p= 0.05) and accelerated GE t(1/2) of liquids (26.3 +/- 2.0 minutes for CC compared to 17.7 +/- 1.4 for CT/TT, p < 0.005). There was no significant association of rs7903146 SNP with GE of solids, gastric accommodation, satiation, fasting, or postprandial GLP-1. CONCLUSION: Our data suggest TCF7L2 is associated with altered gastric functions that may predispose to obesity. PMID- 21707950 TI - A CTSA agenda to advance methods for comparative effectiveness research. AB - Clinical research needs to be more useful to patients, clinicians, and other decision makers. To meet this need, more research should focus on patient centered outcomes, compare viable alternatives, and be responsive to individual patients' preferences, needs, pathobiology, settings, and values. These features, which make comparative effectiveness research (CER) fundamentally patient centered, challenge researchers to adopt or develop methods that improve the timeliness, relevance, and practical application of clinical studies. In this paper, we describe 10 priority areas that address 3 critical needs for research on patient-centered outcomes (PCOR): (1) developing and testing trustworthy methods to identify and prioritize important questions for research; (2) improving the design, conduct, and analysis of clinical research studies; and (3) linking the process and outcomes of actual practice to priorities for research on patient-centered outcomes. We argue that the National Institutes of Health, through its clinical and translational research program, should accelerate the development and refinement of methods for CER by linking a program of methods research to the broader portfolio of large, prospective clinical and health system studies it supports. Insights generated by this work should be of enormous value to PCORI and to the broad range of organizations that will be funding and implementing CER. PMID- 21707951 TI - Mentoring K scholars: strategies to support research mentors. AB - The goal of this paper is to present strategies utilized to support K scholar research mentors. K scholars are generally assistant professors who are close to developing independent research programs. Of all the various types of mentees, K scholars offer the greatest challenges, as well as the greatest rewards, for research mentors. To see one's mentee achieve independent PI status and become an established investigator is one of the great joys of being a research mentor. Research mentors for K scholars, however, may not directly benefit from their mentoring relationship, neither in terms of obtaining data to support their research program or laboratory, nor in assistance with grants or scientific papers. There is a pressing need for the research community to address the workload, institutional expectations, and reward system for research mentors. The dearth of research mentors and role models in clinical translational science parallels the decreasing number of physicians choosing careers in clinical research. While there is limited empirical information on the effectiveness of mentor support mechanisms, this white paper concludes that providing mentor support is critical to expanding the available pool of mentors, as well as providing training opportunities for K scholars. PMID- 21707952 TI - Pharmacotherapy and pregnancy: highlights from the Third International Conference for Individualized Pharmacotherapy in Pregnancy. AB - To address provider struggles to provide evidence-based, rational drug therapy to pregnant women, this third Conference was convened to highlight the current progress and research in the field. Speakers from academic centers, industry, and governmental institutions spoke about: the Food and Drug Administration's role in pregnancy pharmacology and the new labeling initiative; drug registries in pregnancy; the pharmacist's role in medication use in pregnancy; therapeutic areas such as preterm labor, gestational diabetes, nausea and vomiting in pregnancy, and hypertension; breast-feeding and medications; ethical challenges for consent in pregnancy drug studies; the potential for cord blood banks; and concerns about the fetus when studying drugs in pregnancy. The Conference highlighted several areas of collaboration within the current Obstetrics Pharmacology Research Units Network and hoped to educate providers, researchers, and agencies with the common goal to improve the ability to safely and effectively use individualized pharmacotherapy in pregnancy. PMID- 21707953 TI - Bile acids regulate cardiovascular function. AB - Research over the last decade has uncovered roles for bile acids (BAs) that extend beyond their traditional functions in regulating lipid digestion and cholesterol metabolism. BAs are now recognized as signaling molecules that interact with both plasma membrane and nuclear receptors. Emerging evidence indicates that by interacting with these receptors, BAs regulate their own synthesis, glucose and energy homeostasis, and other important physiological events. Herein, we provide a comprehensive review of the actions of BAs on cardiovascular function. In the heart and the systemic circulation, BAs interact with plasma membrane G-protein-coupled receptors, for example, TGR5 and muscarinic receptors, and nuclear receptors, for example, the farnesoid (FXR) and pregnane (PXR) xenobiotic receptors. BA receptors are expressed in cardiovascular tissue, however, the mechanisms underlying BA-mediated regulation of cardiovascular function remain poorly understood. BAs reduce heart rate by regulating channel conductance and calcium dynamics in sino-atrial and ventricular cardiomyocytes and regulate vascular tone via both endothelium dependent and -independent mechanisms. End-stage liver disease, obstructive jaundice, and intrahepatic cholestasis of pregnancy are prominent conditions in which elevated serum BAs alter vascular dynamics. This review focuses on BAs as newly recognized signaling molecules that modulate cardiovascular function. PMID- 21707954 TI - Paroxysmal nocturnal hemoglobinuria from bench to bedside. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease that presents with protean manifestations. Clinical and laboratory investigation over the past 25 years has uncovered most of the basic science underpinnings of PNH and has led to the development of a highly effective targeted therapy. PNH originates from a multipotent hematopoietic stem cell (HSC) that acquires a somatic mutation in a gene called phosphatidylinositol glycan anchor biosynthesis, class A (PIG-A). The PIG-A gene is required for the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Failure to synthesize GPI anchors leads to an absence of all proteins that utilize GPI to attach to the plasma membrane. Two GPI-anchor proteins, CD55 and CD59, are complement regulatory proteins; their absence on the surface of PNH cells leads to complement-mediated hemolysis. The release of free hemoglobin leads to scavenging of nitric oxide and contributes to many clinical manifestations, including esophageal spasm, fatigue, and possibly thrombosis. Aerolysin is a pore-forming toxin that binds GPI-anchored proteins and kills normal cells, but not PNH cells. A fluorescinated aerolysin variant (FLAER) binds GPI-anchor and serves as a novel reagent diagnosing PNH. Eculizumab, a humanized monoclonal antibody against C5, is the first effective drug therapy for PNH. PMID- 21707955 TI - Chronic diseases: the emerging pandemic. PMID- 21707957 TI - Bariatric surgery for diabetes: the International Diabetes Federation takes a position. AB - Type 2 diabetes (T2D) and obesity are both complex and chronic medical disorders, each with an escalating worldwide prevalence. When obesity is severe, and/or available medical therapies fail to control the diabetes, bariatric surgery becomes a cost-effective therapy for T2D. When there are other major comorbidities and cardiovascular risk, the option of bariatric surgery becomes even more worthy of consideration. National guidelines for bariatric surgery need to be developed and implemented for people with T2D. With this in mind, the International Diabetes Federation convened a multidisciplinary working group to develop a position statement. The key recommendations cover describing those eligible for surgery and who should be prioritized, incorporating bariatric surgery into T2D treatment algorithms, performing surgery in centers with multidisciplinary teams that are experienced in the management of both obesity and diabetes, and developing bariatric surgery registries and reporting standards. PMID- 21707958 TI - The Littorina sequence database (LSD)--an online resource for genomic data. AB - We present an interactive, searchable expressed sequence tag database for the periwinkle snail Littorina saxatilis, an upcoming model species in evolutionary biology. The database is the result of a hybrid assembly between Sanger and 454 sequences, 1290 and 147,491 sequences respectively. Normalized and non-normalized cDNA was obtained from different ecotypes of L. saxatilis collected in the UK and Sweden. The Littorina sequence database (LSD) contains 26,537 different contigs, of which 2453 showed similarity with annotated proteins in UniProt. Querying the LSD permits the selection of the taxonomic origin of blast hits for each contig, and the search can be restricted to particular taxonomic groups. The database allows access to UniProt annotations, blast output, protein family domains (PFAM) and Gene Ontology. The database will allow users to search for genetic markers and identifying candidate genes or genes for expression analyses. It is open for additional deposition of sequence information for L. saxatilis and other species of the genus Littorina. The LSD is available at http://mbio serv2.mbioekol.lu.se/Littorina/. PMID- 21707956 TI - Incretin-based therapies. AB - Incretin-based therapies have established a foothold in the diabetes armamentarium through the introduction of oral dipeptidyl peptidase-4 inhibitors and the injectable class, the glucagon-like peptide-1 receptor agonists. In 2009, the American Diabetes Association and European Association for the Study of Diabetes authored a revised consensus algorithm for the initiation and adjustment of therapy in Type 2 diabetes (T2D). The revised algorithm accounts for the entry of incretin-based therapies into common clinical practice, especially where control of body weight and hypoglycemia are concerns. The gut-borne incretin hormones have powerful effects on glucose homeostasis, particularly in the postprandial period, when approximately two-thirds of the beta-cell response to a given meal is due to the incretin effect. There is also evidence that the incretin effect is attenuated in patients with T2D, whereby the beta-cell becomes less responsive to incretin signals. The foundation of incretin-based therapies is to target this previously unrecognized feature of diabetes pathophysiology, resulting in sustained improvements in glycemic control and improved body weight control. In addition, emerging evidence suggests that incretin-based therapies may have a positive impact on inflammation, cardiovascular and hepatic health, sleep, and the central nervous system. In the present article, we discuss the attributes of current and near-future incretin-based therapies. PMID- 21707959 TI - optiFLP: software for automated optimization of amplified fragment length polymorphism scoring parameters. AB - Amplified fragment length polymorphism (AFLP), a widely used method for DNA fingerprinting, has shifted from polyacrylamide gel to capillary electrophoresis over the last years. Currently, most AFLP data are generated in a computer readable format, and several programs are available that automatically score raw data into binary profiles. Good scoring parameters are the key to good AFLP profiles. optiFLP is the first open source program for automatic optimization of AFLP scoring parameters. It searches parameter space to maximize the contrast among groups of AFLP profiles, with the allocation of profiles to groups in either a supervised or an unsupervised mode. The software produces output files ready for use in a range of downstream applications. PMID- 21707961 TI - Ocular prosthesis for a geriatric patient with customised iris: a report of two cases. AB - OBJECTIVE: An ocular prosthesis is given when trauma or disease may lead to enucleation or evisceration of the eye and the combined efforts of the ophthalmologists and the maxillofacial prosthetist can provide a cosmetically acceptable ocular prosthesis. METHODS: An ocular prosthesis is either pre fabricated or custom-made. One of the important factors for achieving a cosmetic result is accurate colour matching of the iris with the contralateral iris. RESULTS: A knowledge of the anatomy of the eye facilitates hand painting of iris and sclera to produce a satisfactory result. CONCLUSION: The custom-made ocular prosthesis allows infinite variations during the fabrication. PMID- 21707962 TI - Abstracts of the Sixth International Symposium on Intensive Care and Emergency Medicine for Latin America. Sao Paulo, Brazil. June 22-25, 2011. PMID- 21707960 TI - The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin. AB - Converging lines of evidence from varied scientific disciplines suggest that cutaneous melanomas comprise biologically distinct subtypes that arise through multiple causal pathways. Understanding the respective relationships of each subtype with etiologic factors such as UV radiation and constitutional factors is the first necessary step toward developing refined prevention strategies for the specific forms of melanoma. Furthermore, classifying this disease precisely into biologically distinct subtypes is the key to developing mechanism-based treatments, as highlighted by recent discoveries. In this review, we outline the historical developments that underpin our understanding of melanoma heterogeneity, and we do this from the perspectives of clinical presentation, histopathology, epidemiology, molecular genetics, and developmental biology. We integrate the evidence from these separate trajectories to catalog the emerging major categories of melanomas and conclude with important unanswered questions relating to the development of melanoma and its cells of origin. PMID- 21707964 TI - Reversal of endocrine resistance in breast cancer: interrelationships among 14-3 3zeta, FOXM1, and a gene signature associated with mitosis. AB - INTRODUCTION: Despite the benefits of estrogen receptor (ER)-targeted endocrine therapies in breast cancer, many tumors develop resistance. 14-3-3 zeta/YWHAZ, a member of the 14-3-3 family of conserved proteins, is over-expressed in several types of cancer, and our previous work showed that high expression of 14-3-3zeta in ER-positive breast cancers was associated with a poor clinical outcome for women on tamoxifen. Therefore, we now probe the role of 14-3-3zeta in endocrine resistance, and we examine the functional dimensions and molecular basis that underlie 14-3-3zeta activities. METHODS: From analyses of four independent breast cancer microarray datasets from nearly 400 women, we characterized a gene signature that correlated strongly with high expression of 14-3-3zeta in breast tumors and examined its association with breast cancer molecular subtypes and clinical-pathological features. We investigated the effects of altering 14-3 3zeta levels in ER-positive, endocrine sensitive and resistant breast cancer cells on the regulation of 14-3-3zeta signature genes, and on cellular signaling pathways and cell phenotypic properties. RESULTS: The gene signature associated with high 14-3-3zeta levels in breast tumors encompassed many with functions in mitosis and cytokinesis, including aurora kinase-B, polo-like kinase-1, CDC25B, and BIRC5/survivin. The gene signature correlated with early recurrence and risk of metastasis, and was found predominantly in luminal B breast cancers, the more aggressive ER-positive molecular subtype. The expression of the signature genes was significantly decreased or increased upon reduction or overexpression of 14-3 3zeta in ER-positive breast cancer cells, indicating their coregulation. 14-3 3zeta also played a critical role in the regulation of FOXM1, with 14-3-3zeta acting upstream of FOXM1 to regulate cell division-signature genes. Depletion of 14-3-3zeta markedly increased apoptosis, reduced proliferation and receptor tyrosine kinase (HER2 and EGFR) signaling, and, importantly, reversed endocrine resistance. CONCLUSIONS: This study reveals that 14-3-3zeta is a key predictive marker for risk of failure on endocrine therapy and serves a pivotal role impacting growth factor signaling, and promoting cell survival and resistance to endocrine therapies. Targeting 14-3-3zeta and its coregulated proteins, such as FOXM1, should prove valuable in restoring endocrine sensitivity and reducing risk of breast cancer recurrence. PMID- 21707965 TI - Fibrous dysplasia of bone associated with soft-tissue myxomas as well as an intra osseous myxoma in a woman with Mazabraud's syndrome: a case report. AB - INTRODUCTION: Mazabraud's syndrome is a rare but well-described disorder characterized by fibrous dysplasia in single or multiple bones associated with one or more soft-tissue myxomas. In this report, we describe what is, to the best of our knowledge, the first case involving an intra-osseous myxoma. This finding supports, and could provide new insight into, the pathological association between fibrous dysplasia and myxomas. CASE PRESENTATION: In this report, we describe the case of a 49-year-old Caucasian woman known for years to have fibrous dysplasia in the left femur and tibia who presented with progressive pain in her left leg and soft swelling in the left quadriceps region. After surgical intervention with excision of the soft-tissue mass, the diagnosis of Mazabraud's syndrome was confirmed. During follow-up, our patient presented with a painless mass located on the lateral side of the left knee, next to a second, intra osseous lesion with the same characteristics in the left lateral tibial plateau. The histopathological examination was consistent with a soft-tissue intra-osseous myxoma. CONCLUSION: In the international literature, 67 cases of Mazabraud's syndrome have been described so far.To our knowledge, the present case report is the first to describe the combination of polyostotic fibrous dysplasia and intra muscular as well as intra-osseous myxoma. PMID- 21707966 TI - A multiplex real-time PCR assay targeting virulence and resistance genes in Salmonella enterica serotype Typhimurium. AB - BACKGROUND: Typhimurium is the main serotype of Salmonella enterica subsp. enterica implicated in food-borne diseases worldwide. This study aimed to detect the prevalence of ten markers combined in a macro-array based on multiplex real time PCR. We targeted characteristic determinants located on pathogenicity islands (SPI-2 to -5, virulence plasmid pSLT and Salmonella genomic island 1 (SGI1)) as well as a specific 16S-23S rRNA intergenic spacer sequence of definitive type 104 (DT104). To investigate antimicrobial resistance, the study also targeted the presence of genes involved in sulfonamide (sul1) and beta lactam (blaTEM) resistance. Finally, the intI1 determinant encoding integrase from class 1 integron was also investigated. RESULTS: A total of 538 unrelated S. Typhimurium strains isolated between 1999 and 2009 from various sources, including food animals, food products, human and environmental samples were studied. Based on the combined presence or absence of these markers, we distinguished 34 different genotypes, including three major genotypes encountered in 75% of the studied strains, Although SPI determinants were almost always detected, SGI1, intI1, sul1 and blaTEM determinants were found 47%, 52%, 54% and 12% of the time respectively, varying according to isolation source. Low-marker patterns were most often detected in poultry sources whereas full-marker patterns were observed in pig, cattle and human sources. CONCLUSION: The GeneDisc(r) assay developed in this study madeit easier to explore variability within serotype Typhimurium by analyzing ten relevant gene determinants in a large collection of strains. This real-time multiplex method constitutes a valuable tool for strains characterization on epidemiological purposes. PMID- 21707967 TI - Survey on medicinal plants and spices used in Beni-Sueif, Upper Egypt. AB - BACKGROUND: This study was conducted to identify medicinal plants and spices used for medicine by the community of Beni-Sueif, Upper Egypt. METHODS: Ethnobotanical data from local people was collected using direct interviews and a semi structured questionnaire. RESULTS: Forty-eight plant species belonging to twenty seven families and forty-seven genera were encountered during the study. Their botanical and vernacular names, plant parts used and medicinal uses are given. Results of the study were analyzed using two quantitative tools. The factor informant consensus indicated the agreement in the use of plants and the fidelity level indicated the ratio between the number of informants who independently suggested the use of a species for the same major purpose and the total number of informants who mentioned the plant for any use. The results of the factor informant consensus showed that the cardiovascular category has the greatest agreement, followed by the immunological, gastrointestinal and respiratory categories. The most important species according to their fidelity are: Hibiscus sabdariffa L. for the cardiovascular category; Trigonella foenum-graecum L. for the immunological category; Mentha piperita L. for the gastrointestinal category and Pimpinella anisum L. for the respiratory category. CONCLUSIONS: Medicinal plants are still used for treatment in Beni-Sueif community despite the availability of prescribed medications. Documentation of this ethnomedicinal knowledge is important. Evaluation of pharmacological activity for the promising medicinal plants is suggested. PMID- 21707968 TI - Solitary Peutz-Jeghers type hamartomatous polyps in the duodenum are not always associated with a low risk of cancer: two case reports. AB - INTRODUCTION: A hamartomatous polyp without associated mucocutaneous pigmentation or a family history of Peutz-Jeghers Syndrome is diagnosed as a solitary Peutz Jeghers type hamartomatous polyp. As compared with Peutz-Jeghers Syndrome, Peutz Jeghers type hamartomatous polyps are diagnosed with a lower risk of cancer and are regarded as a different disorder. CASE PRESENTATION: In case one, we describe an 84-year-old Japanese man with a 14 mm duodenal polyp. Endoscopic mucosal resection was performed and histological examination showed findings suggestive of a hamartomatous polyp with a focus of well-differentiated adenocarcinoma. In case two, we describe a 76-year-old Japanese man who had been treated for prostate, rectal and lung cancer. Upper gastrointestinal endoscopy revealed a duodenal polyp measuring 15 mm in diameter. Endoscopic mucosal resection was performed, and histological examination showed findings suggestive of a hamartomatous polyp. Liver and thyroid cancers were found after the endoscopic treatment. CONCLUSION: Although duodenal solitary hamartomatous polyps are associated with a lower risk of cancer, four patients, including our cases, have been diagnosed with cancerous polyps. Patients with duodenal solitary hamartomatous polyps should be treated by endoscopic or surgical resection and need whole-body screening. PMID- 21707969 TI - Network meta-analysis-highly attractive but more methodological research is needed. AB - Network meta-analysis, in the context of a systematic review, is a meta-analysis in which multiple treatments (that is, three or more) are being compared using both direct comparisons of interventions within randomized controlled trials and indirect comparisons across trials based on a common comparator. To ensure validity of findings from network meta-analyses, the systematic review must be designed rigorously and conducted carefully. Aspects of designing and conducting a systematic review for network meta-analysis include defining the review question, specifying eligibility criteria, searching for and selecting studies, assessing risk of bias and quality of evidence, conducting a network meta analysis, interpreting and reporting findings. This commentary summarizes the methodologic challenges and research opportunities for network meta-analysis relevant to each aspect of the systematic review process based on discussions at a network meta-analysis methodology meeting we hosted in May 2010 at the Johns Hopkins Bloomberg School of Public Health. Since this commentary reflects the discussion at that meeting, it is not intended to provide an overview of the field. PMID- 21707970 TI - Formation of H2 and CH4 by weathering of olivine at temperatures between 30 and 70 degrees C. AB - Hydrocarbons such as CH4 are known to be formed through the Fischer-Tropsch or Sabatier type reactions in hydrothermal systems usually at temperatures above 100 degrees C. Weathering of olivine is sometimes suggested to account for abiotic formation of CH4 through its redox lowering and water splitting properties. Knowledge about the CH4 and H2 formation processes at low temperatures is important for the research about the origin and cause of early Earth and Martian CH4 and for CO2 sequestration. We have conducted a series of low temperature, long-term weathering experiments in which we have tested the CH4 and H2 formation potential of forsteritic olivine.The results show low temperature CH4 production that is probably influenced by chromite and magnetite as catalysts. Extensive analyses of a potential CH4 source trapped in the crystal structure of the olivine showed no signs of incorporated CH4. Also, the available sources of organic carbon were not enough to support the total amount of CH4 detected in our experiments. There was also a linear relationship between silica release into solution and the net CH4 accumulation into the incubation bottle headspaces suggesting that CH4 formation under these conditions could be a qualitative indicator of olivine dissolution.It is likely that minerals such as magnetite, chromite and other metal-rich minerals found on the olivine surface catalyze the formation of CH4, because of the low temperature of the system. This may expand the range of environments plausible for abiotic CH4 formation both on Earth and on other terrestrial bodies. PMID- 21707971 TI - Involvement of gut microbial fermentation in the metabolic alterations occurring in n-3 polyunsaturated fatty acids-depleted mice. AB - BACKGROUND: Western diet is characterized by an insufficient n-3 polyunsaturated fatty acid (PUFA) consumption which is known to promote the pathogenesis of several diseases. We have previously observed that mice fed with a diet poor in n 3 PUFA for two generations exhibit hepatic steatosis together with a decrease in body weight. The gut microbiota contributes to the regulation of host energy metabolism, due to symbiotic relationship with fermentable nutrients provided in the diet. In this study, we have tested the hypothesis that perturbations of the gut microbiota contribute to the metabolic alterations occurring in mice fed a diet poor in n-3 PUFA for two generations (n-3/- mice). METHODS: C57Bl/6J mice fed with a control or an n-3 PUFA depleted diet for two generations were supplemented with prebiotic (inulin-type Fructooligosaccharides, FOS, 0.20 g/day/mice) during 24 days. RESULTS: n-3/-mice exhibited a marked drop in caecum weight, a decrease in lactobacilli and an increase in bifidobacteria in the caecal content as compared to control mice (n-3/+ mice). Dietary supplementation with FOS for 24 days was sufficient to increase caecal weight and bifidobacteria count in both n-3/+ and n-3/-mice. Moreover, FOS increased lactobacilli content in n-3/-mice, whereas it decreased their level in n-3/+ mice. Interestingly, FOS treatment promoted body weight gain in n-3/-mice by increasing energy efficiency. In addition, FOS treatment decreased fasting glycemia and lowered the higher expression of key factors involved in the fatty acid catabolism observed in the liver of n-3/-mice, without lessening steatosis. CONCLUSIONS: the changes in the gut microbiota composition induced by FOS are different depending on the type of diet. We show that FOS may promote lactobacilli and counteract the catabolic status induced by n-3 PUFA depletion in mice, thereby contributing to restore efficient fat storage. PMID- 21707972 TI - Improvement of the observational method for Plasmodium berghei oocysts in the midgut of mosquitoes. AB - BACKGROUND: There is a need for improving the method for counting oocysts of Plasmodium berghei in the midgut of Anopheles mosquitoes. The two methods currently used, the formalin fixation method and the mercurochrome staining method, have contradicting advantages and disadvantages. In the formalin fixation method, the specimen can be preserved but unstained oocysts were often indistinct from the insect tissue. While in the mercurochrome staining method, stained oocysts can be clearly distinguished from insect tissue but the specimen are not well preserved. These two methods were combined in this study to develop a new improved technique in counting the oocysts, in which the specimen can be both stained and preserved well. This technique was evaluated for its accuracy and suitability in observing the oocyst development. FINDINGS: In the improved technique, the parasite-infected midgut was first stained with mercurochrome, and then fixed with formalin. The specimens were finally observed using light microscopy. To evaluate the accuracy in the oocyst counting with the improved technique, mosquitoes were infected with the green fluorescent protein (GFP) expressing parasite. Then, the midgut oocysts were counted using both the GFP marker and the improved technique. Results were then compared and showed that the improved technique retrieved 78%-123% (arithmetic mean = 97%) of the oocysts counted using the GFP marker. Furthermore, it was also possible to evaluate the oocyst development with a green filter using the light microscopy. CONCLUSIONS: The improved technique for oocyst counting will be a useful tool for evaluating midgut oocyst numbers and determining the developmental stage of oocysts in parasite-infected mosquitoes. PMID- 21707973 TI - Gallus Heat shock cognate protein 70, a novel binding partner of Apoptin. AB - BACKGROUND: Chicken anemia virus (CAV) infection of newly hatched chickens induces generalized lymphoid atrophy and causes immunosuppressive. VP3, also known as Apoptin, is non-structural protein of CAV. Apoptin specifically induces apoptosis in transformed or tumor cells but not in normal cells. In particular, there are no known cellular homologues of Apoptin hindering genetic approaches to elucidate its cellular function. Although a number of Apoptin-interacting molecules have been identified, the molecular mechanism underlying Apoptin's action is still poorly understood. To learn more about the molecular mechanism of Apoptin's action, we searched for Apoptin associated proteins. RESULTS: Using yeast two-hybrid and colony-life filter approaches we got five positive yeast clones. Through sequencing and BLASTed against NCBI, one of the clones was confirmed containing Gallus heat shock cognate protein 70 (Hsc70). Hsc70 gene was clone into pRK5-Flag plasmid, coimmunoprecipitation assay show both exogenous Hsc70 and endogenous Hsc70 can interact with Apoptin. Truncated Apoptin expression plasmids were made and coimmunoprecipitation were performed, the results show the binding domain of Apoptin with Hsc70 is located between amino acids 30-60. Truncated expression plasmids of Hsc70 were also constructed and coimmunoprecipitation were performed, the results show the peptide-binding and variable domains of Hsc70 are responsible for the binding to Apoptin. Confocal assays were performed and results show that under physiological condition Hsc70 is predominantly distributed in cytoplasm, whereas Hsc70 is translocated into the nuclei and colocalized with Apoptin in the presence of Apoptin in DF-1 cell. Functional studies show that Apoptin markedly down-regulate the mRNA level of RelA/p65 in DF-1 cell. To explore the effect of Hsc70 on Apoptin-mediated RelA/p65 gene expression, we have searched two Hsc70 RNAi sequences, and found that all of them dramatically inhibited the expression of endogenous Hsc70, with the #2 Hsc70 RNAi sequence being the most effective. Knockdown of Hsc70 show Apoptin-inhibited RelA/p65 expression was abolished. Our data demonstrate that Hsc70 is responsible for the down-regulation of Apoptin induced RelA/p65 gene expression. CONCLUSION: We identified Gallus Hsc70 as an Apoptin binding protein and showed the translocation of Hsc70 into the nuclei of DF-1 cells treated with Apoptin. Hsc70 regulates RelA/p65 gene expression induced by Apoptin. PMID- 21707974 TI - Arthritis, osteomyelitis, septicemia and meningitis caused by Klebsiella in a low birth-weight newborn: a case report. AB - INTRODUCTION: Klebsiella pneumoniae is in most cases a hospital-acquired infection and presents as pneumonia, septicemia and meningitis in patients with some predisposing factors, including prematurity, intravenous catheter, history of antibiotic therapy and intravenous nutrients. CASE PRESENTATION: A low-birth weight, 33-day-old Caucasian girl with respiratory distress syndrome was admitted to our hospital. She developed septicemia, meningitis, polyarticular arthritis and osteomyelitis by nosocomial K. pneumoniae which was resistant to most antibiotics except ciprofloxacin. She was therefore treated with ciprofloxacin and co-trimoxazole for eight weeks. After completion of the treatment course, she completely improved with excellent weight gain and without any adverse effects during three years of follow-up. CONCLUSION: In the resistant strain of K. pneumoniae, ciprofloxacin could be considered as a therapeutic option with the prospect of a good outcome, even in neonates and infants. PMID- 21707975 TI - Identification of a novel de novo mutation in the NIPBL gene in an Iranian patient with Cornelia de Lange syndrome: A case report. AB - BACKGROUND: Cornelia de Lange syndrome is characterized by dysmorphic facial features, hirsutism, severe growth and developmental delay. Germline mutations in the NIPBL gene with an autosomal dominant pattern and in the SMC1A gene with an X linked pattern have been identified in Cornelia de Lange syndrome. CASE PRESENTATION: A two-month-old Iranian boy who showed multiple congenital anomalies was referred to the genetic center of a welfare organization in southwest Iran. He was the second child of a non-consanguineous marriage, born after full term with normal delivery. His birth weight was 3110 g, his length was 46 cm and his head circumference was 30 cm. Both parents were clinically asymptomatic, with no positive history of any deformity in their respective families. CONCLUSIONS: Sequencing of the NIPBL gene from our patient revealed a single-base deletion of thymidine in exon 10 (c.516delT). This mutation presumably results in premature termination at codon 526. We did not observe this mutation in the parents of our patient with Cornelia de Lange syndrome. The results presented here enlarge the spectrum of NIPBL gene mutations associated with Cornelia de Lange syndrome by identifying a novel de novo mutation in an Iranian patient with Cornelia de Lange syndrome and further support the hypothesis that NIPBL mutations are disease-causing mutations leading to Cornelia de Lange syndrome. PMID- 21707976 TI - Immobilization of muskoxen (Ovibos moschatus) with etorphine and xylazine. AB - One hundred and thirty three "wild" muskoxen, 81 of which of known body mass, were successfully immobilized using etorphine (M99), and xylazine (Rompun(r)), delivered by use of a dart gun. A dose of 0.05 mg/kg M99, supplemented by 0.15 mg/kg Rompun was found to be very effective. This dose is much higher than currently recommended e.g. by Handbook of Wildlife Chemical Immobilization. PMID- 21707977 TI - Use of prior odds for missing persons identifications. AB - Identification of missing persons from mass disasters is based on evaluation of a number of variables and observations regarding the combination of features derived from these variables. DNA typing now is playing a more prominent role in the identification of human remains, and particularly so for highly decomposed and fragmented remains. The strength of genetic associations, by either direct or kinship analyses, is often quantified by calculating a likelihood ratio. The likelihood ratio can be multiplied by prior odds based on nongenetic evidence to calculate the posterior odds, that is, by applying Bayes' Theorem, to arrive at a probability of identity. For the identification of human remains, the path creating the set and intersection of variables that contribute to the prior odds needs to be appreciated and well defined. Other than considering the total number of missing persons, the forensic DNA community has been silent on specifying the elements of prior odds computations. The variables include the number of missing individuals, eyewitness accounts, anthropological features, demographics and other identifying characteristics. The assumptions, supporting data and reasoning that are used to establish a prior probability that will be combined with the genetic data need to be considered and justified. Otherwise, data may be unintentionally or intentionally manipulated to achieve a probability of identity that cannot be supported and can thus misrepresent the uncertainty with associations. The forensic DNA community needs to develop guidelines for objectively computing prior odds. PMID- 21707978 TI - The characteristics and prognosis of patients fulfilling the Appropriateness Evaluation Protocol in a medical admission unit; a prospective observational study. AB - BACKGROUND: To examine the prognostic significance of fulfilling at least one of the Appropriateness Evaluation Protocol (AEP) criteria. METHODS: Prospective observational cohort study at medical admission units at a regional teaching hospital in Denmark. 3,050 consecutively admitted patients were included, median age 66 (IQR: 50-77), 48% female.We assessed the fulfilment of the AEP criteria and mortality data, length of stay, readmissions and co-morbidity. We analyzed the association between day of admission and time of day and compared the opinion of the admitting doctors and nurses on the relevancy of admission. RESULTS: 61.9% of the patients fulfilled the AEP criteria. Patients fulfilling were older (p < 0.001), had a higher in-hospital mortality (p < 0.001), a higher 30-days mortality (p < 0.001), a longer length of stay (p < 0.001), more readmissions within 30 days (p < 0.001) and higher co-morbidity (p < 0.001). There were no association between day of admission and fulfilment of AEP criteria, but significantly fewer patients fulfilled the AEP criteria in the morning hours (p < 0.05). The nurses found 79.1% of the admissions relevant with a sensitivity of 84.8% and a specificity of 30.1% with a Kappa of 0.16. The doctors found 76.2% of the admissions relevant with a sensitivity of 86.4% and a specificity of 40.9% and a Kappa of 0.29. CONCLUSIONS: Fulfilment of the AEP criteria adequately reflect increased morbidity and mortality of acutely admitted medical patients. PMID- 21707979 TI - Cutaneous lupus erythematosus after treatment with paclitaxel and bevacizumab for metastatic breast cancer: a case report. AB - INTRODUCTION: The monoclonal anti-vascular endothelial growth factor antibody bevacizumab is increasingly used in the treatment of several malignant tumors. The usual side effects of this drug are hypertension and proteinuria. Paclitaxel is widely used in the treatment of breast cancer and head and neck carcinomas. Neither of these two drugs typically causes skin disorders. Paclitaxel-related cutaneous lupus erythematosus has been described before, but in earlier cases patients had a history of autoimmune disease. CASE PRESENTATION: We report a case of a 65-year-old Caucasian woman who presented with cutaneous lupus erythematosus after receiving paclitaxel-bevacizumab combination treatment as first-line therapy for metastatic breast cancer. Her cutaneous symptoms and increased serum anti-SSA and anti-SSB antibodies disappeared shortly after the discontinuation of therapy. CONCLUSION: We conclude that cutaneous lupus erythematosus can also be seen in patients without earlier anamnesis of autoimmune disorders and that, furthermore, bevacizumab might cause atypical cutaneous side effects. PMID- 21707980 TI - Assessment of vector/host contact: comparison of animal-baited traps and UV light/suction trap for collecting Culicoides biting midges (Diptera: Ceratopogonidae), vectors of Orbiviruses. AB - BACKGROUND: The emergence and massive spread of bluetongue in Western Europe during 2006-2008 had disastrous consequences for sheep and cattle production and confirmed the ability of Palaearctic Culicoides (Diptera: Ceratopogonidae) to transmit the virus. Some aspects of Culicoides ecology, especially host-seeking and feeding behaviors, remain insufficiently described due to the difficulty of collecting them directly on a bait animal, the most reliable method to evaluate biting rates.Our aim was to compare typical animal-baited traps (drop trap and direct aspiration) to both a new sticky cover trap and a UV-light/suction trap (the most commonly used method to collect Culicoides). METHODS/RESULTS: Collections were made from 1.45 hours before sunset to 1.45 hours after sunset in June/July 2009 at an experimental sheep farm (INRA, Nouzilly, Western France), with 3 replicates of a 4 sites*4 traps randomized Latin square using one sheep per site. Collected Culicoides individuals were sorted morphologically to species, sex and physiological stages for females. Sibling species were identified using a molecular assay. A total of 534 Culicoides belonging to 17 species was collected. Abundance was maximal in the drop trap (232 females and 4 males from 10 species) whereas the diversity was the highest in the UV light/suction trap (136 females and 5 males from 15 species). Significant between trap differences abundance and parity rates were observed. CONCLUSIONS: Only the direct aspiration collected exclusively host-seeking females, despite a concern that human manipulation may influence estimation of the biting rate. The sticky cover trap assessed accurately the biting rate of abundant species even if it might act as an interception trap. The drop trap collected the highest abundance of Culicoides and may have caught individuals not attracted by sheep but by its structure. Finally, abundances obtained using the UV-light/suction trap did not estimate accurately Culicoides biting rate. PMID- 21707981 TI - Successful management of aggressive fibromatosis of the neck using wide surgical excision: a case report. AB - INTRODUCTION: Aggressive fibromatosis is a benign tumor, thought to arise from deep musculoaponeurotic structures, rarely found in the head or neck. However, when it does occur in the head and neck region, it tends to be more aggressive and associated with significant morbidity, which may be attributed to the vital vascular, neurological or anatomical structures in close proximity. CASE PRESENTATION: We report the case of a 39-year-old Pakistani man who presented with a two-month history of a lump on the right side of his neck. The mass was excised and histopathological analysis revealed a case of aggressive fibromatosis. CONCLUSION: Due to the rarity of the condition no guidelines are available on the indications and extent of each modality. Due to its aggressive behavior and tendency to invade local structures and recur, a multi-modality management strategy is usually employed. On the basis of this case, we suggest that aggressive surgery is a viable management option and may be successfully used as a single modality treatment. PMID- 21707982 TI - The case study approach. AB - The case study approach allows in-depth, multi-faceted explorations of complex issues in their real-life settings. The value of the case study approach is well recognised in the fields of business, law and policy, but somewhat less so in health services research. Based on our experiences of conducting several health related case studies, we reflect on the different types of case study design, the specific research questions this approach can help answer, the data sources that tend to be used, and the particular advantages and disadvantages of employing this methodological approach. The paper concludes with key pointers to aid those designing and appraising proposals for conducting case study research, and a checklist to help readers assess the quality of case study reports. PMID- 21707983 TI - CLUE: a randomized comparative effectiveness trial of IV nicardipine versus labetalol use in the emergency department. AB - INTRODUCTION: Our purpose was to compare the safety and efficacy of food and drug administration (FDA) recommended dosing of IV nicardipine versus IV labetalol for the management of acute hypertension. METHODS: Multicenter randomized clinical trial. Eligible patients had 2 systolic blood pressure (SBP) measures >=180 mmHg and no contraindications to nicardipine or labetalol. Before randomization, the physician specified a target SBP +/- 20 mmHg (the target range: TR). The primary endpoint was the percent of subjects meeting TR during the initial 30 minutes of treatment. RESULTS: Of 226 randomized patients, 110 received nicardipine and 116 labetalol. End organ damage preceded treatment in 143 (63.3%); 71 nicardipine and 72 labetalol patients. Median initial SBP was 212.5 (IQR 197, 230) and 212 mmHg (IQR 200,225) for nicardipine and labetalol patients (P = 0.68), respectively. Within 30 minutes, nicardipine patients more often reached TR than labetalol (91.7 vs. 82.5%, P = 0.039). Of 6 BP measures (taken every 5 minutes) during the study period, nicardipine patients had higher rates of five and six instances within TR than labetalol (47.3% vs. 32.8%, P = 0.026). Rescue medication need did not differ between nicardipine and labetalol (15.5 vs. 22.4%, P = 0.183). Labetalol patients had slower heart rates at all time points (P < 0.01). Multivariable modeling showed nicardipine patients were more likely in TR than labetalol patients at 30 minutes (OR 2.73, P = 0.028; C stat for model = 0.72) CONCLUSIONS: Patients treated with nicardipine are more likely to reach the physician-specified SBP target range within 30 minutes than those treated with labetalol. PMID- 21707984 TI - Enhanced biosurfactant production through cloning of three genes and role of esterase in biosurfactant release. AB - BACKGROUND: Biosurfactants have been reported to utilize a number of immiscible substrates and thereby facilitate the biodegradation of panoply of polyaromatic hydrocarbons. Olive oil is one such carbon source which has been explored by many researchers. However, studying the concomitant production of biosurfactant and esterase enzyme in the presence of olive oil in the Bacillus species and its recombinants is a relatively novel approach. RESULTS: Bacillus species isolated from endosulfan sprayed cashew plantation soil was cultivated on a number of hydrophobic substrates. Olive oil was found to be the best inducer of biosurfactant activity. The protein associated with the release of the biosurfactant was found to be an esterase. There was a twofold increase in the biosurfactant and esterase activities after the successful cloning of the biosurfactant genes from Bacillus subtilis SK320 into E.coli. Multiple sequence alignment showed regions of similarity and conserved sequences between biosurfactant and esterase genes, further confirming the symbiotic correlation between the two. Biosurfactants produced by Bacillus subtilis SK320 and recombinant strains BioS a, BioS b, BioS c were found to be effective emulsifiers, reducing the surface tension of water from 72 dynes/cm to as low as 30.7 dynes/cm. CONCLUSION: The attributes of enhanced biosurfactant and esterase production by hyper-producing recombinant strains have many utilities from industrial viewpoint. This study for the first time has shown a possible association between biosurfactant production and esterase activity in any Bacillus species. Biosurfactant-esterase complex has been found to have powerful emulsification properties, which shows promising bioremediation, hydrocarbon biodegradation and pharmaceutical applications. PMID- 21707985 TI - Validity of multiplex biomarker model of 6 genes for the differential diagnosis of thyroid nodules. AB - BACKGROUND: Currently the cytological examination of fine needle aspiration (FNA) biopsies is the standard technique for the pre-operative differential diagnosis of thyroid nodules. However, the results may be non-informative in ~20% of cases due to an inadequate sampling and the lack of highly specific, measurable cytological criteria, therefore ancillary biomarkers that could aid in these cases are clearly needed. The aim of our study was to evaluate the mRNA expression levels of 8 candidate marker genes as the diagnostic biomarkers for the discrimination of benign and malignant thyroid nodules and to find a combination of biomarkers with the highest diagnostic value. MATERIALS AND METHODS: mRNA expression levels of eight candidate marker genes - BIRC5, CCND1, CDH1, CITED1, DPP4, LGALS3, MET and TFF3 was measured by real-time RT-PCR in paired nodular and surrounding normal thyroid tissue specimens of 105 consecutive patients undergoing thyroid surgery and compared between different types of thyroid lesions. RESULTS: Significant differences in the mRNA expression levels between the normal and malignant thyroid tissues and between benign and malignant nodules were found for BIRC5, CCND1, CITED1, DPP4, LGALS3, MET and TFF3, but not CDH1. On a single gene basis, relative quantity (RQ) of LGALS3 had the highest diagnostic value for the discrimination of malignant and benign thyroid nodules (AUC = 0.832, P < 0.0001 and 90.9% sensitivity and 65.6% specificity at the optimal cut-off on ROC curve). The only two-marker set that outperformed LGALS3 was RQ sum of LGALS3 and BIRC5 (AUC = 0.841, P < 0.0001). An application of multivariate logistic regression analysis resulted in the generation of a multiplex biomarker model based on LGALS3, BIRC5, TFF3, CCND1, MET and CITED1 that had considerably higher specificity than a single marker or two marker gene based models (AUC = 0.895, P < 0.0001, 70.5% sensitivity and 93.4% specificity). CONCLUSIONS: This study confirmed that mRNA expression levels of 7 out of 8 candidate genes analysed have a diagnostic value for the distinction of benign and malignant thyroid nodules. The multiplex biomarker model based on 6 genes outperformed a single marker or two marker-based models and warrants feasibility studies on FNA biopsies and the validation in a larger cohort of patients. PMID- 21707986 TI - Prevalence of pseudoexfoliation syndrome and pseudoexfoliation glaucoma in Upper Egypt. AB - BACKGROUND: Pseudoexfoliation (PXF) is a recognized risk factor for developing cataract, glaucoma and lens dislocation. PXF is also associated with increased risk of complications during cataract surgery due to poor mydriasis and zonular weakness. The aim of this study is to report the prevalence of pseudoexfoliation among Upper Egyptians attending the ophthalmology clinic of Assiut University Hospital. METHODOLOGY: A retrospective, chart review study conducted in the period from February 2002 to August 2009. A total of 7738 patients aged 40 years or older attending the general ophthalmic clinics were included in this study. A detailed evaluation including ophthalmic and general history, slit lamp biomicroscopy, intraocular pressure measurement, gonioscopy and dilated eye examination were performed. Patients with pseudoexfoliative material on the anterior lens surface and / or the pupillary margin in either or both eyes were labeled as having PXF. RESULTS: Out of the 7738 patients included, three hundred twenty (4.14%) subjects had PXF. Mean age of PXF group was 68.15 years (SD 8.16, range 40-92 years). PXF was bilateral in 82.2% of cases. It was significantly associated with cataract, glaucoma and hearing loss. Of the PXF patients, 65% had cataract, 30.3% had glaucoma and 8.1% had hearing loss. CONCLUSION: Pseudoexfoliation appears to be a common disorder in older individuals in Upper Egypt. PMID- 21707987 TI - Single center experience on talc poudrage morbidity: focus on high talc dosage. AB - Malignant pleural effusion (MPE) is a common clinical problem of concern for most of the pneumologists and thoracic surgeons. A general consensus regarding the use of talc poudrage in treatment of MPE exists, but only few studies analyzed in detail talc insufflation related pulmonary morbidity. In particular, ARDS talc related is caused by physical and chemical effects of the small talc particles (50% particle size <15 MUm) and its occurrence is independent from the underlying disease, the quantity of talc used or the technique of talc instillation. In our series we observed 3 cases only (0.75%) of talc-related lung injury. This data strongly confirm the low rate of talc-related lung injury after talc poudrage in treatment of MPE regardless the amount of talc insufflated. PMID- 21707988 TI - Diagnosing dementia: no easy job. AB - BACKGROUND: From both clinical experience and research we learned that in complex progressive disorders such as dementia, diagnosis includes multiple steps, each with their own clinical and research characteristics. DISCUSSION: Diagnosing starts with a trigger phase in which the GP gradually realizes that dementia may be emerging. This is followed by a disease-oriented diagnosis and subsequently a care -oriented diagnosis. In parallel the GP should consider the consequences of this process for the caregiver and the interaction between both. As soon as a comprehensive diagnosis and care plan are available, monitoring follows. SUMMARY: We propose to split the diagnostic process into four diagnostic steps, followed by a monitoring phase. We recommend to include these steps when designing studies on screening, diagnosis and monitoring of patients with dementia and their families. PMID- 21707989 TI - An arrhythmia classification algorithm using a dedicated wavelet adapted to different subjects. AB - BACKGROUND: Numerous studies have been conducted regarding a heartbeat classification algorithm over the past several decades. However, many algorithms have also been studied to acquire robust performance, as biosignals have a large amount of variation among individuals. Various methods have been proposed to reduce the differences coming from personal characteristics, but these expand the differences caused by arrhythmia. METHODS: In this paper, an arrhythmia classification algorithm using a dedicated wavelet adapted to individual subjects is proposed. We reduced the performance variation using dedicated wavelets, as in the ECG morphologies of the subjects. The proposed algorithm utilizes morphological filtering and a continuous wavelet transform with a dedicated wavelet. A principal component analysis and linear discriminant analysis were utilized to compress the morphological data transformed by the dedicated wavelets. An extreme learning machine was used as a classifier in the proposed algorithm. RESULTS: A performance evaluation was conducted with the MIT-BIH arrhythmia database. The results showed a high sensitivity of 97.51%, specificity of 85.07%, accuracy of 97.94%, and a positive predictive value of 97.26%. CONCLUSIONS: The proposed algorithm achieves better accuracy than other state-of the-art algorithms with no intrasubject between the training and evaluation datasets. And it significantly reduces the amount of intervention needed by physicians. PMID- 21707990 TI - The economics of health and climate change: key evidence for decision making. AB - BACKGROUND: In responding to the health challenges of climate change, those responsible for health policies and resource allocations need to know the resource consequences of their decisions. This article examines the availability and strength of economic evidence for policy makers to draw on in making health policy decisions. METHODS: Relevant literature was obtained using a Medline and INTERNET search of key terms and institutions working in health and climate change. Eighteen available economic studies are presented under three categories of economic evidence: health damage cost, health adaptation cost and health economic evaluation. RESULTS: In economic studies valuing the predicted increased mortality from climate change, the health damages represent an important fraction of overall economic losses. Similarly, when considering broader health protection measures beyond the health sector (e.g. agriculture, water supply) health considerations are central. Global adaptation cost studies carried out so far indicate health sector costs of roughly US$2-5 billion annually (mid-estimates). However, these costs are expected to be an underestimate of the true costs, due to omitted health impacts, omitted economic impacts, and the costs of health actions in other sectors. No published studies compare the costs and benefits of specific health interventions to protect health from climate change. CONCLUSIONS: More economic studies are needed examining the costs and benefits of adaptation measures to inform policy making. There is an urgent need for climate change specific health economic guidelines to ensure robust methods are used, giving comparable results. Broader advocacy and focused training of decision makers is needed to increase the uptake of economic evidence in decision making. Until further climate change-specific economic studies have been conducted, decision makers should selectively draw on published studies of the costs and benefits of environmental health interventions. PMID- 21707991 TI - An unusual case of epidermolysis bullosa complicated by persistent oligoarticular juvenile idiopathic arthritis; lessons to be learned. AB - Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare and severe hereditary skin disease. Oligoarticular Juvenile Idiopathic Arthritis (JIA) although infrequent in the general paediatric population, is the most frequent type of autoimmune joint disease in children. While different in aetiology, both diseases are characterized by gradual deterioration in mobility and function. We report a female patient, diagnosed with RDEB at birth, who presented with inflammatory bowel disease (IBD) at the age of four years, and subsequently developed oligoarticular JIA at seven years of age, and discuss the diagnostic and treatment challenges of this unusual case. This report, besides presenting a unique case, also highlights the important issues that need to be taken into account when assessing and managing patients with such complex conditions. PMID- 21707992 TI - Bacterial infection profiles in lung cancer patients with febrile neutropenia. AB - BACKGROUND: The chemotherapy used to treat lung cancer causes febrile neutropenia in 10 to 40% of patients. Although most episodes are of undetermined origin, an infectious etiology can be suspected in 30% of cases. In view of the scarcity of data on lung cancer patients with febrile neutropenia, we performed a retrospective study of the microbiological characteristics of cases recorded in three medical centers in the Picardy region of northern France. METHODS: We analyzed the medical records of lung cancer patients with neutropenia (neutrophil count < 500/mm(3)) and fever (temperature > 38.3 degrees C). RESULTS: The study included 87 lung cancer patients with febrile neutropenia (mean age: 64.2). Two thirds of the patients had metastases and half had poor performance status. Thirty-three of the 87 cases were microbiologically documented. Gram-negative bacteria (mainly enterobacteriaceae from the urinary and digestive tracts) were identified in 59% of these cases. Staphylococcus species (mainly S. aureus) accounted for a high proportion of the identified Gram-positive bacteria. Bacteremia accounted for 60% of the microbiologically documented cases of fever. 23% of the blood cultures were positive. 14% of the infections were probably hospital-acquired and 14% were caused by multidrug-resistant strains. The overall mortality rate at day 30 was 33% and the infection-related mortality rate was 16.1%. Treatment with antibiotics was successful in 82.8% of cases. In a multivariate analysis, predictive factors for treatment failure were age >60 and thrombocytopenia < 20000/mm(3). CONCLUSION: Gram-negative species were the most frequently identified bacteria in lung cancer patients with febrile neutropenia. Despite the success of antibiotic treatment and a low-risk neutropenic patient group, mortality is high in this particular population. PMID- 21707993 TI - Erectile dysfunction, physical activity and metabolic syndrome: differences in markers of atherosclerosis. AB - BACKGROUND: Erectile dysfunction (ED), impaired arterial elasticity, elevated resting heart rate as well as increased levels of oxidized LDL and fibrinogen associate with future cardiovascular events. Physical activity is crucial in the prevention of cardiovascular diseases (CVD), while metabolic syndrome (MetS) comprises an increased risk for CVD events. The aim of this study was to assess whether markers of subclinical atherosclerosis are associated with the presence of ED and MetS, and whether physical activity is protective of ED. METHODS: 57 MetS (51.3 +/- 8.0 years) and 48 physically active (PhA) (51.1 +/- 8.1 years) subjects participated in the study. ED was assessed by the International Index of Erectile Function (IIEF) questionnaire, arterial elasticity by a radial artery tonometer (HDI/PulseWaveTM CR-2000) and circulating oxLDL by a capture ELISA immunoassay. Fibrinogen and lipids were assessed by validated methods. The calculation of mean daily energy expenditure of physical exercise was based on a structured questionnaire. RESULTS: ED was more often present among MetS compared to PhA subjects, 63.2% and 27.1%, respectively (p < 0.001). Regular physical exercise at the level of > 400 kcal/day was protective of ED (OR 0.12, 95% CI 0.017-0.778, p = 0.027), whereas increased fibrinogen (OR 4.67, 95% CI 1.171 18.627, p = 0.029) and elevated resting heart rate (OR 1.07, 95% CI 1.003-1.138, p = 0.04) were independently associated with the presence of ED. In addition, large arterial elasticity (ml/mmHgx10) was lower among MetS compared to PhA subjects (16.6 +/- 4.0 vs. 19.6 +/- 4.2, p < 0.001), as well as among ED compared to non-ED subjects (16.7 +/- 4.6 vs. 19.0 +/- 3.9, p = 0.008). Fibrinogen and resting heart rate were highest and large arterial elasticity lowest among subjects with both MetS and ED. CONCLUSIONS: Markers of subclinical atherosclerosis associated with the presence of ED and were most evident among subjects with both MetS and ED. Thus, especially MetS patients presenting with ED should be considered at high risk for CVD events. Physical activity, on its part, seems to be protective of ED. TRIAL REGISTRATION: ClinicalTrials.gov NCT01119404. PMID- 21707994 TI - The asthma candidate gene NPSR1 mediates isoform specific downstream signalling. AB - BACKGROUND: Neuropeptide S Receptor 1 (NPSR1, GPRA, GPR154) was first identified as an asthma candidate gene through positional cloning and has since been replicated as an asthma and allergy susceptibility gene in several independent association studies. In humans, NPSR1 encodes two G protein-coupled receptor variants, NPSR1-A and NPSR1-B, with unique intracellular C-termini. Both isoforms show distinct expression pattern in asthmatic airways. Although NPSR1-A has been extensively studied, functional differences and properties of NPSR1-B have not yet been clearly examined. Our objective was to investigate downstream signalling properties of NPSR1-B and functional differences between NPSR1-A and NPSR1-B. METHODS: HEK-293 cells transiently overexpressing NPSR1-A or NPSR1-B were stimulated with the ligand neuropeptide S (NPS) and downstream signalling effects were monitored by genome-scale affymetrix expression-arrays. The results were verified by NPS concentration-response and time series analysis using qRT-PCR, cAMP and Ca2+ assays, and cAMP/PKA, MAPK/JNK and MAPK/ERK pathway specific reporter assays. RESULTS: NPSR1-B signalled through the same pathways and regulated the same genes as NPSR1-A, but NPSR1-B yielded lower induction on effector genes than NPSR1-A, with one notable exception, CD69, a marker of regulatory T cells. CONCLUSIONS: We conclude that NPSR1-B is regulating essentially identical set of genes as NPSR1-A, with few, but possibly important exceptions, and that NPSR1-A induces stronger signalling effects than NPSR1-B. Our findings suggest an isoform-specific link to pathogenetic processes in asthma and allergy. PMID- 21707995 TI - Lactobacillus plantarum (VR1) isolated from an ayurvedic medicine (Kutajarista) ameliorates in vitro cellular damage caused by Aeromonas veronii. AB - BACKGROUND: Lactobacillus plantarum is considered as a safe and effective probiotic microorganism. Among various sources of isolation, traditionally fermented foods are considered to be rich in Lactobacillus spp., which can be exploited for their probiotic attribute. Antibacterial property of L. plantarum has been demonstrated against various enteric pathogens in both in vitro and in vivo systems. This study was aimed at characterizing L. plantarum isolated from Kutajarista, an ayurvedic fermented biomedicine, and assessing its antagonistic property against a common enteropathogen Aeromonas veronii. RESULTS: We report the isolation of L. plantarum (VR1) from Kutajarista, and efficacy of its cell free supernatant (CFS) in amelioration of cytotoxicity caused by Aeromonas veronii. On the part of probiotic attributes, VR1 was tolerant to pH 2, 0.3% bile salts and simulated gastric juice. Additionally, VR1 also exhibited adhesive property to human intestinal HT-29 cell line. Furthermore, CFS of VR1 was antibacterial to enteric pathogens like Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Aeromonas veronii and clinical isolates of P. aeruginosa and E. coli. Detailed study regarding the effect of VR1 CFS on A. veronii cytotoxicity showed a significant decrease in vacuole formation and detrimental cellular changes in Vero cells. On the other hand, A. veronii CFS caused disruption of tight junction proteins ZO-1 and actin in MDCK cell line, which was prevented by pre-incubation with CFS of VR1. CONCLUSIONS: This is the first study to report isolation of L. plantarum (VR1) from Kutajarista and characterisation for its probiotic attributes. Our study demonstrates the antagonistic property of VR1 to A. veronii and effect of VR1 CFS in reduction of cellular damage caused by A. veronii in both Vero and MDCK cell lines. PMID- 21707996 TI - Evaluation of a reproductive health awareness program for adolescence in urban Tanzania--a quasi-experimental pre-test post-test research. AB - BACKGROUND: Sub-Saharan Africa is among the countries where 10% of girls become mothers by the age of 16 years old. The United Republic of Tanzania located in Sub-Saharan Africa is one country where teenage pregnancy is a problem facing adolescent girls. Adolescent pregnancy has been identified as one of the reasons for girls dropping out from school. This study's purpose was to evaluate a reproductive health awareness program for the improvement of reproductive health for adolescents in urban Tanzania. METHODS: A quasi-experimental pre-test and post-test research design was conducted to evaluate adolescents' knowledge, attitude, and behavior about reproductive health before and after the program. Data were collected from students aged 11 to 16, at Ilala Municipal, Dar es Salaam, Tanzania. An anonymous 23-item questionnaire provided the data. The program was conducted using a picture drama, reproductive health materials and group discussion. RESULTS: In total, 313 questionnaires were distributed and 305 (97.4%) were useable for the final analysis. The mean age for girls was 12.5 years and 13.2 years for boys. A large minority of both girls (26.8%) and boys (41.4%) had experienced sex and among the girls who had experienced sex, 51.2% reported that it was by force. The girls' mean score in the knowledge pre-test was 5.9, and 6.8 in post-test, which increased significantly (t=7.9, p=0.000). The mean behavior pre-test score was 25.8 and post-test was 26.6, which showed a significant increase (t=3.0, p=0.003). The boys' mean score in the knowledge pre test was 6.4 and 7.0 for the post-test, which increased significantly (t=4.5, p=0.000). The mean behavior pre-test score was 25.6 and 26.4 in post-test, which showed a significant increase (t=2.4, p=0.019). However, the pre-test and post test attitude scores showed no statistically significant difference for either girls or boys. CONCLUSIONS: Teenagers have sexual experiences including sexual violence. Both of these phenomena are prevalent among school-going adolescents. The reproductive health program improved the students' knowledge and behavior about sexuality and decision-making after the program for both girls and boys. However, their attitudes about reproductive health were not likely to change based on the educational intervention as designed for this study. PMID- 21707997 TI - Toxoplasma gondii peroxiredoxin promotes altered macrophage function, caspase-1 dependent IL-1beta secretion enhances parasite replication. AB - Alternatively activated macrophages (AAM) are a key feature Th2 immunity and have been associated with a variety of roles during helminth infection. The role this cell subset plays in protozoan infection remain relatively unexplored, herein we describe the effects of a redox enzyme (rTgPrx) derived from Toxoplasma gondii on murine macrophage phenotype in vitro. RTgPrx has been previously associated with the maintainance of parasite oxidative balance. Here our experiments show that rTgPrx promotes AAM as indicated by high arginase-1 (arg-1), YM1 and FIZZ expression via both signal transducer and activator of transcription (STAT)6 dependent and -independent mechanisms. Additionally rTgPrx treatment reduced caspase-1 activity and IL-1beta secretion, while simultaneously increasing IL-10 release. Furthermore the in vitro replication of T. gondii (RH strain) was enhanced when macrophages were treated with rTgPrx. This is in contrast with the previously described effects of a Plasmodium berghei ANKA 2-cys-peroxiredoxin that promotes pro-inflammatory cytokine production. These results highlight the role of T. gondii derived redox enzymes as important immune modulators and potentially indicate a role for AAM in modulating immunopathology and promoting parasite replication during T. gondii infection. PMID- 21707998 TI - Antibacterial and resistance-modifying activities of thymoquinone against oral pathogens. AB - BACKGROUND: The presence of resistant bacteria in the oral cavity can be the major cause of dental antibiotic prophylaxis failure. Multidrug efflux has been described for many organisms, including bacteria and fungi as part of their drugs resistance strategy. The discovery of a new efflux pump inhibitor could extend the useful lifetime of some antibiotics. METHODS: In this study, the MICs of thymoquinone (TQ), tetracycline and benzalkonium chloride (BC) were determined in absence and in presence of a sub-MIC doses of thymoquinone (1/2 MIC). In addition the 4,6-diamidino-2-phenylindole (DAPI) efflux assay was carried out to determine the effect of TQ on DAPI cells accumulation. RESULTS: TQ induced a selective antimicrobial activity. Its synergic effect resulted in at least a 4-fold potentiation of the tested antibiotics and antiseptic. In addition, TQ inhibited the DAPI efflux activity in a concentration-dependent manner. The rate of DAPI accumulation in clinical isolates was enhanced with TQ (0 to 200 MUg/ml). There is also a decrease in loss of DAPI from bacteria in the presence of TQ. The concentration causing 50% of DAPI efflux inhibition after 15 minutes was approximately 59 MUg/ml for Pseudomonas aeroginosa and 100 MUg/ml and Staphylococcus aureus respectively. CONCLUSIONS: TQ possesses a selective antibacterial activity against oral bacteria. It is therefore suggested that TQ could be used as a source of natural products with resistance-modifying activity. Further investigation is needed to assess their clinical relevance. PMID- 21707999 TI - The benefits of integrated systems for managing both samples and experimental data: An opportunity for labs in universities and government research institutions to lead the way. AB - Currently most biomedical labs in universities and government funded research institutions use paper lab notebooks for recording experimental data and spreadsheets for managing sample data. One consequence is that sample management and documenting experiments are viewed as separate and distinct activities, notwithstanding that samples and aliquots are an integral part of a majority of the experiments carried out by these labs.Various drivers are pushing labs towards integrated management of sample data and experimental data. These include the ever increasing amounts of both kinds of data, the increasing adoption of online collaborative tools, changing expectations about online communication, and the increasing affordability of electronic lab notebooks and sample management software. There is now an opportunity for smaller labs, which have been slow to move from paper to electronic record keeping, to leapfrog better resourced commercial labs and lead the way in adopting the new generation of tools which permit integrated management of samples and experimental data and a range of tangible benefits to conducting research, including:1. Fewer lost and mislabelled samples2. Clearer visualization of relationships between samples and experiments3. Reduction of experimental error4. More effective search5. Productivity gains6. More efficient use of freezers, leading to cost reduction and enhanced sustainability7. Improved archiving and enhanced memory at the lab and institutional levels. PMID- 21708000 TI - Does the inclusion of 'professional development' teaching improve medical students' communication skills? AB - BACKGROUND: This study investigated whether the introduction of professional development teaching in the first two years of a medical course improved students' observed communication skills with simulated patients. Students' observed communication skills were related to patient-centred attitudes, confidence in communicating with patients and performance in later clinical examinations. METHODS: Eighty-two medical students from two consecutive cohorts at a UK medical school completed two videoed consultations with a simulated patient: one at the beginning of year 1 and one at the end of year 2. Group 1 (n = 35) received a traditional pre-clinical curriculum. Group 2 (n = 47) received a curriculum that included communication skills training integrated into a 'professional development' vertical module. Videoed consultations were rated using the Evans Interview Rating Scale by communication skills tutors. A subset of 27% were double-coded. Inter-rater reliability is reported. RESULTS: Students who had received the professional development teaching achieved higher ratings for use of silence, not interrupting the patient, and keeping the discussion relevant compared to students receiving the traditional curriculum. Patient centred attitudes were not related to observed communication. Students who were less nervous and felt they knew how to listen were rated as better communicators. Students receiving the traditional curriculum and who had been rated as better communicators when they entered medical school performed less well in the final year clinical examination. CONCLUSIONS: Students receiving the professional development training showed significant improvements in certain communication skills, but students in both cohorts improved over time. The lack of a relationship between observed communication skills and patient-centred attitudes may be a reflection of students' inexperience in working with patients, resulting in 'patient-centredness' being an abstract concept. Students in the early years of their medical course may benefit from further opportunities to practise basic communication skills on a one-to-one basis with patients. PMID- 21708001 TI - Arthritis is associated with T-cell-induced upregulation of Toll-like receptor 3 on synovial fibroblasts. AB - INTRODUCTION: Toll-like receptors (TLRs) are likely to play crucial roles in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to determine the key TLRs in synovium and explore their roles in the activation of fibroblast like synoviocytes (FLSs) mediated by T cells in arthritis. METHODS: Pristane induced arthritis (PIA) was established by subcutaneous injection with pristane at the base of the rat's tail. TLR expression in synovium from PIA rats was detected at different time points by performing real-time PCR. Polyinosinic:polycytidylic acid (poly(I:C)) was intra-articularly administrated to PIA rats, and arthritis was monitored macroscopically and microscopically. Synovial TLR3 was detected by immunohistochemical staining. Rat FLSs were stimulated with pristane-primed T cells or pristane-primed, T-cell conditioned medium. The intervention of TLR3 in FLSs was achieved by specific short-hairpin RNA (shRNA) or an antibody. The migration ability of FLSs was measured by using the scratch test, and gene expression was detected by using real-time PCR. FLSs from RA patients were stimulated with various cytokines and TLR ligands, and TLR3 expression was detected by performing real-time PCR. In addition, with different concentrations of poly(I:C) stimulation, TLR3 expression of FLSs from RA patients and patients with osteoarthritis (OA) was compared. RESULTS: Synovium TLR3 displayed early and persistent overexpression in PIA rats. TLR3 was expressed in FLSs, and local treatment with poly(I:C) synergistically aggravated the arthritis. Rat FLSs co-cultured with pristane-primed T cells showed strengthened migration ability and significant upregulation of TLR3, IFN-beta, IL-6 and matrix metalloproteinase 3 (MMP3) expression, which could also be induced by pristane primed, T-cell conditioned medium. The upregulation of cytokines and MMPs was blocked by shRNA or TLR3 antibodies. In RA FLSs with cytokine or TLR ligand stimulation, TLR3 expression exhibited remarkable upregulation. Furthermore, RA FLSs showed higher reactivity than OA FLSs to poly(I:C). CONCLUSIONS: TLR3 in the synovium of PIA rats was overexpressed, and activation of the TLR3 signaling pathway could aggravate this arthritis. The induction of TLR3 in FLSs resulted from T cell-derived inflammatory stimulation and could further mediate FLS activation in arthritis. We conclude that TLR3 upregulation of FLSs activated by T cells results in articular inflammation. PMID- 21708002 TI - A mutation degree model for the identification of transcriptional regulatory elements. AB - BACKGROUND: Current approaches for identifying transcriptional regulatory elements are mainly via the combination of two properties, the evolutionary conservation and the overrepresentation of functional elements in the promoters of co-regulated genes. Despite the development of many motif detection algorithms, the discovery of conserved motifs in a wide range of phylogenetically related promoters is still a challenge, especially for the short motifs embedded in distantly related gene promoters or very closely related promoters, or in the situation that there are not enough orthologous genes available. RESULTS: A mutation degree model is proposed and a new word counting method is developed for the identification of transcriptional regulatory elements from a set of co expressed genes. The new method comprises two parts: 1) identifying overrepresented oligo-nucleotides in promoters of co-expressed genes, 2) estimating the conservation of the oligo-nucleotides in promoters of phylogenetically related genes by the mutation degree model. Compared with the performance of other algorithms, our method shows the advantages of low false positive rate and higher specificity, especially the robustness to noisy data. Applying the method to co-expressed gene sets from Arabidopsis, most of known cis elements were successfully detected. The tool and example are available at http://mcube.nju.edu.cn/jwang/lab/soft/ocw/OCW.html. CONCLUSIONS: The mutation degree model proposed in this paper is adapted to phylogenetic data of different qualities, and to a wide range of evolutionary distances. The new word-counting method based on this model has the advantage of better performance in detecting short sequence of cis-elements from co-expressed genes of eukaryotes and is robust to less complete phylogenetic data. PMID- 21708003 TI - "MY PKU": increasing self-management in patients with phenylketonuria. A randomized controlled trial. AB - BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine metabolism. The inability to convert phenylalanine (Phe) into tyrosine causes Phe to accumulate in the body. Adherence to a protein restricted diet, resulting in reduced Phe levels, is essential to prevent cognitive decline. Frequent evaluation of plasma Phe levels and, if necessary, adjustment of the diet are the mainstay of treatment. We aimed to assess whether increased self management of PKU patients and/or their parents is feasible and safe, by providing direct online access to blood Phe values without immediate professional guidance. METHODS: Thirty-eight patients aged >= 1 year participated in a 10 month randomized controlled trial. Patients were randomized into a study group (1) or a control group (2). Group 2 continued the usual procedure: a phone call or e-mail by a dietician in case of a deviant Phe value. Group 1 was given a personal "My PKU" web page with a graph of their recent and previous Phe values, online general information about the dietary treatment and the Dutch PKU follow up guidelines, and a message-box to contact their dietician if necessary. Phe values were provided on "My PKU" without advice. Outcome measures were: differences in mean Phe value, percentage of values above the recommended range and Phe sample frequency, between a 10-month pre-study period and the study period in each group, and between the groups in both periods. Furthermore we assessed satisfaction of patients and/or parents with the 'My PKU' procedure of online availability. RESULTS: There were no significant differences in mean Phe value, percentage of values above recommended range or in frequency of blood spot sampling for Phe determination between the pre-study period and the study period in each group, nor between the 2 groups during the periods. All patients and/or parents expressed a high level of satisfaction with the new way of disease management. CONCLUSIONS: Increased self-management in PKU by providing patients and/or parents their Phe values without advice is feasible and safe and is highly appreciated. TRIAL REGISTRATION: The trial was registered with The Netherlands National Trial Register (NTR #1171) before recruitment of patients. PMID- 21708004 TI - SKY analysis revealed recurrent numerical and structural chromosome changes in BDII rat endometrial carcinomas. AB - BACKGROUND: Genomic alterations are common features of cancer cells, and some of these changes are proven to be neoplastic-specific. Such alterations may serve as valuable tools for diagnosis and classification of tumors, prediction of clinical outcome, disease monitoring, and choice of therapy as well as for providing clues to the location of crucial cancer-related genes.Endometrial carcinoma (EC) is the most frequently diagnosed malignancy of the female genital tract, ranking fourth among all invasive tumors affecting women. Cytogenetic studies of human ECs have not produced very conclusive data, since many of these studies are based on karyotyping of limited number of cases and no really specific karyotypic changes have yet been identified. As the majority of the genes are conserved among mammals, the use of inbred animal model systems may serve as a tool for identification of underlying genes and pathways involved in tumorigenesis in humans. In the present work we used spectral karyotyping (SKY) to identify cancer related aberrations in a well-characterized experimental model for spontaneous endometrial carcinoma in the BDII rat tumor model. RESULTS: Analysis of 21 experimental ECs revealed specific nonrandom numerical and structural chromosomal changes. The most recurrent numerical alterations were gains in rat chromosome 4 (RNO4) and losses in RNO15. The most commonly structural changes were mainly in form of chromosomal translocations and were detected in RNO3, RNO6, RNO10, RNO11, RNO12, and RNO20. Unbalanced chromosomal translocations involving RNO3p was the most commonly observed structural changes in this material followed by RNO11p and RNO10 translocations. CONCLUSION: The non-random nature of these events, as documented by their high frequencies of incidence, is suggesting for dynamic selection of these changes during experimental EC tumorigenesis and therefore for their potential contribution into development of this malignancy. Comparative molecular analysis of the identified genetic changes in this tumor model with those reported in the human ECs may provide new insights into underlying genetic changes involved in EC development and tumorigenesis. PMID- 21708005 TI - Low expression of aldehyde dehydrogenase 1A1 (ALDH1A1) is a prognostic marker for poor survival in pancreatic cancer. AB - BACKGROUND: Aldehyde dehydrogenase 1 (ALDH1) has been characterised as a cancer stem cell marker in different types of tumours. Additionally, it plays a pivotal role in gene regulation and endows tumour cells with augmented chemoresistance. Recently, ALDH1A1 has been described as a prognostic marker in a pancreatic cancer tissue microarray. The aim of this study was to reevaluate the expression of ALDH1A1 as a prognostic marker on whole-mount tissue sections. METHODS: Real time-quantitative-PCR (qRT-PCR) and Western blotting were used to evaluate the expression profile of ALDH1A1 in seven pancreatic cancer cell lines and one non malignant pancreatic cell line. Immunostaining against ALDH1A1 and Ki-67 was performed on paraffin-embedded samples from 97 patients with pancreatic cancer. The immunohistochemical results were correlated to histopathological and clinical data. RESULTS: qRT-PCR and Western blotting revealed a different expression pattern of ALDH1A1 in different malignant and non-malignant pancreatic cell lines. Immunohistochemical analysis demonstrated that ALDH1A1 was confined to the cellular cytoplasm and occurred in 72 cases (74%), whereas it was negative in 25 cases (26%). High expression of ALDH1A1 was significantly correlated to an increased proliferation rate (Spearman correlation, p = 0.01). Univariate and multivariate analyses showed that decreased expression of ALDH1A1 is an independent adverse prognostic factor for overall survival. CONCLUSIONS: Immunohistochemical analysis on whole-mount tissue slides revealed that ALDH1A1 is more abundantly expressed in pancreatic cancer than initially reported by a tissue microarray analysis. Moreover, high expression of ALDH1A1 correlated significantly with the proliferation of tumour cells. Intriguingly, this study is the first which identifies low expression of ALDH1A1 as an independent adverse prognostic marker for overall survival in pancreatic cancer. PMID- 21708006 TI - Compare the differences of synonymous codon usage between the two species within cardiovirus. AB - BACKGROUND: Cardioviruses are positive-strand RNA viruses in the Picornaviridae family that can cause enteric infection in rodents and also been detected at lower frequencies in other mammals such as pigs and human beings. The Cardiovirus genus consists two distinct species: Encephalomyocarditis virus (EMCV) and Theilovirus (ThV). There are a lot differences between the two species. In this study, the differences of codon usage in EMCV and ThV were compared. RESULTS: The mean ENC values of EMCV and ThV are 54.86 and 51.08 respectively, higher than 40.And there are correlations between (C+G)12% and (C+G)3% for both EMCV and ThV (r = -0.736; r = 0.986, P < 0.01, repectively). For ThV the (C+G)12%, (C+G)3%, axis f'1 and axis f'2 had a significant correlations respectively but not for EMCV. According to the RSCU values, the EMCV species seemed to prefer U, G and C ending codon, while the ThV spice seemed to like using U and A ending codon. However, in both genus AGA for Arg, AUU for Ile, UCU for Ser, and GGA for Gly were chosen preferentially. Correspondence analysis detected one major trend in the first axis (f'1) which accounted for 22.89% of the total variation, and another major trend in the second axis (f'2) which accounted for 17.64% of the total variation. And the plots of the same serotype seemed at the same region at the coordinate. CONCLUSION: The overall extents of codon usage bias in both EMCV and ThV are low. The mutational pressure is the main factor that determines the codon usage bias, but the (C+G) content plays a more important role in codon usage bias for ThV than for EMCV. The synonymous codon usage pattern in both EMCV and ThV genes is gene function and geography specific, but not host specific. Maybe the serotype is one factor effected the codon bias for ThV, and location has no significant effect on the variations of synonymous codon usage in these virus genes. PMID- 21708007 TI - Energy expenditure of interruptions to sedentary behavior. AB - BACKGROUND: Advances in technology, social influences and environmental attributes have resulted in substantial portions of the day spent in sedentary pursuits. Sedentary behavior may be a cause of many chronic diseases including obesity, insulin resistance, type 2 diabetes and the metabolic syndrome. Research demonstrated that breaking up sedentary time was beneficially associated with markers of body composition, cardiovascular health and type 2 diabetes. Therefore, the purpose of this study was to quantify the total energy expenditure of three different durations of physical activity within a 30-minute sedentary period and to examine the potential benefits of interrupting sedentary behavior with physical activity for weight control. METHODS: Participants completed four consecutive 30-minute bouts of sedentary behavior (reading, working on the computer, or doing other desk activities) with and without interruptions of walking at a self-selected pace. Bout one contained no walking interruptions. Bout two contained a 1-minute walking period. Bout three contained a 2-minute walking period. Bout four contained a 5-minute walking period. Body composition and resting metabolic rate were assessed. RESULT: Twenty males and females (18-39 years) completed this study. Results of the repeated measures analysis of variance with post-hoc testing showed that significantly more energy was expended during each 30 minute sedentary bout with a walking break than in the 30 minute sedentary bout (p < 0.05 for all comparisons). On average, participants expended an additional 3.0, 7.4, and 16.5 additional net or activity kilocalories during bouts 2, 3, and 4, respectively compared with bout 1. When extrapolated for a full eight-hour working day, this data shows that an individual would theoretically expend an additional 24, 59 or 132 kilocalories per day, if they stood up and walked at a normal, self selected pace for one, two or five minutes every hour, respectively, compared with sitting for the 8-hour period. CONCLUSIONS: This study demonstrated that making small changes, such as taking a five minute walking break every hour could yield beneficial weight control or weight loss results. Therefore, taking breaks from sedentary time is a potential outlet to prevent obesity and the rise of obesity in developed countries. PMID- 21708008 TI - Peritoneal lymphomatosis confounded by prior history of colon cancer: a case report. AB - BACKGROUND: It is well known that carcinomas of the gastrointestinal tract are frequently associated with peritoneal carcinomatosis. In contrast to that entity extensive involvement of the peritoneal cavity with malignant lymphoma is rare. CASE PRESENTATION: This is the first case reporting coexistence of peritoneal lymphomatosis and a previous history of colon cancer, which is a highly challenging clinical situation. CONCLUSIONS: If not aware of this unusual condition medical history, radiologic finding and laboratory data alone can lead to wrong diagnosis as in this case. PMID- 21708009 TI - Clinicopathological and prognostic significance of HER-2/neu and VEGF expression in colon carcinomas. AB - BACKGROUND: HER-2/neu and VEGF expression is correlated with disease behaviors in various cancers. However, evidence for their expression in colon cancer is rather contradictory both for the protein expression status and prognostic value. HER 2/neu is found to participate in VEGF regulation, and has known correlation with VEGF expression in some tumors. In this study, we investigated HER-2/neu and VEGF expression in Chinese colon patients and explored whether there was any correlation between their expression patterns. METHODS: HER-2/neu and VEGF were investigated immunohistochemically using tumor samples obtained from 317 colon cancer patients with all tumor stages. Correlation of the degree of staining with clinicopathological parameters and survival was investigated. RESULTS: Positive expression rates of HER-2/neu and VEGF in colon cancer were 15.5% and 55.5% respectively. HER-2/neu expression was significantly correlated with tumor size and distant metastases (P < 0.05), but was not an independent prognostic marker of survival (P > 0.05). Expression of VEGF was significantly correlated with tumor size, tumor stage, lymph node metastases, and distant metastases (P < 0.05). The 5-year survival rate in patients with negative and positive VEGF expression was 70.2% and 61.9% respectively; the difference was not statistically significant (P = 0.146). No correlation between HER-2/neu and VEGF expression was detected (P = 0.151). CONCLUSIONS: HER-2/neu and VEGF are not important prognostic markers of colon cancer. The present results do not support any association between HER2/neu and VEGF expression in this setting. PMID- 21708010 TI - Are fish immune systems really affected by parasites? An immunoecological study of common carp (Cyprinus carpio). AB - BACKGROUND: The basic function of the immune system is to protect an organism against infection in order to minimize the fitness costs of being infected. According to life-history theory, energy resources are in a trade-off between the costly demands of immunity and other physiological demands. Concerning fish, both physiology and immunity are influenced by seasonal changes (i.e. temporal variation) associated to the changes of abiotic factors (such as primarily water temperature) and interactions with pathogens and parasites. In this study, we investigated the potential associations between the physiology and immunocompetence of common carp (Cyprinus carpio) collected during five different periods of a given year. Our sampling included the periods with temporal variability and thus, it presented a different level in exposure to parasites. We analyzed which of two factors, seasonality or parasitism, had the strongest impact on changes in fish physiology and immunity. RESULTS: We found that seasonal changes play a key role in affecting the analyzed measurements of physiology, immunity and parasitism. The correlation analysis revealed the relationships between the measures of overall host physiology, immunity and parasite load when temporal variability effect was removed. When analyzing separately parasite groups with different life-strategies, we found that fish with a worse condition status were infected more by monogeneans, representing the most abundant parasite group. The high infection by cestodes seems to activate the phagocytes. A weak relationship was found between spleen size and abundance of trematodes when taking into account seasonal changes. CONCLUSIONS: Even if no direct trade-off between the measures of host immunity and physiology was confirmed when taking into account the seasonality, it seems that seasonal variability affects host immunity and physiology through energy allocation in a trade-off between life important functions, especially reproduction and fish condition. Host immunity measures were not found to be in a trade-off with the investigated physiological traits or functions, but we confirmed the immunosuppressive role of 11-ketotestosterone on fish immunity measured by complement activity. We suggest that the different parasite life-strategies influence different aspects of host physiology and activate the different immunity pathways. PMID- 21708012 TI - Predicting a small molecule-kinase interaction map: A machine learning approach. AB - BACKGROUND: We present a machine learning approach to the problem of protein ligand interaction prediction. We focus on a set of binding data obtained from 113 different protein kinases and 20 inhibitors. It was attained through ATP site dependent binding competition assays and constitutes the first available dataset of this kind. We extract information about the investigated molecules from various data sources to obtain an informative set of features. RESULTS: A Support Vector Machine (SVM) as well as a decision tree algorithm (C5/See5) is used to learn models based on the available features which in turn can be used for the classification of new kinase-inhibitor pair test instances. We evaluate our approach using different feature sets and parameter settings for the employed classifiers. Moreover, the paper introduces a new way of evaluating predictions in such a setting, where different amounts of information about the binding partners can be assumed to be available for training. Results on an external test set are also provided. CONCLUSIONS: In most of the cases, the presented approach clearly outperforms the baseline methods used for comparison. Experimental results indicate that the applied machine learning methods are able to detect a signal in the data and predict binding affinity to some extent. For SVMs, the binding prediction can be improved significantly by using features that describe the active site of a kinase. For C5, besides diversity in the feature set, alignment scores of conserved regions turned out to be very useful. PMID- 21708011 TI - Longitudinal association of physical activity and sedentary behavior during leisure time with health-related quality of life in community-dwelling older adults. AB - BACKGROUND: Evidence on the relation between leisure-time physical activity (LTPA) and health-related quality of life (HRQoL) in older adults is based primarily on clinical trials of physical exercise programs in institutionalized persons and on cross-sectional studies of community-dwelling persons. Moreover, there is no evidence on whether leisure-time sedentary behavior (LTSB) is associated with HRQoL independently of LTPA. This study examined the longitudinal association between LTPA, LTSB, and HRQoL in older community-dwelling adults in Spain. METHODS: Prospective cohort study of 1,097 persons aged 62 and over. In 2003 LTPA in MET-hr/week was measured with a validated questionnaire, and LTSB was estimated by the number of sitting hours per week. In 2009 HRQoL was measured with the SF-36 questionnaire. Analyses were done with linear regression and adjusted for the main confounders. RESULTS: Compared with those who did no LTPA, subjects in the upper quartile of LTPA had better scores on the SF-36 scales of physical functioning (beta 5.65; 95% confidence interval [CI] 1.32-9.98; p linear trend < 0.001), physical role (beta 7.38; 95% CI 0.16-14.93; p linear trend < 0.001), bodily pain (beta 6.92; 95% CI 1.86-11.98; p linear trend < 0.01), vitality (beta 5.09; 95% CI 0.76-9.41; p linear trend < 0.004) social functioning (beta 7.83; 95% CI 2.89-12.75; p linear trend < 0.001), emotional role (beta 8.59; 95% CI 1.97-15.21; p linear trend < 0.02) and mental health (beta 4.20; 95% CI 0.26-8.13; p linear trend < 0.06). As suggested by previous work in this field, these associations were clinically relevant because the beta regression coefficients were higher than 3 points. Finally, the number of sitting hours showed a gradual and inverse relation with the scores on most of the SF-36 scales, which was also clinically relevant. CONCLUSIONS: Greater LTPA and less LTSB were independently associated with better long-term HRQoL in older adults. PMID- 21708013 TI - Spatial and temporal distribution patterns of Anopheles arabiensis breeding sites in La Reunion Island--multi-year trend analysis of historical records from 1996 2009. AB - BACKGROUND: An often confounding facet of the dynamics of malaria vectors is the aquatic larval habitat availability and suitable conditions under which they can thrive. Here, we investigated the impact of environmental factors on the temporal and spatial distribution of larval habitats of Anopheles arabiensis in different locations on La Reunion Island. METHODS: A retrospective examination was made from archival data which provided the complete enumeration of An. arabiensis breeding habitats in three distinct geographic zones--extending North-east, West and South of the island over 14 years, from January 1996 to December 2009. Data on the occurrence and the number of active larval habitats at each of a total of 4376 adjacent ellipsoid grid cells (216,506 square meters each) were used (1) to provide the geographic extent of breeding site availability from year to year and (2) to analyze associations with prevailing environmental factors, habitat types, and locations. RESULTS: Anopheles arabiensis utilized a spectrum of man-made and natural aquatic habitats, most of which were concentrated primarily in the rock pools located in ravines and river fringes, and also in the large littoral marshes and within the irrigated agricultural zones. The numbers of breeding site per sampling grid differed significantly in different parts of the island. In contrast to an originally more widespread distribution across the island in the 1950s, detailed geographic analyses of the data obtained in the period extending from 1996-2009 showed an intriguing clustered distribution of active breeding sites in three discontinuous geographic zones, in which aquatic habitats availability fluctuates with the season and year. Seasonality in the prevalence of anopheles breeding sites suggests significant responsiveness to climatic factors. CONCLUSIONS: The observed retreat of An. arabiensis distribution range to lower altitudinal zones (< 400 m) and the upward shift in the most remote littoral areas in the northeast and southwest regions suggest the possible influence of biogeographic factors, changes in land use and control operations. The results of this study would allow for a more rational implementation of control strategies across the island. PMID- 21708014 TI - Potential role and mechanism of IFN-gamma inducible protein-10 on receptor activator of nuclear factor kappa-B ligand (RANKL) expression in rheumatoid arthritis. AB - INTRODUCTION: IFN-gamma inducible protein-10 (CXCL10), a member of the CXC chemokine family, and its receptor CXCR3 contribute to the recruitment of T cells from the blood stream into the inflamed joints and have a crucial role in perpetuating inflammation in rheumatoid arthritis (RA) synovial joints. Recently we showed the role of CXCL10 on receptor activator of nuclear factor kappa-B ligand (RANKL) expression in an animal model of RA and suggested the contribution to osteoclastogenesis. We tested the effects of CXCL10 on the expression of RANKL in RA synoviocytes and T cells, and we investigated which subunit of CXCR3 contributes to RANKL expression by CXCL10. METHODS: Synoviocytes derived from RA patients were kept in culture for 24 hours in the presence or absence of TNF alpha. CXCL10 expression was measured by reverse transcriptase polymerase chain reaction (RT-PCR) of cultured synoviocytes. Expression of RANKL was measured by RT-PCR and western blot in cultured synoviocytes with or without CXCL10 and also measured in Jurkat/Hut 78 T cells and CD4+ T cells in the presence of CXCL10 or dexamethasone. CXCL10 induced RANKL expression in Jurkat T cells was tested upon the pertussis toxin (PTX), an inhibitor of Gi subunit of G protein coupled receptor (GPCR). The synthetic siRNA for Galphai(2) was used to knock down gene expression of respective proteins. RESULTS: CXCL10 expression in RA synoviocytes was increased by TNF-alpha. CXCL10 slightly increased RANKL expression in RA synoviocytes, but markedly increased RANKL expression in Jurkat/Hut 78 T cell or CD4+ T cell. CXCL10 augmented the expression of RANKL by 62.6%, and PTX inhibited both basal level of RANKL (from 37.4 +/- 16.0 to 18.9 +/- 13.0%) and CXCL10 induced RANKL expression in Jurkat T cells (from 100% to 48.6 +/- 27.3%). Knock down of Galpha(i2) by siRNA transfection, which suppressed the basal level of RANKL (from 61.8 +/- 17.9% to 31.1 +/- 15.9%) and CXCL10-induced RANKL expression (from 100% to 53.1 +/- 27.1%) in Jurkat T cells, is consistent with PTX, which inhibited RANKL expression. CONCLUSIONS: CXCL10 increased RANKL expression in CD4+ T cells and it was mediated by Galpha(i) subunits of CXCR3. These results indicate that CXCL10 may have a potential role in osteoclastogenesis of RA synovial tissue and subsequent joint erosion. PMID- 21708015 TI - Quantitative cardiovascular magnetic resonance in pregnant women: cross-sectional analysis of physiological parameters throughout pregnancy and the impact of the supine position. AB - BACKGROUND: There are physiological reasons for the effects of positioning on hemodynamic variables and cardiac dimensions related to altered intra-abdominal and intra-thoracic pressures. This problem is especially evident in pregnant women due to the additional aorto-caval compression by the enlarged uterus. The purpose of this study was to investigate the effect of postural changes on cardiac dimensions and function during mid and late pregnancy using cardiovascular magnetic resonance (CMR). METHODS: Healthy non-pregnant women, pregnant women at 20th week of gestation and at 32nd week of gestation without history of cardiac disease were recruited to the study and underwent CMR in supine and left lateral positions. Cardiac hemodynamic parameters and dimensions were measured and compared between both positions. RESULTS: Five non-pregnant women, 6 healthy pregnant women at mid pregnancy and 8 healthy pregnant women at late pregnancy were enrolled in the study. In the group of non-pregnant women left ventricular (LV) cardiac output (CO) significantly decreased by 9% (p=0.043) and right ventricular (RV) end-diastolic volume (EDV) significantly increased by 5% (p=0.043) from the supine to the left lateral position. During mid pregnancy LV ejection fraction (EF), stroke volume (SV), left atrium lateral diameter and left atrial supero-inferior diameter increased significantly from the supine position to the left lateral position: 8%, 27%, 5% and 11%, respectively (p<0.05). RV EDV, SV and right atrium supero-inferior diameter significantly increased from the supine to the left lateral position: 25%, 31% and 13% (p<0.05), respectively. During late pregnancy a significant increment of LV EF, EDV, SV and CO was observed in the left lateral position: 11%, 21%, 35% and 24% (p<0.05), respectively. Left atrial diameters were significantly larger in the left lateral position compared to the supine position (p<0.05). RV CO was significantly increased in the left lateral position compared to the supine position (p<0.05). CONCLUSIONS: During pregnancy positional changes affect significantly cardiac hemodynamic parameters and dimensions. Pregnant women who need serial studies by CMR should be imaged in a consistent position. From as early as 20 weeks the left lateral position should be preferred on the supine position because it positively affects venous return, SV and CO. PMID- 21708016 TI - Should chronic hepatitis B mothers breastfeed? a meta analysis. AB - BACKGROUND: Hepatitis B virus (HBV) exists in the breast milk of chronic hepatitis B (CHB) mothers. The authors use a meta-analytic technique to quantify the evidence of an association between breastfeeding and risk of CHB infection among the infants vaccinated against HBV. METHODS: Literature search is performed up to 2010 on the relationship between infantile CHB infection within one-year follow up after immunization with the third-dose hepatitis B vaccine and breastfeeding. Two reviewers independently extract the data and evaluate the methodological quality. A random-effects model is employed to systematically combine the results of all included studies. RESULTS: Based on data from 32 studies, 4.32% (244/5650) of infants born of CHB mothers develop CHB infection. The difference in risk of the infection between breastfed and formula-fed infants (RD) is -0.8%, (95% confidence interval [CI]: -1.6%, 0.1%). Analysis of the data from 16 of the studies finds that RD for mothers who are positive for the HBeAg and/or the HBV DNA, 0.7% (95%CI: -2.0%, 3.5%), is similar to that for those who are negative for these infectivity markers, -0.5% (95%CI: -1.7%, 0.6%). CONCLUSIONS: Breast milk is infectious; yet, breastfeeding, even by mothers with high infectivity, is not associated with demonstrable risk of infantile CHB infection, provided that the infants have been vaccinated against HBV at birth. PMID- 21708017 TI - An intein with genetically selectable markers provides a new approach to internally label proteins with GFP. AB - BACKGROUND: Inteins are proteins that catalyze their own removal from within larger precursor proteins. In the process they splice the flanking protein sequences, termed the N-and C-terminal exteins. Large inteins frequently have a homing endonuclease that is involved in maintaining the intein in the host. Splicing and nuclease activity are independent and distinct domains in the folded structure. We show here that other biochemical activities can be incorporated into an intein in place of the endonuclease without affecting splicing and that these activities can provide genetic selection for the intein. We have coupled such a genetically marked intein with GFP as the N-terminal extein to create a cassette to introduce GFP within the interior of a targeted protein. RESULTS: The Pch PRP8 mini-intein of Penicillium chrysogenum was modified to include: 1) aminoglycoside phosphotransferase; 2) imidazoleglycerol-phosphate dehydratase, His5 from S. pombe ; 3) hygromycin B phosphotransferase; and 4) the transcriptional activator LexA-VP16. The proteins were inserted at the site of the lost endonuclease. When expressed in E. coli, all of the modified inteins spliced at high efficiency. Splicing efficiency was also greater than 96% when expressed from a plasmid in S. cerevisiae. In addition the inteins conferred either G418 or hygromycin resistance, or histidine or leucine prototropy, depending on the inserted marker and the yeast genetic background. DNA encoding the marked inteins coupled to GFP as the N-terminal extein was PCR amplified with ends homologous to an internal site in the yeast calmodulin gene CMD1. The DNA was transformed into yeast and integrants obtained by direct selection for the intein's marker. The His5-marked intein yielded a fully functional calmodulin that was tagged with GFP within its central linker. CONCLUSIONS: Inteins continue to show their flexibility as tools in molecular biology. The Pch PRP8 intein can successfully tolerate a variety of genetic markers and still retain high splicing efficiency. We have shown that a genetically marked intein can be used to insert GFP in one-step within a target protein in vivo. PMID- 21708018 TI - Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases. AB - INTRODUCTION: A proportion of patients receiving infliximab have antibodies toward infliximab (ATI), which are associated with increased risk of infusion reaction and reduced response to treatment. We studied the association of infliximab concentration at treatment initiation and development of ATI as well as the association of the presence of ATI and maintenance of infliximab. METHODS: All patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) receiving infliximab beginning in December 2005 were retrospectively followed until January 2009 or until infliximab discontinuation. Trough serum infliximab and ATI concentrations were measured at each visit. The patients were separated into two groups: ATI(pos) if ATI were detected at least once during the follow-up period and ATI(neg) otherwise. Repeated measures analysis of variance was used to study the association of infliximab concentration at treatment initiation and the development of ATI. Maintenance of infliximab in the two groups was studied by using Kaplan-Meier curves. RESULTS: We included 108 patients: 17 with RA and 91 with SpA. ATI were detected in 21 patients (19%). The median time to ATI detection after initiation of infliximab was 3.7 months (1.7 to 26.0 months). For both RA and SpA patients, trough infliximab concentration during the initiation period was significantly lower for ATI(pos) than ATI(neg) patients. RA patients showed maintenance of infliximab at a median of 19.5 months (5.0 to 31.0 months) and 12.0 months (2.0 to 24.0 months) for ATI(neg) and ATI(pos) groups, respectively (P = 0.08). SpA patients showed infliximab maintenance at a median of 16.0 months (3.0 to 34.0 months) and 9.5 months (3.0 to 39.0 months) for ATI(neg) and ATI(pos) groups, respectively (P = 0.20). Among SpA patients, those who were being treated concomitantly with methotrexate had a lower risk of developing ATI than patients not taking methotrexate (0 of 14 patients (0%) vs. 25 of 77 patients (32%); P = 0.03). CONCLUSIONS: High concentrations of infliximab during treatment initiation reduce the development of ATI, and the absence of ATI may be associated with prolonged maintenance of infliximab. Thus, trough serum infliximab concentration should be monitored early in patients with rheumatic diseases. PMID- 21708019 TI - Association of Rad51 polymorphism with DNA repair in BRCA1 mutation carriers and sporadic breast cancer risk. AB - BACKGROUND: Inter-individual variation in DNA repair capacity is thought to modulate breast cancer risk. The phenotypic mutagen sensitivity assay (MSA) measures DNA strand breaks in lymphocytes; women with familial and sporadic breast cancers have a higher mean number of breaks per cell (MBPC) than women without breast cancer. Here, we explore the relationships between the MSA and the Rad51 gene, which encodes a DNA repair enzyme that interacts with BRCA1 and BRCA2, in BRCA1 mutation carriers and women with sporadic breast cancer. METHODS: Peripheral blood lymphoblasts from women with known BRCA1 mutations underwent the MSA (n = 138 among 20 families). BRCA1 and Rad51 genotyping and sequencing were performed to identify SNPs and haplotypes associated with the MSA. Positive associations from the study in high-risk families were subsequently examined in a population-based case-control study of breast cancer (n = 1170 cases and 2115 controls). RESULTS: Breast cancer diagnosis was significantly associated with the MSA among women from BRCA1 families (OR = 3.2 95%CI: 1.5-6.7; p = 0.004). The Rad51 5'UTR 135 C>G genotype (OR = 3.64; 95% CI: 1.38, 9.54; p = 0.02), one BRCA1 haplotype (p = 0.03) and in a polygenic model, the E1038G and Q356R BRCA1 SNPs were significantly associated with MBPC (p = 0.009 and 0.002, respectively). The Rad51 5'UTR 135C genotype was not associated with breast cancer risk in the population-based study. CONCLUSIONS: Mutagen sensitivity might be a useful biomarker of penetrance among women with BRCA1 mutations because the MSA phenotype is partially explained by genetic variants in BRCA1 and Rad51. PMID- 21708020 TI - Molecular characterization of novel sulfotransferases from the tick, Ixodes scapularis. AB - BACKGROUND: Ixodes scapularis, commonly known as the blacklegged or deer tick, is the main vector of Lyme disease in the United States. Recent progress in transcriptome research has uncovered hundreds of different proteins expressed in the salivary glands of hard ticks, the majority of which have no known function, and include many novel protein families. We recently identified transcripts coding for two putative cytosolic sulfotransferases in these ticks which recognized phenolic monoamines as their substrates. In this current study, we characterize the genetic expression of these two cytosolic sulfotransferases throughout the tick life cycle as well as the enzymatic properties of the corresponding recombinant proteins. Interestingly, the resultant recombinant proteins showed sulfotransferase activity against both neurotransmitters dopamine and octopamine. RESULTS: The two sulfotransferase genes were coded as Ixosc SULT 1 & 2 and corresponding proteins were referred as Ixosc Sult 1 and 2. Using gene specific primers, the sulfotransferase transcripts were detected throughout the blacklegged tick life cycle, including eggs, larvae, nymphs, adult salivary glands and adult midgut. Notably, the mRNA and protein levels were altered upon feeding during both the larval and nymphal life stages. Quantitative PCR results confirm that Ixosc SULT1 was statistically increased upon blood feeding while Ixosc SULT 2 was decreased. This altered expression led us to further characterize the function of these proteins in the Ixodid tick. The sulfotransferase genes were cloned and expressed in a bacterial expression system, and purified recombinant proteins Ixosc Sult 1(R) and 2(R) showed sulfotransferase activity against neurotransmitters dopamine and octopamine as well as the common sulfotransferase substrate p-nitrophenol. Thus, dopamine- or octopamine-sulfonation may be involved in altering the biological signal for salivary secretion in I. scapularis. CONCLUSIONS: Collectively, these results suggest that a function of Ixosc Sult 1 and Sult 2 in Ixodid tick salivary glands may include inactivation of the salivation signal via sulfonation of dopamine or octopamine. PMID- 21708022 TI - Additive and multiplicative hazards modeling for recurrent event data analysis. AB - BACKGROUND: Sequentially ordered multivariate failure time or recurrent event duration data are commonly observed in biomedical longitudinal studies. In general, standard hazard regression methods cannot be applied because of correlation between recurrent failure times within a subject and induced dependent censoring. Multiplicative and additive hazards models provide the two principal frameworks for studying the association between risk factors and recurrent event durations for the analysis of multivariate failure time data. METHODS: Using emergency department visits data, we illustrated and compared the additive and multiplicative hazards models for analysis of recurrent event durations under (i) a varying baseline with a common coefficient effect and (ii) a varying baseline with an order-specific coefficient effect. RESULTS: The analysis showed that both additive and multiplicative hazards models, with varying baseline and common coefficient effects, gave similar results with regard to covariates selected to remain in the model of our real dataset. The confidence intervals of the multiplicative hazards model were wider than the additive hazards model for each of the recurrent events. In addition, in both models, the confidence interval gets wider as the revisit order increased because the risk set decreased as the order of visit increased. CONCLUSIONS: Due to the frequency of multiple failure times or recurrent event duration data in clinical and epidemiologic studies, the multiplicative and additive hazards models are widely applicable and present different information. Hence, it seems desirable to use them, not as alternatives to each other, but together as complementary methods, to provide a more comprehensive understanding of data. PMID- 21708021 TI - Molecular and comparative analysis of Salmonella enterica Senftenberg from humans and animals using PFGE, MLST and NARMS. AB - BACKGROUND: Salmonella species are recognized worldwide as a significant cause of human and animal disease. In this study the molecular profiles and characteristics of Salmonella enterica Senftenberg isolated from human cases of illness and those recovered from healthy or diagnostic cases in animals were assessed. Included in the study was a comparison with our own sequenced strain of S. Senfteberg recovered from production turkeys in North Dakota. Isolates examined in this study were subjected to antimicrobial susceptibility profiling using the National Antimicrobial Resistance Monitoring System (NARMS) panel which tested susceptibility to 15 different antimicrobial agents. The molecular profiles of all isolates were determined using Pulsed Field Gel Electrophoresis (PFGE) and the sequence types of the strains were obtained using Multi-Locus Sequence Type (MLST) analysis based on amplification and sequence interrogation of seven housekeeping genes (aroC, dnaN, hemD, hisD, purE, sucA, and thrA). PFGE data was input into BioNumerics analysis software to generate a dendrogram of relatedness among the strains. RESULTS: The study found 93 profiles among 98 S. Senftenberg isolates tested and there were primarily two sequence types associated with humans and animals (ST185 and ST14) with overlap observed in all host types suggesting that the distribution of S. Senftenberg sequence types is not host dependent. Antimicrobial resistance was observed among the animal strains, however no resistance was detected in human isolates suggesting that animal husbandry has a significant influence on the selection and promotion of antimicrobial resistance. CONCLUSION: The data demonstrates the circulation of at least two strain types in both animal and human health suggesting that S. Senftenberg is relatively homogeneous in its distribution. The data generated in this study could be used towards defining a pathotype for this serovar. PMID- 21708023 TI - Transition metal complexes of an isatinic quinolyl hydrazone. AB - BACKGROUND: The importance of the isatinic quinolyl hydrazones arises from incorporating the quinoline ring with the indole ring in the same compound. Quinoline ring has therapeutic and biological activities. On the other hand, isatin (1H-indole-2,3-dione) and its derivatives exhibit a wide range of biological activities. Also, the indole ring occurs in Jasmine flowers and Orange blossoms. Recently, the physiological and biological activities of quinolyl hydrazones arise from their tendency to form metal chelates with transition metal ions. In this context, we have reported to isolate, characterize and study the biological activity of some transition metal complexes of an isatinic quinolyl hydrazone; 3-[2-(4-methyl quinolin-2-yl)hydrazono] indolin-2-one. RESULTS: Mono- and binuclear as well as dimeric chelates were obtained from the reaction of a new isatinic quinolyl hydrazone with Fe(III), Co(II), Ni(II), Cu(II), VO(II) and Pd(II) ions. The ligand showed a variety of modes of bonding viz. (NNO)2-, (NO)- and (NO) per each metal ion supporting its ambidentate and flexidentate characters. The mode of bonding and basicity of the ligand depend mainly on the type of the metal cation and its counter anion. All the obtained Pd(II)- complexes have the preferable square planar geometry (D4h- symmetry) and depend mainly on the mole ratio (M:L). CONCLUSION: The effect of the type of the metal ion for the same anion (Cl-) is obvious from either structural diversity of the isolated complexes (Oh, Td and D4h) or the various modes of bonding. The isatinic hydrazone uses its lactim form in all complexes (Cl-) except complex 5 (SO42-) in which it uses its lactam form. The obtained Pd(II)- complexes (dimeric, mono- and binuclear) are affected by the mole ratio (M:L) and have the square planar (D4h) geometry. Also, the antimicrobial activity is highly influenced by the nature of the metal ion and the order for S. aureus bacteria is as follows: Nickel(II) > Vanadyl(II) > Cobalt(II) > Copper(II) ~ Palladium(II) >> Iron(III). PMID- 21708024 TI - Enhanced growth and recombinant protein production of Escherichia coli by a perfluorinated oxygen carrier in miniaturized fed-batch cultures. AB - BACKGROUND: Liquid perfluorochemicals (PFCs) are interesting oxygen carriers in medicine and biotechnology with a high solubility for oxygen. They have been repeatedly used for improving oxygen transfer into prokaryotic and eukaryotic cell cultures, however their application is still limited. Here we show the great benefit of air/oxygen saturated perfluorodecalin (PFD) for high cell density cultivation of Escherichia coli in microwell plates and their positive effect on the soluble production of a correctly folded heterologously expressed alcohol dehydrogenase. RESULTS: In EnBase((r)) cultivations the best effect was seen with PFD saturated with oxygen enriched air (appr. 10 MUM oxygen per ml) when PFD was added at the time of induction. In contrast the effect of PFD was negligible when it was added already at the time of inoculation. Optimisation of addition time and content of loaded oxygen into the PFD resulted in an increased the cell density by 40% compared to control cultures, and correspondingly also the product yield increased, demonstrated at the example of a recombinant alcohol dehydrogenase. CONCLUSIONS: PFCs are a valuable additive in miniaturized cell culture formats. For production of recombinant proteins in low cell density shaken cultures the addition of oxygen-enriched PFD makes the process more robust, i.e. a high product yield is not any more limited to a very narrow cell density window during which the induction has to be done. The positive effect of PFD was even more obvious when it was added during high cell density cultures. The effect of the PFD phase depends on the amount of oxygen which is loaded into the PFD and which thus is a matter of optimisation. PMID- 21708026 TI - Who pays for health care in Ghana? AB - BACKGROUND: Financial protection against the cost of unforeseen ill health has become a global concern as expressed in the 2005 World Health Assembly resolution (WHA58.33), which urges its member states to "plan the transition to universal coverage of their citizens". An important element of financial risk protection is to distribute health care financing fairly in relation to ability to pay. The distribution of health care financing burden across socio-economic groups has been estimated for European countries, the USA and Asia. Until recently there was no such analysis in Africa and this paper seeks to contribute to filling this gap. It presents the first comprehensive analysis of the distribution of health care financing in relation to ability to pay in Ghana. METHODS: Secondary data from the Ghana Living Standard Survey (GLSS) 2005/2006 were used. This was triangulated with data from the Ministry of Finance and other relevant sources, and further complemented with primary household data collected in six districts. We implored standard methodologies (including Kakwani index and test for dominance) for assessing progressivity in health care financing in this paper. RESULTS: Ghana's health care financing system is generally progressive. The progressivity of health financing is driven largely by the overall progressivity of taxes, which account for close to 50% of health care funding. The national health insurance (NHI) levy (part of VAT) is mildly progressive and formal sector NHI payroll deductions are also progressive. However, informal sector NHI contributions were found to be regressive. Out-of-pocket payments, which account for 45% of funding, are regressive form of health payment to households. CONCLUSION: For Ghana to attain adequate financial risk protection and ultimately achieve universal coverage, it needs to extend pre-payment cover to all in the informal sector, possibly through funding their contributions entirely from tax, and address other issues affecting the expansion of the National Health Insurance. Furthermore, the pre-payment funding pool for health care needs to grow so budgetary allocation to the health sector can be enhanced. PMID- 21708025 TI - Impairment of adult hippocampal neural progenitor proliferation by methamphetamine: role for nitrotyrosination. AB - Methamphetamine (METH) abuse has reached epidemic proportions, and it has become increasingly recognized that abusers suffer from a wide range of neurocognitive deficits. Much previous work has focused on the deleterious effects of METH on mature neurons, but little is known about the effects of METH on neural progenitor cells (NPCs). It is now well established that new neurons are continuously generated from NPCs in the adult hippocampus, and accumulating evidence suggests important roles for these neurons in hippocampal-dependent cognitive functions. In a rat hippocampal NPC culture system, we find that METH results in a dose-dependent reduction of NPC proliferation, and higher concentrations of METH impair NPC survival. NPC differentiation, however, is not affected by METH, suggesting cell-stage specificity of the effects of METH. We demonstrate that the effects of METH on NPCs are, in part, mediated through oxidative and nitrosative stress. Further, we identify seventeen NPC proteins that are post-translationally modified via 3-nitrotyrosination in response to METH, using mass spectrometric approaches. One such protein was pyruvate kinase isoform M2 (PKM2), an important mediator of cellular energetics and proliferation. We identify sites of PKM2 that undergo nitrotyrosination, and demonstrate that nitration of the protein impairs its activity. Thus, METH abuse may result in impaired adult hippocampal neurogenesis, and effects on NPCs may be mediated by protein nitration. Our study has implications for the development of novel therapeutic approaches for METH-abusing individuals with neurologic dysfunction and may be applicable to other neurodegenerative diseases in which hippocampal neurogenesis is impaired. PMID- 21708027 TI - A short in-frame deletion in NTRK1 tyrosine kinase domain caused by a novel splice site mutation in a patient with congenital insensitivity to pain with anhidrosis. AB - BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disease characterized by the lack of reaction to noxious stimuli and anhidrosis. It is caused by mutations in the NTRK1 gene, which encodes the high affinity tyrosine kinase receptor I for Neurotrophic Growth Factor (NGF). CASE PRESENTATION: We present the case of a female patient diagnosed with CIPA at the age of 8 months. The patient is currently 6 years old and her psychomotor development conforms to her age (RMN, SPECT and psychological study are in the range of normality). PCR amplification of DNA, followed by direct sequencing, was used to investigate the presence of NTRK1 gene mutations. Reverse transcriptase (RT)-PCR amplification of RNA, followed by cloning and sequencing of isolated RT-PCR products was used to characterize the effect of the mutations on NTRK1 mRNA splicing. The clinical diagnosis of CIPA was confirmed by the detection of two splice-site mutations in NTRK1, revealing that the patient was a compound heterozygote at this gene. One of these alterations, c.574+1G>A, is located at the splice donor site of intron 5. We also found a second mutation, c.2206-2 A>G, not previously reported in the literature, which is located at the splice acceptor site of intron 16. Each parent was confirmed to be a carrier for one of the mutations by DNA sequencing analysis. It has been proposed that the c.574+1G>A mutation would cause exon 5 skipping during NTRK1 mRNA splicing. We could confirm this prediction and, more importantly, we provide evidence that the novel c.2206-2A>G mutation also disrupts normal NTRK1 splicing, leading to the use of an alternative splice acceptor site within exon 17. As a consequence, this mutation would result in the production of a mutant NTRK1 protein with a seven aminoacid in-frame deletion in its tyrosine kinase domain. CONCLUSIONS: We present the first description of a CIPA-associated NTRK1 mutation causing a short interstitial deletion in the tyrosine kinase domain of the receptor. The possible phenotypical implications of this mutation are discussed. PMID- 21708029 TI - Global challenges with scale-up of the integrated management of childhood illness strategy: results of a multi-country survey. AB - BACKGROUND: The Integrated Management of Childhood Illness Strategy (IMCI), developed by WHO/UNICEF, aims to contribute to reducing childhood morbidity and mortality (MDG4) in resource-limited settings. Since 1996 more than 100 countries have adopted IMCI. IMCI case management training (ICMT) is one of three IMCI components and training is usually residential over 11 consecutive days. Follow up after ICMT is an essential part of training. We describe the barriers to rapid acceleration of ICMT and review country perspectives on how to address these barriers. METHODS: A multi-country exploratory cross-sectional questionnaire survey of in-service ICMT approaches, using quantitative and qualitative methods, was conducted in 2006-7: 27 countries were purposively selected from all six WHO regions. Data for this paper are from three questionnaires (QA, QB and QC), distributed to selected national focal IMCI persons/programme officers, course directors/facilitators and IMCI trainees respectively. QC only gathered data on experiences with IMCI follow-up. RESULTS: 33 QA, 163 QB and 272 QC were received. The commonest challenges to ICMT scale-up relate to funding (high cost and long duration of the residential ICMT), poor literacy of health workers, differing opinions about the role of IMCI in improving child health, lack of political support, frequent changes in staff or rules at Ministries of Health and lack of skilled facilitators. Countries addressed these challenges in several ways including increased advocacy, developing strategic linkages with other priorities, intensifying pre-service training, re-distribution of funds and shortening course duration. The commonest challenges to follow-up after ICMT were lack of funding (93.1% of respondents), inadequate funds for travelling or planning (75.9% and 44.8% respectively), lack of gas for travelling (41.4%), inadequately trained or few supervisors (41.4%) and inadequate job aids for follow-up (27.6%). Countries addressed these by piggy backing IMCI follow-up with routine supervisory visits. CONCLUSIONS: Financial challenges to ICMT scale-up and follow-up after training are common. As IMCI is accepted globally as one of the key strategies to meet MDG4 several steps need to be taken to facilitate rapid acceleration of ICMT, including reviewing core competencies followed by competency-driven shortened training duration or 'on the job' training, 'distance learning' or training using mobile phones. Linkages with other 'better-funded' programmes e.g. HIV or malaria need to be improved. Routine Primary Health Care (PHC) supervision needs to include follow-up after ICMT. PMID- 21708028 TI - MicroRNA genes preferentially expressed in dendritic cells contain sites for conserved transcription factor binding motifs in their promoters. AB - BACKGROUND: MicroRNAs (miRNAs) play a fundamental role in the regulation of gene expression by translational repression or target mRNA degradation. Regulatory elements in miRNA promoters are less well studied, but may reveal a link between their expression and a specific cell type. RESULTS: To explore this link in myeloid cells, miRNA expression profiles were generated from monocytes and dendritic cells (DCs). Differences in miRNA expression among monocytes, DCs and their stimulated progeny were observed. Furthermore, putative promoter regions of miRNAs that are significantly up-regulated in DCs were screened for Transcription Factor Binding Sites (TFBSs) based on TFBS motif matching score, the degree to which those TFBSs are over-represented in the promoters of the up-regulated miRNAs, and the extent of conservation of the TFBSs in mammals. CONCLUSIONS: Analysis of evolutionarily conserved TFBSs in DC promoters revealed preferential clustering of sites within 500 bp upstream of the precursor miRNAs and that many mRNAs of cognate TFs of the conserved TFBSs were indeed expressed in the DCs. Taken together, our data provide evidence that selected miRNAs expressed in DCs have evolutionarily conserved TFBSs relevant to DC biology in their promoters. PMID- 21708030 TI - Renal function at the time of a myocardial infarction maintains prognostic value for more than 10 years. AB - BACKGROUND: Renal function is an important predictor of mortality in patients with myocardial infarction (MI), but changes in the impact over time have not been well described.We examined the importance of renal function by estimated GFR (eGFR) and se-creatinine as an independent long-term prognostic factor. METHODS: Prospective follow-up of 6653 consecutive MI patients screened for entry in the Trandolapril Cardiac Evaluation (TRACE) study. The patients were analysed by Kaplan-Meier survival analysis, landmark analysis and Cox proportional hazard models. Outcome measure was all-cause mortality. RESULTS: An eGFR below 60 ml per minute per 1.73 m2, consistent with chronic renal disease, was present in 42% of the patients. We divided the patients into 4 groups according to eGFR. Overall, Cox proportional-hazards models showed that eGFR was a significant prognostic factor in the two groups with the lowest eGFR, hazard ratio 1,72 (confidence interval (CI) 1,56-1,91) in the group with the lowest eGFR. Using the eGFR group with normal renal function as reference, we observed an incremental rise in hazard ratio. We divided the follow-up period in 2-year intervals. Landmark analysis showed that eGFR at the time of screening continued to show prognostic effect until 16 years of follow-up. By multivariable Cox regression analysis, the prognostic effect of eGFR persisted for 12 years and of se-creatinine for 10 years. When comparing the lowest group of eGFR with the group with normal eGFR, prognostic significance was present in the entire period of follow-up with a hazard ratio between 1,97 (CI 1,65-2,35) and 1,35 (CI 0,99-1,84) in the 2-year periods. CONCLUSIONS: One estimate of renal function is a strong and independent long-term prognostic factor for 10-12 years following a MI. PMID- 21708031 TI - Obscured phylogeny and possible recombinational dormancy in Escherichia coli. AB - BACKGROUND: Escherichia coli is one of the best studied organisms in all of biology, but its phylogenetic structure has been difficult to resolve with current data and analytical techniques. We analyzed single nucleotide polymorphisms in chromosomes of representative strains to reconstruct the topology of its emergence. RESULTS: The phylogeny of E. coli varies according to the segment of chromosome analyzed. Recombination between extant E. coli groups is largely limited to only three intergroup pairings. CONCLUSIONS: Segment dependent phylogenies most likely are legacies of a complex recombination history. However, E. coli are now in an epoch in which they no longer broadly share DNA. Using the definition of species as organisms that freely exchange genetic material, this recombinational dormancy could reflect either the end of E. coli as a species, or herald the coalescence of E. coli groups into new species. PMID- 21708032 TI - Gestational malaria associated to Plasmodium vivax and Plasmodium falciparum placental mixed-infection followed by foetal loss: a case report from an unstable transmission area in Brazil. AB - Gestational malaria is a multi-factorial syndrome leading to poor outcomes for both the mother and foetus. Although an unusual increasing in the number of hospitalizations caused by Plasmodium vivax has been reported in Brazil, mortality is rarely observed. This is a report of a gestational malaria case that occurred in the city of Manaus (Amazonas State, Brazil) and resulted in foetal loss. The patient presented placental mixed-infection by Plasmodium vivax and Plasmodium falciparum after diagnosis by nested-PCR, however microscopic analysis failed to detect P. falciparum in the peripheral blood. Furthermore, as the patient did not receive proper treatment for P. falciparum and hospitalization occurred soon after drug treatment, it seems that P. falciparum pathology was modulated by the concurrent presence of P. vivax. Collectively, this case confirms the tropism towards the placenta by both of these species of parasites, reinforces the notion that co-existence of distinct malaria parasites interferes on diseases' outcomes, and opens discussions regarding diagnostic methods, malaria treatment during pregnancy and prenatal care for women living in unstable transmission areas of malaria, such as the Brazilian Amazon. PMID- 21708033 TI - Defective response of CD4(+) T cells to retinoic acid and TGFbeta in systemic lupus erythematosus. AB - INTRODUCTION: CD25(+) FOXP3(+) CD4(+) regulatory T cells (Tregs) are induced by transforming growth factor beta (TGFbeta) and further expanded by retinoic acid (RA). We have previously shown that this process was defective in T cells from lupus-prone mice expressing the novel isoform of the Pbx1 gene, Pbx1-d. This study tested the hypothesis that CD4(+) T cells from systemic lupus erythematosus (SLE) patients exhibited similar defects in Treg induction in response to TGFbeta and RA, and that PBX1-d expression is associated with this defect. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from 142 SLE patients and 83 healthy controls (HCs). The frequency of total, memory and naive CD4(+) T cells was measured by flow cytometry on fresh cells. PBX1 isoform expression in purified CD4(+) T cells was determined by reverse transcription polymerase chain reaction (RT-PCR). PBMCs were stimulated for three days with anti-CD3 and anti CD28 in the presence or absence of TGFbeta and RA. The expression of CD25 and FOXP3 on CD4(+) T cells was then determined by flow cytometry. In vitro suppression assays were performed with sorted CD25(+) and CD25(-) FOXP3(+) T cells. CD4(+) T cell subsets or their expansion were compared between patients and HCs with two-tailed Mann-Whitney tests and correlations between the frequencies of two subsets were tested with Spearman tests. RESULTS: The percentage of CD25(-) FOXP3(+) CD4(+) (CD25(-) Tregs) T cells was greater in SLE patients than in HCs, but these cells, contrary to their matched CD25(+) counterparts, did not show a suppressive activity. RA-expansion of TGFbeta induced CD25(+) Tregs was significantly lower in SLE patients than in HCs, although SLE Tregs expanded significantly more than HCs in response to either RA or TGFbeta alone. Defective responses were also observed for the SLE CD25(-) Tregs and CD25(+) FOXP3(-) activated CD4(+) T cells as compared to controls. PBX1 d expression did not affect Treg induction, but it significantly reduced the expansion of CD25- Tregs and prevented the reduction of the activated CD25(+) FOXP3(-) CD4(+) T cell subset by the combination of TGFbeta and RA. CONCLUSIONS: We demonstrated that the induction of Tregs by TGFbeta and RA was defective in SLE patients and that PBX1-d expression in CD4(+) T cells is associated with an impaired regulation of FOXP3 and CD25 by TGFbeta and RA on these cells. These results suggest an impaired integration of the TGFbeta and RA signals in SLE T cells and implicate the PBX1 gene in this process. PMID- 21708034 TI - Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the knee: a randomized controlled study. AB - BACKGROUND: Patients with osteoarthritis (OA) take a variety of health supplements in an attempt to reduce pain and improve function. The aim of this study was to determine the efficacy of methylsulfonylmethane (MSM) in treating patients with knee OA. METHODS: This study was a prospective, randomized, double blind, controlled clinical trial. Forty nine men and women 45-90 (mean 68 +/- SD 7.3) years of age with knee OA according to the American College of Rheumatology clinical criteria for OA of the knee and with radiographic confirmed knee OA were enrolled in the study and randomly assigned into 2 groups: One received MSM in doses of 1.125 grams 3 times daily for 12 weeks and the other received a placebo in the same dosing frequency. The primary outcomes were the WOMAC Osteoarthritis Index for pain, stiffness and physical function, the Aggregated Locomotor Function (ALF) test that evaluates each patient's physical function, the SF-36 quality of life health survey and the visual-analogue-scale (VAS) for pain. The secondary outcomes were Knee Society Clinical Rating System for Knee Score (KSKS) and Function Score (KSFS). Patients were assessed at baseline, 6 weeks and 12 weeks. All continuous variables were tested by the Kolmogorov-Smirnov test for Normal distribution. Changes within the groups and differences between the groups were calculated by repeated measures of analysis (ANOVA) with one nested variable. RESULTS: There were significant differences between treatment groups over time in WOMAC physical function (14.6 mm [CI: 4.3, 25.0]; p = 0.04) and in WOMAC total score (15.0 mm [CI: 5.1, 24.9]; p = 0.03). Treatment groups did not differ significantly in WOMAC pain (12.4 mm [CI: 0.0, 24.8]); p = 0.08) or WOMAC stiffness (27.2 mm [CI: 8.2, 46.2]; p = 0.08). There was a non-significant difference in SF-36 total score between treatment groups (11.6 [CI: 1.0, 22.1]; p = 0.54). A significant difference was found between groups in VAS for pain (0.7 s [CI: -0.9, 2.4]; p = 0.05). Secondary outcomes showed non-significant differences between the two groups. CONCLUSIONS: Patients with OA of the knee taking MSM for 12 weeks showed an improvement in pain and physical function. These improvements, however, are small and it is yet to be determined if they are of clinical significance. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01188213. PMID- 21708035 TI - Odor identity influences tracking of temporally patterned plumes in Drosophila. AB - BACKGROUND: Turbulent fluid landscapes impose temporal patterning upon chemical signals, and the dynamical neuronal responses to patterned input vary across the olfactory receptor repertoire in flies, moths, and locusts. Sensory transformations exhibit low pass filtering that ultimately results in perceptual fusion of temporally transient sensory signals. For example, humans perceive a sufficiently fast flickering light as continuous, but the frequency threshold at which this fusion occurs varies with wavelength. Although the summed frequency sensitivity of the fly antenna has been examined to a considerable extent, it is unknown how intermittent odor signals are integrated to influence plume tracking behavior independent of wind cues, and whether temporal fusion for behavioral tracking might vary according to the odor encountered. RESULTS: Here we have adopted a virtual reality flight simulator to study the dynamics of plume tracking under different experimental conditions. Flies tethered in a magnetic field actively track continuous (non-intermittent) plumes of vinegar, banana, or ethyl butyrate with equal precision. However, pulsing these plumes at varying frequency reveals that the threshold rate, above which flies track the plume as if it were continuous, is unique for each odorant tested. Thus, the capability of a fly to navigate an intermittent plume depends on the particular odorant being tracked during flight. Finally, we measured antennal field potential responses to an intermittent plume, found that receptor dynamics track the temporal pattern of the odor stimulus and therefore do not limit the observed behavioral temporal fusion limits. CONCLUSIONS: This study explores the flies' ability to track odor plumes that are temporally intermittent. We were surprised to find that the perceptual critical fusion limit, determined behaviorally, is strongly dependent on odor identity. Antennal field potential recordings indicate that peripheral processing of temporal cues faithfully follow rapid odor transients above the rates that can be resolved behaviorally. These results indicate that (1) higher order circuits create a perceptually continuous signal from an intermittent sensory one, and that (2) this transformation varies with odorant rather than being constrained by sensory-motor integration, thus (3) offering an entry point for examining the mechanisms of rapid olfactory decision making in an ecological context. PMID- 21708036 TI - Detection of mild cognitive impairment in people older than 65 years of age and its relationship to cardiovascular risk factors (DECRIVAM). AB - BACKGROUND: Studies centered on the detection of cognitive impairment and its relationship to cardiovascular risk factors in elderly people have gained special relevance in recent years. Knowledge of the cardiovascular risk factors that may be associated to cognitive impairment could be very useful for introducing treatments in early stages - thereby possibly contributing to improve patient quality of life.The present study explores cognitive performance in people over 65 years of age in Salamanca (Spain), with special emphasis on the identification of early symptoms of cognitive impairment, with the purpose of detecting mild cognitive impairment and of studying the relationships between this clinical situation and cardiovascular risk factors. METHODS/DESIGN: A longitudinal study is contemplated. The reference population will consist of 420 people over 65 years of age enrolled through randomized sampling stratified by healthcare area, and who previously participated in another study. MEASUREMENT: a) Sociodemographic variables; b) Cardiovascular risk factors; c) Comorbidity; d) Functional level for daily life activities; and e) Study of higher cognitive functions based on a neuropsychological battery especially adapted to the evaluation of elderly people. DISCUSSION: We hope that this study will afford objective information on the representative prevalence of cognitive impairment in the population over 65 years of age in Salamanca. We also hope to obtain data on the relationship between cognitive impairment and cardiovascular risk factors in this specific population group. Based on the results obtained, we also will be able to establish the usefulness of some of the screening tests applied during the study, such as the Mini-Mental State Examination and the 7 Minute Screen test. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01327196. PMID- 21708037 TI - Splash!: a prospective birth cohort study of the impact of environmental, social and family-level influences on child oral health and obesity related risk factors and outcomes. AB - BACKGROUND: Dental caries (decay) is the most prevalent disease of childhood. It is often left untreated and can impact negatively on general health, and physical, developmental, social and learning outcomes. Similar to other health issues, the greatest burden of dental caries is seen in those of low socio economic position. In addition, a number of diet-related risk factors for dental caries are shared risk factors for the development of childhood obesity. These include high and frequent consumption of refined carbohydrates (predominately sugars), and soft drinks and other sweetened beverages, and low intake of (fluoridated) water. The prevalence of childhood obesity is also at a concerning level in most countries and there is an opportunity to determine interventions for addressing both of these largely preventable conditions through sustainable and equitable solutions. This study aims to prospectively examine the impact of drink choices on child obesity risk and oral health status. METHODS/DESIGN: This is a two-stage study using a mixed methods research approach. The first stage involves qualitative interviews of a sub-sample of recruited parents to develop an understanding of the processes involved in drink choice, and inform the development of the Discrete Choice Experiment analysis and the measurement instruments to be used in the second stage. The second stage involves the establishment of a prospective birth cohort of 500 children from disadvantaged communities in rural and regional Victoria, Australia (with and without water fluoridation). This longitudinal design allows measurement of changes in the child's diet over time, exposure to fluoride sources including water, dental caries progression, and the risk of childhood obesity. DISCUSSION: This research will provide a unique contribution to integrated health, education and social policy and program directions, by providing clearer policy relevant evidence on strategies to counter social and environmental factors which predispose infants and children to poor health, wellbeing and social outcomes; and evidence-based strategies to promote health and prevent disease through the adoption of healthier lifestyles and diet. Further, given the absence of evidence on the processes and effectiveness of contemporary policy implementation, such as community water fluoridation in rural and regional communities it's approach and findings will be extremely informative. PMID- 21708038 TI - Characterization of a Bayesian genetic clustering algorithm based on a Dirichlet process prior and comparison among Bayesian clustering methods. AB - BACKGROUND: A Bayesian approach based on a Dirichlet process (DP) prior is useful for inferring genetic population structures because it can infer the number of populations and the assignment of individuals simultaneously. However, the properties of the DP prior method are not well understood, and therefore, the use of this method is relatively uncommon. We characterized the DP prior method to increase its practical use. RESULTS: First, we evaluated the usefulness of the sequentially-allocated merge-split (SAMS) sampler, which is a technique for improving the mixing of Markov chain Monte Carlo algorithms. Although this sampler has been implemented in a preceding program, HWLER, its effectiveness has not been investigated. We showed that this sampler was effective for population structure analysis. Implementation of this sampler was useful with regard to the accuracy of inference and computational time. Second, we examined the effect of a hyperparameter for the prior distribution of allele frequencies and showed that the specification of this parameter was important and could be resolved by considering the parameter as a variable. Third, we compared the DP prior method with other Bayesian clustering methods and showed that the DP prior method was suitable for data sets with unbalanced sample sizes among populations. In contrast, although current popular algorithms for population structure analysis, such as those implemented in STRUCTURE, were suitable for data sets with uniform sample sizes, inferences with these algorithms for unbalanced sample sizes tended to be less accurate than those with the DP prior method. CONCLUSIONS: The clustering method based on the DP prior was found to be useful because it can infer the number of populations and simultaneously assign individuals into populations, and it is suitable for data sets with unbalanced sample sizes among populations. Here we presented a novel program, DPART, that implements the SAMS sampler and can consider the hyperparameter for the prior distribution of allele frequencies to be a variable. PMID- 21708039 TI - Underuse of long-term routine hospital follow-up care in patients with a history of breast cancer? AB - BACKGROUND: After primary treatment for breast cancer, patients are recommended to use hospital follow-up care routinely. Long-term data on the utilization of this follow-up care are relatively rare. METHODS: Information regarding the utilization of routine hospital follow-up care was retrieved from hospital documents of 662 patients treated for breast cancer. Utilization of hospital follow-up care was defined as the use of follow-up care according to the guidelines in that period of time. Determinants of hospital follow up care were evaluated with multivariate analysis by generalized estimating equations (GEE). RESULTS: The median follow-up time was 9.0 (0.3-18.1) years. At fifth and tenth year after diagnosis, 16.1% and 33.5% of the patients had less follow-up visits than recommended in the national guideline, and 33.1% and 40.4% had less frequent mammography than recommended. Less frequent mammography was found in older patients (age > 70; OR: 2.10; 95%CI: 1.62-2.74), patients with comorbidity (OR: 1.26; 95%CI: 1.05-1.52) and patients using hormonal therapy (OR: 1.51; 95%CI: 1.01-2.25). CONCLUSIONS: Most patients with a history of breast cancer use hospital follow-up care according to the guidelines. In older patients, patients with comorbidity and patients receiving hormonal therapy yearly mammography is performed much less than recommended. PMID- 21708041 TI - Shaping public opinion on the issue of childbirth; a critical analysis of articles published in an Australian newspaper. AB - BACKGROUND: The Australian government has announced a major program of reform with the move to primary maternity care, a program of change that appears to be at odds with current general public perceptions regarding how maternity care is delivered. METHODS: A critical discourse analysis of articles published in 'The Age', a newspaper with national distribution, subsequent to the release of the discussion paper by the Australian Government in 2008 was undertaken. The purpose was to identify how Australian maternity services are portrayed and what purpose is served by this representation to the general public. RESULTS: Findings from this critical discourse analysis revealed that Australian maternity services are being portrayed to the general public as an inflexible outdated service struggling to meets the needs of pregnant women and in desperate need of reform. The style of reporting employed in this newspaper involved presenting to the reader the range of expert opinion relevant to each topic, frequently involving polarised positions of the experts on the issue. CONCLUSIONS: The general public are presented with a conflict, caught between the need for changes that come with the primary maternity model of care and fear that these change will undermine safe standards. The discourse; 'Australia is one of the safest countries in which to give birth or be born, what is must be best', represents the situation where despite major deficiencies in the system the general public may be too fearful of the consequences to consider a move away from reliance on traditional medical-led maternity care. PMID- 21708040 TI - Molecular diagnosis of hereditary inclusion body myopathy by linkage analysis and identification of a novel splice site mutation in GNE. AB - BACKGROUND: Many myopathies share clinical features in common, and diagnosis often requires genetic testing. We ascertained a family in which five siblings presented with distal muscle weakness of unknown etiology. METHODS: We performed high-density genomewide linkage analysis and mutation screening of candidate genes to identify the genetic defect in the family. Preserved clinical biopsy material was reviewed to confirm the diagnosis, and reverse transcriptase PCR was used to determine the molecular effect of a splice site mutation. RESULTS: The linkage scan excluded the majority of known myopathy genes, but one linkage peak included the gene GNE, in which mutations cause autosomal recessive hereditary inclusion body myopathy type 2 (HIBM2). Muscle biopsy tissue from a patient showed myopathic features, including small basophilic fibers with vacuoles. Sequence analysis of GNE revealed affected individuals were compound heterozygous for a novel mutation in the 5' splice donor site of intron 10 (c.1816+5G>A) and a previously reported missense mutation (c.2086G>A, p.V696M), confirming the diagnosis as HIBM2. The splice site mutation correlated with exclusion of exon 10 from the transcript, which is predicted to produce an in-frame deletion (p.G545_D605del) of 61 amino acids in the kinase domain of the GNE protein. The father of the proband was heterozygous for the splice site mutation and exhibited mild distal weakness late in life. CONCLUSIONS: Our study expands on the extensive allelic heterogeneity of HIBM2 and demonstrates the value of linkage analysis in resolving ambiguous clinical findings to achieve a molecular diagnosis. PMID- 21708043 TI - Dynamin inhibitors induce caspase-mediated apoptosis following cytokinesis failure in human cancer cells and this is blocked by Bcl-2 overexpression. AB - BACKGROUND: The aim of both classical (e.g. taxol) and targeted anti-mitotic agents (e.g. Aurora kinase inhibitors) is to disrupt the mitotic spindle. Such compounds are currently used in the clinic and/or are being tested in clinical trials for cancer treatment. We recently reported a new class of targeted anti mitotic compounds that do not disrupt the mitotic spindle, but exclusively block completion of cytokinesis. This new class includes MiTMAB and OcTMAB (MiTMABs), which are potent inhibitors of the endocytic protein, dynamin. Like other anti mitotics, MiTMABs are highly cytotoxic and possess anti-proliferative properties, which appear to be selective for cancer cells. The cellular response following cytokinesis failure and the mechanistic pathway involved is unknown. RESULTS: We show that MiTMABs induce cell death specifically following cytokinesis failure via the intrinsic apoptotic pathway. This involves cleavage of caspase-8, -9, -3 and PARP, DNA fragmentation and membrane blebbing. Apoptosis was blocked by the pan-caspase inhibitor, ZVAD, and in HeLa cells stably expressing the anti apoptotic protein, Bcl-2. This resulted in an accumulation of polyploid cells. Caspases were not cleaved in MiTMAB-treated cells that did not enter mitosis. This is consistent with the model that apoptosis induced by MiTMABs occurs exclusively following cytokinesis failure. Cytokinesis failure induced by cytochalasin B also resulted in apoptosis, suggesting that disruption of this process is generally toxic to cells. CONCLUSION: Collectively, these data indicate that MiTMAB-induced apoptosis is dependent on both polyploidization and specific intracellular signalling components. This suggests that dynamin and potentially other cytokinesis factors are novel targets for development of cancer therapeutics. PMID- 21708042 TI - Effect of spinal manipulation on sensorimotor functions in back pain patients: study protocol for a randomised controlled trial. AB - BACKGROUND: Low back pain (LBP) is a recognized public health problem, impacting up to 80% of US adults at some point in their lives. Patients with LBP are utilizing integrative health care such as spinal manipulation (SM). SM is the therapeutic application of a load to specific body tissues or structures and can be divided into two broad categories: SM with a high-velocity low-amplitude load, or an impulse "thrust", (HVLA-SM) and SM with a low-velocity variable-amplitude load (LVVA-SM). There is evidence that sensorimotor function in people with LBP is altered. This study evaluates the sensorimotor function in the lumbopelvic region, as measured by postural sway, response to sudden load and repositioning accuracy, following SM to the lumbar and pelvic region when compared to a sham treatment. METHODS/DESIGN: A total of 219 participants with acute, subacute or chronic low back pain are being recruited from the Quad Cities area located in Iowa and Illinois. They are allocated through a minimization algorithm in a 1:1:1 ratio to receive either 13 HVLA-SM treatments over 6 weeks, 13 LVVA-SM treatments over 6 weeks or 2 weeks of a sham treatment followed by 4 weeks of full spine "doctor's choice" SM. Sensorimotor function tests are performed before and immediately after treatment at baseline, week 2 and week 6. Self-report outcome assessments are also collected. The primary aims of this study are to 1) determine immediate pre to post changes in sensorimotor function as measured by postural sway following delivery of a single HVLA-SM or LVVA-SM treatment when compared to a sham treatment and 2) to determine changes from baseline to 2 weeks (4 treatments) of HVLA-SM or LVVA-SM compared to a sham treatment. Secondary aims include changes in response to sudden loads and lumbar repositioning accuracy at these endpoints, estimating sensorimotor function in the SM groups after 6 weeks of treatment, and exploring if changes in sensorimotor function are associated with changes in self-report outcome assessments. DISCUSSION: This study may provide clues to the sensorimotor mechanisms that explain observed functional deficits associated with LBP, as well as the mechanism of action of SM. TRIAL REGISTRATION: This trial is registered in ClinicalTrials.gov, with the ID number of NCT00830596, registered on January 27, 2009. The first participant was allocated on 30 January 2009 and the final participant was allocated on 17 March 2011. PMID- 21708044 TI - Are there any changes in burden and management of communicable diseases in areas affected by Cyclone Nargis? AB - BACKGROUND: This study aims to assess the situation of communicable diseases under national surveillance in the Cyclone Nargis-affected areas in Myanmar (Burma) before and after the incident. METHODS: Monthly data during 2007, 2008 and 2009 from the routine reporting system for disease surveillance of the Myanmar Ministry of Health (MMOH) were reviewed and compared with weekly reporting from the Early Warning and Rapid Response (EWAR) system. Data from some UN agencies, NGOs and Tri-Partite Core Group (TCG) periodic reviews were also extracted for comparisons with indicators from Sphere and the Inter-Agency Standing Committee. RESULTS: Compared to 2007 and 2009, large and atypical increases in diarrheal disease and especially dysentery cases occurred in 2008 following Cyclone Nargis. A seasonal increase in ARI reached levels higher than usual in the months of 2008 post-Nargis. The number of malaria cases post-Nargis also increased, but it was less clear if this reflected normal seasonal patterns or was specifically associated with the disaster event. There was no significant change in the occurrence of other communicable diseases in Nargis-affected areas. Except for a small decrease in mortality for diarrheal diseases and ARI in 2008 in Nargis-affected areas, population-based mortality rates for all other communicable diseases showed no significant change in 2008 in these areas, compared to 2007 and 2009. Tuberculosis control programs reached their targets of 70% case detection and 85% treatment success rates in 2007 and 2008. Vaccination coverage rates for DPT 3rd dose and measles remained at high though measles coverage still did not reach the Sphere target of 95% even by 2009. Sanitary latrine coverage in the Nargis-affected area dropped sharply to 50% in the months of 2008 following the incident but then rose to 72% in 2009. CONCLUSION: While the incidence of diarrhea, dysentery and ARI increased post-Nargis in areas affected by the incident, the incidence rate for other diseases and mortality rates did not increase, and normal disease patterns resumed by 2009. This suggests that health services as well as prevention and control measures provided to the Nargis-affected population mitigated what could have been a far more severe health impact. PMID- 21708045 TI - Relationship of serum bilirubin concentration to kidney function and 24-hour urine protein in Korean adults. AB - BACKGROUND: The relationships among serum bilirubin concentration, kidney function and proteinuria have yet to be fully elucidated, nor have these relationships been investigated in Korean adults. METHOD: We retrospectively reviewed the medical records of Korean adults who were evaluated at Kosin University Gospel Hospital (Busan, Republic of Korea) during a five-year period from January 2005 to December 2009. We evaluated the relationships among serum bilirubin concentration, estimated glomerular filtration rate (eGFR) and 24-hour urinary protein excretion in a sample of 1363 Korean adults aged 18 years or older. RESULTS: The values of eGFR <60 mL/min/1.73 m2 and 24-hour urine albumin >=150 mg/day were observed in 26.1% (n = 356) and 40.5% (n = 553) of subjects, respectively. Fasting glucose levels >=126 mg/dL were observed in 44.9% (n = 612) of the total sample. After adjustment for potential confounding factors including demographic characteristics, comorbidities and other laboratory measures, total serum bilirubin was positively associated with eGFR and negatively associated with proteinuria both in the whole cohort and in a subgroup of diabetic individuals. CONCLUSIONS: To our knowledge, this is the first hospital-based study specifically aimed at examining the relationships among serum total bilirubin concentration, 24-hour urine protein and kidney function in Korean adults. We demonstrated that serum total bilirubin concentration was negatively correlated with 24-hour urine protein and positively correlated with eGFR in Korean non-diabetic and diabetic adults. PMID- 21708046 TI - Policy environment and male circumcision for HIV prevention: findings from a situation analysis study in Tanzania. AB - BACKGROUND: Male circumcision (MC) has been shown to be effective against heterosexual acquisition of HIV infection and is being scaled up as an additional strategy against HIV in several countries of Africa. However, the policy environment (whether to formulate new specific policy on MC or adapts the existing ones); and the role of various stakeholders in the MC scale up process in Tanzania was unclear. We conducted this study as part of a situation analysis to understand the attitudes of policy makers and other key community and health authority decision makers towards MC, policy and regulatory environment, and the readiness of a health system to accommodate scaling up of MC services. METHODS: We conducted 36 key informants' interviews with a broad range of informants including civil servants, religious leaders, cultural and traditional gatekeepers and other potential informants. Study informants were selected at the national level, regional, district and community levels to represent both traditionally circumcising and non-circumcising communities. RESULTS: Study informants had positive attitudes and strong beliefs towards MC. Key informants in traditionally non-circumcising districts were willing to take their sons for medically performed MC. Religious leaders and traditional gatekeepers supported MC as it has been enshrined in their holy scripts and traditional customs respectively. Civil servants highlighted the need for existence of enabling policy and regulatory environment in the form of laws, regulations and guidelines that will ensure voluntary accessibility, acceptability, quality and safety for those in need of MC services. Majority of informants urged the government to make improvements in the health system at all levels to ensure availability of adequate trained personnel, infrastructure, equipment, and supplies for MC scale up, and insisted on the involvement of different MC stakeholders as key components in effective roll out of medically performed MC programme in the country. CONCLUSIONS: Findings from the situation analysis in Tanzania have shown that despite the absence of a specific policy on MC, basic elements of enabling policy environment at national, regional, district and community levels are in place for the implementation of MC scale up programme. PMID- 21708047 TI - Effectiveness of regular reporting of spirometric results combined with a smoking cessation advice by a primary care physician on smoking quit rate in adult smokers: a randomized controlled trial. ESPIROTAB study. AB - BACKGROUND: Undiagnosed airflow limitation is common in the general population and is associated with impaired health and functional status. Smoking is the most important risk factor for this condition. Although primary care practitioners see most adult smokers, few currently have spirometers or regularly order spirometry tests in these patients. Brief medical advice has shown to be effective in modifying smoking habits in a large number of smokers but only a small proportion remain abstinent after one year. The aim of this study is to evaluate the effectiveness of regular reporting of spirometric results combined with a smoking cessation advice by a primary care physician on smoking quit rate in adult smokers. METHODS/DESIGN: Intervention study with a randomized two arms in 5 primary care centres. A total of 485 smokers over the age of 18 years consulting their primary care physician will be recruited.On the selection visit all participants will undergo a spirometry, peak expiratory flow rate, test of smoking dependence, test of motivation for giving up smoking and a questionnaire on socio-demographic data. Thereafter an appointment will be made to give the participants brief structured advice to give up smoking combined with a detailed discussion on the results of the spirometry. After this, the patients will be randomised and given appointment for follow up visits at 3, 6, 12 and 24 months. Both arms will receive brief structured advice and a detailed discussion of the spirometry results at visit 0. The control group will only be given brief structured advice about giving up smoking on the follow up. Cessation of smoking will be tested with the carbon monoxide test. DISCUSSION: Early identification of functional pulmonary abnormalities in asymptomatic patients or in those with little respiratory symptomatology may provide "ideal educational opportunities". These opportunities may increase the success of efforts to give up smoking and may improve the opportunities of other preventive actions to minimise patient risk. Comparing adult smokers in the intervention group with those in the control group, a minimum improvement expected with respect to the rates of smoking cessation would represent a large number of avoided morbimortality. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01296295. PMID- 21708048 TI - Genome wide association study identifies KCNMA1 contributing to human obesity. AB - BACKGROUND: Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity. METHODS: We performed a GWA analysis in 164 morbidly obese subjects (BMI:body mass index>40 kg/m2) and 163 Swedish subjects (>45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal P<0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n=4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for14 adults. RESULTS: Potassium channel, calcium activated, large conductance, subfamily M, alpha member (KCNMA1) rs2116830*G and BDNF rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for KCNMA1 rs2116830*G with P=2.82*10(-10) and an odds ratio (OR) based on cases vs controls of 1.26 [95% C.I. 1.12-1.41] and for BDNF rs988712*G with P=5.2*10(-17) and an OR of 1.36 [95% C.I. 1.20-1.55]. KCNMA1 rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (P=0.0001) and fat cell (P=0.04) expression of KCNMA1 was increased in obesity. CONCLUSIONS: We have identified KCNMA1 as a new susceptibility locus for obesity, and confirmed the association of the BDNF locus at the genome-wide significant level. PMID- 21708049 TI - Rebound of residual plasma viremia after initial decrease following addition of intravenous immunoglobulin to effective antiretroviral treatment of HIV. AB - BACKGROUND: High dosage of intravenous immunoglobulin (IVIG) has been observed as a possible activator of HIV gene expression in latently infected resting CD4+ T cells, leading to a substantial decrease in both the reservoir and the residual plasma viremia when added to effective ART. IVIG treatment has also been reported to expand T regulatory cells (Tregs). The aim of this study was to evaluate possible long-term effect of IVIG treatment on residual viremia and T-lymphocyte activation. METHODS: Nine HIV-infected subjects on effective ART included in a previously reported study on IVIG treatment were evaluated 48-104 weeks after therapy. In addition, 14 HIV-infected controls on suppressive ART were included. HIV-1 RNA was analyzed in cell-free plasma by using an ultrasensitive PCR-method with a detection limit of 2 copies/mL. T-lymphocyte activation markers and serum interleukins were measured. RESULTS: Plasma residual viremia rebounded to pre treatment levels, 48-104 weeks after the initial decrease that was observed following treatment with high-dosage IVIG. No long-term effect was observed regarding T-lymphocyte activation markers, T-regulatory cells or serum interleukins. In a post-hoc analysis, a correlation between plasma HIV-1-RNA and CD4+ T-cell count was found in both IVIG-treated patients and controls. CONCLUSIONS: These results indicate that the decrease in the latent HIV-1 pool observed during IVIG treatment is transient. Although not our primary objective, we found a correlation between HIV-1 RNA and CD4+ T-cell count suggesting the possibility that patients with a higher CD4+ T-cell count might harbor a larger residual pool of latently infected CD4+ T-cells. PMID- 21708050 TI - Atomic Force Microscope nanolithography on chromosomes to generate single-cell genetic probes. AB - BACKGROUND: Chromosomal dissection provides a direct advance for isolating DNA from cytogenetically recognizable region to generate genetic probes for fluorescence in situ hybridization, a technique that became very common in cyto and molecular genetics research and diagnostics. Several reports describing microdissection methods (glass needle or a laser beam) to obtain specific probes from metaphase chromosomes are available. Several limitations are imposed by the traditional methods of dissection as the need for a large number of chromosomes for the production of a probe. In addition, the conventional methods are not suitable for single chromosome analysis, because of the relatively big size of the microneedles. Consequently new dissection techniques are essential for advanced research on chromosomes at the nanoscale level. RESULTS: We report the use of Atomic Force Microscope (AFM) as a tool for nanomanipulation of single chromosomes to generate individual cell specific genetic probes. Besides new methods towards a better nanodissection, this work is focused on the combination of molecular and nanomanipulation techniques which enable both nanodissection and amplification of chromosomal and chromatidic DNA. Cross-sectional analysis of the dissected chromosomes reveals 20 nm and 40 nm deep cuts. Isolated single chromosomal regions can be directly amplified and labeled by the Degenerate Oligonucleotide-Primed Polymerase Chain Reaction (DOP-PCR) and subsequently hybridized to chromosomes and interphasic nuclei. CONCLUSIONS: Atomic force microscope can be easily used to visualize and to manipulate biological material with high resolution and accuracy. The fluorescence in situ hybridization (FISH) performed with the DOP-PCR products as test probes has been tested succesfully in avian microchromosomes and interphasic nuclei. Chromosome nanolithography, with a resolution beyond the resolution limit of light microscopy, could be useful to the construction of chromosome band libraries and to the molecular cytogenetic mapping related to the investigation of genetic diseases. PMID- 21708052 TI - Neuropeptide S alters anxiety, but not depression-like behaviour in Flinders Sensitive Line rats: a genetic animal model of depression. AB - Neuropeptide S (NPS) and its receptor (NPSR) have been implicated in the mediation of anxiolytic-like behaviour in rodents. However, little knowledge is available regarding the NPS system in depression-related behaviours, and whether NPS also exerts anxiolytic effects in an animal model of psychopathology. Therefore, the aim of this work was to characterize the effects of NPS on depression- and anxiety-related parameters, using male and female rats in a well validated animal model of depression: the Flinders Sensitive Line (FSL), their controls, the Flinders Resistant Line (FRL), and Sprague-Dawley (SD) rats. We found that FSL showed greater immobility in the forced swim test (FST) than FRL, confirming their phenotype. However, NPS did not affect depression-related behaviour in any rat line. No significant differences in baseline anxiety levels between the FSL and FRL strains were observed, but FSL and FRL rats displayed less anxiety-like behaviour compared to SD rats. NPS decreased anxiety-like behaviour on the elevated plus-maze in all strains. The expression of the NPSR in the amygdala, periventricular hypothalamic nucleus, and hippocampus was equal in all male strains, although a trend towards reduced expression within the amygdala was observed in FSL rats compared to SD rats. In conclusion, NPS had a marked anxiolytic effect in FSL, FRL and SD rats, but did not modify the depression related behaviour in any strain, in spite of the significant differences in innate level between the strains. These findings suggest that NPS specifically modifies anxiety behaviour but cannot overcome/reverse a genetically mediated depression phenotype. PMID- 21708051 TI - Tennis elbow. AB - INTRODUCTION: Lateral pain in the elbow affects up to 3% of the population, and is considered an overload injury of the extensor tendons of the forearm where they attach at the lateral epicondyle. Although usually self-limiting, symptoms may persist for over 1 year in up to 20% of people. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for tennis elbow? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 80 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, autologous whole blood injections, corticosteroid injections, combination physical therapies, exercise, extracorporeal shock wave therapy, iontophoresis, low-level laser therapy, manipulation, non-steroidal anti inflammatory drugs (oral and topical), orthoses (bracing), platelet-rich plasma injections, pulsed electromagnetic field treatment, surgery, and ultrasound. PMID- 21708053 TI - Affect status and perception of exacerbation in patients with asthma. AB - Exacerbations occur commonly in patients with asthma but factors affecting perception of dyspnea during exacerbation are not well known. This investigation was designed to determine the effects of negative mood on perception of dyspnea during exacerbation. A total of 47 patient aged 28-78 years (mean age, 52.5 years) admitted with acute asthma had recordings of blood gas pressure, negative mood score, forced expiratory volume in 1 second (FEV(1)), and dyspnea score at admission and at the 72nd hour. Perceived intensity of dyspnea was estimated using a modified Borg scale. The negative mood was assessed with an overall of six mood adjectives (nervous-anxious, sad-blue, and tired-drowsy). High negative mood score was defined as the score above the cutoff point (median score, >7). Borg sore of patients with a high negative mood score was higher than that of patients with a low negative mood score (6.3 +/- 2.5 versus 4.4 +/- 2.4; p = 0.01). The high Borg sore of asthmatic patients with high negative mood persisted even at the 72nd hour (1.6 +/- 0.9 versus 1.0 +/- 0.7; p = 0.01). FEV(1) values of both groups at admission were similar. The negative mood score (beta = 0.68; p = 0.0001) and initial FEV(1) (beta = -0.42; p = 0.01) were the important determinants of Borg score at admission in all patients with multivariate analysis but not arterial oxygen pressure, arterial carbon dioxide pressure, asthma duration, and female sex. This study indicated that emotional factors, as well as the level of airways obstruction, predicted the magnitude of dyspnea at exacerbation of asthmatic patients. Thus, the emotional factors should be taken into account in the treatment of dyspnea at exacerbation. PMID- 21708054 TI - Update on occupational rhinitis and asthma. AB - The workplace is emerging as an increasingly important venue for the development of rhinitis and asthma. There is no question that allergic diseases of the respiratory tract caused by occupational exposure are on the increase. The clinician's diagnostic index of suspicion must be high so that a diagnosis of occupational rhinitis and/or asthma can be made in a timely fashion. Altering the environment of the workplace or removing the patient from that workplace may spare the patient permanent damage. PMID- 21708055 TI - Update on asthma step-therapy. AB - The 2007 NAEPP guidelines elegantly outline an evidence-based stepwise approach to evaluate, attain, and sustain asthma control. A conceptual paradigm shift in the 2007 guidelines is the focus on achievement of current asthma control to minimize future risk. Recently, the Food and Drug Administration (FDA) has revoiced concerns regarding asthma pharmacotherapy-related safety issues. In particular, they give guidance on stepping down of asthma therapy after control is achieved. Unfortunately, there are no published randomized controlled trials addressing this question, and current National Asthma Education and Prevention Program recommendations on this topic are evidence category D. This manuscript reviews some of the recent studies published since release of the Expert Panel Report 3 and FDA warnings that may add to our understanding of this issue. PMID- 21708056 TI - Care of asthma patients in relation to guidelines. AB - Clinical asthma care may have to change to be brought in line with Expert Panel Report 3 (EPR3) guidelines, which recommend increased intensity of therapy (steps) to treat uncontrolled asthma. This study determined if asthma therapy steps can be identified using claims data and if patients have appropriate step up in therapy if their disease is not controlled. A cohort study was performed using an administrative claims database and involving patients 12-64 years old with uncontrolled asthma events (either impairment or risk). Patients were assigned to a preindex step (6 months before the index date) and postindex steps (1 year after the index date). The primary study outcome was a change in therapy steps. We used logistic regression to identify variables predictive of an increase in step. Our algorithm for assigning steps appeared internally valid; patients identified as being at higher steps saw more specialists and had higher levels of asthma risk. Among 14,781 patients for which a step-up option existed, 12.4-41.3% had a step-up in therapy after an uncontrolled asthma event. For all steps, high-risk patients had higher odds of having a step-up in therapy than low risk patients. The odds ratio for appropriate therapy increased with increasing baseline step: from 1.50 for step 2 versus step 1, to 11.41 for step 5 versus step 1. Steps can be assigned using claims data. Bringing care in line with EPR3 guidelines will require significant changes from current practice but will improve quality by reducing use of oral corticosteroids and increasing use of inhaled steroids. PMID- 21708057 TI - Nebulized dehydroepiandrosterone-3-sulfate improves asthma control in the moderate-to-severe asthma results of a 6-week, randomized, double-blind, placebo controlled study. AB - Inhaled dehydroepiandrosterone-3-sulfate (DHEAS), but not dehydroepiandrosterone (DHEA), possesses anti-inflammatory activity in in vitro assays and in models of allergen and lipopolysaccharide challenges. We postulated whether an inhaled suspension of DHEAS delivered via nebulizer would improve asthma control in moderate-to-severe asthma patients. We also characterized the safety profile of an inhaled suspension of DHEAS. Patients receiving at least 500 MUg of fluticasone equivalent plus long-acting beta-agonists (LABA) entered a 5-week run in where the dose of inhaled corticosteroids was reduced to 200 MUg of fluticasone plus LABA per day. Patients were randomized to 70 mg of DHEAS or placebo if their Asthma Control Questionnaire (ACQ) score was >=2.0 and their FEV(1) >= 50%. When compared with control, a statistically significant improvement in ACQ in 6 weeks of treatment with 70 mg of DHEAS was observed. The median improvement in ACQ was -0.72 and -0.43 for the active and placebo groups, respectively (p = 0.0389); the percentage of patients with at least minimally clinically important difference of -0.50 from baseline was significantly greater in the DHEAS group versus the placebo, (59.4% versus 45.7%; p = 0.0236). Asthma symptom scores, the proportion of symptom-free days and symptom nights, although not statistically significant, had positive trends supporting the improvement in ACQ. Fewer patients were withdrawn from the study for respiratory events on DHEAS compared with placebo. There were few adverse events and no changes in sex hormones despite increases in circulating levels of DHEAS. An inhaled suspension of DHEAS delivered via nebulizer improved asthma control scores in subjects with poorly controlled moderate-to-severe asthma. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY ANZCTR.ORG.AU IDENTIFIER: 012607000192482. PMID- 21708058 TI - Skin test sensitivity to mouse predicts allergic symptoms to nasal challenge in urban adults. AB - Epidemiologic studies have shown an association between mouse allergen exposure and asthma morbidity among urban populations, but confirmatory challenge studies in community populations have not been performed. This study was designed to examine the clinical relevance of mouse sensitization using a nasal challenge model. Forty-nine urban adults with asthma underwent skin-prick testing (SPT) and intradermal testing (IDT) with mouse epithelia extract. A positive SPT was defined as a net wheal size >=3 mm and a positive IDT was defined as a net wheal size >=6 mm using a 1:100 dilution of extract (1:10 w/v was obtained from Greer Laboratories (Lenoir, NC) as a single lot [Mus m 1 concentration = 2130 ng/mL]). Mouse-specific IgE (m-IgE) was measured by ImmunoCAP (Phadia, Uppsala, Sweden). Nasal challenge was performed with increasing concentrations of mouse epithelia extract and symptoms were assessed by visual analog scale. A positive challenge was defined as a 20-mm increase in the scale. The age range of the 49 participants was 18-50 years; 41% were men and 86% were black. Fourteen participants were SPT(+) to mouse, 15 participants were SPT(-) but (IDT(+)), and 20 participants were negative on both SPT(-) and IDT(-) (SPT(-)/IDT(-)). Sixty four percent of the SPT(+) group, 40% of the IDT(+) group, and 20% of the SPT( )/IDT(-) group had a positive nasal challenge. Sixty-seven percent (10/15) of those who were either SPT(+) or m-IgE(+) had a positive nasal challenge. SPT or the combination of SPT plus m-IgE performed best in diagnosing mouse allergy. The great majority of mouse-sensitized urban adults with asthma appear to have clinically relevant sensitization. Urban adults with asthma should be evaluated for mouse sensitization using SPT or SPT plus m-IgE testing. PMID- 21708059 TI - Predicting which medication classes interfere with allergy skin testing. AB - Medications often interfere with allergy skin test interpretation. This study was performed to determine which medications interfere with allergy skin tests. We retrospectively reviewed skin-prick test results from patients who had discontinued H(1)-antagonists, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), benzodiazepines, atypical antidepressants, antipsychotics, hypnotics, sedatives, proton pump inhibitors (PPIs), and H(2)-antagonists between 0 and 7 days before allergy skin testing. Ninety-seven subjects had taken second generation H(1)-antihistamines within 7 days of skin testing; all patients who had stopped 3 days before testing had positive histamine controls. Two hundred sixty-eight skin tests performed on patients taking a single medication of interest showed that patients had the following percentages of a positive histamine control: TCAs, 56.5%; SNRIs, 100%; H(2)-blockers, 100%; SSRIs, 97%; PPIs, 97%; benzodiazepines, 85.7%; and atypical antidepressants/sedatives, 92.6%. The 580 patients taking multiple medications of interest showed that the odds ratio and 95% confidence intervals of a negative histamine test for patients taking TCAs were 6.33 (2.11-20.5), for H(1)-blockers were 4.95 (1.78-15.1), for benzodiazepines were 5.01 (1.72-15.80), for atypical antidepressants/sedatives were 3.11 (1.09-9.61), and for H(2)-blockers were 2.91 (0.97-9.37). The odds of a negative histamine test for SSRIs, SNRIs, or PPIs were not significantly increased. SSRIs, SNRIs, and PPIs are unlikely to interfere with skin testing. TCAs, H(1)-blockers, benzodiazepines, quetiapine, and mirtazapine should be discontinued temporarily if clinically able. H(2)-antagonists, bupropion, eszopiclone, trazodone, or zolpidem showed minimal interference with immediate hypersensitivity skin test histamine response. PMID- 21708060 TI - An integrated analysis of the efficacy of fluticasone furoate nasal spray on individual nasal and ocular symptoms of seasonal allergic rhinitis. AB - Intranasal steroids have been shown to affect ocular symptoms of allergic rhinitis (AR). The results of the published literature, however, are not uniform across all products. This study was designed to evaluate whether the effects of fluticasone furoate nasal spray (FFNS) are consistent across different allergy seasons and different geographic regions for individual nasal and ocular symptoms of seasonal allergic rhinitis (SAR). An integrated analysis was performed on data from four randomized, double-blind, placebo-controlled, parallel-group, multicenter trials, designed to evaluate the efficacy and safety of FFNS, 110 micrograms, once daily for 14 days in 1141 adult and adolescent SAR patients exposed to mountain cedar, ragweed, or grass pollen allergen. All patients evaluated severity of seven individual nasal and ocular symptoms on a 4-point categorical scale. The main efficacy measures included change from baseline in daily reflective, morning (A.M.) predose instantaneous, and daily A.M. and evening (P.M.) reflective score for each nasal/ocular symptom. FFNS significantly improved daily mean reflective, A.M. predose instantaneous, and daily A.M. and P.M. reflective scores for nasal itching, sneezing, congestion, rhinorrhea, and ocular itching/burning, tearing/watering, and redness, compared with placebo (p < 0.001 for all versus placebo). The least square (LS) mean treatment differences ranged from -0.44 to -0.33 (p < 0.0001) for the individual nasal symptoms and from -0.22 to -0.19 (p < 0.0001) for the individual ocular symptoms. FFNS also significantly improved daily reflective total nasal symptom scores (TNSS)/reflective total ocular symptom scores (TOSS), and A.M. predose instantaneous TNSS and instantaneous TOSS, compared with placebo (LS mean treatment differences = -1.47, -0.65, -1.49, and -0.63, respectively; p < 0.001 for all). FFNS, 110 micrograms, once daily consistently relieved all nasal and ocular symptoms of SAR across different allergy seasons and geographical locations. PMID- 21708061 TI - Safety of fixed-dose loratadine/montelukast in subjects with allergic rhinitis. AB - The safety of loratadine (second-generation antihistamine) and montelukast (leukotriene receptor antagonist) as monotherapies is well documented. Safety of the fixed-dose, single-tablet therapy loratadine/montelukast (L/M; SCH 445761, containing loratadine [10 mg]/montelukast [10 mg]), for treatment of the symptoms of allergic rhinitis in >3800 subjects is described. Safety data from 19 randomized clinical studies in which subjects were administered L/M are presented. Adverse events (AEs) were defined as any unfavorable and unintended sign, symptom, or laboratory data, including onset of new illness and exacerbation of preexisting conditions. Only AEs with an onset during the treatment period (i.e., treatment emergent) are summarized. Safety was also assessed via clinical laboratory evaluations and monitoring of vital signs and electrocardiogram (ECG). Overall, the incidence of AEs reported with L/M in the 19 studies was low and comparable with placebo, loratadine monotherapy, and montelukast monotherapy. The most frequently reported AE across all studies was headache. Most AEs were not severe and the duration of such events was short lived. Three AEs (headache [4.5%], fatigue [1.2%], and pharyngolaryngeal pain [1.2%]), regardless of relation to treatment, were reported by >1% of subjects in the L/M treatment group of multiple-dose, placebo-controlled studies. There were no clinically significant changes in clinical laboratory analyses or in vital signs, physical findings, or ECG found to be clinically relevant. Administration of the fixed-dose, single-tablet formulation of L/M was well tolerated. In these clinical studies, the safety of L/M was comparable with placebo, loratadine, and montelukast. PMID- 21708063 TI - A solitary mastocytoma presenting with urticaria and angioedema in a 14-year-old boy. AB - Urticaria with angioedema is a common clinical presentation that often poses a challenge for allergists. The differential diagnosis for urticaria is broad, making the evaluation and pinpointing the underlying cause difficult and frustrating for both families and physicians. Certain causes of urticaria such as infections or medications are more common and easier to identify whereas less frequently seen conditions are often overlooked because of their rarity. One such condition is mastocytosis. Mastocytosis is a rare disease that very seldom presents with urticaria but may be associated with significant morbidity and mortality if not recognized in a timely manner. We are presenting a case of a 14 year-old boy who presented with urticaria and angioedema possibly caused by a solitary mastocytoma. The learning points from this case are that mastocytosis should be considered in the differential diagnosis of urticaria and solitary mastocytomas may remain active into adolescence, raising concern for systemic progression. PMID- 21708062 TI - Assessment of humoral and cell-mediated immune response to measles-mumps-rubella vaccine viruses among patients with asthma. AB - Little is known about the influence of asthma status on humoral and cell-mediated immune responses to measles-mumps-rubella (MMR) vaccine viruses. We compared the virus-specific IgG levels and lymphoproliferative response of peripheral blood mononuclear cells to MMR vaccine viruses between asthmatic and nonasthmatic patients. The study subjects included 342 healthy children aged 12-18 years who had received two doses of the MMR vaccine. We ascertained asthma status by applying predetermined criteria. Of the 342 subjects, 230 were available for this study of whom 25 were definite asthmatic patients (10.9%) and the rest of subjects were nonasthmatic patients. The mean of the log-transformed lymphoproliferative responses between definite asthma and nonasthma who had a family history of asthma were for measles, 0.92 +/- 0.31 versus 1.54 +/- 0.17 (p = 0.125); for mumps, 0.98 +/- 0.64 versus 2.20 +/- 0.21 (p = 0.035); and for rubella, 0.12 +/- 0.37 versus 0.97 +/- 0.16 (p = 0.008), respectively, adjusting for the duration between the first MMR vaccination and determination of the immune responses. There were no such differences among children without a family history of asthma. MMR virus-specific IgG levels were not different between study subjects with or without asthma. The study findings suggest asthmatic patients may have a suboptimal cell-mediated immune response to MMR vaccine viruses and a family history of asthma modifies this effect. PMID- 21708064 TI - Functional mapping of rat brain activation following rTMS using activity-induced manganese-dependent contrast. AB - OBJECTIVE: Functional neuroimaging techniques act as the navigator to assess changes in brain activity induced by repetitive transcranial magnetic stimulation (rTMS) in rTMS studies. The aim of this study was to investigate the feasibility of using manganese-enhanced magnetic resonance imaging (MEMRI) to measure the brain activity in rTMS studies. METHODS: Eighteen Wistar rats were randomized into three groups (n = 6) including a high rTMS group, a low rTMS group and a sham stimulation group (controls). They were given rTMS of 10 Hz, 1 Hz or sham stimulation for 5 hours separately. MEMRI was used to assess the changes of brain activity. RESULTS: Compared with the controls, image intensity was enhanced differently in various brain regions on T1-weighted images after rTMS with different frequencies, higher intensity and wider enhancement occurred in the high frequency rTMS group as compared with that in the low frequency rTMS group. CONCLUSION: MEMRI can be used to reveal the changes of brain activity in live rats following rTMS. SIGNIFICANCE: The current experiment might provide a new functional neuroimaging technique for the study of rTMS. PMID- 21708065 TI - CDP-choline treatment increases circulating endothelial progenitor cells in acute ischemic stroke. AB - OBJECTIVES: The increase in circulating endothelial progenitor cells (EPCs) is associated with a better outcome in patients with acute ischemic stroke. CDP choline (citicoline) increases brain plasticity after experimental stroke. Therefore, we study if citicoline treatment could increase the EPC concentration after ischemic stroke. METHODS: Forty-eight patients with a first-ever non lacunar ischemic stroke were consecutively included in the study within 12 hours of symptoms onset. Patients received treatment (n = 26) or non-treatment (n = 22) with oral citicoline (2000 mg/day) from acute phase of ischemic stroke and for 6 weeks. EPC colonies were quantified as early outgrowth colony forming unit endothelial cell (CFU-EC) at admission (before citicoline treatment) and day 7. We defined the EPC increment during the first week as the difference in the numbers of CFU-EC between day 7 and admission. RESULTS: CFU-ECs were similar at baseline between patients treated and non-treated with citicoline (7.7+/-6.1 versus 9.1+/-7.3 CFU-EC, P = 0.819). However, patients treated with citicoline and recombinant tissue-plasminogen activator (rt-PA) showed a higher EPC increment compared to patients treated only with citicoline or non-treated (35.4+/-15.9 versus 8.4 +/- 8.1 versus 0.9 +/- 10.2 CFU-EC, P < 0.0001). In a logistic model, citicoline treatment [odds ratio (OR), 17.6; confidence interval (CI) 95%, 2.3-137.5, P = 0.006] and co-treatment with citicoline and rt-PA (OR, 108.5; CI 95%, 2.9-1094.2, P = 0.001) were independently associated with an EPC increment?4 CFU-EC. CONCLUSION: The administration of citicoline and the co administration of citicoline and rt-PA increase EPC concentration in acute ischemic stroke. PMID- 21708066 TI - Intraoperative facial nerve motor evoked potential monitoring during skull base surgery predicts long-term facial nerve function outcomes. AB - OBJECTIVES: This study was designed to clarify whether facial nerve motor evoked potentials (FNMEPs) elicited by transcranial electrical stimulation during skull base surgery are useful for predicting long-term facial nerve function. METHODS: We analyzed FNMEP findings in 35 patients with skull base tumors. Mean follow-up was 24.4 months. Corkscrew electrodes positioned at C3 or C4 and Cz were used to deliver supramaximal stimuli. FNMEPs were recorded from the orbicularis oculi and oris muscles. RESULTS: The correlation between the final-to-baseline FNMEP ratio and initial or long-term facial nerve function was examined. Initial post operative facial nerve function correlated significantly with the FNMEP ratios in the orbicularis oculi (r = -0.53, P < 0.005) and orbicularis oris (r = -0.80, P < 0.001) muscles. The correlations between FNMEP ratios and facial nerve function remained significant during long-term follow-up (orbicularis oculi muscle: r = 0.43, P < 0.05; orbicularis oris muscle: r = -0.71, P < 0.001). All patients in whom the FNMEP ratio in the orbicularis oculi muscles remained above 50% were assigned to the satisfactory facial nerve function (House-Brackmann Grades i and ii) group at the final examination. DISCUSSION: FNMEP monitoring can predict facial nerve function not only immediately after surgery but also long-term. PMID- 21708067 TI - HIF-1-alpha and survivin involved in the anti-apoptotic effect of 2ME2 after global ischemia in rats. AB - Survivin is an anti-apoptotic gene that decreases the apoptosis by depressing the expression of caspase-3. Hypoxia-inducible factor-1-alpha (HIF-1-alpha) is a transcription factor specifically activated by hypoxia. 2-methoxyestradiol (2ME2) is an estradiol derivative and a known HIF-1-alpha inhibitor. 2ME2 decreased apoptosis by inhibiting HIF-1-alpha. The aim of the present study was to investigate if survivin is involved in the anti-apoptotic effect of 2ME2. Male adult rats were used to make the global ischemia (GI) model. Ten minutes after GI, 2ME2 was injected intraperitoneally (16 mg/kg weight). Rats were killed at 6 hours, 12 hours, 24 hours, 48 hours, 96 hours, and 7 days. GI produced a marked increase in HIF-1-alpha expressions in the hippocampus at 6 hours and peaked at 48-96 hours. The expressions of survivin and caspase-3 were increased lightly in a similar time course. These molecular changes were accompanied by massive cell loss and apoptosis in the hippocampal regions. 2ME2 treatment reduced the expression of HIF-1-alpha, increased survivin expression, and decreased the expression of caspase-3. These results indicate that survivin and HIF-1-alpha were involved in the anti-apoptotic effect of 2ME2 treated following GI. 2ME2 may decrease the HIF-1-alpha expression, up-regulate the survivin expression, inhibit the expression of caspase-3, and finally reduce apoptosis after GI. PMID- 21708068 TI - In vitro culture and characterization of oligodendrocyte precursor cells derived from neonatal rats. AB - OBJECTIVES: The pathologic changes of demyelination after spinal cord injury (SCI) significantly impair functional recovery of lesioned spinal cord. At present, transplantation of myelinating cells is regarded as a promising strategy for treating demyelination following SCI. Hence, the In vitro culture and growth, differentiation and proliferation of oligodendrocyte precursor cells (OPCs) were intensively investigated in this study. METHODS: In vitro cells from cerebral cortices of neonatal rats were primarily cultured and OPCs were then separated by shaking process and differential adhesion. Following cultured in the conditional medium, growth pattern and differentiation of OPCs were continuously studied by both light microscopy and scanning electron microscopy. Furthermore, maturation of OPCs was detected immunochemically and proliferative ability of OPCs In vitro was also evaluated by methyl thiazolyl tetrazolium (MTT) assay. RESULTS: The distinct stratification of glial cells usually developed around 9-10 days in the primary culture. The OPCs were found primarily living on the surface of confluent astrocytes and these cells typically displayed the simple appearance of immature cells. Furthermore, the OPCs progressively developed in the conditional medium, and these differentiated cells underwent dramatic changes of morphology and also expressed different specific markers. Moreover, the OPCs also proved by MTT assay to proliferate significantly while cultured In vitro. DISCUSSION: Demyelination prevents recovery of neural function following SCI. Demyelination has already become a potential therapeutic target for this insidious and challenging problem. The In vitro culture and biological characteristics of OPCs are fundamental and necessary for further investigation of cell transplantation in vivo. Growth pattern, differentiation and proliferation are very vital for therapeutical effects of OPCs following transplantation after SCI. PMID- 21708069 TI - Functional characterization of optimized acellular peripheral nerve graft in a rat sciatic nerve injury model. AB - OBJECTIVES: Acellular grafts are a viable option for use in nerve reconstruction surgeries. Recently, our lab created a novel optimized decellularization procedure that removes immunological material while leaving the majority of the extracellular matrix structure intact. The optimized acellular (OA) graft has been shown to elicit an immune response equal to or less than that elicited by the isograft, the analog of the autograft in the rat model. We investigated the performance of the OA graft to provide functional recovery in a long-term study. METHODS: We performed a long-term functional regeneration evaluation study using the sciatic functional index to quantify recovery of Lewis rats at regular time intervals for up to 52 weeks after graft implantation following 1 cm sciatic nerve resection. OA grafts were compared against other decellularized methods (Sondell treatment and thermal decellularization), as well as the isograft and primary neurorrhaphy. RESULTS: The OA graft supported comparable functional recovery to the isograft and superior regeneration to thermal and Sondell decellularization methods. Furthermore, the OA graft promoted early recovery to a greater degree compared to acellular grafts obtained using either the thermal or the Sondell methods. DISCUSSION: Equivalent functional recovery to the isograft suggests that the OA nerve graft may be a future clinical alternative to the current autologous tissue graft. PMID- 21708070 TI - Flexor reflexes elicited by magnetic and electric stimulation of the sural nerve. AB - OBJECTIVES: We have investigated whether magnetic stimulation of the sural nerve can evoke a flexor reflex recorded from the ipsilateral short head of the biceps femoris muscle. METHODS: The sural nerve was subjected to magnetic stimulation as well as by single-pulse electrical stimulation in healthy subjects. RESULTS: In 87% of the participants, a reflex response was elicited from the short head of biceps femoris muscle by magnetic stimulation of the sural nerve. In terms of latency and amplitude, this reflex response was similar to the flexor reflex response evoked from the same muscle by single-pulse electrical stimulation of the sural nerve. DISCUSSION: Findings indicate that flexor reflexes can easily be evoked from the short head of the biceps femoris muscle by magnetic stimulation of the sural nerve. The late component of the flexor reflex may not only be elicited via nociceptive afferents but may also involve non-nociceptive afferents. PMID- 21708071 TI - Trauma-induced reactive gliosis is reduced after treatment with octanol and carbenoxolone. AB - BACKGROUND: Reactive gliosis and scar formation after brain injury can inhibit the recovery process. As many glial cells utilize gap junctions for intercellular signaling, this study investigated whether two commonly used gap junction blockers, octanol and carbenoxolone, could attenuate reactive gliosis following a minor traumatic brain injury. METHODS: Octanol (710 mg/kg) or carbenoxolone (90 mg/kg) was administered 30 minutes before or after a needle track injury in adult male Sprague-Dawley rats. To mark dividing cells, animals were injected with bromodeoxyuridine (BrdU; 150 mg/kg) intraperitoneally two times per day, 8 hours apart and killed 2 days later. Immunohistochemistry for BrdU and markers for reactive glial cells [glial fibrillary acidic protein (GFAP), ED1, and NG2] were investigated using immunohistochemistry and western blot techniques. RESULTS: Two days after injury, increased cellular proliferation, activated astrocytes and microglia, and upregulation of NG2 expression were observed surrounding the injury site. Octanol and carbenoxolone administrated prior to injury significantly decreased cell proliferation by 60 and 70% respectively. The distance of GFAP immunoreactive astrocytes from the wound margin was decreased by 32 and 18% when octanol was administrated prior to or post injury respectively. Treatment with octanol also decreased the number of reactive microglia by 55% and, when administrated prior to injury, octanol reduced the distance of NG2 expression from the wound by 48%. CONCLUSION: The present study demonstrates that two important components of reactive gliosis, cellular activation and proliferation, can be attenuated by octanol and carbenoxolone. PMID- 21708072 TI - Improvement of the pilocarpine epilepsy model in rat using bone marrow stromal cell therapy. AB - OBJECTIVE: Temporal lobe epilepsy is one of the most common types of epilepsy. Cytotherapy was tried for several neurological disorders. In this investigation, bone marrow stromal cells (BMSCs) were used in order to evaluate the recovery of epileptic rats induced by pilocarpine. METHODS: The rats were divided into four groups: a negative control, treated groups, and epileptic rats treated with the vehicle only. The animals in the chronic phase were monitored for three weeks using Racine scale. BMSCs were labeled with BrdU and injected intravenously. After 6 weeks, the rats were killed and processed in paraffin as well as immunohistochemical techniques. RESULTS: The results of the behavioral test showed that the number of seizures significantly decreased in treatment groups. Histopathology of the tissues from the untreated rats showed cell death and neurophagia. The numerical density of neurons per area was significantly higher in the treated groups than in the untreated ones. BMSCs localized in the hippocampus of the treated animals. DISCUSSION: The results showed that there is structural and functional improvement in the epileptic rats treated with BMSCs. PMID- 21708073 TI - Subarachnoid and basal cistern navigation through the sacral hiatus with guide wire assistance. AB - BACKGROUND: Intraspinal navigation with catheters and fiberscopes has shown feasible results for diagnosis and treatment of intraspinal and intracranial lesions. The most common approach, lumbar puncture, has allowed access to the spinal cord, however, coming with the difficulties of fiberscope damage and decreased torque for guidance. Our objective in this study is to allow an alternate access, the sacral hiatus, with guide wire assistance into the subarachnoid and intracranial structures, while easing the angle of entry and increasing torque. METHODS: We advanced catheters with guide wire and fluoroscopy assistance into the sacral hiatus of three cadavers. After entry, the thecal sac was punctured and the catheter with guide wire was advanced rostrally until positioned in the basal cisterns of the brain. We confirmed catheter placement with contrast injection, autopsy, and dissection. RESULTS: In our study, the sacral hiatus was easily accessed, but resistance was found when attempting to puncture the thecal sac. The advancement of the catheter with guide wire assistance glided easily rostrally until some mild resistance was discovered at entry into the foramen magnum. With redirection, all catheters passed with ease into the basal cisterns. Positioning was confirmed with contrast injection with fluoroscopy evidence, autopsy, and dissection. There was no macroscopic or microscopic evidence of damage to the spinal roots, spinal cord, or cranial nerves. CONCLUSION: The sacral hiatus with guide wire assistance is an accessible conduit for uncomplicated entry into the subarachnoid and basal cistern space without damaging surrounding structures. PMID- 21708074 TI - Whole blood genome-wide expression profiling and network analysis suggest MELAS master regulators. AB - BACKGROUND: The heteroplasmic mitochondrial DNA (mtDNA) mutation A3243G causes the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome as one of the most frequent mitochondrial diseases. The process of reconfiguration of nuclear gene expression profile to accommodate cellular processes to the functional status of mitochondria might be a key to MELAS disease manifestation and could contribute to its diverse phenotypic presentation. OBJECTIVE: To determine master regulatory protein networks and disease-modifying genes in MELAS syndrome. METHODS: Analyses of whole blood transcriptomes from 10 MELAS patients using a novel strategy by combining classic Affymetrix oligonucleotide microarray profiling with regulatory and protein interaction network analyses. RESULTS: Hierarchical cluster analysis elucidated that the relative abundance of mutant mtDNA molecules is decisive for the nuclear gene expression response. Further analyses confirmed not only transcription factors already known to be involved in mitochondrial diseases (such as TFAM), but also detected the hypoxia-inducible factor 1 complex, nuclear factor Y and cAMP responsive element-binding protein-related transcription factors as novel master regulators for reconfiguration of nuclear gene expression in response to the MELAS mutation. Correlation analyses of gene alterations and clinico-genetic data detected significant correlations between A3243G-induced nuclear gene expression changes and mutant mtDNA load as well as disease characteristics. These potential disease-modifying genes influencing the expression of the MELAS phenotype are mainly related to clusters primarily unrelated to cellular energy metabolism, but important for nucleic acid and protein metabolism, and signal transduction. DISCUSSION: Our data thus provide a framework to search for new pathogenetic concepts and potential therapeutic approaches to treat the MELAS syndrome. PMID- 21708075 TI - Evaluation of hyperalgesia in spared nerve injury model using mechanical, thermal, and chemical stimuli in the mouse. AB - OBJECTIVE: Neuropathic pain results from multiple etiological factors and is a debilitating condition often resulting from partial injury to a peripheral nerve. However, the mechanism underlying this syndrome remains unclear. The aim of the present study is to investigate whether a spared nerve injury model with transection of both the common peroneal nerve (CPN) and tibial nerve (TN) branches of the sciatic nerve is associated with pain or hypersensitivity in the mouse. METHODS: A skin and muscle incision was made, and we tightly ligated CPN+TN or the sural nerve (SN) alone as branches of the sciatic nerve. Mechanical and thermal allodynia were tested using von Frey filaments and radiant heat at 1, 1, 3, 5, and 7 days after surgery. RESULTS: The thresholds of mechanical and thermal stimuli were increased and decreased in the CPN+TN-ligated and SN-ligated groups, respectively. Chemical hyperalgesia was estimated using two doses of intraplantar administration of formalin (0.1 and 1%) 1 week after surgery. Then behaviors were videotaped and playback was used to measure time of licking of the hind paws. The licking time induced by 0.1% formalin was significantly shortened in the CPN+TN-ligated group and significantly prolonged in the SN-ligated group. Number of c-Fos-immunoreactive cells in the spinal cord was not affected by CPN+TN ligation, but was significantly increased in the SN-ligated group. DISCUSSION: These findings suggest that changing the combination of nerves in sciatic branch ligation produces different sensitivities to stimuli and SN ligation will be useful for inducing allodynia and hyperalgesia in the mouse. PMID- 21708076 TI - The protective effects of coumestrol against amyloid-beta peptide- and lipopolysaccharide-induced toxicity on mice astrocytes. AB - OBJECTIVES: Estrogen replacement therapy can decrease the risk of developing Alzheimer's disease. Phytoestrogens have been proposed as potential alternatives to estrogen replacement therapy. The purpose of this study was to evaluate the in vitro protective effects of coumestrol on mice astrocytes. METHODS: Different concentrations of coumestrol were tested for their protective efficacy against two toxic insults, lipopolysaccharide (LPS) and amyloid-beta peptide, on astrocytes. The mitochondrial activity of astrocytes was determined, and the protective efficacy and pathway were examined by their specific gene expression and protein change. RESULTS: The results showed that coumestrol induced a modest but significant increase in viability of astrocytes, while the viability of astrocytes was reduced following exposure to LPS and amyloid-beta peptide. The addition of coumestrol could reverse the toxic effect induced by LPS and amyloid beta peptide. Both the LPS and amyloid-beta peptide enhanced interleukin 1, interleukin 6, and tumor necrosis factor-alpha synthesis and these effects were inhibited by 10(-9)M coumestrol. This effect was more obvious on the LPS-induced inflammation. The estrogen receptor expression was upregulated by coumestrol, while the effect was more obvious on estrogen receptor-beta (ER-beta). These effects can be inhibited by extracellular signal-regulated kinase and c-Jun N terminal kinase inhibitors but not p38 inhibitor. DISCUSSION: The current data support a possible role for astrocytes in the mediation of neuroprotection by coumestrol. An indirect extracellular signal-regulated kinase/c-Jun N-terminal kinase signaling pathway to downregulate the expression of interleukin 1, interleukin 6, and the tumor necrosis factor-alpha cytotoxic effect may act in concert with the proposed direct ER-beta biosynethsis pathway to achieve a widespread, global protection of ER-beta positive neurons. PMID- 21708077 TI - Abandoning monitoring eye care utilization in Canada: something doesn't smell right! PMID- 21708078 TI - Pediatric cataracts: hitting the target refraction is not the problem, it's knowing where to aim. PMID- 21708079 TI - Eye care utilization in Canada: disparity in the publicly funded health care system. AB - OBJECTIVES: To examine patterns in, determinants of, and barriers to eye care utilization in Canada. DESIGN: Cross-sectional survey. PARTICIPANTS: All 132,221 respondents to the Canadian Community Health Survey 2005. METHODS: Eye care utilization was self-reported and was defined as having seen or talked on the telephone with an eye care provider (ophthalmologist or optometrist) in a 12 month period. Associations of interest were assessed by prevalence ratios (PR). RESULTS: Forty percent (11 million) of Canadians aged 12 years or older reported utilization of eye care providers. The lowest utilization rates occurred in people aged 30-39 years and the highest in those aged 70 years and older. Utilization was not related to levels of education or household income in people with self-reported glaucoma, cataracts, or diabetes. Among Canadians without these conditions, significantly less utilization occurred in men, in those with less than a postsecondary education, and in those with annual household incomes under $30,000. Canadians residing in Newfoundland and Labrador utilized eye care providers significantly less than those residing in other provinces (adjusted PR 0.80, 95% CI 0.74-0.86). Fourteen percent of glaucoma patients, 37% of diabetic patients, and 41% of people aged 65 years or older did not access eye care providers over a 12-month period. CONCLUSIONS: Marked disparities occur in eye care utilization among Canadians without known eye diseases. A substantial proportion of people at a high risk of vision loss do not access eye care providers. Attributable factors are likely incomplete government coverage, asymptomatic ocular diseases, and lack of perceived benefits of eye care services. PMID- 21708080 TI - Practice patterns of Canadian Ophthalmological Society members in cataract surgery--2010 survey. AB - OBJECTIVE: To establish the cataract surgery practice patterns of the members of the Canadian Ophthalmological Society (COS). STUDY DESIGN: Web-based questionnaire. METHODS: In January 2010, an email with a link to SurveyMonkey was sent from the COS office to its 305 members who had indicated their practice focus is cataract surgery. A reminder email was sent 2 weeks later. All responses were collected anonymously. RESULTS: There was a 32.5% response rate (99 responses), compared with 20.7% in 2009. Two respondents volunteered that they no longer performed cataract surgery and 1 response was incomplete; therefore, 96 responses were analyzed. The results of the 2010 survey were compared to those of the 2009 survey. CONCLUSIONS: While the majority of the practice patterns analyzed were unchanged between the 2009 and 2010 surveys, there appears to be a trend to start nonsteroidal anti-inflammatory drug eye drops earlier preoperatively and an increase in the use of one-piece hydrophobic acrylic, aspheric, and blue-blocking intraocular lenses. The use of the fourth generation fluoroquinolone antibiotic gatifloxacin has increased at the expense of older antibiotics. PMID- 21708081 TI - Long-term visual acuity and initial postoperative refractive error in pediatric pseudophakia. AB - OBJECTIVE: To examine the long-term best-corrected visual acuity (BCVA) in children who, during the amblyogenic period, underwent cataract extraction with intraocular lens (IOL) implantation and to see if initial postoperative refractive error following cataract extraction correlates with long-term BCVA. DESIGN: Retrospective chart review. PARTICIPANTS: Thirty-six eyes of 26 patients were included in the study. At least 2 years of follow-up, an age , 8.5 years at time of IOL implantation, an ability to participate in subjective visual acuity measurement, and an absence of congenital glaucoma and significant trauma were required for inclusion in the study. METHODS: Retrospective review of pseudophakic patients' charts at a tertiary care centre, with attention to initial and long-term pseudophakic refractive error, long-term BCVA, total myopic shift, length of follow-up, age at IOL implantation, and unilateral or bilateral cataract extraction with IOL implantation. RESULTS: Initial pseudophakic spherical equivalent (SE) showed a significant nonlinear relationship with most recentBCVAin unilateral cases and no relationship in bilateral cases (interaction p 0.001). Unilateral cases with initial pseudophakic SE between +1.75 D and +5.00 D showed better long-term BCVA than those with values below +1.75 D or above +5.00 D; this was irrespective of the refractive error of their fellow eye. CONCLUSIONS: In patients receiving lens implants in the first 8 years of life, we recommend aiming for low early postoperative hyperopia, taking into consideration each patient's situation and age. PMID- 21708082 TI - Cataract surgery in the first year of life: aphakic glaucoma and visual outcomes. AB - OBJECTIVE: To report the incidence of aphakic glaucoma following lensectomy in infants in their first year of life and examine the impact of this diagnosis on visual outcome. DESIGN: Retrospective cohort study. PARTICIPANTS: All patients who had lensectomy for congenital cataract during the first year of life at British Columbia Children's Hospital between 1995 and 2006. METHODS: Retrospective review of medical records. RESULTS: Seventy-five eyes of 46 patients (29 bilateral, 17 unilateral) were included. The mean age at lensectomy was 93 days (range, 2-364 days) with a mean follow-up of 77.5 months (range, 36 166 months). Patients with bilateral cataracts had a better visual outcome than those with unilateral cataracts (p < 0.032). Of the patients with measurable visual acuity (VA), 34 of 45 eyes (75.6%) with bilateral cataracts and only 3 of 16 eyes (18.8%) with unilateral cataract achieved a VA of 20/40 or better. Eighteen of 75 eyes (24%) developed aphakic glaucoma at a mean of 30 months following lensectomy. Nine patients (50%) achieved final vision of 20/40 or better. The development of aphakic glaucoma was not associated with worse visual outcomes (p < 0.315). The mean intraocular pressure (IOP) at diagnosis was 28.6+/ 5.9 mm Hg and mean final IOP was 14.1 +/- 3.0 mm Hg, a significant reduction (p < 0.0001). Fifteen of 18 eyes with aphakic glaucoma (83.3%) required surgical intervention to achieve IOP control. CONCLUSIONS: Children with aphakic glaucoma may have good visual outcomes if it is recognized early and managed appropriately. A significant proportion of patients required surgical intervention to control IOP. PMID- 21708083 TI - Accuracy of Plusoptix S04 in children and teens. AB - OBJECTIVE: To compare refraction measurements of young patients obtained using Plusoptix S04 with those obtained using cycloplegic retinoscopy. DESIGN: Cohort study. PARTICIPANTS: Data were collected from 64 patients (128 eyes), aged 2-19 years. METHODS: All eyes underwent photorefraction using Plusoptix S04 with or without cycloplegia and cycloplegic retinoscopy. Eyes with a maximum spherical and cylinder range of 7.00 to +5.00 were excluded from the study. RESULTS: The difference in spherical equivalents between Plusoptix S04 without cycloplegia and cycloplegic retinoscopy was more than +/-0.50 D in 70.2% of the eyes. In 100 eyes (78.1%), photorefraction underestimated the hyperopic refractive error. The cylinder powers determined by Plusoptix S04 and cycloplegic retinoscopy were similar. The difference in the spherical equivalents between Plusoptix S04 with cycloplegia and cycloplegic retinoscopy was +/-0.50 D in 89.8% of the eyes. In 96 eyes (75%), photorefraction with cycloplegia overestimated the hyperopic refractive error. The difference in cylindrical power determined using Plusoptix S04 with cycloplegia and cycloplegic retinoscopy was statistically significant (paired t test, p <0.009). CONCLUSIONS: The statistically significant difference in spherical equivalent values obtained using Plusoptix S04 with or without cycloplegia and cycloplegic retinoscopy suggests that Plusoptix S04 is more in evaluating the cylinder power and axis in young patients. Our results also suggest that Plusoptix S04 is not an accurate tool to estimate the refraction in children. PMID- 21708084 TI - Factors predictive of radiation retinopathy post (125)Iodine brachytherapy for uveal melanoma. AB - OBJECTIVE: To report the host, tumour, and radiation-related predictive factors for developing radiation retinopathy post (125)Iodine brachytherapy for uveal melanoma. DESIGN: A retrospective clinical case series. PARTICIPANTS: Three hundred consecutive patients with uveal melanoma treated with (125)Iodine brachytherapy. METHODS: Electronic chart review of demographic, clinical, treatment, and follow-up data. Proliferative and (or) nonproliferative radiation retinopathy patients were included. Cumulative incidence rates were calculated using Kaplan-Meier estimates. Univariate and multivariate statistical regression analyses were performed to identify factors predictive of radiation retinopathy. RESULTS: The mean follow-up period was 48 months. Radiation retinopathy occurred in 107 patients (36%). Actuarial incidence of radiation retinopathy was 30% (CI 24%-36%) at 24 months post-treatment. In the multivariate model, the predictive factors were a younger age (hazard ratio [HR] 0.98, p < 0.03), diabetes (HR 2.17, p < 0.007), and hypertension (HR 2.17, p < 0.004). Tumour-related factors were proximity to optic disc (HR 0.95, p < 0.02) and proximity to foveola (HR 0.96, p < 0.02). Pretreatment tumour dimensions, other tumour characteristics, and total radiation dose did not demonstrate statistically significant risks for developing radiation retinopathy. CONCLUSIONS: Radiation retinopathy affects 30% of patients 2 years following (125)Iodine brachytherapy for uveal melanoma. The predictive factors for radiation retinopathy are a younger age, comorbidity with diabetes or hypertension, and proximity of the tumour margin to the optic disc or foveola. Identifying the predictive factors for developing radiation retinopathy can modify follow-up for patients at risk, which may permit earlier management of the developing radiation-induced ischemic retinal changes. PMID- 21708085 TI - Boston type 1 keratoprosthesis: the CHUM experience. AB - OBJECTIVE: To describe the characteristics, indications, complications, and outcomes of the patients who underwent Boston type 1 keratoprosthesis (KPro) surgery at the Universite de Montreal affiliated Notre-Dame Hospital. DESIGN: Retrospective case series. PARTICIPANTS: Forty-seven eyes of 43 patients who underwent KPro surgery. METHODS: The charts of all patients who underwent KPro surgery at Notre-Dame Hospital between October 2008 and February 2010 were retrospectively reviewed. Preoperative, intraoperative, and postoperative parameters were collected and analyzed. RESULTS: The indication for Boston type 1 KPro was corneal graft failure in 27 eyes; 20 eyes had KPro as a primary procedure. Preoperative diagnoses included aniridia (34%), mechanical trauma (11%), infections (9%), surgery-related bullous keratopathy (9%), chemical burns (9%), corneal dystrophies (9%), and Stevens-Johnson syndrome (2%). A known history of glaucoma was present in 36 eyes (77%). Median preoperative best corrected visual acuity (BCVA) was hand motion (range, 20/100 to light perception). The assembly of the KPro and surgery were uneventful in all cases. Mean follow-up was 10+/-5 months. MedianBCVA at last follow-up was 20/150 (range, 20/30 to no light perception). The device retention rate was 100% at the end of the follow-up period. Postoperative complications included retroprosthetic membrane in 12 eyes (26%) and glaucoma progression in 11 eyes (23%). CONCLUSIONS: Our study demonstrates an excellent retention rate of the Boston type 1 KPro and an improvement of BCVA in the majority of patients. Many patients undergoing KPro surgery have ocular comorbidities that require ongoing care to prevent further vision loss following KPro surgery. PMID- 21708086 TI - Combined amniotic membrane transplant and anterior stromal puncture in painful bullous keratopathy: clinical outcome and confocal microscopy. AB - OBJECTIVE: To report the outcomes of anterior stromal micropuncture (ASP) combined with amniotic membrane transplantation (AMT) in the management of painful bullous keratopathy (BK) with poor visual potential, and to assess amniotic membrane (AM) retention. DESIGN: Case series, retrospective review. PARTICIPANTS: Twelve eyes of 12 patients with BK causing intractable pain or discomfort and poor visual potential, treated between March 2006 and October 2008 at Gartnavel General Hospital, Glasgow. METHODS: Epithelial debridement was followed by ASP and the amniotic membrane was stabilized with a purse-string 10/0 nylon corneal suture and a bandage contact lens. During a mean follow-up of 67 weeks (range, 27-139 weeks), pain relief, epithelial healing, visual changes, confocal microscopy, and appearance of new bullae were evaluated. Success was defined as complete resolution or significant improvement in pain. RESULTS: Twelve eyes of 12 patients, mean age 61 years (range, 40-88 years), were identified. Corneal epithelial healing was complete in 11 eyes 1 month postoperatively. Pain and conjunctival inflammation resolved in 11 patients (91.67%) and improved from severe to mild in the remaining patient. Incorporation of the AMT was observed on slit-lamp biomicroscopy in all eyes and was confirmed using confocal microscopy at final follow-up. CONCLUSIONS: ASP combined with AMT is safe and effective, alleviates pain and discomfort, reduces ocular inflammation, and promotes epithelial healing and resolution of bullae in patients with BK with poor visual potential. There was long-term evidence of amniotic membrane graft retention in all eyes after the procedure, suggesting that ASP may improve the long-term retention rate of AM. PMID- 21708087 TI - Advanced corneal surface ablation efficacy in myopia: changes in higher order aberrations. AB - OBJECTIVE: To evaluate the change of ocular and corneal higher order aberrations (HOAs) after wavefront-guided advanced surface ablation (WF-ASA) for myopia using 4 different epithelial management techniques (AA-PRK, LASEK, Epi-PRK, and Epi LASIK). DESIGN: Retrospective single centre excimer database analysis. PARTICIPANTS: Two hundred and forty eyes equally divided between the 4 WF-ASA techniques, matched for mean and range of required spherical correction. METHODS: Ocular wavefront aberrations were measured using the wavescan aberrometer and corneal aberrations were obtained from corneal topography elevation maps and calculated by ray-tracing. All data were collected preoperatively and 3 months following treatment. The aberrations were described as Zernike polynomials, and analysis focused on total HOAs and spherical aberration (SA). RESULTS: Three months postoperatively, there was a statistically significant surgically induced increase in total HOAs and SA both for ocular and corneal analysis (p < 0.001). There was no statistically significant difference in the induced ocular SA and HOAs between the groups, but the differences in induced corneal SA and HOAs were significant (p < 0.010). Ocular changes in SA were weakly correlated to preoperative SA (20.30, p < 0.001) but strongly correlated to applied spherical correction (20.68, p < 0.001). Surgically induced corneal SA was weakly correlated to preoperative corneal SA (20.34, p < 0.001) and applied spherical correction (20.46, p < 0.001). CONCLUSIONS: Three months postoperatively, all procedures resulted in an increase in ocular and cornealHOAs and SA. Induced aberrations were most strongly correlated to the applied spherical power correction. Modifying the existing ablation pattern to compensate for induced HOAs might improve the outcome. PMID- 21708088 TI - Efficacy of intravitreal bevacizumab after unresponsive treatment with intravitreal ranibizumab. AB - OBJECTIVE: To evaluate visual outcomes of eyes with choroidal neovascular membrane secondary to age-related macular degeneration that were initially treated with intravitreal ranibizumab then switched to intravitreal bevacizumab due to treatment failure. DESIGN: Retrospective chart review. PARTICIPANTS: Fifty eyes of 50 patients presenting to the Barnes Retina Institute. METHODS: Patients unresponsive to treatment with intravitreal ranibizumab were switched to intravitreal bevacizumab. Main outcome measures included number of intravitreal injections, visual acuity (VA), and resolution of leakage. Mean follow-up was 6 months after the final intravitreal bevacizumab injection. On average, each patient received 3.5 ranibizumab injections and 2.5 bevacizumab injections. Each patient received an average of 6 injections. RESULTS: Resolution of leakage on fluorescein angiography and optical coherence tomography was achieved in 44 eyes (88%). Initial VA ranged from 20/30 to counting fingers (CF) (median VA 20/125). Final VA ranged from 20/20 to CF (median VA 20/100). Change in VA varied from loss of 2 lines to gain of 4 lines, but overall, remained stable (average gain 0.3 lines). Eighteen eyes (36%) had a final VA of >= 20/50 and 18 eyes (36%) had a final VA of <=20/200. CONCLUSIONS: Treatment with intravitreal bevacizumab may be effective, as measured by visual and anatomic criteria, in patients who are unresponsive to treatment with intravitreal ranibizumab. PMID- 21708089 TI - Effect of preoperative vitreous status on visual outcomes following vitrectomy for epiretinal membrane repair. AB - OBJECTIVE: To determine the correlation between clinically observed posterior vitreous detachment (PVD) and both surgical status of the hyaloid and the visual outcome following epiretinal membrane (ERM) surgery. DESIGN: Retrospective chart review. PARTICIPANTS: One hundred and nine eyes of 109 consecutive patients who underwent vitrectomy and repair of idiopathic ERM between January 2006 and September 2008. METHODS: Preoperative exam notes from selected charts were reviewed for the presence or absence of a PVD. Operative notes were queried to whether the hyaloid was attached or detached at the onset of surgery. The postoperative visual acuity (VA) was correlated with the intraoperative status of the hyaloid. Preoperative observation of PVD was correlated with the hyaloid status at the time of vitrectomy. RESULTS: Hyaloid status did not impact postoperative VA. Eyes with an attached hyaloid at the onset of surgery had an average postoperative best corrected visual acuity (BCVA) of 20/60 and eyes with PVDs found during surgery had an average BCVA of 20/60(+1) (p < 0.66). Of the 109 patients, 72 had a preoperative fundoscopic examination whose results positively correlated with the intraoperative status of the hyaloid. CONCLUSIONS: Having an attached hyaloid did not have a significant impact on postoperative visual outcomes in eyes undergoing ERM when compared with outcomes for eyes having a detached hyaloids prior to surgery. Detection of a PVD on preoperative fundoscopic examination was highly sensitive for a "true" PVD, i.e., actual detachment of the posterior hyaloidmembrane as confirmed during surgery. PMID- 21708090 TI - Comparison of nonlaser nonendoscopic endonasal dacryocystorhinostomy with external dacryocystorhinostomy. AB - OBJECTIVE: To compare the success rate of nonlaser nonendoscopic dacryocystorhinostomy (EN-DCR) with that of externalDCR(EX-DCR). DESIGN: Retrospective chart review. PARTICIPANTS: Eighty-eight patients that underwent 102 consecutive EN-DCR or EX-DCR between November 1, 1995, and September 1, 2003. METHODS: All DCRswere performed by a single ophthalmologist. The surgical protocol remained constant, and surgical success was defined as a lack of symptoms that indicated DCR or normal canalicular irrigation. RESULTS: Eighty eight patients were reviewed, equating to 102 cases ofDCR (56 EX-DCRand 46 EN DCR). The average age of patients was 63.2+/-18.2 years old (range, 19-93 years), and the average duration of surgery was 32.1 minutes for EX-DCR and 23.3 minutes for ENDCR (p < 0.0001). Three cases of intraoperative bleed requiring nasal packing were documented in EX-DCR and 2 cases in EN-DCR. The success rates were 89.8% and 90.2% for EX-DCR and EN-DCR, respectively. There was no statistical difference between these 2 numbers. The average follow-up time was 12.8 months (median, 5 months; range, 2-97 months). CONCLUSIONS: We found that the endonasal approach to DCRs was quicker than the external approach and the success and complication rates of both methods were comparable. PMID- 21708091 TI - Contact transcleral photodynamic cyclo-suppression in human eyes: a feasibility study. AB - OBJECTIVE: To evaluate the safety and efficacy of contact transcleral ciliary body photodynamic treatment (CB-PDT) with verteporfin in human eyes. DESIGN: Prospective interventional case series. PARTICIPANTS: Five glaucomatous blind eyes of 5 patients. METHODS: Verteporfin (6 mg/m(2)) was infused in bolus and then the ciliary body was irradiated transclerally with a fibre optic device. Twelve spots were placed 360 degrees and 0.5 mm behind the sclerocorneal limbus. Laser power was 80 mW and irradiation time was 3 minutes. RESULTS: The average intraocular pressure reduction was 30% after the first month and remained below pre-treatment levels throughout a 3-month follow-up. No serious adverse events were reported. CONCLUSIONS: CB-PDT for refractory glaucoma was safe and efficient in human eyes; larger studies are required to evaluate its possible clinical role. PMID- 21708092 TI - Delayed recalcitrant fungal endophthalmitis secondary to Curvularia. PMID- 21708093 TI - Abraxane-induced cystoid macular edema refractory to concomitant intravenous bevacizumab. PMID- 21708094 TI - Pupillary block glaucoma following descemet stripping automated endothelial keratoplasty related to intraoperative floppy-iris syndrome. PMID- 21708095 TI - Congenital choroidal melanoma in an infant. PMID- 21708096 TI - Conjunctival tattooing after evisceration for cosmesis. PMID- 21708097 TI - Recurrence of a rare skin tumour: superficial angiomyxoma in the eyelid. PMID- 21708098 TI - Dinuclear copper complexes of organic claw: potent inhibition of protein tyrosine phosphatases. AB - Three dinuclear copper complexes of organic claw ligands (2,2',2",2'''-(5-R-2 hydroxy-1,3-phenylene)bis(methylene)bis(azanetriyl)tetraacetic acid, R=methyl (H(5)L1), chloro (H(5)L2) and bromo (H(5)L3)): [Cu(2)NaL1(H(2)O)(2)] (1), [Cu(2)HL2(H(2)O)(2)] (2), [Cu(2)NaL3(H(2)O)(2)] (3), have been synthesized and characterized by elemental analyses, infrared spectra, thermo-gravimetric analyses, X-ray diffraction analysis, electrospray ionization mass spectra, pH potentiometric titration, molar conductivity. Their inhibitory effects against human protein tyrosine phosphatase 1B (PTP1B), T cell protein tyrosine phosphatase (TCPTP), Megakaryocyte protein tyrosinephosphatase 2 (PTP-MEG2), srchomology phosphatase 1 (SHP-1) and srchomology phosphatase 2 (SHP-2) are evaluated in vitro. The three copper complexes exhibit potent and almost same inhibition against PTP1B and SHP-1 with IC(50) values ranging from 0.15 to 0.31MUM, about 2-fold stronger inhibition than against PTP-MEG2, 10-fold stronger inhibition than against TCPTP, but almost no inhibition against SHP-2. Kinetic analysis indicates that they are reversible competitive inhibitors of PTP1B. Molecular docking analyses confirm the inhibition model. Fluorescence titration studies suggest that the complexes bond to PTP1B with the formation of a 1:1 complex. The results demonstrate that copper complexes that are potent PTPs inhibitors but have different inhibitory effects over different PTPs, may be explored as new practical inhibitors towards individual PTP with some specificity. PMID- 21708099 TI - Allosteric effects of sulfonate anions on the rates of iron release from serum transferrin. AB - Serum transferrin is the protein that transports ferric ion through the bloodstream and is thus a potential target for iron chelation therapy. However, the release of iron from transferrin to low-molecular-weight chelating agents is usually quite slow. Thus a better understanding of the mechanism for iron release is important to assist in the design of more effective agents for iron removal. This paper describes the effect of sulfonate anions on the rates of iron removal from C-terminal monoferric transferrin by acetohydroxamic acid, deferiprone, nitrilotriacetic acid (NTA), and diethylenetriaminepentaacetic acid at 25 degrees C in 0.1M N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (Hepes) buffer at pH 7.4. These ligands remove iron via a combination of pathways that show saturation and first order dependence on the ligand concentration. The kinetic effects of the anions methanesulfonate, methylenedisulfonate, and ethylenedisulfonate were evaluated. All these anions increase the overall rates of iron release, presumably by binding to an allosteric anion binding site on the protein. The two disulfonates produce a larger acceleration in iron release than the monosulfonate. More detailed studies using methylenedisulfonate show that this anion accelerates the rate of iron release via the saturation pathway. The addition of methylenedisulfonate results in the appearance of a large saturation pathway for iron release by NTA, which otherwise removes iron by a simple first order process. The sulfonate group was selected for these studies because it represents an anionic functional group that can be covalently linked to a therapeutic ligand to accelerate iron release in vivo. The current studies indicate that the binding of the sulfonates to the allosteric site on the protein is quite weak, so that one would not expect a significant acceleration in iron release at clinically relevant ligand concentrations. PMID- 21708100 TI - Dietary selenium influences pancreatic tissue levels of selenoprotein W in chickens. AB - Selenium (Se) influences the levels of selenoprotein W (SelW) in mammals. However, little is known about the pattern of SelW expression in the pancreatic tissue of birds. To investigate the effects of dietary Se levels on the expression of SelW mRNA in the pancreatic tissue of birds, one-day-old chickens were randomly allocated to three groups. The L group was fed a basal diet deficient in Se (containing 0.033mg/kg Se); the M and H groups were fed Se supplemented diets with either 0.15 or 1.5mg/kg Se, respectively (as sodium selenite) for 55days. The pancreatic tissue was collected and examined for Se content and mRNA levels of SelW at 15, 25, 35, 45 and 55days old. In the H group, a significant increase (P<0.05) in mRNA levels of SelW was observed. When the chickens were fed a Se-deficient basal diet, the abundance of SelW mRNA significantly decreased (P<0.05) during the sampling period. In this study, two enzymes were also examined, namely, selenocysteine-tRNA([Ser]Sec) synthase (SecS) and selenophosphate synthetase 1 (SPS1). The mRNA levels of two factors were slightly enhanced in the Se-supplemented groups, and a Se-deficient diet down regulated the mRNA expression of SecS. These data indicate that SelW is expressed in the pancreatic tissue of birds and that the transcription of the SelW gene is very sensitive to dietary Se. Se also has an effect on the mRNA levels of SecS, but has a little effect on SPS1 in this study. PMID- 21708101 TI - Prochelators triggered by hydrogen peroxide provide hexadentate iron coordination to impede oxidative stress. AB - Prochelators are agents that have little affinity for metal ions until they undergo a chemical conversion. Three new aryl boronate prochelators are presented that are responsive to hydrogen peroxide to provide hexadentate ligands for chelating metal ions. TRENBSIM (tris[(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)benzylidene)-2-aminoethyl]amine), TRENBSAM (tris[(2-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)benzoyl)-2-aminoethyl]amine), and TB (tris[(2-boronic acid benzyl)2-aminoethyl]amine) convert to TRENSIM (tris[(salicylideneamino)ethyl]amine), TRENSAM (tris[(2-hydroxybenzoyl)-2 aminoethyl]amine), and TS (tris[2-hydroxybenzyl)2-aminoethyl]amine), respectively. The prochelators were characterized by (11)B NMR, and the structures of TRENBSAM, TRENBSIM, and the Fe(III) complex of TS were determined by X-ray crystallography. Of the three prochelator/chelator pairs, TB/TS was identified as the most promising for biological applications, as they prevent iron and copper-induced hydroxyl radical generation in an in vitro assay. TB has negligible interactions with metal ions, whereas TS has apparent binding constants (log K') at pH 7.4 of 15.87 for Cu(II), 9.67 Zn(II) and 14.42 for Fe(III). Up to 1 mMTB was nontoxic to retinal pigment epithelial cells, whereas 10 MUM TS induced cell death. TS protected cells against H(2)O(2)-induced death, but only within a 1-10 MUM range. TB, on the other hand, had a much broader window of protection, suggesting that it may be a useful agent for preventing metal-promoted oxidative damage. PMID- 21708102 TI - New bis(thiosemicarbazonate) gold(III) complexes inhibit HIV replication at cytostatic concentrations: potential for incorporation into virostatic cocktails. AB - Four bis(thiosemicarbazonate)gold(III) complexes (1-4) with a general formula [Au(L)]Cl {L=L1, glyoxal-bis(N(4)-methylthiosemicarbazone); L2, glyoxal-bis(N(4) ethylthiosemicarbazone); L3, diacetyl-bis(N(4)-methylthiosemicarbazone); L4, diacetyl-bis(N(4)-ethylthiosemicarbazone)} were synthesised and screened for activity against the human immunodeficiency virus (HIV). Complexes 1-4 were characterised using (1)H-NMR and IR spectroscopy; and their purity established by micronanalysis. Complex 3 inhibited viral infection of TZM-bl cells by 98% (IC(50)=6.8+/-0.6MUM) at a non toxic concentration of 12.5MUM while complex 4 inhibited infection of these cells by 72 and 98% (IC(50)=5.3+/-0.4MUM) at concentrations of 6.25 and 12.5MUM respectively. The mechanism of inhibition of infection in TZM-bl cells is presumably as a result of the cytostatic or anti proliferative activity that was observed for complex 4 in real time cell electronic sensing (RT-CES) and carboxyflourescein succinimidyl ester (CFSE) analysis. Treatment of T lymphocytes from HIV infected individuals with 4 decreased CD4+ T cell expression (p=0.0049) as demonstrated by multi-parametric flow cytometry without suppressing cytokine production. None of the ligands (L1 L4) demonstrated anti-viral activity, supporting the importance of metal (gold) complexation in these potential drugs. Complexes 3 and 4 were shown to have ideal lipophilicity values that were similar when shake flask (0.97+/-0.5 and 2.42+/ 0.6) and in silico prediction (0.8 and 1.5) methods were compared. The activity and drug-like properties of complexes 3 and 4 suggests that these novel metal based compounds could be combined with virus inhibitory drugs to work as cytostatic agents in the emerging class of anti-HIV drugs known as virostatics. PMID- 21708103 TI - Green synthesis of graphene oxide sheets decorated by silver nanoprisms and their anti-bacterial properties. AB - A widely soluble graphene oxide sheets decorated by silver nanoprisms were prepared through green synthesis at the room temperature using gelatin as reducing and stabilizing agent. The samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), UV-visible spectroscopy and fluorescence spectra. The results demonstrate that these silver-nanoprisms assembled on graphene oxide sheets are flexible and can form stable suspensions in aqueous solutions. Furthermore, the formation mechanism of soluble graphene oxide sheets decorated by silver nanoprisms was successfully explained. The anti-bacterial properties of graphene oxide sheets decorated by silver nanoprisms were tested against Escherichia coli. This work provides a simple and "green" method for the synthesis of graphene oxide sheets decorated by silver nanoprisms in aqueous solution with promising antibacterial property. PMID- 21708104 TI - Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. AB - BACKGROUND& AIMS: Embryonic biliary precursor cells form a periportal sheet called the ductal plate, which is progressively remodeled to generate intrahepatic bile ducts. A limited number of ductal plate cells participate in duct formation; those not involved in duct development are believed to involute by apoptosis. Moreover, cells that express the SRY-related HMG box transcription factor 9 (SOX9), which include the embryonic ductal plate cells, were proposed to continuously supply the liver with hepatic cells. We investigated the role of the ductal plate in hepatic morphogenesis. METHODS: Apoptosis and proliferation were investigated by immunostaining of mouse and human fetal liver tissue. The postnatal progeny of SOX9-expressing ductal plate cells was analyzed after genetic labeling, at the ductal plate stage, by Cre-mediated recombination of a ROSA26RYFP reporter allele. Inducible Cre expression was induced by SOX9 regulatory regions, inserted in a bacterial artificial chromosome. Livers were studied from mice under normal conditions and during diet-induced regeneration. RESULTS: Ductal plate cells did not undergo apoptosis and showed limited proliferation. They generated cholangiocytes lining interlobular bile ducts, bile ductules, and canals of Hering, as well as periportal hepatocytes. Oval cells that appeared during regeneration also derived from the ductal plate. We did not find that liver homeostasis required a continuous supply of cells from SOX9 expressing progenitors. CONCLUSIONS: The ductal plate gives rise to cholangiocytes lining the intrahepatic bile ducts, including its most proximal segments. It also generates periportal hepatocytes and adult hepatic progenitor cells. PMID- 21708107 TI - Early TIPS with covered stents in high-risk patients with cirrhosis presenting with variceal bleeding: are we ready to dive into the deep end of the pool? AB - BACKGROUND & AIMS: Patients with cirrhosis in Child-Pugh class C or those in class B who have persistent bleeding at endoscopy are at high risk for treatment failure and a poor prognosis, even if they have undergone rescue treatment with a transjugular intrahepatic portosystemic shunt (TIPS). This study evaluated the earlier use of TIPS in such patients. METHODS: We randomly assigned, within 24h after admission, a total of 63 patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy to treatment with a polytetrafluoroethylene-covered stent within 72 h after randomization (early-TIPS group, 32 patients) or continuation of vasoactive-drug therapy, followed after 3-5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation (EBL), with insertion of a TIPS if needed as rescue therapy (pharmacotherapy-EBL group, 31 patients). RESULTS: During a median follow-up of 16 months, rebleeding or failure to control bleeding occurred in 14 patients in the pharmacotherapy-EBL group as compared with 1 patient in the early TIPS group (P = 0.001). The 1-year actuarial probability of remaining free of this composite end point was 50% in the pharmacotherapy-EBL group versus 97% in the early-TIPS group (P < 0.001). Sixteen patients died (12 in the pharmacotherapy-EBL group and 4 in the early-TIPS group, P = 0.01). The 1-year actuarial survival was 61% in the pharmacotherapy-EBL group versus 86% in the early-TIPS group (P < 0.001). Seven patients in the pharmacotherapy-EBL group received TIPS as rescue therapy, but four died. The number of days in the intensive care unit and the percentage of time in the hospital during follow-up were significantly higher in the pharmacotherapy-EBL group than in the early-TIPS group. No significant differences were observed between the two treatment groups with respect to serious adverse events. CONCLUSIONS: In these patients with cirrhosis who were hospitalized for acute variceal bleeding and at high risk for treatment failure, the early use of TIPS was associated with significant reductions in treatment failure and in mortality. PMID- 21708106 TI - A proinflammatory role for interleukin-22 in the immune response to hepatitis B virus. AB - BACKGROUND & AIMS: T-helper (Th)17 cells that secrete interleukin (IL)-22 have immunomodulatory and protective properties in the liver and other tissues. IL-22 induces expression of proinflammatory genes but is also mitogenic and antiapoptotic in hepatocytes. Therefore, it could have multiple functions in the immune response to hepatitis B virus (HBV). METHODS: We examined the role of IL 22 in regulating liver inflammation in HBV transgenic mice and measured levels of IL-22 in HBV-infected patients. RESULTS: In HBV transgenic mice, injection of a single dose of IL-22 increased hepatic expression of proinflammatory genes but did not directly inhibit virus replication. When splenocytes from HBV-immunized mice were transferred into HBV transgenic mice, the severity of the subsequent liver damage was ameliorated by neutralization of IL-22. In this model, IL-22 depletion did not affect interferon gamma-mediated noncytopathic inhibition of virus replication initiated by HBV-specific cytotoxic T cells, but it significantly inhibited recruitment of antigen-nonspecific inflammatory cells into the liver. In patients with acute HBV infections, the percentage of Th17 cells in peripheral blood and concentration of IL-22 in serum were significantly increased. CONCLUSIONS: IL-22 appears to be an important mediator of the inflammatory response following recognition of HBV by T cells in the liver. These findings might be relevant to the development of cytokine-based therapies for patients with HBV infection. PMID- 21708108 TI - The hematopoietic cell transplantation-specific comorbidity index fails to predict outcomes in high-risk AML patients undergoing allogeneic transplantation- investigation of potential limitations of the index. AB - In the context of allogeneic hematopoietic cell transplantation (allo-HSCT), comorbidities are an important risk factor. Use of the hematopoietic cell transplantation-specific comorbidity index (HSCT-CI), which was developed and validated in Seattle, Washington, has been proposed to predict the probability of nonrelapse mortality (NRM) and overall survival (OS) following allo-HSCT. We performed a single-center retrospective study to validate the prognostic impact of HSCT-CI on transplant outcomes in a cohort of high-risk acute myeloid leukemia patients undergoing allo-HSCT between January 2000 and December 2008. The median patient age at the time of transplantation was 53 years (range: 11-76 years). The median pretransplantation HSCT-CI score was 4 (range: 0-10). Among 340 patients, OS at 3 years was 29% (95% confidence interval [CI]: 17%-41%), 40% (33%-47%), and 44% (41%-47%) in the low-, intermediate-, and high-risk HSCT-CI groups (P = .7), respectively. The corresponding NRM at 3 years was 34% (10%-58%), 32% (20%-44%), and 26% (20%-32%; P = .6). In multivariate analysis, we found no predictive value of HSCT-CI for either OS or NRM. The use of HSCT-CI as a decision-making tool for transplantation eligibility should not be considered until its validity has been unequivocally shown in crossvalidation studies. PMID- 21708109 TI - Effect of early posttransplantation tacrolimus concentration on the development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation from unrelated donors. AB - Only limited data are available regarding the relationship between blood concentration of tacrolimus and its efficacy in preventing acute graft-versus host disease (aGVHD). We retrospectively evaluated the effects of the whole blood concentration of tacrolimus, which was measured by an automated microparticle enzyme immunoassay, early after allogeneic hematopoietic stem cell transplantation (HSCT) upon the development of aGVHD. Sixty patients, who underwent allogeneic HSCT from serologically human-leukocyte antigen-matched unrelated donors and received continuous infusion of tacrolimus with short-term methotrexate for GVHD prophylaxis, were included in this study. The target range of the blood concentration of tacrolimus was set at 10 to 20 ng/mL, and the level was maintained within this range in all patients. However, the mean blood concentration of tacrolimus during the third week after HSCT was significantly associated with the grades of aGVHD (17.3 +/- 2.1 in patients with grades 0-I vs 15.9 +/- 2.8 in II-IV and 14.8 +/- 2.1 in III-IV; P < .05 and <.01, respectively). Multivariate analysis also demonstrated that higher age (>=35) of donor (odds ratio [OR] = 4.28) and lower mean blood concentrations of tacrolimus during the second (OR = 0.75; 95% confidence interval [CI]: 0.58-0.98) and third weeks (OR = 0.76; 95% CI: 0.58-0.98) after HSCT were significant risk factors for grades II-IV aGVHD (P < .05). We conclude that the early posttransplantation blood concentration of tacrolimus had a significant impact on the development of moderate-to-severe aGVHD after allogeneic HSCT from an unrelated donor. PMID- 21708110 TI - The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade. AB - The evolution of the incidence, morbidity, and mortality of veno-occlusive disease (VOD) was analyzed in 845 allogeneic hematopoietic stem cell transplantations (allo-HSCTs) performed over 24 years. A total of 117 patients and 73 patients developed VOD following the Seattle and the Baltimore diagnostic criteria, respectively (cumulative incidence 13.8% and 8.8%). The cumulative incidence was significantly higher in the period 1985 to 1996 than in 1997 to 2008 (11.5% vs 6.5%; P = .01). This decline was because of the low incidence of VOD among reduced-intensity conditioning-HSCT (RIC-HSCT) (2.1%) and the reduction among those receiving myeloablative-HSCT from unrelated donors (32.7% vs 10.5%, P = .001). A total of 35 patients had severe VOD (26 with multiorgan failure [MOF]), and 20 died by VOD (cumulative mortality rate 17.3%, Seattle, or 22.5%, Baltimore). The mortality declined since 1997 (from 22% to 9%; P = .06, Seattle, and from 36% to 14%; P = .04, Baltimore), with the introduction of defibrotide being the only relevant change in the management of patients. This occurred even though the severity of VOD was similar in both periods. Among those with MOF, only 2 of 8 (25%) receiving defibrotide died versus 14 of 18 (78%) receiving other treatments (P = .007). Myeloablative conditioning, previous liver disease, poor performance status, and alternative donors were the variables with higher impact on VOD development. In summary, although VOD remains a dreaded early complication of HSCT, technical and therapeutic progress in recent decades have notably reduced its incidence and improved the outcome. PMID- 21708111 TI - Refining repolarization reserve. PMID- 21708112 TI - Zinc deprivation mediates alcohol-induced hepatocyte IL-8 analog expression in rodents via an epigenetic mechanism. AB - Neutrophil infiltration caused by IL-8 production is a central mechanism in alcohol-induced hepatitis. This study was performed to examine if an epigenetic mechanism is involved in alcohol-induced IL-8 production. Mice were pair-fed an alcohol-containing liquid diet for 4 weeks. Alcohol exposure induced hepatitis as indicated by increased expression of keratinocyte-derived cytokine (mouse IL-8) and neutrophil infiltration. Alcohol exposure induced histone 3 hyperacetylation owing to inhibition of histone deacetylase (HDAC) in association with NF-kappaB activation. Cell culture studies showed that alcohol exposure induced IL-8 and cytokine-induced neutrophil chemoattractant-1 (CINC-1, rat IL-8) production in human VL-17A cells and rat H4IIEC3 cells, respectively, dependent on acetaldehyde production, oxidative stress, and zinc release. Zinc deprivation alone induced CINC-1 production and acted synergistically with lipopolysaccharide or tumor necrosis factor-alpha on CINC-1 production. Zinc deprivation induced histone 3 hyperacetylation at lysine 9 through suppression of HDAC activity. Zinc deprivation caused nuclear translocation of NF-kappaB, and reduced HDAC binding to NF-kappaB. Chromatin immunoprecipitation (ChIP) showed that zinc deprivation caused histone 3 hyperacetylation as well as increased NF-kappaB binding to the CINC-1 promoter. In conclusion, inactivation of HDAC caused by zinc deprivation is a novel mechanism underlying IL-8 up-regulation in alcoholic hepatitis. PMID- 21708113 TI - Spatiotemporal and functional behavior of airway dendritic cells visualized by two-photon microscopy. AB - Airway mucosal dendritic cells (DCs), located beneath the epithelium of the conducting airways, are believed to be specialized for immunosurveillance via sampling of antigens from the airway luminal surface. However, the dynamics of airway DC activity has not yet been visualized. We used two-photon microscopy to illuminate the endogenous mucosal DC network in the airways of mice. To characterize DC behavior, we used lung section preparations and an intravital microscopic approach. DCs displayed a heterogeneous movement pattern according to their localization within the airway mucosa: sessile intraepithelial DCs with a dendritiform shape exhibited active probing movements and occasionally formed transepithelial extensions into the airway lumen. In contrast, DCs within the deeper layers of the mucosal tissue migrated fast in an amoeboid manner, without probing movements, and slowed down after aeroallergen challenge. Strikingly, neither of these two mucosal DC populations ingested fluorescently labeled antigens after antigen administration to the airways in the steady state, in contrast to alveolar macrophage/DC populations in the lung periphery. Our results provide a first description of the dynamic behavior of airway mucosal DCs, with their exact role in antigen sampling remaining unclear. PMID- 21708114 TI - Endosomal/lysosomal processing of gangliosides affects neuronal cholesterol sequestration in Niemann-Pick disease type C. AB - Niemann-Pick disease type C (NPC) is a severe neurovisceral lysosomal storage disorder caused by defects in NPC1 or NPC2 proteins. Although numerous studies support the primacy of cholesterol storage, neurons of double-mutant mice lacking both NPC1 and an enzyme required for synthesis of all complex gangliosides (beta1,4GalNAc transferase) have been reported to exhibit dramatically reduced cholesterol sequestration. Here we show that NPC2-deficient mice lacking this enzyme also exhibit reduced cholesterol, but that genetically restricting synthesis to only a-series gangliosides fully restores neuronal cholesterol storage to typical disease levels. Examining the subcellular locations of sequestered compounds in neurons lacking NPC1 or NPC2 by confocal microscopy revealed that cholesterol and the two principal storage gangliosides (GM2 and GM3) were not consistently co-localized within the same intracellular vesicles. To determine whether the lack of GM2 and GM3 co-localization was due to differences in synthetic versus degradative pathway expression, we generated mice lacking both NPC1 and lysosomal beta-galactosidase, and therefore unable to generate GM2 and GM3 in lysosomes. Double mutants lacked both gangliosides, indicating that each is the product of endosomal/lysosomal processing. Unexpectedly, GM1 accumulation in double mutants increased compared to single mutants consistent with a direct role for NPC1 in ganglioside salvage. These studies provide further evidence that NPC1 and NPC2 proteins participate in endosomal/lysosomal processing of both sphingolipids and cholesterol. PMID- 21708116 TI - Rational variety mapping for contrast-enhanced nonlinear unsupervised segmentation of multispectral images of unstained specimen. AB - A methodology is proposed for nonlinear contrast-enhanced unsupervised segmentation of multispectral (color) microscopy images of principally unstained specimens. The methodology exploits spectral diversity and spatial sparseness to find anatomical differences between materials (cells, nuclei, and background) present in the image. It consists of rth-order rational variety mapping (RVM) followed by matrix/tensor factorization. Sparseness constraint implies duality between nonlinear unsupervised segmentation and multiclass pattern assignment problems. Classes not linearly separable in the original input space become separable with high probability in the higher-dimensional mapped space. Hence, RVM mapping has two advantages: it takes implicitly into account nonlinearities present in the image (ie, they are not required to be known) and it increases spectral diversity (ie, contrast) between materials, due to increased dimensionality of the mapped space. This is expected to improve performance of systems for automated classification and analysis of microscopic histopathological images. The methodology was validated using RVM of the second and third orders of the experimental multispectral microscopy images of unstained sciatic nerve fibers (nervus ischiadicus) and of unstained white pulp in the spleen tissue, compared with a manually defined ground truth labeled by two trained pathophysiologists. The methodology can also be useful for additional contrast enhancement of images of stained specimens. PMID- 21708118 TI - Helical peptide arrays for lead identification and interaction site mapping. AB - Libraries composed of linear and cyclic peptides cannot fully represent the higher order structures of most antigenic sites. To map the binding site of ligands or antibodies, a larger part of the three-dimensional space should be sampled. Because parallel synthesis of large arrays of peptides on hydrogels is restricted to relatively small peptides, a simple and robust homodimeric helical system was chosen for antigen presentation. First, it was established in an heterodimeric system that the 26-mer peptide could be synthesized and that the helical coiled-coil peptides interact in the hydrogel in a predictable manner. Next, libraries of homodimeric coiled coils were synthesized into which the epitope was grafted. Using dedicated helical dimeric and trimeric coiled-coil libraries, the epitopes of two anti-HIV-1 gp41 monoclonal antibodies known to interact with helical structures were mapped at high resolution. These mappings precisely reflect existing X-ray data, and the arrays can be applied to lead identification, epitope mapping, and systematic analysis of amino acid contribution to coiled-coil systems. PMID- 21708117 TI - Expression of endoplasmic reticulum stress proteins is a candidate marker of brain metastasis in both ErbB-2+ and ErbB-2- primary breast tumors. AB - The increasing incidence of breast cancer brain metastasis in patients with otherwise well-controlled systemic cancer is a key challenge in cancer research. It is necessary to understand the properties of brain-tropic tumor cells to identify patients at risk for brain metastasis. Here we attempt to identify functional phenotypes that might enhance brain metastasis. To obtain an accurate classification of brain metastasis proteins, we mapped organ-specific brain metastasis gene expression signatures onto an experimental protein-protein interaction network based on brain metastatic cells. Thirty-seven proteins were differentially expressed between brain metastases and non-brain metastases. Analysis of metastatic tissues, the use of bioinformatic approaches, and the characterization of protein expression in tumors with or without metastasis identified candidate markers. A multivariate analysis based on stepwise logistic regression revealed GRP94, FN14, and inhibin as the best combination to discriminate between brain and non-brain metastases (ROC AUC = 0.85, 95% CI = 0.73 to 0.96 for the combination of the three proteins). These markers substantially improve the discrimination of brain metastasis compared with ErbB-2 alone (AUC = 0.76, 95% CI = 0.60 to 0.93). Furthermore, GRP94 was a better negative marker (LR = 0.16) than ErbB-2 (LR = 0.42). We conclude that, in breast carcinomas, certain proteins associated with the endoplasmic reticulum stress phenotype are candidate markers of brain metastasis. PMID- 21708119 TI - An organic-inorganic hybrid nanostructure-functionalized electrode for electrochemical immunoassay of biomarker by using magnetic bionanolabels. AB - A new electrochemical immunoassay of alpha-fetoprotein (AFP) was developed on an organic-inorganic hybrid nanostructure-functionalized carbon electrode by coupling with magnetic bionanolabels. Multi-walled carbon nanotubes (CNTs), single-stranded DNA, thionine and AFP were utilized for the construction of the immunosensor, while the core-shell Fe(3)O(4)-silver nanocomposites were employed for the label of horseradish peroxidase-anti-AFP conjugates (HRP-anti-AFP-AgFe). Electrochemical measurement toward AFP was carried out by using magnetic bionanolabels as traces and H(2)O(2) as enzyme substrate with a competitive-type immunoassay mode. Experimental results indicated that the immunosensors with carbon nanotubes and DNA exhibited better electrochemical responses than those of without carbon nanotubes or DNA. Under optimal conditions, the electrochemical immunosensor by using HRP-anti-AFP-AgFe as signal antibodies exhibited a linear range of 0.001-200 ng mL(-1) AFP with a low detection limit of 0.5 pg mL(-1) at 3s(B). Both intra- and inter-assay coefficients of variation were 7.3%, 9.4%, 8.7% and 10.2%, 7.8%, 9.4% toward 0.01, 30, 120 ng mL(-1) AFP, respectively. The specificity and stability of the electrochemical immunoassay were acceptable. In addition, the methodology was validated for 12 clinical serum specimens including 9 positive specimens and 3 normal specimens, receiving a good correlation with the results obtained from the referenced electrochemiluminescence assay. PMID- 21708120 TI - Electron transfer mediated by membrane-bound d-fructose dehydrogenase adsorbed at an oil/water interface. AB - The catalytic activity of a membrane-bound enzyme, d-fructose dehydrogenase (FDH), at the polarized oil/water (O/W) interface was studied. Multisweep cyclic voltammetry and ac voltammetry were carried out to show the irreversible adsorption of FDH at the interface. Using the thusly prepared FDH-adsorbed O/W interface, clear steady-state catalytic current was observed in amperometry and cyclic voltammetry, where 1,1'-dimethylferrocenium ion (DiMFc(+), electron acceptor) and d-fructose (substrate) were added to the O and W phases, respectively. The observed catalytic current was then analyzed by using two mechanisms. In mechanism (A), the heme c site of FDH, where DiMFc(+) is reduced, was assumed to be located in the O-phase side of the interface. The intramolecular electron transfer in FDH should be affected by the Galvani potential difference of the interface (Delta(O)(W)phi). However, the theoretical equations derived for the catalytic current could not reproduce the experimental data. In mechanism (B), the heme c site was assumed to be in the W-phase side. In this case, Delta(O)(W)phi should affect the interfacial distribution of DiMFc(+). This mechanism could reproduce well the observed potential dependence of the catalytic current. PMID- 21708121 TI - Human diseases with impaired mitochondrial protein synthesis. AB - Mitochondrial respiratory chain deficiencies represent one of the major causes of metabolic disorders that are related to genetic defects in mitochondrial or nuclear DNA. The mitochondrial protein synthesis allows the synthesis of the 13 respiratory chain subunits encoded by mtDNA. Altogether, about 100 different proteins are involved in the translation of the 13 proteins encoded by the mitochondrial genome emphasizing the considerable investment required to maintain mitochondrial genetic system. Mitochondrial protein synthesis deficiency can be caused by mutations in any component of the translation apparatus including tRNA, rRNA and proteins. Mutations in mitochondrial rRNA and tRNAs have been first identified in various forms of mitochondrial disorders. Moreover abnormal translation due to mutation in nuclear genes encoding tRNA-modifying enzymes, ribosomal proteins, aminoacyl-tRNA synthetases, elongation and termination factors and translational activators have been successively described. These deficiencies are characterized by a huge clinical and genetic heterogeneity hampering to establish genotype-phenotype correlations and an easy diagnosis. One can hypothesize that a new technique for gene identification, such as exome sequencing will rapidly allow to expand the list of genes involved in abnormal mitochondrial protein synthesis. PMID- 21708122 TI - Effects of cyclosis on chloroplast-cytoplasm interactions revealed with localized lighting in Characean cells at rest and after electrical excitation. AB - Cytoplasmic streaming in Characean internodes enables rapid intracellular transport and facilitates interactions between spatially remote cell regions. Cyclosis-mediated distant interactions might be particularly noticeable under nonuniform illumination, in the vicinity of light-shade borders where metabolites are transported between functionally distinct cell regions. In support of this notion, chlorophyll fluorescence parameters assessed on a microscopic area of Chara corallina internodal cells (area of inspection, AOI) responded to illumination of nearby regions in asymmetric manner depending on the vector of cytoplasmic streaming. When a beam of white light was applied through a 400-MUm optic fiber upstream of AOI with regard to the direction of cytoplasmic streaming, non-photochemical quenching (NPQ) developed after a lag period in AOI exposed to moderate intensity light. Conversely, no NPQ was induced in the same cell area when the beam position was shifted to an equal distance downstream of AOI. Light-response curves for the efficiency of photosystem II electron transport in chloroplasts differed markedly depending on the illumination pattern (whole-cell versus small area illumination) but these differences were eliminated after the inhibition of cytoplasmic streaming with cytochalasin B. Localized illumination promoted chloroplast fluorescence responses to electrical plasmalemma excitation at high light intensities, which contrasts to the requirement of low to moderate irradiances for observation of the stimulus response coupling under whole-cell illumination. The results indicate that different photosynthetic capacities of chloroplasts under general and localized illumination are related to lateral transport of nonevenly distributed cytoplasmic components between the cell parts with dominant photosynthetic and respiratory metabolism. PMID- 21708105 TI - Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. AB - BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) who have been exposed to thiopurines might have an increased risk of skin cancer. We assessed this risk among patients in France. METHODS: We performed a prospective observational cohort study of 19,486 patients with IBD, enrolled from May 2004 to June 2005, who were followed up until December 31, 2007. The incidence of nonmelanoma skin cancer (NMSC) in the general population, used for reference, was determined from the French Network of Cancer Registries. RESULTS: Before the age of 50 years, the crude incidence rates of NMSC among patients currently receiving or who previously received thiopurines were 0.66/1000 and 0.38/1000 patient years, respectively; these values were 2.59/1000 and 1.96/1000 patient-years for the age group of 50 to 65 years and 4.04/1000 and 5.70/1000 patient-years for patients older than 65 years. Among patients who had never received thiopurines, the incidence of NMSC was zero before the age of 50 years, 0.60/1000 for the ages of 50 to 65 years, and 0.84/1000 for those older than 65 years. A multivariate Cox regression model stratified by propensity score quintiles showed that ongoing thiopurine treatment (hazard ratio [HR], 5.9; 95% confidence interval [CI], 2.1 16.4; P = .0006) and past thiopurine exposure (HR, 3.9; 95% CI, 1.3-12.1; P = .02) were risk factors for NMSC. They also identified age per 1-year increase as a risk factor for NMSC (HR, 1.08; 95% CI, 1.05-1.11; P < .0001). CONCLUSIONS: Ongoing and past exposure to thiopurines significantly increases the risk of NMSC in patients with IBD, even before the age of 50 years. These patients should be protected against UV radiation and receive lifelong dermatologic screening. PMID- 21708123 TI - Efficiency of photosynthesis in a Chl d-utilizing cyanobacterium is comparable to or higher than that in Chl a-utilizing oxygenic species. AB - The cyanobacterium Acaryochloris marina uses chlorophyll d to carry out oxygenic photosynthesis in environments depleted in visible and enhanced in lower-energy, far-red light. However, the extent to which low photon energies limit the efficiency of oxygenic photochemistry in A. marina is not known. Here, we report the first direct measurements of the energy-storage efficiency of the photosynthetic light reactions in A. marina whole cells, and find it is comparable to or higher than that in typical, chlorophyll a-utilizing oxygenic species. This finding indicates that oxygenic photosynthesis is not fundamentally limited at the photon energies employed by A. marina, and therefore is potentially viable in even longer-wavelength light environments. PMID- 21708124 TI - A new target for an old regulator: H-NS represses transcription of bolA morphogene by direct binding to both promoters. AB - The Escherichia coli bolA morphogene is very important in adaptation to stationary phase and stress response mechanisms. Genes of this family are widespread in gram negative bacteria and in eukaryotes. The expression of this gene is tightly regulated at transcriptional and post-transcriptional levels and its overexpression is known to induce round cellular morphology. The results presented in this report demonstrate that the H-NS protein, a pleiotropic regulator of gene expression, is a new transcriptional modulator of the bolA gene. In this work we show that and in vivo the levels of bolA are down-regulated by H-NS and in vitro this global regulator interacts directly with the bolA promoter region. Moreover, DNaseI foot-printing experiments mapped the interaction regions of H-NS and bolA and revealed that this global regulator binds not only one but both bolA promoters. We provide a new insight into the bolA regulation network demonstrating that H-NS represses the transcription of this important gene. PMID- 21708125 TI - Multiple post-translational modifications in hepatocyte nuclear factor 4alpha. AB - To investigate the role of post-translational modifications (PTMs) in the hepatocyte nuclear factor 4alpha (HNF4alpha)-mediated transcription, we took a comprehensive survey of PTMs in HNF4alpha protein by mass-spectrometry and identified totally 8 PTM sites including newly identified ubiquitilation and acetylation sites. To assess the impact of identified PTMs in HNF4alpha-function, we introduced point mutations at the identified PTM sites and, tested transcriptional activity of the HNF4alpha. Among the point-mutations, an acetylation site at lysine 458 was found significant in the HNF4alpha-mediated transcriptional control. An acetylation negative mutant at lysine 458 showed an increased transcriptional activity by about 2-fold, while an acetylation mimic mutant had a lowered transcriptional activation. Furthermore, this acetylation appeared to be fluctuated in response to extracellular nutrient conditions. Thus, by applying an comprehensive analysis of PTMs, multiple PTMs were newly identified in HNF4alpha and unexpected role of an HNF4alpha acetylation could be uncovered. PMID- 21708127 TI - Glutamate-induced metabolic changes influence the cytoplasmic redox state of hippocampal neurons. AB - Brain cell metabolism is intimately associated with intracellular oxidation reduction (redox) balance. Glutamatergic transmission is accompanied with changes in substrate preference in neurons. Therefore, we studied cytoplasmatic redox changes in hippocampal neurons in culture exposed to glutamate. Neurons were transfected with HyPer, a genetically encoded redox biosensor for hydrogen peroxide which allows real-time imaging of the redox state. The rate of fluorescence decay, corresponding to the reduction of the biosensor was found to be augmented by low doses of glutamate (10 MUM) as well as by pharmacological stimulation of NMDA glutamate receptors. Acute chelation of extracellular Ca(2+) abolished the glutamate-induced effect observed on HyPer fluorescence. Additional experiments indicated that mitochondrial function and hence energetic substrate availability commands the redox state of neurons and is required for the glutamate effect observed on the biosensor signal. Furthermore, our results implicated astrocytic metabolism in the changes of neuronal redox state observed with glutamate. PMID- 21708126 TI - Hypochlorite-modified low-density lipoprotein induces the apoptotic machinery in Jurkat T-cell lines. AB - Myeloperoxidase is abundantly present in inflammatory diseases where activation of monocytes/macrophages and T-cell-mediated immune response occurs. The potent oxidant hypochlorous acid (HOCl), generated by the myeloperoxidase-H(2)O(2) chloride system of activated phagocytes, converts low-density lipoprotein (LDL) into a proinflammatory lipoprotein particle. Here, we investigated the apoptotic effect of HOCl-LDL, an in vivo occurring LDL modification, on human T-cell lymphoblast-like Jurkat cells. Experiments revealed that HOCl-LDL, depending on the oxidant:lipoprotein molar ratio, induces apoptosis via activation of caspase 3, PARP cleavage and accumulation of reactive oxygen species. The absence of Fas associated protein with death domain or caspase-8 in mutant cells did not prevent HOCl-LDL induced apoptosis. In contrast, overexpression of the anti-apoptotic Bcl 2 protein protects Jurkat cells against HOCl-LDL-induced apoptosis and prevents accumulation of reactive oxygen species. We conclude that HOCl-LDL-mediated apoptosis in Jurkat cells follows predominantly the intrinsic, mitochondrial pathway. Insitu experiments revealed that an antibody raised against HOCl-LDL recognized epitopes that colocalize both with myeloperoxidase and CD3-positive T cells in human decidual tissue where local stimulation of the immune system occurs. We provide convincing evidence that formation of HOCl-modified (lipo)proteins generated by the myeloperoxidase-H(2)O(2)-chloride system contributes to apoptosis in T-cells. PMID- 21708128 TI - Isolation and identification of dieldrin-degrading Pseudonocardia sp. strain KSF27 using a soil-charcoal perfusion method with aldrin trans-diol as a structural analog of dieldrin. AB - We isolated a novel aerobic dieldrin-degrading bacterium from an enrichment culture in a soil-charcoal perfusion system. Enrichment culture using a soil charcoal perfusion system was an effective way to obtain microorganisms that degrade recalcitrant compounds. The soil-charcoal perfusion was performed using aldrin trans-diol, which was a metabolite of dieldrin. Aldrin trans-diol had higher bioavailability (2.5 mg/l) than dieldrin (0.1-0.25 mg/l), therefore it is possible for microorganisms to utilize it as a substrate in soil. After 100 days of circulation and three exchanges of the medium, the enriched charcoal was harvested and a bacterium isolated. The isolate was designated as strain KSF27 and was found to be closely related to Pseudonocardia spp. as determined by 16S rRNA sequencing analysis. Strain KSF27 degraded aldrin trans-diol by 0.05 MUmol/l from an initial concentration of 25.5 MUmol/l. The metabolite of aldrin trans diol was detected by HPLC/MS and determined to be aldrindicarboxylic acid based on retention time and the MS fragment. Moreover, strain KSF27 degraded dieldrin from 14.06 MUmol/l to 2.01 MUmol/l over a 10-day incubation at 30 degrees C. This strain degraded dieldrin and other persistent organochlorine pesticides, such as alpha-endosulfan, beta-endosulfan, endosulfan sulfate, heptachlor, heptachlor epoxide and chlordecone. PMID- 21708129 TI - Sodium fluoride induces apoptosis and alters bcl-2 family protein expression in MC3T3-E1 osteoblastic cells. AB - Chronic excessive fluoride intake is known to be toxic and can lead to fluorosis and bone pathologies. However, the cellular mechanisms underlying NaF-induced cytotoxicity in osteoblasts are not well understood. The objectives of this study were to determine the effects of fluoride treatment on MC3T3-E1 osteoblastic cell viability, cell cycle analysis, apoptosis and the expression levels of bcl-2 family members: bcl-2 and bax. MC3T3-E1 cells were treated with 10(-5); 5 * 10( 5); 10(-4); 5 * 10(-4) and 10(-3)M NaF for up to 48 h. NaF was found to reduce cell viability in a temporal and concentration dependent manner and promote apoptosis even at low concentrations (10(-5)M). This increased apoptosis was due to alterations in the expression of both pro-apoptotic bax and anti-apoptotic bcl 2. The net result was a decrease in the bcl-2/bax ratio which was found at both the mRNA and protein levels. Furthermore, we also noted that NaF-induced S-phase arrest during the cell cycle of MC3T3-E1 cells. These data suggest that fluoride induced osteoblast apoptosis is mediated by direct effects of fluoride on the expression of bcl-2 family members. PMID- 21708130 TI - Common features and differences in the expression of the three genes forming the UGA regulon in Saccharomyces cerevisiae. AB - The three genes that form the UGA regulon in Saccharomyces cerevisiae are responsible for the transport and degradation of gamma-aminobutyric acid (GABA) in this organism. Despite the differences in the sequence of their promoters, these genes similarly respond to GABA stimuli. The expression of UGA1, UGA2 and UGA4 depends on GABA induction and nitrogen catabolite repression (NCR). The induction of these genes requires the action of at least two positive proteins, the specific Uga3 and the pleiotropic Uga35/Dal81 transcription factors. Here we show that all the members of the UGA regulon, as was already demonstrated for UGA4, are negatively regulated by extracellular amino acids through the SPS amino acid sensor. We also show that this negative effect is caused by a low availability of Uga35/Dal81 transcription factor and that Leu3 transcription factor negatively regulates UGA4 and UGA1 expression but it does not affect UGA2 expression. PMID- 21708131 TI - Bidirectional transcription from human LRRTM2/CTNNA1 and LRRTM1/CTNNA2 gene loci leads to expression of N-terminally truncated CTNNA1 and CTNNA2 isoforms. AB - alpha-Catenins (CTNNAs) are essential for the regulation of cell-cell and cell matrix interactions in tissues. All human CTNNA genes contain antisense oriented leucine rich repeat transmembrane (LRRTM) genes within their seventh introns. Recently, a haplotype upstream of one of the human LRRTM genes, LRRTM1 that resides in CTNNA2, was shown to be associated with handedness and schizophrenia. Here, we show that both CTNNA1 and CTNNA2 contain alternative 5' exons linked to bidirectional promoters that are shared with the antisense oriented LRRTM2 and LRRTM1 genes, respectively. We demonstrate that bidirectional activity of these promoters results in alternative CTNNA1 and CTNNA2 transcripts that are expressed at high levels in the nervous system and show that N-terminally truncated CTNNA1 and CTNNA2 proteins lacking the beta-catenin interaction domain are produced from these alternative CTNNA mRNAs. In addition, our results indicate that the haplotype that affects LRRTM1 expression and is associated with schizophrenia and handedness, could also influence the expression of brain-enriched alternative transcripts of CTNNA2. PMID- 21708132 TI - Preconditioning tachycardia decreases the activity of the mitochondrial permeability transition pore in the dog heart. AB - Cardioprotection by preconditioning is a central issue of current research on heart function. Several reports indicate that preventing the assembly and opening of the mitochondrial permeability transition pore (mPTP) protects the heart against ischemia-reperfusion injury. We have previously reported that brief episodes of tachycardia decrease the infarct size produced by subsequent prolonged occlusion of a coronary artery, indicating that controlled tachycardia is an effective preconditioning manoeuvre. The effects of preconditioning tachycardia on mPTP activity have not been reported. Therefore, in this work we investigated if preconditioning tachycardia protects against calcium-induced mitochondrial swelling, a measure of mPTP activity. We found that tachycardia decreased by 2.5-fold the rate of mitochondrial calcium-induced swelling, a factor that presumably contributes to the cardioprotective effects of tachycardia. The oxidative status of the cell increased after tachycardia, as evidenced by the decrease in the cellular and mitochondrial GSH/GSSG ratio. We also observed increased S-glutathionylation of cyclophilin-D, an essential mPTP component, after tachycardia. This reversible redox modification of cyclophilin-D may account, al least in part, for the decreased mPTP activity produced by preconditioning tachycardia. PMID- 21708134 TI - Phosphorylation of NDRG1 is temporally and spatially controlled during the cell cycle. AB - The tumour metastasis suppressor, N-myc Downstream Regulated Gene (NDRG) 1, is a by the protein kinases SGK1 and GSK3beta, but the relevance of its phosphorylation remains unclear. Analysis of HCT116 cells, either proficient or deficient for p53 revealed NDRG1 protein expression and phosphorylation by SGK1 was increased basally in p53-deficient cells. Treatment with the cell cycle inhibitors, aphidicolin or nocodazole also revealed increased NDRG1 phosphorylation in p53-deficient cells. Finally, phosphorylated NDRG1 was found to co-localise with gamma-tubulin on centromeres and also to the cleavage furrow during cytokinesis. Taken together, this work demonstrates that NDRG1 phosphorylation, by the protein kinase SGK1, is temporally and spatially controlled during the cell cycle, suggesting a role for NDRG1 in successful mitosis. PMID- 21708133 TI - Effects of CFTR gene silencing by siRNA or the luminal application of a CFTR activator on fluid secretion from guinea-pig pancreatic duct cells. AB - AIMS: The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic AMP regulated chloride channel expressed in the apical plasma membrane of pancreatic duct cells where it plays an important role in fluid secretion. The purpose of this study was to elucidate the role of the CFTR chloride channel on ion and fluid secretion from the guinea-pig pancreas by manipulating the expression of CFTR by RNA interference or by luminal application of a CFTR selective activator, MPB91, in isolated cultured pancreatic ducts. MATERIALS AND METHODS: Using cDNA isolated from the guinea-pig small intestine, fragments of the CFTR gene were generated by polymerase chain reaction and directly sequenced. Two different RNA duplexes for small interference RNA (siRNA) were designed from the sequence obtained. Fluid secretion from the isolated guinea-pig pancreatic ducts was measured using video-microscopy. The amount of CFTR chloride channel or AQP1 water channel expressed in pancreatic ducts was examined by immunoblotting with antibodies against CFTR or AQP1, respectively. RESULTS: Guinea-pig CFTR consists of 1481 amino acid residues. An additional glutamine residue was found to be inserted between amino acid residues 403 and 404 of human CFTR. Forskolin stimulated fluid secretion from intact pancreatic ducts was significantly higher in the presence of MPB91 compared to fluid secretion in the absence of MPB91. Both basal and forskolin-stimulated fluid secretion in pancreatic ducts transfected with CFTR specific siRNAs were reduced by ~50% compared to fluid secretion from ducts transfected with scrambled negative control dsRNAs. The amount of CFTR and AQP1 proteins was reduced to 34% and 45% of control, respectively. CONCLUSIONS: The activity of the CFTR chloride channel or the amount of CFTR protein expressed determines the rate of fluid secretion from the isolated guinea-pig pancreatic ducts. PMID- 21708135 TI - Biocatalytic synthesis of polymeric nanowires by micellar templates of ionic surfactants. AB - Micelle-templated polyguaiacol nanowires were successfully prepared via polymerization oxidation of guaiacol (o-methoxy phenol) by peroxidase enzyme in the presence of hydrogen peroxide at mild reaction conditions. The dimensions of the prepared nanowires were controlled by tuning the size and shape of the micelle structure via changing and controlling the type, chain length and molar concentrations of the ionic surfactant. The progress of the reaction and estimation of the size of soft micellar templates were followed by UV-Vis spectroscopy and dynamic light scattering (DLS). The resulting micelle encapsulated or purified polyguaiacol nanowires were characterized using transmission electron microscopy (TEM). PMID- 21708136 TI - FK506 confers chemosensitivity to anticancer drugs in glioblastoma multiforme cells by decreasing the expression of the multiple resistance-associated protein 1. AB - Glioblastoma multiforme (GBM) is the most aggressive of brain tumors and is extremely insensitive to anticancer drugs. Studies have attributed the ABC transporter Mrp1 (ABCC1, multiple-drug resistance protein 1) with conferring chemoresistance in this tumor by extrusion of a wide spectrum of anticancer drugs. Therefore it is crucial to search for and investigate inhibitors of Mrp1 activity in GBM cells, particularly those that could be safe as chemosensitizers to anticancer drugs in clinical studies. We find that in primary cultured or T98G GBM cells exposed to therapeutic plasma concentrations of FK506 (tacrolimus), the expression of Mrp1 was decreased in a dose-dependent manner. The activity of this transporter, measured by CFDA fluorescent substrate extrusion, decreased significantly in primary cultured GBM cells on exposure to FK506 at concentrations of 15 ng/ml. When GBM cells were exposed to anticancer drugs vincristine, etoposide or taxol, cell viability was not affected. However when the anticancer drugs were assayed in combination with FK506, cell viability was significantly decreased by as much as 50% in GBM primary culture. We conclude that FK506 could be a valuable tool for chemosensitization of GBM cells, offering a possible improvement to the current poor therapy available for high-grade human gliomas. PMID- 21708137 TI - Identification of a novel function for the FtsL cell division protein from Escherichia coli K12. AB - Analysis of the essential cell division protein FtsL demonstrates the partial conservation of a cysteine-pair within the trans-membrane region which itself is flanked by histidine-pairs in the cytosol and periplasm. Similar arrangements of such amino acids are seen in proteins known to transport/bind metal ions in biological systems. Heterologous expression of ftsL in Escherichia coli K12 confers a Zn(II)-sensitive phenotype and alteration of the candidate metal-ion binding residues cysteine or histidine substantially alters this phenotype. Whilst the cysteine/histidine replacement derivatives of ftsL were able to complement an otherwise ftsL-null strain, the derivative carrying ftsL lacking the cysteine pair was sensitive to raised metal-ion concentrations in the media. We show that ftsL can confer a metal-ion sensitive phenotype and that trans membrane cysteine residues play a role in FtsL function in elevated metal-ion concentrations. PMID- 21708138 TI - Production of transgenic chickens expressing a tetracycline-inducible GFP gene. AB - There is much interest in using farm animals as 'bioreactors' to produce large quantities of biopharmaceuticals. However, uncontrolled constitutive expression of foreign genes have been known to cause serious physiological disturbances in transgenic animals. The objective of this study was to test the feasibility of the controllable expression of an exogenous gene in the chicken. A retrovirus vector was designed to express GFP (green fluorescent protein) and rtTA (reverse tetracycline-controlled transactivator) under the control of the tetracycline inducible promoter and the PGK (phosphoglycerate kinase) promoter, respectively. G0 founder chickens were produced by infecting the blastoderm of freshly laid eggs with concentrated retrovirus vector. Feeding the chickens obtained with doxycycline, a tetracycline derivative, resulted in emission of green body color under fluorescent light, and no apparent significant physiological dysfunctions. Successful germline transmission of the exogenous gene was also confirmed. Expression of the GFP gene reverted to the pre-induction levels when doxycycline was removed from the diet. The results showed that a tetracycline-inducible expression system in transgenic animals might be a promising solution to minimize physiological disturbances caused by the transgene. PMID- 21708139 TI - Exploring behavioral and molecular mechanisms of nicotine reward in adolescent mice. AB - Tobacco smoking during adolescence has become a prominent preventable health problem faced in the United States. Addictive properties of smoking are thought to have a pronounced effect at a young age, thereby increasing vulnerability to a life-long addiction and decreasing the likelihood of smoking cessation during adulthood. Learning and memory involvement in nicotine reward was assessed in early adolescent (PND 28-34) and adult (PND 70+) male ICR mice by conducting conditioning sessions of nicotine (0.5mg/kg) acquisition at varying time-spans, and evaluating extinction and reinstatement of nicotine preference using Conditioned Place Preference. Acquisition studies resulted in a significant preference for nicotine after 3 days of conditioning for both age groups, but not after only 1 or 2 conditioning days. In the extinction study, adolescent mice exhibited preference for nicotine 72 h after the last conditioning session, whereas preference for nicotine was extinct in adult mice by 72 h. Reinstatement studies showed adolescent mice, but not adult mice, recovering nicotine preference after a priming injection of 0.1mg/kg nicotine on day 9 after the mice underwent extinction. No significant differences were found when nAChRs were quantified in both early adolescent and adult mice using binding techniques including cytisine sensitive, alpha-conotoxin-MII sensitive, and alpha bungarotoxin sensitive nAChRs. Levels of striatal dopamine release were measured in both age groups using a dopamine release assay over a range of nicotine doses, which also resulted in no significant differences. More sensitive assays may facilitate in understanding the mechanisms of nicotine reward in adolescent mice. PMID- 21708141 TI - Rapid, single-step assay for Hunter syndrome in dried blood spots using digital microfluidics. PMID- 21708140 TI - Effect of galangin supplementation on oxidative damage and inflammatory changes in fructose-fed rat liver. AB - The study examined the effects of galangin (GA) on oxidative stress, inflammatory cytokine levels and nuclear factor-kappa B (NF-kappaB) activation in fructose-fed rat liver. Adult male albino Wistar rats were divided into 4 groups. Groups 1 and 4 received the control diet containing starch as the source of carbohydrate while groups 2 and 3 were fed a diet containing fructose. Groups 3 and 4 additionally received GA (100MUg/kg, p.o) from the 15th day. At the end of 60 days, the levels of plasma glucose, insulin and triglycerides, insulin sensitivity indices and oxidative stress markers in the liver were determined. Cytokines of interest were assayed by ELISA and RT-PCR and NF-kappaB p65 nuclear translocation by Western blot and RT-PCR. Compared to control diet-fed animals, fructose-fed animals developed hyperglycemia, hyperinsulinemia, hypertriglyceridemia and insulin resistance (IR) (all p<0.01). GA prevented the rise in plasma glucose, insulin and triglycerides and improved insulin sensitivity. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels in plasma and the mRNA and protein levels of TNF-alpha and transforming growth factor-beta1(TGF-beta(1)) in liver were significantly higher in fructose-fed rats than control rats. However, treatment with GA downregulated the expression of these cytokines. Translocation of NF-kappaB into the nucleus was also increased in fructose diet-fed animals, which was prevented by GA. These results suggest that GA prevents oxidative damage and has a downregulatory effect on the inflammatory pathway in liver of fructose-fed rats. PMID- 21708142 TI - GATA4 loss-of-function mutations in familial atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major source of the substantially increased morbidity and mortality. Growing studies demonstrate that genetic defects play pivotal roles in a subgroup of AF. However, AF is a genetically heterogeneous disorder and the molecular basis of AF in a majority of cases remains unknown. METHODS: The whole coding region of the GATA4 gene, which encodes a zinc-finger transcription factor essential for cardiogenesis, was analyzed in 130 unrelated probands with AF in contrast to 200 unrelated ethnically matched healthy individuals used as controls. The available family members of the probands harboring the identified mutations were genotyped. The functional effect of the mutant GATA4 was characterized using a luciferase reporter assay system. RESULTS: Two novel heterozygous GATA4 mutations, p.S70T and p.S160T, were identified in 2 unrelated families with AF inherited as an autosomal dominant trait, respectively, which co segregated with AF in each family with complete penetrance. Functional analysis showed that the mutations of GATA4 were associated with a significantly decreased transcriptional activity. CONCLUSION: The findings provide new insight into the molecular mechanism involved in the pathogenesis of AF, suggesting the potential implications in the genetic diagnosis and gene-specific therapy of this common arrhythmia. PMID- 21708143 TI - Evolution of nubbin function in hemimetabolous and holometabolous insect appendages. AB - Insects display a whole spectrum of morphological diversity, which is especially noticeable in the organization of their appendages. A recent study in a hemipteran, Oncopeltus fasciatus (milkweed bug), showed that nubbin (nub) affects antenna morphogenesis, labial patterning, the length of the femoral segment in legs, and the formation of a limbless abdomen. To further determine the role of this gene in the evolution of insect morphology, we analyzed its functions in two additional hemimetabolous species, Acheta domesticus (house cricket) and Periplaneta americana (cockroach), and re-examined its role in Drosophila melanogaster (fruit fly). While both Acheta and Periplaneta nub-RNAi first nymphs develop crooked antennae, no visible changes are observed in the morphologies of their mouthparts and abdomen. Instead, the main effect is seen in legs. The joint between the tibia and first tarsomere (Ta-1) is lost in Acheta, which in turn, causes a fusion of these two segments and creates a chimeric nub-RNAi tibia tarsus that retains a tibial identity in its proximal half and acquires a Ta-1 identity in its distal half. Similarly, our re-analysis of nub function in Drosophila reveals that legs lack all true joints and the fly tibia also exhibits a fused tibia and tarsus. Finally, we observe a similar phenotype in Periplaneta except that it encompasses different joints (coxa-trochanter and femur-tibia), and in this species we also show that nub expression in the legs is regulated by Notch signaling, as had previously been reported in flies and spiders. Overall, we propose that nub acts downstream of Notch on the distal part of insect leg segments to promote their development and growth, which in turn is required for joint formation. Our data represent the first functional evidence defining a role for nub in leg segmentation and highlight the varying degrees of its involvement in this process across insects. PMID- 21708144 TI - High sensitivity of C. elegans vulval precursor cells to the dose of posterior Wnts. AB - Cell competence is a key developmental property. The Caenorhabditis elegans vulval competence group consists of P(3-8).p, six cells aligned along the antero posterior axis in a wide central body region. The six cells are not equal in their competence: 1) P3.p quits the competence group in half of the individuals; 2) the posterior cells P7.p and P8.p are less competent than central vulval precursor cells. Competence to adopt a vulval fate is controlled by expression of the HOM-C gene lin-39, and maintained through Wnt signals that are secreted from the tail in a long-range gradient. Here we quantify the LIN-39 protein profile in vulval precursor cells of early L2 stage larvae, prior to P3.p fusion and inductive signaling. We show that LIN-39 levels are very low in P3.p and P4.p, peak in P5.p and progressively decrease until P8.p. This unexpectedly centered profile arises independently from the gonad. Posterior Wnt signaling reduces LIN 39 level in the posterior cells by activating the next-posterior HOM-C gene, mab 5. On the anterior side, P3.p and P4.p competence and division are sensitive to the already low LIN-39 and Wnt doses; most dramatically, each of the cwn-1/Wnt and egl-20/Wnt genes show haplo-insufficience for P3.p fate. In contrast to previous results, we find that these Wnts maintain P3.p and P4.p competence without affecting their LIN-39 level. The centered vulval competence profile is thus under the control of the posterior Wnts and of cross-regulation of three HOM C genes and prepatterns the later induction of vulval fates. PMID- 21708145 TI - Multipotent neural stem cells generate glial cells of the central complex through transit amplifying intermediate progenitors in Drosophila brain development. AB - The neural stem cells that give rise to the neural lineages of the brain can generate their progeny directly or through transit amplifying intermediate neural progenitor cells (INPs). The INP-producing neural stem cells in Drosophila are called type II neuroblasts, and their neural progeny innervate the central complex, a prominent integrative brain center. Here we use genetic lineage tracing and clonal analysis to show that the INPs of these type II neuroblast lineages give rise to glial cells as well as neurons during postembryonic brain development. Our data indicate that two main types of INP lineages are generated, namely mixed neuronal/glial lineages and neuronal lineages. Genetic loss-of function and gain-of-function experiments show that the gcm gene is necessary and sufficient for gliogenesis in these lineages. The INP-derived glial cells, like the INP-derived neuronal cells, make major contributions to the central complex. In postembryonic development, these INP-derived glial cells surround the entire developing central complex neuropile, and once the major compartments of the central complex are formed, they also delimit each of these compartments. During this process, the number of these glial cells in the central complex is increased markedly through local proliferation based on glial cell mitosis. Taken together, these findings uncover a novel and complex form of neurogliogenesis in Drosophila involving transit amplifying intermediate progenitors. Moreover, they indicate that type II neuroblasts are remarkably multipotent neural stem cells that can generate both the neuronal and the glial progeny that make major contributions to one and the same complex brain structure. PMID- 21708147 TI - Inhibition of glycogen synthase kinase-3 enhances the differentiation and reduces the proliferation of adult human olfactory epithelium neural precursors. AB - The olfactory epithelium (OE) contains neural precursor cells which can be easily harvested from a minimally invasive nasal biopsy, making them a valuable cell source to study human neural cell lineages in health and disease. Glycogen synthase kinase-3 (GSK-3) has been implicated in the etiology and treatment of neuropsychiatric disorders and also in the regulation of murine neural precursor cell fate in vitro and in vivo. In this study, we examined the impact of decreased GSK-3 activity on the fate of adult human OE neural precursors in vitro. GSK-3 inhibition was achieved using ATP-competitive (6-bromoindirubin-3' oxime and CHIR99021) or substrate-competitive (TAT-eIF2B) inhibitors to eliminate potential confounding effects on cell fate due to off-target kinase inhibition. GSK-3 inhibitors decreased the number of neural precursor cells in OE cell cultures through a reduction in proliferation. Decreased proliferation was not associated with a reduction in cell survival but was accompanied by a reduction in nestin expression and a substantial increase in the expression of the neuronal differentiation markers MAP1B and neurofilament (NF-M) after 10 days in culture. Taken together, these results suggest that GSK-3 inhibition promotes the early stages of neuronal differentiation in cultures of adult human neural precursors and provide insights into the mechanisms by which alterations in GSK-3 signaling affect adult human neurogenesis, a cellular process strongly suspected to play a role in the etiology of neuropsychiatric disorders. PMID- 21708146 TI - Betaine feeding prevents the blood alcohol cycle in rats fed alcohol continuously for 1 month using the rat intragastric tube feeding model. AB - BACKGROUND: Blood alcohol levels (BAL) cycle up and down over a 7-8 day period when ethanol is fed continuously for one month in the intragastric tube feeding rat model (ITFRM) of alcoholic liver disease. The cycling phenomenon is due to an alternating increase and decrease in the metabolic rate. Recently, we found that S-adenosyl-methionine (SAMe) fed with alcohol prevented the BAL cycle. METHOD: Using the ITFRM we fed rats betaine (2 g/kg/day) with ethanol for 1 month and recorded the daily 24 h urine ethanol level (UAL) to measure the BAL cycle. UAL is equivalent to BAL because of the constant ethanol infusion. Liver histology, steatosis and BAL were measured terminally after 1 month of treatment. Microarray analysis was done on the mRNA extracted from the liver to determine the effects of betaine and alcohol on changes in gene expression. RESULTS: Betaine fed with ethanol completely prevented the BAL cycle similar to SAMe. Betaine also significantly reduced the BAL compared to ethanol fed rats without betaine. This was also observed when SAMe was fed with ethanol. The mechanism involved in both cases is that SAMe is required for the conversion of epinephrine from norepinephrine by phenylethanolamine methyltransferase (PNMT). Epinephrine is 5 to 10 fold more potent than norepinephrine in increasing the metabolic rate. The increase in the metabolic rate generates NAD, permitting ADH to increase the oxidation of alcohol. NAD is the rate limiting factor in oxidation of alcohol by alcohol dehydrogenase (ADH). This explains how SAMe and betaine prevented the cycle. Microarray analysis showed that betaine feeding prevented the up regulation of a large number of genes including TLR2/4, Il-1b, Jax3, Sirt3, Fas, Ifngr1, Tgfgr2, Tnfrsf21, Lbp and Stat 3 which could explain how betaine prevented fatty liver. CONCLUSION: Betaine feeding lowers the BAL and prevents the BAL cycle by increasing the metabolic rate. This increases the rate of ethanol elimination by generating NAD. PMID- 21708148 TI - Parasitological and morphological study of Schistosoma mansoni and diabetes mellitus in mice. AB - Schistosomes are blood-dwelling flukes which are highly dependent on the host metabolism. The aim of this study was to investigate possible relationship between streptozotocin-induced diabetes and the outcome of acute murine schistosomiasis mansoni. Male and female SW mice were treated by a single intraperitoneally injected dose of streptozotocin (180 mg/kg). Seven days after induction, both control and diabetic animals were infected with 70 Schistosoma mansoni cercariae (BH strain). Diabetics and their controls were weighed 45 days after birth and for the last time prior to killing. Susceptibility to infection was evaluated twice a week by quantifying fecal egg excretion 7-9 weeks post infection by the Kato-Katz' thick smear method. Mice were euthanized the day after the last fecal examination was performed. Adult worms were recovered from the portal system and mesenteric veins, whereas liver and intestine were removed for enumeration of egg load. No differences in worm length or in measurements of the reproductive organs, tegument, and suckers were detected. Also oviposition was unaffected as the total number of eggs per female worm from the liver, the small and the large intestine was the same in both groups. An oogram evaluation revealed a lower percentage of mature (23.0% vs. 40.7%) and a higher percentage of immature (69.1% vs. 51.7%) eggs in the small intestine of the diabetic mice. We suggest that principally a hampered egg passage through the intestine tissue caused this reduction and that probably both the eggs and the impaired host response play a role. PMID- 21708149 TI - Identification of substrates of an S-phase cell cycle kinase from Leishmania donovani. AB - Despite the importance of cyclin-Cdk related kinases (CRK) in regulation of cell and life cycle of kinetoplastida parasites, only limited knowledge about their substrates are presently available. Here, the potential substrates were searched for an S-phase LdCyc1-CRK3 complex from Leishmania donovani based on the presence of Cdk target phosphorylation site together with the cyclin interacting Cy-motif in genome-derived putative protein sequences. Three substrates could be identified with one of them being a unique protein with no known homologues. Another identified substrate is similar to MYST family of histone acetyl transferase and the third one contains Ku-70 related conserved domains. All the substrates interact directly with LdCyc1 and are phosphorylated in a Cy-motif dependent manner suggesting the importance of Cy-motif for their functions. PMID- 21708150 TI - Fluorescence ratiometric detection of ligand-induced receptor internalization using extracellular coiled-coil tag-probe labeling. AB - We report a new method for the detection of ligand-induced receptor internalization by fluorescence ratiometric imaging of pH in endosomes in combination with a recently developed posttranslational labeling system based on the formation of a heterodimeric coiled-coil structure. The N-terminus of the beta2-adrenergic receptor expressed on the cell surface was doubly labeled with pH-sensitive fluorescein and pH-insensitive tetramethylrhodamine. A significant increase in the tetramethylrhodamine-to-fluorescein fluorescence intensity ratio was observed after incubation with agonists in a concentration-dependent manner. This simple and accurate method of detecting the agonistic activity of receptors will be useful for high-throughput screening of drug candidates. PMID- 21708151 TI - The PPR-DYW proteins are required for RNA editing of rps14, cox1 and nad5 transcripts in Physcomitrella patens mitochondria. AB - We identified two DYW subclass pentatricopeptide repeat (PPR) proteins, PpPPR_78 and PpPPR_79, as RNA editing factors in the moss Physcomitrella patens. Disruption of each gene by homologous recombination revealed that PpPPR_78 was involved in RNA editing at the rps14 (rps14-C137) and cox1 (cox1-C755) sites and PpPPR_79 at the nad5-1 (nad5-C598) site in the mitochondrial transcripts. RNA editing defects did not affect transcript patterns of the target genes. Thus, DYW subclass PPR proteins seem to be site-specific trans-acting factors for RNA editing. PMID- 21708152 TI - Binding of RhoA by the C2 domain of E3 ligase Smurf1 is essential for Smurf1 regulated RhoA ubiquitination and cell protrusive activity. AB - Smurf1-mediated RhoA ubiquitination and degradation plays key roles in regulation of cell polarity and protrusive activity. However, how Smurf1 recognizes RhoA is still not clear. Here we report that the C2 domain of Smurf1 is necessary and sufficient for binding RhoA, and therefore is crucial for targeting RhoA for ubiquitination. In contrast, the C2 domain is dispensable for Smurf1-mediated ubiquitination of Smad1. Consistent with its biochemical specificity, the C2 domain is essential for Smurf1-regulated protrusion formation but not BMP signaling. Therefore, our study reveals the mechanism of the C2 domain of Smurf1 in substrate selection. PMID- 21708153 TI - Time to burn? Endoscopic ablation for Barrett's esophagus. PMID- 21708155 TI - One colon lumen but two organs. PMID- 21708157 TI - Immunoradiometric assay for human serum amyloid P component. AB - Human serum amyloid P component (SAP) is of increasing interest for its possible pathogenic role in amyloidosis and Alzheimer's disease, and as a therapeutic target in these conditions. We have developed and validated a robust and reproducible immunoradiometric assay (IRMA) for human SAP in serum, plasma and cerebrospinal fluid, and characterized the notable stability of human SAP immunoreactivity during storage of undiluted serum at 4 degrees C and 37 degrees C as well as frozen at -30 degrees C. SAP values were also stable after repeated freeze thawing of highly diluted serum samples. The 100 fold dynamic range of the assay, 0.5-50 MUg/L, encompassed all values seen in blood and cerebrospinal fluid, when tested at suitable dilutions, from both normal healthy individuals and patients, including subjects receiving the SAP-depleting drug, CPHPC. Furthermore by comparing the IRMA values in the presence and absence of calcium, the new assay revealed interference due to the binding of CPHPC by SAP, which was markedly enhanced in heparinized plasma. It is therefore essential that SAP assays in samples from patients on CPHPC be conducted in the absence of free calcium, in order to completely abrogate interference and determine the actual total SAP concentration. Estimates by the IRMA of SAP concentration in 49 serum samples from amyloidosis patients corresponded closely with those obtained by the established standard electro-immunoassay method and by a newly developed commercial ELISA kit (Hycult Biotechnology). PMID- 21708158 TI - Role of the Halloween genes, Spook and Phantom in ecdysteroidogenesis in the desert locust, Schistocerca gregaria. AB - The functional characterization of the Halloween genes represented a major breakthrough in the elucidation of the ecdysteroid biosynthetic pathway. These genes encode cytochrome P450 enzymes catalyzing the final steps of ecdysteroid biosynthesis in the dipteran Drosophila melanogaster and the Lepidoptera Manduca sexta and Bombyx mori. This is the first report on the identification of two Halloween genes, spook (spo) and phantom (phm), from a hemimetabolous orthopteran insect, the desert locust Schistocerca gregaria. Using q-RT-PCR, their spatial and temporal transcript profiles were analyzed in both final larval stage and adult locusts. The circulating ecdysteroid titers in the hemolymph were measured and found to correlate well with changes in the temporal transcript profiles of spo and phm. Moreover, an RNA interference (RNAi)-based approach was employed to study knockdown effects upon silencing of both transcripts in the fifth larval stage. Circulating ecdysteroid levels were found to be significantly reduced upon dsRNA treatment. PMID- 21708156 TI - A novel triple mix radiobinding assay for the three ZnT8 (ZnT8-RWQ) autoantibody variants in children with newly diagnosed diabetes. AB - BACKGROUND AND AIMS: Autoantibodies against the zinc transporter 8 (ZnT8A) are common in type 1 diabetes (T1D). ZnT8A analyses are complicated by the fact that there are three variants of the autoantigen at amino acid position 325 representing ZnT8-R (Arginine), ZnT8-W (Tryptophan) and ZnT8-Q (Glutamin). The aims of the study were: 1) to develop an autoantigen triple mix Radio-Binding Assay (RBA) for ZnT8A; 2) to identify the individual ZnT8-R,-W,-QA reactivity and 3) to validate the triple mix ZnT8A RBA in children with newly diagnosed T1D. METHODS: Serum samples were obtained from 2664 (56% males, n=1436) patients in the Swedish nationwide Better Diabetes Diagnosis (BDD) study representing patients with T1D (97%, n=2582), T2D (1.7%, n=46), MODY (1.0%, n=28) and secondary diabetes (0.3%, n=8). cDNA coding for the C-terminal end of each variant was prepared by site-directed mutagenesis and subcloned into a high efficiency in vitro transcription translation vector. The ZnT8 variants were labeled with 35S-methionine and used in a standard RBA separating free from autoantibody-bound autoantigen with Protein A-Sepharose. RESULTS: ZnT8-TripleA was detected in 1678 (65%) patients with T1D, 4 (9%) T2D, 3 (11%) MODY and in none (0%) of the patients with secondary diabetes. Among the T1D patients ZnT8-RA was detected in 1351 (52%) patients, ZnT8-WA in 1209 (47%) and ZnT8-QA in 790 (31%) demonstrating that 1661 (64%) had one or several ZnT8A. The ZnT8-TripleA assay showed a false positive rate of 1.9% (n=49). Only 1.2% (n=32) of the T1D patients were false negative for ZnT8-TripleA compared to 0/46 (0%) of the T2D patients. The precision (intra assay CV) and reproducibility (inter assay CV) of the ZnT8-TripleA assay did not differ from the RBA of the individual ZnT8 variants. CONCLUSION: We conclude that the ZnT8-TripleA assay had low false positive and false negative rates. The ZnT8-TripleA assay would therefore be highly suitable not only to analyze patient with newly diagnosed diabetes but also for screening the general population since this assay demonstrated high sensitivity and very high specificity. PMID- 21708159 TI - Blocking synaptic transmission with tetanus toxin light chain reveals modes of neurotransmission in the PDF-positive circadian clock neurons of Drosophila melanogaster. AB - Circadian locomotor rhythms of Drosophila melanogaster are controlled by a neuronal circuit composed of approximately 150 clock neurons that are roughly classified into seven groups. In the circuit, a group of neurons expressing pigment-dispersing factor (PDF) play an important role in organizing the pacemaking system. Recent studies imply that unknown chemical neurotransmitter(s) (UNT) other than PDF is also expressed in the PDF-positive neurons. To explore its role in the circadian pacemaker, we examined the circadian locomotor rhythms of pdf-Gal4/UAS-TNT transgenic flies in which chemical synaptic transmission in PDF-positive neurons was blocked by expressed tetanus toxin light chain (TNT). In constant darkness (DD), the flies showed a free-running rhythm, which was similar to that of wild-type flies but significantly different from pdf null mutants. Under constant light conditions (LL), however, they often showed complex rhythms with a short period and a long period component. The UNT is thus likely involved in the synaptic transmission in the clock network and its release caused by LL leads to arrhythmicity. Immunocytochemistry revealed that LL induced phase separation in TIMELESS (TIM) cycling among some of the PDF-positive and PDF negative clock neurons in the transgenic flies. These results suggest that both PDF and UNT play important roles in the Drosophila circadian clock, and activation of PDF pathway alone by LL leads to the complex locomotor rhythm through desynchronized oscillation among some of the clock neurons. PMID- 21708160 TI - Consistent effects of a major QTL for thermal resistance in field-released Drosophila melanogaster. AB - Molecular genetic markers can be used to identify quantitative trait loci (QTL) for thermal resistance and this has allowed characterization of a major QTL for knockdown resistance to high temperature in Drosophila melanogaster. The QTL showed trade-off associations with cold resistance under laboratory conditions. However, assays of thermal tolerance conducted in the laboratory may not necessarily reflect performance at varying temperatures in the field. Here we tested if lines with different genotypes in this QTL show different thermal performance under high and low temperatures in the field using a release recapture assay. We found that lines carrying the QTL genotype for high thermal tolerance were significantly better at locating resources in the field releases under hot temperatures while the QTL line carrying the contrasting genotype were superior at cold temperatures. Further, we studied copulatory success between the different QTL genotypes at different temperatures. We found higher copulatory success in males of the high tolerance QTL genotype under hot temperature conditions, while there was no difference in females at cold temperatures. The results allow relating components of field fitness at different environmental temperatures with genotypic variation in a QTL for thermal tolerance. PMID- 21708161 TI - Functions of duplicated genes encoding CCAP receptors in the red flour beetle, Tribolium castaneum. AB - Crustacean cardioactive peptide (CCAP) is a nonapeptide originally isolated from the shore crab, Carcinus maenas, based on its cardioacceleratory activity. This peptide is highly conserved in insects and other arthropods. In insects CCAP also has an essential role in ecdysis behavior. We previously identified two homologous genes, ccapr-1 and ccapr-2, encoding putative CCAP receptors in the red flour beetle, Tribolium castaneum. In contrast, some insects, including Drosophila melanogaster, carry only one gene encoding a CCAP receptor. Phylogenetic analysis of putative CCAP receptor orthologs reveals a number of independent gene duplications in several insect lineages. In this study, we confirmed that CCAP activates both putative T. castaneum receptors in a heterologous expression system. RNA interference (RNAi) of ccapr-1 and ccapr-2 revealed that ccapr-2 is essential for eclosion behavior in T. castaneum, while RNAi for ccapr-1 did not result in any abnormal phenotype. In vivo cardioacceleratory activity of exogenously applied CCAP was abolished by RNAi of ccapr-2, but not by that of ccapr-1. Thus, only ccapr-2 mediates the cardioacceleratory function, ccapr-1 having apparently lost both functions for eclosion behavior and for cardioacceleration since the recent gene duplication event. PMID- 21708162 TI - Turn the temperature to turquoise: cues for colour change in the male chameleon grasshopper (Kosciuscola tristis) (Orthoptera: Acrididae). AB - Rapid, reversible colour change is unusual in animals, but is a feature of male chameleon grasshoppers (Kosciuscola tristis). Understanding what triggers this colour change is paramount to developing hypotheses explaining its evolutionary significance. In a series of manipulative experiments the author quantified the effects of temperature, and time of day, as well as internal body temperature, on the colour of male K. tristis. The results suggest that male chameleon grasshoppers change colour primarily in response to temperature and that the rate of colour change varies considerably, with the change from black to turquoise occurring up to 10 times faster than the reverse. Body temperature changed quickly (within 10min) in response to changes in ambient temperature, but colour change did not match this speed and thus colour is decoupled from internal temperature. This indicates that male colour change is driven primarily by ambient temperature but that their colour does not necessarily reflect current internal temperature. I propose several functional hypotheses for male colour change in K. tristis. PMID- 21708163 TI - Steroidal regulation of hydrolyzing activity of the dietary carbohydrates in the silkworm, Bombyx mori. AB - Blood sugar is an essential energy source for growth and development and is maintained at a constant level through precise regulation of formation and utilization. Sugars are produced from dietary carbohydrates by enzymatic hydrolysis in the digestive tract, which are under the homeostatic control of paracrine and prandial mechanisms in mammals. Here, we show that dietary carbohydrates hydrolyzing activity of the digestive tract is developmentally regulated by the steroid hormone ecdysone in the silkworm, Bombyx mori. The dietary carbohydrates hydrolyzing activity remained high throughout the last larval period and then decreased to negligible levels until the pupal period. However, dietary carbohydrates digestive activities were constitutively high when the steroidogenic organ, prothoracic glands were ablated. The prothoracic glands produced and released a large amount of ecdysone at the end of the larval period, suggesting that ecdysone is responsible for the decrease in dietary carbohydrates hydrolyzing activity. In fact, ecdysone decreased the activity to negligible levels in silkworms lacking the prothoracic glands. The present results indicate that the dietary carbohydrates hydrolyzing activity is regulated by ecdysone and that an increase in ecdysone titer decreases that activity at the end of the larval period, suggesting that ecdysone is essential for metabolic coordination during development. PMID- 21708164 TI - Subterranean termite prophylactic secretions and external antifungal defenses. AB - Termites exploit environments that make them susceptible to infection and rapid disease transmission. Gram-negative bacteria binding proteins (GNBPs) signal the presence of microbes and in some insects directly damage fungal pathogens with beta-1,3-glucanase activity. The subterranean termites Reticulitermes flavipes and Reticulitermes virginicus encounter soil entomopathogenic fungi such as Metarhizium anisopliae, which can evade host immune responses after penetrating the cuticle. An external defense that prevents invasion of fungal pathogens could be crucial in termites, allowing them to thrive under high pathogenic pressures. We investigated the role of secreted beta-1,3-glucanases in Reticulitermes defenses against M. anisopliae. Our results show that these termites secrete antifungal beta-1,3-glucanases on the cuticle, and the specific inhibition of GNBP associated beta-1,3-glucanase activity with d-delta-gluconolactone (GDL) reduces this activity and can cause significant increases in mortality after exposure to M. anisopliae. Secreted beta-1,3-glucanases appear to be essential in preventing infection by breaking down fungi externally. PMID- 21708165 TI - Nutrient limitation results in juvenile hormone-mediated resorption of previtellogenic ovarian follicles in mosquitoes. AB - Juvenile hormone (JH) is a central hormonal regulator of previtellogenic development in female Aedes aegypti mosquitoes. JH levels are low at eclosion and increase during the first day after adult emergence. This initial rise in JH is essential for female reproductive maturation. After previtellogenic maturation is complete, the mosquito enters a 'state-of-arrest' during which JH synthesis continues at a slower pace and further ovary development is repressed until a blood meal is taken. By examining the relationships between juvenile hormone, follicular resorption and nutrition in A. aegypti, we were able to define a critical role of JH during the previtellogenic resting stage. The rate of follicular resorption in resting stage mosquitoes is dependent on nutritional quality. Feeding water alone caused the rate of follicular resorption to reach over 20% by day 7 after emergence. Conversely, feeding a 20% sucrose solution caused resorption to remain below 5% during the entire experimental period. Mosquitoes fed 3% sucrose show rates of resorption intermediate between water and 20% sucrose and only reached 10% by day 7 after emergence. Follicular resorption is related to JH levels. Ligated abdomens separated from a source of JH (the corpora allata) showed an increase in resorption comparable to similarly aged starved mosquitoes (16%). Resorption in ligated abdomens was reduced to 6% by application of methoprene. The application of methoprene was also sufficient to prevent resorption in intact mosquitoes starved for 48 h (14% starved vs. 4% starved with methoprene). Additionally, active caspases were localized to resorbing follicles indicating that an apoptotic cell-death mechanism is responsible for follicular resorption during the previtellogenic resting stage. Taken together, these results indicate that JH mediates reproductive trade-offs in resting stage mosquitoes in response to nutrition. PMID- 21708166 TI - Night-interrupting light inhibits diapause induction in the Kanzawa spider mite, Tetranychus kanzawai Kishida (Acari: Tetranychidae). AB - The inhibitory effects of the timing, intensity (I(I)) and period (I(T)) of night interrupting light on diapause induction of the Kanzawa spider mite (Tetranychus kanzawai) were investigated in a series of laboratory experiments. During a light and dark period of 8 and 16 h d(-1), respectively, a single 1-h night interrupting light was applied at early (E), middle (M), and late (L) parts of the dark period: i.e., at 3, 7.5, and 12h after the start of the dark period, respectively. No interrupting light was applied in the control treatment. The incidence of diapause was significantly lower in the M treatment (63%) compared to the control treatment (100%). In the E and L treatments, more than 90% of females entered diapause, which was comparable to the control treatment. Since the longest consecutive dark period during the E and L treatments was longer than the critical dark period (CDP) of 10.5-11 hd(-1), during which 50% of females entered diapause, the night-interrupting light probably failed to prevent diapause induction. However, in the M treatment, the longest consecutive dark period was shorter than the CDP; therefore, the night-interrupting light inhibited diapause induction. Moreover, the inhibitory effects of night interrupting light in the M treatment increased as I(I) and I(T) increased. The dose of night-interrupting light (I(I)*I(T)) was significantly negatively related to the incidence of diapause. The median effective dose for 50% disturbance of diapause induction was 2.5 kJ m(-2) at wavelengths between 350 and 1050 nm. Our results suggest that the longest consecutive dark period and the dose of night interrupting light should both be considered when a lighting-based physical control is applied to inhibit diapause induction and consequent overwintering of T. kanzawai in commercial agricultural fields. PMID- 21708167 TI - Transcript profiling of the meiotic drive phenotype in testis of Aedes aegypti using suppressive subtractive hybridization. AB - The meiotic drive gene in Aedes aegypti is tightly linked with the sex determination locus on chromosome 1, and causes highly male-biased sex ratios. We prepared cDNA libraries from testes from the Ae. aegypti T37 strain (driving) and RED strain (non-driving), and used suppressive subtraction hybridization techniques to enrich for T37 testes-specific transcripts. Expressed sequence tags (ESTs) were obtained from a total of 2784 randomly selected clones from the subtracted T37 (subT37) library as well as the primary libraries for each strain (pT37 and pRED). Sequence analysis identified a total of 171 unique genes in the subT37 library and 299 unique genes among the three libraries. The majority of genes enriched in the subT37 library were associated with signal transduction, development, reproduction, metabolic process and cell cycle functions. Further, as observed with meiotic drive systems in Drosophila and mouse, a number of these genes were associated with signaling cascades that involve the Ras superfamily of regulatory small GTPases. Differential expression of several of these genes was verified in Ae. aegypti pupal testes using qRT-PCR. This study increases our understanding of testes gene expression enriched in adult males from the meiotic drive strain as well as insights into the basic testes transcriptome in Ae. aegypti. PMID- 21708168 TI - Recombinant expression of Drosophila melanogaster alpha-L-fucosidase in Trichoplusia ni cells. AB - A cDNA encoding an alpha-l-fucosidase from Drosophila melanogaster was obtained from the recombinant plasmid named pGEM-DmFuca and inserted into the pBacHTeGFPT vector to construct the recombinant donor plasmid which was transposed to the target AcBacmid in Escherichia coli (DH10) by Tn7 transposition function. The AcBacmid-GFP-DmFuca plasmid was used to transfect Tn-5B1-4 cells of the Cabbage looper Trichoplusia ni. SDS-PAGE analysis revealed a band of about 80kDa. Using a polyclonal antiserum raised against alpha-l-fucosidase protein from D. melanogaster Western blotting analysis confirmed that the fusion protein eGFP DmFuca has been successfully expressed in a biologically active form in Tn-5B1-4 cells. The recombinant protein, containing the histidine-tag motif, was purified using an affinity chromatography column. In vitro binding assays the purified eGFP-DmFuca interacts with alpha-l-fucose residues present on the micropyle of the D. melanogaster eggshell, confirming that the alpha-l-fucosidase is a good candidate as receptor involved in gamete interactions in fruit fly. PMID- 21708169 TI - Histopathology and effect on development of the PhopGV on larvae of the potato tubermoth, Phthorimaea operculella (Lepidoptera: Gelechiidae). AB - Larvae of the potato tubermoth (PTM), Phthorimaea operculella, feed on potato plants and tubers and are a major pest in the tropics and subtropics worldwide, causing up to 100% damage. The PTM granulovirus (PhopGV) provides significant potato protection, but little is known about its effect on larval development or its histopathology. Here we show that only 10% of larvae exited from PhopGV treated tubers (1.4*10(8) granule/ml), lagging significantly behind controls, and most of these died by 72 h after emergence. Histopathology studies showed the fat body and epidermis were the principal tissues infected. PhopGV morphogenesis was similar to other GVs, the exception being small vesicles between mature granules. PMID- 21708170 TI - Titin based viscosity in ventricular physiology: an integrative investigation of PEVK-actin interactions. AB - Viscosity is proposed to modulate diastolic function, but only limited understanding of the source(s) of viscosity exists. In vitro experiments have shown that the proline-glutamic acid-valine-lysine (PEVK) rich element of titin interacts with actin, causing a viscous force in the sarcomere. It is unknown whether this mechanism contributes to viscosity in vivo. We tested the hypothesis that PEVK-actin interaction causes cardiac viscosity and is important in vivo via an integrative physiological study on a unique PEVK knockout (KO) model. Both skinned cardiomyocytes and papillary muscle fibers were isolated from wildtype (WT) and PEVK KO mice and passive viscosity was examined using stretch-hold release and sinusoidal analysis. Viscosity was reduced by ~60% in KO myocytes and ~50% in muscle fibers at room temperature. The PEVK-actin interaction was not modulated by temperature or diastolic calcium, but was increased by lattice compression. Stretch-hold and sinusoidal frequency protocols on intact isolated mouse hearts showed a smaller, 30-40% reduction in viscosity, possibly due to actomyosin interactions, and showed that microtubules did not contribute to viscosity. Transmitral Doppler echocardiography similarly revealed a 40% decrease in LV chamber viscosity in the PEVK KO in vivo. This integrative study is the first to quantify the influence of a specific molecular (PEVK-actin) viscosity in vivo and shows that PEVK-actin interactions are an important physiological source of viscosity. PMID- 21708171 TI - Calmodulin binding proteins provide domains of local Ca2+ signaling in cardiac myocytes. AB - Calmodulin (CaM) acts as a common Ca(2+) sensor for many signaling pathways, transducing local Ca(2+) signals into specific cellular outcomes. Many of CaM's signaling functions can be explained by its unique biochemical properties, including high and low affinity Ca(2+)-binding sites with slow and fast kinetics, respectively. CaM is expected to have a limited spatial range of action, emphasizing its role in local Ca(2+) signaling. Interactions with target proteins further fine-tune CaM signal transduction. Here, we focus on only three specific cellular targets for CaM signaling in cardiac myocytes: the L-type Ca(2+) channel, the ryanodine receptor, and the IP(3) receptor. We elaborate a working hypothesis that each channel is regulated by two distinct functional populations of CaM: dedicated CaM and promiscuous CaM. Dedicated CaM is typically tethered to each channel and directly regulates channel activity. In addition, a local pool of promiscuous CaM appears poised to sense local Ca(2+) signals and trigger downstream pathways such as Ca(2+)/CaM dependent-protein kinase II and calcineurin. Understanding how promiscuous CaM coordinates multiple distinct signaling pathways remains a challenge, but is aided by the use of mathematical modeling and a new generation of fluorescent biosensors. This article is part of a special issue entitled "Local Signaling in Myocytes." PMID- 21708172 TI - Intrasubunit and intersubunit interactions controlling assembly of active synaptic complexes during Hin-catalyzed DNA recombination. AB - Serine recombinases, which generate double-strand breaks in DNA, must be carefully regulated to ensure that chemically active DNA complexes are assembled correctly. In the Hin-catalyzed site-specific DNA inversion reaction, two inversely oriented recombination sites on the same DNA molecule assemble into a synaptic complex that uniquely generates inversion products. The Fis-bound recombinational enhancer, together with topological constraints directed by DNA supercoiling, functions to regulate Hin synaptic complex formation and activity. We have isolated a collection of gain-of-function mutants in 22 positions within the catalytic and oligomerization domains of Hin using two genetic screens and by site-directed mutagenesis. One genetic screen measured recombination in the absence of Fis and the other assessed SOS induction as a readout of increased DNA cleavage. These mutations, together with molecular modeling, identify important sites of dynamic intrasubunit and intersubunit interactions that regulate assembly of the active tetrameric recombination complex. Of particular interest are interactions between the oligomerization helix (helix E) and the catalytic domain of the same subunit that function to hold the dimer in an inactive state in the absence of the Fis/enhancer system. Among these is a relay involving a triad of phenylalanines that are proposed to switch positions during the transition from dimers to the catalytically active tetramer. Novel Hin mutants that generate synaptic complexes that are blocked at steps prior to DNA cleavage are also described. PMID- 21708173 TI - Allosteric drugs: the interaction of antitumor compound MKT-077 with human Hsp70 chaperones. AB - Hsp70 (heat shock protein 70 kDa) chaperones are key to cellular protein homeostasis. However, they also have the ability to inhibit tumor apoptosis and contribute to aberrant accumulation of hyperphosphorylated tau in neuronal cells affected by tauopathies, including Alzheimer's disease. Hence, Hsp70 chaperones are increasingly becoming identified as targets for therapeutic intervention in these widely abundant diseases. Hsp70 proteins are allosteric machines and offer, besides classical active-site targets, also opportunities to target the mechanism of allostery. In this work, it is demonstrated that the action of the potent anticancer compound MKT-077 (1-ethyl-2-[[3-ethyl-5-(3-methylbenzothiazolin-2 yliden)]-4-oxothiazolidin-2-ylidenemethyl] pyridinium chloride) occurs through a differential interaction with Hsp70 allosteric states. MKT-077 is therefore an "allosteric drug." Using NMR spectroscopy, we identify the compound's binding site on human HSPA8 (Hsc70). The binding pose is obtained from NMR-restrained docking calculations, subsequently scored by molecular-dynamics-based energy and solvation computations. Suggestions for the improvement of the compound's properties are made on the basis of the binding location and pose. PMID- 21708174 TI - Structure of H/ACA RNP protein Nhp2p reveals cis/trans isomerization of a conserved proline at the RNA and Nop10 binding interface. AB - H/ACA small nucleolar and Cajal body ribonucleoproteins (RNPs) function in site specific pseudouridylation of eukaryotic rRNA and snRNA, rRNA processing, and vertebrate telomerase biogenesis. Nhp2, one of four essential protein components of eukaryotic H/ACA RNPs, forms a core trimer with the pseudouridylase Cbf5 and Nop10 that binds to H/ACA RNAs specifically. Crystal structures of archaeal H/ACA RNPs have revealed how the protein components interact with each other and with the H/ACA RNA. However, in place of Nhp2p, archaeal H/ACA RNPs contain L7Ae, which binds specifically to an RNA K-loop motif absent from eukaryotic H/ACA RNPs, while Nhp2 binds a broader range of RNA structures. We report solution NMR studies of Saccharomyces cerevisiae Nhp2 (Nhp2p), which reveal that Nhp2p exhibits two major conformations in solution due to cis/trans isomerization of the evolutionarily conserved Pro83. The equivalent proline is in the cis conformation in all reported structures of L7Ae and other homologous proteins. Nhp2p has the expected alpha-beta-alpha fold, but the solution structures of the major conformation of Nhp2p with trans Pro83 and of Nhp2p-S82W with cis Pro83 reveal that Pro83 cis/trans isomerization affects the positions of numerous residues at the Nop10 and RNA binding interface. An S82W substitution, which stabilizes the cis conformation, also stabilizes the association of Nhp2p with H/ACA snoRNPs expressed in vivo. We propose that Pro83 plays a key role in the assembly of the eukaryotic H/ACA RNP, with the cis conformation locking in a stable Cbf5-Nop10-Nhp2 ternary complex and positioning the protein backbone to interact with the H/ACA RNA. PMID- 21708175 TI - Structure and organisation of SinR, the master regulator of biofilm formation in Bacillus subtilis. AB - sinR encodes a tetrameric repressor of genes required for biofilm formation in Bacillus subtilis. sinI, which is transcribed under Spo0A control, encodes a dimeric protein that binds to SinR to form a SinR-SinI heterodimer in which the DNA-binding functions of SinR are abrogated and repression of biofilm genes is relieved. The heterodimer-forming surface comprises residues conserved between SinR and SinI. Each forms a pair of alpha-helices that hook together to form an intermolecular four-helix bundle. Here, we are interested in the assembly of the SinR tetramer and its binding to DNA. Size-exclusion chromatography with multi angle laser light scattering and crystallographic analysis reveal that a DNA binding fragment of SinR (residues 1-69) is a monomer, while a SinI-binding fragment (residues 74-111) is a tetramer arranged as a dimer of dimers. The SinR(74-111) chain forms two alpha-helices with the organisation of the dimer similar to that observed in the SinR-SinI complex. The tetramer is formed through interactions of residues at the C-termini of the four chains. A model of the intact SinR tetramer in which the DNA binding domains surround the tetramerisation core was built. Fluorescence anisotropy and surface plasmon resonance experiments showed that SinR binds to an oligonucleotide duplex, 5' TTTGTTCTCTAAAGAGAACTTA-3', containing a pair of SinR consensus sequences in inverted orientation with a K(d) of 300 nM. The implications of these data for promoter binding and the curious quaternary structural transitions of SinR upon binding to (i) SinI and (ii) the SinR-like protein SlrR, which "repurposes" SinR as a repressor of autolysin and motility genes, are discussed. PMID- 21708176 TI - Conformation and sequence evidence for two-fold symmetry in left-handed beta helix fold. AB - The left-handed beta-helix (LbetaH) has received interest recently as it folds as a possible solution for the structure of misfolded proteins associated with prion and Huntington's diseases. Through a combination of sequence and structure analysis, we uncover a novel feature that is common to this unique fold: a two fold symmetry in both sequence and structure, and this feature always coupled with extended loops in the middle of the helix. Since the results reveal a two fold symmetric pattern both in the sequence and structure, it may indicate that the symmetry in tertiary structure is coded by the symmetry in primary sequence, which agrees with Anfisen's proposal that a protein's amino-acid sequence specify its three-dimensional structure. It may also indicate that LbetaH adopts a two fold repeat pattern during the evolution process and symmetry helps maintaining the stability of the helix structure. The two-fold symmetric pattern and extended loops might be important in maintaining stability of helix proteins. This discovery can be useful in understanding the folding mechanisms of this protein fold and provide insights in the relation between sequences and structures. PMID- 21708177 TI - O(6)-methylguanine-DNA methyltransferase (MGMT): impact on cancer risk in response to tobacco smoke. AB - Tobacco, smoked, snuffed and chewed, contains powerful mutagens and carcinogens. At least three of them, N-dimethylnitrosamine, N'-nitrosonornicotine and 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone, attack DNA at the O(6)-position of guanine. The resulting O(6)-alkylguanine adducts are repaired by the suicide enzyme O(6)-methylguanine-DNA methyltransferase (MGMT), which is known to protect against the mutagenic, genotoxic and carcinogenic effects of monofunctional alkylating agents. While in rat liver MGMT was shown to be subject to regulation by genotoxic stress leading to adaptive changes in its activity, in humans evidence of adaptive modulation of MGMT levels is still lacking. Several polymorphisms are known, which are suspected to impact on the risk of developing cancer. In this review we focus on three questions: (a) Has tobacco consumption by smoking or chewing an impact on MGMT expression and MGMT promoter methylation in normal and tumor tissue? (b) Is there an association between MGMT polymorphisms and cancer risk and is this risk related to smoking? (c) Does MGMT protect against tobacco-associated cancer? There are several lines of evidence for an increase of MGMT activity in the normal tissue of smokers compared to non smokers. Furthermore, in tumors developed in smokers a tendency towards an increase of MGMT expression was found. The data points to the possibility that agents in tobacco smoke are able to trigger upregulation of MGMT in normal and tumor tissue. For MGMT promoter methylation data is conflicting. There is some evidence for an association between MGMT polymorphisms and smoking-induced cancer risk. The key question whether or not MGMT protects against tobacco smoke-induced cancer is difficult to answer since prospective studies on smokers versus non smokers are lacking and appropriate animal studies with MGMT transgenic mice exposed to the complex mixture of tobacco smoke have not been performed, which indicates the need for further explorations. PMID- 21708178 TI - Further fMRI validation of the visual half field technique as an indicator of language laterality: a large-group analysis. AB - The best established lateralized cerebral function is speech production, with the majority of the population having left hemisphere dominance. An important question is how to best assess the laterality of this function. Neuroimaging techniques such as functional Magnetic Resonance Imaging (fMRI) are increasingly used in clinical settings to replace the invasive Wada-test. We evaluated the usefulness of behavioral visual half field (VHF) tasks for screening a large sample of healthy left-handers. Laterality indices (LIs) calculated on the basis of the latencies in a word and picture naming VHF task were compared to the brain activity measured in a silent word generation task in fMRI (pars opercularis/BA44 and pars triangularis/BA45). Results confirmed the usefulness of the VHF-tasks as a screening device. None of the left-handed participants with clear right visual field (RVF) advantages in the picture and word naming task showed right hemisphere dominance in the scanner. In contrast, 16/20 participants with a left visual field (LVF) advantage in both word and picture naming turned out to have atypical right brain dominance. Results were less clear for participants who failed to show clear VHF asymmetries (below 20 ms RVF advantage and below 60 ms LVF advantage) or who had inconsistent asymmetries in picture and word naming. These results indicate that the behavioral tasks can mainly provide useful information about the direction of speech dominance when both VHF differences clearly point in the same direction. PMID- 21708180 TI - Time-dependent solutions of the spatially implicit neutral model of biodiversity. AB - Previous research into the neutral theory of biodiversity has focused mainly on equilibrium solutions rather than time-dependent solutions. Understanding the time-dependent solutions is essential for applying neutral theory to ecosystems in which time-dependent processes, such as succession and invasion, are driving the dynamics. Time-dependent solutions also facilitate tests against data that are stronger than those based on static equilibrium patterns. Here I investigate the time-dependent solutions of the classic spatially implicit neutral model, in which a small local community is coupled to a much larger metacommunity through immigration. I present explicit general formulas for the eigenvalues, left eigenvectors and right eigenvectors of the models's transition matrix. The time dependent solutions can then be expressed in terms of these eigenvalues and eigenvectors. Some of these results are translated directly from existing results for the classic Moran model of population genetics (the Moran model is equivalent to the spatially implicit neutral model after a reparameterization); others of the results are new. I demonstrate that the asymptotic time-dependent solution corresponding to just these first two eigenvectors can be a good approximation to the full time-dependent solution. I also demonstrate the feasibility of a partial eigendecomposition of the transition matrix, which facilitates direct application of the results to a biologically relevant example in which a newly invading species is initially present in the metacommunity but absent from the local community. PMID- 21708179 TI - Evidence for a lack of phasic inhibitory properties of habituated stressors on HPA axis responses in rats. AB - This experiment tested the hypothesis that habituation to repeated stressor exposures is produced by phasic inhibitory influence on the neural circuitry that normally drives the paraventricular nucleus of the hypothalamus and subsequently the adrenocortical hormone response to psychological stress. Such a process would be expected to lower the acute response to a novel stressor when experienced concurrently with a habituated stressor. Rats were exposed to restraint or no stress conditions for 14 consecutive days. On the 15th day, the rats were exposed to the control condition (no stress), acute restraint, loud noise, or restraint and loud noise concurrently. Blood was taken and assayed for ACTH and corticosterone and brains were collected to examine c-fos messenger RNA expression in several brain areas. As predicted, the rats that received the same (homotypic) stressor repeatedly and again on the test day displayed low levels of ACTH and corticosterone, similar to the control conditions (i.e., showed habituation). All rats that received a single novel stressor on the test day, regardless of prior stress history, exhibited high levels of ACTH and corticosterone. The rats that received two novel stressors also displayed high levels of ACTH and corticosterone, but little evidence of additivity was observed. Importantly, when a novel stressor was concurrently given with a habituated stressor on the test day, no reduction of HPA axis response was observed when compared to previously habituated rats given only the novel stressor on the test day. In general, c-fos mRNA induction in several stress responsive brain areas followed the same patterns as the ACTH and corticosterone data. These data suggest that habituation of the adrenocortical hormone response to psychological stressors is not mediated by phasic inhibition of the effector system. PMID- 21708181 TI - A DC-81-indole conjugate agent suppresses melanoma A375 cell migration partially via interrupting VEGF production and stromal cell-derived factor-1alpha-mediated signaling. AB - Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) chemicals are antitumor antibiotics inhibiting nucleic acid synthesis. An indole carboxylate-PBD hybrid with six carbon spacer structure (IN6CPBD) has been previously demonstrated to induce melanoma cell apoptosis and reduce metastasis in mouse lungs. This study aimed at investigating the efficacy of the other hybrid compound with four-carbon spacer (IN4CPBD) and elucidating its anti-metastatic mechanism. Human melanoma A375 cells with IN4CPBD treatment underwent cytotoxicity and apoptosis-associated assays. Transwell migration assay, Western blotting, and ELISA were used for mechanistic study. IN4CPBD exhibited potent melanoma cytotoxicity through interrupting G1/S cell cycle progression, increasing DNA fragmentation and hypodipoidic DNA contents, and reducing mitochondrial membrane potential. Caspase activity elevation suggested that both intrinsic and extrinsic pathways were involved in IN4CPBD-induced melanoma apoptosis. IN4CPBD up-regulated p53 and p21, thereby concomitantly derailing the equilibrium between Bcl-2 and Bax levels. Transwell migration assay demonstrated that stromal cell-derived factor-1alpha (SDF-1alpha) stimulated A375 cell motility, while kinase inhibitors treatment confirmed that Rho/ROCK, Akt, ERK1/2, and p38 MAPK pathways were involved in SDF 1alpha-enhanced melanoma migration. IN4CPBD not only abolished the SDF-1alpha enhanced chemotactic motility but also suppressed constitutive MMP-9 and VEGF expression. Mechanistically, IN4CPBD down-regulated Akt, ERK1/2, and p38 MAPK total proteins and MYPT1 phosphorylation. In conclusion, beyond the fact that IN4CPBD induces melanoma cell apoptosis at cytotoxic dose, the interruption in the VEGF expression and the SDF-1alpha-related signaling at cytostatic dose may partially constitute the rationale for its in vivo anti-metastatic potency. PMID- 21708182 TI - Aniline-induced nitrosative stress in rat spleen: proteomic identification of nitrated proteins. AB - Aniline exposure is associated with toxicity to the spleen which is characterized by splenomegaly, hyperplasia, fibrosis, and a variety of sarcomas on chronic exposure in rats. However, mechanisms by which aniline elicits splenotoxic responses are not well understood. Earlier we have shown that aniline exposure leads to increased nitration of proteins in the spleen. However, nitrated proteins remain to be characterized. Therefore, in the current study using proteomic approaches, we focused on characterizing the nitrated proteins in the spleen of aniline-exposed rats. Aniline exposure led to increased tyrosine nitration of proteins, as determined by 2D Western blotting with anti-3 nitrotyrosine specific antibody, compared to the controls. The analyzed nitrated proteins were found in the molecular weight range of 27.7 to 123.6kDa. A total of 37 nitrated proteins were identified in aniline-treated and control spleens. Among them, 25 were found only in aniline-treated rats, 11 were present in both aniline-treated and control rats, while one was found in controls only. The nitrated proteins identified mainly represent skeletal proteins, chaperones, ferric iron transporter, enzymes, nucleic acids binding protein, and signaling and protein synthesis pathways. Furthermore, aniline exposure led to significantly increased iNOS mRNA and protein expression in the spleen, suggesting its role in increased reactive nitrogen species formation and contribution to increased nitrated proteins. The identified nitrated proteins provide a global map to further investigate alterations in their structural and functional properties, which will lead to a better understanding of the role of protein nitration in aniline-mediated splenic toxicity. PMID- 21708184 TI - Metabotropic and ionotropic glutamate receptors as neurobiological targets in anxiety and stress-related disorders: focus on pharmacology and preclinical translational models. AB - Anxiety disorders are amongst the most common and disabling of psychiatric illnesses and have severe health and socio-economic implications. Despite the availability of a number of treatment options there is still a strong medical need for novel and improved pharmacological approaches in treating these disorders. New developments at the forefront of preclinical research have begun to identify the therapeutic potential of molecular entities integral to the biological response to adversity, particularly molecules and processes that may pre-determine vulnerability or resilience, and those that may act to switch off or "unlearn" a response to an aversive event. The glutamate system is an interesting target in this respect, especially given the impact anxiety disorders have on neuroplasticity, cognition and affective function. These areas of research demonstrate expanding and improved evidence-based options for treating disorders where stress in various guises plays an important etiological role. The current review will discuss how these pathways are involved in fear circuitry of the brain and compare the strength of therapeutic rationale as well as progress towards pharmacological validation of the glutamate pathway towards the treatment of anxiety disorders, with a particular focus on metabotropic and ionotropic glutamate receptors. Specific reference to their anxiolytic actions and efficacy in translational disease models of posttraumatic stress disorder, obsessive compulsive disorder, panic disorder and phobia will be made. In addition, the availability of ligands necessary to assist clinical proof of concept studies will be discussed. PMID- 21708183 TI - Xeroderma pigmentosum and other diseases of human premature aging and DNA repair: molecules to patients. AB - A workshop(1) to share, consider and discuss the latest developments in understanding xeroderma pigmentosum and other human diseases caused by defects in nucleotide excision repair (NER) of DNA damage was held on September 21-24, 2010 in Virginia. It was attended by approximately 100 researchers and clinicians, as well as several patients and representatives of patient support groups. This was the third in a series of workshops with similar design and goals: to emphasize discussion and interaction among participants as well as open exchange of information and ideas. The participation of patients, their parents and physicians was an important feature of this and the preceding two workshops. Topics discussed included the natural history and clinical features of the diseases, clinical and laboratory diagnosis of these rare diseases, therapeutic strategies, mouse models of neurodegeneration, molecular analysis of accelerated aging, impact of transcriptional defects and mitochondrial dysfunction on neurodegeneration, and biochemical insights into mechanisms of NER and base excision repair. PMID- 21708185 TI - The effect on cardiorespiratory fitness after an 8-week period of commuter cycling--a randomized controlled study in adults. AB - OBJECTIVE: This study investigated the effect of commuter cycling on cardiorespiratory fitness in men and women. Secondary outcomes included body fat and blood pressure measurements. METHODS: In February 2009, 48 volunteers from the Island of Funen, Denmark were randomly assigned to either "no change in lifestyle" or to "minimum 20 minutes of daily commuter cycling during 8 weeks". Maximal oxygen uptake was assessed directly during a progressive cycle-ergometer test, sum of skinfolds was used as an estimate of body fat, and blood pressure was measured using a Dinamap monitor. Measurements were obtained at baseline and at the conclusion of the 8-week intervention program. RESULTS: Six cyclists dropped out. After 8 weeks VO(2)max (mL O(2) min(-1)) and cardiorespiratory fitness (mL O(2) kg(-1) min(-1)) were significantly improved in the cycling group when compared to the control group. Delta change in VO(2)max between groups equaled 206 mL O(2) min(-1) (p=0.005) and delta change in cardiorespiratory fitness equaled 2.6 mL O(2) kg(-1) min(-1) (p=0.003). Body fatness changed more noticeable (p=0.026) in the cyclists (-12.3+/-7.3 mm) than in the controls ( 0.2+/-7.1 mm). CONCLUSIONS: VO(2)max and cardiorespiratory fitness were significantly improved and body fat reduced as a result of people engaging in 8 weeks of commuter cycling. PMID- 21708186 TI - Association between a healthy lifestyle and general obesity and abdominal obesity in an elderly population at high cardiovascular risk. AB - BACKGROUND: Diet, smoking and physical activity are important modifiable lifestyle factors that can influence body weight and fat accumulation. We assessed the relationship between lifestyle and obesity risk in a baseline analysis of the PREDIMED study, a randomized dietary primary prevention trial conducted in Spain. METHODS: 7000 subjects at high cardiovascular risk were assessed cross-sectionally. A healthy lifestyle pattern (HLP) was determined using a score including: adherence to the Mediterranean diet, moderate alcohol consumption, expending >=200 kcal/day in leisure-time physical activity, and non smoking. RESULTS: Inverse linear trends were observed between the HLP-score and body-mass-index (BMI) or waist circumference (p<0.001). The BMI and waist circumference of participants with a HLP-score=4 were, respectively, 1.3 kg/m(2) (95% CI: 0.9 to 1.7) and 4.3 cm (3.1 to 5.4) lower than those of subjects with an HLP<=1. The odds ratios of general obesity and abdominal obesity for an HLP score of 4 compared to an HPL score<=1 were 0.50 (0.42 to 0.60) and 0.51 (0.41 to 0.62), respectively. CONCLUSION: A combination of four healthy lifestyle behaviors was associated with a lower prevalence of general obesity and abdominal obesity in Mediterranean elderly subjects at high cardiovascular risk. PMID- 21708187 TI - Patterns of adult stepping cadence in the 2005-2006 NHANES. AB - OBJECTIVE: Laboratory studies of adult walking behavior have consistently found that a cadence of 100 steps/min is a reasonable threshold for moderate intensity. The purpose of this study was to determine cadence patterns in free-living adults, and in particular, time spent at increasing cadence increments including 100 steps/min and beyond. METHOD: 3744 adults >=20 years provided at least one valid day (minimally 10/24 h of wear) of minute-by-minute accelerometer determined step data during the 2005-2006 U.S. National Health and Nutrition Examination Survey (NHANES). Means for time spent (min/day) and steps/day were calculated for 8 cadence categories including zero and each incremental cadence band thereafter beginning with 1-19 through 100-119, and beyond to 120+steps/min. RESULTS: U.S. adults accumulate ?4.8 h/day of zero cadence during wearing time, ?8.7 h between 1 and 59 steps/min, ?16 min/day at cadences of 60-79 steps/min, ?8 min at 80-99 steps/min, ?5 min at 100-119 steps/min, and ?2 min at 120+steps/min. CONCLUSION: Self-selected walking at 100+steps/min was a rare phenomenon in this large free-living sample of the U.S. population, but study participants did accumulate ?30 min/day at cadences of 60+steps/min. PMID- 21708188 TI - Composition and bioactivity of polysaccharides from tea seeds obtained by water extraction. AB - In this paper, the composition and biological activities of polysaccharides from tea seed (TSPS) obtained by water extraction were investigated. The properties and chemical compositions of TSPS were analyzed with HPGPC, IC, and IR methods. The results showed that TSPS consisted of three kinds of polysaccharides with the molecular weight of 500 kDa, 130 kDa, and 5 kDa. TSPS consisted of rhamnose, xylose, arabinose, glucose and galactose, GalA, GulA, with a molar ratio of 4.9:1.7:11.1:27.2:14.0:3.4:1, sugar backbone of TSPS might consist of glucose, but branched chain may consist of rhamnose, xylose, arabinose, and galactose. The IR spectrum of TSPS revealed the typical characteristics of polysaccharides and protein. TSPS significantly inhibited the growth of K562 cells, especially, at the concentration of 50 MUg/ml; the inhibition activity of TSPS was the highest with an inhibition ratio beyond 38.44+/-2.22% (P<0.01). TSPS with high concentrations (100, 200 and 400 MUg/ml) had higher proliferation effect on lymphocyte. Results of these studies demonstrated that the polysaccharide had a potential application as natural antitumor drugs. PMID- 21708189 TI - Alterations of RNA maps of IncP-7 plasmid pCAR1 in various Pseudomonas bacteria. AB - RNA transcripts from 199-kb incompatibility P-7 plasmid pCAR1 were analyzed using microarrays with evenly tiled probes with a nine-nucleotide offset in six different Pseudomonas host strains. We re-annotated 12 ORFs based on their RNA maps and on the comparisons with other sequenced IncP-7 plasmids. Ninety six of two hundred ORFs were identified on the IncP-7 backbone related to basic functions of the plasmid (replication, partition and conjugative transfer). More than 90% ORFs on the backbone were transcribed in each host strain, suggesting their importance for the plasmid survival in the host strains. Genes related to partition and conjugative transfer were differentially transcribed host by host, whereas the repA gene encoding replication initiation protein was transcribed at comparable level in each host. As for other plasmid 'accessory genes' of pCAR1 encoding carbazole degradation, putative transporter, or transposase were also differentially transcribed among different host strains. These differences may have resulted in distinct behaviors of the plasmid or of its host strain, and RNA maps of pCAR1 give us important information to understand the plasmid behaviors in different environments. PMID- 21708191 TI - FoxO transcription factors; Regulation by AKT and 14-3-3 proteins. AB - The forkhead box O (FoxO) transcription factor family is a key player in an evolutionary conserved pathway downstream of insulin and insulin-like growth factor receptors. The mammalian FoxO family consists of FoxO1, 3, 4 and 6, which share high similarity in their structure, function and regulation. FoxO proteins are involved in diverse cellular and physiological processes including cell proliferation, apoptosis, reactive oxygen species (ROS) response, longevity, cancer and regulation of cell cycle and metabolism. The regulation of FoxO protein function involves an intricate network of posttranslational modifications and protein-protein interactions that provide integrated cellular response to changing physiological conditions and cues. AKT was identified in early genetic and biochemical studies as a main regulator of FoxO function in diverse organisms. Though other FoxO regulatory pathways and mechanisms have been delineated since, AKT remains a key regulator of the pathway. The present review summarizes the current knowledge of FoxO regulation by AKT and 14-3-3 proteins, focusing on its mechanistic and structural aspects and discusses its crosstalk with the other FoxO regulatory mechanisms. This article is part of a Special Issue entitled: PI3K-AKT-FoxO axis in cancer and aging. PMID- 21708190 TI - An efficient method for the long-term and specific expression of exogenous cDNAs in cultured Purkinje neurons. AB - We present a simple and efficient method for expressing cDNAs in Purkinje neurons (PNs) present in heterogeneous mouse cerebellar cultures. The method combines the transfection of freshly dissociated cerebellar cells via nucleofection with the use of novel expression plasmids containing a fragment of the L7 (Pcp2) gene that, within the cerebellum, drives PN-specific expression. The efficiency of PN transfection (determined 13 days post nucleofection) is approximately 70%. Double and triple transfections are routinely achieved at slightly lower efficiencies. Expression in PNs is obvious after one week in culture and still strong after three weeks, by which time these neurons are well-developed. Moreover, high-level expression is restricted almost exclusively to the PNs present in these mixed cultures, which greatly facilitates the characterization of PN-specific functions. As proof of principle, we used this method to visualize (1) the morphology of living PNs expressing mGFP, (2) the localization and dynamics of the dendritic spine proteins PSD-93 and Homer-3a tagged with mGFP and (3) the interaction of live PNs expressing mGFP with other cerebellar neurons expressing mCherry from a beta-Actin promoter plasmid. Finally, we created a series of L7 plasmids containing different fluorescent protein cDNAs that are suited for the expression of cDNAs of interest as N- and C-terminally tagged fluorescent fusion proteins. In summary, this procedure allows for the highly efficient, long-term, and specific expression of multiple cDNAs in differentiated PNs, and provides a favorable alternative to two procedures (viral transduction, ballistic gene delivery) used previously to express genes in cultured PNs. PMID- 21708192 TI - Are individuals with paradoxical insomnia more hyperaroused than individuals with psychophysiological insomnia? Event-related potentials measures at the peri-onset of sleep. AB - Preliminary QEEG studies suggest that individuals with paradoxical insomnia (Para I) display higher cortical arousal than those with psychophysiological insomnia (Psy-I). Lately, finer measures, such as event-related potentials, and especially the N1 and P2 components have been used to document arousal processes in individuals with insomnia. The objective of the present study was to further circumscribe arousal in Psy-I and Para-I using N1, P2 and the waking processing negativity (wPN). N1 and P2 were recorded in the evening, at sleep-onset and in early stage 2 sleep in 26 good sleepers, 26 Psy-I and 26 Para-I. An oddball paradigm was used and participants received the instruction to ignore all stimuli at all times. Three difference waves (wPNs) were computed to evaluate the transition from wakefulness to sleep onset, from sleep onset to sleep and from wakefulness to sleep. Results revealed that N1 was smaller during wakefulness and sleep onset for Psy-I, while it was larger for Para-I during these same times. P2 was smaller at sleep onset for Psy-I than for Para-I and GS, while P2 during wakefulness and stage 2 sleep was larger for Para-I than GS. WPNs revealed that Psy-I showed fewer changes in information processing, while Para-I showed larger changes between recording times. Psy-I appear to present an inability to inhibit information processing during sleep onset, while Para-I seem to present overall enhanced attentional processing that results in a greater need for inhibition. PMID- 21708193 TI - A novel system for rapid screening of effective siRNA target sites by one step transfection with a single vector. AB - siRNA technique has been widely used to study the gene functions and to develop disease therapeutics. One of the challenges of RNAi application is to obtain the most effective target specific siRNA sequences. Currently the process to select and validate optimal siRNA sites for a given gene, which is usually based on screening by using Western blot, Northern blot or Q-PCR, remains empirical and time consuming. Although few fluorescence-based siRNA sequence selection systems have proven useful, the rapid and efficient screening of siRNA target sites is still challenging. In the paper, we developed a quick and efficient method to screen siRNA target sites with a novel single vector system, which contains the following cassettes: (1) an eGFP reporter gene expression cassette followed by a multiple cloning site and SV40 pA for insertion of a target sequence; (2) siRNA expression cassette containing a dual PoI III promoter driving in opposite directions; and (3) an internal loading control, mCherry reporter gene. Based on this one-step transfection with single vector system, we could rapidly screen effective, target specific siRNA fragments in an unbiased manner by judging the fluorescence intensity ratio of eGFP to mCherry. The generation of this novel vector system will promote the application of siRNA in basic research and disease therapy. PMID- 21708194 TI - Recombination-dependent concatemeric viral DNA replication. AB - The initiation of viral double stranded (ds) DNA replication involves proteins that recruit and load the replisome at the replication origin (ori). Any block in replication fork progression or a programmed barrier may act as a factor for ori independent remodelling and assembly of a new replisome at the stalled fork. Then replication initiation becomes dependent on recombination proteins, a process called recombination-dependent replication (RDR). RDR, which is recognized as being important for replication restart and stability in all living organisms, plays an essential role in the replication cycle of many dsDNA viruses. The SPP1 virus, which infects Bacillus subtilis cells, serves as a paradigm to understand the links between replication and recombination in circular dsDNA viruses. SPP1 encoded initiator and replisome assembly proteins control the onset of viral replication and direct the recruitment of host-encoded replisomal components at viral oriL. SPP1 uses replication fork reactivation to switch from ori-dependent theta-type (circle-to-circle) replication to sigma-type RDR. Replication fork arrest leads to a double strand break that is processed by viral-encoded factors to generate a D-loop into which a new replisome is assembled, leading to sigma type viral replication. SPP1 RDR proteins are compared with similar proteins encoded by other viruses and their possible in vivo roles are discussed. PMID- 21708195 TI - Infectious dengue-1 virus entry into mosquito C6/36 cells. AB - The entry of dengue virus-1 (DENV-1) strain Hawaii into mosquito C6/36 cells was analyzed using a variety of biochemical inhibitors together with electron microscopy. The treatment with ammonium chloride, chlorpromazine, dansylcadaverine and dynasore inhibited virus yields, determined by infectivity titrations, whereas nystatin and methyl-beta-cyclodextrin did not have any effect. The effect of the clathrin and dynamin inhibitors on DENV-1 entry was corroborated by detection of internalized virions using immunofluorescence staining. Furthermore, electron micrographs showed the incoming virions attached to electron-dense invaginations of the plasma membrane and within coated vesicles that resembled clathrin-coated pits and vesicles, respectively. The susceptibility to clathrin and dynamin inhibitors of clinical isolates from recent outbreaks was comparable to that shown by the cell culture-adapted reference strain. Similarly, DENV-3 strain H87 and DENV-4 strain 8124 were also inhibited in the presence of ammonium chloride, chlorpromazine and dynasore, allowing conclude that the infectious entry of DENV serotypes to mosquito cells occurs by low pH-dependent clathrin-mediated endocytosis. PMID- 21708197 TI - Focus. PMID- 21708198 TI - RANTES antagonism: a promising approach to treat chronic liver diseases. AB - Activation of hepatic stellate cells in response to chronic inflammation represents a crucial step in the development of liver fibrosis. However, the molecules involved in the interaction between immune cells and stellate cells remain obscure. Herein, we identify the chemokine CCL5 (also known as RANTES), which is induced in murine and human liver after injury, as a central mediator of this interaction. First, we showed in patients with liver fibrosis that CCL5 haplotypes and intrahepatic CCL5 mRNA expression were associated with severe liver fibrosis. Consistent with this, we detected Ccl5 mRNA and CCL5 protein in 2 mouse models of liver fibrosis, induced by either injection of carbon tetrachloride (CCl(4)) or feeding on a methionine and choline-deficient (MCD) diet. In these models, Ccl5(-/-) mice exhibited decreased hepatic fibrosis, with reduced stellate cell activation and immune cell infiltration. Transplantation of Ccl5-deficient bone marrow into WT recipients attenuated liver fibrosis, identifying infiltrating hematopoietic cells as the main source of Ccl5. We then showed that treatment with the CCL5 receptor antagonist Met-CCL5 inhibited cultured stellate cell migration, proliferation, and chemokine and collagen secretion. Importantly, in vivo administration of Met-CCL5 greatly ameliorated liver fibrosis in mice and was able to accelerate fibrosis regression. Our results define a successful therapeutic approach to reduce experimental liver fibrosis by antagonizing Ccl5 receptors. PMID- 21708196 TI - An injectable synthetic immune-priming center mediates efficient T-cell class switching and T-helper 1 response against B cell lymphoma. AB - Patients with malignant non-Hodgkin's lymphomas (NHL) of B-cell lineages relapse despite initial anti-tumor response to chemotherapy or antibody treatments. Failure to eliminate the tumor is often because of inadequate priming, low cell numbers and suboptimal phenotype of effector T cells. Here we describe a new biomaterial-based controlled-release paradigm to treat weakly immunogenic NHLs by in-situ amplifying the number of functional, antigen-specific T-helper 1 (Th1) cells following immunotherapy. An injectable, synthetic immune priming center (sIPC) consisting of an in-situ crosslinking, chemokine-carrying hydrogel and both DNA- and siRNA dual-loaded microparticles, is reported. This sIPC chemo attracts a large number of immature dendritic cells (DCs) at the site of administration and efficiently co-delivers both DNA antigens and interleukin-10 (IL10)-silencing siRNA to those cells. Using a murine model of A20 B cell lymphoma, we demonstrate that combination of DNA-antigen delivery and IL10 silencing, synergistically activate recruited immature DCs and cause a strong shift towards Th1 response while suppressing Th2 and Th17 cytokines. sIPC-based immunotherapy showed 45% more CD8+ cytotoxic T cell (CTL) response and 53% stronger CD4+ CTL activity compared to naked DNA vaccine. In addition, in-vivo sIPC immunization induced significant protection (p<0.01) against subsequent tumor challenge. Such a multi-modal, injectable system that simultaneously delivers chemokines, siRNA and DNA antigens to DCs marks a new approach to in situ priming and modulation during immunotherapy and could provide effective vaccination strategies against cancers and infectious diseases. PMID- 21708199 TI - NASH animal models: are we there yet? PMID- 21708200 TI - Oral combination therapy: future hepatitis C virus treatment? PMID- 21708201 TI - Safe drugs to fight mutant protein overload and alpha-1-antitrypsin deficiency. PMID- 21708202 TI - Exploring quality of life in families of children living with and without a severe food allergy. AB - This study aimed to explore the impact of food allergy on quality of life in children with food allergy and their primary caregivers, compared to a healthy non-food allergy comparison group. Food allergy children (n=34) and control children (n=15), aged 8-12, and their respective primary caregivers (n=30/n=13), completed generic quality of life scales (PedsQLTM and WHOQOLBREF) and were asked to take photographs and keep a diary about factors that they believed enhanced and/or limited their quality of life, over a one-week period. Questionnaire analysis showed that parents of children with food allergy had significantly lower quality of life in the social relationships domain and lower overall quality of life than the comparison parents. In contrast, children with food allergy had similar or higher quality of life scores compared to comparison children. Content analysis of photograph and diary data identified ten themes that influenced both child and parental quality of life. It was concluded that although food allergy influenced quality of life for some children, their parent's quality of life was hindered to a greater extent. The variability in findings highlights the importance of assessing quality of life in individual families, considering both children with allergies and their primary caregivers. PMID- 21708203 TI - Diversity distributions of killer cell immunoglobulin-like receptor genes and their ligands in the Chinese Shaanxi Han population. AB - In the present study, 17 killer cell immunoglobulin-like receptors (KIR) genes and KIR ligands (human leukocyte antigen [HLA] -A and -B) were detected by using a polymerase chain reaction-sequence-specific primer (PCR-SSP) method in 104 unrelated healthy Han individuals living in Shaanxi province, China. The observed carrier frequencies of the 12 KIR genes ranged from 0.14 to 0.96. KIR2DL4, 3DL2, 3DL3, 2DP1 and 3DP1 were found to be present in every individual. A total of 51 different KIR gene profiles were identified, in which 11 gene profiles exclusively belonged to the study population. Neighbor-joining phylogenetic tree between the studing population and its neighboring ethnic groups was constructed using the observed carrier frequencies of 13 KIR loci. The phylogenetic tree shows that the Shaanxi Han population, Han populations in different regions, Yi, Japanese, and Koreans were in the same cluster. KIR/HLA relationships show that KIR3DS1(-)/3DL1(+)/Bw4(+) was the most common association in the population. In conclusion, the present study findings reveal the high polymorphism of KIRs in the Shaanxi Han population, demonstrate the KIR/HLA association in the study population, and enrich the KIR and HLA gene resources. The obtained KIR data will further the understanding of genetic relationships among populations in different geographic areas, and assist in answering questions regarding KIR/HLA relationships. PMID- 21708204 TI - Changes in cytokine production and composition of peripheral blood leukocytes during pregnancy are not associated with a difference in the proliferative immune response to the fetus. AB - We analyzed peripheral blood from women at term pregnancy for leukocyte composition, in vitro proliferative responses and cytokine production after nonspecific and fetus-specific stimulation. Maternal peripheral blood mononuclear cells (PBMCs) were collected and stimulated with umbilical cord blood (UCB) of the mother's own child, third-party UCB, nonspecific stimulus phytohemagglutinin, and anti-CD3 antibody, with PBMCs of nonpregnant women (cPBMC) as controls. Nine combinations of patient, child, third party child, and controls were selected on basis of sharing one human leukocyte antigen (HLA)-DR antigen. The response of mPBMC upon specific stimulation with fetal antigens was similar to that of cPBMC. No differences were found when comparing the mother's response upon stimulation to her own child with stimulation to that with a control child. Nonspecific stimulation with phytohemagglutinin and anti-CD3 antibody did not reveal a difference in proliferation rate between mPBMC and cPBMC. However, mPBMC contained a higher percentage of CD14(+) cells (p = 0.001) and activated T cells (CD25(dim), p < 0.0001), but a lower percentage CD16(-)CD56(bright) natural killer (NK) cells (p = 0.001) and CD16(+)CD56(+) NK cells (p = 0.003). mPBMC produced more interleukin (IL)-6, IL-10, and IL-17 compared with cPBMC (p < 0.05). We found differences in lymphocyte composition and cytokine production between mPBMC and cPBMC. These differences did not result in quantitative changes in proliferative responses during pregnancy compared with responses in nonpregnant controls. PMID- 21708205 TI - Development and efficacy of a novobiocin-resistant Streptococcus iniae as a novel vaccine in Nile tilapia (Oreochromis niloticus). AB - A novel attenuated Streptococcus iniae vaccine was developed from a virulent strain of Streptococcus iniae (ISET0901) through selection for novobiocin resistance (named ISNO). The safety of ISNO was then evaluated in Nile tilapia (Oreochromis niloticus) through intraperitoneal (IP) injection. When male tilapia (average weight 10 g) were IP injected with 2*10(7) colony-forming units (CFU) of the attenuated S. iniae vaccine strain, no fish died. However, when the same age and size matched tilapia were IP injected with 2*10(7) and 1*10(5)CFU of the virulent parent strain of S. iniae, 100 and 90% fish died, respectively. Backpassage safety studies revealed that ISNO was unable to revert back to a virulent state. When IP vaccinated fish were challenged by the virulent ISET0901 strain of S. iniae, relative percent survival (RPS) values of vaccinated fish at 14, 28, 60, 90, and 180 days post ISNO vaccination (dpv) were 100, 100, 100, 89, and 75%, respectively, The RPS values of ISNO vaccinated fish (IP vaccination) against infections by five heterologous virulent strains of S. iniae (F3CB, 102 F1K, 405 F1K, IF6, and ARS60) at 60 dpv were 78, 90, 100, 100, and 100%, respectively. When tilapia were IP vaccinated by ISNO at dose of 1*10(2), 1*10(3), 1*10(4), 1*10(5), 1*10(6), and 1*10(7)CFU/fish, RPS values at 28 dpv were 81, 94, 100, 100, 100, and 100%, respectively. At 28 dpv, RPS of vaccinated fish by ISNO through bath immersion (1*10(7)CFU/ml) was 88%. ELISA results revealed that protection elicited by ISNO was due to antibody- as well as cell- mediated immunity. Our results suggest that ISNO could be used as a novel safe and efficacious vaccine to protect Nile tilapia from S. iniae infections. PMID- 21708206 TI - Rural-urban differences in the location of influenza vaccine administration. AB - BACKGROUND: Influenza vaccination rates remain lower than Healthy People 2010 goals. The lower rates are prevalent in rural areas despite an expansion of services to nontraditional settings. Little is known about disparities in influenza vaccination rates and location of receipt among rural residents. This study seeks to determine if rural residents differ from urban residents in where they obtain an influenza vaccination, and to determine what factors contribute to these differences. METHODS: Data from 2002-2005 BRFSS were used and combined with the 2006 Area Resource File (analytic n=70,468, unweighted, 48,392,455 weighted). Unadjusted analyses examined the proportions of influenza vaccinations obtained in traditional clinical settings vs. others across rurality: Urban, Large Rural and Small Rural. Multivariable logistic regression models were conducted to identify individual and county-level factors associated with the higher rate of vaccinations in clinical settings. RESULTS: Rural residents, particularly in Small Rural counties (80.8%) were more dependent upon clinical settings than Urban residents (69.1%) for influenza vaccinations. In adjusted analyzes, living in a Large or Small Rural county remained significant related to an increased odds of being vaccinated in a clinical setting (OR 1.17, 95% CI 1.06-1.29 and OR 1.45, 95% CI 1.24-1.69 respectively). Other related contributory factors included socioeconomic factors, health status, health condition, and per capita income of the county. CONCLUSIONS: Rural residents depend upon traditional, clinical settings when an influenza vaccination is sought. The results can be used for further research and programs to improve access to and delivery of influenza vaccinations for disparate populations. PMID- 21708208 TI - The development of Dengue vaccines. Introduction. PMID- 21708209 TI - The contextual fear conditioning deficit presented by spontaneously hypertensive rats (SHR) is not improved by mood stabilizers. AB - OBJECTIVES: We have recently reported that spontaneously hypertensive rats (SHR) present a contextual fear conditioning (CFC) deficit. This deficit is improved by antipsychotic drugs, potentiated by proschizophrenia manipulations and not altered by acute administration of carbamazepine, lamotrigine and valproic acid. Nevertheless, the effects of lithium-a classical mood stabilizer-or repeated treatment with these drugs were not evaluated. The main aim of the present study was to extend our previous work by investigating a possible beneficial effect of acute and/or chronic treatments with lithium or lamotrigine on the acquisition deficit of CFC presented by SHR. METHODS: Rats were submitted to CFC task after an acute treatment with lithium and/or a repeated treatment with lithium and lamotrigine. RESULTS: Our data revealed that the CFC deficit presented by SHR is not improved by acute or repeated treatment with lithium. Repeated lamotrigine treatment potentiated the deficit presented by SHR and impaired CFC in control animals (Wistar Rats). CONCLUSIONS: These data reinforce the absence of beneficial effects of mood stabilizers on the emotional context processing impairment modeled by SHR. PMID- 21708207 TI - Strong viremia control in vaccinated macaques does not prevent gradual Th17 cell loss from central memory. AB - It has been proposed that microbial translocation might play a role in chronic immune activation during HIV/SIV infection. Key roles in fighting bacterial and fungal infections have been attributed to Th17 and Tc17 cells. Th17 cells can be infected with HIV/SIV, however whether effective vaccination leads to their maintenance following viral challenge has not been addressed. Here we retrospectively investigated if a vaccine regimen that potently reduced viremia post-challenge preserved Th17 and Tc17 cells, thus adding benefit in the absence of sterilizing protection. Rhesus macaques were previously vaccinated with replication-competent Adenovirus recombinants expressing HIVtat and HIVenv followed by Tat and gp140 protein boosting. Upon SHIV(89.6P) challenge, the vaccines exhibited a significant 4 log reduction in chronic viremia compared to sham vaccinated controls which rapidly progressed to AIDS [39]. Plasma and cryopreserved PBMC samples were examined pre-challenge and during acute and chronic infection. Control macaques exhibited a rapid loss of CD4(+) cells, including Th17 cells. Tc17 cells tended to decline over the course of infection although significance was not reached. Immune activation, assessed by Ki-67 expression, was associated with elevated chronic viremia of the controls. Significantly increased plasma IFN-gamma levels were also observed. No increase in plasma LPS levels were observed suggesting a lack of microbial translocation. In contrast, vaccinated macaques had no evidence of immune activation within the chronic phase and preserved both CD4(+) T-cells and Tc17 cells in PBMC. Nevertheless, they exhibited a gradual, significant loss of Th17 cells which concomitantly displayed significantly higher CCR6 expression over time. The gradual Th17 cell decline may reflect mucosal homing to inflammatory sites and/or slow depletion due to ongoing low levels of SHIV replication. Our results suggest that potent viremia reduction during chronic SHIV infection will delay but not prevent the loss of Th17 cells. PMID- 21708210 TI - State of the art in benefit-risk analysis: environmental health. AB - Environmental health assessment covers a broad area: virtually all systematic analysis to support decision making on issues relevant to environment and health. Consequently, various different approaches have been developed and applied for different needs within the broad field. In this paper we explore the plurality of approaches and attempt to reveal the state-of-the-art in environmental health assessment by characterizing and explicating the similarities and differences between them. A diverse, yet concise, set of approaches to environmental health assessment is analyzed in terms of nine attributes: purpose, problem owner, question, answer, process, use, interaction, performance and establishment. The conclusions of the analysis underline the multitude and complexity of issues in environmental health assessment as well as the variety of perspectives taken to address them. In response to the challenges, a tendency towards developing and applying more inclusive, pragmatic and integrative approaches can be identified. The most interesting aspects of environmental health assessment are found among these emerging approaches: (a) increasing engagement between assessment and management as well as stakeholders, (b) strive for framing assessments according to specific practical policy needs, (c) integration of multiple benefits and risks, as well as (d) explicit incorporation of both scientific facts and value statements in assessment. However, such approaches are yet to become established, and many contemporary mainstream environmental health assessment practices can still be characterized as relatively traditional risk assessment. PMID- 21708211 TI - Rapid mycotoxin analysis in human urine: a pilot study. AB - A simple and rapid method effective for quantitative determination of deoxynivalenol (DON), T-2 toxin (T-2), HT-2 toxin (HT-2), zearalenone (ZEN), ochratoxin A (OTA), aflatoxins (AFs) B(1), B(2), G(1) and G(2) and fumonisins FB(1) and FB(2) in urine was developed. The urine was diluted with phosphate buffer solution (PBS) and thoroughly mixed. For clean-up and extraction, the mixture was loaded on a MYCO 6in1 IAC. Hybrid triple quadrupole-linear ion trap mass spectrometer (QTrap) was used for the detection. Extra tools for confirmation of selected mycotoxins in positive samples, Information Dependent Acquisition (IDA) experiments, were also developed. The use of immunoaffinity columns followed by the LC-MS/MS analysis showed acceptable average recoveries between 83% and 116% and reached acceptable precision values (relative standard deviation (RSD) <= 14%). In a pilot study with 27 volunteers, OTA, DON and AFG(2) were detected. However, this study needs to be extended in order to understand the relation between the mycotoxins intake and mycotoxin levels in human urine. PMID- 21708213 TI - WITHDRAWN: Effects of choline on sodium arsenite-induced neural tube defects in chick embryos. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21708212 TI - Insights into cholinesterase inhibitory and antioxidant activities of five Juniperus species. AB - In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory and antioxidant activities of the aqueous and ethanol extracts of the leaves, ripe fruits, and unripe fruits of Juniperus communis ssp. nana, Juniperus oxycedrus ssp. oxycedrus, Juniperus sabina, Juniperus foetidissima, and Juniperus excelsa were investigated in the present study. Cholinesterase inhibition of the extracts was screened using ELISA microplate reader. Antioxidant activity of the extracts was tested by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radical scavenging, ferrous ion-chelating, and ferric-reducing antioxidant power (FRAP) assays. Total phenol and flavonoid contents of the extracts were determined spectrophotometrically. The extracts had low or no inhibition towards AChE, whereas the leaf aqueous extract of J. foetidissima showed the highest BChE inhibition (93.94 +/- 0.01%). The leaf extracts usually exerted higher antioxidant activity. We herein describe the first study on anticholinesterase and antioxidant activity by the methods of ferrous ion-chelating, superoxide radical scavenging, and ferric-reducing antioxidant power (FRAP) assays of the mentioned Juniperus species. PMID- 21708214 TI - Relationship between pulmonary and systemic markers of exposure to multiple types of welding particulate matter. AB - Welding results in a unique and complex occupational exposure. Recent epidemiological studies have shown an increased risk of cardiovascular disease following welding fume exposure. In this study, we compared the induction of pulmonary and systemic inflammation following exposure to multiple types of welding fumes. Mice were exposed to 340MUg of manual metal arc stainless steel (MMA-SS), gas metal arc-SS (GMA-SS) or GMA-mild steel (GMA-MS) by pharyngeal aspiration. Mice were sacrificed at 4 and 24h post-exposure to evaluate various parameters of pulmonary and systemic inflammation. Alterations in pulmonary gene expression by a custom designed TaqMan array showed minimal differences between the fumes at 4h. Conversely at 24h, gene expression changes were further increased by SS but not GMA-MS exposure. These findings were associated with the surrogate marker of systemic inflammation, liver acute phase gene induction. Interestingly, stress response genes in cardiovascular tissues were only increased following MMA-SS exposure. These effects were related to the initial level of pulmonary cytotoxicity, as measured by lactate dehydrogenase activity, which was greatest following MMA-SS exposure. In conclusion, varying types of welding fumes elicit quantitatively different systemic inflammatory and/or stress responses. PMID- 21708215 TI - Pharmacokinetics and pharmacodynamics of chlorpyrifos in adult male Long-Evans rats following repeated subcutaneous exposure to chlorpyrifos. AB - Chlorpyrifos (CPF) is a commonly used organophosphorus pesticide. Several pharmacokinetic and pharmacodynamic studies have been conducted in rats in which CPF was administered as a single bolus dose. However, there is limited data regarding the pharmacokinetics and pharmacodynamics following daily exposure. Since occupational exposures often consist of repeated, daily exposures, there is a need to evaluate the pharmacokinetics and pharmacodynamics of CPF under exposure conditions which more accurately reflect real world human exposures. In this study, the pharmacokinetics and pharmacodynamics of CPF were assessed in male Long-Evans rats exposed daily to CPF (0, 3 or 10mg/kg/day, s.c. in peanut oil) over a 10 day study period. Throughout the study, multiple pharmacokinetic (urinary TCPy levels and tissue CPF and metabolite levels) and pharmacodynamic (blood and brain AChE activity) determinants were measured. Average blood AChE activity on day 10 was 54% and 33% of baseline among animals in the 3 and 10mg/kg/day CPF treatment groups, respectively, while average brain AChE activity was 67% and 28% of baseline. Comparable dose-response relationships between brain AChE inhibition and blood AChE inhibition, suggests that blood AChE activity is a valid biomarker of brain AChE activity. The pharmacokinetic and pharmacodynamic measures collected in this study were also used to optimize a rat physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model for multiple s.c. exposures to CPF based on a previously published rat PBPK/PD model for CPF following a single bolus injection. This optimized model will be useful for determining pharmacokinetic and pharmacodynamic responses over a wide range of doses and durations of exposure, which will improve extrapolation of results between rats and humans. PMID- 21708216 TI - Negative regulation of NaF-induced apoptosis by Bad-CAII complex. AB - Fluoride is used to prevent caries in dentistry. However, its mechanism of cytotoxicity induction is unclear. This study was undertaken to determine whether sodium fluoride (NaF) induces apoptosis in human oral cells and if so, whether Bad protein is involved in the process. NaF showed higher cytotoxicity and apoptosis-inducing activity against human oral squamous cell carcinoma cells (HSC 2) than against human gingival fibroblasts (HGF). Western blot analysis showed that NaF enhanced the expression and dephosphorylation of Bad protein. This study demonstrates for the first time that Bad protein forms a complex with carbonic anhydrase II (CAII), and NaF stimulates the detachment of CAII from the Bad-CAII complex and the replacement by the formation of Bad-Bcl-2 complex. Knockdown of Bad and CAII mRNA by siRNA inhibited and enhanced the NaF-induced caspase activation, respectively. The present study suggests that CAII negatively regulates the NaF-induced apoptosis by forming a complex with Bad. PMID- 21708217 TI - Effects of prenatal and postnatal exposure to amitraz on norepinephrine, serotonin and dopamine levels in brain regions of male and female rats. AB - The effects of maternal exposure to amitraz on brain region monoamine levels of male and female offspring rats at 60 days of age were observed. Maternal and offspring body weight, physical and general activity development were unaffected by the exposure of dams to amitraz (20mg/kgbw, orally on days 6-21 of pregnancy and 1-10 of lactation). Male and female offspring were sacrificed at 60 days of age and possible alterations in the content and metabolism of NE, DA and 5-HT were determined in brain regions by HPLC. The results showed that all these neurotransmitter systems were altered in a brain regional-related manner. In male and female offspring, amitraz induced a significant decrease in the prefrontal cortex 5-HT and its metabolite 5-HIAA and DA and its metabolites DOPAC and HVA levels with interaction of sex. Nevertheless, we verified that striatum DA and 5 HT and corresponding metabolite contents decreased in male and female offspring without statistical distinction of sex. In contrast, amitraz did not modify 5-HT content, but caused an increase in 5-HIAA content in the medulla oblongata and hippocampus in male and female offspring. Alterations in the hippocampus DA, DOPAC and HVA levels after amitraz exposure were also observed displaying a sex interaction. NE levels also showed a decrease after amitraz treatment in the prefrontal cortex and striatum without statistical sex interaction, but MHPG levels decreased in both regions with a sex interaction. Amitraz evoked increases in 5-HT turnover in the prefrontal cortex as well as in DA turnover in the striatum and hippocampus but decreases in NE turnover in the hypothalamus, prefrontal cortex and striatum. The present findings indicated that maternal exposure to amitraz altered noradrenergic, serotonergic and dopaminergic neurochemistry in their offspring in the prefrontal cortex, striatum and hippocampus, and those variations could be related to several alterations in the functions in which these brain regions are involved. PMID- 21708218 TI - Calcium signaling during the early development of medaka and zebrafish. AB - The ex-utero fertilization and development of the optically clear embryos of teleost fish have long been favorites of developmental biologists. They have, therefore, provided considerable insight with regards to our understanding of embryonic pattern formation and the early development of vertebrates. These attributes have also been most helpful in the visualization of Ca(2+) signaling events that have been reported to accompany many of the fundamental steps and processes that constitute early embryonic development. These include egg activation; segregation of the cytoplasm from the yolk; cytokinesis; axis determination; cellular rearrangement and germ layer establishment; as well as the formation of the first tissue domains. The developing eggs and embryos of medaka (Oryzias latipes) and zebrafish (Danio rerio) have for many decades been a favorite choice of investigators attempting to visualize Ca(2+) signaling events. In this short review, we have attempted to catalog and present a comparative study of the developmental Ca(2+) signals recorded in these most amenable of vertebrate models. PMID- 21708221 TI - Analysis of codon usage in type 1 and the new genotypes of duck hepatitis virus. AB - In this study, an abundant (A+U)% and low codon bias were revealed in duck hepatitis virus type 1 (DHV-1) and the new serotype strains isolated from Taiwan, South Korea and Mainland China (DHV-N). The general correlation between base composition and codon usage bias suggests that mutational pressure rather than natural selection is the main factor that determines the codon usage bias in these samples. By comparative analysis of the codon usage patterns of 40 ORFs of DHV, we found that all of DHV-1 strains grouped in genotype C; the DHV-N strains isolated in South Korea and China clustered into genotypes B; and the DHV-N strains isolated from Taiwan clustered into genotypes A. The findings revealed that more than one subtype of DHV-1 circulated in East Asia. Furthermore, the results of phylogenetic analyses based on RSCU values and Clustal W method indicated obvious phylogenetic congruities. This suggested that better genome consistency of DHV may exist in nature and phylogenetic analyses based on RSCU values maybe a good method in classifying genotypes of the virus. Our work might give some clues to the features and some evolutionary information of DHV. PMID- 21708222 TI - Robustness of metabolic networks: a review of existing definitions. AB - Describing the determinants of robustness of biological systems has become one of the central questions in systems biology. Despite the increasing research efforts, it has proven difficult to arrive at a unifying definition for this important concept. We argue that this is due to the multifaceted nature of the concept of robustness and the possibility to formally capture it at different levels of systemic formalisms (e.g., topology and dynamic behavior). Here we provide a comprehensive review of the existing definitions of robustness pertaining to metabolic networks. As kinetic approaches have been excellently reviewed elsewhere, we focus on definitions of robustness proposed within graph theoretic and constraint-based formalisms. PMID- 21708223 TI - Hydroxysteroid (17beta) dehydrogenase X in human health and disease. AB - Hydroxysteroid (17beta) dehydrogenase 10 (HSD10), the HSD17B10 gene product, is a mitochondrial NAD(+)-dependent dehydrogenase. There are two outstanding features of this vital enzyme: (a) the versatility of its catalytic endowment is attributed to the flexibility of its active site to accommodate diverse substrates such as steroids, fatty acids, bile acid, and xenobiotics; (b) its capacity to bind other proteins and peptides. For example, it tightly binds with three identical subunits to compose a homotetramer. The homotetramer then binds with two other proteins, namely, RNA (guanine-9-)methyl-transferase domain containing-1 and KIAA0391, to form mitochondrial RNase P. Furthermore, various HSD10 functions are inhibited when the enzyme is bound by amyloid-beta peptide or estrogen receptor alpha. Missense mutations of HSD10 may cause neurodegeneration related to HSD10 deficiency, whereas a silent mutation of HSD10 results in mental retardation, choreoathetosis and abnormal behavior (MRXS10). The clinical condition of some HSD10 patients mimics mitochondrial disorders. Since normal HSD10 function is essential for brain cognitive activity, elevated levels of HSD10 found in brains of Alzheimer disease (AD) patients and mouse AD model might counterbalance the inhibition of HSD10 by amyloid-beta peptide. The investigation of HSD10 may lead to a better understanding of AD pathogenesis. PMID- 21708224 TI - No exercise-induced increase in serum BDNF after cycling near a major traffic road. AB - Commuting by bike has a clear health enhancing effect. Moreover, regular exercise is known to improve brain plasticity, which results in enhanced cognition and memory performance. Animal research has clearly shown that exercise upregulates brain-derived neurotrophic factor (BDNF - a neurotrophine) enhancing brain plasticity. Studies in humans found an increase in serum BDNF concentration in response to an acute exercise bout. Recently, more evidence is emerging suggesting that exposure to air pollution (such as particulate matter (PM)) is higher in commuter cyclists compared to car drivers. Furthermore, exposure to PM is linked to negative neurological effects, such as neuroinflammation and cognitive decline. We carried-out a cross-over experiment to examine the acute effect of exercise on serum BDNF, and the potential effect-modification by exposure to traffic-related air pollution. Thirty eight physically fit, non asthmatic volunteers (mean age: 43, 26% women) performed two cycling trials, one near a major traffic road (Antwerp Ring, R1, up to 260,000 vehicles per day) and one in an air-filtered room. The air-filtered room was created by reducing fine particles as well as ultrafine particles (UFP). PM10, PM2.5 and UFP were measured. The duration (~20min) and intensity of cycling were kept the same for each volunteer for both cycling trials. Serum BDNF concentrations were measured before and 30min after each cycling trial. Average concentrations of PM10 and PM2.5 were 64.9MUg/m(3) and 24.6MUg/m(3) in cycling near a major ring way, in contrast to 7.7MUg/m(3) and 2.0MUg/m(3) in the air-filtered room. Average concentrations of UFP were 28,180 particles/cm(3) along the road in contrast to 496 particles/cm(3) in the air-filtered room. As expected, exercise significantly increased serum BDNF concentration after cycling in the air-filtered room (+14.4%; p=0.02). In contrast, serum BDNF concentrations did not increase after cycling near the major traffic route (+0.5%; p=0.42). Although active commuting is considered to be beneficial for health, this health enhancing effect could be negatively influenced by exercising in an environment with high concentrations of PM. Whether this effect is also present with chronic exercise and chronic exposure must be further elucidated. PMID- 21708225 TI - Adenosine monophosphate-activated protein kinase and peroxisome proliferator activated receptor gamma coactivator 1alpha signaling provides neuroprotection in status epilepticus in rats. AB - Status epilepticus (SE) can cause severe neuronal loss and oxidative damage. Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) can be neuroprotective by inducing the antioxidant system, so we evaluated the role of PGC-1alpha in SE. The expression of PGC-1alpha and one of its target genes, uncoupling protein 2 (UCP2), was upregulated after SE, which may represent an endogenous neuroprotective mechanism. Furthermore, pretreatment with an adenosine monophosphate-activated protein kinase (AMPK) inhibitor significantly attenuated both AMPK and PGC-1alpha activation, followed by downregulation of UCP2 and enhanced oxidative stress and hippocampal neuronal damage. AMPK/PGC 1alpha may be neuroprotective in SE-induced brain damage, at least in part via UCP2. PMID- 21708219 TI - Cholinergic modulation of cognition: insights from human pharmacological functional neuroimaging. AB - Evidence from lesion and cortical-slice studies implicate the neocortical cholinergic system in the modulation of sensory, attentional and memory processing. In this review we consider findings from sixty-three healthy human cholinergic functional neuroimaging studies that probe interactions of cholinergic drugs with brain activation profiles, and relate these to contemporary neurobiological models. Consistent patterns that emerge are: (1) the direction of cholinergic modulation of sensory cortex activations depends upon top-down influences; (2) cholinergic hyperstimulation reduces top-down selective modulation of sensory cortices; (3) cholinergic hyperstimulation interacts with task-specific frontoparietal activations according to one of several patterns, including: suppression of parietal-mediated reorienting; decreasing 'effort' associated activations in prefrontal regions; and deactivation of a 'resting state network' in medial cortex, with reciprocal recruitment of dorsolateral frontoparietal regions during performance-challenging conditions; (4) encoding related activations in both neocortical and hippocampal regions are disrupted by cholinergic blockade, or enhanced with cholinergic stimulation, while the opposite profile is observed during retrieval; (5) many examples exist of an 'inverted-U shaped' pattern of cholinergic influences by which the direction of functional neural activation (and performance) depends upon both task (e.g. relative difficulty) and subject (e.g. age) factors. Overall, human cholinergic functional neuroimaging studies both corroborate and extend physiological accounts of cholinergic function arising from other experimental contexts, while providing mechanistic insights into cholinergic-acting drugs and their potential clinical applications. PMID- 21708226 TI - Monocyte-endothelium-smooth muscle cell interaction in co-culture: proliferation and cytokine productions in response to advanced glycation end products. AB - BACKGROUND: During hyperglycemia, reducing sugars react with the amino groups to form Amadori products which then form advanced glycation end-products (AGEs). Studies have shown that the AGEs and the receptor binding generated reactive oxygen species, and triggered secretion of cytokines contributing to the local regulations of proliferation and inflammation in cells. Interaction of vessel wall cells and monocytes may trigger the processes leading to atherosclerosis. We evaluated the effects of AGEs on smooth muscle cell (SMC) proliferation and cytokine synthesis in co-cultures of human monocytes (THP-1), endothelial cells (HUVEC) and aortic vascular smooth muscle cell (SMC) to clarify the effects of AGEs on vascular cells and to investigate the mechanisms of arteriosclerosis. METHODS: Glycolaldehyde-induced AGEs (glycol-AGEs) was prepared. The THP-1 and HUVEC were cultured with SMC in transwell plates with 100 MUg/ml of glycol-AGEs for 24 to 48 h. RESULTS: The proliferation of SMC was induced by glycol-AGEs in the co-culture system. Moreover, SMC treated with glycol-AGEs also expressed interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), and the level of cytokines expression was significantly elevated in the co-culture system of HUVEC and THP-1 when treated with glycol-AGEs. CONCLUSION: These results suggest that employing a co-culture system is necessary to investigate the synergistic effects of AGEs on intercellular cellular interactions and it creates a more in vivo-like environment for AGEs implicated atherosclerosis research. GENERAL SIGNIFICANCE: All three cell types are required to be investigated together to understand the effects of AGEs on intercellular interactions occurring among these cells. PMID- 21708227 TI - Profiling of isoflavonoids in Iris germanica rhizome extracts by microprobe NMR and HPLC-PDA-MS analysis. AB - Lipophilic and polar extracts of iris rhizomes (Iris germanica) were submitted to a phytochemical profiling by a combination of HPLC-PDA-MS and semi-preparative HPLC/off-line microprobe NMR measurements. A total of 20 compounds were purified in sub-milligram to milligram amounts via two successive chromatographic steps. They were identified as isoflavones, isoflavone glycosides and acetovanillone by analysis of on-line MS and PDA, and off-line NMR data. A new isoflavone glycoside, iriflogenin-4'-O-gentiobioside, was subsequently isolated at preparative scale for full chemical characterization. This study demonstrates the applicability of the HPLC/off-line microprobe NMR approach as a robust means for rapid phytochemical profiling of plant extracts. PMID- 21708228 TI - Spice oil cinnamaldehyde exhibits potent anticandidal activity against fluconazole resistant clinical isolates. AB - Fluconazole resistance is becoming an important clinical concern. We studied the in vitro effects of cinnamaldehyde against 18 fluconazole-resistant Candida isolates. MIC(90) of cinnamaldehyde against different Candida isolates ranged 100 500 MUg/ml. Growth and sensitivity of the organisms were significantly affected by cinnamaldehyde at different concentrations. The rapid irreversible action of this compound on fungal cells suggested membrane-located targets for its action. Insight studies to mechanism suggested that cinnamaldehyde exerts its antifungal activity by targeting sterol biosynthesis and plasma membrane ATPase activity. Inhibition of H(+) (-)ATPase leads to intracellular acidification and cell death. Toxicity against H9c2 rat cardiac myoblasts was studied to exclude the possibility of further associated cytotoxicity. The observed selectively fungicidal characteristics against fluconazole-resistant Candida isolates signify a promising candidature of this essential oil as an antifungal agent in treatments for candidosis. PMID- 21708229 TI - Detection and characterization of interleukin-6 gene variants in Canis familiaris: association studies with periodontal disease. AB - Periodontal disease (PD) is the most common inflammatory disease of the oral cavity of domestic carnivores. In Human Medicine molecular genetics research showed that several genes play a role in the predisposition and progression of this complex disease, primarily through the regulation of inflammatory mediators, but the exactly mechanisms are poorly understood. This study aims to contribute to the characterization of the genetic basis of PD in the dog, a classically accepted model in Periodontology. We searched for genetic variations in the interleukin-6 (IL6) gene, in order to verify its association with PD in a case control study including 25 dogs in the PD case group and 45 dogs in the control group. We indentified and characterized three new genetic variations in IL6 gene. No statistically significant differences were detected between the control and PD cases groups. Our results do not support an evidence for a major role contribution of these variants in the susceptibility to PD in the analyzed population. Nevertheless, the sequence variant I/5_g.105G>A leads to an amino acid change (arginine to glutamine) and was predicted to be possibly damaging to the IL6 protein. A larger cohort and functional studies would be of extreme importance in a near future to understand the possible role of IL6 variants in this disease. PMID- 21708230 TI - Proteome profile of maize (Zea Mays L.) leaf tissue at the flowering stage after long-term adjustment to rice black-streaked dwarf virus infection. AB - Maize rough dwarf disease (MRDD) is a viral disease and causes great yield loss. To better understand the effects of MRDD on plant growth and metabolism, comparative proteomic analysis of leaves from virus-infected and normal plants was performed. In order to eliminate the interference of Ribulose-1, 5 bisphosphate carboxylase with low-abundance proteins, total proteins were pre fractionated by 15% PEG and the proteins from supernatant and precipitated fractions were analyzed by 2-DE, subsequently. Out of approximately 1200 protein spots detected, less than 2% of the spots on the gels were overlapping between the fractions of precipitation and supernatant. We identified 91 differentially accumulated proteins that belong to multiple metabolic/biochemical pathways in plants. Further analysis of these identified proteins indicated that MRDD resulted in dramatic changes in the fundamental metabolism, including glycolysis and starch metabolism, and eventually the significant differences in morphology and development between virus-infected and normal plants. Moreover, MRDD occurrence increased the demands for G-proteins, antioxidant enzymes, lipoxygenases and UDP-glucosyltransferase BX9, which may play important roles in response of plant against virus infection. The results also suggested that MRDD is a complicated disease controlled by multigene participating in different pathways. PMID- 21708231 TI - Transcriptional regulation of antioxidant enzymes by FoxO1 under dehydration stress. AB - Antioxidant defenses are an important part of adaptation to environmental stress for many organisms. This study analyzed responses to dehydration stress by manganese-dependent superoxide dismutase (MnSOD) and catalase, and the role of forkhead box class O type 1 (FoxO1) transcription factor in regulating their up regulation, in selected tissues of the African clawed frogs, Xenopus laevis. Protein and mRNA levels of MnSOD and catalase were analyzed by immunoblotting and PCR. Analysis of FoxO1 included protein and phosphoprotein (FoxO1(ser245)) levels, nuclear versus cytoplasmic distribution, and FoxO1 binding to DNA. MnSOD protein increased significantly in the liver during dehydration whereas catalase rose in the liver and skeletal muscle. This was supported in liver by 1.5-2.2 fold increases in MnSOD and catalase mRNA levels. FoxO1 transcriptional activity was enhanced in liver of dehydrated versus control frogs as evidenced by: (a) 1.8 fold increase in FoxO1 protein in the nucleus, (b) strong decreases in inactive phosphorylated FoxO1(ser245) in total and nuclear extracts, and (c) a 57% increase in FoxO1 binding to DNA in nuclear extracts. The study documents up regulation of MnSOD and catalase in frog organs during dehydration and indicates a role for FoxO1 in controlling expression of these genes in liver. Dehydration rehydration has components of an ischemia-reperfusion event and the oxidative stress that this generates appears to be effectively addressed, at least in X. laevis liver, by enhanced production of antioxidant enzymes under FoxO1 regulation. PMID- 21708220 TI - Beyond faithful conduction: short-term dynamics, neuromodulation, and long-term regulation of spike propagation in the axon. AB - Most spiking neurons are divided into functional compartments: a dendritic input region, a soma, a site of action potential initiation, an axon trunk and its collaterals for propagation of action potentials, and distal arborizations and terminals carrying the output synapses. The axon trunk and lower order branches are probably the most neglected and are often assumed to do nothing more than faithfully conducting action potentials. Nevertheless, there are numerous reports of complex membrane properties in non-synaptic axonal regions, owing to the presence of a multitude of different ion channels. Many different types of sodium and potassium channels have been described in axons, as well as calcium transients and hyperpolarization-activated inward currents. The complex time- and voltage-dependence resulting from the properties of ion channels can lead to activity-dependent changes in spike shape and resting potential, affecting the temporal fidelity of spike conduction. Neural coding can be altered by activity dependent changes in conduction velocity, spike failures, and ectopic spike initiation. This is true under normal physiological conditions, and relevant for a number of neuropathies that lead to abnormal excitability. In addition, a growing number of studies show that the axon trunk can express receptors to glutamate, GABA, acetylcholine or biogenic amines, changing the relative contribution of some channels to axonal excitability and therefore rendering the contribution of this compartment to neural coding conditional on the presence of neuromodulators. Long-term regulatory processes, both during development and in the context of activity-dependent plasticity may also affect axonal properties to an underappreciated extent. PMID- 21708232 TI - Functional activity of the novel Alzheimer's amyloid beta-peptide interacting domain (AbetaID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis. AB - Amyloid-beta peptide (Abeta) plaque in the brain is the primary (post mortem) diagnostic criterion of Alzheimer's disease (AD). The physiological role(s) of Abeta are poorly understood. We have previously determined an Abeta interacting domain (AbetaID) in the promoters of AD-associated genes (Maloney and Lahiri, 2011. Gene. 15,doi:10.1016/j.gene.2011.06.004. epub ahead of print.). This AbetaID interacts in a DNA sequence-specific manner with Abeta. We now demonstrate novel Abeta activity as a possible transcription factor. Herein, we detected Abeta-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma (SK-N-SH) cells treated with FITC conjugated Abeta1-40 localized Abeta to the nucleus in the presence of H2O2-mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter-luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter-CAT fusion clones. Transfected cells were treated with different Abeta peptides and/or H2O2. Abeta treatment of cell cultures produced a DNA sequence-specific response in cells transfected with polymorphic APP clones. Our results suggest the Abeta peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD. PMID- 21708233 TI - Toxicokinetics of bis(2-chloroethoxy)methane following intravenous administration and dermal application in male and female F344/N rats and B6C3F1 mice. AB - In the National Toxicology Program's toxicity studies, rats were more sensitive than mice to Bis(2-chloroethoxy)methane (CEM) - induced cardiac toxicity following dermal application to male and female F344/N rats and B6C3F1 mice. Thiodiglycolic acid (TDGA) is a major metabolite of CEM in rats. It has been implicated that chemicals metabolized to TDGA cause cardiac toxicity in humans. Therefore, the toxicokinetics of CEM and TDGA were investigated in male and female F344/N rats and B6C3F1 mice following a single intravenous administration or dermal application of CEM to aid in the interpretation of the toxicity data. Absorption of CEM following dermal application was rapid in both species and genders. Bioavailability following dermal application was low but was higher in rats than in mice with females of both species showing higher bioavailability than males. CEM was rapidly distributed to the heart, thymus, and liver following both routes of administration. Plasma CEM C(max) and AUC(infinity) increased proportionally with dose, although at the dermal dose of 400mg/kg in rats and 600mg/kg in mice non-linear kinetics were apparent. Following dermal application, dose-normalized plasma CEM C(max) and AUC(infinity) was significantly higher in rats than in mice (p-value<0.0001 for all comparisons except for C(max) in the highest dose groups where p-value=0.053). In rats, dose-normalized plasma CEM C(max) and AUC(infinity) was higher in females than in males: however, the difference was significant only at the lowest dose (p-value=0.009 for C(max) and 0.056 for AUC(infinity)). Similar to rats, female mice also showed higher C(max) and AUC(infinity) in females than in male: the difference was significant only for C(max) at the lowest dose (p-value=0.002). Dose-normalized heart CEM C(max) was higher in rats than in mice and in females than their male counterparts. The liver CEM C(max) was lower compared to that of heart and thymus in both rats and mice following intravenous administration and in rats following dermal application. This is likely due to the rapid metabolism of CEM in the liver as evidenced by the high concentration of TDGA measured in the liver. Dose normalized plasma and heart TDGA C(max) values were higher in rats compared to mice. In rats, females had higher plasma and heart TDGA C(max) than males; however, there was no gender difference in plasma or heart TDGA C(max) in mice. These findings support the increased sensitivity of rats compared to mice to CEM induced cardiac toxicity. Data also suggest that, either CEM C(max) or AUC can be used to predict the CEM-induced cardiac toxicity. Although, both plasma and heart TDGA C(max) was consistent with the observed species difference and the gender difference in rats, the gender difference in mice to cardiac toxicity could not be explained based on the TDGA data. This animal study suggests that toxicologically significant concentrations of CEM and TDGA could possibly be achieved in the systemic circulation and/or target tissues in humans as a result of dermal exposure to CEM. PMID- 21708234 TI - Potentiation of vasoconstriction and pressor response by low concentration of monomethylarsonous acid (MMA(III)). AB - A close link between arsenic exposure and hypertension has been well-established through many epidemiological reports, yet the mechanism underlying it remains unclear. Here we report that nanomolar concentrations of monomethylarsonous acid (MMA(III)), a toxic trivalent methylated arsenic metabolite, can potentiate agonist-induced vasoconstriction and pressor responses. In freshly isolated rat aortic ring, exposure to nanomolar MMA(III) (100-500 nM) potentiated phenylephrine (PE)-induced vasoconstriction while at higher concentrations (>=2.5 MUM), suppression of vasoconstriction and apoptosis of vascular smooth muscle were observed. Potentiation of agonist-induced vasoconstriction was also observed with other contractile agonists and it was retained in endothelium-denuded aortic rings, suggesting that these events are agonist-independent and smooth muscle cell dependent. Interestingly, exposure to MMA(III) resulted in increased myosin light chain phosphorylation while PE-induced Ca2+ influx was not affected, reflecting that Ca2+ sensitization is involved. In line with this, MMA(III) enhanced agonist-induced activation of small GTPase RhoA, a key contributor to Ca2+ sensitization. Of note, treatment of MMA(III) to rats induced significantly higher pressor responses in vivo, demonstrating that this event can occur in vivo indeed. We believe that RhoA-mediated Ca2+ sensitization and the resultant potentiation of vasoconstriction by MMA(III) may shed light on arsenic-associated hypertension. PMID- 21708235 TI - Anisotropic crystal deformation measurements determined using powder X-ray diffraction and a new in situ compression stage. AB - This report addresses the development of experimental and computational estimations of the anisotropic elastic moduli (EM) of single crystals to aid in the a priori (i.e., starting with the crystal structure) prediction of the trend as a function of the direction of applied stress. Experimentally EM values in the normal direction to the X-, Y- and Z-planes of block shaped aspirin and acetaminophen crystals were determined using data generated by the newly designed compression stage housed in our powder X-ray diffractometer. Computational estimations of EM were made using the applicable modules in Material Studio 5.5. The measured EM values normal to the (100), (020) and (002) planes of aspirin, and (20-1), (020) and (001) planes of acetaminophen crystals by both methods succeeded in detected the anisotropic behavior. However, disparity in the relative values between measured EM values by different techniques was observed. This may be attributed to deformation sources other than lattice compression including inelastic processes such as local failure and plasticity as well as deformation at the crystal-probe interfaces due to crystal surface roughness (asperities). The trend of the ratio of the values from the respective methods showed reasonable agreement and promise for the technique. The present approach demonstrated the suitability of the compression stage to determine and predict anisotropic EM of subjected small molecular organic crystals. PMID- 21708236 TI - Drug intercalation in layered double hydroxide clay: application in the development of a nanocomposite film for guided tissue regeneration. AB - It has been proposed that localized and controlled delivery of alendronate and tetracycline to periodontal pocket fluids via guided tissue regeneration (GTR) membranes may be a valuable adjunctive treatment for advanced periodontitis. The objectives of this work were to develop a co-loaded, controlled release tetracycline and alendronate nanocomposite plasticized poly(lactic-co-glycolic acid) (PLGA) film that would form a suitable matrix supporting osteoblast proliferation and differentiation. Alendronate release was successfully controlled, with complete suppression of the burst phase of release by intercalation of alendronate anions in magnesium/aluminum layered double hydroxide (LDH) clay nanoparticles and dispersed in the PLGA film matrix. Tetracycline, loaded as free drug into the film together with alendronate-LDH clay complex released more rapidly than alendronate, but showed evidence of intercalation in the LDH clay particles. The dual drug loaded nanocomposite films were biocompatible with osteoblasts and after 5 week incubations, significant increase in alkaline phosphatase activity and bone nodule formation were observed. PMID- 21708237 TI - Comparative evaluation of silicified microcrystalline cellulose II as a direct compression vehicle. AB - The powder flow and tableting properties of novel silicified microcrystalline cellulose II (SMCCII) were evaluated and compared with current silicified cellulosic I excipients such as ProSolv((r)) SMCC50 and ProSolv((r)) SMCC90. This excipient was prepared by coprocessing cellulose II and silicon dioxide (SiO(2)) at a 95:5 ratio by spray drying. The novel SMCCII yielded more benefits in terms of functionality as compared with the parent cellulose II material. SMCCII had higher bulk and tap densities, better powder packing ability, reduced porosity, increased surface area, and increased flowability. This silicified excipient had the highest brittleness behavior as given by the Heckel, Leuenberger and brittle fracture index analyses. The mechanical properties of SMCCII, such as toughness and Young's modulus were comparable to those of commercial products. SMCCII was the least sensitive material to magnesium stearate, and blending time or reprocessing did not affect its compactibility. It also provided for the fastest compact disintegration and release of griseofulvin. This new material has the potential for use as a direct compression excipient. PMID- 21708238 TI - The influence of drug loading on formulation structure and aerosol performance in carrier based dry powder inhalers. AB - Previous studies have reported that carrier:drug ratio and carrier size influence the aerosol performance of dry powder inhalation systems. These previous studies were complicated by the heterogeneous nature of the carriers used, making it difficult to define an explicit relationship between parameters and performance. Here, the authors studied the influence of drug loading and carrier size on drug aerosol performance using homogeneous spherical model carriers. Different formulations containing drug (salbutamol sulphate) and carriers (polystyrene beads with median diameters of 82.8MUm, 277.5MUm and 582.9MUm, respectively) were prepared by varying the ratio of carrier to drug (from ~5:1 to ~85:1). The surface morphology of the carrier particles and force of adhesion were investigated using atomic force microscopy, while the aerosol performance was evaluated using a multi-stage liquid impinger. The carrier surface morphology for all carrier sizes was homogenous with root-mean square roughness values <=112nm. No significant difference in the force of adhesion between salbutamol sulphate and the three carrier sizes was observed. Significant differences in aerosol performance of salbutamol sulphate (measured as fine particle dose (FPD) and fraction (FPF)<=5MUm) from the carriers were observed. Specifically, as carrier size increased FPF decreased. In comparison, as drug loading increased there was no change in FPF until a critical threshold was exceeded. Such observations suggest that: (A) aerosolisation performance is governed by carrier collisions and (B) when homogeneous carriers are used, the aerosol performance remains constant with respect to drug concentration, until the formulation transitions from an ordered mix to an agglomerated and/or segregated powder bed. PMID- 21708239 TI - Combining experimental design and orthogonal projections to latent structures to study the influence of microcrystalline cellulose properties on roll compaction. AB - Roll compaction is gaining importance in pharmaceutical industry for the dry granulation of heat or moisture sensitive powder blends with poor flowing properties prior to tabletting. We studied the influence of microcrystalline cellulose (MCC) properties on the roll compaction process and the consecutive steps in tablet manufacturing. Four dissimilar MCC grades, selected by subjecting their physical characteristics to principal components analysis, and three speed ratios, i.e. the ratio of the feed screw speed and the roll speed of the roll compactor, were included in a full factorial design. Orthogonal projection to latent structures was then used to model the properties of the resulting roll compacted products (ribbons, granules and tablets) as a function of the physical MCC properties and the speed ratio. This modified version of partial least squares regression separates variation in the design correlated to the considered response from the variation orthogonal to that response. The contributions of the MCC properties and the speed ratio to the predictive and orthogonal components of the models were used to evaluate the effect of the design variation. The models indicated that several MCC properties, e.g. bulk density and compressibility, affected all granule and tablet properties, but only one studied ribbon property: porosity. After roll compaction, Ceolus KG 1000 resulted in tablets with obvious higher tensile strength and lower disintegration time compared to the other MCC grades. This study confirmed that the particle size increase caused by roll compaction is highly responsible for the tensile strength decrease of the tablets. PMID- 21708240 TI - Encecalol angelate, an unstable chromene from Ageratum conyzoides L.: total synthesis and investigation of its antiprotozoal activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In agreement with ethnomedicinal reports, the dichloromethane extract of Ageratum conyzoides L. (Asteraceae) was recently shown to be of considerable activity against Trypanosoma brucei rhodesiense, the etiologic agent of East African Human Trypanosomiasis (East African Sleeping Sickness). Isolated compounds, namely, methoxylated flavonoids as well as the chromene derivative encecalol methyl ether, were less active than the crude extract. The activity of the extract was found to decrease considerably while stored in solution. An unstable compound was detected in the fresh extract by HPLC, which was converted rapidly into the encecalol methyl ether while stored in methanolic solution. This compound, deemed to represent a constituent with antitrypanosomal activity, could not be isolated from the extract in intact form. AIM OF THE STUDY: To elucidate the structure of this unstable compound and to investigate its potential role in the antitrypanosomal activity of the total extract. MATERIALS AND METHODS: UHPLC/ESI-qQTOF MSMS and NMR data of the degraded product indicated its chemical identity as encecalol angelate (1) which was therefore prepared by total synthesis via a linear six steps synthesis, starting from resorcinol and 2-methylbut-3-en-2-ol. RESULTS: Total synthesis, in an overall yield of 15%, led to pure 1, which was chromatographically and spectroscopically identical with the natural product. The compound degraded in methanol with a half-life of approximately 6h to yield encecalol methyl ether (2). The antiprotozoal activity of synthetic encecalol angelate against T. brucei rhodesiense as well as T. cruzi, Leishmania donovani and Plasmodium falciparum was investigated and found to be quite low. CONCLUSIONS: The synthetic approach applied here for the first time also provides access to the related bioactive chromenes encecalin (7) and encecalol (8) with improved yields compared with reported methods. Encecalol angelate, however, is most likely not responsible for the high antitrypanosomal activity of the freshly prepared dichloromethane extract of A. conyzoides. PMID- 21708242 TI - Phytotherapy in medieval Serbian medicine according to the pharmacological manuscripts of the Chilandar Medical Codex (15-16th centuries). AB - The Chilandar Medical Codex is the most significant and best preserved medieval Serbian manuscript and collects together documents on European medical science from the 12th to 15th centuries. It represents the best-known and most complete example of a large collection of medical manuscripts from the Salerno-Montpellier school, written in the vernacular - something which does not exist among the majority of European nations. This paper presents the section of the Codex that deals with phytotherapy, which is contained within the pharmacological manuscripts. An analysis of their contents shows that out of a total of 167 recorded substances, 135 are of plant origin (81%), 13 animal origin (7.7%) and 19 inorganic (11.3%). The recorded plant species are categorised into 63 families, of which the most frequent are: Apiaceae (8.1%), Lamiaceae (8.1%), Asteraceae (5.9%), Rosaceae (5.9%) and Fabaceae (4.4%). All possible plant parts were used in treatments: the whole plant (6%), underground parts (13.7% - root, rhizome, bulb) and aerial parts (80.3% - stem, leaf, flower, buds, fruit, seeds). Of the plants quoted, the following are mentioned most frequently: Vitis sp. (120), Rosa canina (55), Olea europaea (45), Pistacia lentiscus (25), Saccharum officinarum (23), Artemisia absinthium (16) and Foeniculum vulgare (15). The contents of the pharmacological manuscripts of the Chilandar Medical Codex point to the sound contemporary knowledge of the diversity of plant species, their origins, habitat types, the levels of their healing powers, and when and how to gather them and prepare them, as well as the recommended dose for the treatment of specific illnesses. As these manuscripts contain not only common, lay terms for the plants, but also scientific, botanical ones, we can consider them the precursor to Serbian botany. Based on its contents and the way in which they are presented, it can be viewed not only as the first Serbian pharmacopeia, but first Slavic pharmacopeia, too, because similar manuscripts written in the vernacular did not exist during that period among the other Slavic nations, or even most European nations. PMID- 21708241 TI - Subamolide A, a component isolated from Cinnamomum subavenium, induces apoptosis mediated by mitochondria-dependent, p53 and ERK1/2 pathways in human urothelial carcinoma cell line NTUB1. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cinnamomum subavenium has long been used as a traditional Chinese medicine to treat carcinomatous swelling, abdominal pain and other diseases. AIM OF THE STUDY: The goal of this work was to study the cytotoxic effect of subamolide A, a constituent isolated from the stems of Cinnamomum subavenium Miq., and to extend its traditional use for clinical applications in treating human urothelial carcinoma. MATERIALS AND METHODS: Cytotoxic effect of subamolide A was determined by the MTT assay in NTUB1, T24, PC3 and SV-HUC-1 cells treated with various concentrations of subamolide A for three days. Apoptosis was detected by the change of cell morphology and flow cytometry analysis. The reactive oxygen species (ROS) level and mitochondria membrane potential (Deltapsim) were determined by flow cytometry. Western blot analysis was used to quantify the expression of apoptosis-related and stress induced signaling molecules. RESULTS: Subamolide A selectively induced apoptosis in two cancerous human urothelial carcinoma cell lines (NTUB1 and T24) in comparison with normal immortalized uroepithelial cells (SV-HUC-1). Subamolide A reduced mitochondrial membrane potential (Deltapsim) and caused apoptosis of NTUB1 cells. Subamolide A increased Bax/Bcl-2 ratios, the amount of cytochrome c released from the mitochondria, caspase-3 and PARP cleavage, activated p53 and ERK1/2 and ultimately led to apoptosis in NTUB1 cells. Furthermore, a higher dose (10MUM) of subamolide A synergistically enhanced the cytotoxicity of cisplatin and gemcitabine in NTUB1 cells. CONCLUSIONS: The current study demonstrated that subamolide A triggered the mitochondria-dependent apoptotic pathways and p53 and ERK1/2 activation in the human urothelial carcinoma cell line NTUB1. In addition, subamolide A synergistically enhanced cytotoxic effect of CDDP and Gem in NTUB1. These data suggested that subamolide A exhibited a potent anti-proliferation activity. This study supports the traditional use of Cinnamomum subavenium stems with a therapeutic potential for the treatment of human urothelial carcinoma. PMID- 21708243 TI - Porcine Corneal Ocular Reversibility Assay (PorCORA) predicts ocular damage and recovery for global regulatory agency hazard categories. AB - In this study, we examined the capacity of the Porcine Corneal Ocular Reversibility Assay (PorCORA) to classify the reversibility of ocular effects for 32 test compounds (20 reversible, 12 irreversible) from various chemical classes. PorCORA predicted 28 of 32 compounds correctly when compared to historical rabbit eye test data. The correlation coefficient for PorCORA versus historical rabbit test data was 0.84, based on the last day of damaged cornea reversal. These results demonstrate a high correlation between corneal irritation recovery time in the PorCORA and the rabbit eye. When compared to historical Modified Maximal Average Score (MMAS) in rabbit eyes, PorCORA yielded a correlation coefficient of 0.80, demonstrating ability to predict MMAS. PorCORA was highly predictive of regulatory agency ocular hazard classification categories, resulting in 91% accuracy for EU R41 and GHS Category 1. PorCORA was also predictive of EPA Category I (88% accuracy). Overall, the accuracy (88-91%), sensitivity (79-86%), specificity (94%), positive predictivity (94%), and negative predictivity (85 89%) for all three regulatory classifications indicate that ocular irritation hazardous effects were well predicted by the PorCORA. This study suggests that PorCORA could help discriminate between EU R36 and R41, GHS Categories 1 and 2, and EPA Categories I and II. PMID- 21708244 TI - Ursolic acid improves high fat diet-induced cognitive impairments by blocking endoplasmic reticulum stress and IkappaB kinase beta/nuclear factor-kappaB mediated inflammatory pathways in mice. AB - Evidence suggests that obesity-induced cognitive impairments are driven by in brain inflammatory responses and inflammation-mediated brain insulin resistance. Ursolic acid (UA), a triterpenoid compound, has many important biological functions, including antioxidant and anti-inflammatory activities. Here, we evaluated the effect of UA on cognitive impairment induced by a high-fat diet (HFD), and we explored the potential mechanisms mediating this effect. Results showed that UA administration significantly improved the behavioral performance of C57/BL6J mice fed a HFD in both the step-through test and the Morris water maze task. These results were associated with the inhibition of endoplasmic reticulum stress and IkappaB kinase beta/nuclear factor-kappaB-mediated inflammatory signaling and the restoration of insulin signaling and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. UA administration also increased memory-related protein expression in the hippocampus of mice given a HFD. However, the neuroprotective effects of UA were blocked by an intracerebroventricular (i.c.v.) injection of PI-103, a specific PI3K 110alpha inhibitor. These results suggest that UA may be a potent candidate for the prevention and treatment of cognitive deficits caused by type 2 diabetes. PMID- 21708245 TI - Concerning "Absence of neurotoxicity with medicinal grade terbutaline in the rat model," by M.Y. Owens, K.L. Wallace, N. Mamoon, J. Wyatt-Ashmead and W.A. Bennett. PMID- 21708246 TI - Valproic acid-induced DNA damage increases embryonic p27(KIP1) and caspase-3 expression: a mechanism for valproic-acid induced neural tube defects. AB - Valproic acid is a commonly prescribed antiepileptic agent that causes birth defects including neural tube defects. The purpose of this study was to measure DNA damage and downstream changes in cell cycle inhibitors and apoptosis to further elucidate the molecular changes that occur following VPA exposure. Pregnant CD-1 mice were administered a teratogenic dose of VPA (400mg/kg) on gestational day 9 (plug=day 1) and embryos extracted 0.5, 1, 3, 6, and 24h after injection. Western blotting and immunohistochemistry were performed for gammaH2A.X, p21(WAF1/CIP1), p27(KIP1), and cleaved caspase-3. A rapid increase in gammaH2A.X expression was observed a half hour following VPA exposure, followed by a subsequent decrease. p27(KIP1)and cleaved caspase-3 expression was significantly increased 3 and 6h following VPA exposure. Immunohistochemistry revealed increased staining for gammaH2A.X, p27(KIP1), and cleaved caspase 3 in the head, confirming our hypothesis that DNA damage, cell cycle inhibition, and apoptosis are induced by VPA. PMID- 21708247 TI - NADPH-oxidase-dependent reactive oxygen species mediate EGFR transactivation by FPRL1 in WKYMVm-stimulated human lung cancer cells. AB - Cross talk between unrelated cell surface receptors, such as G-protein-coupled receptors (GPCR) and receptor tyrosine kinases (RTK), is a crucial signaling mechanism to expand the cellular communication network. We investigated the ability of the GPCR formyl peptide receptor-like 1 (FPRL1) to transactivate the RTK epidermal growth factor receptor (EGFR) in CaLu-6 cells. We observed that stimulation with WKYMVm, an FPRL1 agonist isolated by screening synthetic peptide libraries, induces EGFR tyrosine phosphorylation, p47(phox) phosphorylation, NADPH-oxidase-dependent superoxide generation, and c-Src kinase activity. As a result of EGFR transactivation, phosphotyrosine residues provide docking sites for recruitment and triggering of the STAT3 pathway. WKYMVm-induced EGFR transactivation is prevented by the FPRL1-selective antagonist WRWWWW, by pertussis toxin (PTX), and by the c-Src inhibitor PP2. The critical role of NADPH oxidase-dependent superoxide generation in this cross-talk mechanism is corroborated by the finding that apocynin or a siRNA against p22(phox) prevents EGFR transactivation and c-Src kinase activity. In addition, WKYMVm promotes CaLu 6 cell growth, which is prevented by PTX and by WRWWWW. These results highlight the role of FPRL1 as a potential target of new drugs and suggest that targeting both FPRL1 and EGFR may yield superior therapeutic effects compared with targeting either receptor separately. PMID- 21708249 TI - Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey. AB - The combination of nitrous oxide gas (N(2)O) and isoflurane (ISO) vapor is commonly used in pediatric surgical procedures for human infants and children to produce unconsciousness and analgesia. Because of obvious limitations it is difficult to thoroughly explore the effects of pediatric anesthetic agents on neurons in human infants or children. Due to the complexity of the primate brain, the monkey is often the animal model of choice for developmental neurotoxicology experiments, and it is in the rhesus monkey that the phenomenon of interest (anesthetic-induced neuronal cell death in the brain) has been previously reported. Recent reports indicate that exposure of the developing brain to general anesthetics that block N-methyl-D-aspartate (NMDA)-type glutamate receptors or potentiate gamma-aminobutyric acid (GABA) receptors can trigger widespread apoptotic cell death in rodents. The present study was performed to determine whether prolonged exposure of developing nonhuman primates to a clinically relevant combination of nitrous oxide and isoflurane produces neuronal damage. Postnatal day (PND) 5-6 rhesus monkeys were exposed to N(2)O (70%) or ISO (1.0%) alone, or N(2)O plus ISO for 8 h. Inhalation of the combination of 70% N(2)O+1% ISO produces a surgical plane of anesthesia. Six hours after completion of anesthetic administration the monkeys were examined for neurotoxic effects. No significant neurotoxic effects were observed for the monkeys exposed to N(2)O or ISO alone. However, neuronal damage was apparent when N(2)O was combined with ISO as indicated by increased numbers of caspase-3-, Silver staining- and Fluoro-Jade C-positive cells in the frontal cortex, temporal gyrus and hippocampus. Electron micrographs indicated typical swelling of the cytoplasm and nuclear condensation in the frontal cortex. These data suggest that prolonged exposure to inhaled anesthetics (a combination of N(2)O and ISO) in the developing rhesus monkey results in neuronal damage, and that the cell death observed is apoptotic and necrotic in nature. PMID- 21708250 TI - Are there endogenous estrone fatty acyl esters in human plasma or ovarian follicular fluid? AB - BACKGROUND: Estrone and its sulfated esters are the most abundant estrogens in blood in men and in women after the menopause. However, previous studies on the esterification of estrone with fatty acids have yielded conflicting results, some studies reporting high nanomolar concentrations of estrone fatty acyl esters in plasma. METHODS: We developed an estrone radioimmunoassay (RIA) method to determine endogenous concentrations of estrone and after saponification, applied it to male and female plasma. In addition, the concentration of estrone fatty acyl esters in ovarian follicular fluid was analyzed by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC MS/MS). RESULTS: By estrone RIA, we did not find measurable amounts of estrone fatty acyl esters in male or female plasma, except for one premenopausal woman who had the highest plasma concentration of nonesterified estrone. The concentration of hydrolyzed estrone fatty acyl esters determined by LC-MS/MS in follicular fluid obtained from women undergoing ovarian stimulation was below the limit of quantification of <10 pmol/l (<2.7 ng/l). CONCLUSIONS: In contrast to previous data by others, our study suggests that estrone fatty acyl esters are in most cases not detectable in plasma of healthy men or healthy nonpregnant women. PMID- 21708251 TI - The interleukin-2 antagonizing antibody MT204 delays allogeneic skin graft rejection in non-human primates and is well tolerated. AB - MT204 is a humanized IgG1 antibody specific for interleukin-2 (IL-2) of human and rhesus monkey origin. It potently antagonizes IL-2 signaling in both CD25(+) and CD25(-) cells by a unique mode of action. MT204 can not only prevent soluble IL-2 from binding to the intermediate affinity IL-2 receptors but can also antagonize IL-2 that is already bound to the CD25 subunit of high affinity IL-2 receptors on the cell surface. As initial steps toward development of a therapeutic antibody, pharmacokinetics (PK) and tolerability of MT204, as well as efficacy were investigated in rhesus monkeys. MT204 was infused by single escalating (2, 10 and 50mg/kg) or repeat dose administrations (50mg/kg, 1 */week for 3 weeks). Over the course of the experiment, the animals were regularly observed for clinical adverse reaction and bled for laboratory investigations (PK, hematology, chemical chemistry and leukocyte subset analysis). For the efficacy study, six rhesus monkeys were grafted with MHC-mismatched rhesus skin and infused with MT204 (50mg/kg), on the day of transplantation and again on days 5 and 12 post grafting. Efficacy was determined by assessment of graft necrosis at different time-points. No obvious adverse effects were observed clinically after single infusion, or after three repeated infusions of 50mg/kg and no MT204-related toxic effects were revealed by hematology or clinical chemistry. In the efficacy study, MT204-treated animals showed a significant delay in graft rejection versus control animals (p=0.025 by Log-rank test). The characteristics of MT204, displaying linear pharmacokinetics, half-life in the range expected for a human IgG, benign safety profile and signs of efficacy, warrant further development of this antibody for therapy. PMID- 21708248 TI - Relationship of electrophilic stress to aging. AB - This review begins with the premise that an organism's life span is determined by the balance between two countervailing forces: (i) the sum of destabilizing effects and (ii) the sum of protective longevity-assurance processes. Against this backdrop, the role of electrophiles is discussed, both as destabilizing factors and as signals that induce protective responses. Because most biological macromolecules contain nucleophilic centers, electrophiles are particularly reactive and toxic in a biological context. The majority of cellular electrophiles are generated from polyunsaturated fatty acids by a peroxidation chain reaction that is readily triggered by oxygen-centered radicals, but propagates without further input of reactive oxygen species (ROS). Thus, the formation of lipid-derived electrophiles such as 4-hydroxynon-2-enal (4-HNE) is proposed to be relatively insensitive to the level of initiating ROS, but to depend mainly on the availability of peroxidation-susceptible fatty acids. This is consistent with numerous observations that life span is inversely correlated to membrane peroxidizability, and with the hypothesis that 4-HNE may constitute the mechanistic link between high susceptibility of membrane lipids to peroxidation and shortened life span. Experimental interventions that directly alter membrane composition (and thus their peroxidizability) or modulate 4-HNE levels have the expected effects on life span, establishing that the connection is not only correlative but causal. Specific molecular mechanisms are considered, by which 4-HNE could (i) destabilize biological systems via nontargeted reactions with cellular macromolecules and (ii) modulate signaling pathways that control longevity-assurance mechanisms. PMID- 21708252 TI - Egg donation pregnancy as an immunological model for solid organ transplantation. AB - In egg donation (ED) pregnancies the fetus is allogeneic to the gestational carrier. During these ED pregnancies the mother has to cope with a higher degree of antigenic dissimilarity compared with spontaneously conceived pregnancies. At the fetal-maternal interface maternal cells and fetal cells come in close contact. Understanding the immune mechanisms at this fetal-maternal interface gives more insight into the question why the (semi-)allogeneic fetus is accepted and not rejected by the mother. The degree of antigenic dissimilarity in ED pregnancies is comparable with that in solid organ transplantations with HLA mismatched unrelated donors. Therefore, the immunologic interactions between mother and child in successful ED pregnancies may be relevant for the induction of immunological tolerance in solid organ transplantation. PMID- 21708253 TI - On the path from chemistry to neuroscience: early explorations in chemical medicine under the mentorship of Dr. Erminio Costa, a neuroscientist with a big brain and a bigger heart. AB - In this short note in tribute to Dr. Erminio Costa, I reflect upon the sabbatical period that I spent with him during his early years at the Fidia-Georgetown Institute for the Neurosciences [FGIN] at the Georgetown University Medical Center. I detail some of the interesting projects that we were involved in at that time, that led us to create strong bridges between chemistry and the neurosciences, and that led in turn to the discovery of various classes of interesting molecular tools such as the peripheral benzodiazepine receptor ligand FGIN-1-27. PMID- 21708254 TI - Pharmacological regulation of gene expression. AB - Pharmacological regulation of gene expression was one of the top professional interests of Dr. Costa. He promoted the idea that drugs can improve the endogenous mechanisms of synaptic plasticity by modulating gene expression. In this article I reflect upon Dr. Costa's leadership in projects undertaken at FGIN that were aimed at elucidating how neurotransmitter receptor activation could affect brain function by modulating genes and their products. I will be presenting examples of how pharmacological tools can change gene expression. These include the ability of drugs of abuse to alter the synthesis of opioid peptides or an endogenous ligand for GABAA receptor. I will conclude with a brief summary of intriguing discoveries about the regulation of nerve growth factor (NGF) and its receptors by beta-receptor agonists, adrenal steroids and cytokines. PMID- 21708255 TI - Laboratory of molecular neurobiology (1988-1994). AB - While Dr. Costa was the Director of FGIN he became interested in the regulation of genes encoding various neurotransmitter receptors. More specifically, there was increasing evidence supporting a role for tetanic stimulation of the NMDA subtype of ionotropic glutamate receptors in the development of long term potentiation and long term depression. Moreover, the protein products of the immediate early gene family, such as c-fos and c-jun, were known modulators of downstream signaling events that facilitated changes in neuronal transcriptomes in response to incoming afferent stimulation. The immediate early gene products were known transcriptional factors that activated gene expression in response to excitatory stimulation. In fact, the expression of c-fos/c-jun was often used to map neuronal circuits linked through a common initiation point such as occurs in focally-evoked seizures. Dr. Costa firmly believed that excitatory and inhibitory transmission was balanced in the central nervous system and that this might come about through changes in the expression of the genes encoding these neurotransmitter receptors. In other words, persistent stimulation of NMDA receptors would be expected to increase expression of the inhibitory GABAA receptors to accommodate the increased excitation. That this receptor crosstalk might occur through the products of the immediate early genes was testable and the focus of the Molecular Neurobiology Laboratory from 1988 to 1994. In a broader sense, stimulation of ionotropic NMDA-selective glutamate receptors has been associated with numerous downstream molecular and cellular processes. How these processes are linked to changes in gene expression has been the focus of studies in the neurosciences for many years. PMID- 21708256 TI - The golden years: a tribute to Erminio Costa. AB - In June of 1968 the NIMH established the Laboratory of Preclinical Pharmacology (LPP) under the leadership of Erminio Costa at St. Elizabeths Hospital in Washington, DC. From its inception until 1985 more than 170 scientists produced over 800 scientific publications that largely influenced the direction of neuroscience research. Under Dr. Costa's scientific guidance LPP made numerous discoveries that contributed to the understanding of neuronal function and push the fledging field of neuroscience forward. Methods were developed to measure the turnover rate of catecholamines, serotonin, acetylcholine and GABA, and to assess the dynamic state of neuronal stores of peptides; the regulation of tyrosine hydroxylase activity was revealed; the molecular mechanisms underlying neurotransmitter receptor signaling and regulation were explored; the concept that opioid peptides function as neuromodulators in structures that are not involved in pain threshold regulation was proposed; the role of GABAergic transmission for the action of benzodiazepines was pioneered; the endogenous mechanisms operative in opiate tolerance were elucidated; and approaches to measure mRNA and evaluate its regulation were introduced. As a tribute to Dr. Costa, this article presents the initial journey and the many contributions to teaching and research that he made from 1963 to 1985, a period that I worked with him and call it "the golden years". PMID- 21708257 TI - Neuropeptide S inhibits stress-stimulated faecal output in the rat. AB - Neuropeptide S (NPS) is a recently identified bioactive peptide that activates an orphan G-protein coupled receptor, called the NPS receptor (NPSR). In rats, NPS and NPSR constitute a novel neuropeptide system expressed both in the central nervous system and in peripheral tissues, controlling visceromotor, neuroendocrine, nociceptive and behavioural responses. To improve the knowledge of the role of the NPS-NPSR system in the gastrointestinal (GI) tract, we investigated: 1- the supraspinal effect of NPS on motor functions of the upper (gastric emptying and gastrointestinal transit) and lower (distal colonic transit and faecal output) GI tract under basal conditions, 2- during pathological states (restraint stress and corticotropin releasing factor (CRF)-induced defecation) in the rat, and 3- the receptor type involved in treatment with NPS using NPS, tachykinin NK(3) and opioid receptor antagonists (([D-Cys(tBu)5]NPS), SR142801 and naloxone, respectively). Intracerebroventricular injection of NPS failed to modify basal gastric emptying, gastrointestinal transit and distal colon propulsion, but significantly and dose-dependently reduced faecal pellet excretion and weight stimulated by restraint stress and CRF. The inhibitory effect of NPS on stress-induced defecation was unmodified by pre-treatment with either the tachykinin or opioid receptor antagonists, but was counteracted by a NPSR antagonist. The present study demonstrates, for the first time, that the supraspinal NPS system, which does not participate in the physiological control of GI motility, plays an inhibitory role on defecation stimulated by restraint stress and CRF. The combination of the ability of NPS to inhibit faecal output together with its known anxiolytic effect may be promising, especially in pathological conditions such as irritable bowel syndrome, where stress and the hyperactivity of the CRF system contribute to the co-morbidity of anxiety with colonic motor symptoms such as diarrhoea. PMID- 21708258 TI - Pharmacologic therapy of heart failure in children: part of a special series on paediatric pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni. AB - Paediatric cardiomyopathy and heart failure are distinct but frequently associated conditions, which have a high mortality. Traditional medical therapy has evolved to incorporate newer classes of heart failure drugs, although the evidence to support efficacy in children is limited. This perspective article discusses the rationale, benefits and limitations of the various classes of drug therapy used in paediatric heart failure due to cardiomyopathy or congenital heart disease. Controversies in management and challenges for future development are highlighted. PMID- 21708259 TI - In vitro maturation of the cisternal organelle in the hippocampal neuron's axon initial segment. AB - Regulation of Ca(2+) concentrations is essential to maintain the structure and function of the axon initial segment (AIS). The so-called cisternal organelle of the AIS is a structure involved in this regulation, although little is known as to how this organelle matures and is stabilized. Here we describe how the cisternal organelle develops in cultured hippocampal neurons and the interactions that facilitate its stabilization in the AIS. We also characterize the developmental expression of molecules involved in Ca(2+) regulation in the AIS. Our results indicate that synaptopodin (synpo) positive elements considered to be associated to the cisternal organelle are present in the AIS after six days in vitro. There are largely overlapping microdomains containing the inositol 1,4,5 triphosphate receptor 1 (IP(3)R1) and the Ca(2+) binding protein annexin 6, suggesting that the regulation of Ca(2+) concentrations in the AIS is sensitive to IP(3) and subject to regulation by annexin 6. The expression of synpo, IP(3)R1 and annexin 6 in the AIS is independent of the neuron activity, as it was unaffected by tetrodotoxin blockage of action potentials and it was resistant to detergent extraction, indicating that these proteins interact with scaffolding and/or cytoskeleton proteins. The presence of ankyrin G seems to be required for the acquisition and maintenance of the cisternal organelle, while the integrity of the actin cytoskeleton must be maintained for the expression IP(3)R1 and annexin 6 to persist in the AIS. PMID- 21708260 TI - Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes. AB - Peroxynitrite has been suggested to be the potent oxidant causing toxicity to neurons and oligodendrocytes (OLs). Our previous studies have illustrated that intracellular zinc liberation contributes to peroxynitrite toxicity to mature OLs. In this study, we further investigated the signaling pathways involved in this event and identified protein kinase C (PKC) as an important early signaling molecule. We found that a non-selective PKC inhibitor bisindolylmaleimide-1 blocked OL toxicity induced by a peroxynitrite generator SIN-1 and exogenous zinc. The protective effects were due to its inhibition on ERK1/2 phosphorylation and ROS generation. The same phenomenon was also observed in OLs following prolonged treatment with phorbol 12 myristate 13 acetate (PMA), which downregulates the conventional and the novel PKC isoforms (cPKCs and nPKCs). To determine the role of specific PKC isoforms, we found that a specific nPKC inhibitor rottlerin significantly reduced SIN-1- or zinc-induced toxicity, whereas Go6976, a cPKC inhibitor, reduced OL toxicity triggered by zinc, but not by SIN-1 at high concentrations. Rottlerin was more potent than Go6976 to attenuate ERK1/2 phosphorylation and ROS generation induced by SIN-1 or zinc. Surprisingly, zinc only induced phosphorylation of PKCtheta, but not PKCdelta. Knockdown of PKCtheta using lentiviral shRNA attenuated SIN-1- or zinc-induced toxicity. These results suggest that PKCtheta might be the major PKC isoform involved in peroxynitrite and zinc toxicity to mature OLs, and provide a rationale for development of specific inhibitors of PKCtheta in the treatment of multiple sclerosis and other neurodegenerative diseases, in which peroxynitrite formation plays a pathogenic role. PMID- 21708261 TI - Nitric oxide and DOPAC-induced cell death: from GSH depletion to mitochondrial energy crisis. AB - The molecular mechanisms inherent to cell death associated with Parkinson's disease are not clearly understood. Diverse pathways, sequence of events and models have been explored in several studies. Recently, we have proposed an integrative mechanism, encompassing the interaction of nitric oxide (*NO) and a major dopamine metabolite, dihydroxyphenylacetic (DOPAC), leading to a synergistic mitochondrial dysfunction and cell death that may be operative in PD. In this study, we have studied the sequence of events underlying the mechanisms of cell death in PC12 cells exposed to *NO and DOPAC in terms of: a) free radical production; b) modulation by glutathione (GSH); c) energetic status and d) outer membrane mitochondria permeability. Using Electron Paramagnetic Resonance (EPR) it is shown the early production of oxygen free radicals followed by a depletion of GSH reflected by an increase of GSSG/GSH ratio in the cells treated with the mixture of *NO/DOPAC, as compared with the cells individually exposed to each of the stimulus. Glutathione ethyl ester (GSH-EE) and N-acetylcysteine (NAC) may rescue cells from death, increasing GSH content and preventing ATP loss in cells treated with the mixture DOPAC/*NO but failed to exert similar effects in the cells challenged only with *NO. The depletion of GSH is accompanied by a decreased activity of mitochondrial complex I. At a later stage, the concerted action of DOPAC and *NO include a rise in the ratio Bax/Bcl-2, an observation not evident when cells were exposed only to *NO. The results support a free radical induced pathway leading to cell death involving the concerted action of DOPAC and *NO and the critical role of GSH in maintaining a functional mitochondria. PMID- 21708263 TI - Selective vulnerability of rat brain regions to unconjugated bilirubin. AB - Hippocampus is one of the brain regions most vulnerable to unconjugated bilirubin (UCB) encephalopathy, although cerebellum also shows selective yellow staining in kernicterus. We previously demonstrated that UCB induces oxidative stress in cortical neurons, disruption of neuronal network dynamics, either in developing cortical or hippocampal neurons, and that immature cortical neurons are more prone to UCB-induced injury. Here, we studied if immature rat neurons isolated from cortex, cerebellum and hippocampus present distinct features of oxidative stress and cell dysfunction upon UCB exposure. We also explored whether oxidative damage and its regulation contribute to neuronal dysfunction induced by hyperbilirubinemia, considering neurite extension and ramification, as well as cell death. Our results show that UCB induces nitric oxide synthase expression, as well as production of nitrites and cyclic guanosine monophosphate in immature neurons, mainly in those from hippocampus. After exposure to UCB, hippocampal neurons presented the highest content of reactive oxygen species, disruption of glutathione redox status and cell death, when compared to neurons from cortex or cerebellum. In particular, the results indicate that cells exposed to UCB undertake an adaptive response that involves DJ-1, a multifunctional neuroprotective protein implicated in the maintenance of cellular oxidation status. However, longer neuronal exposure to UCB caused down-regulation of DJ-1 expression, especially in hippocampal neurons. In addition, a greater impairment in neurite outgrowth and branching following UCB treatment was also noticed in immature neurons from hippocampus. Interestingly, pre-incubation with N acetylcysteine, a precursor of glutathione synthesis, protected neurons from UCB induced oxidative stress and necrotic cell death, preventing DJ-1 down-regulation and neuritic impairment. Taken together, these data point to oxidative injury and disruption of neuritic network as hallmarks in hippocampal susceptibility to UCB. Most importantly, they also suggest that local differences in glutathione content may account to the different susceptibility between brain regions exposed to UCB. PMID- 21708262 TI - Ototrauma induces sodium channel plasticity in auditory afferent neurons. AB - Exposure to intense sound can cause damage to the delicate sensory and neuronal components of the cochlea leading to hearing loss. Such damage often causes the dendrites of the spiral ganglion neurons (SGN), the neurons that provide the afferent innervation of the hair cells, to swell and degenerate thus damaging the synapse. In models of neuropathic pain, axotomy, another form of afferent nerve damage, is accompanied by altered voltage-gated sodium channel (VGSC) expression, leading to neuronal hyperactivity. In this study, adult Wistar rats were exposed to noise which produced a mild, 20 dB hearing threshold elevation and their VGSC expression was investigated. Quantitative PCR showed decreased Na(V)1.1 and Na(V)1.6 mRNA expression in the SGN following noise exposure (29% and 56% decrease respectively) while Na(V)1.7 mRNA expression increased by approximately 20% when compared to control rats. Immunohistochemistry extended these findings, revealing increased staining for Na(V)1.1 along the SGN dendrites and Na(V)1.7 in the cell bodies after noise. These results provide the first evidence for selective changes in VGSC expression following moderate noise-induced hearing loss and could contribute to elevated hearing thresholds and to the generation of perceptual anomalies commonly associated with cochlear damage, such as tinnitus and hyperacusis. PMID- 21708264 TI - Single-cell proteomic analysis of glucosinolate-rich S-cells in Arabidopsis thaliana. AB - Single-cell analysis is essential for understanding the processes of cell differentiation and metabolic specialisation in rare cell types. The amount of single proteins in single cells can be as low as one copy per cell and is for most proteins in the attomole range or below; usually considered as insufficient for proteomic analysis. The development of modern mass spectrometers possessing increased sensitivity and mass accuracy in combination with nano-LC-MS/MS now enables the analysis of single-cell contents. In Arabidopsis thaliana, we have successfully identified nine unique proteins in a single-cell sample and 56 proteins from a pool of 15 single-cell samples from glucosinolate-rich S-cells by nanoLC-MS/MS proteomic analysis, thus establishing the proof-of-concept for true single-cell proteomic analysis. Dehydrin (ERD14_ARATH), two myrosinases (BGL37_ARATH and BGL38_ARATH), annexin (ANXD1_ARATH), vegetative storage proteins (VSP1_ARATH and VSP2_ARATH) and four proteins belonging to the S-adenosyl-l methionine cycle (METE_ARATH, SAHH1_ARATH, METK4_ARATH and METK1/3_ARATH) with associated adenosine kinase (ADK1_ARATH), were amongst the proteins identified in these single-S-cell samples. Comparison of the functional groups of proteins identified in S-cells with epidermal/cortical cells and whole tissue provided a unique insight into the metabolism of S-cells. We conclude that S-cells are metabolically active and contain the machinery for de novo biosynthesis of methionine, a precursor for the most abundant glucosinolate glucoraphanine in these cells. Moreover, since abundant TGG2 and TGG1 peptides were consistently found in single-S-cell samples, previously shown to have high amounts of glucosinolates, we suggest that both myrosinases and glucosinolates can be localised in the same cells, but in separate subcellular compartments. The complex membrane structure of S-cells was reflected by the presence of a number of proteins involved in membrane maintenance and cellular organisation. PMID- 21708265 TI - Expression, purification and characterization of two thermostable endoglucanases cloned from a lignocellulosic decomposing fungi Aspergillus fumigatus Z5 isolated from compost. AB - Two genes encoding endoglucanase, designated as egl2 and egl3, were cloned from a lignocellulosic decomposing fungus Aspergillus fumigatus Z5 and were successfully expressed in Pichia pastoris X33. The deduced amino acid sequences encoded by egl2 and egl3 showed strong similarity with the sequence of glycoside hydrolase family 5. SDS-PAGE and western blot assays indicated that the recombinant enzymes were secreted into the culture medium and the zymogram analysis confirmed that both recombinant enzymes had endoglucanase activity. Several biochemical properties of the two recombinant enzymes were studied: Egl2 and Egl3 showed optimal activity at pH 5.0 and 4.0, respectively, and at 50 and 60 degrees C, respectively. Egl2 and Egl3 showed good pH stability in the range of 4-7, and both enzymes demonstrated good thermostability ranging from 30 to 60 degrees C. The K(m) and V(max) values using carboxymethyl cellulose (CMC, soluble cellulose, polymerized by beta-1, 4-linked glucose residues) as the substrate at optimal conditions were determined. The activities of the enzymes on a variety of cello oligosaccharide substrates were investigated, and Egl2 can hydrolyze cellotetraose and cellopentaose but not cellobiose and cellotriose, whereas Egl3 can hydrolyze all cello-oligosaccharides, except cellobiose. PMID- 21708266 TI - Purification of SUMO-1 modified IkappaBalpha and complex formation with NF kappaB. AB - Covalent modification of proteins with SUMO (Small Ubiquitin-like MOdifier) affects many cellular processes, including transcriptional regulation, DNA repair and signal transduction. Although hundreds of SUMO targets have been identified, many biological outcomes of protein sumoylation remain poorly understood. In particular, biochemical and structural analysis can only be easily conducted if highly pure sumoylated substrates are available. Purification of sumoylated substrates in vitro or in bacteria have been previously reported but separating the sumoylated protein from the undesired unmodified fraction is often technically challenging, inefficient and time consuming. Here we develop a new vector system for in vivo sumoylation in Escherichia coli which improves purification of sumoylated proteins. We describe the purification of IkappaBalpha, its sumoylation, the subsequent separation and purification of the modified and the unmodified forms and the purification of the complex IkappaBalpha-SUMO-1/NF-kappaB. After a first GST affinity chromatography and GST tag removal, a unique metal-ion affinity chromatography using a 6xHis-SUMO-1 tag results in mgs of highly pure SUMO-1 modified IkappaBalpha. Our pure SUMO-1 modified IkappaB/NF-kappaB complex could be a useful tool to identify new interaction partner specific of the SUMO-1 modified IkappaBalpha form. This approach may be extended to other SUMO substrates not isolable by classical chromatography techniques. PMID- 21708267 TI - Cloning, expression, functional validation and modeling of cinnamyl alcohol dehydrogenase isolated from xylem of Leucaena leucocephala. AB - A cDNA encoding cinnamyl alcohol dehydrogenase (CAD), catalyzing conversion of cinnamyl aldehydes to corresponding cinnamyl alcohols, was cloned from secondary xylem of Leucaena leucocephala. The cloned cDNA was expressed in Escherichia coli BL21 (DE3) pLysS cells. Temperature and Zn(2+) ion played crucial role in expression and activity of enzyme, such that, at 18 degrees C and at 2 mM Zn(2+) the CAD was maximally expressed as active enzyme in soluble fraction. The expressed protein was purified 14.78-folds to homogeneity on Ni-NTA agarose column with specific activity of 346 nkat/mg protein. The purified enzyme exhibited lowest Km with cinnamyl alcohol (12.2 MUM) followed by coniferyl (18.1 MUM) and sinapyl alcohol (23.8 MUM). Enzyme exhibited high substrate inhibition with cinnamyl (beyond 20 MUM) and coniferyl (beyond 100 MUM) alcohols. The in silico analysis of CAD protein exhibited four characteristic consensus sequences, GHEXXGXXXXXGXXV; C(100), C(103), C(106), C(114); GXGXXG and C(47), S(49), H(69), L(95), C(163), I(300) involved in catalytic Zn(2+) binding, structural Zn(2+) binding, NADP(+) binding and substrate binding, respectively. Tertiary structure, generated using Modeller 9v5, exhibited a trilobed structure with bulged out structural Zn(2+) binding domain. The catalytic Zn(2+) binding, substrate binding and NADP(+) binding domains formed a pocket protected by two major lobes. The enzyme catalysis, sequence homology and 3-D model, all supported that the cloned CAD belongs to alcohol dehydrogenase family of plants. PMID- 21708268 TI - Preparation of monomeric B27 Lys destripeptide insulin by intein mediated expression in Escherichia coli. AB - The B27K-DTrI insulin (human insulin with B28-30 removed and B27 Thr replaced by Lys) was reported to have superior monomeric property with 80% insulin activity in vivo. It has potential use as a new fast-acting analog of insulin. We cloned the monomeric insulin B27 DTrI precursor (MIP) into the pTWIN1 vector, and prepared by intein mediated expression in Escherichia coli. After tryptic digestion, the MIP was converted to B27K-DTrI insulin. The product was purified by HPLC. The mass spectrometry showed that the molecular mass of purified B27K DTrI was consistent with the theoretical value. PMID- 21708269 TI - Reference-free particle selection enhanced with semi-supervised machine learning for cryo-electron microscopy. AB - Reference-based methods have dominated the approaches to the particle selection problem, proving fast, and accurate on even the most challenging micrographs. A reference volume, however, is not always available and compiling a set of reference projections from the micrographs themselves requires significant effort to attain the same level of accuracy. We propose a reference-free method to quickly extract particles from the micrograph. The method is augmented with a new semi-supervised machine-learning algorithm to accurately discriminate particles from contaminants and noise. PMID- 21708270 TI - The canine baculum: the structure and mechanical properties of an unusual bone. AB - The baculum is an extraskeletal bone located in the penis of a few species in several orders of mammals such as carnivores, insectivores, rodents, bats and primates. This study aims to describe the structure, architecture and mechanical properties of the canine baculum. To this end canine bacula from castrated and uncastrated dogs were collected and examined by light microscopy, micro-computed tomography (microCT) scanning, histological staining, and mechanical testing. Their mineral density and mechanical properties were compared with those of a typical skeletal bone (the radius) in the same dog. Furthermore, a numerical model of a representative baculum was created and its mechanical performance analyzed using the finite element method, in order to try to elucidate its function. Examination of light microscopy images of transverse sections shows that the baculum consists of a typical sandwich structure, with two cortical plates separated, and joined, by loose cancellous bone. MicroCT scans reveal that the mineral density is lower in the baculum than in the radius, both in castrated as well as in uncastrated dogs, resulting in much lower stiffness. Castration was found to decrease the mineral density in both the baculum and the radius. The most likely function of the baculum of the dog is to stiffen the penis to assist intromission, and its much lower mineral density compared to that of the radius may be a mechanism designed to decrease the stiffness somewhat, and thus reduce the risk of fracture during copulation. PMID- 21708271 TI - Dynamic interactions in the fronto-parietal network during a manual stimulus response compatibility task. AB - Attentional orienting can be modulated by stimulus-driven bottom-up as well as task-dependent top-down processes. In a recent study we investigated the interaction of both processes in a manual stimulus-response compatibility task. Whereas the intraparietal sulcus (IPS) and the dorsal premotor cortex (dPMC) were involved in orienting towards the stimulus side facilitating congruent motor responses, the right temporoparietal junction (TPJ), right dorsolateral prefrontal cortex (DLPFC) as well as the preSMA sustained top-down control processes involved in voluntary reorienting. Here we used dynamic causal modelling to investigate the contributions and task-dependent interactions between these regions. Thirty-six models were tested, all of which included bilateral IPS, dPMC and primary motor cortex (M1) as a network transforming visual input into motor output as well as the right TPJ, right DLPFC and the preSMA as task-dependent top-down regions influencing the coupling within the dorsal network. Our data showed the right temporoparietal junction to play a mediating role during attentional reorienting processes by modulating the inter hemispheric balance between both IPS. Analysis of connection strength supported the proposed role of the preSMA in controlling motor responses promoting or suppressing activity in primary motor cortex. As the results did not show a clear tendency towards a role of the right DLPFC, we propose this region, against the usual interpretation of an inhibitory influence in stimulus-response compatibility tasks, to subserve generic monitoring processes. Our DCM study hence provides evidence for context-dependent top-down control of right TPJ and DLPFC as well as the preSMA in stimulus-response compatibility. PMID- 21708272 TI - Effects of hardware heterogeneity on the performance of SVM Alzheimer's disease classifier. AB - Fully automated machine learning methods based on structural magnetic resonance imaging (MRI) data can assist radiologists in the diagnosis of Alzheimer's disease (AD). These algorithms require large data sets to learn the separation of subjects with and without AD. Training and test data may come from heterogeneous hardware settings, which can potentially affect the performance of disease classification. A total of 518 MRI sessions from 226 healthy controls and 191 individuals with probable AD from the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI) were used to investigate whether grouping data by acquisition hardware (i.e. vendor, field strength, coil system) is beneficial for the performance of a support vector machine (SVM) classifier, compared to the case where data from different hardware is mixed. We compared the change of the SVM decision value resulting from (a) changes in hardware against the effect of disease and (b) changes resulting simply from rescanning the same subject on the same machine. Maximum accuracy of 87% was obtained with a training set of all 417 subjects. Classifiers trained with 95 subjects in each diagnostic group and acquired with heterogeneous scanner settings had an empirical detection accuracy of 84.2+/-2.4% when tested on an independent set of the same size. These results mirror the accuracy reported in recent studies. Encouragingly, classifiers trained on images acquired with homogenous and heterogeneous hardware settings had equivalent cross-validation performances. Two scans of the same subject acquired on the same machine had very similar decision values and were generally classified into the same group. Higher variation was introduced when two acquisitions of the same subject were performed on two scanners with different field strengths. The variation was unbiased and similar for both diagnostic groups. The findings of the study encourage the pooling of data from different sites to increase the number of training samples and thereby improving performance of disease classifiers. Although small, a change in hardware could lead to a change of the decision value and thus diagnostic grouping. The findings of this study provide estimators for diagnostic accuracy of an automated disease diagnosis method involving scans acquired with different sets of hardware. Furthermore, we show that the level of confidence in the performance estimation significantly depends on the size of the training sample, and hence should be taken into account in a clinical setting. PMID- 21708273 TI - Magnetic resonance imaging quantification of regional cerebral blood flow and cerebrovascular reactivity to carbon dioxide in normotensive and hypertensive rats. AB - Hypertension afflicts 25% of the general population and over 50% of the elderly. In the present work, arterial spin labeling MRI was used to non-invasively quantify regional cerebral blood flow (CBF), cerebrovascular resistance and CO(2) reactivity in spontaneously hypertensive rats (SHR) and in normotensive Wistar Kyoto rats (WKY), at two different ages (3 months and 10 months) and under the effects of two anesthetics, alpha-chloralose and 2% isoflurane (1.5 MAC). Repeated CBF measurements were highly consistent, differing by less than 10% and 18% within and across animals, respectively. Under alpha-chloralose, whole brain CBF at normocapnia did not differ between groups (young WKY: 61 +/- 3ml/100g/min; adult WKY: 62 +/- 4ml/100g/min; young SHR: 70 +/- 9ml/100g/min; adult SHR: 69 +/- 8ml/100g/min), indicating normal cerebral autoregulation in SHR. At hypercapnia, CBF values increased significantly, and a linear relationship between CBF and PaCO(2) levels was observed. In contrast, 2% isoflurane impaired cerebral autoregulation. Whole brain CBF in SHR was significantly higher than in WKY rats at normocapnia (young SHR: 139 +/- 25ml/100g/min; adult SHR: 104 +/- 23ml/100g/min; young WKY: 55+/- 9ml/100g/min; adult WKY: 71 +/- 19ml/100g/min). CBF values increased significantly with increasing CO(2); however, there was a clear saturation of CBF at PaCO(2) levels greater than 70mmHg in both young and adult rats, regardless of absolute CBF values, suggesting that isoflurane interferes with the vasodilatory mechanisms of CO(2). This behavior was observed for both cortical and subcortical structures. Under either anesthetic, CO(2) reactivity values in adult SHR were decreased, confirming that hypertension, when combined with age, increases cerebrovascular resistance and reduces cerebrovascular compliance. PMID- 21708274 TI - Past and present: Phylogeography of the Bufo gargarizans species complex inferred from multi-loci allele sequence and frequency data. AB - Using multi-locus DNA sequence and frequency data, we examined the phylogeographic patterns of the Asian toad Bufo gargarizans species complex. A total of 166 individuals from 56 sites were genotyped for one mitochondrial locus (516 base pairs, ND2 gene) and five nuclear intron loci (Sox9-2, Rho-3, CCNB2-3, UCH-2, DBI-2; 250-350 base pairs each). We conducted a phylogenetic analysis of the allele sequence data to construct gene trees for each individual locus using Bayesian inference, a multi-locus phylogeny based on all five nuclear loci using POFAD, and a phylogenetic network using the NeighborNet algorithm. Furthermore, we used population-genetic analysis of the allele frequency data to reveal ongoing processes, including an analysis of molecular variance (AMOVA), a Bayesian assignment analysis, and a non-equilibrium Bayesian method for estimating recent migration rate. Our phylogenetic analyses showed that the observed divergence in the B. gargarizans species complex likely dated back to 7 8 million years ago. Repeated range expansions during the inter-glacial periods of Pleistocene likely established the current distribution of genetic diversity, although historical vicariant events were still evidenced. Both the west and the southeast regions may have served as refugia during the glaciation, and the range expansion was in general from west to northeast. Additionally, we detected strong ongoing migration both from west to the other regions and from south to north, which likely represents a meta-population dynamic that has emerged over the past ~10,000 years. The morphologically identified species Bufo tibetanus is not genetically diagnosable, and therefore should be considered a junior synonym of B. gargarizans. PMID- 21708275 TI - Giants and dwarfs: molecular phylogenies reveal multiple origins of annual spurges within Euphorbia subg. Esula. AB - Euphorbia (Euphorbiaceae) comprises over 2150 species and is thus the second largest genus of flowering plants. In Europe, it is represented by more than 100 species with highest diversity in the Mediterranean area; the majority of taxa belong to subgenus Esula Pers., including about 500 taxa. The few available phylogenetic studies yielded contrasting results regarding the monophyly of subg. Esula, and the phylogenetic relationships among its constituents remain poorly understood. We have sampled DNA sequences from the nuclear ribosomal internal transcribed spacer (ITS) and the plastid trnT-trnF region from about 100, predominantly European taxa of subg. Esula in order to infer its phylogenetic history. The plastid data support monophyly of subg. Esula whereas the ITS phylogeny, which is generally less resolved, is indecisive in this respect. Although some major clades have partly incongruent positions in the ITS and plastid phylogenies, the taxonomic content of the major terminal clades is congruent in both trees. As traditional sectional delimitations are largely not corroborated, an improved classification is proposed. Character state reconstruction illustrates that the annual life form developed independently several times in different clades of subgenus Esula from perennial ancestors, and that several morphological traits used in previous classifications of Euphorbia developed in parallel in different lineages. PMID- 21708276 TI - Phylogeny, genetic variability and colour polymorphism of an emerging animal model: the short-lived annual Nothobranchius fishes from southern Mozambique. AB - Nothobranchius are a group of small, extremely short-lived killifishes living in temporary savannah pools in Eastern Africa and that survive annual desiccation of their habitat as dormant eggs encased in dry mud. One mitochondrial (COI) and three nuclear (CX32.2, GHITM, PNP) loci were used to investigate the phylogenetic relationship of Nothobranchius species from southern and central Mozambique. This group shows marked variation in captive lifespan at both the inter- and intraspecific levels; lifespan varies from a few months to over a year. As their distribution encompasses a steep gradient between semi-arid and humid habitats, resulting in contrasting selection pressures on evolution of lifespan and associated life history traits, Mozambican Nothobranchius spp. have recently become a model group in studies of ageing, age-related disorders and life history evolution. Consequently, intraspecific genetic variation and male colour morph distribution was also examined in the recovered clades. Using Bayesian species tree reconstruction and single loci analyses, three large clades were apparent and their phylogenetic substructure was revealed at the inter- and intra-specific levels within those clades. The Nothobranchius furzeri and Nothobranchius orthonotus clades were strongly geographically structured. Further, it was demonstrated that male colour has no phylogenetic signal in N. furzeri, where colour morphs are sympatric, but is associated with two reciprocally monophyletic groups in Nothobranchius rachovii clade, where colour morphs are parapatric. Finally, our analysis showed that a polymorphism in the Melanocortin1 receptor gene (which controls pigmentation in many vertebrates and was a candidate gene of male colouration in N. furzeri) is unrelated to colour phenotypes of the study species. Our results raise significant implications for future comparative studies of the species and populations analysed in the present work. PMID- 21708277 TI - Hippocampal PKA/CREB pathway is involved in the improvement of memory induced by spermidine in rats. AB - Spermidine (SPD) is an endogenous polyamine that modulates N-methyl-D-aspartate (NMDA) receptor function, and has been reported to facilitate memory formation. In the current study we determined whether or not the PKA/CREB signaling pathway is involved in SPD-induced facilitation of memory of inhibitory avoidance task in adult rats. The post-training administration of the cAMP-dependent protein kinase (PKA) inhibitor, N-[2-bromocinnamylamino)ethyl]-5-isoquinoline sulfonamide [H-89, 0.5 rhomol intrahippocampal (ih)] or the antagonist of the NMDA receptor polyamine-binding site (arcaine, 0.02 nmol ih) with SPD (0.2 nmol ih) prevented memory improvement induced by SPD. Intrahippocampal administration of SPD (0.2 nmol) facilitated PKA and cAMP response element-binding protein (CREB) phosphorylation in the hippocampus 180 min, but not 30 min, after administration, and increased translocation of the catalytic subunit of PKA into the nucleus. Arcaine (0.02 nmol) and H-89 (0.5 rhomol) prevented the stimulatory effect of SPD on PKA and CREB phosphorylation. These results suggest that memory enhancement induced by the ih administration of SPD involves the PKA/CREB pathways in rats. PMID- 21708278 TI - Characterisation of the heat shock factor of the human thermodimorphic pathogen Paracoccidioides lutzii. AB - Thermodimorphic fungi include most causative agents of systemic mycoses, but the molecular mechanisms that underlie their defining trait, i.e. the ability to shift between mould and yeast on temperature change alone, remain poorly understood. We hypothesised that the heat shock factor (Hsf), a protein that evolved to sense thermal stimuli quickly, might play a role in this process in addition to the known regulator Drk1 and the Ryp proteins. To test this hypothesis, we characterised the Hsf from the thermodimorph Paracoccidioides lutzii (formerly Paracoccidioides brasiliensis isolate 01). We show in the present work that PlHsf possesses regulatory domains that are exclusive of the Eurotiomycetidae family, suggesting evolutionary specialisation; that it can successfully rescue the otherwise lethal loss of the native protein of Saccharomyces cerevisiae; and that its DNA-binding domain is able to recognise regulatory elements from the promoters of both Drk1 and Ryp1. An in silico screening of all 1 kb sequences upstream of P. lutzii ORFs revealed that 7% of them possess a heat shock element. This is the first description of a heat shock factor in a thermodimorphic fungus. PMID- 21708279 TI - Biopharma business models in Canada. AB - This article provides new insights into the different strategy paths or business models currently being implemented by Canadian biopharma companies. Through a case-study methodology, seven biopharma companies pertaining to three business models were analyzed, leading to a broad set of results emerging from the following areas: activity, business model and strategy; management and human resources; and R&D, technology and innovation strategy. The three business models represented were: model 1 (conventional biotech oriented to new drug development, radical innovation and search for discoveries); model 2 (development of a technology platform, usually in proteomics and bioinformatics); and model 3 (incremental innovation, with shorter and less risky development timelines). PMID- 21708280 TI - Candidate gene studies in gallbladder cancer: a systematic review and meta analysis. AB - Gallbladder cancer (GBC) is the most frequent biliary tract malignancy. Wide variations in GBC incidence and familial and epidemiological data suggest involvement of a genetic component in its etiopathogenesis. A systematic review of genetic association studies in GBC was performed by applying a meta-analysis approach and systematically reviewing PubMed database using appropriate terms. Odds ratios (ORs) and 95% confidence intervals (CIs) were appropriately derived for each gene-disease association using fixed and random effect models. Meta regression with population size and genotyping method was also performed. Study quality was assessed using a 10-point scoring system designed from published guidelines. Following a review of 44 published manuscripts and one unpublished report, 80 candidate gene variants and 173 polymorphisms were analyzed among 1046 cases and 2310 controls. Majority of studies were of intermediate quality. Four polymorphisms with >3 separate studies were included in the meta-analysis [OGG1 (rs1052133), TP53 (rs1042522), CYP1A1 (rs1048943) and GSTM1 null polymorphism]. The meta-analysis demonstrated no significant associations of any of the above polymorphisms with GBC susceptibility except TP53 (rs1042522) polymorphism. To conclude, existing candidate gene studies in GBC susceptibility have so far been insufficient to confirm any association. Future research should focus on a more comprehensive approach utilizing potential gene-gene, gene-environment interactions and high-risk haplotypes. PMID- 21708281 TI - Telomeric DNA in chromosomes of five opisthorchid species. AB - The analysis of telomere repeat distribution in chromosomes of five opisthorchid species (Opisthorchis felineus (Rivolta, 1884), Opisthorchis viverrini (Poirier, 1886), Metorchis xanthosomus (Creplin, 1846), Metorchis bilis (Braun, 1890), Clonorchis sinensis (Cobbold, 1875)) was performed with fluorescent in situ hybridization (FISH) of labeled (TTAGGG)n DNA-probe and PNA telomere probe on mitotic and meiotic chromosomes of these species. It was shown that chromosome telomeres of all studied species contain large clusters of (TTAGGG)n telomeric repeats. Interstitial clusters of the (TTAGGG)n repeats have not been revealed in the chromosomes of any studied species even when FISH of PNA telomere probe on pachytene chromosomes was performed. Furthermore interstitial clusters of the (TTAGGG)n repeats have not been detected in the chromosomes of O. viverrini, one of chromosomes of this species is the result of a fusion of two ancestral opisthorchid chromosomes. PMID- 21708283 TI - Informatics and computational strategies for the study of lipids. AB - The ability to translate vast amounts of information, as obtained from lipidomic analysis, into the knowledge and understanding of biological phenomena is an important challenge faced by the lipidomics community. While many of the informatics and computational tools from other domains such as bioinformatics and metabolomics are also applicable to lipidomics data processing and analysis, new solutions and strategies are needed for the studies of lipidomes at the systems level. This is due to enormous functional and structural diversity of lipids as well as because of their complex regulation at multiple spatial and temporal scales. In order to better understand the lipidomes at the physiological level, lipids need to be modeled not only at the level of biological pathways but also at the level of the biophysical systems they are part of, such as cellular membranes or lipoprotein particles. Herein the current state, recent advances and new opportunities in the field of lipid bioinformatics are reviewed. PMID- 21708282 TI - Lipid analysis and lipidomics by structurally selective ion mobility-mass spectrometry. AB - Recent advances in mass spectrometry approaches to the analysis of lipids include the ability to incorporate both lipid class identification with lipid structural information for increased characterization capabilities. The detailed examination of lipids and their biosynthetic and biochemical pathways made possible by novel instrumental and bioinformatics approaches is advancing research in fundamental cellular and medical studies. Recently, high-throughput structural analysis has been demonstrated through the use of rapid gas-phase separation on the basis of the ion mobility (IM) analytical technique combined with mass spectrometry (IM MS). While IM-MS has been extensively utilized in biochemical research for peptide, protein and small molecule analysis, the role of IM-MS in lipid research is still an active area of development. In this review of lipid-based IM-MS research, we begin with an overview of three contemporary IM techniques which show great promise in being applied towards the analysis of lipids. Fundamental concepts regarding the integration of IM-MS are reviewed with emphasis on the applications of IM-MS towards simplifying and enhancing complex biological sample analysis. Finally, several recent IM-MS lipid studies are highlighted and the future prospects of IM-MS for integrated omics studies and enhanced spatial profiling through imaging IM-MS are briefly described. PMID- 21708284 TI - Comparison of allelic discrimination by dHPLC, HRM, and TaqMan in the detection of BRAF mutation V600E. AB - The V600E mutation in the BRAF oncogene is associated with colorectal carcinomas, with mismatch-repair deficiency and, recently, with nonresponse to epidermal growth factor receptor inhibitor therapy. The use of reliable techniques for its detection is important. The aim of our study was to compare the performance characteristics in V600E detection of denaturing high-performance liquid chromatography (dHPLC) and high-resolution melting (HRM) with TaqMan allelic discrimination as well as direct-sequencing methods in a series of 195 colorectal paraffin-embedded specimens up to the age of 15 years. The effectiveness for obtaining results on mutation status was best using TaqMan (96.9%), followed by dHPLC (93.3%), HRM (88.7%), and sequencing (88.2%). In general, TaqMan was best for analyzing older tissues, whereas sequencing was the least efficient. Heterozygotic V600E was detected in 11.6%, 9.9%, 11.6%, and 9.9% of tissues using TaqMan, dHPLC, HRM, and sequencing, respectively. Result concordances between dHPLC and TaqMan or sequencing were excellent (kappa = 0.9411 and kappa = 0.8988, respectively); for HRM, the concordances were good (kappa = 0.7973 and kappa = 0.7488, respectively). By using DNA dilutions from tumor tissue, a minimum of 10% of V600E harboring cancer content was required for the analysis by dHPLC and HRM. dHPLC could detect four non-V600E mutations, whereas HRM detected one. Our results indicate that dHPLC and HRM are techniques that can be reliably used for the detection of the BRAFV600E mutation in archival paraffin-embedded tissues. PMID- 21708285 TI - Development and clinical implementation of a combination deletion PCR and multiplex ligation-dependent probe amplification assay for detecting deletions involving the human alpha-globin gene cluster. AB - The alpha-thalassemias are a group of hereditary disorders caused by reduced synthesis of the alpha-chain of hemoglobin. We have developed and tested an alpha thalassemia assay that uses both multiplex ligation-dependent probe amplification (MLPA) with Luminex-based detection and deletion PCR technologies. The MLPA assay consisted of 20 probes, 15 of which hybridized to the alpha-globin gene cluster and 5 that served as control probes. A PCR assay was developed to confirm the presence of heterozygous/homozygous 3.7-kb and 4.2-kb deletions. MLPA and PCR results were compared to Southern blot (SB) results from 758 and 133 specimens, respectively. Lastly, MLPA and PCR results were reviewed and summarized from 5386 clinically tested specimens. SB and MLPA results were concordant in 678/687 (99%) specimens. PCR detected all deletions detected by SB with no false positives. No deletions or duplications were identified in 2630 (49%) clinically tested specimens. Extra alpha-globin copies were identified in 76 patients. A deletion of one or two alpha-globin genes was identified in 1251 (23%) and 1349 (25%) specimens, respectively, including 15 different genotypes. A deletion of three (hemoglobin H) and four alpha-globin genes (Hb Bart's) was observed in 65 or 3 specimens, respectively. Six patients had a deletion within the alpha-globin regulatory region MCS-R2. Thus, MLPA plus deletion PCR identify multiple alpha globin gene deletions/duplications in patients being tested for alpha thalassemia. PMID- 21708286 TI - Orphan missense mutations in the cystic fibrosis transmembrane conductance regulator: A three-step biological approach to establishing a correlation between genotype and phenotype. AB - More than 1860 mutations have been found within the human cystic fibrosis transmembrane conductance regulator (CFTR) gene sequence. These mutations can be classified according to their degree of severity in CF disease. Although the most common mutations are well characterized, few data are available for rare mutations. Thus, genetic counseling is particularly difficult when fetuses or patients with CF present these orphan variations. We describe a three-step in vitro assay that can evaluate rare missense CFTR mutation consequences to establish a correlation between genotype and phenotype. By using a green fluorescent protein-tagged CFTR construct, we expressed mutated proteins in COS-7 cells. CFTR trafficking was visualized by confocal microscopy, and the cellular localization of CFTR was determined using intracellular markers. We studied the CFTR maturation process using Western blot analysis and evaluated CFTR channel activity by automated iodide efflux assays. Of six rare mutations that we studied, five have been isolated in our laboratory. The cellular and functional impact that we observed in each case was compared with the clinical data concerning the patients in whom we encountered these mutations. In conclusion, we propose that performing this type of analysis for orphan CFTR missense mutations can improve CF genetic counseling. PMID- 21708287 TI - Performance and clinical evaluation of the 92-gene real-time PCR assay for tumor classification. AB - Accurate determination of cancer origin is necessary to guide optimal treatment but remains a diagnostic challenge. Gene expression profiling technologies have aided the classification of tumors and, therefore, could be applied in conjunction with clinicopathologic correlates to improve accuracy. We report an expanded version of the previously described 92-gene assay to classify 30 main tumor types and 54 histological subtypes, with coverage of >=95% of all solid tumors based on incidence. Increased tissue coverage was achieved through expansion of a reference tumor database containing 2,206 specimens, with a median of 62 samples per main tumor type. The 92-gene classification algorithm demonstrated sensitivities of 87% and 85% for 30 main types and 54 histological subtypes, respectively, in leave-one-out cross validation, and 83% in a test set of 187 tumors representing 28 of the 30 main cancer types. These findings provide further support that broad and diverse tumor classification can be performed using a relatively compact gene set. An additional 300 consecutive cases submitted for clinical testing were profiled to characterize clinical utility in a real-world setting: the 92-gene assay confirmed 78% of samples having a single suspected primary tumor and provided a single molecular prediction in 74% of cases with two or more differential diagnoses. Further development of the 92-gene RT-PCR assay has resulted in a significant expansion in reportable tumor types and histological features with strong performance characteristics and supports the use of molecular classification as an objective standardized adjunct to current methods. PMID- 21708289 TI - Nifedipine inhibits vascular smooth muscle cell proliferation and reactive oxygen species production through AMP-activated protein kinase signaling pathway. AB - The dihydropyridine calcium channel blocker nifedipine induces specific pharmacological effects by binding to L-type calcium channels, which results in a reduced calcium influx in vascular smooth muscle cells (VSMCs) and is currently employed in antihypertensive drug. Dihydropyridine calcium channel blocker is reported to reduce oxidative stress and exhibits anti-proliferative effect in VSMCs. VSMCs are useful in the study of atherosclerosis because they show cell proliferation and reactive oxygen species (ROS) production with growth factor. To determine the mechanisms involved in these effects, we investigated the influence of nifedipine-induced AMP-activated protein kinase (AMPK) activation on VSMC proliferation and ROS production by using rat aortic VSMCs in vitro and in vivo. Nifedipine induced phosphorylation of AMPK in a dose-and time-dependent manner, and inhibited rat VSMC proliferation and ROS production following stimulation with 15% fetal bovine serum (FBS). Nifedipine also blocked the FBS-stimulated cell cycle progression through the G0/G1 arrest. Compound C, a specific inhibitor of AMPK, or AMPK siRNA reduced the nifedipine-mediated inhibition of VSMC proliferation. As an upstream kinase, LKB1 is required for nifedipine-induced AMPK activation in VSMCs. 7 days oral administration of 1 mg/kg nifedipine resulted in activation of LKB1 and AMPK in vivo. These data suggest that nifedipine suppress the VSMC proliferation and ROS production via activating LKB1 AMPK pathway. PMID- 21708290 TI - Towards the molecular epidemiology of Mycobacterium leprae: strategies, successes, and shortcomings. AB - Mycobacterium leprae, the causative agent of leprosy, is an unusual organism that presents unique challenges to those studying the disease through molecular epidemiology. As a consequence, many basic aspects of disease transmission and biology remain unilluminated. In this review, we explore the general principles of molecular epidemiology, and the special difficulties surrounding the application of molecular epidemiology to M. leprae. We briefly discuss the computational tools commonly employed in molecular epidemiology studies. The past decade of developments in molecular strain typing approaches through VNTRs and SNP loci, and their merits and limitations, are discussed. We summarize what has been learned about the transmission and historical origins of leprosy through molecular epidemiology and Bacterial Population Genetics, to date. Lastly, we critically evaluate the strengths and shortcomings of leprosy research, and present recommendations for future work that will hopefully shed light on some of the disease's most fundamental mysteries. PMID- 21708291 TI - Cytokine gene haplotypes with a potential effect on susceptibility to malaria in sympatric ethnic groups in Mali. AB - Cytokines are important players in the immune responses, and an unbalance in pro- and anti-inflammatory cytokine responses may affect parasitemia and pathology in a Plasmodium falciparum infection. Polymorphisms in cytokine genes may affect not only the levels of the protein, but many down-stream functions, such as production of C-reactive protein and immunoglobulin isotype switching. Susceptibility to malaria has been shown to differ between individuals with different genetic backgrounds, as indicated by studies in Fulani and non-Fulani ethnic groups. The aim of this study was to investigate possible interethnic differences in totally twelve single nucleotide polymorphisms (SNPs) in the genes encoding the cytokines IL-1beta, IL-6, IL-10 and TNF. These SNPs are present in the promoter region of the genes, and have previously been associated with cytokine expression and with disease outcome in malaria. The results from the present study suggest that the Fulani ethnic group has a more pro-inflammatory response, due to high frequencies of high-producing alleles of IL1beta and low producing alleles of IL10. IL-6 could potentially also contribute to the relatively lower susceptibility to malaria in the Fulani ethnic group, whereas the TNF polymorphisms analysed in this study rather seem to associate with the severity of the infection and not the susceptibility for the infection itself. We therefore suggest that the polymorphisms analysed in this study all show a potential to influence the relatively lower susceptibility to malaria seen in the Fulani ethnic group as compared to the other sympatric ethnic groups. PMID- 21708292 TI - Surveillance and molecular characterization of human influenza B viruses during 2006-2010 revealed co-circulation of Yamagata-like and Victoria-like strains in eastern India. AB - Acute respiratory illness (ARI) is one of the major health problems in tropical countries of Asia, like India where approximately 0.5 million children in the age group of < 5 years die annually. Previously we have reported the genetic characterization of influenza A (Inf-A) strains circulating in Kolkata, eastern India. This study was initiated to characterize the genetic diversity of the circulating influenza B (Inf-B) viruses. Of 3035 nasal/throat swabs, 494 (16.3%) samples were identified as influenza A/B positive by real time RT-PCR, of which 244 samples were confirmed having Inf-B infection. Comparison of nucleotide (nt) and amino acid (aa) sequences of HA and NA gene of Inf-B viruses revealed co circulation of B/Yamagata and B/Victoria lineages. Of the 32 randomly selected Inf-B strains from Kolkata, seventeen strains possessed reassorted NA gene. There was a single Histidine to Asparagine substitution in the 131st position which is a part of 120 loop on HA1 region along with a deletion at position 178 in the Kolkata strains belonging to the Yamagata lineage. Amino acid substitution was observed at position 198 on NA gene in the strains B/Kol/542/2006, B/Kol/1373/2008, B/Kol/1880/2008, B/Kol/2044/2008 and in all the representative strains isolated during 2009 with respect to the circulating vaccine strains. This substitution is responsible for reduced sensitivity of neuraminidase inhibitors. The results highlight the importance of monitoring Inf-B viruses for development of antiviral resistance among circulating strains. PMID- 21708293 TI - Lactic acid bacteria in the prevention of pneumococcal respiratory infection: future opportunities and challenges. AB - Lactic acid bacteria (LAB) are technologically and commercially important and have various beneficial effects on human health. Several studies have demonstrated that certain LAB strains can exert their beneficial effect on the host through their immunomudulatory activity. Although most research concerning LAB-mediated enhanced immune protection is focused on gastrointestinal tract pathogens, recent studies have centered on whether these immunobiotics might sufficiently stimulate the common mucosal immune system to provide protection to other mucosal sites as well. In this sense, LAB have been used for the development of probiotic foods with the ability to stimulate respiratory immunity, which would increase resistance to infections, even in immunocompromised hosts. On the other hand, the advances in the molecular biology of LAB have enabled the development of recombinant strains expressing antigens from respiratory pathogens that have proved effective to induce protective immunity. In this review we examine the current scientific literature concerning the use of LAB strains to prevent respiratory infections. In particular, we have focused on the works that deal with the capacity of probiotic and recombinant LAB to improve the immune response against Streptococcus pneumoniae. Research from the last decade demonstrates that LAB represent a promising resource for the development of prevention strategies against respiratory infections that could be effective tools for medical application. PMID- 21708294 TI - Exercise ventilatory kinematics in endurance trained and untrained men and women. AB - To determine how increased ventilatory demand impacts ventilatory kinematics, we compared the total chest wall volume variations (V(CW)) of male and female endurance-trained athletes (ET) to untrained individuals (UT) during exercise. We hypothesized that training and gender would have an effect on V(CW) and kinematics at maximal exercise. Gender and training significantly influenced chest wall kinematics. Female ET did not change chest wall end-expiratory volume (V(CW,ee)) or pulmonary ribcage (V(RCp,ee)) with exercise, while female UT significantly decreased V(CW,ee) and V(RCp,ee) with exercise (p<0.05). Female ET significantly increased pulmonary ribcage end-inspiratory volume (V(RCp,ei)) with exercise (p<0.05), while female UT did not change V(RCp,ei) with exercise. Male ET significantly increased V(RCp,ei) with exercise (p<0.05); male UT did not. Men and women had significantly different variation of V(CW) (p<0.05). Women demonstrated the greatest variation of V(CW) in the pulmonary ribcage compartment (V(RCp)). Men had even volumes variation of the V(RCp) and the abdomen (V(Ab)). In conclusion, gender and training had a significant impact on ventilatory kinematics. PMID- 21708295 TI - The presence of N(epsilon)-(Carboxymethyl) lysine in the human epidermis. AB - It is well known that advanced glycation end products (AGEs) are formed in long lived dermal proteins such as collagen, and that their formation is related to skin aging. To examine the distribution of AGEs in skin tissue, we performed immunofluorescence studies on the human skin using an anti-AGEs antibody. Interestingly, AGEs signals were observed not only in the dermis but also in the epidermis. The objectives of this study were to confirm the presence of N(epsilon)-(Carboxymethyl) lysine (CML), an AGE structure, in the epidermis and to characterize the CML-modified proteins. The presence of CML in the stratum corneum (SC) was examined using liquid chromatography-electrospray ionization time-of-flight mass spectrometry. Concordance between the retention times of a compound in the SC hydrolysate and authentic CML, as well as with the specific mass transition of CML, was detected. This result showed that CML is present in the epidermis. In order to characterize the CML-modified proteins in the epidermis, protein samples extracted from the SC were analyzed using two dimensional electrophoresis followed by an amino acid sequence analysis. The clarified peptide sequences covered approximately 27% of the amino acid sequences of cytokeratin 10 (K10). In the immunoblotting experiment following the two dimensional electrophoresis, where protein samples extracted from whole epidermis were used, the position of the major CML-positive spots corresponded to those of K10. Taken together these results showed that CML is present in the human epidermis, and suggest that K10 is one of the target molecules for CML modification in the epidermis. PMID- 21708296 TI - Role of thiamine pyrophosphate in oligomerisation, functioning and import of peroxisomal 2-hydroxyacyl-CoA lyase. AB - During peroxisomal alpha-oxidation, the CoA-esters of phytanic acid and 2 hydroxylated straight chain fatty acids are cleaved into a (n-1) fatty aldehyde and formyl-CoA by 2-hydroxyacyl-CoA lyase (HACL1). HACL1 is imported into peroxisomes via the PEX5/PTS1 pathway, and so far, it is the only known peroxisomal TPP-dependent enzyme in mammals. In this study, the effect of mutations in the TPP-binding domain of HACL1 on enzyme activity, subcellular localisation and oligomerisation was investigated. Mutations of the aspartate 455 and serine 456 residues within the TPP binding domain of the human HACL1 did not affect the targeting upon expression in transfected CHO cells, although enzyme activity was abolished. Gel filtration of native and mutated N-His(6)-fusions, expressed in yeast, revealed that the mutations did not influence the oligomerisation of the (apo)enzyme. Subcellular fractionation of yeast cells expressing HACL1 showed that the lyase activity sedimented at high density in a Nycodenz gradient. In these fractions TPP could be measured, but not when mutated HACL1 was expressed, although the recombinant enzyme was still targeted to peroxisomes. These findings indicate that the binding of TPP is not required for peroxisomal targeting and correct folding of HACL1, in contrast to other TPP dependent enzymes, and suggest that transport of TPP into peroxisomes is dependent on HACL1 import, without requirement of a specific solute transporter. PMID- 21708297 TI - A de novo balanced translocation t(7;12)(p21.2;p12.3) in a patient with Saethre Chotzen-like phenotype downregulates TWIST and an osteoclastic protein-tyrosine phosphatase, PTP-oc. AB - Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with variable expression. Here we report on a female infant with a de novo balanced translocation 46, XX, t(7;12)(p21.2;p12.3) and presenting at birth brachycephaly, antimongolic palpebral fissures, ocular hypertelorism, broad nose with low nasal bridge and low-set ears. This phenotype is suggestive of a subtle form of SCS, given the absence of limbs anomalies. Cloning of both breakpoints revealed that the translocation does not interrupt the TWIST1 coding region, on 7p21, known to be causative for SCS, but downregulates TWIST1 expression due to a position effect. On chromosome 12, the breakpoint translocates a shorter transcript of PTPRO gene, the osteoclastic protein-tyrosine phosphatase, PTP-oc, near to regulatory region of 7p leading to down-regulation of PTP-oc in the proband's fibroblasts. This is a confirmatory case report providing further evidence for TWIST1 haploinsufficiency in SCS, although a possible role of PTP-oc as genetic factor underlying or at least influencing the development of craniosynostosis could not be a priori excluded. PMID- 21708298 TI - Biomarkers of disease and post-mortem changes - Heat stabilization, a necessary tool for measurement of protein regulation. AB - This review focuses on post sampling changes and how the Stabilizor system has been used to control this natural biological process and potential implications on cancer-specific biomarkers due to post sampling changes. Tissue sampling is a major traumatic event that can have drastic effects within a very short timeframe at the molecular level [1] resulting in loss of sample quality due to post-mortem changes. A heat-stabilization technology, using the Stabilizor system, has been developed to quickly and permanently abolish the enzymatic activity that causes these changes post-sampling and so preserve sample quality. The Stabilizor system has been shown to give better sample quality when analyzing a variety of tissues in various proteomic workflows. In this paper we discuss the impact of using heat stabilized tissue in different proteomic applications. Based on our observations regarding the overlap between commonly changing proteins and proteins found to change post-mortem we also highlight a group of proteins of particular interest in cancer studies. PMID- 21708299 TI - Chromatin modifications and remodeling in plant abiotic stress responses. AB - Sensing environmental changes and initiating a gene expression response are important for plants as sessile autotrophs. The ability of epigenetic status to alter rapidly and reversibly could be a key component to the flexibility of plant responses to the environment. The involvement of epigenetic mechanisms in the response to environmental cues and to different types of abiotic stresses has been documented. Different environmental stresses lead to altered methylation status of DNA as well as modifications of nucleosomal histones. Understanding how epigenetic mechanisms are involved in plant response to environmental stress is highly desirable, not just for a better understanding of molecular mechanisms of plant stress response but also for possible application in the genetic manipulation of plants. In this review, we highlight our current understanding of the epigenetic mechanisms of chromatin modifications and remodeling, with emphasis on the roles of specific modification enzymes and remodeling factors in plant abiotic stress responses. This article is part of a Special Issue entitled: Plant gene regulation in response to abiotic stress. PMID- 21708300 TI - The type II collagen N-propeptide, PIIBNP, inhibits cell survival and bone resorption of osteoclasts via integrin-mediated signaling. AB - OBJECTIVE: Type IIB procollagen is characteristic of cartilage, comprising 50% of the extracellular matrix. The NH(2)-propeptide of type IIB collagen, PIIBNP, can kill tumor cells via binding to integrins alpha(V)beta(3) and alpha(V)beta(5). As osteoclasts rely on alpha(V)beta(3) integrins for function in bone erosion, we sought to determine whether PIIBNP could inhibit osteoclast function. METHODS: We undertook in vitro and in vivo experiments to evaluate both osteoblast and osteoclast functions in the presence of recombinant PIIBNP. Adhesion of osteoclasts to PIIBNP was analyzed by staining of attached cells with crystal violet. PIIBNP-induced cell death was evaluated by counting Trypan Blue stained cells. The mechanism of cell death was evaluated by DNA fragmentation, TUNEL staining and western blotting to detect cleaved caspases. To determine the role of alpha(V)beta(3) integrin, osteoclasts were pretreated with alpha(V) or beta(3) integrin specific siRNA before the treatment with PIIBNP. To explore PIIBNP function in vivo, a lipopolysaccharide-induced mouse calvaria lysis model was employed. RESULTS: Osteoclasts adhered to PIIBNP via an RGD-mediated mechanism. When osteoclasts were plated on extracellular matrix proteins, PIIBNP induced apoptosis of osteoclasts via caspase 3/8 activation. Osteoblasts and macrophages were not killed. Reduction of alpha(V) or beta(3) integrin levels on osteoclasts by siRNA reduced cell death in a dose-dependent manner. In vivo, PIIBNP could inhibit bone resorption. CONCLUSION: We conclude that PIIBNP can inhibit osteoclast survival and bone resorption via signal transduction through the alpha(V)beta(3) integrins. Because of this property and the cell specificity, we propose that PIIBNP may play a role in vivo in protecting cartilage from osteoclast invasion and also could be a new therapeutic strategy for decreasing bone loss. PMID- 21708301 TI - Roles of the endoplasmic reticulum stress transducer OASIS in fracture healing. AB - A new type of endoplasmic reticulum (ER) stress transducer, Old Astrocyte Specifically Induced Substance (OASIS), which is induced by bone morphogenetic protein-2 (BMP2), has been reported to activate the transcription of type I collagen and contribute to the secretion of bone matrix proteins in osteoblasts. Here, we examined the role of OASIS in fracture healing using the fracture models in wild-type (WT) and OASIS(-/-) mice. We found that the expression of OASIS mRNA was induced after fracture. Micro-computed tomography indicated that the callus density of OASIS(-/-) mice was less than that of WT mice, and the newly formed bone in OASIS(-/-) mice exhibited a decrease of the bone volume by bone morphometric analysis. Biomechanically, the callus bone strength of OASIS(-/-) mice was inferior to that of WT mice. Based on RT-PCR, in situ hybridization, immunohistochemical, and electrophoretic analyses, it was clarified that the synthesis of type I collagen was impaired in OASIS(-/-) mice. Electron microscopic analysis revealed that OASIS(-/-) osteoblasts in the fracture callus contained the abnormal expansion of the ERs, similar to OASIS(-/-) osteoblasts in the normal skeletal development. Thus, OASIS may play a role in bone formation through the expression of type I collagen and the secretion of bone matrix proteins in fracture healing. PMID- 21708302 TI - What is the role of apolipoprotein E for cognitive functioning across the lifespan? PMID- 21708303 TI - Depression symptoms, low-grade inflammatory activity, and new targets for clinical intervention. PMID- 21708304 TI - Further evidence for vascular mediation of Alzheimer's dementia pathogenesis? PMID- 21708305 TI - Behavioral pharmacology of orofacial movement disorders. AB - Dysfunction in orofacial movement is evident in patients with schizophrenia, Parkinson's disease and Huntington's disease. In animal studies on orofacial dyskinesia, these neurological disorders have been considered as a starting point to examine the pathophysiology and mechanisms underlying the symptoms. There is circumstantial evidence that orofacial dyskinesia in humans might be the consequence of hyperfunctioning mesolimbic-pallidal circuitry, in which the mesolimbic region occupies a central role, in contrast to typical Parkinson-like symptoms which involve hypofunction in the nigrostriato-nigral circuity. Studies in animals suffer from technical difficulties concerning the assessment of orofacial behaviors. There are some experimental designs that provide detailed information on the amplitude and the frequency of the jaw movements. By using such methods, the involvement of neurotransmitter systems and functional neural connections within the basal ganglia has been studied in rat rhythmical jaw movements. Regarding neurotransmitter systems, dopaminergic, cholinergic, gamma aminobutyric acid (GABA)ergic and glutamaterigic systems have been shown to be involved in rat rhythmical jaw movements. The involved neural connections have also been investigated, focusing on the differential role between the dorsal and ventral part of the striatum, the shell and core of the nucleus accumbens and the output pathways from the striatum and the nucleus accumbens. Taking available clinical and experimental evidence, the orofacial dyskinesias are thought to arise when hierarchically lower order output stations of the mesolimbic region start to dysfunction as a consequence of the arrival of distorted information sent by the mesolimbic region. This review seeks to provide an overview of prior and recent findings across several orofacial movement disorders and interpret new insights in the context of the limitations of behavioral pharmacology and prior knowledge of the regulation of behavior by dopamine receptors and other related neuronal systems. PMID- 21708306 TI - Regulation of orofacial movement: dopamine receptor mechanisms and mutant models. AB - Orofacial movements involve complex processes that include generators for down stream patterns, with up-stream regulatory mechanisms. While the neurotransmitter dopamine plays a fundamental role, the role of individual dopamine receptor subtypes and their associated transduction mechanisms is unclear. Here we review systematic, comparative studies of orofacial function in mutant mice with "knockout" of D1, D2, D3, D4 or D5 receptors, or of their critical transduction component DARPP-32 at four levels: general orofacial behaviors within the mouse repertoire, as assessed naturalistically; individual components of orofacial movement, as assessed under non-naturalistic conditions; each of the above, as assessed also under challenge with a D1-like vs a D2-like agonist. Studies in these "knockouts" provide novel insights into the motoric "building blocks" that regulate orofacial function. PMID- 21708307 TI - Regulation of orofacial movement: amino acid mechanisms and mutant models. AB - Generation and regulation of orofacial movements involve complex mechanisms that include primary roles not only for dopamine but also the amino acid neurotransmitters gamma-aminobutyric acid (GABA) and glutamate. However, the roles of individual GABA and glutamate receptor subtypes, subunits and associated processes are unclear. Here we outline studies of motor function in mutant mice with "knockout" of GABA and glutamate receptor subtypes. We then review systematic studies of orofacial movements in mutants with (i) "Knockout" of phospholipase C-related catalytically inactive protein (PRIP), which regulates cell surface expression of GABA(A) receptors containing a gamma2 subunit, and: (ii) Heterozygous deletion of neuregulin-1 which, inter alia, regulates glutamate receptor-mediated processes. Each of GABAergic and glutamatergic sytems regulate specific topographies of orofacial movement both individually and via interactions with dopaminergic processes. PMID- 21708308 TI - The trigeminal circuits responsible for chewing. AB - Mastication is a vital function that ensures that ingested food is broken down into pieces and prepared for digestion. This review outlines the masticatory behavior in terms of the muscle activation patterns and jaw movements and gives an overview of the organization and function of the trigeminal neuronal circuits that are known to take part in the generation and control of oro-facial motor functions. The basic pattern of rhythmic jaw movements produced during mastication is generated by a Central Pattern Generator (CPG) located in the pons and medulla. Neurons within the CPG have intrinsic properties that produce a rhythmic activity, but the output of these neurons is modified by inputs that descend from the higher centers of the brain, and by feedback from sensory receptors, in order to constantly adapt the movement to the food properties. PMID- 21708309 TI - Ultrastructural basis for craniofacial sensory processing in the brainstem. AB - The study of projections and synaptic connectivity of trigeminal sensory and proprioceptive afferents in the 1(st) relay nucleus of the brainstem, helps us to understand where and how the specific craniofacial neural information is transmitted and processed in the CNS. This paper reviews recent findings on the synaptic connectivity of specific craniofacial sensory and proprioceptive afferents in the brainstem. It also deals with neurotransmitters and receptors involved in the presynaptic modulation of the trigeminal primary afferents. Here, we will also review recent findings on the projection and synaptic connectivity of the axons, and terminals in the trigeminal sensory nuclei that express nociceptive markers such as theromosensitive TRP channels TRPV1 and TRPA1, and the purinergic receptor P2X3. The dental pulp is a good model for the study of peripheral pain because it is densely innervated by nociceptive afferents. Finally, we describe the axons innervating the dental pulp and the morphological changes that the myelinated axons undergo during their intradental course. PMID- 21708310 TI - Mechanisms of nociceptive transduction and transmission: a machinery for pain sensation and tools for selective analgesia. AB - Many surgical and dental procedures depend on use of local anesthetics to reversibly eliminate pain. By the blockade of voltage-gated sodium channels, local anesthetics prevent the transmission of nociceptive information. However, since all local anesthetics act non-selectively on all types of axons they also cause a loss of innocuous sensation, motor paralysis and autonomic block. Thus, approaches that produce only a selective blockade of pain fibers are of great potential clinical importance. In this chapter we will review the recent findings describing mechanisms of pain transduction and transmission and introduce novel therapeutic approaches to produce pain-selective analgesia. PMID- 21708311 TI - Peripheral and central mechanisms of orofacial inflammatory pain. AB - Many orofacial pain conditions involve inflammation of orofacial tissues and they range from acute pulpitis (toothache) and mucositis to chronic arthritic conditions affecting the temporomandibular joint (TMJ). This article reviews the peripheral and central neural mechanisms involved in orofacial inflammatory pain states, including the integral role that peripheral and central sensitization play in the pain features that characterize these states. It also outlines the recent evidence for the contribution of non-neural processes, especially those involving glial cells. PMID- 21708313 TI - Physiological mechanisms of neuropathic pain: the orofacial region. AB - Neuropathic pain in the orofacial region is the clinical manifestation of trigeminal nerve injury following oral surgeries such as tooth extraction, dental implantation or tooth pulp treatment. Normally non-noxious touching of the facial skin or oral mucosa elicits strong pain named allodynia, and normally noxious stimulation causes intolerable pain named hyperalgesia in the trigeminal neuropathic pain patients. Although the mechanisms underlying trigeminal neuropathic pain have been studied by many researchers, the detailed mechanisms are still unknown. In this chapter, we are focusing on trigeminal neuropathic pain, and describe our recent studies using animal models of trigeminal neuropathic pain. We also present the clinical assessment of trigeminal neuropathic pain patients to develop the appropriate treatment of trigeminal neuropathic pain. PMID- 21708312 TI - The role of trigeminal interpolaris-caudalis transition zone in persistent orofacial pain. AB - Previous studies have established the role of the medullary dorsal horn or the subnucleus caudalis of the spinal trigeminal complex, a homolog of the dorsal horn of the spinal cord, in trigeminal pain processing. In addition to the medullary dorsal horn, recent studies have pointed out increased excitability and sensitization of trigeminal interpolaris and caudalis transition zone (Vi/Vc) following deep orofacial injury, involving neuron-glia-cytokine interactions. The Vi/Vc transition zone accesses rostral brain regions that are important for descending pain modulation, and somatovisceral and somatoautonomic processing and plays a unique role in coordinating trigeminal nocifensive responses. PMID- 21708314 TI - Neurobiology of estrogen status in deep craniofacial pain. AB - Pain in the temporomandibular joint (TMJ) region often occurs with no overt signs of injury or inflammation. Although the etiology of TMJ-related pain may involve multiple factors, one likely risk factor is female gender or estrogen status. Evidence is reviewed from human and animal studies, supporting the proposition that estrogen status acts peripherally or centrally to influence TMJ nociceptive processing. A new model termed the "TMJ pain matrix" is proposed as critical for the initial integration of TMJ-related sensory signals in the lower brainstem that is both modified by estrogen status, and closely linked to endogenous pain and autonomic control pathways. PMID- 21708315 TI - Macroscopic connection of rat insular cortex: anatomical bases underlying its physiological functions. AB - The insular cortex (IC), which lies on the dorsal bank of the rhinal fissure, receives multi-modal sensory inputs, i.e. visceral, gustatory, nociceptive and thermal information from the sensory thalamic nuclei. In contrast to other primary sensory cortices such as visual, auditory and somatosensory areas, the anatomical features of the IC are quite distinctive; more than a half of the IC is composed of agranular or dysgranular cortex, which lacks a complete granular layer (layer IV). In addition to the characteristic layer structures, the IC has dense reciprocal innervations with the limbic structures, including the amygdala and hypothalamus. Such connectivity implies that sensory information processed in the IC is profoundly related to limbic information. By enabling the visualization of functional connectivity in the central nervous system, recent advancements in optical imaging techniques have opened the possibility to elucidate the mechanisms of sensory information processing from a macroscopic perspective. In this review, anatomical and functional features of the IC are overviewed from the aspect of gustatory processing, a typical sensation processed in the IC. In addition, the recently developed optical imaging techniques and their findings in gustatory information processing are summarized. We discuss how these characteristic features of excitatory propagation in the IC play functional roles in transmitting neural excitation arising from the limbic structures to the frontal and orbital cortices. PMID- 21708316 TI - The balance between excitation and inhibition and functional sensory processing in the somatosensory cortex. AB - The balance between excitation and inhibition (E/I balance) is tightly regulated in adult cortices to maintain proper nervous system function. Disturbed E/I balance is associated with numerous neuropsychological disorders, such as autism, epilepsy and schizophrenia. The present review will discuss aspects of Hebbian and homeostatic mechanisms regulating excitatory and inhibitory balance related to sensory processing in somatosensory cortex of rodents. Additionally, changes in the E/I balance during sensory manipulation will be discussed. PMID- 21708317 TI - Developmental and Comparative Immunology. Editorial. PMID- 21708318 TI - Developmental and Comparative Immunology. Editorial. PMID- 21708319 TI - 3.0T MR-guided laser ablation of a prostate cancer recurrence in the postsurgical prostate bed. AB - Biochemical recurrence of prostate cancer after definitive therapy with radical prostatectomy occurs in 25%-30% of cases. The first known case of magnetic resonance (MR) imaging-guided ablation using laser interstitial thermal therapy (LITT) for locally recurrent prostate cancer after radical prostatectomy is presented. Using 3.0T MR guidance, two laser applicators were placed via a transperineal approach. Laser ablation was performed using MR thermometry to determine the ablation endpoint and lesion coverage. Dynamic contrast-enhanced MR imaging after the procedure showed no definitive abnormal enhancement. The patient had no change in continence or potency after the procedure. PMID- 21708320 TI - Simultaneous complete supraaortic debranching and thoracic aortic endografting in an angiography suite setting. AB - This case series reports an initial experience in three patients treated with simultaneous complete supraaortic debranching and thoracic aortic endografting in an angiography suite setting. The article focuses on logistics and structural considerations of the setting. This includes size and equipment of the angiography suite, extent and supply of conventional surgical instruments, and safety considerations. The clinical outcome of the patients is reported. This limited experience shows that simultaneous aortic arch hybrid procedures can be performed in an angiography suite setting, given the structural and logistic requirements described. PMID- 21708321 TI - Painful pathologic fracture of the humerus: percutaneous osteoplasty with bone marrow nails under hybrid computed tomography and fluoroscopic guidance. AB - A case of a 75-year-old patient with a painful pathologic humeral shaft fracture, with unacceptably high surgical risk and unsatisfactory analgesia is reported. In this case, impaired arm function and persistent pain with conservative management resulted in a poor quality of life. Palliation with image-guided percutaneous osteoplasty was considered. Because of potential cement leakage, inadequate fracture reduction, the site of the fracture, and the mobility of the joints in that area, image-guided percutaneous delivery of metallic bone marrow nails implanted together with polymethyl methacrylate (PMMA) osteoplasty was performed. This procedure achieved humeral shaft stabilization, bone fragment alignment, fracture reduction, and pain relief. PMID- 21708322 TI - Endovascular treatment of lower gastrointestinal bleeding from systemic-to mesenteric venous collateral vessels caused by inferior vena cava occlusion: report of two cases. AB - The present report describes two cases of chronic lower gastrointestinal bleeding caused by systemic-to-mesenteric venous collateral vessels resulting from longstanding inferior vena cava obstruction. They were successfully treated with caval balloon angioplasty and stent placement. No recurrent bleeding was seen at 15 and 24 months of follow up, respectively. PMID- 21708323 TI - Balloon occlusion retrograde transvenous obliteration for inferior mesenteric vein-systemic shunt. AB - Two cases of portosystemic encephalopathy caused by an inferior mesenteric vein (IMV)-internal iliac vein shunt and an IMV-renal vein shunt are presented. IMV and systemic varicosity consisted of a first functional segment, a stagnant segment, and a second functional segment. Both patients underwent balloon occlusion retrograde transvenous obliteration (BRTO), using a microcatheter, to occlude the stagnant segment selectively. Although transient portal vein thrombosis was observed in case 1 and aggravation of esophageal varices was observed in case 2, these complications were tolerable. Following BRTO, the portosystemic encephalopathy in both cases resolved, and serum ammonia levels, although elevated, remained within the normal range. PMID- 21708324 TI - Balloon-occluded retrograde transvenous obliteration of complex gastric varices assisted by temporary balloon occlusion of the splenic artery. AB - Six cases of gastric varices with multiple afferent veins, in which balloon occluded venography of the draining vein showed insufficient filling of gastric varices with contrast medium, were treated by balloon-occluded retrograde transvenous obliteration (BRTO) and temporary balloon occlusion of the splenic artery. The gastric varices were completely filled with sclerosant in all but one patient. No procedure-related complications were encountered. Computed tomography (CT) after the procedure showed complete thrombosis of the varices in five patients and partial thrombosis in one patient. Temporary balloon occlusion of the splenic artery is a useful additional technique for complete obliteration of gastric varices in selected cases. PMID- 21708325 TI - Obliteration of bleeding peristomal varices with balloon-occluded retrograde transvenous obliteration using sodium tetradecyl sulfate foam. PMID- 21708326 TI - Microwave thermoablation treatment of chest wall chondroid hamartoma in a child. PMID- 21708327 TI - Use of a flow-diverting uncovered stent for the treatment of a superior mesenteric artery aneurysm. PMID- 21708328 TI - A late complication of migration after aortic endografting: injury to the superior mesenteric artery. PMID- 21708329 TI - Re: Ischemic skin ulceration complicating glue embolization of type II endoleak after endovascular aneurysm repair. PMID- 21708331 TI - Bill Cook: 1931-2011. PMID- 21708332 TI - Development of embryos. Preface. PMID- 21708333 TI - Embryology of the early foregut. AB - In embryology, no agreement exists how the early foregut differentiates into the respiratory tract and the intestinal tract. In particular, the formation of the early lung anlage as well as the process of separation of trachea and esophagus remains unclear. This process is explained in a rather schematic way and aims more to explain pathologic findings, whereas true embryologic investigations are extremely rare in this field. Here, scanning electron microscopy of the normal foregut development illustrates the steps, which finally leads to the development of larynx and trachea on the one hand, and pharynx and esophagus on the other hand. This study was performed in chicken embryos in accordance to the developmental stages described. As the main results from these illustrations show, we found no evidence for lateral foregut ridges inside the undivided foregut chamber and no fusion of lateral foregut components to form a trachea esophageal septum. PMID- 21708334 TI - Embryology of the midgut. AB - In most textbooks of embryology and pediatric surgery, the puzzling spectrum of midgut "malrotations" is explained by an "impaired" process of rotation of the midgut. However, this "process of rotation" is explained in a rather schematic way and aims more to explain pathologic findings whereas detailed embryologic investigations are still rare in this field. Good animal models which would allow the comparison of normal and abnormal midgut development are missing. In this paper we describe the development of the midgut in form of an atlas. Scanning electron microscopy is used in rat embryos to illustrate the crucial embryologic processes of midgut development. The main result shown in these illustrations is that clear signs of a process of rotation are missing. PMID- 21708335 TI - Embryology of the hindgut. AB - Normal and abnormal development of the hindgut is still in debate. Normal development of the hindgut critically depends on the cloacal membrane. In this study, scanning electron microscopy of staged rat embryos between the gestational days 10-15 was performed to show the normal development of the hindgut and the abnormal development in Danforth's short tail (SD) mice. Our studies in normal and abnormal development indicate that the embryonic cloaca never passes through a stage that is similar to any form of anorectal malformation in neonates, including the so-called "cloacas" in females. To explain the abnormal development in anorectal malformations, further studies are mandatory. PMID- 21708336 TI - The embryology of the diaphragm. AB - Despite the progress in prenatal diagnosis and intervention as well as postnatal therapeutic strategies, congenital diaphragmatic hernia (CDH) is still associated with a meaningful mortality because of the induced pulmonary hypoplasia. An essential key in understanding the pathogenesis of CDH is the underlying embryology, which has been neglected during the last decades. Likewise, the development of the normal diaphragm is still poorly understood. Obsolescent perceptions, mainly formed from histologic sections, are still propagated. In this review we present an atlas of scanning electron microscopy images that depict the normal and defective development of the diaphragm in the nitrofen rat model for CDH. Our findings suggest that the normal diaphragm mainly develops from the posthepatic mesenchymal plate. If the development of the posthepatic mesenchymal plate is impaired, a diaphragmatic defect occurs. PMID- 21708337 TI - Embryology of the testicular descent. AB - Numerous researchers studied the morphology of the testicular descent, including the possible function of the gubernaculum. However, a clear illustration of this process is still missing. The aim of this paper was to illustrate the embryology of the testicular descent in the rat by scanning electron microscopy. In a first phase of the intra-abdominal testicular descent, the testis moves actively from the lower pole of the kidney towards the bladder neck. In a second inguinal phase the testis enters groin and moves in the developing processus vaginalis peritonei caused by the disappearance of the bulb of the gubernaculums testis. PMID- 21708338 TI - Embryology of the distal urethra and external genitals. AB - Faulty ventral openings of the urethra constitute a broad spectrum of malformations that are subsumed under the term "hypospadia." The normal development of the urethra and the genitals critically depends on the following events: (a) formation of the external genitalia, (b) fate of the cloacal membrane, and (c) formation of the distal urethra. The purpose of this study was to demonstrate these events using microsurgical techniques and scanning electron microscopy in staged rat embryos. PMID- 21708339 TI - Arthroplasty or arthrodesis. PMID- 21708340 TI - Identifying risk factors in subtalar arthroereisis explantation: a propensity matched analysis. AB - A case-control study was undertaken to identify differences in patients with flexible flatfoot deformity who required explantation of subtalar arthroereisis compared with those who did not. All patients who required removal of a self locking wedge-type subtalar arthroereisis were identified between 2002 and 2008. Propensity scores matched 22 explanted subtalar arthroereises to 44 controls (nonexplanted arthroereises), resulting in a total of 66 implants that met all inclusion and exclusion criteria. Multivariate logistic regression found that patients who required explantation had a greater odds of radiographic undercorrection, determined from radiographic anteroposterior talar-first metatarsal angles postoperatively, P = .0012, odds ratio (OR) = 1.175 (95% confidence interval [CI] 1.066 to 1.295), or residual transverse plane-dominant deformities, as determined from radiographic calcaneocuboid abduction angles postoperatively, P = .05, OR = 1.096 (95% CI 1.06 to 1.203). Patients with smaller postoperative anteroposterior talocalcaneal angles had a 16.7% reduction in odds for arthroereisis explantation (P = .0019) (95% CI 6.5% to 25.8%). Age, gender, implant size, shape, duration, implant position, surgeon experience, and concomitant procedures were not statistically different between the 2 groups. This study helps identify key factors that may result in subtalar arthroereisis explantation. PMID- 21708341 TI - Displacement of the anterior process of the calcaneus after Evans calcaneal osteotomy. AB - The Evans calcaneal osteotomy is an invaluable tool in the correction of pediatric collapsing pes planovalgus. It has traditionally been performed without the use of fixation. Recently, however, fixation of the Evans osteotomy has been proposed to prevent displacement. A retrospective radiographic study was performed of 33 patients (50 feet) to examine the amount of displacement of the anterior process after performing the Evans osteotomy without fixation. The anterior process height was measured digitally from the radiographs on the lateral view preoperatively, at approximately 6 weeks postoperatively, and at the final follow-up visit. The patients were followed up to a mean of 30.57 (range, 6 to 107) weeks postoperatively. The anterior process showed a statistically significant dorsal displacement of 1.21 mm (95% confidence interval 0.29, 2.12, P = .0001) at 6 weeks postoperatively. This had diminished to an insignificant dorsal displacement of 0.57 mm (95% confidence interval -0.21, 1.34, P = .148) at the final follow-up visit. Clinically and statistically significant improvements in the calcaneal inclination and talar declination angles were observed in the early and late postoperative periods. None of the patients experienced a postoperative complication that required a return to the operating room. PMID- 21708342 TI - Misdiagnosis of OTA type B (Weber B) ankle fractures leading to nonunion. AB - Little is known about the specific etiology of nonunion of stable Orthopaedic Trauma Association (OTA) type B fractures. In the present retrospective cohort study, we investigated all patients with a nonunion in a level 1 trauma center during an 8.5-year period. Patient history, clinical findings, radiographic features, and therapeutic aspects were critically evaluated to be able to predict the nonunion. In the predefined period, 388 patients were treated for a stable OTA type B fracture. Eight patients (2.1%) developed a nonunion. Retrospectively, the radiographic features in 6 of the 8 patients and clinical findings in 1 of the 8 patients could predict the nonunion. We conclude that in almost every nonunion occurring after a "stable" OTA type B fracture in the present study were, in fact, originally unstable fractures. PMID- 21708343 TI - The hematoma block: a simple, effective technique for closed reduction of ankle fracture dislocations. AB - Management of a dislocated ankle fracture can be challenging because of instability of the ankle mortise, a compromised soft tissue envelope, and the potential neurovascular compromise. Every effort should be made to quickly and efficiently relocate the disrupted ankle joint. Within the emergency department setting, narcotics and benzodiazepines can be used to sedate the patient before attempting closed reduction. The combination of narcotics and benzodiazepines provides relief of pain and muscle guarding; however, it conveys a risk of seizure as well as respiratory arrest. An alternative to conscious sedation is the hematoma block, or an intra-articular local anesthetic injection in the ankle joint and the associated fracture hematoma. The hematoma block offers a comparable amount of analgesia to conscious sedation without the additional cardiovascular risk, hospital cost, and procedure time. PMID- 21708344 TI - Cancer survivors: still room for improvement. PMID- 21708345 TI - Adjuvant bisphosphonates for early-stage breast cancer. PMID- 21708347 TI - Stenting as a bridge to surgery for colorectal cancer. PMID- 21708349 TI - Genetics of lung cancer susceptibility and COPD. PMID- 21708350 TI - Postacute rehabilitation in cognitively impaired patients: comprehensive assessment and tailored interventions. PMID- 21708351 TI - Endothelial progenitor cells in cardiovascular disease and hypoxia--potential implications to obstructive sleep apnea. AB - In recent years, endothelial progenitor cells (EPCs) have gained a central role in vascular regeneration and endothelial repair capacity through angiogenesis and restoring endothelial function of injured blood vessels. These bone-marrow derived cells are capable of promoting neovascularization, improving blood perfusion, and facilitating the recovery of ischemic tissues through differentiation into functional endothelial cells and secretion of angiogenic mediators. Obstructive sleep apnea (OSA) syndrome is characterized by recurrent episodes of intermittent hypoxia (IH), which can lead to endothelial dysfunction, atherosclerosis, as well as cardiovascular morbidity and mortality. However, IH also may contribute to cardioprotection and the development of collateral vessels by mobilizing progenitor cells to the circulation and damaged myocardium. Accumulating evidence in recent years suggests that EPCs are decreased in patients with endothelial dysfunction and underlie an increased risk for cardiovascular morbidity in OSA. The current review highlights the potential role of EPCs in the pathogenesis of vascular diseases that is pertinent to OSA. PMID- 21708352 TI - Is it the inflammation or the free radicals that cause ischemia/reperfusion lung injury? PMID- 21708353 TI - Apocynin attenuates ischemia-reperfusion lung injury in an isolated and perfused rat lung model. AB - Apocynin suppresses the generation of reactive oxygen species (ROS) that are implicated in ischemia-reperfusion (I/R) lung injury. We thus hypothesized that apocynin attenuates I/R. Furthermore, we explored the mechanisms by which apocynin may attenuate I/R. I/R was induced in an isolated and perfused rat lung model with ischemia for 1 h followed by reperfusion for 1 h. Apocynin was administered in the circulating perfusate at the onset of ischemia. Hemodynamics, lung injury indices, inflammatory responses, and activation of apoptotic pathways were determined. An increase in lung permeability and lung weight gain was noted after I/R. Peak airway pressure was increased, and pH of circulating perfusate was decreased. The adhesion molecule of neutrophil (CD31) in perfusate was upregulated. The levels of albumin, white blood cell count, and inflammatory cytokines including interleukin-1beta, tumor necrosis factor-alpha, and macrophage inflammatory protein-2 increased in lung lavage fluid; the concentrations of carbonyl and thiobarbituric acid reactive substances were greater in the circulating perfusate; and the expression of myeloperoxidase, JNK, P38, and caspase-3 in lung tissue was greater in the control group. Upregulation and activation of nuclear factor-kappaB (NF-kappaB) in nuclei were found in I/R. The administration of apocynin attenuated these inflammatory responses and lung permeability associated with decreased activation of NF-kappaB. We conclude that I/R is associated with inflammatory responses including the generation of ROS, adhesion protein of neutrophil, cytokines, and the activation of mitogen activated protein kinase and NF-kappaB cascade. The administration of apocynin attenuates the inflammatory responses and I/R in the isolated, perfused rat lung model. PMID- 21708354 TI - Erythromycin prevents the pulmonary inflammation induced by exposure to cigarette smoke. AB - The effect of erythromycin on the inflammation caused by exposure to cigarette smoke was investigated in this study. Mice were exposed either to cigarette smoke or to environmental air (control), and some mice exposed to cigarette smoke were treated with oral erythromycin (100 mg/kg/day for 8 days). Pulmonary inflammation was assessed by determining the cellular content of bronchoalveolar lavage (BAL) fluid. The messenger RNA (mRNA) levels of various mediators, including keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, surfactant protein (SP)-D, granulocyte macrophage colony-stimulating factor (GM CSF), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 in lung tissue were determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. The exposure to cigarette smoke increased significantly the numbers of neutrophils (P = 0.029), macrophages (P = 0.029), and lymphocytes (P = 0.029) recovered in BAL fluid. Moreover, mRNA levels of KC (P = 0.029), MIP-2 (P = 0.029), SP-D (P = 0.029), and GM-CSF (P = 0.057) in the lung tissue were higher in mice exposed to cigarette smoke than in mice exposed to environmental air. In the erythromycin-treated mice that were exposed also to cigarette smoke, both neutrophil and lymphocyte counts were significantly lower in the BAL fluid than those in the vehicle-treated mice (P = 0.029). Erythromycin-treated mice exposed to cigarette smoke showed a trend of lower mRNA levels of KC and TNF-alpha in the lung tissue than those in the vehicle-treated mice, although the statistical significance was not achieved (P = 0.057). Our data demonstrated that erythromycin prevented lung inflammation induced by cigarette smoke, in parallel to the reduced mRNA levels of KC and TNF-alpha. PMID- 21708357 TI - Coated-platelet levels are elevated in patients with transient ischemic attack. AB - Transient ischemic attack (TIA) presents a medical management dilemma because of the high frequency of subsequent ischemic strokes. The ABCD2 score is designed to stratify the short-term risk for stroke in TIA patients. Coated-platelets, which are a subset of procoagulant platelets observed after dual agonist stimulation with collagen and thrombin, are increased in cortical ischemic stroke and decreased in spontaneous intracerebral hemorrhage. Because TIA increases the risk of subsequent ischemic stroke, we conducted a pilot study to investigate whether coated-platelet production is increased in patients with TIA (n = 60) compared with controls (n = 60). Coated-platelet levels were higher in TIA patients versus controls [mean +/- standard deviation (SD), 38.4 +/- 15.1% vs 31.0 +/- 13.2%, P = 0.005], and a significant linear correlation was detected between ABCD2 scores and coated-platelet levels in TIA patients (P = 0.0003, r = 0.45). These findings lend support to the hypothesis that TIA and ischemic stroke represent a spectrum of conditions dependent on similar prothrombotic processes. PMID- 21708355 TI - Nutrient-enhanced diet reduces noise-induced damage to the inner ear and hearing loss. AB - Oxidative stress has been implicated broadly as a cause of cell death and neural degeneration in multiple disease conditions; however, the evidence for successful intervention with dietary antioxidant manipulations has been mixed. In this study, we investigated the potential for protection of cells in the inner ear using a dietary supplement with multiple antioxidant components, which were selected for their potential interactive effectiveness. Protection against permanent threshold shift (PTS) was observed in CBA/J mice maintained on a diet supplemented with a combination of beta-carotene, vitamins C and E, and magnesium when compared with PTS in control mice maintained on a nutritionally complete control diet. Although hair cell survival was not enhanced, noise-induced loss of type II fibrocytes in the lateral wall was significantly reduced (P < 0.05), and there was a trend toward less noise-induced loss in strial cell density in animals maintained on the supplemented diet. Taken together, our data suggest that prenoise oral treatment with the high-nutrient diet can protect cells in the inner ear and reduce PTS in mice. The demonstration of functional and morphologic preservation of cells in the inner ear with oral administration of this antioxidant supplemented diet supports the possibility of translation to human patients and suggests an opportunity to evaluate antioxidant protection in mouse models of oxidative stress-related disease and pathology. PMID- 21708358 TI - Another gap analysis. PMID- 21708356 TI - Nutrient plasma levels achieved during treatment that reduces noise-induced hearing loss. AB - Hearing loss encompasses both temporary and permanent deficits. If temporary threshold shift (TTS) and permanent threshold shift (PTS) share common pathological mechanisms, then agents that reduce PTS also should reduce TTS. Several antioxidant agents have reduced PTS in rodent models; however, reductions in TTS have been inconsistent. This study first determined whether dietary antioxidants (beta-carotene and vitamins C and E) delivered in combination with magnesium (Mg) reliably increase plasma concentrations of the active agents. Then, additional manipulations tested the hypothesis that these nutrients reduce acute TTS insult in the first 24 h after loud sound as well as longer lasting changes in hearing measured up to 7 days postnoise. Saline or nutrients were administered to guinea pigs prior to and after noise exposure. Sound-evoked electrophysiological responses were measured before noise, with tests repeated 1 h postnoise, as well as 1-day, 3-days, 5-days, and 7-days postnoise. All subjects showed significant functional recovery; subjects treated with nutrients recovered more rapidly and had better hearing outcomes at early postnoise times as well as the final test time. Thus, this combination of nutrients, which produced significant increases in plasma concentrations of vitamins C and E and Mg, effectively reduced hearing loss at multiple postnoise times. These data suggest that free radical formation contributes to TTS as well as PTS insults and suggest a potential opportunity to prevent TTS in human populations. PMID- 21708359 TI - How important is anatomy for the young surgeons? PMID- 21708360 TI - Response to Sticca, Macgregor, and Szlabick. PMID- 21708361 TI - Assessing the status of thoracic surgical research and quality improvement programs: a survey of the members of the Canadian Association of Thoracic Surgeons. AB - OBJECTIVES: Assessing the degree of involvement and participation in thoracic surgical research as well as surgical quality improvement conducted across Canadian institutions is difficult as no common data collection system and no prior studies exist. As a pilot investigation, we designed and conducted a membership survey of the Canadian Association of Thoracic Surgeons (CATS) to evaluate the extent of participation in research and quality improvement processes among thoracic surgeons. DESIGN, SETTING, AND PARTICIPANTS: A 45-item needs assessment survey was mailed to all national members of CATS (n = 86) in August 2009. Questions primarily focused on clinical research programs and research activity, research funding, database use and interest, and other methods of quality monitoring. RESULTS: The 49 completed surveys represented a 57.0% response rate and 28 institutions across Canada. Research in basic and clinical science is conducted by 17.0% and 80.9% of the respondents, respectively. The annual budget of research funds is most commonly between $5000 and $50,000. A total of 72.0% (n = 18) of institutions do not have a formal surgery quality assessment program and 92.3% (n = 24) do not participate in a national or international thoracic surgery database. Ten institutions (38.6%) have a local thoracic surgery database for quality monitoring. Other systems of monitoring surgical quality include formal morbidity and mortality rounds (69.2%; n = 8 institutions), formal evaluation of surgical wait times (73.1%; n = 19 institutions), and patient satisfaction surveys (71.4%; n = 10 institutions). Overall, 97.8% of surgeons would be willing to share data on morbidity and mortality with other centers, and 73.1% have a high or very high level of interest in participating in a national thoracic surgery quality database. CONCLUSIONS: A high level of interest and participation exists in thoracic surgery research. However, more robust quality improvement processes are needed for thoracic surgical oncology services. A national thoracic surgery quality improvement database offers a potential means to improve practice effectiveness, standardize surgical outcomes, and promote thoracic research across Canada. PMID- 21708362 TI - Differential diagnosis in a 3-station acute abdominal pain objective structured clinical examination (OSCE): a needs assessment in third-year medical student performance and summative evaluation in the surgical clerkship. AB - BACKGROUND: There is poor interrater reliability in the assessment of a medical student's ability to generate a differential diagnosis list using Likert-based scales in the surgical clerkship. This important clinical skill is tested on the United States Medical Licensing Examination Step 2 Clinical Skills Examination. OBJECTIVE: We hypothesize that third-year medical students in the surgical clerkship will be able to accurately diagnose adult patients with acute abdominal pain after performing a focused history and physical examination in a 3-station Objective Structured Clinical Examination (OSCE). Second, we want to test our hypothesis that service assessments of a student's ability to analyze data will not correspond with OSCE performance. METHODS: In this retrospective study, third year medical student differential diagnosis lists from a 3-station OSCE and medical student clerkship assessments were collected from the 2009-2010 academic year. Differential diagnosis lists were scored for accuracy. Differences between groups were compared with nonparametric statistics, using an alpha = 0.05. RESULTS: Seventy-eight third-year medical students (56.4% female) were evaluated. For 2 stations, more than half of the medical students had the correct diagnosis on the differential diagnosis list (p < 0.0001). For 1 station, less than half of the medical students had the correct diagnosis on the differential diagnosis list (p = 0.0001). There were no differences in the service evaluation scores and the number of correct differential diagnosis lists for the students (p = 0.91). CONCLUSIONS: Third-year medical students are generally accurate with the ability to diagnosis adult patients with acute abdominal pain after performing a history and physical examination. Additionally, surgical service faculty and resident assessments of a student's ability to analyze data do not correspond with OSCE performance. We recommend some changes that might lead to improved grading for third-year medical students in the surgical clerkship. PMID- 21708363 TI - Do new thoracic surgeons feel ready to operate? Self-reported comfort level of thoracic surgery trainees and junior thoracic surgeons with core thoracic surgery procedures. AB - OBJECTIVE: To evaluate and compare self-reported surgical experience and comfort levels of Canadian thoracic surgery trainees and junior thoracic surgeons (<5 years in practice) with respect to core thoracic surgery procedures. METHODS: A modified Delphi process was used to create a survey that was distributed electronically to all Canadian thoracic surgery residents and newly graduated thoracic surgeons. A descriptive summary, including calculation of frequencies, means, proportions, and standard deviations was conducted. Associations between reported experience and comfort level for residents and surgeons were explored separately using the Pearson product moment correlation. The differences between resident and junior surgeons' rating of experience and comfort for each procedure were explored using Fisher exact tests. RESULTS: The response rates were 50% for residents and 85% for staff. Adequate or better experience was reported by residents for 9 of 18 core thoracic surgical procedures and by staff for 10 of 18 procedures. A significant difference in self-reported experience level was found between groups for only 1 of 18 procedures. Staff reported that they would confidently perform 7 of 18 procedures independently at the end of their training. The mean resident response did not reach this level of comfort for any of the 18 procedures. Eight of 16 staff had completed extra training, primarily for personal interest, whereas 4 of 6 residents were planning on further training because of job market factors. DISCUSSION: The results of this study help to characterize the comfort levels of thoracic trainees and new attending thoracic surgeons with core thoracic procedures and might assist training programs in identifying and improving areas of weakness. PMID- 21708364 TI - Effectiveness of laparoscopic computer simulator versus usage of box trainer for endoscopic surgery training of novices. AB - OBJECTIVE: Teaching of laparoscopic skills is a challenge in surgical training programs. Because of the highly technical nature and the steep learning curve, students and residents must learn laparoscopic skills before performing them in the operating room. To improve efficiency of learning and patient safety, research in simulation is essential. Two types of simulators currently in use include virtual reality and box trainers. Our study examined which simulator technique was most effective in teaching novice trainees laparoscopic techniques. DESIGN: This is a prospective, randomized, blinded, controlled trial that enrolled fourth-year medical students and surgical interns to participate in a supervised 6-month laparoscopic training program with either computer simulators or box trainers. Subjects were randomized and trained on appropriate laparoscopic camera skills, instrument handling, object positioning, dissection, ligation, suturing, and knot tying. Students within one group were not allowed to practice, learn or train on the opposing trainers. At time points 0, 2, and 6 months all subjects completed a series of laparoscopic exercises in a live porcine model, which were captured on DVD and scored by blinded expert investigators. RESULTS: Scores improved overall from the pretest to subsequent tests after training with no difference between the virtual reality and box simulator groups. In the medical students specifically, there was overall improvement, and improvement in the needle-transfer and knot-tying skills specifically, with no difference between the box simulator and virtual reality groups. For the interns, both groups showed significant overall improvement with no difference between the virtual reality and box simulator groups or on individual skills. CONCLUSIONS: We conclude that laparoscopic simulator training improves surgical skills in novice trainees. We found both the box trainers and the virtual reality simulators are equally effective means of teaching laparoscopic skills to novice learners. PMID- 21708365 TI - Evaluation of a regional acute care surgery service by residents in general surgery. AB - BACKGROUND: Acute care surgery (ACS) services dedicated to care of acute general surgery patients have been established in many tertiary centers across Canada. Little is known about the impact of this trend on postgraduate education. In this study we aimed to evaluate ACS through a cross-sectional survey of general surgery residents in Winnipeg, Manitoba. METHODS: General surgery residents at the University of Manitoba were asked to complete an anonymous survey. Basic demographic data were obtained. The educational value of ACS was assessed using 10 statements derived from the CanMEDS framework for training physicians. Resident burnout was measured using the Maslach Burnout Inventory, on emotional exhaustion, depersonalization, and personal accomplishment. RESULTS: The response rate was 70% (14/20). ACS was evaluated positively based on the CanMEDS roles by the following proportions of responders: surgical skills (79%), clinical knowledge (100%), communicator (100%), collaborator (100%), manager (86%), health advocate (100%), scholar (64%), and professional (93%). Fifty percent of responders had a high score on emotional exhaustion, 43% on depersonalization, and 0% on low sense of personal accomplishment. The overall burnout was 64%. CONCLUSIONS: ACS provides a comprehensive clinical experience based on the CanMEDS competencies. Despite an increased sense of personal accomplishment, residents experienced a high incidence of burnout, as demonstrated by high scores on emotional exhaustion and depersonalization of patients. PMID- 21708366 TI - Incorporating the SCORE curriculum and web site into your residency. PMID- 21708367 TI - Surgical simulators and hip fractures: a role in residency training? AB - BACKGROUND: Orthopedic surgery residency training requires intellectual and motor skill development. In this study, we utilized a computer-based haptic simulator to examine a potential model for evaluation of resident proficiency and efficiency in the placement of a center guide wire during fixation of an intertrochanteric proximal femur fracture. We hypothesize the junior residents will utilize more fluoroscopy and require more time to complete the task. METHODS: Postgraduate year (PGY) 1-5 residents completed the same task of placing a single central guide pin into a femoral head for a dynamic hip screw construct utilizing a haptic surgical simulator. Residents were divided into 2 groups (PGY 1-2 and PGY 3-5) and then evaluated based on final tip-apex distance (TAD), fluoroscopy time, time to complete the task, total number of distinct attempts at pin placement for each femur construct, as well as final 3-dimensional location of the pin from the isometric center of the femoral head. RESULTS: No statistically significant differences were noted between the 2 groups in total time or for tip-apex distance, anterior/posterior medial/lateral position, anterior/posterior superior/inferior, and lateral x-ray medial/lateral positioning measurements. Significant differences between Groups I and II were observed in anterior/posterior final position on the lateral view (p = 0.01), unique attempts (0.77 and 1.5, p = 0.03), and total fluoroscopic time (18.4 seconds and 12.9 seconds, p = 0.05). CONCLUSIONS: In this study, we displayed that based on our simulator model there was no statistical difference between Group I and II in time to completion, final placement on anterior/posterior (A/P) view, and tip-apex distance. There was a statistically significant difference in the anterior/posterior placement of the wire in lateral view between the 2 groups, fluoroscopy time, and number of attempts per trial. Our findings suggest a computer-based surgical simulator can identify measurable differences in surgical proficiency between junior and senior orthopedic surgery residents and may play an expanding role in resident education. PMID- 21708368 TI - The use of a multidisciplinary morbidity and mortality conference to incorporate ACGME general competencies. AB - BACKGROUND: The Surgical Morbidity and Mortality conference has long been used as an opportunity for both process improvement and resident education. With recent heightened focus on creating environments of safety and on meeting the Accreditation Council for Graduate Medical Education (ACGME) General Competencies, novel approaches are required. With the understanding that the provision of medical care is an inherently multidisciplinary enterprise, we advocate the creation and use of a Multidisciplinary Morbidity and Mortality conference (MM&M) as a means to establish this culture of safety while teaching the ACGME General Competencies to surgery residents. METHODS: A quarterly MM&M conference was implemented to foster communication between disciplines, provide a forum for quality improvement, and enhance patient care. All stakeholders in the perioperative enterprise attend, including the departments of surgery, anesthesia, radiology, pharmacy, nursing, environmental services, risk management, and patient services. Cases that expose system issues with potential to harm patients are discussed in an open, nonconfrontational forum. Solutions are presented and initiatives developed to improve patient outcomes. We retrospectively reviewed the topics presented since the conference's inception, grouping them into 1 of 7 categories. We then evaluated the completion of the improvement initiatives developed after discussion at the conference. RESULTS: Over a 21-month period, 11 cases were discussed with 23 "actionable" initiatives for quality improvement. Cases were grouped by category; procedures (36.5%), process (36.5%), patient-related (9%), communication (9%), medication (9%), device (0%), and ethics (0%). All cases discussed addressed at least 4 of the 6 ACGME General Competencies. CONCLUSIONS: Like the practice of medicine, the occurrence of adverse outcomes is frequently multidisciplinary. An MM&M conference is useful in its potential to meet ACGME General Competencies, engender a culture of patient safety, and rapidly achieve quality improvement and systems health care delivery initiatives in a large academic medical center. PMID- 21708369 TI - Trends in research time, fellowship training, and practice patterns among general surgery graduates. AB - SUMMARY: A comparison of research experience, fellowship training, and ultimate practice patterns of general surgery graduates at a university-based surgical residency program. Research experience correlated with pursuing fellowship training and predicted an eventual academic career. More recently, graduates have been able to obtain fellowships without a dedicated research year, perhaps reflecting shifting fellowship training opportunities. BACKGROUND: We hypothesized that the relationships among dedicated research experience during residency, fellowship training, and career choices is changing as research and fellowship opportunities evolve. METHODS: Comparison of research experience, fellowship training, and ultimate practice patterns of general surgery graduates for 2 decades (1990-1999, n = 82; 2000-2009, n = 98) at a university-based residency program. Main outcome measures were number of years and area of research, fellowship training, and practice setting. RESULTS: Compared by decade, graduates became increasingly fellowship-trained (51.2% vs 67.3%; p < 0.05) and pursuit of fellowship training increased for both research and nonresearch participating graduates. The number of residents completing more than 1 year of research doubled (9.8% vs 22.4%, p < 0.05). By decade, the percentage of female graduates increased significantly (22% vs 41%, p = 0.005), with more women participating in dedicated research (17% vs 51%, p < 0.001) and seeking fellowships. The number of graduates going into specialty practice and academic/clinical faculty positions increased over time. CONCLUSIONS: Surgical residents have completed more dedicated research years and became increasingly fellowship-trained over time. The proportion of female graduates has increased with similar increases in research time and fellowship training in this subgroup. In the earlier decade, dedicated research experiences during surgical residency correlated with pursuing fellowship training, and predicted an eventual academic career. More recently, graduates have obtained fellowships and academic positions without dedicated research time, perhaps reflecting shifting fellowship opportunities. PMID- 21708370 TI - Utility and relevance of diagnostic peritoneal lavage in trauma education. AB - OBJECTIVES: During the last 2 decades, the advent of new technologies in trauma patient care may have resulted in a decreased number of diagnostic peritoneal lavage (DPL) evaluations. In this study, it is hypothesized that fewer DPL are being performed at a midwestern trauma center. Such negative trends may make the inclusion of DPL in current trauma education potentially outdated and no longer universally appropriate in trauma evaluation algorithms. DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational study of a level I trauma center includes patients from January 1998 through September 2010. The total number of trauma-related DPL procedures performed annually during the study period was determined along with accompanying facility and trauma patient level data. RESULTS: A total of 24 DPLs were performed at the target trauma center during the study period. There was a significant decrease (p = 0.0018) in the use of DPL despite a significant increase (p < 0.0001) in the proportion of trauma patients with an injury severity score > 15. CONCLUSIONS: Study data demonstrated a decrease in the use of DPL as a diagnostic modality in the evaluation of blunt abdominal trauma patients at a medium-sized midwestern center. These data provide historic facility-level evidence of a practice change. Such information may support a recommendation that the American College of Surgeons revisit its current curriculum for Advanced Trauma Life Support (ATLS). Specifically, we propose the American College of Surgeons consider changing DPL instruction to an optional component of ATLS. COMPETENCIES: Patient Care, Medical Knowledge, Practice Based Learning and Improvement. PMID- 21708371 TI - Editorial response. PMID- 21708374 TI - Surgical council on resident education (SCORE) portal use at Gundersen Lutheran Medical Center. PMID- 21708372 TI - Bilateral breast fibromatosis: case report and review of the literature. AB - Fibromatosis or desmoid tumor is a benign, slow-growing fibroblastic neoplasm originating from musculoaponeurotic stromal elements. These tumors are characterized by an infiltrative and locally aggressive growth pattern, frequent recurrences, but no metastatic potential. The etiology is unknown, but these tumors have been associated with trauma and genetic disorders. Breast fibromatosis is exceedingly rare and often misdiagnosed, comprising only 0.2% of breast tumors. Clinically, it might mimic other breast lesions, such as carcinoma. Only approximately 6 case series and 100 case reports of this disorder affecting the breast are documented, and only 5 cases of bilateral breast fibromatosis have been reported. We describe the case of a 20-year-old woman who presented to our institution with firm, nontender masses palpable in both breasts. Prior ultrasound was suspicious for carcinoma, and breast core biopsies were suggestive of phyllodes tumor. An excisional biopsy was necessary to establish the diagnosis of breast fibromatosis for both masses. A review of articles published on desmoid tumors and breast fibromatosis was performed with emphasis on articles published in the last 10 years. Fibromatosis should be considered in the differential diagnosis of patients presenting with hard breast lumps suspicious of other diseases. PMID- 21708375 TI - A primer on Caribbean medical schools and students: APDS surgery panel session. PMID- 21708376 TI - Powell's Pearls: eponyms in medical and surgical history. The Smead-Jones closure of abdominal wounds. PMID- 21708377 TI - High-resolution optical coherence tomography findings in solar maculopathy and the differential diagnosis of outer retinal holes. AB - PURPOSE: To characterize the morphology of outer retinal holes caused by solar maculopathy, using spectral-domain optical coherence tomography (SD-OCT). DESIGN: This study is an observational case series. METHODS: The SD-OCT findings of 3 patients (6 eyes) with chronic solar maculopathy are presented. RESULTS: SD-OCT demonstrates a characteristic appearance of partial-thickness hole(s) in the outer retina at the fovea. In 3 of 6 eyes, there is 1 hole directly beneath the umbo. In the remaining 3 eyes, there are multifocal holes spread across the fovea. Holes in more restricted layers, as had been previously reported with time domain OCT, were not seen. In addition, advanced visualization of SD-OCT data demonstrates a hyperreflective ring around the outer retinal hole. CONCLUSIONS: SD-OCT can be used diagnose solar maculopathy. In patients with central scotomas, characteristic outer retinal hole(s) without inner retinal cystic changes may prompt the clinician to uncover an undisclosed history of sungazing. Similar OCT findings can be caused by welder's maculopathy, tamoxifen retinopathy, juxtafoveal macular telangiectasia, foveolar vitreomacular traction, or, rarely, a closed macular hole, achromatopsia, alkyl nitrite abuse, acute retinal pigment epitheliitis, or Stargardt disease. PMID- 21708379 TI - What's in a name: keratoconus, pellucid marginal degeneration, and related thinning disorders. AB - PURPOSE: To discuss the implications of the current nomenclature and use of current diagnostic modalities on the classification and treatment of pellucid marginal degeneration and keratoconus. DESIGN: Perspective analysis of the literature. METHODS: Analysis of published reports on the various treatment methods for pellucid marginal degeneration and keratoconus, and the technologies used in these studies to support the diagnosis and classification of these ectatic disorders. RESULTS: Many studies exploring the different treatment modalities for pellucid marginal degeneration and keratoconus rely mainly on anterior curvature maps to establish the diagnosis of these ectatic disorders, and either do not utilize or disregard information provided by pachymetric maps and posterior elevation maps. In addition, the interchangeability of the nomenclature used to describe these disorders in the literature makes it even more difficult for the clinician to determine the applicability of the results to their patient population. CONCLUSIONS: We propose that future studies minimally include anterior and posterior elevation maps, anterior curvature topography, and full pachymetric maps. This will allow practitioners a better understanding of the study population, and allow them to ascertain when and in whom the treatment modality being explored may be applicable. PMID- 21708378 TI - Analysis of choroidal thickness in age-related macular degeneration using spectral-domain optical coherence tomography. AB - PURPOSE: To understand the relationship between choroidal thickness and various disease factors in patients with age-related macular degeneration (AMD) using spectral-domain optical coherence tomography. DESIGN: Cross-sectional, retrospective analysis. METHODS: Fifty-seven eyes of 47 patients with wet and dry AMD seen between November 2009 and January 2010 at the New England Eye Center, Boston, Massachusetts, were analyzed. Choroidal thickness was measured by 2 independent observers at 11 sites with high-definition horizontal 1-line raster scans through the foveal center. A retrospective chart review was performed to obtain data concerning duration of disease, number of intravitreal anti-vascular endothelial growth factor injections, visual acuity, lens status, and concomitant retinal pathologic features. The Pearson correlation and Student t test were used for statistical analysis for assessment of choroidal thickness changes in wet and dry AMD. RESULTS: The choroid in eyes with wet and dry AMD demonstrated a wide range of thicknesses above and below the normal mean (range, 77.5 to 399.5 MUm; standard deviation [SD], 90.2). Nearly one third (33.3%) of the eyes with AMD measured less than 1 SD below the mean. Eyes with wet AMD demonstrated a mean subfoveal choroidal thickness of 194.6 MUm (SD, 88.4; n = 40) compared with 213.4 MUm (SD, 92.2; n = 17) in the dry AMD group. The choroidal thickness in eyes with dry AMD was correlated inversely with age (r = -0.703; P = .002); however, analysis of the number of intravitreal anti-vascular endothelial growth factor injections, number of years of disease, and visual acuity failed to demonstrate any significant correlations with choroidal thickness. CONCLUSIONS: This study demonstrated that choroidal thickness can be measured by spectral-domain optical coherence tomography and that variable choroidal thickness exists among patients with the clinical diagnosis of wet and dry AMD. However, it is unclear at this time why in some eyes, choroidal thickness either increases or decreases with the disease. Further studies need to be carried out to understand the significance of choroidal thickness with respect to visual function and disease progression over time. PMID- 21708380 TI - Whither motoneurons? AB - In the preceding series of articles, the history of vertebrate motoneuron and motor unit neurobiological studies has been discussed. In this article, we select a few examples of recent advances in neuroscience and discuss their application or potential application to the study of motoneurons and the control of movement. We conclude, like Sherrington, that in order to understand normal, traumatized, and diseased human behavior, it is critical to continue to study motoneuron biology using all available and emerging tools. This article is part of a Special Issue entitled Historical Review. PMID- 21708381 TI - Effects of insulin-like growth factor 1 in preventing acute coronary syndromes: the PRIME study. AB - OBJECTIVE: Insulin-like growth factor-1 (IGF-1) has been associated with cardiovascular risk factors and atherosclerosis. The aim of the present study was to evaluate the prognostic value of IGF-1 concentrations with respect to occurrence of well-defined coronary syndromes. METHODS: The PRIME study is a prospective cohort having included 10,600 subjects from Northern Ireland and France. Detailed information on cardiovascular risk factors, socioeconomic and behavioural variables were collected and a cardiologic examination was performed. At 5-year follow-up, 317 incident cases of coronary events were recorded according to strict protocols. They were matched to 634 age- and centre-paired controls from the same cohort, free of coronary disease. Baseline IGF-1 concentrations were measured, together with variables of lipid and glucose metabolism and markers of vascular and systemic inflammation. RESULTS: Baseline IGF-1 concentration was lower in subjects developing an acute coronary syndrome than in unaffected controls. IGF-1 levels correlated negatively with age, waist circumference, tobacco consumption and markers of inflammation. Subjects in the highest quartile of IGF-1 distribution had a 55% reduction in the relative risk of developing myocardial infarction and a 45% decrease for all-combined acute coronary syndromes. A similar trend, although non-significant, was noted for angina pectoris. Multiple adjustments on classical risk factors and inflammation markers did not affect IGF-1 results. Elevated levels of both IGF-1 and apo A-I conferred a significantly greater risk reduction than either one alone. However, interaction between the two markers was not significant. CONCLUSION: Like HDL markers, high levels of IGF-1 confer protection against coronary artery disease. PMID- 21708382 TI - Increased lipoprotein(a) is associated with polyvascular disease in patients undergoing coronary artery bypass graft. AB - OBJECTIVE: We sought to identify clinical and biochemical predictors of disease in multiple vascular territories, in patients with established coronary heart disease. METHODS: A total of 470 patients (329 men, 141 female) who had undergone coronary artery bypass grafting (CABG) were enrolled in this prospective study. Polyvascular disease was defined on the presence of existing symptomatic or asymptomatic carotid artery stenosis and/or peripheral artery disease, which is present in 32.1% of patients (n=151). RESULTS: Clinical and laboratory features independently associated with the presence of polyvascular disease included age >=65 years, male sex, hypertension, former or current smoker, low BMI, and high Lp(a). Lp(a) was the only biochemical marker that had an independent association with polyvascular disease (OR=1.01 per 1mg/dl increase; 95% CI, 1.00-1.01). The fourth quartile of Lp(a) has significant associations with the risk of two or more vascular territories involvement (OR=1.866; 95% CI, 1.056-3.297), and three vascular territories involvement (OR=4.240; 95% CI, 1.405-12.798). There was a significant trend towards patients with the highest quartile of Lp(a) that has association with more advanced polyvascular disease (test for trend: p=0.008 for involvement of three vascular territories). CONCLUSION: High Lp(a) was independently associated with polyvascular disease in patients who undergo CABG, which is suggestive of an indirect evidence of the pathophysiologic function of Lp(a) in polyvascular disease. PMID- 21708383 TI - Method development and validation for optimised separation of salicylic, acetyl salicylic and ascorbic acid in pharmaceutical formulations by hydrophilic interaction chromatography and response surface methodology. AB - This paper introduces a design of experiments (DOE) approach for method optimisation in hydrophilic interaction chromatography (HILIC). An optimisation strategy for the separation of acetylsalicylic acid, its major impurity salicylic acid and ascorbic acid in pharmaceutical formulations by HILIC is presented, with the aid of response surface methodology (RSM) and Derringer's desirability function. A Box-Behnken experimental design was used to build the mathematical models and then to choose the significant parameters for the optimisation by simultaneously taking both resolution and retention time as the responses. The refined model had a satisfactory coefficient (R2>0.92, n=27). The four independent variables studied simultaneously were: acetonitrile content of the mobile phase, pH and concentration of buffer and column temperature each at three levels. Of these, the concentration of buffer and its cross-product with pH had a significant, positive influence on all studied responses. For the test compounds, the best separation conditions were: acetonitrile/22 mM ammonium acetate, pH 4.4 (82:18, v/v) as the mobile phase and column temperature of 28 degrees C. The methodology also captured the interaction between variables which enabled exploration of the retention mechanism involved. It would be inferred that the retention is governed by a compromise between hydrophilic partitioning and ionic interaction. The optimised method was further validated according to the ICH guidelines with respect to linearity and range, precision, accuracy, specificity and sensitivity. The robustness of the method was also determined and confirmed by overlying counter plots of responses which were derived from the experimental design utilised for method optimisation. PMID- 21708384 TI - Simultaneous determination of bisphenol A and alkylphenol in plant oil by gel permeation chromatography and isotopic dilution liquid chromatography-tandem mass spectrometry. AB - A simple analytical method was developed for the simultaneous analysis of bisphenol A (BPA), nonylphenol (NP) and octylphenol (OP) in plant oil. The target compounds were extracted by cyclohexane/ethyl acetate (1:1), purified by gel permeation chromatography (GPC), and analyzed by liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) in the negative ion mode. An isolator column was attached in front of the injection valve of the LC to separate background contaminants. Recovery studies were performed at three fortification levels. Mean recoveries were from 92.9% to 119.0%, with an acceptable coefficient of variation (4.4-18.5%, n=6). The limits of quantification of the method were 2, 2 and 0.5 MUg/kg for BPA, NP and OP, respectively. This method can be applied for screening and confirming target compounds in plant oil. PMID- 21708385 TI - Gallium ion-assisted room temperature synthesis of small-diameter ZnO nanorods. AB - We report a method for synthesizing small-diameter ZnO nanorods at room temperature (20 degrees C), under normal atmospheric pressure (1 atm), and using a relatively short reaction time (1 h) by adding gallium salts to the reaction solution. The ZnO nanorods were, on average, 92 nm in length and 9 nm in diameter and were single crystalline in nature. Quantitative analyses revealed that gallium atoms were not incorporated into the synthesized nanocrystals. On the basis of the experimental results, we propose a mechanism for the formation of small-diameter ZnO nanorods in the presence of gallium ions. The optical properties were probed by UV-Vis diffuse reflectance spectroscopy. The absorption band of the small-diameter ZnO nanorods was blue-shifted relative to the absorption band of the ~230 nm diameter ZnO nanorods (control samples). Control experiments demonstrated that the absence of metal ion-containing precipitants (except ZnO) at room temperature is essential, and that the ZnO nanorod diameter distributions were narrow for the stirred reaction solution and broad when prepared without stirring. PMID- 21708386 TI - Interfacial chemical bonding effect on the photocatalytic activity of TiO2-SiO2 nanocoupling systems. AB - TiO(2) nanoparticles (NPs) were deposited on the surfaces of SiO(2) microspheres with a mesoporous structure prepared by a hydrolysis-controlled sol-gel technique. The TiO(2) NPs were firmly combined on the surfaces of SiO(2) microspheres through the interfacial Si-O-Ti bonds. The coupling causes the bandgap widening up to 3.37 eV, enhancing the photocatalytic activity for the decomposition of acetaldehyde under illumination of UV-light (330 < lambda < 400 nm). Density functional theory calculations for model clusters suggested that the observed results are derived from the lowering in the valence band edge energy with the interfacial bond formation. PMID- 21708387 TI - Primary, secondary, and tertiary amines for CO2 capture: designing for mesoporous CO2 adsorbents. AB - CO(2) emissions, from fossil-fuel-burning power plants, the breathing, etc., influence the global worming on large scale and the man's work efficiency on small scale. The reversible capture of CO(2) is a prominent feature of CO(2) organic-inorganic hybrid adsorbent to sequester CO(2). Herein, (3-aminopropyl) trimethoxysilane (APTMS), [3-(methylamino)propyl] trimethoxysilane (MAPTMS), and [3-(diethylamino) propyl] trimethoxysilane (DEAPTMS) are immobilized on highly ordered mesoporous silicas (SBA-15) to catch CO(2) as primary, secondary, and tertiary aminosilica adsorbents. X-ray photoelectron spectroscopy was used to analyze the immobilized APTMS, MAPTMS, and DEAPTMS on the SBA-15. We report an interesting discovery that the CO(2) adsorption and desorption on the adsorbent depend on the amine type of the aminosilica adsorbent. The adsorbed CO(2) was easily desorbed from the adsorbent with the low energy consumption in the order of tertiary, secondary, and primary amino-adsorbents while the adsorption amount and the bonding-affinity increased in the reverse order. The effectiveness of amino-functionalized (1(o), 2(o), and 3(o) amines) SBA-15s as a CO(2) capturing agent was investigated in terms of adsorption capacity, adsorption-desorption kinetics, and thermodynamics. This work demonstrates apt amine types to catch CO(2) and regenerate the adsorbent, which may open new avenues to designing "CO(2) basket". PMID- 21708388 TI - Effect of deep brain stimulation on pain in Parkinson disease. AB - Pain is a well-recognized feature of Parkinson disease (PD), and for some patients it is the most disabling symptom. Patients with PD may experience various types of pain, and the treatment of their pain depends on its presumed cause. However, in many patients, both pain that appears to be unrelated to PD and PD-related pain can be alleviated by medical and surgical interventions that target the motor symptoms of PD. In this article we review reports on the improvement of pain in PD by surgical interventions such as subthalamic deep brain stimulation (STN DBS), and discuss the possible mechanisms by which STN DBS improves pain in PD. PMID- 21708389 TI - Molecular staging of marine medaka: a model organism for marine ecotoxicity study. AB - Oryzias melastigma, also called O. dancena, is becoming a very useful model for estuarine and marine ecotoxicity studies. With O. melastigma being adopted by ILSI Health and Environmental Science Institute (HESI) for embryo toxicity testing, improved knowledge of biomarker based embryonic development becomes especially important for mechanism-based toxicity evaluations. Using whole mount in situ hybridization and immunostaining techniques together with widely used molecular markers, this study describes the molecular development of marine medaka embryos, focusing on the brain, eye, heart, pectoral fin, pancreas, liver, muscle and neuron system. These organs are targets of environmental pollutants that disrupt normal embryonic development in medaka and other fish. PMID- 21708390 TI - Eutrophication and hypoxia in four streams discharging in Guanabara Bay, RJ, Brazil, a case study. AB - Four streams in the city of Sao Goncalo, were sampled to evaluate their potential as sources of nutrients to Guanabara Bay aiming to contribute with the government program to decrease the levels of pollution in this area. Imbuacu, Guaxindiba, Marimbondo and Brandoas streams were sampled in 2007, 2008 and 2009. The streams revealed to be hipereutrophic with severe limitation of primary production by nitrogen, as shown by the N/P molar ratio. Phosphate levels were abnormally high varying between 4.35 and 130.82 MUM, whereas nitrate and nitrite ranged from 0.06 to 54.05 MUM and from 0.28 to 19.23 MUM, respectively. The streams also presented severe hypoxia and anoxia, with oxygen values varying from non-detected to 3.72 ml l(-1). Heavy loads of particulate suspended material were recorded in the studied streams, ranging between 6.00 and 400.00 mg l(-1). The streams were considered inexorable sources of nutrients, enhancing the severe eutrophication process in Guanabara Bay. PMID- 21708391 TI - Proteomic changes and molecular effects associated with Cr(III) and Cr(VI) treatments on germinating kiwifruit pollen. AB - The present study is aimed at identifying molecular changes elicited by Cr(III) and Cr(VI) on germinating kiwifruit pollen. To address this question, comparative proteomic and DNA laddering analyses were performed. While no genotoxic effect was detected, a number of proteins whose accumulation levels were altered by treatments were identified. In particular, the upregulation of some proteins involved in the scavenging response, cell redox homeostasis and lipid synthesis could be interpreted as an oxidative stress response induced by Cr treatment. The strong reduction of two proteins involved in mitochondrial oxidative phosphorylation and a decline in ATP levels were also observed. The decrease of pollen energy availability could be one of the causes of the severe inhibition of the pollen germination observed upon exposure to both Cr(III) and Cr(VI). Finally, proteomic and biochemical data indicate proteasome impairment: the consequential accumulation of misfolded/damaged proteins could be an important molecular mechanism of Cr(III) toxicity in pollen. PMID- 21708392 TI - Evaluation of rk39 immunochromatographic test with urine for diagnosis of visceral leishmaniasis. AB - This study evaluates commercially available rK39 immunochromatographic strips using urine for diagnosis of visceral leishmaniasis (VL). Freshly collected urine and serum samples of 280 parasitologically confirmed VL patients and 66 endemic healthy controls (EHC), 48 nonendemic healthy controls (NEHC) and 45 different diseases were tested with rK39 strips. The sensitivity of rK39 in urine was 96.4% while the specificity was low varying from 66.7% in EHC, 77.08% in NEHC to 62.2% in different diseases. With serum, sensitivity was 100% whereas the specificity was 100%, 92.4% and 95.55% for the respective control groups. In the present format, the immunochromatographic strips cannot be used for the diagnosis of VL using urine samples. PMID- 21708393 TI - Phantom investigation of phase-inversion-based dual-frequency excitation imaging for improved contrast display. AB - OBJECTIVE: The goal of this work is to examine the effects of pulse-inversion (PI) technique in combination with dual-frequency (DF) excitation method to separate the high-order nonlinear responses from microbubble contrast agents for improvement of image contrast. DF excitation method has been previously developed to induce the low-frequency ultrasound nonlinear responses from bubbles by using the composition of two high-frequency sinusoids (f(1) and f(2)). MOTIVATION: Although the simple filtering was conventionally utilized to provide signal separation, the PI approach is better in the sense that it minimizes the mutual interferences among these high-order nonlinear responses in the presence of spectral overlap. The novelty of the work is that, in addition to the common PI summation, the PI subtraction was also applied in DF excitation method. METHODS: DF excitation pulses having an envelope frequency of 3MHz (i.e., f(1)=8.5MHz and f(2)=11.5MHz) with pulse lengths of 3-10MUs and the pressure amplitudes from 0.5 to 1.5MPa were used to interrogate the nonlinear responses of SonoVueTM microbubbles in the phantom experiments. The high-order nonlinear responses in the DF excitation were extracted for contrast imaging using PI summation for even order nonlinear components or PI subtraction for odd-order nonlinear ones. RESULTS: Our results indicated that, as compared to the conventional filtering technique, the PI processing effectively increases the contrast-to-tissue ratio (CTR) of the third-order nonlinear response at 5.5MHz and the fourth-order nonlinear response at 6MHz by 2-5dB. For these high-order nonlinear components, the CTR increase varies with the transmission pressures from 0.5 to 1.5MPa due to the microbubbles' displacement induced by the radiation force of DF excitation. CONCLUSIONS: For DF excitation technique, the PI processing can help to extract either the odd-order or the even-order nonlinear components for higher CTR estimates. PMID- 21708394 TI - Iron oxide amended biosand filters for virus removal. AB - Laboratory studies were performed to determine if the addition of iron oxides throughout biosand filter (BSF) media would increase virus removal due to adsorption. The proposed mechanism is electrostatic adsorption of negatively charged virion particles to positively charged iron oxides formed during the corrosion of zerovalent iron. Initial tests conducted using continuous flow, small-scale glass columns showed high MS2 bacteriophage removal in an iron amended sand column (5log10) compared to a sand-only column (0.5log10) over 20 pore volumes. Additionally, two experiments with a column containing iron particles revealed 4log10 and 5log10 removal of rotavirus in the presence of 20 mg/L total organic carbon. Full-scale BSFs with iron particles removed>4log10 MS2 for the duration of the experiment (287 days), while BSF with steel wool removed>4log10 MS2 for the first 160 days. Plug flow for the BSF was shown to depend on uniformity between the iron oxide material and sand media grains. The results suggest that the duration of effective virus removal by iron-amended biosand filtration depends on source water conditions and the quantity and composition of iron material added. Overall, this study provides evidence that iron-amended BSFs may advance the field of point-of-use technologies and bring relief to millions of people suffering from waterborne diseases. PMID- 21708395 TI - Transport and deposition of CeO2 nanoparticles in water-saturated porous media. AB - Ceria nanoparticles are used for fuel cell, metal polishing and automobile exhaust catalyst; however, little is known about the impact of their release to the environment. The stability, transport and deposition of engineered CeO2 nanoparticles through water-saturated column packed with sand were studied by monitoring effluent CeO2 concentration. The influence of solution chemistry such as ionic strength (1-10 mM) and pH (3-9) on the mobility and deposition of CeO2 nanoparticles was investigated by using a three-phase (deposition-rinse reentrainment) procedure in packed bed columns. The results show that water chemistry governs the transport and deposition of CeO2 nanoparticles. Transport is significantly hindered at acidic conditions (pH 3) and high ionic strengths (10 mM and above), and the deposited CeO2 particles may not be re-entrained by increasing the pH or lowering the ionic strength of water. At neutral and alkaline conditions (pH6 and 9), and lower ionic strengths (below 10 mM), partial breakthrough of CeO2 nanoparticles was observed and particles can be partially detached and re-entrained from porous media by changing the solution chemistry. A mathematical model was developed based on advection-dispersion-adsorption equations and it successfully predicts the transport, deposition and re entrainment of CeO2 nanoparticles through a packed bed. There is strong agreement between the deposition rate coefficients calculated from experimental data and predicted by the model. The successful prediction for attachment and detachment of nanoparticles during the deposition and re-entrainment phases is unique addition in this study. This work can be applied to access the risk of CeO2 nanoparticles transport in contaminated ground water. PMID- 21708396 TI - Decay profile and metabolic pathways of quinalphos in water, soil and plants. AB - The widespread occurrence of pesticide residues in different agricultural and food commodities has raised concern among the environmentalists and food chemists. In order to keep a proper track of these materials, studies on their decay profiles in the various segments of ecosystem under varying environmental conditions are needed. In view of this, the metabolites of quinalphos in water and soil under controlled conditions and in plants, namely tomato and radish in field conditions have been analysed and possible pathways suggested. In order to follow the decay of the pesticide, an HPLC procedure has been developed. Studies conducted in water at different temperatures, pH and organic content reveal that the persistence of the pesticide decreases with the increase in all the three variables. In the three different types of soils studied, the effect of pH is more or less apparent on a similar line. On an average a faster decay is observed in the case of plants than in water and soil. The decay profiles in all these cases follow first order kinetics. The metabolites were identified by GC-MS. The investigations reflect that degradation occurs through hydrolysis, S-oxidation, dealkylation and thiono-thiol rearrangement. The pathways seem to be complex and different metabolites were observed with the change in the matrix. Quinalphos oxon, O-ethyl-O-quinoxalin-2-yl phosphoric acid, 2-hydroxy quinoxaline and quinoxaline-2-thiol were observed in all the matrices. Results further indicate that the metabolites, 2-hydroxy quinoxaline and oxon, which are more toxic than parent compound, persist for a longer time. PMID- 21708397 TI - Levels of brominated flame retardants and other pesistent organic pollutants in breast milk samples from Limpopo Province, South Africa. AB - The non-occupational exposure to brominated flame retardants, and other persistent organic pollutants (POPs) was studied by collecting human breast milk samples from mothers residing in Thohoyandou area, a rural district in the Limpopo Province, northern part of South Africa (SA). Of all collected samples to be analysed (n=28), those with large enough milk volumes, (n=14) were quantified for polybrominated diphenyl ethers (PBDEs) (9 congeners: BDE-28, 47, 66, 99, 100, 138, 153, 154, and 183) and hexabromocyclododecane (HBCD) on a GC equipped with dual capillary columns and dual electron-capture detectors (ECD). The levels of PBDE congeners (median sumBDE 1.3 ng/g of lipids) and of HBCD were not far from levels generally found in European studies, and this study may be the first report on the presence of PBDEs and HBCD in SA breast milk. On a congener basis, the finding of comparably high BDE-183 levels suggests a specific PBDE usage, or contamination situation in SA. Apart from BFRs, the high DDT levels found in the breast milk from this area (median and maximum sumDDT levels of about 4600 and over 20,000 ng/g of lipids, respectively; n=28) have earlier been reported. In addition, other POPs (PCBs, HCB and HCHs) were found in SA breast milk, at relatively low levels. To conclude, measurable levels of PBDEs and HBCD, and a specific BDE congener pattern, were found in breast milk from the Limpopo province, SA. A number of other POPs, including DDTs in high levels, were also present. PMID- 21708398 TI - N,N-diethyl-m-toluamide transformation in river water. AB - The paper deals with the aqueous environmental fate of N,N-diethyl-m-toluamide (DEET), one of the most widespread and efficient mosquito repellents. The investigation involved monitoring of the DEET decomposition and the identification of intermediate compounds. Initially, control experiments in the dark and under illumination were performed on sterilized and river water spiked with DEET, with the aim to simulate all possible transformation processes occurring in aquatic system. Under illumination, DEET was degraded and transformed into numerous organic intermediate compounds, 37 of which could be identified. Several isomeric species were formed and characterized by analysing MS and MS(n) spectra, and by comparison with parent molecule fragmentation pathways. These laboratory simulation experiments were verified in the field to check the mechanism previously supposed. River water was sampled and analysed at eight sampling points. Among the transformation products (TPs) identified in river water spiked with DEET, twelve of them were also found in natural river water. The transformation occurring in aquatic systems involved dealkylation, mono- and poly-hydroxylation followed by oxidation of the hydroxyl groups and cleavage of the alkyl chains. Two TPs were principally formed in dark condition, while the others are mainly produced through indirect photolysis processes mediated by natural photosensitizers. PMID- 21708399 TI - Influence of cardiac resynchronization therapy on indices of inflammation, the prothrombotic state and tissue remodeling in systolic heart failure: a pilot study. PMID- 21708400 TI - Factor VIIa-antithrombin complexes in children with ischemic stroke. PMID- 21708401 TI - Association between genotype and plasma levels of thrombin-activated fibrinolysis inhibitor (TAFI) in the development of preeclampsia. AB - INTRODUCTION: The objective was to evaluate if thrombin-activated fibrinolysis inhibitor (TAFI) polymorphisms (G505A, C1040T, and G-438A), and TAFIa plasma levels are associated with preeclampsia. MATERIALS AND METHODS: In a case-control study design, we evaluated preeclampsia patients and women with uncomplicated pregnancies. The TAFI polymorphisms were determined by real-time PCR method, and TAFIa plasma levels were established with a chromogenic assay. RESULTS: We included 87 women in each group. The TAFIa levels in the preeclampsia group were 20.4 MUg/mL (CI 95% 17.3-23.5), while in the control group, they were significantly lower: 13.3 MUg/mL (12.0-14.5, p 0.003). There were no differences in the genotype distribution or allelic frequency of TAFI polymorphisms between the two groups. In preeclampsia patients and controls heterozygous for the G505A polymorphism, the TAFIa values were 22.8 (16.7-28.9 MUg/mL) and 13.2 (11.3-15.0 MUg/mL, p 0.019), respectively. In G505A homozygous polymorphism the TAFIa values were 25.7 (18.7-32.6 MUg/mL) and 13.5 (1.6-21.9 MUg/mL, p 0.041), respectively. In the C1040T and G-438A TAFI wild type polymorphisms, the TAFIa values were 18.3 (12.5-23.9 MUg/mL) and 11.5 (9.9-35.0, p 0.033), and 19.4 (10.9-27.9 MUg/mL) and 12.5 (10.8-14.2 MUg/mL, p 0.006), respectively, without differences in other genotypes. CONCLUSIONS: Preeclampsia by itself may be responsible for the increase in TAFIa values rather than the presence of polymorphisms. PMID- 21708402 TI - Proteomic biomarkers apolipoprotein A1, truncated transthyretin and connective tissue activating protein III enhance the sensitivity of CA125 for detecting early stage epithelial ovarian cancer. AB - OBJECTIVE: The low prevalence of ovarian cancer demands both high sensitivity (>75%) and specificity (99.6%) to achieve a positive predictive value of 10% for successful early detection. Utilizing a two stage strategy where serum marker(s) prompt the performance of transvaginal sonography (TVS) in a limited number (2%) of women could reduce the requisite specificity for serum markers to 98%. We have attempted to improve sensitivity by combining CA125 with proteomic markers. METHODS: Sera from 41 patients with early stage (I/II) and 51 with late stage (III/IV) epithelial ovarian cancer, 40 with benign disease and 99 healthy individuals, were analyzed to measure 7 proteins [Apolipoprotein A1 (Apo-A1), truncated transthyretin (TT), transferrin, hepcidin, beta-2-microglobulin (beta2M), Connective Tissue Activating Protein III (CTAPIII), and Inter-alpha trypsin inhibitor heavy chain 4 (ITIH4)]. Statistical models were fit by logistic regression, followed by optimization of factors retained in the models determined by optimizing the Akaike Information Criterion. A validation set included 136 stage I ovarian cancers, 140 benign pelvic masses and 174 healthy controls. RESULTS: In a training set analysis, the 3 most effective biomarkers (Apo-A1, TT and CTAPIII) exhibited 54% sensitivity at 98% specificity, CA125 alone produced 68% sensitivity and the combination increased sensitivity to 88%. In a validation set, the marker panel plus CA125 produced a sensitivity of 84% at 98% specificity (P=0.015, McNemar's test). CONCLUSION: Combining a panel of proteomic markers with CA125 could provide a first step in a sequential two-stage strategy with TVS for early detection of ovarian cancer. PMID- 21708403 TI - BCL-2, in combination with MVP and IGF-1R expression, improves prediction of clinical outcome in complete response cervical carcinoma patients treated by radiochemotherapy. AB - OBJECTIVES: To investigate whether BCL-2 expression would improve MVP/IGF-1R prediction of clinical outcome in cervix carcinoma patients treated by radiochemotherapy, and suggest possible mechanisms behind this effect. METHODS: Fifty consecutive patients, who achieved complete response to treatment, from a whole series of 60 cases suffering from non-metastatic localized cervical carcinoma, were prospectively included in this study from July 1999 to December 2003. Follow-up was closed in January 2011. All patients received pelvic radiation (45-64.80 Gy in 1.8-2 Gy fractions) with concomitant cisplatin at 40 mg/m2/week doses followed by brachytherapy. Oncoprotein expression was studied by immunohistochemistry in paraffin-embedded tumour tissue. RESULTS: No relation was found between BCL-2 and clinicopathological variables. High MVP/IGF-1R/BCL-2 tumour expression was strongly related to poor local and regional disease-free survival (P<0.0001), distant disease-free survival (P=0.010), disease-free survival (P<0.0001), and cause-specific survival (P<0.0001). NHEJ repair protein Ku70/80 expression was significantly repressed in tumours overexpressing all three oncoproteins (P=0.047). No differences were observed in proliferation (Ki67 expression) or P53 alteration. CONCLUSIONS: BCL-2, MVP, and IGF-1R overexpression were related to poorer clinical outcome in cervical cancer patients who achieved clinical complete response to radiochemotherapy. The NHEJ repair protein Ku70/80 expression could be involved in the regulation of these oncoproteins. PMID- 21708404 TI - Chairside vs. labside ceramic inlays: effect of temporary restoration and adhesive luting on enamel cracks and marginal integrity. AB - OBJECTIVES: To assess the influence of different temporary restorations and luting techniques of labside and chairside ceramic inlays on enamel defects and marginal integrity. METHODS: 120 extracted human third molars received MOD preparations with one proximal box each limited in either enamel or dentin. 64 Cerec 2 inlays and 56 IPS Empress I inlays were randomly assigned to the following groups (fabrication mode: chairside (CS)=no temporary restoration (TR), labside (LS)=TR with Luxatemp (L) inserted with TempBond NE, or Systemp.inlay (SI) without temporary cement), luting technique: SV=Syntac/Variolink II, RX=RelyX Unicem: A: Cerec inlays were luted with (1) CS/SV. (2) CS/SV/Heliobond separately light-cured. (3) CS/RX. (4) LS/L/SV. (5) LS/L/RX. (6) LS/SI/SV. (7) LS/SI/RX. (8) LS/SI/RX with selective enamel etching. B: Empress. (9) L/SV. (10) L/SV/Heliobond separately light-cured. (11) L/RX. (12) SI/SV. (13) SI/SV, Heliobond separately lightcured. (14) SI/RX. (15) SI/RX after selective enamel etching. Before and after thermomechanical loading (TML: loading time of TR 1000*50N+25 thermocycles (TC) between +5 degrees C and +55 degrees C; clinical simulation: 100,000*50N+2500 TC) luting gaps, enamel cracks, and marginal adaptation to enamel and dentin were determined under an SEM microscope (200*) using replicas. RESULTS: Loading time of temporary restorations negatively affected enamel integrity and enamel chipping (p<0.05). Luxatemp resulted in less enamel cracks than Systemp.inlay (p<0.05). Syntac/Variolink achieved better marginal enamel quality than RelyX Unicem in all groups (p<0.05). Marginal quality in dentin revealed no differences when no temporary cement was used (p>0.05). Temporary cement negatively affected dentin margins when RelyX Unicem was used (p<0.05). SIGNIFICANCE: Chairside-fabricated Cerec inlays reduce the risk of enamel cracks and marginal enamel chipping due to omitted temporary restorations. Syntac/Variolink revealed a significantly better performance than RelyX Unicem. PMID- 21708405 TI - Glutathione in the blood and cerebrospinal fluid: a study in healthy male volunteers. AB - Glutathione (GSH) is an important regulator of intracellular redox homeostasis. In the brain, glutathione is considered a major antioxidant, which is also found at high concentrations in the extracellular environment. Altered GSH balance in plasma, blood and cerebrospinal fluid (CSF) has been observed in several disorders suggesting that an impaired antioxidant function is part of the pathophysiology. The aim of the present study was to investigate a possible relationship between glutathione in plasma and CSF. Blood samples were collected from 26 healthy male volunteers at 8a.m., noon, 4p.m. and 8 p.m. At 8a.m. the following morning, blood was drawn and three 6-ml fractions of CSF were collected by lumbar puncture. In CSF, a disrupted gradient was found showing the highest glutathione concentration in the second compared to the first and third fraction (P<0.002). Moreover, correlation and regression analyses between glutathione in plasma and CSF revealed an association between the third fraction CSF and plasma glutathione 8 p.m. the day before lumbar puncture. Thus, if carefully standardised due to the disrupted gradient in CSF, it might be possible to estimate glutathione levels in CSF by analysing plasma in healthy males. PMID- 21708406 TI - Numb chin syndrome: a warning sign of aggressive B-cell malignancy. PMID- 21708407 TI - Incidence and prevalence of myelodysplastic syndromes: data from the Dusseldorf MDS-registry. AB - Population-based data on patients with MDS are scarce. Here we report the incidence and prevalence of MDS based on data from the Dusseldorf MDS Registry. Cases in the city of Dusseldorf in the study period were identified from the MDS Registry. We calculated crude, calendar-year, age- and sex-specific and European Standard Population age-standardized incidence rates as well as point prevalences per 100,000 The crude incidence rate was 4.15/100,000/year and the point prevalence per 100,000 persons of 7. We found that the incidence and prevalence of MDS was higher in men than women and increased sharply with increasing age. PMID- 21708408 TI - Long-term, multicenter evaluation of subconjunctival injection of triamcinolone for non-necrotizing, noninfectious anterior scleritis. AB - PURPOSE: We sought to characterize the long-term outcomes and complications of subconjunctival triamcinolone acetonide injection (STI) for non-necrotizing, noninfectious anterior scleritis. DESIGN: Retrospective, interventional, noncomparative, multicenter study. PARTICIPANTS: Sixty-eight eyes of 53 patients from 9 participating hospitals in the United States, Singapore, and Australia. Only eyes with 6 or more months of follow-up were included. INTERVENTION: Subconjunctival injection of 2 to 8 mg of triamcinolone acetonide was administered to eyes with non-necrotizing, noninfectious anterior scleritis. MAIN OUTCOME MEASURES: Resolution of signs and symptoms, time to recurrence of scleritis, and side effect profile. RESULTS: Median follow-up was 2.3 years (range, 6 months to 8.3 years). Sixty-six eyes (97.0%) experienced improvement of signs and symptoms after 1 injection. Twenty-four months after a single injection, 67.6% of eyes remained recurrence-free, whereas at 48 months, 50.2% were recurrence-free. Some 55.0% of patients who had adverse effects from systemic medications were off all systemic medications at last follow-up; 55.0% of patients who were taking systemic medications at the time of first triamcinolone acetonide injection were not taking prednisone and immunosuppressants at this time; 76.2% of patients still requiring systemic agents had associated systemic disease. Fourteen eyes (20.6%) had ocular hypertension not requiring intraocular pressure (IOP)-lowering therapy. Two eyes (2.9%) were treated with topical IOP-lowering agents alone, and 2 eyes required surgical intervention for glaucoma. None developed scleral necrosis or melt. CONCLUSIONS: This retrospective, international study carried out at 9 hospitals suggests that STI can treat non-necrotizing, noninfectious anterior scleritis with side effects limited to elevated IOP in a few patients. Although no cases of scleral melt or necrosis were observed, we cannot definitively conclude that this may not occur after STI. Intraocular pressure should be closely monitored after STI. Subconjunctival triamcinolone acetonide injection may be useful as adjuvant therapy or to decrease systemic medication burden. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21708409 TI - Social rhythms and vulnerability to bipolar disorder. AB - BACKGROUND: Reduced social rhythmicity is a commonly reported feature of bipolar disorder which may extend to non-clinical populations at risk of bipolar disorder. The aim of the current study was to investigate social rhythms across three groups of participants; a clinical group of bipolar disorder outpatients, and two non-clinical groups with high- and low-vulnerability to bipolar disorder, respectively. It was expected that reduced social rhythmicity would differentiate the clinical group from the low-vulnerability group, but not the high vulnerability group. METHODS: Non-clinical participants were selected on the basis of scores derived from the General Behaviour Inventory and allocated to groups of high (n=36) and low (n=36) trait vulnerability to bipolar disorder. The clinical group (n=15) were volunteers recruited from an outpatient clinic. Participants completed a self-report social rhythmicity measure daily for seven consecutive days. RESULTS: One-way analysis of covariance (age) showed a significant overall effect for group, F (2,83)=4.67, p<.05. Post hoc comparisons revealed significant differences in social rhythms between the two nonclinical groups only. LIMITATIONS: The cross-sectional design of the study limits the strength of conclusions that can be drawn. CONCLUSIONS: The hypothesis was only partially supported. Consistent with expectations, the non-clinical group with higher vulnerability to bipolar disorder recorded lower social rhythmicity than the non-clinical group with lower vulnerability to bipolar disorder. The clinical group however, did not differ in social rhythmicity from the lower vulnerability group. The findings may have consequences for the way in which vulnerability to bipolar disorder is managed. PMID- 21708410 TI - Life and treatment goals of individuals hospitalized for first-episode nonaffective psychosis. AB - First-episode psychosis typically emerges during late adolescence or young adulthood, interrupting achievement of crucial educational, occupational, and social milestones. Recovery-oriented approaches to treatment may be particularly applicable to this critical phase of the illness, but more research is needed on the life and treatment goals of individuals at this stage. Open-ended questions were used to elicit life and treatment goals from a sample of 100 people hospitalized for first-episode psychosis in an urban, public-sector setting in the southeastern United States. Employment, education, relationships, housing, health, and transportation were the most frequently stated life goals. When asked about treatment goals, participants' responses included wanting medication management, reducing troubling symptoms, a desire to simply be well, engaging in counseling, and attending to their physical health. In response to queries about specific services, most indicated a desire for both vocational and educational services, as well as assistance with symptoms and drug abuse. These findings are interpreted and discussed in light of emerging or recently advanced treatment paradigms-recovery and empowerment, shared decision-making, community and social reintegration, and phase-specific psychosocial treatment. Integration of these paradigms would likely promote recovery-oriented tailoring of early psychosocial interventions, such as supported employment and supported education, for first episode psychosis. PMID- 21708411 TI - Antiarrhythmic drugs for the maintenance of sinus rhythm: risks and benefits. AB - Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice, and its complications impose a significant economic burden. The development of more effective agents to manage patients with AF is essential. While clinical trials show no major differences in outcomes between rate and rhythm control strategies, some patients with AF require treatment with antiarrhythmic drugs (AADs) to maintain sinus rhythm, reduce symptoms, improve exercise tolerance, and improve quality of life. Currently available AADs, while effective, have limitations including limited efficacy, adverse events, toxicity, and proarrhythmic potential. The 6 most commonly used AADs (amiodarone, disopyramide, dofetilide [USA but not Europe], flecainide, propafenone, sotalol) have proarrhythmic effects (fewer with amiodarone). Amiodarone is the most effective AAD, but its safety profile limits its usefulness. Recent advances in AAD therapy include dronedarone and vernakalant. Dronedarone, approved by the United States Food and Drug Administration and the European Medicines Authority and others, has been proven efficacious in maintaining sinus rhythm and reducing the incidence of hospitalization due to cardiovascular events or death in patients with AF. The intravenous formulation of vernakalant is approved in the European Union, Iceland, and Norway. Oral vernakalant is currently undergoing evaluation for preventing AF recurrence and appears to be effective with an acceptable safety profile. Treatment should be individualized to the patient with consideration of pharmacologic risks and benefits according to AF management guidelines. Accumulating efficacy and safety data for new and emerging AADs holds promise for improved AF management and outcomes. PMID- 21708412 TI - Percutaneous coronary intervention in Takayasu's arteritis. PMID- 21708413 TI - KmL: a package to cluster longitudinal data. AB - Cohort studies are becoming essential tools in epidemiological research. In these studies, measurements are not restricted to single variables but can be seen as trajectories. Thus, an important question concerns the existence of homogeneous patient trajectories. KmL is an R package providing an implementation of k-means designed to work specifically on longitudinal data. It provides several different techniques for dealing with missing values in trajectories (classical ones like linear interpolation or LOCF but also new ones like copyMean). It can run k-means with distances specifically designed for longitudinal data (like Frechet distance or any user-defined distance). Its graphical interface helps the user to choose the appropriate number of clusters when classic criteria are not efficient. It also provides an easy way to export graphical representations of the mean trajectories resulting from the clustering. Finally, it runs the algorithm several times, using various kinds of starting conditions and/or numbers of clusters to be sought, thus sparing the user a lot of manual re-sampling. PMID- 21708414 TI - Fate of nitrogen for subsurface drip dispersal of effluent from small wastewater systems. AB - Subsurface drip irrigation systems apply effluent from onsite wastewater systems in a more uniform manner at a lower rate than has been possible with other effluent dispersal methods. The effluent is dispersed in a biologically active part of the soil profile for optimal treatment and where the water and nutrients can be utilized by landscape plants. Container tests were performed to determine the fate of water and nitrogen compounds applied to packed loamy sand, sandy loam, and silt loam soils. Nitrogen removal rates measured in the container tests ranged from 63 to 95% despite relatively low levels of available carbon. A Hydrus 2D vadose zone model with nitrification and denitrification rate coefficients calculated as a function of soil moisture content fit the container test results reasonably well. Model results were sensitive to the denitrification rate moisture content function. Two-phase transport parameters were needed to model the preferential flow conditions in the finer soils. Applying the model to generic soil types, the greatest nitrogen losses (30 to 70%) were predicted for medium to fine texture soils and soils with restrictive layers or capillary breaks. The slow transport with subsurface drip irrigation enhanced total nitrogen losses and plant nitrogen uptake opportunity. PMID- 21708415 TI - Toward potent alpha-glucosidase inhibitors based on xanthones: a closer look into the structure-activity correlations. AB - A series of novel xanthone derivatives 6-16 having non-coplanar and flexible structures were synthesized as potent alpha-glucosidase inhibitors. Biological evaluation indicated that compounds 6-12 bearing one or two naphthol moieties exhibited up to 30-fold enhanced activities compared with their corresponding parent compounds 2-5, whereas compounds 13-16 bearing one dihydroxylnaphthalenyl group showed decreased activities compared with their corresponding analogs 6-9 having one naphthol group. Among them, compounds 7-8, 10-12 and 15 were more active than 1-deoxynojirimycin, a well-known inhibitor for alpha-glucosidase. The structure-activity correlations suggested that inhibiting of alpha-glucosidase was a result of multiple interactions with the enzyme, including pi-stacking, hydrophobic effect and conformational flexibility due to the structural non coplanarity. In addition, compounds 4, 8 and 15 showed non-competitive inhibition. PMID- 21708416 TI - Combination of pharmacophore model development and binding mode analyses: identification of ligand features essential for IkappaB kinase-beta (IKKbeta) inhibitors and virtual screening based on it. AB - IkappaB kinase beta (IKKbeta) is an important anti-cancer target that plays crucial role in activating the transcription factor NF-kappaB in response to various inflammatory stimuli. In order to discover novel IKKbeta inhibitors, a 3D chemical-feature-based QSAR pharmacophore model was established. A homology model of IKKbeta enzyme was also developed to study the binding mode of IKKbeta and its inhibitors. The two models were consistent in predicting the binding conformation of IKKbeta inhibitor. Based on the virtual screening using the pharmacophore model, 16 compounds from SPECS database were selected after multiple filtrations for biological test. Two compounds with IC(50) values lower than 10 MUM were discovered. PMID- 21708417 TI - Intraoperative red cell salvage in head and neck surgery. PMID- 21708418 TI - Adsorption of sulfamethoxazole on functionalized carbon nanotubes as affected by cations and anions. AB - The environmental risks of antibiotics have attracted lots of research attention, but their environmental behavior is not clear yet. Functionalized carbon nanotubes (CNTs) were used as model adsorbents and sulfamethoxazole (SMX) was used as a model antibiotic to investigate the effect of both cations (Ca(2+), Cs(+)) and anions (phosphate) on antibiotics adsorption. Various mechanisms (such as electrostatic interaction, hydrophobic interaction, pi-pi and hydrogen bonds) play roles in SMX adsorption. Cations and anions could "wedge into" these mechanisms and thus alter SMX adsorption. This study emphasized that both increased and decreased SMX adsorption could be observed with the addition of cations/anions, depending on environmental conditions (such as pH in this current study). The net effect is the balance between the increased and decreased effects. The contribution of different mechanisms to the overall antibiotic adsorption on solid particles should be identified to accurately predict the apparent effect by cations and anions. PMID- 21708419 TI - Estimating the economic impact of pandemic influenza: An application of the computable general equilibrium model to the U.K. AB - There is concern regarding the impact that a global infectious disease pandemic might have, especially the economic impact in the current financial climate. However, preparedness planning concentrates more upon population health and maintaining a functioning health sector than on the wider economic impact. We developed a single country Computable General Equilibrium model to estimate the economic impact of pandemic influenza (PI) and associated policies. While the context for this development was the United Kingdom, there are lessons to be drawn for application of this methodology, as well as indicative results, to other contexts. Disease scenarios were constructed from an epidemiological model which estimated case fatality rates (mild, moderate and severe) as 0.06%, 0.18% and 0.35%. A clinical attack rate of 35% was also used to produce influenza scenarios, together with preparedness policies, including antivirals and school closure, and the possible prophylactic absence of workers. U.K. cost estimates (in Sterling) are presented, together with relative percentage impacts applicable to similar large economies. Percentage/cost estimates suggest PI would reduce GDP by 0.3% (L 3.5 bn), 0.4% (L 5 bn) and 0.6% (L 7.4 bn) respectively for the three disease scenarios. However, the impact of PI itself is smaller than disease mitigation policies: combining school closure with prophylactic absenteeism yields percentage/cost effects of 1.1% (L 14.7 bn), 1.3% (L 16.3 bn) and 1.4% (L 18.5 bn) respectively for the three scenarios. Sensitivity analysis shows little variability with changes in disease parameters but notable changes with variations in school closure and prophylactic absenteeism. The most severe sensitivity scenario results in a 2.9% (L 37.4 bn), 3.2% (L 41.4 bn) and 3.7% (L 47.5 bn) loss to GDP respectively for the three scenarios. PMID- 21708420 TI - Snorkelling and trampling in shallow-water fringing reefs: risk assessment and proposed management strategy. AB - Shallow reefs (reef flats <1.5 m) in the northern Red Sea are impacted by growing tourism that includes swimmers, snorkellers and reef walkers but have largely been neglected in past studies. We selected a fringing reef along the lagoon of Dahab (Sinai, Egypt) as a model for a management strategy. Point-intercept line transects were used to determine substrate composition, coral community and condition, and the coral damage index (CDI) was applied. Approximately 84% of the coral colonies showed signs of damage such as breakage, partial mortality or algal overgrowth, especially affecting the most frequent coral genus Acropora. Questionnaires were used to determine the visitors' socio-economic background and personal attitudes regarding snorkelling, SCUBA-diving and interest in visiting a prospective snorkelling trail. Experiencing nature (97%) was by far the strongest motivation, and interest in further education about reef ecology and skill training was high. Less experienced snorkellers and divers--the target group for further education and skill training--were those most prepared to financially support such a trail. We therefore recommend a guided underwater snorkelling trail and restricting recreational use to a less sensitive 'ecotourism zone' while protecting the shallow reef flat. Artificial structures can complete the trail and offer the opportunity to snorkel over deeper areas at unfavourable tide or wind conditions. This approach provides a strategy for the management and conservation of shallow-water reefs, which are facing increasing human impact here and elsewhere. PMID- 21708421 TI - Remediation technologies for heavy metal contaminated groundwater. AB - The contamination of groundwater by heavy metal, originating either from natural soil sources or from anthropogenic sources is a matter of utmost concern to the public health. Remediation of contaminated groundwater is of highest priority since billions of people all over the world use it for drinking purpose. In this paper, thirty five approaches for groundwater treatment have been reviewed and classified under three large categories viz chemical, biochemical/biological/biosorption and physico-chemical treatment processes. Comparison tables have been provided at the end of each process for a better understanding of each category. Selection of a suitable technology for contamination remediation at a particular site is one of the most challenging job due to extremely complex soil chemistry and aquifer characteristics and no thumb rule can be suggested regarding this issue. In the past decade, iron based technologies, microbial remediation, biological sulphate reduction and various adsorbents played versatile and efficient remediation roles. Keeping the sustainability issues and environmental ethics in mind, the technologies encompassing natural chemistry, bioremediation and biosorption are recommended to be adopted in appropriate cases. In many places, two or more techniques can work synergistically for better results. Processes such as chelate extraction and chemical soil washings are advisable only for recovery of valuable metals in highly contaminated industrial sites depending on economical feasibility. PMID- 21708422 TI - Binding of heavy metal contaminants onto chitosans--an evaluation for remediation of metal contaminated soil and water. AB - The binding efficiency of chitosan samples for Ag(+), Cd(2+), Cu(2+), Pb(2+) and Zn(2+) has been evaluated in order to consider their application to remediate metal contaminated soil and water. The sorption behaviour of metal ions was assessed using a batch technique at different contact time and initial metal concentration with different background electrolytes. The kinetics followed a pseudo-second-order model, while the equilibrium data correlated well with the Freundlich and Langmuir isotherm models. For example, the maximum sorption capacity (Q) for chitosan was estimated as 1.93 mmol/g for Ag(+), 1.61 mmol/g for Cu(2+), 0.94 mmol/g for Zn(2+), 0.72 mmol/g for Cd(2+) and 0.64 mmol/g for Pb(2+). Covalent interaction between metal ions and functional groups (amino and hydroxyl) of the chitosans was the main binding mechanism. Ion exchange is not an important process. Chitosan and cross-linked chitosans were able to bind metal ions in the presence of K(+), Cl(-) and NO(3)(-). The nature of Cl(-) and NO(3)( ) ions did not affect Zn(2+) binding by the chitosans. Even at 11x dilution, the chitosans were able to retain metal ions on their surfaces. PMID- 21708424 TI - Kinetics as a tool to assess the immobilization of soil trace metals by binding phase amendments for in situ remediation purposes. AB - Many soil remediation techniques consist in decreasing the mobility of trace metals by means of adding trace metal binding phases. For this study, whose aim is to assess the efficiency of soil remediation method by binding phase amendment, a kinetic fractionation method that provides the labile and slowly labile trace metal amounts in soil has been introduced. Manganese oxides (vernadite) and insolubilized humic acids (IHA) have been used as binding phases for the remediation of four heavily polluted soils. Vernadite amendments are effective for lead and cadmium remediation, whereas IHA amendments are only effective for copper remediation. In most cases, the labile metal fractions decrease dramatically in amended soils (up to 50%); on the other hand, the amounts of total extracted metal near the point of thermodynamic equilibrium often show no significant difference between the amended soil and the control soil. These results highlight the utility of kinetic fractionation in assessing the efficiency of soil remediation techniques and, more generally, in evaluating trace metal mobility in soils and its potential advantages compared to extraction schemes performed under equilibrium conditions. In the future, this kinetic method could be considerably simplified so as to consume much less time allowing its routine use. PMID- 21708425 TI - Nitric oxide inhalation, a proposed strategy for early treatment of hemorrhagic shock. AB - Nitric oxide (NO), an endothelial-derived relaxing factor, plays important roles in a variety of pathophysiological conditions such as hemorrhagic shock (HS). So far, the impact of NO administration in HS treatment has been controversial. Through literature review, we summarize here the biphasic effects of NO in early and late phases of HS. Evidence suggests that NO administration is beneficial in the early stage while detrimental in the late stage of HS. We further propose inhalation of NO as a novel therapeutic strategy for the treatment of HS in the early stage. PMID- 21708426 TI - MRI- versus CT-based volume delineation of lumpectomy cavity in supine position in breast-conserving therapy: an exploratory study. AB - PURPOSE: To examine magnetic resonance imaging (MRI) and computed tomography (CT) for lumpectomy cavity (LC) volume delineation in supine radiotherapy treatment position and to assess the interobserver variability. METHODS AND MATERIALS: A total of 15 breast cancer patients underwent a planning CT and directly afterward MRI in supine radiotherapy treatment position. Then, 4 observers (2 radiation oncologists and 2 radiologists) delineated the LC on the CT and MRI scans and assessed the cavity visualization score (CVS). The CVS, LC volume, conformity index (CI), mean shift of the center of mass (COM), with the standard deviation, were quantified for both CT and MRI. RESULTS: The CVS showed that MRI and CT provide about equal optimal visibility of the LC. If the CVS was high, magnetic resonance imaging provided more detail of the interfaces of the LC seroma with the unaffected GBT. MRI also pictured in more detail the interfaces of axillary seromas (if present) with their surroundings and their relationship to the LC. Three observers delineated smaller, and one observer larger, LC volumes comparing the MRI- and CT-derived delineations. The mean +/- standard deviation CI was 32% +/- 25% for MRI and 52% +/- 21% for CT. The mean +/- standard deviation COM shift was 11 +/- 10 mm (range 1-36) for MRI and 4 +/- 3 mm (range 1-10) for CT. CONCLUSIONS: MRI does not add additional information to CT in cases in which the CVS is assessed as low. The conformity (CI) is lower for MRI than for CT, especially at a low CVS owing to greater COM shifts for MRI, probably caused by inadequate visibility of the surgical clips on magnetic resonance (MR) images. The COM shifts seriously dictate a decline in the CI more than the variability of the LC volumes does. In cases in which MRI provides additional information, MRI must be combined with the CT/surgical clip data. PMID- 21708427 TI - Using a reduced spot size for intensity-modulated proton therapy potentially improves salivary gland-sparing in oropharyngeal cancer. AB - PURPOSE: To investigate whether intensity-modulated proton therapy with a reduced spot size (rsIMPT) could further reduce the parotid and submandibular gland dose compared with previously calculated IMPT plans with a larger spot size. In addition, it was investigated whether the obtained dose reductions would theoretically translate into a reduction of normal tissue complication probabilities (NTCPs). METHODS: Ten patients with N0 oropharyngeal cancer were included in a comparative treatment planning study. Both IMPT plans delivered simultaneously 70 Gy to the boost planning target volume (PTV) and 54 Gy to the elective nodal PTV. IMPT and rsIMPT used identical three-field beam arrangements. In the IMPT plans, the parotid and submandibular salivary glands were spared as much as possible. rsIMPT plans used identical dose-volume objectives for the parotid glands as those used by the IMPT plans, whereas the objectives for the submandibular glands were tightened further. NTCPs were calculated for salivary dysfunction and xerostomia. RESULTS: Target coverage was similar for both IMPT techniques, whereas rsIMPT clearly improved target conformity. The mean doses in the parotid glands and submandibular glands were significantly lower for three field rsIMPT (14.7 Gy and 46.9 Gy, respectively) than for three-field IMPT (16.8 Gy and 54.6 Gy, respectively). Hence, rsIMPT significantly reduced the NTCP of patient-rated xerostomia and parotid and contralateral submandibular salivary flow dysfunction (27%, 17%, and 43% respectively) compared with IMPT (39%, 20%, and 79%, respectively). In addition, mean dose values in the sublingual glands, the soft palate and oral cavity were also decreased. Obtained dose and NTCP reductions varied per patient. CONCLUSIONS: rsIMPT improved sparing of the salivary glands and reduced NTCP for xerostomia and parotid and submandibular salivary dysfunction, while maintaining similar target coverage results. It is expected that rsIMPT improves quality of life during and after radiotherapy treatment. PMID- 21708428 TI - Stereotactic fractionated radiotherapy in the treatment of juxtapapillary choroidal melanoma: the McGill University experience. AB - PURPOSE: To report our experience with linear accelerator-based stereotactic fractionated radiotherapy in the treatment of juxtapapillary choroidal melanoma. METHODS AND MATERIALS: We performed a retrospective review of 50 consecutive patients diagnosed with juxtapapillary choroidal melanoma and treated with linear accelerator-based stereotactic fractionated radiotherapy between April 2003 and December 2009. Patients with small to medium sized lesions (Collaborative Ocular Melanoma Study classification) located within 2 mm of the optic disc were included. The prescribed radiation dose was 60 Gy in 10 fractions. The primary endpoints included local control, enucleation-free survival, and complication rates. RESULTS: The median follow-up was 29 months (range, 1-77 months). There were 31 males and 29 females, with a median age of 69 years (range, 30-92 years). Eighty-four percent of the patients had medium sized lesions, and 16% of patients had small sized lesions. There were four cases of local progression (8%) and three enucleations (6%). Actuarial local control rates at 2 and 5 years were 93% and 86%, respectively. Actuarial enucleation-free survival rates at 2 and 5 years were 94% and 84%, respectively. Actuarial complication rates at 2 and 5 years were 33% and 88%, respectively, for radiation-induced retinopathy; 9.3% and 46.9%, respectively, for dry eye; 12% and 53%, respectively, for cataract; 30% and 90%, respectively, for visual loss [Snellen acuity (decimal equivalent), <0.1]; 11% and 54%, respectively, for optic neuropathy; and 18% and 38%, respectively, for neovascular glaucoma. CONCLUSIONS: Linear accelerator-based stereotactic fractionated radiotherapy using 60 Gy in 10 fractions is safe and has an acceptable toxicity profile. It has been shown to be an effective noninvasive treatment for juxtapapillary choroidal melanomas. PMID- 21708429 TI - Involvement of difference in decrease of hemoglobin level in poor prognosis of Stage I and II nasopharyngeal carcinoma: implication in outcome of radiotherapy. AB - PURPOSE: To investigate the effect of hemoglobin (Hb) concentration and the difference in its decrease during treatment on outcome of radiotherapy (RT) alone for patients with Stage I and II nasopharyngeal carcinoma. METHODS AND MATERIALS: A total of 572 patients with Stage I-II nasopharyngeal carcinoma with RT alone between January 2001 and December 2004 were retrospectively analyzed. Patient characteristics, tumor variables, and Hb level, including pre-RT Hb, mid-RT Hb, and dynamic change of Hb between pre- and post- RT and its difference in decrease (?Hb) were subjected to univariate and multivariable analysis to identify factors that predict disease-specific survival (DSS), local regional recurrence-free survival (LRFS), and metastases-free survival (MFS). RESULTS: The 5-year DSS was poorer in the Hb continuous decrease group than in the Hb noncontinuous decrease group (84% vs. 89%; p = 0.008). There was poorer 5-year DSS in patients with ?Hb of >11.5 g/L than in those with ?Hb of <=11.5 g/L (82% vs. 89%; p = 0.001), and poorer LRFS (79% vs. 83%; p = 0.035). Univariate and multivariate analysis showed that Hb decrease difference with greater than 11.5 g/L was an independent prognostic factor for DSS and LRFS. CONCLUSIONS: The difference in decrease of Hb level during the course of radiation treatment appeared as a poor prognostic factor in Stage I and II nasopharyngeal carcinoma patients. PMID- 21708430 TI - Osteoradionecrosis in head-and-neck cancer has a distinct genotype-dependent cause. AB - PURPOSE: We performed a case-control study to establish whether the development of osteoradionecrosis (ORN) was related to a variant allele substituting T for C at -509 of the transforming growth factor-beta1 gene (TGF-beta1). PATIENTS AND METHODS: A total of 140 patients, 39 with and 101 without ORN, who underwent radiotherapy for head-and-neck cancer with a minimum of 2 years follow-up, were studied. None of the patients had clinical evidence of recurrence at this time. DNA extracted from blood was genotyped for the -509 C-T variant allele of the TGF beta1 gene. RESULTS: There were no significant differences in patient, cancer treatment, or tumor characteristics between the two groups. Of the 39 patients who developed ORN, 9 were homozygous for the common CC allele, 19 were heterozygous, and 11 were homozygous for the rare TT genotype. Of the 101 patients without ORN, the distribution was 56 (CC), 33 (CT), and 12 (TT). The difference in distribution was significant, giving an increased risk of ORN of 5.7 (95% CI, 1.7-19.2) for homozygote TT patients (p = 0.001) and 3.6 (95% CI, 1.3-10.0) for heterozygotes (p = 0.004) when compared with patients with the CC genotype. Postradiotherapy dentoalveolar surgery preceding the development of ORN was associated with the CC genotype (p = 0.02). CONCLUSIONS: Our findings support the postulate that the development of ORN is related to the presence of the T variant allele at -509 within the TGF-beta1 gene. PMID- 21708431 TI - Influence of androgen deprivation therapy on all-cause mortality in men with high risk prostate cancer and a history of congestive heart failure or myocardial infarction. AB - PURPOSE: It is unknown whether the excess risk of all-cause mortality (ACM) observed when androgen deprivation therapy (ADT) is added to radiation for men with prostate cancer and a history of congestive heart failure (CHF) or myocardial infarction (MI) also applies to those with high-risk disease. METHODS AND MATERIALS: Of 14,594 men with cT1c-T3aN0M0 prostate cancer treated with brachytherapy-based radiation from 1991 through 2006, 1,378 (9.4%) with a history of CHF or MI comprised the study cohort. Of these, 22.6% received supplemental external beam radiation, and 42.9% received a median of 4 months of neoadjuvant ADT. Median age was 71.8 years. Median follow-up was 4.3 years. Cox multivariable analysis tested for an association between ADT use and ACM within risk groups, after adjusting for treatment factors, prognostic factors, and propensity score for ADT. RESULTS: ADT was associated with significantly increased ACM (adjusted hazard ratio [AHR] = 1.76; 95% confidence interval [CI], 1.32-2.34; p = 0.0001), with 5-year estimates of 22.71% with ADT and 11.62% without ADT. The impact of ADT on ACM by risk group was as follows: high-risk AHR = 2.57; 95% CI, 1.17-5.67; p = 0.019; intermediate-risk AHR = 1.75; 95% CI, 1.13-2.73; p = 0.012; low-risk AHR = 1.52; 95% CI, 0.96-2.43; p = 0.075). CONCLUSIONS: Among patients with a history of CHF or MI treated with brachytherapy-based radiation, ADT was associated with increased all-cause mortality, even for patients with high-risk disease. Although ADT has been shown in Phase III studies to improve overall survival in high-risk disease, the small subgroup of high-risk patients with a history of CHF or MI, who represented about 9% of the patients, may be harmed by ADT. PMID- 21708432 TI - Application of failure mode and effects analysis to intraoperative radiation therapy using mobile electron linear accelerators. AB - PURPOSE: Failure mode and effects analysis (FMEA) represents a prospective approach for risk assessment. A multidisciplinary working group of the Italian Association for Medical Physics applied FMEA to electron beam intraoperative radiation therapy (IORT) delivered using mobile linear accelerators, aiming at preventing accidental exposures to the patient. METHODS AND MATERIALS: FMEA was applied to the IORT process, for the stages of the treatment delivery and verification, and consisted of three steps: 1) identification of the involved subprocesses; 2) identification and ranking of the potential failure modes, together with their causes and effects, using the risk probability number (RPN) scoring system, based on the product of three parameters (severity, frequency of occurrence and detectability, each ranging from 1 to 10); 3) identification of additional safety measures to be proposed for process quality and safety improvement. RPN upper threshold for little concern of risk was set at 125. RESULTS: Twenty-four subprocesses were identified. Ten potential failure modes were found and scored, in terms of RPN, in the range of 42-216. The most critical failure modes consisted of internal shield misalignment, wrong Monitor Unit calculation and incorrect data entry at treatment console. Potential causes of failure included shield displacement, human errors, such as underestimation of CTV extension, mainly because of lack of adequate training and time pressures, failure in the communication between operators, and machine malfunctioning. The main effects of failure were represented by CTV underdose, wrong dose distribution and/or delivery, unintended normal tissue irradiation. As additional safety measures, the utilization of a dedicated staff for IORT, double-checking of MU calculation and data entry and finally implementation of in vivo dosimetry were suggested. CONCLUSIONS: FMEA appeared as a useful tool for prospective evaluation of patient safety in radiotherapy. The application of this method to IORT lead to identify three safety measures for risk mitigation. PMID- 21708433 TI - Manufactured and hand-rolled cigarettes and smokeless tobacco consumption in Mozambique: regional differences at early stages of the tobacco epidemic. AB - BACKGROUND: To describe the use of different types of tobacco (manufactured and hand-rolled cigarettes, and smokeless tobacco) in the adult Mozambican population, across regions. METHODS: A representative sample of 12,902 Mozambicans aged 25-64 years was evaluated in a national household survey conducted in 2003 using a structured questionnaire. The patterns of tobacco consumption were described to highlight the sex-specific differences by age and between urban and rural settings, and between the north, where most of the country's tobacco production is concentrated, and the south of the country, where the wealthiest provinces, closer to the city capital, are located. RESULTS: The prevalence of current tobacco consumption was 39.9% in men and 18.0% in women. Women consumed predominantly smokeless tobacco (prevalence: 10.1%), especially in the north. Hand-rolled and manufactured cigarettes were the most frequently consumed among men (prevalences: 18.7% and 17.2%, respectively). Additionally, hand-rolled cigarette consumption predominantly occurred in the northern provinces and rural settings, whereas manufactured cigarette consumption predominated in the south and urban areas. CONCLUSIONS: The overall tobacco consumption was higher than expected for an African country with scarce economic resources, mostly due to traditional forms of consumption. The gender and regional specific patterns of consumption identified in Mozambique may contribute to the development of culturally adapted and locally grounded actions for tobacco control, and stress the need of locale-specific surveillance data and public health action in this field. PMID- 21708434 TI - Benzodiazepine dependence among multidrug users in the club scene. AB - BACKGROUND: Benzodiazepines (BZs) are among the most frequently prescribed drugs with the potential for abuse. Young adults ages 18-29 report the highest rates of BZ misuse in the United States. The majority of club drug users are also in this age group, and BZ misuse is prevalent in the nightclub scene. BZ dependence, however, is not well documented. This paper examines BZ dependence and its correlates among multidrug users in South Florida's nightclub scene. METHODS: Data were drawn from structured interviews with men and women (N=521) who reported regular attendance at large dance clubs and recent use of both club drugs and BZs. RESULTS: Prevalences of BZ-related problems were 7.9% for BZ dependence, 22.6% BZ abuse, and 25% BZ abuse and/or dependence. In bivariate logistic regression models, heavy cocaine use (OR 2.27; 95% CI 1.18, 4.38), severe mental distress (OR 2.63; 95% CI 1.33, 5.21), and childhood victimization history (OR 2.43; 95% CI 1.10, 5.38) were associated with BZ dependence. Heavy cocaine use (OR 2.14; 95% CI 1.10, 4.18) and severe mental distress (OR 2.16; 95% CI 1.07, 4.37) survived as predictors in the multivariate model. DISCUSSION: BZ misuse is widespread among multidrug users in the club scene, who also exhibit high levels of other health and social problems. BZ dependence appears to be more prevalent in this sample than in other populations described in the literature. Recommendations for intervention and additional research are described. PMID- 21708435 TI - Genotypic characterization by polymerase chain reaction of Staphylococcus aureus isolates associated with bovine mastitis. AB - Staphylococcus aureus is recognized worldwide as a pathogen causing many serious diseases in humans and animals, and is the most common aetiological agent of clinical and subclinical bovine mastitis. The importance of evaluating the combination of S. aureus virulence factors has been emphasized both in human and veterinary medicine, and knowledge about the genetic variability within different S. aureus populations would help in the design of efficient treatments. The aim of the present study was to determine the genetic profiles of S. aureus strains isolated from milk of cows suffering from clinical and subclinical mastitis in Belgium. The presence of about forty virulence-associated genes was investigated by specific polymerase chain reaction (PCR) amplification. A high number of genotypic subtypes were observed, demonstrating further the large variation in the presence of virulence genes in S. aureus isolates and the considerable diversity of strains populations that are able to cause mastitis in cows. In accordance with other studies, we showed that some genes are associated with mastitis-causing S. aureus isolates, whereas others are absent or rarely present. We also further highlighted the presence of conserved gene combinations, namely the enterotoxigenic egc-cluster and the bovine pathogenicity island SaPIbov. Importantly, the presence of isolates carrying genes coding for toxins involved in important human infections makes the milk of cows with mastitis a potential reservoir for these toxins, and therefore a potential danger in human health, which strengthens the importance to consider raw milk consumption and its processing very carefully. PMID- 21708436 TI - Under-recording of ethanol intoxication and poisoning in cause-of-death data: causes and consequences. AB - In the present study we examined how consistently and completely the role of acute alcohol (ethanol) intake as a cause of death is reported on death certificates, how complete and specific the statistical recording of cause-of death data on acute alcohol-induced deaths is, and how the information ultimately appears in the national mortality statistics. Data on all alcohol-positive deaths with blood alcohol concentration of >= 0.50/00 (g/kg) in Finland in 2005 (N = 2348) were reviewed. Overall, a concentration-dependent association was found between forensic-toxicologically determined blood alcohol concentrations and acute alcohol-specific cause-of-death diagnoses. Based on a medico-legal re evaluation of death certificates, acute alcohol-specific causes were found to be underreported nationally at a rate of 8%. For accidental alcohol poisonings alone, the figure was about 1%. This underreporting was not corrected during recording of the cause-of-death data, though individual corrections and changes were observed. Especially, recording of multiple causes suffers from this underreporting of acute alcohol-specific causes. ICD-10 seems to do well in fulfilling the demands for a specific classification of uncomplicated alcohol poisoning. In combined alcohol-drug poisonings, however, ICD-10 shows a bias towards drugs over alcohol, even when alcohol has been specified and reported as the most toxic component by the medico-legal pathologist. Since the national statistics is based on the underlying causes, this state of affairs is likely to result in the underestimation of the role of acute alcohol intake as a cause of death. This observation of underreporting of acute alcohol-specific causes on death certificates should result in a harmonisation of education and principles and practices used in death certification. To increase the coverage and specificity of mortality statistics, based on the underlying causes of death, the coding of all components of alcohol-drug combinations and their classification according to the most important intoxicant or combination of intoxicants is recommended. PMID- 21708437 TI - Post-mortal lesions in freshwater environment. AB - Postmortem animal feeding activity may cause considerable damage to bodies resulting in the modification of wounds, loss of identifying features and injury. Certain postmortem lesions may appear inflicted or non-inflicted antemortem injuries. At present, apart from cases in sea water, no data are available about post mortal lesions performed by aquatic organisms. This note that represents the first report concerning colonisation of a dead body by crustaceans a few hours after death, describes injuries caused by the amphipod Niphargus elegans on the face, and in particular on the eye region, of a young man dead by drowning. The lesions recorded in this case are comparable with the lesions caused by ants. The high plasticity in the food choice can allow Amphipoda to colonise drowning bodies in every moment after dead, however the benthonic behaviour of these animals suggests a more important role in the colonisation during post-mortem submersion periods. PMID- 21708438 TI - Effect of microbubble contrast agent during high intensity focused ultrasound ablation on rabbit liver in vivo. AB - OBJECTIVE: To evaluate the effect of a microbubble contrast agent (SonoVue) during HIFU ablation of a rabbit liver. MATERIALS AND METHODS: HIFU ablations (intensity of 400W/cm(2) for 4s, six times, with a 5s interval between exposures) were performed upon 16 in vivo rabbit livers before and after intravenous injection of a microbubble contrast agent (0.8ml). A Wilcoxon signed rank test was used to compare mean ablation volume and time required to tissue ablation on real-time US. Shape of ablation and pattern of coagulative necrosis were analyzed by Fisher's exact test. RESULTS: The volume of coagulative necrosis was significantly larger in the combination microbubble and HIFU group than in the HIFU alone group (P<0.05). Also, time to reach ablation was shorter in the combination microbubble and HIFU group than in the HIFU alone group (P<0.05). When analyzing the shape of tissue ablation, a pyramidal shape was more prevalently in the HIFU alone group compared to the combination microbubble and HIFU group (P<0.05). Following an analysis of the pattern of coagulative necrosis, non-cavitary necrosis was found in ten and cavitary necrosis in six of the samples in the combination microbubble and HIFU group. Conversely, non cavitary necrosis occurred in all 16 samples in the HIFU alone group (P<0.05). CONCLUSION: HIFU of in vivo rabbit livers with a microbubble contrast agent produced larger zones of ablation and more cavitary tissue necrosis than without the use of a microbubble contrast agent. Microbubble contrast agents may be useful in tissue ablation by enhancing the treatment effect of HIFU. PMID- 21708439 TI - Optimal iodine dose for 3-dimensional multidetector-row CT angiography of the liver. AB - PURPOSE: To clarify the optimal iodine dose of contrast material for 3 dimensional multidetector-row CT angiography (3D-MDCTA) of the venous vasculature of the liver using volume rendering technique. MATERIALS AND METHODS: This study included 103 patients who were randomly assigned to 5 contrast-enhanced MDCT protocol groups with different body-weight-tailored doses of contrast material: 500, 600, 630, 650, and 700 mgI/kg body weight. The arterial, portal, and hepatic parenchymal phases were obtained to evaluate enhancement values of the aorta, portal vein, and hepatic vein. Visualization of the portal and hepatic veins on the volume-rendering images of 3D-MDCTA was evaluated using a 5-point grade. Dunnett's test was used to compare the mean enhancement value and mean grades of image quality (700 mgI/kg dose group was control). RESULTS: The mean enhancement values of portal and hepatic vein in the group with 500 and 600 mgI/kg were significantly lower than those of the control group. During visual assessment, a significantly lower mean grades were observed in 500 mgI/kg groups for the portal vein, and 500 and 600 mgI/kg groups for hepatic vein. There were no significant intergroup differences in mean enhancement values and visual assessment among the groups using 630 mgI/kg or more. CONCLUSION: Iodine doses of 630 mgI/kg was recommended for 3D-MDCTA. PMID- 21708440 TI - Fat-suppressed MR images of both hands obtained using CHESS can be improved by rice pads. AB - When chemical shift selective (CHESS) imaging is used with magnetic resonance imaging (MRI) for simultaneous imaging of both hands for the evaluation of rheumatoid arthritis, the fat suppression effect is poor. We investigated whether these fat-suppressed images using CHESS could be improved with the use of rice pads. T1-weighted images were obtained with CHESS and the same imaging parameters were used with and without rice pads on the coronal plane of both hands in 10 healthy volunteers. Patients were placed in a prone position with both hands extended overhead. The fat-suppression effect was classified into four categories and scored for both sets of images, and visual assessments were made by one radiologist and one radiologic technologist. The evaluation score was 1.1 for the images made without rice pads, and 3.2 for the images made with rice pads. The fat suppression effect was thus significantly better in the images made using rice pads (P<0.0001). Lingering fat signals disappeared almost completely in images of both hands using CHESS with rice pads, and it was confirmed that the images were improved and had good fat suppression. More accurate evaluation of inflammatory sites that occur in rheumatoid arthritis may thus be possible, promising better diagnostic accuracy. PMID- 21708441 TI - Noncontrast chest computed tomography immediately after transarterial chemoembolization in patients with hepatocellular carcinoma: clinical benefits and effect of radiation reduction on image quality in low-dose scanning. AB - PURPOSE: To evaluate the clinical benefits of noncontrast chest computed tomography (CT) immediately after transarterial chemoembolization in patients with hepatocellular carcinoma and to assess the effect of radiation reduction on image quality in low-dose scanning. MATERIALS AND METHODS: From June to October 2010, we performed standard-dose, noncontrast chest CTs immediately after transarterial chemoembolization in 160 patients and low-dose CTs in 88 patients. We reviewed the entire noncontrast chest CTs and follow-up CTs to reveal the clinical benefits of CT evaluation immediately after transarterial chemoembolization. Using two independent readers, we also retrospectively evaluated the radiation dose and image quality in terms of the image noise, contrast between the liver parenchyma and iodized oil and diagnostic acceptability for the evaluation of treatment response after transarterial chemoembolization. RESULTS: In 5.2% of the patients, additional treatment was performed immediately after the interpretation of the noncontrast chest CT, and additional pulmonary lesions were found in 8.5% of the patients. The measured mean dose-length product for the low-dose scanning was 18.4% of that of the standard-dose scanning. The image noise was significantly higher with the low dose scanning (p<0.001). However, all of the low-dose CT scans were diagnostically acceptable, and the mean scores for the subjective assessments of the contrast and diagnostic acceptability showed no significant differences for either reader. CONCLUSION: A noncontrast chest CT immediately after transarterial chemoembolization has some clinical benefits for immediate decision making and detecting pulmonary lesions. Low-dose, noncontrast chest CTs immediately after transarterial chemoembolization consistently provide diagnostically acceptable images and information on treatment response in patients who have undergone transarterial chemoembolization. PMID- 21708442 TI - Transcatheter arterial embolization as therapy of renal angiomyolipomas: the evolution in 15 years of experience. AB - OBJECTIVE: This study aims at presenting the evolution of the embolization technique in treating renal angiomyolipomas (AMLs) either diagnosed in patients with acute bleeding or discovered accidentally. METHODS: Ten patients with renal AMLs have been through thirteen selective transcatheter arterial embolizations for 15 years. Two patients had tuberous sclerosis complex (TSC) with bilateral tumors and were embolized twice. Four embolic materials were employed: PVA particles, Gianturco coils, microspheres and microcoils. Catheterization was achieved by means of 5F Cobra 2 catheters and coaxial microcatheter systems. RESULTS: On an emergency basis, embolization was a first-line treatment. In one case, surgery was necessary; in two patients, a second embolization was performed. When treatment was preventive, a single embolization proved to be sufficient, as well. There was no significant deterioration of the serum creatinine levels in the post-embolization period. CONCLUSION: Selective arterial embolization is a rather safe and effective technique to treat AMLs both urgently and preventively. Different embolic materials can be employed. Microspheres and microcatheters stand for new promising materials. PMID- 21708443 TI - Morphometric characterization of Binswanger's disease: comparison with Alzheimer's disease. AB - BACKGROUND AND PURPOSE: Dementia due to hypertensive vascular disease is a potential target to treat prophylactively before it progresses insidiously. Binswanger's disease (BD) is a type of subcortical vascular dementia, but its clinical features and pathophysiology are still obscure. We therefore tried to find a topographic distribution of brain atrophy in BD by morphometric analysis. METHODS: Twenty patients with BD, 50 patients with AD, and 80 elderly controls were recruited. We contrasted the gray matter atrophy of BD to that of AD to identify a pathognomic pattern using magnetic resonance imaging. We used DARTEL (diffeomorphic anatomical registration through exponential Lie algebra) for voxel based morphometry, expecting that its sophisticated algorithm would work well to deal with the subjects with brain atrophy. RESULTS: Atrophy of cortices was predominant in the posterior cortices in AD but was in the anterior cortices in BD. Atrophy of amygdala and hippocampus was similar in each disease. In contrast, thalamus, caudate nucleus, insula, anterior cingulate cortex, and frontal cortices were significantly more atrophied in BD than in AD (z-score >3). CONCLUSIONS: We demonstrated topographic patterns of brain atrophy in BD. Since affected regions of BD match with the anatomical connections of frontal subcortical circuits, it seems reasonable to suppose that BD pathology is the result of hypertensive vascular disease and subsequent regression from the white matter injuries. PMID- 21708444 TI - Sonographic criteria for therapy follow-up in the course of ultrasound-guided intra-articular injections of hyaluronic acid in hand osteoarthritis. AB - OBJECTIVE: To assess the value of sonographic criteria, based on measurements of joint capsule distension and synovial hyperemia, during the course of repeated ultrasound (US)-guided intra-articular injections of hyaluronic acid (HA) in hand osteoarthritis (OA). MATERIALS AND METHODS: Thirty-three patients (28 females/5 males), with hand OA in 78 joints, were included in this study. Patients underwent sonographic evaluation at baseline and consecutively for 4 weeks at weekly US-guided intra-articular injections of HA (Hyalgan((r))). Measurements of joint thickening and joint inflammation were performed with Grey-scale and semi quantitative Power-Doppler US (PDUS). Sonographic values were correlated with weekly patients self-assessment of pain for each treated joint. RESULTS: The mean (SD) patients self-assessment of pain statistically significantly (p<0.0001) decreased from the first [68.3(22.3)] to the last week [37.3(30.34)]. A steady pain relief could be noticed in 67 (86%) of all treated joints. Over the whole observation period, the mean (SD) joint thickening of all joints markedly decreased from 15.6mm (5.3) to 13.1mm (6.4) (p<0.0001). The PDUS-score before initiation of HA treatment was statistically significantly higher than at the end of therapy (p<0.0001). The decrease in pain statistically significantly correlated with the decrease of joint thickening and PDUS-score between baseline and the end of therapy (p<0.001). CONCLUSION: In this study, we demonstrate the meaningfulness of sonographic evaluation criteria including measurements of joint capsule distension and PDUS vascularization, both significantly correlating with the decrease of pain, during the therapy follow-up of US-guided intra-articular HA-injections in patients with hand OA. PMID- 21708445 TI - Development and validation of a stability-indicating LC method for determining palonosetron hydrochloride, its related compounds and degradation products using naphthalethyl stationary phase. AB - A selective and simple reversed phase HPLC method using naphthalethyl stationary phase was developed and validated for the quantitative determination of palonosetron hydrochloride (PALO), its related compounds and degradation products. Chromatographic separation (R(s)>2) was achieved with linear gradient mode of elution at a flow rate of 1 mL/min and with UV detection at 210 nm. The intra and inter-day coefficients of variation were less than 1.0% (RSD). Consistent recoveries were obtained for PALO (99.2-100.5%) and its impurities (90.0-104.8%). All the analytes exhibited excellent linearity with R2 value greater than 0.998. Limit of detection (LOD) and limit of quantification (LOQ) were determined to be in the range 0.011-0.013 MUg/mL and 0.035-0.046 MUg/mL respectively. The test solution was found to be stable up to 5 days. Induced degradation methods were applied to study the degradation behavior of the drug. LC-MS was used to analyze the degraded samples and possible structural identifications were assigned based upon known reactivity of the drug and molecular weights. The m/z values matched with the hydroxylated, keto and N-oxide metabolites of PALO. The stress samples were assayed against a qualified reference standard and the mass balance was found close to 99.9%. PMID- 21708446 TI - Effects of adding epinephrine to arthroscopic irrigation fluid on cultured chondrocyte survival in vitro. AB - PURPOSE: This study evaluates the effect of low doses of epinephrine contained in common arthroscopic irrigation solutions on viability of in vitro human articular chondrocytes during short-term exposure. METHODS: Isolated cultured human chondrocytes were treated with culture medium, normal saline solution, 1:300,000 epinephrine solution (equivalent to 10 mL of 1:1,000 epinephrine added to a 3-L saline solution bag), or 1:3,000,000 epinephrine solution (equivalent to 1 mL of 1:1,000 epinephrine added to a 3-L saline solution bag) for 1 hour (N = 84). Twenty-four hours after treatment, chondrocyte viability was measured. Statistical analysis was performed with an analysis of variance with Bonferroni post-test. RESULTS: Chondrocyte viability was significantly better when exposed to normal saline solution alone versus high-dose 1:300,000 epinephrine (87.9% +/- 5.4% v 74.6% +/- 9.4%, P < .05). Exposure to low-dose 1:3,000,000 epinephrine had significantly better survival versus high-dose 1:300,000 epinephrine (85.0% +/- 8.3% v 74.6% +/- 9.4%, P < .05). There was no difference in viability after exposure to low-dose 1:3,000,000 epinephrine versus normal saline solution (85.0% +/- 8.3% v 87.9% +/- 5.4%, P > .05). CONCLUSIONS: In vitro, normal saline solution and low-dose 1:3,000,000 epinephrine are significantly less toxic than high-dose 1:300,000 epinephrine to cultured human articular chondrocytes. CLINICAL RELEVANCE: This in vitro study suggests that arthroscopic irrigation fluid containing 1:3,000,000 epinephrine is less chondrotoxic than solutions containing 1:300,000 epinephrine. Surgeons may wish to use the least amount of epinephrine required for adequate visual clarity during surgery. This study does not establish a contraindication to the use of higher doses of epinephrine. PMID- 21708447 TI - Metabolic syndrome in children with and without developmental coordination disorder. AB - Children with developmental coordination disorder (DCD) have higher rates of obesity compared to children with typical motor development, and, as a result may be at increased risk for developing metabolic syndrome (MetS). The purpose of this study was to determine the presence of MetS and its components among children with and without DCD. This nested case-control study classified 63 children scoring below the 16th percentile on the Movement Assessment Battery for Children (M-ABC-2) as probable DCD (pDCD), and 63 controls, all of whom scored above the 16th percentile. Metabolic syndrome was defined using the International Diabetes Federation (IDF) criteria. Eleven children met the criteria for MetS; 8 (72.3%) with pDCD and 3 (27.3%) controls (p = 0.115). Abdominal obesity was found in 39 (30.9%) of children, 29 (46.0%) with pDCD and 10 (15.9%) controls (p < 0.01). Serum triglycerides were higher in pDCD compared to controls, 91.9 mg/dl (63.1) vs. 67.7 mg/dl (33.3) in the control group, p = 0.001. Blood pressure was also significantly higher in the pDCD group, mean systolic BP (110 vs. 105 mmHg, p = 0.01) and mean diastolic BP (69 vs. 65 mmHg, p = 0.01). There were no statistically significant differences between the groups for other components of MetS. The higher prevalence of abdominal obesity and elevated triglycerides and blood pressure in children with pDCD may put them at risk of meeting all criteria of MetS earlier then their peers. PMID- 21708448 TI - Enabling people with developmental disabilities to actively follow simple instructions and perform designated physical activities according to simple instructions with Nintendo Wii Balance Boards by controlling environmental stimulation. AB - The latest researches have adopted software technology turning the Nintendo Wii Balance Board into a high performance standing location detector. This study extended Wii Balance Board functionality to assess whether two people with developmental disabilities would be able to actively perform designated physical activities according to simple instructions by controlling their favorite environmental stimulation using Nintendo Wii Balance Boards. This study was carried out according to an A-B-A-B design. Data showed that both participants significantly increased their target response (performing a designated physical activity) by activating the control system to produce their preferred environmental stimulation during the intervention phases. PMID- 21708450 TI - Visualizing phase relations of the vocal folds by means of high-speed videoendoscopy. AB - OBJECTIVES: To present a method called Fourier image (FI) for analyzing high speed videoendoscopy recordings. These false-color images visualize functional vocal fold properties and allow the quantification of phase relations. Furthermore, reference data for phase asymmetries in normophonic speakers as assessed with this method are provided. STUDY DESIGN: Prospective study. METHODS: Phase relations between parts of the vocal folds were assessed using Fourier analysis of the grayscale fluctuations of corresponding pixel within the endoscopic high-speed videos. This phase information was displayed by means of colors and can thus be used to quantify left-right or anterior-posterior phase asymmetries. These phase relations were assessed in 11 normophonic speakers. RESULTS: Several instructive examples are given, which demonstrate how the FIs can be interpreted. From the cohort of clinically normophonic speakers, all but one displayed at least some extent of phase asymmetry. CONCLUSIONS: The method presented herein can be used to display functional vocal fold properties including the absence of oscillation, glottal insufficiency, and phase relations within one single image. The reference data showed that phase asymmetries seem to be frequent even in normophonic speakers. PMID- 21708449 TI - Insights into the role of elastin in vocal fold health and disease. AB - Elastic fibers are large, complex, and surprisingly poorly understood extracellular matrix macromolecules. The elastin fiber, generated from a single human gene--elastin, is a self assembling integral protein that endows critical mechanical proprieties to elastic tissues and organs such as the skin, lungs, and arteries. The biology of elastic fibers is complex because they have multiple components, a tightly regulated developmental deposition, a multistep hierarchical assembly, and unique biomechanical functions. Elastin is present in vocal folds, where it plays a pivotal role in the quality of phonation. This review article provides an overview of the genesis of elastin and its wide ranging structure and function. Specific distribution within the vocal fold lamina propria across the lifespan in normal and pathological states and its contribution to vocal fold biomechanics will be examined. Elastin and elastin derived molecules are increasingly investigated for their application in tissue engineering. The properties of various elastin-based materials will be discussed and their current and future applications evaluated. A new level of understanding of the biomechanical properties of vocal fold elastin composites and their molecular basis should lead to new strategies for elastic fiber repair and regeneration in aging and disease. PMID- 21708452 TI - Soft computing techniques toward modeling the water supplies of Cyprus. AB - This research effort aims in the application of soft computing techniques toward water resources management. More specifically, the target is the development of reliable soft computing models capable of estimating the water supply for the case of "Germasogeia" mountainous watersheds in Cyprus. Initially, epsilon Regression Support Vector Machines (epsilon-RSVM) and fuzzy weighted epsilon RSVMR models have been developed that accept five input parameters. At the same time, reliable artificial neural networks have been developed to perform the same job. The 5-fold cross validation approach has been employed in order to eliminate bad local behaviors and to produce a more representative training data set. Thus, the fuzzy weighted Support Vector Regression (SVR) combined with the fuzzy partition has been employed in an effort to enhance the quality of the results. Several rational and reliable models have been produced that can enhance the efficiency of water policy designers. PMID- 21708451 TI - Effects of the epilarynx area on vocal fold dynamics and the primary voice signal. AB - For the analysis of vocal fold dynamics, sub- and supraglottal influences must be taken into account, as recent studies have shown. In this work, we analyze the influence of changes in the epilaryngeal area on vocal fold dynamics. We investigate two excised female larynges in a hemilarynx setup combined with a synthetic vocal tract consisting of hard plastic and simulating the vowel /a/. Eigenmodes, amplitudes, and velocities of the oscillations, the subglottal pressures (P(sub)), and sound pressure levels (SPLs) of the generated signal are investigated as a function of three distinctive epilaryngeal areas (28.4 mm(2), 71.0 mm(2), and 205.9 mm(2)). The results showed that the SPL is independent of the epilarynx cross section and exhibits a nonlinear relation to the insufflated airflow. The P(sub) decreased with an increase in the epilaryngeal area and displayed linear relations to the airflow. The principal eigenfunctions (EEFs) from the vocal fold dynamics exhibited lateral movement for the first EEF and rotational motion for the second EEF. In total, the first two EEFs covered a minimum of 60% of the energy, with an average of more than 50% for the first EEF. Correlations to the epilarynx areas were not found. Maximal values for amplitudes (up to 2.5 mm) and velocities (up to 1.57 mm/ms) changed with varying epilaryngeal area but did not show consistent behavior for both larynges. We conclude that the size of the epilaryngeal area has significant influence on vocal fold dynamics but does not significantly affect the resultant SPL. PMID- 21708453 TI - Specific substance of Maruyama (SSM) suppresses immune responses in atopic dermatitis-like skin lesions in DS-Nh mice by modulating dendritic cell functions. AB - BACKGROUND: Specific substance of Maruyama (SSM) is a carcinostatic immunotherapeutic agent extracted from Mycobacterium tuberculosis. The efficacy of SSM induced interleukin(IL)-12 and IFN-gamma production, and inhibition of IL 4, resulting in a shift from Th2 to Th1 in vivo. OBJECTIVE: The DS-Nh mice are a model of human atopic dermatitis (AD), which spontaneously develop dermatitis under conventional conditions. In this study, to determine whether SSM can prevent the development of skin lesions in a murine model of AD. METHODS: DS-Nh mice were injected with SSM 5 days per week for 11 weeks. Pharmacological, histological and serological studies were performed to investigate the therapeutic effect of SSM for DS-Nh mice. Analysis of cytokines responses to SSM using quantitative RT-PCR and flow cytometry were also performed to evaluate their therapeutic mechanisms in these AD model mice. RESULTS: Clinically, erythema, erosions, excoriation, and edema were observed in DS-Nh mice at 16 weeks of age, which advanced with age. Histologically, the relative number of mast cells increased in DS-Nh mice. SSM treatment alleviated the clinical and histological findings in accord with reduced serum IgE level, and increased IgG2a level. TSLP expression was not induced, but IL-1beta, IL-12, IL-17A, and IFN gamma were induced in SSM-treated DS-Nh mice. Overall, SSM treatments increased the number of activated DCs in lesions. SSM induced CD80, CD86, and MHC class II expression on bone marrow-derived DCs. CONCLUSIONS: SSM enhanced IL-12 production, but suppressed TSLP expression, resulting in a shift from Th2 to Th1 responses. This shift suppressed AD-like skin lesions in a similar fashion as the BCG vaccine. Therefore, SSM may be a useful adjuvant for suppressing skin lesions in AD models. PMID- 21708454 TI - Regulatory T cells in cutaneous immune responses. AB - Regulatory T cells (Treg) are a subset of T cells with strong immunosuppressive activity. In the skin, it has recently been revealed that Treg play important roles not only in the maintenance of skin homeostasis but also in the regulation of the immune responses, such as contact hypersensitivity and atopic dermatitis. Furthermore, the skin plays important roles in the induction of Treg in the periphery. In this review, we will provide an overview of the mechanism of Treg mediated immunosuppression and discuss the role of Treg in the skin. PMID- 21708455 TI - Surface chemistry of lipid raft and amyloid Abeta (1-40) Langmuir monolayer. AB - Lipid rafts being rich in cholesterol and sphingolipids are considered to provide ordered lipid environment in the neuronal membranes, where it is hypothesized that the cleavage of amyloid precursor protein (APP) to Abeta (1-40) and Abeta (1 42) takes place. It is highly likely that the interaction of lipid raft components like cholesterol, sphingomylein or GM1 leads to nucleation of Abeta and results in aggregation or accumulation of amyloid plaques. One has investigated surface pressure-area isotherms of the lipid raft and Abeta (1-40) Langmuir monolayer. The compression-decompression cycles and the stability of the lipid raft Langmuir monolayer are crucial parameters for the investigation of interaction of Abeta (1-40) with the lipid raft Langmuir monolayer. It was revealed that GM1 provides instability to the lipid raft Langmuir monolayer. Adsorption of Abeta (1-40) onto the lipid raft Langmuir monolayer containing neutral (POPC) or negatively charged phospholipid (DPPG) was examined. The adsorption isotherms revealed that the concentration of cholesterol was important for adsorption of Abeta (1-40) onto the lipid raft Langmuir monolayer containing POPC whereas for the lipid raft Langmuir monolayer containing DPPG:cholesterol or GM1 did not play any role. In situ UV-vis absorption spectroscopy supported the interpretation of results for the adsorption isotherms. PMID- 21708456 TI - Engineering antibodies and proteins for molecular in vivo imaging. AB - The rapid and ongoing discovery of new disease related biomarkers leads to a dramatic paradigm change in human healthcare and constitutes the basis for a truly personalized medicine. Molecular imaging enables early detection and classification of human diseases and provides valuable data for optimized, target oriented therapies. By now, the biochemical and physiological properties of antibody derivatives or alternative protein scaffolds can be engineered for the detection of a wide range of target structures. The successful application of these reagents in animals, xenograft models and cells in preclinical research clearly demonstrate their utility for molecular imaging. Despite these promising perspectives, only a few antibodies and recombinant proteins are used yet for molecular imaging in human medicine. Especially the high safety demands and the need to eliminate off target effects in humans require extensive research and development efforts. PMID- 21708457 TI - Optogenetic approaches to restoring visual function in retinitis pigmentosa. AB - Retinitis pigmentosa is a hereditary eye disease that affects photoreceptors and leads to blindness. The discovery of a microbial light-gated channel and the subsequent development of similar 'optogenetic' sensors have opened the door to creating artificial photoreceptors in the remaining retinal circuits of retinitis pigmentosa retinas via gene therapy. Here we review recent studies in animal models of retinitis pigmentosa that have combined knowledge of retinal cell types, circuits and computations with the ability to equip cell types with optogenetic sensors in order to restore visual activity. We also discuss the translational potential of this therapy. PMID- 21708458 TI - Optimization of biogas production from cattle manure by pre-treatment with ultrasound and co-digestion with crude glycerin. AB - Biogas production by co-digestion of cattle manure with crude glycerin obtained from biodiesel production was studied after pre-treatment of the cattle manure or mixtures of cattle manure with different amounts of added glycerin with ultrasound. Batch experiments with 1,750 mL of medium containing 1,760 g of screened cattle manure or mixtures of cattle manure (screened or ground) and 70 140 mL or crude glycerin were incubated under mesophilic and thermophilic condition in stirred tank reactors. Under mesophilic conditions, the addition of 4% glycerin to screened manure increased biogas production by up to 400%. Application of sonication (20 kHz, 0.1 kW, and 4 min) to a mixture of manure+4% glycerin increased production of biogas by up to 800% compared to untreated manure. The best results were obtained under thermophilic conditions using sonicated mixtures of ground cattle manure with 6% added glycerin (348 L methane/kg COD removed were obtained). PMID- 21708459 TI - One-step hydrogenation-esterification of furfural and acetic acid over bifunctional Pd catalysts for bio-oil upgrading. AB - This contribution focuses on one-step hydrogenation-esterification (OHE) of furfural and acetic acid, which are difficult to treat and typically present in crude bio-oil, as a model reaction for bio-oil upgrading. A bifunctional catalyst is needed for OHE reaction. Among tested bifunctional catalysts, the 5%Pd/Al(2)(SiO(3))(3) shows the best catalytic performance. Compared to the physical mixture of 5%Pd/C+Al(2)(SiO(3))(3), there is a synergistic effect between metal sites and acid sites over 5%Pd/Al(2)(SiO(3))(3) for the OHE reaction. A moderate reaction condition would be required to obtain high yields of alcohol and ester along with lower byproduct yields. In this work, the optimum selectivity to desired products (alcohol and ester) of 66.4% is obtained, where the conversion of furfural is 56.9%. Other components, typically present in bio oils, have little effects on the OHE of FAL and HAc. This OHE method is a promising route for efficient upgrading of bio-oil. PMID- 21708460 TI - Stimulation of the biosynthesis of carotenes by oxidative stress in Blakeslea trispora induced by elevated dissolved oxygen levels in the culture medium. AB - The adaptive response of the fungus Blakeslea trispora to the oxidative stress induced by elevated dissolved oxygen concentrations during carotene production was investigated by measuring the specific activities of catalase (CAT) and superoxide dismutase (SOD) and the micromorphology of the fungus using a computerized image analysis system. Changes in the ratio of the volume of air (V(a)) over the medium and the volume of medium (V(m)) in the flask caused changes of the morphology of microorganism from clumps to pellets and increases in the specific activities of CAT and SOD. The oxidative stress in B. trispora resulted in a significant increase in carotene production, and a maximum proportion of beta-carotene (60%), gamma-carotene (50%), and lycopene (10%) (as percentages of total carotenes) was observed at a ratio V(a)/V(m) of 15.7, 4.0 and 1.5, respectively. The highest concentration of carotenes (115.0mg/g dry biomass) was obtained in V(a)/V(m) ratio of 9.0. PMID- 21708461 TI - Comparison of near infra-red spectroscopy, neutral detergent fibre assay and in vitro organic matter digestibility assay for rapid determination of the biochemical methane potential of meadow grasses. AB - This paper investigates near infra-red spectroscopy (NIRS) as an indirect and rapid method to assess the biochemical methane potential (BMP) of meadow grasses. Additionally analytical methods usually associated with forage analysis, namely, the neutral detergent fibre assay (NDF), and the in-vitro organic matter digestibility assay (IVOMD), were also tested on the meadow grass samples and the applicability of the models in predicting the BMP was studied. Based on these, regression models were obtained using the partial least squares (PLS) method. Various data pre-treatments were also applied to improve the models. Compared to the models based on the NDF and IVOMD predictions of BMP, the model based on the NIRS prediction of BMP gave the best results. This model, with data pre-processed by the mean normalisation method, had an R(2) value of 0.69, a root mean square error of prediction (RMSEP) of 37.4 and a residual prediction deviation (RPD) of 1.75. PMID- 21708462 TI - Multi-objective optimization of bioethanol production during cold enzyme starch hydrolysis in very high gravity cassava mash. AB - Cold enzymatic hydrolysis conditions for bioethanol production were optimized using multi-objective optimization. Response surface methodology was used to optimize the effects of alpha-amylase, glucoamylase, liquefaction temperature and liquefaction time on S. cerevisiae biomass, ethanol concentration and starch utilization ratio. The optimum hydrolysis conditions were: 224 IU/g(starch) alpha amylase, 694 IU/g(starch) glucoamylase, 77 degrees C and 104 min for biomass; 264 IU/g(starch) alpha-amylase, 392 IU/g(starch) glucoamylase, 60 degrees C and 85 min for ethanol concentration; 214 IU/g(starch) alpha-amylase, 398 IU/g(starch) glucoamylase, 79 degrees C and 117 min for starch utilization ratio. The hydrolysis conditions were subsequently evaluated by multi-objectives optimization utilizing the weighted coefficient methods. The Pareto solutions for biomass (3.655-4.380*10(8)cells/ml), ethanol concentration (15.96-18.25 wt.%) and starch utilization ratio (92.50-94.64%) were obtained. The optimized conditions were shown to be feasible and reliable through verification tests. This kind of multi-objective optimization is of potential importance in industrial bioethanol production. PMID- 21708463 TI - A mechanistic study of the enhancing effect of Tween 80 on the mycelial growth and exopolysaccharide production by Pleurotus tuber-regium. AB - Several new observations related to the enhancement effect of Tween 80 on the mycelial growth and exopolysaccharide production by the submerged fermentation of Pleurotus tuber-regium were reported in the present study. Firstly, it was found that the addition of Tween 80 on the 5th day could significantly increase the glucose consumption rate at the later stage of the fermentation compared to the control. Secondly, addition of Tween 80 could maintain the intact structure of the mycelial pellets of P. tuber-regium with little signs of disintegration as observed under microscope and kept the pH value of the fermentation broth at an acidic level lower than that of the control. Thirdly, the oleic acid (C18:1) composition in the mycelial cell membrane was significantly increased from 2.6% (in the control) to 18.5% (with addition of Tween 80) coincided with a decrease in the concentration of Tween 80 in the culture medium. These new findings provide some important insight to the elucidation of the detailed mechanism by which Tween 80 is used as a stimulatory agent in the submerged fermentation of mushroom mycelium. PMID- 21708464 TI - Cytotoxic diterpenoid quinonemethides from the roots of Pygmacopremna herbacea. AB - Two new diterpenoid quinonemethides (1 and 2) along with two known compounds (3 and 4) were isolated from the hexane and ethyl acetate extracts of root nodules of Pygmacopremna herbacea. The structures of the new compounds were established by spectroscopic data interpretation. Single crystal X-ray diffraction analysis confirmed the structure of 1. The cytotoxic activities of these compounds were evaluated against A 549, HEPG2, MCF-7, PC-3 and HELA cancer cell lines. Compounds 4, 2 and 1 were shown very good cytotoxic activity. PMID- 21708465 TI - Synthesis of an aryloxy oxo pyrimidinone library that displays ALK-selective inhibition. AB - We report the synthesis of a pyrimidinone library that targets anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase. This library was generated in three steps from a versatile commercially available starting material. Some compounds within this library showed single digit micromolar inhibition of ALK in vitro, while showing minimal inhibition of other homologous insulin receptor family kinases including the human insulin receptor kinase (IRK), at the highest concentrations investigated. We also present initial ALK structure-activity relationships for this library. PMID- 21708466 TI - Transformation of thiols to disulfides by epolactaene and its derivatives. AB - In this paper we report a disulfide formation of thiols induced by epolactaene and its derivatives. We previously reported the disulfide formation of N acetylcysteine methyl ester by epolactaene in a 1:1 MeOH/0.5M NaHCO(3) aq solution. The present studies reveal that the disulfide formation proceeds under mild conditions such as in PBS at pH 7.3, suggesting that epolactaene may induce disulfide formation of cellular thiols. This compound induces the disulfide formation of several thiols in a 1:1 MeOH/0.5M NaHCO(3) aq solution at room temperature. Moreover, our results show that the acyl side-chain of epolactaene greatly influences the products of the reaction. We analyzed the reaction mechanism by using thiolysis products of epolactaene derivatives and propose a new reaction mechanism. PMID- 21708467 TI - Synthesis, biological evaluation and docking studies of octane-carboxamide based renin inhibitors with extended segments toward S3' site of renin. AB - Eighteen octane-carboxamide based renin inhibitors with extended segments for mimicking P3' unit of angiotensinogen have been synthesized. The biological evaluation identified novel renin inhibitors with more potent activity than aliskiren. Molecular docking studies showed that the extended amide-tails matched the P3' position of angiotensinogen and exerted interactions with the S3' site of renin. An unexpected pi-pi stacking interaction was observed during docking study for compound 9r, which could be a reasonable explanation for the outstanding potency of this compound. Further study is in progress to reveal a feasibility for developing novel renin inhibitors based on the possible non-classical interactions between the ligands and the new subsite of renin. PMID- 21708468 TI - Discovery and evaluation of 3-phenyl-1H-5-pyrazolylamine-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3). AB - Preclinical investigations and early clinical trial studies suggest that FLT3 inhibitors offer a viable therapy for acute myeloid leukemia. However, early clinical data for direct FLT3 inhibitors provided only modest results because of the failure to fully inhibit FLT3. We have designed and synthesized a novel class of 3-phenyl-1H-5-pyrazolylamine-derived compounds as FLT3 inhibitors which exhibit potent FLT3 inhibition and high selectivity toward different receptor tyrosine kinases. The structure-activity relationships led to the discovery of two series of FLT3 inhibitors, and some potent compounds within these two series exhibited comparable potency to FLT3 inhibitors sorafenib (3) and ABT-869 (4) in both wt-FLT3 enzyme inhibition and FLT3-ITD inhibition on cell growth (MOLM-13 and MV4;11 cells). In particular, the selected compound 12a exhibited the ability to regress tumors in mouse xenograft models using MOLM-13 and MV4;11 cells. PMID- 21708469 TI - Ultrastructure and composition of cell wall appositions in the roots of Asplenium (Polypodiales). AB - Cell wall appositions (CWAs), formed by the deposition of extra wall material at the contact site with microbial organisms, are an integral part of the response of plants to microbial challenge. Detailed histological studies of CWAs in fern roots do not exist. Using light and electron microscopy we examined the (ultra)structure of CWAs in the outer layers of roots of Asplenium species. All cell walls studded with CWAs were impregnated with yellow-brown pigments. CWAs had different shapes, ranging from warts to elongated branched structures, as observed with scanning and transmission electron microscopy. Ultrastructural study further showed that infecting fungi grow intramurally and that they are immobilized by CWAs when attempting to penetrate intracellularly. Immunolabelling experiments using monoclonal antibodies indicated pectic homogalacturonan, xyloglucan, mannan and cellulose in the CWAs, but tests for lignins and callose were negative. We conclude that these appositions are defense-related structures made of a non-lignified polysaccharide matrix on which phenolic compounds are deposited in order to create a barrier protecting the root against infections. PMID- 21708470 TI - Is re-modification of Ross operation necessary? PMID- 21708471 TI - Wavelet-based intensity analysis of mechanomyographic signals during single legged stance following fatigue. AB - The von Tscharner (2000) "intensity analysis" describes the power of a non stationary signal as a function of both frequency and time. The present study applied a version of this intensity analysis that utilizes Morlet wavelets as a means of gaining insight into the application of this technique as alternative to power spectral analysis for the evaluation of postural control strategy during the single-legged stance and to examine the effects of fatigue. Ten subjects (gender balanced, age: 25+/-3 years; height: 169.4+/-11.7 cm; weight: 79.0+/-16.9 kg) participated in two trials consisting of five 15-s dominant-leg stances. Three-uniaxial accelerometers were fixed to the surface of the dominant leg corresponding to VM, VL, SOL, and MMG was recorded at a sampling rate of 1000 Hz. Signals were later analyzed using a variation of the von Tscharner intensity analysis consisting of a filter bank of 11 Morlet wavelets (range: 2.1-131.1Hz). Two Wingate anaerobic tests (WAnT) separated by a 2-min rest were performed to introduce fatigue. Repeated measures ANOVAs showed significant effects for time, gender, trial, and wavelet (p<0.001) and significant interactions for muscle by wavelet, gender by trial, trial by wavelet, and gender by trial by wavelet (p<0.001). Peak total MMG intensity (mean+/-SD) was higher in males than females and higher following fatiguing exercise preWAnT (squared ms(-2)): 42.6+/-4.5 vs. 19.2+/-2.3; postWAnT (squared ms(-2)): 90.4+/-9.1 vs. 28.4+/-2.8. Peak total MMG intensity was compressed to the lower frequencies surrounding ~12 Hz, corresponding to what might be considered physiologic tremor, and a lower peak at ~42 Hz was most prominent in SOL. The intensity analysis is a useful tool in exploring postural control and in studying the effects of fatigue on the mechanical properties of skeletal muscle. PMID- 21708472 TI - Gravitational force modulates muscle activity during mechanical oscillation of the tibia in humans. AB - Mechanical oscillation (vibration) is an osteogenic stimulus for bone in animal models and may hold promise as an anti-osteoporosis measure in humans with spinal cord injury (SCI). However, the level of reflex induced muscle contractions associated with various loads (g force) during limb segment oscillation is uncertain. The purpose of this study was to determine whether certain gravitational loads (g forces) at a fixed oscillation frequency (30 Hz) increases muscle reflex activity in individuals with and without SCI. Nine healthy subjects and two individuals with SCI sat with their hip and knee joints at 90 degrees and the foot secured on an oscillation platform. Vertical mechanical oscillations were introduced at 0.3, 0.6, 1.2, 3 and 5 g force for 20 s at 30 Hz. Non-SCI subjects received the oscillation with and without a 5% MVC background contraction. Peak soleus and tibialis anterior (TA) EMG were normalized to M-max. Soleus and TA EMG were <2.5% of M-max in both SCI and non-SCI subjects. The greatest EMG occurred at the highest acceleration (5 g). Low magnitude mechanical oscillation, shown to enhance bone anabolism in animal models, did not elicit high levels of reflex muscle activity in individuals with and without SCI. These findings support the g force modulated background muscle activity during fixed frequency vibration. The magnitude of muscle activity was low and likely does not influence the load during fixed frequency oscillation of the tibia. PMID- 21708473 TI - Are ghosts scarier than zombies? PMID- 21708474 TI - The role of cell salvage autotransfusion in abdominal aortic aneurysm surgery. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) repairs, both elective and rupture, are associated with significant blood loss often requiring transfusion. Cell salvage autotransfusion has been developed to reduce the need for allogeneic blood. We review the literature to delineate the role of cell salvage in reducing allogeneic blood use in open AAA repairs. METHODS: A systematic search of the English-language literature was performed using the PubMed, Embase and Cochrane databases up to August 2010. RESULTS: Twenty-three studies were identified. Whilst some data are conflicting, cell salvage appears to reduce overall use and exposure to allogeneic blood, and reduces length of intensive care unit and hospital stay after elective AAA repairs. There may be additional benefit by combining cell salvage with other blood-conservation techniques. Use of cell salvage in ruptured AAA repairs consistently reduced blood-product requirements. CONCLUSIONS: Cell salvage appears to reduce blood-product use in both elective and rupture AAA repairs. Owing to the heterogeneity in methodology of published data, further study may be required before cell salvage becomes standard practice in open AAA repairs. PMID- 21708475 TI - The effect of lumbar posture on abdominal muscle thickness during an isometric leg task in people with and without non-specific low back pain. AB - This study investigated the effect of lumbar posture on function of transversus abdominis (TrA) and obliquus internus (OI) in people with and without non specific low back pain (LBP) during a lower limb task. Rehabilitative ultrasound was used to measure thickness change of TrA and OI during a lower limb task that challenged the stability of the spine. Measures were taken in supine in neutral and flexed lumbar postures in 30 patients and 30 healthy subjects. Data were analysed using a two-way (groups, postures) ANOVA. Our results showed that lumbar posture influenced percent thickness change of the TRA muscle but not for OI. An interaction between group and posture was found for TrA thickness change (F(1,56) = 6.818, p = 0.012). For this muscle, only healthy participants showed greater thickness change with neutral posture compared to flexed (mean difference = 6.2%; 95% CI: 3.1-9.3%; p < 0.001). Comparisons between groups for both muscles were not significant. Neutral lumbar posture can facilitate an increase in thickness of the TrA muscle while performing a leg task, however this effect was not observed for this muscle in patients with LBP. No significant difference in TrA and OI thickness change between people with and without non-specific LBP was found. PMID- 21708476 TI - The impact of a musculoskeletal masters course: developing clinical expertise. AB - A common aim of Masters (MSc) courses in the UK, accredited by the Manipulation Association of Chartered Physiotherapists (MACP), is to promote the clinical expertise of practitioners. Few studies have explored the extent to which this is achieved and understanding is further hampered by the contested nature of expertise. This paper reports on the impact of an MACP approved MSc on practitioners and offers a conceptual model of their development towards clinical expertise. A qualitative theory-seeking case study was used, drawing on the procedures and processes of grounded theory. Twenty-six semi-structured interviews were conducted with eleven alumni from one MACP approved MSc programme. Dimensional analysis and the constant comparative method of data analysis, was used to build the conceptual model. Prior to enrolment, practitioners uncritically accepted knowledge from others and followed habitual routines with their patients. Their diet of informal CPD appeared ineffective in developing these attributes. The impact of the MACP approved MSc involved three developmental aspects of clinical expertise: critical understanding of practice knowledge, patient centred practice and capability to learn in, and from, clinical practice. These inter-related aspects of knowledge, practice and learning offer a conceptual model of the development towards clinical expertise. The most powerful experience to trigger change was direct observation and feedback of their clinical practice by an MACP educator; this highlights the value of clinical mentors facilitating less experienced colleagues. The implementation of such mentorship within departments may offer a cost effective and manageable way to support CPD within the workforce. PMID- 21708477 TI - Self-encoded marker for optical prospective head motion correction in MRI. AB - The tracking and compensation of patient motion during a magnetic resonance imaging (MRI) acquisition is an unsolved problem. For brain MRI, a promising approach recently suggested is to track the patient using an in-bore camera and a checkerboard marker attached to the patient's forehead. However, the possible tracking range of the head pose is limited by the fact that the locally attached marker must be entirely visible inside the camera's narrow field of view (FOV). To overcome this shortcoming, we developed a novel self-encoded marker where each feature on the pattern is augmented with a 2-D barcode. Hence, the marker can be tracked even if it is not completely visible in the camera image. Furthermore, it offers considerable advantages over the checkerboard marker in terms of processing speed, since it makes the correspondence search of feature points and marker-model coordinates, which are required for the pose estimation, redundant. The motion correction with the novel self-encoded marker recovered a rotation of 18 degrees around the principal axis of the cylindrical phantom in-between two scans. After rigid registration of the resulting volumes, we measured a maximal error of 0.39 mm and 0.15 degrees in translation and rotation, respectively. In in vivo experiments, the motion compensated images in scans with large motion during data acquisition indicate a correlation of 0.982 compared to a corresponding motion-free reference. PMID- 21708478 TI - Phase I clinical trial of nasopharyngeal radiotherapy and concurrent celecoxib for patients with locoregionally advanced nasopharyngeal carcinoma. AB - We evaluated the incidence of acute toxicity of concurrent cyclooxygenase-2 inhibitor (celecoxib) plus radiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Thirty-four patients received an accumulated radiation dose of 72-76Gy in 36-38 fractions to the primary lesion and 60Gy in 30 fractions to cervical lymph-node lesions. Palpable residual nodes were boosted to 70Gy at the 90% isodose level with an electron field. Celecoxib was administered at escalating doses of 400, 600, and 800mg/day, starting 3days before the first fraction of radiotherapy and continuing throughout the course of radiotherapy. The majority of toxicities were grade 1, with mucositis and weight loss most frequently observed (28 of 34, 82.4%), followed by dermatitis (27 of 34, 79.4%) and otitis (14 of 34, 41.2%). The toxicities were not related to celecoxib dose (all P>0.05). Stomach pain was considered related to celecoxib, which developed in 2 patients at doses of 400mg and 800mg/day. No grade-3 or -4 toxicities or episodes of toxic death occurred. The tumors in 31 patients (31/34, 91.2%) showed a complete response, and 3 patients (3/34, 8.8%) had partial responses. The actuarial local progression-free survival was 96.6% at 1year, and the 2year overall survival rate was 84.6%. Celecoxib can be safely administered concurrently with nasopharyngeal radiotherapy at doses up to 800mg/day. The tumors responded well to treatment warranting further assessment in a phase II trial. PMID- 21708479 TI - Insulin-like growth factor binding protein-3, in association with IGF-1 receptor, can predict prognosis in squamous cell carcinoma of the head and neck. AB - The aim of this study was to investigate the prognostic role of insulin-like growth factor-1 receptor (IGF-1R) and IGF binding protein-3 (IGFBP-3) in patients with squamous cell carcinoma of the head and neck (SCCHN). The clinical data of 131 SCCHN patients who had undergone surgical resection were retrospectively reviewed, and their intratumoral expression of IGF-1R and IGFBP-3 was evaluated by immunohistochemistry. Thirty-six cases (27.5%) experienced tumor recurrence during the median follow-up period of 53.7months (95% CI, 19.0-90.7months). IGF 1R-positivity and IGFBP-3-positivity were observed in 96 (73.3%) and 70 cases (53.4%), respectively. IGFBP-3-positivity was associated with shorter time to progression (TTP) by univariate (P=0.03) and multivariate analyses (95% CI, 0.23 0.91), whereas IGF-1R itself failed to show its prognostic relevance. However, it was revealed that the prognostic role of IGFBP-3 expression was dependent on IGF 1R expression in the analysis of four subgroups classified according to IGF-1R and IGFBP-3 expression: the IGF-1R-positive/IGFBP-3-positive subgroup was the best prognostic group, while the IGF-1R-negative/IGFBP-3-positive subgroup was the worst in terms of TTP (P=0.017). In conclusion, it is suggested that IGFBP-3 expression, in a state of co-expression with IGF-1R, can predict poor prognosis in SCCHN patients. PMID- 21708480 TI - Yes-associated protein promotes cell proliferation by activating Fos Related Activator-1 in oral squamous cell carcinoma. AB - In our previous study, we established an in vitro cellular carcinogenesis model of oral squamous cell carcinoma (OSCC), including a human immortalized oral epithelial cell (HIOEC) and a cancerous cell line (HB96). Microarray analysis showed that the gene encoding Yes-associated protein (YAP) was significantly increased in HB96 cells compared with HIOEC cells. But the underlying mechanism of YAP on oncogenesis, especially its downstream targets, are still not clear. YAP expression in OSCC cell lines and tissue specimens were investigated by using real-time PCR, western blotting and immunohistochemistry staining. YAP put-back plasmid with four mutation sites after YAP-siRNA interference was constructed by site-directed mutagenesis. Cell growth and colony formation were observed after YAP-siRNA interference or YAP put-back again in CAL27 cells. YAP expression was increased in the cellular carcinogenesis models and the clinical samples from primary OSCC patients. Inhibition of YAP by siRNA interference in CAL27 cells significantly inhibited cell proliferation and colony formation in soft agar, but these abilities were rescued when YAP was put-back again. At the same time, Fos Related Activator-1 (Fra-1) was down-regulated when YAP was inhibited by siRNA interference while Fra-1 was rescued when YAP was put-back again. Immunohistochemistry results also indicated that higher levels of YAP were significantly associated with Fra-1 overexpression in OSCC clinical samples. YAP could promote cell proliferation by activating transcription factor Fra-1 in oral squamous cell carcinoma. PMID- 21708481 TI - What real influence does the proto-oncogene c-myc have in OSCC behavior? AB - The influence of c-myc in the carcinogenic process has been previously described although in the specific case of oral tumors it has been poorly tested. Myc proteins are a family of proto-oncogenes involved in the cell proliferation regulation, differentiation and apoptosis. The goal of this paper is to describe the functions of c-myc and its role as oncogene, assessing its expression by immunohistochemistry and genetic amplification studies, and studying its relationship with tumoral clinical and pathological variables, and describing genetic and molecular interactions in OSCC. PMID- 21708482 TI - Natural course and tumor doubling time of nasopharyngeal carcinoma. A study of 15 patients. AB - Nasopharyngeal carcinoma (NPC) is a non-lymphomatous carcinoma that develops in the epithelial lining of the nasopharynx. The knowledge of natural course of tumor progression has been based on anatomical model without clinical correlation. This study is the first to describe and analyze the natural progression of NPC based on clinical information and calculate the tumor growth rate of NPC. Fifteen NPC patients who refused treatment after initial work-up and then subsequent re-presentation at a later time were recruited during the period from January 2003 to August 2009. Clinical data were analyzed and CT scans were used to calculate the tumor volumes. The time interval between the first planning CT image and the subsequent planning CT image was used to calculate the rate of tumor growth in this group of patients. The tumor volume doubling time can be calculated by using the formula DT=tln2/(lnV2-lnV1), where t is the time interval between measurements and V(2) and V(1) are the tumor volumes at the end and beginning of the time interval, respectively. Cranial nerves palsies such as diplopia and systemic upset were the most common reason for re-presentation and the consent for treatment. The median growth rate was 1.63mm(3) per day and the median tumor doubling time was 279days. This study is the first report in the literature looking at the natural progression of nasopharyngeal carcinoma (NPC) based on clinical information. The current study showed that NPC has a propensity to grow superiorly to involve the skull base rather than laterally or anteriorly. Although the tumor growth rate was very variable, the median natural NPC growth rate was 1.63mm(3)/day. PMID- 21708483 TI - Synthesis, spectroscopic characterization and X-ray structure of [1,2a]benzimidazol-2-yl amidine. AB - [1,2a]Benzimidazol-2-yl amidine was synthesized by adding cyclopentanamine to iminoester in ethanol. The structure of amidine 1 was characterized by IR, 1H NMR, 1H-1H NOESY, 13C NMR, DEPT, XHCOR spectra, thermogravimetric analysis (TGA), differential thermal analysis (DTA), differential scanning calorimetry thermograms (DSC), elementary analysis as well as by X-ray diffraction. The single crystals suitable for X-ray measurement were obtained by recrystallization at room temperature. The amidine group of a model was found to have Z configuration in the crystal. This compound crystallizes in a P2(1)/n monoclinic unit cell with parameters a=12.679(2) A, b=8.468(3) A, c=13.108(2) A, beta=96.538(2) degrees , V=1398.2 A3 and Z=4. PMID- 21708484 TI - Homo dinuclear lanthanide(III) complexes of a mesogenic Schiff-base, N,N'-di-(4 decyloxysalicylidene)-1',6'-diaminohexane: synthesis and characterization. AB - A mesogenic Schiff-base, N,N'-di-(4-decyloxysalicylidene)-1',6'-diaminohexane, H2ddsdh (abbreviated as H2L2) that exhibits smectic-B (SmB) mesophase, was synthesized and its structure studied by elemental analysis, mass spectrometry, NMR & IR spectral techniques. The Schiff-base, H2L2, upon condensation with hydrated lanthanide(III) nitrates, yields LnIII complexes of the general composition [Ln2(L2H2)3(NO3)4](NO3)2, where Ln=La, Pr, Nd, Sm, Eu, Gd, Tb, Dy and Ho. IR and NMR spectral data imply a bi-dentate bonding of the Schiff-base in its zwitterionic form (as L2H2) to the LnIII ions through two phenolate oxygens. The POM and DSC studies reveal that none of the LnIII complexes exhibits mesomorphism. Fluorescence studies show that the TbIII complex displays characteristic metal-centered fluorescence (solution state). PMID- 21708486 TI - The cellular immunobiology associated with fetal and neonatal alloimmune thrombocytopenia. AB - Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is caused by maternal antibodies that cross the placenta in connection with pregnancy and destroy fetal platelets. Recently, maternal T cell responses associated with FNAIT have been studied at the clonal level. These T cell clones recognize an integrin beta3 epitope, which is anchored to the HLA-DRB3*0101-encoded MHC molecule DR52a. The same MHC allele is strongly associated with FNAIT. As the production of pathological antibodies reactive with fetal platelets is likely dependent on these T cell responses, there exists a potential for preventing FNAIT by targeting these T cells. PMID- 21708485 TI - High throughput screening of a library based on kinase inhibitor scaffolds against Mycobacterium tuberculosis H37Rv. AB - Kinase targets are being pursued in a variety of diseases beyond cancer, including immune and metabolic as well as viral, parasitic, fungal and bacterial. In particular, there is a relatively recent interest in kinase and ATP-binding targets in Mycobacterium tuberculosis in order to identify inhibitors and potential drugs for essential proteins that are not targeted by current drug regimens. Herein, we report the high throughput screening results for a targeted library of approximately 26,000 compounds that was designed based on current kinase inhibitor scaffolds and known kinase binding sites. The phenotypic data presented herein may form the basis for selecting scaffolds/compounds for further enzymatic screens against specific kinase or other ATP-binding targets in Mycobacterium tuberculosis based on the apparent activity against the whole bacteria in vitro. PMID- 21708487 TI - History of human papillomavirus, warts and cancer: what do we know today? AB - Human papillomavirus has been a cause of infection in humans for thousands of years. The history of papillomaviruses, knowledge of their causative role in benign and malignant disease, and their structural characteristics have led to the development of vaccines to prevent cervical and anogenital cancers. Many questions remain unanswered before HPV vaccines can be optimised; however, the concept of virtual eradication of cervical cancer is not impossible, and remains a realistic aspiration. PMID- 21708488 TI - Intestinal malrotation presenting as midgut volvulus after massive weight loss following laparoscopic sleeve gastrectomy: case report and review of the literature. PMID- 21708489 TI - Determination of carboplatin in human plasma using HybridSPE-precipitation along with liquid chromatography-tandem mass spectrometry. AB - The main purpose of this study was to develop and validate a rapid, specific, sensitive, and reliable LC-MS/MS-based bioanalytical method for the determination of carboplatin in human plasma. The optimal chromatographic behavior of carboplatin was achieved on a Biobasic SCX column (50 mm * 2.1 mm, 5 MUm) using ion exchange chromatography. The total LC analysis time per injection was 2.6 min with a flow rate of 1.5 mL/min with a gradient elution. Optimization with regard to improving recovery and minimizing matrix effects using HybridSPE-precipitation (HybridSPE-PPT) has been evaluated under various extraction conditions. As a result, sample preparation via HybridSPE-PPT with 1% formic acid in acetonitrile in a 96-well format was applied for method validation and sample analysis and showed acceptable recovery of greater than 25% and negligible matrix effects. The method validation was conducted over the curve range of 2.00-2000 ng/mL using 0.0500 mL of plasma sample. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels showed <=4.8% relative standard deviation (RSD) and -13.2 to -3.6% relative errors (RE). The method was successfully applied to determine carboplatin in human plasma samples. PMID- 21708490 TI - Management of exposed, infected implant-based breast reconstruction and strategies for salvage. AB - INTRODUCTION: Complications of implant-based breast reconstruction are rare but mastectomy flap necrosis and peri-implant infection are the most frequent and remain an important cause of early implant failure. This study aimed to compare the results of three different management strategies employed to deal with these complications at our institution. PATIENTS AND METHODS: A consecutive series of 71 infected/exposed prostheses in 68 patients over a 20-year period were analysed. Management strategies included explantation and delayed reconstruction, implant salvage and explantation and immediate autologous reconstruction. RESULTS: Only 19 of 45 (42%), managed with implant removal, went on to delayed reconstruction. Methods of delayed reconstruction were distributed equally between implant-only, implant and autologous tissue and autologous-only reconstructions. The implant was successfully salvaged in nine cases, but reducing the implant size or introducing new tissue as a flap increased the success from 45% to 53%. Three patients with infected implant-only breast reconstruction underwent explantation and immediate conversion to autologous-only reconstructions. CONCLUSIONS: All the three interventions reviewed here have their place in the management of infected implant-based breast reconstructions. It is noteworthy that following implant removal, the likelihood of the patient proceeding to delayed reconstruction of any kind is similar to the likelihood of successful salvage (42% vs. 45%). This study population had high numbers of exposed implants in irradiated fields. Reducing implant size or introducing new tissue in the form of a flap increases the chances of successful implant salvage. In the presence of mild infection, removal of exposed/infected implants and immediate conversion to an autologous-only reconstruction can prove to be successful. PMID- 21708491 TI - Conduction velocity restitution of the human atrium--an efficient measurement protocol for clinical electrophysiological studies. AB - Conduction velocity (CV) and CV restitution are important substrate parameters for understanding atrial arrhythmias. The aim of this work is to (i) present a simple but feasible method to measure CV restitution in-vivo using standard circular catheters, and (ii) validate its feasibility with data measured during incremental pacing. From five patients undergoing catheter ablation, we analyzed eight datasets from sinus rhythm and incremental pacing sequences. Every wavefront was measured with a circular catheter and the electrograms were analyzed with a cosine-fit method that calculated the local CV. For each pacing cycle length, the mean local CV was determined. Furthermore, changes in global CV were estimated from the time delay between pacing stimulus and wavefront arrival. Comparing local and global CV between pacing at 500 and 300 ms, we found significant changes in seven of eight pacing sequences. On average, local CV decreased by 20 +/- 15% and global CV by 17 +/- 13%. The method allows for in vivo measurements of absolute CV and CV restitution during standard clinical procedures. Such data may provide valuable insights into mechanisms of atrial arrhythmias. This is important both for improving cardiac models and also for clinical applications, such as characterizing arrhythmogenic substrates during sinus rhythm. PMID- 21708492 TI - Mechanical and optical dynamic model of lung. AB - A multiscale, multiphysics model generates synthetic images of alveolar compression under spherical indentation at the visceral pleura of an inflated lung. A mechanical model connects the millimeter scale of an indenter tip to the behavior of alveoli, walls, and membrane at the micrometer scale. A finite difference model of optical coherence tomography (OCT) generates the resulting images. Results show good agreement with the experiments performed using a unique indenter-OCT system. The images depict the physical result with the addition of refractive artifacts and speckle. Compression of the alveoli alters the refractive effects, which introduce systematic errors in the computation of alveolar volume. The complete computational model is useful to evaluate new proposed imaging instrumentation and to develop algorithms for obtaining quantitative data on deformation. Among the potential applications, a better understanding of recruitment of alveoli during inflation of a lung, obtained through a combination of models and imaging could lead to improvements in noninvasive treatment of atelectasis. PMID- 21708493 TI - Novel image processing methods for the analysis of calcium dynamics in glial cells. AB - Calcium (Ca(2+)) waves and Ca(2+) oscillations within cells initiate a wide range of physiological processes including control of cell signaling, gene expression, secretion, and cell migration. A thorough analysis of Ca(2+) waves in glial cells provides information not only about the subcellular location of signaling processing events but also about nonneuronal or intercellular signaling pathways, their timing, routes, spatial domains, and coordination. In this study, three novel image processing methods have been applied to the study of Ca(2+) dynamics in cells. These bring additional information to the methods already available in the literature, providing insight into the analysis of calcium dynamics in fluorescence recordings and defining bidimensional maps that give a complete and detailed description of calcium intracellular behavior. The application of these processing methods to glial cells highlighted the complex 2-D Ca(2+) dynamics phenomena, the location of calcium uptake and release microdomains on the endoplasmic reticulum, and the correlation between different calcium signals inside the cell. A perinuclear zone acting as a filter and regulator of intracellular calcium waves was detected: it acts as a controller of calcium fluxes between the cytoplasm and the nucleus. PMID- 21708494 TI - Spectroscopic detection of gastrointestinal dysplasia using optical microsensors. AB - The detection of dysplasia in the gastrointestinal tract can be performed using optical microsensors based on thin-film optical filters and silicon photodiodes. This paper describes two optical microsensors that can be used for spectroscopy data collection in two different spectral bands (one in the violet/blue region and the other in the green region) for which two optical filters were designed and fabricated. An empirical analysis of gastrointestinal spectroscopic data using these specific spectral bands is performed. The obtained results show that it is possible to accurately differentiate dysplastic lesions from normal tissue, with a sensitivity and specificity of 77.8% and 97.6%, respectively. Therefore, the developed filters can be used as a tool to aid in diagnosis. The small size of the optical microsensors can enable, in the future, integration in endoscopic capsules. PMID- 21708495 TI - Automatic segmentation of intracochlear anatomy in conventional CT. AB - Cochlear implant surgery is a procedure performed to treat profound hearing loss. Clinical results suggest that implanting the electrode in the scala tympani, one of the two principal cavities inside the cochlea, may result in better hearing restoration. Segmentation of intracochlear cavities could thus aid the surgeon to choose the point of entry and angle of approach that maximize the likelihood of successful implant insertion, which may lead to more substantial hearing restoration. However, because the membrane that separates the intracochlear cavities is too thin to be seen in conventional in vivo imaging, traditional segmentation techniques are inadequate. In this paper, we circumvent this problem by creating an active shape model with micro CT (MUCT) scans of the cochlea acquired ex vivo. We then use this model to segment conventional CT scans. The model is fitted to the partial information available in the conventional scans and used to estimate the position of structures not visible in these images. Quantitative evaluation of our method, made possible by the set of MUCTs, results in Dice similarity coefficients averaging 0.75. Mean and maximum surface errors average 0.21 and 0.80 mm. PMID- 21708496 TI - A comprehensive model of human ear for analysis of implantable hearing devices. AB - A finite element (FE) model of the human ear including the ear canal, middle ear, and spiral cochlea was constructed from histological sections of human temporal bone. Multiphysics analysis of the acoustics, structure, and fluid coupling in the ear was conducted in the model. The viscoelastic material behavior was applied to the middle ear soft tissues based on dynamic measurements of tissues in our laboratory. The FE model was first validated using the experimental data obtained in human cadaver ears, and then used to investigate the efficiency of the forward and reverse mechanical driving with middle ear implant, and the passive vibration of basilar membrane (BM) with cochlear implant placed in the cochlear scala tympani. The middle ear transfer function and the cochlear function of the BM vibration were derived from the model. This comprehensive ear model provides a novel computational tool to visualize and compute the implantable hearing devices and surgical procedures. PMID- 21708497 TI - Robust shape regression for supervised vessel segmentation and its application to coronary segmentation in CTA. AB - This paper presents a vessel segmentation method which learns the geometry and appearance of vessels in medical images from annotated data and uses this knowledge to segment vessels in unseen images. Vessels are segmented in a coarse to-fine fashion. First, the vessel boundaries are estimated with multivariate linear regression using image intensities sampled in a region of interest around an initialization curve. Subsequently, the position of the vessel boundary is refined with a robust nonlinear regression technique using intensity profiles sampled across the boundary of the rough segmentation and using information about plausible cross-sectional vessel shapes. The method was evaluated by quantitatively comparing segmentation results to manual annotations of 229 coronary arteries. On average the difference between the automatically obtained segmentations and manual contours was smaller than the inter-observer variability, which is an indicator that the method outperforms manual annotation. The method was also evaluated by using it for centerline refinement on 24 publicly available datasets of the Rotterdam Coronary Artery Evaluation Framework. Centerlines are extracted with an existing method and refined with the proposed method. This combination is currently ranked second out of 10 evaluated interactive centerline extraction methods. An additional qualitative expert evaluation in which 250 automatic segmentations were compared to manual segmentations showed that the automatically obtained contours were rated on average better than manual contours. PMID- 21708498 TI - Tissue-specific compartmental analysis for dynamic contrast-enhanced MR imaging of complex tumors. AB - Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provides a noninvasive method for evaluating tumor vasculature patterns based on contrast accumulation and washout. However, due to limited imaging resolution and tumor tissue heterogeneity, tracer concentrations at many pixels often represent a mixture of more than one distinct compartment. This pixel-wise partial volume effect (PVE) would have profound impact on the accuracy of pharmacokinetics studies using existing compartmental modeling (CM) methods. We, therefore, propose a convex analysis of mixtures (CAM) algorithm to explicitly mitigate PVE by expressing the kinetics in each pixel as a nonnegative combination of underlying compartments and subsequently identifying pure volume pixels at the corners of the clustered pixel time series scatter plot simplex. The algorithm is supported theoretically by a well-grounded mathematical framework and practically by plug-in noise filtering and normalization preprocessing. We demonstrate the principle and feasibility of the CAM-CM approach on realistic synthetic data involving two functional tissue compartments, and compare the accuracy of parameter estimates obtained with and without PVE elimination using CAM or other relevant techniques. Experimental results show that CAM-CM achieves a significant improvement in the accuracy of kinetic parameter estimation. We apply the algorithm to real DCE-MRI breast cancer data and observe improved pharmacokinetic parameter estimation, separating tumor tissue into regions with differential tracer kinetics on a pixel-by-pixel basis and revealing biologically plausible tumor tissue heterogeneity patterns. This method combines the advantages of multivariate clustering, convex geometry analysis, and compartmental modeling approaches. The open-source MATLAB software of CAM-CM is publicly available from the Web. PMID- 21708499 TI - Cerebellar input configuration toward object model abstraction in manipulation tasks. AB - It is widely assumed that the cerebellum is one of the main nervous centers involved in correcting and refining planned movement and accounting for disturbances occurring during movement, for instance, due to the manipulation of objects which affect the kinematics and dynamics of the robot-arm plant model. In this brief, we evaluate a way in which a cerebellar-like structure can store a model in the granular and molecular layers. Furthermore, we study how its microstructure and input representations (context labels and sensorimotor signals) can efficiently support model abstraction toward delivering accurate corrective torque values for increasing precision during different-object manipulation. We also describe how the explicit (object-related input labels) and implicit state input representations (sensorimotor signals) complement each other to better handle different models and allow interpolation between two already stored models. This facilitates accurate corrections during manipulations of new objects taking advantage of already stored models. PMID- 21708500 TI - Identification of extended Hammerstein systems using dynamic self-optimizing neural networks. AB - In this paper, a new dynamic self-optimizing neural network (DSONN) with online adjusting hidden layer and weights is proposed for a class of extended Hammerstein systems with non-Gaussian noises. Input vector to the network is first determined by means of system order estimation using a designated input signal. Then the hidden layer is generated online, which consists of a growing step according to the plant dynamics and a revised pruning step used to refine the hidden structure such that the generated model can be a minimal realization with satisfactory performance. The algorithm is capable of adjusting both the network structure and weights simultaneously by using of weight variations as the conditions of structure optimization. An integrated performance including the identification error and an additional entropy penalty term is employed such that the model can attenuate the non-Gaussian noises as well as match the unknown plant automatically with a suitable structure. Convergence of the weights is guaranteed by suitably choosing the learning rates. The proposed DSONN can be established without a priori knowledge of the unknown nonlinearity. The efficiency of the method is illustrated through the applications to three different Hammerstein systems. PMID- 21708501 TI - Global asymptotic stability for a class of generalized neural networks with interval time-varying delays. AB - This paper is concerned with global asymptotic stability for a class of generalized neural networks (NNs) with interval time-varying delays, which include two classes of fundamental NNs, i.e., static neural networks (SNNs) and local field neural networks (LFNNs), as their special cases. Some novel delay independent and delay-dependent stability criteria are derived. These stability criteria are applicable not only to SNNs but also to LFNNs. It is theoretically proven that these stability criteria are more effective than some existing ones either for SNNs or for LFNNs, which is confirmed by some numerical examples. PMID- 21708502 TI - A Bayesian theoretic approach to multiscale complex-phase-order representations. AB - This paper explores a Bayesian theoretic approach to constructing multiscale complex-phase-order representations. We formulate the construction of complex phase-order representations at different structural scales based on the scale space theory. Linear and nonlinear deterministic approaches are explored, and a Bayesian theoretic approach is introduced for constructing representations in such a way that strong structure localization and noise resilience are achieved. Experiments illustrate its potential for constructing robust multiscale complex phase-order representations with well-localized structures across all scales under high-noise situations. Illustrative examples of applications of the proposed approach is presented in the form of multimodal image registration and feature extraction. PMID- 21708503 TI - CoTrade: Confident Co-Training With Data Editing. AB - Co-training is one of the major semi-supervised learning paradigms that iteratively trains two classifiers on two different views, and uses the predictions of either classifier on the unlabeled examples to augment the training set of the other. During the co-training process, especially in initial rounds when the classifiers have only mediocre accuracy, it is quite possible that one classifier will receive labels on unlabeled examples erroneously predicted by the other classifier. Therefore, the performance of co-training style algorithms is usually unstable. In this paper, the problem of how to reliably communicate labeling information between different views is addressed by a novel co-training algorithm named COTRADE. In each labeling round, COTRADE carries out the label communication process in two steps. First, confidence of either classifier's predictions on unlabeled examples is explicitly estimated based on specific data editing techniques. Secondly, a number of predicted labels with higher confidence of either classifier are passed to the other one, where certain constraints are imposed to avoid introducing undesirable classification noise. Experiments on several real-world datasets across three domains show that COTRADE can effectively exploit unlabeled data to achieve better generalization performance. PMID- 21708504 TI - Fast and Accurate Fingerprint Indexing Based on Ridge Orientation and Frequency. AB - This paper describes a new fingerprint indexing approach based on vector and scalar features, obtained from ridge-line orientations and frequencies. A carefully designed set of features and ad-hoc score measures allow the proposed indexing algorithm to be extremely effective and efficient, as confirmed by the results of extensive experiments. The new method markedly outperforms competing state-of-the-art techniques over six publicly available data sets. Furthermore, it can scale to large databases without losing accuracy: on a standard PC, a search over one million fingerprints takes less than 1 s. PMID- 21708505 TI - Prescribed Performance Output Feedback/Observer-Free Robust Adaptive Control of Uncertain Systems Using Neural Networks. AB - A neural network output feedback/observer-free continuous controller for multiple input-multiple-output uncertain nonlinear systems is designed, which is capable of guaranteeing prescribed performance bounds on the system output, as well as the boundedness of all other closed-loop signals, despite the presence of additive external disturbances and unmodeled dynamics. The assumptions that were made concern the satisfaction of an unboundedness observability property and an output Lagrange stability condition of the unmodeled dynamics subsystem and that the nominal system is output feedback equivalent to a strictly passive one. Simulations on an induction motor system illustrate the approach. PMID- 21708506 TI - Toward synergy-based brain-machine interfaces. AB - This paper demonstrates a synergy-based brain-machine interface that uses low dimensional command signals to control a high dimensional virtual hand. First, temporal postural synergies were extracted from the angular velocities of finger joints of five healthy subjects when they performed hand movements that were similar to activities of daily living. Two synergies inspired from the extracted synergies, namely, two-finger pinch and whole-hand grasp, were used in real-time brain control, where a virtual hand with 10 degrees of freedom was controlled to grasp or pinch virtual objects. These two synergies were controlled by electrocorticographic (ECoG) signals recorded from two electrodes of an electrode array that spanned motor and speech areas of an individual with intractable epilepsy, thus demonstrating closed loop control of a synergy-based brain-machine interface. PMID- 21708507 TI - Psychophysiological measurements in a biocooperative feedback loop for upper extremity rehabilitation. AB - This paper examines the usefulness of psychophysiological measurements in a biocooperative feedback loop that adjusts the difficulty of an upper extremity rehabilitation task. Psychophysiological measurements (heart rate, skin conductance, respiration, and skin temperature) were used both by themselves and in combination with task performance and biomechanics. Data fusion was performed with discriminant analysis, and a special adaptive version was implemented that can gradually adapt to a subject. Both healthy subjects and hemiparetic patients participated in the study. The accuracy of the biocooperative controller was defined as the percentage of times it matched the subjects' preferences. The highest accuracy rate was obtained for task performance (approximately 82% for both healthy subjects and patients), with psychophysiological measurements yielding relatively low accuracy (approximately 60%). The adaptive approach increased accuracy of psychophysiological measurements to 76.4% for healthy subjects and 68.8% for patients. Combining psychophysiology with task performance yielded an accuracy rate of 84.7% for healthy subjects and 89.4% for patients. Results suggest that psychophysiological measurements are not reliable as a primary data source in motor rehabilitation, but can provide supplementary information. However, it is questionable whether the amount of additional information justifies the increased complexity of the system. PMID- 21708508 TI - An experimental paradigm to assess postural stabilization: no more movement and not yet posture. AB - A ground reaction based method is proposed to evaluate the hypothesis that a stabilization phase occurs in transitions towards erect posture, following the macroscopic movement and preceding the quiet final erect posture, whose aim is to control and dissipate the residual inertial unbalancing forces occurring at the transition end. The experimental protocol considers three tasks leading to the final erect posture: taking a step forward (F), sit-to-stand (S), and bending the trunk forward (B), The method mainly consists of the fitting of a negative exponential function on the instability time profile following the end of the transition movement. The model parameters Y(0), T, and Y(inf), respectively, quantify the initial instability rate, a time duration related to the stabilization, and the final asymptotic instability rate. Results from a sample of 40 adult able bodied subjects demonstrated that a postural stabilization phase actually occurs: Y(inf) is smaller (0.010, 0.010, and 0.008 m/s(2) for, respectively, F, S, and B tasks) than Y(0) (0.081, 0.137, and 0.057 m/s(2)). Tis in the order of seconds (0.95, 0.51, and 1.00 s). No trial with large values of both Y(0) and T was observed, evidencing that large initial instability rates are quickly controlled and reduced. The Y(0) and T parameters distribution are discussed according to the possible underlying active and/or passive stabilization mechanisms. The test-retest reliability overall figure (mean ICC 0.45 for 12 indexes) increased, when dropping the indexes related to the less reliable B task, to values (mean ICC 0.56 for eight indexes) comparable to published posturographic data. PMID- 21708509 TI - Systematic variation of prosthetic foot spring affects center-of-mass mechanics and metabolic cost during walking. AB - Lower-limb amputees expend more energy to walk than non-amputees and have an elevated risk of secondary disabilities. Insufficient push-off by the prosthetic foot may be a contributing factor. We aimed to systematically study the effect of prosthetic foot mechanics on gait, to gain insight into fundamental prosthetic design principles. We varied a single parameter in isolation, the energy-storing spring in a prototype prosthetic foot, the controlled energy storage and return (CESR) foot, and observed the effect on gait. Subjects walked on the CESR foot with three different springs. We performed parallel studies on amputees and on non-amputees wearing prosthetic simulators. In both groups, spring characteristics similarly affected ankle and body center-of-mass (COM) mechanics and metabolic cost. Softer springs led to greater energy storage, energy return, and prosthetic limb COM push-off work. But metabolic energy expenditure was lowest with a spring of intermediate stiffness, suggesting biomechanical disadvantages to the softest spring despite its greater push-off. Disadvantages of the softest spring may include excessive heel displacements and COM collision losses. We also observed some differences in joint kinetics between amputees and non-amputees walking on the prototype foot. During prosthetic push-off, amputees exhibited reduced energy transfer from the prosthesis to the COM along with increased hip work, perhaps due to greater energy dissipation at the knee. Nevertheless, the results indicate that spring compliance can contribute to push off, but with biomechanical trade-offs that limit the degree to which greater push-off might improve walking economy. PMID- 21708510 TI - Chemical properties of air pollutants and cause-specific hospital admissions among the elderly in Atlanta, Georgia. AB - BACKGROUND: Health risks differ by fine particle (aerodynamic diameter <= 2.5 MUm) component, although with substantial variability. Traditional methods to assess component-specific risks are limited, suggesting the need for alternative methods. OBJECTIVES: We examined whether the odds of daily hospital admissions differ by pollutant chemical properties. METHODS: We categorized pollutants by chemical properties and examined their impacts on the odds of daily hospital admissions among Medicare recipients > 64 years of age in counties in Atlanta, Georgia, for 1998-2006. We analyzed data in two stages. In the first stage we applied a case-crossover analysis to simultaneously estimate effects of 65 pollutants measured in the Aerosol Research and Inhalation Epidemiology Study on cause-specific hospital admissions, controlling for temperature and ozone. In the second stage, we regressed pollutant-specific slopes from the first stage on pollutant properties. We calculated uncertainty estimates using a bootstrap procedure. We repeated the two-stage analyses using coefficients from first-stage models that included single pollutants plus ozone and meteorological variables only. We based our primary analyses on exposures on day of admission. RESULTS: We found that 24-hr transition metals and alkanes were associated with increased odds [0.26%; 95% confidence interval (CI), 0.02-0.48; and 0.37%; 95% CI, 0.04 0.72, respectively] of hospital admissions for cardiovascular disease (CVD). Transition metals were significantly associated with increased hospital admissions for ischemic heart disease, congestive heart failure, and atrial fibrillation. Increased respiratory-related hospital admissions were significantly associated with alkanes. Aromatics and microcrystalline oxides were significantly associated with decreased CVD- and respiratory-related hospital admissions. CONCLUSIONS: The two-stage approach showed transition metals to be consistently associated with increased odds of CVD-related hospital admissions. PMID- 21708511 TI - Residential traffic-related pollution exposures and exhaled nitric oxide in the children's health study. AB - BACKGROUND: The fractional concentration of nitric oxide in exhaled air (FeNO) potentially detects airway inflammation related to air pollution exposure. Existing studies have not yet provided conclusive evidence on the association of FeNO with traffic-related pollution (TRP). OBJECTIVES: We evaluated the association of FeNO with residential TRP exposure in a large cohort of children. METHODS: We related FeNO measured on 2,143 children (ages 7-11 years) who participated in the Southern California Children's Health Study (CHS) to five classes of metrics of residential TRP: distances to freeways and major roads; length of all and local roads within circular buffers around the home; traffic densities within buffers; annual average line source dispersion modeled nitrogen oxides (NOx) from freeways and nonfreeway roads; and predicted annual average nitrogen oxide, nitrogen dioxide, and NOx from a model based on intracommunity sampling in the CHS. RESULTS: In children with asthma, length of roads was positively associated with FeNO, with stronger associations in smaller buffers [46.7%; 95% confidence interval (CI), 14.3-88.4], 12.4% (95% CI, -8.8 to 38.4), and 4.1% (95% CI, -14.6 to 26.8) higher FeNO for 100-, 300-, and 1,000-m increases in the length of all roads in 50-, 100-, and 200-m buffers, respectively. Other TRP metrics were not significantly associated with FeNO, even though the study design was powered to detect exposures explaining as little as 0.4% of the variation in natural log-transformed FeNO (R2 = 0.004). CONCLUSION: Length of road was the only indicator of residential TRP exposure associated with airway inflammation in children with asthma, as measured by FeNO. PMID- 21708513 TI - [Ovarian yolk sac tumour: general review]. AB - Ovarian yolk sac tumour (OYST) is a very rare malignancy arising most often in young women. Preoperative clinical, biological (alpha-foetoprotein) and radiological findings should help to establish the diagnosis of OYST, in order to propose adequate surgical treatment. The aim of surgery is to remove the primary tumour, to obtain an accurate histological diagnosis and to assess the disease extent. In young women, fertility-sparing surgery should be performed, in order to preserve the possibility of pregnancy later on. Chemotherapy has substantially modified the prognosis of these tumours, and practically all patients will be cured. The overall 5-year survival rate is 94% when patients are treated with BEP chemotherapy. Depending on the clinical situation, two to four cycles of the BEP regimen should be administered after surgery. Identification of prognostic factors may help to propose risk-adapted treatment in order to increase the cure rate in patients with a poor prognosis and to decrease toxicity in patients with a low risk of relapse. Fertility preservation represents a major objective in women treated for OYSTs. PMID- 21708512 TI - A meta-analysis of asbestos and lung cancer: is better quality exposure assessment associated with steeper slopes of the exposure-response relationships? AB - BACKGROUND: Asbestos is a well-recognized cause of lung cancer, but there is considerable between-study heterogeneity in the slope of the exposure-response relationship. OBJECTIVE: We considered the role of quality of the exposure assessment to potentially explain heterogeneity in exposure-response slope estimates. DATA SOURCES: We searched PubMed MEDLINE (1950-2009) for studies with quantitative estimates of cumulative asbestos exposure and lung cancer mortality and identified 19 original epidemiological studies. One was a population-based case-control study, and the others were industry-based cohort studies. DATA EXTRACTION: Cumulative exposure categories and corresponding risks were abstracted. Exposure-response slopes [KL (lung cancer potency factor of asbestos)] were calculated using linear relative risk regression models. DATA SYNTHESIS: We assessed the quality of five exposure assessment aspects of each study and conducted random effects univariate and multivariate meta-regressions. Heterogeneity in exposure-response relationships was greater than expected by chance (I2 = 64%). Stratification by exposure assessment characteristics revealed that studies with well-documented exposure assessment, larger contrast in exposure, greater coverage of the exposure history by exposure measurement data, and more complete job histories had higher meta-KL values than did studies without these characteristics. The latter two covariates were most strongly associated with the KL value. Meta-KL values increased when we incrementally restricted analyses to higher-quality studies. CONCLUSIONS: This meta-analysis indicates that studies with higher-quality asbestos exposure assessment yield higher meta-estimates of the lung cancer risk per unit of exposure. Potency differences for predominantly chrysotile versus amphibole asbestos-exposed cohorts become difficult to ascertain when meta-analyses are restricted to studies with fewer exposure assessment limitations. PMID- 21708514 TI - Epigenetic changes in osteosarcoma. AB - Osteosarcoma is one of the most prevalent primary bone tumors. The pathogenesis and molecular development of this tumor remains elusive. The prognosis is unfavorable due to lack of effective treatment methods. Recent advances in the epigenetics have brought a profound impact on the understanding of molecular mechanisms that lead to osteosarcoma. In this review, we summarized the current literature on epigenetic changes that are thought to contribute to the carcinogenesis of osteosarcoma, and discussed the potential diagnostic and therapeutic applications as well as future areas of research. PMID- 21708515 TI - Fingertip calcinosis cutis in an incomplete limited-type systemic scleroderma. PMID- 21708516 TI - [Photodynamic therapy and urothelial carcinoma]. AB - PURPOSE: Photodynamic therapy (PDT) is an innovative therapeutic modality in urologic oncology. MATERIAL AND METHODS: We reviewed the current literature on principles and modalities of PDT in urothelial and penile oncology. RESULTS: PDT has been tested for the treatment recurrent superficial bladder tumors and in situ carcinoma. Carcinologic efficacy has been observed with first generation photosensitizer. The lack of selectivity for tumoral cells was responsible of serious adverse events. Development of selective photosensitizers has reduced the importance of side effects. Data concerning PDT for upper urinary tract and urethra carcinoma are still limited. CONCLUSION: First PDT clinical applications in urothelial oncology have shown some effectiveness at the cost of significant morbidity. The development of selective photosensitizers should help to reduce side effects. PMID- 21708517 TI - [A new scoring system for the diagnosis of BRCA1/2 associated breast-ovarian cancer predisposition]. AB - Criteria have been proposed for genetic testing of breast and ovarian cancer susceptibility genes BRCA1 and BRCA2. Using simulations, this study evaluates the efficiency (sensitivity, positive predictive value [PPV] and specificity) of the various criteria used in France. The efficiency of the criteria published in 1998, which are largely used, is not optimal. We show that some extensions of these criteria provide an increase in sensitivity with a low decrease in specificity and PPV. The study shows that scoring systems (Manchester, Eisinger) have similar efficiency that may be improved. In this aim, we propose a new scoring system that takes into account unaffected individuals and kinship coefficients between family members. This system increases sensitivity without affecting PPV and specificity. Finally, we propose a two-step procedure with a large screening by the physician for recommending genetic counselling, followed by a more stringent selection by the geneticist for prescribing genetic testing. This procedure would result in an increase of genetic counselling activity but would allow the identification of almost 80% of mutation carriers among affected individuals, with a mutation detection rate of 15% and a specificity of 88%. PMID- 21708518 TI - Disseminated fusariosis in immunocompromised patients. AB - Immunocompromised patients are at high risk of developing serious disseminated infections by opportunistic fungi (Aspergillus, Candida, and Fusarium spp), which frequently present as cutaneous lesions, sometimes as a first sign. Prolonged and deep neutropenia, immunodepressive treatments (systemic steroids and chemotherapy) and severe T-cell immunodeficiency are the most important risk factors. We report 2 patients with acute lymphoblastic leukemia, who developed multiple tender erythematous skin lesions on their legs and arms during chemotherapy treatment. Skin biopsies for histology and culture studies established the diagnosis of Fusarium infection. They received treatment with systemic antifungal and granulocyte colony-stimulting factor. The infection responded after recovering from neutropenia. Early diagnosis and treatment is very important to improve the prognosis, because these infections in immunodepressed hosts have a high mortality rate. PMID- 21708519 TI - Beneficial effects of pseudoceramide-containing physiologic lipid mixture as a vehicle for topical steroids. AB - Among the various adverse effects of topical corticosteroids, impairment of the epidermal permeability barrier is well-known. Decreased synthesis of the epidermal lipid consequently leads to structural defects of the stratum corneum. Recently, the beneficial effects of physiologic lipid mixtures containing pseudoceramide on the impaired epidermal permeability barrier have been reported, which suggest that physiologic lipid mixtures may reduce the topical glucocorticoid-induced barrier impairment. In this study, the effect of a pseudoceramide-containing physiologic lipid mixture as a vehicle for a mid potency topical glucocorticoid was evaluated in an oxazolone-induced atopic dermatitis-like murine model. The changes in transepidermal water loss, hydration and skin fold thickness were measured. Inflammatory cells in the dermis, including eosinophils, were counted and Staphylococcus aureus binding assay was performed. Immunohistochemical staining for inflammatory cytokines and antimicrobial peptides were also performed. The topical steroid in physiologic lipid mixture showed a significantly decreased infiltrate of inflammatory cells (p<0.05) and a reduced number of adherent Staphylococcus aureus compared with the results of the topical steroid in polyethylene glycol/ethanol vehicle (p<0.05). In conclusion, the pseudoceramide-containing physiologic lipid mixture as a vehicle for a topical steroid enhanced the anti-inflammatory effect of the topical steroid and accelerated the skin barrier function restoration. PMID- 21708520 TI - Psychological, physical, and social situation of Polish patients with colorectal cancer undergoing first-line palliative chemotherapy. AB - PURPOSE/OBJECTIVES: To assess the psychological, physical, and social situations and needs of patients with colorectal cancer (CRC) diagnosed at an advanced stage of the disease. DESIGN: Quantitative, descriptive. SETTING: An urban comprehensive cancer center in northeastern Poland. SAMPLE: 50 patients undergoing first-line palliative chemo-therapy. METHODS: Participants were asked to fill out an institution-developed questionnaire assessing personal, emotional, physical, and social data. MAIN RESEARCH VARIABLES: Psychological, physical, and social characteristics. FINDINGS: The most frequently reported side effects of chemotherapy were asthenia, loss of taste, and nausea and vomiting. In addition, about 54% of patients were unable to work during treatment. Chemotherapy administration resulted in severe or moderate impediment of activities of daily living in 74% of the patients and negatively influenced their financial situation. About 25% of the patients were reluctant to share the news of their disease with their coworkers; however, most revealed their diagnosis to friends and family. The majority (62%) of patients expected help from family members. Nurses provided emotional support to a much lesser extent than patients' immediate relatives. The majority of patients (80%) needed to express their feelings by talking, but only about 30% considered a nurse to be the preferred person with whom to discuss their disease. CONCLUSIONS: Patients with CRC diagnosed at an advanced stage require considerably more emotional, informative, and instrumental support from nurses, doctors, family, other patients, and priests than was anticipated by the authors. IMPLICATIONS FOR NURSING: Extending routine history taking via the addition of questions to the proposed questionnaire may help to better recognize a particular patient's situation and unique needs. An increasingly patient-focused approach could improve the individual nursing care in this region of Europe. Ultimately, a multidisciplinary team would be required to meet the needs of patients with CRC undergoing chemotherapy. PMID- 21708521 TI - Being a parent of a child with cancer throughout the end-of-life course. AB - PURPOSE/OBJECTIVES: To elucidate parents' experiences when caring at home for their child with incurable cancer and to show how parents give meaning to their experiences throughout the end-of-life (EOL) phase. RESEARCH APPROACH: Interpretative qualitative study. SETTING: Five academic pediatric oncology centers. PARTICIPANTS: 42 parents of 22 children with incurable cancer, cared for at home. METHODOLOGIC APPROACH: An inductive thematic analysis of single and repeated open interviews using phenomenological techniques. FINDINGS: Four EOL stages were identified: becoming aware of the inevitable death, making the child's life enjoyable, managing the change for the worse, and being with the dying child. The essence of parenting during those stages was captured by the notion of being meaningful to the child and preserving the parent-child relationship. Parents were able to cope better with the EOL phase and to sustain their parenting role because of their ability to postpone grief, enjoy their child's expressions of happiness, see the child's identity despite physical impairment, and enjoy the rewards they experienced from being there for their child. CONCLUSIONS: Parenting while losing a child brings parents to the point of an existential crisis. The child's deterioration forces parents to redefine their traditional parenting role. Although the way parents give meaning to their caregiving experience helps them cope, it can decrease their ability to acknowledge the child's needs. INTERPRETATION: Nurses can help parents to face the reality of their child's situation and redefine their role accordingly, such as by providing information and alternative perceptions that fit the child's changed needs while preserving the parent-child relationship. Attention to signals indicating stress disorders is needed. PMID- 21708522 TI - Working through grief and loss: oncology nurses' perspectives on professional bereavement. AB - PURPOSE/OBJECTIVES: To determine facilitators and barriers to managing patient loss from the combined perspectives of oncology nurses and to extract essential components of a supportive intervention. RESEARCH APPROACH: Qualitative, descriptive. SETTING: The comprehensive National Cancer Institute-designated cancer center of a mid-Atlantic university teaching hospital. PARTICIPANTS: 34 nurses from inpatient and outpatient adult and pediatric oncology units. METHODOLOGIC APPROACH: Focus groups were held with oncology staff nurses to identify challenges regarding work-related bereavement, current support for managing grief and loss, and how to support interpersonal functioning and resiliency. MAIN RESEARCH VARIABLES: Work-related bereavement, bereavement support, and interventions and management strategies for bereavement and loss. FINDINGS: Two primary themes emerged: dimensions of work-related loss and working through bereavement. Participants also provided many concrete suggestions for the creation of a supportive self-care environment. CONCLUSIONS: Support issues were numerous, multilevel, and varied. However, addressing those concerns can improve job satisfaction and decrease compassion fatigue. The findings lay the foundation for appropriate interventions to assist nurses in managing those situations. INTERPRETATION: Administrators, managers, and individuals interested in furthering the multifaceted goals of oncology care, including nurses themselves, are challenged to create and maintain mutually supportive environments for providing optimal care to patients and families. PMID- 21708523 TI - Comparison of body composition assessment methods in breast cancer survivors. AB - PURPOSE/OBJECTIVES: To examine and compare the reliability of four body composition methods commonly used in assessing breast cancer survivors. DESIGN: Cross-sectional. SETTING: A rehabilitation facility at a university-based comprehensive cancer center in the southeastern United States. SAMPLE: 14 breast cancer survivors aged 40-71 years. METHODS: Body fat (BF) percentage was estimated via bioelectric impedance analysis (BIA), air displacement plethysmography (ADP), and skinfold thickness (SKF) using both three- and seven site algorithms, where reliability of the methods was evaluated by conducting two tests for each method (test 1 and test 2), one immediately after the other. An analysis of variance was used to compare the results of BF percentage among the four methods. Intraclass correlation coefficient (ICC) was used to test the reliability of each method. MAIN RESEARCH VARIABLE: BF percentage. FINDINGS: Significant differences in BF percentage were observed between BIA and all other methods (three-site SKF, p<0.001; seven-site SKF, p<0.001; ADP, p=0.002). No significant differences (p>0.05) in BF percentage between three-site SKF, seven site SKF, and ADP were observed. ICCs between test 1 and test 2 for each method were BIA=1, ADP=0.98, three-site SKF=0.99, and seven-site SKF=0.94. CONCLUSIONS: ADP and both SKF methods produce similar estimates of BF percentage in all participants, whereas BIA overestimated BF percentage relative to the other measures. Caution is recommended when using BIA as the body composition method for breast cancer survivors who have completed treatment but are still undergoing adjuvant hormonal therapy. IMPLICATIONS FOR NURSING: Measurements of body composition can be implemented very easily as part of usual care and should serve as an objective outcome measure for interventions designed to promote healthy behaviors among breast cancer survivors. PMID- 21708524 TI - Research information knowledge, perceived adequacy, and understanding in cancer clinical trial participants. AB - PURPOSE/OBJECTIVES: To describe the adequacy of research information among people with cancer at the time they accept or decline participation in a cancer clinical trial. DESIGN: Cross-sectional, descriptive. SETTING: An urban, academic, National Cancer Institute-designated comprehensive cancer center. SAMPLE: 197 patients with advanced gastrointestinal cancer. METHODS: Mailed survey; self reported data. MAIN RESEARCH VARIABLES: Adequacy of research information (actual knowledge, perceived adequacy of information, and perceived understanding), cancer clinical trial participation, and satisfaction with the decision to participate. FINDINGS: Most respondents (88%) perceived themselves as having adequate information to make an informed decision regarding cancer clinical trial participation. In addition, 35% demonstrated adequate knowledge of basic clinical research. CONCLUSIONS: Patients decide to accept or decline cancer clinical trials without having adequate knowledge. IMPLICATIONS FOR NURSING: Nurses have an important role in educating patients regarding cancer clinical trials. The ideal teachable moment may not occur at the time of diagnosis; other less stressful opportunities may present when the patient is more receptive. PMID- 21708525 TI - Knowledge and beliefs about cervical cancer and human papillomavirus among Taiwanese undergraduate women. AB - PURPOSE/OBJECTIVES: To assess knowledge and attitudes regarding cervical cancer and human papillomavirus (HPV) among undergraduate women in Taiwan. DESIGN: A descriptive cross-sectional design. SETTING: Five universities in southern Taiwan. SAMPLE: 953 undergraduate women aged 17-36 years. METHODS: The self administered HPV Belief questionnaire was used to collect data on knowledge and beliefs regarding cervical cancer, Pap testing, and HPV. MAIN RESEARCH VARIABLES: Knowledge, beliefs, cervical cancer, Pap testing, HPV, likelihood of cervical cancer, and HPV infection. FINDINGS: Seventy percent of participants agreed that cervical cancer could be prevented and was a severe disease, and 80% knew the purpose of Pap testing. Forty-nine percent were aware of HPV. Undergraduate women with an awareness of HPV were more likely to be older, studying a health-related major, have a higher class standing, have a personal history of gynecologic visits, and have had a Pap test. Neither family history of gynecologic cancer nor sexual experience predicted HPV awareness, although sexual experience had a significant association with the knowledge and beliefs of cervical cancer. Most of the undergraduate women believed themselves unlikely to acquire cervical cancer or HPV infection. CONCLUSIONS: Undergraduate women in Taiwan have limited knowledge of cervical cancer and HPV. Awareness of the likelihood of HPV infection is low among undergraduate women, even those who are sexually active. IMPLICATIONS FOR NURSING: Educational campaigns focusing on cervical cancer screening and HPV infection are needed, particularly for sexually active undergraduate women. PMID- 21708526 TI - Pain severity, satisfaction with pain management, and patient-related barriers to pain management in patients with cancer in Israel. AB - PURPOSE/OBJECTIVES: To examine pain severity, satisfaction with pain management, and patient-related barriers to pain management among patients with cancer in oncology units at a teaching hospital in Israel. DESIGN: Descriptive, cross sectional, correlational design. SETTING: Oncology, hematology, and bone marrow trans-plantation (BMT) departments; oncology, hematology, and BMT daycare units; and a radiation department in an Israeli hospital. SAMPLE: Nonprobability convenience sample (N=144) of ambulatory (n=76) and hospitalized (n=68) patients experiencing pain in the past 24 hours. METHODS: Patients who had experienced pain in the past 24 hours completed the Revised American Pain Society-Patient Outcome Questionnaire, the Barriers Questionnaire-Short Form, and a demographic data questionnaire. MAIN RESEARCH VARIABLES: Pain severity, satisfaction with pain management, and patient-related barriers to pain management. FINDINGS: A significant inverse relationship was observed between patients' pain severity and their expectation of pain relief. Less-educated patients had significantly higher pain severity scores. Ambulatory patients waited longer for their pain medication than hospitalized patients. The greatest barriers to pain control were fear of addiction and the notion that medication should be saved in case the pain gets worse. In addition, ambulatory patients had higher pain barrier scores than hospitalized patients. CONCLUSIONS: The relationship between pain severity and the expectations of patients with cancer regarding pain relief indicate that patients' expected outcomes and barriers may impede optimal pain relief. This study also identified areas of possible weakness within the hospital's pain palliation program. IMPLICATIONS FOR NURSING: Nurses should assess for patients' expectations and barriers that could impede pain relief and provide appropriate interventions. PMID- 21708527 TI - Subjective sleep quality, objective sleep characteristics, insomnia symptom severity, and daytime sleepiness in women aged 50 and older with nonmetastatic breast cancer. AB - PURPOSE/OBJECTIVES: To examine subjective sleep quality in women aged 50 and older as predicted by cancer status, age, number of comorbidities, and symptoms of depressed mood; and to describe objective sleep characteristics, insomnia symptom severity, and daytime sleepiness. DESIGN: Descriptive. SETTING: Urban university and private oncology clinics in the southern United States. SAMPLE: 32 women with and 35 without nonmetastatic breast cancer, aged 50-90 years (X=64.9, SD=4.67). METHODS: Two telephone interviews, the Pittsburgh Sleep Quality Index, Profile of Mood States, three days of home actigraphy, Insomnia Severity Index, Epworth Sleepiness Scale, and medical records review. MAIN RESEARCH VARIABLES: Subjective quality of sleep; secondary objectives were sleep characteristics, insomnia symptoms, and daytime sleepiness. FINDINGS: Poor subjective sleep quality was predicted by depressed mood (p<0.00005). All mean objective sleep characteristics were similar for the breast cancer and comparison groups. Nocturnal awakenings were excessive (9.2 versus 7.3). Mean sleep onset latency was longer for the breast cancer group than for the comparison group (34.8 versus 15.6 minutes). Mean insomnia severity scores for the breast cancer group indicated subthreshold insomnia symptoms, and no clinically significant insomnia for the comparison group (8.9 versus 6.4). Mean daytime sleepiness scores were normal for both groups (7 versus 6). CONCLUSIONS: Subjective sleep quality was predicted by depressed mood only. Sleep in the breast cancer group was characterized by poor sleep quality, frequent nocturnal awakenings, and insomnia symptoms. IMPLICATIONS FOR NURSING: Screening and monitoring in women aged 50 and older with breast cancer may help promote early sleep intervention; however, additional collaborative research regarding the underlying causes of sleep disruption is needed. PMID- 21708528 TI - Texts, tweets, and patient portals. PMID- 21708530 TI - Hematologic malignancy education for stem cell transplantation nurses. PMID- 21708531 TI - Sexual dysfunction after hematopoietic stem cell transplantation. PMID- 21708533 TI - Feasibility, acceptability, and usability of web-based data collection in parents of children with cancer. AB - PURPOSE/OBJECTIVES: To determine the feasibility of Web-based, multisite data collection using electronic instruments and the feasibility, acceptability, and usability of that data collection method to parents of children with cancer. DESIGN: Prototype development and feasibility study. SETTING: Three Children's Oncology Group centers in the United States. SAMPLE: 20 parents of children with cancer who made a treatment decision within the previous six months. METHODS: Eight instruments were translated from print to electronic format and deployed using a secure Web-based server. Parents completed printed versions of two of the instruments to assess comparability of the two formats. A post-survey interview focused on parents' computer experiences and the acceptability and ease of use of the instruments. MAIN RESEARCH VARIABLES: Time to orient parent to Web site, time to complete instruments, investigators' field notes, and postsurvey questionnaire. FINDINGS: Eighty percent of parents preferred the Web-based data collection and found it at least as easy as completing paper-and-pencil instruments. All parents, regardless of their computer expertise, were comfortable with the electronic data collection system. Statistical analysis demonstrated no evidence of systematic or clinically significant bias. CONCLUSIONS: The Web-based data collection was feasible, reliable, and preferred by most study participants. The authors will use this strategy in future intervention trials of parents making treatment decisions. IMPLICATIONS FOR NURSING: Web-based data entry is feasible and acceptable to parents of children with cancer. Future multicenter collaborative studies should develop and test nursing interventions to support parents making treatment decisions. PMID- 21708532 TI - Measuring the process and quality of informed consent for clinical research: development and testing. AB - PURPOSE/OBJECTIVES: To develop and assess the reliability and validity of an observational instrument, the Process and Quality of Informed Consent (P-QIC). DESIGN: A pilot study of the psychometrics of a tool designed to measure the quality and process of the informed consent encounter in clinical research. The study used professionally filmed, simulated consent encounters designed to vary in process and quality. SETTING: A major urban teaching hospital in the northeastern region of the United States. SAMPLE: 63 students enrolled in health related programs participated in psychometric testing, 16 students participated in test-retest reliability, and 5 investigator-participant dyads were observed for the actual consent encounters. METHODS: For reliability and validity testing, students watched and rated videotaped simulations of four consent encounters intentionally varied in process and content and rated them with the proposed instrument. Test-retest reliability was established by raters watching the videotaped simulations twice. Inter-rater reliability was demonstrated by two simultaneous but independent raters observing an actual consent encounter. MAIN RESEARCH VARIABLES: The essential elements of information and communication for informed consent. FINDINGS: The initial testing of the P-QIC demonstrated reliable and valid psychometric properties in both the simulated standardized consent encounters and actual consent encounters in the hospital setting. CONCLUSIONS: The P-QIC is an easy-to-use observational tool that provides a quick assessment of the areas of strength and areas that need improvement in a consent encounter. It can be used in the initial trainings of new investigators or consent administrators and in ongoing programs of improvement for informed consent. IMPLICATIONS FOR NURSING: The development of a validated observational instrument will allow investigators to assess the consent process more accurately and evaluate strategies designed to improve it. PMID- 21708534 TI - Identifying primary concerns in patients newly diagnosed with lung cancer. AB - PURPOSE/OBJECTIVES: To compare illness concerns before and after surgery in patients newly diagnosed with early-stage lung cancer, and to determine whether perceived healthcare environment factors were associated with reduced concerns and cancer-related worry. DESIGN: Participants completed a semistructured interview using the conceptual content cognitive map (3CM) method. Important concepts were identified in a spatial array representative of a cognitive map of the illness. SETTING: A comprehensive cancer center and a Veterans Affairs medical center in the midwestern United States. SAMPLE: 34 men (n=22) and women (n=12), aged 47-83 years (X=65, SD=10), with newly diagnosed lung cancer were interviewed at the time of diagnosis and again three to four weeks after surgery. METHODS: Content and frequency analysis and descriptive statistics were used to characterize the data. Correlation studies and paired t tests were used to determine relationships among the main study variables. MAIN RESEARCH VARIABLES: Illness perceptions, worry, and health environment experience. FINDINGS: Twelve primary content domains were identified pre- and postoperatively (seven negative and five positive). Cancer-related worry was related to negative content and to fears both before and after surgery. Positive health environment perceptions were related to positive content after surgery. CONCLUSIONS: The findings demonstrate important areas of concern that can be targeted to reduce psychological distress and promote adaptation. IMPLICATIONS FOR NURSING: The willingness of nurses to identify concerns, assist patients to participate in care, and identify strategies to manage unresolved issues early in the treatment trajectory is integral to optimize long-term adjustment. PMID- 21708536 TI - The impact of fatigue on role functioning during radiation therapy. AB - PURPOSE/OBJECTIVES: To identify the impact of fatigue, site-specific side effects, and individual characteristics on role activities during radiation therapy. DESIGN: Secondary data analysis. SETTING: A community radiation therapy department in the northeastern region of the United States. SAMPLE: 77 patients receiving radiation therapy for adjuvant or curative intent. METHODS: Items from the Piper Fatigue Scale and the Brief Fatigue Inventory were grouped into primary (i.e., basic activities of daily living), secondary (i.e., work and school activities), and tertiary (i.e., socialization with family and friends) roles according to the Roy Adaptation Model. Paired t tests and multiple regression were used to analyze performance of roles. MAIN RESEARCH VARIABLES: Primary, secondary, and tertiary roles. FINDINGS: Functioning in all three roles declined during treatment, with greater disruption in secondary roles than primary or tertiary roles. Patients maintained their primary and tertiary roles. Patients had greater difficulty maintaining secondary roles such as work and school activities. Treatment to the lung, pelvis, or head and neck; living alone; and an increase in total side-effect scores were associated with increased disruption in role functioning. CONCLUSIONS: Radiation therapy-related fatigue can affect role functioning at the primary, secondary, and tertiary levels. IMPLICATIONS FOR NURSING: Oncology nurses are in an ideal position to design interventions to help patients maintain activities at greatest risk for disruption. Future research where performance of specific activities is the primary outcome of interest is indicated. PMID- 21708535 TI - Chemotherapy-induced peripheral neuropathy: assessment of oncology nurses' knowledge and practice. AB - PURPOSE/OBJECTIVES: To explore oncology nurses' practice behaviors and knowledge of chemotherapy-induced peripheral neuropathy (CIPN) in the assessment of patients with cancer. DESIGN: Cross-sectional, exploratory. SETTING: Two hospital based outpatient chemotherapy clinics in Baltimore, MD. SAMPLE: Self-selected convenience sample of 39 oncology nurses. METHODS: Completion of the principal investigator-developed questionnaire consisting of 16 knowledge and 16 practice behavior items, 8 instruction and perception items, and a 9-item demographic survey. MAIN RESEARCH VARIABLES: CIPN assessment practice behaviors and knowledge; tool reliability. FINDINGS: The mean CIPN knowledge score of 12.6 (SD=1.7) demonstrated knowledge deficits (maximum score of 16). All respondents indicated CIPN assessment is essential in their oncology role, but 75% rated their CIPN assessment skills as fair to poor. Assessment practices did not routinely include neurologic physical assessment. In addition, 82% believed CIPN is a significant problem for patients. Cronbach alpha for the tool was 0.84. CONCLUSIONS: Results indicated participants had knowledge deficits pertaining to CIPN and lacked training, proficiency, and confidence in neurologic physical assessment. Education and training programs are needed to improve knowledge and neurologic assessment skills. IMPLICATIONS FOR NURSING: To date, CIPN nursing assessment guidelines do not exist. Practice guidelines for CIPN nursing assessment and management should be efficient and appropriate to the role of the chemotherapy infusion oncology nurse working in a busy setting where chair turnover time, accuracy, safety, and quality service are competing priorities. PMID- 21708537 TI - Oncology nurses' attitudes toward prognosis-related communication: a pilot mailed survey of oncology nursing society members. AB - PURPOSE/OBJECTIVES: To assess oncology nurses' attitudes toward prognosis-related communication and experiences of the quality of such communication among physicians. DESIGN: Cross-sectional study. SETTING: Nationwide survey in the United States. SAMPLE: 394 Oncology Nursing Society members who completed surveys. METHODS: Pilot mailed survey. MAIN RESEARCH VARIABLES: Demographic variables, measures of attitudes toward and experiences of prognosis-related communication. FINDINGS: Nurses had mixed views of prognosis-related communication and identified common barriers to their own more effective participation in prognosis-related communication. Nurses with more experience and those who worked in inpatient settings were more likely to be present for physicians' prognosis-related communication with patients. CONCLUSIONS: Respondents identified uncertainties regarding the scope of oncology nurses' role in prognosis-related communication. Respondents also identified opportunities for improved interdisciplinary communication, most importantly the inclusion of oncology nurses in prognosis-related communication. IMPLICATIONS FOR NURSING: Opportunities for oncology nurses to bridge some gaps in prognosis-related communication likely exist, although barriers surrounding nurses' role, education, and communication within the context of the larger healthcare team need to be clarified if potential solutions are to be developed. PMID- 21708538 TI - Nurse and physician perspectives on patients with cancer having online access to their laboratory results. AB - PURPOSE/OBJECTIVES: To compare the perspectives of oncology nurses and physicians regarding online access to laboratory results for patients with cancer pre- and postimplementation, and to evaluate the impact on workload. DESIGN: Pre- and postimplementation surveys distributed to nurses and physicians. In addition, a nursing workload study was conducted to measure the number of phone calls received from patients regarding laboratory results. SETTING: The outpatient department of a comprehensive cancer center in a large, urban setting in the northeastern United States with more than 500,000 patient visits each year. SAMPLE: 460 outpatient nurses and 349 attending physicians were surveyed; 10 of those nurses were invited to participate in the nursing workload study, as well. METHODS: A survey was sent to nurses and physicians one month prior to implementation and then repeated six months postimplementation. A nursing workload study was conducted for 16 weeks beginning one month prior to implementation and completed three months postimplementation. MAIN RESEARCH VARIABLES: Nurse and physician perspectives; nursing workload. FINDINGS: Nurses demonstrated greater support than physicians with regard to patient access, their level of comfort with the patient access, and patients' ability to interpret results. Statistical significance was identified in all three questions (p<0.05). Perspectives on workload did not differ by role; nurses and physicians anticipated an increase in workload prior to implementation, but reported that workload decreased or stayed the same postimplementation (p<0.005). The nursing workload study supported that finding because no change was observed in the average number of phone calls per day during the implementation period. CONCLUSIONS: Oncology nurses and physicians have different perspectives on providing patients with cancer with online access to laboratory results. Concerns about increasing workload were not substantiated in the current study. IMPLICATIONS FOR NURSING: Providing patients with online access to their laboratory results is a growing trend. Understanding the perspectives of oncology nurses can inform future directions for increasing health-record transparency for patients with cancer. Future research may explore the impact on the nurse-patient relationship. PMID- 21708539 TI - Oncology update. PMID- 21708541 TI - Developmental analysis of teosinte glume architecture1: A key locus in the evolution of maize (Poaceae). AB - A key event in the evolution of maize from teosinte was a reduction in the cupulate fruitcase and softening of the glumes, which increased the accessibility of kernels for harvest. The teosinte glume architecture1 (tga1) locus largely controls this difference between maize and teosinte, and thus may have played a pivotal role in maize evolution. The teosinte allele (tga1+teosinte) lengthens inflorescence internodes, shortens rachillae, and makes glumes longer, thicker, and harder. Developmental characterization of morphometric traits reveals that differences among genotypes are apparent early in female inflorescence development. Increased hardening in glumes homozygous for tga1+teosinte is correlated with a thicker abaxial mesoderm of lignified cells. Silica deposition in the abaxial epidermal cells of the glumes is also affected. In the maize background, glumes homozygous for tga1+teosinte deposit silica in both the short and long cells of the glume epidermis, whereas glumes homozygous for the maize allele (Tga1+Maize) concentrate silica only in the short cells. Silica deposition also appears to be affected by genetic background. The effects of tga1 appear largely to explain the differences in glume induration between maize and teosinte. The diverse pleiotropic effects of tga1 suggest that it is regulatory in nature. PMID- 21708542 TI - Roles of the af and tl genes in pea leaf morphogenesis: characterization of the double mutant (afaftltl). AB - The pleiofila phenotype (afaftltl double mutant) of Pisum sativum arises from two single-gene, recessive mutations known to affect the identity of leaf pinnae, afila (af), and acacia (tl). The wild-type leaf consists of proximal leaflets and distal tendrils, whereas the pleiofila leaf consists of branched pinnae terminating in small leaflets. Using morphological measurements, histology, and SEM, we characterized the variation in leaf form along the plant axis, in leaflet anatomy, and in leaf development in embryonic, early postembryonic, and late postembryonic leaves of aftl and wild-type plants. Leaves on aftl plants increase in complexity more rapidly during shoot ontogeny than those on wild-type plants. Leaflets of aftl plants have identical histology to wild-type leaflets although they have smaller and fewer cells. Pinna initiation is acropetal in early postembryonic leaves of aftl plants and in all leaves of wild-type plants, whereas in late postembryonic leaves of aftl plants pinna initiation is bidirectional. Most phenotypic differences between these genotypes can be attributed to differential timing (heterochrony) of major developmental events. PMID- 21708543 TI - Anatomy and ultrastructure of the sporophyte of Takakia ceratophylla (Bryophyta). AB - In this study, morphogenesis and structure of the sporophyte of Takakia ceratophylla are characterized beginning with the late embryo and culminating in the fully dehisced capsule. Information is presented on the development, ultrastructure, and anatomy of the three organographic regions of the sporophyte, namely capsule, seta, and foot. Diagnostic features that identify Takakia as a moss include the gradual elongation of seta, persistence of an apical calyptra, expansion of the capsule after cessation of seta elongation, existence of a columella, monoplastidic meiosis, spore ultrastructure (including a perine layer deposited late in spore wall (development), and the structure of the foot. Commonalities with the capsule of the Andreaeopsida include sporogenous tissue that overarchs a central columella, absence of stomata, and lack of a peristome and operculum. Peculiarities of the genus are seen in the internal structure of the capsule, the disintegration of the columella with spore maturation, and the dehiscence of the capsule along a single, spiralled, longitudinal suture line. Passive spore dispersal through longitudinal splitting of the capsule occurs in andreaeopsid mosses, liverworts, hornworts, and seedless vascular plants. The precise mechanism of dehiscence along a spiralled suture is unparalleled in extant archegoniates but finds counterparts in ancestral land plants such as the pteridophyte Tortilicaulis. PMID- 21708544 TI - Gene flow among small populations of a self-incompatible plant: an interaction between demography and genetics. AB - We assessed the effects of population size and genetic relatedness on rates of pollen gene flow into experimental populations of the insect-pollinated, self incompatible plant Raphanus sativus. We created synthetic populations of sizes 2, 5, 10, and 20 with three genetic structures (full siblings, half siblings, and unrelated plants). Following pollination in a natural setting, we conducted a simple paternity exclusion analysis using the allozyme genotypes of progeny to measure apparent gene flow and Monte Carlo simulations to estimate total gene flow. Estimates of apparent pollen gene flow rates ranged from 0 to 100% and were similar in rank to estimates of total gene flow. There were significant effects of population size and relatedness on the rate of apparent gene flow, and there were significant population size by relatedness interactions. Populations of size 2 had higher gene flow rates than larger populations, gene flow being negatively associated with the level of cross-compatibility (as measured by hand pollinations). Gene flow into populations of size 2 was also negatively associated with the distance to the nearest population of size 10 or 20. These results suggest that interactions among demography (population size), genetics (cross-compatibility), and ecology (pollinator behavior) are important influences on pollen gene flow rates into small plant populations. PMID- 21708545 TI - Allozyme diversity in Pinus virginiana (Pinaceae): intraspecific and interspecific comparisons. AB - Two of the four members of subsection Contortae of the genus Pinus occur in the southeastern United States: Pinus virginiana, which ranges throughout the southern and central Appalachian Mountains, and P. clausa, which is restricted to Florida and southern Alabama. We examined allozyme variation within P. virginiana and genetic relationships between this species and the two varieties of P. clausa (var. clausa and var. immuginata). P. virginiana maintains more genetic diversity at both the species (Hes = 0.139) and population (Hep = 0.128) levels than the other three species in the subsection, which may reflect the combination of its widespread distribution and the absence of cone serotiny. Genetic differentiation among populations in P. virginiana was relatively low (GST = 0.053), but significant contrasts in allozyme frequencies and genetic diversity were apparent between populations to the northwest vs. outheast of the Appalachian Mountains. These regional differences likely resulted initially from historical processes that occurred during the Pleistocene and early Holocene, and have been reinforced by modern selective pressures and barriers to gene flow. The mean genetic distance between populations of P. virginiana and P. clausa (D = 0.071) was greater than that between populations of the two varieties of P. clausa (D = 0.012), which suggests that the two varieties diverged at some point after the separation of the two species. PMID- 21708546 TI - Variation in pollinator abundance and selection on fragrance phenotypes in an epiphytic orchid. AB - Extraordinary floral variation is common among some orchids that employ deception to attract pollinators. This variation may be maintained by frequency-dependent selection where rare phenotypes are preferred. Over a 2-yr period, 1993-1994, we monitored the reproductive success of Tolumnia variegata, an obligately outcrossing epiphytic orchid, at three localities in Puerto Rico that differed in pollinator service. Plants varied in floral morphology and fragrance characteristics. Artificial arrays of varying frequencies of scentless and fragrant phenotypes were established to test for frequency-dependent selection. Where pollinators were rare (Cambalache, range of census average = 0-0.2 bees/h), 0.9-1.2% of the flowers were effectively visited (pollinarium removals and pollinations). At Tortuguero where 0.4-1.1 bees/h were observed, 4-9.2% of the flowers were visited. At Pi;atnones where bees were the most abundant (1.4-5.2 bees/h), 20.9-25.0% of the flowers were visited. A significant portion of the variance in all measures of reproductive success (male, female, and combined) was explained by differences among populations, which we attribute mostly to variation in pollinator abundance. Neither the fragrance phenotype nor its frequency had a significant effect on success as revealed by a split-plot ANOVA. There was a significant interaction between population and phenotypic frequencies in all our measures of reproductive success, but only for the 1994 flowering season. Thus, variation in floral fragrance phenotypes is not likely maintained by frequency-dependent selection. High levels of variation remain unexplained. PMID- 21708547 TI - Cryptic self-incompatibility in tristylous Decodon verticillatus (Lythraceae). AB - There is growing evidence that many self-compatible plants control the level of self-fertilization with postpollination processes that give a siring advantage to cross pollen over self pollen through "cryptic self-incompatibility" (CSI). Previous marker-gene experiments with self-compatible, tristylous Decodon verticillatus (Lythraceae) have demonstrated a siring advantage to cross pollen, though the extent to which this advantage results from prezygotic discrimination vs. early acting inbreeding depression is not clear. Here, we provide evidence that prezygotic mechanisms are involved in this siring advantage by comparing pollen tube numbers at various times following cross- and self-pollination conducted in a natural population. In the 24 h following pollination, cross pollen yielded almost twice as many pollen tubes at various positions in the style compared to self pollen. After 36 and 48 h, the difference between pollen types had disappeared, suggesting that the advantage to cross pollen results from differences in the rate of pollen germination and;clor tube growth rather than pollen tube attrition. Comparison of tube numbers after legitimate vs. illegitimate cross-pollination did not reveal any difference, suggesting that D. verticillatus possesses CSI unrelated to heteromorphic self- and intramorph incompatibility found in other heterostylous members of the Lythraceae. CSI resulting from differential pollen tube growth may minimize geitonogamous selfing when cross pollen is abundant, while maximizing fecundity when cross pollen is scarce due to local clonal spread. PMID- 21708548 TI - Phylogenetic analyses of "higher" Hamamelididae based on plastid sequence data. AB - Phylogenetic relationships were examined within the "higher" Hamamelididae using 21 species representing eight families and related outgroups. Chloroplast DNA sequences encoding the matK gene (/1 kilobase) provided 258 informative nucleotide sites. Phylogenetic analysis of this variation produced one most parsimonious tree supporting three monophyletic groups. In this tree, Nothofagus was basal to a well supported clade of remaining "higher" hamamelids, in which Fagaceae, including Fagus, were sister to a clade of core "higher" hamamelids that share wind-pollination, bicarpellate flowers, granular pollen walls, and reduced pollen apertures. Within the core "higher" hamamelids three subclades were resolved, Myricaceae, (Casuarina-(Ticodendron-(Betulaceae))), and (Rhoiptelea-Juglandaceae). Each subclade was well supported but relationships among them were not. The basal position of Nothofagus within the matK tree is consistent with the fossil record of "higher" hamamelids in which Nothofagus pollen appears earlier than microfossils with affinities to other modern "higher" hamamelids. This placement supports the exclusion of Nothofagus from Fagaceae and suggests two hypotheses for the origin of the cupule. The cupule may be ancestral within "higher" hamamelids and subsequently lost in core members of the clade or there may have been two independent origins. It is suggested that the three clades (1) Nothofagaceae, (2) Fagaceae, and (3) Juglandaceae, Rhoiptelea, Myricaceae, Casuarina, Ticodendron, and Betulaceae be considered at the ordinal level and that traditional orders, such as Fagales sensu Cronquist (Fagaceae, Nothofagaceae, and Betulaceae) be abandoned. Comparative analyses of matK sequences with previously published rbcL sequences demonstrate that for the taxa considered here matK sequences produced trees with greater phylogenetic resolution and a higher consistency index. PMID- 21708549 TI - Seed output and the seed bank in Vallisneria americana (Hydrocharitaceae). AB - Seed banks and sexual reproduction are known to be significant in colonization and re-establishment of some aquatic macrophyte communities. For highly clonal aquatic macrophytes, however, there is a lack of information on seed production and seed fate as compared with annual sexual species. The seed bank for three populations of Vallisneria americana in the Huron-Erie corridor of the Great Lakes was sampled and quantified in the spring of 1994, and related to seed production in the previous season at these sites. Seed deposition rates during 1994 were also assessed. Sites varied in the proportion of plants flowering and in their tertiary sex ratios, but did not differ in seed numbers produced per unit area. The size of the seed bank was not significantly related to the previous season's seed output, and estimates of seed deposition in the following year tended to be approximately tenfold greater than seed densities found in the seed bank. The stages between seed production and subsequent seed germination are generally very dynamic, with dispersal, mortality, and predation as likely regulating factors. The potential for seedling establishment in V. americana needs to be assessed more fully before the role of seeds in population processes can be determined. PMID- 21708550 TI - Evaluation of atpB nucleotide sequences for phylogenetic studies of ferns and other pteridophytes. AB - Inferring basal relationships among vascular plants poses a major challenge to plant systematists. The divergence events that describe these relationships occurred long ago and considerable homoplasy has since accrued for both molecular and morphological characters. A potential solution is to examine phylogenetic analyses from multiple data sets. Here I present a new source of phylogenetic data for ferns and other pteridophytes. I sequenced the chloroplast gene atpB from 23 pteridophyte taxa and used maximum parsimony to infer relationships. A 588-bp region of the gene appeared to contain a statistically significant amount of phylogenetic signal and the resulting trees were largely congruent with similar analyses of nucleotide sequences from rbcL. However, a combined analysis of atpB plus rbcL produced a better resolved tree than did either data set alone. In the shortest trees, leptosporangiate ferns formed a monophyletic group. Also, I detected a well-supported clade of Psilotaceae (Psilotum and Tmesipteris) plus Ophioglossaceae (Ophioglossum and Botrychium). The demonstrated utility of atpB suggests that sequences from this gene should play a role in phylogenetic analyses that incorporate data from chloroplast genes, nuclear genes, morphology, and fossil data. PMID- 21708551 TI - A new microphyllous plant from the Lower Devonian of Yunnan Province, China. AB - Sterile and fertile shoots of a microphyllous vascular plant are described from the Lower Devonian Posongchong Formation (? upper Siegenian), Yunnan Province, southern China and placed in the new taxon Halleophyton zhichangense gen. et sp. nov. The sterile axes are characterized by conspicuous, contiguous swollen rhomboidal to hexagonal leaf bases and relatively broad spatulate laminae. The relief of the leaf bases is not so pronounced in the fertile areas, which bear numerous cauline sporangia with two equal valves. In vegetative characters the new fossils, although smaller and more fragmentary, resemble Drepanophycus gaspianus but in the absence of information on the fertile parts of the latter and because of the controversy surrounding the concept of the genus Drepanophycus, we decided to erect a new genus. Its relationship to the lycophytes sensu stricto is equivocal as exact details of the relationship of sporangium with leaf and sporangium vascularization remain unknown. PMID- 21708552 TI - Morphological variation of henequen (Agave fourcroydes, Agavaceae) germplasm and its wild ancestor (A. angustifolia) under uniform growth conditions: diversity and domestication. AB - Extant variants of henequen (Agave fourcroydes Lem.) and wild populations of its putative ancestor A. angustifolia Haw. were grown in the Mexican state of Yucatan for 10 yr under homogeneous conditions. A statistical and numerical analysis of their patterns of morphological variation was performed as part of broader research to provide evidence of its genetic diversity, evolutionary relationships and changes under human selection. A comparison with results of a similar analysis under natural growing conditions was also made. The study indicated the following. (1) Under natural growth conditions, the three putative wild ecotypes are morphologically distinct, but under uniform conditions only populations growing in Tropical subdeciduous forest may be distinguished from the other two, thus indicating the probable existence of only two ecotypes: one growing in Coastal dunes and Tropical subdeciduous forest, and the other growing in Tropical deciduous forest. (2) This last ecotype is the most similar to cultivated variants. Within its populations, the most similar to the cultivated is that known as Chelem White, gathered by artisans for its textile use. (3) The cordage cultivated Sac Ki and Yaax Ki differ from wild populations in four syndromes of domestication: gigantism, greater fibrosity, less thorniness, and less reproductive capacity. The lower cv of their characteristics compared with those of wild populations suggest less genetic diversity. (4) Kitam Ki is probably a textile-cultivated variant of recent introduction and/or a variant in which the artificial selection process has had different direction and intensity. (5) Improved growth conditions in the botanic garden resulted in a decreased cv, an increase in size and fiber content, and a reduction of thorniness for both wild and cultivated variants. Given that wild populations with desirable characteristics exist and that these characteristics are highly plastic and respond positively to cultivation, then selection and cultivation of populations such as those from Tropical deciduous forest may well have been the path taken by the ancient Maya during henequen domestication. PMID- 21708553 TI - The mode of origin of root buds and root sprouts in the clonal tree Sassafras albidum (Lauraceae). AB - The developmental anatomy of root buds and root sprouts was examined in the clonal tree Sassafras albidum. Root samples from 13 clones that varied widely in age and vigor were sectioned and two types of buds were found, "additional" buds and "reparative" buds. Additional buds form during the early growth of uninjured roots and they perennate by growing outwards in concert with the vascular cambium such that bud traces are produced in the secondary xylem. Reparative buds form de novo in response to senescence, injuries, or other types of disturbance. Reparative buds were found on the roots of seven of the clones, whereas additional buds were found on the roots of all 13 clones. The reparative buds had originated in the proliferated pericycle, where they were subtended by sphaeroblasts, or spherical nodules of wood. Few of the reparative buds were vascularized and none were connected with the vasculature of their parent roots. In contrast, most of the additional buds were vascularized, and the leaf traces of several of the additional buds appeared to be contiguous with the conducting xylem of their parent roots. To determine whether both bud types were functional, 82 field-collected root sprouts and 44 incubation-induced sprouts were sectioned at the root-sprout junction and examined for evidence relating to their mode of origin. None of the sprouts were subtended by sphaeroblasts, but 98% were subtended by bud traces, which indicated that they had originated from additional buds. Although reparative buds were more common than additional buds on some of the root samples, they appear to be dysfunctional at sprouting. Additional buds, on the other hand, are able to sprout both as a normal part of clonal spread and from root cuttings. PMID- 21708554 TI - Analysis of form and function in North American columnar cacti (tribe Pachycereeae). AB - Simple and multivariate linear models were used to demonstrate the influence of mechanical design and climate on stem morphology and branching architecture in 25 species of North American columnar cacti. The effect of phyletic inertia was tested by the method of independent contrasts. Stem girth was found to increase significantly slower with increased height within taxa (cross-sectional stem area ;ps [plant height] 0.603), than across taxon (cross-sectional stem area ;ps [plant height] 1.451). Juveniles are shown to be mechanically overbuilt and subsequently grow into more slender adult forms determined in part by structural limitations and the optimization of other stem functions. We make a structural analogy of relatively rigid columnar cacti to concrete columns and compare plants and models with similar growth forms lacking woody skeletons (barrel cacti). Taxa with woody support achieved a surface-to-volume ratio six times greater than taxa without woody support. Across taxon, cooler winter temperatures were associated with larger stem girths, and greater annual precipitation was associated with less frequent branching. The relationship between total plant surface and volume approaches isometry within taxa, but across taxon average individuals are scaled replicates. We hypothesize that architecture and average plant height are adjusted, in an evolutionary sense, to maintain geometric similitude between surface and volume along a climatic gradient. PMID- 21708555 TI - Class II tassel seed mutations provide evidence for multiple types of inflorescence meristems in maize (Poaceae). AB - The tassel seed mutations ts4 and Ts6 of maize cause irregular branching in its inflorescences, tassels, and ears, in addition to feminization of the tassel due to the failure to abort pistils. A comparison of the development of mutant and wild-type tassels and ears using scanning electron microscopy reveals that at least four reproductive meristem types can be identified in maize: the inflorescence meristem, the spikelet pair meristem, the spikelet meristem, and the floret meristem. ts4 and Ts6 mutations affect the fate of specific reproductive meristems in both tassels and ears. ts4 mutants fail to form spikelet meristems from spikelet pair meristems. Ts6 mutants are delayed in the conversion of certain spikelet meristems into floret meristems. Once floret meristems are established in both of these mutants, they form florets that appear normal but fail to undergo pistil abortion in the tassel. The abnormal branching associated with each mutant is suppressed at the base of ears, permitting the formation of normal, fertile spikelets. The classification of the different types of reproductive meristems will be useful in interpretation of gene expression patterns in maize. It also provides a framework for understanding meristem functions that can be varied to diversify inflorescence architectures in the Gramineae. PMID- 21708556 TI - Allozyme frequencies in New Jersey and North Carolina populations of Atlantic white-cedar, Chamaecyparis thyoides (Cupressaceae). AB - The present study was conducted to assess the distribution of genetic variation within and among populations of Chamaecyparis thyoides in both marginal and centrally located populations. Allozyme frequency analyses of ten loci from foliage of four New Jersey populations and two North Carolina populations of C. thyoides showed polymorphic loci = 50%, mean number of alleles per locus = 2.8, effective number of alleles per locus = 1.17, and expected heterozygosity = 0.14. Diversity was highest in two populations from southern New Jersey. The isolated population at High Point, New Jersey had only two polymorphic loci and expected heterozygosity of 0.03. There was no correlation between genetic and geographic distances among populations, implying that cedar must have possessed some means of long-distance dispersal at the end of the last glacial period, rather than advancing northward step by step. PMID- 21708557 TI - Patterns of genotypic variation and phenotypic plasticity of light response in two tropical Piper (Piperaceae) species. AB - Patterns of phenotypic plasticity and genotypic variation in light response of growth and photosynthesis were examined in two species of rain forest shrub that differ in ecological distribution within the forest. We further examined correlations among photosynthetic and growth traits. We hypothesized that the pioneer species, Piper sancti-felicis, would display greater phenotypic plasticity than the shade-tolerant species, Piper arieianum. We further proposed that, in both species, genotypic effects would be more apparent in growth-related traits than photosynthetic traits due to more concentrated selection pressure on gas-exchange traits. P. sancti-felicis did not demonstrate greater phenotypic plasticity of light response. Although many of the traits measured had significant genotype effects, neither species showed any significant effects of genotype on light response of photosynthesis, suggesting little genetic variation for this trait within populations. A principal components analysis clearly illustrated both species and light effects, with the treatments dividing neatly along the axis of the first principal component and the species separating along the second principal component axis. Results indicated general similarities between the species in their trait correlation structure and level of integration among traits, but characteristic differences were observed in the patterns of change between low and high light. Both species had more correlations than expected within groups of growth-related or photosynthetic traits; strong correlations of traits between these two groups were underrepresented. The similar pattern of genetic variation and phenotypic integration observed in these two congeners may be due more to their close phylogenetic relation than to their ecological distributions. PMID- 21708558 TI - Population structure, genetic diversity, and clone formation in Quercus chrysolepis (Fagaceae). AB - Stands of canyon live oak (Quercus chrysolepis, Fagaceae) are maintained for fuelwood, fire management, recreation, and as habitat for wildlife. Information about the link between the oak's reproductive ecology and its extent of genetic diversity is important in developing land management policies that will maintain the long-term viability of populations. Basal sprouting is the primary means of reproduction following fire or cutting, and stands frequently include groups of visibly connected trees in a clustered distribution that suggests cloning. We determined the extent to which clusters of trees were clonal and defined the spatial pattern and diversity of genotypes for six populations across nearly the entire east-west extent of the San Bernardino Mountains in southern California. We mapped over 100 trees at each of five sites and genotyped each tree for allozymes at seven polymorphic loci. We identified clones using these multilocus genotypes and detected an average of 34.4 +/- 7.3 (SD) clones per site, most of which had unique genotypes. In general, clustered trees belong to single clones and most clones consist of few trees (mean = 3.4 +/- 0.6 trees per clone). However, clone size increased significantly with increased individual heterozygosity, suggesting that selection may favor highly heterozygous clones. Clonal diversity and evenness were high relative to reports for most other clonal species; an average of 97% of clones had distinct genotypes, and Simpson's index of diversity averaged 0.95 +/- 0.02. Population genetic analyses of 319 clones from six sites revealed high genetic diversity within sites (mean HS = 0.443). Only a small proportion of the total genetic diversity was explained by variation among sites (mean GST = 0.018), which is consistent with high gene flow among sites (Nm = 9.5). We found no significant substructure among plots within sites, and fixation indices within sites were generally small, suggesting that either little inbreeding occurs, and/or few inbred progeny survive. However, spatial autocorrelation analysis of clones indicated fine-scale genetic structure at distances under 4 m, possibly due to limited seed dispersal. Our data suggest that guidelines for seed collection of canyon live oak for use in restoration can be specified in a manner similar to that recommended for conifer species within the region studied. PMID- 21708559 TI - Impact of the flower smut Ustilago cynodontis (Ustilaginaceae) on the performance of the clonal grass Cynodon dactylon (Gramineae). AB - Effects of the flower-infecting smut fungus Ustilago cynodontis on the growth, survival, and competitiveness of the clonal rhizomatous perennial grass Cynodon dactylon were explored through a series of glasshouse experiments. Ustilago cynodontis sterilized C. dactylon by replacing floral structures with a teliospore-producing fungal stroma. Infection caused a reduction in overall dry matter production and the growth rate of stolons, changed the allocation of resources between roots and shoots, and affected the survival of C. dactylon plants growing in pots under crowded conditions in a naturally lit glasshouse. In mixtures of healthy and infected plants, the growth of infected ones was disproportionally affected. Infection had no effect on the germination or emergence of seedlings. Transmission of the pathogen along stolons was incomplete, especially as the length of the stolon increased. The nutrient status of the soil had no significant effect on stolon growth. Results are discussed in terms of the differential effect of systemic floral smut diseases on tiller forming and clonal rhizomatous perennial grasses. PMID- 21708560 TI - Stomatal density responses of temperate woodland plants over the past seven decades of CO2 increase: a comparison of Salisbury (1927) with contemporary data. AB - We investigated the possible effect of recent (1927-1995) increases in the concentration of atmospheric CO2 on the stomatal densities of leaves of a wide range of tree, shrub, and herb species (N = 60) by making new measurements for comparison with corresponding data reported by E. J. Salisbury in 1927--a time when ice core studies indicate CO2 concentrations ~55 mL/L lower than present. A detailed intraspecific study of the herb Mercurialis perennis showed plants of M. perennis in a Cambridgeshire woodland in 1994 had significantly lower stomatal densities, irrespective of leaf insertion point, compared with their 1927 counterparts. Comparisons made across species using evolutionary comparative methods (independent contrasts) revealed a significant (P 2 increases have influenced leaf morphology in a manner consistent with recent experiments and the palaeoecological record. Further analyses suggested that the strength of the stomatal density response was independent of life form but dependent on "exposure" and the initial leaf stomatal density. Consequently, firmer predictions for future changes in stomatal density across all species, expected as a possible result of anthropogenically related CO2 increases, may now be possible. PMID- 21708561 TI - Pedilanthus diazlunanus (Euphorbiaceae): pollination by hymenopterans in a bird pollinated genus. AB - Pollination in the genus Pedilanthus is commonly effected by hummingbirds. Pollination by vespid wasps in Pedilanthus is documented for the first time based on observations of Pachodynerus nasidens and Eumenes americanus pollinating Pedilanthus diazlunanus. An hypothesis concerning the mechanism by which hummingbird pollination was replaced by insect pollination in Pedilanthus is advanced based on observations of insects on P. bracteatus. PMID- 21708562 TI - Male sterility, protogyny, and pollen-pistil interference in Plantago maritima (Plantaginaceae), a wind-pollinated, self-incompatible perennial. AB - Evolution and maintenance of male sterility in seed plants can be explained by the maternal inheritance of mitochondria, which encode the trait, and by adaptive functions that enhance female fecundity in male-sterile compared to hermaphrodite individuals. Protogyny and male sterility can independently decrease the negative effect of pollen-pistil interference in self-incompatible species. In Plantago maritima, which possesses both traits, protogyny increases seed set in hermaphrodite individuals. This is shown both by a significantly positive association between seed set and retarded dehiscence of the anthers and by a more than 50% reduction in seed set following self-pollination. Male sterility does not seem to increase seed set further, as female and hermaphrodite plants do not differ significantly in mean seed set per capsule. Bagging experiments demonstrate strong self-incompatibility in the study populations. Hence, in P. maritima male sterility seems neither to prevent selfing nor to reduce the effect of pollen-pistil interference. Females had significantly larger stigmas than hermaphrodites, but seed set varied negatively with stigma length among females, indicating that the evolution of unisexuality in P. maritima is not due to prefertilization sex allocation. I therefore conclude that the genetical system of nucleocytoplasmic determination of gender is the main cause for maintenance of male sterility in P. maritima. PMID- 21708563 TI - Molecular evidence for a Mediterranean origin of the Macaronesian endemic genus Argyranthemum (Asteraceae). AB - The internal transcribed spacers (ITS) of nuclear ribosomal DNA were sequenced for 52 species from 32 genera and eight subtribes of Anthemideae. Phylogenetic analyses of ITS data generated trees that are largely incongruent with the recent classification of Anthemideae; most of the subtribes examined are not resolved as monophyletic. However, ITS trees are congruent with morphological, isozyme, phytochemical, and chloroplast DNA (cpDNA) restriction site data in supporting a Mediterranean origin for Argyranthemum, the largest endemic genus of the Atlantic oceanic islands. A combined analysis of ITS sequences and cpDNA restriction sites indicates that Argyranthemum is sister to the other three genera of Chrysantheminae (i.e., Chrysanthemum, Heteranthemis, and Ismelia). Times of divergence of Argyranthemum inferred from the ITS sequences ranged between 0.26 and 2.1 million years ago (mya) and are lower than values previously reported from isozyme and cpDNA data (1.5-3.0 mya). It is likely that rate heterogeneity of the ITS sequences in the Anthemideae accounts for the low divergence-time estimates. Comparison of data for 20 species in Argyranthemum and Chrysantheminae indicates that the cpDNA restriction site approach provided much more phylogenetic information than ITS sequences. Thus, restriction site analyses of the entire chloroplast genome remain a valuable approach for studying recently derived island plants. PMID- 21708564 TI - Carbon exchange between Polysiphonia lanosa (Rhodophyceae) and its brown algal host. AB - Polysiphonia lanosa and its preferred Ascophyllum nodosum host exchange 14C labeled photoassimilates. Exchange was demonstrated by injecting 14C-bicarbonate into air bladders on 15-30 cm cultured sections of field-collected host blades. Each section bore rhizoidally attached Polysiphonia. In a separate set of experiments, Polysiphonia on similar host material was surface treated with 14C bicarbonate in sealed vessels. Movement of radioactive label was detected by autoradiographic and liquid scintillation techniques. On average, 10.5% of total label moved from host to hemiparasite following the first treatment, and 9.7% moved from hemiparasite to host following the second. Reciprocal exchange of tagged photoassimilates may play an important role in the specificity of the relationship between these two algal species. PMID- 21708565 TI - Parental effects on seed mass: seed coat but not embryo/endosperm effects. AB - Many biologists studying environmentally induced parental effects have indirectly suggested that the parental environment alters seed mass by altering the amount of endosperm or embryo tissue in the seed. We tested this hypothesis by measuring the effects of parental temperature on total seed mass, seed coat mass, and embryo/endosperm mass in offspring of Plantago lanceolata. Parental temperature significantly affected total seed and coat mass but not endosperm/embryo mass. Thus, larger seeds do not contain more resources in the embryo or endosperm than do small seeds. Rather they have more coat mass, which probably strongly influences germination. These results suggest caution when making assumptions about the pathways by which environmentally induced parental effects are transmitted in plant species. We also observed that controlled crosses differed significantly in their response to parental temperature, which provides evidence for genetic variation in environmentally induced parental effects, i.e., intergenerational phenotypic plasticity, in natural populations of P. lanceolata. PMID- 21708566 TI - G. Ledyard Stebbins, Jr. and the evolutionary synthesis (1924-1950). AB - This is an historical paper examining the scientific background of George Ledyard Stebbins, Jr. (b. 1906), one of the foremost botanists of this century and one of the architects of the evolutionary synthesis, the intellectual event that brought together genetics and selection theory in the interval between 1920 and 1950. It considers his scientific influence and research, beginning with his Harvard education in 1924 and ending in 1950 with the publication of his book Variation and Evolution in Plants. The paper also more broadly assesses the contributions of other botanists to the evolutionary synthesis, including discussion of the work of Edgar Anderson (1897-1967) and others. It also traces the larger historical patterns of American botany, which saw a shift from East Coast botany as exemplified by Harvard botany, to West Coast botany, as exemplified by California botany. PMID- 21708567 TI - Anatomy and distribution of foliar idioblasts in Scrophularia and Verbascum (Scrophulariaceae). AB - Internal secretory structures have rarely been reported from Scrophulariaceae, and foliar idioblasts only once before, in 1887. Presented here are the first unambiguous descriptions of subepidermal foliar idioblasts in the family, from Scrophularia and Verbascum, genera regarded as closely allied on other grounds. Leaf samples from 183 mostly herbarium specimens (128 species, with 55 replicates) were cleared and stained, which revealed idioblasts in 62 (69.7%) of 89 Scrophularia species and 13 (33.3%) of 39 Verbascum species. We then chose 14 representative species to examine by resin sectioning and scanning electron microscopy. Idioblasts occurred both adaxially and abaxially. Most were conspicuous, in some species penetrating to vasculature level. Idioblasts had a thin primary wall and were empty at maturity. Verbascum and Scrophularia species with and without idioblasts were scattered among the subgeneric taxa without taxonomic clustering; likewise, both types occurred in approximately proportionate numbers throughout the geographic range, except that 14 of 15 North American Scrophularia species had idioblasts. Petals of two species had abundant idioblasts. The 1887 report illustrated a huge idioblast in S. deserti and we also found the largest in either genus in this species. We also noted trichome and stomata types and report that paraveinal mesophyll and foliar endodermis with casparian strip were both absent. PMID- 21708568 TI - Analysis of developmental preformation in the alpine herb Caltha leptosepala (Ranunculaceae). AB - Developmental preformation is ubiquitous among alpine and arctic tundra plant species and may cause a delay in plant morphological responses to environmental variation. The duration of preformation and seasonal pattern of development were examined in Caltha leptosepala to identify characteristics of architecture and development that may influence the timing of plant responses to environmental cues, both within a single growing season and between years. All structures in C. leptosepala are preformed: leaves are initiated one or two growing seasons before they mature and flowers are initiated one growing season before maturation. Features of development and architecture in C. leptosepala, however, appear to differ from the determinate growth patterns of other exclusively preforming species, and may allow within-season variability in the seasonal development and maturation of structures. Cohorts of leaves initiated are asynchronous with maturation cohorts, and each year the number of leaf primordia per plant at snowmelt exceeds the number to mature aboveground. Therefore, some flexibility in whether leaves complete a 2-yr or 3-yr developmental trajectory might occur. Plasticity in reproductive phenotype might also occur via the process of floral abortion. Despite developmental characteristics that might facilitate the expression of phenotypic plasticity, only slight variability was observed in the duration of preformation or in the seasonal pattern of initiation and emergence of structures. Growth patterns of C. leptosepala thus appear to be fundamentally constrained, and limitations to annual growth may assure that sufficient preformed primordia remain belowground at the end of each growing season for maturation of a full cohort during the subsequent season. PMID- 21708569 TI - Conservation of microsatellites among tropical trees (Leguminosae). AB - Although microsatellites or simple sequence repeats (SSRs) have become a popular tool in genetic mapping and gene flow studies, their utility is limited due to paucity of information about DNA sequences in plants. We tested the utility of microsatellite markers characterized for the tropical tree Pithecellobium elegans as a genetic tool for related species. The results indicate that SSR loci are conserved among closely related species, and SSR primers developed for P. elegans could be successfully used as a genetic tool in several species of the tribe Ingeae. This study indicates that there is high potential for the transfer of SSR markers among closely related taxa, circumventing laborious cloning and screening procedures involved in characterizing SSR loci for many species. PMID- 21708570 TI - Genetic diversity and breeding system in a group of neotropical epiphytic ferns (Pleopeltis; Polypodiaceae). AB - Epiphytes are ecologically important components of tropical forests worldwide and yet they have been underrepresented in studies of reproductive biology. Given the presumed ephemeral nature of their substrates, and the importance of dispersal and colonization, epiphytes might be expected to undergo substantial inbreeding to ensure reproductive success, as in weedy terrestrial plants. While there is some evidence for inbreeding in epiphytic angiosperms, the only previous studies of fern epiphytes indicate that they are predominantly outcrossing. The present study reports on the genetic diversity and breeding system of six members of the Neotropical epiphytic fern genus Pleopeltis (Polypodiaceae). A survey of isozyme variability using starch gel electrophoresis revealed high population levels of polymorphism (P = 0.62), allelic diversity (A = 2.3), and individual heterozygosity (Ho = 0.181), but little differentiation among conspecific populations (I 3 0.98; Gst = 0.048), and high interpopulational gene flow rates (Nm > 1). In addition, there was no indication of homozygote excess within populations that might indicate a history of selfing in these ferns: populations generally conformed to Hardy-Weinberg expected genotype frequencies, and both Wright's inbreeding coefficient (Fis) and Holsinger's intragametophytic selfing rates approached zero. Possible mechanisms limiting inbreeding in these ferns include antheridiogen activity and high levels of genetic load that would lead to inbreeding depression upon selfing. PMID- 21708571 TI - The spatial genetic structure of cytoplasmic (cpDNA) and nuclear (allozyme) markers within and among populations of the gynodioecious Thymus vulgaris (Labiatae) in southern France. AB - Recent advances in molecular biology have allowed the development of techniques to contrast spatial differentiation in nuclear and cytoplasmic genes and thus provide important data on relative levels of gene flow by pollen and seed in higher plants. In this paper, we compare the spatial structure of nuclear (allozymes) and cytoplasmic (cpDNA) genes among populations of the gynodioecious Thymus vulgaris in southern France. Based on a combination of three restriction enzymes (CfoI, EcoRV, and PstI), eight chlorotypes (combination of three restriction enzyme patterns revealed by Southern hybridization of Beta vulgaris cpDNA) were identified in the 13 studied populations. One chlorotype was particularly abundant and was detected in nearly all populations. Only one chlorotype was specific to a single population. Up to four different chlorotypes were observed in some populations. An FST of 0.238 (P < 0.002) for cpDNA haplotypes indicates spatial structure of cytoplasmic genes among the studied populations. Similar patterns were found within a single young population (CAB) structured in patches and surrounded by a continuous cover of T. vulgaris where the FST is 0.546 (P < 0.002). No significant correlation between sex and chlorotype nor between cpDNA diversity and female frequency was detected. Allozyme markers showed markedly less spatial structure (FST = 0.021 among populations and 0.019 in the CAB population, P < 0.001). This difference between cpDNA and nuclear allozyme markers suggests that pollen dispersal is more important than seed dispersal both among and within populations. PMID- 21708572 TI - Mating structure and inbreeding and outbreeding depression in the rare plant Gentianella germanica (Gentianaceae). AB - Isolation and small size of populations as a result of habitat destruction and fragmentation may negatively affect plant fitness through pollinator limitation and increased levels of inbreeding. To increase genetic variation in small populations of rare plants artificial gene flow has been suggested as a management tool. We investigated whether pollinator limitation and inbreeding depression could reduce fitness in Gentianella germanica, an endangered biennial of increasingly fragmented calcareous grasslands in Central Europe. We experimentally excluded pollinators and generated progenies by hand-pollinating flowers with pollen from different distances. G. germanica was highly selfing. Pollinator exclusion strongly reduced seed set, indicating that pollinator limitation could potentially reduce plant fitness. Germination rate as well as number of leaves and rosette size of progeny from 10-m crosses was higher than that of progeny from open pollinations, self-, 1-m, and interpopulation crosses. After 6 mo of growth differences in the number of surviving plants persisted, whereas differences in plant size did not. The results suggest that inbreeding depression may reduce plant performance in G. germanica. Outbreeding depression in the performance of progeny from interpopulation crosses indicates that caution is necessary in using artificial interpopulation gene flow as a management tool. PMID- 21708573 TI - Changes in the delta13C values of trees during a tropical rainy season: some effects in addition to diffusion and carboxylation by Rubisco? AB - The d13C values of deciduous and evergreen tree leaves were compared in open and closed- canopy environments throughout a rainy season in Panamá. Newly emerging leaves had higher d13C values than older leaves of all seedlings and trees at all dates sampled. This was apparently not caused by a decline in water use efficiency as leaves develop because instantaneous ci/ca was significantly higher in newly emerging than in expanded leaves on the same twigs of trees in the field as well as on seedlings growing in a controlled, unchanging environment. Higher d13C values in newly emerging leaves occurred across diverse environmental comparisons. For example, leaves emerging during the rainy season had higher d13C values than corresponding mature leaves that had emerged both during the dry season and when water was abundant. The early enrichment in 13C may thus reflect the translocation of carbon to initiate a new leaf. Furthermore, the lack of sensitivity of this enrichment to a microclimate suggests that it might be the result of processes that occur after carbon fixation by Rubisco. Other changes in d13C values as leaves developed may also have resulted from carbon translocation processes. Foliar d13C decreased significantly after most of the leaf biomass of the deciduous Apeiba membranacea had developed. The d13C values of the evergreen Cecropia insignis were lower in the open canopy than in closed-canopy forests at the end of the rainy season. These findings suggest that the d13C values of leaves can yield ecological information about the allocation of carbon within trees. PMID- 21708574 TI - Analysis of amino acids in nectar from pitchers of Sarracenia purpurea (Sarraceniaceae). AB - Sarracenia purpurea L. (northern pitcher plant) is an insectivorous plant with extrafloral nectar that attracts insects to a water-filled pitfall trap. We identified and quantified the amino acids in extrafloral nectar produced by pitchers of S. purpurea. Nectar samples were collected from 32 pitchers using a wick-sampling technique. Samples were analyzed for amino acids with reverse-phase high-performance liquid chromatography with phenylisothiocyanate derivatization. Detectable amounts of amino acids were found in each of the 32 nectar samples tested. Mean number of amino acids in a nectar sample was 9 (SD = 2.2). No amino acid was detected in all 32 samples. Mean amount of amino acids in a nectar sample (i.e., amount per wick) was 351.4 ng (SD = 113.2). Nine amino acids occurred in 20 of the 32 samples (aspartic acid, cysteine, glutamic acid, glycine, histidine, hydroxyproline, methionine, serine, valine) averaging 263.4 ng (SD = 94.9), and accounting for ~75% of the total amino acid content. Nectar production may constitute a significant cost of carnivory since the nectar contains amino acids. However, some insects prefer nectar with amino acids and presence of amino acids may increase visitation and capture of insect prey. PMID- 21708575 TI - Carbon isotopic composition of legumes with photosynthetic stems from mediterranean and desert habitats. AB - The carbon isotopic compositions of leaves and stems of woody legumes growing in coastal mediterranean and inland desert sites in California were compared. The overall goal was to determine what factors were most associated with the carbon isotope composition of photosynthetic stems in these habitats. The carbon isotope signature (d13C) of photosynthetic stems was less negative than that of leaves on the same plants by an average of 1.51 +/- 0.42 ;pp. The d13C of bark (cortical chlorenchyma and epidermis) was more negative than that of wood (vascular tissue and pith) from the same plant for all species studied on all dates. Desert woody legumes had a higher d13C (less negative) and a lower intercellular CO2 concentration (Ci ) (for both photosynthetic tissues) than that of woody legumes from mediterranean climate sites. Differences in the d13C of stems among sites could be entirely accounted for by differences among site air temperatures. Thus, the d13C composition of stems did not indicate a difference in whole-plant integrated water use efficiency (WUE) among sites. In contrast, stems on all plants had a lower stem Ci and a higher d13C than leaves on the same plant, indicating that photosynthetic stems improve long-term, whole-plant water use efficiency in a diversity of species. PMID- 21708576 TI - Why do early-emerging tree seedlings have survival advantages?: a test using Acer rubrum (Aceraceae). AB - In forest understories, tree seedlings that germinate and emerge early in the growing season have significant survival advantages. We hypothesized that (a) early emergence is related to seed size and half-sib family, and (b) increased survival is due to reduced competition for resources. To test these hypotheses, we collected seeds of Acer rubrum from four half-sib families and planted them in the understory of a South Carolina floodplain forest. In one experiment, date of emergence was not related to seed size or half-sib family. However, our method of seed collection may have underestimated variability among half-sib families. In a second experiment, seeds were spread onto 20 understory plots, half of which were trenched to reduce root competition with overstory trees. One-year survival and biomass were greater for early- than for later-emerging cohorts. Trenching changed biomass distribution among aboveground parts and may have increased total biomass, but had essentially no impact on survival or root mass. Variation in plot flooding resulted in large differences in timing of emergence, survival, and biomass. For Acer rubrum, the survival advantage accorded by early emergence may be more related to flooding, light conditions, and genetic heterogeneity than to seed size or avoidance of root competition. PMID- 21708577 TI - Effects of bison and cattle on growth, reproduction, and abundances of five tallgrass prairie forbs. AB - Forb populations were sampled on Kansas tallgrass prairie to examine the effects of native (bison) and domestic (cattle) ungulates on plant growth, reproduction, and species abundances. Five locally and regionally abundant native tallgrass prairie perennials, Baptisia bracteata, Oenothera speciosa, Vernonia baldwinii, Solidago missouriensis, and Salvia azurea, were selected for study. Replicate watershed-level treatments included three grazing regimes (ungrazed, grazed by cattle, and grazed by bison), and two spring fire frequencies (annually burned and burned at 4-yr intervals). The results show that forb responses to ungulates in tallgrass prairie are complex and vary significantly among plant species, ungulate species, fire regimes, and plant life history stages. Some forbs (e.g., B. bracteata, O. speciosa, and V. baldwinii) increased in growth and reproduction in grazed sites, indicating competitive release in response to selective grazing of the dominant warm-season matrix grasses. Forbs that reduced performance in grazed sites are likely negatively affected by disturbances generated by ungulate nongrazing activities, because none of the forbs studied were directly consumed by bison or cattle. Large grazers had no detectable effect on the frequency of plant damage by other herbivores or pathogens. Significant effects of grazers on patterns of flowering and seed production were not congruent with their effects on population densities, indicating that variation in sexual reproduction plays a minor role in regulating local population abundances. Furthermore, the native and domestic ungulates differ significantly in their effects on forb growth and reproduction. PMID- 21708578 TI - Interactions between resources and abiotic conditions control plant performance on subarctic coastal dunes. AB - Both abiotic conditions and resource levels affect the performance of plants on coastal dune systems. On the foredune, environmental factors are particularly limiting for plant growth and these vary along a short topographical gradient, from the foot to the ridge. On subarctic coastal dunes in northeastern Canada, this topographical gradient is paralleled by a plant sequence that typically involves Honckenya peploides, Elymus mollis, and Lathyrus japonicus. In this study, field nutrient additions were carried out to evaluate the importance of N and/or P limitation on foredune plant performance. Also, glasshouse experiments were done to determine the significance of interactions between substrate resources (i.e., nutrients and water), and between substrate resources (i.e., nutrients) and an abiotic condition (i.e., salt spray) on the growth of a dune species. Field nutrient additions did not result in any significant increase in plant biomass, although nutrients were accumulated in the rhizomes of all three species present on the foredune and in the aboveground tissues of Elymus. Glasshouse experiments on Elymus showed that nutrient addition could increase plant biomass. However, water availability and salt spray interfered with nutrient use by the plants. I suggest that such interactions between resources and abiotic conditions may significantly affect plant performance and plant sequence on the foredune of coastal dune systems. PMID- 21708579 TI - Variation in magnesium and nitrogen content in seeds of antelope bitterbrush (Purshia tridentata, Rosaceae). AB - One-hundred and sixty-three seeds from 38 shrubs of antelope bitterbrush (Purshia tridentata) from four different sites were individually analyzed for N and Mg content. Seed nutrient content has previously been shown to affect seedling growth, competitive ability, and adult biomass and seed production, though estimations of nutrient concentration in seeds have always been based on bulk samples of more than one seed. The results from antelope bitterbrush show that individual seeds vary in N and Mg content (coefficient of variation = 15.9 and 10.1%, respectively), with most of the variation being attributable to seed size (over 70%). Larger seeds not only had greater absolute quantities of N and Mg, but also a greater concentration of N. Differences between seeds from the same shrub explained the second largest amount of variation (over 20%), while differences between shrubs and site of growth, though significant, accounted for much less of the variation (just over 5%). Soil N and Mg were not closely related to seed N or Mg at a site, suggesting that decisions on how much N or Mg to allocate to seeds are not entirely based on supply. Shrubs that were browsed most intensively the winter prior to seed production had seeds with higher concentrations of Mg. Differences in seed mineral content between shrubs suggest the possibility for natural selection to operate, though research to determine heritability of this character will be necessary to confirm how much of the observed variation is attributable to plasticity in seed filling. PMID- 21708580 TI - Vallisneria americana (Hydrocharitaceae) as a biomonitor of aquatic ecosystems: comparison of cloned genotypes. AB - We assessed the effects of local environment on survival, growth, and development in six clones (genotypes) of Vallisneria americana grown at five sites in the Huron-Erie Corridor. Detrimental effects of local environment on plant performance (rate of clonal growth, leaf and root production, surface area of leaves and roots, plant biomass, rate of flowering, and turion production) were correlated with sediment toxicity and levels of organic contamination determined in independent studies, and differed among plant genotypes. All surviving clones used in the study ranked environmental quality of the five sites in the same order. Two genotypes, which were tolerant of contaminants, survived the 2 yr of exposure at all sites, while other nontolerant clones died within the 1st yr of study, at the two most contaminated sites. The leaf-to-root surface area ratio was highly indicative of site quality, and was not affected either by year-to year variation, or by differences between genotypes. The use of cloned plants in this biomonitoring study reduced variance, and increased precision and accuracy of site assessment compared to biomonitoring with genetically variable plants. Clones of V. americana tolerant of contaminants were particularly useful in assessing the most contaminated sites. An approach that uses an array of both tolerant and nontolerant clones is recommended. PMID- 21708581 TI - A cladistic analysis of Asarum (Aristolochiaceae) and implications for the evolution of herkogamy. AB - A cladistic analysis of Asarum was conducted to examine relationships among species within the genus and to test the monophyly of several groups of taxa that have often been treated as segregate genera. Thirty-two species were drawn from throughout the range of the genus, representing a broad sample of sections and all segregate genera. The data matrix included 37 characters derived from various aspects of vegetative and floral morphology. A strict consensus of all most parsimonious trees suggests that Asarum s.l. is monophyletic and consists of two main clades: an Asarum clade, which is characterized by connate styles and inferior ovaries, and an Asiasarum-Hexastylis-Heterotropa clade, which is characterized by ridges on the inner perianth surface, dorsal stigmas, and bifid style extensions. The latter is a large and morphologically diverse clade that includes the North American segregate Hexastylis and two Asiatic segregates. Examination of pollination mechanisms in the context of this phylogeny supports the conclusion that herkogamy, and thus obligate insect pollination, is derived from a plesiomorphic condition of autonomous self-pollination. Associated with herkogamy are characters such as glandular trichomes and other ornamentation of the surface of the calyx that probably represent increased specialization to attract insect pollinators. This study also indicates that chromosomal evolution has occurred via aneuploid decrease from an ancestral chromosome number of 2n = 26 to 2n = 24 in Heterotropa. The recognition of two subgenera, subgenus Asarum and subgenus Heterotropa, corresponding to the two clades in the cladistic analysis, is recommended. PMID- 21708582 TI - A survey of anther glands in the mimosoid legume tribes Parkieae and Mimoseae. AB - In a broad survey of anther glands in the mimosoid legume tribes Mimoseae and Parkieae, representatives from 30 genera with anther glands were studied using scanning electron microscopy. Four kinds of anther glands could be distinguished. The Piptadenia-type gland, found in all but four of the genera surveyed, is usually spherical to ellipsoid in shape and often borne on a stipe. The cells making up the gland vary in size among species and are often sculptured. Six different kinds of sculpturing can be recognized: smooth, reticulate, striate, rugulate, scabrate, and papillate. The Gagnebina-type gland is the least specialized, consisting of a simple extension of the connective with irregularly projecting cells. The Prosopis africana-type gland is borne ventrally between the thecae, the connective extending hump-like over the apex of the anther. The Pentaclethra-type gland, found only in the genus Pentaclethra, is distinguished by a median dorsal furrow and a ventral conical structure similar to a food body or osmophore. Anatomical sections revealed two different subtypes within the Piptadenia-type gland. Some glands are composed of a homogeneous matrix of isodiametric cells, whereas others have two layers: a peripheral layer of large radially elongated cells, and a central sphere of smaller isodiametric cells and large air spaces. Some characters of anther glands have clear taxonomic significance, and more detailed surveys within genera will undoubtedly provide additional taxonomic markers. PMID- 21708583 TI - Structural analysis of female and hermaphroditic flowers of a gynodioecious tree, Ocotea tenera (Lauraceae). AB - The evolution of gynodioecy from hermaphroditism involves modifications of floral structure such that male or female fitness is enhanced in hermaphrodites and females, respectively. We present an analysis of structural specialization of flowers of Ocotea tenera, in order to evaluate gender system evolution in this tropical tree species. Significant morphological and anatomical variation was found between high fruiting and low or nonfruiting trees. Female flowers were significantly smaller than hermaphroditic flowers, produced no viable pollen, and made relatively greater allocation to structures that increase female fitness. Hermaphroditic flowers were significantly larger than female flowers, produced copious quantities of pollen, and made relatively greater allocation to male structures. Analyses indicated that changes in allometries between whole-flower growth and growth of reproductive structures may have occurred, which enhance function of the flower and plant as a male or female. Efficiency of nutrient allocation for reproduction is argued to be a factor driving gender system evolution in Ocotea tenera. PMID- 21708584 TI - Light perception for sun-tracking is on the lamina in Crotalaria pallida (Fabaceae). AB - Trifoliolate leaves of Crotalaria pallida Aiton (Fabaceae) exhibit sun-tracking behavior in simulated days and in response to a fixed, oblique light. The site of light perception for sun-tracking is on the lamina, necessitating transport of a signal from the lamina to the site of response (the pulvinule at the base of the leaflet). Evidence for the site of light perception on the lamina includes the following: (1) leaflet movement in response to oblique light is not affected by shading the pulvinule or by illuminating the pulvinule with vertical light; (2) leaflet movement is stopped by shading the lamina while illuminating the pulvinule with oblique light. The proximal end of the leaflet is the most sensitive region for light perception. Light reaching the midveins is not necessary for leaflet reorientation. Presentation times of as little as 10 min followed by darkness resulted in partial leaflet movement in young leaves. This indicates that the signal was not inductive in nature. Estimates of the rate of signal transport range from 3 to 12 cm/h, within the range of phloem transport. PMID- 21708585 TI - Distyly and variation in heteromorphic incompatibility in Gaertnera vaginata (Rubiaceae) endemic to La Reunion Island. AB - Documenting the floral biology of species throughout the Rubiaceae family is of particular interest since heterostyly and dioecy may have evolved more than once in this large family. Unfortunately many species in several tropical regions remain unstudied. The purpose of this paper is to describe the floral biology, the nature of self-incompatibility, morph ratios, and fecundity in natural populations of Gaertnera vaginata, a small tree endemic to the island of La Reunion in the Indian Ocean. Measurements of floral characters in populations across the entire distribution of this species showed that G. vaginata exhibits a reciprocal stigma height and anther height dimorphism characteristic of a distylous species. Pollen grain size and corolla tube length are consistently greater in short-styled plants and long-styled plants produce more pollen per flower. Controlled pollinations in a natural population showed that 25% of the short-styled plants gave at least one fruit on intramorph (illegitimate) pollination, whereas no long-styled plants set fruit on illegitimate pollination. In total, 19.4% of illegitimate pollinations produced fruit on short-styled plants. No self-pollination gave fruit on either morph and between-morph pollinations produced 92.2 and 92.8% for short and long-styled plants, respectively. Overall, short-styled plants were significantly more abundant than long-styled plants. Short-styled plants outnumbered long-styled plants in 16 of the 19 populations. In three of these populations the morph ratio was significantly different from 1:1. In two natural populations, fruit set was significantly higher on long-styled plants, although the number of seeds per fruit was not significantly different between the two morphs. The possible effect of variation in the strength of heteromorphic incompatibility on observed variation in morph abundance and the possible causes for the variation in fruit set are discussed. PMID- 21708587 TI - Immunochemical localization of tetrahydrocannabinol (THC) in cryofixed glandular trichomes of Cannabis (Cannabaceae). AB - Delta 9-tetrahydrocannabinol (THC) localization in glandular trichomes and bracteal tissues of Cannabis, prepared by high pressure cryofixation cryosubstitution, was examined with a monoclonal antibody-colloidal gold probe by electron microscopy (EM). The antibody detected THC in the outer wall of disc cells during the presecretory cavity phase of gland development. Upon formation of the secretory cavity, the immunolabel detected THC in the disc cell wall facing the cavity as well as the subcuticular wall and cuticle throughout development of the secretory cavity. THC was detected in the fibrillar matrix associated with the disc cell and with this matrix in the secretory cavity. The antibody identified THC on the surface of secretory vesicles, but not in the secretory vesicles. Gold label also was localized in the anticlinal walls between adjacent disc cells and in the wall of dermal and mesophyll cells of the bract. Grains were absent or detected only occasionally in the cytoplasm of disc or other cells of the bract. No THC was detected in controls. These results indicate THC to be a natural product secreted particularly from disc cells and accumulated in the cell wall, the fibrillar matrix and surface feature of vesicles in the secretory cavity, the subcuticular wall, and the cuticle of glandular trichomes. THC, among other chemicals, accumulated in the cuticle may serve as a plant recognition signal to other organisms in the environment. PMID- 21708586 TI - Expression of fasciation mutation in apical meristems of soybean, Glycine max (Leguminosae). AB - The phenotype of the apical meristem was used to examine the effect of fasciation mutation at the f locus in different genetic backgrounds in soybean Glycine max (L.) Merr. Comparisons of meristem development in fasciation mutant and wild type were conducted with scanning electron microscope (SEM) on isogenic lines BARC-11 11-ff and BARC-11-11-FF at postgermination and early vegetative stages. Studies of apical meristems of three independently originated fasciation mutants, PI 83945-4, PI 243541, and T173, were carried out at vegetative and early floral transition stages. Corolla Fasciation, the extreme mutant phenotype, was used for comparison of meristem development. Enlargement of the apical meristem and shortened plastochron were observed in the mutant lines 2 d after germination. Similar to Corolla Fasciation, in PI 83945-4, PI 243541, and T173, enlargement of the apical meristem was followed by growth along one axis at the V3 stage and establishment of a ridge-like meristem at the V4 stage. Influence of pedigree on the expression of the fasciation phenotype was demonstrated by different growth patterns (subangular vs. ridge-like) of the apical meristem in BARC-11-11-ff and PI 243541 with the same f gene. During transition of the apical meristem from vegetative to reproductive stage in all mutant lines further production of leaf primordia ceased. The developmental pattern of the apical meristems suggests that the f locus may have the same allele in fasciation mutants of independent origin in soybean. PMID- 21708588 TI - A taxodiaceous seed cone from the Triassic of Antarctica. AB - A silicified seed cone is described from the lower Middle Triassic of A silicified seed cone is described from the lower Middle Triassic of Antarctica. The cone measures up to 3.4 cm long and 1.4 cm wide, and consists of helically arranged cone scales attached to a eustelic axis. Bract and ovuliferous scale are approximately of equal length and fused at the base. The bract is entire and vascularized by a single trace. The ovuliferous scale contains five distal lobes, each vascularized by a terete strand that divides to form a smaller trace to each of the five inverted ovules. Ovules are small and flattened with the three-parted integument attenuated into oppositely positioned lateral wings. The Triassic specimens are compared with both extant and fossil conifer seed cones and believed to have their closest affinities within the Taxodiaceae. PMID- 21708589 TI - The fossil monocot Limnobiophyllum scutatum: resolving the phylogeny of Lemnaceae. AB - More than 200 specimens of Limnobiophyllum scutatum (Dawson) Krassilov have been recovered from lacustrine claystones in the Paleocene Paskapoo Formation near Red Deer, Alberta. The plant was a floating, aquatic angiosperm with helically arranged, ovate leaves attached in small rosettes. Rosettes are interconnected by stolons and bear simple adventitious roots as well as larger branching roots that appear to have vascular tissue. Leaves are pubescent, aerenchymatous, with 12-14 campylodromous primary veins that curve toward the apex, joining a fimbrial vein, often an apical notch. Staminate flowers with two, four-loculate stamens, are borne in the axils of second leaves. Anthers contain monoporate, globose, echinate pollen, 20-25 um in diameter. The pollen wall is 0.8 um thick, with a homogeneous foot layer, granular to slightly columellate infratectal layer and an echinate tectum. Pollen most closely resembles the sporae dispersae genus Pandaniidites Elsik. The completeness of L. scutatum has allowed for its inclusion in a numerical cladistic analysis to resolve relationships among taxa of the Lemnaceae, Pistia, and selected genera of Araceae. Results of the analysis indicate that the Lemnaceae plus Pistia form a monophyletic group within the Araceae. PMID- 21708590 TI - Embryology of the Theaceae - anther and ovule development of Camellia, Franklinia, and Schima. AB - The anther and ovule development of Camellia, Franklinia, and Schima (Theaceae, Camellioideae) were observed. The three genera share the following embryological traits: anther wall formation of basic type, tapetum of glandular type, walls of endothecial cells with secondary thickening, and production of pseudopollen grains in connective, which are dispersed into pollen sacs at anthesis, ovule bitegmic-tenuinucellate, micropyle formed by inner integument alone, hypostase present, and both integuments generally five-to-seven cell layered. One autapomorphy of the Camellioideae found in the present study is the production of pseudopollen. The three genera surveyed differ with respect to the number of middle layers in the anther, the presence or absence of stomata on connective epidermis, morphology of pseudopollen, type of embryo sac formation, form of ovule, ovular vasculature, and the proliferation of ovular epidermis, etc. Among the three genera, Franklinia and Schima are presumed to be closer embryologically, and Schima possesses more numerous specialized features. PMID- 21708591 TI - Chloroplast DNA restriction site study of Verbesina (Asteraceae: Heliantheae). AB - Chloroplast DNA variation was examined for 79 species of Verbesina and 24 outgroups. Two independent analyses of the data were performed. An intergeneric study to elucidate the phylogenetic relationships of Verbesina used 22 genera, most of which are regarded in the literature as closely related to Verbesina. Coreopsis and Hymenoxys served as outgroups for this analysis. The 16 6-bp (base pair) restriction endonucleases used in the intergeneric study revealed 263 phylogenetically informative sites. Wagner analyses of these characters resulted in four equally parsimonious trees with a length of 857 steps and a Consistency Index of 0.492. Results from this study indicate that Verbesina is monophyletic, a member of the tribe Heliantheae, and that its sister taxa are the mostly Mexican genera Podachaenium, Squamopappus, and Tetrachyron. The infrageneric study of Verbesina included species belonging to all of its infrageneric taxa, except the monotypic sect. Stenocarpha. The 17 6-bp restriction endonucleases used in the infrageneric study revealed 137 sites 77 of which were phylogenetically informative. Wagner analyses of these characters generated 180 equally parsimonious trees with a length of 158 steps and a Consistency Index of 0.786. The genera Podachaenium, Squamopappus, and Tetrachyron served as outgroups. Two major clades, which correspond to traditional divisions of the genus based on leaf arrangement, are supported by the study. No support was found for the monophyly of seven of the 11 sections examined; further sampling of sections Lipactinia, Ochractinia, Verbesina, and Ximenesia is needed. Results support a major reassessment of the traditional infrageneric classification of the genus and provide the basis for the reevaluation of the sectional taxonomy of Verbesina. These studies support a North American origin for the genus with several independent introductions into South America producing significant diversity, especially in the Andean region. PMID- 21708592 TI - The functional ecology of gynodioecy in Eritrichum aretioides (Boraginaceae), the alpine forget-me-not. AB - Eritrichum aretioides is a gynodioecious species with female and hermaphrodite individuals. In populations on Pennsylvania Mountain in central Colorado (USA), the frequency of females ranges from 22 to 41%. Flower number and the number of seeds produced per flower were similar in hermaphrodites and females. However, hermaphrodites produced larger flowers, while females produced larger seeds (P < 0.05 for both). In the field, seed germination was higher for seeds from females than for seeds from hermaphrodites (20 vs. 9% germination; P < 0.05). Unvisited flowers and open-pollinated flowers of hermaphrodites had similar pollen receipt (approx 20 pollen grains per stigma), but seed set following autogamous pollination was significantly lower than seed set following natural pollination. This finding indicates that hermaphrodites have a barrier to selfing and implies that the larger seed size and greater establishment advantage of offspring from females is unlikely to have resulted from female outcrossing advantage. Rather, differences in the quality of seed progeny between morphs probably reflect a trade-off in sexual allocation or pleiotropic effects of the sex-determining genes. PMID- 21708593 TI - Clonal structure and patterns of allozyme diversity in the rare endemic Cycladenia humilis var. jonesii (Apocynaceae). AB - The rare endemic Cycladenia humilis var. jonesii (Jones cycladenia) has low levels of sexual reproduction. Enzyme electrophoresis was used to explore possible causes of low seed set and high fruit abortion by assessing the clonal structure and genetic diversity in populations. The seven populations studied were composed of multiple, highly interdigitated clones; thus low fruit set is not likely to be due to a scarcity of mates. Genotype frequencies did not differ significantly from Hardy-Weinberg proportions, suggesting that populations are not highly inbred. Jones cycladenia exhibited high levels of genetic diversity at both the population level (A = 1.7; P = 37; He = 0.14) and the taxon level (A = 2.7; P = 60) in comparison to other plants. These data suggest that genetic drift is unlikely to have left this taxon genetically depauperate. Furthermore, we detected little divergence among geographically disjunct populations of Jones cycladenia (FST = 0.10). In comparison, Jones cycladenia populations were highly differentiated from a population of the taxon's close relative, C. h. var. humilis (mean genetic identity = 0.76). Our study suggests that other reasons for low fruit set in Jones cycladenia, such as resource or pollinator limitation, or genetic load, should be explored in future research. PMID- 21708594 TI - Fossil ectomycorrhizae from the Middle Eocene. AB - Fossil ectomycorrhizae were found recently among permineralized plant remains in the middle Eocene Princeton chert of British Columbia. The ectomycorrhizae are associated with roots of Pinus and have a Hartig net that extends to the endodermis, a pseudoparenchymatous mantle, and contiguous extramatrical hyphae that are simple-septate. The mycorrhizal rootlets lack root hairs and dichotomize repeatedly to form large, coralloid clusters. Reproductive structures are absent. Based on the morphological characteristics, and the identity of the host, the closely related basidiomycete genera Rhizopogon and Suillus are suggested as comparable extant mycorrhizal fungi. These exquisitely preserved specimens represent the first unequivocal occurrence of fossil ectomycorrhizae and demonstrate that such associations were well-established at least 50 million years ago. PMID- 21708595 TI - The structure and function of RuBisCO and their implications for systematic studies. AB - As "the most abundant protein in the world,'' ribulose-1,5-bisphosphate carboxylase (RuBisCO) attracts the attention of genetic engineers and plant phylogeneticists. The active site, which is responsible for almost all carbon fixation on earth, is in the large subunit (LSU). Over 30% of the 476 amino acids in the LSU are involved in intermolecular associations. Using available sequence data, we find that 105 (22%) of the residues are absolutely conserved across 499 seed plants, with an additional 110 demonstrating only one change. Our analyses show that conserved domains are not fully explained by current structural data. This has several implications for systematic studies. First, the number of potentially variable sites is likely to be slightly over 1000, rather than 1428. Second, rates of change can vary greatly across the molecule; functional constraints on amino acids and codon biases greatly increase the potential for homoplasy. Third, some changes are correlated, and thus might be down-weighted accordingly. Fourth, some of the variation in RuBisCO may be adaptive and present insights into the nature of evolutionary change in response to the environment. PMID- 21708596 TI - Fly pollination of Gorteria diffusa (Asteraceae), and a possible mimetic function for dark spots on the capitulum. AB - We investigated the functional significance of raised black spots on the ray florets of Gorteria diffusa (Asteraceae) in South Africa. Field observations showed that G. diffusa is pollinated by a small bee-fly, Megapalpus nitidus (Bombyliidae), which is strikingly similar to the raised spots that occur on some of the ray florets. Removal of the spots resulted in a significant decrease in the rate of fly visits to capitula, but did not significantly affect seed set. Replacement of the spots with simple ink spots also significantly reduced the rate of pollinator visits, suggesting that flies respond to details in the structure of the spots. Investigations using scanning electron microscopy showed that the spots of G. diffusa consist of a complex of different cell types. Differences in epidermal sculpturing may partly explain the UV reflectance pattern of these spots, which is similar to that of the flies. Male flies are strongly attracted to the spots, as well as to other flies sitting in the capitula, although female flies also visit the capitula. We conclude that the spots of G. diffusa mimic resting flies, thereby eliciting mate-seeking and aggregation responses in fly pollinators. Similar dark spots have evolved in unrelated South African Gazania, Dimorphotheca, and Pelargonium species pollinated by bee-flies. PMID- 21708597 TI - Genetic structure of continental and island populations of the Mediterranean endemic Cyclamen balearicum (Primulaceae). AB - Cyclamen balearicum is a self-compatible perennial herb endemic to the western Mediterranean Basin. This species occurs in five geographically isolated terrestrial islands in southern France and on four Balearic islands. In this study, we compare genetic variability and differentiation within and among 11 terrestrial island populations and 17 true island populations. Of nine readable enzyme loci, five were polymorphic in both terrestrial and true islands. F statistics showed a significant heterozygote deficiency in all populations, probably due to high levels of autonomous selfing, restricted gene flow, and subsequent genetic drift. Genetic diversity was higher in terrestrial islands than on the Balearic islands, suggesting that the Balearic islands were colonized when they were in contact with the continent. Population differentiation was greater among terrestrial islands (Fst = 0.417 and Gst = 0.344) than among true islands (Fst = 0.112 and Gst = 0.093). Furthermore, differentiation among populations on the Basses Cevennes terrestrial island was greater (Fst = 0.254) than among populations on the true island of Mallorca (Fst = 0.163). The greater genetic differentiation among terrestrial islands could have been caused by genetic bottlenecks associated with changes in climate and human land use that may have reduced population sizes more severely in terrestrial islands in southern France than on the Balearic islands. PMID- 21708598 TI - The mating system of the tropical understory shrub Ardisia escallonioides (Myrsinaceae). AB - Electrophoretic analysis of progeny arrays was used to determine whether Ardisia escallonioides (Myrsinaceae). a self-compatible tropical understory shrub in south Florida, exhibits a mixed-mating system. Ten seedlings from seven to 16 maternal plants from four populations were analyzed using five polymorphic enzyme systems. Multilocus population out-crossing rates ranged from 0.39 to > 1, with three populations showing high levels of selfing. Both single and multilocus inbreeding coefficients (F) indicated excess homozygosity in seedlings but not adults for three of the four populations. Population outcrossing rate was not positively correlated with increased numbers of flowering plants. The importance of annual variation in population outcrossing rates is discussed with regard to the high temporal variability in seedling recruitment in this species. PMID- 21708599 TI - Mating system of Carapa procera (Meliaceae) in the french guiana tropical forest. AB - The mating system of the tropical rainforest tree Carapa procera was studied for a population located within a sylvicultural trial in French Guiana. We used the mixed-mating model with the genotypes of 47 open-pollinated progenies at ten polymorphic loci, obtained through isozyme analysis. Seeds were collected on both logged and unlogged (control) plots, which were interspersed. A high multilocus outcrossing rate (0.78) was found for the global population. and there was indirect evidence for nonrandom mating for outcrosses. It is argued that this may be due to some kind of positive assortative mating, probably biparental inbreeding. Correlation of selfing between sibs was not significantly different from zero. and the proportion of full-sibs among outcrossed sib-pairs was significant but low (0.16). We found significant differences between outcrossing rates when computing separate estimates for the 14 trees located on logged plots (tm = 0.63) and the 33 trees located on undisturbed plots (tm = 0.85). It is argued that the decrease in density is probably not the only cause of the decrease in outcrossing rate on logged plots. Lastly, several points concerning the reliability of the estimation are outlined. In particular. the downward bias due to ignoring null alleles during genetic interpretations of zymograms is quantified in a few cases by simulating artificial populations. PMID- 21708600 TI - Ecological correlates of achene mass variation in Chrysothamnus nauseosus (Asteraceae). AB - Chrysothamnus nauseosus (Asteraceae) is a complex polymorphic shrub species widely distributed in western North America. In a study of 86 populations belonging to 15 subspecies, achene mass varied among populations over a sevenfold range. Achene mass was closely correlated with capitulum size at the subspecies level, varied little between wild-growing and common-garden-grown members of a population, and was under strong genetic control. Subspecies with the heaviest achenes are restricted to specialized edaphic environments (dunes and badlands) or late seral montane riparian communities, while subspecies that are widely distributed and that occur in early seral habitats have less heavy achenes. Selection on achene mass has apparently been a notable feature of the adaptive radiation of Chrysothamnus nauseosus into the wide array of habitats it currently occupies. Within a wild population, achene mass was greater for plants fruiting in midautumn than for plants fruiting early or late in the autumn, and this same trend was observed within individual plants in garden populations, indicating environmental control, perhaps through resource limitation. Highly significant between-plant differences in achene mass were found in both wild and garden populations, suggesting that within-population genetic variation is sufficient to permit continuing selection. PMID- 21708601 TI - Effects of mycorrhizae on plant growth and dynamics in experimental tall grass prairie microcosms. AB - Experimental microcosms (40 X 52 X 32 cm) containing an assemblage of eight tallgrass prairie grass and forb species in native prairie soil were maintained under mycorrhizal (untreated control) or mycorrhizal-suppressed (fungicide treated) conditions to examine plant growth, demographic, and community responses to mycorrhizal symbiosis. The fungicide benomyl successfully reduced mycorrhizal root colonization in the fungicide-treated microcosms to only 6.4% (an 83% reduction relative to mycorrhizal controls). Suppression of mycorrhizas resulted in a 31% reduction in total net aboveground plant production and changes in the relative production of C4 and C3 plants. The C4 tallgrasses Andropogon gerardi and Sorghastrum nutans produced less plant biomass in the fungicide-treated microcosms, and had a greater ratio of reproductive to vegetative biomass. Cool season C3 grasses, Koeleria pyramidata and Poa pratensis accumulated more biomass and were a significantly greater proportion of total community biomass in mycorrhizal-suppressed microcosms. Forbs showed variable responses to mycorrhizal suppression. The two legumes Amorpha canescens and Dalea purpurea had significantly lower survivorship in the fungicide-treated microcosms, relative to the controls. The results confirm the high mycorrhizal dependency and growth responsiveness of dominant prairie grasses, and indicate that differential growth and demographic responses to mycorrhizal colonization among species may significantly affect plant productivity and species relative abundances in tallgrass prairie. PMID- 21708602 TI - A new fossil fern assignable to Gleicheniaceae from Late Cretaceous sediments of New Jersey. AB - The recent discovery of well-preserved charcoalified rhizomes, petioles. pinnules, sori, and spores from the Upper Cretaceous of New Jersey provides the basis for the description of a new gleicheniaceous fern, Boodlepteris turoniana. The fossils were collected from unconsolidated sediments of Turonian age (~90 MYBP million years before present; Raritan/ Lower Magothy Formation, Potomac Group). These deposits are rich in angiosperms, but also have a limited representation of fern and gymnosperm remains. Fossil specimens from this locality are particularly remarkable in that minute detail, including anatomical features, are often preserved. Some Boodlepteris specimens have cell by cell preservation that reveals the nature and structure of the stele in rhizomes and petioles, and others show minute details of the sori borne on fertile pinnae. Although these specimens are not in organic connection, there are sufficient structural and anatomical details preserved to confidently suggest that they belong to the same taxon. Cladistic analysis of the fossils, both separately and as a reconstruction, support assignment of Boodlepteris to the extant family Gleicheniaceae. PMID- 21708603 TI - Phylogenetic relationships in Saxifragaceae sensu lato: A comparison of topologies based on 18S rDNA and rbcL sequences. AB - Relationships among the morphologically diverse members of Saxifragaceae sensu lato were inferred using 130 18S rDNA sequences. Phylogenetic analyses were conducted using representatives of all 17 subfamilies of Saxifragaceae sensu lato, as well as numerous additional taxa traditionally assigned to subclasses Magnoliidae, Caryophyllidae, Hamamelidae, Dilleniidae, Rosidae, and Asteridae. This analysis indicates that Saxifragaceae should be narrowly defined (Saxifragaceae sensu stricto) to consist of ~30 herbaceous genera. Furthermore, Saxifragaceae s. s. are part of a well-supported clade (referred to herein as Saxifragales) that also comprises lteoideae, Pterostemonoideae, Ribesioideae, Penthoroideae, and Tetracarpaeoideae, all traditional subfamilies of Saxifragaceae sensu lato, as well as Crassulaceae and Haloragaceae (both of subclass Rosidae). Paeoniaceae (Dilleniideae), and Hamamelidaceae, Cercidiphyllaceae, and Daphniphyllaceae (all of Hamamelidae). The remaining subfamilies of Saxifragaceae sensu lato fall outside this clade. Francoa (Francooideae) and Bauera (Baueroideae) are allied, respectively, with the rosid families Greyiaceae and Cunoniaceae. Brexia (Brexioideae), Parnassia (Parnassioideae), and Lepuropetolon (Lepuropetaloideae) appear in a clade with Celastraceae. Representatives of Phyllonomoideae, Eremosynoideae, Hydrangeoideae, Escallonioideae, Montinioideae, and Vahlioideae are related to taxa belonging to an expanded asterid clade (Asteridae sensu lato). The relationships suggested by analysis of 18S rDNA sequences are highly concordant with those suggested by analysis of rbcL sequences. Furthermore, these relationships are also supported in large part by other lines of evidence, including embryology. serology, and iridoid chemistry. PMID- 21708604 TI - Cladistic analysis of phylogenetic relationships among tribes Cicereae, Trifolieae, and Vicieae (Leguminosae). AB - A cladistic analysis of tribes Cicereae, Trifolieae, and Vicieae was carried out using 33 morphological, anatomical, karyological, and chemotaxonomical characteristics. Transformation polarities of the character states were developed by comparison with the character states of the genus Galega, the sister group of the tribes. Cicereae and Vicieae were found to be a monophyletic group, and Trifolieae was its sister group. The seven synapomorphic characters of Cicereae and Vicieae were presumed to be: germination hypogeal vs. epigeal; first leaf in seedlings scarious vs. laminous; leaves paripinnately and tendrilous vs. imparipinnately and etendrilous; postchalazal vascular bundle present in seed coats vs. absent; a cotyledon flap present at antihilar side vs. absent; radicles short in seeds vs. long; and plumules long in seeds vs. short. PMID- 21708605 TI - Phylogenetic relationships of Lecythidaceae: a cladistic analysis using rbcL sequence and morphological data. AB - This study examined in detail the rbcL sequence and morphological support for subfamilial relationships and monophyly of Lecythidaceae. Initially we needed to establish relationships of Lecythidaceae among other dicot families. To complete this we examined 47 rbcL sequences of 25 families along with molecular observations from several large analyses of rbcL data. All analyses strongly support the monophyly of the asterid III grouping. This analysis revealed Lecythidaceae to be paraphyletic and indicated potential outgroup relationships with Sapotaceae. Once relationships had been evaluated using molecular data we then concentrated on analyzing separate and combined morphological and molecular databases. The topology of the morphological data set was similar to the rbcL sequence and combined data sets except for the positioning of Napoleonaeoideae, Grias, Gustavia, and Oubanguia. According to the combined results, Planchonioideae, Lecythidoideae. and Foetidioideae are monophyletic, whereas the subfamily Napoleonaeoideae are paraphyletic. Nested within Napolconaeoideae, we found Asteronthos forms a strongly supported clade with Oubanguia (Scytopetalaceae). Foetidia, the only genus of Foetidioideae, is sister to Planchonioideae, and this clade is sister to Lecythidoideae. The [(Planchonioideae, Foetidioideae) Lecythidoideae are sister to Asteranthos/Oubanguia. Napoleonaeoideae are sister to the rest of Lecythidaceae. PMID- 21708606 TI - A phylogeny of the chloroplast gene rbcL in the Leguminosae: taxonomic correlations and insights into the evolution of nodulation. AB - Phylogenetic analysis of the chloroplast-encoded rbcL gene in Leguminosae are consistent with previous hypotheses in suggesting that the family as a whole is monophyletic, but that only two of its three subfamilies are natural. The earliest dichotomies in the family appear to have involved tribes Cercideae or Cassieae (subtribe Dialiinae), followed by Detarieae/ Macrolobieae, all of which are members of subfamily Caesalpinioideae. The remainder of the family is divided into two clades: (1) Mimosoideae and the caesalpinioid tribes Caeasalpinieae and Cassieae (subtribes Ceratoniinae and Cassiinae); (2) Papilionoideae. Basal groups within Papilionoideae are, as expected, elements of the grade tribes Sophoreae and Swartzieae. Major clades within Papilionoideae include: (1) a Genistoid Alliance comprising Genisteae, Crotalarieae, Podalyrieae, Thermopsideae, Euchresteae, and also some Sophoreae; (2) a clade marked by the absence of one copy of the chloroplast inverted repeat, with which are associated Robinieae. Loteae, and some Sophoreae; (3) Phaseoleae, Desmodieae. Psoraleeae, and most Millettieae, a group also marked by presence of pseudoracemose inflorescences; and (4) a well-supported clade comprising Aeschynomeneae, Adesmieae, and some Dalbergieae. Nodulation is most parsimoniously optimized on the rbcL strict consensus tree as three parallel gains, occurring in Papilionoideae, the caesalpioioid ancestors of Mimosoideae, and in the genus Chamaecrista (Caesalpinieae: Cassieae). PMID- 21708607 TI - Using restriction-site variation of PCR-amplified cpDNA genes for phylogenetic analysis of tribe Cheloneae (Scrophulariaceae). AB - Data from restriction-site variation of three PCR-amplified chloroplast genic regions (trnK, rps2, and rbcL) were used to assess the utility of PCR-based methodology for phylogenetic reconstruction. Seventeen genera from tribe Cheloneae s.l. (Scrophulariaceae), and one genus each from Solanaceae, Acanthaceae, and Bignoniaceae, representing 32 taxa, were sampled. Phylogenetic reconstruction, based on a combined data set of 138 variable restriction sites, revealed a monophyletic clade of North American Cheloneae, which were not inconsistent with a polyphyletic Scrophulariaceae. Separate analyses of individual genie regions were unable to completely resolve the phylogeny, but were adequate for resolving relationships of major clades among the taxa sampled. We suggest that analysis of PCR-product restriction-site variation is useful for phylogenetic reconstruction above the species level. PMID- 21708608 TI - Clarification of the relationship beteen Apiaceae and Araliaceae based on matK and rbcL sequence data. AB - Apiaceae and Araliaceae (Apiales) represent a particularly troublesome example of the difficulty in understanding evolutionary relationships between tropical temperate family pairs. Previous studies based on rbcL sequence data provided insights at higher levels, but were unable to resolve fully the family-pair relationship. In this study, sequence data from a more rapidly evolving gene, matK, was employed to provide greater resolution. In Apiales, matK sequences evolve an average of about two times faster than rbcL sequences. Results of phylogenetic analysis of matK sequences were first compared to those obtained previously from rbcL data; the two data sets were then combined and analyzed together. Molecular analyses confirm the polyphyly of apiaceous subfamily Hydrocotyloideae and suggest that some members of this subfamily are more closely related to Araliaceae than to other Apiaceae. The remainder of Apiaceae forms a monophyletic group with well-defined subclades corresponding to subfamilies Apioideae and Saniculoideae. Both the matK and the combined rbcL-matK analyses suggest that most Araliaceae form a monophyletic group, including all araliads sampled except Delarbrea and Mackinlaya. The unusual combination of morphological characters found in these two genera and the distribution of matK and rbcL indels suggest that these taxa may be the remnants of an ancient group of pro-araliads that gave rise to both Apiaceae and Araliaceae. Molecular data indicate that the evolutionary history of the two families is more complex than simple derivation of Apiaceae from within Araliaceae. Rather, the present study suggests that there are two well-defined "families," both of which may have been derived from a lineage (or lineages) or pro-araliads that may still have extant taxa. PMID- 21708609 TI - SEM studies on vessels in ferns. 2. Pteridium. AB - Xylem from roots and rhizomes of two infraspecific taxa of Pteridium aquilinum was studied by means of scanning electron microscopy (SEM). All tracheary elements proved to be vessels. End wall perforation plates were all scalariform, lacked pit membrane remnants in at least the central part of the perforation plate, and varied with respect to width of bars, from wide to tenuous, and with respect to presence of pit membrane remnants. In addition, porose pit membranes on walls that are likely all lateral vessel-to-vessel walls must be considered to be perforations also, although different from those on end walls. Lateral wall perforation plates, hypothesized by one worker on the basis of tylosis presence but denied by another on the basis of light microscopy, were confirmed by demonstration of pores with SEM. In addition, lateral walls of Pteridium vessels bear some grooves interconnecting pit apertures; this feature is newly figured by SEM for ferns. Lateral wall pitting that is not porose may either have striate thickenings of the primary wall or be smooth. Vessel presence and degree of specialization in Pteridium vessels may bear a relationship to the wide ecological tolerances of the genus. PMID- 21708610 TI - Cell division patterns in the apices of subterranean axis and aerial shoot of Psilotum nudum (Psilotaceae): morphological and phylogenetic implications for the subterranean axis. AB - The cell division pattern in the apical meristem of Psilotum nudum was examined using epi-illumination microscopy and a paraffin method. In the subterranean axis, about half of the derivative cells of the apical cell produce tetrahedral daughter apical cells by the first three or more oblique divisions. Roughly half of these apical cells give rise to the apical meristems of axes, whereas the other half do not. Various relative activities of the mother and daughter apical cells give rise to disordered branching patterns. In the ill-organized apical meristem as well as the leafless and capless structure, the Psilotum subterranean axis differs from the basic organs of vascular plants such as stem and root and seems to be an independent organ. The cell division pattern characteristic of the subterranean axis persists in the young unbranched aerial shoots, although fewer daughter apical cells are produced. Dichotomous branching of the aerial shoots, as in a variety of organs of pteridophytes, involves loss of the mother apical cell followed by appearance of two daughter apical cells. PMID- 21708611 TI - A comparative anatomical and biochemical analysis in salsola (Chenopodiaceae) species with and without a Kranz type leaf anatomy: a possible reversion of C4 to C3 photosynthesis. AB - Leaf anatomy was studied by light and electron microscopy and the leaf activities of RUBP carboxylase, PEP carboxylase, and malic enzyme were assayed in: Salsola australis and S. oreophila grown on the West Pamirs at 1800 m altitude; in S. australis grown on the East Pamirs at 3860 m; and in S. arbusculiformis grown in the Kisil-Kum desert in Middle Asia near 500 m. Carbon isotope fractionation ratio values also were measured on whole leaf tissue for 18 Salsola species field collected in these and other regions of the former USSR. S. australis leaves are cylindrical and in cross section exhibit a peripheral ring of mesophyll and then an inner ring of bundle sheath type cells; and its biochemical characteristics and deltaC values are typical of a C4 species of the NADP-malic enzyme malate forming group. These traits were expressed independent of the plant growth altitude up to 4000 m. C4 type deltaC values were obtained in 14 of the Salsola species. Anatomical, structural, and biochemical features typical of the C4 syndrome were absent in S. oreophila and S. arbusculiformis. Four Salsola species, including these two, had C3-type deltaC values. Their cylindrical leaves in cross section exhibited two to three peripheral rings as layers of palisade parenchyma. Although their vascular bundles were surrounded by green bundle sheath cells, their organelle numbers were comparable to those in mesophyll cells. Neither bundle sheath cell wall thickenings nor dimorphic chloroplasts in two leaf cell types were observed. In S. oreophila, there was a high activity of RuBP carboxylase, but a low activity of C4 cycle enzymes. Interpretation of these data lends evidence to the hypothesis that a small group of C3 Salsola species, including S. oreophila, S. arbusculiformis, S. montana, and S. pachyphylla, arose as the result of a reversion of a C4 to a C3 type of photosynthetic CO2 fixation in the cooler climates of Middle Asia. PMID- 21708612 TI - Hybridization between introduced smooth cordgrass (Spartina alterniflora; Poaceae) and native California cordgrass (S. foliosa) in San Francisco Bay, California, USA. AB - Introduced Spartina alterniflora (smooth cordgrass) is rapidly invading intertidal mudflats in San Francisco Bay, California. At several sites, S. alterniflora co-occurs with native S. foliosa (California cordgrass), a species endemic to California salt marshes. In this study, random amplified polymorphic DNA markers (RAPDs) specific to each Spartina species were identified and used to test for hybridization between the native and introduced Spartina species in the greenhouse and in the field. Greenhouse crosses were made using S. alterniflora as the pollen donor and S. foliosa as the maternal plant, and these crosses produced viable seeds. The hybrid status of the crossed offspring was confirmed with the RAPD markers. Hybrids had low self-fertility but high fertility when back-crossed with S. foliosa pollen. Hybrids were also found established at two field sites in San Francisco Bay; these hybrids appeared vigorous and morphologically intermediate between the parental species. Field observations suggested that hybrids were recruiting more rapidly than the native S. foliosa. Previous work identified competition from introduced S. alterniflora as a threat to native S. foliosa. In this study, we identify introgression and the spread of hybrids as an additional, perhaps even more serious threat to conservation of S. foliosa in San Francisco Bay. PMID- 21708613 TI - Morphological and molecular variation among populations of octoploid Fragaria virginiana and F. chiloensis (Rosaceae) from North America. AB - Relationships among 37 North American octoploid strawberry populations were studied by evaluating 44 morphological traits and 36 randomly amplified polymorphic DNA (RAPD) markers. Both data sets were analyzed by principal components analysis and UPGMA clustering based on genetic distances. Morphological data defined five groups: east of the Missouri River (Fragaria virginiana ssp. virginiana), the Black Hills (F. virginiana ssp. virginiana and ssp. glauca), from the eastern Cascades to the eastern Rocky Mountains (F. virginiana ssp. glauca), the western Cascades and Olympic Peninsula (F. virginiana ssp. platypetala), and the Pacific coast (F. chiloensis). Canonical discriminant analysis clearly discriminated populations into these provenances, suggesting that these groups are morphologically distinct. RAPD data defined three groups, one with F. virginiana ssp. virginiana and ssp. glauca, another with F. chiloensis, and a third with F. virginiana ssp. platypetala. The latter was more similar to F. chiloensis than F. virginiana, suggesting it is likely a subspecies of F. chiloensis. All octoploid North American strawberries have likely derived from a common ancestor and have differentiated into F. chiloensis and F. virginiana by adapting to moister and drier environments, respectively. PMID- 21708614 TI - The mating system of an hydrophilous angiosperm Posidonia australis (Posidoniaceae). AB - The hydrophilous seagrass Posidonia australis has a wide range of multilocus outcrossing rates (t), which vary from 0 to 0.89, with "apparent'' outcrossing rates varying from 0 to 0.42 among the seven populations sampled. This pattern of outcrossing rate indicates that water pollination (hydrophily) is less uniform than wind pollination and more similar to animal pollination in its variability. Variation in levels of outcrossing between populations may be due to differences in water movement; for example, open bays have greater pollen dispersal and higher outcrossing rates. Considerable pollen movement within meadows was inferred from a high frequency of nonmaternal alleles in the pollen pool. The distribution of genetic diversity among populations (GST = 0.229) suggests moderate gene flow on the local scale. These results demonstrate that successful submarine cross-pollination occurs in the hydrophile P. australis, which has a diverse mating system with populations that range from predominantly inbred to predominantly outcrossed. PMID- 21708615 TI - Morph-biased male sterility in the tropical distylous shrub Erythroxylum havanense (Erythroxylaceae). AB - This study explores whether ecological factors, such as pollinators and pollen flow, or variation in pollen and ovule development account for the observed differences (approximately twofold) in the reproductive output of pin and thrum individuals of Erythroxylum havanense. The importance of ecological factors was assessed by means of comparison of the identity of pollinators and the rates of flower visitation, and by performing controlled hand pollinations and measurements of fruit set. In addition, we described the pollen and ovule development of thrum and pin individuals. Our results indicate that pollinators of E. havanense do not distinguish between floral morphs. The differences in fruit set between pin and thrum plants held even after hand pollination and, therefore, the observed differences in reproductive output between floral morphs of E. havanense cannot be explained in terms of asymmetrical pollen flow. There were no differences in the pattern of gynoecium development between the pin and thrum morphs, however androecium development showed marked differences between the morphs, and there was a resemblance between the developmental pathways leading to male sterility of the thrum morph of E. havanense with that of species with cytoplasmic male sterility (CMS). PMID- 21708616 TI - Antheridiogen production and response in Polypodiaceae species. AB - Antheridiogen chemicals secreted by living fern gametophytes have been shown to influence production of male gametangia and thus mating systems in a large number of terrestrial fern species. Antheridiogens have not previously been thought to be prevalent in the Polypodiaceae, a large family composed mostly of tropical epiphytes. This study presents bioassay methods more sensitive than previously used to detect antheridiogen and demonstrates that antheridiogens are also operative in the Polypodiaceae and in epiphytic species. Seven species in six genera (Campyloneurum angustifolium, C. phyllitidis, Lepisorus thunbergianus, Microgramma heterophylla, Phlebodium aureum, Phymatosorus scolopendria, and Polypodium pellucidum) were tested for the presence of an antheridiogen system. All species tested except P. aureum were induced to produce antheridia precociously by their own antheridiogen and by that of Pteridium aquilinum (APt). Phlebodium aureum responded to APt and promoted antheridium formation in Onoclea sensibilis but did not respond to its own antheridiogen. Spores of all species except P. aureum were induced to germinate in darkness by antheridiogen of the same species and by APt and to form antheridia in the dark, further enhancing the possibility of intergametophytic mating. PMID- 21708617 TI - Pollination biology and outcrossing rates in hermaphroditic Schiedea lydgatei (Caryophyllaceae). AB - The influence of outcrossing and pollination biology on the maintenance of hermaphroditism was studied for Schiedea lydgatei (Caryophyllaceae: Alsinoideae), a species endemic to Moloka'i in the Hawaiian Islands. Schiedea lydgatei is the only hermaphroditic species in an otherwise dimorphic clade and hermaphroditism is likely the result of a reversal from a gynodioecious ancestor. Both wind and native moths in the family Pyralidae are responsible for pollination in S. lydgatei. Outcrossing rates were generally high (0.80), especially in years when the greatest number of plants were flowering. The combination of high outcrossing rates and substantial inbreeding depression indicates that at present females would not be favored in the population. Pollination by both wind and insects is consistent with the hypothesis that hermaphroditism is the result of a relatively recent reversal, as the ancestor of S. lydgatei was probably wind pollinated and gynodioecious with few females in the populations. A shift from wind to predominately insect pollination on Moloka'i may have resulted in increased outcrossing rates and prevented the expression of high inbreeding depression among progeny of hermaphrodites, a condition that would select against females and favor a reversal to hermaphroditism. Because few females were likely to have been present in ancestral populations that colonized Moloka'i, founder effect is another potential explanation for loss of females. In either case, current high levels of outcrossing prevent re-establishment of females in populations of S. lydgatei. PMID- 21708618 TI - Reproductive and vegetative morphology of Polyptera (Juglandaceae) from the Paleocene of Wyoming and Montana. AB - The morphology, systematics, and ecology of the extinct juglandaceous genus Polyptera are interpreted on the basis of infructescences, fruits, staminate catkins, pollen, and compound leaves from the Paleocene of Wyoming and Montana. The elongate infructescences of Polyptera manningii bear numerous helically arranged sessile fruits. The fruit is a pyramidal nut with a vascularized husk and a multilobed disk-like wing adaptive for wind dispersal. Associated staminate catkins bear numerous helically arranged florets, each with six or more stamens. Pollen from the anthers is triporate and isopolar, with ultrastructure diagnostic of Juglandaceae, but with a pattern of exinous thinning characteristic of the extinct dispersed pollen type Maceopolipollenites anellus (Nichols et Ott) comb. nov. The correlated leaves, Juglandiphyllites glabra (Brown ex Watt) comb. nov., are deciduous, pinnately compound, and have five to seven petiolulate finely serrate leaflets. Systematically, Polyptera shows relationships both with the Hicorieae and the Juglandeae. Occurrences in the Torrejonian and Tiffanian stages of the Paleocene place Polyptera as the oldest unequivocal record of Juglandaceae. Polyptera manningii typically occurs in low-diversity assemblages of 8-15 species, and usually is a dominant or subdominant constituent of floodplain assemblages. It may have been an early-successional colonizer. PMID- 21708619 TI - Examination of subfamilial phylogeny in Bromeliaceae using comparative sequencing of the plastid locus ndhF. AB - Parsimony analysis of 31 sequences of the chloroplast locus ndhF was used to address questions of subfamilial phylogeny in Bromeliaceae. Results presented here are congruent with those from chloroplast DNA restriction site analysis in recognizing a clade containing Bromelioideae and Pitcairnioideae, and in resolving Tillandsioideae near the base of the family. Placements of several taxonomically difficult genera (e.g., Glomeropitcairnia and Navia) corroborate those of traditional treatments; however, these data suggest that Brocchinia (Pitcairnioideae) is the sister group to the remainder of Bromeliaceae. Further evidence for the paraphyly of Pitcairnioideae includes the resolution of Puya as the sister group to Bromelioideae. Implications for taxonomic realignment at the subfamily level are considered. PMID- 21708620 TI - Reexamination of series relationships of South American wild potatoes (Solanaceae: Solanum sect. Petota): evidence from chloroplast DNA restriction site variation. AB - Chloroplast DNA (cpDNA) restriction enzyme site analysis was used to test hypotheses of series and superseries affiliations of 76 taxa, representing 11 of the 13 South American series (material unavailable for two series) of wild potatoes (Solanum sect. Petota) recognized in the latest classification by Hawkes. The cladistic results, combined with those from earlier cpDNA studies of 30 taxa of the Mexican and Central American species (representing eight series; ser. Conicibaccata and ser. Tuberosa have representatives in Mexico and in South America), support four main clades for 17 of the 19 series examined in sect. Petota: (1) the Mexican and Central American diploid species, exclusive of S. bulbocastanum, S. cardiophyllum, and S. verrucosum, (2) S. bulbocastanum and S. cardiophyllum (ser. Bulbocastana, ser. Pinnatisecta), (3) South American diploid species constituting all of ser. Piurana, but also members of ser. Conicibaccata, ser. Megistacroloba, ser. Tuberosa, and ser. Yungasensia, (4) all Mexican and Central American polyploid species (ser. Longipedicellata, ser. Demissa), S. verrucosum (diploid Mexican species in ser. Tuberosa), and South American diploid and polyploid members of ser. Acaulia, ser. Circaeifolia, ser. Commersoniana, ser. Conicibaccata, ser. Cuneoalata, ser. Lignicaulia, ser. Maglia, ser. Megistacroloba, ser. Tuberosa, and ser. Yungasensia. Each of these clades contains morphologically and reproductively very diverse species, and there are no evident morphological features that unite members within a clade to therefore distinguish them. These results strongly suggest a need for a reevaluation of the series and superseries classifications of sect. Petota. PMID- 21708621 TI - Molecular phylogeny and evolution of Monilinia (Sclerotiniaceae) based on coding and noncoding rDNA sequences. AB - The nuclear internal transcribed spacers, the 5.8S subunit, ~560 bp of the small subunit, and ~320 bp of the large subunit of the nuclear ribosomal DNA repeat from 17 species of Monilinia and eight species of closely related genera were sequenced. Phylogenies were constructed using maximum parsimony. The results support the hypothesis that Monilinia is not monophyletic. A fundamental distinction was found between the section Junctoriae and the section Disjunctoriae. Four evolutionary lineages were identified within the Disjunctoriae: one species on Crataegus, one group of species on dry stone fruits of rosaceous hosts, one group of species on capsular fruits of ericaceous hosts, and one group of species on sweet berry fruits of ericaceous hosts. Comparisons between branching topologies of hosts and Monilinia species suggest that although cospeciation among hosts and parasites has been the rule, several host jumps have taken place. Sclerotinia pirolae was determined to be a true member of the Disjunctoriae. The closest taxon groups to the Junctoriae were found to be Botrytis and Sclerotinia, with Ciborinia being the closest taxon group to the Disjunctoriae. There is evidence of an increased rate of ssrRNA evolution in the lineage of species that attack ericaceous berries. PMID- 21708622 TI - Decline of photosynthetic capacity with leaf age in relation to leaf longevities for five tropical canopy tree species. AB - The effect of leaf aging on photosynthetic capacities was examined for upper canopy leaves of five tropical tree species in a seasonally dry forest in Panama. These species varied in mean leaf longevity between 174 and 315 d, and in maximum leaf life span between 304 and 679 d. The light-saturated CO2 exchange rates of leaves produced during the primary annual leaf flush measured at 7-8 mo of age were 33-65% of the rates measured at 1-2 mo of age for species with leaf life span of < 1 yr. The negative regression slopes of photosynthetic capacity against leaf age were steeper for species with shorter maximum leaf longevity. In all species, regression slopes were less steep than the slopes predicted by assuming a linear decline toward the maximum leaf age (20-80% of the predicted decline rate). Maximum oxygen evolution rates and leaf nitrogen content declined faster with age for species with shorter leaf life spans. Statistical significance of regression slopes of oxygen evolution rates against leaf age was strongest on a leaf mass basis (r = 0.49-0.87), followed by leaf nitrogen basis (r = 0.48-0.77), and weakest on a leaf area basis (r = 0.35-0.70). PMID- 21708623 TI - The effects of herbivory on neighbor interactions along a coastal marsh gradient. AB - Many current theories of community function are based on the assumption that disturbances such as herbivory act to reduce the importance of neighbor interactions among plants. In this study, we examined the effects of herbivory (primarily by nutria, Myocastor coypus) on neighbor interactions between three dominant grasses in three coastal marsh communities, fresh, oligohaline, and mesohaline. The grasses studied were Panicum virgatum, Spartina patens, and Spartina alterniflora, which are dominant species in the fresh, oligohaline, and mesohaline marshes, respectively. Additive mixtures and monocultures of transplants were used in conjunction with exclosure fences to determine the impact of herbivory on neighbor interactions in the different marsh types. Herbivory had a strong effect on all three species and was important in all three marshes. In the absence of herbivores, the impact of neighbors was significant for two of the species (Panicum virgatum and Spartina patens) and varied considerably between environments, with competition intensifying for Panicum virgatum and decreasing for Spartina patens with increasing salinity. Indications of positive neighbor effects (mutualisms) were observed for both of these species, though in contrasting habitats and to differing degrees. In the presence of herbivores, however, competitive and positive effects were eliminated. Overall, then, it was observed that in this case, intense herbivory was able to override other biotic interactions such as competition and mutualism, which were not detectable in the presence of herbivores. PMID- 21708624 TI - Substrate water potential constraints on germination of the strangler fig Ficus aurea (Moraceae). AB - Palms are the most common support hosts for strangler fig (Ficus aurea) in the tropical dry forest. At Hummingbird Cay Tropical Field Station in the Bahamas, viable F. aurea seeds scattered on open soil germinate within 6 d in the laboratory at 27C in light or darkness. To test the hypothesis that water relations between seed and substrate can restrict the site of F. aurea establishment, fig seeds were imbibed in mannitol solutions with water potential (psi) from 0 MPa to -2.0 MPa. At psi > -1.0 MPa, germination ranges from 70 to 90%. Below -1.0 MPa, germination drops under 4%. Seedling growth rate slows linearly with decreasing psi, due to reduced cell enlargement in the radicle. Sensitivity of F. aurea seeds to psi stress is similar to that of mesophytic crops with "threshold'' psi of -1.2 to -1.5 MPa, below which germination and/or seedling growth stops. F. aurea shows no evidence of xerophytic adaptation in germination physiology. In the field, psi of humus in palm leaf bases does not drop below -1.0 to -1.1 MPa, while humus in terrestrial sites reaches psi F. aurea germination and seedling growth is met by humus in palm leaf bases, not by terrestrial sites. In dry forests, this restricts F. aurea establishment to the crown of palm trees. PMID- 21708625 TI - Organogenesis of Fascicled ear mutant inflorescences in maize (Poaceae). AB - The ontogeny of staminate tassels and pistillate ears in the maize mutant Fascicled ear was examined using scanning electron microscopy. The normal pattern of inflorescence development is perturbed by the Fascicled ear mutation at the transition stage. The Fascicled ear mutation promotes the development of an abnormal transition stage axis that is both shorter and broader than the wild type. The inflorescence apical meristem then undergoes a bifurcation, and two inflorescence axes arise in place of a single axis. Each derived inflorescence apical meristem may undergo a similar perturbation sequence. This expression of the Fascicled ear mutation may be repeated one to several times, which leads to the development of a fascicled pistillate inflorescence and a fascicled central spike in the staminate inflorescence. The apical meristems of some tassel branches are also bifurcated. Subsequent organogenesis during paired-spikelet and floral development in Fascicled ear plants follows the pattern of normal maize. However, triplet spikelets are occasionally observed. The organogenic disruption by the Fascicled ear mutation that we describe will aid genetic and molecular analysis on the regulation of inflorescence development in maize and other members of the genus Zea. PMID- 21708626 TI - The role of the epidermis as a stiffening agent in Tulipa (Liliaceae) stems. AB - We investigated the hypothesis that the epidermis is a tension-stressed "skin'' whose contribution to stem stiffness depends on the turgor pressure exerted on it by an hydrostatically inflated inner "core'' of tissues. This hypothesis was tested by relying on the intensities of bending stresses due to stem flexure, which must reach their maximum levels at the outer surface of epidermis such that damage to the surface of the stem should produce the most significant decrease in overall flexural stiffness. We discerned whether the principal tension supporting members at the stem surface (cellulosic microfibrils) were oriented parallel or normal to stem length by comparing the bending stiffness of stems before and after their surface cells first received three parallel longitudinal incisions followed by one helical incision, and by comparing the bending stiffness of stems for which the sequence of cuts was reversed. The same protocol was also applied to stems with various water potentials to determine the effect of hydrostatic pressure on stem stiffness contributed by the surface. Based on the behavior of 82 turgid Tulipa stems, parallel cuts reduced, on average, stem stiffness by 8%, whereas a subsequent helical incision further reduced stiffness by 42%. In contrast, an initial helical incision reduced stem stiffness by 50%, while three subsequent parallel cuts through the same stems did not significantly further reduce stiffness. These results suggested that the net orientation of cellulose microfibrils in the outer epidermal walls was parallel to stem length. This was confirmed by microscopic observations of cells with dichroic staining and polarized light. The responses to surgical damage were directly proportional to stem water potential. We thus conclude that the epidermis, probably in conjunction with a single layer of subepidermal collenchyma cells, acts as a tension-stiffening agent that can contribute as much as 50% to overall stem stiffness We present a simple mechanical model that can account for all our observations. PMID- 21708627 TI - Preferential exclusion of hybrids in mixed pollinations between oilseed rape (Brassica napus) and weedy B. campestris (Brassicaceae). AB - In most experimental hybridizations between oilseed rape (Brassica napus) and weedy B. campestris, either intra- or interspecific pollen has been applied to individual flowers. Under field conditions, however, stigmas will often receive a mixture of the two types of pollen, thereby allowing for competition between male gametophytes and/or seeds within pods. To test whether competition influences the success of hybridization, pollen from the two species was mixed in different proportions and applied to stigmas of both species. The resulting seeds were scored for paternity by isozyme and randomly amplified polymorphic DNA analysis. Using data on the proportion of fully developed seeds and the proportion of these seeds that were hybrids, a statistical model was constructed to estimate the fitness of conspecific and heterospecific pollen and the survival of conspecific and heterospecific zygotes to seeds. B. campestris pollen in B. napus styles had a significantly lower fitness than the conspecific pollen, whereas no difference between pollen types was found in B. campestris styles. Hybrid zygotes survived to significantly lower proportions than conspecific zygotes in both species, with the lowest survival of hybrid zygotes in B. napus pods. This is in contrast to the higher survival of hybrid seeds in B. napus than in B. campestris pods when pollinations are made with pure pollen. Altogether, the likelihood of a foreign pollen grain producing a seed was much lower on B. napus than on B. campestris. In addition, pods on B. napus developed to a lower extent the more heterospecific pollen was in the mix, whereas this had no effect on B. campestris. PMID- 21708628 TI - Competition and the compensatory regulation of fruit and seed set in the perennial herb Epilobium dodonaei (Onagraceae). AB - I studied the effects of competition and soil fertilization on variation of seed yield components of the outcrossing perennial Epilobium dodonaei Vill. using a randomized complete block design. Fertilization as a main effect was not significant. Competition, however, reduced the number of flower buds per shoot ( 29%), the number of ovules per fruit (-12%), and the number of ripe fruits per shoot (-51%). In addition, competition caused an increase in abortion of flower buds. Consequently the fruit/flower bud ratio decreased from 0.71 to 0.47. Average seed mass was not reduced significantly by competition. Some of the negative effects of competition on fruit production were mitigated by fertilization. However, competition considerably reduced the proportion of late aborted seeds, which resulted in an increase of the seed/ovule ratio from 0.31 to 0.49 (+58%). As a consequence of this compensation, the reduction in the number of seeds per shoot due to competition was not significant. At the level of the genet, competition had a strong effect on seed yield due to decreases in the number of shoots produced. I discuss patterns of regulation at consecutive levels of reproduction. Shoots of plants suffering from competition initially invested less in reproductive structures than the control and showed a higher abortion rate of less costly structures early in reproductive development, but also had a lower abortion rate later in their development. The observed compensatory pattern in yield components illustrates the fine-tuning regulation capacity at different levels of reproductive development in plants. PMID- 21708629 TI - Reproductive effort and floral photosynthesis in Spiranthes cernua (Orchidaceae). AB - This study examined the cost of reproduction and photosynthetic characteristics of the reproductive structures of Spiranthes cernua, an agamospermic, terrestrial orchid. Reproduction was frequent: two-thirds of the plants flowered at least 2 yr in a row and one-fourth of the consecutive-year runs were ~3 yr. Neither a significant decrease in leaf area nor a reduced likelihood of flowering was observed following 1 or 2 yr of inflorescence production. While there was a tendency for plants producing >16 flowers to have decreased size the next year, plants with the greatest number of flowers (31+) were the most likely to reproduce. Leaf and reproductive gas exchange were measured in the field. Low but positive rates of net photosynthesis were documented at all stages of inflorescence development. The average rates of photosynthesis for each stage were: leaves, 9.2 mmol CO2/m2s; inflorescence in bud, 3.7 mmol CO2/m2s; inflorescence in flower, 2.5 mmol CO2/m2s and infructescence, 0.2 mmol CO2/m2s. Based on diurnal gas exchange, the contribution of leaves and reproductive structures to seasonal carbon assimilation was 91.6 and 8.4%, respectively. The role of the inflorescence as a source and sink for carbon assimilation may lower the cost of reproduction and support frequent inflorescence production. PMID- 21708630 TI - Genetic and cytological analyses of a partial-female-sterile mutant (PS-1) in soybean (Glycine max; Leguminosae). AB - Soybean partial-female-sterile mutant 1 (PS-1) was recovered from a gene-tagging study. The objectives were to study the inheritance, linkage, allelism, and certain aspects of the reproductive biology of the PS-1 mutant. For inheritance and linkage tests, PS-1 was crossed to flower color mutant Harosoy-w4 and to chlorophyll-deficient mutant CD-1, also recovered from the gene-tagging study. For allelism tests, reciprocal crosses were made with PS-1 and three other partial-sterile mutants (PS-2, PS-3, and PS-4) recovered from the same gene tagging study. The PS-1 mutant is inherited in a 3:1 ratio and is a single recessive gene. Linkage results indicated that the gene for partial sterility in PS-1 is not linked either to the w4 locus or to the CD-1 locus. Allelism tests showed that the gene in PS-1 is nonallelic to the gene in PS-2, PS-3, and PS-4. Investigations of developing and mature pollen indicated no differences in morphology, stainability, or fluorescence between normal and partial-sterile genotypes. The PS-1 mutant is completely male fertile. Confocal scanning laser microscopy was used to determine that early embryo abortion in PS-1 is due indirectly to abnormal migration of the fused polar nucleus, which prevented it from being fertilized. Subsequent absence of endosperm development leads directly to abortion of the proembryo. PMID- 21708631 TI - Desiccation-time limits of photosynthetic recovery in Equisetum hyemale (Equisetaceae) spores. AB - The chlorophyllous spores of Equisetum survive desiccation, yet cannot tolerate this quiescent state for more than ~2 wk. The hypothesis that spore viability of Equisetum hyemale L. is limited by inhibition of photosynthetic recovery was tested using chlorophyll a fluorescence and oxygen-exchange analyses. Experimental spores were desiccated at 2% relative humidity and 25C for time periods of 24 h, 1 wk, and 2 wk, and then rehydrated at 200 mmol photons/m2s (PAR) and 25C for up to 24 h. Spores desiccated for 24 h recovered photosynthetic competence very rapidly during rehydration, reaching the O2 compensation point in 6.3 ~ 0.3 (mean +/- SE) min. Recovery of photosynthetic performance of spores desiccated for 1 wk was slower, as judged by significantly slower increases of (1) photochemical efficiency of photosystem (PS) II, (2) PS II quinoneB-reducing center concentration, (3) quinoneB concentration, (4) water-oxidation activity, (5) rate of light-induced O2 evolution, and (6) apparent quantum yield of net O2 exchange. Photosystem-II and whole-spore photosynthetic competence of 2-wk desiccated spores was increasingly impaired, and did not recover during rehydration. Origin fluorescence yield and dark respiration were not affected by desiccation time following rehydration. The results suggest that the extremely short viability of disseminated spores of Equisetum hyemale is due to the inability to recover losses of water oxidation and photosystem II-core function following 2 wk of desiccation. PMID- 21708632 TI - The fossil record of Eucommia (Eucommiaceae) in North America. AB - Reproductive and vegetative remains of Eucommia from 25 localities in the United States, Canada, and Mexico document the wide distribution of this genus in North America during the Cenozoic. Autofluorescent elastic latex filaments bearing capitate termini are preserved in nearly all of the remains and provide conclusive evidence of their affinity to Eucommia. Four species of Eucommia are recognized on the basis of the characteristic samaras: E. eocenica from middle Eocene strata of the Mississippi Embayment in Missouri, Tennessee and Mississippi; E. montana from early Eocene to early Oligocene localities in British Columbia, Washington, Oregon, Utah, Colorado, and Montana; E. constans from Neogene rocks in central Mexico; and E. jeffersonensis n. sp. from the latest Eocene or earliest Oligocene John Day Formation of Oregon. Atypical specimens of E. montana and E. eocenica are the first records of two-seeded fruits for the genus. Eucommia leaves from Eocene localities in British Columbia and Mississippi are the first records of Eucommia foliage in North America whose identifications are confirmed by the presence of capitate latex strands. These leaves and a specimen from Oregon are referred to E. rolandii n. sp. Fruit evolution in Eucommia may have involved increases in samara size and symmetry, and reduction in seed number from two to one, perhaps as adaptations for wind dispersal. All fossil Eucommia samaras from North America are smaller and less symmetrical than those of the living species, E. ulmoides. Preliminary flight tests of E. ulmoides samaras and of models of the fossils suggest that E. ulmoides fruits are aerodynamically better suited for wind dispersal than the fossils. PMID- 21708633 TI - Presence of paratracheal water storage tissue does not alter vessel characters in cactus wood. AB - This research tested hypotheses that the presence of water storage tissues immediately adjacent to vessels would protect vessels from cavitation and would result in evolution of broader vessels that occur in fewer, smaller clusters relative to vessels surrounded by a matrix of fibers. We examined 21 species that have dimorphic wood, that is, at one stage in their life they produce a wood with a fibrous matrix surrounding the vessels and at another stage they produce wood with abundant paratracheal parenchyma or wide-band tracheids. In only one species were vessels in the water storage matrix broader than those in the fibrous matrix of the same plant. In most specimens, fibrous wood had smaller clusters of vessels than water storage wood, and a greater percentage of vessels in fibrous wood were solitary. Presence of abundant paratracheal water storage tissue was not correlated with a reduced number or size of rays. Axial masses in fibrous wood were not consistently narrower than those of water storage wood, consequently their vessels were not consistently closer to water stored in rays. Wood strength may be more important than conduction safety in determining vessel cluster size and widths of rays and axial masses. PMID- 21708634 TI - Effects of virus infection and growth irradiance on fitness components and photosynthetic properties of Eupatorium makinoi (Compositae). AB - We examined the effects of geminivirus infection on fitness components and on photosynthetic properties of the host plant, Eupatorium makinoi, grown at two irradiance levels in a natural-light greenhouse. Under the low-light condition (13% full sunlight), more than a half of the infected plants died during the 9-mo experiment, while most of uninfected plants survived. Growth rate was also lowered by infection. At high light (50% full sunlight), by contrast, virus infection did not cause mortality despite slight decrease in growth rate. Flowering occurred only at high light, and reproductive outputs of the plants were markedly reduced by the infection. Infected leaves had distinct yellow variegations and, when compared with uninfected leaves, they showed (1) comparable light-saturated photosynthetic rate per unit area, but (2) lower initial slope of light-response curve of photosynthesis on an incident irradiance basis. The lower initial slope was mainly due to reduction of light-harvesting chlorophyll-protein complexes in the variegated parts. Since the differences in plant performance, depending both on infection and on growth irradiance, were largely explained by the differences in growth rate and/or plant size, the reduced photosynthetic production in the infected plants would be a major factor explaining the inferior performance of the host plants. PMID- 21708635 TI - The matK gene: sequence variation and application in plant systematics. AB - Although the matK gene has been used in addressing systematic questions in four families, its potential application to plant systematics above the family level has not been investigated. This paper examines the rates, patterns, and types of nucleotide substitutions in the gene and addresses its utility in constructing phylogenies above the family level. Eleven complete sequences from the GenBank representing seed plants and liverworts and nine partial sequences generated for genera representing the monocot families Poaceae, Joinvilleaceae, Cyperaceae, and Smilacaceae were analyzed. The study underscored the high rate of substitution in the gene and the presence of mutationally conserved sectors. The use of different sectors of the gene and the cumulative inclusion of informative sites showed that the 3' region was most useful in resolving phylogeny, and that the topology and robustness of the tree reached a plateau after the inclusion of 100 informative sites from that region for the taxa used. The impact of using partial sequencing on sample size is addressed. The presence of a relatively conserved 3' region and the less conserved 5' region provides two sets of characters that can be used at different taxonomic levels from the tribal to the division levels. PMID- 21708636 TI - Molecular systematics and a revised taxonomy of the onocleoid ferns (Dryopteridaceae: Onocleeae). AB - Nucleotide sequences of the chloroplast-encoded rbcL gene were determined for all five species of the onocleoid ferns (Dryopteridaceae tribe Onocleeae), including both varieties of Onoclea sensibilis, and for outgroup member Blechnum glandulosum. Together with GenBank sequences of three additional onocleoid accessions and four additional taxa representing the outgroup Blechnaceae, these were analyzed cladistically under the optimality criteria of maximum parsimony and maximum likelihood. Maximum parsimony yielded a single most-parsimonious tree with the three accessions of Onoclea sensibilis var. sensibilis left as an unresolved trichotomy. Maximum likelihood yielded a single set of three optimal trees whose only topological variation was in the trivial positioning of the three accessions of Onoclea sensibilis var. sensibilis relative to each other. Thus tree topologies of the onocleoid ingroup under maximum parsimony and maximum likelihood were completely congruent. Matteuccia orientalis and M. intermedia formed the basalmost ingroup clade strongly separated from the remaining taxa and sister to them. Onoclea sensibilis is strongly separated from its sister clade of Matteuccia struthiopteris plus Onocleopsis hintonii, and the two varieties of Onoclea sensibilis are well differentiated from each other. Matteuccia struthiopteris and Onocleopsis hintonii form the least strongly supported clade. Levels of sequence divergence among onocleoid taxa are compared with values from other taxa, and morphological and chromosomal data used in previous, noncladistic studies of the onocleoids are reevaluated in light of this rbcL phylogeny. Matteuccia orientalis and M. intermedia should be recognized in their own genus Pentarhizidium, and the previously recognized varieties of Onoclea sensibilis are supported at least at varietal rank and possibly at the rank of species. Molecular and morphological data bearing on the circumscriptions of Matteuccia and Onocleopsis are equivocal but perhaps most concordant with their continued recognition as monotypic genera. PMID- 21708637 TI - The embryology and systematic relationships of Prionium serratum (Juncaceae: Juncales). AB - Although Prionium is included in Juncaceae, rbcL sequence data indicate that Juncaceae is paraphyletic, with most genera closer to Cyperaceae than to Prionium. Cyperaceae and Juncales have embryological synapomorphies: thus embryology is used to test the monophyly of Juncaceae. The embryology of Prionium is described and its systematic position discussed. Material was prepared using standard methods of paraffin embedding. Additional embryological data were extracted from the literature. The anther in Prionium is tetrasporangiate, and the wall has an epidermis, an endothecium and middle layer, and an irregularly bilayered, glandular secretory tapetum. Microsporogenesis is probably simultaneous; pollen is ulcerate with a granular exine, in tetrahedral and cross tetrads, and trinucleate at release. The trilocular ovary contains many crassinucellate ovules probably having a Polygonum-type embryo sac. Endosperm is helobial and the embryo is of the Onagrad type, Juncus variation. The seed is testal-tegmic and germination is epigeal. The embryology of Prionium is most like that of Juncaceae, which shares several synapomorphies with Cyperaceae. Some of the characters in Cyperaceae may be interpreted as specialized forms of those found in Juncaceae. Embryology supports the monophyly of Cyperaceae and Juncales, but not Juncaceae; thus the position of Prionium remains unresolved. PMID- 21708638 TI - Studies in Annonaceae. XXVIII. Macromorphological variation of recent invaders in northern Central America: the case of Malmea (Annonaceae). AB - Cluster analysis is used to reveal patterns of macromorphological variation in a species complex of Malmea (Annonaceae) distributed in eastern Mexico, Guatemala, Belize, and Honduras. Of 53 characters, 24 are important for the clustering of 238 herbarium specimens into 12 clusters. No cluster is exclusively specified by any character or combination of characters. Neither can any geographical pattern be detected, except for the clustering of specimens from Los Tuxtlas Tropical Biological Station, Veracruz. A new subspecies from this area, M. depressa subsp. abscondita, is described. Malmea gaumeri and M. leiophylla are brought into synonymy with M. depressa. Distribution patterns of Mexican and Central American taxa of Malmea are largely concordant with those of South American taxa, which spread into Cental America after the Pliocene closure of the Isthmus of Panama. A phytogeographical novelty is presented, however, as the distribution of M. depressa subsp. abscondita within the Sierra de los Tuxtlas shows an hitherto unknown pattern: the new subspecies is distributed only on the northeastern slopes of this mountain range, and is geographically separated from M. depressa subsp. depressa, which occurs only on the southwestern slopes. PMID- 21708639 TI - Is Ginkgo biloba (Ginkgoaceae) really an oviparous plant? AB - Germination of Ginkgo biloba seeds with intact and removed sarcotesta was compared to test the role of the seed coat in germination biology. The presence of an intact sarcotesta significantly reduced total germination percentage when compared to seeds with the sarcotesta removed. Some seeds were also cold stratified. This treatment was not necessary for germination, but it did improve total germination percentage. The seeds were collected during the period of natural abscission. Contrary to the accepted literature, we found that Ginkgo seeds contain well-developed embryos at the time of dispersal. These data demonstrate that the seed coat contributes to winter dormancy of G. biloba, and that the phenology of this species is less primitive than popularly believed. PMID- 21708640 TI - The Maryland mammoth allele reduces floral stimulus activity in stem piece explants of Nicotiana tabacum (Solanaceae). AB - The response of axillary buds to floral stimulus activity in stem pieces was examined in two near-isogenic cultivars of tobacco that differ in the recessive maryland mammoth (mm) allele, which confers short-day behavior. All axillary buds from day-neutral plants assayed on six-internode stem pieces made few nodes (less than 20) before flowering, while axillary buds from plants homozygous for mm assayed on six-internode stem pieces either did not flower in noninductive conditions or made many nodes before flowering in inductive conditions. About 80% of day-neutral axillary buds grafted onto day-neutral stem pieces did not respond to floral stimulus in stem pieces, indicating that the floral stimulus in stem pieces is ephemeral. In other graft combinations, the proportion of axillary buds that did respond to floral stimulus in stem pieces was substantially reduced from the 20% of day-neutral buds on day-neutral stem pieces that responded. These results indicate that the mm allele probably reduces both the amount of floral stimulus activity in stem pieces and the competence of axillary buds to respond. PMID- 21708641 TI - Frequency and direction of hybridization in sympatric populations of Pinus taeda and P. echinata (Pinaceae). AB - Two naturally occurring, sympatric, northern Georgia populations of Pinus taeda L. (loblolly pine) and P. echinata Mill. (shortleaf pine) were examined with respect to genetic diversity within populations and the frequency, spatial distribution, and morphology of putative hybrids. Shortleaf pine predominated at the "road" site while loblolly pine predominated at the "granite outcrop" site. Hybrid individuals were identified by their IDH allozyme genotype, the only such locus known to be fixed for different alleles in the two species. All allozymatically detectable hybrids (34 at the road site and two at the granite outcrop site) were juveniles that were distributed in open, sunny patches. A similar pattern of recruitment was seen for juveniles of the parental species. Hybrids were spatially distant from mature shortleaf pine, suggesting that shortleaf pine was not the seed parent. Discriminant analysis on needle characteristics indicated that loblolly pine was easily distinguished from shortleaf pine and the hybrids, but that shortleaf pine and the hybrids were barely distinguishable from each other. A diagnostic cpDNA restriction site marker indicated that shortleaf pine sired all the hybrids at both sites. No evidence of later generation hybridization was found. PMID- 21708642 TI - Ontogenetic phenotypic plasticity during the reproductive phase in Arabidopsis thaliana (Brassicaceae). AB - While phenotypic plasticity has been the focus of much research and debate in the recent ecological and evolutionary literature, the developmental nature of the phenomenon has been mostly overlooked. A developmental perspective must ultimately be an integral part of our understanding of how organisms cope with heterogeneous environments. In this paper I use the rapid cycling Arabidopsis thaliana to address the following questions concerning developmental plasticity. (1) Are there genetic and/or environmental differences in parameters describing ontogenetic trajectories? (2) Is ontogenetic variation produced by differences in genotypes and/or environments for two crucial traits of the reproductive phase of the life cycle, stem elongation and flower production? (3) Is there ontogenetic variability for the correlation between the two characters? I found genetic variation, plasticity, and variation for plasticity affecting at least some of the growth parameters, indicating potential for evolution via heterochronic shifts in ontogenetic trajectories. Within-population differences among families are determined before the onset of the reproductive phase, while among-population variation is the result of divergence during the reproductive phase of the ontogeny. Finally, the ontogenetic profiles of character correlations are very distinct between the ecologically meaningful categories of early- and late flowering "ecotypes" in this species, and show susceptibility to environmental change. PMID- 21708643 TI - Hybridization and introgression in Carpobrotus spp. (Aizoaceae) in California. I. Morphological evidence. AB - Individuals of the invasive non-native plant species Carpobrotus edulis, its native or naturalized congener C. chilensis, and putative hybrids are found throughout coastal California. This study characterized morphological variation within the genus and assessed the extent of hybridization and direction of introgression between C. edulis and C. chilensis. Twelve randomly selected Carpobrotus individuals from each of 49 sample locations were classified as "C. edulis," "C. chilensis," or one of three intermediate morphotype classes, and compared for clonal, vegetative, and fruit characters. Univariate comparisons showed that C. edulis individuals had deeper mats with more cover within the mat boundary, longer, wider, more serrate leaves, and wider fruits with more carpels than intermediate and C. chilensis morphotype classes. Carpobrotus edulis and intermediates had more lateral branches than did C. chilensis, suggesting that hybrids tend to vary toward C. edulis. Discriminant function analysis (DFA) identified the following characters as discriminating significantly among Carpobrotus groups: leaf length, leaf width, leaf length/width, number of lateral branches, number of carpels, and fruit diameter. Using these characters, DFA correctly classified 98% of apparently pure C. edulis and C. chilensis, but only 76% of all Carpobrotus individuals when putative hybrids were included. Principal components analysis showed that C. edulis and C. chilensis cluster into distinct morphotypes, but that hybrids overlap with both groups, particularly with C. edulis. The genus Carpobrotus in California resembles a large hybrid swarm, with putative hybrids forming a large portion of the overall population and tending to vary toward C. edulis. PMID- 21708644 TI - Hybridization and introgression in Carpobrotus spp. (Aizoaceae) in California. II. Allozyme evidence. AB - Morphological evidence has indicated that hybridization and introgression are occurring between Carpobrotus edulis L., a nonindigenous, invasive species in California (Bolus), and its putative native congener, C. chilensis. The identification of allozyme markers has enabled us to quantify hybridization and the extent of introgression between these species. Samples from 20 individuals of each of five morphological types (both parent species and three hybrid phenotypes) were collected from 39 populations along the coast of California from the Mexico to Oregon borders. Ten enzyme systems revealed a total of 17 resolvable loci, eight of which were polymorphic for the genus. Five of the polymorphic loci easily differentiate C. edulis and C. chilensis. Allele frequencies among the morphologically defined types are consistent with estimations of allele frequency changes due to first- and second-generation backcrossing. In comparison to long-lived, herbaceous perennials and widespread species, C. edulis and intermediate types have more variation in their populations (P = 41.73, Ap = 2.11, Ho = 0.246, and P = 38.13, Ap = 2.06, Ho = 0.216, respectively) than C. chilensis (P = 11.76, Ap = 2.00, Ho = 0.082). Indirect estimates of gene flow indicate four of the five morphological types are outcrossing. Gene flow between previously allopatric species may have broad implications if it results in an increase in fitness; further experimentation is needed to determine the ultimate ecological consequences of this phenomenon and its possible threat to limited, remaining natural habitat in California. PMID- 21708645 TI - Self-incompatibility RNases from three plant families: homology or convergence? AB - In the Rosaceae, Scrophulariaceae, and Solanaceae, the stylar product of the self incompatibility (S-) locus is an RNase. Using protein sequence data from 34 RNase genes (three fungal RNases, seven angiosperm non-S RNases, 11 Rosaceae S-alleles, three Scrophulariaceae S-alleles, and ten Solanaceae S-alleles) we reconstructed the genealogy of angiosperm RNases using the neighbor joining method and two distance metrics in order to assess whether use of S-RNases in these families is the result of homology or convergence. Four monophyletic groups of angiosperm RNases were found: the S-RNases of each of the three families and a group comprising most of the angiosperm non-S RNases. The S-RNases of the Scrophulariaceae and Solanaceae were found to be homologous but strong inference concerning the homology or convergence of S-RNases from the Rosaceae with those of the other families was not possible because of uncertain placement of both the root and two of the angiosperm non-S RNases. The most recent common ancestor of the Rosaceae and both the Scrophulariaceae and Solanaceae is shared by ~80% of dicot families. If the -RNases of the Rosaceae are homologous to those of the Scrophulariaceae and Solanaceae, then many other dicot families might be expected to share RNases as the mechanism of gametophytic self-incompatibility. PMID- 21708646 TI - Comparative pollination biology of Venezuelan columnar cacti and the role of nectar-feeding bats in their sexual reproduction. AB - The floral biology, reproductive system, and visitation behavior of pollinators of four species of columnar cacti, Stenocereus griseus, Pilosocereus moritzianus, Subpilocereus repandus, and Subpilocereus horrispinus, were studied in two arid zones in the north of Venezuela. Our results support the hypothesis that Venezuelan species of columnar cacti have evolved toward specialization on bat pollination. Additional information on the floral biology of a fifth species, Pilosocereus lanuginosus, was also included. All species showed the typical traits that characterize the pollination syndrome of chiropterophily. All species but Pilosocereus moritzianus were obligate outcrossers. Nectar and pollen were restricted to nocturnal floral visitors. Two species of nectar-feeding bats, Leptonycteris curasoae Miller and Glossophaga longirostris Miller, were responsible for practically all the fruit set in these cacti. Frequency of bat visitation per flower per night was highly variable within and between species of cactus, with average frequencies varying between 27 and 78 visits/flower/night. In general terms, the pattern of floral visitation through the night was significantly correlated with the pattern of nectar production and nectar sugar concentration for all species of cactus. Under natural pollination, fruit:flower ratios varied from 0.46 in Subpilocereus repandus to 0.76 in Stenocereus griseus. The efficiency of bat pollination in terms of seed:ovule ratio was high in all species, varying between 0.70 and 0.94. PMID- 21708647 TI - Climate influences on growth and reproduction of Pinus banksiana (Pinaceae) at the limit of the species distribution in eastern North America. AB - The presence of conflicts in the allocation of resources among the different functions of an organism is a fundamental postulate of modern ecology. It is assumed that reproduction occurs at a cost because it monopolizes resources that could be used for other functions (e.g., growth). These conflicts may be particularly evident under stressful conditions, such as under low water or nutrient availability, or under severe climatic conditions. There we may expect to find strong negative relationships between an organism's growth and reproduction. We studied a population of Pinus banksiana (Pinaceae) at the northern limit of the species distribution, in subarctic Québec (Canada) where Pinus banksiana occupies nutrient-poor, sandy terraces along the Great Whale river. Serotinous cones of Pinus banksiana produced between 1969 and 1992 were sampled to estimate interannual variations in several variables representing reproduction, and to relate these to climate and tree growth. Climate appears to influence each developmental stage involved in the production of viable seeds, from the time of cone initiation to that of seed maturation. In general, reproductive variables are positively related to high temperatures during the three growing seasons required for seed production; growth is also positively correlated to summer temperatures. Consequently, investment in maturing seeds is positively associated with growth. Thus, both reproduction and growth covary with climate: during relatively warm and long growing seasons, resource allocation to both functions increases. Under these conditions, no trade-off is apparent. PMID- 21708648 TI - Effects of fire on sandhill herbs: nutrients, mycorrhizae, and biomass allocation. AB - Differences in growth responses, tissue and soil inorganic nutrients, and mycorrhizal relationships of four herbaceous species were studied on burned and unburned sandhill sites in south-central Florida, USA. Three species, (Aristida stricta, Liatris tenuifolia var. laevigata, and Pityopsis graminifolia) responded positively to conditions following the burn by increased vegetative growth and flowering. The fourth species, Balduina angustifolia, is a fire-sensitive biennial and its first-year rosettes were, with an occasional exception, unable to survive or resprout following fire. Availability of all soil inorganic nutrients examined (Ca, K, Mg, and P) was low, as were total nitrogen, soil organic matter, and pH. There was a slight nutrient pulse of phosphorus into the soil following burning. For two species (Aristida and Liatris), shoot tissue concentrations of several inorganic nutrients (especially N and P) were higher on the burned site than the unburned site following burning. These differences generally dissipated over time since burning. The high concentration of tissue nutrients postburn followed by a decline on the burned site may result from rapid nutrient uptake after fire and dilution of this concentration following restoration of plant mass. Despite low levels of soil inorganic nutrients, including phosphorus, mycotrophy was absent or weakly developed among the herbaceous species examined, except for the tap-rooted Balduina angustifolia. Colonization of host plants by vesicular mycorrhizal fungi was unaffected by burning. Mycorrhizal inoculum potentials of sandhill soil were extremely low, varying seasonally from (mean +/- 1 SE) 0.3 +/- 0.2 to 3.8 +/- 0.7%. PMID- 21708649 TI - Root distribution and seasonal production in the northwestern Sonoran Desert for a C3 subshrub, a C4 bunchgrass, and a CAM leaf succulent. AB - To investigate root distribution with depth, which can affect competition for water, surface areas of young and old roots were determined in 4-cm-thick soil layers for the C3 subshrub Encelia farinosa Torrey and A. Gray, the C4 bunchgrass Pleuraphis rigida Thurber, and the CAM (crassulacean acid metabolism) leaf succulent Agave deserti Engelm. At a site in the northwestern Sonoran Desert these codominant perennials had mean rooting depths of only 9-10 cm for isolated plants. Young roots had mean depths of 5-6 cm after a winter wet period, but 11 13 cm after a summer wet period. Young roots were most profuse in the winter for E. farinosa, which has the lowest optimum temperature for root growth, and in the summer for P. rigida, which has the highest optimum temperature. Roots for interspecific pairs in close proximity averaged 2-3 cm shallower for A. deserti and a similar distance deeper for the other two species compared with isolated plants, suggesting partial spatial separation of their root niches when the plants are in a competitive situation. For plants with a similar root surface area, the twofold greater leaf area and twofold higher maximal transpiration rate of E. farinosa were consistent with its higher root hydraulic conductivity, leading to a fourfold higher estimated maximal water uptake rate than for P. rigida. Continuous water uptake accounted for the shoot water loss by A. deserti, which has a high shoot water-storage capacity. A lower minimum leaf water potential for P. rigida than for A. deserti indicates greater ability to extract water from a drying soil, suggesting that temporal niche separation for water uptake also occurs. PMID- 21708650 TI - Origin and relationships of Saintpaulia (Gesneriaceae) based on ribosomal DNA internal transcribed spacer (ITS) sequences. AB - Phylogenetic relationships of eight species of Saintpaulia H. Wendl., 19 species of Streptocarpus Lindl. (representing all major growth forms within the genus), and two outgroups (Haberlea rhodopensis Friv., Chirita spadiciformis W. T. Wang) were examined using comparative nucleotide sequences from the two internal transcribed spacers (ITS) of nuclear ribosomal DNA. The length of the ITS 1 region ranged from 228 to 249 base pairs (bp) and the ITS 2 region from 196 to 245 bp. Pairwise sequence divergence across both spacers for ingroup and outgroup species ranged from 0 to 29%. Streptocarpus is not monophyletic, and Saintpaulia is nested within Streptocarpus subgenus Streptocarpella. Streptocarpus subgenus Streptocarpus is monophyletic. The ITS sequence data demonstrate that the unifoliate Streptocarpus species form a clade, and are also characterized by a unique 47-bp deletion in ITS 2. The results strongly support the monophyly of (1) Saintpaulia, and (2) Saintpaulia plus the African members of the subgenus Streptocarpella of Streptocarpus. The data suggest the evolution of Saintpaulia from Streptocarpus subgenus Streptocarpella. The differences in flower and vegetative characters are probably due to ecological adaptation leading to a relatively rapid radiation of Saintpaulia. PMID- 21708651 TI - Phylogenetic relationships of the Raphidophyceae and Xanthophyceae as inferred from nucleotide sequences of the 18S ribosomal RNA gene. AB - Some earlier studies suggested an evolutionary relationship between the Raphidophyceae (chloromonads) and Xanthophyceae (yellow-green algae), whereas other studies suggested relationships with different algal classes or the öomycete fungi. To evaluate the relationships, we determined the complete nucleotide sequences of the 18S ribosomal RNA gene from the raphidophytes Vacuolaria virescens, Chattonella subsalsa, and Heterosigma carterae, and the xanthophytes Vaucheria bursata, Botrydium stoloniferum, Botrydiopsis intercedens, and Xanthonema debile. The results showed that the Xanthophyceae were most closely related to the Phaeophyceae. A cladistic analysis of combined data sets (nucleotide sequences, ultrastructure, and pigments) suggested the Raphidophyceae are the sister taxon to the Phaeophyceae-Xanthophyceae clade, but the bootstrap value was low (40%). The raphidophyte genera were united with high (100%) bootstrap values, supporting a hypothesis based upon ultrastructural features that marine and freshwater raphidophytes form a monophyletic group. We examined the relationship between Vaucheria, a siphoneous xanthophyte alga, and the öomycetes, and we confirmed that Vaucheria is a member of the class Xanthophyceae. Partial nucleotide sequences of the 18S rRNA gene from eight xanthophytes (including Bumillariopsis filiformis, Heterococcus caespitiosus, and Mischococcus sphaerocephalus) produce a phylogeny that is not congruent with the current morphology-based classification scheme. PMID- 21708652 TI - Phylogenetic relationships of Rhododendroideae (Ericaceae). AB - The Rhododendroideae are usually recognized as a subfamily within Ericaceae. This group has been considered primitive (i.e., occupying the ancestral or basal position relative to all other Ericaceae) due to the occurrence of separate petals in several taxa, deciduous corollas, and septicidally dehiscent capsules. Previous molecular studies using rbcL and nr18s sequences have indicated that Rhododendroideae may be paraphyletic and cladistically derived (i.e., the relative position in the geneology of Ericaceae is not basal). The matK sequences of 42 taxa from traditional Rhododendroideae and potentially related clades were obtained via standard gene amplication and double-stranded dideoxy sequencing. Phylogenetic analyses of these sequences using Actinidia chinensis as the outgroup indicate that the Rhododendroideae are paraphyletic. Trees obtained in the analyses indicate an expanded rhododendroid clade that includes four major subclades - empetroid, rhodo, ericoid, and phyllodocoid. The ericoid clade is sister to the phyllodocoid clade and the empetroid clade is sister to the rhodo clade. Relationships within the clades are generally well resolved except within the rhodo clade where matK data indicate that Rhododendron is probably paraphyletic. Daboecia and Calluna are included within the ericoid clade; Erica is paraphyletic. Cassiope lies outside the rhododendroid clade. The relationships indicated by the matK data suggest that sympetalous flowers are likely plesiomorphic within rhododendroids. PMID- 21708653 TI - Fossil mushrooms from Miocene and Cretaceous ambers and the evolution of Homobasidiomycetes. AB - Two species of fossil mushrooms that are similar to extant Tricholomataceae are described from Cretaceous and Miocene ambers. Archaeomarasmius leggetti gen. et sp. nov., from mid-Cretaceous amber of New Jersey, resembles the extant genera Marasmius and Marasmiellus. Two fruiting bodies of Archaeomarasmius were found. One consists of a complete pileus with stipe, and the other consists of a fragment of a pileus. The latter was accidentally exposed, and zxsubsequently was used for molecular systematics studies (attempts to amplify ribosomal DNA were unsuccessful) and electron microscopy. The spores are smooth and broadly elliptic with a distinct hilar appendage. Protomycena electra gen. et sp. nov., which is represented by a single complete fruiting body from Miocene amber of the Dominican Republic, is similar to the extant genus Mycena. Based on comparison to extant Marasmieae and Myceneae, Archaeomarasmius and Protomycena were probably saprophytes of leaf litter or wood debris. The poor phylogenetic resolution for extant homobasidiomycetes limits the inferences about divergence times of homobasidiomycete clades that can be drawn from Archaeomarasmius and Protomycena. The ages of these fossils lend support to hypotheses that the cosmopolitan distributions of certain mushroom taxa could be due to fragmentation of ancestral ranges via continental drift. Anatomical and molecular studies have suggested that there has been extensive convergence and parallelism in the evolution of homobasidiomycete fruiting body form. Nevertheless, the striking similarity of these fossils to extant forms suggests that in certain lineages homobasidiomycete macroevolution has also involved long periods during which there has been little morphological change. PMID- 21708654 TI - A cyanolichen from the Lower Devonian Rhynie chert. AB - The 400 million-year-old Rhynie chert has provided a wealth of information about various types of fungal interactions that existed in this Early Devonian paleoecosystem. In this paper we report the first unequivocal evidence of a lichen symbiosis from the Rhynie chert. Specimens of a new genus, Winfrenatia, consist of a thallus of superimposed layers of aseptate hyphae and, on the upper surface, numerous uniform depressions. Extending into the base of each depression are hyphae that form a three-dimensional netlike structure. Enclosed within each of the net spaces is a coccoid cyanobacterium, each cell of which is surrounded by a thick sheath. These photobiont cells divide in three planes, resulting in cell clusters of up to perhaps 64 individuals. The photobiont is parasitized by the fungus in the base of each net as new cyanobacterial cells are formed distally. Reproduction is by endospores and soredia. Affinities of the mycobiont appear closest to members of the Zygomycetes, while the photobiont is most similar to coccoid cyanobacteria of the Gloeocapsa and Chroococcidiopsis types. We speculate that this cyanobacterial symbiosis was well adapted to exploit and colonize new ecological niches, especially in the periodically desiccated environment postulated for the Rhynie chert paleoecosystem. PMID- 21708655 TI - Is Phellinites digiustoi the oldest homobasidiomycete? AB - The oldest generally accepted fossil of mushroom-forming fungi (homobasidiomycetes) is Phellinites digiustoi, from the Jurassic of Patagonia. The next-oldest homobasidiomycete fossil does not occur until about 70 million years later, in the mid-Cretaceous. The goal of this project was to reassess the identity of Phellinites and refine the minimum-age estimate for the origin of homobasidiomycetes. We examined the holotype of Phellinites digiustoi and a second collection from the type locality. Thin sections were prepared from both collections. Phellinites has a cellular structure, confirming that it is biological in origin, but there are no hyphae, spores, or other fungal structures. Rather, Phellinites appears to be the outer bark (rhytidome) of a conifer. Fossils of Araucariaceae are common in the region where Phellinites was found, and so it is plausible that Phellinites is the bark of an Araucaria-like tree. The minimum age of the mushroom-forming fungi, based on direct fossil evidence, is revised to the mid-Cretaceous. PMID- 21708656 TI - BRIEF COMMUNICATION Geographic parthenogenesis in a tropical forest tree. AB - As evidenced by embryological studies, certain tropical tree species can reproduce asexually via seed; however, it has generally been assumed that such apomictic reproduction is facultative. Here I report the existence of a population of the lowland Malaysian rain forest tree Garcinia scortechinii King that consists entirely of pistillate individuals (40 female trees and no male trees recorded within a 25-ha area). This constitutes the first documented observation of a geographically segregated, obligately asexual population among wild tropical trees. Six additional Garcinia species showed a trend toward female bias relative to other dioecious tree species studied, an observation that is consistent with facultative apomixis. The more surprising result for G. scortechinii runs counter to the generalization that obligate apomicts occur only in environments in which the absence of competitors might enable persistence of taxa that lack genetic recombination through mixis. PMID- 21708657 TI - The genetic control of plastid division in higher plants. AB - The division of plastids is an important part of plastid differentiation and development and in distinct cell types, such as leaf mesophyll cells, results in large populations of chloroplasts. The morphology and population dynamics of plastid division have been well documented, but the molecular controls underlying plastid division are largely unknown. With the isolation of Arabidopsis mutants in which specific aspects of plastid and proplastid division have been disrupted, the potential exists for a detailed knowledge of how plastids divide and what factors control the rate of division in different cell types. It is likely that knowledge of plant homologues of bacterial cell division genes will be essential for understanding this process in full. The processes of plastid division and expansion appear to be mutually independent processes, which are compensatory when either division or expansion are disrupted genetically. The rate of cell expansion appears to be an important factor in initiating plastid division and several systems involving rapid cell expansion show high levels of plastid division activity. In addition, observation of plastids in different cell types in higher plants shows that cell-specific signals are also important in the overall process in determining not only the differentiation pathway of plastids but also the extent of plastid division. It appears likely that with the exploitation of molecular techniques and mutants, a detailed understanding of the molecular basis of plastid division may soon be a reality. PMID- 21708658 TI - Localization of plastid DNA replication on a nucleoid structure. AB - Plastids contain multiple copies of the plastid genome that are arranged into discrete aggregates, termed nucleoids. Nucleoid molecular organization and its possible role in ensuring genome continuity have not yet been carefully explored. We examined the relationship between plastid DNA synthesis and nucleoid cytology in the unicellular chrysophyte Ochromonas danica, which is useful for such work because the genomes in each plastid are arranged in a single ring-shaped nucleoid. Immunocytochemical detection of thymidine analog incorporation into replicating DNA revealed that plastid DNA synthesis occurs at several sites along the ring nucleoid simultaneously, and that all plastids of a single cell display similar replication patterns. Plastid DNA replication was observed in G1, S, and G2 phase cells. Pulse-chase-pulse labelling with two different thymidine analogs revealed that new sites are activated as cells progress through the cell cycle while some old sites continue. The double labelling patterns suggest that the individual genomes are arranged consecutively, either singly or in clusters, along the nucleoid perimeter and that the selection of which genome replicates when is a matter of chance. These observations eliminate a number of alternative hypotheses concerning plastid DNA organization, and suggest how cells might maintain a constancy of plastid DNA amount and why plastid genome variants segregate so rapidly during mitosis. PMID- 21708659 TI - Quantitative determination of calcium oxalate and oxalate in developing seeds of soybean (Leguminosae). AB - Developing soybean seeds accumulate very large amounts of both soluble oxalate and insoluble crystalline calcium (Ca) oxalate. Use of two methods of detection for the determination of total, soluble, and insoluble oxalate revealed that at +16 d postfertilization, the seeds were 24% dry mass of oxalate, and three fourths of this oxalate (18%) was bound Ca oxalate. During later seed development, the dry mass of oxalate decreased. Crystals were isolated from the seeds, and X-ray diffraction and polarizing microscopy identified them as Ca oxalate monohydrate. These crystals were a mixture of kinked and straight prismatics. Even though certain plant tissues are known to contain significant amounts of oxalate and Ca oxalate during certain periods of growth, the accumulation of oxalate during soybean seed development was surprising and raises interesting questions regarding its function. PMID- 21708660 TI - Comparative floral development and evolution in tribe Caesalpinieae (Leguminosae: Caesalpinioideae). Haematoxylum. AB - Floral organogenesis and development of the tropical legume trees Haematoxylum campechianum (logwood) and H. brasiletto (brazilwood) were studied using scanning electron microscopy. The aims were to compare ontogenies, and to elucidate the relationships of Haematoxylum with other genera of Caesalpinieae, the basal tribe of Caesalpinioideae. Flowers of Haematoxylum are in racemes or fascicles, lack bracteoles, and are pentamerous, hermaphroditic, and either actinomorphic or zygomorphic. Whorls arise in acropetal order except for the carpel, which arises concurrently with the outer stamens. Sepal order is bidirectional (a rare condition) within the whorl in both. Petals and outer stamens are initiated bidirectionally in H. campechianum, and unidirectionally in H. brasiletto. Inner stamens are initiated unidirectionally in both. In H. campechianum, time of petal initiation overlaps with that of outer stamens, and initiation of the two stamen whorls overlap. In both, the gynoecium becomes stipitate, and a hypanthium forms late in development. Both show many plesiomorphic states at anthesis; H. brasiletto alone shows several specialized states (expressed late in development), including a fused, gibbous calyx cup, a zygomorphic corolla, lightly aggregated filaments held together by hairs, and fenestrations in the stamen column. Ontogenetic divergence late in ontogeny characterizes differences at anthesis between related species. PMID- 21708661 TI - Concepts and terminology of apical dominance. AB - Apical dominance is the control exerted by the shoot apex over lateral bud outgrowth. The concepts and terminology associated with apical dominance as used by various plant scientists sometimes differ, which may lead to significant misconceptions. Apical dominance and its release may be divided into four developmental stages: (I) lateral bud formation, (II) imposition of inhibition on lateral bud growth, (III) release of apical dominance following decapitation, and (IV) branch shoot development. Particular emphasis is given to discriminating between Stage III, which is accompanied by initial bud outgrowth during the first few hours of release and may be promoted by cytokinin and inhibited by auxin, and Stage IV, which is accompanied by subsequent bud outgrowth occurring days or weeks after decapitation and which may be promoted by auxin and gibberellin. The importance of not interpreting data measured in Stage IV on the basis of conditions and processes occurring in Stage III is discussed as well as the correlation between degree of branching and endogenous auxin content, branching mutants, the quantification of apical dominance in various species (including Arabidopsis ), and apical control in trees. PMID- 21708662 TI - Influence of atmospheric CO2 enrichment, soil N, and water stress on needle surface wax formation in Pinus palustris (Pinaceae). AB - Interactive effects of increasing atmospheric CO2 with resource limitations on production of surface wax in plants have not been studied. Pinus palustris seedlings were grown for 1 yr at two levels of soil N (40 or 400 kg N_ha-1_yr-1) and water stress (-0.5 or -1.5 MPa xylem pressure potential) in open-top field chambers under two levels of CO2 (365 or 720 mumol/mol). Needle surface wax content was determined at 8 mo (fall) and 12 mo (spring) and epicuticular wax morphology was examined using scanning electron microscopy (SEM) at 12 mo. Wax content expressed on both a leaf area and dry mass basis was increased due to main effects of low N and water stress. No main effects of CO2 were observed; however, a CO2 x N interaction at 12 mo indicated that under low soil N the elevated CO2 treatment had less wax (surface area or dry mass basis) compared to its ambient counterpart. Morphologically, low N needle surfaces appeared rougher compared to those of high N needles due to more extensive wax ridges. Although the main effect of water treatment on wax density was not reflected by changes in wax morphology, the CO2 x N interaction was paralleled by alterations in wax appearance. Decreases in density and less prominent epicuticular wax ridges resulting from growth under elevated CO2 and limiting N suggest that dynamics of plant/atmosphere and plant/pathogen interactions may be altered. PMID- 21708663 TI - Population and genetic structure of the West African rain forest liana Ancistrocladus korupensis (Ancistrocladaceae). AB - Ancistrocladus korupensis D. W. Thomas & Gereau (Ancistrocladaceae) is a recently described liana from Cameroon. Its leaves yield the alkaloid michellamine B, which shows in vitro activity against HIV. The only known population is limited to ~15,000 ha within Korup National Park and its immediate surroundings. This study: (1) describes ecological patterns (geographic range, population density, stage and size class distributions, host tree characteristics, and seed dispersal patterns) of A. korupensis ; (2) quantifies patterns of genetic variation on species and subpopulation levels and fine-scale genetic structure; (3) describes variation in michellamine B content; and (4) makes conservation recommendations based on ecological and genetic data. Ecological data from 457 individuals from seven sites indicate that the A. korupensis population is dominated by canopy climbing individuals. Population densities are low with values ranging from 2.5 to 12.9 individuals/ha. Reproduction data suggest limited seed dispersal, episodic fruiting, and no vegetative reproduction. Allozyme data indicate low genetic diversity with only 7.1% of the 14 loci polymorphic. Values for Hobs and He were 0.022 (_ 0.000 SE) and 0.041 (_ 0.000 SE), respectively. Wright's F statistics analysis suggests that A. korupensis is highly inbred (FIS = 0.455) with moderate levels of subpopulation differentiation (FST = 0.1153). Michellamine B content was best predicted by leaf type but also showed a significant relationship for stage class. The occurrence of rare, private alleles in most of the sites, low overall population size and density, and low availability of individuals for recruitment into the adult stage class are important considerations for the rational management of A. korupensis. PMID- 21708664 TI - Nutrient sensitivity of the cost of male function in gynodioecious Phacelia linearis (Hydrophyllaceae). AB - Allocation trade-offs should be measured as opportunity costs, estimating what individuals sacrifice in one function by allocating to others. We investigated opportunity costs of male function in gynodioecious Phacelia linearis, asking whether nutrient limitation contributes to them. This hypothesis predicts that hermaphrodites experience greater nutrient stress than females, and that hermaphrodite disadvantages in production might decrease with nutrient supply. We cultivated hermaphrodites and females at two nutrient levels, scoring individuals for prereproductive leaf number at 5 wk, and biomass, nitrogen concentration, and fruit and seed production at 16 wk. Nutrient treatments caused final growth differences of two orders of magnitude. No gender difference appeared at 5 wk, but at 16 wk hermaphrodites produced less stem, leaf, and inflorescence biomass than females, and made fewer fruits. Hermaphrodites' shoot-size disadvantage was marginally significantly more severe at low nutrients than high nutrients. Significant gender x nutrient interactions for root fraction and whole-plant nitrogen concentration indicate greater nutrient stress in hermaphrodites than females. Hermaphrodites also acquired less total nitrogen than females. Nutrient limitation contributes to opportunity costs of male function, but there must be other contributors. Possibilities include limitations in other resources, gender effects on morphology, and genetic trade-offs not directly involving allocation or morphology. PMID- 21708665 TI - Submarine pollination in the marine angiosperm Zostera marina (Zosteraceae). I. The influence of floral morphology on fluid flow. AB - An understanding of the process of submarine pollination should provide insight into the evolutionary and reproductive ecology of the marine angiosperms (seagrasses). The flow around the reproductive organs of the seagrass Zostera marina L. (Potamogetonales) was, therefore, examined in a flow chamber. The phenological emergence of flowers during (1) pollen capture and (2) pollen release, and by fruit during (3) seed release, led to a reduction in flow rate toward the inflorescence. This change in flow due to floral emergence was associated with a 50% increase in the fluid shear stress [tau = (2.2 _ 0.3) x 10 3 Pa for an immature flower vs. tau = (3.1 _ 0.5) x 10-3 Pa for a receptive flower]. The Reynolds number (Re) and fluid shear stress around inflorescences and infructescences were comparable, indicating a dynamic similarity in the processes of pollen capture and fruit dehiscence [Re = 47 _ 5, tau = (1.6 _ 0.3) x 10-3 Pa for inflorescences; Re = 38 _ 5, tau = (1.3 _ 0.1) x 10-3 Pa for infructescences]. These results indicate that the emergence of reproductive organs leads to changes in fluid shear stress, which will affect the release, transport, and capture of particles including pollen. Theoretical considerations of these observations using aerosol-filtration theory suggest that pollen capture in Z. marina occurs through direct interception of pollen by stigmas. PMID- 21708666 TI - Submarine pollination in the marine angiosperm Zostera marina (Zosteraceae). II. Pollen transport in flow fields and capture by stigmas. AB - Flow chamber observations of the filamentous pollen of Zostera marina L. (Potamogetonales) revealed that pollen rotated and moved toward inflorescences where they were captured by stigmas. The mechanics of this abiotic pollination process were examined and found to be related to the flow environment around emergent flowers. The translational movement of pollen was imparted by the advection of the fluid (e.g., pollen kinetic energy, K, ranged from 0.8 x 10-14 to 2.4 x 10-14 J, and the average K of the fluid was _ 0.7 x 10-14 J), while the rotational motion was imparted by the fluid shear stress (tau) within the velocity gradient (e.g., pollen shear stress, sigmat = omegamu where omega is the rotational velocity and mu is the dynamic viscosity, ranged from 3.4 x 10-4 to 26 x 10-4 Pa, and the average fluid shear stress was tau _ 10 x 10-4 Pa; Ackerman, 1997, American Journal of Botany 84: 1099-1109). These results indicate that there is a greater potential for pollination by filamentous pollen relative to spherical pollen. Functionally, while spherical pollen needs to be directly upstream from stigmas to be captured, filamentous pollen need only be in the vicinity of inflorescences and flowers to be captured by stigmas. Thus, in addition to direct interception on stigmas, filamentous pollen can be captured while they rotate past flowers or when they are redirected through the velocity gradient towards flowers. Filamentous pollen is an adaptation to submarine pollination in seagrasses. PMID- 21708667 TI - Chloroplast DNA phylogeny, reticulate evolution, and biogeography of Paeonia (Paeoniaceae). AB - The coding region of the mat K gene and two intergenic spacers, psb A-trn H and trn L(UAA)-trn F(GAA), of cpDNA were sequenced to study phylogenetic relationships of 32 Paeonia species. In the psb A-trn H intergenic spacer, short sequences bordered by long inverted repeats have undergone inversions that are often homoplasious mutations. Insertions/deletions found in the two intergenic spacers, mostly resulting from slipped-strand mispairing, provided relatively reliable phylogenetic information. The mat K coding region, evolving more rapidly than the trnL-trn F spacer and more slowly than the psb A-trn H spacer, produced the best resolved phylogenetic tree. The mat K phylogeny was compared with the phylogeny obtained from sequences of internal transcribed spacers (ITS) of nuclear ribosomal DNA. A refined hypothesis of species phylogeny of section Paeonia was proposed by considering the discordance between the nuclear and cpDNA phylogenies to be results of hybrid speciation followed by inheritance of cpDNA of one parent and fixation of ITS sequences of another parent. The Eurasian and western North American disjunct distribution of the genus may have resulted from interrruption of the continuous distribution of ancestral populations of extant peony species across the Bering land bridge during the Miocene. Pleistocene glaciation may have played an important role in triggering extensive reticulate evolution within section Paeonia and shifting distributional ranges of both parental and hybrid species. PMID- 21708668 TI - Systematics of Nothofagus (Nothofagaceae) based on rDNA spacer sequences (ITS): taxonomic congruence with morphology and plastid sequences. AB - Phylogenetic relationships were examined within the southern beech family Nothofagaceae using 22 species representing the four currently recognized subgenera and related outgroups. Nuclear ribosomal DNA sequences encoding the 5.8s rRNA and two flanking internal transcribed spacers (ITS) provided 95 phylogenetically informative nucleotide sites from a single alignment of ~588 bases per species. Parsimony analysis of this variation produced two equally parsimonious trees supporting four monophyletic groups, which correspond to groups designated by pollen type. These topologies were compared to trees from reanalyses of previously reported rbcL sequences and a modified morphological data set. Results from parsimony analysis of the three data sets were highly congruent, with topological differences restricted to the placement of a few terminal taxa. Combined analysis of molecular and morphological data produced six equally parsimonious trees. The consensus of these trees suggests two basal clades within Nothofagus. Within the larger of the two clades, tropical Nothofagus (subgenus Brassospora) of New Guinea and New Caledonia are strongly supported as sister to cool-temperate species of South America (subgenus Nothofagus). Most of the morphological apomorphies of the cupule, fruit, and pollen of Nothofagus are distributed within this larger clade. An area cladogram based on the consensus of combined data supports three trans-Antarctic relationships, two within pollen groups and one between pollen groups. Fossil data support continuous ancestral distributions for all four pollen groups prior to continental drift; therefore, vicariance adequately explains two of these disjunctions. Extinction of trans-Antarctic sister taxa within formerly widespread pollen groups explains the third disjunction; this results in a biogeographic pattern indicative of phylogenetic relationship not vicariance. For the biogeographically informative vicariant clades, area relationships based on total evidence support the recently advanced hypothesis that New Zealand and Australia share a unique common ancestry. Contrary to previous thought, the distribution of extant Nothofagus is informative on the area relationships of the Southern Hemisphere, once precise phylogenetic relationships are placed in the context of fossil data. PMID- 21708669 TI - Chromosome evolution in the genus Mikania (Compositae). AB - Karyotypic analysis of ten species of the genus Mikania was carried out using Feulgen staining. Species belonging to the following sections were analyzed: Section Thyrsigerae containing M. additicia (2n = 34), M. hemisphaerica, M. lanuginosa, and M. punctata (2n = 36), and Mikania sericea (2n = 42), which adds a new basic chromosome number (x = 21) to the genus and to the tribe Eupatorieae; Section Corymbosae with M. hastato-cordata (2n = 34) and M. involucrata and M. microptera with 2n = 36 chromosomes; Section Spicato-Racemosae with M. sessilifolia, with 2n = 108 chromosomes. One unidentified species with 2n = 34 chromosomes was also analyzed. All the species studied show one large pair of chromosomes with a secondary constriction in the middle region of the long arm. The morphology of this chromosome suggests that it can be considered as a cytological marker for the genus. Because of the distinctive inflorescence types found in the genus Mikania and the high frequency of species with x = 18, a correlation between morphological and chromosomal evolution is discussed. The present study suggests that the basic original chromosome number for the genus is x = 18, from which the others (x = 17, 19, 20, 21) have been derived by aneuploidy to form the observed aneuploid series. PMID- 21708670 TI - An electronic device for continuous, in vivo measurement of forces exerted by twining vines. AB - Contact forces are important in maintaining the twining habit of viny stems. A stem twining around a supporting pole puts itself into tension and uses a helical geometry to generate normal loads that are large relative to stem mass per unit length (Silk and Hubbard, Journal of Biomechanics 24(7):599-606, 1991). An electronic pressure-sensing device has been constructed to provide continuous, in vivo measurements of the forces exerted by twining stems. The pressure-sensing element is based on a thin beam load cell that is sheared by a twining stem ascending a split pole. Preliminary results show that after morning glory stems begin to coil around a supporting pole, the twining force increases in an oscillatory fashion over 3 or 4 d, corresponding to positions at least 200 mm from the apex. The force-measuring device should reveal relationships between twining forces and developmental attributes or environmental factors. PMID- 21708671 TI - Comparative ultrastructure of plasmodesmata of Chara and selected bryophytes: toward an elucidation of the evolutionary origin of plant plasmodesmata. AB - We have used transmission electron microscopy to examine plasmodesmata of the charophycean green alga Chara zeylanica, and of the putatively early divergent bryophytes Monoclea gottschei (liverwort), Notothylas orbicularis (hornwort), and Sphagnum fimbriatum (moss), in an attempt to learn when seed plant plasmodesmata may have originated. The three bryophytes examined have desmotubules. In addition, Monoclea was found to have branched plasmodesmata, and plasmodesmata of Sphagnum displayed densely staining regions around the neck region, as well as ring-like wall specializations. In Chara, longitudinal sections revealed endoplasmic reticulum (ER) that sometimes appeared to be associated with plasmodesmata, but this was rare, despite abundant ER at the cell periphery. Across all three fixation methods, cross-sectional views showed an internal central structure, which in some cases appeared to be connected to the plasma membrane via spoke-like structures. Plasmodesmata were present even in the incompletely formed reticulum of forming cell plates, from which we conclude that primary plasmodesmata are formed at cytokinesis in Chara zeylanica. Based on these results it appears that plasmodesmata of Chara may be less specialized than those of seed plants, and that complex plasmodesmata probably evolved in the ancestor of land plants before extant lineages of bryophytes diverged. PMID- 21708672 TI - Arabidopsis (Brassicaceae) flower development and gynoecium patterning in wild type and Ettin mutants. AB - Screening for mutations that alter flower development in Arabidopsis has led to the identification of two general types of genetic loci: those affecting meristem and organ identity, and those affecting growth and development independent of identity. ettin (ett) mutants belong to the latter class and exhibit pleiotropic phenotypes distinct from previously described Arabidopsis mutants. These phenotypes include increases in sepal and petal number, decreases in stamen number and anther locule number, and gross alteration of tissue patterning in the gynoecium. To determine when and how differences in ett floral meristems originate, flower development was compared between the wild type and ett mutants. ett floral meristems exhibit increases in abaxial sepal and petal primordia number without apparent increases in meristem size. Extra sepal and petal primordia develop into normal organs. In contrast, stamen and carpel primordia exhibit alterations in shape and form, subsequent to premature elongation of the terminal floral meristem. Phenotypes are allele-strength dependent. The stigma develops precociously and style differentiation is basally and abaxially misplaced in ett gynoecia. The data are discussed in the context of a model suggesting that two concentric boundaries specify the apical-basal pattern of gynoecium differentiation. PMID- 21708673 TI - Noteworthy idioblastic sclereids in the stems of Eulychnia (Cactaceae). AB - Stems of Eulychnia (a genus of six to nine species of candelabriform or arborescent cacti) have a parenchymatic cortex with two distinct regions. The outer chlorenchymatic layer is characterized by a conspicuous parallel striping, whereas the inner cortex region devoid of chlorophyll has a coarsely granular aspect. Stem samples from nine accessions, collected in the field or taken from cultivation, were studied from resin-embedded microtome sections and maceration. Two different forms of lignified sclereids were found dispersed in the cortex and the pith. The sclereids of the outer palisade-like cortex layer are distinctly elongated and strictly oriented at right angle to the stem surface, whereas those of the inner cortex and pith are globular or subglobular and conspicuously enlarged compared with the surrounding parenchyma cells. The ontogeny of the sclereids was studied from stem samples of different ages. Formation of the secondary cell walls starts only after cell growth is completed. A screening of numerous South American cacti for the presence of idioblastic sclereids showed that these structures are unique for the genus Eulychnia. Finally, functional aspects of the sclereids are shortly discussed. It is assumed that the sclereids contribute to the mechanical support and reinforcement of the plants. PMID- 21708674 TI - Leaf anatomy and subgeneric affiliations of C3 and C4 species of Suaeda (Chenopodiaceae) in North America. AB - The halophytic genus Suaeda (Chenopodiaceae) includes species with the C3 and C4 photosynthetic pathways. North American species of this genus were investigated to determine whether C3 and C4 leaf anatomy are consistent within the two sections of Suaeda, Chenopodina and Limbogermen, present on this continent. All species from section Chenopodina were found to possess C3 anatomy, whereas all species from section Limbogermen were found to be C4 species. Characteristics of leaf anatomy and chloroplast ultrastructure are similar to those reported from C3 and C4 species, respectively, from the Eastern Hemisphere. All species from section Limbogermen have the suaedoid type of leaf anatomy, characterized by differentiation of the mesophyll into palisade parenchyma and a chlorenchymatous sheath surrounding central water-storage tissue, as well as leaf carbon isotope ratios (_13C) of above -20. All species from section Chenopodina have austrobassioid leaf anatomy without a chlorenchymatous sheath and _13C values of below -20. According to our literature review, the photosynthetic pathway has now been reported for about half (44) of the Suaeda species worldwide. The C3 and C4 photosynthetic syndromes are with few exceptions distributed along sectional or subsectional lines. These findings throw new light on the infrageneric taxonomy of this genus. PMID- 21708675 TI - Genetic variation of morphological characters within a single isolate of the endomycorrhizal fungus Glomus clarum (Glomaceae). AB - The nature of variation in morphological characters in spores of arbuscular endomycorrhizal fungi (Order Glomales, Class Zygomycetes) has received little attention, despite the importance of these characters in modern taxonomy of the order. We tested the hypothesis that genetic variation exists in spore size and color (presumably important taxonomic characters) within a single isolate of the glomalean fungus Glomus clarum. Phenotypic variation in size and color of spores was determined from a pot culture population (designated P). A 10% selection pressure was imposed on replicate pot cultures of the first progeny culture generation (G1) by selecting the smallest, largest, yellowest, and whitest spores from the P generation and inoculating Sorghum bicolor plants. The experiment was repeated for another generation (G2), but with a 5% selection pressure. In both the G1 and G2 generations, significant differences in spore size and color were observed among the various treatments, indicating substantial genetic variation in these characters. Despite efforts to keep the physical environment constant across generations, we observed variation in the overall means of spore size and color among the generations (regardless of treatment), indicating a strong nongenetic influence on character expression. This study provides empirical evidence that will help delimit species boundaries among isolates of Glomus clarum and similar morphospecies. It also demonstrates a promising method to help elucidate the nature of character diversity in obligately asexual fungi. PMID- 21708676 TI - Vessel contents of leaves after excision - a test of Scholander's assumption. AB - A test was attempted of the assumption that, when a leaf is cut, the xylem still contains water under tension beyond the first vessel cross walls. This assumption enabled Scholander to argue that the balance pressure in his pressure chamber measured the tension in water columns in the vessels before cutting. The numbers of embolized vessels were counted, after rapid freezing of petiole and midrib samples of sunflower leaves, in the cryo-scanning electron microscope. Counts were made on leaves still attached to the plant and at intervals after cutting from the plant (up to 16 min) during a short spring day's transpiration. The lengths of vessels in the leaves, measured by latex particle perfusion, showed that 8% of vessels in the mid-petioles and 0% in the midribs should be opened by cutting. The changing percentages of embolized vessels (E) with time showed that: (1) in intact plants E was close to zero until midday when it rose to ~40%, and then fell progressively to near zero by 1600; (2) in excised leaves there was no detectable change in E immediately after cutting, and, in all but two time courses, no change as large as the 8% of opened vessels within 16 min; (3) but briefly, when E was high (midday), it rose further after cutting to a plateau (_E = 30-40%) in 4 min. From this rate of emptying, the estimated maximum pressure difference between vessels and parenchyma was of the order of 0.05-0.2 MPa (0.5 to 2 bar) at this time. (4) All these changes occurred in the petioles 1 h before they were found in the midribs. The test failed because the expected large pressure difference between vessels and parenchyma was not present. Further, the embolized vessels were refilled at the time of peak transpiration, which would be impossible with any substantial tension in the vessels. Because these results contradict the whole basis of the Cohesion Theory, a second experiment was carried out to test them, and is reported in a companion paper. PMID- 21708677 TI - Vessel contents during transpiration - embolisms and refilling. AB - A test was made of the previous unexpected observation that embolized vessels were refilled during active transpiration. The contents of individual vessels in petioles of sunflower plants were examined, after snap-freezing at 2-h intervals during a day's transpiration, in the cryo-scanning electron microscope, and assessed for the presence of liquid or gas (embolism) contents. Concurrent measurements were made of irradiance, leaf temperature, transpiration rate, and leaf water potential (by pressure chamber). Up to 40% of the vessels were already embolized by 0900 (transpiration rate ~5 _g_cm-2_s-1, water potential about -300 J/kg), and the proportion declined to a minimum (as low as 4%) at 1500. This was the time of highest transpiration rate (~25 _g_cm-2_s-1) and most negative water potential (-600 to -700 J/kg). Images of vessels with mixed gas and liquid contents showed water being extruded through pits in the walls of the vessels to refill them. The data indicate that: (1) the water columns are weak and break under quite small tensions; (2) embolisms are repaired by refilling the vessels with water on a short time scale (minutes) throughout the day; (3) the vigor of this refilling process is adjusted by the plant on a longer time scale (hours) to the intensity of the water stress; (4) the pressure chamber balance pressure (P) does not measure tension in the vessels; (5) P is also not a measure of water stress (as measured by vessel embolization); and (6) P is a measure of the plant's response to water stress, i.e., a measure of the vigor of the refilling process. The test confirms the previous observations and negates all the assumptions and evidences of the Cohesion Theory. The data are fully consistent with the Compensating Pressure Theory, which predicted the relations demonstrated in this experiment. Using the assumptions of that theory it is easy to outline a simple mechanism by which the refilling of vessels might be achieved by reverse osmosis, and the adjustment in (3) might be achieved by osmoregulation in the starch sheath. PMID- 21708678 TI - Cotton fibers can undergo cell division. AB - Ovular culture was used to determine the cell cycle aspects of cotton fiber cells. Each ovule (Gossypium hirsutum, cultivar, MD51 ne) grown under the conditions used has ~10 000 fiber cells at 4 d postanthesis. About 25% of these cells divide when ovules are cultured at 34C. Mitosis occurs after fiber cells differentiate, producing multicelled fibers. The basal and tip cells of multicelled fibers have the same characteristics as the polar ends of single celled fibers. Most cell division occurs in ovules cultured at 2-3 d postanthesis. Multicelled fibers are rare in ovules cultured at 1 d postanthesis and absent if cultured at 7 d postanthesis. No multicelled fibers are detectable on ovules sampled from the plant regardless of age. Fiber cell division occurs in the absence of exogenous hormones. The addition of IAA and GA3 to the medium lowers the frequency of multicelled fibers. IAA alone further reduces their frequency, while GA3 by itself has no effect. The number of fiber cells per cultured ovule ranges between 9462 and 11 087 and is not significantly different from the 9892 seen in the plant at 4 d postanthesis. These findings show that a subpopulation of fiber cells, fully differentiated in appearance, retain cell cycle functions up to 4 d postanthesis. PMID- 21708679 TI - Genetics of adaptive radiation in Hawaiian and Cook Islands species of Tetramolopium (Asteraceae; Astereae). I. Nuclear RFLP marker diversity. AB - Thirty-three nuclear RFLP (restriction fragment length polymorphism) probes were used to study genetic diversity in Hawaiian and Cook Islands species of Tetramolopium for comparison with previous morphological and isozyme studies and to provide greater resolution of the events associated with adaptive radiation in the genus. Levels of RFLP diversity are greater than those reported for isozymes, yet are still low in comparison to continental species. Genetic differentiation is greatest among species in sections rather than among sections and is concordant with the hypothesis of phyletic sorting of initial variability as suggested for morphological traits. Hypothesized introgression between T. lepidotum and T. filiforme is supported, but the evidence suggests bidirectional gene flow. Systematic relationships derived from the data agree with hypotheses based on morphology in the placement of populations within their respective species and the recognition of three main lineages within Hawaii. Inclusion of the Cook Islands species, however, renders section Tetramolopium paraphyletic, contradicting morphological, ecological, and crossing evidence. Interpreting these results in light of evidence from previous studies, the genetic diversity and relationships seen among species and sections of Hawaiian and Cook Islands Tetramolopium reflect the recent and rapid evolution of this group, limited addition of new variability, and phyletic sorting. PMID- 21708680 TI - Effect of salinity on growth, ion content, and cell wall chemistry in Atriplex prostrata (Chenopodiaceae). AB - Atriplex prostrata Boucher, a facultative halophyte, exhibits significant reduction in height and biomass and in the width of the cortex and vascular tissue under saline conditions. Therefore, the goal of this investigation was to determine the effect of salinity on plant growth as well as on the patterns of lignification, peroxidase activity, and extensin deposition. Biomass, leaf area, internode length, water potential, photosynthesis, transpiration, and ion content were measured. In addition, lignin, peroxidase, and extensin were, respectively, examined via phloroglucinol staining, peroxidase staining, and immunostaining with extensin antibody on tissue prints of free-hand stem sections. Length of internodes and leaf area significantly decreased with increased salinity, and net photosynthesis declined dramatically as well. There was a significant accumulation of Na+ in organs when plants were grown in saline solutions, while the concentration of K+, Ca2+, and Mg2+ decreased. The signals in tissue prints showed that soluble peroxidase and extensin accumulated in the first three internodes of A. prostrata grown under saline conditions. In contrast, lignification was reduced under saline growth conditions in the third and fourth internodes. These results indicate that extensin may replace lignin in providing mechanical support for cells, while stems remain in a juvenile stage because of growth retardation caused by salinity. PMID- 21708681 TI - Reproductive allocation and resource compensation in male-sterile and hermaphroditic plants of Plantago lanceolata (Plantaginaceae). AB - Gynodioecy is a breeding system in which hermaphrodites coexist with male steriles. Theoretical models predict that without any compensation in female fitness male steriles will disappear from a population due to their reproductive disadvantage. In the present study I investigated whether male-sterile (MS), partially male-sterile (IN), and hermaphroditic (H) plants of Plantago lanceolata differed in reproductive growth and allocation. Offspring of three interpopulation crosses segregating all three sex morphs were grown under nitrogen-limited conditions in a growth chamber. Independent of the genetic background MS plants attained a higher vegetative and reproductive dry mass and a higher reproductive output than H plants, whereas IN plants had intermediate values. When corrected for the mass of the pollen, the dry mass differences between the sex morphs were much reduced but still present. However, when whole plant allocation was expressed on the basis of nitrogen, the differences between the sex morphs disappeared. Thus the sex morphs took up similar amounts of nitrogen but distributed them differently. The MS and IN plants used the nitrogen saved by not producing pollen for additional vegetative as well as reproductive growth. The data presented in this study suggest that resource compensation is one of the main mechanisms responsible for the maintenance of MS and IN plants in gynodioecious P. lanceolata. PMID- 21708682 TI - Pollination by deceit in nutmeg (Myristica insipida, Myristicaceae): floral displays and beetle activity at male and female trees. AB - Pollination by deceit in Myristica insipida, a beetle-pollinated nutmeg, was hypothesized to operate on intersexual differences in flower production and longevity, producing a daily fluctuation between floral display maxima and minima. Sticky traps were used to continuously monitor beetle activity. Flower production and naturally occurring intersexual differences in display were recorded. Male and female trees flowered in synchrony producing daily display maxima at 1800-0600 and display minima at 1400-1800. Rewarding male trees produced three times the number of flowers of female trees, but the greater longevity of female flowers reduced the intersexual difference in display maxima to a factor of two. There was no intersexual difference in display minima. Beetles were demonstrated to be sensitive to differences in both maximum and minimum displays on rewarding male trees, a necessary prerequisite for directional selection on display size. Beetle captures were significantly higher at male trees during floral display maxima, and no intersexual differences in capture rate occurred during floral display minima. However, capture rates at male trees did not decline as predicted, and the pattern of captures was consistent with crepuscular activity. Beetle captures at male and female trees were lower from 1800 to 0600 and 1000 to 1400, and higher from 0600 to 1000 and 1400 to 1800, but the differences were only significant at female trees. These data suggests that foraging errors are numerous, frequent, and the result of overall foraging activity. PMID- 21708683 TI - Patterns of wing size variation in seeds of the lily Cardiocrinum cordatum (Liliaceae). AB - We examined the patterns of variation in wing-loading and its related characteristics in Cardiocrinum cordatum to clarify the factors that determine the variation in seed dispersal ability in this species. The square root of wing loading of a seed of a plant was not significantly correlated with basal stem diameter of a plant, indicating that large plants did not necessarily produce seeds with high dispersal ability. This result was inconsistent with the hypothesis that large plants produce seeds with high dispersal ability to avoid high mortality of seeds and seedlings in the vicinity of the parents. On the other hand, the square root of wing-loading of a seed of a fruit was negatively dependent on seed number of a fruit. Thus, many-seeded fruits produced seeds with high dispersal ability. This was because the projected surface area per seed was large in large fruits and large fruits contained large numbers of seeds. The cost per seed of producing fruit structures was small for many-seeded fruits. Thus, high dispersal ability of seeds in many-seeded fruits may be a result of an effective resource allocation pattern in which a high proportion of resources are allocated to those many-seeded fruits, enabling seeds to develop large wings and thus reducing the structural cost of fruits per seed. PMID- 21708684 TI - Distance-dependent performance of asexual progeny in Allium vineale (Liliaceae). AB - Local adaptation within and among populations may have an impact on processes ranging from speciation to the evolution of mixed breeding systems and dispersal strategies. It is also one potential factor that could favor the production of asexual over sexual propagules. This field experiment tested whether asexually produced bulbils of Allium vineale demonstrate local adaptation to the parental microsite at the scale of natural dispersal from the parent (5, 25, 50, 100, and 1000 cm). Both "home'' and randomly chosen "away'' genotypes were planted at each location to determine the relative performance of the "home'' genotype. Overall, bulbil performance declined with distance from the parent. In particular, "home'' bulbils outperformed "away'' bulbils at a distance of 25 cm from the parent, indicating that local adaptation has occurred at the scale of natural dispersal in this species. The variance in propagule performance also increased at farther distances from the parent, indicating that the predictability of offspring performance decreases with distance. Fine-scale local adaptation within the range of seed dispersal in this population may be one factor favoring asexual reproduction in Allium vineale. PMID- 21708685 TI - Microgeographic genetic structure and gene flow in Hibiscus moscheutos (Malvaceae) populations. AB - Microgeographic genetic variation in populations of a wetland macrophyte, Hibiscus moscheutos L. (Malvaceae), was investigated using allozyme polymorphism. The species is a self-compatible insect-pollinated perennial, and seeds are water dispersed (hydrochory). Six hundred plants were analyzed from eight brackish and two freshwater populations within the Rhode River watershed/estuarine system. The genetic structure of the populations was assessed by fixation indices and spatial autocorrelation analyses. The degree of genetic differentiation among sites and gene flow between all paired combinations of sites (M ) was analyzed using three hypothetical gene flow models. Fixation indices indicated almost complete panmixia within populations, and spatial autocorrelations showed that genotypes were randomly distributed within sites, most likely the result of water dispersal of seeds. Allele frequencies were significantly different among sites, and estimated FST indicated moderate genetic differentiation (_ = 0.062). Genetic differences between populations were mostly explained by a gene flow model that accounted for the location of populations relative to the tidal stream. The importance of hydrochory in affecting spatial genetic structure was thus suggested both within and among H. moscheutos populations. PMID- 21708686 TI - Japanese maple (Acer palmatum var. Matsumurae, Aceraceae) recruitment patterns: seeds, seedlings, and saplings in relation to conspecific adult neighbors. AB - We analyzed the spatial patterns among seeds, seedlings, saplings, and conspecific adult trees of the cool-temperate tree species Acer palmatum var. Matsumurae in a conifer-hardwood mixed forest in northern Japan, using two models that consider the influence of each adult within the neighborhood of the offspring. The results showed that recruitment patterns of each stage could be characterized and that significant shifts occur between successive stages. Sound seeds were more widely dispersed than unsound seeds; the mean dispersal distance (MDD) was 41.5 m for sound seeds, but only 12.6 m for unsound seeds. Most seedlings were located near conspecific adult trees, with a MDD of 14.3 m. Saplings, however, were more dispersed away from conspecific adult trees, with an MDD of more than 35 m. Light and gap distributions did not strongly affect the spatial distribution of the offspring; most saplings were located under nonconspecific canopies. These results suggest that the recruitment pattern of Japanese maple offspring is strongly affected by conspecific adult neighbors, rather than by light and gap distributions, with close proximity to conspecific adult trees reducing the growth and survival of seedlings during the transition to saplings. PMID- 21708687 TI - Comparison of flagellated and nonflagellated sperm in plants. AB - Differences among flagellated and nonflagellated sperm in land plants are striking, but close examination reveals similarities in pattern of cytoskeleton and in nuclear structure. The microtubular cytoskeleton of flowering plant sperm consists of microtubule bundles arranged obliquely around the nucleus, terminating in cellular extensions. Microtubules are linked into bundles that branch and rejoin along the axis of the sperm cell, forming a cytoskeleton that determines cell shape but does not actively participate in cell movement. Generative cells and sperm share a pattern of microtubules not found in somatic cells. This pattern is initiated in the generative cell, one division before sperm formation, a situation parallel to spermatogenous cell development in vascular plants with flagellated sperm. Chromatin in flagellated and nonflagellated sperm is condensed by specialized histones. PMID- 21708688 TI - Taking physiology to the field: an introduction to the symposium. PMID- 21708689 TI - Overcoming the constraints of long range radio telemetry from animals: getting more useful data from smaller packages. AB - Many species carry out their most interesting activities where they cannot readily be observed or monitored. Marine mammals are extreme among this group, accomplishing their most astounding activities both distant from land and deep in the sea. Collection, storage and transmission of data about these activities are constrained by the energy requirements and size of the recording loggers and transmitters. The more bits of information collected, stored and transmitted, the more battery is required and the larger the tag must be. We therefore need to be selective about the information we collect, while maintaining detail and fidelity. To accomplish this in the study of marine mammals, we have designed "intelligent" data logger/transmitters that provide context-driven data compression, data relay, and automated data base storage. We later combine these data with remotely sensed environmental information and other oceanographic data sets to recreate the environmental context for the animal's activity, and we display the combined data using computer animation techniques. In this way, the system can provide near real time "observation" of animal behavior and physiology from the remotest parts of the globe. PMID- 21708690 TI - Spring and autumn territoriality in song sparrows: same behavior, different mechanisms? AB - Vertebrates show a diverse array of social behaviors associated with territoriality. Field and laboratory experiments indicate that underlying themes including mechanisms-may exist. For example in birds, extensive evidence over many decades has implicated a role for testosterone in the activation of territorial aggression in reproductive contexts. Territoriality at other times of the year appeared to be independent of gonadal hormone control. One obvious question is-why this diversity of control mechanisms for an apparently similar behavior? Control of testosterone secretion during the breeding season must balance the need to compete with other males (that tends to increase testosterone secretion), and the need to provide parental care (that requires lower testosterone concentrations). Regulation of aggressive behaviors by testosterone in the non-breeding season may incur substantial costs. A series of experiments on the male song sparrow, Melospiza melodia morphna, of western Washington State have revealed possible mechanisms to avoid these costs. Song sparrows are sedentary and defend territories in both breeding and non-breeding seasons. Dominance interactions, territorial aggression and song during the non-breeding season are essentially identical to those during the breeding season. Although in the non-breeding season plasma testosterone and estradiol levels are very low, treatment with an aromatase inhibitor decreases aggression and simultaneous implantation of estradiol restores territorial behavior. These data suggest that the mechanism by which testosterone regulates territorial behavior at the neural level remains intact throughout the year. How the hormonal message to activate such behavior gets to the brain in different season does, however, appear to be different. PMID- 21708691 TI - The Analysis of 13C/12C Ratios in Exhaled CO2: Its Advantages and Potential Application to Field Research to Infer Diet, Changes in Diet Over Time, and Substrate Metabolism in Birds. AB - Stable isotopes are becoming an increasingly powerful tool for studying the physiological ecology of animals. The (13)C/(12)C ratios of animal tissues are frequently used to reconstruct the diet of animals. This usually requires killing the subjects. While there is an extensive medical literature on measuring the (13)C/(12)C ratio of exhaled CO(2) to determine substrate digestion and oxidation, we found little evidence that animal physiologists or physiological ecologists have applied (13)C/(12)C breath analysis in their studies. The analysis breath (13)C/(12)C ratios has the advantage of being non-invasive and non-destructive and can be repeatedly used on the same individual. Herein we briefly discuss the medical literature. We then discuss research which shows that, not only can the breath(13)C/(12)C ratio indicate what an animal is currently eating, but also the animal's diet in the past, and any changes in diet have occurred over time. We show that naturally occurring (13)C/(12)C ratios in exhaled CO(2) provides quantitative measure of the relative contribution of carbohydrates and lipids to flight metabolism. This technique is ripe for application to field research, and we encourage physiological ecologists to add this technique to their toolbox. PMID- 21708692 TI - Assessing immunological function in toxicological studies of avian wildlife. AB - Laboratory and field studies have demonstrated that the immune system is sensitive to environmental contaminants. Testing protocols have been developed to screen for immunotoxic effects and elucidate mechanisms of toxicity in laboratory rodents. Similar methods have been applied to wildlife species in captivity and the wild. Several epizootics in wildlife have been associated with elevated exposure to contaminants. This paper discusses immunotoxicological techniques used in studies of avian wildlife. Measurements of immunological structure include peripheral white blood cell counts and the mass and cellularity of immune organs such as the thymus, spleen, and bursa of Fabricius. While contaminants can alter these measures of immunological structure, such measures do not directly assess how the immune system functions, i.e., responds to specific challenges. The two most commonly used in vivo immune function tests in birds are the phytohemagglutinin (PHA) skin response for T cell-mediated immunity and the sheep red blood cell (SRBC) hemagglutination assay for antibody-mediated immunity. In vitro tests of immune function in avian wildlife include proliferation of lymphocytes in response to various mitogens and phagocytosis of fluorescent particles by monocytes. While optimization of in vitro techniques for wildlife species is often time-consuming, these assays usually require only a single blood sample and can elucidate mechanisms of toxicity. In immunological studies of wildlife, investigators should consider factors that may influence immune responses, including age, body condition, date, developmental stage of the immune system, and time required for the progression of immune responses. PMID- 21708693 TI - Reproductive effort and reproductive nutrition of female desert tortoises: essential field methods. AB - I used three innovative, nondestructive field methods (gas dilution, doubly labeled water and radiography) to measure individual energy and water budgets of wild, female desert tortoises (Gopherus agassizii). With these budgets, I evaluated whether body reserves help females produce eggs independent of rainfall and food availability. Female desert tortoises used large seasonal and annual changes in metabolism and body water, protein and energy reserves to survive and produce eggs. Although lipid reserves are important to female desert tortoises, nitrogen or crude protein appears to be the primary limiting resource for producing eggs. By reducing metabolic rates 90%, females conserved enough body reserves to produce eggs during extreme drought conditions; this is an effective bet-hedging reproductive pattern in an extreme and unpredictable environment. PMID- 21708694 TI - Energetic bottlenecks and other design constraints in avian annual cycles. AB - The flexible phenotypes of birds and mammals often appear to represent adjustments to alleviate some energetic bottleneck or another. By increasing the size of the organs involved in digestion and assimilation of nutrients (gut and liver), an individual bird can increase its ability to process nutrients, for example to quickly store fuel for onward flight. Similarly, an increase in the exercise organs (pectoral muscles and heart) enables a bird to increase its metabolic power for sustained flight or for thermoregulation. Reflecting the stationary cost of organ maintenance, changes in the size of any part of the "metabolic machinery" will be reflected in Basal Metabolic Rate (BMR) unless changes in metabolic intensity also occur. Energetic bottlenecks appear to be set by the marginal value of organ size increases relative to particular peak requirements (including safety factors). These points are elaborated using the studies on long-distance migrating shorebirds, especially red knots Calidris canutus. Red knots encounter energy expenditure levels similar to experimentally determined ceiling levels of ca. 5 times BMR in other birds and mammals, both during the breeding season on High Arctic tundra (probably mainly a function of costs of thermoregulation) and during winter in temperate coastal wetlands (a function of the high costs of processing mollusks, prey poor in nutrients but rich in shell material and salt water). During migration, red knots phenotypically alternate between a "fueling [life-cycle] stage" and a "flight stage." Fueling red knots in tropical areas may encounter heat load problems whilst still on the ground, but high flight altitudes during migratory flights seem to take care of overheating and unacceptably high rates of evaporative water loss. The allocation principles for the flexible phenotypes of red knots and other birds, the costs of their organ flexibility and the ways in which they "organize" all the fast phenotypic changes, are yet to be discovered. PMID- 21708695 TI - Ecological and evolutionary physiology of desert birds: a progress report. AB - The adaptive significance of mechanisms of energy and water conservation among species of desert rodents, which avoid temperature extremes by remaining within a burrow during the day, is well established. Conventional wisdom holds that arid zone birds, diurnal organisms that endure the brunt of their environment, occupy these desert climates because of the possession of physiological design features common to all within the class Aves. We review studies that show that desert birds may have evolved specific features to deal with hot desert conditions including: a reduced basal metabolic rate (BMR) and field metabolic rate (FMR), and lower total evaporative water loss (TEWL) and water turnover (WTO).Previous work on the comparative physiology of desert birds relied primarily on information gathered on species from the deserts of the southwestern U.S., which are semi-arid habitats of recent geologic origin. We include data on species from Old World deserts, which are geologically older than those in the New World, and place physiological responses along an aridity axis that includes mesic, semi arid, arid, and hyperarid environments.The physiological differences between desert and mesic birds that we have identified using the comparative method could arise as a result of acclimation to different environments, of genetic change mediated by selection, or both. We present data on the flexibility of BMR and TEWL in Hoopoe Larks that suggest that phenotypic adjustments in these variables can be substantial. Finally, we suggest that linkages between the physiology of individual organism and its life-history are fundamental to the understanding of life-history evolution. PMID- 21708696 TI - Physiological condition and reproductive consequences in adelie penguins. AB - Animals must make "decisions" (e.g., when or whether to breed, the effort to put into a breeding episode) by integrating physiological, environmental and social inputs. This integration can be studied only in a field context. In Adelie penguins (Pygoscelis adeliae) reproduction is constrained by foraging ecology, mode of transport, and the extreme latitude at which they live. The decision whether to breed in a given year is influenced by body conditions. Adelie penguins must fast for several weeks during the early reproductive stages and use stored fat for metabolic energy. Females that return to the colony, but do not breed, are 10-12% lighter than females that do breed. Birds that are relatively low in body mass tend to have lower reproductive success than heavier birds, and an individual's reproductive success is positively correlated with the body fat stores it had on arrival. After eggs are laid, parents alternate in attending the nest. Nest failure occurs if one parent does not make a timely return and its fasting partner must eventually leave. During normal-length fasts plasma corticosterone and glucose levels do not change. Blood beta-hydroxybutyrate levels gradually increase during the fast while uric acid levels remain low, but in birds with the longest fasts (>~50 days), ketone levels may fall and uric acid levels increase, indicative of a switch from using fat to using body proteins for metabolism. In incubating males, hematocrit and hemoglobin concentrations also increase, suggesting dehydration can accompany energy stress during the breeding fast. PMID- 21708697 TI - Balancing requirements for stability and maneuverability in cetaceans. AB - The morphological designs of animals represent a balance between stability for efficient locomotion and instability associated with maneuverability. Morphologies that deviate from designs associated with stability are highly maneuverable. Major features affecting maneuverability are positions of control surfaces and flexibility of the body. Within odontocete cetaceans (i.e., toothed whales), variation in body design affects stability and turning performance. Position of control surfaces (i.e., flippers, fin, flukes, peduncle) provides a generally stable design with respect to an arrow model. Destabilizing forces generated during swimming are balanced by dynamic stabilization due to the phase relationships of various body components. Cetaceans with flexible bodies and mobile flippers are able to turn tightly at low turning rates, whereas fast swimming cetaceans with less flexibility and relatively immobile flippers sacrifice small turn radii for higher turning rates. In cetaceans, body and control surface mobility and placement appear to be associated with prey type and habitat. Flexibility and slow, precise maneuvering are found in cetaceans that inhabit more complex habitats, whereas high-speed maneuvers are used by cetaceans in the pelagic environment. PMID- 21708698 TI - Control of posture, depth, and swimming trajectories of fishes. AB - Perturbations vary in period and amplitude, and responses to unavoidable perturbations depend on response time and scale. Disturbances due to unavoidable perturbations occur in three translational planes and three rotational axes during forwards and backwards swimming. Stability depends on hydrodynamic damping and correcting forces, which may be generated by propulsors (powered) or by control surfaces moving with the body (trimming). Hydrostatic forces affecting body orientation (posture) result in negative metacentric heights amplifying rolling disturbances. The ability to counteract perturbations and correct disturbances is greater for fishes with more slender bodies, which appears to affect habitat choices. Postural control problems are greatest at low speeds, and are avoided by some fishes by sitting on the bottom. In currents, body form and behavior affect lift, drag, weight, and friction and hence speeds to which posture can be controlled. Self-correcting and regulated damping and trimming mechanisms are most important in stabilizing swimming trajectories. Body resistance, fin trajectory, multiple propulsors, and long-based fins damp self generated locomotor disturbances. Powered control using the tail evolved early in chordates, and is retained by most groups, although fishes, especially acanthopterygians, make greater use of appendages. As with most areas of stability, little is known of control costs. Costs and benefits of low-density inclusions and hydrodynamic mechanisms for depth control vary with habits and habitats. Control may make substantial contributions to energy budgets. PMID- 21708699 TI - Maneuvering hydrodynamics of fish and small underwater vehicles. AB - The understanding of fish maneuvering and its application to underwater rigid bodies are considered. The goal is to gain insight into stealth. The recent progress made in NUWC is reviewed. Fish morphology suggests that control fins for maneuverability have unique scalar relationships irrespective of their speed type. Maneuvering experiments are carried out with fish that are fast yet maneuverable. The gap in maneuverability between fish and small underwater vehicles is quantified. The hydrodynamics of a dorsal fin based brisk maneuvering device and a dual flapping foil device, as applied to rigid cylindrical bodies, are described. The role of pectoral wings in maneuvering and station keeping near surface waves is discussed. A pendulum model of dolphin swimming is presented to show that body length and tail flapping frequency are related. For nearly neutrally buoyant bodies, Froude number and maneuverability are related. Analysis of measurements indicates that the Strouhal number of dolphins is a constant. The mechanism of discrete and deterministic vortex shedding from oscillating control surfaces has the property of large amplitude unsteady forcing and an exquisite phase dependence, which makes it inherently amenable to active control for precision maneuvering. Theoretical control studies are carried out to demonstrate the feasibility of maneuverability of biologically inspired bodies under surface waves. The application of fish hydrodynamics to the silencing of propulsors is considered. Two strategies for the reduction of radiated noise are developed. The effects of a reduction of rotational rate are modeled. The active cambering of blades made of digitally programmable artificial muscles, and their thrust enhancement, are demonstrated. Next, wake momentum filling is carried out by artificial muscles at the trailing edge of a stator blade of an upstream stator propulsor, and articulating them like a fish tail. A reduction of radiated noise, called blade tonals, is demonstrated theoretically. PMID- 21708700 TI - Maneuvering and stability performance of a robotic tuna. AB - The Draper Laboratory Vorticity Control Unmanned Undersea Vehicle (VCUUV) is the first mission-scale, autonomous underwater vehicle that uses vorticity control propulsion and maneuvering. Built as a research platform with which to study the energetics and maneuvering performance of fish-swimming propulsion, the VCUUV is a self-contained free swimming research vehicle which follows the morphology and kinematics of a yellowfin tuna. The forward half of the vehicle is comprised of a rigid hull which houses batteries, electronics, ballast and hydraulic power unit. The aft section is a freely flooded articulated robot tail which is terminated with a lunate caudal fin. Utilizing experimentally optimized body and tail kinematics from the MIT RoboTuna, the VCUUV has demonstrated stable steady swimming speeds up to 1.2 m/sec and aggressive maneuvering trajectories with turning rates up to 75 degrees per second. This paper summarizes the vehicle maneuvering and stability performance observed in field trials and compares the results to predicted performance using theoretical and empirical techniques. PMID- 21708701 TI - Stability versus maneuverability in aquatic locomotion. AB - The dictionary definition of stability as "Firmly established, not easily to be changed" immediately indicates the conflict between stability and maneuverability in aquatic locomotion. The present paper addresses several issues resulting from these opposing requirements. Classical stability theory for bodies moving in fluids is based on developments in submarine and airship motions. These have lateral symmetry, in common with most animals. This enables the separation of the equations of motion into two sets of 3 each. The vertical (longitudinal) set, which includes motions in the axial (surge), normal (heave) and pitching directions, can thus be separated from the lateral-horizontal plane which includes yaw, roll and sideslip motions. This has been found useful in the past for longitudinal stability studies based on coasting configurations but is not applicable to the analysis of turning, fast starts and vigorous swimming, where the lateral symmetry of the fish body is broken by bending motions. The present paper will also examine some of the aspects of the stability vs. maneuverability tradeoff for these asymmetric motions. An analysis of the conditions under which the separation of equations of motions into vertical and horizontal planes is justified, and a definition of the equations to be used in cases where this separation is not accurate enough is presented. PMID- 21708702 TI - Mechanisms and implications of animal flight maneuverability. AB - Accelerations and directional changes of flying animals derive from interactions between aerodynamic force production and the inertial resistance of the body to translation and rotation. Anatomical and allometric features of body design thus mediate the rapidity of aerial maneuvers. Both translational and rotational responsiveness of the body to applied force decrease with increased total mass. For flying vertebrates, contributions of the relatively heavy wings to whole-body rotational inertia are substantial, whereas the relatively light wings of many insect taxa suggest that rotational inertia is dominated by the contributions of body segments. In some circumstances, inertial features of wing design may be as significant as are their aerodynamic properties in influencing the rapidity of body rotations. Stability in flight requires force and moment balances that are usually attained via bilateral symmetry in wingbeat kinematics, whereas body roll and yaw derive from bilaterally asymmetric movements of both axial and appendicular structures. In many flying vertebrates, use of the tail facilitates the generation of aerodynamic torques and substantially enhances quickness of body rotation. Geometrical constraints on wingbeat kinematics may limit total force production and thus accelerational capacity in certain behavioral circumstances. Unitary limits to animal flight performance and maneuverability are unlikely, however, given varied and context-specific interactions among anatomical, biomechanical, and energetic features of design. PMID- 21708703 TI - Bird maneuvering flight: blurred bodies, clear heads. AB - While useful in describing the efficiency of maneuvering flight, steady-state (i.e., fixed wing) models of maneuvering performance cannot provide insight to the efficacy of maneuvering, particularly during low-speed flapping flight. Contrasted with airplane-analogous gliding/high speed maneuvering, the aerodynamic and biomechanical mechanisms employed by birds at low flight speeds are violent, with rapidly alternating forces routinely being developed. The saltatory nature of this type of flight results in extreme linear and angular displacements of the bird's body; however, birds isolate their heads from these accelerations with cervical reflexes. Experiments with pigeons suggest this ability to isolate the visual and vestibular systems is critical to controlled flapping flight: birds wearing collars that prohibited the neck from isolating the head from the angular accelerations of induced rolls frequently exhibited (50% of flights) a loss of vestibular and/or visual horizon and were unable to maintain controlled flight. PMID- 21708704 TI - Quantifying dynamic stability and maneuverability in legged locomotion. AB - Animals can swerve, dodge, dive, climb, turn and stop abruptly. Their stability and maneuverability are remarkable, but a challenge to quantify. Formal stability analysis can allow for quantitative comparisons within and among species. Stability analysis used in concert with a template (a simple, general model that serves as a guide for control) can lead to testable hypotheses of function. Neural control models postulated without knowledge of the animal's mechanical (musculo-skeletal) system can be counterproductive and even destabilizing. Perturbations actively corrected by reflex feedback in one direction can result in perturbations in other directions because the system is coupled dynamically. The passive rate of recovery from a perturbation in one direction differs from rates in other directions. We hypothesize that animals might exert less neural control in directions that rapidly recover via passive dynamics (e.g., in body orientation and rotation). By contrast, animals are likely to exert more neural control in directions that recover slowly or not at all via passive dynamics (e.g., forward velocity and heading). Neural control best enhances stability when it works with the natural, passive dynamics of the mechanical system. Measuring maneuverability is more challenging and new, general metrics are needed. Templates reveal that simple analyses of summed forces and quantification of the center of pressure can lead to valuable hypotheses, whereas kinematic descriptions may be inadequate. The study of stability and maneuverability has direct relevance to the behavior and ecology of animals, but is also critical if animal design is to be understood. Animals appear to be grossly over-built for steady-state, straight-ahead locomotion, as they appear to possess too many neurons, muscles, joints and even too many appendages. The next step in animal locomotion is to subject animals to perturbations and reveal the function of all their parts. PMID- 21708705 TI - Stability and manoeuvrability of terrestrial vertebrates. AB - For a standing animal to be statically stable, a vertical line through its centre of mass must pass through the polygon of support defined by its feet. Statically stable gaits are possible for quadrupeds but do not seem to be used. Physical and mathematical models have shown that bipedal gaits can be dynamically stable. Accelerations and decelerations of animals may be limited by muscle strength, by the coefficient of friction with the ground or by considerations of stability. Cornering ability similarly may be limited by strength or by the coefficient of friction. It may be faster to use a longer route involving corners of larger radius than a shorter one with sharper corners. PMID- 21708706 TI - Stick insects walking along inclined surfaces. AB - In the experiments stick insects walk on an inclined substrate such that the legs of one side of the body point uphill and the legs of the other side point downhill. In this situation the vertical axis of the body is rotated against the inclination of the substrate as if to compensate for the effect of substrate inclination. A very small effect has been found when the experiment was performed with animals standing on a tilted platform which shows that the effect depends on the behavioral context. When, however, animals first walked along the inclined surface and then, before measurement, stopped walking spontaneously, a rotation of the body has been observed similar to that in walking animals. In a second experiment it was tested whether the observed body rotation is caused by the change of direction of gravity vector or by the fact that on an inclined surface gravity necessarily has a component pulling the body sideways. Experiments with animals standing on horizontal ground and additional weights applied pulling the body to the side showed similar body rotations supporting the latter idea. In a simulation study it could be shown that the combined activity of proportional feedback controllers in the leg joints is sufficient to explain the observed behavior. This is however only possible if the gain factors of coxa-trochanter joint controller and of femur-tibia joint controller show a ratio in the order of 1 : 0.05 to 1 : 1.8. In order to describe the behavior of animals standing on a tilted platform, a ratio of 1 : 1.7 is necessary. In walking animals, this body rotation requires to change the trajectories of stance and swing movements. The latter have been studied in more detail. During swing, the femur-tibia joint is more extended in the uphill legs. Conversely, the coxa-trochanter joint appears to be more elevated in the downhill legs which compensates the smaller lift in the femur-tibia joint. The results are discussed in the context of different hypotheses. PMID- 21708707 TI - Low impedance walking robots. AB - For both historical and technological reasons, most robots, including those meant to mimic animals or operate in natural environments,3 use actuators and control systems that have high (stiff) mechanical impedance. By contrast, most animals exhibit low (soft) impedance. While a robot's stiff joints may be programmed to closely imitate the recorded motion of an animal's soft joints, any unexpected position disturbances will generate reactive forces and torques much higher for the robot than for the animal. The dual of this is also true: while an animal will react to a force disturbance by significantly yielding position, a typical robot will greatly resist.These differences cause three deleterious effects for high impedance robots. First, the higher forces may cause damage to the robot or to its environment (which is particularly important if that environment includes people). Second, the robot must acquire very precise information about its position relative to the environment so as to minimize its velocity upon impact. Third, many of the self-stabilizing effects of natural dynamics are "shorted out"4 by the robot's high impedance, so that stabilization requires more effort from the control system.Over the past 5 yr, our laboratory has designed a series of walking robots based on "Series-Elastic Actuators" and "Virtual Model Control." Using these two techniques, we have been able to build low-impedance walking robots that are both safe and robust, that operate blindly without any model of upcoming terrain, and that add minimal control effort in parallel to their self-stabilizing passive dynamics. We have discovered that it is possible to achieve surprisingly effective ambulation from rather simple mechanisms and control systems. After describing the historical and technological motivations for our approach, this paper gives an overview of our methods and shows some of the results we have obtained. PMID- 21708708 TI - Advances in insect physiology volume 28. PMID- 21708709 TI - A brief history of vertebrate functional morphology. AB - The discipline of functional morphology grew out of a comparative anatomical tradition, its transformation into a modern experimental science facilitated largely by technological advances. Early morphologists, such as Cuvier, felt that function was predictable from organismal form, to the extent that animals and plants represented perfect adaptations to their habits. However, anatomy alone could not reveal how organisms actually performed their activities. Recording techniques capable of capturing fast motion were first required to begin to understand animal movement. Muybridge is most famous for his pioneering work in fast photography in the late 19th century, enabling him to "freeze" images of even the fastest horse at a full gallop. In fact, contemporary kinematic analysis grew directly out of the techniques Muybridge developed. Marey made perhaps an even greater contribution to experimental science through his invention of automatic apparati for recording events of animal motion. Over the first half of the 20th century, scientists developed practical methods to record activity patterns from muscles of a living, behaving human or animal. The technique of electromyography, initially used in clinical applications, was co-opted as a tool of organismal biologists in the late 1960s. Comparative anatomy, kinematic analysis and electromyography have for many years been the mainstay of vertebrate functional morphology; however, those interested in animal form and function have recently begun branching out to incorporate approaches from experimental biomechanics and other disciplines (see accompanying symposium papers), and functional morphology now stands at the threshold of becoming a truly integrative, central field in organismal biology. PMID- 21708710 TI - A molecular mechanism for variations in muscle function in rainbow trout. AB - Salmonids undergo a developmental transition from parr to smolt that involves a number of physiological and morphological changes. In recent years, my laboratory has studied shifts in red muscle function at this parr-smolt transformation (PST) in rainbow trout, Oncorhynchus mykiss. Parr red muscle has faster contraction kinetics than smolts, including faster rates of activation and relaxation and a faster maximum shortening velocity. At PST, a transition in swimming behavior is also observed, with lower tailbeat frequencies and longer EMG duty cycles in the older smolts. Lastly, there is molecular correlate to changes in kinetics and behavior. During PST, there is a developmental reduction in the number of myosin heavy chain (MHC) isoforms in the red muscle of rainbow trout. Since MHC composition of muscle can determine contractile properties, these molecular results suggest a mechanism for the transition in red muscle kinetics and steady swimming. The red muscle of parr is more likely to contain the fast-twitch or white isoform of MHC, resulting in faster contractile properties of that muscle and higher tailbeat frequencies during steady swimming. Lastly, experimental work supports the conclusion that the shift in kinetics causes the observed shift in swimming behavior. PMID- 21708711 TI - Functional Morphology and Biochemical Indices of Performance: Is there a Correlation Between Metabolic Enzyme Activity and Swimming Performance? AB - Comparative physiologists and ecologists have searched for a specific morphological, physiological or biochemical parameter that could be easily measured in a captive, frozen, or preserved animal, and that would accurately predict the routine behavior or performance of that species in the wild. Many investigators have measured the activity of specific enzymes in the locomotor musculature of marine fishes, generally assuming that high specific activities of enzymes involved in aerobic metabolism are indicators of high levels of sustained swimming performance and that high activities of anaerobic metabolic enzymes indicate high levels of burst swimming performance. We review the data that support this hypothesis and describe two recent studies we have conducted that specifically test the hypothesis that biochemical indices of anaerobic or aerobic capacity in fish myotomal muscle correlate with direct measures of swimming performance. First, we determined that the maximum speed during escapes (C starts) for individual larval and juvenile California halibut did not correlate with the activity of the enzyme lactate dehydrogenase, an index of anaerobic capacity, in the myotomal muscle, when the effects of fish size are factored out using residuals analysis. Second, we found that none of three aerobic capacity indices (citrate synthase activity, 3-hydroxy-o-acylCoA dehydrogenase activity, and myoglobin concentration) measured in the slow, oxidative muscle of juvenile scombrid fishes correlated significantly with maximum sustained speed. Thus, there was little correspondence between specific biochemical characteristics of the locomotor muscle of individual fish and whole animal swimming performance. However, it may be possible to identify biochemical indices that are accurate predictors of animal performance in phylogenetically based studies designed to separate out the effects of body size, temperature, and ontogenetic stage. PMID- 21708712 TI - The Intracardiac Shunt as a Source of Myocardial Oxygen in a Turtle, Trachemys scripta. AB - The functional significance of many features of the reptilian cardiopulmonary system remains unknown; particularly the importance of cardiac shunts. One hypothesis for a physiological function for shunts is that they play a role in myocardial oxygenation and are therefore important when cardiac work is elevated. In this study we examined cardiac function by monitoring electrocardiograms in red-eared slider turtles (Trachemys scripta) with a reduced myocardial oxygen supply. Exposing the animals to a hypoxic gas mixture reduced oxygen levels in the pulmonary venous return. When cardiac work was elevated during hypoxia, the electrocardiogram changed in a manner consistent with myocardial hypoxia, suggesting enrichment of the luminal blood with oxygen by the intracardiac shunt facilitates cardiac performance. PMID- 21708713 TI - The functional morphology of penile erection: tissue designs for increasing and maintaining stiffness. AB - Inflatable penises have evolved independently at least four times in amniotes, specifically in mammals, turtles, squamates, and the archosaurs. Males in these lineages therefore share the functional problem of building a penis out of soft and flexible tissues that can increase its flexural stiffness and resist bending during copulation. Research on penile erectile tissues in mammals and turtles shows that these two taxa have convergently evolved an axial orthogonal array of collagen fibers to reinforce the penis during erection and copulation; in both lineages, the collagen fibers in the array are crimped and folded in the flaccid penis. Collagen fiber straightening during erection increases the stiffness of the tissue and allows changes in penile radius that increase its second moment of area: both of these changes increase the flexural stiffness of the penis as a whole. And once erect, axial orthogonal arrays have the highest flexural stiffness of any fiber arrangement. The high degree of anatomical convergence (to the level of microanatomical features) within mammals and turtles suggests that the stiffness requirements for copulation produce an extremely restrictive selective regime in organisms that evolve inflatable penises. PMID- 21708714 TI - Functional morphology and developmental biology of zebrafish: reciprocal illumination from an unlikely couple. AB - Functional morphology has benefited greatly from the input of techniques and thinking from other disciplines. This has been especially productive in situations where each discipline has made significant contributions to a particular research topic. A combination of methodologies from functional morphology and developmental biology has allowed us to characterize feeding mechanics of first-feeding larval zebrafish (Danio rerio). Contrary to kinematic patterns commonly seen in adult teleosts, larval zebrafish showed no lateral abduction during the expansive phase of a suction-feeding event. Instead, dorsoventral expansion of the buccal chamber, more typical of patterns seen in primitive fishes, characterized the expansive phase. Moreover, a pronounced preparatory phase during which the buccal chamber is constricted by the protractor hyoideus was consistently seen in first-feeding larval kinematics. Key kinematic variables associated with first feeding correlated significantly with the hydrodynamic regime as measured by the Reynolds number. Using the tools of both functional morphology and developmental biology we have not only determined which cranial muscles are important for successful feeding but also uncovered important physiological differences in muscle structure. Muscles necessary for the rapid dorsoventral expansion of the head are composed primarily of fast twitch fibers while those involved in more tonic contractions such as hyoid protraction have more slow-twitch muscle fibers. While most evolutionary developmental studies have examined mechanisms responsible for large evolutionary changes in morphology, we propose that the type of data uncovered in functional studies can lead to the generation of hypotheses concerning the developmental mechanisms responsible for smaller intra- and/or interspecific changes. PMID- 21708715 TI - Functional morphology and virtual models: physical constraints on the design of oscillating wings, fins, legs, and feet at intermediate reynolds numbers. AB - Why do some animals swim by rowing appendages back and forth while others fly by flapping them up and down? One hypothesis suggests the answer lies in the sharply divergent physical environments encountered by small, slow animals, and large, fast animals. Flapping appendages allow large animals to move through a fluid environment quickly and efficiently. As size and speed decrease, however, viscous drag increasingly dominates the force balance, with negative consequences for both rowing and flapping appendages. Nevertheless, comparative data suggest that flapping does not occur in animals at Reynolds numbers (Re) less than about 15. I used a computer simulation experiment to address the question, "Below what Re is rowing more effective than flapping?" The simulation, which employed a simple quasi-steady, blade-element model of virtual oscillating appendages, has several important results. First, the mechanical efficiency of both rowing and flapping decrease dramatically with scale. Second, the performance of rowing can increase substantially by taking advantage of several dynamic shape modifications, including area and span reduction during the recovery stroke. Finally, the relative performance of rowing and flapping is dependent on the advance ratio, which is a function of the travel speed relative to the oscillation frequency. The model predicts that rowing is more efficient than flapping at Re < 20 for animals moving throughout the range of typically observed advance ratios. PMID- 21708716 TI - Experimental hydrodynamics of fish locomotion: functional insights from wake visualization. AB - Despite enormous progress during the last twenty years in understanding the mechanistic basis of aquatic animal propulsion-a task involving the construction of a substantial data base on patterns of fin and body kinematics and locomotor muscle function-there remains a key area in which biologists have little information: the relationship between propulsor activity and water movement in the wake. How is internal muscular force translated into external force exerted on the water? What is the pattern of fluid force production by different fish fins (e.g., pectoral, caudal, dorsal) and how does swimming force vary with speed and among species? These types of questions have received considerable attention in analyses of terrestrial locomotion where force output by limbs can be measured directly with force plates. But how can forces exerted by animals moving through fluid be measured? The advent of digital particle image velocimetry (DPIV) has provided an experimental hydrodynamic approach for quantifying the locomotor forces of freely moving animals in fluids, and has resulted in significant new insights into the mechanisms of fish propulsion. In this paper we present ten "lessons learned" from the application of DPIV to problems of fish locomotion over the last five years. (1) Three-dimensional DPIV analysis is critical for reconstructing wake geometry. (2) DPIV analysis reveals the orientation of locomotor reaction forces. (3) DPIV analysis allows calculation of the magnitude of locomotor forces. (4) Swimming speed can have a major impact on wake structure. (5) DPIV can reveal interspecific differences in vortex wake morphology. (6) DPIV analysis can provide new insights into the limits to locomotor performance. (7) DPIV demonstrates the functional versatility of fish fins. (8) DPIV reveals hydrodynamic force partitioning among fins. (9) DPIV shows that wake interaction among fins may enhance thrust production. (10) Experimental hydrodynamic analysis can provide insight into the functional significance of evolutionary variation in fin design. PMID- 21708717 TI - From odor molecules to plume tracking: an interdisciplinary, multilevel approach to olfaction in stomatopods. AB - Like many marine crustaceans, mantis shrimp rely on their sense of smell to find food, mates, and habitat. In order for olfaction to function, odorant molecules in the surrounding fluid must gain access to the animal's chemosensors. Thus fluid motion is important for olfaction, both in terms of the large scale fluid movements (currents, waves, etc.) that advect the odorants to the vicinity of the sensors, and the small-scale viscosity dominated flows that determine odorant access to the surface of the sensor. In order to understand how stomatopods interpret their chemical environment, I investigated how stomatopod chemosensory morphology and the movement of the structures bearing the chemosensors affect fluid access to the sensor surface in Gonodactylaceus mutatus. Preliminary results from new directions are presented, including mathematical modeling of molecular flux at the sensor surface, field studies of the effects of ambient flow on odor sampling behavior, and flume experiments testing the ability of stomatopods to trace odor plumes. Finally, I show how the use of multiple techniques from several disciplines leads to new ideas about the functional morphology of stomatopod antennules. PMID- 21708718 TI - Using functional morphology to examine the ecology and evolution of specialization. AB - Researchers strive to understand what makes species different, and what allows them to survive in the time and space that they do. Many models have been advanced which encompass an array of ecological, evolutionary, mathematical, and logical principles. The goal has been to develop ecological theories that can, among other things, make specific and robust predictions about how and where organisms should live and what organisms should utilize. The role of functional morphology is often an under-appreciated parameter of these models. A more complete understanding of how anatomical features work to allow the organism to accomplish certain tasks has allowed us to revisit some of these ideas with a new perspective. We illustrate our view of this role for functional morphology in ecology by considering the issue of specialization: we attempt to align several definitions of specialization based upon shared ecological and evolutionary principles, and we summarize theoretical predictions regarding why an organism might specialize. Kinematic studies of prey capture in several types of fishes are explored with regard to the potential ecological and evolutionary consequences of specialization, most notably in the area of trade-offs. We suggest that a functional morphological perspective can increase our understanding of the ecological concepts of specialization and it consequences. The kinds of data that functional morphologists collect can help us to quantify organismal performance associated with specialization and the union of functional morphology with ecology can help us to better understand not just how but why organisms interact in the manner that they do. PMID- 21708719 TI - Evolutionary approaches for studying functional morphology: examples from studies of performance capacity. AB - Performance studies have long been a cornerstone of evolutionary studies of adaptation because of their purported importance for fitness. Nevertheless, for most systems, the mechanistic link among habitat use, morphology and performance is poorly understood. Further, few studies consider how behavior affects the relationship between morphology and performance. Here, I highlight the utility of considering both of these neglected areas by discussing studies in two systems: (1) the evolution of habitat use in Caribbean Anolis lizards, and (2) the evolution of limb function in desert lizards. Caribbean Anolis lizards partition the habitat via selection of different perch diameters, and surface diameter also exerts a strong effect on locomotor performance. Phylogenetic analyses show that Anolis species tend to avoid using perches in which their performance is submaximal, and also show that species with large performance breadths use a greater range of habitats. The underlying basis of this performance to habitat use link is a trade-off between the ability to sprint quickly on broad surfaces and the ability to move effectively on narrow surfaces. Studies of the kinematics of high-speed locomotion in five morphologically distinct lizard species reveal that some species exhibited behaviors that greatly enhanced their performance abilities relative to other species, suggesting that behavior can play a key role in the link between morphology and performance. Overall, these findings underscore the value of using a mechanistic approach for studying the links between habitat use, morphology and behavior. PMID- 21708720 TI - Themes from variation: probing the commonalities of symbiotic associations. AB - Research on symbiosis (including antagonistic and mutualistic associations) wrestles, directly or indirectly, with the paradox: why are symbiotic associations so prevalent in the biosphere in the face of ubiquitous immune or antibiotic defenses among organisms? The symposium "Living Together: the Dynamics of Symbiotic Interactions" considered several questions: 1. How do symbiotic species partners come together? Do symbioses share similar patterns of signal recognition and response? 2. What roles do nutrients and metabolites play in symbiotic interactions, and how are metabolic exchanges affected by environmental changes? 3. In what ways do the dynamics of multispecies symbioses differ from two-species associations? 4. How do antagonistic (parasitic, pathogenic) symbioses differ from mutualistic ones? In what ways do changes in the biotic and physical environment affect the evolutionary balance of symbiotic associations? 5. What are the coevolutionary patterns of symbiotic associations? 6. Which research techniques, and strategies of experimental design, might be useful across a broad range of symbiotic associations?Two themes emerged from the symposium. First, all the participants have incorporated multiple techniques and perspectives into their work, approaches which facilitate the understanding of symbiotic dynamics at several levels of biological organization. Secondly, many of the papers addressed genetic and environmental variation in symbiotic interactions. Such approaches are useful tools for analysis of the mechanics of interspecies interactions and for characterization of the most important factors which influence them. They provide us with the tools to evaluate symbioses in a world of complexity, variation and change. PMID- 21708721 TI - Investigation of Four Classes of Non-nodulating White Sweetclover (Melilotus alba annua Desr.) Mutants and Their Responses to Arbuscular-Mycorrhizal Fungi. AB - The nitrogen-fixing symbiosis between Rhizobiaceae and legumes is one of the best studied interactions established between prokaryotes and eukaryotes. The plant develops root nodules in which the bacteria are housed, and atmospheric nitrogen is fixed into ammonia by the rhizobia and made available to the plant in exchange for carbon compounds. It has been hypothesized that this symbiosis evolved from the more ancient arbuscular mycorrhizal (AM) symbiosis, in which the fungus associates with roots and aids the plant in the absorption of mineral nutrients, particularly phosphate. Support comes from several fronts: 1) legume mutants where Nod(-) and Myc(-) co-segregate, and 2) the fact that various early nodulin (ENOD) genes are expressed in legume AM. Both strongly argue for the idea that the signal transduction pathways between the two symbioses are conserved. We have analyzed the responses of four classes of non-nodulating Melilotus alba (white sweetclover) mutants to Glomus intraradices (the mycorrhizal symbiont) to investigate how Nod(-) mutations affect the establishment of this symbiosis. We also re-examined the root hair responses of the non-nodulating mutants to Sinorhizobium meliloti (the nitrogen-fixing symbiont). Of the four classes, several sweetclover sym mutants are both Nod(-) and Myc(-). In an attempt to decipher the relationship between nodulation and mycorrhiza formation, we also performed co-inoculation experiments with mutant rhizobia and Glomus intraradices on Medicago sativa, a close relative of M. alba. Even though sulfated Nod factor was supplied by some of the bacterial mutants, the fungus did not complement symbiotically defective rhizobia for nodulation. PMID- 21708722 TI - The transmission of digenetic trematodes: style, elegance, complexity. AB - Traditionally, the field of parasitology has dealt with eukaryotic animals, to the exclusion of viruses, bacteria, fungi, etc., which is the way it will be approached here. The focus of the present paper will be on certain ecological aspects of the life cycles and life-history strategies employed by the Digenea, a diverse group of platyhelminths that includes some 25,000 species. More specifically, the review will consider the nature of host/parasite interactions within molluscan intermediate hosts and the manner in which these interactions, or lack thereof, function in structuring trematode infracommunities within these molluscan intermediate hosts. Literature in this area suggests that predation/competition may be a significant structuring force for infracommunities in certain marine prosobranchs, but not others, and that temporal/spatial factors may be involved as structuring mechanisms in at least some freshwater pulmonates. PMID- 21708723 TI - Phylogenetic diversity and physiology of termite gut spirochetes. AB - The hindgut microbiota of termites includes an abundant and morphologically diverse population of spirochetes. However, our understanding of these symbionts has remained meager since their first observation in termite guts by Leidy over a century ago, in part because none had ever been isolated in culture. Recently, this situation has changed dramatically with the application of cultivation independent molecular methods to determine their phylogeny, and with the isolation of the first pure cultures. The emerging picture is that earth's termites constitute an enormous reservoir of novel spirochetes, which possess metabolic properties (H(2)/CO(2)-acetogenesis and N(2) fixation) hitherto unrecognized in spirochetes and which contribute to the carbon, nitrogen and energy requirements of their termite host. These discoveries help to explain the enigmatic dominance of CO(2)-reductive acetogenesis over methanogenesis in the hindgut of many termites, as well as the old observation that elimination of spirochetes from the gut results in decreased termite survival. PMID- 21708724 TI - Mutualistic fermentative digestion in the gastrointestinal tract: diversity and evolution. AB - All animals, including humans, are adapted to life in a microbial world. Anaerobic habitats have existed continuously throughout the history of the earth, the gastrointestinal tract being a contemporary microniche. Since microorganisms colonize and grow rapidly under the favorable conditions in the gut they could compete for nutrients with the host. This microbial challenge has modified the course of evolution in animals, resulting in selection of complex animal-microbe relationships that vary tremendously, ranging from competition to cooperation. The ecological and evolutionary interactions between herbivorous dinosaurs and the first mammalian herbivores and their food plants are reconstructed using knowledge gained during the study of modern living vertebrates, especially foregut and hindgut fermenting mammals. The ruminant is well adapted to achieve maximal digestion of roughage using the physiological mechanism at the reticulo omasal orifice which selectively retains large particles in the reticulo-rumen. However, the most obvious feature of all ruminants is the regurgitation, rechewing and reswallowing of foregut digesta termed rumination. Foregut fermenting mammals also share interesting and unique features in two enzymes, stomach lysozyme and pancreatic ribonuclease which accompany and are adaptations to this mode of digestion. The microbial community inhabiting the gastrointestinal tract is represented by all major groups of microbes (bacteria, archaea, ciliate protozoa, anaerobic fungi and bacteriophage) and characterized by its high population density, wide diversity and complexity of interactions. The development and application of molecular ecology techniques promises to link distribution and identity of gastrointestinal microbes in their natural environment with their genetic potential and in situ activities. PMID- 21708725 TI - Comparative microbial diversity in the gastrointestinal tracts of food animal species. AB - Molecular tools based on small subunit (SSU) rDNA gene sequences offer a powerful and rapid tool for the analysis of complex microbial communities found in the gastrointestinal tracts (GIT) of food animal species. Extensive comparative sequence analysis of SSU rRNA molecules representing a wide diversity of organisms shows that different regions of the molecule vary in sequence conservation. Oligonucleotides complementing regions of universally conversed SSU rRNA sequences are used as universal probes, while those complementing more variable regions of sequence are useful as selective probes targeting species, genus, or phylogenetic groups. Different approaches derive different information and this is highly dependent on the type of target nucleic acid employed and the conceptual and technical basis used for nucleic acid probe design. Generally these approaches can be divided into DNA-based methods employing empirically characterized probes and rRNA-based methods based on comparative sequence analysis for design and interpretation of "rational" probes. Polymerase chain reaction (PCR) based techniques can also be applied to the analysis of microbial communities in the GIT. Direct cloning of SSU rDNA genes amplified from these complex communities can be used to determine the extent of diversity in these GIT communities. Denaturing gradient gel electrophoresis (DGGE) is another powerful tool for profiling microbial diversity of microbial communities in GI tracts. Sequence analysis of the excised DGGE amplicons can then be used to presumptively identify predominant bacterial species. Examples of how these molecular approaches are being used to study the microbial diversity of communities from steers fed different diets, swine fed probiotics, and Atlantic salmon fed aquaculture diets are presented. PMID- 21708726 TI - Distribution of wolbachia within Drosophila reproductive tissue: implications for the expression of cytoplasmic incompatibility. AB - A PCR based quantitative assay was used to determine Wolbachia infection levels in three different Drosophila strains. In addition, confocal microscopy was used to confirm and calibrate these results. Wolbachia infection levels ranged from 2,600 to 18,500 per egg. Single ovaries and testes from each of the three strains were also assayed using the calibrated quantitative PCR assay. A general correlation was found between bacterial levels in eggs and those found in ovaries and testis. These infection levels were consistent with the expression of cytoplasmic incompatibility (CI). In two strains of D. simulans, although the overall bacterial numbers were not significantly different, they exhibited different levels of CI. A direct correlation between the number of infected developing sperm cysts in these strains and CI levels was observed. This calibrated assay should provide a useful baseline for future comparative work, particularly between laboratories. PMID- 21708727 TI - Effects of wolbachia on genetic divergence between populations: mainland-island model. AB - Cytoplasmic incompatibility (CI) induced by intracellular bacteria is a possible mechanism for speciation. Growing empirical evidence suggests that bacteria of the group Wolbachia may indeed act as isolating factors in recent insect speciation. Wolbachia are cytoplasmically transmitted and can cause uni- or bidirectional CI. We present a mainland-island model to investigate how much impact Wolbachia can have on genetic divergence between populations. In the first scenario we assume that the island population has diverged at a selected locus and ask whether genetic divergence will be maintained after introduction of migration from the mainland. In the second we explore whether divergence will originate under migration. For simplicity, the host organisms are modeled as haploid sexuals. Simulations show that if each population is initially infected with a different strain of Wolbachia, then higher levels of divergence occur at the locally selected locus than in the absence of Wolbachia. A weaker effect is seen when there is only unidirectional CI caused by a single strain of Wolbachia on the island. CI increases divergence because it reduces effective migration between mainland and island. Migrants suffer from being confronted with the wrong CI system and this also applies to their matrilineal descendants. Moreover, there is a strong linkage disequilibrium between host genotype and infection state, which helps to maintain Wolbachia differences between the populations in the face of migration A sex bias in migration can either increase or decrease the effect of Wolbachia on divergence. Results support the view that Wolbachia has the potential for increasing divergence between populations and thus could enhance probabilities of speciation. PMID- 21708728 TI - Host specificity in ectomycorrhizal communities: what do the exceptions tell us? AB - Classic ectomycorrhizal symbioses are mutualisms that involve the exchange of fixed carbon for mineral nutrients between plant roots and fungi. They are unique in the way they contain features of both intimate and diffuse symbioses. The degree of host specificity varies, particularly among the fungi. Here we examine two exceptional cases of specificity to see what they tell us about the advantages of specificity, how it is initiated, and the potential role that it plays in complex ecosystems. The first case involves non-photosynthetic epiparasitic plants, which contrary to virtually all other plants, exhibit high levels of specificity toward their fungal hosts. The second case involves suilloid fungi; this is the largest monophyletic group of ectomycorrhizal fungi that is essentially restricted to associations with a single plant family. In both cases, new symbioses are initiated by dormant propagules that are stimulated to germinate by chemical cues from the host. This reduces the cost of wasting propagules on non-hosts. The advantages of specificity remain unclear in both cases, but we argue that increased benefit to the specialist may result from specialized physiological adaptations. We reexamine the idea that specialist fungi may help their hosts compete in complex ecosystems by reducing facultative epiparasitism by other plants, and suggest an alternative hypothesis for the observed pattern. PMID- 21708729 TI - Fungal endophytes: common host plant symbionts but uncommon mutualists. AB - Fungal endophytes are extremely common and highly diverse microorganisms that live within plant tissues, but usually remain asymptomatic. Endophytes traditionally have been considered plant mutualists, mainly by reducing herbivory via production of mycotoxins, such as alkaloids. However, the vast majority of endophytes, especially horizontally-transmitted ones commonly found in woody plants, apparently have little or no effect on herbivores. For the systemic, vertically-transmitted endophytes of grasses, mutualistic interactions via increased resistance to herbivores and pathogens are more common, as predicted by evolutionary theory. However, even in these obligate symbioses, endophytes are often neutral or even pathogenic to the host grass, depending on endophyte and plant genotype and environmental conditions.We present a graphical model based upon variation in nitrogen flux in the host plant. Nitrogen is a common currency in endophyte/host and plant/herbivore interactions in terms of limitations to host plant growth, enhanced uptake by endophytes, demand for synthesis of nitrogen-rich alkaloids, and herbivore preference and performance. Our graphical model predicts that low alkaloid-producing endophytes should persist in populations when soil nutrients and herbivory are low. Alternatively, high alkaloid endophytes are favored under increasing herbivory and increasing soil nitrogen, at least to some point. At very high soil nitrogen levels, uninfected plants may be favored over either type of infected plants. These predictions are supported by patterns of infection and alkaloid production in nature, as well by a manipulative field experiment. However, plant genotype and other environmental factors, such as available water, interact with the presence of the endophyte to influence host plant performance. PMID- 21708730 TI - Partner choice in nitrogen-fixation mutualisms of legumes and rhizobia. AB - Mutualistic interactions are widespread and obligatory for many organisms, yet their evolutionary persistence in the face of cheating is theoretically puzzling. Nutrient-acquisition symbioses between plants and soil microbes are critically important to plant evolution and ecosystem function, yet we know almost nothing about the evolutionary dynamics and mechanisms of persistence of these ancient mutualisms. Partner-choice and partner-fidelity are mechanisms for dealing with cheaters, and can theoretically allow mutualisms to persist despite cheaters.Many models of cooperative behavior assume pairwise interactions, while most plant microbe nutrient-acquisition symbioses involve a single plant interacting with numerous microbes. Market models, in contrast, are well suited to mutualisms in which single plants attempt to conduct mutually beneficial resource exchange with multiple individuals. Market models assume that one partner chooses to trade with a subset of individuals selected from a market of potential partners. Hence, determining whether partner-choice occurs in plant-microbe mutualisms is critical to understanding the evolutionary persistence and dynamics of these symbioses. The nitrogen-fixation/carbon-fixation mutualism between leguminous plants and rhizobial bacteria is widespread, ancient, and important for ecosystem function and human nutrition. It also involves single plants interacting simultaneously with several to many bacterial partners, including ineffective ("cheating") strains. We review the existing literature and find that this mutualism displays several elements of partner-choice, and may match the requirements of the market paradigm. We conclude by identifying profitable questions for future research. PMID- 21708731 TI - Coevolution and maladaptation. AB - Many of the most commonly cited examples of exquisite adaptation are of coevolved symbioses. As we learn more about the coevolutionary process, however, it is becoming increasingly evident that coevolution may also keep populations moderately maladapted much of the time. As a result, coevolving populations may only rarely occupy adaptive peaks, because the selective landscape is under continual change through reciprocal selection on the species themselves. These shifting patterns of coadaptation are further shaped by the geographic structure of most species. Selection mosaics across landscapes and coevolutionary hotspots can favor different evolutionary trajectories in different populations. The combined action of gene flow, random genetic drift, and local extinction of populations may then continually remold these local patterns, creating a geographic mosaic in the degrees of maladaptation found within local interactions. Recent mathematical models of the geographic mosaic of coevolution suggest that complex mosaics of maladaptation are a likely consequence of spatially structured species interactions. These models indicate that the spatial structure of maladaptation may depend upon the type of coevolutionary interaction, the underlying selection mosaic, and patterns of gene flow across landscapes. By maintaining local polymorphisms and driving the divergence of populations, coevolution may produce spatial patterns of maladaptation that are a source of ongoing innovation and diversification in species interactions. PMID- 21708732 TI - Molecular genetic perspectives on avian brood parasitism. AB - Advances in molecular genetic techniques have provided new approaches for addressing evolutionary questions about brood parasitic birds. We review recent studies that apply genetic data to the systematics, population biology, and social systems of avian brood parasites and suggest directions for future research. Recent molecular systematics studies indicate that obligate brood parasitism has evolved independently in seven different avian lineages, a tally that has increased by one in cuckoos (Cuculiformes) and decreased by one in passeriforms (Passeriformes) as compared to conventional taxonomy. Genetic parentage analyses suggest that brood parasitic birds are less promiscuous than might be expected given their lack of nesting and parental care behavior. Host specificity in brood parasites, which has important implications for host parasite coevolution, has been evaluated using both population genetic and parentage analyses. Female lineages are faithful to particular host species over evolutionarily significant time scales in both common cuckoos (Cuculus canorus) and indigobirds (Vidua spp.), but differences in the host-specificity of male parasites has resulted in different patterns of diversification in these two lineages. Future research on brood parasitism will benefit from the availability of comprehensive molecular phylogenies for brood parasites and their hosts and from advances in functional genomics. PMID- 21708733 TI - Coevolutionary genetics of Plasmodium malaria parasites and their human hosts. AB - Malaria has been invoked, perhaps more than any other infectious disease, as a force for the selection of human genetic polymorphisms. Evidence for genome shaping interactions can be found in the geographic and ethnic distributions of the hemoglobins, blood group antigens, thalassemias, red cell membrane molecules, human lymphocyte antigen (HLA) classes, and cytokines. Human immune responses and genetic variations can correspondingly influence the structure and polymorphisms of Plasmodium populations, notably in genes that affect the success and virulence of infection. In Africa, where the burden from Plasmodium falciparum predominates, disease severity and manifestations vary in prevalence among human populations. The evolutionary history and spread of Plasmodium species inform our assessment of malaria as a selective force. Longstanding host-pathogen relationships, as well as recent changes in this dynamic, illustrate the selective pressures human and Plasmodium species place on one another. Investigations of malaria protection determinants and virulence factors that contribute to the complexity of the disease should advance our understanding of malaria pathogenesis. PMID- 21708735 TI - Plant and animal physiological ecology, comparative physiology/biochemistry, and evolutionary physiology: opportunities for synergy: an introduction to the symposium. AB - Both plant biologists and animal biologists seek to understand how their focal organisms have evolved to interact with the environment. Despite this similarity in goals, the differing biology of plants and animals as well as other factors have led these scientific communities to diverge. Scientific discoveries that have occurred in each community in relative isolation may advance progress in the other community and set the stage for broad scientific syntheses. The accompanying papers, summarized herein, exemplify such discoveries, and collectively argue that the plant and animal ecophysiological communities have much to gain from improved cooperation and communication. PMID- 21708736 TI - Plants versus animals: do they deal with stress in different ways? AB - Both plants and animals respond to stress by using adaptations that help them evade, tolerate, or recover from stress. In a synthetic paper A. D. Bradshaw (1972) noted that basic biological differences between plants and animals will have diverse evolutionary consequences, including those influencing how they deal with stress. For instance, Bradshaw argued that animals, because they have relatively well-developed sensory and locomotor capacities, can often use behavior and movement to evade or ameliorate environmental stresses. In contrast, he predicted that plants will have to emphasize increased physiological tolerance or phenotypic plasticity, and also that plants should suffer stronger selection and show more marked differentiation along environmental gradients. Here we briefly review the importance of behavior in mitigating stress, the behavioral capacities of animals and plants, and examples of plant responses that are functionally similar to behaviors of animals. Next, we try to test some of Bradshaw's predictions. Unfortunately, critical data often proved non-comparable: plant and animal biologists often study different stressors (e.g., water versus heat) and measure different traits (photosynthesis versus locomotion). Nevertheless, we were able to test some of Bradshaw's predictions and some related ones of our own. As Bradshaw predicted, the phenology of plants is more responsive to climate shifts than is that of animals and the micro-distributions of non-mobile, intertidal invertebrates ("plant" equivalents) are more sensitive to temperature than are those of mobile invertebrates. However, mortality selection is actually weaker for plants than for animals. We hope that our review not only redraws attention to some fascinating issues Bradshaw raised, but also encourages additional tests of his predictions. Such tests should be informative. PMID- 21708737 TI - Atmospheric CO2 as a Global Change Driver Influencing Plant-Animal Interactions. AB - Plants respond to changes in atmospheric carbon dioxide. To herbivores, the decreased leaf protein contents and increased C/N ratios common to all leaves under elevated atmospheric carbon dioxide imply a reduction in food quality. In addition to these fine-scale adjustments, the abundance of C(3) and C(4) plants (particularly grasses) are affected by atmospheric carbon dioxide. C(4) grasses currently predominate over C(3) grasses in warmer climates and their distributions expand as atmospheric carbon dioxide levels decreased during glacial periods. C(4) grasses are a less nutritious food resource than C(3) grasses both in terms of reduced protein content and increased C/N ratios. There is an indication that as C(4)-dominated ecosystems expanded 6-8 Ma b.p., there were significant species-level changes in mammalian grazers. Today there is evidence that mammalian herbivores differ in their preference for C(3) versus C(4) food resources, although the factors contributing to these patterns are not clear. Elevated carbon dioxide levels will likely alter food quality to grazers both in terms of fine-scale (protein content, C/N ratio) and coarse-scale (C(3) versus C(4)) changes. PMID- 21708738 TI - Physiology on a landscape scale: plant-animal interactions. AB - We explore in this paper how animals can be affected by variation in climate, topography, vegetation characteristics, and body size. We utilize new spatially explicit state-of-the-art models that incorporate principles from heat and mass transfer engineering, physiology, morphology, and behavior that have been modified to provide spatially explicit hypotheses using GIS. We demonstrate how temporal and spatial changes in microclimate resulting from differences in topography and vegetation cover alter animal energetics, and behavior. We explore the impacts of these energetic predictions on elk energetics in burned and unburned stands of conifer in winter in Yellowstone National Park, chuckwalla lizard distribution limits in North America, California Beechey Ground squirrel and Dusky Footed woodrat mass and energy requirements and activity patterns on the landscape, their predator prey interactions with a rattlesnake, Crotalus viridis, and shifts in that food web structure due to topographic and vegetative variation. We illustrate how different scales of data/observation provide different pieces of information that may collectively define the real distributions of a species. We then use sensitivity analyses of energetic models to evaluate hypotheses about the effects of changes in core temperature (fever) global climate (increased air temperature under a global warming scenario) and vegetation cover (deforestation) on winter survival of elk, the geographic distribution of chuckwallas and the activity overlap of predator and prey species within a subset of commonly observed species in a terrestrial food web. Variation in slope and aspect affect the spatial variance in solar radiation incident on the ground, hence ground surface temperature, at the same elevation, same hourly 2 m air temperatures, and wind speeds. We illustrate visually how spatial effects and landscape heterogeneity make statistical descriptions of animal responses problematic, since multiple distributions of their responses to climate, topography, and vegetation on the landscape can yield the same descriptive statistics, especially at high (30 m) resolution. This preliminary analysis suggests that the model has far-reaching implications for hypothesis testing in ecology at a variety of spatial and temporal scales. PMID- 21708739 TI - Shared signals and the potential for phylogenetic espionage between plants and animals. AB - Until recently, the study and understanding of plant and animal signalling and response mechanisms have developed independently. Recent biochemical and molecular work is producing a growing list of elements involved in responses to biotic and abiotic stimuli that are very similar across kingdoms. Some of the more interesting examples of these include prostaglandin/octadecanoid-mediated responses to wounding, steroid-based signalling systems, and pathogen-recognition mechanisms. Some of these similarities probably represent evolutionary convergence; others may be ancestral to plants and animals. Ecological and evolutionary implications of such overlaps include the existence of pathogens that can cause disease in plants and animals, the ability of herbivores to manipulate plant responses, usurpation of microbial mechanisms and genes by herbivorous animals and plants, evolution of plant defenses exploiting shared signals in animals, and the medicinal use of plants by humans. Comparative study of the signalling and response mechanisms used by plants, animals, and microbes provides novel and useful insights to the ecology and evolution of interactions across kingdoms. PMID- 21708740 TI - Sensing and responding to hypoxia, molecular and physiological mechanisms. AB - In order to adapt to low oxygen it is necessary first to be able to detect hypoxia, then to initiate the appropriate defense mechanisms. There are two basic detectors: molecular sensors that are directly linked to gene regulation and metabolic indicators that are triggered when the cell goes into a state of energy imbalance. The molecular responses to oxygen deprivation are characterized in a variety of cell types and include activation of oxygen sensors, signaling through specific promoter elements and subsequent downstream adaptations. Many of the components are highly conserved across species. In the brain, the most hypoxic vulnerable of all vertebrate tissues, low oxygen quickly results in a fall in ATP and a consequent increase in adenosine. Both changes act as metabolic indicators of cellular energy crisis and effect mechanisms to reduce metabolic demand. Important lessons on the potential scope of such mechanisms can be provided by the anoxic tolerant turtle brain. Anoxia provokes an early release of adenosine which mediates channel arrest, causes a reduction in K(+) efflux and Ca(2+) influx, and inhibits excitatory neurotransmitter release. There is a differential expression between normoxic and anoxic turtle brains of transcripts encoding the immediate early gene products c-fos and c-jun, the HSP-70 and the apoptosis regulators bcl-2 and bax. PMID- 21708741 TI - How terrestrial organisms sense, signal, and respond to carbon dioxide. AB - Because of anthropogenic increases in atmospheric CO(2) content, there is a need to understand how organisms sense and respond to CO(2) variation. An important distinction is whether CO(2) responses result from direct effects of CO(2) on signal-transduction pathways, enzyme catalysis, or regulatory processes, as opposed to indirect, secondary responses that are a consequence of the direct effects. In plants, direct effects occur because rising CO(2) A) increases the activity of Ribulose-1,5-bisphopshate carboxylase/oxygenase (Rubisco) via its role as a substrate for RuBP carboxylation and its inhibition of RuBP oxygenation; B) reduces stomatal aperture; C) alters mitochondrial respiration; and D) possibly reduces transcription of genes for Rubisco activase and carbonic anhydrase. Because of these direct effects, the carbon and water balance of plants is altered leading to secondary effects on growth, resource partitioning and defense compound synthesis. Reduced investment in photosynthetic protein is one of the characteristic acclimation responses of plants to high CO(2). This is modulated by increased carbohydrate levels, probably in concert with hormone signals from the roots. Roots are hypothesized to be the main control points for CO(2) acclimation because they are well situated to integrate the carbohydrate status of the plant. In higher fungi, development of the mushroom fruiting body is inhibited at high CO(2), but the mechanism is poorly known. Fungal CO(2) sensing may serve to position the spore-bearing tissue above the soil boundary layer to ensure effective spore dispersal. The animals that are most sensitive to anthropogenic CO(2) enrichment are insects. Many insects have a well-developed ability to sense CO(2) variation as a means of locating food. Unlike plants, insects have CO(2) receptors that can detect variation in CO(2) as low as 0.5 ppm. However, the sensitivity of these receptors is reduced in atmospheres with double or triple current levels of CO(2), indicating some insect species may be threatened by rising atmospheric CO(2). PMID- 21708742 TI - Temporal dispersal: ecological and evolutionary aspects of zooplankton egg banks and the role of sediment mixing. AB - Zooplankton egg banks are the accumulation of diapausing embryos of planktonic animals buried in the sediments of many aquatic ecosystems. These eggs, which are analogous life history stages to the seeds of many plants, can survive in a ready to-hatch state for periods ranging from a few years to greater than a century. Their presence in ponds, lakes and near-shore marine environments has substantial implications for understanding trajectories of ecological and evolutionary change. When the sediments of lakes are structured in historical sequence, diapausing eggs extracted from different sediment ages can provide a means of studying past changes in community or population-genetic structure. A completely different aspect of egg banks derives from the fact that hatching of diapausing eggs can influence, through what can be thought of as temporal dispersal, population and community response to environmental change. Eggs hatching from diapause introduce to current environments species or genotypes laid at times in the distant past. In addition, egg banks create extended generation overlap that can play an important role in maintaining diversity in a fluctuating environment when different types (species or genotypes) are favored at different times. These distinct aspects of egg banks (i.e., their direct impact on ecological and evolutionary processes versus their usefulness in reconstructing historical changes), are potentially in conflict because for old eggs to hatch, the sediments must be at least partially mixed. This same mixing, however, degrades the accuracy of the historical record. Both aspects are possible, however, even within a single lake when sediment-mixing intensity is spatially heterogeneous. PMID- 21708743 TI - The dynamics of "dead wood": maintenance of water transport through plant stems. AB - The lack of mobility in plants is often interpreted as a sign of their passivity in the face of environmental variation. This view is perhaps most firmly entrenched with regard to water transport through the xylem in which water flows through the lumen of cells that are "dead" (i.e., lack any cytoplasm or nucleus) at maturity. However, recent work demonstrates that a number of active, physiological processes may be involved in maintaining the transport capacity of this essential pathway. Here we review work relating to both embolism repair and the effect of ion concentrations on xylem hydraulic properties as examples of such dynamic processes. PMID- 21708744 TI - Is there a single biochemical adaptation to anhydrobiosis? AB - Even though water is required for the maintenance of biological integrity, numerous organisms are capable of surviving loss of virtually all their cellular water and existing in a state known as anhydrobiosis. Over the past three decades we and others have established that disaccharides such as trehalose and sucrose are almost certainly involved in stabilizing the dry cells. We discuss here some of the evidence behind the mechanism of this stabilization. Until the past few years this mechanism has been sufficiently appealing that a consensus has been developing that acquisition of these sugars in the cytoplasm may be both necessary and sufficient for anhydrobiosis. We show here that there are other routes to achieve the effects conferred by the sugars and that other adaptations are almost certainly required, at least in environmental conditions that are less than optimal. Under optimal storage conditions, the presence of the sugars alone may be sufficient to stabilize even mammalian cells in the dry state, findings that are already finding use in human clinical medicine. PMID- 21708745 TI - Is stress more than a disease? A comparative look at the adaptativeness of stress. PMID- 21708746 TI - Causes and consequences of stress. AB - Stress involves real or perceived changes within an organism in the environment that activate an organism's attempts to cope by means of evolutionarily ancient neural and endocrine mechanisms. Responses to acute stressors involve catecholamines released in varying proportion at different sites in the sympathetic and central nervous systems. These responses may interact with and be complemented by intrinsic rythms and responses to chronic or intermittent stressors involving the hypothalamic-pituitary-adrenal axis. Varying patterns of responses to stressors are also affected by an animal's assessment of their prospects for successful coping. Subsequent central and systemic consequences of the stress response include apparent changes in affect, motivation, and cognition that can result in an altered relationship to environmental and social stimuli. This review will summarize recent developments in our understanding of the causes and consequences of stress. Special problems that need to be explored involve the manner in which ensembles of adaptive responses are assembled, how autonomic and neurohormonal reflexes of the stress response come under the influence of environmental stimuli, and how some specific aspects of the stress response may be integrated into the life history of a species. PMID- 21708747 TI - Stress in fishes: a diversity of responses with particular reference to changes in circulating corticosteroids. AB - Physical, chemical and perceived stressors can all evoke non-specific responses in fish, which are considered adaptive to enable the fish to cope with the disturbance and maintain its homeostatic state. If the stressor is overly severe or long-lasting to the point that the fish is not capable of regaining homeostasis, then the responses themselves may become maladaptive and threaten the fish's health and well-being. Physiological responses to stress are grouped as primary, which include endocrine changes such as in measurable levels of circulating catecholamines and corticosteroids, and secondary, which include changes in features related to metabolism, hydromineral balance, and cardiovascular, respiratory and immune functions. In some instances, the endocrine responses are directly responsible for these secondary responses resulting in changes in concentration of blood constituents, including metabolites and major ions, and, at the cellular level, the expression of heat shock or stress proteins. Tertiary or whole-animal changes in performance, such as in growth, disease resistance and behavior, can result from the primary and secondary responses and possibly affect survivorship.Fishes display a wide variation in their physiological responses to stress, which is clearly evident in the plasma corticosteroid changes, chiefly cortisol in actinopterygian fishes, that occur following a stressful event. The characteristic elevation in circulating cortisol during the first hour after an acute disturbance can vary by more than two orders of magnitude among species and genetic history appears to account for much of this interspecific variation. An appreciation of the factors that affect the magnitude, duration and recovery of cortisol and other physiological changes caused by stress in fishes is important for proper interpretation of experimental data and design of effective biological monitoring programs. PMID- 21708748 TI - Ethological Aspects of Stress in a Model Lizard, Anolis carolinensis. AB - Research on the stress response in reptiles can provide a useful comparative perspective for understanding how the constituent elements of the response can be put into service of diverse behavioral adaptations. A summary of the neural and endocrine causes and consequences of specific behavioral patterns seen in the small diurnal lizard, Anolis carolinensis, has provided a model for the exploration of the dynamics of autonomic and neurohormonal contributions to adaptive behavior. In this species, changes in body color provide indices of the flux of circulating stress-relevant hormones, and are seen in situations from spontaneous exploration through agonistic behavior. Furthermore, captive adult males spontaneously and consistently manifest social dominance relationships that provide many of the elements of a stress-mediated adaptive behavioral patterns. These patterns include suppressed reproduction and long-term coping apparently based more on stress-mediated changes in motivation than acquired changes in behavior. PMID- 21708749 TI - Neurocircuitry of stress integration: anatomical pathways regulating the hypothalamo-pituitary-adrenocortical axis of the rat. AB - The hypothalamo-pituitary-adrenocortical (HPA) axis is recruited by the organism in response to real or perceived threats to homeostasis ("stress"). Regulation of this neuroendocrine system is accomplished by modulation of secretory tone in hypophysiotrophic neurons of the medial parvocellular paraventricular nucleus. Excitation of these neurons is mediated by several sources: direct (and perhaps indirect) inputs from brainstem neurons regulating autonomic tone/arousal; circumventricular organs monitoring blood and CSF constituents; and local-circuit neurons within the hypothalamus and basal forebrain. The latter are predominantly GABAergic; notably, these areas are targets for descending GABAergic input from limbic structures, and may promote PVN secretory activity via disinhibition. Neurosecretory paraventricular nucleus neurons are inhibited by glucocorticoid dependent and -independent mechanisms. Glucocorticoid negative feedback appears to act both locally and in extrahypothalamic loci, and is likely integrated in a region- and stressor-specific manner. Inhibitory input to the medial parvocellular paraventricular nucleus emanate predominantly from the bed nucleus of the stria terminalis and hypothalamus, and are likely regulated by neuroendocrine homeostats. Descending limbic inhibitory information appears to act through excitation of these inhibitory inputs. Overall, integration of stressful information is a multi-faceted process integrating prior experience and real or anticipated homeostatic disruption into appropriate activation and deactivation of the hypothalamo-pituitary-adrenocortical axis. PMID- 21708750 TI - The role of corticotropin-releasing factor receptors in stress and anxiety. AB - Corticotropin releasing factor (CRF) is a critical integrator of the hypothalamic pituitary-adrenal (HPA) axis in response to stress. CRF and its related molecule urocortin (UCN) bind CRF receptor 1 (CRFR1) and CRFR2 with distinct affinities. Mice deficient for CRFR1 or CRFR2 were generated in order to determine the physiological role of these receptors. While CRFR1-mutant mice show a depleted stress response and display anxiolytic-like behavior, CRFR2-mutant mice are hypersensitive to stress and display anxiogenic-like behavior. Both CRFR1- and CRFR2-mutant mice show normal basal feeding and weight gain, but CRFR2-mutant mice exhibit decreased food intake following a stress of food deprivation. While CRFR2-mutant mice display increased levels of CRF mRNA in the central nucleus of the amygdala (cAmyg) but not in the paraventricular nucleus of the hypothalamus (PVN), the CRFR1-mutant mice express high levels of CRF in the PVN but normal levels in the cAmyg. CRFR2-mutant mice also display increased levels of Ucn mRNA and protein in the edinger westphal nucleus (EW) as well as an increased number of cells expressing Ucn. The levels of these CRF-receptor ligands reflect the state of the receptor-deficient mice. These results demonstrate a possible modulatory function of CRFR2 in response to CRFR1 stimulation of the HPA axis or anxiety. PMID- 21708751 TI - A hassle a day may keep the doctor away: stress and the augmentation of immune function. AB - Stress may be defined as a sequence of events, that begins with a stimulus (stressor), that is recognized by the brain (stress perception), and which results in the activation of physiologic fight/flight/fright systems within the body (stress response). Many evolutionary selection pressures are stressors, and one of the primary functions of the brain is to perceive stress, warn the body of danger, and enable an organism to respond. We hypothesized that under acute conditions, just as the stress response prepares the cardiovascular and musculoskeletal systems for fight or flight, it may also prepare the immune system for challenges (e.g., wounding) which may be imposed by a stressor (e.g., an aggressor). Initial studies showed that acute (2h) stress induced a significant trafficking of immune cells to the skin. Since the skin is an organism's major protective barrier, we hypothesized that this leukocyte redistribution may serve to enhance skin immunity during acute stress. We tested this hypothesis using the delayed type hypersensitivity (DTH) reaction, which mediates resistance to various infectious agents, as a model for skin immune function. Acute stress administered immediately before antigen exposure significantly enhanced skin DTH. Adrenalectomy (ADX) eliminated the stress induced enhancement of DTH while administration of physiological doses of corticosterone and/or epinephrine to ADX animals enhanced skin DTH in the absence of stress. These studies showed that changes in leukocyte distribution and circulating stress hormones are systemic mediators of the immunoenhancing effects of acute stress. We recently identified gamma interferon as a local cytokine mediator of a stress-induced immunoenhancement. Our results suggest that during acute stress the brain sends preparatory warning signals to the immune system just as it does to other fight/flight systems of the body. PMID- 21708752 TI - Developmental changes in interrenal responsiveness in anuran amphibians. AB - Basal activity of the hypothalamo-pituitary-interrenal (HPI) axis changes over development in larval amphibians, but development of the responsiveness of this axis to an external stressor has not been studied. We compared developmental changes in whole-body corticosterone content of two anuran amphibian species, Rana pipiens (family Ranidae) and Xenopus laevis (family Pipidae). We also examined developmental changes in the responsiveness of the HPI axis by subjecting tadpoles of different developmental stages to a laboratory shaking/confinement stress and to ACTH injection. We measured whole-body corticosterone content as an indicator of the activity of the HPI axis. Whole body corticosterone content of R. pipiens remained low during premetamorphosis and prometamorphosis but increased dramatically at metamorphic climax and remained elevated in juvenile frogs. By contrast, whole-body corticosterone content of X. laevis was highest during premetamorphosis, declined at the onset of prometamorphosis, increased at metamorphic climax and remained at climax levels in juvenile frogs. Premetamorphic and prometamorphic tadpoles of both species showed strong corticosterone responses to both shaking stress and ACTH injection. The magnitude and pattern of response differed among developmental stages, with premetamorphic tadpoles of both species showing greater responsiveness to stress and ACTH. Our results show that interrenal responsiveness is developed in premetamorphic tadpoles, suggesting that at these stages tadpoles are capable of mounting an increase in stress hormone production in response to changes in the external environment. Our results also highlight the importance of comparative studies in understanding the development of the stress axis. PMID- 21708753 TI - Cortisol and Pacific Salmon: A New Look at the Role of Stress Hormones in Olfaction and Home-stream Migration. AB - Pacific salmon (genus Oncorhynchus) exhibit an interesting and uncommon life history pattern that combines semelparity, anadromy, and navigation (homing). During smoltification, young salmon imprint on the chemical composition of their natal stream water (the home-stream olfactory bouquet or "HSOB"); they then migrate to the ocean where they spend a few years feeding prior to migrating back to their natal freshwater stream to spawn. Upstream migration is guided by the amazing ability to discriminate between the chemical compositions of different stream waters and thus identify and travel to their home-stream. Pacific salmon demonstrate marked somatic and neural degeneration changes during home-stream migration and at the spawning grounds. The appearance of these pathologies is correlated with a marked elevation in plasma cortisol levels. While the mechanisms of salmonid homing are not completely understood, it is known that adult salmon continuously utilize two of their primary sensory systems, olfaction and vision, during homing. Olfaction is the primary sensory system involved in freshwater homing and "HSOB" recognition, and will be emphasized here. Previously, we proposed that the increase in plasma cortisol during Pacific salmon home-stream migration is adaptive because it enhances the salmon's ability to recall the imprinted memory of the "HSOB" (Carruth, 1998; Carruth et al., 2000b). Elevated plasma concentrations of cortisol could prime the hippocampus or other olfactory regions of the brain to recall this memory and, therefore, aid in directing the fish to their natal stream. Thus, specific responses of salmon to stressors could enhance reproductive success. PMID- 21708754 TI - Stress, neuropeptides, and feeding behavior: a comparative perspective. AB - Stress inhibits feeding behavior in all vertebrates. Data from mammals suggest an important role for hypothalamic neuropeptides, in particular the melanocortins and corticotropin-releasing hormone (CRH)-like peptides, in mediating stress induced inhibition of feeding. The effects of CRH on food intake are evolutionarily ancient, as this peptide inhibits feeding in fishes, birds, and mammals. The effects of melanocortins on food intake have not been as extensively studied, but available evidence suggests that the anorexic role of neuronal melanocortins has been conserved. Although there is evidence that CRH and the melanocortins influence hypothalamic circuitry controlling food intake, these peptides may have a more primitive role in modulating visuomotor pathways involved in the recognition and acquisition of food. Stress rapidly reduces visually guided prey-catching behavior in toads, an effect that can be mimicked by administration of CRH, while corticosterone and isoproterenol are without effect. Melanocortins also reduce prey-oriented turning movements and, in addition, facilitate the acquisition of habituation to a moving prey item. The effects of these neuropeptides are rapid, occurring within 30 min after administration. Thus, changes in neuroendocrine status during stress may dramatically influence the efficacy with which visual stimuli release feeding behavior. By modulating visuomotor processing these neuropeptides may help animals make appropriate behavioral decisions during stress. PMID- 21708755 TI - Social interaction over time, implications for stress responsiveness. AB - Behavioral interaction during social situations is a continuum of action, response, and reaction. The temporal nature of social interaction creates a series of stressful situations, such as aggression, displacement from resources, and the variable psychological challenge of adapting to dynamic social hierarchies. The ebb and flow of neurochemical and endocrine secretions during social stress provide a unique tool for understanding individualized responses to stress. Each social station is an adaptive response to a stressful social condition, resulting in unique neuroendocrine and behavioral responses. By examining the temporal changes of limbic monoamines and plasma glucocorticoids, aspects of mechanisms for adaptation emerge. The similarity of temporal patterns induced by social stress among fish, reptiles and primates are remarkable. Even different specific coping mechanisms point out the similarity of vertebrate stress responses. The lizard Anolis carolinensis exhibits a unique sign stimulus generated during social stress by the sympathetic nervous system that serves as a temporal landmark to distinguish neuroendocrine patterns. During social interaction dominant males have a shorter latency to eyespot darkening than opponents, inhibiting aggressive display. Eyespot coloration can be delayed using a serotonin reuptake inhibitor, causing dominant social status in many animals to be lost. Reversal of social status via serotonergic activation appears to mimic chronic serotonergic activity. The pattern of eyespot darkening, faster in dominant males, is coincident with that for serotonergic activity. The fundamental temporal relationship between dominant and subordinate limbic monoaminergic activity over a continuous course of social interaction appears to be a two-phase response, temporally specific to brain region, and always faster in dominant individuals. PMID- 21708756 TI - Endocrine responses to unpredictable environmental events: stress or anti-stress hormones? AB - In addition to seasonal changes in morphology, physiology and behavior that occur in predictable annual cycles, there are facultative responses to unpredictable events known as labile (i.e., short-lived) perturbation factors (LPFs). These rapid behavioral and physiological changes have been termed the "emergency" life history stage (ELHS) and serve to enhance life-time fitness. Glucocorticosteroids interacting with other hormones in the hypothalamo-pituitary-adrenal (HPA) cascade, initiate and orchestrate the ELHS within minutes to hours. Components of the ELHS include: redirection of behavior from a normal life history stage to increased foraging, irruptive-type migration during the day, enhanced restfulness at night, elevated gluconeogenesis and recovery once the perturbation passes. These physiological and behavioral changes allow an individual to avoid potential deleterious effects of stress that may result from chronically elevated levels of circulating glucocorticosteroids over days and weeks. In other words, acute rises in glucocorticosteroids following perturbations of the environment may actually avoid chronic stress and serve primarily as "anti-stress" hormones. Several field studies in diverse habitats indicate that free-living populations have elevated circulating levels of corticosteroids when in an ELHS. However, expression of an ELHS may not always be advantageous and there is accumulating evidence from birds that the adrenocortical responses to LPFs are modulated both on seasonal and individual levels. These data suggest that glucocorticosteroid secretions in response to LPFs not only trigger physiological and behavioral responses but also allow flexibility so that the response is integrated in relation to time of year (normal LHS) as well as individual differences owing to body condition, disease and social status. PMID- 21708757 TI - The lesser-known protostome taxa: an introduction and a tribute to robert p. Higgins. AB - Most biologists are familiar only with a few of the approximately 40 extant animal phyla. The purpose of this symposium was to renew interest in the lesser known invertebrate taxa, encourage their use in research and teaching and to promote the relevance of high-level systematic studies. This paper reviews the two major views of metazoan evolutionary relationships with particular attention to the lesser-known taxa and to some of the new and/or conflicting terminology used in current animal phylogenetic study. The current use of lesser-known taxa in research is briefly described, and the discussion that followed the symposium is summarized. The paper concludes with a brief history of the symposium and a tribute to Robert P. Higgins, who organized three "Symposia on the Lesser-Known Invertebrates" over the past 25 yr. PMID- 21708758 TI - Ultrastructure, biology, and phylogenetic relationships of kinorhyncha. AB - The article summarizes current knowledge mainly about the (functional) morphology and ultrastructure, but also about the biology, development, and evolution of the Kinorhyncha. The Kinorhyncha are microscopic, bilaterally symmetrical, exclusively free-living, benthic, marine animals and ecologically part of the meiofauna. They occur throughout the world from the intertidal to the deep sea, generally in sediments but sometimes associated with plants or other animals. From adult stages 141 species are known, but 38 species have been described from juvenile stages. The trunk is arranged into 11 segments as evidenced by cuticular plates, sensory spots, setae or spines, nervous system, musculature, and subcuticular glands. The ultrastructure of several organ systems and the postembryonic development are known for very few species. Almost no data are available about the embryology and only a single gene has been sequenced for a single species. The phylogenetic relationships within Kinorhyncha are unresolved. Priapulida, Loricifera, and Kinorhyncha are grouped together as Scalidophora, but arguments are found for every possible sistergroup relationship within this taxon. The recently published Ecdysozoa hypothesis suggests a closer relationship of the Scalidophora, Nematoda, Nematomorpha, Tardigrada, Onychophora, and Arthropoda. PMID- 21708759 TI - Two dimensions of biodiversity research exemplified by nematomorpha and gastrotricha. AB - Biodiversity research combines two dimensions, the horizontal one that contains species diversity, patterns among this diversity and its interconnections and the vertical one that deals with the history of biodiversity, i.e., its phylogeny. With these tight interconnections, the importance of so-called "lesser known groups" such as Nematomorpha and Gastrotricha can be shown. Two examples are the life cycle of Nematomorpha and the phylogenetic position of Gastrotricha. The life cycle of Nematomorpha is only partially known and almost no conclusions can be made about the impact of Nematomorpha on their hosts. For the phylogenetic position of Gastrotricha, alternative hypotheses are available, mainly due to different results of morphological and molecular (18S rDNA) analyses. It is demonstrated how these different hypotheses influence character interpretation and reconstruction among Protostomia (Gastroneuralia). PMID- 21708760 TI - An introduction to loricifera, cycliophora, and micrognathozoa. AB - Loriciferans, cycliophorans and micrognathozoans are amongst the latest groups of animals to be discovered. Other than all being microscopic, they have very different body plans and are not closely related. Loriciferans were originally assigned to the Aschelminthes. However, both new molecular and ultrastructural researches have shown that Aschelminthes consist of two unrelated groups, Cycloneuralia and Gnathifera. Cycloneuralia may be included in the Ecdysozoa, including all molting invertebrates, and Gnathifera are more closely related to Platyhelminthes. The phylum Loricifera shares many apomorphic characters (e.g., scalids on the introvert) with both Priapulida and Kinorhyncha, and can be included in the taxon Scalidophora, a subgroup of Cycloneuralia. Cycliophora was originally allied to the Entoprocta and Ectoprocta (Bryozoa) based on ultrastructual research. Subsequent molecular data show they may be related to Rotifera and Acanthocephala, within the taxon Gnathifera. The phylogenetic position of Cycliophora is therefore not settled, and more ultrastructural and molecular data are needed. Micrognathozoa is the most recent major group of animals to be described. They show strong affinities with both Rotifera and Gnathostomulida (within the taxon Gnathifera), especially in the fine structure of the pharyngeal apparatus, where the jaw elements have cuticular rods with osmiophilic cores. Furthermore the micrognathozoans have two rows of multiciliated cells that form a locomotory organ, similar to that seen in some gastrotrichs and interstitial annelids. This character is never seen in Rotifera or in the monociliated Gnathostomulida. Rotifera and Acanthocephala always have a syncytial epidermis (Syndermata). Micrognathozoa lack this characteristic feature. Therefore, they are postulated to be placed basally in the Gnathifera, either as a sister-group to Gnathostomulida or as a sister-group to Rotifera + Acanthocephala. PMID- 21708761 TI - Current status of the tardigrada: evolution and ecology. AB - The Tardigrada are bilaterally symmetrical micrometazoans with four pairs of lobopod legs terminating in claws or sucking disks. They occupy a diversity of niches in marine, freshwater, and terrestrial environments throughout the world. Some have a cosmopolitan distribution, while others are endemic. About 900 species have been described thus far, but many more species are expected as additional habitats are investigated. Most are less than 1 mm in body length and are opaque or translucent, exhibiting colors such as brown, green, orange, yellow, red, or pink in the cuticle and/or gut. Marine species are more variable in body shape and overall appearance and generally exhibit low population density with high species diversity. Reproductive modes include sexual reproduction and parthenogenesis, but much remains to be known about development. Tardigrades have a hemocoel-type of fluid-filled body cavity, a complete digestive tract, and a lobed dorsal brain with a ventral nerve cord with fused ganglia. Recent molecular analyses and additional morphological studies of the nervous system have confirmed the phylogenetic position of tardigrades as a sister group of the arthropods. The ability of tardigrades to undergo cryptobiosis has long intrigued scientists. Although tardigrades are active only when surrounded by a film of water, they can enter latent states in response to desiccation (anhydrobiosis), temperature (cryobiosis), low oxygen (anoxybiosis), and salinity changes (osmobiosis). Cryptobiotic states aid in dispersal. PMID- 21708762 TI - Rotifers: exquisite metazoans. AB - Rotifers comprise a modestly sized phylum (~1,850 species) of tiny (ca. 50-2,000 MUm), bilaterally symmetrical, eutelic metazoans, traditionally grouped within the pseudocoelomates or Aschelminthes. These saccate to cylindrically shaped protostomes possess three prominent regions (corona, trunk, foot). They are distinguished by a ciliated, anterior corona (used in locomotion and food gathering) and a pharynx equipped with a complex set of jaws. Unfortunately, these generalizations grossly oversimplify a rich and fascinating diversity. Chief among the charms of the study of rotifers are their ecological importance, ease of culture (including chemostat technology), and the fact that much remains unknown about this exquisite phylum. PMID- 21708763 TI - Acanthocephalan phylogeny and the evolution of parasitism. AB - The study of parasite evolution relies on the identification of free-living sister taxa of parasitic lineages. Most lineages of parasitic helminths are characterized by an amazing diversity of species that complicates the resolution of phylogenetic relationships. Acanthocephalans offer a potential model system to test various long-standing hypotheses and generalizations regarding the evolution of parasitism in metazoans. The entirely parasitic Acanthocephala have a diversity of species that is manageable with regards to constructing global phylogenetic hypotheses, exhibit variation in hosts and habitats, and are hypothesized to have close phylogenetic affinities to the predominately free living Rotifera. In this paper, I review and test previous hypotheses of acanthocephalan phylogenetic relationships with analyses of the available 18S rRNA sequence database. Maximum-parsimony and maximum-likelihood inferred trees differ significantly with regard to relationships among acanthocephalans and rotifers. Maximum-parsimony analysis results in a paraphyletic Rotifera, placing a long-branched bdelloid rotifer as the sister taxon of Acanthocephala. Maximum likelihood analysis results in a monophyletic Rotifera. The difference between the two optimality criteria is attributed to long-branch attraction. The two analyses are congruent in terms of relationships within Acanthocephala. The three sampled classes are monophyletic, and the Archiacanthocephala is the sister taxon of a Palaeacanthocephala + Eoacanthocephala clade. The phylogenetic hypothesis is used to assess the evolution of host and habitat preferences. Acanthocephalan lineages have exhibited multiple radiations into terrestrial habitats and bird and mammal definitive hosts from ancestral aquatic habitats and fish definitive hosts, while exhibiting phylogenetic conservatism in the type of arthropod intermediate host utilized. PMID- 21708764 TI - Unsegmented annelids? Possible origins of four lophotrochozoan worm taxa. AB - In traditional classification schemes, the Annelida consists of the Polychaeta and the Clitellata (the latter including the Oligochaeta and Hirudinida). However, recent analyses suggest that annelids are much more diverse than traditionally believed, and that polychaetes are paraphyletic. Specifically, some lesser-known taxa (previously regarded as separate phyla) appear to fall within the annelid radiation. Abundant molecular, developmental, and morphological data show that the Siboglinidae, which includes the formerly recognized Pogonophora and Vestimentifera, are derived annelids; recent data from the Elongation Factor 1alpha (EF-1alpha) gene also suggest that echiurids are of annelid ancestry. Further, the phylogenetic origins of two other lesser-known groups of marine worms, the Myzostomida and Sipuncula, have recently been called into question. Whereas some authors advocate annelid affinities, others argue that these taxa do not fall within the annelid radiation. With advances in our understanding of annelid phylogeny, our perceptions of body plan evolution within the Metazoa are changing. The evolution of segmentation probably is more plastic than traditionally believed. However, as our understanding of organismal evolution is being revised, we are also forced to reconsider the specific characters being examined. Should segmentation be considered a developmental process or an ontological endpoint? PMID- 21708765 TI - The phylogenetic position of entoprocta, ectoprocta, phoronida, and brachiopoda. AB - Ectoprocts, phoronids and brachiopods are often dealt with under the heading Tentaculata or Lophophorata, sometimes with entoprocts discussed in the same chapter, for example in Ruppert and Barnes (1994). The Lophophorata is purported to be held together by the presence of a "lophophore," a mesosomal tentacle crown with an upstream-collecting ciliary band. However, the mesosomal tentacle crown of pterobranchs has upstream-collecting ciliary bands with monociliate cells, similar to those of phoronids and brachiopods, although its ontogeny is not well documented. On the contrary, the ectoproct tentacle crown carries a ciliary sieving system with multiciliate cells and the body does not show archimery, neither during ontogeny nor during budding, so the tentacles cannot be characterized as mesosomal. The entoprocts have tentacles without coelomic canals and with a downstream-collecting ciliary system like that of trochophore larvae and adult rotifers and serpulid and sabellid annelids. Planktotrophic phoronid and brachiopod larvae develop tentacles at an early stage, but their ciliary system resembles those of echinoderm and enteropneust larvae. Ectoproct larvae are generally non-feeding, but the planktotrophic cyphonautes larvae of certain gymnolaemates have a ciliary band resembling that of the adult tentacles. The entoprocts have typical trochophore larvae and many feed with downstream collecting ciliary bands. Phoronids and brachiopods are thus morphologically on the deuterostome line, probably as the sister group of the "Neorenalia" or Deuterostomia sensu stricto. The entoprocts are clearly spiralians, although their more precise position has not been determined. The position of the ectoprocts is uncertain, but nothing in their morphology indicates deuterostome affinities. "Lophophorata" is thus a polyphyletic assemblage and the word should disappear from the zoological vocabulary, just as "Vermes" disappeared many years ago. PMID- 21708766 TI - Progress in nemertean biology: development and phylogeny. AB - This paper reviews progress in developmental biology and phylogeny of the Nemertea, a common but poorly studied spiralian taxon of considerable ecological and evolutionary significance. Analyses of reproductive biology (including calcium dynamics during fertilization and oocyte maturation), larval morphology and development and developmental genetics have significantly extended our knowledge of spiralian developmental biology. Developmental genetics studies have in addition provided characters useful for reconstructing metazoan phylogeny. Reinvestigation of the cell lineage of Cerebratulus lacteus using fluorescent tracers revealed that endomesoderm forms from the 4d cell as in other spiralians and that ectomesoderm is derived from the 3a and 3b cells as in annelids, echiurans and molluscs. Studies examining blastomere specification show that cell fates are established precociously in direct developers and later in indirect developers. Morphological characters used to estimate the phylogenetic position of nemerteans are critically re-evaluated, and cladistic analyses of morphology reveal that conflicting hypotheses of nemertean relationships result because of different provisional homology statements. Analyses that include disputed homology statements (1, gliointerstitial cell system 2, coelomic circulatory system) suggest that nemerteans form the sister taxon to the coelomate spiralian taxa rather than the sister taxon to Platyhelminthes. Analyses of small subunit rRNA (18S rDNA) sequences alone or in combination with morphological characters support the inclusion of the nemerteans in a spiralian coelomate clade nested within a more inclusive lophotrochozoan clade. Ongoing evaluation of nemertean relationships with mitochondrial gene rearrangements and other molecular characters is discussed. PMID- 21708767 TI - Modulation of the crayfish escape reflex--physiology and neuroethology. AB - We review here factors that control the excitability of the giant neuron-mediated tail-flip escape behavior in crayfish, focusing especially on recent findings concerning serotonergic modulation. Serotonin can either facilitate or inhibit escape depending on concentration and pattern of application. Low concentrations facilitate while high ones inhibit; however, if high concentrations arise gradually they facilitate instead of inhibiting. The effects of serotonin can also be altered by social experience, with application regimens that cause facilitation in social isolates coming to produce inhibition after an extended period of living as a subordinate. Attempts to understand both the possible physiological basis of some of these complexities and their possible function are discussed. Neuroethological investigations indicate that giant neuron-mediated escape is inhibited during the initial fights that establish social relationships and is facilitated in their immediate aftermath. Once the relationship of a pair is well-established, the presence of the dominant tends to suppress giant neuron mediated escape (but not tail-flip escape mediated by non-giant circuitry) in the subordinate, but the presence of the subordinate has relatively little effect on the dominant. These patterns of modulation can be seen as consistent with the known variations in serotonin's effect as a function of concentration and social experience and may provide a biological reason for these variations. PMID- 21708768 TI - Decision-making in the leech nervous system. AB - Previous models of behavioral choice have described two types of hierarchy, a decision hierarchy, in which different classes of decisions are made at each level (Tinbergen, 1951), and a behavioral hierarchy, in which one behavior will take precedence over others (Davis, 1985). Most experimental work on the neuronal basis of decision-making has focussed on the latter of these: a behavioral hierarchy is described for an animal, and the neuronal basis for this hierarchy, hypothesized to depend on inhibitory interactions, is investigated. Although the concept of "dedicated command neurons" has been useful for guiding these studies, it appears that such neurons are rare. We present evidence that in the leech, most neurons, including high-level decision neurons, are active in more than one behavior. We include data from one newly-identified neuron that elicits both swimming and crawling motor patterns. We suggest that decisions are made by a "combinatorial code": what behavior is produced depends on the specific combination of decision neurons that are active at a particular time. Finally, we discuss how decision neurons may be arranged into a decision hierarchy, with neurons at each sequential level responsible for choosing between a narrower range of behaviors. We suggest additional sensory information is incorporated at each level to inform the decision. PMID- 21708769 TI - Behavioral, cellular, and molecular analysis of memory in aplysia I: intermediate term memory. AB - Serotonin (5HT) induces short-term and long-term synaptic facilitation (STF and LTF, respectively) at sensory neuron to motor neuron (SN-MN) synapses in Aplysia, and these forms of plasticity are thought to contribute to short-term and long term memory for behavioral sensitization. Recent evidence in Aplysia has identified a third phase of synaptic facilitation-intermediate-term facilitation (ITF)-that is temporally and mechanistically distinct from STF and LTF. Here, we review the findings of recent studies that have examined this unique intermediate term phase at molecular, cellular, and behavioral levels. The results indicate that, at tail SN-MN synapses, multiple forms of ITF can be distinguished; they are induced via distinct mechanisms and use parallel molecular pathways for their expression. Moreover, we have incorporated the temporal and molecular features of these different forms of ITF at tail SN-MN synapses into behavioral analyses, and found that they accurately predict distinct forms of intermediate-term memory for sensitization of the tail-elicited siphon withdrawal reflex. These findings indicate that different types of experiences engage distinct molecular pathways in the service of memory retention over the same time domain. PMID- 21708770 TI - Behavioral, Cellular, and Molecular Analysis of Memory in Aplysia II: Long-Term Facilitation. AB - Long-term facilitation (LTF) of Aplysia tail sensory neuron-motor neuron (SN-MN) synapses provides a synaptic correlate of memory for long-term behavioral sensitization of the tail-siphon withdrawal reflex. LTF can be induced by repeated exposures of serotonin (5HT) in the isolated pleural-pedal ganglion preparation. In addition, we have shown previously (Sherff and Carew, 1999) that LTF can also be induced by coincident 5HT exposure comprised of a single 25-min exposure of 5HT at the SN cell body and a 5 min pulse of 5HT at the SN-MN synapses. If synaptic 5HT is applied either 15 min before or after somatic 5HT, LTF is significantly reduced or is not induced at all. These results show that two anatomically remote cellular compartments can functionally interact within a surprisingly short time period. In this chapter, we discuss some of the mechanistic implications of this temporal constraint. We also find that coincident LTF and LTF induced by repeated pulses of 5HT differ (1) in whether they induce another temporal phase of facilitation (intermediate-term facilitation, ITF, expressed up to 1.5 hr after 5HT), and (2) in their requirements for protein synthesis. The results described both in this paper and in the preceding companion paper show that there are multiple forms of both ITF and LTF that differ in their induction and expression requirements, and at least in some instances, the different temporal phases of facilitation, and perhaps comparable phases of memory, can be induced independently of each other. PMID- 21708771 TI - Understanding vertebrate brain evolution. AB - Four major questions can be asked about vertebrate brain evolution: 1) What major changes have occurred in neural organization and function? 2) When did these changes occur? 3) By what mechanisms did these changes occur? 4) Why did these changes occur? Comparative neurobiologists have been very successful in recognizing major changes in brain structure. They have also made progress in understanding the functional significance of these changes, although this understanding is primarily limited to sensory centers, rather than integrative or motor centers, because of the relative ease of manipulating the relevant stimuli. Although neuropaleontology continues to provide important insights into when changes occurred, this approach is generally limited to recognizing variation in overall brain size, and sometimes brain regions, as interpreted from the surface of an endocranial cast. In recent years, most new information regarding when neural changes occurred has been based on cladistical analysis of neural features in extant taxa. Historically, neurobiologists have made little progress in understanding how and why brains evolve. The emerging field of evolutionary developmental biology appears to be the most promising approach for revealing how changes in development and its processes produce neural changes, including the emergence of novel features. Why neural changes have occurred is the most difficult question and one that has been the most ignored, in large part because its investigation requires a broad interdisciplinary approach involving both behavior and ecology. PMID- 21708772 TI - Grades in neural complexity: how large is the span? AB - The span of complexity in brains, between the simplest flatworms and the most advanced mammals is exceedingly great, measured by the number of different anatomical parts, physiological processes, sensory discriminations, and behavioral alternatives in the repertoire. Most evolution of brains has been adaptive radiation within the same grade of complexity. Distinct grades of complexity have appeared a dozen or more times and quite often in the retrograde direction. Advancement has not been inevitable or obviously advantageous in survival value but has happened-long before primates or mammals or vertebrates. Compare cuttlefish and the most advanced gastropods, bees and the best brine shrimp, primates and the most advanced reptiles known-all twigs with common branches. This repeated achievement of evolution has had all too little study in respect of the detailed listing of differences between major taxa of distinct grades of complexity. Connectivity at the level now known for the mammalian cortex is much needed in other classes, with estimates of reciprocity, intrinsic differentiation, dendritic parcellation and afferent and efferent connections, both locally and projecting to other centers, each done quantitatively to permit comparison. Physiological system organization, personality properties of neurons and circuits, proclivities and emergent phenomena at several integrative levels are sketchily known only for parts of a few systems. Examples are given of opportunities for new research that can more adequately characterize grades of brains. PMID- 21708773 TI - How to build fast muscles: synchronous and asynchronous designs. AB - In animals, muscles are the most common effectors that translate neuronal activity into behavior. Nowhere is behavior more restricted by the limits of muscle performance than at the upper range of high-frequency movements. Here, we see new and multiple designs to cope with the demands for speed. Extremely rapid oscillations in force are required to power cyclic activities such as flight in insects or to produce vibrations for sound. Such behaviors are seen in a variety of invertebrates and vertebrates, and are powered by both synchronous and asynchronous muscles. In synchronous muscles, each contraction/relaxation cycle is accompanied by membrane depolarization and subsequent repolarization, release of activator calcium, attachment of cross-bridges and muscle shortening, then removal of activator calcium and cross-bridge detachment. To enable all of these to occur at extremely high frequencies a suite of modifications are required, including precise neural control, hypertrophy of the calcium handling machinery, innovative mechanisms to bind calcium, and molecular modification of the cross bridges and regulatory proteins. Side effects are low force and power output and low efficiency, but the benefit of direct, neural control is maintained. Asynchronous muscles, in which there is not a 1:1 correspondence between neural activation and contraction, are a radically different design. Rather than rapid calcium cycling, they rely on delayed activation and deactivation, and the resonant characteristics of the wings and exoskeleton to guide their extremely high-frequency contractions. They thus avoid many of the modifications and attendant trade-offs mentioned above, are more powerful and more efficient than high-frequency synchronous muscles, but are considerably more restricted in their application. PMID- 21708774 TI - Physiological ecology of rocky intertidal organisms: a synergy of concepts. AB - The rocky intertidal zone is among the most physically harsh environments on earth. Marine invertebrates and algae living in this habitat are alternatively pounded by waves and exposed to thermal extremes during low tide periods (Denny and Wethey, 2001). Additionally, they must deal with strong selective pressures related to predation and competition for space (Connell, 1961). As a result, the steep physical gradient and spatially condensed community has made the rocky intertidal zone an ideal "natural laboratory" to study the coupled role of physical and biological factors in determining the abundance and distribution of organisms in nature (Connell, 1961; Paine, 1966, 1994). PMID- 21708775 TI - The study of vertical zonation on rocky intertidal shores--a historical perspective. AB - Intertidal zonation, observed from earliest studies of the marine littoral zone, was first studied in the U.S. by ecologists with a botanical orientation. Using the physiological methods favored by Cowles, Clements, and Shelford, these early studies sought causal and deterministic explanations. By the 1930s, the limitations of these studies became apparent and ecologists returned to more descriptive approaches. With the creation of year round research laboratories on the west coast, ecologists soon shed the botanical orientation and began to adopt more stochastic and non-deterministic approaches to intertidal ecology, approaches that still characterize the research tradition. PMID- 21708776 TI - Thermal physiology and vertical zonation of intertidal animals: optima, limits, and costs of living. AB - Temperature's pervasive effects on physiological systems are reflected in the suite of temperature-adaptive differences observed among species from different thermal niches, such as species with different vertical distributions (zonations) along the subtidal to intertidal gradient. Among the physiological traits that exhibit adaptive variation related to vertical zonation are whole organism thermal tolerance, heart function, mitochondrial respiration, membrane static order (fluidity), action potential generation, protein synthesis, heat-shock protein expression, and protein thermal stability. For some, but not all, of these thermally sensitive traits acclimatization leads to adaptive shifts in thermal optima and limits. The costs associated with repairing thermal damage and adapting systems through acclimatization may contribute importantly to energy budgets. These costs arise from such sources as: (i) activation and operation of the heat-shock response, (ii) replacement of denatured proteins that have been removed through proteolysis, (iii) restructuring of cellular membranes ("homeoviscous" adaptation), and (iv) pervasive shifts in gene expression (as gauged by using DNA microarray techniques). The vertical zonation observed in rocky intertidal habitats thus may reflect two distinct yet closely related aspects of thermal physiology: (i) intrinsic interspecific differences in temperature sensitivities of physiological systems, which establish thermal optima and tolerance limits for species; and (ii) 'cost of living' considerations arising from sub-lethal perturbation of these physiological systems, which may establish an energetics-based limitation to the maximal height at which a species can occur. Quantifying the energetic costs arising from heat stress represents an important challenge for future investigations. PMID- 21708777 TI - Causes and consequences of thermal tolerance limits in rocky intertidal porcelain crabs, genus petrolisthes. AB - Vertical zonation of intertidal organisms, from the shallow subtidal to the supralittoral zones, is a ubiquitous feature of temperate and tropical rocky shores. Organisms that live higher on the shore experience larger daily and seasonal fluctuations in microhabitat conditions, due to their greater exposure to terrestrial conditions during emersion. Comparative analyses of the adaptive linkage between physiological tolerance limits and vertical distribution are the most powerful when the study species are closely related and occur in discrete vertical zones throughout the intertidal range. Here, I summarize work on the physiological tolerance limits of rocky intertidal zone porcelain crab species of the genus Petrolisthes to emersion-related heat stress. In the eastern Pacific, Petrolisthes species live throughout temperate and tropical regions, and are found in discrete vertical intertidal zones in each region. Whole organism thermal tolerance limits of Petrolisthes species, and thermal limits of heart and nerve function reflect microhabitat conditions. Species living higher in the intertidal zone are more eurythermal than low-intertidal congeners, tropical species have the highest thermal limits, and the differences in thermal tolerance between low- and high-intertidal species is greatest for temperate crabs. Acclimation of thermal limits of high-intertidal species is restricted as compared to low-intertidal species. Thus, because thermal limits of high intertidal species are near current habitat temperature maxima, global warming could most strongly impact intertidal species. PMID- 21708778 TI - The Heat-Shock Response: Its Variation, Regulation and Ecological Importance in Intertidal Gastropods (genus Tegula). AB - The enhanced synthesis of heat-shock proteins (hsps), called the heat-shock (or stress) response, is activated when environmental stress denatures proteins. Hsp synthesis is activated at the upper temperatures of an organism's thermal range and is therefore thought to be critical for enhancing thermal tolerance limits in ectothermic animals. Here I show that the two temperate sister species T. brunnea and T. montereyi that occupy the subtidal and low-intertidal zone differ from the low- to mid-intertidal T. funebralis (and the subtropical mid-intertidal T. rugosa) in (i) heat tolerance, (ii) the onset temperature of their main hsp, hsp70 (70 kDa), (iii) the temperature of maximal hsp70 synthesis, (iv) the upper temperature of hsp synthesis, and (v) the recovery from a thermal stress typical for the mid-intertidal zone. A regulatory model in which hsps themselves regulate their own transcription and synthesis through a negative autoregulatory feedback mechanism can explain acclimation-induced but not interspecific variation in the onset temperature of hsp70 synthesis. Transplanting species across their vertical distribution limits showed that interspecific differences in the stress response are likely to prevent species occurring lower from inhabiting sites higher in the rocky intertidal zone. Endogenous levels of a hsp of a molecular mass of 72 kDa, hsp72, changed little with heat stress in a species' native thermal environment. The results therefore confirm the importance of interspecific differences in the stress response for setting limits to an organism's thermal environment. However, the role of hsps as short-term indicators of sublethal heat stress within a species' native thermal environment may be limited without a better understanding of their functional and regulatory characteristics. PMID- 21708779 TI - Molecular chaperones in ectothermic marine animals: biochemical function and gene expression. AB - The intertidal zone has historically functioned as an important natural laboratory for testing ideas about how physical factors such as temperature influence organismal physiology and in turn influence the distribution patterns of organisms. Key to our understanding of how the physical environment helps structure organismal distribution is the identification of physiological processes that have ecological relevance. We have focused on biochemical- and molecular-level physiology that would contribute to thermal tolerance and maintenance of a functional intracellular protein pool in the face of extreme and fluctuating environmental temperatures. Past research has addressed processes central to protein homeostasis (e.g., protein ubiquitination) and the molecular ecology of molecular chaperones, a.k.a. heat shock proteins (Hsps), in ectothermic animals. In this presentation, we focus on two new developments regarding the biology of heat shock proteins as molecular chaperones in intertidal organisms. First, we present data on the functional characteristics of the transcriptional factor, HSF1 and discuss how these data relate to the plasticity of Hsp gene expression observed in intertidal organisms in nature. Second, we present data on the biochemical function of heat shock proteins purified from our non-model study organisms and discuss the temperature relationships of these molecules as they assist in protein folding in situ. PMID- 21708780 TI - Patterns of variation in levels of hsp70 in natural rocky shore populations from microscales to mesoscales. AB - An important step in connecting the organismal response to thermal stress to patterns of community structure is determining at what scale discernable levels of variation are manifested. The temperature signal to which organisms may potentially respond varies at many spatial scales including microhabitat, tidal height, site and latitude. A number of studies have taken physiological assessment of the heat shock response (HSR) into the intertidal both as a tool for examining the HSR in nature and for examining the utility of HSR molecules as population or community level indicators. Most commonly, immunodetection of the total pool of the Hsp70 family of isoforms is used. Here we present data on levels of Hsp70 in intertidal organisms from microhabitat to the mesoscale. Our data and previously published work show that Hsp70 levels vary at all scales examined, similar to other physical and biological variables of interest. This demonstrates both the potential utility of Hsp70 detection as a molecular tool for field biologists and to the care that must be taken in assessing scale of variation when looking for potential bioindicator molecules. PMID- 21708781 TI - Ecological Genetics of Mpi and Gpi Polymorphisms in the Acorn Barnacle and the Spatial Scale of Neutral and Non-neutral Variation. AB - Different allozyme genotypes at the mannose phosphate isomerase (Mpi) locus in the northern acorn barnacle (Semibalanus balanoides) show a strong association with distinct intertidal microhabitats. In estuaries along the Maine Coast, the FF homozygote has higher fitness in exposed, high-tide level microhabitats while the SS homozygote has higher fitness under algal cover or at low-tide microhabitats. These patterns are consistent with a Levene (1953) model of balancing selection. In these same samples, polymorphisms at the glucose phosphate isomerase locus (Gpi) and mitochondrial DNA (mtDNA) show no fitness differences among microhabitats, providing intra-genomic controls supporting selection at or near Mpi. Here we report a similar analysis of genotype-by microhabitat associations at sites in Narragansett Bay, Rhode Island, close to the southern range limit of S. balanoides. Genotype zonation at Mpi between high- and low-tide microhabitats is significantly different between Maine and Narragansett Bay due to opposite zonation patterns for the SF and FF genotypes. Enzyme activity data are consistent with this "reverse" zonation. At Gpi, there is significant microhabitat zonation in Narragansett Bay, while this locus behaves as a neutral marker in Maine. Mt DNA shows no significant microhabitat zonation in either Rhode Island or Maine. The Mpi data suggest that Levene-type selection for alternative genotypes in alternative habitats may operate at scales of both 10's of meters and 100's of kilometers. The Gpi data show how an apparently neutral locus can exhibit non-neutral variation under different environmental conditions. We argue that both Mpi and Gpi provide important genetic variation for adaptation to environmental heterogeneity that is recruited under distinct conditions of stress and carbohydrate substrate availability. PMID- 21708782 TI - How do we Measure the Environment? Linking Intertidal Thermal Physiology and Ecology Through Biophysics. AB - Recent advances in quantifying biochemical and cellular-level responses to thermal stress have facilitated a new exploration of the role of climate and climate change in driving intertidal community and population ecology. To fruitfully connect these disciplines, we first need to understand what the body temperatures of intertidal organisms are under field conditions, and how they change in space and time. Newly available data logger technology makes such an exploration possible, but several potential pitfalls must be avoided. Body temperature during aerial exposure is driven by multiple, interacting climatic factors, and extremes during low tide far exceed those during submersion. Moreover, because of effects of body size and morphology, two organisms exposed to identical climatic conditions can display very different body temperatures, which can also be substantially different from the temperature of the surrounding air. These same factors drive the temperature recorded by data loggers, and one logger type is unlikely to serve as an effective proxy for all organisms at a site. Here I describe the difficulties involved in quantifying patterns of body temperature in intertidal organisms, and explore the implications of this complexity for intertidal physiological ecology. I do so using data from temperature loggers designed to mimic the thermal characteristics of the mussel Mytilus californianus, and deployed at multiple sites along the West Coast of the United States. Results indicate a highly intricate pattern of thermal stress, where the interaction of climate with the dynamics of the tidal cycle determines the timing and magnitude of temperature extremes, creating a unique "thermal signal" at each site. PMID- 21708783 TI - The ecomechanics of mussel attachment: from molecules to ecosystems. AB - One aspect of the physiological ecology of intertidal organisms is their mechanical design, which can be explored at many hierarchical levels, from molecules to ecosystems. Mechanical structures, as with any other physiological feature, require energy to construct and maintain, are subject to manufacturing and evolutionary constraints, and influence ecological performance. This contribution focuses on the ecomechanics of mussel attachment, which contributes to the competitive dominance of mussels on many wave-swept shores. Examples are presented to illustrate the hierarchical nature of mussel attachment, how levels of the hierarchy are interrelated, and where gaps in our knowledge remain. For example, water motion generates forces that mechanically deform byssal threads, but may also enhance the rate at which threads subsequently restore their original toughness. Furthermore, the ability of mussels to sense and respond to changes in their flow environment by producing a stronger attachment may be subject to physiological constraints, which in turn may have important consequences for the ecological response of mussels to shifts in wave climate. Thus an integrative approach to the study of byssal attachment is needed to fully understand this important aspect of the physiological ecology of mussels on rocky intertidal shores. PMID- 21708784 TI - Energetic constraints, size gradients, and size limits in benthic marine invertebrates. AB - Populations of marine benthic organisms occupy habitats with a range of physical and biological characteristics. In the intertidal zone, energetic costs increase with temperature and aerial exposure, and prey intake increases with immersion time, generating size gradients with small individuals often found at upper limits of distribution. Wave action can have similar effects, limiting feeding time or success, although certain species benefit from wave dislodgment of their prey; this also results in gradients of size and morphology. The difference between energy intake and metabolic (and/or behavioral) costs can be used to determine an energetic optimal size for individuals in such populations. Comparisons of the energetic optimal size to the maximum predicted size based on mechanical constraints, and the ensuing mortality schedule, provides a mechanism to study and explain organism size gradients in intertidal and subtidal habitats. For species where the energetic optimal size is well below the maximum size that could persist under a certain set of wave/flow conditions, it is probable that energetic constraints dominate. When the opposite is true, populations of small individuals can dominate habitats with strong dislodgment or damage probability. When the maximum size of individuals is far below either energetic optima or mechanical limits, other sources of mortality (e.g., predation) may favor energy allocation to early reproduction rather than to continued growth. Predictions based on optimal size models have been tested for a variety of intertidal and subtidal invertebrates including sea anemones, corals, and octocorals. This paper provides a review of the optimal size concept, and employs a combination of the optimal energetic size model and life history modeling approach to explore energy allocation to growth or reproduction as the optimal size is approached. PMID- 21708785 TI - Physiological community ecology: variation in metabolic activity of ecologically important rocky intertidal invertebrates along environmental gradients. AB - Rocky intertidal invertebrates live in heterogeneous habitats characterized by steep gradients in wave activity, tidal flux, temperature, food quality and food availability. These environmental factors impact metabolic activity via changes in energy input and stress-induced alteration of energetic demands. For keystone species, small environmentally induced shifts in metabolic activity may lead to disproportionately large impacts on community structure via changes in growth or survival of these key species. Here we use biochemical indicators to assess how natural differences in wave exposure, temperature and food availability may affect metabolic activity of mussels, barnacles, whelks and sea stars living at rocky intertidal sites with different physical and oceanographic characteristics. We show that oxygen consumption rate is correlated with the activity of key metabolic enzymes (e.g., citrate synthase and malate dehydrogenase) for some intertidal species, and concentrations of these enzymes in certain tissues are lower for starved individuals than for those that are well fed. We also show that the ratio of RNA to DNA (an index of protein synthetic capacity) is highly variable in nature and correlates with short-term changes in food availability. We also observed striking patterns in enzyme activity and RNA/DNA in nature, which are related to differences in rocky intertidal community structure. Differences among species and habitats are most pronounced in summer and are linked to high nearshore productivity at sites favored by suspension feeders and to exposure to stressful low-tide air temperatures in areas of low wave splash. These studies illustrate the great promise of using biochemical indicators to test ecological models, which predict changes in community structure along environmental gradients. Our results also suggest that biochemical indices must be carefully validated with laboratory studies, so that the indicator selected is likely to respond to the environmental variables of interest. PMID- 21708786 TI - Biogeography, Competition, and Microclimate: The Barnacle Chthamalus fragilis in New England. AB - Geographic limits of species are commonly associated with climatic or physical boundaries, but the mechanisms of exclusion at the limits of distribution are poorly understood. In some intertidal populations, the strengths of interactions with natural enemies are mediated by microclimate, and determine geographic limits. The northern limit of the barnacle Chthamalus fragilis in New England is the south side of Cape Cod, Massachusetts. South of the cape, Chthamalus has a refuge from competition in the high intertidal, which is too hot for survival of its superior competitor Semibalanus balanoides. North of the cape, the high intertidal is cooler, and Semibalanus survives, so Chthamalus has no refuge. Thus, geographic variation in the strength of competition may determine the geographic limit of Chthamalus. Intolerance of cold by Chthamalus cannot account for the geographic limit: transplants of Chthamalus 80 km beyond its northern limit survived up to 8 yr in the absence of competition with Semibalanus. At the geographic limit of Chthamalus in the Cape Cod Canal there are two bridges, 5 km apart. On the southern bridge, Chthamalus is abundant and occupies a refuge above Semibalanus. On the northern bridge in 2001, only 7 individual Chthamalus were present. Despite the proximity of the bridges, their microclimates are very different. The southern bridge, where Chthamalus is abundant, is up to 8 degrees C hotter than the northern bridge. This higher temperature creates a refuge in the high intertidal for Chthamalus. On the cooler northern bridge, there is no refuge for Chthamalus. Because of the difference in temperatures of the water masses that meet in the canal, heat storage in the rock of the bridge piers causes the temperatures to differ between the bridges. Thus, geographic change in microclimate alters the strength of competition, and determines the geographic limit."When we travel from south to north, or from a damp region to a dry, we invariably see some species gradually getting rarer and rarer, and finally disappearing; and the change in climate being conspicuous, we are tempted to attribute the whole effect to its direct action. But this is a very false view: we forget that each species, even where it most abounds, is constantly suffering enormous destruction at some period of its life, from enemies or from competitors for the same place and food; and if these enemies or competitors be in the least degree favoured by any slight change of climate, they will increase in numbers, and as each area is already fully stocked with inhabitants, the other species will decrease."-Charles Darwin, On the Origin of Species, 1859, p. 69. PMID- 21708787 TI - Water temperature, predation, and the neglected role of physiological rate effects in rocky intertidal communities. AB - Ecologists and physiologists working on rocky shores have emphasized the effects of environmental stress on the distribution of intertidal organisms. Although consumer stress models suggest that physical extremes may often reduce predation and herbivory through negative impacts on the physiological performance of consumers, few field studies have rigorously tested how environmental variation affects feeding rates. I review and analyze field experiments that quantified per capita feeding rates of a keystone predator, the sea star Pisaster ochraceus, in relation to aerial heat stress, wave forces, and water temperature at three rocky intertidal sites on the Oregon coast. Predation rates during 14-day periods were unrelated to aerial temperature, but decreased significantly with decreasing water temperature. There was suggestive but inconclusive evidence that predation rates also declined with increasing wave forces. Data-logger records suggested that thermal stress was rare in the wave-exposed habitats that I studied; sea star body temperatures likely reached warm levels (>24 degrees C) on only 9 dates in 3 yr. In contrast, wind-driven upwelling regularly generated 3 to 5 degrees C fluctuations in water temperature, and field and laboratory results suggest that such changes significantly alter feeding rates of Pisaster. These physiological rate effects, near the center of an organism's thermal range, may not reduce growth or fitness, and thus are distinct from the effects of environmental stress. This study underscores the need to consider organismal responses both under "normal" conditions, as well as under extreme conditions. Examining both kinds of responses is necessary to understand how different components of environmental variation regulate physiological performance and the strength of species interactions in intertidal communities. PMID- 21708788 TI - Environmental Stress, Bottom-up Effects, and Community Dynamics: Integrating Molecular-Physiological and Ecological Approaches. AB - Environmental stress and nutrient/productivity models predict the responses of community structure along gradients of physical conditions and bottom-up effects. Although both models have succeeded in helping to understand variation in ecological communities, most tests have been qualitative. Until recently, two roadblocks to more quantitative tests in marine environments have been a lack of (1) inexpensive, field-deployable technology for quantifying (e.g.) temperature, light, salinity, chlorophyll, and productivity, and (2) methods of quantifying the sub-organismal mechanisms linking environmental conditions to their ecological expression. The advent of inexpensive remote-sensing technology, adoption of molecular techniques such as quantification of heat-shock proteins and RNA:DNA ratios, and the formation of interdisciplinary alliances between ecologists and physiologists has begun to overcome these roadblocks. An integrated eco-physiological approach focuses on the determinants of: distributional limits among microhabitat patches and along (local-scale) environmental gradients (e.g., zonation); among-site (mesoscale) differences in community pattern; and geographic (macroscale) differences in ecosystem structure. These approaches promise new insights into the physiological mechanisms underlying variation in processes such as species interactions, physical disturbance, survival and growth. Here, we review two classes of models for community dynamics, and present examples of ecological studies of these models in consumer-prey systems. We illustrate the power of new molecular tools to characterize the sub-organismal responses of some of the same consumers and prey to thermal stress and food concentration. Ecological and physiological evidence tends to be consistent with model predictions, supporting our argument that we are poised to make major advances in the mechanistic understanding of community dynamics along key environmental gradients. PMID- 21708789 TI - Denying evolution. Creationism, scientism and the nature of science. PMID- 21708790 TI - High altitude: an exploration of human adaptation. PMID- 21708791 TI - Engineering highly thermostable xylanase variants using an enhanced combinatorial library method. AB - A new directed evolution method was used to enhance the thermostability of the wild-type GH11 xylanase 2 (known as BD-11) from Hypocrea jecorina (Trichoderma reesei). Both Look-Through Mutagenesis (LTMTM), which is a method for rapidly screening selected positions in the protein sequence for amino acids that introduce favorable properties, and Combinatorial Beneficial Mutagenesis (CBMTM), which is a method for identifying the best ensemble of individual mutations, were employed to enhance the stability of an enzyme that has been thoroughly engineered by various means during the past 20 years. A diverse set of novel mutations was discovered, including N71D, Y73G, T95G and Y96Q. When these mutations were combined into a single construct (Hjx-81), the purified protein was active even after heating at 100 degrees C for 20 min. This time-effective method should be generally applicable for quickly improving the physico-chemical properties of other industrial and therapeutic enzymes in only several months time. PMID- 21708792 TI - Hepatitis C prevalence in England remains low and varies by ethnicity: an updated evidence synthesis. AB - BACKGROUND: Previous evidence synthesis estimates of Hepatitis C Virus (HCV) in England did not consider excess HCV risk in ethnic minority populations. We incorporate new information on HCV risk among non-injectors by ethnic group, and additional information on injecting prevalence in order to generate new and updated estimates of HCV prevalence risk in England for 2005. METHODS: Bayesian evidence synthesis was used to combine multiple sources of data that directly or indirectly provide information on the populations at risk, or prevalence of HCV infection. HCV data were modelled by region, age group and sex as well as ethnicity for never-injectors and by injecting status (ex and current). RESULTS: Overall HCV antibody prevalence in England was estimated at 0.67% [95% credible interval (95% CrI): 0.50-0.94] of those aged 15-59 years, or 203 000 (153 000, 286 000) individuals. HCV prevalence in never-injectors remains low, even after accounting for ethnicity, with a prevalence of 0.05% (95% CrI 0.03-0.10) in those of white/other ethnicity and 0.76% (0.48-1.23) in South Asians. Estimates are similar to 2003, although patterns of injecting drug use are different, with an older population of current injecting drug users and lower estimated numbers of ex-injectors, but higher HCV prevalence. CONCLUSIONS: Incorporating updated information, including data on ethnicity and improved data on injectors, gave similar overall estimates of HCV prevalence in England. Further information on HCV in South Asians and natural history of injecting are required to reduce uncertainty of estimates. This method may be applied to other countries and settings. PMID- 21708793 TI - Implications of blood type for ovarian reserve. AB - BACKGROUND: We explored the relevance of blood type to ovarian reserve, as reflected by early follicular phase FSH levels. METHODS: For this cross-sectional observational study, early follicular phase serum levels of FSH (mIU/ml) and estradiol (E2, pg/ml), and information on blood type (A, B, AB and O) and patient age were procured for female patients, <= 45 years age (n= 544), who were undergoing fertility evaluation at one of two tertiary care facilities. Serum FSH > 10 mIU/ml was taken to reflect diminished ovarian reserve (DOR). Data distribution for FSH and age was analyzed and non-parametric tests used for comparisons across blood groups. Multivariable logistic regression analyses determined the relationship between elevated FSH and respective blood types after adjusting for age and study site. RESULTS: Prevalence of blood types according to order of frequency was: O (45%), A (35%), B (16%) and AB (5%). After adjusting for age and study site, patients with blood type O were twice as likely to exhibit FSH > 10 mIU/ml compared with those with A or AB blood types [odds ratio (OR) 2.36; 95% confidence interval (CI) 1.27-4.41; P= 0.007], and three times as likely to manifest FSH > 12 m IU/ml (OR 3.48, 95% CI 1.46-7.32, P= 0.004). The B blood group antigen failed to exhibit any relationship with ovarian reserve as reflected by baseline FSH (P> 0.05). CONCLUSIONS: The A blood group antigen appears to be protective for ovarian reserve, whereas blood type O appears to be associated with DOR, in a relationship that is independent of advancing age. Further studies are needed to establish causality and identify the underlying mechanisms for the association. PMID- 21708794 TI - Offspring searching for their sperm donors: how family type shapes the process. AB - BACKGROUND: This study examines the findings from the largest survey to date of donor-inseminated (DI) offspring and focuses on respondents' learning of the method of their conception and their desire to contact their donor. METHODS: Online questionnaires were completed by 741 DI offspring, of whom 61.8% have heterosexual parents and 38.2% have lesbian parents. Respondents were recruited via the Donor Sibling Registry, a non-profit US-based international registry that facilitates communication between donor-conceived offspring and their non biological and biological relatives. Data were collected on family composition, offspring's feelings regarding the method of their conception, communication within families, donor anonymity and their search for their donors. This investigation focuses on the relationship between family type (single or dual parent and lesbian or heterosexual parent/s) and offspring's reactions to learning of their DI conception. RESULTS: Offspring of lesbian parents learned of their DI origins at earlier ages than offspring of heterosexual parents. In the latter families, disclosure tended to occur earlier in single-parent than in dual parent families. Disclosure was most likely to be confusing to offspring of heterosexual parents, particularly when it occurred at an older age. The vast majority of offspring in all types of families desired contact with their donor; however, comfort in expressing curiosity regarding one's donor was lowest in dual parent heterosexual families, with about one-quarter reporting an inability to discuss their origins with their social father. CONCLUSIONS: Although the findings are not based on a random sample, the desire among offspring surveyed here is for greater openness and contact with their donor. A variety of strategies are needed for offspring of heterosexual couples to benefit optimally from the general trend toward openness in gamete donation. PMID- 21708795 TI - Protecting children from sexual abuse by health care providers. AB - Sexual abuse or exploitation of children is never acceptable. Such behavior by health care providers is particularly concerning because of the trust that children and their families place on adults in the health care profession. The American Academy of Pediatrics strongly endorses the social and moral prohibition against sexual abuse or exploitation of children by health care providers. The academy opposes any such sexual abuse or exploitation by providers, particularly by the academy's members. Health care providers should be trained to recognize and abide by appropriate provider-patient boundaries. Medical institutions should screen staff members for a history of child abuse issues, train them to respect and maintain appropriate boundaries, and establish policies and procedures to receive and investigate concerns about patient abuse. Each person has a responsibility to ensure the safety of children in health care settings and to scrupulously follow appropriate legal and ethical reporting and investigation procedures. PMID- 21708796 TI - Underimmunization in Ohio's Amish: parental fears are a greater obstacle than access to care. AB - OBJECTIVE: Holmes County, Ohio, one of the largest Amish communities in the world, has persistently low immunization rates. Studies of other Amish communities have revealed that parents do not immunize their children because of lack of access to immunizations. Our study explored reasons that Amish parents in the previously uninvestigated Holmes County population exempt themselves from immunizations. METHODS: In January 2007, questionnaires for assessing attitudes regarding immunizations were mailed to a random sampling of 1000 Amish parents in Holmes County. RESULTS: Thirty-seven percent of the parents responded. Among the 359 respondents, 68% stated that all of their children had received at least 1 immunization, and 17% reported that some of their children had received at least 1 immunization. Only 14% of the parents reported that none of their children had received immunizations. Eighty-six percent of the parents who completely exempted their children from vaccines stated that the main reason they do not vaccinate their children is concern over adverse effects. Many parents indicated that they allow their children to receive only some vaccines because of concern about the way certain vaccines are produced. CONCLUSIONS: The reasons that Amish parents resist immunizations mirror reasons that non-Amish parents resist immunizations. Even in America's closed religious communities, the major barrier to vaccination is concern over adverse effects of vaccinations. If 85% of Amish parents surveyed accept some immunizations, they are a dynamic group that may be influenced to accept preventative care. Underimmunization in the Amish population must be approached with emphasis on changing parental perceptions of vaccines in addition to ensuring access to vaccines. PMID- 21708797 TI - A meta-analysis of interventions that target children's screen time for reduction. AB - BACKGROUND: Screen time, especially television viewing, is associated with risk of overweight and obesity in children. Although several interventions have been developed to reduce children's screen time, no systematic review of these interventions exists to date. OBJECTIVE: This is a systematic review and meta analysis of interventions targeting a reduction in children's screen time. METHODS: Effect sizes and associated 95% confidence intervals (CIs) were calculated by using a random-effects model. Heterogeneity tests, moderator analyses, assessment of bias, and sensitivity analyses were conducted. Reliability was assessed with Cohen's kappa. RESULTS: The systematic search identified 3002 documents; 33 were eligible for inclusion, and 29 were included in analyses. Most reported preintervention and postintervention data and were published in peer-reviewed journals. Although heterogeneity was present, no moderators were identified. Overall Hedges g (-0.144 [95% CI: -0.217 to -0.072]) and standard mean difference (SMD) (-0.148 [95% CI: -0.224 to -0.071]) indicated that interventions were linked with small but statistically significant reductions in screen time in children. The results were robust; the failsafe N was large, and the funnel plot and trim-and-fill methods identified few missing studies. CONCLUSIONS: Results show that interventions to reduce children's screen time have a small but statistically significant effect. As the evidence base expands, and the number of screen-time interventions increases, future research can expand on these findings by examining the clinical relevance and sustainability of effects, conducting a more thorough analysis of effect modifiers, and identifying critical components of effective interventions. PMID- 21708798 TI - Trends in the use of standardized tools for developmental screening in early childhood: 2002-2009. AB - BACKGROUND: Early identification of developmental delays is essential for optimal early intervention. An American Academy of Pediatrics (AAP) 2002 Periodic Survey of Fellows found <25% of respondents consistently used appropriate screening tools. Over the past 5 years, new research and education programs promoted screening implementation. In 2006, the AAP issued a revised policy statement with a detailed algorithm. Since the 2002 Periodic Survey, no national surveys have examined the effectiveness of policy, programmatic, and educational enhancements. OBJECTIVE: The goal of this study was to compare pediatricians' use of standardized screening tools from 2002 to 2009. METHODS: A national, random sample of nonretired US AAP members were mailed Periodic Surveys (2002: N=1617, response rate: 55%; 2009: N=1620, response rate: 57%). chi(2) analyses were used to examine responses across survey years; a multivariate logistic regression model was developed to compare differences in using >=1 formal screening tools across survey years while controlling for various individual and practice characteristics. RESULTS: Pediatricians' use of standardized screening tools increased significantly between 2002 and 2009. The percentage of those who self reported always/almost always using >=1 screening tools increased over time (23.0%-47.7%), as did use of specific instruments (eg, Ages & Stages Questionnaire, Parents' Evaluation of Developmental Status). No differences were noted on the basis of physician or practice characteristics. CONCLUSIONS: The percentage of pediatricians who reported using >=1 formal screening tools more than doubled between 2002 and 2009. Despite greater attention to consistent use of appropriate tools, the percentage remains less than half of respondents providing care to patients younger than 36 months. Given the critical importance of developmental screening in early identification, evaluation, and intervention, additional research is needed to identify barriers to greater use of standardized tools in practice. PMID- 21708799 TI - Comparison of the World Health Organization growth velocity standards with existing US reference data. AB - OBJECTIVE: The goal of this study was to compare World Health Organization (WHO) growth velocity standards with reference data based on US children. METHODS: Comparisons were made between reference values for weight and length gains based on serial data from US children and the WHO child growth standards. We compared weight velocities for boys and girls for selected percentiles (5th, 25th, 50th, 75th, and 95th) for 1-month intervals from birth to 6 months, 2-month intervals up to 12 months, and 3-month intervals up to 24 months. For length, we compared 2 month intervals from birth to 6 months and 3-month intervals up to 24 months. RESULTS: WHO and US monthly weight increments were similar at the 5th percentile up to 3 months of age; values for other US percentiles were below the WHO percentiles ~150 g on average. From 3 months onward, the US values converged to a narrow range of <100 g between estimated percentiles. Two- and 3-month weight gains showed similar variations. Differences between the WHO and US values were more pronounced at the lower end of the distribution. For length, medians were in closer agreement, but as occurred with weight, values at the outer US percentiles converged to a narrower range with increasing age compared with those of the WHO standards. CONCLUSIONS: There are important differences between the WHO standards and the reference values for growth velocity based on US data. The WHO values are a better tool for assessing growth velocity and making clinical decisions. PMID- 21708800 TI - Children, adolescents, obesity, and the media. AB - Obesity has become a worldwide public health problem. Considerable research has shown that the media contribute to the development of child and adolescent obesity, although the exact mechanism remains unclear. Screen time may displace more active pursuits, advertising of junk food and fast food increases children's requests for those particular foods and products, snacking increases while watching TV or movies, and late-night screen time may interfere with getting adequate amounts of sleep, which is a known risk factor for obesity. Sufficient evidence exists to warrant a ban on junk-food or fast-food advertising in children's TV programming. Pediatricians need to ask 2 questions about media use at every well-child or well-adolescent visit: (1) How much screen time is being spent per day? and (2) Is there a TV set or Internet connection in the child's bedroom? PMID- 21708801 TI - Mevalonate kinase deficiency: a survey of 50 patients. AB - OBJECTIVE: The goal of this study was to describe the spectrum of clinical signs of mevalonate kinase deficiency (MKD). METHODS: This was a retrospective French and Belgian study of patients identified on the basis of MKD gene mutations. RESULTS: Fifty patients from 38 different families were identified, including 1 asymptomatic patient. Symptoms began during the first 6 months of life in 30 patients (60%) and before the age of 5 years in 46 patients (92%). Symptoms consisted of febrile diarrhea and/or rash in 23 of 35 patients (66%). Febrile attacks were mostly associated with lymphadenopathy (71%), diarrhea (69%), joint pain (67%), skin lesions (67%), abdominal pain (63%), and splenomegaly (63%). In addition to febrile attacks, 27 patients presented with inflammatory bowel disease, erosive polyarthritis, Sjogren syndrome, and other chronic neurologic, renal, pulmonary, endocrine, cutaneous, hematologic, or ocular symptoms. Recurrent and/or severe infections were observed in 13 patients, hypogammaglobulinemia in 3 patients, and renal angiomyolipoma in 3 patients. Twenty-nine genomic mutations were identified; the p.Val377Ile mutation was the most frequently found (29 of 38 families). Three patients died of causes related to MKD. The disease remained highly active in 17 of the 31 surviving symptomatic patients followed up for >5 years, whereas disease activity decreased over time in the other 14 patients. Interleukin 1 antagonists were the most effective biological agents tested, leading to complete or partial remission in 9 of 11 patients. CONCLUSION: MKD is not only an autoinflammatory syndrome but also a multisystemic inflammatory disorder, a possible immunodeficiency disorder, and a condition that predisposes patients to the development of renal angiomyolipoma. PMID- 21708802 TI - Elevated blood pressure during sleep and wake in children with sleep-disordered breathing. AB - OBJECTIVE: Sleep-disordered breathing (SDB) in adults has been associated with elevated blood pressure (BP); however, the effects of severity of SDB on BP in children are uncertain. We addressed this issue by measuring BP noninvasively and continuously during sleep in children with a range of severities of SDB and in a group of nonsnoring control children. METHODS: A total of 105 children referred for assessment of SDB and 36 nonsnoring controls were studied. Routine polysomnography (PSG) was performed with continuous BP monitoring. Children were assigned to groups according to obstructive apnea/hypopnea index (OAHI). BP data were categorized as quiet awake (recorded before sleep onset), non-rapid eye movement sleep 1 and 2 combined, slow-wave sleep, and rapid eye movement sleep. RESULTS: BP during awake before sleep onset and during overnight sleep was elevated by 10 to 15 mm Hg in the 3 SDB groups compared with the control group; this finding was independent of SDB severity. BP during stable sleep (with respiratory events and movements excluded) was also elevated in the children with OSA compared with the control group. BP was elevated in rapid eye movement sleep compared with the non-rapid eye movement sleep, and heart rate was higher during wake state than in all sleep states. CONCLUSIONS: We recorded BP continuously overnight and found that SDB, regardless of the severity, was associated with increased BP during sleep and wake compared with nonsnoring control children. These findings highlight the importance of considering the cardiovascular effects of SDB of any severity in children, and the need to review current clinical management that focuses primarily on more severe SDB. PMID- 21708804 TI - Parents' experiences of expanded newborn screening evaluations. AB - OBJECTIVE: Abnormal results of newborn screening for common metabolic diseases are known to create substantial distress for parents. We explored parents' perceptions during diagnostic evaluations for newer disorders that are less well understood. METHODS: Thirty families completed 48 open-ended interviews before and/or after parents received confirmatory test results for their infants. Qualitative content analysis was used to analyze the data. RESULTS: Parents were shocked by the notification of the abnormal test result. Their urgent and often frustrating searches for information dominated the early phase of the screening process. Treatment center personnel were mainly informative and reassuring, but waiting for results exacerbated parents' distress. Equivocal results from diagnostic testing created uncertainties for parents regarding their infants' long-term health. After counseling, some parents reported inaccurate ideas about the disorders despite exposure to large amounts of information. Regardless of the challenges and anxieties of the evaluation, nearly every parent thought newborn screening was an important program for infant health. CONCLUSIONS: The evaluation of a newborn for an abnormal screening result was highly stressful for parents. To help reduce parents' distress, improvements in communications and clinical services are needed. Recommendations of useful Internet sites and discussions of this information may benefit parents. Tailoring counseling to meet the needs of culturally and educationally diverse families is needed. Families and infants with equivocal results are a new group of patients who merit comprehensive clinical follow-up. PMID- 21708803 TI - Media use and child sleep: the impact of content, timing, and environment. AB - BACKGROUND: Media use has been shown to negatively affect a child's sleep, especially in the context of evening use or with a television in the child's bedroom. However, little is known about how content choices and adult co-use affect this relationship. OBJECTIVE: To describe the impact of media content, timing, and use behaviors on child sleep. METHODS: These data were collected in the baseline survey and media diary of a randomized controlled trial on media use in children aged 3 to 5 years. Sleep measures were derived from the Children's Sleep Habits Questionnaire. Media diaries captured time, content title, and co use of television, video-game, and computer usage; titles were coded for ratings, violence, scariness, and pacing. Nested linear regression models were built to examine the impact of timing, content, and co-use on the sleep problem score. RESULTS: On average, children consumed 72.9 minutes of media screen time daily, with 14.1 minutes occurring after 7:00 pm. Eighteen percent of parents reported at least 1 sleep problem; children with a bedroom television consumed more media and were more likely to have a sleep problem. In regression models, each additional hour of evening media use was associated with a significant increase in the sleep problem score (0.743 [95% confidence interval: 0.373-1.114]), as was daytime use with violent content (0.398 [95% confidence interval: 0.121-0.676]). There was a trend toward greater impact of daytime violent use in the context of a bedroom television (P=.098) and in low-income children (P=.07). CONCLUSIONS: Violent content and evening media use were associated with increased sleep problems. However, no such effects were observed with nonviolent daytime media use. PMID- 21708805 TI - Adults with chronic health conditions originating in childhood: inpatient experience in children's hospitals. AB - OBJECTIVE: To describe the rate of increase of the population of adults seeking care as inpatients in children's hospitals over time. PATIENTS AND METHODS: We analyzed data from January 1, 1999, to December 31, 2008, from patients hospitalized at 30 academic children's hospitals, including growth rates according to age group (pediatric: aged <18 years; transitional: aged 18-21 years; or adult: aged >21 years) and disease. RESULTS: There were 3 343 194 hospital discharges for 2 143 696 patients. Transitional patients represented 2.0%, and adults represented 0.8%, totaling 59 974 patients older than 18 years. The number of unique patients, admissions, patient-days, and charges increased in all age groups over the study period and are projected to continue to increase. Resource use was disproportionately higher in the older ages. The growth of transitional patients exceeded that of others, with 6.9% average annual increase in discharges, 7.6% in patient-days, and 15% in charges. Chronic conditions occurred in 87% of adults compared with 48% of pediatric patients. Compared with pediatric patients, the rates of increase of inpatient-days increased significantly for transitional age patients with cystic fibrosis, malignant neoplasms, and epilepsy, and for adults with cerebral palsy. Annual growth rates of charges increased for transitional and adult patients for all diagnoses except cystic fibrosis and sickle cell disease. CONCLUSIONS: The population of adults with diseases originating in childhood who are hospitalized at children's hospitals is increasing, with varying disease-specific changes over time. Our findings underscore the need for proactive identification of strategies to care for adult survivors of pediatric diseases. PMID- 21708806 TI - Supporting the health care transition from adolescence to adulthood in the medical home. AB - Optimal health care is achieved when each person, at every age, receives medically and developmentally appropriate care. The goal of a planned health care transition is to maximize lifelong functioning and well-being for all youth, including those who have special health care needs and those who do not. This process includes ensuring that high-quality, developmentally appropriate health care services are available in an uninterrupted manner as the person moves from adolescence to adulthood. A well-timed transition from child- to adult-oriented health care is specific to each person and ideally occurs between the ages of 18 and 21 years. Coordination of patient, family, and provider responsibilities enables youth to optimize their ability to assume adult roles and activities. This clinical report represents expert opinion and consensus on the practice based implementation of transition for all youth beginning in early adolescence. It provides a structure for training and continuing education to further understanding of the nature of adolescent transition and how best to support it. Primary care physicians, nurse practitioners, and physician assistants, as well as medical subspecialists, are encouraged to adopt these materials and make this process specific to their settings and populations. PMID- 21708807 TI - Standard terminology for fetal, infant, and perinatal deaths. AB - Accurately defining and reporting perinatal deaths (ie, fetal and infant deaths) is a critical first step in understanding the magnitude and causes of these important events. In addition to obstetric health care providers, neonatologists and pediatricians should know the current US definitions and reporting requirements for live births, fetal deaths, and infant deaths. Correct identification of these vital events will improve our local, state, and national data so that these deaths can be better addressed and reduced. PMID- 21708808 TI - Food commercials increase preference for energy-dense foods, particularly in children who watch more television. AB - OBJECTIVE: Our aim was to determine if levels of television viewing (a proxy measure for habitual commercial exposure) affect children's food preference responses to television food commercials. METHODS: A total of 281 children aged 6 to 13 years from northwest England viewed toy or food television commercials followed by a cartoon on 2 separate occasions; they then completed 3 food preference measures, a commercial recognition task, and a television viewing questionnaire. RESULTS: After viewing the food commercials, all children selected more branded and nonbranded fat-rich and carbohydrate-rich items from food preference checklists compared with after viewing the toy commercials. The food preferences of children with higher habitual levels of television viewing were more affected by food commercial exposure than those of low television viewers. After viewing food commercials, high television viewing children selected a greater number of branded food items compared with after the toy commercials as well as compared with the low television viewers. Children correctly recognized more food commercials than toy commercials. CONCLUSIONS: Exposure to television food commercials enhanced high television viewers' preferences for branded foods and increased reported preferences for all food items (branded and nonbranded) relative to the low television viewers. This is the first study to demonstrate that children with greater previous exposure to commercials (high television viewers) seemed to be more responsive to food promotion messages than children with lower previous advertising exposure. PMID- 21708809 TI - High-dose docosahexaenoic acid supplementation of preterm infants: respiratory and allergy outcomes. AB - BACKGROUND: Docosahexaenoic acid (DHA) has been associated with downregulation of inflammatory responses. OBJECTIVE: To report the effect of DHA supplementation on long-term atopic and respiratory outcomes in preterm infants. METHODS: This study is a multicenter, randomized controlled trial comparing the outcomes for preterm infants <33 weeks' gestation who consumed expressed breast milk from mothers taking either tuna oil (high-DHA diet) or soy oil (standard-DHA) capsules. Data collected included incidence of bronchopulmonary dysplasia (BPD) and parental reporting of atopic conditions over the first 18 months of life. RESULTS: Six hundred fifty-seven infants were enrolled (322 to high-DHA diet, 335 to standard), and 93.5% completed the 18-month follow-up. There was a reduction in BPD in boys (relative risk [RR]: 0.67 [95% confidence interval (CI): 0.47-0.96]; P=.03) and in all infants with a birth weight of <1250 g (RR: 0.75 [95% CI: 0.57 0.98]; P=.04). There was no effect on duration of respiratory support, admission length, or home oxygen requirement. There was a reduction in reported hay fever in all infants in the high-DHA group at either 12 or 18 months (RR: 0.41 [95% CI: 0.18-0.91]; P=.03) and at either 12 or 18 months in boys (RR: 0.15 [0.03-0.64]; P=.01). There was no effect on asthma, eczema, or food allergy. CONCLUSIONS: DHA supplementation for infants of <33 weeks' gestation reduced the incidence of BPD in boys and in all infants with a birth weight of <1250 g and reduced the incidence of reported hay fever in boys at either 12 or 18 months. PMID- 21708810 TI - Atypical hemolytic-uremic syndrome in a child presenting with malignant hypertension. PMID- 21708811 TI - Distracted driving among adolescents: challenges and opportunities. PMID- 21708812 TI - Unintentional paediatric ingestion poisonings and the role of imitative behaviour. AB - OBJECTIVE: To quantify the relationship between imitative behaviour and poisonings in children. SETTING: USA. METHODS: This study is based on the evaluation of a large national database of unintentional oral ingestion poisonings involving children aged <5 years treated in US hospital emergency departments during 2004 and 2005. It begins with the premise that, among other factors, oral drug poisonings can result from children observing and imitating adult behaviour, but that non-oral drug and non-drug poisonings (to be referred to as non-drug poisonings) generally do not, because children do not see adults ingesting non-drug products. The study then compares and contrasts the child poisonings between the two poisoning categories. Differences in the poisoning rate between the oral drug and non-drug categories are estimated by the age and sex of the children. A binary logistic regression analysis is also conducted using non-drug poisonings as a control group to compare against oral drug poisonings. RESULTS: There was a significant increase in the relative likelihood of oral drug poisonings beginning at age 20-23 months that is consistent with the expected onset of complicated imitative behaviours in children. Based upon our analysis, imitative behaviour may have contributed to about 17,300 child poisonings treated annually in the emergency department, possibly accounting for about 20% of poisonings involving children aged <5 years and 30% of the poisoning injuries involving children aged 20-59 months. CONCLUSIONS: Comprehensive efforts to prevent poisoning need to address the problem of imitative behaviour in children. Caregivers should never ingest medications in the presence of children. PMID- 21708813 TI - Alcohol-induced memory blackouts as an indicator of injury risk among college drinkers. AB - BACKGROUND: An alcohol-induced memory blackout represents an amnesia to recall events but does not involve a loss of consciousness. Memory blackouts are a common occurrence among college drinkers, but it is not clear if a history of memory blackouts is predictive of future alcohol-related injury above and beyond the risk associated with heavy drinking episodes. OBJECTIVE: To determine whether baseline memory blackouts can prospectively identify college students with alcohol-related injury in the next 24 months after controlling for heavy drinking days. METHODS: Data were analysed from the College Health Intervention Project Study (CHIPS), a randomised controlled trial of screening and brief physician intervention for problem alcohol use among 796 undergraduate and 158 graduate students at four university sites in the USA and one in Canada, conducted from 2004 to 2009. Multivariate analyses used generalised estimating equations with the logit link. RESULTS: The overall 24-month alcohol-related injury rate was 25.6%, with no significant difference between men and women (p=0.51). Alcohol induced memory blackouts at baseline exhibited a significant dose-response on odds of alcohol-related injury during follow-up, increasing from 1.57 (95% CI 1.13 to 2.19) for subjects reporting 1-2 memory blackouts at baseline to 2.64 (95% CI 1.65 to 4.21) for students acknowledging 6+ memory blackouts at baseline. The link between memory blackouts and injury was mediated by younger age, prior alcohol-related injury, heavy drinking, and sensation-seeking disposition. CONCLUSIONS: Memory blackouts are a significant predictor of future alcohol related injury among college drinkers after adjusting for heavy drinking episodes. PMID- 21708814 TI - Social and cultural influences on tobacco-related health disparities among South Asians in the USA. AB - OBJECTIVE: To explore and understand key cultural contexts of tobacco use among South Asian communities in the USA. DESIGN: Focus groups, with homogeneous compositions of gender, generational status and length of time in the USA, were conducted in two distinct South Asian ethnic enclaves. Focus group findings were triangulated with observational data regarding the availability of culturally specific tobacco from commercial ethnic outlets and cultural events. SUBJECTS: Respondents included 88 men and women of South Asian descent, aged 18-65 years, immigrant and native born, representing diversity of religion, socioeconomic status and region of origin, with the use of at least one culturally specific tobacco product in previous 24 months. RESULTS: A large number of culturally specific products were commonly used by community members. Knowledge of product specific health risks was lacking or inaccurate. Many culturally specific tobacco products were considered to have beneficial properties. South Asian tobacco items were used to preserve cultural traditions and express ethnic identity in a new dominant culture. The social and cultural values ascribed to use helped distinguish community members from mainstream society and from other minority populations. CONCLUSIONS: Many cultural factors govern tobacco use among diverse global populations. Especially for migrants with a common regional origin, the role of ethnic identity may strongly influence culturally specific tobacco patterns. Qualitative inquiry helps elucidate such culturally framed behaviour in culturally diverse populations. These cultural contexts should be integrated into research and practice. Understanding multidimensional factors influencing non traditional tobacco use is essential to ensure that comprehensive tobacco control strategies address tobacco-related disparities. PMID- 21708815 TI - ESC criteria for ECG interpretation in athletes: better but not perfect. PMID- 21708816 TI - The GRACE score's performance in predicting in-hospital and 1-year outcome. PMID- 21708817 TI - Optimal antithrombotic treatment during primary percutaneous coronary intervention? PMID- 21708818 TI - Dual-chamber pacemaker in persistent left superior vena cava. PMID- 21708819 TI - Comparison of diagnostic criteria to detect undiagnosed diabetes in hyperglycaemic patients with acute coronary syndrome. AB - BACKGROUND: Elevated plasma glucose levels on admission (APG) are very common in patients with acute coronary syndrome (ACS) and can be the first indication of diabetes mellitus. OBJECTIVE: To provide insight into the prevalence of previously undiagnosed diabetes and to compare different methods of diagnosing diabetes in patients with ACS. METHODS: Patients with ACS with elevated APG who participated in the BIOMArCS 2 glucose trial underwent an oral glucose tolerance test (OGTT) prior to discharge. 130 patients were included who underwent metabolic assessment. Of these, 109 had an OGTT and 13 patients had pre-existing diabetes. RESULTS: The OGTT results were categorised as (previously) undiagnosed diabetes in 35% of patients (fasting plasma glucose (FPG) >=7.0 mmol/l or 2-h post-load glucose >=11.1 mmol/l) and impaired glucose metabolism in 44% (FPG 6.1 6.9 mmol/l or post-load glucose 7.8-11.0 mmol/l), so only 21% had a normal glucose metabolism. Undiagnosed diabetes could not be adequately predicted with APG, FPG or HbA1c (area under the ROC curve 0.61, 0.75 and 0.72, respectively). Patients with abnormal glucose metabolism were significantly older, had higher admission HbA1c values, a higher Killip classification and more often had a prior stroke than patients with normal glucose metabolism. CONCLUSION: 79% of hyperglycaemic patients with ACS were found to have abnormal glucose metabolism. As APG, HbA1c and FPG had a low sensitivity to detect undiagnosed diabetes, an OGTT appears to be the best test to assess the presence of previously undiagnosed diabetes or impaired glucose metabolism in hyperglycaemic patients with ACS. PMID- 21708820 TI - Seizure-induced asystole. PMID- 21708821 TI - Geographic access to cancer care: a disparity and a solution. AB - BACKGROUND The rising cancer incidence in developing countries outpaces easy access to care. Time and effort spent on travel for care is a burden to patients and detracts from patient centredness, efficiency, and equitability. In Trinidad and Tobago, significant distress was observed among patients who made long journeys to the single public cancer clinic. The journey time among non radiotherapy patients was measured. METHODS Over 19 weekdays in June 2007, the study assessed estimated travel time per visit (ETT), reason for visit for care, and number of visits per patient during their treatment course up to the time of study, and compared the findings with ETT to nearest centres for the US population. RESULTS 1447 episodes of care utilised 5296 h of patient travel time. Median ETT was 3.75 h (IQR 2-5 h, range 0.5 9 h). 74.1% of patients spent 2.25-9 h ETT. 44% of patients spent >4 h ETT. Median number of visits per patient was 34 (IQR 23-43; range 13 62). Median total ETT per patient was 127.5 h. Median ETT to the centre (1.75 h) was eight times greater than in the USA (13 min). More than 70% of patients attended for reasons other than chemotherapy. CONCLUSIONS Cancer patients endured a burden of long travel times in 2007. The prevailing policy of the Ministry of Health to build a single centralised modern centre would not have alleviated this burden. Based on these findings, three outlying cancer clinics were created which now provide non-radiotherapy oncology management of patients nearer their homes. PMID- 21708823 TI - Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. AB - BACKGROUND: Lifestyle interventions focusing on weight loss remain the cornerstone of non-alcoholic fatty liver disease (NAFLD) management. Despite this, the weight losses achieved in research trials are not easily replicated in the clinic and there is an urgent need for therapies independent of weight loss. Aerobic exercise is not well sustained and the effectiveness of the better tolerated resistance exercise upon liver lipid and mediators of liver lipid has not been assessed. METHODS: Sedentary adults with clinically defined NAFLD were assigned to 8 weeks of resistance exercise (n=11) or continued normal treatment (n=8). RESULTS: 8 weeks of resistance exercise elicited a 13% relative reduction in liver lipid (14.0 +/- 9.1 vs. 12.2 +/- 9.0; p<0.05). Lipid oxidation (submaximal RQ -0.020 +/- 0.010 vs. -0.004 +/- 0.003; p<0.05), glucose control ( 12% vs. +12% change AUC; p<0.01) and homeostasis model assessment insulin resistance (5.9 +/- 5.9 to 4.6 +/- 4.6 vs. 4.7 +/- 2.1 to 5.1 +/- 2.5; p<0.05) were all improved. Resistance exercise had no effect on body weight, visceral adipose tissue volume, or whole body fat mass (p>0.05). CONCLUSION: This is the first study to demonstrate that resistance exercise specifically improves NAFLD independent of any change in body weight. These data demonstrate that resistance exercise may provide benefit for the management for non-alcoholic fatty liver, and the long-term impact of this now requires evaluation. PMID- 21708822 TI - Longitudinal study of infectious intestinal disease in the UK (IID2 study): incidence in the community and presenting to general practice. AB - OBJECTIVES: To estimate, overall and by organism, the incidence of infectious intestinal disease (IID) in the community, presenting to general practice (GP) and reported to national surveillance. DESIGN: Prospective, community cohort study and prospective study of GP presentation conducted between April 2008 and August 2009. SETTING: Eighty-eight GPs across the UK recruited from the Medical Research Council General Practice Research Framework and the Primary Care Research Networks. PARTICIPANTS: 6836 participants registered with the 88 participating practices in the community study; 991 patients with UK-acquired IID presenting to one of 37 practices taking part in the GP presentation study. MAIN OUTCOME MEASURES: IID rates in the community, presenting to GP and reported to national surveillance, overall and by organism; annual IID cases and GP consultations by organism. RESULTS: The overall rate of IID in the community was 274 cases per 1000 person-years (95% CI 254 to 296); the rate of GP consultations was 17.7 per 1000 person-years (95% CI 14.4 to 21.8). There were 147 community cases and 10 GP consultations for every case reported to national surveillance. Norovirus was the most common organism, with incidence rates of 47 community cases per 1000 person-years and 2.1 GP consultations per 1000 person-years. Campylobacter was the most common bacterial pathogen, with a rate of 9.3 cases per 1000 person-years in the community, and 1.3 GP consultations per 1000 person years. We estimate that there are up to 17 million sporadic, community cases of IID and 1 million GP consultations annually in the UK. Of these, norovirus accounts for 3 million cases and 130,000 GP consultations, and Campylobacter is responsible for 500,000 cases and 80,000 GP consultations. CONCLUSIONS: IID poses a substantial community and healthcare burden in the UK. Control efforts must focus particularly on reducing the burden due to Campylobacter and enteric viruses. PMID- 21708824 TI - Effects of haptoglobin polymorphisms and deficiency on susceptibility to inflammatory bowel disease and on severity of murine colitis. AB - BACKGROUND: Haptoglobin (Hp) is a haemoglobin-binding protein with immunomodulatory properties. Its gene (16q22) harbours a common polymorphism with two different alleles: Hp1 and Hp2. Genotype Hp22 has been shown to be over represented in different immune diseases. Results in Crohn's disease (CD) are contradictory. AIMS: To determine whether Hp plays a role in inflammatory bowel disease, both genetically and functionally. METHODS: 1061 patients with CD, 755 with ulcerative colitis (UC) and 152 with primary sclerosing cholangitis, as well as 452 healthy controls, were genotyped using touch-down PCR. To confirm association results, 464 CD trios and 151 UC trios were genotyped. Serum Hp concentrations were determined in 62 individuals of different genotype. Colitis was induced in mice with dextran sulphate sodium (DSS) and oxazolone (Oxa). Cytokine production was evaluated by mRNA quantification in colonic tissue and ELISA on supernatants of mesenteric lymph node cells. RESULTS: Prevalence of Hp2 was higher in CD and UC than in controls. In the confirmatory cohorts, Hp2 was over-transmitted to the affected offspring. Serum Hp concentrations were higher in individuals with genotypes Hp11 and Hp21 than in those with Hp22 (1.38 vs 0.89 g/l). DSS- and Oxa-induced colitis were more severe in Hp-deficient mice than in control mice and accompanied by higher concentrations (although not statistically significantly different) of tissue mRNA for cytokines. Interleukin-17 production was significantly higher in the presence of Hp-deficient serum compared with wild type serum. CONCLUSIONS: The Hp gene may play a role in susceptibility to inflammatory bowel disease. Its implication in other immune diseases underscores the common pathways between these diseases. Experimental models of colitis showed that Hp has a protective role in inflammatory colitis, most likely by inhibiting the production of Th1 and Th17 cytokines. PMID- 21708825 TI - Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour. AB - BACKGROUND AND AIMS: The majority of gastrointestinal stromal tumors (GISTs) have KIT mutations; however, epigenetic abnormalities that could conceivably potentiate the aggressiveness of GISTs are largely unidentified. Our aim was to establish epigenetic profiles associated with the malignant transformation of GISTs. METHODS: Methylation of four tumor suppressor genes, RASSF1A, p16, CDH1, and MGMT was analyzed in GISTs. Additionally, genome-wide DNA methylation profiles were compared between small, malignant-prone, and malignant GISTs using methylated GpG island amplification microarrays (MCAM) in a training set (n=40). Relationships between the methylation status of genes identified by MCAM and clinical features of the disease were tested in a validation set (n=75). RESULTS: Methylation of RASSF1A progressively increased from small to malignant GISTs. p16 was specifically methylated in malignant-prone and malignant GISTs. MCAM analysis showed that more genes were methylated in advanced than in small GISTs (average of 473 genes vs 360 genes, respectively, P=0.012). Interestingly, the methylation profile of malignant GISTs was prominently affected by their location. Two genes, REC8 and PAX3, which were newly-identified via MCAM analysis, were differentially methylated in small and malignant GISTs in the training and validation sets. Patients with methylation of at least REC8, PAX3, or p16 had a significantly poorer prognosis (P=0.034). CONCLUSION: Our results suggest that GIST is not, in epigenetic terms, a uniform disease and that DNA methylation in a set of genes is associated with aggressive clinical behavior and unfavorable prognosis. The genes identified may potentially serve as biomarkers for predicting aggressive GISTs with poor survivability. PMID- 21708827 TI - Kupffer cell activation and portal hypertension. PMID- 21708826 TI - TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres. AB - BACKGROUND AND AIMS: Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC. METHODS: In a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in 'telomere biology' genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately. RESULTS: Carriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within TERC transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. TERC mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC risk allele was associated with higher levels of TERC mRNA and the formation of longer telomeres. CONCLUSIONS: Common genetic variation at TERC is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres. PMID- 21708828 TI - Discrepancy between participants' understanding and desire to know in informed consent: are they informed about what they really want to know? AB - BACKGROUND: Participants' understanding of clinical trials is important in informed consent. However, little is known about what information participants really want to know. AIMS: To demonstrate the existence of a discrepancy between participants' understanding and their desire to know. METHODS: The participants in clinical trials at Seoul National University Hospital were surveyed. The survey consisted of 11 statements based on the essential elements of informed consent. The participants gave two responses to each statement on a five-point Likert scale to rate their subjective understanding and desire to know, respectively. Information discrepancy was defined as the difference between these two ratings: if understanding exceeded desire to know for a particular item, it was defined as 'over-informed'; if desire to know exceeded understanding for a particular item, it was defined as 'under-informed'. RESULTS: Participants reported good understanding of 'voluntariness', 'duration', 'study involves research' and poor understanding of 'confidentiality', 'compensation', 'benefits', 'procedures' and 'risks or discomforts'. For 'risks or discomforts', 'who to contact', 'voluntariness', 'duration' and 'procedures', participants reported high desire to know compared with 'confidentiality', 'purpose', 'study involves research' and 'benefits'. The elements 'study involves research', 'voluntariness', 'duration', 'purpose' and 'who to contact' were over-informed, while 'compensation', 'risks or discomforts', 'procedures', 'confidentiality' and 'benefits' were under-informed. Participants over 50 years of age, those without a college education and those whose participation was less voluntary were relatively less informed about the clinical trials. CONCLUSIONS: An information discrepancy was observed between the participants' understanding and their desire to know. By putting more emphasis on under-informed elements, the quality of informed consent could be improved. PMID- 21708829 TI - Privacy, confidentiality and abortion statistics: a question of public interest? AB - The precise nature and scope of healthcare confidentiality has long been the subject of debate. While the obligation of confidentiality is integral to professional ethical codes and is also safeguarded under English law through the equitable remedy of breach of confidence, underpinned by the right to privacy enshrined in Article 8 of the Human Rights Act 1998, it has never been regarded as absolute. But when can and should personal information be made available for statistical and research purposes and what if the information in question is highly sensitive information, such as that relating to the termination of pregnancy after 24 weeks? This article explores the case of In the Matter of an Appeal to the Information Tribunal under section 57 of the Freedom of Information Act 2000, concerning the decision of the Department of Health to withhold some statistical data from the publication of its annual abortion statistics. The specific data being withheld concerned the termination for serious fetal handicap under section 1(1)d of the Abortion Act 1967. The paper explores the implications of this case, which relate both to the nature and scope of personal privacy. It suggests that lessons can be drawn from this case about public interest and use of statistical information and also about general policy issues concerning the legal regulation of confidentiality and privacy in the future. PMID- 21708830 TI - Moral duties and euthanasia: why to kill is not necessarily the same as to let die. AB - David Shaw's response to Hugh McLachlan's criticism of his proposed new perspective on euthanasia is ineffectual, mistaken and unfair. It is false to say that the latter does not present an argument to support his claim that there is a moral difference between killing and letting die. It is not the consequences alone of actions that constitute their moral worth. It can matter too what duties are breached or fulfilled by the particular moral agents who are involved. PMID- 21708831 TI - Do guidelines on euthanasia and physician-assisted suicide in Dutch hospitals and nursing homes reflect the law? A content analysis. AB - To describe the content of practice guidelines on euthanasia and assisted suicide (EAS) and to compare differences between settings and guidelines developed before or after enactment of the euthanasia law in 2002 by means of a content analysis. Most guidelines stated that the attending physician is responsible for the decision to grant or refuse an EAS request. Due care criteria were described in the majority of guidelines, but aspects relevant for assessing these criteria were not always described. Half of the guidelines described the role of the nurse in the performance of euthanasia. Compared with hospital guidelines, nursing home guidelines were more often stricter than the law in excluding patients with dementia (30% vs 4%) and incompetent patients (25% vs 4%). As from 2002, the guidelines were less strict in categorically excluding patients groups (32% vs 64%) and in particular incompetent patients (10% vs 29%). Healthcare institutions should accurately state the boundaries of the law, also when they prefer to set stricter boundaries for their own institution. Only then can guidelines provide adequate support for physicians and nurses in the difficult EAS decision-making process. PMID- 21708832 TI - Risk of disclosure of participating in an internet-based HIV behavioural risk study of men who have sex with men. AB - As the frequency of internet-based research has increased, it is important for researchers to consider how the conditions in which data are collected may influence the risks to participants. In particular, because internet-based data collection often occurs outside a clinical or research setting, there may be unintentional disclosures of a participant's involvement in a research study of which the researcher is unaware. The current analysis examined the responses of men who have sex with men participating in an internet-based HIV behavioural risk study when queried about the possible disclosure of their participation in the study. Fewer than 2% of participants indicated that their participation in the research study was disclosed, and all but one indicated no negative outcomes associated with the disclosure. As the field of online research continues to expand, it is important to consider risks that are unique to internet-based research, and to monitor these risks to ensure that the confidentiality of research subjects is maintained. PMID- 21708833 TI - A clear case for conscience in healthcare practice. AB - The value of conscience in healthcare ethics is widely debated. While some sources present it as an unquestionably positive attribute, others question both the veracity of its decisions and the effect of conscientious objection on patient access to health care. This paper argues that the right to object conscientiously should be broadened, subject to certain previsos, as there are many benefits to healthcare practice in the development of the consciences of practitioners. While effects such as the preservation of moral integrity are widely considered to benefit practitioners, this paper draws on the work of Hannah Arendt to offer several original arguments in defence of conscience that may more directly benefit patients, namely that a pang of conscience may be useful in rapidly unfolding situations in which there is no time to reflect satisfactorily upon activities and that, given the hierarchical nature of healthcare institutions, a right to defy authority on the basis of conscience may benefit junior staff who lack the institutional power to challenge the orders of superiors. PMID- 21708834 TI - Thanking and reciprocating under the New Zealand organ donation system. AB - Organ donation and transplantation has been extensively addressed in the biomedical and bioethics literature in relation to debates around organ allocation and procurement strategies, and concerns about consent, coercion and commodification. This article addresses the topic sociologically, drawing on data from face-to-face in-depth interviews undertaken between 2008 and 2010 with organ and tissue recipients, anonymous altruistic donors and donor family members to discuss questions of reciprocity and intercorporeality that arise in the course of tissue exchange. In particular, the article examines the place of anonymity protocol for organ donors and transplantation recipients in New Zealand and their responses to conventions and scripts surrounding this rule. The article concludes by calling for discussion to re-examine anonymity protocol and rituals around organ donation and transplantation, citing lessons from gamete donation policies and recent law in New Zealand as productive for thinking through matters of personhood and identity relating to organ transfer. PMID- 21708835 TI - Trends in acute myocardial infarction treatment between 1998 and 2007 in a Belgian area (Charleroi). AB - BACKGROUND/OBJECTIVES: To describe the evolution of the therapeutic practices over 10 years of follow-up of acute myocardial infarction (AMI) in Charleroi and to analyse the factors influencing the choice of treatments and the mortality of these patients. METHODS: The Charleroi register of ischaemic cardiopathies is the oldest register of infarctions in the French-speaking community of Belgium and is one of the very rare registers that allows identifying tendencies over 25 years. Analyses presented hereafter relate only patients in the 25-69-year age range over time from 1998 to 2007. The data were analysed in five periods of 2 years. Treatment evolutions over time were analysed using chi-squared tests for trend and logistic regression analyses identify factors influencing the type of treatment. RESULTS: The present study shows a marked increase in the utilization of percutaneous transluminal coronary angioplasty (PTCA) between 1998-1999 and 2006-2007. The use of thrombolytic agents on approximately one-third of the patients treated remained fairly stable between 1998 and 2007. A lower proportion of patients with a history of AMI received thrombolytic agents. Thrombolysis seems beneficial for men and without effect for women. The use of beta-blockers continued to increase until the 2000-2001 period and remained fairly stable for the two following periods. 42% of patients were administered three medications (angiotensin-converting enzyme inhibitors, antiplatelet drugs, and beta blockers). Association of PTCA with antiplatelet drugs, beta-blockers, and thrombolysis was observed for 58.7, 50.6, and 25.7%, respectively. These associations were still observed after adjustment for gender, age, and comorbidity. The factors associated with fatality were specifically old-aged patients, antecedents of diabetes, hypercholesterolaemia and oral antiplatelet drugs, and beta-blockers therapies and PTCA. CONCLUSIONS: The evolution of the therapeutic data on AMI in this register confirms the use and the efficacy of thrombolytic therapy. PTCA becomes the main coronary reperfusion treatment with less risk of bleeding. Angiotensin-converting enzyme inhibitors were without effect on mortality. PMID- 21708836 TI - Complexity analysis of spontaneous brain activity: effects of depression and antidepressant treatment. AB - Magnetoencephalography (MEG) allows the real-time recording of neural activity and oscillatory activity in distributed neural networks. We applied a non-linear complexity analysis to resting-state neural activity as measured using whole-head MEG. Recordings were obtained from 20 unmedicated patients with major depressive disorder and 19 matched healthy controls. Subsequently, after 6 months of pharmacological treatment with the antidepressant mirtazapine 30 mg/day, patients received a second MEG scan. A measure of the complexity of neural signals, the Lempel-Ziv Complexity (LZC), was derived from the MEG time series. We found that depressed patients showed higher pre-treatment complexity values compared with controls, and that complexity values decreased after 6 months of effective pharmacological treatment, although this effect was statistically significant only in younger patients. The main treatment effect was to recover the tendency observed in controls of a positive correlation between age and complexity values. Importantly, the reduction of complexity with treatment correlated with the degree of clinical symptom remission. We suggest that LZC, a formal measure of neural activity complexity, is sensitive to the dynamic physiological changes observed in depression and may potentially offer an objective marker of depression and its remission after treatment. PMID- 21708837 TI - Endocannabinoids and the cardiovascular response to stress. AB - Stress activates the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), resulting in cardiovascular responses. The endocannabinoid system (ECS), a ubiquitously expressed lipid signalling system, modulates both HPA and SNS activity. The purpose of this review is to explore the possible involvement/role of the ECS in the cardiovascular response to stress. The ECS has numerous cardiovascular effects including modulation of blood pressure, heart rate, the baroreflex, and direct vascular actions. It is also involved in a protective manner in response to stressors in cardiac preconditioning, and various stressors (for example, pain, orthostasis and social stress) increase plasma levels of endocannabinoids. Given the multitude of vascular effects of endocannabinoids, this is bound to have consequences. Beneficial effects of ECS upregulation could include cardioprotection, vasodilatation, CB(2)-mediated anti inflammatory effects and activation of peroxisome proliferator-activated receptors. Negative effects of endocannabinoids could include mediation of the effects of glucocorticoids, CB(1)-mediated metabolic changes, and metabolism to vasoconstrictor products. It is also likely that there is a central role for the ECS in modulating cardiovascular activity via the HPA and SNS. However, much more work is required to fully integrate the role of the ECS in mediating many of the physiological responses to stress, including cardiovascular responses. PMID- 21708838 TI - Effects of acute alcohol consumption on alcohol-related cognitive biases in light and heavy drinkers are task-dependent. AB - We investigated (1) the effects of alcohol on cognitive biases for alcohol related cues, (2) the effects of drinking status on alcohol-related cognitive biases and (3) the similarity of any effects of alcohol across two measures of alcohol cognitive bias. Healthy, heavy and light social alcohol users (n = 72) were examined in a single-blind placebo-controlled design. Participants received 0.00 g/kg, 0.13 g/kg or 0.40 g/kg of alcohol in a between-subjects design and then completed both a modified Stroop task and a visual probe task. Modified Stroop data indicated a main effect of cue type, which was qualified by drinking status, with heavier drinkers slower to respond to alcohol-related cues. Visual probe data, in contrast, indicated a significant interaction effect between validity (valid: alcohol-related, invalid: neutral) and drink condition. Participants receiving a moderate dose of alcohol (0.40 g/kg) were faster to respond to alcohol-related stimuli compared with participants receiving a low dose of alcohol or placebo. These data indicate that the cognitive processes assayed by the visual probe and Stroop tasks may not be mediated by a common underlying mechanism. PMID- 21708839 TI - Ulnar neuropathy caused by an anconeus epitrochlearis: clinical and electrophysiological findings. PMID- 21708840 TI - The dorsal metacarpal arteries: anatomical study. Feasibility of pedicled metacarpal bone flaps. AB - The vascular anatomy of the dorsal aspect of the hand is variable. Nevertheless the presence of the first and the second dorsal metacarpal artery (DMA) is constant. DMA3 and 4 are more variable. The anatomical study presented demonstrates the segmental vascularization of the metacarpal bones and the possibility of harvesting metacarpal bone flaps. The reliability of such a flap decreases from the second to the fifth metacarpal bone regarding the frequency of presence of the DMAs. The authors describe six new vascularized bone flaps from the third and the fourth metacarpal bones pedicled on the second or the third dorsal metacarpal artery in an anterograde or retrograde flow mode. This study suggests that the radial and the ulnar side of the third metacarpal bone could be harvested respectively on the DMA2 and DMA3. The radial side of the fourth metacarpal bone could also be a reliable vascularized bone donor site. Flaps can be used proximally or distally based to repair bone defects either on metacarpal and carpal bones or on proximal phalanges. PMID- 21708841 TI - Comparison of surgical treatment and nonoperative management for radial longitudinal deficiency. AB - We compared the radiological and functional outcomes in patients with radial longitudinal deficiency treated surgically with those managed nonoperatively and correlated the ease of performance of activities with radiological and functional parameters in the two groups. A retrospective analysis was done in 446 type 3 and 4 hands (modified Bayne classification) over 20 years comparing the subjective assessment, objective and functional scores in nonoperatively managed hands (Group 1; n = 137) to hands managed with centralization or radialization (Group 2; n = 309). The subjective, objective and functional measures were significantly better in Group 2. Improved alignment, finger and wrist range of motion and grip strength were related to improvement in functional score. Surgical treatment of radial longitudinal deficiency provides improvement in cosmesis, function and ease of performance of activities when compared with nonoperatively managed hands. PMID- 21708842 TI - Bone bridge resection for correction of distal radial deformities after partial growth plate arrest: two cases and surgical technique. AB - Partial closure of the growth plate is an uncommon complication in the distal radius even though distal radial fractures are among the most common injuries in children. We report two cases of resection of a bony bridge in the distal radial growth plate in boys aged 8 and 9 years with a description of the operative technique. PMID- 21708843 TI - The EPCRC project to revise the European Association for Palliative Care (EAPC) guidelines on the use of opioids for cancer pain. PMID- 21708844 TI - A call to arms for the palliative medicine research community. PMID- 21708845 TI - Cancer pain research: time to reset the strategy and the agenda. PMID- 21708846 TI - Evidence-based medicine: what is the evidence that it has made a difference? AB - Evidence-based medicine (EBM) has, over the past 20 years, made us all more critical in our thinking about the efficacy and safety of interventions. This is evident in the higher standards of our spoken and written work, formal and informal, and in our approach to the subject. The downside has been the coincidence of the squeeze on healthcare funding with the emergence of the EBM ideas - it has been all too easy to misuse the tools of EBM to deny patients access to treatment, and this, together with the off-putting political correctness of the EBM approach in some quarters, has made clinicians uneasy. Clinicians have to make decisions about therapy for the individual patient. Ideally this is guided by the best available evidence and their experience. EBM can guide one as to the population efficacy and safety of a particular intervention, but as we all know few patients are average. That guidance can only be given if there is adequate evidence, and the difficulty with guidance about symptom control is often the paucity of evidence of sufficient quality to yield credible guidance. Palliative care is often a 'complex intervention', and here EBM struggles to untangle which components, if any, of the complex interventions are important. The trial and review methodologies for complex intervention are wanting. Tom Chalmers, a grandfather of the EBM movement, argued late in his career that the most important function of the EBM approach was to frame the research agenda. This we think is correct. The process of systematic review of a topic throws up the deficits in trial methods and the lacunae in the data, and this then can show the way forward. PMID- 21708847 TI - How well is cancer pain treated? AB - There are currently two indicators, Morphine Consumption Data and the Pain Management Index, that have been widely used to assess the efficacy of cancer pain treatment. Both are based on the World Health Organization guidelines for cancer pain and both have limitations in their ability to assess the quality of pain care for cancer patients. The published studies that have used these methods all report that cancer pain is generally undertreated in a wide range of clinical settings and care models. PMID- 21708848 TI - Is oral morphine still the first choice opioid for moderate to severe cancer pain? A systematic review within the European Palliative Care Research Collaborative guidelines project. AB - The aim of this systematic review was to evaluate the evidence that oral morphine can be recommended as the first choice opioid in the treatment of moderate to severe cancer pain in updating the European Association for Palliative Care opioid recommendations. A systematic literature review was performed to update the 2007 Cochrane review 'Oral morphine for cancer pain'. The literature search was conducted on MedLine, EMBASE and Cochrane Central Register of Controlled Trials databases. The search strategy, limited in time (from 1 July 2006 to 31 October 2009), was aimed to be as extensive as possible using both text words and MeSH/EMTREE terms; a hand search of the reference lists of identified papers was also performed. Randomized clinical trials, containing data on efficacy and/or side effects of morphine, were identified. Among the papers retrieved from the cited databases and the Cochrane review, 17 eligible studies, for a total of 2053 patients, and a meta-analysis were selected. These studies do not add significant information to the previous Cochrane review confirming the limitation of efficacy and tolerability data on opioid-naive and non-selected populations of cancer patients treated with morphine and suggesting that oral morphine, oxycodone and hydromorphone have similar efficacy and toxicity in this patient population. PMID- 21708849 TI - The second step of the analgesic ladder and oral tramadol in the treatment of mild to moderate cancer pain: a systematic review. AB - BACKGROUND: To analyse the evidence supporting the widespread use of modified analgesic ladders or oral tramadol as alternatives to codeine/paracetamol for mild to moderate cancer pain. METHODS: A systematic review of the literature was independently performed by two authors. The level of evidence and risk/benefit ratio were assessed in all the selected trials. A comprehensive analysis of the level of evidence, risk/benefit ratio and strength of the recommendations was carried out. The analysis was performed using the GRADE system. RESULTS: Eighteen papers were included into the analysis. The level of evidence was low or very low for all the trials, and as a result the risk/benefit ratio was uncertain. Likewise, the strength of the final recommendations was considered weak negative for either the use of modified analgesic ladders (by-passing the second step of the World Health Organization (WHO) analgesic ladder) or the use of oral tramadol as an alternative to codeine/paracetamol in the second step of the WHO analgesic ladder. CONCLUSIONS: Data supporting the role of modified two-step analgesic ladders or oral tramadol as an alternative to codeine/paracetamol are insufficient to recommend their routine use in cancer patients with mild to moderate cancer pain. PMID- 21708850 TI - Starting step III opioids for moderate to severe pain in cancer patients: dose titration: a systematic review. AB - The European Association for Palliative Care recommendation for starting morphine for cancer pain is dose titration with immediate release (IR) oral morphine given every 4 h with additionally doses for breakthrough pain. As part of a EU 6th framework programme to revise the guidelines we review the evidence regarding starting treatment and dose titration of opioids in adult patients with moderate to severe cancer pain. Relevant papers were identified though a systematic search in Medline for papers published until the end of 2009. We identified 15 relevant papers. Thirteen papers were descriptive papers reporting the results from starting treatment with oral morphine (six studies), starting treatment with intravenous morphine (two studies) and starting treatment with transdermal fentanyl (four studies). All treatment strategies resulted in acceptable pain control and were well tolerated. Two randomized controlled trials were identified. One study compared starting opioid treatment with intravenous morphine versus IR oral morphine and one study compared IR oral morphine versus sustained release oral morphine. PMID- 21708851 TI - Management of opioid-induced nausea and vomiting in cancer patients: systematic review and evidence-based recommendations. AB - The objectives were to review the existing literature on management of opioid induced nausea and vomiting in cancer patients and summarize the findings into evidence-based recommendations. Systematic searches of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were performed, using free text and MeSH/EMTREE search terms. The searches were limited to articles published in English from each database set-up date to 31 July 2009. Reference lists and relevant international conference proceedings were hand-searched. Fifty-five studies were identified, providing data on 5741 patients. The studies were classified into: (A) studies in which treatment of nausea/vomiting was the primary outcome (a total of 18 studies, of which eight studies specifically addressed opioid-induced emesis); and (B) studies in which nausea/vomiting were secondary or tertiary outcomes (37 studies). The existing evidence had several limitations, there was a lack of consistency and the overall quality was grade D. By applying the principles of the Grading of Recommendations Assessment, Development and Evaluations (GRADE) system, three weak recommendations were formulated. The current evidence is too limited to give evidence-based recommendations for the use of antiemetics for opioid-induced nausea or vomiting in cancer patients. The evidence suggests that nausea and vomiting in cancer patients receiving an opioid might be reduced by changing the opioid or opioid administration route. The evidence was also too limited to prioritize between symptomatic treatment and adjustment of the opioid treatment. PMID- 21708852 TI - A systematic review of oxycodone in the management of cancer pain. AB - BACKGROUND: Oxycodone is often used as an opioid analgesic for moderate to severe cancer-related pain, but its use varies across Europe. This systematic literature review forms the basis of guidelines for oxycodone use within the European Palliative Care Research Collaborative opioid guidelines project conducted on behalf of the European Association for Palliative Care. OBJECTIVES: The objective of this study was to identify and assess the quality of evidence for the use of oxycodone for cancer pain in adults. METHODS: The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MedLine, EMBASE and CINAHL were systematically searched in addition to hand searching of relevant journals. Studies were included if they reported a clinical outcome relevant to the use of oxycodone in adult patients with moderate to severe cancer pain. Any form and route of oxycodone was included except intrathecal. No direct comparator was required for inclusion and studies were excluded if patients had previously switched from another strong opioid because of intolerable adverse effects or poor efficacy. This is a narrative systematic review, using the GRADE approach to assess the quality of studies and to formulate guidelines. RESULTS: Twenty-nine original studies were identified including a meta-analysis and 14 randomized controlled trials. The identified meta-analysis included three trials comparing oxycodone to morphine and one comparing oxycodone to hydromorphone. Four other randomized trials compared oxycodone with other opioids. The remaining randomized controlled trials compared different routes of administration or formulations of oxycodone. No additional studies that would have been suitable for addition to the meta-analysis were identified. CONCLUSIONS: There is no evidence from the included trials of a significant difference in analgesia or adverse effects between oxycodone and morphine or hydromorphone. The evidence was graded as high quality on the basis of a well-conducted meta-analysis, with no limitations likely to affect the outcome, in addition to consistency in the results of the other studies. The research was conducted using participants relevant to cancer and palliative care populations. Oxycodone can be recommended as an alternative to morphine or hydromorphone for cancer-related pain. PMID- 21708853 TI - The role of hydromorphone in cancer pain treatment: a systematic review. AB - The aim of this systematic review is to evaluate the scientific evidence for the efficacy and side effects of hydromorphone in the management of moderate to severe cancer pain. Randomized and non-randomized clinical trials, reporting data on efficacy and/or side effects of hydromorphone, were identified. Thirteen eligible studies, involving 1208 patients, were selected. Seven studies compared hydromorphone with other opioids (five with morphine, one with oxycodone and one with fentanyl and buprenorphine) and five of them were randomized controlled trials (RCTs). Most of the studies were conducted on patients already receiving opioid treatment, often at stabilized doses, and most had methodological limitations. The RCTs comparing hydromorphone with morphine and oxycodone showed similar analgesic results, while the comparison of side effects showed minor differences, not consistent across studies. Due to clinical and methodological heterogeneity of the studies, a meta-analysis was not performed. In conclusion there is evidence to support the efficacy and tolerability of hydromorphone for moderate to severe cancer pain as an alternative to morphine and oxycodone, while there is no evidence to demonstrate its superiority or inferiority in comparison with morphine as the first choice opioid for the same indication. PMID- 21708854 TI - Transdermal opioids as front line treatment of moderate to severe cancer pain: a systemic review. AB - BACKGROUND: To assess the role of transdermal opioids as a front-line approach to moderate to severe cancer pain. METHODS: A systematic review of the literature was performed by two authors. An analysis of the level of evidence and risk/benefit ratio was performed for all of the selected trials. A combined analysis of the included studies to assess the level of evidence, risk/benefit ratio and strength of the recommendations was performed to determine the place of transdermal opioids in the treatment of cancer when compared with oral morphine. RESULTS: Thirteen papers were included in the analysis. The level of evidence was considered low for transdermal opioids (without distinction between transdermal fentanyl and transdermal buprenorphine) or transdermal fentanyl, and very low for transdermal buprenorphine. The risk/benefit ratio was considered uncertain for both transdermal opioids (fentanyl and buprenorphine) considered together and transdermal fentanyl or buprenorphine alone. The strength of the final recommendations (using the GRADE system) was weak negative for transdermal opioids (transdermal fentanyl plus transdermal buprenorphine) and transdermal fentanyl, and strong negative for transdermal buprenorphine. CONCLUSIONS: The use of slow release oral morphine probably remains the preferred approach for these patients, with the use of transdermal opioids to be reserved for selected patients. PMID- 21708855 TI - Is oral methadone better than placebo or other oral/transdermal opioids in the management of pain? AB - AIM: To address the question: is oral methadone better than placebo, or other oral/transdermal opioids in the management of cancer pain? METHOD: A literature search was performed to identify relevant studies. Search strategies included: (1) methadone (title) AND placebo (title or abstract) AND pain (title or abstract); (2) methadone (title) AND randomized (title or abstract) AND pain (title or abstract) AND cancer (title or abstract). Papers were reviewed for relevance to first-line opioid therapy. RESULTS: No studies were identified comparing methadone to placebo for cancer pain. A single study compared methadone to placebo for neuropathic pain and demonstrated evidence of analgesic effect at a dose of 20 mg/day but not at a dose of 10 mg/day. Four studies compared oral methadone to either oral morphine, or oral morphine and transdermal fentanyl in a first-line setting: Gourlay 1986 (N = 18), Ventafridda 1986 (N =54), Bruera 2004 (N = 106) and Mercadante 2008 (N = 108). All studies demonstrated comparable, but not superior, analgesia with, overall, a comparable adverse effect profile. The duration of the study period for the three largest studies was 28 days. Two of these studies, Ventafridda 1986 and Mercadante 2008, indicated that, over time, the opioid escalation index was lower for methadone than for morphine. One study that used a 2:1 dose ratio between morphine and methadone was associated with a high attrition rate in the first week because of excessive sedation. This effect was not seen in the study that used a 4:1 morphine to methadone dose ratio with dose titration. CONCLUSION: This limited data suggests that (1) methadone may be an equally effective candidate for first-line opioid therapy, (2) that it is possibly less expensive, (3) that there may be a propensity to sedation and dose accumulation unless there is close monitoring and conservative dose selection and (4) that it should be initiated with a calculated dose based on a morphine to methadone dose ratio of not less than 4:1. PMID- 21708856 TI - European Palliative Care Research Collaborative pain guidelines: opioid switching to improve analgesia or reduce side effects. A systematic review. AB - According to a Cochrane review on opioid switching, sound evidence on the practice of substituting one strong opioid with another to improve pain control and reduce adverse effects was lacking in 2004. A systematic search strategy was developed to include studies after 2004, with adult cancer patients switching between strong opioids and reporting estimates of effect on pain and adverse effects. The search retrieved 288 publications (71 duplicates); 187 abstracts and 19 full papers were excluded. Eleven papers met the inclusion criteria; none were randomized controlled trials/meta-analyses. Studies comprised 280 patients (group size 10-32). A variety of opioids and switching strategies were studied. Pain intensity was significantly reduced in the majority of studies. Serious adverse effects were improved. Due to serious design limitations, the level of evidence was low (D). Randomized trials, with standardization of cohort classification, use of outcomes and analysis are warranted to establish the practice of opioid switching. PMID- 21708857 TI - Conversion ratios for opioid switching in the treatment of cancer pain: a systematic review. AB - In this paper we describe the results of a systematic search of the literature on conversion ratios during opioid switching. This is part of a project of the European Palliative Care Research Collaboration to update the European Association for Palliative Care recommendations for the use of opioid analgesics in the treatment of cancer pain. Studies were eligible for inclusion if they involved adult patients with chronic cancer pain, contained data on opioid conversion ratios, were prospective and were written in English. Thirty-one studies were identified and included. The majority of the studies had methodological flaws and were not designed to explore or demonstrate equianalgesic dose data. However, the data allow some recommendations to be made that could be helpful to clinicians for whom there are few reliable experimental data on which to base dosing guidelines. Switching to transdermal fentanyl (TDfe) or buprenorphine (TDbu) is an option for patients with stable, controlled pain. Reliable and consistent studies show a ratio of 100 : 1 between oral morphine (ORmo) and TDfe. A ratio of 75 : 1 between ORmo and TDbu may be appropriate, but the supporting evidence here is much less robust. Data are relatively consistent to support a conversion ratio between ORmo and oral hydromorphone (ORhy) of 5 : 1. Despite some limitations, there is evidence to support the use of an approximate conversion ratio of ORmo:oral oxycodone (ORox) of 1.5 : 1. The conversion between ORox and ORhy is estimated to be 1 : 4. When switching from different opioids to methadone the conversion ratio is highly variable, ranging from 5 : 1 to 10 : 1 and much higher in some studies. The derived ratios are influenced by several factors, including the reasons for switching and previous opioid doses. An individual treatment decision and strict monitoring is recommended for patients considered at risk. PMID- 21708858 TI - Opioids for the management of breakthrough cancer pain in adults: a systematic review undertaken as part of an EPCRC opioid guidelines project. AB - The usual management of cancer related breakthrough pain is with supplemental doses of analgesics (commonly opioids) at a dose proportional to the total around the-clock opioid dose. The aim of this review, undertaken as part of a European Palliative Care Research Collaborative (EPCRC) project, to update the EAPC guidelines on opioid analgesics in cancer pain was to determine the evidence for the utility of opioids in the management of breakthrough pain in patients with cancer. Randomized controlled trials of opioids used as rescue medication were identified using electronic search strategies. Outcome measures sought were reduction in pain intensity measured by an appropriate scale, adverse effects, attrition, and patient satisfaction. The date of the final search was 31 July 2009. Eight studies (790 patients) met the inclusion criteria. Most studies investigated rescue medication delivery via the buccal or nasal transmucosal routes. Intravenous morphine has been compared with the transmucosal route and the two found to be effective. The oral route has not been formally tested although found to be an inferior comparator in one study. Most studies showed no meaningful relationship between the effective dose of transmucosal opioid and the around-the-clock scheduled medication or the previous rescue medication, although one study found a fixed proportion of either intravenous morphine or transmucosal fentanyl to be efficacious. PMID- 21708859 TI - A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: a European Palliative Care Research Collaborative opioid guidelines project. AB - BACKGROUND: Opioid use in patients with renal impairment can lead to increased adverse effects. Opioids differ in their effect in renal impairment in both efficacy and tolerability. This systematic literature review forms the basis of guidelines for opioid use in renal impairment and cancer pain as part of the European Palliative Care Research Collaborative's opioid guidelines project. OBJECTIVE: The objective of this study was to identify and assess the quality of evidence for the safe and effective use of opioids for the relief of cancer pain in patients with renal impairment and to produce guidelines. SEARCH STRATEGY: The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MedLine, EMBASE and CINAHL were systematically searched in addition to hand searching of relevant journals. SELECTION CRITERIA: Studies were included if they reported a clinical outcome relevant to the use of selected opioids in cancer-related pain and renal impairment. The selected opioids were morphine, diamorphine, codeine, dextropropoxyphene, dihydrocodeine, oxycodone, hydromorphone, buprenorphine, tramadol, alfentanil, fentanyl, sufentanil, remifentanil, pethidine and methadone. No direct comparator was required for inclusion. Studies assessing the long-term efficacy of opioids during dialysis were excluded. DATA COLLECTION AND ANALYSIS: This is a narrative systematic review and no meta-analysis was performed. The Grading of RECOMMENDATIONS Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of the studies and to formulate guidelines. MAIN RESULTS: Fifteen original articles were identified. Eight prospective and seven retrospective clinical studies were identified but no randomized controlled trials. No results were found for diamorphine, codeine, dihydrocodeine, buprenorphine, tramadol, dextropropoxyphene, methadone or remifentanil. CONCLUSIONS: All of the studies identified have a significant risk of bias inherent in the study methodology and there is additional significant risk of publication bias. Overall evidence is of very low quality. The direct clinical evidence in cancer-related pain and renal impairment is insufficient to allow formulation of guidelines but is suggestive of significant differences in risk between opioids. RECOMMENDATIONS: RECOMMENDATIONS regarding opioid use in renal impairment and cancer pain are made on the basis of pharmacokinetic data, extrapolation from non-cancer pain studies and from clinical experience. The risk of opioid use in renal impairment is stratified according to the activity of opioid metabolites, potential for accumulation and reports of successful or harmful use. Fentanyl, alfentanil and methadone are identified, with caveats, as the least likely to cause harm when used appropriately. Morphine may be associated with toxicity in patients with renal impairment. Unwanted side effects with morphine may be satisfactorily dealt with by either increasing the dosing interval or reducing the 24 hour dose or by switching to an alternative opioid. PMID- 21708860 TI - Spinal opioids in adult patients with cancer pain: a systematic review: a European Palliative Care Research Collaborative (EPCRC) opioid guidelines project. AB - BACKGROUND: A systematic review, undertaken according to an initiative to revise European Association for Palliative Care guidelines on the use of opioids for cancer pain, which aimed to analyse analgesic efficacy and side effects of spinal opioids in adult cancer patients previously treated with systemic opioids. METHODS: Search strategy elaborated with MeSH terms and words related to cancer, palliative care, pain, spinal route and opioids. PubMed, Embase and Cochrane assessed in Nov 2009. Studies were analysed and classified according to quality of evidence and strength of recommendation. RESULTS: Out of 2939 abstracts, 44 articles were selected (nine randomized controlled trials (RCTs), two non randomized cohort studies, 28 uncontrolled prospective studies, and five case series). Relief of pain and/or side effects were reported in 42 articles; however, there were few studies of high quality design (RCTs) and these studies had methodological limitations that reduced their quality of evidence to very low. CONCLUSION: There are few RCTs and these are of very low quality. As a result, they provide weak recommendation for using spinal opioids in adult cancer patients. Further studies are clearly needed. PMID- 21708861 TI - Systematic review of the role of alternative application routes for opioid treatment for moderate to severe cancer pain: an EPCRC opioid guidelines project. AB - The European Palliative Care Research Collaboration is updating the EAPC recommendations on opioids in cancer pain management. A systematic literature search on Medline on the use of alternative routes for opioid application identified 242 papers, with 72 publications included in the final evaluation. Two or more alternative routes of opioid application were compared in 18 papers with a total of 674 patients. The best evidence base was available for the subcutaneous route. A comparison of subcutaneous and intravenous routes found no differences, confirming both routes as feasible, effective and safe. Efficacy and safety of the rectal route was comparable to the parenteral route. The side effect profile seemed to be very similar for the subcutaneous, intravenous, rectal or transdermal routes. Local side effects were reported for rectal application as well as for subcutaneous and transdermal administration. In conclusion, the systematic review found good evidence that subcutaneous administration of morphine or other opioids is an effective alternative for cancer patients if oral treatment is not possible. However, for a number of patients intravenous, rectal or transdermal therapy will offer a good alternative to the subcutaneous route. The review found no significant differences in efficacy or side effects between the alternative application routes. PMID- 21708862 TI - A systematic review of combination step III opioid therapy in cancer pain: an EPCRC opioid guideline project. AB - BACKGROUND: The use of combinations of opioids is a common clinical practice; however, this is not advocated by the World Health Organization (WHO) analgesic ladder. As opioid combination therapy becomes used increasingly, a review of the evidence on this practice was conducted. AIMS: To carry out a systematic review of the use of strong opioids in combination in cancer pain. METHODS: The following databases were searched electronically: Embase (1980-2010 week 2), Medline (1950-2010 week 1) and the Cochrane Database of Systematic Reviews (fourth quarter 2009). Only strong opioids as defined by the WHO ladder and full opioid agonists were examined. Only studies conducted in human, adult patients with chronic cancer pain were eligible. Studies must have contained data on efficacy and/or side effects in the key point. Appraisal was conducted using predetermined criteria set by the EAPC guideline development group. All potential papers were reviewed independently by both authors. RESULTS: In total 596 articles were retrieved resulting in only two eligible studies, which were rated as grade C and grade D evidence. These examined morphine in combination with oxycodone or fentanyl/methadone. CONCLUSION: Only a weak recommendation can be used to support combination opioid therapy. This recommendation is also based on the caveat that the desirable effects of combination opioid therapy is outweighed by any disadvantages that this would confer. Prospective randomized trials are needed to clarify the benefits and safety of combination opioid therapy. PMID- 21708863 TI - The effects of liver impairment on opioids used to relieve pain in cancer patients. PMID- 21708864 TI - A qualitative study of earplug use as a health behavior: the role of noise injury symptoms, self-efficacy and an affinity for music. AB - The use of earplugs in loud music venues is confined to a small minority who wish to avoid hearing damage from excessive noise exposure. Using the framework of the health belief model (HBM), structured interviews were held with 20 earplug wearing clubbers. Qualitative analysis revealed the HBM constructs relevant to understanding this group's motivation to protect their hearing. Personal experience of noise injury symptoms was the most common cue triggering earplug use. Awareness of the benefits of earplugs and appreciation of the long-term implications of hearing damage, affinity for music and high self-efficacy were also key variables underlying this health behaviour. PMID- 21708865 TI - Do parents maintain or exacerbate pediatric functional abdominal pain? A systematic review and meta-analysis. AB - Parents may maintain or exacerbate functional abdominal pain (FAP) in children through modeling of physical symptoms and solicitous responses to the child's complaints. This systematic review and meta-analysis aimed to examine these relationships. Parents of children with FAP reported more physical symptoms than parents of healthy children (effect size d = .36). As all studies were cross sectional or retrospective, the causal direction was unclear. For parental responses to child complaints, not enough studies were available to perform a meta-analysis. We conclude that the present literature is unfit to establish whether parents maintain or exacerbate pediatric FAP through the processes investigated. PMID- 21708866 TI - Posttraumatic growth in mothers and fathers of children with severe illnesses. AB - Posttraumatic growth (PTG) can occur after various types of trauma but has not been studied prospectively in parents of children with chronic diseases. In this study, PTG was assessed in 126 parents of 67 children with type 1 diabetes or cancer three years after diagnosis. Most parents (62.7%) reported at least a moderate degree of PTG. Quality of family relationships, parental psychological distress and child medical characteristics assessed one month after diagnosis, and parents' gender, explained 34 percent of PTG variance. The findings confirm that a severe disease of a child can lead to personal growth in the child's parents. PMID- 21708867 TI - Avoidance orientation moderates the effect of threatening messages. AB - This study investigated the influence of individual differences in people's dispositional avoidance orientation on the persuasive effects of low- and high threat messages promoting moderate drinking. First, participents (N = 99) individual differences in avoidance orientation were assessed, after which they were provided with either high- or low-threat messages about the consequences of drinking too much alcohol. The primary outcome measures were information acceptance, attitude and intention. Results showed that participants low in avoidance orientation were more likely to be persuaded by the low-threat message, whereas participants high in avoidance orientation were more likely to be persuaded by the high-threat message. PMID- 21708868 TI - Utilizing qualitative data from nominal groups: exploring the influences on treatment outcome prioritization with rheumatoid arthritis patients. AB - The nominal group technique generates quantitative data through a process of experts ranking items of interest. This article focuses on the additional collection of qualitative data from nominal groups with rheumatoid arthritis (RA) patients, used to explore the influences on prioritizing treatment outcomes. Across all groups, the top five outcomes with the highest importance scores were identified as: pain; joint damage; fatigue; activities of daily living; and mobility. Qualitative findings showed that the personal impact of RA influenced decisions on how to rank specific outcomes through four domains: disease impact; adaptation to illness; external resources and stressors; and social expectations. PMID- 21708869 TI - The effect of optimism on depression: the mediating and moderating role of insomnia. AB - This article aims to clarify if insomnia exerts a mediating or moderating effect on the optimism-depression association in Chinese college students. 529 Chinese college students completed the Beck Depression Inventory (BDI-II), the Pittsburgh Sleep Quality Index (PSQI), the Revised Life Orientation Test (LOT-R) and the Multidimensional Scale of Social Support (MSPSS). The results failed to show any moderating effect but after adjustment for age, gender and social support, a mediating effect was observed. In conclusion, insomnia qualifies as a mediator, suggesting considerable variance in depressive symptoms of college students could be due to change in their sleep status. PMID- 21708870 TI - Adjustment and coping in spousal caregivers following a traumatic spinal cord injury: an interpretative phenomenological analysis. AB - Semi-structured interviews were conducted with 11 spousal caregivers to people with a traumatic spinal cord injury and were subjected to interpretative phenomenological analysis (IPA). Here, we present two inter-related master themes: (1) coping with the spousal caregiver role; and (2) putting the pieces back together again. Within these, the analysis describes how regular venting of emotion, social support and focusing on the positive aspects of the situation all promoted coping. Adjustment was reportedly hindered by the introduction of paid caregivers as this represented a loss of privacy and power for the participants. The findings are discussed in relation to the wider literature and recommendations for future caregiver support are highlighted. PMID- 21708871 TI - Impacts of a book reading club intervention on enhancing parents' positive thinking. AB - This study investigated the effects of participating in a book reading club on improving parents' positive interactions with children and positive thinking. A total of 85 parent volunteers were randomized into the experimental or comparison group. The Parent Questionnaire was used to measure positive thinking and interaction with children. Additionally interview results were used to triangulate and elucidate the findings. The findings revealed a positive impact on parents' positive thinking and interaction with children and that these were significant predictors of parents' positive thinking. Implications and recommendations are presented. PMID- 21708872 TI - Perceived risk of developing diabetes in early adulthood: beliefs about inherited and behavioral risk factors across the life course. AB - This study aimed to determine how college students perceive their risk of developing diabetes over their life course, with specific emphasis on their beliefs about the influence of inherited versus behavioral risk factors. A bivariate ordered probit regression model was used to simultaneously predict perceived risk for 10-year absolute risk of diabetes and lifetime absolute risk of diabetes. Ten-year and lifetime absolute risk were both increased when the respondent self-identified with a race/ethnicity other than non-Hispanic white (beta = 0.42, p < .001 and beta = 0.33, p = .004, respectively), and when the respondent had an increasing number of family members with diabetes (beta = 0.33, p < .001 and beta = 0.45, p < .001, respectively). Beliefs linking behavioral risk factors to perceived risk of developing diabetes across the life course were not statistically significant. The absence of significant association between perceptions of behavioral risk as factors for developing diabetes and perceived risk for diabetes over the life course supports the need for educational interventions about behavioral and genetic causes of diabetes among the college aged population. PMID- 21708873 TI - Bilateral traumatic chylothorax treated by thoracic duct embolization: a rare treatment for an uncommon problem. AB - Prolonged chylothorax is a rare, life-threatening, pleural effusion that may be encountered in the setting of trauma. Conservative treatment may be successful and is the traditional approach in cases of limited chyle output. Early surgical intervention is required in cases with large refractory chyle output, but may be associated with substantial morbidity and mortality. Percutaneous thoracic duct embolization is an uncommon, minimally invasive, safe and effective treatment alternative. We report a case of successful thoracic duct embolization to treat large-volume chylothorax due to blunt trauma. PMID- 21708874 TI - The association of arterial shear and flow-mediated dilation in diabetes. AB - While adjusting flow-mediated dilation (FMD), a measure of vascular function, for shear rate may be important when evaluating endothelial-dependent vasodilation, the relationship of FMD with shear rate in study populations with cardiovascular risk factors is unclear. We aimed to investigate the association of four measures of shear rate (peak shear rate (SR(peak)) and shear rate area under the curve through 30 seconds (SR(AUC 0-30)), 60 seconds (SR(AUC 0-60)), and time to peak dilation (SR(AUC 0-ttp))) with FMD in 50 study subjects with type 2 diabetes and mild hypertension undergoing baseline FMD testing for an exercise intervention trial. Associations among measures of shear rate and FMD were evaluated using Pearson's correlations and R(2). The four measures of shear rate were highly correlated within subjects, with Pearson's correlations ranging from 0.783 (p < 0.001) to 0.972 (p < 0.001). FMD was associated with each measure of shear rate, having a correlation of 0.576 (p < 0.001) with SR(AUC 0-30), 0.529 (p < 0.001) with SR(AUC 0-60), and 0.512 (p < 0.001) with SR(peak). Nine of 50 subjects (18%) did not dilate following the shear stimulus. Among the 41 responders, FMD had a correlation of 0.517 (p < 0.001) with SR(AUC 0-ttp) and similar correlations to those found in the full sample for SR(AUC 0-30), SR(AUC 0-60), and SR(peak). In conclusion, shear rate appears to explain up to a third of between-person variability in FMD response and our results support the reporting of shear rate and FMD with and without adjustment for shear rate in similar clinical populations with CVD risk factors. PMID- 21708875 TI - Relationship between central and peripheral atherosclerosis and left ventricular dysfunction in a community population. AB - We aimed to determine the relationships between resting left ventricular (LV) wall motion abnormalities (WMAs), aortic plaque, and peripheral artery disease (PAD) in a community cohort. A total of 1726 Framingham Heart Study Offspring Cohort participants (806 males, 65 +/- 9 years) underwent cardiovascular magnetic resonance with quantification of aortic plaque volume and assessment of regional left ventricular systolic function. Claudication, lower extremity revascularization, and ankle-brachial index (ABI) were recorded at the most contemporaneous examination visit. WMAs were associated with greater aortic plaque burden, decreased ABI, and claudication in age- and sex-adjusted analyses (all p < 0.001), which were not significant after adjustment for cardiovascular risk factors. In age- and sex-adjusted analyses, both the presence (p < 0.001) and volume of aortic plaque were associated with decreased ABI (p < 0.001). After multivariable adjustment, an ABI <= 0.9 or prior revascularization was associated with a threefold odds of aortic plaque (p = 0.0083). Plaque volume significantly increased with decreasing ABI in multivariable-adjusted analyses (p < 0.0001). In this free-living population, associations of WMAs with aortic plaque burden and clinical measures of PAD were attenuated after adjustment for coronary heart disease risk factors. Aortic plaque volume and ABI remained strongly negatively correlated after multivariable adjustment. Our findings suggest that the association between coronary heart disease and non-coronary atherosclerosis is explained by cardiovascular risk factors. Aortic atherosclerosis and PAD remain strongly associated after multivariable adjustment, suggesting shared mechanisms beyond those captured by traditional risk factors. PMID- 21708876 TI - Association of lipoprotein-associated phospholipase A(2) and endothelial function in the Multi-Ethnic Study of Atherosclerosis (MESA). AB - Mechanisms underlying the role of lipoprotein-associated phospholipase A(2) (Lp PLA(2)) in atherosclerotic development are not completely understood. We evaluated the relationship of Lp-PLA(2) with endothelial dysfunction, an early manifestation of atherosclerosis, in a cohort without known clinical cardiovascular disease. A total of 2809 participants in the Multi-Ethnic Study of Atherosclerosis underwent plasma Lp-PLA(2) mass and activity measurement and brachial artery flow-mediated vasodilation testing. In adjusted linear regression models, higher Lp-PLA(2) mass and activity levels were not associated with lower endothelial function (-0.04%, p = 0.51 and -0.09%, p = 0.10, respectively). Among individuals with subclinical atherosclerosis based on ankle-brachial index (ABI) or carotid intima-media thickness (IMT), Lp-PLA(2) mass and activity were not associated with lower endothelial function (-0.03%, p = 0.88 and -0.31%, p = 0.16 for ABI < 1.00; 0.01%, p = 0.94 and -0.15%, p = 0.20 for abnormal carotid IMT). In summary, Lp-PLA(2) is not associated with endothelial dysfunction, suggesting its role in atherosclerosis development is primarily related to other factors. PMID- 21708877 TI - Images in vascular medicine: spontaneous pseudoaneurysm of the extracranial internal carotid artery. PMID- 21708878 TI - Unusual presentation of long-standing aortic coarctation. PMID- 21708879 TI - Deprivation of Liberty Safeguards in England: implementation costs. AB - BACKGROUND: The Deprivation of Liberty Safeguards (DoLS), introduced into the Mental Capacity Act 2005, were fully implemented on 1 April 2009 in England and Wales. The government estimated 20 000 assessments for DoLS at a cost of L600 per assessment. Aims To estimate the costs likely to be incurred with the implementation of DoLS in England. METHOD: The cost of conducting a single DoLS assessment was estimated using resource-utilisation data ascertained from 37 professionals, secretarial staff and independent mental capacity advocates involved with DoLS assessments in six diverse local DoLS offices. RESULTS: The estimated average cost of a single DoLS assessment was L1277. CONCLUSIONS: The estimated average cost of a single DoLS assessment was significantly higher than the L600 estimated by the government. However, the allocated budget, based on 20 000 estimated DoLS assessments in the first year of its implementation, is likely to be adequate because a significantly lower number of assessments (only 5200) were conducted in the first 9 months after its implementation. PMID- 21708880 TI - Affective disorders, anxiety disorders and the risk of alcohol dependence and misuse. AB - BACKGROUND: It is unclear whether common affective disorders and anxiety disorders increase the risk of alcohol dependence and alcohol misuse. Aims To investigate whether affective disorders and anxiety disorders increase the risk of alcohol dependence and alcohol misuse. METHOD: This study is a retrospective cohort study based on data collected from the 2007 Australia Mental Health and Well-Being survey. Both Poisson and logistic regression models were used for multivariate analysis. RESULTS: Participants with affective disorders (relative risk (RR) = 5.46, 95% CI 4.08-7.31 for alcohol dependence within 5 years of onset; RR = 2.77, 95% CI 1.93-3.99 after first 5 years) and anxiety disorders (RR = 3.33, 95% CI 2.37-4.68 for alcohol dependence within first 5 years of onset; RR = 3.56, 95% CI 2.72-4.64 after first 5 years) were at higher risk of alcohol misuse and alcohol dependence. CONCLUSIONS: Common affective disorders and anxiety disorders may increase the risk of alcohol dependence and alcohol misuse among the Australian population. PMID- 21708881 TI - Course of auditory vocal hallucinations in childhood: 5-year follow-up study. AB - BACKGROUND: In a baseline study among 7- and 8-year-old children with auditory vocal hallucinations, only limited functional impact was observed. AIMS: To assess 5-year course and predictors of auditory vocal hallucinations, as well as 5-year incidence and its risk factors. METHOD: A sample of 337 children, 12 and 13 years of age, were reassessed on auditory vocal hallucinations and associated symptoms after a mean follow-up period of 5.1 years. RESULTS: The 5-year persistence and incidence rates were 24% and 9% respectively, with more new cases arising in urban areas.Both persistent and incident auditory vocal hallucinations were associated with problem behaviour in the clinical range of psychopathology as measured with the Child Behavior Checklist, particularly at follow-up, as well as with other psychotic symptoms, particularly at baseline. Persistence was predicted by baseline auditory vocal hallucinations severity,particularly in terms of external attribution of voices and hearing multiple voices, and was associated with worse primary school test scores and lower secondary school level. CONCLUSIONS: First onset of auditory vocal hallucinations in middle childhood is not uncommon and is associated with psychopathological and behavioural comorbidity. Similarly,persistence of auditory vocal hallucinations in childhood is not uncommon and is associated with psychopathological,behavioural and cognitive alterations. PMID- 21708882 TI - Efflux transport is an important determinant of ethinylestradiol glucuronide and ethinylestradiol sulfate pharmacokinetics. AB - 17alpha-ethinylestradiol (EE) undergoes extensive conjugation to 17alpha ethinylestradiol-3-O-glucuronide (EEG) and 17alpha-ethinylestradiol-3-O-sulfate (EES). Thus, oral contraceptive drug-drug interaction (DDI) studies usually characterize metabolite pharmacokinetics, with changes typically attributed to modulation of metabolism. EE passively diffuses through plasma membranes, but its conjugates are hydrophilic and require active transport. Unlike EE metabolism, EEG and EES transport has not been explored in vivo as a potential mechanism of DDIs. Recent in vitro studies demonstrated that EEG is transported by multidrug resistance-associated protein (MRP) 2 and MRP3 and EES is a breast cancer resistance protein (BCRP) substrate. In the study presented here, pharmacokinetics of EE and conjugates were studied in TR- rats, which lack Mrp2, have marginal hepatic Bcrp expression, and overexpress hepatic Mrp3. EE pharmacokinetics in TR- rats were comparable to wild type; however, EEG and EES systemic exposures were altered markedly. EEG exposure was greatly increased: 20 fold and >100-fold after intravenous and oral EE administration, respectively. In contrast, EES exposure was lower in TR- rats: 65% decreased (intravenously) and 83% decreased (orally). In intestinal and liver perfusions, EE intestinal permeability and metabolism and hepatic clearance were unchanged in TR- rats; however, secretion of EEG into intestinal lumen was halved, EEG was not detected in TR- bile, and EES biliary excretion was 98% decreased. After oral EE administration to Mrp2- and Bcrp-knockout mice, EEG exposure increased 46- and 2 fold, respectively, whereas EES concentrations were decreased modestly. In conclusion, altered efflux transport resulted in major alterations of EEG and EES pharmacokinetics, highlighting transport as a potential site of DDIs with EE conjugates. PMID- 21708883 TI - Brucellosis with very high ferritin levels: report of five cases. AB - Brucellosis is a zoonotic disease caused by a kind of Brucella bacteria, which commonly appears in humans and rarely causes mortality. In our study, five cases, who were diagnosed by evaluation of clinical findings and serological tests, they also had very high ferritin levels, were reported. Ages of the patients were 16, 12, 10, 16 and 8 years, respectively. Serum ferritin levels were 1200, 985, 886, 748 and 435 ng/ml, respectively. We observed that complaints of the patients reduced after the treatment and ferritin levels returned to its normal range. In the situations of extremely evaluated serum ferritin which is an acute-phase reactant, its levels are able to raise in brucellosis, without existing hemochromatosis and Still's disease. PMID- 21708884 TI - Antimetastatic potential of vernolide-A, a sesquiterpenoid from Vernonia cinerea L. AB - The inhibitory effect of vernolide-A (C(21)H(28)O(7)) on lung metastasis induced by B16F-10 melanoma cells was studied using C57BL/6 mice. Vernolide-A was administered in three different modalities such as simultaneously with tumor, prophylactic to tumor and after tumor development. Maximum inhibition in the metastasis was observed when vernolide-A was administered simultaneously with tumor. There was 89.39% inhibition of lung tumor nodule formation and 88.51% increase in the life span of metastatic tumor-bearing animals. Highly elevated levels of lung hydroxyproline, lung uronic acid, lung hexosamine, serum sialic acid, serum gamma-glutamyl transpeptidase (GGT) and serum vascular endothelial growth factor (VEGF) in the metastatic control animals were found to be significantly lowered in the vernolide-A-treated animals. Histopathological analysis of lung tissues also correlated with these results. Vernolide-A administration downregulated the expression of matrix metalloproteinase-2 (MMP 2), MMP-9, extracellular-signal-regulated kinase-1 (ERK-1), ERK-2 and VEGF in the lung tissue of B16F-10 melanoma challenged animals. In the in vitro system, vernolide-A showed a significant inhibition of invasion of B16F-10 melanoma cells across the collagen matrix. Vernolide-A treatment also inhibited the migration of B16F-10 melanoma cells across a polycarbonate filter in vitro. Vernolide-A could inhibit MMP-2 and MMP-9 protein expression in gelatin zymographic analysis of B16F-10 cells. (3)H-thymidine proliferation assay showed that vernolide-A could inhibit the proliferation of B16F-10 melanoma cells in vitro. These results indicate that vernolide-A could inhibit the metastatic progression of B16F-10 melanoma cells in mice. PMID- 21708887 TI - Retraction of: Amelioration of hepatic fibrosis via beta-glucosylceramide mediated immune modulation is associated with altered CD8 and NKT lymphocyte distribution. PMID- 21708888 TI - Human lymphoblastoid B-cell lines reprogrammed to EBV-free induced pluripotent stem cells. AB - Generation of patient-specific induced pluripotent cells (iPSCs) holds great promise for regenerative medicine. Epstein-Barr virus immortalized lymphoblastoid B-cell lines (LCLs) can be generated from a minimal amount of blood and are banked worldwide as cellular reference material for immunologic or genetic analysis of pedigreed study populations. We report the generation of iPSCs from 2 LCLs (LCL-iPSCs) via a feeder-free episomal method using a cocktail of transcription factors and small molecules. LCL-derived iPSCs exhibited normal karyotype, expressed pluripotency markers, lost oriP/EBNA-1 episomal vectors, generated teratomas, retained donor identity, and differentiated in vitro into hematopoietic, cardiac, neural, and hepatocyte-like lineages. Significantly, although the parental LCLs express viral EBNA-1 and other Epstein-Barr virus latency-related elements for their survival, their presence was not detectable in LCL-iPSCs. Thus, reprogramming LCLs could offer an unlimited source for patient specific iPSCs. PMID- 21708889 TI - Increase in circulating CD4+CD25+Foxp3+ T cells in patients with Philadelphia negative chronic myeloproliferative neoplasms during treatment with IFN-alpha. AB - Recent reports have described complete or major molecular remission in patients with polycythemia vera after long-term treatment with the immunomodulatory agent IFN-alpha2. Accordingly, there are reasons to believe that the immune system is a key player in eradicating the JAK2 mutated clone in these patients. Foxp3(+) regulatory T cells play a pivotal role in maintaining immune homeostasis and, importantly, preventing immune reactivity to self-antigens; however, their suppressive activity can compromise an effective antitumor immune response, and high frequencies of regulatory T cells in peripheral blood have been reported in both hematologic and solid cancers. We have analyzed the number, phenotype, and function of circulating CD4(+)CD25(+)Foxp3(+) T cells in patients with chronic myeloproliferative neoplasms. Surprisingly, we found a marked expansion of this subset of lymphocytes in patients treated with IFN-alpha2 (13.0%; 95% confidence interval [CI] 10.8% to 15.2%) compared with healthy donors (6.1%; 95% CI 4.9% to 7.2%), patients with untreated chronic myeloproliferative neoplasms (6.9%; 95% CI 5.8% to 7.4%), or patients treated with hydroxyurea (5.8%; 95% CI 4.3% to 7.4%; P < .0001). PMID- 21708891 TI - Have we drawn the wrong conclusions about the value of care pathways? Is a Cochrane review appropriate? AB - Care pathways are used increasingly worldwide to organize patient care. However, different views exist about their effectiveness. One of the reasons for this is that pathways are complex interventions. A recent Cochrane review was published which reported positive results, but although the Cochrane team performed excellent work with an enormous commitment, the conclusions may be inappropriate. To fully understand the potential and problems of care pathways, it is important to define (a) exactly what we are talking about (b) whether the study methods are appropriate, and (c) whether we can properly define the outcomes. PMID- 21708890 TI - Transient receptor potential vanilloid 1 mediates pain in mice with severe sickle cell disease. AB - Pain is the leading cause of emergency department visits, hospitalizations, and daily suffering in individuals with sickle cell disease (SCD). The pathologic mechanisms leading to the perception of pain during acute RBC sickling episodes and development of chronic pain remain poorly understood and ineffectively treated. We provide the first study that explores nociceptor sensitization mechanisms that contribute to pain behavior in mice with severe SCD. Sickle mice exhibit robust behavioral hypersensitivity to mechanical, cold, and heat stimuli. Mechanical hypersensitivity is further exacerbated when hypoxia is used to induce acute sickling. Behavioral mechanical hypersensitivity is mediated in part by enhanced excitability to mechanical stimuli at both primary afferent peripheral terminal and sensory membrane levels. In the present study, inhibition of the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) with the selective antagonist A-425619 reversed the mechanical sensitization at both primary afferent terminals and isolated somata, and markedly attenuated mechanical behavioral hypersensitivity. In contrast, inhibition of TRPA1 with HC 030031 had no effect on mechanical sensitivity. These results suggest that the TRPV1 receptor contributes to primary afferent mechanical sensitization and a substantial portion of behavioral mechanical hypersensitivity in SCD mice. Therefore, TRPV1-targeted compounds that lack thermoregulatory side effects may provide relief from pain in patients with SCD. PMID- 21708892 TI - Vinegar for decreasing catheter-associated bacteriuria in long-term catheterized patients: a randomized controlled trial. AB - PURPOSE: The purpose of this study was to evaluate the effect of rice vinegar administered via nasogastric feeding tube on catheter-associated bacteriuria in patients with long-term urinary catheterization. METHOD: The authors conducted a randomized controlled trial (n = 60) to compare treatment with dilute vinegar and usual care. The authors recruited patients with chronic catheters from a long term care facility in northern Taiwan. The experimental group received 100 ml of diluted rice vinegar each day for 4 weeks, whereas the control group received 100 ml of water. The authors analyzed urine weekly and cultured it on Day 28. RESULTS: The generalized estimating equation results showed significant between group differences in urinary pH, bacterial titer, and turbidity. No patient in the experimental group, but three in the control group, exhibited symptomatic urinary tract infection (UTI). Rice vinegar may decrease bacteriuria. Medicinal use of vinegar may decrease the risk of symptomatic UTI, but further study is needed to determine the effects of ingesting vinegar for a longer period and with a larger sample size. PMID- 21708893 TI - Sleep and psychomotor vigilance in female shiftworkers. AB - The purpose of this study was to evaluate the relationships between sleep and psychomotor vigilance in female nurses and the changes in these variables over time. Participants comprised 16 staff registered nurses (10 day, 6 night; aged 30 65 years [M = 47.6; SD = 8.1]) who wore wrist actigraphs continuously and completed a 10-min psychomotor vigilance test (PVT-192, Ambulatory Monitoring, Inc., Ardsley, New York) and the Stanford Sleepiness Scale (SSS) in their homes before and after work for three consecutive 24-hr periods. Repeated measures ANOVA revealed that night nurses slept significantly less than day nurses, F(1, 15) = 26.06, p <= .001; M = 227.88 +/- 37.03 min versus M = 365.75 +/- 59.01 min, respectively, daily for three consecutive days. Night nurses napped more frequently and had more changes in the length of their main sleep periods than day nurses. Day nurses reported more wake episodes during main sleep periods. Night nurses were sleepier after work than day nurses; both groups had increased sleepiness after work for the first 2 days and similar psychomotor vigilance test results. These findings suggest that sleep deprivation, irregular sleep patterns, and sleepiness are significant issues for shiftworking nurses. Future study of the characteristics of sleep and sleepiness in a larger sample would be useful to evaluate the focus for interventions to improve sleep and alertness in shiftworking nurses. PMID- 21708894 TI - The effects of music as therapy on the overall well-being of elderly patients on maintenance hemodialysis. AB - In this study, the authors explored the use of music during hemodialysis (HD) as a complementary therapy to improve overall well-being in elderly patients. The authors recruited a convenience sample of 88 patients on maintenance HD from a teaching hospital in northern Taiwan and randomly assigned them to either an experimental group (n = 44) or a control group (n = 44). In the first week, participants in the experimental group created their own music playlists. During the second week, these participants listened to music from their own playlists during each HD session (three times/week). The authors evaluated the effects of music as therapy by assessing its impact on perceived stressors and adverse reactions during HD (HD Adverse Reactions Self-Assessment Scale and HD Stressor Scale [HSS]) and measuring changes in physiological indices during the course of the music listening. After 1 week of the use of music as therapy during HD, the authors noted significant reductions in the frequency and severity of adverse reactions during dialysis and in scores on the HSS, p < .001. The authors also observed significantly decreased respiratory rate and significantly increased finger temperature and oxygen saturation, p < .001, during the same period. In conclusion, listening to music during HD may promote overall patient well-being. It may thus serve as a complementary form of therapy that facilitates care and delivery of adequate dialysis and thus improves overall patient well-being in the long run. PMID- 21708895 TI - Characterization of human invariant natural killer T cells expressing FoxP3. AB - Recently described forkhead box protein 3 (FoxP3) transcription factor is a key molecule in CD4+ CD25hi+ T-cell characterization. Invariant NK T (iNKT) cells are also characterized as regulatory cells modulating the immune response by rapidly producing T(h)1 and T(h)2 cytokines. We aimed to analyze cellular markers important in regulatory features of human iNKT cells and to study their role in functional assays. iNKT cells were single cell sorted from peripheral mononuclear cells of healthy individuals after immunostaining of invariant TCR alpha-chain. We found FoxP3 expression in human iNKT clones. Randomly selected iNKT cell clones (CD4+, double negative, CD8+) expressed FoxP3 mRNA and protein at different levels upon stimulation as supported by various approaches. FoxP3 mRNA and protein expression was detected in unstimulated iNKT cells as well. Furthermore, different stimulations changed the FoxP3 expression in iNKT cells over time and the most dramatic changes were observed upon anti-CD3 stimulation. Both the supernatant of iNKT cells and iNKT cells themselves exerted similar stimulation effects on PBMC proliferation in functional assays and these stimulations showed a negative correlation with FoxP3 expression. Our data indicate that the FoxP3 expression in iNKT cells may be a key transcriptional factor in controlling the regulatory function of the iNKT cells. PMID- 21708897 TI - The cultural divide: exploring communication barriers between scientists and clinicians. AB - Despite remarkable advances in basic biomedical science that have led to improved patient care, there is a wide and persistent gap in the abilities of researchers and clinicians to understand and appreciate each other. In this Editorial, the authors, a scientist and a clinician, discuss the rift between practitioners of laboratory research and clinical medicine. Using their first-hand experience and numerous interviews throughout the United States, they explore the causes of this 'cultural divide'. Members of both professions use advanced problem-solving skills and typically embark on their career paths with a deeply felt sense of purpose. Nonetheless, differences in classroom education, professional training environments, reward mechanisms and sources of drive contribute to obstacles that inhibit communication, mutual respect and productive collaboration. More than a sociological curiosity, the cultural divide is a significant barrier to the bench to-bedside goals of translational medicine. Understanding its roots is the first step towards bridging the gap. PMID- 21708898 TI - Parkin' control: regulation of PGC-1alpha through PARIS in Parkinson's disease. PMID- 21708899 TI - Innovating immunology: an interview with Ruslan Medzhitov. PMID- 21708900 TI - Zebrafish as a model for normal and malignant hematopoiesis. AB - Zebrafish studies in the past two decades have made major contributions to our understanding of hematopoiesis and its associated disorders. The zebrafish has proven to be a powerful organism for studies in this area owing to its amenability to large-scale genetic and chemical screening. In addition, the externally fertilized and transparent embryos allow convenient genetic manipulation and in vivo imaging of normal and aberrant hematopoiesis. This review discusses available methods for studying hematopoiesis in zebrafish, summarizes key recent advances in this area, and highlights the current and potential contributions of zebrafish to the discovery and development of drugs to treat human blood disorders. PMID- 21708901 TI - The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA), which is caused by inactivating mutations in the survival motor neuron 1 (SMN1) gene, is characterized by loss of lower motor neurons in the spinal cord. The gene encoding SMN is very highly conserved in evolution, allowing the disease to be modeled in a range of species. The similarities in anatomy and physiology to the human neuromuscular system, coupled with the ease of genetic manipulation, make the mouse the most suitable model for exploring the basic pathogenesis of motor neuron loss and for testing potential treatments. Therapies that increase SMN levels, either through direct viral delivery or by enhancing full-length SMN protein expression from the SMN1 paralog, SMN2, are approaching the translational stage of development. It is therefore timely to consider the role of mouse models in addressing aspects of disease pathogenesis that are most relevant to SMA therapy. Here, we review evidence suggesting that the apparent selective vulnerability of motor neurons to SMN deficiency is relative rather than absolute, signifying that therapies will need to be delivered systemically. We also consider evidence from mouse models suggesting that SMN has its predominant action on the neuromuscular system in early postnatal life, during a discrete phase of development. Data from these experiments suggest that the timing of therapy to increase SMN levels might be crucial. The extent to which SMN is required for the maintenance of motor neurons in later life and whether augmenting its levels could treat degenerative motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), requires further exploration. PMID- 21708903 TI - Mitochondria: isolation, structure and function. AB - Mitochondria are complex organelles constantly undergoing processes of fusion and fission, processes that not only modulate their morphology, but also their function. Yet the assessment of mitochondrial function in skeletal muscle often involves mechanical isolation of the mitochondria, a process which disrupts their normally heterogeneous branching structure and yields relatively homogeneous spherical organelles. Alternatively, methods have been used where the sarcolemma is permeabilized and mitochondrial morphology is preserved, but both methods face the downside that they remove potential influences of the intracellular milieu on mitochondrial function. Importantly, recent evidence shows that the fragmented mitochondrial morphology resulting from routine mitochondrial isolation procedures used with skeletal muscle alters key indices of function in a manner qualitatively similar to mitochondria undergoing fission in vivo. Although these results warrant caution when interpreting data obtained with mitochondria isolated from skeletal muscle, they also suggest that isolated mitochondrial preparations might present a useful way of interrogating the stress resistance of mitochondria. More importantly, these new findings underscore the empirical value of studying mitochondrial function in minimally disruptive experimental preparations. In this review, we briefly discuss several considerations and hypotheses emerging from this work. PMID- 21708904 TI - Cerebral blood flow alteration in neuroprotection following cerebral ischaemia. AB - The best neuroprotectant for acute ischaemic stroke would always be the rapid return of oxygen and glucose to physiological levels. This is currently provided by thrombolysis which restores blood flow to the ischaemic region. The attempt to confer neuroprotection by targeting the brain parenchyma has shown promise in experimental stroke models, but has unequivocally failed to translate to the clinic. Neuroprotective therapy primarily targets the biochemical cascade that produces cell death following cerebral ischaemia. However, these agents may also alter signal transduction that controls cerebral blood flow, for example glutamate, which may affect the outcome after ischaemia. In these cases, neuroprotection may potentially be due to the improved access to oxygen and glucose rather than biochemical prevention of cell death. Improvement in cerebral blood flow is an important but often overlooked effect of neuroprotective therapy, analogous to the protective effects of drug-induced hypothermia. This short review will discuss cerebral blood flow alteration and protection of the brain in the context of ischaemic preconditioning, oxygen sensing and thrombolysis. Future neuroprotection studies in cerebral ischaemia require stringent monitoring of cerebral blood flow, plus other physiological parameters. This will increase the chances that any protection observed may be able to translate to human therapy. PMID- 21708905 TI - Cysteine modification reveals which subunits form the ligand binding site in human heteromeric 5-HT3AB receptors. AB - The ligand binding site of Cys-loop receptors is formed by residues on the principal (+) and complementary (-) faces of adjacent subunits, but the subunits that constitute the binding pocket in many heteromeric receptors are not yet clear. To probe the subunits involved in ligand binding in heteromeric human 5 HT(3)AB receptors, we made cysteine substitutions to the + and - faces of A and B subunits, and measured their functional consequences in receptors expressed in Xenopus oocytes. All A subunit mutations altered or eliminated function. The same pattern of changes was seen at homomeric and heteromeric receptors containing cysteine substitutions at A(R92) (- face), A(L126)(+), A(N128)(+), A(I139)(-), A(Q151)(-) and A(T181)(+), and these receptors displayed further changes when the sulphydryl modifying reagent methanethiosulfonate-ethylammonium (MTSEA) was applied. Modifications of A(R92C)(-)- and A(T181C)(+)-containing receptors were protected by the presence of agonist (5-HT) or antagonist (d-tubocurarine). In contrast modifications of the equivalent B subunit residues did not alter heteromeric receptor function. In addition a double mutant, A(S206C)( )(/E229C)(+), only responded to 5-HT following DTT treatment in both homomeric and heteromeric receptors, indicating receptor function was inhibited by a disulphide bond between an A+ and an A- interface in both receptor types. Our results are consistent with binding to an A+A- interface at both homomeric and heteromeric human 5-HT(3) receptors, and explain why the competitive pharmacologies of these two receptors are identical. PMID- 21708906 TI - Switching control of sympathetic activity from forebrain to hindbrain in chronic dehydration. AB - We investigated the mechanisms responsible for increased blood pressure and sympathetic nerve activity (SNA) caused by 2-3 days dehydration (DH) both in vivo and in situ preparations. In euhydrated (EH) rats, systemic application of the AT(1) receptor antagonist Losartan and subsequent pre-collicular transection (to remove the hypothalamus) significantly reduced thoracic (t)SNA. In contrast, in DH rats, Losartan, followed by pre-collicular and pontine transections, failed to reduce tSNA, whereas transection at the medulla-spinal cord junction massively reduced tSNA. In DH but not EH rats, selective inhibition of the commissural nucleus tractus solitarii (cNTS) significantly reduced tSNA. Comparable data were obtained in both in situ and in vivo (anaesthetized/conscious) rats and suggest that following chronic dehydration, the control of tSNA transfers from supra brainstem structures (e.g. hypothalamus) to the medulla oblongata, particularly the cNTS. As microarray analysis revealed up-regulation of AP1 transcription factor JunD in the dehydrated cNTS, we tested the hypothesis that AP1 transcription factor activity is responsible for dehydration-induced functional plasticity. When AP1 activity was blocked in the cNTS using a viral vector expressing a dominant negative FosB, cNTS inactivation was ineffective. However, tSNA was decreased after pre-collicular transection, a response similar to that seen in EH rats. Thus, the dehydration-induced switch in control of tSNA from hypothalamus to cNTS seems to be mediated via activation of AP1 transcription factors in the cNTS. If AP1 activity is blocked in the cNTS during dehydration, sympathetic activity control reverts back to forebrain regions. This unique reciprocating neural structure-switching plasticity between brain centres emphasizes the multiple mechanisms available for the adaptive response to dehydration. PMID- 21708907 TI - Protective conditioning of the brain: expressway or roadblock? AB - The brain responds to noxious stimulation with protective signalling. Over the last decades, a number of experimental strategies have been established to study endogenous brain protection. Pre-, per-, post- and remote 'conditioning' are now widely used to unravel the underlying mechanisms of endogenous neuroprotection. Some of these strategies are currently being tested in clinical trials to protect the human brain against anticipated damage or to boost protective responses during or after injury. Here we summarize the principles of 'conditioning' research and current efforts to translate this knowledge into effective treatment of patients. Conditioning to induce protected brain states provides an experimental window into endogenous brain protection and can lead to the discovery of drugs mimicking the effects of conditioning. Mechanisms of endogenous brain tolerance can be activated through a wide variety of stimuli that signal 'danger' to the brain. These danger signals lead to the induction of regulator and effector mechanisms, which suppress death and induce survival pathways, decrease metabolism, as well as increase substrate delivery. We conclude that preclinical research on endogenous brain protection has greatly benefited from conditioning strategies, but that clinical applications are challenging, and that we should not prematurely rush into ill-designed and underpowered clinical trials. PMID- 21708908 TI - Towards a re-definition of 'cardiac hypertrophy' through a rational characterization of left ventricular phenotypes: a position paper of the Working Group 'Myocardial Function' of the ESC. AB - Many primary or secondary diseases of the myocardium are accompanied with complex remodelling of the cardiac tissue that results in increased heart mass, often identified as cardiac 'hypertrophy'. Although there have been numerous attempts at defining such 'hypertrophy', the present paper delineates the reasons as to why current definitions of cardiac hypertrophy remain unsatisfying. Based on a brief review of the underlying pathophysiology and tissue and cellular events driving myocardial remodelling with or without changes in heart dimensions, as well as current techniques to detect such changes, we propose to restrict the use of the currently popular term 'hypertrophy' to cardiac myocytes that may or may not accompany the more complex tissue rearrangements leading to changes in shape or size of the ventricles, more broadly referred to as 'remodelling'. We also discuss the great potential of genetically modified (mouse) models as tools to define the molecular pathways leading to the different forms of left ventricle remodelling. Finally, we present an algorithm for the stepwise assessment of myocardial phenotypes applicable to animal models using well-established imaging techniques and propose a list of parameters most suited for a critical evaluation of such pathophysiological phenomena in mouse models. We believe that this effort is the first step towards a much auspicated unification of the terminology between the experimental and the clinical cardiologists. PMID- 21708909 TI - microRNA-Seq reveals cocaine-regulated expression of striatal microRNAs. AB - MicroRNAs (miRNAs) are small RNAs that modulate gene expression by binding target mRNAs. The hundreds of miRNAs expressed in the brain are critical for synaptic development and plasticity. Drugs of abuse cause lasting changes in the limbic regions of the brain that process reward, and addiction is viewed as a form of aberrant neuroplasticity. Using next-generation sequencing, we cataloged miRNA expression in the nucleus accumbens and at striatal synapses in control and chronically cocaine-treated mice. We identified cocaine-responsive miRNAs, synaptically enriched and depleted miRNA families, and confirmed cocaine-induced changes in protein expression for several predicted synaptic target genes. The miR-8 family, known for its roles in cancer, is highly enriched and cocaine regulated at striatal synapses, where its members may affect expression of cell adhesion molecules. Synaptically enriched cocaine-regulated miRNAs may contribute to long-lasting drug-induced plasticity through fine-tuning regulatory pathways that modulate the actin cytoskeleton, neurotransmitter metabolism, and peptide hormone processing. PMID- 21708911 TI - Changes in lifestyle reduce breast cancer risk, model shows. PMID- 21708910 TI - Changes in patient characteristics in anti-tumour necrosis factor clinical trials for rheumatoid arthritis: results of an analysis of the literature over the past 16 years. AB - OBJECTIVE: To evaluate changes in baseline patient characteristics and entry criteria of randomised, controlled studies of tumour necrosis factor alpha (TNFalpha) inhibitors in rheumatoid arthritis (RA) patients. METHODS: A systematic literature review was performed using predefined inclusion criteria to identify randomised, double-blind, controlled trials that evaluated TNFalpha inhibitors in adult RA patients. Entry criteria and baseline clinical characteristics were evaluated over time for methotrexate-experienced and methotrexate-naive study populations. Enrolment start date for each trial was the time metric. The anchor time was the study with the earliest identifiable enrolment start date. RESULTS: 44 primary publications (reporting the primary study endpoint) from 1993 to 2008 met the inclusion criteria. Enrolment start dates of August 1993 and May 1997 were identified as time anchors for the 37 methotrexate-experienced studies and the seven methotrexate-naive studies, respectively. In methotrexate-experienced trials, no significant change was observed over the years included in this study in any inclusion criteria (including swollen joint counts and C-reactive protein (CRP)), but a significant decrease over time was observed in the baseline swollen joint count, CRP and total Sharp or van der Heijde modified Sharp score, but not in baseline tender joint counts. In the methotrexate-naive studies, significant decreases over the years were observed in swollen joint and tender joint inclusion criteria, but not in baseline tender joint count, baseline CRP, CRP inclusion criteria or baseline total Sharp or van der Heijde modified Sharp score. CONCLUSION: Inclusion criteria and baseline characteristics of RA patients enrolled in studies of TNFalpha inhibitors have changed, with more recent trials enrolling cohorts with lower disease activity, especially in methotrexate-experienced trials. PMID- 21708912 TI - "Co-development" is key to promoting universal access to healthcare. PMID- 21708913 TI - Protests mount to cuts in translation services in the Netherlands. PMID- 21708914 TI - Cuts in legal aid will deter lawyers from taking on complex clinical negligence cases. PMID- 21708915 TI - Foundation trusts still struggle to hit cancer treatment targets, finds Monitor. PMID- 21708916 TI - American Medical Association backs health reform despite challenges from some members. PMID- 21708917 TI - Social enterprises need to prove value for money, says public spending watchdog. PMID- 21708918 TI - The use of external consultants by NHS commissioners in England: what lessons can be drawn for GP commissioning? AB - OBJECTIVES: To describe the current use of external support by commissioners in the English NHS; assess what impact it is having; explore the factors influencing effectiveness; and draw out the implications for the future of NHS commissioning. METHODS: (1) Two national surveys of primary care trust managers. (2) Qualitative interviews and focus groups with representatives of 12 firms providing support services to commissioners. (3) Focus groups in three primary care trusts and interviews with representatives of two strategic health authorities (SHAs). RESULTS: The majority of survey respondents reported using external support (89% in 2010). Satisfaction levels were reasonably high, with most rating the service received as excellent or good. Perceived impact in the case study sites was mixed, but benefits were reported in a number of areas. There were cases where external support had not achieved its goals. Several factors contributed to success or failure, including difficulties around procuring external support; building effective working relationships; and implementing the ideas generated by external partners. There was evidence that commissioners do not always use support in a way that takes full advantage of the skills existing in external organizations. There was also some evidence that poorer performing organizations may be less successful in using external support effectively. CONCLUSIONS: External support can play a role in improving the quality of commissioning. However, certain pitfalls must be avoided if it is to be used effectively. The role of external support will evolve (and may expand) as commissioning responsibilities are transferred to general practice consortia. PMID- 21708919 TI - Raising the profile of simulation and modelling in health services planning and implementation. PMID- 21708920 TI - The political abuse of international health system comparisons. AB - Though the science of medicine subscribes to learning from best practices and the transmission of superior treatment regimens across national boundaries, the same ethos does not inform political debates surrounding health system reform. The Canadian and English health systems have been used - and, more frequently - abused by American politicians in their quest to support their own model of reform, or preserve the status quo. PMID- 21708921 TI - Diarrhoea after broad spectrum antimicrobials. PMID- 21708922 TI - Alberta University medical dean resigns after students detect plagiarism in his speech. PMID- 21708923 TI - MPs push for ban on smoking in cars with children. PMID- 21708924 TI - BMA meeting: Trust in doctors is key to meeting the challenges facing the NHS, says BMA chairman. PMID- 21708925 TI - B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. AB - T follicular helper cells (Tfh cells) localize to follicles where they provide growth and selection signals to mutated germinal center (GC) B cells, thus promoting their differentiation into high affinity long-lived plasma cells and memory B cells. T-dependent B cell differentiation also occurs extrafollicularly, giving rise to unmutated plasma cells that are important for early protection against microbial infections. Bcl-6 expression in T cells has been shown to be essential for the formation of Tfh cells and GC B cells, but little is known about its requirement in physiological extrafollicular antibody responses. We use several mouse models in which extrafollicular plasma cells can be unequivocally distinguished from those of GC origin, combined with antigen-specific T and B cells, to show that the absence of T cell-expressed Bcl-6 significantly reduces T dependent extrafollicular antibody responses. Bcl-6(+) T cells appear at the T-B border soon after T cell priming and before GC formation, and these cells express low amounts of PD-1. Their appearance precedes that of Bcl-6(+) PD-1(hi) T cells, which are found within the GC. IL-21 acts early to promote both follicular and extrafollicular antibody responses. In conclusion, Bcl-6(+) T cells are necessary at B cell priming to form extrafollicular antibody responses, and these pre-GC Tfh cells can be distinguished phenotypically from GC Tfh cells. PMID- 21708926 TI - HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. AB - Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. We report that the glycolytic pathway is actively regulated during the differentiation of inflammatory T(H)17 and Foxp3-expressing regulatory T cells (T(reg) cells) and controls cell fate determination. T(H)17 but not T(reg) cell-inducing conditions resulted in strong up-regulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited T(H)17 development while promoting T(reg) cell generation. Moreover, the transcription factor hypoxia-inducible factor 1alpha (HIF1alpha) was selectively expressed in T(H)17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1alpha dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between T(H)17 and T(reg) cells. Lack of HIF1alpha resulted in diminished T(H)17 development but enhanced T(reg) cell differentiation and protected mice from autoimmune neuroinflammation. Our studies demonstrate that HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of T(H)17 and T(reg) cells. PMID- 21708927 TI - E4F1 deficiency results in oxidative stress-mediated cell death of leukemic cells. AB - The multifunctional E4F1 protein was originally discovered as a target of the E1A viral oncoprotein. Growing evidence indicates that E4F1 is involved in key signaling pathways commonly deregulated during cell transformation. In this study, we investigate the influence of E4F1 on tumorigenesis. Wild-type mice injected with fetal liver cells from mice lacking CDKN2A, the gene encoding Ink4a/Arf, developed histiocytic sarcomas (HSs), a tumor originating from the monocytic/macrophagic lineage. Cre-mediated deletion of E4F1 resulted in the death of HS cells and tumor regression in vivo and extended the lifespan of recipient animals. In murine and human HS cell lines, E4F1 inactivation resulted in mitochondrial defects and increased production of reactive oxygen species (ROS) that triggered massive cell death. Notably, these defects of E4F1 depletion were observed in HS cells but not healthy primary macrophages. Short hairpin RNA mediated depletion of E4F1 induced mitochondrial defects and ROS-mediated death in several human myeloid leukemia cell lines. E4F1 protein is overexpressed in a large subset of human acute myeloid leukemia samples. Together, these data reveal a role for E4F1 in the survival of myeloid leukemic cells and support the notion that targeting E4F1 activities might have therapeutic interest. PMID- 21708928 TI - FoxM1 mediates the progenitor function of type II epithelial cells in repairing alveolar injury induced by Pseudomonas aeruginosa. AB - The alveolar epithelium is composed of the flat type I cells comprising 95% of the gas-exchange surface area and cuboidal type II cells comprising the rest. Type II cells are described as facultative progenitor cells based on their ability to proliferate and trans-differentiate into type I cells. In this study, we observed that pneumonia induced by intratracheal instillation of Pseudomonas aeruginosa (PA) in mice increased the expression of the forkhead transcription factor FoxM1 in type II cells coincidentally with the induction of alveolar epithelial barrier repair. FoxM1 was preferentially expressed in the Sca-1(+) subpopulation of progenitor type II cells. In mice lacking FoxM1 specifically in type II cells, type II cells showed decreased proliferation and impaired trans differentiation into type I cells. Lungs of these mice also displayed defective alveolar barrier repair after injury. Expression of FoxM1 in the knockout mouse lungs partially rescued the defective trans-differentiation phenotype. Thus, expression of FoxM1 in type II cells is essential for their proliferation and transition into type I cells and for restoring alveolar barrier homeostasis after PA-induced lung injury. PMID- 21708929 TI - Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44. AB - Tissue fibrosis is a major cause of morbidity, and idiopathic pulmonary fibrosis (IPF) is a terminal illness characterized by unremitting matrix deposition in the lung. The mechanisms that control progressive fibrosis are unknown. Myofibroblasts accumulate at sites of tissue remodeling and produce extracellular matrix components such as collagen and hyaluronan (HA) that ultimately compromise organ function. We found that targeted overexpression of HAS2 (HA synthase 2) by myofibroblasts produced an aggressive phenotype leading to severe lung fibrosis and death after bleomycin-induced injury. Fibroblasts isolated from transgenic mice overexpressing HAS2 showed a greater capacity to invade matrix. Conditional deletion of HAS2 in mesenchymal cells abrogated the invasive fibroblast phenotype, impeded myofibroblast accumulation, and inhibited the development of lung fibrosis. Both the invasive phenotype and the progressive fibrosis were inhibited in the absence of CD44. Treatment with a blocking antibody to CD44 reduced lung fibrosis in mice in vivo. Finally, fibroblasts isolated from patients with IPF exhibited an invasive phenotype that was also dependent on HAS2 and CD44. Understanding the mechanisms leading to an invasive fibroblast phenotype could lead to novel approaches to the treatment of disorders characterized by severe tissue fibrosis. PMID- 21708932 TI - Metal recycling, the environment and human health. PMID- 21708931 TI - The aminobisphosphonate pamidronate controls influenza pathogenesis by expanding a gammadelta T cell population in humanized mice. AB - There are few antiviral drugs for treating influenza, and the emergence of antiviral resistance has further limited the available therapeutic options. Furthermore, antivirals are not invariably effective in severe influenza, such as that caused by H5N1 viruses. Thus, there is an urgent need to develop alternative therapeutic strategies. Here, we show that human Vgamma9Vdelta2 T cells expanded by the aminobisphosphonate pamidronate (PAM) kill influenza virus-infected cells and inhibit viral replication in vitro. In Rag2(-/-)gammac(-/-) immunodeficient mice reconstituted with human peripheral mononuclear cells (huPBMCs), PAM reduces disease severity and mortality caused by human seasonal H1N1 and avian H5N1 influenza virus, and controls the lung inflammation and viral replication. PAM has no such effects in influenza virus-infected Rag2(-/-)gammac(-/-) mice reconstituted with Vgamma9Vdelta2 T cell-depleted huPBMCs. Our study provides proof-of-concept of a novel therapeutic strategy for treating influenza by targeting the host rather than the virus, thereby reducing the opportunity for the emergence of drug-resistant viruses. As PAM has been commonly used to treat osteoporosis and Paget's disease, this new application of an old drug potentially offers a safe and readily available option for treating influenza. PMID- 21708933 TI - Generation of construction and demolition waste in Portugal. AB - In line with the growing concern around the world about construction and demolition waste (CDW) management, an attempt has been made to quantify the amount of CDW generated in Portugal, a country where no reliable/official data exist. This is an increasingly important concern of companies, businesses and municipalities involved with CDW, in a context of rising demands and more demanding recent legislation. One methodology is presented to quantify the present generation, and another to extrapolate this generation over the next few years, up to 2020. It is concluded that at present substantially less CDW is generated than the figure usually cited for Portugal, based on Spanish estimates, although it is predicted that this value will be higher on a 10-15 year timescale, reaching over 400 kg person-1 year-1. PMID- 21708930 TI - CIN85 drives B cell responses by linking BCR signals to the canonical NF-kappaB pathway. AB - CIN85, an adaptor protein which binds the C-terminal domain of tyrosine phosphorylated Cbl and Cbl-b, has been thought to be involved in the internalization and subsequent degradation of receptors. However, its physiological function remains unclear. To determine its role in B cells, we used Mb1-cre to generate mice with a B cell-specific deletion of CIN85. These mice had impaired T cell-independent type II antibody responses in vivo and diminished IKK beta activation and cellular responses to B cell receptor (BCR) cross-linking in vitro. Introduction of a constitutively active IKK-beta construct corrected the defective antibody responses as well as cellular responses in the mutant mice. Together, our results suggest that CIN85 links the BCR to IKK-beta activation, thereby contributing to T cell-independent immune responses. PMID- 21708934 TI - Physical training has several benefits for people with cystic fibrosis. PMID- 21708935 TI - Elbow flexor and extensor muscle weakness in lateral epicondylalgia. AB - OBJECTIVE: To evaluate whether deficits of elbow flexor and extensor muscle strength exist in lateral epicondylalgia (LE) in comparison with a healthy control population. DESIGN: Cross-sectional study. PARTICIPANTS: 150 participants with unilateral LE were compared with 54 healthy control participants. MAIN OUTCOME MEASURES: Maximal isometric elbow flexion and extension strength were measured bilaterally using a purpose-built standing frame such that gripping was avoided. RESULTS: The authors found significant side differences in elbow extensor (-6.54 N, 95% CI -11.43 to -1.65, p=0.008, standardised mean difference (SMD) -0.45) and flexor muscle strength (-11.26 N, 95% CI -19.59 to -2.94, p=0.009, SMD -0.46) between LE and control groups. Within the LE group, only elbow extensor muscle strength deficits between sides was significant (affected unaffected: -2.94 N, 95% CI -5.44 to -0.44). CONCLUSION: Small significant deficits of elbow extensor and flexor muscle strength exist in the affected arm of unilateral LE in comparison with healthy controls. Notably, comparing elbow strength between the affected and unaffected sides in unilateral epicondylalgia is likely to underestimate these deficits. Trial Registration Australian New Zealand Clinical Trials Register ACTRN12609000051246. PMID- 21708936 TI - Relationship between biomarkers of cigarette smoke exposure and biomarkers of inflammation, oxidative stress, and platelet activation in adult cigarette smokers. AB - BACKGROUND: Cigarette smoking is a risk factor for several diseases, including cardiovascular disease, chronic obstructive pulmonary disease, and lung cancer, but the role of specific smoke constituents in these diseases has not been clearly established. METHODS: The relationships between biomarkers of potential harm (BOPH), associated with inflammation [white blood cell (WBC), high sensitivity C-reactive protein (hs-CRP), fibrinogen, and von Willebrand factor (vWF)], oxidative stress [8-epi-prostaglandin F(2alpha) (8-epiPGF(2alpha))] and platelet activation [11-dehydro-thromboxin B(2) (11-dehTxB(2))], and machine measured tar yields (grouped into four categories), biomarkers of exposure (BOE) to cigarette smoke: nicotine and its five metabolites (nicotine equivalents), 4 methylnitrosamino-1-(3-pyridyl)-1-butanol (total NNAL), carboxyhemoglobin, 1 hydroxypyrene, 3-hydroxypropylmercapturic acid, and monohydroxybutenyl mercapturic acid, were investigated in 3,585 adult smokers and 1,077 nonsmokers. RESULTS: Overall, adult smokers had higher levels of BOPHs than nonsmokers. Body mass index (BMI), smoking duration, tar category, and some of the BOEs were significant factors in the multiple regression models. Based on the F value, BMI was the highest ranking factor in the models for WBC, hs-CRP, fibrinogen, and 8 epiPGF(2alpha), respectively, and gender and smoking duration for 11-dehTxB(2) and vWF, respectively. CONCLUSIONS: Although several demographic factors and some BOEs were statistically significant in the model, the R(2) values indicate that only up to 22% of the variability can be explained by these factors, reflecting the complexity and multifactorial nature of the disease mechanisms. IMPACT: The relationships between the BOEs and BOPHs observed in this study may help with the identification of appropriate biomarkers and improve the design of clinical studies in smokers. PMID- 21708938 TI - Differentials in survival for childhood cancer in Australia by remoteness of residence and area disadvantage. AB - BACKGROUND: It is not known whether improvements in cancer survival over recent decades have benefited children from different geographic locations equally. This is the first study to produce national survival estimates for childhood cancer in Australia by remoteness of residence and area-based socioeconomic status. METHODS: The study utilized population-based data from the Australian Paediatric Cancer Registry for children diagnosed with cancer from 1996 onward who were at risk of mortality between January 2001 and December 2006 (n = 6,289). Remoteness was specified according to the Australian Standard Geographical Classification Remoteness Areas, whereas an index of area disadvantage was obtained from census information. Five-year relative survival estimates were produced by the period method for all cancers and the most common diagnostic groups, with corresponding age-sex adjusted mortality hazard ratios calculated using Poisson regression. RESULTS: Overall, children with cancer from remote/very remote areas had a significantly lower survival rate than their counterparts in major cities (HR = 1.55, 95% CI = 1.08-2.23). Survival was also lower for children with leukemia living in inner regional (HR = 1.52, 95% CI = 1.11-2.08) or outer regional areas (HR = 1.53, 95% CI = 1.03-2.28). There was weak evidence (P(grad) = 0.051) of a trend toward poorer survival by greater area disadvantage for all childhood cancers. CONCLUSIONS: Some variation in prognosis by place of residence was present for children with cancer in Australia, particularly among leukemia patients. IMPACT: Treatment, clinical or area-related factors that contribute to these survival differentials need to be identified. PMID- 21708937 TI - Genetic variation in IGF2 and HTRA1 and breast cancer risk among BRCA1 and BRCA2 carriers. AB - BACKGROUND: BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers. METHODS: A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made. RESULTS: Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2). CONCLUSIONS: We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers. IMPACT: These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers. PMID- 21708939 TI - Metal fluoride complexes of Na,K-ATPase: characterization of fluoride-stabilized phosphoenzyme analogues and their interaction with cardiotonic steroids. AB - The Na,K-ATPase belongs to the P-type ATPase family of primary active cation pumps. Metal fluorides like magnesium-, beryllium-, and aluminum fluoride act as phosphate analogues and inhibit P-type ATPases by interacting with the phosphorylation site, stabilizing conformations that are analogous to specific phosphoenzyme intermediates. Cardiotonic steroids like ouabain used in the treatment of congestive heart failure and arrhythmias specifically inhibit the Na,K-ATPase, and the detailed structure of the highly conserved binding site has recently been described by the crystal structure of the shark Na,K-ATPase in a state analogous to E2.2K(+).P(i) with ouabain bound with apparently low affinity (1). In the present work inhibition, and subsequent reactivation by high Na(+), after treatment of shark Na,K-ATPase with various metal fluorides are characterized. Half-maximal inhibition of Na,K-ATPase activity by metal fluorides is in the micromolar range. The binding of cardiotonic steroids to the metal fluoride-stabilized enzyme forms was investigated using the fluorescent ouabain derivative 9-anthroyl ouabain and compared with binding to phosphorylated enzyme. The fastest binding was to the Be-fluoride stabilized enzyme suggesting a preformed ouabain binding cavity, in accord with results for Ca-ATPase where Be fluoride stabilizes the E2-P ground state with an open luminal ion access pathway, which in Na,K-ATPase could be a passage for ouabain. The Be-fluoride stabilized enzyme conformation closely resembles the E2-P ground state according to proteinase K cleavage. Ouabain, but not its aglycone ouabagenin, prevented reactivation of this metal fluoride form by high Na(+) demonstrating the pivotal role of the sugar moiety in closing the extracellular cation pathway. PMID- 21708940 TI - Protein phosphatase 2A and neutral sphingomyelinase 2 regulate IRAK-1 protein ubiquitination and degradation in response to interleukin-1beta. AB - The IL-1beta signaling cascade is initiated by the phosphorylation of IL-1beta receptor-associated kinase-1 (IRAK-1), followed by its ubiquitination and degradation. This paper investigates the regulation of IRAK-1 degradation in primary hepatocytes and in HEK cells overexpressing the IL-1beta receptor. We provide evidence that protein phosphatase 2A (PP2A) is a negative regulator of the phosphorylation, Lys(48)-linked ubiquitination, and degradation of IRAK-1. PP2A catalytic activity increased within 30 min of stimulation with IL-1beta. siRNA against PP2A catalytic subunit (PP2Ac) or treatment with pharmacological inhibitor, okadaic acid, enhanced IRAK-1 Lys(48)-linked ubiquitination and degradation. Direct interaction between PP2Ac and IRAK-1 was observed, suggesting that IRAK-1 might be a PP2A substrate. The mechanisms of PP2A activation by IL 1beta involved neutral sphingomyelinase-2 (NSMase-2) and an accumulation of ceramide. Overexpression of NSMase-2 delayed IRAK-1 degradation in a PP2A dependent manner, whereas NSMase-2 silencing had the opposite effect. The addition of sphingomyelinase, ceramide, or a proteasome inhibitor all led to retention of IRAK-1 at the cell membrane and to increased JNK phosphorylation. This study suggests that NSMase-2- and PP2A-dependent regulation of IRAK-1 degradation is a novel mechanism to fine tune the magnitude of IL-1beta response. PMID- 21708941 TI - A conserved non-canonical motif in the pseudoactive site of the ROP5 pseudokinase domain mediates its effect on Toxoplasma virulence. AB - The ROP5 family is a closely related set of polymorphic pseudokinases that are critical to the ability of Toxoplasma to cause disease. Polymorphisms in ROP5 also make it a major determinant of strain-specific differences in virulence. ROP5 possesses all of the major kinase motifs required for catalysis except for a substitution at the catalytic Asp. We show that this substitution in the catalytic loop of ROP5 is part of a motif conserved in other pseudokinases of both Toxoplasma and human origin, and that this motif is required for the full activity in vivo of ROP5. This suggests evolutionary selection at this site for a biochemical function, rather than simple drift away from catalysis. We present the crystal structures of a virulent isoform of ROP5 both in its ATP-bound and unbound states and have demonstrated that despite maintaining the canonical ATP binding motifs, ROP5 binds ATP in a distorted conformation mediated by unusual magnesium coordination sites that would not be predicted from the primary sequence. In addition, we have mapped the polymorphisms spread throughout the primary sequence of ROP5 to two major surfaces, including the activation segment of ROP5. This suggests that the pseudoactive site of this class of pseudokinases may have evolved to use the canonical ATP-binding motifs for non-catalytic signaling through allostery. PMID- 21708942 TI - Phosphatidate phosphatase activity plays key role in protection against fatty acid-induced toxicity in yeast. AB - The PAH1-encoded phosphatidate (PA) phosphatase in Saccharomyces cerevisiae is a pivotal enzyme that produces diacylglycerol for the synthesis of triacylglycerol (TAG) and simultaneously controls the level of PA used for phospholipid synthesis. Quantitative lipid analysis showed that the pah1Delta mutation caused a reduction in TAG mass and an elevation in the mass of phospholipids and free fatty acids, changes that were more pronounced in the stationary phase. The levels of unsaturated fatty acids in the pah1Delta mutant were unaltered, although the ratio of palmitoleic acid to oleic acid was increased with a similar change in the fatty acid composition of phospholipids. The pah1Delta mutant exhibited classic hallmarks of apoptosis in stationary phase and a marked reduction in the quantity of cytoplasmic lipid droplets. Cells lacking PA phosphatase were sensitive to exogenous fatty acids in the order of toxicity palmitoleic acid > oleic acid > palmitic acid. In contrast, the growth of wild type cells was not inhibited by fatty acid supplementation. In addition, wild type cells supplemented with palmitoleic acid exhibited an induction in PA phosphatase activity and an increase in TAG synthesis. Deletion of the DGK1 encoded diacylglycerol kinase, which counteracts PA phosphatase in controlling PA content, suppressed the defect in lipid droplet formation in the pah1Delta mutant. However, the sensitivity of the pah1Delta mutant to palmitoleic acid was not rescued by the dgk1Delta mutation. Overall, these findings indicate a key role of PA phosphatase in TAG synthesis for protection against fatty acid-induced toxicity. PMID- 21708943 TI - Greatwall and Polo-like kinase 1 coordinate to promote checkpoint recovery. AB - Checkpoint recovery upon completion of DNA repair allows the cell to return to normal cell cycle progression and is thus a crucial process that determines cell fate after DNA damage. We previously studied this process in Xenopus egg extracts and established Greatwall (Gwl) as an important regulator. Here we show that preactivated Gwl kinase can promote checkpoint recovery independently of cyclin dependent kinase 1 (Cdk1) or Plx1 (Xenopus polo-like kinase 1), whereas depletion of Gwl from extracts exhibits no synergy with that of Plx1 in delaying checkpoint recovery, suggesting a distinct but related relationship between Gwl and Plx1. In further revealing their functional relationship, we found mutual dependence for activation of Gwl and Plx1 during checkpoint recovery, as well as their direct association. We characterized the protein association in detail and recapitulated it in vitro with purified proteins, which suggests direct interaction. Interestingly, Gwl interaction with Plx1 and its phosphorylation by Plx1 both increase at the stage of checkpoint recovery. More importantly, Plx1-mediated phosphorylation renders Gwl more efficient in promoting checkpoint recovery, suggesting a functional involvement of such regulation in the recovery process. Finally, we report an indirect regulatory mechanism involving Aurora A that may account for Gwl-dependent regulation of Plx1 during checkpoint recovery. Our results thus reveal novel mechanisms underlying the involvement of Gwl in checkpoint recovery, in particular, its functional relationship with Plx1, a well characterized regulator of checkpoint recovery. Coordinated interplays between Plx1 and Gwl are required for reactivation of these kinases from the G(2)/M DNA damage checkpoint and efficient checkpoint recovery. PMID- 21708944 TI - DnaA protein DNA-binding domain binds to Hda protein to promote inter-AAA+ domain interaction involved in regulatory inactivation of DnaA. AB - Chromosomal replication is initiated from the replication origin oriC in Escherichia coli by the active ATP-bound form of DnaA protein. The regulatory inactivation of DnaA (RIDA) system, a complex of the ADP-bound Hda and the DNA loaded replicase clamp, represses extra initiations by facilitating DnaA-bound ATP hydrolysis, yielding the inactive ADP-bound form of DnaA. However, the mechanisms involved in promoting the DnaA-Hda interaction have not been determined except for the involvement of an interaction between the AAA+ domains of the two. This study revealed that DnaA Leu-422 and Pro-423 residues within DnaA domain IV, including a typical DNA-binding HTH motif, are specifically required for RIDA-dependent ATP hydrolysis in vitro and that these residues support efficient interaction with the DNA-loaded clamp.Hda complex and with Hda in vitro. Consistently, substitutions of these residues caused accumulation of ATP-bound DnaA in vivo and oriC-dependent inhibition of cell growth. Leu-422 plays a more important role in these activities than Pro-423. By contrast, neither of these residues is crucial for DNA replication from oriC, although they are highly conserved in DnaA orthologues. Structural analysis of a DnaA.Hda complex model suggested that these residues make contact with residues in the vicinity of the Hda AAA+ sensor I that participates in formation of a nucleotide interacting surface. Together, the results show that functional DnaA-Hda interactions require a second interaction site within DnaA domain IV in addition to the AAA+ domain and suggest that these interactions are crucial for the formation of RIDA complexes that are active for DnaA-ATP hydrolysis. PMID- 21708946 TI - The N terminus of the adhesion G protein-coupled receptor GPR56 controls receptor signaling activity. AB - GPR56 is an adhesion G protein-coupled receptor that plays a key role in cortical development. Mutations to GPR56 in humans cause malformations of the cerebral cortex, but little is known about the normal function of the receptor. We found that the large N terminus (NT) of GPR56 is cleaved from the rest of the receptor during processing but remains non-covalently associated with the seven transmembrane region of the receptor, as indicated by coimmunoprecipitation of the two GPR56 fragments from both transfected cells and native tissue. We also found that truncation of the GPR56 NT results in constitutive activation of receptor signaling, as revealed by increased GPR56-stimulated signaling upon transfection of HEK-293 cells with truncated GPR56, greatly enhanced binding of beta-arrestins by truncated GPR56 relative to the full-length receptor, extensive ubiquitination of truncated GPR56, and cytotoxicity induced by truncated GPR56 that could be rescued by cotransfection of cells with beta-arrestin 2. Furthermore, we found that the GPR56 NT is capable of homophilic trans-trans interactions that enhance receptor signaling activity. On the basis of these findings, we suggest a model of receptor activation in which the large N terminus of GPR56 constrains receptor activity but N-terminal interactions (GPR56 NT with an extracellular ligand and/or GPR56 NT homophilic trans-trans associations) can remove this inhibitory influence of the N terminus to activate receptor signaling. PMID- 21708945 TI - The mechanism of superoxide production by the antimycin-inhibited mitochondrial Q cycle. AB - Superoxide production from antimycin-inhibited complex III in isolated mitochondria first increased to a maximum then decreased as substrate supply was modulated in three different ways. In each case, superoxide production had a similar bell-shaped relationship to the reduction state of cytochrome b(566), suggesting that superoxide production peaks at intermediate Q-reduction state because it comes from a semiquinone in the outer quinone-binding site in complex III (Q(o)). Imposition of a membrane potential changed the relationships between superoxide production and b(566) reduction and between b(562) and b(566) redox states, suggesting that b(562) reduction also affects semiquinone concentration and superoxide production. To assess whether this behavior was consistent with the Q-cycle mechanism of complex III, we generated a kinetic model of the antimycin-inhibited Q(o) site. Using published rate constants (determined without antimycin), with unknown rate constants allowed to vary, the model failed to fit the data. However, when we allowed the rate constant for quinol oxidation to decrease 1000-fold and the rate constant for semiquinone oxidation by b(566) to depend on the b(562) redox state, the model fit the energized and de-energized data well. In such fits, quinol oxidation was much slower than literature values and slowed further when b(566) was reduced, and reduction of b(562) stabilized the semiquinone when b(566) was oxidized. Thus, superoxide production at Q(o) depends on the reduction states of b(566) and b(562) and fits the Q-cycle only if particular rate constants are altered when b oxidation is prevented by antimycin. These mechanisms limit superoxide production and short circuiting of the Q-cycle when electron transfer slows. PMID- 21708947 TI - Routing misfolded proteins through the multivesicular body (MVB) pathway protects against proteotoxicity. AB - The secretory pathway maintains multiple quality control checkpoints. Initially, endoplasmic reticulum-associated degradation pathways monitor protein folding to retain and eliminate aberrant products. Despite its broad client range, some molecules escape detection and traffic to Golgi membranes. There, a poorly understood mechanism termed Golgi quality control routes aberrant proteins for lysosomal/vacuolar degradation. To better understand Golgi quality control, we examined the processing of the obligate substrate Wsc1p. Misfolded Wsc1p does not use routes of typical vacuolar membrane proteins. Instead, it partitions into intralumenal vesicles of the multivesicular body (MVB) pathway, mediated by the E3 ubiquitin ligase Rsp5p. Its subsequent transport to the vacuolar lumen is essential for complete molecule breakdown. Surprisingly, the transport mode plays a second crucial function in neutralizing potential substrate toxicity. Eliminating the MVB sorting signal diverted molecules to the vacuolar limiting membrane, resulting in the generation of toxic by-products. These data demonstrate a new role of the MVB pathway in protein quality control. PMID- 21708948 TI - Electrostatic interactions involving the extreme C terminus of nuclear export factor CRM1 modulate its affinity for cargo. AB - The toroid-shaped nuclear protein export factor CRM1 is constructed from 21 tandem HEAT repeats, each of which contains an inner (B) and outer (A) alpha helix joined by loops. Proteins targeted for export have a nuclear export signal (NES) that binds between the A-helices of HEAT repeats 11 and 12 on the outer surface of CRM1. RanGTP binding increases the affinity of CRM1 for NESs. In the absence of RanGTP, the CRM1 C-terminal helix, together with the HEAT repeat 9 loop, modulates its affinity for NESs. Here we show that there is an electrostatic interaction between acidic residues at the extreme distal tip of the C-terminal helix and basic residues on the HEAT repeat 12 B-helix that lies on the inner surface of CRM1 beneath the NES binding site. Small angle x-ray scattering indicates that the increased affinity for NESs generated by mutations in the C-terminal helix is not associated with large scale changes in CRM1 conformation, consistent with the modulation of NES affinity being mediated by a local change in CRM1 near the NES binding site. These data also suggest that in the absence of RanGTP, the C-terminal helix lies across the CRM1 toroid in a position similar to that seen in the CRM1-Snurportin crystal structure. By creating local changes that stabilize the NES binding site in its closed conformation and thereby reducing the affinity of CRM1 for NESs, the C-terminal helix and HEAT 9 loop facilitate release of NES-containing cargo in the cytoplasm and also inhibit their return to the nucleus. PMID- 21708949 TI - Vesicle-associated membrane protein-2 (VAMP2) mediates cAMP-stimulated renin release in mouse juxtaglomerular cells. AB - Renin is essential for blood pressure control. Renin is stored in granules in juxtaglomerular (JG) cells, located in the pole of the renal afferent arterioles. The second messenger cAMP stimulates renin release. However, it is unclear whether fusion and exocytosis of renin-containing granules is involved. In addition, the role of the fusion proteins, SNAREs (soluble N-ethylmaleimide sensitive factor attachment proteins), in renin release from JG cells has not been studied. The vesicle SNARE proteins VAMP2 (vesicle associated membrane protein 2) and VAMP3 mediate cAMP-stimulated exocytosis in other endocrine cells. Thus, we hypothesized that VAMP2 and/or -3 mediate cAMP-stimulated renin release from JG cells. By fluorescence-activated cell sorting, we isolated JG cells expressing green fluorescent protein and compared the relative abundance of VAMP2/3 in JG cells versus total mouse kidney mRNA by quantitative PCR. We found that VAMP2 and VAMP3 mRNA are expressed and enriched in JG cells. Confocal imaging of primary cultures of JG cells showed that VAMP2 (but not VAMP3) co localized with renin-containing granules. Cleavage of VAMP2 and VAMP3 with tetanus toxin blocked cAMP-stimulated renin release from JG cells by ~50% and impaired cAMP-stimulated exocytosis by ~50%, as monitored with FM1-43. Then we specifically knocked down VAMP2 or VAMP3 by adenoviral-mediated delivery of short hairpin silencing RNA. We found that silencing VAMP2 blocked cAMP-induced renin release by ~50%. In contrast, silencing VAMP3 had no effect on basal or cAMP stimulated renin release. We conclude that VAMP2 and VAMP3 are expressed in JG cells, but only VAMP2 is targeted to renin-containing granules and mediates the stimulatory effect of cAMP on renin exocytosis. PMID- 21708950 TI - Histone deacetylase 9 deficiency protects against effector T cell-mediated systemic autoimmunity. AB - Co-repressor histone deacetylase 9 (HDAC9) plays a key role in the development and differentiation of many types of cells, including regulatory T cells. However, the biological function of HDAC9 in T effector cells is unknown. Systemic autoimmune diseases like lupus, diabetes, and rheumatoid arthritis have dysfunctional effector T cells. To determine the role of HDAC9 in systemic autoimmunity, we created MRL/lpr mice with HDAC9 deficiency that have aberrant effector T cell function. HDAC9 deficiency led to decreased lympho-proliferation, inflammation, autoantibody production, and increased survival in MRL/lpr mice. HDAC9-deficient mice manifested Th2 polarization, decreased T effector follicular cells positive for inducible co-stimulator, and activated T cells in vivo compared with HDAC9-intact MRL/lpr mice. HDAC9 deficiency also resulted in increased GATA3 and roquin and decreased BCL6 gene expression. HDAC9 deficiency was associated with increased site-specific lysine histone acetylation at H3 (H3K9, H3K14, and H3K18) globally that was localized to IL-4, roquin, and peroxisome proliferator-activated receptor-gamma promoters with increased gene expression, respectively. In kidney and spleen, HDAC9 deficiency decreased inflammation and cytokine and chemokine production due to peroxisome proliferator activated receptor gamma overexpression. These findings suggest that HDAC9 acts as an epigenetic switch in effector T cell-mediated systemic autoimmunity. PMID- 21708951 TI - The 64th Symposium of the Society for General Physiologists: optogenetics and superresolution microscopy take center stage. PMID- 21708952 TI - Dynamical systems theory in physiology. PMID- 21708953 TI - Ionic mechanisms and Ca2+ dynamics underlying the glucose response of pancreatic beta cells: a simulation study. AB - To clarify the mechanisms underlying the pancreatic beta-cell response to varying glucose concentrations ([G]), electrophysiological findings were integrated into a mathematical cell model. The Ca(2+) dynamics of the endoplasmic reticulum (ER) were also improved. The model was validated by demonstrating quiescent potential, burst-interburst electrical events accompanied by Ca(2+) transients, and continuous firing of action potentials over [G] ranges of 0-6, 7-18, and >19 mM, respectively. These responses to glucose were completely reversible. The action potential, input impedance, and Ca(2+) transients were in good agreement with experimental measurements. The ionic mechanisms underlying the burst-interburst rhythm were investigated by lead potential analysis, which quantified the contributions of individual current components. This analysis demonstrated that slow potential changes during the interburst period were attributable to modifications of ion channels or transporters by intracellular ions and/or metabolites to different degrees depending on [G]. The predominant role of adenosine triphosphate-sensitive K(+) current in switching on and off the repetitive firing of action potentials at 8 mM [G] was taken over at a higher [G] by Ca(2+)- or Na(+)-dependent currents, which were generated by the plasma membrane Ca(2+) pump, Na(+)/K(+) pump, Na(+)/Ca(2+) exchanger, and TRPM channel. Accumulation and release of Ca(2+) by the ER also had a strong influence on the slow electrical rhythm. We conclude that the present mathematical model is useful for quantifying the role of individual functional components in the whole cell responses based on experimental findings. PMID- 21708954 TI - Time-dependent changes in membrane excitability during glucose-induced bursting activity in pancreatic beta cells. AB - In our companion paper, the physiological functions of pancreatic beta cells were analyzed with a new beta-cell model by time-based integration of a set of differential equations that describe individual reaction steps or functional components based on experimental studies. In this study, we calculate steady state solutions of these differential equations to obtain the limit cycles (LCs) as well as the equilibrium points (EPs) to make all of the time derivatives equal to zero. The sequential transitions from quiescence to burst-interburst oscillations and then to continuous firing with an increasing glucose concentration were defined objectively by the EPs or LCs for the whole set of equations. We also demonstrated that membrane excitability changed between the extremes of a single action potential mode and a stable firing mode during one cycle of bursting rhythm. Membrane excitability was determined by the EPs or LCs of the membrane subsystem, with the slow variables fixed at each time point. Details of the mode changes were expressed as functions of slowly changing variables, such as intracellular [ATP], [Ca(2+)], and [Na(+)]. In conclusion, using our model, we could suggest quantitatively the mutual interactions among multiple membrane and cytosolic factors occurring in pancreatic beta cells. PMID- 21708955 TI - Na+,K+-pump stimulation improves contractility in isolated muscles of mice with hyperkalemic periodic paralysis. AB - In patients with hyperkalemic periodic paralysis (HyperKPP), attacks of muscle weakness or paralysis are triggered by K(+) ingestion or rest after exercise. Force can be restored by muscle work or treatment with beta(2)-adrenoceptor agonists. A missense substitution corresponding to a mutation in the skeletal muscle voltage-gated Na(+) channel (Na(v)1.4, Met1592Val) causing human HyperKPP was targeted into the mouse SCN4A gene (mutants). In soleus muscles prepared from these mutant mice, twitch, tetanic force, and endurance were markedly reduced compared with soleus from wild type (WT), reflecting impaired excitability. In mutant soleus, contractility was considerably more sensitive than WT soleus to inhibition by elevated [K(+)](o). In resting mutant soleus, tetrodotoxin (TTX) suppressible (22)Na uptake and [Na(+)](i) were increased by 470 and 58%, respectively, and membrane potential was depolarized (by 16 mV, P < 0.0001) and repolarized by TTX. Na(+),K(+) pump-mediated (86)Rb uptake was 83% larger than in WT. Salbutamol stimulated (86)Rb uptake and reduced [Na(+)](i) both in mutant and WT soleus. Stimulating Na(+),K(+) pumps with salbutamol restored force in mutant soleus and extensor digitorum longus (EDL). Increasing [Na(+)](i) with monensin also restored force in soleus. In soleus, EDL, and tibialis anterior muscles of mutant mice, the content of Na(+),K(+) pumps was 28, 62, and 33% higher than in WT, respectively, possibly reflecting the stimulating effect of elevated [Na(+)](i) on the synthesis of Na(+),K(+) pumps. The results confirm that the functional disorders of skeletal muscles in HyperKPP are secondary to increased Na(+) influx and show that contractility can be restored by acute stimulation of the Na(+),K(+) pumps. Calcitonin gene-related peptide (CGRP) restored force in mutant soleus but caused no detectable increase in (86)Rb uptake. Repeated excitation and capsaicin also restored contractility, possibly because of the release of endogenous CGRP from nerve endings in the isolated muscles. These observations may explain how mild exercise helps locally to prevent severe weakness during an attack of HyperKPP. PMID- 21708957 TI - Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. AB - Both the innate and adaptive immune systems contribute to tumor immunosurveillance in mice and humans; however, there is a paucity of direct evidence of a role for natural killer (NK) cells in this important process. In this study, we investigated the intratumoral phenotypic profile and functions of NK cells in primary human tumor specimens of non-small cell lung carcinoma (NSCLC). We used in situ methods to quantify and localize NK cells using the NKp46 marker and we characterized their phenotype in blood, tumoral, and nontumoral samples of NSCLC patients. Intratumoral NK cells displayed a profound and coordinated alteration of their phenotype, with a drastic reduction of NK cell receptor expression specifically detected in the tumoral region. According to their altered phenotype, intratumoral NK cells exhibited profound defects in the ability to activate degranulation and IFN-gamma production. We found that the presence of NK cells did not impact the clinical outcome of patients with NSCLC. Finally, we showed that tumor cells heterogeneously express ligands for both activating and inhibitory NK receptors. Taken together, our results suggest that the NSCLC tumor microenvironment locally impairs NK cells, rendering them less tumorcidal and thereby supportive to cancer progression. PMID- 21708958 TI - The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. AB - The anti-CTL-associated antigen 4 (anti-CTLA-4) antibody ipilimumab is the first agent to show improved survival in a randomized phase III trial that enrolled patients with metastatic melanoma. Studies are ongoing to identify mechanisms that elicit clinical benefit in the setting of anti-CTLA-4 therapy. We previously reported that treated patients had an increase in the frequency of T cells expressing the inducible costimulator (ICOS) molecule, a T-cell-specific molecule that belongs to the CD28/CTLA-4/B7 immunoglobulin superfamily. ICOS and its ligand (ICOSL) have been shown to play diverse roles in T-cell responses such as mediating autoimmunity as well as enhancing the development/activity of regulatory T cells. These seemingly opposing roles have made it difficult to determine whether the ICOS/ICOSL pathway is necessary for antitumor responses. To determine whether the ICOS/ICOSL pathway might play a causal role in the antitumor effects mediated by anti-CTLA-4, we conducted studies in ICOS sufficient and ICOS-deficient mice bearing B16/BL6 melanoma. We show that ICOS(+) T cells comprised a population of Th1 cytokine producing and tumor antigen specific effector cells. Furthermore, in the absence of ICOS, antitumor T-cell responses elicited by anti-CTLA-4 are significantly diminished, thereby impairing tumor rejection. Our findings establish that the ICOS/ICOSL pathway is necessary for the optimal therapeutic effect of anti-CTLA-4, thus implicating this pathway as a target for future combinatorial strategies to improve the efficacy of anti CTLA-4 therapy. PMID- 21708959 TI - Short answer question case series: the perils of urine toxicology testing. PMID- 21708960 TI - Short answer question case series: a complex case of fever and headache. PMID- 21708961 TI - An investigation of factors supporting the psychological health of staff in a UK emergency department. AB - STUDY OBJECTIVE: Research indicates emergency department doctors experience high levels of stress. Poor psychological health affects staff well-being and patient care, with considerable organisational and financial cost. This study compares levels of psychological health in medical, nursing and administrative staff from a UK emergency department with an orthopaedic comparison department. The study investigates the influence of coping strategies and the support people receive from their colleagues (ie, social support). METHODS: Comparative design, using self-report questionnaires comparing emergency (n=73) and orthopaedic (n=63) staff. Measures included: General Health Questionnaire-12, Hospital Anxiety and Depression Scale, Brief COPE, and questions relating to social identity and social support. RESULTS: The proportion of staff experiencing clinically significant levels of distress was higher than would be expected in the general population. The increased risk of psychological distress previously shown for emergency doctors is not present here for other emergency staff members. Better psychological health was associated with greater use of problem-focused coping and less use of maladaptive coping. Social support was associated with better psychological health and greater use of problem-focused coping. CONCLUSIONS: Priority should be given to developing and evaluating interventions to improve psychological health for this group. Findings suggest that coping strategies and social support are important factors to incorporate into such interventions. PMID- 21708962 TI - Short answer question case series: postlytic gastrointestinal bleeding. PMID- 21708963 TI - [Irma LeVasseur]. PMID- 21708964 TI - A hedgehog-like appearance resulting from Hari acupuncture. PMID- 21708965 TI - Seniors overmedicalized, experts say. PMID- 21708966 TI - Can rationing possibly be rational? PMID- 21708967 TI - Effects of multidisciplinary integrated care on quality of care in residential care facilities for elderly people: a cluster randomized trial. AB - BACKGROUND: Sophisticated approaches are needed to improve the quality of care for elderly people living in residential care facilities. We determined the effects of multidisciplinary integrated care on the quality of care and quality of life for elderly people in residential care facilities. METHODS: We performed a cluster randomized controlled trial involving 10 residential care facilities in the Netherlands that included 340 participating residents with physical or cognitive disabilities. Five of the facilities applied multidisciplinary integrated care, and five provided usual care. The intervention, inspired by the disease management model, consisted of a geriatric assessment of functional health every three months. The assessment included use of the Long-term Care Facility version of the Resident Assessment Instrument by trained nurse assistants to guide the design of an individualized care plan; discussion of outcomes and care priorities with the family physician, the resident and his or her family; and monthly multidisciplinary meetings with the nurse-assistant, family physician, psychologist and geriatrician to discuss residents with complex needs. The primary outcome was the sum score of 32 risk-adjusted quality-of-care indicators. RESULTS: Compared with the facilities that provided usual care, the intervention facilities had a significantly higher sum score of the 32 quality-of care indicators (mean difference - 6.7, p = 0.009; a medium effect size of 0.72). They also had significantly higher scores for 11 of the 32 indicators of good care in the areas of communication, delirium, behaviour, continence, pain and use of antipsychotic agents. INTERPRETATION: Multidisciplinary integrated care resulted in improved quality of care for elderly people in residential care facilities compared with usual care. TRIAL REGISTRATION: www.controlled trials.com trial register no. ISRCTN11076857. PMID- 21708968 TI - Compulsory licensing of generic drugs remains mired in quagmires. PMID- 21708970 TI - Improving quality of care in nursing homes: what works? PMID- 21708972 TI - Software tool determines odds of breaching patient privacy. PMID- 21708973 TI - No scrubs. No shoes. No serving. PMID- 21708974 TI - Jagesh Shah: a quantitative approach to cell biology. Interview by Caitlin Sedwick. PMID- 21708975 TI - Evolution: structural and functional diversity of cadherin at the adherens junction. AB - Adhesion between cells is essential to the evolution of multicellularity. Indeed, morphogenesis in animals requires firm but flexible intercellular adhesions that are mediated by subcellular structures like the adherens junction (AJ). A key component of AJs is classical cadherins, a group of transmembrane proteins that maintain dynamic cell-cell associations in many animal species. An evolutionary reconstruction of cadherin structure and function provides a comprehensive framework with which to appreciate the diversity of morphogenetic mechanisms in animals. PMID- 21708976 TI - Cohesin, condensin, and the intramolecular centromere loop together generate the mitotic chromatin spring. AB - Sister chromatid cohesion provides the mechanistic basis, together with spindle microtubules, for generating tension between bioriented chromosomes in metaphase. Pericentric chromatin forms an intramolecular loop that protrudes bidirectionally from the sister chromatid axis. The centromere lies on the surface of the chromosome at the apex of each loop. The cohesin and condensin structural maintenance of chromosomes (SMC) protein complexes are concentrated within the pericentric chromatin, but whether they contribute to tension-generating mechanisms is not known. To understand how pericentric chromatin is packaged and resists tension, we map the position of cohesin (SMC3), condensin (SMC4), and pericentric LacO arrays within the spindle. Condensin lies proximal to the spindle axis and is responsible for axial compaction of pericentric chromatin. Cohesin is radially displaced from the spindle axis and confines pericentric chromatin. Pericentric cohesin and condensin contribute to spindle length regulation and dynamics in metaphase. Together with the intramolecular centromere loop, these SMC complexes constitute a molecular spring that balances spindle microtubule force in metaphase. PMID- 21708977 TI - miR669a and miR669q prevent skeletal muscle differentiation in postnatal cardiac progenitors. AB - Postnatal heart stem and progenitor cells are a potential therapeutic tool for cardiomyopathies, but little is known about the mechanisms that control cardiac differentiation. Recent work has highlighted an important role for microribonucleic acids (miRNAs) as regulators of cardiac and skeletal myogenesis. In this paper, we isolated cardiac progenitors from neonatal beta-sarcoglycan (Sgcb)-null mouse hearts affected by dilated cardiomyopathy. Unexpectedly, Sgcb null cardiac progenitors spontaneously differentiated into skeletal muscle fibers both in vitro and when transplanted into regenerating muscles or infarcted hearts. Differentiation potential correlated with the absence of expression of a novel miRNA, miR669q, and with down-regulation of miR669a. Other miRNAs are known to promote myogenesis, but only miR669a and miR669q act upstream of myogenic regulatory factors to prevent myogenesis by directly targeting the MyoD 3' untranslated region. This finding reveals an added level of complexity in the mechanism of the fate choice of mesoderm progenitors and suggests that using endogenous cardiac stem cells therapeutically will require specially tailored procedures for certain genetic diseases. PMID- 21708979 TI - Phosphoinositide 3-kinase signaling pathway mediated by p110alpha regulates invadopodia formation. AB - Invadopodia are extracellular matrix-degrading protrusions formed by invasive cancer cells that are thought to function in cancer invasion. Although many invadopodia components have been identified, signaling pathways that link extracellular stimuli to invadopodia formation remain largely unknown. We investigate the role of phosphoinositide 3-kinase (PI3K) signaling during invadopodia formation. We find that in human breast cancer cells, both invadopodia formation and degradation of a gelatin matrix were blocked by treatment with PI3K inhibitors or sequestration of D-3 phosphoinositides. Functional analyses revealed that among the PI3K family proteins, the class I PI3K catalytic subunit p110alpha, a frequently mutated gene product in human cancers, was selectively involved in invadopodia formation. The expression of p110alpha with cancerous mutations promoted invadopodia-mediated invasive activity. Furthermore, knockdown or inhibition of PDK1 and Akt, downstream effectors of PI3K signaling, suppressed invadopodia formation induced by p110alpha mutants. These data suggest that PI3K signaling via p110alpha regulates invadopodia-mediated invasion of breast cancer cells. PMID- 21708978 TI - The p25 subunit of the dynactin complex is required for dynein-early endosome interaction. AB - Cytoplasmic dynein transports various cellular cargoes including early endosomes, but how dynein is linked to early endosomes is unclear. We find that the Aspergillus nidulans orthologue of the p25 subunit of dynactin is critical for dynein-mediated early endosome movement but not for dynein-mediated nuclear distribution. In the absence of NUDF/LIS1, p25 deletion abolished the localization of dynein-dynactin to the hyphal tip where early endosomes abnormally accumulate but did not prevent dynein-dynactin localization to microtubule plus ends. Within the dynactin complex, p25 locates at the pointed end of the Arp1 filament with Arp11 and p62, and our data suggest that Arp11 but not p62 is important for p25-dynactin association. Loss of either Arp1 or p25 significantly weakened the physical interaction between dynein and early endosomes, although loss of p25 did not apparently affect the integrity of the Arp1 filament. These results indicate that p25, in conjunction with the rest of the dynactin complex, is important for dynein-early endosome interaction. PMID- 21708980 TI - Pak1 regulates focal adhesion strength, myosin IIA distribution, and actin dynamics to optimize cell migration. AB - Cell motility requires the spatial and temporal coordination of forces in the actomyosin cytoskeleton with extracellular adhesion. The biochemical mechanism that coordinates filamentous actin (F-actin) assembly, myosin contractility, adhesion dynamics, and motility to maintain the balance between adhesion and contraction remains unknown. In this paper, we show that p21-activated kinases (Paks), downstream effectors of the small guanosine triphosphatases Rac and Cdc42, biochemically couple leading-edge actin dynamics to focal adhesion (FA) dynamics. Quantitative live cell microscopy assays revealed that the inhibition of Paks abolished F-actin flow in the lamella, displaced myosin IIA from the cell edge, and decreased FA turnover. We show that, by controlling the dynamics of these three systems, Paks regulate the protrusive activity and migration of epithelial cells. Furthermore, we found that expressing Pak1 was sufficient to overcome the inhibitory effects of excess adhesion strength on cell motility. These findings establish Paks as critical molecules coordinating cytoskeletal systems for efficient cell migration. PMID- 21708982 TI - Daily hemodialysis and caregivers burden. PMID- 21708981 TI - SPARC promotes pericyte recruitment via inhibition of endoglin-dependent TGF beta1 activity. AB - Pericytes migrate to nascent vessels and promote vessel stability. Recently, we reported that secreted protein acidic and rich in cysteine (SPARC)-deficient mice exhibited decreased pericyte-associated vessels in an orthotopic model of pancreatic cancer, suggesting that SPARC influences pericyte behavior. In this paper, we report that SPARC promotes pericyte migration by regulating the function of endoglin, a TGF-beta1 accessory receptor. Primary SPARC-deficient pericytes exhibited increased basal TGF-beta1 activity and decreased cell migration, an effect blocked by inhibiting TGF-beta1. Furthermore, TGF-beta mediated inhibition of pericyte migration was dependent on endoglin and alphaV integrin. SPARC interacted directly with endoglin and reduced endoglin interaction with alphaV integrin. SPARC deficiency resulted in endoglin-mediated blockade of pericyte migration, aberrant association of endoglin in focal complexes, an increase in alphaV integrins present in endoglin immunoprecipitates, and enhanced alphaV integrin-mediated activation of TGF-beta. These results demonstrate that SPARC promotes pericyte migration by diminishing TGF-beta activity and identify a novel function for endoglin in controlling pericyte behavior. PMID- 21708983 TI - Why did mother nature provide us with two kidneys? PMID- 21708984 TI - Targeted treatment in primary care for low back pain: the treatment system and clinical training programmes used in the IMPaCT Back study (ISRCTN 55174281). AB - BACKGROUND: The IMPaCT Back study (IMplementation to improve Patient Care through Targeted treatment for Back pain) is a quality improvement study which aims to investigate the effects of introducing and supporting a subgrouping for targeted treatment system for patients with low back pain (LBP) in primary care. This paper details the subgrouping for targeted treatment system and the clinical training and mentoring programmes aimed at equipping clinicians to deliver it. THE SUBGROUPING AND TARGETED TREATMENT SYSTEM: This system differs from 'one-size fits all' usual practice as it suggests that first contact health care practitioners should systematically allocate LBP patients to one of the three subgroups according to key modifiable prognostic indicators for chronicity. Patients in each subgroup (those at low, medium or high risk of chronicity) are then managed according to a targeted treatment system of increasing complexity. THE SUBGROUPING TOOLS: Subgrouping tools help guide clinical decision-making about treatment and onward referral. Two subgrouping tools have been used in the IMPaCT Back study, a 9-item version used by participating physiotherapists and a 6-item version used by GPs. The targeted treatments. The targeted treatments include a minimal intervention delivered by GPs (for those patients at low risk of poor outcome) or referral to primary care physiotherapists who can apply physiotherapy approaches to addressing pain and disability (for those at medium risk) and additional cognitive-behavioural approaches to help address psychological and social obstacles to recovery (for those at high risk). THE TRAINING PACKAGES: Building on previous interventions for other pilot studies and randomized trials, we have developed and delivered clinical training and support programmes for GPs and physiotherapists. DISCUSSION: This paper describes in detail the IMPaCT Back study's subgrouping for targeted treatment system and the training and mentoring packages aimed at equipping clinicians to deliver it, within the IMPaCT Back study. STUDY REGISTRATION: ISRCTN55174281. PMID- 21708985 TI - Organizational climate determinants of resident safety culture in nursing homes. AB - PURPOSE OF THE STUDY: In recent years, there has been an increasing focus on the role of safety culture in preventing costly adverse events, such as medication errors and falls, among nursing home residents. However, little is known regarding critical organizational determinants of a positive safety culture in nursing homes. The aim of this study was to identify organizational climate predictors of specific aspects of the staff-rated resident safety culture (RSC) in a sample of nursing homes. DESIGN AND METHODS: Staff at 4 Michigan nursing homes responded to a self-administered questionnaire measuring organizational climate and RSC. Multiple regression analyses were used to identify organizational climate factors that predicted the safety culture dimensions nonpunitive response to mistakes, communication about incidents, and compliance with procedures. RESULTS: The organizational climate factors efficiency and work climate predicted nonpunitive response to mistakes (p < .001 for both scales) and compliance with procedures (p < .05 and p < .001 respectively). Work stress was an inverse predictor of compliance with procedures (p < .05). Goal clarity was the only significant predictor of communication about incidents (p < .05). IMPLICATIONS: Efficiency, work climate, work stress, and goal clarity are all malleable organizational factors that could feasibly be the focus of interventions to improve RSC. Future studies will examine whether these results can be replicated with larger samples. PMID- 21708986 TI - Infection of polarized airway epithelial cells by normal and small-colony variant strains of Staphylococcus aureus is increased in cells with abnormal cystic fibrosis transmembrane conductance regulator function and is influenced by NF kappaB. AB - The infection of nonphagocytic host cells by Staphylococcus aureus and more particularly by small-colony variants (SCVs) may contribute to the persistence of this pathogen in the lungs of cystic fibrosis (CF) patients. The development of chronic infections is also thought to be facilitated by the proinflammatory status of CF airways induced by an activation of NF-kappaB. The aim of this study was to compare the infection of non-CF and CF-like airway epithelial cells by S. aureus strains (normal and SCVs) and to determine the impact of the interaction between cystic fibrosis transmembrane conductance regulator (CFTR) and NF-kappaB on the infection level of these cells by S. aureus. We developed an S. aureus infection model using polarized airway epithelial cells grown at the air-liquid interface and expressing short hairpin RNAs directed against CFTR to mimic the CF condition. A pair of genetically related CF coisolates with the normal and SCV phenotypes was characterized and used. Infection of both cell lines (non-CF and CF-like) was more productive with the SCV strain than with its normal counterpart. However, both normal and SCV strains infected more CF-like than non CF cells. Accordingly, inhibition of CFTR function by CFTRinh-172 increased the S. aureus infection level. Experimental activation of NF-kappaB also increased the level of infection of polarized pulmonary epithelial cells by S. aureus, an event that could be associated with that observed when CFTR function is inhibited or impaired. This study supports the hypothesis that the proinflammatory status of CF tissues facilitates the infection of pulmonary epithelial cells by S. aureus. PMID- 21708987 TI - Analysis of the networks controlling the antimicrobial-peptide-dependent induction of Klebsiella pneumoniae virulence factors. AB - Antimicrobial peptides (APs) impose a threat to the survival of pathogens, and it is reasonable to postulate that bacteria have developed strategies to counteract them. Polymyxins are becoming the last resort to treat infections caused by multidrug-resistant Gram-negative bacteria and, similar to APs, they interact with the anionic lipopolysaccharide. Given that polymyxins and APs share the initial target, it is possible that bacterial defense mechanisms against polymyxins will be also effective against host APs. We sought to determine whether exposure to polymyxin will increase Klebsiella pneumoniae resistance to host APs. Indeed, exposure of K. pneumoniae to polymyxin induces cross-resistance not only to polymyxin itself but also to APs present in the airways. Polymyxin treatment upregulates the expression of the capsule polysaccharide operon and the loci required to modify the lipid A with aminoarabinose and palmitate with a concomitant increase in capsule and lipid A species containing such modifications. Moreover, these surface changes contribute to APs resistance and also to polymyxin-induced cross-resistance to APs. Bacterial loads of lipid A mutants in trachea and lungs of intranasally infected mice were lower than those of wild-type strain. PhoPQ, PmrAB, and the Rcs system govern polymyxin-induced transcriptional changes, and there is a cross talk between PhoPQ and the Rcs system. Our findings support the notion that Klebsiella activates a defense program against APs that is controlled by three signaling systems. Therapeutic strategies directed to prevent the activation of this program could be a new approach worth exploring to facilitate the clearance of the pathogen from the airways. PMID- 21708988 TI - Long polar fimbriae of enterohemorrhagic Escherichia coli O157:H7 bind to extracellular matrix proteins. AB - Adherence to intestinal cells is a key process in infection caused by enterohemorrhagic Escherichia coli (EHEC). Several adhesion factors that mediate the binding of EHEC to intestinal cells have been described, but the receptors involved in their recognition are not fully characterized. Extracellular matrix (ECM) proteins might act as receptors involved in the recognition of enteric pathogens, including EHEC. In this study, we sought to characterize the binding of EHEC O157:H7 to ECM proteins commonly present in the intestine. We found that EHEC prototype strains as well as other clinical isolates adhered more abundantly to surfaces coated with fibronectin, laminin, and collagen IV. Further characterization of this phenotype, by using antiserum raised against the LpfA1 putative major fimbrial subunit and by addition of mannose, showed that a reduced binding of EHEC to ECM proteins was observed in a long polar fimbria (lpf) mutant. We also found that the two regulators, H-NS and Ler, had an effect in EHEC Lpf-mediated binding to ECM, supporting the roles of these tightly regulated fimbriae as adherence factors. Purified Lpf major subunit bound to all of the ECM proteins tested. Finally, increased bacterial adherence was observed when T84 cells, preincubated with ECM proteins, were infected with EHEC. Taken together, these findings suggest that the interaction of Lpf and ECM proteins contributes to the EHEC colonization of the gastrointestinal tract. PMID- 21708989 TI - The Neisseria meningitidis macrophage infectivity potentiator protein induces cross-strain serum bactericidal activity and is a potential serogroup B vaccine candidate. AB - A gene encoding a 29-kDa protein from Neisseria meningitidis serogroup B strain MC58 with homology to the macrophage infectivity potentiator (MIP) protein of Legionella pneumophila was cloned and expressed in Escherichia coli, and the purified soluble recombinant protein (rMIP) was used for immunization studies. Analysis of the predicted amino acid sequences of MIP from 13 well-characterized meningococcal strains, isolated from carriers or patients and differing in serogroup, serotype, and subtype, showed that the protein was highly conserved (98 to 100%), with only three distinct sequence types (designated I, II, and III) found. Western blotting showed that the MIP protein was expressed at similar levels by all of these strains. Immunization of mice with type I MC58 rMIP in detergent micelles and liposomes containing monophosphoryl lipid A (MPLA) induced high levels of surface-reactive antibodies with serum bactericidal activity (SBA) titers of 1/1,024 against the homologous strain. Bactericidal antibodies were also induced with the protein in saline alone and liposomes alone (titers, 1/128) but not following adsorption to Al(OH)(3). Significantly, antisera raised against type I rMIP administered in saline or liposomes killed strains of heterologous sequence types II and III with similar SBA titers (1/128 to 1/256). Taken together, these findings suggest that rMIP can provide cross-strain protection against meningococci and should be considered a potential antigen for inclusion in new vaccines against meningococcal infection. PMID- 21708990 TI - Complement-mediated bactericidal activity of anti-factor H binding protein monoclonal antibodies against the meningococcus relies upon blocking factor H binding. AB - Binding of the complement-downregulating protein factor H (fH) to the surface of the meningococcus is important for survival of the organism in human serum. The meningococcal vaccine candidate factor H binding protein (fHbp) is an important ligand for human fH. While some fHbp-specific monoclonal antibodies (MAbs) block binding of fH to fHbp, the stoichiometry of blocking in the presence of high serum concentrations of fH and its effect on complement-mediated bactericidal activity are unknown. To investigate this question, we constructed chimeric antibodies in which the human IgG1 constant region was paired with three murine fHbp-specific binding domains designated JAR 3, JAR 5, and MAb502. By surface plasmon resonance, the association rates for binding of all three MAbs to immobilized fHbp were >50-fold higher than that for binding of fH to fHbp, and the MAb dissociation rates were >500-fold lower than that for fH. While all three MAbs elicited similar C1q-dependent C4b deposition on live bacteria (classical complement pathway), only those antibodies that inhibited binding of fH to fHbp (JAR 3 and JAR 5) had bactericidal activity with human complement. MAb502, which did not inhibit fH binding, had complement-mediated bactericidal activity only when tested with fH-depleted human complement. When an IgG1 anti-fHbp MAb binds to sparsely exposed fHbp on the bacterial surface, there appears to be insufficient complement activation for bacteriolysis unless fH binding also is inhibited. The ability of fHbp vaccines to elicit protective antibodies, therefore, is likely to be enhanced if the antibody repertoire is of high avidity and includes fH-blocking activity. PMID- 21708991 TI - CD23b isoform expression in human schistosomiasis identifies a novel subset of activated B cells. AB - Resistance to schistosomiasis is associated with increased levels of serum parasite-specific IgE. IgE exerts its functions through its cellular receptors, FcepsilonRI and FcepsilonRII/CD23; however, its functional significance in humans requires further characterization. We previously reported that increased levels of CD23(+) B cells correlate with resistance to schistosomiasis in hyperexposed populations and sought to define their potential function and relationship with IgE. We found that CD23(+) B cells are a heterogeneous cell population with functional and phenotypic differences. Circulating CD23(+) B cells are uniquely activated in schistosomiasis and express the CD23b isoform and CXCR5, the homing receptor for lymphoid follicles. High CXCR5 expression by CD23(+) B cells was associated with the capacity to home to the cognate ligand CXCL13. CD23-bound IgE cross-linking increased surface expression of CXCR5, suggesting that CD23(+) B cells home directly into the lymphoid follicles upon antigen capture. As human schistosomiasis is an intravascular parasitic infection associated with a high antigenic burden in the blood, circulating CD23(+) B cells may play a role in the capture and shuttling of antigens directly to splenic follicles, highlighting a new role for circulating B cells. This function likely plays an important role in the development of protective immunity to infection with schistosomes. PMID- 21708992 TI - Context-dependent activation kinetics elicited by soluble versus outer membrane vesicle-associated heat-labile enterotoxin. AB - Enterotoxigenic Escherichia coli (ETEC) is the leading cause of traveler's diarrhea and children's diarrhea worldwide. Among its virulence factors, ETEC produces heat-labile enterotoxin (LT). Most secreted LT is associated with outer membrane vesicles that are rich in lipopolysaccharide. The majority of prior studies have focused on soluble LT purified from ETEC periplasm. We investigated the hypothesis that the extracellular vesicle context of toxin presentation might be important in eliciting immune responses. We compared the polarized epithelial cell responses to apically applied soluble LT and LT-containing vesicles (LT(+) vesicles) as well as controls using a catalytically inactive mutant of LT and vesicles lacking LT. Although vesicle treatments with no or catalytically inactive LT induced a modest amount of interleukin-6 (IL-6), samples containing catalytically active LT elicited higher levels. A combination of soluble LT and LT-deficient vesicles induced significantly higher IL-6 levels than either LT or LT(+) vesicles alone. The responses to LT(+) vesicles were found to be independent of the canonical LT pathway, because the inhibition of cyclic AMP response element (CRE)-binding protein (CREB) phosphorylation did not lead to a decrease in cytokine gene expression levels. Furthermore, soluble LT caused earlier phosphorylation of CREB and activation of CRE compared with LT(+) vesicles. Soluble LT also led to the activation of activator protein 1, whereas LT(+) vesicle IL-6 responses appeared to be mediated by NF-kappaB. In summary, the results demonstrate that soluble LT and vesicle-bound LT elicit ultimately similar cytokine responses through distinct different activation pathways. PMID- 21708993 TI - Caspase-1 activation of interleukin-1beta (IL-1beta) and IL-18 is dispensable for induction of experimental cerebral malaria. AB - Malaria infection is initiated by sporozoite invasion of hepatocytes and asexual reproduction of liver stages, processes that are regarded to be "clinically and diagnostically silent." Merozoites, which egress from hepatocytes, infect erythrocytes in periodic cycles and induce disease. How the host innate immune system contributes to disease outcomes and to the induction of effector cells during malaria remains unclear. Likewise, how the initial liver stages may shape responses to blood-stage parasites is unknown. Here, using both sporozoite- and blood-stage-induced infections with the rodent malaria parasite Plasmodium berghei ANKA, we show that the MyD88 and Toll-like receptor 2/4 (TLR2/4) pathways play critical roles in the development of experimental cerebral malaria (ECM). Strikingly, an absolute dependence on MyD88 and TLR2/4 was observed when infections were initiated with sporozoites. In addition, we show that caspase-1 activation of interleukin-1beta (IL-1beta) and IL-18, which is associated with the inflammasome pathway, does not contribute to P. berghei ANKA-induced immunopathology. Consistent with these data, prophylactic cover with the IL-1beta antagonist anakinra did not reduce the incidence of ECM. Therefore, we propose that protection against ECM due to loss of TLR signaling functions is caused by effector mechanisms other than IL-1beta activation. PMID- 21708994 TI - Borrelia burgdorferi linear plasmid 38 is dispensable for completion of the mouse tick infectious cycle. AB - Borrelia burgdorferi, the causative agent of Lyme disease, exists in a complex enzootic cycle, transiting between its vector, Ixodes ticks, and a diverse range of vertebrate hosts. B. burgdorferi linear plasmid 38 (lp38) contains several genes that are differentially regulated in response to conditions mimicking the tick or mouse environments, suggesting that these plasmid-borne genes may encode proteins important for the B. burgdorferi infectious cycle. Some of these genes encode potential virulence factors, including hypothetical lipoproteins as well as a putative membrane transport system. To characterize the role of lp38 in the B. burgdorferi infectious cycle, we constructed a shuttle vector to selectively displace lp38 from the B. burgdorferi genome and analyzed the resulting clones to confirm the loss of lp38. We found that, in vitro, clones lacking lp38 were similar to isogenic wild-type bacteria, both in growth rate and in antigenic protein production. We analyzed these strains in an experimental mouse-tick infectious cycle, and our results demonstrate that clones lacking lp38 are fully infectious in a mouse, can efficiently colonize the tick vector, and are readily transmitted to a naive host. PMID- 21708995 TI - Allelic variation of the Lyme disease spirochete adhesin DbpA influences spirochetal binding to decorin, dermatan sulfate, and mammalian cells. AB - After transmission by an infected tick, the Lyme disease spirochete, Borrelia burgdorferi sensu lato, colonizes the mammalian skin and may disseminate systemically. The three major species of Lyme disease spirochete--B. burgdorferi sensu stricto, B. garinii, and B. afzelii--are associated with different chronic disease manifestations. Colonization is likely promoted by the ability to bind to target tissues, and Lyme disease spirochetes utilize multiple adhesive molecules to interact with diverse mammalian components. The allelic variable surface lipoprotein decorin binding protein A (DbpA) promotes bacterial binding to the proteoglycan decorin and to the glycosaminoglycan (GAG) dermatan sulfate. To assess allelic variation of DbpA in GAG-, decorin-, and cell-binding activities, we expressed dbpA alleles derived from diverse Lyme disease spirochetes in B. burgdorferi strain B314, a noninfectious and nonadherent strain that lacks dbpA. Each DbpA allele conferred upon B. burgdorferi strain B314 the ability to bind to cultured kidney epithelial (but not glial or endothelial) cells, as well as to purified decorin and dermatan sulfate. Nevertheless, allelic variation of DbpA was associated with dramatic differences in substrate binding activity. In most cases, decorin and dermatan sulfate binding correlated well, but DbpA of B. afzelii strain VS461 promoted differential binding to decorin and dermatan sulfate, indicating that the two activities are separable. DbpA from a clone of B. burgdorferi strain N40 that can cause disseminated infection in mice displayed relatively low adhesive activity, indicating that robust DbpA-mediated adhesive activity is not required for spread in the mammalian host. PMID- 21708996 TI - Differential response of the human renal proximal tubular epithelial cell line HK 2 to Shiga toxin types 1 and 2. AB - Shiga toxins (Stxs) are expressed by the enteric pathogens Shigella dysenteriae serotype 1 and certain serotypes of Escherichia coli. Stx-producing bacteria cause bloody diarrhea with the potential to progress to acute renal failure. Stxs are potent protein synthesis inhibitors and are the primary virulence factors responsible for renal damage that may follow diarrheal disease. We explored the use of the immortalized human proximal tubule epithelial cell line HK-2 as an in vitro model of Stx-induced renal damage. We showed that these cells express abundant membrane Gb(3) and are differentially susceptible to the cytotoxic action of Stxs, being more sensitive to Shiga toxin type 1 (Stx1) than to Stx2. At early time points (24 h), HK-2 cells were significantly more sensitive to Stxs than Vero cells; however, by 72 h, Vero cell monolayers were completely destroyed while some HK-2 cells survived toxin challenge, suggesting that a subpopulation of HK-2 cells are relatively toxin resistant. Fluorescently labeled Stx1 B subunits localized to both lysosomal and endoplasmic reticulum (ER) compartments in HK-2 cells, suggesting that differences in intracellular trafficking may play a role in susceptibility to Stx-mediated cytotoxicity. Although proinflammatory cytokines were not upregulated by toxin challenge, Stx2 selectively induced the expression of two chemokines, macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta. Stx1 and Stx2 differentially activated components of the ER stress response in HK-2 cells. Finally, we demonstrated significant poly(ADP-ribose) polymerase (PARP) cleavage after exposure to Stx1 or Stx2. However, procaspase 3 cleavage was undetectable, suggesting that HK-2 cells may undergo apoptosis in response to Stxs in a caspase 3-independent manner. PMID- 21708997 TI - The Sbi protein is a multifunctional immune evasion factor of Staphylococcus aureus. AB - The second immunoglobulin-binding protein (Sbi) of Staphylococcus aureus has two N-terminal domains that bind the Fc region of IgG in a fashion similar to that of protein A and two domains that can bind to the complement protein C3 and promote its futile consumption in the fluid phase. It has been proposed that Sbi helps bacteria to avoid innate immune defenses. By comparing a mutant defective in Sbi with mutants defective in protein A, clumping factor A, iron-regulated surface determinant H, and capsular polysaccharide, it was shown that Sbi is indeed an immune evasion factor that promotes bacterial survival in whole human blood and the avoidance of neutrophil-mediated opsonophagocytosis. Sbi is present in the culture supernatant and is also associated with the cell envelope. S. aureus strains that expressed truncates of Sbi lacking N-terminal domains D1 and D2 (D1D2) or D3 and D4 (D3D4) or a C-terminal truncate that was no longer retained in the cell envelope were analyzed. Both the secreted and envelope-associated forms of Sbi contributed to immune evasion. The IgG-binding domains contributed only when Sbi was attached to the cell, while only the secreted C3-binding domains were biologically active. PMID- 21708999 TI - IL-6 antisense-mediated growth inhibition in a head and neck squamous cell carcinoma cell line. AB - The growth of tumor cells can be regulated by a variety of cytokines. To investigate the pathogenesis of head and neck cancer and explore a new therapeutic approach for the carcinoma, the role of interleukin-6 (IL-6) in the growth of a human head and neck squamous cell carcinoma (HNSCC) cell line was examined. Whether or not IL-6 is increased in HNSCC and whether or not IL-6 antisense oligonucleotide treatment could decrease proliferation and angiogenic activity of HNSCC cell lines, was determined. Established human HNSCC cell lines were screened for IL-6 expression at both mRNA and protein levels. By using a 15 mer antisense phosphorothioate oligonucleotide targeting a sequence in the second exon of the IL-6 gene, modulation of IL-6 and vascular endothelial growth factor (VEGF) expression was examined in UMSCC IIA in cell supernatants by capture enzyme-linked immunosorbent assay (ELISA), and in cell lysates by reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, cell growth was determined by cell count. Endothelial cell migration was measured using a modified Boyden chamber. IL-6 was identified in the supernatant of the cell culture medium, indicating that these cells secreted IL-6, and the mRNAs of IL-6 were shown to be present in the cell lysates. IL-6 antisense oligonucleotide treatment resulted in a significant reduction of IL-6 protein expression compared to the sense control. The antisense oligonucleotides targeting IL-6 mRNA, also, inhibited cell growth and IL-6 production as well as VEGF expression. The addition of conditioned medium from IL-6 antisense-treated tumor cells resulted in decreased endothelial cell migration and tubule formation. Taken together, these findings indicate that endogenous IL-6 plays an important role in the growth of HNSCC and exerts its action by an autocrine growth mechanism, and that therapeutic trials with antisense oligonucleotides targeted to IL-6 mRNA may have some value for the treatment of HNSCC due to a decrease of neovascularization. PMID- 21708998 TI - Protective efficacy and safety of Brucella melitensis 16MDeltamucR against intraperitoneal and aerosol challenge in BALB/c mice. AB - Brucellosis is a zoonosis of nearly worldwide distribution. Vaccination against this pathogen is an important control strategy to prevent the disease. Currently licensed vaccine strains used in animals are unacceptable for human use due to undesirable side effects and modest protection. Substantial progress has been made during the past 10 years toward the development of improved vaccines for brucellosis. In part, this has been achieved by the identification and characterization of live attenuated mutants that are safer in the host but still can stimulate an adequate immune response. In the present study, the identification and characterization of the mucR mutant (BMEI 1364) as a vaccine candidate for brucellosis was conducted. BALB/c mice were vaccinated intraperitoneally at a dose of 10(5) CFU with the mutant to evaluate safety and protective efficacy against intraperitoneal and aerosol challenge. All animals vaccinated with the vaccine candidate demonstrated a statistically significant degree of protection against both intraperitoneal and aerosol challenge. Safety was revealed by the absence of Brucella associated pathological changes, including splenomegaly, hepatomegaly, or granulomatous disease. These results suggest that the 16MDeltamucR vaccine is safe, elicits a strong protective immunity, and should be considered as a promising vaccine candidate for human use. PMID- 21709000 TI - Adipocyte-derived factor as a modulator of oxidative estrogen metabolism: implications for obesity and estrogen-dependent breast cancer. AB - The role of body fat as a risk factor for breast cancer has been well established. A decrease in the urinary 2/16alpha-hydroxyestrone ratio has also been shown to be a risk marker for breast cancer. These two observations are connected by the fact that obese women have decreased levels of 2-hydroxyestrone. To test the hypothesis that fat depots secrete factors that inhibit 2 hydroxylation, the effect of substances released into the media from adipocytes incubated in Krebs-Ringer buffer, on estrogen metabolism by MCF-7 cells in minimum essential medium eagle (MEM) plus adipocyte-conditioned media (ACM) was studied. The 1:1 ACM-MEM culture system resulted in a substantial and highly significant decrease in 2-hydroxylation of estradiol. This inhibition was partially reversed by the addition of indole-3-carbinol, a potent inducer of 2 hydroxylation of estradiol. Centrifugal sizing showed that the active 2 hydroxylation inhibitor in the medium had a molecular weight of about 30 kDa. These results suggest a mechanism for the decrease in 2-hydroxylation of estradiol that is observed in obese women and the increase in 2-hydroxylation observed in women with depleted fat depots. PMID- 21709001 TI - Performance of novel nanofibrous biopolymer membrane for guided bone regeneration within rat mandibular defect. AB - BACKGROUND/AIM: A novel nanofibrous membrane of a degradable biopolymer poly (lactide-co-epsilon-caprolactone) (PLCL) for guided bone regeneration (GBR) was designed and its tissue compatibility and ability to promote the regeneration of new bone were investigated in a rat mandibular defect model. MATERIALS AND METHODS: The nanofibrous structuring of the PLCL polymer was facilitated by a solvent-induced phase separation method using camphene as the porogen. The PLCL membrane was implanted in a critical-sized (5 mm diameter) defect of the rat mandible. RESULTS: The assessment of cell compatibility conducted using undifferentiated pre-osteoblast cells (MC3T3-E1) showed favorable cell adhesion and growth on the nanofiber PLCL membrane with an active cytoskeletal processes and increment in the cell population with culture time. In vivo results at four weeks post-operation demonstrated that the PLCL nanofibrous membrane induced better guided new bone formation than the defect control group while protecting the bone defect against the ingrowth of fibrous tissues. CONCLUSION: Based on these results, the newly-developed PLCL nanofibrous biopolymer may be useful as a biocompatible and bone regenerative guidance membrane in dentistry. PMID- 21709003 TI - Subcutenous xenografts of human T-lineage acute lymphoblastic leukemia Jurkat cells in nude mice. AB - BACKGROUND: Human T-acute lymphoblastic leukemia (T-ALL) Jurkat cells are often used for in vitro screening of anticancer compounds; however, in vivo models employing Jurkat cells have not yet been sufficiently described. In this report, the growth characteristics and histology of tumor masses developed following subcutaneous (s.c.) implantation of Jurkat cells into nude mice are presented. MATERIALS AND METHODS: Five million Jurkat cells in MatrigelTM were injected s.c. into female CrTac:Ncr-Foxn1(nu) mice. Serial tumor volumes were determined and tumor sections were stained with hematoxylin/eosin and examined histologically. RESULTS: Tumors developed in 86.4% of the mice at a median of 39 days post implantation. Tumor regressions and small stationary tumors were observed in 47.4% of the tumor-bearing animals. The remaining animals displayed progressive tumor growth reaching a volume of 1000 mm(3) at median day 48 post-implantation. The tumor histology was consistent with lymphoblastic lymphoma. CONCLUSION: Due to frequent spontaneous regressions, this model is not appropriate for evaluation of T-ALL targeting therapeutics. PMID- 21709002 TI - Competition between substrates of the efflux pump system of Salmonella enteritidis. AB - AIM: To determine whether tetracycline competes with ethidium bromide (EB), used as substrate of efflux pumps, for extrusion by the efflux pump system of Salmonella enteritidis NCTC 13349 reference strain. MATERIALS AND METHODS: Evaluation of efflux of EB in competition with tetracycline was conducted with the aid of an automated EB method and by EB agar method. RESULTS: The EB agar method demonstrated that the accumulation of EB by S. enteritidis NCTC 13349 reference strain is reduced by high concentrations of tetracycline and that tetracycline accumulates within the cells. The use of the automated EB method confirmed the EB agar results and demonstrated that accumulation of EB is not affected by tetracycline unless the concentration of the antibiotic exceeds 100 mg/l. CONCLUSION: These results suggest that tetracycline is preferentially retained and that EB is preferentially extruded by the efflux pump of Sientintidis NCTC 13349. PMID- 21709004 TI - Corneal damage induced in adult mice by a single intraperitoneal injection of N ethyl-N-nitrosourea. AB - AIM: The morphological response and cell kinetics of the mouse cornea to various doses of N-ethyl-N-nitrosourea (ENU) was examined. MATERIALS AND METHODS: ENU at a dose of 50, 100, 200, 400, or 600 mg/kg was injected intraperitoneally into female BALB/c mice at seven weeks of age. Sequential morphological features and cell kinetics (TUNEL assay as apoptosis marker, PCNA immunostaining as proliferative activity marker, and p63 immunostaining as corneal stem cell marker) of corneal damage caused by 600 mg/kg of ENU were also analyzed 6, 12, 24 and 72 h, and 7 days after exposure. Moreover, older mice (25 to 34 weeks of age) received the same dosage and were sacrificed 7 days later. Both eyes of all mice were analyzed histopathologically and morphometrically, by using the parameters of corneal epithelial thickness. RESULTS: All ENU-treated mice in the 600 mg/kg group developed corneal damage characterized by desquamation and loss of epithelial cells within 7 days. Corneal epithelial thickness was significantly reduced in the 600 mg/kg group as compared to the control group and decreased to approximately half of the normal thickness. Although the number of TUNEL-positive epithelial cells in the ENU-treated mice was similar to that of the control mice, ENU inhibited the proliferative activity of epithelial cells showing PCNA positivity 72 h after treatment. The p63-positivity of epithelial cells decreased in the central cornea of mice treated with 600 mg/kg of ENU. Older mice did not develop corneal damage from exposure to ENU. CONCLUSION: ENU induced corneal damage in adult mice, and epithelial cell loss was caused by the inhibition of corneal epithelial proliferation. This is the first report to describe ENU induced corneal injury in adult mice. PMID- 21709005 TI - Calpain inhibition restores basal autophagy and suppresses MNU-induced photoreceptor cell death in mice. AB - AIM: A single systemic administration of N-methyl-N-nitrosourea (MNU) causes retinal degeneration involving photoreceptor cell death within 7 days. MNU induced photoreceptor cell death is due to apoptosis, and is a reliable animal model for human retinitis pigmentosa. The purpose of this study was to elucidate the involvement of calpain-mediated autophagy, as well as apoptosis on the cell death cascade caused by MNU and to evaluate the efficacy of calpain inhibitor SNJ 1945. MATERIALS AND METHODS: Seven-week-old BALB/c mice were left untreated or received an intraperitoneal (i.p.) injection of MNU. The MNU-exposed mice received an i.p. injection of SNJ-1945 or vehicle alone (distilled water containing 0.5% carboxymethyl cellulose) 3 h prior to MNU and once daily thereafter until sacrifice. Eyes were examined histologically, histochemically, and morphometrically to analyze the photoreceptor cell ratio and retinal damage ratio. The retinal expression of caspase-3, microtubule-associated protein light chain 3 (LC3), autophagy-related protein 5 (Atg5), and alpha-spectrin was determined by Western blot analysis. RESULTS: During the 72-h period after MNU exposure, the caspase-3 expression increased and the LC3 and Atg5 expression decreased, indicating increased levels of apoptosis and decreased levels of autophagy, as compared with the MNU-unexposed control mouse retina. MNU-induced photoreceptor cell death was caused by increased calpain activation as measured by alpha-spectrin proteolysis products, while SNJ-1945 ameliorated photoreceptor cell death by blocking calpain activation and restoring basal autophagy. CONCLUSION: Calpain activation is involved in MNU-induced photoreceptor cell death, and calpain inhibition effectively restored photoreceptor cell autophagy and photoreceptor cell death in mice. PMID- 21709006 TI - Immune reactivity to dengue and Aedes albopictus mosquitoes in the population from Macao, China, before dengue occurrence. AB - A serological survey was conducted in Macao, China, in 753 individuals, with the objective of looking for antibodies to the mosquito, Aedes albopictus (Skuse 1894) (Diptera: Culicidae), and to dengue, before the occurrence of any autochthonous dengue cases. Blood samples were collected at several public health services, a questionnaire was answered, and enzyme-linked immunosorbant assay (ELISA) and Western blot techniques were performed with extracts of mosquito head and thorax (HT). Anti-Aedes albopictus IgG antibodies were present in titres 1:10(2)-1:10(3) in 9%, and in titres 1:10(4)-1:10(5) in 42% of the sera tested. This reactivity was more frequent (59%) in the population which had resided only in Macao in the 2 years previous to the survey, as opposed to those that had also resided in other areas (50%). From the 230 reactive sera selected for immunoblot, 48 (21%) reacted with a wide range of proteins from above 224 kDa to 21 kDa, with different patterns according to individual sera. Proteins in the intervals 35.3 28.7 kDa and 28.7-21.1 kDa were labelled by the greatest number of sera, 15 and 19 respectively. The presence of anti-Aedes albopictus antibodies presented a statistical relation to skin reaction to mosquito bites, but immunoblot patterns did not. Anti-dengue IgG antibodies were found in 48% of the subjects, with a higher proportion in people who had resided out of Macao, or who were nationals from dengue-endemic neighboring countries. Anti-dengue reactivity was in agreement with anti-mosquito reactivity in half of the population. It would be interesting to see if this proportion has changed since dengue became endemic in Macao in 2001. PMID- 21709007 TI - Extract of Hedyotis diffusa Willd influences murine leukemia WEHI-3 cells in vivo as well as promoting T- and B-cell proliferation in leukemic mice. AB - Medicinal plants and herbs are widely used in the treatment of various types of cancer in Taiwan, China and many other countries. Hedyotis diffusa Willd (HDW) has been known as a traditional Chinese medicine for a long time, and possesses various bioactivities and anticancer activity. There is no available information on the effects of HDW extracts in leukemic mice and on immune responses in vivo. In this study, we established murine WEHI-3 leukemia in BALB/c mice and hypothesized that an aqueous HDW extract might have antileukemia effects on leukemic animals in vivo. The major characteristic of leukemic mice was an enlarged spleen after intraperitoneal injection with WEHI-3 cells. HDW extract reduced the weights of spleen and liver, but had no significant effect on body weight in WEHI-3 leukemic mice. HDW extract increased the percentage of CD11b cell surface marker (monocytes), but it reduced the percentage of CD3 (T-cell) and CD19 (B-cell) markers. However, HDW extract did not affect the level of Mac-3 and there was no influence on phagocytosis by macrophages from peripheral blood mononuclear cells and the peritoneal cavity in leukemic mice. The isolated splenocytes from HDW extract-treated leukemic mice demonstrated an increase of T- and B-cell proliferation in vivo. Based on these results, HDW extract would appear to have antileukemia activity in WEHI-3 cell-induced leukemia in vivo. PMID- 21709008 TI - Effect of melatonin on cyclooxygenase-2 expression and nuclear factor-kappa B activation in RAW264.7 macrophage-like cells stimulated with fimbriae of Porphyromonas gingivalis. AB - BACKGROUND: The possible link between melatonin and anti-inflammatory activity is currently a focus of interest. In the present study, COX-2 expression and NF kappaB activation in RAW264.7 macrophage-like cells stimulated with the fimbriae of Porphyromonas gingivalis, an oral anaerobe, in the absence and presence of melatonin were investigated. MATERIALS AND METHODS: The cytotoxicity of melatonin and indole against RAW264.7 cells was determined using a cell counting kit. The regulatory effect of melatonin, and of indole on the expression of COX-2 mRNA stimulated by exposure to the fimbriae was investigated by Northern blot analysis. NF-kappaB activation was evaluated by both electrophoretic mobility shift assay and Western blot analysis. RESULTS: The half maximal (50%) effective concentration (EC(50)) values for melatonin and indole were 3300 MUM and 130 MUM, respectively. Melatonin at non-cytotoxic concentrations significantly inhibited the fimbria-induced expression of COX-2. The fimbria-stimulated binding of NF kappaB to its consensus sequence and phosphorylation-dependent proteolysis of inhibitor kappaB-alpha were markedly inhibited by melatonin. However, indole did not inhibit COX-2 expression and NF-kappaB activation. CONCLUSION: Melatonin may be able to prevent diseases induced by oral bacteria. PMID- 21709009 TI - Morphological features of osteoblasts cultured on ultraviolet-irradiated titanium plates. AB - BACKGROUND: Although we have recently established optimal experimental conditions of ultraviolet (UV)-irradiation for titanium plates (e.g. wavelength and exposure time) which enhanced osteoblast adhesion to the plates, the effects of UV irradiation on cell structure are still unclear. MATERIALS AND METHODS: Digital stereomicroscopy was used to investigate morphological alterations of non-stained viable and hematoxylin-eosin (HE)-stained cells on UV-irradiated and non-UV irradiated titanium plates for up to 24 hours. RESULTS: In 24 hours, significant expansion of HE-stained cells (area, perimeter and sprouting processes) was observed on UV-irradiated plates. The sprouting processes appeared within 40 minutes of inoculation under both conditions, however, significant cell area expansion, which occurred in 5 minutes, was observed only on UV-irradiated plates. CONCLUSION: UV-enhanced cell attachment was related to morphological alteration which occurred immediately after inoculation. Digital stereomicroscopic evaluation was able to define and quantify morphological alterations of viable cells in an opaque environment. PMID- 21709010 TI - Effects of grape extracts on the in vitro activity of enzymes involved in oxidative stress regulation. AB - BACKGROUND/AIM: A number of in vitro and in vivo studies have investigated the potential preventive activity of grape extracts against different diseases, and have mostly focused on their antioxidant properties. The present study examined the effects of 21 extracts from stem, skin and berry from Greek grape varieties on the activity of enzymes involved in regulation of oxidative stress, namely xanthine oxidase (XO), catalase (CAT) and superoxide dismutase (SOD). MATERIALS AND METHODS: The effects of the extracts on the enzymatic activity of XO, CAT and SOD were studied spectrophotometrically. RESULTS: The tested extracts inhibited CAT and XO activity, while higher extract concentrations are required to induce SOD. However, stem and skin extracts exhibited a different inhibitory pattern against CAT and XO compared to berry extracts. The observed differences are possibly attributed to the extract polyphenolic composition. CONCLUSION: Although the induction of SOD activity suggests an antioxidant capacity, the inhibition of CAT and XO indicates a pro-oxidant action. In general, the extracts showed pro oxidant activity, possibly dependent on both their polyphenolic composition and concentration. PMID- 21709011 TI - The effect of CYP1A1 and GSTM1 gene polymorphisms in bladder cancer development in a Turkish population. AB - BACKGROUND: The aim of this study was to investigate a possible association of the CYP1A1 Ile462Val and GSTM1 null polymorphisms with the risk of developing bladder cancer in a Turkish population. PATIENTS AND METHODS: The study constituted 176 patients with bladder cancer and 97 healthy individuals. Evaluation of CYP1A1 Ile462Val gene polymorphism was performed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). GSTM1 null gene polymorphism was exclusively determined by PCR. Our results were examined by statistical analyses. RESULTS: There were no significant differences in CYP1A1 genotype frequencies between patients and controls. Furthermore, the frequency of GSTM1 null genotype was higher in patients compared to controls, but it did not reach significance (p=0.622 chi(2)=0.243 OR=0.94 95% CI=0.75-1.18). Significance was discovered in combined analysis of CYP1A1 and GSTM1 genotypes. In the present study, GSTM1 null genotype with CYP1A1 Ile/Ile genotype combination was significantly more frequent in the patient group than in controls (p=0,04, chi(2)=4.217). At the same time, possessing both GSTM1 null genotype and CYP1A1 Val variants (Ile/Val+Val/Val) were significantly higher in control group than in patients (p=0.017, chi(2)=5.468). When the pathological tumor grades were assessed, the frequency of CYP1A1 Val mutant variant with GSTM1 null genotype combination was higher in patients with medium and high-grade tumors than in those with low-grade tumors (p=0.06, chi(2)=3.527, OR=1.36 95% CI=1.03-1.78). CONCLUSION: We suggest that the CYP1A1 Ile/Ile genotype with GSTM1 null genotype combination may contribute to the development of bladder cancer in this Turkish population. PMID- 21709012 TI - Serum levels of HSP90 in the continuum of breast ductal and lobular lesions. AB - BACKGROUND: Heat-shock protein 90 (HSP90) is an abundant protein in mammalian cells. It interacts with a variety of proteins that play key roles in breast neoplasia. This is the first study to assess serum levels of HSP90 in atypical ductal hyperplasia (ADH), lobular neoplasia (LN), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and infiltrative lobular carcinoma (ILC). PATIENTS AND METHODS: Serum concentrations of HSP90 in women with benign (n=34), ADH (n=26), DCIS (n=30), IDC (n=29), LN (n=20) and ILC (n=9) lesions were determined with immunoenzymatic assays. For the evaluation of serum concentrations along the transition from benign through precursor and preinvasive to invasive lesion, the severity of diagnosis was treated as an ordinal variable. RESULTS: No significant association was demonstrated between serum HSP90 levels and the severity of the lesion in ductal and lobular series. The post hoc comparison between the lobular and ductal precursor lesions (i.e. ADH vs. LN) did not yield a statistically significant difference. Similarly, the post hoc comparison between the lobular and ductal invasive carcinomas (i.e. IDC vs. ILC) did not point to a statistically significant difference. CONCLUSION: This is the first study evaluating HSP90 serum levels in both lobular and ductal lesions of the breast. Contrary to published pathological findings according to which HSP90 exhibits significant variability along both series, such a finding was not replicated for the level of serum HSP90 concentrations. PMID- 21709013 TI - Effect of Agaricus blazei Murrill extract on HT-29 human colon cancer cells in SCID mice in vivo. AB - Agaricus blazei Murrill (ABM) popularly known as 'Cogumelo do Sol' in Brazil, or 'Himematsutake' in Japan, is a mushroom native to Brazil and widely cultivated in Japan for its medicinal uses and is now considered one of the most important edible and culinary-medicinal biotechnological species. This study is the first tumor growth model to evaluate the amelioratory effect of ABM extract using HT-29 human colon cancer cells in severe combined immunodeficiency (SCID) mice. Forty SCID mice were inoculated with HT-29 cells to induce tumor formation and were then divided into four groups. All the four groups (control, low, medium and high concentration treatment) of mice were separately orally administered 0 mg, 1.125 mg, 4.5 mg or 45 mg ABM extract daily. After six weeks of treatment, 8 out of the 40 mice had not survived including one mouse which scored +++ (tumor up to 15 mm diameter) and four mice which scored ++++ (tumor over 15 mm diameter) in the control group and three mice which scored ++++ on the low-dose ABM treatment. After high- or medium-dose treatment, all ten mice in each group survived. The oral administration of ABM does not prevent tumor growth, as shown by increased tumor mass, but compared with the control group, the tumor mass seems to grow more slowly depending on the ABM dose. PMID- 21709014 TI - Proliferation of the synovial lining cell layer in suggested metal hypersensitivity. AB - Synovial tissues in joints with prostheses display characteristic morphological changes in cases with aseptic failure, particularly macrophage infiltration. Since proliferation of the synovial lining cell layer represents a feature characteristic of autoimmune joint diseases, the possibility of morphological changes of the synovial lining cell layer in periprosthetic tissues was investigated. Synovial biopsies from five groups of morphologically well-defined lesions (osteoarthritis, rheumatoid arthritis, aseptic loosened metal-on polyethylene and metal-on-metal arthroplasty and suggested metal hypersensitivity) were compared using a conventional staining method and immunohistochemistry. The synovial lining cell layer was substantially enlarged in both rheumatoid arthritis and cases suggestive of metal hypersensitivity. Macrophage infiltrates were apparent in rheumatoid arthritis and all specimens from retrieved hip arthroplasties. Although both synovial and subsynovial macrophages were positive for CD163 (indicating synovial M2 macrophages), the remaining fibroblast-like synoviocytes and scattered stromal fibroblasts showed a positive reaction with the D2-40 antibody (indicating fibroblast-like synoviocytes). Furthermore, in contrast to CD163-positive macrophages, the enlarged D2-40-positive fibroblast-like synoviocytes displayed cytoplasmatic tubular projections. Proliferation of the periprosthetic synovial lining cell layer occurred in cases with unexplained groin pain following metal-on-metal hip resurfacing arthroplasty, suggestive of hypersensitivity. Despite some important study limitations, the present observation adds to the evidence that metal hypersensitivity shares characteristic morphological features with autoimmune diseases of the joints. PMID- 21709015 TI - Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy in elderly patients. AB - BACKGROUND: The treatment of peritoneal malignancies in elderly patients with cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is an ongoing question due to the high associated surgical risk. PATIENTS AND METHODS: Thirty patients, 11 (36.7%) older than 65 years, were submitted to CRS plus HIPEC. Criteria of patient eligibility were: peritoneal carcinomatosis of different origin, T3-4 gastric cancer, ECOG performance status <=2, no extra abdominal extension and no evidence of bowel obstruction. The median follow-up was 21.5 months (range: 1-63). The purpose of this retrospective study, was to evaluate the feasibility of this approach in elderly patients, with special reference to postoperative morbidity, mortality and survival. RESULTS: We have recorded, in elderly patients, higher grade 3 and 4 morbidity and mortality, similar mean duration of cytoreductive surgery, of postoperative hospital stay, of median survival and of overall survival rates. CONCLUSION: Since there no statistical differences, in terms of morbidity and mortality, CRS with HIPEC may also be suitable for elderly patients. PMID- 21709016 TI - Cervical cone measurements and residual disease in LLETZ conisation for cervical intraepithelial neoplasia. AB - AIM: To investigate the oncologically safe limits of excision in large loop excision of the transformation zone (LLETZ) conisation performed for cervical pathology. PATIENTS AND METHODS: A retrospective study conducted at the Colposcopy Unit in a University Hospital setting. Three hundred and sixty-one cases of LLETZ conisation were conducted in a 2-year period. Data concerning age, cone dimensions, lesion types and excision margins were recorded. RESULTS: The mean age of women was 36.7 years, with 181 (50.5%) low-grade squamous intraepithelial lesion cases, 166 (45.7%) high-grade squamous intraepithelial lesion, and 14 (3.8%) with stage-IA1 cervical carcinoma. Mean conisation depth and cone volume were 10.9 mm and 2.2 ml, respectively. Incomplete removal of lesions occurred in 25% of women and correlated to severity of cervical intraepithelial neoplasia and conisation depth. The higher the grade of the lesion, the greater the percentage of residual disease. Conisation depth exceeding 10 mm, in our cohort, led to significantly less residual disease. CONCLUSION: Results indicate that a conisation depth of <10 mm may be a risk factor predicting positive resection margins, while cone volume is an inappropriate clinical marker. PMID- 21709017 TI - The effect of smoking on post-operative finger range of motion in patients with tendon grafts. AB - BACKGROUND: The finger range of motion (ROM) was evaluated in patients with hand flexor tendon replacement using a tendon graft and the effect of smoking was investigated. The first hypothesis was: a tendon graft increases the post operative ROM. The second hypothesis was: smoking has a negative effect on the final finger ROM. PATIENTS AND METHODS: Fifty seven autologous tendon grafts in 48 patients were included. The patients were grouped as non-smokers or smokers ("light" or "heavy"). The modified Strickland system and Total Active Motion (TAM) system, were chosen for the evaluation. RESULTS: The first hypothesis was proved by all the measurements. The post-operative status assessed by the Strickland method was different between the non-smokers and smokers with a better score in the smokers. CONCLUSION: A significant ROM improvement occurs after reconstruction and is even slightly better in smokers than in non-smokers. PMID- 21709018 TI - Vacuum-assisted breast biopsy: more cores, more hematomas? AB - BACKGROUND: Vacuum-assisted breast biopsy (VABB) is used for the diagnosis of non palpable breast lesions. Hematoma has been recognized as the main complication of the procedure. Its main disadvantage is the underestimation rate. Generally speaking, approximately up to 24 cores are excised in most published series. It has been suggested that excision of more cores per lesion can reduce the underestimation rate. The present study aims to evaluate hematoma formation with regard to the number of cores excised. PATIENTS AND METHODS: A total of 660 women underwent VABB; 232 women were allocated to the standard protocol (24-36 cores excised, 2-3 offsets) and 428 women were allocated to the extended protocol (96 cores excised, 8 offsets). Cases were derived from a double blind study, as well as from the periods before (standard protocol) and after (mainly extended protocol) the study. In all cases, the occurrence of organized hematomas within the subsequent 20 days was followed up by ultrasound. RESULTS: In the standard protocol, the frequency of clinically significant and subsequently organized hematomas was 3.5%. However, in the extended protocol the respective hematoma percentage was 7.5%. Clinically significant and subsequently organized hematomas were significantly more frequent in the extended protocol (Pearson's chi squared=4.29, p=0.038). CONCLUSION: Despite the superiority of the extended protocol in terms of underestimation, the approximately two-fold increase in hematoma occurrence prompts the need for careful patient selection prior to its performance. PMID- 21709019 TI - Characteristics of patients with a retained wireless capsule endoscope (WCE) necessitating laparotomy for removal of the capsule. AB - AIM: A capsule endoscope is a wireless miniature camera used to take images of the small bowel mucosa. Retention of the wireless capsule endoscope (WCE), defined as at least two weeks' retention or an obstruction demanding removal by laparotomy, is the main and practically only complication of the procedure. The aim of this study was to evaluate the characteristics of patients with a retained WCE necessitating laparotomy for removal of the capsule or capsule fragments. PATIENTS AND METHODS: The medical records of 555 patients who had undergone the WCE procedure over a 7-year period (2002-2008) were reviewed. The indications for the WCE procedure were, obscure gastrointestinal bleeding, Crohn's disease, abdominal pain and suspicion of malignancy. RESULTS: A retained WCE requiring operative treatment was found in 10 cases (in nine patients, twice in one patient). The WCE retention frequency of 1.8% (10/555) equalled that in the literature. CONCLUSION: The retention rate of WCE capsules is low and routine examination of the small bowel with MRI or CT is not necessary before WCE. These examinations were enable to predict WCE retention according to our results. PMID- 21709020 TI - PERK integrates autophagy and oxidative stress responses to promote survival during extracellular matrix detachment. AB - Mammary epithelial cells (MECs) detached from the extracellular matrix (ECM) produce deleterious reactive oxygen species (ROS) and induce autophagy to survive. The coordination of such opposing responses likely dictates whether epithelial cells survive ECM detachment or undergo anoikis. Here, we demonstrate that the endoplasmic reticulum kinase PERK facilitates survival of ECM-detached cells by concomitantly promoting autophagy, ATP production, and an antioxidant response. Loss-of-function studies show that ECM detachment activates a canonical PERK-eukaryotic translation initiation factor 2alpha (eIF2alpha)-ATF4-CHOP pathway that coordinately induces the autophagy regulators ATG6 and ATG8, sustains ATP levels, and reduces ROS levels to delay anoikis. Inducible activation of an Fv2E-DeltaNPERK chimera by persistent activation of autophagy and reduction of ROS results in lumen-filled mammary epithelial acini. Finally, luminal P-PERK and LC3 levels are reduced in PERK-deficient mammary glands, whereas they are increased in human breast ductal carcinoma in situ (DCIS) versus normal breast tissues. We propose that the normal proautophagic and antioxidant PERK functions may be hijacked to promote the survival of ECM-detached tumor cells in DCIS lesions. PMID- 21709021 TI - A conditional mouse model for measuring the frequency of homologous recombination events in vivo in the absence of essential genes. AB - The ability to detect and repair DNA damage is crucial to the prevention of various diseases. Loss of function of genes involved in these processes is known to result in significant developmental defects and/or predisposition to cancer. One such DNA repair mechanism, homologous recombination, has the capacity to repair a wide variety of lesions. Knockout mouse models of genes thought to be involved in DNA repair processes are frequently lethal, making in vivo studies very difficult, if not impossible. Therefore, we set out to develop an in vivo conditional mouse model system to facilitate investigations into the involvement of essential genes in homologous recombination. To test our model, we measured the frequency of spontaneous homologous recombination using the pink-eyed unstable mouse model, in which we conditionally excised either Blm or full-length Brca1 (breast cancer 1, early onset). These two genes are hypothesized to have opposing roles in homologous recombination. In summary, our in vivo data supports in vitro studies suggesting that BLM suppresses homologous recombination, while full-length BRCA1 promotes this process. PMID- 21709023 TI - Epidemiology of Major League Baseball injuries. AB - BACKGROUND: Little is known about the injury rates in Major League Baseball (MLB) players, as a formal injury surveillance system does not exist. The goal of this study was to characterize the epidemiology of MLB injuries over a 7-year period. HYPOTHESIS: Injuries in MLB would be common. STUDY DESIGN: Descriptive epidemiologic study. METHODS: The authors analyzed the MLB disabled list data from 2002 through 2008. Injuries were analyzed for differences between seasons, as well as during seasons on a monthly basis. The injuries were categorized by major anatomic zones and then further stratified based on injury type. Position specific subanalyses for pitcher and position players were performed. RESULTS: From the 2002 season through the 2008 season, an average of 438.9 players per year were placed on the disabled list, for a rate of 3.61 per 1000 athlete exposures. There was a significant 37% increase in injuries between 2005 and 2008. The highest injury rate during the season was during the month of April (5.73/1000 exposures) and the lowest in September (0.54/1000 exposures). No differences were noted in the injury rates between the National League and the American League (incidence rate ratio [IRR] = 1.06; 95% confidence interval [CI] = 0.98, 1.15). Pitchers experienced 34% higher incidence rates for injury compared with fielders during the study period (IRR = 1.34; 95% CI = 1.25, 1.44). Among all player injuries, upper extremity injuries accounted for 51.4% while lower extremity injuries accounted for 30.6%. Injuries to the spine and core musculature accounted for 11.7% while other injuries and illnesses were 6.3% of the total disabled list entries. There was a significant association between position played and anatomic region injured (P < .001), with pitchers experiencing a significantly greater proportion of injuries to the upper extremity (67.0%; 95% CI = 63.1%, 70.9%) compared with fielders (32.1%; 95% CI = 29.1%, 35.1%). Conversely, fielders experienced a significantly greater proportion of injuries to the lower extremity (47.5%; 95% CI = 43.8%, 51.1%) compared with pitchers (16.9%; 95% CI = 14.9%, 18.8%). The mean number of days on the disabled list was 56.6. Overall, a greater proportion of disability days were experienced by pitchers (62.4%; 95% CI = 62.0%, 62.8%; P < .001) compared with fielders (37.6%; 95% CI = 37.3%, 37.9%). CONCLUSION: Injuries in MLB resulting in disabled list designation are common. Upper extremity injuries were predominant in pitchers, while lower extremity injuries are more common in position players. These data may be used in the development of a formal MLB injury database, as well as in the development and implementation of specific preseason training and in-season conditioning for injury prevention. PMID- 21709022 TI - H3K4 trimethylation by Set1 promotes efficient termination by the Nrd1-Nab3-Sen1 pathway. AB - In Saccharomyces cerevisiae, the Nrd1-Nab3-Sen1 pathway mediates the termination of snoRNAs and cryptic unstable transcripts (CUTs). Both Nrd1 and the Set1 histone H3K4 methyltransferase complex interact with RNA polymerase II (Pol II) during early elongation, leading us to test whether these two processes are functionally linked. The deletion of SET1 exacerbates the growth rate and termination defects of nrd1 mutants. Set1 is important for the appropriate recruitment of Nrd1. Additionally, Set1 modulates histone acetylation levels in the promoter-proximal region via the Rpd3L deacetylase and NuA3 acetyltransferase complexes, both of which contain PHD finger proteins that bind methylated H3K4. Increased levels of histone acetylation reduce the efficiency of Nrd1-dependent termination. We speculate that Set1 promotes proper early termination by the Nrd1 Nab3-Sen1 complex by affecting the kinetics of Pol II transcription in early elongation. PMID- 21709024 TI - Analysis of risk factors for glenoid bone defect in anterior shoulder instability. AB - BACKGROUND: Glenoid bone defect is frequently associated with anterior shoulder instability and is considered one of the major causes of recurrence of instability after shoulder stabilization. HYPOTHESIS: Some risk factors are significantly associated with the presence, size, and type of glenoid bone defect. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: One hundred sixty-one patients affected by anterior shoulder instability underwent morphologic evaluation of the glenoid by computed tomography scans to assess the presence, size, and type of glenoid bone defect (erosion or bony Bankart lesion). Bone loss greater than 20% of the area of the inferior glenoid was considered "critical" bone defect (at risk of recurrence). Outcomes were correlated with the following predictors: age, gender, arm dominance, frequency of dislocation, age at first dislocation, timing from first dislocation, number of dislocations, cause of first dislocation, generalized ligamentous laxity, type of sport, and manual work. RESULTS: Glenoid bone defect was observed in 72% of the cases. Presence of the defect was significantly associated with recurrence of dislocation compared with a single episode of dislocation, increasing number of dislocations, male gender, and type of sport. Size of the defect was significantly associated with recurrent dislocation, increasing number of dislocations, timing from first dislocation, and manual work. Presence of a critical defect was significantly associated with number of dislocations and age at first dislocation. Bony Bankart lesion was significantly associated with male gender and age at first dislocation. CONCLUSION: The number of dislocations and age at first dislocation are the most significant predictors of glenoid bone loss in anterior shoulder instability. PMID- 21709025 TI - On the shoulders of giants. PMID- 21709026 TI - Arthroscopic management of femoroacetabular impingement in athletes. AB - BACKGROUND: Hip pathology is a significant source of pain and dysfunction among athletic individuals and femoroacetabular impingement is often a causative factor. Arthroscopic intervention has been proposed to address the joint damage and underlying impingement. HYPOTHESIS: Arthroscopy may be effective in the management of symptomatic femoroacetabular impingement in athletes. STUDY DESIGN: Case series, Level of evidence, 4. METHODS: All patients undergoing hip arthroscopy at 1 institution were prospectively assessed with a modified Harris hip score obtained preoperatively and postoperatively at 3, 12, 24, 60, and 120 months. This report consists of a cohort of 200 patients identified who underwent arthroscopic management of femoroacetabular impingement, participated in athletic activities, and had achieved minimum 1-year follow up. RESULTS: There was 100% follow-up at an average of 19 months (range, 12-60 months). A total of 116 athletes had achieved 2-year follow-up. For the entire cohort, the average age was 28.6 years (range, 11-60 years) with 148 males and 52 females. There were 159 cam, 31 combined, and 10 pincer lesions. There were 23 professional, 56 intercollegiate, 24 high school, and 97 recreational athletes. The male:female ratio was 2.8:1 among cam lesions and 1:1 among pincer lesions. The median preoperative score was 72 with a postoperative score of 96 and the median improvement was 20.5 points, which was statistically significant (P < .001). Ninety-five percent of professional athletes and 85% of intercollegiate athletes were able to return to their previous level of competition. There were 5 transient neurapraxias (all resolved) and 1 minor heterotopic ossification. One athlete (0.5%) underwent conversion to total hip arthroplasty and 4 (2%) underwent repeat arthroscopy. For the group with minimum 2-year follow up, the median improvement was 21 points with a postoperative score of 96. CONCLUSION: The data substantiate successful outcomes in the arthroscopic management of femoroacetabular impingement with few complications and most athletes were able to resume activities. PMID- 21709027 TI - Outcomes after the arthroscopic treatment of femoroacetabular impingement in a mixed group of high-level athletes. AB - BACKGROUND: Femoroacetabular impingement has become more widely recognized in the athletic patient population. The purpose of the present study was to review the clinical outcome after arthroscopic treatment of femoroacetabular impingement in a mixed population of high-level athletes. HYPOTHESIS: Arthroscopic treatment of femoroacetabular impingement results in significant improvement in clinical outcome and a high rate of return to play. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: High-level athletes who underwent arthroscopic treatment of femoroacetabular impingement (rim trimming, labral refixation or debridement, femoral osteochondroplasty) with a minimum of 1-year follow-up were retrospectively identified. All patients completed hip-specific outcome scores (Modified Harris Hip Score [MHHS] and Hip Outcome Score [HOS]) at baseline and most recent follow-up. RESULTS: Forty-seven patients with an average age of 22.8 +/- 6.2 years met the study criteria with a mean follow-up of 27.0 +/- 5.5 months. Thirty-three patients (70.2%) were available for follow-up. The level of competition was 27.7% varsity high school, 53.2% college, and 19.1% professional athletes. There were statistically significant improvements in the mean MHHS score (preoperative, 68.6 +/- 12.8; postoperative, 88.5 +/- 17.7; P = .002) as well as the HOS score (preoperative, 78.8 +/- 11.3; postoperative, 91.4 +/- 14.0; P = .03). There was a significant improvement in the alpha angle, with 76.4 degrees +/- 14.5 degrees preoperatively and 51.4 degrees +/- 11.7 degrees postoperatively (P = .0003). Seventy-nine percent of patients were able to return to play after hip arthroscopy at a mean of 9.4 +/- 4.7 months (range, 4-26 months); of those patients, 92.3% were able to return to the same level of competition. At 2-year follow-up, 73% of patients were able to return to play. CONCLUSION: Arthroscopic treatment of femoroacetabular impingement in a mixed group of high-level athletes may result in a significant improvement in hip functional outcome: 78% of athletes were able to return to play at 1 year and 73% of athletes were able to play at 2-year follow-up. PMID- 21709028 TI - Radiographic comparison of surgical hip dislocation and hip arthroscopy for treatment of cam deformity in femoroacetabular impingement. AB - BACKGROUND: Whether open or arthroscopic techniques are employed, the goal of femoroacetabular impingement (FAI) surgery is to achieve impingement-free range of motion. While arthroscopic approaches have improved and gained popularity, an objective evaluation of the surgical correction achieved with this approach compared with open surgery remains to be defined in the literature. PURPOSE: This study was undertaken to compare the efficacy of arthroscopic osteoplasty and open surgical dislocation in treating FAI dysmorphology in a consecutive series of patients. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Surgical treatment was performed in 60 male patients under 40 years of age for symptomatic FAI refractory to nonoperative management. Patients were matched (not randomized) to treatment groups: 30 patients (15 left and 15 right hips) underwent arthroscopic cam and/or rim osteoplasty with labral debridement and/or refixation by an arthroscopic surgeon; and 30 (14 left and 16 right hips) underwent open surgical dislocation, cam and/or rim osteoplasty, and labral debridement or refixation by a hip preservation surgeon. Anteroposterior (AP) pelvis and extended-neck (Dunn) lateral radiographs were obtained and the depth of resection and arc of resection were measured by assessment of anterior femoral head-neck offset, AP and lateral alpha angle, and beta angle on preoperative and postoperative radiographs. RESULTS: In the arthroscopic group, the extended-neck lateral alpha angle was reduced by a mean of 17.2 degrees (28.3%, P < .05), AP alpha angle was reduced by a mean of 12.6 degrees (16.8%), anterior head-neck offset improved 5.0 mm (111%, P < .05), and beta angle increased by a mean of 23.1 degrees . In the open dislocation group, the extended-neck lateral alpha angle was reduced by a mean of 21.2 degrees (30.7%, P < .05), AP alpha angle was reduced by a mean of 20.1 degrees (25.7%), anterior head-neck offset improved 6.56 mm (108%, P < .05), and beta angle increased by a mean of 18.35 degrees . CONCLUSION: Arthroscopic osteoplasty can restore head-neck offset and achieve similar depth, arc, and proximal-distal resection with comparable efficacy to open surgical dislocation for anterior and anterosuperior cam and focal rim impingement deformity. The open technique, however, may allow greater correction of posterosuperior loss of femoral offset and may be favorable for FAI patterns that demonstrate considerable proximal femoral deformity on AP radiographs. PMID- 21709029 TI - "At-risk" positioning and hip biomechanics of the Peewee ice hockey sprint start. AB - BACKGROUND: Femoroacetabular impingement (FAI) is becoming a prevalent overuse injury diagnosis among hockey players. In the adult ice hockey stride, the "at risk" hip position, defined by internal rotation during flexion and external rotation during abduction, reportedly increases hip vulnerability to labral injury as a result of FAI. HYPOTHESIS: Peewee youth ice hockey players display the kinematics for both described at-risk hip positions (internal rotation during flexion and external rotation during abduction) in the ice hockey sprint start. STUDY DESIGN: Descriptive laboratory study. METHODS: Twelve healthy male Peewee ice hockey players (mean age, 10.8 +/- 0.6 years) participated in this study. Thirty-five anatomic landmarks were used to analyze the 3-dimensional kinematic and kinetic variables of the hip associated with the ice hockey sprint start. Ten high-speed (120-Hz) infrared cameras recorded the trials, which were subsequently analyzed with Motion Monitor software. The sprint start was recorded over 4 defined periods of motion: start, push, swing, and even. RESULTS: In the "push" period, 11.5 degrees of external rotation was observed concurrently with 13.2 degrees of abduction in the push leg, and 6.8 degrees of internal rotation occurred with 33.8 degrees of flexion in the lead leg. During the recovery phase of the "swing" period, maximum internal rotation was 5.6 degrees with concurrent hip flexion of 44.2 degrees in the push leg, while lead leg internal rotation reached a maximum of 10.8 degrees with hip flexion of 35.1 degrees during the "even" period. CONCLUSION: During the sprint start, youth ice hockey players externally rotate in abduction during the push-off phase and internally rotate through increasing hip flexion during the recovery phase, displaying the at-risk hip positions of the ice hockey skating stride. CLINICAL RELEVANCE: During the sprint start, youth ice hockey players position their hips in a manner that can cause impingement of the femoral neck against the acetabulum and potentially lead to labral tears and/or articular cartilage damage. This knowledge could be applied to assist in the prevention of overuse injuries of the hip as youth hockey players mature and increase in skill level. PMID- 21709030 TI - Preoperative and postoperative sagittal plane hip kinematics in patients with femoroacetabular impingement during level walking. AB - BACKGROUND: Femoroacetabular impingement (FAI) has been linked to osteoarthritis. Treatment options range from nonoperative to operative, and current outcome measures are generally subjective or not conducted under actual activities of daily living. Thus, there is a need for the use of motion capture techniques to quantitatively assess the outcome of surgical intervention for those treated for FAI. HYPOTHESIS: The gait of FAI patients 1 year after operative treatment (arthroscopic hip reshaping) will be significantly closer to the normal range and pattern of hip flexion motion, relative to pretreatment. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Eleven patients between 18 and 44 years of age with diagnosed FAI were enrolled in this study. Kinematics and kinetics for this group of patients were collected using motion capture techniques before arthroscopic bone-reshaping surgery and again 1 year after surgery. Pain and perceived activity level (Tegner scale) were also collected. All collected data were compared using a paired t test. RESULTS: Overall hip sagittal plane range of motion increased on the affected side from 27.6 degrees +/- 5.0 degrees to 30.7 degrees +/- 4.3 degrees (P = .02). The presence of abnormal reversals (second order change in the slope in the hip flexion/extension curve) that was present in 5 patients preoperatively disappeared or was reduced in prevalence and magnitude in 4 of the patients postoperatively. Additionally, pain decreased and activity level increased postoperatively. CONCLUSION: The results supported the hypothesis that surgical intervention for FAI restores more normal patterns of gait and provides objective support that the surgical procedure is useful. The results help establish motion capture as a potential method for quantitatively assessing the outcome in FAI surgical interventions. The presence of abnormal reversals in hip flexion has been reported in end-stage hip osteoarthritis, and the presence of these reversals in FAI patients reinforces the idea of FAI being a precursor to hip osteoarthritis. PMID- 21709031 TI - Surgical treatment of femoroacetabular impingement improves hip kinematics: a computer-assisted model. AB - BACKGROUND: Femoroacetabular impingement (FAI) is now recognized as the most common cause of early osteoarthritis in the nondysplastic hip. While the surgical treatment of FAI has demonstrated favorable clinical outcomes, the ability of an osteoplasty to reliably improve hip kinematics and range of motion remains unknown. PURPOSE: This study used computer-assisted 3-dimensional (3D) analysis to assess differences in hip range of motion before and after the arthroscopic surgical treatment of symptomatic FAI. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Ten patients with symptomatic, focal cam and/or pincer impingement lesions underwent high-resolution computed tomography scans and computer-assisted 3D modeling of the involved hip before and after corrective arthroscopic surgery by the senior author. Cam location, alpha angle, neck-shaft angle, femoral version, and acetabular version at 12-o'clock through 3-o'clock positions were measured. The model was subsequently dynamized to define the preoperative and postoperative range of motion and location of impingement with hip flexion, internal rotation, and internal rotation at 90 degrees of hip flexion. Statistical analysis of preoperative and postoperative hip flexion and internal rotation at 90 degrees of hip flexion was performed using paired t tests with P < .05 defined as significant. RESULTS: The cam lesion was located between 12 o'clock and 5 o'clock in all cases. Mean preoperative alpha angle was 59.8 degrees (range, 36 degrees -76 degrees ). Mean femoral version was 12.5 degrees (range, -15 degrees to 32 degrees ). Mean preoperative hip flexion was 107.40 degrees +/- 11.6 degrees , and mean internal rotation at 90 degrees of hip flexion was 19.10 degrees +/- 13.0 degrees . The location of impingement was unique in each case and not predictable based on simple radiographic measures (ie, alpha angle) alone. Corrective femoral and rim osteoplasty resulted in significant improvements in both hip flexion (3.8 degrees ; P = .002) and internal rotation (9.3 degrees ; P = .0002). Mean postoperative alpha angle was 36.4 degrees (range, 22 degrees -46 degrees ). CONCLUSION: Focal cam and/or rim osteoplasty can reliably improve hip kinematics and range of motion in patients with symptomatic FAI, particularly the limitation of internal rotation in a flexed position. Computed tomography-based computer modeling can localize regions of anticipated mechanical impingement in symptomatic patients. A complete osteoplasty in these defined regions, through an arthroscopic or open approach, predictably improves range of motion and may help to eliminate the recurrent mechanical collision and secondary chondral injury associated with FAI. PMID- 21709032 TI - Hip arthroscopy after traumatic hip dislocation. AB - BACKGROUND: Traumatic posterior dislocation of the hip joint usually results from high-energy trauma, which can cause additional injuries that may need to be addressed after reduction. PURPOSE: This study was undertaken to present arthroscopic findings after traumatic posterior hip dislocation in patients with mechanical hip symptoms. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: All patients treated with hip arthroscopy between 2002 and 2006 for mechanical hip symptoms after traumatic posterior hip dislocation with subsequent closed reduction were included in this study. The time between closed reduction and arthroscopy, arthroscopic findings and treatment, preoperative and last follow-up WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) scores, and last follow-up radiographs were analyzed. Complications or the need for further surgical treatment are reported. RESULTS: There were 17 patients (13 male, 4 female) with an average age of 28.5 years (range, 19-37 years). The average time between closed reduction and arthroscopy was 3 months. Fourteen patients had anterior labral tears, 6 had posterior labral tears, 16 had acetabular chondral damage, all had femoral chondral damage, and 14 had intra articular fragments. The preoperative WOMAC score was 46; the last follow-up (average 45 months) WOMAC score was 87 (range, 45-93); this was considered statistically significant (P = .001). One patient required total hip replacement for osteoarthritis and 1 presented with osteonecrosis and is waiting for hip replacement. CONCLUSION: The clearest indication for arthroscopy after traumatic posterior hip dislocation was loose fragments inside the joint. Arthroscopy was also performed in every patient with mechanical hip symptoms. Intra-articular damage was demonstrated in every case. Most of the patients had significant improvement after hip arthroscopy. PMID- 21709033 TI - Cross-sectional analysis of iliopsoas muscle-tendon units at the sites of arthroscopic tenotomies: an anatomic study. AB - BACKGROUND: Arthroscopic iliopsoas tenotomies are performed at the level of the labrum, femoral neck, and lesser trochanter. The composition and percentage of the iliopsoas muscle-tendon unit (MTU) that is released when the tendon is cut at these sites has not been reported to date. HYPOTHESIS: Cutting the iliopsoas tendon at the 3 common sites of arthroscopic tenotomies does not release the entire iliopsoas MTU. STUDY DESIGN: Descriptive laboratory study. METHODS: Forty iliopsoas MTUs from 20 embalmed cadavers were isolated at the level of the hip joint and released from their insertion on the lesser trochanter. Circumferential measurements of the composite MTU and the isolated iliopsoas tendon were then made at (1) the MTU's insertion on the lesser trochanter, (2) the Wettstein et al site of transcapsular release, and (3) the Alpert et al release site at the level of the labrum. Single proportion testing was performed using the Student t test to determine if significant differences existed between the average circumference of the iliopsoas MTUs or the isolated tendons at the 3 levels at which they were measured. RESULTS: The average circumference of the iliopsoas-muscle belly complex at the level of the labrum, the transcapsular release site, and the lesser trochanter was 68, 58, and 46 mm, respectively. The average circumference of the iliopsoas tendon at these same levels was 27, 31, and 27 mm, respectively. Thus, at the level of the labrum, transcapsular release site, and lesser trochanter, the iliopsoas MTU is composed of 40% tendon/60% muscle belly, 53% tendon/47% muscle belly, and 60% tendon/40% muscle belly, respectively. CONCLUSION: Cutting the iliopsoas tendon at the labrum, head-neck junction, or lesser trochanter does not result in a release of the entire iliopsoas MTU. CLINICAL RELEVANCE: The results of this study document that releasing the iliopsoas tendon at the lesser trochanter preserves 40% of the MTU and does not result in a complete detachment of the iliopsoas MTU. PMID- 21709034 TI - Vascular safe zones in hip arthroscopy. AB - BACKGROUND: Hip arthroscopy is an evolving surgical technique being performed in greater numbers because of advances in skill, improved technology, and increased demand. Identifying vascular safe zones using anatomic and intracapsular landmarks provides a valuable intraoperative guide to reduce the risk of damage to the femoral head blood supply during femoral neck osteoplasty and psoas tendon release. PURPOSE: This series is presented to identify vascular safe zones for use in hip arthroscopy. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The authors analyzed 76 consecutive contrast-enhanced magnetic resonance scans obtained from patients with diagnosed femoral acetabular impingement. High resolution 3-dimensional images were reconstructed to visualize the vasculature. The medial femoral circumflex artery (MFCA) course was traced from the anterior thigh to the femoral head. Specific attention was paid to its proximity to the psoas tendon at the site of release and the retinacular vessel course in relation to the femoral neck using a clock-face orientation. RESULTS: The MFCA was found inserting on the posterior superior femoral neck from the 10:30 to 12-o'clock position on the femoral neck shaft, just posterior to the lateral synovial fold, and progressed on the femoral neck via an average of 4 retinacular vessels (range, 2-6). Ninety-seven percent of vessels were posterior to the 12-o'clock position. The MFCA passes posteriorly a mean distance of 50% +/- 8% between the lesser trochanter and inferior femoral head/acetabular junction, located a mean 15 +/- 0.37 mm medial to the medial cortex of the femoral neck. The MFCA was within the middle third zone in 100% of the measurements. CONCLUSION: The authors defined the following 2 safe zones: the femoral neck osteoplasty safe zone is on the anterior half of the femoral neck; the psoas tendon release safe zone is astride the middle third of the medial hip capsule (bordered by the lesser trochanter and inferior femoral head/acetabular junction). PMID- 21709035 TI - Arthroscopic disease classification and interventions as an adjunct in the treatment of acetabular dysplasia. AB - BACKGROUND: Treatment of hip dysplasia has focused on corrective osteotomy surgery, while hip arthroscopy remains controversial. Improved understanding of intra-articular disease patterns associated with hip dysplasia will help delineate the role of arthroscopy as an adjunct to osteotomy surgery for dysplastic hips. PURPOSE: The authors set out to describe the intra-articular disease patterns of patients undergoing combined hip arthroscopy and periacetabular osteotomy for the treatment of symptomatic acetabular dysplasia with associated mechanical symptoms. Secondly, they wanted to identify the potential role for arthroscopy in treating intra-articular problems as an adjunct to acetabular reorientation surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Seventy-three hips in 71 patients undergoing arthroscopy for mechanical symptoms before a redirectional osteotomy of the acetabulum were reviewed. Radiographic findings of acetabular dysplasia were compared with intraoperative labral and chondral disease patterns. Arthroscopic interventions were recorded. RESULTS: Labral tears and acetabular cartilage lesions were present in 65.8% and 68.5% of hips, respectively. Combined acetabular articular cartilage lesions and labral disease were observed in 58.9% of hips. When disease was present, acetabular labrum and chondral lesions were primarily located at the anterior (81.0%, 76.0%) and superolateral (66.7%, 84.0%) labrochondral junctions. A lateral center-edge angle <15 degrees was associated with an increased likelihood of acetabular chondromalacia, as well as moderate to severe acetabular cartilage disease. An acetabular inclination of >20 degrees was associated with an increased risk of larger labral tears (>2 cm). Sixty-three percent had at least 1 arthroscopic treatment of central compartment disease, most commonly acetabular chondroplasty (30.1%), partial labral resection (26.0%), and labral repair (16.4%). CONCLUSION: Acetabular rim disease is common in symptomatic acetabular dysplasia, and 63% of cases have a central compartment abnormality amenable to arthroscopic treatment. Lateral center-edge angle <15 degrees and acetabular inclination >20 degrees are associated with more severe labrochondral disease. PMID- 21709036 TI - Arthroscopic treatment for acetabular labral tears of the hip without bony dysmorphism. AB - BACKGROUND: Surgical treatment for labral tears of the hip has shown good results in patients with bony impingement lesions; however, results are also affected by the correction of bony abnormalities. This study evaluates the outcome of arthroscopic treatment for acetabular labral tears without associated dysplasia or bony impingement lesions. HYPOTHESIS: Based on the structural importance of the acetabular labrum, labral tear debridement or repair can relieve pain and improve function. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The study included 81 patients who were categorized according to 4 morphologic labral tear types. The tear type, degree of synovitis, and chondral damage were analyzed with the use of multivariate regression analysis and correlated to the clinical outcome. The outcome was assessed utilizing the modified Harris hip score (MHHS) and the nonarthritic hip score (NAHS). RESULTS: There were 81 patients (81 hips), including 20 men and 61 women, with 41 right and 40 left hips. Their mean age was 44 years. Overall, at an average follow-up of 3 years the mean MHHS had improved by 18 points (95% confidence interval [CI], 13-23) and the mean NAHS by 17 points (95% CI, 12-22). An improvement after arthroscopic treatment was noticed in all types of labral tears of the hip. The level of synovitis and of chondral lesions was found to have a significant negative effect on the clinical outcome. CONCLUSION: Arthroscopic treatment for acetabular labral tears of the hip without dysplasia or bony impingement lesions has good short- to midterm results. The best outcome is expected in the absence of synovitis and chondral lesions. PMID- 21709037 TI - Role of the acetabular labrum and the iliofemoral ligament in hip stability: an in vitro biplane fluoroscopy study. AB - BACKGROUND: Recent biomechanical reports have described the function of the acetabular labrum and iliofemoral ligament in providing hip stability, but the relative stability provided by each structure has not been well described. HYPOTHESIS: Both the iliofemoral ligament and acetabular labrum are important for hip stability by limiting external rotation and anterior translation, with increased stability provided by the iliofemoral ligament compared with the acetabular labrum. STUDY DESIGN: Controlled laboratory study. METHODS: Fifteen fresh-frozen male cadaveric hips were utilized for this study. Each specimen was selectively skeletonized down to the hip capsule. Four tantalum beads were embedded into each femur and pelvis to accurately measure hip translations and rotations using biplane fluoroscopy while either a standardized 5 N.m external or internal rotation torque was applied. The hips were tested in 4 hip flexion angles (10 degrees of extension, neutral, and 10 degrees and 40 degrees of flexion) in the intact state and then by sectioning and later repairing the acetabular labrum and iliofemoral ligament in a randomized order. RESULTS: External rotation significantly increased from the intact condition (41.5 degrees +/- 7.4 degrees ) to the sectioned iliofemoral ligament condition (54.4 degrees +/- 6.6 degrees ) and both-sectioned condition (61.5 degrees +/- 5.7 degrees ; P < .01), but there was no significant increase in external rotation when the labrum alone was sectioned (45.6 degrees +/- 5.9 degrees ). The intact and fully repaired conditions were not significantly different. External rotation and internal rotation significantly decreased when the hip flexion angle decreased from 40 degrees of flexion to 10 degrees of extension (P < .01) regardless of sectioned condition. Anterior translation varied significantly across sectioned conditions but not across flexion angles (P < .001). The ligament-sectioned (1.4 +/- 0.5 mm), both-sectioned (2.2 +/- 0.2 mm), and labrum-repaired (1.1 +/- 0.2 mm) conditions all resulted in significantly greater anterior translation than the intact condition (-0.4 +/- 0.1 mm) (P < .001). CONCLUSION: The iliofemoral ligament had a significant role in limiting external rotation and anterior translation of the femur, while the acetabular labrum provided a secondary stabilizing role for these motions. CLINICAL RELEVANCE: These results suggest that, if injured, both the acetabular labrum and iliofemoral ligament should be surgically repaired to restore native hip rotation and translation. In addition, a careful repair of an arthroscopic capsulotomy should be performed to avoid increased external hip rotation and anterior translation after arthroscopy. PMID- 21709038 TI - Strains across the acetabular labrum during hip motion: a cadaveric model. AB - BACKGROUND: Labral tears commonly cause disabling intra-articular hip pain and are commonly treated with hip arthroscopy. However, the function and role of the labrum are still unclear. HYPOTHESES: (1) Flexion, adduction, and internal rotation (a position clinically defined as the position for physical examination known as the impingement test) places greatest circumferential strain on the anterolateral labrum and posterior labrum; (2) extension with external rotation (a position clinically utilized during physical examination to assess for posterior impingement and for anterior instability) places significant circumferential strains on the anterior labrum; (3) abduction with external rotation during neutral flexion-extension (the position the extremity rests in when a patient lies supine) places the greatest load on the lateral labrum. STUDY DESIGN: Descriptive laboratory study. METHODS: Twelve cadaveric hips (age, 79 years) without labral tears or arthritis were studied. Hips were dissected free of soft tissues, except the capsuloligamentous structures. Differential variable reluctance transducers were placed in the labrum anteriorly, anterolaterally, laterally, and posteriorly to record circumferential strains in all 4 regions as the hip was placed in 36 different positions. RESULTS: The posterior labrum had the greatest circumferential strains identified; the peak was in the flexed position, in adduction or neutral abduction-adduction. The greatest strains anteriorly were in flexion with adduction. The greatest strains anterolaterally were in full extension. External rotation had greater strains than neutral rotation and internal rotation. The greatest strains laterally were at 90 degrees of flexion with abduction, and external or neutral rotation. In the impingement position, the anterolateral strain increased the most, while the posterior labrum showed decreased strain (greatest magnitude of strain change). When the hip is externally rotated and in neutral flexion-extension or fully extended, the posterior labrum has significantly increased strain, while the anterolateral labrum strain is decreased. CONCLUSION: These are the first comprehensive strain data (of circumferential strain) analyzing the whole hip labrum. For the intact labrum, the greatest strain change was at the posterior acetabulum, whereas clinically, acetabular labral tears occur most frequently anterolaterally or anteriorly. The results are consistent with the impingement test as an assessment of anterolateral acetabular labral stress. The hyperextension-rotation test, often used clinically to assess anterior hip instability and posterior impingement, did not show a change in strain anteriorly, but did reveal an increase in strain posteriorly. CLINICAL RELEVANCE: Although this study does not include muscular forces across the hip joint, it does provide a clue as to the stresses about the labrum through the complete range of motions of the hip, which may help in providing a better understanding of the cause of labral tears and in the protection of labral repairs. PMID- 21709039 TI - Effect of acetabular labrum tears on hip stability and labral strain in a joint compression model. AB - BACKGROUND: Acetabular labrum tears are now commonly diagnosed in young and active patients. Because the role of the acetabular labrum is incompletely understood, it is critical to determine how these tears affect native hip biomechanics. HYPOTHESIS: Radial and circumferential labral tears significantly decrease hip stability and significantly alter strain patterns in the anterior and anterior-superior acetabular labrum. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty-two human cadaveric hips without evidence of degeneration or dysplasia were assigned to a circumferential tear (n = 11) and a radial tear (n = 11) group. The hips were tested in a neutral position with an average compressive force of 25 N. In the circumferential tear group, the labral states were intact; 1-, 2-, and 3-cm circumferential tears; a 3-cm partial labrectomy; and a full labrectomy. In the radial tear group, the labral states were intact; a radial tear; a 1-, 2-, and 3-cm partial labrectomy; and a full labrectomy. The effect of labral injury on the stability ratio (peak dislocation force/compressive loads) and labral strain in the anterior and anterior-superior labrum was analyzed using repeated-measures analysis of variance. RESULTS: There was no significant difference in stability ratio after circumferential tears 3 cm or less in size compared with the intact labral state. Strain in the anterior and anterior-superior labrum was either unchanged or increased after circumferential labral tear. There was no significant difference in stability ratio after a radial tear or a 1-cm partial labrectomy compared with the intact labral state. A 2-cm partial labrectomy significantly decreased the stability ratio. Anterior and anterior-superior labral strain significantly decreased after a radial tear. CONCLUSION: Under the influence of joint compression in a neutral hip position, the acetabular labrum continues to resist femoral head dislocation despite detachment from the acetabular rim. A radial tear in the acetabular labrum decreases adjacent labral strain, but removal of 2 cm or more of the acetabular labrum is needed before hip stability decreases. CLINICAL RELEVANCE: The findings suggest that the acetabular labrum continues to function to resist femoral head translation despite chondral-labral separation and that labral preservation, particularly with larger tears, may be important for maintaining hip stability. Further studies are needed to determine the effect of partial labral excision on the stability ratio with the hip in provocative positions such as extension, external rotation, and abduction. PMID- 21709040 TI - Defining a safety margin for labral suture anchor insertion using the acetabular rim angle. AB - BACKGROUND: Suture anchors are commonly used to reattach a torn labrum to the acetabular rim. The acetabular rim anatomy is not uniform, and the safety margin for inserting suture anchors is unknown. The acetabular rim angle is an anatomic measurement that is indicative of the safety margin for inserting suture anchors. PURPOSE: To investigate the acetabular rim angle as a function of clock position, to evaluate the effect of drill depth on the acetabular rim angle, and to evaluate the effect of rim trimming on the acetabular rim angle. STUDY DESIGN: Descriptive laboratory study. METHODS: Three-dimensional acetabular models were reconstructed from computed tomography scans of 20 nonpaired cadaveric hip specimens, and the acetabular rim angle, which quantifies the angle between the subchondral margin and the outer cortex of the acetabulum, was measured from the 8- to 4-o'clock positions. At each position, the acetabular rim angle was measured for 5 drill depths (10, 12.5, 15, 20, and 25 mm) to simulate different lengths of suture anchors or drill bit depths on the acetabular rim angle. To simulate rim trimming, the acetabular rim angle was measured at the points that would become the suture anchor insertion points after 2.5- and 5-mm rim trimming. RESULTS: Clock position, drill depth, and rim trimming all had significant effects on the acetabular rim angle (P < .0001). The acetabular rim angle was largest at the 2-o'clock and smallest at the 3-o'clock position. Greater drill depths provided smaller acetabular rim angles, whereas rim trimming provided larger acetabular rim angles. CONCLUSION: The acetabular rim angle varied significantly as a function of the location on the acetabular rim. A shorter drill depth and a greater amount of rim trimming provided a larger acetabular rim angle. CLINICAL RELEVANCE: Surgeons should be aware of the acetabular rim variations, especially in the anterosuperior quadrant, as well as the effects of drill depth and rim trimming, when selecting the optimal insertion angle for suture anchor placement to avoid articular cartilage penetration. The acetabular safety angle was smallest at the 3-o'clock position. Therefore, extra care must be taken when drilling or inserting anchors around the 3-o'clock position. PMID- 21709041 TI - Tears of the ligamentum teres: prevalence in hip arthroscopy using 2 classification systems. AB - BACKGROUND: The ligamentum teres (LT) anatomy has been known for many years. While its functionality remains debatable, it is well recognized that the LT can be a source of pain in the hip joint. In 1997, a landmark publication by Gray and Villar established a classification for LT tears and increased the awareness of LT disorders. However, the incidence of LT tears and the various tear types is unknown. PURPOSE: The authors report the prevalence of LT tears in a population of patients who underwent hip arthroscopy, using both the Gray and Villar classification and a new descriptive classification. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between February 2008 and January 2011, 616 hip arthroscopies were performed by the senior author. After excluding revision surgeries, a total of 558 surgeries (502 patients) were included in the study. Data were collected regarding patients' demographics, mechanism of injury, range of motion, magnetic resonance results, and intraoperative findings. Preoperative hip-specific questionnaire scores and pain level were recorded as well. Ligamentum teres tears were classified according to Gray and Villar's classification, and were also categorized using a descriptive grading system as follows: 0, no tear; 1, <50% tear; 2, >50% tear; or 3, 100% tear. RESULTS: A total of 284 (51%) of the 558 surgeries in this cohort revealed LT tears. According to the descriptive grading system, 22% were grade 1, 24% were grade 2, and 5% were grade 3. According to the Gray and Villar classification 3.7% had full rupture, 43% had a partial tear, and 4.5% had a degenerative tear. Patients with LT tears were significantly older and had worse preoperative functional scores; they did, however, have a greater range of motion. Intraoperatively, an association with larger labral tear size and acetabular chondral damage was found. Magnetic resonance arthrography was found to have low accuracy and sensitivity in detection of LT tears. No correlation to the pain level was found. CONCLUSION: Ligamentum teres tears had a higher prevalence in this study than was published in the past, most probably attributable to a lower threshold used in defining a tear. The incidence is defined both using the Gray and Villar classification, as well as a new descriptive classification system that categorizes the LT according to amount of tearing. PMID- 21709042 TI - Efficacy of hip arthroscopy in the management of synovial chondromatosis. AB - BACKGROUND: Synovial chondromatosis can result in intra-articular loose bodies. Open arthrotomy has been the conventional treatment for this condition in the hip. Hip arthroscopy, however, is a minimally invasive approach and avoids potential problems with open arthrotomy. PURPOSE: This series was described to evaluate the role of arthroscopy in treatment and outcome of synovial chondromatosis of the hip at early to intermediate follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty-nine patients had arthroscopic treatment for synovial chondromatosis of the hip. All loose bodies were intracapsular and smaller than 10 mm. Radiographs of the painful hip, computed tomography (CT), and gadolinium-enhanced magnetic resonance imaging (MRI) were obtained preoperatively. Intraoperatively, loose bodies were removed, and partial synovectomy, partial labrectomy, chondroplasty, and microfracture were done as needed. RESULTS: There were 14 women and 15 men (mean age, 41 years; mean duration of symptoms, 52 months). All patients had hip pain and 63% reported mechanical hip symptoms. Twenty-three patients were followed for at least 12 months (mean, 64 months). Loose bodies could be seen in the imaging studies of 52% of patients: 8 on radiographs and 7 with CT or gadolinium-enhanced MRI. At surgery, 23 of the 29 (79%) patients had torn labra and femoral head changes. There were an average of 35 loose bodies per patient. Twenty-five of the 29 (86%) had acetabular chondral findings. Five of the 29 patients (17%) eventually underwent total hip reconstruction surgery at a mean of 52 months; 5 of these patients had grade III/IV lesions at the time of arthroscopy. Eleven of the 23 patients (48%) had good to excellent outcomes at an average of 60 months. Recurrent symptoms were seen in 7 patients, and revision arthroscopy was done for 1 patient at 1-year follow-up, 2 patients at 4 years, 1 at 5 years, and 1 at 7 year follow-up. Complications included transient perineal and pedal paresthesia in 2 patients. CONCLUSION: Patients with synovial chondromatosis with hip central compartment loose bodies that were less than 10 mm benefited from hip arthroscopy. Imaging studies alone failed to establish the diagnosis in 14 of 29 patients (48%). Diagnosis was made by direct visualization via arthroscopy. For patients with grade I/II cartilage change, early diagnosis and treatment via arthroscopy helped. It is a valid and effective treatment at early to intermediate follow-up. PMID- 21709043 TI - Pulmonary adenocarcinoma seeding along a fine needle aspiration tract in a dog. PMID- 21709044 TI - Severe disease in neonatal calves with detection of cytopathic BVDV. PMID- 21709045 TI - Tetralogy of Fallot in a three-month-old lamb: clinical, ultrasonographic and laboratory findings. PMID- 21709046 TI - Seroprevalence of Streptococcus equi in working horses in Lesotho. PMID- 21709047 TI - Characteristics of epileptic episodes in UK dog breeds: an epidemiological approach. AB - In this study, previously unreported cohort characteristics and seizure patterns for canine epilepsy were identified from a series of UK-based epileptic dogs containing 1260 cases from 79 known pedigree breeds and a group of crossbreed dogs. PMID- 21709048 TI - Malignant catarrhal fever in kune kune pigs in the UK. PMID- 21709049 TI - A pilot survey of bovine norovirus in northern Italy. PMID- 21709050 TI - Use of a deslorelin implant to control aggression in a male bearded dragon (Pogona vitticeps). PMID- 21709051 TI - Investigations of pestivirus infection in wild Caprinae in Europe. PMID- 21709052 TI - Selected haematological and plasma chemistry parameters in juvenile and adult degus (Octodon degus). AB - Thirty-five juvenile (mean age 6.3 weeks) and 35 adult (mean age 2.0 years) healthy degus (Octodon degus) were studied to investigate selected haematological and plasma biochemistry parameters. Animals were anaesthetised with isoflurane, and blood was withdrawn from the cranial vena cava. Erythrocyte, haematocrit and neutrophil counts (including the percentage of neutrophils) were significantly higher in the adult degus than in the juveniles. In contrast, the reticulocyte count, mean corpuscular volume, mean corpuscular haemoglobin, number of platelets and percentage of lymphocytes were significantly lower in the adult animals. Total protein and globulin levels were significantly higher in the adult degus. The albumin:globulin ratio and plasma levels of urea nitrogen, cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, potassium, total calcium and inorganic phosphorus were significantly lower in adults than in juveniles. PMID- 21709053 TI - Secretion of IL-1beta triggered by dynasore in murine peritoneal macrophages. AB - The interaction of lipopolysaccharide-primed murine peritoneal macrophages with ivermectin, an antiparasite drug which potentiates P2X(4) receptors and dynasore which inhibits the GTPase activity of dynamin, a protein contributing to the internalization of plasma membrane proteins, was tested. Murine peritoneal macrophages express P2X(4) receptors which are mostly intracellular. In cells from P2X(7)-knockout mice (KO mice), 10 um adenosine triphosphate (ATP) provoked a transient increase of the intracellular concentration of calcium. Ivermectin had no effect by itself but potentiated the increase of the intracellular concentration of calcium by ATP. The combination of ATP plus ivermectin also decreased the intracellular concentration of potassium and promoted the secretion of IL-1beta. Concentrations of dynasore above 50 um affected the integrity of mitochondria (MTT test) and of the plasma membrane (release of lactate dehydrogenase, LDH). At a 10 um concentration, dynasore had no effect on the responses to ATP and on the internalization of P2X(4) receptors. By itself dynasore promoted the release of potassium and the secretion of IL-1beta after activation of caspase-1. In conclusion, our results confirm that ivermectin potentiates the responses coupled to P2X(4) receptors probably by interaction with an allosteric site. We also show that this potentiation triggers the release of IL-1beta by macrophages. As opposed to ivermectin, dynasore has no effect on P2X(4) receptors. This drug triggers a potassium efflux via a mechanism which does not involve purinergic receptors and generates, in consequence, the activation of caspase-1 and the secretion of IL-1beta. PMID- 21709054 TI - A variety of novel lipid A structures obtained from Francisella tularensis live vaccine strain. AB - F. tularensis is a Gram-negative coccobacillus that causes tularemia. Its LPS has nominal biological activity. Currently, there is controversy regarding the structure of the lipid A obtained from F. tularensis live vaccine strain (LVS). Therefore, to resolve this controversy, the purification and structural identification of this LPS was crucial. To achieve this, LPS from F. tularensis LVS was acid hydrolyzed to obtain crude lipid A that was methylated and purified by HPLC and the fractions were analyzed by MALDI-TOF MS. The structure of the major lipid A species was composed of a glucosamine disaccharide backbone substituted with four fatty acyl groups and a phosphate (1-position) with a molecular mass of 1505. The major lipid A component contained 18:0[3-O(16:0)] in the distal subunit and two 18:0(3-OH) fatty acyl chains at the 2- or 3-positions of the reducing subunit. Additional variations in the lipid A species include: heterogeneity in fatty acyl groups, a phosphate or a phosphoryl galactosamine at the 1-position, and a hexose at the 4' or 6' position, some of which have not been previously described for F. tularensis LVS. This analysis revealed that lipid A from F. tularensis LVS is far more complex than originally believed. PMID- 21709055 TI - Information technology systems for critical care triage and medical response during an influenza pandemic: a review of current systems. AB - OBJECTIVES: To assess local, state, federal, and global pandemic influenza preparedness by identifying pandemic plans at the local, state, federal, and global levels, and to identify any information technology (IT) systems in these plans to support critical care triage during an influenza pandemic in the Canadian province of Ontario. METHODS: The authors used advanced MEDLINE and Google search strategies and conducted a comprehensive review of key pandemic influenza Web sites. Descriptive data extraction and analysis for IT systems were conducted on all of the included pandemic plans. RESULTS: A total of 155 pandemic influenza plans were reviewed: 29 local, 62 state, 63 federal, and 1 global. We found 70 plans that examined IT systems (10 local, 33 state, 26 federal, 1 global), and 85 that did not (19 local, 29 state, 37 federal). Of the 70 plans, 64 described surveillance systems (10 local, 32 state, 21 federal, 1 global), 2 described patient data collection systems (1 state, 1 federal); 4 described other types of IT systems (4 federal), and none were intended for triage. CONCLUSIONS: Although several pandemic plans have been drafted, the majority are high-level general documents that do not describe IT systems. The plans that discuss IT systems focus strongly on surveillance, which fails to recognize the needs of a health care system responding to an influenza pandemic. The best examples of the types of IT systems to guide decision making during a pandemic were found in the Kansas and the Czech Republic pandemic plans, because these systems were designed to collect both patient and surveillance data. Although Ontario has yet to develop such an IT system, several IT systems are in place that could be leveraged to support critical care triage and medical response during an influenza pandemic. PMID- 21709057 TI - American Heart Association atrial fibrillation research summit: a conference report from the American Heart Association. PMID- 21709058 TI - Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction. AB - BACKGROUND: Current guidelines for the diagnosis of acute myocardial infarction (AMI), among other criteria, also require a rise and/or fall in cardiac troponin (cTn) levels. It is unknown whether absolute or relative changes in cTn have higher diagnostic accuracy and should therefore be preferred. METHODS AND RESULTS: In a prospective, observational, multicenter study, we analyzed the diagnostic accuracy of absolute (Delta) and relative (Delta%) changes in cTn in 836 patients presenting to the emergency department with symptoms suggestive of AMI. Blood samples for the determination of high-sensitive cTn T and cTn I ultra were collected at presentation and after 1 and 2 hours in a blinded fashion. The final diagnosis was adjudicated by 2 independent cardiologists. The area under the receiver operating characteristic curve for diagnosing AMI was significantly higher for 2-hour absolute (Delta) versus 2-hour relative (Delta%) cTn changes (area under the receiver operating characteristic curve [95% confidence interval], high-sensitivity cTn T: 0.95 [0.92 to 0.98] versus 0.76 [0.70 to 0.83], P<0.001; cTn I ultra: 0.95 [0.91 to 0.99] versus 0.72 [0.66 to 0.79], P<0.001). The receiver operating characteristic curve-derived cutoff value for 2 hour absolute (Delta) change was 0.007 MUg/L for high-sensitivity cTn T and 0.020 MUg/L for cTn I ultra (both cutoff levels are half of the 99th percentile of the respective cTn assay). Absolute changes were superior to relative changes in patients with both low and elevated baseline cTn levels. CONCLUSIONS: Absolute changes of cTn levels have a significantly higher diagnostic accuracy for AMI than relative changes, and seem therefore to be the preferred criteria to distinguish AMI from other causes of cTn elevations. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT00470587. PMID- 21709059 TI - Mortality and readmission of patients with heart failure, atrial fibrillation, or coronary artery disease undergoing noncardiac surgery: an analysis of 38 047 patients. AB - BACKGROUND: The postoperative risks for patients with coronary artery disease (CAD) undergoing noncardiac surgery are well described. However, the risks of noncardiac surgery in patients with heart failure (HF) and atrial fibrillation (AF) are less well known. The purpose of this study is to compare the postoperative mortality of patients with HF, AF, or CAD undergoing major and minor noncardiac surgery. METHODS AND RESULTS: Population-based data were used to create 4 cohorts of consecutive patients with either nonischemic HF (NIHF; n=7700), ischemic HF (IHF; n=12 249), CAD (n=13 786), or AF (n=4312) who underwent noncardiac surgery between April 1, 1999, and September 31, 2006, in Alberta, Canada. The main outcome was 30-day postoperative mortality. The unadjusted 30-day postoperative mortality was 9.3% in NIHF, 9.2% in IHF, 2.9% in CAD, and 6.4% in AF (each versus CAD, P<0.0001). Among patients undergoing minor surgical procedures, the 30-day postoperative mortality was 8.5% in NIHF, 8.1% in IHF, 2.3% in CAD, and 5.7% in AF (P<0.0001). After multivariable adjustment, postoperative mortality remained higher in NIHF, IHF, and AF patients than in those with CAD (NIHF versus CAD: odds ratio 2.92; 95% confidence interval 2.44 to 3.48; IHF versus CAD: odds ratio 1.98; 95% confidence interval 1.70 to 2.31; AF versus CAD: odds ratio 1.69; 95% confidence interval 1.34 to 2.14). CONCLUSIONS: Although current perioperative risk prediction models place greater emphasis on CAD than HF or AF, patients with HF or AF have a significantly higher risk of postoperative mortality than patients with CAD, and even minor procedures carry a risk higher than previously appreciated. PMID- 21709060 TI - Saphenous vein grafts with multiple versus single distal targets in patients undergoing coronary artery bypass surgery: one-year graft failure and five-year outcomes from the Project of Ex-Vivo Vein Graft Engineering via Transfection (PREVENT) IV trial. AB - BACKGROUND: Limited information exists on the intermediate-term graft patency and 5-year clinical outcomes of patients receiving saphenous vein grafts with multiple (m-SVG) versus single distal targets (s-SVG) during coronary artery bypass graft (CABG) surgery in the current era. METHODS AND RESULTS: We studied the association of the use of m-SVG versus s-SVG conduits with 1-year SVG failure (defined as >=75% angiographic stenosis) and 5-year clinical events (death; death or myocardial infarction [MI]; and death, MI, or revascularization) in 3014 patients undergoing their first CABG surgery enrolled in the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV. Of 3014 patients enrolled in PREVENT IV, 1045 (34.7%) had >=1 m-SVGs during CABG. Vein graft failure at 1 year was higher for m-SVG compared with s-SVG (adjusted odds ratio 1.24, 95% confidence interval 1.03 to 1.48). At 5 years, the adjusted composite of death, MI (including perioperative MI), or revascularization (hazard ratio 1.15, 95% confidence interval 1.00 to 1.31) and death or MI (hazard ratio 1.21, 95% confidence interval 1.03 to 1.43) were significantly higher in patients receiving m-SVGs. CONCLUSIONS: In patients undergoing first CABG surgery, the use of m-SVG was associated with a higher 1-year vein graft failure rate and trends toward worse clinical outcomes. Additional studies are needed to better understand the most appropriate conduit to improve long-term graft patency and clinical outcomes of patients undergoing CABG surgery. In the meantime, these data should encourage the use of s-SVG over m-SVG when feasible. PMID- 21709061 TI - Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. AB - BACKGROUND: The prevalence of heart failure with preserved ejection fraction is increasing. The prognosis worsens with pulmonary hypertension and right ventricular (RV) failure development. We targeted pulmonary hypertension and RV burden with the phosphodiesterase-5 inhibitor sildenafil. METHODS AND RESULTS: Forty-four patients with heart failure with preserved ejection fraction (heart failure signs and symptoms, diastolic dysfunction, ejection fraction >=50%, and pulmonary artery systolic pressure >40 mm Hg) were randomly assigned to placebo or sildenafil (50 mg thrice per day). At 6 months, there was no improvement with placebo, but sildenafil mediated significant improvements in mean pulmonary artery pressure (-42.0+/-13.0%) and RV function, as suggested by leftward shift of the RV Frank-Starling relationship, increased tricuspid annular systolic excursion (+69.0+/-19.0%) and ejection rate (+17.0+/-8.3%), and reduced right atrial pressure (-54.0+/-7.2%). These effects may have resulted from changes within the lung (reduced lung water content and improved alveolar-capillary gas conductance, +15.8+/-4.5%), the pulmonary vasculature (arteriolar resistance, 71.0+/-8.2%), and left-sided cardiac function (wedge pulmonary pressure, -15.7+/ 3.1%; cardiac index, +6.0+/-0.9%; deceleration time, -13.0+/-1.9%; isovolumic relaxation time, -14.0+/-1.7%; septal mitral annulus velocity, -76.4+/-9.2%). Results were similar at 12 months. CONCLUSIONS: The multifaceted response to phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction includes improvement in pulmonary pressure and vasomotility, RV function and dimension, left ventricular relaxation and distensibility (structural changes and/or ventricular interdependence), and lung interstitial water metabolism (wedge pulmonary pressure decrease improving hydrostatic balance and right atrial pressure reduction facilitating lung lymphatic drainage). These results enhance our understanding of heart failure with preserved ejection fraction and offer new directions for therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01156636. PMID- 21709062 TI - Association between myocardial infarction and fractures: an emerging phenomenon. AB - BACKGROUND: Data on the association between myocardial infarction (MI) and fractures are scarce. Recent changes in the epidemiology of MI justify exploring this relationship. We evaluated whether MI constitutes a risk factor for osteoporotic fracture and examined secular trends in this association. METHODS AND RESULTS: Consecutive Olmsted County, Minnesota, residents with incident MI diagnosed in 1979 to 2006 and community control subjects individually matched (1:1) to cases on age, sex, and year of onset (n=6642) were followed up through 2009. Outcome measures were time to osteoporotic fracture, overall and by anatomic site, and death. Fracture incidence rates were stable in controls but increased markedly over time among MI cases. Accordingly, although an overall excess of fracture risk after MI was observed (adjusted hazard ratio, 1.32; 95% confidence interval, 1.12 to 1.56), substantial temporal variations were noted (1979 to 1989: hazard ratio, 0.81; 95% confidence interval, 0.58 to 1.12; 1990 to 1999: hazard ratio, 1.47; 95% confidence interval, 1.10 to 1.96; 2000 to 2006: hazard ratio, 1.73; 95% confidence interval, 1.32 to 2.27; P for trend <0.001). Trends were similar regardless of age, sex or fracture site. Conversely, the overall hazard ratio for death in MI cases versus controls did not change materially despite a continuous decline in 30-day case fatality rate (12.5% in 1979 to 1989; 6.7% in 2000 to 2006). Observed changes in the baseline prevalence of cardiovascular risk factors, MI characteristics, and comorbidities did not fully account for the trends in fracture risk. CONCLUSIONS: Over the past decades, the association between MI and osteoporotic fractures increased steadily. The trend is consistent with the displacement of post-MI outcomes toward noncardiovascular events, highlighting the need for comprehensive prevention strategies to accommodate the changing epidemiology of MI. PMID- 21709063 TI - Cost-effectiveness of statin therapy for primary prevention in a low-cost statin era. AB - BACKGROUND: With wide availability of low-cost generics, primary prevention with statins has become less expensive. We projected the cost-effectiveness of expanded statin prescribing strategies using low-cost generics and identified conditions under which aggressive prescribing ceases to be cost-effective. METHODS AND RESULTS: We simulated expanded statin prescribing strategies with the coronary heart disease policy model, a Markov model of the US population >35 years of age. If statins cost $4/mo, treatment thresholds of low-density lipoprotein cholesterol >160 mg/dL for low-risk persons (0 to 1 risk factor), >130 mg/dL for moderate-risk persons (>=2 risk factors and 10-year risk <10%), and >100 mg/dL for moderately high-risk persons (>=2 risk factors and 10-year risk >10%) would reduce annual healthcare costs by $430 million compared with Adult Treatment Panel III guidelines. Lowering thresholds to >130 mg/dL for persons with 0 risk factors and >100 mg/dL for persons with 1 risk factor and treating all moderate- and moderately high-risk persons regardless of low-density lipoprotein cholesterol would provide additional health benefits for $9900 per quality-adjusted life-year. These findings are insensitive to most adverse effect assumptions (including statin-associated diabetes mellitus and severe hypothetical effects) but are sensitive to large reductions in the efficacy of statins or to a long-term disutility burden for which a patient would trade 30 to 80 days of life to avoid 30 years of statins. CONCLUSIONS: Low-cost statins are cost-effective for most persons with even modestly elevated cholesterol or any coronary heart disease risk factors if they do not mind taking a pill daily. Adverse effects are unlikely to outweigh benefits in any subgroup in which statins are found to be efficacious. PMID- 21709065 TI - Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. AB - BACKGROUND: In the Platelet Inhibition and Patient Outcomes (PLATO) trial, a prespecified subgroup analysis showed a significant interaction between treatment and region (P=0.045), with less effect of ticagrelor in North America than in the rest of the world. METHODS AND RESULTS: Reasons for the interaction were explored independently by 2 statistical groups. Systematic errors in trial conduct were investigated. Statistical approaches evaluated the likelihood of play of chance. Cox regression analyses were performed to quantify how much of the regional interaction could be explained by patient characteristics and concomitant treatments, including aspirin maintenance therapy. Landmark Cox regressions at 8 time points evaluated the association of selected factors, including aspirin dose, with outcomes by treatment. Systematic errors in trial conduct were ruled out. Given the large number of subgroup analyses performed and that a result numerically favoring clopidogrel in at least 1 of the 4 prespecified regions could occur with 32% probability, chance alone cannot be ruled out. More patients in the United States (53.6%) than in the rest of the world (1.7%) took a median aspirin dose >=300 mg/d. Of 37 baseline and postrandomization factors explored, only aspirin dose explained a substantial fraction of the regional interaction. In adjusted analyses, both Cox regression with median maintenance dose and landmark techniques showed that, in patients taking low-dose maintenance aspirin, ticagrelor was associated with better outcomes compared with clopidogrel, with statistical superiority in the rest of the world and similar outcomes in the US cohort. CONCLUSIONS: The regional interaction could arise from chance alone. Results of 2 independently performed analyses identified an underlying statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, myocardial infarction, or stroke with ticagrelor compared with clopidogrel is associated with a low maintenance dose of concomitant aspirin. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872. PMID- 21709066 TI - Cardiology Patient Page. Depression after heart attack: why should I be concerned about depression after a heart attack? PMID- 21709064 TI - Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. AB - BACKGROUND: Adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase was assessed in a randomized, double-blind, placebo-controlled, phase 2 study in patients with advanced heart failure. METHODS AND RESULTS: Thirty-nine patients received intracoronary adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase or placebo. Seven efficacy parameters were assessed in 4 domains: symptoms (New York Heart Association class, Minnesota Living With Heart Failure Questionnaire), functional status (6-minute walk test, peak maximum oxygen consumption), biomarker (N-terminal prohormone brain natriuretic peptide), and left ventricular function/remodeling (left ventricular ejection fraction, left ventricular end-systolic volume), plus clinical outcomes. The primary end point success criteria were prospectively defined as achieving efficacy at 6 months in the group-level (concordant improvement in 7 efficacy parameters and no clinically significant worsening in any parameter), individual-level (total score for predefined clinically meaningful changes in 7 efficacy parameters), or outcome end points (cardiovascular hospitalizations and time to terminal events). Efficacy in 1 analysis had to be associated with at least a positive trend in the other 2 analyses. This combination of requirements resulted in a probability of success by chance alone of 2.7%. The high-dose group versus placebo met the prespecified criteria for success at the group-level, individual-level, and outcome analyses (cardiovascular hospitalizations) at 6 months (confirmed at 12 months) and demonstrated improvement or stabilization in New York Heart Association class, Minnesota Living With Heart Failure Questionnaire, 6-minute walk test, peak maximum oxygen consumption, N-terminal prohormone brain natriuretic peptide levels, and left ventricular end-systolic volume. Significant increases in time to clinical events and decreased frequency of cardiovascular events were observed at 12 months (hazard ratio=0.12; P=0.003), and mean duration of cardiovascular hospitalizations over 12 months was substantially decreased (0.4 versus 4.5 days; P=0.05) on high-dose treatment versus placebo. There were no untoward safety findings. CONCLUSIONS: The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study demonstrated safety and suggested benefit of adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase in advanced heart failure, supporting larger confirmatory trials. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00454818. PMID- 21709067 TI - Unusual fibrillation in the emergency department after fall. PMID- 21709068 TI - Letter by Frydrychowicz and Markl regarding article, "Association between aneurysm shoulder stress and abdominal aortic aneurysm expansion: a longitudinal follow-up study". PMID- 21709069 TI - Letter by Nguyen regarding article, "Acetaminophen increases blood pressure in patients with coronary artery disease". PMID- 21709071 TI - Future of clinical trials for pulmonary hypertension. PMID- 21709070 TI - Current capabilities and challenges for optical coherence tomography as a high impact cardiovascular imaging modality. PMID- 21709072 TI - Sudden cardiac arrest without overt heart disease. PMID- 21709073 TI - Dysautonomia from bilateral carotid artery dissection. PMID- 21709074 TI - Protein phosphatases and the regulation of mitosis. AB - Dynamic control of protein phosphorylation is necessary for the regulation of many cellular processes, including mitosis and cytokinesis. Indeed, although the central role of protein kinases is widely appreciated and intensely studied, the importance of protein phosphatases is often overlooked. Recent studies, however, have highlighted the considerable role of protein phosphatases in both the spatial and temporal control of protein kinase activity, and the modulation of substrate phosphorylation. Here, we will focus on recent advances in our understanding of phosphatase structure, and the importance of phosphatase function in the control of mitotic spindle formation, chromosome architecture and cohesion, and cell division. PMID- 21709075 TI - Pharmacokinetics of once-daily darunavir-ritonavir and atazanavir-ritonavir over 72 hours following drug cessation. AB - The object of this study was to investigate the pharmacokinetics of darunavir ritonavir and atazanavir-ritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavir-ritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0- to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0- to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC(50)] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the protein-binding corrected IC(50) for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval of 24 h which were above the cutoff used to define therapeutic concentrations. PMID- 21709076 TI - Quantification of amikacin in bronchial epithelial lining fluid in neonates. AB - Amikacin efficacy is based on peak concentrations and the possibility of reaching therapeutic levels at the infection site. This study aimed to describe amikacin concentrations in the epithelial lining fluid (ELF) through bronchoalveolar lavage (BAL) in newborns. BAL fluid was collected in ventilated neonates treated with intravenous (i.v.) amikacin. Clinical characteristics, amikacin therapeutic drug monitoring serum concentrations, and the concentrations of urea in plasma were extracted from the individual patient files. Amikacin and urea BAL fluid concentrations were determined using liquid chromatography with pulsed electrochemical detection (LC-PED) and capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C(4)D), respectively. ELF amikacin concentrations were converted from BAL fluid concentrations through quantification of dilution (urea in plasma/urea in BAL fluid) during the BAL procedure. Twenty-two observations in 17 neonates (postmenstrual age, 31.9 [range, 25.1 to 41] weeks; postnatal age, 3.5 [range, 2 to 37] days) were collected. Median trough and peak amikacin serum concentrations were 2.1 (range, 1 to 7.1) mg/liter and 39.1 (range, 24.1 to 73.2) mg/liter; the median urea plasma concentration was 30 (8 to 90) mg/dl. The median amikacin concentration in ELF was 6.5 mg/liter, the minimum measured concentration was 1.5 mg/liter, and the maximum (peak) was 23 mg/liter. The highest measured ELF concentration was reached between 6 and 14.5 h after i.v. amikacin administration, and an estimated terminal elimination half-life was 8 to 10 h. The median and highest (peak) ELF amikacin concentrations observed in our study population were, respectively, 6.5 and 23 mg/liter. Despite the frequent use of amikacin in neonatal (pulmonary) infections, this is the first report of amikacin quantification in ELF in newborns. PMID- 21709077 TI - Genetic organization and mode of action of a novel bacteriocin, bacteriocin 51: determinant of VanA-type vancomycin-resistant Enterococcus faecium. AB - Bacteriocin 51 (Bac 51) is encoded on the mobile plasmid pHY (6,037 bp), which was isolated from vancomycin-resistant Enterococcus faecium VRE38. Bacteriocin 51 is active against E. faecium, E. hirae, and E. durans. Sequence analysis of pHY showed that it encodes nine open reading frames (ORFs) from ORF1 to ORF9 (in that order). Genetic analysis suggested that ORF1 and ORF2, which were designated bacA and bacB, respectively, are the bacteriocin and immunity genes. bacA encodes a 144-amino-acid protein. The deduced BacA protein has a typical signal sequence at its amino terminus, and a potential signal peptidase-processing site corresponding to the V-E-A sequence is located between the 37th and 39th amino acids. The predicted mature BacA protein consists of 105 amino acids. A potential promoter sequence was identified upstream of the start codon. bacB encodes a 55 amino-acid protein. No obvious promoter or terminator sequence was identified between bacA and bacB. Northern blot analysis of bacA and bacB with a bacA RNA probe produced a transcript of approximately 700 nucleotides, which corresponded to the combined nucleotide sizes of bacA and bacB, indicating that transcription was initiated from the promoter upstream of bacA, continued through bacB, and was terminated at the terminator downstream of bacB. The transcription start site was determined to be the T nucleotide located 6 nucleotides downstream from the -10 promoter sequence. These results indicate that bacA and bacB constitute an operon and that bacA is the bacteriocin structural gene while bacB is the immunity gene. The purified C-terminally His tagged BacA protein of Bac 51 showed bacteriostatic activity against the indicator strain. The purified C-terminally His tagged BacA protein of Bac 32 (whose mature BacA protein has 54 amino acids) and the culture filtrates of the Bac 31- and Bac 43-producing E. faecalis strain FA2-2 showed bactericidal activity. Bac 31 and Bac 43 are pore-forming bacteriocins, unlike the newly characterized bacteriocin Bac 51. PMID- 21709078 TI - Determination of tissue penetration and pharmacokinetics of linezolid in patients with diabetic foot infections using in vivo microdialysis. AB - Staphylococcus aureus and other Gram-positive organisms, including methicillin resistant S. aureus, continue to be the predominant pathogens associated with diabetic foot infections. Consequently, linezolid is often used to treat these infections. The purpose of the current study was to describe the pharmacokinetic profile and determine the level of penetration of linezolid into healthy thigh tissue and infected wound tissue of the same extremity in 9 diabetic patients with chronic lower limb infections by use of in vivo microdialysis. Hourly plasma and dialysate samples were obtained over a 12-h dosing interval following 3 to 4 doses of linezolid (600 mg intravenously every 12 h). Plasma protein binding was also assessed at 1, 6, and 12 h postdose. The means +/- standard deviations (SD) for the maximum concentration in serum (C(max)), the volume of distribution at terminal phase (V(z)), and the half-life (t(1/2)) for linezolid in plasma were 11.99 +/- 3.67 MUg/ml, 0.71 +/- 0.25 liters/kg of body weight, and 4.71 +/- 1.23 h, respectively. Mean protein binding was 14.78% (range, 3.85 to 32.03%). The mean areas under the concentration-time curves from 0 to 12 h for the free, unbound fraction of linezolid (fAUC(0-12) values) +/- SD for plasma, wound tissue, and thigh tissue were 51.24 +/- 12.72, 82.76 +/- 59.01, and 92.52 +/- 60.44 MUg . h/ml, respectively. Tissue penetration ratios (tissue fAUC to plasma fAUC) were similar for thigh (1.42; range, 1.08 to 2.23) and wound (1.27; range, 0.86 to 2.26) tissues (P = 0.648). With the currently approved dosing regimen, linezolid penetrated well into both healthy thigh tissue and infected wound tissue in these diabetic patients. PMID- 21709079 TI - Increasing chloramphenicol resistance in Streptococcus pneumoniae isolates from Papua New Guinean children with acute bacterial meningitis. AB - In Papua New Guinean (PNG) children with acute bacterial meningitis (ABM), all Haemophilus influenzae isolates were resistant to chloramphenicol. Although Streptococcus pneumoniae isolates had a median chloramphenicol MIC of 3 MUg/ml, it was >=4 MUg/ml in 42.8%, and the likelihood of an area under the 24-hour concentration-time curve/MIC ratio of >100 h at a MIC of >=4 MUg/ml was approximately 50%. All isolates were ceftriaxone sensitive. These data support ceftriaxone rather than conventional chloramphenicol for all PNG children with suspected ABM. PMID- 21709080 TI - Activity of ceftaroline and epidemiologic trends in Staphylococcus aureus isolates collected from 43 medical centers in the United States in 2009. AB - A Staphylococcus aureus surveillance program was initiated in the United States to examine the in vitro activity of ceftaroline and epidemiologic trends. Susceptibility testing by Clinical and Laboratory Standards Institute broth microdilution was performed on 4,210 clinically significant isolates collected in 2009 from 43 medical centers. All isolates were screened for mecA by PCR and evaluated by pulsed-field gel electrophoresis. Methicillin-resistant S. aureus (MRSA) were analyzed for Panton-Valentine leukocidin (PVL) genes and the staphylococcal cassette chromosome mec (SCCmec) type. All isolates had ceftaroline MICs of <=2 MUg/ml with an MIC(50) of 0.5 and an MIC(90) of 1 MUg/ml. The overall resistance rates, expressed as the percentages of isolates that were intermediate and resistant (or nonsusceptible), were as follows: ceftaroline, 1.0%; clindamycin, 30.2% (17.4% MIC >= 4 MUg/ml; 12.8% inducible); daptomycin, 0.2%; erythromycin, 65.5%; levofloxacin, 39.9%; linezolid, 0.02%; oxacillin, 53.4%; tetracycline, 4.4%; tigecycline, 0%; trimethoprim-sulfamethoxazole, 1.6%; vancomycin, 0%; and high-level mupirocin, 2.2%. The mecA PCR was positive for 53.4% of the isolates. The ceftaroline MIC(90)s were 0.25 MUg/ml for methicillin susceptible S. aureus and 1 MUg/ml for MRSA. Among the 2,247 MRSA isolates, 51% were USA300 (96.9% PVL positive, 99.7% SCCmec type IV) and 17% were USA100 (93.4% SCCmec type II). The resistance rates for the 1,137 USA300 MRSA isolates were as follows: erythromycin, 90.9%; levofloxacin, 49.1%; clindamycin, 7.6% (6.2% MIC >= 4 MUg/ml; 1.4% inducible); tetracycline, 3.3%; trimethoprim-sulfamethoxazole, 0.8%; high-level mupirocin, 2.7%; daptomycin, 0.4%; and ceftaroline and linezolid, 0%. USA300 is the dominant clone causing MRSA infections in the United States. Ceftaroline demonstrated potent in vitro activity against recent S. aureus clinical isolates, including MRSA, daptomycin-nonsusceptible, and linezolid-resistant strains. PMID- 21709081 TI - The SLCO1B1 rs4149032 polymorphism is highly prevalent in South Africans and is associated with reduced rifampin concentrations: dosing implications. AB - Among patients with tuberculosis, rifampin plasma concentrations and sputum conversion rates have been reported to be lower in Africans. Rifampin is a substrate of P-glycoprotein (coded for by the ABCB1 gene) and organic anion transporting polypeptide 1B1 (coded for by SLCO1B1). The objectives were to identify genetic polymorphisms of drug transporters and the transcriptional regulators pregnane X receptor (PXR) and constitutive androstane receptor (CAR) with an impact on rifampin pharmacokinetics in South Africans. Fifty-seven patients with tuberculosis from Cape Town underwent pharmacokinetic sampling during treatment with rifampin, pyrazinamide, isoniazid, and ethambutol. DNA was genotyped for ABCB1, SLCO1B1, PXR, and CAR polymorphisms by using real-time PCR. NONMEM was used for data analysis. The allele frequency of the SLCO1B1 rs4149032 polymorphism was 0.70. Patients heterozygous and homozygous for this polymorphism had reductions in the bioavailability (and, thus, the area under the curve [AUC]) of rifampin of 18% and 28%, respectively. Simulations showed that increasing the daily rifampin dose by 150 mg in patients with the polymorphism would result in plasma concentrations similar to those of wild-type individuals and reduce the percentage of patients with peak plasma concentrations (C(max)) below 8 mg/liter from 63% to 31%. ABCB1, PXR, and CAR polymorphisms were not associated with differences in rifampin pharmacokinetics. SLCO1B1 rs4149032 was present in most patients and was associated with substantially reduced rifampin exposure. These data suggest that the standard recommended dose of rifampin should be reconsidered for South Africans. PMID- 21709083 TI - Lack of an effect of standard and supratherapeutic doses of linezolid on QTc interval prolongation. AB - A double-blind, placebo-controlled, four-way crossover study was conducted in 40 subjects to assess the effect of linezolid on corrected QT (QTc) interval prolongation. Time-matched, placebo-corrected QT intervals were determined predose and at 0.5, 1 (end of infusion), 2, 4, 8, 12, and 24 h after intravenous dosing of linezolid 600 and 1,200 mg. Oral moxifloxacin at 400 mg was used as an active control. The pharmacokinetic profile of linezolid was also evaluated. At each time point, the upper bound of the 90% confidence interval (CI) for placebo corrected QTcF values (i.e., QTc values adjusted for ventricular rate using the correction methods of Fridericia) for linezolid 600 and 1,200-mg doses were <10 ms, which indicates an absence of clinically significant QTc prolongation. At 2 and 4 h after the moxifloxacin dose, corresponding to the population T(max), the lower bound of the two-sided 90% CI for QTcF when comparing moxifloxacin to placebo was >5 ms, indicating that the study was adequately sensitive to assess QTc prolongation. The pharmacokinetic profile of linezolid at 600 mg was consistent with previous observations. Systemic exposure to linezolid increased in a slightly more than dose-proportional manner at supratherapeutic doses, but the degree of nonlinearity was small. At a supratherapeutic single dose of 1,200 mg of linezolid, no treatment-related increase in adverse events was seen compared to 600 mg of linezolid, and no clinically meaningful effects on vital signs and safety laboratory evaluations were noted. PMID- 21709082 TI - Daptomycin antibiotic lock therapy in a rat model of staphylococcal central venous catheter biofilm infections. AB - Antibiotic lock therapy (ALT) is an adjunctive procedure to prevent or treat central venous catheter infections, ensuing catheter-related bacteremia, and catheter-related metastatic infections. Daptomycin is a cyclic lipopeptide that is rapidly bactericidal against methicillin-susceptible and -resistant Staphylococcus aureus. The efficacies of daptomycin against central venous catheter biofilms, catheter-related bacteremia, and catheter-related metastatic infections were evaluated by adapting a previously reported central venous catheter biofilm model in rats. Combined daptomycin ALT and systemic dosing resulted in the clearance of an established in vivo S. aureus central venous catheter biofilm after just two daily ALT treatments (30 min with daptomycin at 5 mg/ml) with concurrent systemic daptomycin dosing (40 mg/kg of body weight/day subcutaneously [s.c.]; equivalent exposure of 6 mg/kg/day in people). Daptomycin ALT solutions formulated in either saline or lactated Ringer's solution were equally fast in eradicating established in vivo methicillin-resistant Staphylococcus epidermidis (MRSE) central venous catheter biofilms. However, the lactated Ringer's formulation was superior to that of saline in sustaining the bacterial clearance of treated central venous catheters (83% versus 50%). In MRSE infected central venous catheter studies, 3 days of daptomycin or vancomycin ALT (18 h at 5 mg/ml) with systemic s.c. dosing (40 mg/kg/day daptomycin or 100 mg/kg/day vancomycin) was equally effective 1 week posttherapy in maintaining cleared central venous catheters (90% [n = 10] versus 100% [n = 8]). These results suggest that daptomycin ALT, along with systemic dosing, could be an effective treatment option for the prevention or eradication of staphylococcal central venous catheter biofilm infections, thereby reducing the occurrence of catheter-related bacteremia or catheter-related metastatic infections. PMID- 21709084 TI - Postantibiotic effect of fidaxomicin and its major metabolite, OP-1118, against Clostridium difficile. AB - Fidaxomicin (FDX), a narrow-spectrum antibiotic recently shown to be superior to vancomycin in providing sustained clinical response to Clostridium difficile infection, was investigated along with its major metabolite, OP-1118, with regard to their postantibiotic effects (PAE). FDX was found to have a prolonged PAE (10 h versus ATCC strains and 5.5 h versus a clinical isolate), and OP-1118's PAE was longer than that of the standard comparator, vancomycin (3 versus 0 to 1.5 h, respectively). PMID- 21709085 TI - Knockdown of USP18 increases alpha 2a interferon signaling and induction of interferon-stimulating genes but does not increase antiviral activity in Huh7 cells. AB - The current standard of care for hepatitis C virus (HCV) patients is cotreatment with human alpha interferon (IFN-alpha) and ribavirin. The host factor USP18 functions to regulate the interferon signaling pathway by acting as an off switch. In order to understand whether the inhibition of USP18 represents a valid target for the enhancement of interferon treatment for chronic viral diseases, we have used a wide range of RNA interference (RNAi) reagents to suppress USP18 gene expression in Huh7 cell lines. We demonstrate that a USP18 knockdown results in IFN-alpha2a signaling (measured by increased IFN-stimulated response element [ISRE] reporter gene activity, 2',5'-oligoadenylate synthetase [2-5 OAS] expression, and ISG15 induction) that is increased by ~100-fold, whereas the antiviral (AV) potency in both the Huh7 HCV subgenomic replicon assay and the Huh7.5 HCV infectious virus assay increased by ~3-fold. While the degree of the USP18 knockdown of USP18 elicited by the different RNAi reagents correlated with the enhancement of IFN-alpha2a signaling, it did not correlate with the enhancement of AV activity. The failure of increased IFN-alpha2a signaling to fully translate into increased AV potency was also observed for encephalomyocarditis virus (EMCV) assays using Huh7.5 cells. These data suggest that the IFN-mediated AV response in Huh7.5 cells has only a limited dependence on USP18 activity. PMID- 21709086 TI - Combinations of macrolide resistance determinants in field isolates of Mannheimia haemolytica and Pasteurella multocida. AB - Respiratory tract infections in cattle are commonly associated with the bacterial pathogens Mannheimia haemolytica and Pasteurella multocida. These infections can generally be successfully treated in the field with one of several groups of antibiotics, including macrolides. A few recent isolates of these species exhibit resistance to veterinary macrolides with phenotypes that fall into three distinct classes. The first class has type I macrolide, lincosamide, and streptogramin B antibiotic resistance and, consistent with this, the 23S rRNA nucleotide A2058 is monomethylated by the enzyme product of the erm(42) gene. The second class shows no lincosamide resistance and lacks erm(42) and concomitant 23S rRNA methylation. Sequencing of the genome of a representative strain from this class, P. multocida 3361, revealed macrolide efflux and phosphotransferase genes [respectively termed msr(E) and mph(E)] that are arranged in tandem and presumably expressed from the same promoter. The third class exhibits the most marked drug phenotype, with high resistance to all of the macrolides tested, and possesses all three resistance determinants. The combinations of erm(42), msr(E), and mph(E) are chromosomally encoded and intermingled with other exogenous genes, many of which appear to have been transferred from other members of the Pasteurellaceae. The presence of some of the exogenous genes explains recent reports of resistance to additional drug classes. We have expressed recombinant versions of the erm(42), msr(E), and mph(E) genes within an isogenic Escherichia coli background to assess their individually contributions to resistance. Our findings indicate what types of compounds might have driven the selection for these resistance determinants. PMID- 21709087 TI - A small amount of fat does not affect piperaquine exposure in patients with malaria. AB - Dihydroartemisinin-piperaquine is a new, highly effective, and well-tolerated combination treatment for uncomplicated falciparum malaria. The lipophilic characteristic of piperaquine suggests that administration together with fat will increase the oral bioavailability of the drug, and this has been reported for healthy volunteers. This pharmacokinetic study monitored 30 adult patients with uncomplicated falciparum malaria for 4.5 months to evaluate the effects of the concomitant intake of fat on the total piperaquine exposure. The fixed-drug combination of dihydroartemisinin-piperaquine was given with water to fasting patients (n = 15) or was coadministered with 200 ml milk containing 6.4 g fat (n = 15). The drug combination was generally well tolerated, and there were no severe adverse effects reported for either group during the study. Total piperaquine exposure (area under the concentration-time curve from zero to infinity [AUC(0-infinity)]; results are given as medians [ranges]) were not statistically different between fed (29.5 h . MUg/ml [20.6 to 58.7 h . MUg/ml]) and fasting (23.9 h . MUg/ml [11.9 to 72.9 h . MUg/ml]) patients, but the interindividual variation was reduced in the fed group. Overall, none of the pharmacokinetic parameters differed statistically between the groups. Total piperaquine exposure correlated well with the day 7 concentrations in the fasted group, but the fed group showed a poor correlation. In conclusion, the coadministration of 6.4 g fat did not have any significant effect on piperaquine pharmacokinetics in the treatment of uncomplicated malaria. PMID- 21709088 TI - Determination of pentapeptide repeat units in Qnr proteins by the structure-based alignment approach. AB - The Qnr proteins belong to the pentapeptide repeat protein family. Despite each pentapeptide repeat unit being an important structural determinant, accurately determining pentapeptide repeat units in the Qnr proteins through sequence-based alignments has been challenging. In the present study, the pentapeptide repeat units of the nine representative Qnr proteins have been precisely determined via the structure-based alignment approach using homology modeling and superposition of their best models. PMID- 21709089 TI - Characterization of Salmonella enterica serovar Typhimurium isolates harboring a chromosomally encoded CMY-2 beta-lactamase gene located on a multidrug resistance genomic island. AB - Since 2004, extended-spectrum cephalosporin (ESC)-resistant Salmonella enterica serovar Typhimurium (S. Typhimurium) isolates have been detected from cattle in the northern major island of Japan, Hokkaido. Resistance to ESCs was found to be mediated by CMY-2 type beta-lactamase among 22 epidemiologically unrelated isolates showing indistinguishable pulsed-field gel electrophoresis patterns. Southern blot analysis using I-CeuI-digested genomic DNA demonstrated that the CMY-2 beta-lactamase gene (bla(CMY-2)) was integrated in a 2.5-Mb chromosomal fragment. Genetic analysis of S. Typhimurium isolate L-3553 indicated that bla(CMY-2) was located on a unique 125-kb genomic island, GI-VII-6, which consists of 140 open reading frames. Pairwise alignment of GI-VII-6 and Escherichia coli plasmid pAR060302 (size, 167 kb) revealed that a large proportion of GI-VII-6 (99%) shows a high sequence similarity (>99%) with pAR060302. GI-VII-6 contains 11 antimicrobial resistance genes including sul1, qacEDelta1, aadA2, and dfrA12 in the aadA2 region; sugE1 and bla(CMY-2) in the bla(CMY-2) region; and sul2, strA, strB, tet(A), and floR in the floR region. Two directly repeated IS26 copies were present at both ends of GI-VII-6. Junction regions of GI-VII-6 were flanked by an 8-bp direct repeat, indicating that GI-VII 6 was acquired by transposition involving IS26 transposase. PCR scanning revealed that the overall structure of GI-VII-6 was almost identical in the 22 isolates. Phylogenetic analysis suggested that S. Typhimurium isolates harboring GI-VII-6 belong to a different genomic lineage than other whole-genome-sequenced S. Typhimurium strains. These data indicate that a particular clone of S. Typhimurium harboring GI-VII-6 has spread among the cattle population in Hokkaido, Japan. PMID- 21709090 TI - A high-throughput screening assay for inhibitors of bacterial motility identifies a novel inhibitor of the Na+-driven flagellar motor and virulence gene expression in Vibrio cholerae. AB - Numerous bacterial pathogens, particularly those that colonize fast-flow areas in the bladder and gastrointestinal tract, require motility to establish infection and spread beyond the initially colonized tissue. Vibrio cholerae strains of serogroups O1 and O139, the causative agents of the diarrheal illness cholera, express a single polar flagellum powered by sodium motive force and require motility to colonize and spread along the small intestine. Therefore, motility may be an attractive target for small molecules that can prevent and/or block the infective process. In this study, we describe a high-throughput screening (HTS) assay to identify small molecules that selectively inhibit bacterial motility. The HTS assay was used to screen an ~8,000-compound structurally diverse chemical library for inhibitors of V. cholerae motility. The screen identified a group of quinazoline-2,4-diamino analogs that completely suppressed motility without affecting the growth rate in broth. A further study on the effects of one analog, designated Q24DA, showed that it induces a flagellated but nonmotile (Mot(-)) phenotype and is specific for the Na(+)-driven flagellar motor of pathogenic Vibrio species. A mutation conferring phenamil-resistant motility did not eliminate inhibition of motility by Q24DA. Q24DA diminished the expression of cholera toxin and toxin-coregulated pilus as well as biofilm formation and fluid secretion in the rabbit ileal loop model. Furthermore, treatment of V. cholerae with Q24DA impacted additional phenotypes linked to Na(+) bioenergetics, such as the function of the primary Na(+) pump, Nqr, and susceptibility to fluoroquinolones. The above results clearly show that the described HTS assay is capable of identifying small molecules that specifically block bacterial motility. New inhibitors such as Q24DA may be instrumental in probing the molecular architecture of the Na(+)-driven polar flagellar motor and in studying the role of motility in the expression of other virulence factors. PMID- 21709091 TI - Novel trichomonacidal spermicides. AB - Metronidazole, the U.S. Food and Drug Administration-approved drug against trichomoniasis, is nonspermicidal and thus cannot offer pregnancy protection when used vaginally. Furthermore, increasing resistance of Trichomonas vaginalis to 5 nitro-imidazoles is a cause for serious concern. On the other hand, the vaginal spermicide nonoxynol-9 (N-9) does not protect against sexually transmitted diseases and HIV in clinical situations but may in fact increase their incidence due to its nonspecific, surfactant action. We therefore designed dually active, nonsurfactant molecules that were capable of killing Trichomonas vaginalis (both metronidazole-susceptible and -resistant strains) and irreversibly inactivating 100% human sperm at doses that were noncytotoxic to human cervical epithelial (HeLa) cells and vaginal microflora (lactobacilli) in vitro. Anaerobic energy metabolism, cell motility, and defense against reactive oxygen species, which are key to survival of both sperm and Trichomonas in the host after intravaginal inoculation, depend crucially on availability of free thiols. Consequently, molecules were designed with carbodithioic acid moiety as the major pharmacophore, and chemical variations were incorporated to provide high excess of reactive thiols for interacting with accessible thiols on sperm and Trichomonas. We report here the in vitro activities, structure-activity relationships, and safety profiles of these spermicidal antitrichomonas agents, the most promising of which was more effective than N-9 (the OTC spermicide) in inactivating human sperm and more efficacious than metronidazole in killing Trichomonas vaginalis (including metronidazole-resistant strain). It also significantly reduced the available free thiols on human sperm and inhibited the cytoadherence of Trichomonas on HeLa cells. Experimentally in vitro, the new compounds appeared to be safer than N-9 for vaginal use. PMID- 21709092 TI - Reduction in membrane phosphatidylglycerol content leads to daptomycin resistance in Bacillus subtilis. AB - Daptomycin (DAP) is a cyclic lipopeptide that disrupts the functional integrity of the cell membranes of Gram-positive bacteria in a Ca(2+)-dependent manner. Here we present genetic, genomic, and phenotypic analyses of an evolved DAP resistant isolate, Dap(R)1, from the model bacterium Bacillus subtilis 168. Dap(R)1 was obtained by serial passages with increasing DAP concentrations, is 30 fold more resistant than the parent strain, and displays cross-resistance to vancomycin, moenomycin, and bacitracin. Dap(R)1 is characterized by aberrant septum placement, notably thickened peptidoglycan at the cell poles, and pleiotropic alterations at both the transcriptome and proteome levels. Genome sequencing of Dap(R)1 revealed 44 point mutations, 31 of which change protein sequences. An intermediate isolate that was 20-fold more resistant to DAP than the wild type had only three of these point mutations: mutations affecting the cell shape modulator gene mreB, the stringent response gene relA, and the phosphatidylglycerol synthase gene pgsA. Genetic reconstruction studies indicated that the pgsA(A64V) allele is primarily responsible for DAP resistance. Allelic replacement with wild-type pgsA restored DAP sensitivity to wild-type levels. The additional point mutations in the evolved strain may contribute further to DAP resistance, serve to compensate for the deleterious effects of altered membrane composition, or represent neutral changes. These results suggest a resistance mechanism by which reduced levels of phosphatidylglycerol decrease the net negative charge of the membrane, thereby weakening interaction with the positively charged Ca(2+)-DAP complex. PMID- 21709093 TI - Human pharmacokinetics and safety profile of finafloxacin, a new fluoroquinolone antibiotic, in healthy volunteers. AB - Finafloxacin is a new fluoroquinolone antibiotic with the unique property of increasing antibacterial activity at pH values lower than neutral. Whereas its antibacterial activity at neutral pH matches that of other quinolones in clinical use, it is expected to surpass this activity in tissues and body fluids acidified by the infection or inflammation processes. Pharmacokinetic parameters of oral single and multiple doses of up to 800 mg of finafloxacin and safety/tolerability observations were assessed in a phase I study including 95 healthy volunteers. Finafloxacin is well absorbed after oral administration, generating maximum concentrations (C(max)s) in plasma at least comparable to those of other fluoroquinolones, with a half-life of around 10 h. About one-third of the dose is excreted unchanged in the urine. Renal elimination appears to be a saturable process leading to slight increases of the area under the concentration-time curve extrapolated to infinity and dose normalized (AUC(infinity,norm)) at dosages of 400 mg and above. Safety and tolerability data characterize finafloxacin as a drug with a favorable safety profile. In particular, adverse reactions regarded as class-typical of fluoroquinolones, such as, e.g., electrocardiogram (ECG) changes, neurotoxic effects, or hypoglycemia, were not observed in the study population. PMID- 21709094 TI - In vitro spectrum of activity of finafloxacin, a novel, pH-activated fluoroquinolone, under standard and acidic conditions. AB - Finafloxacin is a novel fluoroquinolone that exhibits enhanced antibacterial activity under acidic conditions. The aim of this study was to define the in vitro pH-activity relationship. Finafloxacin exhibited optimal antibacterial activity between pH 5.0 and 6.0 at which MICs were 4- to 8-fold lower than those determined at neutral pH. These observations were then confirmed against a larger collection of bacteria. These data suggest that finafloxacin could potentially offer a therapeutic advantage within acidic foci of infection. PMID- 21709096 TI - In vitro potency of various polymyxin B components. PMID- 21709095 TI - Melatonin attenuates colistin-induced nephrotoxicity in rats. AB - Colistin-induced nephrotoxicity is a dose-limiting adverse effect when colistin is used against Gram-negative pathogens. This study examined the nephroprotective effect of melatonin against colistin in rats. Rats (n = 7 per group) were treated intravenously twice daily with saline, colistin (at increasing doses from 0.5 to 4.0 mg/kg), melatonin (5 mg/kg), or both melatonin and colistin for 7 days. The severity of renal alteration was examined both biochemically and histologically. The effect of coadministration of melatonin on colistin pharmacokinetics was investigated. Significantly lower urinary N-acetyl-beta-d-glucosaminidase excretion was observed from day 1 in the colistin-melatonin group compared to the colistin group (P < 0.0001). Plasma creatinine increased significantly (P = 0.023) only in the colistin group on day 6. Significant histological abnormalities (P < 0.0001) were detected only in the kidneys of the colistin group. Melatonin altered colistin pharmacokinetics; the total body clearance in the colistin-melatonin group (1.82 +/- 0.26 ml/min/kg) was lower than in the colistin group (4.28 +/- 0.93 ml/min/kg). This is the first study demonstrating the protective effect of melatonin against colistin-induced nephrotoxicity, which indicates that colistin-induced nephrotoxicity is mediated through oxidative stress. It also highlights the potential of coadministering an antioxidant to widen the therapeutic window of this very important last-line antibiotic. PMID- 21709097 TI - Characterization of treatment failure in efficacy trials of drugs against Plasmodium vivax by genotyping neutral and drug resistance-associated markers. AB - Plasmodium vivax intervention trials customarily report uncorrected treatment failure rates. Application of recrudescence-reinfection genotyping and drug resistance single-nucleotide polymorphism typing to a 4-arm comparative efficacy trial illustrated that molecular approaches can assist in understanding the relative contributions of true drug resistance (recurrent with same genotype) and new infections to treatment failure. The PCR-corrected adequate clinical and parasitologic response may constitute an informative secondary endpoint in future P. vivax drug trials. PMID- 21709098 TI - Pharmacokinetics of amodiaquine and desethylamodiaquine in pregnant and postpartum women with Plasmodium vivax malaria. AB - In order to study the pharmacokinetic properties of amodiaquine and desethylamodiaquine during pregnancy, 24 pregnant women in the second and third trimesters of pregnancy and with Plasmodium vivax malaria were treated with amodiaquine (10 mg/kg of body weight/day) for 3 days. The same women were studied again at 3 months postpartum. Plasma was analyzed for amodiaquine and desethylamodiaquine by use of a liquid chromatography-tandem mass spectrometry method. Individual concentration-time data were evaluated using noncompartmental analysis. There were no clinically relevant differences in the pharmacokinetics of amodiaquine and desethylamodiaquine between pregnant (n = 24) and postpartum (n = 18) women. The results suggest that the current amodiaquine dosing regimen is adequate for the treatment of P. vivax infections during pregnancy. PMID- 21709099 TI - Genomewide scan reveals amplification of mdr1 as a common denominator of resistance to mefloquine, lumefantrine, and artemisinin in Plasmodium chabaudi malaria parasites. AB - Multidrug-resistant Plasmodium falciparum malaria parasites pose a threat to effective drug control, even to artemisinin-based combination therapies (ACTs). Here we used linkage group selection and Solexa whole-genome resequencing to investigate the genetic basis of resistance to component drugs of ACTs. Using the rodent malaria parasite P. chabaudi, we analyzed the uncloned progeny of a genetic backcross between the mefloquine-, lumefantrine-, and artemisinin resistant mutant AS-15MF and a genetically distinct sensitive clone, AJ, following drug treatment. Genomewide scans of selection showed that parasites surviving each drug treatment bore a duplication of a segment of chromosome 12 (translocated to chromosome 04) present in AS-15MF. Whole-genome resequencing identified the size of the duplicated segment and its position on chromosome 4. The duplicated fragment extends for ~393 kbp and contains over 100 genes, including mdr1, encoding the multidrug resistance P-glycoprotein homologue 1. We therefore show that resistance to chemically distinct components of ACTs is mediated by the same genetic mutation, highlighting a possible limitation of these therapies. PMID- 21709100 TI - Comparative study of the genetic barriers and pathways towards resistance of selective inhibitors of hepatitis C virus replication. AB - Hepatitis C virus (HCV) inhibitors include direct-acting antivirals (DAAs) such as NS3 serine protease inhibitors, nucleoside and nonnucleoside polymerase inhibitors, and host-targeting antivirals (HTAs) such as cyclophilin inhibitors that have been developed in recent years. Drug-resistant HCV variants have been reported both in vitro and in the clinical setting for most classes of drugs. We report a comparative study in which the genetic barrier to drug resistance of a representative selection of these inhibitors is evaluated employing a number of resistance selection protocols. The NS3 protease inhibitors VX-950 and BILN 2061, the nucleoside polymerase inhibitor 2'-C-methylcytidine, three nonnucleoside polymerase inhibitors (thiophene carboxylic acid, benzimidazole, and benzothiadiazine), and DEB025 were included. For each drug and passage in the selection process, the phenotype and genotype of the drug-resistant replicon were determined. For a number of molecules (BILN 2061 and nonnucleoside inhibitors), drug-resistant variants were readily selected when wild-type replicon-containing cells were directly cultured in the presence of high concentrations of the inhibitor. Resistance to DEB025 could be selected only following a lengthy stepwise selection procedure. For some DAAs, the signature mutations that emerged under inhibitor pressure differed depending on the selection protocol that was employed. Replication fitness of resistant mutants revealed that the C445F mutation in the RNA-dependent RNA polymerase can restore loss of fitness caused by a number of unfit resistance mutations. These data provide important insights into the various pathways leading to drug resistance and allow a direct comparison of the genetic barriers of various HCV drugs. PMID- 21709101 TI - Coresistance to isoniazid and ethionamide maps to mycothiol biosynthetic genes in Mycobacterium bovis. AB - A search to identify new mechanisms of isoniazid resistance in Mycobacterium bovis led to the isolation of mutants defective in mycothiol biosynthesis due to mutations in genes coding for the glycosyltransferase (mshA) or the cysteine ligase (mshC). These mutants showed low-level resistance to isoniazid but were highly resistant to ethionamide. This study further illustrates that mutations in mycothiol biosynthesis genes may contribute to isoniazid or ethionamide resistance across mycobacterial species. PMID- 21709102 TI - Evaluation of the antimicrobial activity of lysostaphin-coated hernia repair meshes. AB - Bacterial infections by antibiotic-resistant Staphylococcus aureus strains are among the most common postoperative complications in surgical hernia repair with synthetic mesh. Surface coating of medical devices/implants using antibacterial peptides and enzymes has recently emerged as a potentially effective method for preventing infections. The objective of this study was to evaluate the in vitro antimicrobial activity of hernia repair meshes coated by the antimicrobial enzyme lysostaphin at different initial concentrations. Lysostaphin was adsorbed on pieces of polypropylene (Ultrapro) mesh with binding yields of ~10 to 40% at different coating concentrations of between 10 and 500 MUg/ml. Leaching of enzyme from the surface of all the samples was studied in 2% (wt/vol) bovine serum albumin in phosphate-buffered saline buffer at 37 degrees C, and it was found that less than 3% of adsorbed enzyme desorbed from the surface after 24 h of incubation. Studies of antibacterial activity against a cell suspension of S. aureus were performed using turbidity assay and demonstrated that the small amount of enzyme leaching from the mesh surface contributes to the lytic activity of the lysostaphin-coated samples. Colony counting data from the broth count (model for bacteria in wound fluid) and wash count (model for colonized bacteria) for the enzyme-coated samples showed significantly decreased numbers of CFU compared to uncoated samples (P < 0.05). A pilot in vivo study showed a dose dependent efficacy of lysostaphin-coated meshes in a rat model of S. aureus infection. The antimicrobial activity of the lysostaphin-coated meshes suggests that such enzyme-leaching surfaces could be efficient at actively resisting initial bacterial adhesion and preventing subsequent colonization of hernia repair meshes. PMID- 21709103 TI - Polymorphisms in isoniazid and prothionamide resistance genes of the Mycobacterium tuberculosis complex. AB - Sequence analyses of 74 strains that encompassed major phylogenetic lineages of the Mycobacterium tuberculosis complex revealed 10 polymorphisms in mshA (Rv0486) and four polymorphisms in inhA (Rv1484) that were not responsible for isoniazid or prothionamide resistance. Instead, some of these mutations were phylogenetically informative. This genetic diversity must be taken into consideration for drug development and for the design of molecular tests for drug resistance. PMID- 21709104 TI - Identification of a novel benzimidazole that inhibits bacterial biofilm formation in a broad-spectrum manner. AB - Bacterial biofilm formation causes significant industrial economic loss and high morbidity and mortality in medical settings. Biofilms are defined as multicellular communities of bacteria encased in a matrix of protective extracellular polymers. Because biofilms have a high tolerance for treatment with antimicrobials, protect bacteria from immune defense, and resist clearance with standard sanitation protocols, it is critical to develop new approaches to prevent biofilm formation. Here, a novel benzimidazole molecule, named antibiofilm compound 1 (ABC-1), identified in a small-molecule screen, was found to prevent bacterial biofilm formation in multiple Gram-negative and Gram positive bacterial pathogens, including Pseudomonas aeruginosa and Staphylococcus aureus, on a variety of different surface types. Importantly, ABC-1 itself does not inhibit the growth of bacteria, and it is effective at nanomolar concentrations. Also, coating a polystyrene surface with ABC-1 reduces biofilm formation. These data suggest ABC-1 is a new chemical scaffold for the development of antibiofilm compounds. PMID- 21709105 TI - In vitro cross-resistance to daptomycin and host defense cationic antimicrobial peptides in clinical methicillin-resistant Staphylococcus aureus isolates. AB - We investigated the hypothesis that methicillin-resistant Staphylococcus aureus (MRSA) isolates developing reduced susceptibilities to daptomycin (DAP; a calcium dependent molecule acting as a cationic antimicrobial peptide [CAP]) may also coevolve reduced in vitro susceptibilities to host defense cationic antimicrobial peptides (HDPs). Ten isogenic pairs of clinical MRSA DAP-susceptible/DAP resistant (DAP(s)/DAP(r)) strains were tested against two distinct HDPs differing in structure, mechanism of action, and origin (thrombin-induced platelet microbicidal proteins [tPMPs] and human neutrophil peptide-1 [hNP-1]) and one bacterium-derived CAP, polymyxin B (PMB). Seven of 10 DAP(r) strains had point mutations in the mprF locus (with or without yyc operon mutations), while three DAP(r) strains had neither mutation. Several phenotypic parameters previously associated with DAP(r) were also examined: cell membrane order (fluidity), surface charge, and cell wall thickness profiles. Compared to the 10 DAP(s) parental strains, their respective DAP(r) strains exhibited (i) significantly reduced susceptibility to killing by all three peptides (P < 0.05), (ii) increased cell membrane fluidity, and (iii) significantly thicker cell walls (P < 0.0001). There was no consistent pattern of surface charge profiles distinguishing DAP(s) and DAP(r) strain pairs. Reduced in vitro susceptibility to two HDPs and one bacterium-derived CAP tracked closely with DAP(r) in these 10 recent MRSA clinical isolates. These results suggest that adaptive mechanisms involved in the evolution of DAP(r) also provide MRSA with enhanced survivability against HDPs. Such adaptations appear to correlate with MRSA variations in cell membrane order and cell wall structure. DAP(r) strains with or without mutations in the mprF locus demonstrated significant cross-resistance profiles to these unrelated CAPs. PMID- 21709107 TI - Mortality rate in patients with diastolic dysfunction and normal systolic function. AB - BACKGROUND: Diastolic dysfunction (DD) is known to be associated with increased mortality rate in the presence of impaired systolic function. However, few prognostic data exist regarding the effect of DD in patients with normal systolic function. METHODS: We reviewed clinical records and echocardiographic findings of consecutive patients who underwent an outpatient echocardiogram that revealed normal systolic function (ejection fraction, >=55%) from January 1, 1996, through December 31, 2005. Diastolic function was graded using echocardiographic Doppler variables designated as normal, mild (grade I, ie, impaired relaxation pattern), moderate (grade II, ie, pseudonormal pattern), or severe (grade III, ie, restrictive filling pattern) dysfunction. Propensity analysis was performed to compare outcomes among the groups. RESULTS: A total of 36 261 patients were identified (mean [SD] age, 58.3 [15.4] years; 54.4% female) with a mean (SD) follow-up time of 6.2 (2.3) years. In 65.2% of the cohort, DD was present, with mild DD being the most prevalent type of dysfunction. A total of 5789 deaths occurred during the follow-up period. The unadjusted survival rate was worse according to the presence and degree of DD (P <.001). However, after propensity matching, only moderate and severe DD were associated with an increased mortality risk (hazard ratio, 1.58; 95% confidence interval, 1.20-2.08; and hazard ratio, 1.84; 1.29-2.62, respectively; P <.001 for each). CONCLUSIONS: In this single center study of patients with normal ejection fraction who presented for outpatient echocardiography, the presence of moderate or severe DD was an independent predictor of mortality. Mild DD, although prevalent, did not affect survival rate. PMID- 21709106 TI - Recombinant phenotyping of cytomegalovirus UL54 mutations that emerged during cell passages in the presence of either ganciclovir or foscarnet. AB - Selection of human cytomegalovirus variants in the presence of ganciclovir or foscarnet led to 18 DNA polymerase mutations, 14 of which had not been previously studied. Using bacterial artificial chromosome technology, each of these mutations was individually transferred into the genome of a reference strain. Following reconstitution of infectious viral stocks, each mutant was assessed for its drug susceptibility and growth kinetics in cell culture. Computer-assisted three-dimensional (3D) modeling of the polymerase was also used to position each of the mutations in one of four proposed structural domains and to predict their influence on structural stability of the protein. Among the 10 DNA polymerase mutations selected with ganciclovir, 7 (P488R, C539R, L545S, V787L, V812L, P829S, and L862F) were associated with ganciclovir resistance, whereas 2 (F595I and V946L) conferred only foscarnet resistance. Among the eight mutations selected with foscarnet, only two (T552N and S585A) conferred foscarnet resistance, whereas four (N408D, K500N, L802V, and L957F) had an impact on ganciclovir susceptibility. Surprisingly, the combination of mutations, some of which were not associated with resistance for a specific antiviral, resulted in increasing resistance effects. 3D modeling suggested that none of the mutated residues were directly involved in the polymerase catalytic site but rather had an influence on drug susceptibility by modifying the structural flexibility of the protein. Our study significantly adds to the number of DNA polymerase mutations conferring in vitro drug resistance and emphasizes the point that evaluation of individual mutations may not accurately reflect the phenotype conferred by multiple mutations. PMID- 21709108 TI - Diastolic dysfunction and heart failure with preserved ejection fraction in women. PMID- 21709109 TI - Prognostic role of ambulatory blood pressure measurement in patients with nondialysis chronic kidney disease. AB - BACKGROUND: Ambulatory blood pressure (BP) measurement allows a better risk stratification in essential hypertension compared with office blood pressure measurement, but its prognostic role in nondialysis chronic kidney disease has been poorly investigated. METHODS: The prognostic role of daytime and nighttime systolic BP (SBP) and diastolic BP (DBP) in comparison with office measurements was evaluated in 436 consecutive patients with chronic kidney disease. Primary end points were time to renal death (end-stage renal disease or death) and time to fatal and nonfatal cardiovascular events. Quintiles of BP were used to classify patients. RESULTS: The mean (SD) age of the patients was 65.1 (13.6) years, and the glomerular filtration rate was 42.9 (19.7) mL/min/1.73 m(2); 41.7% of the participants were women, 36.5% had diabetes, and 30.5% had cardiovascular disease. Office-measured SBP/DBP values were 146 (19)/82 (12) mm Hg; daytime SBP/DBP was 131 (17)/75 (11) mm Hg, and nighttime SBP/DBP was 122 (20)/66 (10) mm Hg. During follow-up (median, 4.2 years), 155 and 103 patients reached the renal and cardiovascular end points, respectively. Compared with a daytime SBP of 126 to 135 mm Hg, patients with an SBP of 136 to 146 mm Hg and those with an SBP higher than 146 mm Hg had an increased adjusted risk of the cardiovascular end point (hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.13-4.41 and 3.07; 1.54-6.09) and renal death (1.72; 1.02-2.89 and 1.85; 1.11-3.08). Nighttime SBPs of 125 to 137 mm Hg and higher than 137 mm Hg also increased the risk of the cardiovascular end point (HR, 2.52; 95% CI, 1.11-5.71 and 4.00; 1.77-9.02) and renal end point (1.87; 1.03-3.43 and 2.54; 1.41-4.57) with respect to the reference SBP value of 106-114 mm Hg. Office measurement of BP did not predict the risk of the renal or cardiovascular end point. Patients who were nondippers and those who were reverse dippers had a greater risk of both end points. CONCLUSION: In chronic kidney disease, ambulatory BP measurement and, in particular, nighttime BP measurement, allows more accurate prediction of renal and cardiovascular risk; office measurement of BP does not predict any outcome. PMID- 21709110 TI - Ambulatory blood pressure measurements in chronic kidney disease: ready to (rock and) roll? PMID- 21709112 TI - Seeding trials and the subordination of science. PMID- 21709111 TI - Study of neurontin: titrate to effect, profile of safety (STEPS) trial: a narrative account of a gabapentin seeding trial. AB - BACKGROUND: Seeding trials, clinical studies conducted by pharmaceutical companies for marketing purposes, have rarely been described in detail. METHODS: We examined all documents relating to the clinical trial Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) produced during the Neurontin marketing, sales practices, and product liability litigation, including company internal and external correspondence, reports, and presentations, as well as depositions elicited in legal proceedings of Harden Manufacturing vs Pfizer and Franklin vs Warner-Lambert, most which were created between 1990 and 2009. Using a systematic search strategy, we identified and reviewed all documents related to the STEPS trial in order to identify key themes related to the trial's conduct and determine the extent of marketing involvement in its planning and implementation. RESULTS: Documents demonstrated that STEPS was a seeding trial posing as a legitimate scientific study. Documents consistently described the trial itself, not trial results, to be a marketing tactic in the company's marketing plans. Documents demonstrated that at least 2 external sources questioned the validity of the study before execution, and that data quality during the study was often compromised. Furthermore, documents described company analyses examining the impact of participating as a STEPS investigator on rates and dosages of gabapentin prescribing, finding a positive association. None of these findings were reported in 2 published articles. CONCLUSION: The STEPS trial was a seeding trial, used to promote gabapentin and increase prescribing among investigators, and marketing was extensively involved in its planning and implementation. PMID- 21709113 TI - Pulmonary artery rupture from invasive hemodynamic monitoring. PMID- 21709114 TI - Pulmonary artery catheterization in the intensive care unit: just numbers floating by? PMID- 21709115 TI - Declines in physician acceptance of medicare and private coverage. PMID- 21709116 TI - Prediction of risk of falling, physical disability, and frailty by rate of decline in grip strength: the women's health and aging study. PMID- 21709117 TI - Low serum cholesterol level and increased ischemic stroke mortality. PMID- 21709118 TI - Number needed to treat: implementation for diets. PMID- 21709119 TI - Dietary fiber prevents both morbidity and mortality from respiratory disease. PMID- 21709120 TI - More health care is not necessarily better health care. PMID- 21709121 TI - Improving the prediction of incident atrial fibrillation. PMID- 21709122 TI - Safety of opioids in older adults. PMID- 21709123 TI - Bleeding associated with antiplatelet agents and warfarin therapy in the emergency department. PMID- 21709124 TI - A painful setback: misinterpretation of analgesic safety in older adults may inadvertently worsen pain care. PMID- 21709125 TI - Do not abandon cultures. PMID- 21709126 TI - Uncertainties in the dose from full-body airport screening. PMID- 21709127 TI - Outcomes and processes at a camp for youth with HIV/AIDS. AB - The impact of HIV/AIDS on the lives of youth with this chronic illness suggests the need for additional support as youth develop. Summer camp can serve as a therapeutic intervention for youth with HIV/AIDS. Using a case study employing observations, focus groups, and interviews, we examined outcomes associated with participation in a camp for youth with HIV/AIDS, and program processes that influenced outcomes. Findings showed that camp played a major developmental role for youth. Three outcomes of camp emerged: (a) forming caring connections (awareness of commonalities, lack of isolation); (b) feeling reprieve and recreation (fun activities, anticipation of and reflection on camp, sense of freedom); and (c) increasing knowledge, attitudes, and skills (conflict management, disclosure, skill learning and education, medication adherence). Processes included formal and informal education, staff-camper interactions, long term relationships, outside-of-camp support, activities, planning for camper needs, accessibility, and freedom from worry. We discuss implications for youth programs. PMID- 21709128 TI - Senses, bodily knowledge, and autoethnography: unbeknown knowledge from an ICU experience. AB - In this article, I discuss the possibilities and limits of bodily knowledge for research. The text is based on my personal experiences as a patient in an intensive care unit (ICU). It seems that through my senses I unconsciously gained knowledge of the time I spent in the ICU. To describe this specific form of bodily knowledge, I introduce the concept of "unbeknown" knowledge, and suggest that autoethnography is a useful method for analyzing this knowledge. In conclusion, I maintain that there is a certain hierarchy for both senses and knowledge and, in spite of the possible vagueness and fuzziness of the concept, unbeknown knowledge both enhances recovery and can be used for research purposes. PMID- 21709129 TI - Health care provider perspectives on informal supporters' involvement in HIV care. AB - Positive social support has been associated with medication adherence and slowed disease progression among people living with HIV. The nature of support within the medical context itself has not been adequately investigated, however. The purpose of our study was to describe HIV health care providers' perspectives on informal supporter-oriented health care and whether and how the involvement of patients' adult informal supporters in health care and health care decision making is helpful or beneficial. We conducted in-depth qualitative interviews with 11 HIV specialists between March and September, 2005. Using directed qualitative content analysis, we first describe the frequency and course of others' involvement and the type of support provided. We then situate these findings within the context of role theory and consider the meaning they have in terms of the negotiated relationships among and between patients, providers, and informal supporters. Finally, we provide research and clinical recommendations based on these findings that are designed to improve patient care. PMID- 21709130 TI - Inhibition of the acetyltransferases p300 and CBP reveals a targetable function for p300 in the survival and invasion pathways of prostate cancer cell lines. AB - Inhibitors of histone deacetylases have been approved for clinical application in cancer treatment. On the other hand, histone acetyltransferase (HAT) inhibitors have been less extensively investigated for their potential use in cancer therapy. In prostate cancer, the HATs and coactivators p300 and CBP are upregulated and may induce transcription of androgen receptor (AR)-responsive genes, even in the absence or presence of low levels of AR. To discover a potential anticancer effect of p300/CBP inhibition, we used two different approaches: (i) downregulation of p300 and CBP by specific short interfering RNA (siRNA) and (ii) chemical inhibition of the acetyltransferase activity by a newly developed small molecule, C646. Knockdown of p300 by specific siRNA, but surprisingly not of CBP, led to an increase of caspase-dependent apoptosis involving both extrinsic and intrinsic cell death pathways in androgen-dependent and castration-resistant prostate cancer cells. Induction of apoptosis was mediated by several pathways including inhibition of AR function and decrease of the nuclear factor kappa B (NF-kappaB) subunit p65. Furthermore, cell invasion was decreased upon p300, but not CBP, depletion and was accompanied by lower matrix metalloproteinase (MMP)-2 and MMP-9 transcriptions. Thus, p300 and CBP have differential roles in the processes of survival and invasion of prostate cancer cells. Induction of apoptosis in prostate cancer cells was confirmed by the use of C646. This was substantiated by a decrease of AR function and downregulation of p65 impairing several NF-kappaB target genes. Taken together, these results suggest that p300 inhibition may be a promising approach for the development of new anticancer therapies. PMID- 21709132 TI - Barriers in the implementation of a physical activity intervention in primary care settings: lessons learned. AB - Barriers encountered in implementing a physical activity intervention in primary health care settings, and ways to address them, are described in this paper. A randomized comparison trial was designed to examine the impact of health care providers' written prescriptions for physical activity, with or without additional physical activity resources, to adult, nonpregnant patients on preventive care or chronic disease monitoring visits. Following abysmal recruitment outcomes, the research protocol was altered to make it more appealing to all the participants, i.e., health care providers, office personnel, and patients. Various barriers--financial, motivational, and executive--to the implementation of health promotion interventions in primary health care settings were experienced and identified. These barriers have been classified by the different participants in the research process, viz., healthcare providers, administrative personnel, researchers, and patients. Some of the barriers identified were lack of time and reimbursement for health promotion activities, and inadequate practice capacity, for health care providers; increased time and labor demands for administrative personnel; constrained access to participants, and limited funding, for researchers; and superseding commitments, and inaccurate comprehension of the research protocol, for patients. Solutions suggested to overcome these barriers include financial support, e.g., funding for researchers, remuneration for health care organization personnel, reimbursement for providers, payment for participants, and free or subsidized postage, and use of health facilities; motivational strategies such as inspirational leadership, and contests within health care organizations; and partnerships, with other expert technical and creative entities, to improve the quality, efficiency, and acceptability of health promotion interventions. PMID- 21709131 TI - Practical suicide-risk management for the busy primary care physician. AB - Suicide is a public health problem and a leading cause of death. The number of people thinking seriously about suicide, making plans, and attempting suicide is surprisingly high. In total, primary care clinicians write more prescriptions for antidepressants than mental health clinicians and see patients more often in the month before their death by suicide. Treatment of depression by primary care physicians is improving, but opportunities remain in addressing suicide-related treatment variables. Collaborative care models for treating depression have the potential both to improve depression outcomes and decrease suicide risk. Alcohol use disorders and anxiety symptoms are important comorbid conditions to identify and treat. Management of suicide risk includes understanding the difference between risk factors and warning signs, developing a suicide risk assessment, and practically managing suicidal crises. PMID- 21709133 TI - Epidemiology of osteoporosis in an isolated Sardinian population by using quantitative ultrasound. AB - This study aimed at estimating the prevalence of osteoporosis and osteopenia in a Sardinian isolated population using hand quantitative ultrasound and at investigating the associated factors. The authors utilized a subset of data from a large population-based epidemiologic survey carried out in the Ogliastra region of Sardinia between 2003 and 2008. The sample consists of 6,326 men and women aged >=30 years, who underwent quantitative ultrasound at the phalanges, bioelectrical impedance, anthropometric measurements, blood tests, and a standardized epidemiologic questionnaire collecting sociodemographic, lifestyle, medical, physiologic, and pharmacologic data. The T-score thresholds for amplitude-dependent speed of sound of -3.2 standard deviations and between -3.2 and -1 standard deviations were used to diagnose osteoporosis and osteopenia, respectively. Prevalence of osteoporosis was 17.0% in women and 5.2% in men. Logistic regression analysis revealed that factors associated with osteoporosis were age, anthropometric and bioimpedance measures, alkaline phosphatase levels, and menopause in women. High education, exercise, and beer consumption seem to be protective factors, whereas a family history of osteoporosis is a risk factor. Results show that osteoporosis in this population is comparable with that found in different countries, suggesting that quantitative ultrasound could be used more widely to detect high-risk individuals for preventing osteoporotic fractures. PMID- 21709134 TI - Association of small artery elasticity with incident cardiovascular disease in older adults: the multi-ethnic study of atherosclerosis. AB - Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45-84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events. PMID- 21709136 TI - Interactions of key charged residues contributing to selective block of neuronal sodium channels by MU-conotoxin KIIIA. AB - Voltage-gated sodium channels are important in initiating and propagating nerve impulses in various tissues, including cardiac muscle, skeletal muscle, the brain, and the peripheral nerves. Hyperexcitability of these channels leads to such disorders as cardiac arrhythmias (Na(v)1.5), myotonias (Na(v)1.4), epilepsies (Na(v)1.2), and pain (Na(v)1.7). Thus, there is strong motivation to identify isoform-specific blockers and the molecular determinants underlying their selectivity among these channels. MU-Conotoxin KIIIA blocks rNa(v)1.2 (IC(50), 5 nM), rNa(v)1.4 (37 nM), and hNa(v)1.7 (97 nM), expressed in mammalian cells, with high affinity and a maximal block at saturating concentrations of 90 to 95%. Mutations of charged residues on both the toxin and channel modulate the maximal block and/or affinity of KIIIA. Two toxin substitutions, K7A and R10A, modulate the maximal block (52-70%). KIIIA-H12A and R14A were the only derivatives tested that altered Na(v) isoform specificity. KIIIA-R14A showed the highest affinity for Na(v)1.7, a channel involved in pain signaling. Wild-type KIIIA has a 2-fold higher affinity for Na(v)1.4 than for Na(v)1.7, which can be attributed to a missing outer vestibule charge in domain III of Na(v)1.7. Reciprocal mutations Na(v)1.4 D1241I and Na(v)1.7 I1410D remove the affinity differences between these two channels for wild-type KIIIA without affecting their affinities for KIIIA-R14A. KIIIA is the first MU-conotoxin to show enhanced activity as pH is lowered, apparently resulting from titration of the free N terminus. Removal of this free amino group reduced the pH sensitivity by 10-fold. Recognition of these molecular determinants of KIIIA block may facilitate further development of subtype-specific, sodium channel blockers to treat hyperexcitability disorders. PMID- 21709138 TI - Cancer of unknown primary: progress in the search for improved and rapid diagnosis leading toward superior patient outcomes. AB - This paper explores the enigma of cancer of unknown primary (CUP) in relation to rapidly improving molecular diagnostic approaches. It is based on the first global collaboration meeting on improving research and clinical outcomes in CUP organized by the CUP Foundation. We review the difficulties of classifying this widely heterogeneous disease and the available diagnostic and pathological evaluative techniques, focusing on molecular profiling. Retrospective studies in CUP patients are shown to provide indirect validation of the accuracy of several platforms of gene expression profiling assays that may identify CUP subsets that respond favorably to active chemotherapy regimens. This review concludes that the recent major improvements in pathologic and molecular diagnostics, coupled with new improved therapies for several specific advanced solid tumors, need to be harmonized with more evidence from clinical-translational trials. All patients with CUP could thus be appropriately managed without the constant uncertainty that has previously severely hampered patient care and optimal outcomes. The longer-term objective is to understand the biology of highly metastatic disease, leading to the development of future global therapeutic programs. Current clinical studies, such as CUP-ONE, will address some of these issues. PMID- 21709135 TI - Association of osteoarthritis with serum levels of the environmental contaminants perfluorooctanoate and perfluorooctane sulfonate in a large Appalachian population. AB - Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are persistent environmental contaminants that affect metabolic regulation, inflammation, and other factors implicated in the pathogenesis of osteoarthritis (OA). However, the link between these compounds and OA remains unknown. In this study, the authors investigated the association of OA with PFOA and PFOS in a population of 49,432 adults from 6 PFOA-contaminated water districts in the mid-Ohio Valley (2005 2006). Participants completed a comprehensive health survey; serum levels of PFOA, PFOS, and a range of other blood markers were also measured. Medical history, including physician diagnosis of osteoarthritis, was assessed via self report. Analyses included adjustment for demographic and lifestyle characteristics, body mass index, and other potential confounders. Reported OA showed a significant positive association with PFOA serum levels (for highest quartile of PFOA vs. lowest, adjusted odds ratio = 1.3, 95% confidence interval: 1.2, 1.5; P-trend = 0.00001) and a significant inverse association with PFOS (for highest quartile vs. lowest, adjusted odds ratio = 0.8, 95% confidence interval: 0.7, 0.9; P-trend = 0.00005). The relation between PFOA and OA was significantly stronger in younger and nonobese adults. Although the cross-sectional nature of this large, population-based study limits causal inference, the observed strong, divergent associations of reported OA with PFOA and PFOS may have important public health and etiologic implications and warrant further investigation. PMID- 21709139 TI - Notch1 and Notch2 have opposite prognostic effects on patients with colorectal cancer. PMID- 21709141 TI - Salivary gland gene expression atlas identifies a new regulator of branching morphogenesis. AB - During organ development, local changes in gene expression govern morphogenesis and cell fate. We have generated a microanatomical atlas of epithelial gene expression of embryonic salivary glands. The mouse submandibular salivary gland first appears as a single mass of epithelial cells surrounded by mesenchyme, and it undergoes rapid branching morphogenesis to form a complex secretory organ with acini connected to an extensive ductal system. Using laser capture microdissection, we collected samples from 14 distinct epithelial locations at embryonic days 12.5, 13.5, 14, and 15, and characterized their gene expression by microarray analysis. These microarray results were evaluated by qPCR of biological replicates and by comparisons of the gene expression dataset with published expression data. Using this gene expression atlas to search for novel regulators of branching morphogenesis, we found a substantial reduction in mRNA levels of GSK3beta at the base of forming clefts. This unexpected finding was confirmed by immunostaining, and inhibition of GSK3beta activity enhanced salivary gland branching. This first microanatomical expression atlas of a developing gland characterizes changes in local gene expression during salivary gland development and differentiation, which should facilitate the identification of key genes involved in tissue morphogenesis. PMID- 21709140 TI - Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. AB - The 12th St Gallen International Breast Cancer Conference (2011) Expert Panel adopted a new approach to the classification of patients for therapeutic purposes based on the recognition of intrinsic biological subtypes within the breast cancer spectrum. For practical purposes, these subtypes may be approximated using clinicopathological rather than gene expression array criteria. In general, systemic therapy recommendations follow the subtype classification. Thus, 'Luminal A' disease generally requires only endocrine therapy, which also forms part of the treatment of the 'Luminal B' subtype. Chemotherapy is considered indicated for most patients with 'Luminal B', 'Human Epidermal growth factor Receptor 2 (HER2) positive', and 'Triple negative (ductal)' disease, with the addition of trastuzumab in 'HER2 positive' disease. Progress was also noted in defining better tolerated local therapies in selected cases without loss of efficacy, such as accelerated radiation therapy and the omission of axillary dissection under defined circumstances. Broad treatment recommendations are presented, recognizing that detailed treatment decisions need to consider disease extent, host factors, patient preferences, and social and economic constraints. PMID- 21709142 TI - Overview of screening: where we are and where we may be headed. AB - This volume of Epidemiologic Reviews continues a discussion about screening within the evidence community that has been going on for many years. From various perspectives, the authors of these reviews consider the benefits and harms of screening for multiple conditions; the balance between benefits and harms (and costs) is often not clear. With few exceptions, the contribution of screening to improving the health of the public is small, yet it has become a popular and growing form of prevention. It may be that we are learning that the magnitude of benefit from screening is less than we hoped, and the harms may be greater than we thought. Perhaps we should not think of screening as our primary prevention strategy but rather use screening to make a real, but limited contribution to population health for a few conditions. We might target screening to smaller subpopulations with the highest potential benefit and the lowest potential harm. The payoff for population health could be greater if we shifted some resources we now devote to screening to developing, testing, and implementing alternative approaches to preventing the important threats to population health. There needs to be a wider discussion about these issues with the public. PMID- 21709143 TI - Organized colorectal cancer screening in integrated health care systems. AB - Colorectal cancer (CRC) is an ideal target for early detection and prevention through screening. Noninvasive screening options are the guaiac fecal occult blood test and the fecal immunochemical test. Organized screening offers the promise of uniformly delivering screening to all members of a population who are eligible and due. Organized screening is defined as an explicit policy with defined age categories, method, and interval for screening in a defined target population with a defined implementation and quality assurance structure, and tracking of cancer in the population. The UK National Health Service; the Ontario, Canada Ministry of Health and Long-Term Care; and the US Veteran's Health Administration have used varied organized approaches to deliver guaiac fecal occult blood test screening to their populations. Kaiser Permanente Northern California began CRC screening in the 1960s, initially using flexible sigmoidoscopy. Implementation of organized fecal immunochemical test outreach was associated with improved Healthcare Effectiveness Data and Information Set CRC screening rates between 2005 and 2010 from 37% to 69% and from 41% to 78% in the commercial and Medicare populations, respectively. Organized fecal immunochemical test screening has been associated with an increase in annually detected CRCs, almost entirely because of increased detection of localized-stage cancers. PMID- 21709144 TI - Interpreting overdiagnosis estimates in population-based mammography screening. AB - Estimates of overdiagnosis in mammography screening range from 1% to 54%. This review explains such variations using gradual implementation of mammography screening in the Netherlands as an example. Breast cancer incidence without screening was predicted with a micro-simulation model. Observed breast cancer incidence (including ductal carcinoma in situ and invasive breast cancer) was modeled and compared with predicted incidence without screening during various phases of screening program implementation. Overdiagnosis was calculated as the difference between the modeled number of breast cancers with and the predicted number of breast cancers without screening. Estimating overdiagnosis annually between 1990 and 2006 illustrated the importance of the time at which overdiagnosis is measured. Overdiagnosis was also calculated using several estimators identified from the literature. The estimated overdiagnosis rate peaked during the implementation phase of screening, at 11.4% of all predicted cancers in women aged 0-100 years in the absence of screening. At steady-state screening, in 2006, this estimate had decreased to 2.8%. When different estimators were used, the overdiagnosis rate in 2006 ranged from 3.6% (screening age or older) to 9.7% (screening age only). The authors concluded that the estimated overdiagnosis rate in 2006 could vary by a factor of 3.5 when different denominators were used. Calculations based on earlier screening program phases may overestimate overdiagnosis by a factor 4. Sufficient follow-up and agreement regarding the chosen estimator are needed to obtain reliable estimates. PMID- 21709146 TI - Enhanced analgesic responses after preferential delivery of morphine and fentanyl to the olfactory epithelium in rats. AB - BACKGROUND: Centrally acting opioid analgesics such as morphine and fentanyl are effective, but their efficacy is often limited by a delayed response or side effects resulting from systemic first pass before reaching the brain and the central nervous system (CNS). It is generally accepted that drugs applied to the nasal cavity can directly access the brain and the CNS, which could provide therapeutic advantages such as rapid onset and lower systemic exposure. The olfactory region of the nasal cavity has been implicated in facilitating this direct nose-to-CNS transfer. If the fraction of opioid administered to the olfactory region could be improved, there could be a larger fraction of drug directly delivered to the CNS, mediating greater therapeutic benefit. METHODS: We have developed a pressurized olfactory delivery (POD) device to consistently and noninvasively deposit a majority of drug on the olfactory region of the nasal cavity in Sprague-Dawley rats. Using the tail-flick latency test and analysis of plasma and CNS tissue drug exposure, we compared distribution and efficacy of the opioids morphine and fentanyl administered to the nasal olfactory region with the POD device or the nasal respiratory region with nose drops or systemically via intraperitoneal injection. RESULTS: Compared with nose drop administration, POD administration of morphine resulted in a significantly higher overall therapeutic effect (area under the curve [over the time course] [AUC](effect)) without a significant increase in plasma drug exposure (AUC(plasma)). POD of morphine resulted in a nose-to-CNS direct transport percentage of 38% to 55%. POD of fentanyl led to a faster (5 vs 10 minutes) and more intense analgesic effect compared with nasal respiratory administration. Unlike intraperitoneal injection or nose drop administration, both morphine and fentanyl given by the POD device to olfactory nasal epithelium exhibited clockwise (plasma) versus effect hysteresis after nasal POD administration, consistent with a direct nose-to-CNS drug transport mechanism. CONCLUSIONS: Deposition of opioids to the olfactory region within the nasal cavity could have a significant impact on drug distribution and pharmacodynamic effect, and thus should be considered in future nasally administered opioid studies. PMID- 21709145 TI - Genetic screening. AB - Current approaches to genetic screening include newborn screening to identify infants who would benefit from early treatment, reproductive genetic screening to assist reproductive decision making, and family history assessment to identify individuals who would benefit from additional prevention measures. Although the traditional goal of screening is to identify early disease or risk in order to implement preventive therapy, genetic screening has always included an atypical element-information relevant to reproductive decisions. New technologies offer increasingly comprehensive identification of genetic conditions and susceptibilities. Tests based on these technologies are generating a different approach to screening that seeks to inform individuals about all of their genetic traits and susceptibilities for purposes that incorporate rapid diagnosis, family planning, and expediting of research, as well as the traditional screening goal of improving prevention. Use of these tests in population screening will increase the challenges already encountered in genetic screening programs, including false positive and ambiguous test results, overdiagnosis, and incidental findings. Whether this approach is desirable requires further empiric research, but it also requires careful deliberation on the part of all concerned, including genomic researchers, clinicians, public health officials, health care payers, and especially those who will be the recipients of this novel screening approach. PMID- 21709147 TI - Special article: Future directions in malignant hyperthermia research and patient care. AB - Malignant hyperthermia (MH) is a complex pharmacogenetic disorder of muscle metabolism. To more closely examine the complexities of MH and other related muscle disorders, the Malignant Hyperthermia Association of the United States (MHAUS) recently sponsored a scientific conference at which an interdisciplinary group of experts gathered to share new information and ideas. In this Special Article, we highlight key concepts and theories presented at the conference along with exciting new trends and challenges in MH research and patient care. PMID- 21709149 TI - IL-15Ralpha of radiation-resistant cells is necessary and sufficient for thymic invariant NKT cell survival and functional maturation. AB - The development of invariant NKT (iNKT) cells depends on the thymus. After positive selection by CD4(+)CD8(+)CD1d(+) cortical thymocytes, iNKT cells proceed from CD44(low)NK1.1(-) (stage 1) to CD44(high)NK1.1(-) (stage 2), and then to CD44(high)NK1.1(+) (stage 3) cells. The programming of cytokine production occurs along the three differentiation stages, whereas the acquisition of NK receptors occurs at stage 3. Stage 3 thymic iNKT cells are specifically reduced in Il15ra( /-) mice. The mechanism underlying this homeostatic deficiency and whether the IL 15 system affects other thymic iNKT cell developmental events remain elusive. In this study, we demonstrate that increased cell death contributed to the reduction of stage 3 cells in Il15ra(-/-) mice, as knockout of Bim restored this population. IL-15-dependent upregulation of Bcl-2 in stage 3 cells affected cell survival, as overexpression of hBcl-2 partially restored stage 3 cells in Il15ra( /-) mice. Moreover, thymic iNKT cells in Il15ra(-/-) mice were impaired in functional maturation, including the acquisition of Ly49 and NKG2 receptors and the programming of cytokine production. Finally, IL-15Ralpha expressed by radiation-resistant cells is necessary and sufficient to support the survival as well as the examined maturation events of thymic iNKT cells. PMID- 21709148 TI - Cytosolic DNA-activated human dendritic cells are potent activators of the adaptive immune response. AB - Recent studies in cell lines and genetically engineered mice have demonstrated that cytosolic dsDNA could activate dendritic cells (DCs) to become effector APCs. Recognition of DNA might be a major factor in antimicrobial immune responses against cytosolic pathogens and also in human autoimmune diseases such as systemic lupus erythematosus. However, the role of cytosolic dsDNA in human DC activation and its effects on effector T and B cells are still elusive. In this study, we demonstrate that intracellular dsDNA is a potent activator of human monocyte-derived DCs as well as primary DCs. Activation by dsDNA depends on NF kappaB activation, partially on the adaptor molecule IFN-promoter stimulator-1 and the novel cytosolic dsDNA receptor IFI16, but not on the previously recognized dsDNA sentinels absent in melanoma 2, DNA-dependent activator of IFN regulatory factor 3, RNA polymerase III, or high-mobility group boxes. More importantly, we report for the first time, to our knowledge, that human dsDNA activated DCs, rather than LPS- or inflammatory cytokine mixture-activated DCs, represent the most potent inducers of naive CD4(+) T cells to promote Th1-type cytokine production and generate CD4(+) and CD8(+) cytotoxic T cells. dsDNA-DCs, but not LPS- or mixture-activated DCs, induce B cells to produce complement fixing IgG1 and IgG3 Abs. We propose that cytosolic dsDNA represents a novel, more effective approach to generate DCs to enhance vaccine effectiveness in reprogramming the adaptive immune system to eradicate infectious agents, autoimmunity, allergy, and cancer. PMID- 21709150 TI - TLR2 ligand induces protection against cerebral ischemia/reperfusion injury via activation of phosphoinositide 3-kinase/Akt signaling. AB - This study examined the effect of TLR2 activation by its specific ligand, Pam3CSK4, on cerebral ischemia/reperfusion (I/R) injury. Mice (n = 8/group) were treated with Pam3CSK4 1 h before cerebral ischemia (60 min), followed by reperfusion (24 h). Pam3CSK4 was also given to the mice (n = 8) 30 min after ischemia. Infarct size was determined by triphenyltetrazolium chloride staining. The morphology of neurons in brain sections was examined by Nissl staining. Pam3CSK4 administration significantly reduced infarct size by 55.9% (p < 0.01) compared with untreated I/R mice. Therapeutic treatment with Pam3CSK4 also significantly reduced infarct size by 55.8%. Morphologic examination showed that there was less neuronal damage in the hippocampus of Pam3CSK4-treated mice compared with untreated cerebral I/R mice. Pam3CSK4 treatment increased the levels of Hsp27, Hsp70, and Bcl2, and decreased Bax levels and NF-kappaB-binding activity in the brain tissues. Administration of Pam3CSK4 significantly increased the levels of phospho-Akt/Akt and phospho-GSK-3beta/GSK-3beta compared with untreated I/R mice. More significantly, either TLR2 deficiency or PI3K inhibition with LY29004 abolished the protection by Pam3CSK4. These data demonstrate that activation of TLR2 by its ligand prevents focal cerebral ischemic damage through a TLR2/PI3K/Akt-dependent mechanism. Of greater significance, these data indicate that therapy with a TLR2-specific agonist during cerebral ischemia is effective in reducing injury. PMID- 21709151 TI - Macrophage-specific expression of urokinase-type plasminogen activator promotes skeletal muscle regeneration. AB - Macrophages (Mp) and the plasminogen system play important roles in tissue repair following injury. We hypothesized that Mp-specific expression of urokinase-type plasminogen activator (uPA) is sufficient for Mp to migrate into damaged muscle and for efficient muscle regeneration. We generated transgenic mice expressing uPA only in Mp, and we assessed the ability of these mice to repair muscle injury. Mp-only uPA expression was sufficient to induce wild-type levels of Mp accumulation, angiogenesis, and new muscle fiber formation. In mice with wild type uPA expression, Mp-specific overexpression further increased Mp accumulation and enhanced muscle fiber regeneration. Furthermore, Mp expression of uPA regulated the level of active hepatocyte growth factor, which is required for muscle fiber regeneration, in damaged muscle. In vitro studies demonstrated that uPA promotes Mp migration through proteolytic and nonproteolytic mechanisms, including proteolytic activation of hepatocyte growth factor. In summary, Mp derived uPA promotes muscle regeneration by inducing Mp migration, angiogenesis, and myogenesis. PMID- 21709153 TI - Activated microglia are less vulnerable to hemin toxicity due to nitric oxide dependent inhibition of JNK and p38 MAPK activation. AB - In intracerebral hemorrhage, microglia become rapidly activated and remove the deposited blood and cellular debris. To survive in a harmful hemorrhagic or posthemorrhagic condition, activated microglia must be equipped with appropriate self-defensive mechanism(s) to resist the toxicity of hemin, a component released from damaged RBCs. In the current study, we found that activation of microglia by pretreatment with LPS markedly reduced their vulnerability to hemin toxicity in vitro. Similarly, intracorpus callosum microinjection of LPS prior to hemin treatment reduced the brain tissue damage caused by hemin and increased microglial density in the penumbra in rats. LPS induced the expressions of inducible NO synthase (iNOS) and heme oxygenase (HO)-1, the rate-limiting enzyme in heme degradation in microglia. The preventive effect by LPS was significantly diminished by an iNOS inhibitor, L-N(6)-(1-iminoethyl)lysine, whereas it was mimicked by a NO donor, diethylamine-NONOate, both suggesting the crucial role of NO in the modulation of hemin-induced toxicity in activated microglia. We further found that NO reduced hemin toxicity via inhibition of hemin-induced activation of JNK and p38 MAPK pathways in microglia. Whereas HO-1 expression in LPS stimulated microglia was markedly blocked by L-N(6)-(1-iminoethyl)lysine, the HO 1 inhibitor, tin protoporphyrin, increased iNOS expression and decreased the susceptibility of LPS-activated microglia to hemin toxicity. The data indicate that the mutual interaction between NO and HO-1 plays a critical role in modulating the adaptive response of activated microglia to hemin toxicity. Better understanding of the survival mechanism of activated microglia may provide a therapeutic strategy to attenuate the devastating intracerebral hemorrhagic injury. PMID- 21709152 TI - TNF receptor 1 mediates dendritic cell maturation and CD8 T cell response through two distinct mechanisms. AB - TNF-alpha and its two receptors (TNFR1 and 2) are known to stimulate dendritic cell (DC) maturation and T cell response. However, the specific receptor and mechanisms involved in vivo are still controversial. In this study, we show that in response to an attenuated mouse hepatitis virus infection, DCs fail to mobilize and up-regulate CD40, CD80, CD86, and MHC class I in TNFR1(-/-) mice as compared with the wild-type and TNFR2(-/-) mice. Correspondingly, virus-specific CD8 T cell response was dramatically diminished in TNFR1(-/-) mice. Adoptive transfer of TNFR1-expressing DCs into TNFR1(-/-) mice rescues CD8 T cell response. Interestingly, adoptive transfer of TNFR1-expressing naive T cells also restores DC mobilization and maturation and endogenous CD8 T cell response. These results show that TNFR1, not TNFR2, mediates TNF-alpha stimulation of DC maturation and T cell response to mouse hepatitis virus in vivo. They also suggest two mechanisms by which TNFR1 mediates TNF-alpha-driven DC maturation, as follows: a direct effect through TNFR1 expressed on immature DCs and an indirect effect through TNFR1 expressed on naive T cells. PMID- 21709154 TI - Novel immunogenic peptides elicit systemic anaphylaxis in mice: implications for peptide vaccines. AB - Peptide-based therapies are showing increasing potential for the development of vaccines and in the treatment of many important diseases. We previously reported two peptide conjugate vaccines that protected mice against pneumococcal disease. During this study, we observed an unexpected phenomenon; several vaccine candidates induced a rapid, fatal anaphylaxis after booster injection of the peptide conjugate. Further investigation indicated the reaction was mediated by the production of peptide-specific IgE and the release of histamine. Notably, among seven peptides tested, all of which bound the same mAb that selected them from a phage library, only four elicited this severe reaction. Sequence alignment analysis of all peptides revealed unique clusters of acidic amino acid residues in the allergenic peptides. Substitution of the acidic amino acid residues, ED, of peptide MP2 with their amine equivalents, QN, eliminated the anaphylactic effects but did not affect the production of peptide-specific IgG. These results have important implications for both the study of allergens and the development of future peptide-based therapies. PMID- 21709155 TI - A critical role for granzymes in antigen cross-presentation through regulating phagocytosis of killed tumor cells. AB - Granzymes A and B (GrAB) are known principally for their role in mediating perforin-dependent death of virus-infected or malignant cells targeted by CTL. In this study, we show that granzymes also play a critical role as inducers of Ag cross-presentation by dendritic cells (DC). This was demonstrated by the markedly reduced priming of naive CD8(+) T cells specific for the model Ag OVA both in vitro and in vivo in response to tumor cells killed in the absence of granzymes. Reduced cross-priming was due to impairment of phagocytosis of tumor cell corpses by CD8alpha(+) DC but not CD8alpha(-) DC, demonstrating the importance of granzymes in inducing the exposure of prophagocytic "eat-me" signals on the dying target cell. Our data reveal a critical and previously unsuspected role for granzymes A and B in dictating immunogenicity by influencing the mode of tumor cell death and indicate that granzymes contribute to the efficient generation of immune effector pathways in addition to their well-known role in apoptosis induction. PMID- 21709157 TI - TpF1 from Treponema pallidum activates inflammasome and promotes the development of regulatory T cells. AB - Human syphilis is a multistage disease, with diverse and wide-ranging manifestations caused by Treponema pallidum. Despite the fact that a cell mediated immune response takes part in the course of syphilis, T. pallidum often manages to evade host immunity and, in untreated individuals, may trigger chronic infection. With this study, we demonstrate for the first time, to our knowledge, that Treponema pallidum induces a regulatory T (Treg) response in patients with secondary syphilis and we found that the miniferritin TpF1, produced by the bacterium, is able to expand this response and promote the production of TGF beta. Accordingly, TpF1 stimulates monocytes to release IL-10 and TGF-beta, the key cytokines in driving Treg cell differentiation. Interestingly, we also found that TpF1 stimulates monocytes to synthesize and release several proinflammatory cytokines, such as TNF-alpha, IL-6, and IL-1beta, the latter following the activation of the multiprotein complex inflammasome. Collectively, these data strongly support a central role for TpF1 both in the inflammation process, which occurs in particular during the early stage of syphilis, and in the long-term persistence of the spirochete within the host by promoting Treg response and TGF beta production. PMID- 21709156 TI - Proapoptotic and antiapoptotic actions of Stat1 versus Stat3 underlie neuroprotective and immunoregulatory functions of IL-11. AB - Current therapies for multiple sclerosis target inflammation but do not directly address oligodendrocyte protection or myelin repair. The gp130 family cytokines ciliary neurotrophic factor, leukemia inhibitory factor, and IL-11 have been identified as oligodendrocyte growth factors, and IL-11 is also strongly immunoregulatory, but their underlying mechanisms of action are incompletely characterized. In this study, we demonstrate that these effects of IL-11 are mediated via differential regulation of apoptosis in oligodendrocytes versus Ag presenting dendritic cells (DCs), and are dependent on lineage-specific activity of the transcription factors Stat1 versus Stat3. Focal demyelinating lesions induced in cerebral cortices of IL-11Ralpha(-/-) mice using stereotactic microinjection of lysolecithin were larger than in controls, and remyelination was delayed. In IL-11Ralpha(-/-) mice, lesions displayed extensive oligodendrocyte loss and axonal transection, and increased infiltration by inflammatory cells including CD11c(+) DCs, CD3(+) lymphocytes, and CD11b(+) phagocytes. In oligodendrocyte progenitor cell (OPC) cultures, IL-11 restricted caspase 9 activation and apoptosis, and it increased myelination in OPC-neuron cocultures. Importantly, siRNA inhibition of Stat1 enhanced the antiapoptotic effects of IL-11 on OPCs, but IL-11 induced apoptosis in the presence of Stat3 silencing. In contrast, IL-11 augmented caspase activation and apoptosis in cultures of CD11c(+) DCs, but not in CD11b(+) or CD3(+) cells. Inhibition of Stat3 exacerbated the proapoptotic effects of IL-11 on DCs, whereas they were ablated in Stat1(-/-) cultures. Collectively, these findings reveal novel mechanisms underlying the actions of a neuroprotective and immunoregulatory member of the gp130 cytokine family, suggesting avenues to enhance oligodendrocyte viability and restrict CNS inflammation in multiple sclerosis. PMID- 21709158 TI - M2 macrophages induced by prostaglandin E2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4+ Th1 cells. AB - Monocytes attracted by tumor-induced chronic inflammation differentiate to APCs, the type of which depends on cues in the local tumor milieu. In this work, we studied the influence of human cervical cancer cells on monocyte differentiation and showed that the majority of cancer cells either hampered monocyte to dendritic cell differentiation or skewed their differentiation toward M2-like macrophages. Blocking studies revealed that M2 differentiation was caused by tumor-produced PGE(2) and IL-6. TGF-beta, IL-10, VEGF, and macrophage colony stimulating factor did not play a role. Notably, these CD14(+)CD163(+) M2 macrophages were also detected in situ. Activation of cancer cell-induced M2-like macrophages by several TLR-agonists revealed that compared with dendritic cells, these M2 macrophages displayed a tolerogenic phenotype reflected by a lower expression of costimulatory molecules, an altered balance in IL-12p70 and IL-10 production, and a poor capacity to stimulate T cell proliferation and IFN-gamma production. Notably, upon cognate interaction with Th1 cells, these tumor-induced M2 macrophages could be switched to activated M1-like macrophages that expressed high levels of costimulatory molecules, produced high amounts of IL-12 and low amounts of IL-10, and acquired the lymphoid homing marker CCR7. The effects of the interaction between M2 macrophages and Th1 cells could partially be mimicked by activation of these APCs via CD40 in the presence of IFN-gamma. Our data on the presence, induction, and plasticity of tumor-induced tolerogenic APCs in cervical cancer suggest that tumor-infiltrated Th1 cells can stimulate a tumor rejecting environment by switching M2 macrophages to classical proinflammatory M1 macrophages. PMID- 21709159 TI - The tuberous sclerosis complex-mammalian target of rapamycin pathway maintains the quiescence and survival of naive T cells. AB - Naive T cells receive stimulation from the positive selecting ligand in the periphery for their survival. This stimulation does not normally lead to overt activation of T cells, as the T cells remain largely quiescent until they receive either antigenic or lymphopenic stimuli. The underlying mechanism responsible for survival and quiescence of the naive T cells remains largely unknown. In this study, we report that T cell-specific deletion of Tsc1, a negative regulator of mammalian target of rapamycin, resulted in both spontaneous losses of quiescence and cellularity, especially within the CD8 subset. The Tsc1-deficient T cells have increased cell proliferation and apoptosis. Tsc1 deletion affects the survival and quiescence of T cells in the absence of antigenic stimulation. Loss of quiescence but not cellularity was inhibited by rapamycin. Our data demonstrate that tuberous sclerosis complex-mammalian target of rapamycin maintains quiescence and survival of T cells. PMID- 21709160 TI - Processing of HEBP1 by cathepsin D gives rise to F2L, the agonist of formyl peptide receptor 3. AB - The peptide F2L was previously characterized as a high-affinity natural agonist for the human formyl peptide receptor (FPR) 3. F2L is an acetylated 21-aa peptide corresponding with the N terminus of the intracellular heme-binding protein 1 (HEBP1). In the current work, we have investigated which proteases were able to generate the F2L peptide from its precursor HEBP1. Structure-function analysis of F2L identified three amino acids, G(3), N(7), and S(8), as the most important for interaction of the peptide with FPR3. We expressed a C-terminally His-tagged form of human HEBP1 in yeast and purified it to homogeneity. The purified protein was used as substrate to identify proteases generating bioactive peptides for FPR3 expressing cells. A conditioned medium from human monocyte-derived macrophages was able to generate bioactivity from HEBP1, and this activity was inhibited by pepstatin A. Cathepsin D was characterized as the protease responsible for HEBP1 processing, and the bioactive product was identified as F2L. We have therefore determined how F2L, the specific agonist of FPR3, is generated from the intracellular protein HEBP1, although it is unknown in which compartment the processing by cathepsin D occurs in vivo. PMID- 21709161 TI - Using machine learning for concept extraction on clinical documents from multiple data sources. AB - OBJECTIVE: Concept extraction is a process to identify phrases referring to concepts of interests in unstructured text. It is a critical component in automated text processing. We investigate the performance of machine learning taggers for clinical concept extraction, particularly the portability of taggers across documents from multiple data sources. METHODS: We used BioTagger-GM to train machine learning taggers, which we originally developed for the detection of gene/protein names in the biology domain. Trained taggers were evaluated using the annotated clinical documents made available in the 2010 i2b2/VA Challenge workshop, consisting of documents from four data sources. RESULTS: As expected, performance of a tagger trained on one data source degraded when evaluated on another source, but the degradation of the performance varied depending on data sources. A tagger trained on multiple data sources was robust, and it achieved an F score as high as 0.890 on one data source. The results also suggest that performance of machine learning taggers is likely to improve if more annotated documents are available for training. CONCLUSION: Our study shows how the performance of machine learning taggers is degraded when they are ported across clinical documents from different sources. The portability of taggers can be enhanced by training on datasets from multiple sources. The study also shows that BioTagger-GM can be easily extended to detect clinical concept mentions with good performance. PMID- 21709162 TI - Design and evaluation of a wireless electronic health records system for field care in mass casualty settings. AB - BACKGROUND: There is growing interest in the use of technology to enhance the tracking and quality of clinical information available for patients in disaster settings. This paper describes the design and evaluation of the Wireless Internet Information System for Medical Response in Disasters (WIISARD). MATERIALS AND METHODS: WIISARD combined advanced networking technology with electronic triage tags that reported victims' position and recorded medical information, with wireless pulse-oximeters that monitored patient vital signs, and a wireless electronic medical record (EMR) for disaster care. The EMR system included WiFi handheld devices with barcode scanners (used by front-line responders) and computer tablets with role-tailored software (used by managers of the triage, treatment, transport and medical communications teams). An additional software system provided situational awareness for the incident commander. The WIISARD system was evaluated in a large-scale simulation exercise designed for training first responders. A randomized trial was overlaid on this exercise with 100 simulated victims, 50 in a control pathway (paper-based), and 50 in completely electronic WIISARD pathway. All patients in the electronic pathway were cared for within the WIISARD system without paper-based workarounds. RESULTS: WIISARD reduced the rate of the missing and/or duplicated patient identifiers (0% vs 47%, p<0.001). The total time of the field was nearly identical (38:20 vs 38:23, IQR 26:53-1:05:32 vs 18:55-57:22). CONCLUSION: Overall, the results of WIISARD show that wireless EMR systems for care of the victims of disasters would be complex to develop but potentially feasible to build and deploy, and likely to improve the quality of information available for the delivery of care during disasters. PMID- 21709163 TI - Text mining for the Vaccine Adverse Event Reporting System: medical text classification using informative feature selection. AB - OBJECTIVE: The US Vaccine Adverse Event Reporting System (VAERS) collects spontaneous reports of adverse events following vaccination. Medical officers review the reports and often apply standardized case definitions, such as those developed by the Brighton Collaboration. Our objective was to demonstrate a multi level text mining approach for automated text classification of VAERS reports that could potentially reduce human workload. DESIGN: We selected 6034 VAERS reports for H1N1 vaccine that were classified by medical officers as potentially positive (N(pos)=237) or negative for anaphylaxis. We created a categorized corpus of text files that included the class label and the symptom text field of each report. A validation set of 1100 labeled text files was also used. Text mining techniques were applied to extract three feature sets for important keywords, low- and high-level patterns. A rule-based classifier processed the high-level feature representation, while several machine learning classifiers were trained for the remaining two feature representations. MEASUREMENTS: Classifiers' performance was evaluated by macro-averaging recall, precision, and F-measure, and Friedman's test; misclassification error rate analysis was also performed. RESULTS: Rule-based classifier, boosted trees, and weighted support vector machines performed well in terms of macro-recall, however at the expense of a higher mean misclassification error rate. The rule-based classifier performed very well in terms of average sensitivity and specificity (79.05% and 94.80%, respectively). CONCLUSION: Our validated results showed the possibility of developing effective medical text classifiers for VAERS reports by combining text mining with informative feature selection; this strategy has the potential to reduce reviewer workload considerably. PMID- 21709164 TI - What makes for an effective stop-smoking service? AB - BACKGROUND: The English network of stop-smoking services (SSSs) is among the best value life-preserving clinical intervention in the UK NHS and is internationally renowned. However, success varies considerably across services, making it important to examine the factors that influence their effectiveness. METHODS: Data from 126,890 treatment episodes in 24 SSSs in 2009-10 were used to assess the association between intervention characteristics and success rates, adjusting for key smoker characteristics. Treatment characteristics examined were setting (eg, primary care, specialist clinics, pharmacy), type of support (eg, group, one to-one) and medication (eg, varenicline, single nicotine replacement therapy (NRT), combination of two or more forms of NRT). The main outcome measure was abstinence from smoking 4 weeks after the target quit date, verified by carbon monoxide concentration in expired air. RESULTS: There was substantial variation in success rates across intervention characteristics after adjusting for smoker characteristics. Single NRT was associated with higher success rates than no medication (OR 1.75, 95% CI 1.39 to 2.22); combination NRT and varenicline were more successful than single NRT (OR 1.42, 95% CI 1.06 to 1.91 and OR 1.78, 95% CI 1.57 to 2.02, respectively); group support was linked to higher success rates than one-to-one support (OR 1.43, 95% CI 1.16 to 1.76); primary care settings were less successful than specialist clinics (OR 0.80, 95% CI 0.66 to 0.99). CONCLUSIONS: Routine clinic data support findings from randomised controlled trials that smokers receiving stop-smoking support from specialist clinics, treatment in groups and varenicline or combination NRT are more likely to succeed than those receiving treatment in primary care, one-to-one and single NRT. All smokers should have access to, and be encouraged to use, the most effective intervention options. PMID- 21709165 TI - Low cognitive ability in early adulthood is associated with reduced lung function in middle age: the Vietnam experience study. AB - OBJECTIVE: Reduced lung function has been linked to poorer cognitive ability later in life. In the present study, the authors examined the converse: whether there was a prospective association between cognitive ability in early adulthood and lung function in middle age. METHODS: Participants were 4256 male Vietnam-era US veterans. Cognitive ability was assessed by the Army General Technical Test on enlistment when participants were, on average, 20 years old (range: 17-34). Data on ethnicity and place of service were extracted from army files. Smoking behaviour, alcohol consumption, basic socio-demographics and whether participants had a physician-diagnosed chronic disease were determined by telephonic interview in middle age in 1985. Forced expiratory volume in one second (FEV(1)) was measured by spirometry at a 3-day medical examination in 1986. Height and weight were also measured. RESULTS: In linear regression models, poor cognitive ability in early adulthood was associated with reduced lung function in middle age, first adjusting for age and height, beta=0.17, p<0.001, then additionally adjusting for circumstantial, socio-demographic, lifestyle and health factors, beta=0.12, p=0.001. The same results were obtained when the analysis was confined to non smokers. CONCLUSION: Not only is lung function related to subsequent cognitive ability, but poor cognitive ability earlier in life is also associated with reduced lung function in middle age. PMID- 21709166 TI - British guidelines on the management of asthma: what's new for 2011? PMID- 21709167 TI - Metabolic surgery and obstructive sleep apnoea: the protective effects of bariatric procedures. AB - The global epidemic of obesity and the worldwide prevalence of obstructive sleep apnoea (OSA) are both increasing. Epidemiological studies reveal an association between obesity, weight gain and OSA. Metabolic or bariatric operations provide sustained weight loss and resolve or improve the symptoms of OSA in the majority of morbidly obese individuals. These operations also modulate the metabolic profile to improve glycaemic control, to decrease cardiovascular risk and obesity related mortality. The beneficial effects of metabolic operations on OSA include mechanical weight-dependent and metabolic weight-independent effects that are achieved through the BRAVE effects: (Bile flow alteration; Reduction of gastric size; Anatomical gut rearrangement and altered flow of nutrients; Vagal manipulation; and Enteric gut hormone modulation). These result in an improvement in insulin resistance, adipokines, cytokines and systemic inflammation. A literature analysis was performed with statistical pooling of available surgical and medical studies to determine whether the weighted mean decrease in body mass index and sleep apnoea severity (measured by the apnoea-hypopnoea index) are larger in metabolic surgical studies than in non-surgical weight loss studies (diet, exercise and medication). However, heterogeneity across available trials, poor follow-up measures and a deficiency in comparative studies between surgical and non-surgical therapy precludes definitive statements regarding the relative benefits of surgical therapy. Further research is required to quantify robustly the effects and mechanisms of sleep apnoea resolution by metabolic surgery, which may reveal novel non-surgical treatments or enhanced surgical strategies in the management of this multisystem sleep disorder. PMID- 21709168 TI - Identification of quantitative trait loci for murine autoimmune pancreatitis. AB - BACKGROUND AND AIMS: Autoimmune pancreatitis (AIP) represents a rare but clinically relevant cause of pancreatic inflammation. Using MRL/Mp mice as a model of spontaneous AIP, the genetic basis of the disease was studied. METHODS: To identify quantitative trait loci (QTL) of AIP, an advanced intercross line was studied, originating from MRL/MpJ parental mice and the following three mouse strains: Cast (healthy controls), BXD2 (susceptible to collagen induced arthritis), and NZM (a model of lupus erythematosus). This concept was chosen to identify both general autoimmune disease associated loci and AIP specific QTL. Therefore, generation G4 of outbred intercross mice was characterised phenotypically by scoring histopathological changes of the pancreas and genotyped with single nucleotide polymorphism (SNP) arrays. Data were analysed with the R implementation of HAPPY. RESULTS: Five QTLs, correlating with the severity of AIP, were identified. Two of them mapped to chromosome 4 and one to chromosomes 2, 5, and 6, respectively. The QTL on chromosome 6 displays the highest LOD score (5.4) and contains the C-type lectin domain family 4 member a2 in its peak region, which encodes a receptor protein of dendritic cells that has previously been implicated in autoimmune diseases such as Sjogren's syndrome. AIP candidate genes of other QTL's include heterogeneous nuclear ribonucleoprotein A3; nuclear factor, erythroid derived 2, like 2; Sjogren syndrome antigen B; and ubiquitin protein ligase E3 component n-recognin 3. CONCLUSIONS: This study has identified QTLs and putative candidate genes of murine AIP. Their functional role and relevance to human AIP will be studied further. PMID- 21709169 TI - A RaDiCAL approach to gene discovery. PMID- 21709170 TI - Mortality and cancer incidence among British agricultural pesticide users. AB - BACKGROUND: Although the acute effects of pesticides in humans are well known, uncertainty still exists about the health effects of chronic low-level exposure to pesticides. AIMS: To compare mortality and cancer incidence experienced by a cohort of British pesticide users to that of the Great Britain (GB) population. METHODS: The Pesticide Users Health Study (PUHS) comprises users of agricultural pesticides who have Certificates of Competence under the Control of Pesticides Regulations 1986. Participants were followed up between 1987 and 2004 (cancer incidence) or 2005 (mortality). Standardized mortality ratios (SMRs) and Standardized incidence ratios (SIRs) were estimated for outcomes of interest identified from the literature. RESULTS: Altogether, 62,960 pesticide users were followed up for 829,709 person-years (to 31 December 2005). Most participants were male (94%) and based in England (86%). All-cause mortality was lower for both men [SMR 0.58, 95% confidence interval (CI) 0.55-0.60] and women (SMR 0.71, 95% CI 0.52-0.98) compared to the GB population. Mortality and incidence were below those expected for all cancers combined among men (SMR 0.71, 95% CI 0.66 0.77; SIR 0.85, 95% CI 0.81-0.90), particularly for cancers of the lip, oral cavity and pharynx, digestive organs and respiratory system. The incidence of testicular cancer, non-melanoma skin cancer and multiple myeloma were above expected. Mortality from injury by machinery was significantly above expected for men (SMR 4.21, 95% CI 2.11-8.42). CONCLUSIONS: This study suggests that pesticide users in the PUHS are generally healthier than the national population but may have excesses of non-melanoma skin cancer, testicular cancer and multiple myeloma. PMID- 21709171 TI - Absenteeism following a workplace intervention for older food industry workers. AB - BACKGROUND: The effects of workplace interventions on sickness absence are poorly understood, in particular in ageing workers. AIMS: To analyse the effects of a senior programme on sickness absence among blue-collar food industry workers of a food company in Finland. METHODS: We followed up 129 employees aged 55 years or older, who participated in a senior programme (intervention group), and 229 employees of the same age from the same company who did not participate (control group). Total sickness absence days and spells of 1-3, 4-7, 8-21 and >21 days were recorded for the members of the intervention group from the year before joining the programme and for the control group starting at age 54 years. Both groups were followed for up to 6 years. RESULTS: The median number of sickness absence days per person-year increased significantly from baseline in both groups during the follow-up. Compared with the control group, the intervention group had increased risk for 1-3 days spells [rate ratio 1.34 (1.21-1.48)] and 4-7 days spells [rate ratio 1.23 (1.07-1.41)], but the risk for >21 days spells was decreased [rate ratio 0.68 (0.53-0.88)] after participation in the senior programme. CONCLUSIONS: A programme to enhance individual work well-being in ageing workers may increase short-term but reduce long-term sickness absence. PMID- 21709172 TI - The cytokinin receptors of Arabidopsis are located mainly to the endoplasmic reticulum. AB - The plant hormone cytokinin is perceived by membrane-located sensor histidine kinases. Arabidopsis (Arabidopsis thaliana) possesses three cytokinin receptors: ARABIDOPSIS HISTIDINE KINASE2 (AHK2), AHK3, and CYTOKININ RESPONSE1/AHK4. The current model predicts perception of the cytokinin signal at the plasma membrane. However, cytokinin-binding studies with membrane fractions separated by two-phase partitioning showed that in the wild type, as well as in mutants retaining only single cytokinin receptors, the major part of specific cytokinin binding was associated with endomembranes. Leaf epidermal cells of tobacco (Nicotiana benthamiana) expressing receptor-green fluorescent protein fusion proteins and bimolecular fluorescence complementation analysis showed strong fluorescence of the endoplasmic reticulum (ER) network for all three receptors. Furthermore, separation of the microsomal fraction of Arabidopsis plants expressing Myc-tagged AHK2 and AHK3 receptors by sucrose gradient centrifugation followed by immunoblotting displayed the Mg2+-dependent density shift typical of ER membrane proteins. Cytokinin-binding assays, fluorescent fusion proteins, and biochemical fractionation all showed that the large majority of cytokinin receptors are localized to the ER, suggesting a central role of this compartment in cytokinin signaling. A modified model for cytokinin signaling is proposed. PMID- 21709174 TI - Reexamining the evidence for a pitch-sensitive region: a human fMRI study using iterated ripple noise. AB - Human neuroimaging studies have identified a region of auditory cortex, lateral Heschl's gyrus (HG), that shows a greater response to iterated ripple noise (IRN) than to a Gaussian noise control. Based in part on results using IRN as a pitch evoking stimulus, it has been argued that lateral HG is a general "pitch center." However, IRN contains slowly varying spectrotemporal modulations, unrelated to pitch, that are not found in the control stimulus. Hence, it is possible that the cortical response to IRN is driven in part by these modulations. The current study reports the first attempt to control for these modulations. This was achieved using a novel type of stimulus that was generated by processing IRN to remove the fine temporal structure (and thus the pitch) but leave the slowly varying modulations. This "no-pitch IRN" stimulus is referred to as IRNo. Results showed a widespread response to the spectrotemporal modulations across auditory cortex. When IRN was contrasted with IRNo rather than with Gaussian noise, the apparent effect of pitch was no longer statistically significant. Our findings raise the possibility that a cortical response unrelated to pitch could previously have been errantly attributed to pitch coding. PMID- 21709173 TI - Cognitive and neural effects of semantic encoding strategy training in older adults. AB - Prior research suggests that older adults are less likely than young adults to use effective learning strategies during intentional encoding. This functional magnetic resonance imaging (fMRI) study investigated whether training older adults to use semantic encoding strategies can increase their self-initiated use of these strategies and improve their recognition memory. The effects of training on older adults' brain activity during intentional encoding were also examined. Training increased older adults' self-initiated semantic encoding strategy use and eliminated pretraining age differences in recognition memory following intentional encoding. Training also increased older adults' brain activity in the medial superior frontal gyrus, right precentral gyrus, and left caudate during intentional encoding. In addition, older adults' training-related changes in recognition memory were strongly correlated with training-related changes in brain activity in prefrontal and left lateral temporal regions associated with semantic processing and self-initiated verbal encoding strategy use in young adults. These neuroimaging results demonstrate that semantic encoding strategy training can alter older adults' brain activity patterns during intentional encoding and suggest that young and older adults may use the same network of brain regions to support self-initiated use of verbal encoding strategies. PMID- 21709175 TI - Direction-sensitive codes for observed head turns in human superior temporal sulcus. AB - Humans and other primates are adept at using the direction of another's gaze or head turn to infer where that individual is attending. Research in macaque neurophysiology suggests that anterior superior temporal sulcus (STS) contains a direction-sensitive code for such social attention cues. By contrast, most human functional Magnetic resonance imaging (fMRI) studies report that posterior STS is responsive to social attention cues. It is unclear whether this functional discrepancy is caused by a species difference or by experimental design differences. Furthermore, social attention cues are dynamic in naturalistic social interaction, but most studies to date have been restricted to static displays. In order to address these issues, we used multivariate pattern analysis of fMRI data to test whether response patterns in human right STS distinguish between leftward and rightward dynamic head turns. Such head turn discrimination was observed in right anterior STS/superior temporal gyrus (STG). Response patterns in this region were also significantly more discriminable for head turn direction than for rotation direction in physically matched ellipsoid control stimuli. Our findings suggest a role for right anterior STS/STG in coding the direction of motion in dynamic social attention cues. PMID- 21709177 TI - Local computation of decision-relevant net sensory evidence in parietal cortex. AB - To investigate the contribution of parietal cortex to perceptual decisions, we trained monkeys on a perceptual decision task that allowed simultaneous experimental control over how much sensory evidence was provided for each of 3 possible alternative choices and recorded single unit activity and local field potentials (LFPs) from the lateral intraparietal area (LIP). While both the behavior and the spiking activity were largely determined by the difference between how much supporting sensory evidence was provided for a particular choice (pro evidence) and how much sensory evidence was provided for the other alternatives (anti evidence), the LFP reflected roughly the sum of these 2 components. Furthermore, the firing rates showed an earlier influence of the anti evidence than the pro evidence. These observations indicate that LIP does not simply receive already precomputed decision signals but that it plays an active role in computing the decision-relevant net sensory evidence and that this local computation is reflected in the LFP. The results further demonstrate that the competition between the different alternatives cannot solely be mediated by lateral or feedback inhibition, as proposed by a major class of decision models but that feedforward inhibition makes an important contribution. PMID- 21709176 TI - Visual motion responses in the posterior cingulate sulcus: a comparison to V5/MT and MST. AB - Motion processing regions apart from V5+/MT+ are still relatively poorly understood. Here, we used functional magnetic resonance imaging to perform a detailed functional analysis of the recently described cingulate sulcus visual area (CSv) in the dorsal posterior cingulate cortex. We used distinct types of visual motion stimuli to compare CSv with V5/MT and MST, including a visual pursuit paradigm. Both V5/MT and MST preferred 3D flow over 2D planar motion, responded less yet substantially to random motion, had a strong preference for contralateral versus ipsilateral stimulation, and responded nearly equally to contralateral and to full-field stimuli. In contrast, CSv had a pronounced preference to 2D planar motion over 3D flow, did not respond to random motion, had a weak and nonsignificant lateralization that was significantly smaller than that of MST, and strongly preferred full-field over contralateral stimuli. In addition, CSv had a better capability to integrate eye movements with retinal motion compared with V5/MT and MST. CSv thus differs from V5+/MT+ by its unique preference to full-field, coherent, and planar motion cues. These results place CSv in a good position to process visual cues related to self-induced motion, in particular those associated to eye or lateral head movements. PMID- 21709178 TI - Interhemispheric differences in auditory processing revealed by fMRI in awake rhesus monkeys. AB - Lesion studies in monkeys have suggested a modest left hemisphere dominance for processing species-specific vocalizations, the neural basis of which has thus far remained unclear. We used contrast agent-enhanced functional magnetic resonance imaging to map the regions of the rhesus monkey brain involved in processing conspecific vocalizations as well as human speech and emotional sounds. Control conditions included scrambled versions of all 3 stimuli and silence. Compared with silence, all stimuli activated widespread parts of the auditory cortex and subcortical auditory structures with a right hemispheric bias at the level of the auditory core. However, comparing intact with scrambled sounds revealed a leftward bias in the auditory belt and the parabelt. The left-sided dominance was stronger and more robust for human speech than for rhesus vocalizations and hence does not reflect conspecific call selectivity but rather the processing of complex spectrotemporal patterns, such as those present in human speech and in some of the rhesus monkey vocalizations. This was confirmed by regressing brain activity with a model-derived parameter indexing the prevalence of such patterns. Our results indicate that processing of vocal sounds in the lateral belt and parabelt is asymmetric in monkeys, as predicted from lesion studies. PMID- 21709179 TI - Dynamic changes in the medial temporal lobe during incidental learning of object location associations. AB - The role of the medial temporal lobe (MTL) in associative memory encoding has been the focus of many memory experiments. However, there has been surprisingly little investigation of whether the contributions of different MTL subregions (amygdala, hippocampus [HPC], parahippocampal [PHc], perirhinal cortex [PRc], and temporal polar cortex [TPc]) shift across multiple presentations during associative encoding. We examined this issue using event-related functional magnetic resonance imaging and a multivoxel pattern classification analysis. Subjects performed a visual search task, becoming faster with practice to locate objects whose locations were held constant across trials. The classification analysis implicated right HPC and amygdala early in the task when the speed-up from trial to trial was greatest. The same analysis implicated right PRc and TPc late in learning when speed-up was minimal. These results suggest that associative encoding relies on complex patterns of neural activity in MTL that cannot be expressed by simple increases or decreases of blood oxygenation level dependent signal during learning. Involvement of MTL subregions during encoding of object-location associations depends on the nature of the learning phase. Right HPC and amygdala support active integration of object and location information, while right PRc and TPc are involved when object and spatial representations become unitized into a single representation. PMID- 21709180 TI - Golgi glycosylation and human inherited diseases. AB - The Golgi factory receives custom glycosylates and dispatches its cargo to the correct cellular locations. The process requires importing donor substrates, moving the cargo, and recycling machinery. Correctly glycosylated cargo reflects the Golgi's quality and efficiency. Genetic disorders in the specific equipment (enzymes), donors (nucleotide sugar transporters), or equipment recycling/reorganization components (COG, SEC, golgins) can all affect glycosylation. Dozens of human glycosylation disorders fit these categories. Many other genes, with or without familiar names, well-annotated pedigrees, or likely homologies will join the ranks of glycosylation disorders. Their broad and unpredictable case-by-case phenotypes cross the traditional medical specialty boundaries. The gene functions in patients may be elusive, but their common feature may include altered glycosylation that provide clues to Golgi function. This article focuses on a group of human disorders that affect protein or lipid glycosylation. Readers may find it useful to generalize some of these patient based, translational observations to their own research. PMID- 21709183 TI - Understanding health care disparities in the US territories. PMID- 21709182 TI - Calcium signaling in smooth muscle. AB - Changes in intracellular Ca(2+) are central to the function of smooth muscle, which lines the walls of all hollow organs. These changes take a variety of forms, from sustained, cell-wide increases to temporally varying, localized changes. The nature of the Ca(2+) signal is a reflection of the source of Ca(2+) (extracellular or intracellular) and the molecular entity responsible for generating it. Depending on the specific channel involved and the detection technology employed, extracellular Ca(2+) entry may be detected optically as graded elevations in intracellular Ca(2+), junctional Ca(2+) transients, Ca(2+) flashes, or Ca(2+) sparklets, whereas release of Ca(2+) from intracellular stores may manifest as Ca(2+) sparks, Ca(2+) puffs, or Ca(2+) waves. These diverse Ca(2+) signals collectively regulate a variety of functions. Some functions, such as contractility, are unique to smooth muscle; others are common to other excitable cells (e.g., modulation of membrane potential) and nonexcitable cells (e.g., regulation of gene expression). PMID- 21709181 TI - Developmental control of oocyte maturation and egg activation in metazoan models. AB - Production of functional eggs requires meiosis to be coordinated with developmental signals. Oocytes arrest in prophase I to permit oocyte differentiation, and in most animals, a second meiotic arrest links completion of meiosis to fertilization. Comparison of oocyte maturation and egg activation between mammals, Caenorhabditis elegans, and Drosophila reveal conserved signaling pathways and regulatory mechanisms as well as unique adaptations for reproductive strategies. Recent studies in mammals and C. elegans show the role of signaling between surrounding somatic cells and the oocyte in maintaining the prophase I arrest and controlling maturation. Proteins that regulate levels of active Cdk1/cyclin B during prophase I arrest have been identified in Drosophila. Protein kinases play crucial roles in the transition from meiosis in the oocyte to mitotic embryonic divisions in C. elegans and Drosophila. Here we will contrast the regulation of key meiotic events in oocytes. PMID- 21709184 TI - Quality of care in the US territories. AB - BACKGROUND: Health care quality in the US territories is poorly characterized. We used process measures to compare the performance of hospitals in the US territories and in the US states. METHODS: Our sample included nonfederal hospitals located in the United States and its territories discharging Medicare fee-for-service (FFS) patients with a principal discharge diagnosis of acute myocardial infarction (AMI), heart failure (HF), or pneumonia (PNE) (July 2005 June 2008). We compared risk-standardized 30-day mortality and readmission rates between territorial and stateside hospitals, adjusting for performance on core process measures and hospital characteristics. RESULTS: In 57 territorial hospitals and 4799 stateside hospitals, hospital mean 30-day risk-standardized mortality rates were significantly higher in the US territories (P<.001) for AMI (18.8% vs 16.0%), HF (12.3% vs 10.8%), and PNE (14.9% vs 11.4%). Hospital mean 30 day risk-standardized readmission rates (RSRRs) were also significantly higher in the US territories for AMI (20.6% vs 19.8%; P=.04), and PNE (19.4% vs 18.4%; P=.01) but was not significant for HF (25.5% vs 24.5%; P=.07). The higher risk standardized mortality rates in the US territories remained statistically significant after adjusting for hospital characteristics and core process measure performance. Hospitals in the US territories had lower performance on all core process measures (P<.05). CONCLUSIONS: Compared with hospitals in the US states, hospitals in the US territories have significantly higher 30-day mortality rates and lower performance on every core process measure for patients discharged after AMI, HF, and PNE. Eliminating the substantial quality gap in the US territories should be a national priority. PMID- 21709185 TI - Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression. AB - PURPOSE: This phase II trial was designed to assess the efficacy and safety of cetuximab, gemcitabine, and oxaliplatin followed by cetuximab, capecitabine, and radiation therapy in locally advanced pancreatic cancer (LAPC). PATIENTS AND METHODS: Treatment-naive eligible patients (n = 69) received intravenous gemcitabine (1,000 mg/m(2)) and oxaliplatin (100 mg/m(2)) every 2 weeks for four doses, followed by radiation (50.4 Gy to the gross tumor only) with concurrent capecitabine (825 mg/m(2) twice daily on radiation treatment days). Cetuximab (500 mg/m(2)) was started on day 1 of chemotherapy and was continued every 2 weeks during chemotherapy and chemoradiotherapy. Diagnostic cytology specimens were immunostained for Smad4(Dpc4) expression. RESULTS: Median overall survival time was 19.2 months (95% CI, 14.2 to 24.2 months), and 1-year, 2-year, and 4 year actuarial overall survival rates were 66.0%, 25.02%, and 11.3%, respectively. Acneiform rash correlated with improved survival (P = .001), but initial CA19-9, borderline resectable initial stage, and surgical resection (n = 7) did not. The 1-year and 2-year radiographic local progression rates were 22.8% and 61.0%, respectively. The worst acute toxic effects were GI toxicity (32% and 10% for grades 2 and 3, respectively); fatigue (26% and 6% for grades 2 and 3, respectively); sensory neuropathy (9% and 1% for grades 2 and 3, respectively); and acneiform rash (54% and 3% for grades 2 and 3, respectively). Smad4(Dpc4) expression correlated with a local rather than a distant dominant pattern of disease progression (P = .016). CONCLUSION: This regimen appears effective and has acceptable toxicity. The primary end point (1-year overall survival rate > 45%) was met, with encouraging survival duration. Smad4(Dpc4) immunostaining correlated with the pattern of disease progression. Prospective validation of Smad4(Dpc4) expression in cytology specimens as a predictive biomarker is warranted and may lead to personalized treatment strategies for patients with localized pancreatic cancer. PMID- 21709186 TI - Relapsed or refractory anaplastic large-cell lymphoma in children and adolescents after Berlin-Frankfurt-Muenster (BFM)-type first-line therapy: a BFM-group study. AB - PURPOSE: To evaluate risk factors for outcome in children and adolescents with relapse of anaplastic large-cell lymphoma (ALCL) after comparable first-line therapy. PATIENTS AND METHODS: We analyzed a population-based cohort of 74 children with relapsed ALCL after Berlin-Frankfurt-Muenster-type first-line therapy between April 1990 and December 2003. The recommended salvage strategy was reinduction chemotherapy followed by autologous hematopoietic stem-cell transplantation (SCT). RESULTS: With a median follow-up time of 8.4 years (range, 4.5 to 16.4 years), the 5-year overall survival (OS) rate after first relapse was 57% +/- 6%. Survival correlated with time of relapse and clinically advanced dissemination. Five-year OS of 16 patients who experienced progression during first-line therapy was 25% +/- 11% compared with 66% +/- 6% for 58 patients with a later relapse (P = .002). Five-year OS of 11 patients with bone marrow or CNS involvement was 27% +/- 13% compared with 62% +/- 6% for 63 patients without involvement (P = .001). Five-year event-free survival (EFS) and OS of 39 children who received the recommended autologous SCT were 59% +/- 8% and 77% +/- 7%, respectively. EFS after autologous SCT was significantly associated with time to relapse (progression: n = 3; EFS, 0; later relapse: n = 36; EFS, 64% +/- 8%; P = .014) and CD3 expression (CD3 negative: n = 25; EFS, 72% +/- 9%; CD3 positive: n = 11; EFS, 18% +/- 12%; P < .001), but not with site of relapse, conditioning regimen, or graft manipulation. No relapses occurred among 10 patients with relapsed CD3-positive ALCL treated with allogeneic SCT. CONCLUSION: Reinduction chemotherapy followed by autologous SCT proved feasible and efficacious for patients with a first relapse of CD3-negative ALCL after first-line therapy. Patients with progression during first-line therapy or relapsed CD3-positive ALCL may benefit from allogeneic SCT. PMID- 21709187 TI - Spinal instability neoplastic score: an analysis of reliability and validity from the spine oncology study group. AB - PURPOSE: Standardized indications for treatment of tumor-related spinal instability are hampered by the lack of a valid and reliable classification system. The objective of this study was to determine the interobserver reliability, intraobserver reliability, and predictive validity of the Spinal Instability Neoplastic Score (SINS). METHODS: Clinical and radiographic data from 30 patients with spinal tumors were classified as stable, potentially unstable, and unstable by members of the Spine Oncology Study Group. The median category for each patient case (consensus opinion) was used as the gold standard for predictive validity testing. On two occasions at least 6 weeks apart, each rater also scored each patient using SINS. Each total score was converted into a three category data field, with 0 to 6 as stable, 7 to 12 as potentially unstable, and 13 to 18 as unstable. RESULTS: The kappa statistics for interobserver reliability were 0.790, 0.841, 0.244, 0.456, 0.462, and 0.492 for the fields of location, pain, bone quality, alignment, vertebral body collapse, and posterolateral involvement, respectively. The kappa statistics for intraobserver reliability were 0.806, 0.859, 0.528, 0.614, 0.590, and 0.662 for the same respective fields. Intraclass correlation coefficients for inter- and intraobserver reliability of total SINS score were 0.846 (95% CI, 0.773 to 0.911) and 0.886 (95% CI, 0.868 to 0.902), respectively. The kappa statistic for predictive validity was 0.712 (95% CI, 0.676 to 0.766). CONCLUSION: SINS demonstrated near-perfect inter- and intraobserver reliability in determining three clinically relevant categories of stability. The sensitivity and specificity of SINS for potentially unstable or unstable lesions were 95.7% and 79.5%, respectively. PMID- 21709188 TI - Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. AB - PURPOSE: Secondary somatic BRCA1/2 mutations may restore BRCA1/2 protein in hereditary ovarian carcinomas. In cell lines, BRCA2 restoration mediates resistance to platinum chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. We assessed primary and recurrent BRCA1/2-mutated ovarian carcinomas to define the frequency of secondary mutations and correlate these changes with clinical outcomes. METHODS: Neoplastic cells were isolated with laser capture microdissection, and DNA was sequenced at the site of the known germline BRCA1/2 mutation. When secondary mutations were found that restored wild-type sequence, haplotyping was performed using single nucleotide polymorphisms in tumor and paired lymphocyte DNA to rule out retention of the wild-type allele. RESULTS: There were 64 primary and 46 recurrent ovarian carcinomas assessed. Thirteen (28.3%) of 46 (95% CI, 17.3% to 42.6%) recurrent carcinomas had a secondary mutation compared with two (3.1%) of 64 (95% CI, 1.0% to 10.7%) primary carcinomas (P = .0003, Fisher's exact test). Twelve (46.2%) of 26 (95% CI, 28.7% to 64.7%) platinum-resistant recurrences had secondary mutations restoring BRCA1/2, compared with one (5.3%) of 19 (95% CI, 1.2% to 24.8%) platinum sensitive recurrences (P = .003, Fisher's exact test). Six (66.7%) of nine (95% CI, 34.8% to 87.8%) women with prior breast carcinoma had a recurrent carcinoma with a secondary mutation, compared with six (17.1%) of 35 (95% CI, 8.2% to 32.8%) with no history of breast carcinoma (P = .007, Fisher's exact test). CONCLUSION: Secondary somatic mutations that restore BRCA1/2 in carcinomas from women with germline BRCA1/2 mutations predict resistance to platinum chemotherapy and may also predict resistance to PARP inhibitors. These mutations were detectable only in ovarian carcinomas of women whom have had previous chemotherapy, either for ovarian or breast carcinoma. PMID- 21709189 TI - Occurrence of multiple subsequent neoplasms in long-term survivors of childhood cancer: a report from the childhood cancer survivor study. AB - PURPOSE: Childhood cancer survivors experience an increased incidence of subsequent neoplasms (SNs). Those surviving the first SN (SN1) remain at risk to develop multiple SNs. Because SNs are a common cause of late morbidity and mortality, characterization of rates of multiple SNs is needed. PATIENTS AND METHODS: In a total of 14,358 5-year survivors of childhood cancer diagnosed between 1970 and 1986, analyses were carried out among 1,382 survivors with an SN1. Cumulative incidence of second subsequent neoplasm (SN2), either malignant or benign, was calculated. RESULTS: A total of 1,382 survivors (9.6%) developed SN1, of whom 386 (27.9%) developed SN2. Of those with SN2, 153 (39.6%) developed more than two SNs. Cumulative incidence of SN2 was 46.9% (95% CI, 41.6% to 52.2%) at 20 years after SN1. The cumulative incidence of SN2 among radiation-exposed survivors was 41.3% (95% CI, 37.2% to 45.4%) at 15 years compared with 25.7% (95% CI, 16.5% to 34.9%) for those not treated with radiation. Radiation-exposed survivors who developed an SN1 of nonmelanoma skin cancer (NMSC) had a cumulative incidence of subsequent malignant neoplasm (SMN; ie, malignancies excluding NMSC) of 20.3% (95% CI, 13.0% to 27.6%) at 15 years compared with only 10.7% (95% CI, 7.2% to 14.2%) for those who were exposed to radiation and whose SN1 was an invasive SMN (excluding NMSC). CONCLUSION: Multiple SNs are common among aging survivors of childhood cancer. SN1 of NMSC identifies a population at high risk for invasive SMN. Survivors not exposed to radiation who develop multiple SNs represent a population of interest for studying genetic susceptibility to neoplasia. PMID- 21709190 TI - Role of American Society of Clinical Oncology in low- and middle-income countries. AB - The American Society of Clinical Oncology (ASCO) is a global community of health care professionals whose stated purpose is to "make a world of difference" by improving cancer care around the world. Unfortunately, cancer survival rates vary significantly among countries with differing financial and infrastructural resources. Because ASCO is a professional oncology society committed to conquering cancer through research, education, prevention, and delivery of high quality patient care, it is ideally suited to address this issue. ASCO could bring together oncology professionals and other necessary stakeholders from around the world to improve cancer care and lessen suffering for patients worldwide. As part of the ongoing commitment of ASCO to the future of cancer care, the Leadership Development Program was created to foster the leadership skills of early and midcareer oncologists and provide these participants with a working knowledge of the depth and breadth of the organization. As participants in the inaugural class of the ASCO Leadership Development Program, we were charged with investigating how ASCO might favorably affect cancer prevention and treatment in resource-poor countries in a cost-effective, scalable, and sustainable fashion. ASCO can significantly influence cancer care in low- and middle-income countries through a comprehensive approach that promotes cancer awareness and education, improves clinical practice by identifying and removing barriers to delivery of quality cancer care, and fosters innovation to initiate novel solutions to complex problems. PMID- 21709191 TI - Complete resolution of life-threatening bleomycin-induced pneumonitis after treatment with imatinib mesylate in a patient with Hodgkin's lymphoma: hope for severe chemotherapy-induced toxicity? PMID- 21709192 TI - Prognostic validity of a novel American Joint Committee on Cancer Staging Classification for pancreatic neuroendocrine tumors. AB - PURPOSE: The American Joint Committee on Cancer (AJCC) staging manual (seventh edition) has introduced its first TNM staging classification for pancreatic neuroendocrine tumors (NETs) derived from the staging algorithm for exocrine pancreatic adenocarcinomas. This classification has not yet been validated. METHODS: Patients with pancreatic NETs treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I to IV) based on the new AJCC classification. Kaplan-Meier analyses for overall survival (OS) were performed based on age, race, histologic grade, incidental diagnosis, and TNM staging (European Neuroendocrine Tumors Society [ENETS] v AJCC) using log-rank tests. Survival time was measured from time of initial diagnosis to date of last contact or date of death. Multivariate modeling was performed using Cox proportional hazards regression. Weighted Cohen's kappa coefficient was computed to evaluate the agreement of ENETS and AJCC classifications. RESULTS: We identified 425 patients with pancreatic NETs. On the basis of histopathologic grade, 5-year survival rates for low-, intermediate-, and high-grade tumors were 75%, 62%, and 7%, respectively (P < .001). When using the ENETS classification, 5 year OS rates for stages I, II, III, and IV were 100%, 88%, 85%, and 57%, respectively (P < .001). Subsequently, using the AJCC classification, 5-year OS rates for stages I, II, III, and IV were 92%, 84%, 81%, and 57%, respectively (P < .001). Both the novel AJCC classification and the ENETS classification were highly prognostic for survival. CONCLUSION: The AJCC TNM classification for pancreatic NETs is prognostic for OS and can be adopted in clinical practice. PMID- 21709193 TI - Immunotherapy for glioblastoma: the devil is in the details. PMID- 21709194 TI - Comprehensive geriatric assessment in the decision-making process in elderly patients with cancer: ELCAPA study. AB - PURPOSE: To identify Comprehensive Geriatric Assessment (CGA) components independently associated with changes in planned cancer treatment. PATIENTS AND METHODS: We prospectively included 375 consecutive elderly patients with cancer (ELCAPA01 study) assessed by geriatricians using the CGA. Multivariate analysis was used to identify factors associated with changes in the cancer treatment (intensification, decrease, or delayed > 2 weeks). Change was defined as a difference between the initial treatment proposal and the final treatment selected in a multidisciplinary meeting. RESULTS: Mean age was 79.6 years (standard deviation [SD], 5.6 years), and 197 (52.5%) were women. The most common tumor location was the digestive system (58.7%). The mean number of comorbidities was 4.2 (SD, 2.7) per patient, and the mean Cumulative Illness Rating Scale for Geriatrics score was 11.8 (SD, 5.3). After the CGA, the initial cancer treatment plan was modified for 78 (20.8%) of 375 patients (95% CI, 16.8 to 25.3), usually to decrease treatment intensity (63 [80.8%] of 78 patients). By univariate analysis, cancer treatment changes were associated with Eastern Cooperative Oncology Group performance status >= 2 (73.3% in the group with changes v 41.1% in the in the group without changes; P < .001), dependency for one or more activities of daily living (ADL; 59.0% v 24.2%; P < .001), malnutrition (81.8% v 51.2%; P < .001), cognitive impairment (38.5% v 24.9%; P = .023), depression (52.6% v 21.7%; P < .001), and greater number of comorbidities (mean, 4.8 [SD, 2.9] v 4.0 [SD, 2.6]; P = .02). By multivariate analysis, factors independently associated with cancer treatment changes were a lower ADL score (odds ratio [OR], 1.25 per 0.5-point decrease; CI, 1.04 to 1.49; P = .016) and malnutrition (OR, 2.99; CI, 1.36 to 6.58; P = .007). CONCLUSION: Functional status assessed by the ADL score and malnutrition were independently associated with changes in cancer treatment. PMID- 21709195 TI - Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. AB - PURPOSE: The human epidermal growth factor receptor (HER) family consists of four members: ErbB-1 (HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4). These receptors activate numerous downstream pathways in response to extracellular ligands, regulating diverse processes that include differentiation, migration, proliferation, and survival. Alterations in these genes play a role in the development and progression of many human cancers. In gastric carcinomas (GCs), expression of HER1 and HER2 is thought to be a prognostic factor and target of novel biologic agents. The effect of HER3 or HER4 expression in GC has not been sufficiently studied. In this study, we explored the gene and protein expression of the HER family in GC to establish new potential prognostic factors. PATIENTS AND METHODS: Immunohistochemistry and fluorescence in situ hybridization were performed in 221 patients with GC using tissue microarray. Correlation between the expression or amplification of HER genes and the clinicopathologic parameters was statistically analyzed. RESULTS: Alterations of members of the HER family were significantly associated with the parameters involved in tumor progression, including depth of tumor invasion, involved lymph nodes, and tumor stage. In addition, HER2 amplification and HER3 expression were significantly related to worse survival. CONCLUSION: These results reveal that all members of the HER family are expressed in GC. Furthermore, expression of HER2 and HER3 is a significant predictor of poor survival in GC. Therefore, the development of HER targeted agents and agents targeting downstream signaling pathways provides new possibilities in the treatment of GC. PMID- 21709196 TI - Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial. AB - PURPOSE: The management of glioblastoma multiforme (GBM) in elderly patients with poor performance status is not well established. A trial evaluating the efficacy and safety of temozolomide alone in this population was undertaken. PATIENTS AND METHODS: Patients age 70 years or older with newly diagnosed GBM and postoperative Karnofsky performance score (KPS) less than 70 were eligible for this nonrandomized phase II trial. Treatment consisted of 150 to 200 mg/m(2)/d temozolomide for 5 days every 4 weeks until disease progression. Radiotherapy was not administered. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, quality of life, and cognition. RESULTS: Seventy patients (median age, 77 years; median KPS, 60) were enrolled between July 2007 and February 2009. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 13% and 14% of patients, respectively. Median PFS was 16 weeks (95% CI, 10 to 20 weeks), and median OS was 25 weeks (95% CI, 19 to 28 weeks), comparing favorably with a 12- to 16-week OS expected from a purely supportive approach. Twenty-three patients (33%) improved their KPS by 10 or more points, and 18 (26%) became capable of self-care (KPS >= 70). Overall quality of life and cognition improved over time before disease progression. In the 31 tumors evaluated for O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, a methylated status indicated longer PFS (26 v 11 weeks; P = .03) and OS (31 v 19 weeks; P = .03). CONCLUSION: Temozolomide has an acceptable tolerance in elderly patients with GBM and KPS less than 70. It is associated with improvement of functional status in 33% of patients and appears to increase survival compared with supportive care alone, especially in patients with methylated MGMT promoter. PMID- 21709197 TI - Standardization of estrogen receptor measurement in breast cancer suggests false negative results are a function of threshold intensity rather than percentage of positive cells. AB - PURPOSE: Recent misclassification (false negative) incidents have raised awareness concerning limitations of immunohistochemistry (IHC) in assessment of estrogen receptor (ER) in breast cancer. Here we define a new method for standardization of ER measurement and then examine both change in percentage and threshold of intensity (immunoreactivity) to assess sources for test discordance. METHODS: An assay was developed to quantify ER by using a control tissue microarray (TMA) and a series of cell lines in which ER immunoreactivity was analyzed by quantitative immunoblotting in parallel with the automated quantitative analysis (AQUA) method of quantitative immunofluorescence (QIF). The assay was used to assess the ER protein expression threshold in two independent retrospective cohorts from Yale and was compared with traditional methods. RESULTS: Two methods of analysis showed that change in percentage of positive cells from 10% to 1% did not significantly affect the overall number of ER positive patients. The standardized assay for ER on two Yale TMA cohorts showed that 67.9% and 82.5% of the patients were above the 2-pg/MUg immunoreactivity threshold. We found 9.1% and 19.7% of the patients to be QIF-positive/IHC negative, and 4.0% and 0.4% to be QIF-negative/IHC-positive for a total of 13.1% and 20.1% discrepant cases when compared with pathologists' judgment of threshold. Assessment of survival for both cohorts showed that patients who were QIF-positive/pathologist-negative had outcomes similar to those of patients who had positive results for both assays. CONCLUSION: Assessment of intensity threshold by using a quantitative, standardized assay on two independent cohorts suggests discordance in the 10% to 20% range with current IHC methods, in which patients with discrepant results have prognostic outcomes similar to ER-positive patients with concordant results. PMID- 21709198 TI - Langerhans cell histiocytosis masquerading as aneurysmal bone cyst. PMID- 21709200 TI - Hemophagocytic lymphohistiocytosis in chronic lymphocytic leukemia. PMID- 21709199 TI - Calcium plus vitamin D supplementation and the risk of nonmelanoma and melanoma skin cancer: post hoc analyses of the women's health initiative randomized controlled trial. AB - PURPOSE: In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial. METHODS: Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication. RESULTS: Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; P(interaction) = .038), which was not observed in women without history of NMSC. CONCLUSION: Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation. PMID- 21709201 TI - Clinical development of vascular disrupting agents: what lessons can we learn from ASA404? PMID- 21709202 TI - Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small cell lung cancer. AB - PURPOSE: This phase III trial was conducted to test whether the novel vascular disrupting agent ASA404 (vadimezan), when combined with first-line platinum-based chemotherapy, improves survival in patients with advanced non-small-cell lung cancer (NSCLC) versus chemotherapy alone. PATIENTS AND METHODS: Patients with advanced stage IIIB or IV NSCLC, stratified by sex and tumor histology, were randomly assigned 1:1 to paclitaxel (200 mg/m(2)) and carboplatin (area under the curve, 6.0) with or without ASA404 (1,800 mg m(2)), given intravenously once every 3 weeks for six cycles followed by maintenance ASA404 or placebo. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: One thousand two hundred ninety-nine patients were randomly assigned. The trial was stopped for futility at interim analysis. At final analysis, there was no difference in OS seen between ASA404 (n = 649) and placebo (n = 650) arms: median OS was 13.4 and 12.7 months respectively (hazard ratio [HR], 1.01; 95% CI, 0.85 to 1.19; P = .535). Similarly, no OS difference was seen in the histologic (squamous or nonsquamous) and sex (male or female) strata. Median PFS was 5.5 months in both arms (HR, 1.04; P = .727), while ORR was 25% in both arms (P = 1.0). Overall rate of adverse events (AEs) was comparable between the ASA404 and placebo arms. Grade 4 neutropenia (27% v 19%) and infusion site pain (10% v 0.5%) were reported more frequently in the ASA404 arm. CONCLUSION: The addition of ASA404 to carboplatin and paclitaxel, although generally well tolerated, failed to improve frontline efficacy in advanced NSCLC. PMID- 21709203 TI - Tamoxifen chemoprevention and cardiac disease. PMID- 21709204 TI - Edmonton Symptom Assessment System screening and depression at the end of life. PMID- 21709205 TI - Estrogen receptor: a never ending story? PMID- 21709206 TI - Mammographic density, response to hormones, and breast cancer risk. AB - BACKGROUND: Percent mammographic density (PMD) is a strong risk factor for breast cancer that changes in response to changes in hormone exposure. We have examined the magnitude of the association of hormone exposure with PMD according to subsequent breast cancer risk. METHODS: In three case-control studies, with 1,164 patient cases and 1,155 controls nested in cohorts of women screened with mammography, we examined the association of PMD measured in the baseline mammogram with risk of breast cancer in the following 1 to 8 years (mean, 3 years), according to use of oral contraceptives (OCs) in premenopausal women, menopause, and hormone therapy (HT) in postmenopausal women. All statistical comparisons are adjusted for age and other risk factors. RESULTS: In premenopausal women who later developed breast cancer (patient cases), PMD was 5.3% greater in past users of OCs than in nonusers (P = .06). In controls, OC users had 2% less density than nonusers (P = .44; test for interaction P = .06). The difference in PMD between premenopausal and postmenopausal women for patient cases was 8.5% (P < .001) and for controls, 3.9% (P = .01; test for interaction P = .03). In postmenopausal women, PMD was 6% greater in patients who used HT than in never users (P < .001). Controls who used HT had 1.6% greater PMD (P = .26) than never users (test for interaction P = .001). Differences in PMD resulted mainly from differences in the dense area of the mammogram. CONCLUSION: Differences in PMD associated with differences in hormone exposure were greater in women who later developed breast cancer than in controls in each of the hormone exposures examined. PMID- 21709207 TI - Activation of peroxisome proliferator-activated receptor-{delta} enhances regenerative capacity of human endothelial progenitor cells by stimulating biosynthesis of tetrahydrobiopterin. AB - The mechanisms underlying the regenerative capacity of endothelial progenitor cells (EPCs) are not fully understood. We hypothesized that biosynthesis of tetrahydrobiopterin is an important mechanism responsible for the stimulatory effects of peroxisome proliferator-activated receptor-delta (PPARdelta) activation on regenerative function of human EPCs. Treatment of human EPCs with a selective PPARdelta agonist GW501516 for 24 hours increased the levels of mRNA, protein, and enzymatic activity of GTP cyclohydrolase I (GTPCH I), as well as the production of tetrahydrobiopterin. The effects of GW501516 were mediated by suppression of PTEN expression, thereby increasing phosphorylation of AKT. The AKT signaling also mediated GW501516-induced phosphorylation of endothelial NO synthase. In addition, activation of PPARdelta significantly enhanced proliferation of EPCs. This effect was abolished by the GTPCH I inhibitor, 2,4 diamino-6-hydroxypyrimidine, or genetic inactivation of GTPCH I with small interfering RNA but not by inhibition of endothelial NO synthase with N(G)-nitro l-arginine methyl ester. Supplementation of NO did not reverse 2,4-diamino-6 hydroxypyrimidine-inhibited 5-bromodeoxyuridine incorporation. Furthermore, transplantation of human EPCs stimulated re-endothelialization in a mouse model of carotid artery injury. Pretreatment of EPCs with GW501516 significantly enhanced the ability of transplanted EPCs to repair denuded endothelium. GTPCH I small interfering RNA transfection significantly inhibited in vivo regenerative capacity of EPCs stimulated with GW501516. Thus, in human EPCs, activation of PPARdelta stimulates expression and activity of GTPCH I and biosynthesis of tetrahydrobiopterin via PTEN-AKT signaling pathway. This effect enhances the regenerative function of EPCs. PMID- 21709208 TI - Tetrahydrobiopterin: important endothelial mediator independent of endothelial nitric oxide synthase. PMID- 21709209 TI - Aerobic exercise training-induced left ventricular hypertrophy involves regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin ii, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin (1-7). AB - Aerobic exercise training leads to a physiological, nonpathological left ventricular hypertrophy; however, the underlying biochemical and molecular mechanisms of physiological left ventricular hypertrophy are unknown. The role of microRNAs regulating the classic and the novel cardiac renin-angiotensin (Ang) system was studied in trained rats assigned to 3 groups: (1) sedentary; (2) swimming trained with protocol 1 (T1, moderate-volume training); and (3) protocol 2 (T2, high-volume training). Cardiac Ang I levels, Ang-converting enzyme (ACE) activity, and protein expression, as well as Ang II levels, were lower in T1 and T2; however, Ang II type 1 receptor mRNA levels (69% in T1 and 99% in T2) and protein expression (240% in T1 and 300% in T2) increased after training. Ang II type 2 receptor mRNA levels (220%) and protein expression (332%) were shown to be increased in T2. In addition, T1 and T2 were shown to increase ACE2 activity and protein expression and Ang (1-7) levels in the heart. Exercise increased microRNA 27a and 27b, targeting ACE and decreasing microRNA-143 targeting ACE2 in the heart. Left ventricular hypertrophy induced by aerobic training involves microRNA regulation and an increase in cardiac Ang II type 1 receptor without the participation of Ang II. Parallel to this, an increase in ACE2, Ang (1-7), and Ang II type 2 receptor in the heart by exercise suggests that this nonclassic cardiac renin-angiotensin system counteracts the classic cardiac renin angiotensin system. These findings are consistent with a model in which exercise may induce left ventricular hypertrophy, at least in part, altering the expression of specific microRNAs targeting renin-angiotensin system genes. Together these effects might provide the additional aerobic capacity required by the exercised heart. PMID- 21709210 TI - Chronic selective endothelin A receptor antagonism reduces serum uric acid in hypertensive chronic kidney disease. PMID- 21709212 TI - Visual search by action category. AB - Humans are sensitive to different categories of actions due to their importance in social interactions. However, biological motion research has been heavily tilted toward the use of walking figures. Employing point-light animations (PLAs) derived from motion capture data, we investigated how different activities (boxing, dancing, running, and walking) related to each other during action perception, using a visual search task. We found that differentiating between actions requires attention in general. However, a search asymmetry was revealed between boxers and walkers, i.e., searching for a boxer among walkers is more efficient than searching for a walker among boxers, suggesting the existence of a critical feature for categorizing these two actions. The similarities among the various actions were derived from hierarchical clustering of search slopes. Walking and running proved to be most related, followed by dancing and then boxing. Signal detection theory was used to conduct a non-parametric ROC analysis, revealing that human performance in visual search is not fully explained by low-level motion information. PMID- 21709211 TI - Dopamine receptor type 5 in the primary cilia has dual chemo- and mechano-sensory roles. AB - Polycystic kidney disease is characterized by cardiovascular irregularities, including hypertension. Dopamine, a circulating hormone, is implicated in essential hypertension in humans and animal models. Vascular endothelial primary cilia are known to function as mechano-sensory organelles. Although both primary cilia and dopamine receptors play important roles in vascular hypertension, their relationship has never been explored. To determine the roles of the dopaminergic system and mechano-sensory cilia, we studied the effects of dopamine on ciliary length and function in wild-type and mechano-insensitive polycystic mutant cells (Pkd1(-/)(-) and Tg737(orpk/orpk)). We show for the first time that mouse vascular endothelia exhibit dopamine receptor-type 5 (DR5), which colocalizes to primary cilia in cultured cells and mouse arteries in vivo. DR5 activation increases cilia length in arteries and endothelial cells through cofilin and actin polymerization. DR5 activation also restores cilia function in the mutant cells. In addition, silencing DR5 completely abolishes mechano-ciliary function in WT cells. We found that DR5 plays very important roles in ciliary length and function. Furthermore, the chemo-sensory function of cilia can alter the mechano sensory function through changes in sensitivity to fluid-shear stress. We propose that ciliary DR5 has functional chemo- and mechano-sensory roles in endothelial cells. PMID- 21709213 TI - Expression of a functional VEGFR-1 in tumor cells is a major determinant of anti PlGF antibodies efficacy. AB - PlGF, one of the ligands for VEGFR-1, has been implicated in tumor angiogenesis. However, more recent studies indicate that genetic or pharmacological inhibition of PlGF signaling does not result in reduction of microvascular density in a variety of tumor models. Here we screened 12 human tumor cell lines and identified 3 that are growth inhibited by anti-PlGF antibodies in vivo. We found that efficacy of anti-PlGF treatment strongly correlates with VEGFR-1 expression in tumor cells, but not with antiangiogenesis. In addition, PlGF induced VEGFR-1 signaling and biological responses in tumor cell lines sensitive to anti-PlGF, but not in refractory tumor cell lines or in endothelial cells. Also, genetic ablation of VEGFR-1 signaling in the host did not affect the efficacy of PlGF blockade. Collectively, these findings suggest that the role of PlGF in tumorigenesis largely consists of promoting autocrine/paracrine growth of tumor cells expressing a functional VEGFR-1 rather than stimulation of angiogenesis. PMID- 21709214 TI - Repeating patterns of virioplankton production within an estuarine ecosystem. AB - The Chesapeake Bay, a seasonally variable temperate estuary, provides a natural laboratory for examining the fluctuations and impacts of viral lysis on aquatic microorganisms. Viral abundance (VA) and viral production (VP) were monitored in the Chesapeake Bay over 4 1/2 annual cycles, producing a unique, long-term, interannual study of virioplankton production. High and dynamic VP rates, averaging 7.9 * 10(6) viruses per mL per h, indicate that viral lysis impacts a significant fraction of microorganisms in the Chesapeake. Viral-mediated bacterial mortality, VA, VP, and organic carbon release all displayed similar interannual and seasonal trends with higher values in 2003 and 2006 than in 2004 and 2005 and peaks in early spring and summer. Surprisingly, higher rates of viral lysis occurred in winter, resulting in a magnified effect of viral lysis on bacterioplankton during times of reduced productivity. Viral lysis directly impacted the organic carbon pool, contributing on average 76 MUg of C per L per d, an amount capable of sustaining ~55% of Chesapeake Bay bacterial production. The observed repeating interannual patterns of VP and lysis are likely interlinked with seasonal cycles of host abundance and diversity, which are in turn driven by annual cycles in environmental conditions, emphasizing the complex interplay of seasonality and microbial ecology in the Chesapeake Bay. PMID- 21709215 TI - Lte1 promotes mitotic exit by controlling the localization of the spindle position checkpoint kinase Kin4. AB - For a daughter cell to receive a complete genomic complement, it is essential that the mitotic spindle be positioned accurately within the cell. In budding yeast, a signaling system known as the spindle position checkpoint (SPOC) monitors spindle position and regulates the activity of the mitotic exit network (MEN), a GTPase signaling pathway that promotes exit from mitosis. The protein kinase Kin4 is a central component of the spindle position checkpoint. Kin4 primarily localizes to the mother cell and associates with spindle pole bodies (SPBs) located in the mother cell to inhibit MEN signaling. In contrast, the kinase does not associate with the SPB in the bud. Thus, only when a MEN bearing SPB leaves the mother cell and the spindle is accurately positioned along the mother-bud axis can MEN signaling occur and cell division proceed. Here, we describe a mechanism ensuring that Kin4 only associates with mother cell-located SPBs. The bud-localized MEN regulator Lte1, whose molecular function has long been unclear, prevents Kin4 that escapes into the bud from associating with SPBs in the daughter cell. PMID- 21709216 TI - Development of a spinal locomotor rheostat. AB - Locomotion in immature animals is often inflexible, but gradually acquires versatility to enable animals to maneuver efficiently through their environment. Locomotor activity in adults is produced by complex spinal cord networks that develop from simpler precursors. How does complexity and plasticity emerge during development to bestow flexibility upon motor behavior? And how does this complexity map onto the peripheral innervation fields of motorneurons during development? We show in postembryonic Xenopus laevis frog tadpoles that swim motorneurons initially form a homogenous pool discharging single action potential per swim cycle and innervating most of the dorsoventral extent of the swimming muscles. However, during early larval life, in the prelude to a free-swimming existence, the innervation fields of motorneurons become restricted to a more limited sector of each muscle block, with individual motorneurons reaching predominantly ventral, medial, or dorsal regions. Larval motorneurons then can also discharge multiple action potentials in each cycle of swimming and differentiate in terms of their firing reliability during swimming into relatively high-, medium-, or low-probability members. Many motorneurons fall silent during swimming but can be recruited with increasing locomotor frequency and intensity. Each region of the myotome is served by motorneurons spanning the full range of firing probabilities. This unfolding developmental plan, which occurs in the absence of movement, probably equips the organism with the neuronal substrate to bend, pitch, roll, and accelerate during swimming in ways that will be important for survival during the period of free-swimming larval life that ensues. PMID- 21709217 TI - OUROBOROS is a master regulator of the gametophyte to sporophyte life cycle transition in the brown alga Ectocarpus. AB - The brown alga Ectocarpus siliculosus has a haploid-diploid life cycle that involves an alternation between two distinct generations, the sporophyte and the gametophyte. We describe a mutant, ouroboros (oro), in which the sporophyte generation is converted into a functional, gamete-producing gametophyte. The life history of the mutant thus consists of a continuous reiteration of the gametophyte generation. The oro mutant exhibited morphological features typical of the gametophyte generation and accumulated transcripts of gametophyte generation marker genes. Genetic analysis showed that oro behaved as a single, recessive, Mendelian locus that was unlinked to the IMMEDIATE UPRIGHT locus, which has been shown to be necessary for full expression of the sporophyte developmental program. The data presented here indicate that ORO is a master regulator of the gametophyte-to-sporophyte life cycle transition and, moreover, that oro represents a unique class of homeotic mutation that results in switching between two developmental programs that operate at the level of the whole organism. PMID- 21709218 TI - Sugar-regulated cation channel formed by an insect gustatory receptor. AB - Insects sense the taste of foods and toxic compounds in their environment through the gustatory system. Genetic studies using fruit flies have suggested that putative seven-transmembrane gustatory receptors (Grs) expressed in gustatory sensory neurons are required for responses to specific tastants. We reconstituted sugar responses of Bombyx mori Gr-9 (BmGr-9), a silkworm Gr, in two heterologous expression systems. Xenopus oocytes or HEK293T cells expressing BmGr-9 selectively responded to D-fructose with an influx of extracellular Ca(2+) and a nonselective cation current conductance in a G protein-independent manner. Outside-out patch-clamp recording of BmGr-9-expressing cell membranes provides evidence supporting the hypothesis that BmGr-9 constitutes a ligand-gated ion channel. The fructose-activated current associated with BmGr-9 was suppressed by other hexoses, including glucose and sorbose. The activation and inhibition of insect Gr ion channels may be the molecular basis for the decoding system that discriminates subtle differences in sweet taste. Finally, Drosophila melanogaster Gr43a (DmGr43a), a BmGr-9 ortholog, also responded to D-fructose, suggesting that DmGr43a relatives appear to compose the family of fructose receptors. PMID- 21709219 TI - Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. AB - Vertebrates typically harbor a rich gastrointestinal microbiota, which has coevolved with the host over millennia and is essential for several host physiological functions, in particular maturation of the immune system. Recent studies have highlighted the importance of a single bacterial species, segmented filamentous bacteria (SFB), in inducing a robust T-helper cell type 17 (Th17) population in the small-intestinal lamina propria (SI-LP) of the mouse gut. Consequently, SFB can promote IL-17-dependent immune and autoimmune responses, gut-associated as well as systemic, including inflammatory arthritis and experimental autoimmune encephalomyelitis. Here, we exploit the incomplete penetrance of SFB colonization of NOD mice in our animal facility to explore its impact on the incidence and course of type 1 diabetes in this prototypical, spontaneous model. There was a strong cosegregation of SFB positivity and diabetes protection in females, but not in males, which remained relatively disease-free regardless of the SFB status. In contrast, insulitis did not depend on SFB colonization. SFB-positive, but not SFB-negative, females had a substantial population of Th17 cells in the SI-LP, which was the only significant, repeatable difference in the examined T-cell compartments of the gut, pancreas, or systemic lymphoid tissues. Th17-signature transcripts dominated the very limited SFB-induced molecular changes detected in SI-LP CD4(+) T cells. Thus, a single bacterium, and the gut immune system alterations associated with it, can either promote or protect from autoimmunity in predisposed mouse models, probably reflecting their variable dependence on different Th subsets. PMID- 21709220 TI - Major source of antigenic peptides for the MHC class I pathway is produced during the pioneer round of mRNA translation. AB - The MHC class I antigen presentation pathway allows the immune system to distinguish between self and nonself. Despite extensive research on the processing of antigenic peptides, little is known about their origin. Here, we show that mRNAs carrying premature stop codons that prevent the production of full-length proteins via the nonsense-mediated decay pathway still produce a majority of peptide substrates for the MHC class I pathway by a noncanonical mRNA translation process. Blocking the interaction of the translation initiation factor eIF4E with the cap structure suppresses the synthesis of full-length proteins but has only a limited effect on the production of antigenic peptides. These results reveal an essential cell biological function for a class of translation products derived during the pioneer round of mRNA translation and will have important implications for understanding how the immune system detects cells harboring pathogens and generates tolerance. PMID- 21709221 TI - Perceptual and neural consequences of rapid motion adaptation. AB - Nervous systems adapt to the prevailing sensory environment, and the consequences of this adaptation can be observed in the responses of single neurons and in perception. Given the variety of timescales underlying events in the natural world, determining the temporal characteristics of adaptation is important to understanding how perception adjusts to its sensory environment. Previous work has shown that neural adaptation can occur on a timescale of milliseconds, but perceptual adaptation has generally been studied over relatively long timescales, typically on the order of seconds. This disparity raises important questions. Can perceptual adaptation be observed at brief, functionally relevant timescales? And if so, how do its properties relate to the rapid adaptation seen in cortical neurons? We address these questions in the context of visual motion processing, a perceptual modality characterized by rapid temporal dynamics. We demonstrate objectively that 25 ms of motion adaptation is sufficient to generate a motion aftereffect, an illusory sensation of movement experienced when a moving stimulus is replaced by a stationary pattern. This rapid adaptation occurs regardless of whether the adapting motion is perceived. In neurophysiological recordings from the middle temporal area of primate visual cortex, we find that brief motion adaptation evokes direction-selective responses to subsequently presented stationary stimuli. A simple model shows that these neural responses can explain the consequences of rapid perceptual adaptation. Overall, we show that the motion aftereffect is not merely an intriguing perceptual illusion, but rather a reflection of rapid neural and perceptual processes that can occur essentially every time we experience motion. PMID- 21709222 TI - Neural and computational mechanisms of postponed decisions. AB - We consider the mechanisms that enable decisions to be postponed for a period after the evidence has been provided. Using an information theoretic approach, we show that information about the forthcoming action becomes available from the activity of neurons in the medial premotor cortex in a sequential decision-making task after the second stimulus is applied, providing the information for a decision about whether the first or second stimulus is higher in vibrotactile frequency. The information then decays in a 3-s delay period in which the neuronal activity declines before the behavioral response can be made. The information then increases again when the behavioral response is required. We model this neuronal activity using an attractor decision-making network in which information reflecting the decision is maintained at a low level during the delay period, and is then selectively restored by a nonspecific input when the response is required. One mechanism for the short-term memory is synaptic facilitation, which can implement a mechanism for postponed decisions that can be correct even when there is little neuronal firing during the delay period before the postponed decision. Another mechanism is graded firing rates by different neurons in the delay period, with restoration by the nonspecific input of the low-rate activity from the higher-rate neurons still firing in the delay period. These mechanisms can account for the decision making and for the memory of the decision before a response can be made, which are evident in the activity of neurons in the medial premotor cortex. PMID- 21709223 TI - Systems analysis identifies an essential role for SHANK-associated RH domain interacting protein (SHARPIN) in macrophage Toll-like receptor 2 (TLR2) responses. AB - Precise control of the innate immune response is essential to ensure host defense against infection while avoiding inflammatory disease. Systems-level analyses of Toll-like receptor (TLR)-stimulated macrophages suggested that SHANK-associated RH domain-interacting protein (SHARPIN) might play a role in the TLR pathway. This hypothesis was supported by the observation that macrophages derived from chronic proliferative dermatitis mutation (cpdm) mice, which harbor a spontaneous null mutation in the Sharpin gene, exhibited impaired IL-12 production in response to TLR activation. Systems biology approaches were used to define the SHARPIN-regulated networks. Promoter analysis identified NF-kappaB and AP-1 as candidate transcription factors downstream of SHARPIN, and network analysis suggested selective attenuation of these pathways. We found that the effects of SHARPIN deficiency on the TLR2-induced transcriptome were strikingly correlated with the effects of the recently described hypomorphic L153P/panr2 point mutation in Ikbkg [NF-kappaB Essential Modulator (NEMO)], suggesting that SHARPIN and NEMO interact. We confirmed this interaction by co-immunoprecipitation analysis and furthermore found it to be abrogated by panr2. NEMO-dependent signaling was affected by SHARPIN deficiency in a manner similar to the panr2 mutation, including impaired p105 and ERK phosphorylation and p65 nuclear localization. Interestingly, SHARPIN deficiency had no effect on IkappaBalpha degradation and on p38 and JNK phosphorylation. Taken together, these results demonstrate that SHARPIN is an essential adaptor downstream of the branch point defined by the panr2 mutation in NEMO. PMID- 21709224 TI - Disruption of adult expression of sexually selected traits by developmental exposure to bisphenol A. AB - Exposure to endocrine disrupting compounds (EDCs), such as bisphenol A (BPA), may cause adverse health effects in wildlife and humans, but controversy remains as to what traits are most sensitive to EDCs and might serve as barometers of exposure. Expression of sexually selected traits that have evolved through intrasexual competition for mates and intersexual choice of mating partner are more dependent on developmental and physical condition of an animal than naturally selected traits and thus might be particularly vulnerable to disruption by developmental exposure to EDCs. We have used the deer mouse (Peromyscus maniculatus) as a model to test this hypothesis. Adult male-male competition for mates in this species is supported by enhanced spatial navigational and exploratory abilities, which enable males to search for prospective, widely dispersed females. Male deer mice exposed to BPA or ethinyl estradiol (EE) through maternal diet showed no changes in external phenotype, sensory development, or adult circulating concentrations of testosterone and corticosterone, but spatial learning abilities and exploratory behaviors were severely compromised compared with control males. Because these traits are not sexually selected in females, BPA exposure predictably had no effect, although EE exposed females demonstrated enhanced spatial navigational abilities. Both BPA exposed and control females preferred control males to BPA-exposed males. Our demonstration that developmental exposure to BPA compromises cognitive abilities and behaviors essential for males to reproduce successfully has broad implications for other species, including our own. Thus, sexually selected traits might provide useful biomarkers to assess risk of environmental contamination in animal and human populations. PMID- 21709225 TI - Statistical structure of host-phage interactions. AB - Interactions between bacteria and the viruses that infect them (i.e., phages) have profound effects on biological processes, but despite their importance, little is known on the general structure of infection and resistance between most phages and bacteria. For example, are bacteria-phage communities characterized by complex patterns of overlapping exploitation networks, do they conform to a more ordered general pattern across all communities, or are they idiosyncratic and hard to predict from one ecosystem to the next? To answer these questions, we collect and present a detailed metaanalysis of 38 laboratory-verified studies of host-phage interactions representing almost 12,000 distinct experimental infection assays across a broad spectrum of taxa, habitat, and mode of selection. In so doing, we present evidence that currently available host-phage infection networks are statistically different from random networks and that they possess a characteristic nested structure. This nested structure is typified by the finding that hard to infect bacteria are infected by generalist phages (and not specialist phages) and that easy to infect bacteria are infected by generalist and specialist phages. Moreover, we find that currently available host-phage infection networks do not typically possess a modular structure. We explore possible underlying mechanisms and significance of the observed nested host-phage interaction structure. In addition, given that most of the available host-phage infection networks examined here are composed of taxa separated by short phylogenetic distances, we propose that the lack of modularity is a scale dependent effect, and then, we describe experimental studies to test whether modular patterns exist at macroevolutionary scales. PMID- 21709226 TI - Outer membrane adhesion factor multivalent adhesion molecule 7 initiates host cell binding during infection by gram-negative pathogens. AB - The initial binding of bacteria to host cells is crucial to the delivery of virulence factors and thus is a key determinant of the pathogen's success. We report a multivalent adhesion molecule (MAM) that enables a wide range of gram negative pathogens to establish high-affinity binding to host cells during the early stages of infection. MAM7 binds to the host by engaging in both protein protein (with fibronectin) and protein-lipid (with phosphatidic acid) interactions with the host cell membrane. We find that MAM7 expression on the outer membrane of a gram-negative pathogen is necessary for virulence in a nematode infection model and for efficient killing of cultured mammalian host cells. Expression of MAM7 on nonpathogenic strains produced a tool that can be used to impede infection by gram-negative bacterial pathogens. Targeting or exploiting MAM7 might prove to be important in combating gram-negative bacterial infections. PMID- 21709227 TI - Resting-state activity in development and maintenance of normal brain function. AB - One of the most intriguing recent discoveries concerning brain function is that intrinsic neuronal activity manifests as spontaneous fluctuations of the blood oxygen level-dependent (BOLD) functional MRI signal. These BOLD fluctuations exhibit temporal synchrony within widely distributed brain regions known as resting-state networks. Resting-state networks are present in the waking state, during sleep, and under general anesthesia, suggesting that spontaneous neuronal activity plays a fundamental role in brain function. Despite its ubiquitous presence, the physiological role of correlated, spontaneous neuronal activity remains poorly understood. One hypothesis is that this activity is critical for the development of synaptic connections and maintenance of synaptic homeostasis. We had a unique opportunity to test this hypothesis in a 5-y-old boy with severe epileptic encephalopathy. The child developed marked neurologic dysfunction in association with a seizure disorder, resulting in a 1-y period of behavioral regression and progressive loss of developmental milestones. His EEG showed a markedly abnormal pattern of high-amplitude, disorganized slow activity with frequent generalized and multifocal epileptiform discharges. Resting-state functional connectivity MRI showed reduced BOLD fluctuations and a pervasive lack of normal connectivity. The child underwent successful corpus callosotomy surgery for treatment of drop seizures. Postoperatively, the patient's behavior returned to baseline, and he resumed development of new skills. The waking EEG revealed a normal background, and functional connectivity MRI demonstrated restoration of functional connectivity architecture. These results provide evidence that intrinsic, coherent neuronal signaling may be essential to the development and maintenance of the brain's functional organization. PMID- 21709228 TI - Rapid increase in clusters of synaptophysin at onset of homosynaptic potentiation in Aplysia. AB - Imaging studies have shown that even the earliest phases of long-term plasticity are accompanied by the rapid recruitment of synaptic components, which generally requires actin polymerization and may be one of the first steps in a program that can lead to the formation of new stable synapses during late-phase plasticity. However, most of those results come from studies of long-term potentiation in rodent hippocampus and might not generalize to other forms of synaptic plasticity or plasticity in other brain areas and species. For example, recruitment of presynaptic proteins during long-term facilitation by 5HT in Aplysia is delayed for several hours, suggesting that whereas activity-dependent forms of plasticity, such as long-term potentiation, involve rapid recruitment of presynaptic proteins, neuromodulatory forms of plasticity, such as facilitation by 5HT, involve more delayed recruitment. To begin to explore this hypothesis, we examined an activity-dependent form of plasticity, homosynaptic potentiation produced by tetanic stimulation of the presynaptic neuron in Aplysia. We found that homosynaptic potentiation involves presynaptic but not postsynaptic actin and a rapid (under 10 min) increase in the number of clusters of the presynaptic vesicle-associated protein synaptophysin. These results indicate that rapid recruitment of synaptic components is not limited to hippocampal potentiation and support the hypothesis that activity-dependent types of plasticity involve rapid recruitment of presynaptic proteins, whereas neuromodulatory types of plasticity involve more delayed recruitment. PMID- 21709229 TI - Dehydro-alpha-lapachone, a plant product with antivascular activity. AB - Antivascular agents have become a standard of treatment for many malignancies. However, most of them target the VEGF pathway and lead to refractoriness. To improve the diversity of options for antivascular therapy, we applied a high throughput screen for small molecules targeting cell adhesion. We then assayed the resulting antiadhesion hits in a transgenic zebrafish line with endothelial expression of EGFP (Tg(fli1:EGFP)(y1)) to identify nontoxic molecules with antivascular activity selective to neovasculature. This screen identified dehydro alpha-lapachone (DAL), a natural plant product. We found that DAL inhibits vessel regeneration, interferes with vessel anastomosis, and limits plexus formation in zebrafish. Furthermore, DAL induces vascular pruning and growth delay in orthotopic mammary tumors in mice. We show that DAL targets cell adhesion by promoting ubiquitination of the Rho-GTPase Rac1, which is frequently up-regulated in many different cancers. PMID- 21709231 TI - Suppression of immune responses by nonimmunogenic oligodeoxynucleotides with high affinity for high-mobility group box proteins (HMGBs). AB - The activation of innate immune responses by nucleic acids is central to the generation of host responses against pathogens; however, nucleic acids can also trigger the development and/or exacerbation of pathogenic responses such as autoimmunity. We previously demonstrated that the selective activation of nucleic acid-sensing cytosolic and Toll-like receptors is contingent on the promiscuous sensing of nucleic acids by high-mobility group box proteins (HMGBs). From this, we reasoned that nonimmunogenic nucleotides with high-affinity HMGB binding may function as suppressing agents for HMGB-mediated diseases, particularly those initiated and/or exacerbated by nucleic acids. Here we characterize an array of HMGB-binding, nonimmunogenic oligodeoxynucleotides (ni-ODNs). Interestingly, we find that binding affinity is rather independent of nucleotide sequence, but is instead dependent on length and structure of the deoxyribose backbone. We further show that these ni-ODNs can strongly suppress the activation of innate immune responses induced by both classes of nucleic acid-sensing receptors. We also provide evidence for the suppressive effect of an ni-ODN, termed ISM ODN, on the induction of adaptive immune responses and in mouse models of sepsis and autoimmunity. We discuss our findings in relation to the critical role of HMGBs in initiating immune responses and the possible use of these ni-ODNs in therapeutic interventions. PMID- 21709230 TI - GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. AB - Type 1 diabetes (T1D) is an autoimmune disease characterized by insulitis and islet beta-cell loss. Thus, an effective therapy may require beta-cell restoration and immune suppression. Currently, there is no treatment that can achieve both goals efficiently. We report here that GABA exerts antidiabetic effects by acting on both the islet beta-cells and immune system. Unlike in adult brain or islet alpha-cells in which GABA exerts hyperpolarizing effects, in islet beta-cells, GABA produces membrane depolarization and Ca(2+) influx, leading to the activation of PI3-K/Akt-dependent growth and survival pathways. This provides a potential mechanism underlying our in vivo findings that GABA therapy preserves beta-cell mass and prevents the development of T1D. Remarkably, in severely diabetic mice, GABA restores beta-cell mass and reverses the disease. Furthermore, GABA suppresses insulitis and systemic inflammatory cytokine production. The beta-cell regenerative and immunoinhibitory effects of GABA provide insights into the role of GABA in regulating islet cell function and glucose homeostasis, which may find clinical application. PMID- 21709232 TI - Myosin-II inhibition and soft 2D matrix maximize multinucleation and cellular projections typical of platelet-producing megakaryocytes. AB - Cell division, membrane rigidity, and strong adhesion to a rigid matrix are all promoted by myosin-II, and so multinucleated cells with distended membranes- typical of megakaryocytes (MKs)--seem predictable for low myosin activity in cells on soft matrices. Paradoxically, myosin mutations lead to defects in MKs and platelets. Here, reversible inhibition of myosin-II is sustained over several cell cycles to produce 3- to 10-fold increases in polyploid MK and a number of other cell types. Even brief inhibition generates highly distensible, proplatelet like projections that fragment readily under shear, as seen in platelet generation from MKs in vivo. The effects are maximized with collagenous matrices that are soft and 2D, like the perivascular niches in marrow rather than 3D or rigid, like bone. Although multinucleation of other primary hematopoietic lineages helps to generalize a failure-to-fission mechanism, lineage-specific signaling with increased polyploidy proves possible and novel with phospho regulation of myosin-II heavy chain. Label-free mass spectrometry quantitation of the MK proteome uses a unique proportional peak fingerprint (ProPF) analysis to also show upregulation of the cytoskeletal and adhesion machinery critical to platelet function. Myosin-inhibited MKs generate more platelets in vitro and also in vivo from the marrows of xenografted mice, while agonist stimulation activates platelet spreading and integrin alphaIIbbeta3. Myosin-II thus seems a central, matrix-regulated node for MK-poiesis and platelet generation. PMID- 21709233 TI - Comparative transcriptome and metabolite analysis of oil palm and date palm mesocarp that differ dramatically in carbon partitioning. AB - Oil palm can accumulate up to 90% oil in its mesocarp, the highest level observed in the plant kingdom. In contrast, the closely related date palm accumulates almost exclusively sugars. To gain insight into the mechanisms that lead to such an extreme difference in carbon partitioning, the transcriptome and metabolite content of oil palm and date palm were compared during mesocarp development. Compared with date palm, the high oil content in oil palm was associated with much higher transcript levels for all fatty acid synthesis enzymes, specific plastid transporters, and key enzymes of plastidial carbon metabolism, including phosphofructokinase, pyruvate kinase, and pyruvate dehydrogenase. Transcripts representing an ortholog of the WRI1 transcription factor were 57-fold higher in oil palm relative to date palm and displayed a temporal pattern similar to its target genes. Unexpectedly, despite more than a 100-fold difference in flux to lipids, most enzymes of triacylglycerol assembly were expressed at similar levels in oil palm and date palm. Similarly, transcript levels for all but one cytosolic enzyme of glycolysis were comparable in both species. Together, these data point to synthesis of fatty acids and supply of pyruvate in the plastid, rather than acyl assembly into triacylglycerol, as a major control over the storage of oil in the mesocarp of oil palm. In addition to greatly increasing molecular resources devoted to oil palm and date palm, the combination of temporal and comparative studies illustrates how deep sequencing can provide insights into gene expression patterns of two species that lack genome sequence information. PMID- 21709234 TI - Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria monocytogenes. AB - The generation of reactive oxygen species (ROS) is inherent to immune responses. ROS are crucially involved in host defense against pathogens by promoting bacterial killing, but also as signaling agents coordinating the production of cytokines. Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca(2+) permeable channel gated via binding of ADP-ribose, a metabolite formed under conditions of cellular exposure to ROS. Here, we show that TRPM2-deficient mice are extremely susceptible to infection with Listeria monocytogenes (Lm), exhibiting an inefficient innate immune response. In a comparison with IFNgammaR deficient mice, TRPM2(-/-) mice shared similar features of uncontrolled bacterial replication and reduced levels of inducible (i)NOS-expressing monocytes, but had intact IFNgamma responsiveness. In contrast, we found that levels of cytokines IL 12 and IFNgamma were diminished in TRPM2(-/-) mice following Lm infection, which correlated with their reduced innate activation. Moreover, TRPM2(-/-) mice displayed a higher degree of susceptibility than IL-12-unresponsive mice, and supplementation with recombinant IFNgamma was sufficient to reverse the unrestrained bacterial growth and ultimately the lethal phenotype of Lm-infected TRPM2(-/-) mice. The severity of listeriosis we observed in TRPM2(-/-) mice has not been reported for any other ion channel. These findings establish an unsuspected role for ADP-ribose and ROS-mediated cation flux for innate immunity, opening up unique possibilities for immunomodulatory intervention through TRPM2. PMID- 21709235 TI - Genetic diversity and population structure of the endangered marsupial Sarcophilus harrisii (Tasmanian devil). AB - The Tasmanian devil (Sarcophilus harrisii) is threatened with extinction because of a contagious cancer known as Devil Facial Tumor Disease. The inability to mount an immune response and to reject these tumors might be caused by a lack of genetic diversity within a dwindling population. Here we report a whole-genome analysis of two animals originating from extreme northwest and southeast Tasmania, the maximal geographic spread, together with the genome from a tumor taken from one of them. A 3.3-Gb de novo assembly of the sequence data from two complementary next-generation sequencing platforms was used to identify 1 million polymorphic genomic positions, roughly one-quarter of the number observed between two genetically distant human genomes. Analysis of 14 complete mitochondrial genomes from current and museum specimens, as well as mitochondrial and nuclear SNP markers in 175 animals, suggests that the observed low genetic diversity in today's population preceded the Devil Facial Tumor Disease disease outbreak by at least 100 y. Using a genetically characterized breeding stock based on the genome sequence will enable preservation of the extant genetic diversity in future Tasmanian devil populations. PMID- 21709237 TI - Habitat fragmentation reduces nest survival in an Afrotropical bird community in a biodiversity hotspot. AB - Ecologists have long hypothesized that fragmentation of tropical landscapes reduces avian nest success. However, this hypothesis has not been rigorously assessed because of the difficulty of finding large numbers of well-hidden nests in tropical forests. Here we report that in the East Usambara Mountains in Tanzania, which are part of the Eastern Arc Mountains, a global biodiversity hotspot, that daily nest survival rate and nest success for seven of eight common understory bird species that we examined over a single breeding season were significantly lower in fragmented than in continuous forest, with the odds of nest failure for these seven species ranging from 1.9 to 196.8 times higher in fragmented than continuous forest. Cup-shaped nests were particularly vulnerable in fragments. We then examined over six breeding seasons and 14 study sites in a multivariable survival analysis the influence of landscape structure and nest location on daily nest survival for 13 common species representing 1,272 nests and four nest types (plate, cup, dome, and pouch). Across species and nest types, area, distance of nest to edge, and nest height had a dominant influence on daily nest survival, with area being positively related to nest survival and distance of nest to edge and nest height being both positively and negatively associated with daily nest survival. Our results indicate that multiple environmental factors contribute to reduce nest survival within a tropical understory bird community in a fragmented landscape and that maintaining large continuous forest is important for enhancing nest survival for Afrotropical understory birds. PMID- 21709236 TI - Premotor functional connectivity predicts impulsivity in juvenile offenders. AB - Teenagers are often impulsive. In some cases this is a phase of normal development; in other cases impulsivity contributes to criminal behavior. Using functional magnetic resonance imaging, we examined resting-state functional connectivity among brain systems and behavioral measures of impulsivity in 107 juveniles incarcerated in a high-security facility. In less-impulsive juveniles and normal controls, motor planning regions were correlated with brain networks associated with spatial attention and executive control. In more-impulsive juveniles, these same regions correlated with the default-mode network, a constellation of brain areas associated with spontaneous, unconstrained, self referential cognition. The strength of these brain-behavior relationships was sufficient to predict impulsivity scores at the individual level. Our data suggest that increased functional connectivity of motor-planning regions with networks subserving unconstrained, self-referential cognition, rather than those subserving executive control, heightens the predisposition to impulsive behavior in juvenile offenders. To further explore the relationship between impulsivity and neural development, we studied functional connectivity in the same motor planning regions in 95 typically developing individuals across a wide age span. The change in functional connectivity with age mirrored that of impulsivity: younger subjects tended to exhibit functional connectivity similar to the more impulsive incarcerated juveniles, whereas older subjects exhibited a less impulsive pattern. This observation suggests that impulsivity in the offender population is a consequence of a delay in typical development, rather than a distinct abnormality. PMID- 21709238 TI - Epidermal ablation of Dlx3 is linked to IL-17-associated skin inflammation. AB - In an effort to understand the role of Distal-less 3 (Dlx3) in cutaneous biology and pathophysiology, we generated and characterized a mouse model with epidermal ablation of Dlx3. K14cre;Dlx3(Kin/f) mice exhibited epidermal hyperproliferation and abnormal differentiation of keratinocytes. Results from subsequent analyses revealed cutaneous inflammation that featured accumulation of IL-17-producing CD4(+) T, CD8(+) T, and gammadelta T cells in the skin and lymph nodes of K14cre;Dlx3(Kin/f) mice. The gene expression signature of K14cre;Dlx3(Kin/f) skin shared features with lesional psoriatic skin, and Dlx3 expression was markedly and selectively decreased in psoriatic skin. Interestingly, cultured Dlx3 null keratinocytes triggered cytokine production that is potentially linked to inflammatory responses in K14cre;Dlx3(Kin/f) mice. Thus, Dlx3 ablation in epidermis is linked to altered epidermal differentiation, barrier development, and IL-17-associated skin inflammation. This model provides a platform that will allow the systematic exploration of the contributions of keratinocytes to cutaneous inflammation. PMID- 21709239 TI - Cyclin D1 promotes neurogenesis in the developing spinal cord in a cell cycle independent manner. AB - Neural stem and progenitor cells undergo an important transition from proliferation to differentiation in the G1 phase of the cell cycle. The mechanisms coordinating this transition are incompletely understood. Cyclin D proteins promote proliferation in G1 and typically are down-regulated before differentiation. Here we show that motoneuron progenitors in the embryonic spinal cord persistently express Cyclin D1 during the initial phase of differentiation, while down-regulating Cyclin D2. Loss-of-function and gain-of-function experiments indicate that Cyclin D1 (but not D2) promotes neurogenesis in vivo, a role that can be dissociated from its cell cycle function. Moreover, reexpression of Cyclin D1 can restore neurogenic capacity to D2-expressing glial-restricted progenitors. The neurogenic function of Cyclin D1 appears to be mediated, directly or indirectly, by Hes6, a proneurogenic basic helic-loop-helix transcription factor. These data identify a cell cycle-independent function for Cyclin D1 in promoting neuronal differentiation, along with a potential genetic pathway through which this function is exerted. PMID- 21709240 TI - Overlapping activation-induced cytidine deaminase hotspot motifs in Ig class switch recombination. AB - Ig class-switch recombination (CSR) is directed by the long and repetitive switch regions and requires activation-induced cytidine deaminase (AID). One of the conserved switch-region sequence motifs (AGCT) is a preferred site for AID mediated DNA-cytosine deamination. By using somatic gene targeting and recombinase-mediated cassette exchange, we established a cell line-based CSR assay that allows manipulation of switch sequences at the endogenous locus. We show that AGCT is only one of a family of four WGCW motifs in the switch region that can facilitate CSR. We go on to show that it is the overlap of AID hotspots at WGCW sites on the top and bottom strands that is critical. This finding leads to a much clearer model for the difference between CSR and somatic hypermutation. PMID- 21709241 TI - Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction. AB - In the most accepted model for hair cell mechanotransduction, a cluster of myosin motors located at the stereocilia upper tip-link density (UTLD) keeps the tip link under tension at rest. Both myosin VIIa (MYO7A) and myosin 1c have been implicated in mechanotransduction based on functional studies. However, localization studies are conflicting, leaving open the question of which myosin localizes at the UTLD and generates the tip-link resting tension. Using immunofluorescence, we now show that MYO7A and sans, a MYO7A-interacting protein, cluster at the UTLD. Analysis of the immunofluorescence intensity indicates that eight or more MYO7A molecules are present at each UTLD, consistent with a direct role for MYO7A in maintaining tip-link tension. MYO7A and sans localization at the UTLD is confirmed by transfection of hair cells with GFP-tagged constructs for these proteins. Cotransfection studies in a heterologous system show that MYO7A, sans, and the UTLD protein harmonin-b form a tripartite complex and that each protein is capable of interacting with one another independently. We propose that MYO7A, sans, and harmonin-b form the core components of the UTLD molecular complex. In this complex, MYO7A is likely the motor element that pulls on CDH23 to exert tension on the tip-link. PMID- 21709242 TI - Taste-independent detection of the caloric content of sugar in Drosophila. AB - Feeding behavior is influenced primarily by two factors: nutritional needs and food palatability. However, the role of food deprivation and metabolic needs in the selection of appropriate food is poorly understood. Here, we show that the fruit fly, Drosophila melanogaster, selects calorie-rich foods following prolonged food deprivation in the absence of taste-receptor signaling. Flies mutant for the sugar receptors Gr5a and Gr64a cannot detect the taste of sugar, but still consumed sugar over plain agar after 15 h of starvation. Similarly, pox neuro mutants that are insensitive to the taste of sugar preferentially consumed sugar over plain agar upon starvation. Moreover, when given a choice between metabolizable sugar (sucrose or D-glucose) and nonmetabolizable (zero-calorie) sugar (sucralose or L-glucose), starved Gr5a; Gr64a double mutants preferred metabolizable sugars. These findings suggest the existence of a taste-independent metabolic sensor that functions in food selection. The preference for calorie rich food correlates with a decrease in the two main hemolymph sugars, trehalose and glucose, and in glycogen stores, indicating that this sensor is triggered when the internal energy sources are depleted. Thus, the need to replenish depleted energy stores during periods of starvation may be met through the activity of a taste-independent metabolic sensing pathway. PMID- 21709243 TI - GIGANTEA directly activates Flowering Locus T in Arabidopsis thaliana. AB - Plants perceive environmental signals such as day length and temperature to determine optimal timing for the transition from vegetative to floral stages. Arabidopsis flowers under long-day conditions through the CONSTANS (CO)-FLOWERING LOCUS T (FT) regulatory module. It is thought that the environmental cues for photoperiodic control of flowering are initially perceived in the leaves. We have previously shown that GIGANTEA (GI) regulates the timing of CO expression, together with FLAVIN-BINDING, KELCH REPEAT, F BOX protein 1. Normally, CO and FT are expressed exclusively in vascular bundles, whereas GI is expressed in various tissues. To better elucidate the role of tissue-specific expression of GI in the flowering pathway, we established transgenic lines in which GI is expressed exclusively in mesophyll, vascular bundles, epidermis, shoot apical meristem, or root. We found that GI expressed in either mesophyll or vascular bundles rescues the late-flowering phenotype of the gi-2 loss-of-function mutant under both short day and long-day conditions. Interestingly, GI expressed in mesophyll or vascular tissues increases FT expression without up-regulating CO expression under short day conditions. Furthermore, we examined the interaction between GI and FT repressors in mesophyll. We found that GI can bind to three FT repressors: SHORT VEGETATIVE PHASE (SVP), TEMPRANILLO (TEM)1, and TEM2. Finally, our chromatin immunoprecipitation experiments showed that GI binds to FT promoter regions that are near the SVP binding sites. Taken together, our data further elucidate the multiple roles of GI in the regulation of flowering time. PMID- 21709244 TI - Adjacent visual representations of self-motion in different reference frames. AB - Recent investigations indicate that retinal motion is not directly available for perception when moving around [Souman JL, et al. (2010) J Vis 10:14], possibly pointing to suppression of retinal speed sensitivity in motion areas. Here, we investigated the distribution of retinocentric and head-centric representations of self-rotation in human lower-tier visual motion areas. Functional MRI responses were measured to a set of visual self-motion stimuli with different levels of simulated gaze and simulated head rotation. A parametric generalized linear model analysis of the blood oxygen level-dependent responses revealed subregions of accessory V3 area, V6(+) area, middle temporal area, and medial superior temporal area that were specifically modulated by the speed of the rotational flow relative to the eye and head. Pursuit signals, which link the two reference frames, were also identified in these areas. To our knowledge, these results are the first demonstration of multiple visual representations of self motion in these areas. The existence of such adjacent representations points to early transformations of the reference frame for visual self-motion signals and a topography by visual reference frame in lower-order motion-sensitive areas. This suggests that visual decisions for action and perception may take into account retinal and head-centric motion signals according to task requirements. PMID- 21709245 TI - Emergence of social cohesion in a model society of greedy, mobile individuals. AB - Human wellbeing in modern societies relies on social cohesion, which can be characterized by high levels of cooperation and a large number of social ties. Both features, however, are frequently challenged by individual self-interest. In fact, the stability of social and economic systems can suddenly break down as the recent financial crisis and outbreaks of civil wars illustrate. To understand the conditions for the emergence and robustness of social cohesion, we simulate the creation of public goods among mobile agents, assuming that behavioral changes are determined by individual satisfaction. Specifically, we study a generalized win-stay-lose-shift learning model, which is only based on previous experience and rules out greenbeard effects that would allow individuals to guess future gains. The most noteworthy aspect of this model is that it promotes cooperation in social dilemma situations despite very low information requirements and without assuming imitation, a shadow of the future, reputation effects, signaling, or punishment. We find that moderate greediness favors social cohesion by a coevolution between cooperation and spatial organization, additionally showing that those cooperation-enforcing levels of greediness can be evolutionarily selected. However, a maladaptive trend of increasing greediness, although enhancing individuals' returns in the beginning, eventually causes cooperation and social relationships to fall apart. Our model is, therefore, expected to shed light on the long-standing problem of the emergence and stability of cooperative behavior. PMID- 21709247 TI - Multiple mating and clutch size in invertebrate brooders versus pregnant vertebrates. AB - We summarize the genetic literature on polygamy rates and sire numbers per clutch in invertebrate animals that brood their offspring and then compare findings with analogous data previously compiled for vertebrate species displaying viviparity or other pregnancy-like syndromes. As deduced from molecular parentage analyses of several thousand broods from more than 100 "pregnant" species, invertebrate brooders had significantly higher mean incidences of multiple mating than pregnant vertebrates, a finding generally consistent with the postulate that clutch size constrains successful mate numbers in species with extended parental care. However, we uncovered no significant correlation in invertebrates between brood size and genetically deduced rates of multiple mating by the incubating sex. Instead, in embryo-gestating animals otherwise as different as mammals and mollusks, polygamy rates and histograms of successful mates per brooder proved to be strikingly similar. Most previous studies have sought to understand why gestating parents have so many mates and such high incidences of successful multiple mating; an alternative perspective based on logistical constraints turns the issue on its head by asking why mate numbers and polygamy rates are much lower than they theoretically could be, given the parentage-resolving power of molecular markers and the huge sizes of many invertebrate broods. PMID- 21709246 TI - miR-23a regulation of X-linked inhibitor of apoptosis (XIAP) contributes to sex differences in the response to cerebral ischemia. AB - It is increasingly recognized that the mechanisms underlying ischemic cell death are sexually dimorphic. Stroke-induced cell death in males is initiated by the mitochondrial release of apoptosis-inducing factor, resulting in caspase independent cell death. In contrast, ischemic cell death in females is primarily triggered by mitochondrial cytochrome c release with subsequent caspase activation. Because X-linked inhibitor of apoptosis (XIAP) is the primary endogenous inhibitor of caspases, its regulation may play a unique role in the response to injury in females. XIAP mRNA levels were higher in females at baseline. Stroke induced a significant decrease in XIAP mRNA in females, whereas no changes were seen in the male brain. However, XIAP protein levels were decreased in both sexes after stroke. MicroRNAs (miRNAs) predominantly induce translational repression and are emerging as a major regulators of mRNA and subsequent protein expression after ischemia. The miRNA miR-23a was predicted to bind XIAP mRNA. miR-23a directly bound the 3' UTR of XIAP, and miR-23a inhibition led to an increase in XIAP mRNA in vitro, demonstrating that XIAP is a previously uncharacterized target for miR-23a. miR-23a levels differed in male and female ischemic brains, providing evidence for sex-specific miRNA expression in stroke. Embelin, a small-molecule inhibitor of XIAP, decreased the interaction between XIAP and caspase-3 and led to enhanced caspase activity. Embelin treatment significantly exacerbated stroke-induced injury in females but had no effect in males, demonstrating that XIAP is an important mediator of sex-specific responses after stroke. PMID- 21709248 TI - Altered temporal patterns of anxiety in aged and amyloid precursor protein (APP) transgenic mice. AB - Both normal aging and dementia are associated with dysregulation of the biological clock, which contributes to disrupted circadian organization of physiology and behavior. Diminished circadian organization in conjunction with the loss of cholinergic input to the cortex likely contributes to impaired cognition and behavior. One especially notable and relatively common circadian disturbance among the aged is "sundowning syndrome," which is characterized by exacerbated anxiety, agitation, locomotor activity, and delirium during the hours before bedtime. Sundowning has been reported in both dementia patients and cognitively intact elderly individuals living in institutions; however, little is known about temporal patterns in anxiety and agitation, and the neurobiological basis of these rhythms remains unspecified. In the present study, we explored the diurnal pattern of anxiety-like behavior in aged and amyloid precursor protein (APP) transgenic mice. We then attempted to treat the observed behavioral disturbances in the aged mice using chronic nightly melatonin treatment. Finally, we tested the hypothesis that time-of-day differences in acetylcholinesterase and choline acetyltransferase expression and general neuronal activation (i.e., c-Fos expression) coincide with the behavioral symptoms. Our results show a temporal pattern of anxiety-like behavior that emerges in elderly mice. This behavioral pattern coincides with elevated locomotor activity relative to adult mice near the end of the dark phase, and with time-dependent changes in basal forebrain acetylcholinesterase expression. Transgenic APP mice show a similar behavioral phenomenon that is not observed among age-matched wild-type mice. These results may have useful applications to the study and treatment of age- and dementia related circadian behavioral disturbances, namely, sundowning syndrome. PMID- 21709249 TI - Paracatenula, an ancient symbiosis between thiotrophic Alphaproteobacteria and catenulid flatworms. AB - Harnessing chemosynthetic symbionts is a recurring evolutionary strategy. Eukaryotes from six phyla as well as one archaeon have acquired chemoautotrophic sulfur-oxidizing bacteria. In contrast to this broad host diversity, known bacterial partners apparently belong to two classes of bacteria--the Gamma- and Epsilonproteobacteria. Here, we characterize the intracellular endosymbionts of the mouthless catenulid flatworm genus Paracatenula as chemoautotrophic sulfur oxidizing Alphaproteobacteria. The symbionts of Paracatenula galateia are provisionally classified as "Candidatus Riegeria galateiae" based on 16S ribosomal RNA sequencing confirmed by fluorescence in situ hybridization together with functional gene and sulfur metabolite evidence. 16S rRNA gene phylogenetic analysis shows that all 16 Paracatenula species examined harbor host species specific intracellular Candidatus Riegeria bacteria that form a monophyletic group within the order Rhodospirillales. Comparing host and symbiont phylogenies reveals strict cocladogenesis and points to vertical transmission of the symbionts. Between 33% and 50% of the body volume of the various worm species is composed of bacterial symbionts, by far the highest proportion among all known endosymbiotic associations between bacteria and metazoans. This symbiosis, which likely originated more than 500 Mya during the early evolution of flatworms, is the oldest known animal-chemoautotrophic bacteria association. The distant phylogenetic position of the symbionts compared with other mutualistic or parasitic Alphaproteobacteria promises to illuminate the common genetic predispositions that have allowed several members of this class to successfully colonize eukaryote cells. PMID- 21709250 TI - Mycosporine-like amino acids are multifunctional molecules in sea hares and their marine community. AB - Molecules of keystone significance are relatively rare, yet mediate a variety of interactions between organisms. They influence the distribution and abundance of species, the transfer of energy across multiple trophic levels, and thus they play significant roles in structuring ecosystems. Despite their potential importance in facilitating our understanding of ecological systems, only three molecules thus far have been proposed as molecules of keystone significance: saxitoxin and dimethyl sulfide in marine communities and tetrodotoxin in riparian communities. In the course of studying the neuroecology of chemical defenses, we identified three mycosporine-like amino acids (MAAs)--N-ethanol palythine (= asterina-330), N-isopropanol palythine (= aplysiapalythine A), and N-ethyl palythine (= aplysiapalythine B)--as intraspecific alarm cues for sea hares (Aplysia californica). These alarm cues are released in the ink secretion of sea hares and cause avoidance behaviors in neighboring conspecifics. Further, we show that these three bioactive MAAs, two [aplysiapalythine A (APA) and -B (APB)] being previously unknown molecules, are present in the algal diet of sea hares and are concentrated in their defensive secretion as well as in their skin. MAAs are known to be produced by algae, fungi, and cyanobacteria and are acquired by many aquatic animals through trophic interactions. MAAs are widely used as sunscreens, among other uses, but sea hares modify their function to serve a previously undocumented role, as intraspecific chemical cues. Our findings highlight the multifunctionality of MAAs and their role in ecological connectivity, suggesting that they may function as molecules of keystone significance in marine ecosystems. PMID- 21709251 TI - PW1 gene/paternally expressed gene 3 (PW1/Peg3) identifies multiple adult stem and progenitor cell populations. AB - A variety of markers are invaluable for identifying and purifying stem/progenitor cells. Here we report the generation of a murine reporter line driven by Pw1 that reveals cycling and quiescent progenitor/stem cells in all adult tissues thus far examined, including the intestine, blood, testis, central nervous system, bone, skeletal muscle, and skin. Neurospheres generated from the adult PW1-reporter mouse show near 100% reporter-gene expression following a single passage. Furthermore, epidermal stem cells can be purified solely on the basis of reporter gene expression. These cells are clonogenic, repopulate the epidermal stem-cell niches, and give rise to new hair follicles. Finally, we demonstrate that only PW1 reporter-expressing epidermal cells give rise to follicles that are capable of self-renewal following injury. Our data demonstrate that PW1 serves as an invaluable marker for competent self-renewing stem cells in a wide array of adult tissues, and the PW1-reporter mouse serves as a tool for rapid stem cell isolation and characterization. PMID- 21709252 TI - RefilinB (FAM101B) targets filamin A to organize perinuclear actin networks and regulates nuclear shape. AB - The intracellular localization and shape of the nucleus plays a central role in cellular and developmental processes. In fibroblasts, nuclear movement and shape are controlled by a specific perinuclear actin network made of contractile actin filament bundles called transmembrane actin-associated nuclear (TAN) lines that form a structure called the actin cap. The identification of regulatory proteins associated with this specific actin cytoskeletal dynamic is a priority for understanding actin-based changes in nuclear shape and position in normal and pathological situations. Here, we first identify a unique family of actin regulators, the refilin proteins (RefilinA and RefilinB), that stabilize specifically perinuclear actin filament bundles. We next identify the actin binding filamin A (FLNA) protein as the downstream effector of refilins. Refilins act as molecular switches to convert FLNA from an actin branching protein into one that bundles. In NIH 3T3 fibroblasts, the RefilinB/FLNA complex organizes the perinuclear actin filament bundles forming the actin cap. Finally, we demonstrate that in epithelial normal murine mammary gland (NmuMG) cells, the RefilinB/FLNA complex controls formation of a new perinuclear actin network that accompanies nuclear shape changes during the epithelial-mesenchymal transition (EMT). Our studies open perspectives for further functional analyses of this unique actin based network and shed light on FLNA function during development and in human syndromes associated with FLNA mutations. PMID- 21709253 TI - Gene flow increases fitness at the warm edge of a species' range. AB - According to theory, gene flow to marginal populations may stall or aid adaptation at range limits by swamping peripheral populations with maladaptive gene flow or by enhancing genetic variability and reducing inbreeding depression, respectively. We tested these contrasting predictions by manipulating patterns of gene flow of the annual plant, Mimulus laciniatus, at its warm range limit. Gene flow was experimentally applied by using crosses within warm-limit populations (selfed and outcrossed), between warm-limit populations, and between warm-limit and central range populations across two elevational transects. We measured the fitness of offspring in a common garden at the warm-edge species range limit. All sources of gene flow increased seedling emergence at the range limit, suggesting local inbreeding depression at both range limit populations; however, lifetime reproductive success only increased significantly when pollen originated from another warm-limit population. Center-to-warm-edge gene flow was maladaptive by delaying time to development at this warm, fast-drying range limit, whereas edge to-edge gene flow hastened emergence time and time to reproduction. By empirically testing theory on the effects of gene flow on the formation of geographic range limits, we find benefits of gene flow among populations to be greatest when gene flow is between populations occupying the same range limit. Our results emphasize the overlooked importance of gene flow among populations occurring near the same range limit and highlight the potential for prescriptive gene flow as a conservation option for populations at risk from climate change. PMID- 21709255 TI - Chemotactic cell trapping in controlled alternating gradient fields. AB - Directed cell migration toward spatio-temporally varying chemotactic stimuli requires rapid cytoskeletal reorganization. Numerous studies provide evidence that actin reorganization is controlled by intracellular redistribution of signaling molecules, such as the PI4,5P2/PI3,4,5P3 gradient. However, exploring underlying mechanisms is difficult and requires careful spatio-temporal control of external chemotactic stimuli. We designed a microfluidic setup to generate alternating chemotactic gradient fields for simultaneous multicell exposure, greatly facilitating statistical analysis. For a quantitative description of intracellular response dynamics, we apply alternating time sequences of spatially homogeneous concentration gradients across 300 MUm, reorienting on timescales down to a few seconds. Dictyostelium discoideum amoebae respond to gradient switching rates below 0.02 Hz by readapting their migration direction. For faster switching, cellular repolarization ceases and is completely stalled at 0.1 Hz. In this "chemotactically trapped" cell state, external stimuli alternate faster than intracellular feedback is capable to respond by onset of directed migration. To investigate intracellular actin cortex rearrangement during gradient switching, we correlate migratory cell response with actin repolymerization dynamics, quantified by a fluorescence distribution moment of the GFP fusion protein LimEDeltacc. We find two fundamentally different cell polarization types and we could reveal the role of PI3-Kinase for cellular repolarization. In the early aggregation phase, PI3-Kinase enhances the capability of D. discoideum cells to readjust their polarity in response to spatially alternating gradient fields, whereas in aggregation competent cells the effect of PI3-Kinase perturbation becomes less relevant. PMID- 21709254 TI - Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures. AB - The initial step in HIV-1 infection occurs with the binding of cell surface CD4 to trimeric HIV-1 envelope glycoproteins (Env), a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120). The design of soluble versions of trimeric Env that display structural and functional properties similar to those observed on intact viruses is highly desirable from the viewpoint of designing immunogens that could be effective as vaccines against HIV/AIDS. Using cryoelectron tomography combined with subvolume averaging, we have analyzed the structure of SOSIP gp140 trimers, which are cleaved, solubilized versions of the ectodomain of trimeric HIV-1 Env. We show that unliganded gp140 trimers adopt a quaternary arrangement similar to that displayed by native unliganded trimers on the surface of intact HIV-1 virions. When complexed with soluble CD4, Fab 17b, which binds to gp120 at its chemokine coreceptor binding site, or both soluble CD4 and 17b Fab, gp140 trimers display an open conformation in which there is an outward rotation and displacement of each gp120 protomer. We demonstrate that the molecular arrangements of gp120 trimers in the closed and open conformations of the soluble trimer are the same as those observed for the closed and open states, respectively, of trimeric gp120 on intact HIV-1 BaL virions, establishing that soluble gp140 trimers can be designed to mimic the quaternary structural transitions displayed by native trimeric Env. PMID- 21709256 TI - Terrestrial planet formation. AB - Advances in our understanding of terrestrial planet formation have come from a multidisciplinary approach. Studies of the ages and compositions of primitive meteorites with compositions similar to the Sun have helped to constrain the nature of the building blocks of planets. This information helps to guide numerical models for the three stages of planet formation from dust to planetesimals (~10(6) y), followed by planetesimals to embryos (lunar to Mars sized objects; few 10(6) y), and finally embryos to planets (10(7)-10(8) y). Defining the role of turbulence in the early nebula is a key to understanding the growth of solids larger than meter size. The initiation of runaway growth of embryos from planetesimals ultimately leads to the growth of large terrestrial planets via large impacts. Dynamical models can produce inner Solar System configurations that closely resemble our Solar System, especially when the orbital effects of large planets (Jupiter and Saturn) and damping mechanisms, such as gas drag, are included. Experimental studies of terrestrial planet interiors provide additional constraints on the conditions of differentiation and, therefore, origin. A more complete understanding of terrestrial planet formation might be possible via a combination of chemical and physical modeling, as well as obtaining samples and new geophysical data from other planets (Venus, Mars, or Mercury) and asteroids. PMID- 21709257 TI - Pathway for lipid A biosynthesis in Arabidopsis thaliana resembling that of Escherichia coli. AB - The lipid A moiety of Escherichia coli lipopolysaccharide is a hexa-acylated disaccharide of glucosamine that makes up the outer monolayer of the outer membrane. Arabidopsis thaliana contains nuclear genes encoding orthologs of key enzymes of bacterial lipid A biosynthesis, including LpxA, LpxC, LpxD, LpxB, LpxK and KdtA. Although structurally related lipid A molecules are found in most other gram-negative bacteria, lipid A and its precursors have not been directly detected in plants previously. However, homozygous insertional knockout mutations or RNAi knock-down constructs of Arabidopsis lpx and kdtA mutants revealed accumulation (or disappearance) of the expected monosaccharide or disaccharide lipid A precursors by mass spectrometry of total lipids extracted from 10-day old seedlings of these mutants. In addition, fluorescence microscopy of lpx-gfp fusions in transgenic Arabidopsis plants suggests that the Lpx and KdtA proteins are expressed and targeted to mitochondria. Although the structure of the lipid A end product generated by plants is still unknown, our work demonstrates that plants synthesize lipid A precursors using the same enzymatic pathway present in E. coli. PMID- 21709258 TI - Many-body interactions in quasi-freestanding graphene. AB - The Landau-Fermi liquid picture for quasiparticles assumes that charge carriers are dressed by many-body interactions, forming one of the fundamental theories of solids. Whether this picture still holds for a semimetal such as graphene at the neutrality point, i.e., when the chemical potential coincides with the Dirac point energy, is one of the long-standing puzzles in this field. Here we present such a study in quasi-freestanding graphene by using high-resolution angle resolved photoemission spectroscopy. We see the electron-electron and electron phonon interactions go through substantial changes when the semimetallic regime is approached, including renormalizations due to strong electron-electron interactions with similarities to marginal Fermi liquid behavior. These findings set a new benchmark in our understanding of many-body physics in graphene and a variety of novel materials with Dirac fermions. PMID- 21709259 TI - Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion. AB - Combination regimens that include artemisinin derivatives are recommended as first line antimalarials in most countries where malaria is endemic. However, the mechanism of action of artemisinin is not fully understood and the usefulness of this drug class is threatened by reports of decreased parasite sensitivity. We treated Plasmodium falciparum for periods of a few hours to mimic clinical exposure to the short half-life artemisinins. We found that drug treatment retards parasite growth and inhibits uptake of hemoglobin, even at sublethal concentrations. We show that potent artemisinin activity is dependent on hemoglobin digestion by the parasite. Inhibition of hemoglobinase activity with cysteine protease inhibitors, knockout of the cysteine protease falcipain-2 by gene deletion, or direct deprivation of host cell lysate, significantly decreases artemisinin sensitivity. Hemoglobin digestion is also required for artemisinin induced exacerbation of oxidative stress in the parasite cytoplasm. Arrest of hemoglobin digestion by early stage parasites provides a mechanism for surviving short-term artemisinin exposure. These insights will help in the design of new drugs and new treatment strategies to circumvent drug resistance. PMID- 21709260 TI - Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex. AB - Nuclear factor of activated T cells (NFAT) proteins are Ca(2+)-regulated transcription factors that control gene expression in many cell types. NFAT proteins are heavily phosphorylated and reside in the cytoplasm of resting cells; when cells are stimulated by a rise in intracellular Ca(2+), NFAT proteins are dephosphorylated by the Ca(2+)/calmodulin-dependent phosphatase calcineurin and translocate to the nucleus to activate target gene expression. Here we show that phosphorylated NFAT1 is present in a large cytoplasmic RNA-protein scaffold complex that contains a long intergenic noncoding RNA (lincRNA), NRON [noncoding (RNA) repressor of NFAT]; a scaffold protein, IQ motif containing GTPase activating protein (IQGAP); and three NFAT kinases, casein kinase 1, glycogen synthase kinase 3, and dual specificity tyrosine phosphorylation regulated kinase. Combined knockdown of NRON and IQGAP1 increased NFAT dephosphorylation and nuclear import exclusively after stimulation, without affecting the rate of NFAT rephosphorylation and nuclear export; and both NRON-depleted T cells and T cells from IQGAP1-deficient mice showed increased production of NFAT-dependent cytokines. Our results provide evidence that a complex of lincRNA and protein forms a scaffold for a latent transcription factor and its regulatory kinases, and support an emerging consensus that lincRNAs that bind transcriptional regulators have a similar scaffold function. PMID- 21709261 TI - Proton transfer via a transient linear water-molecule chain in a membrane protein. AB - High-resolution protein ground-state structures of proton pumps and channels have revealed internal protein-bound water molecules. Their possible active involvement in protein function has recently come into focus. An illustration of the formation of a protonated protein-bound water cluster that is actively involved in proton transfer was described for the membrane protein bacteriorhodopsin (bR) [Garczarek F, Gerwert K (2006) Nature 439:109-112]. Here we show through a combination of time-resolved FTIR spectroscopy and molecular dynamics simulations that three protein-bound water molecules are rearranged by a protein conformational change that resulted in a transient Grotthuss-type proton transfer chain extending through a hydrophobic protein region of bR. This transient linear water chain facilitates proton transfer at an intermediate conformation only, thereby directing proton transfer within the protein. The rearrangement of protein-bound water molecules that we describe, from inactive positions in the ground state to an active chain in an intermediate state, appears to be energetically favored relative to transient incorporation of water molecules from the bulk. Our discovery provides insight into proton-transfer mechanisms through hydrophobic core regions of ubiquitous membrane spanning proteins such as G-protein coupled receptors or cytochrome C oxidases. PMID- 21709262 TI - Highly selective synthesis of conjugated dienoic and trienoic esters via alkyne elementometalation-Pd-catalyzed cross-coupling. AB - All four stereoisomers (7-10) of ethyl undeca-2,4-dienoate were prepared in >= 98% isomeric purity by Pd-catalyzed alkenylation (Negishi coupling) using ethyl (E)- and (Z)-beta-bromoacrylates. Although the stereoisomeric purity of the 2Z,4E isomer (8) prepared by Suzuki coupling using conventional alkoxide and carbonate bases was <= 95%, as reported earlier, the use of CsF or (n)Bu(4)NF as a promoter base has now been found to give all of 7-10 in >= 98% selectivity. Other widely known methods reveal considerable limitations. Heck alkenylation was satisfactory for the syntheses of the 2E,4E and 2E,4Z isomers of >= 98% purity, but the purity of the 2Z,4E isomer was <= 95%. Mutually complementary Horner-Wadsworth-Emmons and Still-Gennari (SG) olefinations are also of considerably limited scopes. Neither 2E,4Z nor 2Z,4Z isomer is readily prepared in >= 90% selectivity. In addition to (2Z,4E)-dienoic esters, some (2Z,4E,6E)- and (2Z,4E,6Z)-trienoic esters have been prepared in >= 98% selectivity by a newly devised Pd-catalyzed alkenylation-SG olefination tandem process. As models for conjugated higher oligoenoic esters, all eight stereoisomers for ethyl trideca-2,4,6-trienoate (23 30) have been prepared in >= 98% overall selectivity. PMID- 21709263 TI - Sialylation and fucosylation of epidermal growth factor receptor suppress its dimerization and activation in lung cancer cells. AB - Protein glycosylation is an important posttranslational process, which regulates protein folding and functional expression. Studies have shown that abnormal glycosylation in tumor cells affects cancer progression and malignancy. In the current study, we have identified sialylated proteins using an alkynyl sugar probe in two different lung cancer cell lines, CL1-0 and CL1-5 with distinct invasiveness derived from the same parental cell line. Among the identified sialylated proteins, epidermal growth factor receptor (EGFR) was chosen to understand the effect of sialylation on its function. We have determined the differences in glycan sequences of EGFR in both cells and observed higher sialylation and fucosylation of EGFR in CL1-5 than in CL1-0. Further study suggested that overexpression of sialyltransferases in CL1-5 and alpha1,3 fucosyltransferases (FUT4 or FUT6) in CL1-5 and A549 cells would suppress EGFR dimerization and phosphorylation upon EGF treatment, as compared to the control and CL1-0 cells. Such modulating effects on EGFR dimerization were further confirmed by sialidase or fucosidase treatment. Thus, increasing sialylation and fucosylation could attenuate EGFR-mediated invasion of lung cancer cells. However, incorporation of the core fucose by alpha1,6-fucosylatransferase (FUT8) would promote EGFR dimerization and phosphorylation. PMID- 21709264 TI - Biocompatible artificial DNA linker that is read through by DNA polymerases and is functional in Escherichia coli. AB - A triazole mimic of a DNA phosphodiester linkage has been produced by templated chemical ligation of oligonucleotides functionalized with 5'-azide and 3'-alkyne. The individual azide and alkyne oligonucleotides were synthesized by standard phosphoramidite methods and assembled using a straightforward ligation procedure. This highly efficient chemical equivalent of enzymatic DNA ligation has been used to assemble a 300-mer from three 100-mer oligonucleotides, demonstrating the total chemical synthesis of very long oligonucleotides. The base sequences of the DNA strands containing this artificial linkage were copied during PCR with high fidelity and a gene containing the triazole linker was functional in Escherichia coli. PMID- 21709265 TI - Membrane tension regulates motility by controlling lamellipodium organization. AB - Many cell movements proceed via a crawling mechanism, where polymerization of the cytoskeletal protein actin pushes out the leading edge membrane. In this model, membrane tension has been seen as an impediment to filament growth and cell motility. Here we use a simple model of cell motility, the Caenorhabditis elegans sperm cell, to test how membrane tension affects movement and cytoskeleton dynamics. To enable these analyses, we create transgenic worm strains carrying sperm with a fluorescently labeled cytoskeleton. Via osmotic shock and deoxycholate treatments, we relax or tense the cell membrane and quantify apparent membrane tension changes by the membrane tether technique. Surprisingly, we find that membrane tension reduction is correlated with a decrease in cell displacement speed, whereas an increase in membrane tension enhances motility. We further demonstrate that apparent polymerization rates follow the same trends. We observe that membrane tension reduction leads to an unorganized, rough lamellipodium, composed of short filaments angled away from the direction of movement. On the other hand, an increase in tension reduces lateral membrane protrusions in the lamellipodium, and filaments are longer and more oriented toward the direction of movement. Overall we propose that membrane tension optimizes motility by streamlining polymerization in the direction of movement, thus adding a layer of complexity to our current understanding of how membrane tension enters into the motility equation. PMID- 21709266 TI - Three-dimensional nanometer-scale optical cavities of indefinite medium. AB - Miniaturization of optical cavities has numerous advantages for enhancing light matter interaction in quantum optical devices, low-threshold lasers with minimal power consumption, and efficient integration of optoelectronic devices at large scale. However, the realization of a truly nanometer-scale optical cavity is hindered by the diffraction limit of the nature materials. In addition, the scaling of the photon life time with the cavity size significantly reduces the quality factor of small cavities. Here we theoretically present an approach to achieve ultrasmall optical cavities using indefinite medium with hyperbolic dispersion, which allows propagation of electromagnetic waves with wave vectors much larger than those in vacuum enabling extremely small 3D cavity down to (lambda/20)(3). These cavities exhibit size-independent resonance frequencies and anomalous scaling of quality factors in contrast to the conventional cavities, resulting in nanocavities with both high Q/V(m) ratio and broad bandwidth. PMID- 21709267 TI - Raft domains of variable properties and compositions in plasma membrane vesicles. AB - Biological membranes are compartmentalized for functional diversity by a variety of specific protein-protein, protein-lipid, and lipid-lipid interactions. A subset of these are the preferential interactions between sterols, sphingolipids, and saturated aliphatic lipid tails responsible for liquid-liquid domain coexistence in eukaryotic membranes, which give rise to dynamic, nanoscopic assemblies whose coalescence is regulated by specific biochemical cues. Microscopic phase separation recently observed in isolated plasma membranes (giant plasma membrane vesicles and plasma membrane spheres) (i) confirms the capacity of compositionally complex membranes to phase separate, (ii) reflects the nanoscopic organization of live cell membranes, and (iii) provides a versatile platform for the investigation of the compositions and properties of the phases. Here, we show that the properties of coexisting phases in giant plasma membrane vesicles are dependent on isolation conditions--namely, the chemicals used to induce membrane blebbing. We observe strong correlations between the relative compositions and orders of the coexisting phases, and their resulting miscibility. Chemically unperturbed plasma membranes reflect these properties and validate the observations in chemically induced vesicles. Most importantly, we observe domains with a continuum of varying stabilities, orders, and compositions induced by relatively small differences in isolation conditions. These results show that, based on the principle of preferential association of raft lipids, domains of various properties can be produced in a membrane environment whose complexity is reflective of biological membranes. PMID- 21709268 TI - Entropy and the driving force for the filling of carbon nanotubes with water. AB - The spontaneous filling of hydrophobic carbon nanotubes (CNTs) by water observed both experimentally and from simulations is counterintuitive because confinement is generally expected to decrease both entropy and bonding, and remains largely unexplained. Here we report the entropy, enthalpy, and free energy extracted from molecular dynamics simulations of water confined in CNTs from 0.8 to 2.7-nm diameters. We find for all sizes that water inside the CNTs is more stable than in the bulk, but the nature of the favorable confinement of water changes dramatically with CNT diameter. Thus we find (i) an entropy (both rotational and translational) stabilized, vapor-like phase of water for small CNTs (0.8-1.0 nm), (ii) an enthalpy stabilized, ice-like phase for medium-sized CNTs (1.1-1.2 nm), and (iii) a bulk-like liquid phase for tubes larger than 1.4 nm, stabilized by the increased translational entropy as the waters sample a larger configurational space. Simulations with structureless coarse-grained water models further reveal that the observed free energies and sequence of transitions arise from the tetrahedral structure of liquid water. These results offer a broad theoretical basis for understanding water transport through CNTs and other nanostructures important in nanofluidics, nanofiltrations, and desalination. PMID- 21709269 TI - Progressive Cenozoic cooling and the demise of Antarctica's last refugium. AB - The Antarctic Peninsula is considered to be the last region of Antarctica to have been fully glaciated as a result of Cenozoic climatic cooling. As such, it was likely the last refugium for plants and animals that had inhabited the continent since it separated from the Gondwana supercontinent. Drill cores and seismic data acquired during two cruises (SHALDRIL I and II) in the northernmost Peninsula region yield a record that, when combined with existing data, indicates progressive cooling and associated changes in terrestrial vegetation over the course of the past 37 million years. Mountain glaciation began in the latest Eocene (approximately 37-34 Ma), contemporaneous with glaciation elsewhere on the continent and a reduction in atmospheric CO(2) concentrations. This climate cooling was accompanied by a decrease in diversity of the angiosperm-dominated vegetation that inhabited the northern peninsula during the Eocene. A mosaic of southern beech and conifer-dominated woodlands and tundra continued to occupy the region during the Oligocene (approximately 34-23 Ma). By the middle Miocene (approximately 16-11.6 Ma), localized pockets of limited tundra still existed at least until 12.8 Ma. The transition from temperate, alpine glaciation to a dynamic, polythermal ice sheet took place during the middle Miocene. The northernmost Peninsula was overridden by an ice sheet in the early Pliocene (approximately 5.3-3.6 Ma). The long cooling history of the peninsula is consistent with the extended timescales of tectonic evolution of the Antarctic margin, involving the opening of ocean passageways and associated establishment of circumpolar circulation. PMID- 21709270 TI - Micropatterned mammalian cells exhibit phenotype-specific left-right asymmetry. AB - Left-right (LR) asymmetry (handedness, chirality) is a well-conserved biological property of critical importance to normal development. Changes in orientation of the LR axis due to genetic or environmental factors can lead to malformations and disease. While the LR asymmetry of organs and whole organisms has been extensively studied, little is known about the LR asymmetry at cellular and multicellular levels. Here we show that the cultivation of cell populations on micropatterns with defined boundaries reveals intrinsic cell chirality that can be readily determined by image analysis of cell alignment and directional motion. By patterning 11 different types of cells on ring-shaped micropatterns of various sizes, we found that each cell type exhibited definite LR asymmetry (p value down to 10(-185)) that was different between normal and cancer cells of the same type, and not dependent on surface chemistry, protein coating, or the orientation of the gravitational field. Interestingly, drugs interfering with actin but not microtubule function reversed the LR asymmetry in some cell types. Our results show that micropatterned cell populations exhibit phenotype-specific LR asymmetry that is dependent on the functionality of the actin cytoskeleton. We propose that micropatterning could potentially be used as an effective in vitro tool to study the initiation of LR asymmetry in cell populations, to diagnose disease, and to study factors involved with birth defects in laterality. PMID- 21709271 TI - Attachment figures activate a safety signal-related neural region and reduce pain experience. AB - Although it has long been hypothesized that attachment figures provide individuals with a sense of safety and security, the neural mechanisms underlying attachment-induced safety have not been explored. Here, we investigated whether an attachment figure acts as a safety signal by exploring whether viewing an attachment figure during a threatening experience (physical pain) led to increased activity in a neural region associated with safety signaling, the ventromedial prefrontal cortex (VMPFC), and corresponding reductions in pain. Female participants in long-term romantic relationships were scanned as they received painful stimuli while viewing pictures of their partner and control images (stranger, object). Consistent with the idea that the attachment figure may signal safety, results revealed that viewing partner pictures while receiving painful stimulation led to reductions in self-reported pain ratings, reductions in pain-related neural activity (dorsal anterior cingulate cortex, anterior insula), and increased activity in the VMPFC. Moreover, greater VMPFC activity in response to partner pictures was associated with longer relationship lengths and greater perceived partner support, further highlighting a role for the VMPFC in responding to the safety value of the partner. Last, greater VMPFC activity while viewing partner pictures was associated with reduced pain ratings and reduced pain-related neural activity. An implication of these findings is that, in the same way that stimuli that historically have threatened survival (e.g., snakes, spiders) are considered to be prepared fear stimuli, attachment figures, who have historically benefited survival, may serve as prepared safety stimuli, reducing threat- or distress-related responding in their presence. PMID- 21709272 TI - Opposite-sex siblings decrease attraction, but not prosocial attributions, to self-resembling opposite-sex faces. AB - Contextual cues of genetic relatedness to familiar individuals, such as cosocialization and maternal-perinatal association, modulate prosocial and inbreeding-avoidance behaviors toward specific potential siblings. These findings have been interpreted as evidence that contextual cues of kinship indirectly influence social behavior by affecting the perceived probability of genetic relatedness to familiar individuals. Here, we test a more general alternative model in which contextual cues of kinship can influence the kin-recognition system more directly, changing how the mechanisms that regulate social behavior respond to cues of kinship, even in unfamiliar individuals for whom contextual cues of kinship are absent. We show that having opposite-sex siblings influences inbreeding-relevant perceptions of facial resemblance but not prosocial perceptions. Women with brothers were less attracted to self-resembling, unfamiliar male faces than were women without brothers, and both groups found self-resemblance to be equally trustworthy for the same faces. Further analyses suggest that this effect is driven by younger, rather than older, brothers, consistent with the proposal that only younger siblings exhibit the strong kinship cue of maternal-perinatal association. Our findings provide evidence that experience with opposite-sex siblings can directly influence inbreeding-avoidance mechanisms and demonstrate a striking functional dissociation between the mechanisms that regulate inbreeding and the mechanisms that regulate prosocial behavior toward kin. PMID- 21709273 TI - More randomization in phase II trials: necessary but not sufficient. PMID- 21709274 TI - Randomized phase II trials: a long-term investment with promising returns. AB - Given the multitude of novel anticancer drugs and the limited resources available to study them, phase II trials should identify drugs with the highest probability of succeeding in subsequent phase III trials. Currently, single-arm phase II trial results are interpreted relative to historical control subjects, introducing selection bias and confounding that may limit the validity of the conclusions. The rate of success (defined as a statistically significant difference between arms) in phase III oncology trials is only 40%, suggesting that current phase II trials are insufficiently informative. However, simulation studies suggest that randomized phase II trials would have lower error rates and greater predictive power for phase III results. Randomized phase II trials may also be more informative than single-arm phase II trials because of the hypotheses being tested, the variety of possible endpoints, and the opportunities for biomarker discovery. There are a wide variety of randomized phase II designs that can be used, including the randomized discontinuation design, the delayed start design, adaptive (Bayesian) designs, selection designs, and phase II/III designs. The barriers to widespread adoption of randomized phase II trials include time to completion, sample size considerations, and ethical concerns, but none are insurmountable. We conclude that randomized phase II trials are a worthy investment considering finite patient and financial resources and should be the rule rather than the exception for evaluating novel therapies in oncology. PMID- 21709275 TI - Comment on: Ferrannini. Learning from glycosuria. Diabetes 2011;60:695-696. PMID- 21709277 TI - MicroRNAs in beta-cell biology, insulin resistance, diabetes and its complications. PMID- 21709278 TI - Diabetes complications: the microRNA perspective. PMID- 21709279 TI - The paradox of progress: environmental disruption of metabolism and the diabetes epidemic. PMID- 21709280 TI - Maternal environment and the transgenerational cycle of obesity and diabetes. PMID- 21709281 TI - Insulin-induced hypoglycemia and its effect on the brain: unraveling metabolism by in vivo nuclear magnetic resonance. PMID- 21709285 TI - Retraction. Inhibition of NADPH oxidase attenuates vasospasm after experimental subarachnoid hemorrhage in rats. PMID- 21709282 TI - Epigenetics and diabetes risk: not just for imprinting anymore? PMID- 21709286 TI - World congress on insulin resistance, diabetes, and cardiovascular disease: Part 1. PMID- 21709287 TI - Does therapy with anti-TNF-alpha improve glucose tolerance and control in patients with type 2 diabetes? PMID- 21709288 TI - General practitioners' barriers to physical activity negatively influence type 2 diabetic patients' involvement in regular physical activity. PMID- 21709289 TI - Optimal timing of cataract surgery and panretinal photocoagulation for diabetic retinopathy. PMID- 21709290 TI - Comment on: Ekinci et al. Dietary salt intake and mortality in patients with type 2 diabetes. Diabetes Care 2011;34:703-709. PMID- 21709292 TI - Temporal trends in recording of diabetes on death certificates: results from Translating Research Into Action for Diabetes (TRIAD). AB - OBJECTIVE: To determine the frequency that diabetes is reported on death certificates of decedents with known diabetes and describe trends in reporting over 8 years. RESEARCH DESIGN AND METHODS: Data were obtained from 11,927 participants with diabetes who were enrolled in Translating Research into Action for Diabetes, a multicenter prospective observational study of diabetes care in managed care. Data on decedents (N=2,261) were obtained from the National Death Index from 1 January 2000 through 31 December 2007. The primary dependent variables were the presence of the ICD-10 codes for diabetes listed anywhere on the death certificate or as the underlying cause of death. RESULTS: Diabetes was recorded on 41% of death certificates and as the underlying cause of death for 13% of decedents with diabetes. Diabetes was significantly more likely to be reported on the death certificate of decedents dying of cardiovascular disease than all other causes. There was a statistically significant trend of increased reporting of diabetes as the underlying cause of death over time (P<0.001), which persisted after controlling for duration of diabetes at death. The increase in reporting of diabetes as the underlying cause of death was associated with a decrease in the reporting of cardiovascular disease as the underlying cause of death (P<0.001). CONCLUSIONS: Death certificates continue to underestimate the prevalence of diabetes among decedents. The increase in reporting of diabetes as the underlying cause of death over the past 8 years will likely impact estimates of the burden of diabetes in the U.S. PMID- 21709293 TI - Blood pressure trajectories prior to death in patients with diabetes. AB - OBJECTIVE: The goals of this study were to examine trajectories of blood pressure (BP) in adults with diabetes and investigate the association of trajectory patterns with mortality. RESEARCH DESIGN AND METHODS: A nonconcurrent longitudinal design was used to monitor 3,766 Medicare patients with diabetes from 2005 through 2008. Data were extracted from a registry of Medicare beneficiaries, which was developed by a large academic practice that participated in the Physician Group Practice Medicare Demonstration. The relationship between BP trajectories and all-cause mortality was modeled using multilevel mixed effects linear regression. RESULTS: During the 4-year study period, 10.7% of the patients died, half of whom were aged>=75 years. The crude and adjusted models both showed a greater decline in systolic and diastolic BP in patients who died than in those who did not die. In a model adjusted for age, sex, race, medications, and comorbidities, the mean systolic BP decreased by 3.2 mmHg/year (P<0.001) in the years before death and by 0.7 mmHg/year (P<0.001) in those who did not die (P<0.001 for the difference in slopes). Similarly, diastolic BP declined by 1.3 mmHg/year for those who died (P<0.001) and by 0.6 mmHg/year for those who did not die (P<0.001); the difference in slopes was significant (P=0.021). CONCLUSIONS: Systolic and diastolic BP both declined more rapidly in the 4 years before death than in patients who remained alive. PMID- 21709294 TI - A prospective study of prepregnancy dietary iron intake and risk for gestational diabetes mellitus. AB - OBJECTIVE: It is important to identify modifiable factors that may lower gestational diabetes mellitus (GDM) risk. Dietary iron is of particular interest given that iron is a strong prooxidant, and high body iron levels can damage pancreatic beta-cell function and impair glucose metabolism. The current study is to determine if prepregnancy dietary and supplemental iron intakes are associated with the risk of GDM. RESEARCH DESIGN AND METHODS: A prospective study was conducted among 13,475 women who reported a singleton pregnancy between 1991 and 2001 in the Nurses' Health Study II. A total of 867 incident GDM cases were reported. Pooled logistic regression was used to estimate the relative risk (RR) of GDM by quintiles of iron intake controlling for dietary and nondietary risk factors. RESULTS: Dietary heme iron intake was positively and significantly associated with GDM risk. After adjusting for age, BMI, and other risk factors, RRs (95% CIs) across increasing quintiles of heme iron were 1.0 (reference), 1.11 (0.87-1.43), 1.31 (1.03-1.68), 1.51 (1.17-1.93), and 1.58 (1.21-2.08), respectively (P for linear trend 0.0001). The multivariate adjusted RR for GDM associated with every 0.5-mg per day of increase in intake was 1.22 (1.10-1.36). No significant associations were observed between total dietary, nonheme, or supplemental iron intake and GDM risk. CONCLUSIONS: These findings suggest that higher prepregnancy intake of dietary heme iron is associated with an increased GDM risk. PMID- 21709295 TI - Gestational diabetes mellitus in relation to maternal dietary heme iron and nonheme iron intake. AB - OBJECTIVE: Higher heme iron intake is associated with increased type 2 diabetes risk. However, no previous study has evaluated gestational diabetes mellitus (GDM) risk in relation to heme iron intake during pregnancy. We investigated associations of maternal preconceptional and early pregnancy heme and nonheme iron intake with subsequent GDM risk. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study of 3,158 pregnant women. A food frequency questionnaire was used to assess maternal diet. Multivariable generalized linear regression models were used to derive estimates of relative risks (RRs) and 95% CIs. RESULTS: Approximately 5.0% of the cohort developed GDM (n=158). Heme iron intake was positively and significantly associated with GDM risk (Ptrend=0.04). After adjusting for confounders, women reporting the highest heme iron intake levels (>=1.52 vs. <0.48 mg per day) experienced a 3.31-fold-increased GDM risk (95% CI 1.02-10.72). In fully adjusted models, we noted that a 1-mg per day increase in heme iron was associated with a 51% increased GDM risk (RR 1.51 [95% CI 0.99 2.36]). Nonheme iron was inversely, though not statistically significantly, associated with GDM risk, and the corresponding RRs were 1.00, 0.83, 0.62, and 0.61 across quartiles of nonheme iron intake (Ptrend=0.08). CONCLUSIONS: High levels of dietary heme iron intake during the preconceptional and early pregnancy period may be associated with increased GDM risk. Associations of GDM risk with dietary nonheme iron intake are less clear. Confirmation of these findings by future studies is warranted. PMID- 21709296 TI - Changes over time in glycemic control, insulin sensitivity, and beta-cell function in response to low-dose metformin and thiazolidinedione combination therapy in patients with impaired glucose tolerance. AB - OBJECTIVE: In the Canadian Normoglycemia Outcome Evaluation (CANOE) trial, low dose rosiglitazone/metformin reduced the risk of diabetes in subjects with impaired glucose tolerance by 66% over a median of 3.9 years. We evaluate the temporal changes in glycemic control, insulin sensitivity, and beta-cell function during this trial. RESEARCH DESIGN AND METHODS: CANOE participants (n=207) underwent annual oral glucose tolerance testing, enabling temporal comparison of glycemia, insulin sensitivity (Matsuda index), and beta-cell function (insulin secretion-sensitivity index-2 [ISSI-2]) between the rosiglitazone/metformin and placebo arms. RESULTS: Glycemic parameters and insulin sensitivity improved in the rosiglitazone/metformin arm in year 1, but deteriorated in the years thereafter as in the placebo arm. Generalized estimating equation analysis confirmed that both insulin sensitivity and beta-cell function decreased over time (Matsuda: beta=-0.0515, P<0.0001; ISSI-2: beta=-6.6507, P<0.0001), with no significant time-by-treatment interaction (Matsuda: P=0.57; ISSI-2: P=0.22). CONCLUSIONS: Despite preventing incident diabetes, low-dose rosiglitazone/metformin did not modify the natural history of worsening insulin resistance and beta-cell dysfunction. PMID- 21709297 TI - Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. AB - OBJECTIVE: Increased oxidative stress (OS) and impaired anti-OS defenses are important in the development and persistence of insulin resistance (IR). Several anti-inflammatory and cell-protective mechanisms, including advanced glycation end product (AGE) receptor-1 (AGER1) and sirtuin (silent mating-type information regulation 2 homolog) 1 (SIRT1) are suppressed in diabetes. Because basal OS in type 2 diabetic patients is influenced by the consumption of AGEs, we examined whether AGE consumption also affects IR and whether AGER1 and SIRT1 are involved. RESEARCH DESIGN AND METHODS: The study randomly assigned 36 subjects, 18 type 2 diabetic patients (age 61+/-4 years) and 18 healthy subjects (age 67+/-1.4 years), to a standard diet (>20 AGE equivalents [Eq]/day) or an isocaloric AGE restricted diet (<10 AGE Eq/day) for 4 months. Circulating metabolic and inflammatory markers were assessed. Expression and activities of AGER1 and SIRT1 were examined in patients' peripheral blood mononuclear cells (PMNC) and in AGE stimulated, AGER1-transduced (AGER1+), or AGER1-silenced human monocyte-like THP 1 cells. RESULTS: Insulin and homeostasis model assessment, leptin, tumor necrosis factor-alpha and nuclear factor-kappaB p65 acetylation, serum AGEs, and 8-isoprostanes decreased in AGE-restricted type 2 diabetic patients, whereas PMNC AGER1 and SIRT1 mRNA, and protein levels normalized and adiponectin markedly increased. AGEs suppressed AGER1, SIRT-1, and NAD+ levels in THP-1 cells. These effects were inhibited in AGER1+ but were enhanced in AGER1-silenced cells. CONCLUSIONS: Food-derived pro-oxidant AGEs may contribute to IR in clinical type 2 diabetes and suppress protective mechanisms, AGER1 and SIRT1. AGE restriction may preserve native defenses and insulin sensitivity by maintaining lower basal OS. PMID- 21709298 TI - Diabetes performance measures: current status and future directions. PMID- 21709299 TI - Patterns of glycemia in normal pregnancy: should the current therapeutic targets be challenged? PMID- 21709300 TI - Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. PMID- 21709301 TI - Iron and diabetes revisited. PMID- 21709304 TI - Are MSER features really interesting? AB - Detection and description of affine-invariant features is a cornerstone component in numerous computer vision applications. In this note, we analyze the notion of maximally stable extremal regions (MSERs) through the prism of the curvature scale space, and conclude that in its original definition, MSER prefers regular (round) regions. Arguing that interesting features in natural images usually have irregular shapes, we propose alternative definitions of MSER which are free of this bias, yet maintain their invariance properties. PMID- 21709302 TI - What's next for diabetes prevention? PMID- 21709305 TI - Nonparametric Scene Parsing via Label Transfer. AB - While there has been a lot of recent work on object recognition and image understanding, the focus has been on carefully establishing mathematical models for images, scenes, and objects. In this paper, we propose a novel, nonparametric approach for object recognition and scene parsing using a new technology we name label transfer. For an input image, our system first retrieves its nearest neighbors from a large database containing fully annotated images. Then, the system establishes dense correspondences between the input image and each of the nearest neighbors using the dense SIFT flow algorithm [28], which aligns two images based on local image structures. Finally, based on the dense scene correspondences obtained from SIFT flow, our system warps the existing annotations and integrates multiple cues in a Markov random field framework to segment and recognize the query image. Promising experimental results have been achieved by our nonparametric scene parsing system on challenging databases. Compared to existing object recognition approaches that require training classifiers or appearance models for each object category, our system is easy to implement, has few parameters, and embeds contextual information naturally in the retrieval/alignment procedure. PMID- 21709306 TI - Introduction: laboratory invertebrates: only spineless, or spineless and painless? PMID- 21709307 TI - Invertebrate models for biomedical research, testing, and education. AB - Invertebrate animals have been used as medicinals for 4,000 years and have served as models for research and teaching since the late 1800s. Interest in invertebrate models has increased over the past several decades as the research community has responded to public concerns about the use of vertebrate animals in research. As a result, invertebrates are being evaluated and recognized as models for many diseases and conditions. Their use has led to discoveries in almost every area of biology and medicine--from embryonic development to aging processes. Species range from terrestrial invertebrates such as nematodes and insects to freshwater and marine life including planarians, crustaceans, molluscs, and many others. The most often used models are the fruit fly Drosophila melanogaster and the minuscule nematode Caenorhabditis elegans. Topics in this article are categorized by biologic system, process, or disease with discussion of associated invertebrate models. Sections on bioactive products discovered from invertebrates follow the models section, and the article concludes with uses of invertebrates in teaching. The models reviewed can serve as references for scientists, researchers, veterinarians, institutional animal care and use committees (IACUCs), and others interested in alternatives to vertebrate animals. PMID- 21709308 TI - Culture and maintenance of selected invertebrates in the laboratory and classroom. AB - Invertebrate species have been used for many years in the laboratory and teaching environment. We discuss some of the most commonly maintained invertebrates--the nematode (Caenorhabditis elegans), the California sea hare (Aplysia californica), the fruit fly (Drosophila melanogaster), terrestrial hermit crabs, the horseshoe crab (Limulus polyphemus), and cephalopods--and briefly describe general techniques for culturing them in captivity. The aim of this article is to give potential users an idea of the materials, methods, and effort required to maintain each type of organism in a laboratory or classroom setting. PMID- 21709309 TI - Invertebrate resources on the internet. AB - The use of invertebrates in research laboratories, classroom teaching, and public displays has greatly increased over the past 20 years, accompanied by a corresponding increase in the amount of online information and literature about invertebrates. This brief overview of Internet resources is intended to aid both novice and experienced individuals in the search for such information. PMID- 21709310 TI - Pain and suffering in invertebrates? AB - All animals face hazards that cause tissue damage and most have nociceptive reflex responses that protect them from such damage. However, some taxa have also evolved the capacity for pain experience, presumably to enhance long-term protection through behavior modification based on memory of the unpleasant nature of pain. In this article I review various criteria that might distinguish nociception from pain. Because nociceptors are so taxonomically widespread, simply demonstrating their presence is not sufficient. Furthermore, investigation of the central nervous system provides limited clues about the potential to experience pain. Opioids and other analgesics might indicate a central modulation of responses but often peripheral effects could explain the analgesia; thus reduction of responses by analgesics and opioids does not allow clear discrimination between nociception and pain. Physiological changes in response to noxious stimuli or the threat of a noxious stimulus might prove useful but, to date, application to invertebrates is limited. Behavior of the organism provides the greatest insights. Rapid avoidance learning and prolonged memory indicate central processing rather than simple reflex and are consistent with the experience of pain. Complex, prolonged grooming or rubbing may demonstrate an awareness of the specific site of stimulus application. Tradeoffs with other motivational systems indicate central processing, and an ability to use complex information suggests sufficient cognitive ability for the animal to have a fitness benefit from a pain experience. Available data are consistent with the idea of pain in some invertebrates and go beyond the idea of just nociception but are not definitive. In the absence of conclusive data, more humane care for invertebrates is suggested. PMID- 21709311 TI - Nociceptive behavior and physiology of molluscs: animal welfare implications. AB - Molluscs have proven to be invaluable models for basic neuroscience research, yielding fundamental insights into a range of biological processes involved in action potential generation, synaptic transmission, learning, memory, and, more recently, nociceptive biology. Evidence suggests that nociceptive processes in primary nociceptors are highly conserved across diverse taxa, making molluscs attractive models for biomedical studies of mechanisms that may contribute to pain in humans but also exposing them to procedures that might produce painlike sensations. We review the physiology of nociceptors and behavioral responses to noxious stimulation in several molluscan taxa, and discuss the possibility that nociception may result in painlike states in at least some molluscs that possess more complex nervous systems. Few studies have directly addressed possible emotionlike concomitants of nociceptive responses in molluscs. Because the definition of pain includes a subjective component that may be impossible to gauge in animals quite different from humans, firm conclusions about the possible existence of pain in molluscs may be unattainable. Evolutionary divergence and differences in lifestyle, physiology, and neuroanatomy suggest that painlike experiences in molluscs, if they exist, should differ from those in mammals. But reports indicate that some molluscs exhibit motivational states and cognitive capabilities that may be consistent with a capacity for states with functional parallels to pain. We therefore recommend that investigators attempt to minimize the potential for nociceptor activation and painlike sensations in experimental invertebrates by reducing the number of animals subjected to stressful manipulations and by administering appropriate anesthetic agents whenever practicable, welfare practices similar to those for vertebrate subjects. PMID- 21709312 TI - Anesthesia, analgesia, and euthanasia of invertebrates. AB - Invertebrate animals have long played an important role in biomedical research in such fields as genetics, physiology, and development. However, with few exceptions, scientists, veterinarians, and technicians have paid little attention to the anesthesia, analgesia, and euthanasia of these diverse creatures. Indeed, some standard research procedures are routinely performed without anesthesia. Yet various chemical agents are available for the immobilization or anesthesia of invertebrates, ranging from gases or volatile liquids that can be pumped into either an anesthetic chamber (for terrestrial species) or a container of water (aquatic species), to benzocaine and other substances for fish. Many invertebrates are not difficult to immobilize or anesthetize and the procedures recommended in this article appear to be safe; however, none should be considered totally risk-free. Analgesia of invertebrates is as yet a largely unexplored field; until scientific data are available, other measures can promote the well being of these animals in the laboratory. For euthanasia, various methods (physical or chemical or a combination of both) have been recommended for different taxa of invertebrates, but most have not been properly studied under laboratory conditions and some can be problematic in the context of research procedures and tissue harvesting. Furthermore, relevant data are scattered, sometimes available only in languages other than English, and there is no international approach for seeking and collating such information. In this article I review various methods of anesthesia, analgesia, and euthanasia for terrestrial and aquatic invertebrates, as well as areas requiring further research. PMID- 21709313 TI - Philosophical background of attitudes toward and treatment of invertebrates. AB - People who interact with or make decisions about invertebrate animals have an attitude toward them, although they may not have consciously worked it out. Three philosophical approaches underlie this attitude. The first is the contractarian, which basically contends that animals are only automata and that we humans need not concern ourselves with their welfare except for our own good, because cruelty and neglect demean us. A second approach is the utilitarian, which focuses on gains versus losses in interactions between animals, including humans. Given the sheer numbers of invertebrates-they constitute 99% of the animals on the planet- this attitude implicitly requires concern for them and consideration in particular of whether they can feel pain. Third is the rights-based approach, which focuses on humans-treatment of animals by calling for an assessment of their quality of life in each human-animal interaction. Here scholars debate to what extent different animals have self-awareness or even consciousness, which may dictate our treatment of them. Regardless of the philosophical approach to invertebrates, information and education about their lives are critical to an understanding of how humans ought to treat them. PMID- 21709314 TI - IACUC Challenges in Invertebrate Research. AB - With billions of individuals and possibly hundreds of thousands of genera, invertebrates represent the largest number and greatest diversity of all animals used in research. Although the capacity for nociception is recognized in many invertebrate taxa, researchers and IACUC members are challenged by a lack of clear understanding of invertebrate welfare and by differing standards of moral concern for these taxa. In practice this has led IACUCs to consider invertebrates in two major groups: species worthy of increased moral concern approximating that shown to vertebrate species (this group includes cephalopods and to some extent decapod crustaceans) and all others. This dichotomy has led to differences in how invertebrate research is regulated and documented. This article presents two case studies illustrating specific concerns in invertebrate research protocols and then provides relevant information to address practical IACUC matters related to regulatory and ethical issues, sourcing and record keeping, risk management, assessment of pain and nociception in invertebrates, housing and husbandry, invasive procedures, veterinary care, and humane endpoints. PMID- 21709315 TI - Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. AB - Cancer cells feature altered glucose metabolism that allows their rapid growth. They consume large amounts of glucose to produce lactate, even in the presence of ample oxygen, which is known as the Warburg effect. Pyruvate kinase M2 (PKM2) contributes to the Warburg effect by previously unknown mechanisms. Hypoxia inducible factor 1 (HIF-1) mediates PKM2 gene transcription and glucose reprogramming in cancer cells. The recent discovery of novel physical and functional interactions between PKM2 and HIF-1 in cancer cells has provided insight into molecular mechanisms underlying the Warburg effect. PMID- 21709316 TI - A breast cancer meta-analysis of two expression measures of chromosomal instability reveals a relationship with younger age at diagnosis and high risk histopathological variables. AB - Breast cancer in younger patients often presents with adverse histopathological features, including increased frequency of estrogen receptor negative and lymph node positive disease status. Chromosomal instability (CIN) is increasingly recognised as an important prognostic variable in solid tumours. In a breast cancer meta-analysis of 2423 patients we examine the relationship between clinicopathological parameters and two distinct chromosomal instability gene expression signatures in order to address whether younger age at diagnosis is associated with increased tumour genome instability. We find that CIN, assessed by the two independently derived CIN expression signatures, is significantly associated with increased tumour size, ER negative or HER2 positive disease, higher tumour grade and younger age at diagnosis in ER negative breast cancer. These data support the hypothesis that chromosomal instability may be a defining feature of breast cancer biology and clinical outcome. PMID- 21709318 TI - Direct and inverted nematic dispersions for soft matter photonics. AB - General properties and recent developments in the field of nematic colloids and emulsions are discussed. The origin and nature of pair colloidal interactions in the nematic colloids are explained and an overview of the stable colloidal 2D crystalline structures and superstructures discovered so far is given. The nature and role of topological defects in the nematic colloids is discussed, with an emphasis on recently discovered entangled colloidal structures. Applications of inverted nematic emulsions and binding force mechanisms in nematic colloids for soft matter photonic devices are discussed. PMID- 21709317 TI - Targeting cancer with peptide aptamers. AB - A major endeavour in cancer chemotherapy is to develop agents that specifically target a biomolecule of interest. There are two main classes of targeting agents: small molecules and biologics. Among biologics (e.g.: antibodies), DNA, RNA but also peptide aptamers are relatively recent agents. Peptide aptamers are seldom described but represent attractive agents that can inhibit a growing panel of oncotargets including Heat Shock Proteins. Potential pitfalls and coming challenges towards successful clinical trials are presented such as optimizing the delivery of peptide aptamers thanks to Nanotechnology. PMID- 21709319 TI - Numerical investigations of the dynamics of two-component vesicles. AB - We examined the dynamics of the deformation and phase separation of two-component vesicles. First, we numerically investigated the effects of (i) thermal noise, (ii) hydrodynamic flow induced by the line tension of the domain boundary and (iii) composition-dependent bending rigidity on the coarsening dynamics of a phase-separated pattern on the surfaces of vesicles with fixed shapes. The dynamical exponent z (N(DB) ~ t(-z), the total length of the domain boundaries) of the coarsening of the phase-separated pattern was found to decrease from z = 1/3 under no thermal noise to 1/5 < z < 1/4 when including the effects of thermal noise. We also found that the hydrodynamic effect enhances the coarsening in a bicontinuous phase separation for a spherical vesicle. In phase separations of a shape-fixed tubular vesicle, a band-like phase separation with periodicity along the longer axis of the tube occurs because of the composition-dependent bending rigidity and the higher curvatures at the tube end-caps. Second, we also explored the dynamics of shape deformation coupled with phase separation through the bending rigidity of the membrane which depends on the local composition in lipids and found that the composition-dependent bending rigidity crucially influences the phase separation and deformation of the vesicle. The results of simulations are in good agreement with experimentally observed behavior known as 'shape convergence' (Yanagisawa et al 2008 Phys. Rev. Lett. 100 148102). PMID- 21709320 TI - Roles of bond orientational ordering in glass transition and crystallization. AB - It is widely believed that crystallization in three dimensions is primarily controlled by positional ordering, and not by bond orientational ordering. In other words, bond orientational ordering is usually considered to be merely a consequence of positional ordering and thus has often been ignored. This one order-parameter (density) description may be reasonable when we consider an equilibrium liquid-solid transition, but may not be enough to describe a metastable state and the kinetics of the transition. Here we propose that bond orientational ordering can play a key role in (i) crystallization, (ii) the ordering to quasi-crystal and (iii) vitrification, which occurs under rather weak frustration against crystallization. In a metastable supercooled state before crystallization, a system generally tends to have bond orientational order at least locally as a result of a constraint of dense packing. For a system interacting with hard-core repulsions, the constraint is intrinsically of geometrical origin and thus the basic physics is the same as nematic ordering of rod-like particles upon densification. Furthermore, positional ordering is easily destroyed even by weak frustration such as polydispersity and anisotropic interactions which favour a symmetry not consistent with that of the equilibrium crystal. Thus we may say that vitrification can be achieved by disturbing and prohibiting long-range positional ordering. Even in such a situation, bond orientational ordering still survives, accompanying its critical-like fluctuations, which are the origin of dynamic heterogeneity for this case. This scenario naturally explains both the absence of positional order and the development of bond orientational order upon cooling in a supercooled state. Although our argument is speculative in nature, we emphasize that this physical picture can coherently explain crystallization, vitrification, quasi crystallization and their relationship in a natural manner. For a strongly frustrated system, even bond orientational order can be destroyed. Even in such a case there may still appear a structural signature of dense packing, which is linked to slow dynamics. PMID- 21709321 TI - Asymmetric distribution of cone-shaped lipids in a highly curved bilayer revealed by a small angle neutron scattering technique. AB - We have investigated the lipid sorting in a binary small unilamellar vesicle (SUV) composed of cone-shaped (1,2-dihexanoyl-sn-glycero-3-phosphocholine: DHPC) and cylinder-shaped (1,2-dipalmitoyl-sn-glycero-3-phosphocholine: DPPC) lipids. In order to reveal the lipid sorting we adopted a contrast matching technique of small angle neutron scattering (SANS), which extracts the distribution of deuterated lipids in the bilayer quantitatively without steric modification of lipids as in fluorescence probe techniques. First the SANS profile of protonated SUVs at a film contrast condition showed that SUVs have a spherical shape with an inner radius of 190 A and a bilayer thickness of 40 A. The SANS profile of deuterated SUVs at a contrast matching condition showed a characteristic scattering profile, indicating an asymmetric distribution of cone-shaped lipids in the bilayer. The characteristic profile was described well by a spherical bilayer model. The fitting revealed that most DHPC molecules are localized in the outer leaflet. Thus the shape of the lipid is strongly coupled with the membrane curvature. We compared the obtained asymmetric distribution of the cone-shaped lipids in the bilayer with the theoretical prediction based on the curvature energy model. PMID- 21709322 TI - Solvation effects in phase transitions in soft matter. AB - Phase transitions in polar binary mixtures can be drastically altered by even a small amount of salt. This is because the preferential solvation strongly depends on the ambient composition. Together with a summary of our research on this problem, we present some detailed results on the role of antagonistic salt composed of hydrophilic and hydrophobic ions. These ions tend to segregate at liquid-liquid interfaces and selectively couple to water-rich and oil-rich composition fluctuations, leading to mesophase formation. In our two-dimensional simulation, the coarsening of the domain structures can be stopped or slowed down, depending on the interaction parameter (or the temperature) and the salt density. We realize stripe patterns at the critical composition and droplet patterns at off-critical compositions. In the latter case, charged droplets emerge with considerable size dispersity in a percolated region. We also give the structure factors among the ions, accounting for the Coulomb interaction and the solvation interaction mediated by the composition fluctuations. PMID- 21709323 TI - Fabrication and structural analysis of polyrotaxane fibers and films. AB - Polyrotaxane (PR), a typical example of topological supramolecular architecture, consists of multiple cyclic molecules threaded onto a linear polymer backbone and capped with bulky end-groups. The PR system of polyethylene glycol and alpha cyclodextrin (alpha-CD) has been extensively studied for its facile synthesis, unique molecular structure, and possible applications for various smart materials. We have previously demonstrated the fabrication of PR-based fibers without chemical cross-links by wet spinning of PR solution. In this paper, we investigate the crystal structure of alpha-CDs in PR fibers and the effect of drawing on it. The alpha-CDs in PR fiber are found to form hexagonal channel-type structure. The drawing process promotes formation of the packing arrangement of alpha-CDs in the c-axis because of the sliding of alpha-CD molecules along the polymer backbone. In addition, we demonstrate the preparation of an elastomeric PR film having similar network structure to the fibers and ethylene glycol oligomer as plasticizer. PMID- 21709324 TI - Insights on raft behavior from minimal phenomenological models. AB - We construct a simple phenomenological theory of phase separation in ternary mixtures of cholesterol and saturated and unsaturated lipids. Such separation is relevant to the formation of 'rafts' in the plasma membrane. We also show how simple cross-linking of proteins which prefer one form of lipid to the other can trigger raft-formation, the first step in a signaling pathway. PMID- 21709325 TI - Hierarchical self-assembly of two-length-scale multiblock copolymers. AB - The self-assembly in diblock copolymer-based supramolecules, obtained by hydrogen bonding short side chains to one of the blocks, as well as in two-length-scale linear terpolymers results in hierarchical structure formation. The orientation of the different domains, e.g. layers in the case of a lamellar-in-lamellar structure, is determined by the molecular architecture, graft-like versus linear, and the relative magnitude of the interactions involved. In both cases parallel and perpendicular arrangements have been observed. The comb-shaped supramolecules approach is ideally suited for the preparation of nanoporous structures. A bicontinuous morphology with the supramolecular comb block forming the channels was finally achieved by extending the original approach to suitable triblock copolymer-based supramolecules. PMID- 21709327 TI - Shear banding in thixotropic and normal emulsions. AB - When made to flow, yield stress materials rarely flow homogeneously. This is mostly attributed to the fact that such materials show a transition from a solid- to a liquid-like state when the stress exceeds some critical value: the yield stress. Thus, if the stress is heterogeneous, so is the flow. Here we consider emulsion flows in a cone-plate geometry that, for Newtonian fluids, correspond to a homogeneous stress situation and show that shear banding can also be observed either due to wall slip or to the existence of a critical shear rate. By means of velocity profiles obtained using a confocal laser scanning microscope combined with a rheometer we conclude that the last type of shear banding occurs only in thixotropic yield stress materials. PMID- 21709326 TI - Dynamical membrane curvature instability controlled by intermonolayer friction. AB - We study a dynamical curvature instability caused by a local chemical modification of a phospholipid membrane. In our experiments, a basic solution is microinjected close to a giant unilamellar vesicle, which induces a local chemical modification of some lipids in the external monolayer of the membrane. This modification causes a local deformation of the vesicle, which then relaxes. We present a theoretical description of this instability, taking into account both the change of the equilibrium lipid density and the change of the spontaneous membrane curvature induced by the chemical modification. We show that these two types of changes of the membrane properties yield different dynamics. In contrast, it is impossible to distinguish them when studying the equilibrium shape of a vesicle subjected to a global modification. In our model, the longest relaxation timescale is related to the intermonolayer friction, which plays an important part when there is a change in the equilibrium density in one monolayer. We compare our experimental results to the predictions of our model by fitting the measured time evolution of the deformation height to the solution of our dynamical equations. We obtain good agreement between theory and experiments. Our fits enable us to estimate the intermonolayer friction coefficient, yielding values that are consistent with previous measurements. PMID- 21709328 TI - Non-equilibrium dynamics of 2D liquid crystals driven by transmembrane gas flow. AB - Free-standing films composed of several layers of chiral smectic liquid crystals (SmC*) exhibited unidirectional director precession under various vapor transfers across the films. When the transferred vapors were general organic solvents, the precession speed linearly depended on the momentum of the transmembrane vapors, where the proportional constant was independent of the kind of vapor. In contrast, the same SmC* films under water transfer exhibited precession in the opposite direction. As a possible reason for the rotational inversion, we suggest the competition of two origins for the torques, one of which is microscopic and the other macroscopic. Next, we tried to move an external object by making use of the liquid crystal (LC) motion. When a solid or a liquid particle was set on a film under vapor transfer, the particle was rotated in the same direction as the LC molecules. Using home-made laser tweezers, we measured the force transmitted from the film to the particle, which we found to be several pN. PMID- 21709329 TI - Surfactant-induced friction reduction for hydrogels in the boundary lubrication regime. AB - We studied the ability of surfactants to reduce friction by boundary lubrication for a bulk hydrogel sliding on a solid surface in an aqueous solution. A piece of negatively charged polyelectrolyte hydrogel was slid across solid surfaces with various levels of hydrophobicity, using a strain-controlled parallel-plate rheometer in water. A dramatic reduction in the sliding friction, especially in the low velocity region, was detected by the addition of a surfactant to the water medium. This friction reduction was only observed in gel-solid friction but not in solid-solid friction, indicating that the soft and wet nature of the gel surface was crucial for this surfactant-induced friction reduction. This phenomenon reveals that surfactants can remain at the gel-mated interface, thus preventing direct interfacial interaction between the sliding surfaces, and significantly decreasing the frictional stress. The reported dramatic reduction in friction highlights the frictional characteristics of soft and wet hydrogel materials. PMID- 21709330 TI - Hydration, phase separation and nonlinear rheology of temperature-sensitive water soluble polymers. AB - The collapse of a poly(N-isopropylacrylamide) (PNIPAM) chain upon heating and the phase diagrams of aqueous PNIPAM solutions with a very flat lower critical solution temperature (LCST) phase separation line are theoretically studied on the basis of cooperative dehydration (simultaneous dissociation of bound water molecules in a group of correlated sequence), and compared with the experimental observation of temperature-induced coil-globule transition by light scattering methods. The transition becomes sharper with the cooperativity parameter sigma of hydration. The reentrant coil-globule-coil transition and cononsolvency in a mixed solvent of water and methanol are also studied from the viewpoint of competitive hydrogen bonds between polymer-water and polymer-methanol. The downward shift of the cloud-point curves (LCST cononsolvency) with the mol fraction of methanol due to the competition is calculated and compared with the experimental data. Aqueous solutions of hydrophobically modified PNIPAM carrying short alkyl chains at both chain ends (telechelic PNIPAM) are theoretically and experimentally studied. The LCST of these solutions is found to shift downward along the sol-gel transition curve as a result of end-chain association (association-induced phase separation), and separate from the coil-globule transition line. Associated structures in the solution, such as flower micelles, mesoglobules, and higher fractal assembly, are studied by ultra small-angle neutron scattering with theoretical modeling of the scattering function. Dynamic mechanical modulus, nonlinear stationary viscosity, and stress build-up in start up shear flows of the associated networks are studied on the basis of the affine and non-affine transient network theory. The molecular conditions for thickening, strain hardening, and stress overshoot are found in terms of the nonlinear amplitude A of the chain tension and the tension-dissociation coupling constant g. PMID- 21709331 TI - Micellization kinetics of diblock copolymers in a homopolymer matrix: a self consistent field study. AB - Self-consistent field theory is used to calculate free energy barriers and reaction rates for the spontaneous association and dissociation of micelles formed of block copolymers in a homopolymer matrix. The barriers are prohibitively large for copolymers of typical molecular weights when the unimer (free surfactant) concentration is near the equilibrium critical micelle concentration (CMC). As a result, polymeric micelles normally cannot reach true thermodynamic equilibrium. The rates of association and dissociation are, however, sensitive to unimer concentration, making it possible to form or destroy micelles at observable rates in sufficiently highly supersaturated or subsaturated solutions, respectively, even when both reactions are suppressed near the equilibrium CMC. The barrier to dissociation is particularly sensitive to unimer concentration, and vanishes when the unimer concentration is only slightly (for example, a percentage of a few tens) below the equilibrium CMC. PMID- 21709332 TI - International Symposium on Non-Equilibrium Soft Matter 2010. PMID- 21709333 TI - Morphology and rheology of an immiscible polymer blend subjected to a step electric field under shear flow. AB - We have investigated the structural change of an immiscible polymer blend in shear flow when subjected to a step electric field. During the process three dimensional images were successfully constructed with a confocal scanning laser microscope and at the same time the transient shear stress was also measured. The interface tensor was calculated from the images. Several factors are incorporated into the shear stress, such as the bulk viscosity, the interfacial tension and the Maxwell stress. We performed an experiment to separate the Maxwell stress from the total shear stress. The results are discussed in terms of the interface tensor. PMID- 21709334 TI - Onsager's variational principle in soft matter. AB - In the celebrated paper on the reciprocal relation for the kinetic coefficients in irreversible processes, Onsager (1931 Phys. Rev. 37 405) extended Rayleigh's principle of the least energy dissipation to general irreversible processes. In this paper, I shall show that this variational principle gives us a very convenient framework for deriving many established equations which describe the nonlinear and non-equilibrium phenomena in soft matter, such as phase separation kinetics in solutions, gel dynamics, molecular modeling for viscoelasticity nemato-hydrodynamics, etc. Onsager's variational principle can therefore be regarded as a solid general basis for soft matter physics. PMID- 21709335 TI - Kaleidoscopic morphologies from ABC star-shaped terpolymers. AB - Star-shaped terpolymers of the ABC type composed of incompatible polymer components give a variety of ordered structures with mesoscopic length scales depending on their composition ratio. Their peculiar features are summarized in this report. Polymer components adopted are polyisoprene (I), polystyrene (S) and poly(2-vinylpyridine) (P), and many monodisperse samples of the I(X)S(Y)P(Z) type were anionically prepared. Firstly our focus is on molecules of the I(1.0)S(1.0)P(x(1)) type, where x(1) is only a variable. The complex but systematic morphology change was displayed within the range 0.2 <= x(1) <= 10, that is, their structures change from spherical plus lamellae structure for I(1.0)S(1.0)P(0.2) to periodic tilings (0.4 <= x(1) <= 1.9), then to lamellae-in lamella (3.0 <= x(1) <= 4.9) and lamellae-in-cylinder (7.9 <= x(1) <= 10) structures with increasing x(1). Here if we pay attention to the structural variation of the P domain inclusively, it transforms from sphere to cylinder, lamella and then to matrix, which is the same as that for linear polymers. Among them, several periodic Archimedean tiling patterns can be naturally formed when the relative lengths of the three chains are close to one another. Moreover, it has been found that the tiling zone is spread out widely. For example, the series I(1.0)S(1.8)P(x(2)) (with 0.8 <= x(2) <= 2.9) and the other series I(1.0)S(y)P(2.0) (with 1.1 <= y <= 2.7) show mostly Archimedean tilings. Additionally, block copolymer/homopolymer blends with a composition of I(1.0)S(2.7)P(2.5) reveal a quasicrystalline tiling with dodecagonal symmetry. Furthermore, a zinc-blende-type four-branched network structure was created just a little outside of the tiling region for a block copolymer/homopolymer blend of I(1.0)S(2.3)P(0.8). When some more asymmetry in chain length is introduced, hyperbolic tiling on a gyroid membrane has successfully been constructed for the sample I(1.0)S(1.8)P(3.2) and it transforms into a hierarchical cylinders-in lamella structure with further increase in P content to I(1.0)S(1.8)P(6.4). Thus, kaleidoscopic morphologies have been generated from ABC star-shaped terpolymers and their structural change has turned out to be very sensitive to relative compositions. PMID- 21709336 TI - Effects of hydrodynamic interactions in binary colloidal mixtures driven oppositely by oscillatory external fields. AB - The collective dynamics in a binary mixture of colloidal particles which are driven in opposite directions by an external oscillatory field is examined by computer simulations in two spatial dimensions. Both Brownian dynamics (BD) computer simulations, which ignore solvent-mediated hydrodynamic interactions between the colloidal particles, and multi-particle collision dynamics (MPCD) simulations, which include hydrodynamic interactions, are employed. We first review recent results obtained by BD. Depending on the driving frequency and amplitude, lane formation parallel to the drive and band formation perpendicular to the drive occur. Band formation is stable only in a finite window of oscillation frequencies and driving strengths and is taken over by lane formation if the driving force is increased or the oscillation frequency is decreased. MPCD simulations, on the other hand, reveal that band formation is blurred by hydrodynamic interactions. During the front collisions of oppositely driven particles there is a strong vortical movement of the solvent which tends to mix particles and broaden the interface of the bands. This can either lead to a novel intermittent dynamical behaviour or to band rupture into local clusters. These effects, which are absent for BD, are characterized by the strengths of the enstrophy and its spectrum. We finally discuss possible experimental realizations of the models employed. PMID- 21709337 TI - Regional coherence evaluation in mild cognitive impairment and Alzheimer's disease based on adaptively extracted magnetoencephalogram rhythms. AB - This study assesses the connectivity alterations caused by Alzheimer's disease (AD) and mild cognitive impairment (MCI) in magnetoencephalogram (MEG) background activity. Moreover, a novel methodology to adaptively extract brain rhythms from the MEG is introduced. This methodology relies on the ability of empirical mode decomposition to isolate local signal oscillations and constrained blind source separation to extract the activity that jointly represents a subset of channels. Inter-regional MEG connectivity was analysed for 36 AD, 18 MCI and 26 control subjects in delta, theta, alpha and beta bands over left and right central, anterior, lateral and posterior regions with magnitude squared coherence-c(f). For the sake of comparison, c(f) was calculated from the original MEG channels and from the adaptively extracted rhythms. The results indicated that AD and MCI cause slight alterations in the MEG connectivity. Computed from the extracted rhythms, c(f) distinguished AD and MCI subjects from controls with 69.4% and 77.3% accuracies, respectively, in a full leave-one-out cross-validation evaluation. These values were higher than those obtained without the proposed extraction methodology. PMID- 21709338 TI - Prediction of paroxysmal atrial fibrillation using recurrence plot-based features of the RR-interval signal. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia and increases the risk of stroke. Predicting the onset of paroxysmal AF (PAF), based on noninvasive techniques, is clinically important and can be invaluable in order to avoid useless therapeutic intervention and to minimize risks for the patients. In this paper, we propose an effective PAF predictor which is based on the analysis of the RR-interval signal. This method consists of three steps: preprocessing, feature extraction and classification. In the first step, the QRS complexes are detected from the electrocardiogram (ECG) signal and then the RR-interval signal is extracted. In the next step, the recurrence plot (RP) of the RR-interval signal is obtained and five statistically significant features are extracted to characterize the basic patterns of the RP. These features consist of the recurrence rate, length of longest diagonal segments (L(max )), average length of the diagonal lines (L(mean)), entropy, and trapping time. Recurrence quantification analysis can reveal subtle aspects of dynamics not easily appreciated by other methods and exhibits characteristic patterns which are caused by the typical dynamical behavior. In the final step, a support vector machine (SVM)-based classifier is used for PAF prediction. The performance of the proposed method in prediction of PAF episodes was evaluated using the Atrial Fibrillation Prediction Database (AFPDB) which consists of both 30 min ECG recordings that end just prior to the onset of PAF and segments at least 45 min distant from any PAF events. The obtained sensitivity, specificity, positive predictivity and negative predictivity were 97%, 100%, 100%, and 96%, respectively. The proposed methodology presents better results than other existing approaches. PMID- 21709339 TI - Identification of high-risk acute coronary syndromes by spectral analysis of ear photoplethysmographic waveform variability. AB - There is a need for robust techniques for early and accurate diagnosis of acute coronary syndromes (ACSs), to avoid inappropriate discharge of patients. This study examined the use of frequency spectrum analysis of heart rate variability (HRV) and photoplethysmogram (PPG) waveform variability for the identification of high-risk ACS patients defined by an elevated cardiac troponin level. The study cohort comprised a convenience sample of adult patients presenting to the emergency department of the Prince of Wales Hospital over a 4 month period complaining of non-traumatic chest pain. Valid electrocardiogram (ECG) and earlobe PPG waveforms together with troponin I test results were obtained from 52 patients at presentation, 4 of which were troponin I positive (Trop 0+). Frequency spectrum analysis was performed on the beat-to-beat HRV and PPG waveform variability (PPGV). The Trop 0+ were found to have significantly higher normalized mid-frequency power (MF(nu)) in HRV (P = 0.017), PPG amplitude variability (P = 0.009) and the cross-spectrum of HRV and PPGV (P = 0.001), which were attributed to reflex sympathetic response to myocardial ischemia. MF(nu) of PPG amplitude had the best overall performance in detecting Trop 0+, with ROC area under the curve of 0.93. The results demonstrate the potential use of ear PPG waveform to identify high-risk heart disease patients, and further highlight the utility of frequency spectrum analysis of PPGV in critical care. PMID- 21709340 TI - Is it necessary to plan with safety margins for actively scanned proton therapy? AB - In radiation therapy, a plan is robust if the calculated and the delivered dose are in agreement, even in the case of different uncertainties. The current practice is to use safety margins, expanding the clinical target volume sufficiently enough to account for treatment uncertainties. This, however, might not be ideal for proton therapy and in particular when using intensity modulated proton therapy (IMPT) plans as degradation in the dose conformity could also be found in the middle of the target resulting from misalignments of highly in-field dose gradients. Single field uniform dose (SFUD) and IMPT plans have been calculated for different anatomical sites and the need for margins has been assessed by analyzing plan robustness to set-up and range uncertainties. We found that the use of safety margins is a good way to improve plan robustness for SFUD and IMPT plans with low in-field dose gradients but not necessarily for highly modulated IMPT plans for which only a marginal improvement in plan robustness could be detected through the definition of a planning target volume. PMID- 21709341 TI - X-ray coherent scattering form factors of tissues, water and plastics using energy dispersion. AB - A key requirement for the development of the field of medical x-ray scatter imaging is accurate characterization of the differential scattering cross sections of tissues and phantom materials. The coherent x-ray scattering form factors of five tissues (fat, muscle, liver, kidney, and bone) obtained from butcher shops, four plastics (polyethylene, polystyrene, lexan (polycarbonate), nylon), and water have been measured using an energy-dispersive technique. The energy-dispersive technique has several improvements over traditional diffractometer measurements. Most notably, the form factor is measured on an absolute scale with no need for scaling factors. Form factors are reported in terms of the quantity x = lambda(-1)sin (theta/2) over the range 0.363-9.25 nm( 1). The coherent form factors of muscle, liver, and kidney resemble those of water, while fat has a narrower peak at lower x, and bone is more structured. The linear attenuation coefficients of the ten materials have also been measured over the range 30-110 keV and parameterized using the dual-material approach with the basis functions being the linear attenuation coefficients of polymethylmethacrylate and aluminum. PMID- 21709342 TI - Terahertz pulsed imaging of freshly excised human colonic tissues. AB - We present the results from a feasibility study which measures properties in the terahertz frequency range of excised cancerous, dysplastic and healthy colonic tissues from 30 patients. We compare their absorption and refractive index spectra to identify trends which may enable different tissue types to be distinguished. In addition, we present statistical models based on variations between up to 17 parameters calculated from the reflected time and frequency domain signals of all the measured tissues. These models produce a sensitivity of 82% and a specificity of 77% in distinguishing between healthy and all diseased tissues and a sensitivity of 89% and a specificity of 71% in distinguishing between dysplastic and healthy tissues. The contrast between the tissue types was supported by histological staining studies which showed an increased vascularity in regions of increased terahertz absorption. PMID- 21709343 TI - A direction-selective flattening filter for clinical photon beams. Monte Carlo evaluation of a new concept. AB - A new concept for the design of flattening filters applied in the generation of 6 and 15 MV photon beams by clinical linear accelerators is evaluated by Monte Carlo simulation. The beam head of the Siemens Primus accelerator has been taken as the starting point for the study of the conceived beam head modifications. The direction-selective filter (DSF) system developed in this work is midway between the classical flattening filter (FF) by which homogeneous transversal dose profiles have been established, and the flattening filter-free (FFF) design, by which advantages such as increased dose rate and reduced production of leakage photons and photoneutrons per Gy in the irradiated region have been achieved, whereas dose profile flatness was abandoned. The DSF concept is based on the selective attenuation of bremsstrahlung photons depending on their direction of emission from the bremsstrahlung target, accomplished by means of newly designed small conical filters arranged close to the target. This results in the capture of large-angle scattered Compton photons from the filter in the primary collimator. Beam flatness has been obtained up to any field cross section which does not exceed a circle of 15 cm diameter at 100 cm focal distance, such as 10 * 10 cm(2), 4 * 14.5 cm(2) or less. This flatness offers simplicity of dosimetric verifications, online controls and plausibility estimates of the dose to the target volume. The concept can be utilized when the application of small- and medium-sized homogeneous fields is sufficient, e.g. in the treatment of prostate, brain, salivary gland, larynx and pharynx as well as pediatric tumors and for cranial or extracranial stereotactic treatments. Significant dose rate enhancement has been achieved compared with the FF system, with enhancement factors 1.67 (DSF) and 2.08 (FFF) for 6 MV, and 2.54 (DSF) and 3.96 (FFF) for 15 MV. Shortening the delivery time per fraction matters with regard to workflow in a radiotherapy department, patient comfort, reduction of errors due to patient movement and a slight, probably just noticable improvement of the treatment outcome due to radiobiological reasons. In comparison with the FF system, the number of head leakage photons per Gy in the irradiated region has been reduced at 15 MV by factors 1/2.54 (DSF) and 1/3.96 (FFF), and the source strength of photoneutrons was reduced by factors 1/2.81 (DSF) and 1/3.49 (FFF). PMID- 21709344 TI - Experimental results from a prototype slit-slat collimator with mixed multiplexed and non-multiplexed data. AB - We have previously shown with simulations that a gain in signal-to-noise ratio (SNR) can be obtained by using mixed multiplexed (MX) and non-MX data in a slit slat SPECT system as compared to using non-MX data only. We have now developed a prototype slit-slat collimator for a conventional gamma camera in order to validate these simulation results. The prototype collimator consists of seven slits and multiple parallel slats. Image reconstruction is performed using a modified OSEM algorithm, which takes into account geometric sensitivity variations and attenuation, but not scatter or resolution effects. Here, we first describe the calibration of the system and then we present the experimental validation with phantom experiments. SPECT acquisitions using different geometric and anthropomorphic phantoms were performed with and without multiplexing. The results show that reconstruction of the MX projections with the non-MX projections eliminates artefacts caused by multiplexing. SNR gains obtained using the mixed MX and non-MX configurations were in the range of 26% to 51% for different phantoms. The results were in agreement with our previously published simulation work, proving that combining MX and non-MX data can result in artefact free reconstructed images with improved SNR. PMID- 21709345 TI - Experimental verification of IMPT treatment plans in an anthropomorphic phantom in the presence of delivery uncertainties. AB - Clinically relevant intensity modulated proton therapy (IMPT) treatment plans were measured in a newly developed anthropomorphic phantom (i) to assess plan accuracy in the presence of high heterogeneity and (ii) to measure plan robustness in the case of treatment uncertainties (range and spatial). The new phantom consists of five different tissue substitute materials simulating different tissue types and was cut into sagittal planes so as to facilitate the verification of co-planar proton fields. GafChromic films were positioned in the different planes of the phantom, and 3D-IMPT and distal edge tracking (DET) plans were delivered to a volume simulating a skull base chordoma. In addition, treatments planned on CTs of the phantom with HU units modified were delivered to simulate systematic range uncertainties (range-error treatments). Finally, plans were delivered with the phantom rotated to simulate spatial errors. Results show excellent agreement between the calculated and the measured dose distribution: >99% and 98% of points with a gamma value <1 (3%/3 mm) for the 3D-IMPT and the DET plan, respectively. For both range and spatial errors, the 3D-IMPT plan was more robust than the DET plan. Both plans were more robust to range than to the spatial uncertainties. Finally, for range error treatments, measured distributions were compared to a model for predicting delivery errors in the treatment planning system. Good agreement has been found between the model and the measurements for both types of IMPT plan. PMID- 21709346 TI - High-yield room temperature route to copper sulfide hollow nanospheres and their electrochemical properties. AB - CuS hollow nanospheres have been successfully synthesized in high yield by reacting anhydrous cupric sulfate (CuSO(4).5H(2)O) with thioacetamide (TAA) in ethylene glycol (EG) with the assistance of cetyltrimethylammonium bromide (CTAB). The products were characterized systematically by XRD, EDX, FESEM, TEM and BET measurement and size analysis, CV, LSV and CP. FESEM and TEM images revealed that the as-prepared CuS hollow nanospheres had a mean diameter of about 500 nm with a hollow cavity of about 340 nm and shell thickness of about 80 nm. The spheres were constructed by numerous nanoflakes. The Brunauer-Emmett-Teller (BET) surface area of the as-synthesized products was measured to be 99.77 m(2)g( 1). The Barrett-Joyner-Halenda (BJH) model analysis showed that the as-prepared CuS materials had a main pore size distribution of around 25 nm. CV curves, LSV of CuS for oxygen electroreduction and CP curves showed that the as-prepared CuS nanospheres were potential candidates which can be used as cathode catalysts for the oxygen reduction reaction (ORR) in alkaline media. PMID- 21709347 TI - Silicon nano-well arrays for reliable pattern transfer and locally confined high temperature reactions. AB - Si nano-well arrays, with precisely controlled undercut Si sidewall profiles and flat bottomed pockets, enable uniform nanoscale pattern transfer from resists to metal deposits without degradation of the initial lithographic resolution, as verified by the formation of arrays of Au nano-dots with 10 nm diameter. An additional functionality of the Si nano-wells as local nano-reactors, where the patterned material is enclosed in a Si pocket during high temperature reaction, is demonstrated by thermally inducing a phase transformation of the as-deposited A1 phase of FePt nano-dots to the high coercivity, chemically ordered L1(0) phase. PMID- 21709348 TI - Fabrication of reliable semiconductor nanowires by controlling crystalline structure. AB - One-dimensional SnO(2) nanomaterials with wide bandgap characteristics are attractive for flexible and/or transparent displays and high-performance nano electronics. In this study, the crystallinity of SnO(2) nanowires was regulated by controlling their growth temperatures. Moreover, the correlation of the crystallinity of nanowires with optical and electrical characteristics was analyzed. When SnO(2) nanowires were grown at temperatures below 900 degrees C, they showed various growth directions and abnormal discontinuity in their crystal structures. On the other hand, most nanowires grown at 950 degrees C exhibited a regular growth trend in the direction of [100]. In addition, the low temperature photoluminescence measurement revealed that the higher growth temperatures of nanowires gradually decreased the 500 nm peak rather than the 620 nm peak. The former peak is derived from the surface defect related to the shallow energy level and affects nanowire surface states. Owing to crystallinity and defects, the threshold voltage range (maximum-minimum) of SnO(2) nanowire transistors was 1.5 V at 850 degrees C, 1.1 V at 900 degrees C, and 0.5 V at 950 degrees C, with dispersion characteristics dramatically decreased. This study successfully demonstrated the effects of nanowire crystallinity on optical and electrical characteristics. It also suggested that the optical and electrical characteristics of nanowire transistors could be regulated by controlling their growth temperatures in the course of producing SnO(2) nanowires. PMID- 21709349 TI - Synthesis and oxidation of luminescent silicon nanocrystals from silicon tetrachloride by very high frequency nonthermal plasma. AB - Silicon nanocrystals have recently attracted significant attention for applications in electronics, optoelectronics, and biological imaging due to their size-dependent optical and electronic properties. Here a method for synthesizing luminescent silicon nanocrystals from silicon tetrachloride with a nonthermal plasma is described. Silicon nanocrystals with mean diameters of 3-15 nm are synthesized and have a narrow size distribution with the standard deviation being less than 20% of the mean size. Control over crystallinity is achieved for plasma pressures of 1-12 Torr and hydrogen gas concentrations of 5-70% through adjustment of the plasma power. The size of nanocrystals, and resulting optical properties, is mainly dependent on the gas residence time in the plasma region. Additionally the surface of the nanocrystals is covered by both hydrogen and chlorine. Oxidation of the nanocrystals, which is found to follow the Cabrera Mott mechanism under ambient conditions, is significantly faster than hydrogen terminated silicon due to partial termination of the nanocrystal surface by chlorine. PMID- 21709350 TI - Buckling of a single-layered graphene sheet on an initially strained InGaAs thin plate. AB - The elastic buckling behavior of a defect-free single-layered graphene sheet deposited on a strained InGaAs substrate is investigated. Such a buckled sandwich structure can be formed by local etching of an initially strained InGaAs substrate. We numerically investigated the necessary buckling conditions for a single-layered graphene sheet of circular geometry on an initially strained InGaAs thin plate. A criterion for buckling for various axisymmetric buckling shapes was obtained. It is shown that for a thin circular InGaAs plate with a monolayer graphene sheet of radius 80 nm and thickness 4 nm three axisymmetric buckling shapes can be obtained. For an initial value of the elastic deformation of the plate of 3%, the in-plane strain in graphene can reach a value of 1%. This deformation is shown to be distributed inhomogeneously along the radius of the graphene monolayer. PMID- 21709351 TI - Exploration of the shapes of double-walled vesicles with a confined inner membrane. AB - We investigate double-walled vesicles as a simple model system for multi vesicular structures, where the inner membrane is confined within the outer membrane. Various shapes of double-walled vesicles in two dimensions are obtained by means of our recently-developed discrete space variation method, and the shapes of each layer are found to be interdependent. Confined within the outer membrane, an inner membrane with a larger surface area always shows a cristae shape. As previous simulations and theoretical analyses of a single-walled vesicle have been done before, the geometric properties of double-walled vesicles, including the mean square radius of gyration and volume within the vesicle membrane, are studied in detail as functions of the pressure and surface area. It is found that due to the inter-space restriction of each layer, double walled vesicles exhibit different behaviors compared with the previously-observed scaling laws of single-walled vesicles. It is straightforward to extend this study to more complicated and realistic biological systems, such as those including electrostatic interactions between membranes and solvent, phase separation, and cooperative interactions between multicomponent membranes. PMID- 21709352 TI - Crowding of polymer coils and demixing in nanoparticle-polymer mixtures. AB - The Asakura-Oosawa-Vrij (AOV) model of colloid-polymer mixtures idealises nonadsorbing polymers as effective spheres that are fixed in size and impenetrable to hard particles. Real polymer coils, however, are intrinsically polydisperse in size (radius of gyration) and may be penetrated by smaller particles. Crowding by nanoparticles can affect the size distribution of polymer coils, thereby modifying effective depletion interactions and thermodynamic stability. To analyse the influence of crowding on polymer conformations and demixing phase behaviour, we adapt the AOV model to mixtures of nanoparticles and ideal, penetrable polymer coils that can vary in size. We perform Gibbs ensemble Monte Carlo simulations, including trial nanoparticle-polymer overlaps and variations in the radius of gyration. Results are compared with predictions of free-volume theory. Simulation and theory consistently predict that ideal polymers are compressed by nanoparticles, and that compressibility and penetrability stabilise nanoparticle-polymer mixtures. PMID- 21709353 TI - Optimized transport properties of LaAlO3/SrTiO3 heterointerfaces by variation of pulsed laser fluence. AB - We show the influence of pulsed laser deposition fluence on the transport properties of the LaAlO(3)/SrTiO(3) (LAO/STO) heterointerface. Structural characterization by x-ray diffraction and medium energy ion spectrometry enables us to deduce that the electronic behaviour is extremely sensitive to the stoichiometry of the LAO layer as well as the structural quality of the STO surface. An optimum balance of these two quantities is demonstrated for an intermediate laser fluence. PMID- 21709354 TI - A density functional theory study of Mn nanowires on the Si(001) surface. AB - The structure of experimentally observed Mn nanolines on the Si(001) surface is investigated using density functional theory (DFT) and the DFT + U method. A candidate line structure consisting of a two-atom sub-unit is proposed, based on total energy and appearance in simulated scanning tunnelling microscopy images. The electronic and magnetic properties of this structure are investigated. The atoms in the line are strongly antiferromagnetically coupled with individual Mn atoms having moments of 4 u(B). The atoms in the sub-unit are seen to move further apart by 0.57 A upon forcing ferromagnetic alignment. PMID- 21709355 TI - Enhanced silicon oxidation on titanium-covered Si(001). AB - We report on a core level photoemission study of the formation of an ultrathin SiO(x) layer grown at the interface of a titanium-covered Si(001) surface. Oxygen exposure at room temperature induces a large chemical shift of the Si 2p state, predominantly assigned to Si(4+). The results indicate that a SiO(2 - delta) layer, close to the stoichiometry of SiO(2), is formed below the TiO(x) film. The thickness of the SiO(2 - delta) layer is estimated to be ~ 0.9 nm, corresponding to three to four oxide layers. Further chemical shift caused by annealing is attributed to the formation of titanium silicate (TiSi(x)O(y)). PMID- 21709357 TI - Workplace aesthetics: Impact of environments upon employee health? AB - Associations between self-reported need for aesthetic improvements in the workplace and the need for ergonomic improvement and health factors were investigated to determine the possible impact of aesthetic needs on job performance. The need for aesthetic improvements were compared with the need for ergonomic improvements. All employees at a Swedish broadcasting company were invited to participate in this cross sectional study. Of those who fulfilled the inclusion criteria the participation rate was 74% (1961/2641). Demographic data was obtained from company files and pre-validated questionnaire was used for data collections from the participants. additional questions on needs for improvement were developed, tested for repeatability, and demonstrated to be within acceptable limits. Differences between 'high rank' and 'low rank' aesthetic needs and ergonomic needs were correlated to set ups of demographic, work environmental and organisational and health variables.The perceived needs for aesthetic and ergonomic improvements showed significantly different distributions (p<0.001). Aesthetic needs were more frequently reported than ergonomic needs. There was no significant gender related difference in response distribution of aesthetic or ergonomic needs, whereas differences between occupational groups were shown (0.006 and 0.003). 'High rank' needs for aesthetic improvement were associated to psychologically demanding work, negative work stress, sleep disturbances, problems at work, musculoskeletal pain and lower age. Gender and physical training did not differ between 'high and low rank' responders regarding neither aesthetic nor ergonomic needs. Sick leave was stronger related to ergonomics. The independently tested associations with aesthetic needs were similar to, but fewer than those for ergonomic needs with regard to the variable set ups. Sixteen studied factors out of 24, showed significant difference between 'high and low rank' aesthetic needs, and 21/24 of ergonomic needs, independently tested. The study results show a relation between work place aesthetics and health and well being. Future work health promotion and prevention may benefit from the inclusion of an assessment of workplace aesthetics. PMID- 21709358 TI - Occupational health and safety issues affecting young workers: a literature review. AB - Many overview articles, reports, book chapters and literature reviews have examined the health and safety of young workers. These sources discuss the relationships between the work conditions of young workers and the various indicators of accidents and occupational diseases. Breslin et al. [12,13] conducted two literature reviews of quantitative studies to determine which factors best predicted work accidents and occupational disorders in young people. The present article proposes a review of young people's occupational health and safety (OHS) factors (e.g., demographic, individual, professional, organizational, temporal and operational factors) in both qualitative and quantitative studies. Five types of problems were analyzed in greater depth, namely MSD symptoms, respiratory, allergy and toxicological problems, mental health and well-being, alcohol and drug consumption, and fatigue. This review likewise examines related dimensions that allow us to adopt a more global perspective on this subject by considering such elements as young people's values, their knowledge and attitudes, safety practices in companies, the safe integration of young people, and rehabilitation. A total of 189 scientific articles were selected on the basis of certain criteria. These articles came from refereed OHS journals published between 1994 and 2005. PMID- 21709359 TI - On long term sick leave due to musculoskeletal diseases and disorders. Experiences of work demands. AB - OBJECTIVE: The rate of sick leave is higher in the public sector than in the private sector in several countries, making it essential to thoroughly investigate employees in the public sector. The following research question was investigated: How do employees on long-term sick leave (> 8 weeks) due to musculoskeletal disorders or diseases describe their work demands? METHODS: This paper is from the larger Rogaland RTW case study. The informants were female employees (n=8) in the first-line public sector with different types of musculoskeletal diseases or disorders. Qualitative interviews were conducted using a semi-structured interview guide based on two measures: Worker Role Interview and Work Environmental Impact Scale. Data was analysed by condensing and categorizing meaning. RESULTS: Fifty-one work demands were described, only five of which were physical demands. Demands were sometimes described as merely negative or positive for the work performance, but also as both. Most of the negative demands were emotional and cognitive challenges in mastering the work tasks. Most of the demands (n= 36) were experienced to be claimed by the employee herself, with only a few being claimed by the employer or environment (n=7) or by both (n=8). CONCLUSIONS: Eight employees in the public sector on long-term sick leave due to musculoskeletal problems experienced mostly cognitive and emotional demands, and defined themselves as the work-demand claimer. The results of this study point to the importance of broadening the perspective in work rehabilitation for workers absent due to diagnosis of the musculoskeletal system. PMID- 21709360 TI - Barriers to and possibilities of returning to work after a multidisciplinary rehabilitation programme. A qualitative interview study. AB - OBJECTIVE: The aim of this qualitative study was to explore experiences of sick listed persons of not returning to work during a six-year period after participation in an extensive multidisciplinary rehabilitation programme. PARTICIPANTS: The study comprised ten participants with musculoskeletal disorders, mainly neck and back pain. METHODS: Semi-structured interviews were conducted and analysed by manifest content analysis. RESULTS: This led to identification of three primary categories and six sub-categories, which described the participants' experiences of barriers to and possibilities of returning to work, and indicated what strategies they used to cope with everyday life. The participants described that the main barriers to returning to work were pain and somatic symptoms, fatigue, and not fulfilling the work requirements. Participants considered physical activity a key factor in coping with pain. Most participants thought that they had residual work ability, and could utilise this if they could get a modified job adapted to their own capacity. CONCLUSIONS: Our study highlights the importance of utilising residual working ability at workplaces. Finding flexible work possibilities requires an understanding and supportive attitude on the part of both the employer and the social insurance office. PMID- 21709361 TI - Turkish version of the Cornell Musculoskeletal Discomfort Questionnaire: cross cultural adaptation and validation. AB - OBJECTIVE: This study documented the cross-cultural adaptation, validity, and reliability of the Cornell Musculoskeletal Discomfort Questionnaire (CMDQ) in the Turkish language. PARTICIPANTS: The participant group included 48 Turkish workers. METHODS: The cross-cultural adaptation included the translation, synthesis, back-translation, expert committee review and pretest stages. The adapted Turkish version of the CMDQ (T-CMDQ) was validated through self administration of the tool and a Visual Analog Scale (VAS) among participants. RESULTS: The validity of the T-CMDQ was good; Kappa coefficients between the responses given on the VAS and on the T-CMDQ indicated substantial to almost perfect agreement (ranged between 0.62-0.92 across body parts), and Spearman rank correlation coefficients between the VAS scores and T-CMDQ severity scale responses were all significant (ranged between 0.46-0.83 across body parts). Test retest reliability of the T-CMDQ was satisfactory; Kappa coefficients, which ranged between 0.56-0.97 across the three scales, indicated moderate to almost perfect agreement between test-retest responses across body parts. CONCLUSIONS: This study produced the T-CMDQ with good psychometric properties, presented the first formal validation of the CMDQ and provided useful insights on the cross cultural adaptation process of a subjective data collection tool which was originally developed in English, into the Turkish language. PMID- 21709362 TI - Effects of wearing a tight necktie on cervical range of motion and upper trapezius muscle activity during computer work. AB - OBJECTIVE: This study examined the effects of wearing a tight necktie on cervical range of motion and upper trapezius muscle activity. METHODS AND PARTICIPANTS: Thirty computer workers were recruited. First, the active cervical ROM of the participants while wearing or not wearing a tight necktie was measured using the CROM instrument. Subsequently, upper trapezius muscle activity was measured while working at a visual display terminal with and without a tight necktie. RESULTS: The neck flexion, neck extension, and lateral flexion of the subjects' cervical range of motion were significantly decreased when wearing a tight necktie compared to without it. The activity of the upper trapezius muscle significantly increased when working while wearing a tight necktie compared to without. CONCLUSION: It is especially important for male workers to select and tie neckties appropriately in order to prevent musculoskeletal injuries induced by limitation of cervical ROM or repetitive cumulative tension increase of the upper trapezius. PMID- 21709364 TI - Work-related mild-moderate traumatic brain injury and the construction industry. AB - BACKGROUND: Consequences of traumatic brain injury underscore the need to study high-risk groups. Few studies have investigated work-related traumatic brain injuries (WrTBIs) in the construction industry. OBJECTIVE: To examine WrTBIs in Ontario for the construction industry compared to other industries. METHODS: A retrospective study of individuals who sustained a WrTBI and had a clinical assessment as an outpatient at a hospital-based referral centre. Data were collected for a number of factors including demographic, injury and occupation and were analyzed according to the Person-Environment-Occupation (PEO) model. PARTICIPANTS: 435 individuals who sustained a WrTBI. RESULTS: There were 19.1% in the construction industry, 80.9% in other industries. Compared to other industries, individuals in the construction industry were more likely to be male, to not have attained post-secondary education, and experience multiple traumas. WrTBIs in the construction industry were commonly due to elevated work. The construction occupations involved included skilled workers and general labourers, and compared to other industries, WrTBIs occurred most often for those employed for a short duration in the construction industry. CONCLUSIONS: Construction industry workers experience serious WrTBIs that are amenable to prevention. Use of the PEO model increased our understanding of WrTBIs in the construction industry. PMID- 21709363 TI - Destructive managerial leadership and psychological well-being among employees in Swedish, Polish, and Italian hotels. AB - OBJECTIVE: The aim of this cross-sectional exploratory study was to investigate destructive managerial leadership in the hotel industry in Sweden, Poland, and Italy in relation to psychological well-being among employees. METHODS AND PARTICIPANTS: 554 questionnaires were collected from employees in all occupational groups within hotels. The Copenhagen Psychosocial Questionnaire (COPSOQ) measured working conditions, particularly iso-strain or high work demands combined with low control and poor social support, and psychological well being, defined in terms of mental health, vitality, and behavioural stress. Items adapted from the Global Leadership and Organisational Behaviour Effectiveness (GLOBE) research program questionnaire measured autocratic, malevolent, and self centred leadership styles. Differences in ratings between countries were estimated, as well as the relationship between destructive managerial leadership on an organisation level and employee psychological well-being on an individual level. The relationship between destructive leadership and psychological well being among employees was adjusted for employees' reported iso-strain. RESULTS: Autocratic and malevolent leadership were at the organisation level related to low vitality among employees and self-centred leadership was significantly associated with poormental health, low vitality, and high behavioural stress. Autocratic and malevolent leadership were more strongly related to iso-strain than was self-centred leadership. Variations in leadership practice between countries were seen in autocratic and malevolent leadership. CONCLUSION: This exploratory study suggests a significant association between destructive managerial leadership on the organisation level and poor psychological well-being among employees on an individual level. Interventions to decrease iso-strain and enhance psychological well-being among employees could be directed at an organisation level. PMID- 21709365 TI - Employment-related information for clients receiving mental health services and clinicians. AB - OBJECTIVE: Clients receiving public mental health services and clinicians require information to facilitate client access to suitable employment services. However, little is known about the specific employment-related information needs of these groups. This study aimed to identify employment-related information needs among clients, clinicians and employment specialists, with a view to developing a new vocational information resource. PARTICIPANTS: Employment-related information needs were identified via a series of focus group consultations with clients, clinicians, and employment specialists (n=23). METHODS: Focus group discussions were guided by a common semi-structured interview schedule. RESULTS: Several categories of information need were identified: countering incorrect beliefs about work; benefits of work; disclosure and managing personal information; impact of earnings on welfare entitlements; employment service pathways; job preparation, planning and selection; and managing illness once working. Clear preferences were expressed about effective means of communicating the key messages in written material. CONCLUSIONS: This investigation confirmed the need for information tailored to clients and clinicians in order to activate clients' employment journey and to help them make informed decisions about vocational assistance. PMID- 21709366 TI - Job satisfaction and short sickness absence due to the common cold. AB - OBJECTIVE: This study investigated whether short episodes of sickness absence were associated with job satisfaction. PARTICIPANTS: 199 wage earners who reported sick due to the common cold between January 2003 and April 2003. METHODS: Job satisfaction was assessed on the first day of sickness absence and associated with the duration of sickness absence using a multiple logistic regression model to which demographics, working conditions, and the week day on which sick-leave was taken were stepwise added as covariates. RESULTS: Workers with low job satisfaction scores had higher odds (odds ratio [OR] =3.85; 95% confidence interval [CI] 1.74 to 8.51) of being > 3 days absent from work due to the common cold compared to satisfied workers. However, the duration of sickness absence due to the common cold was more strongly related to the day of taking sick-leave with workers who reported sick on Monday or Tuesday being longer absent (OR=5.36; 95% CI 1.44 to 9.90) than those who reported sick on Friday. CONCLUSIONS: When having a common cold, dissatisfied workers are longer absent from work although the duration of short episodes of sickness absence seems to be determined by the week day on which sick-leave is taken rather than working conditions or perceptions about work. PMID- 21709367 TI - Depressive feelings, feelings of unhappiness, and subsequent psychological wellbeing among workers. AB - OBJECTIVE: A depressive state and feelings of unhappiness in daily life are regarded as indispensable factors for the diagnosis of major depression. These factors are also speculated to contribute to subsequent psychological wellbeing. METHODS AND PARTICIPANTS: A total of 3190 men, aged 33 to 59 years, from a workplace in Japan participated in this one-year prospective study conducted from 2007 to 2008; 3141 men completed both evaluations (98.5%). The prevalences of depressive states and feelings of unhappiness were evaluated using a questionnaire. After one year, psychological wellbeing was evaluated using the General Health Questionnaire (GHQ) 12-item version. Analysis of variance and a logistic regression analysis were used for the analysis. RESULTS: The prevalence of no depressive feelings and no feelings of unhappiness among the workers were 73.5% among men in their 30s, 76.9% among men in their 40s, and 83.2% among men in their 50s. The mean GHQ score among participants with or without of depressive feelings and feelings of unhappiness was significantly higher than that among participants who had no depressive feelings and no feelings of unhappiness (control group). In contrast, the mean GHQ score among the participants in their 50s who had only depressive feelings did not differ from that in the control group of participants in their 50s according to a multivariate analysis. CONCLUSIONS: Compared with depressive feelings, feelings of unhappiness were a stronger contributing factor to psychological wellbeing as measured using the GHQ questionnaire, especially among subjects in their 50s, in a one-year follow-up study. PMID- 21709368 TI - Medical care surrounding work-related back injury claims among Washington State Union Carpenters, 1989-2003. AB - OBJECTIVE: We describe medical care received through workers' compensation (WC) and union-provided insurance surrounding work-related back injuries and examine relationships between care provided and time off work among a large cohort of carpenters. METHODS AND PARTICIPANTS: Union records identified a cohort of 20,642 carpenters working in Washington State from 1989-2003 and their private health insurance claims. These data were linked to workers' compensation files from this state-run program including records of medical care. RESULTS: Over 74,000 WC medical encounters resulted from 2959 work-related back injuries. Eleven percent received private care for musculoskeletal back pain within 90 days of work related injury; this proportion increased with increasing lost days. Delay to physical therapy was more prevalent among those out of work longest. The proportion of claimants with care from both systems and from private utilization only increased after the first 90 days and, for the subset with at least one paid lost work day, after return to work. CONCLUSIONS: Examination of medical care through both systems versus solely in workers' compensation provides a more complete understanding of back injury care while also demonstrating complexity. Differences in outcomes based upon treatment shortly after injury are worthy of further exploration. PMID- 21709369 TI - Risks and health effects in operating room personnel. AB - OBJECTIVE: The objective was to find the factors that pose a possible health risk to OR personnel. Work-related health problems of operating room (OR) personnel were signalled by an occupational physician and preparations for the development of new Worker's Health Surveillance (WHS) were started with a systematic review of the literature. METHODS: A systematic review was performed of articles in Pubmed, published from January 1991 to December 2007, concerning risks or health effects in the working conditions of OR personnel. RESULTS: Twenty-three articles reported that workers in the OR are exposed to infectious agents, noise, anaesthetic gases and radiation. Eleven studies reported elevated risk for (allergic) skin diseases, musculoskeletal complaints and infectious diseases. CONCLUSIONS: Factors that form a health risk for workers in the operating room are infectious agents, noise, anaesthetic gases and radiation. Health effects on workers in the OR are (allergic) skin disorders, musculoskeletal complaints and infectious diseases. PMID- 21709370 TI - Exploration of the prevalence and correlates of depression among South Korean workers with injuries. AB - OBJECTIVE: This study identified the prevalence of depression and explored demographic and psycho-social factors that predict depression among workers with on-the-job injuries in South Korea. PARTICIPANTS: Participants consisted of 549 Korean workers with injuries; 80% were males. Ages ranged from 20 to 60 years old (mean, 42.2; SD=9.27). METHODS: Each participant completed a self-administered questionnaire. Analyses were conducted using multiple linear regression to explore predictors of depression. Depression was measured by the Korean version of the Beck Depression Inventory and items drawn from the Work Potential Profile scale and AUDIT-K were used. RESULTS: More than half of study participants needed professional assessment and treatment for depression. Preoccupation with health, subjective economic stability, self-image, employment status, and alcohol problems were significant predictors of depression. CONCLUSIONS: Policymakers and practitioners working with workers with injuries should be aware of the extent of serious mental health issues among such workers. There is also a need for enhanced rehabilitation services for depression treatment. PMID- 21709371 TI - Anti-Amyloid-beta Single-Chain Antibody Brain Delivery Via AAV Reduces Amyloid Load But May Increase Cerebral Hemorrhages in an Alzheimer's Disease Mouse Model. AB - Accumulation of amyloid-beta protein (Abeta) in the brain is thought to be a causal event in Alzheimer's disease (AD). Immunotherapy targeting Abeta holds great promise for reducing Abeta in the brain. Here, we evaluated the efficacy and safety of anti-Abeta single-chain antibody (scFv59) delivery via recombinant adeno-associated virus (rAAV) on reducing Abeta deposits in an AD mouse model (TgAbetaPPswe/PS1dE9). First, delivery of scFv59 to the brain was optimized by injecting rAAV serotypes 1, 2, and 5 into the right lateral ventricle. Symmetrical high expression of scFv59 was found throughout the hippocampus and partly in the neocortex in both hemispheres via rAAV1 or rAAV5, while scFv59 expression via rAAV2 was mostly limited to one hemisphere. rAAV1, however, induced apoptosis and microglial activation but rAAV5 did not. Therefore, rAAV5 was selected for therapeutic scFv59 delivery in TgAbetaPPswe/PS1dE9 mice. rAAV5 was similarly injected into the ventricle of 10-month-old TgAbetaPPswe/PS1dE9 mice and 5 months later its efficacy and safety were evaluated. Immunoreactive Abeta deposits reduced in the hippocampus. Abeta42 levels in cerebrospinal fluid (CSF) tended to increase and the Abeta40 : 42 ratio decreased in CSF, suggesting that Abeta42 was relocated from the parenchyma to CSF. Hemorrhages associated with a focal increase in blood vessel amyloid were found in the brain. While immunotherapy has great potential for clearing cerebral Abeta, caution for cerebrovascular effects should be exercised when rAAV-mediated anti-Abeta immunotherapy is applied. PMID- 21709372 TI - Decreased sAbetaPPbeta, Abeta38, and Abeta40 cerebrospinal fluid levels in frontotemporal dementia. AB - To improve the etiological diagnosis of neurodegenerative dementias like Alzheimer's disease (AD) or frontotemporal dementia (FTD), we evaluated the value of individual and combined measurements of the following relevant cerebrospinal fluid (CSF) biomarkers: Tau, 181p-Tau, Abeta38, Abeta40, Abeta42, sAbetaPPalpha, and sAbetaPPbeta. This study conducted in two centers included patients with FTD (n = 34), AD (n = 52), as well as a control group of persons without dementia (CTRL, n = 42). Identical clinical criteria and pre-analytical conditions were used while CSF biomarkers were measured using commercial single and multiplex quantitative immunoassays. Thorough statistical analyses, including ROC curves, logistic regressions, and decision trees, were performed. We validated in AD the specific increase of p-Tau levels and the decrease of Abeta42 levels, two biological hallmarks of this disease. Tau concentrations were highest in AD and intermediate in FTD when compared to CTRL. The most interesting results were obtained by focusing on amyloid biomarkers as we found out in FTD a significant decrease of sAbetaPPbeta, Abeta38, and Abeta40 levels. Abeta38 in particular was the most useful biomarker to differentiate FTD subjects from the CTRL population. Combining p-Tau and Abeta38 led us to correctly classifying FTD patients with sensitivity at 85% and specificity at 82%. Significant changes in amyloid biomarkers, particularly for Abeta38, are therefore seen in FTD. This could be quite useful for diagnosis purposes and it might provide additional evidence on the interrelationship between Tau and AbetaPP biology which understanding is essential to progress towards optimal therapeutic and diagnostic approaches of dementia. PMID- 21709373 TI - Associations of anti-hypertensive treatments with Alzheimer's disease, vascular dementia, and other dementias. AB - We investigated whether angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACE-Is) are more strongly associated with Alzheimer's disease (AD), vascular dementia (VaD), and other dementias, than other anti-hypertensive drugs. We conducted a nested case-control analysis within the UK general practice research database, with prospectively recorded anti hypertensive prescribing data. We sampled cases aged >=60 years and diagnosed between 1997-2008 (5,797 with AD, 2,186 with VaD, 1,214 with unspecified/other dementia) which were matched to up to four controls by age, general practice and gender. We computed odds-ratios and dose response effects for AD, vascular and unspecified/other dementia, comparing those prescribed ARBs or ACE-Is for at least six months with patients prescribed other anti-hypertensives. We controlled for matching factors, co-morbidities, smoking status, an area measure of socioeconomic status, consultation rate and blood pressure and accounted for reverse causality by introducing time-lags of up to eight years prior to diagnosis/index date. Patients diagnosed with AD, vascular and unspecified/other dementia had fewer prescriptions for ARBs and ACE-Is. Inverse associations with AD were strongest for ARBs (odds-ratio; 0.47, 95%CI, 0.37-0.58) compared with ACE Is (odds-ratio; 0.76, 95%CI, 0.69-0.84) (p(difference) < 0.001). Associations of ARBs with AD were stronger than for vascular dementia (p(difference) = 0.01) and unspecified/other dementia (p(difference) = 0.23). There were inverse dose response relationships between ARBs and ACE-Is with AD (both p(trend) < 0.01). The inverse association of ACE-Is with AD diminished when using longer time lags but the ARB-AD association persisted. Patients with AD were around half as likely to be prescribed ARBs. Further randomized controlled trial evidence is required to rigorously test these findings. PMID- 21709374 TI - Role of OLR1 and its regulating hsa-miR369-3p in Alzheimer's disease: genetics and expression analysis. AB - The oxidized LDL receptor 1 gene (OLR1) rs1050283 single nucleotide polymorphism (SNP) has been previously shown to be associated with Alzheimer's disease (AD). An association analysis of OLR1 was carried out in a population of 443 patients with AD as compared with 393 age-matched controls. In addition, an expression analysis of OLR1 and its regulatory hsa-miR369-3p was performed in peripheral mononuclear blood cells (PBMC) from 20 patients and 15 controls. Logistic regression analysis, adjusted for gender and apolipoprotein E (ApoE) status, showed a statistically significant association of OLR1 rs1050283 under the assumption of a dominant model (CC and CT individuals versus TT: p = 0.014, OR: 1.50, 95%CI: 1.08-2.08) and a genotypic model (TC versus TT: p = 0.002, OR: 1.61, 95%CI: 1.14-2.26). No significant differences in OLR1 expression was observed between patients and controls (p > 0.05). However, stratifying patients according to the rs1050283 status, significantly decreased relative PBMC expression levels of OLR1 were observed in carriers of CC+CT genotypes as compared with TT carriers (0.13 +/- 0.013 versus 0.46 +/- 0.028, p = 0.022), whereas no differences in relative expression levels of the hsa-miR369-3p were observed (p > 0.05). The effect observed was not due to the presence of the ApoE epsilon4 allele. The OLR1 rs1050283 SNP likely acts as a risk factor for sporadic AD. The presence of at least one C allele is associated with a decreased expression of OLR1 mRNA in the absence of hsa-miR369-3p de-regulation, suggesting that the presence of the polymorphic allele influences the binding of hsa-miR369-3p to its 3'UTR consensus sequence. Nevertheless, the limited power of the study requires further investigations with a larger sample size. PMID- 21709375 TI - Volumes of lateral temporal and parietal structures distinguish between healthy aging, mild cognitive impairment, and Alzheimer's disease. AB - Distinguishing amnestic mild cognitive impairment (MCI) from Alzheimer's disease (AD) and healthy aging depends mainly on clinical evaluation, and, ultimately, on investigator's judgment. Clinical evaluation in vivo is based primarily on cognitive assessments. The present study explores the potential of volumetric magnetic resonance imaging of parietal and lateral temporal brain structures to support the diagnosis of AD and to distinguish AD patients from patients with MCI and healthy control subjects (HCS). 52 age-matched HCS, 18 patients with MCI, and 59 patients with probable late onset AD were investigated. Using computational, neuromorphometric procedures gray matter (GM) was automatically parcellated into 28 local regions of interest, the volumes of which were computed. The left hippocampus (sensitivity/specificity: 80.8-90.4%/55.6-86.4%) and the right hippocampus (73.1-90.4%/66.7-84.7%) provided highest diagnostic accuracy in separating all three diagnostic groups. Promising diagnostic values for distinguishing MCI from HCS were found for the left superior parietal gyrus (61.5%/55.6%) and left supramarginal gyrus (65.4%/66.7%), and for distinguishing subjects with MCI from AD patients for the right middle temporal gyrus (77.8%/79.7%), left inferior temporal gyrus (83.3%/72.9%), and right superior temporal gyrus (77.8%/71.2%). The left superior temporal pole (92.3%/84.7%), left parahippocampal gyrus (86.5%/81.4%), left Heschl's gyrus (86.5%/79.7%), and the right superior temporal pole (82.7%/78.0%) revealed most promising diagnostic values for distinguishing AD patients from HCS. Data revealed that lateral temporal and parietal GM volumes distinguish between HCS, MCI, and AD as accurate as hippocampal volumes do; hence, these volumes can be used in the diagnostic procedure. Results also suggest that cognitive functions associated with these brain regions, e.g., language and visuospatial abilities, may be tested more extensively to obtain additional information that might enhance the diagnostic accuracy further. PMID- 21709376 TI - Treatment with a gamma-ketoaldehyde scavenger prevents working memory deficits in hApoE4 mice. AB - Both inflammation and oxidative injury are features of Alzheimer's disease (AD), but the contribution of these intertwined phenomena to the loss of working memory in this disease is unclear. We tested the hypothesis that highly reactive gamma ketoaldehydes that are formed both by non-enzymatic free radical catalyzed lipid peroxidation and by cyclooxygenases may be causally linked to the development of memory impairment in AD. We found that levels of gamma-ketoaldehyde protein adducts were increased in the hippocampus of brains obtained postmortem from patients with AD compared to age-matched controls, but that levels of gamma ketoaldehyde protein adducts in the cerebellum were not different in the two groups. Moreover, immunohistochemistry revealed that adducts localized to hippocampal pyramidal neurons. We tested the effect of an orally available gamma ketoaldehyde scavenger, salicylamine, on the development of spatial working memory deficits in hApoE4 targeted replacement mice, a mouse model of dementia. Long-term salicylamine supplementation did not significantly alter body weight or survival, but protected against the development of age-related deficits in spatial working memory in 12-14 month old ApoE4 mice. These findings suggest that gamma-ketoaldehyde adduct formation is associated with damage to hippocampal neurons in patients with AD and can contribute to the pathogenesis of spatial working memory deficits in hApoE4 mice. These data provide a rational basis for future studies exploring whether gamma-ketoaldehyde scavengers may mitigate the development of cognitive dysfunction in patients with AD. PMID- 21709377 TI - Cost-effectiveness of a health intervention program with risk reductions for getting demented: results of a Markov model in a Swedish/Finnish setting. AB - Risk scores based on modifiable factors have recently been developed for dementia. This study aims to estimate the cost-effectiveness of a potential preventive intervention program meant to lower the score related to increased dementia risk. Analyses were based on a Markov model adapted to Swedish circumstances. Risk score categories and risk probabilities were derived from the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) study in Finland. Figures of costs, utilities, and mortality were obtained from literature or databases. One-way sensitivity analysis and probabilistic sensitivity analysis were carried out to investigate the robustness of the model and to identify which model inputs had most impact on the results. In the base case, the usual care had a cost of 621,000 SEK and utilities of 11.8438 quality-adjusted life year (QALYs). The intervention had a cost of 599, 026 SEK and utilities of 11.8950 QALYs. The cost was 21,974 SEK lower in the intervention with 0.0511 QALYs gained over a 20 years horizon, indicating absolute dominance. The support for cost effectiveness was insensitive to changes in the value of QALY for demented, mortality, and risk of dementia. If the intervention program was assumed to run every year, the incremental cost-effectiveness ratio did not show absolute dominance but was still under the willingness-to-pay level. The probabilistic sensitivity analysis indicated cost effectiveness in 67% of the samplings given a willingness-to-pay level of 600,000 SEK/year. This is a promising outlook for future research on preventive interventions in dementia, emphasizing the need of conducting multi-domain randomized trials. PMID- 21709379 TI - The new European Regulation 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP Regulation): basic features. Preface. PMID- 21709378 TI - Meta-analysis of plasma amyloid-beta levels in Alzheimer's disease. AB - Plasma amyloid-beta (Abeta) levels have been proposed as biomarkers of Alzheimer's disease (AD), but studies have produced inconsistent results. We present a meta-analytic review of cross-sectional studies that examined plasma Abeta levels in AD and cognitively normal subjects, and longitudinal studies that used baseline plasma Abeta levels to predict conversion from normal cognition to AD. Medline and EMBASE databases were searched to generate an initial list of relevant studies, and selected authors approached for additional data. Twelve cross- sectional studies (n = 1483) and seven longitudinal (n = 3920) met the inclusion criteria for meta-analysis. Random effects model was used to calculate the weighted mean difference (WMD) by Review Manager Version 4.2. In longitudinal studies, cognitively normal individuals who converted to AD had higher baseline Abeta1-40 and Abeta1-42 levels (WMD: 10.29, z = 3.80, p = 0.0001 and WMD: 8.01, z = 2.76, p = 0.006, respectively), and non-significantly increased Abeta1 42/Abeta1-40 ratio (WMD: 0.03, z = 1.65, p = 0.10). In cross sectional studies, compared to cognitively normal individuals, AD patients had marginally but non significantly lower Abeta1-42 levels (WMD:-2.84, z = 1.73, p = 0.08), but Abeta1 40 levels were not significantly different (WMD: 3.43, z = 0.40, p = 0.69). Our systematic review suggests a model of differential longitudinal changes in plasma Abeta levels in cognitively stable individuals versus those who go on to develop AD dementia. Baseline Abeta1-40 and Abeta1-42 levels in cognitively normal elderly individuals might be predictors of higher rates of progression to AD, and should be further explored as potential biomarkers. PMID- 21709380 TI - The CLP Regulation: origin, scope and evolution. AB - The CLP Regulation implements in the EU the UN Globally Harmonised System of Classification and Labelling applying the "building block approach", that is taking on board the hazard classes and categories which are close to the existing EU system in order to maintain the level of protection of human health and environment. This Regulation applies to all substances and mixtures placed on the market and besides to classification, packaging and labelling it provides for the notification of the classification and labelling of substances to the Classification & Labelling Inventory established by ECHA. It came into force on 20 January 2009 but a transitional period is foreseen until 1 June 2015 for the full application. At the end of this period the "substance" and "preparation" Directives (respectively 67/548/EEC and 99/45/EC) will be repealed. PMID- 21709381 TI - Information gathering for CLP classification. AB - Regulation 1272/2008 includes provisions for two types of classification: harmonised classification and self-classification. The harmonised classification of substances is decided at Community level and a list of harmonised classifications is included in the Annex VI of the classification, labelling and packaging Regulation (CLP). If a chemical substance is not included in the harmonised classification list it must be self-classified, based on available information, according to the requirements of Annex I of the CLP Regulation. CLP appoints that the harmonised classification will be performed for carcinogenic, mutagenic or toxic to reproduction substances (CMR substances) and for respiratory sensitisers category 1 and for other hazard classes on a case-by-case basis. The first step of classification is the gathering of available and relevant information. This paper presents the procedure for gathering information and to obtain data. The data quality is also discussed. PMID- 21709382 TI - Classification & Labelling Inventory: role of ECHA and notification requirements. AB - The CLP Regulation introduces the criteria of the UN Globally Harmonised System of Classification and Labelling (UN GHS) in the EU. The European Chemicals Agency (ECHA) manages the CLP related tasks - such as harmonised classification and labelling, handling requests for alternative names and maintaining the Classification & Labelling Inventory (C&L) - to ensure consistent implementation in the EU. The obligations for industry depend on their role in the supply chain. Manufacturers and importers have to notify to ECHA the identity and classification and labelling of substances within one month of placing them on the market either on their own or in a mixture, and regardless of the quantitity. As of 3 January 2011 ECHA has received some 3.1 million notifications of over 107 000 substances. This information is stored in the C&L Inventory and accessible to Member State Competent Authorities. The non-confidential information will be made publicly available on ECHA's website in 2011. PMID- 21709383 TI - CLP application to nanomaterials: a specific aspect. AB - This paper aims at describing some relevant aspects related to the classification, labelling and packaging of nanomaterials. Concerns have been raised about potential adverse effects to humans or the environment as result of impacts of nanomaterials. The new Regulation (EC) no. 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP) does not contain any specific definition or provision related to nanomaterials nevertheless they are covered by the definition of substance set in the Regulation. It is recognized that different particle sizes or forms of the same substance can have different classification. Thus, if substances are placed on the market both at nanoscale and as bulk, a separate classification and labelling may be required if the available data on the intrinsic properties indicate a difference in hazard class between the two forms. CLP Regulation requires the manufacturer or importer to ensure that the information used to classify relates to the forms or physical states in which the substance is placed on the market and in which it can reasonably be expected to be used. Moreover, CLP demands testing relating to physical hazards to be performed if such information is missing or not adequate to conclude on classification. Further developments of the CLP guidance documents and implementation tools are needed in order to cover nanomaterials more specifically. PMID- 21709384 TI - CLP Regulation and the transport of dangerous goods. AB - Regulations concerning different modes of transport of dangerous goods are well harmonized at global level: they were then looked at as a model for developing Globally Harmonized System of Classification and Labelling of Chemicals (GHS), (on which CLP Regulations is based). Transport regulations do not cover some hazard classes, such as germ cell mutagenicity, carcinogenicity, reproductive toxicity, having been evaluated that such hazards are not relevant in transport because in general, in case of accident, no repeated and prolonged exposure takes place. Other differences with CLP Regulation are related to the use of "building block approach". Transport labels, which were used as a basis for GHS, can be used, instead of CLP pictograms, on packages during transport. PMID- 21709385 TI - CLP Regulation and REACH Regulation: links, implementation and control in Italy. AB - In the last years the European policy for the management of chemicals is deeply changed after entering into force of the European Regulations (EC) no. 1907/2006 and (EC) no. 1272/2008. The implementation of the two Regulations requests a strong effort both from the enterprises and from national and regional institutions. The activities already realised or that are planned for the implementation of one of them could support the implementation of the other one. The crucial point is the creation of the surveillance coordination through a network that involves also the professional figures currently present in the border areas in order to check the compliance with the European legislation of substances on their own, in mixtures or in articles before they are put on European market. PMID- 21709386 TI - CLP activities and control in Ireland. AB - The 10(th) December 2010 marked a new beginning for Regulation (EC) no. 1272/2008 on the classification, labelling and packaging of substances and mixtures (CLP) in Ireland with the start of its operational phase. It was on this date that the administrative and enforcement provisions for CLP were encompassed in the new Chemicals Amendment Act, 2010. In this Act, the Health and Safety Authority, known as the "the Authority" is named as Competent Authority (CA) for CLP, along with the Minister for Agriculture, Fisheries and Food, in respect of pesticides and plant protection products and the Beaumont Hospital Board with responsibility for receiving information relating to emergency health response. In practice, the Authority has been de facto CA for CLP since its publication on the 31(st) December 2008, given its role in existing classification and labelling regimes. This article focuses on the work undertaken by the Authority on CLP at a National, European and International level including its implementation, training, helpdesk, guidance, enforcement and awareness raising activities. PMID- 21709387 TI - The National helpdesk activity in Italy: report of the first year (2010). AB - National CLP heldpesk is a service established in every Member State providing advice to companies and other stakeholders on the obligations they may have under CLP. In Italy the national helpdesk is located into the Center of Chemical Substances (CSC) in the National Institute of Health. Helpdesks will provide with wide ranging information on the provisions of CLP. They will also advice on the responsibilities the suppliers of chemical substances have to fulfill under these Regulations. Too specific questions cannot be answered as the aim of the helpdesk is to give a general interpretation of CLP principles and requirements instead of solving tailor made problems. PMID- 21709388 TI - Ecological studies of cancer incidence in an area interested by dumping waste sites in Campania (Italy). AB - Cancer incidence was investigated in an area which has been affected by the illegal practices of dumping hazardous waste and setting fire to mismanaged waste. For the 35 municipalities of this area that are served by a Cancer Registry, municipal standardized incidence ratios (SIR) and hierarchical Bayesian estimators (BIR) were computed. Moreover, municipal spatial clustering and a Poisson regression by municipality index of waste-related exposure were performed for 10 cancer types. Increased municipality SIRs were found for some cancer types. The BIRs confirmed the increases for liver cancer in two municipalities. Statistically significant clusters were detected for liver, lung, leukaemia and soft tissue sarcomas. In the regression analysis, testis cancer showed significant trend with the index of waste-related exposure (RR = 1.18). PMID- 21709389 TI - Residential proximity to industrial sites in the area of Taranto (Southern Italy). A case-control cancer incidence study. AB - The association between cancer incidence and the residence near polluting facilities in an industrial area nearby Taranto has been investigated. Age, sex and occupational exposure were controlled as confounding variables in a case control study (658 cases, 2092 controls). High risks were evidenced close to the steel mill (OR: 3.54), coke plant (OR: 4.80), mineral deposit (OR: 3.33) and shipbuilding (OR: 4.29) for pleural neoplasm, and to the steel mill (OR: 1.65) and shipbuilding (OR: 1.79) for lung cancer. After adjustment for occupational exposure, increasing trends of risk were observed both for lung and bladder cancers. Cancer risks were evidenced near industrial sites and the introduction of "occupational exposure" as a confounder modified significantly the risks with respect to distance from the source of pollution, particularly for pleural, lung and bladder cancers. PMID- 21709390 TI - Bladder cancer and occupational exposure: estimating the workers potentially at risk in Italy. AB - Bladder cancer is one of the most common occupational tumours. The objective of this study is to evaluate the number of workers potentially at risk in Italy. Economic activities entailing bladder cancer risk were selected on the basis of the excesses resulting from studies reporting risk estimates. Firms and the number of workers potentially at risk were retrieved from the National Institute for Occupational Safety and Prevention (ISPESL) database of enterprises. Excluding low level exposures, the number of workers (blue-collars) likely exposed to bladder cancer risk in the industry and services is 366 175 +/- 11 096 (248 573 +/- 7 533 men, and 117 603 +/- 3564 women). The North-Western area of Italy shows the majority of workers potentially at risk (86 625 +/- 2625 men, and 27 225 +/- 725 women). Quantify the number of exposed workers is the first step for performing analyses on occupational cancer risks. National database of enterprises may be useful in identifying potential risk situations for worker's health. PMID- 21709391 TI - The role of post-migration living difficulties on somatization among first generation immigrants visited in a primary care service. AB - The role of post-migration living difficulties (PMLD) on somatization was studied in 101 first generation immigrants visited in primary care. Premigratory traumas and post-traumatic stress disorder (PTSD) were also assessed. About one third of patients somatized. Sociodemographic variables were similar in somatizers and non somatizers. Premigratory traumas, PTSD and the likelihood to report at least one serious or very serious PMLD were higher in somatizers. Four kinds of PMLD were more frequent in somatizers: worries about unavailability of health assistance, working problems, discrimination and poor social help. Traumas and PTSD influenced the effect of PMLD on somatization. Findings suggest that in specific samples of primary care immigrants severe premigratory traumas increase the sensitivity to PMLD and in turn distress due to PMLD amplifies the tendency to somatize. PMID- 21709392 TI - Sexual behaviour reported by a sample of Italian MSM before and after HIV diagnosis. AB - In 2006 we conducted a cross-sectional study involving hospital clinical centres in five Italian cities to compare the sexual behaviour of HIV-positive MSM (men who have sex with men) before and after the diagnosis of HIV infection. Each centre was asked to enrol 30 HIV-positive persons aged >= 18 years. The questionnaire was administered to 143 MSM on average 9 years after HIV diagnosis. After diagnosis there was a decrease in the number of sexual partners: the percentage of persons who reported having had more than 2 partners decreased from 95.8% before diagnosis to 76.2% after diagnosis. After diagnosis, there was a significant decrease in the percentage of persons who had never (or not always) used a condom with their stable partner for anal sex from 69.2% before diagnosis to 26.6% after diagnosis and for oral-genital sex from 74.8% before diagnosis to 51.7% after diagnosis. Though at-risk behaviour seems to decrease after diagnosis, seropositive MSM continue to engage in at-risk practices: one fourth of them did not use a condom during sexually transmitted infections (STI) episodes, 12.5% of the participants had had sex for money, and 8.4% had paid for sex. The study shows that our sample of Italian HIV-positive MSM, though aware of being infected, engage in sexual behaviours that could sustain transmission of HIV and other STIs. The results could constitute the first step in implementing national prevention programs for persons living with HIV. PMID- 21709393 TI - Development and validation of predictive MoSaiCo (Modello Statistico Combinato) on emergency admissions: can it also identify patients at high risk of frailty? AB - The prospective historical cohort study develops and validates a method of identifying patients at high risk of emergency admission to hospital in the population of the Province of Ravenna (no. = 296 641). The main outcome measure is: emergency hospital admission analyzed using multivariate logistic regression (MoSaiCo - Modello Statistico Combinato). To validate the findings, the coefficients for 30 most powerful variables found on half of the population (derivation data set) were then applied to the rest of the population (validation data set). The key predicting factors included some demographic variables, social variables, clinical variables and use of health/social services. Discriminatory power and validation both reached good results. Risk score increases when variables indicating the individual vulnerability raise. The predictive frailty risk resulting from MoSaiCo allows to stratify the population, to organize care services, to provide a practical planning tool in the field of case management and management of frail patients. PMID- 21709394 TI - A flexible tool for calculating the consequences of a hypothetical nuclear accident. AB - The paper presents a parametric model, implemented on a personal computer, for calculating contamination and doses following a hypothetical nuclear accident. The model is embedded in the high level environment of Mathematica and uses the Gaussian solution for the plume structure at short and medium distances and a wedge-like behaviour for long distances calculation. Along with the usual effects, like the influence of a local wet ground deposition or the corrections due to build-up, the model deals also with other aspects, such as the long distance behaviour of the plume, by taking into account random wind direction variations. A rather sophisticated approach is used, in particular, when evaluating food contamination and doses, allowing also for consideration of a possible ban of food consumption. Several tens of functions are on hand of the user who can take full advantage of the very flexible tools introduced in the recent version 7 of Mathematica. Some examples of the power of the tool are shown with reference to the radiological consequences of an hypothetical accidental release in a EPR reactor. PMID- 21709395 TI - Influence of mode of delivery on pelvic organ support 6 months postpartum. AB - AIMS: The aims of this study were to describe pelvic organ support 6 months postpartum among women who delivered by cesarean section, spontaneous and instrumental vaginal delivery, and to evaluate the differences between the groups. METHODS: This was a cross-sectional study of 382 primigravid women who gave birth at Donostia Hospital during 2007. Pelvic organ support was explored 6 months postpartum using the pelvic organ prolapse quantification (POPQ) system. Joint hypermobility, height and weight were also assessed. RESULTS: POPQ stage >=II was present in 7.7, 18.1 and 29.0% of women who delivered by cesarean section, spontaneous and instrumental vaginal delivery, respectively. Spontaneous vaginal delivery increased the risk by more than three times (OR 3.19; 95% CI 1.07-9.49) while instrumental vaginal delivery increased it more than fivefold (OR 5.52; 95% CI 1.79-17.30) in comparison with cesarean section. Instrument assisted delivery did not increase the risk of prolapse in women who delivered vaginally. CONCLUSIONS: Cesarean section is associated with a lower prevalence of pelvic organ prolapse after delivery. Instrument- assisted delivery is not associated with an increased risk of postpartum prolapse among women who delivered vaginally. PMID- 21709396 TI - Soft tissue cover for an exposed transplanted kidney with a pedicled myocutaneous anterolateral thigh perforator and vastus lateralis flap. AB - Surgical wound infection after a renal transplant procedure can lead to graft loss in the presence of host immunosuppression and graft exposure to the environment. Early cover of the wound with well-vascularized tissue will facilitate early wound healing and preservation of the graft. The pedicle anterolateral thigh perforator flap is a popular flap used for soft tissue reconstruction in the groin and perineum. We present a case of an anterolateral thigh flap used to cover an exposed transplanted kidney after surgical wound breakdown. PMID- 21709397 TI - Morphometric differences between the medial and lateral meniscus in healthy men - a three-dimensional analysis using magnetic resonance imaging. AB - The objective of this work was to characterize tibial plateau coverage and morphometric differences of the medial (MM) and lateral meniscus (LM) in a male reference cohort using three-dimensional imaging. Coronal multiplanar reconstructions of a sagittal double-echo steady state with water excitation magnetic resonance sequence (slice thickness: 1.5 mm, and in-plane resolution: 0.37 * 0.70 mm) were analyzed in 47 male participants without symptoms, signs or risk factors of knee osteoarthritis of the reference cohort of the Osteoarthritis Initiative. The medial and lateral tibial (LT) plateau cartilage area and the tibial, femoral and external surfaces of the MM and LM were manually segmented throughout the entire knee. This process was assisted by parallel inspection of a coronal intermediately weighted turbo spin echo sequence. Measures of tibial coverage, meniscus size, and meniscus position were computed three-dimensionally for the total menisci, the body, and the anterior and the posterior horn. The LM was found to cover a significantly greater (p < 0.001) proportion of the LT plateau (59 +/- 6.8%) than the MM of the medial plateau (50 +/- 5.5%). Whereas the volume of both menisci was similar (2.444 vs. 2.438 ml; p = 0.92), the LM displayed larger tibial and femoral surface areas (p < 0.05) and a smaller maximal (7.2 +/- 1.0 vs. 7.7 +/- 1.1 mm; p < 0.01) and mean thickness (2.7 +/- 0.3 vs. 2.8 +/- 0.3 mm; p < 0.001) than the medial one. Also, the LM displayed less (physiological) extrusion than the medial one. These data may guide strategies for meniscal tissue engineering and transplantation aiming to restore normal joint conditions. PMID- 21709398 TI - Inhibition of the experimental induction of benign prostatic hyperplasia: a possible role for fluted pumpkin (Telfairia occidentalis Hook f.) seeds. AB - INTRODUCTION: Pumpkins are thought to be useful in the management of benign prostatic hyperplasia (BPH). The ability of a 15% Telfairia occidentalis seeds incorporated diet to inhibit hormonal induction of BPH in rats was studied. MATERIALS AND METHODS: Twenty male Wistar rats were divided into 4 equal groups - one test group and three control groups. The test group was placed on the test diet and was given subcutaneous injections of dihydrotestosterone (DHT) and estradiol valerate (ratio 10:1) every other day for 28 days. One control group, 'no test diet' (ND) group, received the hormones, but was placed on a normal diet. The other two control groups, 'no hormone' (NH) and 'no hormone/test diet' (NHD), received subcutaneous olive oil (vehicle) for the same duration and were placed on the test and normal diets, respectively. Markers of BPH and hormone profile were determined using standard methods. RESULTS: The mean relative prostate weight (*10(3)) was reduced in the test group (3.6 +/- 0.2) relative to the ND group (4.0 +/- 0.4). The protein content (mg/tissue) of the rats' prostates decreased significantly (p < 0.05) from 68.3 +/- 2.7 in the ND group to 43.4 +/- 3.9 in the test group. Serum prostatic acid phosphatase levels (U/l) decreased significantly (p < 0.05) from 4.8 +/- 0.4 in the ND group to 4.0 +/- 0.9 in the test group. Histological findings corroborate these data. The testosterone:estradiol ratio (*10(3)) was significantly (p < 0.05) increased from 7.1 +/- 0.1 in the ND group to 8.4 +/- 0.4 in the test group. CONCLUSION: The test diet inhibited the induction of BPH in rats and may act by increasing the testosterone:estradiol ratio. PMID- 21709399 TI - Simultaneous correction of anterior and apical vaginal prolapse with the modified placement of the transobturator-guided mesh (Anterior ProliftTM) set. AB - AIM: Modified placement of the Anterior ProliftTM (MODAP) in patients with prolapse of the anterior and middle vaginal compartment is described. It was performed in order to achieve simultaneous tension-free correction of the anterior and middle vaginal compartment without excessive use of the mesh. MATERIAL AND METHODS: MODAP was performed in 32 patients. The anterior part of the mesh was placed transobturatorily. Surplus of the central part of the mesh was longitudinally divided and fixed around the cervix. Posterior mesh arms were passed through the sacrospinous ligament. All patients were analyzed regarding anatomy and symptoms 1 year after surgery. RESULTS: Cure of pelvic organ prolapse was achieved in 28 of 32 (87.5%) patients. The position of Ba and C points was significantly corrected (p = 0.00). Deterioration of the posterior compartment occurred in 1 case. Symptoms of pelvic organ prolapse were significantly corrected (p = 0.05 up to p = 0.00) except for rectal emptying. CONCLUSION: MODAP makes an improvement of both anatomy support and symptoms in cases with mixed insufficiency of the anterior vaginal wall and apical vaginal support. PMID- 21709400 TI - Successful management of metastatic urothelial carcinoma with gemcitabine and Paclitaxel chemotherapy in a hemodialysis patient. AB - This is the first report of urothelial carcinoma (UC) in a hemodialysis (HD) patient treated with almost the same doses of gemcitabine and paclitaxel (GP) as those administered to patients with normal renal function. There have been some reports of UC treated with cisplatin-based chemotherapy in HD patients. However, there have only been a few reports of UC treated with GP in HD patients. Furthermore, to our knowledge, there has not been any report of UC in a HD patient treated with almost the same doses of GP as those in patients with normal renal function. Following cystectomy for bladder cancer, a 73-year-old woman undergoing HD developed lung metastasis and received combination chemotherapy with almost the same doses of GP as those in patients with normal renal function. After three cycles were completed, metastatic tumors disappeared and there has not been any recurrence or metastasis for 1 year to date. Furthermore, there were no grade 3 or 4 adverse effects during this treatment. PMID- 21709401 TI - Congenital omphalocele and polyhydramnios: a study of 52 cases. AB - INTRODUCTION: Unlike gastroschisis, congenital omphalocele is often associated with other anomalies and is frequently complicated by polyhydramnios. We examined the relationships between polyhydramnios, pregnancy outcome and fetal prognosis. PATIENTS AND METHODS: Clinical data from cases diagnosed antenatally with congenital omphalocele from 1993 to 2006 were analyzed retrospectively. RESULTS: Fifty-two cases were diagnosed antenatally with congenital omphalocele, and 38 of these pregnancies resulted in delivered infants. Of these 38 pregnancies, 55.3% were preterm births before 37 weeks of gestation. The mean birth weight was 2,148 g (n = 38). Associated anomalies were recognized in 29 cases (76.3%), including 13 cases (34.2%) of chromosomal aberrations. There were 2 cases of trisomy 13, 10 cases of trisomy 18 and 1 case of trisomy 21. Polyhydramnios was detected in 14 cases (36.8%), and other anomalies were present in all of these cases. DISCUSSION: For antenatal evaluation in cases of congenital omphalocele, it is important to examine the fetus for associated anomalies or underlying disease, especially when polyhydramnios is detected. PMID- 21709402 TI - Cerebrospinal fluid biomarkers for Alzheimer's disease: the present and the future. AB - Alzheimer's disease (AD) is the major cause of dementia in the elderly. The biochemical changes that precede AD may be present up to 20 years before the clinical manifestation of the disease. The translational development of AD biomarkers may be theoretically achieved via two different strategies: the first strategy can be defined as 'knowledge-based' (deductive method), while the second one is a hypothesis-generating 'unbiased' approach (inductive strategy). The 'knowledge-based' approach relies on a direct understanding of the neuropathological processes that underlie the development of AD. In contrast, the 'unbiased' approach involves the use of modern techniques including proteomics and bioinformatics that allow unbiased investigations of numerous putative markers that may be informative with regard to AD. Cerebrospinal fluid (CSF) dosage of neuropathological AD-associated proteins has already been incorporated into the neurochemical diagnosis of AD, attesting the relevance of translational research. In the last few years, biomarker discovery research has successfully utilized genomics and proteomics for the identification of several promising molecular markers for AD. In the present article, we discuss the present state of the art and the future challenges in the search of CSF biomarkers for AD. PMID- 21709403 TI - First-trimester screening for trisomy 21 with adjustment for biochemical results of previous pregnancies. AB - OBJECTIVE: To investigate the effect of associations in serum free beta-hCG and PAPP-A between successive pregnancies on the performance of screening for trisomy 21 at 11-13 weeks' gestation. METHODS: In 8,499 women with two consecutive pregnancies, including 49 women with fetal trisomy 21 in the second pregnancy, the correlation in serum free beta-hCG multiples of the median (MoM) and PAPP-A MoM between pregnancies was determined, and the effects of correcting for the correlation on the performance of screening was estimated. RESULTS: There were significant associations between pregnancies in free beta-hCG MoM (r = 0.4435) and PAPP-A MoM (r = 0.4796). In screening by maternal age and biochemistry at a risk cutoff of 1 in 100, in the second pregnancies the false-positive rate was 35.5% for those with screen-positive results in the first pregnancy, and this was reduced to 17.1% after adjustment for the results of the first pregnancy. Similarly, in women with screen-negative results in the first pregnancy, adjustment for the results improved the detection rate in the second pregnancy from 66.7 to 81.2%. CONCLUSIONS: In screening for trisomy 21, adjustment for the biochemical findings in a previous pregnancy has major effects on individual patient-specific risks, increases the detection rate and reduces the false positive rate. PMID- 21709404 TI - Interaction between exercise, dietary restriction and age-related bone loss in a rodent model of male senile osteoporosis. AB - BACKGROUND: The pathophysiology of age-related bone loss and whether age-related bone loss can be prevented by exercise are still a matter of debate. OBJECTIVE: It was the aim of this study to investigate the long-term effects of exercise and mild food restriction on bone mineral density (BMD) and bone geometry in the appendicular skeleton of aging male rats. METHODS: Male Sprague-Dawley rats were studied from 5 to 23 months of age. The rats were divided into 4 groups: baseline, free access to food and running wheels (RW), fed to pair weight with the RW group (PW) and sedentary control animals with free access to food (SED). All rats were housed individually. Volumetric BMD and geometry of femurs and tibiae were assessed by peripheral quantitative computed tomography (pQCT). In addition, the tibial shafts were analyzed by cortical bone histomorphometry. RESULTS: At the end of the experiment, RW and PW rats had similar body weight. The body weight of SED rats was 31% greater than that of RW rats. pQCT analysis of femurs and tibiae as well as histomorphometric analysis of the tibial shafts showed that dietary restriction resulted in an enlargement of the marrow cavity and cortical thinning at the femoral and tibial shafts relative to the RW and SED groups. Voluntary running exercise provided no additional protection against age related bone loss when compared with the 31% heavier SED control rats. Neither exercise nor increased body weight in SED animals could completely prevent age related bone loss between 19 and 23 months of age. CONCLUSION: We conclude that dietary restriction had clear negative effects on BMD and bone geometry and that running wheel exercise provided partial protection but could not prevent age related bone loss. PMID- 21709405 TI - CT angiography source images with modern multisection CT scanners: attention to technical principles is crucial. PMID- 21709407 TI - Blood C-reactive protein concentration with ABCD2 is a better prognostic tool than ABCD2 alone. AB - BACKGROUND: Increased C-reactive protein (CRP) is a known predictor of vascular events in asymptomatic individuals and stroke patients. Only a few studies included transient ischaemic attack (TIA) patients. We assessed CRP levels in addition to traditional risk factors in a cohort of patients with TIA to examine the relationship of these parameters to the occurrence of ischaemic stroke. METHODS: This is a prospective, longitudinal clinical evaluation of the efficacy of CRP as a prognostic indicator. CRP levels were measured in 194 TIA patients and in 1,024 asymptomatic individuals (recruited from a project on stroke prevention, the PrATO, which was ongoing at the same time in the Aosta Valley). A clinical risk score was determined using the ABCD2 score in TIA patients. The area under the receiver operating characteristic curve (AUC) was used to evaluate the significance of the markers as predictors. Two models were evaluated: model 1 used the ABCD2 score and model 2 used serum CRP levels in addition to the ABCD2) score. The primary outcome was an ischaemic stroke. RESULTS: Within 2 years ischaemic strokes occurred in 33/194 patients. The Cox proportional hazards models, after adjustments for conventional risk factors, identified CRP levels >=3 mg/l and ABCD2 scores >=4 as independent predictors of stroke. The corresponding AUCs were 0.565 and 0.636, based on model 1 and model 2, respectively; this represented a statistically significant difference (p = 0.043). The absolute integrated discrimination improvement was 0.0249 (p = 0.007) and the relative integrated discrimination improvement was 2.3710. The net benefit became significant from a predicted probability >=10% and was 0.077 when based on model 1 and 0.087 when based on model 2. CONCLUSIONS: Routine CRP measurements in the acute phase might be a useful tool for identifying TIA patients who are at a higher risk of ischaemic stroke. The additional use of CRP levels for the risk assessment in TIA patients improves risk definition in terms of the ABCD2 score alone. PMID- 21709408 TI - Prediction of silent ischemic lesions after carotid artery stenting using virtual histology intravascular ultrasound. AB - BACKGROUND: A major concern with carotid artery stenting (CAS) is the potential for cerebral embolism. The purpose of this study was to determine whether virtual histology intravascular ultrasound (VH-IVUS) can predict the risk of a silent ischemic lesion after CAS. METHODS: We performed CAS in 45 patients with carotid stenosis. Before CAS, we assessed plaque characteristics by VH-IVUS. We also performed diffusion-weighted magnetic resonance imaging of the brain before and after CAS to detect newly appearing ipsilateral silent ischemic lesions (NISIL). RESULTS: In the patient group that was positive for NISIL (P group: n = 18), the relative fibrofatty (FF) area identified by VH-IVUS in 5 cross-sections including the most stenotic lesion was significantly larger than that in areas of the NISIL negative group (N group: n = 27; 32.7 +/- 13.2 and 18.3 +/- 9.8%, respectively; p < 0.001). The relative fibrous area was significantly lower in the P group than in the N group (59.2 +/- 9.5 and 74.6 +/- 9.1%, respectively; p < 0.001). There were no differences in the relative dense calcium and necrotic core areas between the P and N groups. From the analysis of receiver operating characteristic curves, most reliable cutoff values for predicting NISIL were a relative FF area of 30% in the most stenotic lesion. In multivariate logistic regression analysis, the relative FF area was an independent predictor of NISIL (p = 0.005). CONCLUSIONS: Quantitative tissue characterization of atherosclerotic lesions of carotid arteries using VH-IVUS was useful to predict NISIL after CAS. However, the positive predictive value determined by VH-IVUS was not superior to that determined by a noninvasive method. PMID- 21709409 TI - Plasma C3 and C3a levels in cryptogenic and large-vessel disease stroke: associations with outcome. AB - BACKGROUND AND PURPOSE: Inflammation seems to be a key player in the pathophysiology of stroke. In this study, we compared plasma C3 and C3a levels in cryptogenic and large-vessel disease (LVD) subtypes of ischemic stroke and control subjects and evaluated their association to outcome at 3 months and 2 years. METHODS: C3 and C3a levels in plasma of 79 cryptogenic stroke and 73 LVD stroke patients, sampled within 10 days and at 3 months after stroke, and age- and sex-matched control subjects from the Sahlgrenska Academy Study on Ischemic Stroke were measured by ELISA. Functional outcome was assessed with the modified Rankin Scale. RESULTS: Plasma C3 was increased in both stroke groups at both time points. Systemic elevation of C3a was limited to the acute phase in the cryptogenic stroke group, whereas plasma C3a levels in the LVD group were also elevated at the 3-month follow-up. In the LVD group, plasma C3 levels in the upper third at the 3-month follow-up were associated with an unfavorable outcome after 3 months independently of age and sex: odds ratio (OR) 5.56; 95% confidence interval (CI) 1.03-29.93; p = 0.045; as well as after 2 years: OR 4.75; 95% CI 1.11-20.30; p = 0.036. In the cryptogenic stroke group, high plasma C3a levels in the acute phase were associated with an unfavorable outcome after 3 months: OR 3.75; 95% CI 1.01-13.96; p = 0.049 in univariate analysis but not after adjustment for age and sex (p = 0.050). CONCLUSIONS: Plasma C3 and C3a levels are elevated in cryptogenic and LVD stroke and the predictive value of these markers may depend on stroke subtype. Further studies on the role of the complement system in ischemic stroke outcome based on larger patient populations and controlling for the effect of infections, are clearly warranted. PMID- 21709410 TI - Is stroke etiology a determining factor for the pattern of secondary immune alterations? PMID- 21709411 TI - Polymorphism in a human chromosome-specific interstitial telomere-like sequence at 22q11.2. AB - Interstitial telomeric sequences (ITSs) are common in human. We previously reported the presence of an ITS at 22q11.2 which is in the vicinity of the genomically unstable region involved in 22q11 rearrangements. Recently, we studied the molecular status of the ITS 22q11.2 in the normal population. The amplification of an ITS at 22q11.2 showed different patterns ranging from 1-4 kb, confirming the highly polymorphic nature of this sequence. The linkage analysis of the ITS at 22q11.2 in members of 10 different families demonstrated a strong relation between offspring and parents. In contrast, the study of a DiGeorge case and his 2 parents revealed the presence of a novel allele probably inherited from the father. These results open an avenue for the use of this sequence as an allelic marker, and its implication in 22q11.2-related pathogenesis. PMID- 21709412 TI - Centromere conversion and retention in somatic cell hybrids. AB - The generation of somatic cell hybridization-derived cell lines between highly divergent species affords the opportunity to examine the concept of 'genome dominance' in the context of genetic and epigenetic changes. While whole-scale genome dominance has been well documented in natural hybrids among closely related species, an examination of centromere position and sequence retention in 2 marsupial-eutherian hybrids has revealed a mechanism for 'centromere dominance' as a driving force in the generation of stable somatic cell hybrids following an initial period of genomic instability. While one somatic cell hybrid cell line appeared to retain marsupial centromere sequences which remained competent to recruit the centromere-specific histone variant CENP-A in a Chinese hamster background, fusion events between marsupial and mouse-derived chromosomes in another hybrid line led to a centromere sequence conversion from one species to the other. We postulate that the necessity to maintain an epigenetically defined centromere following genome hybridization may be responsible for retention of specific chromosomes and may result in rapid sequence turnover to facilitate the recruitment of CENP-A containing histones. PMID- 21709413 TI - Comparative chromosome painting of four Siberian Vespertilionidae species with Aselliscus stoliczkanus and human probes. AB - Vespertilionidae is the largest chiropteran family that comprises species of different specialization and wide geographic distribution. Up to now, only a few vespertilionid species have been studied by molecular cytogenetic approaches. Here, we have investigated the karyotypic relationships of 4 Vespertilionidae species from Siberia by G-banding and comparative chromosome painting. Painting probes from Aselliscus stoliczkanus were used to establish interspecific homologous chromosomal segments in Myotis dasycneme (2n = 44), Murina hilgendorfi (2n = 44), Plecotus auritus (2n = 32), and Vespertilio murinus (2n = 38). Robertsonian translocations and a few inversions differentiated the karyotypes of the examined species. Painting of P. auritus karyotype with human probes revealed 3 previously undetected cryptic segments homologous to human chromosomes (Homo sapiens, HSA) 8, 15, and 19, respectively. As a consequence, the existence of 2 HSA 4 + 8 syntenies in the P. auritus karyotype has been proven. In addition, a pericentric inversion or centromere shift was revealed on the smallest metacentric P. auritus chromosome 16/17 using the HSA 16 probe explaining the different G-banding pattern in comparison to the homologous Myotis chromosome 16/17. PMID- 21709414 TI - Molecular cytogenetic mapping of Humulus lupulus sex chromosomes. AB - Dioecy is relatively rare in plants and sex determination systems vary among such species. A good example of a plant with heteromorphic sex chromosomes is hop (Humulus lupulus). The genotypes carrying XX or XY chromosomes correspond to female and male plants, respectively. Until now no clear cytogenetic markers for the sex chromosomes of hop have been established. Here, for the first time the sex chromosomes of hop are clearly identified and characterized. The high copy sequence of hop (HSR1) has been cloned and localized on chromosomes by fluorescence in situ hybridization. The HSR1 repeat has shown subtelomeric location on autosomes with the same intensity of the signal. The signal has been present in the subtelomeric region of the long arm and in the near-centromeric region but absent in the telomeric region of the short arm of the X chromosome. At the same time the signal has been found in the telomeric region only of the long arm of the Y chromosome. This finding indicates that the sex chromosomes of hop have evolved from a pair of autosomes via ancient translocation or inversion. The observation of the meiotic configuration of the sex bivalents shows the location of a pseudoautosomal region on the long arms of X and Y chromosomes. PMID- 21709415 TI - Structural heterozygosity, duplication of telomeric (TTTAGGG)(n) clusters and B chromosome architecture in Tradescantia virginiana L. AB - Fluorescent in situ hybridization, C-banding/DAPI, and CMA(3)-fluorescence were performed to reveal the cytomolecular constitution of the standard (A) and supernumerary (B) chromosomes of an autotetraploid Tradescantia virginiana L. The analyses show that translocations and/or inversions have occurred during the evolution of the T. virginiana karyotype, generating a significant level of structural heterozygosity. Regarding the structural level, the present paper confirms the occurrence of small subterminal duplications and/or inversions in T. virginiana already suggested by previous authors. Interestingly, many of the distal chromosome segments in T. virginiana possess duplicated subterminal telomere clusters, heterochromatin, 5S and 45S rDNAs orderly intermixed and share this complex cytomolecular architecture with the common type of a B chromosome. Based on the obtained results, it is proposed that in T. virginiana the B chromosome may have arisen via excision from the distal region of an A chromosome. The nascent B could have retained much of the ancestral sequence arrangement, including duplicated telomeric cluster(s), heterochromatin and rDNA, but developed a new centromere/kinetochore to successfully propagate through the cell cycle. PMID- 21709416 TI - De novo partial trisomy 18p and partial monosomy 18q in a patient with anorectal malformation. AB - Anorectal malformations (ARM) encompass a broad clinical spectrum which ranges from mild anal stenosis to severe anorectal anomalies such as complex cloacal malformations. The overall incidence of ARM is around 1 in every 2,500 live births. Although causative genes for a few syndromic forms have been identified, the molecular genetic background of most ARM remains unknown. The present report describes a patient with a de novo 13.2-Mb deletion of chromosome 18q22.3-qter and a 2.2-Mb de novo duplication of chromosomal region 18pter-p11.32 located at the telomeric end of chromosome 18q. The patient presented with ARM and the typical features of 18q- syndrome (De-Grouchy syndrome). The combination of a partial duplication of the short arm and a partial deletion of the long arm of chromosome 18 has been described in 16 previous cases. However, this is the first report of an association between this complex chromosomal rearrangement and ARM. PMID- 21709417 TI - Who should treat coronary left main disease--a battle of the titans? PMID- 21709418 TI - Possible sites of therapeutic action in restless legs syndrome: focus on dopamine and alpha2delta ligands. AB - Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by abnormal sensations that occur primarily at rest or during sleep, which are alleviated by movement of the affected limb. The pathophysiology of RLS remains unclear, although roles for dopamine dysfunction and brain iron deficiency have been proposed. The hypothalamic A11 dopaminergic circuit is used to explain the dopamine dysfunction in RLS and the potential therapeutic actions of dopamine D(2) agonists. Modulation of central and peripheral neuronal circuits may also explain the potential therapeutic sites of action of opioids, adenosine receptor ligands, and voltage-gated calcium channel alpha(2)delta ligands in RLS. The known and possible therapeutic benefits of these agents and their relationship to dopaminergic dysfunction in RLS are discussed in this review. PMID- 21709419 TI - Intravenous thrombolysis for acute cerebral ischemia in Belgrade, Serbia: comparison with Lille, France. AB - BACKGROUND: Worse socioeconomic situation is associated with worse outcomes in stroke cases. Whether it also influences outcomes in patients treated with intravenous thrombolysis remains unknown. The aim of this study was to test the hypothesis that outcomes are less favorable in patients treated with intravenous thrombolysis in Belgrade, Serbia, than in Lille, France. METHODS: We compared outcomes at day 7 and month 3, between 123 consecutive stroke patients treated with intravenous thrombolysis in Belgrade and 273 in Lille. RESULTS: At month 3, there was no significant difference between Belgrade and Lille in patients' excellent outcomes [modified Rankin Scale 0-1; 49.6 vs. 45.4%, odds ratio (OR): 1.21, 95% confidence interval (CI): 0.79-1.86] or in death (11.4 vs. 16.1%, OR 0.67, 95% CI: 0.35-1.27). However, compared with a subgroup of age-matched patients from Lille, Belgrade patients tended to have worse outcomes. Patients from Belgrade were 16 years younger (p < 0.0001), more likely to be men (OR 2.40, 95% CI: 1.52-3.78), and more likely to be smokers (OR 2.24, 95% CI: 1.43-3.51). Also, a trend for a slightly higher rate of symptomatic hemorrhagic transformation was registered in this group (7.3 vs. 3.3%, OR 2.32, 95% CI: 0.90 5.99). In Belgrade, patients arrived 27 min earlier to the hospital (p < 0.0001), but their door-to-needle time was 37 min longer (p < 0.0001). Compared with a subgroup of age-matched patients from Lille, they tended to have worse outcomes. CONCLUSION: Intravenous thrombolysis-treated stroke patients in Belgrade have similar outcomes and rates of complications as those from Lille. PMID- 21709420 TI - Intravenous recombinant tissue plasminogen activator therapy for stroke patients receiving maintenance hemodialysis: the Stroke Acute Management with Urgent Risk Factor Assessment and Improvement (SAMURAI) rt-PA registry. AB - BACKGROUND: To examine the therapeutic effect of intravenous recombinant tissue plasminogen activator (rt-PA) therapy for stroke patients receiving maintenance hemodialysis (HD). methods: Of 600 stroke patients receiving intravenous rt-PA using 0.6 mg/kg alteplase who were enrolled in a multicenter observational study in Japan, 4 patients (3 men, 64-77 years old) on maintenance HD were studied. RESULTS: The primary kidney disease requiring HD was glomerulonephritis in 2 patients, diabetic nephropathy in 1, and undetermined in 1. The duration of HD ranged between 1.2 and 28 years. Three patients developed stroke on the day of HD, including 1 during HD and another just after HD. All patients had stroke in the carotid arterial territory. Pretreatment NIH Stroke Scale scores ranged between 4 and 20, and decreased by 2-5 points at 7 days. One patient needed intravenous antihypertensive therapy before rt-PA; he developed an ectopic cortical hematoma and intraventricular hemorrhage after rt-PA. The other 3 did not develop hemorrhagic complications. The modified Rankin Scale score at 3 months was 0 in 1 patient, 2 in 2 patients, and 4 in 1 patient. CONCLUSIONS: rt PA therapy for stroke patients receiving maintenance HD might improve the stroke outcome. Ectopic hematoma was a unique complication in our case series. PMID- 21709421 TI - Fatty acids and hypoxia stimulate the expression and secretion of the adipokine ANGPTL4 (angiopoietin-like protein 4/ fasting-induced adipose factor) by human adipocytes. AB - BACKGROUND/AIMS: Hypoxia occurs in white adipose tissue in obesity, modulating the expression and release of specific inflammation-related adipokines. ANGPTL4 (angiopoietin-like protein 4/fasting-induced adipose factor), which is implicated in angiogenesis, lipid metabolism and glucose homeostasis, is a major hypoxia sensitive gene; recent studies indicate that ANGPTL4 expression is also regulated by fatty acids. We have examined the effects of hypoxia and fatty acids, alone and together, on the expression and release of ANGPTL4 by human adipocytes. METHODS: Human adipocytes were differentiated and incubated with fatty acids (250 MUM) in normoxia (21% O(2)) or hypoxia (1% O(2)). ANGPTL4 mRNA was measured by real-time PCR and the protein in the medium determined by ELISA. RESULTS: In normoxia, ANGPTL4 gene expression was upregulated by palmitic, oleic, arachidonic and eicosapentaenoic acids, and ANGPTL4 release was increased. In contrast, there was no effect of lauric or myristic acids. Hypoxia alone increased the expression and secretion of ANGPTL4, and lauric, myristic, arachidonic and eicosapentaenoic acids each further increased expression and release in hypoxic adipocytes. CONCLUSION: The expression and secretion of ANGPTL4 by human adipocytes is upregulated by both hypoxia and fatty acids. The stimulatory effect of fatty acids on ANGPTL4 production is augmented under hypoxic conditions. PMID- 21709422 TI - Olmesartan induces renoprotective effects by stimulating angiotensin type 2 receptors and reducing oxidative stress in diabetic nephropathy. AB - BACKGROUND: Angiotensin receptor blockers reduce the progression of diabetic nephropathy primarily by inhibiting angiotensin type 1 (AT(1)) receptors. In the present study, we investigated the role of angiotensin type 2 (AT(2)) receptors on the renoprotective effects of olmesartan in diabetic nephropathy. METHODS: Six week-old mice were treated with streptozotocin and divided into four groups: the OLM group (mice treated with olmesartan), the OLM+Ang II group (mice treated with olmesartan and angiotensin II), the OLM+PD group (mice treated with olmesartan and the AT(2) antagonist PD 123319), and the vehicle group. Nondiabetic mice were used as controls. We measured blood glucose levels and urinary excretions of albumin and 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is a marker for oxidative stress. RESULTS: Although urinary albumin excretion in the OLM and OLM+Ang II groups showed a tendency to be reduced compared to the vehicle group, it was significantly lower compared to the OLM+PD group. Urinary excretion of 8-OHdG was also significantly lower in the OLM and OLM+Ang II groups compared to the OLM+PD group. CONCLUSIONS: In diabetic nephropathy, the renoprotective effects of olmesartan are due not only to the blockade of AT(1) receptors, but also to a reduction in oxidative stress via stimulation of AT(2) receptors. PMID- 21709423 TI - Effects of immobilization stress on kidneys of Wistar male rats: a morphometrical and stereological analysis. AB - This paper verifies the morphological changes induced by immobilization stress on the kidney of rats by using stereological methods. Fifteen 4-week-old Wistar male rats were randomly assigned to control (n = 7) and stressed (n = 8) groups. Stress stimuli were performed over 5 weeks by immobilization of the rats for 2 h daily in a rigid opaque plastic cylinder that restrained their movements. Increases in the adrenal mass index (p < 0.05) and decreases in serum testosterone levels (p < 0.05) demonstrated the efficacy of the stressor stimuli. Stressed rats presented diminished body weight gain when compared to controls (p < 0.05). The mean values of kidney weight, kidney volume, kidney volume index and glomerular volume density were significantly lower in the stressed group (p < 0.05); nevertheless, no significant difference was found in the cortical/medullar ratio or in the volume-weighted mean glomerular volume. The number of glomeruli per kidney was 45% lower in the stressed group (p < 0.0001), but no change in serum creatinine levels was found. However, the morphological alterations may have serious implications predisposing individuals to renal disease and hypertension in adult life. PMID- 21709424 TI - Decreased kidney function is a significant factor associated with silent cerebral infarction and periventricular hyperintensities. AB - BACKGROUND/AIMS: Silent cerebral lacunar infarction (SCI) and periventricular hyperintensities (PVH) have been reported to be markers of ischemic cerebral small-vessel disease and risk factors for future cerebrovascular events in the general population. The relationship between CKD and SCI/PVH is examined. METHODS: In this cross-sectional study, brain magnetic resonance imaging was performed with a 1.5-T system in 324 predialysis CKD patients and in 60 normal subjects. RESULTS: SCI was found in 103 CKD patients (31.8%), and PVH was found in 174 CKD patients (53.7%). SCI/PVH were more prevalent in patients with higher blood pressure, advanced age and decreased kidney function. There was a significant association between the prevalence of SCI/PVH and the CKD stage, with greater prevalence of SCI/PVH as the CKD stage advanced (p < 0.0001). PVH grade also advanced as the CKD stage advanced. The estimated glomerular filtration rate was a significant factor associated with the presence of SCI/PVH, independent of any other factors. There was a strong association between the prevalence of SCI/PVH (p < 0.0001). CONCLUSION: In CKD patients, decreased kidney function is a significant factor associated with SCI/PVH, both of which are significantly associated with each other. These results suggest that CKD patients with SCI/PVH are at greater risk of future cerebrovascular events. PMID- 21709425 TI - Global regulatory systems operating in Bacilysin biosynthesis in Bacillus subtilis. AB - In Bacillus subtilis, bacilysin is a nonribosomally synthesized dipeptide antibiotic composed of L-alanine and L-anticapsin. The biosynthesis of bacilysin depends on the bacABCDEywfG operon (bac operon)and the adjacent ywfH gene. To elucidate the effects of global regulatory genes on the expression of bac operon, we used the combination of lacZ fusion analysis and the gel mobility shift assays. The cell density-dependent transition state induction of the bac operon was clearly shown. The basal expression level of the bac operon as well as transition state induction of bac is directly ComA dependent. Three Phr peptides, PhrC, PhrF and PhrK, are required for full-level expression of ComA-dependent bac operon expression, but the most important role seemed to be played by PhrC in stimulating bac expression through a RapC-independent manner. Spo0A is another positive regulator which participates in the transition state induction of bac both directly by interacting with the bac promoter and indirectly by repressing abrB expression. AbrB and CodY proteins do not only directly repress the bac promoter, but they also mutually stimulate the transition state induction of bac indirectly, most likely by antagonizing their repressive effects without preventing each other's binding since both proteins can bind to the bac promoter simultaneously. PMID- 21709426 TI - The GTPase function of YvcJ and its subcellular relocalization are dependent on growth conditions in Bacillus subtilis. AB - We have recently shown that the Bacillus subtilis GTPase YvcJ is involved in the phosphorylation of an unidentified cellular component and that the deletion of yvcJ induced a decrease in competence efficiency. In this paper, we report that growth conditions influence both the YvcJ-dependent phosphorylation event and the localization of this protein. More precisely, we have observed that YvcJ can be localized in the cell either as a helical-like pattern or as foci close to the poles and the septa depending on growth phase and on growth medium. In addition, we show that the mutation of the catalytic lysine residue (K22) located in the Walker A motif of YvcJ, and necessary for its GTPase activity, induces a decrease in competence efficiency similar to that observed for the yvcJ null mutant. This mutation also inhibits the YvcJ-dependent phosphorylation event. Furthermore, a phylogenetic analysis of the YvcJ homologues shows that this protein is ancient in Bacteria (being possibly present in their last common ancestor) and has been conserved in a number of major bacterial phyla, suggesting that this protein has an important function in this domain of life. To sum up, even if the precise cellular role of this ancient protein remains unknown, our data show that the GTPase activity of B. subtilis YvcJ and its function in the phosphorylation of a cellular component are influenced by the growth conditions, and are important for the effect of YvcJ on competence efficiency. PMID- 21709427 TI - Genetic evidence for a TatC dimer at the core of the Escherichia coli twin arginine (Tat) protein translocase. AB - The twin arginine protein transport (Tat) system transports folded proteins across the cytoplasmic membranes of prokaryotes and the thylakoid membranes of plant chloroplasts. In Escherichia coli, the TatB and TatC components form a multivalent receptor complex that binds Tat substrates. Here, we have used a genetic fusion approach to construct covalent TatC oligomers in order to probe the organisation of TatC. A fused dimer of TatC supported Tat transport activity and was fully stable in vivo. Inactivating point mutations in one or other of the TatC units in the fused TatC dimer did not inactivate TatC function, indicating that only one TatC protomer in the TatC fused dimer needs to be active. Larger covalent fusions of TatC also supported Tat transport activity but were degraded in vivo to release smaller TatC forms. Taken together, these results strongly suggest that TatC forms a functional dimer, and support the idea that there is an even number of TatC protomers in the TatBC complex. PMID- 21709428 TI - Previous chemoembolization response after transcatheter arterial chemoembolization (TACE) can predict the anti-tumor effect of subsequent TACE with miriplatin in patients with recurrent hepatocellular carcinoma. AB - AIM: The purpose of this retrospective study was to evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) with miriplatin in patients with unresectable hepatocellular carcinoma (HCC). METHODS: From 2007 to 2010, 122 consecutive patients with unresectable HCC were treated by TACE with miriplatin-lipiodol suspension in our institute. Twenty-two patients (18%) had a solitary nodule and 100 patients (82%) had multiple nodules. Ninety-eight patients (80%) had a history of TACE. RESULTS: Thirty-five of the 122 treated patients (29%) showed complete response (CR). And no serious complications were observed. Patients who had shown CR after previous TACE (pre-CR) were significantly more likely to show CR in the current study compared with patients who had shown less successful responses after previous TACE (56 vs. 20%, p = 0.003). Multivariate analysis revealed that response after previous TACE (pre-CR, risk ratio: 4.76; p = 0.035), tumor multiplicity (solitary, risk ratio: 9.69; p = 0.003), and injection artery (peripheral to segmental hepatic artery, risk ratio: 5.28;p = 0.040) were significant independent predictors associated with CR after TACE using miriplatin. CONCLUSION: In repetition of TACE treatment, switching the TACE agent from epirubicin or cisplatin to miriplatin offered a favorable treatment effect, especially in patients who had shown a CR after previous TACE. PMID- 21709430 TI - Efficacy and safety of two analogs of L-carnitine on rats made insulin resistant by a high-fructose diet. AB - AIM: To evaluate the efficacy and safety of 2 analogs of L-carnitine on rats made insulin resistant by a high-fructose diet. METHODS: Using rats made insulin resistant by a high-fructose diet, we investigated the impact of 2 analogs of L carnitine (25 mg/kg) and L-carnitine (250 mg/kg) on glucose, triglycerides and cholesterol blood levels, and liver glycogen. We also evaluated the safety of both analogs by the assessment of some biochemical and hematological parameters, a histological analysis and a study of embryotoxicity. RESULTS: Both analogs reduced the levels of triglycerides in the liver and plasma, but only analog 2 reduced the cholesterol levels in insulin-resistant rats. No changes were observed in glycogen content. Safety evaluations revealed alterations in blood lymphocytes and embryotoxicity data. CONCLUSION: This study demonstrated that the 2 analogs maintain the pharmacological properties of L-carnitine but have a different efficacy, potency and toxicity. PMID- 21709429 TI - Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of losartan and its main metabolite EXP-3174 in rats: possible role of CYP3A4 and P-gp inhibition by HMG-CoA reductase inhibitors. AB - The present study was designed to investigate the effects of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (atorvastatin, pravastatin, simvastatin) on the pharmacokinetics of losartan and its active metabolite EXP-3174 in rats. Pharmacokinetic parameters of losartan and EXP-3174 in rats were determined after oral and intravenous administration of losartan (9 mg/kg) without and with HMG-CoA reductase inhibitors (1 mg/kg). The effect of HMG CoA reductase inhibitors on P-gp and cytochrome (CYP) 3A4 activity were also evaluated. Atorvastatin, pravastatin and simvastatin inhibited CYP3A4 activities with IC50 values of 48.0, 14.1 and 3.10 MUmol/l, respectively. Simvastatin (1-10 MUmol/l) enhanced the cellular uptake of rhodamine-123 in a concentration dependent manner. The area under the plasma concentration-time curve (AUC0 infinity) and the peak plasma concentration of losartan were significantly (p < 0.05) increased by 59.6 and 45.8%, respectively, by simvastatin compared to those of control. The total body clearance (CL/F) of losartan after oral administration with simvastatin was significantly decreased (by 34.8%) compared to that of controls. Consequently, the absolute bioavailability (F) of losartan after oral administration with simvastatin was significantly increased by 59.4% compared to that of control. The metabolite-parent AUC ratio was significantly decreased by 25.7%, suggesting that metabolism of losartan was inhibited by simvastatin. In conclusion, the enhanced bioavailability of losartan might be mainly due to inhibition of P-gp in the small intestine and CYP3A subfamily-mediated metabolism of losartan in the small intestine and/or liver and to reduction of the CL/F of losartan by simvastatin. PMID- 21709432 TI - Dermocosmetics for dry skin: a new role for botanical extracts. AB - Dry skin is associated with a disturbed skin barrier and reduced formation of epidermal proteins and lipids. During recent years, skin-barrier-reinforcing properties of some botanical compounds have been described. Searching the PubMed database revealed 9 botanical extracts that specifically improve skin barrier and/or promote keratinocyte differentiation in vivo after topical application. The topical application of Aloe vera (leaf gel), Betula alba (birch bark extract), Helianthus annuus (sunflower oleodistillate), Hypericum perforatum (St. John's wort extract), Lithospermum erythrorhizon (root extract), Piptadenia colubrina (angico-branco extract) and Simarouba amara (bitter wood extract) increased skin hydration, reduced the transepidermal water loss, or promoted keratinocyte differentiation in humans in vivo. The topical application of Rubia cordifolia root extract and rose oil obtained from Rosa spp. flowers stimulated keratinocyte differentiation in mouse models. The underlying mechanisms of these effects are discussed. It is concluded that some botanical compounds display skin barrier-reinforcing properties that may be used in dermocosmetics for dry skin. However, more investigations on the mode of action and more vehicle-controlled studies are required. PMID- 21709431 TI - Skin disinfection by plasma-tissue interaction: comparison of the effectivity of tissue-tolerable plasma and a standard antiseptic. AB - Wound healing disorders frequently occur due to biofilm formation on wound surfaces requiring conscientious wound hygiene. Often, the application of conventional liquid antiseptics is not sufficient and sustainable as (1) the borders and the surrounding of chronic wounds frequently consist of sclerotic skin, impeding an effectual penetration of these products, and (2) the hair follicles representing the reservoir for bacterial recolonization of skin surfaces are not affected. Recently, it has been reported that tissue-tolerable plasma (TTP), which is used at a temperature range between 35 and 45 degrees C, likewise has disinfecting properties. In the present study, the effectivity of TTP and a standard liquid antiseptic was compared in vitro on porcine skin. The results revealed that TTP was able to reduce the bacterial load by 94%, although the application of the liquid antiseptic remained superior as it reduced the bacteria by almost 99%. For in vivo application, however, TTP offers several advantages. On the one hand, TTP enables the treatment of sclerotic skin as well, and on the other hand, a sustainable disinfection can be realized as, obviously, also the follicular reservoir is affected by TTP. PMID- 21709433 TI - [Eosinophilic cellulitis and eosinophilic cellulitis (Wells' syndrome)]. PMID- 21709434 TI - [Classification and diagnosis of diseases with hypereosinophilia]. PMID- 21709435 TI - [Eosinophilic fasciitis]. PMID- 21709436 TI - [A role of pathogens and danger signals in allergic inflammation]. PMID- 21709437 TI - [Analysis of 76 patients with urticaria and angioedema induced by non-steroidal anti-inflammatory drugs (NSAIDs) in Japan]. AB - BACKGROUND: The pathogenesis of urticaria and angioedema induced by non-steroidal anti-inflammatory drugs (NSAIDs) is still obscure. We analyzed the clinical characteristics of patients with NSAIDs-induced urticaria and angioedema without asthma in Japan. METHODS: We retrospectively collected the cases of NSAIDs induced urticaria and angioedema from Japanese medical journals in 2000-2009. RESULTS: Seventy-six patients were analyzed. The male/female ratio was 1:2.5 and the mean age was 38.1 years. Urticaria was most frequent clinical manifestation in 3 groups; urticaria alone, urticaria and angioedema, and angioedema alone. Time interval from drug administration to onset was 5 minutes to 48 hours by aspirin at a dose of 25-1000 mg. Skin prick test was performed with aspirin in 33 patients, and the results were negative in all patients. Meloxicam, a selective cyclooxygenase-2 (COX-2) inhibitor, and celecoxib, a new selective COX-2 inhibitor, were administered safely in 4 of 6 patients and in 2 of 3 patients with NSAIDs-induced urticaria, respectively. These drugs were administered safely in all administered patients with NSAIDs-induced angioedema. Tiaramidehydrochroride (a basic COX-1 inhibitor) was safely used in 23 administered patients with NSAIDs-induced angioedema. Leukotriene receptor antagonists were effective in 2 of 5 patients administered, but aggravated symptoms in the others. CONCLUSION: Diversity of NSAIDs-induced urticaria and angioedema was shown in this study. Pathogenesis of NSAIDs-induced urticaria and angioedema without asthma seems to be different from that of NSAIDs-induced asthma. PMID- 21709438 TI - [Two cases of royal jelly allergy provoked the symptoms at the time of their first intake]. AB - Two young women were suffered from several symptoms after the intake of royal jelly at their first time. According to the positive skin prick test reactions of raw royal jelly, royal jelly allergy was diagnosed. As the reasons why the symptoms appeared at the time of their first intake, we guessed the possibility that 1) they had been sensitized for royal jelly formerly, or 2) their symptoms were induced by the cross-reactivity between royal jelly and other allergens such as bee, honey and pollens. As to our cases, no related allergens were found in one case, but in another case co-existence of mugwort allergy was suspected from the results of both skin prick test and specific IgE titers. Originally royal jelly allergy has been regarded as class 1 allergic reaction developed by the sensitization of itself. But we speculated the possibility that there can also be cases of class 2 royal jelly allergy by the mechanism of cross-reaction with pollens. PMID- 21709439 TI - Polymorphisms in the hypoxia-inducible factor-1alpha gene confer susceptibility to pancreatic cancer. AB - The transcription factor hypoxia-inducible factor-1 (HIF-1) has alpha and beta subunits. Recent studies have shown that the HIF-1alpha gene may have C1772T and G1790A single nucleotide polymorphisms (SNPs). These SNPs may increase the stability and activity of HIF-1alpha. In the present study, we looked for these SNPs by genotyping circulating mononuclear cells from 263 patients with pancreatic ductal adenocarcinoma (PDAC), using 271 healthy volunteers as controls. As a result, both SNPs were more frequent in PDAC patients than in healthy volunteers (C1772T: 21 vs. 11%, p < 0.01; G1790A: 25 vs. 8%, p < 0.01). Further, both SNPs were associated with higher risks for PDAC (C1772T: OR=2.156, 95% CI: 1.324-3.511, p < 0.05; G1790A: OR=3.716, 95% CI: 2.213-6.238, p < 0.01). We also stained HIF-1alpha by immunohistochemistry in 68 PDAC tumors to examine their HIF-1alpha expression levels. To this end, we designed a semi-quantitative method that was based on the staining intensity and frequency of HIF-1alpha positive cells. As a result, the G1790A SNP, but not C1772T SNP, was associated with an increased HIF-1alpha expression. We also related genotyping data to patient's survival times, serum CA19-9, and tumor's volumes, grades, stages and lymph-node metastasis. The C1772T SNP was not associated with any of these parameters. In contrast, the G1790A SNP was associated with increases in serum CA19-9 and in tumor volumes. In conclusion, the C1772T and G1790A SNPs in the HIF 1alpha gene increase the susceptibility to pancreatic cancer. In addition, the G1790A SNP is associated with increases in tumor-produced HIF-1alpha and in the progression of the cancer. PMID- 21709440 TI - Heparan sulfate D-glucosaminyl 3-O-sulfotransferase-3B1, a novel epithelial mesenchymal transition inducer in pancreatic cancer. AB - Epithelial-mesenchymal transition (EMT) is a critical early event in tumorigenesis. The contribution of heparan sulfate (HS) to EMT has not been fully elucidated. HS D-glucosaminyl 3-O-sulfotransferase-3B1 (3-OST-3B1) participates in the final step of HS fine structure biosynthesis, whose involvement in cancer has yet to be determined. This study demonstrated that following treatment with trichostatin-A, a histone deacetylase inhibitor, 3-OST-3B1 gene expression was activated in the pancreatic cancer cell line, PANC-1. By chromatin immunoprecipitation analysis, permissive histone modifications including an increase in histone H3 lysine 9 monoactylation (H3 ac K9) but a decrease in methylated histone H3 (H3 me K9) were observed accompanying transcriptional activation of 3-OST-3B1. Functional, results revealed that increased 3-OST-3B1 levels were involved in the promotion of EMT processes. In vitro studies demonstrated that overexpression of 3-OST-3B1 in both pancreatic cancer cells and vascular endothelial cells could trigger an EMT-like phenotype as evidenced by the up-regulation of Snail at the mRNA and protein level, and its nuclear translocation. And 3-OST-3B1 appeared to be sufficient for the development of a more mesenchymal phenotype in vivo. Together, the results from this study unveiled a distinct function for 3-OST-3B1 as an EMT inducer in cancer and provided a link between histone modification and EMT modulation. PMID- 21709441 TI - Epigenetic fingerprint in endometrial carcinogenesis: the hypothesis of a uterine field cancerization. AB - Transcriptional silencing by CpG island hypermethylation plays a critical role in endometrial carcinogenesis. In a collection of benign, premalignant and malignant endometrial lesions, a methylation profile of a complete gene panel, such steroid receptors (ERalpha, PR), DNA mismatch repair (hMLH1), tumor-suppressor genes (CDKN2A/P16 and CDH1/E-CADHERIN) and WNT pathway inhibitors (SFRP1, SFRP2, SFRP4, SFRP5) was investigated in order to demonstrate their pathogenetic role in endometrial lesions. Our results indicate that gene hypermethylation may be an early event in endometrial endometrioid tumorigenesis. Particularly, ERalpha, PR, hMLH1, CDKN2A/P16, SFRP1, SFRP2 and SFRP5 revealed a promoter methylation status in endometrioid carcinoma, whereas SFRP4 showed demethylation in cancer. P53 immunostaining showed weak-focal protein expression level both in hyperplasic lesions and in endometrioid cancer. Non-endometrioid cancers showed very low levels of epigenetic methylations, but strong P53 protein positivity. Fisher exact test revealed a statistically significant association between hMLH1, CDKN2A/P16 and SFRP1 genes methylation and endometrioid carcinomas and between hMLH1 gene methylation and peritumoral endometrium (p < 0.05). Our data confirm that the methylation profile of the peritumoral endometrium is different from the altered molecular background of benign endometrial polyps and hyperplasias. Therefore, our findings suggest that the methylation of hMLH1, CDKN2A/P16 and SFRP1 may clearly distinguish between benign and malignant lesions. Finally, this study assessed that the use of an epigenetic fingerprint may improve the current diagnostic tools for a better clinical management of endometrial lesions. PMID- 21709442 TI - The relative contribution of pro-apoptotic p53-target genes in the triggering of apoptosis following DNA damage in vitro and in vivo. AB - The p53 pathway displays a large degree of redundancy in the expression of a number of pro-apoptotic mechanisms following DNA damage that, among others, involves increased expression of several pro-apoptotic genes through transactivation. Spatial and temporal cellular contexts contribute to the complexity of the regulation of apoptosis, hence different genes may show a cell- and tissue-dependent specificity with regard to the regulation of cell death and act in concert or show redundancy with one and another. We used siRNA technology to assess the effect of multiple ablations of documented pro-apoptotic p53 target genes (PPG) in the colorectal cancer cell line HCT116 and generated mice deficient in both of the extrinsic and intrinsic PPGs genes Dr5 and Puma following treatment with chemotherapeutics and ionizing radiation. DR5, Fas, Bax, Bad, Puma and Bnip3L were induced by 5-FU and adriamycin (ADR) in HCT116 cells in a p53-dependent manner. The resulting caspase 3/7 activity in HCT116 cells following treatment were suppressed by ablated expression of the PPGs in the extrinsic as well as the intrinsic pathway. To our surprise, knocking-down any of the PPGs concomitantly with DR5 did not further inhibit caspase 3/7 activity whereas inhibiting DR5-expression in HCT116Bax knockdown (kd) and HCT116Fas kd did, suggesting that these genes act downstream or in synergy with DR5. This was supported by our in vivo observations, since Puma and Dr5 were equally efficient in protecting cells of the spleen from sub-lethal radiation-induced apoptosis but less effective compared with irradiated p53-/- mice. To our surprise, Dr5-/-; Puma-/- mice did not show additive protection from radiation-induced apoptosis in any of the investigated organs. Our data indicates that the intrinsic pathway may rely on extrinsic signals to promote cell death in a cell- and tissue-dependent manner following DNA damage. Furthermore, p53 must rely on mechanisms independent of DR5 and PUMA to initiate apoptosis following gamma-radiation in the spleen and thymus in vivo. PMID- 21709443 TI - Enhanced antitumor activity of low-dose continuous administration schedules of topotecan in prostate cancer. AB - PURPOSE: The objective of this study was to determine the antitumor effects of alternate dosing schedules of topotecan in prostate cancer. RESULTS: A concentration-dependent increase in cytotoxicity was observed in PC-3 and LNCaP cells after topotecan treatment using conventional and metronomic protocols. A significant increase in potency (2.4-18 fold, after 72 hr) was observed following metronomic dosing compared to conventional dosing administration in both cell lines. Metronomic dosing also increased the percentage of PC-3 cells in the G2/M, compared to control, but did not alter LNCaP cell cycle distribution. Metronomic dosing increased p21 protein expression in LNCaP and PC-3 cells compared to conventional dosing. The observed in vitro activity was confirmed using an in vivo model of human prostate cancer. Metronomic dosing and continuous infusion decreased tumor volume significantly (p < 0.05) compared to control and conventional topotecan treatment, but had no effect on tumor vascular staining. METHODS: The cytotoxicity of topotecan after conventional or metronomic dosing was determined by examining cellular morphology, mitochondrial enzymatic activity (MTT), total cellular protein (SRB), annexin V and propidium iodine (PI) staining, cell cycle and western blot analysis in human prostate cancer cell lines (PC-3 and LNCaP) and the effects metronomic or continuous infusion on tumor growth in an in vivo tumor xenograft model. CONCLUSIONS: These data support the hypothesis that low-dose continuous administration of topotecan increases potency compared to conventional dosing in prostate cancer. These data also suggest the novel finding that the enhanced antitumor activity of topotecan following low dose exposure correlates to alterations in cell cycle and increased p21 expression. PMID- 21709444 TI - A novel Rad18 ubiqitin ligase-mediated pathway for repair of camptothecin-induced DNA damage. PMID- 21709445 TI - The Myc-ARF-Egr1 pathway: unleashing the apoptotic power of c-Myc. PMID- 21709447 TI - Current world literature. PMID- 21709448 TI - Determination of kidney function before tenofovir initiation: four-fold difference in need of tenofovir dose reduction depending on method used. PMID- 21709449 TI - CCR5 chemokine receptor polymorphism in patients with HIV-1 from Western India. PMID- 21709450 TI - Effect of expanded HIV testing programs on the status of newly diagnosed HIV infected patients in two Veterans Health Administration facilities: 1999-2009. PMID- 21709451 TI - High frequency of HIV-1 dual infections in Cameroon, West Central Africa. PMID- 21709452 TI - Increasing HIV subtype diversity in Canadian-born patients living in Southern Alberta, Canada. PMID- 21709453 TI - Human rights abuses, ethics, and the protection of subjects when conducting research on intravenous drug users in China. PMID- 21709454 TI - Human rights, ethics, and the protection of intravenous drug users are much improved in China. PMID- 21709458 TI - Helping patients with weight loss. PMID- 21709459 TI - Where's nursing at the WHO? PMID- 21709460 TI - A public health nursing shortage. PMID- 21709461 TI - Education and advocacy. PMID- 21709462 TI - Caring for patients and ourselves. PMID- 21709465 TI - Pain control in the elderly. PMID- 21709463 TI - Caring for patients and ourselves. PMID- 21709464 TI - Overhauling health practices. PMID- 21709466 TI - Nurse staffing matters-again. PMID- 21709468 TI - Postarthroscopy experience improves with telephone follow-up. PMID- 21709469 TI - Long-term effects of ARDS after ICU stay. PMID- 21709471 TI - Heart failure process measures positively related to outpatient survival. PMID- 21709472 TI - Advances in trauma care. PMID- 21709476 TI - International nursing comes to Malta. PMID- 21709481 TI - Living well with multiple sclerosis. AB - OVERVIEW: Improvements in magnetic resonance imaging and the advent of disease modifying therapies in the past 15 years have changed the diagnosis and treatment of multiple sclerosis, an autoimmune disorder affecting the central nervous system. Accordingly, the nursing role has become more complex, involving advocacy, education, research, counseling, and medication administration. This article reviews the pathophysiology of the disorder, the available therapies to treat it, and the challenges patients face when making treatment decisions at various stages in the course of the disease. PMID- 21709483 TI - Cultivating quality: a program to train inpatient pediatric nurses in insulin pump use. PMID- 21709484 TI - Evidence-based practice, step by step: evaluating and disseminating the impact of an evidence-based intervention: show and tell. AB - This is the 11th article in a series from the Arizona State University College of Nursing and Health Innovation's Center for the Advancement of Evidence-Based Practice. Evidence-based practice (EBP) is a problem-solving approach to the delivery of health care that integrates the best evidence from studies and patient care data with clinician expertise and patient preferences and values. When delivered in a context of caring and in a supportive organizational culture, the highest quality of care and best patient outcomes can be achieved.The purpose of this series has been to give nurses the knowledge and skills they need to implement EBP consistently, one step at a time. The final article in the series will be published in the September issue. PMID- 21709485 TI - Multiple sclerosis and sexuality. PMID- 21709486 TI - Before the signal fades. PMID- 21709487 TI - A special issue on ultraviolet radiation and its effects on the eye. PMID- 21709488 TI - The mechanisms and consequences of ultraviolet-induced immunosuppression in the skin and eye. AB - Ultraviolet radiation (UVR) of the skin results in immune suppression to antigens encountered shortly after the exposure. The pathways leading to the downregulation in immunity are complex, initiated by chromophores located at the surface of the skin and ending with the generation of immunosuppressive mediators and regulatory cells. Ultraviolet-induced immunosuppression can be considered not only as beneficial, such as in preventing chronic inflammatory responses and allergic and automimmune reactions, but it can also be detrimental, such as in the lack of control of skin tumors and infectious diseases. The eye is an immune privileged site through a wide variety of mechanisms that allow selected immune responses without causing inflammation. The role of UVR in altering immune responses in the eye is not clear and is discussed in relation to photokeratitis, herpetic stromal keratitis, and pterygium. PMID- 21709489 TI - RSO interview with John Cuellar. Interview by Rene Michel. PMID- 21709490 TI - How long to air sample? Practical considerations for short-term air sampling. AB - Transportable (e.g., "giraffe") air samplers can be used for both short-term "grab-sampling" situations involving a few minutes to several hours, as well as for long-term retrospective air sampling situations that typically last a week. It is the short-term coverage situation which begs the question: "how long a sampling time is adequate?" The basis for the answer (which depends mainly on the selected volumetric sampling rate and the counter sensitivity, as well as the concentration level to be measured) can be simply viewed as follows: that an adequate activity must be measureable on the air filter sample at the cessation of sampling. Equations for selection of sampling times are presented, as are example calculations for alpha counters in order to measure various target concentrations and exposures. The concepts presented here can be readily adapted to other counting systems as well as to different sampling flow rates. PMID- 21709491 TI - 131I activity in urine to the sewer system due to thyroidal treatments. AB - In nuclear medicine, estimating the radioactivity contained in the urine of patients treated with I and discharged to the environment could prevent the exposure of a population to radioactive effluents and the pollution of the aquatic environment with ionizing radiation. This can be a regulatory requirement (as in Spain) or requested by the sewer authority. Seventy-nine differentiated thyroid cancer cases (undergone as inpatients) and 187 hyperthyroidism cases (undergone as outpatients) were treated in our hospital with I throughout the year 2009. In hyperthyroidism treatments, the effective elimination constant was used to calculate the corresponding discharged activity in the urine, giving an activity level always below 0.7 GBq. In differentiated thyroid cancer treatments, patient's urine was collected in storage tanks during the hospitalization. Measurements of external exposure at 1 m made every day were used to calculate the activity contained in the urine. The tank activity was always below 15 GBq, but always higher than 2 GBq. Obtained results show that effective doses to sewage workers, received from liquid discharges, can only be reduced to less than 10 MUSv if storage tanks are installed. Without tanks, 157 MUSv can be reached, above the constrain dose used in nuclear installations (100 MUSv). Our calculations may be helpful to the regulatory authority to review the clinical radiation waste normative, especially in countries where the discharges are released directly into public sewage plants. PMID- 21709492 TI - Systematic approach to training occupationally exposed workers in Ghana and the rest of Africa. AB - The International Basic Safety Standards requires that all personnel on whom protection and safety depends be trained and qualified. The Radiation Protection Institute of the Ghana Atomic Energy Commission has adopted a systematic approach to training those occupationally exposed to ionizing radiation in the course of their work. In collaboration with the International Atomic Energy Agency several training courses have been implemented at the national level and in the African region. From 1993 to 2008, more than 400 occupationally exposed workers in Ghana were trained on radiation safety. Several African regional training events on radiation safety have also been executed with a total participation number of 583 individuals. The training events have contributed towards upgrading the safety culture within institutions that have participated. PMID- 21709493 TI - The use of photographic film to pinpoint accelerator beam losses. AB - Following removal of a superconducting wiggler that has a maximum magnetic-field of 7 T in a high-energy synchrotron facility, sufficient lead shielding was placed upstream of the removal point in the normal-conducting electron storage ring to account for any radiation sources from the upstream components. As is customary in such cases, when vacuum has been breached, there is a period of time required for vacuum re-conditioning of the ring. During this re-conditioning phase, poor vacuum contributes to gas bremsstrahlung formation that typically is visualized as an increase in overall radiation exposure from standard operating conditions. However, in this case, new radiation patterns emerged and persisted throughout the re-commissioning phase. Subsequently, additional shielding was then placed upstream but still failed to resolve the source of radiation. The radiation source point consisted of two distinct components: a point parallel to the position originally covered by the wiggler and a strong forward-directed peak (i.e., bremsstrahlung). The only feedback mechanism to track the beam position is the beam position monitors (BPM's). BPM's were located forward and aft of the parallel source point. The BPM's suggested that the beam was in the correct position. To investigate the elevated radiation level, commercial photographic film was used as a monitoring ruler and the focal point of the radiation source was clearly identified using this novel approach. The silver halide grain contained within the film emulsion possessed sufficient cross section and was activated from Ag to Ag, which has a half-life of 2.39 min and emits easily detectable radiation. Further, the exposed film is ready for reuse after 25 min due to the short half-life of Ag. The proposed method proved to be an easy, economic, and effective approach to rapidly and qualitatively identify the location of the beam losses. PMID- 21709494 TI - Decontamination of a technetium contaminated fume hood in a research laboratory. AB - After 4 y of working with 99Tc in milligram to gram quantities to make many different compounds and provide the resource for the generation of several publications, work in one of the fume hoods used by the University of Nevada, Las Vegas (UNLV), radiochemistry program started to cause an increase in contamination events that were discovered in weekly surveys. It was decided that the hood should be cleaned out when the researchers were away during the winter break in December 2009. The hood, until just before the winter break, held equipment from years of operation. PMID- 21709496 TI - Canada's efforts in developing capabilities in radiological population monitoring. AB - Population monitoring is an important component of radiological and nuclear emergency preparedness and response. Since 2002, Canada has been investing in developing national capabilities in radiological population monitoring. This paper summarizes Canada's efforts in developing methods and techniques in biological dosimetry and in vivo and in vitro bioassay techniques. There are still many gaps to fill that require further efforts. Integration of different monitoring methods and techniques in order to have the best assessment of radiation dose to support medical management and integration of Canada's efforts with international efforts are recommended. PMID- 21709495 TI - International workshop on emergency radiobioassay: considerations, gaps and recommendations. AB - An international workshop on emergency radiobioassay was held in Ottawa, Canada, 1-3 September 2010. Sixty-five scientists and public health officials from five countries attended the workshop and gave 36 presentations. During the workshop, many considerations were raised, gaps identified, and recommendations given for emergency radiobioassay for both preparedness and response in case of a radiological or nuclear incident. In short, some bioassay methods and protocols need to be developed, validated, and exercised; national and international radiobioassay laboratory networks should be established; and communications and collaborations among public health officials, monitoring experts, and medical staff are encouraged. All these activities are required to make us better prepared for an RN emergency. PMID- 21709497 TI - Evaluation of Cuprimine(r) and Syprine(r) for decorporation of radioisotopes of cesium, cobalt, iridium and strontium. AB - Cuprimine(r) and Syprine(r) are therapeutics approved by the USFDA to treat copper overload in Wilson Disease (a genetic defect in copper transport) by chelation and accelerated excretion of internally-deposited copper. These oral therapeutics are based on the respective active ingredients D-penicillamine (DPA) and N,N'-bis (2-aminoethyl) -1,2-ethanediamine dihydrochloride (Trien). Cuprimine is considered the primary treatment, although physicians are increasingly turning to Syprine as a first-line therapy. Both drugs exhibit oral systemic activity and low toxicity; their biological effects and safety are established. Previous in vivo studies using a rodent animal model established the decorporation potential of Cuprimine and Syprine for (60)Co and (210)Po. Currently these studies are being expanded to evaluate the in vivo decorporation efficacy of these drugs for several additional radionuclides. In this report, results of this investigation are discussed using the radionuclides (137)Cs, (60)Co, (192)Ir and (85)Sr. Short term 48-h pilot studies were undertaken to evaluate DPA and Trien for their in vivo decorporation potential using male Wistar-Han rats. In these studies, a radionuclide solution was administered to the animals by intravenous (IV) injection, followed by a single IV dose of either DPA or Trien. Control animals received the radionuclide alone. Results show effective decorporation of (60)Co by DPA within the time frame evaluated. DPA and Trien were also modestly effective in decorporation of (137)Cs and (85)Sr, respectively. The study did not find DPA or Trien effective for decorporation of (192)Ir. Based on these encouraging findings, further studies to evaluate the dose-response profiles and timing of the chelator administration post exposure to radionuclides are warranted. PMID- 21709498 TI - Molecularly imprinted polymers for (90)Sr urine bioassay. AB - A molecularly imprinted polymer (MIP) comprising dicyclohexano-18-crown-6 (DCH18C6) was synthesized as a Sr-selective sorbent for urine bioassay purposes. MIP particles (326 +/- 2 nm diameter) were formed using acetone and acetonitrile (1:3 v/v) as the porogen, methacrylic acid (MAA) as the functional monomer and ethylene glycol dimethacrylate (EGDMA) as the cross-linker. The DCH18C6-MIP particles were impregnated with additional DCH18C6 and treated further with NaOH to attain better binding affinity for Sr(2+). The effects of pH, ionic strength and amount of particles were evaluated for optimal extraction of (90)Sr(2+) from urine samples, as measured by liquid scintillation analysis (LSA). After up to 94% of (90)Y was removed by precipitation with TiO(2), DCH18C6-MIP particles were applied for selective SPE of (90)Sr remaining in the urine matrix for final LSA. PMID- 21709499 TI - PROCORAD's proficiency tests as a means of analyzing capacities in emergency situations. AB - Beyond the metrological evaluation indispensable to prove objectively the capability of a medical laboratory to perform analysis, the comparison of analytical performances regarding the specificity, rapidity and trueness of the available methods is a real interest of international comparison exercises. The objective of this paper is to present and discuss the main results of proficiency testing organized by PROCORAD in the radiobioassay field illustrated by exercises for in vitro "surprise" analysis when no information is available on the nuclides involved, which can be the case in an emergency situation. PMID- 21709500 TI - Rapid urinary output normalization method using specific gravity. AB - Spot urine samples are often taken for emergency radiobioassay to provide a quick dose assessment for contaminated individuals. The subsequent dosimetric analysis requires a urinary output normalization method to adjust spot sampling to daily urine excretion. A rapid specific gravity method that was developed for 24-h urinary output correction is described. Spot urine samples were collected from volunteers of different race, gender, and age to validate the normalization method. Results show that a specific gravity test is a fast, easy and robust method to correct the urine excretion in the event of a radiation emergency. PMID- 21709501 TI - An emergency bioassay method for actinides in urine. AB - A rapid bioassay method has been developed for the sequential measurements of actinides in human urine samples. The method involves actinide separation from a urine matrix by co-precipitation with hydrous titanium oxide (HTiO), followed by anion exchange and extraction chromatography column purification, and final counting by alpha spectrometry after cerium fluoride micro-precipitation. The minimal detectable activities for the method were determined to be 20 mBq L(-1) or less for plutonium, uranium, americium and curium isotopes, with an 8-h sample turn-around time. Spike tests showed that this method would meet the requirements for actinide bioassay following a radiation emergency. PMID- 21709502 TI - Rapid determination of uranium isotopes in urine by inductively coupled plasma mass spectrometry. AB - Following a radiological or nuclear emergency involving uranium exposure, rapid analytical methods are needed to analyze the concentration of uranium isotopes in human urine samples for early dose assessment. The inductively coupled plasma mass spectrometry (ICP-MS) technique, with its high sample throughput and high sensitivity, has advantages over alpha spectrometry for uranium urinalysis after minimum sample preparation. In this work, a rapid sample preparation method using an anion exchange chromatographic column was developed to separate uranium from the urine matrix. A high-resolution sector field ICP-MS instrument, coupled with a high sensitivity desolvation sample introduction inlet, was used to determine uranium isotopes in the samples. The method can analyze up to 24 urine samples in two hours with the limits of detection of 0.0014, 0.10, and 2.0 pg mL(-1) for (234)U, (235)U, and (238)U, respectively, which meet the requirement for isotopic analysis of uranium in a radiation emergency. PMID- 21709503 TI - Laboratory evaluation of a SpectraMax microplate reader and test strips for field measurement of creatinine in spot urine samples in the event of a radiological accident. AB - The fear that terrorists might use radiological or nuclear (RN) devices to attack others is a new but growing phenomenon, arising mainly from the events of 11 September 2001. Research on rapid analytical methods that can allow analyses of large numbers of people who may become internally contaminated with radionuclides due to a RN accident is still limited. To contribute to this bioassay capacity for emergency response, the Radiation Protection Bureau of Health Canada has identified and evaluated two new portable SpectraMax plate readers (model 250 and Plus 384) and one brand of dry reagent strips for rapid measurement of creatinine in spot urine samples. Concentrations of creatinine in spot urine samples provide a means of adjusting or normalizing urine collections to 24 h, upon which accurate internal dose assessments due to the radionuclides can be made. Preliminary test results of the devices showed the two SpectraMax plate readers and the TECO dry creatinine reagent strips were portable, rapid and reliable for urinary creatinine measurements in spot samples, suggesting they can be used in rapid dose screening of people. PMID- 21709504 TI - Analysis of urine for pure beta emitters: methods and application. AB - Bioassay for individual radionuclides is an essential and first step in estimation of radiation risk to nuclear facilities workers and people who are exposed to the contaminated environment in the event of a nuclear accident or radiological attack. Urine is a frequently used biological sample for this purpose. Tritium and (14)C are important radionuclides for workers in nuclear reactors and radiopharmaceutical laboratories. A method for the determination of tritium and (14)C in organic and inorganic forms in urine has been developed. It involves activated charcoal absorption of organic matter followed by combustion to separate tritiated water from organically-bound tritium. Inorganic (14)C from organically-bound (14)C, the separated tritium and (14)C were measured using liquid scintillation counting. Iodine-129, a long-lived beta emitter, is normally released to the atmosphere during the operation of nuclear facilities, especially in reprocessing plants. The high concentration of iodine in the thyroid makes this radionuclide an important source of exposure to exposed populations. A simple method has been developed in this work for the determination of (129)I in urine by anion exchange preconcentration, extraction purification and liquid scintillation counting. Using accelerator mass spectrometry, urine samples can be analyzed for low level (129)I in both organic and inorganic forms after active charcoal adsorption and solvent extraction separation. Condensed water collected daily from the reactor hall in a Danish research reactor and monthly urine samples from the staff working in the reactor building were collected from 2003 2010 and analyzed using this method, and the results are presented and discussed. PMID- 21709505 TI - Emergency radiobioassay preparedness exercises through the NIST radiochemistry intercomparison program. AB - The present challenge for the international emergency radiobioassay community is to analyze contaminated samples rapidly while maintaining high quality results. The National Institute of Standards and Technology (NIST) runs a radiobioassay measurement traceability testing program to evaluate the radioanalytical capabilities of participating laboratories. The NIST Radiochemistry Intercomparison Program (NRIP) started more than 10 years ago, and emergency performance testing was added to the program seven years ago. Radiobioassay turnaround times under the NRIP program for routine production and under emergency response scenarios are 60 d and 8 h, respectively. Because measurement accuracy and sample turnaround time are very critical in a radiological emergency, response laboratories' analytical systems are best evaluated and improved through traceable Performance Testing (PT) programs. The NRIP provides participant laboratories with metrology tools to evaluate their performance and to improve it. The program motivates the laboratories to optimize their methodologies and minimize the turnaround time of their results. Likewise, NIST has to make adjustments and periodical changes in the bioassay test samples in order to challenge the participating laboratories continually. With practice, radioanalytical measurements turnaround time can be reduced to 3-4 h. PMID- 21709506 TI - Rapid methods for the isolation of actinides Sr, Tc and Po from raw urine. AB - Rapid methods for the isolation and analysis of individual actinides (Th, U, Pu, Am/Cm) and Sr, Tc and Po from small volumes of raw urine have been developed. The methods involve acidification of the sample and the addition of aluminum nitrate or aluminum chloride salting-out agent prior to isolation of the desired analyte using a tandem combination of prefilter material and extraction chromatographic resin. The method has been applied to the separation of individual analytes from spiked urine samples. Analytes were recovered in high yield and radionuclide purity with separation times as low as 30 min. The chemistry employed is compatible with automation on the ARSIIe instrument. PMID- 21709507 TI - Rapid determination of (237)Np and plutonium isotopes in urine by inductively coupled plasma mass spectrometry and alpha spectrometry. AB - A new rapid separation method was developed for the measurement of plutonium and neptunium in urine samples by inductively-coupled plasma mass spectrometry (ICP MS) and/or alpha spectrometry with enhanced uranium removal. This method allows separation and preconcentration of plutonium and neptunium in urine samples using stacked extraction chromatography cartridges and vacuum box flow rates to facilitate rapid separations. There is an increasing need to develop faster analytical methods for emergency response samples. There is also enormous benefit to having rapid bioassay methods in the event that a nuclear worker has an uptake (puncture wound, etc.) to assess the magnitude of the uptake and guide efforts to mitigate dose (e.g., tissue excision and chelation therapy). This new method focuses only on the rapid separation of plutonium and neptunium with enhanced removal of uranium. For ICP-MS, purified solutions must have low salt content and low concentration of uranium due to spectral interference of (238)U(1)H(+) on m/z 239. Uranium removal using this method is enhanced by loading plutonium and neptunium initially onto TEVA resin, then moving plutonium to DGA resin where additional purification from uranium is performed with a decontamination factor of almost 1*10(5). If UTEVA resin is added to the separation scheme, a decontamination factor of ~3 * 10(6) can be achieved. PMID- 21709508 TI - Preliminary studies of an 18-crown-6 ether modified magnetic cation exchange polymer in rapid (90)Sr bioassay. AB - A cation exchange polymer resin embedded with magnetic nanoparticles and modified with crown ether was developed for urinalysis to rapidly monitor levels of (90)Sr exposure in humans who have been involved in a nuclear event. Invention of the resin matrix of 2-acrylamido-2-methyl-1-propanesulfonic acid cross-linked with divinylbenzene incorporated a Sr(2+) chelating agent, di-tert-butyl-cyclohexano 18-crown-6 through surface immobilization using a molecular modifier 1-octanol. The performance of these magnetic cation exchange resin particles was investigated by separating (90)Sr in the presence of (90)Y progeny. Masking agents and precipitants were examined to ascertain that sodium hydroxide at pH 7.5 was capable of selectively removing 89 +/- 2% (90)Y before subsequent (90)Sr uptake. Preliminary investigations in rapid urinalysis were successful in isolating 83 +/- 2% (90)Sr when pH was optimized to 9, with a sample turnover time <2 h, which is promising for radiological emergencies. PMID- 21709509 TI - Investigation of magnetic nanoparticles for the rapid extraction and assay of alpha-emitting radionuclides from urine: demonstration of a novel radiobioassay method. AB - In the event of an accidental or intentional release of radionuclides into a populated area, massive numbers of people may require radiobioassay screening as triage for dose-reduction therapy or identification for longer-term follow-up. If the event released significant levels of beta- or alpha-emitting radionuclides, in vivo assays would be ineffective. Therefore, highly efficient and rapid analytical methods for radionuclide detection from submitted spot urine samples (<=50 mL) would be required. At present, the quantitative determination of alpha emitting radionuclides from urine samples is highly labor intensive and requires significant time to prepare and analyze samples. Sorbent materials that provide effective collection and enable rapid assay could significantly streamline the radioanalytical process. The authors have demonstrated the use of magnetic nanoparticles as a novel method of extracting media for four alpha-emitting radionuclides of concern (polonium, radium, uranium and americium) from chemically-unmodified and pH-2 human urine. Herein, the initial experimental sorption results are presented along with a novel method that uses magnetic nanoparticles to extract radionuclides from unmodified human urine and then collect the magnetic field-induced particles for subsequent alpha-counting-source preparation. Additionally, a versatile human dose model is constructed that determines the detector count times required to estimate dose at specific protective-action thresholds. The model provides a means to assess a method's detection capabilities and uses fundamental health physics parameters and actual experimental data as core variables. The modeling shows that, with effective sorbent materials, rapid screening for alpha-emitters is possible with a 50-mL urine sample collected within 1 wk of exposure/intake. PMID- 21709510 TI - Use of epidemiological data and direct bioassay for prioritization of affected populations in a large-scale radiation emergency. AB - Following a radiation emergency, evacuated, sheltered or other members of the public would require monitoring for external and/or internal contamination and, if indicated, decontamination. In addition, the potentially-impacted population would be identified for biodosimetry/bioassay or needed medical treatment (chelation therapy, cytokine treatment, etc.) and prioritized for follow-up. Expeditious implementation of these activities presents many challenges, especially when a large population is affected. Furthermore, experience from previous radiation incidents has demonstrated that the number of people seeking monitoring for radioactive contamination (both external and internal) could be much higher than the actual number of contaminated individuals. In the United States, the Department of Health and Human Services is the lead agency to coordinate federal support for population monitoring activities. Population monitoring includes (1) monitoring people for external contamination; (2) monitoring people for internal contamination; (3) population decontamination; (4) collecting epidemiologic data regarding potentially exposed and/or contaminated individuals to prioritize the affected population for limited medical resources; (5) administering available pharmaceuticals for internal decontamination as deemed necessary by appropriate health officials; (6) performing dose reconstruction; and (7) establishing a registry to conduct long-term monitoring of this population for potential long-term health effects. This paper will focus on screening for internal contamination and will describe the use of early epidemiologic data as well as direct bioassay techniques to rapidly identify and prioritize the affected population for further analysis and medical attention. PMID- 21709514 TI - TIOP III: important guidance for nursing practice. PMID- 21709515 TI - Should children with type 1 diabetes be hospitalized at diagnosis? PMID- 21709516 TI - Health beliefs and practices of Muslim women during Ramadan. AB - There are clear exemptions in Islam from fasting in Ramadan during sickness, pregnancy, and breastfeeding. Yet, some Muslim women still elect to fast while sick, pregnant, or breastfeeding because of a confluence of social, religious, and cultural factors. Little is known about the physiological effects of fasting during Ramadan on the mother or her unborn baby, and thus nurses and other healthcare providers are faced with the difficult task of providing appropriate medical advice to Muslim women regarding the safety and impact of their fasting. This article describes what is known about this topic and suggests that healthcare professionals learn as much as possible about the multicultural best practices and research-driven information about fasting in order to help Muslim women make informed decisions. PMID- 21709518 TI - Mentoring fathers of children newly diagnosed with T1DM. AB - PURPOSE: To pilot test a social support intervention for fathers of children <13 years old newly diagnosed with type 1 diabetes mellitus (T1DM). DESIGN AND METHODS: The pilot study was part of a larger randomized, controlled clinical trial. Father participants (28 fathers of children newly diagnosed) were recruited from two pediatric diabetes centers. For 12 months fathers (n = 19) and their spouses in the experimental arm received social support (home visits and phone calls). Control group fathers (n = 9) and their spouses received the phone number of an experienced parent (but not formally educated to provide social support) to call as needed. RESULTS: Fathers in the intervention group had significantly greater confidence but scored higher on worry at 12 months than control group fathers. Fathers in the two groups did not differ significantly in disease-related concerns or perceived disease impact on the family, nor did they differ significantly in perceived amount and helpfulness of their daily management. However, mothers overall perceived fathers as contributing more care and help than fathers perceived themselves (p > .10). Fathers in the experimental arm identified parent mentors as individuals they would seek advice regarding day to-day management and community agencies. Over this 4.5 year study, 6 of 28 father participants and two of the three father mentors dropped out. CLINICAL IMPLICATIONS: Nurses caring for families with young children newly diagnosed with T1DM should consider fathers social support needs and encourage their participation in day-to-day management. PMID- 21709519 TI - Perinatal implications of sickle cell disease. AB - Sickle cell disease (SCD) affects millions of people across the globe. In the United States, approximately 70,000 to 100,000 people have the disease, and 2 million have the sickle cell trait. SCD occurs once in every 500 African American births, and once in 36,000 Hispanic American births. Women with SCD can have more adverse maternal outcomes such as preeclampsia, eclampsia, preterm labor, placental abruption, intrauterine growth restriction, and low birthweight. Providing comprehensive nursing care to women with SCD is a challenge, particularly during labor and birth, with nursing management aimed at attaining healthy birth outcomes while preventing or treating manifestations of the disease. Labor and delivery nurses are responsible for specific knowledge and care practices for these women, including differentiating the pain of sickle cell crisis from contraction pain and monitoring maternal and fetal oxygenation, as oxygenation is jeopardized in laboring sickle cell patients. Intrapartum nursing care also requires vigilance in the need for emergency cesarean birth. Nursing interventions include symptom management, pain management, ensuring patient safety, and educating patients. Coordination of care and clear communication between the members of the healthcare team, patient, and family are essential elements to ensure a positive outcome for perinatal patients with SCD. PMID- 21709521 TI - Review of interventions to relieve postpartum pain from perineal trauma. AB - As an increased risk for infection and potentially significant source of pain, perineal trauma can negatively impact a mother's postpartum recovery. A variety of nursing interventions aimed at relieving perineal pain are largely based on localized cooling. Unfortunately, these interventions may not follow best practice for providing adequate pain relief or preventing perineal postpartum infection. This article provides a review of the literature related to utilizing localized cooling for postpartum perineal pain relief, suggests clinical guidelines for safe implementation of these measures, and calls for further research for evidence of nursing interventions to relieve pain caused by perineal trauma. PMID- 21709522 TI - Developing low-literacy health education materials for women. AB - Research has consistently shown that people absorb information significantly better when written information is provided in conjunction with verbal explanations. Despite this, studies also show that many written health education materials do not have readability levels that are appropriate for women who have low literacy skills. This article summarizes the process and essential considerations, such as content of the material, readability, layout, design, culture, language, and medium of delivery in the development of low-literacy health education materials. PMID- 21709523 TI - Hospital-to-home transition of mothers of preterm infants. AB - PURPOSE: To describe mothers' experiences during the first month after their preterm infant's hospital discharge. STUDY DESIGN AND METHODS: Descriptive phenomenology with a sample of 10 mothers who were mostly single, under 25, and African American. Institutional review board approval and informed consents were obtained. Data were collected two times. First, mother's demographic data were collected before the infant's hospital discharge. Second, an in-depth interview was conducted between 2 and 4 weeks after the infant's discharge. Interviews were digitally audio-taped and transcribed verbatim. Data were analyzed using the Colaizzi seven-step process. RESULTS: There were five theme clusters that described mothers' experiences: dealing with an expected pregnancy outcome; experiencing the reality of taking care of a baby alone; struggling to adjust to the maternal role; enhancing maternal inner strength; and changing the maternal lifestyle. CLINICAL IMPLICATIONS: This study's findings reveal that mothers value teaching and coaching from nursery care providers. However, a more structured and individualized approach to discharge preparation including assessment of mother's competence in infant care may be needed. PMID- 21709524 TI - The process of "persevering toward normalcy" after childbirth. AB - PURPOSE: To construct a theory of fatigue and sleep in nondepressed lower-income urban women in the 6 months after childbirth. DESIGN AND METHODS: We conducted this grounded theory study by recruiting participants from an inpatient postpartum unit in a Midwestern urban tertiary care facility. Sixteen participants, all of whom were negative for depressive symptoms, were interviewed at 1, 3, and 6 months postpartum. RESULTS: Participants engaged in "Persevering Toward Normalcy," in which they worked to minimize fatigue and maximize sleep by accessing flexible, dynamic social support networks, which enabled them to nap or sleep on weekends. The participants' fortitude, perseverance to "keep going" and push beyond exhaustion until their bodies "got used to" the lack of sleep and ongoing fatigue enabled them to continue working, pay rent, put food on the table, and keep children in school. At the onset of the study, participants firmly believed their fatigue would ease, and sleep would gradually improve as infant and family routines were established. Until such time, they simply needed to "deal with it." CLINICAL IMPLICATIONS: In the early weeks postpartum, women can be taught how and when to access social support to promote sleep and prevent severe fatigue. Instruction on sleep hygiene and infant day/night entrainment may help women maximize sleep opportunities and infants establish a routine. To provide effective assistance, it is also necessary to understand the woman's individual sleep environment, as well as her socioeconomic and cultural contexts. PMID- 21709525 TI - Key messages from the current USDA and DHHS dietary guidelines. PMID- 21709526 TI - Integrating informatics competencies into practice. PMID- 21709528 TI - Tuberculosis: global voices and images. PMID- 21709529 TI - Avoiding confusion of maternal heart rate with fetal heart rate during labor. PMID- 21709531 TI - Avastin and Lucentis are equally effective in treating AMD. PMID- 21709532 TI - Acknowledging associate topical editors of Optometry and Vision Science. PMID- 21709534 TI - Association between peripheral vascular disease indexes and the numbers of vessels obstructed in patients with coronary artery disease. AB - INTRODUCTION: The numbers of vessels obstructed in patients with coronary artery disease (CAD) is an important prognostic factor. Pulse wave velocity (PWV), ankle brachial index (ABI) and the estimated glomerular filtration rate (eGFR) are associated with increasing CAD risks; however, the association between the numbers of vessels obstructed and PWV, ABI and eGFR is not clear. METHODS: PWV, ABI and eGFR of 58 patients underwent coronary angiography for angina pectoris and acute coronary syndrome were measured. The variables that may be related to the number of vessels involved were analyzed using univariate linear regression followed by stepwise multivariate linear regression to determine the best-fit model. RESULTS: The average PWV, ABI and eGFR were 1523 +/- 281 cm/sec, 1.16 +/- 0.06 and 76.0 +/- 16.7 mL/min/1.73 m(2) for patients with no CAD; 1496 +/- 230 cm/sec, 1.14 +/- 0.09 and 82.3 +/- 12.4 mL/min/1.73 m(2) for 1-vessel CAD; 1733 +/- 298 cm/sec, 1.07 +/- 0.17 and 63.0 +/- 26.3 mL/min/1.73 m(2) for 2-vessel CAD and 1996 +/- 664 cm/sec, 0.99 +/- 0.19 and 56.2 +/- 27.3 mL/min/1.73 m(2) for 3 vessel CAD. Age, diabetes, hypertension, pulse pressure, serum creatinine, eGFR, ABI and PWV were correlated with the numbers of vessel obstructed in univariate regression. In stepwise multivariate linear regression, diabetes, PWV and ABI was independently linked to the numbers of vessels obstructed (P=0.021, 0.004 and 0.025). CONCLUSION: Noninvasive indexes for atherosclerotic vascular disease including PWV and ABI are linked to the number of vessels obstructed in patients with CAD. PMID- 21709535 TI - Molecular machinery of autophagy and its implication in cancer. AB - Autophagy is an intracellular lysosome-dependent catabolic process that is indispensable for maintaining cellular homeostasis through the turnover and elimination of defective or redundant proteins and damaged or aged organelles. Recent studies suggest that autophagy may be closely associated with tumorigenesis and the response of tumor cells to chemotherapeutic drugs. This article reviews recent advances in understanding the molecular mechanisms underlying the regulation of autophagy and the role of autophagy in oncogenesis and anticancer therapy. It is paradoxical that autophagy acts as a mechanism for tumor suppression and contributes to the survival of tumors. In addition, whether autophagy in response to chemotherapies results in cell death or instead protects cancer cells from death is complicated, depending on the nature of the cancer and the drug. PMID- 21709536 TI - Peptostreptococcus anaerobius infective endocarditis complicated by spleen infarction. AB - Peptostreptococcus sp., which are normal flora of human mucocutaneous surfaces, can be recovered in mixed infections involving the skin, soft tissue, respiratory tract, gastrointestinal tract and genitourinary tract. Peptostreptococci are rarely reported to be the cause of infective endocarditis. Because of their fastidiousness, peptostreptococci are difficult to isolate and are often overlooked. The authors report a case of Peptostreptococcus infective endocarditis of a native mitral valve complicated by splenic infarction. The authors also review the literature to identify features of infective endocarditis caused by Peptostreptococcus anaerobius. PMID- 21709537 TI - The calcified abdomen. PMID- 21709538 TI - Clinical experience with daptomycin for outpatient parenteral antibiotic therapy. AB - The investigation reviewed the experience of a single institution using outpatient parenteral antibiotic therapy with daptomycin as monotherapy. After institutional review board approval, patients discharged from Baystate Medical Center on daptomycin as monotherapy were investigated for clinical outcome. The authors present their data descriptively comparing the success rates of daptomycin therapy according to clinical factors. Thirty-three persons were included, and all of them survived during the therapy. All patients received 6 to 8 mg/kg/day of daptomycin administered over 30 minutes, were treated between 2 to 8 weeks and received 74% to 90% of therapy after hospital discharge. Ninety-four percent of patients studied were clinically cured. Thirty-three percent of patients with osteomyelitis required surgery for cure, but all successfully completed treatment. Twelve percent had complications that did not alter treatment course. No elevations of creatine phosphokinase were noted; however, this was inconsistently checked. These results indicate that outpatient parenteral antibiotic therapy using daptomycin is a suitable agent for patients with selected Gram-positive bacterial infections. After a relatively brief hospitalization, the majority of patients can complete at least three fourths of total treatment duration outside of the hospital. PMID- 21709539 TI - Dietary and pharmacological management of severe catabolic conditions. AB - INTRODUCTION: Nutritional debilitation is among the most devastating and life threatening complications of cancers and various chronic diseases. It arises from a complex interaction between the illness and the host. This process includes cytokine production, release of lipid-mobilizing and proteolysis-inducing agents and alterations in intermediary metabolism. As a result, many patients develop cachexia with progressive body fat and muscle tissue wasting with associated worsening of their clinical status and a lower quality of life. This review will provide up-to-date information about different pharmacological management of cachexia. FINDINGS: Until recently, the 2 major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cachexia has led to newer therapeutic interventions for treating several aspects of the syndrome. These include antiserotonergic agents, branched-chain amino acids, eicosapentanoic acid, melanocortin antagonists and antimyostatin agents-all of which act on the feeding regulatory circuitry to increase appetite and inhibit illness-derived catabolic elements. CONCLUSIONS: Information from this review will guide health care providers in limiting weight loss and improve performance status of the cachectic patients through dietary and pharmacological therapy, with the hope that such approach would extend patients survival and improve their quality of life. PMID- 21709540 TI - Elevated adipose triglyceride lipase in newly diagnosed type 2 diabetes mellitus with hypertension. AB - INTRODUCTION: Adipose triglyceride lipase (ATGL) is a recently identified triacylglycerol lipase responsible for adiposity lipolysis. Its pathophysiologic role in humans remains unknown. MATERIAL AND METHODS: In this study, the authors investigated the levels of plasma ATGL among patients with type 2 diabetes mellitus (T2DM), patients with T2DM and hypertension and control subjects. They also assessed the association between plasma ATGL and body composition and metabolic parameters. RESULTS AND CONCLUSIONS: Plasma ATGL levels significantly increased in patients with T2DM and hypertension compared with those with T2DM (78.3 +/- 23.4 versus 65.1 +/- 22.8 MUg/L, P < 0.01). No gender differences were found among plasma ATGL levels. Furthermore, they found that the plasma ATGL level was positively correlated with total cholesterol (r = 0.17, P < 0.05) and high-density lipoprotein C (r = 0.16, P < 0.05) in simple regression analysis of pooled data, whereas, in multiple stepwise regression analysis, diastolic blood pressure, total cholesterol and homeostasis model assessment of insulin resistance were independently related factors with plasma ATGL levels (Y = 13.662 + 0.343 * waist + 0.268 * diastolic blood pressure + 0.053 * 2hPin + 0.966 * homeostasis model assessment of insulin resistance). This work indicates the potential link of ATGL with the pathogenesis of insulin resistance and T2DM. PMID- 21709541 TI - Pus in the ventricles of a patient with a lumbar cerebrospinal fluid drain for a thoracoabdominal aneurysm repair. PMID- 21709542 TI - Amino acid substitutions in the hepatitis C virus core region are associated with postoperative recurrence and survival of patients with HCV genotype 1b-associated hepatocellular carcinoma. AB - OBJECTIVE: We researched the molecular marker for prognosis of postoperative patients with hepatocellular carcinoma (HCC). BACKGROUND: The association of amino acid substitutions in the hepatitis C virus (HCV) core region and hepatocarcinogenesis has recently been explored. We investigated if these amino acid substitutions are associated with recurrence or survival in patients with HCC after attempted curative treatment by hepatectomy. METHODS: A total of 163 patients infected with HCV genotype 1b who previously underwent hepatectomy for primary, not recurrent HCC were analyzed. Amino acid substitutions in the HCV core region were measured by direct sequencing. Postoperative recurrence or survival rates were compared according to tumor characteristics, tumor markers, and amino acid substitutions in the core region. RESULTS: Recurrence rates after hepatectomy were higher in patients bearing a methionine at residue 91 of the HCV core region than in patients with leucine (P = 0.0002). Survival was also decreased in patients with methionine at this residue from that seen in patients with leucine at this position (P = 0.0061). The associations between amino acid substitutions at residue 91 of the HCV core region and either recurrence or survival rates were independent of liver function, progression of HCC, or tumor marker levels. CONCLUSIONS: Amino acid substitutions at residue 91 of the HCV core region are associated with postoperative recurrence or survival in patients infected with HCV genotype 1b who developed HCC and treated by hepatectomy. This factor should be taken into consideration for the postoperative management of patients with HCC. PMID- 21709543 TI - Results of systematic second-look surgery plus HIPEC in asymptomatic patients presenting a high risk of developing colorectal peritoneal carcinomatosis. AB - PURPOSE: To analyze the impact of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) performed 1 year after resection of the primary tumor in asymptomatic patients at high risk of developing peritoneal carcinomatosis (PC). PATIENTS AND METHODS: From 1999 to 2009, 41 patients without any sign of recurrence on imaging studies underwent second-look surgery aimed at treating limited PC earlier and more easily. They were selected based on 3 primary tumor-associated criteria: resected minimal synchronous macroscopic PC (n = 25), synchronous ovarian metastases (n = 8), and perforation (n = 8). RESULTS: PC was found and treated with complete surgery plus HIPEC in 23 of the 41 (56%) patients. The other patients underwent complete abdominal exploration plus systematic HIPEC. Median follow-up was 30 (9-109) months. One patient died postoperatively at day 69. Grade 3-4 morbidity was low (9.7%). The 5-year overall survival rate was 90% and the 5-year disease-free survival rate was 44%. Peritoneal recurrences occurred in 7 patients (17%), 6 of whom had macroscopic PC discovered during the second-look (26%), and one patient had no macroscopic PC (6%). In the univariate analysis, the presence of PC at second-look surgery was a significant risk factor for recurrence (P = 0.006). CONCLUSION: Selection criteria for high-risk patients appear to be accurate. In these patients, the second-look strategy treated peritoneal carcinomatosis preventively or at an early stage, yielding promising results. This study has allowed us to design a multicentric randomized trial (comparing the second-look + HIPEC approach versus standard follow-up alone), which is beginning. PMID- 21709544 TI - Postmortem image analysis of sheep cortical leptomeningeal space and vasculature: theoretical implications on brain surface dialysis. AB - The vascular surface distribution of the subarachnoid space has not been studied extensively. The aim of our study was to develop a method of computer-assisted estimation of the distribution of the vascular network in the cortical leptomeninges and subarachnoid space and model it to aid the study of the physiology of brain surface dialysis. Nine sheets of leptomeningeal tissue were obtained from adult sheep. Fourteen image sample areas of 4 cm2 each were acquired and processed with ImageJ. The vascular and nonvascular areas of the cortical subarachnoid space were identified using a "projected surface" approach. The modeling equations were used to predict the behavior of brain surface dialysis processes. The mean surface area of identified subarachnoid vessels was 0.354 +/- 0.02 cm2 per 1 cm2 of tissue. The mean meningeal area with unidentified vessels was 0.646 +/- 0.02 cm2/1 cm2, and the difference between these surfaces was significant (p < 0.0001). The modeling equations used predict that modifying the vessel diameter of the subarachnoid space could alter the efficiency of brain surface dialysis. The computer-assisted modeling of the vascular surface of the cortical subarachnoid space may be a useful tool in depicting its morphology and assessing the physiology during brain surface dialysis. PMID- 21709545 TI - Development of an informational web site for recruiting research participants: process, implementation, and evaluation. AB - Internet-based research is increasing, yet there is little known about recruitment approaches that target the Internet. Investigators have been slow to discuss how to plan, develop, and enhance recruitment using the Internet when well-concealed or disparate populations, sensitive topics, or qualitative methods are interspersed into the aims of the study. The twofold purpose of this article was to (1) highlight the major steps and strategies undertaken to develop and implement an innovative Web site for recruiting high-genetic-risk couples who were considering preimplantation genetic diagnosis use, and (2) present the recruitment results and lessons learned based on enrollment, self-evaluation, and descriptive data. The Web site was developed using a five-step process designed by the investigators. A significant step in the process was determining the Web site objectives, which were enacted through contextual and design decisions, and also by incorporating a brief video and study logo into the Web site. The recruitment results indicate that, of the 22 participant couples, ~82% were recruited via the Internet versus traditional recruitment approaches (ie, clinics, newsletters) and that the majority of couples viewed the Web site prior to enrolling in the study. In conclusion, developing a Web site using the five step process can facilitate recruitment. PMID- 21709546 TI - A comparison of lurkers and posters within infertility online support groups. AB - Current research shows that online support groups can offer people affected by infertility a unique and valuable source of social support. However, to date most research has focused on the experiences of people who post messages to online infertility support groups; in comparison, little is known about how "lurkers" (i.e., those individuals who read messages but do not post messages) use and benefit from online infertility support groups. The purpose of the present study was to compare the use and experience of online infertility support groups between lurkers and posters. A total of 295 participants who were recruited from several online infertility support groups completed an online questionnaire containing questions about their use and experience of online support groups and measures of loneliness, social support, marital satisfaction, and perceived infertility-related stress. Differences between lurkers and posters were analyzed using Mann-Whitney U and chi or Fisher exact tests. Results revealed that compared with posters, lurkers visited the online support groups less often and scored significantly lower in overall satisfaction with the online support group. However, both lurkers and posters reported gaining a range of unique benefits from access to an online support group. Furthermore, there were no significant differences in loneliness, social support, infertility-related stress, and marital satisfaction between lurkers and posters. These findings suggest that reading messages posted to online support groups may be as beneficial as interacting with the group. PMID- 21709547 TI - Chromosomal abnormalities in fetuses with ultrasonographically detected neural tube defects. AB - We analyzed the karyotype of fetuses with ultrasonographically detected neural tube defects (NTDs). In our study, we included a total of 194 fetuses with NTDs. We analyzed the type of NTD, the karyotype, maternal age, fetal gestational age at diagnosis, and fetal sex. Of the 194 fetuses with NTDs, 87 were anencephalic and 107 had other, nonanencephalic, NTDs. A total of 12 fetuses were shown to have chromosomal abnormalities. Three of 87 anencephalic fetuses (3.45%) had chromosomal abnormalities. The sex ratio for anencephalic fetuses was 65.5% : 34.5% for female and male fetuses. Nine of 107 fetuses with other NTDs (8.41%) had chromosomal abnormalities. Seven fetuses had isolated NTDs and a further seven fetuses had additional ultrasonographic anomalies. Two of the latter had abnormal karyotypes. The sex ratio of all other NTD cases was 67.3% : 32.7% for female and male fetuses. The high number of chromosomal abnormalities justifies prenatal karyotyping in all fetuses with ultrasonographically diagnosed NTDs. PMID- 21709548 TI - Anticalcifying nanoparticle antibody titer is an independent risk factor for coronary artery calcification. AB - BACKGROUND: Calcium phosphate deposition is present even in the early phases of the atherosclerotic plaque formation. Calcifying nanoparticles (CNPs), previously known as nanobacteria, have emerged as a potential causative agent for pathological calcification in human vasculature. This study investigates the relationship between the anti-CNPs antibody titers and the extent of coronary calcification. METHODS: A total of 197 consecutive patients undergoing multidetector computed tomography were enrolled in this study. The patients with coronary artery calcification (CAC; n=103) were included in the CAC group, and those without calcification (n=94) were determined as controls. The commercially available enzyme-linked immunosorbent assay kits were used to detect IgG antibodies against CNPs in serum samples. RESULTS: Mean titers of anti-CNPs antibodies were higher in individuals with CAC than in the control group (0.4 +/- 0.4 vs. 0.19 +/- 0.21U; P<0.0001). Multivariate logistic regression analysis revealed that high anti-CNPs antibody levels were an independent correlate of CAC in addition to conventional risk factors such as age, hypertension, diabetes mellitus, and low levels of high-density lipoprotein cholesterol. When the CAC scores were subcategorized: score 0, 1-100, 101-400, and more than 400, they still correlated significantly with the anti-CNPs antibody, especially in the group having CAC scores greater than 400 (P<0.0001). CONCLUSION: Anti-CNPs antibodies are an independent risk factor for CAC and the antibody levels correlate with CAC scores. PMID- 21709549 TI - Newer renin-angiotensin-aldosterone system blocker combinations: is there an advantage? AB - PURPOSE OF REVIEW: The necessity for new and more effective management approaches to achieve blood pressure goals is still present in spite of the number of antihypertensive medications available. One of the cornerstones of successful therapy is implementation of drug combinations that act on complementary biological pathways. This review article focuses on the evaluation of recent data supporting newer combinations involving inhibition of the renin-angiotensin aldosterone system (RAAS) with other drug classes such as calcium channel blockers (CCBs) and diuretics. RECENT FINDINGS: New angiotensin receptor blockers as well as renin inhibitors, with a more robust blood pressure-lowering effect than their predecessors, have emerged recently. The data presented in this text also strongly supports a combination therapy approach as initial therapy to achieve blood pressure goals in a timely fashion. Additionally, the blood pressure-lowering effect is more robust with lower-dose, single-pill combinations than with highest doses of single agents alone. Therefore, using combination agents is less prone to side effects. The challenges for such single-pill combinations remain affordability. For this reason, payers and patients have traditionally not preferred such agents in spite of better blood pressure control and adherence rates. SUMMARY: The new combinations of renin inhibitors and the new angiotensin receptor blocker combinations add to the armamentarium of agents to control blood pressure. Whereas the new angiotensin receptor blocker offers greater efficacy on blood pressure control over other agents in the class and the availability of the only chlorthalidone combination, no outcome data exist yet with any of the new agents. PMID- 21709550 TI - Role of collaborative care models including pharmacists in improving blood pressure management in chronic kidney disease patients. AB - PURPOSE OF REVIEW: Inadequately controlled blood pressure is considered an important risk factor for both chronic kidney disease (CKD) progression and cardiovascular disease progression in CKD patients. Patients with CKD and hypertension are typically followed in primary care practice settings and blood pressure is not controlled in a sizeable proportion. This review will focus on the evidence which demonstrates the important role of the pharmacist in collaboration with physicians within primary care practices to improve blood pressure management in CKD patients. RECENT FINDINGS: Several lines of evidence show that pharmacists working in collaboration with primary care physicians can improve blood pressure management as compared with usual care with a physician alone. The major effects of pharmacist intervention are to intensify antihypertensive regimens and improve medication adherence. SUMMARY: Currently, hypertension is not well controlled in a significant proportion of individuals with CKD. Recent studies in the CKD population support evidence from the general population that pharmacists as part of the collaborative care team improves blood pressure management. Research is needed to demonstrate cost-effectiveness of collaborative care models in management of hypertension and other comorbid conditions in CKD patients. PMID- 21709551 TI - Role of tissue kallikrein in regulation of tubule function. AB - PURPOSE OF REVIEW: Recent studies have provided compelling evidence that tissue kallikrein exerts kinin-independent effects on several renal transporters including the epithelial Na+ channel (ENaC), the epithelial calcium channel TRPV5 (transient receptor potential channel vanilloid subtype 5), and the colonic H+,K+ ATPase. This review focuses on the role of tissue kallikrein in the regulation of renal sodium and potassium handling. RECENT FINDINGS: Tissue kallikrein is a serine protease involved in the generation of kinins in many organs including the kidney, and most of the renal tissue kallikrein function involves its ability to generate kinins. Tissue kallikrein, through its catalytic activity, acts directly on ENaC in order to modulate its activity but is not critical for the regulation of renal sodium homeostasis. Tissue kallikrein deficient mice exhibit net transepithelial K+ absorption in cortical collecting ducts because of abnormal activation of the colonic H+,K+-ATPase in intercalated cells and reduced K+ secretion by principal cells secondary to decreased ENaC activity. Tissue kallikrein is a kaliuretic factor that provides a rapid and aldosterone independent protection against hyperkalemia after a dietary K+load. SUMMARY: Tissue kallikrein produced by connecting tubule cells regulates apical transporters by acting from the tubular lumen. Studies have demonstrated the existence of autocrine/paracrine regulatory mechanisms of K+ transport in the distal nephron. PMID- 21709552 TI - Use of estimated glomerular filtration rate for drug dosing in the chronic kidney disease patient. AB - PURPOSE OF REVIEW: Assessment of kidney function is necessary to stage chronic kidney disease (CKD) and appropriately dose medications. The Cockcroft-Gault equation provides an estimate of creatinine clearance (eClCr) and is the method commonly referenced in pharmacokinetic studies. The Modification of Diet in Renal Disease (MDRD) and CKD-Epidemiology Collaboration (EPI) equations provide an estimate of glomerular filtration rate (eGFR), with the MDRD eGFR now automatically reported by most clinical laboratories. This review describes the differences in the Cockcroft-Gault, MDRD, and CKD-EPI equations and considerations when applying estimates from these equations for drug dosing. RECENT FINDINGS: Studies evaluating drug-dosing regimens using eClCr and eGFR differ in their results depending on the population in which the equation is applied, the adjustment factors used to account for body size, and the number of dosing levels for a particular medication. The largest study to evaluate drug regimen design by method concluded that either the eGFR or Cockcroft-Gault estimates could be used for drug dosing. Differences in methodology among studies are a key factor in evaluating these results and will be highlighted in this review. SUMMARY: The Cockcroft-Gault, MDRD, and CKD-EPI equations provide reasonable estimates of kidney function; however, clinicians must understand the limitations when using these estimates for drug regimen design. PMID- 21709554 TI - Utilization of kidneys from donation after circulatory determination of death. AB - PURPOSE OF REVIEW: The present review describes the recent experience with kidney transplantation using donation after circulatory determination of death (DCDD) including efforts to expand the potential pool of DCDD donors. RECENT FINDINGS: The use of DCDD kidneys represents a growing source of kidneys for transplantation in the USA, although not to the same extent as in Europe. Expansion of the potential donor pool has included the use of kidneys with extended time to donor arrest and pediatric donors. The use of machine perfusion for DCDD kidneys has failed to demonstrate significant benefit. SUMMARY: DCDD kidneys continue to demonstrate increased rates of delayed graft function and primary nonfunction when compared with kidneys recovered after donation after brain death (DBD) likely due to increased warm ischemic time during recovery. Despite early complications, DCDD kidneys show comparable function and survival after the immediate postoperative period and have been demonstrated to provide a survival benefit to recipients over waiting for DBD kidneys. The effect of machine perfusion on DCDD kidneys may decrease delayed graft function but has no effect on long-term function. Despite concerns, the increasing number of DCDD donors does not appear to be directly responsible for decreased numbers of DBD donors. PMID- 21709553 TI - Structural mechanisms underlying the function of epithelial sodium channel/acid sensing ion channel. AB - PURPOSE OF REVIEW: The epithelial sodium channel/degenerin family encompasses a group of cation-selective ion channels that are activated or modulated by a variety of extracellular stimuli. This review describes findings that provide new insights into the molecular mechanisms that control the function of these channels. RECENT FINDINGS: Epithelial sodium channels facilitate Na+ reabsorption in the distal nephron and hence have a role in fluid volume homeostasis and arterial blood pressure regulation. Acid-sensing ion channels are broadly distributed in the nervous system where they contribute to the sensory processes. The atomic structure of acid-sensing ion channel 1 illustrates the complex trimeric architecture of these proteins. Each subunit has two transmembrane spanning helices, a highly organized ectodomain and intracellular N-terminus and C-terminus. Recent findings have begun to elucidate the structural elements that allow these channels to sense and respond to extracellular factors. This review emphasizes the roles of the extracellular domain in sensing changes in the extracellular milieu and of the residues in the extracellular-transmembrane domains interface in coupling extracellular changes to the pore of the channel. SUMMARY: Epithelial sodium channels and acid-sensing ion channels have evolved to sense extracellular cues. Future research should be directed toward elucidating how changes triggered by extracellular factors translate into pore opening and closing events. PMID- 21709555 TI - Kidney paired donation: advancements and future directions. AB - PURPOSE OF REVIEW: Kidney paired donation (KPD) has become a viable option for patients in need of a kidney transplant who have a willing, but incompatible living donor. The purpose of this review is to highlight the recent advances in KPD including shipping live-donor kidneys to their intended recipient, enrolling compatible pairs, and combining KPD with desensitization. RECENT FINDINGS: KPD has been expanded and facilitated by multiple organizations. KPD chains have been extended from single-center two-way 'swaps' to transcontinental KPD chains in which living-donor organs have been shipped without compromising outcomes. Living donor kidneys have been shipped transcontinentally on commercial airlines with great success. Enrollment of compatible donor--recipient pairs, particularly those with blood group O donors, is one strategy that has been employed to extend KPD to even more patients. It has also become more apparent that KPD can be successfully combined with desensitization in order to transplant our most immunologically challenging patients. SUMMARY: KPD is becoming an established method of transplantation at transplant centers throughout the world. Advancements have been made through shipping living-donor kidneys, combining KPD with desensitization, and enrolling compatible pairs. PMID- 21709556 TI - Psoriatic juvenile idiopathic arthritis: a tale of two subgroups. AB - PURPOSE OF REVIEW: The International League of Associations for Rheumatology criteria parse out juvenile idiopathic arthritis (JIA) into seven groups, with the aim of creating homogeneous subgroups suitable for clinical and research evaluation. However, prior studies have shown that psoriatic JIA (psJIA) may be a heterogeneous entity. RECENT FINDINGS: PsJIA is composed of two subgroups, differentiated by age at onset. Older children with psJIA have features of spondyloarthritis, including relative male preponderance, increased risk of axial involvement, and enthesitis. Extrapolating from studies on adults with psoriatic arthritis, the mechanism of older-onset PsJIA appears to involve autoinflammatory dysregulation centered at the synovial-entheseal complex; there may also be a role for gut inflammation in a subset of patients. In contrast, patients with early-onset PsJIA bear similarities to early-onset oligoarticular and polyarticular JIA patients, including female preponderance, antinuclear antibody (ANA) positivity, and certain human leukocyte antigen types, suggesting a possible role for traditional autoimmune mechanisms. Both groups, however, share a high frequency of dactylitis. SUMMARY: This review demonstrates that PsJIA is a heterogeneous entity, with different clinical, genetic, and possibly pathophysiological features. Future studies are needed to explore the mechanisms of arthritis in both subgroups, particularly in the early-onset children. PMID- 21709557 TI - Aging and osteoarthritis. AB - PURPOSE OF REVIEW: Osteoarthritis is strongly linked to aging but the mechanisms for this link are incompletely understood. The recent literature was reviewed to find studies providing new insights into the connection between aging and osteoarthritis. RECENT FINDINGS: Basic aging studies in nonarticular cells suggest that a cell stress or cell damage response contributes to chronic inflammation that promotes age-related diseases. This cellular response results in the senescence-associated secretory phenotype which has many of the characteristics of an osteoarthritic chondrocyte in terms of the cytokines, chemokines, and proteases produced. Oxidative stress can promote cell senescence and studies have shown a role for oxidative stress in altering cell signaling pathways in chondrocytes that can disrupt the response to growth factors. Mitochondria are an important source of reactive oxygen species and studies continue to support a role for the mitochondria in osteoarthritis, including work suggesting changes in energy production. Cell death occurs in osteoarthritic cartilage and recent studies suggest autophagy may play a role in determining if a cell lives or dies when stressed. SUMMARY: Continued progress is being made on characterizing aging-related changes in cartilage. Additional studies are needed that focus on the tissues outside of the articular cartilage that play a role in osteoarthritis. Because osteoarthritis occurs in older adults who also have age related changes in muscle, bone, fat, and the nervous system, it is likely that a more general and systemic approach will be needed to better understand the link between aging and osteoarthritis. PMID- 21709558 TI - Genetics of osteoarthritis. AB - PURPOSE OF REVIEW: A number of reasonably powered osteoarthritis genome-wide association scans are now in the final phases of their analysis, leaving us all with baited breath. This review highlights some of the osteoarthritis signals and subsequent insights that have emerged from the candidate studies and smaller scale scans that have preceded these more powered studies, and which could therefore be considered as appetizers to the hopeful treats to follow. RECENT FINDINGS: If one applies the strict criteria of genome-wide significance thresholds, only two current signals pass muster: GDF5 and 7p22. If one relaxes slightly, other signals emerge, such as DIO2, SMAD3 and ASPN. After these, however, we enter the realm where faith takes precedence. SUMMARY: The search for osteoarthritis susceptibility loci has not been as successful as many had anticipated. This reflects many factors, including the heterogeneous nature of the disease, the tendency to use less severe phenotypes in genetic searches and the reliance on underpowered studies. We do, however, have some successes and in the very near future others will emerge from the more powered scans. Hopefully, combining the current with the new will help our attempts to understand the cause of this complex, common arthritis. PMID- 21709559 TI - Preconception cardiovascular risk factors and pregnancy outcome. AB - BACKGROUND: Pregnancy-related cardiovascular conditions are associated with both poorer pregnancy outcomes and cardiovascular disease later in life. Little is known about the relationship between preconception cardiovascular risk factor levels and pregnancy complications. METHODS: Data from the Cardiovascular Risk in Young Finns Study were linked with birth registry data for 1142 primiparous women. Age-standardized levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, blood pressure, insulin, and glucose from the study visit prior to last menstrual period were calculated. These factors were examined as predictors of gestational age, preterm birth (<37 weeks), birthweight, low birthweight (<2500 g), small-for-gestational age (weight <10th percentile for gestational age), hypertensive disorders of pregnancy, and gestational diabetes, using linear and Poisson regression with adjustment for age, body mass index, smoking, and socioeconomic status. RESULTS: Higher triglycerides were associated with a higher risk of hypertensive disorders (adjusted risk ratio [aRR] = 1.42 [95% confidence interval (CI) = 0.90-2.23]), preeclampsia (1.70 [1.08-2.65]), and gestational diabetes (1.68 [1.25-2.25]). After removing women with pregnancy complications (n = 30), the estimated aRR for the association between systolic blood pressure and preterm birth was 1.23 (95% CI = 0.99-1.54); for HDL-c and low birthweight, 0.97 (0.73-1.28); for diastolic blood pressure and small-for-gestational-age, 0.98 (0.81-1.20); and for systolic blood pressure and small-for-gestational-age, 1.18 (0.97-1.45). CONCLUSIONS: High lipid levels before pregnancy predict an increased risk of preeclampsia and gestational diabetes. Reported associations between these pregnancy complications and later cardiovascular disease of the mother are probably explained, at least in part, by maternal conditions that precede pregnancy. Interventions to improve cardiovascular health before pregnancy may reduce risk of pregnancy complications. PMID- 21709560 TI - Are associations between neighborhood socioeconomic characteristics and body mass index or waist circumference based on model extrapolations? AB - BACKGROUND: We investigated whether neighborhood socioeconomic characteristics, measured within person-centered areas (ie, centered on individuals' residences) are associated with body mass index (BMI [kg/m2]) and waist circumference. We used propensity-score matching as a diagnostic and validation tool to examine whether socio-spatial segregation (and related structural confounding) allowed us to estimate neighborhood socioeconomic effects adjusted for individual socioeconomic characteristics without excessive model extrapolations. METHODS: Using the RECORD (Residential Environment and CORonary heart Disease) Cohort Study, we conducted cross-sectional analyses of 7230 adults from the Paris region. We first estimated the relationships of 3 neighborhood socioeconomic indicators (education, income, real estate prices) with BMI and waist circumference using traditional multilevel regression models adjusted for individual covariates. Second, we examined whether these associations persisted when estimated among participants exchangeable based on their probability of living in low-socioeconomic-status neighborhoods (propensity-score matched samples). RESULTS: After adjustment for covariates, BMI/waist circumference increased with decreasing neighborhood socioeconomic status, especially with neighborhood education measured within 500-m radius buffers around residences; associations were stronger for women. With propensity-score matching techniques, there was some overlap in the odds of exposure between exposed and unexposed populations. As a function of socio-spatial segregation and an indicator of whether the data support inferences, sample size decreased by 17%-59% from the initial to the propensity-score matched samples. Propensity-score matched models confirmed relationships obtained from models in the entire sample. CONCLUSIONS: Overall, adjusted associations between neighborhood socioeconomic variables and BMI/waist circumference were empirically estimable in the French context, without excessive model extrapolations, despite the extent of socio-spatial segregation. PMID- 21709562 TI - Physiology of gas exchange during anaesthesia. AB - Mechanical ventilation is a prerequisite for many surgical interventions. Furthermore, during states of severe gas exchange disturbance or impaired neurological conditions with the threat of aspiration or cardiovascular instability, it is a life-saving intervention on every ICU. Even the induction of anaesthesia disturbs the physiological lung function, due to changes in chest wall mechanics and diaphragm relaxation, generating atelectases, gas exchange disturbance and ventilation-perfusion mismatch. Additionally, the application of positive pressure to lung structures elicits ventilator-induced lung injury, with the severity of injury dependent on the applied volume, peak pressures and levels of positive end-expiratory pressure. Although these pathophysiological changes may be of minor importance for the majority of ventilated patients in the operating room, these mechanisms may harm patients during surgical interventions with the need for one-lung ventilation or with underlying co-morbidities such as chronic obstructive pulmonary disease (COPD) or acute respiratory distress syndrome (ARDS). This review provides an outline of the major components of the pathophysiological changes associated with general anaesthesia and describes the additional risks in patients with COPD and ARDS as common co-morbidities in every hospital. PMID- 21709561 TI - Electrocardiographic QT interval and mortality: a meta-analysis. AB - BACKGROUND: Extremely abnormal prolongation of the electrocardiographic QT interval is associated with malignant ventricular arrhythmias and sudden cardiac death. However, the implications of variations in QT-interval length within normal limits for mortality in the general population are still unclear. METHODS: We performed a meta-analysis to investigate the relation of QT interval with mortality endpoints. Inverse-variance weighted random-effects models were used to summarize the relative risks across studies. Twenty-three observational studies were included. RESULTS: The pooled relative risk estimates comparing the highest with the lowest categories of QT-interval length were 1.35 (95% confidence interval = 1.24-1.46) for total mortality, 1.51 (1.29-1.78) for cardiovascular mortality, 1.71 (1.36-2.15) for coronary heart disease mortality, and 1.44 (1.01 2.04) for sudden cardiac death. A 50 milliseconds increase in QT interval was associated with a relative risk of 1.20 (1.15-1.26) for total mortality, 1.29 (1.15-1.46) for cardiovascular mortality, 1.49 (1.25-1.76) for coronary heart disease mortality, and 1.24 (0.97-1.60) for sudden cardiac death. CONCLUSIONS: We found consistent associations between prolonged QT interval and increased risk of total, cardiovascular, coronary, and sudden cardiac death. QT-interval length is a determinant of mortality in the general population. PMID- 21709564 TI - Beyond communication: the role of standardized protocols in a changing health care environment. AB - BACKGROUND: Communication errors have grave consequences in health care settings. The situation-background-assessment-recommendation (SBAR) protocol has been theorized to improve communication by creating a common language between nurses and physicians in acute care situations. This practice is gaining acceptance across the health care field. However, as yet, there has been little investigation of the ways in which SBAR may have an impact on how health care professionals operate beyond the creation of a common language. PURPOSE: The purposes of the study were to explore the implementation of the SBAR protocol and investigate the potential impact of SBAR on the day-to-day experiences of nurses. METHODS: We performed a qualitative case study of 2 hospitals that were implementing the SBAR protocol. We collected data from 80 semistructured interviews with nurses, nurse manager, and physicians; observation of nursing and other hospital activities; and documents that pertained to the implementation of the SBAR protocol. Data were analyzed using a thematic approach. FINDINGS: Our analysis revealed 4 dimensions of impact that SBAR has beyond its use as a communication tool: schema formation, development of legitimacy, development of social capital, and reinforcement of dominant logics. PRACTICE IMPLICATIONS: The results indicate that SBAR may function as more than a tool to standardize communication among nurses and physicians. Rather, the findings indicate that SBAR may aid in schema development that allows rapid decision making by nurses, provide social capital and legitimacy for less-tenured nurses, and reinforce a move toward standardization in the nursing profession. Our findings further suggest that standardized protocols such as SBAR may be a cost-effective method for hospital managers and administrators to accelerate the socialization of nurses, particularly new hires. PMID- 21709565 TI - Gadofosveset: parameter optimization for steady-state imaging of the thoracic and abdominal vasculature. AB - PURPOSE: Comparison of 3 optimized pulse sequences for thoracoabdominal contrast enhanced magnetic-resonance angiography by signal-to-noise measurements and time dependent T1 mapping in the steady state after injection of 0.03 mmol/kg BW gadofosveset. MATERIALS AND METHODS: After institutional review board approval, 15 healthy volunteers (19-46 years, mean age: 31.5 years) were included in this prospective, intraindividual comparison study. All examinations were performed at 1.5 T. Three pulse sequences: volume interpolated breath-hold examination (VIBE) sequences as VIBESEMI (echo time [TE]: 1.64 milliseconds, repetition time [TR]: 3.77 milliseconds, FA: 15 degrees, voxel size: 1.2 * 1.2 * 1.2 mm) with short TR, VIBEOPT (TE: 2.2 milliseconds, TR: 5.2, FA: 15 degree, voxel size: 1.2 * 1.2 * 1.2 mm) with long TR, and a typical 3-dimensional fast low angle shot (FLASH) sequence (TE: 1.39 milliseconds, TR: 3.77 milliseconds, FA: 25 degree, voxel size: 1.0 * 0.8 * 1.0 mm) were repeated 10, 20, 30, and 40 minutes after the injection of 0.03 mmol/kg BW gadofosveset (mean dose: 9.7 mL). Mean signal-to noise ratio (SNR) and contrast-to-noise ratio (CNR) were computed for the aorta and the inferior vena cava (IVC). Three-dimensional gradient echo sequences with variable flip angles were performed for T1 mapping 0 to 50 minutes postinjection (p.i.). Additional phantom measurements were performed to compare the sequences. RESULTS: Significantly higher SNR values of the FLASH were found at every point compared with VIBEOPT (P = 0.002-P = 0.004), but only 10, respectively, 20 minutes p.i. to VIBESEMI. No significant differences of SNR were obtained between VIBESEMI and VIBEOPT. In the aorta, the maximal percentage gain of SNR was 29.2% for 3D-FLASH compared with VIBESEMI. Similar, but mostly not significant, results were obtained regarding the SNR in the IVC with the 3D-FLASH sequence yielding higher SNR versus both comparators (P = 0.007-P = 0.466). Except 10 minutes p.i., CNR analysis yielded higher values for the VIBESEMI versus both comparators in the aorta as well as in the IVC. No statistical significant difference was found for the VIBESEMI versus the 3D-FLASH sequence in all comparisons. Regarding the phantom measurements, statistically significant higher SNR was found for the VIBESEMI versus the 3D-FLASH. The T1 time in the aorta decreased p.i. from 1227 +/- 383 milliseconds to 141 +/- 27 milliseconds and showed over the time a slow reincrease to 175 +/- 29 milliseconds at 50 minutes p.i. CONCLUSION: Ten to 30 minutes after injection of gadofosveset, a relatively constant longitudinal relaxation is given. In this steady state, no additional improvements were obtained by theoretically optimized sequence parameters in the VIBEOPT with a longer TR. PMID- 21709566 TI - Optimal time on HAART for prevention of mother-to-child transmission of HIV. AB - OBJECTIVES: To determine the impact of time between initiating highly active antiretroviral therapy (HAART) and delivery-duration of antenatal HAART-on perinatal HIV infection. DESIGN: We conducted a retrospective cohort analysis of pregnant HIV-infected women in Lusaka, Zambia. Women in our cohort were receiving HAART and had an infant HIV polymerase chain reaction test between 3 and 12 weeks of life. METHODS: We examined factors associated with infant HIV infection and performed a locally weighted regression analysis to examine the effect of duration of antenatal HAART on perinatal HIV infection. RESULTS: : From January 2007 to March 2010, 1813 HIV-infected pregnant women met inclusion criteria. Mean gestational age at first antenatal visit was 21 weeks (SD +/- 6), median CD4+ cell count was 231 cells per microliter (interquartile range: 164-329), and median duration of antenatal HAART was 13 weeks (interquartile range 8-19). Fifty nine (3.3%) infants were HIV infected. Duration of antenatal HAART was the most important predictor of perinatal HIV transmission. Compared with women initiating HAART at least 13 weeks before delivery, women on HAART for <=4 weeks had a 5.5 fold increased odds of HIV transmission (95% confidence interval: 2.6 to 11.7). Locally weighted regression analysis suggested limited additional prophylactic benefit beyond 13 weeks on antenatal HAART. CONCLUSIONS: Low rates of mother-to child HIV transmission can be achieved within programmatic settings in Africa. Maximal effectiveness of prevention of mother-to-child transmission programs is achieved by initiating HAART at least 13 weeks before delivery. PMID- 21709567 TI - Vaccine-induced HIV-specific CD8+ T cells utilize preferential HLA alleles and target-specific regions of HIV-1. AB - Most T cell-based HIV-1 vaccine candidates induce responses of limited breadth for reasons that are unclear. We evaluated vaccine-induced T-cell responses in individuals receiving an HIV-1 recombinant adenoviral vaccine. Certain HLA alleles (B27, B57, B35, and B14) are preferentially utilized to mount HIV specific responses, whereas other alleles (A02 and B07) are rarely utilized (P < 0.001). This preference seems due to 4 following factors individually or in combination: higher affinity of specific peptides to specific HLA alleles; higher avidity of T-cell receptor; HLA and peptide interaction; and/or higher surface expression of certain HLA. Thus, HLA immunodominance plays a substantial role in vaccine-induced T-cell responses. PMID- 21709568 TI - Performance evaluation of the Alere PIMA CD4 test for monitoring HIV-infected individuals in resource-constrained settings. AB - BACKGROUND: Enumeration of CD4+ T-lymphocytes is important in the management of HIV. However, standard laboratory systems based on flow cytometry are expensive, complicated, and thus unavailable to most resource-limited settings where a low cost and fully automated point-of-care CD4 testing system is required. In attempts to address this issue, a study was conducted to validate the Alere PIMA point-of-care CD4 test. METHOD: Duplicate values of the absolute number of CD4+ T lymphocytes in 203 HIV-infected blood samples obtained using the PIMA system were compared with the two predicate single-platform FACSCount and the dual-platform FACSCan (Becton Dickinson Biosciences). RESULTS: The overall absolute CD4+ T lymphocyte count obtained using the PIMA system correlated highly with the FACSCount (r = 0.957; mean bias, -54.2 cells/MUL; limit of agreement, -190.9 to +82.5 cells/MUL) and the FACSCan (r = 0.957; mean bias -44.0 cells/MUL; limit of agreement, -179.7 to +91.6 cells/MUL). Good correlation and low biases were also observed for samples with CD4+ T-lymphocyte count ranges of 0 to 200 and 0 to 350 cells/MUL. Additionally, there was no significant difference in absolute CD4+ T lymphocyte counts noted between the duplicate samples using the PIMA system. CONCLUSIONS: This new point-of-care product is a simple and reliable system and should contribute significantly to the simplification of performing CD4 testing and thus increase access for patients in resource-limited settings. The inability to obtain values for the frequency (%) of CD4+ T-lymphocyte count is one limitation of the PIMA system, the addition of which would be of value for clinical staging or monitoring in HIV-infected pediatric patients. PMID- 21709571 TI - HLA-DRB1 gene polymorphism is associated with idiopathic dilated cardiomyopathy: a meta-analysis. AB - OBJECTIVE: Some studies have reported that the HLA-DRB1 allele was associated with idiopathic dilated cardiomyopathy. However, there have been inconsistent results among different studies. To clarify the association of HLA-DRB1 and idiopathic dilated cardiomyopathy, a meta-analysis of case-control studies was performed. METHODS: PubMed database, Science Citation Index database, The Cochrane Central Register of Controlled Trials database, China National Knowledge Information database, Chinese Biomedical Literature database, Wanfang database, and VIP database in China were searched. Search terms included dilated cardiomyopathy and DRB1. Five case-control studies were included in the present meta-analysis to assess the association between HLA-DRB1*1401, HLA-DRB1*0901, HLA DRB1*0301, and idiopathic dilated cardiomyopathy. RESULTS: A total of four studies were included in our meta-analysis for HLA-DRB1*1401 and HLA-DRB1*0901. The pooled odds ratio (OR) was 2.6 [95% confidence interval (CI) 1.11-6.11, P<0.05] and 0.70 (95% CI 0.48-1.00, P=0.05), respectively. For the HLA-DRB1*0301 allele, just three studies were included in our meta-analysis. The pooled OR was 0.49 (95% CI 0.27-0.91, P<0.05). The present meta-analysis indicated that the frequency of HLA-DRB1*1401 was higher in idiopathic dilated cardiomyopathy patients than in healthy people, whereas HLA-DRB1*0901 and HLA-DRB1*0301 were higher in healthy people than in idiopathic dilated cardiomyopathy patients. CONCLUSION: The HLA-DRB1*1401 allele might be a risk factor for idiopathic dilated cardiomyopathy and HLA-DRB1*0901 and HLA-DRB1*0301 might protect humans from idiopathic dilated cardiomyopathy. PMID- 21709569 TI - Drug resistance and viral tropism in HIV-1 subtype C-infected patients in KwaZulu Natal, South Africa: implications for future treatment options. AB - BACKGROUND: Drug resistance poses a significant challenge for the successful application of highly active antiretroviral therapy (HAART) globally. Furthermore, emergence of HIV-1 isolates that preferentially use CXCR4 as a coreceptor for cell entry, either as a consequence of natural viral evolution or HAART use, may compromise the efficacy of CCR5 antagonists as alternative antiviral therapy. METHODS: We sequenced the pol gene of viruses from 45 individuals failing at least 6 months of HAART in Durban, South Africa, to determine the prevalence and patterns of drug-resistance mutations. Coreceptor use profiles of these viruses and those from 45 HAART-naive individuals were analyzed using phenotypic and genotypic approaches. RESULTS: Ninety-five percent of HAART-failing patients had at least one drug-resistant mutation. Thymidine analog mutations (TAMs) were present in 55% of patients with 9% of individuals possessing mutations indicative of the TAM1 pathway, 44% had TAM2, whereas 7% had mutations common to both pathways. Sixty percent of HAART-failing subjects had X4/dual//mixed-tropic viruses compared with 30% of HAART-naive subjects (P < 0.02). Genetic coreceptor use prediction algorithms correlated with phenotypic results with 60% of samples from HAART-failing subjects predicted to possess CXCR4-using (X4/dual/mixed viruses) versus 15% of HAART-naive patients. CONCLUSIONS: The high proportion of TAMs and X4/dual/mixed HIV-1 viruses among patients failing therapy highlight the need for intensified monitoring of patients taking HAART and the problem of diminished drug options (including CCR5 antagonists) for patients failing therapy in resource-poor settings. PMID- 21709572 TI - The reconciliation of pressure and light: a clinical case of complementary use of fractional flow reserve and optical coherence tomography. AB - An interesting case of acute coronary syndrome occurring shortly after a cardiac catheterization is reported. Different tests and imaging modalities for coronary artery disease have been performed in this patient. The potential for integration of the information available is underscored in order to overcome their inherent limitations. PMID- 21709573 TI - Invasive imaging technologies: can we reconcile light and sound? AB - Since the introduction of intravascular, catheter-based invasive imaging and diagnostic tools in the catheterization laboratories two decades ago, the functional assessment of angiographically moderate or ambiguous lesions by fractional flow reserve measurements represents the established standard of care today. Likewise, intravascular ultrasound (IVUS) is widely accepted to guide treatment strategy in complex lesions, such as long or left main stem lesions. Developments are driven by the clinical interest to optimize treatment, prevent periprocedural complications, understand treatment failure and understand progression of atherosclerosis. As a result, a variety of devices are now clinically available that enable detection and monitoring of specific plaque features over time, such as the presence of necrotic core by IVUS-VH, a lipid core plaque by near infrared (NIR) spectroscopy or a thin fibrous cap atheroma by optical coherence tomography (OCT). As the physical boundaries for both light and sound are different, these imaging technologies offer different advantages and limitations. Light-based technologies offer unparalleled high image resolution (OCT) or unparalleled high sensitivity and specificity for distinct plaque components (NIR spectroscopy), whereas conventional IVUS offers a much better tissue penetration. From a clinical perspective, both types of information are valuable. Ideally, this information should easily and in real time be available in the catheterization laboratory, consisting of co-registered datasets gained during a single catheter pullback. On this background, a combined NIR spectroscopy and IVUS catheter has recently been introduced for clinical use. The article discusses the potential and limitations of these different technologies. They may allow advanced coronary plaque diagnosis in a fast, accurate, reliable, user- and patient-friendly manner and, as such, can help to improve clinical practice today and therapeutic options in the future. PMID- 21709570 TI - Comparison of abacavir/lamivudine and tenofovir/emtricitabine among treatment naive HIV-infected patients initiating therapy. AB - BACKGROUND: Controversy about the relative performance of abacavir (ABC)/lamivudine (3TC) and tenofovir (TDF)/emtricitabine (FTC) in initial combination antiretroviral therapy (cART) exists. METHODS: We compared the times to regimen failure (composite of virologic failure or switching/stopping nucleosides for any reason) according to nucleoside backbone in treatment-naive patients starting cART in a retrospective observational cohort study. Additional endpoints included virologic failure, switching/stopping nucleosides for nonvirologic reasons, and virologic suppression. Treatment-naive noninjection drug user individuals in the Canadian Observational Cohort initiating ABC/3TC containing or TDF/FTC-containing cART with efavirenz, nevirapine, lopinavir/ritonavir, or atazanavir/ritonavir with >=6 months follow-up were included. Multivariable proportional hazards regression models accounting for competing risks were used to model outcomes. RESULTS: One thousand seven hundred sixty-four individuals (588 ABC/3TC, 1176 TDF/FTC) were included. Median (interquartile range) follow-up times were 34 (23-50) and 20 (13-30) months, respectively. Time to regimen failure was similar for ABC/3TC versus TDF/FTC [adjusted hazard ratio, (aHR) = 0.96, 95% CI = 0.80 to 1.17] after adjusting for baseline viral load (VL), sex, province, third antiretroviral agent, year of cART initiation, HLA-B*5701 test availability, and rate of VL testing. No differences were observed in time to virologic failure (aHR = 0.84, 95% CI = 0.58 to 1.20), switching/stopping nucleosides for nonvirologic reasons (aHR = 1.02, 95% CI = 0.81 to 1.28), or virologic suppression (aHR = 0.96, 95% CI = 0.83 to 1.10). There was no statistical interaction between backbone and baseline VL for any outcome. Results were similar when stratified by baseline VL <= 100,000 or > 100,000 copies per milliliter. CONCLUSIONS: In our naive noninjection drug user HIV-infected patients starting cART, there was no difference in time to regimen failure, virologic failure, switching/stopping nucleosides, or virologic suppression with ABC/3TC versus TDF/FTC. PMID- 21709574 TI - The status of coronary artery lesions in patients with conduction disturbance. AB - BACKGROUND: Conduction disturbances are related to coronary artery lesions. However, the types of coronary artery lesions prevalent among patients having conduction disturbances are still uncertain. OBJECTIVE: To investigate the status of coronary artery lesions in 107 consecutive symptomatic patients admitted to the fourth affiliated hospital of Harbin Medical University between 2005 and 2009 to receive pacemaker implantation. METHODS: All of the patients previously underwent coronary angiography for detection of symptoms related to coronary artery disease. The coronary angiographic study included stenosis severity and classification of pathological anatomy. Eighty patients had obvious coronary artery lesions; therefore, 80 age-matched individuals with more than 50% coronary artery lesions but without conduction disturbance composed the control group. The differences in the status of coronary artery lesions were studied between the groups. RESULTS: Third-degree atrioventricular block (AVB) was diagnosed in 51 patients (47.7%); 49 (45.8%) had sick sinus syndrome and 7 (6.5%) had Mobitz II, second-degree AVB. Individuals with type IV lesions accounted for 51.3% of the patients with coronary artery lesions, whereas those with type II lesions had the second highest prevalence (26.3%). Patients with type III and I lesions accounted for 15 and 7.5% of the cases, respectively. This distribution was significantly different from those in the control group in which the most prevalent types were type III and IV (46.8 and 31.6%, P < 0.05, respectively). CONCLUSION: The prevalence of coronary lesion types was different for patients with conduction disturbance from those without it; both left anterior descending artery and right coronary artery appeared to be involved in patients with conduction disturbance. PMID- 21709575 TI - An atrial mass: the value of echocardiographic three-dimensional reconstruction. AB - An 88-year-old lady was referred to our Heart Failure Clinic with a history of 'occasional' breathlessness. Electrocardiography showed sinus rhythm and no other major abnormalities and N-terminal pro-B-type natriuretic peptide (NT-proBNP) was normal. Transthoracic echocardiography showed a non-dilated left ventricle with good systolic function. A bright and well-circumscribed, echogenic mass appeared inside a mildly dilated left atrium, visible in both parasternal and apical views. A three-dimensional echocardiographic reconstruction showed no mass within the left atrium; however, an extracardiac mass impinging its posterior wall was seen. Suspicion of an intrathoracic tumour was raised and cardiac magnetic resonance showed a hiatus hernia immediately adjacent to the left atrium. Care must be taken when evaluating masses in or close to the heart. PMID- 21709576 TI - Jailed side branches: fate of unapposed struts studied with 3D frequency-domain optical coherence tomography. AB - We report the case of a 64-year-old man treated for stable angina with two bare metal stents in the proximal-mid segment of the left anterior descending artery at the bifurcation with the first diagonal and second septal branches without final kissing balloon dilatation. Seven months later he complained of recurrent angina. Frequency-domain optical coherence tomography (OCT) with three dimensional (3D) reconstruction was performed, showing a thick rim of neointimal proliferation at the ostium of both branches, causing severe restenosis. Deployment of a stent in a bifurcation main branch without opening the struts at the side-branch ostium may facilitate focal restenosis. PMID- 21709577 TI - Intravascular imaging findings in severe coronary vasospasm. AB - Appropriate diagnosis of patients with chest pain and no significant angiographic coronary artery disease remains challenging. We present the case of a 65-year-old woman with recurrent chest pain that was triggered by exertion as well as emotional stress. She underwent coronary angiography and intravascular ultrasound which demonstrated no atherosclerosis. Coronary flow reserve assessment was also normal suggesting no significant microvascular disease. Intracoronary infusion of acetylcholine, however, resulted in an increase in blood velocity and epicardial vasoconstriction, confirmed by chest pain, electrocardiogram changes and complete closure of a coronary artery by angiography, suggesting the diagnosis of coronary vasospasm or variant angina. This report highlights the importance of considering vasoconstriction when markedly increased blood velocity is observed in response to acetylcholine. PMID- 21709578 TI - Computed tomography-coronary angiography in the detection of coronary artery disease. AB - Computed tomography-coronary angiography (CT-CA) is a well-tolerated and reliable non-invasive imaging technique and can now be achieved at low levels of radiation exposure. CT-CA is highly valuable to exclude coronary artery disease, but due to over- and underestimation of the severity of coronary lesions, CT-CA cannot replace invasive coronary angiography. Coronary calcium scoring has an incremental independent prognostic value beyond traditional risk factor scores (Framingham, European Score) and may be useful to reclassify risk in asymptomatic individuals at intermediate risk. Appropriate indications for CT-CA are evolving, but studies are lacking to demonstrate that CT coronary imaging improves patient outcome. PMID- 21709579 TI - Combined surgical and angioplasty management of coronary artery aneurysms including the giant form. AB - Coronary artery aneurysms are a rare form of coronary artery disease. Due to the rarity of these aneurysms, particularly of the giant form, it is difficult to establish a standardized treatment. We report the case of a 65-year-old man who presented with symptoms of an acute coronary syndrome. A posterobasal myocardial infarction was diagnosed with a giant right coronary artery aneurysm as the underlying pathology. Two aneurysms of the left anterior descending artery were also revealed. The management strategy included ligation of the giant aneurysm coupled with distal coronary artery bypass grafting of the right coronary artery. This was complemented with a delayed percutaneous coronary intervention of the left anterior descending artery aneurysms. PMID- 21709580 TI - Imaging techniques in coronary atherosclerotic disease: dobutamine stress echocardiography--evidence and perspectives. AB - Dobutamine stress echocardiography is the most widely disseminated noninvasive technique for the assessment of coronary artery disease. Its results are important for clinical decisions. It is a versatile technique with high sensitivity and specificity for detecting viable myocardium at jeopardy. More recently, strain rate imaging has been applied to stress echocardiography. This approach relies on tissue Doppler or two-dimensional strain imaging to quantify myocardial deformation. The application of contrast echocardiographic techniques to stress echocardiography enables left ventricular opacification for border enhancement and myocardial perfusion imaging. Thus, this application is not limited to stress echocardiography, but has utility whenever image quality adversely affects wall motion assessment. Recently, three-dimensional stress echocardiography imaging has been proposed as an alternative approach to assess myocardial ischemia. PMID- 21709581 TI - Penetrating atherosclerotic ulcer of the ascending aorta: the role of computed tomography scan. AB - Asymptomatic penetrating atherosclerotic ulcer is a rare pathology of the ascending aorta, more frequent in the descending thoracic aorta, even in multiple localizations. We present a case report of a patient with penetrating atherosclerotic ulcer and the preoperative role of the computed tomography scan. PMID- 21709582 TI - The effects of acute amiodarone on short- and long-duration ventricular defibrillation threshold in canines. AB - INTRODUCTION: Some studies have shown that the defibrillation threshold (DFT) differs between short-duration ventricular fibrillation (SDVF, <1 minute) and long-duration ventricular fibrillation (LDVF > 1 minute). The goal of this study is to evaluate the effects of acute intravenous amiodarone on SDVF-DFT and LDVF DFT and its possible mechanism as well. METHODS: Twelve open-chest dogs were randomly divided into 2 groups (control group, normal saline, 10 mL.kg.h maintenance, n = 6; amiodarone group, loading dose 10 mg/kg over 10 minutes, maintenance dose 5 mg.kg.h, n = 6). VF was electrically induced and recorded with a 12 * 12 unipolar electrode plaque (2-mm spacing) sutured on the left ventricular epicardium and a plunge needle (6 unipolar electrode) inserted in the left ventricular apex. The DFTs of SDVF and LDVF were determined 20 seconds and 3 minutes after VF induction, respectively. Restitution was estimated from activation recovery intervals during pacing from the plaque and plunge needle electrodes. The activation rate was estimated by Fast Fourier Transform analysis of VF at same electrodes. The VF cycle length was defined as the reciprocal of the activation rate. The epicardial and transmural dispersion of the maximal slope of the restitution curve and VF cycle length of SDVF and LDVF were calculated, respectively. RESULTS: : In controls, LDVF-DFT was higher than SDVF DFT (645 +/- 61 vs. 520 +/- 63 V, P < 0.01). Amiodarone did not significantly alter SDVF-DFTs (496 +/- 49 vs. 552 +/- 69 V, P > 0.05) but decreased LDVF-DFT by 31% (P < 0.01). Compared with control, amiodarone significantly reduced the maximum slope of the restitution curve (1.12 +/- 0.35 vs. 0.81 +/- 0.25, P = 0.03) and its epicardial dispersion (0.32 +/- 0.07 vs. 0.24 +/- 0.04,coefficient of variation, P = 0.017). Amiodarone significantly increased the SDVF-CL (92 +/- 8 vs. 99 +/- 10 milliseconds, P < 0.01) and epicardial dispersion 0.14 +/- 0.06 vs. 0.18 +/- 0.05, P < 0.01. Amiodarone did not change the LDVF-CL (228 +/- 12 vs. 226 +/- 10 milliseconds, P > 0.05) or epicardial dispersion (0.17 +/- 0.03 vs. 0.15 +/- 0.02, P > 0.05) compared with control. However, the drug significantly decreased the transmural dispersion of LDVF-CL (68 +/- 28 vs. 39 +/ 14 milliseconds, P < 0.01) without changing the transmural dispersion of SDVF-CL (29 +/- 22 vs. 32 +/- 30 milliseconds, P > 0.05). CONCLUSIONS: Acute amiodarone significantly decreased the LDVF-DFT. The decreased transmural dispersion of LDVF CL by amiodarone might contribute to the decreased LDVF-DFT. PMID- 21709583 TI - Chronic beta-adrenoceptor antagonist treatment controls cardiovascular remodeling in heart failure in the aging spontaneously hypertensive rat. AB - Selective beta1-adrenoceptor antagonists are part of standard therapy to prolong survival in human heart failure. This study has measured structural, functional, and electrical changes in the cardiovascular system of aging male spontaneously hypertensive rats (SHRs) to determine whether beta1-adrenoceptor antagonist treatment can prevent or reverse the development of cardiovascular remodeling and heart failure in these rats. Fifteen-month-old male Wistar-Kyoto (WKY) rats or SHRs were treated with increasing metoprolol doses (30 mg.kg.d for 4 weeks, then 50 mg.kg.d for 4 weeks, then 80 mg.kg.d for 16 weeks po). Cardiovascular structure and function were determined using organ wet weight, in vivo echocardiography, histological analysis of inflammation and collagen, isolated heart and thoracic aortic ring preparations, and single cell microelectrode measurements. From 15 months, untreated SHRs developed left ventricular dilation, hypertrophy, inflammatory cell infiltration and fibrosis, and action potential prolongation together with progressive systolic, diastolic, and endothelial dysfunction and increased cardiac stiffness. Treatment with metoprolol decreased systolic blood pressure at 21 months only but improved survival, decreased ventricular weight, prevented chamber dilation, reduced inflammation, decreased fibrosis, attenuated action potential prolongation, improved systolic and diastolic function, decreased stiffness and improved endothelium-independent vascular responses. Chronic metoprolol treatment markedly attenuated both cardiac and vascular remodeling in the aging SHRs, thus attenuating the onset of heart failure and improving survival, independent of blood pressure reduction. PMID- 21709584 TI - Iodine-123 fluoropropyl-carbomethoxy-3-beta-(4-iodophenyltropane) single-photon emission computed tomography findings before and after electroconvulsive therapy in major depressive disorder with Parkinsonism. AB - BACKGROUND: To date, only a few cases of improvement of Parkinsonism in depressed patients treated with electroconvulsive therapy (ECT) have been reported. However, no functional imaging data are available to support this finding. OBJECTIVE: To describe the first observation of increase in dopamine transporter uptake after ECT. METHODS: Iodine-123 fluoropropyl-carbomethoxy-3-beta-(4 iodophenyltropane) single-photon emission computed tomographic imaging was conducted in a 77-year-old depressed patient displaying symptoms of Parkinson disease (PD) before and after a series of 12 bilateral ECTs. RESULTS: The patient displayed improvement in PD symptoms and increase in dopamine transporter uptake after ECT. CONCLUSIONS: Our observation suggests that the PD symptoms and decrease in striatal uptake appearing in the context of a depressive episode might warrant further attention, as they might be reversible. PMID- 21709585 TI - Effects of topical brinzolamide on infantile nystagmus syndrome waveforms: eyedrops for nystagmus. AB - BACKGROUND: Recent advances in infantile nystagmus syndrome (INS) surgery have uncovered the therapeutic importance of proprioception. In this report, we test the hypothesis that the topical carbonic anhydrase inhibitor (CAI) brinzolamide (Azopt) has beneficial effects on measures of nystagmus foveation quality in a subject with INS. METHODS: Eye movement data were taken, using a high-speed digital video recording system, before and after 3 days of the application of topical brinzolamide 3 times daily in each eye. Nystagmus waveforms were analyzed by applying the eXpanded Nystagmus Acuity Function (NAFX) at different gaze angles and determining the longest foveation domain (LFD) and compared to previously published data from the same subject after the use of a systemic CAI, contact lenses, and convergence and to other subjects before and after eye muscle surgery for INS. RESULTS: Topical brinzolamide improved foveation by both a 51.9% increase in the peak value of the NAFX function (from 0.395 to 0.600) and a 50% broadening of the NAFX vs Gaze Angle curve (the LFD increased from 20 degrees to 30 degrees ). The improvements in NAFX after topical brinzolamide were equivalent to systemic acetazolamide or eye muscle surgery and were intermediate between those of soft contact lenses or convergence. Topical brinzolamide and contact lenses had equivalent LFD improvements and were less effective than convergence. CONCLUSIONS: In this subject with INS, topical brinzolamide resulted in improved foveation INS waveforms over a broadened range of gaze angles. Its therapeutic effects were equivalent to systemic CAI. Although a prospective clinical trial is needed to prove efficacy or effectiveness in other subjects, an eyedrops-based therapy for INS may emerge as a viable addition to optical, surgical, behavioral, and systemic drug therapies. PMID- 21709586 TI - Common variants of the ACE gene and aneurysmal subarachnoid hemorrhage in a Danish population: a case-control study. AB - OBJECTIVE: The intron 16 insertion/deletion (I/D) polymorphism in the angiotensin converting enzyme (ACE) gene has been associated with rupture of intracranial aneurysms, but the effect of haplotypes within ACE has not been studied. This study investigated whether ACE haplotypes including the I/D polymorphism are associated with aneurysmal subarachnoid hemorrhage. METHODS: The hypothesis was tested with a case-control design in 176 patients with aneurysmal subarachnoid hemorrhage and with 498 hospital controls. Through the pairwise tagging principle, single nucleotide polymorphisms (rs4291 A/T, rs4295 C/G, rs4305 C/T, rs4311 C/T, rs4331 T/C, rs4343 C/T) in the ACE gene were genotyped along with the I/D polymorphism. Haplotypes were estimated using the PHASE software. RESULTS: Fifty-five haplotypes were identified with 3 of these having a frequency above 5%: ACCCCIT (41.6+/-0.4%), TGTTTDC (32.1+/-0.5%), and ACCTTDC (9.5+/-0.2%). No significant difference in distribution of alleles, genotypes, haplotypes, or haplotype pairs between the 2 populations was found. Specifically, we could not reproduce previously reported associations between the ACE I genotype and intracranial aneurysms. When subdivided into groups of aneurysm location, we found a trend toward an association between homozygotes of the ACCCCIT haplotype and middle cerebral artery aneurysms, odds ratio=2.9 (1.0 to 7.6), which however proved insignificant (P=0.22) after correction for multiple testing. CONCLUSION: In this Danish population, ACE haplotypes and the I/D polymorphism did not contribute significantly to the overall risk of intracranial aneurysm rupture. Larger studies are needed to delineate the association between ACE polymorphism and ruptured middle cerebral artery aneurysms. PMID- 21709587 TI - Are optimal cerebral perfusion pressure and cerebrovascular autoregulation related to long-term outcome in patients with aneurysmal subarachnoid hemorrhage? AB - BACKGROUND AND OBJECTIVES: Continuous assessment of the cerebrovascular autoregulation (CVA) through use of the pressure reactivity index (PRx), a moving linear correlation coefficient between mean arterial blood pressure and intracranial pressure, has been effective in optimizing cerebral perfusion pressure (CPPopt) in traumatic brain injured (TBI) patients. This study investigates the feasibility of measuring CPPopt in patients with aneurysmal subarachnoid hemorrhage (aSAH) by continuously assessing the CVA. METHODS: Twenty nine aSAH patients were enrolled, and data from CVA status, CPPopt, and periods when CPP was below, within, or above CPPopt were computed daily. Outcome was assessed at 6 months with the Glasgow Outcome Scale. Mann-Whitney U test was used to analyze differences in the duration of impaired CVA and duration of CPP below CPPopt in patients with good and poor outcomes. Multivariable logistic regression analysis was used to identify independent predictors of outcome. RESULTS: CVA monitoring data were available for all 29 patients with a total monitoring time of 2757 h. The duration of impaired CVA was 36.5% (interquartile range: 24.6 to 49.8) of the total monitoring time in 15 patients with good outcome and 71.6% of the total monitoring time (51.2 to 80.0) in 14 patients with poor outcome (Mann Whitney U test 3.295, P=0.0010). PRx-based CPPopt could be identified in 26 patients (89.6%) with a total monitoring time of 2691 h. The duration of CPP below the CPPopt range was 28.0% (interquartile range: 18.0 to 47.0) of the total monitoring time in patients with good outcome and 76.0% (48.5 to 82.5) in patients with poor outcome (Mann-Whitney U test 2.779, P=0.0054). Glasgow Coma Scale score and duration of impaired CVA were independently associated with 6 month outcome (Glasgow Coma Scale score odds ratio: 1.95, 95% confidence interval: 1.01-3.75; duration of impaired CVA odds ratio: 0.88, 95% confidence interval: 0.78-0.99). CONCLUSIONS: The assessment of CVA and CPPopt is feasible in aSAH patients and may provide important information regarding long-term outcome. A PRx above the 0.2 threshold and a CPP below the CPPopt range are associated with worse outcome. PMID- 21709588 TI - Periscapular abscess: unusual cause of shoulder pain in children. AB - Periscapular abcess is an extremely rare clinical condition. Diagnosis and treatment can be delayed because the clinical picture often resembles septic arthritis of the shoulder. Early diagnosis and prompt surgical treatment are mandatory, as delayed treatment can be fatal due to sepsis. Previously, four cases of periscapular abcess were described in English literature. We describe two pediatric patients with periscapular abcess, who were treated surgically and healed without any complication. PMID- 21709589 TI - Annual review of advances in non-small cell lung cancer research: a report for the year 2010. PMID- 21709590 TI - A systematic review and Canadian consensus recommendations on the use of biomarkers in the treatment of non-small cell lung cancer. AB - INTRODUCTION: Greater understanding of molecular pathways important in cell growth and proliferation of thoracic malignancies, particularly non-small cell lung cancer (NSCLC), has resulted in intense clinical and translational research. There is now considerable interest in personalizing treatment based on an understanding of tumor histology and molecular abnormalities. However, there is a multiplicity of data, often with discordant results resulting in confusion and uncertainty among clinicians. METHODS: We conducted a systematic review and a consensus meeting of Canadian lung cancer oncologists and pathologists to make recommendations on the use of biomarkers in NSCLC. PubMed covering 2005 to March 2010 was searched using MESH terms for NSCLC and randomized trials, plus text words for the biomarkers of interest. Conference proceedings from 2005 to 2009 ASCO, ESMO, IASLC, and USCAP were also searched. The articles were reviewed by pairs of oncologists and pathologists to determine eligibility for inclusion. RESULTS: Ten oncologists and pathologists reviewed and summarized the literature at a meeting attended by 37 individuals. Draft recommendations were formulated and agreed upon by consensus process. There is some evidence that histology is prognostic for survival. There is evidence from multiple randomized clinical trials to recommend the following: histologic subtype is predictive of treatment efficacy and for some agents toxicity. Immunohistochemistry testing should be performed on NSCLC specimens that cannot be classified accurately with conventional H&E staining. As EGFR mutations are predictive of benefit from tyrosine kinase inhibitors, diagnostic NSCLC samples should be routinely tested for EGFR-activating mutations. Clinical data on K-RAS mutations are inconsistent, therefore testing is not recommended. There is insufficient evidence to recommend other biomarker testing. No biomarkers to date reliably predict improved efficacy for anti-VEGF therapy. Routine assessment for EML4/ALK mutations is not recommended at present, although emerging data suggest that it may become valuable in the near future. CONCLUSIONS: Assessment of NSCLC biomarkers is becoming increasingly important. Therefore, adequate diagnostic material must be obtained for accurate histologic subtyping and relevant molecular biology assays. PMID- 21709592 TI - Type-II cadherins modulate neural activity in cultured rat hippocampal neurons. AB - Cadherins, cell adhesion molecules widely expressed in the nervous system, are thought to be involved in synapse formation and function. To explore the role of cadherins in neuronal activity, we performed electrophysiological and morphological analyses of rat hippocampal cultured neurons overexpressing type-II cadherins, such as cadherin-6B and cadherin-7. We found that cadherin-6B increased but cadherin-7 decreased the number of protrusions of dendritic spines, and affected the frequency of miniature excitatory postsynaptic currents. Our results suggest that type-II cadherins may modulate neural activity by regulating neuronal morphology. PMID- 21709593 TI - Microsurgical management of hypoglossal schwannomas over 3 decades: a modified grading scale to guide surgical approach. AB - BACKGROUND: Schwannomas originating from the hypoglossal nerve are extremely rare. Microsurgical resection with the goal for cure has traditionally been associated with a high risk of postoperative deficits. OBJECTIVE: To summarize our clinical experience using tailored cranial base approaches for these formidable lesions. METHODS: The clinical records of 13 patients were retrospectively reviewed. In addition, all reported patients in the literature were reviewed. The extreme lateral infrajugular transcondylar-transtubercular exposure approach was used in all of our patients. Based on our experience and literature analysis, we propose the following modified grading scale to facilitate surgical planning: type A, intradural tumors; type B, dumbbell-shaped tumors; type C, extracranial tumors; and type D, peripheral tumors. RESULTS: All 13 patients underwent total, near-total, or subtotal tumor resection. Eight patients were men, 5 were women (mean age, 41.7 years). Sural nerve graft reconstruction for the hypoglossal nerve was performed in 4 patients. Three of the 4 patients in whom nerve reconstruction was performed regained satisfactory movement of their tongue. In the review of the literature, the mean patient age was 45.8 years. Patients presented with tongue atrophy (91.6%), headache (60.9%), and dysphagia (31.8%). The tumors were categorized as type A in 31.7% of these patients, type B in 38.6%, type C in 6.2%, and type D in 23.4%. CONCLUSION: The extreme lateral infrajugular transcondylar-transtubercular exposure approach, which is a modification of the extreme lateral suboccipital approach, provides sufficient exposure for most intracranial dumbbell-shaped hypoglossal schwannomas. Hypoglossal nerve reconstruction using a sural nerve graft improves tongue atrophy and movement for patients with resected nerves. PMID- 21709594 TI - Subthalamic nucleus targeting using interpeduncular cistern as an internal landmark. AB - BACKGROUND: Internal landmarks for the subthalamic nucleus (STN) have been used in past. This study uses a yet-unused internal landmark to refine STN targeting. OBJECTIVE: To determine the effect of the width of the interpeduncular cistern (IPC) on STN targeting during placement of deep brain stimulation (DBS) for Parkinson disease. METHODS: Fifty consecutive patients with Parkinson disease underwent 90 STN DBS implantations. X, Y, and Z coordinates for the tip of the DBS electrodes and the active contact were recorded. Internal landmarks such as width of the third ventricle, width of IPC at a predefined point, and anterior commissure-posterior commissure length were measured. Statistical analysis was done using linear regression analysis and Pearson correlation coefficient. RESULTS: The average IPC diameter at the predefined point was 7.59 mm (range, 5- to 14 mm). Average X, Y, and Z coordinates for the location of the tip of lead were 11.5, -3.5, -5.4, and those of the location of active contact were 12.5, 1.9, -1.4 from the midcommissural point. The mediolateral location of the tip of the DBS as well as the location of the active contact for long-term stimulation were greatly dependent on IPC width (r = 0.83) (P = .0022). CONCLUSION: The width of the IPC is a strong predictor of laterality of STN DBS electrode placement in patients with Parkinson disease. It can be used as an additional internal landmark for refining STN targeting using the simple formula X coordinate for STN target = 0.6 * IPC width + 7 mm. PMID- 21709595 TI - Multiple intracranial aneurysms treated by multiple treatment modalities. PMID- 21709596 TI - Importance of preserved periosteum around jugular foramen neurinomas for functional outcome of lower cranial nerves: anatomic and clinical studies. AB - BACKGROUND: Surgical removal of jugular foramen (JF) neurinomas remains controversial because of their radicality in relation to periosteal sheath structures. OBJECTIVE: To clarify the particular meningeal structures of the JF with the aim of helping to eliminate surgical complications of the lower cranial nerves (LCNs). METHODS: We sectioned 6 JFs and examined histological sections using Masson trichrome stain. A consecutive series of 25 patients with JF neurinomas was also analyzed, and the MIB-1 index of each excised tumor was determined. RESULTS: In the JF, meningeal dura disappeared at the nerve entrance, forming a jugular pocket. JF neurinomas were classified into 4 types: subarachnoid (type A by the Samii classification), foraminal (type B), epidural (type C), and episubdural (type D). After an average follow-up of 9.2 years, tumors recurred in 9 cases (36%). Type A tumors did not show regrowth, unlike type B tumors, in which all recurred. Radical surgery by the modified Fisch approach did not contribute to tumor radicality in type C and D tumors, even in cases in which LCN function was sacrificed. In preserved periosteum, postoperative LCN deterioration was decreased. Bivariate correlation analysis revealed that jugular pocket extension, tumor removal, MIB-1 greater than 3%, and reoperation or gamma knife use were significant recurrence factors. CONCLUSION: For LCN preservation, the periosteal layer covering the cranial nerves must be left intact except in patients with a subarachnoid tumor. To prevent tumor regrowth, postoperative gamma knife treatment is recommended in tumors with an MIB-1 greater than 3%. PMID- 21709597 TI - Epidural cortical stimulation of the left dorsolateral prefrontal cortex for refractory major depressive disorder. AB - BACKGROUND: A significant number of patients with major depressive disorder are unresponsive to conventional therapies. For these patients, neuromodulation approaches are being investigated. OBJECTIVE: To determine whether epidural cortical stimulation at the left dorsolateral prefrontal cortex is safe and efficacious for major depressive disorder through a safety and feasibility study. METHODS: Twelve patients were recruited in this randomized, single-blind, sham controlled study with a 104-week follow-up period. The main outcome measures were Hamilton Depression Rating Scale-28 (HDRS), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Function (GAF), and Quality of Life Enjoyment and Satisfaction (QLES) questionnaire. An electrode was implanted over Brodmann area 9/46 in the left hemisphere. The electrode provided long-term stimulation to this target via its connections to an implanted neurostimulator in the chest. RESULTS: During the sham-controlled phase, there was no statistical difference between sham and active stimulation, although a trend toward efficacy was seen with the active stimulation group. In the open-label phase, we observed a significant improvement in outcome scores for the HDRS, MADRS, and GAF but not the QLES (HDRS: df = 7, F = 7.72, P < .001; MADRS: df = 7, F = 8.2, P < .001; GAF: df = 5, F = 16.87, P < .001; QLES: df = 5, F = 1.32, P > .2; repeated measures ANOVA). With regard to the HDRS, 6 patients had >= 40% improvement, 5 patients had >= 50% improvement, and 4 subjects achieved remission (HDRS < 10) at some point during the study. CONCLUSION: Epidural cortical stimulation of the left dorsolateral prefrontal cortex appears to be a safe and potentially efficacious neuromodulation approach for treatment-refractory major depressive disorder. PMID- 21709598 TI - Smallpox variolation during the revolutionary war. PMID- 21709599 TI - Borrelia burgdorferi sensu lato bacteremia in Slovenian children with solitary and multiple erythema migrans. AB - To establish the frequency and characteristics of Borrelia burgdorferi sensu lato bacteremia in Slovenian children with solitary and multiple erythema migrans, 1164 patients were included in this prospective study. Bacteremia was established in 11.4% of all patients, 15.8% of patients with multiple erythema migrans, and in 7.6% of patients with solitary erythema migrans. Bacteremia can be detected in children, with untreated erythema migrans, up to 39 days after the onset of skin rash. PMID- 21709600 TI - The GNB3 C825T polymorphism as a pharmacogenetic marker in the treatment of hypertension, obesity, and depression. AB - Heterotrimeric guanine-binding proteins (G proteins) transmit signals from the cell surface to intracellular signal cascades. The beta3-subunit encoded by the gene GNB3 is widely expressed and, therefore, involved in various physiological and pathophysiological processes. A C825T polymorphism located in exon 10 of GNB3 was described in 1998 and the T allele was associated with alternative splicing and with increased signal transduction in human cells and tissues. In several disease-association studies, the 825T allele could be linked to hypertension, obesity, and depression. Meta-analysis available for hypertension and depression confirmed association with these phenotypes. On the basis of these findings, subsequent studies investigated whether the C825T polymorphism serves as a pharmacogenetic marker. Most pharmacogenetic investigations have focused on the treatment of hypertension, obesity, and depression. In this study, we will comprehensively describe and discuss these studies. PMID- 21709601 TI - A polymorphism located at an ATG transcription start site of the heme oxygenase-2 gene is associated with classical Parkinson's disease. AB - AIM: Oxidative stress and iron deposition is related to Parkinson's disease (PD). Heme oxygenase 2 (HMOX2) catalyzes the cleavage of the heme ring to form biliverdin with release of iron and carbon monoxide. This study aims to analyze variations in the HMOX2 gene in patients with PD. MATERIALS AND METHODS: We mapped four single nucleotide polymorphisms (SNPs) and copy number variations of the HMOX2 gene in 691 patients with PD and 747 healthy individuals. RESULTS: We identified a highly homogeneous association of the HMOX2 SNP rs2270363 homozygous G/G genotype with patients with classical PD phenotype compared with healthy individuals. We identified three patients with PD and two control individuals with a single copy of the HMOX2 gene. No individuals with zero or more than two gene copies were identified. CONCLUSION: We describe for the first time, copy number variations in the HMOX2 gene and an association of the SNP rs2270363 with PD risk. PMID- 21709602 TI - Renal graft function and low-dose cyclosporine affect mycophenolic acid pharmacokinetics in kidney transplantation. AB - BACKGROUND: In kidney transplantation, the pharmacokinetics of mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is influenced by concomitant immunosuppressive therapy, including cyclosporine (CsA). However, whether in the setting of immunosuppressive therapy minimization CsA still affects MPA pharmacokinetics, particularly in relation to varying degree of renal graft function deterioration, remains ill defined. METHODS: One hundred thirty five complete MPA profiles were sequentially collected from 56 kidney transplant recipients given MMF and low-dose CsA as part of their immunosuppressive therapy. MPA pharmacokinetic parameters were correlated with blood CsA area under the curve (AUC0-12) and graft function as measured glomerular filtration rate (GFR). The relative contribution of CsA exposure and GFR to MPA kinetics in relation to other clinical parameters was determined by multivariate analysis. RESULTS: Dose adjusted MPA AUC0-12 negatively correlated with CsA AUC0-12. MPA exposure significantly increased when CsA AUC0-12 was below 2000 ng hr/mL. Stratification of MPA profiles according to stages of renal dysfunction showed that dose adjusted MPA AUC0-12 was higher (P<0.001) in patients with severe (stage 4: 70.37+/-27.93 MUg hr/mL/g MMF) than in those with mild (stage 2: 47.46+/-11.66 MUg hr/mL/g MMF) or moderate (stage 3; 47.48+/-15.22 MUg hr/mL/g MMF) renal insufficiency. At multivariate analysis GFR, serum albumin and hemoglobin levels, use of gastroprotective medications, and time posttransplant were identified as independent determinants of MPA AUC0-12. CONCLUSION: In stable renal transplant recipients given MMF, tapering CsA dose and deterioration of renal graft function contribute to increased MPA exposure. Thus, monitoring plasma MPA pharmacokinetics should be advised, especially in patients on minimized CsA therapy with severe renal insufficiency. PMID- 21709603 TI - Pubertal development is normal in adolescents after renal transplantation in childhood. AB - BACKGROUND: This study was conducted to evaluate the pubertal development in adolescents after renal transplantation (RTx) in childhood. METHODS: We performed a retrospective review of medical records of 109 RTx recipients (72 males) transplanted at the median age of 4.5 years (range: 0.9-15.8 years). Data on the clinical signs of puberty, growth, bone age, medication, and graft function of 98 patients were analyzed. Furthermore, serum levels of reproductive hormones in 87 patients were assessed to evaluate the progression and outcome of pubertal development. RESULTS: The age at the onset of puberty averaged 12.7 years (range: 9.4-16.2 years) in 55 males and 10.7 years (range: 8.9-12.7 years) in 29 females. The mean age at menarche was 12.5 years (range: 10.5-14.5 years). Twenty-two percent of the boys and none of the girls had a moderately delayed onset of puberty. Children who underwent RTx before the age of 5 years reached puberty earlier than those transplanted at later age (boys 12.3+/-1.2 vs. 13.4+/-1.5 years, P<0.01; girls 10.3+/-0.9 vs. 11.0+/-1.0 years, P>0.05). The mean length of puberty was 3.9 and 4.7 years for boys and girls, respectively. The bone age was delayed in practically all, and final height was reached at the mean age of 18.1 and 16.0 years in boys and girls, respectively. Pubertal maturation resulted in acceptable final height and reproductive hormone status in great majority of the patients. CONCLUSION: Pubertal development was normal in all female and most male adolescents after RTx in childhood. PMID- 21709591 TI - Menopause and risk of diabetes in the Diabetes Prevention Program. AB - OBJECTIVE: The study objectives were to examine the association between menopause status and diabetes risk among women with glucose intolerance and to determine if menopause status modifies response to diabetes prevention interventions. METHODS: The study population included women in premenopause (n = 708), women in natural postmenopause (n = 328), and women with bilateral oophorectomy (n = 201) in the Diabetes Prevention Program, a randomized placebo-controlled trial of lifestyle intervention and metformin among glucose-intolerant adults. Associations between menopause and diabetes risk were evaluated using Cox proportional hazard models that adjusted for demographic variables (age, race/ethnicity, family history of diabetes, history of gestational diabetes mellitus), waist circumference, insulin resistance, and corrected insulin response. Similar models were constructed after stratification by menopause type and hormone therapy use. RESULTS: After adjustment for age, there was no association between natural menopause or bilateral oophorectomy and diabetes risk. Differences by study arm were observed in women who reported bilateral oophorectomy. In the lifestyle arm, women with bilateral oophorectomy had a lower adjusted hazard for diabetes (hazard ratio [HR], 0.19; 95% CI, 0.04-0.94), although observations were too few to determine if this was independent of hormone therapy use. No significant differences were seen in the metformin (HR, 1.29; 95% CI, 0.63-2.64) or placebo arms (HR, 1.37; 95% CI, 0.74-2.55). CONCLUSIONS: Among women at high risk for diabetes, natural menopause was not associated with diabetes risk and did not affect response to diabetes prevention interventions. In the lifestyle intervention, bilateral oophorectomy was associated with a decreased diabetes risk. PMID- 21709604 TI - Universal prophylaxis with fluconazole for the prevention of early invasive fungal infection in low-risk liver transplant recipients. AB - BACKGROUND: Although antifungal prophylaxis in high-risk liver transplant recipients (LTR) seems to be clearly justified, the efficacy of universal prophylaxis (UP) including low-risk patients is controversial. METHODS: From the study cohort RESITRA-REIPI, which prospectively analyzed 1010 LTR (September 2003 to February 2005) in 12 Spanish hospitals, we compared the incidence of early invasive fungal infection (IFI, first 90 days) between centers performing or not UP with fluconazole (for a minimum of 7 days) in low-risk LTR (none of the following: posttransplant renal failure, urgent transplant/retransplant, or choledochojejunostomy). RESULTS: Three of 12 centers used UP. A total of 799 LTR were considered as low-risk patients (206 included in the UP group and 593 did not). We reported a total of 11 episodes of early IFI (six due to Candida albicans, one due to C. guillermondii, and three due to Aspergillus fumigatus) in 10 patients (incidence: 1.2%), with two cases of death attributable to IFI (18%) in both patients with invasive aspergillosis. There were no differences in the incidence of IFI between the patients receiving or not UP (4/206:1.9% vs. 6/593:1%, respectively; P=0.36). CONCLUSIONS: IFI is infrequent in LTR not fulfilling major high-risk factors criteria, and prophylaxis with fluconazole in this low-risk group does not seem to be justified. PMID- 21709605 TI - Addition of a water-soluble propofol formulation to preservation solution in experimental kidney transplantation. AB - BACKGROUND: Novel interventions that protect against ischemia and reperfusion injury are needed to improve early graft function after kidney transplantation. Propofol, a widely used anesthetic, has proven an efficient membrane-targeted antioxidant and cytoprotective agent. METHODS: The cytoprotective effects of propofol and its reaction intermediate dipropofol on hypothermic proximal tubular epithelial cells were compared with other phenolic antioxidants. For delivery of propofol into kidney grafts, a water-soluble cyclodextrin complex of propofol was prepared. The therapeutic effects of this propofol formulation were studied in a porcine autotransplantation model using 45 min of warm ischemia and 22 hr of hypothermic preservation. RESULTS: Propofol and dipropofol effectively protected tubular cells from hypothermic injury in vitro. Delivery of propofol to porcine kidneys was achieved by adding the cyclodextrin complex of propofol to the preservation solution during machine perfusion. This preservation strategy significantly prevented lipid peroxidation and tended to attenuate the increase in renovascular resistance during the early reperfusion period after autologous kidney transplantation. The antioxidant effects of propofol were followed by a modest improvement in renal function in the first 10 days after transplantation. Treatment with propofol during organ preservation did not reduce neutrophil infiltration into the graft. CONCLUSION: We consider propofol to be a promising renoprotective agent that may attenuate hypothermic and ischemic acute kidney injury in renal transplantation. The novel application of cyclodextrin carrier systems enabled delivery of the water-insoluble propofol to the graft during hypothermic preservation. PMID- 21709606 TI - Combined CD4 T-cell and antibody response to human minor histocompatibility antigen DBY after allogeneic stem-cell transplantation. AB - BACKGROUND: Antibody responses to HY antigens in male recipients are frequent after transplantation of stem cells from female donors (Miklos et al., Blood 2005; 105: 2973; Miklos et al., Blood 2004; 103: 353). However, evidence that this B-cell immunity is accompanied by T-cell responses to the cognate antigens is scarce. Here, we examined T- and B-cell responses to DBY antigen in a male patient who received hematopoietic stem cells from a human leukocyte antigen identical female sibling. MATERIALS AND METHODS: We used 93 overlapping peptides representing the entire DBY protein to detect and characterize T-cell and antibody responses to DBY by enzyme-linked immunosorbent spot (ELISPOT) and enzyme-linked immunosorbent assay. RESULTS: High frequency CD4+ T cells specific for a unique DBY peptide were detected in the patient blood. We isolated the corresponding T-cell clone and characterized the recognized epitope as an 18-mer peptide restricted by human leukocyte antigen-DRB1*0101. Upon stimulation, this clone produced cytokines with no evidence of Th1 or Th2 polarization. Remarkably, this clone also recognized the DBX homologue peptide and responded to female donor dendritic cells stimulated with poly I/C or lipopolysaccharide, indicating that the peptide was endogenously processed in these cells. High titer DBY specific antibodies were also found in the patient serum which, in contrast to the T-cell response, did not cross-react with DBX. CONCLUSION: We show here the development of a coordinated B and T-cell response to DBY in a recipient of sex mismatched allogeneic hematopoietic stem-cell transplantation. Our findings support a role for CD4+ T cells in the development of humoral immunity to minor histocompatibility antigens. PMID- 21709607 TI - Brain biochemical correlates of the plasma homocysteine level: a proton magnetic resonance spectroscopy study in the elderly subjects. AB - BACKGROUND: An elevated plasma homocysteine level has been reported to be associated with various neuropsychiatric diseases. However, little is known about the brain biochemical changes associated with the higher plasma homocysteine level. The main goal of this study was to examine the sex difference in brain biochemical concentrations using brain proton magnetic resonance spectroscopy (H MRS), and to elucidate the biochemical changes associated with plasma homocysteine levels by sex in healthy elderly subjects. METHODS: Seventy elderly subjects without any clinical psychiatric and neurological disease underwent 3-T brain H MRS. MRS spectra were acquired from voxels placed on the left side of the basal ganglia, frontal lobe, and hippocampus. Brain biochemical concentrations were compared between the elderly male and female participants. Correlations between these biochemical concentrations and plasma homocysteine levels by sex were analyzed. RESULTS: Female participants had significantly higher levels of choline in the left frontal lobe and hippocampus, and lower creatine and myo inositol, in the left basal ganglia than did males. A higher homocysteine level was correlated with a lower N-acetylaspartate (NAA) concentration in the left hippocampus in elderly women (r = -0.44; p = 0.03) but not in elderly men. CONCLUSIONS: This study found that there was a sex difference in brain biochemical concentrations in the elderly participants. A higher plasma homocysteine level was associated with a lower NAA in the hippocampus of elderly women. The sex difference in association between brain biochemical concentrations and plasma homocysteine levels needs further investigation. We speculate that after menopause, women lose protection of estrogen from the neurotoxic effects of homocysteine in the hippocampus. Future studies are required to examine this speculation. PMID- 21709608 TI - Relationship of amyloid-beta burden with age-at-onset in Alzheimer disease. AB - OBJECTIVE: To investigate the relationship between in vivo brain amyloid-beta (Abeta) burden, measured by C-labeled Pittsburgh Compound B (C-PiB) retention, and age-at-onset in patients with Alzheimer disease (AD). DESIGN: Cross-sectional study. SETTING: University Dementia Clinic. PARTICIPANTS: Twenty-two AD patients including 11 early-onset AD (EOAD: onset <65 years) and 11 late-onset AD (LOAD: onset >=65years) cases with matched dementia severity, duration of illness, and apolipoprotein E epsilon4 allele number. INTERVENTION: C-PiB positron emission tomography scans. MEASUREMENTS: Both region of interest and voxel-based analyses were performed to compare C-PiB retention between EOAD and LOAD groups, and to test linear relationship between age-at-onset and C-PiB retention. RESULTS: Both region of interest (ROI) and voxel-based analyses revealed that EOAD patients had significantly higher C-PIB retentions than LOAD patients in diffuse brain regions including frontal, lateral parietal, lateral temporal, and occipital cortex, and basal ganglia. Subgroup analyses showed that negative correlation between age-at onset and C-PiB retention was significant in LOAD but not in EOAD. CONCLUSIONS: Our finding of a heavier Abeta burden in the brain of living EOAD patients than LOAD patients is in agreement with those from postmortem studies. The inverse relationship between age-at-onset and Abeta burden is possibly associated with aging-related decrease of brain or cognitive reserve and with aging-related increase of brain vulnerability. PMID- 21709609 TI - Circadian clock gene polymorphisms and sleep-wake disturbance in Alzheimer disease. AB - OBJECTIVES: One of the hypothesized causes of the breakdown in sleep-wake consolidation often occurring in individuals with Alzheimer disease (AD) is the dysfunction of the circadian clock. The goal of this study is to report indices of sleep-wake function collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes. DESIGN: One week of ad libitum ambulatory sleep data collection. SETTING: At-home collection of sleep data and in-laboratory questionnaire. PARTICIPANTS: Two cohorts of AD participants. Cohort 1 (N = 124): individuals with probable AD recruited from the Stanford/Veterans Affairs, National Institute on Aging Alzheimer's Disease Core Center (N = 81), and the Memory Disorders Clinic at the University of Nice School of Medicine (N = 43). Cohort 2 (N = 176): individuals with probable AD derived from the Alzheimer's Disease Neuroimaging Initiative data set. MEASUREMENTS: Determination of sleep-wake state was obtained by wrist actigraphy data for 7 days in Cohort 1 and by the Neuropsychiatric Inventory questionnaire for Cohort 2. Both cohorts were genotyped by using an Illumina Beadstation (Illumina, San Diego, CA), and 122 circadian-related single-nucleotide polymorphisms (SNPs) were examined. In Cohort 1, an additional polymorphism (variable-number tandem repeat in per3) was also determined. RESULTS: Adjusting for multiple tests, none of the candidate gene SNPs were significantly associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation. Although the study was powered sufficiently to identify moderate-sized correlations, we found no relationships likely to be of clinical relevance. CONCLUSIONS: It is unlikely that a relationship with a clinically meaningful correlation exists between the circadian rhythm-associated SNPs and WASO in individuals with AD. PMID- 21709610 TI - Microstructural alteration of the anterior cingulum is associated with apathy in Alzheimer disease. AB - OBJECTIVES: To identify regional alterations of white matter integrity associated with apathy in Alzheimer disease (AD). DESIGN: Cross-sectional study. SETTING: University Dementia Clinic. PARTICIPANTS: Fifty-one very mild or mild probable AD subjects. INTERVENTION: Volumetric magnetic resonance imaging with diffusion tensor imaging. MEASUREMENTS: Volume of interest analyses were performed to compare regional fractional anisotropy (FA) between apathy and apathy-free group, and to test linear relationship between regional FA and apathy severity. Apathy was assessed by the Neuropsychiatric Inventory. RESULTS: Apathy group showed significantly lower FA values than apathy-free group in the left anterior cingulum (A-C), regardless of concomitant depression and psychotropic medications. Left A-C FA values also had significant linear relationship with apathy-composite scores as a measure of apathy severity, even after controlling gray matter density of the ipsilateral anterior cingulate cortex. CONCLUSIONS: Our findings support that communication failure between the anterior cingulate cortex and other brain structures via the A-C contributes to the development and aggravation of apathy in AD, additionally supporting the general notion of disconnection syndrome for clinical manifestation of AD. PMID- 21709611 TI - Effects of socially stimulating group intervention on lonely, older people's cognition: a randomized, controlled trial. AB - OBJECTIVE: Loneliness may predict impaired cognition among older people. The aim of this study was to determine the effects of socially stimulating group intervention on cognition among older individuals suffering from loneliness. DESIGN: A randomized controlled trial. SETTING AND PARTICIPANTS: Two hundred thirty-five participants (>=75 years) in seven day care centers in Finland. INTERVENTION: Group intervention was based on the effects of closed-group dynamics and peer support. The three-month intervention was aimed to enhance interaction and friendships between participants and to socially stimulate them. Each group was facilitated by two specifically trained professionals. In addition to active discussions, the groups included three types of activities depending on the participants' interests: 1) therapeutic writing; 2) group exercise; and 3) art experiences. MEASUREMENTS: Cognition was measured by the Alzheimer's Disease Assessment Scale (ADAS-Cog), and mental function was measured by the 15D measure. RESULTS: The intervention and control groups were similar at baseline with respect to their demographics, disease burden, depression, and cognition. The ADAS-Cog scale improved more in the intervention group than in the control group within the three-month period, with mean changes being -2.6 points (95% confidence interval [CI]: -3.4 to -1.8) and -1.6 points (95% CI: -2.2 to -1.0), respectively. The dimension of mental function in the 15D showed significant improvement at 12 months in the intervention group (+0.048, 95% CI: +0.013 to +0.085) compared with the control group (-0.027, 95% CI: -0.063 to +0.010). CONCLUSION: Psychosocial group intervention improved lonely older people's cognition. PMID- 21709612 TI - Cognitive functioning and the natural course of depressive symptoms in late life. AB - OBJECTIVES: To investigate whether specific domains of cognitive functioning predict the natural course of depressive symptoms in older people. DESIGN AND PARTICIPANTS: Using the nationally representative, population-based cohort of the Longitudinal Aging Study Amsterdam, 281 participants with clinically relevant depressive symptoms (Center for Epidemiological Studies Depression Scale >=16) aged 55 years and older were followed longitudinally during a period of 6 years. MEASUREMENTS: Using a maximum of 14 successive Center for Epidemiological Studies Depression Scale observations, three clinical course types of depressive symptoms were defined. At baseline, general cognitive functioning was assessed using the Mini-Mental State Exam, memory performance (immediate recall and retention) by means of the auditory verbal learning test, and processing speed by means of a timed coding task. RESULTS: Remission, fluctuating course, and chronic course were seen in 22%, 50%, and 28%, respectively. In univariate analyses, a slowed processing speed was associated with a chronic course of depressive symptoms, as compared with remission (mean: 21.5, SD: 6.6, versus mean: 24.6, SD: 6.8, t = 2.78, df = 139, p < 0.001). Using multivariate regression techniques, this association remained significant after correcting for potential confounders and a number of risk factors for vascular brain damage (odds ratio: 1.08, 95% confidence interval: 1.01-1.14). Neither global cognitive functioning nor memory performance was associated with any course type of depressive symptoms. CONCLUSION: We found an independent association of a slowed processing speed with a poor natural course of depressive symptoms in older people. In clinical practice, when dealing with an older depressed person with comorbid cognitive decline, processing speed might be a more useful tool than the Mini-Mental State Exam in predicting the prognosis. PMID- 21709613 TI - Homocysteine and cognitive function in very elderly nondemented subjects. AB - OBJECTIVES: To examine the association of homocysteine with cognitive functioning in very elderly community-dwelling individuals (80 years or older). METHODS: Two hundred twenty-eight nondemented community-dwelling individuals were assessed with a broad neuropsychological battery. Bloods were drawn to measure homocysteine, serum vitamin B12, and folate levels and APOE genotype. RESULTS: Higher homocysteine levels were associated with poorer executive-language functioning scores (r = -0.311). The association persisted when serum B12 and folate levels were controlled for (r = -0.308). Homocysteine levels were not associated with memory score (r = 0.120). CONCLUSIONS: In very elderly, nondemented community dwellers, high homocysteine levels are associated with poorer executive-language functioning but not with memory. This possible differential effect of homocysteine on cognitive functions suggests that it may affect only specific brain regions or mechanisms underlying healthy executive functioning. PMID- 21709614 TI - Successful electroconvulsive therapy in a 95-year-old man with a cardiac pacemaker--a case report. PMID- 21709615 TI - Oral mucositis. AB - Oral mucositis remains one of the most common and troubling side effects of standard chemoradiation regimens used for the treatment of head and neck cancer. Virtually all patients who receive cumulative radiation doses of more than 30 Gy that includes oral mucosal fields will develop the condition. Not only does mucositis cause extreme discomfort, often necessitating opioid analgesia, but it is also associated with increased use of health resources and cost of treatment. The incremental cost of mucositis in patients with head and neck cancer is more than $17 000 (US). Much has been learned about the pathobiology that underlies the condition. The departure from the historical paradigm of direct cell death as being the primary cause for mucosal injury in favor of a more comprehensive view of the impact of chemoradiation on all the cells of the mucosa, has resulted in a picture of mucositis pathogenesis, which is biologically broad based. Although there are currently few treatment options for oral mucositis at the moment, the recognition that its underlying biology is complex has provided a range of treatment options that are currently being developed. PMID- 21709616 TI - Novel therapeutic target for head and neck squamous cell carcinoma: HGF-MET signaling pathway. AB - Head and neck squamous cell carcinoma (HNSCC) represents a devastating type of malignancy characterized by its high incidence of regional and distant metastases at the time of diagnosis. Vital physiological functions in the upper aerodigestive tract are often impaired as a result of the disease and treatment for the disease, giving rise to severe morbidity in patients suffering from this type of cancer. It is crucial to delineate the aberrant growth signaling pathways in HNSCC cells and develop specific target therapies for the disease to improve the treatment outcome. Although the epidermal growth factor receptor pathway has been extensively studied in HNSCC and anti-epidermal growth factor receptor therapy has already shown promise in treating HNSCC in phase III clinical trials, the signaling pathway that accounts for the highly invasive phenotype of HNSCC needs to be defined and also therapeutically targeted. The hepatocyte growth factor-MET signaling pathway has been studied extensively over the past two decades and it is now clear that it plays an important role in mediating invasive growth of many types of cancer. Here, we review comprehensively the evidence on hepatocyte growth factor-MET cascade being a key in the signaling pathway in mediating invasive growth of HNSCC and the potential of this signaling pathway to be a therapeutic target for the treatment of HNSCC. PMID- 21709617 TI - Design issues in head and neck clinical trials: a statistician's perspective. AB - The purpose of this article is to present some of the challenges the trial statistician meets when designing a clinical trial of the head and neck cancer. In recent years, the field of head and neck cancer has been facing some exciting evolutions, such as the arrival of newly targeted therapies and findings of disease causality and prognosis. These evolutions are accompanied by challenges in trial methodology that continue even today, and will most likely grow in importance in the future. This article focuses essentially on the design of phase III trials and discusses three major topics: should the trial be designed for a broad or a targeted population? Is there a concern for lack of equipoise and if so, how will it affect the trial results? What are the key elements that need to be taken into consideration when choosing, defining, and measuring the primary endpoint? PMID- 21709618 TI - Early prediction of local control in head and neck cancer after chemoradiotherapy by FDG-PET. AB - OBJECTIVE: To determine the utility of 2-deoxy-2-[F]fluoro-D-glucose positron emission tomography (FDG-PET) for assessment of early locoregional clinical outcome of chemoradiotherapy for head and neck squamous cell carcinomas (HNSCCs). METHODS: From July 2002 to July 2008, a total of 35 patients with HNSCCs underwent FDG-PET before and between 4 and 7 weeks (median: 5 weeks) after the end of concurrent chemoradiotherapy. FDG uptake of primary sites and metastatic lymph nodes was measured as standardized uptake values (SUVs) and was analyzed in relation to local control. RESULTS: Visual inspection showed a sensitivity of 88.2% and a negative predictive value of 93.1%, but the positive predictive value was only 37.5%. Setting a posttreatment SUV of 3.0 and percentage change of 60 as cut-off values, positive predictive value increased to 81.3% and overall accuracy increased to 89.9% using the combined analysis of these two parameters. The local control rate was not associated with T, the N category, or the tumor node metastasis stage. In contrast, combined analysis of the posttreatment SUV and the percentage change in SUV was a useful indicator of locoregional control. In particular, combined evaluation of SUVs was very effective for assessment of therapeutic effects with reference to metastatic lymph nodes. CONCLUSION: Early follow-up with FDG-PET is thus considered helpful further in choosing optimal therapy and for making an accurate prognosis. PMID- 21709619 TI - Isolation of a bis-iodurated tetra-THF as a trace product from the oxidation of squalene with RuO4 and its double ring expansion to a novel bis-THF-bis-THP compound. AB - A novel bis-iodurated polyether compound, based on an unprecedented tetra-THF backbone, has been isolated as a trace by-product of the oxidation of squalene with the catalytic system RuO2(cat.)/NaIO4. The double erythro configuration of the central portion of the molecule furnishes the first indirect support of the previously postulated pathway operating in the oxidative pentacyclization of the isoprenoid substrate. A bidirectional double oxidative bis-cyclization is invoked to explain the formation of this compound. The isolated substance was successfully subjected to a double rearrangement-ring expansion to give a novel bis-THF-bis-THP compound. PMID- 21709620 TI - Study of organic honey from the Northeast Portugal. AB - Concerns about traces of numerous toxic substances and authenticity have prompted consumer demand for honey that is certified as organic, based on strict ecological, natural principles and traceability. The present study aims to characterize organic honey samples (n = 73) from Northeast Portugal, with respect to floral nectar origin, physicochemical parameters and microbial safety. The phenols and flavonoids contents, often referred to as responsible for honey's bioactive properties, were also assessed. All organic honey samples were classified as monofloral lavender (Lavandula sp.), exceeded in quality the international physicochemical standards and showed low microbiological counts (yeast, moulds and aerobic mesophiles), with negative results in respect to fecal coliforms, Salmonella and sulphite-reducing Clostridium spp. Correlation of the palynological, physicochemical and microbiological results is necessary to check the authenticity, quality and sanitation of honey. Although not required by international legislation, results of those assessments provide a complete outlook and elucidation of the organic honey's properties, which could promote its valorisation. PMID- 21709621 TI - Enantioselective addition of allyltin reagents to amino aldehydes catalyzed with bis(oxazolinyl)phenylrhodium(III) aqua complexes. AB - Bis(oxazolinyl)phenylrhodium(III) aqua complexes, (Phebox)RhX2(H2O) [X = Cl, Br], were found to be efficient Lewis acid catalysts for the enantioselective addition of allyl- and methallyltributyltin reagents to amino aldehydes. The reactions proceed smoothly in the presence of 5-10 mol % of (Phebox)RhX2(H2O) complex at ambient temperature to give the corresponding amino alcohols with modest to good enantioselectivity (up to 94% ee). PMID- 21709622 TI - Keeping an eye on myocilin: a complex molecule associated with primary open-angle glaucoma susceptibility. AB - MYOC encodes a secretary glycoprotein of 504 amino acids named myocilin. MYOC is the first gene to be linked to juvenile open-angle glaucoma (JOAG) and some forms of adult-onset primary open-angle glaucoma (POAG). The gene was identified as an up-regulated molecule in cultured trabecular meshwork (TM) cells after treatment with dexamethasone and was originally referred to as trabecular meshwork inducible glucocorticoid response (TIGR). Elevated intraocular pressure (IOP), due to decreased aqueous outflow, is the strongest known risk factor for POAG. Increasing evidence showed that the modulation of the wild-type (wt) myocilin protein expression is not causative of glaucoma while some misfolded and self assembly aggregates of mutated myocilin may be associated with POAG in related or unrelated populations. The etiology of the disease remains unclear. Consequently, a better understanding of the molecular mechanisms underlying POAG is required to obtain early diagnosis, avoid potential disease progression, and develop new therapeutic strategies. In the present study, we review and discuss the most relevant studies regarding structural characterizations, expressions, molecular interactions, putative functions of MYOC gene and/or its corresponding protein in POAG etiology. PMID- 21709623 TI - Synthesis of key fragments of amphidinolide Q--a cytotoxic 12-membered macrolide. AB - beta-hydroxy aldehyde and alkyl ketone moieties were effectively synthesized as key intermediates of amphidinolide Q, a cytotoxic macrolide from the cultured dinoflagellate Amphidinium sp.. The asymmetric center of the former derivative was produced by Sharpless asymmetric epoxidation, followed by E-selective 1,4 addition to give the sp2 methyl group. Derivatization of the L-ascorbic acid derivative by Evans asymmetric alkylation and Peterson olefination provided the latter intermediate. The coupling reaction of the segments was examined. PMID- 21709624 TI - Recent developments in molecular dynamics simulations of fluorescent membrane probes. AB - Due to their sensitivity and versatility, the use of fluorescence techniques in membrane biophysics is widespread. Because membrane lipids are non-fluorescent, extrinsic membrane probes are widely used. However, the behaviour of these probes when inserted in the bilayer is often poorly understood, and it can be hard to distinguish between legitimate membrane properties and perturbation resulting from probe incorporation. Atomistic molecular dynamics simulations present a convenient way to address these issues and have been increasingly used in recent years in this context. This article reviews the application of molecular dynamics to the study of fluorescent membrane probes, focusing on recent work with complex design fluorophores and ordered bilayer systems. PMID- 21709625 TI - Gastric pH and motility in a porcine model of acute lung injury using a wireless motility capsule. AB - BACKGROUND: Evaluation of gastric pH and motility in a porcine model of acute lung injury using a novel, wireless motility capsule. MATERIAL/METHODS: A motility capsule was applied into the stomach of 7 Pietrain pigs with acute lung injury induced by high volume saline lavage. Wireless transmission of pH, pressure and temperature data was performed by a recorder attached to the animal's abdomen. Gastric motility was evaluated using pH and pressure values, and capsule location was confirmed by autopsy. RESULTS: Gastric pH values were statistically significantly different (P<0.003) in the animals over time and ranged from 1.15 to 9.94 [5.73 +/- 0.47 (mean +/- SD)] with an interquartile range of 0.11 to 2.07. The capsule pressure recordings ranged from 2 to 4 mmHg [2.6 +/- 0.5 mmHg (mean +/- SD)]. There was no change in pressure patterns or sudden rise of pH >3 pH units during 24 hours. All animals had a gastroparesis with the capsules located in the stomach as indicated by the pressure and pH data and confirmed by necropsy. CONCLUSIONS: The preliminary data show that Pietrain pigs with acute lung injury have a high variability in gastric pH and severely disturbed gastric motility. PMID- 21709626 TI - Regulation of the instantaneous inward rectifier and the delayed outward rectifier potassium channels by Captopril and Angiotensin II via the Phosphoinositide-3 kinase pathway in volume-overload-induced hypertrophied cardiac myocytes. AB - BACKGROUND: Early development of cardiac hypertrophy may be beneficial but sustained hypertrophic activation leads to myocardial dysfunction. Regulation of the repolarizing currents can be modulated by the activation of humoral factors, such as angiotensin II (ANG II) through protein kinases. The aim of this work is to assess the regulation of IK and IK1 by ANG II through the PI3-K pathway in hypertrophied ventricular myocytes. MATERIAL/METHODS: Cardiac eccentric hypertrophy was induced through volume-overload in adult male rats by aorto-caval shunt (3 weeks). After one week half of the rats were given captopril (2 weeks; 0.5 g/l/day) and the other half served as control. The voltage-clamp and western blot techniques were used to measure the delayed outward rectifier potassium current (IK) and the instantaneous inward rectifier potassium current (IK1) and Akt activity, respectively. RESULTS: Hypertrophied cardiomyocytes showed reduction in IK and IK1. Treatment with captopril alleviated this difference seen between sham and shunt cardiomyocytes. Acute administration of ANG II (10-6M) to cardiocytes treated with captopril reduced IK and IK1 in shunts, but not in sham. Captopril treatment reversed ANG II effects on IK and IK1 in a PI3-K-independent manner. However in the absence of angiotensin converting enzyme inhibition, ANG II increased both IK and IK1 in a PI3-K-dependent manner in hypertrophied cardiomyocytes. CONCLUSIONS: Thus, captopril treatment reveals a negative effect of ANG II on IK and IK1, which is PI3-K independent, whereas in the absence of angiotensin converting enzyme inhibition IK and IK1 regulation is dependent upon PI3-K. PMID- 21709627 TI - Phage therapy of Cronobacter-induced urinary tract infection in mice. AB - BACKGROUND: Cronobacter spp. is an opportunistic pathogen causing rare but dangerous cases of meningitis, sepsis and urinary tract infection. Phage therapy overcomes antibiotic resistance and represents an alternative approach to standard antimicrobial treatment. There are no published studies on the use of phages against Cronobacter spp. in vivo. The aim of our study was to prove the effects of isolated Cronobacter-specific phages on renal colonization in a model of urinary tract infection in mice. MATERIAL/METHODS: Urinary tract infection was induced by transurethral application of Cronobacter turicensis (1011 CFU/ml). Simultaneously, isolated Cronobacter-specific phages were administered intraperitoneally (1011 PFU/ml). After 24 hours, kidneys and bladder were collected and used for cultivation and analysis of gene expression and oxidative stress markers. RESULTS: Phage therapy reduced the number of Cronobacter colonies in the kidney by 70%. Higher levels of malondialdehyde were reduced by phage therapy without affecting the antioxidant status. The expression of pro inflammatory cytokines tumor necrosis factor-alpha and monocyte chemoattractant protein-1 increased by the infection and was attenuated by phage therapy. CONCLUSIONS: Phage therapy proved effective in the prevention of ascending renal infection in a murine model of urinary tract infection. Long-term effects and safety of the treatment are currently unknown. Further studies should test phage therapy in other Cronobacter infection models. PMID- 21709628 TI - Changes in bacterial resistance patterns in children with urinary tract infections on antimicrobial prophylaxis at University Hospital in Split. AB - BACKGROUND: We assessed prevalence and resistance of uropathogens on antimicrobial agents (AA) from urine cultures (UC) in children hospitalized with urinary tract infections (UTI) at University Hospital in Split. MATERIAL/METHODS: During the 7-year period, children hospitalized only once with UTI alone were compared to those repeatedly hospitalized, and who received long-term antimicrobial prophylaxis (LTAP), as well as those with associated anomalies of the urinary system (US). RESULTS: E. coli was the most frequent isolate (67.7%) with resistance to ampicillin by 69.5%, amoxicillin/clavulonic acid by 3.5%, cephalexin by 6.6%, trimethoprim/sulfamethoxazole (TMP-SMX) by 27.5%, and nitrofurantoin by 0.4%. For other uropathogens, AA resistance rates were the following: 64.3%, 5.8%, 10.5%, 21.3%, and 7.9%. The high or increasing resistance to TMP-SMX is characterized by all uropathogens. Patients with anomalies of US showed a lower prevalence of E. coli and Enterococcus sp., but a higher prevalence of Pseudomonas sp., ESBL-producing E. coli and Klebsiella sp. than those without US anomalies. Repeatedly hospitalized patients showed a lower prevalence of E. coli, but a higher prevalence of Pseudomonas sp. and Klebsiella sp. than patients hospitalized only once. Both groups displayed significantly less resistance of Enterococcus sp. In patients receiving LTAP before hospitalization, E. coli was significantly more resistant to ampicillin, amoxicillin/clavulonic acid and TMP/SMX than in those without LTAP. CONCLUSIONS: Based on our results, we recommend excluding ampicillin altogether, and reconsideration of further use of TMP-SMX, as well as use of nitrofurantoin, cephalexin and amoxicillin/clavulonic acid for LTAP in our region. PMID- 21709629 TI - A comparison of pain level and entropy changes following core stability exercise intervention. AB - BACKGROUND: As reported in our previous studies, the complexity of physiologic time series is a sensitive measure of muscle fatigability. This study compared the differences between 2 different analyses following 4 weeks of core stability exercises (CSE) in subjects with and without chronic low back pain (LBP). We examined whether the observed Shannon (information) entropy, as compared with median frequency (MF), was able to differentiate fatigability of the thoracic and lumbar parts of the erector spinae (ES) muscles following the intervention. MATERIAL/METHODS: In total, 32 subjects participated in this study. There were 13 subjects in the CSE intervention group (average age 50.4 +/- 9.1 years) and 19 subjects in the control group (average age 46.6 +/- 9.1 years). The CSE group performed the specific exercise intervention, but the control group was asked to maintain their current activity and/or exercise levels. The endurance of the back muscles was determined by using a modified version of the isometric fatigue test as originally introduced by Sorensen. RESULTS: Pain level decreased significantly for all subjects (F=25.29, p=0.001), but there was no difference between groups (F=0.42, p=0.52). The MF was not different between groups following treatment (F=0.81, p=0.37). Although there was no entropy level changes following treatment (F=0.01, p=0.93), the interactions between muscles and groups following treatment were significant (F=7.25, p=0.01). The entropy level decreased in both thoracic ES muscles following intervention in the exercise group, while remaining the same in the control group. CONCLUSIONS: Although the change in pain level was not different between groups, the Shannon entropy measure more sensitively differentiated the exercise intervention than did MF. In addition, the results also suggested that complexity is related to muscle fatigue, which corresponds to the values of entropy between groups. Further studies are needed to investigate the effectiveness of nonlinear time series of EMG data for fatigability. PMID- 21709630 TI - Electrocardiographic changes in hospitalized patients with leptospirosis over a 10-year period. AB - BACKGROUND: The aim of this study was to investigate the incidence and type of ECG changes in patients with leptospirosis regardless of clinical evidence of cardiac involvement. MATERIAL/METHODS: A total of 97 patients with serologically confirmed leptospirosis treated at the University Hospital for Infectious Diseases "Dr. Fran Mihaljevic" in Zagreb, Croatia, were included in this retrospective study. A 12-lead resting ECG was routinely performed in the first 2 days after hospital admission. Thorough past and current medical history was obtained, and careful physical examination and laboratory tests were performed. RESULTS: Abnormal ECG findings were found in 56 of 97 (58%) patients. Patients with abnormal ECG had significantly elevated values of bilirubin and alanine aminotransferase, lower values of potassium and lower number of platelets, as well as more frequently recorded abnormal chest x-ray. Non-specific ventricular repolarization disturbances were the most common abnormal ECG finding. Other recorded ECG abnormalities were sinus tachycardia, right branch conduction disturbances, low voltage of the QRS complex in standard limb leads, supraventricular and ventricular extrasystoles, intraventricular conduction disturbances, atrioventricular block first-degree and atrial fibrillation. Myopericarditis was identified in 4 patients. Regardless of ECG changes, the most commonly detected infection was with Leptospira interrogans serovar Australis, Leptospira interrogans serovar Saxkoebing and Leptospira kirschneri serovar Grippotyphosa. CONCLUSIONS: The ECG abnormalities are common at the beginning of disease and are possibly caused by the direct effect of leptospires or are the non-specific result of a febrile infection and metabolic and electrolyte abnormalities. New studies are required for better understanding of the mechanism of ECG alterations in leptospirosis. PMID- 21709631 TI - Treatment failure of gentamicin in pediatric patients with oropharyngeal tularemia. AB - BACKGROUND: Tularemia is a zoonotic infection, and the causative agent is Francisella tularensis. A first-line therapy for treating tularemia is aminoglycosides (streptomycin or, more commonly, gentamicin), and treatment duration is typically 7 to 10 days, with longer courses for more severe cases. MATERIAL/METHODS: We evaluated 11 patients retrospectively. Failure of the therapy was defined by persistent or recurrent fever, increased size or appearance of new lymphadenopathies and persistence of the constitutional syndrome with elevation of the levels of the proteins associated with the acute phase of infection. RESULTS: We observed fluctuating size of lymph nodes of 4 patients who were on the 7th day of empirical therapy. The therapy was switched to streptomycin alone and continued for 14 days. The other 7 patients, who had no complications, were on cefazolin and gentamycin therapy until the serologic diagnosis. Then we evaluated them again and observed that none of their lymph nodes regressed. We also switched their therapy to 14 days of streptomycin. After the 14 days on streptomycin therapy, we observed all the lymph nodes had recovered or regressed. During a follow-up 3 weeks later, we observed that all their lymph nodes had regressed to the clinically non-significant dimensions (<1 cm). CONCLUSIONS: All patients were first treated with gentamicin, but were than given streptomycin after failure of gentamicin. This treatment was successful in all patients. The results of our study suggest that streptomycin is an effective choice of first-line treatment for pediatric oropharyngeal tularemia patients. PMID- 21709632 TI - Correlation of Peroxisome Proliferator-Activated Receptor-gamma (PPAR-gamma) and Retinoid X Receptor-alpha (RXR-alpha) expression with clinical risk factors in patients with advanced carotid atherosclerosis. AB - BACKGROUND: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and its nuclear partners, the Retinoid X Receptors (RXRs), have been recognized as crucial players in the pathogenesis of atherosclerosis. The present study aimed to assess the clinical significance of PPAR-gamma and RXR-alpha expression in different cellular populations localized within advanced carotid atherosclerosis lesions. MATERIAL/METHODS: PPAR-gamma and RXR-alpha expression was assessed by immunohistochemistry in 134 carotid atherosclerotic plaques obtained from an equal number of patients that underwent endarterectomy procedure for vascular repair, and was correlated with patients' medical history, risk factors and medication intake. RESULTS: Increased incidence of low PPAR-gamma expression in both macrophages and smooth muscle cells was noted in patients presenting coronary artery disease (p=0.032 and p=0.046, respectively). PPAR-gamma expression in smooth muscle cells was borderline down-regulated in symptomatic compared to asymptomatic patients (p=0.061), reaching statistical significance when analyzing groups of patients with specific cerebrovascular events; amaurosis fugax (p=0.008), amaurosis fugax/stroke (p=0.020) or amaurosis fugax/transient ischemic attack patients (p=0.028) compared to asymptomatic patients. Low RXR alpha expression in macrophages was more frequently observed in hypertensive (p=0.048) and hyperlipidemic patients (p=0.049). Increased incidence of low RXR alpha expression in smooth muscle cells was also noted in patients presenting advanced carotid stenosis grade (p=0.015). CONCLUSIONS: PPAR-gamma and RXR-alpha expression down-regulation in macrophages and smooth muscle cells was associated with a more pronounced disease progression in patients with advanced carotid atherosclerotic lesions. PMID- 21709633 TI - Variation in KCNQ1 is associated with therapeutic response to sulphonylureas. AB - BACKGROUND: We aimed to analyse quantitative effects of treatment with sulphonylurea in addition to metformin on parameters of glycemic control in relation to KCNQ1 genotypes, and to identify factors predictive for the response to sulphonylurea treatment. MATERIAL/METHODS: Effect of 6-month sulphonylurea therapy in addition to metformin on glycemic control according to KCNQ1 genotypes was evaluated in 87 patients with type 2 diabetes who failed to achieve glycemic control on metformin monotherapy. KCNQ1 rs163184 (T>G) polymorphism was determined by real-time PCR with melting analysis of unlabeled probe. RESULTS: The reduction in fasting plasma glucose (DeltaFPG) after 6-month sulphonylurea therapy significantly differed among 3 KCNQ1 genotype groups (ANOVA, p=0.017). In a recessive genetic model, carriers of the T-allele (TT+TG) achieved significantly lower FPG levels in comparison with patients with the GG genotype (6.95 +/- 0.13 vs. 7.50 +/- 0.21 mmol/L, p=0.033). Consequently, DeltaFPG was significantly higher in the TT+TG group compared to the GG group (1.58 +/- 0.13 vs. 1.04 +/- 0.18 mmol/L, p=0.016). In multiple linear regression analysis KCNQ1 genotype (p=0.016) and baseline FPG (p<0.001) were the only significant independent predictors of DeltaFPG (R2=0.48). CONCLUSIONS: Our results suggest that the magnitude of FPG reduction after 6-month sulphonylurea treatment in addition to metformin in patients with type 2 diabetes is related to the variation in KCNQ1. The FPG response to sulphonylureas was significantly lower in carriers of the risk GG genotype. PMID- 21709634 TI - Assessment of sleep patterns, energy expenditure and circadian rhythms of skin temperature in patients with acute coronary syndrome. AB - BACKGROUND: There is no simple and practical way to monitor sleep patterns in patients in acute care units. We designed this study to assess sleep patterns, energy expenditure and circadian rhythms of patients' skin temperature in the coronary care unit (CCU) utilizing a new portable device. MATERIAL/METHODS: The SenseWear Armband (SWA) was used to record sleep duration, distribution over 24 hr, energy expenditure and the circadian rhythms of skin temperature in 46 patients with acute coronary syndrome (ACS) for the first 24 hr in the CCU and upon transfer to the ward. An advanced analysis was used to extract and compare data associated with the above variables in the two settings. RESULTS: Patients in the CCU had a reduced night's sleep duration (5.6 +/- 2.2 hr) with more frequent and significantly shorter night sessions (p=0.015) than patients in the ward. Energy expenditure and METs (metabolic equivalents of a task) were significantly lower in the CCU than in the ward. However, the midline-estimating statistic of rhythm (MESOR) and acrophase for skin temperature did not exhibit any significant difference between the two settings. CONCLUSIONS: Patients with ACS have sleep fragmentation and shorter nocturnal sleep duration in the CCU compared to the ward. On the other hand, there was no difference in the circadian rhythms of skin temperature between patients in the CCU and the general wards. PMID- 21709635 TI - Assessment of spinal appearance in female patients with adolescent idiopathic scoliosis treated operatively. AB - BACKGROUND: Body deformities in patients with scoliosis significantly affect appearance perception. The majority of studies on this topic have analyzed the relation between radiological and clinical assessment performed by doctors, and patients' perception of deformity. The object of this study was to adapt the Spinal Appearance Questionnaire (SAQ) to Polish conditions and to explore the perception of trunk deformity by female patients with adolescent idiopathic scoliosis. MATERIAL/METHODS: Forty female patients who underwent surgical treatment for adolescent idiopathic scoliosis using the Cotrel-Dubousset method were asked to complete a Polish version of the Spinal Appearance Questionnaire. The mean preoperative Cobb angle of the thoracic curve in the study group was 55.3 degrees (SD 9.7). In the final postoperative examination the Cobb angle was 29.1 degrees (SD 10.1). RESULTS: The general results of the SAQ demonstrated that the patients achieved a median of 34.48 points, showing a positive assessment of their appearance. Patients rated themselves most critically in the general, chest, surgical scar, symmetry of shoulders and waist domains. The logistic regression model revealed that only the size of the thoracic apical translation, with a model coefficient of -0.9138 (SE=0.350; p=0.013), has a statistically significant (p=0.002) influence on a good general result in the SAQ. CONCLUSIONS: Patients assessed their appearance positively after surgical treatment. A higher thoracic apical translation value is related to a lower probability of achieving a good general result in the Spinal Appearance Questionnaire. PMID- 21709636 TI - Human internal thoracic artery grafts exhibit severe morphological and functional damage and spasmic vasomotion due to oxidative stress. AB - BACKGROUND: The internal thoracic artery (ITA) is the first choice for myocardial revascularization, but atherosclerotic lesions and perioperative vasospasm may still limit its functionality. Oxidative stress via the peroxynitrite - poly-(ADP ribose) polymerase (PARP) cascade plays an important role in the pathogenesis of impaired vascular tone via endothelial injury. We aimed to investigate and describe the histology, PARP activation and functionality of ITA grafts and to assess the possible beneficial effect of PARP-inhibition. MATERIAL/METHODS: ITA specimens from 47 patients (26 men, mean age 66.2 +/- 1.7 years) who underwent coronary bypass surgery were processed for histological and immunohistochemical studies for oxidative stress and PARP activation, and were functionally tested with acetylcholine (ACh) and sodium nitroprusside (SNP) with or without PARP inhibition. RESULTS: The sections showed atherosclerotic alterations and oxidative and nitrosative stress were evidenced by positive 3-nitrotyrosine, 4 hydroxynonenal and PAR stainings. Functionally, 88.1% reacted to K-Krebs, 68.7% exhibited contraction after 1 uM phenylephrine, 29.9% exhibited relaxation to 30 uM Ach, and all precontracted segments relaxed to 30 uM SNP. High amplitude vasomotion was observed in 47.8% of the segments, which could be abolished by the application of 10 uM SNP.Incubation of the preparations with PJ34 did not improve endothelium-dependent vasodilation. CONCLUSIONS: ITA grafts are severely damaged both morphologically and functionally in patients undergoing coronary artery bypass surgery, but PARP inhibition cannot improve their functional characteristics. The topical use of SNP to the ITA during the operation may improve vascular functions by dilating the vessels and eliminating the eventual spasmic vasomotion.
PMID- 21709637 TI - Association of MMP1-1607 1G/2G and TIMP1 372 T/C gene polymorphisms with risk of primary open angle glaucoma in a Polish population. AB - BACKGROUND: Primary open angle glaucoma (POAG) is considered to be a leading cause of irreversible blindness worldwide. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) have been extensively studied as POAG risk factors. Recently, several single-nucleotide polymorphisms (SNPs) for MMPs and TIMPs encoding genes have been reported in POAG patients. The aim of this study was to investigate association of the -1607 1G/2G MMP1 and 372 T/C TIMP1 gene polymorphisms with risk of POAG in a Polish population. MATERIAL/METHODS: In the present case-control study we examined a group of 449 unrelated Caucasian subjects consisting of 196 POAG patients (66 males and 130 females; mean age 70 +/- 14) and 253 controls (72 males and 181 females; mean age 67 +/- 16). The MMP1 1607 1G/2G and TIMP1 372 T/C gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The odds ratios (ORs) and 95% confidence intervals (CIs) for each genotype and allele were calculated. RESULTS: We found a statistically significant increase of the 2G/2G genotype (OR 1.73; 95% CI 1.05-2.86; p=0.019) as well as the 2G allele frequency (OR 1.34; 95% CI 1.03-1.75; p=0.017) of MMP1 in POAG patients in comparison to healthy controls. There were no differences in the genotype and allele distributions and odds ratios of the TIMP1 polymorphism between patients and controls group. We also did not find any association of TIMP1 with MMP1 gene-gene interaction and risk of POAG occurrence. CONCLUSIONS: In conclusion, we suggest that the -1607 1G/2G polymorphism of MMP1 gene may be considered as an important risk factor associated with primary open angle glaucoma in a Polish population. However, further in vivo study is needed to evaluate biological importance of MMPs polymorphisms as a risk factor of POAG.
PMID- 21709638 TI - Association between Takayasu arteritis and ulcerative colitis - case report and review of serological HLA analysis. AB - BACKGROUND: Takayasu arteritis and ulcerative colitis are immune-mediated inflammatory diseases; genetic factors are assumed to play an important role in the pathogenesis of these 2 diseases. However, the coexistence of these 2 diseases has rarely been reported. CASE REPORT: In this report, we present a rare case of a 29-year-old man with a 4 years history of ulcerative colitis who developed Takayasu arteritis. He was found to carry the following human leukocyte antigens (HLA): A11, A24, B52, B62, DR4, and DR9. CONCLUSIONS: We present a case report and review of the pertinent literature on serological analysis of HLA haplotype of the patients who exhibit both these diseases. In patients with both Takayasu arteritis and ulcerative colitis, high frequency of HLA-A24, B52, and DR 2 is observed. The pathological relevance of HLA-A24, B52, and DR2 to concomitant Takayasu arteritis and ulcerative colitis requires further investigation. PMID- 21709639 TI - Severe thrombocytopenia related to trastuzumab infusion. AB - BACKGROUND: Trastuzumab is a humanized, monoclonal antibody that interferes with the HER2/neu receptor and binds selectively to the HERB2 protein which causes uncontrolled proliferation of malignant breast cells. CASE REPORT: We report a case of severe thrombocytopenia related to trastuzumab administration. Three days after the first dose of single-agent trastuzumab, the patient was admitted to the hospital with nose bleeding, petechiae and platelet counts of 5 * 109/L. CONCLUSIONS: The patient showed a self-limiting trastuzumab-related thrombocytopenia. Among the reported cases of trastuzumab-induced severe thrombocytopenia, this patient is the only one who did not interrupt trastuzumab treatment. It is possible that our patient showed progressive reduction of immune mediated thrombocytopenia caused by trastuzumab administration. PMID- 21709640 TI - Serpiginous-like choroiditis as sign of intraocular tuberculosis. AB - BACKGROUND: Tuberculosis is a world-wide public health problem which may clinically present in many different ways. Here we report on a patient with presumed serpiginous choroiditis (PSC) found to have latent ocular tuberculosis. CASE REPORT: The clinical history and physical examination, complete blood count, erythrocyte sedimentation rate, chest radiograph, fundus fluorescein angiography, tuberculin skin test, serological tests, and systemic evaluation carried out by consultant internist of a 42-year-old man with PSC were evaluated. The patient presented with gradual painless loss of central vision in his left eye and dark rings in the central visual field of the right eye. Upon examination, he was found to have 1 round choroidal lesion centered in the left macula and multiple serpiginous-like choroidal lesions in the right eye. Based on positive tuberculin skin test result, the patient was initially treated with anti-tubercular therapy combined with systemic corticosteroids. An immunosuppressive agent (Azathioprine) was consequently administered due to unsatisfactory response to initial therapy and the vicinity of the pathological process to the right fovea. CONCLUSIONS: It is important to remember that tubercular choroiditis may present with clinical features of serpiginous choroiditis, requiring timely and appropriate therapy and close observation in order to prevent the progression of visual loss and recurrences.
PMID- 21709641 TI - Measurement and comparison of skin dose using OneDose MOSFET and Mobile MOSFET for patients with acute lymphoblastic leukemia. AB - BACKGROUND: Total body irradiation is a protocol used to treat acute lymphoblastic leukemia in patients prior to bone marrow transplant. It is involved in the treatment of the whole body using a large radiation field with extended source-skin distance. Therefore measuring and monitoring the skin dose during the treatment is important. Two kinds of metal oxide semiconductor field effect transistor (OneDose MOSFET and mobile MOSEFT) dosimeter are used during the treatment delivery to measure the skin dose to specific points and compare it with the target prescribed dose. The objective of this study was to compare the variation of skin dose in patients with acute lymphatic leukemia (ALL) treated with total body irradiation (TBI) using OneDose MOSFET detectors and Mobile MOSFET, and then compare both results with the target prescribed dose. MATERIAL/METHODS: The measurements involved 32 patient's (16 males, 16 females), aged between 14-30 years, with an average age of 22.41 years. One-Dose MOSFET and Mobile MOSFET dosimetry were performed at 10 different anatomical sites on every patient. RESULTS: The results showed there was no variation between skin dose measured with OneDose MOSFET and Mobile MOSFET in all patients. Furthermore, the results showed for every anatomical site selected there was no significant difference in the dose delivered using either OneDose MOSFET detector or Mobile MOSFET as compared to the prescribed dose. CONCLUSIONS: The study concludes that One-Dose MOSFET detectors and Mobile MOSFET both give a direct read-out immediately after the treatment; therefore both detectors are suitable options when measuring skin dose for total body irradiation treatment. PMID- 21709642 TI - A connection between the Efferent Auditory System and Noise-Induced Tinnitus Generation. Reduced contralateral suppression of TEOAEs in patients with noise induced tinnitus. AB - BACKGROUND: Subjective tinnitus is an auditory perception that is not caused by external stimulation, its source being anywhere in the auditory system. Furthermore, evidence exists that exposure to noise alters cochlear micromechanics, either directly or through complex feed-back mechanisms, involving the medial olivocochlear efferent system. The aim of this study was to assess the role of the efferent auditory system in noise-induced tinnitus generation. MATERIAL/METHODS: Contralateral sound-activated suppression of TEOAEs was performed in a group of 28 subjects with noise-induced tinnitus (NIT) versus a group of 35 subjects with normal hearing and tinnitus, without any history of exposure to intense occupational or recreational noise (idiopathic tinnitus-IT). Thirty healthy, normally hearing volunteers were used as controls for the efferent suppression test. RESULTS: Suppression of the TEOAE amplitude less than 1 dB SPL was considered abnormal, giving a false positive rate of 6.7%. Eighteen out of 28 (64.3%) patients of the NIT group and 9 out of 35 (25.7%) patients of the IT group showed abnormal suppression values, which were significantly different from the controls' (p<0.0001 and p<0.045, respectively). CONCLUSIONS: The abnormal activity of the efferent auditory system in NIT cases might indicate that either the activity of the efferent fibers innervating the outer hair cells (OHCs) is impaired or that the damaged OHCs themselves respond abnormally to the efferent stimulation. PMID- 21709643 TI - Diagnosis, treatment and outcome of glutaric aciduria type I in Zhejiang Province, China. AB - BACKGROUND: Glutaric aciduria type I (GA I; MIM 231670) is a rare autosomal recessive disorder resulting from glutaryl-CoA dehydrogenase deficiency. This article reports our experience in the diagnosis, treatment and outcome of GA I patients in Zhejiang Province, China. MATERIAL/METHODS: A total of 129,415 newborns (accounting for approximately one-tenth of the annual births in Zhejiang Province) and 9640 high-risk infants were screened for inborn errors of metabolism in the Neonatal Screening Center of Zhejiang Province during a 3-year period. Tandem mass spectrometry and gas chromatography-mass spectrometry were used for diagnosis of the patients. Dietary modification, carnitine supplementation and aggressive treatment of intercurrent illnesses were adapted for GA I patients. RESULTS: Three infants were diagnosed with GA I by high-risk screening (detection rate: 1/3,213) and 2 were diagnosed by newborn screening (incidence: 1/64,708). Four patients (3 by high-risk screening and 1 by neonatal screening) undergoing MRI examination showed remarkable changes on T2-weighted image. Four patients accepted timely treatment, and in the patient diagnosed by neonatal screening, treatment was delayed until hypotonia appeared 3 months later. Neuropsychological assessment showed mental and motor retardation in 3 patients after treatment, including the patient diagnosed by neonatal screening. CONCLUSIONS: Individualized timely treatment and close monitoring of GA I patients needs to be optimized in China. Appropriate communication with parents may help to achieve successful management of GA I patients.
PMID- 21709644 TI - Predictors of symptoms of posttraumatic stress in Chinese university students during the 2009 H1N1 influenza pandemic. AB - BACKGROUND: The university environment poses a high risk of spreading infectious diseases, particularly the 2009 pandemic influenza H1N1, as it is a mass gathering place for youth. This study aimed to evaluate the predictors of stress symptoms among Chinese university students during the 2009 H1N1 influenza pandemic. MATERIAL/METHODS: We used a self-reported questionnaire, the PTSD (posttraumatic stress disorder) Checklist-Civilian Version (PCL-C) to evaluate the stress symptoms among Chinese university students from Heilongjiang (n=455), Beijing (n=106), Shanghai (n=419) and Sichuan (n=102). We then analyzed the predictors of stress symptoms. RESULTS: The proportion of university students enrolled in this study who met symptomatic criteria for PTSD was 2% (22 students). The mean PCL-C total score in the sample was 22.09 +/- 8.01. The correlational analyses revealed a significant positive relationship between the PCL-C total score and area, and university grade (P<0.01). Moreover, a negative relationship was found between the PCL-C total score and gender, having H1N1 influenza, having family members, friends or acquaintances having H1N1 influenza, and being afraid of H1N1 influenza (P<0.01). The regression analyses showed that in North China, female gender, having H1N1 influenza, having family members or acquaintances with H1N1 influenza, and being afraid of H1N1 influenza were significant predictors of the stress symptoms. CONCLUSIONS: In North China, female gender, having H1N1 influenza, having family members, friends, or acquaintances with H1N1 influenza, and being afraid of H1N1 influenza were significant predictors of the stress symptoms. PMID- 21709645 TI - Systematic overview of the efficacy of nonpenetrating glaucoma surgery in the treatment of open angle glaucoma. AB - BACKGROUND: To evaluate the intraocular pressure (IOP)-lowering effects achieved by nonpenetrating glaucoma surgery (NPGS) and its modifications in patients with open angle glaucoma. MATERIAL/METHODS: Randomized controlled trials evaluating patients with primary and secondary open angle glaucoma treated with NPGS were identified through systematic searches. The main outcome measures were the percentage IOP reduction and the complete success rate. Complete success was defined as target endpoint IOP (usually less than 21 mm Hg) without medications. The pooled estimates were calculated using the random effects model. RESULTS: Both deep sclerectomy (DS) and viscocanalostomy (VCO) were less effective than trabeculectomy (TE) in lowering IOP, with the percentage IOP reductions at 2 years being 35.2% for DS, 30.2% for VCO, and 45.6% for TE. Intraoperative use of implants and mitomycin C (MMC) increased IOP-lowering effects of DS, with IOP reductions at 2 years of 41.1% and 41.7%, respectively. The complete success rates at 4 years were 35.4% for DS, and 22.7% for VCO, lower than that of TE (47.6%). The complete success rates of DS with implants and MMC of 64.6% and 52.1%, respectively, at 4 years, were greater than that of primary DS. NPGS caused major complications in fewer patients than did TE. CONCLUSIONS: Primary deep sclerectomy and primary viscocanalostomy, which can significantly lower IOP, were associated with fewer complications than was TE. However, the IOP-lowering effects of both NPGS seem to be lower than that of primary TE. The efficacy of DS can be improved with the intraoperative use of implants and MMC. PMID- 21709646 TI - Modulating gut microbiota as an anti-diabetic mechanism of berberine. AB - Berberine, one of the main constituents of a Chinese traditional herb used to treat bacterial diarrhea, has an effect of lowering glucose, which has been recently confirmed by many studies. However, the mechanism of berberine's antidiabetic effect has not yet been well explained. Recent evidence suggests that the gut microbiota composition is associated with obesity and type 2 diabetes, which are closely associated with a low-grade inflammatory state. The protective effect against diabetes of gut microbiota modulation with probiotics or antibiotics has been confirmed in recent observations. Berberine has significant antimicrobial activity against several microbes through inhibiting the assembly function of FtsZ and halting the bacteria cell division. Because berberine acts topically in the gastrointestinal tract and it is poorly absorbed, berberine might modulate gut microbiota without systemic anti-infective activity. Our hypothesis is that gut microbiota modulation may be one mechanism of the antidiabetic effect of berberine. Our hypothesis may provide a novel explanation for berberine's therapeutic effect in patients with diabetes mellitus. PMID- 21709647 TI - Publications in ISI-indexed public health journals from mainland China, Hong Kong and Taiwan during 1999-2008. AB - BACKGROUND: There has been a steady increase in China's annual research output. We aimed to investigate the research output in public health from 3 major regions of China: mainland China (ML), Hong Kong (HK) and Taiwan (TW). MATERIAL/METHODS: We retrieved papers published in 105 public health-related journals from ML, HK and TW with the applications of the ISI Web of Knowledge database. The total papers, impact factor, times cited, papers published in the highest impact factor journals, and most often published journals were analyzed for quantity and quality comparisons among the 3 regions. RESULTS: Totally, 2587 papers were published during 1999-2008, including 1089 (42.1%) from ML, 471 (18.2%) from HK, and 1027 (39.7%) from TW. The total annual number of papers from the 3 regions increased significantly, from 140 in 1999 to 424 in 2008. The average impact factor of papers from TW (2.588) was higher than those from HK (2.531) and ML (1.568). The average number of times cited of each paper from TW was 8.84, followed by 8.34 from HK and 5.90 from ML. Excluding publications in Biomedical and Environmental Sciences, papers from ML had higher average IF and average times cited. TW had the most articles published in the highest impact factor journals, and HK had the highest total IF of most often published journals. CONCLUSIONS: The total number of papers in public health from China increased significantly during 1999-2008. ML contributed the highest annual paper output compared with HK and TW, but papers from ML are more often locally published and less frequently cited. PMID- 21709648 TI - Effectiveness of appliance therapy in reducing overjet and open bite associated with thumb sucking habit. AB - AIM: The aim of this paper was to compare the effectiveness of appliance therapy and reward therapy in reducing overjet and open bite associated with thumb sucking habit. METHODS: Thirty nine subjects (17 males and 22 females) with chronic thumb sucking habit were allocated to three groups: group A (positive reinforcement), group B (modified triple loop corrector), and group C (control). Pre-treatment and post-treatment study casts were evaluated for changes in overjet and open bite. Data from measurements of the three groups were statistically analyzed using a non-parametric Kruskal-Wallis test and Mann Whitney U tests. All statistical computation was performed with SPSS 15.0 software. Significance was set at 0.05 level. RESULTS: Statistically significant reductions in mean overjet and open bite were seen for the group treated with appliance therapy when compared to other two groups (P<0.05). CONCLUSION: Appliance therapy was significantly more superior in reducing the overjet and open bite associated with thumb sucking habit. Early interception of these habits is recommended to reduce the incidence of malocclusion in children. PMID- 21709649 TI - In vivo early plaque formation on zirconia and feldspathic ceramic. AB - AIM: Zirconia is a ceramic material with optimal aesthetic and mechanical properties that make it adapt to esthetic recontructions in narrow spaces. Aim of this split mouth clinical trial is to compare amount and structure of early plaque coated to zirconia and feldspathic ceramic. METHODS: Four patients were included in this study. A removable acrylic device was manufactured for each subject and equipped on the lingual surface in correspondence to molar teeth with eight specimens. Four zirconia samples were positioned on the right side (test) of the device, and 4 feldspathic ceramic samples were positioned on the left side (control). One test and one control samples were harvested from each device at 6, 12, 24 and 36 hours after oral environment exposition. A total of four samples for each group were collected at each timepoint; three of these were used for reverse transcription polymerase chain reaction analysis to evaluate the bacteria plaque amount; the remaining sample was used for scanning electron microscopy analysis to observe the bacteria plaque structure. RESULTS: No significant differences were detected in terms of bacteria amount between test and control group at each timepoint. At scanning electron microscopy evaluation especially at 36 hou, bacteria plaque structure coated to zirconia surface appeared less uniform and compact compared to feldspathic ceramic. CONCLUSION: Zirconia material may be considered adapt to prosthetic reconstructions that require high mechanical and aesthetic properties and that are exposed to the oral environment. PMID- 21709650 TI - Histological and functional changes in retrodiscal tissue following anterior articular disc displacement in the rabbit: review of the literature. AB - AIM: Numerous studies have shown how the disc displacement, which usually occurs in an antero-medial direction, can be a factor contributing to temporomandibular joint (TMJ) pain and dysfunction. The aim of this study was to ascertain, through a critical review of the literature, current knowledge relating to anterior articular disc (ADD) in the rabbit that constitutes an extremely suitable animal model for studying the human TMJ. METHODS: An electronic search of the MEDLINE database was performed without applying time or language restrictions and using the following key words: TMD, anterior disc displacement, rabbit, bilaminar zone. This was followed by a manual search. The articles identified were assessed to verify their pertinence, or otherwise, to the topic of investigation. RESULTS: The articles examined were divided into the following groups according to the topic (histological and/or functional) they dealt with: experimental animal models, joint changes, elastic fibers, collagen, chondrocytes and nervous tissue. CONCLUSION: The papers reviewed covered many aspects, both microscopic and histochemical, of the dysfunctional picture o anterior ADD, furnishing a vast body of useful information, not only from the point of view of the results recorded, but also as regards the various surgical and analytical methods used. PMID- 21709651 TI - Radiographical evaluation of bone quality after extraction of mandibular impacted and semi-impacted third molars. AB - AIM: The association between bone quality and fracture risk in the mandibular angle with the presence of impacted/semi-impacted third molars and after their extraction is controversial. This study aimed to assess mandibular bone quality in digital radiographies of patients after extraction of impacted/semi-impacted lower third molars. METHODS: A total of 130 sets of digital panoramic radiographies were selected and divided into the following three groups: Group 1 with 50 panoramic radiographies of patients with impacted/semi-impacted lower third molars, Group 2 with 30 panoramic radiographies of patients with lower third molar agenesis, and Group 3 with 50 panoramic radiographies of patients after extraction of impacted/semi-impacted lower third molars. The mandibular angular cortex was the anatomical structure used as parameter for bone quality assessment. ANOVA and Student's t test were applied for comparison between groups. RESULTS: Mandibular angular cortical width was significantly lower when the third molar was present in both genders (P<0.05). Agenesis of the third molar in women was associated with lower thickness of the mandibular cortex when compared with patients who had their third molar extracted (P<0.05). CONCLUSION: It can be concluded that the absence of impacted/semi-impacted lower third molars, was associated with a significant increase in cortical width. PMID- 21709652 TI - Comparison by means of bispectral index score, between anxiolysis induced by diazepam and sedation induced by midazolam. AB - AIM: Bispectral Index Score (BIS) is an objective tool to assess sedation depth. Benzodiazepines have different pharmacological profiles and diazepam may be safer than midazolam in this setting. The aim of this study was to compare BIS values observed during anxiolysis after diazepam versus sedation after midazolam. METHODS: Thirty-six patients were randomly assigned to 3 groups: group 1 was treated with i.v. diazepam, groups 2 and 3 with iv midazolam 1 and 3 mg, respectively. Sedation was monitored clinically and by means of BIS. BIS values were evaluated as area under the curve (AUC) and compared by variance analysis. The statistical comparison of other data was performed by variance analysis or, alternatively, the chi2 according to Yates. The statistical significance was indicated by P values <0.05. RESULTS: AUC values were significantly lower after midazolam when compared to AUC values registered in diazepam treated patients; 22.6% of the group 3 patients showed BIS values <80, versus 0.4% of group 1 patients. CONCLUSION: Diazepam has a safer profile, with BIS values and clinical conditions according to the definition of minimal and/or moderate sedation. Diazepam represents the safer drug for anxiety management in dentistry, because regularly produces a state of sedation during which verbal contact with the patient is maintained and carry a margin of safety wide enough to render loss of consciousness unlikely. PMID- 21709653 TI - Ectopic mandibular third molar: report of two cases by intraoral and extraoral access. AB - Ectopic third molar displacement is a rare event in the population. The etiology of this infrequent condition has not been completely clarified. Optimal management is still unclear. In symptomatic patients surgical removal, after a careful preoperative planning, is the recommended treatment. Several surgical approaches, both extraoral and intraoral, have been described, depending on the ectopic molar position. This paper reports two cases of ectopic third molar, one located in the coronoid process and the other one in the lower edge of the mandibular body. Both teeth were removed successfully by an intraoral and extraoral approach respectively. PMID- 21709654 TI - Oral features in five adult patients with Wolf-Hirschhorn syndrome. AB - The Wolf-Hirschhorn syndrome (WHS) is a rare genetic condition presenting with severe mental disability, growth retardation, muscular hypotonia, seizures, craniofacial abnormalities and defects in the cardiovascular, genitourinary and digestive apparata. To date, few data about oral status of afflicted patients were reported, and this syndrome is still unfamiliar among dental and maxillofacial professionals. Aim of the present case series was to provide oral data from five patients with WHS (3 women and 2 men) aged 19-41 years. All patients entered in a long-stay Institution with an inner dental service in 1998 and underwent regular dental examination and hygiene treatment. Neither tooth agenesis or dental size and shape anomalies were found in the analyzed subjects except for one man showing multiple cone-shaped teeth. At the beginning, bad dental and periodontal conditions with gingival signs and recurrent mucosal inflammation were found in all patients. After motivation of their tutors, dental and periodontal parameters were recorded during periodic assessments and a large decrease in the gingival index was found over time. These data could aware dentists about the therapeutic modalities to improve oral health of WHS patients. PMID- 21709655 TI - Permission to be therapeutic: which carbon dioxide is beneficial. PMID- 21709656 TI - Fluid expanders: looking afterload(s). PMID- 21709657 TI - Rectal microcirculatory alterations after elective on-pump cardiac surgery. AB - BACKGROUND: Hemodynamic changes, related to on-pump cardiac surgery, have been reported to impair intestinal perfusion. However, until recently, direct in vivo observation of the intestinal microcirculation was not clinically feasible, and the concept of altered intestinal blood flow in the setting of cardiac surgery depended on indirect observations from other techniques, such as tonometry and microdialysis. To establish the incidence of intestinal microvascular alterations after cardiac surgery, we performed direct in vivo observation of the microcirculation in a clinically accessible part of the intestinal tract in this setting. METHODS: A single-center prospective observational study was conducted in postoperative elective on-pump cardiac surgery patients. Simultaneously, sidestream dark field (SDF) imaging and automated gas tonometry were performed in the rectal pouch within 30 minutes after ICU admission. RESULTS: The rectal median microvascular flow index was 3(3-3) and the proportion of perfused vessels (PPV) was 85% (72-93). The median rectal-to-arterial partial carbon dioxide pressure difference (DeltaPCO(2)) was 1.5 (-1.5-8.3) mmHg; 6 (21%) patients had a DeltaPCO(2)> 8.3 mmHg, among them 2 (7%) with values> 10.5 mmHg. CONCLUSION: After elective on-pump cardiac surgery, direct in vivo observation of rectal mucosa revealed a PPV <90% in 54% of all patients. At the same time, rectal microcirculatory blood flow appeared to be unaltered. Combining rectal SDF imaging with rectal tonometry revealed a 7% incidence of rectal-to-arterial pCO(2) gap >1.4,kPa, suggesting non-dysoxic perfusion in the majority of patients, despite the observed percentage of non-perfused crypts. PMID- 21709658 TI - Effects on cardiac function of a novel low viscosity plasma expander based on polyethylene glycol conjugated albumin. AB - BACKGROUND: Plasma expanders have become increasingly advantageous when compared to blood transfusion, due to their long shelf-life and cost-effectiveness. A new generation of plasma expander based on polyethylene glycol (PEG) conjugated to human serum albumin (PEG-HSA) has shown positive microvascular effects during extreme hemodilution and fluid resuscitation from severe hemorrhagic shock. PEG conjugation increases uniformly albumin molecular weight (MW) and colloidal osmotic pressure, with minor effects on viscosity. METHODS: This study was designed to test the hypothesis that PEG-HSA improves and maintains cardiac function during anemic condition, independently of its lower viscosity, compared to plasma expanders with higher viscosity. To accomplish this objective, we compared PEG-HSA to colloids of different MWs and viscosities, dextran 70 kDa (moderate viscosity plasma expander, MVPE) and dextran 2000 kDa (high viscosity plasma expander, HVPE). Cardiac function was analyzed using indices derived from left ventricular pressure volume, and were assessed using a miniaturized conductance catheter, in two experimental models: 1) hemodilution and 2) resuscitation from hemorrhagic shock. RESULTS: After hemodilution, PEG-HSA increased cardiac output compared to MVPE through the entire observation period, and HVPE increased stroke work compared to MVPE. After resuscitation, PEG-HSA increased stroke work compared to HVPE through the entire observation period. In both experimental protocols, cardiac functional changes induced by PEG-HSA were sustained over the observation time. CONCLUSION: PEG-HSA, a low viscosity plasma expander, had beneficial effects on cardiac function when compared to conventional colloidal plasma expanders with higher viscosities. Maintenance of homeostasis during hemodilution and resuscitation from hemorrhagic shock using PEG-HSA will lead to a significant decrease of the use of blood, thus alleviating in part, forecasted blood shortages, and significantly reducing morbidity and mortality associated with the use of blood in transfusion medicine. PMID- 21709659 TI - Effects of hypercapnia and hypercapnic acidosis on attenuation of ventilator associated lung injury. AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with impaired gas exchange, severe inflammation and alveolar damage including cell death. Patients with ALI or ARDS typically experience respiratory failure and thus require mechanical ventilation for support, which itself can aggravate lung injury. Recent developments in this field have revealed several therapeutic strategies that improve gas exchange, increase survival and minimize the deleterious effects of mechanical ventilation. Among those strategies is the reduction in tidal volume and allowing hypercapnia to develop during ventilation, or actively inducing hypercapnia. Here, we provide an overview of hypercapnia and the hypercapnic acidosis that typically follows, as well as the therapeutic effects of hypercapnia and acidosis in clinical studies and experimental models of ALI. Specifically, we review the effects of hypercapnia and acidosis on the attenuation of pulmonary inflammation, reduction of apoptosis in alveolar epithelial cells, improvement in sepsis-induced ALI and the therapeutic effects on other organ systems, as well as the potentially harmful effects of these strategies. The clinical implications of hypercapnia and hypercapnic acidosis are still not entirely clear. However, future research should focus on the intracellular signaling pathways that mediate ALI development, potentially focusing on the role of reactive biological species in ALI pathogenesis. Future research can also elucidate how such pathways may be targeted by hypercapnia and hypercapnic acidosis to attenuate lung injury. PMID- 21709660 TI - Non invasive ventilation in cardio-surgical patients. AB - Non invasive ventilation (NIV), primarily applied in cardiogenic pulmonary edema, decompensated COPD and hypoxemic respiratory failure, has also found a wide application in the postoperative period. The expanding indications to the transcatheter treatment of diseased left heart valves have led to an increase in cardiac interventional and diagnostic procedures in severely fragile cardiac patients. As an essential part of post cardiac surgery care is ventilatory support, NIV use has expanded to cardiosurgical patients. The objective of this study was to investigate the application and the results of preventive and curative NIV in patients after cardiac surgery. Despite limited data and the necessity of randomized trials, the NIV should be considered in selected patients with postoperative acute respiratory failure as a tool to both prevent and treat acute respiratory failure following patient weaning from mechanical ventilation and tracheal extubation. The knowledge and the real time assessment of the possible effects of positive pressure ventilation on cardiopulmonary interactions in the clinical scenario of cardiac surgery will prompt the intensivists to tailor the respiratory support by non invasive ventilation to the individual patient. The influence on the cardiovascular system of positive pressure and volume delivered through the airways, which can be highly favorable on the impaired left heart and less favorable on the diseased right heart, should be considered when applying NIV in a cardio-surgical patient. As a consequence, the application of NIV in this setting requires an expertly skilled team, continuous hemodynamic monitoring and echocardiographic assessment. PMID- 21709661 TI - Postoperative delirium and postoperative cognitive dysfunction in the elderly - what are the differences? AB - Postoperative cognitive impairment is an increasingly common problem as more elderly patients undergo major surgery. Cognitive deficits in the postoperative period cause severe problems and are associated with a marked increase in morbidity and mortality. There are two main entities of postoperative cognitive decline, delirium and postoperative cognitive dysfunction, which are often reported as being part of the same continuum. Although there are similarities in the predisposing factors, it seems unlikely that they share the same pathophysiology. Both have multifactorial pathogenesis but differ in numerous other ways, with delirium being well-defined and acute in onset and postoperative cognitive dysfunction (POCD) being subtler and with longer duration. This review aims to provide an overview of the differences in the diagnosis of the two entities and to illustrate the methodological problems that can be encountered when evaluating cognitive deficits postoperatively. PMID- 21709662 TI - Chest ultrasounds to guide manual reexpansion of a postoperative pulmonary atelectasis: a case report. AB - Reexpansion of a pulmonary atelectasis is often difficult, even after removing possible causes of bronchial obstruction. Chest ultrasounds, inexpensive and readily available at the patient bedside, may offer valuable support to guide recruitment maneuvers. We report the case of a 57-year-old woman that developed a complete collapse of the left lung seven days after undergoing an intestinal resection for perforation. A mucous plug occluding the main bronchus was removed with bronchoscopy, but persistent hypoxemia required mechanical ventilation; 24 hours later, an attempt to wean the patient from the ventilator failed. Chest X rays revealed the persistence of a partial collapse of the left inferior lobe associated with a pleural effusion. A chest ultrasound confirmed the presence of a lung consolidation and of a modest pleural effusion. Manual reexpansion was then attempted, and ventilatory pressures as well as the duration of forced inspirations were based on real-time ultrasound images. Complete reexpansion was achieved within a few minutes and confirmed by chest X-ray. The patient was weaned from mechanical ventilation on the same day and discharged from ICU three days later. PMID- 21709663 TI - Reply to: limitations of volumetric indices obtained by transthoracic thermodilution. PMID- 21709665 TI - Intratracheal instillation of epinephrine in life-threatening hemoptysis. PMID- 21709666 TI - Treatment of Tetani infection using sevoflurane and AnaConDa: cases of transient renal impairment. PMID- 21709667 TI - Elf3 plays a role in regulating bronchiolar epithelial repair kinetics following Clara cell-specific injury. AB - E74-like transcription factor-3 (Elf3), a member of the E26 transformation specific transcription factor family, is strongly expressed in epithelial-rich tissues, such as small intestine, fetal lung, and various lung cancers. Although previous studies have shown a defect in terminal differentiation of the small intestinal epithelium of Elf3-deficient (Elf3-/-) mice during embryonic development, very little is known about the role Elf3 may play in repair of the airway epithelium after injury. In order to investigate whether Elf3 is involved in regeneration of the bronchiolar epithelium after Clara cell-specific injury, we administered naphthalene to both wild-type (Elf3+/+) and Elf3-/- mice. Histopathological analysis revealed no significant difference in the extent of naphthalene-induced Clara cell necrosis between Elf3+/+ mice and Elf3-/- mice. In the bronchiolar epithelium of Elf3-/- mice, there was a substantial delay in the kinetics of cell proliferation and mitosis along with Clara cell renewal, whereas in the peribronchiolar interstitium, there was a significantly greater level of cell proliferation and mitosis in Elf3-/- mice than in Elf3+/+ mice. Last, the intensity of immunopositive signal for transforming growth factor-beta type II receptor, which is a well-known transcriptional target gene of Elf3 and involved in the induction of epithelial cell differentiation, was significantly lower in the bronchiolar epithelium of Elf3-/- mice when compared with Elf3+/+ mice. Taken together, our results suggest that Elf3 plays an important role in the regulation of lung cell proliferation and differentiation during repair of the injured bronchiolar airway epithelium. PMID- 21709668 TI - NSAIDs inhibit neovascularization of choroid through HO-1-dependent pathway. AB - Intraocular neovascularization is the leading cause of severe visual loss and anti-vascular endothelial growth factor (VEGF) therapy is currently performed for choroidal neovascularization (CNV). Despite its potent anti-angiogenic effect, there are concerns about its long-term safety. Non-steroidal anti-inflammatory drugs (NSAIDs) are common therapeutic agents used for treating inflammatory diseases, and their anti-stress effects are attracting attention now. We studied the effects of topical NSAIDs on CNV, focusing on anti-stress proteins. Cultured retinal pigment epithelium (RPE) cells were treated with NSAIDs: bromfenac, indomethacin, or vehicle control. Transcription factor NF-E2-related factor 2 (Nrf2) and its downstream anti-oxidant protein heme oxygenase (HO)-1 were assessed using western blot and immunohistochemistry. As a result, NSAIDs induced translocation of Nrf2 into the nucleus and the robust expression of HO-1 in a dose- and time-dependent manner. Flow cytometric analysis revealed that bromfenac inhibited H(2)O(2)-induced apoptosis in cultured RPE cells. Next, we studied the effects of topical bromfenac on laser-induced CNV model in rat. The expressions of Nrf2 and HO-1, infiltrations of ED-1-positive macrophages at CNV lesions and size were analyzed. VEGF in the ocular fluid of these rats was also measured using enzyme-linked immunosorbent assay. Rats administered an inhibitor of HO-1 stannic mesoporphyrin (SnMP) were also studied. The results showed that topical bromfenac led to translocation of Nrf2 and induction of HO-1 in CNV lesions and that the number of infiltrating macrophages at the CNV lesion decreased. The sizes of CNV lesions were significantly smaller in bromfenac-treated rats than control CNV, and the effects were diminished by SnMP. VEGF increased in the ocular fluid after laser treatment and was inhibited by bromfenac and SnMP canceling these effects. NSAIDs inhibit CNV through the novel anti-stress protein HO-1-dependent pathway, indicating its potential therapeutic value for various intraocular angiogenic diseases including CNV. PMID- 21709669 TI - MicroRNA-148a is down-regulated in human pancreatic ductal adenocarcinomas and regulates cell survival by targeting CDC25B. AB - MicroRNAs (miRNAs: short non-coding RNAs) are emerging as a class of potential novel tumor markers, as their dysregulation is being increasingly reported in various types of cancers. In the present study, we investigated the transcription status of miRNA-148a (miR-148a) in human pancreatic ductal adenocarcinoma (PDAC) and its role in the regulation of the dual specificity protein phosphatase CDC25B. We observed that miR-148a exhibited a significant 4-fold down-regulation in PDAC as opposed to normal pancreatic ductal cells. In addition, we observed that stable lentiviral-mediated overexpression of miR-148a in the pancreatic cancer cell line IMIM-PC2, inhibited tumor cell growth and colony formation. Furthermore, CDC25B was identified as a potential target of miR-148a by in silico analysis using PicTar, Targetscan and miRanda in conjunction with gene ontology analysis. The proposed interaction between miR-148a and the 3' untranslated region (UTR) of CDC25B was verified by in-vitro luciferase assays. We demonstrate that the activity of a luciferase reporter containing the 3'UTR of CDC25B was repressed in the presence of miR-148a mimics, confirming that miR-148a targets the 3'UTR of CDC25B. Finally, CDC25B was down-regulated at the protein level in miR-148a overexpressing IMIM-PC2-cells, and in transiently transfected pancreatic cell lines (as detected by Western blot analysis), as well as in patient tumor samples (as detected by immunohistochemistry). In summary, we identified CDC25B as a novel miR-148a target which may confer a proliferative advantage in PDAC. PMID- 21709670 TI - Intrarectal administration of oxygenated perfluorodecalin promotes healing of murine colitis by targeting inflammatory hypoxia. AB - Intestinal inflammation is associated with enhanced mucosal hypoxia, which contributes to the ongoing inflammatory process and hampers appropriate mucosal healing. We questioned whether local treatment with an oxygen (O(2))-carrying and -releasing molecule (oxygenated perfluorodecalin, O(2)-PFD) could positively influence the course of experimental colitis. The impact of intrarectal (IR) treatment with O(2)-PFD was tested using the murine dextran sodium sulfate (DSS) induced model of distal colitis, both in preventive and therapeutic settings. Colonic mucosal hypoxia was visualized by pimonidazole staining. Colonic permeability was evaluated with FITC-dextran. In the preventive study, mice treated with O(2)-PFD were protected against DSS colitis compared with saline treated mice, as demonstrated by reduced shortening of colon length, reduced colonic tumor necrosis factor-alpha levels and a lower histological inflammation score (P<0.05 for all parameters). In the therapeutic study, administration of O(2)-PFD resulted in accelerated recovery of colitis compared with saline-treated littermates, and this was reflected by a better weight evolution, lower myeloperoxidase activity and a lower histological inflammation score (P<0.05 for all parameters). It was found that O(2)-PFD established its therapeutic effects through (1) intrinsic anti-inflammatory effects of the PFD molecule and (2) O(2) induced preservation and healing of the intestinal epithelial surface. Further in vitro and in vivo studies showed that the barrier-protective activity of O(2)-PFD was obtained through prevention of colonocyte apoptosis and stimulation of colonocyte proliferation during inflammatory hypoxia. These data show that IR treatment with O(2)-PFD promotes colitis healing by the combined actions of direct anti-inflammatory effects and O(2)-induced restitution of the epithelial barrier. As such, O(2)-PFD enemas could be an attractive treatment option for patients with distal inflammatory bowel disease. PMID- 21709671 TI - Development and characterization of xenograft model systems for adenoid cystic carcinoma. AB - Adenoid cystic carcinoma (ACC) is one of the most common malignancies to arise in human salivary glands, and it also arises in the glandular tissue of other organ systems. To address the paucity of experimental model systems for this tumor type, we have undertaken a program of transplanting tissue samples of human ACC into immunodeficient nu/nu mice to create xenograft model systems. In 17 of 23 attempts (74%), xenograft tumors were successfully grown. In all cases, the histologic appearance of the donating tumor was recapitulated in the subsequent xenograft. Characterization of a subset of xenograft models by immunohistochemical biomarkers and by RNA transcript microarray analysis showed good fidelity in the recapitulation of gene expression patterns in the xenograft tumors compared with the human donor tumors. As ACC is known to frequently contain a t(6;9) translocation that fuses the MYB and NFIB genes, fluorescence in situ hybridization (FISH) of 12 ACC xenograft models was performed that assayed MYB locus break-apart and MYB-NFIB locus fusion. Of 12 xenograft models, 11 (92%) revealed MYB locus rearrangement and 10 (83%) showed evidence of fusion of the MYB and NFIB loci. The two related xenograft models (derived from primary and metastatic tumors, respectively, of the same human subject) were karyotyped, showing a t(1;6) translocation, suggesting MYB translocation to a novel fusion partner gene. Overall, our results indicate that ACC is amenable to xenografting and that ACC xenograft models recapitulate the molecular and morphologic characteristics of human tumors, suggesting utility as valid experimental and preclinical model systems for this disease. PMID- 21709672 TI - Determining the contribution of NPM1 heterozygosity to NPM-ALK-induced lymphomagenesis. AB - Heterozygous expression of Nucleophosmin (NPM1) predisposes to hematological malignancies in the mouse and cooperates with Myc in lymphomagenesis. NPM1 is therefore regarded as a haploinsufficient tumor suppressor. Heterozygous loss of NPM1 occurs as a result of the t(2;5), which generates the oncogenic fusion tyrosine kinase, NPM-anaplastic lymphoma kinase (ALK), a molecule underlying the pathogenesis of anaplastic large cell lymphoma (ALCL). Given the aforementioned role of NPM1 as a tumor suppressor, we hypothesized that NPM1 heterozygosity would cooperate with NPM-ALK in lymphomagenesis. In the event, we observed no difference in tumor latency, incidence or phenotype in NPM-ALK-transgenic mice heterozygous for NPM1 relative to transgenic mice expressing both NPM1 alleles. We propose that although the t(2;5) simultaneously reduces NPM1 allelic dosage and creates the NPM-ALK fusion protein, the two events do not cooperate in the pathogenesis of ALCL in our mouse model. These data indicate that a tumor suppressive role for NPM1 may depend on cellular and/or genetic context. PMID- 21709673 TI - Life imitates op art. PMID- 21709674 TI - Vision and olfaction say UNC-le to G proteins. PMID- 21709675 TI - Cajal revisited: does the VMH make us fat? PMID- 21709676 TI - Net(o) excitement for kainate receptors. PMID- 21709678 TI - Milestone in Anhui. PMID- 21709677 TI - Measuring and interpreting neuronal correlations. AB - Mounting evidence suggests that understanding how the brain encodes information and performs computations will require studying the correlations between neurons. The recent advent of recording techniques such as multielectrode arrays and two photon imaging has made it easier to measure correlations, opening the door for detailed exploration of their properties and contributions to cortical processing. However, studies have reported discrepant findings, providing a confusing picture. Here we briefly review these studies and conduct simulations to explore the influence of several experimental and physiological factors on correlation measurements. Differences in response strength, the time window over which spikes are counted, spike sorting conventions and internal states can all markedly affect measured correlations and systematically bias estimates. Given these complicating factors, we offer guidelines for interpreting correlation data and a discussion of how best to evaluate the effect of correlations on cortical processing. PMID- 21709679 TI - Mapping higher order structure of chromatin domains. PMID- 21709680 TI - The long reach of noncoding RNAs. PMID- 21709683 TI - Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3. AB - The basic helix-loop-helix PAS (Per, Arnt, Sim) domain transcription factor gene NPAS3 is a replicated genetic risk factor for psychiatric disorders. A knockout (KO) mouse model exhibits behavioral and adult neurogenesis deficits consistent with human illness. To define the location and mechanism of NPAS3 etiopathology, we combined immunofluorescent, transcriptomic and metabonomic approaches. Intense Npas3 immunoreactivity was observed in the hippocampal subgranular zone-the site of adult neurogenesis--but was restricted to maturing, rather than proliferating, neuronal precursor cells. Microarray analysis of a HEK293 cell line over expressing NPAS3 showed that transcriptional targets varied according to circadian rhythm context and C-terminal deletion. The most highly up-regulated NPAS3 target gene, VGF, encodes secretory peptides with established roles in neurogenesis, depression and schizophrenia. VGF was just one of many NPAS3 target genes also regulated by the SOX family of transcription factors, suggesting an overlap in neurodevelopmental function. The parallel repression of multiple glycolysis genes by NPAS3 reveals a second role in the regulation of glucose metabolism. Comparison of wild-type and Npas3 KO metabolite composition using high-resolution mass spectrometry confirmed these transcriptional findings. KO brain tissue contained significantly altered levels of NAD(+), glycolysis metabolites (such as dihydroxyacetone phosphate and fructose-1,6-bisphosphate), pentose phosphate pathway components and Kreb's cycle intermediates (succinate and alpha-ketoglutarate). The dual neurodevelopmental and metabolic aspects of NPAS3 activity described here increase our understanding of mental illness etiology, and may provide a mechanism for innate and medication-induced susceptibility to diabetes commonly reported in psychiatric patients. PMID- 21709684 TI - Disambiguating ventral striatum fMRI-related BOLD signal during reward prediction in schizophrenia. AB - Reward detection, surprise detection and prediction-error signaling have all been proposed as roles for the ventral striatum (vStr). Previous neuroimaging studies of striatal function in schizophrenia have found attenuated neural responses to reward-related prediction errors; however, as prediction errors represent a discrepancy in mesolimbic neural activity between expected and actual events, it is critical to examine responses to both expected and unexpected rewards (URs) in conjunction with expected and UR omissions in order to clarify the nature of ventral striatal dysfunction in schizophrenia. In the present study, healthy adults and people with schizophrenia were tested with a reward-related prediction error task during functional magnetic resonance imaging to determine whether schizophrenia is associated with altered neural responses in the vStr to rewards, surprise prediction errors or all three factors. In healthy adults, we found neural responses in the vStr were correlated more specifically with prediction errors than to surprising events or reward stimuli alone. People with schizophrenia did not display the normal differential activation between expected and URs, which was partially due to exaggerated ventral striatal responses to expected rewards (right vStr) but also included blunted responses to unexpected outcomes (left vStr). This finding shows that neural responses, which typically are elicited by surprise, can also occur to well-predicted events in schizophrenia and identifies aberrant activity in the vStr as a key node of dysfunction in the neural circuitry used to differentiate expected and unexpected feedback in schizophrenia. PMID- 21709686 TI - The functional in vitro response to CD40 ligation reflects a different clinical outcome in patients with chronic lymphocytic leukemia. AB - Malignant B lymphocytes from chronic lymphocytic leukemia (CLL) patients maintain the capacity to respond to CD40 ligation, among other microenvironmental stimuli. In this study, we show that (i) leukemic CLL cells stimulated with the soluble form of CD40L in vitro show differential responses in terms of upregulation of surface markers (CD95 and CD80) and induction of chemokines (CCL22 and CCL17) expression/secretion, and that (ii) these changes are mirrored by a distinct activation of intracellular signalling pathways including increase in IKKalpha/beta phosphorylation and upregulation of antiapoptotic proteins (BCL-2 and MCL-1). CLL patients can then be segregated into two distinct functional subsets. We defined the responsive subset of cases CD40L dependent, considering the capacity to respond as a sign of persistent need of this stimulation for the leukemic expansion. Conversely, we named the unresponsive cases CD40L independent, considering them less dependent on this microenvironmental signal, presumably because of a higher autonomous proliferative and survival potential. Importantly, we report that (iii) the two functional subsets show an opposite clinical outcome, with CD40L-independent cases having a shorter time to progression. This indicates that the functional differences observed in vitro may reflect a different leukemic potential in vivo likely responsible for a distinct clinical course. PMID- 21709685 TI - Translating biomarkers to clinical practice. AB - Biomarkers are the measurable characteristics of an individual that may represent risk factors for a disease or outcome, or that may be indicators of disease progression or of treatment-associated changes. In general, the process by which biomarkers, once identified, might be translated into clinical practice has received scant attention in recent psychiatric literature. A body of work in diagnostic development suggests a framework for evaluating and validating novel biomarkers, but this work may be unfamiliar to clinical and translational researchers in psychiatry. Therefore, this review focuses on the steps that might follow the identification of putative biomarkers. It first addresses standard approaches to characterizing biomarker performance, followed by demonstrations of how a putative biomarker might be shown to have clinical relevance. Finally, it addresses ways in which a biomarker-based test might be validated for clinical application in terms of efficacy and cost-effectiveness. PMID- 21709687 TI - Anti-inflammatory effects of apocynin, an inhibitor of NADPH oxidase, in airway inflammation. AB - Oxidative stress is implicated in the pathogenesis of allergic asthma and remains an attractive target for the prevention of the disease. Herein, we investigated the anti-inflammatory effects of apocynin, a NADPH oxidase (NOX) inhibitor, in both in vitro and in vivo allergen-induced experimental asthma mediated by Th2 hyperresponsiveness. Apocynin showed potential antioxidant activities and inhibitory effects on the activation of redox-sensitive transcription factors, such as NF-kappaB and AP-1, induced by pro-inflammatory stimuli, such as TNF alpha, lipopolysaccharide and Poly I:C, and that inhibited the production of pro inflammatory cytokines, such as TNF-alpha, IL-1beta and IL-6. In in vivo experimental asthma model, moreover, apocynin significantly attenuated ovalbumin induced airway hyperresponsiveness and inflammation, as shown by the attenuation of total inflammatory cell and soluble product influx into bronchoalveolar lavage fluid, such as macrophages, eosinophils, IL-4, IL-5, IL-12, IL-13 and TNF-alpha. Apocynin also significantly reduced lung inflammation in the tissues. Altogether, these results suggest that apocynin may be useful in the treatment of inflammatory diseases induced by oxidative stress through NOX activity. PMID- 21709688 TI - Gene expression: Transcriptome to proteome and back to genome. PMID- 21709689 TI - New approaches to disease mapping in admixed populations. AB - Admixed populations such as African Americans and Hispanic Americans are often medically underserved and bear a disproportionately high burden of disease. Owing to the diversity of their genomes, these populations have both advantages and disadvantages for genetic studies of complex phenotypes. Advances in statistical methodologies that can infer genetic contributions from ancestral populations may yield new insights into the aetiology of disease and may contribute to the applicability of genomic medicine to these admixed population groups. PMID- 21709690 TI - Diabetes and prostate cancer risk in the REDUCE trial. AB - Men with diabetes mellitus are less likely to be diagnosed with prostate cancer (PCa). As diabetic men have lower serum PSA, it is unclear if this is due to lower PCa incidence or reflects detection bias from fewer PSA-triggered biopsies. To account for differential biopsy rates, we used multivariate regression to examine the link between diabetes and PCa risk in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which required all subjects to undergo biopsy regardless of PSA. We further tested for interaction between diabetes and obesity. Diabetes status and body mass index (BMI) measurements were obtained at baseline. On multivariate analysis, diabetes was not associated with PCa risk (odds ratio (OR) 1.01, 95% confidence interval 0.79-1.30, P=0.92) or risk of low- or high-grade disease (all P >= 0.65). When stratified by obesity, diabetes was also not associated with PCa risk in any BMI category (all P >= 0.15). However, there was suggestion of effect modification by obesity for high-grade disease (P interaction=0.053). Specifically, diabetes was associated with decreased risk of high-grade PCa in normal-weight men but increased risk in obese men (OR 0.35 vs 1.38). In the REDUCE trial, when all men underwent biopsy, diabetes was not associated with lower PCa risk, but rather equal risk of PCa, low-grade PCa and high-grade PCa. PMID- 21709691 TI - The impact of PSA testing frequency on prostate cancer incidence and treatment in older men. AB - To quantify the downstream impact of PSA testing on cancer characteristics and utilization of cancer therapies among men aged 70 or older, we utilized patients diagnosed with prostate cancer in 2004-2005 in the Surveillance, Epidemiology and End Results (SEER)-Medicare and their Medicare claims before their cancer diagnosis during 2000-2005. Among men in the highest testing group (4-6 PSA tests), 75% were diagnosed with low- or intermediate-risk of disease, but 77% received treatments within 180 days of cancer diagnosis. More than 45% of newly diagnosed patients in 2004-2005 had 4-6 PSA tests before their cancer diagnosis during 2000-2005. Men in the high testing group were 3.57 times more likely to receive cancer treatments (either surgery, radiation or hormonal therapy) when compared with men who had no previous PSA testing during the same time period. Among men aged 75+ diagnosed with low-risk cancer, men in the high testing group were 78% more likely to receive treatment than those who had no previous PSA testing. In conclusion, given the lack of evidence of effective treatment for elderly patients diagnosed with low- and intermediate-risk prostate cancer and our inability to distinguish indolent from aggressive cancer, more frequent PSA testing among elderly population may exacerbate the risk of overdiagnosis and overtreatment. PMID- 21709692 TI - Novel functions of endocytic player clathrin in mitosis. AB - Clathrin has been widely recognized as a pivotal player in endocytosis, in which several adaptors and accessory proteins are involved. Recent studies suggested that clathrin is also essential for cell division. Here this review mainly focuses on the clathrin-dependent mechanisms involved in spindle assembly and chromosome alignment. In mitosis, clathrin forms a complex with phosphorylated TACC3 to ensure spindle stability and proper chromosome alignment. The clathrin regulated mechanism in mitosis requires the crosstalk among clathrin, spindle assembly factors (SAFs), Ran-GTP and mitotic kinases. Meanwhile, a coordinated mechanism is required for role transitions of clathrin during endocytosis and mitosis. Taken together, the findings of the multiple functions of clathrin besides endocytosis have expanded our understanding of the basic cellular activities. PMID- 21709694 TI - Chemotherapy: Have a break. PMID- 21709693 TI - Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1. AB - Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by the transcription factors Oct4, Sox2, and Klf4 in combination with c-Myc. Recently, Sox2 plus Oct4 was shown to reprogram fibroblasts and Oct4 alone was able to reprogram mouse and human neural stem cells (NSCs) into iPS cells. Here, we report that Bmi1 leads to the transdifferentiation of mouse fibroblasts into NSC-like cells, and, in combination with Oct4, can replace Sox2, Klf4 and c-Myc during the reprogramming of fibroblasts into iPS cells. Furthermore, activation of sonic hedgehog signaling (by Shh, purmorphamine, or oxysterol) compensates for the effects of Bmi1, and, in combination with Oct4, reprograms mouse embryonic and adult fibroblasts into iPS cells. One- and two-factor iPS cells are similar to mouse embryonic stem cells in their global gene expression profile, epigenetic status, and in vitro and in vivo differentiation into all three germ layers, as well as teratoma formation and germline transmission in vivo. These data support that converting fibroblasts with Bmi1 or activation of the sonic hedgehog pathway to an intermediate cell type that expresses Sox2, Klf4, and N-Myc allows iPS generation via the addition of Oct4. PMID- 21709696 TI - Genetics: A new tool for the KIT. PMID- 21709697 TI - Hematology: Preventing relapse. PMID- 21709699 TI - Experimental arthritis: Dermal fibroblasts have MSC-like immunosuppressive effects in vivo. PMID- 21709701 TI - Experimental arthritis: Inducing tolerogenic DCs in arthritis. PMID- 21709698 TI - Challenging issues in pediatric oncology. AB - Improvements in protocol-driven clinical trials and supportive care for children and adolescents with cancer have reduced mortality rates by more than 50% over the past three decades. Overall, the 5-year survival rate for patients with pediatric cancer has increased to approximately 80%. Recognition of the biological heterogeneity within specific subtypes of cancer, the discovery of genetic lesions that drive malignant transformation and cancer progression, and improved understanding of the basis of drug resistance will undoubtedly catalyze further advances in risk-directed treatments and the development of targeted therapies, boosting the cure rates further. Emerging new treatments include novel formulations of existing chemotherapeutic agents, monoclonal antibodies against cancer-associated antigens, and molecular therapies that target genetic lesions and their associated signaling pathways. Recent findings that link pharmacogenomic variations with drug exposure, adverse effects, and efficacy should accelerate efforts to develop personalized therapy for individual patients. Finally, palliative care should be included as an essential part of cancer management to prevent and relieve the suffering and to improve the quality of life of patients and their families. PMID- 21709702 TI - Acute coronary syndromes: the unfulfilled promise of erythropoietin in patients with MI. AB - Over the past 5-10 years, the positive effects of erythropoietin on myocardial infarction have been reported in several experimental, animal models. However, the results of the REVEAL study call into question the beneficial effects of erythropoietin in humans presenting with myocardial infarction. PMID- 21709703 TI - Vascular disease: lowering LDL cholesterol reduces atherosclerotic risk in patients with chronic kidney disease. PMID- 21709704 TI - Vascular disease: now official: smoking promotes peripheral artery disease in women. PMID- 21709705 TI - Stem cells: injection during CABG surgery helps failing hearts. PMID- 21709706 TI - Atherosclerosis: easy CIMT measures will do. PMID- 21709708 TI - Diabetes: long-term use of insulin glargine might increase the risk of breast cancer. PMID- 21709709 TI - Cancer: safe 131I treatment for children with advanced DTC. PMID- 21709707 TI - Diabetes mellitus and periodontitis: a tale of two common interrelated diseases. AB - Diabetes mellitus (a group of metabolic disorders characterized by hyperglycemia) and periodontitis (a microbially induced inflammatory disorder that affects the supporting structures of teeth) are both common, chronic conditions. Multiple studies have demonstrated that diabetes mellitus (type 1 and type 2) is an established risk factor for periodontitis. Findings from mechanistic studies indicate that diabetes mellitus leads to a hyperinflammatory response to the periodontal microbiota and also impairs resolution of inflammation and repair, which leads to accelerated periodontal destruction. The cell surface receptor for advanced glycation end products and its ligands are expressed in the periodontium of individuals with diabetes mellitus and seem to mediate these processes. The association between the two diseases is bidirectional, as periodontitis has been reported to adversely affect glycemic control in patients with diabetes mellitus and to contribute to the development of diabetic complications. In addition, meta analyses conclude that periodontal therapy in individuals with diabetes mellitus can result in a modest improvement of glycemic control. The effect of periodontal infections on diabetes mellitus is potentially explained by the resulting increase in levels of systemic proinflammatory mediators, which exacerbates insulin resistance. As our understanding of the relationship between diabetes mellitus and periodontitis deepens, increased patient awareness of the link between diabetes mellitus and oral health and collaboration among medical and dental professionals for the management of affected individuals become increasingly important. PMID- 21709711 TI - Cellular microbiology: bacterial pea shooters. PMID- 21709712 TI - A novel molecular therapy using bioengineered adenovirus for human gastrointestinal cancer. AB - Replication-selective tumor-specific viruses constitute a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus mediated lysis of tumor cells after selective viral propagation within the tumor. Human telomerase is highly active in more than 85? of primary cancers, regardless of their tissue origins, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1 genes. Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter would allow for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with gastrointestinal tumors. We demonstrated that intratumoral injection of Telomelysin mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes. Moreover, using noninvasive whole-body imaging, we found that intratumoral injection of Telomelysin followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of oncolytic virotherapy as a promising strategy in the management of human gastrointestinal cancer. PMID- 21709713 TI - The excitement of multiple noradrenergic cell groups in the rat brain related to hyperbaric oxygen seizure. AB - The mechanism of oxygen toxicity for central nervous system and hyperbaric oxygen (HBO) seizure has not been clarified. Noradrenergic cells in the brain may contribute to HBO seizure. In this study, we defined the activation of noradrenergic cells during HBO exposure by c-fos immunohistochemistry. Electroencephalogram electrodes were pre-implanted in all animals under general anesthesia. In HBO seizure animals, HBO was induced with 5 atm of 100% oxygen until manifestation of general tonic convulsion. HBO non-seizure animals were exposed to 25 min of HBO. Control animals were put in the chamber for 120 min without pressurization. All animals were processed for c-fos immunohistochemical staining. All animals in the HBO seizure group showed electrical discharge on EEG. In the immunohistochemistry, c-fos was increased in the A1, A2 and A6 cells of the HBO seizure group, and in the A2 and A6 cells of the HBO non-seizure group, yet was extremely low in all three cell types in the control group. These results suggest the participation of noradrenaline in HBO seizure, which can be explained by the early excitement of A1 cells due to their higher sensitivity to high blood pressure, hyperoxia, or by the post-seizure activation of all noradrenergic cells. PMID- 21709710 TI - Endocrine incidentalomas--challenges imposed by incidentally discovered lesions. AB - Endocrine glands are among the organs that most frequently harbor incidentally discovered lesions. Pituitary, thyroid, parathyroid and adrenal incidentalomas are increasingly encountered in everyday practice with variable clinical implications. The major concerns are the risks of malignancy and hormonal hypersecretion mostly in the form of subclinically functioning tumors. Pituitary incidentalomas are usually microadenomas and most of the time clinically unimportant; however, incidentally discovered larger lesions require a more careful diagnostic and therapeutic approach. Thyroid incidentalomas are extremely common; exclusion of malignancy is the main concern in this clinical setting. Although parathyroid adenomas are not uncommon, these lesions are frequently missed owing to their small size and due to clinical unawareness. Adrenal incidentalomas carry a small but finite risk of malignancy. An intriguing challenge regarding incidentally discovered adrenal lesions is that a substantial proportion is associated with hormonal alterations, mainly in the form of subtle cortisol excess. Although still largely controversial, evidence is emerging that so-called subclinical hypercortisolism may not be completely harmless. The best biochemical criterion of subtle cortisol excess remains elusive. Surgical intervention in selected cases results in some beneficial effects, but more data are required in order to routinely support surgery in this clinical setting. This Review provides a brief overview of the prevalence, clinical effect and management of endocrine incidentalomas with a focus on data regarding the diagnostic and therapeutic challenges imposed by incidentally discovered adrenal lesions. PMID- 21709714 TI - Expansion of CpG methylation in the SFRP2 promoter region during colorectal tumorigenesis. AB - Secreted frizzled-related protein 2, (SFRP2) is a Wnt inhibitor whose promoter CpGs were recently found to be methylated at high frequency in colorectal cancers (CRCs). We hypothesized that the pattern of SFRP2 methylation may differ throughout the promoter during progressive tumorigenesis. Using combined bisulfite restriction analysis (COBRA), two methylation-sensitive regions (Regions A and B) of the SFRP2 promoter were investigated in 569 specimens of colorectal tissue:222 CRCs, 103 adenomatous polyps (APs), 208 normal colonic mucosa from CRC patients (N-Cs), and 36 normal colonic mucosa from subjects with no evidence of colorectal neoplasia at colonoscopy (N-Ns). Extensive (including both Regions A and B) and partial (either Region A or B) SFRP2 methylation levels were found in 61.7% and 24.8% of CRCs, 8.7% and 37.9% of APs, 3.9% and 39.9% of N Cs, and 0% and 30.6% of N-Ns, respectively. Extensive methylation of the SFRP2 promoter was present primarily in CRCs, while partial methylation was common in APs. Whereas APs with the KRAS mutant showed no correlation to any pattern of SFRP2 methylation, extensive methylation of the SFRP2 promoter was significantly associated with KRAS mutant CRCs (p<.0001), suggesting that genetic alteration in the RAS-RAF pathway might precede the spread of CpG methylation through the SFRP2 promoter, which is observed in over 60% of advanced colorectal tumors. PMID- 21709715 TI - Aberrant methylation of p21 gene in lung cancer and malignant pleural mesothelioma. AB - Suppression of p21 has been implicated in the genesis and progression of many human malignancies. DNA methylation is an important mechanism of gene silencing in human malignancies. In this study, we examined the expression status and aberrant methylaion of p21 in lung cancers and malignant pleural mesotheliomas (MPM). We used 12 small cell lung cancer (SCLC) cell lines, 13 non-small cell lung cancer (NSCLC) cell lines, 50 primary NSCLCs, 6 MPM cell lines and 10 primary MPMs. The expression and methylation of p21 was examined by reverse transcription-PCR (RT-PCR), Western blotting and methylation-specific PCR (MSP) assay. Loss of p21 protein expression was observed in 7 SCLC cell lines (58.3%), 5 NSCLC cell lines (38.5%) and 3 MPM cell lines (50%) while mRNA expression was lost in 2 SCLC cell lines (16.7%), 2 NSCLC cell lines (15.4%) and none of the MPM cell lines. Aberrant methylation of p21 was found in 8.3% of SCLC cell lines, 30.2% of NSCLCs and 6.3% of MPMs. Among primary NSCLCs, methylation in adenocarcinomas was significantly more frequent than in squamous cell carcinomas. Loss of p21 expression was frequently observed in lung cancers and MPMs and aberrant methylation was one of the mechanisms of suppression of p21, especially in NSCLCs. PMID- 21709716 TI - A one-message question in a structured interview: investigating psychological needs of children and adolescents with eating disorders directed toward their mothers. AB - The purpose of this study was to investigate the psychological needs of children and adolescents with eating disorders (ED) directed toward their mothers. Patients with ED have low self-assertion and various abnormal eating behaviors. Therefore, mothers face difficulty in understanding their children's psychological needs, and the mother-child relationship is sometimes strained. We developed a One-Message Question (OMQ)-structured interview. The OMQ was easy to answer, and it helped the patients with ED. We examined the relationship between psychological needs and illness phase of the children and adolescents, and we discuss the viability of implementing the OMQ in clinical settings. The subjects were 23 patients and their parents. Their parents were just asked about the patients' background. The mean age of the patients was 15.8 years, and the average age of ED onset was 13.5 years. The EDs were anorexia nervosa (n=20) and bulimia nervosa (n=3). The phases of patients' illness were identified as anorexic (n=5), bulimic (n=7), chronic (n=3), and stable (n=8). All subjects provided specific responses to the OMQ-structured interview. Data analyses revealed the following seven categories of patients' psychological needs directed toward their mothers:attachment, cooperation in meeting their goals, longing for love, changing attitude toward family members, respect for self-reliance, expression of apology, and expression of appreciation. These findings suggested that the OMQ-structured interview may prove useful for mothers to understand their children's psychological needs and may encourage positive interactions as a foundation for future recovery. PMID- 21709717 TI - Inhibitory effect of 1alpha-hydroxyvitamin D3 on N-nitrosobis(2-oxopropyl)amine induced cholangiocarcinogenesis in Syrian hamsters. AB - Sixty-three male 5-week-old Syrian hamsters received the carcinogen N nitrosobis(2-oxopropyl)amine (BOP) s.c. in 5 weekly injections (the first, 70 mg/kg body, and the remaining, 20mg/kg each). The hamsters that received BOP were given intragastric administration of 0.2 ml of medium chain triglyceride (MCT) with or without 0.04 MUg of 1alpha-hydroxyvitamin D3 [1alpha(OH)D3] through a feeding tube for 12 weeks. Thus, 3 groups were assigned:Group 1;BOP alone (n=20), Group 2;BOP+MCT (n=18) and Group 3;BOP+1alpha(OH)D3 (n=25). The mean body weight of Group 3 was lower than those of Groups 1 and 2 at the end of the experiment (p<0.001,Tukey-Kramer HSD test). At the end of week 12, all surviving hamsters were put to sleep. The incidences of liver tumors were 80%, 72% and 32% in Groups 1, 2 and 3, respectively. The incidence of tumors in Group 3 was significantly lower than in Group 1 and Group 2 (p<0.05, chi2-test). All tumors were cholangiocarcinoma. These results indicated that BOP-induced cholangiocarcinogenesis was suppressed by the supplemental administration of 1alpha(OH)D3. PMID- 21709718 TI - The relation between insulin resistance and lifestyle in Japanese female university students. AB - Using the homeostasis model assessment (HOMA) index, we investigated the link between insulin resistance and lifestyle in Japanese female university students. We used data for 57 Japanese female university students (21.0+/-0.8 years) who were enrolled in a cross-sectional investigation study. We performed full blood examinations, and anthropometric parameters, nutrient oral intake and daily step counts were measured. The mean HOMA index for the subjects was 1.3+/-0.6, and 12 subjects were over the level of 1.6, which is considered to indicate insulin resistance in Japan. The HOMA index was positively correlated with abdominal circumference (r=0.542, p<0.0001), triglycerides, low density lipoprotein (LDL) cholesterol and systolic blood pressure. In addition, the HOMA index was negatively correlated with n-3 fatty acid and positively correlated with the n 6/n-3 fatty acid ratio (r=0.304, p=0.0216). Daily step count was negatively correlated with the HOMA index, but not at a significant level (r=-0.237, p=0.0809). Higher HOMA index in some Japanese female university students was noted, and that was associated with lifestyle, especially n-6/n-3 fatty acid ratio of nutrient oral intake. PMID- 21709719 TI - Prediction of discharge outcome with the full outline of unresponsiveness (FOUR) score in neurosurgical patients. AB - To identify the diagnostic properties of the Full Outline of Unresponsiveness (FOUR) score and the discharge outcome, 318 patients were studied. The evaluators rated the patients on admission or when they had mental status alteration with the FOUR score. The course of treatment was determined based on the clinical. The mortality rate and Glasgow Outcome Scale were recorded. Adjusted regression models and prognostic performance were tested by calculation of the receiver operating characteristic curve. One-hundred and twenty-two patients (40.1%) had a poor outcome defined as a Glasgow Outcome Scale score from 3-5, and 38 patients (12.5%) died. The area under the characteristic curve (AUC) for poor outcome and in-hospital mortality were 0.88 (95% CI, 0.83-0.92) and 0.92 (95% CI, 0.87-0.97). The cut-off point of 14 showed sensitivity and specificity of the total FOUR score predicting poor outcomes at 0.77 (95% CI, 0.69-0.84) and 0.95 (95% CI, 0.90 0.97), while the cut-off point of 10 showed the values for in-hospital mortality at 0.71 (95% CI, 0.55-0.83) and 0.93 (95% CI, 0.90-0.96). The total FOUR score showed satisfactory prognostic value for predicting outcome. The cut-off points for the poor outcome and in-hospital mortality are 14 and 10, respectively. PMID- 21709720 TI - A case of surgery for kyphosis of the thoracolumbar spine in an elderly patient with dysphagia. AB - Here we report a case of surgery for kyphosis of the thoracolumbar spine in an elderly patient, in whom surgery was performed because the patient had developed intractable digestive symptoms. The case was that of a 76-year-old female with complaints of back pain and dysphagia. When videofluoroscopic examination (VF) of swallowing was performed in the cardia of the stomach, images that indicated stagnation and the reflux of food were observed. It was easier for the patient to swallow food in the extension position. We performed corrective fusion of the posterior spine. After the surgery, the kyphosis angle was improved to 27 degrees , the patient's back pain was alleviated, and it became easier for the patient to swallow food. VF also showed that the patient's difficulties with the passage of food had improved. We believe that surgery is a good treatment option for cases of kyphosis with digestive symptoms and deteriorating activities of daily living (ADL), even in the absence of pain and paralysis. VF is also useful for performing evaluations before and after surgery. PMID- 21709721 TI - Churg-Strauss syndrome with necrosis of toe tips. AB - Churg-Strauss syndrome (CSS) is a granulomatous necrotizing vasculitis of unknown etiology associated with bronchial asthma. Despite affecting small to medium sized vessels, necrosis of the digits due to vasculitis is extremely rare. We report a case of CSS with necrosis of the toe tips. A 37-year-old woman with asthma, who had been diagnosed with CSS 2 years ago, was admitted to our hospital with an exacerbation of CSS. The patient had a high grade fever and complained of abdominal pain and numbness of the lower extremities. Blood examination revealed marked eosinophilia. The fever pattern, abdominal pain and blood eosinophilia showed improvement by combination treatment with prednisolone and cyclophosphamide. However, the color of her right toe tips changed, and necrosis finally resulted despite antithrombotic therapy. Arteriography showed narrowing of the dorsalis pedis artery and of the more peripheral arteries of her right leg. Stump plasty with negative pressure dressing therapy for the toe tips, but not amputation, was done to preserve the leg function. While numbness of the extremities remained, no recurrence of necrosis was seen. Clinicians need to be aware that rare complications of CSS, including necrosis of the digits, can occur. PMID- 21709722 TI - Fostering Canadian drug research and development for neglected tropical diseases. PMID- 21709723 TI - Non-destructive characterization of structural hierarchy within aligned carbon nanotube assemblies. AB - Understanding and controlling the hierarchical self-assembly of carbon nanotubes (CNTs) is vital for designing materials such as transparent conductors, chemical sensors, high-performance composites, and microelectronic interconnects. In particular, many applications require high-density CNT assemblies that cannot currently be made directly by low-density CNT growth, and therefore require post processing by methods such as elastocapillary densification. We characterize the hierarchical structure of pristine and densified vertically aligned multi-wall CNT forests, by combining small-angle and ultra-small-angle x-ray scattering (USAXS) techniques. This enables the nondestructive measurement of both the individual CNT diameter and CNT bundle diameter within CNT forests, which are otherwise quantified only by delicate and often destructive microscopy techniques. Our measurements show that multi-wall CNT forests grown by chemical vapor deposition consist of isolated and bundled CNTs, with an average bundle diameter of 16 nm. After capillary densification of the CNT forest, USAXS reveals bundles with a diameter >4 MUm, in addition to the small bundles observed in the as-grown forests. Combining these characterization methods with new CNT processing methods could enable the engineering of macro-scale CNT assemblies that exhibit significantly improved bulk properties. PMID- 21709724 TI - Recent national trends in Salvia divinorum use and substance-use disorders among recent and former Salvia divinorum users compared with nonusers. AB - CONTEXT: Media and scientific reports have indicated an increase in recreational use of Salvia divinorum. Epidemiological data are lacking on the trends, prevalence, and correlates of S. divinorum use in large representative samples, as well as the extent of substance use and mental health problems among S. divinorum users. OBJECTIVE: To examine the national trend in prevalence of S. divinorum use and to identify sociodemographic, behavioral, mental health, and substance-use profiles of recent (past-year) and former users of S. divinorum. DESIGN: Analyses of public-use data files from the 2006-2008 United States National Surveys on Drug Use and Health (N = 166,453). SETTING: Noninstitutionalized individuals aged 12 years or older were interviewed in their places of residence. MAIN MEASURES: Substance use, S. divinorum, self-reported substance use disorders, criminality, depression, and mental health treatment were assessed by standardized survey questions administered by the audio computer assisted self-interviewing method. RESULTS: Among survey respondents, lifetime prevalence of S. divinorum use had increased from 0.7% in 2006 to 1.3% in 2008 (an 83% increase). S. divinorum use was associated with ages 18-25 years, male gender, white or multiple race, residence of large metropolitan areas, arrests for criminal activities, and depression. S. divinorum use was particularly common among recent drug users, including users of lysergic acid diethylamide (53.7%), ecstasy (30.1%), heroin (24.2%), phencyclidine (22.4%), and cocaine (17.5%). Adjusted multinomial logistic analyses indicated polydrug use as the strongest determinant for recent and former S. divinorum use. An estimated 43.0% of past year S. divinorum users and 28.9% of former S. divinorum users had an illicit or nonmedical drug-use disorder compared with 2.5% of nonusers. Adjusted logistic regression analyses showed that recent and former S. divinorum users had greater odds of having past-year depression and a substance-use disorder (alcohol or drugs) than past-year alcohol or drug users who did not use S. divinorum. CONCLUSION: S. divinorum use is prevalent among recent or active drug users who have used other hallucinogens or stimulants. The high prevalence of substance use disorders among recent S. divinorum users emphasizes the need to study health risks of drug interactions. PMID- 21709725 TI - No association between variant N-acetyltransferase genes, cigarette smoking and Prostate Cancer susceptibility among men of African descent. AB - OBJECTIVE: We evaluated the individual and combination effects of NAT1, NAT2 and tobacco smoking in a case-control study of 219 incident prostate cancer (PCa) cases and 555 disease-free men. METHODS: Allelic discriminations for 15 NAT1 and NAT2 loci were detected in germ-line DNA samples using TaqMan polymerase chain reaction (PCR) assays. Single gene, gene-gene and gene-smoking interactions were analyzed using logistic regression models and multi-factor dimensionality reduction (MDR) adjusted for age and subpopulation stratification. MDR involves a rigorous algorithm that has ample statistical power to assess and visualize gene gene and gene-environment interactions using relatively small samples sizes (i.e., 200 cases and 200 controls). RESULTS: Despite the relatively high prevalence of NAT1*10/*10 (40.1%), NAT2 slow (30.6%), and NAT2 very slow acetylator genotypes (10.1%) among our study participants, these putative risk factors did not individually or jointly increase PCa risk among all subjects or a subset analysis restricted to tobacco smokers. CONCLUSION: Our data do not support the use of N-acetyltransferase genetic susceptibilities as PCa risk factors among men of African descent; however, subsequent studies in larger sample populations are needed to confirm this finding. PMID- 21709726 TI - Recent Patents and Advances in the Next-Generation Sequencing Technologies. AB - We are now witnessing a new genomic revolution due to the arrival and continued advancements in the next-generation high-throughput sequencing technologies, which encompass sequencing by synthesis including fluorescent in situ sequencing (FISSEQ) and pyrosequencing, sequencing by ligation including using polony amplification and supported oligonucleotide detection (SOLiD), sequencing by hybridization in combination with sequencing-by-ligation and nanopore technology, nanopore sequencing and other novel sequencing technologies using nano-transistor array, scanning tunneling microscopy and nanowire molecule sensors etc. We review here major technologies and recent patents for achieving high-throughput, ultra fast, extremely cheap, and highly accurate sequencing. We will see enormous impacts of these next-generation sequencing methods for solving complex biological problems and for ushering in the practice of personalized medicine. PMID- 21709727 TI - Non-invasive diode laser activation of transient receptor potential proteins in nociceptors. AB - We investigated diode laser (980 nm) evoked activation of transient receptor potential proteins (TRPV1 and TRPV2). C and A-delta (Adelta) nociceptor families are primarily responsible for pain mediation in the peripheral nervous system. TRPV1 proteins have been associated with heat evoked pain in C fibers while Adelta fibers have been associated with TRPV2. Diode laser stimulation allows a margin of safety between non-invasive activation and damage (19, 22, 34). Laser pulses (20-50 ms, 0.1-10 W, 980 nm) were used to stimulate: A) in vitro: excised patches from HEK293 cells expressing TRPV1; B) in vitro: rat DRG nociceptors expressing either TRPV1 or TRPV2; and C) in vivo: C-fibers of the rat saphenous nerve (SN) trunk. Cell currents were recorded using standard patch clamp methods. The SN was also stimulated electrically with bipolar electrodes. Stimulation (20 50 ms) of HEK and DRG cells expressing TRPV1 was highly reproducible. Activation and peak currents were achieved at estimated peak temperatures of 55 degrees C and 70 degrees C. Threshold activation was also observed in DRG neurons expressing TRPV2. The conduction velocity for laser-activated saphenous nerve afferents was in the C fiber range (0.5-1 m/s). Electrically stimulated nerve contained stimulation artifacts and complex neural components with conduction velocities ranging from 0.3-30 m/s. Diode laser activation of TRPV1 protein is a reproducible and effective means to probe TRP activity in both in vivo and in vitro preparations. PMID- 21709728 TI - In search of durable positive psychology interventions: Predictors and consequences of long-term positive behavior change. AB - A number of positive psychology interventions have successfully helped people learn skills for improving mood and building personal resources (e.g., psychological resilience and social support). However, little is known about whether intervention activities remain effective in the long term, or whether new resources are maintained after the intervention ends. We address these issues in a 15-month follow-up survey of participants from a loving-kindness meditation intervention. Many participants continued to practice meditation, and they reported more positive emotions (PEs) than those who had stopped meditating or had never meditated. All participants maintained gains in resources made during the initial intervention, whether or not they continued meditating. Continuing meditators did not differ on resources at baseline, but they did show more PE and a more rapid PE response to the intervention. Overall, our results suggest that positive psychology interventions are not just efficacious but of significant value in participants' real lives. PMID- 21709729 TI - Processes Linking Social Class and Racial Socialization in African American Dual Earner Families. AB - We examined the links between social class, occupational self-direction, self efficacy, and racial socialization in a sample of 128 two-parent African American couples raising adolescents. A series of multivariate, multilevel models revealed that mothers' SES was connected to self-efficacy via its association with occupational self-direction; in turn, self-efficacy partially explained the association between occupational self-direction and racial socialization. The link between maternal self-efficacy and racial socialization depended on whether or not children had experienced discrimination. For fathers, a strong link between SES and occupational self-direction emerged, but significant associations were not found between occupational self-direction and self-efficacy, or self efficacy and racial socialization. The discussion focuses on mother-father differences and the role of child effects in racial socialization. PMID- 21709730 TI - Substance abuse and rehabilitation: responding to the global burden of diseases attributable to substance abuse. AB - Alcohol, tobacco, and illegal drug use are pervasive throughout the world. Substance use problems are among the major contributors to the global disease burden, which includes disability and mortality. The benefits of treatment far outweigh the economic costs. Despite the availability of treatment services, however, the vast majority of people with substance use disorders do not seek or use treatment. Barriers to and unmet need for evidence-based treatment are widespread even in the United States. Women, adolescents, and young adults are especially vulnerable to adverse effects from substance abuse, but they face additional barriers to getting evidence-based treatment or other social/medical services. Substance use behaviors and the diseases attributable to substance use problems are preventable and modifiable. Yet the ever-changing patterns of substance use and associated problems require combined research and policy-making efforts from all parts of the world to establish a viable knowledge base to inform for prevention, risk-reduction intervention, effective use of evidence based treatment, and rehabilitation for long-term recovery. The new international, open-access, peer-reviewed Substance Abuse and Rehabilitation (SAR) journal strives to provide an effective platform for sharing ideas for solutions and disseminating research findings globally. Substance use behaviors and problems have no boundaries. The journal welcomes papers from all regions of the world that address any aspect of substance use, abuse/dependence, intervention, treatment, and policy. The "open-access" journal makes cutting edge knowledge freely available to practitioners and researchers worldwide, and this is particularly important for addressing the global disease burden attributable to substance abuse. PMID- 21709732 TI - ? AB - O metodo Grade of Membership (GoM) tem sido cada vez mais utilizado por demografos brasileiros e tem a vantagem de possuir um parametro que mensura a heterogeneidade individual, com base nas correlacoes nao-observaveis entre as categorias de resposta das variaveis de interesse, gerando um medida do grau de pertencimento de cada individuo a perfis extremos. Alguns autores, contudo, chamam atencao para questoes importantes na calibragem dos modelos finais que utilizam o programa GoM versao 3.4, como o problema de identificabilidade - solucoes multiplas para parametros estimados. Neste artigo, e sugerido um procedimento capaz de identificar um modelo final com solucao unica que descreva os tipos puros mais fidedignos a base de dados, em uma tentativa de otimizacao. Para ilustrar esse processo, utilizou-se uma base de dados correspondente a um levantamento economico e sociodemografico de uma populacao de pequenos agricultores residentes ao longo da Rodovia Transamazonica, no Estado do Para. Tambem identificou-se a existencia de instabilidade nos parametros estimados pelo programa GoM 3.4, sendo proposto um metodo de estabilizacao de seus valores. Com esses procedimentos combinados, os usuarios do programa GoM 3.4 poderao descrever sua base de dados de forma mais adequada e responder as criticas sobre questoes de identificabilidade e estabilidade dos modelos resultantes. Essas solucoes empiricas sao relevantes por afetarem calculos de prevalencia e de incidencia de eventos de interesse, alem de trazerem consequencias importantes sobre o ponto e o momento corretos para intervencoes de politicas publicas ou de planejamento prospectivo em analises de projecao. PMID- 21709733 TI - Break-up of New Orleans Households after Hurricane Katrina. AB - Theory and evidence on disaster-induced population displacement have focused on individual and population-subgroup characteristics. Less is known about impacts on households. I estimate excess incidence of household break-up due to Hurricane Katrina by comparing a probability sample of pre-Katrina New Orleans resident adult household heads and non-household heads (N = 242), traced just over a year later, with a matched sample from a nationally representative survey over an equivalent period. One in three among all adult non-household heads, and one in two among adult children of household heads, had separated from the household head 1 year post-Katrina. These rates were, respectively, 2.2 and 2.7 times higher than national rates. A 50% higher prevalence of adult children living with parents in pre-Katrina New Orleans than nationally increased the hurricane's impact on household break-up. Attention to living arrangements as a dimension of social vulnerability in disaster recovery is suggested. PMID- 21709731 TI - Gold(I)-Catalyzed Intramolecular Hydroamination of N-Allylic,N'-Aryl Ureas to form Imidazolidin-2-ones. AB - Treatment of N-allylic,N'-aryl ureas with a catalytic 1:1 mixture of di-tert butyl-o-biphenylphoshphine gold(I) chloride and silver hexafluorophosphate (1 mol %) in chloroform at room temperature led to 5-exo hydroamination to form the corresponding imidazolidin-2-ones in excellent yield. In the case of N-allylic ureas that possessed an allylic alkyl, benzyloxymethyl, or acetoxymethyl substituent, gold(I)-catalyzed 5-exo hydroamination leads to formation of the corresponding trans-3,4-disubstituted imidazolidin-2-ones in excellent yield with >=50:1 diastereoselectivity. PMID- 21709734 TI - Gender and racial/ethnic differences in addiction severity, HIV risk, and quality of life among adults in opioid detoxification: results from the National Drug Abuse Treatment Clinical Trials Network. AB - PURPOSE: Detoxification often serves as an initial contact for treatment and represents an opportunity for engaging patients in aftercare to prevent relapse. However, there is limited information concerning clinical profiles of individuals seeking detoxification, and the opportunity to engage patients in detoxification for aftercare often is missed. This study examined clinical profiles of a geographically diverse sample of opioid-dependent adults in detoxification to discern the treatment needs of a growing number of women and whites with opioid addiction and to inform interventions aimed at improving use of aftercare or rehabilitation. METHODS: The sample included 343 opioid-dependent patients enrolled in two national multi-site studies of the National Drug Abuse Treatment Clinical Trials Network (CTN001-002). Patients were recruited from 12 addiction treatment programs across the nation. Gender and racial/ethnic differences in addiction severity, human immunodeficiency virus (HIV) risk, and quality of life were examined. RESULTS: Women and whites were more likely than men and African Americans to have greater psychiatric and family/social relationship problems and report poorer health-related quality of life and functioning. Whites and Hispanics exhibited higher levels of total HIV risk scores and risky injection drug use scores than African Americans, and Hispanics showed a higher level of unprotected sexual behaviors than whites. African Americans were more likely than whites to use heroin and cocaine and to have more severe alcohol and employment problems. CONCLUSIONS: Women and whites show more psychopathology than men and African Americans. These results highlight the need to monitor an increased trend of opioid addiction among women and whites and to develop effective combined psychosocial and pharmacologic treatments to meet the diverse needs of the expanding opioid-abusing population. Elevated levels of HIV risk behaviors among Hispanics and whites also warrant more research to delineate mechanisms and to reduce their risky behaviors. PMID- 21709737 TI - ACT HEALTHY: A Combined Cognitive-Behavioral Depression and Medication Adherence Treatment for HIV-Infected Substance Users. AB - The two most common comorbid conditions with HIV are substance use disorders and depression, and individuals with comorbid HIV, depression, and substance dependence face a more chronic and treatment-resistant course. As an example of how to adapt evidence-based approaches to a complex comorbid population, the current case study examined the integration of a combined depression and HIV medication adherence treatment. The resulting intervention, ACT HEALTHY, combines a brief behavioral activation approach specifically developed to treat depression in individuals receiving residential substance abuse treatment (LETS ACT; Daughters et al., 2008) with a brief cognitive-behavioral approach to improving HIV medication adherence (Life-Steps; Safren et al., 1999; Safren et al., 2009). The current case series demonstrates the use of ACT HEALTHY among 3 depressed HIV positive, low-income African Americans entering residential substance abuse treatment. PMID- 21709738 TI - Whole Field Strain Measurement on Complex Surfaces by Digital Speckle Pattern Interferometry. AB - Digital Speckle Pattern Interferometry (DSPI), originally known as electronic speckle pattern interferometry (ESPI), is an interferometry based method applicable for conducting 3-dimensional whole field strain characterization. The present DSPI systems are suited for analyzing a relatively simple surface (e.g., a plane surface). However, few existing systems are able to accurately determine strain distributions on a surface with significant contour complexity. Here, we present development of a novel DSPI system that allows strain characterization of a sample with a complex surface. In the described DSPI system, deformations and contours as well as an absolute phase value are determined. Furthermore, variations in measurement sensitivity are considered. We describe a principle and methodology using two examples in the area of mechanical engineering and biomedical engineering, and discuss potential usages and future directions. PMID- 21709739 TI - Comment: How Should Indirect Evidence Be Used? AB - Indirect evidence is crucial for successful statistical practice. Sometimes, however, it is better used informally. Future efforts should be directed toward understanding better the connection between statistical methods and scientific problems. PMID- 21709740 TI - Corynebacterium macginleyi isolated from a corneal ulcer. AB - We report the isolation of Corynebacterium macginleyi from the corneal ulcer culture of a patient, later enrolled in the Steroids for Corneal Ulcer Trial (SCUT). To our knowledge this is the first published report from North America of the recovery of C. macginleyi from a serious ocular infection. PMID- 21709736 TI - Gene Expression Signatures of Lymph Node Metastasis in Oral Cancer: Molecular Characteristics and Clinical Significances. AB - Even though lymph node metastasis accounts for the vast majority of cancer death in patients with oral cancer (OC), the molecular mechanisms of lymph node metastasis remain elusive. Genome-wide microarray analyses and functional studies in vitro and in vivo, along with detailed clinical observations, have identified a number of molecules that may contribute to lymph node metastasis. These include lymphangionenic cytokines, cell adhesion molecules, basement membrane-interacting molecules, matrix enzymes and relevant downstream signaling pathways. However, defined gene signatures from different studies are highly variable, which hinders their translation to clinically relevant applications. To date, none of the identified signatures or molecular biomarkers has been successfully implemented as a diagnostic or prognostic tool applicable to routine clinical practice. In this review, we will first introduce the significance of lymph node metastasis in OC, and clinical/experimental evidences that support the underlying molecular mechanisms. We will then provide a comprehensive review and integrative analysis of the existing gene expression studies that aim to identify the metastasis related signatures in OC. Finally, the remaining challenges will be discussed and our insights on future directions will be provided. PMID- 21709741 TI - Mediators of Tyrosine Phosphorylation in Innate Immunity: From Host Defense to Inflammation onto Oncogenesis. AB - Cells respond to extracellular cues through a variety of receptors on the surface. These signals once transduced across the cell membrane, activate protein tyrosine kinases, which through phosphorylation of substrates on key tyrosine residues, are able to control cellular growth, activation and differentiation pathways. Recent data suggest that protein tyrosine kinases are critical in integrating signals from various cellular receptors, including pathogen detection receptors that mediate the host innate immune response. In this article, we have reviewed the roles of tyrosine kinases of the Tec, FAK, Fps, Fer, Syk, Src and TAM-receptor families in toll-like receptor signaling. The shared roles of these tyrosine phosphorylation mediators in host defense, inflammation, autoimmune disease and oncogenesis provides promising avenues for the use of their inhibitors in multiple disorders. PMID- 21709742 TI - The Invisible Work of Being a Patient and Implications for Health Care: "[the doctor is] my business partner in the most important business in my life, staying alive" AB - In a distributed system of care, patients shuffle among many clinicians and spend the majority of their time away from the treatment center. Although we see the results of patients' work (e.g., medication taken, arrived at appointment) we do not see the work itself. By failing to see this work, industry overlooks issues with vital implications for their business. To lift the veil of invisibility from patients' work, we conducted a longitudinal field study to uncover the invisible work breast cancer patients do to obtain information, bridge inter-institutional care, manage dependencies and resolve inconsistent recommendations. In this paper we provide detailed examples of this work and explore the impact on patients and health-care operations; identify patterns of work with implications for patient centered research and design; and propose common information spaces to improve patients' work through designs that highlight dependencies, preserve state information, link recommendations to justifications, and track task progress. PMID- 21709744 TI - Characterization of phenolics by LC-UV/vis, LC-MS/MS and sugars by GC in Melicoccus bijugatus Jacq. 'Montgomery' fruits. AB - Fruits of the native South American tree Melicoccus bijugatus Jacq. (Sapindaceae) are consumed for both dietary and medicinal purposes, but limited information is available about the phytochemistry and health value of M. bijugatus fruits. Fruit tissues of the Florida Montgomery cultivar were assessed for sugars, using gas chromatography, and for total phenolics, using UV spectroscopy. Reverse phase high performance liquid chromatography (HPLC) fingerprints of crude methanolic pulp, embryo and seed coat extracts were obtained at 280 nm. Phenolics were characterised by both HPLC UV/vis analysis and HPLC electrospray ionization tandem mass spectrometry. Major sugars detected in the pulp and embryo extracts were sucrose, followed by glucose and fructose. The glucose:fructose ratio was 1:1 in the pulp and 0.1:1 in the embryo. Total phenolic concentrations of the fruit tissues were in the order: seed coat > embryo > pulp. Phenolic acids were identified mostly in pulp tissues. Phenolic acids, flavonoids, procyanidins and catechins were identified in embryo tissues, and higher molecular weight procyanidins were identified in seed coat tissues. This study provides new information about the phytochemistry and the potential health value of the Montgomery cultivar M. bijugatus fruit tissues. PMID- 21709743 TI - Three-Dimensional Culture of Cells and Matrix Biomolecules for Engineered Tissue Development and Biokinetics Model Validation. AB - There has been considerable progress in cellular and molecular engineering due to recent advances in multiscale technology. Such technologies allow controlled manipulation of physiochemical interactions among cells in tissue culture. In particular, a novel chemomechanical bioreactor has recently been designed for the study of bone and cartilage tissue development, with particular focus on extracellular matrix formation. The bioreactor is equally significant as a tool for validation of mathematical models that explore biokinetic regulatory thresholds (Saha, A. K., and Kohles, S. S., 2010, "A Distinct Catabolic to Anabolic Threshold Due to Single-Cell Nanomechanical Stimulation in a Cartilage Biokinetics Model," J. Nanotechnol. Eng. Med., 1(3), p. 031005; 2010, "Periodic Nanomechanical Stimulation in a Biokinetics Model Identifying Anabolic and Catabolic Pathways Associated With Cartilage Matrix Homeostasis," J. Nanotechnol. Eng. Med., 1(4), p. 041001). In the current study, three-dimensional culture protocols are described for maintaining the cellular and biomolecular constituents within defined parameters. Preliminary validation of the bioreactor's form and function, expected bioassays of the resulting matrix components, and application to biokinetic models are described. This approach provides a framework for future detailed explorations combining multiscale experimental and mathematical analyses, at nanoscale sensitivity, to describe cell and biomolecule dynamics in different environmental regimes. PMID- 21709745 TI - The prevalence and clinical significance of inhalant withdrawal symptoms among a national sample. AB - BACKGROUND: Inhalants are among the most common and dangerous forms of substance use, but very little research on inhalant use disorders exist. Unlike other substances, the Diagnostic and Statistical Manual, 4th edition (DSM-IV) indicates that inhalants do not have an associated withdrawal syndrome among persons who meet criteria for inhalant dependence. METHODS: Using data from the National Epidemiologic Survey on Alcohol and Related Conditions, this study examines the prevalence of withdrawal symptoms among inhalant users. Prevalence of inhalant withdrawal symptoms for inhalants was also compared with the prevalence of cocaine withdrawal symptoms to help determine the presence of an inhalant withdrawal syndrome. RESULTS: Approximately 47.8% of persons who met criteria for inhalant dependence reported experiencing three or more inhalant-related withdrawal symptoms that were clinically significant. Among those with inhalant dependence, almost half of the withdrawal symptoms were as common as the corresponding withdrawal symptoms experienced by persons with cocaine dependence. Furthermore, the percentage of persons with inhalant dependence reporting clinically significant inhalant withdrawal symptoms was almost equal to the percentage of persons with cocaine dependence reporting clinically significant cocaine withdrawal symptoms. CONCLUSIONS: These data provide evidence for an inhalant-related withdrawal syndrome among persons with inhalant dependence. Revisions to DSM-IV should consider including inhalant withdrawal as a diagnostic criterion for this disorder. PMID- 21709746 TI - Semi-automated Algorithm for Localization of Dermal/ Epidermal Junction in Reflectance Confocal Microscopy Images of Human Skin. AB - The examination of the dermis/epidermis junction (DEJ) is clinically important for skin cancer diagnosis. Reflectance confocal microscopy (RCM) is an emerging tool for detection of skin cancers in vivo. However, visual localization of the DEJ in RCM images, with high accuracy and repeatability, is challenging, especially in fair skin, due to low contrast, heterogeneous structure and high inter- and intra-subject variability. We recently proposed a semi-automated algorithm to localize the DEJ in z-stacks of RCM images of fair skin, based on feature segmentation and classification. Here we extend the algorithm to dark skin. The extended algorithm first decides the skin type and then applies the appropriate DEJ localization method. In dark skin, strong backscatter from the pigment melanin causes the basal cells above the DEJ to appear with high contrast. To locate those high contrast regions, the algorithm operates on small tiles (regions) and finds the peaks of the smoothed average intensity depth profile of each tile. However, for some tiles, due to heterogeneity, multiple peaks in the depth profile exist and the strongest peak might not be the basal layer peak. To select the correct peak, basal cells are represented with a vector of texture features. The peak with most similar features to this feature vector is selected. The results show that the algorithm detected the skin types correctly for all 17 stacks tested (8 fair, 9 dark). The DEJ detection algorithm achieved an average distance from the ground truth DEJ surface of around 4.7MUm for dark skin and around 7-14MUm for fair skin. PMID- 21709747 TI - A Generalized System for Photo-Responsive Membrane Rupture in Polymersomes. AB - Polymersomes are vesicles whose membranes are comprised of self-assembled block co-polymers. We recently showed that co-encapsulating conjugated multi-porphyrin dyes in a polymersome membrane with ferritin protein in the aqueous lumen confers photo-lability to the polymersome. In the present study, we illustrate that the photo-lability can be extended to vesicles containing dextran, an inert and inexpensive polysaccharide, as the luminal solute. Here we explore how structural features of the polymersome/porphyrin/dextran composite affect its photo response. Increasing dextran molecular weight, decreasing block copolymer molecular weight, and altering fluorophore-membrane interactions results in increasing the photo-responsiveness of the polymersomes. Amphiphilic interactions of the luminal encapsulant with the membrane coupled with localized heat production in the hydrophobic bilayer likely cause differential thermal expansion in the membrane and the subsequent membrane rupture. This study suggests a general approach to impart photo-responsiveness to any biomimetic vesicle system without chemical modification, as well as a simple, bio-inert method for constructing photo-sensitive carriers for controlled release of encapsulants. PMID- 21709748 TI - HIV-1 Tat: Its Dependence on Host Factors is Crystal Clear. AB - HIV-1 transcription is regulated at the level of elongation by the viral Tat protein together with the cellular elongation factor P-TEFb, which is composed of cyclin T1 and Cdk9 subunits. The crystal structure of a Tat:P-TEFb complex (Tahirov, T.H.; Babayeva, N.D.; Varzavand, K.; Cooper, J.J.; Sedore, S.C.; and Price, D.H. Crystal structure of HIV-1 Tat complexed with human P-TEFb. Nature2010, 465, 747-751) reveals molecular details of Tat and its interactions that have eluded investigators for more than two decades and provides provocative insights into the mechanism of Tat activation. PMID- 21709749 TI - New Synthetic Approach for the Incorporation of 3,2-Hydroxypyridinone (HOPO) Ligands: Synthesis of Structurally Diverse Poly HOPO Chelators. AB - The HOPO sulfonamide reagent, 3, was prepared from commercial 2,3 dihydroxypyridine in four steps in good yields. Sulfonamide 3 readily underwent selective alkylation with dibromides in the presence of base or could be coupled to alcohols using Mitsunobu conditions. The utility of this nucleophilic HOPO reagent was demonstrated by the synthesis some tris and tetraHOPO chelators. This approach for tethering HOPO ligands is unique and flexible as shown by the preparation of HOPO/iminocarboxylic acid chelator 17. PMID- 21709750 TI - 3D Microperiodic Hydrogel Scaffolds for Robust Neuronal Cultures. AB - Three-dimensional (3D) microperiodic scaffolds of poly(2-hydroxyethyl methacrylate) (pHEMA) have been fabricated by direct-write assembly of a photopolymerizable hydrogel ink. The ink is initially composed of physically entangled pHEMA chains dissolved in a solution of HEMA monomer, comonomer, photoinitiator and water. Upon printing 3D scaffolds of varying architecture, the ink filaments are exposed to UV light, where they are transformed into an interpenetrating hydrogel network of chemically cross-linked and physically entangled pHEMA chains. These 3D microperiodic scaffolds are rendered growth compliant for primary rat hippocampal neurons by absorption of polylysine. Neuronal cells thrive on these scaffolds, forming differentiated, intricately branched networks. Confocal laser scanning microscopy reveals that both cell distribution and extent of neuronal process alignment depend upon scaffold architecture. This work provides an important step forward in the creation of suitable platforms for in vitro study of sensitive cell types. PMID- 21709751 TI - NEIGHBORHOOD CONTEXT AND THE GENDER GAP IN ADOLESCENT VIOLENT CRIME. AB - Although researchers consistently demonstrate that females engage in less criminal behavior than males across the life course, research on the variability of the gender gap across contexts is sparse. To address this issue, we examine the gender gap in self-reported violent crime among adolescents across neighborhoods. Multilevel models using data from the Project of Human Development in Chicago Neighborhoods (PHDCN) indicate that the gender gap in violent crime decreases as levels of neighborhood disadvantage increase. Further, the narrowing of the gender gap is explained by gender differences in peer influence on violent offending. Neighborhood disadvantage increases exposure to peer violence for both sexes, but peer violence has a stronger impact on violent offending for females than for males, producing the reduction in the gender gap at higher levels of disadvantage. We also find that the gender difference in the relationship between peer violence and offending is explained, in part, by (1) the tendency for females to have more intimate friendships than males, and (2) the moderating effect of peer intimacy on the relationship between peer violence and self reported violent behavior. PMID- 21709752 TI - Space-time least-squares finite element method for convection-reaction system with transformed variables. AB - We present a method to solve a convection-reaction system based on a least squares finite element method (LSFEM). For steady-state computations, issues related to recirculation flow are stated and demonstrated with a simple example. The method can compute concentration profiles in open flow even when the generation term is small. This is the case for estimating hemolysis in blood. Time-dependent flows are computed with the space-time LSFEM discretization. We observe that the computed hemoglobin concentration can become negative in certain regions of the flow; it is a physically unacceptable result. To prevent this, we propose a quadratic transformation of variables. The transformed governing equation can be solved in a straightforward way by LSFEM with no sign of unphysical behavior. The effect of localized high shear on blood damage is shown in a circular Couette-flow-with-blade configuration, and a physiological condition is tested in an arterial graft flow. PMID- 21709753 TI - Measuring resetting of brain dynamics at epileptic seizures: application of global optimization and spatial synchronization techniques. AB - Epileptic seizures are manifestations of intermittent spatiotemporal transitions of the human brain from chaos to order. Measures of chaos, namely maximum Lyapunov exponents (STL(max)), from dynamical analysis of the electroencephalograms (EEGs) at critical sites of the epileptic brain, progressively converge (diverge) before (after) epileptic seizures, a phenomenon that has been called dynamical synchronization (desynchronization). This dynamical synchronization/desynchronization has already constituted the basis for the design and development of systems for long-term (tens of minutes), on-line, prospective prediction of epileptic seizures. Also, the criterion for the changes in the time constants of the observed synchronization/desynchronization at seizure points has been used to show resetting of the epileptic brain in patients with temporal lobe epilepsy (TLE), a phenomenon that implicates a possible homeostatic role for the seizures themselves to restore normal brain activity. In this paper, we introduce a new criterion to measure this resetting that utilizes changes in the level of observed synchronization/desynchronization. We compare this criterion's sensitivity of resetting with the old one based on the time constants of the observed synchronization/desynchronization. Next, we test the robustness of the resetting phenomena in terms of the utilized measures of EEG dynamics by a comparative study involving STL(max), a measure of phase (phi(max)) and a measure of energy (E) using both criteria (i.e. the level and time constants of the observed synchronization/desynchronization). The measures are estimated from intracranial electroencephalographic (iEEG) recordings with subdural and depth electrodes from two patients with focal temporal lobe epilepsy and a total of 43 seizures. Techniques from optimization theory, in particular quadratic bivalent programming, are applied to optimize the performance of the three measures in detecting preictal entrainment. It is shown that using either of the two resetting criteria, and for all three dynamical measures, dynamical resetting at seizures occurs with a significantly higher probability (alpha = 0.05) than resetting at randomly selected non-seizure points in days of EEG recordings per patient. It is also shown that dynamical resetting at seizures using time constants of STL(max) synchronization/desynchronization occurs with a higher probability than using the other synchronization measures, whereas dynamical resetting at seizures using the level of synchronization/desynchronization criterion is detected with similar probability using any of the three measures of synchronization. These findings show the robustness of seizure resetting with respect to measures of EEG dynamics and criteria of resetting utilized, and the critical role it might play in further elucidation of ictogenesis, as well as in the development of novel treatments for epilepsy. PMID- 21709754 TI - P-glycoprotein and alloimmune T-cell activation. AB - P-glycoprotein (P-gp), the human multidrug resistant (MDR1) gene product and cancer multidrug resistance-associated adenosine triphosphate (ATP)-binding cassette (ABC) transporter, is physiologically expressed on peripheral blood mononuclear cells, but its role in cellular immunity is only beginning to be elucidated. A role of P-gp in the secretion of several T-cell and antigen presenting cell-derived cytokines has been described, and additional functions of the molecule have been identified in lymphocyte survival and antigen presenting cell differentiation. Taken together, these findings provide compelling evidence that P-gp serves several distinct functions in the initiation of primary immune responses, and a critical role of the molecule in functional alloimmune responses is now established. Here, we will review the current understanding of P-gp function in alloimmune T-cell activation via both T-cell and antigen presenting cell-dependent mechanisms, which is relevant to the field of clinical transplantation, where P-gp has been found to be a marker of acute and chronic allograft rejection. Indeed, current in vitro findings raise the possibility that P-gp could represent a novel therapeutic target in acute and chronic allograft rejection, the major causes of allograft dysfunction and ultimate graft loss. PMID- 21709755 TI - Exercise Intervention for Cancer Survivors with Heart Failure: Two Case Reports. AB - RATIONALE: Cardiotoxicity is a troubling long-term side effect of chemotherapy cancer treatment, affecting therapy and quality of life (QOL). Exercise is beneficial in heart failure (HF) patients and in cancer survivors without HF, but has not been tested in cancer survivors with treatment induced HF. METHODS: We present case studies for two survivors: a 56-year old female Hodgkin's lymphoma survivor (Pt 1) and a 44-year old male leukemia survivor (Pt 2). We conducted a 16-week exercise program with the goal of 30 minutes of exercise performed 3 times per week at a minimum intensity of 50% heart rate reserve (HRR) or '12' rating of perceived exertion (RPE). RESULTS: Pt 1 improved from 11.5 minutes of exercise split over two bouts at an RPE of 14 to a 30 minute bout at an RPE of 15. Pt 2 improved from 11 minutes of exercise split over two bouts at an RPE of 12 to an 18 minute bout at an RPE of 12. Both improved in VO(2) peak (Pt 1: 13.9 to 14.3 mlO(2)/kg/min; Pt 2: 12.5 to 18.7 mlO(2)/kg/min). Ejection fraction increased for Pt 2 (25-30% to 35-40%) but not for Pt 1 (35-40%). QOL as assessed by the SF-36 Physical Component Scale (PCS) improved from 17.79 to 25.31 for Pt 1 and the Mental Component Scale (MCS) improved from 43.84 to 56.65 for Pt 1 and from 34.79 to 44.45 for Pt 2. CONCLUSIONS: Properly designed exercise interventions can improve physical functioning and quality of life for this growing group of survivors. PMID- 21709756 TI - Is less more? A preliminary investigation of the number of response categories in self-reported pain. AB - The purpose of this study was to conduct a preliminary investigation of the number of response options for self-reports of pain interference. Responses to interference items of the 11-category Brief Pain Inventory (BPI) were obtained in a sample of 434 persons from two sites and modeled using the partial credit model. In successive calibrations, response categories were collapsed and new scores were generated. Scores based on two to three categories produced poor results. Four to five categories yielded better results. However, scoring using more than five categories did not appreciably improve the reliability, person separation, or validity of scores. These results suggest that fewer response categories-as few as five or six-may function as well as the 11 response categories that are conventionally used. The results are preliminary since the number of response categories actually presented was not manipulated in the study design. Future research should compare the reliability and validity of scores based on the BPI interference items when items are presented with the conventionally 11-response format, versus presentation with fewer response options. PMID- 21709757 TI - Effects of a Telephone-Based Exercise Intervention for Dementia Caregiving Wives: A Randomized Controlled Trial. AB - Despite the importance of self-care for dementia caregivers, few interventions have included a focus on health behaviors. The current study reports outcomes of a telephone-based exercise intervention designed for women caring for a spouse with dementia. Caregivers (N = 137) were randomized to intervention or control conditions. Participants with at or below-median exercise scores at baseline had a significantly greater increase in exercise at six-month follow-up compared to their control counterparts. At 6 months, participants had greater reductions in perceived stress relative to controls. Participants also reported significantly greater increases in exercise self-efficacy than caregivers in the control group at both follow-up points. . Results indicate that spouse caregivers are able to increase their physical activity and that a focus on exercise in multi-component interventions may be beneficial. Debate and discussion is needed to inform expectations for program impacts and their maintenance and to explore the interface between enhanced self-care and caregiving perceptions. PMID- 21709758 TI - Measuring Love: Sexual Minority Male Youths' Ideal Romantic Characteristics. AB - Research examining how sexual minorities characterize love within same-sex relationships is scarce. In this study, we examined the validity of Sternberg's Triangular Theory of Love in a sample of sexual minority male youth (N = 447). To test the adequacy of the theory for our population, we examined the psychometric properties of the Triadic Love Scale (TLS) and tested whether the three underlying constructs of the theory (Intimacy, Passion, and Commitment) emerged when participants were asked to consider their ideal relationship with another man. Using confirmatory factor analysis (CFA), we found support for the three factor solution to characterize sexual minority male youths' ideal romantic relationship, after minimizing item cross-loadings and adapting the content of the Passion subscale. We discuss the implications of our findings regarding the measurement of the TLS among sexual minority male youth and propose ways to enhance its measurement in future research. PMID- 21709759 TI - Remediating Computational Deficits at Third Grade: A Randomized Field Trial. AB - The major purposes of this study were to assess the efficacy of tutoring to remediate 3rd-grade computational deficits and to explore whether remediation is differentially efficacious depending on whether students experience mathematics difficulty alone or concomitantly with reading difficulty. At 2 sites, 127 students were stratified on mathematics difficulty status and randomly assigned to 4 conditions: word recognition (control) tutoring or 1 of 3 computation tutoring conditions: fact retrieval, procedural computation and computational estimation, and combined (fact retrieval + procedural computation and computational estimation). Results revealed that fact retrieval tutoring enhanced fact retrieval skill, and procedural computation and computational estimation tutoring (whether in isolation or combined with fact retrieval tutoring) enhanced computational estimation skill. Remediation was not differentially efficacious as a function of students' mathematics difficulty status. PMID- 21709760 TI - Locostatin Disrupts Association of Raf Kinase Inhibitor Protein With Binding Proteins by Modifying a Conserved Histidine Residue in the Ligand-Binding Pocket. AB - Raf kinase inhibitor protein (RKIP) interacts with a number of different proteins and regulates multiple signaling pathways. Here, we show that locostatin, a small molecule that covalently binds RKIP, not only disrupts interactions of RKIP with Raf-1 kinase, but also with G protein-coupled receptor kinase 2. In contrast, we found that locostatin does not disrupt binding of RKIP to two other proteins: inhibitor of kappaB kinase alpha and transforming growth factor beta-activated kinase 1. These results thus imply that different proteins interact with different regions of RKIP. Locostatin's mechanism of action involves modification of a nucleophilic residue on RKIP. We observed that after binding RKIP, part of locostatin is slowly hydrolyzed, leaving a smaller RKIP-butyrate adduct. We identified the residue alkylated by locostatin as His86, a highly conserved residue in RKIP's ligand-binding pocket. Computational modeling of the binding of locostatin to RKIP suggested that the recognition interaction between small molecule and protein ensures that locostatin's electrophilic site is poised to react with His86. Furthermore, binding of locostatin would sterically hinder binding of other ligands in the pocket. These data provide a basis for understanding how locostatin disrupts particular interactions of RKIP with RKIP binding proteins and demonstrate its utility as a probe of specific RKIP interactions and functions. PMID- 21709762 TI - Research into the Language of the Patient: Improving Clinical Outcomes. PMID- 21709764 TI - Response of patients with sickle cell anaemia and end-stage renal disease to erythropoietin treatment. PMID- 21709761 TI - Targeted Nanocarriers for Imaging and Therapy of Vascular Inflammation. AB - Vascular inflammation is a common, complex mechanism involved in pathogenesis of a plethora of disease conditions including ischemia-reperfusion, atherosclerosis, restenosis and stroke. Specific targeting of imaging probes and drugs to endothelial cells in inflammation sites holds promise to improve management of these conditions. Nanocarriers of diverse compositions and geometries, targeted with ligands to endothelial adhesion molecules exposed in inflammation foci are devised for this goal. Imaging modalities that employ these nanoparticle probes include radioisotope imaging, MRI and ultrasound that are translatable from animal to human studies, as well as optical imaging modalities that at the present time are more confined to animal studies. Therapeutic cargoes for these drug delivery systems include diverse anti-inflammatory agents, anti proliferative drugs for prevention of restenosis, and antioxidants. This article reviews recent advances in the area of image-guided translation of targeted nanocarrier diagnostics and therapeutics in nanomedicine. PMID- 21709763 TI - New Nanomedicine Approaches Using Gold-thioguanine Nanoconjugates as Metallo ligands. AB - Gold-thioguanine nanoconjugates (AuNP-TG) of size 3-4 nm were synthesized and the ratio between gold and 6-Thioguanine (TG) was estimated as ~1:1.5 using a cyanide digestion method and confirmed by flame atomic absorption spectroscopic analysis. AuNP-TG constructs showed high in vitro stability under different pH conditions and biologically relevant solutions for a period of 24 hours. Reaction of AuNP-TG with europium or platinum salts resulted in the formation of organized self assembled metallo-networks. PMID- 21709765 TI - Multivalent Vaccine for Lymphatic Filariasis. AB - Lymphatic filariasis is a mosquito borne parasitic infection that cause severe economic burden in several parts of the world. Currently there is no vaccine available to prevent this infection in human. Multidrug therapy is effective, however, requires annual treatment and there is significant concern of drug resistance. In this manuscript we describe development of a multivalent DNA based vaccine comprising BmALT-2 and BmHSP antigens of lymphatic filariasis. Challenge experiments using third stage infective larvae of Brugia malayi in a mouse model suggested that nearly 90% protection can be achieved using the multivalent formulation in a DNA prime protein boost approach. The vaccination regimen induced significant IgG antibody responses and ELISPOT analysis for secreted cytokines from the spleen cells of vaccinated animals showed that these cells produce significant amount of IL-4. Results from this study thus show that a multivalent vaccine formulation of BmALT-2 and BmHSP is an excellent vaccine for lymphatic filariasis and significant protection can be achieved against a challenge infection with B. malayi in a mouse model. PMID- 21709766 TI - STIM2 Contributes to Enhanced Store-operated Ca Entry in Pulmonary Artery Smooth Muscle Cells from Patients with Idiopathic Pulmonary Arterial Hypertension. AB - Pulmonary vasoconstriction and vascular remodeling are two major causes for elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with idiopathic pulmonary arterial hypertension (IPAH). An increase in cytosolic free Ca(2+) concentration ([Ca(2+)](cyt)) in pulmonary artery smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation, which causes pulmonary vascular remodeling. Store-operated Ca(2+) entry (SOCE), induced by depletion of stored Ca(2+) in the sarcoplasmic reticulum (SR), can increase [Ca(2+)](cyt) in PASMC independent of other means of Ca(2+) entry. Stromal interaction molecule (STIM) proteins, STIM1 and STIM2, were recently identified as both sensors for store depletion and signaling molecules to open store-operated Ca(2+) channels. We previously reported that SOCE was significantly enhanced in PASMC from IPAH patients compared to PASMC from normotensive control subjects. Enhanced SOCE plays an important role in the pathophysiological changes in PASMC associated with pulmonary arterial hypertension. In this study, we examine whether the expression level of STIM1 and STIM2 is altered in IPAH-PASMC compared to control PASMC and whether these putative changes in STIM1/2 expression level are responsible for enhanced SOCE and proliferation in IPAH-PASMC. Compared to control PASMC, the protein expression level of STIM2 was significantly increased whereas STIM1 protein expression was not significantly changed. In IPAH-PASMC, siRNA-mediated knockdown of STIM2 decreased SOCE and proliferation, while knockdown of STIM2 in control PASMC had no effect on either SOCE or proliferation. Overexpression of STIM2 in control PASMC failed to enhance SOCE or proliferation. These data indicate that enhanced protein expression of STIM2 is necessary, but not sufficient, for enhanced SOCE and proliferation of IPAH-PASMC. PMID- 21709767 TI - Recent Applications of Acyclic (Diene)iron Complexes and (Dienyl)iron Cations in Organic Synthesis. AB - Complexation of (tricarbonyl)iron to an acyclic diene serves to protect the ligand against oxidation, reduction and cycloaddition reactions while the steric bulk of this adjunct serves to direct the approach reagents to unsaturated groups attached to the diene onto the face opposite to iron. Furthermore, the Fe(CO)(3) moiety can serve to stabilize carbocation centers adjacent to the diene (i.e. pentadienyl-iron cations). Recent applications of these reactivities to the synthesis of polyene, cyclopropane, cycloheptadiene and cyclohexenone containing natural products or analogs will be presented. PMID- 21709768 TI - Heterogeneous Risk Preferences and the Welfare Cost of Business Cycles. AB - I study the welfare cost of business cycles in a complete-markets economy where some people are more risk averse than others. Relatively more risk-averse people buy insurance against aggregate risk, and relatively less risk-averse people sell insurance. These trades reduce the welfare cost of business cycles for everyone. Indeed, the least risk-averse people benefit from business cycles. Moreover, even infinitely risk-averse people suffer only finite and, in my empirical estimates, very small welfare losses. In other words, when there are complete insurance markets, aggregate fluctuations in consumption are essentially irrelevant not just for the average person - the surprising finding of Lucas (1987) - but for everyone in the economy, no matter how risk averse they are. If business cycles matter, it is because they affect productivity or interact with uninsured idiosyncratic risk, not because aggregate risk per se reduces welfare. PMID- 21709770 TI - An integrated solution and analysis of bioluminescence tomography and diffuse optical tomography. AB - While diffuse optical tomography (DOT) has been studied for years, bioluminescence tomography (BLT) is emerging as a promising optical molecular imaging tool. These two modalities have different goals. DOT is for reconstruction of optical parameters of a medium such as a breast from surface measurements induced by external sources. BLT is for reconstruction of a bioluminescent source distribution in a medium such as a mouse from surface measurements induced by internal bioluminescent sources. However, an important pre-requisite for BLT reconstruction is the knowledge on the distribution of optical parameters within the medium, which is the output of DOT. In this paper, we propose a mathematical model integrating BLT and DOT at the fundamental level; that is, performing the two types of reconstructions simultaneously instead of doing them sequentially. The model is introduced through minimizing the difference between predicted quantities and boundary measurements, as well as incorporating regularization terms. Then, we show the solution existence, introduce numerical schemes and prove convergence of the numerical solution. We also present numerical results to illustrate the utility of our approach. PMID- 21709769 TI - Why Do We Need ADAMTS13? PMID- 21709771 TI - Hierarchical Bayesian nonparametric mixture models for clustering with variable relevance determination. AB - We propose a hierarchical Bayesian nonparametric mixture model for clustering when some of the covariates are assumed to be of varying relevance to the clustering problem. This can be thought of as an issue in variable selection for unsupervised learning. We demonstrate that by defining a hierarchical population based nonparametric prior on the cluster locations scaled by the inverse covariance matrices of the likelihood we arrive at a 'sparsity prior' representation which admits a conditionally conjugate prior. This allows us to perform full Gibbs sampling to obtain posterior distributions over parameters of interest including an explicit measure of each covariate's relevance and a distribution over the number of potential clusters present in the data. This also allows for individual cluster specific variable selection. We demonstrate improved inference on a number of canonical problems. PMID- 21709772 TI - A Pilot Study of Psychotherapist Trainees' Alpha-Amylase and Cortisol Levels During Treatment of Recently Suicidal Clients With Borderline Traits. AB - Psychotherapists often experience stress while providing psychotherapy, in particular when working with difficult presentations such as suicidality. As part of a larger study on the treatment of recently suicidal college students with borderline traits, 6 therapists in training collected their own salivary samples for alpha-amylase (AA) and cortisol (C) analyses immediately before and after sessions with 2 selected clients. On average, samples were collected for the same therapist-patient dyad throughout the year-long study to ensure that data reflected therapist responses across stages of treatment. Therapists also completed a working alliance questionnaire and rated perceived session difficulty immediately after each selected session. Contrary to expectations, therapists demonstrated elevated levels of stress as measured by AA and C at presession relative to postsession levels. Greater session difficulty was related to more pronounced declines in AA, whereas a stronger working alliance was linked to more pronounced reductions in C. Results suggest that physiological stress responses while working with recently suicidal clients with borderline traits occur primarily in terms of session anticipatory anxiety, whereas AA and C changes may be affected differently by factors such as session difficulty and working alliance. This is a pilot study, limited by its sample size, but the design, findings, and inclusion of physiological measures present an initial step in an essential line of research. PMID- 21709773 TI - Octogenarian Reports of Lifetime Spiritual Experiences: Types of Experience and Early Life Predictors. AB - This study assessed lifetime histories of discrete spiritual experiences recalled by 144 octogenarian men studied since adolescence and 80 spouses. Women were more likely to report discrete spiritual experiences, as were those from higher socioeconomic backgrounds and those judged more open to experience as young adults. Factor analysis revealed four types of experiences related to beauty/nature, negative life events, protection by a sacred other, and traditional religious settings. Men from better childhood environments more commonly reported spiritual experiences concerning negative life events. Those with serious childhood illnesses were less likely to report experiences of feeling protected by a sacred other. PMID- 21709774 TI - Synthesis and Properties of Nanoparticle Forms Saponite Clay, Cancrinite Zeolite and Phase Mixtures Thereof. AB - The low-temperature synthesis (90 degrees C) of nanoparticle forms of a pure phase smectic clay (saponite) and zeolite (cancrinite) is reported, along with phase mixtures thereof. A synthesis gel corresponding to the Si:Al:Mg unit cell composition of saponite (3.6:0.40:3.0) and a NaOH/Si ratio of 1.39 affords the pure phase clay with disordered nanolayer stacking. Progressive increases in the NaOH/Si ratio up to a value of 8.33 results in the co-crystallization of first garronite and then cancrinite zeolites with nanolath morphology. The resulting phase mixtures exhibit a compound particulate structure of intertwined saponite nanolayers and cancrinite nanolaths that cannot be formed through physical mixing of the pure phase end members. Under magnesium-free conditions, pure phase cancrinite nanocrystals are formed. The Si/Al ratio of the reaction mixture affects the particle morphology as well as the chemical composition of the cancrinite zeolite. Ordinarily, cancrinite crystallizes with a Si/Al ratio of 1.0, but a silicon-rich form of the zeolite (Si/Al=1.25) is crystallized at low temperature from a silica rich synthesis gel, as evidenced by (29)Si NMR spectroscopy and XEDS-TEM. Owing to the exceptionally high external surface areas of the pure phase clay (875 m(2)/g) and zeolite end members (8.9 - 40 m(2)/g), as well as their unique mixed phase composites (124 - 329 m(2)/g), these synthetic derivatives are promising model nanoparticles for studies of the bioavailability of poly-aromatic hydrocarbons immobilized in silicate bearing sediments and soils. PMID- 21709775 TI - The effect of the glass transition temperature on the toughness of photopolymerizable (meth)acrylate networks under physiological conditions. AB - The purpose of this study is to evaluate how the toughness of photopolymerizable (meth)acrylate networks is influenced by physiological conditions. By utilizing two ternary (meth)acrylate networks, MA-co-MMA-co-PEGDMA and 2HEMA-co-BMA-co PEGDMA, relationships between glass transition temperature (T(g)), water content and state, and toughness were studied by varying the weight ratio of the linear monomers (MA to MMA or 2HEMA to BMA). Differential scanning calorimetry and thermogravimetric analysis were performed to evaluate the thermal behavior and water content as a function of either MA or 2HEMA concentration while tensile strain-to-failure tests were performed at 37 degrees C to determine network toughness. Both networks exhibited a maximum in toughness in PBS in the composition corresponding to a T(g) close to the testing temperature. This toughness maximum was achieved by adjusting the glass transition temperature and/or hydrophilicity through changes in chemistry. These relationships may be utilized to design tough photopolymerizable networks for use in mechanically rigorous biomedical applications. PMID- 21709776 TI - Child-Report Data and Assessment of the Social Environment in Schools. AB - OBJECTIVES: This study tested the quality of data collected with the online ESSP for Children from a diverse sample of 1,172 third through fifth graders. METHODS: Mplus confirmatory factor analysis (CFA) procedures for ordinal and clustered data were used. RESULTS: Of 80 original items, 61 loaded on 13 dimensions in a first-order model that had good fit in three random subsamples. Children in grades 3 through 5 may not be reliable reporters about neighborhood adults' caring. However, 12 statistically sound and independent dimensions related to school, peers, family, and well-being were obtained. CONCLUSIONS: The ESSP for Children provides school staff with quality data to use in conjunction with family and teacher ESSP data to guide intervention choices in schools. PMID- 21709777 TI - A Confirmatory Factor Analysis of Home Environment and Home Social Behavior Data from the Elementary School Success Profile for Families. AB - The purpose of the current study was to test the factor structure and scale quality of data provided by caregivers about the home environment and child behavior at home using the Elementary School Success Profile (ESSP) for Families. The ESSP for Families is one component of the ESSP, an online social environmental assessment that also collects information from students and teachers. Confirmatory factor analyses with Mplus and weighted least squares means and variances adjusted estimation took into account the hierarchical nature and ordinal level of the data. The sample comprised caregivers of 692 third- through fifth-grade students from 13 elementary schools in four districts. A primary model and an alternative model were tested. Models were tested on a random calibration sample and validated with another sample. A nine-factor first order solution demonstrated superior fit to the data. Scores from the nine scales also demonstrated acceptable internal consistency reliability. Implications for practice and further research are presented. PMID- 21709778 TI - Impulse control disorders in Parkinson's disease: clinical characteristics and implications. AB - Impulse control disorders (ICDs), specifically those related to excessive gambling, eating, sex and shopping, have been observed in a subset of people with Parkinson's disease (PD). Although some initial case reports claimed that dopamine replacement therapies, particularly dopamine agonists, cause ICDs, more recent, larger and better controlled studies indicate a more complicated picture. While dopamine replacement therapy use is related to ICDs, other vulnerabilities, some related to PD and/or its treatment directly and others seemingly unrelated to PD, have also been associated with ICDs in PD. This suggests a complex etiology with multiple contributing factors. As ICDs occur in a sizable minority of PD patients and can be associated with significant distress and impairment, further investigation is needed to identify factors that can predict who may be more likely to develop ICDs. Clinical implications are discussed and topics for future research are offered. PMID- 21709779 TI - HPV pseudovirions as DNA delivery vehicles. AB - "The ability of HPV pseudovirions to efficiently deliver DNA into cells suggests several potential applications in basic biology, including the characterization of virion biology and measurement of protective neutralizing antibody titers in vitro and in vivo, as well as their employment for more direct medical applications". PMID- 21709780 TI - NMR characterization of general compartment size distributions. AB - The influence of molecular diffusion on the nuclear magnetic resonance (NMR) signal can be exploited to estimate compartment size distributions in heterogeneous specimens. Theoretical relationships between the NMR signal intensity at long diffusion times and the moments of a general distribution of isolated pores with characteristic shapes (planar, cylindrical or spherical) are established. A numerical method based on expressing a general diffusion attenuated NMR signal profile in a series of complete orthogonal basis functions is introduced and subsequently employed to estimate the moments of the compartment size distribution. The results on simulated and real data obtained from controlled water-filled microcapillaries demonstrate the power of the approach to create contrast based not only on the mean of the compartment size but also its variance. The technique can be employed to address a variety of problems such as characterizing distributions of droplet sizes in emulsions and of apparent axon diameters in nerve fascicles. PMID- 21709781 TI - The role of problem solving in complex intraverbal repertoires. AB - We examined whether typically developing preschoolers could learn to use a problem-solving strategy that involved self-prompting with intraverbal chains to provide multiple responses to intraverbal categorization questions. Teaching the children to use the problem-solving strategy did not produce significant increases in target responses until problem solving was modeled and prompted. Following the model and prompts, all participants showed immediate significant increases in intraverbal categorization, and all prompts were quickly eliminated. Use of audible self-prompts was evident initially for all participants, but declined over time for 3 of the 4 children. Within-session response patterns remained consistent with use of the problem-solving strategy even when self prompts were not audible. These findings suggest that teaching and prompting a problem-solving strategy can be an effective way to produce intraverbal categorization responses. PMID- 21709782 TI - Increasing following headway with prompts, goal setting, and feedback in a driving simulator. AB - We evaluated the effects of prompting, goal setting, and feedback on following headway of young drivers in a simulated driving environment and assessed whether changes produced in following headway were associated with reductions in hard braking when drivers were and were not using cell phones. Participants were 4 university students. During baseline, drivers spent half of the time talking on cell phones while driving. At the start of the intervention, drivers were prompted to increase following headway while on the cell phones and were provided a specific target for following headway. Drivers were given feedback on increasing following headway when on cell phones at the end of each session. The intervention package was associated with an increase in following headway and a decrease in hard braking when participants were on and off the cell phones. Cell phone use did not affect any of the measures. PMID- 21709783 TI - Training preschool children to use visual imagining as a problem-solving strategy for complex categorization tasks. AB - It has been suggested that verbally sophisticated individuals engage in a series of precurrent behaviors (e.g., covert intraverbal behavior, grouping stimuli, visual imagining) to solve problems such as answering questions (Palmer, 1991; Skinner, 1953). We examined the effects of one problem solving strategy--visual imagining--on increasing responses to intraverbal categorization questions. Participants were 4 typically developing preschoolers between the ages of 4 and 5 years. Visual imagining training was insufficient to produce a substantial increase in target responses. It was not until the children were prompted to use the visual imagining strategy that a large and immediate increase in the number of target responses was observed. The number of prompts did not decrease until the children were given a rule describing the use of the visual imagining strategy. Within-session response patterns indicated that none of the children used visual imagining prior to being prompted to do so and that use of the strategy continued after introduction of the rule. These results were consistent for 3 of 4 children. Within-session response patterns suggested that the 4th child occasionally imagined when prompted to do so, but the gains were not maintained. The results are discussed in terms of Skinner's analysis of problem solving and the development of visual imagining. PMID- 21709784 TI - Using multiple-exemplar training to teach a generalized repertoire of sharing to children with autism. AB - The current study examined the utility of multiple-exemplar training to teach children with autism to share. Stimuli from 3 of 4 categories were trained using a treatment package of video modeling, prompting, and reinforcement. Offers to share increased for all 3 children following the introduction of treatment, with evidence of skill maintenance. In addition, within-stimulus-category generalization of sharing was evident for all participants, although only 1 participant demonstrated across-category generalization of sharing. Offers to share occurred in a novel setting, with familiar and novel stimuli, and in the presence of novel adults and peers for all participants during posttreatment probes. PMID- 21709785 TI - The role of negative reinforcement in infant caregiving: an experimental simulation. AB - We observed 11 undergraduates in an experiment designed to simulate infant caregiving. In negative reinforcement conditions experienced by all participants, a targeted caregiving response (e.g., rocking a baby doll) produced escape from, and avoidance of, a recorded infant cry. Nine participants' caregiving was shown to be controlled by this negative reinforcement contingency. Nine participants experienced an extinction condition that consisted of an inescapable cry, and the previously reinforced caregiving responses of 2 of these participants were resistant to extinction. For both of these participants, the previously reinforced response was eliminated when an alternative form of caregiving was reinforced. These results highlight the role of negative reinforcement in infant caregiving and suggest the need for additional research on the effects of crying on caregivers as well as the development of effective strategies for minimizing infant crying. PMID- 21709786 TI - Infant sign training and functional analysis. AB - We taught manual signs to typically developing infants using a reversal design and caregiver-nominated stimuli. We delivered the stimuli on a time-based schedule during baseline. During the intervention, we used progressive prompting and reinforcement, described by Thompson et al. (2004, 2007), to establish mands. Following sign training, we conducted functional analyses and verified that the signs functioned as mands. These results provide preliminary validation for the verbal behavior functional analysis methodology and further evidence of the functional independence of verbal operants. PMID- 21709787 TI - Check-in/check-out: a systematic evaluation and component analysis. AB - Tier 2 interventions are implemented similarly across students and thus serve as an efficient and cost-effective method of behavior support in school settings. Check-in/check-out is a Tier 2 intervention with documented effectiveness (e.g., Hawken & Horner, 2003; Todd, Campbell, Meyer, & Horner, 2008). Key features of the intervention include brief morning and afternoon meetings with the intervention coordinator, use of a point card on which the teacher monitors student behavior, and teacher feedback at predetermined times. The present study sought to add to the literature by examining the relative contributions of the teacher-feedback components of check-in/check-out via the use of a component analysis. Working with 4 children in a general education setting, we first evaluated the effectiveness of the procedure using reversal designs. Next, we systematically removed teacher-feedback components to assess effects on problem behavior and academic engagement. For 3 of 4 participants, we were able to remove all teacher-feedback sessions and the point card; for the 4th participant, we removed only 2 of 3 teacher-feedback sessions due to time constraints. PMID- 21709788 TI - Comparison of progressive prompt delay with and without instructive feedback. AB - We examined the effectiveness and efficiency of 2 instructional arrangements using progressive prompt delay (PPD) with 3 young children with autism and 1 child with developmental delays. Specifically, we compared PPD with instructive feedback (IF) to PPD without IF in an adapted alternating treatment design. The results suggested that (a) children with autism and developmental delays can learn when PPD is used with IF, (b) IF can be an effective method of instruction for young children with autism and developmental delays, and (c) the combination of PPD and IF can increase the efficiency of instruction. Data collected 8 to 9 weeks after instruction ended showed that participants maintained mastery of 58% to 92% of the acquired behaviors. We discuss these results within the constraints and limitations of the data and recommend areas for future research. PMID- 21709789 TI - Further analysis of picture interference when teaching word recognition to children with autism. AB - Previous research indicates that pairing pictures with associated words when teaching sight-word reading may hinder acquisition (e.g., Didden, Prinsen, & Sigafoos, 2000; Singh & Solman, 1990; Solman & Singh, 1992). The purpose of the current study was to determine whether this phenomenon was due to a previously learned association between the spoken word and picture (i.e., blocking) or due to the mere presence of a picture as an extrastimulus prompt (i.e., overshadowing). Three participants were taught to recognize words that were presented alone or paired with pictures that the participants either could or could not identify prior to training. All participants learned the words more quickly when they were presented alone rather than with pictures, regardless of their prior learning history with respect to pictures representing the words. This finding is consistent with the phenomenon of overshadowing. Nonetheless, consistent with blocking, all participants also acquired the words presented alone more quickly if they could not identify the associated pictures prior to training. Together, these findings have important implications for using prompts when teaching skills to individuals with developmental disabilities. PMID- 21709791 TI - Using trained pouched rats to detect land mines: another victory for operant conditioning. AB - We used giant African pouched rats (Cricetomys gambianus) as land mine-detection animals in Mozambique because they have an excellent sense of smell, weigh too little to activate mines, and are native to sub-Saharan Africa, and therefore are resistant to local parasites and diseases. In 2009 the rats searched 93,400 m(2) of land, finding 41 mines and 54 other explosive devices. Humans with metal detectors found no additional mines. On average, the rats emitted 0.33 false alarm for every 100 m(2) searched, which is below the threshold given by International Mine Action Standards for accrediting mine-detection animals. These findings indicate that Cricetomys are accurate mine-detection animals and merit continued use in this capacity. PMID- 21709793 TI - Increasing response variability of mand frames with script training and extinction. AB - We examined the effects of script training and extinction on response variability of mand frames used by children with autism. Results demonstrated that extinction following script training was effective for increasing variability for 2 of the 3 participants. PMID- 21709794 TI - Resistance to disruption in a classroom setting. AB - Substantial experimental evidence indicates that behavior reinforced on a denser schedule is more resistant to disruption than is behavior reinforced on a thinner schedule. The present experiment studied resistance to disruption in a natural educational environment. Responding during familiar activities was reinforced on a multiple variable-interval (VI) 7-s VI 30-s schedule for 6 participants with developmental disabilities. Resistance to disruption was measured by presenting a distracting item. Response rates in the disruption components were compared to within-session response rates in prior baseline components. Results were consistent with the predictions of behavioral momentum theory for 5 of 6 participants. PMID- 21709795 TI - Replications and extensions in arousal assessment for sex offenders with developmental disabilities. AB - Three adult male sex offenders with developmental disabilities participated in phallometric assessments that involved repeated measures of arousal when exposed to various stimuli. Arousal assessment outcomes were similar to those obtained by Reyes et al. (2006). Additional data-analysis methods provided further information about sexual preferences, thus replicating and extending previous research. The results provide preliminary data for establishing a preference gradient by age. Implications for the use of repeated measures and preference gradients in arousal assessments are discussed. PMID- 21709796 TI - Using noncontingent reinforcement to increase compliance with wearing prescription prostheses. AB - We evaluated the effects of noncontingent reinforcement (NCR) on compliance with wearing foot orthotics and a hearing aid with 2 individuals. Results showed that NCR increased the participants' compliance with wearing prescription prostheses to 100% after just a few 5-min sessions, and the behavior change was maintained during lengthier sessions. The results are discussed in terms of the potential value-altering effects of NCR. PMID- 21709797 TI - Establishing compliance with liquid medication administration in a child with autism. AB - Children with autism often display difficulty with swallowing pills and liquid medications. In the current study, stimulus fading and positive reinforcement established compliance with liquid medication administration in a young boy with autism. The boy's mother eventually administered liquid medication on her own. PMID- 21709798 TI - Sequential treatment of a feeding problem using a pacifier and flipped spoon. AB - Parents may be reluctant to treat the feeding disorder of a chronically ill child who exhibits distressed behavior during feeding. In this study, we identified a child with chronic medical problems and a feeding disorder who cried during feedings. We introduced treatment components sequentially to address parental concerns about crying. First, we used a pacifier to reduce crying, and then we used a flipped spoon to increase mouth clean. The results showed that a sequential approach to treatment can be effective for children with complex medical and behavioral problems. PMID- 21709799 TI - Using teacher greetings to increase speed to task engagement. AB - We used a multiple baseline design across participants to determine if teacher greetings would reduce the latency to task engagement. Three participants were identified by their respective teachers as having difficulty initiating task appropriate engagement at the beginning of class. Latency was measured from teacher greeting until the participant was actively engaged for 5 consecutive seconds. Results showed that teacher greetings were effective at reducing latency to task engagement for all participants. PMID- 21709800 TI - The impact of checklist-based training on teachers' use of the zone defense schedule. AB - We assessed the impact of checklist-based training on teaching teams' use of the zone defense schedule. Three teaching teams (lead teacher plus 2 assistant teachers) in an inclusive early childhood program participated. A multiple baseline design across teams was used to determine whether accurate implementation of the zone defense schedule increased when checklist-based training was provided. All teaching teams reached the preestablished criterion, implementing a minimum of 80% of checklist items accurately for 3 consecutive observations. PMID- 21709801 TI - Assessing the social acceptability of the functional analysis of problem behavior. AB - Although the clinical utility of the functional analysis is well established, its social acceptability has received minimal attention. The current study assessed the social acceptability of functional analysis procedures among 10 parents and 3 teachers of children who had recently received functional analyses. Participants completed a 9-item questionnaire, and results suggested that functional analysis procedures were socially acceptable. PMID- 21709802 TI - Animal research in the Journal of Applied Behavior Analysis. AB - This review summarizes the 6 studies with nonhuman animal subjects that have appeared in the Journal of Applied Behavior Analysis and offers suggestions for future research in this area. Two of the reviewed articles described translational research in which pigeons were used to illustrate and examine behavioral phenomena of applied significance (say-do correspondence and fluency), 3 described interventions that changed animals' behavior (self-injury by a baboon, feces throwing and spitting by a chimpanzee, and unsafe trailer entry by horses) in ways that benefited the animals and the people in charge of them, and 1 described the use of trained rats that performed a service to humans (land-mine detection). We suggest that each of these general research areas merits further attention and that the Journal of Applied Behavior Analysis is an appropriate outlet for some of these publications. PMID- 21709803 TI - College-level instruction: derived relations and programmed instruction. AB - Recent research has demonstrated the effectiveness of programmed instruction that integrates derived relations to teach college-level academic material. This method has been demonstrated to be effective and economical in the teaching of complex mathematics and biology concepts. Although this approach may have potential applications with other domains of college learning, more studies are needed to evaluate important technological variables. Studies that employ programmed instruction are discussed in relation to future directions for research. PMID- 21709804 TI - Multivariate Exponential Survival Trees And Their Application to Tooth Prognosis. AB - This paper is concerned with developing rules for assignment of tooth prognosis based on actual tooth loss in the VA Dental Longitudinal Study. It is also of interest to rank the relative importance of various clinical factors for tooth loss. A multivariate survival tree procedure is proposed. The procedure is built on a parametric exponential frailty model, which leads to greater computational efficiency. We adopted the goodness-of-split pruning algorithm of LeBlanc and Crowley (1993) to determine the best tree size. In addition, the variable importance method is extended to trees grown by goodness-of-fit using an algorithm similar to the random forest procedure in Breiman (2001). Simulation studies for assessing the proposed tree and variable importance methods are presented. To limit the final number of meaningful prognostic groups, an amalgamation algorithm is employed to merge terminal nodes that are homogenous in tooth survival. The resulting prognosis rules and variable importance rankings seem to offer simple yet clear and insightful interpretations. PMID- 21709805 TI - A Functional Type I Interferon Pathway Drives Resistance to Cornea Herpes Simplex Virus Type 1 Infection by Recruitment of Leukocytes. AB - Type I interferons are critical antiviral cytokines produced following herpes simplex virus type-1 (HSV-1) infection that act to inhibit viral spread. In the present study, we identify HSV-infected and adjacent uninfected corneal epithelial cells as the source of interferon-alpha. We also report mice deficient in the A1 chain of the type I IFN receptor (CD118(-/-)) are extremely sensitive to ocular infection with low doses (100 PFU) of HSV-1 as seen by significantly elevated viral titers in the cornea compared to wild type (WT) controls. The enhanced susceptibility correlated with a loss of CD4(+) and CD8(+) T cell recruitment and aberrant chemokine production in the cornea despite mounting an adaptive immune response in the draining mandibular lymph node of CD118(-/-) mice. Taken together, these results highlight the importance of IFN production in both the innate immune response as well as eliciting chemokine production required to facilitate adaptive immune cell trafficking. PMID- 21709806 TI - Clinical Approach to the Treatment of Painful Diabetic Neuropathy. AB - Painful neuropathy is a common and often progressive complication of diabetes. Patients frequently report symptoms of tingling, burning, lancinating pain, hyperesthesia and allodynia. The natural history of the disease may vary from intermittent mild symptoms to severe chronic daily pain; the latter is often associated with diminished quality of life. There are a variety of pharmaceutical agents from different medicinal categories available for the symptomatic treatment of painful diabetic neuropathy, however selecting an agent is often challenging given the breadth of choices and lack of consistent guidelines. As a result, many patients remain untreated or undertreated.This article presents a practical clinical approach to the treatment of pain in diabetic neuropathy. Recommendations for first, second and third line medications are based on specific evidence for the treatment of painful diabetic neuropathy as well as safety, tolerability, drug interactions and cost. Additional topics of discussion include breakthrough pain, opioid use and topical therapies. This review does not comprehensively discuss all possible treatments for painful neuropathy, but provides a systematic approach designed to guide clinicians in tailoring therapies to the individual patient. PMID- 21709807 TI - The Biological Implausibility of the Nature-Nurture Dichotomy & What It Means for the Study of Infancy. AB - Since the time of the Greeks, philosophers and scientists have wondered about the origins of structure and function. Plato proposed that the origins of structure and function lie in the organism's nature whereas Aristotle proposed that they lie in its nurture. This nature/nurture dichotomy and the emphasis on the origins question has had a powerful effect on our thinking about development right into modern times. Despite this, empirical findings from various branches of developmental science have made a compelling case that the nature/nurture dichotomy is biologically implausible and, thus, that a search for developmental origins must be replaced by research into developmental processes. This change in focus recognizes that development is an immensely complex, dynamic, embedded, interdependent, and probabilistic process and, therefore, renders simplistic questions such as whether a particular behavioral capacity is innate or acquired scientifically uninteresting. PMID- 21709809 TI - Host-Guest Interactions between Calixarenes and Cp(2)NbCl(2). AB - The possible inclusion complexes of Cp(2)NbCl(2) into calixarenes hosts have been investigated. The existence of a true inclusion complex in the solid state was confirmed by a combination of NMR, ab-initio calculations, thermogravimetric analysis, FTIR, Raman and PXRD. Ab-initio calculations, (1)H NMR solution and solid state (13)C CP MAS NMR results demonstrated that p-sulfonic calix[6]arene does form an inclusion complex with Cp(2)NbCl(2). Raman spectroscopy showed, for the inclusion compound of p-sulfonic calix[6]arene-Cp(2)NbCl(2), a band between 500-850 cm(-1) characteristic of Nb-O vibration. This result suggests that Nb(V) may engage in coordination with the oxygen of the sulfonate group, as part of the host-guest interaction. However, it is important to mention that the niobocene dichloride (Cp(2)NbCl(2)) dissolves in water and undergoes oxidation and hydrolysis processes to yield Cp(2)NbCl(2)(OH) species. For that reason this band does not exclude that the Nb-O band belongs to Cp(2)NbCl(2)(OH). Solid State (13)C CP MAS NMR and solution (1)H NMR spectroscopies together with ab-initio results showed that Cp(2)NbCl(2) is included in the p-sulfonic calix[6]arene cavity, with both Cp rings inside the cavity. In contrast, the solution (1)H NMR results demonstrated that calix[6]arene does not form inclusion complex with Cp(2)NbCl(2) in CDCl(3) solution. Cp(2)NbCl(2) is not included in the calix[6]arene cavity, possibly due to the lack of sulfonate heads which promote Nb-O interactions and assist the inclusion of Cp(2)NbCl(2) into the cavity. PMID- 21709808 TI - Effects of individual differences in verbal skills on eye-movement patterns during sentence reading. AB - This study is a large-scale exploration of the influence that individual reading skills exert on eye-movement behavior in sentence reading. Seventy one non college-bound 16-24 year-old speakers of English completed a battery of 18 verbal and cognitive skill assessments, and read a series of sentences as their eye movements were monitored. Statistical analyses were performed to establish what tests of reading abilities were predictive of eye-movement patterns across this population and how strong the effects were. We found that individual scores in rapid automatized naming and word identification tests (i) were the only participant variables with reliable predictivity throughout the time-course of reading; (ii) elicited effects that superceded in magnitude the effects of established predictors like word length or frequency; and (iii) strongly modulated the influence of word length and frequency on fixation times. We discuss implications of our findings for testing reading ability, as well as for research of eye-movements in reading. PMID- 21709810 TI - Optimizing eHealth breast cancer interventions: which types of eHealth services are effective? AB - Little is known about the effective elements of Interactive Cancer Communication Systems (ICCSs). A randomized trial explored which types of services of a multifaceted ICCS benefited patients and the nature of the benefit. Women with breast cancer (N=450) were randomized to different types of ICCS services or to a control condition that provided internet access. The Comprehensive Health Enhancement Support System (CHESS), served as the ICCS. ICCS services providing information and support, but not coaching such as cognitive behavior therapy, produced significant benefits in health information competence and emotional processing. Provision of Information and Support ICCS services significantly benefited women with breast cancer. More complex and interactive services designed to train the user had negligible effects. PMID- 21709811 TI - Double-Gyroid Network Morphology in Tapered Diblock Copolymers. AB - We report the formation of a double-gyroid network morphology in normal-tapered poly(isoprene-b-isoprene/styrene-b-styrene) [P(I-IS-S)] and inverse-tapered poly(isoprene-b- styrene/isoprene-b-styrene) [P(I-SI-S)] diblock copolymers. Our tapered diblock copolymers with overall poly(styrene) volume fractions of 0.65 (normal-tapered) and 0.67 (inverse-tapered), and tapered regions comprising 30 volume percent of the total polymer, were shown to self-assemble into the double gyroid network morphology through a combination of small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM). The block copolymers were synthesized by anionic polymerization, where the tapered region between the pure poly(isoprene) and poly(styrene) blocks was generated using a semi-batch feed with programmed syringe pumps. The overall composition of these tapered copolymers lies within the expected network-forming region for conventional poly(isoprene-b-styrene) [P(I-S)] diblock copolymers. Dynamic mechanical analysis (DMA) clearly demonstrated that the order-disorder transition temperatures (T(ODT)'s) of the network-forming tapered block copolymers were depressed when compared to the T(ODT) of their non-tapered counterpart, with the P(I-SI-S) showing the greater drop in T(ODT). These results indicate that it is possible to manipulate the copolymer composition profile between blocks in a diblock copolymer, allowing significant control over the T(ODT), while maintaining the ability to form complex network structures. PMID- 21709812 TI - Plasmonic enhanced emissions from cubic NaYF(4):Yb: Er/Tm nanophosphors. AB - A metal shell was used in this study to provide significant enhancement of the up converted emission from cubic NaYF(4) nanoparticles, creating a valuable composite material for labeling in biology and other applications - use of the cubic form of the material obviates the need to undertake a high temperature transformation to the naturally more efficient hexagonal phase. The NaYF(4) matrix contained ytterbium sensitizer and an Erbium (Er) or Thulium (Tm) activator. The particle sizes of the as-synthesized nanoparticles were in the range of 20-40 nm with a gold shell thickness of 4-8 nm. The gold shell was macroscopically amorphous. The synthesis method was based on a citrate chelation. In this approach, we exploited the ability of the citrate ion to act as a reductant and stabilizer. Confining the citrate ion reductant on the nanophosphor surface rather than in the solution was critical to the gold shell formation. The plasmonic shell enhanced the up-conversion emission of Tm from visible and near infrared regions by up to a factor of 8, in addition to imparting a visible color arising from the plasmon absorption of the gold shell. The up-conversion enhancement observed with Tm and Er were different for similar gold coverages, with local crystal field changes as a possible route to enhance up-conversion emission from high symmetry structural hosts. These novel up-converting nanophosphor particles combine the phosphor and features of a gold shell, providing a unique platform for many biological imaging and labeling applications. PMID- 21709813 TI - Unzipping of Double-stranded DNA in Engineered alpha-Hemolysin Pores. AB - Biological protein alpha-hemolysin nanopore is under intense investigation as a potential platform for rapid and low-cost DNA sequencing. However, due to its narrow constriction, analysis of DNA in the alpha-hemolysin pore has long time been restricted to single strands. In this paper, we report that by introducing new surface functional groups into the alpha-hemolysin pore, facilitated unzipping of double-stranded DNA through the channel could be achieved. Since the mean residence time of the DNA events is dependent on the length of the duplex, and also varies with the nucleotide base composition, the modified protein pore approach offers the potential for rapid double-stranded DNA analysis, including sequencing. PMID- 21709814 TI - Dose-Weighted Adjusted Mantel-Haenszel Tests for Numeric Scaled Strata in a Randomized Trial. AB - A recent three-arm parallel groups randomized clinical prevention trial had a protocol deviation causing participants to have fewer active doses of an in office treatment than planned. The original statistical analysis plan stipulated a minimal assumption randomization-based extended Mantel-Haenszel (EMH) trend test of the high frequency, low frequency, and zero frequency treatment groups and a binary outcome. Thus a dose-weighted adjusted EMH (DWAEMH) test was developed with an extra set of weights corresponding to the number of active doses actually available, in the spirit of a pattern mixture model. The method can easily be implemented using standard statistical software. A set of Monte Carlo simulations using a logistic model was undertaken with (and without) actual dose-response effects through 1000 replicates for empirical power estimates (and 2100 for empirical size). Results showed size was maintained and power was improved for DWAEMH versus EMH and logistic regression Wald tests in the presence of a dose effect and treatment by dose interaction. PMID- 21709815 TI - Seizures in Women with Preeclampsia: Mechanisms and Management. PMID- 21709816 TI - Maitotoxin: An Inspiration for Synthesis. AB - Maitotoxin holds a special place in the annals of natural products chemistry as the largest and most toxic secondary metabolite known to date. Its fascinating, ladder-like, polyether molecular structure and diverse spectrum of biological activities elicited keen interest from chemists and biologists who recognized its uniqueness and potential as a probe and inspiration for research in chemistry and biology. Synthetic studies in the area benefited from methodologies and strategies that were developed as part of chemical synthesis programs directed toward the total synthesis of some of the less complex members of the polyether marine biotoxin class, of which maitotoxin is the flagship. This account focuses on progress made in the authors' laboratories in the synthesis of large maitotoxin domains with emphasis on methodology development, strategy design, and structural comparisons of the synthesized molecules with the corresponding regions of the natural product. The article concludes with an overview of maitotoxin's biological profile and future perspectives. PMID- 21709818 TI - Fetal neurosurgery: current state of the art. AB - Congenital CNS abnormalities have been targets for prenatal intervention since the founding of fetal surgery 30 years ago, but with historically variable results. Open fetal neurosurgery for myelomenigocele has demonstrated the most promising results of any CNS malformation. Improvements in the understanding of congenital diseases and in fetal surgical techniques have reopened the door to applying fetal surgery to other congenital CNS abnormalities. Advances in gene therapy, bioengineering and neonatal neuroprotection will aid in the future expansion of fetal neurosurgery to other CNS disorders. PMID- 21709817 TI - Clinical epidemiology and pharmacology of CYP2D6 inhibition related to breast cancer outcomes. AB - Adjuvant tamoxifen therapy of breast cancer patients with estrogen receptor positive tumors reduces the rate of breast cancer recurrence by approximately a half. Tamoxifen is metabolized by several polymorphic enzymes, including cytochrome P450 2D6 (CYP2D6), to more active metabolites. We have reviewed the clinical pharmacology of tamoxifen and evaluated the evidence from clinical epidemiology studies regarding the association between CYP2D6 inhibition and tamoxifen effectiveness. We conclude that the impact of CYP2D6 inhibition on tamoxifen effectiveness is likely to be null or small, at least in the populations studied so far. Understanding the effect of variations in tamoxifen metabolism on breast cancer outcomes, if any, will likely require a broader perspective, including examination of the complete metabolic pathway and subgroups of patients with other markers of potentially poor tamoxifen response. PMID- 21709819 TI - Analysis of Histone Exchange during Chromatin Purification. AB - Central to the study of chromosome biology are techniques that permit the purification of small chromatin sections for analysis of associated DNA and proteins, including histones. Chromatin purification protocols vary greatly in the extent of chemical cross-linking used to prevent protein dissociation/re association during isolation. Particularly for genome-wide analyses, chromatin purification requires a balanced level of fixation that captures native protein protein and protein/DNA interactions, yet leaving chromatin sections soluble and accessible to affinity reagents. We have applied a relative quantification methodology called I-DIRT (isotopic differentiation of interactions as random or targeted) for optimizing levels of chemical cross-linking for affinity purification of cognate chromatin sections. We show that fine-tuning of chemical cross-linking is necessary for isolation of chromatin sections when minimal histone/protein exchange is required. PMID- 21709820 TI - Cognitive Pretesting and the Developmental Validity of Child Self-Report Instruments: Theory and Applications. AB - OBJECTIVE: In the context of the importance of valid self-report measures to research and evidence-based practice in social work, an argument-based approach to validity is presented and the concept of developmental validity introduced. Cognitive development theories are applied to the self-report process of children and cognitive pretesting is reviewed as a methodology to advance the validity of self-report instruments for children. An application of cognitive pretesting is presented in the development of the Elementary School Success Profile. METHOD: Two phases of cognitive pretesting were completed to gather data about how children read, interpret and answer self-report items. RESULTS: Cognitive pretesting procedures identified validity problems with numerous items leading to modifications. CONCLUSIONS: Cognitive pretesting framed by an argument-based approach to validity holds significant potential to improve the developmental validity of child self-report instruments. PMID- 21709821 TI - SOCIAL ENVIRONMENTAL RISK AND PROTECTION: A TYPOLOGY WITH IMPLICATIONS FOR PRACTICE IN ELEMENTARY SCHOOLS. AB - Social environmental assessments can play a critical role in prevention planning in schools. The purpose of this study was to describe the importance of conducting social environmental assessments, demonstrate that complex social environmental data can be simplified into a useful and valid typology, and illustrate how the typology can guide prevention planning in schools. Data collected from 532 3(rd) through 5(th) graders using the Elementary School Success Profile were analyzed in the study. A latent profile analysis based on eight child-report social environmental dimensions identified five patterns of social environmental risk and protection. The classes were labeled High Protection, Moderate Protection, Moderate Protection/Peer Risk, Little Protection/Family Risk, and No Protection//School Risk. Class membership was significantly associated with measures of well-being, social behavior and academic performance. The article illustrates how the typology can be used to guide decisions about who to target in school-based preventions, which features of the social environment to target, and how much change to seek. Information is provided about online resources for selecting prevention strategies once these decisions are made. PMID- 21709822 TI - Alternative Schooling Strategies and the Religious Lives of American Adolescents. AB - I analyze the effects of Catholic schooling, Protestant schooling, and homeschooling on adolescents' religious lives and test three mechanisms through which these schooling strategies might influence religiosity: friendship networks, network closure, and adult mentors. Data from Wave 1 of the National Survey of Youth and Religion suggest that Catholic schoolers attend religious services more frequently and value their faith more highly than public schoolers, but attend religious education classes and youth group less often. Protestant schoolers' involvement in their local congregation is similar to public schoolers', but their faith plays a more salient role in their life and they are more active in private religious activities. Homeschoolers do not differ significantly from public schoolers on any outcome considered. Moreover, friendship networks, network closure, and adult mentors play a very limited role in mediating the relationships between schooling strategies and adolescent religiosity. Interpretations of these findings are presented and discussed. PMID- 21709823 TI - KNOWLEDGE GAPS AMONG SCHOOL STAFF AND THE ROLE OF HIGH QUALITY ECOLOGICAL ASSESSMENTS IN SCHOOLS. AB - OBJECTIVE: The purpose of the current study was to examine the practice validity of a new ecological assessment instrument for 3(rd) through 5(th) graders in terms of whether it provided school staff with new knowledge about students. METHOD: Pre-assessment knowledge of school staff was compared to data obtained from 21 children and their parents on 29 measures. Data were collected using the Elementary School Success Profile (ESSP). School staff pre-assessment knowledge was compared to obtained data across seven domains of children's lives (neighborhood, school, family, peers, parent educational involvement, well-being, and home behavior), data sources (child and parent), and grade level of students. RESULTS: Pre-assessment knowledge was not highly correlated with obtained data; pre-assessment expectations matched obtained data only about 41% of the time; and knowledge varied by domain, source, and grade level. CONCLUSIONS: Ecological assessments can address gaps in school staff's knowledge of targetable factors that influence the success of students. PMID- 21709824 TI - NONLINEAR TUBE-FITTING FOR THE ANALYSIS OF ANATOMICAL AND FUNCTIONAL STRUCTURES. AB - We are concerned with the estimation of the exterior surface and interior summaries of tube-shaped anatomical structures. This interest is motivated by two distinct scientific goals, one dealing with the distribution of HIV microbicide in the colon and the other with measuring degradation in white-matter tracts in the brain. Our problem is posed as the estimation of the support of a distribution in three dimensions from a sample from that distribution, possibly measured with error. We propose a novel tube-fitting algorithm to construct such estimators. Further, we conduct a simulation study to aid in the choice of a key parameter of the algorithm, and we test our algorithm with validation study tailored to the motivating data sets. Finally, we apply the tube-fitting algorithm to a colon image produced by single photon emission computed tomography (SPECT) and to a white-matter tract image produced using diffusion tensor imaging (DTI). PMID- 21709825 TI - Beyond the Core: The Hot Topic(al) Alternative to the Survey-Based Introduction to Sociology Course. AB - In the following paper we argue that the conventional "Introduction to Sociology" survey course should be restructured because such courses try to survey an unsurveyable body of knowledge and they do not teach the application of sociological research. The conventional intro course should be replaced with an intro course that surveys the types of social dynamics that sociologists typically research and the methods they use to do so. We propose a semester-long intro course with four case study learning-units that are chosen for their coverage of the underlying sociological dynamics, methods, and core concepts. We contend that case study learning-units which concentrate on topical issues and core sociological concepts are better suited for an introduction course. PMID- 21709826 TI - Preeclampsia and the Anti-Angiogenic State. AB - Preeclampsia is a major cause of maternal and fetal morbidity and mortality worldwide, however, its etiology remains unclear. Abnormal placental angiogenesis during pregnancy resulting from high levels of anti-angiogenic factors, soluble Flt1 (sFlt1) and soluble endoglin (sEng), has been implicated in preeclampsia pathogenesis. Accumulating evidence also points to a role for these anti angiogenic proteins as serum biomarkers for the clinical diagnosis and prediction of preeclampsia. Uncovering the mechanisms of altered angiogenic factors in preeclampsia may also provide insights into novel preventive and therapeutic options. PMID- 21709827 TI - A Mild, Large-Scale Synthesis of 1,3-Cyclooctanedione: Expanding Access to Difluorinated Cyclooctyne for Copper-Free Click Chemistry. AB - We report the large-scale synthesis of 1,3-cyclooctanedione in five steps with 29% yield. This molecule is a synthetic precurser to difluorinated cyclooctyne, which participates in a bioorthogonal copper-free click reaction with azides. The final step demonstrates the first successful application of the Wacker-Tsuji oxidation to form a cyclic 1,3-dione. PMID- 21709828 TI - Diffuse cavernous haemangioma of the rectum and anus: an unusual case of rectal bleeding with challenging management. AB - Diffuse cavernous haemangioma of the rectum (DCHR) is an uncommon vascular pathology usually diagnosed in younger patients (5-25 years old) with painless, recurrent rectal bleeding. Here, an unusual case of an older patient with sigmoid adenocarcinoma and concomitant diffuse DCHR from the rectum to the distal edge of the anal canal is reported.The purpose of this article is to report this unusual case and to discuss pitfalls in diagnosis, preoperative assessment and treatment of DCHR. PMID- 21709829 TI - Surfers ankle: a bony spur of the talar neck. AB - A 27-year-old competitive surfer presented with a history of a painful right ankle. He was able to recall an injury to his right ankle 4-5 years previously, sustained while surfing. The mechanism described was that he had dropped a considerable height during take-off, sustaining an impact injury from the board. He recalled immediate pain and swelling followed by 2-3 weeks of pain and a limp; he continued to surf, albeit with difficulty, despite this.Investigations found him to have a bony spur on the anterolateral part of the talus. This case shows how this injury is similar to those observed in other sports. PMID- 21709830 TI - Subsequent bilateral thalamic haemorrhage. AB - Simultaneous or subsequent bilateral thalamic haemorrhage is rare, and most reported cases are from Asian countries. An 80-year-old white Cuban man, with a history of arterial hypertension, suffered sudden onset of right hemiparesis. Computed tomography (CT) scan showed a left posteromedial thalamic haemorrhage. Two days later his condition suddenly deteriorated: blood pressure was 220/105 mm Hg, he was stuporous and tetraplegic, respiration was ataxic, and his gaze was fixed and deviated downward and inward. CT scan showed haemorrhages in both thalami, extending to the ventricles. 32 h later the patient died. There are few previous publications of simultaneous or subsequent bilateral thalamic haemorrhages and this is the first report involving a Hispanic patient. Prognosis in patients with bilateral thalamic haemorrhage is poor, and the mechanism underlying the development of subsequent and symmetrical bleeding is not clear. PMID- 21709831 TI - Osseous ankylosis of the proximal and distal interphalangeal joints of a finger following a snakebite. AB - We present a previously unreported case of osseous ankylosis of both the proximal and distal interphalangeal joints of a finger, as a result of a snakebite. PMID- 21709832 TI - Chronic valproic acid intoxication: reversal by naloxone. AB - A 76-year-old woman being treated with sodium valproate for bipolar depression presented with a 4-day history of acute confusion and tremulousness. She had apnoeic episodes, a reduced conscious level and generalised myoclonic movements. Her plasma valproate concentration was 848 MUmol/litre (normal range 300-600 MUmol/litre). Administration of naloxone 0.8 mg led to rapid clinical improvement. Naloxone may be useful in reversing the features of chronic valproate toxicity. PMID- 21709834 TI - Measles: an adult case during a local outbreak. AB - A young man presented with a rash and febrile illness, which was initially diagnosed as a non-specific viral infection. As he became more unwell, however, his rash progressed and the diagnosis of measles was proposed, which was later confirmed by serology. He made a full recovery after supportive treatment. PMID- 21709833 TI - Venous air embolism through central venous access. AB - An 25-year-old man was buried by an avalanche during off-slope skiing. He was rescued by his companions and resuscitated by mouth-to-mouth ventilation. The emergency physician from a helicopter based emergency medical service placed two venous lines in both external jugular veins and secured the airway with a tracheal tube. When transferred to the emergency department an additional central venous catheter was inserted via his right femoral vein. The subsequent computed tomography scan revealed several small air bubbles adjacent to the endothelium of the brachiocephalic vein. In an experimental setting, it was shown that air could enter the circulation via a central venous catheter within a few seconds, but measured values of embolising air were smaller than the calculated values when applying the law of Hagen-Poiseuille. Nevertheless, it is important to keep the lumens of a central venous catheter filled with saline before any manipulation in order to prevent or attenuate venous air embolism. PMID- 21709835 TI - Antenatal diagnosis of fetal meconium peritonitis and decreased postnatal morbidity. PMID- 21709836 TI - Bleeding small bowel diverticulosis. AB - Diverticular disease affecting the small bowel, specifically the jejunum, is rare with an incidence of 1-2% in the general population. We report a case of a 67 year-old man who presented with clinical signs and symptoms suggesting peptic ulcer disease, but complications resulting from small bowel diverticular disease should be borne in mind as they may mimic the above pathology. The diagnosis of small bowel diverticulosis can often be challenging in someone who presents or develops massive gastrointestinal bleed, and in these cases a prompt diagnosis is of the utmost importance. The best line of treatment in these cases would be a laparascopic assisted exploration or an exploratory laparotomy with resection of the lesion and primary anastomosis. PMID- 21709837 TI - Aseptic spondylodiscitis in a patient with polymyalgia rheumatica. PMID- 21709841 TI - An unusual cause for fever of unknown origin in a patient with a prosthetic valve. AB - A case of Wegener granulomatosis as a cause for fever of unknown origin (FUO) and secondary involvement of endocardium in association with mitral valve prosthesis is presented. Although the patient was referred as a case of unresolving pneumonia, her unresponsiveness to broad spectrum antibiotics including infective endocarditis treatment prompted investigation for a non-infectious aetiology for her FUO, leading to a diagnosis of Wegener granulomatosis. PMID- 21709842 TI - Tauhyroid storm induced by trauma due to spear-fishing gun trident impaction in the neck. AB - A rare case of thyroid storm induced by thyroid gland injury because of penetrating neck trauma is reported. The injury was the result of a spear-fishing gun trident impaction in the neck. The diagnosis of thyroid gland injury was suspected by preoperative clinical examination and established during neck exploration in the theatre. The gland injury led to thyroid storm owing to the rupture of acini and liberation of thyroxine (T4) into the bloodstream. Withdrawal of the impacted trident along with subtotal thyroid lobectomy and repair of soft tissue damage in addition to supported treatments, which corrected the hyperthyroid state, led to uneventful recovery. PMID- 21709843 TI - Neonatal carnitine palmitoyltransferase II deficiency: failure of treatment despite prolonged survival. AB - Carnitine palmitoyltransferase (CPT) deficiencies are disorders of mitochondrial fatty acid oxidation (FAO). In fatty acid oxidation, long-chain fatty acids need the carnitine cycle to be transported from the cytosol to the mitochondria. In CPT II deficiency, long-chain acylcarnitines cannot be metabolised to carnitine and acyl-CoA, leading to accumulation of toxic long-chain acylcarnitines. Three clinical presentations of CPT II deficiency have been identified: the adult form, the infantile form and the neonatal form. The neonatal form of CPT II is the most severe and all reported patients died within a few days to 6 weeks after birth. The first case of a patient with neonatal CPT II deficiency surviving beyond the neonatal period is described. Unfortunately, the infant died at the age of 6 months due to untreatable cardiac arrhythmias. PMID- 21709844 TI - A case of Hashimoto encephalopathy in a Malay woman with Graves disease. AB - Hashimoto encephalopathy (HE) is a poorly recognised steroid-responsive encephalopathy, with prominent neuropsychiatric features. Diagnosis is often difficult due to its heterogeneous clinical presentation, especially since the thyroid status or anti-thyroid antibody titres may not be related to the disease state. Here, the case of a 23-year-old Malay woman with Graves disease who presented with progressive encephalopathy diagnosed as HE is presented. She responded dramatically to high dose intravenous and then oral corticosteroid. A month after the initiation of treatment, she regained full independency. PMID- 21709845 TI - Complete resolution of primary sclerosing peritonitis ("abdominal cocoon") following long term therapy for Tropheryma whipplei: a case report and review of literature. AB - A 53-year-old man was admitted to our internal medicine unit with intestinal obstruction and signs of systemic inflammatory disease. Clinical history was unremarkable until a few months earlier, when he began suffering from Achilles tendonitis. Diagnostic procedures, including laparotomy, revealed diffuse thickening of the peritoneum resembling sclerosing encapsulating peritonitis. Biopsies showed reactive fibrosis. No known secondary causes were found and surgery was technically not feasible. Clinical conditions worsened daily until, on the basis of the overall spectrum of clinical and radiological findings, Whipple's disease was hypothesised and specific therapy administered, with prompt clinical improvement. Complete disappearance of the cocoon was demonstrated at 1 year clinical/ultrasound/computed tomography follow-up. PMID- 21709846 TI - Look back in reverence. PMID- 21709848 TI - A common minimum programme needed in post-graduate training in psychiatry. PMID- 21709847 TI - Some Basic Considerations in the practice of Psychotherapy in the Indian setting. PMID- 21709849 TI - Principles of transactional analysis. AB - Transactional analysis is part of a comprehensive system of individual and social psychiatry. It offers an indigenous approach to group therapy by making maximum therapeutic use of the tmsactions which continually lake place between those present. These transactions are analyzed into exteropsychic, neopsychic and archaeopsychic components, called colloquially Parent, Adult and Child, respectively. These components manifest themselves as complete ego states which reproduce the ego states of parental figures or are autonomous, or are revivals of fixated archaic ego states from childhood.Patients are instructed in the principles of structural and transactional analysis through the use of the clinical material in the group proceedings. They can then proceed to the more advanced phases of game analysis and script analysis with the therapeutic goal of attaining social control. They are then able to conduct their relationships with others in an autonomous way at their own options, and are no longer victims of unconscious, uncontrolled compulsions to exploit or be exploited. PMID- 21709850 TI - Psychotropic drugs : what's in a name ? PMID- 21709851 TI - Fluoxetine induced acute dystonia. PMID- 21709853 TI - Non responsiveness to ect -- an additional pre-requisite for clozapine therapy. PMID- 21709852 TI - Towards greater integration with other medical specialities. PMID- 21709854 TI - Dr. Andrade replies. PMID- 21709855 TI - Poisson-Nernst-Planck Equations for Simulating Biomolecular Diffusion-Reaction Processes I: Finite Element Solutions. AB - In this paper we developed accurate finite element methods for solving 3-D Poisson-Nernst-Planck (PNP) equations with singular permanent charges for electrodiffusion in solvated biomolecular systems. The electrostatic Poisson equation was defined in the biomolecules and in the solvent, while the Nernst Planck equation was defined only in the solvent. We applied a stable regularization scheme to remove the singular component of the electrostatic potential induced by the permanent charges inside biomolecules, and formulated regular, well-posed PNP equations. An inexact-Newton method was used to solve the coupled nonlinear elliptic equations for the steady problems; while an Adams Bashforth-Crank-Nicolson method was devised for time integration for the unsteady electrodiffusion. We numerically investigated the conditioning of the stiffness matrices for the finite element approximations of the two formulations of the Nernst-Planck equation, and theoretically proved that the transformed formulation is always associated with an ill-conditioned stiffness matrix. We also studied the electroneutrality of the solution and its relation with the boundary conditions on the molecular surface, and concluded that a large net charge concentration is always present near the molecular surface due to the presence of multiple species of charged particles in the solution. The numerical methods are shown to be accurate and stable by various test problems, and are applicable to real large-scale biophysical electrodiffusion problems. PMID- 21709856 TI - Multi Groups Cooperation based Symbiotic Evolution for TSK-type Neuro-Fuzzy Systems Design. AB - In this paper, a TSK-type neuro-fuzzy system with multi groups cooperation based symbiotic evolution method (TNFS-MGCSE) is proposed. The TNFS-MGCSE is developed from symbiotic evolution. The symbiotic evolution is different from traditional GAs (genetic algorithms) that each chromosome in symbiotic evolution represents a rule of fuzzy model. The MGCSE is different from the traditional symbiotic evolution; with a population in MGCSE is divided to several groups. Each group formed by a set of chromosomes represents a fuzzy rule and cooperate with other groups to generate the better chromosomes by using the proposed cooperation based crossover strategy (CCS). In this paper, the proposed TNFS-MGCSE is used to evaluate by numerical examples (Mackey-Glass chaotic time series and sunspot number forecasting). The performance of the TNFS-MGCSE achieves excellently with other existing models in the simulations. PMID- 21709857 TI - FT-MIR and Raman spectroscopy coupled to multivariate analysis for the detection of clenbuterol in murine model. AB - A fast and simple screening method for the determination of clenbuterol at the ppb level in a murine model was demonstrated by Mid Infrared (MIR) and Raman spectroscopy in conjunction with multivariate analysis. In order to build the calibration models to quantify clenbuterol in rat meat, mixtures of rat meat and clenbuterol were prepared in a range of 5-10,000 ppb. Partial Least Square (PLS) analysis was used to build the calibration model. The results shown that Mid Infrared and Raman spectroscopy were efficient, but Mid Infrared (R(2) = 0.966 and SEC = 0.27) were superior to Raman (R(2) = 0.914 and SEC = 1.167). The SIMCA model developed showed 100% classification rate of rat meat samples with or without clenbuterol. The results were confirmed with contaminated meat samples from animals treated with clenbuterol. Chemometric models represent an attractive option for meat quality screening without sample pretreatments which can identify veterinary medicinal products at the ppb level. PMID- 21709858 TI - Green chemiluminescence from a bis-cyclometalated iridium(III) complex with an ancillary bathophenanthroline disulfonate ligand. AB - The reaction of a fluorinated iridium complex with cerium(IV) and organic reducing agents generates an intense emission with a significant hypsochromic shift compared to contemporary chemically-initiated luminescence from metal complexes. PMID- 21709859 TI - Live encapsulation of a Keggin polyanion in NH2-MIL-101(Al) observed by in situ time resolved X-ray scattering. AB - The templating effect of the Keggin polyanion derived from phosphotungstic acid (PTA) during the synthesis of NH(2)-MIL-101(Al) has been investigated by means of in situ SAXS/WAXS. Kinetic analysis and structural observations demonstrate that PTA acts as a nucleation site and that it stabilizes the precursor phase NH(2) MOF-235(Al). Surprisingly kinetics of formation are little changed. PMID- 21709860 TI - Negative photochromism of a TCF chromophore. AB - A novel negative photochromic compound has been designed and synthesized. The structure of the compound consists of a tricyanofuran (TCF) moiety and a quinoline moiety, bridged by a double bond. Upon irradiation with visible light, the neutral thermostable form of the compound quickly transforms to a cyclic zwitterionic form with over 90% conversion efficiency. PMID- 21709861 TI - An all-organic steroid-D-pi-A modular design drives ferroelectricity in supramolecular solids and nano-architectures at RT. AB - Confluence of a modular design approach and self-assembly with a 'steroid-D-pi-A' module generates spontaneous polarization in solids and for the first time in nano-architectures constituted from organogels, at room temperature (RT). PMID- 21709862 TI - Self-assembled monolayers of clamped oligo(phenylene-ethynylene-butadiynylene)s. AB - Rigid rod oligo(phenylene-ethynylene-butadiynylene)s (oPEBs), "half-rings" of two rigid rods connected via a molecular clamp unit, and shape-persistent macrocycles (cyclic "half-ring dimers") are synthesized and their self-assembled monolayers (SAMs) are investigated by scanning tunneling microscopy (STM) at the interface of 1,2,4-trichlorobenzene (TCB)/highly oriented pyrolytic graphite (HOPG). The results are important for the design of molecular building blocks for two dimensional nanoscale architectures on solid surfaces. PMID- 21709863 TI - Visible-light-driven surface reconstruction of mesoporous TiO2: toward visible light absorption and enhanced photocatalytic activities. AB - The surface structure of mesoporous TiO(2) is reconstructed via a visible-light driven reaction with benzyl alcohol molecules at mild, anaerobic conditions, which substantially extends its visible-light absorption and photocatalytic activities. PMID- 21709864 TI - Facile synthesis of hollow palladium/copper alloyed nanocubes for formic acid oxidation. AB - Hollow PdCu alloyed nanocubes were successfully synthesized by a novel one-pot template-free strategy through tuning the surface energy difference of the crystal planes by alloying. Compared with the solid nanoparticles, the hollow nanocubes exhibit superior electrocatalytic activity and stability for formic acid oxidation. PMID- 21709865 TI - Conformational effects, molecular orbitals, and reaction activities of bis(phthalocyaninato) lanthanum double-deckers: density functional theory calculations. AB - The conformational effects on the frontier molecular orbital energy and stability for reduced, neutral, and oxidized bis(phthalocyaninato) lanthanum double-deckers have been revealed on the basis of density functional theory calculations. Calculation results indicate that the frontier orbital coupling degree changes along with the molecular conformation of the double-decker compound, first decreasing along with the increase of rotation angle beta from 0 to 20 degrees and then increasing along with the increase of rotation angle beta from 20 to 45 degrees . In addition, the stability for the three forms of double-decker changes in the same order, but first increasing and then decreasing along with the change of the rotation angle beta in the range of 0 to 45 degrees with a rotation energy barrier of (31.3 +/- 3.1) kJ mol(-1) at 20 degrees . This reveals that the rotation of the two phthalocyanine rings for the reduced, neutral, and oxidized bis(phthalocyaninato) lanthanum double-deckers are able to occur at room temperature. Nevertheless, the superior coordination reaction activity of the neutral bis(phthalocyaninato) lanthanum double-decker complex over their reduced form in forming sandwich-type tris(phthalocyaninato) lanthanum triple-decker compounds has also been clearly clarified on the basis of comparative calculations on the Fukui function of [La(Pc)(2)] and [La(Pc)(2)](-) using the DFT method. Fukui function analysis reveals the reaction center of the 18 electron-pi-conjugated core in the bis(phthalocyaninato) lanthanum double-decker molecule against both electrophilic and radical attack. Nevertheless, the larger global chemical softness (S) for the neutral [La(Pc)(2)] than the reduced form [La(Pc)(2)](-) indicates the higher reaction activity of the former form over the latter one. This explains well the experimental findings that only the neutral instead of the reduced form of bis(tetrapyrrole) rare earth double-decker complexes, containing at least one phthalocyanine ligand, could be employed as starting materials towards the preparation of tris(tetrapyrrole) rare earth triple-decker complexes by a solution process. PMID- 21709866 TI - Protein stability in an ionic liquid milieu: on the use of differential scanning fluorimetry. AB - Protein stability is a major bottleneck in the biotechnological application of ionic liquid-containing solvents, either in the frame of biocatalysis or protein storage. Herein, differential scanning fluorimetry was successfully implemented as a high throughput method to fast scan the impact of a number of cholinium based ionic liquids on the stability of proteins. PMID- 21709867 TI - A new highly adaptable design of shear-flow device for orientation of macromolecules for Linear Dichroism (LD) measurement. AB - This article presents a new design of flow-orientation device for the study of bio-macromolecules, including DNA and protein complexes, as well as aggregates such as amyloid fibrils and liposome membranes, using Linear Dichroism (LD) spectroscopy. The design provides a number of technical advantages that should make the device inexpensive to manufacture, easier to use and more reliable than existing techniques. The degree of orientation achieved is of the same order of magnitude as that of the commonly used concentric cylinders Couette flow cell, however, since the device exploits a set of flat strain-free quartz plates, a number of problems associated with refraction and birefringence of light are eliminated, increasing the sensitivity and accuracy of measurement. The device provides similar shear rates to those of the Couette cell but is superior in that the shear rate is constant across the gap. Other major advantages of the design is the possibility to change parts and vary sample volume and path length easily and at a low cost. PMID- 21709868 TI - Using liquid crystals as a readout system in urinary albumin assays. AB - Detecting human serum albumin (HSA) in urine samples is a standard procedure for the diagnosis of kidney problems and the prognosis of patients with chronic kidney diseases (CKDs). In this study, we developed a HSA assay by incorporating a thin layer of liquid crystals (LCs) as a readout system such that the presence of HSA in urine samples can be detected as optical signals. In combination with dilution protocols, this assay can be used to estimate the concentration range of HSA simply by counting the number of bright spots. Our results show that the assay can detect HSA at concentrations as low as 15 MUg mL(-1). It is anticipated that this assay can provide a faster and simpler alternative for the diagnosis and prognosis of patients with kidney diseases. PMID- 21709869 TI - Nonionic diethanolamide amphiphiles with unsaturated C18 hydrocarbon chains: thermotropic and lyotropic liquid crystalline phase behavior. AB - The neat and lyotropic liquid crystalline phase behavior of three nonionic diethanolamide amphiphiles with C18 hydrocarbon chains containing one, two or three unsaturated bonds has been examined. This has allowed the effect of degree of unsaturation on the phase behavior of diethanolamide amphiphiles to be investigated. Neat linoleoyl and linolenoyl diethanolamide undergo a transition from a glassy liquid crystal to a liquid crystal at ~-85 degrees C, while neat oleoyl diethanolamide undergoes a transition at ~-60 degrees C to a liquid crystalline material before re-crystallizing at -34 degrees C. Oleoyl diethanolamide then undergoes a third transition from a crystalline phase to a smectic liquid crystalline phase at ~5 degrees C. In the absence of water, the transition temperature from a smectic liquid crystal to an isotropic liquid decreases with increasing unsaturation. The addition of water results in the formation of a lamellar phase (L(alpha)) for all three amphiphiles. The lamellar phase is stable under excess water conditions up to temperatures of at least 70 degrees C. Approximate partial binary amphiphile-water phase diagrams generated for the three unsaturated C18 amphiphiles indicate that the excess water point for each amphiphile occurs at ~60% (w/w) amphiphile. PMID- 21709870 TI - Conformational behaviour, hydrogen bond competition and intramolecular dynamics in vanillin derivatives: acetovanillone and 6-hydroxy-3-methoxyacetophenone. AB - The conformational landscape of the structural isomers acetovanillone (apocynin, AV) and 6-hydroxy-3-methoxyacetophenone (HMAP) has been investigated in a supersonic jet using Fourier transform microwave spectroscopy. Two conformers have been detected in the jet-cooled expansion for each molecule (s-cis and s trans in AV; s-trans and a-trans for HMAP), differing in the relative orientation of the acetyl and methoxy groups. Both molecules are stabilized by O-H...O or O H...O=C hydroxyl intramolecular hydrogen bonds, either constraining the local conformations of the methoxy group in AV, or that of the acetyl group in HMAP. Internal rotation splittings have been observed in both conformers of each molecule, originated by the acetyl group, that yield information on the influence of the intramolecular hydrogen bonds on the methyl torsion. The similar internal rotation barriers in both molecules (6.6 and 7.4 kJ mol(-1) in AV; 7.3 and 7.0 kJ mol(-1) in HMAP) suggest that the acetyl torsion is only slightly affected by intramolecular hydrogen bonding. The absence of torsional tunnellings due to the methoxy group indicates torsional barriers above 10.2 and 8.9 kJ mol(-1) for AV conformers, 10.1 and 10.4 kJ mol(-1) for HMAP. Conformational ratios and relative free energies have been estimated from relative intensity measurements of the spectral lines. Ab initio (MP2) and density functional calculations using the recent M05-2X empirical functional have been used to aid the experimental work in describing the structures, internal rotation barriers and isomerization potentials. PMID- 21709871 TI - Fabrication of multi-structure nanocarbons from carbon xerogel: a unique scaffold towards bio-imaging. AB - A novel route has been developed to fabricate different carbon nanostructures having individual morphology of carbon nanoparticles: nanofullerene, nanocube, nanoleaf and porous nanorods, through the combustion of carbon xerogel with nitric acid. These fabricated nanostructures exhibited bright green fluorescence under the exposure of UV light. PMID- 21709872 TI - Layer inversion in organic heterostructures. AB - Thermally activated layer inversion of ultrathin pentacene/para-sexiphenyl organic heterostructures is observed using a combination of reflectance difference spectroscopy and scanning tunneling microscopy. The heterostructures are formed by deposition of sub-monolayer pentacene (PEN) on top of well ordered para-sexiphenyl (p-6P) layers on Cu(110) at 15 K. When the sample temperature is raised, these heterostructures invert, with pentacene molecules diffusing through the para-sexiphenyl buffer layer and getting in direct contact with the substrate. The observed irreversible inversion demonstrates that the p 6P/PEN/Cu(110) is energetically preferred over PEN/p-6P/Cu(110). Furthermore, the onset temperature of the inversion increases with the layer thickness of para sexiphenyl indicating a corresponding increase of the kinetic barrier for the inversion. Our results demonstrate the strong influence of the configuration of organic heterostructures on their thermal stability, especially for the very thin layers. PMID- 21709873 TI - Enhancement of green-light photoluminescence of Ta2O5 nanoblock stacks. AB - In this study we have explored the structural, electronic, and photoluminescence (PL) properties of Ta(2)O(5) nanoblock stacks. The Ta(2)O(5) nanoblocks were synthesized by the hot filament metal-oxide vapor deposition (HFMOVD) technique and randomly arranged in large-area stacks. Field-emission scanning electron microscopy (FESEM) showed most of the stacking Ta(2)O(5) nanoblocks to be 21 nm wide. Energy dispersive spectroscopy (EDS) analysis verified the presence of only the elements Ta and O. X-Ray photoemission spectroscopy (XPS) not only revealed the electronic structures and chemical properties of the stacking Ta(2)O(5) nanoblocks but also their stoichiometric Ta/O ratio of ~0.416 (i.e. Ta:O = 2.08 : 5). Photoluminescence (PL) spectroscopy showed very strong green-light emissions, which emerged from the trap-levels of the oxygen vacancies within the Ta(2)O(5) bandgap. The PL intensities were linearly enhanced by increasing the laser power and the excitation time. The PL results suggest that the nanoblocks are excellent visible-light emitters. PMID- 21709874 TI - Proton transport properties in an ionic liquid having a hydroxyl group. AB - An ionic liquid having a hydroxyl group, choline bis(trifluoromethylsulfonyl)amide ([N(111(2OH))][N(Tf)(2)]), was synthesized to investigate the effect of hydroxyl groups on the proton transport. 1,1,1 Trifluoro-N-(trifluoromethylsulfonyl)methanesulfoneamide (HN(Tf)(2)) as a proton source was mixed with the choline derivative at various molar ratios. Their thermal properties, viscosities, and ionic conductivities were investigated. [N(111(2OH))][N(Tf)(2)] showed a melting point at 27 degrees C, and its thermal stability was higher than 400 degrees C. The viscosity of [N(111(2OH))][N(Tf)(2)]/HN(Tf)(2) mixtures increased as the acid molar fraction increased. The ionic conductivity of [N(111(2OH))][N(Tf)(2)] was 2.1 * 10(-3) S cm(-1) at 25 degrees C; the ionic conductivity monotonously decreased as the acid molar fraction increased. There was a clear correlation between the ionic conductivity and the viscosity for the mixtures of the choline derivative and the acid. PFG-NMR measurements were carried out to investigate the diffusion behavior of protons. Although the acid and the hydroxyl group were indistinguishable by (1)H NMR, the self-diffusion coefficient of the (1)H of the hydroxyl group and the acid was larger than those of other (1)H nuclei. This difference suggests that a fast intermolecular proton transfer exists between the hydroxyl group and the acid. PMID- 21709875 TI - Combined reflection and transmission microscope for telemedicine applications in field settings. AB - We demonstrate a field-portable upright and inverted microscope that can image specimens in both reflection and transmission modes. This compact and cost effective dual-mode microscope weighs only ~135 grams (<4.8 ounces) and utilizes a simple light emitting diode (LED) to illuminate the sample of interest using a beam-splitter cube that is positioned above the object plane. This LED illumination is then partially reflected from the sample to be collected by two lenses, creating a reflection image of the specimen onto an opto-electronic sensor-array that is positioned above the beam-splitter cube. In addition to this, the illumination beam is also partially transmitted through the same specimen, which then casts lensfree in-line holograms of the same objects onto a second opto-electronic sensor-array that is positioned underneath the beam splitter cube. By rapid digital reconstruction of the acquired lensfree holograms, transmission images (both phase and amplitude) of the same specimen are also created. We tested the performance of this field-portable microscope by imaging various micro-particles, blood smears as well as a histopathology slide corresponding to skin tissue. Being compact, light-weight and cost-effective, this combined reflection and transmission microscope might especially be useful for telemedicine applications in resource limited settings. PMID- 21709876 TI - Diverse macroporous spheres synthesized by multiple emulsion polymerization for protein analyses. AB - Hydrophilic and hydrophobic spheres (1-2 mm) with macropores (50 MUm) were synthesized by SDS stabilized O/W/O and W/O/W emulsion polymerization, respectively. The hydrophilic spheres were functionalized with trypsin for protein digestion and on-line integrated with the hydrophobic spheres for the subsequent sample clean-up and enrichment with almost no back pressure. PMID- 21709877 TI - Top-down fabrication of crystalline metal-organic framework nanosheets. AB - Crystalline metal-organic framework (MOF) nanosheets have been fabricated via top down delamination from bulk crystals of a layered MOF, {Zn(TPA)(H(2)O).DMF}(n) (MOF-2), and characterized by Tyndall scattering, scanning electron microscopy and atomic force microscopy measurements. The delaminated MOF-2 nanosheets exhibit remarkable amine intercalation property and reversible amine exchangeability. PMID- 21709878 TI - Plasma-electrolysis synthesis of TiO2 nano/microspheres with optical absorption extended into the infra-red region. AB - A novel plasma-electrolysis method is introduced to synthesize high-quality TiO(2) nano/microspheres that exhibited excellent optical absorption covering the range from ultraviolet to infra-red. Both experimental and theoretical results show that the oxygen vacancies in the TiO(2) spheres are primarily responsible for this wide absorption. PMID- 21709879 TI - Design of a reversible biotin analog and applications in protein labeling, detection, and isolation. AB - To expand the applicability of the biotin-(strept)avidin system, a biotin analog with reversible binding under non-denaturing conditions has been designed, and its applications in protein labeling, detection, and isolation have been evaluated. PMID- 21709880 TI - Chiral N-heterocyclic carbene catalyzed annulation of alpha,beta-unsaturated aldehydes with 1,3-dicarbonyls. AB - Chiral N-heterocyclic carbene catalyzed annulations of ynals and enals with 1,3 dicarbonyls have been described. The two reactions provided direct and efficient methods for enantioselective synthesis of functionalized dihydropyranones. Comparatively, the reactions starting from ynals were atom-economical; furthermore the reactions of enals demonstrated broader substrate compatibility. PMID- 21709881 TI - Three-dimensional continuous particle focusing in a microfluidic channel via standing surface acoustic waves (SSAW). AB - Three-dimensional (3D) continuous microparticle focusing has been achieved in a single-layer polydimethylsiloxane (PDMS) microfluidic channel using a standing surface acoustic wave (SSAW). The SSAW was generated by the interference of two identical surface acoustic waves (SAWs) created by two parallel interdigital transducers (IDTs) on a piezoelectric substrate with a microchannel precisely bonded between them. To understand the working principle of the SSAW-based 3D focusing and investigate the position of the focal point, we computed longitudinal waves, generated by the SAWs and radiated into the fluid media from opposite sides of the microchannel, and the resultant pressure and velocity fields due to the interference and reflection of the longitudinal waves. Simulation results predict the existence of a focusing point which is in good agreement with our experimental observations. Compared with other 3D focusing techniques, this method is non-invasive, robust, energy-efficient, easy to implement, and applicable to nearly all types of microparticles. PMID- 21709882 TI - Organogel formation rationalized by Hansen solubility parameters. AB - Some organic compounds gelate particular solvents by forming a network of anisotropic fibres. We show that Hansen solubility parameters can be used to predict the range of solvents that are likely to be gelled by any given gelator. PMID- 21709891 TI - Novel self-crosslinked poly(aryl ether sulfone) for high alkaline stable and fuel resistant alkaline anion exchange membranes. AB - Novel self-crosslinked alkaline anion exchange membranes with high alkaline stability, excellent dimensional stability and extraordinary methanol resistance were synthesized successfully without using any catalyst or a separate crosslinker. PMID- 21709892 TI - Unprecedented incorporation of alpha-emitter radioisotope 213Bi into porphyrin chelates with reference to a daughter isotope mediated assistance mechanism. AB - For the first time, alpha-emitter radioisotope (213)Bi has been incorporated into porphyrin chelates, with rates matching with the short period of the radionuclide. An in situ transmetalation mechanism involving the daughter isotope (209)Pb is expected to boost the (213)Bi radiolabeling process. PMID- 21709893 TI - Multi-responsive copolymers: using thermo-, light- and redox stimuli as three independent inputs towards polymeric information processing. AB - We report on triple responsive polymers, exhibiting a distinct and reversible lower critical solution temperature in water that can be altered by light and redox stimuli, and we suggest their evaluation for molecular information processing. PMID- 21709894 TI - Synthesis and structure of all-syn-1,2,3,4-tetrafluorocyclohexane. AB - Preparation of the all-syn isomer of 1,2,3,4-tetrafluorocyclohexane is reported; X-ray structural studies shows a conformation with two of the C-F bonds oriented 1,3-diaxial to each other and (19)F-NMR reveals a through space diaxial (4)J(FF) coupling constant of 29 Hz. PMID- 21709896 TI - Temperature-dependent intensity anomalies in amino acid esters: weak hydrogen bonds in protected glycine, alanine and valine. AB - Esters of glycine, alanine and valine are investigated by FTIR and Raman spectroscopy in supersonic jets as gas phase model systems for the neutral peptide N-terminus. The NH-stretching vibrations exhibit very large temperature- and substitution-dependent intensity anomalies which are related to weak, bifurcated intramolecular hydrogen bonds to the carbonyl group. Comparison to theory is only satisfactory at low temperature. Spectral NH aggregation shifts are small or even negligible and the associated IR intensity is remarkably low. In the case of valine, chirality recognition effects are nevertheless detected and rationalized. Comparison to quantum-chemical calculations for dimers shows that dispersion interactions are essential. It also rules out cooperative hydrogen bond topologies and points at deficiencies in standard harmonic treatments with the linear dipole approximation. PMID- 21709895 TI - Electrochemical reduction of O2 in 1-butyl-1-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide ionic liquid containing Zn2+ cations: deposition of non-polar oriented ZnO nanocrystalline films. AB - The influence of the Zn(2+) concentration and temperature on the electrochemical reduction of O(2) in a solution of zinc bis(trifluoromethanesulfonyl)imide (Zn(TFSI)(2)) salt in 1-butyl-1-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide (PYR(14)TFSI) ionic liquid is presented. ZnO nanocrystalline films were then electrodeposited, under enhanced O(2) reduction, at temperatures in the 75-150 degrees C range. Their morphology, chemical composition, structural and optical properties were analyzed. In contrast to the polar-oriented ZnO usually obtained from aqueous and conventional solvent based electrolytes, nanocrystalline films oriented along non-polar directions, (11 10) and (11 20), were obtained from this ionic liquid electrolyte. A significant content of carbon was detected in the films, pointing to the active participation and crucial effect of pyrrolidinium cation (and/or byproducts) during the electrodeposition. The films showed semiconducting behavior with an optical gap between 3.43 and 3.53 eV as measured by optical transmittance. Their room temperature photoluminescence spectra exhibited two different bands centered at ~3.4 and ~2.2 eV. The intensity ratio between both bands was found to depend on the deposition temperature. This work demonstrates the great potential of ionic liquids based electrolytes for the electrodeposition of ZnO nanocrystalline thin films with innovative microstructural and optoelectronic properties. PMID- 21709897 TI - Magnetic isotope effect and theory of atomic orbital hybridization to predict a mechanism of chemical exchange reactions. AB - A novel approach is suggested to investigate the mechanisms of chemical complexation reactions based on the results of Fujii with co-workers; they have experimentally observed that several metals and metalloids demonstrate mass independent isotope fractionation during the reactions with the DC18C6 crown ether using solvent-solvent extraction. In this manuscript, the isotope fractionation caused by the magnetic isotope effect is used to understand the mechanisms of chemical exchange reactions. Due to the rule that reactions are allowed for certain electron spin states, and forbidden for others, magnetic isotopes show chemical anomalies during these reactions. Mass-independent fractionation is suggested to take place due to the hyperfine interaction of the nuclear spin with the electron spin of the intermediate product. Moreover, the sign of the mass-independent fractionation is found to be dependent on the element and its species, which is also explained by the magnetic isotope effect. For example, highly negative mass-independent isotope fractionation of magnetic isotopes was observed for reactions of DC18C6 with SnCl(2) species and with several Ru(III) chloro-species, and highly positive for reactions of this ether with TeCl(6)(2-), and with several Cd(II) and Pd(II) species. The atomic radius of an element is also a critical parameter for the reaction with crown ether, particularly the element ions with [Kr]4d(n)5s(m) electron shell fits the best with the DC18C6 crown ring. It is demonstrated that the magnetic isotope effect in combination with the theory of orbital hybridization can help to understand the mechanism of complexation reactions. The suggested approach is also applied to explain previously published mass-independent fractionation of Hg isotopes in other types of chemical exchange reactions. PMID- 21709899 TI - Laws of thermal diffusion of individual molecules on the gold surface. AB - By molecular dynamics simulations, we describe and discuss the mobility of single molecules on a metal surface. The calculated trajectories of 28 different molecules show that diffusion, subdiffusion and superdiffusion regimes exist. The trajectories also share some common features, which are expressed in the form of power laws that link the length of the path walked by the molecule, the molecular mass, and the surface-molecule interaction energy. The values of the exponents of the laws are easily rationalized and provide insight into the molecular behaviour on the surface. The calculations also show that the adsorption is governed by the combination of van der Waals and Coulomb molecule-surface interactions. PMID- 21709898 TI - Nuclear spin relaxation due to chemical shift anisotropy of gas-phase 129Xe. AB - Nuclear spin relaxation provides detailed dynamical information on molecular systems and materials. Here, first-principles modeling of the chemical shift anisotropy (CSA) relaxation time for the prototypic monoatomic (129)Xe gas is carried out, both complementing and predicting the results of NMR measurements. Our approach is based on molecular dynamics simulations combined with pre parametrized ab initio binary nuclear shielding tensors, an "NMR force field". By using the Redfield relaxation formalism, the simulated CSA time correlation functions lead to spectral density functions that, for the first time, quantitatively determine the experimental spin-lattice relaxation times T(1). The quality requirements on both the Xe-Xe interaction potential and binary shielding tensor are investigated in the context of CSA T(1). Persistent dimers Xe(2) are found to be responsible for the CSA relaxation mechanism in the low-density limit of the gas, completely in line with the earlier experimental findings. PMID- 21709900 TI - Thermal decay of TEMPO in acidic media via an N-oxoammonium salt intermediate. AB - Disproportionation of TEMPO in acids leads to the formation of an N-oxoammonium salt, which can further decompose under thermal conditions, yielding the corresponding hydroxylamine, N(2)O, CO(2) and a series of dimerisation products. Overall, acid-catalysed thermal decay of TEMPO leads to ca. 80% yield of hydroxylamine. PMID- 21709901 TI - Cobalt(II)-catalyzed asymmetric hydrosilylation of simple ketones using dipyridylphosphine ligands in air. AB - In the presence of PhSiH(3) as the hydride donor, catalytic amounts of non racemic dipyridylphosphine and an easy-to-handle cobalt salt Co(OAc)(2).4H(2)O formed in situ an effective catalyst system for the asymmetric reduction of a diverse range of aryl alkyl ketones with moderate-to-excellent enantioselectivities (up to 96% ee). This approach tolerated the handling of both catalyst and reactants under air without special precautions. PMID- 21709902 TI - Functionalized 3(2H)-furanones via photooxygenation of (beta-keto)-2-substituted furans: application to the biomimetic synthesis of merrekentrone C. AB - Photooxygenation of (beta-keto)-2-substituted furans leads, in a one pot operation, to functionalized 3(2H)-furanones with good to excellent yields. This methodology was applied as a key-step to the concise and biomimetic synthesis of the sesquiterpene merrekentrone C. The precursor to merrekentrone C, keto difuran, was synthesized using a cross coupling of alpha-iodo-3-acetylfuran with an alkenyl furan under Fenton-type conditions. PMID- 21709903 TI - Janus-type AT nucleosides: synthesis, solid and solution state structures. AB - Novel Janus-type nucleoside analogues (1a-d) were synthesized. Their pyrimido[4,5 d]pyrimidine base moiety has one face with a bidentate Watson-Crick donor acceptor (DA) H-bond array of adenine and the other face with an acceptor-donor (AD) H-bond array of thymine. These nucleosides may self-associate through the self-complementary base pair. Indeed, in the solid state, compound 6d displayed a honeycomb-like supramolecular structure with tetrameric membered cavities formed through the combination of reverse Watson-Crick base pairs and aromatic stacking, in which the solvent molecules were accommodated. The result of temperature dependent CD studies showed that the free nucleosides can form higher order chiral structures in aqueous solution. PMID- 21709904 TI - Understanding hydration of Zn2+ in hydrothermal fluids with ab initio molecular dynamics. AB - With ab initio molecular dynamics simulations, the free-energy profiles of hydrated Zn(2+) are calculated for both gaseous and aqueous systems from ambient to supercritical conditions, and from the derived free-energy information, the speciation of hydrated Zn(2+) has been revealed. It is shown that the 4, 5 and 6 fold complexes coexist in both phases at ambient condition. As T-P increases a clear trend is found for both phases: the 6 fold states gradually become unstable and cannot exist stably any more over 620 K, but in contrast, the 4 and 5 fold states can hold up to 1000 K with similar probabilities. It is found that the stability of the 4 and 5 fold states has an entropic origin. This study constitutes a relatively complete speciation picture for aqua-zinc complexes over a broad T-P range. PMID- 21709905 TI - Full emission color tuning in luminogens constructed from tetraphenylethene, benzo-2,1,3-thiadiazole and thiophene building blocks. AB - Full color luminogens are constructed from tetraphenylethene, benzo-2,1,3 thiadiazole and thiophene building blocks. OLED fabricated using one of the luminogens exhibits orange-red electroluminescence with high luminance and efficiencies of 8330 cd m(-2), 6.1 cd A(-1) and 3.1%, respectively. PMID- 21709906 TI - Strong halogen bonding of 1,2-diiodoperfluoroethane and 1,6-diiodoperfluorohexane with halide anions revealed by UV-Vis, FT-IR, NMR spectroscopes and crystallography. AB - The spectroscopic methods UV-Vis absorption, FT-IR and (13)C and (19)F NMR demonstrate that 1,2-diiodoperfluoroethane (DIPFE) and 1,6-diiodoperfluorohexane (DIPFH) display strong halogen bonding with halide anions. A 1 : 1 stoichiometry of DIPFE or DIPFH with halide anion is confirmed, and the bonding constants and molar extinction coefficients are obtained. With the same halide, DIPFH possesses greater bonding constants and molar extinction coefficients than DIPFE. Furthermore, the bonding constants present in this article are far greater than those of all halogen bonding complexes reported. Interestingly, the FT-IR spectrum indicates that halogen bonding promotes a conversion from gauche to trans conformer of DIPFE. The X-ray data further confirm a 1 : 1 stoichiometry and all DIPFE and DIPFH exist in trans conformers in cocrystals which were assembled with halide anions. As potential persistent organic pollutions, iodinated perfluoroalkanes have been paid much attention. The present study will benefit current research of their separation and recognition in environmental samples. PMID- 21709907 TI - Tuning the electrical transport properties of n-type CdS nanowires via Ga doping and their nano-optoelectronic applications. AB - Gallium-doped n-type CdS nanowires (NWs) were successfully synthesized via a thermal evaporation method. The conductivities of the CdS NWs were dramatically improved by nearly nine orders of magnitude after Ga doping, and could be further tuned over a wide range by adjusting the doping level. High-performance metal insulator-semiconductor field-effect transistors (MISFETs) were constructed based on the single CdS : Ga NW with high-kappa Si(3)N(4) dielectrics and top-gate geometries. In contrast to back-gate FETs, the MISFETs revealed a substantial improvement in device performance. Nano-light emitting diodes (nanoLEDs) were fabricated from the CdS : Ga NWs by using a n-NW/p(+)-Si substrate hybrid device structure. The nanoLEDs showed a bright yellow emission at a low forward bias. It is expected that the Ga-doped CdS NWs with controlled electrical transport properties will have important applications in nano-optoelectronic devices. PMID- 21709908 TI - A tetrapyridine ligand with a rigid tetrahedral core forms metal-organic frameworks with PtS type architecture. AB - A new tetradentate, pyridine ligand with a rigid tetrahedral core can be prepared in good yield by a cross-coupling methodology. Two metal organic framework structures of Cu(II) with PtS-type topology having a carbon atom as the tetrahedral node have been characterized utilising this ligand. PMID- 21709909 TI - From attraction to repulsion: anion-pi interactions between bromide and fluorinated phenyl groups. AB - Anion-pi interactions in crystals of fluorobenzyl ammonium salts depend on the degree of fluorination at the aromatics. PMID- 21709910 TI - Microencapsulation using an oil-in-water-in-air 'dry water emulsion'. AB - We describe the first example of a tri-phasic oil-in-water-in-air 'dry water emulsion'. The method combines highly stable oil-in-water emulsions prepared using branched copolymer surfactants, with aqueous droplet encapsulation using 'dry water' technology. PMID- 21709912 TI - The charging of the carbon nanotube/oligothiophene interphase as studied by in situ electron spin resonance/UV-Vis-NIR spectroelectrochemistry. AB - A detailed in situ Electron Spin Resonance (ESR)/UV-Vis-NIR spectroelectrochemical study of the oligothiophene/single walled carbon nanotube (SWCNT) interphase is presented to provide an insight into the interaction of nanotubes with oligothiophenes. Used as electrode materials these composites are followed in situ with respect to the paramagnetic and diamagnetic states formed upon electrochemical charging. The variation of the oligomer chain length and the type, position and number of substituents at the oligomer is used to understand the structural influence on the formation of the charged states in the material upon electrochemical reaction. For beta,beta'-dihexylsexithiophene (beta,beta' DHST)-SWCNT the enlarged current in the composite and a decreased radical cation concentration can be explained by the formation of pi-dimers. By interaction with SWCNTs the pi-dimerization of oligothiophenes and the formation of multi pi-stack structures occur. For alpha,omega-dicyano-beta,beta'-dibutylquaterthiophene (DCNDBQT)-SWCNT a new paramagnetic structure of the oligomer is formed as an intermediate which undergoes follow-up reactions. Using different substituted oligothiophenes their interaction with nanotubes can be understood with respect to the structure of the oligomer. PMID- 21709911 TI - Ethanol and water adsorption in methanol-derived ZIF-71. AB - A room temperature method for synthesizing zeolitic imidizolate framework 71 (ZIF 71) is described. The methanol-based synthesis results in >95% yields (based on Zn) and produces crystals with 70% greater surface area than reported earlier. Ethanol uptake into the ZIF compares favorably with a recent modeling-based study. Water uptake was significantly higher than model predictions. PMID- 21709913 TI - Structure-activity relationships in group 3 metal catalysts for asymmetric intramolecular alkene hydroamination. An investigation of ligands based on the axially chiral 1,1'-binaphthyl-2,2'-diamine motif. AB - From a series of N,N'-disubstituted-1,1'-binaphthyl-2,2'-diamines, several group 3 metal complexes were synthesized via an in situ procedure. These chiral complexes were subsequently applied to catalysis of intramolecular alkene hydroamination. Significant structure-activity relationships were observed, most notably a reversal of stereoselectivity for cyclopentyl versus diphenylmethyl substituents. PMID- 21709915 TI - Lithography. PMID- 21709914 TI - Integrated microfluidic array plate (iMAP) for cellular and molecular analysis. AB - Just as the Petri dish has been invaluable to the evolution of biomedical science in the last 100 years, microfluidic cell assay platforms have the potential to change significantly the way modern biology and clinical science are performed. However, an evolutionary process of creating an efficient microfluidic array for many different bioassays is necessary. Specifically for a complete view of a cell response it is essential to incorporate cytotoxic, protein and gene analysis on a single system. Here we present a novel cellular and molecular analysis platform, which allows access to gene expression, protein immunoassay, and cytotoxicity information in parallel. It is realized by an integrated microfluidic array plate (iMAP). The iMAP enables sample processing of cells, perfusion based cell culture, effective perturbation of biologic molecules or drugs, and simultaneous, real-time optical analysis for different bioassays. The key features of the iMAP design are the interface of on-board gravity driven flow, the open access input fluid exchange and the highly efficient sedimentation based cell capture mechanism (~100% capture rates). The operation of the device is straightforward (tube and pump free) and capable of handling dilute samples (5-cells per experiment), low reagent volumes (50 nL per reaction), and performing single cell protein and gene expression measurements. We believe that the unique low cell number and triple analysis capabilities of the iMAP platform can enable novel dynamic studies of scarce cells. PMID- 21709916 TI - Synthesis, characterization, plasmid cleavage and cytotoxicity of cancer cells by a copper(II) complex of anthracenyl-terpyridine. AB - Metallo-organic compounds are interesting to study for their antitumor activity and related applications. This paper deals with the syntheses, characterization, structure determination of a copper complex of anthracenyl terpyridine (1) and its plasmid cleavage and cytotoxicity towards different cancer cell lines. The complex binds CT-DNA through partial intercalation mode. The plasmid cleavage studies carried out using pBR322 and pUC18 resulted in the formation of all the three forms of the plasmid DNA. Plasmid cleavage studies carried out with a non redoxable Zn(2+) complex (2) supported the role of the redox activity of copper in 1. The complex 1 showed remarkable antiproliferative activity against cancer cell lines, viz., cervical (HeLa, SiHa, CaSki), breast (MCF-7), liver (HepG2) and lung (H1299). A considerable lowering was observed in the IC(50) values of HPV infected (viz., HeLa, SiHa, CaSki) vs. non-HPV-infected cell lines (MCF-7, HepG2, H1299). Antiproliferative activity of 1 was found to be much higher than the carboplatin when treated with the same cell lines. Incubation of the cells with 1 results in granular structures only with the HPV-infected cells and not with others as studied by phase contrast and fluorescence microscopy. The lower IC(50) value observed in case of 1 with HPV-infected cell lines may be correlated with the involvement of HPV oncoprotein. The role of HPV has been further augmented by transfecting the MCF-7 cells (originally not possessing HPV copy) with e6 oncoprotein cDNA. To our knowledge this is the first copper complex that causes cell death by interacting with HPV oncoprotein followed by exhibition of remarkable antiproliferative activity. PMID- 21709917 TI - Nitroimidazole and glucosamine conjugated heteroscorpionate ligands and related copper(II) complexes. Syntheses, biological activity and XAS studies. AB - New nitroimidazole and glucosamine conjugated heteroscorpionate ligands, namely 2,2-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1 yl)ethyl)acetamide (L(MN)) and 1,3,4,6-tetra-O-acetyl-2-{[bis(3,5-dimethyl-1H pyrazol-1-yl)acetyl]amino}-2-deoxy-beta-D-glucopyranose (L(DAC)), respectively, were synthesized by direct coupling of preformed side chain acid and amine components. The related copper(II) complexes {[(L(MN))(2)Cu]Cl(2)}, and {[(L(DAC))(2)Cu]Cl(2)} have been prepared from the reaction of CuCl(2)*2H(2)O with L(MN) or L(DAC) ligand in methanol solution. Single crystal structural characterization was undertaken for the L(MN) ligand. In the absence of a coordinated metal core, the overall arrangement of the ligand is determined by some loose intra- and inter-molecular nonbonding contacts. X-Ray Absorption Spectroscopy (XAS) has been used to probe the local structure of the two copper(II) complexes, {[(L(MN))(2)Cu]Cl(2)} and {[(L(DAC))(2)Cu]Cl(2)}. The EXAFS analysis has permitted the identification of the local environment of the copper site. Copper interacts with 2 units of ligand in both complexes, and it is found to be 6-fold coordinated. Its local structure is described by four Cu-N and two Cu-O interactions to form a pseudo-octahedron core, with a 0.14 A lengthening of the Cu-O bond length in the case of L(DAC) complex with respect to the L(MN) one, likely due to the higher steric hindrance of the glucosamine moiety. The XANES analysis agrees with these results, also confirming the Cu(II) formal copper oxidation state for both complexes. The new copper(II) complexes {[(L(MN))(2)Cu]Cl(2)} and {[(L(DAC))(2)Cu]Cl(2)} as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity towards a panel of several human tumour cell lines. The results reported here indicate that both copper(II) complexes show similar spectra of cytotoxicity and very low resistance factors (RF < 2) against C13* ovarian cancer cells which have acquired resistance to cisplatin. PMID- 21709918 TI - The development of aqueous transfer hydrogenation catalysts. AB - This review discusses the development of aqueous phase, homogeneous, transfer hydrogenation catalysis. Transfer hydrogenation catalysts, based on Ru, Ir and Rh, reduce organic substrates in water by assisting the transfer of hydrogen from simple donor species. These catalysts are expected to have significant benefits when compared with organic phase catalysts, including greater activity, greater selectivity and smaller environmental impact. They will therefore be expected to make a significant contribution to homogeneous catalysis and 'green chemistry'. Here, we comprehensively examine these catalysts, paying special attention to structural features. PMID- 21709919 TI - Cyclopalladated complexes of perylene imine: mononuclear complexes with five- or six-membered metallacycles. AB - Mononuclear palladium complexes [Pd(C^N)L(2)] (HC^N = 3-C(20)H(11)CH=NC(6)H(4)-p C(2)H(5)) have been prepared with Pd bound to the peri site or to the ortho site of the perylenyl fragment. These metallations correspond, respectively to six membered (L(2) = S(2)COMe (3); acac (4); Cl, PMe(3) (5); Cl, PPh(3) (6); S(2)CNEt(2) (7)) or five-membered (L(2) = S(2)COMe (8); acac (9)) isomeric palladacyclic compounds. The X-ray structures of 3, 5, 7 and 8 show that the perylenyl fragment remains essentially flat for 3, 7 and 8 and twisted for 5. Intermolecular pi-pi stacking of perylenyl rings is observed only for 7. All palladium complexes exhibit fluorescence associated to the perylene fragments, with emission quantum yields (in solution at room temperature) in the range 0.01 0.12 (compared to 0.13 for the free imine), and emission lifetimes ~ 1 ns. The complexes with five-membered palladacycles show lower quantum yields than their six-membered analogs. The similarity in shape of the luminescence spectra of these metallated complexes with perylene, although red-shifted, strongly suggests a perylene-dominated intraligand pi-pi* emissive state, metal-perturbed by interaction of the perylene orbitals with the palladium fragment. PMID- 21709920 TI - High fidelity neuronal networks formed by plasma masking with a bilayer membrane: analysis of neurodegenerative and neuroprotective processes. AB - Spatially defined neuronal networks have great potential to be used in a wide spectrum of neurobiology assays. We present an original technique for the precise and reproducible formation of neuronal networks. A PDMS membrane comprising through-holes aligned with interconnecting microchannels was used during oxygen plasma etching to dry mask a protein rejecting poly(ethylene glycol) (PEG) adlayer. Patterns were faithfully replicated to produce an oxidized interconnected array pattern which supported protein adsorption. Differentiated human SH-SY5Y neuron-like cells adhered to the array nodes with the micron-scale interconnecting tracks guiding neurite outgrowth to produce neuronal connections and establish a network. A 2.0 MUm track width was optimal for high-level network formation and node compliance. These spatially standardized neuronal networks were used to analyse the dynamics of acrylamide-induced neurite degeneration and the protective effects of co-treatment with calpeptin or brain derived neurotrophic factor (BDNF). PMID- 21709921 TI - Proton coupled electron transfer of ubiquinone Q2 incorporated in a self assembled monolayer. AB - We present a complete study of the reduction of ubiquinone Q(2) (UQ(2)) in simpler aqueous medium, over a pH range of 2.5 to 12.5. The short isoprenic chain ubiquinones (UQ(2)) were incorporated in a self-assembled monolayer. Under these conditions, the global 2e(-) electrochemical reaction can be described on the basis of a nine-member square scheme. The thermodynamic constants of the system were determined. The global 2e(-) process is controlled by the uptake of the second electron. The elementary electrochemical rate constants obtained by fitting of the experimental rate constant were k(s4) = 1.5 s(-1) for QH(+)(2)<-> QH(2), k(s5) = 1.5 s(-1) for QH<-> QH(-) and k(s6) = 1 s(-1) for Q(-)<-> Q(2-). The three electrochemical reactions QH(+)(2)<-> QH(2), QH<-> QH(-) and Q(-)<-> Q(2-) are successively involved when increasing the pH. Protonations can occur or not, before or after the electron uptake and the reaction paths are, from low to high pH: e(-), H(+)e(-), e(-)H(+), H(+)e(-)H(+), H(+)e(-) and e(-)H(+). PMID- 21709922 TI - A new method for screening potential sII and sH hydrogen clathrate hydrate promoters with model potentials. AB - A new predictive computational method for classifying clathrate hydrate promoter molecules is presented, based on the interaction energies between potential promoters and the water networks of sII and sH clathrates. The motivation for this work is identifying promoters for storing hydrogen compactly in clathrate hydrates. As a first step towards achieving this goal, we have developed a general method aimed at distinguishing between molecules that form sII clathrate hydrates and molecules that can-together with a weakly interacting help gas-form sH clathrate hydrates. The new computational method calculates differences in estimated formation energies of the sII and the sH clathrate hydrate. Model interaction potentials have been used, including the electrostatic interactions with newly calculated partial charges for all the considered potential promoter molecules. The methodology can discriminate between the clathrate structure types (sII or sH) formed by each potential promoter with good selectivity, i.e., better than achieved with a simple van der Waals diameter criterion. PMID- 21709923 TI - Atomistic mechanism of charge separation upon photoexcitation at the dye semiconductor interface for photovoltaic applications. AB - Charge separation in excited states upon visible light absorption is a central process in photovoltaic solar cell applications. Employing state-of-the-art first principles calculations based on time-dependent density functional theory (TDDFT), we simulate electron-hole dynamics in real time and illustrate the microscopic mechanism of charge separation at the interface between organic dye molecules and oxide semiconductor surfaces in dye-sensitized solar cells. We found that electron-hole separation proceeds non-adiabatically on an ultrafast timescale <100 fs at an anthocyanin/TiO(2) interface, and it is strongly mediated by the vibrations of interface Ti-O bonds, which anchor the dye onto the TiO(2) surface. The obtained absorption spectrum and electron injection timescale agree with experimental measurements. PMID- 21709924 TI - Graphical prediction of quantum interference-induced transmission nodes in functionalized organic molecules. AB - Quantum interference (QI) in molecular transport junctions can lead to dramatic reductions of the electron transmission at certain energies. In a recent work [Markussen et al., Nano Lett., 2010, 10, 4260] we showed how the presence of such transmission nodes near the Fermi energy can be predicted solely from the structure of a conjugated molecule when the energies of the atomic p(z) orbitals do not vary too much. Here we relax the assumption of equal on-site energies and generalize the graphical scheme to molecules containing different atomic species. We use this diagrammatic scheme together with tight-binding and density functional theory calculations to investigate QI in linear molecular chains and aromatic molecules with different side groups. For the molecular chains we find a linear relation between the position of the transmission nodes and the side group pi orbital energy. In contrast, the transmission functions of functionalized aromatic molecules generally display a rather complex nodal structure due to the interplay between molecular topology and the energy of the side group orbital. PMID- 21709926 TI - Electroless galvanic inks on inorganic WO3/Al boards. AB - A tungsten trioxide (WO(3)) coated aluminium (Al) substrate exhibits a reversible color change without light irradiation or an electric power supply. The sample turns blue upon exposure to an aqueous acid solution, but exposure to oxygen restores the original light yellow color. This color change is due to the galvanic redox reaction between WO(3) and Al. PMID- 21709927 TI - CdSe/ZnS quantum dot-Cytochrome c bioconjugates for selective intracellular O2- sensing. AB - We demonstrate that the coupling system of negatively capped CdSe/ZnS QDs with an oxidized Cytochrome c (Cyt c) is capable of the fluorescent imaging of a superoxide radical (O(2)-) with high sensitivity and specificity in living cells, without interference from other Reactive Oxygen Species (ROS) or relevant intracellular components. PMID- 21709928 TI - Ab initio molecular dynamics simulations of a binary system of ionic liquids. AB - This work presents first insights into the structural properties of a binary mixture of ionic liquids from the perspective of ab initio molecular dynamics simulations. Simulations were carried out for a one-to-one mixture of 1-ethyl-3 methyl-imidazolium thiocyanate and 1-ethyl-3-methyl-imidazolium chloride and compared to pure 1-ethyl-3-methyl-imidazolium thiocyanate. PMID- 21709929 TI - Isolated tricuspid valve prolapsed: identification using two- and three dimensional echocardiography and transoesophageal echocardiography. AB - We present a case of isolated prolapse of the tricuspid anterior leaflet in an asymptomatic 34-year-old man who was referred to our hospital for a routine check up. We performed two-and three-dimensional transoesophageal echocardiography (TEE). We found three-dimensional TEE a useful, non-invasive tool that can provide additional information to two-dimensional echocardiography in the assessment of tricuspid valve prolapse. PMID- 21709931 TI - The role of platelets in defence against pathogens. AB - Many more platelets are present in healthy mammals than are necessary for routine haemostasis. Thus, they could have other functions. Platelets have many of the attributes of innate immune function including Toll-like receptors. They also contain a wide range of anti-microbial peptides in storage granules. Platelets play an important role in bacterial infections, both in disease progress and in defence mechanisms depending on circumstances. Similar mechanisms are used in defence against fungi. Platelets are also involved in viral diseases, either in protecting from the immune system or in killing viruses that activate platelets. Finally, platelets have a role in defence against parasitic diseases, in particular malaria, that should not be ignored, and may aggravate some of the worst aspects. Platelets also have receptors for IgE and are implicated via parasitic disorders in development and problems of allergy. PMID- 21709932 TI - Bleeding with anticoagulant treatments. AB - Anticoagulation with vitamin K antagonists (VKAs) is effective in the prevention and treatment of thrombotic complications in many clinical conditions, including atrial fibrillation (that represents today the most frequent indication for anticoagulant treatment), venous thromboembolism, acute coronary syndromes and after invasive cardiac procedures. Bleeding is the most important complication of VKAs and a major concern for both physicians and patients, limiting a more widespread prescription of the treatment. As a result, a non negligible proportion of all the subjects who would have a clear clinical indication for anticoagulation do not receive an effective treatment. This review analyses the treatment- and person-associated risk factors for bleeding during VKAs. New oral anticoagulant drugs seems to overcome at least some of the limitations of VKAs. Potentially, they can allow a less demanding and more stable anticoagulant treatment, with less side-effects allowing that more patients can receive an appropriate anticoagulant treatment. Based on the so far available phase III clinical studies, it is possible to assume that these new drugs are associated with a risk of bleeding, that is probably related to the intensity of treatment. PMID- 21709933 TI - Correlation of Cesarean rates to maternal and infant mortality rates: an ecologic study of official international data. AB - OBJECTIVE: To correlate international official data on Cesarean delivery rates to infant and maternal mortality rates and low weight-at-birth rates; and to test the hypothesis that Cesarean rates greater than 15% correlate to higher maternal and infant mortality rates. METHODS: Analyses were based on the most recent official data (2000-2009) available for 193 countries. Exponential models were compared to quadratic models to regress infant mortality rates, neonatal mortality rates, maternal mortality rates, and low weight-at-birth rates to Cesarean rates. Separate regressions were performed for countries with Cesarean rates greater than 15%. RESULTS: In countries with Cesarean rates less than 15%, higher Cesarean rates were associated to lower infant, neonatal, and maternal mortality rates, and to lower rates of low weight-at-birth. In countries with Cesarean rates greater than 15%, Cesarean rates were not significantly associated with infant or maternal mortality rates. CONCLUSIONS: There is an inverse exponential relation between countries' rates of Cesarean deliveries and infant or maternal mortality rates. Very low Cesarean rates (less than 15%) are associated with poorer maternal and child outcomes. Cesarean rates greater than 15% were neither correlated to higher maternal nor child mortality, nor to low weight-at-birth. PMID- 21709934 TI - [New method for determining endemic levels]. AB - OBJECTIVE: Design an instrument for determining endemic levels or ranges using simple calculations; identify and estimate the parameters related to the dynamic transmission of communicable diseases. METHODS: The parameters for establishing a theoretical curve of expected incidence based on the logistic growth model were identified. The parameters were estimated by nonlinear regression based on the cumulative incidence data from the previous five years. The weekly cumulative incidence of cases of influenza-like illness in Argentina in 2009 was used as an example. It was compared to the 2004-2008 case series in order to determine the cumulative and non-cumulative endemic levels. RESULTS: According to the cumulative endemic levels identified, the country entered the outbreak area in week 2. The data from previous years showed that the maximum expected number of cases or carrying capacity (K) was 1 090 660. When the non-cumulative levels were considered, the outbreak was present in 34 out of 51 weeks. A range of 1.05 to 1.13 was estimated for the basic reproductive rate (R0) in the non-epidemic period from 2004-2008. CONCLUSIONS: The new method facilitated the determination of endemic levels using a simple procedure with the identification of parameters that are important for transmission. Although it has limitations such as the fact that the equation used is more appropriate for evaluating diseases with a pronounced annual cycle and less accurate for cycles of less than 1 year, it can be considered a valuable alternative method for determining endemic ranges and a new contribution to the study of epidemic outbreaks at local health surveillance levels. PMID- 21709935 TI - [Prevalence of diabetes mellitus and impaired glucose tolerance in indigenous people from Aldeia Jaguapiru, Brazil]. AB - OBJECTIVE: To determine the prevalence of diabetes mellitus (DM) and impaired glucose tolerance in indigenous people from Aldeia Jaguapiru, in Dourados, state of Mato Grosso do Sul. METHODS: Between August 2007 and July 2008, individuals aged 18-69 years were evaluated. To obtain the simple random sample for the study, 349 houses were picked from among the total 1 255 houses in the village. Pregnant women, nonindigenous individuals, and their descendents, and those using glucocorticoids were excluded from the sample. Six hundred and six people were studied (268 men and 338 women). Capillary glucose was measured with a glucose meter, and the oral glucose tolerance test was performed as necessary. RESULTS: A 4.5% prevalence was observed for DM and 2.2% for impaired glucose tolerance, with higher frequency among women. Among diabetics, 44.4% had not been previously diagnosed. Obesity was present in 14.2% of men and 30.8% of women. The prevalence of hypertension was 29.7% for the overall group and 67.5% in diabetics and individuals with impaired glucose tolerance. There was no statistical relationship between smoking and the presence of DM and impaired glucose tolerance. CONCLUSIONS: The prevalence of DM and impaired glucose tolerance was lower in this sample compared to the Brazilian population. However, the prevalence of obesity was higher, and that of hypertension was similar. Nutritional guidance and encouragement of physical activity are recommended in Jaguapiru as preventive measures for DM. PMID- 21709936 TI - Effect of a two-component intervention to change hospital practice from early to delayed umbilical cord clamping in the Peruvian Amazon. AB - OBJECTIVE: To investigate the effect of a two-component intervention to change hospital practice with regard to the timing of umbilical cord clamping. METHODS: A pre-/post-study design was used to measure the effect of a two-component intervention on mean time to clamp the umbilical cord. The study took place at Hospital Iquitos "Cesar Garayar Garcia" in Iquitos, Peru. A total of 224 women were recruited from the hospital labor room: 112 pre-intervention, from 18 May-3 June 2009, and 112 post-intervention, from 6-20 July 2009. The intervention consisted of 1) a "best practice" three-day training workshop on birthing, and 2) a hospital directive. All deliveries were observed and the time between delivery of the first shoulder and clamping of the umbilical cord was measured with a digital stopwatch. RESULTS: The mean time between delivery and cord clamping before the intervention was 56.8 seconds (95% confidence interval [CI]: 51.0, 62.7). This increased to 169.8 seconds (95% CI: 153.8, 185.8) following the intervention. The difference in mean time to clamp remained significant in multivariate analyses (beta adjusted = 113.2 seconds, 95% CI: 96.6, 129.9). CONCLUSIONS: Hospital policy and practice can be successfully changed from early to delayed umbilical cord clamping using a simple, two-component intervention. PMID- 21709937 TI - Stakeholder perceptions of a total market approach to family planning in Nicaragua. AB - OBJECTIVE: To assess private-sector stakeholders' and donors' perceptions of a total market approach (TMA) to family planning in Nicaragua in the context of decreased funding; to build evidence for potential strategies and mechanisms for TMA implementation (including public-private partnerships (PPPs)); and to identify information gaps and future priorities for related research and advocacy. METHODS: A descriptive exploratory study was conducted in various locations in Nicaragua from March to April 2010. A total of 24 key private-sector stakeholders and donors were interviewed and their responses analyzed using two questionnaires and a stakeholder analysis tool (PolicyMakerTM software). RESULTS: All survey participants supported a TMA, and public-private collaboration, in family planning in Nicaragua. Based on the survey responses, opportunities for further developing PPPs for family planning include building on and expanding existing governmental frameworks, such as Nicaragua's current coordination mechanism for contraceptive security. Obstacles include the lack of ongoing government engagement with the commercial (for-profit) sector and confusion about regulations for its involvement in family planning. Strategies for strengthening existing PPPs include establishing a coordination mechanism specifically for the commercial sector and collecting and disseminating evidence supporting public private collaboration in family planning. CONCLUSIONS: There was no formal or absolute opposition to a TMA or PPPs in family planning in Nicaragua among a group of diverse nongovernmental stakeholders and donors. This type of study can help identify strategies to mobilize existing and potential advocates in achieving articulated policy goals, including diversification of funding sources for family planning to achieve contraceptive security. PMID- 21709938 TI - [Consumer use of nutrition labels in the city of Natal, Brazil]. AB - OBJECTIVE: To determine the percentage of consumers who read nutrition labels and the association between reading the labels and sociodemographic variables, and to identify suggestions from consumers to make nutrition labels more effective as a source of information. METHODS: For this cross-sectional study carried out in 2008, 368 adults randomly selected from 23 supermarkets in the city of Natal, Brazil, were interviewed. Data were obtained through a semistructured questionnaire including eight closed questions and 10 open questions. RESULTS: The mean age of participants was 40.99 years (+/- 13.58). The interviews showed that 94.6% of the participants read the nutrition labels and that 96.8% considered the labels important or very important; however, only 3.8% stated that they fully understand the labels. There was a significant association between being motivated to read food labels to make healthier choices (35.7%) and higher family income and schooling (P < 0.0001). The measures mentioned by study participants to increase readability and usage included having qualified professionals provide guidance concerning the labels in supermarkets (73.9%) and disseminating through the media information on food labels, what they are, why they are important, and their role (42.9%). CONCLUSIONS: Consumers did use the labels for nutritional guidance, especially those with higher income and schooling. However, the need to improve the labels was evident, as was the importance of providing opportunities for consumers to learn about the nutritional characteristics of food products. PMID- 21709939 TI - [Assessment of attention deficit hyperactivity: SNAP-IV scale adapted to Argentina]. AB - OBJECTIVE: Assess the usefulness of the SNAP-IV scale as an instrument for detecting attention deficit hyperactivity disorder (ADHD) in Argentine children aged 4 to 14 years. METHODS: The SNAP-IV scale was adapted and administered to a group of 1 230 schoolchildren in the province of Buenos Aires, Argentina. The diagnosis was determined with the clinical control, based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. The sensitivity and specificity, as well as the cut-off scores for the SNAP-IV scale in the population studied, were determined. RESULTS: The score on the SNAP-IV scale with the best correlation between sensitivity and specificity was established in order to determine the true positive cases that in fact had a clinical diagnosis. The cut-off scores obtained were: 1.66 (15/27 points) for the attention deficit subscale and 1.77 (16/27 points) for hyperactivity/impulsivity in the population studied. CONCLUSIONS: The SNAP-IV scale for detection of ADHD is considered to be valid in the population studied as long as the cut-off scores are modified to obtain the best sensitivity/specificity ratio based on the cultural and socioeconomic features of the population. PMID- 21709940 TI - Human leptospirosis in the Caribbean, 1997-2005: characteristics and serotyping of clinical samples from 14 countries. AB - OBJECTIVE: To determine the frequency of human leptospirosis in the sera of suspected clinical cases sent by 14 Caribbean countries for diagnosis to a regional laboratory in 1997-2005. METHODS: All serum samples were initially tested using the immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA) for leptospirosis. Demographic data (such as age and sex), month of the year and clinical manifestations that had been observed by the attending physician were related to seropositivity. The microscopic agglutination test (MAT) was used to serotype sera using a panel of 23 international serovars. RESULTS: Of 3 455 samples tested, 452 (13.1%) were seropositive for IgM antibodies to leptospirosis by the ELISA, with frequencies significantly (P < 0.05; chi2) different across countries and years. Among seropositive patients, the frequency of detection of leptospirosis (23.1%) was significantly higher in the age groups 1-20 years and 31-40 years combined compared with other age groups; and in male patients (72.1%) compared with female patients (19.7%) (P < 0.05; chi2). Chills, jaundice, vomiting, weakness, diarrhea, and kidney failure/problems were significantly (P < 0.05; chi2) exhibited at a higher frequency in seropositive, rather than seronegative patients. Using the MAT on 100 sera tested, 98 (98%) were seropositive, of which the serogroup Icterohaemorrhagiae was most prevalent with the detection of serovars Copenhageni (70%), Icterohaemorrhagiae (67%), and Mankarso (29%). CONCLUSIONS: Since only 13.1% of the suspected cases of leptospirosis were seropositive for IgM ELISA antibodies, other clinical conditions may have been responsible for the clinical manifestations observed, or the patient may have had chronic leptospirosis (IgG). In the Caribbean, serovars of the serogroup Icterohaemorrhagiae were responsible for most infections in the cases tested. PMID- 21709941 TI - [Household storage and use of medications in a population served by the family health strategy in Brazil]. AB - OBJECTIVE: To identify families served by the family health strategy (FHS) storing medicines at home, to evaluate storage conditions, and to investigate medicine use practices. METHODS: The study was conducted in a municipality in the state of Sao Paulo with two FHS units serving 1 867 households. The sample was selected by means of stratified random sampling. Data collection was conducted through semistructured interviews from July to October 2008. RESULTS: One resident was interviewed in each of the 280 households visited. Medicines were found in 255 households (91.1%). Of 326 storage locations, 217 (75.8%) were inadequate (easily accessible to children or exposed to moisture, light). Of the 2 578 medicines identified, 2 059 medicines (79.9%) in 236 (84.3%) households had safety or identification problems. Of the 280 respondents, 179 (63.9%) used medications. Of these, 24 were self-medicating, only one with an over-the-counter drug. Only 44 users had the prescription for their medication, and 21 did not follow the prescription in terms of dosage or had interrupted the treatment. CONCLUSIONS: Non-adherence to recommended treatment can lead to negative outcomes, such as inefficiency (using dosages lower than prescribed), poisoning (using dosages higher than prescribed), and other adverse reactions. PMID- 21709942 TI - [Blood supply during disasters: the experience of Chile in 2010]. AB - A review of the management of blood supply and its administration during disasters was conducted based on the experience of several events that occurred primarily from 2000-2010, particularly the earthquake that measured 8.8 on the Richter scale that struck central and southern Chile on 27 February 2010. The objective was to provide information that could be useful in improving response plans and strategies during potential future disasters. The descriptive information on response procedures was obtained from interviews, internal reports, and the computer database from the Maule regional blood production center. The results lead to the conclusion that to respond efficiently and effectively to the need for blood in the immediate wake of a disaster it is essential to have both a centralized management system that facilitates the supply and administration of blood and volunteers with competence in health that are willing to swiftly arrive during these events. A change in the profile of blood donors during such emergencies was also observed. In Chile, for example, during the two weeks after the earthquake, the ratio of male/female donors was reversed. There was 61.1% participation by women, whereas in the week before the event women accounted for only 37%. PMID- 21709943 TI - Importance of animal/human health interface in potential Public Health Emergencies of International Concern in the Americas. AB - This study analyzed the importance of zoonoses and communicable diseases common to man and animals as potential Public Health Emergencies of International Concern to build an evidence base for future efforts to reduce risk of infection at the animal/human health interface. The events recorded in the World Health Organization (WHO) Event Management System (EMS) database for the Americas during the 18 months since the implementation of the 2005 revised version of WHO's International Health Regulations (15 June 2007-31 December 2008) were the main source for this analysis. Of the 110 events recorded by the EMS for the Americas during the study period, 86 were classified as communicable diseases-77 (70.0%) "within the animal/human health interface," 9 (8.2%) "not common to man and animals," 16 (14.5%) "syndromes with unknown etiologies," and 8 (7.3%) "product related/ other." Of the 77 events within the animal/human health interface, 48 were "substantiated" (the presence of hazard was confirmed and/or human cases occurred clearly in excess of normal expectancy). These results confirm previous research and underscore the importance of the animal/human health interface as well as inter-sectoral collaboration. PMID- 21709944 TI - Guatemala never again: progress and challenges in the protection of research subjects. PMID- 21709945 TI - A call for a broader framework for health research in Chile. PMID- 21709946 TI - [On the viability of introducing the inactivated polio vaccine in Colombia]. PMID- 21709947 TI - Usefulness of proximal esophageal pH monitoring. PMID- 21709948 TI - Interstitial lung disease and gastroesophageal reflux disease: key role of esophageal function tests in the diagnosis and treatment. AB - CONTEXT: Gastroesophageal reflux disease (GERD) is common in patients with respiratory disorders and interstitial lung fibrosis from diverse disease processes. However, a cause-effect relationship has not been well demonstrated. It is hypothesized that there might be more than a coincidental association between GERD and interstitial lung damage. There is still confusion about the diagnostic steps necessary to confirm the presence of GERD, and about the role of effective control of GERD in the natural history of these respiratory disorders. OBJECTIVES: To determine the prevalence of GERD in patients with respiratory disorders and lung involvement; the sensitivity of symptoms in the diagnosis of GERD; and the role of esophageal function tests (manometry and 24- hour pH monitoring) in the diagnosis and treatment of these patients. METHODS: Prospective study based on a database of 44 patients (29 females) with respiratory disorders: 16 patients had idiopathic pulmonary fibrosis, 11 patients had systemic sclerosis associated interstitial lung disease, 2 patients had polymyositis associated interstitial lung disease, 2 patients had Sjogren associated interstitial lung disease, 2 patients had rheumatoid artrithis associated interstitial lung disease, 1 patient had undifferentiated connective tissue diseases associated interstitial lung disease and 10 patients had sarcoidosis. The average forced vital capacity (% predicted) was 64.3%. All patients had esophageal function tests. RESULTS: Thirty patients (68%) had pathologic reflux (average DeMeester score: 45, normal <14.7). The average number of reflux episodes recorded 20 cm above the lower esophageal sphincter was 24. Sensitivity and specificity of heartburn were 70% and 57%, of regurgitation 43% and 57%, and of dysphagia 33% and 64%. Twelve patients with GERD underwent a laparoscopic fundoplication which was tailored to the manometric profile: three patients in which peristalsis was normal had a total fundoplication (360 degrees ) and nine patients in which the peristalsis was absent had a partial anterior fundoplication (180 degrees ). CONCLUSIONS: The results of our study show that: (a) abnormal reflux was present in about 2/3 of patients with respiratory disorders (idiophatic pulmonary fibrosis, connective tissue disorders and sarcoidosis), and it extended to the upper esophagus in most patients; (b) the sensitivity and specificity of reflux symptoms was very low; and (c) esophageal function tests were essential to establish the diagnosis of abnormal reflux, to characterize the esophageal function and guide therapy. Long term follow-up will be necessary to determine if control of reflux alters the natural history of these respiratory disorders. PMID- 21709949 TI - Gastroesophageal reflux disease and vocal disturbances. AB - CONTEXT: Gastroesophageal reflux disease is a chronic disease in which gastroduodenal contents reflux into the esophagus. The clinical picture of gastroesophageal reflux disease is usually composed by heartburn and regurgitation (typical manifestations). Atypical manifestations (vocal disturbances and asthma) may also be complaint. OBJECTIVE: To analyse the clinical, endoscopic, manometric and pHmetric aspects of patients suffering from gastroesophageal reflux disease associated with vocal disturbances. METHODS: Fifty patients with gastroesophageal reflux disease were studied, including 25 with vocal disturbances (group 1 - G1) and 25 without these symptoms (group 2 - G2). All patients were submitted to endoscopy, manometry and esophageal pHmetry (2 probes). The group 1 patients were submitted to videolaryngoscopy. RESULTS: Endoscopic findings: non-erosive reflux disease was observed in 95% of G1 patients and 88% of G2. Videolaryngoscopy: vocal fold congestion, asymmetry, nodules and polyps were observed in G1 patients. Manometric findings: pressure in the lower esophageal sphincter (mm Hg): 11.6 +/- 5.2 in G1 and 14.0 +/- 6.2 in G2 (P = 0.14); pressure in the upper esophageal sphincter (mm Hg): 58.4 +/- 15.9 in G1 and 69.5 +/- 30.7 in the controls. pHmetric findings: De Meester index: 34.0 +/- 20.9 in G1 and 15.4 +/- 9.4 in G2 (P<0.001); number of reflux episodes in distal probe: 43.0 +/- 20.4 in G1 and 26.4 +/- 17.2 in G2 (P = 0.003); percentage of time with esophageal pH value lower than 4 units (distal sensor): 9.0% +/- 6.4% in G1 and 3.4% +/- 2.1% in G2 (P<0.001); number of reflux episodes in proximal probe: 7.5 +/- 10.9 in G1 and 5.3 +/- 5.7 in G2 (P = 0.38); percentage of time with esophageal pH values lower than 4 units (Proximal probe): 1.2 +/- 2.7 in G1 and 0.5 +/- 0.7 in G2 (P = 0.21). CONCLUSIONS: 1) The clinical, endoscopic, and manometric findings observed in patients with vocal disturbance do not differ from those without these symptoms; 2) gastroesophageal reflux intensity is higher in patients with vocal disturbance; 3) patients without vocal disturbance can also present reflux episodes in the proximal probe. PMID- 21709950 TI - Does low dose (13)C-urea breath test maintain a satisfactory accuracy in diagnosing Helicobacter pylori infection? AB - CONTEXT: The standard doses of (13)C-urea in (13)C-urea breath test is 75 mg. OBJECTIVE: To assess the diagnostic accuracy of (13)C-urea breath test containing 25 mg of (13)C-urea comparing with the standard doses of 75 mg in the diagnosis of Helicobacter pylori infection. METHODS: Two hundred seventy adult patients (96 males, 174 females, median age 41 years) performed the standard (13)C-urea breath test (75 mg (13)C-urea) and repeated the (13)C-urea breath test using only 25 mg of (13)C-urea within a 2 week interval. The test was performed using an infrared isotope analyzer. Patients were considered positive if delta over baseline was >4.00/00 at the gold standard test. RESULTS: One hundred sixty-one (59.6%) patients were H. pylori negative and 109 (40.4%) were positive by the gold standard test. Using receiver operating characteristic analysis we established a cut-off value of 3.4% as the best value of 25 mg (13)C-urea breath test to discriminate positive and negative patients, considering the H. pylori prevalence (95% CI: 23.9-37.3) at our setting. Therefore, we obtained to 25 mg (13)C-urea breath test a diagnostic accuracy of 92.9% (95% CI: 88.1-97.9), sensitivity 83.5% (95% CI: 75.4-89.3), specificity 99.4% (95% CI: 96.6-99.9), positive predictive value 98.3% (95% CI: 92.4-99.4), and negative predictive value 93.0% (95% CI: 88.6-96.1). CONCLUSIONS: Low-dose (13)C-urea breath test (25 mg (13)C-urea) does not reach accuracy sufficient to be recommended in clinical setting where a 30% prevalence of H. pylori infection is observed. Further studies should be done to determine the diagnostic accuracy of low doses of (13)C-urea in the urea breath test. PMID- 21709951 TI - Helicobacter pylori has no influence on distal gastric cancer survival. AB - CONTEXT: There is some evidence that Helicobacter pylori correlates with distal gastric cancer genesis. However, few studies analyzed the survival related to H. pylori infection. OBJECTIVE: To correlate gastric cancer survival and H. pylori infection. METHODS: Sixty-eight patients with distal gastric cancer that underwent subtotal gastrectomy were studied. Minimal follow-up was 1 month. H. pylori infection was confirmed by biopsy. RESULTS: Thirty-four patients (19 males (55.9%), mean age 60.9 +/- 14.03, range 33-82 years) were H. pylori positive. Thirty-four patients (16 males (47.1%), mean age 57.9 +/- 13.97, range 27-85 years) were H. pylori negative. Groups were comparable in regards to age (P = 0.4), gender (P = 0.5), stage [T (P = 0.2), N (P = 0.6) and M (P = 0.9)]. Survival was not different when groups were compared [P = 0.1616 (hazard ratio 0.6834, 95% CI 0.4009 to 1.1647)]. CONCLUSIONS: H. pylori infection does not affect distal gastric cancer survival. PMID- 21709952 TI - Nutritional profile of asymptomatic alcoholic patients. AB - CONTEXT: Alcoholism may interfere with nutritional status, but reports are often troubled by uncertainties about ingested diet and organ function, as well as by ongoing abuse and associated conditions. OBJECTIVE: To identify nutritional and body compartment changes in stable alcoholics without confounding clinical and dietetic variables, a prospective observational pilot study was designed. Three well-matched populations were considered: subjects with chronic alcoholic pancreatitis, alcoholics without visceral disease, and healthy never-drinking adults (controls). METHODS: Subjects (n = 60) were asymptomatic males with adequate diet, no superimposed disease or complication, and alcohol-free for at least 6 months. After exclusions, 48 patients were compared. Variables encompassed dietary recall, bioimpedance analysis, biochemical profile and inflammatory markers. Main outcome measures were body fat, lean body mass, serum lipids, C-reactive protein, and selected minerals and vitamins. RESULTS: Both alcoholic populations suffered from reduced lean body mass (P = 0.001), with well maintained body fat.Magnesium was depleted, and values of vitamin D and B12 correlated with alcohol abuse. LDL and total cholesterol was increased in alcoholics without pancreatitis (P = 0.04), but not in those with visceral damage. C-reactive protein and serum amyloid A correlated with duration of excessive drinking (P = 0.01). CONCLUSIONS: Undernutrition (diminished lean body mass, risk of magnesium and vitamin deficiencies) contrasted with dyslipidemia and increased cardiovascular risk. This second danger was masked during chronic pancreatitis but not in alcoholics without visceral disease. Further studies should focus special requirements of this population. PMID- 21709953 TI - Prospective study of ultrasound with perflutrene contrast compared to magnetic resonance imaging in the diagnosis of hepatic hemangiomas. AB - CONTEXT: The incidence of hepatic hemangiomas ranges from 0.4% to 20% in the general population. Conventional ultrasound is usually the first diagnostic method to identify these hemangiomas, typically as an incidental finding. Ultrasonography with second generation contrast materials is being used in various areas of hepatology, yielding similar results to those obtained with computerized tomography and magnetic resonance imaging in the diagnosis of hepatic hemangiomas. OBJECTIVE: To evaluate the agreement between ultrasound with perflutrene contrast and magnetic resonance imaging in the diagnosis of hepatic hemangiomas. METHODS: A total of 37 patients were prospectively examined between January 2006 and August 2008. A total of 57 hepatic nodules were documented in this group as incidental findings on routine ultrasound exams. The 37 patients were administered perflutrene contrast without adverse reactions, and were all submitted to magnetic resonance exams. RESULTS: Conventional ultrasound identified 15 patients with nodules typical of hemangiomas and 22 patients with other nodules. In 35 patients, the contrast characteristics were consistent with hepatic hemangiomas. CONCLUSION: Agreement between the data obtained from ultrasound with contrast and magnetic resonance was 94.5%. In discordant cases, the magnetic resonance diagnosis prevailed. In the case which presented indeterminate findings on contrast ultrasonography, magnetic resonance was repeated after 3 months, confirming the diagnosis of a hepatic hemangioma. A biopsy was performed on the suspected malignant nodule which also confirmed the presence of a hepatic hemangioma. Ultrasonography with contrast has the advantages of being more accessible to the public at large and lower cost than magnetic resonance. The results of our study highlight the need for a new protocol in hepatic nodules incidentally identified on conventional ultrasonography. In the case of typical hemangiomas, conventional ultrasound is sufficient for diagnosis. However, for poorly defined nodules, ultrasonography with contrast is indicated. After confirming the presence of a hepatic hemangioma on contrast ultrasonography, no further exams are needed to finalize the diagnosis. PMID- 21709954 TI - HBV and HCV serological markers in patients with the hepatosplenic form of mansonic schistosomiasis. AB - CONTEXT: Blood transfusion is one of the major risk factors for the transmission of the hepatitis B (HBV) and C (HCV) viruses. However, there are no reports describing the endoscopic transmission of these viruses in patients with the hepatosplenic form of schistosomiasis. OBJECTIVE: To estimate the prevalence of serological markers of HBV and HCV in patients with the hepatosplenic form of schistosomiasis and evaluate the possible risk factors associated with these infections. METHODS: A cross-sectional study was conducted on 230 patients with hepatosplenic form of schistosomiasis who attended a university hospital in Recife, Northeastern Brazil, from February to August 2008. The patients answered a standardized questionnaire about risk factors. Serum samples were analyzed for anti-HBc total, anti-HBs, HBsAg, and anti-HCV using enzyme-linked immunosorbent assays. Univariate analysis and multiple logistic regression were performed. RESULTS: The prevalence was 30% for anti-HBc total and/or HBsAg and 7.4% for anti HCV. There was a higher frequency of the serological markers in females and in patients aged .50 years. A significant association was detected between the presence of anti-HCV and the receipt of six or more blood transfusions. There was no association of history and number of digestive endoscopies with the serological markers analyzed. CONCLUSIONS: We observed a higher prevalence of serological markers for HBV and a lower prevalence of anti-HCV. Our results indicate that females and patients of an advanced age are the most affected categories and that patients that received multiple transfusions are at a higher probability of HCV infection. PMID- 21709955 TI - Prevalence of celiac disease in siblings of Iranian patients with celiac disease. AB - CONTEXT: Celiac disease, one of the best-known autoimmune human leukocyte antigen dependent disorders, has a relatively increased prevalence in first-degree relatives. OBJECTIVE: To determine the prevalence of celiac disease in siblings of patients with confirmed celiac disease. METHODS: Siblings of confirmed celiac disease patients in our center were identified and enrolled in this study. Their serum immunoglobulin A and tissue transglutaminase antibody-enzyme-linked immunosorbent assay (anti-tissue transglutaminase, immunoglobulin A, and immunoglobulin G) were measured and multiple endoscopic duodenal biopsy specimens were obtained with parental consensus. Celiac disease was confirmed by observation of characteristic histological changes. RESULTS: A total of 49 children (male, 29; female, 20; age, 2-16 years) with confirmed celiac disease in a pediatric gastroenterology ward were studied from 1999 to 2006. We found 30 siblings (female, 16) all shared in both parents. The only measurement available was for immunoglobulin A tissue transglutaminase antibody. A duodenal biopsy was performed in all 30 siblings. Clinical findings such as abdominal pain, fatigue, growth retardation and diarrhea were found in 53.3% of the completely studied siblings, and positive serology without histological changes was identified in four cases. Both serology and biopsy (confirmed new cases) were positive in 2 of the 30 siblings. CONCLUSION: High prevalence of celiac disease among siblings of patients with confirmed celiac disease necessitates serologic screening (and confirmatory biopsy if indicated) in families having celiac disease. It is advantageous to diagnose the disease as soon as possible because early diagnosis and diet intervention may prevent serious complications such as growth retardation, short stature, chronic diarrhea, and malignancy. PMID- 21709956 TI - The value of high-resolution anoscopy in the diagnosis of anal cancer precursor lesions in HIV-positive patients. AB - CONTEXT: Anal cancer, although a still rare disease, is being observed in ascending rates among some population segments known to be at risk for the development of the disease. Human papillomavirus (HPV) infection, immunodepression and anal intercourse are some factors associated with the development of the malignancy. Its similarities to cervical cancer have led to many studies aiming to establish guidelines for detecting and treating precursor lesions of anal cancer, with the goal of prevention. High-resolution anoscopy is routinely used for the diagnosis of anal cancer precursor lesions in many centers but the medical literature is still deficient concerning the role of this diagnostic modality. OBJECTIVES: To evaluate diagnostic validation and precision measures of high-resolution anoscopy in comparison to histopathological results of anal biopsies performed in HIV-positive patients treated at the Tropical Medicine Foundation of Amazonas, AM, Brazil. To observe any possible association between some risk factors for the development of anal cancer and the presence of anal squamous intraepithelial lesions. METHODS: A hundred and twenty-eight HIV positive patients were submitted to anal canal cytological sampling for the detection of HPV infection by a PCR based method. High-resolution anoscopy was then performed after topical application of acetic acid 3% in the anal canal for 2 minutes. Eventual acetowhite lesions that were detected were recorded in respect to location, and classified by their tinctorial pattern, distribution aspect, relief, surface and vascular pattern. Biopsies of acetowhite lesions were performed under local anesthesia and the specimens sent to histopathological analysis. The patients were interviewed for the presence of anal cancer risk factors. RESULTS: The prevalences of anal HPV infection and of anal squamous intraepithelial lesions in the studied population were, respectively, 79% and 39.1%. High-resolution anoscopy showed sensibility of 90%, specificity of 19.23%, positive predictive value of 41.67%, negative predictive value of 75%, and a kappa coefficient of 0.076. From the analyzed lesions, high-grade squamous intraepithelial lesions was more frequently observed in association to dense (68%), flat (61%), smooth (61%), non-papillary (83%) and normal vascular pattern (70%) acetowhite lesions, while low-grade squamous intraepithelial lesions tended to be associated to dense (66%), flat-raised or raised (68%), granular (59%), non papillary (62%) and normal vascular pattern (53%) acetowhite lesions. No statistical significance was observed as to the association of epidemiological characteristics and of most of the investigated anal cancer risk factors and presence of acetowhite lesions or anal squamous intraepithelial lesions. However, anal receptive sex and anal HPV infection were significantly associated to anal squamous intraepithelial lesions (P = 0.0493 and P = 0.006, respectively). CONCLUSION: High-resolution anoscopy demonstrated to be a sensitive, but not specific test for the detection of anal squamous intraepithelial lesions. Risk factors anal receptive sex and anal HPV infection were significantly associated to the presence of anal squamous intraepithelial lesions. Based on high resolution anoscopy image data, acetowhite lesions relief and surface pattern were prone to distinguish between low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions. PMID- 21709957 TI - Islet transplantation in rodents. Do encapsulated islets really work? AB - CONTEXT: Diabetes mellitus type I affects around 240 million people in the world and only in the USA 7.8% of the population. It has been estimated that the costs of its complications account for 5% to 10% of the total healthcare spending around the world. According to World Health Organization, 300 million people are expected to develop diabetes mellitus by the year 2025. The pancreatic islet transplantation is expected to be less invasive than a pancreas transplant, which is currently the most commonly used approach. OBJECTIVES: To compare the encapsulated and free islet transplantation in rodents looking at sites of islet implantation, number of injected islets, viability and immunosuppression. METHODS: A literature search was conducted using MEDLINE/PUBMED and SCIELO with terms about islet transplantation in the rodent from 2000 to 2010. We found 2,636 articles but only 56 articles from 2000 to 2010 were selected. RESULTS: In these 56 articles used, 34% were encapsulated and 66% were nonencapsulated islets. Analyzing both types of islets transplantation, the majority of the encapsulated islets were implanted into the peritoneal cavity and the nonencapsulated islets into the liver, through the portal vein. In addition, the great advantage of the peritoneal cavity as the site of islet transplantation is its blood supply. Both vascular endothelial cells and vascular endothelial growth factor were used to stimulate angiogenesis of the islet grafts, increasing the vascularization rapidly after implantation. It also has been proven that there is influence of the capsules, since the larger the capsule more chances there are of central necrosis. In some articles, the use of immunosuppression demonstrated to increase the life expectancy of the graft. CONCLUSION: While significant progress has been made in the islets transplantation field, many obstacles remain to be overcome. Microencapsulation provides a means to transplant islets without immunosuppressive agents and may enable the performance of xenotransplantation. The use of alternative donor sources, fewer islets per capsule and the appropriate deployment location, such as the peritoneal cavity, may give a future perspective to the application of immunoprotective capsules and viability in clinical practice. A variety of strategies, such as genetic engineering, co encapsulation, improvement in oxygen supply or the establishment of hypoxia resistance will also improve the islet transplantation performance. It remains to be determined which combination of strategies with encapsulation can fulfill the promise of establishing a simple and safe transplantation as a cure for diabetes. PMID- 21709958 TI - Hepatic and biochemical repercussions of a polyunsaturated fat-rich hypercaloric and hyperlipidic diet in Wistar rats. AB - CONTEXT: Non-alcoholic fatty liver disease is characterized by lipid deposits in the hepatocytes and has been associated with obesity, dyslipidemia and type-2 diabetes. It is considered a hepatic manifestation of the metabolic syndrome, of which the main component is insulin resistance leading to hyperinsulinemia and increased production of inflammatory cytokines. Saturated fat promotes hypertriglyceridemia and hyperinsulinemia, reduces levels of high-density cholesterol and increases levels of low-density cholesterol, while polyunsaturated fat is associated with hypolipidemic, antiinflammatory and imunoregulating action. OBJECTIVE: To evaluate the hepatic and biochemical repercussions of a polyunsaturated fat-rich diet in Wistar rats. METHODS: Twenty two rats were distributed equally in two groups: GI - standard diet (Biobase Bio tec Ratos e Camundongos(r)) providing 3.000 kcal/kg and GII - hypercaloric and hyperlipidic diet providing 4.250 kcal/kg (omega-6:omega-3 = 3:1). The animals were euthanized after 23 weeks of experiment. The weight, biochemical parameters and hepatohistological changes were registered. RESULTS: Findings were submitted to variance analysis with the level of statistical significance at 5%. The average weight did not differ significantly between the groups at baseline (P = 0.711), but was greater in Group II by the end of the experiment (P = 0.000). The levels of triglycerides (P = 0.039), total cholesterol (P = 0.015) and HDL (P = 0.005) were higher in Group I than in Group II. Macrovesicular steatosis was significantly more common in Group II than in Group I (P = 0.03). CONCLUSION: Hypercaloric and hyperlipidic diet rich in polyunsaturated fat promotes weight gain and favors the development of hepatic steatosis while reducing serum levels of triglycerides, total cholesterol and HDL. PMID- 21709959 TI - Endoscopic treatment for gastric perforation using T-tag and a plastic protection chamber: a short-term survival study. AB - CONTEXT: The endoscopic gastric perforation is a consequence of some endoscopic procedures and now a way to manage abdominal organs. This is the reason why endoscopists are studying a safe endoscopic repair. OBJECTIVE: To evaluate an endoscopic closure method for the gastric opening in natural orifice transenteric surgery DESIGN: Short-term survival animal study. METHODS: Ten White Landrace pigs underwent a gastric perforation of 1.8 cm in diameter under general anesthesia. The opening was repaired with stitch assembled in a T-tag anchor placed through the gastric wall with a needle. A plastic transparent chamber, adapted to the endoscope tip protected the abdominal organs from the needle puncture outside the stomach. Six T-tags were placed in most cases and the stitches were tied with a metallic tie-knot, forming three sutures. The animals received liquids in the same operative day. One shoot antibiotic was used. The leakage test was performed with a forceps and by air distention. RESULTS: No complication was detected in the postoperative course. One month later the endoscopy revealed a scar and some suture material was observed in all animals. The antral anterior gastric wall was clear with few adhesions in the laparotomy performed in the same time. The adhesions were intense in an animal in which a cholecystectomy was performed before the repair. CONCLUSION: The endoscopic repair using T-tag and a protector chamber is feasible, easy to perform and safe. Further studies are needed to show the real value of this kind of procedure. PMID- 21709960 TI - Celiac disease screening in patients with scleroderma. AB - Both celiac disease and scleroderma have autoimmune etiology and affect the bowel causing diarrhea. As an association of autoimmune disease in a single individual is not rare, it is important to know if a patient with scleroderma may also have celiac disease. To analyze this we studied 105 scleroderma patients and 97 volunteers for IgA-EmA by indirect immunofluorescence assay. We could not find a higher prevalence of this autoantibody in scleroderma patients. The authors conclude that there is no need to screen scleroderma patients with diarrhea for celiac disease unless there is a clear clinical indication for this. PMID- 21709961 TI - [Conditions for universal access to health in Latin America: social rights, social protection and financial and political constraints]. AB - After a brief review of the concept of health equity and its social and sectoral determinants, some macroeconomic aspects of health expenditure in Latin America are considered. Given the significant contemporary tensions with regard to social rights and the definition of health benefits, three emblematic experiences are analyzed in very different health systems, namely those of Chile, Colombia and Mexico. They cover different aspects, such as the guarantee of health benefits, the reduction of forms of implicit rationing and/or barriers to admission, and also aspects related to the quality of services. PMID- 21709962 TI - [Social rights and financial constraints: tragic choices on universalization]. PMID- 21709963 TI - [Social protection and health systems in Latin America: avenues and obstacles to the right to health]. PMID- 21709964 TI - [Health reform and equity in Latin America]. PMID- 21709965 TI - [Some comments on the health reforms in Latin America from the Spanish perspective]. PMID- 21709966 TI - [Reduction of social rights]. PMID- 21709968 TI - [Regional cooperation and integration in health in South America: the contribution of Unasur-Health]. AB - The scope of this study is to discuss the process of integration of South America in the domain of health, from the constitution of the Union of South American Nations (Unasur), in May 2008, through to the emergence of the Unasur Council of Health, in 2009, and its ongoing development in the past year (2009-2010). This study is descriptive in nature and the medium of investigation was the case study. The authors present the main constituent elements of the South-American Health Agenda, with particular emphasis on the area of development and management of human resources in health, which was coordinated by Brazil in the past year. The authors conclude that this interchange will contribute to minimization of the asymmetries amongst the countries, collaborating to improve the quality of life and health conditions in the region. PMID- 21709969 TI - [The pharmaceutical industry and the sustainability of healthcare systems in developed countries and in Latin America]. AB - The global economic crisis and its impact on public finances in most developed countries are giving rise to cost-containment policies in healthcare systems. Prevailing legislation on medication requires the safety, quality, and efficacy of these products. A few countries include efficiency criteria, primarily for new medication that they wish to include in public financing. The appropriate use of generic and "biosimilar medication" is very important for maintaining the financial equilibrium of the Health Services. The problem in Latin America is that not all multisource products are bioequivalent and not all countries have the resources to conduct bioequivalence studies in vivo. The European Medicines Agency in 2005 adopted guidelines on "biosimilar medicines" and thirteen of them were subsequently approved for general release. Benchmarking of this model by other countries would be important. The influence of the pharmaceutical industry on political and administrative areas is enormous and control is necessary. The pharmaceutical companies claim that they act with corporate social responsibility, therefore, they must ensure this responsibility toward society. PMID- 21709970 TI - [New professionalism, medical education and healthcare systems]. AB - The scope of this paper is to discuss how so-called "new professionalism" can help in how the education of physicians is conducted, by taking into account the effects of globalization both on the situation of health and on the needs of health professionals with particular emphasis on European Union countries, which are engaged in a profound process of reform in university education. To achieve this, first we present the basic concepts of "new professionalism" and the key strategies of current medical education, which is to train physicians capable of dealing with ethical, scientific and professional challenges that are arising at the beginning of this century. The interdependence of reforms in the undergraduate, graduate and ongoing training areas is then emphasized. The challenges and difficulties to be faced when switching to different stages of medical education are then outlined. It was concluded that, notwithstanding recent reforms in medical education, their great complexity and the still limited availability of contrasting assessments of their results, there are strong synergies between the principles and values of the "new professionalism" and the objectives of the reforms. PMID- 21709971 TI - [Good governance of publicly-produced health services: ideas for moving forward]. AB - The good performance of publicly-produced health services is of vital importance, well beyond the health sector. Taking into account the great complexity of the health services in the public sector due both to their public and professional nature, we identify seven Gordian Knots as being responsible for the most frequent problems of publicly produced health services in Spain and Latin America. From the concept of good governance we take its character as a normative and ethical benchmark and its potential to renew and invigorate the government of the public sector. From comparative analysis of publicly-produced health services in the best performing countries, we extract eight characteristics which contribute significantly to good performance. A final reflection is on the relevance of the importance of offsetting the potential hostility to a reformist impulse of the status-quo with alliances that strengthen public trust and the social contract between health professionals and citizens based on the values of public health systems. PMID- 21709972 TI - [Evidence of the public-private mix in healthcare systems in countries with duplicated coverage: greater inequities and segmentation in National Health Systems]. AB - This paper seeks to identify the potential negative effects of private health insurance on the universality of National Health Systems. It systematizes the operational concepts of the public-private mix model and presents the results from international research into duplicated and supplementary coverage that shows that universality is negatively affected by inequities derived from duplicated coverage though not from supplementary coverage. It demystifies the supplementary nature of private health insurance as the villain in the Brazilian healthcare system and recommends that public policies should be fully oriented to improving the public health system instead of private health insurance. PMID- 21709973 TI - [The organization of regional and integrated healthcare delivery systems: challenges facing Brazil's Unified Health System]. AB - This article examines the causes of the segmentation/fragmentation in the healthcare process and the benefits of the constitution of networks set up to rationalize expenditures, optimize resources and ensure care tailored to the needs of the users. Its main purpose is to analyze the current challenges facing Brazil's Unified Health System, in order to promote improved integration between services. Among the challenges, those related to the insufficiency of resources due to low public funding, the training and education processes and their effects on the availability of health professionals to work in the public health system and the difficulties in the decentralization of health services and actions in the context of the Brazilian Federation Pact should be stressed. The paper concludes that, besides the efforts to tackle these challenges, the organization of regionalized networks integrated with the Unified Health System also depends on the improvement of intergovernmental management in the health regions to bolster the agreement on responsibilities among the government areas and the qualification of primary healthcare to coordinate care and ensure its continuity at other levels of the system. PMID- 21709974 TI - [Governance and political economy of PHC policies in Latin America]. AB - The development of implementation processes of PHC policies in Latin America, is a challenge yet to be tackled. It is necessary to acknowledge the political economy related to the implementation processes of PHC policies in Latin America from a governance perspective, characterized by the regulatory strategies used and the political processes. The promotion of social values, organizational policies or the introduction of new financial incentives are components of different forms of governance used in health system reforms. The institutional factors of social protection systems in Latin America are considered. Their potential, redistribution limitations and the political economy disputes of the reform strategies are explained by the conflict between the economic and related interests and values of the actors involved. This dynamic of the political process influences regulatory modes inherent in the processes of implementation of PHC policies. The State's governing capacity and levels of health system segmentation impinge on the effectiveness of reform strategies for resolving the conflicts in the policies implemented. PMID- 21709975 TI - [The sustainability of the Spanish National Health System]. AB - The Spanish National Health System (SNHS) has sustainability problems resulting from weaknesses in institutional design and governance compounded by the economic crisis it faces. The global economic crisis has had a particularly virulent impact in Spain, characterized by high levels of unemployment and public and private debt. Fiscal adjustment policies implemented may significantly compromise the SNHS. Along with general funding problems, the strong territorial decentralization of health jurisdictions in the Autonomous Communities has not been backed up by efficient State-level health coordination. The SNHS suffers from problems in its rules of governance, its autonomous financing system, human resource policies and diversity of direct and indirect management models in different Autonomous Communities. A reform strategy in Spanish healthcare governancemust be articulated within the context of a broader review of public policies to stabilize the lines of defense of the welfare state. Within the scope of the health sector, the financing system must be improved and institutional changes to increase efficiency must be implemented. PMID- 21709976 TI - [Waiting lists in public systems: from expanding supply to timely access? Reflections on Spain's National Health System]. AB - The paper discusses the issue of waiting times based on a study of Spain's National Health System (Sistema Nacional de Salud, SNS), focusing on the national context, management issues and local practices. Observation visits and interviews with health personnel and managers conducted in the metropolitan areas of the Autonomous Communities of Madrid, Andalusia, Catalonia and Basque Country were complemented by secondary data and a review of the literature. There is unanimity as to the positive results of the SNS, but cutting waiting times seems to be one key aspect requiring improvement. Two directions were identified for complementary measures: guaranteed maximum waiting times in the macro-social sphere associated with local measures to increase service integration and primary care resolution rates. The peculiarities of the Spanish decentralisation process and the existence of economic, political and health profession corporate interests were mentioned as factors hampering waiting list regulation, transparency and management. A comprehensive approach to this issue shows the need to shift discussion from waiting list monitoring and/or expanded supply to guaranteed timely access. That is the quality differential that primary care oriented systems must bring to public health systems. PMID- 21709977 TI - [Mexican health insurance: uncertain universal coverage]. AB - The Mexican health system is comprised of the Department of Health, state labor social security and the private sector. It is undergoing a reform process initiated in 1995 to achieve universal coverage and separate the regulation, financing and service functions; a reform that after fifteen years is incomplete and problematic. The scope of this paper is to assess the problems that underlie the successive reforms. Special emphasis is given to the last reform stage with the introduction of the "Insurance of the People" aimed at the population without labor social security. In the analysis, health reform is seen as part of the Reform of the State in the context of neoliberal reorganization of society. Unlike other Latin American countries, this process did not include a new Constitution. The study is based on official documents and a systematic review of the process of the implementation of the System of Social Health Protection and its impact on coverage and access to health services. The analysis concludes that it is unlikely that universal population coverage will be accomplished much less universal access to services. However, reforms are leading to the commodification of the health system even in the context of a weak private sector. PMID- 21709978 TI - [Scope and potential of Primary Healthcare in Argentina]. AB - This paper is part of the "Southern cone countries multicentric study of primary healthcare: healthcare models, health system integration and intersectoral relations in urban contexts in Argentina, Brazil, Paraguay and Uruguay". Its scope is to contextualize, describe and analyze the current state of the PHC strategy in Argentina and its potential for transforming the fragmented and segmented health system. The data-gathering methodology was review of the literature, study of documents, interviews with key informants and workshop discussions with stakeholders of the system. The dimensions of the data analysis were: (1) stewardship capability; (2) PHC financing; (3) provision, human resources and comprehensiveness; (4) integration and continuity. The transversal analytical categories in all the dimensions were the segmentation and fragmentation of governance and the health system. For this reason, the dynamics and actions of the social actors involved in the healthcare system and their position in relation to PHC were analyzed. The paper contains a theoretical introduction on the scope of current definitions of PHC and the description of the social, economic, political and epidemiological context of healthcare policies in Argentina. PHC based on the proposed dimensions is then analyzed. PMID- 21709979 TI - [The Colombian healthcare system: 20 years of achievements and problems]. AB - An overview of some of the key processes and results of Colombia's National Health System is presented. A systematic review of the literature evaluating the quality of the evidence published in indexed journals and literature not published in journals was made. Health system financial resources have seen a sustained increase while spending on health has remained at around 8% of GNP. Coverage, measured by affiliation to contributory and subsidized regimes, is in the order of 92% of the total population. The Mandatory Health Plan, defining the benefits to which one has access, has been broadly maintained but has been hampered by mechanisms for making legal complaints, thereby leading to financial deficits. The health system has contributed towards improving the poorest sector's income, but inequalities persist due to the lack of universal coverage, differences in health plans and the system's expenditure according to the population's income. Advances made in the National Health System have been positive but universality has not been achieved and this has stagnated in matters regarding access to services and equality. PMID- 21709980 TI - [The Integrated National Healthcare System in Uruguay and the challenges for Primary Healthcare]. AB - The article examines the results of the overview of PHC (Primary Healthcare) in Uruguay in 2009, within the context of the multicentric study of PHC with a view to identifying possibilities of redefining PHC as a strategy to achieve universal healthcare systems, taking into account the healthcare system's segmentation and fragmentation. The methodology included document analysis, key informant interviews and triangulation of information sources. The results presented are based on the analytical model structured in five dimensions: delivery, financing, resources, and integrated and intersectoral PHC. At the macro level, one can observe the recent implementation of a sector reform through the creation of the Integrated National Health System (SNIS) that favors the development of the PHC from an integrative standpoint. Actions have been defined to overcome the segmentation of the system and the fragmentation of care. However, at an operational level, the segmentation that existed before the SNIS as well as the low levels of healthcare coordination have yet to be modified. This is related to management ability and organizational factors. The lack of adequate human resources for the implementation of the PHC strategy is identified as a relevant factor. PMID- 21709981 TI - [Primary Healthcare Reform in Portugal on two fronts: autonomous family healthcare units and management of groupings of Health Centers]. AB - In 2005, Portugal began a reform of Primary Health Care. This reform process through to April 2010 is described and analyzed. During this period the Mission for Primary Health Care was responsible for conducting a profound reconfiguration. The main objectives for this reform were to improve accessibility, efficiency, quality and continuity of care and increase the satisfaction of professionals and citizens. The main features are voluntary adhesion, teamwork, mandatory information system, performance-sensitive payment, contracting and evaluation. The reconfiguration of health centers was two pronged. First, there was the formation of small autonomous functional units, known as Family Health Units (USF) providing services with proximity and quality. The second measure involved the aggregation of resources and management structures, groups of health centers (ACES), seeking to achieve efficiency and economies of scale. The FHU proved to offer simultaneously more efficiency, accessibility, better working environment, greater citizen satisfaction, namely better quality. The importance of strong political support, the creation of a structure responsible for the design and implementation of reform and good liaison with the media are stressed. PMID- 21709982 TI - [Family Health Reform in Portugal: analysis of its implementation]. AB - Primary healthcare in Portugal is undergoing a major reform, of which family health units (FHU) are one of the more visible results. This study aimed to evaluate the FHU implementation process from 2006 onwards. Methods from a previous study of primary healthcare implementation in Brazil were used. Dimensions studied included comprehensiveness of care, organization of care, and the political-institutional perspective. The main improvements identified included better availability of care, team work, technical quality of care, innovative management practices, sustainability of the model, working conditions and infrastructure improvements. Main challenges remaining include integration with hospital care, political and institutional gray areas, need for better information systems, integration within health centers and workflow organization. These data may be useful for management decision-makers when making adjustments and corrections in the reform process. PMID- 21709983 TI - [Primary Healthcare in Paraguay: overview and prospects]. AB - This paper presents an overview of Primary Health Care (PHC) in Paraguay, as part of a multicentric study, seeking to identify the possibilities of PHC as a factor for reorganizing the health system. The methodology adopts the comprehensive PHC concept, and takes into consideration the system's segmentation, formed by the public sector of the Ministry of Health and Welfare, Social Security, a not-for profit private sector, a private for-profit sector and a mixed sector. The study analyzes 5 dimensions: stewardship, financing, resources, integration/continuity, intersectorality/participation, through reviewing data from the literature and official documents, and key informant interviews (experts, decision-makers, professionals and civil society). Advances in health policy legislation since the 1990, with gratuity for all age groups, have been observed. Public spending on health is among the lowest in Latin America. PHC is provided through different vertical programs, with poor coordination and articulation, though a recent political shift prioritizes the progressive implementation of Family Health teams. In conclusion, PHC can contribute to improve health, equity and participation. PMID- 21709984 TI - [Primary healthcare: a multidimensional study on challenges and potential in the Sao Paulo Metropolitan Region (SP, Brazil)]. AB - This paper presents some results of a case study in the Metropolitan Region of Sao Paulo (SP, Brazil) as part of a multicentric study conducted in Argentina, Brazil, Paraguay and Uruguay. The aim is to evaluate Primary Health Care (PHC) as a strategy to achieve integrated and universal healthcare systems. The methodological approach was based on five analytical dimensions: stewardship capability; financing; provision; comprehensiveness and intersectoral approach. The techniques included literature review, document analysis and interviews with key informants: policy makers; managers, experts, users and professionals. The results were organized in response to the challenges and possibilities of PHC as a structural system according to the five dimensions. The following emerged from the interviews: different interpretations on the concept and role of PHC and a consensus as the gateway to the system; weaknesses in funding; challenges in health workforce administration and the need for new legal-institutional design for regional management. The potential aspects were: broader coverage/universality, PHC as the basis for the organization of the system; connection with the territory and understanding specific population needs. PMID- 21709985 TI - [Interview with Professor Gilles Dussault: the challenges facing contemporary health systems, by Eleonor Minho Conill, Ligia Giovanella and Jose-Manuel Freire]. PMID- 21709986 TI - Dioxin-induced changes in epididymal sperm count and spermatogenesis. AB - A single in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gestation day 15 decreased epididymal sperm count in adult rats and thus was used to establish a tolerable daily intake for TCDD. However, several laboratories have been unable to replicate these findings. Moreover, conflicting reports of TCDD effects on daily sperm production suggest that spermatogenesis may not be as sensitive to the adverse effects of TCDD as previously thought. We performed a PubMed search using relevant search terms linking dioxin exposure with adverse effects on reproduction and spermatogenesis. Developmental exposure to TCDD is consistently linked with decreased cauda epididymal sperm counts in animal studies, although at higher dose levels than those used in some earlier studies. However, the evidence linking in utero TCDD exposure and spermatogenesis is not convincing. Animal studies provide clear evidence of an adverse effect of in utero TCDD exposure on epididymal sperm count but do not support the conclusion that spermatogenesis is adversely affected. The mechanisms underlying decreased epididymal sperm count are unknown; however, we contest [corrected] that epididymal function is the key target for the adverse effects of TCDD. PMID- 21709987 TI - [The influence of sociosanitary conditions on the quality of life of the elderly in a municipality in the Southeast of Brazil]. AB - This study sought to evaluate sociosanitary conditions and their impact on the quality of life of the elderly living in the Teixeiras Municipality in the Southeast Region (MG) of Brazil. Two questionnaires were used: one created specifically to characterize the population in terms of sociosanitary conditions, and WHOQOL-bref, to evaluate quality of life. The correlation between the sociosanitary conditions and quality of life scores were analyzed by logistic regression analysis. Among the variables with a strong correlation with quality of life scores the following stand out: use of medication, need of medical care, lack of private health insurance, comorbidities, sleep problems, and retirement. The results of this study indicate that sociosanitary conditions are high risk factors for low quality of life scores in the elderly. This must be taken into consideration to establish health strategies and policies for this age group. PMID- 21709988 TI - [The impact of chronic disease on the quality of life of the elderly in Sao Paulo (SP, Brazil)]. AB - The aim of this article is to evaluate the impact of chronic disease on the quality of life of elderly people living in Sao Paulo (SP, Brazil). METHODS: cross-sectional study of individuals over 60; application of a standardized questionnaire and the Short-Form 36 item questionnaire. Statistical analysis describes the clinical and demographic data and ANOVA was used for the correlation of the SF-36 domains with age and the number of morbidities. 353 individuals were evaluated. The mean age was 71.6 years, with 48.7% men and 51.3% women. The women presented the worst levels of quality of life in all domains evaluated. ANOVA revealed significant variation in the quality of life in several areas as the number of morbidities increased. The most compromised domain was physical aspects (p<0.05). The same analysis, applied to the average of the domains by age group, showed an inverse relation of Functional Capacity (p<0.05) with age. The increase in the number of morbidities and the increasing age significantly affect several areas of quality of life in the elderly. The SF-36 appears to be a valid instrument for assessing quality of life of the elderly Brazilian population. PMID- 21709989 TI - [Understanding the elderly user of auditory prostheses]. AB - The main goal was to identify the factors involved in the application for and use of auditory prostheses by the elderly as well as their awareness of the Policy of Care to Auditory Health. 25 elderly people of both sexes using auditory prostheses in Vitoria (Espirito Santo, Brazil) were selected. They were contacted by telephone to participate in the research by answering a questionnaire. The results demonstrated that most of the elderly people interviewed (52%) use the device all day which suggests good adaptation to the process. Thirteen elderly people reported that they contacted the prosthesis company of their own accord. The advantages involved better communication and listening to TV (64%) while the difficulties were due to noisy environments; 56% were unable to understand what was being said at lectures, in church, and on the telephone, 72% reported no improvement with the prosthesis. 88% of the elderly participants are unaware of donation policies for auditory devices and 100% are unaware of this kind of service. Research and practices in health services about auditory issues still have far to go. There is a need for a change in management with the objective of putting into action policies which define the responsibilities of the State. PMID- 21709990 TI - [Use and access of the elderly to primary health care services in Porto Alegre (RS, Brasil)]. AB - A cross-sectional study was carried out in the second semester of 2004 by means of a household survey with 292 elderly people in a Southern Brazilian city, selected by probabilistic sampling. The objectives were: to describe the use and geographic access of the elderly to primary healthcare (PHC) in Porto Alegre (RS), and to analyze the association between variables of interest to the study and access to PHC. Descriptive and bivariate analysis was used. The primary health care services were used by 49.7% of the respondents, motivated by their location, quality and "free service." The factors negatively associated with the use of PHC services were "level of education" and "perception of good health" and the variable related positively was "self-diagnosed chronic condition". The elderly exposed to frailty related with economic and health conditions were more likely to use PHC, showing signs of equity in the health system. On the other hand, it is necessary to broaden the coverage to the elderly that do not have access, as well as implement healthcare strategies to meet the heterogenous demands of this age group. PMID- 21709991 TI - [Falls and associated factors in institutionalized elderly people in Pelotas (RS, Brazil)]. AB - The ageing of the population generates interest among health professionals, because of its importance for health. A cross-sectional study was carried out including institutionalized subjects aged over 65 from Pelotas (RS, Brazil). The aim was to investigate the prevalence of falls and associated factors. The prevalence of falls was 33.5%; the most frequent place in which falls occurred was the bedroom (37%). Of all falls, 16.9% resulted in a fracture. Approximately 70% of the falls took place at the institution in which the subjects live. Ankles and hips were the most frequently anatomic sites fractured (33,3%). The prevalence of falls among the elderly was high and the consequences of such falls are worrying. Prevention strategies by healthcare professionals and managers are urgently needed in order to minimize the burden of falls and thus enhance the quality of life of institutionalized elderly people. PMID- 21709992 TI - [Prevalence of housebound elderly people in the urban region of Belo Horizonte (Minas Gerais, Brazil)]. AB - The aim of this article is to estimate the prevalence and the socio-demographic and health profile of housebound elderly people registered at a Family Health Unit in the urban region of Belo Horizonte (Minas Gerais, Brazil). A household survey was conducted between May and July 2006 with 275 elderly people selected via cluster sampling. The svy suite of commands in Stata 9.0 was used to deal adequately with the cluster sample structure and to allow the incorporation of fractions of expansion in the analyses. Among the 275 elderly, 22.4% (IC95%: 14.7; 32.4) were restricted to their homes. The prevalence of this condition was greater among women, people over 80 and suspected of suffering from cognitive impairment (p-valor < 0.05). The majority of housebound people had incomes below the minimum wage, reported history of falls, depression and indicated physical disorders as the cause of the restriction. The large contingent of low-income housebound elderly with several health problems, reinforces the need for incorporation of proposals for promotion and vigilance of the health of the elderly, which extend beyond the boundaries of the healthcare units. PMID- 21709993 TI - [The "Farmacia Popular do Brasil" Program and aspects of public provision of medicines in Brazil]. AB - In 2004, the Federal Government introduced the "Farmacia Popular do Brasil" Program, which was an example of policy innovation, establishing a co-payment scheme as a strategy for access to medication. The study analyzed the original model of the Program. Data were obtained from interviews with key stakeholders, program documents and user prescriptions and registers. The results showed widespread expansion of the PFPB network and in the number of people attended. Despite the ever-increasing number of people attended with prescriptions from the private sector, a large demand from public sector users, namely the original focus of the program, was observed. From the standpoint of the federative pact, the program reinstates the centralized model of essential medication distribution which, in the decentralized public system is under state and municipal responsibility. The results point to the difficulty in compliance by states and municipalities with medication distribution responsibilities, mainly in the North and Northeast regions of Brazil. The study concludes that the population has been consistently turning to the PFPB for essential medication it has not been able to access in the public sector. PMID- 21709994 TI - [The reality of the oral/dental health of the elderly in the Brazilian Southeast]. AB - The scope of this work was to describe the alterations revealed in oral/dental structures resulting from ageing and to verify, through the national scientific production, with emphasis on the Southeastern region, the prevaling oral/dental problems in the elderly. A review of the literature on the theme of ageing in the context of dentistry was conducted. The results pointed to the fact that the elderly population is the fastest growing population segment. The prevailing oral/dental problems in this age bracket are radicular caries and periodontal illness, which contribute to the vast majority of dental extractions. In the Southeastern region of Brazil, the use of prostheses is low when compared with the high rate of tooth loss and the percentage of partially toothed elderly people; the value of the CPOD index is high and the elderly have a positive perception on their teeth, despite the fact that oral/dental problems have a negative impact on their lives. It is concluded that the inclusion of a dental surgeon in the healthcare team of the institutions and the systematization of oral/dental hygiene are pressing needs, in addition to the need for ongoing work of guidance for the the oral/dental healthcare of the elderly. Broadening of the study in this area is also fundamental to ensure dental care and treatment of these individuals. PMID- 21709995 TI - [Daily eating habits of obese women living in Rocinha Shanytown (Rio de Janeiro, RJ, Brazil)]. AB - This article presents conclusions of research conducted at Ensp/Fiocruz, as part of a master's degree course. One of the objectives of the research to investigate the eating habits of women living in the Rocinha Shantytown (Rio de Janeiro, RJ, Brazil) from a socio-anthropological perspective. The results revealed that the eating habits of the group were repetitive, with few variations in the menu consisting basically of rice, bean, sugars and fats. We further observed the rejection of industrialized and canned products. This food consumption pattern seems to conform to Brazilian food culture revealing the preservation of the national identity based on feeding habits. Consequently, it is necessary to set aside presuppositions regarding the relationship between food consumption and obesity, especially with respect to the predominant idea of changes in diet with the incorporation of a "modern" or "western" diet that prevail in studies in the field of nutrition in Brazil. In this sense, we signaled the need to reassert a multidimensional approach for studies about food and nutrition in the country. This proposal involves overcoming restricted conceptual outlooks and the creation of new avenues of investigation. PMID- 21709996 TI - [An overview of South-South Cooperation on Health]. AB - This article presents a brief overview of the meaning of technical cooperation within the United Nations, underscoring the political dimension, i.e. the relationship among States. It also emphasizes the importance of health in this context, using the Americas and Brazil as a benchmark. It illustrates the new paradigm called South-South Cooperation by analyzing an experience in the health field, stressing the triangulation of an intergovernmental agency. In conclusion, it summarizes the arguments that place a given process of international cooperation within the framework of this paradigm. PMID- 21709997 TI - [Health and territorialization from the perpective of development]. AB - The relationship between health and development is complex and lies in the field of political economy, given that it involves different social, political, and economic interests. In the Brazilian case, this association is particularly relevant in terms of the territorial dimension, in light of the central role of healthcare services in the organization of the urban network and the demarcation of territorial schedules and limits. In the theoretical-conceptual field, this study explores analytical areas that approach the relations between health and development, as well as between health and the territorial issue; and analyzes the history of the decentralization and regionalization policy in the Unified National Health System (SUS) and Federal investments that constitute the basis for its spatial evolution. Based on this conceptual review and empirical data, the study attempts to establish theoretical and political-institutional connections between health and development. The aim is thus to support the discussion on challenges facing a new role for health in the Brazilian development model, historically marked by economic and social inequalities with strong territorial overtones. PMID- 21710001 TI - The "indigenous" category in the 2010 Brazilian National Census. PMID- 21710002 TI - Research priorities in epidemiology in the Brazilian Pantanal. PMID- 21710003 TI - [Evaluation of the Program for Humanization of Prenatal and Childbirth Care in Brazil: a systematic review]. AB - The Program for Humanization of Prenatal and Childbirth Care (PHPN) was launched in Brazil in 2000, with quantitative criteria for obstetric care and SISPRENATAL as the database. The current study pooled the national data on prenatal care using SISPRENATAL and other data sources. This was a systematic review of prenatal care with an online search of articles in MEDLINE, EMBASE, and SciELO. The study compiled publications since 2001 that used PHPN process indicators. A meta-analysis was performed, estimating the mean proportion of each process indicator with its respective 95%CI. Process indicators increased over the target period, but SISPRENATAL showed low coverage for PHPN as compared to other data sources. The PHPN faces the challenge of proper data recording through SISPRENATAL. Priorities should include awareness-raising on the importance of data recording, training for inclusion of data in the system, and more accessible and less cumbersome data recording tools. PMID- 21710004 TI - [Prevalence of pre-hypertension and arterial hypertension and evaluation of associated factors in children and adolescents in public schools in Salvador, Bahia State, Brazil]. AB - This study aimed to assess pre-hypertension and hypertension-related factors in 1,125 seven- to-14-year-old subjects enrolled in the public school system in Salvador, Bahia State, Brazil. Exposure variables, namely body mass index, waist circumference, gender, age, physical activity, environmental and housing status, family income, diet, schooling, and maternal age were analyzed by polytomous logistic regression, and the outcome variable was categorized as normal, pre hypertensive, and hypertensive. Prevalence of high blood pressure was 14.1%, including the prevalence of both hypertension (4.8%) and pre-hypertension (9.3%). An association was shown between pre-hypertension and overweight (OR: 3.13; 95%CI: 1.75-5.57). Hypertension was associated with overweight (OR: 3.02; 95%CI: 1.45-6.28), female gender (OR: 2.49; 95%CI: 1.24-4.98), and high-risk eating patterns (OR: 1.93; 95%CI: 1.04-3.56). In short, prevalence of pre-hypertension and hypertension in children and adolescents was higher among girls and individuals with overweight and inadequate diet. PMID- 21710005 TI - [Validity and reliability of the work ability index (WAI) in nurses' work]. AB - This article assesses the validity and reliability of the work ability index (WAI) for 1,436 nurses in three public hospitals in Rio de Janeiro, Brazil. The study estimated the dimensional validity by means of exploratory factor analysis, as well as correlational validity, relating WAI to theoretically relevant constructs. Reliability was evaluated by internal consistency analysis, using Cronbach's alpha and McDonald's omega. Factor analysis indicated a two dimensional structure explaining 52.8% of the accumulated variance for the principal components and 42% for the principal axes. The theoretical hypotheses for the construct's validity were confirmed, with direct and significant correlation between the WAI and the reward, control, and self-rated health scores; an inverse and significant correlation with the scale on need for recovery after work, minor psychological disorders, effort, over-commitment, and demand. In conclusion, the WAI showed adequate psychometric properties. PMID- 21710006 TI - [Survival and risk factors for neonatal mortality in a cohort of very low birth weight infants in the southern region of Sao Paulo city, Brazil]. AB - Population studies can help identify the complex set of risk factors for neonatal mortality among very low birth weight infants. A cohort (2000-2001) of 213 live newborns with birth weight < 1,500g in the southern region of Sao Paulo city, Brazil, was studied (112 neonatal deaths and 101 survivors). Data were obtained from home interviews and hospital records. Survival analysis and multiple Cox regression were performed. The high mortality in the delivery room and in the first day of life among neonates < 1,000g and < 28 weeks gestational age and the absence of survival in neonates < 700g suggest that care was actively oriented towards newborns with better prognosis. Increased risk of neonatal mortality was associated with maternal residence in slum areas, history of previous cesarean(s), history of induced abortion(s), adolescent motherhood, vaginal bleeding, and lack of prenatal care. Cesarean section and referral of the newborn to the hospital nursery showed protective effects. Birth weight less than 1,000g and Apgar index < 7 were associated with increased risk. The high mortality was due to poor living conditions and to maternal and neonatal characteristics. Improvement in prenatal and neonatal care could reduce neonatal mortality in these infants. PMID- 21710007 TI - [The meaning of health in sexual relations according to women treated under the Unified National Health System in Natal, Rio Grande do Norte State, Brazil]. AB - The aim of this article is to discuss the social representations of "health in sexual relations" as reported by women treated under the Unified National Health System (SUS) in Natal, Rio Grande do Norte, Brazil. A total of 150 women were tested using the free word recall test, with "health in sexual relations" as the stimulus. Women were also asked about their sources of information on the subject. The results were obtained with content analysis and the EVOC software. We identified three representational dimensions: prevention, relationship with the partner, and quality of life. The central nucleus of social representation consisted of the elements "prevention" and "condoms". Likely sources for representation were television, health services, and dialogue with family members and partners. Representations were composed of concepts related to prevention, a good partner relationship, and overall well-being. The results illustrate the need to expand women's sexual health aspects that are considered relevant by the health system. PMID- 21710008 TI - The relationship between levels of income inequality and dental caries and periodontal diseases. AB - The objective of this study was to evaluate the association between income inequality at a lagged time of 2 and 11 years with two short latency outcomes (untreated dental caries and gingivitis) and two long latency outcomes (edentulism and periodontal attachment loss > 8mm). We used data from the Brazilian oral health survey in 2002-2003. Our analysis included 13,405 subjects aged 35-44 years. Different lagged Gini at municipal level were fitted using logistic and negative binomial multilevel analyses. Covariates included municipal per capita income, equivalized income, age, sex, time since last dental visit and place of residence (rural versus urban). Crude estimates showed that only untreated dental caries was associated with current and lagged Gini, but in adjusted models only current Gini remained significant with a ratio of 1.19 (95%CI: 1.09-1.30) for every ten-point increase in the Gini coefficient. We conclude that lagged Gini showed no association with oral health; and current income Gini was associated with current dental caries but not with periodontal disease. PMID- 21710009 TI - Quality of life among the Brazilian adult population using the generic SF-8 questionnaire. AB - The objective of this study was to assess the quality of life in the Brazilian adult population, based on the U.S. standard population. It involved a cross sectional population-based study with probabilistic sampling of 2,420 individuals (725 men and 1695 women) aged 40 or more in different geographic regions of Brazil. A socio-demographic questionnaire and the SF-8 (Short Form-8) were administered in interview form. Descriptive statistics, analysis of variance, the Mann-Whitney test and Tukey's test were used in the analysis. Females, populations in the northeastern region, the population of the regions of Brasilia (Distrito Federal), Campo Grande (Mato Grosso do Sul State) and Goiania (Goias State), Brazil, demonstrated worse quality of life. Age, education and income had influence over quality of life domains. This study presents quality of life estimates for the Brazilian adult population, based on the SF-8 questionnaire. The mean values on the subscales and components of the SF-8 appeared to be influenced by gender, geographic region, family income, age and schooling. PMID- 21710010 TI - [Smoking, work status, and gender: analysis of the Brazilian National Household Sample Survey, 2008]. AB - This study investigated whether men's and women's work status is associated with current smoking, after adjusting for schooling, income, and health, besides discussing hypotheses for such associations. The sample included individuals 15 to 64 years of age living in metropolitan areas, currently in the work force, and interviewed in the Brazilian National Household Sample Survey (PNAD) in 2008. Prevalence ratios (PR) and 95% confidence intervals (95%CI) were obtained by Poisson regression. After adjusting, smoking prevalence was statistically higher in individuals with informal jobs (men, PR = 1.31, 95%CI: 1.24-1.38; women, PR = 1.22, 95%CI: 1.12-1.31) or who were unemployed (men, PR = 1.31, 95%CI: 1.18-1.44; women, PR = 1.16, 95%CI: 1.03-1.32). Our results confirm that work status is an independent dimension of social inequalities in smoking. The social gradient was steeper in men, but the association between work status and smoking was present in both genders. PMID- 21710011 TI - [Non-communicable chronic diseases: performance of medical care in Primary Health Care in southern Brazil]. AB - A cross-sectional study was performed to assess knowledge and performance on the prevention of risk factors for chronic non-communicable diseases (CNCD) in adults, among primary care physicians in the urban health system in Pelotas, Rio Grande do Sul State, Brazil. The study included observation of 422 consultations by 61 physicians. 58.8% of the patient consultations for CNCD and 25.3% of those for other reasons lacked any preventive recommendations and/or measurement of weight, height, and blood pressure. For patients with CNCD, the most frequent recommendations were weight loss, more physical activity, and reduced fat and salt intake. Among patients without CNCD, only 39.1% received any recommendations related to primary prevention. Physician performance for the prevention of CNCD was poor, and focused mainly on tertiary prevention (counseling patients who were already diagnosed with CNCD) as compared to primary prevention (preventing the incidence of CNCD). PMID- 21710012 TI - [Cognitive development of premature children at school age: a proposal for a hierarchical model to investigate risk factors]. AB - Cognitive impairment is a neurodevelopmental sequela that is more prevalent in very low birth weight (VLBW) premature children. There are few Brazilian studies on this group's cognitive development at school age. The current study proposes a theoretical discussion on the determinants of cognitive development at school age in VLBW preterm children, using a hierarchical analytical model. According to this model, biological and environmental factors interrelate on several levels (distal, intermediate, and proximal), resulting in changes in cognitive development. The aim is to investigate the possible mediation of variables and their interrelationships and the resulting events that could lead to cognitive impairment as the outcome. Selection of risk factors was based on a literature review of factors associated with adverse cognitive outcomes. Better understanding of the interrelationships between these factors could lead to more appropriate prevention and intervention in this group, thereby increasing their chances of educational and social inclusion. PMID- 21710013 TI - [Cancer mortality trends in Rio Branco, Acre State, Brazil, 1980-2006]. AB - Time trends in cancer incidence and mortality in the Western Amazon remain unknown. This study explored age-standardized cancer mortality rates according to anatomical site in Rio Branco, Acre State, Brazil, by constructing linear regression time trend models. Cancer mortality showed an increasing but inconstant trend in men and stability in women. At the end of the time series, the highest cancer rates among women were for the cervix, lung, liver and intrahepatic biliary tract, stomach, and breast. Among men, the highest rates were for cancer of the lung, prostate, liver and intra-hepatic biliary tract, stomach, and esophagus. The study showed an increasing mortality time trend for cancer of the prostate, breast, and lung and declining mortality rates for cervical cancer in women, lung cancer in men, and stomach cancer in both sexes. The high mortality rate from liver cancer merits attention, considering the high hepatitis B and C infection rates in the State of Acre. PMID- 21710014 TI - Physical environment and life expectancy at birth in Mexico: an eco epidemiological study. AB - The objective of this ecological study was to ascertain the effects of physical environment on life expectancy at birth, using data from all 32 Mexican states. 50 environmental indicators with information about demography, housing, poverty, water, soils, biodiversity, forestry resources, and residues were included in exploratory factor analysis. Four factors were extracted: population vulnerability/susceptibility, and biodiversity (FC1), urbanization, industrialization, and environmental sustainability (FC2), ecological resilience (FC3), and free-plague environments (FC4). Using OLS regressions, FC2, FC3, and FC4 were found to be positively associated with life expectancy at birth, while FC1 was negatively associated. This study suggests that physical environment is an important macro-determinant of the health of the Mexican population, and highlights the usefulness of ecological concepts in epidemiological studies. PMID- 21710015 TI - Nutritional factors associated with chronic non-communicable diseases - the Bambui Project: a population-based study. AB - The increase of chronic non-communicable diseases has been significant. The objective of this study was to identify factors related to food intake, anthropometry and biochemical measurements associated with chronic non communicable diseases. It involved a cross-sectional study among a representative sample of adults and elderly people in Bambui, Minas Gerais State, Brazil. Anthropometric, biochemical and nutrient intake data were evaluated. The study included 409 individuals (55.3% of whom were women), with a mean age of 40.6+/ 16.0 years. There was found to be a 14% rate of obesity associated with high/very high triglycerides and arterial hypertension. Arterial hypertension was present in 22.4% of subjects and correlated with age > 60 years, insufficient protein intake, obesity and high cholesterol. Diabetes was found in 3.7% and was associated with large waist circumference, excessive saturated fatty acids and arterial hypertension. The factors associated with chronic non-communicable diseases were obesity, high total cholesterol, triglycerides and excessive consumption of saturated fatty acids. The identification of the nutritional factors associated with chronic non-communicable diseases can support future interventions. PMID- 21710016 TI - [Completeness of data on live birth certificates and death certificates for early neonatal and fetal deaths in the Ribeirao Preto Region, Sao Paulo State, Brazil, 2000-2007]. AB - This study aimed to evaluate the completeness of data on nine items included in both the certificate of live birth (CLB) and death certificate (DC), as well as the retrieval of data on early neonatal deaths. The study assessed live birth and early neonatal and fetal death records in municipalities in the Ribeirao Preto Region, Sao Paulo State, Brazil, from 2000 to 2007. Database matching for live births and deaths allowed retrieving data on early neonatal deaths. Data completion was good on the CLB and poor on the DC. Retrieval of data related to mortality was satisfactory, except for maternal schooling, number of live born children, and stillbirths. The findings highlight the need to improve completion of the DC and showed that the retrieval process improved the completeness of data from the database on early neonatal deaths. The use of reports on local investigation of deaths is recommended as a strategy to make mortality databases more complete. PMID- 21710017 TI - [The effects of Brazilian Federal regulation on health financing]. AB - The article aimed to analyze the impacts of earmarking revenues and conditional transfers on the supply of health financing in Brazil. After analyzing the role of these Federal regulation mechanisms on decentralized healthcare administration, the article verified the effects on total expenditure in health and disaggregated by level of government, evaluated whether transfers by the Unified National Health System (SUS) were consistent with the evolution in the decentralized supply, and measured the inequalities in per capital health spending by municipalities. The conclusions showed the complementary relationship between earmarking revenues and conditional transfers according to supply, which: (1) increased the share of State and Municipal governments in health financing; (2) provided incentives for the decentralization of primary care according to Federal guidelines; and (3) reduced the inequalities between municipalities in per capita health expenditures. PMID- 21710018 TI - [An infant feeding update program at healthcare centers and its impact on breastfeeding and morbidity]. AB - This study evaluated the impact of an infant feeding update program on exclusive breastfeeding and the incidence of diarrhea and respiratory illness in infants. A randomized cluster field study was conducted in the city of Porto Alegre, Rio Grande do Sul State, Brazil, with 20 healthcare centers. Health professionals received information on the Ten Steps to Healthy Feeding for Children up to Two Years of Age. We evaluated 619 infants 6-9 months of age. The results showed longer duration of exclusive breastfeeding (p = 0.02) in the intervention group but no significant differences in the incidence of diarrhea or respiratory symptoms. Complementary analyses showed that exclusive breastfeeding was longer in the group of children without the occurrence of diarrhea (p = 0.001) or respiratory symptoms (p = 0.03). The data suggest that the training was insufficient to affect incidence of illness, but that it was effective in extending exclusive breastfeeding. PMID- 21710019 TI - [Factors associated with benzodiazepine prescription by local health services in Coronel Fabriciano, Minas Gerais State, Brazil]. AB - Numerous countries have witnessed increasing misuse of benzodiazepines. This cross-sectional study assessed the factors associated with prescription of benzodiazepines for users of the Municipal Health Service in Colonel Fabriciano, Minas Gerais State, Brazil. Data were collected from official records on drug prescription (n = 1,866) from September to October 2006. Bivariate and multivariate analyses using Poisson regression were performed. Prolonged benzodiazepine use was independently associated with benzodiazepine type and patient participation in health programs. Concomitant use of other psychoactive drugs was independently associated with age and participation in health programs. Type of benzodiazepine (clonazepam or diazepam) was independently associated with age and gender, as well as with participation in health programs. Factors associated with benzodiazepine prescription show the problem's extent and should be considered in planning interventions to rationalize the use of these drugs in Brazil, particularly through health program planning. PMID- 21710020 TI - [Diabetes mellitus: factors associated with prevalence in the elderly, control measures and practices, and health services utilization in Sao Paulo, Brazil]. AB - This study analyzes factors associated with diabetes prevalence according to demographic and socioeconomic variables, health status, and lifestyle among 872 elderly living in the city of Sao Paulo, Brazil, in addition to health services utilization and control measures and practices. Reported diabetes prevalence among the elderly was 17.9%, a higher rate than in the adult population. The highest diabetes rates in elderly individuals were associated with: bad or very bad self-rated health, never having consumed alcohol or having stopped drinking, widowhood, and at least one hospitalization in the previous 12 months, independently of age. Among the elderly, 69.9% routinely sought out health services due to their diabetes, and 96.1% received treatment at the services they turned to. There is a lack of information, knowledge, and use of control measures for diabetes among the elderly. Health policies focusing on professional training and family orientation are needed to promote lifestyle changes among the elderly. PMID- 21710023 TI - Multiple queens in founding colonies of the neotropical ant Pachycondyla striata Smith (Formicidae: Ponerinae). AB - In social insects, the typical mode of colony foundation occurs when a single queen is inseminated by a male and establishes a new colony, although we can find interspecific and intraspecific variations in queen number and queen-mating frequencies in a single colony. This study aimed to verify the queen number in Pachycondyla striata (Smith) colonies and to evaluate the level of aggressiveness among workers. We collected 14 colonies of P. striata. The behaviors of individuals from five multiple-queen colonies maintained in laboratory were studied by the method of scan sampling. In order to evaluate aggressiveness, dyadic encounters among heterocolonial and homocolonial workers were performed. The results showed that colonies of P. striata can have two or more mated queens (polygynous colonies) besides to monogynous ones (colony containing one queen). Because in polygynous colonies the number of workers was relatively low, such colonies could represent colonies in the foundation phase that characterize a pleometrosis state. In fact, ovarian development analysis from queens showed that the number of queens in the colonies seemed to be unstable. Despite a few cases of oophagy (egg cannibalism), social hierarchy among queens is unclear in comparison to other Pachycondyla species. In addition, aggressiveness increased with distance among nests. Nearby colonies (less than 1 m apart) showed a low level of aggressiveness, suggesting the presence of polydomy, that is, a unique colony can occupy multiple nests. Polygyny associated to polydomy in founding colonies may confer benefits on growth and dispersion of colonies in the studied environments. PMID- 21710024 TI - Community structure of lice (Insecta: Phthiraptera) from two sympatric gull species: kelp gull (Larus dominicanus) and Franklin's gull (Larus pipixcan) in Talcahuano, Chile. AB - A total of 1,177 lice of four species were collected from 124 kelp gulls (Larus dominicanus) and 137 lice of the same four species from 60 Franklin's gulls (Larus pipixcan). The louse Saemundssonia lari (O Fabricius) (Phthiraptera: Philopteridae) was the most numerous on both gull species, with infestation rates of 4.9 on kelp gulls and 1.8 on Franklin's gulls. The second most abundant louse was Quadraceps punctatus (Burmeister), with a high infestation rate but low prevalence on kelp gulls; those parameters were much lower among lice from Franklin's gulls. The composition and community structure of the lice were similar on both host species, but not their infestation rates. In addition, the feather mite Zachvatkinia larica Mironov (Acari: Avenzoariidae) is recorded from kelp gulls and Franklin's gulls for the first time, while the gamasid mite Larinyssus sp. is recorded from kelp gulls, also for the first time. The population parameters of all species of ectoparasites are discussed. PMID- 21710025 TI - Body size, symmetry and courtship behavior of Dysdercus maurus Distant (Hemiptera: Pyrrhocoridae). AB - This study analyses the role of body size and symmetry in the sexual selection and courtship behavior of Dysdercus maurus Distant. Sexual conflicts signaled by coercive mating, female resistance, and pre-copulation fights illustrate the mating system. Male-female struggles were observed in all mating attempts. Females tried to reject males by pushing or running and even by vigorously shaking their bodies, in attempts to dislodge the male from their dorsum. In spite of sexual conflicts during courtship, females actively chose their mates based on morphological and behavioral traits. Larger males with more symmetrical tibiae and longer tarsi that are better copula imposers were more successful in sexual competition. Evidence is presented that sexual conflict and female mate choice should not be mutually excluded. PMID- 21710026 TI - Cassava shoot infestation by larvae of Neosilba perezi (Romero & Ruppell) (Diptera: Lonchaeidae) in Sao Paulo State, Brazil. AB - Among the pests of cassava, the shoot fly, Neosilba perezi (Romero & Ruppell), is one of the most prevalent. It attacks mainly the terminal shoots and causes infested plants to produce lateral shoots. Reports on this species are rare or inexistent; thus, the purpose of this study was to assess three different areas for N. perezi infestation. The survey began in March 2008 and finished in February 2009. Fortnightly analyses were performed starting 45 days after planting, calculating the rate of infestation by N. perezi larvae in each study area. The areas were correlated separately for each parameter: fortnightly mean temperature, fortnightly mean rainfall, and plant age. The N. perezi larvae occurrence rate was higher in area 1 - which presented the highest population peaks in autumn and winter. There was only a single population peak in area 2, in winter; and area 3 presented the weakest population peak among the three, in November. The shoot fly population dynamics in the studied region is separately correlated to temperature, rainfall and plant age: temperatures above 23oC, relatively high rainfall and older plants seem to have a negative effect on populations of this insect. PMID- 21710027 TI - Feeding behavior of two exotic aphid species on their original hosts in a new invaded area. AB - Greenidea ficicola Takahashi and Greenidea psidii van der Goot (Aphididae: Greenideinae) are Asian aphid species newly introduced in Brazil associated with Moraceae and Myrtaceae. The feeding behavior of G. ficicola and G. psidii was investigated on their respective host plants, Ficus benjamina (Moraceae) and Psidium guajava (Myrtaceae), using the Electrical Penetration Graph (EPG). Fifteen females of each aphid species were monitored during 24h using a DC-EPG GIGA-4 monitor. The time spent in phloem phase (waveforms E1 and E2) was 13.6% of the total recording time for G. ficicola and 0.8% for G. psidii. The average time in the pathway phase (waveforms C and pd) represented 50% of the total time for both species. Aphids spent more time in non-penetration and stylet pathway activities than in the phloem phase or actual feeding. The principal component analysis (PCA) showed that the two species formed different groups in relation to EPG parameters, despite some overlapping. The probing patterns with multiple penetrations of short duration in the sieve elements for both species may indicate apparent unsuitability for sustained feeding on their respective host plants. These results suggest that these two exotic species are in the process of adaptation to their host plants in their new environment and/or the plants may present either chemical or physical barriers against these insects. PMID- 21710028 TI - Immature stages of the Brazilian crescent butterfly Ortilia liriope (Cramer) (Lepidoptera: Nymphalidae). AB - We provide the first information on the morphology of the immature stages (egg, larva, and pupa), oviposition and larval behavior, and host plant, for the Brazilian crescent butterfly Ortilia liriope (Cramer), based on material from Santarem Municipality, Para State, Northern Brazil. Females of O. liriope lay eggs in clusters. After hatching, larvae eat the exochorion and remain gregarious in all but the final instar. The host plant recorded in the study site is Justicia sp. (Acanthaceae). Despite the scarcity of data on the immature stages of Neotropical Melitaeini, we can already say that some morphological and behavioral traits observed in the immature stages of O. liriope are also present in all known genera in this tribe. PMID- 21710029 TI - A new species of Neoblattella Shelford (Blattellidae: Pseudophyllodromiinae) from Amazonas State, Brazil. AB - Neoblattella mista sp. nov. is described and illustrated based on male genitalia and morphological characters of a single specimen collected in the town of Coari, State of Amazonas, Brazil. By studying the literature on the genus, we determined that N. mista sp. nov. differs from the other four known complexes in the morphology of its genital structures, including the supra-anal plate, subgenital plate, right and left phallomeres, median genital sclerite and tergal modification in the abdomen, and is placed in the new "mista complex". PMID- 21710030 TI - New morphological aspects and phylogenetic considerations of Cicindis Bruch (Coleoptera: Carabidae: Cicindini). AB - Cicindis Bruch is a monospecific genus of carabid beetles endemic to Argentina. In this contribution, Cicindis horni Bruch is re-described, with addition of new morphological features of male internal sac, female genital tract and elytral closure. New information on the species' habitat and distribution is also provided. The phylogenetic placement and relationships of Cicindis within the family Carabidae are discussed on the basis of a cladistic analysis. Terminal taxa included representatives of all subfamilies of Carabidae and supertribes of Carabinae, with a major sampling of those taxa considered to be closely related to Cicindini by previous authors. The phylogenetic analysis shows the basal position of Cicindis in a clade that includes Ozaeninae, Omophronini, Scaritinae and Conjuncta. A close relationship of Cicindis with Ozaenini + Metriini is supported by the particular closure of the procoxa and the ventral position of the oviduct with respect to the spermatheca. PMID- 21710031 TI - Taxonomic review of the genus Tachardiella Cockerell (Hemiptera: Kerriidae), with a key to species of lac insects recorded from the New World. AB - The lac insect genus Tachardiella Cockerell is reviewed and 17 species are recognized, including one new species. The adult female of Tachardiella palobrea Kondo & Gullan sp. n. is described and illustrated based on material collected in Argentina on 'brea', Parkinsonia praecox (Fabaceae). The adult female of Tachardiella argentina (Dominguez) is redescribed and a lectotype is designated based on newly discovered syntype material in the Bohart Museum of Entomology, University of California, Davis (BME). Diagnoses and notes are provided for the other species of Tachardiella studied and a lectotype is designated for Tachardiella ferrisi Chamberlin. A taxonomic key to separate all known species of lac insects in the New World is provided. PMID- 21710032 TI - Differential susceptibility of adults and nymphs of Blattella germanica (L.) (Blattodea: Blattellidae) to infection by Metarhizium anisopliae and assessment of delivery strategies. AB - Microbial insecticides for cockroach control, such as those containing entomopathogenic fungi, may be an alternative to reduce contamination by chemicals in housing and food storage environments. Virulence of isolate ESALQ1037 belonging to the Metarhizium anisopliae complex against nymphs and adults of Blattella germanica (L.), and its infectivity following exposure of insects to a contaminated surface or to M. anisopliae-bait were determined under laboratory conditions. Estimated LD50 15 d following topical inoculation was 2.69 x 10(5) conidia per adult, whereas for nymphs the maximum mortality was lower than 50%. Baits amended with M. anisopliae conidia had no repellent effect on targets; adult mortality was inferior to 25%, and nymphs were not susceptible. All conidia found in the digestive tract of M. anisopliae-bait fed cockroaches were unviable, and bait-treated insects that succumbed to fungal infection showed a typical mycelial growth on mouthparts and front legs, but not on the hind body parts. As opposed to baits, the use of a M. anisopliae powdery formulation for surface treatment was effective in attaining high mortality rates of B. germanica. Both nymphs and adults were infected when this delivery strategy was used, and mycelia growth occurred all over the body surface. Our results suggest that the development of powders or similar formulations of M. anisopliae to control B. germanica may provide faster and better results than some of the strategies based on baits currently available. PMID- 21710034 TI - Antibiosis and antixenosis of six commonly produced potato cultivars to the green peach aphid, Myzus persicae Sulzer (Hemiptera: Aphididae). AB - The antibiotic and antixenotic resistance of six commonly produced potato cultivars in Iran including Aozonia, Agria, Cosima, Cosmos, Kondor and Savalan to the green peach aphid, Myzus persicae Sulzer, were investigated under laboratory conditions at 20 +/- 2oC, 65 +/- 5% RH and 16:8h (L:D) in 2009. Antibiosis experiments showed significant differences in the developmental time, nymphal survivorship, fecundity, adult longevity of the green peach aphid among the potato cultivars. Intrinsic rate of natural increase (r m) for apterous aphids varied significantly with the potato cultivars on which the aphids were reared. This value ranged from 0.225 to 0.293 females/female/day, which was lowest on Cosmos and highest on Aozonia. Additionally, the estimated net reproductive rate (R0) and finite rate of increase (lambda) for apterous aphids were the lowest on Cosmos. For the antixenosis experiment, no significant difference was found in aphid's preference to the potato cultivars. However, Aozonia was preferred more than the other five cultivars by the apterous aphids. Therefore, our results demonstrated that among the investigated cultivars the Cosmos cultivar is moderately resistant to the green peach aphid. PMID- 21710033 TI - Toxicity of ethanolic extracts from Lippia origanoides and Gliricidia sepium to Tetranychus cinnabarinus (Boisduval) (Acari: Tetranychidae). AB - Botanical compounds with insecticidal and acaricidal activities have been used in pest management with different levels of success. Toxicity of ethanolic extracts obtained from wild oregano (Lippia origanoides) and gliricidia (Gliricidia sepium) to Tetranychus cinnabarinus (Boisduval) were evaluated. Mite population was collected from black bean plants growing in Urachiche Municipality, Yaracuy State, Venezuela. Ethanolic extracts of wild oregano and gliricidia leaves were evaluated at different concentrations (5, 10, 15, and 20%) using the leaf disk immersion technique. The presence of alkaloids, flavonoids, phenols and tannins, essential oils and saponins was verified in the plant material used in our study. Tetranychus cinnabarinus oviposition decreased at a rate of 43.7% or 57% when 5% oregano or gliricidia extracts were used, respectively. Also, 10% oregano or gliricidia extracts caused 42.2% or 72.5% of mortality to T. cinnabarinus, respectively. Ethanolic extracts showed acaricidal effects on T. cinnabarinus, as evidenced by maximum mortality (96.6% and 100% caused by wild oregano and gliricidia, respectively) when used at a concentration of 20%. Our results showed that gliricidia and wild oregano are promising for the management of T. cinnabarinus, although their field efficacy remains to be evaluated. PMID- 21710035 TI - Induction of insect plant resistance to the spittlebug Mahanarva fimbriolata Stal (Hemiptera: Cercopidae) in sugarcane by silicon application. AB - Changes in the agroecosystem with the increase of green cane harvesting in Brazil affected the insect populations associated to this crop, and secondary pests like the spittlebug Mahanarva fimbriolata Stal, became much more important. Many studies have demonstrated the active role played by silicon in plant defense against herbivory. The objective of this study was to evaluate the effects of silicon applications on the biology of the spittlebug reared on two resistant (SP79-1011 and SP80-1816) and one susceptible (SP81-3250) sugarcane cultivars. Sugarcane plants were grown under greenhouse conditions and submitted to different treatments: with and without silicon fertilizer in two different soil type (sandy and clay soil). The newly hatched nymphs were transferred to sugarcane roots and placed into boxes with lids, to keep a moistened and dark environment favoring their growth and maintenance of the root system, providing food access to the developing nymphs. After emergence, adult males and females were placed in cages for mating and oviposition. The silicon absorbed and accumulated in the plant caused an increase in nymphal mortality, and depending on the sugarcane cultivar tested this element also provided an increase in the duration of the nymphal stage and a decrease in the longevity of males and females. 'SP79-1011' presented the highest silicon content in leaves, and M. fimbriolata had the highest nymph mortality and the shortest female longevity. The pre-oviposition period, fecundity and egg viability were not affected by the silicon content in plants or the cultivar used. PMID- 21710036 TI - Epidemiological study of myiases in the Hospital do Andarai, Rio de Janeiro, including reference to an exotic etiological agent. AB - Myiases are infestations with dipteran larvae in both necrosed and living tissues, the food source of these insects. These illnesses occur in warm humid climates, and are most frequent in developing countries. We assessed the epidemiological aspects and the influence of climate on the occurrence of myiases and the bioagents in patients admitted to the federal Hospital do Andarai in Rio de Janeiro from February 2007 to 2008. The influence of abiotic factors (temperature, humidity, and rainfall) on the incidence of myiases was investigated by using the Pearson's correlation test. Of the 40 patients studied, the prevalence of myiases was higher in adults, particularly in the 40 to 65 year old (37.5%) African descent males (57.5%). Most of the injuries were caused by trauma (62.5%). Some patients made use of licit (50%) and illicit drugs (17.2%). The occurrence of myiases was not affected by the abiotic factors investigated. The cases reported here were treated in only one hospital, indicating that the disease is relatively common. The most frequent bioagent was Cochliomyia hominivorax (Coquerel), but Cochliomyia macellaria (Fabricius), Chrysomya albiceps (Wiedemann) and Dermatobia hominis (Wiedemann) (Diptera: Calliphoridae) were also detected causing myiases. Chrysomya albiceps is an exotic etiologic agent of myiases. PMID- 21710037 TI - Description of the female of Evandromyia rupicola (Martins, Godoy & Silva) with a review of the rupicola series (Diptera: Psychodidae: Phlebotominae). AB - The rupicola series was proposed initially for Evandromyia rupicola (Martins et al) and Evandromyia correalimai (Martins et al), and recently extended with the inclusion of Evandromyia gaucha Andrade-Filho et al and Evandromyia grimaldii Andrade-Filho et al. The female of E. rupicola is here described and illustrated for the first time and its male is redescribed and drawn on the basis of specimens captured in forest on the coast of the state of Sao Paulo, Brazil. The head and genitalia of both sexes of E. correalimai are also illustrated. The distinctive traits among females of the four species and of males of E. rupicola, E. correalimai and E. grimaldii, and the distribution range of these species are commented. PMID- 21710038 TI - [Fruit flies (Diptera: Tephritidae) and their parasitoids (Hymenoptera: Braconidae) associated to host plants in the southern region of Bahia State]. AB - The association among Anastrepha species, braconid parasitoids and host fruits in southern Bahia is recorded. Doryctobracon areolatus (Szepligeti) was associated with A. serpentina (Wied.) in Pouteria caimito, A. bahiensis Lima in Helicostylis tomentosa, A. sororcula Zucchi in Eugenia uniflora, and A. obliqua (Macquart) in Spondias purpurea. Anatrepha obliqua was unique in fruits of Averrhoa carambola, but associated with D. areolatus, Asobara anastrephae (Muesebeck) and Utetes anastrephae (Viereck). In Achras sapota, A. serpentina was associated with A. anastrephae and D. areolatus, while in Psidium guajava, A. fraterculus (Wied.) and A. sororcula were associated with D. areolatus and U. anastrephae. PMID- 21710039 TI - First record of Spintherophyta semiaurata (Klug) (Coleoptera: Chrysomelidae) damaging strawberry flowers. AB - Spintherophyta semiaurata (Klug) is reported for the first time damaging flowers of strawberry (Fragaria x ananassa) in the municipality of Sao Jose dos Pinhais, State of Parana, Brazil. PMID- 21710040 TI - First report of the red palm mite, Raoiella indica Hirst (Acari: Tenuipalpidae), in Brazil. AB - The presence of the red palm mite, Raoiella indica Hirst, is reported for the first time in Brazil. This invasive mite was found in July 2009 infesting coconut palms and bananas in urban areas of Boa Vista, State of Roraima, in northern Brazil. Comments on the possible pathways of R. indica into the country, present and potential impact of its introduction and mitigating measures to prevent or to delay the mite spread in Brazil are presented. PMID- 21710041 TI - Neochrysocharis formosa (Westwood) (Hymenoptera: Eulophidae), a newly recorded parasitoid of the tomato moth, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae), in Argentina. AB - We report the first record of Neochrysocharis formosa (Westwood) parasitizing larvae of the tomato moth, Tuta absoluta (Meyrick), in tomato crops in Northern Buenos Aires Province, Argentina. Tomato moth larvae were sampled during four consecutive growing cycles, between 2003 and 2005, in 10 sites. Neochrysocharis formosa was present only in organic outdoor and protected crops, and predominantly during the late season. Parasitism rates varied from 1.5% to 5%. The finding of this species is a new record for Argentina and South America, and T. absoluta is a new host record. PMID- 21710042 TI - [Compliment to surgery]. PMID- 21710043 TI - [The "ethical" repair of the abdominal wall]. PMID- 21710044 TI - [Functional results of parathyroid autotransplantation in one single pocket for treatment of secondary hyperparathyroidism]. AB - OBJECTIVE: To evaluate the operation and surgical time of autotransplanted parathyroid in a single site comparing it to the implant performed in five and twenty locations. METHODS: Patients who underwent total parotidectomy with auto implant (Ptx-AI) for secondary and tertiary hyperparathyroidism were evaluated in groups of 20 implant sites (A), 5 sites (B) and single site (C), compared as for Functional Status (FE) of the implant and the surgical time of the procedure. Four functional states were determined according to the systemic level of PTH: 1 below normal, 2-normal, 3-high, no more than three times and 4 - more than three times higher. RESULTS: There were 349 patients subjected to Ptx-AI for renal hyperparathyroidism from 1994 to 2009. For the functional study, 101 patients were eligible for the following observations: group A (n = 30) - 16.6% EF1, 50% EF2, 23.3% EF3 and 10%EF4; group B (n = 41) - 14.6% EF1, 58.5% EF2, 22% EF3 and 4.9% EF4; Group C (n = 30) - 17% EF1, 57% EF2, 20%EF3 and 6% EF4 (p = 0.9, x2). But in group C the mean operative time of implant was statistically lower (7.9 minutes) compared to the average of 5 site (18.6 minutes) and 20-site (44 minutes) implants in 66 evaluated patients (p<0,0001, ANOVA). CONCLUSION: The self-implantation in a single site decreases the operative time without changing its functionality. PMID- 21710045 TI - Warthin's tumor of the parotid gland: study of 70 cases. AB - OBJECTIVE: To report the clinical characteristics, treatment and complication of Warthin tumors. METHODS: we conducted a retrospective study of 70 patients undergoing resection of papillary lymphomatous cystadenoma. VARIABLES: age, sex, ethnicity, presence or absence of smoking, primary site of tumor, tumor size in cm, presence of bilateral tumor, type of operation, multicentricity, treatment complications, recurrence and follow up. RESULTS: Forty-four patients (62.8%) were male and 26 (37.2%) female, with a mean age of 56.7; smoking was present in 55 (78.6%) patients; 66 (94.3%) tumors were unilateral and four (5.7%) bilateral, with an average size of 4.1 cm on physical examination. The complications were 14 (19%) cases of facial paresis and / or paralysis, seroma in 10 (13.8%), Frey's syndrome in three (4%), hematoma in two (2.7%) and wound infection in one (1.5%) case. CONCLUSIONS: Warthin tumors have a higher incidence in male smokers and predominantly unilateral location of the parotid gland. Superficial parotidectomy with preservation of facial nerve was effective in 100% cases. Complications were transient paresis or paralysis, seroma, Frey syndrome, hematoma and wound infection. PMID- 21710046 TI - Bile duct injury following cholecystectomy. AB - OBJECTIVE: To describe the epidemiological, clinical and surgical features of patients with iatrogenic bile duct injury (IBDI) attending the General Hospital of Fortaleza (HGF) during the period from 2005 to 2009. METHODS: We conducted a retrospective study of medical records of patients admitted to HGF with the diagnosis of IBDI, evaluating the following variables: gender, age, origin, conditions of cholecystectomy, type of surgery, symptoms, exams performed, surgical findings, classification of injury, treatment, complications, total duration of hospitalization and discharge conditions. RESULTS: There were 27 confirmed cases of IBDI. Two injuries occurred during laparoscopic cholecystectomy. Only one patient was diagnosed intraoperatively. The most frequent sign was jaundice after cholecystectomy. Hepato-duodenal Y-en-Roux anastomosis was the most often employed surgical technique (85.2%). Most patients were discharged from hospital in good clinical condition (88.8%), however, we found high morbidity rates for this disease, exemplified by the multiple hospitalizations and longer hospital stay (mean 31 days). CONCLUSION: Most injuries occurred during open cholecystectomy, jaundice was the most frequent sign upon admission. There was a high hospitalization length of stay, caused by postoperative complications, which could be explained by delayed diagnosis resulting in a large delay in treatment. PMID- 21710047 TI - Gallbllader cancer: 10 years of experience at an Amazon reference hospital. AB - OBJECTIVE: To evaluate the epidemiological aspects of surgical patients with gallbladder cancer (GC) enrolled in a University Hospital in Bethlehem (State of Para - PA), in the period 1999-2009. METHODS: observational, retrospective, descriptive and analytical study of secondary sources of patients with GC in the period 1999-2009. We analyzed 75 medical records, with 34 patients studied. The information collected was used for the TNM tumor staging of GC and to characterize the clinical and surgical population. RESULTS: 79% were female, mean age 66.2 +/- 11 years and duration of symptoms was 10.8 +/- 17.2 months, with no statistical relationship with the stage of disease. Pain in right upper quadrant, nausea and jaundice prevailed as signs / symptoms. Gallstones were present in 91% of cases and were positive in 100% of patients with stage I / II. The sensitivity of ultrasound to preoperatively suggest GC was 14.28%. The simplest operation performed was cholecystectomy, with the predominant intraoperative finding being hepatic invasion. Adenocarcinoma was the predominant histologic type, especially for stages III and IV. CONCLUSION: The present study showed high incidence of gallstone disease. Advanced stage adenocarcinoma was the most prevalent. This resulted in a low rate of operations with curative intent, in 30% of the patients, and a mortality rate of 21%. The appreciation of symptoms and early investigation by imaging could facilitate treatment in early stages of GC, providing a better prognosis for patients. PMID- 21710048 TI - Indices of diagnostic abdominal ultrasonography in acute appendicitis: influence of gender and physical constitution, time evolution of the disease and experience of radiologist. AB - OBJECTIVE: To assess the value of abdominal ultrasonography in the diagnosis of acute appendicitis and the influence of gender, physical constitution, experience of the radiologist and the time evolution of the disease on the results of diagnostic indices. METHODS: We prospectively evaluated 156 patients with clinical diagnosis of acute appendicitis who underwent laparoscopic appendectomy and abdominal ultrasonography, together with pathology of the excised appendices. Patients were allocated in relation to BMI in both groups (below or above 25 kg/m2) and radiologists, in three groups according to their professional experience (less than five years, between five and 10 years and more than 10 years). The survey also assessed the influence of gender and time of disease progression using the median of 36 hours. RESULTS: The sensitivity and specificity of abdominal ultrasonography for diagnosing appendicitis were 64.9 and 72% respectively. Gender, body mass index, length of experience of the radiologists in the three groups and time of onset of symptoms showed no significant differences in the establishment of sonographic diagnosis of acute appendicitis. CONCLUSION: The abdominal ultrasonography showed low sensitivity and specificity and little contribution to the diagnosis of acute appendicitis. Gender, physical constitution, the experience of the radiologist and time of onset of symptoms did not affect the outcome of the sonography. PMID- 21710049 TI - Interval cytoreduction in advanced ovarian cancer: Santa Casa Sao Paulo experience. AB - OBJECTIVE: To analyze the interval cytoreduction in patients with advanced ovarian cancer. METHODS: A prospective study was carried out with 25 patients with advanced ovarian cancer (stages IIIC or IV) who underwent interval cytoreduction. Nonresectability criteria were based on the ones from Gustave Rousy Institute. After induction chemotherapy and rapprochement we evaluated the rates of optimal surgery and the morbidity and mortality of the procedure in addition to the overall survival at two years. RESULTS: optimal cytoreduction was possible in 17 patients (68%) with morbidity and mortality from 8% to 4%. The overall survival at two years was 68%. CONCLUSION: The interval cytoreduction is an alternative therapy in advanced ovarian cancer, allowing optimal cytoreduction opportunity to patients suffering from unresectable disease, with acceptable morbidity and mortality. PMID- 21710050 TI - Study of arterial pattern of 200 renal pedicle through angiotomography. AB - OBJECTIVE: To investigate the prevalence and distribution of renal arteries and their branches in vivo, correlating the particularities found in them with sex and laterality. METHODS: Two hundred renal pedicles were studied by CT angiography and its arteries analyzed according to number, position of origin, size, length and trajectory in relation to renal segments. Its frequency and laterality were surveyed regarding gender and age. RESULTS: There were multiple arteries in 61.5% of the pedicles (56% in the right and 67% in the left), occurring in 65% of men and 58% of women. The aortic origin to the multiple arteries was more frequent on the right and, more often, the renal arteries originated between vertebrae L1 and L2 as pre-hilar division of the main artery. The average length of the main artery was higher in right kidneys with a single artery. There was no difference between the diameters of the main renal arteries. CONCLUSION: There is a higher prevalence of multiple renal arteries than the one described in the literature, with no difference for gender or laterality. The renal arteries originated more frequently between vertebrae L1 and L2, with divisions of the pre-hilar route and main artery to the hilum of the kidney. The average length of the main artery is greater on the right and in kidneys with single artery. There was no difference in diameter between the main renal artery between kidneys with single and multiple arteries. PMID- 21710052 TI - Healing of the abdominal wall after parcial hepatectomy. AB - OBJECTIVE: To evaluate the wound healing of the abdominal wall incision in hepatectomized rats as for the concentration of collagen, inflammatory reaction and angiogenesis. METHODS: We used 48 rats randomly assigned to laparotomy with or without hepatectomy. The scars were studied in the 3rd, 7th and 14th postoperative days. We analyzed the density of collagen by the histochemical method and angiogenesis, by immunohistochemistry. RESULTS: The analysis showed a lower total collagen concentration in skin and subcutaneous tissue in the abdominal scars of the experiment group (p3 = 0.011, p7 = 0.004 and p14 = 0.008). The density of collagen I was lower in the hepatectomy group, especially in the third day, in the skin, subcutaneous tissue (p = 0.038) and in the aponeurotic plane (p = 0.026). There was a lower concentration of collagen III in the two abdominal wall layers studied, although not statistically significant. The inflammatory response was similar at all times in both groups. It was found that angiogenesis was developed earlier in the control group (p3 = 0.005 and p7 = 0.012) and later in the experimental group (p14 = 0.048). CONCLUSION: Hepatectomy leads to a delay in the healing process, interfering with collagen synthesis and angiogenesis. PMID- 21710051 TI - Fatal trauma injuries in a Brazilian big metropolis: a study of autopsies. AB - OBJECTIVE: This study aims to review a series of deaths by trauma in a large metropolis. The intention is to identify preventable causes of death. METHODS: We prospectively studied 500 unselected and consecutive cases of death associated with trauma. The study variables were: mechanism of injury, etiology, site of injury, surgical intervention, medical malpractice, damaged organs and the prevention of mortality. The cases were grouped according to the mechanism of injury in: penetrating trauma, blunt trauma, poisoning, drowning, burns and suffocation. RESULTS: We examined 418 (83.6%) males and 82 (16.4%) females (mean age 39 +/- 19.6 years, ranging from three to 91 years). Penetrating trauma accounted for 217 (43%) cases, while blunt trauma accounted for 40% of cases. The most common mechanism of injury in death by penetrating trauma was gunshot, representing 41% of cases. Within the set of blunt trauma, the most common mechanism was traffic accident, which represented 22% of total deaths. There were 71 (14%) cases of preventable deaths: thromboembolism in 35 (7%), infectious complications in 25 (5%), medical malpractice in seven (1%) and treatable lesions in outpatients in five (1%). CONCLUSION: This study shows that traumatic death in the city of Sao Paulo is associated with serious and complex injuries. Prevention of these types of death would be related to the control of violence. PMID- 21710053 TI - Current role of imaging methods in the diagnosis of cystic solid pancreas neoplasms: part II. AB - The authors address the value of endoscopic retrograde cholangiopancreatography, ultrasonography, computed tomography, magnetic resonance imaging and endoscopic ultrasound for the diagnosis of cystic and solid neoplasms of the pancreas, demonstrating that each of them is of great importance to undoubtedly increase the diagnostic accuracy of the biliopancreatic system diseases. The best method for each of several tumors is then determined. PMID- 21710054 TI - Simultaneous left colectomy and standard hepatectomy reformed by laparoscopy. AB - Laparoscopic approaches have been increasingly used in patients with colorectal or liver cancer. Simultaneous colectomy and hepatectomy are considered safe techniques and present similar oncological results regardless of the location of the primary tumor when there are fewer than four liver metastases, since there is no increase in morbidity or decrease in survival. The development of laparoscopic techniques and materials has made the combined resection of the colon and liver a very attractive option. The aim of this study is to demonstrate the synchronous resection of the sigmoid tumor and single liver metastasis treated by purely laparoscopic colectomy and liver left lateral sectorectomy. PMID- 21710055 TI - [Idiopathic pneumoperitoneum: case report]. AB - Idiopathic pneumoperitoneum is considered a rare condition, as only twenty cases have been described in the last thirty years. The authors report a case of idiopathic massive pneumoperitoneum in a patient aged 45, showing the possible causes of this clinical picture based on a review of medical literature. PMID- 21710056 TI - [Testicular sarcoidosis: a diagnosis to be considered]. AB - Sarcoidosis is a disease of unknown etiology, characterized by the presence of noncaseating granulomas in multiple organs. We present a case of testicular sarcoidosis in a white, 55-year-old man who has come to our department complaining of bilateral testicular discomfort and weight loss. PMID- 21710057 TI - Achievements and new challenges in Nursing Science. PMID- 21710058 TI - [The pain and behavior of women during labor and the different positions for childbirth]. AB - This study evaluated the pain intensity and behavior during labor and delivery, among women who had natural childbirth, without analgesia, in one of the following positions: semi-sitting, lying on the left side, and lithotomy. This is a descriptive, cross-sectional and correlational study. The instruments used were a validated questionnaire that evaluates pain and behavior during labor and childbirth, from the women's perspective, and two pain scales: one analog and one alphanumerical. It was observed that the pain among women who had childbirth in a lithotomy position was significantly smaller compared to those lying on the left side (p=0.003), though women chose the positions. There was an association between pain and behavior. Pain in labor and childbirth were associated among each other, as was the behavior in these two moments. The results point at an association between the position at childbirth and pain, but it was not possible to identify factors to explain this association; therefore, there is a need for longitudinal studies. PMID- 21710059 TI - [Nursing consultation in child care: the experience of nurses in the Family Health Strategy]. AB - The objective of this study was to understand the meaning that the nurses working in the Family Health Strategy assign to the nursing consultation in child care. The theoretical framework was Symbolic Interactionism, and the methodological was the Grounded Theory. Data collection was performed with seven nurses by means of a semi-structured interview and participant observation. The comparative data analysis identified the conceptual category: Promoting individual and collective changes by means of comprehensive care. It was found that nurses value the nursing consultation in child care, they consider it important and acknowledge its potential to promote significant comprehensive changes regarding children, their families, and in the context of the community, in the preventive as well as in the curative aspect, and thus they feel fulfilled. Nevertheless, nurses deal with personal and structural difficulties, and are affected by the beliefs, values and social conditions of the assisted population, and, therefore, recognize they need better preparation to perform this activity. PMID- 21710060 TI - [Pediatric Patient Classification System: construction and validation of care categories]. AB - Patient classification is essential for managing a hospital unit. Literature, however, does not present conceptualizations of pediatric patient categories. The objectives of this study were to define and validate pediatric patient care categories, according to the level of dependency of the nursing team. The care categories were defined based on a literature review, and the content of the proposed categories was validated by a group of judges involved in managing and providing care in a pediatric unit, and by judges involved in pediatric education and research as well as in the construction of patient instruments. Five care categories were established and validated: Minimal, Intermediate, High dependency, Semi-intensive and Intensive. The validation of the care categories were the basis for constructing a system for the classification of pediatric patients, that may contribute with the decision making process of nurses working in management and health care. PMID- 21710061 TI - [Preventing school violence: an evaluation of an intervention program]. AB - School violence (bullying), is currently considered a growing public health issue across the globe. It is essential to intervene in order to improve the quality of life of children/adolescents at school. Therefore, it should be a research priority to include the issue in the agenda of nurses. The objective of this study was to evaluate the results of an anti-violence program implemented with 307 secondary level students in a school in Lisbon. The evaluation before and after the program was performed using a questionnaire that was elaborated and validated for this study. We found that before the intervention, there was a high level of bullying (50% victims and 35% aggressors), and that the aggressions also included teachers (7%) and other school workers (9%). The program consisted of building awareness/preparation in teachers and parents and practicing social competencies among the students. After the intervention significant results were observed in the global reduction of school violence. PMID- 21710062 TI - [Life styles in adolescence: sexual behavior of Portuguese adolescents]. AB - Recent studies have shown that adolescents have initiated their sex lives earlier and earlier, without, however, receiving consistent sex education. The objectives of this study were to analyze the sexual behavior of adolescent high school students and identify the habits of sexual health in sexually active adolescent high school students. An exploratory study was conducted with 680 adolescents, whose age ranged between 15 and 19 years. Results showed that most participants had not initiated their sex life; boys are those who most report having had sexual relations; not all the interviewed adolescents used condoms during sex; most adolescents do not practice sexual health surveillance. It is important for sexually active adolescents to receive health care and counseling. Health institutions and their workers must be proactive in trying to approach adolescents. PMID- 21710063 TI - [Listening to the mothers of individuals with oral fissures]. AB - This descriptive study was performed using a qualitative approach. The objective was to listen and report on the etiology of the malformation and learn about the beliefs of relatives regarding the manifestation of oral fissures. Data collection was performed from March to June 2009 using semi-structured interview and analyzed using content analysis. Five categories emerged: mother's reaction, feelings of the mothers and of the family, the behavior of the team, knowledge of the causes, and beliefs. The results permitted to learn about the beliefs regarding the theme and adjust the orientations of the nursing tem and other health professionals to mothers of individuals with oral fissures, helping the relatives throughout all the phases of child development during the therapeutic process. PMID- 21710064 TI - [Family discussion in the family health strategy: a working process under construction]. AB - The objective was to follow the working process of a family health team in their regular meetings held to discuss family cases. This study used a qualitative approach, founded on the theoretical and methodological framework institutional schizoanalytic analysis. Seventeen meetings were followed, which counted with the participation of an average of 7 to 8 of the 17 workers participating in the study. The team held discussions on the families, and classified them according to the risk criteria, reviewed what had been accomplished in the meting and searched for action alternatives. There were disagreements when participants faced differences and difficulties to be heard by their colleagues, which were gradually overcome, and made it possible for the members to share care situations they had in common. The team made an effort to analyze the how they take care of the families and to get them to integrate. It was concluded that the meetings favor the production of care and the construction of group work as the team, while delivering care, deals with the subjectivities produced in their practice. PMID- 21710065 TI - [Skin lesions in the intraoperative period of cardiac surgery: incidence and characterization]. AB - The main objective of this exploratory, descriptive cohort study was to verify the incidence of patients submitted to cardiac surgery who developed skin lesions during the intraoperative period, and characterize the lesions. Data collection was performed at the Surgery Department of a public teaching hospital, of tertiary health care, mostly surgical, specialized in cardiology, and located in Sao Paulo. The study sample consisted of 182 patients. The study was performed with a significant p (<0.05) in nonparametric statistical tests. The incidence found for patients submitted to cardiac surgery who developed skin lesions due to the preoperative period was 20.9%. It was observed that 19.2% of lesions were Pressure Ulcers (PU) in stage I; 1.1% of lesions were abrasive; 1.1% incisive; 0.5% lacerative; 0.5% superficial electrical burns; and 0.5% PU in stage II. PMID- 21710066 TI - [Nursing professionals' knowledge about erythropoietin]. AB - This study was performed with the objective to evaluate the knowledge that nursing professionals have about the process of preserving, preparing and administering erythropoietin (EPO). This exploratory, descriptive study used a quantitative approach. It was performed at a Dialysis Center, from January to March 2009, and consisted on applying a questionnaire to 40 nursing professionals. All ethical aspects were taken into consideration. About the interaction of EPO with the patients' blood pressure, 87.5% had inadequate knowledge; only 32% knew the ideal temperature to preserve the drug, and 52.5% believe that it should be removed from the refrigerator about 15 to 30 minutes before its administration; intravenous administration was the most reported. Among the care before the administration, the most frequent was checking the expiration date; 57.5% used exclusive syringe for the administration and 95% usually register having administered the drug. PMID- 21710067 TI - [(Lack of) control of clinical and anthropometrical parameters in individuals with coronary artery disease]. AB - This cross-sectional study evaluated the clinical and anthropometrical parameters of 100 individuals with coronary artery disease, who were assisted at preventive cardiology outpatient clinic at a public hospital in Salvador/BA. Data collection was performed through interviews and both clinical and laboratory evaluations. The results were analyzed as averages and percentages. Most participants were black men, aged <60 years, married, low education level and small income, unemployed and diagnosed with myocardial infarction. Most reported having arterial hypertension, dyslipidemia, a sedentary lifestyle, and had quit smoking and drinking. All women and 82% of the men had an increased abdominal circumference, 19% had causal blood glucose>200 mg/dl, 36% was overweight, 28% were obese, 65% were in soma stage of hypertension, 65% had low HDL-C and 43% had high total cholesterol. It was observed that individuals with high cardiovascular risk and deficient socioeconomic conditions show a lack of control of several cardiovascular risk factors, thus demanding effective health care practices to control the illness. PMID- 21710068 TI - [The importance of communication during the postoperative recovery period]. AB - The objective of this study was to learn about the importance of communication when the nursing team gives postoperative orientations to patients and/or relatives at a private institution, and learn their perception about those orientations. This cross-sectional, descriptive study was performed using a qualitative approach, having Interpersonal Communication and Content Analysis as the theoretical and methodological frameworks, respectively. Participants were 16 patients interviewed in the postoperative period. Results showed that the nursing team focused the orientations on the instrumental techniques of the professions and did not approach the individuals in a holistic manner. It was also observed that when the nurse stands away from the patient and/or does not provide appropriate information, it generates feelings of anxiety, fear, insecurity and a sensation of lack of care in the patients. On the other hand, when the nursing team is present and provides coherent information, patients reported high satisfaction and a feeling of being well cared for. PMID- 21710069 TI - [The experience of disease in cystic fibrosis: the paths to comprehensive care]. AB - Cystic Fibrosis is a chronic disease with an extensive impact on family life. The experience of disease is the manner how individuals respond to the disease, assigning meaning meanings and searching for ways to deal with it in their daily lives. The objective of this study was to understand the experience of Cystic Fibrosis in the family context. This is an ethnographic study, performed with families of children assisted at a teaching hospital located in the state of Sao Paulo. Results were divided into the themes past, present and future, and all phases were permeated with the search for the meaning of the disease and social support, the importance of religion and spirituality, and child's socialization. Knowing the experience in the disease and the social network is indispensible when planning comprehensive care. This is an innovative approach in health care for chronic diseases. PMID- 21710070 TI - [Health care support to patients with AIDS: the convoy model and nursing]. AB - The objective of the present study was to know the relationship and the exchange of support between patients with AIDS and the people around them. This study is based on the convoy model of social relations, which, as one of its features, presents the network as three concentric circles. Participants were people who were hospitalized and talked about the health care support their received from the people close to them, i.e., those belonging to the internal convoy circle. Most participants described the circle as being composed by a maximum of five members, with relatives being the most common. Health professionals must know patients and their convoy, and be able to recognize them in the pscychosocial and cultural context so as to favor the acceptance of being HIV-positive, the need to make changes to their lifestyle, help with health care and adhere to the treatment. PMID- 21710071 TI - [Social representations of people with diabetes regarding their perception of family support for the treatment]. AB - The objective of this qualitative study was to identify the social representations that people with diabetes have on their perception of family support for the treatment. The Theory of Social Representations was used as the theoretical and methodological framework. Participants were 41 people with diabetes assisted at a university in the state of Sao Paulo in 2007. The focal group strategy was used for data collection, and thematic content analysis was performed. Results revealed three categories: family support is present in the everyday life of people with diabetes; the family does not always support the person with diabetes in his or her needs; the person with diabetes assumes the responsibility to trigger family support. Participants see family support as a relevant factor for the treatment, but they also point out that excessive control from relatives limits their autonomy and originates ambiguous feelings. The multiprofessional team must take into consideration that knowing social representations helps improve the health care delivered to people with diabetes. PMID- 21710072 TI - [Profile of the elderly trauma victims assisted at an Emergency Unit]. AB - The objective of this study was to identify the epidemiological profile of elderly victims assisted at the Emergency unit of a university hospital. This is a quantitative, descriptive and cross-sectional study. Data treatment was performed using descriptive statistics, charts and tables. Most victims lived in de Campinas (93.5%) and were females (66.7%) with ages between 70 and 74, and presented comorbidities (77.8%), of which arterial hypertension was the most common. As for the type of accident that resulted in the trauma, the highest incidence was falling from their own height (79.6%). The resulting lesions were characterized by the predominance of superficial lesions (22.7%) followed by mild brain injury (15.1%). As to the victim's destination in the first 24 hours, 49.1% were discharged and 22.2% were admitted for surgery. PMID- 21710073 TI - [Quality of life and voluntary work among the elderly]. AB - This cross-sectional, comparative study was performed with the objective to evaluate the quality of life of elderly individuals who perform volunteer work, compared to those who do not. The WHO Quality of Life questionnaire was applies in a group of 166 elderly individuals who performed volunteer work and to another 33 who did not. Results show most are women, single and with high-level education. Compared to No statistically significant difference was found between the groups for the quality of life scores in the physical and environmental domains (p>0.05). In the psychological and social relations domains, and in the global evaluation, it was observed that volunteers had higher scores (p<0.05). In the linear regression model, performing volunteer work appeared as a determinant for better quality of life in the psychological domain and global evaluation. It is suggested that volunteer work is a mechanism to promote quality of life among the elderly, and can be encouraged by health professionals. PMID- 21710074 TI - [Urinary incontinence and the criteria of frailness among the elderly outpatients]. AB - The objectives of this study were to verify the occurrence of urinary incontinence (UI) and its characteristics in pre-frail and frail elderly patients of a geriatrics outpatient clinic, compare the presence of frailness criteria among the elderly with and without UI and identify among the frailty criteria the chance of risk for UI among those elderly outpatients. Participants were 100 elderly individuals, with an average age of 76.2 years; 65 participants reported UI, 71.3% of which presented three or more frailness criteria. The occurrence of UI was greater in frail participants (p=0.0011). Multivariate analysis showed that the criteria slowness (OR=4.99) and exhaustion (OR=4.85) has a statistically significant relation with UI. The occurrence of UI was high and participants who presented slowness have a risk almost five times greater to presenting UI while those reporting exhaustion have a risk five times greater for UI compared to those without these criteria. PMID- 21710075 TI - [Living with mental disorders: family members' perspective have on primary care]. AB - The objective of this qualitative study was to identify the service that is offered to the family members of patients with mental disorders at Primary Care Units, and understand the everyday life of that family. Data collection was performed from May to June 2007, by means of semi-structured interviews and observation of five families at their homes. Thematic analysis of the data was performed, generating two categories: 1) mental disorder from the family's perspective and the relation with the health service; 2) living with the mental illness. Result confirm the importance of seeing the family of patients with mental disorders as clients of the care process, and the need to prepare health professionals to answer the needs of the people that seek these services. PMID- 21710076 TI - [Mental health care today]. AB - The objective of this study was to identify the sociodemographic characteristics of caregivers to people who have been discharged from psychiatric hospitalization. A quantitative exploratory study was performed at an outpatient clinic of a mental health service. The sample consisted of patients who had been discharged and their caregivers. A questionnaire was used, and the study was approved by the local research ethics committee. Of the 48 discharged patients, 21 had a caregiver. All the identified caregivers were relatives of the patients, and their average age was 46.6 years. In 38% of cases, the patient's mother was the caregiver. In terms of marital status, 61.9% of the caregivers were married or living in common-law relationships, and only one caregiver did not have children. The main source of income for 28.6% of the participants was temporary keeping eventual jobs. By knowing who is the caregiver of a patient discharged from psychiatric hospitalization it is possible to identify the characteristics that may help to determine the best treatment and professional support for that population. PMID- 21710077 TI - [Involuntary commitment: implication for psychiatric nursing practice]. AB - The characteristics of involuntary psychiatric commitment (IPI) may cause implications on the nursing/patient relationship. The objectives of this study were to list the forms of nursing care delivered to psychiatric patients, according to the type of commitment; analyze the reaction of the nursing team towards the IPI patient, and discuss on the implications that IPI have on the practice o psychiatric nursing. A field research was performed with the nursing team of a psychiatric institution in Rio de Janeiro. After 50 hours of participant observation and 9 of focal group meetings, we found that the teams are concerned with the clinical evolution of the patients. No references of the nursing team to the IPI patient were observed. There are no records or actions of any kind that would suggest a specific look towards this type of patient. Nursing professionals are not able to clearly identify this type of patient, thus the care is provided as per the patient's needs or requests. PMID- 21710078 TI - [The teaching-learning process in mental health: the student's perspective about psychosocial rehabilitation and citizenship]. AB - The current national mental health policies confirm the need to encourage teaching, research and extension practices that favor new professional attitude. A previous study has shown that the students' representation about the competencies required in mental health fall into categories about the concepts of competence, cognitive resources, expressed feelings, and the concept of health and illness, but with no reference to themes related to the users' citizenship or psychosocial rehabilitation, which are central concepts in the course discipline. In this study, an analysis was made of the representation about these concepts, the knowledge and skills identified as being necessary to practice rehabilitation. Participants were students of a public university, attending the Mental Health Nursing class. The results show that students value the users' needs, but the representations about citizenship and psychosocial rehabilitation are founded on common sense about hazards and basic rights like health and leisure. PMID- 21710079 TI - [Schizophrenia: adherence to treatment and beliefs about the disorder and the drug treatment]. AB - This study verified the adherence of people with schizophrenia to the medication, identified and compared their beliefs about the disorder and the drug among patients who adhered and those who did not. Participants were 14 patients of a psychiatric outpatient clinic. Semi-structured interviews and the Morisky-Green test were performed. The data was analyzed using a quali-quantitative approach. Results showed that 64.3% of patients do not adhere to treatment. Most participants considered the drug capable of reducing the seriousness and severity of the disorder. However, the drawbacks for patients that did not adhere to the treatment were more expressive. Side effects were the cause for interrupting the treatment for 80% of patients who intentionally did not adhere to treatment. It was observed there is insufficient knowledge about schizophrenia and the drug treatment. Patients referred to faith as a strategy to cope with the process they were experiencing. This study points at the need for strategies directed towards the promotion of drug treatment adherence among people with schizophrenia. PMID- 21710080 TI - [Work as a source of pleasure: evaluating a Psychosocial Care Center team]. AB - The objective of this study was to evaluate the pleasure at work felt by the members of a Psychosocial Care Center team. This qualitative case study used Forth Generation Evaluation. This study was performed in Foz do Iguacu, Parana, Brazil, in November and December 2006. Participants were 10 tem members. Data collection was performed through observation and individual interviews. The analysis was initiated at the same time as the data collection, and the final analysis was performed as per the following steps: data ordering, classification and final analysis. The following analysis themes were developed: work characteristics at the psychological care center, suffering and coping with suffering at work. During the evaluation, the participants showed pleasure and fulfillment with their work by expressing pride, fulfillment and appreciation of what they deliver. Pleasure occurs during the development of psychosocial care, because they always have the freedom to rearrange their manner of working, making possible to develop activities and attitudes capable of giving them pleasure. PMID- 21710081 TI - [Characterization of the physical symptoms of stress in the emergency health care team]. AB - Nursing professionals working in Emergency Care suffer from the physical symptoms of stress in their everyday activity. The objective of this study was to characterize these symptoms using the Occupational Stress Indicator, a semi structured instrument. To do this, the authors created open questions that were applied in interviews that were recorded and analyzed. The researchers listed the following physical symptoms: headache, a sensation of fatigue, leg pain, and tachycardia. According to reports form the workers, pain always resulted from emotional stress or appeared after providing emergency care, which suggests the workers find it very difficult to differentiate physical from mental stress. The investigation found that there is a need for measures to follow workers in their working activity. A manual was created, containing basic suggestions to improve the quality of life of the health team. PMID- 21710082 TI - [Coaching: a reference model for the practice of nurse-leaders in the hospital context]. AB - The objectives of the present study was to evaluate the leadership of nurses by using the coaching strategy as a managerial tool, and identify, measure and analyze the acquisition of competencies from the view of nurse-coaches. This is a descriptive, cross-sectional, exploratory and field study that was performed using a quantitative approach. Situational Leadership was selected as the theoretical framework and the research instrument was submitted to statistical and content analyses and was applied on 11 nurse leaders of a large scale private general hospital located in Sao Paulo. The results showed that participants gained new knowledge, confirmed the Situational Leadership model as the recognized being a coach leader, with a style that is mainly aimed at tasks and people, according to the situation involved, and pointed out the following skills as determinant of coaches: communication, giving and receiving feedback, assigning and gaining power and having an influence. Finally, the attitudes reflected the practice of coaching. PMID- 21710083 TI - [Caring for the patient in the process of dying at the Intensive Care Unit]. AB - The objective of this study is to characterize how nursing care is performed at the ICU to patients with no possibility of cure. Ten nurses were interviewed. The field study was performed at the Intensive Care Unit of a public teaching hospital. For the nurses, there is no uniform pattern of care. Furthermore, according to their reports, it was observed that there is an overestimation of the technical care over the emotional, social and spiritual aspects. It was, however, observed that nurses are strongly with the suffering of the family in view of their loss. Results show that nurses must understand death as a part of the life cycle and review care as the essence of nursing, thus increasing the discussions on the issue in both the academic and daily practice environments. PMID- 21710084 TI - Microbial contamination of procedure gloves after opening the container and during exposure in the environment. AB - The objective of this study was to quantify the colony forming units (cfu) on latex procedure gloves in the beginning, middle, and end of the containers in real (professional) and controlled (researcher) gloving situations; evaluate the microbial load of the gloves, considering the time of exposure in the environment. This comparative prospective study was conducted at an intensive care unit of a teaching hospital. The microbiological data was collected from the gloves using digital-pressure. Microbiological evaluations were performed on 186 pairs of gloves: 93 in the control group and 93 in real gloving situations. In the control group, the average cfu was 4.7 against 6.2 in the real gloving situation. Hence, no statistically significant difference was found (p=.601). In addition, the cfu values of gloves in the beginning, middle and end of the containers also did not show any significant differences (p>.05). The most common strain was Staphylococcus spp. The time of exposure in the environment did not increase the cfu value of the latex gloves. PMID- 21710085 TI - [Monitoring the physical processes of sterilization in hospitals in the state of Goias]. AB - The objective of this descriptive study was to identify the physical, chemical and biological controls of the sterilization process by saturated steam in Pasteur autoclaves at Material and Sterilization Centers (MSC). The data was obtained by interviewing the worker responsible for the MSC of the largest hospital in every city in the interior of Goias that had population of at least 20,000, in the period from August 2005 to June 2006. A total 44 municipalities participated. The analysis was performed using SPSS software. In 31 (94.0%) hospitals there were no nurses exclusive to the MSC, the workers responsible for the center were nursing aides and technicians. Most did not perform any physical, chemical and biological control of the sterilization process, and, in one case only these controls were performed simultaneously. Failing to monitor the sterilization cycles, and thus not ensuring the quality of the processes, is a risk to the population being assisted. PMID- 21710086 TI - Early postnatal hospital discharge: the consequences of reducing length of stay for women and newborns. AB - The objective of this study is to examine the literature and identify most salient outcomes of early postnatal discharge for women, newborns and the health system. An electronic search strategy was designed including the following sources: Web of Science, Scopus, ProQuest and PubMed/MEDLINE, using the following terms: (early AND discharge) OR (length AND stay) AND (postpartum OR postnatal) AND (effect* OR result OR outcome). Content analysis was used to identify and summarise the findings and methods of the research papers. The evidence available is not enough to either reject or support the practice of early postnatal discharge; different studies have reported different outcomes for women and newborns. The need of systematic clinical research is discussed. PMID- 21710087 TI - [Type 1 diabetes mellitus: evidence from the literature for appropriate management in children's perspective]. AB - The objective of this study was to identify the evidence available in the literature that address, for children's perspective, factors that are relevant for an appropriate management of type 1 diabetes mellitus. An integrative review was performed on the PubMed, CINAHL, LILACS, CUIDEN and PsycINFO databases, covering the period from 1998 to 2008 and using the following keywords: type 1 diabetes mellitus, child, prevention and control, triggering factors, emergencies, self care, learning and health education. Nineteen of the surveyed articles were selected, and their analysis revealed the following categories: living with diabetes; self care and glucose profile; the actions of family, friends and health professionals; and school. The evidence show that children appreciate the support they receive from their relatives, which have a direct relationship with being prepared for self care. Other members apart from their network are also valued. Areas that deserve attention are the school, the personal experience of each child, and health education. PMID- 21710088 TI - [Factors associated to the quality of life of adolescents with type 1 diabetes mellitus]. AB - The objective of this study was to perform a literature review of the factors that may influence the Health Related Quality of Life (HRQL) of adolescents with type 1 diabetes mellitus using the PICO strategy. PubMed/MEDLINE, ISI Web of Knowledge and EMBASE were the databases used. A larger survey of articles was possible by combining standardized and non-standardized descriptors. Though HRQL is a specific construct used to evaluate aspects related to the repercussions of health, illness, and treatment, it appears that sociodemographic, psychosocial, and family-related aspects have a significant effect on HRQL. PMID- 21710089 TI - [Evidence-based practices published in Brazil: identification and analysis of their types and methodological approches]. AB - This is an integrative review of Brazilian studies on evidence-based practices (EBP) in health, published in ISI/JCR journals in the last 10 years. The aim was to identify the specialty areas that most accomplished these studies, their foci and methodological approaches. Based on inclusion criteria, 144 studies were selected. The results indicate that most EBP studies addressed childhood and adolescence, infectious diseases, psychiatrics/mental health and surgery. The predominant foci were prevention, treatment/rehabilitation, diagnosis and assessment. The most used methods were systematic review with or without meta analysis, protocol review or synthesis of available evidence studies, and integrative review. A strong multiprofessional expansion of EBP is found in Brazil, contributing to the search for more selective practices by collecting, recognizing and critically analyzing the produced knowledge. The study also contributes to the analysis itself of ways to do research and new research possibilities. PMID- 21710090 TI - Radiographic evaluation of furcal perforations sealed with different materials in dogs' teeth. AB - OBJECTIVE: The objective of this work was to evaluate, using radiographic images, the behavior of four materials used to repair root perforations in dogs' teeth. MATERIAL AND METHODS: Second and third premolars of 6 dogs were used. The 48 teeth were randomly divided into 4 groups (n=12) and the perforations were sealed with one of the following materials: MTA, AH Plus, Vitremer and gutta-percha. Dogs were submitted to general anesthesia, teeth were radiographed and pulp was accessed. Perforations were done, at the maximum curve of the pulp floor, sealed and the accessed coronal cavity was filled with glass ionomer cement (Vidrion R). After 90 days, the dogs were sacrificed and the last x-ray image was taken. Images were analyzed for the presence/absence of periodontal lesions at the perforation region. Data were analyzed statistically by chi-square test at 5% significance level. RESULTS: There were no statistically significant differences (p>0.05) among AH Plus, Vitremer and gutta-percha groups. MTA produced the smallest number of periodontal lesions (p<0.05). CONCLUSIONS: It may be concluded that none of the tested materials was able to preserve the integrity of the periodontal tissues in the furcation region, and the use of MTA resulted in the least formation of adjacent periodontal bone lesions revealed by the radiographic comparisons. PMID- 21710091 TI - Bond strength of three luting agents to zirconia ceramic - influence of surface treatment and thermocycling. AB - OBJECTIVE: This in vitro study aimed to evaluate the influence of different surface treatments, 3 luting agents and thermocycling on microtensile bond strength (uTBS) to zirconia ceramic. MATERIAL AND METHODS: A total of 18 blocks (5x5x4 mm) were fabricated from zirconia ceramic (ICE Zirkonia) and duplicated into composite blocks (Alphadent). Ceramic blocks were divided into 3 groups (n=6) according to the following surface treatments: airborne-particle abrasion (AA), silica-coating, (SC) (CoJet) and silica coating followed by silane application (SCSI) (ESPE Sil). Each group was divided into 3 subgroups (n=2) according to the 3 luting agents used. Resin-modified glass-ionomer cement (RMGIC, Ketac Cem Plus), self-adhesive resin cement (UN, RelyX Unicem) and adhesive resin cement (ML, MultiLink Automix) were used for bonding composite and zirconia blocks. Each bonding assembly was cut into microbars (10 mm long and 1+/ 0.1 mm2). Seven specimens of each subgroup were stored in water bath at 37oC for 1 week. The other 7 specimens were stored in water bath at 37oC for 30 days then thermocycled (TC) for 7,500 cycles. uTBS values were recorded for each specimen using a universal testing machine. Statistical analyses were performed using a 3 way ANOVA model followed by serial 1-way ANOVAs. Comparison of means was performed with Tukey's HSD test at (alpha=0.05). RESULTS: uTBS ranged from 16.8 to 31.8 MPa after 1 week and from 7.3 to 16.4 MPa after 30 days of storage in water and thermocycling. Artificial aging significantly decreased uTBS (p<0.05). Considering surface treatment, SCSI significantly increased uTBS (p<0.05) compared to SC and AA. Resin cements (UN and ML) demonstrated significantly higher uTBS (p<0.05) compared to RMGIC cement. CONCLUSIONS: Silica coating followed by silane application together with adhesive resin cements significantly increased uTBS, while thermocycling significantly decreased uTBS. PMID- 21710092 TI - Use of occlusal sealant in a community program and caries incidence in high- and low-risk children. AB - OBJECTIVE: The aims of this study were to investigate the effectiveness of sealant placement under the guidelines of the Oral Health Promotion Program for Children and Adolescents (Portugal), and to test the influence of clinical and socioeconomic variables on the DMFT increment in 277 children, born in 1997. MATERIAL AND METHODS: A dental hygienist performed the initial examinations and sealant placement (Helioseal, Vivadent) on the permanent first molars in 2005. These activities were registered in dental records that were assessed in 2007. Children were classified according to caries risk at baseline [high (HR: DMFT+dmft>0); low (LR: DMFT+dmft=0) risk] and sealant placement as follows: HR-S and LR-S Groups (with sealant placement); HR-NS and LR-NS Groups (without sealant placement). A calibrated dentist performed the final examination in 2007 at school, based on the World Health Organization recommendations. The variables collected were: dental caries, visible dental plaque, malocclusions, and socioeconomic level (questionnaire sent to children's parents). For univariate (Chi-square or Fisher tests) and multivariate (Multiple logistic regression) analyses the DMFT increment >0 was selected as dependent variable. RESULTS: Approximately 17.0% of the children showed DMFT increment>0 (mean=0.25). High risk children presented a significant increase in the number of decayed and/or filled teeth. These children had 7.94 more chance of developing caries. Children who did not receive sealant were 1.8 more prone to have DMFT increment >0. CONCLUSION: It appears that sealant placement was effective in preventing dental caries development. Moreover, the variables "risk" and "sealant placement" were predictors for DMFT increment in the studied children. PMID- 21710093 TI - Effect of different light curing methods on mechanical and physical properties of resin-cements polymerized through ceramic discs. AB - OBJECTIVE: The aim of this study was to compare the polimerization ability of three different light-curing units (quartz tungsten halogen, light-emitting diodes and plasma arc) and their exposure modes (high-intensity and soft-start) by determination of microhardness, water sorption and solubility, and diametral tensile strength of 5 dual-curing resin cements. MATERIAL AND METHODS: A total of 720 disc-shaped samples (1 mm height and 5 mm diameter) were prepared from different dual-curing resin cements (Duolink, Nexus, Bifix-QM, Panavia F and RelyX Unicem). Photoactivation was performed by using quartz tungsten halogen (high-power and soft-up modes), light-emitting diode (standard and exponential modes) and plasma arc (normal and ramp-curing modes) curing units through ceramic discs. Then the samples (n=8/per group) were stored dry in the dark at 37 degrees C for 24 h. The Vickers hardness test was performed on the resin cement layer with a microhardness tester (Shimadzu HMV). For sorption and solubility tests; the samples were stored in a desiccator at 37 degrees C and weighed to a constant mass. The samples were weighed both before and after being immersed in deionized water for different periods of time (24 h and 7 days) and being desiccated. The diametral tensile strength of the samples was tested in a universal testing machine at a crosshead speed of 0.5 mm/min. Data were analyzed statistically by nonparametric Kruskal Wallis and Mann-Whitney U tests at 5% significance level. RESULTS: Resin cement and light-curing unit had significant effects (p<0.05) on microhardness, diametral tensile strength, water solubility and sorption. However, no significant differences (p>0.05) were obtained with different modes of LCUs. CONCLUSION: The study indicates that polymerization of resin cements with different light-curing units may result in various polymer structures, and consequently different mechanical and physical properties. PMID- 21710094 TI - Resistance of three implant-abutment interfaces to fatigue testing. AB - The design and retentive properties of implant-abutment connectors affect the mechanical resistance of implants. A number of studies have been carried out to compare the efficacy of connecting mechanisms between abutment and fixture. OBJECTIVES: The aims of this study were: 1) to compare 3 implant-abutment interfaces (external hexagon, internal hexagon and cone-in-cone) regarding the fatigue resistance of the prosthetic screw, 2) to evaluate the corresponding mode of failure, and 3) to compare the results of this study with data obtained in previous studies on Nobel Biocare and Straumann connectors. MATERIALS AND METHODS: In order to duplicate the alternating and multivectorial intraoral loading pattern, the specimens were submitted to the rotating cantilever beam test. The implants, abutments and restoration analogs were spun around their longitudinal axes while a perpendicular force was applied to the external end. The objective was to determine the force level at which 50% of the specimens survived 10(6) load cycles. The mean force levels at which 50% failed and the corresponding 95% confidence intervals were determined using the staircase procedure. RESULTS: The external hexagon interface presented better than the cone in-cone and internal hexagon interfaces. There was no significant difference between the cone-in-cone and internal hex interfaces. CONCLUSION: Although internal connections present a more favorable design, this study did not show any advantage in terms of strength. The external hexagon connector used in this study yielded similar results to those obtained in a previous study with Nobel Biocare and Straumann systems. However, the internal connections (cone-in-cone and internal hexagon) were mechanically inferior compared to previous results. PMID- 21710095 TI - Tensile bond strength of indirect composites luted with three new self-adhesive resin cements to dentin. AB - OBJECTIVE: The aims of this study were to evaluate the tensile bond strengths between indirect composites and dentin of 3 recently developed self-adhesive resin cements and to determine mode of failure by SEM. MATERIAL AND METHODS: Exposed dentin surfaces of 70 mandibular third molars were used. Teeth were randomly divided into 7 groups: Group 1 (control group): direct composite resin restoration (Alert) with etch-and-rinse adhesive system (Bond 1 primer/adhesive), Group 2: indirect composite restoration (Estenia) luted with a resin cement (Cement-It) combined with the same etch-and-rinse adhesive, Group 3: direct composite resin restoration with self-etch adhesive system (Nano-Bond), Group 4: indirect composite restoration luted with the resin cement combined with the same self-etch adhesive, Groups 5-7: indirect composite restoration luted with self adhesive resin cements (RelyX Unicem, Maxcem, and Embrace WetBond, respectively) onto the non-pretreated dentin surfaces. Tensile bond strengths of groups were tested with a universal testing machine at a constant speed of 1 mm/min using a 50 kgf load cell. Results were statistically analyzed by the Student's t-test. The failure modes of all groups were also evaluated. RESULTS: The indirect composite restorations luted with the self-adhesive resin cements (groups 5-7) showed better results compared to the other groups (p<0.05). Group 4 showed the weakest bond strength (p>0.05). The surfaces of all debonded specimens showed evidence of both adhesive and cohesive failure. CONCLUSION: The new universal self-adhesive resins may be considered an alternative for luting indirect composite restorations onto non-pretreated dentin surfaces. PMID- 21710096 TI - In vitro adherence of Candida albicans isolated from patients with chronic periodontitis. AB - Adherence is considered an extremely important virulence factor in yeast. OBJECTIVE: The aim of this study was to analyze the adherence to epithelial cells of C. albicans isolated from patients with chronic periodontitis in comparison to healthy patients. MATERIAL AND METHODS: Candida albicans cells isolated from individuals with chronic periodontitis (n=25) and healthy controls (n=25) were included in this study. Suspensions of C. albicans (10(6) cells/mL) and epithelial cells (10(5) cells/mL) were mixed and incubated at 37oC for 1 h. The number of yeasts adhered to 25 epithelial cells was counted. RESULTS: The number of C. albicans cells adhered to epithelial cells was statistically higher in the chronic periodontitis group than in the control group (Student's t-test, p=0.000). CONCLUSION: The results of the present study suggest a higher Candida adherence of samples isolated from patients with chronic periodontitis. PMID- 21710097 TI - Immunohistochemical staining of Langerhans cells in HPV-positive and HPV-negative cases of oral squamous cells carcinoma. AB - The Human Papillomavirus (HPV) has been strongly implicated in development of some cases of oral squamous cell carcinoma (OSCC). However, the immunological system somehow reacts against the presence of this virus. Among the cells involved in such mechanism of defense Langerhans cells (LC) stand out, which are responsible for processing and presenting antigens. OBJECTIVES: The purposes of this study were to investigate the presence of HPV DNA and to evaluate the immunohistochemical reactivity for Langerhans cells between HPV-positive and HPV negative OSCC. Twenty-seven cases of OSSC were evaluated. MATERIAL AND METHODS: DNA was extracted from paraffin-embedded tissue samples and amplified by Polymerase Chain Reaction (PCR) for the detection of HPV DNA. Viral typing was performed by dot blot hybridization. Immunohistochemistry was performed by the Streptavidin-biotin technique. RESULTS: From the 27 cases, 9 (33.3%) were HPV positive and 18 (66.0%) HPV-negative. HPV 18 was the most prevalent viral type (100% cases) and infection with HPV-16 (co-infection) was detected in only 1 case. In the OSCC specimens examined, immunoreactivity to S-100 antibody was detected in all cases, with a mean number of 49.48+/-30.89 Langerhans cells positive for immunostaining. The mean number of immunostained Langerhans cells was smaller in the HPV-positive cases (38 cells/case) than in the HPV-negative cases (42.5 cells/case), but this difference was not significant (p=0.38). CONCLUSIONS: The low frequency of detection of HPV DNA in OSCC indicates a possible participation of the virus in the development and progression of only a subgroup of these tumors. There was no association between the immunohistochemical labeling for Langerhans cells (S-100+) and HPV infection of in OSSC. These findings suggest that the presence of HPV in such OSCC cases could not alter the immunological system, particularly the Langerhans cells. PMID- 21710098 TI - Standards of teeth preparations for anterior resin bonded all-ceramic crowns in private dental practice in Jordan. AB - OBJECTIVES: To investigate if general dental practitioners (GDPs) in private practice in Jordan follow universal guidelines for preparation of anterior teeth for resin bonded all-ceramic crowns (RBCs). MATERIAL AND METHODS: A sample (n=100) of laboratory models containing 208 tooth preparations for IPS Empress and In Ceram, featuring work from different GDPs, was obtained from 8 commercial dental laboratories. Aspects of preparations were quantified and compared with accepted criteria defined following a review of the literature and recommendations of the manufactures' guidelines. RESULTS: Subgingival margins on the buccal aspect were noticed in 36% of the preparations, 54% demonstrated overpreparation with a tendency to overprepare the teeth on the mesiodistal plane more than buccolingual plane. Twenty percent of samples presented a shoulder finish line while a chamfer margin design was noticed in 39%. Twenty-nine percent and 12% of samples had either a feathered or no clear margin design respectively. Incisal underpreparation was observed in 18% of dies of each type. Only 17% of all preparations were found to follow the recommended anatomical labial preparations while 29% of the RBC preparations were found to have the recommended axial convergence angle. In total, 43% of preparations were found to have the recommended depth of the finish line. CONCLUSIONS: It was found that relevant guidelines for RBC preparations were not being fully adhered to in private practice in Jordan. PMID- 21710099 TI - Conventional dual-cure versus self-adhesive resin cements in dentin bond integrity. AB - During post preparation, the root canal is exposed to the oral cavity, and endodontic treatment may fail because of coronal leakage, bacterial infection and sealing inability of the luting cement. OBJECTIVE: this study quantified the interfacial continuity produced with conventional dual-cure and self-adhesive resin cements in the cervical (C), medium (M) and apical (A) thirds of the root. MATERIAL AND METHODS: Forty single-rooted human teeth were restored using Reforpost # 01 conical glass-fiber posts and different materials (N=10 per group): group AC=AdperTM ScotchBondTM Multi-purpose Plus + AllCem; group ARC=AdperTM ScotchBondTM Multi-purpose Plus + RelyX ARC; group U100=RelyX U100; and group MXC=Maxcem Elite. After being kept in 100% humidity at 37 degrees C for 72 hours, the samples were sectioned parallel to their longitudinal axis and positive epoxy resin replicas were made. The scanning electron micrographs of each third section of the teeth were combined using Image Analyst software and measured with AutoCAD-2002. We obtained percentage values of the interfacial continuity. RESULTS: Interfacial continuity was similar in the apical, medium and cervical thirds of the roots within the groups (Friedman test, p>0.05). Comparison of the different cements in a same root third showed that interfacial continuity was lower in MXC (C=45.5%; M=48.5%; A=47.3%) than in AC (C=85.9%, M=81.8% and A=76.0%), ARC (C=83.8%, M=82.4% and A=75.0%) and U100 (C=84.1%, M=82.4% and A=77.3%) (Kruskal-Wallis test, p<0.05). CONCLUSIONS: Allcem, Rely X ARC and U100 provide the best cementation; cementation was similar among root portions; in practical terms, U100 is the best resin because it combines good cementation and easy application and none of the cements provides complete interfacial continuity. PMID- 21710100 TI - Citations to papers from Brazilian institutions: a more effective indicator to assess productivity and the impact of research in graduate programs. AB - A recent assessment of 4400 postgraduate courses in Brazil by CAPES (a federal government agency dedicated to the improvement of the quality of and research at the postgraduate level) stimulated a large amount of manifestations in the press, scientific journals and scientific congresses. This gigantic effort to classify 16,400 scientific journals in order to provide indicators for assessment proved to be puzzling and methodologically erroneous in terms of gauging the institutions from a metric point of view. A simple algorithm is proposed here to weigh the scientometric indicators that should be considered in the assessment of a scientific institution. I conclude here that the simple gauge of the total number of citations accounts for both the productivity of scientists and the impact of articles. The effort spent in this exercise is relatively small, and the sources of information are fully accessible. As an exercise to estimate the value of the methodology, 12 institutions of physics (10 from Brazil, one from the USA and one from Italy) have been evaluated. PMID- 21710101 TI - Taurine inhibits serum deprivation-induced osteoblast apoptosis via the taurine transporter/ERK signaling pathway. AB - Taurine has positive effects on bone metabolism. However, the effects of taurine on osteoblast apoptosis in vitro have not been reported. The aim of this study was to investigate the activity of taurine on apoptosis of mouse osteoblastic MC3T3-E1 cells. The data showed that 1, 5, 10, or 20 mM taurine resulted in 16.7, 34.2, 66.9, or 63.75% reduction of MC3T3-E1 cell apoptosis induced by the serum deprivation (serum-free alpha-MEM), respectively. Taurine (1, 5, or 10 mM) also reduced cytochrome c release and inhibited activation of caspase-3 and -9, which were measured using fluorogenic substrates for caspase-3/caspase-9, in serum deprived MC3T3-E1 cells. Furthermore, taurine (10 mM) induced extracellular signal-regulated kinase (ERK) phosphorylation in MC3T3-E1 cells. Knockdown of the taurine transporter (TAUT) or treatment with the ERK-specific inhibitor PD98059 (10 MUM) blocked the activation of ERK induced by taurine (10 mM) and abolished the anti-apoptotic effect of taurine (10 mM) in MC3T3-E1 cells. The present results demonstrate for the first time that taurine inhibits serum deprivation induced osteoblast apoptosis via the TAUT/ERK signaling pathway. PMID- 21710102 TI - Air pollution and cardiovascular hospital admissions in a medium-sized city in Sao Paulo State, Brazil. AB - The objective of the present study was to estimate the contribution of environmental pollutants to hospital admissions for cardiovascular disease. A time series ecological study was conducted on subjects aged over 60 years and living in Sao Jose dos Campos, Brazil, with a population near 700,000 inhabitants. Hospital admission data of public health patients (SUS) were obtained from DATASUS for the period between January 1, 2004 and December 31, 2006, according to the ICD-10 diagnoses I20 to I22 and I24. Particulate matter with less than 10 um in aerodynamic diameter, sulfur dioxide and ozone were the pollutants examined, and the control variables were mean temperature and relative humidity. Data on pollutants were obtained from the Sao Paulo State Sanitary Agency. The generalized linear model Poisson regression with lags of up to 5 days was used. There were 1303 hospital admissions during the period. Exposure to particulate matter was significantly associated with hospitalization for cardiovascular disease 3 days after exposure (RR = 1.006; 95%CI = 1.000 to 1.010) and an increase of 16 ug/m(3) was associated with a 10% increase in risk of hospitalization; other pollutants were not associated with hospitalization. Thus, it was possible to identify the role of exposure to particulate matter as an environmental pollutant in hospitalization for cardiovascular disease in a medium sized city in Southeastern Brazil. PMID- 21710103 TI - Modulation of murine blastocyst hatching in vitro by glutamine and tryptophan. AB - Enrichment of culture media with amino acids improves embryo development. However, little is known about the specific action of each amino acid during embryogenesis. The present study was undertaken to examine the effect of L glutamine (Gln) and tryptophan (Trp) on mouse embryo hatching, expansion and viability in vitro. Blastocysts were collected from 6- to 8-week-old female BALB/c mice (N = 30) and cultured in M2 medium containing either 0.125, 0.25 or 0.5 mM Trp, 1 mM Gln, or M2 alone. Gln significantly increased (100%; P < 0.05) blastocyst hatching at 24 h compared to M2 alone or Trp; moreover, Trp inhibited blastocyst hatching when compared to M2 alone (P < 0.05) at 72 h. In contrast, the percentage of embryos reaching the state of expanded blastocyst at 48 h was significantly higher in medium with 1 mM Gln (66.6%; P < 0.05) or with 0.125 mM Trp (61.1%; P < 0.05). Unexpectedly, Trp increased the percentage of degenerated blastocysts after 48 h (67.7%; P < 0.05), while Gln preserved blastocyst viability. These results suggest that Gln may enhance blastocyst hatching, expansion and viability in vitro. PMID- 21710104 TI - Innovative neurophysiological methods in itch research: long-latency evoked potentials after electrical and thermal stimulation in patients with atopic dermatitis. AB - The aim of this study was to examine the findings of innovative neurophysiological methods of itch research. Short-latency and pain-related somatosensory-evoked potentials after electrical stimulation, as well as long latency evoked potentials after thermal stimulation were studied in 38 patients with atopic dermatitis (AD) and 26 healthy volunteers. Quantitative Sensory Testing of thermal perception was performed in 22 patients with AD from the main AD group and in 15 healthy volunteers. Brain hyperactivity to electrical stimuli, delayed thermal-evoked potentials and elevated thermal thresholds were revealed in patients with AD compared with healthy controls. The data indicate small nerve fibre dysfunction in patients with AD, which may contribute to the pathogenesis of AD and chronic itch. The study demonstrates objective approaches to assess the function of small nerve fibres in patients with chronic itch. PMID- 21710105 TI - Tinea capitis and tinea corporis with a severe inflammatory response due to Trichophyton tonsurans. AB - Trichophyton tonsurans is an anthropophilic dermatophyte, with a worldwide distribution, although its prevalence varies considerably between different geographical regions. Whereas in North America infections due to this fungus are exceptionally common, on the European continent they appear relatively seldom. Although T. tonsurans is primarily associated with tinea capitis, it can also be the cause of tinea corporis and tinea unguium. The course of infection is usually only mildly symptomatic. We describe here two cases of urease-positive T. tonsurans infections with atypically extensive cutaneous lesions and severe inflammatory responses. . PMID- 21710106 TI - Prevalence of acne vulgaris in Chinese adolescents and adults: a community-based study of 17,345 subjects in six cities. AB - Acne vulgaris is a common skin condition in adolescents. The prevalence of acne is thought to vary between ethnic groups and countries. A large-scale community based study was performed in six cities in China to determine the prevalence and possible risk factors for acne in the Chinese population. A total of 17,345 inhabitants were included in this study. Of these, 1,399 were found to have acne. No acne was found in subjects under 10 years of age, and only 1.6% in the 10-year old group had acne. Prevalence then increased rapidly with age, up to 46.8% in the 19-year-old group. After that, it declined gradually with age. Acne was rare in people over 50 years of age. In subjects in their late teens and 20s, acne was more prevalent in males, while in those over 30 years of age it was more prevalent in females. In subjects with acne, 68.4% had mild; 26.0% had moderate and 5.6% had severe acne. In adult acne, persistent acne was much more common (83.3%) than late-onset acne (16.7%). Smoking and drinking were found to be associated with adolescent acne, while no association was found between diet and acne. These results suggest that the prevalence of acne in the Chinese population is lower than that in Caucasian populations, and that adult acne is not uncommon in Chinese subjects. PMID- 21710107 TI - Primary cutaneous melanoma arising in agminated melanocytic nevi: CDKN2A and CDK4 mutation screening. PMID- 21710108 TI - Profile and pattern of Stevens-Johnson syndrome and toxic epidermal necrolysis in a general hospital in Singapore: treatment outcomes. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but potentially life-threatening, reactions to medications. Both conditions have significant morbidity and mortality. The aim of this study was to document the epidemiological features, aetiologies, treatment and clinical outcomes of retrospectively reviewed data of all patients with SJS or TEN treated from January 2004 to November 2010 in a general hospital. There were 18 cases of SJS, seven cases of SJS/TEN overlap and three cases of TEN. Mean age was 50.6 years, with a range of 13-85 years. The male/female ratio was 1. Drugs accounted for 26 cases; one case was caused by Neisseria gonorrhoea infection. Anti-convulsants (35.7%) were the most common implicated drugs followed by antibiotics (28.5%), non-steroidal anti-inflammatory drugs (NSAIDS) (14.3%), allopurinol (7.1%) and traditional Chinese medication (7.1%). In seven cases, multiple drugs were implicated. Most SJS cases (88%) were treated with corticosteroids, of which 61% were given high-dose systemic corticosteroids. No infective complications were observed. Six out of the seven SJS/TEN overlap syndrome and all three TEN cases were given intravenous immunoglobulins. One patient with TEN died. In conclusion, anti-convulsants, especially carbamazepine, were the most frequently implicated drugs, followed by antibiotics and NSAIDS. High-dose corticosteroids were effective in SJS, whereas intra-venous immunoglobulin were useful in TEN and SJS/TEN overlap syndrome. PMID- 21710109 TI - Impact of environmental controls on childhood asthma. AB - Exposure to allergens early in life can lead to sensitization and the development of childhood asthma. It is thought that increased exposure with the advent of modern housing is likely contributing to the rise in prevalence of childhood asthma during the past few decades. The progression from allergen exposure to sensitization and asthma development has been noted with respect to dust mites, pets, cockroach, mouse, mold, tobacco smoke, endotoxin, and air pollution, although some have found a protective effect with pet and endotoxin exposure. Recent studies have shown that allergen remediation may be beneficial in reducing asthma morbidity and development, although there is also some evidence to the contrary. Examples of allergen remediation that have been studied include the use of dust mite-impermeable covers, high-efficiency particulate air filtration, integrated pest management, home repairs, ventilation improvement, and pet removal. Several multifaceted, randomized controlled trials have shown that reducing multiple early allergen exposures with environmental controls is associated with a decreased risk of asthma. PMID- 21710110 TI - Bony and soft tissue landmarks of the ACL tibial insertion site: an anatomical study. AB - PURPOSE: To identify and describe reliable landmarks for tibial tunnel placement in anatomical ACL reconstruction. METHODS: Eight non-paired cadaveric knees were used. After dissection, the tibial plateaus, menisci and ACL insertions were grossly observed to identify anatomical landmarks and relate them to the ACL insertion site. The specimens were scanned with a laser scanner, and 3 Dimensional images were obtained. Measurements of the ACL tibial insertion were taken. The center of the ACL and its bundles was measured regarding the distance from the medial tibial eminence and intermeniscal ligament. RESULTS: The medial tibial eminence demonstrated a constant relationship with the ACL tibial insertion site center and its bundles, as well as the intermeniscal ligament. The anterior root of the lateral meniscus had a variable relationship with the ACL tibial insertion. The length of the ACL tibial insertion was 18.1 +/- 2.8 mm and the width was 10.7 +/- 1.9 mm. The width of the AM bundle was 11.1 +/- 2.1 mm and the PL 7.9 +/- 2.0 mm. The ACL center was 9.1 +/- 1.5 mm posterior to the intermeniscal ligament and 5.7 +/- 1.1 mm anterior to a projected line from the apex of the medial tibial eminence. The center of the AM bundle was at 4.6 +/- 0.7 mm posterior to the intermeniscal ligament. The center of the PL bundle was 1.4 +/- 0.7 mm anterior to the medial tibial eminence. CONCLUSION: The medial tibial eminence and the intermeniscal ligament may be used as landmarks to guide the correct tunnel placement in an anatomical ACL reconstruction. PMID- 21710111 TI - Anatomic double-bundle and over-the-top single-bundle with additional extra articular tenodesis: an in vivo quantitative assessment of knee laxity in two different ACL reconstructions. AB - PURPOSE: Combinations of intra- and extra-articular procedures have been proposed for anterior cruciate ligament reconstruction with the aim of achieving an optimal control of translational and rotational knee laxities. Recently, the need for better reproducing the structural and functional behavior of the native anterior cruciate ligament led to the definition of anatomic double-bundle surgical approach. This study aimed to quantitatively verify whether the in vivo static and dynamic behavior obtained using over-the-top single-bundle with extra articular tenodesis reconstruction was comparable to the results achieved by anatomic double-bundle approach. METHODS: Thirty-five consecutive patients, with an isolated anterior cruciate ligament injury, were included in the study. Standard clinical laxities and pivot-shift test were quantified before and after anterior cruciate ligament reconstruction by means of a surgical navigation system dedicated to kinematic assessment; displacements of medial and lateral compartment during stress tests were also analyzed. RESULTS: Single-bundle with extra-articular tenodesis approach presented statistically better laxity reduction in varus/valgus stress test at full extension and in internal/external rotation at 90 degrees of flexion; lateral plasty controlled better the lateral compartment during drawer test and varus/valgus stress test both at 0 degrees and 30 degrees of flexion and both the compartments during internal/external rotation at 90 degrees of flexion. On the other hand, pivot-shift phenomenon was better controlled by anatomic double-bundle reconstruction. CONCLUSIONS: Both the reconstructions worked similarly for static knee laxity. The extra-articular procedure played an important role in better constraining the displacement of lateral tibial compartment, whereas the anatomic double-bundle reconstruction better restored the dynamic behavior of knee joint highlighted under pivot-shift stress test. STUDY DESIGN: Case series. PMID- 21710112 TI - Isokinetic muscle strength and knee function associated with double femoral pin fixation and fixation with interference screw in anterior cruciate ligament reconstruction. AB - PURPOSE: Intensive scheduling in sports requires athletes to resume physical activity shortly after injury. The purpose of this study was to investigate early isokinetic muscle strength and knee function on bone-patellar tendon-bone (BPTB) ACL reconstruction with double femoral pin fixation or interference screw technique. METHODS: A prospective study was conducted from 2008 to 2009, with 48 athletes who received femoral BPTB fixation with interference screw (n = 26) or double pin (n = 22). Clinical (IKDC objective score and hop test) and isokinetic muscle strength (peak torque (PT), PT/body weight and flexion/extension rate (F/E) in 60 and 240 degrees /s) were analyzed at 6 months of follow-up. RESULTS: Analysis at baseline showed no differences between groups before surgery related to age, gender, associated injury, Tegner or Lysholm score; thus showing that groups were similar. During follow-up, however, there were significant differences between the two groups in some of the isokinetic muscle strength: PT/BW 60 degrees /s (Double Pin = 200% +/- 13% vs. Interference Screw = 253% +/- 16%*, *P = 0.01); F/E 60 degrees /s (Double Pin = 89% +/- 29%* vs. Interference Screw = 74% +/- 12%, *P = 0.04). No statistical differences between groups were observed on IKDC objective score, hop test and complications. CONCLUSION: The significant muscle strength outcome of the interference screw group found in this study gives initial evidence that this fixation technique is useful for athletes that may need accelerated rehabilitation. Early return to sports ability signaled by isokinetic muscle strength is of clinical relevance as it is one of the main goals for athletes' rehabilitation. PMID- 21710115 TI - Gut overgrowth harms the critically ill. PMID- 21710113 TI - Endoscopic versus open bursectomy of lateral malleolar bursitis. AB - PURPOSE: Compare the result of endoscopic versus open bursectomy in lateral malleolar bursitis. MATERIALS AND METHODS: Prospective evaluation of 21 patients (22 ankles) undergoing either open or endoscopic excision of lateral malleolar bursitis. The median age was 64 (38-79) years old. The median postoperative follow-up was 15 (12-18) months. RESULTS: Those patients undergoing endoscopic excision showed a higher satisfaction rate (excellent 9, good 2) than open excision (excellent 4, good 3, fair 1). The wounds also healed earlier in the endoscopic group although the operation time was slightly longer. One patient in the endoscopic group had recurrence of symptoms but complications in the open group included one patient with skin necrosis, one patient with wound dehiscence, and two patients of with superficial peroneal nerve injury. CONCLUSIONS: Endoscopic resection of the lateral malleolar bursitis is a promising technique and shows favorable results compared to the open resection. LEVEL OF EVIDENCE: Therapeutic studies-Investigating the result of treatment, Level II. PMID- 21710116 TI - Prematurity: influence on mother's locus of control. AB - The aim of the present study was to compare the beliefs of mothers of term infants with the beliefs of mothers of preterm infants in regards to their locus of control mainly influencing their personal health and well-being. Mother's beliefs regarding the level of internal (self), social external (other individuals) and fatalistic external control (e.g. chance, destiny, and religion) were assessed while mothers were admitted to hospital postnatally. Thirty-five mothers of preterm infants under 32 weeks of gestation, and 35 mothers of term infants (>= 37 weeks of gestation) were included and participated within the first three days after delivery. Between the group of mothers of term infants and the group of mothers of preterm infants there was a significant difference in the level of fatalistic external control of health and disease they experienced. Mother's beliefs regarding internal and social external control did not differ between the two groups. When dealing with the mothers of preterm infants one should consider their strong beliefs that health and disease are largely dependent on fatalistic external factors. This might help to improve mother-child interaction and as a consequence also neurobehavioral development of the preterm infant. PMID- 21710117 TI - Clinical efficacy of OROS(r) hydromorphone in patients suffering from severe chronic pain: A Study undertaken in routine clinical practice. AB - INTRODUCTION: Strong opioids are efficient drugs for treating chronic pain. In cancer patients, strong opioids are the mainstay of pain management, but in non cancer pain caution is advised due to possible adverse effects, addictive potential and drug abuse. AIMS: We studied the efficacy of OROS((r)) hydromorphone in the treatment of chronic pain, the appearance and frequency of any adverse effects, the impact upon quality of life. METHODS: Between April 2008 and May 2009 197 patients who received OROS hydromorphone for the treatment of severe chronic pain were monitored for 90 days. Seventy patients had cancer related pain and 127 suffered pain due to non-malignant diseases, mostly degenerative joint disease. RESULTS: During the monitoring period, the average pain score on the VAS scale fell from 8.1 to 3.3. A total of 70 adverse effects (AE) were reported and 17 patients stopped treatment due to these AE. The most frequent AEs included drowsiness, headache, vertigo, nausea, vomiting and constipation. According to patients, their quality of life greatly improved during the monitoring period. CONCLUSION: The severity of patients' pain decreased during treatment with OROS hydromorphone with few adverse effects. The observed pain relief was accompanied by an improvement in the quality of the patients' lives. PMID- 21710118 TI - The spatial scale of competition from recruits on an older cohort in Atlantic salmon. AB - Competitive effects of younger cohorts on older ones are frequently assumed to be negligible in species where older, larger individuals dominate in pairwise behavioural interactions. Here, we provide field estimates of such competition by recruits on an older age class in Atlantic salmon (Salmo salar), a species where observational studies have documented strong body size advantages which should favour older individuals in direct interactions. By creating realistic levels of spatial variation in the density of underyearling (YOY) recruits over a 1-km stretch of a stream, and obtaining accurate measurements of individual growth rates of overyearlings (parr) from capture-mark-recapture data on a fine spatial scale, we demonstrate that high YOY density can substantially decrease parr growth. Models integrating multiple spatial scales indicated that parr were influenced by YOY density within 16 m. The preferred model suggested parr daily mass increase to be reduced by 39% when increasing YOY density from 0.0 to 1.0 m( 2), which is well within the range of naturally occurring densities. Reduced juvenile growth rates will in general be expected to reduce juvenile survival (via increased length of exposure to freshwater mortality) and increase generation times (via increased age at seaward migrations). Thus, increased recruitment can significantly affect the performance of older cohorts, with important implications for population dynamics. Our results highlight that, even for the wide range of organisms that rely on defendable resources, the direction of competition among age classes cannot be assumed a priori or be inferred from behavioural observations alone. PMID- 21710119 TI - Increase of patients co-colonised or co-infected with methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium or extended spectrum beta-lactamase-producing Enterobacteriaceae. AB - PURPOSE: To determine the incidence of patients co-colonised or co-infected with methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium or extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in four German tertiary care hospitals. METHODS: This study was conducted at four tertiary care hospitals (all with >1,000 beds) in different geographic regions in Germany (Berlin in the east, Luebeck in the north, Freiburg in the southwest and Nuernberg in the southeast). Routine surveillance data on MRSA, vancomycin-resistant enterococci (VRE) and ESBL-producing bacteria were analysed from 2007 to 2009. Co-colonisation or co-infection was defined as a patient having positive cultures for at least two of the following resistant pathogens: MRSA, VRE faecium or different species of ESBL-producing Enterobacteriaceae within one calendar year. RESULTS: A total of 896,822 patients were analysed, of which 10,066 patients harboured MRSA, VRE faecium and/or ESBL producing Enterobacteriaceae, and 542 patients co-harboured at least two of those resistant pathogens. In 2009, 7.6% of the MRSA patients, 13.7% of the VRE faecium patients and even 16.1% of the ESBL-producing Enterobacteriaceae patients were co colonised or co-infected. The incidence of patients with co-infection or co colonisation increased steadily from 5 (2007) to 7 per 10,000 patients (2009). CONCLUSIONS: Patients harbouring ESBL-producing Enterobacteriaceae or VRE faecium had a higher risk of being co-colonised or co-infected compared to what was to be extrapolated from their overall incidence. This might be linked to their gastrointestinal reservoir and impracticality to decolonise the gut of resistant VRE and ESBL-producing Enterobacteriaceae. PMID- 21710120 TI - Biliary tract infection caused by Vibrio fluvialis in an immunocompromised patient. PMID- 21710122 TI - Prolonged duration of surgery: a new look at the causes. PMID- 21710121 TI - Outcomes of post-cataract surgery endophthalmitis referred to a tertiary center from local hospitals in the south of China. AB - BACKGROUND: Endophthalmitis after cataract surgery is an uncommon but devastating complication. Prophylactic intracameral injection of cefuroxime 1 mg at the end of surgery decreases the incidence five-fold. The visual outcome can be good (53% of cases having a visual acuity [VA] of better than 20/40) if treatment is initiated rapidly and follows the Endophthalmitis Vitrectomy Study (EVS) guidelines; but even with the best treatment, some patients end up with a poor visual outcome. Previous studies on postoperative endophthalmitis mainly focus on the cases performed in metropolitan tertiary hospitals; however, little information is available on the cases performed in local hospitals in rural areas. METHODS: We retrospectively reviewed the medical records of patients with acute endophthalmitis following cataract surgery, which were performed in local hospitals and later treated at the Zhongshan Ophthalmic Center between 1 January 1998 and 31 December 2009. Details of each case, including the interval from symptoms to presentation, initial treatment in local hospitals, microorganisms isolated, treatment, and visual outcome, were recorded. Cross-tabulations were conducted in order to identify the prognostic factors of final visual outcome. RESULTS: Forty-six patients referred from 36 local hospitals and later treated at the Zhongshan Ophthalmic Center were reviewed over the audit period. Most of these cases occurred in April. Gram-positive bacteria were the predominant etiology, with fungal infection accounting for 15%. Even though 54% of patients had symptoms within 3 days post-cataract surgery, they did not present to a tertiary center until a mean of 10 days. The main initial treatment in local hospitals is systemic antibiotics, instead of the intravitreal injection of antibiotics. A high proportion of cases (27/46) received immediate pars plana vitrectomy (PPV) in the tertiary center, and the antibiotic used for intravitreal injection was mainly tobramycin. The final visual outcome was poor, with only three cases having a VA >=20/40. CONCLUSION: A relatively high rate of fungal endophthalmitis suggests that sterilization patterns in local hospitals should be further revised. A delayed presentation, inappropriate treatment procedures, poor presenting VA, and causative organism virulence may account for the unfavorable visual outcome in this study. PMID- 21710123 TI - Retrospective evaluation of the dose equivalence of Botox((r)) and Dysport ((r)) in the management of blepharospasm and hemifacial spasm: a novel paradigm for a never ending story. AB - Botox((r)) and Dysport((r)) are the preparations of botulinum neurotoxin most widely used for therapeutic purposes. Several studies have addressed the topic of the equivalency ratio (D/B ratio) to be used in clinical practice and whether a reliable value exists is still a matter of debate. To this purpose, we ideated a novel paradigm by retrospectively examining the patients affected by hemifacial spasm and blepharospasm. We compared the pairs of treatments with a switch from one brand to the other undergone by the same patient in consecutive sessions with overlapping clinical outcome. Out of 2006 treatments, we found 51 treatment pairs. D/B ratio was extremely variable (range 1.2-13.3) and in most cases (65%) it was between 1:3 and 1:5. In conclusion, even if the 1:4 ratio might be reliable for clinical purpose, a true bioequivalence between Dysport((r)) and Botox((r)) might not exist due to the intrinsic difference in their pharmacokinetic properties. PMID- 21710124 TI - Limb-shaking transient ischemic attacks in an adult PHACE syndrome: a case report and review of the literature. AB - PHACE syndrome is a neuro-cutaneous syndrome characterized by malformations of the Posterior fossa, facial Hemangiomas, Arterial anomalies, Cardiac anomalies, and abnormalities of the Eye. The arterial abnormalities usually involve the cervical and cerebral vasculature and include congenital abnormalities and progressive cerebral vasculopathy. The progressive cerebral vasculopathy leads to increased risk for arterial ischemic stroke (AIS) in patients with PHACE syndrome. Here we described the clinical neurological sequelae, the malformation of brain, the cervical and cerebral vasculopathy in a 23-year-old female of PHACE syndrome. Besides, she presented AIS with limb-shaking transient ischemic attack, a rare clinical presentation of AIS in patients of PHACE syndrome. PMID- 21710125 TI - Spontaneous resolution of syrinx: report of two cases in adults with Chiari malformation. AB - Idiopathic syringomyelia is a disease with variable clinical course. We report here two cases of spontaneous resolution of cervical syrinx in adults previously diagnosed of Chiari-syringomyelia complex. They are added to the nine cases previously reported, and documented the need for careful surgical indication in this disease based on the radiological images of spinal cord cavitation. PMID- 21710126 TI - Origin of isolated vertigo in rotational vertebral artery syndrome. AB - Rotational vertebral artery syndrome (RVAS) is characterized by recurrent attacks of paroxysmal vertigo, nystagmus, and ataxia induced by head rotation. Although recent report has described the RVAS as an important but unrecognized cause of isolated vascular vertigo, the locus of injury site responsible for isolated vertigo in RVAS is still unclear. We report here two patients with RVAS who had a stereotypic clinical presentation characterized by recurrent attacks of isolated vertigo induced by head rotation. The pattern of nystagmus observed in our patients with RVAS can be best explained by the stimulation of the vestibular labyrinth bilaterally or unilaterally. In RVAS, the isolated vertigo may occur due to transient ischemia of the superior vestibular labyrinth. RAVS should be considered in the differential diagnosis of positional vertigo, especially when vertigo is developed while sitting or standing position. PMID- 21710127 TI - Intracranial extraaxial ependymoma in children: a rare case report and review of the literature. AB - Intracranial extraaxial ependymomas (IEAEs) are extremely rare. We present a pediatric patient with IEAE misdiagnosed as a meningioma preoperatively, successfully treated surgically with a favorite outcome. The literature about IEAEs was briefly reviewed. Thereafter we discuss the clinical characteristics of the disease. PMID- 21710128 TI - High APOE epsilon 4 allele frequencies associated with Alzheimer disease in a Tunisian population. AB - The goal of the study was to examine the Apolipoprotein E (APOE) genotypes in a Tunisian sample of patients with Alzheimer disease (AD) and normal controls, and to compare the results with the findings from the literature. A hospital-based case-control study of two groups (58 patients with AD, 71 controls) was conducted. Patients received a detailed clinical history, neurological examination, neuropsychological testing and brain imaging. A neurological examination and the Arabic version of the Mini-Mental State Examination were made for controls. Genotyping was performed using the PCR restriction fragment length polymorphism (PCR-RFLP) method. There were no statistical differences in age (p = 0.05) and gender (p = 0.046) between the two groups. The APOE epsilon4/4 genotype was over represented in the AD group in comparison with the controls (13.3 vs. 2.8%). A significant increased risk of AD among APOE epsilon4 allele carriers was observed. The odds ratio for the association of AD patients with homozygous and heterozygous epsilon4 allele was, respectively, 5.40 (1.35-21.48) and 2.90 (1.27 6.62). Our results in addition to previously published genetic studies suggest that AD disease is multifactor in origin. Ethnicity, genetic and environmental factors contribute to AD risk in different ethnic groups. PMID- 21710129 TI - Early-onset SCA17 with 43 TBP repeats: expanding the phenotype? AB - The SCA17 clinical phenotype includes characteristics associated with cerebellar and cortical atrophy such as ataxia, dementia, epilepsy, chorea and parkinsonian features. Here we describe the case of a 38-year-old male presenting with ataxia, cognitive impairment and seizures, who was found to carry 43 repeats on one allele of the TATA-binding protein (TBP) gene. Therefore, genetic analysis of TBP gene triplets was performed on the patient's entire family, identifying three asymptomatic carriers of the same allele. A neuroradiological phenotype appeared to segregate with this allele, suggesting that it may play at least a contributory role in the determination of SCA17. PMID- 21710130 TI - Effects of inducible nitric oxide synthase blockade within the periaqueductal gray on cardiovascular responses during mechanical, heat, and cold nociception. AB - We have examined the role of inducible nitric oxide synthase (iNOS) within the dorsolateral periaqueductal gray mater (dlPAG) on cardiovascular responses during mechanical, thermal, and cold nociception in anesthetized rats. Mechanical stimulus was applied by a unilateral hindpaw pinch for 10 s that increased mean arterial pressure (MAP) and heart rate (HR). Bilateral microdialysis of a selective iNOS inhibitor, aminoguanidine (AGN; 10 MUM), into the dlPAG for 30 min augmented MAP and HR responses during a mechanical stimulation. The cardiovascular responses recovered following discontinuation of the drug. Heat stimulus was generated by immersing one hindpaw metatarsus in a water bath at 52 degrees C for 10 s, and this increased MAP and HR. Administration of AGN into the PAG potentiated these cardiovascular responses. Cardiovascular responses recovered following discontinuation of the drug. In contrast, application of a cold stimulus by immersing one hindpaw at 10 degrees C for 10 s resulted in depressor and bradycardic responses. A second cold stimulus resulted in a response that was not significantly different from that prior to or after recovery from the AGN infusion. These results demonstrate that iNOS within the dlPAG plays a differential role in modulating cardiovascular responses during mechanical-, heat-, and cold-mediated nociception. PMID- 21710131 TI - Evidence of diffuse damage in frontal and occipital cortex in the brain of patients with post-traumatic stress disorder. AB - A number of MRI studies have shown focal or diffuse cortical gray matter (GM) abnormalities in patients with post-traumatic stress disorder (PTSD). However, the results of these studies are unclear regarding the cortical regions involved in this condition, perhaps due to the heterogeneity of the PTSD population included or to the differences in the methodology used for the quantification of the brain structures. In this study, we assessed differences in cortical GM volumes between a selected group of 25 drug-naive PTSD patients with history of adulthood trauma and 25 matched non-traumatized controls. Analyses were performed by using two different automated methods: the structural image evaluation using normalization of atrophy (SIENAX) and the voxel-based morphometry (VBM), as we trusted that if these complementary techniques provided similar results, it would increase the confidence in the validity of the assessment. Results of SIENAX and VBM analyses similarly showed that cortical GM volume decreases in PTSD patients when compared to healthy controls, particularly in the frontal and occipital lobes. These decreases seem to correlate with clinical measures. Our findings suggest that in drug-naive PTSD patients with a history of adulthood trauma, brain structural damage is diffuse, with a particular prevalence for the frontal and occipital lobes, and is clinically relevant. PMID- 21710132 TI - Isolated hypalgesia in ipsilateral face without hearing disorders: a variant of AICA infarction. AB - We reported a 78-year-old woman who had a sudden-onset episode of vertigo, nausea and vomiting. Half an hour later, she felt right hemiataxia, and then noticed numbness on the entire right side of the face. She did not complain of hearing disorders or sensory disorders of left half body involving face. Pure tone audiogram and auditory brainstem responses were normal. Magnetic resonance imaging showed right hypersignals in the dorsolateral pons and middle cerebellar peduncle, as well as in cerebellum. Magnetic resonance angiography showed occlusion of the right anterior inferior cerebellar artery (AICA). Neuroradiological findings suggested ischemia in the whole territory of the right AICA. This is a case of AICA infarction and clinicians should be aware that sensory defect was only in the ipsilateral face without hearing disorders can be the manifestation of AICA infarction. PMID- 21710133 TI - Evaluation of the virulence of Xanthomonas campestris pv. campestris mutant strains lacking functional genes in the OxyR regulon. AB - Xanthomonas campestris pv. campestris causes black rot in cruciferous crops. Hydrogen peroxide (H(2)O(2)) production and accumulation is an important initial response in plant defense against invading microbes. The role of genes involved in the bacterial H(2)O(2) protection system in pathogenicity was evaluated. Mutants of katA (encoding a monofunctional catalase) and, to a lesser extent, katG (encoding a catalase-peroxidase) and oxyR (encoding a H(2)O(2) sensor and a transcription regulator), are hypersensitive to H(2)O(2) treatments that mimic the plant H(2)O(2) burst. These data correlate with the results of pathogenicity testing that show katA, katG, and oxyR mutants are avirulent on a compatible plant. Moreover, exposure to H(2)O(2) (1, 2, and 4 mM) highly induces the expression of genes in the OxyR regulon, including katA, katG, and ahpC. The avirulent phenotype of the oxyR mutant is partly because of its inability to mount an adaptive response upon exposure to an H(2)O(2) burst. Our data provide insights into important roles of a transcription regulator and other genes involved in peroxide stress protection in the virulence of X. campestris pv. campestris. PMID- 21710134 TI - Artificial neural network analysis of circulating tumor cells in metastatic breast cancer patients. AB - A cut-off of 5 circulating tumor cells (CTCs) per 7.5 ml of blood in metastatic breast cancer (MBC) patients is highly predictive of outcome. We analyzed the relationship between CTCs as a continuous variable and overall survival in immunohistochemically defined primary tumor molecular subtypes using an artificial neural network (ANN) prognostic tool to determine the shape of the relationship between risk of death and CTC count and to predict individual survival. We analyzed a training dataset of 311 of 517 (60%) consecutive MBC patients who had been treated at MD Anderson Cancer Center from September 2004 to 2009 and who had undergone pre-therapy CTC counts (CellSearch((r))). Age; estrogen, progesterone receptor, and HER2 status; visceral metastasis; metastatic disease sites; therapy type and line; and CTCs as a continuous value were evaluated using ANN. A model with parameter estimates obtained from the training data was tested in a validation set of the remaining 206 (40%) patients. The model estimates were accurate, with good discrimination and calibration. Risk of death, as estimated by ANN, linearly increased with increasing CTC count in all molecular tumor subtypes but was higher in ER+ and triple-negative MBC than in HER2+. The probabilities of survival for the four subtypes with 0 CTC were as follows: ER+/HER2- 0.947, ER+/HER2+ 0.959, ER-/HER2+ 0.902, and ER-/HER2- 0.875. For patients with 200 CTCs, they were ER+/HER2- 0.439, ER+/HER2+ 0.621, ER-/HER2+ 0.307, ER-/HER2- 0.130. In this large study, ANN revealed a linear increase of risk of death in MBC patients with increasing CTC counts in all tumor subtypes. CTCs' prognostic effect was less evident in HER2+ MBC patients treated with targeted therapy. This study may support the concept that the number of CTCs, along with the biologic characteristics, needs to be carefully taken into account in future analysis. PMID- 21710135 TI - Birth weight and other prenatal factors and risk of breast cancer in Asian Americans. AB - Little is known about the role of birth weight and other prenatal factors in the etiology of breast cancer in Asian-Americans. We investigated the relation between birth weight and other prenatal factors and breast cancer risk in a population-based case-control study in Los Angeles County that included 2,259 Asian-American women with incident, histologically confirmed breast cancer and 2,019 control women, who were frequency matched to cases on age, Asian ethnicity, and neighborhood of residence. Breast cancer risk nearly doubled (odds ratio (OR) = 1.97, 95% confidence interval (CI) = 1.15-3.39) among those with high (>= 4000 g) birth weight compared to those with low (<2500 g) birth weight after adjusting for age at menarche, parity, adult body mass index, and other covariates. Risk increased 8% per 500 g increase in birth weight (P trend = 0.10). We observed a significant relationship between birth weight and age at menarche in both cases and controls. Mean birth weight was higher (2948 g) for control women who had early menarche (age <= 11 years) compared to those who had menarche late (age >= 15 years) (2807 g) (P trend = 0.016); results were similar among case patients (P trend = 0.020). Older maternal age was also a risk factor; risk increased by 6% (95% CI = 1.01-1.12) per 5 years increase in maternal age with adjustment for parity and other risk factors. Our results support the hypothesis that high birth weight and older maternal age at pregnancy may have contributed to the rising breast cancer incidence in Asian-Americans. PMID- 21710136 TI - Behavior problems at 5 years of age and maternal mental health in autism and intellectual disability. AB - We examined child behavior problems and maternal mental health in a British population-representative sample of 5 year-old children with an autism spectrum disorder (ASD), controlling for the presence of an intellectual disability (ID). Behavior problems were significantly higher in children with ASD with/out ID compared to typically developing children, but compared to children with ID only hyperactivity was significantly higher in children with ASD/ID. After controlling for ID and maternal mental health, the presence of ASD significantly increased the odds for hyperactivity, conduct problems and emotional symptoms. Negative maternal outcomes (serious mental illness, psychological distress, and physical health limitations) were not consistently elevated in ASD. The findings highlight the early age at which behavior problems emerge in ASD, and suggest that at this age , there may not be a clear disadvantage for maternal mental health associated with having a child with ASD in the family, over and above that conferred by child behavior problems. PMID- 21710138 TI - Double impact of sterilizing pathogens: added value of increased life expectancy on pest control effectiveness. AB - Sterilizing pathogens are commonly assumed not to affect longevity of infected individuals, and if they do then negatively. Examples abound, however, of species in which the absence of reproduction actually increases life expectancy. This happens because by decreasing the energy outlay on reproduction individuals with lowered reproduction can live longer. Alternatively, fertile individuals are more susceptible to predators or parasitoids if the latter can capitalize on mating signals of the former. Here we develop and analyze an SI epidemiological model to explore whether and to what extent does such a life expectancy prolongation due to sterilizing pathogens affect host dynamics. In particular, we are interested in an added value of increased life expectancy on the possibility of successful pest control, that is, the effect of increased lifespan and hence increased potential of the infected individuals to spread the disease on pest control effectiveness. We show that although the parameter range in which we observe an effect of increased lifespan of the sterilized individuals is not large, the effect itself can be significant. In particular, the increase in pest control effectiveness can be very dramatic when disease transmission efficiency is close to birth rate, mortality rate of susceptibles is relatively high (i.e., the species is relatively short-lived), and sterilization efficiency is relatively high. Our results thus characterize pathogens that are promising candidates for an effective pest control and that might possibly be engineered if not occurring naturally. PMID- 21710137 TI - The effects of instructions on mothers' ratings of child attention deficit/hyperactivity disorder symptoms. AB - We examined whether instructional materials describing how to rate child ADHD symptoms would improve the accuracy of mothers' ratings of ADHD symptoms presented in standard child behavior stimuli, and whether instructions would be equally effective across a range of maternal depressive symptoms and family incomes. A community sample of 100 mothers with 5 to 12 year old sons were randomly assigned to either receive or not receive the instructions. All mothers watched standard video recordings of boys displaying nonproblem behavior, ADHD symptoms, ADHD plus oppositional behaviors, or ADHD plus anxious behaviors, and then rated the ADHD symptoms of the boys in the videos. These ratings were compared to ratings of the boys' ADHD symptoms made by objective coders. Results indicated an interaction such that the instructional materials improved the agreement between mothers' and coders' ratings, but only for mothers at lower family income levels. The instructional materials improved all mothers' open ended responses regarding knowledge of ADHD. All mothers rated more ADHD symptoms in boys with comorbid oppositional or anxious behaviors, and this effect was not reduced by the instructional materials. The potential utility of these instructions to improve the accuracy of ratings of child ADHD symptoms is explored. PMID- 21710139 TI - Continuum modeling and numerical simulation of cell motility. AB - This work proposes a continuum-mechanical model of cell motility which accounts for the dynamics of motility-relevant protein species. For the special case of fish epidermal keratocytes, the stress and cell-substrate traction responses are postulated to depend on selected protein densities in accordance with the structural features of the cells. A one-dimensional version of the model is implemented using Arbitrary Lagrangian-Eulerian finite elements in conjunction with Lagrange multipliers for the treatment of kinematic constraints related to surface growth. Representative numerical tests demonstrate the capacity of the proposed model to simulate stationary and steady crawling states. PMID- 21710140 TI - Progressive myoclonic epilepsy-associated gene KCTD7 is a regulator of potassium conductance in neurons. AB - The potassium channel tetramerization domain-containing protein 7 (KCTD7) was named after the structural homology of its predicted N-terminal broad complex, tramtrack and bric a brac/poxvirus and zinc finger domain with the T1 domain of the Kv potassium channel, but its expression profile and cellular function are still largely unknown. We have recently reported a homozygous nonsense mutation of KCTD7 in patients with a novel form of autosomal recessive progressive myoclonic epilepsy. Here, we show that KCTD7 expression hyperpolarizes the cell membrane and reduces the excitability of transfected neurons in patch clamp experiments. We found the expression of KCTD7 in the hippocampal and Purkinje cells of the murine brain, an expression profile consistent with our patients' phenotype. The effect on the plasma membrane resting potential is possibly mediated by Cullin-3, as we demonstrated direct molecular interaction of KCTD7 with Cullin-3 in co-immunoprecipitation assays. Our data link progressive myoclonic epilepsy to an inherited defect of the neuron plasma membrane's resting potential in the brain. PMID- 21710141 TI - Inflammatory bowel disease associated arthropathy. AB - Arthritis is the most common extraintestinal manifestation of inflammatory bowel disease (IBD) and can have a significant impact on morbidity and quality of life. IBD-associated arthropathy is considered a subtype of seronegative spondyloarthropathy, with axial, peripheral, or a combination of both joint manifestations. Peripheral arthritis is generally non-erosive and the oligoarticular variant particularly may correlate with intestinal disease activity. Axial arthritis may include inflammatory back pain, sacroiliitis, or ankylosing spondylitis, and is less likely to correlate with gastrointestinal symptoms. While there have been advances in identifying predisposing genetic factors and in elucidating pathophysiology of inflammatory bowel disease, the mechanisms surrounding the development of arthritis in IBD remain unclear. Treatment of inflammatory bowel disease is not always sufficient for control of arthritis. While treatment with biologic agents is promising, there remains a great need for larger, randomized studies to address optimal therapy of IBD associated arthropathy. PMID- 21710142 TI - Musculoskeletal education in US medical schools: lessons from the past and suggestions for the future. AB - Despite the prevalence of musculoskeletal disorders in the United States, physicians have received inadequate training during medical school on how to examine, diagnose, and manage these conditions. This article provides an overview of the existing literature on undergraduate medical musculoskeletal education, including learning objectives, researched methodology, and currently utilized assessment tools. A discussion of challenges to and suggested approaches for the implementation of medical school musculoskeletal curricula is presented. PMID- 21710143 TI - The P2Y(12) receptor as a target of antithrombotic drugs. PMID- 21710144 TI - The effect of estrogen on bone marrow-derived rat mesenchymal stem cell maintenance: inhibiting apoptosis through the expression of Bcl-xL and Bcl-2. AB - Mesenchymal Stem Cells (MSCs) have high therapeutic value for regenerative medicine and tissue engineering due to their differentiation potential and non immunogenic characteristics. They are also considered as an effective in vivo delivery agent because of their ability to migrate to the site of injury. A major roadblock in their use for cell-based therapies is their rareness in vivo. Therefore, it is important to obtain increased number of functional MSCs in vitro in order to have adequate numbers for therapeutic regiments. We aimed to investigate the role of estrogen and its mechanism in obtaining more MSCs. MSCs were isolated from female and ovariectomized rats and cultured in the presence and absence of 10(-7) M estrogen. In the presence of estrogen, not only their CFU F activity increased but also apoptotic rate decreased as shown by TUNEL staining leading to obtain more MSCs. Also the number of the cells in the colonies increased upon estrogen treatment. To reveal the mechanism of this effect, we focused on Bcl-2 family of proteins. Our immunoblotting experiments combined with knockdown studies suggested a critical role for anti-apoptotic Bcl-x(L) and Bcl 2. Estrogen treatment up regulated the expression Bcl-x(L) and Bcl-2. When we knocked down the expression of bcl-x ( L ) and bcl-2, MSCs lacking these genes showed an increase in the apoptotic rate in contrast to normal MSCs following estrogen treatment. Therefore, estrogen treatment will be of great advantage for cell-based therapies in order to get more functional MSCs and may provide opportunities to develop new strategies for debilitating diseases. PMID- 21710145 TI - Development of a human extracellular matrix for applications related with stem cells and tissue engineering. PMID- 21710146 TI - Use of the suture anchor in interpositional arthroplasty of temporomandibular joint ankylosis. AB - BACKGROUND: The purpose of this article is to demonstrate the use of a mini suture anchor to attach the temporal myofascial flap to the head of the mandibular condyle in interpositional arthroplasty for the treatment of temporomandibular joint (TMJ) ankylosis. CASE REPORT: A 29-year-old patient, with unilateral posttraumatic temporomandibular joint osseous ankylosis and pre operative maximal interincisal distance of 9 mm, was treated by the interpositional gap arthroplasty using the temporal myofascial flap. After rotation, the flap and the TMJ capsule were attached to the lateral pole of the condyle by a non-absorbable mini suture anchor. The surgery was uneventful. On the first post-operative day, the range of motion was considerably improved, with a maximal interincisal distance of 26 mm, a mandibular protrusion of 1 mm and a lateral mandibular excursion of 4 mm to the left and 7 mm to the right. On the 20th post-operative day, the maximal interincisal distance was 30 mm, protrusion 4 mm, the lateral excursion to the right 7 mm and to the left 5 mm. On the third post-operative month, the maximal interincisal distance reached 40 mm. DISCUSSION: The mini suture anchor demonstrated to be a good tool for the fixation of the temporalis myofascial flap to the condyle, also allowing with the same suture to attach the capsular tissue to the lateral surface of the condyle. The bone-anchored suture permits the restoration of a more physiologic TMJ anatomy. The treatment of TMJ ankylosis should be comprehensive; physiotherapy plays an important role in the rehabilitation period to restore the normal function. PMID- 21710147 TI - Fluorescence enhancement effect for the determination of adenosine 5' monophosphate with 9-anthracene carboxylic acid-cetyl trimethyl ammonium bromide system. AB - A fluorimetric method based on fluorescence enhancement effect was developed for the determination of adenosine 5'-monophosphate (AMP) with 9-anthracene carboxylic acid (9-ANCA)-cetyl trimethyl ammonium bromide (CTAB) system. Fluorescence intensity of 9-ANCA was decreased by the addition of CTAB but addition of AMP again rose the intensity of 9-ANCA gradually. The observed fluorescence enhancement is attributed to the competitive binding reaction of 9 ANCA and adenosine to CTAB. The enhancement in the fluorescence intensity was found proportional to the concentration of AMP over the range 2.0 * 10(-4) to 1.2 * 10(-3) mol dm(-3). The ion pair complex is formed spontaneously between 9-ANCA and CTAB. Since the binding interaction is larger for the adenosine-CTAB pair, the fluorophore 9-ANCA will be released. The quantum yield of free 9-ANCA is higher therefore its fluorescence observed at 417 nm wavelength is enhanced. This mechanism of competitive molecular interaction is further confirmed by conductometric measurements. The method was applied successfully for the determination of AMP from pharmaceutical sample. The method is more selective, sensitive and relatively free from interferences. PMID- 21710148 TI - Heterologous expression of stress-responsive DUF538 domain containing protein and its morpho-biochemical consequences. AB - As a usual response, plants induce/activate various proteins which are thought to be involved in defense mechanisms against the biotic and abiotic stresses they may be confronted with. The novel DUF538 domain containing proteins with unknown functions have been found to be induced/activated in response to different environmental stress stimuli in plants. In order to perform biochemical studies with these new plant stress-responsive proteins, a cDNA containing DUF538 domain was amplified from Celosia cristata full-length leaf expression library using a specific primer set. The isolated cDNA was subsequently expressed in Escherichia coli as a part of maltose-binding fusion protein (MBP-DUF538 construct) and purified at the yield of about 32 mg per liter of cell culture by affinity chromatography without affecting the recombinant bacterial cell growth. The purified fusion product was exogenously applied (10 MUg per 4 cm(2)) on the leaves of Nicotiana tobaccum L. The results revealed that fused DUF538 protein does not induce morphological reposes, but elevates redox enzyme activities including catalase, peroxidase, polyphenol oxidase and phenyalanine ammonia lyase. This is the first time ever time report with respect to the heterologous expression of a plant stress-responsive DUF538 domain that may provide a basis to study its physiological roles and biochemical activities in vitro and in vivo. PMID- 21710149 TI - Social network disruption as a major factor associated with psychological distress 3 years after the 2004 Niigata-Chuetsu earthquake in Japan. AB - OBJECTIVES: The 2004 Niigata-Chuetsu earthquake of Japan caused a great deal of damage, and people living in the affected region are still struggling to reconstruct their lives. The aim of this study was to determine factors associated with psychological distress in people living in a town at the epicenter 3 years after the earthquake. METHODS: We conducted a cross-sectional study from June 2007 to January 2008. Participants included 225 individuals living in Kawaguchi (age >=20 years) who reported psychological symptoms. Information on family structure, employment status, alcohol use, social network, and extent of house damage was elicited by public health nurses conducting structured interviews. Levels of psychological distress were assessed with the Kessler Psychological Distress Scale (K10), with a K10 score >=25 defined as psychological distress. RESULTS: The mean age of participants was 66.1 +/- 12.9 years. The prevalence of psychological distress varied among different employment classes, being 5/73 (6.8%) for participants with paid employment, 12/50 (24.0%) for full-time housewives, and 11/101 (10.9%) for those who were unemployed (chi(2) = 8.42, P = 0.015). It also varied between participants who had lost contact with people in the community and those who had no change in social contact [9/20 (45.0%) vs. 19/189 (10.1%), respectively; chi(2) = 19.04, P < 0.001]. Multiple logistic regression analysis showed that age [odds ratio (OR) 0.95, 95% confidence interval (CI) 0.91-0.98], poor or loss of contact with people in the community (OR 6.97, 95% CI 1.85-26.2), and lack of employment (full time housewives or unemployed individuals) (OR 6.74, 95% CI 1.62-28.0) were associated with psychological distress. CONCLUSIONS: People who lose their social network are at a very high risk for post-earthquake psychological distress and require appropriate care. PMID- 21710150 TI - Evidence of tubular damage in the very early stage of chronic kidney disease of uncertain etiology in the North Central Province of Sri Lanka: a cross-sectional study. AB - BACKGROUND: In the North Central Province of Sri Lanka, chronic kidney disease of uncertain etiology (CKDue) has increased markedly over the past 15-20 years. METHODS: From around 4,700 patients who were followed up, 106 affected patients who visited two local clinics in the endemic area for CKDue on August 10, 2009 and 10 pedigrees of 10 of these cases with familial clustering of CKDue participated in this study. Urine samples, collected from affected patients (n = 106), unaffected relative controls (n = 81), and Japanese controls (n = 50), were analyzed for two tubular markers: alpha1-microglobulin and N-acetyl-beta-D: glucosaminidase. Urine samples from patients with CKDue stages 1-4 (n = 101) and all the samples from unaffected relatives and Japanese controls were analyzed for urinary cadmium concentration. RESULTS: Urinary excretion of alpha1-microglobulin was elevated even in the earliest stage of CKDue compared with its levels in unaffected relative controls. Urinary excretion of N-acetyl-beta-D: glucosaminidase was elevated only in stage 5. In contrast, urinary cadmium excretion was similar in CKDue patients and in the unaffected relative controls, and levels in both these groups were significantly lower than the level in the Japanese controls. All levels were below the threshold level for renal toxicity, indicating the absence of any evidence of cadmium toxicity. CONCLUSIONS: The present study indicates that renal tubular damage occurs in the very early stage of CKDue and demonstrates the existence of familial clustering, suggesting that CKDue is likely to be the outcome of exposure to an unknown nephrotoxin in susceptible subjects in the endemic region. PMID- 21710153 TI - [Joint injuries of the hand]. PMID- 21710152 TI - [The isocentric C-arm. Visualization of fracture reduction and screw position in the radius]. AB - In addition to conventional C-arms which can be used for intraoperative imaging, C-arm image amplifiers with an option for three-dimensional imaging (ISO-C3D) are available to visualize reduction of fragments and positions of implants. In ten cadaver wrists intra-articular steps and intra-articular screw positions were simulated. Images obtained by conventional two-dimensional C-arm image amplifier, computed tomography and ISO-C3D were evaluated by four investigators using a questionnaire. For 2D image amplifier scans the investigators rated the quantity of the articular steps correctly in 45%, incorrectly in 51% and were uncertain in 4%. Concerning CT scans these values were 57, 40 and 3%, respectively. With a slow 190 degrees ISO-C3D mode the investigators rated the steps correctly in 47%, incorrectly in 44% and were uncertain in 9%. The positions of the tip of the screw were rated correctly for 2D scans in 56%, incorrectly in 40% and were uncertain in 4%. For CT screw positions were assessed correctly in 40%, incorrectly in 43% and were uncertain in 17%. For ISO-C3D in fast 190 degrees mode the rating was correct in 59%, wrong in 30% and uncertain in 11%. In the slow Iso-C3D mode the results were inferior with correct assessment in 51%, wrong results in 36% and uncertain evaluation in 13%. In our cadaveric study, ISO-C3D scans have been found valuable for intraoperative controls of implant positions and assessment of intra-articular steps. PMID- 21710154 TI - Inguinal recurrence of early stage endometrial cancer after 7 months of surgical staging: the role of PET-CT in diagnosis and management. AB - The inguinal area is an unexpected recurrence site for early stage endometrial cancer. A 45 year old woman who underwent surgical staging for endometrial cancer presented with a right groin mass at the seventh month of follow-up. Fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) revealed pathologic activity accumulation in only the inguinal mass and no distant metastasis. Based on the PET-CT results, local treatment for the isolated single recurrence was chosen instead of a systemic treatment option. The mass was excised with right inguinal superficial lymph node dissection. Histopathologic examination revealed the recurrence of an endometrioid-type adenocancer. In conclusion, the inguinal region should be considered for recurrences, even at the early stage. PET-CT may be a helpful method for diagnosis, excluding systemic metastasis, and planning the treatment in such cases. PMID- 21710155 TI - A retrospective study of salvage surgery for recurrent nasopharyngeal carcinoma. AB - BACKGROUND: Nasopharyngeal carcinoma is sensitive to radiotherapy. When there is local relapse, re-irradiation treatment is inevitably associated with serious complications and decreased quality of life. Surgical resection offers an alternative treatment option with acceptable morbidity. METHODS: Seventy-one consecutive patients with primary recurrence of nasopharyngeal carcinoma after radiation underwent nasopharyngectomy from January 1, 1990 to June 30, 2006. Follow-up ranged from 12 to 127 months. RESULTS: The actuarial 1-, 2-, 3-, and 5 year survival rates were 88.1, 62.1, 48.9, and 42.1%, respectively. The 1-, 2-, 3 , and 5-year local control rates were 74.6, 61.9, 56.3, and 53.5%, respectively. There was no surgical mortality. The 3-year overall survival rates for recurrent T1, T2, T3, and T4 disease after surgery were 56, 61.1, 30.6, and 0%, respectively; the corresponding 5-year overall survival rates were 49.1, 24.7, 0, and 0%, respectively. Other prognostic factors with a negative effect on survival include lymph node metastasis, invasion of skull base and parapharyngeal space, and positive margin. CONCLUSIONS: Advances in skull base surgery make possible the effective control of primary recurrence of nasopharyngeal carcinoma for patients with rT1 and rT2 stages, with acceptable mortality and morbidity. PMID- 21710156 TI - Synchronous and metachronous ureteric metastases from adenocarcinoma of the colon. AB - Primary adenocarcinoma of the ureter occurs in only <1%. Furthermore, metastatic carcinoma to the ureter is very rare and has been described to occur from breast, lung, stomach and prostate cancers. However, metastases to the ureter from colon cancers are extremely rare, and have been largely reported as incidental post mortem cases. We describe two cases of asymptomatic ureteric metastases secondary to adenocarcinoma of the colon; one is synchronous, whilst the other is a metachronous ureteric metastasis. With the increasing use of radiological imaging modalities such as CT and MRI (Clin Imaging 2001;25:197-202, 2001), together with increasing survival rates of primary cancers, asymptomatic ureteric metastases are more likely to be diagnosed. In summary, metastatic ureteric carcinoma of colonic origin must be considered as a differential diagnosis when there is a radiological abnormality of the ureter in patients with a history of adenocarcinoma of the colon. This should be considered even in patients with colon adenocarcinoma who have previously undergone adjuvant chemotherapy with curative intent. PMID- 21710157 TI - Successful treatment of primary malignant lymphoma of the penis by organ preserving rituximab-containing chemotherapy. AB - Primary penile lymphoma is extremely rare. Here we report the case of a 67-year old man with the chief complaints of difficulty in urination and priapism, who was eventually diagnosed with primary malignant lymphoma of the penis. Pathological examination of excision biopsy of the left inguinal lymph node revealed malignant CD20+ diffuse large B-cell lymphoma. We treated this patient with a systemic rituximab-chemotherapy regimen and obtained good results, in terms of both functional and cosmetic outcomes. Soluble interleukin-2 receptor was a useful tumor marker for evaluating the therapeutic effect. The patient has been in remission for 10 months after the discontinuation of chemotherapy. PMID- 21710158 TI - Schnitzler's syndrome associated with pancreatitis: a disease of IL-1 dysregulation. AB - Schnitzler's syndrome (SS) is a rare inflammatory disease of unknown origin characterized by chronic urticaria and monoclonal gammopathy (usually IgM) associated with at least two of the following components: fever, arthralgia or arthritis, bone pain, hepato- and/or splenomegaly, lymphadenopathy, elevated erythrocyte sedimentation rate, leukocytosis, and/or abnormal findings on bone morphological investigations. To date, about 100 cases have been described with only 4 being reported in the USA. The mean time to diagnosis from the onset of disease is 5.4 years, given the varied symptoms with which patients may present. The pathogenesis of SS remains unknown but likely involves dysregulation of the IL-1 pathway. We describe here a 48-year-old woman with a monoclonal IgM gammopathy and a 3-year history of chronic pruritic urticarial dermatosis, unexplained fevers, chronic polyarthritis, lymphadenopathy, leukocytosis, hepatomegaly, and weight loss. She also had a history of chronic pancreatitis as well as a family history of recurrent pancreatitis. The diagnosis of Schnitzler's syndrome was made, and she was successfully treated with the IL-1 receptor antagonist, anakinra. PMID- 21710159 TI - Copulation patterns in captive hamadryas baboons: a quantitative analysis. AB - For primates, as for many other vertebrates, copulation which results in ejaculation is a prerequisite for reproduction. The probability of ejaculation is affected by various physiological and social factors, for example reproductive state of male and female and operational sex-ratio. In this paper, we present quantitative and qualitative data on patterns of sexual behaviour in a captive group of hamadryas baboons (Papio hamadryas), a species with a polygynous monandric mating system. We observed more than 700 copulations and analysed factors that can affect the probability of ejaculation. Multilevel logistic regression analysis and Akaike's information criterion (AIC) model selection procedures revealed that the probability of successful copulation increased as the size of female sexual swellings increased, indicating increased probability of ovulation, and as the number of females per one-male unit (OMU) decreased. In contrast, occurrence of female copulation calls, sex of the copulation initiator, and previous male aggression toward females did not affect the probability of ejaculation. Synchrony of oestrus cycles also had no effect (most likely because the sample size was too small). We also observed 29 extra-group copulations by two non-adult males. Our results indicate that male hamadryas baboons copulated more successfully around the time of ovulation and that males in large OMUs with many females may be confronted by time or energy-allocation problems. PMID- 21710160 TI - Exploration of optimal teicoplanin dosage based on pharmacokinetic parameters for the treatment of intensive care unit patients infected with methicillin-resistant Staphylococcus aureus. AB - Severely ill intensive care unit (ICU) patients are frequently at risk of developing methicillin-resistant Staphylococcus aureus (MRSA) infections. It is generally accepted that a trough level of >10 MUg/mL teicoplanin (TEC) is appropriate for most such infections. The present study was designed to determine how TEC exposure and patient characteristics affect microbiological response in the treatment of MRSA infections. All patients studied were admitted to Aichi Medical University Hospital ICU between May 2005 and April 2010. Fifty-nine patients were prescribed TEC and 33 of those patients used to treat MRSA infection. Outcome was classified as either cure or failure, and logistic regression analysis was performed to determine which covariates, including severity, significantly influenced the microbiological response. Satisfactory outcomes were obtained in 19 of the 33 patients. Although the cured and failed groups showed adequate trough concentrations, the area under the serum concentration curve (AUC(0-24)) on the third day was significantly higher for the cured group (897.6 +/- 71.7) than for the failed group (652.9 +/- 83.4) (p < 0.05). The results suggested that at least 800 MUg h/mL TEC AUC(0-24) were required to obtain microbiological cure. The higher AUC(0-24), the better the outcome. In our study, higher initial AUC(0-24) was associated with a better microbiological outcome, which demonstrates the importance of the loading dose of TEC, especially for ICU patients. Moreover, the present findings are useful for optimizing the individual dose of TEC using AUC(0-24) in the treatment of MRSA infected patients. PMID- 21710161 TI - Does antimicrobial homogeneity index influence surgical site infection? A 10-year study in lung, breast, and general surgery. AB - To address whether hospital antimicrobial use influences surgical site infection (SSI), we investigated factors including antimicrobial homogeneity index (AHI), an indicator of prescription diversity, with a retrospective study during 120 months for patients undergoing lung, breast, and general surgery (n = 4,510). We analyzed the odds ratios of background factors for SSI and the correlation between AHI and drug susceptibility in isolates of SSI. A total of 243 cases of SSI (5.4%) occurred. Factors that significantly contributed for SSI were operative time [odds ratio (OR), 1.78; 95% confidence interval (CI), 1.33-2.39; P < 0.001], American Society of Anesthesiologists' score (OR, 1.68, 95% CI, 1.23 2.28; P < 0.001), endoscopic use (OR, 0.10, 95% CI, 0.04-0.24; P < 0.001), lung and breast surgery versus general surgery (OR, 0.12, 95% CI, 0.06-0.22; P < 0.001), increased AHI (OR, 0.72, 95% CI, 0.55-0.95; P = 0.020), and older age (OR, 2.08, 95% CI, 1.39-3.11; P < 0.001). AHI showed a positive correlation coefficient (CC, P < 0.05) with susceptibility to ampicillin (CC = +0.327), cefotaxime (CC = +0.142), imipenem/cilastatin (CC = +0.101), and sulbactam/cefoperazone (CC = +0.145). AHI, which has been described to help prevent drug resistance, was associated with increased susceptibility in microbes of SSI. This finding in part may explain that increase in AHI reduced SSI. PMID- 21710162 TI - In vitro activity of azithromycin against Mycoplasma genitalium and its efficacy in the treatment of male Mycoplasma genitalium-positive nongonococcal urethritis. AB - Many recent studies have shown that Mycoplasma genitalium is among the pathogens responsible for Chlamydia trachomatis-negative nongonococcal urethritis (NGU). A single 1-g dose of azithromycin (AZM) has been recommended for the treatment of NGU, including M. genitalium-positive NGU, irrespective of whether it is positive or negative for Chlamydia trachomatis. The purpose of this study was to determine the minimal inhibitory concentrations of AZM against Mycoplasma genitalium strains, and to assess its clinical efficacy against Mycoplasma genitalium positive NGU. Seven Mycoplasma genitalium strains were obtained from the American Type Culture Collection, and susceptibility testing of seven antimicrobial agents was performed using a broth microdilution method. Thirty men with M. genitalium positive NGU were enrolled in this study and treated with a single 1-g dose of AZM. AZM and clarithromycin (CAM) were highly active against M. genitalium strains. Fluoroquinolone activities were moderate, and of the three fluoroquinolones tested, gatifloxacin (GFLX) and sparfloxacin (SPFX) were more active than levofloxacin (LVFX). In 25 of 30 (83.3%) men treated with a single 1 g dose of AZM, M. genitalium was eradicated from first-void urine samples, as determined by polymerase chain reaction. AZM was highly active against M. genitalium, and a single 1-g dose of AZM for M. genitalium-positive NGU was tolerated in Japan. These findings may be helpful in establishing optimal treatment for M. genitalium-positive NGU. PMID- 21710163 TI - Degradation p-chloronitrobenzene in ozone-loaded system with perfluorodecalin solvent. AB - Study was carried out for the removal of hazardous organic compound from aqueous solution by using water/perfluorodecalin loaded ozone two-phase system. p Chloronitrobenzene was used as hazardous organics to examine the efficiency of the two-phase ozonation system. Effects of initial pH in water, stirring speed, initial molar ratio of O(3)/p-chloronitrobenzene (M), and free radical scavenger on the removal rate of p-chloronitrobenzene were investigated respectively. It was revealed that ozone had low decomposed rate coefficient k = 0.0035 min(-1) and solubility of 61.94 mg/L at 25 degrees C in perfluorocarbon. In contrast to pH 2.0, higher level of pH (8.0) in water increased the removal rate of p chloronitrobenzene in water/perfluorocarbon two-phase ozonation system. Removal rate of p-chloronitrobenzene was increased with the elevation of initial M value in water/perfluorocarbon two-phase ozonation system. Stirring speed was needed to control with proper level of speed in water/perfluorocarbon two-phase system. Compared to the conventional gas/water ozonation system, NaHCO(3) (20 mmol/L) had no obvious negative effect on the p-chloronitrobenzene degradation in water/perfluorocarbon ozonation system. Oxidation efficiency of ozonation in water/perfluorocarbon system was superior to that of in conventional gas/water system. PMID- 21710164 TI - Detections of eleven organophosphorus insecticides and one herbicide threatening Pacific salmonids, Oncorhynchus spp., in California, 1991-2010. AB - California's surface water monitoring results from 1991 through 2010 were analyzed to determine whether 12 organophosphorus insecticides and herbicides (i.e., azinphos methyl, bensulide, dimethoate, disulfoton, ethoprop, fenamiphos, methamidophos, methidathion, methyl parathion, naled, phorate, and phosmet) and their degradates have been detected above maximum concentration limits (MCLs) in Pacific salmonid habitats. Methidathion, methyl parathion, phorate, phosmet, and the oxygen analogue of naled (DDVP) detections exceeded MCLs. Methyl parathion detections may be accounted for by monthly use trends, while methidathion detections may be explained by yearly use trends. There were inadequate phorate, phosmet, or DDVP data to evaluate for correlations with use. PMID- 21710165 TI - Monitoring MRD with flow cytometry: an effective method to predict relapse for ALL patients after allogeneic hematopoietic stem cell transplantation. AB - This study evaluated the prognostic value of minimal residual disease (MRD) monitoring by four-color flow cytometry (FCM) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). MRD was examined with four-color FCM at different time points in 139 patients (including pediatric and adult patients) with ALL after allo-HSCT. Real-time quantitative polymerase chain reaction (RQ-PCR) was applied to evaluate the MRD of Philadelphia chromosome-positive ALL (Ph+ ALL) patients. Patients who were FCM-positive (FCM+) after transplantation had a lower event-free survival (EFS) of 0.54 and a higher cumulative incidence of relapse (CIR) of 0.54 compared to an EFS of 0.80 and a CIR of 0.08 in FCM-negative (FCM-) patients (EFS, p < 0.001; CIR, p < 0.001). Similar results were obtained in high risk patients and Ph+ ALL patients. Moreover, a FCM+ status after the second month post-HSCT (defined as MRD positive) proved to be a predictor of leukemia relapse. Multivariate analysis for EFS, OS and CIR showed that MRD status after transplantation was an independent prognostic factor (p < 0.001, p = 0.013, and p < 0.001, respectively). A good correlation was found between the MRD results of FCM and RQ-PCR (n = 126 pairs, Spearman r = 0.8139, p < 0.001). MRD monitoring by four-color FCM post-transplantation is an important tool for relapse prediction in ALL patients. Prompt and appropriate pre-emptive anti-leukemia treatment could be considered based on the status of MRD after HSCT. PMID- 21710166 TI - Efficacy of rituximab in immune thrombocytopenic purpura: a retrospective survey. AB - We conducted a retrospective survey to assess prescription practice, response rates to rituximab, and the predictive indicators for a response to rituximab therapy in patients with primary or secondary immune thrombocytopenic purpura (ITP). Data were collected retrospectively from 40 consecutive patients with ITP attending our hospital: 29 (72.5%) had primary ITP and 11 (27.5%) had secondary ITP. Rituximab was given either as four weekly injections (375 mg/m(2)) or two injections of 1,000 mg given 2 weeks apart in 30 and 10 patients, respectively. The primary objective was to evaluate overall (OR) and complete response (CR) to rituximab therapy for ITP. OR was excellent and rapid and similar when secondary ITP was excluded from the analysis: OR was achieved in 28 (71.8%) patients and CR in 22 (56.4%). But, at >6 months, of the 28 responders, only 10 of 22 of the evaluable responses (45.5%) were sustained. In addition, except for the nonsignificant occurrence of antinuclear antibodies, no clinical or biological factors were predictive for OR or CR after the rituximab therapy. Twelve patients received a second course of rituximab. Overall, rituximab therapy achieved a response in two thirds of the patients, but the responders exhibited a high rate of early relapses, with no obvious difference according to the regimen of administration or rituximab dose. PMID- 21710167 TI - Postpartum anemia I: definition, prevalence, causes, and consequences. AB - This review provides a status on the definition, prevalence, causes, and consequences of anemia in women who have given childbirth, i.e., postpartum anemia. The diagnosis of iron deficiency anemia relies on a full blood count including hemoglobin, serum ferritin, and serum soluble transferrin receptor, which appear to be reliable indicators of anemia and iron status 1 week postpartum while serum transferrin saturation is an unreliable indicator several weeks after delivery. It is recommended that postpartum anemia should be defined by hemoglobin <110 g/L at 1 week postpartum and <120 g/L at 8 weeks postpartum. The major causes of postpartum anemia are prepartum anemia combined with acute bleeding anemia due blood losses at delivery. Normal peripartum blood losses are approximately 300 ml, but hemorrhage >500 ml occur in 5-6% of the women. In healthy women after normal delivery, the prevalence of anemia (hemoglobin <110 g/L) 1 week postpartum is 14% in iron-supplemented women and 24% in non supplemented women. In consecutive series of European women, the prevalence of anemia 48 h after delivery is approximately 50%. In developing countries, the prevalence of postpartum anemia is in the range of 50-80%. Postpartum anemia is associated with an impaired quality of life, reduced cognitive abilities, emotional instability, and depression and constitutes a significant health problem in women of reproductive age. PMID- 21710168 TI - The effect of energy drinks on cortisol levels, cognition and mood during a fire fighting exercise. AB - RATIONALE: Acute stress has been associated with changes in cognitive performance and mood, and these have been in part associated with stress-related increased release of cortisol. Both glucose and caffeine consumed in isolation have been shown to moderate cortisol response and affect cognitive performance and affect mood; however, there has been very little research into their behavioural and physiological effects when taken in combination. The aim of this study was to assess the effect of the two substances in combination under stressful and physically demanding conditions (fire-fighting training) on cognition, mood and cortisol release. METHODS: Using a double-blind, mixed measures design, 81 participants were administered a 330-ml drink containing either (1) 50 g glucose and 40 mg caffeine, (2) 10.25 g of fructose/glucose and 80 mg caffeine or a placebo drink and tested across a range of cognitive tasks, mood and physiological measures. RESULTS: The results showed an increase in grip strength and improved memory performance after ingestion of the drink containing 50 g glucose and 40 mg caffeine, and both active drinks resulted in improved performance on the information-processing task compared to the placebo. In terms of mood effects, the drink containing 50 g glucose and 40 mg caffeine led to a reduction in anxiety and significantly reduced self-reported levels of stress following the fire-fighter training. CONCLUSIONS: Based on the results of this study, in situations of stress combined with physical performance, administration of an energy drink containing glucose and caffeine might be an easy to implement and cost effective way to maintain mental performance levels and to ameliorate the negative effects of stress on mood. PMID- 21710169 TI - The alpha2-adrenergic antagonist idazoxan counteracts prepulse inhibition deficits caused by amphetamine or dizocilpine in rats. AB - RATIONALE: Prepulse inhibition (PPI) is the reduction in startle response magnitude when intense stimuli are closely preceded by other weak stimuli. Animal models used to investigate sensorimotor gating deficits include both the stimulation of dopamine receptors (e.g., amphetamine or apomorphine) and the blockade of NMDA-glutamate receptors (e.g., dizocilpine or phencyclidine). OBJECTIVES: We assessed the effects of idazoxan (an alpha(2)-adrenergic antagonist) on amphetamine- and dizocilpine-induced PPI disruptions in adult female Sprague-Dawley rats. METHODS: In experiment 1, rats were tested for PPI in a bimodal paradigm with an acoustic prepulse and a tactile startle stimulus. Interactions of amphetamine (1 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) were assessed, with all rats receiving all drug doses in a counterbalanced order. In experiment 2, dizocilpine (0.05 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) interactions were analyzed. RESULTS: Amphetamine (1 mg/kg) caused a significant reduction in PPI. Both the 1- and 2-mg/kg doses of idazoxan significantly counteracted this effect. Dizocilpine (.05 mg/kg) effectively inhibited PPI, and the 2-mg/kg idazoxan dose significantly counteracted this impairment. CONCLUSIONS: These results suggest that the effectiveness of atypical antipsychotics such as clozapine in counteracting sensorimotor gating deficits reported in previous studies (e.g., Swerdlow and Geyer, Pharmacol Biochem Behav 44:741-744, 1993; Bakshi et al., J Pharmacol Exp Ther 271:787-794, 1994) may be related to their alpha(2)-antagonist effects, which may be a critical mechanism of the therapeutic effects of atypical antipsychotics in schizophrenia. PMID- 21710170 TI - Stress- and cue-elicited craving and reactivity in marijuana-dependent individuals. AB - RATIONALE: Cue-elicited craving and stress responses have been identified as predictors of relapse in drug dependence, but little research exists on the contribution of these factors to marijuana use specifically. OBJECTIVES: The aims of the present study were to evaluate (1) responses to a psychological stressor, (2) responses to marijuana-related cues, and (3) if an exposure to a psychological stressor augmented craving subsequently elicited by marijuana related cue exposure in marijuana-dependent individuals. METHODS: Subjective (craving, stress), neuroendocrine (adrenocorticotropic hormone (ACTH), cortisol), and physiologic responses to the presentation of neutral and marijuana cues were assessed after randomization to a stress (Trier Social Stress Task (TSST)) or non stress control condition in marijuana-dependent individuals. Outcome measures were assessed at baseline, post-stressor/pre-neutral cue, post-neutral cue, and post-marijuana cue. RESULTS: Eighty-seven participants completed procedures (stress group, n = 45; non-stress group, n = 42). The stress group had a significant increase over the non-stress group in stress rating (p < 0.001), craving (p = 0.028), cortisol (p < 0.001), and ACTH (p < 0.001) after the completion of the TSST. An increased craving response for all participants was seen following the presentation of the marijuana cues (p = 0.005). Following the TSST or non-stress condition, the non-stress group had an increase in craving to marijuana cues as compared to neutral cues (p = 0.002); an increase in craving was not observed in the stress group (p = 0.404). CONCLUSIONS: Marijuana cue exposure and a social stressor increased craving in marijuana-dependent individuals. Completion of the TSST did not increase craving response to subsequent marijuana cue exposure. PMID- 21710171 TI - Effect of substituting live feed with formulated feed on the reproductive performance and fry survival of Siamese fighting fish, Betta splendens (Regan, 1910). AB - This study aimed to elucidate the effect of partial or complete replacement of live feed (LF) (Tubifex) with formulated feed (FF) on the reproductive performance of Betta splendens. Three hundred B. splendens fry (average weight 0.19 +/- 0.01 g) were equally distributed into five different groups, each with three replicates. They were fed for 105 days with following different diets: control (C)-100% LF; T1-75% LF, 25% FF; T2-50% LF, 50% FF; T3-25% LF, 75% FF, and T4-100% FF. Results showed that the average number of hatched larvae (654 +/- 101) and fry survival after 2 weeks of rearing (428 +/- 70), after completion of three spawning, were recorded highest in the control group, which was, however, not significantly different from the T1, T2, and T3 groups. At the end of the feeding trial, the highest hatching percentage (90.3%) was registered in the T2 group, which was not significantly different from the control and T1 groups. The T2 group also recorded highest fry survival (65.54%) after completion of three spawning, which was not significantly (P < 0.05) different from the T1 and T3 groups. Control diet contained higher saturated fatty acid (63.23%) than formulated diet (29.80%). In the whole-body tissue, highest level of EPA (0.42%) and DHA (3.13%) were found in the T4 group followed by T3 group. The DHA/EPA ration was recorded highest in the T2 group (10.96%), which did not differ significantly from the T1 and T3 groups. Significant positive correlation was observed between saturated fatty acid levels in fish whole-body tissue and number of hatched larvae (Y = 30.81 * -825.3, R(2) = 0.968) and fry survival after 2 weeks of rearing (Y = 21.38 * -580.9, R(2) = 0.967). Considering all these factors, it can be concluded that the live feed Tubifex can be replaced up to 50% without any adverse effect on the reproductive performance and fry survival of B. splendens. PMID- 21710172 TI - Histological assessment of cerebellar granule cell layer in postmortem brain; a useful marker of tissue integrity? AB - Tissue quality control measures are routinely performed in brain banks with the assessment of brain pH being the most common measure. In some brain banks the assessment of the RNA integrity number is also performed, although this requires access to specialised equipment and is more expensive. The aim of this study is to determine if there is a correlation between the visual assessment of cerebellar granule cell integrity and brain pH or RIN. One hundred and five consecutive cases from the NSW Tissue Resource Centre, Sydney, Australia were accessed. The cerebrum was hemisected and one hemisphere sliced parasagittally at approximately 1-2 cm intervals and frozen. The other hemisphere was fixed in 15% buffered formalin for 2-3 weeks. The contralateral cerebellar hemisphere was preserved in the same manner as the cerebral hemisphere. Samples of fixed tissue were embedded in paraffin, 7 MUm sections cut and stained routinely with hematoxylin and eosin. The granular cell layer (GCL) was assessed microscopically to determine the degree of autolytic degradation. Degradation was graded as nil, mild, moderate or severe. Brain tissue pH and RIN were measured using standardised protocols. This study showed that both brain pH and RIN significantly correlated with the severity of the degradation of the cerebellar granule cell layer. This additional screening tool can be performed during routine histological review of the cerebellar tissue to assess the suitability for further investigation of tissue quality. PMID- 21710173 TI - MR of the liver: from breakthrough to clinical application. PMID- 21710174 TI - Common and unusual diseases involving the iliopsoas muscle compartment: spectrum of cross-sectional imaging findings. AB - Although relatively uncommon, many different infectious, hemorrhagic and neoplastic disease processes may involve the iliac and psoas muscles and are increasingly diagnosed especially in referral hospitals. Furthermore, the iliopsoas compartment may become injured during trauma, percutaneous instrumentation, laparoscopic or open surgical procedures. State-of-the-art cross sectional imaging including volumetric multidetector CT and multiplanar MRI acquisitions allows prompt detection, comprehensive visualization and confident characterization of most iliopsoas lesions, and the possibility to guide percutaneous biopsy and drainage. The pertinent regional anatomy is reviewed in correlation with disease pathways and imaging modalities. Neoplastic lesions, purulent and mycobacterial iliopsoas infections are discussed with examples. Imaging plays the key role in the differentiation of primary versus secondary abscesses due to intestinal, urinary and musculoskeletal infections, that determines medical therapy and surgical need. The iliopsoas compartment may become involved through direct extension by retroperitoneal, skeletal and pelvic tumors, and should be carefully scrutinized when reviewing oncologic imaging studies since it represents one of the preferred sites of skeletal muscle metastatization. Iliopsoas hemorrhages due to trauma, aortic aneurysms and anticoagulation are reviewed, with a special focus on determining whether the bleeding comes from aneurysmal rupture or from coagulopathy, a critical differentiation to decide about medical or surgical treatment. Postoperative complications involving the iliopsoas compartment are discussed with examples, including retroperitoneal bleeding, infections, urinary leaks and collections following various surgical or instrumentation procedures. Emphasis is placed on choosing the correct imaging modality and technique, particularly to detect active bleeding or urine leakage, and to reduce artifacts related to presence of metallic implants. PMID- 21710175 TI - Mesenteric Fibromatosis Mimicking Metastasis: A Case Report and Review of Literature. PMID- 21710176 TI - Marked improvement of calcinosis in adult dermatomyositis with etidronate therapy. AB - We report a 26-year-old woman with severe calcinosis associated with dermatomyositis. Although calcinosis of the skin or muscles is unusual in adults with dermatomyositis, this patient developed subcutaneous calcinosis with tenderness on the arms, axillary areas, shoulder areas, chest, abdomen, pelvis, and limbs. The calcinosis steadily increased and spread until joint motions were severely limited. Radiographic examination showed extensive soft-tissue calcification with a reticular pattern and severe osteoporosis. The patient was treated with oral etidronate (800 mg/day for 3 months every 6 months) to prevent calcification of the lesions. Three months later, the patient showed a dramatic improvement in symptoms with softening of the calcinosis, reduced pain, and marked increase in joint mobility. Radiographic examination showed marked decreases in the size of the calcified lesions compared to pre-treatment findings, and this effect persisted with a constant progressive efficacy for 3 years. The 3-year course of etidronate therapy also resulted in marked improvement of the severe osteoporosis and the patient was able to return to work and enjoy a normal life. We propose etidronate as a beneficial and effective therapy for calcinosis with osteoporosis. PMID- 21710177 TI - FGF23 analysis of a Chinese family with autosomal dominant hypophosphatemic rickets. AB - Autosomal dominant hypophosphatemic rickets (ADHR; MIM 193100) is a hereditary disorder characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D(3) levels. Recent studies have shown that the fibroblast growth factor 23 (FGF23) gene is responsible for this disease. FGF23 protein is a phosphaturic factor that is elevated in several diseases associated with hypophosphatemia and rickets but varies with disease status in ADHR. In the present study we observed a Chinese family of Han ethnic origin diagnosed with ADHR. The proband is a 30-year-old woman with no history of rickets but with multiple tooth abscesses as a young adult. She presented with progressive painful swelling of the left ankle after a blunt trauma at 26 years of age. She developed back pain, generalized weakness, and fatigue, and she could barely walk at age 27. She was found to have severe hypophosphatemia, low ratio of phosphorus tubule maximum (TmP) to glomerular filtration rate (GFR) (TmP/GFR), and elevated alkaline phosphatase at age 28. Her brother, 26 years old, presented with fatigue at 24 years of age and is normophosphatemic. The parents of this family had no history of rickets or hypophosphatemia. Direct sequence analysis of genomic DNA demonstrated a single heterozygous c.527G>A (p.R176Q) mutation in the FGF23 gene in three family members, including the proband, her brother, and their mother. Intact FGF23 assay of seven time points during the oral phosphate loading test showed no significant relationship between intact FGF23 and serum phosphorus levels of the subject with ADHR and a control. It is probably the first report of a Chinese family with ADHR. PMID- 21710178 TI - Transposition behavior of nonautonomous a hAT superfamily transposon nDart in rice (Oryza sativa L.). AB - Transposable elements (TEs) have a significant impact on the evolution of gene function and genome structures. An endogenous nonautonomous transposable element nDart was discovered in an albino mutant that had an insertion in the Mg protoporphyrin IX methyltransferase gene in rice. In this study, we elucidated the transposition behavior of nDart, the frequency of nDart transposition and characterized the footprint of nDart. Novel independent nDart insertions in backcrossed progenies were detected by DNA blotting analysis. In addition, germinal excision of nDart occurred at very low frequency compared with that of somatic excision, 0-13.3%, in the nDart1-4(3-2) and nDart1-A loci by a locus specific PCR strategy. A total of 253 clones from somatic excision at five nDart loci in 10 varieties were determined. nDart rarely caused deletions beyond target site duplication (TSD). The footprint of nDart contained few transversions of nucleotides flanking to both sides of the TSD. The predominant footprint of nDart was an 8-bp addition. Precise excision of nDart was detected at a rate of only 2.2%, which occurred at two loci among the five loci examined. Furthermore, the results in this study revealed that a highly conserved mechanism of transposition is involved between maize Ac/Ds and rice Dart/nDart, which are two-component transposon systems of the hAT superfamily transposons in plant species. PMID- 21710180 TI - Timing of intrauterine insemination: an attempt to unravel the enigma. AB - INTRODUCTION: Controlled ovarian stimulation (COS) with intrauterine insemination (IUI) is an effective treatment in cases of cervical factor, unexplained infertility and mild male factor. The optimal timing of IUI after human chorionic gonadotrophin (hCG) after COS with clomiphene citrate is debatable and may be a factor limiting success of same. This study was designed to scientifically determine if variation in the timing of IUI could affect the cycle outcome. MATERIALS AND METHODS: In a prospective randomized trial couples with mild male factor, unexplained infertility and mild endometriosis who underwent COS with IUI were recruited. COS was achieved with clomiphene citrate. Two hundred and four women underwent 461 cycles of IUI. Women were randomized to two groups: group I (104 patients, 231 cycles) had IUI 36 h after hCG, while group II (100 patients, 230 cycles) had IUI 24 h after hCG. Primary outcome included pregnancy rate per couple and per cycle. RESULTS: Fifty-four patients had pregnancy with and pregnancy rate per couple and per cycle were 32.6 and 14.7% in group I and 20 and 8.6% in group II, respectively (not statistically different). CONCLUSIONS: Altering timing of IUI after COS does not enhance pregnancy rates. IUI 36 h after hCG has marginally better pregnancy rates than 24 h. Timing of insemination may be kept at 24 or 36 h after hCG injection to suit the convenience of the clinic or care provider. The lack of statistical significance indicates need for larger studies to draw guidelines. PMID- 21710179 TI - Treatment of osteopenia. AB - The majority of osteoporotic fractures happen in individuals with BMD t-scores in the osteopenic range (-2,5< t-score <-1). However, widespread use of anti osteoporotic medication in this group based on t-score alone is not advisable because: 1) the number needed to treat is much higher (NNT>100) than in patients with fractured and t-score below -2,5 (NNT 10-20); 2)while specific osteoporosis treatments have demonstrated significant reductions of the fracture risk in patients with t-score <-2, 5, the efficacy in patients in the osteopenic range is less well established. Therefore, an osteopenic t-score does not in itself constitute a treatment imperative. Generally, osteopenia has to be associated with either low energy fracture(s) or very high risk for future fracture as assessed with risk calculators like FRAX to warrant specific osteoporosis therapy. Vertebral fractures are now conveniently assessed using lateral x-rays from DXA machines. In the vast majority of cases antiresorptive treatments (mainly hormone replacement therapy and SERMS in younger and bisphosphonates or Denosumab in older women) are the treatments of choice in this group of patients, only rarely is anabolic therapy indicated. PMID- 21710181 TI - Quality of life experienced by adolescents and young adults with congenital heart disease. AB - This study aimed to assess the quality of life (QOL) experienced by adolescents and young adults with congenital heart disease (CHD) and to determine which factors negatively affect adjustment and which factors increase resilience. The participants in the study were 74 patients with CHD (41 males and 33 females) ranging in age from 12 to 26 years (mean age, 18.76 +/- 3.86 years). Demographic information and a complete clinical history were obtained. The participants were interviewed regarding topics such as social support, family educational style, self-image, and physical limitations. They responded to questions in a standardized psychiatric interview (SADS-L) and completed a self-report questionnaire (WHOQOL-BREF) for assessment of QOL. Compared with the Portuguese population as a whole, the study patients had better QOL, especially with regard to the environmental dimension (t = 3.754; P = 0.000) and social relationships (t = 2.333; P = 0.022). Patients who had undergone surgery experienced poorer QOL in the physical dimension (t = -1.989; P = 0.050), in social relationships (t = 2.012; P = 0.048) and overall (Mann-Whitney U = 563.000; P = 0.037). Social support played a positive role in the QOL of the patients, both in the physical dimension (t = 3.287; P = 0.002) and in social relationships (t = 3.669; P = 0.000). A higher school achievement also was associated with higher levels of QOL overall (Mann-Whitney U = 457.000; P = 0.046) as well as in the physical (t = 2.045; P = 0.045) and environmental (t = 2.413; P = 0.018) dimensions. Physical limitations had a detrimental impact on general QOL (Mann-Whitney U = 947.500; P = 0.001) and on the physical (t = -2.910; p = 0.005) and psychological (t = 2,046; P = 0.044) dimensions. Patients with CHD tended to perceive QOL as better when their social networks were supportive. PMID- 21710182 TI - Tako-tsubo syndrome in a 12-year-old girl: exhausted heart, not broken heart. AB - We report the case of a 12-year-old girl with Tako-tsubo cardiomyopathy. She was successfully treated in our Pediatric Intensive Care Unit for acute left ventricular failure, which occurred after a brief submersion in sea water. At 2 month follow-up she showed an almost complete recovery of cardiac function. We consider Tako-tsubo syndrome, which is rarely reported in the pediatric population, to be the most likely diagnosis. PMID- 21710183 TI - Benign outcome of pulmonary hypertension in neonates with a restrictive patent foramen ovale versus result for neonates with an unrestrictive patent foramen ovale. AB - Premature closure or restriction of foramen ovale (FO) is a rare but known entity. FO diameter <2 mm and Doppler velocity >120 cm/s, diameter <3 mm with Doppler velocity measured gradient >5 mmHg have all being used by various authors to describe this entity. Some neonates with restrictive FO have been noted to have severe pulmonary hypertension with no clinical signs or symptoms and with spontaneous resolution without any intervention. Seven consecutive neonates were indentified in the database between 01/01/2003 and 06/30/2010 with diagnosis of restrictive PFO (diameter <2 mm) with structurally normal heart and their initial and follow-up echocardiogram as well as hospital medical records were reviewed. As a control, seven neonates with diagnosis of pulmonary hypertension and respiratory distress syndrome or meconium aspiration syndrome were randomly selected. Eighty-six percent of the patients in the control group were symptomatic and required treatment as compared to 14% in the restrictive FO group (p = 0.03). Further, the fall in the peak instantaneous pulmonary artery pressure on follow-up echocardiogram was greater in the restrictive FO group compared with the non-restrictive group (p = 0.03). Patients with pulmonary hypertension and a restrictive FO with no other associated congenital heart disease and/or lung pathology behave differently when compared to neonates with non-restrictive FO and pulmonary hypertension with associated lung disease. They seldom manifest symptoms requiring intervention and tend to show a faster drop in their pulmonary artery pressure toward the normal. PMID- 21710184 TI - Fetal alcohol spectrum disorders: a population based study of premature mortality rates in the mothers. AB - Fetal alcohol spectrum disorders (FASD) are associated with an increase in risk for mortality for people with an FASD and their siblings. In this study we examine mortality rates of birth mothers of children with FASD, using a retrospective case control methodology. We utilized the North Dakota FASD Registry to locate birth certificates for children with FASD which we used to identify birth mothers. We then searched for mothers' death certificates. We then compared the mortality rates of the birth mothers with an age matched control group comprised of all North Dakota women who were born and died in the same year as the birth mother. The birth mothers of children with FASD had a mortality rate of 15/304 = 4.93%; (95% CI 2.44-7.43%). The mortality rate for control mothers born in same years as the FASD mothers was 126/114,714 = 0.11% (95% CI 0.09 0.13%). Mothers of children with an FASD had a 44.82 fold increase in mortality risk and 87% of the deaths occurred in women under the age of 50. Three causes of death (cancer, injuries, and alcohol related disease) accounted for 67% of the deaths in the mothers of children with FASD. A diagnosis of FASD is an important risk marker for premature death in the mothers of children diagnosed with an FASD. These women should be encouraged to enter substance abuse treatment. PMID- 21710185 TI - Dietary management of infantile colic: a systematic review. AB - Infantile colic, the cause of 10-20% of all early paediatrician visits, can lead to parental exhaustion and stress. A systematic review was conducted to examine whether dietary change provides an effective therapy for infantile colic. Six databases were searched from 1960, and 24 studies selected for inclusion. In breastfed infants, evidence suggests that a hypoallergenic maternal diet may be beneficial for reducing symptoms of colic. In formula-fed infants, colic may improve after changing from a standard cow's milk formula to either a hydrolysed protein formula or a soy-based formula. Fibre-supplemented formulae had no effect. Removal of poorly digested carbohydrates from the infant's diet has promise, but additional clinical studies must be conducted before a recommendation can be made. Use of a universal definition to measure symptoms of infantile colic and consistent analysis of urine and faecal samples would improve the evidence in this area. PMID- 21710186 TI - Smoking cessation intervention for pregnant women: a call for extension to the postpartum period. AB - The association between smoking during pregnancy and adverse maternal/neonatal health outcomes is widely acknowledged, and recent health care reform has filled a much-needed gap by extending prenatal smoking cessation intervention coverage to all pregnant women on Medicaid. While more extensive coverage will improve quit rates during pregnancy, there continues to be a need to address high relapse rates in the postpartum period for both the insured and the uninsured. Smoking during the postpartum period exposes infants directly and indirectly to negative health effects, and has additional costs to mothers and society. Approximately 80% of women who quit smoking during pregnancy relapse in the first year postpartum, highlighting a need for effective continuing care that supports them through the challenging postpartum period when stress is high and motivations to stay quit may change. Existing relapse prevention interventions, typically delivered during pregnancy, have been found to be of little benefit during the postpartum period, suggesting the need for a more formal continuing care approach. Phone-based protocols are promising because they address the need for flexible access, and are known to be effective at increasing quit rates and sustained cessation. PMID- 21710188 TI - Induction of hemodialysis therapy in a case with factor XIII deficiency. PMID- 21710187 TI - Public health impact of human papillomavirus vaccination on prevention of cervical cancer in France. AB - OBJECTIVE: To evaluate the cervical cancer (CC) reduction at individual and population level following different prevention strategies (age-specific vaccination and/or screening) in France. METHODS: A lifetime Markov model was constructed with 11 health states covering the progression from human papillomavirus (HPV) infection to the development of precancerous lesions, CC and death. A screening module took into account the effects of detection and early treatment. Cohorts of girls were entered into the model at age 11 years; the model was run for 95 years using one-year cycles. RESULTS: Vaccination combined with screening substantially reduced the incidence of precancerous lesions and CC compared with screening alone. Vaccination was beneficial regardless of age at vaccination, but the greatest benefit was obtained with an early vaccination. The clinical results were the best for vaccination at 11-13 years when lifetime horizon was considered, and for vaccination at 15-17 years for shorter observation period. CONCLUSION: The model results indicate that HPV vaccination offers additional protection against CC when combined with screening. The optimum starting age for vaccination varies depending on the observation period duration. PMID- 21710189 TI - A retrospective assessment comparing pharmacist-managed anticoagulation clinic with physician management using international normalized ratio stability. AB - To assess the rates of therapeutic international normalized ratio (INR) levels between pharmacist-managed clinics compared to traditional physician-management and to determine the variation in rates of therapeutic INR levels between pharmacist-managed clinic data compared to physician-management. Retrospective, randomized, chart review. Referral only, outpatient, pharmacist based anticoagulation clinic under a community based tertiary care health system. Sixty four patients with at least 1 year's worth of visits to the pharmacist managed clinic were reviewed for INR stability. The average percentage of visits within the defined therapeutic range, was 71.1% for the physician-managed group versus 81.1% for the pharmacist-managed group (P < 0.0001). The estimated variance in average therapeutic INR rates was double for the physician-managed group (365.7) versus the pharmacist-managed group (185.2) (P = 0.004). The pharmacist-managed anti-coagulation clinic had higher rates of INRs determined to be therapeutic and also exhibited significantly less variability in therapeutic INR rates relative to the physician-managed service. PMID- 21710190 TI - A general Monte Carlo/simulated annealing algorithm for resonance assignment in NMR of uniformly labeled biopolymers. AB - We describe a general computational approach to site-specific resonance assignments in multidimensional NMR studies of uniformly (15)N,(13)C-labeled biopolymers, based on a simple Monte Carlo/simulated annealing (MCSA) algorithm contained in the program MCASSIGN2. Input to MCASSIGN2 includes lists of multidimensional signals in the NMR spectra with their possible residue-type assignments (which need not be unique), the biopolymer sequence, and a table that describes the connections that relate one signal list to another. As output, MCASSIGN2 produces a high-scoring sequential assignment of the multidimensional signals, using a score function that rewards good connections (i.e., agreement between relevant sets of chemical shifts in different signal lists) and penalizes bad connections, unassigned signals, and assignment gaps. Examination of a set of high-scoring assignments from a large number of independent runs allows one to determine whether a unique assignment exists for the entire sequence or parts thereof. We demonstrate the MCSA algorithm using two-dimensional (2D) and three dimensional (3D) solid state NMR spectra of several model protein samples (alpha spectrin SH3 domain and protein G/B1 microcrystals, HET-s(218-289) fibrils), obtained with magic-angle spinning and standard polarization transfer techniques. The MCSA algorithm and MCASSIGN2 program can accommodate arbitrary combinations of NMR spectra with arbitrary dimensionality, and can therefore be applied in many areas of solid state and solution NMR. PMID- 21710191 TI - Inverse association between eczema and meningioma: a meta-analysis. AB - BACKGROUND AND PURPOSE: The pathogenesis of primary brain tumors may be related to immune response. Prior studies have shown a strong association between allergy and glioma; however, so far no significant association has been established between allergy and meningioma. Here, we conducted a meta-analysis of published studies to investigate the association of meningioma with the overall and specific allergic conditions. METHODS: PubMed, EMBASE database, and Cochrane Library were searched for pertinent citations published between January 1979 and October 2009. We used the following searching strategy (brain tumor [Text Word] OR meningioma [Text Word]) AND (allergy [Text Word] OR atopy [Text Word] OR asthma [Text Word] OR eczema [Text Word] OR hay fever [Text Word]) to search for relevant studies. Random effect model was used to estimate the association between allergic conditions and meningioma. RESULT: A total of 7 studies (5 case control studies and 2 cohort studies) were included in the analysis, involving 54,391 participants, of whom 2,656 had meningioma. When compared to non-allergic conditions, the pooled odds ratio (OR) with any allergic conditions for meningioma was 0.91 (95% CI: 0.79-1.04, p = 0.163), suggesting that there is no significant association between meningioma and allergic conditions. Interestingly, further analysis showed that eczema had significantly inverse association with meningioma (OR, 0.75; 95% CI: 0.65-0.87, p < 0.05). On the other hand, no significant association was found for asthma (OR, 0.88; 95% CI: 0.75 1.04, p = 0.126) and hay fever (OR, 0.90; 95% CI: 0.79-1.03, p = 0.137). CONCLUSION: In conclusion, there was a significantly negative association between eczema and meningioma, suggesting that eczema may reduce the risk of meningioma. Although it was not statistically significant association between meningioma and other specific allergic conditions such as asthma and hay fever, further studies with large sample size may be needed to determine its relationship. PMID- 21710193 TI - Primary care physician compliance with colorectal cancer screening guidelines. AB - OBJECTIVE: To assess self-reported compliance to colorectal cancer (CRC) screening guidelines among primary care physicians (PCPs) and to assess physician and practice characteristics associated with reported compliance. METHODS: Survey data from 984 PCPs in Arizona were used. Self-reported CRC screening practices, recommendations, and compliance with guidelines were assessed. Physician and practice characteristics associated with guideline compliance were also evaluated. RESULTS: While 77.5% of physicians reported using national screening guidelines, only 51.7% reported recommendations consistent with the guidelines. Younger physicians were significantly more likely to report compliance with screening guidelines (OR = 1.50, 95% CI = 1.07-2.10) as were female clinicians (OR = 1.46, 95% CI = 1.11-1.92). Physicians practicing in solo (OR = 0.33, 95% CI = 0.19-0.58), group (OR = 0.36, 95% CI = 0.21-0.62), or community health centers (OR = 0.37, 95% CI = 0.17-0.81) were significantly less likely to report following guidelines as compared to those in academic practice. Guideline compliance was higher for fecal occult blood test (FOBT) (65.0%) than colonoscopy (56.7%); overuse of screening for these modalities was reported among 34.4% of physicians. CONCLUSIONS: PCPs are not adequately following CRC screening guidelines. Further studies are needed to clarify the reasons for this lack of compliance, especially as guidelines become more complex. PMID- 21710194 TI - Drug-related problems in Parkinson's disease: the role of community pharmacists in primary care. AB - OBJECTIVE: Although Parkinson's disease is a common disorder in the elderly, there have been very few studies of the role of the pharmaceutical care services in detecting and reducing problems associated with drug treatment in community settings. The aim of this study was therefore to investigate the type and frequency of drug-related problems identified in patients with Parkinson's disease by community pharmacists over an 8-month period and to assess the pharmaceutical service interventions, the type and frequency of intervention outcomes and the clinical benefits for the patients. SETTING: Community pharmacies in Germany. METHOD: Thirty-two community pharmacists recruited 113 outpatients with idiopathic Parkinson's disease who were receiving anti Parkinsonian medication. MAIN OUTCOME MEASURE: Drug-related problems. RESULTS: A total of 331 drug-related problems were identified by the pharmacists. Patients not receiving a medication, despite the presence of an indication or symptom, accounted for the highest proportion of drug-related problems (26.3%). The pharmacists proposed a total of 474 interventions, the most common of which was giving the patient treatment advice (19.6%). Intervention outcomes were recorded for 215 of the 331 drug-related problems, for which there were 553 individual outcome results. Adjustments of the drug regimen accounted for the highest percentage of individual results (43.6%). CONCLUSION: Structured pharmaceutical care processes by community pharmacists have the potential to make a valuable contribution to health care and enhance the health outcomes of patients with Parkinson's disease. PMID- 21710192 TI - The After Breast Cancer Pooling Project: rationale, methodology, and breast cancer survivor characteristics. AB - The After Breast Cancer Pooling Project was established to examine the role of physical activity, adiposity, dietary factors, supplement use, and quality of life (QOL) in breast cancer prognosis. This paper presents pooled and harmonized data on post-diagnosis lifestyle factors, clinical prognostic factors, and breast cancer outcomes from four prospective cohorts of breast cancer survivors (three US-based and one from Shanghai, China) for 18,314 invasive breast cancer cases diagnosed between 1976 and 2006. Most participants were diagnosed with stage I-II breast cancer (84.7%). About 60% of breast tumors were estrogen receptor (ER)+/progesterone receptor (PR)+; 21% were ER-/PR-. Among 8,118 participants with information on HER-2 tumor status, 74.8% were HER-2- and 18.5% were HER-2+. At 1-2 years post-diagnosis (on average), 17.9% of participants were obese (BMI >= 30 kg/m2), 32.6% were overweight (BMI 25-29 kg/m2), and 59.9% met the 2008 Physical Activity Guidelines for Americans (>= 2.5 h per week of moderate activity). During follow-up (mean = 8.4 years), 3,736 deaths (2,614 from breast cancer) and 3,564 recurrences have been documented. After accounting for differences in year of diagnosis and timing of post-diagnosis enrollment, five year overall survival estimates were similar across cohorts. This pooling project of 18,000 breast cancer survivors enables the evaluation of associations of post diagnosis lifestyle factors, QOL, and breast cancer outcomes with an adequate sample size for investigation of heterogeneity by hormone receptor status and other clinical predictors. The project sets the stage for international collaborations for the investigation of modifiable predictors for breast cancer outcomes. PMID- 21710195 TI - Psychological impact of screening and prediction in type 1 diabetes. AB - Screening programs designed to identify persons at risk for type 1 diabetes via genetic and antibody testing are controversial because they typically target children, provide only a crude estimate of type 1 diabetes risk, and offer no means of preventing the disease. For this reason, genetic and antibody testing for type 1 diabetes risk is usually limited to carefully conducted research studies. The psychological impact of such screening programs include cognitive, emotional, and behavioral sequelae; the available literature has focused primarily on parents, and usually mothers, since the target of screening is usually infants or young children. Diabetes risk is a difficult construct to effectively communicate. Many individuals fail to accurately understand risk; inaccurate risk perceptions may increase over time and have been associated with early study withdrawal. Simply asking study participants if they understand the risk information provided is insufficient. Anxiety and worry are common reactions to learning that you or a loved one is at increased risk for type 1 diabetes. For most people, anxiety and worry dissipate with time but some individuals may be particularly vulnerable to prolonged anxiety or depression. Although there is no known means to prevent type 1 diabetes in at-risk individuals, families often report increased surveillance of those at risk and behavior changes to prevent the disease, potentially threatening the internal validity of the study. PMID- 21710196 TI - Long-term results of breast volume replacement using an inframammary adipofascial flap after breast-conserving surgery. AB - We have used an inframammary adipofascial flap for breast-conserving reconstruction in the inferior portion of the breast since 2005. The aim herein is to report this oncoplastic procedure in detail, including the long-term results. The surgical procedure was as follows: A skin incision is made at the inframammary line. After partial resection of the breast, a tongue-shaped flap of the fat and the anterior sheath of the rectus abdominis muscle are pulled up in the inframammary area. The flap is then inserted into the breast area where the tumor was removed, and it is secured with absorbable sutures to the surrounding breast tissue. When making the flap, it is very important to preserve several intercostal perforators around the inframammary line. Cosmetic results at more than 5 years after the operation in the 5 patients were assessed using photographs. The results were found to be good in 4 cases (80%) and poor in 1 case. The poor outcome was a case with 100% fat necrosis of the flap. This surgical procedure is easy to perform, and the long-term cosmetic outcomes were good, without complications. We consider this procedure to be useful for breast conserving reconstruction after breast cancer occurring in the inferior portion of the breast. PMID- 21710197 TI - Current concepts in pacing 2010-2011: the right and wrong way to pace. AB - OPINION STATEMENT: Over five decades have passed since the first permanent cardiac pacemakers were introduced into clinical medicine. Evolving technology and falling costs have demanded adaptation to clinical practice and implantation trends and, with the advent of evidenced-based medicine, the specific roles and benefits of individual pacemaker technologies have never been so carefully scrutinized. Pacing mode choice continues to be a subject of great controversy, and there are great regional variations in practice. We believe that single chamber atrial pacing use (AAI/R) has become an anachronism that should generally be abandoned (obviously with rare exceptional cases) and be replaced by dual chamber pacemakers (DDD/R) equipped with modern pacing algorithms that minimize patient exposure to ventricular pacing. Also, in patients with atrioventricular (AV) block, randomized clinical trials have failed to show improvement in clinically relevant outcomes such as mortality, stroke, and heart failure, particularly in the elderly, which has led some to advocate that DDD/R devices should never be offered to elderly AV block patients. However, we believe that the elderly, like the young, come in many "shapes and sizes" and individualized medicine compels us to consider each pacemaker candidate as unique. Implanting DDD/R devices in chronologically older, yet physiologically younger, patients is justifiable and good medical practice. Where right ventricular (RV) pacing is necessary and unavoidable, physicians should consider routinely placing RV leads on the RV mid- or outflow tract septum because these location are as good, if not better, for patients than the current practice of RV apical lead placement. In patients with AV block and asymptomatic yet moderate to severely depressed left ventricular systolic function, primary cardiac resynchronization therapy (CRT) should be strongly considered. Compelling clinical trial evidence does not yet exist to indicate that CRT should be the standard of care in patients with AV block and intact left ventricular systolic function. Right ventricular septal lead placement remains a reasonable option. PMID- 21710199 TI - Shifts in xylem vessel diameter and embolisms in grafted apple trees of differing rootstock growth potential in response to drought. AB - We investigated responses of plant growth rate, hydraulic resistance, and xylem cavitation in scion-rootstock-combinations of Malus domestica L. cv. Honeycrisp scions grafted onto a high-shoot vigor (HSV) rootstock, (semi-dwarfing Malling111), or onto a low-shoot vigor (LSV) rootstock, (dwarfing Budagovsky 9), in response to substrate moisture limitation. Adjustments in xylem vessel diameter and frequency were related to hydraulic resistance measurements for high versus low- vigor apple trees. We observed a greater tolerance to water deficit in the high-shoot compared to the low-shoot vigor plants under water deficit as evidenced by increased growth in several plant organs, and greater scion anatomical response to limited water availability with ca. 25% increased vessel frequency and ca. 28% narrower current season xylem ring width. Whereas water limitation resulted in greater graft union hydraulic resistance of high-shoot vigor trees, the opposite was true when water was not limiting. The graft union of the low-shoot vigor rootstock exhibited higher hydraulic resistance under well watered conditions. Scions of high-shoot vigor rootstocks had fewer embolisms at low plant water status compared to scions of low-shoot vigor rootstocks, presumably as a result of large differences in xylem vessel diameter. Our results demonstrated that anatomical differences were related to shifts in hydraulic conductivity and cavitation events, a direct result of grafting, under limited soil water. PMID- 21710200 TI - The distressed (Type D) personality. A risk marker for poor health outcomes in ICD patients. AB - The distressed (Type D) personality is an emerging risk marker for poor health outcomes in patients with cardiovascular disease. Patients with this personality disposition are typified by a general propensity to experience psychological distress. The contribution focuses on the impact of Type D personality on psychological distress, quality of life, ventricular tachyarrhythmias, and mortality in implantable cardioverter-defibrillator (ICD) patients and examines the relative influence of this vulnerability factor compared to ICD shocks and markers of disease severity in relation to these outcomes. PMID- 21710198 TI - Neuronal and morphological bases of cognitive decline in aged rhesus monkeys. AB - Rhesus monkeys provide a valuable model for studying the basis of cognitive aging because they are vulnerable to age-related decline in executive function and memory in a manner similar to humans. Some of the behavioral tasks sensitive to the effects of aging are the delayed response working memory test, recognition memory tests including the delayed nonmatching-to-sample and the delayed recognition span task, and tests of executive function including reversal learning and conceptual set-shifting task. Much effort has been directed toward discovering the neurobiological parameters that are coupled to individual differences in age-related cognitive decline. Area 46 of the dorsolateral prefrontal cortex (dlPFC) has been extensively studied for its critical role in executive function while the hippocampus and related cortical regions have been a major target of research for memory function. Some of the key age-related changes in area 46 include decreases in volume, microcolumn strength, synapse density, and alpha1- and alpha2-adrenergic receptor binding densities. All of these measures significantly correlate with cognitive scores. Interestingly, the critical synaptic subtypes associated with cognitive function appear to be different between the dlPFC and the hippocampus. For example, the dendritic spine subtype most critical to task acquisition and vulnerable to aging in area 46 is the thin spine, whereas in the dentate gyrus, the density of large mushroom spines with perforated synapses correlates with memory performance. This review summarizes age-related changes in anatomical, neuronal, and synaptic parameters within brain areas implicated in cognition and whether these changes are associated with cognitive decline. PMID- 21710202 TI - Dynamic localization of the actin-bundling protein cortexillin I during cell migration. AB - Cortexillins are actin-bundling proteins that play a critical role in regulating cell morphology and actin cytoskeleton reorganization in Dictyostelium. Here, we investigated dynamic subcellular localization of cortexillin I in chemotaxing Dictyostelium cells. Most of the cortexillin I was enriched on the lateral sides of moving cells. Upon chemoattractant stimulation, cortexillin I was rapidly released from the cortex followed by a transient translocation to the cell cortex with a peak at ~5 s and a subsequent decrease to basal levels, indicating that localization of cor-texillin I at the cortex in chemotaxing cells is controlled by two more signaling components, one for the initial delocalization from the cortex and another for the translocation to the cortex ~5 s after chemoattractant stimulation. Loss of cortexillins leads to reduced cell polarity and an increased number of lateral pseudopodia during chemotaxis, suggesting that cortexillins play an inhibitory role in producing pseudopodia along the lateral sides of the cell. Cells lacking cortexillins displayed extended chemoattrac-tant-mediated Arp2/3 complex translocation kinetics to the cortex. Our present study provides a new insight into the function of cortexillins during reorganization of the actin cytoskeleton and cell migration. PMID- 21710201 TI - Circadian rhythms and sleep--the metabolic connection. AB - The circadian system coordinates mammalian physiology and behavior with the environmental light-dark cycle. It allocates sleep to the inactivity phase using various mechanisms involving neurotransmitters, nuclear receptors, and protein kinases. These pathways are related to metabolism, indicating that the circadian system and sleep are connected via metabolic parameters. This suggests that organs other than the brain may "sleep." A hypothetic view on this aspect is presented providing a different perspective on sleep regulation. PMID- 21710204 TI - PKR-dependent mechanisms of interferon-alpha for inhibiting hepatitis B virus replication. AB - Interferon-alpha (IFN-alpha) inhibits the replication of hepatitis B virus (HBV) in vivo and in vitro, but the molecular mechanism of this inhibition has been elusive. We found that while HBV replication in transfected human hepatoma Huh-7 cell was severely inhibited by IFN-alpha treatment as reported previously, this inhibition was markedly impaired in the cell in which the expression of IFN inducible, double-stranded RNA-dependent protein kinase (PKR) was stably and specifically suppressed through RNA-interference. Intracellular level of viral capsids was down-regulated likewise in a PKR-dependent manner, whereas that of HBV transcripts including the viral RNA pregenome was not affected by IFN-alpha treatment. Ectopic expression of PKR also resulted in the reduction of viral capsids with concomitant increase of phosphorylated eIF2alpha. These results suggested that PKR functions as a key mediator of IFN-alpha in opposing HBV replication, most likely through the inhibition of protein synthesis. PMID- 21710203 TI - Priming by rhizobacterium protects tomato plants from biotrophic and necrotrophic pathogen infections through multiple defense mechanisms. AB - A selected strain of rhizobacterium, Pseudomonas putida strain LSW17S (LSW17S), protects tomato plants (Lycopersicon esculentum L. cv. Seokwang) from bacterial speck by biotrophic Pseudomonas syringae pv. tomato strain DC3000 (DC3000) and bacterial wilt by necrotrophic Ralstonia solanacearum KACC 10703 (Rs10703). To investigate defense mechanisms induced by LSW17S in tomato plants, transcription patterns of pathogenesis-related (PR) genes and H(2)O(2) production were analyzed in plants treated with LSW17S and subsequent pathogen inoculation. LSW17S alone did not induce transcriptions of employed PR genes in leaves and roots. DC3000 challenge following LSW17S triggered rapid transcriptions of PR genes and H(2)O(2) production in leaves and roots. Catalase infiltration with DC3000 attenuated defense-related responses and resistance against DC3000 infection. Despite depriving H(2)O(2) production and PR1b transcription by the same treatment, resistance against Rs10703 infection was not deterred significantly. H(2)O(2) is indispensable for defense signaling and/or mechanisms primed by LSW17S and inhibition of bacterial speck, however, it is not involved in resistance against bacterial wilt. PMID- 21710205 TI - TGF-beta1 stimulates mouse macrophages to express APRIL through Smad and p38MAPK/CREB pathways. AB - A proliferation-inducing ligand (APRIL), a new TNF family member, supports B-cell survival and tumor cell proliferation. APRIL is secreted as a soluble protein by macrophages, dendritic cells and activated T cells. However, factors involved in regulation of APRIL expression are as yet unknown. In this study, we investigated the effect of TGF-beta1 on APRIL expression in P388D1, a mouse macrophage cell line. TGF-beta1 induced APRIL mRNA expression in a time- and dose-dependent manner. One nanogram per milliliter of TGF-beta1 was optimal and APRIL transcripts appeared as early as 3 h after stimulation. Based on our studies, which included overexpression of Smad3, DN-Smad3, and sh-Smad3, we found that Smad3 mediates APRIL transcription at least partially. Further, experiments using inhibitors revealed that p38MAPK and CREB are also involved in TGF-beta1-induced APRIL expression. These results suggest that TGF-beta1, through Smad3 and p38MAPK/CREB signaling pathways, stimulates APRIL expression in macrophages. PMID- 21710206 TI - FVE, an Arabidopsis homologue of the retinoblastoma-associated protein that regulates flowering time and cold response, binds to chromatin as a large multiprotein complex. AB - Some genetic studies indicate that plant homologues of proteins involved in chromatin modification and remodeling in other organisms may regulate plant development. Previously, we described an Arabidopsis mutant with altered cold responsive gene expression (acg1) displaying a late flowering phenotype, a null allele of fve. FVE is a homologue of the mammalian retinoblastoma-associated protein (RbAp), one component of a histone deacetylase (HDAC) complex involved in transcriptional repression, and has been shown to be involved in the deacetylation of the FLOWERING LOCUS C (FLC) chromatin encoding for a repressor of flowering. In an effort to gain insight into the biochemical functions of FVE, we overexpressed FVE tagged with the hemagglutinin (HA) and FLAG epitope at the N terminus in acg1 mutants. The results of physiological and molecular analyses demonstrated that FVE overexpression in acg1 rescued the mutant phenotypes, including late flowering and alterations in floral pathway gene expression such as FLC, SUPPRESSOR OF OVEREXPRESSION OF CO1 (SOC1), and FLOWERING LOCUS T (FT), and also super-induced cold-responsive reporter gene expression. The chromatin immunoprecipitation experiments revealed the amplification of specific DNA regions of FLC and COLD-REGULATED 15A (COR15A), indicating that FVE may bind to the FLC and COR15A chromatin. Gel-filtration chromatography and the immunoprecipitation of putative FVE complexes showed that FVE forms a protein complex of approximately 1.0 MDa. These results demonstrate that FVE may exist as a multiprotein complex, similar to the mammalian HDAC complex harboring RbAp, to regulate flowering time and cold response by associating with the FLC and COR chromatin. PMID- 21710207 TI - Incidence, treatment and outcome of rectal stenosis following transanal endoscopic microsurgery. AB - BACKGROUND: As an alternative to more radical abdominal surgery, transanal endoscopic microsurgery (TEM) offers a minimally invasive solution for the excision of certain rectal polyps and early-stage rectal tumours. The patient benefits of TEM as compared to radical abdominal surgery are clear; nevertheless, some drawback is possible. The aim of our study was to determine the risk factors, treatment and outcomes of rectal stenosis following TEM. METHODS: We analysed a series of 354 consecutive patients who underwent TEM for benign or malignant rectal tumours between 1997 and 2009. We recorded the maximum histological diameter of the lesion, and whether the lesion was circumferential. Rectal stenosis was defined as a rectal narrowing not allowing passage of a 12 mm sigmoidoscope. RESULTS: Histological results with a measured specimen diameter were available in 304 of the 354 cases. There were 11 stenoses in total (3.6%), 7 stenoses due to 9 circumferential lesions (78%) and 4 due to lesions with a maximum diameter >= 5 cm (3.2%). Two patients presented as emergencies, and the other 9 patients reported symptoms of increased stool frequency at follow-up. Three of the stenoses were associated with recurrent disease. All stenoses were treated by a combination of endoscopic/radiological balloon dilatation or surgically with Hegar's dilators. A median of two procedures were required to treat stenoses until resolution of symptoms. CONCLUSIONS: Rectal stenosis following TEM excision is rare. It is predictable in patients with circumferential lesions but is rare in patients with non-circumferential lesions with a maximum diameter >= 5 cm. It is effectively treated with surgical or balloon dilatation. Most patients require repeated treatments. PMID- 21710208 TI - Laparoscopic right hemicolectomy with intracorporeal anastomosis: Letter to the "How I do it" article by Y.-H. Ho, Tech Coloproctol (2010) 14:359-363. PMID- 21710209 TI - Mental health community based funding: Ohio's experience in revising its funding allocation methodology. AB - Over the past 20 years, states have increasingly moved away from centrally financed, state-operated facilities to financing models built around community based service delivery mechanisms. This paper identifies four important broad factors to consider when developing a funding formula to allocate state funding for community mental health services to local boards in an equitable manner, based on local community need: (1) funding factors used by other states; (2) state specific legislative requirements; (3) data availability; and (4) local variation of factors in the funding formula. These considerations are illustrated with the recent experience of Ohio using available evidence and data sources to develop a new community-based allocation formula. We discuss opportunities for implementing changes in formula based mental health funding related to Medicaid expansions for low income adults scheduled to go into effect under the new Patient Protection and Affordable Care Act. PMID- 21710210 TI - Induction of a high-yield lovastatin mutant of Aspergillus terreus by 12C6+ heavy ion beam irradiation and the influence of culture conditions on lovastatin production under submerged fermentation. AB - Heavy-ion beams, possessing a wide mutation spectrum and increased mutation frequency, have been used effectively as a breeding method. In this study, the heavy-ion beams generated by the Heavy-Ion Research Facility in Lanzhou were used to mutagenize Aspergillus terreus CA99 for screening high-yield lovastatin strains. Furthermore, the main growth conditions as well as the influences of carbon and nitrogen sources on the growth and the lovastatin production of the mutant and the original strains were investigated comparatively. The spores of A. terreus CA99 were irradiated by 15, 20, 25, and 30 Gy of 80 MeV/u (12)C(6+) heavy ion beams. Based on the lovastatin contents in the fermentation broth, a strain designated as A. terreus Z15-7 has been selected from the clone irradiated by the heavy-ion beam. When compared with the original strain, the content of lovastatin in the fermentation broth of A. terreus Z15-7 increased 4-fold. Moreover, A. terreus Z15-7 efficiently used the carbon and nitrogen sources for the growth and production of lovastatin when compared to the original strain. The maximum yield of lovastatin, 916.7 MUg/ml, was obtained as A. terreus Z15-7 was submerged cultured in the chemically defined medium supplemented with 3% glycerol as a carbon source, 1% corn meal as an organic nitrogen source, and 0.2% sodium nitrate as an inorganic nitrogen source at 30 degrees C in the shake flask. The result shows that heavy-ion beam irradiation is an effective method for the mutation breeding of lovastatin production of A. terreus. PMID- 21710211 TI - Molecular characterization of N-terminal pro-sequence of keratinase Ker P from Pseudomonas aeruginosa: identification of region with chaperone activity. AB - In silico analysis of keratinase Ker P from Pseudomonas aeruginosa revealed that its full gene of 1,497 bp constituted of a 72-bp signal sequence along with a long 520 bp pro-sequence and 905 bp core region. Position specific multiple sequence alignment of Ker P protein with other distant proteases revealed high variability within their N-terminal regions while the core protein was considerably conserved. Ker P (F1) and its four N-terminal truncations (F2-F5) lacking 72, 177, 405, 507 bp, respectively, were cloned and constitutively expressed as extracellular protein in pEZZ-18 secretory vector with Escherichia coli HB101 as the expression host. Ker P F1, Ker P F2, Ker P F3 and Ker P F4 products were active whereas no keratinolytic activity was obtained in Ker P F5. Further analysis revealed that only 187 bp pro-sequence region is required for correct folding of the protein into its active conformation and, thus, has chaperone-like activity. Further, comparative biochemical characterization revealed that the full-length keratinase Ker P F1 was catalytically more efficient than the truncated forms. Among the truncated enzymes, keratinase Ker P F4 exhibited better thermostability than Ker P F2 with a t(1/2) of >1 h at 60 degrees C. It also had a higher V (max) and K (m) on casein as compared with Ker P F2. However, no significant variation was observed with respect to kinetics on synthetic substrates. PMID- 21710212 TI - Large-scale production of the immunomodulator c-di-GMP from GMP and ATP by an enzymatic cascade. AB - (3'-5')-Cyclic diguanylate (c-di-GMP) is a bacterial second messenger with immunomodulatory activities in mice suggesting potential applications as a vaccine adjuvant and as a therapeutic agent. Clinical studies in larger animals or humans will require larger doses that are difficult and expensive to generate by currently available chemical or enzymatic synthesis and purification methods. Here we report the production of c-di-GMP at the multi-gram scale from the economical precursors guanosine monophosphate (GMP) and adenosine triphosphate by a "one-pot" three enzyme cascade consisting of GMP kinase, nucleoside diphosphate kinase, and a mutated form of diguanylate cyclase engineered to lack product inhibition. The c-di-GMP was purified to apparent homogeneity by a combination of anion exchange chromatography and solvent precipitation and was characterized by reversed phase high performance liquid chormatography and mass spectrometry, nuclear magnetic resonance spectroscopy, and further compositional analyses. The immunomodulatory activity of the c-di-GMP preparation was confirmed by its potentiating effect on the lipopolysaccharide-induced interleukin 1beta, tumor necrosis factor alpha, and interleukin 6 messenger RNA expression in J774A.1 mouse macrophages. PMID- 21710213 TI - [Nutrition in older persons. Basis for functionality and quality of life]. AB - With increasing age alterations of metabolism, appetite regulation, and body composition have been observed. As a consequence the risk of malnutrition is much higher in older than in younger persons. Though the highest prevalence rates have been described for the hospital and rehabilitation setting, most older persons with overt malnutrition are found in the community. Here persons with chronic comorbidity and low functionality show the highest risk. Routine screening for malnutrition is therefore indicated in older persons. For the successful treatment of malnutrition it is important to consider also medical and social etiologic factors before starting nutritional therapy. With regard to the preservation of muscle mass and muscle strength, adequate protein intake deserves careful consideration. Besides the implementation of regular snacks between meals, temporary application of oral supplements which are high in energy and protein is indicated. Especially during and after hospital stays, the beneficial interaction between nutrition and exercise has to be considered with regard to functionality and quality of life in older persons. PMID- 21710215 TI - [Improved radiological surveillance control of septic arthritis by USPIO contrast enhanced MRI?]. PMID- 21710214 TI - Influenza and HIV: lessons from the 2009 H1N1 influenza pandemic. AB - Influenza is a common respiratory disease in adults, including those infected with HIV. In the spring of 2009, a pandemic influenza A (H1N1) virus (pH1N1) emerged. In this article, we review the existing literature regarding pH1N1 virus infection in HIV-infected adults, which suggests that susceptibility to pH1N1 virus infection and severity of influenza illness are likely not increased in HIV infected adults without advanced immunosuppression or comorbid conditions. The risk of influenza-related complications, however, may be increased in those with advanced immunosuppression or high-risk comorbid conditions. Prevention and treatment of high-risk comorbid conditions and annual influenza vaccination should continue to be part of HIV clinical care to help prevent influenza illness and complications. Additional information about pH1N1 vaccine immunogenicity and efficacy in HIV-infected patients would be useful to guide strategies to prevent influenza virus infection in this population. PMID- 21710216 TI - [Arthroplasty for rheumatic elbow joints]. AB - Without proper treatment rheumatoid arthritis can lead to pain, instability and destruction of the elbow joint. As with artificial knee replacement various designs are available and in general non-constrained and semi-constrained designs are preferred. Fully constrained designs should be avoided due to high loosening rates. Results have shown a significant pain reduction, however, a restricted range of motion has to be expected. Restrictions in load-bearing and mobility are among the major problems after elbow arthroplasty in patients with rheumatoid arthritis which have to be discussed with the patient before surgery. Future studies will have to evaluate the effectiveness of new modular designs. PMID- 21710217 TI - [Endoprostheses of the hip joint]. AB - In many cases rheumatoid arthritis leads to functional disturbances and deformities of the hip joint despite intensive conservative treatment. Joint replacement becomes necessary to preserve mobility and independence. The choice of implant and fixation system depends on the results of clinical and radiological examinations and the individual patient situation (e.g. age, bone quality, deformities of adjacent joints). The procedure, pre-operative and postoperative treatment, all require special expertise. If possible surgical procedures should be carried out in specialized surgical institutions by surgeons experienced in rheumatology and orthopedics. PMID- 21710218 TI - Closed-loop and open-loop control of posture and movement during human trunk bending. AB - Closed-loop (CL) and open-loop (OL) types of motor control during human forward upper trunk bending are investigated. A two-joint (hip and ankle) biomechanical model of the human body is used. The analysis is performed in terms of the movements along eigenvectors of the motion equation ("eigenmovements" or "natural synergies"). Two analyzed natural synergies are called "H-synergy" (Hip) and "A synergy" (Ankle) according to the dominant joint in each of these synergies. Parameters of CL control were estimated using a sudden support platform displacement applied during the movement execution. The CL gain in the H-synergy increased and in the A-synergy decreased during the movement as compared with the quiet standing. The analysis of the time course of OL control signal suggests that the H-synergy (responsible for the prime movement, i.e. bending per se) is controlled according to the EP theory whereas for the associated A-synergy (responsible for posture adjustment, i.e. equilibrium maintenance) muscle forces and gravity forces are balanced for any its final amplitude and therefore the EP theory is not applicable to its control. PMID- 21710219 TI - Paving the way for invasive species: road type and the spread of common ragweed (Ambrosia artemisiifolia). AB - Roads function as prime habitats and corridors for invasive plant species. Yet despite the diversity of road types, there is little research on the influence of these types on the spread of invaders. Common ragweed (Ambrosia artemisiifolia), a plant producing large amounts of allergenic pollen, was selected as a species model for examining the impact of road type on the spread of invasive plants. We examined this relationship in an agricultural region of Quebec, Canada. We mapped plant distribution along different road types, and constructed a model of species presence. Common ragweed was found in almost all sampling sites located along regional (97%) and local paved (81%) roads. However, verges of unpaved local roads were rarely (13%) colonized by the plant. A model (53% of variance explained), constructed with only four variables (paved regional roads, paved local roads, recently mown road verges, forest cover), correctly predicted (success rate: 89%) the spatial distribution of common ragweed. Results support the hypothesis that attributes associated with paved roads strongly favour the spread of an opportunistic invasive plant species. Specifically, larger verges and greater disturbance associated with higher traffic volume create propitious conditions for common ragweed. To date, emphasis has been placed on controlling the plant in agricultural fields, even though roadsides are probably a much larger seed source. Strategies for controlling the weed along roads have only focused on major highways, even though the considerable populations along local roads also contribute to the production of pollen. Management prioritizations developed to control common ragweed are thus questionable. PMID- 21710221 TI - Congruence among encounters, norms, crowding, and management in a marine protected area. AB - Over the past few decades, recreation and tourism use has increased at many marine protected areas, generating concerns about impacts of this increasing use on experiences and conditions at these areas (e.g., crowding, conflict). This article uses data from Molokini Shoal Marine Life Conservation District in Hawai'i to examine: (a) reported encounters, crowding, normative tolerances for various use levels, and support of use related management strategies at this site; and (b) whether users who encounter higher use levels than their norms feel more crowded and are more supportive of restrictive management strategies. Data were obtained from onsite pre-trip and post-trip questionnaires of 712 passengers on commercial snorkel and dive tours visiting this site. Norms were measured with acceptance of 12 photographs depicting levels of boat use. On average, users would accept seeing no more than approximately 16 boats at one time at Molokini and this number was observed on over 20% of trips to the site. Although the majority of users expected to escape crowds at Molokini, 67% felt crowded and up to 79% supported actions that would directly restrict use at this site (e.g., limit number of boats). Users who encountered more boats than their normative tolerance felt more crowded and were more supportive of these management strategies. Findings suggest that this marine protected area is operating over its capacity and management is needed to improve experiences and conditions. PMID- 21710220 TI - The potential influence of seasonal climate variables on the net primary production of forests in eastern China. AB - Knowledge of the effects of climate factors on net primary production (NPP) is pivotal to understanding ecosystem processes in the terrestrial carbon cycle. Our goal was to evaluate four different categories of effects (physical, climatic, NDVI, and all effects[global]) as predictors of forest NPP in eastern China. We developed regression models with data from 221 NPP in eastern China and identified the best model with each of the four categories of effects. Models explained a large part of the variability in NPP, ranging from 46.8% in global model to 36.5% in NDVI model. In the most supported global model, winter temperature and sunshine duration negatively affected NPP, while winter precipitation positively affected NPP. Thus, winter climate conditions play an important role in modulating forest NPP of eastern China. Spring temperature had a positive affect on NPP, which was likely because a favorable warm climate in the early growing season promotes forest growth. Forest NPP was also negatively affected by summer and autumn temperatures, possibly because these are related to temperature induced drought stress. In the NDVI model, forest NPP was affected by NDVI in spring (positive), summer (negative) and winter (negative) seasons. Our study provides insight into seasonal effects of climate and NPP of forest in China, as well as useful knowledge for the development of climate-vegetation models. PMID- 21710222 TI - Institutional, individual, and socio-cultural domains of partnerships: a typology of USDA Forest Service recreation partners. AB - Federal land management agencies, such as the USDA Forest Service, have expanded the role of recreation partners reflecting constrained growth in appropriations and broader societal trends towards civic environmental governance. Partnerships with individual volunteers, service groups, commercial outfitters, and other government agencies provide the USDA Forest Service with the resources necessary to complete projects and meet goals under fiscal constraints. Existing partnership typologies typically focus on collaborative or strategic alliances and highlight organizational dimensions (e.g., structure and process) defined by researchers. This paper presents a partner typology constructed from USDA Forest Service partnership practitioners' conceptualizations of 35 common partner types. Multidimensional scaling of data from unconstrained pile sorts identified 3 distinct cultural dimensions of recreation partners--specifically, partnership character, partner impact, and partner motivations--that represent institutional, individual, and socio-cultural cognitive domains. A hierarchical agglomerative cluster analysis provides further insight into the various domains of agency personnel's conceptualizations. While three dimensions with high reliability (RSQ = 0.83) and corresponding hierarchical clusters illustrate commonality between agency personnel's partnership suppositions, this study also reveals variance in personnel's familiarity and affinity for specific partnership types. This real world perspective on partner types highlights that agency practitioners not only make strategic choices when selecting and cultivating partnerships to accomplish critical task, but also elect to work with partners for the primary purpose of providing public service and fostering land stewardship. PMID- 21710223 TI - The use of alcohol as a moderator for tinnitus-related distress. AB - Tinnitus is an auditory phantom percept with a tone, hissing, or buzzing sound in the absence of any objective physical sound source. Persons with tinnitus engage in a number of health behaviors to manage tinnitus. This can go from prescription medication, masking devices, behavioral training techniques to cortical implants. Potentially less adaptive methods of coping with tinnitus, such as the use of alcohol, are poorly studied. The purpose of this study was to further explore the neurobiological mechanism of tinnitus improvement by the use of alcohol. We observed differences in the alpha, beta and gamma frequency band when comparing resting-state EEG before and after alcohol intake. More precisely increased synchronized alpha1 activity was found in the posterior cingulate cortex and decreased synchronized alpha2 activity was demonstrated in orbitofrontal cortex, ventrolateral prefrontal cortex and subcallosal anterior cingulate cortex after alcohol intake. Increased synchronized activity was found in a region between the pregenual and dorsal anterior cingulate cortex and the left insula for beta and decreased activity in the precuneus after alcohol intake. For the gamma frequency band decreased synchronized activity in the precuneus and the posterior cingulate cortex was demonstrated after alcohol intake. Region of interest analyses in auditory cortices and parahippocampal area revealed however no differences in the different frequency bands before and after alcohol consumption. PMID- 21710224 TI - What is the outcome of applying principlism? AB - The four principles approach to bioethics, an approach most associated with the work of Tom Beauchamp and James Childress, is supposed to provide a framework for reasoning through moral issues in medicine. One might wonder, if one were to guide one's thinking by the method suggested by principlism, will one identify and perform the objectively morally right action? Will one's decision making be justified, and consequently, will the action that flows from that decision itself be justified? In this paper, I show that principlism can, and has been, characterized in these two different ways. I also argue that when it is understood according to the first characterization, the view cannot be put into practice. However, when it is understood as an account of justification, there is reason to think that it is indeed action-guiding. Given the problems that confront the first version of the view, perhaps it is best to understand principlism, and biomedical ethical theories generally, not as action-guiding theories of right action, but rather, as procedures by which one's decisions and actions in medicine can achieve a reasonable degree of moral justification. PMID- 21710225 TI - Influence of cultivation parameters on growth and microcystin production of Microcystis aeruginosa (Cyanophyceae) isolated from Lake Chao (China). AB - Microcystis aeruginosa isolated in 2005 from the shallow eutrophic Lake Chao (Anhui, China) was investigated in terms of growth parameters and microcystin production under varying nutrient concentrations (P, N) and pH values (abiotic factors) as well as under the influence of spent medium of the non-toxic cyanobacterium Synechocystis sp. (biotic factors). Stimulating effects on growth were observed at the alkaline pH value (10.5), whereas toxin production was significantly increased under phosphate-P limitation (0.6 mg L(-1) medium). Within a broad range of nitrate-N concentrations (41.2-247.2 mg L(-1) medium), no significant influence on cell growth and microcystin production was observed; however, N-starvation resulted in a typical decrease of growth and toxicity. In addition, cryopreservation of M. aeruginosa evidenced the decrease of toxin production by time-dependent exposure with the cryoprotectant dimethyl sulfoxide under thawing conditions without affecting the growth of the cyanobacterial cells. PMID- 21710226 TI - L-glutamine supplementation prevents myenteric neuron loss and has gliatrophic effects in the ileum of diabetic rats. AB - BACKGROUND: Peripheral neuropathy caused chronically by diabetes mellitus is related to exacerbation of oxidative stress and a significant reduction in important endogenous antioxidants. L: -Glutamine is an amino acid involved in defense mechanisms and is a substrate for the formation of glutathione, the major endogenous cellular antioxidant. AIM: This study investigated the effects of 2% L: -glutamine supplementation on peripheral diabetic neuropathy and enteric glia in the ileum in rats. METHODS: Male Wistar rats were divided into four groups: normoglycemics (N), normoglycemics supplemented with L: -glutamine (NG), diabetics (D), and diabetics supplemented with L: -glutamine (DG). After 120 days, the ileums were processed for HuC/D and S100 immunohistochemistry. Quantitative and morphometric analysis was performed. RESULTS: Diabetes significantly reduced the number of HuC/D-immunoreactive myenteric neurons per unit area and per ganglion in group D compared with normoglycemic animals (group N). L: -Glutamine (2%) prevented neuronal death induced by diabetes (group DG) compared with group D. The glial density per unit area did not change with diabetes (group D) but was significantly reduced after L: -glutamine supplementation (groups NG and DG). Ganglionic glial density was similar among the four groups. The neuronal area was not altered in groups D and DG. Glial size was reduced in group D; this was reversed by L: -glutamine supplementation (group DG). CONCLUSIONS: We concluded that 2% L: -glutamine had neuroprotective effects directly on myenteric neurons and indirectly through glial cells, which had gliatrophic effects. PMID- 21710227 TI - Can quality of care for patients with cirrhosis be measured? AB - INTRODUCTION: The ultimate purpose of measuring quality of care is to discriminate between healthcare providers in order to motivate improvement. Recently, a set of evidence-based indicators has been proposed for measurement of processes of care for patients with cirrhosis, for example early endoscopy for variceal bleeding. The objective of this study was to determine whether these indicators can be measured in a reliable and automated fashion in routine practice. MATERIALS AND METHODS: We applied the top five indicators, based on agreement of a panel of experts, to hospitalized adults at our institution over a 3-year period. RESULTS: Only two of the indicators could be reliably measured on the basis of the published wording, and these two still required physician chart review. After applying some assumptions, the indicators were met in 46-100% of cases. None of the indicators was linked to a single physician or institution in all cases, and none occurred with sufficient frequency to discriminate quality between providers. CONCLUSION: Measuring quality of care in cirrhosis is a laudable objective, but current indicators are not yet ready for administrative use. PMID- 21710228 TI - Biliary access with conventional methods or with suprapapillary puncture: safety is the main issue we need to query first. PMID- 21710229 TI - Genotypic characterization of toxigenic group C and G streptococci isolated in Chennai, South India. PMID- 21710230 TI - Effect of pH on the denitrifying enzyme activity in pasture soils in relation to the intrinsic differences in denitrifier communities. AB - The effects of pH on denitrifying enzyme activity (DEA) and on the ratio of the denitrification products, N(2)O and N(2), were determined in three pasture soils differing in cattle impact. The linkage between intrinsic differences in the denitrifying communities and pH effects on relative N(2)O production was also assessed. Soil pH values were adjusted just before DEA determination to obtain soil slurries with a range of pH values. The intrinsic differences in the denitrifier communities were assessed by measuring the kinetic constants of NO(3)(-) and N(2)O reductions. DEA for all three soils was highest at pH 8.4, regardless of native soil pH. Because DEA has typically been measured at native soil pH, our results suggest that DEA might have been underestimated in many previous studies. Further, relative N(2)O production at different pH values did not differ among the soils, even though the denitrifier communities differed in their intrinsic capability to reduce NO(3)(-) all the way to N(2), suggesting that the ratio of denitrification products (N(2)O and N(2)) is pH-specific rather than soil-specific. This suggests that manipulations of soil pH will alter N(2)O fluxes from agricultural soils. PMID- 21710231 TI - Coiling and migration of peritoneal catheter into the breast: a very rare complication of ventriculoperitoneal shunt. AB - Upward migration of distal catheter of a ventriculoperitoneal shunt with coiling is very rare. Pseudocyst and galactorrhea are known breast-related complications. Here, we report a 13-year-old girl, known case of myelomeningocele and shunted hydrocephalus, who presented with right breast pseudocyst due to distal tube migration and coiling of the catheter. Plain radiography was not diagnostic because of severe levoscoliosis, but chest computed tomography scan was confirmatory of shunt coiling lateral to the breast. The possible mechanisms causing this uncommon complication are described. PMID- 21710232 TI - A Monte Carlo evaluation of three Compton camera absorbers. AB - We present a quantitative study on the performance of cadmium zinc telluride (CZT), thallium-doped sodium iodide (NaI(Tl)) and germanium (Ge) detectors as potential Compton camera absorbers. The GEANT4 toolkit was used to model the performance of these materials over the nuclear medicine energy range. CZT and Ge demonstrate the highest and lowest efficiencies respectively. Although the best spatial resolution was attained for Ge, its lowest ratio of single photoelectric to multiple interactions suggests that it is most prone to inter-pixel cross talk. In contrast, CZT, which demonstrates the least positioning error due to multiple interactions, has a comparable spatial resolution with Ge. Therefore, we modelled a Compton camera system based on silicon (Si) and CZT as the scatterer and absorber respectively. The effects of the detector parameters of our proposed system on image resolution were evaluated and our results show good agreement with previous studies. Interestingly, spatial resolution which accounted for the least image degradation at 140.5 keV became the dominant degrading factor at 511 keV, indicating that the absorber parameters play some key roles at higher energies. The results of this study have validated the predictions by An et al. which state that the use of a higher energy gamma source together with reduction of the absorber segmentation to sub-millimetre could achieve the image resolution of 5 mm required in medical imaging. PMID- 21710233 TI - Evaluation of linear array MOSFET detectors for in vivo dosimetry to measure rectal dose in HDR brachytherapy. AB - The study aimed to assess the suitability of linear array metal oxide semiconductor field effect transistor detectors (MOSFETs) as in vivo dosimeters to measure rectal dose in high dose rate brachytherapy treatments. The MOSFET arrays were calibrated with an Ir192 source and phantom measurements were performed to check agreement with the treatment planning system. The angular dependence, linearity and constancy of the detectors were evaluated. For in vivo measurements two sites were investigated, transperineal needle implants for prostate cancer and Fletcher suites for cervical cancer. The MOSFETs were inserted into the patients' rectum in theatre inside a modified flatus tube. The patients were then CT scanned for treatment planning. Measured rectal doses during treatment were compared with point dose measurements predicted by the TPS. The MOSFETs were found to require individual calibration factors. The calibration was found to drift by approximately 1% +/-0.8 per 500 mV accumulated and varies with distance from source due to energy dependence. In vivo results for prostate patients found only 33% of measured doses agreed with the TPS within +/-10%. For cervix cases 42% of measured doses agreed with the TPS within +/-10%, however of those not agreeing variations of up to 70% were observed. One of the most limiting factors in this study was found to be the inability to prevent the MOSFET moving internally between the time of CT and treatment. Due to the many uncertainties associated with MOSFETs including calibration drift, angular dependence and the inability to know their exact position at the time of treatment, we consider them to be unsuitable for in vivo dosimetry in rectum for HDR brachytherapy. PMID- 21710234 TI - Correlational study of vascular endothelial growth factor expression and microvessel density in primary malignant gastric lymphoma. AB - Vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) in primary malignant gastric lymphoma were studied, and their correlation as well as its clinical significance was analyzed. Thirty-five patients diagnosed with primary malignant gastric lymphoma were enrolled in this study. VEGF expression in the tumor tissues was detected by immunohistochemistry. Microvessel density in tumors was counted with Weidner's method and compared with MVD in normal tissues 5 cm away from tumor site. Collected data were analyzed statistically. Our results showed that VEGF expression and MVD in tumor tissues were higher than those in normal tissues, and the difference between these two groups was significant (P < 0.01). As VEGF expression was elevated, MVD was also increased in tumor tissues. Statistical analysis revealed that VEGF expression was positively correlated with MVD (r = 0.392, P < 0.05). VEGF was highly expressed in primary malignant gastric lymphoma and positively correlated with MVD. These results strongly suggest that anti-angiogenesis therapy investigated in gastric lymphoma is a prospective clinical trial. PMID- 21710235 TI - Characteristics of colorectal cancer in the human immunodeficiency virus-infected African American population. AB - Colorectal Cancer (CRC) is the second leading cause of cancer mortality in the United States. African Americans (AAs) have the highest incidence of CRC of any American ethnic group. Survival from CRC in AAs is lower than in Caucasians, and the mean age of CRC development in AAs is younger. The AA community also has a high rate of HIV infection, accounting for 50.3% of all cases despite making up only 13.6% of the population. This retrospective cohort study identified 17 AA HIV patients with CRC. The patients were matched with 42 HIV-negative CRC patients (controls), based on age, sex, and TNM stage. Data were obtained from 3 hospitals in New Jersey: St. Michael's Medical Center, Trinitas Medical Center and St. Joseph's Medical Center. The age, sex, HIV status, tumor site, stage, drug usage, Hepatitis C status, and survival outcome of subjects and controls were compared. Data from the Surveillance Epidemiology & End Results (SEER) specific to AAs were also compared. The mean age of CRC diagnosis was younger, 50.7 years (median: 52 years, range: 35-71 years), versus 59.42 years (median: 66 years) (P < 0.0001) in the SEER AA population. Of the patients, 29.4% were diagnosed with CRC at less than 45 years of age, versus only 6.35% of the SEER AA population (P < 0.0002). The male-to-female ratio was 11:6. Seven individuals used IV drugs, and 7 had hepatitis C. The mean CD4+ T-cell count was 510.81 cells/mm(3) (median 419). At the time of CRC diagnosis, the average duration of HIV infection was 7.6 years (range 0-22.4 years).Of patients, 87.5% had left sided CRC, versus 57.55% of the SEER population (P < 0.024). Of the patients, 52.94% had stage III-IV, at diagnosis, versus 43.84% in SEER. There was no statistically significant survival difference between the cases and controls. In our cohort of HIV-infected AA's with CRC, the staging and outcome of CRC did not appear to be affected by the degree of immunosuppression. HIV-infected AA with CRC presented with a higher percentage of left-sided CRC than AA's without HIV. Additionally, AAs with HIV tended to be younger at the time of CRC diagnosis. Our findings suggest that screening for CRC should be offered to HIV-infected AAs before the age of 45, and that sigmoidoscopy with fecal occult blood testing might be an acceptable screening modality. However, the exact age of initiation, optimal frequency, and preferred method of screening (colonoscopy vs. sigmoidoscopy) in this population requires further study. PMID- 21710236 TI - Prognostic factors of Chinese patients with T/NK-cell lymphoma: a single institution study of 170 patients. AB - T/natural killer-cell lymphoma (T/NKCL) is a heterogeneous group of lymphoma and has a higher incidence in Asia than in Western countries. T/NKCL is presented with various clinicopathologic features, and in general, associated with a poor clinical outcome. This study aims to analyze the clinical prognostic factors in patients with T/NKCL. From January 1999 to December 2009, a total of 170 patients with T/NKCL, except mycosis fungoides, were included in this retrospective study. The diagnosis was established according to World Health Organization classification. The clinical characteristics and prognostic factors were evaluated. Of the 170 patients, mainly peripheral T-cell lymphoma-unspecified (65 cases), precursor T-lymphoblastic lymphoma/leukemia (31 cases) and nasal NK/T cell lymphoma (NKTCL, 19 cases), advanced disease (Ann Arbor stages III-IV) was presented in 68.8% and extranodal involvement was in 71.2% of the patients. According to the international prognostic index (IPI), 77 cases were categorized as high/intermediate or high-risk group. Using the prognostic index for peripheral T-cell lymphoma-unspecified (PIT), 87 cases were classified as group 3 or 4. Most of the initial regimens were CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-based chemotherapy (87.6%). Cumulative probability of overall survival at 5 years was 43%, and the median survival time was 44.5 months. Univariate analysis revealed that factors associated with a poor outcome were poor performance status (ECOG > 1) (P = 0.001), advanced disease (P = 0.009), the presence of B symptom (P = 0.001), multiple extranodal involvement (P = 0.005), bone marrow involvement (P = 0.003), elevated lactic dehydrogenase level (P = 0.019), IPI (P < 0.001), PIT (P < 0.001), abnormal white blood cell count (P = 0.016), decreased platelet count (P = 0.005) and serum Epstein-Barr virus (EBV) IgA positivity (P = 0.016). In the multivariate analysis, PIT (P < 0.001; relative risk, 3.221; 95% CI = 2.115-4.907) and EBV serum IgA (P = 0.049; relative risk, 1.901; 95% CI = 1.002-3.606) remained independent factors predictive for overall survival. The PIT may therefore be a useful index for risk stratification in patients with T/NKCL. The serum EBV antibody test could be a simple and quick marker to predict the outcome of the patients. PMID- 21710237 TI - Comparative adherence to oxybutynin or tolterodine among older patients. AB - PURPOSE: To compare persistence of oxybutynin or tolterodine therapy among older patients newly prescribed one of these drugs. METHODS: We conducted a retrospective cohort study of Ontarians aged 66 years and older who were newly prescribed either drug between January 1, 2000 and December 31, 2007. Persistence with treatment was defined on the basis of refills for the drug within a grace period equal to 50% of the prescription duration. RESULTS: We identified 31,996 patients newly treated with oxybutynin and 24,855 newly treated with tolterodine. After 2 years of follow-up, persistence on oxybutynin (9.4%) was significantly lower than that on tolterodine (13.6%, p < 0.0001). The median time to discontinuation of oxybutynin and tolterodine was 68 and 128 days, respectively. CONCLUSIONS: Our findings suggest that the tolerability of these drugs differs substantially. PMID- 21710238 TI - Mifepristone treatment results in differential regulation of glycerolipid biosynthesis in baby hamster kidney cells expressing a mifepristone-inducible ABCA1. AB - ATP binding cassette A1 (ABCA1) transports cholesterol, phospholipids and lipophilic molecules to and across cellular membranes. We examined if ABCA1 expression altered cellular de novo glycerolipid biosynthesis in growing Baby hamster kidney (BHK) cells. Mock BHK cells or cells expressing a mifepristone inducible ABCA1 (ABCA1) were incubated plus or minus mifepristone and then with [(3)H]serine or [(3)H]inositol or [(3)H]ethanolamine or [methyl-(3)H]choline or [(3)H]glycerol or [(14)C]oleate and radioactivity incorporated into glycerolipids determined. Mifepristone did not affect [1,3-(3)H]glycerol or [(14)C]oleate or [(3)H]ethanolamine or [methyl-(3)H]choline uptake in BHK cells. In contrast, [(3)H]glycerol and [(14)C]oleate incorporated into phosphatidylserine (PtdSer) were elevated 2.4-fold (p < 0.05) and 54% (p < 0.05), respectively, upon ABCA1 induction confirming increased PtdSer biosynthesis from these precursors. However, mifepristone inhibited [(3)H]serine uptake and incorporation into PtdSer indicating that PtdSer synthesis from serine in BHK cells is dependent on serine uptake. Mifepristone stimulated [(3)H]inositol uptake in mock and ABCA1 cells but not its incorporation into phosphatidylinositol indicating that its synthesis from inositol is independent of inositol uptake in BHK cells. [(3)H]glycerol and [(14)C]oleate incorporated into triacylglycerol were reduced and into diacylglycerol elevated only in mifepristone-induced ABCA1 expressing cells due to a decrease in diacylglycerol acyltransferase-1 (DGAT-1) activity. The presence of trichostatin A, a class I and II histone deacetylase inhibitor, reversed the ABCA1-mediated reduction in DGAT-1 activity but did not affect DGAT-1 mRNA expression. Thus, mifepristone has diverse effects on de novo glycerolipid synthesis. We suggest that caution should be exercised when using mifepristone inducible systems for studies of glycerolipid metabolism in cells expressing glucocorticoid responsive receptors. PMID- 21710239 TI - How does sacral modulation work best? Placement and programming techniques to maximize efficacy. AB - Since receiving approval from the US Food and Drug Administration in 1997, sacral neuromodulation (SNM) has become the recommended treatment of urinary urge incontinence, urgency-frequency, nonobstructive urinary retention, and fecal incontinence. The manufacturer has introduced different technical modifications while surgeons and researchers have adapted and published various innovations and alterations of the technique. This review summarizes the current knowledge and recommendations of SNM preoperative decision making, the implantation technique, and available programming parameters and algorithms based on MEDLINE research, manufacturer instructions, and the approach of an experienced neurourological team. The primary steps and technical aspects to optimize SNM efficacy were the introduction of the tined-lead electrode and the development of the InterStim II impulse generator (both developed by Medtronic, Inc., Minneapolis, MN). The initiation of the staged implantation technique for sequential evaluation and implantation with the definitive quadripolar electrode completes the treatment algorithm so that an increased responder rate of SNM for all indications can be achieved. PMID- 21710241 TI - The onion fly modulates the adult eclosion time in response to amplitude of temperature cycle. AB - To confirm whether the amplitude of diel temperature cycles causes a phase shift of adult eclosion rhythm of the onion fly, Delia antiqua, the peak time (O(E)) of adult eclosion was determined under various thermoperiods with a fixed temperature either in the warm or cool phase and temperature differences ranging from 1 degrees C to 4 degrees C between the two phases. Irrespective of the temperature level during the warm or cool phase, O(E) occurred earlier with decreasing amplitude of the temperature cycle. The results strongly support the previous conclusion of Tanaka and Watari (Naturwissenschaften 90:76-79, 2003) that D. antiqua responds to the amplitude of temperature cycle as a cue for the circadian adult eclosion timing. The phase advance was larger in thermoperiods with a fixed warm-phase temperature than in those with a fixed cool-phase temperature. This might be ascribed to the interaction between the amplitude and level of temperature in the thermoperiodic regimes. PMID- 21710240 TI - Mediastinal fetal rhabdomyoma in nevoid basal cell carcinoma syndrome: a case report and review of the literature. PMID- 21710242 TI - Protective effects of caffeic acid phenethyl ester (CAPE) on intestinal damage in necrotizing enterocolitis. AB - OBJECTIVE: To determine the preventative effect of caffeic acid phenethyl ester (CAPE) in necrotizing enterocolitis (NEC) in an experimental rat model of NEC. MATERIALS AND METHODS: Thirty newborn Sprague-Dawley rats were randomly divided into three groups; as NEC, NEC + CAPE and control. NEC was induced by enteral formula feeding, subjected to hypoxia-hyperoxia and cold stress. Pups in the NEC + CAPE group were treated with CAPE at a dose of 30 mg/kg daily by intraperitoneal route from the first day to the end of the study. All pups were executed on the fourth day. Proximal colon and ileum were allocated for histopathologic and biochemical evaluation, including xanthine oxidase (XO), total antioxidant status (TAS), total oxidant status (TOS), malonaldehyde (MDA) and myeloperoxidase (MPO) activities. RESULTS: The pups in the NEC + CAPE group had better histopathologic and apoptosis evaluations (TUNEL and caspase-9) and the severity of bowel damage was significantly lower in the NEC + CAPE group compared to the NEC group (P < 0.01). The clinical sickness scores and body weight in the NEC + CAPE group was significantly better compared to the NEC group (P < 0.05). Tissue MDA, MPO, XO levels and TOS were remarkably reduced in the NEC + CAPE group, however, TAS was significantly increased in the NEC + CAPE group (P < 0.05). CONCLUSION: Treatment with CAPE reduces the intestinal damage in NEC. PMID- 21710243 TI - Features and outcomes of neonatal neuroblastoma. AB - PURPOSE: Neonatal neuroblastoma (NNBL) is a rare tumour with few reported cases in the literature. The prognosis of NNBL is unclear with reported survival between 76 and 91%. The growing use of ante-natal ultrasound (USS) in recent years has resulted in an increasing incidence of NNBL. The purpose of this study is to review our experience with incidence, clinical features and outcome of NNBL in those children diagnosed ante-natally compared to those diagnosed post natally. METHODS: Twelve cases of NNBL were detected ante-natally or in the neonatal period (0-28 days) from a cohort of 120 children diagnosed with neuroblastoma (10%) over a 10-year period at the study institutions. Review of these 12 children forms the basis of this report. RESULTS: Ante-natal diagnosis (ADNB) was made in six children (50%) and post-natal diagnosis (PDNB) in six (50%). Tumour site in both cohorts were predominantly adrenal and tumour staging was similar in both groups. There was no difference in outcome in ADNB compared to PDNB with overall 100% survival for the entire group. CONCLUSIONS: NNBL is a subset of neuroblastoma with apparent excellent outcome irrespective of the time of diagnosis. Clinical features and outcomes of ADNB are no different to PDNB. PMID- 21710244 TI - Oxidative damage to guanine nucleosides following combination chemotherapy with 5 fluorouracil and oxaliplatin. AB - PURPOSE: Recent in vitro and animal studies have suggested that the cytotoxicity of 5-fluorouracil and oxaliplatin is linked to increased formation of reactive oxygen species (ROS). This prospective study was undertaken to examine the generation of oxidative stress, in 106 colorectal cancer patients, by 5 fluorouracil and oxaliplatin combination (FOLFOX) therapy as measured by urinary excretion of 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydro guanosine (8-oxoGuo). METHODS: The amounts of 8-oxoGuo and 8-oxodG were measured in 3 spot urine samples from 106 patients by using ultra performance liquid chromatography and tandem mass spectrometry. Furthermore, we collected information on other clinical and demographic variables hypothesized to be associated with oxidative stress. Repeated measures linear mixed models were used to model the relationship between urinary concentrations of 8-oxoGuo and 8-oxodG and the treatment effect and the other variables. RESULTS: The analysis showed that chemotherapy increased the excretion of 8-oxoGuo and 8-oxodG around 15% (P < 0.0001 and P = 0.02, respectively) though there was a significant interaction with CRP levels. Additionally, we found that sex, smoking status, age, and c reactive protein were related to urinary excretion of 8-oxoGuo and 8-oxodG in colorectal cancer patients. CONCLUSION: These results indicate that FOLFOX induces ROS in patients and that ROS-generating mechanisms interact. PMID- 21710245 TI - Imatinib mesylate in thymic epithelial malignancies. AB - PURPOSE: Thymic epithelial tumors (TETs) are rare tumors of the mediastinum, with an estimated incidence of about 3 cases per 100,000 inhabitants. Although anthracycline- and platinum-based chemotherapy is an active treatment for TETs, novel systemic therapeutic options are especially needed for metastatic disease, which is virtually incurable. On the basis of the radiographic response obtained with imatinib (Novartis Pharma, Basel, Switzerland) in a patient with thymic carcinoma harboring the V560del c-KIT mutation, a phase II trial was initiated at the Department of Molecular and Clinical Oncology and Endocrinology of University "Federico II of Naples" with the purpose to test imatinib in TETs. METHODS: Imatinib was daily delivered at the dose of 400 mg to patients affected by TETs, who had progressed after at least one chemotherapy regimen. Positivity of c-KIT on immunohistochemistry was not mandatory for study entry. Radiographic responses were measured by CT scans performed every 3 months, according to the RECIST criteria. Toxicity was graded according to the Common Toxicity Criteria of the National Cancer Institute, version 3.0. RESULTS: Fifteen patients with advanced TETs were enrolled from March 2008 to May 2010. Three patients presented with thymic carcinomas. Two of these three patients presented c-kit expression on immunohistochemistry. No patient harbored a known c-kit activating mutation. Imatinib was very well tolerated, with no toxicity-related death. Diarrhea and migraine were the most frequent events, occurring both in 20% of patients, but were manageable and mild. No radiographic responses were recorded. Median progression-free survival was 3 months (interquartile range, 2.5-4). Median overall survival was not reached. The study was terminated before it reached its target accrual of 42 patients, because of the lack of responses and low accrual rate. CONCLUSIONS: This trial indicates the lack of effectiveness of imatinib in unselected patients with thymic epithelial tumors. Nevertheless, imatinib may represent a valuable option in selected patients with TETs, such as those harboring the V560del c-KIT mutation. PMID- 21710246 TI - Association between CYP1A1 polymorphism and colorectal cancer risk: a meta analysis. AB - Colorectal cancer is one of the most common forms of cancer and is the third leading cause of cancer-related death worldwide. Published data on the association between CYP1A1 (MspI and Ile ( 462 ) Val) polymorphisms and colorectal cancer risk are inconclusive. To address these issues, we carried out a meta-analysis of available case-control study. Online electronic searches of PubMed were performed. We identified 17 studies (6,673 colorectal cancer patients and 8,102 control subjects) that examined the association between CYP1A1 (MspI and Ile ( 462 ) Val) polymorphisms and risk of colorectal cancer. For CYP1A1 MspI polymorphism, we performed a meta-analysis from 13 studies including 5,468 cases and 6,492 controls. Overall, there was no statistically significant association between CYP1A1 MspI polymorphism and colorectal cancer susceptibility. In the subgroup analyses based on ethnicities, no statistically significant associations were observed in all genetic models. With respect to CYP1A1 Ile ( 462 ) Val polymorphism, a total of 14 studies including 6,654 cases and 7,859 controls were involved in this meta-analysis. The CYP1A1 Ile ( 462 ) Val polymorphism was associated with risk of colorectal cancer. Ethnic subgroup analyses revealed that significant associations were found in Asians and Caucasians. In summary, this meta-analysis suggests that CYP1A1 Ile ( 462 ) Val polymorphism was a low penetrance susceptibility gene in colorectal cancer development. On the contrary, CYP1A1 MspI polymorphism does not seem capable of modifying colorectal cancer risk. PMID- 21710248 TI - Polymorphisms of myostatin gene (MSTN) in four goat breeds and their effects on Boer goat growth performance. AB - Polymorphisms of myostatin (MSTN) gene were investigated as a candidate marker for goat growth in 687 individuals by gene sequencing and polymerase chain reaction restriction fragment length polymorphism methods. Three potential genotypes (AA, AB and BB) of 5 bp indel (1,256 TTTTA/-) in 5'UTR were detected in four breeds. The polymorphism (CC, CD and DD) of substitution (1,388 T/A) in exon 1 was only segregating in Boer. Genotype AB resulted in significant increases in body weights at birth (BW0), 90 (BW90) and 300 (BW300) days of age, and birth body length compared to BB (P < 0.05). Whilst genotype CD contributed to heavier BW0 and BW90, and larger birth body height (BH) compared to CC (P < 0.05). Individuals either with AB or CD genotype also had greater values in other body sizes, although no significant differences appeared (P > 0.05). When in combination, the combined genotype ABCD displayed positive impacts on better growth traits in BW0, BW90, BW300, BH and BCG (P < 0.05). These results indicate that these markers in myostatin (MSTN) are associated with Boer growth and may be useful for marker assisted selection. PMID- 21710247 TI - Determination of the complete mitochondrial DNA sequence of Octopus minor. AB - In this study, we have determined the complete nucleotide sequence of the mitochondrial genome of Octopus minor. It is 15,974 nucleotide pairs and encodes 13 proteins, two ribosomal RNAs and 22 tRNAs of the mitochondrion's own protein synthesizing system. Seven of thirteen proteins are encoded by the H-strand, while the other six proteins, as well as the two ribosomal RNAs are encoded by the L-strand. The nucleotide composition of the proteins showed a nucleotide bias against G encoded by the H-strand, while they showed a nucleotide bias against A and C encoded by the L-strand. Two of the 13 protein coding genes of O. minor began with the unorthodox translation initiation codon ATA and all others use the standard ATG. In addition, six of thirteen mt proteins of O. minor have unambiguous termination codons. There are four cases where tRNA genes appear to overlap. The long noncoding region (LNCR) of O. minor was 930 nucleotides and no repeated sequences were found in this LNCR. The gene arrangements of O. minor showed remarkable similarity to that of O. ocellatus and O. vulgaris. Phylogenetic analysis demonstrated that O. minor appears as sister taxan to the monophyletic group combined by O. ocellatus and O. vulgaris, suggesting a relative distant genetic relationship between O. minor and the other two octopus species. PMID- 21710249 TI - Cyclophosphamide followed by mizoribine as maintenance therapy against refractory steroid-dependent nephrotic syndrome. PMID- 21710250 TI - Physiopathology of idiopathic nephrotic syndrome: lessons from glucocorticoids and epigenetic perspectives. AB - Idiopathic nephrotic syndrome (INS) has been studied for decades in attempt to understand the physiopathological mechanisms explaining the disease. It is recognized as a multifactorial disease, with immunological components targeting kidney functions. Many hypotheses have been discussed or tested, including the role of a circulating factor, polymorphisms of genes implicated in lymphocyte maturation and differentiation, and DNA epigenetic modifications. In the present review, the data supporting these different (and probably combinatorial) hypotheses have been reviewed in order to identify and discuss the possible pathways implicated in the physiopathology of INS. PMID- 21710251 TI - Iron deficiency in children with early chronic kidney disease. AB - Iron deficiency (ID) contributes to the development of anemia in patients with chronic kidney disease (CKD). The frequency of ID in children with early CKD has not previously been reported. This was a retrospective chart review of children with CKD stages 2 and 3 followed at the CKD clinic of Children's Hospital of Michigan. ID was defined as low ferritin and transferrin saturation <20%. Patients on iron supplements were considered as iron-deficient cases. There were 50 patients included in the study (72% male) with a mean age of 10.31 (+/-5.21). The mean glomerular filtration rate (GFR) was 55.4 ml/min/1.73 m(2) (+/-14.61). ID was present in 42% of patients, out of whom almost half (42.9%) presented with anemia. Females had a higher frequency of ID (64.3%). The frequency of ID with anemia increased from 4.3% to 29.6%, (p = 0.03) in stage 2 to stage 3 CKD, respectively. The frequency of ID without anemia also increased with progression of CKD from stage 2 to stage 3, however, the difference was not statistically significant. ID is frequent in patients with early CKD. Monitoring of iron tests and treatment of ID is important in this population of patients. PMID- 21710252 TI - Histamine receptor expression, hippocampal plasticity and ammonia in histidine decarboxylase knockout mice. AB - Genetic ablation of the histamine producing enzyme histidine decarboxylase (HDC) leads to alteration in exploratory behaviour and hippocampus-dependent learning. We investigated how brain histamine deficiency in HDC knockout mice (HDC KO) affects hippocampal excitability, synaptic plasticity, and the expression of histamine receptors. No significant alterations in: basal synaptic transmission, long-term potentiation (LTP) in the Schaffer collateral synapses, histamine induced transient changes in the CA1 pyramidal cell excitability, and the expression of H1 and H2 receptor mRNAs were found in hippocampal slices from HDC KO mice. However, when compared to WT mice, HDC KO mice demonstrated: 1. a stronger enhancement of LTP by histamine, 2. a stronger impairment of LTP by ammonia, 3. no long-lasting potentiation of population spikes by histamine, 4. a decreased expression of H3 receptor mRNA, and 5. less potentiation of population spikes by H3 receptor agonism. Parallel measurements in the hypothalamic tuberomamillary nucleus, the origin of neuronal histamine, demonstrated an increased expression of H3 receptors in HDC KO mice without any changes in the spontaneous firing of "histaminergic" neurons without histamine and their responses to the H3 receptor agonist (R)-alpha-methylhistamine. We conclude that the absence of neuronal histamine results in subtle changes in hippocampal synaptic transmission and plasticity associated with alteration in the expression of H3 receptors. PMID- 21710254 TI - Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species and down-regulation of Bcl-2. AB - A high resistance and heterogeneous response to conventional anti-cancer chemotherapies characterize malignant cutaneous melanoma, the most aggressive and deadly form of skin cancer. Withaferin A (WFA), a withanolide derived from the medicinal plant Withania somnifera, has been reported for its anti-tumorigenic activity against various cancer cells. For the first time, we examined the death inducing potential of WFA against a panel of four different human melanoma cells and investigated the cellular mechanisms involved. WFA induces apoptotic cell death with various IC50 ranging from 1.8 to 6.1 MUM. The susceptibility of cells toward WFA-induced apoptosis correlated with low Bcl-2/Bax and Bcl-2/Bim ratios. In all cell lines, the apoptotic process triggered by WFA involves the mitochondrial pathway and was associated with Bcl-2 down regulation, Bax mitochondrial translocation, cytochrome c release into the cytosol, transmembrane potential (DeltaPsim) dissipation, caspase 9 and caspase 3 activation and DNA fragmentation. WFA cytotoxicity requires early reactive oxygen species (ROS) production and glutathione depletion, the inhibition of ROS increase by the antioxidant N-acetylcysteine resulting in complete suppression of mitochondrial and nuclear events. Altogether, these results support the therapeutic potential of WFA against human melanoma. PMID- 21710253 TI - Cell proliferation and neuroblast differentiation in the rat dentate gyrus after intrathecal treatment with adipose-derived mesenchymal stem cells. AB - Mesenchymal stem cells (MSC) have emerged as a new therapeutic tool for a number of clinical applications, because they have multipotency and paracrine effects via various factors. In the present study, we investigated the effects of adipose derived MSC (Ad-MSC) transplantation via intrathecal injection through the cisterna magna on cell proliferation and differentiation of endogenous stem cells in the hippocampal dentate gyrus (DG) using Ki-67 (a marker for proliferating cells), and doublecortin (DCX, a marker for neuroblasts). The transplanted Ad-MSC were detected in the meninges, not in the hippocampal parenchyma. However, the number of Ki-67-immunoreactive cells was significantly increased by 83% in the DG 2 days after single Ad-MSC injection, and by 67% at 23 days after repeated Ad-MSC treatment compared with that in the vehicle-treated group after Ad-MSC transplantation. On the other hand, the number of DCX-immunoreactive cells in the DG was not changed at 2 days after single Ad-MSC injection; however, it was significantly increased by 62% 9 days after single Ad-MSC injection. At 23 days after repeated Ad-MSC application, the number of DCX-immunoreactive cells was much more increased (223% of the vehicle-treated group). At this time point, DCX protein levels were also significantly increased compared with those in the vehicle-treated group. These results suggest that the intrathecal injection of Ad MSC could enhance endogenous cell proliferation, and the repeated Ad-MSC injection could be more efficient for an enhancement of endogenous cell proliferation and differentiation in the brain. PMID- 21710255 TI - Elevated transcription of the p53 gene in early S-phase leads to a rapid DNA damage response during S-phase of the cell cycle. AB - p53 induces the transcription of genes that negatively regulate progression of the cell cycle in response to DNA damage or other cellular stressors, and thus participates in maintaining genome stability. Under stress conditions, p53 must be activated to prohibit the replication of cells containing damaged DNA. However, in normal, non-stressed cells, p53 activity must be inhibited. Previous studies have demonstrated that p53 transcription is activated before or during early S-phase in cells progressing from G(0)/G(1) into S-phase. Since this is not what would be predicted from a gene involved in growth arrest and apoptosis, in this study, we provide evidence that this induction occurs to provide sufficient p53 mRNA to ensure a rapid response to DNA damage before exiting S-phase. When comparing exponentially growing Swiss3T3 cells to those synchronized to enter S phase simultaneously and treated with the DNA damaging agent camptothecin, we found that with cells in S-phase, p53 protein levels increased earlier, Bax and p21 transcription was activated earlier and to a greater extent and apoptosis occurred earlier and to a greater extent. These findings are consistent with p53 transcription being induced in S-phase to provide for a rapid DNA-damage response during S-phase of the cell cycle. PMID- 21710256 TI - Early dropout from psychotherapy for depression with group- and network-model therapists. AB - Administrative data were used to examine early dropout among 16,451 health plan members calling to request psychotherapy for depression. Compared to members referred to group-model therapists, those referred to network-model therapists were more likely to drop out before the initial visit (OR 2.33, 95% CI 2.17-2.50) but less likely to drop out after the first visit (OR 0.45, 95% CI 0.43-0.48). These differences were unaffected by adjustment for neighborhood income and educational attainment, antidepressant use, or generosity of insurance coverage. Efforts to increase the effectiveness of psychotherapy may required different strategies in group- and network-model practice. PMID- 21710257 TI - Predicting program start-up using the stages of implementation measure. AB - Recent efforts to better understand the process of implementation have been hampered by a lack of tools available to define and measure implementation progress. The Stages of Implementation Completion (SIC) was developed as part of an implementation trial of MTFC in 53 sites, and identifies the duration of time spent on implementation activities and the proportion of activities completed. This article examines the ability of the first three stages of the SIC (Engagement, Consideration of Feasibility, Readiness Planning) to predict successful program start-up. Results suggest that completing SIC stages completely, yet relatively quickly, predicts the likelihood of successful implementation. PMID- 21710258 TI - Targeting of a developmentally regulated epitope of CD43 for the treatment of acute leukemia. AB - Previously, we developed a JL1 mouse monoclonal antibody that specifically recognizes the leukemic cells of T, B, and myeloid lineages, but not the peripheral blood cells and pluripotent hematopoietic stem cells. Here, we identified that JL1 mAb recognized a specific epitope of human CD43 and validated its potential as an anti-leukemic targeting agent. After the comprehensive screening of JL1 Ag in the human thymocyte cDNA library, multiple fusion gene constructs encoding human CD43 were generated to identify its specific epitope to JL1 antibody. JL1 antibody interacted with a developmentally regulated and non glycosylated epitope of the human CD43 extracellular domain (AA 73-81, EGSPLWTSI). In an in vivo leukemia model using NOD/SCID mice injected with CCRF CEM7 cells, JL1 antibody induced effective cytotoxicity in tumor cells and prolonged survival (p < 0.05). Saporin conjugation to JL1 antibody effectively depleted tumor cells in in vitro cytotoxic assays and also prolonged survival in a leukemic mouse model (p < 0.001). These preclinical results further support the therapeutic potential of the JL1 antibody in the management of acute leukemia. PMID- 21710260 TI - Recombinant expression, activity screening and functional characterization identifies three novel endo-1,4-beta-glucanases that efficiently hydrolyse cellulosic substrates. AB - The hydrolysis of cellulose into fermentable sugars is a costly and rate-limiting step in the production of biofuels from renewable feedstocks. Developing new cellulase systems capable of increased cellulose hydrolysis rates would reduce biofuel production costs. With this in mind, we screened 55 fungal endoglucanases for their abilities to be expressed at high levels by Aspergillus niger and to hydrolyze amorphous cellulose at rates significantly greater than that obtained with TrCel5A, one of the major endoglucanases in the Trichoderma reesei cellulase system. This screen identified three endoglucanases, Aureobasidium pullulans ApCel5A, Gloeophyllum trabeum GtCel12A and Sporotrichum thermophile StCel5A. We determined that A. niger expressed the three endoglucanases at relatively high levels (>=0.3 g/l) and that the hydrolysis rate of ApCel5A and StCel5A with carboxymethylcellulose 4M as substrate was five and two times greater than the T. reesei Cel5A. The ApCel5A, GtCel12A and StCel5A enzymes also demonstrated significant synergy with Cel7A/CbhI, the major exoglucanase in the T. reesei cellulase system. The three endoglucanases characterized in this study are, therefore, promising candidate endoglucanases for developing new cellulase systems with increased rates of cellulose saccharification. PMID- 21710259 TI - Maternal weight change before pregnancy in relation to birthweight and risks of adverse pregnancy outcomes. AB - Maternal weight change before pregnancy can be considered as an indicator of maternal energy balance and nutritional status before conception, and may be involved in early life programming. We aimed to investigate the association of maternal Weight Change Before Pregnancy (WCBP) with fetal growth and adverse pregnancy outcomes. Data are from the French EDEN mother-child cohort where 1,756 mother-child pairs had information on mother's weight at 20 years, weight just before pregnancy, fetal anthropometry at second and third trimesters, infant's birthweight and pregnancy complications. The average annual WCBP between 20 years and start of pregnancy (in kg/year) was categorized as: "Weight Loss" (n = 320), "Moderate weight gain" (n = 721) and "High weight gain" (n = 715). The associations of WCBP with fetal and newborn characteristics and with adverse pregnancy outcomes were analyzed, adjusting for maternal and pregnancy characteristics, including the mother's prepregnancy BMI. Interactions between WCBP and prepregnancy BMI were tested. Birthweight and estimated fetal weight in the third trimester increased significantly with increasing WCBP in mothers with BMI <25 kg/m(2). In these mothers, weight loss before pregnancy was associated with a higher risk of newborns small for gestational age (SGA). Whatever the prepregnancy BMI, WCBP was positively associated with a maternal risk of gestational diabetes and hypertension. The ponderal history of mothers before pregnancy can impact on fetal growth and on pregnancy outcomes such as gestational diabetes or hypertension. Our analysis is the first to report that in non-overweight women, those who lost weight before pregnancy are at higher risk of having SGA newborns. PMID- 21710261 TI - Hydrodynamic study of an internal airlift reactor for microalgae culture. AB - Internal airlift reactors are closed systems considered today for microalgae cultivation. Several works have studied their hydrodynamics but based on important solid concentrations, not with biomass concentrations usually found in microalgae cultures. In this study, an internal airlift reactor has been built and tested in order to clarify the hydrodynamics of this system, based on microalgae typical concentrations. A model is proposed taking into account the variation of air bubble velocity according to volumetric air flow rate injected into the system. A relationship between riser and downcomer gas holdups is established, which varied slightly with solids concentrations. The repartition of solids along the reactor resulted to be homogenous for the range of concentrations and volumetric air flow rate studied here. Liquid velocities increase with volumetric air flow rate, and they vary slightly when solids are added to the system. Finally, liquid circulation time found in each section of the reactor is in concordance with those employed in microalgae culture. PMID- 21710262 TI - Identification of a novel HLA-A2-restricted cytotoxic T lymphocyte epitope from cancer-testis antigen PLAC1 in breast cancer. AB - Identification of cytotoxic T lymphocyte (CTL) epitopes from tumor antigens is essential for the development of peptide vaccines against tumor immunotherapy. Among all the tumor antigens, the caner-testis (CT) antigens are the most widely studied and promising targets. PLAC1 (placenta-specific 1, CT92) was considered as a novel member of caner-testis antigen, which expressed in a wide range of human malignancies, most frequently in breast cancer. In this study, three native peptides and their analogues derived from PLAC1 were predicted by T cell epitope prediction programs including SYFPEITHI, BIMAS and NetCTL 1.2. Binding affinity and stability assays in T2 cells showed that two native peptides, p28 and p31, and their analogues (p28-1Y9 V, p31-1Y2L) had more potent binding activity towards HLA-A*0201 molecule. In ELISPOT assay, the CTLs induced by these four peptides could release IFN-gamma. The CTLs induced by these four peptides from the peripheral blood mononuclear cells (PBMCs) of HLA-A*02+ healthy donor could lyse MCF-7 breast cancer cells (HLA-A*0201+, PLAC1+) in vitro. When immunized in HLA-A2.1/Kb transgenic mice, the peptide p28 could induce the most potent peptide specific CTLs among these peptides. Therefore, our results indicated that the peptide p28 (VLCSIDWFM) could serve as a novel candidate epitope for the development of peptide vaccines against PLAC1-positive breast cancer. PMID- 21710263 TI - p70 S6K1 nuclear localization depends on its mTOR-mediated phosphorylation at T389, but not on its kinase activity towards S6. AB - The protein kinase p70 S6K1 is regulated in response to cytokines, nutrients and growth factors, and plays an important role in the development of a variety of human diseases. Mammalian target of rapamycin (mTOR) is known to phosphorylate and thereby activate p70 S6K1. p70 S6K1 phosphorylates different cytoplasmic and nuclear substrates involved in the regulation of protein synthesis, cell cycle, cell growth and survival. Recently, we have shown that mTOR-mediated phosphorylation of p70 S6K1 at T389 also regulates its nucleocytoplasmic localization. Since this phosphorylation is associated with its kinase activity the question whether p70 S6K1 phosphorylation or kinase activity is essential for its proper localization remained elusive. Recently, the chemical compound PF 4708671 has been demonstrated to block p70 S6K1 kinase activity while inducing its phosphorylation at T389. This potential of PF-4708671 to separate p70 S6K1 activity from its T389 phosphorylation allowed us to demonstrate that the proper nucleocytoplasmic localization of this kinase depends on its mTOR-mediated phosphorylation but not on its kinase activity. These findings provide important insights into the regulation of p70 S6K1 and allow a more detailed understanding of subcellular enzyme localization processes. PMID- 21710264 TI - Diffusion tensor imaging and tractography for assessment of renal allograft dysfunction-initial results. AB - OBJECTIVES: To evaluate MR diffusion tensor imaging (DTI) as non-invasive diagnostic tool for detection of acute and chronic allograft dysfunction and changes of organ microstructure. METHODS: 15 kidney transplanted patients with allograft dysfunction and 14 healthy volunteers were examined using a fat saturated echo-planar DTI-sequence at 1.5 T (6 diffusion directions, b = 0, 600 s/mm2). Mean apparent diffusion coefficient (ADC) and mean fractional anisotropy (FA) were calculated separately for the cortex and for the medulla and compared between healthy and transplanted kidneys. Furthermore, the correlation between diffusion parameters and estimated GFR was determined. RESULTS: The ADC in the cortex and in the medulla were lower in transplanted than in healthy kidneys (p < 0.01). Differences were more distinct for FA, especially in the renal medulla, with a significant reduction in allografts (p < 0.001). Furthermore, in transplanted patients a correlation between mean FA in the medulla and estimated GFR was observed (r = 0.72, p < 0.01). Tractography visualized changes in renal microstructure in patients with impaired allograft function. CONCLUSIONS: Changes in allograft function and microstructure can be detected and quantified using DTI. However, to prove the value of DTI for standard clinical application especially correlation of imaging findings and biopsy results is necessary. PMID- 21710265 TI - Computed tomography angiography of the carotid arteries at low kV settings: a prospective randomised trial assessing radiation dose and diagnostic confidence. AB - OBJECTIVE: To assess radiation dose and diagnostic image quality of a low-dose (80 kV) versus a standard-dose (120 kV) protocol for computed tomography angiography (CTA) of the supra-aortic arteries. METHODS: 64-slice CTA of the supra-aortic arteries was performed in 42 consecutive patients using randomly either 80 or 120 kV at 300 absolute mAs. Intravascular attenuation values, contrast-to-noise (CNR) and signal-to-noise ratio (SNR) measurements were performed at three levels. Two readers assessed image quality by using a four point scale. The effective dose (ED) was calculated to assess the differences in radiation exposure. RESULTS: Intravascular attenuation values at 80 kV were higher in the common carotid artery, the carotid bifurcation and the internal carotid artery (p < 0.001). CNR and SNR differed at the internal carotid artery, with higher values in the 80-kV group (p > 0.05). Both readers revealed a significantly better image quality at 120 kV only at the common carotid artery (p < 0.001; p = 0.007). Mean ED was significantly lower at 80-kV (1.23 +/- 0.09 vs. 3.99 +/- 0.33 mSv; p < 0.001). CONCLUSION: Tube voltage reduction to 80 kV in CTA of the supra-aortic arteries allows for significant radiation dose reduction but has limitations at the level of the common carotid artery. PMID- 21710267 TI - Step and shoot coronary CT angiography using 256-slice CT: effect of heart rate and heart rate variability on image quality. AB - OBJECTIVE: To evaluate the effect of heart rate variability (HRV) and heart rate (HR) on intra-image "motion" and inter-image "stairstep" artefacts in step-and shoot coronary CT angiography (CCTA) using a wide detector CT scanner. METHODS: 66 patients underwent step-and-shoot CCTA using 256-slice CT. Patients were divided into two groups (Group 1: HR <65 bpm, Group 2 >=65bpm). Motion artefacts were quantified using a 5-point-scale. Stairstep artefacts were defined by measurements of misalignment. Image noise, contrast-to-noise-ratio (CNR), signal to-noise-ratio (SNR), and radiation dose were assessed. RESULTS: Mean HR was 66 +/- 16.7 bpm (range: 45-125 bpm) and mean HRV was 10.7 +/- 17.5 bpm. A significant correlation between HR and stairstep artefacts (r = 0.46, p < 0.001) and motion artefacts (r = 0.63, p < 0.001) was found. Group 2 showed significantly increased step artefacts with a mean misalignment of 1.4 mm compared to 0.4 mm in Group 1 (p < 0.001). There was no significant effect of HRV on stairstep artefacts (r = 0.15, p = 0.416) and motion artefacts (r = 0.13, p = 0.311). No significant differences in image noise, CNR, SNR, and radiation dose were seen. CONCLUSIONS: Unlike CCTA using narrow CT detectors, HRV has no significant effect on motion and stairstep artefacts using a wide CT detector with high z-coverage. However, a higher HR still increases stairstep and motion artefacts. PMID- 21710266 TI - Accuracy of hydro-multidetector row CT in the local T staging of oesophageal cancer compared to postoperative histopathological results. AB - OBJECTIVE: To evaluate the accuracy of multidetector computed tomography with water filling (Hydro-MDCT) in the T-staging of patients with oesophageal cancer. MATERIALS AND METHODS: There were 131 consecutive patients who were preoperatively and prospectively examined in the prone position on arterial phase contrast-enhanced MDCT, after ingestion of 1,000-1,500 ml tap water and effervescent granules. Two readers staged the local tumour growth (T-staging) independently. They assessed tumour location, size, presence of stenosis, and morphology of the outer border of the oesophageal wall and perioesophageal fat planes on CT. CT findings were compared with histopathological results from resected specimens. Data were analyzed using the SPSS statistical package. RESULTS: Both readers obtained a high sensitivity of 95% and a high positive predictive value of 96%. Accurate local staging was achieved in 76.3% and 68.7% for readers 1 and 2, respectively. Inter-reader agreement was excellent (weighted kappa value of 0.93 and un-weighted kappa of 0.89). CONCLUSION: Using the hydro technique and applying specific assessment criteria, MDCT appears to be an accurate, non-invasive diagnostic tool for local tumour staging of oesophageal cancer. PMID- 21710268 TI - An iterative two-threshold analysis for single-subject functional MRI of the human brain. AB - OBJECTIVES: Current thresholding strategies for the analysis of functional MRI (fMRI) datasets may suffer from specific limitations (e.g. with respect to the required smoothness) or lead to reduced performance for a low signal-to-noise ratio (SNR). Although a previously proposed two-threshold (TT) method offers a promising solution to these problems, the use of preset settings limits its performance. This work presents an optimised TT approach that estimates the required parameters in an iterative manner. METHODS: The iterative TT (iTT) method is compared with the original TT method, as well as other established voxel-based and cluster-based thresholding approaches and spatial mixture modelling (SMM) for both simulated data and fMRI of a hometown walking task at different experimental settings (spatial resolution, filtering and SNR). RESULTS: In general, the iTT method presents with remarkable sensitivity and good specificity that outperforms all conventional approaches tested except for SMM in a few cases. This also holds true for challenging conditions such as high spatial resolution, the absence of filtering, high noise level, or a low number of task repetitions. CONCLUSION: Thus, iTT emerges as a good candidate for both scientific fMRI studies at high spatial resolution and more routine applications for clinical purposes. PMID- 21710270 TI - Assessing response in bone metastases in prostate cancer with diffusion weighted MRI. AB - OBJECTIVES: To determine whether changes in ADC of bone metastases secondary to prostate carcinoma are significantly different in responders compared with progressors on chemotherapy. METHODS: Twenty-six patients with known bone metastases secondary to prostate carcinoma underwent diffusion-weighted MRI of the lumbar spine and pelvis at baseline and 12 weeks following chemotherapy. RECIST assessment of staging CT and PSA taken at the same time points were used to classify patients as responders, progressors or stable. ADC (from b = 0,50,100,250,500,750 smm-2) and ADC(slow) (from b = 100,250,500,750 smm-2) were calculated for up to 5 lesions per patient. RESULTS: Mean ADC/ADC(slow) in lesions from responders and progressors showed a significant increase. Although the majority of lesions demonstrated an ADC/ADC(slow) rise, some lesions in both responders and progressors demonstrated a fall in ADC beyond the limits of reproducibility. CONCLUSIONS: Mean ADC is not an appropriate measure of response in bone metastases. The heterogeneity of changes in ADC is likely to be related to the composition of bone marrow with changes that have opposing effects on ADC. PMID- 21710271 TI - Focal nodular hyperplasia-like lesions in patients with cavernous transformation of the portal vein: prevalence, MR findings and natural history. AB - PURPOSE: To retrospectively investigate the prevalence, MR findings, natural history, and association with other hepatic lesions of focal nodular hyperplasia (FNH)-like lesions in a cohort of consecutive patients with cavernous transformation of the portal vein (CTPV). MATERIALS AND METHODS: This retrospective IRB-approved study comprised 58 patients (32 men, 26 women; average age, 50 years) with CTPV who underwent liver MR imaging between 2000 and 2008. MR images were assessed by two radiologists in consensus for the presence of (a) FNH like lesions and other liver lesions, and (b) other imaging findings. Patients were assigned to a stable or progressive clinical course based on lesion characteristics at follow-up. RESULTS: Twelve of 58 patients (21%) had 38 FNH like lesions (average size, 1.3 cm). Common findings of FNH-like lesions were isointensity on T2-weighted images (82%), intense and homogeneous enhancement during the arterial phase, and lack of washout during the hepatic venous and interstitial phases (100%). FNH-like lesions were found with other benign liver lesions (1 hemangioma, 1 adenoma) in two patients. Three (25%) patients with FNH like lesions showed a progressive clinical course. CONCLUSION: FNH-like lesions are commonly detected in patients with CTPV. Most lesions demonstrate benign imaging findings and stable clinical course. PMID- 21710272 TI - Recent advances in colorectal cancer research: the microenvironment impact. PMID- 21710273 TI - Diffuse uterine leiomyomatosis in a child. AB - Leiomyomas are the most common benign uterine tumor; however, this entity is relatively uncommon in the pediatric population. Although leiomyomas most commonly present as solitary uterine masses, unusual patterns of growth have been described including diffuse leiomyomatosis. In this condition, the myometrium of the uterus is symmetrically expanded by innumerable confluent leiomyomas; this pattern of growth is quite uncommon and has never been reported in a pediatric patient. This case report illustrates the imaging appearance of diffuse uterine leiomyomatosis in an otherwise healthy 16-year-old girl. PMID- 21710274 TI - US and MRI of a pharyngeal hairy polyp with pathological correlation. AB - Hairy polyps are uncommon developmental malformations of the oropharynx. They are frequently pedunculated and can cause respiratory distress in the neonate. Hairy polyps are usually diagnosed with MRI but can be well seen at US. To our knowledge, the sonographic features have not been previously reported. PMID- 21710275 TI - Monozygotic twin pair showing discordant phenotype for X-linked thrombocytopenia and Wiskott-Aldrich syndrome: a role for epigenetics? AB - Despite our increasing characterization of the molecular basis for many primary immunodeficiency states, significant heterogeneity in clinical and immunological phenotype exists. Epigenetic alterations have been implicated in the pathogenesis of immune dysregulation and may provide a unique paradigm to help us understand the phenotypic heterogeneity in primary immunodeficiency. The occurrence of X linked thrombocytopenia (XLT) and Wiskott-Aldrich syndrome (WAS) in monozygotic twins is a rare occurrence which allows for the exploration of epigenetic alterations and associated phenotypic heterogeneity. We describe a pair of monozygotic twin brothers with a missense mutation in the WAS gene consistent with reduced expression of the WAS protein, a XLT phenotype, and a good prognosis. Despite this genotype and anticipated mild phenotype in both twins, a discordant phenotype has evolved in which one twin demonstrates asymptomatic thrombocytopenia and the other symptomatic thrombocytopenia, infectious complications, and autoimmunity. Characterization of the potential epigenetic contribution to the spectrum of XLT and WAS is described and the implications of these findings are discussed. PMID- 21710276 TI - Acute exposure to 50-Hz magnetic fields increases interleukin-6 in young healthy men. AB - Some epidemiologic studies have suggested that extremely low frequency magnetic fields might affect human health and, in particular, that the incidence of certain types of cancer might increase among individuals living or working in environments exposed to such fields. This study is part of a broad study we conducted in humans. The study presented here was designed to look for possible effects of acute exposure to 50-Hz magnetic fields (10 MUT) on the interleukin 1 beta (IL-1beta), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin-1 receptor antagonist (IL-1RA), and the interleukin-2 receptor (IL-2R) production. Thirty-two young men (20-30 years old) were divided into two groups (sham-exposed or control group and exposed group) of 16 subjects each. All subjects participated in two 24-h experiments to evaluate the effects of both continuous and intermittent (1 h "off" and 1 h "on" with the field switched "on" and "off" every 15 s) exposure to linearly polarized magnetic fields. The subjects were exposed to the magnetic field from 2300 to 0800 while recumbent. Blood samples were collected during each session at 11:00, 17:00, 22:00, 01:00, 04:00, 06:00, and 08:00. Results showed that exposure to 50-Hz magnetic fields (10 MUT) significantly increases IL-6 when subjects were exposed to an intermittent magnetic field. However, no effect has been observed on interleukin IL-1beta, IL 2, IL-1RA, and IL-2R. PMID- 21710278 TI - Moral issues in workplace health promotion. AB - PURPOSE: There is debate to what extent employers are entitled to interfere with the lifestyle and health of their workers. In this context, little information is available on the opinion of employees. Within the framework of a workplace health promotion (WHP) program, moral considerations among workers were investigated. METHODS: Employees from five companies were invited to participate in a WHP program. Both participants (n = 513) and non-participants (n = 205) in the program filled in a questionnaire on individual characteristics, lifestyle, health, and opinions regarding WHP. RESULTS: Nineteen percent of the non participants did not participate in the WHP program because they prefer to arrange it themselves, and 13% (also) preferred to keep private life and work separate. More participants (87%) than non-participants (77%) agreed with the statement that it is good that employers try to improve employees' health (chi(2) = 12.78, p = 0.002), and 26% of the non-participants and 21% of the participants think employer interference with their health is a violation of their privacy. Employees aged 50 year and older were more likely to agree with the latter statement than younger workers (OR = 1.56, 95% CI 1.02-2.39). CONCLUSION: This study showed that most employees support the importance of WHP, but in a modest group of employees, moral considerations may play a role in their decision whether or not to participate in WHP. Older workers were more likely to resist employer interference with their health. Therefore, special attention on such moral considerations may be needed in the communication, design, and implementation of workplace health promotion programs. PMID- 21710279 TI - Molecular mechanisms of pyrethroid insecticide neurotoxicity: recent advances. AB - Synthetic pyrethroid insecticides were introduced into widespread use for the control of insect pests and disease vectors more than three decades ago. In addition to their value in controlling agricultural pests, pyrethroids are at the forefront of efforts to combat malaria and other mosquito-borne diseases and are also common ingredients of household insecticide and companion animal ectoparasite control products. The abundance and variety of pyrethroid uses contribute to the risk of exposure and adverse effects in the general population. The insecticidal actions of pyrethroids depend on their ability to bind to and disrupt voltage-gated sodium channels of insect nerves. Sodium channels are also important targets for the neurotoxic effects of pyrethroids in mammals but other targets, particularly voltage-gated calcium and chloride channels, have been implicated as alternative or secondary sites of action for a subset of pyrethroids. This review summarizes information published during the past decade on the action of pyrethroids on voltage-gated sodium channels as well as on voltage-gated calcium and chloride channels and provides a critical re-evaluation of the role of these three targets in pyrethroid neurotoxicity based on this information. PMID- 21710281 TI - To make the most of what we have: extracting phenological data from nestling measurements. AB - To study the ecological and evolutionary effects of climate change on timing of annual events, scientists need access to data that have been collected over long time periods. High-quality long-term phenology data are rare and costly to obtain and there is therefore a need to extract this information from other available data sets. Many long-term studies on breeding birds include detailed information on individually marked parents and offspring, but do not include information on timing of breeding. Here, we demonstrate how a study of repeated standard measurements of white-throated dipper Cinclus cinclus nestlings in our study system in southernmost Norway can be used for modeling nestling growth, and how this statistical model can be used to estimate timing of breeding for birds with sparser data. We also evaluate how the accuracies of nestling growth models based on different morphological traits (mass and feather length) differ depending on the nestling age, present user guidelines and demonstrate how they can be applied to an independent data set. In conclusion, the approach presented is likely to be useful for a wide variety of species, even if the preferred measurement may differ between species. PMID- 21710280 TI - Temporal and spatial expression of cyclin H in rat spinal cord injury. AB - Cyclin H regulates cell cycle transitions; it always forms trimeric cyclin dependent protein kinases (CDK)-activating kinase (CAK) complex with CDK7 and MAT1 that phosphorylates a threonine residue in the CDK2 T loop region. However, neither the expression nor function of cyclin H in the central nervous system (CNS) injury is still clear. Therefore, we studied cyclin H in a rat spinal cord contusion model. Injury markedly increased cyclin H protein expression throughout the thoracic spinal cord but did not increase CDK7. However, double immunofluorescent staining for proliferating cell nuclear antigen (PCNA) and cell markers revealed increases of cyclin H and CDK2 in proliferating microglia and astrocytes, and the co-immunoprecipitation studies shown that the associations of cyclin H with CDK2 were enhanced evidently after injury. Our data suggest that cyclin H may play a proliferative role in spinal cord injury (SCI). PMID- 21710283 TI - Potential sources of early-postnatal increase in myofibre number in pig skeletal muscle. AB - In pigs, myogenesis is a biphasic phenomenon with the formation of primary and secondary fibres. Hyperplasia was reported to be accomplished around 90 days of gestation. However, some studies suggest a substantial increase in the total fibre number (TFN) from birth to weaning by counting fibre number in the muscle cross sections. The aim of this study was to establish in which way TFN increases after birth and whether this increase is imputable to new (tertiary) myofibres and/or fibre elongation. The semitendinosus muscle of 128 piglets was examined at days 1 (n = 63), 7 (n = 12), 21 (n = 12), and 28 (n = 41) of age. TFN was increased at days 7, 21 and 28 of age when compared with day 1 (P < 0.01). From day 1 to 28, TFN increased from 463 * 10(3) to 825 * 10(3). Microscopy of longitudinal and transversal serial sections revealed that at day 7 of age very small fibres expressing the embryonic myosin heavy chain (MyHC) isoform were apparent all over the muscle. In addition, intrafascicular terminations of normal sized fibres expressed the embryonic MyHC isoform. These data suggest that the TFN in the pig muscle is not fixed at birth and its postnatal increase may be related to both elongation of existing muscle fibres and genesis of tertiary myofibres, mainly between birth and 3 weeks of age. PMID- 21710282 TI - Climate change, phenological shifts, eco-evolutionary responses and population viability: toward a unifying predictive approach. AB - The debate on emission targets of greenhouse gasses designed to limit global climate change has to take into account the ecological consequences. One of the clearest ecological consequences is shifts in phenology. Linking these shifts to changes in population viability under various greenhouse gasses emission scenarios requires a unifying framework. We propose a box-in-a-box modeling approach that couples population models to phenological change. This approach unifies population modeling with both ecological responses to climate change as well as evolutionary processes. We advocate a mechanistic embedded correlative approach, where the link from genes to population is established using a periodic matrix population model. This periodic model has several major advantages: (1) it can include complex seasonal behaviors allowing an easy link with phenological shifts; (2) it provides the structure of the population at each phase, including the distribution of genotypes and phenotypes, allowing a link with evolutionary processes; and (3) it can incorporate the effect of climate at different time periods. We believe that the way climatologists have approached the problem, using atmosphere-ocean coupled circulation models in which components are gradually included and linked to each other, can provide a valuable example to ecologists. We hope that ecologists will take up this challenge and that our preliminary modeling framework will stimulate research toward a unifying predictive model of the ecological consequences of climate change. PMID- 21710284 TI - On the nanostructure of micrometer-sized cellulose beads. AB - The analysis of the porosity of materials is an important and challenging field in analytical chemistry. The gas adsorption and mercury intrusion methods are the most established techniques for quantification of specific surface areas, but unfortunately, dry materials are mandatory for their applicability. All porous materials that contain water and other solvents in their functional state must be dried before analysis. In this process, care has to be taken since the removal of solvent bears the risk of an incalculable alteration of the pore structure, especially for soft materials. In the present paper, we report on the use of small-angle X-ray scattering (SAXS) as an alternative analysis method for the investigation of the micro and mesopores within cellulose beads in their native, i.e., water-swollen state; in this context, they represent a typical soft material. We show that even gentle removal of the bound water reduces the specific surface area dramatically from 161 to 109 m(2) g(-1) in cellulose bead sample type MT50 and from 417 to 220 m(2) g(-1) in MT100. Simulation of the SAXS curves with a bimodal pore size distribution model reveals that the smallest pores with radii up to 10 nm are greatly affected by drying, whereas pores with sizes in the range of 10 to 70 nm are barely affected. The SAXS results were compared with Brunauer-Emmett-Teller results from nitrogen sorption measurements and with mercury intrusion experiments. PMID- 21710285 TI - Double-pulse laser-induced breakdown spectroscopy for analysis of molten glass. AB - A mobile double-pulse laser-induced breakdown spectroscopy system for industrial environments is presented. Its capabilities as a process analytical technique for the recovery of metals from molten inorganic wastes are investigated. Using low melting glass doped with different amounts of additives as a model system for recycling slags, the optimum number of shots, laser inter-pulse and acquisition delay times are optimized for solid and liquid (1200 degrees C) glass. Limits of detection from 7 ppm (Mn) to 194 ppm (Zn) are achieved working at a distance of 75 cm from the sample. To simplify the quantification of molten samples in an industrial furnace, the possibility is examined of using solid standards for analysis of molten material. PMID- 21710286 TI - Poly(3-alkylthiophenes): new sorption materials for solid phase microextraction of drugs isolated from human plasma. AB - A novel sorbent in solid phase microextraction (SPME) method based on poly(3 alkylthiophenes) was used in the isolation of linezolid from human plasma samples following liquid chromatography determination. The effect of extraction time on the sorption capacity of the SPME process was studied and pointed at 10 min both for adsorption and desorption. Poly(3-methylthiophene) and poly(3-nonylthiophene) were applied for the extraction of linezolid from water solutions. In plasma samples, four coatings including polythiophene and poly(3-penthylthiophene) were investigated. With these measurements, correlation coefficients were calculated in the range from 0.9820 to 0.9995, and the relative standard deviations were below 15%. That allowed claiming that the synthesized and described materials can be successfully applied in the analysis of linezolid also from other matrices such as urine or blood. PMID- 21710287 TI - Diagnosing gestational diabetes: can expert opinions replace scientific evidence? AB - Preventive medical interventions should be based on the highest level of scientific evidence. Actual criteria for diagnosing gestational diabetes mellitus (GDM) are neither uniform nor based on pregnancy outcomes. An expert panel from the International Association of Diabetes in Pregnancy Study Groups recently proposed that all pregnant women undergo a one-step 75 g OGTT, and defined new lower cut-off points to diagnose GDM (Metzger BE et al. Diabetes Care 33: 676 682). These criteria will double the prevalence of GDM, as 18% of all pregnant women will be labelled as abnormal. A recent article in Diabetologia (Ryan EA 54:480-486) claimed that maternal glucose is a weak predictor of big babies, that a single OGTT is poorly reproducible, and that expected benefits from intervention would be, at best, modest. This Commentary discusses other objections and argues that guidelines on any new GDM diagnostic strategy should be based on the results of randomised controlled trials rather than on disputable expert opinions. PMID- 21710288 TI - New approaches for the evaluation of renal vascular function in diabetes. AB - In this issue of Diabetologia, two new approaches are described for the assessment of intra-renal blood flow in people with diabetes. The first approach used the technique of dynamic assessment of the resistance index (RI) in the renal interlobar arteries before and after administration of sublingual glyceryl trinitrate, and the second used MRI to assess total renal blood flow in relation to mean arterial pressure, thereby enabling direct measurement of overall renal RI. The results of the first study raise the possibility that dynamic evaluation of the intra-renal RI could be used as an early detector of vascular alterations in type 2 diabetes, before the onset of microalbuminuria. The results of the second study suggest that decreases in renal blood flow in people with longstanding type 1 diabetes reflect intra-renal vascular stiffening and raise the possibility that in microalbuminuric patients it may also reflect increased intraglomerular pressure. PMID- 21710289 TI - Type 2 diabetes: unravelling the interaction between genetic predisposition and lifestyle. PMID- 21710290 TI - Talking and driving: applications of crossmodal action reveal a special role for spatial language. AB - Talking reduces attention resulting in real-world crash risks to drivers that talk on a phone and drive. Driving is a behavior that is very demanding on spatial attention, suggesting potentially large interference by spatial codes in language. The current study investigated how different types of verbal codes influence visual attention during dual-task performance. In two experiments, participants performed a spatial or non-spatial verbal task while simultaneously performing a visual attention task. The results showed a larger decrement to visual attention performance when participants were concurrently engaged in a spatial verbal task. The results of the second experiment isolated this effect to the right cerebral hemisphere, consistent with a role for shared right parietal resources. These results are consistent with the idea that processing codes are an important component of coordinating talking and driving but generally inconsistent with a broad class of bottleneck approaches that describes dual-task decrements but treats component tasks as cognitively equivalent. PMID- 21710291 TI - Delayed periportal enhancement: a characteristic finding on contrast ultrasound in idiopathic portal hypertension. AB - PURPOSE: Differentiation of idiopathic portal hypertension (IPH) from cirrhosis is not always easy because of their similar clinical features. This prospective study aimed to use contrast-enhanced ultrasound (US) in studying dynamic behavior of microbubble for characteristic enhancement features in IPH. METHODS: The study had 101 subjects: 8 IPH, 47 cirrhosis, and 36 controls, and additional ten cirrhosis for data validation. Contrast-enhanced US with perflubutane microbubble agent was performed in the early-phase (0-60 s) to compare hepatic enhancements among the three groups. RESULTS: Onset time of enhancement in the hepatic artery was not different among the groups, but that in the portal vein was longer in cirrhosis (19.9 +/- 5.2 s; p = 0.0014) and IPH (22.9 +/- 5.0 s; p = 0.0007) than in controls (16.6 +/- 3.4 s). As for parenchymal enhancement, all controls showed homogeneous enhancement, while all IPH showed delayed periportal enhancement. Cirrhosis had three patterns: 14 with homogeneous enhancement, 28 with diffuse heterogeneous enhancement, and 5 with IPH-like delayed periportal enhancement. Homogeneous enhancement was more frequent in controls than in cirrhosis/IPH (p < 0.0001), and delayed periportal enhancement was more frequent in IPH than in control/cirrhosis (p < 0.0001). The duration of intensity difference between hypoenhancement/delayed enhancement area and surrounding parenchyma which exceeded the half of the mean value of the maximum intensity difference (8.75 dB for IPH, 6.95 dB for cirrhosis) was longer in IPH (15.6 +/- 6.9 s) than cirrhosis (10.2 +/- 5.3 s; p = 0.0119). The data in cirrhosis were validated in the additional ten subjects. CONCLUSIONS: Delayed periportal enhancement on the sonograms based on perflubutane microbubble agent may be a characteristic of IPH. PMID- 21710292 TI - The effect of post-exercise hydrotherapy on subsequent exercise performance and heart rate variability. AB - We investigated the effect of hydrotherapy on time-trial performance and cardiac parasympathetic reactivation during recovery from intense training. On three occasions, 18 well-trained cyclists completed 60 min high-intensity cycling, followed 20 min later by one of three 10-min recovery interventions: passive rest (PAS), cold water immersion (CWI), or contrast water immersion (CWT). The cyclists then rested quietly for 160 min with R-R intervals and perceptions of recovery recorded every 30 min. Cardiac parasympathetic activity was evaluated using the natural logarithm of the square root of mean squared differences of successive R-R intervals (ln rMSSD). Finally, the cyclists completed a work-based cycling time trial. Effects were examined using magnitude-based inferences. Differences in time-trial performance between the three trials were trivial. Compared with PAS, general fatigue was very likely lower for CWI (difference [90% confidence limits; -12% (-18; -5)]) and CWT [-11% (-19; -2)]. Leg soreness was almost certainly lower following CWI [-22% (-30; -14)] and CWT [-27% (-37; -15)]. The change in mean ln rMSSD following the recovery interventions (ln rMSSD(Post interv)) was almost certainly higher following CWI [16.0% (10.4; 23.2)] and very likely higher following CWT [12.5% (5.5; 20.0)] compared with PAS, and possibly higher following CWI [3.7% (-0.9; 8.4)] compared with CWT. The correlations between performance, ln rMSSD(Post-interv) and perceptions of recovery were unclear. A moderate correlation was observed between ln rMSSD(Post-interv) and leg soreness [r = -0.50 (-0.66; -0.29)]. Although the effects of CWI and CWT on performance were trivial, the beneficial effects on perceptions of recovery support the use of these recovery strategies. PMID- 21710293 TI - Tissue-specific uptake and bioconcentration of the oral contraceptive norethindrone in two freshwater fishes. AB - The environmental presence of the oral contraceptive norethindrone (NET) has been reported and shown to have reproductive effects in fish at environmentally realistic exposure levels. The current study examined bioconcentration potential of NET in fathead minnow (Pimephales promelas) and channel catfish (Ictalurus punctatus). Fathead minnows were exposed to 50 MUg/l NET for 28 days and allowed to depurate in clean water for 14 days. In a minimized 14-day test design, catfish were exposed to 100 MUg/l NET for 7 days followed by 7-day depuration. In the fathead test, tissues (muscle, liver, and kidneys) were sampled during the uptake (days 1, 3, 7, 14, and 28) and depuration (days 35 and 42) phases. In the catfish test, muscle, liver, gill, brain, and plasma were collected during the uptake (days 1, 3, and 7) and depuration (day 14) stages. NET tissue levels were determined by gas chromatography-mass spectrometry (GC-MS). Accumulation of NET in tissues was greatest in liver followed by plasma, gill, brain, and muscle. Tissue-specific bioconcentration factors (BCFs) ranged from 2.6 to 40.8. Although NET has been reported to elicit reproductive effects in fish, the present study indicated a low potential to bioconcentrate in aquatic biota. PMID- 21710294 TI - Surgical technique: revision ACL reconstruction with a rectangular tunnel technique. AB - BACKGROUND: We developed the rectangular tunnel ACL reconstruction (RT ACLR) using a 10-mm wide bone-patellar tendon-bone (BTB) graft through rectangular tunnels with a rectangular aperture to reduce tunnel size: the cross-sectional area of the tunnels of 50 mm(2) (5 * 10 mm) in RT ACLR is less than that of 79 mm(2) in a conventional 10-mm round tunnel technique presuming the technique would be more suitable in revision ACLR with previous improperly placed tunnels. DESCRIPTION OF TECHNIQUE: Two contiguous 5-mm tunnels inside the anatomic ACL femoral and tibial attachment areas along their long axes, and they are expanded with a 5 * 10-mm dilator into parallelepiped ones. PATIENTS AND METHODS: We indicated and intended to perform the RT ACLR procedure in 31 patients requiring revision between 2004 and 2008. Eighteen of the 31 patients treated with the procedure were followed a minimum of 24 months (mean, 38 months; range, 24 to 73 months). We evaluated ROM, obtained IKDC scores, and determined stability with KT 1000. RESULTS: The procedure could be applied in 30 of the 31 cases. One of the 18 reruptured the graft at 28 months. Of the remaining 17 patients with followup of 24 months or longer, 15 had full ROM, while the remaining two lost 5 degrees of flexion; 11 were classified as normal and six were nearly normal according to the IKDC evaluation. Stability measured with KT-1000 was 1.0 +/- 1.5 mm. CONCLUSION: The RT ACLR technique provided acceptable results after one-stage revision ACLR. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21710295 TI - Chaperonin containing T-complex polypeptide (CCT) subunit expression in oral mucosal wounds and fibroblasts. AB - Mucosal wound healing in adults has been reported to feature diminished scar formation compared to healing skin wounds. We sought to determine if the expression pattern of chaperonin containing T-complex polypeptide (CCT) subunits in mucosal wounds and fibroblasts is different from that observed in skin wounds and fibroblasts. We found that CCT-beta is the only subunit message to be reduced in wounded mucosa versus unwounded control, and this reduction was confirmed at the protein level. In contrast, mRNA levels of CCT-zeta, -delta, -eta, and epsilon were significantly increased in mucosal wounds. The increase in CCT-eta was also confirmed at the protein level. Expression levels of CCT-alpha, -beta, delta; -epsilon, and -theta mRNAs were significantly increased in adult mucosal fibroblasts in culture compared to skin-derived fibroblasts. Western blot analyses confirmed a modest increase in CCT-beta in adult mucosal fibroblasts relative to skin fibroblasts, but CCT-eta protein was unaffected. These differences may contribute to the reported difference in healing outcomes between these two tissue types. PMID- 21710296 TI - The facilitative effects of bilobalide, a unique constituent of Ginkgo biloba, on synaptic transmission and plasticity in hippocampal subfields. AB - Bilobalide, a unique constituent of Ginkgo biloba, has been reported to potentiate population spikes in hippocampal CA1 pyramidal cells and to protect the brain against cell death. In this study, the effects of bilobalide on synaptic transmission and its plasticity in rat hippocampal subfields were electrophysiologically investigated. Bilobalide (50 MUM) significantly potentiated the input-output relationship at Schaffer collateral (SC)-CA1 synapses but not at medial perforant path (MPP)-dentate gyrus (DG), lateral perforant path (LPP)-DG, or mossy fiber (MF)-CA3 synapses. Facilitative effects of bilobalide on synaptic plasticity were only observed at MPP-DG synapses, in which the induction of long-term depression was blocked in the presence of bilobalide. However, no effect on synaptic plasticity was observed at SC-CA1 synapses. These results suggest that bilobalide has differential effects on synaptic efficacy in each hippocampal subfield. PMID- 21710297 TI - Pancreatic polypeptide meal response may predict gastric band-induced weight loss. AB - BACKGROUND: Unknown hormonal and neural satiety signals are thought to drive sustainable weight loss following laparoscopic adjustable gastric banding (LAGB). The objective of this study was to investigate whether the structurally related satiety hormones pancreatic polypeptide (PP) and peptide YY (PYY) influence total percentage weight loss after LAGB. METHODS: A cross-sectional study examined 17 postoperative individuals who had already achieved a mean of 28% LAGB-induced weight loss (range, 10-38%). A prospective study assessed plasma PP and PYY meal responses in 16 obese individuals prior to LAGB. RESULTS: In the cross-sectional study, individuals with higher weight loss had lower PP meal responses (2-h AUC, R = -0.60, p = 0.01) and lower fasting PYY levels (R = -0.55, p = 0.02). In the prospective study, subsequent mean weight loss was 20% (range, 5-50%) after a mean of 53 months. Low preoperative PP meal response (2-h AUC) predicted significantly higher subsequent weight loss after LAGB (R = -0.56, p = 0.024). The eight individuals with the lowest PP meal response lost more weight than the eight with the highest PP meal response (median 25% vs. 14%, p = 0.004). When compared across all three groups, mean PP meal responses did not differ. Fasting PYY levels, however, were significantly lower in the postoperative group compared to the group tested pre-operatively, or the BMI-matched controls (-30%, p = 0.03). CONCLUSIONS: PYY appears reduced in proportion to weight loss following LAGB, possibly representing attempted orexigenic homeostatic compensation. Although PP responses appear unchanged by weight loss status, low PP meal response may predict higher weight loss. PP meal response may be a biological marker that could predict an individual's susceptibility to the mechanism underlying LAGB-induced weight loss. PMID- 21710298 TI - Gastric band erosion in 63 cases: endoscopic removal and rebanding evaluated. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) remains the most popular bariatric procedure performed in Australia and Europe. Gastric band erosion is a significant complication that results in band removal. The aim of this study is to assess the prevalence of band erosion and its subsequent management with a particular focus on rebanding results. METHODS: Patients who underwent LAGB in a prospective cohort study from August 1996 to October 2010 were evaluated. Patients that developed band erosion were identified and clinical presentations, band characteristics and subsequent management were evaluated. RESULTS: One thousand eight hundred seventy-four morbidly obese patients underwent LAGB. Band erosion developed in 63 patients (3.4%). Median preoperative BMI was 41.5 kg/m(2) (range 30-61 kg/m(2)). Median time from operation to diagnosis was 39 months (range 6-132 months). Twenty nine patients (46%) were asymptomatic (sudden loss of restriction, weight gain, turbid fluid, or absence of fluid). Symptoms included abdominal pain in 24 (38%), obstruction in 7 (11%), recurrent port infection in 5 (8%), reflux symptoms in 2 (3%) and sepsis in 2 (3%). Fourteen patients (22%) had discolouration of the fluid in their band. Endoscopic removal was attempted in 50 patients with successful removal in 46 (92%). Median number of endoscopies prior to removal was 1.0 (range 1-5). The median duration of the procedure was 46 min (range 17-118 min). Rebanding was performed in 29 patients and 5 (17%) experienced a second erosion. Mean percentage excess weight loss was 54% in the remaining 22 patients with at least 3 months follow-up. CONCLUSIONS: Band erosion prevalence was 3.4%. Endoscopic removal of eroded gastric bands was proven safe and effective. Band erosion is now preferably managed endoscopically in our institution. Rebanding following erosion results in acceptable weight loss but an unacceptable reerosion rate. PMID- 21710299 TI - Obstructed metabolite diffusion within skeletal muscle cells in silico. AB - Using a Monte Carlo simulation technique, we have modeled 3D diffusion of low molecular weight metabolites inside a skeletal muscle cell. The following structural elements are considered: (i) a regular lattice of actin and myosin filaments inside a myofibril, (ii) the membranes of sarcoplasmic reticulum and mitochondria surrounding the myofibrils, (iii) a set of myofibrils inside a skeletal muscle cell encircled by the outer cell membrane, and (iv) an additional set of regular intracellular structures ("macrocompartments") embedded into the cell interior. The macrocompartments are considered to simulate diffusion restrictions because of hypothetical cylindrical structures (16-22 MUm in diameter) suggested earlier (de Graaf et al. Biophys J 78: 1657-1664, 2000). This model allowed us to calculate the apparent coefficients of particle diffusion in the radial and axial directions, D(app)(?) and D(app)(II), respectively. Particle movements in the axial direction are considered, at first approximation, as unrestricted diffusion (D(app)(II) = const). The apparent coefficient of radial diffusion, D(app)(?), decreases with time because of particle collisions with myofilaments and other rigid obstacles. Results of our random walk simulations are in fairly good agreement with experimental data on NMR measurements of restricted radial diffusion of phosphocreatine in white and red skeletal muscles of goldfish (Kinsey et al. NMR Biomed 12:1-7, 1999). Particle reflections from the low-permeable borders of macrocompartments (efficient diameter, D(eff)(MC) ~ 9.2-10.4 MUm) are the prerequisite for agreeing theoretical and experimental data. The low-permeable coverage of hypothetical macrocompartments (99.8% of coverage) provides the main contribution to time-dependent decrease in D(app)(?). PMID- 21710300 TI - Mykhailo Mykytovych Lapinsky (1862-1947). PMID- 21710301 TI - Learning physical examination skills outside timetabled training sessions: what happens and why? AB - Lack of published studies on students' practice behaviour of physical examination skills outside timetabled training sessions inspired this study into what activities medical students undertake to improve their skills and factors influencing this. Six focus groups of a total of 52 students from Years 1-3 using a pre-established interview guide. Interviews were recorded, transcribed and analyzed using qualitative methods. The interview guide was based on questionnaire results; overall response rate for Years 1-3 was 90% (n = 875). Students report a variety of activities to improve their physical examination skills. On average, students devote 20% of self-study time to skill training with Year 1 students practising significantly more than Year 3 students. Practice patterns shift from just-in-time learning to a longitudinal selfdirected approach. Factors influencing this change are assessment methods and simulated/real patients. Learning resources used include textbooks, examination guidelines, scientific articles, the Internet, videos/DVDs and scoring forms from previous OSCEs. Practising skills on fellow students happens at university rooms or at home. Also family and friends were mentioned to help. Simulated/real patients stimulated students to practise of physical examination skills, initially causing confusion and anxiety about skill performance but leading to increased feelings of competence. Difficult or enjoyable skills stimulate students to practise. The strategies students adopt to master physical examination skills outside timetabled training sessions are self-directed. OSCE assessment does have influence, but learning takes place also when there is no upcoming assessment. Simulated and real patients provide strong incentives to work on skills. Early patient contacts make students feel more prepared for clinical practice. PMID- 21710302 TI - Real-time detection of changes in the electrophoretic mobility of a single cell induced by hyperosmotic stress. AB - Living cells survive environmentally stressful conditions by initiating a stress response. We monitored changes in the electrophoretic mobility (EPM) of single, optically trapped yeast cells under hyperosmotic stress conditions using optical tweezers combined with a position detector. We studied the dynamics of the EPM stress response for cells at different phases of the cell cycle. PMID- 21710303 TI - Characterizing weak protein-protein complexes by NMR residual dipolar couplings. AB - Protein-protein interactions occur with a wide range of affinities from tight complexes characterized by femtomolar dissociation constants to weak, and more transient, complexes of millimolar affinity. Many of the weak and transiently formed protein-protein complexes have escaped characterization due to the difficulties in obtaining experimental parameters that report on the complexes alone without contributions from the unbound, free proteins. Here, we review recent developments for characterizing the structures of weak protein-protein complexes using nuclear magnetic resonance spectroscopy with special emphasis on the utility of residual dipolar couplings. PMID- 21710304 TI - Zinc modulates copper coordination mode in prion protein octa-repeat subdomains. AB - In this work we present and analyse XAS measurements carried out on various portions of Prion-protein tetra-octa-repeat peptides in complexes with Cu(II) ions, both in the presence and in the absence of Zn(II). Because of the ability of the XAS technique to provide detailed local structural information, we are able to demonstrate that Zn acts by directly interacting with the peptide, in this way competing with Cu for binding with histidine. This finding suggests that metal binding competition can be important in the more general context of metal homeostasis. PMID- 21710305 TI - Arsenic-induced changes in morphological, physiological, and biochemical attributes and artemisinin biosynthesis in Artemisia annua, an antimalarial plant. AB - Present study is the first to explore physiological, biochemical and molecular changes in the medicinal plant Artemisia annua under arsenic (As) stress. A. annua grown hydroponically in a nutrient solution was spiked with increasing doses of As (0, 1,500, 3,000 and 4,500 MUg l(-1)) for 7 days. Plants accumulated As in a dose dependent manner with bioconcentration factor 13.4 and translocation factor 0.97. While a similar trend of As accumulation was observed under soil culture experiments, the transfer factor went up to 2.1, depicting high efficiency of As translocation from roots to shoots by A. annua. Plants raised in 0-3,000 MUg l(-1) As containing nutrient solution registered increase in root length, biomass, and carotenoid contents without any visual toxicity symptoms. A dose dependent increase in the activities of enzymes such as superoxide dismutase, ascorbate peroxidase, glutathione reductase and guaiacol peroxidase followed by a gradual decline at higher concentrations suggested their role in alleviating oxidative stress. Significant increase in the levels of thiols, GSH, and pcs gene transcript up to 3,000 MUg l(-1) As attested their roles in As detoxification. Enhanced artemisinin production (an antimalarial compound) under As stress and upregulation of the transcripts (measured by RT-PCR) of the genes HMGR, FDS, ADS, and CYP71AV1 involved in artemisinin biosynthesis reaffirmed induction of artemisinin biosynthesis in A. annua under As stress. The results of the present study vividly suggested that A. annua has considerable As tolerance, and thus can be successfully cultivated in As contaminated fields. PMID- 21710306 TI - Comparative toxicity of antifouling compounds on the development of sea urchin. AB - In the present study, embryotoxicity experiments using the sea urchin Lytechinus variegatus were carried out to better clarify the ecotoxicological effects of tributyltin (TBT) and triphenyltin (TPT) (the recently banned antifouling agents), and Irgarol and Diuron (two of the new commonly used booster biocides). Organisms were individually examined to evaluate the intensity and type of effects on embryo-larval development, this procedure has not been commonly used, however it showed to be a potentially suitable approach for toxicity assessment. NOEC and LOEC were similar for compounds of same chemical class, and IC10 values were very close and showed overlapping of confidence intervals between TBT and TPT, and between Diuron and Irgarol. In addition, IC10 were similar to NOEC values. Regardless of this, the observed effects were different. Embryo development was interrupted at the gastrula and blastula stages at 1.25 and 2.5 MUg l(-1) of TBT, respectively, whereas pluteus stage was reached with the corresponding concentrations of TPT. Furthermore, embryos reached the prism and morula stages at 5 MUg l(-1) of TPT and TBT, respectively. The effects induced by Irgarol were also more pronounced than those caused by Diuron. Pluteus stage was always reached at any tested Diuron concentration, while embryogenesis was interrupted at blastula/gastrula stages at the highest concentrations of Irgarol. Therefore, this study proposes a complementary approach for interpreting embryo larval responses that may be employed together with the traditional way of analysis. Consequently, this application leads to a more powerful ecotoxicological assessment tool focused on embryotoxicity. PMID- 21710308 TI - A pilot study of uterine artery embolization with tris-acryl gelatin microspheres in guinea pigs. AB - OBJECTIVE: This study was designed to establish guinea pigs as an animal model for uterine artery embolization (UAE) with tris-acryl gelatin microspheres (TAGM). METHODS: Twenty-five female adult guinea pigs were randomly divided into two groups, including a uterine artery casting mould group (n=10) and a UAE group (n=15). Pelvic angiography and vascular casting mould were performed in the first group. The anatomical characters of the pelvic cavity in guinea pigs were described. In the second group, the technical feasibility of performing UAE with TAGM in guinea pigs was investigated. The histopathological slides of the uterus of guinea pigs after UAE were examined to inspect the outcomes of UAE. RESULTS: The uterine artery springs from the internal iliac artery, ascends tortuously along the cervix, and gives off vertically 8-10 branches to the cervix uteri and uterine horns. The diameters of the trunk of the uterine artery and its first branch were 0.32+/-0.027 mm and 0.14+/-0.01 mm, respectively. For UAE animals, the dosages of 40-120 and 100-300 MUm TAGM were 0.033+/-0.003 ml and 0.015+/ 0.002 ml, respectively. On histopathological slides, embosphere particles were found in the first branches of the uterine artery, the subserous arteries, and the intramural arteries. Inflammatory reactions in the uterus were common in guinea pigs after UAE. Local or dispersed areas of necrosis in uterus also were observed in a few guinea pigs. CONCLUSIONS: Guinea pigs are an appropriate and feasible model for UAE with TAGM. PMID- 21710307 TI - Predicting survival in prostate cancer: the role of quality of life assessment. AB - PURPOSE: While the use of quality of life (QoL) assessment has been increasing in clinical oncology, few studies have examined its prognostic significance in prostate cancer. We investigated the association between QoL at presentation and survival in prostate cancer. METHODS: We retrospectively reviewed 673 patients treated at two single-system cancer centers between January 2001 and December 2008. QoL was evaluated using EORTC-QLQ-C30. Patient survival was defined as the time interval between the date of first patient visit and the date of death/date of last contact. Univariate and multivariate Cox regression was performed to evaluate the prognostic significance of QoL. RESULTS: Mean age at presentation was 63.2 years. Patient stage of disease at diagnosis was I, 4; II, 464; III, 76; IV, 107; and 22 indeterminate. Median overall survival was 89.1 months (95% CI: 46.1-132.0). QoL scales predictive of survival upon univariate analysis were physical, role, emotional, social, fatigue, nausea/vomiting, pain, dyspnea, insomnia, loss of appetite, and constipation (p < 0.01 for all). Multivariate analyses found fatigue (p = 0.02) and constipation (p = 0.01) to be significantly associated with survival. CONCLUSIONS: Baseline QoL provides useful prognostic information in prostate cancer. These findings have important implications for patient stratification in clinical trials and may aid decision making in clinical practice. PMID- 21710309 TI - Newly designed Y-configured single-catheter stenting for the treatment of hilar type nonanastomotic biliary strictures after orthotopic liver transplantation. AB - PURPOSE: This study was designed to introduce our novel technique of percutaneous single catheter placement into the hilar bile ducts strictures while fulfilling the purpose of bilateral biliary drainage and stenting. We investigated the efficacy and safety of the technique for the treatment of hilar nonanastomotic biliary strictures. METHODS: Ten patients who were post-orthotopic liver transplantation between July 2000 and July 2010 were enrolled in this study. Percutaneous Y-configured single-catheter stenting for bilateral bile ducts combined with balloon dilation was designed as the main treatment approach. Technical success rate, clinical indicators, complications, and recurrent rate were analyzed. RESULTS: Technical success rate was 100%. Nine of the ten patients had biochemical normalization, cholangiographic improvement, and clinical symptoms relief. None of them experienced recurrence in a median follow-up of 26 months after completion of therapy and removal of all catheters. Complications were minor and limited to two patients. The one treatment failure underwent a second liver transplantation but died of multiple system organ failure. CONCLUSIONS: Percutaneous transhepatic Y-configured single-catheter stenting into the hilar bile ducts is technically feasible. The preliminary trial of this technique combined with traditional PTCD or choledochoscopy for the treatment of hilar biliary strictures after orthotopic liver transplantation appeared to be effective and safe. Yet, further investigation is needed. PMID- 21710311 TI - CONSORT recommendations in abstracts of randomised, controlled trials on migraine and headache. AB - A CONSORT statement on the content of abstracts of randomised, controlled trials (RCTs) was published in 2008. I therefore reviewed the abstracts from 2009 to 2010 published on RCTs in Cephalalgia, Headache and other (non-headache) journals. The following items were reviewed: number of patients, reporting of response either in percentages or absolute values, the use of p values, and effect size with its precision. The latter was recommended in the CONSORT statement. A total of 46 abstracts were reviewed and effect size with 95% confidence intervals was only reported in seven abstracts. The influence of the CONSORT statement on reporting in abstracts has so far only had a limited influence on the headache literature. PMID- 21710312 TI - Obesity, depression, and health services costs among middle-aged women. AB - BACKGROUND: Both obesity and depression have been associated with significant increases in health care costs. Previous research has not examined whether cost increases associated with obesity could be explained by confounding effects of depression. OBJECTIVE: Examine whether the association between obesity and health care costs is explained by co-occurring depression. DESIGN: Cross-sectional study including telephone survey and linkage to health plan records. PARTICIPANTS: 4462 women aged 40 to 65 enrolled in prepaid health plan in the Pacific Northwest. MAIN MEASURES: The telephone survey included self-report of height and weight and measurement of depression by the Patient Health Questionnaire (PHQ9). Survey data were linked to health plan cost accounting records. KEY RESULTS: Compared to women with BMI less than 25, proportional increases in health care costs were 65% (95% CI 41% to 93%) for women with BMI 30 to 35 and 157% (95% CI 91% to 246%) for women with BMI of 35 or more. Adjustment for co-occurring symptoms of depression reduced these proportional differences to 40% (95% CI 18% to 66%) and 87% (95% CI 42% to 147%), respectively. Cost increases associated with obesity were spread across all major categories of health services (primary care visits, outpatient prescriptions, inpatient medical services, and specialty mental health care). CONCLUSIONS: Among middle-aged women, both obesity and depression are independently associated with substantially higher health care costs. These cost increases are spread across the full range of outpatient and inpatient health services. Given the high prevalence of obesity, cost increases of this magnitude have major policy and public health importance. PMID- 21710313 TI - Drug benefit changes under Medicare Advantage Part D: heterogeneous effects on pharmaceutical use and expenditures. AB - BACKGROUND: Although Medicare Part D improved drug benefits for many beneficiaries, its impact on the coverage of Medicare Advantage Part D (MAPD) enrollees depended on their pre-existing benefits and whether they had gap coverage under Part D. OBJECTIVE: To examine changes in prescription drug utilization and expenditures associated with drug benefit changes resulting from the implementation of Part D. PATIENTS: We studied 248,773 continuously enrolled MAPD patients in eight states. Patients whose insurance product or Census block could not be identified or who had atypical benefits, low-income subsidies or Medicaid coverage were excluded. MAIN MEASURES: The main outcomes were changes in prescription drug days supply and expenditures from 2005 to 2006 and 2005 to 2007. DESIGN: We linked Census data with 2005-7 MAPD claims, encounter, enrollment, and benefits data and estimated associations of the outcomes with changes in drug benefits, controlling for 2005 comorbidities, demographics, and Census population characteristics. KEY RESULTS: MAPD enrollees whose drug benefits became potentially less generous after Part D had the smallest increases in drug utilization and expenditures (e.g., drug expenditures increased by $130 between 2005 and 2006), while those who potentially gained the most from Part D experienced the largest increases ($302). The differences in benefit design changes had a stronger association with drug utilization and outcomes among patients at high risk of gap entry than among the entire sample. CONCLUSIONS: Although Medicare Part D unambiguously improved drug coverage for many elderly, it led to heterogeneous changes in drug benefits among MAPD enrollees, who already had generic and sometimes branded drug benefits. After 2006, benefits were worse for individuals who had branded drug coverage in 2005 but now had a coverage gap, but benefits may have improved for individuals who acquired branded drug coverage. Commensurate with these differential changes in benefits following Part D, changes in drug utilization and expenditures varied substantially as well. PMID- 21710314 TI - Provider and practice characteristics associated with use of rapid HIV Testing by general internists. AB - BACKGROUND: Rapid HIV testing could increase routine HIV testing. Most previous studies of rapid testing were conducted in acute care settings, and few described the primary care providers' perspective. OBJECTIVE: To identify characteristics of general internal medicine physicians with access to rapid HIV testing, and to determine whether such access is associated with differences in HIV-testing practices or perceived HIV-testing barriers. DESIGN: Web-based cross-sectional survey conducted in 2009. PARTICIPANTS: A total of 406 physician members of the Society of General Internal Medicine who supervise residents or provide care in outpatient settings. MAIN MEASURES: Surveys assessed provider and practice characteristics, HIV-testing types, HIV-testing behavior, and potential barriers to HIV testing. RESULTS: Among respondents, 15% had access to rapid HIV testing. In multivariable analysis, physicians were more likely to report access to rapid testing if they were non-white (OR 0.45, 95% CI 0.22, 0.91), had more years since completing training (OR 1.06, 95% CI 1.02, 1.10), practiced in the northeastern US (OR 2.35; 95% CI 1.28, 4.32), or their practice included a higher percentage of uninsured patients (OR 1.03; 95% CI 1.01, 1.04). Internists with access to rapid testing reported fewer barriers to HIV testing. More respondents with rapid than standard testing reported at least 25% of their patients received HIV testing (51% versus 35%, p = 0.02). However, access to rapid HIV testing was not significantly associated with the estimated proportion of patients receiving HIV testing within the previous 30 days (7.24% vs. 4.58%, p = 0.06). CONCLUSION: Relatively few internists have access to rapid HIV testing in outpatient settings, with greater availability of rapid testing in community-based clinics and in the northeastern US. Future research may determine whether access to rapid testing in primary care settings will impact routinizing HIV testing. PMID- 21710315 TI - Risk of newly diagnosed type 2 diabetes is reduced in users of alendronate. AB - To study the risk of developing type 1 (T1D) or type 2 (T2D) diabetes among users of drugs against osteoporosis compared to nonusers. Nationwide cohort study in Denmark with all users of drugs against osteoporosis (n = 103,562) as exposed and three age- and sex-matched nondiabetic control subjects (n = 310,683) randomly selected from the background population. The main outcome variable was an incident diagnosis of diabetes after the baseline date. Among users of alendronate, etidronate, and raloxifene, no change in the risk of T1D was observed. However, the risk of developing T2D was reduced with all three drugs (alendronate: hazard ratio [HR] = 0.71, 95% confidence interval [CI] 0.59-0.85, etidronate: HR = 0.77, 95% CI 0.69-0.86, raloxifene: HR = 0.46, 95% CI 0.25 0.87). For alendronate, a dose-dependent risk reduction was observed (>=1 defined daily dose (DDD) per day: HR = 0.22, 95% CI 0.12-0.41, P for trend <0.01), while this was not the case for etidronate and raloxifene. Antiresorptive drugs do not seem associated with an increased risk of diabetes, but they may perhaps provide a protective effect related to the suppression of bone turnover. However, further studies are needed. PMID- 21710316 TI - Solvent dielectric effect and side chain mutation on the structural stability of Burkholderia cepacia lipase active site: a quantum mechanical/molecular mechanics study. AB - Quantum mechanical and molecular dynamics methods were used to analyze the structure and stability of neutral and zwitterionic configurations of the extracted active site sequence from a Burkholderia cepacia lipase, histidyl-seryl glutamin (His86-Ser87-Gln88) and its mutated form, histidyl-cysteyl-glutamin (His86-Cys87-Gln88) in vacuum and different solvents. The effects of solvent dielectric constant, explicit and implicit water molecules and side chain mutation on the structure and stability of this sequence in both neutral and zwitterionic forms are represented. The quantum mechanics computations represent that the relative stability of zwitterionic and neutral configurations depends on the solvent structure and its dielectric constant. Therefore, in vacuum and the considered non-polar solvents, the neutral form of the interested sequences is more stable than the zwitterionic form, while their zwitterionic form is more stable than the neutral form in the aqueous solution and the investigated polar solvents in most cases. However, on the potential energy surfaces calculated, there is a barrier to proton transfer from the positively charged ammonium group to the negatively charged carboxylat group or from the ammonium group to the adjacent carbonyl oxygen and or from side chain oxygen and sulfur to negatively charged carboxylat group. Molecular dynamics simulations (MD) were also performed by using periodic boundary conditions for the zwitterionic configuration of the hydrated molecules in a box of water molecules. The obtained results demonstrated that the presence of explicit water molecules provides the more compact structures of the studied molecules. These simulations also indicated that side chain mutation and replacement of sulfur with oxygen leads to reduction of molecular flexibility and packing. PMID- 21710318 TI - Optimizing technology development and adoption in medical imaging using the principles of innovation diffusion, part I: theoretical, historical, and contemporary considerations. AB - The pioneering work performed in the social sciences on diffusion of innovation can be applied to medical imaging and shed valuable insights as to how innovation is analyzed and adopted within the population of end-users. Successful innovation must take into account unique stakeholder differences, changes in communication and social interactions, and shifting priorities in market economics. The dramatic changes currently underway in current medical imaging practice provides unique innovation opportunities to those individuals and companies which can utilize this knowledge and effect change in objective and reproducible means. Successful innovation should rely upon data-driven objective analysis, which can scientifically validate the inherent strengths and weaknesses of the innovation, when compared with the idea or technology it supercedes. PMID- 21710317 TI - Changes in TWIK-related acid sensitive K+-1 and -3 channel expressions from neurons to glia in the hippocampus of temporal lobe epilepsy patients and experimental animal model. AB - In the present study, we analyzed expressions of tandem of P domains in a weak inwardly rectifying K+ channel (TWIK)-related acid-sensitive K+ (TASK) channel-1 and -3 in the hippocampus of patients with temporal lobe epilepsy (TLE) and in rat model. In the control human subjects, TASK-1, and -3 immunoreactivity was observed in pyramidal neurons and dentate granule cells. In TLE patients, TASK-1 and -3 immunoreactivity was rarely observed in neurons. However, TASK-1 immunoreactivity was observed in astrocytes, and TASK-3 immunoreactivity was detected in both astrocytes and microglia. In the rat hippocampus, TASK-1 immunoreactivity was observed in astrocytes within normal and epileptic hippocampus. The alterations in TASK-3 immunoreactivity in the rat hippocampus were similar to those in the human hippocampus. These findings reveal that TASK-1 and -3 are differentially expressed in the normal and epileptic hippocampus, and suggest that TASK channels may contribute to the properties of the epileptic hippocampus. PMID- 21710319 TI - Automated tracking and analysis of phospholipid vesicle contours in phase contrast microscopy images. AB - In this article, we propose a method for automated tracking and analysis of vesicle contours in video sequences acquired by phase contrast microscopy. The contour is determined in each frame of the selected video sequence by detecting the transition between the interior and exterior of the vesicle that is reflected in the image intensity gradients. The resulting contour points are represented in the polar coordinate system, i.e., with uniform angular sampling and with coordinates that originate from the vesicle center of mass, enabling the analysis of the vesicle shape and its membrane fluctuations. By analyzing artificial images with known ground-truth contours, the accuracy and precision of the proposed method was estimated to be 34.1 and 26.9 nm for image signal-to-noise ratio of 23 dB and pixel size of 35 nm, respectively. The proposed method was evaluated on quasi-spherical vesicles made up of different proportions of 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and cholesterol and exposed to different temperatures. The results show that the method is robust and efficient in terms of speed and quantitative description of vesicle fluctuations. The magnitude of vesicle membrane fluctuations increased with temperature, while the bending rigidity of the membrane was increasing for temperatures up to 20 degrees C and decreasing for higher temperatures irrespective of the vesicle molecular structure. PMID- 21710320 TI - CD24 interacts with and promotes the activity of c-src within lipid rafts in breast cancer cells, thereby increasing integrin-dependent adhesion. AB - Expression of the glycosylphosphatidylinositol-anchored membrane protein CD24 correlates with a poor prognosis for many human cancers, and in experimental tumors can promote metastasis. However, the mechanism by which CD24 contributes to tumor progression remains unclear. Here we report that in MTLy breast cancer cells CD24 interacts with and augments the kinase activity of c-src, a protein strongly implicated in promoting invasion and metastasis. This occurs within and is dependent upon intact lipid rafts. CD24-augmented c-src kinase activity increased formation of focal adhesion complexes, accelerated phosphorylation of FAK and paxillin and consequently enhanced integrin-mediated adhesion. Loss and gain of function approaches showed that c-src activity is necessary and sufficient to mediate the effects of CD24 on integrin-dependent adhesion and cell spreading, as well as on invasion. Together these results indicate that c-src is a CD24-activated mediator that promotes integrin-mediated adhesion and invasion, and suggest a mechanism by which CD24 might contribute to tumor progression through stimulating the activity of c-src or another member of the Src family. PMID- 21710322 TI - A meta-analysis of preoperative localization techniques for patients with primary hyperparathyroidism. AB - BACKGROUND: Reported accuracy of preoperative localization imaging for primary hyperparathyroidism (pHPT) varies. The purpose of this study is to determine the accuracy of ultrasound, sestamibi-single photon emission computed tomography (SPECT), and four-dimensional computed tomography (4D-CT) as preoperative localization strategies. METHODS: A meta-analysis was performed of studies investigating the accuracy of ultrasound, sestamibi-SPECT, and 4D-CT for preoperative localization in pHPT. Electronic databases were systematically searched, and two independent reviewers reviewed results using specific criteria. Study quality was assessed using a validated measure for diagnostic imaging studies. Study heterogeneity and pooled results were calculated. RESULTS: 43 studies met criteria for inclusion, and data were available for extraction in 19 ultrasound, 9 sestamibi-SPECT, and 4 4D-CT studies. Ultrasound had pooled sensitivity and positive predictive value (PPV) of 76.1% (95% CI 70.4-81.4%) and 93.2% (90.7-95.3%), respectively. Sestamibi-SPECT had pooled sensitivity and PPV of 78.9% (64-90.6%) and 90.7% (83.5-96.0%), respectively. Only two 4D-CT studies investigated patients undergoing initial parathyroidectomy. Results suggested sensitivity and PPV of 89.4% and 93.5%, respectively. CONCLUSIONS: Ultrasound and sestamibi-SPECT are similar in ability to preoperatively localize abnormal parathyroid glands in pHPT. Accuracy may be improved with 4D-CT; however, further investigation is required. Choice of preoperative imaging strategy depends on numerous patient, institutional, and economic factors of which the surgeon must be aware. PMID- 21710321 TI - BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain. AB - Bone Morphogenetic Protein 9 (BMP9) has been recently found to be the physiological ligand for the activin receptor-like kinase 1 (ALK1), and to be a major circulating vascular quiescence factor. Moreover, a soluble chimeric ALK1 protein (ALK1-Fc) has recently been developed and showed powerful anti-tumor growth and anti-angiogenic effects. However, not much is known concerning BMP9. This prompted us to investigate the human endogenous sources of this cytokine and to further characterize its circulating form(s) and its function. Analysis of BMP9 expression reveals that BMP9 is produced by hepatocytes and intrahepatic biliary epithelial cells. Gel filtration analysis combined with ELISA and biological assays demonstrate that BMP9 circulates in plasma (1) as an unprocessed inactive form that can be further activated by furin a serine endoprotease, and (2) as a mature and fully active form (composed of the mature form associated with its prodomain). Analysis of BMP9 circulating levels during mouse development demonstrates that BMP9 peaks during the first 3 weeks after birth and then decreases to 2 ng/mL in adulthood. We also show that circulating BMP9 physiologically induces a constitutive Smad1/5/8 phosphorylation in endothelial cells. Taken together, our results argue for the role of BMP9 as a hepatocyte-derived factor, circulating in inactive (40%) and active (60%) forms, the latter constantly activating endothelial cells to maintain them in a resting state. PMID- 21710324 TI - Impact of pegylated interferon therapy on outcomes of patients with hepatitis C virus-related hepatocellular carcinoma after curative hepatic resection. AB - BACKGROUND: Several published reports investigating the effects of interferon (IFN) therapy on survival and tumor recurrence after curative resection of hepatocellular carcinoma (HCC) have been inconclusive. The aim of this study is to investigate the efficacy of pegylated-IFN (peg-IFN) therapy after curative hepatic resection for HCC in patients infected with hepatitis C virus (HCV). METHODS: Data from 175 patients who underwent curative hepatic resection for HCC associated with HCV were retrospectively collected and analyzed; 75 patients received peg-IFN therapy after surgery, whereas 100 patients did not receive IFN therapy. To overcome biases resulting from the different distribution of covariates in the two groups, a one-to-one match was created using propensity score analysis. After matching, patient outcomes were analyzed. RESULTS: After one-to-one matching, patients (n = 38) who received peg-IFN therapy after surgery and patients (n = 38) who did not receive IFN therapy had the same preoperative and operative characteristics. The 3- and 5-year overall survival rates of patients who received peg-IFN therapy after hepatic resection were significantly higher than those of patients who did not receive IFN therapy (P = 0.00135). The 3- and 5-year overall survival rates were 100 and 91.7% and 76.6 and 50.6% in the peg-IFN group and non-IFN group, respectively. There was no significant difference in disease-free survival between the two matched groups (P = 0.886). CONCLUSION: Peg-IFN therapy may be effective as an adjuvant chemopreventive agent after hepatic resection in patients with HCV-related HCC. PMID- 21710325 TI - Incidental papillary microcarcinoma of the thyroid--further evidence of a very low malignant potential: a retrospective clinicopathologic study with up to 30 years of follow-up. PMID- 21710326 TI - Oral vitamin B12 therapy. PMID- 21710327 TI - Radiofrequency ablation of concomitant and recurrent pulmonary metastases after surgery for colorectal liver metastases. AB - BACKGROUND: To evaluate our experience of radiofrequency ablation (RFA) of pulmonary metastases in patients with resected colorectal liver metastases who had concomitant or recurrent pulmonary metastases. METHODS: Clinical and treatment variables of patients undergoing RFA were collected, and their association with survival was examined. Survival analysis was performed by the Kaplan-Meier method. RESULTS: RFA was performed as concomitant sequential treatment of extrahepatic pulmonary metastases after hepatectomy in 19 patients (30%) and as salvage treatment for pulmonary recurrences after hepatectomy in 45 patients (70%). Patients undergoing sequential treatment had a median survival of 31 (95% confidence interval [CI] 21.8-40.6) months compared to 59 (95% CI 35.0 82.0) months in the salvage treatment group (P = 0.142). The disease-free survival (DFS) was 9 (95% CI 1.0-18.8) months in the sequential treatment group and 16 (95% CI 8.1-23.1) months in the salvage treatment group (P = 0.023). Liver metastases occurring within 12 months of the primary tumor negatively influenced overall survival (OS) and DFS in the sequential treatment group (P = 0.003 and P = 0.091). Poorly differentiated tumor (P = 0.001) was associated with a poorer OS, and prehepatectomy carcinoembryonic antigen > 200 ng/ml (P = 0.017) and bilateral pulmonary metastases (P = 0.030) were associated with a shorter DFS in the salvage treatment group. CONCLUSIONS: The DFS and OS of patients undergoing sequential RFA of extrahepatic pulmonary metastases after hepatectomy appeared shorter when compared to patients who underwent RFA as salvage treatment for pulmonary recurrences after hepatectomy. It nonetheless remains better than the historical results of chemotherapy alone and thus supports the use of RFA as an ablative technology to achieve tumor control. PMID- 21710328 TI - Reproducibility of BOLD localization of interictal activity in patients with focal epilepsy: intrasession and intersession comparisons. AB - OBJECT: Simultaneous EEG-fMRI recordings allow the identification of haemodynamic changes induced by neuronal activity during ictal or interictal epileptiform events (IEDs). We evaluated the reproducibility of continuous EEG-fMRI (cEEG fMRI) in patients with focal epilepsy. MATERIALS AND METHODS: We studied 15 patients with focal epilepsy (8 cryptogenic and 7 symptomatic) and frequent interictal abnormalities. Each patient underwent two cEEG-fMRI acquisitions (runs) in the same day (session) and 8 patients repeated the examination after one month. cEEG-fMRI reproducibility was defined by the existence of partially overlapping clusters between activation maps obtained from different runs. RESULTS: We detected IEDs in 40 out of 46 EEG-fMRI runs and a related significant BOLD-response in all 40 runs. A prevalent positive BOLD response was detected in 12 patients and a prevalent negative response in 3 subjects. Statistical maps included a mean of 10 significant clusters. Nearly 30% of clusters were reproducible in both intrasession and intersession comparisons, with a mean overlap of 30%. Reproducibility did not differ between positive and negative BOLD responses. DISCUSSION: Among the reproducible clusters, those with the highest percentage of overlap were concordant with the EEG electric field in all patients and they were localized in the same lobe as the brain lesion in patients with symptomatic epilepsy. We hypothesize that reproducible clusters could be more consistently related to the irritative zone than non-reproducible ones. CONCLUSION: The evaluation of cluster reproducibility could improve our knowledge of IED-related BOLD response. Moreover, it could enhance the reliability of cEEG fMRI to identify the irritative zone in focal epileptic patients. PMID- 21710329 TI - Convergence process of volumetric liver regeneration after living-donor hepatectomy. AB - BACKGROUND: We investigated the long-term profiles of liver regeneration after living-donor hepatectomy. METHODS: Thirty-three donors participated in the study. Preoperative and postoperative liver volume was calculated using computed tomography. Volume assessment was repeated at 1 week, 2 weeks, 1 month, 3 months, 6 months, 12 months, and 4 years postoperatively. RESULTS: Donors were divided into the right (n = 23; residual liver volume, 42%) and left (n = 10; residual liver volume, 63%) groups according to the operative procedures. The restoration ratio to the preoperative liver volume (right vs. left groups) were 51%, 57%, 64%, 74%, 77%, 81%, and 88% vs. 69%, 72%, 76%, 79%, 83%, 84%, and 91% at 1 week, 2 weeks, 1 month, 3 months, 6 months, 12 months, and 4 years, respectively; the interindividual variation in the restoration ratio to the preoperative liver volume became narrower with time. CONCLUSION: Liver resection in humans resulted in rapid regeneration during the first 3 months, followed by a more moderate rate of regeneration thereafter, in proportion to the amount of liver mass resected. The volume of the regenerating liver appeared to converge towards the individual preoperative volume with time. However, the liver volume was not restored to the preoperative volume at 4 years after the resection. PMID- 21710330 TI - Disease characteristics of inflammatory bowel disease (IBD): findings from a tertiary care centre in South Asia. AB - BACKGROUND: Inflammatory bowel diseases (IBD) include ulcerative colitis (UC) and Crohn's disease (CD), which are chronic inflammatory conditions affecting the gastrointestinal tract. There are only few published data on disease characteristics of IBD related to South Asia. OBJECTIVE: To provide the disease characteristics of the IBD patients who presented to a tertiary care hospital in South Asia. METHODS: Patients with an established diagnosis of IBD were identified after a review of their medical records and demographics, and disease characteristics and indications for surgical treatment were analyzed. RESULTS: A total of 184 patients (women = 101, 54.9%; UC = 153, 83.2%) were included. Female preponderance was observed for UC (male/female ratio =1:1.5) and male for CD (male/female = 2:1). Mean age at the time of diagnosis was 36.3 (range 7-71) years. CD was diagnosed at a significantly younger age than UC (27.35 +/- 10.22 vs. 38.14 +/- 13.05 years, p < 0.0001). CD showed a peak age of onset in the third decade and that for UC was in the fourth decade. The mean duration of IBD was 8.17 (range 1-28) years. Presenting complaint of the majority (73.7%) of UC patients was blood and mucous diarrhea and that for CD (77.4%, 24/31) was left sided abdominal pain. Only 9.5% (n = 18) had at least one extra-intestinal manifestation. Among UC patients, 51.7% (n = 79) had left-sided colitis and panproctocolitis was found in 18.3% (n = 28). In IBD patients, 14.1% (n = 26) underwent surgery. Only one patient developed malignancy. CONCLUSIONS: The majority of UC patients had left-sided colitis. CD compared to UC was diagnosed at a younger age. However, compared to data reported for some Western countries, extra-intestinal manifestations and malignancy rates were lower. PMID- 21710331 TI - The abdominal compartment syndrome: review, experience report and description of an innovative biological mesh application. AB - Intra abdominal hypertension (IAH) is defined as an intra-abdominal pressure (IAP) >12 mmHg. Abdominal compartment syndrome (ACS) is defined as an IAP above 20 mmHg with evidence of organ dysfunction/failure. The real incidence of the ACS is not clear, because there are few perspective studies. The origin of ACS can be divided into retroperitoneal, intraperitoneal, parietal and intestinal, and the diagnostic algorithm includes base and toxicological laboratory examinations, thorax X-ray, abdomen X-ray, abdomen TC, peritoneal washing, abdomen ultrasonography, diagnostic laparoscopy, and measurement of IAP. To allow a suitable decompression and avoid the damages to the abdominal organs, abdominal wall normally is not sutured primarily but secondarily and there are many methods of temporary closing: absorbable net, non-absorbable nets, 'Bogota bag', 'vacuum pack ice', gradual approximation of side cutaneous edges on the half-way line with permanence of an ample ventral hernia that could be subsequently repaired, and the use of 'skin expanders'. Since January 2000, until December 2008, eight patients were submitted to laparostomy, four of them for re-laparotomy, with mortality incidence of 37.5%. The defective size to fill was on the average 300 cm as reported by Bradley and Bradley (J Clin Invest 26:1010-1015, 1947). The abdominal wall reconstruction was performed using ample muscle edges derived from the slip in medial sense of the rectus muscle of the abdomen 'unmoored' through an incision 1 cm distant from semi-lunar line, and using absorbable prosthesis to cover the solution of continuity, thus allowing the closing of defects over 30 cm. We have found median post surgical hernia in one patient corrected in accordance with the time using polypropylene prosthesis. In one patient with parietal disaster and multiple traumatic splanchnic ruptures, we have used a pure pork-derived acellular collagen mesh (Permacol((r))) to close the wound, leaving enough space between fascia extremities, to solve the IAP. The employment of ample muscle edges represents the ideal solution in the reconstruction of the abdominal walls after laparotomic operations, offering a valid dynamic support preferable in comparison with the employment of alloplastic material. In consideration of the limits of this technique in the enormous parietal disaster ACS treatment, we describe a new kind of innovative mesh application (Permacol((r))), most often used for parietal disaster or enormous incisional hernias, which can easily be preferred to dual mesh prosthesis, having a better biological profile and no capacity to produce intestinal adherences. PMID- 21710332 TI - Injectable acellular hydrogels for cardiac repair. AB - Injectable hydrogels are being developed as potential translatable materials to influence the cascade of events that occur after myocardial infarction. These hydrogels, consisting of both synthetic and natural materials, form through numerous chemical crosslinking and assembly mechanisms and can be used as bulking agents or for the delivery of biological molecules. Specifically, a range of materials are being applied that alter the resulting mechanical and biological signals after infarction and have shown success in reducing stresses in the myocardium and limiting the resulting adverse left ventricular (LV) remodeling. Additionally, the delivery of molecules from injectable hydrogels can influence cellular processes such as apoptosis and angiogenesis in cardiac tissue or can be used to recruit stem cells for repair. There is still considerable work to be performed to elucidate the mechanisms of these injectable hydrogels and to optimize their various properties (e.g., mechanics and degradation profiles). Furthermore, although the experimental findings completed to date in small animals are promising, future work needs to focus on the use of large animal models in clinically relevant scenarios. Interest in this therapeutic approach is high due to the potential for developing percutaneous therapies to limit LV remodeling and to prevent the onset of congestive heart failure that occurs with loss of global LV function. This review focuses on recent efforts to develop these injectable and acellular hydrogels to aid in cardiac repair. PMID- 21710333 TI - The biocompatibility manifesto: biocompatibility for the twenty-first century. PMID- 21710334 TI - The influence of sodium carboxymethylcellulose on drug release from polyethylene oxide extended release matrices. AB - Anionic polymer sodium carboxymethylcellulose (CELLOGEN(r) HP-HS and/or HP-12HS) was investigated for its ability to influence the release of three model drugs propranolol hydrochloride, theophylline and ibuprofen from polyethylene oxide (POLYOXTM WSR 1105 and/or Coagulant) hydrophilic matrices. For anionic ibuprofen and non-ionic theophylline, no unusual/unexpected release profiles were obtained from tablets containing a mixture of two polymers. However, for cationic propranolol HCl, a combination of polyethylene oxide (PEO) with sodium carboxymethylcellulose (NaCMC) produced a significantly slower drug release compared to the matrices with single polymers. The potential use of this synergistic interaction can be a design of new extended release pharmaceutical dosage forms with a more prolonged release (beyond 12 h) using lower polymer amount, which could be particularly beneficial for freely water-soluble drugs, preferably for once daily oral administration. In order to explain changes in the obtained drug release profiles, Fourier transform infrared absorption spectroscopy was performed. A possible explanation for the more prolonged propranolol HCl release from matrices based on both PEO and NaCMC may be due to a chemical bond (i.e. ionic/electrostatic intermolecular interaction) between amine group of the cationic drug and carboxyl group of the anionic polymer, leading to a formation of a new type/form of the active (i.e. salt) with sustained release pattern. PMID- 21710335 TI - Investigation of design space for freeze-drying: use of modeling for primary drying segment of a freeze-drying cycle. AB - In this work, we explore the idea of using mathematical models to build design space for the primary drying portion of freeze-drying process. We start by defining design space for freeze-drying, followed by defining critical quality attributes and critical process parameters. Then using mathematical model, we build an insilico design space. Input parameters to the model (heat transfer coefficient and mass transfer resistance) were obtained from separate experimental runs. Two lyophilization runs are conducted to verify the model predictions. This confirmation of the model predictions with experimental results added to the confidence in the insilico design space. This simple step-by-step approach allowed us to minimize the number of experimental runs (preliminary runs to calculate heat transfer coefficient and mass transfer resistance plus two additional experimental runs to verify model predictions) required to define the design space. The established design space can then be used to understand the influence of critical process parameters on the critical quality attributes for all future cycles. PMID- 21710336 TI - A quantitative correlation of the effect of density distributions in roller compacted ribbons on the mechanical properties of tablets using ultrasonics and X ray tomography. AB - Enabling the paradigm of quality by design requires the ability to quantitatively correlate material properties and process variables to measureable product performance attributes. In this study, we show how heterogeneities in compacted ribbon densities quantitatively correlate to tablet mechanical properties. These density variations, which have been purposely modulated by internal and external lubrications, are characterized longitudinally and transversally by nondestructive ultrasonic and X-ray micro-computed tomography measurements. Subsequently, different transversal regions of the compacted ribbon are milled under the same conditions, and granules with nominally the same particle size distribution are utilized to manufacture cylindrical tablets, whose mechanical properties are further analyzed by ultrasonic measurements. We consider three different ribbon conditions: no lubrication (case 1); lubricated powder (case 2); and lubricated tooling (hopper, side sealing plates, feed screws, and rolls) (case 3). This study quantitatively reveals that variation in local densities in ribbons (for case 1) and process conditions (i.e., internal case 2 and external lubrication case 3) during roller compaction significantly affect the mechanical properties of tablets even for granules with the same particle size distribution. For case 1, the mechanical properties of tablets depend on the spatial location where granules are produced. For cases 2 and 3, the ribbon density homogeneity was improved by the use of a lubricant. It is demonstrated that the mechanical performances of tablets are decreased due to applied lubricant and work-hardening phenomenon. Moreover, we extended our study to correlate the speed of sound to the tensile strength of the tablet. It is found that the speed of sound increases with the tensile strength for the tested tablets. PMID- 21710337 TI - Analysis of structural variability in pharmaceutical excipients using solid-state NMR spectroscopy. AB - Polysaccharide-based excipients comprise the majority of most solid dosage forms and can vary dramatically in terms of structural and functionally related properties. Analytical methods for characterizing these important formulation components are crucial. Solid-state NMR spectroscopy (SSNMR) can provide a wealth of information on these materials while offering the advantages of non destructive sample preparation and selectivity. The overall objective of this work is to identify SSNMR parameters that can be used to detect differences among these excipients. Excipients were obtained from a wide range of suppliers and analyzed as received; (13)C SSNMR spectra were acquired using a Chemagnetics CMX 300 spectrometer operating at approximately 75 MHz. The resolution of SSNMR signals of many excipients allows for positive identification of the major form present. Alginic acid and sodium alginate can be differentiated based on carbonyl peak position. Analysis of relative peak intensities provides insight into the purity of a carrageenan sample compared to known standards. The SSNMR spectrum of starch can be used to identify the source and to quantitate the amorphous and crystalline content. Relaxation values and peak areas of starch derivatives can be related to the degree of hydrolysis, providing an alternative method for determining dextrose equivalent. Differences in peak intensities and relaxation time values of HPMC samples can be correlated to the amount of methoxy subsituent groups. Important characteristics of excipients such as form identification, structural differences, crystalline and amorphous content, and water content variations can be detected using SSNMR spectroscopy. PMID- 21710338 TI - Neutron and light scattering studies of light-harvesting photosynthetic antenna complexes. AB - Small-angle neutron scattering (SANS) and dynamic light scattering (DLS) have been employed in studying the structural information of various biological systems, particularly in systems without high-resolution structural information available. In this report, we briefly present some principles and biological applications of neutron scattering and DLS, compare the differences in information that can be obtained with small-angle X-ray scattering (SAXS), and then report recent studies of SANS and DLS, together with other biophysical approaches, for light-harvesting antenna complexes and reaction centers of purple and green phototrophic bacteria. PMID- 21710339 TI - Effects of paracetamol, non-steroidal anti-inflammatory drugs, acetylsalicylic acid, and opioids on bone mineral density and risk of fracture: results of the Danish Osteoporosis Prevention Study (DOPS). AB - Pain medication has been associated with fractures. We found higher weight in paracetamol and non-steroidal anti-inflammatory drugs (NSAID) users and lower vitamin D levels in opioid and acetylsalicylic acid users. None of the pain medications influenced bone mineral density or loss. NSAID were associated with an increased fracture risk. INTRODUCTION: To study the effects of use of paracetamol, non-steroidal anti-inflammatory drugs (NSAID), acetylsalicylic acid (ASA), and opioids on bone mineral density (BMD) and risk of fractures. METHODS: Two-thousand sixteen perimenopausal women followed for 10 years as part of a partly randomised comprehensive cohort study on hormone therapy (HT). BMD was measured at baseline and after 10 years by DXA (Hologic). RESULTS: Paracetamol users were heavier (70.4 +/- 13.4 vs. 67.7 +/- 11.9 kg, 2p < 0.01) than non users. NSAID users were heavier (71.6 +/- 15.6 vs. 67.8 +/- 11.9 kg, 2p = 0.04) than non-users. ASA users had lower 25-hydroxy-vitamin D (25OHD) levels (21.9 +/- 9.3 vs. 25.3 +/- 12.4 ng/ml, 2p < 0.01) than non-users. Opioid users had lower 25OHD (21.4 +/- 8.4 vs. 25.2 +/- 12.3 ng/ml) and lower intake of vitamin D (2.2 +/- 1.1 vs. 3.1 +/- 3.0 MUg/day, 2p < 0.01) than non-users. Despite these differences, no baseline differences were present in spine, hip, forearm or whole body BMD. Over 10 years, no differences were present in BMD alterations except a small trend towards a higher BMD gain in the spine in users of paracetamol, NSAID, ASA, and opioids compared to non-exposed. After adjustment, NSAID exposed sustained more fractures (HR = 1.44, 95% CI 1.07-1.93) than non-users. For users of paracetamol and opioids, a non-significant trend towards more fractures was present after adjustment. For ASA users, no excess risk of fractures was present. CONCLUSION: Significant differences exist between subjects exposed to pain medications and non-users. Despite an absence of an effect over time on BMD, users of NSAID experienced more fractures than expected. The reasons for this have to be explored in further studies. PMID- 21710340 TI - Overcoming poor tabletability of pharmaceutical crystals by surface modification. AB - PURPOSE: To test the hypothesis that coating particles with a highly bonding polymer is effective in improving tabletability of poorly compressible drugs. METHODS: Micronized acetaminophen (d (90) < 10 MUm, Form I) was coated with 1% 10% (wt%) hydroxypropyl cellulose (HPC) by spray-drying. Phase nature of acetaminophen powders was identified using powder X-ray diffractometry, SEM, and thermal analysis. Powder tabletability was evaluated on a compaction simulator. Mechanical properties of acetaminophen and HPC were determined by nanoindentation. RESULTS: Spray-drying successfully produced acetaminophen particles enveloped with a layer of HPC but did not cause any detectable phase change of acetaminophen. At 200 MPa, physical mixtures containing up to 40% HPC could not be compressed into intact tablets. In contrast, acetaminophen coated with 1% to 10% HPC could form strong tablets (tensile strength was 1.9-7.0 MPa) at 200 MPa. Under a given compaction pressure, tablet tensile strength increased sharply with the amount of HPC coating. The profoundly improved tabletability of acetaminophen confirmed the effectiveness of the particle coating approach in improving tableting performance of drugs. CONCLUSIONS: HPC coating by spray drying profoundly enhances tabletability of acetaminophen. This strategy is expected to have transformative effects on formulation development of poorly compressible drugs. PMID- 21710342 TI - Relationship between the rewarding and aversive effects of morphine and amphetamine in individual subjects. AB - Drugs of abuse have been reported to produce both rewarding and aversive effects, as evidenced by their ability to induce both conditioned place preferences (CPPs) and conditioned taste aversions (CTAs), respectively. Although several attempts have been made to assess the relationship between the rewarding and aversive effects of drugs in independent groups, it is unknown to what extent (if any) preferences and aversions are related in individual animals. The present study assessed this relationship by examining the ability of morphine (5 and 10 mg/kg) and amphetamine (3 and 5 mg/kg) to induce both place preferences and taste aversions in the same animal, using a concurrent CTA/CPP design. There was no consistent relationship between the ability of morphine or amphetamine at either dose to increase time spent on the drug-paired side and the ability to suppress consumption of the drug-paired taste. These results support the position that drugs of abuse have multiple stimulus effects, both rewarding and aversive, that condition place preferences and taste aversions independently. PMID- 21710341 TI - Liposomes containing (-)-gossypol-enriched cottonseed oil suppress Bcl-2 and Bcl xL expression in breast cancer cells. AB - PURPOSE: We have demonstrated that (-)-gossypol-enriched cottonseed oil [(-) GPCSO] can down-regulate Bcl-2 expression in MCF-7 and primary cultured human breast cancer epithelial cells (PCHBCECs). However, this agent has not been evaluated in vivo due to its limited solubility. We aimed to develop liposomes containing (-)-GPCSO to suppress Bcl-2/Bcl-xL expression. METHODS: (-)-GPCSO liposomes were prepared and evaluated for effects on breast cancer cell viability, MDA-MB-231 xenograft tumor growth, cellular Bcl-2 and Bcl-xL mRNA levels, and chemosensitivity to paclitaxel. RESULTS: (-)-GPCSO liposomes prepared had excellent stability. Cytotoxicity of (-)-GPCSO liposomes was significantly reduced compared to (-)-GPCSO in culture medium. Bcl-2 and Bcl-xL mRNA expression was down-regulated by (-)-GPCSO in culture medium or (-)-GPCSO liposomes in MDA MB-231 cells. In PCHBCECs, Bcl-2 and Bcl-xL expression were down-regulated by (-) GPCSO liposomes. (-)-GPCSO in culture medium induced only a mild reduction in Bcl xL. In the MDA-MB-231 xenograft tumor model, (-)-GPCSO liposomes exhibited tumor suppressive activity and significantly reduced intratumoral Bcl-2 and Bcl-xL expression. Cytotoxicity of paclitaxel was increased by pretreatment with (-) GPCSO liposomes in MDA-MB-231 and PCHBCECs. CONCLUSIONS: Findings suggest that ( )-GPCSO liposomes warrant continued investigation as a chemosensitizer for breast cancers exhibiting Bcl-2-/Bcl-xL-mediated drug resistance. PMID- 21710343 TI - Impact of N-acetylcysteine on contrast-induced nephropathy defined by cystatin C in patients with ST-elevation myocardial infarction undergoing primary angioplasty. AB - BACKGROUND: The aim of this study was to assess the effects of N-acetylcysteine (N-ACC) on contrast-induced nephropathy (CIN) defined by Cystatin C (Cys-C) serum levels and to evaluate the influence of Cys-C on clinical outcome in patients with ST-elevation myocardial infarction (STEMI). METHODS: In total, 251 patients with STEMI undergoing primary percutaneous coronary intervention (PCI) were randomized to either high-dose N-ACC (2 * 1200 mg/d for 48 h) with optimal hydration or placebo plus optimal hydration. Serum Cys-C was measured at baseline, immediately, 24, 48 and 72 h after PCI. CIN was defined as an increase in serum Cys-C levels of 25% or more from baseline within 72 h after PCI. Major adverse cardiac events (MACE)--defined as death, recurrent infarction and congestive heart failure--within 6 months were recorded. RESULTS: Baseline Cys-C was 1294 +/- 611 and 1352 +/- 811 ng/mL (p = 0.54) for the N-ACC and placebo group, respectively. There was a steady increase in Cys-C in both groups within the first 72 h after randomization. CIN occurred in 74.6 and in 70.4% of patients in the N-ACC and placebo group, respectively (p = 0.46). The magnitude of increase in the serum concentration of Cys-C was an independent predictor for MACE after 6 months of follow-up. CONCLUSIONS: High-dose N-ACC does not provide additional benefit over placebo with respect to Cys-C defined CIN in STEMI patients undergoing primary PCI. The magnitude of increase in Cys-C serum levels in the early course after STEMI is a predictor of medium-term MACE. PMID- 21710344 TI - Persistent hiccup caused by peripherally inserted central catheter migration. AB - A peripherally inserted central catheter (PICC) provides an important access for patients requiring prolonged intravenous infusion. However, intravascular migration and subsequent malposition of a PICC may be caused by its flexibility and thinness and by changes in intrathoracic pressure and body position. In this report, we describe one case of persistent hiccup whose PICC migrated to and was bent and folded in the right subclavian vein. PMID- 21710345 TI - Characterization of MHC class I transcripts of a Malaysian cynomolgus macaque by high-throughput pyrosequencing and EST libraries. AB - We characterized the repertoire of MHC class I transcripts of a Malaysian cynomolgus macaque by the study of EST libraries derived from the mRNA extracted from six tissues (thymus, spleen, bone marrow, liver, heart and pancreas). The MHC class I transcripts present in a lymph node of the same animal were characterized by pyrosequencing of amplified cDNA fragments (515 bp from exon 2 to the beginning of exon 4). All pyrosequence consensus sequences, but three corresponding to rare transcripts, were identical to those obtained from EST libraries. In total, we characterized 19 classical class I transcripts in the Malaysian macaque studied here. By means of high-throughput sequencing of exon 2 amplified from the genomic DNA (190 bp), we characterized 38 classical class I genes in the genome of this animal. By comparison, using the same method, we found 23 classical class I genes in the genome of a MHC homozygous Mauritian animal (H2/H2). All these results suggested that the Malaysian animal was most probably heterozygous. This study reveals that the high-throughput pyrosequencing allows not only to characterize the MHC class I transcripts but also to estimate the number of MHC class I genes in the genome of cynomolgus macaque. PMID- 21710346 TI - Defining the turkey MHC: identification of expressed class I- and class IIB-like genes independent of the MHC-B. AB - The MHC of the turkey (Meleagris gallopavo) is divided into two genetically unlinked regions; the MHC-B and MHC-Y. Although previous studies found the turkey MHC-B to be highly similar to that of the chicken, little is known of the gene content and extent of the MHC-Y. This study describes two partially overlapping large-insert BAC clones that genetically and physically map to the turkey MHC chromosome (MGA18) but to a region that assorts independently of MHC-B. Within the sequence assembly, 14 genes were predicted including new class I- and class IIB-like loci. Additional unassembled sequences corresponded to multiple copies of the ribosomal RNA repeat unit (18S-5.8S-28S). Thus, this newly identified MHC region appears to represent a physical boundary of the turkey MHC-Y. High resolution multi-color fluorescence in situ hybridization studies confirm rearrangement of MGA18 relative to the orthologous chicken chromosome (GGA16) in regard to chromosome architecture, but not gene order. The difference in centromere position between the species is indicative of multiple chromosome rearrangements or alternate events such as neocentromere formation/centromere inactivation in the evolution of the MHC chromosome. Comparative sequencing of commercial turkeys (six amplicons totaling 7.6 kb) identified 68 single nucleotide variants defining nine MHC-Y haplotypes. Sequences of the new class I- and class IIB-like genes are most similar to MHC-Y genes in the chicken. All three loci are expressed in the spleen. Differential transcription of the MHC-Y class IIB-like loci was evident as one class IIB-like locus was only expressed in some individuals. PMID- 21710347 TI - Performance of rK39 immunochromatography and freeze-dried direct agglutination tests in the diagnosis of imported visceral leishmaniasis. AB - Visceral leishmaniasis (VL) is one of the neglected tropical diseases that require a global policy for integrated control programs. The disease is fatal if untreated, affects ~500,000 persons/year, and is most prevalent in poor countries. Treatment is expensive and carries a risk of toxicity. Therefore, sensitive and specific diagnosis of VL is crucial to avoid under- or overdiagnosis. Selecting an appropriate serological diagnostic test is an issue of controversy and depends on geographic location. The study aimed to evaluate the performance of two serological techniques: recombinant antigen K39 (rK39) immunochromatographic (IC) lateral flow assay (InBios, USA) that uses a recombinant Leishmania antigen K39 and the specific IgG detection by direct agglutination test (DAT, for the diagnosis of imported VL in non-endemic region (Saudi Arabia). The diagnostic accuracy of the two assays was assessed using bone marrow aspiration, direct microscopic examination, and culture on NNN agar as the "gold standard". The bone marrow specimens from Indian, Sudanese, and Bengali patients (n = 98) with suspected VL features were cultured. Thirty-five specimens were positive (36%). The sensitivity and specificity of rK39-IC test were 89% (95% CI 78-99) and 92% (95% CI 85-99), respectively. DAT (with cutoff >=1:1,600) showed comparable results (sensitivity 94%; 95% CI 87-101 and specificity 95%; 95% CI 90-100). To conclude, the performance of rK39-IC test and DAT is comparable. Both tests are moderately sensitive and specific and could be used to facilitate the global drive to eliminate this disease. The rK39-IC test is a rapid, easy-to-perform test and can be used as a point-of-care diagnostic method. PMID- 21710348 TI - Sarcocystis acanthocolubri sp. n. infecting three lizard species of the genus Acanthodactylus and the problem of host specificity. Light and electron microscopic study. AB - In the present investigation, macroscopic sarcocysts of Sarcocystis acanthocolubri were observed in muscles of 42 (4.3%) out of 975 Acanthodactylus sp. lizards collected from different geographical areas in Egypt. The infection rate was 6.4% in Acanthodactylus boskianus, 2.1% in Acanthodactylus sculentus, and 5% in Acanthodactylus paradalis. The highest infection rate was recorded in the lizards captured from Baltem (10% in A. boskianus and 8% in A. paradalis). The infection rate was usually higher in females (7.4%) than in males (3.8%). Moreover, the highest infection rate was recorded in summer (7.53%), autumn (3.57%), and spring (3.11%), and the lowest was recorded in winter (0.91%). Also, old animals had higher infection rates (10.8%) than young ones (0-2.7%). Macrocysts measured 0.95 * 10.12 mm. Both macroscopic and microscopic sarcocysts were enclosed only by a primary cyst wall, which had many finger-like, stalkless, and non-branched protrusions giving it a striated appearance. The primary cyst wall measured 3.9 MUm. A dark granulated ground substance was found directly underneath the protrusions and is extended interiorly dividing the cyst cavity into many compartments containing the parasites (metrocytes and merozoites). Metrocytes were found directly under the ground substance and usually multiply asexually by endodyogeny producing two merozoites from each metrocyte. Both metrocytes and merozoites had the apical complex structures characteristic to the genus Sarcocystis. Transmission experiments with three snake species indicated that the snake Spalerosophis diadema is the proper final host belonging to the family Colubridae. The prepatent period was 16 days, while the patent period was 35 days. The results obtained from the present investigation revealed that this is a new species which was named Sarcocystis acanthocolubri. PMID- 21710349 TI - Ancyrocephalidae (Monogenea) of Lake Tanganyika: II: description of the first Cichlidogyrus spp. parasites from Tropheini fish hosts (Teleostei, Cichlidae). AB - Although Lake Tanganyika hosts the most diverse endemic cichlid fish assemblage, its monogenean parasite fauna has hardly been documented. The cichlid tribe Tropheini has generated great interest because of its systematic position within the Haplochromini s.l. and its diversity in trophic morphology, reproductive behaviour and population structure. It has the potential to host a diverse Monogenea fauna. Here, we describe the first Cichlidogyrus spp.: Cichlidogyrus steenbergei sp. n., Cichlidogyrus irenae sp. n. and Cichlidogyrus gistelincki sp. n. The three host species, Limnotilapia dardennii, Ctenochromis horei and Gnathochromis pfefferi, are all infected by a single unique Cichlidogyrus sp. The genital and haptoral structure of the new species suggests a close relationship, which might mirror the close affinities between the hosts within the Tropheini. Based on haptoral configuration, the new species belong to a morphological group within the genus containing parasites both of West African cichlids and of Haplochromini, and hence, do not represent a new organisation of the attachment organ (as has recently been described of congeners infecting the ectodine cichlid Ophthalmotilapia). PMID- 21710350 TI - The effects of interleukin (IL)-12 and IL-4 deficiency on worm development and granuloma formation in Schistosoma japonicum-infected mice. AB - CD4(+) T-helper (Th) cell is widely recognized to be capable of influencing worm development and egg granuloma formation after schistosome infection. Interleukin (IL)-12 and IL-4 play key roles in regulation of Th cell differentiation. In the present study, we subcutaneously inoculated mice with hybridoma cells secreting monoclonal antibodies to neutralize IL-12 and IL-4 and explored the effects of IL 12 and IL-4 deficiency on the worm development and granuloma formation in mice infected with cercariae of Schistosoma japonicum. It was found that deficiency of host IL-12 and IL-4 supported normal parasite survival and fecundity. However, worm development (length and female fecundity) was significantly enhanced in anti IL-12-treated mice. Mean length of worms in anti-IL-12-treated group was significantly greater than that of intact controls on day 28 after infection (females, 11.84 +/- 1.20 mm vs. 9.45 +/- 1.34; males, 9.35 +/- 1.21 mm vs. 8.10 +/- 0.85 mm, p < 0.05). Liver egg load per pair of worms (1,770.12 +/- 470.67 vs. 806.08 +/- 232.37, p < 0.05) and uterine egg load of ovigerous females (93.08 +/- 27.85 vs. 46.05 +/- 34.24, p < 0.05) in anti-IL-12-treated mice were significantly higher than those in intact control 28 days postinfection. But these effects diminished 42 days postinfection (p > 0.05). Granuloma size in anti IL-12-treated mice was significantly larger than that in intact mice 42 days postinfection (398.3 +/- 80.7 MUm vs. 294.4 +/- 72.2 MUm, p < 0.05). Granuloma fibrosis dramatically intensified in anti-IL-12-treated mice but diminished in anti-IL-4-treated mice. The results suggest that IL-12 may play an impeditive role in the development of S. japonicum and in granuloma formation as well as fibrosis. IL-4 may promote granuloma formation but have no effect on worm development. PMID- 21710351 TI - Longitudinal prospective study of matrix metalloproteinase-9 as a serum marker in gliomas. AB - The objective of this study was to evaluate if longitudinal measurements of serum matrix metalloproteinase-9 (MMP-9) correlated with disease status or survival in adults with gliomas. Serum samples were collected prospectively and concurrently with MRI scans at multiple time points during the course of the disease. MMP-9 levels were determined by ELISA and correlated with radiographic disease status and survival. Forty-one patients with low-grade gliomas, 105 with anaplastic gliomas, and 197 with glioblastoma enrolled in this study from August 2002 to September 2008. A total of 1,684 serum samples (97.1% of all MMP-9 samples) had a matching MRI scan. No statistically significant association was observed between levels of serum MMP-9 and radiographic disease status in low-grade gliomas (P = 0.98), anaplastic gliomas (P = 0.39) or glioblastomas (P = 0.33). Among patients with glioblastoma, longitudinal increases in MMP-9 had a weak association with shorter survival (HR = 1.1 per each doubling in MMP-9 levels, 95% CI, 1.0-1.3, P = 0.04) but they were not independently associated with survival when adjusted for age, extent of resection, and performance status. Changes in serum MMP-9 were not associated with survival in the anaplastic glioma cohort. Serum MMP-9 showed no utility in determining glioma disease status and was not a clinically relevant prognostic marker of survival. PMID- 21710352 TI - Do arbuscular mycorrhizal fungi affect the allometric partition of host plant biomass to shoots and roots? A meta-analysis of studies from 1990 to 2010. AB - Arbuscular mycorrhizas (AM) are ubiquitous root symbioses with often pervasive effects on the plant host, one of which may be above- and belowground biomass allocation. A meta-analysis was conducted on 516 trials that were described in 90 available articles to examine whether AM colonization could result in a modification of partitioning of plant biomass in shoots and roots. It was hypothesized that alleviating plant nutrient limitations could result in a decrease of root to shoot (R/S) ratio in AM plants or, alternatively, the direction of shifts in the R/S ratio would be determined by the changes in total dry biomass. In our analysis, we considered four types of stresses: drought stress, single heavy metal stress, multiple heavy metal stress, and other potential abiotic plant stress factors. When disregarding any factors that could regulate effects, including stress status and mode of propagation, the overall AM effect was a significant modification of biomass towards shoot growth. However, the responses of stressed and clonally propagated plants differed from those of seed-grown unstressed plants. Our meta-analysis detected a considerable decline in the R/S ratio when plants were grown from seeds in the absence of abiotic stresses. Moreover, we demonstrate that additional regulators of the AM-mediated impact on R/S ratio were presence of competition from other plants, plant growth outcome of the symbiosis, growth substrate volume, experimental duration, and the identities of both plant and AM fungus. Our results indicate that a prediction of AM effects on R/S allocation becomes more accurate when considering regulators, most notably propagation mode and stress. We discuss possible mechanisms through which stress and other regulators may operate. PMID- 21710353 TI - Arbuscular mycorrhiza maintains nodule function during external NH4+ supply in Phaseolus vulgaris (L.). AB - The synergistic benefits of the dual inoculation of legumes with nodule bacteria and arbuscular mycorrhizae (AM) are well established, but the effect of an external NH(4)(+) supply on this tripartite relationship is less clear. This effect of NH(4)(+) supply was investigated with regards to the growth and function of the legume host and both symbionts. Nodulated Phaseolus vulgaris seedlings with and without AM, were grown in a sand medium with either 0 N, 1 mM or 3 mM NH(4)(+). Plants were harvested at 30 days after emergence and measurements were taken for biomass, N(2) fixation, photosynthesis, asparagine concentration, construction costs and N nutrition. The addition of NH(4)(+) led to a decline in the percentage AM colonization and nodule dry weights, although AM colonization was affected to a lesser extent. NH(4)(+) supply also resulted in a decrease in the reliance on biological nitrogen fixation (BNF); however, the AM roots maintained higher levels of NH(4)(+) uptake than their non-AM counterparts. Furthermore, the non-AM plants had a higher production of asparagine than the AM plants. The inhibitory effects of NH(4)(+) on nodule function can be reduced by the presence of AM at moderate levels of NH(4)(+) (1 mM), via improving nodule growth or relieving the asparagine-induced inhibition of BNF. PMID- 21710354 TI - Inhibition of cyclooxygenase-2 and inducible nitric oxide synthase by silymarin in proliferating mesenchymal stem cells: comparison with glutathione modifiers. AB - Silymarin, a mixture of flavonolignans, is extracted from milk thistle (Silybum marianum) and has a strong antioxidant activity and exhibits anticarcinogenic, anti-inflammatory, and cytoprotective effects. In this study we attempted to determine whether silymarin and the glutathione modifiers, buthionine sulfoxamine (BSO) and N-acetylcysteine (NAC), are involved in regulation of cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) in proliferating mesenchymal stem cells (MSCs). Cellular glutathione was manipulated during a 14-day culture using BSO, NAC and silymarin. At intervals of 2, 7 and 14 days, cells were collected and COX-2 and iNOS levels were measured. In parallel, generation of cellular H(2)O(2) and glutathione were measured. Supplementation of the culture media with BSO caused a dose-dependent decrease in MSC proliferation, whereas NAC or silymarin elevated the proliferation (p < 0.05). Treatment of MSC with NAC or silymarin caused a significant decrease in COX-2 levels. However, COX-2 levels in cells treated with high levels of NAC (1.0 mM) were significantly lower than those in MSCs treated with high levels of silymarin (100 MUM). BSO (1.0 and 5.0 MUM) caused a significant increase in COX-2 on days 2, 7 and 14. BSO caused a significant increase in iNOS, whereas NAC or silymarin decreased cellular iNOS. Overall result show that glutathione, iNOS and COX-2 in proliferating MSCs are affected by silymarin treatment. It appears that glutathione is the main target of silymarin, and in consequence iNOS and COX-2 are affected in response to silymarin treatment. PMID- 21710355 TI - The inclusion of 'then-test' questions in post-test questionnaires alters post test responses: a randomized study of bias in health program evaluation. AB - OBJECTIVES: Program evaluations are frequently based on 'then-test' data, i.e., pre-test collected in retrospect. While the application of the then-test has practical advantages, little is known about the validity of then-test data. Because of the collection of then-test in close proximity to post-test questions, this study was aimed at exploring whether the presence of then-test questions in post-test questionnaires influenced subjects' responses to post-test. PATIENTS AND METHODS: To test the influence of then-test questions, we designed a randomized three-group study in the context of chronic disease self-management programs. Interventions had comparable goals and philosophies, and all 949 study participants filled out identical Health Education Impact Questionnaires (heiQ) at pre-test. At post-test, participants were then randomized to one of the following three groups: Group A responded to post-test questions only (n = 331); Group B filled out transition questions in addition to post-test (n = 304); and Group C filled out then-test questions in addition to post-test (n = 314). RESULTS: Significant post-test differences were found in six of eight heiQ scales, with respondents who filled out then-test questions reporting significantly higher post-test scores than respondents of the other groups. CONCLUSIONS: This study provides evidence that the inclusion of then-test questions alters post-test responses, suggesting that change scores based on then test data be interpreted with care. PMID- 21710356 TI - Mycophenolate mofetil therapy for juvenile dermatomyositis with immune thrombocytopenic purpura. AB - A 6-year-old girl, who had received corticosteroid and cyclosporine on the diagnosis of interstitial pneumonitis related to juvenile dermatomyositis, developed severe thrombocytopenia. Her thrombocytopenia was resistant to repeated intravenous immunoglobulin administration and methylprednisolone pulse therapy. After additional treatment with mycophenolate mofetil (MMF), instead of cyclosporine, the thrombocytopenia improved, facilitating a reduction in the dose of corticosteroid without exacerbation of the interstitial pneumonitis. We propose MMF as effective option in the treatment of immune thrombocytopenic purpura with autoimmune disease. PMID- 21710357 TI - Which subgroup of rheumatoid arthritis patients benefits from switching to tocilizumab versus etanercept after previous infliximab failure? A retrospective study. AB - A retrospective study of 39 rheumatoid arthritis (RA) patients with an inadequate response to infliximab was conducted. The responses of subjects switching from infliximab to tocilizumab (n = 23) were compared to those of subjects switching to etanercept (n = 16). Disease activity was assessed by the Disease Activity Score 28-CRP ([C-reactive protein] DAS28-CRP), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). Twenty-two patients completed 48 weeks of tocilizumab treatment, and 15 patients completed 48 weeks of etanercept treatment. In both treatment groups, 1 patient each discontinued treatment because of lack of efficacy. No serious adverse events occurred during the study, and no patients in either group withdrew due to adverse events. At week 48, there was a significant reduction from baseline in DAS28-CRP, SDAI, and CDAI values after switching to either tocilizumab or etanercept, and there was no significant difference in efficacy, as measured by the DAS28-CRP, SDAI, and CDAI, between the two treatment groups (p = 0.12, 0.76, and 0.86, respectively). These results suggest that safety and tolerability were similar for both treatments. A switch from infliximab to either tocilizumab or etanercept in patients with RA who have not responded to infliximab is a feasible, well-tolerated treatment option. PMID- 21710358 TI - Non-uniform distribution of strain during stretch of relaxed skeletal muscle fibers from rat soleus muscle. AB - Tension and regional average sarcomere length (L(s)) behavior were examined during repeated stretches of single, permeabilized, relaxed muscle fibers isolated from the soleus muscles of rats. We tested the hypothesis that during stretches of single permeabilized fibers, the global fiber strain is distributed non-uniformly along the length of a relaxed fiber in a repeatable pattern. Each fiber was subjected to eight constant-velocity stretch and release cycles with a strain of 32% and strain rate of 54% s(-1). Stretch-release cycles were separated by a 4.5 min interval. Throughout each stretch-release cycle, sarcomere lengths were measured using a laser diffraction technique in which 20 contiguous sectors along the entire length of a fiber segment were scanned within 2 ms. The results revealed that: (1) the imposed length change was not distributed uniformly along the fiber, (2) the first stretch-release cycle differed from subsequent cycles in passive tension and in the distribution of global fiber strain, and (3) a characteristic "signature" for the L(s) response emerged after cycle 3. The findings support the conclusions that longitudinal heterogeneity exists in the passive stiffness of individual muscle fibers and that preconditioning of fibers with stretch-release cycles produces a stable pattern of sarcomere strains. PMID- 21710359 TI - Enormous influence of TNIK knockdown on intracellular signals and cell survival. AB - Basic cellular activities and coordinated cell actions are governed by intracellular signals, among which the Wnt signaling cascade plays an important role in tissue polarity and cell adhesion or movement through the activation of c Jun N-terminal kinase (JNK) pathway. As one of the central transcriptional factors, Traf2- and Nck-interacting kinase (TNIK) mediates the transactivation of Wnt target genes and promotes the activity of c-Jun N-terminus kinase (JNK)2 when overexpressed. To further understand the function of TNIK, changes in intracellular signals were detected in colon cancer cell lines using a knockdown strategy. In this study, we found that the short-hairpin RNA-mediated knockdown of TNIK decreased the expressions of CD44, c-MYC and cyclin D1, which was consistent with the results of a TCF-4 reporter assay. Our data showed, for the first time, that the activation of both JNK1 and JNK2 by TNFalpha could be blocked through TNIK knockdown, which dampened the AP1 luciferase activity accordingly. In addition, adenovirus mediated the downregulation of TNIK triggered intrinsic apoptosis in SW480 cells by activating caspase-9 and PARP-1. We conclude that TNIK is essential for the activation of both the canonical Wnt pathway and the JNK pathway, and serves as a pro-survival factor. PMID- 21710360 TI - Semantic dementia: a specific network-opathy. AB - Semantic dementia (SD) is a unique syndrome in the frontotemporal lobar degeneration spectrum. Typically presenting as a progressive, fluent anomic aphasia, SD is the paradigmatic disorder of semantic memory with a characteristic anatomical profile of asymmetric, selective antero-inferior temporal lobe atrophy. Histopathologically, most cases show a specific pattern of abnormal deposition of protein TDP-43. This relatively close clinical, anatomical and pathological correspondence suggests SD as a promising target for future therapeutic trials. Here, we discuss outstanding nosological and neurobiological challenges posed by the syndrome and propose a pathophysiological model of SD based on sequential, regionally determined disintegration of a vulnerable neural network. PMID- 21710361 TI - Recombinant human angiopoietin-1 ameliorates the expressions of ZO-1, occludin, VE-cadherin, and PKCalpha signaling after focal cerebral ischemia/reperfusion in rats. AB - This study was performed to determine whether recombinant human angiopoietin-1 (Ang-1) decreases the permeability of the blood-brain barrier (BBB) in focal cerebral ischemia and reperfusion rats, whether Ang-1 opens the BBB by affecting tight junction associated proteins zonula occluden-1 (ZO-1), occludin and adherens junction protein vascular endothelial (VE)-cadherin, and whether the protein kinase C (PKC)alpha/myosin light chain (MLC) signaling pathway involves in it. The rats were divided into eight groups randomly: (1) sham-operated group, (2) ischemia group, (3-5) ischemia-reperfusion (middle cerebral artery occlusion and reperfusion (MCAO/R) 12 h, 48 h, and 7 days) and 0.9% saline groups, (6-8) ischemia-reperfusion (MCAO/R 12 h, 48 h, and 7 days) and Ang-1 groups. The BBB permeability was assessed by Evans blue extravasation. The messenger RNA and protein expressions of ZO-1, occludin, and VE-cadherin were determined by reverse transcription-polymerase chain reaction, western blot, and immunohistochemistry assays. The BBB permeability was significantly decreased after Ang-1 injection. The expressions of ZO-1, occludin, and VE-cadherin were increased after Ang-1 injection. These were in accordance with the results of immunohistochemistry assays. PKCalpha and phosphorylated MLC (p-MLC) expressions were decreased after Ang-1 injection. This study demonstrated that Ang-1 may decrease the permeability of BBB in MCAO/R rat by upregulation of ZO-1, occludin, and VE-cadherin. The decreased expressions of PKCalpha and p-MLC induced by Ang-1 also involved in this process. PMID- 21710362 TI - Association study between BDNF C-281A polymorphism and paranoid schizophrenia in Polish population. AB - Brain-derived neurotrophic factor (BDNF) is one of the candidate genes for schizophrenia. Polymorphism C-281A (rs28383487) in BDNF gene leads to the reduction of promoter activity in the hippocampal neurons in vitro. To our knowledge, this is the first study to examine the influence of alleles and genotypes of BDNF C-281A polymorphism on development, as well as the clinical course (age of onset, suicidal behaviour and psychopathology) of paranoid schizophrenia. The psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) as subscale scores and also single-item scores. We have also performed the haplotype analysis with val66met BDNF polymorphism, which is known to be involved in the pathogenesis of schizophrenia. We have not found significant differences in the distribution of genotypes and alleles between schizophrenic patients and controls in both the overall analysis, as well as sex stratified. Also, we have not shown statistically significant differences between genotype groups and PANSS scale. However, an association between C-281A polymorphism and time of the first episode of paranoid schizophrenia was revealed. Genotype C/A had been connected with later age of onset of paranoid schizophrenia in men but not in women (p < 0.01). The C-281A and val66met polymorphisms have been in a strong linkage disequilibrium (D' = 0.9875; p < 0.05). The haplotype analysis has shown a tendency to a significantly lower frequency of the Met-C haplotype in the schizophrenia group compared to the controls. PMID- 21710364 TI - Positive effects of language treatment for the logopenic variant of primary progressive aphasia. AB - Despite considerable recent progress in understanding the underlying neurobiology of primary progressive aphasia (PPA) syndromes, relatively little attention has been directed toward the examination of behavioral interventions that may lessen the pervasive communication problems associated with PPA. In this study, we report on an individual with a behavioral profile and cortical atrophy pattern consistent with the logopenic variant of PPA. At roughly two-and-a-half years post onset, his marked lexical retrieval impairment prompted administration of a semantically based intervention to improve word retrieval. The treatment was designed to improve self-directed efforts to engage the participant's relatively preserved semantic system in order to facilitate word retrieval. His positive response to an intensive (2-week) dose of behavioral treatment was associated with improved lexical retrieval of items within trained categories, and generalized improvement for naming of untrained items that lasted over a 6-month follow-up interval. These findings support the potential value of intensive training to achieve self-directed strategic compensation for lexical retrieval difficulties in logopenic PPA. Additional insight was gained regarding the neural regions that supported improved performance by the administration of a functional magnetic resonance imaging protocol before and after treatment. In the context of a picture-naming task, post-treatment fMRI showed increased activation of left dorsolateral prefrontal regions that have been implicated in functional imaging studies of generative naming in healthy individuals. The increased activation in these frontal regions that were not significantly atrophic in our patient (as determined by voxel-based morphometry) is consistent with the notion that neural plasticity can support compensation for specific language loss, even in the context of progressive neuronal degeneration. PMID- 21710365 TI - Responses of bark beetle-associated bacteria to host monoterpenes and their relationship to insect life histories. AB - Bark beetles that colonize living conifers and their microbial associates encounter constitutive and induced chemical defenses of their host. Monoterpene hydrocarbons comprise a major component of these allelochemicals, and many are antibiotic to insects, fungi, and bacteria. Some bark beetle species exhaust these defenses by killing their host through mass attacks mediated by aggregation pheromones. Others lack adult aggregation pheromones and do not engage in pheromone-mediated mass attacks, but rather have the ability to complete development within live hosts. In the former species, the larvae develop in tissue largely depleted of host terpenes, whereas in the latter exposure to these compounds persists throughout development. A substantial literature exists on how monoterpenes affect bark beetles and their associated fungi, but little is known of how they affect bacteria, which in turn can influence beetle performance in various manners. We tested several bacteria from two bark beetle species for their ability to grow in the presence of a diversity of host monoterpenes. Bacteria were isolated from the mountain pine beetle, Dendroctonus ponderosae Hopkins, which typically kills trees during colonization, and the red turpentine beetle, Dendroctonus valens LeConte, which often lives in their host without causing mortality. Bacteria from D. ponderosae were gram-positive Actinobacteria and Bacilli; one yeast also was tested. Bacteria from D. valens were Actinobacteria, Bacilli, and gamma-Proteobacteria. Bacteria from D. valens were more tolerant of monoterpenes than were those from D. ponderosae. Bacteria from D. ponderosae did not grow in the presence of alpha-pinene and 3-carene, and grew in, but were inhibited by, beta-pinene and beta-phellandrene. Limonene and myrcene had little inhibitory effect on bacteria from either beetle species. Tolerance to these antibiotic compounds appears to have resulted from adaptation to living in a terpene-rich environment. PMID- 21710366 TI - The allelochemical L-DOPA increases melanin production and reduces reactive oxygen species in soybean roots. AB - The non-protein amino acid, L-3,4-dihydroxyphenylalanine (L-DOPA), is the main allelochemical released from the roots of velvetbean and affects seed germination and root growth of several plant species. In the work presented here, we evaluated, in soybean roots, the effects of L-DOPA on the following: polyphenol oxidase (PPO), superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities; superoxide anion (O.-2), hydrogen peroxide (H(2)O(2)), and melanin contents; and lipid peroxidation. To this end, 3-day-old seedlings were cultivated in half-strength Hoagland's solution (pH 6.0), with or without 0.1 to 1.0 mM L-DOPA in a growth chamber (at 25 degrees C, with a light/dark photoperiod of 12/12 hr and a photon flux density of 280 MUmol m(-2) s(-1)) for 24 hr. The results showed that L-DOPA increased the PPO activity and, further, the melanin content. The activities of SOD and POD increased, but CAT activity decreased after the chemical exposure. The contents of reactive oxygen species (ROS), such as O.-2 and H(2)O(2), and the levels of lipid peroxidation significantly decreased under all concentrations of L-DOPA tested. These results suggest that L DOPA was absorbed by the soybean roots and metabolized to melanin. It was concluded that the reduction in the O.-2 and H(2)O(2) contents and lipid peroxidation in soybean roots was due to the enhanced SOD and POD activities and thus a possible antioxidant role of L-DOPA. PMID- 21710367 TI - Images in endocrine pathology: case 1. PMID- 21710368 TI - Learning curves of novice anesthesiology residents performing simulated fibreoptic upper airway endoscopy. AB - BACKGROUND: In various medical and surgical specialties, it is essential to acquire fibreoptic upper airway endoscopy skills for successful endotracheal intubation, especially when faced with a difficult airway. The aim of our study was to evaluate the learning curves of residents performing fibreoptic upper airway endoscopy in the simulation environment. METHODS: Following a standardized video and practice session, 16 residents newly enrolled in the anesthesiology program performed nasal fibreoptic endoscopy of the upper airway (endpoint being the carina) on a high fidelity simulator. Weekly 20-min sessions continued for a period of one month. Each attempt was designated as either a "success" or a "failure" based on the study participant's ability or inability to visualize the carina in <=60 sec and with <=five collisions with the simulated mucosal wall. Proficiency was attained when the downward graphical trend of the cumulative sum (CUSUM) analysis crossed two adjacent boundary lines, i.e., an acceptable failure rate was reached. RESULTS: The residents' mean number of attempts at fibreoptic airway endoscopy was 47 (9) with a range of 32-64. Time to visualization of the carina was 51 (36) sec. Three classical patterns of CUSUM trends were observed: proficient (n = 7); not proficient with a downward (improvement) trend (n = 3); and not proficient with an upward (worsening) trend (n = 6). The number of attempts at which proficiency was achieved varied from 27 to 58. CONCLUSION: There is a large variation in the learning curves of residents performing fibreoptic upper airway endoscopy. The training for fibreoptic airway endoscopy should be tailored to the needs of each individual. PMID- 21710369 TI - Nanoporous membrane-sealed microfluidic devices for improved cell viability. AB - Cell-laden microfluidic devices have broad potential in various biomedical applications, including tissue engineering and drug discovery. However, multiple difficulties encountered while culturing cells within devices affecting cell viability, proliferation, and behavior has complicated their use. While active perfusion systems have been used to overcome the diffusive limitations associated with nutrient delivery into microchannels to support longer culture times, these systems can result in non-uniform oxygen and nutrient delivery and subject cells to shear stresses, which can affect cell behavior. Additionally, histological analysis of cell cultures within devices is generally laborious and yields inconsistent results due to difficulties in delivering labeling agents in microchannels. Herein, we describe a simple, cost-effective approach to preserve cell viability and simplify labeling within microfluidic networks without the need for active perfusion. Instead of bonding a microfluidic network to glass, PDMS, or other solid substrate, the network is bonded to a semi-permeable nanoporous membrane. The membrane-sealed devices allow free exchange of proteins, nutrients, buffers, and labeling reagents between the microfluidic channels and culture media in static culture plates under sterile conditions. The use of the semi-permeable membrane dramatically simplifies microniche cell culturing while avoiding many of the complications which arise from perfusion systems. PMID- 21710370 TI - Microfabricated thermal conductivity sensor: a high resolution tool for quantitative thermal property measurement of biomaterials and solutions. AB - Obtaining accurate thermal properties of biomaterials plays an important role in the field of cryobiology. Currently, thermal needle, which is constructed by enclosing a manually winded thin metal wire with an insulation coating in a metallic sheath, is the only available device that is capable of measuring thermal conductivity of biomaterials. Major drawbacks, such as macroscale sensor size, lack of versatile format to accommodate samples with various shapes and sizes, neglected effects of heat transfer inside the probe and thermal contact resistance between the sensing element and the probe body, difficult to mass produce, poor data repeatability and reliability and labor-intense sensor calibration, have significantly reduced their potential to be an essential measurement tool to provide key thermal property information of biological specimens. In this study, we describe the development of an approach to measure thermal conductivity of liquids and soft bio-tissues using a proof-of-concept MEMS based thermal probe. By employing a microfabricated closely-packed gold wire to function as the heater and the thermistor, the presented thermal sensor can be used to measure thermal conductivities of fluids and natural soft biomaterials (particularly, the sensor may be directly inserted into soft tissues in living animal/plant bodies or into tissues isolated from the animal/plant bodies), where other more standard approaches cannot be used. Thermal standard materials have been used to calibrate two randomly selected thermal probes at room temperature. Variation between the obtained system calibration constants is less than 10%. By incorporating the previously obtained system calibration constant, three randomly selected thermal probes have been successfully utilized to measure the thermal conductivities of various solutions and tissue samples under different temperatures. Overall, the measurements are in agreement with the recommended values (percentage error less than 5%). The microfabricated thermal conductivity sensor offers superior characteristics compared to those traditional macroscopic thermal sensors, such as, (a) reduced thermal mass and thermal resistivity, (b) improved thermal contact between sensor and sample, (c) easy to manufacture with mass production capability, (d) flexibility to reconfigure sensor geometries for measuring samples with various sizes and shapes, and (e) reduced calibration workload for all sensors microfabricated from the same batch. The MEMS based thermal conductivity sensor is a promising approach to overcome the inherent limitations of existing macroscopic devices and capable of delivering accurate thermal conductivity measurement of biomaterials with various shapes and sizes. PMID- 21710371 TI - Microfabricated scaffold-guided endothelial morphogenesis in three-dimensional culture. AB - Morphogenesis is a fundamental process by which new blood vessels are formed during angiogenesis. The ability to control angiogenesis would lead to improvements in tissue engineering constructions; indeed, the study of angiogenesis has numerous clinical applications, for example, in the investigation of metastatic cancer, peripheral and coronary vascular disease, and wound healing. Conventional in vitro organotypic cell culture approaches to these studies are limited primarily by their reliance on microvascular vessel formation through a random process of morphogenesis that lacks the spatial reproducibility and orientation needed for high-throughput drug testing. We have developed a bioreactor system for scaffold-guided tubulogenesis coupled with 3-D organotypic culture to spatially control vessel formation and its orientation. To create microchannels to guide microvessel formation, we fabricated rigid scaffolds using photolithography and light curing epoxy, and soft scaffolds formed by a polydimethylsiloxane (PDMS) stamp directly into collagen. Scaffolds seeded with dermal microvascular endothelial cells were placed between gelled layers of collagen containing dermal fibroblasts within a Transwell filter system and cultured for up to 2 weeks to allow for vessel maturation. Morphological analysis of thin tissue sections following standard histology and immunohistochemical detection of endothelial cells, fibroblasts, and basement membrane confirmed vessel formation along the microchannel walls with either scaffold. This system may also provide a means to explore revascularization within decellularized extracellular matrices, the culture of microvessel networks with controlled geometries, and possibly the spatial guidance of angiogenesis for interfacing with an external microfluidic supply network. As a new tool for guided angiogenesis, our approach introduces new possibilities for identification of anti-angiogenic therapeutics. PMID- 21710372 TI - Monitoring environmental levels of trace elements near a hazardous waste incinerator: human health risks after a decade of regular operations. AB - In 1998, we initiated an environmental surveillance program of the only hazardous waste incinerator (HWI) in Spain. The concentrations of a number of metals (As, Be, Cd, Cr, Hg, Mn, Ni, Pb, Sn, Tl, and V) were analyzed in soil and vegetation samples collected around the facility. Since then, periodical measurements of these same elements have been performed in both matrices. In 2009 and 2010, soil and vegetation samples were again collected, and the levels of the above elements were determined. In general terms, the temporal trends in metal concentrations were not homogeneous, showing significant changes between the baseline and the latest surveys. Metal levels in soil and herbage samples analyzed in the current survey were similar to recent data reported for other urban and industrial areas, being notably lower than the reference values set by national regulatory organisms. Moreover, more than 10 years after regular operations of the HWI, exposure to metals would not mean, either now or in past surveys, any carcinogenic or non-carcinogenic health risks for the population living in the neighborhood. PMID- 21710373 TI - Carnitine supplementation modulates high dietary copper-induced oxidative toxicity and reduced performance in laying hens. AB - This experiment was conducted to evaluate the effects of L-carnitine on performance, egg quality and certain biochemical parameters in laying hens fed a diet containing high levels of copper proteinate. Forty-eight 42-week-old laying hens were divided into four groups with four replicates. The laying hens were fed with a basal diet (control) or the basal diet supplemented with either 400 mg carnitine (Car)/kg diet, 800 mg copper proteinate (CuP)/kg diet or 400 mg carnitine + 800 mg copper (Car+CuP)/kg diet, for 6 weeks. Supplemental CuP decreased feed consumption (p < 0.01), feed efficiency and egg production (p < 0.001), as compared to control. The combination of Car and CuP increased (p < 0.001) egg production and feed efficiency as compared to CuP. The activities of alanine aminotransferase (p < 0.05) and alkaline phosphatase (p < 0.01) were increased, while lactate dehydrogenase activity was decreased (p < 0.001) by supplemental CuP and Car+CuP. Supplemental CuP caused an increase in plasma malondialdehyde (p < 0.01) and nitric oxide levels (p < 0.05). In the Car+CuP group, this increase was observed to have been reduced significantly (p < 0.05). Furthermore, Car+CuP increased (p < 0.05) glucose level. These results indicate that the carnitine and copper combination may prevent the possible adverse effects of high dietary copper on performance and lipid peroxidation in hens. PMID- 21710374 TI - In the beginning was the familiar voice: personally familiar voices in the evolutionary and contemporary biology of communication. AB - The human voice is described in dialogic linguistics as an embodiment of self in a social context, contributing to expression, perception and mutual exchange of self, consciousness, inner life, and personhood. While these approaches are subjective and arise from phenomenological perspectives, scientific facts about personal vocal identity, and its role in biological development, support these views. It is our purpose to review studies of the biology of personal vocal identity-the familiar voice pattern-as providing an empirical foundation for the view that the human voice is an embodiment of self in the social context. Recent developments in the biology and evolution of communication are concordant with these notions, revealing that familiar voice recognition (also known as vocal identity recognition or individual vocal recognition) has contributed to survival in the earliest vocalizing species. Contemporary ethology documents the crucial role of familiar voices across animal species in signaling and perceiving internal states and personal identities. Neuropsychological studies of voice reveal multimodal cerebral associations arising across brain structures involved in memory, emotion, attention, and arousal in vocal perception and production, such that the voice represents the whole person. Although its roots are in evolutionary biology, human competence for processing layered social and personal meanings in the voice, as well as personal identity in a large repertory of familiar voice patterns, has achieved an immense sophistication. PMID- 21710375 TI - Is nocturnal blood pressure reduction the secret to reducing the rate of progression of hypertensive chronic kidney disease? AB - Hypertension is a significant risk factor for cardiovascular and renal disease. Lowering blood pressure (BP) has been shown to reduce the incidence of cardiovascular disease, but randomized trials have not demonstrated a benefit of lowering BP for the progression of renal disease except in secondary analyses in patients with significant proteinuria. Recently, there has been increasing interest in measuring BP outside of the clinic, using both home and ambulatory blood pressure monitoring (ABPM). ABPM has the advantage of measuring BP throughout both the day and night. Elevated nighttime BP and a lack of decline in BP from day to night (nondipping) are more potent risk factors for cardiovascular and renal outcomes than elevated daytime or clinic BP. Studies have shown that it is possible to lower nighttime BP and restore normal dipping with the administration of antihypertensive medications in the evening, known as chronotherapy. Evening administration of antihypertensives not only lowers nighttime BP but also is associated with decreased urinary protein excretion, decreased cardiovascular events, and decreased all-cause mortality. Reducing nighttime BP may slow the progression of chronic kidney disease and may be the key to linking the treatment of hypertension with improved renal outcomes. PMID- 21710376 TI - Aesthetics and ethics in engineering: insights from Polanyi. AB - Polanyi insisted that scientific knowledge was intensely personal in nature, though held with universal intent. His insights regarding the personal values of beauty and morality in science are first enunciated. These are then explored for their relevance to engineering. It is shown that the practice of engineering is also governed by aesthetics and ethics. For example, Polanyi's three spheres of morality in science--that of the individual scientist, the scientific community and the wider society--has parallel entities in engineering. The existence of shared values in engineering is also demonstrated, in aesthetics through an example that shows convergence of practitioner opinion to solutions that represent accepted models of aesthetics; and in ethics through the recognition that many professional engineering institutions hold that the safety of the public supersedes the interests of the client. Such professional consensus can be seen as justification for studying engineering aesthetics and ethics as inter subjective disciplines. PMID- 21710377 TI - Dynamic chemistry of anion recognition. AB - In the past 40 years, anion recognition by synthetic receptors has grown into a rich and vibrant research topic, developing into a distinct branch of Supramolecular Chemistry. Traditional anion receptors comprise organic scaffolds functionalized with complementary binding groups that are assembled by multistep organic synthesis. Recently, a new approach to anion receptors has emerged, in which the host is dynamically self-assembled in the presence of the anionic guest, via reversible bond formation between functional building units. While coordination bonds were initially employed for the self-assembly of the anion hosts, more recent studies demonstrated that reversible covalent bonds can serve the same purpose. In both cases, due to their labile connections, the molecular constituents have the ability to assemble, dissociate, and recombine continuously, thereby creating a dynamic combinatorial library (DCL) of receptors. The anionic guests, through specific molecular recognition, may then amplify (express) the formation of a particular structure among all possible combinations (real or virtual) by shifting the equilibria involved towards the most optimal receptor. This approach is not limited to solution self-assembly, but is equally applicable to crystallization, where the fittest anion-binding crystal may be selected. Finally, the pros and cons of employing dynamic combinatorial chemistry (DCC) vs molecular design for developing anion receptors, and the implications of both approaches to selective anion separations, will be discussed. PMID- 21710378 TI - Multistate and phase change selection in constitutional multivalent systems. AB - Molecular architectures and materials can be constitutionally self-sorted in the presence of different biomolecular targets or external physical stimuli or chemical effectors, thus responding to an external selection pressure. The high selectivity and specificity of different bioreceptors or self-correlated internal interactions may be used to describe the complex constitutional behaviors through multistate component selection from a dynamic library. The self-selection may result in the dynamic amplification of self-optimized architectures during the phase change process. The sol-gel resolution of dynamic molecular/supramolecular libraries leads to higher self-organized constitutional hybrid materials, in which organic (supramolecular)/inorganic domains are reversibily connected. PMID- 21710379 TI - Automated projection spectroscopy and its applications. AB - This chapter presents the NMR technique APSY (automated projection spectroscopy) and its applications for sequence-specific resonance assignments of proteins. The result of an APSY experiment is a list of chemical shift correlations for an N dimensional NMR spectrum (N>=3). This list is obtained in a fully automated way by the dedicated algorithm GAPRO (geometric analysis of projections) from a geometric analysis of experimentally recorded, low-dimensional projections. Because the positions of corresponding peaks in multiple projections are correlated, thermal noise and other uncorrelated artifacts are efficiently suppressed. We describe the theoretical background of the APSY method and discuss technical aspects that guide its optimal use. Further, applications of APSY-NMR spectroscopy for fully automated sequence-specific backbone and side chain assignments of proteins are described. We discuss the choice of suitable experiments for this purpose and show several examples. APSY is of particular interest for the assignment of soluble unfolded proteins, which is a time consuming task by conventional means. With this class of proteins, APSY-NMR experiments with up to seven dimensions have been recorded. Sequence-specific assignments of protein side chains in turn are obtained from a 5D TOCSY-APSY-NMR experiment. PMID- 21710380 TI - Fragment-based approaches and computer-aided drug discovery. AB - Fragment-based design has significantly modified drug discovery strategies and paradigms in the last decade. Besides technological advances and novel therapeutic avenues, one of the most significant changes brought by this new discipline has occurred in the minds of drug designers. Fragment-based approaches have markedly impacted rational computer-aided design both in method development and in applications. The present review illustrates the importance of molecular fragments in many aspects of rational ligand design, and discusses how thinking in "fragment space" has boosted computational biology and chemistry. PMID- 21710381 TI - Tunneling spectroscopy of organic monolayers and single molecules. AB - Basic concepts in tunneling spectroscopy applied to molecular systems are presented. Junctions of the form M-A-M, M-I-A-M, and M-I-A-I'-M, where A is an active molecular layer, are considered. Inelastic electron tunneling spectroscopy (IETS) is found to be readily applied to all the above device types. It can provide both vibrational and electron spectroscopic data about the molecules comprising the A layer. In IETS there are no strong selection rules (although there are preferences) so that transitions that are normally IR, Raman, or even photon-forbidden can be observed. In the electronic transition domain, spin and Laporte forbidden transitions may be observed. Both vibrational and electronic IETS can be acquired from single molecules. The negative aspect of this seemingly ideal spectroscopic method is the thermal line width of about 5 k(B)T. This limits the useful measurement of vibrational IETS to temperatures below about 10 K. In the case of most electronic transitions where the intrinsic linewidth is much broader, useful experiments above 100 K are possible. One further limitation of electronic IETS is that it is generally limited to transitions with energy less than about 20,000 cm(-1). IETS can be identified by peaks in d(2) I/dV (2) vs bias voltage plots that occur at the same position (but not necessarily same intensity) in either bias polarity.Elastic tunneling spectroscopy is discussed in the context of processes involving molecular ionization and electron affinity states, a technique we call orbital mediated tunneling spectroscopy, or OMTS. OMTS can be applied readily to M-I-A-M and M-I-A-I'-M systems, but application to M-A-M junctions is problematic. Spectra can be obtained from single molecules. Ionization state results correlate well with UPS spectra obtained from the same systems in the same environment. Both ionization and affinity levels measured by OMTS can usually be correlated with one electron oxidation and reduction potentials for the molecular species in solution. OMTS can be identified by peaks in dI/dV vs bias voltage plots that do not occur at the same position in either bias polarity. Because of the intrinsic width of the ionization and affinity transitions, OMTS can be applied at temperatures above 500 K.This is not a comprehensive review of more than 20 years of research and there are many excellent papers that are not cited here. An absence of a citation is not a reflection on the quality of the work. PMID- 21710382 TI - The long journey: actin on the road to pro- and eukaryotic cells. AB - Actin-like proteins comprise a large group of polymorphic proteins that readily form filaments engaged in cytoskeletal functions. Various members have been identified in prokaryotic and eukaryotic cells, e.g. MreB, ParM and Ta0583, and actin and the actin-related proteins, ARPs, respectively. Therefore, it is assumed that an ancestor of actin/MreB/ParM already existed in the last common progenitor of all cells. In eubacteria and archaea, actin-like proteins are either membrane-associated or freely soluble, and their activities are related to motility, cell shape maintenance, subcellular organization and cell cycle progression. In eukaryotes, all these functions are executed by actin in various isoforms. Additional functions have been described for actin and ARPs in the nucleus of the eukaryotic cell, and some of those were also discovered in prokaryotes. In the current essay, we compare structures and selected functions of prokaryotic and eukaryotic actins and discuss various aspects on how actins may have found their way into bacteria, into the eukaryotic cytoplasm and into the nuclear compartment. PMID- 21710384 TI - The clivus: anatomy, normal variants and imaging pathology. AB - The clivus is one of the most central parts of the skull base. As diseases of the clivus evade clinical evaluation imaging plays a pivotal role in establishing a diagnosis. This article combines the description of anatomy and pathology with an extensive pictorial essay. Starting with the development and normal macroscopic anatomy of the clivus the reader is then introduced to a large variety of normal variations and developmental disorders some of them with clinical significance. Typical examples of non-neoplastic and neoplastic masses of the clivus and their differential diagnoses are provided. The article concludes with a review of inflammatory disease and trauma. PMID- 21710385 TI - Does habitat fragmentation cause stress in the agile antechinus? A haematological approach. AB - Although the vertebrate stress response is essential for survival, frequent or prolonged stress responses can result in chronic physiological stress, which is associated with a suite of conditions that can impair survivorship and reproductive output. Anthropogenic habitat fragmentation and degradation are potential stressors of free-living vertebrates, and in theory could result in chronic stress. To address this issue, we compared haematological indicators of stress and condition in agile antechinus (Antechinus agilis) populations in 30 forest fragments and 30 undisturbed, continuous forest sites (pseudofragments) in south-eastern Australia over 2 years. In peripheral blood, the total leucocyte count was lower and the neutrophil/lymphocyte ratio and percentage of eosinophils in the total leucocyte population was higher in fragment than pseudofragment populations, indicating that fragment populations were probably experiencing higher levels of stress hormone-mediated and/or parasite infection-related chronic physiological stress. The total erythrocyte count and haematocrit were higher and mean erythrocyte haemoglobin content was lower in fragment than pseudofragment populations. This suggests that fragment populations showed possible signs of regenerative anaemia, a syndrome associated with elevated hypothalamus-pituitary-adrenal axis mediated stress. However, mean erythrocyte volume was also lower in fragments, and red blood cell distribution width did not differ between the study populations, findings which were not consistent with this diagnosis. Whole blood and mean cell haemoglobin concentrations were similar in fragment and pseudofragment populations. We suggest that where anthropogenic activity results in habitat fragmentation and degradation, chronic stress could contribute to a decline in agile antechinus populations. The broader implication is that chronic stress could be both symptomatic of, and contributing to, decline of some vertebrate populations in anthropogenically fragmented and degraded habitats. PMID- 21710387 TI - ESPR uroradiology task force and ESUR paediatric working group: imaging recommendations in paediatric uroradiology, part IV: Minutes of the ESPR uroradiology task force mini-symposium on imaging in childhood renal hypertension and imaging of renal trauma in children. AB - Two new recommendations of the European Society of Radiology task force and the European Society of Uroradiology workgroup on paediatric uroradiology are presented. One deals with diagnostic imaging in children after trauma to the urinary tract-renal trauma, in particular. The other concerns the evaluation of suspected renal hypertension. Available data in the paediatric literature are either unsatisfactory or controversial for both of these clinical settings. Therefore, the following consensus-based proposals aim at outlining effective imaging algorithms to reduce invasive imaging procedures while optimising diagnostic accuracy. The objective of following a more uniform imaging approach is to facilitate future meta-analysis as well as multicentre and other more evidence-based studies. The practise in paediatric radiology is typically based on local availability and on the limitations of professional expertise and equipment, balanced against the perceived needs of the individual child. Although this is unlikely to change in the near future, it does not release the physicians in charge of diagnostic imaging from their responsibility in choosing and providing state-of-the-art imaging and management protocols that are adapted specifically for use in children. PMID- 21710389 TI - Stepped approach for prediction of syndrome Z in patients attending sleep clinic: a north Indian hospital-based study. AB - PURPOSE: Syndrome Z is the occurrence of metabolic syndrome (MS) with obstructive sleep apnea. Knowledge of its risk factors is useful to screen patients requiring further evaluation for syndrome Z. METHODS: Consecutive patients referred from sleep clinic undergoing polysomnography in the Sleep Laboratory of AIIMS Hospital, New Delhi were screened between June 2008 and May 2010, and 227 patients were recruited. Anthropometry, body composition analysis, blood pressure, fasting blood sugar, and lipid profile were measured. MS was defined using the National Cholesterol Education Program (adult treatment panel III) criteria, with Asian cutoff values for abdominal obesity. RESULTS: Prevalence of MS and syndrome Z was 74% and 65%, respectively. Age, percent body fat, excessive daytime sleepiness (EDS), and DeltaSaO(2) (defined as difference between baseline and minimum SaO(2) during polysomnography) were independently associated with syndrome Z. Using a cutoff of 15% for level of desaturation, the stepped predictive score using these risk factors had sensitivity, specificity, positive predictive value, and negative predictive value of 75%, 73%, 84%, and 61%, respectively for the diagnosis of syndrome Z. It correctly characterized presence of syndrome Z 75% of the time and obviated need for detailed evaluation in 42% of the screened subjects. CONCLUSIONS: A large proportion of patients presenting to sleep clinics have MS and syndrome Z. Age, percent body fat, EDS, and DeltaSaO(2) are independent risk factors for syndrome Z. A stepped predictive score using these parameters is cost-effective and useful in diagnosing syndrome Z in resource-limited settings. PMID- 21710390 TI - In tribute to Corwin Hansch, father of QSAR. PMID- 21710392 TI - Daniel B. Hardy, Ph.D. PMID- 21710393 TI - The developmental origins of health and disease: today's perspectives and tomorrow's challenges. PMID- 21710394 TI - Developmental origin of reproductive and metabolic dysfunctions: androgenic versus estrogenic reprogramming. AB - Polycystic ovary syndrome (PCOS) is one of the most common fertility disorders, affecting several million women worldwide. Women with PCOS manifest neuroendocrine, ovarian, and metabolic defects. A large number of animal models have evolved to understand the etiology of PCOS. These models provide support for the contributing role of excess steroids during development in programming the PCOS phenotype. However, considerable phenotypic variability is evident across animal models, depending on the quality of the steroid administered and the perinatal time of treatment relative to the developmental trajectory of the fetus/offspring. This review focuses on the reproductive and metabolic phenotypes of the various PCOS animal models that have evolved in the last decade to delineate the relative roles of androgens and estrogens in relation to the timing of exposure in programming the various dysfunctions that are part and parcel of the PCOS phenotype. Furthermore, the review addresses the contributory role of the postnatal metabolic environment in exaggerating the severity of the phenotype, the translational relevance of the various animal models to PCOS, and areas for future research. PMID- 21710395 TI - Placental dysfunction and fetal programming: the importance of placental size, shape, histopathology, and molecular composition. AB - Normal function of the placenta is pivotal for optimal fetal growth and development. Fetal programming commonly is associated with placental dysfunction that predisposes to obstetric complications and suboptimal fetal outcomes. We consider several clinical phenotypes for placental dysfunction that likely predispose to fetal programming. Some of these reflect abnormal development of the chorioallantoic placenta in size, shape, or histopathology. Others result when exogenous stressors in the maternal environment combine with maladaptation of the placental response to yield small placentas with limited reserve, as typical of early-onset intrauterine growth restriction and preeclampsia. Still others reflect epigenetic changes, including altered expression of imprinted genes, altered enzymatic activity, or altered efficiencies in nutrient transport. Although the human placenta is a transient organ that persists only 9 months, the effects of this organ on the offspring remain for a lifetime. PMID- 21710396 TI - The early origins of cardiovascular health and disease: who, when, and how. AB - Almost 30 years ago, a series of epidemiological studies popularized the early programming theory that had resulted from observed associations between low birthweight and increased cardiovascular morbidity and mortality later in life. Since then, several clinical and experimental models have been created to understand the principles and mechanisms of this fascinating phenomenon and describe its relevance to the pathophysiology of cardiovascular and many other chronic diseases. Despite the growing body of published evidence, the specific mechanisms mediating early programming effects are still elusive. Moreover, many controversial issues have arisen regarding the characteristics of the most commonly used clinical and experimental models, the existence of potential windows of susceptibility for different organs, and the presence of sex differences in its pathophysiology. Therefore, this review synthesizes some of the antecedents behind the early programming theory and discusses some of the controversial issues surrounding it. Early programming has been extensively linked to several chronic diseases; however, for the purposes of this review we have concentrated on the potential role of this entity in the pathophysiology of chronic cardiovascular diseases. PMID- 21710397 TI - In utero origins of adult insulin resistance and vascular dysfunction. AB - The metabolic syndrome (or syndrome X) is a constellation of risk factors including insulin resistance, hypertension, dyslipidemia, and central obesity that predispose to the development of cardiovascular disease and type 2 diabetes in adult life. Insulin resistance is believed to be a critical pathophysiological event early in the disease process, impacting both skeletal muscle metabolic function and vascular responses. Adverse changes in insulin sensitivity have been found to originate in utero; for instance, prenatal events such as placental insufficiency/oxidative stress leading to altered fetal growth trajectories are associated with increased rates of metabolic syndrome in adult life. Such intrauterine insults result in reduced skeletal muscle mass in conjunction with altered insulin signaling, decreased oxidative fibers, and impaired mitochondrial function. These developmental disturbances set the stage for development of muscle triglyceride accumulation and depressed insulin sensitivity in childhood. Abnormalities of vascular structure and function arising from deprived intrauterine conditions that are exacerbated by insulin resistance account for the progression of hypertension from childhood to adulthood. Arterial changes initiated in utero include reduced endothelial nitric oxide (NO) bioavailability, vascular smooth muscle cell proliferation and inflammation, events leading to endothelial dysfunction, and atherosclerosis that are present in those destined for metabolic syndrome. In addition, the hypertensive phenotype that is a hallmark of metabolic syndrome may also be traced to blunted kidney development and renin-angiotensin system activation in growth-restricted offspring. The summative impact of these intrauterine programmed changes in terms of influencing adult health and disease encompasses dietary and lifestyle factors introduced postnatally. Establishing novel therapeutic interventions aimed at preventing and/or reducing in utero-induced insulin resistance and vascular dysfunction warrants investigation because the numbers of low birthweight babies continue to increase. PMID- 21710400 TI - Permanent implications of intrauterine growth restriction on cholesterol homeostasis. AB - Susceptibility to disease begins during fetal life, and adverse events in utero are a critical factor in determining quality of life and overall health. In fact, up to 50% of metabolic syndrome diseases can be attributed to an adverse in utero environment. However, the mechanisms linking impaired fetal development to augmented cholesterol, an important clinical risk factor characterizing the metabolic syndrome and cardiovascular disease, remain elusive. This review discusses the latest research in the fetal programming of cholesterol homeostasis from both clinical studies and animal models. It also underscores the role of the placenta as an important mediator in cholesterol homeostasis during pregnancy and uncovers some of the molecular mechanisms underlying how the homeostatic mechanisms in liver may be impaired in fetal and postnatal life due to undernutrition and/or hypoxia. PMID- 21710398 TI - The intrauterine growth restriction phenotype: fetal adaptations and potential implications for later life insulin resistance and diabetes. AB - The intrauterine growth restricted (IUGR) fetus develops unique metabolic adaptations in response to exposure to reduced nutrient supply. These adaptations provide survival value for the fetus by enhancing the capacity of the fetus to take up and use nutrients, thereby reducing the need for nutrient supply. Each organ and tissue in the fetus adapts differently, with the brain showing the greatest capacity for maintaining nutrient supply and growth. Such adaptations, if persistent, also have the potential in later life to promote nutrient uptake and storage, which directly lead to complications of obesity, insulin resistance, reduced insulin production, and type 2 diabetes. PMID- 21710401 TI - Schizophrenia trial participation: perceived inclusion barriers and beliefs about antipsychotics. AB - BACKGROUND: Patient recruitment is the universal rate-limiting factor for randomized controlled trials (RCTs) in all medical specialties. This study examined the opinions on perceived inclusion barriers and beliefs about antipsychotics of a group of psychiatrists participating in a pragmatic RCT on antipsychotic drugs in schizophrenia (the GiSAS trial). METHODS: A survey of all clinicians working in the trial recruiting centers was performed exploring factors associated to the respondents' opinions. RESULTS: Of 465 clinicians, 278 (59.8%) responded to the questionnaire. Respondents (n=278) were mainly influenced by clinical and trial-related barriers (89%). Factors such as work setting and antipsychotic prescription choices appeared to be related to perceived inclusion barriers. Most respondents believed in the superiority of SGAs (62.9%), one-third indicating drug company representatives as the most important source of information; this was related to further optimism towards SGAs. CONCLUSIONS: Respondents were affected mainly by system-related barriers, whereas personal barriers were given less weight. The influence of industry mediated information could have affected opinions on SGAs and the lack of uncertainty about antipsychotics attitudes towards trial participation. PMID- 21710399 TI - Fetal programming of adipose tissue: effects of intrauterine growth restriction and maternal obesity/high-fat diet. AB - A newly recognized primary cause of obesity epidemic is the developmental programming effects of (1) intrauterine growth-restricted (IUGR) newborns exposed in utero to undernutrition, and (2) normal or excessive weight newborns exposed to maternal obesity and high-fat (HF) diets. The mechanisms contributing to offspring obesity have been extensively studied in animal models with adipose tissue identified as one of the principal targets of programming. IUGR and HF offspring exhibit programmed adipocytes, such that an intrinsic enhanced lipogenesis and adipocyte proliferation contribute to the development of obesity. This is attributed to early induction of adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR)gamma, whose activity is enhanced under limited or excess nutrient availability. Nonetheless, this occurs via different mechanisms involving PPARgamma coregulators: In IUGR, it is upregulation of coactivators, whereas in HF newborns, it is downregulation of corepressors. Thus preventive therapeutic interventions will require target specific modalities that depend on the primary etiology. PMID- 21710402 TI - Psychological and neuroendocrine responses to social stress and to the administration of the alpha-2-receptor antagonist, yohimbine, in highly trained endurance athletes in comparison to untrained healthy controls. AB - INTRODUCTION: Several clinical studies suggest antidepressive and anxiolytic effects of regular endurance training. The mechanisms by which exercise exerts these effects are still unclear. It was hypothesized that athletes might show a diminished reaction to psychosocial stress and noradrenergic stimulation. METHODS: 12 male athletes and 12 healthy untrained male controls underwent a challenge paradigm on 3 separate days: the alpha-2-receptor antagonist yohimbine (0.4 mg/kg), placebo or a psychosocial stress test (SST) were administered. Responses were measured by psychometric scales, plasma cortisol, blood pressure and heart rate. RESULTS: Before testing, psychometric variables and cortisol levels were not different between the 2 groups. In comparison to placebo conditions, both the social stress test and the administration of yohimbine were followed by significant increases of anxiety symptoms, plasma cortisol, heart rate and blood pressure in both groups. However, these responses were not significantly different between the group of athletes and the control group. DISCUSSION: These results do not support the hypotheses that high aerobic fitness is associated with attenuated psychological and neuroendocrine responses to yohimbine or to psychosocial stress. PMID- 21710403 TI - Weight changes and their associations with demographic and clinical characteristics in risperidone maintenance treatment for schizophrenia. AB - OBJECTIVE: This study aimed to characterize weight changes in schizophrenia patients taking risperidone as part of a randomized, controlled, open-label clinical trial. METHODS: A total of 374 patients with schizophrenia who had been clinically stabilized following an acute episode were randomly assigned to a 'no dose-reduction' group (initial optimal therapeutic doses continued throughout the study), a '4-week group' (initial optimal therapeutic doses continued for 4 weeks followed by a half dose reduction that was maintained until the end of the study) or a '26-week group' (initial optimal therapeutic doses continued for 26 weeks followed by a half dose reduction until the end of the study). Participants were assessed monthly using standardized assessment instruments during the first 6 months, and then every 2 months until the last recruited patient completed the 1 year follow-up. Weight gain was defined as gaining at least 7% of initial body weight, weight loss as losing at least 7% of initial body weight. A BMI <18.5 kg m-2 was defined as underweight, 18.5-24.9 kg m-2 as normal range, and >= 25 kg m 2 as overweight or obese. RESULTS: At the end of follow-up, of the patients who started within the underweight range (n=22), 77.3% gained weight, whereas 4.5% lost weight. The corresponding figures were 39.6% and 4.8% in patients who started at normal weight (n=273), respectively, and 17.7% and 17.7% in patients who started at overweight (n=79), respectively. At the same time, 59.1% of the patients who started at underweight range went into the normal weight and 13.6% into the overweight/obese range, respectively, while 24.5% of those who started at normal weight went into the overweight/obese range, and 1.1% into underweight range, respectively; 20.3% of those who started at overweight range went into normal weight at the end of the follow-up. Multiple logistic regression analyses revealed that being underweight or normal weight at study entry predicted weight gain compared to being overweight, whereas being overweight at entry was associated with a higher likelihood of weight loss compared to being normal weight. No correlation was found between weight change and dose reduction. CONCLUSIONS: Weight change is a common, long-term, but heterogeneous side effect in risperidone maintenance treatment for stable schizophrenia patients. Special attention should be paid to fluctuations in weight that may occur throughout the course of treatment with risperidone. PMID- 21710404 TI - Augmentation treatment with amisulpride in schizophrenic patients partially responsive to olanzapine. AB - OBJECTIVE: The association of antipsychotics is a widespread therapeutic resource in clinical practice. The purpose of the present work was to evaluate the efficacy and safety of amisulpride augmentation in patients responding at least partially to olanzapine. METHODS: In this observational 3-months open-label investigation, we evaluated the effectiveness of the addition of amisulpride to 49 subjects, after having scored at least 25 on the brief psychiatric rating scale (BPRS) following olanzapine monotherapy for 6 weeks. Patients were assessed at baseline, 1 and 3 months using the BPRS, the clinical global impression severity of illness (CGI-S) scale and the Udvalg for Kliniske Undersogelser side effect rating scale (UKU). RESULTS: In subjects who were at least partially responsive to monotherapy with olanzapine, coadjuvant treatment with amisulpride achieved a statistically significant improvement in mental status over a 3 month period as measured by the BPRS, CGI and UKU scales. The response rate (>20% reduction in BPRS score) was 75.51%. CONCLUSIONS: Amisulpride augmentation, in a group of patients partially or non-responsive to olanzapine, may lead to an improvement in schizophrenic symptoms. However, these results are subject to several limitations making it difficult to derive firm clinical recommendations, and underscoring the need for future research into the value of these therapeutic alternatives in poor responders. PMID- 21710406 TI - Probable interaction between trazodone and carbamazepine. AB - The need to maintain long-term treatment of chronic pathologies makes the appearance of interactions possible when such therapies incorporate other drugs to deal with the aggravation of the same or other intercurrent pathologies. A case is presented in which the addition of trazodone to a chronic treatment with carbamazepine (CBZ) is associated with symptoms typical for intoxication by this antiepileptic, accompanied by a raised serum concentration. When the trazodone was suspended, these symptoms lessened and the concentration of CBZ decreased progressively, suggesting a probable interaction between the 2 drugs. PMID- 21710405 TI - Proton magnetic resonance spectroscopy study of brain metabolite changes after antipsychotic treatment. AB - INTRODUCTION: Proton magnetic resonance spectroscopy (1H MRS) enables the observation of brain function in vivo. The aim of our study was to evaluate the effects of antipsychotic medication on metabolite levels in the brain of schizophrenic patients based on a 1H MRS examination. METHODS: We examined 42 patients previously diagnosed with chronic schizophrenia twice: firstly, after the neuroleptic wash-out (baseline) and secondly, under stable medication (follow up, after treatment). The study had a naturalistic design and several different neuroleptic medications were used during the treatment phase. The clinical evaluation, MRI and MRS procedures were performed. The group of 26 healthy controls were also examined to compare MRS results. RESULTS: We found a significantly lower NAA/Cr (N-acetylaspartate/creatine) ratio in the frontal lobe and thalamus in patients (after the wash-out) as compared to controls. After treatment a significant decrease of the Glx/Cr ratio in the temporal lobe and a trend for an increase of the NAA/Cr ratio in the thalamus were observed. CONCLUSION: Our results confirm that antipsychotic medication modifies brain metabolism measured by means of 1H MRS. The pattern of the changes suggests a neuroprotective action of antipsychotic medication in schizophrenia. PMID- 21710407 TI - Influence of the 393T>C polymorphism of the GNAS1 gene on the intensity of opiate withdrawal. AB - There are high interindividual differences regarding the intensity of withdrawal symptoms. in opiate addicts. This study was carried out in order to test whether the intensity of withdrawal is influenced by the 393T>C polymorphism of the GNASI gene. Only patients addicted exclusively to opiates were included. Thirty-three out of 39 patients undergoing inpatient detoxification treatment achieved a drug free state. During the most intense period of withdrawal (stop of methadone and following days) TT homozygotes (n=4) had a significantly higher pulse rate (primary outcome criterion) than C-allele carriers (n=29). This study and a previous study about GNB3 825C> T underline the possible role of G-protein polymorphisms in the interindividual variability of opiate withdrawal. PMID- 21710408 TI - Increased brain membrane fluidity in schizophrenia. AB - Recent findings showing significant correlations between phospholipase A2 (PLA2) activity and structural changes in schizophrenic brains contribute to the membrane hypothesis of schizophrenia, which was hampered because a clean functional link between elevated PLA2 activity and brain structure was missing (Neuroimage, 2010; 52: 1314-1327). We measured membrane fluidity parameters and found that brain membranes isolated from the prefrontal cortex of schizophrenic patients showed significantly increased flexibility of fatty acid chains. Our findings support a possible link between elevated PLA2 activity in cortical areas of schizophrenic patients and subsequent alterations of the biophysical parameters of neuronal membranes leading to structural changes in these areas. PMID- 21710410 TI - An international, multidisciplinary, service-learning program: an option in the dental school curriculum. AB - INTRODUCTION: Many health professions students who treat Spanish-speaking patients in the United States have little concept of their culture and health related traditions. The lack of understanding of these concepts may constitute major barriers to healthcare for these patients. International service-learning experiences allow students to work directly in communities from which patients immigrate and, as a result, students gain a better understanding of these barriers. OBJECTIVE: This article describes the implementation of an international, multidisciplinary, service-learning program in a dental school in the United States. PROGRAM DESCRIPTION: The Indiana University International Service-Learning program in Hidalgo, Mexico began in 1999 as an alternative spring break travel and clinical experience for medical students, focusing on the treatment of acute health problems. Travel-related preparatory sessions were offered, and no learning or service objectives had been developed. The program has evolved to include a multidisciplinary team of dental, medical, nursing, public health and social work students and faculty. The experience is now integrated into a curriculum based on the service-learning model that allows students to use their clinical skills in real-life situations and provides structured time for reflection. The program aims to enhance teaching and foster civic responsibility in explicit partnership with the community. Preparatory sessions have evolved into a multidisciplinary graduate level course with defined learning and service objectives. PROGRAM EVALUATION METHODS: In order to assess the program's operation as perceived by students and faculty and to evaluate student's perceptions of learning outcomes, evaluation tools were developed. These tools included student and faculty evaluation questionnaires, experiential learning journals, and a strengths, weaknesses, opportunities and threats analysis. FINDINGS: Evaluation data show that after program participation, students perceived an increase in their cultural awareness, cross-cultural communication skills and understanding of barriers and disparities faced by Latinos in the United States. Faculty evaluations offer insights into the lessons learned through the implementation process. CONCLUSION: The development of a service-learning based curriculum has posed challenges but has enriched international service experiences. PMID- 21710411 TI - Interprofessional communication of prognosis: teaching to bridge the gaps. AB - CONTEXT AND OBJECTIVES: The communication of patient prognosis is an essential component of modern healthcare. Previous research has focussed on clinician-to patient communication only, while the interaction between different professionals in a clinical setting remains relatively unexplored. The research reported here investigated how multidisciplinary clinicians (nursing, medicine and allied health) communicated prognosis information in these professional groups in an acute care setting. METHODS: A case series method was utilised with a sample of patients with haematological malignancies in an acute haematology ward in a metropolitan city of Australia. Data were provided by clinician interviews (nursing, medical and allied health) and patient notes. The data were examined in three individual case studies, which were then collectively analysed as an overarching case series. RESULTS: Thematic analysis of the case series resulted in three major findings for the study. The second finding that 'Clinicians are unprepared to discuss prognosis' was the focus of this paper. Identified barriers to prognosis communication were role delineations and a lack of shared values between disciplines. The state of unpreparedness has serious implications for how members of the staffing groups interact with patients and their families. CONCLUSION: Overall, the findings offer support for the need for educational strategies to prepare pre-service health students (future clinicians) to discuss prognosis in clinical settings. Medical, nursing and allied health clinicians tend to discuss prognosis from either a psychosocial or scientific viewpoint. Pre service health students may benefit from increased communication and teamwork skills, familiarity with framing devices to understand and discuss prognosis and increased understanding of the roles and values of other health professions, in order to bridge communication gaps. PMID- 21710412 TI - General population and medical student perceptions of good and bad doctors in Mozambique. AB - CONTEXT: A key element of the doctor-patient relationship is to understand the patient's and doctor's perceptions of quality care. OBJECTIVES: To assess the perceptions of good and bad doctors among first-year medical students and local community members in a semi-urban, African settings. METHODS: Using open-ended and closed dichotomous questions, 115 first-year medical students in Beira, Mozambique were surveyed regarding their perceptions of a 'good' and 'bad' doctor. Students then surveyed 611 community members in a predominately poor, semi-urban neighbourhood. RESULTS: Answers to open-ended questions provided by both groups produced the same four most important positive characteristics, with good diagnostic and therapeutic skills and dedication ranked highest. Closed ended questions revealed that local community members felt that being concerned/considerate and diagnosing well were equally important (19.5% and 17.5%, respectively) compared to students (17.5% and 41.2%, respectively). The most important negative characteristics to the open-ended question for both groups were discrimination and contemptuous behaviour: 29.3% for community members and 27.4% for medical students. The biggest difference between groups was poor attending skills: 17.3% by community members and 3.9% by medical students. CONCLUSION: This study highlights differences and similarities between the perceptions of medical students and community members concerning a 'good' and a 'bad' doctor. Our data suggest that perceptions are guided by the experiences and values of those interviewed. Results indicate that medical education in developing countries should focus on patient-centered care, including communication skills and attitudes, besides training knowledgeable doctors. PMID- 21710413 TI - Developing culturally-oriented strategies for communicating women's health issues: a church-based intervention. AB - CONTEXT: In developing countries, messages on maternal health are often developed and conveyed without due regard to the literacy and cultural context of communities. Culturally-acceptable approaches are, however, necessary to increase awareness on womens health issues, especially in cultures where oral tradition is important. OBJECTIVE: To describe the processes adopted to engage church-based women support groups to develop innovative culturally-based strategies for communicating womens health matters. METHODS: We utilized an activity-oriented workgroup discussion methodology to engage 30 participants from 15 churches (two per church) in a two-day workshop located in an urban community in southeast Nigeria. The recruitment process included initial visits to 25 churches with an expression of interest form, followed by an invitation letter to the 15 churches that completed and returned the form. Participants were female church leaders, 26 years of age and older, from different occupations and educational levels. They attended a 16-hour (two-day) small group workshop, conducted in an adult-learning format. RESULTS: Six groups of five participants each used the Women and Health Learning Package (WHLP) to create and develop a dialogue on adolescent health, a drama on violence against women, a song on nutrition and womens health, a story on use of medicines by women, a quiz on cervical cancer and a poster on family planning. Thirteen of the 15 churches submitted a written report of the workshop to their local churches one month after the workshop as well as a copy to the workshop facilitator. Of the 13 churches, three organized a workshop to increase awareness on women s health issues in their local churches within three months of the workshop. CONCLUSION: Activity-oriented workshops can be a useful way of developing culturally- appropriate communication strategies for increasing awareness on womens health issues among church-based women groups. PMID- 21710414 TI - Canadian and Australian licensing policies for international medical graduates: a web-based comparison. AB - CONTEXT: The increasing global mobility of physicians and severe physician shortages of many countries has led to an increasing reliance on International Medical Graduates (IMGs) by countries including Australia and Canada. OBJECTIVES: A web-based comparison of licensing policies for IMGs in Australia and Canada to inform and improve policies in each country. METHODS: The research involved identification of relevant government and medical regulatory bodies' official websites documenting information on the licensing process for IMGs from each respective country; in-depth examination and comparison of the licensing processes outlined on these sites; and compilation of a comprehensive list of similarities and differences. FINDINGS: While difficult entry requirements are imposed in Canada, once full registration is achieved IMGs have the same membership rights as Canadian medical graduates and their separate status (nominally) ends. In Australia, IMGs are allowed relatively easy access to temporary or conditional licenses, especially in designated underserviced areas or areas of need in order to fulfil resource demands. However IMGs are predominantly restricted to practise in limited and less prestigious positions within the medical hierarchy. DISCUSSION: The Canadian process for recertifying IMGs can be characterized as being based on the integration/assimilation of IMGs with domestically trained doctors. In contrast, Australia has pursued a different strategy of parallelism of its IMGs. CONCLUSIONS: The findings provide insights into how each country balances national licensing requirements with physician shortages in a globalized environment in order to provide healthcare for its citizens. PMID- 21710415 TI - Photo-elicitation as a Public Health Teaching and Learning Tool. PMID- 21710416 TI - "I'm worried about what I missed": GP registrars' views on learning needs to deliver effective healthcare to ethnically and culturally diverse patient populations. AB - INTRODUCTION: It is widely accepted that medical undergraduate and postgraduate education should address issues related to human diversity. Despite the growth of guidelines and training resources, little is known about primary healthcare professionals' perceptions about their work with patients from diverse communities. OBJECTIVE: This research explored GP Registrars' views of their learning needs in relation to delivering effective healthcare to ethnically and culturally diverse patient populations. METHODS: The study was based on a naturalistic inquiry design, involving qualitative methods. Current GP Registrars of the postgraduate GP Western Training Programme, Galway, Ireland, were invited to participate in focus groups. Three different focus groups were conducted with a total of 31 GP Registrar participants. A thematic analysis following the principles of framework analysis was applied. RESULTS: GP Registrars reported considerable professional uncertainty and occupational stress when consulting with patients from diverse communities. They perceived their training in relation to healthcare for patients from diverse backgrounds as inadequate and desired more training. They identified concrete learning needs, which were mainly related to factual knowledge, with less emphasis on communication skills and attitude awareness. CONCLUSIONS: Educators should take GP Registrars' views into account in the development of diversity training in medical education. GP Registrars' attention to specific knowledge related to human diversity may, nonetheless, be too narrow. This training should also encourage acknowledgment of the doctor's professional uncertainty, awareness of the doctor's own attitudes, and development of generic skills such as a patient-centred approach to best meet the needs of diverse population groups. PMID- 21710417 TI - Bringing explicit insight into cognitive psychology features during clinical reasoning seminars: a prospective, controlled study. AB - CONTEXT: Facets of reasoning competence influenced by an explicit insight into cognitive psychology features during clinical reasoning seminars have not been specifically explored. OBJECTIVE: This prospective, controlled study, conducted at the University of Geneva Faculty of Medicine, Switzerland, assessed the impact on sixth-year medical students' patient work-up of case-based reasoning seminars, bringing them explicit insight into cognitive aspects of their reasoning. METHODS: Volunteer students registered for our three-month Internal Medicine elective were assigned to one of two training conditions: standard (control) or modified (intervention) case-based reasoning seminars. These seminars start with the patient's presenting complaint and the students must ask the tutor for additional clinical information to progress through case resolution. For this intervention, the tutors made each step explicit to students and encouraged self reflection on their reasoning processes. At the end of their elective, students' performances were assessed through encounters with two standardized patients and chart write-ups. FINDINGS: Twenty-nine students participated, providing a total of 58 encounters. The overall differences in accuracy of the final diagnosis given to the patient at the end of the encounter (control 63% vs intervention 74%, p = 0.53) and of the final diagnosis mentioned in the patient chart (61% vs 70%, p = 0.58) were not statistically significant. The students in the intervention group significantly more often listed the correct diagnosis among the differential diagnoses in their charts (75% vs 97%, p = 0.02). CONCLUSION: This case-based clinical reasoning seminar intervention, designed to bring students insight into cognitive features of their reasoning, improved aspects of diagnostic competence. PMID- 21710418 TI - Validation of the Catalan version of the communication skills attitude scale (CSAS) in a cohort of south European medical and nursing students. AB - CONTEXT: The relevance of healthcare student training in communication skills has led to the development of instruments for measuring attitudes towards learning communication skills. One such instrument is the Communication Skills Attitude Scale (CSAS), developed in English speaking students and adapted to different languages and cultures. No data is available on the performance of CSAS with South European students. The aims of the present study were to translate the CSAS into the Catalan language and study its psychometric properties in South European healthcare students. METHODS: A total of 569 students from the School of Medicine of the Universitat Autonoma de Barcelona (UAB) participated. Students completed a Catalan version of the CSAS and provided demographic and education information. FINDINGS: Principal component analysis with oblimin rotation supported a two factor original structure with some modifications. In general, internal consistency and test-retest reliability of the scales were satisfactory, especially for the factor measuring positive attitudes. Relationships of student responses on the two factors with demographic and education variables were consistent with previous work. Students with higher positive attitudes tended to be female, to be foreign students and to think that their communication skills needed improving. Students with higher negative attitudes tended to be male and to have parents that were doctors or nurses. CONCLUSIONS: These data support the internal validity of a Catalan version of the CSAS and support its use in future research and educational studies related to attitudes towards learning communication skills for South European students who speak Catalan. PMID- 21710420 TI - "Everyone's dressed the same": pre-clerkship medical students learn who's who on the healthcare team. PMID- 21710419 TI - Human trafficking: an evaluation of Canadian medical students' awareness and attitudes. AB - CONTEXT: Human trafficking is a human rights violation prevalent globally. Current guidelines highlight healthcare professionals' key role in responding to human trafficking, emphasizing the importance of medical education in raising awareness of trafficking. OBJECTIVE: To assess pre-clerkship medical students' awareness of human trafficking and attitudes towards learning about trafficking in the medical curriculum at Canada's largest medical school. METHODS: An anonymous, classroom-based questionnaire was designed, piloted and administered to first- and second-year medical students at one large Canadian medical school with a diverse student population. The questionnaire sought demographic data and information on students' self-perceived awareness of human trafficking and interest in learning about trafficking and other community health issues. RESULTS: 262 medical students completed the questionnaire (70.0% response). Most participants reported that they were not knowledgeable (48.5%) or only somewhat knowledgeable (45.4%) about human trafficking. 88.9% of participants were not familiar with signs and symptoms of trafficked persons. While students' responses indicated that they prioritized other social issues, a majority of participants (76.0%) thought that trafficking was important to learn about in medical school, especially identifying trafficked persons and their health needs. CONCLUSIONS: These medical students of one Canadian medical school demonstrated limited familiarity with the issue of human trafficking but largely felt that they should be taught more about this issue during their medical education. This assessment of early medical students' awareness of human trafficking is relevant to medical educators and the organizations that could develop the required educational curricula and resources. PMID- 21710421 TI - Inspiring health advocacy in family medicine: a qualitative study. AB - CONTEXT: The Canadian Medical Education Directions for Specialists identifies health advocacy as an essential role for physicians. Health advocacy is also an integral part of the principles of family medicine. It relates to the physician's responsibility to identify and respond appropriately to the social determinants of health and the healthcare needs of vulnerable and marginalized populations. The competencies related to health advocacy are regarded by medical educators as difficult to integrate into residency training. OBJECTIVES: This qualitative study investigates what family medicine residents, educators and physicians perceive inspires them to engage in health advocacy, and explores how best to incorporate related competencies into medical training. METHODS: In-depth, semi structured interviews conducted with a purposive sample of four family medicine residents, three physicians and two educators who self-identified or were identified by peers as health advocates. Interviews were recorded, transcribed and analyzed using framework analysis. Transcripts were made available to the participants to ensure transcript accuracy. FINDINGS: Early exposure to social injustice, parental influences, role modeling and internal motivators were seen as important inspirations for health advocacy. CONCLUSION: Creating an enabling and nurturing environment prior to and during residency training may be necessary to sustain the motivation to engage in health advocacy. Findings from this study suggest possibilities for a resident-guided participatory curriculum development process around health advocacy. Recommendations for promoting health advocacy in postgraduate training include effective integration of health advocacy in the curriculum by providing protected time and resources, providing experiential learning opportunities and fostering a community of practice for physician health advocates. PMID- 21710422 TI - Three years of medical humanities at a new Nepalese medical school. PMID- 21710423 TI - Pedagogy for rural health. AB - CONTEXT: As the body of literature on rural health has grown, the need to develop a unifying theoretical framework has become more apparent. There are many different ways of seeing the same phenomenon, depending on the assumptions we make and the perspective we choose. A conceptual and theoretical basis for the education of health professionals in rural health has not yet been described. APPROACH: This paper examines a number of theoretical frameworks that have been used in the rural health discourse and aims to identify relevant theory that originates from an educational paradigm. The experience of students in rural health is described phenomenologically in terms of two complementary perspectives, using a geographic basis on the one hand, and a developmental viewpoint on the other. The educational features and implications of these perspectives are drawn out. DISCUSSION: The concept of a 'pedagogy of place' recognizes the importance of the context of learning and allows the uniqueness of a local community to integrate learning at all levels. The theory of critical pedagogy is also found relevant to education for rural health, which would ideally produce 'transformative' graduates who understand the privilege of their position, and who are capable of and committed to engaging in the struggles for equity and justice, both within their practices as well as in the wider society. CONCLUSION: It is proposed that a 'critical pedagogy of place,' which gives due acknowledgement to local peculiarities and strengths, while situating this within a wider framework of the political, social and economic disparities that impact on the health of rural people, is an appropriate theoretical basis for a distinct rural pedagogy in the health sciences. PMID- 21710424 TI - Mixed methods evaluation of an international internet-based continuing medical education course for pediatric HIV providers in Pune, India. AB - CONTEXT: Studies of HIV care in Pune, a high-HIV-prevalence city in India, have shown that a significant proportion of practitioners were not adhering to national guidelines due to inadequate awareness and understanding. OBJECTIVES: This study examined the effectiveness of a pilot Internet-based continuing medical education course in increasing knowledge of pediatric HIV diagnosis and treatment among providers in Pune. The study also explored perceived factors limiting the effectiveness of the pilot course. METHODS: The mixed methods evaluation design consisted of quantitative pre- and post-course knowledge assessments, and qualitative focus groups and in-depth interviews conducted on site with healthcare providers with experience treating HIV to explore the barriers to optimal course utilization, the applicability of the course content, and the systemic barriers to the implementation of physician knowledge. FINDINGS: There were significant increases (p<0.05) in mean knowledge scores on the global knowledge assessment and for two of five individual course modules. Perceived barriers to optimal course utilization were identified as being related to Internet access. The course content was reported to be generally useful, although certain guidelines and information were described as not congruent with local resource availability. Participants reported that the major barriers to implementing their knowledge were stigma that prevented patients from seeking care and financial resource limitations affecting physician practice. DISCUSSION AND CONCLUSIONS: This course resulted in a modest increase in pediatric HIV knowledge among Pune healthcare providers. Identification of perceived factors limiting the effectiveness of the course provides guidance for improving future Internet-based courses. PMID- 21710425 TI - Medical students' perspectives on clinical empathy training. AB - CONTEXT: There is a need for studies specifically addressing the barriers to empathy training from the perspective of medical students. The objective of this study was to evaluate attitudes of 3rd and 4th year medical students regarding their training in clinical empathy at a public teaching hospital and medical school. METHODS: A questionnaire assessing students' satisfaction with, and opinions on, empathy training, as well as barriers to training, was distributed during the last quarter of the year. RESULTS: Of 188 eligible participants, 157 (84%) responded. Approximately one-half of the respondents said empathy could be taught. Eighty-one percent of respondents felt that their empathy had increased or stayed the same during their training. When asked about barriers for learning empathy, the majority of respondents chose time pressure and lack of good role models. Respondents rated breaking bad news, talking to patients about medical mistakes and taking care of dying or demanding patients as areas in need of more empathy-related training. CONCLUSIONS: Although the majority of students were satisfied with their training of clinical empathy, our study highlights the need for innovative methods to address concerns regarding barriers to practicing empathy, as well as the need for more training in how to demonstrate empathy in challenging clinical situations. PMID- 21710426 TI - Follow the leader. PMID- 21710427 TI - Teamwork: a graduating medical student's perspective. PMID- 21710428 TI - In the news! An opinion--bad apples or bad basket? PMID- 21710429 TI - Making a difference: an interview with Sister Jeanne Devos promoting social justice for the underserved. [Interviewed by Michael Glasser]. PMID- 21710431 TI - Mark Q. Martindale: shedding new light on developmental diversity. AB - The Saint-Petersburg Society of Naturalists awarded the 2009 "Alexander Kowalevsky Medal" to Mark Q. Martindale, Professor of Organismal Biology at the University of Hawaii and Director of the Kewalo Marine Laboratory, Honolulu. This international award inaugurated first in 1910 was re-established only in 2001. In memory of Alexander Onufrievich Kowalevsky, it is awarded to outstanding zoologists and embryologists who have made great contributions to the field of embryology and developmental biology from an evolutionary perspective. Mark Q. Martindale has worked on a wide range of animals, mostly marine species, in contrast to many evo-devo researchers who often use a single "well-established" model organism. His work demonstrates how the insights gained by studying less "popular" animal taxa not only complement, but also significantly enrich our knowledge of the evolution of metazoan body plans and of the events that have led to the current animal diversity. PMID- 21710432 TI - The biopolitics of frozen embryos. AB - The unresolved debate about frozen embryos has left open the discussion on "what to do with them". There are only three ways to deal with frozen embryos: 1) to leave them frozen indefinitely; 2) to defrost and discard them and 3) to use them for research. In this paper, we suggest that the application of current scientific knowledge, instead of inappropriately referring to ethical principles or to the concept of person, could help with the decision about what to do with hundreds of thousands of frozen embryos, thus bringing the sensitive debate on bioethical issues to shared practical solutions. We face a new individual only when a new functional copy of his genome is formed. In both natural and artificial animal and plant reproduction, this principle applies. This status occurs in humans at the 4-8 cell stage. Acknowledgement of this factual datum would allow advocates of all religious and ideological beliefs to defend their principles and to realign their positions to a setting within the boundaries of current scientific knowledge. PMID- 21710433 TI - Regulation of cell fate determination by Skp1-Cullin1-F-box (SCF) E3 ubiquitin ligases. AB - The developing embryo is patterned by a complex set of signals and interactions resulting in changes in cell division, cell fate determination and differentiation. An increasing body of evidence points to the role of the ubiquitin proteasome system (UPS) and ubiquitin-mediated protein degradation as a major mechanism of protein regulation, crucial for control of developmental processes. The specific and irreversible signal generated by protein degradation can function as an integrator of cell signaling events, coupled with other post translational protein modifications, but also as a master switch for differentiation in its own right. The UPS also displays more subtle mechanisms of regulating signaling than decreasing protein levels, such as proteolytic processing and altering subcellular localization. In particular, the SCF E3 ligase family plays pivotal roles in regulating diverse developmental events in varied species. This review will focus on the role played by SCF E3 ligases in cell fate determination and differentiation. PMID- 21710434 TI - The role of pericytes in angiogenesis. AB - Pericytes are branched cells embedded within the basement membrane of capillaries and post-capillary venules. They provide an incomplete investment to endothelial cells, thus reinforcing vascular structure and regulating microvascular blood flow. Pericytes exert an important role on endothelial cell proliferation, migration and stabilization. Endothelial cells, in turn, stimulate expansion and activation of the pericyte precursor cell population. The balance between the number of endothelial cells and pericytes is highly controlled by a series of signaling pathway mechanisms operating in an autocrine and/or paracrine manner. In this review, we will first examine the molecular aspects of the pericyte activating factors secreted by endothelial cells, such as platelet derived growth factor B (PDGF-B), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-beta) and angiopoietins (Angs), as well as signaling pathways involving Notch and ephrins. We will then consider the complex and multivarious contribution of pericytes to the different aspects of angiogenesis with particular emphasis on the potential role of these cells as targets in tumor therapy. PMID- 21710435 TI - Rab11 is required for cell adhesion, maintenance of cell shape and actin cytoskeleton organization during Drosophila wing development. AB - Intracellular protein trafficking is a key factor in maintaining epithelial cell adhesion and cell shape. Small monomeric Rab GTPases are key players involved in intracellular membrane transport. Rab11, a subfamily of the Ypt/Rab gene family of ubiquitously expressed GTPases, is associated with recycling endosomes, and acts as a master molecule in regulating vesicular trafficking. Wing epithelium of Drosophila has been chosen to address the involvement of Rab11 in trafficking of a cell adhesion molecule, the betaPS integrin. Here, we show that Rab11 immunocolocalizes with trans-Golgi network and it is enriched in the centrosomal/recycling endosomal area labeled by gamma-Tubulin. Furthermore, Rab11 is required for transcytic and exocytic trafficking of betaPS integrin; alterations of Rab11 function by different genetic procedures in wings results in the formation of blisters. We show altered activity of Rab11 affects cell adhesion, cell shape and organization in the actin-cytoskeleton during wing morphogenesis. Finally, using a genetic approach, we demonstrate that Rab11 interacts with the betaPS integrin. Collectively, our data suggest that Rab11 regulates cell adhesion, maintenance of cell shape and actin-cytoskeleton organization during Drosophila wing development. PMID- 21710436 TI - Highly efficient cryopreservation of human induced pluripotent stem cells using a dimethyl sulfoxide-free solution. AB - Human induced pluripotent stem (hiPS) cells have great potential for regenerative medicine and drug discovery. It is essential to establish highly efficient and reliable methods for hiPS cell cryopreservation. We examined cryopreservation of hiPS cells by the vitrification method using a dimethyl sulfoxide Me2SO-free and serum-free medium, VS2E, that uses Euro-Collins solution as a base with 40% (v/v) ethylene glycol and 10% (w/v) polyethylene glycol as cryoprotectants. This combination of vitrification and cryoprotectants resulted in a higher recovery rate of hiPS cells than with a commercially-available vitrification solution, DAP213, which contained Me2SO and serum components. After vitrification and warming, hiPS cells were cultured easily. Even after several subculturing steps, cells expressed undifferentiated cell markers, such as Oct-3/4 and SSEA-4, and also exhibited alkaline phosphatase activity. The pluripotency of hiPS cells was maintained, as demonstrated by teratoma formation upon hiPS cell transplantation into severe combined immunodeficient mice. Thus, we successfully preserved hiPS cells under liquid nitrogen with high efficiency using Me2SO-free vitrification solution and rapid cooling. PMID- 21710437 TI - Co-localization of neural cell adhesion molecule and fibroblast growth factor receptor 2 in early embryo development. AB - During development there is a multitude of signaling events governing the assembly of the developing organism. Receptors for signaling molecules such as fibroblast growth factor receptor 2 (FGFR2) enable the embryo to communicate with the surrounding environment and activate downstream pathways. The neural cell adhesion molecule (NCAM) was first characterized as a cell adhesion molecule highly expressed in the nervous system, but recent studies have shown that it is also a signaling receptor. Using a novel single oocyte adaptation of the proximity ligation assay, we here show a close association between NCAM and FGFR2 in mouse oocytes and 2-cell embryos. Real-time PCR analyses revealed the presence of messenger RNA encoding key proteins in downstream signaling pathways in oocytes and early mouse embryos. In summary these findings show a co-localization of NCAM and FGFR2 in early vertebrate development with intracellular signaling pathways present to enable a cellular response. PMID- 21710438 TI - Neuronal induction and regional identity by co-culture of adherent human embryonic stem cells with chicken notochords and somites. AB - The role of somites and notochords in neuroectoderm differentiation from the embryonic ectoderm and its subsequent patterning into regional compartments along rostro-caudal and dorso-ventral axes, especially in humans, remains elusive. Here, we demonstrate the co-culture effect of somites and notochords isolated from chicken embryos on the neuronal differentiation and regional identity of an adherent culture of human embryonic stem cells (hESCs). Notochord increased the efficiency and speed of neuronal induction, whereas somites had a weak neuronal inducing effect on hESCs. However, a synergistic effect was not observed when notochords and somites were used together. Moreover, in somite and notochord co culture groups, hESCs-derived neuronal cells expressed HOXB4, OTX2, IRX3 and PAX6, indicative of dorsal hindbrain and ventral anterior identities, respectively. Our results reveal the influence of embryonic notochord and somite co-culture in providing neuronal induction as well as rostro-caudal and dorso ventral regional identity of hESCs-derived neuronal cells. This study provides a model through which in vivo neuronal induction events may be imitated. PMID- 21710439 TI - Dynamic expression of manganese superoxide dismutase during mouse embryonic organogenesis. AB - The balance between reactive oxygen species production and antioxidant defense enzymes in embryos is necessary for normal embryogenesis. To determine the dynamic expression profile of manganese superoxide dismutase (MnSOD) in embryos, which is an essential antioxidant enzyme in embryonic organogenesis, the expression level and distribution of MnSOD mRNA and protein were investigated in mouse embryos, as well as extraembryonic tissues on embryonic days (EDs) 7.5 18.5. MnSOD mRNA levels were remarkably high in extraembryonic tissues rather than in embryos during these periods. MnSOD protein levels were also higher in extraembryonic tissues than in embryos until ED 16.5, but the opposite trend was found after ED 17.5. MnSOD mRNA was observed in the chorion, allantois, amnion, ectoderm, ectoplacental cone and neural fold at ED 7.5 and in the neural fold, gut, ectoplacental cone, outer extraembryonic membranes and primitive heart at ED 8.5. After removing the extraembryonic tissues, the prominent expression of MnSOD mRNA in embryos was seen in the sensory organs, central nervous system and limbs on EDs 9.5-12.5 and in the ganglia, spinal cord, sensory organ epithelia, lung, blood cells and vessels, intestinal and skin epithelia, hepatocytes and thymus on EDs 13.5-18.5. Strong MnSOD immunoreactivity was observed in the choroid plexus, ganglia, myocardium, blood vessels, heapatocytes, pancreatic acinus, osteogenic tissues, brown adipose tissue, thymus and skin. These findings suggest that MnSOD is mainly produced from extraembryonic tissues and then may be utilized to protect the embryos against endogenous or exogenous oxidative stress during embryogenesis. PMID- 21710440 TI - CXCL14 expression during chick embryonic development. AB - Chemokines are small secreted signalling molecules best known for their roles as chemoattractants for cells of the immune system. CXCL12 and its receptor CXCR4 comprise one chemokine signalling pathway with essential functions in non-immune cell types during embryonic development. CXCL14, a chemokine-encoding gene related to CXCL12, is developmentally regulated in zebrafish and Xenopus embryos, but its role during embryogenesis remains unknown. Here we describe the embryonic expression pattern of CXCL14 in an amniote, the chick. Although expression in some regions is conserved with that of fish and frog, chick CXCL14 displays a complex pattern of expression in several novel sites. We analyse the expression pattern in the branchial arches, trigeminal placode and ganglion, inner ear, dorsal midline of the brain, somites, trunk neural tube and limb bud. Expression in several domains raises the possibility that CXCL14 may be involved in some of the same developmental events during which CXCL12-CXCR4 signalling is known to play a role. PMID- 21710441 TI - Prediction of in vivo bone forming potency of bone marrow-derived human mesenchymal stem cells. AB - Human mesenchymal stem cells (MSC) have attracted much attention for tissue regeneration including repair of non-healing bone defects. Heterogeneity of MSC cultures and considerable donor variability however, still preclude standardised production of MSC and point on functional deficits for some human MSC populations. We aimed to identify functional correlates of donor-dependency of bone formation in order to develop a potency assay predicting the therapeutic capacity of human MSC before clinical transplantation. MSC from 29 donors were characterised in vitro and results were correlated to bone formation potency in a beta-tricalcium-phosphate (beta-TCP)-scaffold after subcutaneous implantation into immunocompromised mice. In contrast to osteogenic in vitro differentiation parameters, a doubling time below 43.23 hours allowed to predict ectopic bone formation at high sensitivity (81.8%) and specificity (100%). Enriched conditions adapted from embryonic stem cell expansion rescued bone formation of inferior MSC populations while growth arrest of potent MSC by mitomycin C abolished bone formation, establishing a causal relationship between neo-bone formation and growth. Gene expression profiling confirmed a key role for proliferation status for the bone forming ability suggesting that a rate limiting anabolism and open chromatin determined and predicted the therapeutic potency of culture-expanded MSC. Proliferation-based potency testing and switch to enriched expansion conditions may pave the way for standardised production of MSC for bone repair. PMID- 21710442 TI - The effects of cyclic tensile strain on the organisation and expression of cytoskeletal elements in bovine intervertebral disc cells: an in vitro study. AB - It is still relatively unclear how intervertebral disc (IVD) cells sense a mechanical stimulus and convert this signal into a biochemical response. Previous studies demonstrated that the cytoskeletal elements are mechano-responsive in many cell types and may contribute to mechano-signalling pathways. The objective of this study was to determine the response of cells from the outer annulus fibrosus (OAF) to physiological levels of cyclic tensile strain; further, cells from the nucleus pulposus (NP) were also subjected to an identical loading regime to compare biological responses across the IVD populations. We determined whether the organisation and expression of the major cytoskeletal elements and their associated accessory proteins are responsive to mechanical stimulation in these cells, and whether these changes correlated with either a catabolic or anabolic phenotype. OAF and NP cells from immature bovine IVD were seeded onto Flexcell(r) type I collagen coated plates. Cells were subjected to cyclic tensile strain (10 %, 1 Hz) for 60 minutes. Post-loading, cells were processed for immunofluorescence microscopy, RNA extracted for quantitative PCR and protein extracted for Western blotting analysis. F-actin reorganisation was evident in OAF and NP cells subjected to tensile strain; strain induced beta-actin at the transcriptional and translational level in OAF cells. beta-tubulin mRNA and protein synthesis increased in strained OAF cells, but vimentin expression was significantly inhibited. Cytoskeletal element organisation and expression were less responsive to strain in NP cells. Tensile strain increased type I collagen and differentially regulated extracellular matrix (ECM)-degrading enzymes' mRNA levels in OAF cells. Strain induced type II collagen transcription in NP cells, but had no effect on the transcription of any other genes analysed. Tensile strain induces different mechano-responses in the organisation and/or expression of cytoskeletal elements and on markers of IVD metabolism. Differential mechano regulation of anabolic and catabolic ECM components in the OAF and NP populations reflects their respective mechanical environments in situ. PMID- 21710443 TI - Nucleus pulposus cell-matrix interactions with laminins. AB - The cells of the nucleus pulposus (NP) region of the intervertebral disc play a critical role in this tissue's generation and maintenance, and alterations in NP cell viability, metabolism, and phenotype with aging may be key contributors to progressive disc degeneration. Relatively little is understood about the phenotype of NP cells, including their cell-matrix interactions which may modulate phenotype and survival. Our previous work has identified strong and region-specific expression of laminins and laminin cell-surface receptors in immature NP tissues, suggesting laminin cell-matrix interactions are uniquely important to the biology of NP cells. Whether these observed tissue-level laminin expression patterns reflect functional adhesion behaviors for these cells is not known. In this study, we examined NP cell-matrix interactions with specific matrix ligands, including various laminin isoforms, using quantitative assays of cell attachment, spreading, and adhesion strength. NP cells were found to attach in higher numbers and exhibited rapid cell spreading and higher resistance to detachment force on two laminin isoforms (LM-511,LM-332) identified to be uniquely expressed in the NP region, as compared to another laminin isoform (LM 111) and several other matrix ligands (collagen, fibronectin). Additionally, NP cells were found to attach in higher numbers to laminins as compared to cells isolated from the disc's annulus fibrosus region. These findings confirm that laminin and laminin receptor expression documented in NP tissues translates into unique functional NP cell adhesion behaviors that may be useful tools for in vitro cell culture and biomaterials that support NP cells. PMID- 21710445 TI - Gene expression analysis in calcific tendinopathy of the rotator cuff. AB - We evaluated the expression of several genes involved in tissue remodelling and bone development in patients with calcific tendinopathy of the rotator cuff. Biopsies from calcified and non-calcified areas were obtained from 10 patients (8 women and 2 men; average age: 55 years; range: 40-68) with calcific tendinopathy of the rotator cuff. To evaluate the expression of selected genes, RNA extraction, cDNA synthesis and quantitative polymerase chain reaction (PCR) were performed. A significantly increased expression of tissue transglutaminase (tTG)2 and its substrate, osteopontin, was detected in the calcific areas compared to the levels observed in the normal tissue from the same subject with calcific tendinopathy, whereas a modest increase was observed for catepsin K. There was also a significant decrease in mRNA expression of Bone Morphogenetic Protein (BMP)4 and BMP6 in the calcific area. BMP-2, collagen V and vascular endothelial growth factor (VEGF) did not show significant differences. Collagen X and matrix metalloproteinase (MMP)-9 were not detectable. A variation in expression of these genes could be characteristic of this form tendinopathy, since an increased level of these genes has not been detected in other forms of tendon lesions. PMID- 21710444 TI - Role of hypoxia and growth and differentiation factor-5 on differentiation of human mesenchymal stem cells towards intervertebral nucleus pulposus-like cells. AB - There is evidence that mesenchymal stem cells (MSCs) can differentiate towards an intervertebral disc (IVD)-like phenotype. We compared the standard chondrogenic protocol using transforming growth factor beta-1 (TGFbeta) to the effects of hypoxia, growth and differentiation factor-5 (GDF5), and coculture with bovine nucleus pulposus cells (bNPC). The efficacy of molecules recently discovered as possible nucleus pulposus (NP) markers to differentiate between chondrogenic and IVD-like differentiation was evaluated. MSCs were isolated from human bone marrow and encapsulated in alginate beads. Beads were cultured in DMEM (control) supplemented with TGFbeta or GDF5 or under indirect coculture with bNPC. All groups were incubated at low (2 %) or normal (20 %) oxygen tension for 28 days. Hypoxia increased aggrecan and collagen II gene expression in all groups. The hypoxic GDF5 and TGFbeta groups demonstrated most increased aggrecan and collagen II mRNA levels and glycosaminoglycan accumulation. Collagen I and X were most up regulated in the TGFbeta groups. From the NP markers, cytokeratin-19 was expressed to highest extent in the hypoxic GDF5 groups; lowest expression was observed in the TGFbeta group. Levels of forkhead box F1 were down-regulated by TGFbeta and up-regulated by coculture with bNPC. Carbonic anhydrase 12 was also down-regulated in the TGFbeta group and showed highest expression in the GDF5 group cocultured with bNPC under hypoxia. Trends in gene expression regulation were confirmed on the protein level using immunohistochemistry. We conclude that hypoxia and GDF5 may be suitable for directing MSCs towards the IVD-like phenotype. PMID- 21710446 TI - Developmental plasticity of human foetal femur-derived cells in pellet culture: self assembly of an osteoid shell around a cartilaginous core. AB - This study has examined the osteogenic and chondrogenic differentiation of human foetal femur-derived cells in 3-dimensional pellet cultures. After culture for 21 28 days in osteogenic media, the pellets acquired a unique configuration that consisted of an outer fibrous layer, an osteoid-like shell surrounding a cellular and cartilaginous region. This configuration is typical to the cross section of the foetal femurs at the same age and was not observed in pellets derived from adult human bone marrow stromal cells. Time course study showed that after 7-14 days, the cells of the inner cellular region were viable, proliferated rapidly, and were immuno-positive for c-myc, as well as for bone sialoprotein and type I collagen. After 21-28 days, the cells accumulated at the inner edge of the osteoid shell. The direction of osteoid formation thus differed from that of periosteal bone formation. Following micro-dissection of the human foetal femurs into epiphyses, bone cylinder and hypertrophic cartilage, epiphyseal chondrocytes and osteoblasts both gave rise to osteoid-shell forming cells. These studies demonstrate the developmental plasticity of human foetal skeletal and epiphyseal chondrocytes and suggest that the microenvironment modulates lineage commitment and matrix formation. Furthermore, this ex vivo model offers a new approach to delineate human bone development as well as a model with potential application for evaluation of therapeutic compounds for bone formation. PMID- 21710447 TI - Variations in BARE-1 insertion patterns in barley callus cultures. AB - The stability of aging barley calli was investigated with the barley retroelement 1 (BARE-1) retrotransposon specific inter-retrotransposon amplified polymorphism (IRAP) technique. Mature embryos of barley (Hordeum vulgare cv. Zafer-160) were cultured on callus induction MS medium supplemented with 3 mg/L 2,4-D and maintained on the same medium for 60 days. Ten IRAP primers were used in 25 different combinations. The similarity index between 30-day-old and 45-day-old calli was 84%; however, the similarity index between mature embryos and 45-day old calli was 75%. These culture conditions caused BARE-1 retrotransposon alterations to appear as different band profiles. This is the first report of the use of the IRAP technique in barley in an investigation of callus development. PMID- 21710448 TI - A novel polymorphism of the GDF10 gene and its association with body measurement traits in Chinese indigenous cattle. AB - Body measurement traits are known to play numerous important roles in the assessment of productivity and economic value. They are influenced by several factors, among which genetic factors are predominant. The gene GDF10 is involved in skeletal morphogenesis and is associated with body measurement traits. It may be an important candidate gene for marker-assisted selection. We used the PCR SSCP technology to examine a possible association of the single nucleotide polymorphism (SNP) (G142A) of the bovine GDF10 gene with body measurement traits in 417 animals belonging to six different Chinese cattle populations: Xue long (Xl), Luxi (Lx), Qinchuan (Qc), Jiaxian red (Jx), Xianang (Xn), and Nanyang (Ny). In the Jx population, least squares analysis revealed significant effects on hip width, chest depth and chest circumference. The animals with the GG genotype had higher mean values than those with the GA genotype for all three traits. We conclude that the SNP of the GDF10 gene could be a very useful genetic marker for body traits in Jx cattle reproduction and breeding. PMID- 21710449 TI - Molecular diagnosis of Eimeria species affecting naturally infected Gallus gallus. AB - We used PCR to test various protocols and define a technique for DNA extraction directly from chicken-shed stool samples for the identification of Eimeria species that parasitize birds. It was possible to extract and amplify DNA of seven Eimeria species from field stool samples, using both protocols tested; extractions made with phenol/chloroform protocols gave the best results. The primers were specific and sensitive, allowing amplification of samples containing as few as 20 oocysts, both in individual and in a multiplex PCR. Individualized PCR with the phenol/chloroform DNA extraction protocol detected a larger number of Eimeria species. Molecular diagnosis was found to be practical and precise, and can be used for monitoring and epidemiological studies of Eimeria. PMID- 21710450 TI - Isolation and characterization of 21 novel polymorphic microsatellite loci in the Chinese soft-shelled turtle Pelodiscus sinensis. AB - Twenty-one novel polymorphic microsatellite loci were isolated from the Chinese soft-shelled turtle, Pelodiscus sinensis (Trionychidae). This is a commonly consumed Asian species, especially in China, where it is reared in large numbers on farms. We screened 34 unrelated individuals from Wuhu of Anhui province in China and detected high levels of polymorphism for all 21 loci, with the number of alleles/locus ranging from 5 to 23 (mean 15.67). The expected and observed heterozygosities ranged from 0.421 to 0.946 and from 0.324 to 0.941, respectively. Hence, these microsatellites could facilitate studies on genetic diversity and population structure and marker-assisted breeding of this vulnerable species. PMID- 21710451 TI - Anatomic changes due to interspecific grafting in cassava (Manihot esculenta). AB - Cassava rootstocks of varieties UnB 201 and UnB 122 grafted with scions of Manihot fortalezensis were prepared for anatomic study. The roots were cut, stained with safranin and alcian blue, and examined microscopically, comparing them with sections taken from ungrafted roots. There was a significant decrease in number of pericyclic fibers, vascular vessels and tyloses in rootstocks. They exhibited significant larger vessels. These changes in anatomic structure are a consequence of genetic effects caused by transference of genetic material from scion to rootstock. The same ungrafted species was compared. This is the first report on anatomic changes due to grafting in cassava. PMID- 21710452 TI - Clinical and genetic characterization of complete androgen insensitivity syndrome in a Chinese family. AB - We studied a family with two cousins who were diagnosed with complete androgen insensitivity syndrome, an X-linked disorder caused by mutations in the androgen receptor gene. A pedigree analysis and a molecular study using PCR and DNA sequencing clarified each female family member's androgen receptor status and revealed a mutation consisting of the deletion of exon 2 and surrounding introns of the androgen receptor gene. Based on the relative nucleotide positions, we concluded that the deletion mutation in exon 2 and its surrounding introns was approximately 6000 to 7000 bp. This mutation, never previously fully characterized using DNA sequencing, was responsible for complete androgen insensitivity syndrome in this family. Pedigree analysis with a molecular study of the androgen receptor gene in affected families facilitates genetic counseling provided to family members. PMID- 21710453 TI - Isolation and partial characterization of a root-specific promoter for stacking multiple traits into cassava (Manihot esculenta CRANTZ). AB - Cassava can be cultivated on impoverished soils with minimum inputs, and its storage roots are a staple food for millions in Africa. However, these roots are low in bioavailable nutrients and in protein content, contain cyanogenic glycosides, and suffer from a very short post-harvest shelf-life, and the plant is susceptible to viral and bacterial diseases prevalent in Africa. The demand for improvement of cassava with respect to these traits comes from both farmers and national agricultural institutions. Genetic improvement of cassava cultivars by molecular biology techniques requires the availability of appropriate genes, a system to introduce these genes into cassava, and the use of suitable gene promoters. Cassava root-specific promoter for auxin-repressed protein was isolated using the gene walking approach, starting with a cDNA sequence. In silico analysis of promoter sequences revealed putative cis-acting regulatory elements, including root-specific elements, which may be required for gene expression in vascular tissues. Research on the activities of this promoter is continuing, with the development of plant expression cassettes for transformation into major African elite lines and farmers' preferred cassava cultivars to enable testing of tissue-specific expression patterns in the field. PMID- 21710454 TI - A novel missense mutation T101N in the melanocortin-4 receptor gene associated with obesity. AB - Mutations in the melanocortin-4 receptor (MC4R) are associated with severe obesity, independent of their effect on cortisol or thyroid-stimulating hormone levels. We examined a morbidly obese male (BMI = 62 kg/m2) with a binge-eating disorder and eight family members for mutations in the MC4R gene and potential differences in leptin levels. Fifty healthy individuals served as controls. Sequence analysis revealed a novel heterozygous missense mutation (c.302 C>A, p.T101N) located in the second transmembrane domain of the receptor, which was not detected in controls. The Fisher exact test revealed an association between the T101N mutation and history of obesity (P < 0.05) in the family. The Kruskal Wallis test showed an association between the mutation and the leptin/BMI ratio (P < 0.05), while there was no association between the T101N mutation and diabetes or arterial hypertension in the family. Although the available family was small, we could show a significant association between the heterozygous T101N mutation and obesity. PMID- 21710455 TI - Zinc finger protein A20 overexpression inhibits monocyte homing and protects endothelial cells from injury induced by high glucose. AB - Diabetes mellitus causes vascular lesions and may ultimately lead to atherosclerosis. One of the earliest steps in the development of atherosclerotic lesions is the adhesion of monocytes to endothelial cells of the vessel wall. It is currently unknown whether zinc finger protein A20 is able to protect endothelial cells from injury caused by high levels of glucose and monocyte homing. In our study, adhesion of monocytes to the vessel wall endothelium was detected by measuring the rolling velocity of monocytes along human umbilical vein endothelial cells (HUVECs). Activation of NF-kappaB was analyzed through Western blot. HUVEC apoptosis was monitored by TUNEL in situ end-labeling and flow cytometry. High glucose concentrations (25 mM) stimulated monocytes, reducing the velocity at which they roll along HUVECs. Stimulation of monocytes with high levels of glucose also induced HUVEC apoptosis. Overexpression of the zinc finger protein A20 inhibited monocyte recruitment, NF-kappaB activation, P selectin expression, and HUVEC apoptosis induced by high glucose levels. We conclude that zinc finger protein A20 can protect HUVECs from injury induced by high levels of glucose and potentially could be used to develop treatments against diabetic vascular lesions. PMID- 21710456 TI - Genetic relationships of the Japanese persimmon Diospyros kaki (Ebenaceae) and related species revealed by SSR analysis. AB - Simple sequence repeat (SSR) molecular markers based on 18 primers were employed to study the genetic relationship of Japanese persimmon (Diospyros kaki) specimens. Two hundred and sixty-two bands were detected in 30 Japanese persimmon samples, including 14 Japanese and 10 Chinese genotypes of Japanese persimmon (Diospyros kaki) and six related species, D. lotus, D. glaucifolia, D. oleifera, D. rhombifolia, D. virginiana, and Jinzaoshi (unclassified - previously indicated to be D. kaki). All SSR primers developed from D. kaki were successfully employed to reveal the polymorphism in other species of Diospyros. Most of the primers were highly polymorphic, with a degree of polymorphism equal to or higher than 0.66. The results from the neighbor-joining dendrogram and the principal coordinate analysis diagram were the same; i.e., the Chinese and Japanese genotypes and related species were separated and the relationships revealed were consistent with the known pedigrees. We also concluded that 'Xiangxitianshi' from Xiangxi municipality, Hunan Province, China, is actually a sport or somaclonal variant of 'Maekawa-Jirou', and that 'Jinzaoshi' should be classified as a distinct species of Diospyros. We found that SSR markers are a valuable tool for the estimation of genetic diversity and divergence in Diospyros. PMID- 21710457 TI - Molecular characterization and RAPD analysis of Juniperus species from Iran. AB - The genus Juniperus L. (Cupressaceae), an aromatic evergreen plant, consists of up to 68 species around the world. We classified five species of Juniperus found in Iran using molecular markers to provide a means for molecular identification of Iranian species. Plants were collected (three samples of each species) from two different provinces of Iran (Golestan and East Azarbayejan). The DNA was extracted from the leaves using a Qiagen Dneasy Plant Mini Kit. Amplification was performed using 18 ten-mer RAPD primers. Genetic distances were estimated based on 187 RAPD bands to construct a dendrogram by means of unweighted pair group method of arithmetic means. It was found that J. communis and J. oblonga were differentiated from the other species. Genetic distance values ranged from 0.19 (J. communis and J. oblonga) to 0.68 (J. communis and J. excelsa). Juniperus foetidissima was found to be most similar to J. sabina. Juniperus excelsa subspecies excelsa and J. excelsa subspecies polycarpos formed a distinct group. PMID- 21710458 TI - Interactions between rare-earth ions and DNA of Bashibai sheep. AB - The interaction between rare-earth ions and DNA from Bashibai sheep was studied by microcalorimetry and electrochemistry. The DNA chain was found to have four to five binding sites for rare-earth ions. The binding affinity was about 10-5-10-6 M. It was also found that smaller ions caused more heat to be released in the process of binding and bound more readily to the nucleic acid chain. This is attributed to the enhanced ability of polarization of smaller ions and reduced steric hindrance compared to larger ions. The electrochemistry results show that rare-earth ions could be inserted into the DNA helix, producing a new complex with electrochemically active groups. The rare-earth ions and DNA complex reached equilibrium after a 90-min incubation at room temperature. PMID- 21710459 TI - Genetic diversity and flooding survival in Aegiphila sellowiana (Lamiaceae), a typical tree species from upland riparian forests. AB - Saplings of Aegiphila sellowiana were submitted to flooding and analysis of genetic diversity in order to investigate flooding tolerance as well as its genetic determination. This response is important because it means that some lines could be planted in degraded riparian areas. Leaves were sampled from each plant, and they were submitted to different flooding periods. Mortality of saplings was 40, 80, 50, 53.3, 33.3, and 33.3% in flooding for 15, 18, 25, 50, 80 days, and flooding for 50 days followed by re-aeration for 30 days, respectively. From the total number of flooded plants, 46.7% died in the first seven days of treatment, while 53.3% survived the flooding. The percentage of polymorphic loci (P(p)), Nei's genetic diversity (H) and the Shannon index (I) were slightly higher for the group that survived the stress of flooding (surviving: P(p) (%) = 67.48, H = 0.184, I = 0.287; not surviving: P(p) (%) = 66.67, H = 0.165, I = 0.261). Analysis of molecular variance showed that 5.88% of the genetic variability was due to the differences between groups of plants surviving and not surviving flooding, while 94.12% was due to genetic differences between individuals within these groups. Similar results were obtained by principal coordinate analysis. Based on these results, we can assume the existence of environment-specific genotypes and the genetic determination of flooding tolerance in A. sellowiana. Thus, some lines of A. sellowiana could be used in the reforestation of riparian habitats, especially in uplands along riverbanks. PMID- 21710460 TI - Subject: Contribution of Maistro et al. in Genetics and Molecular Research (2010); 9(4): 2114-2122. PMID- 21710462 TI - Assessment of genetic diversity of wheat genotypes by resistance gene analog-EST markers. AB - Resistance gene analog-expressed sequence tag (RGA-EST)-based markers have been used for variety discrimination and studies of genetic diversity in wheat. Our aim is to increase the competitiveness of public wheat breeding programs through intensive use of modern selection technologies, mainly marker-assisted selection. The genetic diversity of 77 wheat nucleotide binding site (NBS)-containing RGA ESTs was assessed. Resistant and susceptible bread wheat (Triticum aestivum) genotypes were used as sources of DNA for PCR amplifications. In our previous studies, the F2 individuals derived from the combinations PI178383 x Harmankaya99, Izgi2001 x ES14, and Sonmez2001 x Aytin98 were evaluated for yellow rust resistance at both seedling and adult stages to identify DNA markers. We have now examined the genetic variability among the resistant and susceptible Turkish wheat cultivars for yellow rust disease and the mean genetic distance between the cultivars. The highest similarity was 0.500 between Harmankaya99 and Sonmez2001. The lowest similarity was 0.286 between Aytin98, PI178383 and Aytin98, ES14. A relatively high level (49.5%) of polymorphism was observed with 77 RGA-EST primers across the six wheat genotypes, despite the fact that all of them were local cultivars from geographically close locations. RGA-EST sequences were compared by BlastX algorithms for amino acid sequences to determine the polymorphic categories among the combinations. BlastX analyses of six RGA-ESTs that gave polymorphic patterns for all combinations were NBS-LRR class RGA, NB ARC domain containing protein, NBS-type resistance protein RGC5, NBS-LRR-S/ TPK stem rust resistance protein, and putative MLA1 proteins, while 38 RGA-EST gave a monomorphic pattern. PMID- 21710463 TI - Association of KCNJ11 with impaired glucose regulation in essential hypertension. AB - KCNJ11 is one of the candidate genes for type 2 diabetes, confirmed by genome wide association study, but there are little data on the relationship between KCNJ11 and impaired glucose regulation in essential hypertension patients. To identify the effect of E23K and I337V in the KCNJ11 gene on susceptibility to impaired glucose regulation, we conducted a case control study in 1125 essential hypertension patients with or without impaired glucose regulation among a Han Chinese population. We also evaluated the impact of two SNPs on insulin sensitivity and glucose tolerance estimated through an oral glucose tolerance test. In our case control study, no association of E23K and I337V with impaired glucose regulation was found using any genotypic models. However, lysine carriers of E23K showed a significant association with decreased insulin (30 min) and Cederholm index, and valine carriers of I337V showed association with a lower Cederholm index. All the quantitative tests were performed by linear regression, with adjustment for gender, age, body mass index, blood pressure, and angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment. These findings provided evidence that the KCNJ11 gene plays a role in the pathogenesis of decreased insulin sensitivity in essential hypertension patients. PMID- 21710464 TI - Analysis of the polymorphisms XRCC1Arg194Trp and XRCC1Arg399Gln in gliomas. AB - XRCC genes (X-ray cross-complementing group) were discovered mainly for their roles in protecting mammalian cells against damage caused by ionizing radiation. Studies determined that these genes are important in the genetic stability of DNA. Although the loss of some of these genes does not necessarily confer high levels of sensitivity to radiation, they have been found to represent important components of various pathways of DNA repair. To ensure the integrity of the genome, a complex system of DNA repair was developed. Base excision repair is the first defense mechanism of cells against DNA damage and a major event in preventing mutagenesis. Repair genes may play an important role in maintaining genomic stability through different pathways that are mediated by base excision. In the present study, we examined XRCC1Arg194Trp and XRCC1Arg399Gln polymorphism using PCR-RFLP in 80 astrocytoma and glioblastoma samples. Patients who had the allele Trp of the XRCC1Arg194Trp polymorphism had an increased risk of tumor development (OR = 8.80; confidence interval at 95% (95%CI) = 4.37-17.70; P < 0.001), as did the allele Gln of XRCC1Arg399Gln (OR = 1.01; 95%CI = 0.53-1.93; P = 0.971). Comparison of overall survival of patients did not show significant differences. We suggest that XRCC1Arg194Trp and XRCC1Arg399Gln polymorphisms are involved in susceptibility for developing astrocytomas and glioblastomas. PMID- 21710465 TI - In vitro genotoxicity assessment of caffeic, cinnamic and ferulic acids. AB - Phenols are a large and diverse class of compounds, many of which occur naturally in a variety of food plants; they exhibit a wide range of biological effects, including antibacterial, anti-inflammatory, antiallergic, hepatoprotective, antithrombotic, antiviral, anticarcinogenic, and vasodilatory actions. We examined the genotoxic and clastogenic potential of three phenolic compounds: caffeic, cinnamic and ferulic acids, using the comet and micronucleus assays in vitro. Drug-metabolizing rat hepatoma tissue cells (HTCs) were used. Three different concentrations (50, 500 and 1500 MUM) of these phenolic acids were tested on the HTCs for 24 h. The caffeic, cinnamic and ferulic acids were not genotoxic by the comet assay (P > 0.05). However, the micronucleus test showed an increase in the frequency of micronucleated cells for the three compounds, indicating that these substances have clastogenic effects in HTC. PMID- 21710466 TI - Molecular diversity analysis of eggplant (Solanum melongena) genetic resources. AB - Eggplant (Solanum melongena), a vegetable that is cultivated worldwide, is of considerable importance to agriculture in China. We analyzed the diversity of this plant using inter-simple sequence repeat (ISSR) and RAPD procedures to subdivide 143 Chinese-cultivated eggplants based on coefficient of parentage, genetic diversity index (GDI) and canonical discriminant analysis. ISSR markers were more effective than RAPD markers for detecting genetic diversity, which ranged from 0.10-0.51, slightly lower than what is known from other crops. Our ISSR/RAPD data provide molecular evidence that coincides with morphological-based classification into three varieties and further subdivision into eight groups, except for two groups. Intensive use of elite parents and extensive crossing within groups have resulted in increased coefficient of parentage and proportional contribution but decreased GDI during the past decades. The mean coefficient of parentage and proportional contribution increased from 0.05 to 0.10% and from 3.22 to 6.46% during 1980-1991 and 1992-2003, respectively. The GDI of landraces was 0.21, higher than the 0.09 and 0.08 calculated for the hybrid cultivars released during the two periods. The recent introduction of alien genotypes into eggplant breeding programs may broaden the genetic base. PMID- 21710467 TI - Elucidation of thermotolerance diversity in cotton (Gossypium hirsutum L.) using physio-molecular approaches. AB - Cotton (Gossypium hirsutum) is an important cash crop, but high temperature during its growing season is one of the major factors that limit its productivity. This problem compels plant breeders to breed for heat tolerance, which can help to overcome this challenge. It is very important to make a comprehensive screening of heat-tolerant genotypes so that only the best are chosen. Here we report the combined use of several techniques that can help breeders to screen their germplasm. Twelve cultivated cotton genotypes were evaluated for thermotolerance, using assays that included electrolyte leakage, chlorophyll accumulation and protein profiling, as well as RAPDs to assess genetic diversity. Two genotypes (B-557 and NIAB-78) showed tolerant behavior in three thermotolerance assays. RAPD analysis results showed maximum similarity in a range of 86.7-66.7% between the genotypes MNH-554 and CIM-443. We conclude that combined use should be made of relative electrolyte leakage, chlorophyll stability and differential display with SDS-PAGE to aid in screening for stress tolerance. RAPD-based diversity analysis will further help to improve the efficiency of breeding programs. PMID- 21710469 TI - The extreme plasticity of killer cell Ig-like receptor (KIR) haplotypes differentiates rhesus macaques from humans. AB - NK cells are essential in shaping immune responses and play an important role during pregnancy and in controlling infections. Killer cell immunoglobulin-like receptors (KIRs) educate the NK cell and determine its state of activation. Our goal was to determine how the KIR repertoire of the rhesus macaque (Macaca mulatta) has been shaped during evolution. The presence or absence of 22 KIR gene groups was determined in 378 animals. Some unexpected observations were made in an outbred colony comprising animals of different origins. For instance, the KIR region appears to be highly plastic, and an unprecedented number of genotypes and haplotypes was observed. In contrast to humans, there is no distinction between group A and B haplotypes in the rhesus macaque, suggesting that different selective forces may be operative. Moreover, specific genes appear to be either present or absent in animals of different geographic origins. This extreme plasticity may have been propelled by co-evolution with the rhesus macaque MHC class I region, which shows signatures of expansion. The mosaic-like complexity of KIR genotypes as observed at the population level may represent an effective strategy for surviving epidemic infections. PMID- 21710468 TI - Novel stem/progenitor cell population from murine tracheal submucosal gland ducts with multipotent regenerative potential. AB - The airway epithelium is in direct contact with the environment and therefore constantly at risk for injury. Basal cells (BCs) have been found to repair the surface epithelium (SE), but the contribution of other stem cell populations to airway epithelial repair has not been identified. We demonstrated that airway submucosal gland (SMG) duct cells, in addition to BCs, survived severe hypoxic ischemic injury. We developed a method to isolate duct cells from the airway. In vitro and in vivo models were used to compare the self-renewal and differentiation potential of duct cells and BCs. We found that only duct cells were capable of regenerating SMG tubules and ducts, as well as the SE overlying the SMGs. SMG duct cells are therefore a multipotent stem cell for airway epithelial repair This is of importance to the field of lung regeneration as determining the repairing cell populations could lead to the identification of novel therapeutic targets and cell-based therapies for patients with airway diseases. PMID- 21710470 TI - Liver cancer: still a long way to go. PMID- 21710471 TI - Telaprevir, boceprevir, cytochrome P450 and immunosuppressive agents--a potentially lethal cocktail. PMID- 21710473 TI - Copper toxicity in Wilson disease explained in a new way. PMID- 21710472 TI - Anti-chemokine therapy for the treatment of hepatic fibrosis: an attractive approach. PMID- 21710474 TI - A glimpse at the future of hepatitis C therapy: the INFORM trial. PMID- 21710475 TI - Alpha-fetoprotein in hepatocellular carcinoma surveillance: wake not the dead. PMID- 21710476 TI - Treatment implication from the potential association between nonalcoholic fatty liver disease and cardiovascular disease. PMID- 21710477 TI - Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms. AB - Programmed death-1 receptor (PD-1) is expressed on T cells following TCR activation. Binding of this receptor to its cognate ligands, programmed death ligand (PDL)-1 and PDL-2, down-regulates signals by the TCR, promoting T-cell anergy and apoptosis, thus leading to immune suppression. Here, we find that using an anti-PD-1 antibody (CT-011) with Treg-cell depletion by low-dose cyclophosphamide (CPM), combined with a tumor vaccine, induces synergistic antigen-specific immune responses and reveals novel activities of each agent in this combination. This strategy led to complete regression of established tumors in a significant percentage of treated animals, with survival prolongation. We show for the first time that combining CT-011 and CPM significantly increases the number of vaccine-induced tumor-infiltrating CD8(+) T cells, with simultaneous decrease in infiltrating Treg cells. Interestingly, we find that CT-011 prolongs Treg-cell inhibition induced by CPM, leading to a sustainable significant synergistic decrease of splenic and tumor-infiltrated Treg cells. Surprisingly, we find that the anti-tumor effect elicited by the combination of CT-011 and CPM is dependent on both CD8(+) and CD4(+) T-cell responses, although the antigen we used is a class I MHC-restricted peptide. Thus, we describe a novel and effective therapeutic approach by combining multiple strategies to target several tumor-mediated immune inhibitory mechanisms. PMID- 21710478 TI - A quantifiable proliferative burst of tissue macrophages restores homeostatic macrophage populations after acute inflammation. AB - Macrophage (MO) biology is routinely modelled in the peritoneal cavity, a vascular tissue readily infiltrated by leukocytes during inflammation. After several decades of study, no consensus has emerged regarding the importance of in situ proliferation versus peripheral monocyte recruitment for the maintenance of tissue resident MOs. By applying specific measures of mitosis, we have monitored tissue MO proliferation during newborn development, adulthood and acute resolving inflammation in young adult mice. Despite the vascular nature of the tissue and ease of peripheral leukocyte entry, tissue MOs in the newborn increase in number by local proliferation. On the contrary, in the adult, tissue MO proliferation is considerably reduced and most likely provides homeostatic control of cell numbers. Importantly, during an acute inflammatory response, when substantial numbers of inflammatory MOs are recruited from the circulation, tissue-resident MOs survive and then undergo a transient and intense proliferative burst in situ to repopulate the tissue. Our data indicate that local proliferation is a general mechanism for the self-sufficient renewal of tissue MOs during development and acute inflammation and not one restricted to non-vascular tissues, which has implications for the therapeutic modulation of MO activity during the resolution of inflammation. PMID- 21710480 TI - Randomized clinical trial of tissue glue versus absorbable sutures for mesh fixation in local anaesthetic Lichtenstein hernia repair. AB - BACKGROUND: Chronic pain may be a long-term problem related to mesh fixation and operative trauma after Lichtenstein hernioplasty. The aim of this study was to compare the feasibility and safety of tissue cyanoacrylate glue versus absorbable sutures for mesh fixation in Lichtenstein hernioplasty. METHODS: Lichtenstein hernioplasty was performed under local anaesthesia as a day-case operation in one of three hospitals. The patients were randomized to receive either absorbable polyglycolic acid 3/0 sutures (Dexon((r)); 151 hernias) or 1 ml butyl-2 cyanoacrylate tissue glue (Glubran((r)); 151 hernias) for fixation of lightweight mesh (Optilene((r))). Wound complications, pain, discomfort and recurrence were identified at 1 and 7 days, 1 month and 1 year after surgery. RESULTS: A total of 302 patients were included in the study. The mean(s.d.) duration of operation was 34(12) min in the glue group and 36(13) min in the suture group (P = 0.113). The need for analgesics was similar during the first 24 h after surgery. Five wound infections (3.4 per cent) were detected in the glue group and two (1.4 per cent) in the suture group (P = 0.448). The recurrence rate at 1 year was 1.4 per cent in each group (P = 1.000). The rates of foreign body sensation, acute and chronic pain were similar in the two groups. Logistic regression analysis showed that the type of mesh fixation did not predict chronic pain 1 year after surgery. CONCLUSION: Mesh fixation without sutures in Lichtenstein hernioplasty was feasible without compromising postoperative outcome. REGISTRATION NUMBER: NCT00659542 (http://www.clinicaltrials.gov). PMID- 21710481 TI - Two-stage hepatectomy for multiple bilobar colorectal liver metastases. AB - BACKGROUND: As surgical resection of colorectal liver metastases (CLM) remains the only treatment for cure, efforts to extend the surgical indications to include patients with multiple bilobar CLM have been made. This study evaluated the long-term outcome, safety and efficacy of two-stage hepatectomy (TSH) for CLM in a large cohort of patients. METHODS: Patients undergoing surgery between December 1996 and December 2009 were reviewed. The early postoperative and long term outcomes as well as the patterns of failure to complete TSH and its clinical implications were analysed. RESULTS: Eighty patients were scheduled to undergo TSH. Sixty-one patients had completion of TSH combined with (58 patients), or without (3) portal vein embolization/ligation (PVE/PVL). Five patients were excluded after first-stage hepatectomy and 14 after PVE/PVL. The 5-year overall survival rate and median survival in patients who completed TSH were 32 per cent and 39.6 months respectively, and corresponding recurrence-free values were 11 per cent and 9.4 months respectively. Six patients were alive beyond 5 years after TSH. Multivariable logistic regression analysis showed that failure to complete TSH was driven by two independent prognostic scenarios: three or more CLM in the future remnant liver (FRL) combined with age over 70 years predicted tumour progression after first-stage hepatectomy, and three or more CLM in the FRL combined with carcinomatosis at the time of first-stage hepatectomy predicted the development of additional FRL metastases after PVE/PVL. CONCLUSION: A therapeutic strategy using TSH provided acceptable long-term survival with no postoperative mortality. Further efforts are needed to increase the number of patients who undergo TSH successfully. PMID- 21710482 TI - Long-term results after laparoscopic reoperation for failed antireflux procedures. AB - BACKGROUND: Surgery for failed antireflux procedures is technically more demanding than primary fundoplication. The success rate does not equal that of the primary procedures. This retrospective analysis aimed to assess long-term subjective and objective outcomes in patients who underwent laparoscopic surgery for fundoplication failure. METHODS: Objective and subjective outcomes were assessed by radiological and endoscopic methods, symptom questionnaire and quality-of-life index at a minimum follow-up of 12 (mean 75.8) months. RESULTS: The study included 129 consecutive patients who had laparoscopic redo surgery after fundoplication had failed. The most frequent patterns of failure were hiatal herniation (50 patients) and slippage (45). Resolution of the symptoms that led to redo surgery was achieved in 27 of 37 and 11 of 16 patients operated for recurrence and for dysphagia respectively. Objective failure was demonstrated in 16 of 39 patients with herniation and six of 22 with slippage. Seven patients underwent an additional surgical procedure. CONCLUSION: Long-term assessment of objective and subjective results after laparoscopic repair for failed fundoplication revealed a high failure rate that increased with the length of follow-up. Unexpected and untreated oesophageal shortening may be responsible for this failure rate. PMID- 21710479 TI - PLP-dependent enzymes as entry and exit gates of sphingolipid metabolism. AB - Sphingolipids are membrane constituents as well as signaling molecules involved in many essential cellular processes. Serine palmitoyltransferase (SPT) and sphingosine-1-phosphate lyase (SPL), both PLP (pyridoxal 5'-phosphate)-dependent enzymes, function as entry and exit gates of the sphingolipid metabolism. SPT catalyzes the condensation of serine and a fatty acid into 3-keto dihydrosphingosine, whereas SPL degrades sphingosine-1-phosphate (S1P) into phosphoethanolamine and a long-chain aldehyde. The recently solved X-ray structures of prokaryotic homologs of SPT and SPL combined with functional studies provide insight into the structure-function relationship of the two enzymes. Despite carrying out different reactions, the two enzymes reveal striking similarities in the overall fold, topology, and residues crucial for activity. Unlike their eukaryotic counterparts, bacterial SPT and SPL lack a transmembrane helix, making them targets of choice for biochemical characterization because the use of detergents can be avoided. Both human enzymes are linked to severe diseases or disorders and might therefore serve as targets for the development of therapeutics aiming at the modulation of their activity. This review gives an overview of the sphingolipid metabolism and of the available biochemical studies of prokaryotic SPT and SPL, and discusses the major similarities and differences to the corresponding eukaryotic enzymes. PMID- 21710483 TI - Reply to Professor William J Waddell's letter concerning my paper entitled 'Long term feeding effects of stevioside sweetener on some toxicological parameters of growing male rats'. PMID- 21710484 TI - Single-molecule colocalization studies shed light on the idea of fully emitting versus dark single quantum dots. AB - In this report the correlation between the solution photoluminescence (PL) quantum yield and the fluorescence emission of individual semiconductor quantum dots (QDs) is investigated. This is done by taking advantage of previously reported enhancement in the macroscopic quantum yield of water-soluble QDs capped with dihydrolipoic acid (DHLA) when self-assembled with polyhistidine-appended proteins, and by using fluorescence coincidence analysis (FCA) to detect the presence of "bright" and "dark" single QDs in solution. This allows for changes in the fraction of the two QD species to be tracked as the PL yield of the solution is progressively altered. The results clearly indicate that in a dispersion of luminescent nanocrystals, "bright" (intermittently emitting) single QDs coexist with "permanently dark" (non-emitting) QDs. Furthermore, the increase in the fraction of emitting QDs accompanies the increase in the PL quantum yield of the solution. These findings support the idea that a dispersion of QDs consists of two optically distinct populations of nanocrystals--one is "bright" while the other is "dark;" and that the relative fraction of these two populations defines the overall PL yield. PMID- 21710485 TI - A new approach to in-situ "micromanufacturing": microfluidic fabrication of magnetic and fluorescent chains using chitosan microparticles as building blocks. AB - An in situ microfluidic assembly approach is described that can both produce microsized building blocks and assemble them into complex multiparticle configurations in the same microfluidic device. The building blocks are microparticles of the biopolymer chitosan, which is intentionally selected because its chemistry allows for simultaneous intraparticle and interparticle linking. Monodisperse chitosan-bearing droplets are created by shearing off a chitosan solution at a microfluidic T-junction with a stream of hexadecane containing a nonionic detergent. These droplets are then interfacially crosslinked into stable microparticles by a downstream flow of glutaraldehyde (GA). The functional properties of these robust microparticles can be easily varied by introducing various payloads, such as magnetic nanoparticles and/or fluorescent dyes, into the chitosan solution. The on-chip connection of such individual particles into well-defined microchains is demonstrated using GA again as the chemical "glue" and microchannel confinement as the spatial template. Chain flexibility can be tuned by adjusting the crosslinking conditions: both rigid chains and semiflexible chains are created. Additionally, the arrangement of particles within a chain can also be controlled, for example, to generate chains with alternating fluorescent and nonfluorescent microparticles. Such microassembled chains could find applications as microfluidic mixers, delivery vehicles, microscale sensors, or miniature biomimetic robots. PMID- 21710486 TI - Fast and cost-effective purification of gold nanoparticles in the 20-250 nm size range by continuous density gradient centrifugation. AB - A multilayer quasi-continuous density gradient centrifugation method for separating 20-250 nm metal colloids with high size resolution while maintaining particle stability is presented. Colloidal mixtures containing monodisperse gold nanospheres and clusters thereof, in particular, gold dimers, are purified with yields up to 94%. The rapid method uses standard laboratory equipment. PMID- 21710487 TI - High-throughput measurement, correlation analysis, and machine-learning predictions for pH and thermal stabilities of Pfizer-generated antibodies. AB - Generating stable antibodies is an important goal in the development of antibody based drugs. Often, thermal stability is assumed predictive of overall stability. To test this, we used different internally created antibodies and first studied changes in antibody structure as a function of pH, using the dye ANS. Comparison of the pH(50) values, the midpoint of the transition from the high-pH to the low pH conformation, allowed us for the first time to rank antibodies based on their pH stability. Next, thermal stability was probed by heating the protein in the presence of the dye Sypro Orange. A new data analysis method allowed extraction of all three antibody unfolding transitions and showed close correspondence to values obtained by differential scanning calorimetry. T(1%) , the temperature at which 1% of the protein is unfolded, was also determined. Importantly, no correlations could be found between thermal stability and pH(50) , suggesting that to accurately quantify antibody stability, different measures of protein stability are necessary. The experimental data were further analyzed using a machine-learning approach with a trained model that allowed the prediction of biophysical stability using primary sequence alone. The pH stability predictions proved most successful and were accurate to within pH +/-0.2. PMID- 21710488 TI - The S. mansoni glycoprotein omega-1 induces Foxp3 expression in NOD mouse CD4+ T cells. AB - Immunization with Schistosoma mansoni soluble antigen preparations protects non obese diabetic (NOD) mice against the development of type 1 diabetes. These preparations have long been known to induce Th2 responses in vitro and in vivo. Recently, two separate groups have reported that omega-1, a well-characterized glycoprotein in S. mansoni soluble egg antigens (SEA), which with IL-4 inducing principle of S. mansoni eggs (IPSE/alpha-1) is one of the two major glycoproteins secreted by live eggs, is a major SEA component responsible for this effect. We found that omega-1 induces Foxp3 as well as IL-4 expression when injected in vivo. We confirmed that omega-1 conditions DCs to drive Th2 responses and further demonstrated that omega-1 induces Foxp3(+) T cells from NOD mouse naive T cells. In contrast, IPSE/alpha-1 did not drive Foxp3 responses. The in vitro development of Foxp3-expressing T cells by omega-1 was TGF-beta- and retinoic acid-dependent. Our work, therefore, identifies omega-1 as an important factor for the induction of Foxp3(+) T cells by SEA in NOD mice. PMID- 21710489 TI - Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor. AB - Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naive T cells remain unclear. MSC influence on the differentiation of naive and memory CD4(+) T cells toward the Th17 phenotype was examined. CD4(+) T cells exposed to Th17-skewing conditions exhibited reduced CD25 and IL-17A expression following MSC co-culture. Inhibition of IL-17A production persisted upon re-stimulation in the absence of MSCs. These effects were attenuated when cell-cell contact was prevented. Th17 cultures from highly purified naive- and memory-phenotype responders were similarly inhibited. Th17 inhibition by MSCs was reversed by indomethacin and a selective COX-2 inhibitor. Media from MSC/Th17 co-cultures contained increased prostaglandin E2 (PGE2) levels and potently suppressed Th17 differentiation in fresh cultures. MSC-mediated Th17 inhibition was reversed by a selective EP4 antagonist and was mimicked by synthetic PGE2 and a selective EP4 agonist. Activation-induced IL-17A secretion by naturally occurring, effector memory Th17 cells from a urinary obstruction model was also inhibited by MSC co culture in a COX-dependent manner. Overall, MSCs potently inhibit Th17 differentiation from naive and memory T-cell precursors and inhibit naturally occurring Th17 cells derived from a site of inflammation. Suppression entails cell-contact-dependent COX-2 induction resulting in direct Th17 inhibition by PGE2 via EP4. PMID- 21710490 TI - Interleukin-6 signalling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in human oral squamous cell carcinoma. AB - Lymph node metastasis is associated with resistance to conventional therapy and poor survival of patients with oral squamous cell carcinoma (OSCC). Although lymphangiogenesis is well known to be associated with the occurrence of lymph node metastasis in various cancers, the precise mechanisms of lymphangiogenesis in OSCC are largely unknown. IL-6, a potent pro-inflammatory cytokine, has been shown to play active roles in various cancers, including OSCC. This study aimed to investigate the involvement of IL-6 signalling in lymphatic metastasis and to evaluate the efficacy of tocilizumab, a humanized anti-human IL-6 receptor antibody, as an anti-lymphangiogenic agent for OSCC. This investigation confirmed that levels of expression of IL-6 protein and VEGF-C mRNA in OSCC tissues were significantly correlated with lymph node metastasis in patients with OSCC, as assessed by immunohistochemical analysis and real-time quantitative RT-PCR. In vitro studies showed that IL-6 regulated VEGF-C mRNA expression in a human OSCC cell line, SAS cells, through the phosphoinositide 3-kinase-Akt pathway. In addition, treatment with tocilizumab led to markedly reduced VEGF-C mRNA expression and OSCC-related lymphangiogenesis in SAS xenografts. Together, these data suggest that tocilizumab acted as expected: it inhibited lymph node metastasis in OSCC by reducing tumour lymphangiogenesis. PMID- 21710491 TI - Interleukin-6 promotes tumorigenesis by altering DNA methylation in oral cancer cells. AB - Worldwide oral squamous cell carcinoma (OSCC) accounts for more than 100,000 deaths each year. Chronic inflammation constitutes one of the key risk factors for OSCC. Accumulating evidence suggests that aberrant DNA methylation may contribute to OSCC tumorigenesis. This study investigated whether chronic inflammation alters DNA methylation and expression of cancer-associated genes in OSCC. We established an in vitro model of interleukin (IL)-6 mediating chronic inflammation in OSCC cell lines. Thereafter, we measured the ability of IL-6 to induce global hypomethylation of long interspersed nuclear element-1 (LINE-1) sequences, as well as CpG methylation changes using multiple methodologies including quantitative pyrosequencing, methylation-specific multiplex ligation dependent probe amplification and sensitive melting analysis after real-time methylation-specific polymerase chain reaction (PCR). Gene expression was investigated by quantitative reverse transcriptase-PCR. IL-6 induced significant global LINE-1 hypomethylation (p=0.016) in our in vitro model of inflammatory stress in OSCC cell lines. Simultaneously, IL-6 induced CpG promoter methylation changes in several important putative tumor suppressor genes including CHFR, GATA5 and PAX6. Methylation changes correlated inversely with the changes in the expression of corresponding genes. Our results indicate that IL-6-induced inflammation promotes tumorigenesis in the oral cavity by altering global LINE-1 hypomethylation. In addition, concurrent hypermethylation of multiple tumor suppressor genes by IL-6 suggests that epigenetic gene silencing may be an important consequence of chronic inflammation in the oral cavity. These findings have clinical relevance, as both methylation and inflammation are suitable targets for developing novel preventive and therapeutic measures. PMID- 21710492 TI - ERK2 is essential for the growth of human epithelioid malignant mesotheliomas. AB - Members of the extracellular signal-regulated kinase (ERK) family may have distinct roles in the development of cell injury and repair, differentiation and carcinogenesis. Here, we show, using a synthetic small-molecule MEK1/2 inhibitor (U0126) and RNA silencing of ERK1 and 2, comparatively, that ERK2 is critical to transformation and homeostasis of human epithelioid malignant mesotheliomas (MMs), asbestos-induced tumors with a poor prognosis. Although MM cell (HMESO) lines stably transfected with shERK1 or shERK2 both exhibited significant decreases in cell proliferation in vitro, injection of shERK2 cells, and not shERK1 cells, into immunocompromised severe combined immunodeficiency (SCID) mice showed significant attenuated tumor growth in comparison to shControl (shCon) cells. Inhibition of migration, invasion and colony formation occurred in shERK2 MM cells in vitro, suggesting multiple roles of ERK2 in neoplasia. Microarray and quantitative real-time PCR analyses revealed gene expression that was significantly increased (CASP1, TRAF1 and FAS) or decreased (SEMA3E, RPS6KA2, EGF and BCL2L1) in shERK2-transfected MM cells in contrast to shCon-transfected MM cells. Most striking decreases were observed in mRNA levels of Semaphorin 3 (SEMA3E), a candidate tumor suppressor gene linked to inhibition of angiogenesis. These studies demonstrate a key role of ERK2 in novel gene expression critical to the development of epithelioid MMs. After injection of sarcomatoid human MM (PPMMill) cells into SCID mice, both shERK1 and shERK2 lines showed significant decreased tumor growth, suggesting heterogeneous effects of ERKs in individual MMs. PMID- 21710493 TI - The NP9 protein encoded by the human endogenous retrovirus HERV-K(HML-2) negatively regulates gene activation of the Epstein-Barr virus nuclear antigen 2 (EBNA2). AB - Epstein-Barr virus (EBV) is a human tumour virus that efficiently growth transforms primary human B-lymphocytes in vitro. The viral nuclear antigen 2 (EBNA2) is essential for immortalisation of B-cells and stimulates viral and cellular gene expression through interaction with DNA-bound transcription factors. Like its cellular homologue Notch, it associates with the DNA-bound repressor RBPJkappa (CSL/CBF1) thereby converting RBPJkappa into the active state. For instance, both EBNA2 and Notch activate the cellular HES1 promoter. In EBV-transformed lymphocytes, the RNA of the NP9 protein encoded by human endogenous retrovirus HERV-K(HML-2) Type 1 is strongly up-regulated. The NP9 protein is detectable both in EBV-positive Raji cells, a Burkitt's lymphoma cell line, and in IB4, an EBV-transformed human lymphoblastoid cell line. NP9 binds to LNX that forms a complex with the Notch regulator Numb. Therefore, the function of NP9 vis-a-vis Notch and EBNA2 was analysed. Here, we show that NP9 binds to EBNA2 and negatively affects the EBNA2-mediated activation of the viral C- and LMP2A promoters. In contrast, NP9 did neither interfere in the activation of the HES1 promoter by Notch nor the induction of the viral LMP1 promoter by EBNA2. In an electrophoretic mobility shift analysis, NP9 reduced the binding of EBNA2 to DNA-bound RBPJkappa by about 50%. The down-regulation of EBNA2-activity by NP9 might represent a cellular defence mechanism against viral infection or could, alternatively, represent an adaptation of the virus to prevent excessive viral protein production that might otherwise be harmful for the infected cell. PMID- 21710494 TI - Interleukin (IL)-18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor. AB - Interleukin (IL)-18 is a proinflammatory and immune-enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)gamma. We previously reported that IL-18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (pro-IL-18) in vitro. In addition, IL-18 was reported as a potential biomarker of EOC. Here, we further investigated its role as a serological marker in human EOC and addressed its possible biological activity in vivo. Our data indicate that immunoreactive IL-18 is increased in EOC patients' sera at diagnosis as compared with age-matched healthy women. IL-18 levels were higher in the ascitic fluids than in sera, suggesting a local production in the peritoneal cavity. Indeed, immunohistochemical analysis of tumors showed IL-18 expression in cytokeratine positive neoplastic cells, although also scattered histiocytes and some lymphoid cells stained for IL-18. The detection of human IL-18 in sera and ascitic fluids of immunodeficient mice, orthotopically implanted with human EOC cells, further suggested that circulating IL-18 is tumor-derived. However, IL-18 is not an EOC specific biomarker, as increased serum levels were found also in some endometrial cancer patients. By means of a new monoclonal antibody, we characterized IL-18 present in the ascitic fluid as pro-IL-18, which is biologically inactive. Accordingly, IFNgamma was not increased in EOC patients' sera and ascitic fluids and showed no correlation with IL-18 levels. Altogether these data indicate that IL-18 in EOC fluids is predominantly tumor-derived and that its lack of biological activity may represent a mechanism of tumor-escape. PMID- 21710495 TI - UV irradiation of immunized mice induces type 1 regulatory T cells that suppress tumor antigen specific cytotoxic T lymphocyte responses. AB - We previously showed that exposure to UV radiation after immunization suppresses Th1 and Th2 immune responses, leading to impaired Ab and allo-immune responses, but the impact of UV radiation after immunization on anti-tumor immune responses mediated by tumor-specific CD8(+) T cell responses remains less clear. Furthermore, the exact phenotypic and functional characteristics of regulatory T cell population responsible for the UV-induced immunosuppression still remain elusive. Using the MBL-2 lymphoma cell line engineered to express OVA as a surrogate tumor Ag, here we demonstrate that UV irradiation after tumor Ag immunization suppresses the anti-tumor immune response in a manner dependent on the immunizing Ag. This suppression was mediated by interleukin (IL)-10 released from CD4(+) CD25(+) T cells, by which impaired the induction of cytotoxic T lymphocytes (CTL) able to kill Ag-expressing tumor cells. In addition, we generated a panel of T cell clones from UV-irradiated and non-irradiated mice, and all of the clones derived from UV-irradiated mice had a Tr1-type regulatory T cell phenotype with expression of IL-10 and c-Maf, but not Foxp3. These Tr1-type regulatory T cell clones suppressed tumor rejection in vivo as well as Th cell activation in vitro in an IL-10 dependent manner. Given that suppression of Ag specific CTL responses can be induced in Ag-sensitized mice by UV irradiation, our results may imply that exposure to UV radiation during premalignant stage induces tumor-Ag specific Tr1 cells that mediate tumor-Ag specific immune suppression resulting in the promotion of tumor progression. PMID- 21710496 TI - MAGE-A10 is a nuclear protein frequently expressed in high percentages of tumor cells in lung, skin and urothelial malignancies. AB - MAGE-A10 is a highly immunogenic member of the MAGE-A family of cancer/testis tumor-associated antigens (C/T TAAs). Studies performed with broadly reactive antibodies have helped to initially characterize this TAA. However, no specific reagents have been developed so far, thus preventing a thorough analysis of its expression in healthy and tumoral tissues. We have produced MAGE-A10 gene product in soluble recombinant form, and we have used it to generate specific monoclonal antibodies (mAbs). One of these reagents, recognizing an epitope located at the COOH terminus of the MAGE-A10 gene product, was used to stain a multitumor tissue microarray comprising more than 2,500 paraffin-embedded specimens including healthy tissues, benign tumors and malignancies of different histological origin. MAGE-A10 protein was identified as an intranuclear protein of an apparent molecular weight of 70 kDa, expressed in normal spermatogonia and spermatocytes but in no other healthy tissue. Most importantly, this C/T TAA appears to be expressed in high (>50%) percentages of cancer cells from a number of malignancies, including lung, skin and urothelial tumors. Unexpectedly, high expression of MAGE-A10 TAA at the protein level was also detectable in gynecological malignancies and stomach and gall bladder cancers. The characterization of MAGE-A10-specific reagents might set the stage for the development of targeted active immunotherapy by clarifying potential indications and by allowing the selection of patients eligible for treatment and the monitoring of its effectiveness. PMID- 21710498 TI - Effects of interferon treatment on development and progression of hepatocellular carcinoma in patients with chronic virus infection: a meta-analysis of randomized controlled trials. AB - Available literature on the effects of interferon (IFN) treatment on development and progression of hepatocellular carcinoma (HCC) in patients with chronic virus infection reports controversial results. The primary objective of this meta analysis was to evaluate the effect of IFN on HCC risk in patients with chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection; IFN's efficacy on local tumor progression and survival of advanced HCC patients was also assessed. All randomized controlled trials (RCTs) comparing IFN with no antiviral treatment were selected. Finally, we identified 11 RCTs including 1,772 patients, who met our inclusion criteria to perform this meta-analysis. Our analysis results showed that IFN significantly decreased the overall HCC incidence in HCV-infected patients [relative risk (RR)=0.39; 95% confidence interval (CI)=0.26-0.59; p=0.000], subgroup analysis indicated that IFN decreased HCC incidence in HCV related cirrhotic patients evidently (RR=0.44; 95% CI=0.28-0.68; p=0.000); but HCC incidence in nonresponders to initial antiviral therapy did not reduce by maintenance IFN therapy (RR=0.96; 95% CI=0.59-1.56; p=0.864). Analysis results also demonstrated that IFN did not significantly affect the overall rate of HCC in HBV-infected patients although there was a trend favoring IFN therapy (RR=0.23; 95% CI=0.05-1.04; p=0.056). Besides, IFN did not improve one-year overall survival of advanced HCC patients significantly (RR=1.61; 95% CI=0.96 2.69; p=0.072); however, a quantitative analysis on local tumor progression could not be performed owing to lack of unified definitions among trials included in our study. By this meta-analysis, we conclude that IFN therapy is effective in reducing overall HCC risk in chronic HCV-infected patients; using it in this subpopulation seems promising, but its administration in other subpopulations still requires further exploration. PMID- 21710497 TI - EpCAM- and EGFR-targeted selective gene therapy for biliary cancers using Z33 fiber-modified adenovirus. AB - A critical issue in adenovirus (Ad)-based cancer gene therapy is to improve the specificity of gene delivery to cancer cells for better efficacy and safety. We explored methods of retargeting Ad vectors for selective gene therapy of human biliary cancers using the Ad incorporating an IgG Fc-binding motif (Z33) from the Staphylococcus protein A (Ad-FZ33) combined with tumor-specific antibodies. Flow cytometry analysis revealed high-expression levels of epithelial cell adhesion molecule (EpCAM) and epidermal growth factor receptor (EGFR) on human biliary cancer cells. Ad-FZ33 expressing LacZ combined with antibodies against EpCAM or EGFR, followed by beta-gal assay, demonstrated highly efficient gene transduction in these biliary cancer cells, compared to the treatment with control antibody or without antibody. Ad-FZ33 expressing uracil phosphoribosyl transferase (UPRT), an enzyme which greatly enhances the toxicity of 5-fluorouracil (FU), combined with antibodies against EpCAM or EGFR, remarkably enhanced the sensitivity of biliary cancer cells to 5-FU. By contrast, the treatment did not affect the 5-FU sensitivity of the cells not expressing EpCAM or EGFR including normal hepatocytes. Finally, treatments with the UPRT-expressing Ad-FZ33 with antibodies against EpCAM or EGFR, followed by 5-FU administration, significantly suppressed the growth of biliary cancer xenografts in nude mice. These results indicate that the gene therapy mediated by the Z33 fiber modified Ad with anti-EpCAM or anti EGFR antibodies offers a potentially effective therapeutic modality against biliary cancers. PMID- 21710499 TI - YB-1 dependent virotherapy in combination with temozolomide as a multimodal therapy approach to eradicate malignant glioma. AB - The human Y-box binding protein 1 (YB-1) is known to be a promising target for cancer therapy. We have demonstrated that YB-1 plays an important role in the adenoviral life cycle by regulating the adenoviral E2-gene expression. Thus, we studied the oncolytic effect of the recombinant adenovirus Ad-Delo3-RGD, in which the transactivation domain CR3 of the E1A protein is ablated to enable viral replication only in YB-1 positive cancer cells. In vitro Southern Blot analysis and cytopathic effect assays demonstrate high anti-glioma potency, which was significantly increased in combination with temozolomide (TMZ), daunorubicin and cisplatin. Since vascular endothelial growth factor (VEGF) is thought to promote the hypervascular phenotype of primary, malignant brain tumors, we also tested Ad Delo3-RGD in regard to the inhibition of VEGF expression. Indeed, we found that Ad-Delo3-RGD induced VEGF down regulation, which was even amplified under hypoxic conditions. Tumor-bearing nudemice treated with the YB-1 dependent oncolytic adenovirus showed significantly smaller tumors than untreated controls. Furthermore, combination therapy with TMZ led to a regression in all treated animals with complete tumor regression in 33 % of analyzed mice, which was verified by bioluminescence imaging and histological studies. In addition, histopathological evaluation revealed enhanced apoptosis and a reduction in tumor vessel formation, indicating that Ad-Delo3-RGD has an anti-angiogenic effect in addition to its oncolytic capacity in vivo. Hence, our results demonstrate that the combination therapy of YB-1 dependent virotherapy and TMZ is effective in a xenograft glioma mouse model and might be useful in a YB-1 based clinical setting. PMID- 21710500 TI - Antabuse (disulfiram) as an affordable and promising anticancer drug. PMID- 21710502 TI - Tumour lysis syndrome in children: experience of last decade. AB - The strategy against tumour lysis syndrome (TLS) had been hyperhydration, urine alkalinization, and allopurinol. Recently, rasburicase was added to the armament against this life-threatening condition. In Korea, rasburicase is used as a rescue therapy for cases with allopurinol-resistant hyperuricemia, because of the restriction by the National Health Insurance. We reviewed our experiences to re assess the risk factors of TLS and the efficacy of rasburicase. Medical records were retrospectively reviewed for 396 children who were diagnosed as positive with acute leukemia and non-Hodgkin lymphoma between the years 2000 and 2009. The risk factors for TLS were analyzed statistically, and those before and after the availability of rasburicase were compared. Sixty eight patients (17.2%) had TLS. Multivariate analysis showed that pre-chemotherapy hypophosphatemia was a risk factor for TLS, in addition to the known risk factors of hyperuricemia and high lactate dehydrogenase concentration. The availability of rasburicase as a rescue therapy did not negate the importance of uric acid as a risk factor of TLS. Rasburicase as a second line treatment for intractable hyperuricemia was not effective in reducing the incidence of TLS. Pre-chemotherapy hypophosphatemia was a significant independent risk factor for TLS. PMID- 21710503 TI - The IPOS new International Standard of Quality Cancer Care: integrating the psychosocial domain into routine care. PMID- 21710504 TI - How do we establish a biological marker for a behaviorally defined disorder? Autism as a test case. AB - We discuss the recent push to develop support vector machines and other cluster analyses as a means for biological signatures as early screens for autism. These methods not only hold great promise but also require careful consideration prior to implementation. We outline three validity tests and potential methods for addressing them. PMID- 21710505 TI - Zebrafish neurotoxicity from aphantoxins--cyanobacterial paralytic shellfish poisons (PSPs) from Aphanizomenon flos-aquae DC-1. AB - Aphanizomenon flos-aquae (A. flos-aquae), a cyanobacterium frequently encountered in water blooms worldwide, is source of neurotoxins known as PSPs or aphantoxins that present a major threat to the environment and to human health. Although the molecular mechanism of PSP action is well known, many unresolved questions remain concerning its mechanisms of toxicity. Aphantoxins purified from a natural isolate of A. flos-aquae DC-1 were analyzed by high-performance liquid chromatography (HPLC), the major component toxins were the gonyautoxins1 and 5 (GTX1 and GTX5, 34.04% and 21.28%, respectively) and the neosaxitoxin (neoSTX, 12.77%). The LD50 of the aphantoxin preparation was determined to be 11.33 MUg/kg (7.75 MUg saxitoxin equivalents (STXeq) per kg) following intraperitoneal injection of zebrafish (Danio rerio). To address the neurotoxicology of the aphantoxin preparation, zebrafish were injected with low and high sublethal doses of A. flos-aquae DC-1 toxins 7.73 and 9.28 MUg /kg (5.3 and 6.4 MUg STXeq/kg, respectively) and brain tissues were analyzed by electron microscopy and RT-PCR at different timepoints postinjection. Low-dose aphantoxin exposure was associated with chromatin condensation, cell-membrane blebbing, and the appearance of apoptotic bodies. High-dose exposure was associated with cytoplasmic vacuolization, mitochondrial swelling, and expansion of the endoplasmic reticulum. At early timepoints (3 h) many cells exhibited characteristic features of both apoptosis and necrosis. At later timepoints apoptosis appeared to predominate in the low-dose group, whereas necrosis predominated in the high-dose group. RT-PCR revealed that mRNA levels of the apoptosis-related genes encoding p53, Bax, caspase-3, and c-Jun were upregulated after aphantoxin exposure, but there was no evidence of DNA laddering; apoptosis could take place by pathways independent of DNA fragmentation. These results demonstrate that aphantoxin exposure can cause cell death in zebrafish brain tissue, with low doses inducing apoptosis and higher doses inducing necrosis. PMID- 21710506 TI - Experimental test of absorption flattening correction for circular dichroism of particle suspensions. AB - There are well established theoretical models for correction for absorption flattening of circular dichroism (CD) measurements on particle suspensions. However, these have not been directly tested experimentally. We describe a test system with the chiral tris(ethylenediamine)Co(III) complex dissolved in water trapped inside sephadex particles, suspended in 1-butanol. Independent measurements of particle size distribution, volume fraction, and the absorbance of the suspension are used to calculate the required CD correction. The corrected CD signal is found to agree rather well with that for the same amount of Co complex dispersed uniformly throughout the sample cell. This holds for different particle volume fractions and Co-complex concentrations inside the particles. The correction seems to work despite a substantial scattering contribution to the absorbance, which is not considered in the theoretical models. PMID- 21710507 TI - Characterization of new topical ketoprofen formulations prepared by drug entrapment in solid lipid matrices. AB - This paper describes the evaluation of a new pharmaceutical formulation based on ketoprofen entrapment in a solid lipid particle (SLP) matrix. The drug-SLP samples, which were elaborated using a processing technology based on supercritical CO(2) , consisted of a model of a controlled-release system for topical applications. Some of the samples contained silanized TiO(2) as an additional ingredient to increase the interaction between drug and lipid matrix. The study of the sample features relied on reversed-phase high-performance liquid chromatography with a C(18) column and ultraviolet spectroscopic detection at 266 nm. Characterization assays comprised the determination of the overall amount of ketoprofen in the samples, the assessment of the release-permeation kinetic profiles, and the evaluation of impurities and decomposition products. The release and permeation of encapsulated ketoprofen were assayed at 32 degrees C and pH 6.8 by using a static diffusion cell. Results showed a sustained drug delivery for at least 24 h. Besides, no degradation species were detected throughout the release-permeation processes, which indicated that the stability of the drug in the SLP system was preserved. PMID- 21710508 TI - Toward an integrated human clearance prediction strategy that minimizes animal use. AB - Prediction of human clearance plays a critical role in early drug discovery and development. However, there is no consensus on the most appropriate method to gather such data. A variety of in vivo and in vitro methods exist and a comparison of in vitro data from a standard set of compounds has been called for. This paper compares the predictive capacity of human liver microsomes and single species scaling (SSS) from rat and non-human primate for a standard set of compounds representing marketed drugs. The results enable a framework to be proposed wherein compounds are selected using in vitro methods alone or in vitro methods combined with SSS in the rat. Further investigation of this framework has the potential to increase the efficiency of drug discovery and reduce animal use. PMID- 21710509 TI - Enhancement and degradation of the R2* relaxation rate resulting from the encapsulation of magnetic particles with hydrophilic coatings. AB - The effects of including a hydrophilic coating around the particles are studied across a wide range of particle sizes by performing Monte Carlo simulations of protons diffusing through a system of magnetic particles. A physically realistic methodology of implementing the coating by cross boundary jump scaling and transition probabilities at the coating surface is developed. Using this formulation, the coating has three distinct impacts on the relaxation rate: an enhancement at small particle sizes, a degradation at intermediate particle sizes, and no effect at large particles sizes. These varied effects are reconciled with the underlying dephasing mechanisms by using the concept of a full dephasing zone to present a physical picture of the dephasing process with and without the coating for all sizes. The enhancement at small particle sizes is studied systemically to demonstrate the existence of an optimal ratio of diffusion coefficients inside/outside the coating to achieve maximal increase in the relaxation rate. PMID- 21710510 TI - On the road towards chemically modified organisms endowed with a genetic firewall. PMID- 21710511 TI - A process for the synthesis of formic acid by CO2 hydrogenation: thermodynamic aspects and the role of CO. PMID- 21710512 TI - Mutual activation: Suzuki-Miyaura coupling through direct cleavage of the sp2 C-O bond of naphtholate. PMID- 21710513 TI - Dynamic one-pot three-component catalytic asymmetric transformation by combination of hydrogen-bond-donating and amine catalysts. PMID- 21710514 TI - A highly active titanium dioxide based visible-light photocatalyst with nonmetal doping and plasmonic metal decoration. PMID- 21710515 TI - Duality in catalyst design: the synergistic coupling of steric and stereoelectronic control over polyolefin microstructure. PMID- 21710516 TI - Practical one-pot preparation of magnesium di(hetero)aryl- and magnesium dialkenylboronates for Suzuki-Miyaura cross-coupling reactions. PMID- 21710517 TI - Gold-catalyzed transformation of 2-alkynyl arylazides: efficient access to the valuable pseudoindoxyl and indolyl frameworks. PMID- 21710518 TI - Simple determination of double-bond positions in long-chain olefins by cross metathesis. PMID- 21710519 TI - No contribution of an inductive effect to secondary deuterium isotope effects on acidity. PMID- 21710520 TI - Interfacial photoreduction of supercritical CO2 by an aqueous catalyst. PMID- 21710521 TI - High charge mobility in discotic liquid-crystalline triindoles: just a core business? PMID- 21710522 TI - Photoisomerization around a fulvene double bond: coherent population transfer to the electronic ground state? AB - Photoisomerization around a central fulvene-type double bond is known to proceed through a conical intersection at the perpendicular geometry. The process is studied with an indenylidene-dihydropyridine model compound, allowing the use of visible excitation pulses. Transient absorption shows that 1) stimulated emission shifts to the red and loses oscillator strength on a 50 fs timescale, and 2) bleach recovery is highly nonexponential and not affected by solvent viscosity or methyl substitution at the dihydropyridine ring. Quantum-chemical calculations are used to explain point 1 as a result of initial elongation of the central C=C bond with mixing of S(2) and S(1) states. From point 2 it is concluded that internal conversion of S(1)->S(0) does not require torsional motion to the fully perpendicular state. The S(1) population appears to encounter a sink on the torsional coordinate before the conical intersection is reached. Rate equations cannot model the observed ground-state recovery adequately. Instead the dynamics are best described with a strongly damped oscillatory contribution, which could indicate coherent S(1)-S(0) population transfer. PMID- 21710523 TI - Femtosecond decay dynamics of intact adenine and thymine base pairs in a supersonic jet. AB - We investigated the decay dynamics of the DNA base pairs adenine-adenine (A(2)), adenine-thymine (AT), and thymine-thymine (T(2)) produced in a supersonic jet by femtosecond (fs) time-resolved photoionization spectroscopy. The base pair was excited by a fs pump pulse at 267 nm and the population change of its excited state was monitored by non-resonant three-photon ionization using a fs probe pulse at 800 nm after a certain time delay. All of the transients recorded in the mass channel of the parent ion exhibited a tri-exponential decay, with time constants ranging from 100 fs to longer than 100 ps. Most of these time constants coincide well with the previous values deduced indirectly from the transients of protonated adenine (AH(+)) and thymine (TH(+)), which were assumed to be produced by fragmentation of the base-pair ions. Notably, for the transient of T(2), we observed a new decay component with a time constant of 2.3 ps, which was absent in the transient of TH(+). We suggest that the new decay component arises from the decay of stacked T(2) dimers that are mostly ionized to T(2)(+), whereas the decay signal recorded in the mass channel of TH(+) is merely from the relaxation of hydrogen-bonded T(2) dimers. From the amplitude of the new decay component, the population of the stacked T(2) dimers relative to the hydrogen-bonded dimers was estimated to be ~2 % in the supersonic jet, which is about fifteen times higher than the theoretical value. PMID- 21710525 TI - Sulfonated cyclofructan 6 based stationary phase for hydrophilic interaction chromatography. AB - A stationary phase composed of silica-bonded sulfonated cyclofructan 6 (SCF6) was synthesized and evaluated for hydrophilic interaction chromatography (HILIC). The separation of a large variety of polar compounds was evaluated on different versions of the stationary phase and compared with the same separations obtained with commercially available HILIC columns. The new columns successfully separate polar and hydrophilic compounds including beta blockers, xanthines, salicylic acid related compounds, nucleic acid bases, nucleosides, maltooligosaccharides, water soluble vitamins and amino acids. The separation conditions were optimized by changing the composition and the pH of the mobile phase. The dependence of analyte retention on temperature was studied using van't Hoff plots. The newly synthesized stationary phase showed broad applicability for HILIC mode separations. PMID- 21710526 TI - Silica-based and organic monolithic capillary columns for LC: recent trends in proteomics. AB - The use of monolithic liquid chromatography (LC) columns for proteomics, covering the scientific literature from 2004 to the beginning of 2011, is reviewed. Attention is paid to recent developments in column technology and materials, focusing on silica-based and organic (polystyrene and methacrylate) monolithic capillary columns for proteomics. The applicability of these columns is illustrated by examples of the analysis of (complex) protein digests and proteins conveniently summarized in tables. Furthermore, characteristics of column materials are compared and future trends and prospects are presented. PMID- 21710527 TI - Determination of bisphenol-A levels in human amniotic fluid samples by liquid chromatography coupled with mass spectrometry. AB - Bisphenol A (BPA) is one of the environmental endocrine-disrupting chemicals used widely in common consumer products. There is an increasing concern about human exposure to BPA, particularly in fetuses, due to the potential adverse effects related to the estrogenic activity of BPA. In assessing environmental exposure to BPA, it is essential to have a sensitive, accurate, and specific analytical method, particularly for low BPA levels in complex sample matrices. In this study, we developed and validated an accurate, sensitive, and robust liquid chromatography-mass spectrometry (LC-MS) method for determining the BPA concentrations in human amniotic fluid (AF). In this method, BPA and the internal standards (13)C(12) -BPA were extracted from 500 MUL of human AF using solid phase extraction. Calibration curves were linear over a concentration range of 0.3-100 ng/mL for BPA. The analytes were quantitatively determined using LC-MS operated in a negative electrospray ionization selected ion monitoring mode. This validated method has been used successfully in the clinical sample analysis of BPA in second-trimester AF specimens. PMID- 21710528 TI - Photocatalytically active polyelectrolyte/nanoparticle films for the elimination of a model odorous gas. AB - Virtually transparent films of Aeroxide TiO(2) P25 were fabricated via layer-by layer assembly with sodium poly(styrene sulfonate). Nanoscale films are formed on model surfaces for characterization or inside of cylindrical reactors for investigating the catalytic properties. Films are fairly homogeneous and smooth over large areas and show different optical interference colors depending on film thickness. The application-relevant photocatalytic performance of such films toward on-flow degradation of hydrogen sulfide under UV-A irradiation was investigated. Scanning electron microscopy reveals a nanoporous structure allowing for the permeation of gas. Consequently, the catalytic efficiency of the films increases with increasing film thickness retaining a considerable activity of the corresponding nanoparticle powder. Scheme 1 depicts in a general way the functionalized reactor and the principle of the measurement. PMID- 21710529 TI - Application of poly(3-hexylthiophene) functionalized with an anchoring group in dye-sensitized solar cells. AB - A series of three poly(3-hexylthiophene) functionalized either with a cyanoacetic acid (CA) or a rhodanine-3-acetic acid anchoring groups were synthesized and characterized. The TiO(2) based dye-sensitized solar cells have been fabricated and performances were tested. We show that shorter chain length (15 thiophene units) linked to CA binding group gives good performances as J(sc) , V(oc) , FF and eta(%) were 6.93(mA . cm(-2) ), 0.65(V), 0.67 and 3.02%, respectively. A maximum IPCE of ~50% at 500 nm was recorded with a liquid electrolyte, under AM 1.5 simulated solar irradiance. PMID- 21710530 TI - Well-defined biobased segmented polyureas synthesis via a TBD-catalyzed isocyanate-free route. AB - Via an isocyanate-free route, a series of segmented polyureas (PUs) were synthesized from (potentially) renewable resources. To the best of our knowledge, the present work shows for the first time that the organic superbase guanidine 1,5,7-triazabicyclododecene (TBD) which was originally developed as a catalyst for the ring-opening polymerization of lactones, lactides or cyclic carbonates, is also a promising catalyst for the transurethanization between dicarbamates and diamino-terminated poly(propylene glycol) (PPGda) providing PUs via an isocyanate free strategy. The renewable segmented PUs contain monodisperse hard segments (HSs). This well-defined structure was verified by the DMTA plots of the PUs, showing a sharp glass transition, a sharp flow transition and a flat rubbery plateau. The flow and maximum use temperature (Tfl ) of the PUs increases with the increasing number of urea groups in the corresponding dicarbamates. In addition, at constant HS length, the length of the soft-segment (SS) can be changed to adjust the properties of the PU materials, enabling their application as adhesives, soft elastomers, or rigid plastics. PMID- 21710531 TI - Diversified applications of chemically modified 1,2-polybutadiene. AB - Commercially available 1,2-PB was transformed into a well-defined reactive intermediate by quantitative bromination. The brominated polymer was used as a polyfunctional macroinitiator for the cationic ring-opening polymerization of 2 ethyl-2-oxazoline to yield a water-soluble brush polymer. Nucleophilic substitution of bromide by 1-methyl imidazole resulted in the formation of polyelectrolyte copolymers consisting of mixed units of imidazolium, bromo, and double bond. These copolymers, which were soluble in water without forming aggregates, were used as stabilizers in the heterophase polymerization of styrene and were also studied for their ionic conducting properties. PMID- 21710532 TI - Renewable polyethylene mimics derived from castor oil. AB - An increasing number of reports on the syntheses of carbohydrate- and plant oil based polymers has been published in ongoing efforts to produce plastic materials from renewable resources. Although many of these polymers are biodegradable and this is a desirable property for certain applications, in some cases non degradable polymers are needed for long-term use purposes. Polyolefins are one of the most important classes of materials that have already taken their places in our daily life. On the other hand, their production relies on fossil resources. Therefore, within this contribution, we discuss synthetic routes toward a number of polyethylene mimics derived from fatty acids via thiol-ene and ADMET polymerization reactions in order to establish more sustainable routes toward this important class of polymers. Two different diene monomers were thus prepared from castor oil derived platform chemicals, their polymerization via the two mentioned routes was optimized and compared to each other, and their thermal properties were investigated. PMID- 21710533 TI - Cytomegalovirus associated hemophagocytic lymphohistiocytosis in patients suffering from Crohn's disease treated by azathioprine: a series of four cases. PMID- 21710534 TI - Association of peroxisome proliferator-activated receptor gamma polymorphisms with inflammatory bowel disease in a Hungarian cohort. AB - BACKGROUND: Inflammatory bowel disease (IBD) shows increasing incidence in the last few years in Eastern Europe, including Hungary. Since genetic susceptibility of patients plays an important role in the development and pathogenesis of IBD, it is important to identify new susceptibility genes. Peroxisome proliferator activated receptor gamma (PPARgamma) is expressed in the colon and has protective effects against inflammatory processes. Our aim was to examine the association of four polymorphisms of PPARgamma in a well-characterized Hungarian IBD cohort. METHODS: In all, 575 Crohn's disease (CD), 103 ulcerative colitis (UC) patients, and 486 sex- and age-matched controls were examined. Four polymorphisms of PPARgamma (rs10865710 [C-681G], rs2067819, rs3892175, and rs1801282 [Pro12Ala]) were genotyped by TaqMan genotyping assays. RESULTS: The Pro12Ala polymorphism showed significant association with CD when the frequencies of the homozygous variants (Pro/Pro vs. Ala/Ala) were compared. The minor Ala/Ala genotype was significantly less frequent in CD patients compared to the controls (odds ratio [OR] = 0.33; 95% confidence interval [CI] = 012-0.94; P = 0.03), suggesting a potential protective effect of the Ala allele. The GAGG haplotype of PPARgamma confers a protective effect in CD; however, it is not significant, but in UC it has a protective effect with a significant level (OR = 0.14; 95% CI: 0.05-0.42; P = 3.78 * 10(-5) ), while GAGC increases the risk of UC (OR = 6.70; 95% CI: 3.41 13.17; P = 3.85 * 10(-10) ). CONCLUSIONS: In the present study we demonstrated a significant association between PPARgamma polymorphisms and the development of CD and UC at single loci level and also in haplotype combinations. PMID- 21710535 TI - Computed tomography enterography findings correlate with tissue inflammation, not fibrosis in resected small bowel Crohn's disease. AB - BACKGROUND: It has become commonplace to categorize small intestinal Crohn's disease (CD) as "active" vs. "inactive" or "inflammatory" vs. "fibrotic" based on computed tomography enterography (CTE) findings. Data on histologic correlates of CTE findings are lacking. We aimed to compare CTE findings with histology from surgically resected specimens. We tested the hypothesis that CTE findings can distinguish tissue inflammation from fibrosis. METHODS: Patients who underwent CTE within 3 months before intestinal resection for CD were retrospectively studied. Radiologists blinded to history and histology scored findings on CTE. Pathologists blinded to history and imaging scored resected histology. We compared histology with CTE findings and radiologists assessment of whether the stricture was likely "active" or "inactive." RESULTS: In all, 22 patients met inclusion criteria. Inflammatory CTE findings correlated with histologic inflammation (rho = 0.52). Strictures believed to be "active" on CTE were more inflamed at histology (P = 0.0002). Strictures lacking inflammatory findings on CTE or considered "inactive" were not associated with greater histologic fibrosis or significant histologic inflammation. Upstream dilation was associated with greater tissue fibrosis in univariate (P = 0.014) but not in multivariate analysis (P = 0.53). Overall, histologic fibrosis correlated best with histologic inflammation (rho = 0.52). Strictures on CTE with the most active disease activity also had the most fibrosis on histology. CONCLUSIONS: CTE findings of mesenteric hypervascularity, mucosal hyperenhancement, and mesenteric fat stranding predict tissue inflammation. However, small bowel stricture without CTE findings of inflammation does not predict the presence of tissue fibrosis. Therefore, caution should be used when using CTE criteria to predict the presence of scar tissue. PMID- 21710537 TI - Can we kill an extra bird with the same stone? PMID- 21710538 TI - Enterolith and small bowel perforation in Crohn's disease. PMID- 21710539 TI - Occupational mortality associated with inflammatory bowel disease in the United States 1984-1998. AB - BACKGROUND: The occurrence of Crohn's disease (CD) and ulcerative colitis (UC) is shaped by environmental influences. Many such environmental risk factors vary potentially with occupational exposure. We used a large national database to study the occupational variation of mortality associated with CD and UC. METHODS: The National Occupational Mortality Surveillance database contains data from the death certificate linked with information about the occupation and industry of each deceased individual. Deaths were grouped by gender, ethnicity, disease type, occupation, and industry. Mortality by occupation and industry were expressed as age-adjusted proportional mortality ratio. RESULTS: A total of 3110 inflammatory bowel disease (IBD) patients were included in the present analysis. IBD mortality was low among blue collar workers and high among white collar workers. It was low among farming occupations, manufacturing occupations, and manual laborers. It was high among secretaries, professionals, sales workers, homemakers, managerial occupations, and teachers. There was a strong correlation between the occupational distribution of CD and UC that applied to men and women alike. The overall distribution among different industries corroborated the patterns observed with respect to the occupational distribution. CONCLUSIONS: The correlations between the occupational distribution of CD and UC support the contention that environmental influences shape the occurrence of both diseases. Such influence must vary by occupation and, to a lesser extent, also by industry. It must be similar for both types of IBD. PMID- 21710541 TI - Lithium protects against oxidative stress-mediated cell death in alpha-synuclein overexpressing in vitro and in vivo models of Parkinson's disease. AB - Lithium has recently been suggested to have neuroprotective properties in relation to several neurodegenerative diseases. In this study, we examined the potential cytoprotective effect of lithium in preventing oxidative stress-induced protein accumulation and neuronal cell death in the presence of increased alpha synuclein levels in vitro and in vivo. Specifically, lithium administration was found to protect against cell death in a hydrogen peroxide-treated, stable alpha synuclein-enhanced green fluorescent protein (EGFP)-overexpressing dopaminergic N27 cell line. Lithium feeding (0.255% lithium chloride) of 9-month-old pan neuronal alpha-synuclein transgenic mice over a 3-month period was also sufficient to prevent accumulation of oxidized/nitrated alpha-synuclein as a consequence of chronic paraquat/maneb administration in multiple brain regions, including the glomerular layer, mitral cells, and the granule cell layer of the olfactory bulb (OB), striatum, substantia nigra pars compacta (SNpc) and Purkinje cells of the cerebellum. Lithium not only prevented alpha-synuclein-mediated protein accumulation/aggregation in these brain regions but also protected neuronal cells including mitral cells and dopaminergic SNpc neurons against oxidative stress-induced neurodegeneration. These results suggest that lithium can prevent both alpha-synuclein accumulation and neurodegeneration in an animal model of PD, suggesting that this drug, already FDA-approved for use in bipolar disorder, may constitute a novel therapy for another human disease. PMID- 21710542 TI - Association between measures of trochlear morphology and structural features of patellofemoral joint osteoarthritis on MRI: the MOST study. AB - The sulcus angle has been widely used in the literature as a measure of trochlear morphology. Recently, lateral trochlear inclination and trochlear angle have been reported as alternatives. The purpose of this study was to determine the association between measures of trochlear morphology and patellofemoral joint (PFJ) cartilage damage and bone marrow lesions (BMLs). Nine hundred seven knees were selected from the Multicenter Osteoarthritis Study, a cohort study of persons aged 50-79 years with or at risk for knee OA. Trochlear morphology was measured using lateral trochlear inclination, trochlear angle, and sulcus angle on axial MRI images; cartilage damage and BMLs were graded on MRI. We determined the association between quartiles of each trochlear morphology variable with the presence or absence of cartilage damage and BMLs in the PFJ using logistic regression. The strongest associations were seen with lateral trochlear inclination and lateral PFJ cartilage damage and BMLs, with knees in the lowest quartile (flattened lateral trochlea) having more than two times the odds of lateral cartilage damage and BMLs compared to those in the highest quartile (p < 0.0001). Lateral trochlear inclination may be the best method for assessment of trochlear morphology as it was strongly association with structural damage in the PFJ. PMID- 21710544 TI - miR 488* inhibits androgen receptor expression in prostate carcinoma cells. AB - Androgen receptor (AR) is a ligand-dependent transcription factor, which plays a significant role in prostate carcinogenesis. Blockade of AR and its ligand, androgen is the basis for the treatment of prostate cancer (PCa). Nevertheless, a modest increase in the critical levels of AR mRNA and corresponding protein is sufficient for the development of resistance to antiandrogen therapy. A strategy to further downregulate AR mRNA and protein expression in combination with antiandrogen therapy may prevent or delay the development of androgen-independent PCa. Recent studies show that microRNAs (miRNAs) perform tumor suppressor functions in various cancers. In this study, we demonstrate that the overexpression of miR 488* downregulates the transcriptional activity of AR and inhibits the endogenous AR protein production in both androgen-dependent and androgen-independent PCa cells. In addition, miR 488* blocks the proliferation and enhances the apoptosis of PCa cells. Our data indicate that miR 488* targets AR and is a potential modulator of AR mediated signaling. Our findings provide insight for utilizing miRNAs as novel therapeutics to target AR in PCa. PMID- 21710545 TI - Gemcitabine depletes regulatory T-cells in human and mice and enhances triggering of vaccine-specific cytotoxic T-cells. AB - Particle-mediated epidermal delivery (PMED) is a potent genetic vaccination method. However, a recent report found PMED only poorly and infrequently triggered antigen-specific cytotoxic T-cells in cancer patients. Here, we show that injection of the chemotherapeutic drug Gemcitabine in mice results in improvement of the efficacy of subsequent PMED vaccination against NY-ESO-1. We found in mice and in cancer patients that administration of Gemcitabine induces a transient reduction in the percentage of regulatory T-cells among CD4-positive cells. The higher relative sensitivity of regulatory T-cells compared to other CD4-positive T-cells toward cytostatic drugs can be linked to the higher frequency of proliferating cells in the regulatory compartment compared to the nonregulatory CD4-compartment in healthy people and cancer patients. Thus, by affecting regulatory T-cells more than other lymphocyte subsets, chemotherapeutic agents can create a transient hyperimmunoreactive window. Such a window would provide an ideal timepoint to administer a vaccine expected to induce a therapeutically relevant anticancer cytotoxic T-cell response. PMID- 21710546 TI - Presubiculum layer III conveys retrosplenial input to the medial entorhinal cortex. AB - Navigation is mediated by a network of brain areas, and research has focused on the head-direction system in the presubiculum (PrS), the grid cell containing medial entorhinal cortex (EC) (MEC) and place cells in the hippocampus. Less research addressed the interactions of the retrosplenial cortex (RSC) and the navigational system, although it is well established that damage to the RSC leads to navigational deficits. We previously showed that RSC provides a dense input to deep layers of MEC and to superficial layers of PrS. In this study we use confocal microscopical analysis and show that the dense projection from the caudal part of the ventral retrosplenial granular cortex targets neurons in Layer III of PrS, which provide input to superficial layers of MEC. Our high resolution anatomical data indicate that sparsely spiny pyramidal neurons in Layer III of PrS that originate projections to Layer III of MEC are the main target of these retrosplenial projections. Retrosplenial axonal boutons were found to equally contact spines and shafts of basal dendrites in Layer III, but contacts on shafts are more prominent close to the soma, indicating the potential for efficient synaptic transfer. These observations suggest that neurons in Layer III of PrS have an important role in mediating RSC contributions to navigation. PMID- 21710547 TI - Monitoring cytoplasmic protein complexes with blue native gel electrophoresis and stable isotope labelling with amino acids in cell culture: analysis of changes in the 20S proteasome. AB - Analysis of protein complexes is of increasing interest in the field of proteomics. A challenge is to develop methods for monitoring changes in the quantity and subunit composition of protein complexes on a proteome-wide scale. Here, we describe the combination of 1-D blue native polyacrylamide gel electrophoresis (BN-PAGE) with stable isotope labelling of amino acids in cell culture (SILAC) and tandem mass spectrometry (MS/MS). Cleared lysates from normal and perturbed samples, one incorporating heavy stable isotopes and the other light isotopes, are co-separated by blue native PAGE and then analysed and quantitated with MS/MS and appropriate software. This permits the analysis of cytoplasmic complexes. To demonstrate this technique, we explored how the 20S proteasome changes when the Pre9/alpha3 subunit, the only non-essential subunit of this complex, was deleted. Our results showed that DeltaPre9/alpha3 cells can form the 20S proteasome complex, although with reduced efficiency. This involves an increase in expression of the alpha4 subunit. Our findings suggest this technique as an approach for the study of quantitative and qualitative differences in protein complexes, from cleared cell lysates. PMID- 21710548 TI - High-sensitive protein analysis by FESI-CE-MALDI-MS. AB - Capillary zone electrophoresis (CZE) and matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) are two techniques highly suitable for the separation and detection of intact proteins. Herein, based on the use of a recently introduced iontophoretic fraction collection interface for the coupling of CE and MALDI-MS, the potential of the combination of both techniques for the analysis of intact proteins is assessed. To further provide a bioanalytical platform with high-sensitivity capabilities, field-enhanced sample injection is integrated as on online preconcentration strategy upstream from the electrokinetic separation. Under optimized conditions, more than 3200- and 4800 fold improvement, respectively in terms of peak height and peak area, as well as LODs ranging from 5 to 10 nM, has been achieved. PMID- 21710549 TI - An allelic ladder based upon reference alleles for mtDNA SNP analysis using the SNaPshot technique. AB - The analysis of mitochondrial DNA (mtDNA) single-nucleotide polymorphisms (SNPs) using the SNaPshot technique (Applied Biosystems) is a fast and sensitive method for the reliable identification of disease-associated mtDNA SNPs, genetic ancestry mtDNA SNPs and forensically important mtDNA SNPs. The detection of many SNPs in one multiplex PCR and one subsequent multiplex minisequencing reaction is challenging for laboratories who want to establish this technique, due to the problem that there is no allelic ladder available for mtDNA SNP analysis via SNaPshot technique. Normally, the laboratory has to invent long-term testing and studies. The interpretation of false and correct alleles is up to some specialists knowing the expected and the estimated size of each allele SNP. We here present a protocol to assemble up to 84 alleles of 42 different mtDNA SNPs in an allelic ladder that is based upon reference alleles. We recommend using allelic ladders/reference alleles for SNP analysis to maintain high-quality analysis standards. PMID- 21710550 TI - Proteomic analysis of a spring wheat cultivar in response to prolonged cold stress. AB - Cold represents one of the major abiotic factors influencing plant growth and development worldwide. We analysed the long-term responsiveness of an Iranian spring wheat (cv. Kohdasht) to cold from a proteomic point of view, in order to unravel the molecular mechanisms helping a cold-sensitive cultivar to survive exposure to suboptimal temperatures. Plants were grown at 20 or 4 degrees C until entering the reproductive stage and a cross-comparison on the leaf proteomes was performed. Quantitative analyses on protein alterations occurring upon low temperature exposure showed a reinforcement in ascorbate recycling (dehydroascorbate reductase, ascorbate peroxidase) and protein processing (proteasome subunit, cysteine proteinase), as well as the accumulation of the enzyme devoted to tetrapyrrole resynthesis (glutamate semialdehyde aminomutase). In contrast, among proteins down-regulated after cold stress, we could identify some key Krebs cycle enzymes (isocitrate dehydrogenase, malate dehydrogenase), together with many photosynthesis-related proteins (oxygen-evolving complex proteins, ATP synthase subunits, ferredoxin NADPH oxidoreductase and some Calvin cycle enzymes). Physiological and biochemical parameters (such as shoot apex dissection, chlorophyll, proline and sugar content determination) sustained proteomics findings allowing the present research to contribute to the current knowledge on these long-term responses, which may be crucial to stress adaptation under field conditions. PMID- 21710551 TI - Electrokinetic particle translocation through a nanopore containing a floating electrode. AB - Electrokinetic particle translocation through a nanopore containing a floating electrode is investigated by solving a continuum model, composed of the coupled Poisson-Nernst-Planck (PNP) equations for the ionic mass transport and the modified Stokes equations for the flow field. Two effects due to the presence of the floating electrode, the induced-charge electroosmosis (ICEO) and the particle floating electrode electrostatic interaction, could significantly affect the electrokinetic mobility of DNA nanoparticles. When the electrical double layers (EDLs) of the DNA nanoparticle and the floating electrode are not overlapped, the particle-floating electrode electrostatic interaction becomes negligible. As a result, the DNA nanoparticle could be trapped near the floating electrode arising from the induced-charge electroosmosis when the applied electric field is relatively high. The presence of the floating electrode attracts more ions inside the nanopore resulting in an increase in the ionic current flowing through the nanopore; however, it has a limited effect on the deviation of the current from its base current when the particle is far from the pore. PMID- 21710552 TI - Development of a low-density DNA microarray for diagnosis of target-site mutations of pyrethroid and organophosphate resistance mutations in the whitefly Bemisia tabaci. AB - BACKGROUND: Rapid and accurate detection of mutations related to insecticide resistance is essential for development of resistance management strategies to support sustainable agriculture. The M918V, L925I and T929V mutations of the voltage-gated sodium channel gene (vgsc) and the F392W mutation of the acetylcholinesterase I gene (ace1) are reportedly associated with resistance to pyrethroids and organophosphates, respectively, in Bemisia tabaci. In order to detect known base substitutions in the ace1 and vgsc genes, a low-density microarray with an allele-specific probe was developed. RESULTS: Specific regions of the ace1 and vgsc gene mutations were amplified by multiplex asymmetrical PCR using Cy3-labelled primers, and then the PCR products were hybridised on the microarray. After analysing the probe signal data, the microarray containing 12 allele-specific probes produced a unique pattern of probe signals for field DNA samples of B. tabaci. To determine the optimal cut-off value of each probe, receiver operating characteristic (ROC) curve analysis was conducted using SPSS. Among 60 individual samples, microarray data for 57 samples were consistent with direct sequencing data. CONCLUSION: Although many molecular detection methods have been employed to monitor insecticide resistance, the present microarray provides rapid and accurate identification of target mutations in B. tabaci for resistance management. PMID- 21710553 TI - Concentrations and environmental risk of chlorothalonil in air near potato fields in Prince Edward Island, Canada. AB - BACKGROUND: Chlorothalonil is used extensively in Prince Edward Island for the control of blight on potatoes, and has been measured throughout summer months in ambient air monitoring studies. This study was designed to characterize near field drift of chlorothalonil, and to evaluate how exposure to measured air concentrations might impact upon local wildlife species. RESULTS: Air samples were collected using high-volume samplers at three distances downwind of sprayed potato fields, and at four different time intervals. Chlorothalonil was detected in 73% of prespray samples (from < 0.013 to 0.440 ug m(-3)). The mean air concentration 0 m away from the field edge during spray was 5.8 ug m(-3), which was 7-41 times higher than concentrations measured in similar studies. Air concentrations were found to decline exponentially both with distance and time, although 0 m and 30 m concentrations at 2 h post-spray remained significantly (3 times) higher than prespray (P < 0.05). Wind speed was not found to be significantly correlated with air concentration; however, increases in temperature were found to be significantly correlated with increases in air concentrations at all sample times, at 0 m and 30 m distances. CONCLUSION: Frequent prespray detections and high post-spray concentrations suggest that both chronic and acute exposures to non-target species are occurring; however, risk calculations suggest a relatively low risk of effects to representative species. One measurement showed that a human-health-based short-term guideline had been exceeded, indicating that potential impacts to humans from chlorothalonil under current application conditions cannot be discounted. PMID- 21710554 TI - Effect of amphotericin B nanodisks on plant fungal diseases. AB - BACKGROUND: The development of water-soluble nanodevices extends the potential use of compounds developed for other purposes (e.g. antifungal drugs or antibiotics) for applications in agriculture. For example, the broad-spectrum, water-insoluble, macrolide polyene antibiotic amphotericin B (AMB) could be used to inhibit phytopathogenic fungi. A new formulation embedding AMB in nanodisks (NDs) enhances antibiotic solubility and confers protection against environmental damage. In the present study, AMB-NDs were tested for efficacy against several phytopathogenic fungi in vitro and on infected living plants (chickpea and wheat). RESULTS: Compared with AMB in dimethylsulfoxide (DMSO), AMB-NDs increased the sensitivity of several fungal species to this antimycotic in vitro. Sensitivity varied with fungal species as well as with the forma specialis. Phytophthora cinnamomi, previously reported as insensitive to other polyene antimycotics, remained unaffected at the doses examined. Some effect against disease symptoms were obtained with AMB-NDs against fusarium wilt in chickpea, whereas the results were highly variable in wheat, depending on both the species and treatment regimen. CONCLUSION: The results confirm that formulation of AMB into ND increases its effectiveness against phytopathogenic fungi in vitro, opening the possibility for its use on infected plants in the field. PMID- 21710555 TI - Enhanced activity of an insecticidal protein, trypsin modulating oostatic factor (TMOF), through conjugation with aliphatic polyethylene glycol. AB - BACKGROUND: Trypsin modulating oostatic factor (TMOF), a decapeptide (Tyr-Asp-Pro Ala-Pro(6)) isolated from the ovaries of the adult yellow fever mosquito, Aedes aegypti, regulates trypsin biosynthesis. TMOF per os is insecticidal to larval mosquitoes and a good model for the development of technologies to enhance protein insecticide activity by reduced catabolism and/or enhanced delivery to the target. RESULTS: TFA-TMOF-K (TFA = trifluoro acetyl) allowed the specific conjugation of monodispersed, aliphatic polyethylene glycol (PEG) to the amino group of lysine-producing TMOF-K-methyl(ethyleneglycol)(7)-O-propionyl (TMOF-K PEG(7) P). The addition of lysine to TMOF reduced its per os larval mosquitocidal activity relative to the parent TMOF, but conjugation of TMOF-K with methyl(ethyleneglycol)(7)-O-propionyl increased its toxicity 5.8- and 10.1-fold above that of TMOF and TMOF-K for Ae. aegypti. Enhanced insecticidal activity was also found for larval Ae. albopictus and for neonates of Heliothis virescens and Heliocoverpa zea. Only TMOF-K was found by MS/MS in the hemolymph for H. virescens fed on TMOF-K-PEG(7) P. No TMOF, TMOF-K or PEGylated TMOF-K was detected in the hemolymph after topical applications. CONCLUSIONS: This research suggests that aliphatic PEG polymers can be used as a new method for increasing the activity of insecticidal proteins. PMID- 21710556 TI - Capillary electrophoresis method for plasmatic determination of imatinib mesylate in chronic myeloid leukemia patients. AB - Imatinib (IMAT) is a tyrosine kinase inhibitor that has been used for the treatment of chronic myeloid leukemia (CML). Despite the efficacy of IMAT therapy, some cases of treatment resistance have been described in CML. Developing a plasma method is important since there are several studies that provided a higher correlation between IMAT plasma concentration and response to treatment. Therefore, in this investigation we validated a method by CE as an alternative, new, simple and fast electrophoretic method for IMAT determination in human plasma. The analysis was performed using a fused silica capillary (50 MUm id*46.5 cm total length, 38.0 cm effective length); 50 mmol/L sodium phosphate buffer, pH 2.5, as BGE; hydrodynamic injection time of 20 s (50 mbar); voltage of 30 kV; capillary temperature of 35 degrees C and detection at 200 nm. Plasma samples pre-treatment involved liquid-liquid extraction with methyl-tert butyl ether as the extracting solvent. The method was linear from 0.125 to 5.00 MUg/mL. The LOQ was 0.125 MUg/mL. Mean absolute recovery of IMAT was 67%. The method showed to be precise and accurate with RSD and relative error values lower than 15%. Furthermore, the application of the method was performed in the analysis of plasma samples from CML patients undergoing treatment with IMAT. PMID- 21710557 TI - Improved method for immunostaining of mucin separated by supported molecular matrix electrophoresis by optimizing the matrix composition and fixation procedure. AB - Mucins are a family of heavily glycosylated high molecular mass proteins that have great potential as novel clinical biomarkers for the diagnosis of various malignant tumors. Supported molecular matrix electrophoresis (SMME) is a new type of membrane electrophoresis that can be used to characterize mucins. In SMME, mucins migrate in a molecular matrix supported by membrane materials. Here, we have developed an immunostaining method for the identification of SMME-separated mucins. The novel method involves stably fixing the mucins onto the SMME membrane and optimizing the molecular matrix for the fixation process. We applied this technique for the detection of MUC1 produced from three cancer cell lines (T47D, HPAF-II and BxPC3) and also analyzed their O-linked glycans by mass spectrometry. Our results revealed that properties of the MUC1 molecules from the three cell lines are different in terms of migrating position in SMME and glycan profile. The present method allows simple and rapid characterization of mucins in terms of both glycans and core proteins. The method will be a useful tool for the exploration of mucin alterations associated with various diseases such as cancer. PMID- 21710558 TI - Maximum likelihood estimation in generalized linear models with multiple covariates subject to detection limits. AB - The analysis of data subject to detection limits is becoming increasingly necessary in many environmental and laboratory studies. Covariates subject to detection limits are often left censored because of a measurement device having a minimal lower limit of detection. In this paper, we propose a Monte Carlo version of the expectation-maximization algorithm to handle large number of covariates subject to detection limits in generalized linear models. We model the covariate distribution via a sequence of one-dimensional conditional distributions, and sample the covariate values using an adaptive rejection metropolis algorithm. Parameter estimation is obtained by maximization via the Monte Carlo M-step. This procedure is applied to a real dataset from the National Health and Nutrition Examination Survey, in which values of urinary heavy metals are subject to a limit of detection. Through simulation studies, we show that the proposed approach can lead to a significant reduction in variance for parameter estimates in these models, improving the power of such studies. PMID- 21710559 TI - Examining the match between assessed eating disorder recovery and subjective sense of recovery: preliminary findings. AB - This study examined how individuals, clinically assessed as fully or partially recovered from an eating disorder (ED), subjectively perceived themselves in terms of stage of change in the recovery process. Individuals formerly seen for an ED at a Midwestern clinic were recruited. Using validated definitions of recovery, 18 were fully recovered (physical, behavioural and psychological recovery), and 15 were partially recovered (only physical and behavioural recovery); these groups were compared on overall stage of change and confidence related to this stage, dieting stage of change and internality of motivation. The fully and partially recovered groups endorsed being fully recovered (overall and for dieting) at similar rates. There were trends for the fully recovered group seeking change primarily for themselves and being more confident in their stage of change choice. Results have implications for approaches when a client's assessed recovery stage does not match her subjective sense of recovery and for better understanding recovery from an ED. PMID- 21710560 TI - Suppression subtractive hybridization identifies bacterial genomic regions that are possibly involved in hBD-2 regulation by enterocytes. AB - SCOPE: Human beta-defensin 2 (hBD-2) is an inducible antimicrobial peptide synthesized by the epithelium to counteract bacterial adherence and invasion. It has been suggested that probiotic bacteria sustain gut barrier function via induction of defensins. The goals of this study were (i) to evaluate the potential immunomodulatory effects of 11 different Lactobacillus fermentum strains isolated from Kimere, an African fermented pearl millet (Pennisetum glaucum) dough, on the hBD-2 secretion by human intestinal CaCo-2 cell line and (ii) to examine genetic differences between two strains of L. fermentum (K2-Lb4 and K11-Lb3) which differed in their effect on the production of hBD-2 in this study. METHODS AND RESULTS: Totally, 46 strains of L. fermentum from Kimere were isolated and characterized using molecular biology methods including pulsed-field gel electrophoresis patterns. After performing time- and dose-experiments, CaCo-2 cells were incubated with or without bacteria for 12 h. L. fermentum PZ1162 was included as the positive control. Cell-free supernatants were analyzed for hBD-2 protein by enzyme-linked immunosorbent assay (ELISA). To identify potential bacterial genes associated with hBD-2 regulation, suppression subtractive hybridization (SSH) was used. Among the 11 strains tested, only two strains of bacteria, K11-Lb3 and K2-Lb6, significantly induced the production of hBD-2 by CaCo-2 cells. This effect was strain-specific, dose-dependent and particularly seems to be bacterial genomic-dependent as manifested by SSH. L. fermentum strains with and without hBD-2 inducing effect differed in genes encoding proteins involved in glycosylation of cell-wall proteins e.g. glycosyltransferase, UDP-N-acetylglucosamine 2-epimerase, rod shape-determining protein MreC, lipoprotein precursors, sugar ABC transporters, and glutamine ABC transporter ATP-binding protein. CONCLUSION: This study implies that certain strains of L. fermentum isolated from Kimere may stimulate the intestinal innate defense through the induction of hBD-2. The molecular basis of hBD-2 induction by L. fermentum strain K11-Lb3 may be based on glycosylated cell-surface structures synthesized with the aid of glycosyltransferase, UDP-N-acetylglucosamine 2 epimerase, and rod shape-determining protein MreC. PMID- 21710561 TI - Metabolites and tissue distribution of resveratrol in the pig. AB - SCOPE: trans-Resveratrol (RES) and/(or) its metabolites exert many effects in vivo. Our aim was to study the metabolism and tissue distribution of RES using the pig, a mammal physiologically close to humans. METHODS AND RESULTS: Forty seven tissues, organs and fluids were analyzed 6 h after intragastric RES administration (5.9 mg/kg body weight) using HPLC-MS/MS. Twelve RES and seven dihydroresveratrol (DH-RES) metabolites were detected. DH-RES was the main metabolite in cecum, colon and rectum, whereas RES-3-O-glucuronide was the most abundant one in fluids and organs. Approximately 74.5% of the total RES administered was recovered in the form of RES, DH-RES and derived metabolites (65.1% along the gastrointestinal tract, 7.7% in urine, 1.2% in bile and 0.5% in organs). We report here, for the first time, the occurrence of RES ribosyl sulfate derivative, DH-RES diglucuronide, DH-RES sulfoglucuronide and DH-RES disulfate as well as the metabolic profile of RES and DH-RES in the aorta, lymph, lymph node, ovaries, uterus, cerebellum, pancreas, urinary bladder tissue, fat and muscle. CONCLUSION: This study contributes to the clarification of the metabolism and tissue distribution of RES and could help to further understand the mechanisms underlying its effects. PMID- 21710562 TI - Trans-resveratrol simultaneously increases cytoplasmic Ca(2+) levels and nitric oxide release in human endothelial cells. AB - SCOPE: The aim of this study was to investigate whether the dietary polyphenol trans-resveratrol (t-Resv) increases [Ca(2+)](c) in endothelial cells, leading to a simultaneous augmentation of nitric oxide (NO) biosynthesis. METHODS AND RESULTS: We have separately and simultaneously measured [Ca(2+)](c) and NO in human endothelial cells using the Ca(2+) indicator fura-2 and the NO-sensitive fluorescent probe 4,5-diaminofluorescein. In ~30% of cells, t-Resv (30 MUM) induced an increase in [Ca(2+)](c) with a transient as well as sustained component and a simultaneous increase in NO biosynthesis. This effect was reduced by non-selective Ca(2+) channel blockers, inhibition of intracellular Ca(2+) release, inhibition of endothelial nitric oxide synthase (eNOS) and, to a lesser extent, inhibition of extracellular signal-regulated kinase 1/2 (ERK 1/2) or 5' adenosine monophosphate-activated protein kinase (AMPK). t-Resv did not modify in vitro eNOS activity, suggesting that the observed stimulation of NO generation proceeds via mobilisation of Ca(2+) and not through direct effects on eNOS. CONCLUSION: We therefore show, for the first time, that t-Resv induces a concentration-dependent, simultaneous increase in [Ca(2+)](c) and NO biosynthesis that could be linked to its endothelium-dependent vasorelaxant effect. Under the assumption that t-Resv exhibits similar behaviour in human blood vessels in vivo, the pharmacological properties described here may contribute to the beneficial cardiovascular effects of this polyphenol by improving endothelial function. PMID- 21710563 TI - Immunological evaluation of the alcohol-soluble protein fraction from gluten-free grains in relation to celiac disease. AB - Celiac disease (CD) is a gluten-sensitive enteropathy with an immune basis. We established the immune reactivity of the alcohol-soluble fraction from two minor cereals (tef and millet) and two pseudocereals (amaranth and quinoa) which are believed to be nontoxic based on taxonomy. Grains were examined in intestinal T cell lines (iTCLs), cultures of duodenal explants from HLA-DQ2(+) CD patients and HLA-DQ8 transgenic mice for signs of activation. Our data indicated that tef, millet, amaranth, and quinoa did not show any immune cross-reactivity toward wheat gliadin, and therefore confirming their safety in the diet of CD patients. PMID- 21710564 TI - From the genome sequence to the protein inventory of Bacillus subtilis. AB - Owing to the low number of proteins necessary to render a bacterial cell viable, bacteria are extremely attractive model systems to understand how the genome sequence is translated into actual life processes. One of the most intensively investigated model organisms is Bacillus subtilis. It has attracted world-wide research interest, addressing cell differentiation and adaptation on a molecular scale as well as biotechnological production processes. Meanwhile, we are looking back on more than 25 years of B. subtilis proteomics. A wide range of methods have been developed during this period for the large-scale qualitative and quantitative proteome analysis. Currently, it is possible to identify and quantify more than 50% of the predicted proteome in different cellular subfractions. In this review, we summarize the development of B. subtilis proteomics during the past 25 years. PMID- 21710565 TI - Proteome analysis of host-pathogen interactions: Investigation of pathogen responses to the host cell environment. AB - Infectious diseases are still a major health risk, and thus a better understanding of the interaction between human host cells and pathogenic microbes is urgently required. Since the interplay between both partners is highly complex, genome-wide analysis by OMICs approaches will likely make a major contribution to the elucidation of the pathophysiology of infection processes. In the concert of OMICs technologies, proteomics is particularly important because it reveals changes in the active players of the cell and has thus a close relationship to the phenotypic changes observed. While proteomic studies of in vitro-grown microbial pathogens are routinely established in many labs, in vivo proteomic approaches are still rare. Here, we will review the challenges and recent developments of proteomic analysis of microbial pathogens derived from cell culture or in vivo infection settings and summarize some lessons that have been learned from these studies. PMID- 21710566 TI - Proteomic methods unravel the protein quality control in Escherichia coli. AB - Protein quality control is an essential process in all living organisms. A network of folding helper proteins and proteases ushers proteins into their native conformation, safeguards their structure under adverse environmental conditions, and, if all else fails, degrades proteins at the end of their life time. Escherichia coli is a versatile model organism used in the analysis of fundamental cellular processes. Much of what we know about protein quality control has been discovered in this microorganism. In the investigation of the mode of action, regulation and substrate specificity of chaperones, thiol disulfide isomerases and proteases, proteomic methods have been playing a key role. Here, we provide a condensed overview about the protein quality control network in E. coli and the remarkable contributions of proteomics to our current knowledge. PMID- 21710567 TI - The dynamic protein partnership of RNA polymerase in Bacillus subtilis. AB - In prokaryotes, transcription results from the activity of a 400 kDa RNA polymerase (RNAP) protein complex composed of at least five subunits (2alpha, beta, beta', omega). To ensure adequate responses to changing environmental cues, RNAP activity is tightly controlled by means of interacting regulatory proteins. Here, we report the affinity-purification of the Bacillus subtilis RNAP complexes from cells in different growth states and stress conditions, and the quantitative assessment by mass spectrometry of the dynamic changes in the composition of the RNAP complex. The stoichiometry of RNA polymerase was determined by a comparison of two mass spectrometry-based quantification methods: a label-based and a label free method. The validated label-free method was then used to quantify the proteins associated with RNAP. The levels of sigma factors bound to RNAP varied during growth and exposure to stress. Elongation factors, helicases such as HelD and PcrA, and novel unknown proteins were also associated with RNAP complexes. The content in 6S RNAs of purified RNAP complexes increased at the onset of the stationary phase. These quantitative variations in the protein and RNA composition of the RNAP complexes well correlate with the known physiology of B. subtilis cells under different conditions. PMID- 21710568 TI - Status quo in physiological proteomics of the uncultured Riftia pachyptila endosymbiont. AB - Riftia pachyptila, the giant deep-sea tube worm, inhabits hydrothermal vents in the Eastern Pacific ocean. The worms are nourished by a dense population of chemoautotrophic bacterial endosymbionts. Using the energy derived from sulfide oxidation, the symbionts fix CO(2) and produce organic carbon, which provides the nutrition of the host. Although the endosymbionts have never been cultured, cultivation-independent techniques based on density gradient centrifugation and the sequencing of their (meta-) genome enabled a detailed physiological examination on the proteomic level. In this study, the Riftia symbionts' soluble proteome map was extended to a total of 493 identified proteins, which allowed for an explicit description of vital metabolic processes such as the energy generating sulfide oxidation pathway or the Calvin cycle, which seems to involve a reversible pyrophosphate-dependent phosphofructokinase. Furthermore, the proteomic view supports the hypothesis that the symbiont uses nitrate as an alternative electron acceptor. Finally, the membrane-associated proteome of the Riftia symbiont was selectively enriched and analyzed. As a result, 275 additional proteins were identified, most of which have putative functions in electron transfer, transport processes, secretion, signal transduction and other cell surface-related functions. Integrating this information into complex pathway models a comprehensive survey of the symbiotic physiology was established. PMID- 21710569 TI - Global absolute quantification of a proteome: Challenges in the deployment of a QconCAT strategy. AB - In this paper, we discuss the challenge of large-scale quantification of a proteome, referring to our programme that aims to define the absolute quantity, in copies per cell, of at least 4000 proteins in the yeast Saccharomyces cerevisiae. We have based our strategy on the well-established method of stable isotope dilution, generating isotopically labelled peptides using QconCAT technology, in which artificial genes, encoding concatenations of tryptic fragments as surrogate quantification standards, are designed, synthesised de novo and expressed in bacteria using stable isotopically enriched media. A known quantity of QconCAT is then co-digested with analyte proteins and the heavy:light isotopologues are analysed by mass spectrometry to yield absolute quantification. This workflow brings issues of optimal selection of quantotypic peptides, their assembly into QconCATs, expression, purification and deployment. PMID- 21710570 TI - Immune proteomics of Staphylococcus aureus. AB - Immune proteomics is an increasingly powerful tool for the investigation of the adaptive immune response to natural encounters between micro-organisms and their hosts. The versatile species Staphylococcus aureus serves to illustrate how these techniques can be employed to appreciate the complexity and diversity of the host pathogen interactions in unprecedented detail and completeness. Such knowledge is important for the development of effective vaccines as well as informative diagnostic and novel therapeutic tools. From high-resolution immune proteome studies, general rules underlying the human adaptive immune response to S. aureus colonization and infection are beginning to emerge against a background of extreme diversity: S. aureus carriers develop immune memory for their colonizing strain, but even non-carriers are frequently exposed to S. aureus, resulting in specific antibodies. During bacterial invasion, immune-competent individuals rapidly mount an antibody response to a large panel of S. aureus antigens. However, every patient starts from a personal baseline antibody profile reflecting his or her history of encounters with S. aureus. PMID- 21710571 TI - The relationship among compulsive buying, compulsive internet use and temperament in a sample of female patients with eating disorders. AB - The aim of the present study was to investigate the association among compulsive buying (CB), compulsive internet use (CIU) and reactive/regulative temperament in a sample of 60 female patients with eating disorders. All patients were assessed by means of the Compulsive Buying Scale, the CIU scale, the Eating Disorder Inventory-2, the Behavioral Inhibition System/Behavioral Activation System scales, the Dimensional Assessment of Personality Pathology and the effortful control scale of the Adult Temperament Questionnaire. The results showed a positive association between CB and CIU, both categorized as impulse control disorders, not otherwise specified. Both CB and CIU showed significantly positive correlations with emotional lability, excitement seeking and lack of effortful control (more specifically lack of inhibitory and lack of activation control). The implication of these findings for the treatment of both disorders will be discussed. PMID- 21710572 TI - A grounded theory exploration of the onset of anorexia in adolescence. AB - OBJECTIVES: Relatively little research has been conducted investigating the individual's point of view of anorexia. This research explored young people's experiences of the onset of anorexia. It was anticipated that this would improve clinicians' knowledge in this area, which could then inform establishing alliance and progress through interventions. METHOD: A qualitative grounded theory design was employed. Eight participants aged between 13 and 17 years took part in an interview. The procedure of analysis involved moving between the interviews and generating codes. RESULTS: Superordinate themes emerged and the three main findings are presented. Firstly, it was found that emotions were experienced as overwhelming. Secondly, that the level of awareness of anorexia develops. Finally, that emotional responses and the level of awareness of anorexia impact on the ability to utilise interpersonal interactions. The findings shed light on the personal experiences of this time and help to highlight areas for clinicians to address. PMID- 21710573 TI - The concept of leakage in threat assessment. AB - Leakage in the context of threat assessment is the communication to a third party of an intent to do harm to a target. Third parties are usually other people, but the means of communication vary, and include letters, diaries, journals, blogs, videos on the internet, emails, voice mails, and other social media forms of transmission. Leakage is a type of warning behavior that typically infers a preoccupation with the target, and may signal the research, planning, and implementation of an attack. Nomothetic data suggest that leakage occurs in a majority of cases of attacks on and assassinations of public figures, adult mass murders, adolescent mass murders, and school or campus shootings: very low frequency, but catastrophic acts of intended and targeted violence. Idiographic or case data illustrate the various permutations of leakage. We discuss the operational importance of the concept, place it in the context of other warning behaviors, emphasize the need for further research, and outline risk management strategies for the mitigation of such acts of violence in both law enforcement and clinical mental health settings. PMID- 21710574 TI - Telomere length, telomerase activity and osteogenic differentiation are maintained in adipose-derived stromal cells from senile osteoporotic SAMP6 mice. AB - Adipose tissue provides for a rich and easily accessible source of multipotent stromal cells and thus offers the potential for autologous cell-based therapy for a number of degenerative diseases. Senile osteoporosis is characterized by a reduction in bone quality, which is associated with inadequacies in bone marrow stromal cell (BMSC) differentiation. In the present study, we have characterized adipose-derived stromal cells (ASCs) isolated from aged osteoporotic mice and evaluated their suitability as a source of osteogenic precursor cells. Significant reductions in both tibia bone quality and telomere length in liver tissue were observed in the senescence-accelerated mouse prone 6 strain (SAMP6), as compared to the control age-matched senescence-accelerated mouse resistant 1 strain (SAMR1), thus confirming osteoporosis and accelerated ageing traits in this model. ASCs isolated from inguinal fat expressed mesenchymal surface markers and were capable of differentiating along the osteoblast, adipocyte and chondrocyte lineages. Telomere length was not compromised in ASCs from SAMP6 mice but was actually found to be significantly increased as compared to control SAMR1 mice. Furthermore, ASCs from both strains were comparable in terms of telomerase activity, p21 mRNA expression, SA-beta-gal activity and proliferative capacity. The overall osteogenic and adipogenic potential of ASCs was comparable between SAMP6 and SAMR1 strains, as determined by quantitative molecular, biochemical and histological analyses. In conclusion, adipose tissue may represent a promising autologous cell source for the development of novel bone regenerative therapeutic strategies in the treatment of age-related osteoporosis. PMID- 21710575 TI - Determination of cyantraniliprole and its major metabolite residues in vegetable and soil using ultra-performance liquid chromatography/tandem mass spectrometry. AB - A rapid, highly sensitive and selective method was developed for the determination of the cyantraniliprole and its major metabolite J9Z38 in cucumber, tomato and soil by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Target compounds were extracted with acetonitrile and an aliquot cleaned with primary and secondary amine. Two pairs of precursor product ion transitions for cyantraniliprole and J9Z38 were measured and evaluated. Average recoveries for cucumber, tomato and soil at three levels (10, 50 and 100 ug/kg) ranged from 74.7 to 96.2% with intra-day relative standard deviation (RSD) of 2.6-15.1% and inter-day RSD of 3.4-13.3%. The limit of quantitation for cyantraniliprole and J9Z38 were determined to be 5 and 10 ug/kg in samples (cucumber, tomato and soil), respectively. This method was used to determine the cyantraniliprole and J9Z38 residues in real cucumber, tomato and soil samples for studies on their dissipation. The trial results showed that the half-lives of cyantraniliprole obtained after treatments were 2.2, 2.8 and 9.5 days in cucumber, tomato and soil in Zhejiang, respectively, and that the average levels of cyantraniliprole and J9Z38 residues in cucumber and tomato were all <0.01 mg/kg with the interval of 10 days after treatment. PMID- 21710576 TI - Phenotypic and functional characterization of human bone marrow stromal cells in hollow-fibre bioreactors. AB - The transplantation of human bone marrow stromal cells (BMSCs) is a novel immunotherapeutic approach that is currently being explored in many clinical settings. Evidence suggests that the efficacy of cell transplantation is directly associated with soluble factors released by human BMSCs. In order to harness these secreted factors, we integrated BMSCs into large-scale hollow-fibre bioreactor devices in which the cells, separated by a semipermeable polyethersulphone (PES) membrane, can directly and continuously release therapeutic factors into the blood stream. BMSCs were found to be rapidly adherent and exhibited long-term viability on PES fibres. The cells also preserved their immunophenotype under physiological fluid flow rates in the bioreactor, and exhibited no signs of differentiation during device operation, but still retained the capacity to differentiate into osteoblastic lineages. BMSC devices released growth factors and cytokines at comparable levels on a per-cell basis to conventional cell culture platforms. Finally, we utilized a potency assay to demonstrate the therapeutic potential of the collected secreted factors from the BMSC devices. In summary, we have shown that culturing BMSCs in a large scale hollow-fibre bioreactor is feasible without deleterious effects on phenotype, thus providing a platform for collecting and delivering the paracrine secretions of these cells. PMID- 21710577 TI - HPLC-ELSD analysis of spectinomycin dihydrochloride and its impurities. AB - A simple, rapid and reliable reversed-phase ion-pair chromatography method by HPLC coupled to an evaporative light scattering detector (ELSD) has been developed to simultaneously determine chloride, spectinomycin and its related substances in a sample. The column was a TSKgel ODS-100V. The mobile phase was ACN/aqueous solution of 15 mM ammonium acetate adjusted with TFA to pH 3.0 (2:98 v/v), in an isocratic mode. The drift tube temperature was set at 50 degrees C and the nebulizing gas flow rate of air was 3.5 L/min for ELSD detection. Almost all of the reported degradation compounds of spectinomycin such as actinamine, actinospectinoic acid and biosynthesis intermediates such as dihydrospectinomycin diastereoisomers were baseline separated. MS was utilized for the identification of spectinomycin and its seven related substances. The method for the assay of spectinomycin was successfully validated with respect to accuracy, precision (RSD less than 2%), linearity (throughout the linear range 0.025-3 mg/mL, r=0.9993), sensitivity (LOD: 100 ng on column) and robustness. The experimental results demonstrated that the simultaneous determination of chloride, spectinomycin and related substances is feasible in a single run, which suggests applicability in routine assays. PMID- 21710578 TI - Global detection and identification of components from crude and processed traditional Chinese medicine by liquid chromatography connected with hybrid ion trap and time-of-flight-mass spectrometry. AB - We herein present a chemical profiling method to efficiently process the information acquired by ultra fast liquid chromatography (UFLC)-electrospray ionization source in combination with hybrid ion trap and high-resolution time-of flight mass spectrometry (UFLC-(ESI)-IT-TOF/MS), facilitating the structural determination of serial components contained in crude or processed traditional Chinese medicine (TCM). Under the optimized UFLC and IT-TOF-MS(n) conditions, over 39 compounds were separated and detected in crude or processed Fructus corni within 25 min. The components were identified by comparing the mass spectra and retention time with reference compounds, or tentatively assigned by elucidating low-energy collision-induced dissociation (CID) fragment ions and matching empirical molecular formula with that of the published compounds. Several factors in the processing procedure were examined. The experimental results demonstrate that the chemical reactions that occurred in the processing procedure can be used to elucidate the processed mechanism of F. corni, which is regularly affected by the processing conditions. This study provides a novel approach and methodology to identify the complicated components from various complex mixtures such as crude TCM, processed TCM, and biological samples. It can be used as a valid analytical method for further understanding the processing mechanism of TCM, along with the intrinsic quality control of TCM and its processed product. PMID- 21710579 TI - A pilot investigation of emotion-focused two-chair dialogue intervention for self criticism. AB - Self-criticism plays a key role in many psychological disorders and predicts poor outcome in psychotherapy. Yet, psychotherapy research directly targeting self critical processes is limited. In this pilot study, we examined the efficacy of an emotion-focused intervention, the two-chair dialogue task, on self-criticism, self-compassion and the ability to self-reassure in times of stress, as well as on depressive and anxiety symptoms among nine self-critical clients. Results showed that the intervention was associated with significant increases in self compassion and self-reassuring, and significant reductions in self-criticism, depressive symptoms and anxiety symptoms. Effect sizes were medium to large, with most clients exhibiting low and non-clinical levels of symptomatology at the end of therapy, and maintaining gains over a 6-month follow-up period. Although preliminary, these finding suggest that emotion-focused chair work might be a promising intervention addressing self-criticism. KEY PRACTITIONER MESSAGE: Self criticism is an important process in a variety of clinical disorders and predicts poor outcome in brief therapy for depression. Yet, little is known about how self criticism can be effectively addressed in psychological treatment. Practitioners can benefit from increasing their awareness of self-critical processes in their clinical work, and from directly working with emotions in addressing self criticisim. Emotion-focused two-chair dialogue intervention can be effective in reducing self-criticism, increasing self-compassion, and decreasing depressive and anxiety symptoms, and these improvements are largely maintained six months after therapy. PMID- 21710580 TI - Simultaneous determination of aliskiren and hydrochlorothiazide from their pharmaceutical preparations using a validated stability-indicating MEKC method. AB - A stability-indicating MEKC method was developed and validated for the simultaneous determination of aliskiren (ALI) and hydrochlorothiazide (HCTZ) in pharmaceutical formulations using ranitidine as an internal standard (IS). Optimal conditions for the separation of ALI, HCTZ and its major impurity chlorothiazide (CTZ), IS and degradation products were investigated. The method employed 47 mM Tris buffer and 47 mM anionic detergent SDS solution at pH 10.2 as the background electrolyte. MEKC method was performed on a fused-silica capillary (40 cm) at 28 degrees C. Applied voltage was 26 kV (positive polarity) and photodiode array (PDA) detector was set at 217 nm. The method was validated in accordance with the ICH requirements. The method was linear over the concentration range of 5-100 and 60-1200 MUg/mL for HCTZ and ALI, respectively (r(2) >0.9997). The stability-indicating capability of the method was established by enforced degradation studies combined with peak purity assessment using the PDA detection. Precision and accuracy evaluated by RSD were lower than 2%. The method proved to be robust by a fractional factorial design evaluation. The proposed MEKC method was successfully applied for the quantitative analysis of ALI and HCTZ both individually and in a combined dosage tablet formulation to support the quality control. PMID- 21710581 TI - Methodology for determining major constituents of ayahuasca and their metabolites in blood. AB - There is an increasing interest in potential medical applications of ayahuasca, a South American psychotropic plant tea with a long cultural history of indigenous medical and religious use. Clinical research into ayahuasca will require specific, sensitive and comprehensive methods for the characterization and quantitation of these compounds and their metabolites in blood. A combination of two analytical techniques (high-performance liquid chromatography with ultraviolet and/or fluorescence detection and gas chromatography with nitrogen phosphorus detection) has been used for the analysis of some of the constituents of ayahuasca in blood following its oral consumption. We report here a single methodology for the direct analysis of 14 of the major alkaloid components of ayahuasca, including several known and potential metabolites of N,N dimethyltryptamine and the harmala alkaloids in blood. The method uses 96-well plate/protein precipitation/filtration for plasma samples, and analysis by HPLC ion trap-ion trap-mass spectrometry using heated electrospray ionization to reduce matrix effects. The method expands the list of compounds capable of being monitored in blood following ayahuasca administration while providing a simplified approach to their analysis. The method has adequate sensitivity, specificity and reproducibility to make it useful for clinical research with ayahuasca. PMID- 21710582 TI - Determination of enantiomeric purity of S-amlodipine by chiral LC with emphasis on reversal of enantiomer elution order. AB - An LC method was developed and prevalidated for the enantiomeric purity determination of S-amlodipine in polar organic solvent chromatography using a chlorine-containing cellulose-based chiral stationary phase (CSP). The concentration of formic acid (FA) (0.01-0.2%) in the mobile phase containing acetonitrile as the main solvent was found to influence the elution order of amlodipine enantiomers as well as the enantioresolution. A reversal of the enantiomer elution order of amlodipine was only observed with chiral stationary phases with both electron-withdrawing (chloro) and electron-donating groups (methyl) on the phenyl moieties of the chiral selector, namely cellulose tris(3 chloro-4-methylphenylcarbamate) and cellulose tris(4-chloro-3 methylphenylcarbamate). The highest enantioresolution (Rs : 4.1) value was obtained at the lowest FA concentration (0.01%) using cellulose tris(4-chloro-3 methylphenylcarbamate) as the chiral selector and the enantiomeric impurity, R amlodipine, eluted first under these conditions. Therefore, the mobile phase selected for the prevalidation of the method consisted of ACN/0.1% DEA/0.01% FA and the temperature was set at 25 degrees C. The method was prevalidated by means of the strategy based on the total measurement error and the accuracy profile. The method was found to be selective and the limit of quantification was found to be about 0.05% for R-amlodipine, while the limit of detection was close to 0.02%. PMID- 21710583 TI - Separation of polyphenols using porous polyamide resin and assessment of mechanism of retention. AB - A porous polyamide resin is shown to possess hydrogen bond acceptor properties suitable for the separation of polyphenolic solutes such as phenolic acids, flavonols and flavonoids. The separation is achieved in the presence of solvent mixtures of acetic acid and ethanol. The extent of hydrogen bond adsorption is reviewed based on data obtained from the elution behaviour of a variety of simple polyphenolic solutes. Polyamide adsorption chromatography was applied for the purification of resveratrol and polydatin from Polygonum cuspidatum Sieb. & Zucc. PMID- 21710584 TI - Multifunctional organic-inorganic composite luminescent nanospheres. AB - A simple general strategy was successfully developed for the preparation of magnetic-luminescent multifunctional nanocomposites by incorporating fluorescent (pyrene) and magnetic (Fe(3)O(4)) components simultaneously into a poly(styrene co-methacrylic acid) [poly(St-co-MAA)] copolymer matrix. The nanospheres so prepared were characterized using scanning electron microscopy (SEM), powder X ray diffraction (XRD) and Fourier transform infrared (FTIR) analysis. The prepared magnetic-fluorescent inorganic-organic nanocomposites have excellent magnetic and photoluminescent properties. They can be used in magnetic separation of trace amounts of sample, fluorescence detection and imaging applications, including magnetic resonance imaging (MRI) and fluorescence imaging. The fluorescence quenching of the nanospheres in the presence of different amounts of Cu(2+) ions was also investigated. Under optimal experimental conditions, the relative fluorescence intensity of the composite nanosphere colloidal solution is proportional to the concentration of Cu(2+) ions, which indicates that these multifunctional nanocomposites can be used for the magnetic separation and fluorescence detection of Cu(2+) ions. PMID- 21710585 TI - Regenerative medicine and connective tissues: cartilage versus tendon. AB - Progress in medicine over recent decades has notably increased life expectancy in the Western world. Such advance implies that the treatment of degenerative processes associated with ageing has become one of the major tasks of current medicine and therapeutics. High expectation relies on stem cell research in order to apply cell therapies to ameliorate degenerative processes, remarkably those concerning the circulatory, locomotor and nervous systems. However, the skeletal connective tissues have revealed that cell plasticity is a factor of major importance in regenerative therapies. Most evidence indicates that connective tissue cells of cartilage, tendons, ligaments and fascia share common progenitors during their differentiation, which are regulated by a number of director genes and a panel of miRNAs coupled with transforming growth factor-beta signalling. Furthermore, we know that not only stem cells but also differentiated cells from these tissues may dedifferentiate and redifferentiate, even one into another. Hence, modulation of cell plasticity might be a potential target for regenerative therapies in the future. In this review, we highlight classical concepts about the properties and differentiation of the connective tissues and their relation with recent advances in the study of stem cells, significant for regenerative medicine, paying special attention to cartilage and tendons. PMID- 21710586 TI - Serum inverts and improves the fluorescence response of an aptamer beacon to various vitamin D analytes. AB - A dominant aptamer loop structure from a library of nearly 100 candidate aptamer sequences developed against immobilized 25-hydroxyvitamin D(3) (calcidiol) was converted into a 5'-TYE 665 and 3'-Iowa black-labelled aptamer beacon. The aptamer beacon exhibited a mild 'lights on' reaction in buffer as a function of increasing concentrations of several vitamin D analogues and metabolites, with a limit of detection of approximately 200 ng/mL, and was not specific for any particular congener. In 10% or 50% human serum, the same aptamer beacon inverted its fluorescence behaviour to become a more intense 'lights off' reaction with an improved limit of detection in the range 4-16 ng/mL. We hypothesized that this drastic change in fluorescence behaviour was due to the presence of creatinine and urea in serum, which might destabilize the quenched beacon, causing an increase in fluorescence followed by decreasing fluorescence as a function of vitamin D concentrations that may bind and quench increasingly greater fractions of the denatured beacons. However, the results of several control experiments in the presence of physiological or greater concentrations of creatinine and urea, alone or combined in buffer, failed to produce the beacon fluorescence inversion. Other possible mechanistic hypotheses are also discussed. PMID- 21710587 TI - When is old too old for preimplantation genetic diagnosis for reciprocal translocations? PMID- 21710588 TI - Prenatal diagnosis of a nasal cyst in association with deletion 22q11 syndrome: a report of two cases. PMID- 21710589 TI - Second trimester fetal nasal bone length in a low-risk Turkish population. AB - OBJECTIVE: To define normal values of second trimester fetal nasal bone length (NBL) in a low-risk Turkish population. METHOD: Prenatal records of singleton fetuses who underwent second trimester ultrasonographic examination in the 16 to 23 weeks of pregnancy were retrospectively analyzed for NBL and biometric measurements (BPD, FL and HL). The relationship among NBL and gestational age (GA), biparietal diameter (BPD), femur length (FL) and humerus length (HL) was determined. Additionally, percentile values of NBL for each gestational week were provided. RESULTS: A total of 1467 fetuses were included in this study. There was a significant linear association among NBL and GA (R(2) = 0.709), BPD (R(2) = 0.752), FL (R(2) = 0.742) and HL (R(2) = 0.747). Fifth percentile values of fetal NBL were 3.11 mm for 16th, 3.50 mm for 17th, 3.70 mm for 18th, 4.10 mm for 19th, 4.50 mm for 20th, 4.62 mm for 21st, 5.24 mm for 22nd and 5.37 mm for 23rd gestational weeks. CONCLUSION: The study provides normal ranges of NBL between 16 and 23 weeks of pregnancy in a low-risk Turkish population. Future studies with larger sample sizes including pregnancies carrying high risk for aneuploidy are needed to define cut-off values for NBL. PMID- 21710590 TI - Protective effect of Pycnogenol(r) on ovariectomy-induced bone loss in rats. AB - Pycnogenol(r) (PYC) is a natural plant extract from the bark of Pinus pinaster and has potent antioxidant activities. The protective effect of PYC on bone loss was studied in multiparous ovariectomized (OVX) female rats. Pycnogenol(r) (30 or 15 mg/kg body weight/day) was administered orally to 8-month-old OVX rats for 3 months. At the end of the experiment, bone strength was measured by a three-point bending test and bone mineral density was estimated by peripheral quantitative computed tomography. Ovariectomy significantly decreased femur bone strength and bone density. Supplementation with PYC suppressed the bone loss induced by OVX. The OVX treatment significantly increased serum osteocalcin (OC) and C-terminal telopeptide of type I collagen (CTx). Supplementation with PYC reduced the serum OC and CTx in OVX rats to a level similar to that of the sham-operated group. The results indicated that orally administered PYC can decrease the bone turnover rate in OVX rats, resulting in positive effects on the biomechanical strength of bone and bone mineral density. PMID- 21710591 TI - Synthesis, characterisation, and mass spectrometric detection of a pegylated EPO mimetic peptide for sports drug testing purposes. AB - Erythropoietin (EPO) and other erythropoiesis-stimulating agents possess a high misuse potential in elite sport due to their ability to increase the oxygen transport capacity, which plays a vital role in enhancing endurance performance. Currently, a new generation of EPO-mimetic peptides is under development from which peginesatide (also referred to as HematideTM), a pegylated homodimeric peptide of approximately 45 kDa with no structural relationship to erythropoietin, is the most advanced drug candidate undergoing phase-III clinical trials. Since preventive doping research aims at the development of detection methods before a drug receives clinical approval, a selective and sensitive assay has to be established knowing that conventional doping control assays for EPO will not succeed in detecting peginesatide. Thus, a pegylated EPO-mimetic peptide simulating the structure and properties of the lead drug candidate peginesatide was synthesised as a model compound for this new class of emerging drugs and characterised by means of gel electrophoresis, matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry, as well as liquid chromatography/electrospray ionisation tandem mass spectrometry (LC/ESI-MS/MS) after proteolytic digestion. Based on these results, a mass spectrometric detection method of the product in plasma was developed targeting a pentapeptide fragment after protein precipitation and subtilisin digestion. Its fitness for purpose was evaluated by the determination of selected method characteristics focusing particularly on specificity, recovery (ca. 60%), and limit of detection (1 ng/mL). PMID- 21710592 TI - Staggered multistep elution solid-phase extraction capillary electrophoresis/tandem mass spectrometry: a high-throughput approach in protein analysis. AB - An approach based on staggered multistep elution solid-phase extraction (SPE) capillary electrophoresis/tandem mass spectrometry (CE/MS/MS) was developed in the analysis of digested protein mixtures. On-line coupling of SPE with CE/MS was achieved using a two-leveled two-cross polydimethylsiloxane (PDMS)-based interface. Multistep elution SPE was used prior to CE to provide an additional dimension of separation, thus extending the separation capacity for the peptide mixture analysis. By decreasing in the number of co-eluting peptides, problems stemming from ionization suppression and finite MS/MS duty cycle were reduced. As a result, sequence coverage increased significantly using multistep elution SPE CE/MS/MS compared to one-step elution SPE-CE/MS/MS in the analysis of a single protein tryptic digest (49% vs. 18%) and a six protein tryptic digest (22-71% vs. 10-44%). A staggered CE method was incorporated to increase the throughput. The electropherograms of consecutive CE runs were partially overlapped by injecting the sample plug at a fixed time interval. With the use of a 5 min injection interval, slightly poor results were obtained in comparison with the sequential CE method while the total analysis time was reduced to 28%. PMID- 21710593 TI - One-pot synthesis of a new antifungal polymerisable monomer and its characterisation by coordination-ion spray mass spectrometry. AB - We have investigated the synthesis of a new antifungal agent with a polymerisable moiety for the prevention of denture stomatisis. Nystatin (antifungal polyene) is modified in one step by reaction with isocyanatoethylmethacrylate to afford a new polymerisable antifungal agent in good yield (90%). In order to prove the monografting of the acrylate derivative and to localise the new group in the skeleton of the molecule, a rapid and efficient analytical method involving electrospray ionisation mass spectrometry (ESI-MS) was developed for the study. In view of the structures of such antifungal agents, their complexation with metal cations was investigated by Coordination-Ion Spray Mass Spectrometry (CIS MS). This mass spectrometry study covers two aspects: improving the MS signal to overcome the low ionisation efficiency in ESI-MS and exploring the complexation behaviour of the induced structure to optimise the antifungal properties. PMID- 21710594 TI - Alteration of micromilled carbonate delta18O during Kiel Device analysis. AB - Isotopic analysis of carbonate material has been greatly facilitated by the development of autosampling devices such as the Kiel III Carbonate Device, allowing rapid automated analysis of small sample sizes. This analysis is facilitated by holding samples and acid at temperatures around 70 degrees C prior to reaction. In most situations this has no measurable effect on sample powders on practical timeframes, but, when analyzing exceptionally fine-grained material produced by micromilling, the delta(18)O of both aragonite and calcite is altered by -0.1 0/00/day. Laboratories that use this technique should thoroughly test and correct for this phenomenon and avoid storing pre-weighed materials within the Kiel Device or similar drying oven prior to analysis. PMID- 21710595 TI - Identification of phase I and phase II metabolites of benfluron and dimefluron in rat urine using high-performance liquid chromatography/tandem mass spectrometry. AB - Biotransformation products of two potential antineoplastic agents, benfluron and dimefluron, are characterized using our integrated approach based on the combination of high-performance liquid chromatography (HPLC) separation of phase I and phase II metabolites followed by photodiode-array UV detection and electrospray ionization tandem mass spectrometry (MS/MS). High mass accuracy measurement allows confirmation of an elemental composition and metabolic reactions according to exact mass defects. The combination of different HPLC/MS/MS scans, such as reconstructed ion current chromatograms, constant neutral loss chromatograms or exact mass filtration, helps the unambiguous detection of low abundance metabolites. The arene oxidation, N-oxidation, N demethylation, O-demethylation, carbonyl reduction, glucuronidation and sulfation are typical mechanisms of the metabolite formation. The interpretation of their tandem mass spectra enables the distinction of demethylation position (N- vs. O-) as well as to differentiate N-oxidation from arene oxidation for both phase I and phase II metabolites. Two metabolic pathways are rather unusual for rat samples, i.e., glucosylation and double glucuronidation. The formation of metabolites that lead to a significant change in the chromophoric system of studied compounds, such as the reduction of carbonyl group in 7H-benzo[c]fluorene-7-one chromophore, is reflected in their UV spectra, which provides valuable complementary information to MS/MS data. PMID- 21710596 TI - Time-resolved selected ion flow tube mass spectrometric quantification of the volatile compounds generated by E. coli JM109 cultured in two different media. AB - Preliminary measurements have been made of the volatile compounds emitted by the bacterium E. coli JM109 cultured in the commonly used media Dulbecco's modified Eagle's medium (DMEM) and lysogeny broth (LB) using selected ion flow tube mass spectrometry, SIFT-MS, as a step towards the real time, non-invasive monitoring of accidental infections of mammalian cell cultures. In one procedure, the culture medium alone and the E. coli cells/medium combination were held at 37 degrees C in bottles sealed with septa for a given time period, usually overnight, to allow the bacterium to proliferate, after which the captured headspace was analysed directly by SIFT-MS. Several compounds were seen to be produced by the E. coli cells that depended on the liquid medium used: when cultured in DMEM, copious amounts of ethanol, acetaldehyde and hydrogen sulphide were produced; in LB ammonia is the major volatile product. In a second procedure, to ensure aerobic conditions prevailed in the cell culture, selected volatile compounds were monitored by SIFT-MS in real time for several hours above the open-to-air E. coli/DMEM culture held at close to 37 degrees C. The temporal variations in the concentrations of some compounds, which reflect their production rates in the culture, indicate maxima. Thus, the maxima in the ethanol and acetaldehyde production are a reflection of the reduction of glucose from the DMEM by the vigorous E. coli cells and the maximum in the hydrogen sulphide level is an indication of the loss of the sulphur-bearing amino acids from the DMEM. Serendipitously, emissions from DMEM inadvertently infected with the bacterium C. testosteroni were observed when large quantities of ammonia were seen to be produced. The results of this preliminary study suggest that monitoring volatile compounds might assist in the early detection of bacterial infection in large scale bioreactors. PMID- 21710597 TI - Structural characterization and identification of biflavones in Selaginella tamariscina by liquid chromatography-diode-array detection/electrospray ionization tandem mass spectrometry. AB - Biflavonoids, a special class of flavonoids, are widely distributed in gymnosperm plants and have various biological activities. They are also major bioactive ingredients in Selaginella tamariscina. In this work, we report the use of high performance liquid chromatography with a diode-array detector (HPLC-DAD) and electrospray ionization multi-stage tandem mass spectrometry (ESI-MS(n)) to study the fragmentation behavior of three main types of biflavonoids using seven biflavonoid reference compounds and analyze the biflavonoids in Selaginella tamariscina. The most useful fragmentations in terms of structural identification are those involving the C-ring cleavage of biflavonoids. For amentoflavone-type biflavonoids (containing flavonoid parts I and II), fragmentation on the flavonoid part II at positions 1/3 and 0/4 are the primary pathways, whereas the chances are greater for C-ring cleavage fragmentation occurring on flavonoid part I at positions 1/3 and 1/4 for robustaflavone-type biflavonoids. However, the predominant diagnostic ions of the specific C-O-C-connected hinokiflavone-type biflavonoids are a series of ions resulting from the rupture of the connective C O bond. Based on the fragmentation patterns of these reference compounds, 17 biflavonoids were identified in an extract of Selaginella tamariscina, three of which have not been previously reported as constituents of this plant. This study provides a powerful approach for the online structural elucidation and identification of different types of biflavonoids and positional isomers from Selaginella tamariscina and other biflavonoids distributed in related plants and prescriptions. PMID- 21710598 TI - Mass spectrometric characterization of urinary metabolites of the selective androgen receptor modulator S-22 to identify potential targets for routine doping controls. AB - Drugs that promote anabolic processes with limited undesirable effects are of considerable therapeutic interest; some notable examples include those for the treatment of cancer cachexia and muscle-wasting diseases. Anabolic properties are not only therapeutically beneficial to critically ill and debilitated patients, but are also desirable to athletes seeking artificial enhancements in endurance, strength and accelerated recovery. The use of anabolic agents in the clinical setting is being reconsidered with the emergence of a new class of drugs referred to as SARMs (selective androgen receptor modulators). SARMs have the potential to complement or even replace anabolic androgenic steroidal use with the benefit of a reduction of the undesirable side effects associated with steroid administration alone. Arylpropionamide-based SARMs such as andarine (S-4) and S 22 have shown promising therapeutic properties and have attracted the interest of elite and amateur athletes despite the absence of clinical approval, and evidence for trafficking and misuse in sport has been obtained by doping control authorities. In this communication, the elucidation of urinary metabolites of the SARM drug candidate S-22 is compared with earlier in vitro metabolism studies. Following oral administration of illicit S-22, urine samples were collected after 62 and 135 h and analyzed for the active drug and its major metabolic products. Liquid chromatography interfaced with high-resolution/high-accuracy (tandem) mass spectrometry was used to identify and/or confirm the predicted target analytes for sports drug testing purposes. S-22 was detected in both specimens accompanied by its glucuronic acid conjugate. This was the B-ring hydroxylated derivative of S-22 plus the corresponding glucuronide (with the phase-II metabolites being the more abundant analytes). In addition, the samples collected 62 h post administration also contained the phase-I metabolite hydroxylated at the methyl residue (C-20) and the B-ring depleted degradation product ('dephenylated' S-22) together with the corresponding carboxy analog that was previously reported for canine metabolism. The obtained data supports future efforts to effectively screen for and confirm the misuse of the non-approved S-22 drug candidate in doping controls. PMID- 21710599 TI - Nonlinear behavior during semi-quantitative analysis of thin organic layers by laser desorption mass spectrometry. AB - Characterization of the surface coverage and thickness of an organic thin film is particularly important in organic electronics and optoelectronics. For surface coverage down to the submonolayer level there is still a need for characterization methods which are easily applicable. In the present work we report on the evaluation of laser desorption mass spectrometry (LD-MS) for its use in thickness determination of organic thin films. Whereas LD-MS is well established as a soft ionization method for small molecules, its capability for use in quantitative analysis is nearly unexplored. We carried out experiments with two different molecules, 7,7,8,8-tetracyanoquinodimethane and hexabenzocoronene, in a series of experiments with increasing surface coverage. The obtained data were analyzed by plotting the LD signal intensities versus the relative layer thickness and they reveal a nonlinear behavior, which can be classified into regions of different desorption/ionization efficiencies. Visualization by atomic force microscopy reveals that the first efficiency change corresponds to the transition between incomplete and complete coverage of the metal surface by analyte molecules. A second transition is observed at high layer thickness where the signal intensity stays constant, independent of further thickness increments, and this is attributed to the limited penetration depth of the laser beam. The intermediate region between the two transitions shows a linear behavior and can thus be used for semi-quantitative thickness measurements. The efficiency change observed at the point of complete surface coverage is particularly useful for thin layer preparation of organic field effect transistors, where complete surface coverage is a minimum requirement. PMID- 21710601 TI - Editorial: which influenza subtype should be added to the next vaccine? PMID- 21710600 TI - Quantitative aspects in electrospray ionization ion trap and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of malto oligosaccharides. AB - Mass spectrometry is widely applied in carbohydrate analysis, but still quantitative evaluation of data is critical due to different ionization efficiencies of the constituents in a mixture. Different size and chemical structure of the analytes cause their uneven distribution in droplets (electrospray ionization, ESI) or matrix spots (matrix-assisted laser desorption/ionization, MALDI). In addition, instrumental parameters affect final ion yields. In order to study and optimize the latter, an equimolar mixture of malto-oligosaccharides (DP1-6) was analyzed using varying target masses for ESI as well as different matrices and laser power for MALDI. The sodium adducts and derivatives for positive ion mode (hydrazones with Girard's T Reagent, GT) and negative ion mode (reductively aminated with o-aminobenzoic acid, oABA) were studied. Negatively charged oABA-labeled malto-oligosaccharides turned out to be unsuitable for quantification of the malto-oligomeric composition. Best agreement was achieved when applying target masses in the range of the highest homolog in the mixture in electrospray ionization ion trap (ESI-IT) (1-2% deviation with GT label or as Na(+) adducts). Matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS) gave best results when the laser power was adjusted significantly over the desorption/ionization threshold (1% deviation with GT label). Both parameters show significant influence on the determined oligomeric composition. Consequently, estimation and even quantitative determination of amounts of oligosaccharides in a mixture can be achieved when the analytes are labeled and the proper instrumental parameters are used. PMID- 21710603 TI - The development of perceptual expertise for faces and objects in autism spectrum conditions. AB - Previous research indicates that individuals with autism spectrum conditions (ASC) do not develop face expertise to the same extent as typical individuals. Yet it remains unclear whether this atypicality is specific to faces or related to more pervasive perceptual or cognitive deficits involved in the actual process of gaining expertise. To address this question, we examined the extent to which adults with ASC were capable of developing expertise with non-face objects. To become experts, all participants completed a 2-week training program with novel objects, known as Greebles. Level of expertise was assessed throughout training by measuring the ability to identify Greebles on an individual level. The perceptual strategies acquired as a result of expertise were measured through an inversion effect task completed before and after training, in which performance with upright Greebles and faces was compared to performance with inverted Greebles and faces. After expertise training, it was found that individuals in both the ASC and the typical group successfully achieved expertise and showed an enhanced Greeble inversion effect as a result of training. The development of an inversion effect with Greebles suggests that individuals with ASC may employ the same processing strategies as the typical group. Although exploratory, these findings have implications for understanding the nature of the face processing deficit in ASC as well as offering potential insights into face processing interventions for individuals with ASC. PMID- 21710604 TI - Vascular endothelial growth factor polymorphisms in patients with steroid-induced femoral head osteonecrosis. AB - To investigate an association between steroid-induced femoral head osteonecrosis (FHON) and functional vascular endothelial growth factor (VEGF) gene (-2578A/C, 1154A/G, -634C/G, and +405C/G) polymorphisms polymerase chain reaction restriction fragment length polymorphism genotyping was performed in 160 patients (86 idiopathic FHON and 74 steroid-induced FHON) and 160 gender- and age-matched controls. The steroid-induced subgroup had a significantly lower prevalence of 1154A allele (7.4% vs. 18.1%, odds ratio (OR) = 0.363) and genotype carrying 1154A (14.9% vs. 32.5%, OR = 0.333 in a recessive model) than controls. In a dominant model, the frequency of genotype carrying +405G (74.3% vs. 84.4%, OR = 0.492) was significantly lower in steroid-induced FHON than in controls. The distribution of haplotypes was significantly different between controls and FHON patients (p = 0.00011). Especially, when haplotypes were classified into high (CGCG and AAGG) or low (CGGC and AGGC) VEGF inducing haplotypes, patients with steroid-induced FHON had a significantly lower prevalence of high inducing haplotypes (7.4% vs. 15.9%, OR = 0.424) and a significantly higher prevalence of low inducing haplotypes (4.7% vs. 0.6%, OR = 7.894) than controls. Low inducing VEGF haplotypes may confer an increased risk and high inducing haplotypes have a protective effect for the development of steroid-induced FHON in Korea. PMID- 21710605 TI - Migration responses of outer and inner meniscus cells to applied direct current electric fields. AB - Injuries to the inner regions of the knee meniscus do not heal and can result in degenerative changes to the articular surface, ultimately leading to osteoarthritis. A possible stimulus to enhance meniscus healing is to use electric fields that induce galvanotaxis. In this study, a novel characterization of the effects of direct current electric fields on migration characteristics of meniscus cells was performed. Primary and passaged inner and outer meniscus cells were exposed to varying electric field strengths from 0 to 6 V/cm. Cell migration was tracked using time lapse digital photography, and cell displacement and cathodal direct velocity were quantified. Cytoskeletal staining was performed to examine actin distribution and nuclear content. Cell adhesion strength was quantified as a function of wall shear stress. Meniscus cells exhibited cathodal migration and cell elongation perpendicular to the applied electric field accompanied by actin reorganization. Outer meniscus cells migrated quicker and exhibited lower adhesion strengths when compared to inner meniscus cells. Passaged cells exhibited higher migration characteristics when compared to primary cells. Overall, this study demonstrated that electric fields can significantly enhance and direct meniscus cell migration and suggests the potential for their incorporation in strategies of meniscus repair and tissue engineering. PMID- 21710606 TI - Revision of the Shoulder Normalization Tests is required to include rhomboid major and teres major. AB - The four "Shoulder Normalization Tests" were found previously to be a parsimonious set of isometric tests that produce maximal voluntary isometric contractions (MVIC) in the supraspinatus, infraspinatus, subscapularis, trapezius, serratus anterior, deltoid, latissimus dorsi, and pectoralis major [Boettcher et al. (2008). J Orthop Res 26:1591-1597]. However, these tests have not been validated for rhomboid major and teres major. In the current study, these Shoulder Normalization Tests were evaluated and compared to three other tests that could possibly elicit maximum activity in rhomboid major and teres major: abduction/extension in 90 degrees abduction; adduction at 90 degrees abduction; and extension in 30 degrees abduction. No statistical difference was found in the mean activation of rhomboid major and teres major in these additional MVIC tests compared to the Shoulder Normalization Tests. However, the extension MVIC test produced maxima for at least 50% of subjects in rhomboid major, teres major, and latissimus dorsi. We concluded that the original Shoulder Normalization Tests should be expanded to include the extension MVIC test. The EMG normalization reference value for any of the above muscles would be the maximum EMG level generated across these Revised Shoulder Normalization Tests. PMID- 21710607 TI - Effects of aging and degeneration on the human intervertebral disc during the diurnal cycle: a finite element study. AB - A significant biochemical change that takes place in intervertebral disc degeneration is the loss of proteoglycans in the nucleus pulposus. Proteoglycans attract fluid, which works to reduce mechanical stresses in the solid matrix of the nucleus and provide a hydrostatic pressure to the annulus fibrosus, whose fibrous nature accommodates this stress. Our goals are to develop an osmo poroelastic finite element model to study the relationship between proteoglycan content and the stress distribution within the disc and to analyze the effects of degeneration on the disc's diurnal mechanical response. Stress in the annulus increased with degeneration from ~0.2 to 0.4 MPa, and an increase occurred in the center of the nucleus from 1.2 to 1.6 MPa. The osmotic pressure in the central nucleus region decreased the most with degeneration, from ~0.42 to ~0.1 MPa in a severely dehydrated disc. A 3% decrease in diurnal fluid lost with degeneration equated to ~21% decrease in fluid exchange, and hence a decrease in nutrients that require convection to enter the disc. We quantified the increases in internal stresses in the nucleus and annulus throughout the various stages of degeneration, suggesting that these changes lead to further remodeling of the tissue. PMID- 21710608 TI - Green synthesis of lead sulfide nanoparticles by the lead resistant marine yeast, Rhodosporidium diobovatum. AB - Biosynthesis of nanoparticles using microorganisms has attracted a lot of attention in recent years as this route has the potential to lead to synthesis of monodisperse nanoparticles. Here, we report the intracellular synthesis of stable lead sulfide nanoparticles by a marine yeast, Rhodosporidium diobovatum. The PbS nanoparticles were characterized by UV-visible absorption spectroscopy, X-ray diffraction (XRD) and energy dispersive atomic spectroscopy (EDAX). UV-visible absorption scan revealed a peak at 320 nm, a characteristic of the nanosize range. XRD confirmed the presence of PbS nanoparticles of cubic structure. Crystallite size as determined from transmission electron microscopy was found to be in the range of 2-5 nm. Elemental analysis by EDAX revealed the presence of particles composed of lead and sulfur in a 1:2 ratio indicating that PbS nanoparticles were capped by a sulfur-rich peptide. A quantitative study of lead uptake through atomic absorption spectrometry revealed that 55% of lead in the medium was accumulated in the exponential phase, whereas a further 35% was accumulated in the stationary phase; thus, the overall recovery of PbS nanoparticles was 90%. The lead-exposed yeast displayed a marked increase (280% over the control) in nonprotein thiols in the stationary phase. PMID- 21710609 TI - Dorsally-derived oligodendrocytes in the spinal cord contribute to axonal myelination during development and remyelination following focal demyelination. AB - In the developing spinal cord, the majority of oligodendrocytes are derived from the ventral ventricular zone. Several recent studies suggested that a small number of oligodendrocyte precursor cells (OPCs) can also be generated in the dorsal spinal cord. However, it is not clear whether these dorsal oligodendrocyte precursor cells participate in myelination and remyelination. To investigate the fate and potential function of these dorsally-derived oligodendrocytes (dOLs) in the adult spinal cord, Cre-lox genetic fate mapping in transgenic mice was employed. We used the Pax3(Cre) knock-in mouse to drive Cre expression in the entire dorsal epithelium and the Rosa26-lacZ or Z/EG reporter line to trace their spatial distribution and population dynamics in the spinal cord. The dorsal OPCs generated from the Pax3-expressing domains migrate into all regions of spinal cord and subsequently undergo terminal differentiation and axonal myelination. In response to a focal demyelination injury, a large number of newly differentiated oligodendrocytes originated from dOLs, suggesting that dOLs may provide an important source of OPCs for axonal remyelination in multiple sclerosis or spinal cord injury. PMID- 21710610 TI - Hepatic control elements promote long-term expression of human coagulation factor IX gene in hydrodynamically transfected mice. AB - BACKGROUND: Long-term expression of the delivered target gene is critical for successful gene therapy. Recently, hepatic control region I (HCR I) originating from the apolipoprotein (apo)C-I pseudogene was shown to be a critical element for long-term gene expression in the liver of mice. HCR II is another hepatic control region of apoC-I. METHODS: HCR I, HCR II and HCR I/II-containing plasmids encoding factor IX were prepared and hydrodynamically transferred into the liver of normal and hemophilia B mice. Factor IX expression, clotting activity and formation of antibodies against the expressed gene product were compared. RESULTS: HCR I-, HCR II- and HCR I/II-containing plasmids all induced long-term gene expression in both normal and hemophilia B mice. Post-transfection factor IX expression in the hemophilia B mice remained above 500 ng/ml for 210 days. Antibodies against human factor IX were detected at a low level in the serum, although they had no effect on the levels and clotting activity of the expressed factor IX. CONCLUSIONS: We have shown in mouse models that hydrodynamic transfection of pBS-HCRII-HP-FIXA and pBS-HCRI/II-HP-FIXA was able to induce and maintain the expression and clotting activity of human factor IX for a long period of time at a potentially therapeutic level. With an appropriate delivery system, this type of plasmid vector could be clinically useful for the hepatic expression of therapeutic genes including human factor IX. PMID- 21710611 TI - Assessment of cell infiltration in myocardial infarction: a dose-dependent study using micrometer-sized iron oxide particles. AB - Myocardial infarction (MI) is a leading cause of death and disabilities. Inflammatory cells play a vital role in the process of postinfarction remodeling and repair. Inflammatory cell infiltration into the infarct site can be monitored using T 2-weighted MRI following an intravenous administration of iron oxide particles. In this study, various doses of micrometer-sized iron oxide particles (1.1-14.5 MUg Fe/g body weight) were injected into the mouse blood stream before a surgical induction of MI. Cardiac MRIs were performed at 3, 7, 14, and 21 days postinfarction to monitor the signal attenuation at the infarct site. A dose dependent phenomenon of signal attenuation was observed at the infarct site, with a higher dose leading to a darker signal. The study suggests an optimal temporal window for monitoring iron oxide particles-labeled inflammatory cell infiltration to the infarct site using MRI. The dose-dependent signal attenuation also indicates an optimal iron oxide dose of approximately 9.1-14.5 MUg Fe/g body weight. A lower dose cannot differentiate the signal attenuation, whereas a higher dose would cause significant artifacts. This iron oxide-enhanced MRI technique can potentially be used to monitor cell migration and infiltration at the pathological site or to confirm any cellular response following some specific treatment strategies. PMID- 21710612 TI - Parallel imaging with nonlinear reconstruction using variational penalties. AB - A new approach based on nonlinear inversion for autocalibrated parallel imaging with arbitrary sampling patterns is presented. By extending the iteratively regularized Gauss-Newton method with variational penalties, the improved reconstruction quality obtained from joint estimation of image and coil sensitivities is combined with the superior noise suppression of total variation and total generalized variation regularization. In addition, the proposed approach can lead to enhanced removal of sampling artifacts arising from pseudorandom and radial sampling patterns. This is demonstrated for phantom and in vivo measurements. PMID- 21710613 TI - B1(+) phase mapping at 7 T and its application for in vivo electrical conductivity mapping. AB - In this study, a new approach to measure local electrical conductivity in tissue is presented, which is based on the propagating B1(+) phase and the homogeneous Helmholtz equation. This new MRI technique might open future opportunities for tumor and lesion characterization based on conductivity differences, while it may also find application in radio frequency safety assessment. Prerequisites for conductivity mapping using only the B1(+) phase (instead of the complex B1(+) field) are addressed. Furthermore it was found that the B1(+) phase can be derived directly from the measurable transceive phase arg(B1(+)B1(-)) in the head. Validation for a human head excited by a 7 T-birdcage coil using simulations and measurements showed that it is possible to measure in vivo conductivity patterns in the brain using B1(+) phase information only. Conductivity contrast between different brain tissues is clearly observed. The measured mean values for white matter, gray matter and cerebrospinal fluid differed 54%, 26%, and -13% respectively from literature values. The proposed method for B1(+) phase measurements is very suited for in vivo applications, as the measurement is short (less than a minute per imaged slice) and exposes the patient to low RF power, contrary to earlier proposed approaches. PMID- 21710615 TI - Effects of antiresorptive treatment on nonvertebral fracture outcomes. AB - Various definitions of nonvertebral fracture have been used in osteoporosis trials, precluding comparisons of efficacy. Using only subgroups of nonvertebral fractures for trial outcomes may underestimate the benefits and cost effectiveness of treatments. The objectives of this study were to determine (1) the effect of antiresorptive treatment on various nonvertebral fracture outcomes, (2) whether risk reduction from antiresorptive treatment is greater for nonvertebral fractures that have stronger associations with low BMD, and (3) sample size estimates for clinical trials of osteoporosis treatments. Study-level data were combined from five randomized fracture-prevention trials of antiresorptive agents that reduce the risk of nonvertebral fracture in postmenopausal women: alendronate, clodronate, denosumab, lasofoxifene, and zoledronic acid. Pooled effect estimates were calculated with random-effects models. The five trials included 30,118 women; 2997 women had at least one nonvertebral fracture. There was no significant heterogeneity between treatments for any outcome (all p > 0.10). Antiresorptive treatment had similar effects on all fractures (summary hazard ratio [HR] = 0.76, 95% CI 0.70-0.81), high-trauma fractures (HR = 0.74, 95% CI 0.57-0.96), low-trauma fractures (HR = 0.77, (95% CI 0.71-0.83), nonvertebral six (ie, hip, pelvis, leg, wrist, humerus, and clavicle) fractures (HR = 0.73, 95% CI 0.66-0.80), other than nonvertebral six fractures (HR = 0.78, 95% CI 0.70-0.87), and all fractures other than finger, face, and toe (HR = 0.75, 95% CI 0.70-0.81). Risk reduction was not greater for fractures with stronger associations with low BMD (p = 0.77). A trial of all nonvertebral fractures would require fewer participants (n = 2641 per arm) than one of a subgroup of six fractures (n = 3289), for example. In summary, antiresorptive treatments reduced all nonvertebral fractures regardless of degree of trauma or special groupings, supporting the use of all nonvertebral fractures as a standard endpoint of osteoporosis trials and the basis for estimating the benefits and cost-effectiveness of treatments. PMID- 21710614 TI - Serum 25-hydroxyvitamin D and clinical fracture risk in a multiethnic cohort of women: the Women's Health Initiative (WHI). AB - Low 25-hydroxyvitamin D [25(OH)D] levels have been linked to hip fracture in white women. To study the association of 25(OH)D with risk of fracture in multiethnic women, we performed a nested case-control study within the prospective Women's Health Initiative (WHI) Observational Study. Incident fractures were identified in 381 black, 192 Hispanic, 113 Asian, and 46 Native American women over an average of 8.6 years. A random sample of 400 white women who fractured was chosen. One control individual was selected per case and matched on age, race/ethnicity, and blood draw date. 25(OH)D, parathyroid hormone, and vitamin D-binding protein (DBP) were measured in fasting baseline serum. Conditional logistic regression models were used to calculate the odds ratio (OR) and 95% CI. In multivariable models, higher 25(OH)D levels compared with levels less than 20 ng/mL were associated with a lower risk of fracture in white women (20 to <30 ng/mL: OR = 0.82, 95% CI 0.58-1.16; <=30.0 ng/mL: OR = 0.56, 95% CI 0.35-0.90; p trend = 0.02). In contrast, higher 25(OH)D (>=20 ng/mL) compared with levels less than 20 ng/mL were associated with a higher risk of fracture in black women (OR = 1.45, 95% CI 1.06-1.98; p trend = 0.043). Higher 25(OH)D (>=30.0 ng/mL) was associated with higher fracture risk in Asian women after adjusting for DBP (OR = 2.78, 95% CI 0.99-7.80; p trend = 0.04). There was no association between 25(OH)D and fracture in Hispanic or Native American women. Our results suggest divergent associations between 25(OH)D and fracture by race/ethnicity. The optimal level of 25(OH)D for skeletal health may differ in white and black women. PMID- 21710618 TI - Measurement of intraocular and intracranial pressure: is there a relationship? AB - OBJECTIVE: To study whether noninvasive, intraocular pressure (IOP) measurements significantly correlate with standard intracranial pressure (ICP) measurements. METHODS: This prospective, blinded study enrolled 46 patients who were undergoing medically indicated lumbar puncture (LP). IOP was measured by applanation tonometry immediately prior to measuring LP opening pressure. One patient was excluded due to unsuccessful ICP measurement. RESULTS: In the 45 patients to successfully undergo IOP and ICP measurement, there was no significant relationship between ICP and average IOP for both eyes (r = -0.005). There was no significant relationship between ICP and IOP in either eye, when studied individually(r = 0.03 ocular dexter [OD], r = -0.05 ocular sinister [OS]). There was no significant relationship between ICP and IOP when the eye best correlated to the patient's ICP was chosen (r = -0.01). INTERPRETATION: No significant relationship between ICP and IOP was observed. Noninvasive IOP measurements do not predict ICP. PMID- 21710619 TI - Inflammation after trauma: microglial activation and traumatic brain injury. AB - OBJECTIVE: Patient outcome after traumatic brain injury (TBI) is highly variable. The underlying pathophysiology of this is poorly understood, but inflammation is potentially an important factor. Microglia orchestrate many aspects of this response. Their activation can be studied in vivo using the positron emission tomography (PET) ligand [11C](R)PK11195 (PK). In this study, we investigate whether an inflammatory response to TBI persists, and whether this response relates to structural brain abnormalities and cognitive function. METHODS: Ten patients, studied at least 11 months after moderate to severe TBI, underwent PK PET and structural magnetic resonance imaging (including diffusion tensor imaging). PK binding potentials were calculated in and around the site of focal brain damage, and in selected distant and subcortical brain regions. Standardized neuropsychological tests were administered. RESULTS: PK binding was significantly raised in the thalami, putamen, occipital cortices, and posterior limb of the internal capsules after TBI. There was no increase in PK binding at the original site of focal brain injury. High PK binding in the thalamus was associated with more severe cognitive impairment, although binding was not correlated with either the time since the injury or the extent of structural brain damage. INTERPRETATION: We demonstrate that increased microglial activation can be present up to 17 years after TBI. This suggests that TBI triggers a chronic inflammatory response particularly in subcortical regions. This highlights the importance of considering the response to TBI as evolving over time and suggests interventions may be beneficial for longer intervals after trauma than previously assumed. PMID- 21710620 TI - Complete remission in nonsyndromic childhood-onset epilepsy. AB - OBJECTIVE: Determine the probability of attaining complete remission in children with nonsyndromic epilepsy (NSE) over the course of >=10 years from initial diagnosis; identify early predictors of complete remission; and assess the risk of relapse after achieving complete remission. METHODS: In a prospective community-based cohort, complete remission was defined as 5 years seizure-free and medication-free. Any subsequent seizure for any reason was a relapse. Univariate and bivariate analyses were conducted with standard methods including the Kaplan-Meier approach. Proportional hazards modeling was used for multivariable analysis. RESULTS: Of 613 cohort members, 347 had NSEs, of whom 294 (85%) were followed >=10 years (maximum = 17.9). A total of 170 in 294 (58%) achieved complete remission, 10 of whom (6%) relapsed. Seizure outcome at 2 years (remission, pharmacoresistant, unclear) (p < 0.0001) and underlying cause (p < 0.0001) distinguished groups with complete remission ranging from ~20% to ~75%. Older age at onset was independently associated with a poorer chance of complete remission. Relapses occurred up to 7.5 years after attaining complete remission and were marginally associated with underlying cause (p = 0.06). INTERPRETATION: Complete remission occurs in over one-half of young people with NSE and generally persists. Meaningful but imperfect predication is possible based on underlying cause and early seizure control. The finding of age effects may play a role in meaningful identification of phenotypes, which could become fruitful targets for genetic and imaging investigations in these otherwise poorly differentiated epilepsies. PMID- 21710621 TI - Contrast gain control abnormalities in idiopathic generalized epilepsy. AB - OBJECTIVE: The origin of neural hyperexcitability underlying idiopathic generalized epilepsy (IGE) is not known. The objective of this study is to identify evidence of hyperexcitability in precisely measured visual evoked responses and to understand the nature of changes in excitation and inhibition that lead to altered responses in human patients with IGE. METHODS: Steady-state visual-evoked potentials (VEPs) to contrast reversing gratings were recorded over a wide range of stimulus contrast. VEPs were analyzed at the pattern reversal rate using spectral analysis. Ten patients with IGE and 13 healthy subjects participated. All subjects had normal visual acuity and had no history of photic induced seizures or photoparoxysmal electroencephalograph (EEG) activity. RESULTS: At a group level, the amplitude of visual responses did not saturate at high stimulus contrast in patients, as it did in the control subjects. This reflects an abnormality in neuronal gain control. The VEPs did not have sufficient power to reliably distinguish patients from controls at an individual level. Parametric modeling using a standard gain control framework showed that the abnormality lay in reduced inhibition from neighboring neurons rather than increased excitatory response to the stimulus. INTERPRETATION: Visual evoked responses reveal changes in a fundamental mechanism regulating neuronal sensitivity. These changes may give rise to hyperexcitability underlying generalized epilepsy. PMID- 21710622 TI - Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions. AB - OBJECTIVE: Multiple sclerosis (MS) lesions develop around small, inflamed veins. New lesions enhance with gadolinium on magnetic resonance imaging (MRI), reflecting disruption of the blood-brain barrier (BBB). Single time point results from pathology and standard MRI cannot capture the spatiotemporal expansion of lesions. We investigated the development and expansion of new MS lesions, focusing on the dynamics of BBB permeability. METHODS: We performed dynamic contrast-enhanced (DCE) MRI in relapsing-remitting MS. We obtained data over 65 minutes, during and after gadolinium injection. We labeled spatiotemporal enhancement dynamics as centrifugal when initially central enhancement expanded outward and centripetal when initially peripheral enhancement gradually filled the center. RESULTS: We detected 34 enhancing lesions in 200 DCE-MRI scans. In 65%, enhancement first appeared as a closed ring; in 18%, as a nodule; and in 18%, as an open ring. Lesions with initially nodular enhancement were smaller than those initially enhancing as rings (p < 0.0001). All initially nodular lesions enhanced centrifugally, whereas initially ringlike lesions enhanced centripetally, becoming nodular if small (82%) or nearly nodular if larger (18%). Open-ring lesions were periventricular or juxtacortical and enhanced centripetally. Centrifugally enhancing lesions evolved into centripetally enhancing lesions over several days. INTERPRETATION: The rapid change of enhancement dynamics from centrifugal to centripetal reflects the outward growth of MS lesions around their central vein and suggests that factors mediating lesion growth and tissue repair derive from different locations at different times. We propose a model of new lesion growth that unites our imaging observations with existing pathology data. PMID- 21710623 TI - 2010 revisions to McDonald criteria for diagnosis of multiple sclerosis: impact of 3-Tesla magnetic resonance imaging. PMID- 21710624 TI - Opposite effect of inflammation on subventricular zone versus hippocampal precursors in brain injury. AB - OBJECTIVE: Inflammation promotes epidermal wound healing but is considered detrimental to recovery from central nervous system injury. Sick infants have increased levels of cytokines in their cerebrospinal fluid that correlate with poor neurological outcome. In this study, we investigated the role of neuroinflammation and more specifically interleukin 6 (IL-6) in the amplification of subventricular zone (SVZ) and subgranular zone (SGZ) neural precursors after neonatal brain injury. METHODS: Neonatal hypoxia/ischemia (H/I) was induced in P6 rat pups, and IL-6 was quantified with or without indomethacin administration. Neural precursor responses were evaluated by neurosphere assays as well as by stereological analyses. Studies were performed to determine how IL-6 and leukemia inhibiting factor (LIF) affect SVZ cell expansion, proliferation, and self renewal. RESULTS: Consistent with earlier studies, medially situated SVZ cells expanded after H/I. Contrary to our expectations, indomethacin significantly decreased both the initial reactive increase in these precursors and their ability to self-renew. By contrast, indomethacin increased proliferation in the SGZ and lateral SVZ. Indomethacin diminished the accumulation of microglia/macrophages and IL-6 production after H/I. In vitro IL-6 enhanced neurosphere growth, self-renewal, and tripotentiality and was more effective than LIF in promoting self-renewal. Enhanced precursor self-renewal also was obtained using prostaglandin E2, which is downstream of cyclooxygenase 2 and a target of indomethacin. INTERPRETATION: These data implicate neuroinflammation and in particular IL-6 as a positive effector of primitive neural precursor expansion after neonatal brain injury. These findings have important clinical implications, as indomethacin and other anti-inflammatory agents are administered to premature infants for a variety of reasons. PMID- 21710625 TI - NOA-05 phase 2 trial of procarbazine and lomustine therapy in gliomatosis cerebri. AB - OBJECTIVE: The NOA-05 multicenter trial was performed to analyze the efficacy of primary chemotherapy with procarbazine and lomustine (PC) in patients with gliomatosis cerebri (GC) and to define clinical, imaging, and molecular factors influencing outcome. METHODS: Thirty-five patients with previously untreated GC were treated with up to six 56-day courses of 110mg/m(2) lomustine on day 1 and 60mg/m(2) procarbazine on days 8 to 21. The primary endpoint was the rate of patients without therapy failure (defined as progressive disease, death from any cause, or termination of PC therapy before the end of course 4) at 8 months after the beginning of PC chemotherapy. RESULTS: The failure-free survival rate at 8 months was 50.3%. Median progression-free survival was 14 months. At progression, 12 patients received salvage radiotherapy. Median overall survival was 30 months. Multivariate analysis revealed isocitrate dehydrogenase 1 (IDH1) gene mutation (hazard ratio [HR], 0.11; 95% confidence interval [CI], 0.02-0.58) and initial presentation without a bilateral symmetrical infiltration pattern on magnetic resonance imaging (HR 0.07, 95%CI 0.01-0.54) as independent prognostic factors associated with prolonged survival. IDH1 mutation was significantly associated with MGMT promoter methylation and an oligodendroglial tumor component. INTERPRETATION: PC chemotherapy is effective in GC. With the NOA-05 trial being the first prospective multicenter trial in GC, PC chemotherapy can be regarded as a promising option for the primary therapy of these tumors. PMID- 21710627 TI - Revised McDonald criteria: the persisting importance of cerebrospinal fluid analysis. PMID- 21710628 TI - A dynamic view of the blood-brain barrier in active multiple sclerosis lesions. PMID- 21710629 TI - Restless legs syndrome-associated MEIS1 risk variant influences iron homeostasis. AB - Restless legs syndrome (RLS) is a frequent sleep disorder that is linked to disturbed iron homeostasis. Genetic studies identified MEIS1 as an RLS predisposing gene, where the RLS risk haplotype is associated with decreased MEIS1 mRNA and protein expression. We show here that RNA interference treatment of the MEIS1 worm orthologue increases ferritin expression in Caenorhabditis elegans and that the RLS-associated haplotype leads to increased expression of ferritin and DMT1 in RLS brain tissues. Additionally, human cells cultured under iron-deficient conditions show reduced MEIS1 expression. Our data establish a link between the RLS MEIS1 gene and iron metabolism. PMID- 21710630 TI - Use of space, activity patterns, and foraging behavior of red howler monkeys (Alouatta seniculus) in an Andean forest fragment in Colombia. AB - Howler monkeys are among the most studied primates in the Neotropics, however, behavioral studies including estimation of food availability in Andean forests are scarce. During 12 months we studied habitat use, behavior, and feeding ecology of two groups of red howler monkeys (Alouatta seniculus) in an isolated fragment in the Colombian Andes. We used a combination of focal animal and instantaneous sampling. We estimated fruit production (FP) using phenology transects, and calculated young leaf abundance by observing marked trees. The home range area used by each group was 10.5 and 16.7 ha and daily distances traveled were 431 +/- 228 and 458 +/- 259 m, respectively. We found that both groups spent most of their time resting (62-64%). Resting time did not increase with leaf consumption as expected using a strategy of energy minimization. We did not find a relationship between daily distances traveled and leaf consumption. However, howlers consumed fruits according to their availability, and the production of young leaves did not predict feeding time on this resource. Overall, our results are similar to those found on other forest types. We found that despite limited FP in Andean forests, this did not lead to a higher intake of leaves, longer resting periods, or shorter traveling distances for red howlers. PMID- 21710632 TI - Forensic surface metrology: tool mark evidence. AB - Over the last several decades, forensic examiners of impression evidence have come under scrutiny in the courtroom due to analysis methods that rely heavily on subjective morphological comparisons. Currently, there is no universally accepted system that generates numerical data to independently corroborate visual comparisons. Our research attempts to develop such a system for tool mark evidence, proposing a methodology that objectively evaluates the association of striated tool marks with the tools that generated them. In our study, 58 primer shear marks on 9 mm cartridge cases, fired from four Glock model 19 pistols, were collected using high-resolution white light confocal microscopy. The resulting three-dimensional surface topographies were filtered to extract all "waviness surfaces"-the essential "line" information that firearm and tool mark examiners view under a microscope. Extracted waviness profiles were processed with principal component analysis (PCA) for dimension reduction. Support vector machines (SVM) were used to make the profile-gun associations, and conformal prediction theory (CPT) for establishing confidence levels. At the 95% confidence level, CPT coupled with PCA-SVM yielded an empirical error rate of 3.5%. Complementary, bootstrap-based computations for estimated error rates were 0%, indicating that the error rate for the algorithmic procedure is likely to remain low on larger data sets. Finally, suggestions are made for practical courtroom application of CPT for assigning levels of confidence to SVM identifications of tool marks recorded with confocal microscopy. PMID- 21710633 TI - Novel approach to the semi-empirical universal theory for secondary electron yield. AB - The universal semi-empirical equation has been commonly used to quantitatively describe the energy dependence of the secondary electron yield (SEY). It is even used as a first reliability test for experimental data. The equation is based on the assumption that the stopping power is constant along the electron trajectory. In this article, we derive a novel analytical expression based on a more advanced model which considers linear stopping power dependence on penetration depth. Although coinciding with the universal equation at low energies, the novel function has lower intensity in the higher energy range. The models were compared with experimental SEY data of different metals, taken from literature, as well as freshly cleaved highly oriented pyrolytic graphite, measured in the frame of this work. It is confirmed that the novel expression better describes the experimental data. PMID- 21710634 TI - Ab initio prediction of protein-ligand binding structures by replica-exchange umbrella sampling simulations. AB - We have developed a prediction method for the binding structures of ligands with proteins. Our method consists of three steps. First, replica-exchange umbrella sampling simulations are performed along the distance between a putative binding site of a protein and a ligand as the reaction coordinate. Second, we obtain the potential of mean force (PMF) of the unbiased system using the weighted histogram analysis method and determine the distance that corresponds to the global minimum of PMF. Third, structures that have this global-minimum distance and energy values around the average potential energy are collected and analyzed using the principal component analysis. We predict the binding structure as the global minimum free energy state on the free energy landscapes along the two major principal component axes. As test cases, we applied our method to five protein ligand complex systems. Starting from the configuration in which the protein and the ligand are far away from each other in each system, our method predicted the ligand binding structures in excellent agreement with the experimental data from Protein Data Bank. PMID- 21710635 TI - Importance of CH/pi hydrogen bonds in recognition of the core motif in proline recognition domains: an ab initio fragment molecular orbital study. AB - We examined CH/pi hydrogen bonds in protein/ligand complexes involving at least one proline residue using the ab initio fragment molecular orbital (FMO) method and the program CHPI. FMO calculations were carried out at the Hartree-Fock (HF)/6-31G*, HF/6-31G**, second-order Moller-Plesset perturbation (MP2)/6-31G*, and MP2/6-31G** levels for three Src homology 3 (SH3) domains and five proline recognition domains (PRDs) complexed with their corresponding ligand peptides. PRDs use a conserved set of aromatic residues to recognize proline-rich sequences of specific ligands. Many CH/pi hydrogen bonds were identified in these complexes. CH/pi hydrogen bonds occurred, in particular, in the central part of the proline-rich motifs. Our results suggest that CH/pi hydrogen bonds are important in the recognition of SH3 and PRDs by their ligand peptides and play a vital role in the signal transduction system. Combined use of the FMO method and CHPI analysis is a valuable tool for the study of protein/protein and protein/ligand interactions and may be useful in rational drug design. PMID- 21710636 TI - Rapid evaluation of the binding energies between peptide amide and DNA base. AB - The binding energies and the equilibrium hydrogen bond distances as well as the potential energy curves of 20 hydrogen-bonded amide-base dimers are evaluated from the analytic potential energy function established in our laboratory recently. The analytic potential energy function is used to calculate the N H...N, N-H...O=C, C-H...N, and C-H...O=C dipole-dipole attractive interaction energies and C=O...O=C, N-H...H-N, and N-H...H-C dipole-dipole repulsive interaction energies in the 20 dimers composed of DNA bases adenine, guanine, cytosine, or thymine and peptide amide. The calculation results show that the potential energy curves obtained from the analytic potential energy function are in good agreement with those obtained from MP2/6-311+G** calculations by including the basis set superposition error (BSSE) correction. For all the 20 dimers, the analytic potential energy function yields the binding energies of the MP2/6-311+G** with BSSE correction within the error limits of 0.50 kcal/mol for 19 dimers, only one difference is larger than 0.50 kcal/mol and the difference is only 0.61 kcal/mol. The analytic potential energy function produces the equilibrium hydrogen bond distances of the MP2/6-311+G** with BSSE correction within the error limits of 0.030 A for all the 20 dimers. The analytic potential energy function is further applied to four more complicated DNA base-peptide amide systems involving amino acid side chain and beta-sheet. The values of the binding energies and equilibrium hydrogen bond distances obtained from the analytic potential energy function are also in good agreement with those obtained from MP2 calculations with the BSSE correction. These results demonstrate that the analytic potential energy function can be used to evaluate the binding energies in hydrogen-bonded peptide amide-DNA base dimers quickly and accurately. PMID- 21710637 TI - Proteomic profiling reveals compartment-specific, novel functions of ascidian sperm proteins. AB - In this study, we performed extensive proteomic analysis of sperm from the ascidian Ciona intestinalis. Sperm were fractionated into heads and flagella, followed by further separation into Triton X-100-soluble and -insoluble fractions. Proteins from each fraction and whole sperm were separated by isoelectric focusing using two different pH ranges, followed by SDS-PAGE at two different polyacrylamide concentrations. In total, 1,294 protein spots representing 304 non-redundant proteins were identified by mass spectrometry (MALDI-TOF). On comparison of the proteins in each fraction, we were able to identify the proteins specific to different sperm compartments. Further comparison with the testis proteome allowed the pairing of proteins with sperm specific functions. Together with information on gene expression in developing embryos and adult tissues, these results provide insight into novel cellular and functional aspects of sperm proteins, such as distinct localization of actin isoforms, novel Ca(2+)-binding proteins in axonemes, localization of testis specific serine/threonine kinase, and the presence of G-protein coupled signaling and ubiquitin pathway in sperm flagella. PMID- 21710639 TI - Speaking freely: my experiences in individual psychotherapies, group therapies, and growth groups. AB - This article traces the author's experiences in sensitivity, Tavistock, and psychotherapy groups, an experience in individual psychotherapy, and two experiences in psychoanalysis. Group work was very helpful in learning how the author came across to others in general and in improving the author's ways of being helpful to others. Although the experience was valuable, difficulties emerged in the first psychoanalysis, largely because of the psychoanalyst's belief that psychoanalysis was the best form of treatment for everyone. Desiring a variety of approaches, the author undertook a second analysis with more of an integrative and intuitive therapist, which worked better for her. Lasting lessons are shared from this series of personal therapy experiences. PMID- 21710638 TI - Eomesodermin, HAND1, and CSH1 proteins are induced by cellular stress in a stress activated protein kinase-dependent manner. AB - Eomesodermin (Eomes) is a transcription factor essential for trophoblast development. Stress stimuli activate stress-activated protein kinase (MAPK8/9) and modulate transcription factors in trophoblast stem cells (TSC). In this study, we test the hypothesis that stress-induced Eomes upregulation and downstream trophoblast development are MAPK8/9-dependent. Immunocytochemical and immunoblot assays suggest that Eomes is induced by hyperosmolar stress in a dose- and time-dependent manner. Two MAPK8/9 inhibitors that work by different mechanisms, LJNKl1 and SP600125, block induction of Eomes protein by stress. During normal TSC differentiation, the transcription factor heart and neural crest derivatives expressed 1 (HAND1) is dependent on Eomes, and chorionic somatomammotropin hormone 1 (CSH1) expression is dependent on HAND1. Similar to Eomes, HAND1 and CSH1 induction by stress are MAPK8/9-dependent, and CSH1 is induced in nearly all stressed TSC. CSH1 induction normally requires downregulation of the transcription factor inhibitor of differentiation 2 (ID2) as well as HAND1 upregulation. It was shown previously that hyperosmolar stress induces AMP-activated protein kinase (PRKAA1/2)-dependent ID2 loss in a MAPK8/9 independent manner. Inhibition of PRKAA1/2 with compound C and LJNKl1, more than MAPK8/9 inhibitors alone, inhibits the induction of CSH1 by stress. Taken together these data suggest that stress-induced MAPK8/9 and PRKAA1/2 regulate transcription factors Eomes/HAND1 and ID2, respectively. Together this network mediates induction of CSH1 by stress. Therefore, stress triggers a proportional increase in a normal early TSC differentiation event that could be adaptive in inducing CSH1. But the flexibility of TSC to undergo stress-induced differentiation could lead to pathophysiological consequences if stress endured and TSC differentiation became unbalanced. PMID- 21710640 TI - Automated gene oscillation phase classification for zebrafish presomitic mesoderm cells. AB - Zebrafish somitogenesis is governed by a segmentation clock that generates oscillations of gene expression in the zebrafish presomitic mesoderm (PSM) cells. The segmentation clock causes cells to undergo repeated cycles of transcriptional activation and repression, which can be divided into eight phases based on their distinct mRNA co-localizations. Recognizing different gene oscillation phases of cells is important in zebrafish research, but manual analysis is time-consuming and difficult. In this article, an effective automated gene oscillation phase classification framework is established for zebrafish PSM cell images. The framework consists of three major steps: (1) identify the individual cells by a two-stage segmentation procedure; (2) extract multiple features on each cell patch to measure the subcellular mRNA distribution; (3) employ a support vector machine (SVM) with a combined kernel to complete feature fusion and classification. To evaluate the effectiveness of this framework, a dataset containing 2,227 cell samples is constructed. Experimental results on this dataset indicate that our approach can achieve reasonably good performance for this gene oscillation classification problem. The feature sets NF9 and SPIN introduced in this article have proved to be superior to other cell features in this problem. Besides, the kernel fusion method used in the third step provides a way to combine heterogeneous features together, i.e., numerical feature set and histogram-based feature set, and classification performance with the combined kernel is better than single feature. PMID- 21710641 TI - Flow cytometric assay using two fluorescent proteins for the function of the internal ribosome entry site of hepatitis C virus. AB - The initiation of translation in hepatitis C virus (HCV) occurs at the internal ribosome entry site (IRES) located at the 5'-end of its genomic RNA. To study the function of HCV IRES, we constructed a reporter plasmid that generates a bicistronic mRNA encoding two fluorescent proteins: cap-dependent DsRed2 and IRES dependent Azami Green (AG). We introduced the plasmid into Huh7.5.1 and HEK293 cells and measured the relative IRES activity from the ratio of AG's signal to DsRed2's in individual cells using flow cytometry. To compare our method and a conventional biochemical method, we constructed a structurally similar reporter in which Renilla and Firefly luciferases replace DsRed2 and AG, respectively. With these systems, we found that the IRES A164G substitution decreased its activity, that interferon alpha affected the IRES activity in a cell type specific manner, and that a synthetic micro-RNA targeting IRES was able to suppress the gene expression. In conclusion, the two methods were comparable in sensitivity in the studies of IRES mutations and host cell types. We discussed the significance of our findings and potential advantage of the cytometric assay: application to the molecular study of the HCV translation and to screening anti IRES drugs. PMID- 21710642 TI - CD133 positive progenitor endothelial cell lines from human cord blood. AB - Endothelial progenitor cells (EPCs) modulate postnatal vascularization and contribute to vessel regeneration in adults. Stem cells and progenitor cells were found in umbilical cord blood, bone marrow, and mobilized peripheral blood cells, from where they were isolated and cultured. However, the yield of progenitor cells is usually not sufficient for clinical application and the quality of progenitor cells varies. The aim of the study was the immortalization of early progenitor cells with high proliferative potential, capable to differentiate to EPCs and, further, toward endothelial cells. Two cell lines, namely HEPC-CB.1 and HEPC-CB.2 (human endothelial progenitor cells-cord blood) were isolated. As assessed by specific antibody labeling and flow cytometric analysis, they express a panel of stem cell markers: CD133, CD13, CD271, CD90 and also endothelial cell markers: CD202b, CD309 (VEGFR2), CD146, CD105, and CD143 but they do not present markers of finally differentiated endothelial cells: CD31, vWf, nor CD45 which is a specific hematopoietic cell marker. Using the multiplex Cytometric Bead Assay, the simultaneous production of proangiogenic cytokines IL8, angiogenin, and VEGF was demonstrated in normoxia and was shown to be increased by hypoxia. Both cell lines, similarly as mature endothelial cells, underwent in vitro pre-angiogenic process, formed pseudovessel structures and present an accelerated angiogenesis in hypoxic conditions. To date, these are the first CD133 positive established cell lines from human cord blood cells. PMID- 21710643 TI - Collaborative development of anatomy workshops for medical and dental students in Cambodia. AB - After Phnom Penh was liberated from the Khmer Rouge in 1979, health science education in Cambodia had to be completely rebuilt. In this article, the authors report the results of a teaching collaboration between the University of Melbourne (Australia), the International University (Cambodia), and the University of Health Sciences (Cambodia). The main objectives in this collaboration were to provide the opportunity for dental and medical students in Cambodia to attend resourced anatomy workshops and to provide an opportunity for anatomy teachers in Cambodia to gain experience in implementing anatomy workshops of the style that are routinely used in the medical and dental curricula at the University of Melbourne. Experienced anatomy educators from the Department of Anatomy and Cell Biology, University of Melbourne, designed and resourced a series of workshops and then delivered these in collaboration with Cambodian teaching staff in Phnom Penh. The Cambodian students who participated in the workshops were incredibly engaged and enthusiastic. The students' evaluations (by questionnaire) indicated a very positive response to the workshops. All of the workshop resources were donated to the two universities so that the staff could continue to implement similar workshops, and plans were developed to continue our collaboration by developing more resourced workshops for this purpose in the future. Two staff members from Cambodia will travel to Melbourne to participate in anatomy workshops and dissection classes at the University of Melbourne. We hope that this extension of the collaboration provides further support and impetus for the development of anatomy education in Cambodia in the future. PMID- 21710644 TI - Fine-needle aspiration diagnosis of metastatic intestinal-type sinonasal adenocarcinoma. AB - Fine-needle aspiration biopsy is a reliable and accurate method for the diagnosis of nodal metastases of head and neck cancers. We report the cytopathologic findings of a case of metastatic sinonasal intestinal type adenocarcinoma (ITAC) in a 58-year-old man who presented with enlarged cervical lymph nodes on a follow up imaging study, 5 months after resection of a sinonasal ITAC. Ultrasound-guided fine needle aspiration of the station 2B lymph node yielded moderately cellular smears with abundant background mucin pools, numerous naked, atypical nuclei, and rare cells with signet ring cell morphology. Rare mitoses, apoptotic bodies, and necrotic debris were also present. Occasional clusters of signet ring cells were also seen in the cell block sections. Immunoperoxidase stains showed these cells to be positive for CK20 and villin. The differential diagnosis included a metastatic signet ring cell adenocarcinoma from the gastrointestinal tract and a metastatic sinonasal ITAC. Review of the previously resected sinonasal ITAC revealed a similar morphology with signet ring cells and abundant extracellular mucin production; the immunostaining results were also similar to those obtained on previously resected sinonasal ITAC. This case emphasizes the importance of considering primary head and neck tumors with intestinal phenotype and immunophenotype in the differential diagnoses of cervical lymph node metastases with signet ring cell morphology. PMID- 21710645 TI - Evaluation of CINtec PLUS(r) testing as an adjunctive test in ASC-US diagnosed SurePath(r) preparations. AB - The CINtec PLUS(r) system is an immunohistochemical cocktail composed of antibodies against p16(INK4a) (surrogate of HPV infection) and Ki-67 (proliferation marker) meant to improve the sensitivity and specificity for detecting high-grade dysplasia (HGD). In the presence of dysplasia, a red chromogen marks Ki-67 expression in the nucleus and a brown chromogen marks cytoplasmic p16(INK4a) expression. Only cells showing dual staining are interpreted as positive. This retrospective study examined the performance of CINtec PLUS testing when performed on ASC-US diagnosed samples. Comparison was made to high-risk HPV DNA test results and colposcopic biopsy results. Technical considerations in the interpretation of this immunohistochemical stain are additionally discussed. CINtec PLUS showed modest sensitivity (64%) and specificity (53%) in identifying the presence of HGD at surgical biopsy. Positive and negative predictive values for HGD were 28% and 83%, respectively. HR-HPV DNA test yielded sensitivity of 100% and specificity of 21%. During interpretation, squamous metaplasia and endocervical cells were seen to show individual staining for p16(INK4a) or Ki-67. Individual staining, when present within three dimensional cellular groups common to SurePath(r) preparations, can be time intensive to interpret necessitating thoughtful examination at high power. The Pap test with HR-HPV DNA testing is a highly sensitive test. A specific test is needed to prevent false positives and over treatment. The CINtec(r) system provides a modest increase in specificity beyond HR-HPV DNA testing. Future study of its appropriateness and cost-ffectiveness in a treatment algorithm are warranted. PMID- 21710646 TI - Z-axis video for cytology database is a useful tool for the case presentation prior to the cytology training workshop. AB - We have built a database on the Internet managing z-axis video for cytology (Zavic), and report on a new style of case discussion supported by the Zavic database. Z-axis video for cytology is a movie file derived from the video recording of a microscopic field with changes in the focus. We used it for the case presentation of EUS-FNA of pancreatic lesions on the Internet prior to a training workshop. The attendees were asked to observe the Zavic and to make diagnoses of 20 cases before the workshop. Fourteen attendees also observed lesions under a microscope on that day, and the results were compared with those of Zavic observation. The evaluation of the Zavic database (DB) was surveyed by a questionnaire. The average number of accurate diagnoses by 46 Zavic observers was 10.8. These accuracies for those who observed both the Zavic and glass slides were 11.57 and 11.43, respectively, for the videos and slides. Compared with Zavic observation alone, the diagnoses with glass slide observation were shifted to a correct diagnosis in two cases, but were shifted to an incorrect diagnosis in two cases. Approximately 60% of Zavic observers replied in the questionnaire that the movies on Zavic DB started to play within 3-4 seconds after clicking the play button. We successfully carried out the new style of case discussion supported by the Zavic DB. It was evaluated favorably by many attendees, who were psychologically still dependent on the glass slide observation. PMID- 21710647 TI - Cell block interpretation is helpful in the diagnosis of granulomas on cytology. PMID- 21710648 TI - Urine cytopathology: challenges, pitfalls, and mimics. AB - Urine cytopathology is a useful and noninvasive tool in the diagnosis and follow up of urothelial neoplasia, which remains complementary to emerging molecular tests. These specimens may be challenging and there are numerous mimics and diagnostic pitfalls with which to contend. This review discusses these various entities and includes consideration of ancillary tests that may be useful in the diagnostic procedure. PMID- 21710649 TI - Triage of cervical cytological diagnoses of atypical squamous cells by DNA methylation of paired boxed gene 1 (PAX1). AB - Detection of cervical high-grade squamous intraepithelial lesions (HSIL) in patients with equivocal cytological abnormalities, such as atypical squamous cells (ASC) of undetermined significance (ASCUS) or inability to exclude high grade squamous intraepithelial lesions (ASC-H) is still a challenge. This study tested the efficacy of PAX1 methylation analysis in the triage of cervical ASCUS and ASC-H and compared its performance with Hybrid Capture 2 (HC2) HPV test. A hospital-based case-control study was conducted. Cervical scrapings from patients with ASCUS or ASC-H were used for the quantitative methylation analysis of PAX1 methylation by MethyLight and HPV testing by HC2. Patients with ASC-H or ASCUS with repeated abnormal smears underwent colposcopic biopsy and subsequent therapies. Diagnoses were made by histopathology at a follow-up of 2 years. The efficacies of detecting high-grade lesions were compared. Fifty-eight cervical scrapings with cytological diagnosis of ASCUS (n = 41) and ASC-H (n = 17) were analyzed. One of the 41 (2.4%) ASCUS patients and seven of 17 (41.2%) ASC-H patients were confirmed to have HSIL. After dichotomy of the PMR, PAX1 methylation rates were significantly higher in ASC developing HSIL compared with those developing reactive atypia (87.5% vs. 12.5%, P < 0.001). Testing PAX1 methylation in cervical swabs of patients with ASC confers better sensitivity (87.5% vs. 62.5%) and specificity (98.0% vs. 86.0%) than HC2 HPV testing. We show for the first time that PAX1 hypermethylation analysis may be a better choice than HC2 in the triage of ASCUS and ASC-H. PMID- 21710650 TI - Cytologic features of sclerosing hemangioma of the lung on crush preparations. AB - Sclerosing hemangioma of the lung is a rare benign neoplasm. The majority of the literature published on sclerosing hemangioma has focused on the histologic features, while only a few case reports have described the cytologic features. We report two additional cases of sclerosing hemangioma of the lung in which the cytologic material was prepared at the time of frozen section. Because of the rarity of this lesion and the overlapping cytologic features with other primary malignant lung tumors, awareness of the cytologic features of sclerosing hemangioma may help to avoid a diagnosis of malignancy. This is especially true pre- and intraoperatively because a limited resection may suffice if a diagnosis of sclerosing hemangioma can be established. PMID- 21710651 TI - Bone marrow processing with the AMICUSTM separator system. AB - ABO incompatible bone marrow transplantation (BMT) requires processing of the donated bone marrow (BM), either erythrocyte depletion, or also a volume reduction. The AMICUSTM system was introduced in the field of peripheral blood mononuclear cell collection, showing a good performance regarding efficiency and safety. To evaluate the performance of the MNC collection program of the Amicus device for BM, we analysed our data obtained from the Amicus and the Fenwal CS3000omnixTM plus device. METHODS: From 2005 to 2008, we performed 22 automated erythrocyte depletions of BM for ABO mismatched BMT in 21 patients, 11 with the Amicus (A; 10 patients) and 11 with the CS3000 (F; 11) device. RESULTS: There were no statistical differences in donor age, recipient age, type of ABO mismatch, and CD34+ cell yield [group A pre 7.03 post 4.93 vs. group F pre 8.55 and post 6.2 * 10E06 cells per kilogram of bodyweight] for both devices. The efficiency for the CD34+ cell collection was lower, but not statistically significant, in the Amicus device (70% +/- 12 vs. 84% +/- 12; U-test P = 0.123). The erythrocyte volume in the final product was higher but not statistically significant different in the Amicus device (9.46 +/- 2.3 vs. 6.98 +/- 3.3 ml; U test P = 0.17). During the evaluation period, no technical problems were observed. All patients but one, who died at d + 11, showed a sustained engraftment. CONCLUSIONS: We conclude that, in principle, the Amicus device can be used for MNC collection from BM to deplete erythrocytes from BM grafts in allogeneic stem cell transplantations. PMID- 21710652 TI - Neonatal and delivery outcomes in women with multiple sclerosis. AB - OBJECTIVE: To determine (1) whether the risk of adverse neonatal and delivery outcomes differs between mothers with and without multiple sclerosis (MS) and (2) whether risk is differentially associated with clinical factors of MS. METHODS: This retrospective cohort study analyzed data from the British Columbia (BC) MS Clinics' database and the BC Perinatal Database Registry. Comparisons were made between births to women with MS (n = 432) and to a frequency-matched sample of women without MS (n = 2,975) from 1998 to 2009. Outcomes included gestational age, birth weight, assisted vaginal delivery, and Caesarean section. Clinical factors examined included age at MS onset, disease duration, and disability. Multivariate regression models adjusting for confounding factors were built for each outcome. RESULTS: Babies born to MS mothers did not have a significantly different mean gestational age or birth weight compared to babies born to mothers without MS. MS was not significantly associated with assisted vaginal delivery (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.50-1.16; p = 0.20) or Caesarean section (OR, 0.94; 95% CI, 0.69-1.28; p = 0.69). There was a slightly elevated risk of adverse delivery outcomes among MS mothers with greater levels of disability, although findings were not statistically significant. Disease duration and age at MS onset were not significantly associated with adverse outcomes. INTERPRETATION: This study provides reassurance to MS patients that maternal MS is generally not associated with adverse neonatal and delivery outcomes. However, the suggestion of an increased risk with greater disability warrants further investigation; these women may require closer monitoring during pregnancy. PMID- 21710653 TI - Impact of evidence-based clinical guidelines on the adoption of postmastectomy radiation in older women. AB - BACKGROUND: Although postmastectomy radiation therapy (PMRT) improves survival for patients with high-risk breast cancer, previous literature suggested that it is underused. The impact of recent clinical guidelines on PMRT use is unknown. Accordingly, the authors used the Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort to determine whether the use of PMRT has increased in response to evidence-based guidelines. METHODS: In total, 38,322 women aged >=66 years who underwent mastectomy for invasive breast cancer between 1992 and 2005 were identified. Time trends in the receipt of PMRT for low-risk (T1/T2 N0), intermediate-risk (T1/T2 N1), and high-risk (T3/T4 and/or N2/N3) patients were characterized. Multivariate logistic regression identified risk factors for PMRT omission. RESULTS: The receipt of PMRT by patients with high-risk breast cancer increased from 36.5% (95% confidence interval, 26%-46.9%) to 57.7% (95% confidence interval, 46.9%-68.4%) between 1996 and 1998 with the publication of landmark clinical trials. However no further increase in PMRT use was observed between 1999 and 2005 despite publication of multiple guidelines endorsing its use; during this period, only 54.8% (2729 of 4978) of high-risk patients received PMRT. Within this high-risk group, patients with smaller tumors or less advanced lymph node disease were at risk for PMRT omission. CONCLUSIONS: After an initial increase in PMRT use in response to clinical trials, the use of PMRT did not increase further in response to guideline publication, and nearly 50% of patients with high-risk breast cancer still do not receive PMRT. Additional research is needed to determine how clinical guidelines can be used to bridge the gap between level I evidence and clinical practice. PMID- 21710654 TI - On the evolution of arterial vascular patterns of tetrapods. AB - The factors that explain the diverse arrangement of the major arteries of tetrapods are not known. Here, I aim to illuminate some of the underpinnings of these patterns. I review the variation in the sauropsid left, right, and dorsal aortae regarding the origin of the gastrointestinal blood vessels and the relative diameters of left and right aortae where they join together to form the dorsal aorta. I focus on these features because the quality of blood that flows through these aortae can vary depending on the state of cardiac shunting and the size of the vessel can provide insight into the quantity of blood borne by the vessels. I then place the information in a phyletic, historical, and ecological context. The plesiomorphic pattern is for the gastrointestinal vessels to arise as segmental arteries from the dorsal aorta, which is formed from the confluence of left and right aortae with similar diameters. The pattern is well conserved with only two major variations. First, in several clades of reptiles (testudines, crocodilians, lizards of the genera Varanus and Hydrosaurus) a substantial portion of the gastrointestinal arteries arises from the left aorta, leaving the diameter of the left aorta smaller than the right at their confluence. I hypothesize that this vascular arrangement facilitates growth by allowing more alkaline blood to flow to the somatic (body wall) and appendicular circulations, which may promote bone deposition and inhibit resorption, whereas hypercapnic, acidic blood flows to the digestive viscera, which may provide CO(2) as a substrate for the synthesis of gastric acid, bicarbonate, fatty acids, glutamine, purine rings, as well as glucose from lactate. Second, in some snakes and lizards with snake-like body forms, such as Amphisbaenidae, the diameters of left and right aortae are asymmetrical at their confluence with the left aorta exceeding the right, but in members of the amphibian order Gymnophiona the right generally exceeds the left. This condition is associated with asymmetrical development of the lungs. PMID- 21710655 TI - Male reproductive apparatus and spermatophore morphology of the hermit crabs Pagurus brevidactylus and P. criniticornis (Anomura, Paguridae). AB - Spermatozoa of most crustacean species are nonmotile and are packed into spermatophores. In Decapoda, spermatophores are highly variable in morphology and can be useful in the solving of taxonomic and systematic questions, especially among the Anomura. In this study, the morphology and morphometry of the spermatophores of the western Atlantic hermit crabs Pagurus brevidactylus and P. criniticornis are described. The abdomen of fresh male specimens was dissected to expose the reproductive system and to extract the spermatophores, which were analyzed by stereoscopic, light, and scanning electron microscopy. The vas deferens can be divided macroscopically in three regions, all of them containing spermatophores. Tripartite spermatophores are composed of an elongated cylindrical main ampulla, a triangular accessory ampulla, a narrow cylindrical peduncle, and a round pedestal. Dimensions of the spermatophore components are positively correlated to the size of the crab. Morphological patterns observed in this study resemble those of other pagurid hermit crabs investigated to date. The morphological character distribution confirms classifications based on adult morphology and molecular analysis. PMID- 21710656 TI - Folivory, frugivory, and postcanine size in the cercopithecoidea revisited. AB - At a given body mass, folivorous colobines have smaller postcanine teeth than frugivorous cercopithecines. This distinction is a notable exception to the general tendency for folivorous primates to have relatively larger postcanine tooth rows than closely related frugivores. The reason for this anomalous pattern is unclear, but one potential explanation is that the difference in facial size between these two subfamilies confounds the comparison-i.e., it may be that the large postcanine teeth of cercopithecines are a consequence of their large faces. The goal of this study was to test this hypothesis. Phylogenetic comparative methods were used to examine the relationships among postcanine area, facial size, and body mass in 29 anthropoid primates, including eight colobines and eight cercopithecines. Results indicate that there is a strong and highly significant partial correlation between postcanine area and facial size when body mass is held constant, which supports the hypothesis that facial size has an important influence on postcanine size. Moreover, colobines have larger postcanine teeth relative to facial size than cercopithecines. Surprisingly, when facial size is held constant, the partial correlation between postcanine area and body mass is weak and nonsignificant. These results suggest that facial size may be more appropriate than body mass for size-adjusting postcanine measurements in some contexts. A phylogenetic comparative test of the association between diet and relative postcanine size (scaled using facial size) confirms that folivorous anthropoids are characterized by relatively large postcanine teeth in comparison to closely related nonfolivores. PMID- 21710657 TI - Hiding inequality beneath prosperity: patterns of cranial injury in middle period San Pedro de Atacama, Northern Chile. AB - The Middle Period in San Pedro de Atacama (AD 400-1000) stands out as a time of great prosperity that was, in part, associated with high levels of interaction with foreign polities, including the highland state of Tiwanaku. Although previous studies have demonstrated an increase in rates of violence during the subsequent Regional Developments Period (AD 1000-1400), this does not mean that the Middle Period was a time of peace and tranquility. Here, the prevalence of violence in four contemporary cemeteries is analyzed, exploring potential sources of conflict, including social inequality. Cranial trauma was documented through the presence, location, size, and state of healing of all wounds and was found in 14.7% of the sample (61/415; including two cases of perimortem trauma). Skeletal remains were also analyzed for demographic data to investigate differences in patterns of violence related to sex and age. Notably, most of the trauma centered on the anterior portion of the skull, suggesting the prominence of face-to-face confrontations that involved both sexes. Correlations between trauma and items in the mortuary assemblage that may have been associated with prestige or an elevated social standing in two cemeteries from the Solcor ayllu indicate that individuals from the more elite cemetery were subjected to significantly less traumatic injury. These data suggest that people did not share equally in the benefits of this period's affluence and that there were tensions in Atacameno society despite seemingly widespread prosperity. PMID- 21710658 TI - Rensch's rule, Bergmann's effect and adult sexual dimorphism in wild monogamous owl monkeys (Aotus azarai) of Argentina. AB - Some monogamous primates are characterized by biparental care, territoriality, and a reduced level of physical dimorphism. In others, the relationship between those behavioral patterns and dimorphism is less clear. I tested Bergmann's and Rensch's rules using Aotus spp. body mass data and I characterized the extent of sexual dimorphism in body mass, dental and physical measurements in a socially monogamous owl monkey population (n = 91 adults) from the Argentinean Gran Chaco. A. azarai azarai from the Argentinean Chaco is larger than the more tropical owl monkey species (r = 0.7, N = 6 species), but there is no apparent increase in sexual dimorphism with increased body mass. The body masses of adult male and female A. a. azarai were remarkably similar (Mean = 1.26 kg); there were no marked sex differences in most skeletal measurements, but males had higher and wider upper and lower canines than did females. Body mass and neck circumference were positively and strongly related (r = 0.533, n = 52), and the body mass of adults was not a reliable indicator of their age (r = 0.03, n = 10). The data illustrate the complexities inherent in examining and summarizing within population variation in skeletal and nonskeletal measurements and contribute to a better understanding of the relationships between monogamous behavioral patterns and sexual dimorphism. PMID- 21710659 TI - The relative efficacy of functional and developmental cranial modules for reconstructing global human population history. AB - This study tests the relative efficacy of human cranial modules, defined on the basis of developmental and functional criteria, for reconstructing neutral genetic population history. Specifically, two hypotheses were tested: 1) The "basicranial hypothesis" predicts that the endochondrally ossifying basicranium will be more reliable for reconstructing population history than intramembranously ossifying regions of the human cranium. This is based on the assumption that early ossification of the basicranium and its distinct functional constraints produce a cranial structure that is relatively immune to non-neutral evolutionary forces. 2) The "single function hypothesis" predicts that cranial regions associated with a single (sensory) function are less reliable indicators of neutral genetic history. Here the prediction is based on the logic that complex, multi-functional, integrated cranial regions are less likely toexhibit homoplasy and, therefore, provide a more accurate morphological proxy for genetic relationships. The congruence between craniometric affinity matrices and neutral genetic population matrices based on autosomal microsatellite and classical markers was assessed using a series of Mantel and Dow-Cheverud tests. The results did not support the predictions of the "basicranial hypothesis," as the endochondrally ossifying basicranium was not significantly more congruent with the genetic data than intramembraneously ossifying modules. Moreover, although the results provided some support for the "single function hypothesis," defining cranial modules on the basis of anatomical or functional complexity did not provide a consistent means of predicting their phylogenetic efficacy. These results have important implications for building an accurate inference model of cranial evolution in the human fossil record. PMID- 21710661 TI - Gene therapy with adenovirus-delivered indoleamine 2,3-dioxygenase improves renal function and morphology following allogeneic kidney transplantation in rat. AB - BACKGROUND: Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the tryptophan catabolism, has recently emerged as an important immunosuppressive enzyme involved in the regulation of both physiologic (maternal tolerance), as well as pathologic (neoplasia, autoimmune diseases, asthma) processes. Accumulating evidence points to a role for IDO in suppressing T-cell responses, thereby promoting tolerance. In the present study, we investigate the effects of adenovirus-mediated gene therapy with IDO on the acute rejection of the transplanted kidneys. METHODS: The experiments were performed in a rat Fisher to Lewis acute renal rejection model. RGD modified adenovirus carrying IDO gene (RGD AdTIDO, n = 9) or RGD modified adenovirus carrying green fluorescent protein gene (RGD-AdTL, n = 8) were injected into the renal artery of the donor kidney before transplantation. A group receiving saline (n = 8) served as control. Rats were sacrificed after 7 days. RESULTS: Successful gene delivery was confirmed with real-time polymerase chain reaction and immunohistochemistry. RGD-AdTIDO significantly decreased elevated plasma creatinine (93.7 +/- 18.9 umol/l) compared to the RGD-AdTL (248.2 +/- 43.6 umol/l) and saline (228.3 +/- 46.4 umol/l) treated rats. Moreover, RGD-AdTIDO therapy diminished the infiltration of CD8+ T cells and macrophages into the graft and reduced renal interstitial pre fibrosis. Also, it limited the up-regulation of kidney injury molecule-1, interleukin (IL)-2, IL-17 and transforming growth factor-beta mRNA expression, and increased foxp3 mRNA expression compared to controls. CONCLUSIONS: RGD-AdTIDO therapy improves renal function and morphology in a clinically relevant model of acute rejection. PMID- 21710662 TI - A novel way of visualizing the ductal and aortic arches by real-time three dimensional ultrasound with live xPlane imaging. AB - OBJECTIVE: To describe a novel method of visualizing the ductal and aortic arches by real-time three-dimensional echocardiography with live xPlane imaging. METHODS: Live xPlane imaging was used to display the ductal- and aortic-arch views in 107 women with singleton pregnancies, including seven cases with suspected congenital heart defects (CHDs). The three vessels and trachea (3VT) view was obtained in such an orientation that either the pulmonary artery or the aorta was parallel to the direction of the ultrasound beam. The xPlane reference line was then placed across the targeted vessel, which in a normal case would provide an image of the corresponding arch view as a dual-image display. RESULTS: Once the 3VT view had been obtained, live xPlane imaging showed the aortic and ductal arches in all 100 normal cases. In seven cases with suspected CHD, the 3VT view was abnormal in five cases and normal in the other two. However, the ductal arch view demonstrated by live xPlane imaging was abnormal in five cases of conotruncal anomalies and normal in two cases in which conotruncal anomalies were excluded. CHDs were confirmed at autopsy following termination of pregnancy in five cases and on postnatal echocardiography in one case. The heart was found postnatally to be normal in one case of suspected CHD; in this case live xPlane imaging showed that the observed abnormal 3VT view was caused by a tortuous course of the thoracic aorta associated with an abnormal diaphragm. CONCLUSION: Live xPlane imaging is a novel and relatively simple method of visualizing the ductal- and aortic-arch views, and may potentially be a useful tool in the screening of fetal conotruncal and aortic-arch anomalies. PMID- 21710663 TI - Supraventricular tachycardia in a neonate with the prenatal diagnosis of a single left superior vena cava. PMID- 21710665 TI - Aflatoxin accumulation in whole crop maize silage as a result of aerobic exposure. AB - BACKGROUND: Most of the maize silage stored in horizontal silos is exposed to air and can be spoiled by fungi. Potentially toxigenic fungi have been found in maize silage, and about 300 mycotoxins have been detected. Among these mycotoxins, the most harmful for feed and food safety are aflatoxins. The aim of the study was to set up a specific method to detect aflatoxins in maize silage, and to investigate whether aflatoxin contamination in maize silage depends on the level of field contamination of the crop, and whether the occurrence of aerobic spoilage during ensiling has any effect on the final contamination of the silage. RESULTS: A method for the determination of aflatoxin B(1), B(2), G(1) and G(2) in maize silage using high-performance liquid chromagraphy with fluorescence detection has been developed and validated. Recoveries of aflatoxin B(1), B(2), G(1), and G(2) spiked over the 0.25 to 5 ug kg(-1) range averaged 74-94%. The results of laboratory scale and farm scale ensiling experiments indicated that aflatoxins could increase when silage is exposed to air during conservation or during the feed-out phase. CONCLUSIONS: The method here proposed to detect aflatoxins in silages has proved to be sensitive and is able to detect levels of 0.1 and 0.5 ng mL(-1) for AFB(1) and AFG(1), and between 0.025 and 0.125 ng mL(-1) for AFB(2) and AFG(2). This study also provides evidence of aflatoxin accumulation in whole crop maize silage as a result of aerobic exposure. PMID- 21710664 TI - Timing of cholecystectomy after mild biliary pancreatitis. AB - BACKGROUND: The aim of the study was to evaluate recurrent biliary events as a consequence of delay in cholecystectomy following mild biliary pancreatitis. METHODS: Between 2004 and 2007, patients with acute pancreatitis were registered prospectively in 15 Dutch hospitals. Patients with mild biliary pancreatitis were candidates for cholecystectomy. Recurrent biliary events requiring admission before and after cholecystectomy, and after endoscopic sphincterotomy (ES), were evaluated. RESULTS: Of 308 patients with mild biliary pancreatitis, 267 were candidates for cholecystectomy. Eighteen patients underwent cholecystectomy during the initial admission, leaving 249 potential candidates for cholecystectomy after discharge. Cholecystectomy was performed after a median of 6 weeks in 188 patients (75.5 per cent). Before cholecystectomy, 34 patients (13.7 per cent) were readmitted for biliary events, including 24 with recurrent biliary pancreatitis. ES was performed in 108 patients during the initial admission. Eight (7.4 per cent) of these patients suffered from biliary events after ES and before cholecystectomy, compared with 26 (18.4 per cent) of 141 patients who did not have ES (risk ratio 0.51, 95 per cent confidence interval 0.27 to 0.94; P = 0.015). Following cholecystectomy, eight (3.9 per cent) of 206 patients developed biliary events after a median of 31 weeks. Only 142 (53.2 per cent) of 267 patients were treated in accordance with the Dutch guideline, which recommends cholecystectomy or ES during the index admission or within 3 weeks thereafter. CONCLUSION: A delay in cholecystectomy after mild biliary pancreatitis carries a substantial risk of recurrent biliary events. ES reduces the risk of recurrent pancreatitis but not of other biliary events. PMID- 21710666 TI - Single-molecule determination of the face-specific adsorption of Amelogenin's C terminus on hydroxyapatite. PMID- 21710667 TI - Simultaneous concentration and separation of proteins in a nanochannel. PMID- 21710668 TI - Chemical evolution of a bacterium's genome. PMID- 21710669 TI - A short and efficient synthesis of neodysiherbaine A by using catalytic oxidative cyclization. PMID- 21710670 TI - Reversible halide-modulated nickel-nickel bond cleavage: metal-metal bonds as design elements for molecular devices. PMID- 21710672 TI - Emanuel Vogel (1927-2011). PMID- 21710671 TI - LiMn(1-x)Fe(x)PO4 nanorods grown on graphene sheets for ultrahigh-rate performance lithium ion batteries. PMID- 21710673 TI - Deciding whether to go with the flow: evaluating the merits of flow reactors for synthesis. AB - The fine chemicals and pharmaceutical industries are transforming how their products are manufactured, where economically favorable, from traditional batchwise processes to continuous flow. This evolution is impacting synthetic chemistry on all scales-from the laboratory to full production. This Review discusses the relative merits of batch and micro flow reactors for performing synthetic chemistry in the laboratory. PMID- 21710674 TI - Multicomponent reaction design in the quest for molecular complexity and diversity. AB - Multicomponent reactions have become increasingly popular as tools for the rapid generation of small-molecule libraries. However, to ensure sufficient molecular diversity and complexity, there is a continuous need for novel reactions. Although serendipity has always played an important role in the discovery of novel (multicomponent) reactions, rational design strategies have become much more important over the past decade. In this Review, we present an overview of general strategies that allow the design of novel multicomponent reactions. The challenges and opportunities for the future will be discussed. PMID- 21710676 TI - Hydrogen electrocatalysis on single crystals and on nanostructured electrodes. AB - We investigate hydrogen evolution on plain and nanostructured electrodes with a theory developed by us. On electrodes involving transition metals the most strongly adsorbed hydrogen is often only a spectator, while the reaction proceeds via a weakly adsorbed species. For Pt(111) the isotherms for both species are calculated. We explain why a nanostructure consisting of a monolayer of Pd on Au(111) is a good catalysts, and predict that Rh/Au(111) should be even better. Our calculations for a fair number of metals are in good agreement with experiment. PMID- 21710678 TI - From atomic to molecular anions: a neutral receptor captures cyanide using strong C-H hydrogen bonds. AB - The multifaceted character of cyanide as an acceptor of hydrogen bonds from a receptor has been examined for the first time using electronic-structure theory and spectroscopic measurements (UV/Vis and NMR titrations). Motivated by the similar size and charge of the cyanide pseudohalide and the monoatomic chloride ion, strong interactions of cyanide with a rigid macrocyclic triazolophane receptor have been predicted by theory and confirmed by experimental findings. It was found that both anions bind with similar strength in the gas phase (computed) and in the solution phase (experimental) via C-H hydrogen bonds. Theoretical calculations predict that the heterodiatomic cyanide prefers to bind in the plane of the macrocycle along the north-south axis. Examination of the possible binding modes reveal low computed barriers for in-plane rotation. The predicted model is consistent with the experimental data. Overall, the binding of a molecular anion within the cavity of a triazolophane receptor has been characterized where the computed and experimental binding energies are consistent with the classification of cyanide as a pseudohalide in the context of supramolecular chemistry. PMID- 21710677 TI - Cyclodextrin and adamantane host-guest interactions of modified hyperbranched poly(ethylene imine) as mimetics for biological membranes. PMID- 21710679 TI - Adsorption of supramolecular building blocks on graphite: a force field and density functional theory study. PMID- 21710680 TI - Multicolor fluorescence of a styrylquinoline dye tuned by metal cations. AB - A styrylquinoline dye with a dipicolylamine (DPA) moiety (1) has been synthesized. The dye 1 in acetonitrile demonstrates multicolor fluorescence upon addition of different metal cations. Compound 1 shows a green fluorescence without cations. Coordination of 1 with Cd(2+) shows a blue emission, while with Hg(2+) and Pb(2+) exhibits yellow and orange emissions, respectively. The different fluorescence spectra are due to the change in intramolecular charge transfer (ICT) properties of 1 upon coordination with different cations. The DPA and quinoline moieties of 1 behave as the electron donor and acceptor units, respectively, and both units act as the coordination site for metal cations. Cd(2+) coordinates with the DPA unit. This reduces the donor ability of the unit and decreases the energy level of HOMO. This results in an increase in HOMO-LUMO gap and blue shifts the emission. Hg(2+) or Pb(2+) coordinate with both DPA and quinoline units. The coordination with the quinoline unit decreases the energy level of LUMO. This results in a decrease in HOMO-LUMO gap and red shifts the emission. Addition of two different metal cations successfully creates intermediate colors; in particular, the addition of Cd(2+) and Pb(2+) at once creates a bright white fluorescence. PMID- 21710681 TI - Glycosynthase-mediated assembly of xylanase substrates and inhibitors. AB - An exo-beta-xylosidase mutant with glycosynthase activity was created to aid in the synthesis of xylanase substrates and inhibitors. Simple monosaccharides were easily elaborated into di-, tri- and tetrasaccharides by using this enzyme. Some products proved to be surprisingly potent inhibitors of xylanases from glycoside hydrolase families 10 and 11. PMID- 21710683 TI - Auxiliary-controlled asymmetric [3+2]-dipolar cycloaddition of azomethine ylides generated from Au-catalyzed intramolecular redox reaction of nitronyl alkynes. PMID- 21710682 TI - Enhanced refoldability and thermoactivity of fluorinated phosphotriesterase. PMID- 21710684 TI - Bt maize and integrated pest management--a European perspective. AB - The European corn borer (Ostrinia nubilalis), the Mediterranean corn borer (Sesamia nonagrioides) and the western corn rootworm (Diabrotica virgifera virgifera) are the main arthropod pests in European maize production. Practised pest control includes chemical control, biological control and cultural control such as ploughing and crop rotation. A pest control option that is available since 1996 is maize varieties that are genetically engineered (GE) to produce insecticidal compounds. GE maize varieties available today express one or several genes from Bacillus thuringiensis (Bt) that target corn borers or corn rootworms. Incentives to growing Bt maize are simplified farm operations, high pest control efficiency, improved grain quality and ecological benefits. Limitations include the risk of resistance evolution in target pest populations, risk of secondary pest outbreaks and increased administration to comply with licence agreements. Growers willing to plant Bt maize in the European Union (EU) often face the problem that authorisation is denied. Only one Bt maize transformation event (MON810) is currently authorised for commercial cultivation, and some national authorities have banned cultivation. Spain is the only EU member state where Bt maize adoption levels are currently delivering farm income gains near full potential levels. In an integrated pest management (IPM) context, Bt maize can be regarded as a preventive (host plant resistance) or a responsive pest control measure. In any case, Bt maize is a highly specific tool that efficiently controls the main pests and allows combination with other preventive or responsive measures to solve other agricultural problems including those with secondary pests. PMID- 21710685 TI - The susceptibility of small fruits and cherries to the spotted-wing drosophila, Drosophila suzukii. AB - BACKGROUND: The spotted-wing drosophila, Drosophila suzukii Matsumura, is native to Asia and was first detected in the North American mainland and Europe in 2008 2010. Drosophila suzukii is a serious economic pest to stone and small fruits because the female lays eggs within ripening fruit on a plant before harvest, which can lead to crop loss. The aim of this study was to evaluate the susceptibility of blackberries, blueberries, cherries, grapes, raspberries and strawberries to D. suzukii among various ripeness stages and cultivars. RESULTS: In 26 no-choice and choice replicated laboratory cage tests on ripeness stages, fruits were generally susceptible to D. suzukii once fruits started to color. Few D. suzukii developed on green fruit, wine grapes or overripe blueberries. In seven cultivar tests, D. suzukii preferences ranged from no differences to fourfold differences for specific cultivars of blackberries, blueberries, raspberries and wine grapes. As brix levels increased, more eggs were laid or more D. suzukii developed on blackberries, blueberries, cherries, raspberries and strawberries. In a choice test of various fruit types, strawberries, raspberries, blackberries, cherries and blueberries were more susceptible to D. suzukii than green table grapes ('Thompson'). CONCLUSION: The results suggest that fruits may become susceptible to D. suzukii as they start to turn color, and that specific varieties of grapes and overripe blueberries have low susceptibility to D. suzukii. PMID- 21710686 TI - Uncommon associations in target resistance among French populations of Myzus persicae from oilseed rape crops. AB - Within the framework of a molecular exploration of target resistance in populations of Myzus persicae on oilseed rapes in France, (1) the S431F mutation (coding gene ace2), although previously reckoned to be rare, revealed to be frequent, (2) M918L (phenotypically characterised) and L932F (both on para) were found for the first time in M. persicae, and (3) a linkage was revealed between M918L and S431F. While until recently populations developing on French oilseed rapes were dominated by genotypes possessing pyrethroid target resistance and esterase overproduction, to date a different type of dominating genotype, equipped with carbamate and pyrethroid target resistance, seems to be invading such fields. PMID- 21710687 TI - Brief communication: evidence of Bartonella quintana infections in skeletons of a historical mass grave in Kassel, Germany. AB - In 2008, a mass grave was found on the grounds of the University of Kassel, Germany. Historians hypothesized that the individuals died in a typhoid fever epidemic in winter 1813/14. To test this hypothesis, the bones were investigated on the presence of specific DNA of pathogens linked to the historical diagnosis oftyphoid fever. It was possible to prove the specific DNA of Bartonella quintana in three individuals, suggesting that their cause of death is linked to an epidemic background. PMID- 21710689 TI - Tid1, CHIP and ErbB2 interactions and their prognostic implications for breast cancer patients. AB - ErbB2 (HER2/neu) is overexpressed in about 25-30% of breast malignancies, and up regulation of ErbB2 in breast cancer patients is associated with poor prognosis. It is known that the carboxyl terminus of heat shock cognate 70 interacting protein (CHIP) efficiently down-regulates ErbB2 in vitro. Human tumourous imaginal disc 1 (Tid1, DnaJa3), a co-chaperone of heat shock protein 70 (Hsp70), also suppresses ErbB2 expression in breast cancer cell lines. However, the intracellular interactions among Tid1, CHIP, and ErbB2 remain elusive, and the utilization of Tid1 and CHIP as breast cancer biomarkers has never been proposed. Herein, we analysed the expression and correlations among Tid1, CHIP, and ErbB2 in a total of 183 breast cancer histology sections, including 30 fresh tissue specimens, using immunohistochemistry (IHC) and immunoblotting assay. A computerized image analysis system was used for IHC scoring and determining relative immunoblot intensity. The immunohistochemical expression of Tid1 and CHIP were positively correlated with each other but were both inversely correlated to that of ErbB2. Odds ratio analyses showed that lower expression of Tid1 has a relatively higher risk of unfavourable tumour grade, later pathological stage, larger tumour size, and microscopic features of a more malignant histology including lymphovascular invasion, stromal inflammatory response, and tumour necrosis. Expression of CHIP displayed similar characteristics. Furthermore, expression of Tid1 and/or CHIP increases patients' 10-year overall and disease-free survival rate. Empirically, we also demonstrated that Tid1, CHIP, and ErbB2 interacted with each other through immunofluorescence or co-immunoprecipitation analyses. Functionally, Tid1 and CHIP acted synergistically to degrade ErbB2 in vitro. Conversely, Tid1 cannot compensate for the loss of proteolytic function noted in CHIP mutations for degradation of ErbB2. Overall, our data suggest that Tid1 and CHIP play pivotal roles in affecting the levels of ErbB2 protein, and that both are significant prognostic indicators of breast cancer patient survival. PMID- 21710690 TI - Aberrantly expressed AURKC enhances the transformation and tumourigenicity of epithelial cells. AB - Over-expression of AURKC has been detected in human colorectal cancers, thyroid carcinoma and several cancer cell lines. However, the regulation and clinical implications of over-expressed AURKC in cancer cells are unclear. Here we show that elevated AURKC increases the proliferation, transformation and migration of cancer cells. Importantly, the kinase activity of AURKC is required for these tumour-associated properties. Analysis of human cancer specimens shows that the expression of AURKC is increased in cervical cancer, and is highly correlated with staging in colorectal cancer. Over-expressed AURKC-GFP localizes to the centromeric regions of mitotic chromosomes and results in a decreased level of AURKB, a key regulator of spindle checkpoint. Expression of AURKC is down regulated by PLZF, a transcriptional repressor, through recruitment to its promoter region. The expression levels of PLZF and AURKC mRNA display opposite patterns in human cervical and colorectal cancers. Taken together, our results provide important insights into human cancers with AURKC expression, which may serve as a potential target for cancer therapy in the future. PMID- 21710691 TI - The molecular pathogenesis of STAT3-driven gastric tumourigenesis in mice is independent of IL-17. AB - Chronic activation of the gastric mucosal adaptive immune response is a characteristic trait of gastric cancer. It has recently emerged that a new class of T helper (Th) cells, defined by their ability to produce interleukin (IL)-17A (Th17), is associated with a host of inflammatory responses, including gastritis. However, the role of these Th17 cells in the pathogenesis of gastric cancer is less clear. To formally address this, we employed gp130(F/F) mice, which spontaneously develop gastric inflammation-associated tumours akin to human intestinal-type gastric cancer. At the molecular level, these tumours demonstrate hyper-activation of the latent transcription factor signal transducer and activator of transcription (STAT)3 via the IL-6 cytokine family member, IL-11. In gp130(F/F) mice, the generation of Th17 cells, as well as the gastric expression of IL-17a and other Th17-related factors (Rorgammat, IL-23), were augmented compared to wild-type gp130(+/+) mice. Consistent with a role for IL-6 and STAT3 in regulating IL-17A, increased Th17 generation and gastric expression of Th17 related factors in gp130(F/F) mice were reduced to wild-type levels in gp130(F/F) :Stat3(-/+) mice displaying normalized STAT3 activity, and also in gp130(F/F) :IL 6(-/-) mice. Importantly, genetic ablation of IL-17A in gp130(F/F) :IL-17a(-/-) mice did not suppress the initiation and growth of gastric tumours. Furthermore, IL-17A and RORC gene expression was strongly increased in human gastric biopsies from patients with gastritis, but not gastric cancer. Collectively, our data suggest that increased expression of Th17-related factors does not correlate with the molecular pathogenesis of gastric tumourigenesis. PMID- 21710692 TI - Frequent promoter hypermethylation of BRCA2, CDH13, MSH6, PAX5, PAX6 and WT1 in ductal carcinoma in situ and invasive breast cancer. AB - Epigenetic changes are considered to be a frequent event during tumour development. Hypermethylation of promoter CpG islands represents an alternative mechanism to inactivate tumour suppressor genes, DNA repair genes, cell cycle regulators and transcription factors. In search of epigenetic events related to progression, we used MS-MLPA (ME-0002-B1, MRC-Holland, Amsterdam, The Netherlands) to compare the methylation status of 25 breast cancer-related genes between laser-microdissected ductal carcinoma in situ (DCIS) and adjacent invasive ductal cancer (IDC) lesions in 33 breast cancer patients. Using absolute methylation percentages or, alternatively, a 15% cut-off for methylation, promoter methylation in DCIS and IDC was not significantly different for any of the genes studied. Aberrant methylation in at least 50% of both the DCIS and adjacent IDC lesions was observed for PAX6, BRCA2, PAX5, WT1, CDH13 and MSH6. Methylation of MSH6, however, was also frequent in normal breast tissue. In contrast, CDKN2A, CHFR, PYCARD and one of the two analysed RB1 CpG loci were rarely (<5%) methylated in both lesions. CDKN2A and GSTP1 showed significantly (p < 0.002) higher mean methylation levels in increasing grades (I, II, III) of DCIS (1% versus 4% versus 7% for CDKN2A and 6% versus 26% versus 28% for GSTP1). The mean number of methylated genes per sample increased with increasing grades of DCIS (p = 0.014) and IDC (p = 0.109). In contrast to the observations in DCIS, none of the analysed genes showed significantly higher methylation levels with increasing grades of IDC. In conclusion, there were no differences in promoter methylation between DCIS and IDC in the 25 analysed genes, suggesting that DCIS, at the epigenetic level, is as advanced as IDC. Promoter hypermethylation of PAX6, BRCA2, PAX5, WT1, CDH13 and MSH6 seems to be a frequent early event in breast cancer and methylation levels of GSTP1 (and CDKN2A, although still low) seem to increase with increasing DCIS grade. PMID- 21710694 TI - Narrow-bore core-shell particles and monolithic columns in the analysis of silybin diastereoisomers. AB - Two chromatographic narrow-bore columns, a novel 2.6 MUm particle-packed KinetexTM C18 core-shell (50*2.1 mm id) and monolithic Chromolith((r)) FastGradient RP-18e (50*2 mm id), were evaluated for the analysis of diastereoisomers of the flavonolignans silybin and 23-O-acetylsilybin under isocratic conditions. The main advantages of the core-shell column are markedly higher efficiency (hmin =2.8 versus 5.6 for silybin A) and better peak symmetry. The Kinetex column exhibits only a slight change in the height equivalent of the theoretical plate with a higher linear velocity of the mobile phase. The monolithic column shows notably higher selectivity in terms of selectivity factor (1.21 versus 1.12) in the analysis of critical-pair of diastereoisomers (silybin A and silybin B) and enables shorter run duration (approx. twofold) together with lower backpressure. The resolution power was found to be comparable, but the Kinetex column required a higher pressure of the mobile phase that, together with the higher chance of clogging, can be a disadvantage in the separation of biological samples. Successful baseline separation of silybin diastereoisomers in real pharmaceutical sample on monolithic column was accomplished. PMID- 21710693 TI - Orthotopic xenografts of RCC retain histological, immunophenotypic and genetic features of tumours in patients. AB - Renal cell carcinoma (RCC) is an aggressive malignancy with limited responsiveness to existing treatments. In vivo models of human cancer, including RCC, are critical for developing more effective therapies. Unfortunately, current RCC models do not accurately represent relevant properties of the human disease. The goal of this study was to develop clinically relevant animal models of RCC for preclinical investigations. We transplanted intact human tumour tissue fragments orthotopically in immunodeficient mice. The xenografts were validated by comparing the morphological, phenotypic and genetic characteristics of the kidney tumour tissues before and after implantation. Twenty kidney tumours were transplanted into mice. Successful tumour growth was detected in 19 cases (95%). The histopathological and immunophenotypic features of the xenografts and those of the original tumours largely overlapped in all cases. Evaluation of genetic alterations in a subset of 10 cases demonstrated that the grafts largely retained the genetic features of the pre-implantation RCC tissues. Indeed, primary tumours and corresponding grafts displayed identical VHL mutations. Moreover, an identical pattern of DNA copy amplification or loss was observed in 6/10 cases (60%). In summary, orthotopic engrafting of RCC tissue fragments can be successfully used to generate animal models that closely resemble RCC in patients. These models will be invaluable for in vivo preclinical drug testing and for deeper understanding of kidney carcinogenesis. The raw data of the SNP array analysis has been submitted to the GEO database (Accession No. GSE29062). PMID- 21710695 TI - Comparison of different liquid chromatography stationary phases in LC-HRMS metabolomics for the detection of recombinant growth hormone doping control. AB - Growth hormone (GH) is a polypeptide suspected of being used in horse racing to speed up physical performances. Despite scientific advances in the recent years, the control of its administration remains difficult. In order to improve it, a metabolomics study through LC-high resolution mass spectrometry measurements was recently initiated to assess the metabolic perturbations caused by recombinant equine growth hormone administration. Few tens of ions not identified structurally were highlighted as compounds responsible for the modification of metabolic profiling observed in treated animals. This previous work was based on the use of Uptisphere Strategy NEC as the chromatographic column. In parallel, more and more metabolomics studies showed the interest of the use of new chromatographic supports such as hydrophilic interaction chromatography for the analysis of polar compounds. It is in this context that an investigation was conducted on Uptisphere HDO and Luna hydrophilic interaction chromatography stationary phases to generate and process urinary metabolomics fingerprints, which could allow to establish a comparison with Uptisphere Strategy NEC. The chromatographic column the most adapted for the detection of new biomarkers of GH administration has been used to set up a relevant statistical model based on the analysis of more than hundred biological samples. PMID- 21710696 TI - Analysis of beta-blockers in groundwater using large-volume injection coupled column reversed-phase liquid chromatography with fluorescence detection and liquid chromatography time-of-flight mass spectrometry. AB - Atenolol, nadolol, metoprolol, bisoprolol and betaxolol were simultaneously determined in groundwater samples by large-volume injection coupled-column reversed-phase liquid chromatography with fluorescence detection (LVI-LC-LC-FD) and liquid chromatography-time-of-flight mass spectrometry (LC-TOF-MS). The LVI LC-LC-FD method combines analyte isolation, preconcentration and determination into a single step. Significant reductions in costs for sample pre-treatment (solvent and solid phases for clean up) and method development times are also achieved. Using LC-TOF-MS, accurate mass measurements within 3 ppm error were obtained for all of the beta-blockers studied. Empirical formula information can be obtained by this method, allowing the unequivocal identification of the target compounds in the samples. To increase the sensitivity, a solid-phase extraction step with Oasis MCX cartridge was carried out yielding recoveries of 79-114% (n=5) with RSD 2-7% for the LC-TOF-MS method. SPE gives a high purification of beta-blockers compared with the existing methods. A 100% methanol wash was allowed for these compounds with no loss of analytes. Limit of quantification was 1-7 ng/L for LVI-LC-LC-FD and 0.25-5 ng/L for LC-TOF-MS. As a result of selective extraction and effective removal of coextractives, no matrix effect was observed in LVI-LC-LC-FD and LC-TOF-MS analyses. The methods were applied to detect and quantify beta-blockers in groundwater samples of Almeria (Spain). PMID- 21710697 TI - Chemical correlation between Shuanghuanglian injection and its three raw herbs by LC fingerprint. AB - Shuanghuanglian injection, a famous composite formula in China, is a combination of Flos lonicerae japonicae, Radix scutellariae and Fructus forsythiae. To develop a method to overall evaluate the correlation between the formula and its three raw herbs, the representative LC fingerprint of Shuanghuanglian injection was established from 12 batches of samples. Ten peaks were selected as the common peaks to evaluate the similarities of different samples from different manufacturers. Hierarchical clustering analysis was used as a powerful pattern recognition tool to identify and classify Shuanghuanglian injection from different factories. In addition, chemical correlation between the formula and the three raw herbs was evaluated qualitatively through comparison of their chromatograms under the same HPLC conditions. The results showed that peak 1, 2, 3 and 9 in the formula fingerprint were characteristic components of Flos lonicerae japonicae, peaks 5, 6 and 8 were that of F. forsythiae, peak 10 was that of R. scutellariae, while peak 7 was the common component of Flos lonicerae japonicae and F. forsythiae, peak 4 was addressed to F. forsythiae and it was also the product of the manufacturing procedure. PMID- 21710698 TI - Liver disease on the rise; obesity cited as cause. Weight loss, a healthy diet, and exercise may help prevent non-alcoholic fatty liver disease, a precursor to chronic liver disease. PMID- 21710699 TI - Extra pounds are bad for your heart. Period. After all is said and done, whether you're apple-or-pear-shaped doesn't matter. PMID- 21710700 TI - 4 new genes identified as raising Alzheimer's disease risk. A multi-center research project unveils more targets to study for potential future treatment. PMID- 21710701 TI - Motivation, behavior change, and weight management. Motivation-enforced weight loss programs conducted via the Internet may be the silver bullet for the nation's obesity epidemic. PMID- 21710703 TI - Can drugs use to treat cognitive impairment help me with age-related memory problems? PMID- 21710702 TI - Advances in non-small-cell lung cancer treatment. Strategies include repeat biopsies and counting circulating cells. PMID- 21710704 TI - [IV. Others: 3. Hypokalemia or hypercalcemia-induced renal injuries]. PMID- 21710705 TI - [Fewer malaria deaths in Zanzibar]. PMID- 21710706 TI - [Influenza vaccination of pregnant women and the experiences related to the pandemic influenza A-virus H1N1 infection in Hungary, 2009]. AB - During the influenza A-H1N1 pandemic, only about 16% of pregnant women were vaccinated against the virus, despite their higher expected mortality risk. According to the official data, five pregnant women died. In addition, the high fever that occurs in influenza increases the risk of some congenital abnormalities. The vaccine used in Hungary is not associated with severe complications in pregnant women and their fetuses, therefore, it can be administered during any stage of pregnancy. The author discusses the causes that deterred pregnant women from being vaccinated. The main problem seems to be that some physicians were under-informed and were reluctant to take responsibility. PMID- 21710707 TI - [Current treatment of multiple sclerosis]. AB - Multiple sclerosis (MS) is an autoimmune and degenerative disorder. In the past decades, the introduction of parenteral immunomodulatory therapies brought significant progress. These agents increase the number of relapses (shubs) by about 30%, and some of them has been shown to halter the accumulation of neurological symptoms and the development of disability. As first-line agents, interferon beta and glatiramer acetate (consisting of amino acids) can be used. Some new therapeutic strategies have been developed as a result of biotechnological development. The advantage of humanised monoclonal antibodies is that they affect the autoimmune inflammatory process more selectively. Among monoclonal antibodies, natalizumab, which binds to alpha-4-beta-1 integrin receptors and inhibits the migration of T-lymphocytes into the central nervous system, is available from February 2010 in Hungary, recommended as second-line treatment. The efficacy of natalizumab in decreasing relapse rate is > 60%. However, its use is associated with progressive multifocal leukoencephalopathy (PML) in one out of 1000 treated patient. Currently it is recommended as second line treatment, if the patient has active disease despite immunomodulatory therapy. Among orally administered agents, a preparation containing fingolimod is expected to become available next year, and another pill, cladribin has been also found to be efficient in randomised, controlled phase III trials. Fingolimod acts on sphingosine 1-phosphate receptors-1 (S1P1). Cladribine is a purine nucleotide analogue, and its efficacy is based on long-term reduction of CD4+ and CD8+ lymphocytes. Further promising oral immunomodulatory agents are laquinimod and BG000012 (dimethylfumarate), which are currently being tested in phase III clinical trials in relapsing-remitting MS. The most efficient treatment should be chosen on the basis of the activity, aetiology and the posited pathomechanism of the disease. With the increasing number of therapeutic options, choosing the treatment that is optimal for the patient while also considering side effects might be challenging for both the patients and physicians. PMID- 21710708 TI - [Anti-atherosclerotic effect of pioglitazone--the first evidence of the role of triglyceride/HDL ratio]. AB - The presence of multiple risk factors can multiply exponentially the risk of cardiovascular events, thus cardiovascular diseases are more severe in diabetes mellitus. One of the challenges we face today is the application of drugs that, besides improving glucose homeostasis, also have antiatherosclerotic effect. Such candidates are glitazones, which have pleiotropic efficiency beyond their main effect: they improve distribution of adipose tissue, blood pressure and endothelial function and also have anti-inflammatory and anti-coagulation capacity. Regarding the effects on lipid metabolism, there are differences between various glitazones: improvements are mainly achieved by pioglitazone, which markedly reduces triglyceride levels, and also elevates HDL levels and decreases the ratio of small, dense LDL-particles. Studies on clinical outcomes also show the superiority of pioglitazone. Imaging of blood vessels (carotis-IMT, intracoronary ultrasound technique) also suggest a greater efficiency of pioglitazone. According to the latest analysis of the PERISCOPE study, the stability of the coronary plaque was associated only with the triglyceride/ HDL ratio in case of pioglitazone. The newest data also revealed that pioglitazone uniquely increases the cholesterol-efflux attributed to HDL-related macrophages. On the basis of the latest results, pioglitazone not only improves glucose homeostasis, but also has a remarkable anti-atherosclerotic effect, which is primarily due to its favourable lipid metabolism profile. PMID- 21710710 TI - [Disabled person's satisfaction with health and social care--an internationally developed instrument]. AB - INTRODUCTION: Quality of health and social care is being assessed by largely different methods. Obtaining comparable and valuable data is difficult. Thus, internationally developed instruments have special value. SAMPLE AND METHODS: A set of instruments has been developed simultaneously using World Health Organization's instrument development method. One of these is the instrument "Quality of Care and Support for People with Disabilities". Response scales contain five options for physically and three for intellectually disabled persons. Psychometric analysis of the Hungarian instrument version was based on interviews with 151 physically and 166 intellectually disabled persons. RESULTS: Answering rate was high, above 95% with the exception of one item. Internal consistency of the two instrument versions by Cronbach's alpha is 0.845 and 0.745 respectively. Lowest satisfaction was found in the domain "information" in both groups that correlates significantly with health conditions at p < 0.01 and p < 0.05 level respectively. CONCLUSIONS: The field trial confirms validity and reliability of the instrument. Its wider use may help the evaluation of satisfaction concerning different components of quality of care, consequently better tailoring of services to needs. PMID- 21710709 TI - [The significance of generic valsartan in the treatment of patients]. AB - The renin-angiotensin-aldosterone system (RAAS) is involved in the regulation of electrolyte and water balance primarily; however, it also influences vascular function and increases blood pressure--especially under pathological conditions. Hypertension, post-myocardial infarction state, and heart failure are, for example, associated with excessive systemic and/or local activation of the RAAS. Angiotensin II (AT-II) generated by the latter, contributes--along with additional factors and through its deleterious effects (vasoconstriction, endothelial dysfunction, atherosclerosis, prothrombotic state, fibrosis, etc.)- to damage to the target organs involved in the sequence of cardiovascular events. Inhibiting the RAAS at different levels is of therapeutic importance--its purpose is to delay disease progression, to prevent end organ damage, and to achieve a better outcome. As AT-II acts on several (AT1 and AT2) receptors, using angiotensin receptor blocking (ARB) agents with a high selectivity for the AT1 receptor is the rational choice. In view of its favourable therapeutic properties and efficacy demonstrated by morbidity and mortality studies, a generic formulation of appropriate quality, containing valsartan as active substance could prove to be the ideal treatment for patients with hypertension and other cardiovascular disorders. PMID- 21710711 TI - [Environment, illness--or necessary paradigm change in medicine]. PMID- 21710712 TI - [The relevance of high stimulus rate ABR and recurrent vertigo and its clinical significance]. AB - OBJECTIVE: To study the relevance of the high stimulus rate auditory brainstem response(auditory brainstem response, ABR) test in recurrent vertigo, investigate the cause of recurrent vertigo, and provide important help for the clinical treatment. METHOD: One hundred and one cases with recurrent vertigo were retrospectively analyzed, and high stimulus rate ABR were tested and compared in attack episodes and intermittent episodes. RESULT: The abnormal difference between ABR I and V latency was selected as parameters. The abnormal rate of high stimulation ABR was 56.4% in patients with recurrent episodes of vertigo many times (2 and above), of which the highest rate was 71.9% in MV patients, and the second one was BPPV. The abnormal rate of high stimulation ABR was 14.9% in patients during medication or intermittent episodes. The abnormal rate in all groups decreased obviously as compared to attack episodes. CONCLUSION: Abnormal rate of high stimulus rate ABR correlates well with recurrent vertigo significantly. The inner ear microcirculation may result in the attack of recurrent vertigo. PMID- 21710713 TI - [Contralateral suppressions of transient evoked otoacoustic emissions in diabetes mellitus patients]. AB - OBJECTIVE: To investigate the contralateral suppressions of transient evoked otoacoustic emissions (TEOAE) in diabetes mellitus patients with normal hearing. METHOD: The pure tone audiometry, acoustic immittance and TEOAE tests were performed in 30 diabetes mellitus patients with normal hearing and 30 healthy controls. The efferent system functions were evaluated by contralateral suppression of TEOAE. RESULT: There were no significant differences of pure tone thresholds and amplitudes of TEOAE between the two groups. The contralateral suppressions of TEOAE in diabetes mellitus patients were significantly lower than that in controls (P<0.05 at 2000 and 4000 Hz respectively). CONCLUSION: The nerve functions of central nerve system can be damaged in diabetes mellitus patients with normal hearing. PMID- 21710714 TI - [Modified pedicled cranial periosteum compound flap to reconstruct the defect of anterior cranial fossa complicated with cerebrospinal fluid leakage]. AB - OBJECTIVE: To explore the effect of modified pedicled cranial periosteum compound flap in reconstructing the defect of anterior cranial fossa complicated with cerebrospinal fluid leakage. METHOD: Seven nasal and sinus tumor cases with defects and CSF were undertaken reconstructing surgery with the flap, of which 1 was benign and the others were malignancies. The transferred flap pedicled with the frontal branch of the superficial temporal artery and complemented with ipsilateral supraorbital and/or supratraochlear artery. RESULT: All cases healed without failure, one case with adjuvant radiotherapy experienced partial free frontal bone necrosis and healed by ways of drainage through temporal incision. The inner surface of the flap in the nasal cavity was smooth. CONCLUSION: Frontal cranial periosteum compound flap have some advantages, such as adequate quantity, good blood supply and easily making,so it can be choose as an important method to reconstruct the defects of anterior cranial fossa and CSF leakage. PMID- 21710715 TI - [A clinical analysis of 33 cases of Kimura's disease]. AB - OBJECTIVE: To improve the diagnosis and treatment of Kimura's disease (KD) by investigating its clinical characteristics, pathological features and complications. METHOD: The clinical data of 33 cases of KD were analyzed retrospectively. RESULT: Of 33 cases, 22 showed the mass on head and neck, while in the other cases, the mass distributed in the region of groin, axillary fossa, hilum of lung and mesentery. Regional lymph nodes were involved in 21 cases and major salivary glands were invaded in 8 cases. Twenty-three cases had typical peripheral eosinophilia, although only in 2 patients the quantity of serum total IgE increased markedly. Urine abnormalities happened to 7 cases, such as massive proteinuria (3 cases) and hematuria (2 cases). Among 6 cases which underwent bone marrow aspiration, 2 showed eosinophilia. Two cases were complicated with nephritic syndrome. Six cases were combined with local inflammation on head and neck and 2 cases were combined with malignant tumor. CONCLUSION: Mass on the head and neck is the typical clinical manifestation in KD, with regional lymph nodes and major salivary glands involved most. Serum total IgE and histopathologic examination should always be done to confirm KD, especially in the cases with unknown eosinophilia increasing. PMID- 21710716 TI - [The diagnosis and countermeasure for the nose-source otitis media]. AB - OBJECTIVE: To propose the concept of rhinogenic otitis media and explore its pathomechanism through analyzing the diagnosis and treatment on secretory otitis media caused by unhealthy nasal cavity structure. METHOD: Conservative treatment and correlative operation under nasoscope were undertaken in 176 otitis media patients with unhealthy nasal cavity structure. RESULT: Of 176 cases, 156 cases recovered completely (88.64%), 18 cases got effective treatment (10.23%), and 2 cases got ineffective treatment (1.14%). CONCLUSION: One important cause of the secretory otitis media is unhealthy nasal cavity structure, so correcting the unhealthy nasal cavity structure is the main ways to treat rhinogenic otitis media. PMID- 21710717 TI - [Study on the expression and clinical significance of MMP9 and MVD in the external auditory canal and middle ear squamous cell carcinoma]. AB - OBJECTIVE: To investigate the expression and clinical significance of MMP9 and MVD in the carcinogenesis of squamous cell carcinoma of external auditory canal and middle ear. METHOD: Immunohistochemical SP method was used to detect the expression of MMP9 and MVD proteins in 26 squamous cell carcinoma tissues of external auditory canal and middle ear and 20 normal external ear canal skin tissues. RESULT: The positive rate of MMP9 in squamous cell carcinoma tissues of external auditory canal and middle ear was 73.1% (19/26) lower than that in the normal external ear canal skin tissues 25.0% (5/20). The positive rates of CD34 were 33.58 +/- 3.04 and 22.50 +/- 5.22, respectively. The positive rates of MMP9 and CD34 were correlated with the histological grade and tumor grade, but had no relationship with age and sex. The positive rates between MMP9 and CD34 were related (r=0.42, P<0.05). CONCLUSION: MMP9 may be involved in the carcinogenesis of squamous cell carcinoma of external auditory canal and middle ear, and may play an important role in the invasion and metastasis of squamous cell carcinoma of external auditory canal and middle ear. MMP9 and CD34 play a cooperative role in the process of squamous cell carcinoma of external auditory canal and middle ear. PMID- 21710718 TI - [To analyze the etiology of benign paroxysmal positional vertigo]. AB - OBJECTIVE: To analyze the occurrence and probable etiological factors of benign paroxysmal positional vertigo (BPPV). METHOD: one hundred and twenty four BPPV cases were inquired histories, classified into different groups and analyzed relevant diseases. All patients were taken Caloric tests before Canal repositioning procedure, and compared the differences of unilateral weakness (UW) and semicircular canal involved between BPPV patients with and without relevant diseases. RESULT: There were 97 (78.2%) patients with relevant diseases while 27 (21.8%) without. Ninety-two (74.2%) patients with abnormal UW. To compare the normal and abnormal UW, posterior canal and lateral canal with abnormal UW values, unilateral or bilateral of abnormal UW values, consistency of abnormal UW side and BPPV side between BPPV patients with and without relevant diseases, there were no significant differences (Chi-square values were 0.000, 0.000, 0.306, 0.027, P>0.05). CONCLUSION: BPPV patients with relevant diseases are common, which mainly occurs in middle-aged or aged people and female. Otolith ecclesiis and dysfunction of semicircular canal may have the same etiological factors. Caloric tests may do help to analyze the BPPV etiological factors. PMID- 21710719 TI - [A clinical diagnosis and treatment of ethmoid bone gasification in company with infection]. AB - OBJECTIVE: To explore a rare anatomic malformation of ethmoid and its clinical features, as well as an effective way of treatment. METHOD: Four cases from 2000 2009 of the first affiliated hospital of china medical university were studied according to the symptom,CT scanning, pathological examination and treatment process, respectively. RESULT: Ethmoid bone gasification complicated with infection resulted in a rare anatomic and pathological disorder. The symptom and treatment were largely dependent on the size of gasification and degree of infection. CONCLUSION: CT Scanning plays a critical role in the diagnosis. In most case,a surgical treatment under endoscope is generally applied as a suitable way for clinical therapy. The regular reexamination is recommended for preventing recurrence. PMID- 21710720 TI - [Location of tympanic segment and mastoid segment of facial nerve and prevention of prosopoplegia in operations]. AB - OBJECTIVE: To study the location of facial nerve and prevent facial nerve injury in middle ear surgery according to dissection of temporal bone and experience of middle ear surgery. METHOD: Thirty sides of temporal bones were exposed tympanic and mastoid segment of facial nerve with facial nerve decompression. The course of facial nerve was located by the markers of middle ear. RESULT: Tympanic segment of facial nerve passed between horizontal semicircular canal and stapes,then superior and anterior to the cochleariform process. Mastoid segment of facial nerve located in posterior wall of tympanic cavity. The mastoid segment of facial nerve travelled below the level of horizontal semicircular canal and annulus membrane tympani, and the extension line of its posterior margin and posterior-one-third of horizontal semicircular canal intersected to form an included angle (117.04 +/- 2.42) degrees. External genu of facial nerve located anterior and inferior to the horizontal semicircular canal. The shortest distance was (1.97 +/- 0.53) mm between middle point of horizontal semicircular canal and facial nerve, (1.03 +/- 0.29) mm between incus short process and facial nerve, (0.93 +/- 0.25) mm between cochleariform process and facial nerve, (1.18 +/- 0.42) mm between head of stapes and facial nerve, (3.08 +/- 0.28) mm between tympani sulcus and facial nerve at the vestibule window level, and (2.13 +/- 0.34) mm between tympani sulcus and facial nerve at round window level, respectively. CONCLUSION: Horizontal semicircular canal carina, incus short process, stapes, annulus membrane tympani and cochleariform process are ideal landmarks of tympanic and mastoid segment of facial nerve, which are helpful in middle ear surgery. PMID- 21710721 TI - [The value of short daytime ApneaGraph in assessing obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To determine whether there was agreement between the short daytime ApneaGraph (dAG) and nocturnal ApneaGraph (nAG) in diagnosing sleep respiratory events initially and identifying the site of obstruction in airway. METHOD: Twenty four patients diagnosed OSAHS by PSG were enrolled. The apnea-hypopnea index (AHI), apnea index (AI), obstructive apnea-hypopnea index (OAHI), central apnea hypopnea index (CAHI), mixed apnea index (MAHI), lowest oxygen saturation (LSaO2) and the proportion of upper/lower obstruction (UPPER, LOWER) of patients were measured using both dAG and nAG. RESULT: There were no significant differences between nAG and dAG for the following parameters: AHI, AI, CAHI, MAHI, OAHI, the proportion of upper/lower obstruction, or LSaO2 (P>0.05). There were significant positive correlations between nAG and dAG with regard to AHI, AI, MAHI, OAHI, the proportion of upper/lower obstruction , LSaO2 except CAHI. CONCLUSION: The dAG has similar results with nAG in early diagnosis of sleep respiratory events and identifying the level of airway obstruction. The time saving dAG is of considerable referential importance in diagnosis of sleep respiratory events and analysing the level of airway obstruction. PMID- 21710722 TI - [Using ESR technology observe the change of free radicals in cochlea after acute acoustic trauma]. AB - OBJECTIVE: To observe the changes of free radicals in the cochlea of guinea pigs after noise exposure directly using electron spin resonance (ESR) technology. METHOD: Forty-two guinea pigs as experimental group were given (125 +/- 1) dB SPL noise exposure for 2 hours, and then investigated auditory function immediately, at 2, 6, 12, 24, 48 and 72 hour. After ABR examinations, 21 animals decollated and extracted cochlea immediately and then placed the cochleas to liquid nitrogen for deep freezing and measuring free radicals using ESR technology. Another 21 animals observed hair cells morphology by AgNO3 staining. Meantime, 6 animals without noise exposure were served as negative control group. RESULT: A few free radicals were detected in the cochlea at control group and the relative value of free radicals were (21.68 +/- 1.27) dB SPL. After noise exposure, the relative value of free radicals increased obviously and achieved to the max of (147.01 +/- 4.95) dB SPL at 2 h and gradually decreased near the normal level. CONCLUSION: Free radicals in the cochlea increase evidently and have a concentration-time rule after acute acoustic trauma. The ESR method can be used to examine the content of free radicals in cochlea for its direct, objective and sensitive characters. PMID- 21710723 TI - [Depyrogenation in key manufacturing processes of Reduning injection]. AB - OBJECTIVE: To investigate the effect of removing bacterial endotoxin in the key processes of Reduning injection. METHOD: The content of bacterial endotoxins was detected by kenitic-turbidimetry and the removal efficacy was studied before and after using 0.8% of activated carbon and ultrafiltration with molecular weight cut-off of 10 x 10(3). RESULT: The adsorption rate of bacterial endotoxins was 78.7% by using activated carbon, while the removal efficacy of bacterial endotoxins was 99.6% with ultrafiltration membrane at cut-off molecular weight 10 x 10(3). CONCLUSION: The key technology can effectively guarantee the safety of Reduning injection. PMID- 21710724 TI - [Studies on key processes of Fufang Kushen injection]. AB - OBJECTIVE: To study the key processes of Fufang Kushen injection for technical upgrading. METHOD: Total alkaloids (sum of matrine, oxymatrine, sophoridine and oxysophoridine) and macrozamin were selected as quality evaluation markers. The key processes of percolation with acetic acid and discoloration with activated carbon were optimized by orthogonal experiment design, and process of purification with alcohol was investigated by single factor method. RESULT: The optimal condition of percolation process is as follows: the medicinal materials are soaked for 9 h with 4 times water containing 0.8% acetic acid, then percolation starts at flow-rate of 5 mL x min(-1) x kg(-1) and adding 2 times 0.8% acetic acid solution is added at the same velocity. Purification process is that the concentrated solution is precipitated by 60%, 80% and 90% alcohol in turn. Discoloration process is that 6 activated carbon is added into the solution which is heated at 60 degrees C for 20 minutes. CONCLUSION: The optimal extraction process is not only simple, saving the industrial cycle, reducing the potential risk, but also decreasing the acetic acid amount to guarantee the acid insoluble ash as well as the functional ingredients. PMID- 21710725 TI - [Rapid determination of puerarin in Xiaoke pill powder by near-infrared spectroscopy]. AB - OBJECTIVE: To determine the content of puerarin in Xiaoke pill powder rapidly by near-infrared spectroscopy. METHOD: Near-infrared diffuse reflectance spectroscopy technology was used to collect NIR spectra of Xiaoke pills powder. With HPLC analysis values as reference, the fast determination method of puerarin was established with partial least squares (PLS). RESULT: The R2, RMSECV and RPD of the calibration model for puerarin were 0.980 1, 0.131 and 7.09. The average relative deviation of the predication set was 3.2%. CONCLUSION: The method is accurate, fast and simple, which could be generalized to the on-line quality control of Xiaoke pill powder production. PMID- 21710726 TI - [Preparation of beta-CD inclusion of volatile oil from Nardostachyos Radix et Rhizoma]. AB - OBJECTIVE: To study optimal process conditions for the inclusion of volatile oil from Nardostachyos Radix et Rhizoma using saturated water solution method. METHOD: The optimal technology of inclusion was identified respectively by the utilization ratio of volatile oils and the yield of inclusion compound in an orthogonal experiment design, and the inclusion efficiency was evaluated by TLC, UV, IR, SE and GC-MS. RESULT: The optimum preparation conditions for inclusion were established as follows: volatile oil: beta-CD was 1: 6, the inclusion temperature was 40 degrees C, the stirring speed and time were in 300 r x min(-1) and for 1 h. The analysis results showed that a new substance was conformed. The change of the volatile oil component was found before and after inclusion. CONCLUSION: The optimal process conditions are easy for operation, and high in utilization ratio of volatile oils and the yield of inclusion compound. PMID- 21710727 TI - [Study on processing technics of Tibetan medicine Nanhanshuishi]. AB - OBJECTIVE: To study the heat processing technics of Nanhanshuishi. METHOD: To find the best processing technic, the single factor experiments and orthogonal experiments were designed basing on the processing technics summarized by consulting documents, scriptures and investigating some Tibetan hospitals, meanwhile, the content of Ca, Fe, Mn, Zn, and Cu in the processed Nanhanshuishi in single factor experiments and orthogonal experiments were detected. RESULT: The best processing technic of Nanhanshuishi was as follows: Nanhanshuishi was crashed to 10-20 mm in diameter, the ratio of the weight of Aconiti Kusnezoffii Radix and potassium nitrate was 1: 2, and the boiling time was 3 h. CONCLUSION: The work in this article provided a basic processing technic data for clarifying the mechanism of processing and establishing the perfect processing technics of Nanhanshuishi. PMID- 21710728 TI - [Quick finding of absorption ingredients of Paeoniae Radix Alba by SEMAC]. AB - OBJECTIVE: To establish a method for quick finding of the absorption ingredients of Paeoniae Radix Alba in order to select the index of quality control. METHOD: The absorption ingredients of three concentration of Paeoniae Radix Alba were investigated with the in vitro-everted intestinal sac (VEIS) model. The intestinal sac fluids of jejunum and ileum were collected in different time and detected by HPLC. The accumulative absorption quantity of albiflorin and paeoniflorin were calculated, respectively. RESULT: Five ingredients could be detected. In different concentrations of Paeoniae Radix Alba, albiflorin and paeoniflorin in various intestinal sections were the linear absorption (R2 > 0.9), conformed to the zero order absorption rate. The values of Ka in the jejunum and ileum were increased along with the raised dosage of the Paeoniae Radix Alba (P < 0.05), indicating a passive absorption manner. CONCLUSION: SEMAC could be used as a tool to find the absorption ingredients of Paeoniae Radix Alba. Compared with the jejunum, the ileum could provide the more absorption information. It was showed that the optimal detecting time was 60 min. PMID- 21710729 TI - [Composition and thermal stability of traditional Tibetan mineral medicine Nanhanshuishi]. AB - OBJECTIVE: To determine the composition, structure, trace elements and thermal stability of Tibetan medicine Nanhanshuishi. METHOD: The trace elements, the structure, and the thermal stability of Nanhanshuishi were assayed and calculated by X-ray fluorescence spectrometry (XRF), inductively coupled plasma optical emission spectrometer (ICP-OES), atomic fluorescence spectrometry (AFS), inductively coupled plasma mass spectrometry (ICP-MS), X-ray power diffraction (XRD), TG-DTA. RESULT: The results indicated that the phase is mainly made up of CaCO3 (Rhombohedral, R-3c) in Nanhanshuishi. The analysis of elements show that Nanhanshuishi is rich in Ca and O, and contains other more than 20 minor elements, such as Si, Mg, Fe, Al, Na, K, Zn, Mn, Pb, As, Hg etc. The result of TG DTA show that the weight of Nanhanshuishi starts to decline from near 700 degrees C and get steady above 850 degrees C. CONCLUSION: The study provided scientific data for the establishment of quality standards of Tibetan medicine Nanhanshuishi. PMID- 21710730 TI - [Metabolomics study of anti-inflammatory action of Radix Paeoniae Rubra and Radix Paeoniae Alba by ultraperformance liquid chromatography-mass spectrometry]. AB - OBJECTIVE: To compare the anti-inflammatory effect of Radix Paeoniae Rubra and Radix Paeoniae Alba by animal experiment and metabolimic analysis. METHOD: To establish the rats model of toes swelling caused by carrageenan, study the anti inflammatory effect of Radix Paeoniae Rubra and Radix Paeoniae Alba. The serum samples were analyzed by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS), to find out the potential identification biomarker by PLS-DA. RESULT: Both of the extracts of Radix Paeoniae Rubra and Radix Paeoniae Alba have good effects of inhibition to swelling caused by carrageenan in 0.5-1 h, and the extract of Radix Paeoniae Rubra also show significant inhibition in 2-3 h. Glutathione( GSH), gamma-aminobutyric acid (GABA), prostaglandin F2alpha (PGF2alpha), prostaglandinE3 (PGE3), leukotrieneA4 (LTA4), prostaglandinE2 ( PGE2) are proven to be significant expressed biomarkers. Radix Paeoniae Rubra and Radix Paeoniae Alba may have great influence on PGF2alpha and PGE3. There was also significant difference between the effects of Radix Paeoniae Rubra and Radix Paeoniae Alba, which suggested the difference of anti-inflammatory between the two herbs. CONCLUSION: The results of metabolomics are related with the results of classic pharmaco- experiment, which is helpful for the further research of the mechanism of action of Radix Paeoniae Rubra and Radix Paeoniae Alba. PMID- 21710731 TI - [Metabolomics study of anti-platelet effect of Radix Paeoniae Rubra and Radix Paeoniae Alba by UPLC-MS]. AB - OBJECTIVE: To study the anti-platelet effect and influence of Radix Paeoniae Rubra and Radix Paeoniae Alba on rat's endogenous metabolites by animal experiment and UPLC-MS based metabolomic method. METHOD: After administration of 80% ethanol extracts of Radix Paeoniae Rubra and Radix Paeoniae Alba for 6 d, the serum samples were analyzed by ultra-performance liquid chromatography- mass spectrometry (UPLC-MS) and partial least squares-discriminant analysis (PLS-DA) to find out the potential biomarker. RESULT: Both of the extracts of Radix Paeoniae Rubra and Radix Paeoniae Alba have good effects of inhibition on platelet coacervation, and the effect of Radix Paeoniae Alba is better than that of Radix Paeoniae Rubra. Malic acid, alpha-acetone dicarboxylic acid, leukotrieneA4 (LTA4), prostaglandinE2 (PGE2) and prostaglandin F2alpha (PGF2alpha) are proved to be significant expressed biomarkers. CONCLUSION: Metabolomics is helpful for the further research of the mechanism of anti platelet action of Radix Paeoniae Rubra and Radix Paeoniae Alba. PMID- 21710732 TI - [Simultaneous quantitation of adonifoline and senecionine in Senecio herbs by UPLC-MS]. AB - OBJECTIVE: To develop an UPLC-MS method for the simultaneously quantitation of adonifoline and senecinine in Senecio herbs. METHOD: UPLC-Micro 2000 was used for quantification in SIR mode under ESI+. Monocrotaline was used as the internal standard. Chromatography was performed on a Shiseido Capcell Pak MG (2.0 mm x 50 mm, 3 microm) column at 30 degrees C using an gradient elution of acetonitrile 0.5% formic acid in water at the flow rate of 0.3 mL x min(-1). The injection volume was 2 microL. RESULT: Good linearity was obtained for quantitation of adonifoline over the range of 1.02-816.00 microg x L(-1) (r = 0.998 0). And recoveries at different concentration levels were between 95.73% and 103.0% with RSDs no more than 2.5%. For quantification of senecionine, the linear range was between 1.08-860.56 microg x L(-1) (r = 0.997 6). And recoveries at different concentration levels were between 95.67% and 101.5% with RSDs no more than 2.3%. Good reproducibility and precision were also achieved. CONCLUSION: The new developed UPLC method is sensitive, accurate and reliable enough for the quantitation of adonifoline and senecionine in Senecio herbs thus can be used for the limit detection of pyrrolizidne alkaloids in S. scandens. It can also be used for the identification of fake drugs of S. scandens such as S. vulgaris. The developed method was served for the quality evaluation of Herba Senecionis Scandentis. PMID- 21710733 TI - [Simultaneous determination of five glycosides in Aidi injection by RP-HPLC ELSD]. AB - OBJECTIVE: To develop a RP-HPLC-ELSD method for the simultaneous determination of five glycosides in Aidi injection. METHOD: The separation was carried out at 35 degrees C on a Kromasil C18 column (4.6 mm x 250 mm, 5 microm) eluted with acetonitrile and water as the mobile phases in gradient mode. The flow rate was 1.0 mL x min(-1). The SHIMADZU ELSD-LT II detector was used. The detector temperature was at 40 degrees C and the pressure of carrier gas N2 was 0.35 MPa. RESULT: The linear response (the natural logarithm of peak areas with corresponding mass) ranges were 21.2-212 mg x L(-1) for syringin, 30.8-308 mg x L(-1) for ginsenoside Rg1, 24.8-248 mg x L(-1) for ginsenoside Re, 25.6-256 mg x L(-1) for ginsenoside Rb1, 31.2-312 mg x L(-1), for astragaloside IV, respectively. The average recoveries (n = 9) of five glycosides were greater than 97.6%, and RSD were less than 1.1%. CONCLUSION: The results demonstrated that this method had adequate accuracy and selectivity to measure the concentrations of five glycosides in Aidi injection. PMID- 21710734 TI - [Simultaneous determination of five constituents in Scrophularia ningpoensis by HPLC]. AB - OBJECTIVE: To develop an HPLC method for the simultaneous quantitation of five constituents in Scrophularia ningpoensis. METHOD: Samples were analyzed on an Agilent SB-C18 column(4.6 mm x 250 mm, 5 microm) eluted with acetonitrile and water containing 0.03% phosphate acid as mobile phases in a linear gradient mode. The flow rate was kept at 1.0 mL x min(-1), and the column temperature was set to 30 degrees C. The DAD detector wavelengths were 210, 280, 330 nm. RESULT: The linear ranges were 50-400 mg x L(-1) for harpagide, 1-40 mg x L(-1) for harpagoside, 1-20 mg x L(-1) for cinnamic acid, 0.5-4.5 mg x L(-1) for acteoside,1-60 mg x L(-1) for angoroside C, respectively. The average recoveries of the five constituents were 100.8% (RSD 0.62%), 101.7% (RSD 0.32%), 98.8% (RSD 0.48%), 99.9% (RSD 1.4%), 99.2% (RSD 1.1%), respectively. CONCLUSION: Through the validation, the method was proved to be sensitive, accurate, repeatable, and can be used for quality control of the roots of S. ningpoensis. PMID- 21710735 TI - [UPLC characteristic chromatographic profile of Paeoniae Radix Alba]. AB - OBJECTIVE: To develop an UPLC method of determining the characteristic chromatographic profiles of Paeoniae Radix Alba for quality control. METHOD: The UPLC characteristic chromatographic profiles of fifteen batches of Paeoniae Radix Alba were determined on an HSS T3 Column (2.1 mm x 100 mm, 1.8 microm) eluted with the mobile phases of water containing 0.05% phosphoric acid and acetonitrile in gradient mode. The detection wavelength was set at 230 nm. RESULT: The common mode of the UPLC characteristic chromatographic profile was set up. There were 15 common peaks, five of which were identified, and the similar degrees of the fifteen samples to the common mode were between 0.891 and 0.996. CONCLUSION: The method was time-saving and can be used for the quality control of Paeoniae Radix Alba. PMID- 21710736 TI - [UPLC characteristic chromatographic profile of Moutan Cortex]. AB - OBJECTIVE: To develop an UPLC method of determining the characteristic chromatographic profiles of Moutan Cortex for quality control of the medicine. METHOD: The UPLC characteristic chromatographic profiles of fifteen batches of Moutan Cortex were determined on an HSS T3 column (2.1 mm x 100 mm, 1.8 microm) eluted with the mobile phase consisted of water containing 0.05% phosphoric acid and acetonitrile in gradient mode and the detection wavelength was set at 254 nm. RESULT: The common mode of the UPLC characteristic chromatographic profile was set up under the established condition. There were 20 common peaks in the characteristic chromatographic profile of fifteen samples, ten of which were identified, and the similar degrees of the fifteen batches to the common mode were between 0.973-0.998. CONCLUSION: The method was fast and accurate. The characteristic chromatographic profile of Moutan Cortex with high specificity can be used to control the quality of Moutan Cortex. PMID- 21710737 TI - [UPLC characteristic chromatographic profile of Persicae Semen]. AB - OBJECTIVE: To develop an UPLC method of determining the characteristic chromatographic profile of Persicae Semen for controlling the drug quality quickly and accurately. METHOD: The UPLC characteristic chromatographic profiles of fifteen batches of Persicae Semen were determined on an HSS T3 column (2.1 mm x 100 mm, 1.8 microm) eluted with the mobile phase consisted of acetonitrile water containing 0.05% phosphoric acid in gradient mode and the detection wavelength was at 254 nm. RESULT: The common mode of the UPLC characteristic chromatographic profile was set up. There were 12 common peaks in the fingerprints of fifteen samples, six of which were identified, and the similar degrees of the fifteen batches to the common mode were between 0.884-0.996. CONCLUSION: The method was quick and accurate. The characteristic chromatographic profile of Persicae Semen with high specificity can be used to control the quality of Persicae Semen. PMID- 21710738 TI - [A new natural saponin from fruits of Siraitia grosvenorii]. AB - OBJECTIVE: To study the chemical constituents in the fruits of Siraitia grosvenorii. METHOD: Isolation and purification of the constituents were carried out on column chromatography. Their structures were identified by NMR and MS spectral analysis. RESULT: Six compounds were isolated and elucidated as mogroside IIIA1 (1), siamenoside I (2), mogroside IVa (3), mogroside IVe (4), mogroside V (5) and 11-oxo-mogroside V(6), respectively. CONCLUSION: Compound 1, mogrol-24-O-beta-D-glucopyranosyl (1 --> 2)-[beta-D-glucopyranosyl(1 --> 6) ] beta-D-glucopyranoside, was identified as a new natural product from the fruits of S. grosvenorii. PMID- 21710739 TI - [Study on HPLC fingerprints of Senecio scandens and S. scandens]. AB - OBJECTIVE: To develop an HPLC method for fingerprint study of both Senecio scandens and S. scandens. METHOD: Fingerprints of the two Senecio herbs were compared. And the concentrations of main peaks in them were semi-quantified as chlorogenic acid or hyperoside. Chromatography was performed on a Shiseido Capcell Pak MG II C18 (4.6 mm x 250 mm, 5 microm) column using a gradient elution of acetonitrile-water containing 0.2% acetic acid. And detection wavelength was 360 nm. RESULT: Significant difference was found in the fingerprint of the two herbs. Eleven peaks were picked out for the evaluation of S. scandens and S. scandens, respectively. They were identified to be either organic acid compounds or flavones by HPLC-UV and LC-ESI-MS analysis. And semi-quantification of them showed the concentrations of organic acid compounds and flavones in S. scandens were 2.29- and 15.56- folds of those in S. scandens, respectively. CONCLUSION: The developed HPLC method is suitable for the fingerprint study for both of S. scandens and S. scandens. It is robust and producible enough to be used for the quality evaluation on S. scandens. PMID- 21710740 TI - [Characteristic chromatographic profile of Paeoniae Radix and its application in quality control of crude and processed drugs of different origins and processing methods]. AB - OBJECTIVE: To establish a HPLC method of characteristic chromatographic profile for the quality control of Paeoniae Radix. METHOD: The 67 batches of samples were analyzed on a Polaris C18-A column with a gradient elution of acetonitrile and phosphate solution (pH 3.0) at a flow rate of 1.0 mL x min(-1) and detected at 230 nm. RESULT: Nine main marker peaks were identified and semi-quantificated. By the similarity evaluation software for chromatographic fingerprint of traditional Chinese medicine (Version 2004A) and hierarchical clustering analysis, 67 batches of Paeoniae Radix were classified. CONCLUSION: The method can be applied for quality assessment of Paeoniae Radix. PMID- 21710741 TI - [Isolation of endophytic fungi from Huperzia serrata and their acetylcholinesterase inhibitory activity]. AB - A total of 127 strains of endophytic fungi were isolated from roots, branches and leaves of Huperzia serrata. These strains were identified into 19 genera based on morphological characters and ribosomal DNA (rDNA) sequence analysis, there into Penicillium, Aspergillus and Podospora were dominant populations in H. serrata. From analysis results we found some endophytic fungi showed a certain degree of tissue preference. The isolation rate and colonization rate of stems were both larger than those of leaf and roots. After testing the acetylcholinesterase (AChE) inhibitory activity of these endophytic fungi, a total of 39 endophytic fungi belonging to 15 genera showed AChE inhibition. Eleven endophytic fungi showed potent AChE inhibition, 7 of which were isolated from leaf. The research not only provided theoretical basis for developing and utilizing the resources of endophytic fungi in H. serrata but also showed a new path for searching medicines resource which has AChE inhibitory activity. PMID- 21710742 TI - [Dynamic change of active component content in different parts of Prunella vulgaris]. AB - OBJECTIVE: Through determination of the dynamic change of the active component in different parts of Prunella vulgaris at different growth stages, to find the optimal harvest time. METHOD: Total flavonoids content was determined by using the spectrophotometric method, and the content of ursolic acid and oleanolic acid was determined by HPLC. The contents of ash and extract were determined according to the methods in Chinese Pharmacopeia (2005 edition). RESULT: There existed the active components in all parts of P. vulgaris, but the active component contents in different parts of P. vulgaris of at different growth stages, changed very obviously. CONCLUSION: In Yangtze-Huaihai region, the optimal harvest time of Prunella spike best harvest is at the end of June, and Prunellastem at the end of May. All parts of P. vulgaris have medicinal value. PMID- 21710743 TI - [Testing methods for seed quality of Glycyrrhiza uralensis]. AB - OBJECTIVE: The aim of this study was to optimize the testing methods for seed quality, and to provide a basis for establishing seed testing rules and quality grading standard of Glycyrrhiza uralensis. METHOD: Referring to the International Seed Testing Rules made by ISTA and Rules for agricultural seed testing (GB/T 3543-1995) issued by China, the seed quality of G. uralensis from different collection areas was measured. RESULT AND CONCLUSION: The seed testing methods for quality items of G. uralensis, including sampling, purity analysis, verification of genuineness, weight of 1 000 seeds, percentage germination, moisture content and seed viability of G. uralensis had been initially established. PMID- 21710744 TI - [Effective method for isolation of total RNA from Fagopyrum cymosum callus]. AB - OBJECTIVE: To establish a method for isolation of the total RNA from Fagopyrum cymosum callus. METHOD: The improved method combining that of CTAB extraction with the LiCl precipitation was used to isolate the total RNA from the four F. cymosum callus. The quality of the RNA was detected by UV spectrophotometric analysis, 0.8% non-denaturing agarose gel electrophoresis and RNA reverse transcription. RESULT: The bands of 28S and 18S could be seen clearly by agarose gel electrophoresis, and the value of A260/A280 was between 1.9 and 2.0. The cDNA which was reverse-transcribed by the total RNA showed a wide length rage of 500 bp-5 kb. CONCLUSION: The RNA extracted by this method meets the requirement of reverse transcription-polymerase chain reaction (RT-PCR), construction of cDNA libraries, et al. This improved method can be used to isolate the total RNA from F. cymosum callus with the advantage of simpleness, efficiency and low cost. PMID- 21710745 TI - [Pollen vigor and development of germplasm of Dendrobium officinale]. AB - OBJECTIVE: To provide the theoretical basis and applied technology for breeding superior species of Dendrobium officinale. METHOD: The peroxidase solution was used to test the pollen vigor in different flowering time and storage conditions. Cross, self and opening pollination were conducted in the green house, the subsidiary pollination by insects was carried out outdoors. RESULT: The pollen of D. officinale was still in vigor when the flower faded. The pollen vigor was only 29.4% in the buds, 70.6% in the bloom day, and decreased to 31.9% a week later, it remained still 21.2% 20 days later under the condition of dry and 4 degrees C. The fructification rate was about 82.6% and 7.3%, respectively, when the cross and self pollination performed by hand in the whole flowering time, the rate was 0 in the green house and outdoors. CONCLUSION: The pollen of D. officinale was still in vigor during the whole flowering time, the fructification rate was 0 in the green house and outdoors resulted from the specific structure of flower. The wild resources of D. officinale were protected and germplasm was developed effectively through the artificial cross pollination. PMID- 21710746 TI - [Study on discriminating nephrotoxic components in Zexie]. AB - OBJECTIVE: To sift and identify the nephrotoxic components in Zexie for controlling the quality of the herb. METHOD: The fractions of zexie were prepared by Pre-HPLC, then the nephrotoxicity of the fraction was sifted using LLC-PK1 labelled with fluorescein diacetate and MTT assay. Finally, the compounds in the most obvious nephrotoxic fraction were identified with LC-MS. RESULT: Using MTT and FDA assay, similar results were obtained. Fraction C13 was found to be the most toxic with FDA assay, in which three compounds, alisol C, 16, 23-oxido alisol B and alisol O, were detected and characterized by multi -stage mass spectrometric analysis. CONCLUSION: Alisol C, 16, 23-oxido-alisol B and alisol O in Zexie may cause nephrotoxicity. PMID- 21710747 TI - [Simultaneous characterization of two types of major active components in Kushen by high performance liquid chromatography coupled to multi-stage mass spectrometry]. AB - In this study, a high performance liquid chromatography coupled with multi-stage mass spectrometry method was developed for simultaneous characterization of alkaloids and flavonoids, the main active components, in Kushen with diverse physical and chemical properties. Forty-two major constituents, including sixteen Kushen alkaloids and twenty-six Kushen flavonoids were tentatively identified. Additionally, useful and characteristic fragmentation pathways of two types of Kushen alkaloids, namely cytisine-type and sparteine-type, in positive ions mode were proposed and summarized, which would lay a foundation for the rapid identification of the active ingredients in traditional Chinese medicine Kushen. PMID- 21710748 TI - [Studies on identification and secondary metabolites of endophytic fungi strain E8 from Curcuma wenyujin]. AB - OBJECTIVE: To identify the endophyte strain E8 with high activity from Curcuma wenyujin and study its secondary metabolites. METHOD: The strain E8 was identified by morphological observation and ITS sequence analysis. Manifold chromatographic methods were used to separate and purify the chemical constituents of fermentation broth from strain E8, and their structures were identified by physiochemical properties and spectral data. RESULT: The strain E8 belongs to P. oxalicum. Four compounds were isolated from the fermentation broth of this strain and elucidated as chrysophanol, emodin, secalonic acid A and beta sitosterol. CONCLUSION: The endophyte P. oxalicum was isolated from medicinal plant Curcuma wenyujin for the first time. Four compounds were first isolated from endophytic fungus in C. wenyujin. Thus, microbial fermentation is a new access for these compounds production. PMID- 21710749 TI - [Fingerprint analysis of gamboge by HPLC]. AB - OBJECTIVE: To establish the chromatographic fingerprint for the quality control of gamboge. METHOD: Analysis on a Luna C8 (4.6 mm x 250 mm, 5 microm) column eluted with mobile phases containing acetonitrile and 0.1% glacial acetic acid in water in gradient mode. The flow rate was 1.0 mL x min(-1) and the detection wavelength was at 362 nm. The temperature of column was 25 degrees C. And data of 11 batches of gamboge samples from different sources were analysed by "similarity evaluation for chromatographic Fingerprint of Traditional Chinese Medicine" software. RESULT: Thirteen common peaks were selected in chromatograms, and all the common peeks were separated effectively. CONCLUSION: The precision, repeatability, and stability of this method were satisfying. The method developed can be used to identify and evaluate the quality of gamboge. PMID- 21710750 TI - [Simultaneous assay of paeoniflorin and albiflorin in Paeoniae Radix Alba by QAMS]. AB - OBJECTIVE: To develop a method of quantitative analysis of multi-components by single marker (QAMS) for simultaneously determining paeoniflorin and albiflorin in Paeoniae Radix Alba. METHOD: Using paeoniflorin as the internal reference substance, the relative correction factor (RCF) of albiflorin was determined by HPLC and UPLC with good reproducibility. The contents of paeoniflorin in 16 samples of Paeoniae Radix Alba were authentically determined by the external standard method, and the content of albiflorin was calculated according to the RCF. The contents of these two components in the samples were determined with the external standard method. RESULT: No siginificant differences between the quantitative results of QAMS method and external standard method were observe. CONCLUSION: It is a convenient and accurate method to determine multi-components when some authentic standard substances were unavailable. It can be used to control the quality of Paeoniae Radix Alba PMID- 21710752 TI - [Effects of sinensetin on proliferation and apoptosis of human gastric cancer AGS cells]. AB - OBJECTIVE: To study the effects and mechanisms of sinensetin on proliferation and apoptosis of human AGS gastric cancer cells. METHOD: MTT assay was used to detect the growth inhibition rates of human AGS gastric cancer cells treated with sinsesectin in different concentrations and times. The cell cycle distribution was measured by flow cytometry. The apoptosis was examined by Annexin-FITC/PI staining and DNA fragment analysis. The apoptosis morphology was observed by inverted fluorescence microscope after Hoechst 33342 staining. The protein expressions of p21 and p53 were detected by western blot. RESULT: MTT assay showed that sinensetin inhibited the growth of AGS gastric cancer cells in a dose and time-dependent manner. Sinensetin blocked AGS cells in G2/ M and increased the apoptosis rates of AGS cells in a dose-dependent manner. DNA ladder was observed in cells treated with 60 micromol x L(-1) sinensetin for 48 h. The typical apoptotic morphological changes including cell nucleus shrinkage, chromatin condensation and apoptotic bodies were observed when treated with different dose of sinensetin. Western blot showed that sinensetin increased expressions of p53 and p21 in a dose-dependent manner. CONCLUSION: Sinensetin could inhibit human AGS gastric cancer cells proliferation and induce cell cycle block in G2/M phase and apoptosis. The up regulation of p53 and p21 protein might be one of the mechanisms. PMID- 21710751 TI - [Antiatherogenic effect of Radix Salviae Miltiorrhizae and Fructus Crataegi on experimental atherosclerosis in rats]. AB - OBJECTIVE: To investigate the antiatherogenic effect and possible mechanisms of the extracts of Radix Salviae Miltiorrhizae (RSM) or Fructus Crataegi (FC), as well as their interaction. METHOD: Wistar rats were randomly divided into 2 groups: normal group and model group. The atherosclerotic model rats were injected VD3 and ovalbumin, while fed with high cholesterol diet. After the model was determined successfully, all model rats were divided into normal group, model group, Xuezhikang group, RSM group, FC group, mixture of RSM and FC group. Each group was given the corresponding drugs for 4 weeks. After 12 weeks, blood serum were analyzed for total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C), superoxide dismutase ( SOD), malondialdehyde (MDA) and nitric oxide (NO). And the blood plasma also analyzed for levels of endothelin (ET), 6-keto prostaglandin F1alpha (6-keto-PGF1alpha), thromboxane B2 (TXB2), C-reactive protein (CRP), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor alpha (TNF alpha) and so on. At last, the pathological observation of aorta was carried out. RESULT: Compared with those in model group, the TC, TG, LDL-C, ET, TXB2 and MDA levels and TXB2/PGF1alpha ratio were reduced, while the HDL-C, the serum SOD, No and 6-keto-PGF1alpha level were raised in the intervention groups. Although the levels of CRP, IL-6 and IL-8 were lower than model group, there was no obvious effect on the releasing of TNF-alpha. CONCLUSION: RSM and FC could inhibit the atherogenesis formation and development, which might be due to regulating the lipid metabolism, enhancing the antioxidation, and reducing the release of inflammatory factors. PMID- 21710753 TI - [Effects of total glucosides of peony on expression of inflammatory cytokines and phosphorylated MAPK signal molecules in hippocampus induced by fibrillar Abeta42]. AB - OBJECTIVE: To observe the effects of hippocampal Abeta42 deposition on the expression of inflammatory cytokines and phosphorylated MAPK signal molecules as well as the intervention of AD by total glucosides of paeony (TGP). METHOD: 12 week-old female SD rats were stereotactic injected one-time with a fibrillar Abeta42 positioning hippocampus to replicate AD pathology model and interfered with TGP. The expression of inflammatory cytokines and phosphorylated MAPK pathway signaling molecules were observed by immunohistochemistry (SABC), and SABC images were analyzed by image analysis software. RESULT: Compared with the control group, the IL-1beta, IL-6 and p-p38, p-JNK, p-MEK3/6 positive stained areas of AD pathology model group increased and their staining intensity decreased (the protein expression quantity inversely proportional to the staining intensity), while the IL-1beta, IL-6 and p-p38, p-JNK, p-MEK3/6 positive stained areas of the treatment groups decreased and their staining intensity increased compared with AD pathology model group. CONCLUSION: Abeta42 deposition in hippocampus can induce the brain inflammation and the over-expression of IL 1beta, IL-6 and p-p38, p-JNK, p-MEK3/6. Inhibiting the over-expression of inflammatory cytokines and phosphorylated MAPK signaling molecules may be a major antagonistic mechanism of TGP against AD. PMID- 21710754 TI - [Effect of traditional Chinese medicine injections on type I allergy]. AB - OBJECTIVE: To investigate allergic reactions of traditional Chinese medicine (TCM) injections, and to determine the contents of serum IgE and histamine in sensitized animal. The correlation between the preceding contents in serum and allergic reactions may be found, thus offering experimental evidences for advancing the accuracy of anticipation by type I allergy. METHOD: We carried out passive cutaneous anaphylaxis (PCA) tests,active systemic anaphylaxis (ASA) tests and anaphylactoid reactions using three TCM injections, and determined the contents of serum OVA-sIgE, total serum IgE and histamine in sensitized animals by ELISA method. RESULT: The results of PCA test were negative, and there was no significant difference for total serum IgE level between experimental group and normal saline group. In the study of adjuvant effect in TCM injections + OVA (at the dose level that doesn't cause allergic reactions), the PCA results of SHL and YXC were positive and there was a increase in content of serum OVA-sIgE, while the PCA result of QKL was negative with a unobvious increase in the content of serum OVA-sIgE. The content of total serum IgE wasn't remarkably increased in each group and the results of ASA test were all positive. Three injections all caused anaphylactoid symptoms in guinea pigs in different doses or injection speed and the response intensity was found to be dosage and injection speed dependant. Furthermore, there was no significant difference for the content of total serum IgE in each group, whereas serum histamine concentration in every experimental group was markedly higher than normal saline group. CONCLUSION: SHL and YXC increase the sensitivity of guinea pigs on OVA, and three TCM injections can cause allergic reactions in guinea pig. Allergic reactions of three TCM injections are correlated with specific IgE antibodies and histamine contents. PMID- 21710755 TI - [Research methods of anti-HIV-1 inhibitors targeting at Vif-APOBEC3G axis]. AB - The mammalian APOBEC3G protein (apolipoprotein B mRNA-editing enzyme catalytic polypeptide 3 protein G, APOBEC3G) is an important component of the cellular innate immune response to retroviral infection. APOBEC3G can extinguish HIV-1 (human immunodeficiency virus type 1) infectivity by its incorporation into virus particles and subsequent cytosine deaminase activity to block replication of HIV 1. HIV-1 Vif (viral infectivity factor) suppresses various APOBEC3 proteins through a common mechanism which induces the degradation of target proteins. Therefore, the interrelation of Vif-APOBEC3G has been extensively studied, which represents attractive targets for the development of novel inhibitors. We summarize the papers in which the detection technique and methods have been developed to assay the anti-HIV activity and its mechanism, such as western blotting, co-immunoprecipitation, pulse-chase experiments, bioluminescence resonance energy transfer, biomolecular interaction analysis. This review is towards developing therapeutics aimed at the Vif-APOBEC3G axis. PMID- 21710756 TI - [Application of functional MRI on evaluation of cholinergic drugs and other neurotransmitter drugs and its prospect in traditional Chinese medicine evaluation]. AB - This article summarizes the progress of the application of functional magnetic resonance image (fMRI) on neuropharmacology. Cholinergic drugs are types of neurotransmitters which are usually used to treat neurological disorders. fMRI is widely used in the research of evaluation of cholinergic drugs. This article systematically summerizes the research of drug evaluation on memory, attention, emotion and vision by fMRI using the cholinergic drugs for example. Combined with the charactors and disciplines of traditional Chinese medicine (TCM), this article also makes a prospect of the application of fMRI on traditional Chinese medicine evaluation, especially the drugs on brain disease and emotional modulation. PMID- 21710757 TI - [Effect of buprenorphine on postoperative analgesia following remifentanil-based anesthesia]. AB - BACKGROUND: It is well known that buprenorphine compete with remifentanil for receptor binding. I have examined the effect of buprenorphine administration on postoperative analgesia following remifentanil-based anesthesia. METHODS: In this study, I enrolled 30 patients who had undergone open reduction and internal fixation for fractures at the extremities under general anesthesia. Anesthesia was maintained with continuous infusion of remifentanil, and buprenorphine was administered at the end of surgery. Postoperative pain and side effects were evaluated in all patients. RESULTS: Seventeen patients (57%) required additional analgesic treatment within 1 hour of initial administration of buprenorphine. Buprenorphine therapy in patients who had undergone lower limb surgery was not as effective as that in patients who had undergone upper limb surgery. Incidence of nausea and vomiting in the study population was high(37%). CONCLUSIONS: Buprenorphine is effective to some degree as a postoperative analgesic following remifentanil-based anesthesia, but is not sufficient in cases of severe postoperative pain. PMID- 21710758 TI - [Efficacy of continuous epidural saline infusion in cerebrospinal fluid hypovolemia: report of 5 cases]. AB - We identified the sites of leakage by cisternography in 5 patients with cerebrospinal fluid hypovolemia and treated them by continuous epidural infusion with physiological saline solution. The results showed improvement in symptoms in all 5 patients, and lasting favorable results were obtained in 3 of them. Epidural saline infusion is achieved by inserting an epidural catheter that anesthesiologists routinely use, and the procedure and management are both simple. Adverse effects are the same as for ordinary epidural punctures. If the site of the cerebrospinal fluid leak has been specified and the treatment method is understood by the patient, we think that continuous epidural infusion with physiological saline is safe and effective method of treating cerebrospinal fluid hypovolemia. PMID- 21710759 TI - [Effectiveness of low dose PCEA for postoperative pain after laparoscopic gynecological surgeries--a comparison of laparoscopic ovarian cystectomy and myomectomy]. AB - BACKGROUND: We evaluated the effectiveness of low-dose patient-controlled epidural analgesia (PCEA) in the patients undergoing laparoscopic gynecological surgery, and investigated the difference of postoperative pain between patients for laparoscopic ovarian cystectomy and those for myomectomy. METHODS: Thirteen patients (ASA PS 1 or 2), scheduled for laparoscopic surgery, were enrolled in this study. They were divided into two groups of ovarian cystectomy (group C, n=17) and myomectomy (group M, n=13). After administering epidural bolus of 0.2% ropivacaine 6 ml, droperidol 2.5 mg, and buprenorphine hydrochloride 0.1 mg, PCEA was started: 1 ml x hr(-1) background infusion; 0.2% ropivacaine 54 ml, droperidol 5 mg, and buprenorphine hydrochloride 0.3 mg; 1 ml epidural bolus with a 30-minute lockout interval. We evaluated postoperative pain using visual analogue scale (VAS) at rest and on movement, adverse effects such as respiratory and cardiovascular depression, nausea and vomiting for 48 hours after surgery. RESULTS: VAS at rest with group M was significantly higher than that of group C (11 +/- 2 vs. 6 +/- 2, P=0.048), and VAS on movement of group M was also higher than that of group C (25 +/- 3 vs. 18 +/- 2, P=0.023): however, we found good analgesic effect of less than VAS 3 in both groups. Severe adverse effects were not observed. CONCLUSIONS: These findings suggest that low dose PCEA is effective for patients who undergo laparoscopic gynecological surgery. PMID- 21710760 TI - [Usefulness of preoperative lower limb venous ultrasound imaging in all gynecologic and obstetric surgical cases]. AB - BACKGROUND: Perioperative venous thromboembolism (VTE) has been increasing in gynecologic and obstetric practice. Lower extremity venous ultrasound use in the detection of VTE has been studied and has proven both reliable and efficient. However, there have been very few reports of the preventive effect on VTE-related complication of preoperative lower limb venous ultrasonography in gynecologic and obstetric surgical cases. METHODS: Preoperative lower limb venous ultrasound imaging in gynecologic and obstetric surgical cases were performed to examine the presence or absence of deep vein thrombosis (DVT) and findings indicating the risk of DVT formation. RESULTS: Among 226 subjects, DVT and mural thrombus were observed in two and four subjects, respectively. Vasodilation within the soleus muscle was observed in the left leg in 10 subjects and the right leg in 15 subjects. Venous stasis was observed in 16 subjects. Fatal complications resulting from perioperative VTE could be avoided by preoperative thrombolytic therapy and prophylactic inferior vena cava filter placement based on preoperative screening. CONCLUSIONS: Our results suggest that preoperative lower limb venous ultrasonography was useful for the prevention of serious complications caused by perioperative VTE in gynecologic and obstetric surgical cases. PMID- 21710761 TI - [Control of postoperative nausea and vomiting by preventive administration of dexamethasone]. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) are the most frequent side effects after anesthesia. Patients with persistent PONV continue to be impaired in performing their normal daily activities. We studied the controlling effect of dexamethasone (4 mg) before the induction of general anesthesia in the prevention of PONV. METHODS: Ninety-one patients were divided into respiratory surgery group (dexamethasone N=22, none N=23) and gynecology group (dexamethasone N=22, none N=24), respectively. Dexamethasone group received dexamethasone 4 mg before the induction of general anesthesia. PONV and antiemetic requirements were recorded. RESULTS: In the dexamethasone group (respiratory surgery, gynecology), the incidences of PONV during the initial 24 hour postoperative period were 36.4% (N=8), and 18.2% (N=4), respectively. In the none group, the incidences were 43.5% (N=10), and 41.7% (N=10), respectively Antiemetic requirements were 22.7% (N=5), 9.1% (N=2), 39.1% (N=9), and 20.1% (N=5), respectively (NS). In gynecology group, in almost all the patients droperidol was used in epidural anesthesia. Combination of dexamethasone and droperidol may have greater antiemetic action than a single drug. CONCLUSIONS: Combination therapy with dexamethasone and droperidol may reduce PONV in patients undergoing surgery. PMID- 21710762 TI - [Airway problem during the operation with beach-chair position: a case of arytenoid dislocation and the relationship between intra-cuff pressure of endotrachial tube and the neck position]. AB - Shoulder arthroscopy has been performed in beach-chair position. In our hospital, the postoperative complications of the airway were reported in the patients who had undergone the operation in this position (hoarseness: 4 cases, paralysis of recurrent nerve: 2 cases, arytenoids dislocation: 1 case). We assumed that the neck bending during operation causes these complications. We investigated the relationship between the neck position and the intra-cuff pressure of endotrachial tube. The results showed that the neck bending significantly increases the intra-cuff pressure of endotrachial tube. Therefore, we conclude that it is necessary to pay attention to neck position to avoid postoperative complications of the airway in the patients who have the operation in beach-chair position. PMID- 21710763 TI - [Examination of acute kidney injury after abdominal aortic aneurysm surgery]. AB - BACKGROUND: Either suprarenal or infrarenal aortic clamping markedly reduces renal blood flow. This aortic clamping may cause postoperative acute kidney injury(AKI). METHODS: Fifty-four patients undergoing open abdominal aortic aneurysm (AAA) surgery were included in a retrospective study. Postoperative AKI defined as an absolute increase in serum creatinine (Cre) of more than or equal to 0.3 mg x dl(-1) or an increase in Cre of more than or equal to 50% within 48 hours after the end of the procedure. RESULTS: Thirteen patients developed AKI, but none of them required dialysis. The patients with AKI had higher preoperative Cre, longer operation, longer clamp time and more use of diuretics intra- and postoperatively. CONCLUSIONS: AKI occurred in 24.1% of patients undergoing AAA surgery. Risk factors for AKI were preoperative Cre, operation time, clamp time and use of diuretics. PMID- 21710764 TI - [Adverse events during transcranial muscle evoked potential monitoring]. AB - BACKGROUND: Transcranial muscle evoked potential (TC-MsEP) monitoring is available to assess spinal cord motor tract function for preventing paralysis in spine surgery. Recently, the quality of monitoring has improved. However, adverse events such as torn tracheal tube, bitten tongue, and mandibular fracture are reported. METHODS: We reviewed retrospectively adverse events with TC-MsEP monitoring by Multipulse D-185 (Digitimer Ltd., the U.K.) during spine surgery in our hospital. In addition, we compared the number of cases with transformed tracheal tubes in cases using Multipulse D-185 and in cases using the other stimulation device. RESULTS: Since June 2007, Multipulse D-185 is applied as a stimulating device of TC-MsEP, and we experienced two adverse events of lasceration of tongue and teeth dislocation. There was a significant difference (P=0.02) in the number of transformed tracheal tube between Multipulse D-185 (11 of 20) and the other stimulation device (2 of 19). CONCLUSIONS: It seems that two adverse events were due to excessive masseter muscles contraction with TC-MsEP monitoring. Prevention for bite injury and ventilation strategy for tube occlusion or stenosis using Multipulse D-185 for TC-MsEP are necessary. PMID- 21710765 TI - [Use of StyletScope in a patient with airway injury]. AB - A forty-year old man hanged himself and was transported to our hospital. On arrival his consciousness was clear but he showed dyspnea, dysphagia, and oral bleeding. Tracheal intubation was attempted but was failed and emergency tracheostomy was successfully accomplished. Tracheoplasty was soon scheduled under general anesthesia because of subcutaneous emphysema. An ordinary laryngoscope could not give a view of the larynx at all. Orotracheal intubation was accomplished with StyletScope. It worked very well for the destroyed trachea. StyletScope is a useful device for intubation, especially in difficult airway management. PMID- 21710767 TI - [Case of fulminant-malignant hyperthermia occurring on sixth sevoflurane anesthesia]. AB - We report a case of fulminant-malignant hyperthermia that occurred after five uneventful sevoflurane anesthetic procedures. A 7-year-old girl with bronchial asthma was scheduled for closure of palatal fistula under general anesthesia, after five previous uneventful operations under sevoflurane anesthesia. Anesthesia was induced with propofol and vecuronium, and maintained with nitrous oxide, oxygen, and sevoflurane. Body temperature at the beginning of operation was 37.0 degrees C. After 5 hr 10 min, sudden tachycardia and elevations in body temperature and PET(CO2) were noticed. Sevoflurane was discontinued and body surface cooling, hyperventilation with 100% oxygen, and administration of dantrolene sodium 2 mg x kg(-1), furosemide 4 mg, and 7% NaHCO3 solution 10 ml were started on a suspicion of malignant hyperthermia. Body temperature, heart rate, and PET(CO2) reached to 40.1 degrees C, 190 beats x min(-1), and 60 mmHg, respectively, with metabolic acidosis. Twenty minutes after starting dantrolene infusion, these values decreased to 38 degrees C, 150 beats x min(-1), and 39 mmHg, respectively. Laboratory examination showed that serum potassium, CK, AST, ALT, and LDH concentrations and urine myoglobin level were within normal ranges. Clinical symptoms of this patient fulfilled the diagnostic criteria of fulminant malignant hyperthermia. The trigger drug was considered to be sevoflurane despite the five previous uneventful sevoflurane anesthetic procedures. PMID- 21710766 TI - [Case of Rett syndrome monitored with BIS and neuromuscular monitor during total intravenous anesthesia]. AB - We describe a case of 8-year-old female patient with Rett syndrome undergoing bilateral tonsillectomy and adenotomy. She was monitored with BIS and neuromuscular monitor using TOF during total intravenous anesthesia (TIVA) with propofol, remifentanil, ketamine and rocuronium. A relatively high infusion rate of propofol (10 mg x kg x hr(-1)) was maintained to keep BIS between 60 and 70 during the surgical procedure, and rocuronium 10 mg IV was administered for tracheal intubation without its further administration during the surgical procedure. Although prolonged effects of anesthetics, analgesics and neuromuscular blockade were reported frequently, she took uneventful course during anesthesia and surgery. Her recovery from anesthesia and neuromuscular blockade was also smooth associated with satisfactory sedated states. BIS and neuromuscular monitor may be useful in TIVA for a patient with Rett syndrome. PMID- 21710768 TI - [Patient whose surgery was postponed due to complete atrioventricular block on arrival at operating theater]. AB - An 86-year-old woman with low cardiac function was scheduled to undergo hip fracture surgery. Preoperative electrocardiogram showed complete left bundle brunch block, first degree atrioventricular block, left axis deviation and bigeminy. However, her electrocardiogram had changed to complete atrioventricular block on arrival at operating theater. ACC/AHA guideline on perioperative cardiovascular evaluation and care for non cardiac surgery indicates the assessment of both the urgency of the surgery and cardiac complications. Because complete atrioventricular block is classified to "active cardiac conditions", we decided to postpone the surgery for more detailed evaluation and treatment of cardiac conditions. In spite of the discontinuation of digoxin and carvegilol, complete atrioventricular block continued for a week, and the permanent pacemaker was inserted. The surgery was performed 2 weeks following the insertion of the pacemaker without any problems under combined general and lumbar epidural anesthesia. PMID- 21710769 TI - [Use of sugammadex in a patient with limb girdle muscular dystrophy]. AB - Limb girdle muscular dystrophy, a chronic progressive muscular atrophic disease, leads to high sensitivity to depolarizing and non-depolarizing neuromuscular blocking agents. We report the successful use of the sugammadex in a patient with limb girdle muscular dystrophy (dysferlinopathy, Miyoshi distal myopathy) to reverse rocuronium-induced neuromuscular block. After neuromuscular recovery to a train-of-four ratio = 43%, we administered 3.2 mg x kg(-1) of sugammadex (200 mg) intravenously, reversing neuromuscular blockade to a train-of-four ratio = 95% within 3 min. Sugammadex can be used to reverse rocuronium-induced neuromuscular blockade in patients with limb girdle muscular dystrophy. PMID- 21710770 TI - [Noncardiac ST elevation during the ileus operation]. AB - A 59-year-old man had undergone the esophagectomy for esophageal carcinoma. Subsequently, he was scheduled to undergo the operation for ileus. He had midazolam 1 mg intramuscular injection before the surgery. General anesthesia was induced with thiamylal 62.5 mg and vecuronium 6 mg and maintained with sevoflurane, fentanyl, air and oxygen. ST elevation up to 0.3 mV occurred 45 minutes after the start of the operation, but his hemodynamic status was stable. We administered a nitrovasodilator, but the ST elevation rose gradually without hemodynamic instability until the end of the operation. He was then admitted to the cardiac care unit. The evidence of acute coronary syndrome (ACS) was not found, althrough the ST elevation did not decline to the baseline. Suddenly, a physician watching the patient and his ECG compressed his chest and interrupted its motion. Surprisingly, the ST elevation was improved. In this case, the gastric tube after esophagectomy had been extended to the ileus and the movement of the heart was influenced in the crowded mediastinal space. When ST elevation was found with no evidence of ACS, we must consider other reason than ACS. PMID- 21710771 TI - [Case of coronary vasospasm during lumbar discectomy in prone position]. AB - A 62-year-old man with hypertension was scheduled for discectomy at L4-5 in prone position. Anesthesia was induced with propofol 70 mg, fentanyl 0.75 mg and rocuronium 40 mg and maintained with sevoflurane 0.8-2.0% in oxygen 2 l x min(-1) and nitrous oxide 2 l x min(-1). Just before the end of surgery, ST elevation with hypotension on the ECG was observed for only a few seconds, followed by ventricular fibrillation (Vf). Immediately, lidocaine 50 mg, nitroglycerine 0.5 mg and methoxamine 6 mg were administered intravenously, and sinus rhythm and normal blood pressure returned from Vf within one minute. This case achieved a complete response to quick administration of the coronary vasodilator and antiarrhythmic agent, in this case whose coronary spasm was suspected on the basis of ST elevation in the first place. We have to be careful of various initiating factors for coronary spasm each time during anesthesia as it is difficult to assess its clinical risk, especially in prone position because actual coronary flow is much lower and cardiac resuscitation is difficult in a sudden cardiac complication. PMID- 21710772 TI - [Case of bilateral obturator neuropathy after caesarean section]. AB - We describe a case of bilateral obturator neuropathy after caesarean section. A 33-year-old woman expecting her first baby had rotational acetabular osteotomy 8 and 9 years ago. After the surgery, she complained of weakness in the lower limbs and diagnosed as bilateral obturator neuropathy by orthopedist. Rotational acetabular osteotomy is known as one of the causes of narrow mid-pelvis diameter and it raises probability of caesarean section. Contracted pelvis may cause obturator neuropathy after delivery and we need to exclude complications by epidural blockade. PMID- 21710773 TI - [Anticoagulant therapy in a pregnant patient with prosthetic mitral valve emergency for caesarian section and postoperative bleeding]. AB - Pregnant patients with prosthetic valve need anticoagulation therapy during pregnancy to prevent stuck valve. Regarding the thrombosed valve, there is a dilemma between anticoagulation to prevent further thrombus formation and postoperative bleeding after caesarian section until valve replacement surgery. A 35-year-old woman in her 34th weeks of pregnancy with a thrombus on prosthetic mitral valve was scheduled for emergency caesarian section under general anesthesia. Anticoagulation therapy with heparin was started after admission to the intensive care unit targeting the range between 70-100 second of activated partial thromboplastin time to prevent further thrombus formation. Heparin was administered intravenously (25,000 units per day), but APTT was kept over 110 seconds. Abdominal wall hematoma was detected by percutaneous echo next day and surgery for removal of hematoma was performed. Mitral valve replacement surgery was performed on the postoperative third days successfully. Postoperative anticoagulation therapy with heparin should be started carefully in consideration of physiological change of clotting ability after the termination of pregnancy. PMID- 21710775 TI - [General anesthesia with propofol for a pediatric patient on a ketogenic diet]. AB - There are several specific considerations regarding seizure control during the perioperative period in patients who are on a ketogenic diet (KD). A KD is high in fat and low in protein and carbohydrates and has a long history of use for treatment of intractable seizures in children. Maintaining therapeutic ketosis and modifying the acid-base balance are particularly important for preventing seizures in patients on a KD. We report a case in which a 3-year-old boy with seizure was on a KD and scheduled for the treatment of left undescended testis under propofol anesthesia and acetate Ringer administration. Induction and maintaining of anesthesia using propofol was safe and reasonable for a patient on a KD. PMID- 21710774 TI - [Case of ventricular fibrillation in patients with brugada type electrocardiogram during surgery]. AB - We described a case of ventricular fibrillation in patients with Brugada type electrocardiogram (ECG) during surgery. A 63-year-old man underwent lung lobectomy under combined general and epidural anesthesia. His preoperative ECG showed Brugada type, but he was asymptomatic and did not have a family history of sudden death. Anesthesia was induced using propofol, vecuronium and fentanyl, and maintained using propofol and lidocaine via epidural catheter. One hour into operation, ventricular fibrillation developed. After cardiac compression in a few seconds, sinus rhythm was restored and blood pressure was elevated. When the wound was sutured, ventricular fibrillation occurred again. Defibrillation was attempted immediately and sinus rhythm was restored. We diagnosed coronary spastic angina after acetylcholine challenge test. Previous report describes that the incidence of vasospasm in Brugada type ECG cases is relatively higher than those with the normal ECG. In addition, ventricular fibrillation might be induced by local anesthetics because these agents were administrated 10 minutes before the few events and balance of autonomic nervous system was changed. We conclude that strict monitoring and immediate treatment for ventricular fibrillation are important for anesthetic management in asymptomatic patient with Brugada type ECG. PMID- 21710776 TI - [Peripheral nerve blocks for a patient with spondylolysis undergoing anterior cruciate ligament reconstruction]. AB - A 24-year-old man, 178 cm tall and weighting 82 kg, underwent anterior cruciate ligament reconstruction. We gave general anesthesia and ultrasound-guided combined femoral and sciatic nerve block. Neuraxial blocks increase the risk of neuropathy in the patient with spondylolysis compared with peripheral nerve blocks. In this report, we describe the successful postoperative pain control with peripheral nerve blocks to a patient with spondylolysis. PMID- 21710777 TI - [The i-gel: its efficacy in 120 patients undergoing general anesthesia]. AB - BACKGROUND: The i-gel, which has been introduced into clinical practice in Japan in 2010, has a potential role in maintaining a clear airway during general anesthesia. METHODS: We retrospectively studied the efficacy of the i-gel in 120 patients who had undergone elective surgery under general anesthesia. RESULTS: It was always possible to insert the i-gel at the first attempt. However, there was gasleak around the device in 5 patients, and the device was reinserted. It was possible to obtain adequate ventilation via the i-gel in 117 patients (97.5%) within two attempts at insertion. Insertion was judged easy in 106 patients, somewhat difficult in 12 patients, and difficult in 2 patients. The mean minimum airway pressure at which gas leaked around the device was 26.4 cmH2O, with no gasleak at the airway pressure of 30 cmH2O in 66 of 120 patients. In no patients, did any airway complications, such as airway obstruction, occur during positive pressure ventilation, during the return of spontaneous breathing around the end of surgery, and during emergence from anesthesia. After removal of the i-gel, there was no stain of blood on the device. CONCLUSIONS: We believe that the i-gel is useful in maintaining a clear airway during general anesthesia. PMID- 21710778 TI - [Introduction of hospital information system and anesthesia information management system into the perianesthetic practice at Osaka City University Hospital]. AB - BACKGROUND: Recently, the hospital information systems (HIS) and anesthesia information management systems (AIMS) have been rapidly improved and have been introduced into the clinical practice in Japan drastically; however, few reports have detailed their influences on clinical practice. We here report our experience. METHODS: We introduced HIS (EGMAIN-EX, Fujitsu Co., Ltd.) in our preoperative evaluation clinic and in the postoperative care unit. AIMS (ORSYS, Philips Electronics Japan) was introduced almost only to the intraoperative management. RESULTS: It became easy for us to acquire patient's information and to share it with the medical staffs in the other departments. However, we had to invest large human resources for the introduction and maintenance of the HIS and the AIMS. CONCLUSIONS: Though AIMS is more useful in anesthetic management than HIS, it seems to be more suitable for coordination with the medical staffs in the other departments to use HIS for perioperative management than to use AIMS. PMID- 21710779 TI - [2009 Japanese Society of Latex Allergy guidelines for the safe management of latex allergy]. AB - Latex allergy is an IgE-mediated reaction to natural latex antigen. Operating room equipment frequently includes medical devices, such as surgical gloves, intravenous lines, and urinary catheters, which are made from latex or contain latex. These products can trigger an allergic reaction that can result in anaphylactic shock. Removal of natural rubber and latex-containing products from the operating room and avoidance of external and internal exposure of patients to latex antigen will prevent such allergic reactions. Updated guidelines for the safe management of latex allergy were published in 2009 by the Japanese Society of Latex Allergy. The previous guidelines regarding this topic were published in 2006. The new guidelines consist of 11 chapters that deal with background, exposure to latex antigen and development of sensitization, high-risk groups, natural rubber products, allergic reactions triggered by natural rubber products, diagnosis, latex-fruit syndrome, countermeasures and treatments in emergencies, prevention and safe management in the hospital, countermeasures in daily life, and limits for application of the guidelines. We had a case that required management according to the 2009 guidelines. A 49-year-old male doctor with a history of allergy to latex gloves was scheduled for laparoscopic cholecystectomy under general and epidural anesthesia for recurrent, acute cholecystitis. The anesthesia and operation were performed uneventfully with latex-free medical devices and machines in a latex-safe environment in the operating room under the new guidelines. Safe anesthetic management under the 2009 guidelines should be available for all operations in Japan on patients with latex allergy. PMID- 21710780 TI - [Out-of-hospital tracheal intubation practice by advanced level ambulance crews and reeducation program for skill retention: survey of emergency life saving technicians]. AB - BACKGROUND: Five years have passed since out-of-hospital tracheal intubation training for advanced level ambulance crews (emergency life saving technicians: ELSTs) was started in Japan. Herein, we reviewed results of the initial training and reeducation program. METHODS: Using a questionnaire sent by post, we surveyed out-of-hospital tracheal intubations performed by 19 ELSTs trained at Hiroshima University Hospital. RESULTS AND CONCLUSIONS: Sixty-three tracheal intubations were attempted between 2004 and 2009, of which 56 (89%) were successful and 7 (11%) unsuccessful, with ventilation maintained using another means such as a laryngeal mask airway or bag-valve-mask in the latter cases. Esophageal intubation occurred in 6 cases, but were immediately recognized and dealt with appropriately. Only 1 failed intubation patient, in whom esophageal intubation was changed to bag-valve-mask ventilation, survived until discharge. The average number of yearly intubation attempts (1.2) was small, thus nearly all ELSTs replied that they desired a reeducation program to maintain their intubation skills. Furthermore, some expressed a preference to receive reeducation under conditions close to actual emergency settings. That latter finding reflects the difficulty of out-of-hospital tracheal intubation performed in adverse conditions, such as in inappropriate patient or rescuer positions, and secretion or bleeding in the oral cavity. PMID- 21710781 TI - [From the stethoscope to the scanner, from the cupping glass to transplantation (Brief history of organ transplantation)]. PMID- 21710782 TI - [From the "charitable physician" to the full-time practitioner, the mutation of the medical corps]. PMID- 21710783 TI - [Dynamics and stakes of healthcare personnel training]. PMID- 21710784 TI - [Sociologic evolution of healthcare personnel. From servant to Council of the Nurse Order]. PMID- 21710785 TI - [Social action of the C.G.O.S.: 50 years of evolution]. PMID- 21710786 TI - [Reform of health profession training: an opportunity for new professions]. PMID- 21710787 TI - [From lost professions to transformed professions at public care hospitals - Hospitals of Paris]. PMID- 21710788 TI - [From the National School of Public Health to the School of High Studies on Public Health]. PMID- 21710789 TI - [Evolution of the function of hospital director]. PMID- 21710790 TI - [The expectations of patients in the core of profession evolution]. PMID- 21710791 TI - [For a history of health care services professions: the significance of the labor market]. PMID- 21710792 TI - Amplification of neuromuscular transmission by postjunctional folds. AB - Previously, suggestions have been made that postjunctional folds at the vertebrate motor end plate might, in some way, serve to enhance neuromuscular transmission. This suggestion was examined quantitatively using a model junction with geometry similar to that seen in mammalian 'fast twitch' muscles. It was found that the depolarization produced at the top of an interfold by a quantum of acetylcholine is significantly greater than that produced in the absence of folds because of the series resistance of the interfold myoplasm. As a result, voltage sensitive sodium channels in the postsynaptic membrane are activated more readily. In the model, activation of as few as four interfolds by eight quanta is sufficient for excitation to spread to the remainder of the muscle. With no folds, 19 quanta are required. PMID- 21710794 TI - [The 111st Annual Meeting of the Japanese Surgical Society. Abstracts]. PMID- 21710795 TI - [Angiotensin II antagonists and cancer: the straw fire is extinguished]. PMID- 21710797 TI - [Abstracts of the 23rd Spring Meeting of the Japanese Society of Allergology. May 14-15, 2011, Chiba, Japan]. PMID- 21710798 TI - [Abstracts of the 115th Annual Meeting of the Japanese Ophthalmological Society. May 12-15, 2011. Tokyo, Japan]. PMID- 21710796 TI - [Abstracts of the 86th Annual Meeting of the Japanese Society for Tuberculosis. June 2-3, 2011. Tokyo, Japan]. PMID- 21710799 TI - Recent developments in health law. India's evolving patent laws and WTO obligations: the rejection of Abbott Laboratories' application for a new Kaletra patent. PMID- 21710800 TI - Council selects Stuart Segelnick to receive Tillis Award. PMID- 21710801 TI - Accountability. Too much to do? PMID- 21710802 TI - Onward and upward. PMID- 21710803 TI - What is in a name? A higher cost! PMID- 21710804 TI - Clinical and cost comparisons for hysterectomy via abdominal, standard laparoscopic, vaginal and robot-assisted approaches. AB - INTRODUCTION: The goal of this study was to compare outcomes and costs of four methods of hysterectomy: abdominal, standard laparoscopic, vaginal and robot assisted approaches. METHODS: We conducted a retrospective medical chart review of 1474 consecutive hysterectomy patients with benign indications. RESULTS: Implementation of a robotics program at our institution resulted in reductions in abdominal (33 percent to 8 percent) and laparoscopic (29 percent to 5 percent) hysterectomies. Robotic surgery demonstrated the least blood loss and shortest hospital stays (both p < 0.0001), despite greater case complexity. Overall complication rates were highest for abdominal procedures (14 percent) and similar across minimally invasive approaches (8 to 9 percent). Conversion rates were four times greater in laparoscopic than vaginal or robotic hysterectomy (p = 0.01). Vaginal hysterectomy, performed in the least complex cases, had the lowest major complication rate (1.5 percent) and lowest costs. Costs for robotic surgery were similar to abdominal and laparoscopic approaches when robots were not depreciated as direct surgical expenses. CONCLUSIONS: Vaginal hysterectomy was the least expensive surgical option. Robotic surgery reduced morbidity, conversions and hospital stays even in complex cases, without incurring additional costs beyond purchase of the robotic system. PMID- 21710805 TI - Testosterone: is there a role in heart failure? PMID- 21710806 TI - Quality focus: SDFMC successfully completes Ninth Statement of Work. PMID- 21710807 TI - DAKOTACARE update: DAKOTACARE creates a culture of wellness. PMID- 21710808 TI - Health related quality of life among the people living with HIV. AB - Identifying the level of health related quality of life (HQoL) and their influencing factors in human immunodeficiency virus (HIV) positive people is of extreme importance in implementing an interventional program to support this group. This cross sectional study was an attempt to determine the level and factors associated with HQoL among the people living with HIV. A convenient sample of 82 HIV-infected people from three NGOs and one Infectious Disease Hospital (IDH), were interviewed using an interviewer administered, semi structured questionnaire developed by adopting the "WHOQOL-HIV BREF instrument". A majority of the respondents were with low Quality of Life (QoL) in all the domains of HQoL. The proportion of respondents with low QoL was highest in the domain of social relationship (64.6%) followed by psychological domain (59.8%), physical domain (58.5%), level of independence domain (56.1%), environmental domain (52.4%) and spirituality domain (52.4%) of HQoL. Bivariate analysis revealed that the overall perception of QoL was better in the respondents living in urban area, who were employed and asymptomatic of the centre for disease control (CDC) stage of HIV. The perception of overall health was higher in females, all respondents less than 35 years of age, asymptomatic of the CDC stage of disease and with a current CD4 count greater than 200 cell/mm3. These findings highlight the need for enhanced socio-psychosocial support and a better environment for improving the health related quality of life among people living with HIV. PMID- 21710809 TI - Usefulness of light emitting diode (LED) fluorescent microscopy as a tool for rapid and effective method for the diagnosis of pulmonary tuberculosis. AB - BACKGROUND: Tuberculosis remains world's leading cause of death from a single infectious agent. Fluorescence microscopy offers well-described benefits, comparing with brightfield microscopy, for the evaluation sputum smear samples for tuberculosis. We evaluated the diagnostic performance of fluorescence microscopy, using novel Light Emitting Diode (LED) technology as an alternative to the conventional fluorescence microscopy by Auramine stain as well as brightfield microscopy by Ziehl-Neelsen (ZN) stain. OBJECTIVES: The objective of the study was to see the usefulness of LED fluorescent microscopy in the diagnosis of pulmonary tuberculosis. METHODS: This is a prospective study consisted of 150 sputum samples from the patients of NIDCH, Mohakhali. All samples were stained by auramine and ZN stain at BSMMU and culture was done in Lowenstein-Jensen (L-J) media as gold standard at NTRL, Mohakhali. RESULTS: In this study total 66 (44%) out of 150 sputum specimens were positive for Mycobacterium Tuberculosis by culture. Sensitivity and specificity documented for the different modalities were 95.38% and 94.11%, respectively, for the LED assessment; 68.18% and 90.47%, respectively, for the CFM assessment; and 56.06% and 97.61%, respectively, for brightfield microscopy by ZN stain. The difference in their case detection rate was statistically significant (chi2=119.38, p<0.001). CONCLUSION: Fluorescence Microscopy (FM) is more sensitive than ZN for diagnosis of pulmonary tuberculosis. However, since FM is more sensitive and rapid, using this method (LED) in clinical laboratories with large specimen numbers is recommended. PMID- 21710810 TI - Evaluation of management, control, complications and psychosocial aspects of diabetics in Bangladesh: DiabCare Bangladesh 2008. AB - DiabCare Bangladesh 2008 evaluated the current status of diabetes care in Bangladesh as a continuation of similar cross-sectional study conducted previously in 1998. The current study recruited 1952 patients from general hospitals, diabetes clinics and referral clinics to study current scenario of diabetes management from 01 March 2009 to 31 March 2009. We report the results of type 2 diabetic population who constituted 95.3% (n=1860). Results showed deteriorating glycaemic control with mean HbAlc of 8.6 +/- 2.0% with only 23.1% of the patients achieving American Diabetes Association (ADA) target of <7%. 896 (47.0%) patients were hypertensive and 850 (94.9%) were on antihypertensive medication. 70.8% of patients had LDL levels >2.6 mmol/L; 43.8% had triglycerides >2.2 mmol/L; 44.1% had HDL<1 mmol/L despite 48% of the patients being on lipid lowering agents. Microvascular, macrovascular and severe late complications were reported in 39.2%, 9.9% and 12.1% patients respectively. The rates of diabetic complications were cataract 12.9%, microalbuminuria 15.7%, neuropathy symptoms 31.7%, leg amputation 1.2% and history of angina pectoris was 6.6%. Quality of life evaluation showed that about half of patients have poor quality of life. Also, there was poor adherence to diet, exercise and self testing of blood glucose. In conclusion, majority of the patients were still not satisfactorily controlled. There is an urgent need for effective remedial measures to increase adherence to practice guidelines and to educate both patients and healthcare personnel on importance of achieving clinical targets for metabolic control. PMID- 21710811 TI - Birthweight of the babies delivered by chronic energy deficient mothers in National Nutrition Program (NNP) intervention area. AB - An operational research was done to explore the effect of targeted food supplementation by comparing the birthweight of the babies of two areas (intervention & nonintervention). This record-based study was carried out in Kapasia and Savar upazila of Dhaka division, relying on the primary organizational data of 565 mothers. In the National Nutrition Program (NNP) area only fifty percent moderate to severe malnourished [Chronic Energy Deficiency (CED) II & III] mothers were preferably targeted for onsite food support while 34 of them managed to complete the full course. The mean (+/- SD) BMI of the supplemented mothers were lower (16.21 +/- 0.77) kg/m2, than non-supplemented mothers in Kapasia (17.14 +/- .82) kg/m2 and Savar 17.03 +/- 1.19) kg/m2 area. The mean (+/- SD) birth-weight for non NNP (Savar) category Mean (+/- SD) 2470+/- 366.03 grams, for NNP (Kapasia) non-supplemented group 2720.18 (+/- 368.63) grams and in Kapasia good supplemented group it was 2752.94 (+/- 344.86) grams. Supplemented and non-supplemented mothers of NNP mothers were four times more likely to deliver normal birthweight babies [odds ratio with 95%CI 3.84 (2.01, 7.34)] and [odds ratio with 95%CI 3.90 (2.17, 7.01)] than mothers of control area when adjusted for sociodemographic variables. Birth weight status improved with better CED levels. Birth weight adjusted for CED status, had no significant association with food supplementation. In this study, the basic findings were food supplementation could not increase birth-weight significantly as other effects contributed to improve birthweight were removed. As fully supplemented CED III mothers gave birth almost same weighted babies in comparison to the babies of CED I mothers; the recovery from the probability of being less weighted than the current status might be considered as a potential effect of food supplementation. PMID- 21710812 TI - Lipid profile in minor thalassemic patients: a historical cohort study. AB - Minor beta thalassemia is a disorder without any special symptom which only causes mild anemia. In thalassemic patients accelerated erythropoiesis and enhanced cholesterol consumption have been suggested as the dominant mechanism for low level of lipoproteins. Hyperlipidemia is a risk factor for cardiovascular diseases and hence, low level of serum lipids can act as a protective factor. Because of the differences between social, economic, cultural conditions, dietary habits and genetics patterns among Iranians with other nations, this survey was conducted to verify these parameters among our thalassemia minor subjects. This study was carried out on 100 thalassemia carriers and 200 normal controls. Blood samples were collected and the biochemical evaluation was performed for measuring serum total cholesterol, LDL, HDL, TG, VLD. Descriptive statistical tables, independent t-test, Mann-Whitney and Chi-square were used for analyzing the data. The average values of serum total cholesterol, TG, LDL, HDL and VLDL in thalassemia minor subjects were 163.63 +/- 34.28, 159.74 +/- 157.54, 90.97 +/- 23.94, 34.97 +/- 8.07 and 73.44 +/- 72.43 mg/dl respectively. Moreover, the mean levels of total cholesterol, TG, LDL, HDL and VLDL in normal subjects were 192.77 +/- 37.27, 155.67 +/- 109.58, 123.42 +/- 33.57, 38.02 +/- 15.6 and 71.57 +/- 50.5 mg/dl respectively. The amount of serum total cholesterol and LDL in thalassemia carriers was significantly lower than normal subjects that shows the potential decline of cardiovascular and brain vessels diseases among thalassemia minor subjects compared to control group while other factors between the two groups did not show any significant difference. PMID- 21710813 TI - Higher prevalence of cytomegalovirus pp65 antigenemia associated with lower CD4+ T lymphocyte count. AB - Sixty seven immunocompromised patients were studied prospectively to observe the association of Cytomegalovirus (CMV) pp65 antigenemia with CD4+ T-lymphocyte count, a marker of cellular immunity. This study was conducted in three different groups of immunocompromised patients including HIV infected patients, patients with haematological malignancy and kidney transplanted patients. Result of the study indicate that proportion of severely immunocompromised patients having lower cellular immunity (< or = 200/microl) in all the three groups were comparable and ranged from 44% to 50%. The study also indicated that high prevalence of CMV pp65 antigenemia was associated with lower level of cell mediated immunity (< or = 200/microl). pp65 antigen was detected in 40% of patients with low immunity in contrast with 20% and 22.72% in the patient with intermediate immunity and in group without gross immune deficiency respectively. Lower level of cellular immunity was also associated with high level of CMV pp65 antigen. This was indicated by 75% patients with low immunity having high level of CMV pp65 antigen. It may perhaps be concluded that CMV infection occurred in a higher rate in immunocompromised patients and this is highly associated with the lower immune status of the immunocompromised patients as well as the level of CMV pp65 is higher in the patients with lower cellular immunity. This perhaps indicate that CMV infection is more severe in patients with low cellular immune response. PMID- 21710814 TI - Safety and efficacy of the supracostal access for percutaneous nephrolithotomy: our initial experience. AB - The aim of this study was to evaluate the safety and efficacy of the supracostal access for percutaneous nephrolithotomy (PCNL). Between July 2007 and June 2010, 122 patients underwent PCNL, of whom 28 (23%) had supracostal access. All procedures were performed in a single sitting under general anesthesia. The data were analysed for indications, stone clearance rates and the complications associated with supracostal puncture. The indications for a supracostal access were staghorn stones (50%), pelvis stones (28.5%), calyceal stones in high-lying kidney (18%) and upper ureter/ureteric stones (3.5%). All tracts were made in the 11th intercostal space. Single tract access was used in 22 cases (78%), but 6 (22%) required a second tract. Additional punctures were required mainly for staghorn stones (4 out of 14). Overall, 82% of the patients were rendered stone free or had clinically insignificant residual stones with PCNL monotherapy, and this increased to 96% with secondary procedures. In patients with staghorn stones, they were completely cleared in 78%. Overall complication rate was 28% and included hydrothorax in 3 (10%) patients, which required insertion of a chest tube. One (3.5%) patient developed haemothorax secondary to injury of the intercostal artery, pelvic perforation in 1 (3.5%), perinephric collection in 1 (3.5%), infection/sepsis in 2 (7%). Except those patients who had complication, all other patient recovered uneventfully. Postoperative hospital stay ranged from 2 to 9 days. In conclusion, supracostal access gives high clearance rate with acceptable complications and should not be avoided for fear of chest complications. PMID- 21710815 TI - Free Health Camps at 476 Upazillas in Bangladesh. PMID- 21710816 TI - Pharmacoeconomic evaluation of the MF59--adjuvanted influenza vaccine in the elderly population in Italy. AB - INTRODUCTION: Influenza vaccination has proven effective in the reduction of influenza-like illness (ILI) cases and influenza-related hospitalizations, drug consumption, primary care consultations and deaths in the elderly population. The aim of this study is the assessment of the financial budget impact of a seasonal vaccination program based on the use of the MF59 adjuvanted vaccine as compared with the traditional vaccine or the absence of vaccination in Italian elderly population. METHODS: A pharmacoeconomic simulation model was developed to simulate the effect of the three different vaccination programs during a single influenza season. Health economics and demographic data were taken from specific Italian sources, and vaccine effectiveness data derived from published literature. Direct medical costs were considered according to current Italian prices and tariffs. RESULTS: About 83% of the 12 million people of at least 65 years of age currently resident in Italy can be considered at high risk for influenza complications due to underlying chronic diseases. Absence of vaccination could lead to more than 2 million ILl cases, and 29,000 related deaths. The vaccination program with a coverage rate of 65.6% would lead to an estimated 1.5 million ILl cases (26.9% reduction) with a standard vaccine and to 1.3 million (35.8% reduction) with the MF59 adjuvanted vaccine with a relative increase of avoided cases of 33,1%. The standard vaccination program produced a moderate direct cost increase of about 50 million Euro (+4.6%), whereas the adjuvanted vaccine provided an estimated saving of about 74 million Euro (-6.8%), both compared to the non vaccination. Cost savings were mainly related to hospital admissions avoided in the elderly population (>or=65 years of age). CONCLUSIONS: The vaccination with the MF59 adjuvanted vaccine resulted more effective and cost saving when compared with the standard vaccination and with no vaccination, thus representing the optimal strategy for the elderly population. The standard vaccine, even though a light cost increase, still proved to be effective compared to the null option, with the initial cost for the vaccination program nearly offset by healthcare resources savings obtained during the season. PMID- 21710817 TI - A food borne outbreak of Salmonella enterica serotype Brandenburg as a hint to compare human, animal and food isolates identified in the years 2005-2009 in Italy. AB - INTRODUCTION: There are only a few reported cases of Salmonella enterica serotype Brandenburg foodborne outbreaks in the literature. In Italy Brandenburg is consistently present among the top ten serotypes from human source, but at low prevalences. MATERIALS AND METHODS: Fifty-five S. Brandenburg isolates from human, animal, environmental and food sources, including twelve isolates from a foodborne outbreak, were genotyped by Pulsed-Field Gel Electrophoresis (PFGE). RESULTS AND DISCUSSION: Eight pulsogroups and 19 pulsotypes were detected, with a unique pulsotype being attributed to the outbreak strains. Molecular subtyping can reliably complement the epidemiological investigations. Moreover, mapping molecular types of Salmonella isolates from human and non-human source may greatly contribute to risk assessment, by tracking possible animal sources, so improving cost-effectiveness of the prevention and control strategies. PMID- 21710818 TI - Nigerian dental students' compliance with the 4As approach to tobacco cessation. AB - OBJECTIVE: To assess the Nigerian dental students' present effort at tobacco cessation assistance using the simple stepwise 4As model. METHODS: A cross sectional survey of all the final level dental students in the Nigerian premier dental schools was carried out using a pretested self administered questionnaire. RESULTS: The response rate was 98.9%. Majority (95.6%) of the respondents routinely take history of tobacco use. A total of 93.9% of the respondents routinely advice patient who smoke to quit but only 46.1% actually counsel patient on how to quit. Six-tenth of the respondents knew about nicotine replacement therapy but only 36.1% knew the role antidepressant therapy in tobacco cessation. Majority (87.2%) want cigarette sales to adolescents banned, 73.9% want adverts of cigarettes prohibited, 81.1% want cigarette smoking banned in public areas and only 2.8% will permit smoking in a dental office. CONCLUSIONS: The survey revealed deficiency in compliance to the 4As approach to tobacco cessation among Nigerian dental students. The incorporation of proper tobacco counseling cessation protocol, with emphasis on the pharmacological therapy, into the dental curriculum is therefore desirable. Dental professionals at all levels should be involved effectively with tobacco cessation to significantly reduce the morbidity and mortality of tobacco use. PMID- 21710819 TI - Early co-circulation of different clades of influenza A/H1N1v pandemic virus in northern Italy. AB - INTRODUCTION: The spatial diffusion over time of pandemic influenza A/HINI virus (A/HIN1v) was surveyed in Northern Italy (nearly 10 million inhabitants)from April to December 2009, and the molecular characteristics of circulating viruses were analyzed to identify the appearance of drift variants. About 45% of analyzed samples were laboratory-confirmed cases of A/HINlv. Sporadic cases occurred until the middle of June 2009, then, case numbers began to increase delineating distinct epidemiological phases of viral circulation. METHODS: RNA was extracted using RNeasy Mini kit (QIAGEN GmbH, Germany). Virological diagnosis of A/HINlv infection was carried out by real-time RT-PCR assay. Sequence analysis of hemagglutinin (HA) gene was performed through a RT-PCR assay specific for a 995 bp fragment (nt. 64-1,058) in the HAl domain. The nucleotide sequences were obtained by automated DNA sequencing. The HAl sequences were aligned with other sequences collected from GenBank database by ClustalX software. The multiple sequence alignment was used to perform a basic phylogenetic analysis and a phylogenetic tree from HA sequences was constructed. RESULTS: The HA gene sequences ofA/HINlv analyzed segregated into three genetically distinct clades and were characterized by the appearance of amino acid variations that were progressively fixed in the field viral population under scrutiny. CONCLUSIONS: These data suggest an early co-circulation of genetically distinct A/HNINv variants and emphasize the importance of a close molecular surveillance to detect rapidly the spread of new viral variants and to define their epidemiological impact. PMID- 21710820 TI - Community survey on blood donation practices in a northern state of Nigeria. AB - INTRODUCTION: Volunteer blood donors account for less than half of the blood supply in developing countries; and few countries have mobilized efforts to encourage voluntary blood donation (VBD). The objective of this study was to determine the knowledge and blood donation practices among adults in a state in Northern Nigeria. METHODS: Descriptive cross sectional study using multistage sampling technique was carried out among 936 respondents. Semi structured interviewer administered questionnaire was used to generate relevant data and information from the respondents. Data entry and analysis was done using EPI-info software package. RESULTS: The knowledge of the respondents on blood donation was low. Less than half 432 (46.2%) knew some indications for blood transfusion. Two hundred and twelve (22.6%) respondents had donated blood in the past but only 1% of these were VBD while 95% were donations based on blood needs by family members, relations and friends. Few respondents 112 (12%) had received blood transfusion in the past, and the main source of blood transfused was paid commercial donors 50 (44.6%). The fear of HIV screening was a major hindrance and limitation to voluntary blood donation among respondents. CONCLUSION: The gaps in knowledge & practice of VBD can be addressed through public awareness campaigns, and motivational programmes such as free medical services for voluntary blood donors. PMID- 21710821 TI - Air pollution and related respiratory diseases: the experience of a local health authority in Liguria (north Italy). AB - BACKGROUND: Numerous epidemiological studies have shown that air pollution due to both industry and heavy traffic has short- and long-term effects on health. The study was carried out in an industrial area with heavy urban and motorway traffic in the Province of Genoa (Italy). METHODS: The study was carried out from June 2005 to July 2008. An epidemiologic study was conducted by monitoring an elementary/middle school situated in an area of recent industrial development and an elementary/middle school located in an area free from sources of industrial pollution. Furthermore, we conducted an investigation of workers in commercial premises situated in one area of heavy vehicular traffic. In the study areas, environmental monitoring campaigns were carried out in order to determine the association between indoor and outdoor pollution and respiratory disorders. RESULTS AND DISCUSSION: The study did not bring to light any specific health problems attributable with certainty to industrial emissions. The impact of pollution caused by motor traffic proved to be greater than that due to industrial emissions. More exhaustive sampling campaigns should be implemented in order to quantify the effects of specific sources of emissions and to correlate these sources with pollutants (industry, urban traffic, motorway traffic). PMID- 21710823 TI - Procalcitonin: a possible marker of invasive fungal infection in high risk patients? PMID- 21710822 TI - Epidemiologic pattern of falls among inpatients in Ain Shams University Hospitals in Cairo, Egypt. AB - BACKGROUND: Patient falls and injuries during hospitalization is a good quality indicator of safety of inpatients. Data on inpatients falls are deficient in Egyptian hospitals. Ain Shams university hospitals do not have any recording system for falls. AIM: This study aimed at estimating the incidence density of falls and describing pattern and risk factors contributing to falls in Ain shams university hospitals. SUBJECTS AND METHODS: A prospective follow up study was conducted on inpatients admitted to Ain Shams university hospitals. Patients were followed up for a maximum of two weeks for the occurrence of fall. An interview questionnaire addressed to in-patients was designed to investigate the incident of fall. Type of fall, provisional cause, consequences, night or day timing of fall, walking condition in hospital and past history of fall were among the factors investigated in the incident of fall. Questionnaire assessing the basic and instrumental daily activities for the elderly (>60 years) was completed. RESULTS: 1779 patients were included in the study in eight different wards with a mean age of 41.8 years. The incidence density of falls was 9 per 1000 patient days. Logistic regression analysis identified male gender, walking difficulties in-hospital and history offalls before hospitalization as independent risk factors for falls among below 60 years patients. CONCLUSION: Incidence of falls is relatively high among the studied university hospitals. Identified risk factors differed among adults compared to elderly. RECOMMENDATIONS: Measuring, monitoring and assessing fall rates are strongly recommended using a valid and reliable tool to improve quality of health services. PMID- 21710824 TI - Tick removal. AB - Ticks are blood feeding external parasites which can cause local and systemic complications to human body. A lot of tick-borne human diseases include Lyme disease and virus encephalitis, can be transmitted by a tick bite. Also secondary bacterial skin infection, reactive manifestations against tick allergens, and granuloma's formation can be occurred. Tick paralysis is a relatively rare complication but it can be fatal. Except the general rules for tick bite prevention, any tick found should be immediately and completely removed alive. Furthermore, the tick removal technique should not allow or provoke the escape of infective body fluids through the tick into the wound site, and disclose any local complication. Many methods of tick removal (a lot of them are unsatisfactory and/or dangerous) have been reported in the literature, but there is very limited experimental evidence to support these methods. No technique will remove completely every tick. So, there is not an appropriate and absolutely effective and/or safe tick removal technique. Regardless of the used tick removal technique, clinicians should be aware of the clinical signs of tick-transmitted diseases, the public should be informed about the risks and the prevention of tick borne diseases, and persons who have undergone tick removal should be monitored up to 30 days for signs and symptoms. PMID- 21710825 TI - Comparison of physiological motion filters for in vivo cardiac ARFI. AB - Acoustic radiation force impulse (ARFI) imaging is being utilized to investigate mechanical properties ofcardiac tissue. The underlying physiological motion, however, presents a major challenge. This paper aims to investigate the effectiveness of various physiological motion filters using in vivo canine data with a simulated ARFI push pulse. Ideally, the motion filter will exactly model the physiological motion and, when subtracted from the total displacement, leave only the simulated ARFI displacement profile. We investigated three temporal quadratic motion filters: (1)interpolation, (2) extrapolation and (3) a weighted technique. Additionally, the various motion filters were compared when using 1-D versus 2-D autocorrelation methods to estimate motion. It was found that 2D autocorrelation always produced better physiological motion estimates regardless of the type of filter used. The extrapolation filter gives the most accurate estimate of the physiological motion at times immediately after the ARFI push (0.1 ms) while a close-time interpolation filter using displacement estimates at times before full tissue recovery gives the most accurate estimates at later times after the ARFI push (0.7 ms). While improvements to the motion filter during atrial systole and the onset of ventricular systole are needed, the weighted, close-time interpolation and extrapolation motion filters all offer promising results for estimating cardiac physiological motion more accurately, while allowing faster ARFI frame rates than previous motion filters. This study demonstrates the ability to eliminate physiological motion in a clinically feasible manner, opening the door for more extensive clinical experimentation. PMID- 21710826 TI - Software beamforming: comparison between a phased array and synthetic transmit aperture. AB - The data-transfer and computation requirements are compared between software based beamforming using a phased array (PA) and a synthetic transmit aperture (STA). The advantages of a software-based architecture are reduced system complexity and lower hardware cost. Although this architecture can be implemented using commercial CPUs or GPUs, the high computation and data-transfer requirements limit its real-time beamforming performance. In particular, transferring the raw rf data from the front-end subsystem to the software back end remains challenging with current state-of-the-art electronics technologies, which offset the cost advantage of the software back end. This study investigated the tradeoff between the data-transfer and computation requirements. Two beamforming methods based on a PA and STA, respectively, were used: the former requires a higher data transfer rate and the latter requires more memory operations. The beamformers were implemente;d in an NVIDIA GeForce GTX 260 GPU and an Intel core i7 920 CPU. The frame rate of PA beamforming was 42 fps with a 128-element array transducer, with 2048 samples per firing and 189 beams per image (with a 95 MB/frame data-transfer requirement). The frame rate of STA beamforming was 40 fps with 16 firings per image (with an 8 MB/frame data transfer requirement). Both approaches achieved real-time beamforming performance but each had its own bottleneck. On the one hand, the required data-transfer speed was considerably reduced in STA beamforming, whereas this required more memory operations, which limited the overall computation time. The advantages of the GPU approach over the CPU approach were clearly demonstrated. PMID- 21710827 TI - Lesion detectability in diagnostic ultrasound with short-lag spatial coherence imaging. AB - We demonstrate a novel imaging technique, named short-lag spatial coherence (SLSC) imaging, which uses short distance (or lag) values of the coherence function of backscattered ultrasound to create images. Simulations using Field II are used to demonstrate the detection of lesions of varying sizes and contrasts with and without acoustical clutter in the backscattered data. B-mode and SLSC imaging are shown to be nearly equivalent in lesion detection, based on the contrast-to-noise ratio (CNR) of the lesion, in noise-free conditions. The CNR of the SLSC image, however, can be adjusted to achieve an optimal value at the expense of image smoothness and resolution. In the presence of acoustic clutter, SLSC imaging yields significantly higher CNR than B-mode imaging and maintains higher image quality than B-mode with increasing noise. Compression of SLSC images is shown to be required under high-noise conditions but is unnecessary under no- and low-noise conditions. SLSC imaging is applied to in vivo imaging of the carotid sheath and demonstrates significant gains in CNR as well as visualization of arterioles in the carotid sheath. SLSC imaging has a potential application to clutter rejection in ultrasonic imaging. PMID- 21710828 TI - Effect of graphite concentration on shear-wave speed in gelatin-based tissue mimicking phantoms. AB - Elasticity-based imaging modalities are becoming popular diagnostic tools in clinical practice. Gelatin-based, tissue mimicking phantoms that contain graphite as the acoustic scattering material are commonly used in testing and validating elasticity-imaging methods to quantify tissue stiffness. The gelatin bloom strength and concentration are used to control phantom stiffness. While it is known that graphite concentration can be modulated to control acoustic attenuation, the impact of graphite concentration on phantom elasticity has not been characterized in these gelatin phantoms. This work investigates the impact of graphite concentration on phantom shear stiffness as characterized by shear wave speed measurements using impulsive acoustic-radiation-force excitations. Phantom shear-wave speed increased by 0.83 (m/s)/(dB/(cm MHz)) when increasing the attenuation coefficient slope of the phantom material through increasing graphite concentration. Therefore, gelatin-phantom stiffness can be affected by the conventional ways that attenuation is modulated through graphite concentration in these phantoms. PMID- 21710830 TI - Celebrating 25 years of service to oncologists. PMID- 21710829 TI - Performance of new GPU-based scan-conversion algorithm implemented using OpenGL. AB - A new GPU-based scan-conversion algorithm implemented using OpenGL is described. The compute performance of this new algorithm running on a modem GPU is compared to the performance of three common scan-conversion algorithms (nearest-neighbor, linear interpolation and bilinear interpolation) implemented in software using a modem CPU. The quality of the images produced by the algorithm, as measured by signal-to-noise power, is also compared to the quality of the images produced using these three common scan-conversion algorithms. PMID- 21710831 TI - Restrospective on the last quarter-century in medical oncology. PMID- 21710832 TI - Restrospective on the last quarter-century in surgical oncology. PMID- 21710833 TI - Restrospective on the last quarter-century in radiation oncology. PMID- 21710834 TI - Restrospective on the last quarter-century in hematologic oncology. PMID- 21710835 TI - Chronic inflammation and cancer: the role of the mitochondria. AB - Accumulating evidence shows that chronic inflammation can promote all stages of tumorigenesis, including DNA damage, limitless replication, apoptosis evasion, sustained angiogenesis, self-sufficiency in growth signaling, insensitivity to anti-growth signaling, and tissue invasion/metastasis. Chronic inflammation is triggered by environmental (extrinsic) factors (eg, infection, tobacco, asbestos) and host mutations (intrinsic) factors (eg, Ras, Myc, p53). Extensive investigations over the past decade have uncovered many of the important mechanistic pathways underlying cancer-related inflammation. However, the precise molecular mechanisms involved and the interconnecting crosstalk between pathways remain incompletely understood. We review the evidence implicating a strong association between chronic inflammation and cancer, with an emphasis on colorectal and lung cancer. We summarize the current knowledge of the important molecular and cellular pathways linking chronic inflammation to tumorigenesis. Specifically, we focus on the role of the mitochondria in coordinating life- and death-signaling pathways crucial in cancer-related inflammation. Activation of Ras, Myc, and p53 cause mitochondrial dysfunction, resulting in mitochondrial reactive oxygen species (ROS) production and downstream signaling (eg, NFkappaB, STAT3, etc.) that promote inflammation-associated cancer. A recent murine transgenic study established that mitochondrial metabolism and ROS production are necessary for K-Ras-induced tumorigenicity. Collectively, inflammation-associated cancers resulting from signaling pathways coordinated at the mitochondrial level are being identified that may prove useful for developing innovative strategies for both cancer prevention and cancer treatment. PMID- 21710836 TI - The relationship between inflammation and cancer is analogous to that between fuel and fire. PMID- 21710837 TI - Inflammation in cancer: a therapeutic target? PMID- 21710839 TI - Darbepoetin alfa controversies, from dosage issues to safety concerns: the larger lesson. PMID- 21710838 TI - Iron and the anemia of chronic disease: vindication for the non-essential role of iron supplementation. PMID- 21710840 TI - HER2-targeted therapies: how far we've come--and where we're headed. PMID- 21710841 TI - High-dose interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma: still the standard. PMID- 21710842 TI - Seroepidemiology of toxoplasmosis in renal patients. AB - Toxoplasmosis is an important parasitic disease in immunosuppressed patients. This prospective study was conducted to determine the seroprevalence, associated risk factors and the incidence of clinically confirmed toxoplasmosis among renal patients at the University of Malaya Medical Center, Kuala Lumpur, Malaysia. We interviewed 247 renal patients, each of whom answered an epidemiological questionnaire, and collected blood samples for measurement of anti-Toxoplasma IgG and IgM antibodies by ELISA. Overall seroprevalence of latent toxoplasmosis was observed in 126 (51%) renal patients. Race (Malays), marital status (married) and primary level of education, were all factors associated with a greater chance of Toxoplasma infection. A case of clinically confirned toxoplasmosis was diagnosed in a renal transplant recipient as a result of immunosuppression. Based on the findings obtained, this preliminary study shows a high prevalence of latent toxoplasmosis in renal patients. Risk factors may have significantly contributed to Toxoplasma acquisition in these patients. We recommend further studies be carried out to monitor for trends in toxoplasmosis among immunosuppressed patients. PMID- 21710843 TI - Overview of human clonorchiasis sinensis in China. AB - The objective of the survey was to determine the current status, trends and transmission factors for Clonorchis sinensis infection in China and to provide updated information for development control strategies. This was part of a nationwide survey of major human parasitic diseases carried out during 2000-2002 sampled by the stratified randomized cluster sampling method. Fecal examination was conducted using the Kato-Katz thick smear method and egg count per gram of feces (EPG) was determined for the egg-positive patients. A questionnaire and a case-control study were applied to analyze the transmission factors for C. sinensis infection. The overall prevalence rate of C. sinensis infection was 0.58% in 356,629 residents from 688 sampled pilot sites in 31 provinces, autonomous regions and municipalities (PAM) of China. The infection rates of C. sinensis in Guangdong, Jilin, Guangxi Zhuang autonomous region, Anhui and Heilongjiang were higher than the other PAM, they were 5.35, 4.77, 3.71, 0.67 and 0.48%, respectively. In Guangxi, moderate and heavy infections were found in 29.14% and 11.52%, respectively, of the total infected. Heavy infections were not found in any of the other provinces except for 2 heavily infected cases in Heilongjiang. The prevalence rate increased with age for residents aged < 35 years and remained at high levels in those aged 25-60 years. The infection rate in males was 1.64 times that of females. The C. sinensis egg positivity rates in fishermen, businessmen, physicians and teachers were higher than others. Among the 38 ethnic groups, the prevalences in the Han (3.20%) and the Zhuang (3.15%) were the highest; no cases were found among the Zang, Miao, Man and other 29 ethnic groups. Significant differences in prevalences were also found among counties of different economic levels. C. sinensis infection is prevalent in hilly and plains regions of northeast and southcentral China, representing two highly endemic areas in the North and the South. An increasing trend in prevalence was seen in endemic areas. The infection was mainly detected in young and middle aged males. A higher prevalence was observed in those with a better education and a higher income. Consumption of raw (or under-cooked) fresh water fish or shrimp were the main risk factors responsible for transmission of the parasite. PMID- 21710844 TI - Gastrointestinal helminthes in stray cats (Felis catus) from Aizawl, Mizoram, India. AB - Gastrointestinal helminthes were collected from 27 necropsied stray cats (Felis catus) in Aizawl, Mizoram, India from January 2005 to April, 2009. The examined cats showed mixed helminthic infections, with an overall prevalence of 85.2%. Five nematodes, 2 cestodes and 1 trematode were identified. The most common helminthes were Taenia taeniaeformis (70.4%), Toxocara cati (59.3%), Physaloptera praeputalis (44.4%), Dipylidium caninum (40.7%), Spirocerca felineus (18.5%), Gnathostoma spinigerum (11.1%), Ancylostoma tubaeforme (7.4%) and Opisthorchis sp (3.7%). Co-infection with T. taeniaeformis and T. cati was seen in 48.1% (13/27), indicating the possibility of these cats were paratenic hosts for toxocariasis in cats. PMID- 21710845 TI - Population dynamics of adult mosquitoes (Diptera: Culicidae) in malaria endemic villages of Kuala Lipis, Pahang, Malaysia. AB - Mosquitoes in malaria endemic areas needs to be monitored constantly in order to detect demographic changes that could affect control measures. A 12-month mosquito population survey was conducted in several malaria endemic areas in Pos Lenjang, Kuala Lipis, Pahang, Malaysia. Collection of mosquitoes using a human landing catch technique was carried out indoors and outdoors for 12 hours from 7:00 PM to 7:00 AM for 42 nights. Anopheles maculatus Theobald (31.0%), Armigeres flavus Leicester (11.3%), Armigeres annulitarsis Leicester (11.0%), Culex vishnui Theobald (9.6%) and Aedes albopictus Skuse (7.0%) were the predominant species caught in the study area. The salivary gland and midgut of all anopheline mosquitoes were dissected to determine the presence of malaria parasites but none were positive. A high rate of human biting by An. maculatus was detected during December, but the rate was lower in January. Mosquito larvae were carried by the rapid current of the river downstream causing a decrease in the larvae population. Of the five predominant species, only Ar. annulitarsis exhibited a significant positive correlation in numbers with monthly rainfall (p < 0.05). An. maculatus biting activity peaked during 10:00 PM to 11:00 PM. Ae. albopictus, Ar. annulitarsis, and Ar. flavus exhibited similar activities which peaked during 7:00 PM to 8.00 PM. PMID- 21710846 TI - The efficacy and physical condition of olyset insecticide-treated nets after 5 years use in rural Lao PDR. AB - We assessed the insecticidal efficacy of Olyset nets after 5 years of use in rural villages of Lao PDR and evaluated the relationship between the physical condition of the nets and their insecticidal effect. Our results showed that most of the Olyset nets remained effective after 5 years of use; however, there was no significant relationship between the physical condition of the nets (ie, presence of holes, level of stains) and the insecticidal effect. The presence of large holes in polyester nets compared to the Olyset nets suggest the Olyset nets are stronger; however, nearly half of Olyset nets had small holes or had been previously repaired. Interestingly, the insecticide concentration and knockdown (KD) rate for 3 stored nets was low compared to the other nets routinely used in the house. To maintain the effectiveness of Olyset nets in rural villages of Lao PDR and other areas, residents should be advised to repair and store the nets appropriately and avoid exposure to high temperatures and direct sunlight for long periods. PMID- 21710847 TI - Temporal and spatial distribution, sex ratio and fecundity of the eye fly siphunculina funicola (Diptera: Chloropidae) at aggregation sites during diurnal and nocturnal periods. AB - The present study was aimed to determine the distribution and abundance of the eye fly Siphunculina funicola (de Meijere) in Thailand and to investigate the sex ratio and fecundity of eye flies from aggregation sites collected during the day time and night-time. The flies were collected from several provinces in central Thailand and Phuket in the south. Observations were regarding the relative abundance of eye flies in different regions and seasons. During 2007 and 2008, large populations of eye flies were noted at resting sites in central Thailand with both day and night collections. Males flies outnumbered female flies. Smaller populations were seen in Chumphon and Surat Thani Provinces with increasing numbers in Krabi and Phuket Provinces in the south. The gravid rate was nil in the few females collected in Chomphon and Surat Thani but were 3.9% and 36.3% in Krabi and Phuket, respectively. The gravid rates were higher during the dry season or during dry spells than during wet and rainy periods, suggesting egg retention by the females when oviposition sites (presumably soil) were dry. Numerous day and night collections were made in Chon Buri Province. In most collections males predominated but there was no differences in the numbers of flies collected during the two time periods. There was a slightly greater percentage of females (still lower than males) during the night collections. During the dry and hot season, due to lack of optimum oviposition sites because of dryness, the eggs were retained in the females. A series of day time collections at the end of April 2008 and in February-March 2009 had higher numbers of gravid females. Day time collections in May 2008 (start of the rainy season) showed a moderate number of gravid females, but the gravid rates were low during the rainy season, indicating higher oviposition activity by females. PMID- 21710848 TI - Molluscicidal effect of Eomecon chionantha alkaloids against Oncomelania hupensis snails. AB - The molluscicidal effects of Eomecon chionantha alkaloids (ECA) against Oncomelania hupensis snails were determined by immersion method. The molluscicidal effect was positively related to ECA concentration, immersion time and temperature of the immersion solution. The mortality of the snails reached 100% by 72 hours in ECA at a concentration of 2.5 mg/l at 25 degrees C. The alanine aminotransferase (ALT) level of liver cells treated with ECA was higher than controls at 24 and 36 hours (57.7 and 60.3 U/l versus 39.2 and 49.2 U/1, respectively) but the level decreased at 48-72 hours after treatment. The decrease points to the toxic effect of ECA against liver cells. After ECA treatment, the liver cells were edematous with swollen or disintegrating nuclei; they were enlarged and had vacuolated rER; they had dilated and vesiculated mitochondria with broken crests further indicating a hepatotoxic effect of ECA in O. hupensis snails. ECA has a molluscicidal effect that may be of practical use in the field to control O. hupensis snails. PMID- 21710849 TI - Detection of dengue infection by combining the use of an NS1 antigen based assay with antibody detection. AB - We analyzed the utility of a commercial NS1 antigen based ELISA (Panbio Dengue Early ELISA) for detection of dengue infection during the early acute phase and anti-Dengue IgM capture ELISA for detecting dengue infection in patients in dengue endemic settings. A total of 145 serum samples collected from febrile suspected dengue patients were tested for the presence of anti-dengue IgM antibody using IgM antibody Capture ELISA (MAC ELISA) and the presence of dengue virus antigen using PanBio Dengue NS1 Antigen Capture ELISA. Of the 145 patient samples tested, 88 (60.7%) were positive for either NS1 antigen or IgM antibody by MAC ELISA. Dengue NS1 antigen-capture ELISA gave an overall positivity rate of 65.9% (58/88), and IgM ELISA gave an overall positivity rate of 60.2% (53/88). Only NS1 antigen can be used to test during the first two days of fever. MAC ELISAbegins to show positive by the third day of illness and gradually its positivity increases. From Day 3 to Day 7, no significant difference in detection rates was seen between the NS1 assay and MAC ELISA. The NS1 antigen assay may be a useful tool for detecting dengue infection during first few days of fever. PMID- 21710850 TI - Detection of distribution of avian influenza H5N1 virus by immunohistochemistry, chromogenic in situ hybridization and real-time PCR techniques in experimentally infected chickens. AB - Ten specific pathogen free (SPF) chickens were inoculated intranasally with avian influenza virus subtype H5N1. Evaluation revealed distribution of the virus in twelve organs: liver, intestine, bursa, lung, trachea, thymus, heart, pancreas, brain, spleen, kidney, and esophagus. Immunohistochemistry (IHC), chromogenic in situ hybridization (CISH), and real-time polymerase chain reaction (PCR) were developed and compared for detection of the virus from the organs. The distribution of avian influenza H5N1 in chickens varied by animal and detecting technique. The heart, kidneys, intestines, lungs, and pancreas were positive with all three techniques, while the others varied by techique. The three techniques can be used to detect avian influenza effectively, but the pros and cons of each technique need to be determined. The decision of which technique to use depends on the objective of the examination, budget, type and quality of samples, laboratory facilities and technician skills. PMID- 21710851 TI - Viral factors involved in adapter-related protein complex 2 alpha 1 subunit mediated regulation of human immunodeficiency virus type 1 replication. AB - The presence of siRNA against adapter-related protein complex 2 alpha 1 subunit (AP2alpha) enhances human immunodeficiency virus type 1 (HIV-1) replication by up regulating nuclear transport of viral genome. In this report, we examined possible viral factors involved in AP2alpha-mediated regulation of HIV-1 replication, namely, Gag matrix protein (MA), integrase (IN) and Vpr. Replication of mutant viruses lacking the nucleophilic property of one of these viral proteins was significantly enhanced by treating cells with AP2alpha siRNA, indicating that Gag MA, IN or Vpr is not specifically involved in AP2alpha mediated enhancement of viral replication. In contrast, AP2alpha siRNA showed no effect on the level of gene transduction mediated by HIV-1-derived lentiviral vector (LV). Although virus-like LV particle and parental HIV-1 particle are composed of almost equivalent viral structural proteins, LV particles lack three accessory proteins, Vif, Vpr and Vpu, and a large portion of the HIV-1 genome. Vif, Vpr and Vpu were dispensable for AP2alpha siRNA-mediated enhancement of HIV 1 replication, indicating that a particular part of the HIV-1 genomic fragment deleted in the LV genome might be required for the enhancing effect of AP2alpha siRNA on viral replication. Taken together, these results suggest that an as yet undetermined gene fragment of the HIV-1 genome is involved in AP2alpha-mediated regulation of HIV-1 replication. PMID- 21710852 TI - Seroprevalence of cytomegalovirus infection in pregnant women and associated role in obstetric complications: a preliminary study. AB - The objective of this study was to determine the seroprevalence of cytomegalovirus (CMV) infections through antenatal screening data and the association of this virus with obstetric complications. Serum samples from 125 apparently healthy pregnant women sent for antenatal screening from various hospitals in Malaysia between January 2007 and December 2008, were examined for CMV specific IgM and IgG antibodies using an enzyme-linked immunosorbent assay method. Of the 125 pregnant women tested, anti-CMV IgG antibody was found in 105 (84%) of the cases and anti-CMV IgM in 9 cases (7.2%). Both CMV IgM and IgG were also found in another 37 women whose serum samples were sent for investigation of various obstetric complications: 17 cases of spontaneous abortions, 15 cases of fetal anomalies detected during ultrasound examination, 1 case of incomplete abortion, 3 cases with premature delivery of infant with congenital anomalies and 1 case of infertility. Our preliminary data which only represented a small study group has shown the prevalence of CMV infection among the local population and the association of CMV in obstetric complications. PMID- 21710853 TI - Longitudinal ocular survey of 202 Filipino patients with multi-bacillary (MB) leprosy treated with 2 year WHO-multiple drug therapy. AB - The aim of this study was to describe the ocular conditions in multibacillary (MB) leprosy patients treated with 2 year WHO multiple drug therapy (MDT), consisting of dapsone, clofazimine and rifampin, a regimen expected to reduce ocular complications of leprosy. We conducted comprehensive eye examinations in 202 Filipino MB leprosy patients before, during, and after WHO 2 year MDT. Assessments were carried out for at least 5 years. Inflammatory "lepra" reactions occurred in 62% (reversal reaction, 52%; erythema nodosum leprosum, 10%); most were mild. Eye abnormalities consisted mostly of diminished corneal sensitivity before MDT (6%) and lagopthalmos (n = 7, 3.4%). Six of 7 lagopthalmos cases occurred in a subset of 132 patients with facial patches (5%). Visual acuity scores, intra-ocular pressures and pupil cycle times were unremarkable. Bacillary invasion, keratitis, episcleritis, iridocyclitis, ectropion, synechiae, glaucoma and cataract formation were not detected. Scleral clofazimine pigmentation was frequent, resolving in most within 3 years of treatment cessation. Facial patches at presentation may denote a higher risk for lagopthalmos. We propose the generally low rates of ocular problems reflected mild lepra reactions, due to anti-inflammatory properties of clofazimine, a relatively young cohort, and a readily accessible community-based clinic permitting earlier diagnosis and prompt treatment. PMID- 21710854 TI - Synovial fluid adenosine deaminase activity to diagnose tuberculous septic arthritis. AB - There are reports of a correlation between high adenosine deaminase (ADA) levels in body fluid and tuberculosis (TB) infection, but none have evaluated synovial fluid ADA and TB arthritis. The objectives of this study were to determine the proper cut-off level for synovial fluid adenosine deaminase (SF-ADA) and the sensitivity and specificity of SF-ADA to diagnose TB arthritis. Between January 2006 and December 2007, SF-ADA were determined using the modified Giusti's method on patients over 15 years of age with clinically suspected TB arthritis or having an unknown etiology of their arthritis. Synovial fluid culture for TB was performed in all patients as a gold standard test. Forty cases were included in the study, with a female to male ratio of 1.7:1 and a mean age of 52.3 +/- 17.4 years (range, 16-80). The median duration of symptoms was 60 days. The prevalence of TB arthritis was 16.7% (6 cases) while the remaining cases were rheumatoid arthritis (8), non-TB bacterial septic arthritis (3), and miscellaneous (23). The mean SF-ADA levels in patients with TB arthritis and non-TB arthritis were 35.7 +/- 10.4 (range, 20-51) and 15.4 +/- 9 (range, 2-34) U/1, respectively. The cut off value for the diagnosis of TB arthritis was 31 U/1, with a sensitivity of 83.3% (95% CI 35.9-99.6), a specificity of 96.7% (95% CI 82.8-99.9) and an agreement Kappa of 0.8 (p < 0.001). SF-ADA levels higher than 31 U/1 were highly correlated with a diagnosis of TB arthritis, with a high sensitivity and specificity. SF-ADA may be considered as a less invasive and time-consuming diagnostic tool for TB arthritis. PMID- 21710855 TI - NRAMP1 polymorphism and susceptibility to lung tuberculosis in Surabaya, Indonesia. AB - The aim of this study was to evaluate the role of three polymorphisms (D543N, TGTG deletion in 3' UTR, INT4 G/C) of NRAMP1 to susceptibility to lung tuberculosis (TB) disease. The results showed that homozygous TGTG deletion in 3'UTR of NRAMP1 was found more frequent in lung tuberculosis patients than in healthy nurses working in a TB ward. This 4 base deletion might cause malfunction of NRAMP1 protein so that it fails as Fe2+ ion transporter causing macrophage unable to eliminate Mycobacterium tuberculosis. PMID- 21710856 TI - Evaluation of a new quality assessment strategy for blinded rechecking of random sputum smears for TB in Delhi, India. AB - This study was conducted at the New Delhi Tuberculosis Center, Delhi, India, from 1 January 2006 to 31 December 2007 to assess the feasibility of implementing random blinded rechecking (RBRC), a quality assurance strategy, and its impact on the performance of tuberculosis smear microscopy in Delhi, RBRC activities are carried out monthly at District Tuberculosis Centers (DTCs). Forty thousand five hundred and six slides were rechecked during the study period. RBRC, as a method of quality assurance was found to be feasible for a large application. The quality of sputum microscopy improved, with a significant reduction in the number of false positive and false negative errors in 2007 compared to 2006. The number of microscopy centers reporting high false errors decreased significantly in 2007. PMID- 21710857 TI - Case-control study of ectopic pregnancies in Myanmar: infectious etiological factors. AB - We studied the role of infections in ectopic pregnancy and the different methods of detecting Chlamydia trachomatis infection using serology, cervical and tubal PCR assays, by using a hospital-based, case-control study conducted between November 2007 and September 2009. The sample size was 339 with 113 cases and 226 controls. The cases were women admitted for the management of ectopic pregnancy while the controls were women admitted for spontaneous miscarriage. Both cases and controls were tested for syphilis and chlamydial infection by serology. In addition, cervical samples from controls and both cervical and tubal samples from cases were examined for the presence of chlamydia and gonococcal DNA. Sociodemographic data and past histories were collected using set Proforma. Independent variables for multivariate analysis included previous history of spontaneous abortion, ectopic pregnancy, symptoms of sexully transmitted infections (STI), and use of contraception. Women with a previous history of ectopic pregnancy (adjusted OR 28.3; 95% CI 5.8-138.8; p = 0.01) and a past history of having had symptoms of STI (adjusted OR 11.06; 95% CI 5.45-22.44; p = 0.0005) were significantly more likely to have an ectopic pregnancy than those without such a history. Syphilis serology was positive in 13.3% of ectopic pregnancy cases compared to only 3.5% of controls (crude OR 0.24; 95% CI -0.10 0.58; p = 0.001). From cervical swabs, chlamydia DNA was detected significantly more frequently in cases than controls (8.0% vs 2.2%; crude OR 0.261; 95% CI 0.09-0.80, p = 0.012) but gonorrhea DNA detection rates were not significantly different (3.5% vs 0.9%, crude OR 0.24; 95% CI -0.04-1.35; p = 0.1). Chlamydia was positive in cases only as diagnosed tubal samples for PCR in 17 (15.0%), cervical samples for PCR in 9 (8.0%) and IgM ELISA in 6 (5.3%). Among the three STI tested for in this study, C. trachomatis was the most frequently associated with ectopic pregnancy and was more frequently diagnosed by PCR on tubal samples than PCR on cervical samples or chlamydia IgM serology. PMID- 21710859 TI - Inhibitory effect of formulated lemongrass shampoo on Malassezia furfur: a yeast associated with dandruff. AB - Lemongrass (Cymbopogon citratus Stapf) has been used in cooking and in many traditional medicines; the essential oil contains citral as a major constituent. This study evaluated the antifungal activity of lemongrass oil against Malassezia furfur, an opportunistic yeast associated with dandruff, by using a broth dilution assay. From the minimum fungicidal concentration (MFC) obtained, the oil was then incorporated at different percentages into shampoo formulations. The formulated shampoos were kept at room temperature (28 degrees-30 degrees C) and under accelerated condition (45 degrees C). At the end of the first and sixth weeks, after preparation, all formulations were tested again and the appearance was recorded. Selection of an appropriate formula was based on antifungal activity against M. furfur, the physical appearance, the chemical properties and stability of the formula. Two percent lemongrass oil shampoo provided the required qualities necessary for commercial use. After being kept for 6 weeks at 28 degrees-30 degrees C and 45 degrees C, this formulated shampoo gave MFCs against M. furfur of 75 microl/ml and 18.75 microl/ml, respectively. PMID- 21710858 TI - Antimicrobial resistance patterns of uropathogens among children in Istanbul, Turkey. AB - Urinary tract infections are a common cause of end-stage renal disease in Turkey. This prospective study investigated the antibiotic resistance patterns of uropathogens in order to recommend appropriate therapeutic protocols for children with urinary tract infections in Istanbul, Turkey. Between October 2007 and October 2008, children presenting with a first episode of urinary tract infection to a pediatric outpatient clinic were enrolled in the study. Urine samples were cultured, and antimicrobial susceptibility testing was performed. Children with proven urinary tract infections underwent imaging studies where available. A total of 126 children with a first episode of community-acquired urinary tract infection were enrolled in the study. The median age was 60.6 months; 84.1% of the children were female. Of the 126 urine samples, Escherichia coli was the leading uropathogen (81.7%), followed by Proteus spp (7.1%), Klebsiella spp (4.0%), Enterococcus spp (3.2%), Enterobacter spp (2.4%), and Pseudomonas spp (1.6%). Among the isolated uropathogens, resistance to ampicillin (85.0%), amoxicillin-clavulanate (73.8%), cefazolin (37.3%) and trimethoprim sulfamethoxazole (42.9%) was remarkable. A large number of Enterococcus species were resistant to all antimicrobial agents except vancomycin. A country-based evaluation of antibiotic susceptibility is needed to modify antibiotic treatment. Resistance to antimicrobial agents commonly used to treat urinary tract infections (nitrofurantoin, cefixime) is less a problem than resistance to other antimicrobials (aminopenicillins, cephalosporins, trimethoprim-sulfamethoxazole) frequently prescribed for other indications. PMID- 21710860 TI - Identification of major allergens of wildflower honey. AB - The aim of this study was to identify the major allergens of wildflower honey in local patients with atopic disease. SDS-PAGE revealed ten protein bands of 25 to 110 kDa, with a heavy cluster in region of 40-75 kDa. Immunoblotting demonstrated seven IgE-binding bands of 39 to 110 kDa. The 60 kDa protein had the highest frequency of IgE-binding (100%) followed by 54 kDa protein (95%), thus identified as the major allergens of wildflowerhoney. Our findings indicate that the allergen extract used for diagnosis of honey allergy contains both the 54 kDa and 60 kDa proteins. PMID- 21710861 TI - Incorporation of private demand into cost-benefit analysis of a universal Hib vaccination program in Thailand. AB - Conjugate Hib vaccines are costly and Hib meningitis incidence in Thailand is relatively low comparing to western countries; a decision tree model was used for cost-benefit analysis (CBA) of a universal conjugate Hib vaccination program in Thailand. Tangible and intangible costs and benefits of the program, occurring from birth to 60 years of age from the provider and client perspectives, were included in the cost analysis. With a birth cohort of 740,109, at a cost of USD 8 million (THB 288 million), the program will potentially prevent 77 deaths, 19 cases of severe disability, 135 cases of meningitis, and 628 cases of pneumonia resulting in a net benefit of about USD 70 million to society. The program is cost-effective only if intangible benefits are included in the model. PMID- 21710863 TI - Perceptions of couples about contraception in eastern India. AB - This community-based, cross-sectional study was conducted in sampled villages and municipal wards of Paschim Medinipur District of West Bengal, India among 2,000 respondents, 3/4 were from rural and 1/4 from urban areas, to determine perceptions of couples about contraception. Decision-making about fertility and contraception was mostly made by the husband. Forty-four point three percent of rural and 77.6% of urban women preferred a birth spacing of > or = 3 years. The ideal interval between marriage and first pregnancy was considered to be > or = 3 years in nearly two thirds of women. With increasing literacy level among women, the ideal birth interval between pregnancies also increased. Eighty-nine point four percent of women had correct knowledge of family planning. Only 49.4% of women knew about the Copper-T contraceptive device. PMID- 21710862 TI - Low-density lipoprotein cholesterol goal attainment among Malaysian dyslipidemic patients. AB - The aim of the present study was to evaluate Malaysian dyslipidemic patient treatment practices and outcomes. Factors contributing to success in reaching treatment goal were determined. A retrospective review of the records of dyslipidemic patients who attended the Universiti Sains Malaysia Hospital in 2007 was conducted. All the patients were receiving standard recommended doses of statins. Records were analysed for 890 patients. Patients were divided into three categories: 384 patients (43.1%) had coronary heart disease or coronary heart disease risk equivalents, 216 patients (24.3%) had moderate risk for coronary heart disease and 290 patients (32.6%) had low risk. Statins were the most commonly prescribed drug group (92%), of which atorvastatin was the most commonly prescribed drug (50.6%). The overall success rate for reaching goal was 64.2%. The percentages of patients achieving low-density lipoprotein cholesterol targets in the coronary heart disease and coronary heart disease risk equivalents, moderate, and low-risk groups were 50.5, 66.7, and 80.3%, respectively (p < 0.001). Multiple logistic regression showed achievement of therapeutic goal declined with increasing risk group. The baseline low-density lipoprotein cholesterol value was inversely related to therapeutic goal attainment. An inadequate proportion of dyslipidemic patients achieved the National Cholesterol Education Program therapeutic goals for low-density lipoprotein cholesterol, especially those in the coronary heart disease and coronary heart disease risk equivalent group. The achievement of this goal was dependent on baseline low density lipoprotein cholesterol levels. PMID- 21710864 TI - The knowledge, attitudes and practices of soldiers in a gendarmerie command headquarters about family planning and venereal diseases. AB - The objective of this study was to determine the knowledge, attitudes and practices of young male soldiers about family planning. This was a cross sectional study conducted at the Gendarmerie Command Headquarters, Elazig City, eastern Turkey, carried out on 14 April 2004. One hundred ninety-one of 209 soldiers who were present at the Gendarmerie Command Headquarters were included in the study. A questionnaire, developed by the researchers evaluating the goals of the study, was filled out by the subjects prior to the Family Planning Seminar given to the soldiers. Data were assessed using SPSS and the chi-square test was used for statistical analysis. Defining family planning correctly, being familiar with planning methods and a knowledge of sexually transmitted diseases (STD) and their prevention was found to be at low levels among soldiers. A knowledge of family planning, birth control methods, identification and prevention of STD was higher with higher levels of education. The most familiar family planning methods were condom and oral contraceptive use. Soldiers constitute one of the most significant target groups for education programs. PMID- 21710865 TI - Home-based caregivers' knowledge regarding anti-retroviral therapy in Namibia. AB - Lack of practical knowledge among home-based caregivers (HBCs) on HIV/AIDS, anti retroviral treatment (ART) and poor individual adherence to treatment are among the root causes of ineffective ART service delivery in Namibia. The purpose of the study was to investigate the knowledge of HBCs in Namibia regarding ART. The study was a descriptive, cross-sectional study in which 89 participants completed self-administered questionnaires to assess their knowledge regarding ART. Knowledge of HBCs on ART was above average in some aspects, there was still lack of knowledge on necessity of post-test counseling. Training organizations should put emphasis on the necessity of post-test counseling, consequence of poor adherence and type of facilities that issue ART. PMID- 21710866 TI - A grading system for reproductive and child health indicators in southern India. AB - This study was carried out to develop a system for grading local government sectors (LGS) in regard to reproductive and child health (RCH). RCH indicators for Udupi District in southern India over a one year period were graded. All 146 LGS in 3 municipalities were ranked using the grading system into one of 5 grades. The grading system is based on 14 RCH indicators. There was a wide disparity in RCH among LGS, even though the overall key RCH indicators were good. Using this new grading system for each of the 146 LGS in Udupi District, Udupi, Karkala and Kundapura administrative divisions were all within the first three grades. This new system of grading care in the LGS based on RCH indicators, can be used as an easy reference tool to assess and compare the performance of each LGS. A similar system could be adapted by other countries using RCH indicators. PMID- 21710867 TI - Health seeking behavior among Malaysians with acute diarrheal disease. AB - About 1.8 million people die annually from acute diarrheal disease globally. A nationwide cross-sectional survey was conducted via face-to-face interview with eligible subjects to determine the incidence and health seeking behavior of Malaysians with acute diarrheal disease (ADD). An acute diarrheal episode was defined as having three or more loose stools in any 24 hour period during the four weeks period prior to the interview. The exclusion criteria included pre existing chronic diarrhea, such as with cancer of the bowel, ulcerative colitis or Chrohn's disease. Forty three point three percent of those with ADD (95% CI 41.3-45.4) sought treatment for the illness. Younger age groups (0-4 years, 67.7%; 95% CI 61.5-73.4; 5-9 years, 56.5%; 95% CI 48.6-64.1) were more likely to seek care for ADD. Seventy-one point eight percent of those seeking treatment, (95% CI 69.0-74.4) did so within 12 hours of the onset of symptoms. Most people with ADD sought treatment at private clinics. The main reasons given for not seeking treatment were the illness was mild and did not warrant treatment and the practice of self-medication (22.4%; 95% CI 20.0-24.9). These findings show self medication is a major health seeking behavior among Malaysians with ADD. Self medication of ADD deserves more in-depth study to ensure it is safe. PMID- 21710868 TI - Effects of a multidisciplinary supervised exercise program on motor performance and quality of life in community-dwelling chronic stroke survivors in Korean. AB - Studies of strengthening and physical conditioning rehabilitation programs on stroke survivors have shown an increase in their physical function and quality of life (QOL). In this study the effectiveness of two exercise regimens was assessed: 1) a 24-week multidisciplinary supervised exercise program and 2) a 24 week self-monitored conditioning exercise program. Twenty-eight subjects (17 men and 11 women) were allocated to take part in either a multidisciplinary supervised program or a self-monitored exercise program. The primary outcomes were the results of the Wolf Motor Function Test (Korean version), Motor Activity Log (Korean version) and Stroke Short Form--Quality of Life assessment (Korean version). Both groups showed improvement in motor capacity and quality of life, but the improvements achieved by the multidisciplinary supervised group were greater than those of the self-monitored group. A multidisciplinary supervised program was more effective than a self-monitored program for stroke rehabilitation. PMID- 21710869 TI - Exercise and physical activity among healthy elderly Iranians. AB - The aim of this qualitative study was to explore the experiences of elderly Iranians regarding exercise. Sixteen healthy elderly people participated in semi structured interviews conducted in 2009 in Tehran, Iran. A qualitative content analysis was used to analyze the participants' experiences and perceptions regarding physical activity. Five main categories were studied: 1). kinds of exercise activities, 2). common activities, 3). engaging in reasonable activities, 4). barriers to physical activity, and 5). effects of exercising on life. Distinctive themes within each of the categories were identified. The findings of this study show the current perceptions regarding physical activity and exercise in elderly Iranians. PMID- 21710870 TI - Effect of an essential oil-containing mouth rinse on VSC-producing bacteria on the tongue. AB - The objective of the present study was to investigate the inhibitory effect of a commercially available essential oil-containing mouth rinse 12 hours after a single rinse and two weeks of twice daily rinsing, on volatile sulphur compounds (VSC) producing bacteria on the tongue. The study was a randomized, double-blind, controlled crossover design. Thirty-six healthy subjects, aged 20-48 years, volunteered to participate in the study. Subjects were randomly assigned to rinse twice daily with either an essential oil-containing mouth rinse (Cool Mint Listerine Antiseptic) or a negative control rinse. Bacteria samples were taken from the dorsum of the tongue at baseline, after the first rinse and two weeks later. They were plated on OOPS medium to enumerate the VSC-producing bacteria. Intergroup comparisons of log10 transformed colony-forming units of the samples were made using analysis of covariance. Each comparison was performed at a 5% significance level. The mean VSC-producing bacteria in subjects using the essential oil mouth rinse were significantly lower than those using the control rinse twice daily. In healthy subjects, rinsing with an essential oil-containing mouth rinse can have a significant effect on VSC-producing bacteria on the tongue and may be useful for controlling intrinsic oral malodor over prolonged periods. PMID- 21710872 TI - Wild mushroom poisonings in Hong Kong. PMID- 21710871 TI - Shear bond strength of some sealants under saliva contamination. AB - The purpose of this in vitro study was to compare the shear bond strength of different types of sealant to non-contaminated and saliva-contaminated enamel. The buccal surfaces of 60 sound permanent third molars were individually embedded in self-curing acrylic resin and wet ground with 1,000-grit silicone carbide paper to obtain a flat enamel surface. The specimens were randomly assigned to one of three groups: 1) non-fluoride-releasing resin sealant (Concise), 2) fluoride-releasing resin sealant (Clinpro), 3) glass-ionomer sealant (Fuji VII). Each group was divided into 2 subgroups (n = 10): non-contaminated and saliva contaminated with 0.02 ml of fresh human saliva for 20 seconds and then blowed dried prior to sealant placement. All samples were thermocycled 2,000 cycles. The specimens were tested using an Instron running at a crosshead speed of 0.05 mm/min. Stereomicroscope examinations were carried out to evaluate failure sites of the sealants. Data were analyzed with one-way ANOVA and the Turkey test at a siginificance level of p < 0.05. Comparison of the different types of sealant revealed the shear bond strength of the glass-ionomer sealant was the same for the non-contaminated and saliva-contaminated subgroups. The shear bond strength was lower in both the fluoride and non-fluoride releasing resin-based sealant groups contaminated with saliva than in the fluoride and non-fluoride releasing resin-based sealant groups not contaminated with saliva. Comparison of the different types of sealant also revealed the shear bond strength of the glass ionomer sealant had a significantly lower shear bond strength than the fluoride and non-fluoride releasing resin-based sealant groups for both the non contaminated and saliva-contaminated subgroups. The fluoride and non-fluoride releasing resin-based sealant groups were not significantly different from each other. The modes of failure were mostly mixed with the glass-ionomer sealant in both the non-contaminated and saliva-contaminated subgroups of this sealant. The resin-based sealant groups (both fluoride and non-fluoride releasing) had cohesive/mixed failure in the non-contaminated and adhesive/mixed failure in the saliva-contaminated subgroups. In conclusion, saliva-contamiantion did not affect the shear bond strength of glass-ionomer sealant but the glass-ionomer sealant had the lowest shear bond strength. PMID- 21710873 TI - Navigating the maze. Strategies for successful partnerships in HIV care. PMID- 21710875 TI - The ghosts of Christmas past. How would those we've lost guide us today? PMID- 21710874 TI - Obstacle course: the role of health care providers in helping to overcome stigma, denial, and ignorance. PMID- 21710876 TI - Compassion in the storm. A doctor breaks down barriers one patient at a time. PMID- 21710877 TI - Lies, damned lies, and statistics. PMID- 21710878 TI - The skeletal frog appliance for maxillary molar distalization. PMID- 21710879 TI - Extraction of a geminated central incisor. PMID- 21710880 TI - The readers' corner. Cone-beam computed tomography in orthodontics. PMID- 21710881 TI - Clinical application of a modified lip bumper. PMID- 21710882 TI - Evaluation of facial asymmetry with three-dimensional cone-beam computed tomography. PMID- 21710883 TI - Combining quantity & quality. Adding new revenue streams can enable your practice to offer higher levels of service. PMID- 21710884 TI - Well connected. PMID- 21710885 TI - Rejuvenate your practice. PMID- 21710886 TI - Aim for your target. PMID- 21710887 TI - Rooted in caregiving. PMID- 21710888 TI - Practice mini-makeovers. These four practices realized they needed to change--and they did, for the better. PMID- 21710889 TI - Keep your patient collections healthy. PMID- 21710890 TI - 6 tips to improve your leasing arrangement. PMID- 21710891 TI - Selling to a corporation poses challenges. PMID- 21710892 TI - Their loss, your gain. PMID- 21710893 TI - Tests, missed appointments require you to follow up. PMID- 21710894 TI - Courage and innovation. Leadership must transition from MBAs to doctors. PMID- 21710895 TI - In the homestretch. PMID- 21710896 TI - Balance supply and demand to perfect your practice schedule. PMID- 21710897 TI - Both sides of the table. PMID- 21710898 TI - Do happy staff = happy patients? PMID- 21710899 TI - Don't reform malpractice suits: end them. PMID- 21710900 TI - The payment gauntlet. PMID- 21710901 TI - Healing can begin in your waiting room. PMID- 21710902 TI - A perfect storm may threaten the private practice model. PMID- 21710903 TI - Fringe benefits. PMID- 21710904 TI - Last impressions. PMID- 21710905 TI - 10 steps to successful EHR implementation. PMID- 21710906 TI - Power to the patient. PMID- 21710907 TI - The phone is your friend when used properly. PMID- 21710908 TI - Exercise is not a four-letter word. PMID- 21710909 TI - How ready are we for disasters? PMID- 21710910 TI - Building relationships: the key to preceptoring nursing students. AB - Preceptorship is a form of support offered to student nurses in the clinical setting by a registered nurse (preceptor) who offers guidance and acts as a role model to the student. Research suggests this can be a rewarding role for preceptors, but there are challenges which may impact on their ability to develop the role to its full potential. To better understand the experiences of being a preceptor and the factors that impact on the role, a qualitative descriptive study was undertaken in a small provincial hospital in New Zealand. A purposeful sample of five registered nurse preceptors completed semi-structured audio-taped interviews. Data analysis was completed using a step-by-step process informed by Burnard (1991). The key finding of this research was the importance of the preceptor and student nurse establishing a professional working relationship. This then enables the preceptor to better assess, and assist promoting in the student's level of knowledge and understand. At that point the preceptor can determine whether it is safe to allow the student more practice opportunities, or whether constant supervision is still required. Rostering students with one preceptor for the entire placement would better enable both parties to develop a cohesive working relationship, and result in a more positive, effective placement for both the student and preceptor. PMID- 21710911 TI - Utilising the Hand Model to promote a culturally safe environment for international nursing students. AB - The rising number of international students studying outside their own country poses challenges for nursing education. Numbers are predicted to grow and economic factors are placing increasing pressure on tertiary institutions to accept these students. In adapting to a foreign learning environment international students must not only adapt to the academic culture but also to the socio-cultural context. The most significant acculturation issues for students are English as a second language, differences in education pedagogy and social integration and connectedness. Students studying in New Zealand need to work with Maori, the indigenous people, and assimilate and practice the unique aspects of cultural safety, which has evolved in nursing as part of the response to the principles underpinning the Treaty of Waitangi. The Hand Model offers the potential to support international students in a culturally safe manner across all aspects of acculturation including those aspects of cultural safety unique to New Zealand. The model was originally developed by Lou Jurlina, a nursing teacher, to assist her to teach cultural safety and support her students in practising cultural safety in nursing. The thumb, represents 'awareness', with the other four digits signifying 'connection" 'communication', 'negotiation' and 'advocacy' respectively. Each digit is connected to the palm where the ultimate evaluation of the Hand Model in promoting cultural safety culminates in the clasping and shaking of hands: the moment of shared meaning. It promotes a sense of self worth and identity in students and a safe environment in which they can learn. PMID- 21710912 TI - Understanding and evaluating historical sources in nursing history research. AB - All nurse researchers need to address, in the manner most appropriate to their research methodology, issues of quality related to their research material. This concern is not about the care needed in generating data, rather it relates to understanding and evaluating material that already exists. This article describes four historical sources relevant to the history of nursing in New Zealand and uses them to explain how nurse researchers can evaluate their research material. The dimensions of this evaluation are the provenance, purpose, context, veracity and usefulness of the historical sources. The article explains the questions that need to be addressed in each dimension of the evaluation. The different kinds of information available in the four historical sources are illustrated by references to individual nurses. PMID- 21710913 TI - Our story: Peter Harley: a beacon of humility and professionalism. PMID- 21710914 TI - Our voice... it is in our stories... PMID- 21710915 TI - Position statement: structure of critical care units. PMID- 21710916 TI - Parochialism and biased reviews. PMID- 21710917 TI - Life's frenzies, fluxes and fevers. PMID- 21710918 TI - Rhode Island metabolic newborn screening: the effect of early identification. A case report of argininosuccinic aciduria (ASA). PMID- 21710919 TI - Genetics in autism diagnosis: adding molecular subtypes to neurobehavioral diagnoses. PMID- 21710920 TI - Myoclonic astatic epilepsy and the role of the ketogenic diet. AB - The ketogenic diet remains one of the most effective treatments for medically refractory childhood epilepsy. In spite of the long history of its use, relatively little is known about the mechanism of action. The diet's efficacy in a wide range of epilepsy syndromes suggests that it may have multiple mechanisms of action, each of which may be more relevant to a specific disease state. Further research is necessary to define the mechanism of action, which may, in turn, lead to easier means to provide the therapeutic benefit. PMID- 21710921 TI - The role of new genetic technology in investigating autism and developmental delay. PMID- 21710922 TI - Vulvovaginal atrophy: a common--and commonly overlooked--problem. PMID- 21710923 TI - Less than optimal oral health care during pregnancy in Rhode Island women: oral health care as a part of prenatal care. PMID- 21710925 TI - The oracular words from Delphi. PMID- 21710924 TI - Acute renal failure from a pelvic arteriovenous malformation. PMID- 21710926 TI - What have we done for you lately? More on Medicaid. Who's your partner? PMID- 21710927 TI - The Justice League. PMID- 21710929 TI - Physician assistants. State efforts aim at increasing education, clearing the way for physician-PA practices in Arkansas. PMID- 21710930 TI - Improving patient safety by creating lasting behavior change: lessons learned from hand hygiene. PMID- 21710931 TI - Limb shaking, vomiting and vitamin D deficiency. AB - Vitamin D deficiency has been identified as a medical concern for centuries. Often regarded in the context of young children and the elderly, vitamin D deficiency has become a common diagnosis in the adolescent population. Associations with other chronic conditions have not been fully explored, but medical personnel must be acutely aware in order to provide the best care. Our case presents an adolescent with a known eating disorder diagnosis and symptoms that ultimately led to an added diagnosis of Vitamin D deficiency. PMID- 21710932 TI - MRSA infections in children. AB - MRSA infections continue to be a serious and formidable challenge to health care providers and their prevalence is increasing exponentially. In the past, MRSA infections were observed only in hospitalized patients whereas now they are encountered in the outpatient setting. Understanding the pattern of the widespread distribution of MRSA as well as the factors associated with its spread are paramount to its recognition and eradication. The current state of MRSA transmission, control and management is reviewed. PMID- 21710933 TI - Medicaid proposals off target. PMID- 21710934 TI - An unusual presentation of invasive squamous cell carcinoma of the upper extremities in a patient with a history of severe electrical burns and chronic thermal and chemical exposure. AB - This is a case report that depicts an atypical presentation of very aggressive, metachronous invasive squamous cell carcinomas of the upper extremities in a patient with no prior history of precancerous or cancerous skin lesions and no significant solar radiation exposure. Potentially causative factors that played a role in the emergence of this aggressive form of skin cancer in this case study are multifactorial: (1) chronic thermal exposure of 3000 degrees F daily to his hands for an eight to ten-year time period; (2) chronic chemical exposure of DMSO solvent and higher levels of chemical contaminants such and finally; (3) a form of chronic immunosuppression as a result of his severe electrical burns that resulted in widespread second and third burns throughout his body. PMID- 21710935 TI - The who, what, where, why, and when of contracts. PMID- 21710936 TI - New technologies for the management of major extremity wounds. AB - Soft tissue reconstruction for large or difficult defects, particularly of distal extremities, may be associated with a variety of problems. Crush injuries and infection are often background settings requiring use of considerable resources, time, and skilled personnel for appropriate treatment. Harvested tissue, known as a flap, is used for transferring healthy, viable tissue from one location to the area of tissue loss. Conventional techniques, procedures, and imaging studies used in soft tissue wounds are associated with limitations that often mandate the use of microvascular tissue transfer for lack of a clear alternative. Newer technology, however, may provide an alternative in a significant number of cases. The developments of the perforator flap, digital subtraction angiography, and real-time laser-assisted indocyanine green fluorescent-dye angiography have enabled the use of local tissue for reconstruction heretofore not thought possible. Three cases with distal extremity soft tissue defects were reconstructed using local perforator flaps designed by using these innovative technologies. PMID- 21710937 TI - The hidden burden of atrial fibrillation on healthcare spending and resources in Mississippi. PMID- 21710938 TI - Inaugural address of the president, 143th annual session, May, 2011. Dad/PawPaw. PMID- 21710939 TI - Joseph and Jefferson Davis, the community health centers, Mississippi, and 11 billion dollars. PMID- 21710940 TI - Impressions of rural medical care in Kenya. PMID- 21710941 TI - This month in the Mississippi morbidity report. Escherichia coli O157:H7 outbreak in Public Health District IV. PMID- 21710942 TI - Mississippi now nationally recognized as no. 1 in childhood immunization rates. PMID- 21710944 TI - State nullification of the Patient Protection and Affordable Care Act of 2010: is it an option? PMID- 21710943 TI - Addiction as a brain disease. PMID- 21710945 TI - Leaping hurdles. Antitrust clearance costly, offers no guarantee: AHA. PMID- 21710946 TI - Rallying for health. AHRQ data tool nearly falls under budget ax until advocates say it's too useful. PMID- 21710947 TI - Scary stuff. Worrying about cellphones, ACOs and health improvement. PMID- 21710948 TI - No fat, all muscle. Children's hospitals GME shouldn't be in sights of budget cutters. PMID- 21710949 TI - Navigating the benchmarks. Revenue cycle executives talk about what they use and their impact. Interviewed by Melanie Evans. PMID- 21710950 TI - Losing some advantage. Reform law's changes to affect Medicare Advantage plans- plus and minus. PMID- 21710951 TI - Femtosecond laser capsulotomy and manual continuous curvilinear capsulorrhexis parameters and their effects on intraocular lens centration. AB - PURPOSE: To measure and compare sizing and positioning parameters of femtosecond laser capsulotomy with manual continuous curvilinear capsulorrhexis (CCC). METHODS: Femtosecond capsulotomies (Alcon-LenSx Lasers Inc) and CCC were carried out in 20 eyes of 20 patients, respectively. Intraocular lens (IOL) decentration, circularity, vertical and horizontal diameters of capsulotomies, and capsule overlap were measured with Adobe Photoshop (Adobe Systems Inc) 1 week, 1 month, and 1 year after surgery. Between-group differences of parameters and predictors of IOL decentration were determined with repeated measures analysis of variance, chi-square test, and logistic regression analyses. RESULTS: Vertical diameter of CCC was statistically significantly higher in the first week and month. Significantly higher values of capsule overlap over 1 year and circularity in the first week showed more regular femtosecond capsulotomies. Horizontal IOL decentration was statistically significantly higher in the CCC group over 1 year. A significant difference was noted between the two groups in dichotomized horizontal decentration values at 0.4 mm with chi-square test after 1 week and 1 year (P=.035 and P=.016, respectively). In univariable general estimating equation models, type of capsulorrhexis (P<.01) and capsule overlap (P=.002) were significant predictors of horizontal decentration. Vertical diameter showed significant correlation to the overlap in the CCC group (1 week: r=-0.91; 1 month: r=-0.76, P<.01; 1 year: r=-0.62, P<.01), whereas no significant correlation was noted in the femtosecond group (P>.05). CONCLUSIONS: More precise capsulotomy sizing and centering can be achieved with femtosecond laser. Properly sized, shaped, and centered femtosecond laser capsulotomies resulted in better overlap parameters that help maintain proper positioning of the IOL. PMID- 21710952 TI - Clinical outcomes of photoastigmatic refractive keratectomy for the correction of residual refractive errors following cataract surgery. AB - PURPOSE: To assess the clinical outcomes of photoastigmatic refractive keratectomy (PARK) for the correction of residual refractive errors after cataract surgery. METHODS: This study evaluated 88 eyes of 66 consecutive patients with mean spherical equivalent refraction of -3.16+/-1.71 diopters (D) who underwent PARK to correct refractive errors after phacoemulsification with intraocular lens (IOL) implantation. Patient age at the time of surgery was 65.2+/-12.7 years. Safety, efficacy, predictability, stability, and adverse events of the surgery were assessed 1, 3, 6, and 12 months postoperatively. RESULTS: At 1 year postoperatively, uncorrected distance visual acuity and corrected distance visual acuity were 0.08+/-0.16 logMAR (Snellen 20/25) and 0.08+/-0.11 logMAR (Snellen 20/16), respectively. Safety and efficacy indices were 1.08+/-0.25 and 0.76+/-0.28, respectively. At 1 year, 68% of eyes were within +/-0.50 D and 88% were within +/-1.00 D of targeted correction. Manifest refraction changes of -0.06+/-1.06 D occurred from 1 week to 1 year. No vision threatening complications occurred during the observation period. CONCLUSIONS: Photoastigmatic refractive keratectomy is safe and moderately effective in the correction of residual refractive errors in pseudophakic eyes, suggesting its viability as a surgical option for the treatment of such eyes. PMID- 21710953 TI - Retropupillary fixation of iris-claw intraocular lens versus transscleral suturing fixation for aphakic eyes without capsular support. AB - PURPOSE: Retropupillary fixation of an iris-claw intraocular lens (IOL) (Verisyse, Abbott Medical Optics) was performed for aphakic eyes without sufficient capsular support, and safety and recovery of the procedure were compared with transscleral suturing fixation. METHODS: This interventional case series comprised 11 eyes of 10 aphakic patients without capsular support undergoing retropupillary fixation of the Verisyse, and 21 eyes of 20 patients undergoing transscleral suturing fixation of foldable acrylic IOLs (15 eyes of 14 patients, SuperFlex620H [Rayner Intraocular Lenses Ltd]) and polymethylmethacrylate IOLs (6 eyes of 6 patients, CP60NS [CORNEAL Laboratoire]). Surgical time was measured. Corrected distance visual acuity (CDVA) and intraocular pressure (IOP) were examined preoperatively and 1 day, 1 and 2 weeks, and 1 and 6 months postoperatively. RESULTS: No complications occurred in the Verisyse group, whereas complications were reported in seven eyes in the transscleral suturing fixation group throughout follow-up. Mean CDVA (logMAR) in the transscleral suturing group 1 day after surgery was significantly worse than preoperative CDVA (P<.05). In the Verisyse group, no significant changes in CDVA were noted at any time point. Mean IOP at postoperative day 1 in the transscleral suturing fixation group was significantly higher than that in the Verisyse group (P=.0126). Mean surgical time of Verisyse implantation (20.0 +/- 8.9 min) was significantly shorter than transscleral suturing fixation (49.7 +/- 18.9 min) (P<.0001). CONCLUSIONS: Retropupillary fixation of an iris-claw IOL provides early visual recovery, has a low risk of postoperative increase in IOP, and is a time-saving method compared with transscleral suturing fixation for aphakic eyes without sufficient capsular support. PMID- 21710954 TI - Implantable collamer posterior chamber intraocular lenses: a review of potential complications. AB - PURPOSE: To review the peer-reviewed literature reporting postoperative complications of the most recent models of Visian Implantable Collamer posterior chamber intraocular lenses (ICL, STAAR Surgical Co). METHODS: A literature search of the PubMed database was performed to identify all articles related to ICL complications. Articles were obtained and reviewed to identify those that reported complications using the latest ICL designs. RESULTS: Cataract was the major postoperative complication reported: 136 (5.2%) in 2592 eyes. Of those, 43.4% (n=59) were reported within 1 year, 15.4% (n=21) between 1 and 3 years, and 35.3% (n=48) >= 3 years after ICL implantation. Twenty-one (15.4%) cataracts were reported as surgically induced, 46 (33.8%) eyes had poor vault (<200 MUm), and cataract surgery was carried out in 27.9% (n=38) of eyes. Early acute intraocular pressure increase was also reported to be relatively frequent, whereas acute pupillary block was less frequent and mostly resolved with additional iridotomies. A total of 42 ICLs were explanted due to cataract and IOP. Reported endothelial cell loss varied from 9.9% at 2 years to 3.7% 4 years postoperatively. This loss was reported to be more pronounced within the first 1 to 2 years, with stability or lower progression after that time. CONCLUSIONS: The majority of reported complications after ICL implantation are cataract formation. The improvements in lens geometry and more accurate nomograms applied to the selection of the lens to be implanted, in addition to the surgeon's learning curve, might be factors in the decreased occurrence of postoperative complications reported currently. PMID- 21710956 TI - Efficiency of workplace surveys conducted by Finnish occupational health services. AB - In Finland, workplace surveys are used to identify and assess health risks and problems caused by work and make suggestions for continuous improvement of the work environment. With the aid of the workplace survey, occupational health services can be tailored to a company. The aims of this study were to determine how occupational health professionals gather data via the workplace survey and the effect survey results have on companies. A total of 259 occupational health nurses and 108 occupational health physicians responded to the questionnaire: 84.2% were women and 15.8% were men. The mean age of the respondents was 48.8 years (range, 26 to 65 years). Usually occupational health nurses and foremen and sometimes occupational health physicians and occupational safety and health representatives initiate the workplace survey. More than 90% of the surveys were followed by action proposals, and about 50% of these were implemented. The proposals implemented most often concerned personal protective equipment and less often leadership. Survey respondents should have both the opportunity and the authority to affect resources, the work environment, work arrangements, and tools. Teamwork among occupational health and safety professionals, management, and employees is vital for cost-effectively solving today's complex problems at workplaces around the globe. PMID- 21710957 TI - Health disparities of coal miners and coal mining communities: the role of occupational health nurses. AB - This article investigates how the health disparities of Appalachian coal miners and coal mining communities could be decreased through a partnership with occupational health nurses. On-site health clinics managed by occupational health nurses working in the coal mining industry are proposed as a means to improve health care outcomes. Health effects, economic considerations, environmental impacts, and U.S. coal mining legislation and regulation are examined. An epidemiological approach is presented to the unique health effects experienced by Appalachian coal miners and coal mining communities within the context of existent socioeconomic disparities. The long-standing health crisis in Appalachian coal mining communities requires a multidisciplinary approach led by occupational health nurses. PMID- 21710959 TI - Lockout and tagout procedures to prevent occupational injury and fatality. AB - Hazardous energy control programs that include lockout and tagout procedures as well as worker training can prevent serious injury and death during machine maintenance. PMID- 21710960 TI - Learning health equity frameworks within a community of scholars. AB - Scholars in nursing science have long espoused the concept of health equity without specifically using the term or dialoguing about the social determinants of health and social justice. This article describes the development, implementation, and evaluation of a doctoral and postdoctoral seminar collective entitled "Health Equity: Conceptual, Linguistic, Methodological, and Ethical Issues." The course enabled scholars-in-training to consider the construct and its nuances and frame a personal philosophy of health equity. An example of how a group of emerging scholars can engage in the important, but difficult, discourse related to health equity is provided. The collective provided a forum for debate, intellectual growth, and increased insight for students and faculty. The lessons learned by all participants have the potential to enrich doctoral and postdoctoral scientific training in nursing science and may serve as a model for other research training programs in the health sciences. PMID- 21710961 TI - Simulation in an undergraduate nursing curriculum: implementation and impact evaluation. AB - Although endorsed by nursing professional bodies and incorporated into undergraduate nursing curricula, high-fidelity simulation has undergone little evaluation at the program or curriculum levels. A comprehensive program evaluation of a Simulation Demonstration Project was undertaken to explore the influence of simulation across an undergraduate curriculum in a college of nursing. The focus of the evaluation was on program activities accomplished (implementation evaluation) and the extent to which program objectives and outcomes were met (impact evaluation). The Nursing Education Simulation Framework (NESF) was used to arrange multiple variables to be explored and to support the use of diverse simulation-related data sources. The framework was helpful in both guiding the evaluation and interpreting the results at the curriculum level from implementation and impact perspectives. Although continued use and testing of the NESF is warranted, findings from the study supported the utility of the NESF in program evaluation of simulation at the curriculum level. PMID- 21710962 TI - Clinical imagination: dynamic case studies using an attribute listing matrix. AB - The Attribute Listing Matrix Case Study (ALMCS) is an active instructional strategy for use in the classroom or clinical laboratory designed to engage the learner at the analysis, synthesis, and evaluation levels of Bloom's cognitive domain. Random numbers are used to generate multiple versions of case studies within a matrix that contains categories of real-world variables. Nursing students, either individually or in small groups, can then use the nursing process to analyze the patient case and design an individualized care plan. The ALMCS can be readily adapted to any level of nursing education and to any clinical specialty. It can be used in the classroom to show students how they will apply theoretical knowledge to real clinical situations, or it can be used for summative assessment by generating a random case for students to respond to in an examination. PMID- 21710963 TI - Responding to demands to change nursing education: use of curriculum mapping to assess curricular content. AB - Nurse educators are endeavoring to assess and revise their undergraduate curriculum for a variety of reasons. Legislation passed in California mandates that universities must offer more seamless associate degree-to-baccalaureate of science in nursing degree programs and must ensure that course content in their programs is not redundant across program types. A nursing education consortium, including a university, two community colleges, and four hospital partners, formed a working group to assess all undergraduate curricula. This working group included faculty from all three academic institutions and nurse educators from area service provider partners. This article describes the use of curriculum mapping using a tool formed based on the American Association of Colleges of Nursing's Essentials of Baccalaureate Education for Professional Nursing Practice to assess the three curricula and the outcomes and implications of the assessment. PMID- 21710964 TI - Undergraduate nursing student self-efficacy in patient education in a context based learning program. AB - Educating patients is one recognized strategy to reduce health risks and costs associated with illness and hospitalization. Context-based learning (CBL) has been advocated in nursing education due to its identified advantages, such as students' increased self-confidence. The aim of this comparative, quasi experimental study was to examine the influence of CBL on undergraduate nursing student self-efficacy in patient education. Twenty-two first-year and 36 third year nursing students completed the Health Promotion Disease Prevention Inventory examining smoking, exercise, and nutrition. The results show a statistically significant difference between first-year and third-year students in the smoking domain. Third-year students displayed more efficacy related to knowledge about smoking than did first-year students. Both first-year and third-year students indicated that receiving factual information on risk factors was the most helpful source of self-efficacy information. The finding supports the notion that CBL is effective in developing students' self-efficacy. PMID- 21710966 TI - Products and mechanism of acene dimerization. A computational study. AB - The high reactivity of acenes can reduce their potential applications in the field of molecular electronics. Although pentacene is an important material for use in organic field-effect transistors because of its high charge mobility, its reactivity is a major disadvantage hindering the development of pentacene applications. In this study, several reaction pathways for the thermal dimerization of acenes were considered computationally. The formation of acene dimers via a central benzene ring and the formation of acene-based polymers were found to be the preferred pathways, depending on the length of the monomer. Interestingly, starting from hexacene, acene dimers are thermodynamically disfavored products, and the reaction pathway is predicted to proceed instead via a double cycloaddition reaction (polymerization) to yield acene-based polymers. A concerted asynchronous reaction mechanism was found for benzene and naphthalene dimerization, while a stepwise biradical mechanism was predicted for the dimerization of anthracene, pentacene, and heptacene. The biradical mechanism for dimerization of anthracene and pentacene proceeds via syn or anti transition states and biradical minima through stepwise biradical pathways, while dimerization of heptacene proceeds via asynchronous ring closure of the complex formed by two heptacene molecules. The activation barriers for thermal dimerization decrease rapidly with increasing acene chain length and are calculated (at M06-2X/6-31G(d)+ZPVE) to be 77.9, 57.1, 33.3, -0.3, and -12.1 kcal/mol vs two isolated acene molecules for benzene, naphthalene, anthracene, pentacene, and heptacene, respectively. If activation energy is calculated vs the initially formed complex of two acene molecules, then the calculated barriers are 80.5, 63.2, 43.7, 16.7, and 12.3 kcal/mol. Dimerization is exothermic from anthracene onward, but it is endothermic at the terminal rings, even for heptacene. Phenyl substitution at the most reactive meso-carbon atoms of the central ring of acene blocks the reactivity of this ring but does not efficiently prevent dimerization through other rings. PMID- 21710965 TI - Traceless and site-specific ubiquitination of recombinant proteins. AB - Protein ubiquitination is a post-translational modification that regulates almost all aspects of eukaryotic biology. Here we discover the first routes for the efficient site-specific incorporation of delta-thiol-L-lysine (7) and delta hydroxy-L-lysine (8) into recombinant proteins, via evolution of a pyrrolysyl tRNA synthetase/tRNA(CUA) pair. We combine the genetically directed incorporation of 7 with native chemical ligation and desulfurization to yield an entirely native isopeptide bond between substrate proteins and ubiquitin. We exemplify this approach by demonstrating the synthesis of a ubiquitin dimer and the first synthesis of ubiquitinated SUMO. PMID- 21710967 TI - Transparent large-strain thermoplastic polyurethane magnetoactive nanocomposites. AB - Organically modified superparamagnetic MnFe(2)O(4)/thermoplastic polyurethane elastomer (TPU) nanocomposites (0.1-8 wt %) were prepared by solvent mixing followed by solution casting. Linear aliphatic alkyl chain modification of spherical MnFe(2)O(4) provided compatibility with the TPU containing a butanediol extended polyester polyol-MDI. All MnFe(2)O(4)/TPU nanocomposite films were superparamagnetic and their saturation magnetization, sigma(s), increased with increasing MnFe(2)O(4) content. All nanocomposite films exhibited large deformations (>10 mm) under a magneto-static field. This is the first report of large actuation of magnetic nanoparticle nanocomposites at low-loading levels of 0.1 wt % (0.025 vol %). The maximum actuation deformation of the MnFe(2)O(4)/TPU nanocomposite films increased exponentially with increasing nanoparticle concentration. An empirical correlation between the maximum displacement, saturation magnetization, and magnetic nanoparticle loading is proposed. The cyclic deformation actuation of a 6 wt % surface modified MnFe(2)O(4)/TPU, in a low magnetic field 151 < B(y) < 303 Oe, exhibited excellent reproducibility and controllability. MnFe(2)O(4)/TPU nanocomposite films (0.1-2 wt %) were transparent and semitransparent over the wavelengths from 350 to 700 nm. PMID- 21710968 TI - Biochemical characterization of a multidomain deubiquitinating enzyme Ubp15 and the regulatory role of its terminal domains. AB - Deubiquitinating enzymes (DUBs) have emerged as essential players in a myriad of cellular processes, yet the regulation of DUB function remains largely unknown. While some DUBs rely on the formation of complex for regulation of enzymatic activity, many DUBs utilize interdomain interactions to regulate catalysis. Here we report the biochemical characterization of a multidomain deubiquitinating enzyme, Ubp15, from Saccharomyces cerevisiae. Steady-state kinetic investigation showed that Ubp15 is a highly active DUB. We identified active-site residues that are required for catalysis. We have also identified key residues on Ubp15 required for ubiquitin binding and catalysis. We further demonstrated that Ubp15's enzymatic activity is regulated by the N- and C-terminal domains that flank the catalytic core domain. Moreover, we demonstrated that Ubp15 physically interacts with a WD40 repeat-containing protein, Cdh1, by copurification experiments. Interestingly, unlike other DUBs that specifically interact with WD40 repeat-containing proteins, Cdh1 does not function in stimulating Ubp15's activity. The possible cellular function of Ubp15 in cell cycle regulation is discussed in view of the specific interaction between Ubp15 and Cdh1, an activator of the anaphase-promoting complex/cyclosome (APC/C). PMID- 21710970 TI - Water in the active site of ketosteroid isomerase. AB - Classical molecular dynamics simulations were utilized to investigate the structural and dynamical properties of water in the active site of ketosteroid isomerase (KSI) to provide insight into the role of these water molecules in the enzyme-catalyzed reaction. This reaction is thought to proceed via a dienolate intermediate that is stabilized by hydrogen bonding with residues Tyr16 and Asp103. A comparative study was performed for the wild-type (WT) KSI and the Y16F, Y16S, and Y16F/Y32F/Y57F (FFF) mutants. These systems were studied with three different bound ligands: equilenin, which is an intermediate analog, and the intermediate states of two steroid substrates. Several distinct water occupation sites were identified in the active site of KSI for the WT and mutant systems. Three additional sites were identified in the Y16S mutant that were not occupied in WT KSI or the other mutants studied. The number of water molecules directly hydrogen bonded to the ligand oxygen was approximately two in the Y16S mutant and one in the Y16F and FFF mutants, with intermittent hydrogen bonding of one water molecule in WT KSI. The molecular dynamics trajectories of the Y16F and FFF mutants reproduced the small conformational changes of residue 16 observed in the crystal structures of these two mutants. Quantum mechanical/molecular mechanical calculations of (1)H NMR chemical shifts of the protons in the active site hydrogen-bonding network suggest that the presence of water in the active site does not prevent the formation of short hydrogen bonds with far-downfield chemical shifts. The molecular dynamics simulations indicate that the active site water molecules exchange much more frequently for WT KSI and the FFF mutant than for the Y16F and Y16S mutants. This difference is most likely due to the hydrogen bonding interaction between Tyr57 and an active site water molecule that is persistent in the Y16F and Y16S mutants but absent in the FFF mutant and significantly less probable in WT KSI. PMID- 21710971 TI - Pa0148 from Pseudomonas aeruginosa catalyzes the deamination of adenine. AB - Four proteins from NCBI cog1816, previously annotated as adenosine deaminases, have been subjected to structural and functional characterization. Pa0148 (Pseudomonas aeruginosa PAO1), AAur1117 (Arthrobacter aurescens TC1), Sgx9403e, and Sgx9403g have been purified and their substrate profiles determined. Adenosine is not a substrate for any of these enzymes. All of these proteins will deaminate adenine to produce hypoxanthine with k(cat)/K(m) values that exceed 10(5) M(-1) s(-1). These enzymes will also accept 6-chloropurine, 6 methoxypurine, N-6-methyladenine, and 2,6-diaminopurine as alternate substrates. X-ray structures of Pa0148 and AAur1117 have been determined and reveal nearly identical distorted (beta/alpha)(8) barrels with a single zinc ion that is characteristic of members of the amidohydrolase superfamily. Structures of Pa0148 with adenine, 6-chloropurine, and hypoxanthine were also determined, thereby permitting identification of the residues responsible for coordinating the substrate and product. PMID- 21710972 TI - Alternate charging and discharging of capacitor to enhance the electron production of bioelectrochemical systems. AB - A bioelectrochemical system (BES) can be operated in both "microbial fuel cell" (MFC) and "microbial electrolysis cell" (MEC) modes, in which power is delivered and invested respectively. To enhance the electric current production, a BES was operated in MFC mode first and a capacitor was used to collect power from the system. Then the charged capacitor discharged electrons to the system itself, switching into MEC mode. This alternate charging and discharging (ACD) mode helped the system produce 22-32% higher average current compared to an intermittent charging (IC) mode, in which the capacitor was first charged from an MFC and then discharged to a resistor, at 21.6 Omega external resistance, 3.3 F capacitance and 300 mV charging voltage. The effects of external resistance, capacitance and charging voltage on average current were studied. The average current reduced as the external resistance and charging voltage increased and was slightly affected by the capacitance. Acquisition of higher average current in the ACD mode was attributed to the shorter discharging time compared to the charging time, as well as a higher anode potential caused by discharging the capacitor. Results from circuit analysis and quantitatively calculation were consistent with the experimental observations. PMID- 21710974 TI - Hydrogen-treated TiO2 nanowire arrays for photoelectrochemical water splitting. AB - We report the first demonstration of hydrogen treatment as a simple and effective strategy to fundamentally improve the performance of TiO(2) nanowires for photoelectrochemical (PEC) water splitting. Hydrogen-treated rutile TiO(2) (H:TiO(2)) nanowires were prepared by annealing the pristine TiO(2) nanowires in hydrogen atmosphere at various temperatures in a range of 200-550 degrees C. In comparison to pristine TiO(2) nanowires, H:TiO(2) samples show substantially enhanced photocurrent in the entire potential window. More importantly, H:TiO(2) samples have exceptionally low photocurrent saturation potentials of -0.6 V vs Ag/AgCl (0.4 V vs RHE), indicating very efficient charge separation and transportation. The optimized H:TiO(2) nanowire sample yields a photocurrent density of ~1.97 mA/cm(2) at -0.6 V vs Ag/AgCl, in 1 M NaOH solution under the illumination of simulated solar light (100 mW/cm(2) from 150 W xenon lamp coupled with an AM 1.5G filter). This photocurrent density corresponds to a solar-to hydrogen (STH) efficiency of ~1.63%. After eliminating the discrepancy between the irradiance of the xenon lamp and solar light, by integrating the incident photon-to-current-conversion efficiency (IPCE) spectrum of the H:TiO(2) nanowire sample with a standard AM 1.5G solar spectrum, the STH efficiency is calculated to be ~1.1%, which is the best value for a TiO(2) photoanode. IPCE analyses confirm the photocurrent enhancement is mainly due to the improved photoactivity of TiO(2) in the UV region. Hydrogen treatment increases the donor density of TiO(2) nanowires by 3 orders of magnitudes, via creating a high density of oxygen vacancies that serve as electron donors. Similar enhancements in photocurrent were also observed in anatase H:TiO(2) nanotubes. The capability of making highly photoactive H:TiO(2) nanowires and nanotubes opens up new opportunities in various areas, including PEC water splitting, dye-sensitized solar cells, and photocatalysis. PMID- 21710973 TI - Anticancer activity, attenuation on the absorption of calcium in mitochondria, and catalase activity for manganese complexes of N-substituted di(picolyl)amine. AB - In order to find multifunction anticancer complexes, three Mn(II) complexes of N substituted di(2-pyridylmethyl)amine were characterized and used as agents to interfere with the functions of mitochondria and the metabolite of O(2) in cancer cells. It was found that carboxylate-bridged dimanganese(II) systems are good models of catalase and exhibit good inhibition of the proliferation of U251 and HeLa cells. The inhibiting activity of these manganese(II) complexes on the tumor cells in vitro was related to their disproportionating H(2)O(2) activity. The reaction of carboxylate-bridged dimanganese Mn(II) complex with H(2)O(2) forms a stable Mn(III)-(MU-O)(2)-Mn(IV) complex. Extensive experimental results show that chloride-bridged dimanganese(II) complexes could inhibit the swelling of calcium(II) overloaded mitochondria, and carboxylate-bridged manganese(II) complexes enhance the swelling of calcium(II) overloaded mitochondria. These results indicate that the interactions between Mn(II) complexes of N-substituted di(picolyl)amine and mitochondria are influenced by the structure and conformation of the complexes. Mn(II) complexes of N-substituted di(picolyl)amine could be developed as multifunctional anticancer complexes to interfere with the absorption of calcium(II) in mitochondria and the metabolite of O(2) through the H(2)O(2) or ROS involved signaling induced apoptosis of cancer cells. PMID- 21710975 TI - Arabidopsis thaliana NIP7;1: an anther-specific boric acid transporter of the aquaporin superfamily regulated by an unusual tyrosine in helix 2 of the transport pore. AB - Plant nodulin-26 intrinsic proteins (NIPs) are members of the aquaporin superfamily that serve as multifunctional transporters of uncharged metabolites. In Arabidopsis thaliana, a specific NIP pore subclass, known as the NIP II proteins, is represented by AtNIP5;1 and AtNIP6;1, which encode channel proteins expressed in roots and leaf nodes, respectively, that participate in the transport of the critical cell wall nutrient boric acid. Modeling of the protein encoded by the AtNIP7;1 gene shows that it is a third member of the NIP II pore subclass in Arabidopsis. However, unlike AtNIP5;1 and AtNIP6;1 proteins, which form constitutive boric acid channels, AtNIP7;1 forms a channel with an extremely low intrinsic boric acid transport activity. Molecular modeling and molecular dynamics simulations of AtNIP7;1 suggest that a conserved tyrosine residue (Tyr81) located in transmembrane helix 2 adjacent to the aromatic arginine (ar/R) pore selectivity region stabilizes a closed pore conformation through interaction with the canonical Arg220 in ar/R region. Substitution of Tyr81 with a Cys residue, characteristic of established NIP boric acid channels, results in opening of the AtNIP7;1 pore that acquires a robust, transport activity for boric acid as well as other NIP II test solutes (glycerol and urea). Substitution of a Phe for Tyr81 also opens the channel, supporting the prediction from MD simulations that hydrogen bond interaction between the Tyr81 phenol group and the ar/R Arg may contribute to the stabilization of a closed pore state. Expression analyses show that AtNIP7;1 is selectively expressed in developing anther tissues of young floral buds of A. thaliana, principally in developing pollen grains of stage 9-11 anthers. Because boric acid is both an essential nutrient as well as a toxic compound at high concentrations, it is proposed that Tyr81 modulates transport and may provide an additional level of regulation for this transporter in male gametophyte development. PMID- 21710976 TI - Synthesis and biological evaluation of a polyglutamic acid-dopamine conjugate: a new antiangiogenic agent. AB - Dopamine has previously been shown to inhibit angiogenesis in vitro and in vivo, but its clinical applications in this context are severely limited by its short half-life. Here we report the synthesis of a polyglutamic acid-dopamine conjugate and show that conjugation significantly extends (from 1 to 24 h) dopamine's antiangiogenic activity in vitro and in vivo. These findings form the basis for the development of a new class of agents for the treatment of angiogenesis dependent diseases. PMID- 21710977 TI - The cat that caught the canary: what to do with single-molecule trapping. AB - It has recently become possible to trap individual fluorescent biomolecules in aqueous solution by using real-time tracking and active feedback to suppress Brownian motion. We propose areas of investigation in which anti-Brownian electrokinetic (ABEL) trapping of single molecules is likely to lead to significant new insights into biomolecular dynamics. PMID- 21710978 TI - "Supramolecular circuitry": three chemiluminescent, Cucurbit[7]uril-controlled on/off switches. AB - Three Cucurbit[7]uril-controlled chemiluminescent on/off switches based on the lucigenin motif have been synthesized. Light emission is triggered upon addition of sodium peroxide, interrupted or dimmed in the presence of Cucurbit[7]uril, and restored upon injection of a competitive guest. The process, which can be mimicked by a simple resistor-capacitor circuit, is rationalized by examining the role of the macrocyclic host on the network of equilibria involved in the chemiluminescent process. PMID- 21710979 TI - Domino process optimized via ab initio study for an alternative access to bicyclic lactams. AB - A totally new acid-free domino process to access highly functionalized bicyclic gamma- and delta-lactams starting from commercially available and inexpensive ethoxymethylene derivatives is reported. Mechanisms elucidated by computational calculations led to new reaction conditions that boosted the yields up to 3.5 times higher. PMID- 21710980 TI - Use of Tetragenococcus halophilus as a starter culture for flavor improvement in fish sauce fermentation. AB - The potential of Tetragenococcus halophilus as a starter culture for flavor improvement in fish sauce fermentation was elucidated. Four strains of T. halophilus isolated from fish sauce mashes were inoculated to anchovy mixed with 25% NaCl with an approximate cell count of 10(6) CFU/mL. The alpha-amino content of 6-month-old fish sauce samples inoculated with T. halophilus was 780-784 mM. The addition of T. halophilus MRC10-1-3 and T. halophilus MCD10-5-10 resulted in a reduction of histamine (P < 0.05). Fish sauce inoculated with T. halophilus showed high contents of total amino acids with predominantly high glutamic acid. Major volatile compounds in fish sauce were 2-methylpropanal, 2-methylbutanal, 3 methylbutanal, and benzaldehyde. T. halophilus-inoculated fish sauce samples demonstrated the ability to reduce dimethyl disulfide, a compound contributing to a fecal note. The use of T. halophilus for fish sauce fermentation improves amino acid profiles and volatile compounds as well as reduces biogenic amine content of a fish sauce product. PMID- 21710982 TI - Theoretical study of Pt(PR3)(2)(AlCl3) (R = H, Me, Ph, or Cy) including an unsupported bond between transition metal and non-transition metal elements: geometry, bond strength, and prediction. AB - The molecular structure and the binding energy of Pt(PR(3))(2)(AlCl(3)) (R = H, Me, Ph, or Cy) were investigated by DFT, MP2 to MP4(SDTQ), and CCSD(T) methods. The optimized structure of Pt(PCy(3))(2)(AlCl(3)) (Cy = cyclohexyl) by the DFT method with M06-2X and LC-BLYP functionals agrees well with the experimental one. The MP4(SDTQ) and CCSD(T) methods present similar binding energies (BE) of Pt(PH(3))(2)(AlCl(3)), indicating that these methods provide reliable BE value. The DFT(M06-2X)-calculated BE value is close to the MP4(SDTQ) and CCSD(T) calculated values, while the other functionals present BE values considerably different from the MP4(SDTQ) and CCSD(T)-calculated values. All computational methods employed here indicate that the BE values of Pt(PMe(3))(2)(AlCl(3)) and Pt(PPh(3))(2)(AlCl(3)) are considerably larger than those of the ethylene analogues. The coordinate bond of AlCl(3) with Pt(PR(3))(2) is characterized to be the sigma charge transfer (CT) from Pt to AlCl(3). This complex has a T-shaped structure unlike the well-known Y-shaped structure of Pt(PMe(3))(2)(C(2)H(4)), although both are three-coordinate Pt(0) complex. This T-shaped structure results from important participation of the Pt d(sigma) orbital in the sigma-CT; because the Pt d(sigma) orbital energy becomes lower as the P-Pt-P angle decreases, the T shaped structure is more favorable for the sigma-CT than is the Y-shaped structure. [Co(alcn)(2)(AlCl(3))](-) (alcn = acetylacetoneiminate) is theoretically predicted here as a good candidate for the metal complex, which has an unsupported M-Al bond because its binding energy is calculated to be much larger than that of Pt(PCy(3))(2)(AlCl(3)). PMID- 21710983 TI - Physicochemical characterization of alpha-, beta-, and gamma-cyclodextrins bioesterified with decanoate chains used as building blocks of colloidal nanoparticles. AB - Nanoparticles of amphiphilic alpha-, beta-, and gamma-cyclodextrins were obtained by formulation of cyclodextrins enzymatically transesterified with vinyl decanoate. The product of this synthesis is a mixture of bioesterified cyclodextrins with various degrees of substitution (DS) presenting for a same DS different regio-isomers. In a first step, the efficiency of a MALDI-TOF procedure to characterize the average molecular weight of the derivative bulk mixture was demonstrated by comparing the results with those obtained from complementary NMR and HPLC techniques. In a second step, the ultrastructure of nanoparticles prepared from three different batches of synthesis was investigated and correlated with the average molecular weight and DS of the parent derivative. PMID- 21710984 TI - N-Alkynyl imides (ynimides): synthesis and use as a variant of highly labile ethynamine. AB - This study describes the first reliable synthesis of N-alkynyl imides (ynimides). This was accomplished with a copper-catalyzed coupling reaction between alkynyl(triaryl)bismuthonium salts and five-membered imides. We also found that it was possible to utilize N-ethynyl phthalimide as a variant of the highly labile ethynamine. 4-Amino-1,2,3-triazole was successfully obtained via the CuAAC reaction of N-ethynyl phthalimide with azide followed by hydrazinolysis of the phthaloyl protecting group. PMID- 21710981 TI - Alcohol-, diol-, and carbohydrate-substituted indenoisoquinolines as topoisomerase I inhibitors: investigating the relationships involving stereochemistry, hydrogen bonding, and biological activity. AB - The DNA-relaxing enzyme topoisomerase I (Top1) can be inhibited by heterocyclic compounds such as indolocarbazoles and indenoisoquinolines. Carbohydrate and hydroxyl-containing side chains are essential for the biological activity of indolocarbazoles. The current study investigated how similar functionalities could be "translated" to the indenoisoquinoline system and how stereochemistry and hydrogen bonding affect biological activity. Herein is described the preparation and assay of indenoisoquinolines substituted with short-chain alcohols, diols, and carbohydrates. Several compounds (including those derived from sugars) display potent Top1 poisoning and antiproliferative activities. The Top1 poisoning activity of diol-substituted indenoisoquinolines is dependent upon stereochemistry. Although the effect is striking, molecular modeling and docking studies do not indicate any reason for the difference in activity due to similar calculated interactions between the ligand and Top1-DNA complex and ambiguity about the binding mode. A stereochemical dependence was also observed for carbohydrate-derived indenoisoquinolines. Although similar trends were observed in other classes of Top1 inhibitors, the exact nature of this effect has yet to be elucidated. PMID- 21710985 TI - Performance of school bus retrofit systems: ultrafine particles and other vehicular pollutants. AB - This study evaluated the performance of retrofit systems for diesel-powered school buses, a diesel oxidation catalyst (DOC) muffler and a spiracle crankcase filtration system (CFS), regarding ultrafine particles (UFPs) and other air pollutants from tailpipe emissions and inside bus cabins. Tailpipe emissions and in-cabin air pollutant levels were measured before and after retrofitting when the buses were idling and during actual pick-up/drop off routes. Retrofit systems significantly reduced tailpipe emissions with a reduction of 20-94% of total particles with both DOC and CFS installed. However, no unequivocal decrease was observed for in-cabin air pollutants after retrofitting. The AC/fan unit and the surrounding air pollutant concentrations played more important roles for determining the in-cabin air quality of school buses than did retrofit technologies. Although current retrofit systems reduce children's exposure while waiting to board at a bus station, retrofitting by itself does not protect children satisfactorily from in-cabin particle exposures. Turning on the bus engine increased in-cabin UFP levels significantly only when the wind blew from the bus' tailpipe toward its hood with its windows open. This indicated that wind direction and window position are significant factors determining how much self released tailpipe emissions may penetrate into the bus cabin. The use of an air purifier was found to remove in-cabin particles by up to 50% which might be an alternative short-to-medium term strategy to protect children's health. PMID- 21710986 TI - Exposure to CuO nanoparticles changes the fatty acid composition of protozoa Tetrahymena thermophila. AB - In the current study, the toxicity mechanism of nanosized CuO (nCuO) to the freshwater ciliated protozoa Tetrahymena thermophila was studied. Changes in fatty acid profile, lipid peroxidation metabolites and reactive oxygen species (ROS) were measured. Bulk CuO and CuSO(4) served as controls for size and solubility and 3,5-dichorophenol (3,5-DCP) as a control for a chemical known to directly affect the membrane composition. Exposure to all copper compounds induced the generation of ROS, whereas nCuO was most potent. The latter effect was not solely explained by solubilized Cu-ions and was apparently particle related. 24 h exposure of protozoa to 80 mg/L of nCuO (EC50) significantly decreased the proportion of two major unsaturated fatty acids (UFA) (C18:3 cis 6,9,12, C18:2 cis-9,12), while it increased the relative amount of two saturated fatty acids (SFA) (C18:0, C16:0). Analogous effect was not observed when protozoa were exposed to equitoxic suspensions of bulk CuO, Cu-ions or 3,5-DCP. As changes in the UFA:SFA upon exposure of protozoa to nCuO were not detected at 2 h exposure and no simultaneous dose- or time-dependent lipid peroxidation occurred, it is likely that one of the adaptation mechanisms of protozoa to nCuO was lowering membrane fluidity by the inhibition of de novo synthesis of fatty acid desaturases. This is the first study of the effects of nanoparticles on the membrane fatty acid composition. PMID- 21710987 TI - From micelle supramolecular assemblies in selective solvents to isoporous membranes. AB - The supramolecular assembly of PS-b-P4VP copolymer micelles induced by selective solvent mixtures was used to manufacture isoporous membranes. Micelle order in solution was confirmed by cryo-scanning electron microscopy in casting solutions, leading to ordered pore morphology. When dioxane, a solvent that interacts poorly with the micelle corona, was added to the solution, polymer-polymer segment contact was preferential, increasing the intermicelle contact. Immersion in water gave rise to asymmetric porous membranes with exceptional pore uniformity and high porosity. The introduction of a small number of carbon nanotubes to the casting solution improved the membrane stability and the reversibility of the gate response in the presence of different pH values. PMID- 21710988 TI - pH-sensitive interaction of HMG-CoA reductase inhibitors (statins) with organic anion transporting polypeptide 2B1. AB - The human organic anion transporting polypeptide 2B1 (OATP2B1, SLCO2B1) is ubiquitously expressed and may play an important role in the disposition of xenobiotics. The present study aimed to examine the role of OATP2B1 in the intestinal absorption and tissue uptake of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitors (statins). We first investigated the functional affinity of statins to the transporter as a function of extracellular pH, using OATP2B1-transfeced HEK293 cells. The results indicate that OATP2B1-mediated transport is significant for rosuvastatin, fluvastatin and atorvastatin, at neutral pH. However, OATP2B1 showed broader substrate specificity as well as enhanced transporter activity at acidic pH. Furthermore, uptake at acidic pH was diminished in the presence of proton ionophore, suggesting proton gradient as the driving force for OATP2B1 activity. Notably, passive transport rates are predominant or comparable to active transport rates for statins, except for rosuvastatin and fluvastatin. Second, we studied the effect of OATP modulators on statin uptake. At pH 6.0, OATP2B1-mediated transport of atorvastatin and cerivastatin was not inhibitable, while rosuvastatin transport was inhibited by E 3-S, rifamycin SV and cyclosporine with IC(50) values of 19.7 +/- 3.3 MUM, 0.53 +/- 0.2 MUM and 2.2 +/- 0.4 MUM, respectively. Rifamycin SV inhibited OATP2B1 mediated transport of E-3-S and rosuvastatin with similar IC(50) values at pH 6.0 and 7.4, suggesting that the inhibitor affinity is not pH-dependent. Finally, we noted that OATP2B1-mediated transport of E-3-S, but not rosuvastatin, is pH sensitive in intestinal epithelial (Caco-2) cells. However, uptake of E-3-S and rosuvastatin by Caco-2 cells was diminished in the presence of proton ionophore. The present results indicate that OATP2B1 may be involved in the tissue uptake of rosuvastatin and fluvastatin, while OATP2B1 may play a significant role in the intestinal absorption of several statins due to their transporter affinity at acidic pH. PMID- 21710989 TI - High-accuracy measurements of OH(*) reaction rate constants and IR and UV absorption spectra: ethanol and partially fluorinated ethyl alcohols. AB - Rate constants for the gas phase reactions of OH(*) radicals with ethanol and three fluorinated ethyl alcohols, CH(3)CH(2)OH (k(0)), CH(2)FCH(2)OH (k(1)), CHF(2)CH(2)OH (k(2)), and CF(3)CH(2)OH (k(3)) were measured using a flash photolysis resonance-fluorescence technique over the temperature range 220 to 370 K. The Arrhenius plots were found to exhibit noticeable curvature for all four reactions. The temperature dependences of the rate constants can be represented by the following expressions over the indicated temperature intervals: k(0)(220 370 K) = 5.98 * 10(-13)(T/298)(1.99) exp(+515/T) cm(3) molecule(-1) s(-1), k(0)(220-298 K) = (3.35 +/- 0.06) * 10(-12) cm(3) molecule(-1) s(-1) [for atmospheric modeling purposes, k(0)(T) is essentially temperature-independent below room temperature, k(0)(220-298 K) = (3.35 +/- 0.06) * 10(-12) cm(3) molecule(-1) s(-1)], k(1)(230-370 K) = 3.47 * 10(-14)(T/298)(4.49) exp(+977/T) cm(3) molecule(-1) s(-1), k(2)(220-370 K) = 3.87 * 10(-14)(T/298)(4.25) exp(+578/T) cm(3) molecule(-1) s(-1), and k(3)(220-370 K) = 2.48 * 10( 14)(T/298)(4.03) exp(+418/T) cm(3) molecule(-1) s(-1). The atmospheric lifetimes due to reactions with tropospheric OH(*) were estimated to be 4, 16, 62, and 171 days, respectively, under the assumption of a well-mixed atmosphere. UV absorption cross sections of all four ethanols were measured between 160 and 215 nm. The IR absorption cross sections of the three fluorinated ethanols were measured between 400 and 1900 cm(-1), and their global warming potentials were estimated. PMID- 21710990 TI - Affibody-attached hyperbranched conjugated polyelectrolyte for targeted fluorescence imaging of HER2-positive cancer cell. AB - A hyperbranched conjugated polyelectrolyte (HCPE) with a core-shell structure is designed and synthesized via alkyne polycyclotrimerization and click chemistry. The HCPE has an emission maximum at 565 nm with a quantum yield of 12% and a large Stokes shift of 143 nm in water. By virtue of its poly(ethylene glycol) shell, this polymer naturally forms spherical nanoparticles that minimize nonspecific interaction with biomolecules in aqueous solution, consequently allowing for efficient bioconjugation with anti-HER2 affibody via carbodiimide activated coupling reaction. The resulting affibody-attached HCPE can be utilized as a reliable fluorescent probe for targeted cellular imaging of HER2 overexpressed cancer cells such as SKBR-3. Considering its low cytotoxicity and good photostability, the HCPE nanoprobe holds great promise in practical imaging tasks. This study also provides a molecular engineering strategy to overcome the intrinsic limitations of traditional fluorescent polymers (e.g., chromophore tethered polymers and linear conjugated polyelectrolytes) for bioconjugation and applications. PMID- 21710991 TI - Development and evaluation of micro push-pull tests to investigate micro-scale processes in porous media. AB - Soils and sediments are porous media characterized by heterogeneities across a wide range of spatial scales. Physical, chemical, and biological properties have been found to show great variation even at subcentimeter scales. Here we present a new micro technique for the in situ study of chemical and microbiological reactions in water-saturated porous media at the mm-scale. This technique combines micro suction cups with the principle of single-well injection withdrawal tests ("push-pull" tests). Push-pull tests have been used extensively on larger scales in groundwater research to obtain quantitative information of physical, chemical, and microbiological characteristics of an aquifer. The micro push-pull technique presented here was developed and validated using a thin-slab chamber filled with sand. A porous micro cup was used to inject about 250 MUL of a test solution into the water-saturated sand pack and then to slowly extract about 850 MUL water from the same point. The extraction-phase breakthrough curves of the solutes were modeled considering advection, dispersion, and molecular diffusion without fitting any parameters. As an example we quantified the degradation of citrate injected into the water-saturated sand pack inoculated with denitrifying bacteria. The results show that the new technique can be used to assess local microbial degradation processes under in situ conditions on the micro scale. PMID- 21710992 TI - Spatial and temporal variation of watertype-specific no-effect concentrations and risks of Cu, Ni, and Zn. AB - Geographical and temporal variations in metal speciation were calculated and water-type specific sensitivities were derived for a range of aquatic species, using surveillance water chemistry data that cover almost all surface water types in The Netherlands. Biotic ligand models for Cu, Zn, and Ni were used to normalize chronic no-effect concentrations (NOEC) determined in test media toward site-specific NOEC for 372 sites sampled repeatedly over 2007-2010. Site-specific species sensitivity distributions were constructed accounting for chemical speciation. Sensitivity of species as well as predicted risks shifted among species over space and time, due to changes in metal concentrations, speciation, and biotic ligand binding. Sensitivity of individual species (NOEC) and of the ecosystem (HC5) for Cu, Ni, and Zn showed a spatial variation up to 2 orders of magnitude. Seasonality of risks was shown, with an average ratio between lowest and highest risk of 1.3, 2.0, and 3.6 for Cu, Ni, and Zn, respectively. Maximum risks of Cu, Ni, and Zn to ecosystems were predicted in February and minimum risks in September. A risk assessment using space-time specific HC5 of Cu and Zn resulted in a reduction of sites at risk, whereas for Ni the number of sites at risks increased. PMID- 21710993 TI - Molecular mechanism for eliminylation, a newly discovered post-translational modification. AB - The newly discovered bacterial phosphothreonine lyases perform a post translational modification of host cell signaling proteins through a novel catalytic mechanism that irreversibly removes the phosphate group from a phosphorylated threonine via beta-elimination. This "eliminylation" reaction is shown by ab initio QM/MM studies to proceed via an E1cB-like pathway, in which the carbanion intermediate is stabilized by an enzyme oxyanion hole provided by Lys104 and Tyr158 of SpvC. PMID- 21710994 TI - Relativistic effect on 77Se NMR chemical shifts of various selenium species in the framework of zeroth-order regular approximation. AB - The relativistic effects on absolute magnetic shielding tensors (sigma(Se)) are explicitly evaluated for various selenium species (40 species) with the DFT(BLYP) GIAO method. Calculations are performed under relativistic and nonrelativistic conditions with the Slater-type basis sets in ADF 2010 in the framework of ZORA, employing the optimized structures under nonrelativistic conditions at B3LYP of Gaussian 03. Quadruple zeta all electron with four polarization functions (QZ4Pae) are mainly applied to evaluate sigma(Se). Ranges of the effect on diamagnetic (sigma(d)(Se)), paramagnetic shielding tensors (sigma(p)(Se)), and sigma(d+p)(Se) (= sigma(d)(Se) + sigma(p)(Se)) are -24 to -20 ppm, -115 to -3 ppm, and -136 to -26 ppm, respectively. The spin-orbit terms (sigma(so)(Se)) are evaluated to be 92-225 ppm with QZ4Pae, which clarifies the effect on total shielding tensors (sigma(t)(Se) = sigma(d+p)(Se) + sigma(so)(Se)) to be -8 to 152 ppm, at the spin-orbit ZORA level. The calculated sigma(t)(Se) values reproduced well the observed values. PMID- 21710995 TI - Cyano-bridged homodinuclear copper(II) complexes. AB - The synthesis and structural analysis (single crystal X-ray data) of two mononuclear ([Cu(L(1))(CN)]BF(4) and [Cu(L(3))(CN)](BF(4))) and three related, cyanide-bridged homodinuclear complexes ([{Cu(L(1))}(2)(CN)](BF(4))(3).1.35 H(2)O, [{Cu(L(2))}(2)(CN)](BF(4))(3) and [{Ni(L(3))}(2)(CN)](BF(4))(3)) with a tetradentate (L(1)) and two isomeric pentadentate bispidine ligands (L(2), L(3); bispidines are 3,7-diazabicyclo[3.3.1]nonane derivatives) are reported, together with experimental magnetic, electron paramagnetic resonance (EPR), and electronic spectroscopic data and a ligand-field-theory-based analysis. The temperature dependence of the magnetic susceptibilities and EPR transitions of the dicopper(II) complexes, together with the simulation of the EPR spectra of the mono- and dinuclear complexes leads to an anisotropic set of g- and A-values, zero-field splitting (ZFS) and magnetic exchange parameters (Cu1: g(z) = 2.055, g(x) = 2.096, g(y) = 2.260, A(z) = 8, A(x) = 8, A(y) = 195 * 10(-4) cm(-1), Cu2: g and A as for Cu(1) but rotated by the Euler angles alpha = -6 degrees , beta = 100 degrees , D(exc) = -0.07 cm(-1), E(exc)/D(exc) = 0.205 for [{Cu(L(1))}(2)(CN)](BF(4))(3).1.35 H(2)O; Cu1,2: g(z) = 2.025, g(x) = 2.096, g(y) = 2.240, A(z) = 8, A(x) = 8, A(y) = 190 * 10(-4)cm(-1), D(exc) = -0.159 cm(-1), E(exc)/D(exc) = 0.080 for [{Cu(L(2))}(2)(CN)](BF(4))(3)). Thorough ligand-field theory-based analyses, involving all micro states and all relevant interactions (Jahn-Teller and spin-orbit coupling) and DFT calculations of the magnetic exchange leads to good agreement between the experimental observations and theoretical predictions. The direction of the symmetric magnetic anisotropy tensor D(exc) in [{Cu(L(2))}(2)(CN)](BF(4))(3) is close to the Cu...Cu vector (22 degrees ), that is, nearly perpendicular to the Jahn-Teller axis of each of the two Cu(II) centers, and this reflects the crystallographically observed geometry. Antisymmetric exchange in [{Cu(L(1))}(2)(CN)](BF(4))(3).1.35 H(2)O causes a mixing between the singlet ground state and the triplet excited state, and this also reflects the observed geometry with a rotation of the two Cu(II) sites around the Cu...Cu axis. PMID- 21710997 TI - Exploring the binding ability of polyammonium hosts for anionic substrates: selective size-dependent recognition of different phosphate anions by bis macrocyclic receptors. AB - Binding of mono-, di-, and triphosphate, adenosine diphosphate (ADP), and adenosine triphosphatase (ATP) with receptors L1-L3, composed of two [9]aneN(3) units separated by a 2,9-dimethylene-1,10-phenanthroline (L1), a 2,6 dimethylenepyridine (L2), or a 2,3-dimethylenequinoxaline (L3) spacer, has been studied by means of potentiometric titrations, (1)H and (31)P NMR measurements in aqueous solutions, and molecular modeling calculations. In the case of inorganic phosphates, the binding properties of the receptors appear to be determined by their geometrical features, in particular the distance between the two [9]aneN(3) units imposed by the spacer separating the two macrocyclic units. While L1 is able to selectively bind triphosphate over di- and monophosphate, L3 selectively coordinates the smaller monophosphate anion. Finally, L2 shows preferential binding of diphosphate. (1)H and (31)P NMR measurements show that the complexes are essentially stabilized by charge-charge and hydrogen-bonding interactions between the anion and the protonated amine groups of the macrocyclic subunits of the receptors. Molecular dynamics simulations suggest that the larger distance between the two macrocyclic units of L1 allows this receptor to form a larger number of hydrogen-bonding contacts with triphosphate, justifying its selectivity toward this anion. Conversely, in the case of L3, the two facing [9]aneN3 units give rise to a cleft of appropriate dimensions where the small monophosphate anion can be conveniently hosted. Considering nucleotide coordination, L1 is a better receptor for ATP and ADP than L2, thanks to the higher ability of phenanthroline to establish stabilizing pi stacking and hydrophobic interactions with the adenine units of the guests. PMID- 21710998 TI - Coordination properties of 2,5-dimesitylpyridine: an encumbering and versatile ligand for transition-metal chemistry. AB - To overcome the unfavorable steric pressures associated with 2,6-disubstitution in encumbering pyridine ligands, the coordination chemistry of a 2,5 disubstituted variant, namely, 2,5-dimesitylpyridine (2,5-Mes(2)py), is reported. This diaryl pyridine shows good binding ability to a range of transition-metal fragments with varying formal oxidation states and coligands. Treatment of 2.0 equiv of 2,5-Mes(2)py with monovalent Cu and Ag triflate sources generates complexes of the type [M(2,5-Mes(2)py)(2)]OTf (M = Cu, Ag; OTf = OSO(2)CF(3)), which feature long M-OTf distances and a substrate-accessible primary coordination sphere. Combination of 2,5-Mes(2)py with Cu(OTf)(2) and Pd(OAc)(2) produces four-coordinate complexes featuring cis- and trans-2,5-Mes(2)py orientations, respectively. The four-coordinate palladium complex Pd(OAc)(2)(2,5 Mes(2)py)(2) is found to resist py-ligand dissociation at room temperature in solution, but functions as a precatalyst for the aerobic C-H bond olefination of benzene at elevated temperatures. This C-H bond activation chemistry is compared with a similar Pd-based system featuring 2,6-disubstituted pyridines. 2,5 Mes(2)py also readily supports mono- and dinuclear divalent Co complexes, and the solution-phase equilibria between such species are detailed. The coordination studies presented highlight the potential of 2,5-Mes(2)py to function as an encumbering ancillary for the stabilization of low-coordinate complexes and as a supporting ligand for metal-mediated transformations. PMID- 21710996 TI - Enhancing the stiffness of electrospun nanofiber scaffolds with a controlled surface coating and mineralization. AB - A new method was developed to coat hydroxyapatite (HAp) onto electrospun poly(lactic-co-glycolic acid) (PLGA) nanofibers for tendon-to-bone insertion site repair applications. Prior to mineralization, chitosan and heparin were covalently immobilized onto the surface of the fibers to accelerate the nucleation of bone-like HAp crystals. Uniform coatings of HAp were obtained by immersing the nanofiber scaffolds into a modified, 10-fold-concentrated simulated body fluid (m10SBF) for different periods of time. The new method resulted in thicker and denser coatings of mineral on the fibers compared to those produced by previously reported methods. Scanning electron microscopy measurements confirmed the formation of nanoscale HAp particles on the fibers. A mechanical property assessment demonstrated a higher stiffness with respect to previous coating methods. A combination of the nanoscale fibrous structure and bonelike mineral coating could mimic the structure, composition, and function of mineralized tissues. PMID- 21710999 TI - FTIR matrix-isolation study of the reaction products of vanadium atoms with propene: observation of allylvanadium hydride as a precursor to sacrificial hydrogenation of propene. AB - Vanadium atoms have been reacted with different partial pressures of propene in Ar under matrix-isolation conditions, and the products have been observed using Fourier transform infrared (FTIR) spectroscopy. Under dilute propene in Ar conditions, new features are observed in the IR spectra corresponding to a C-H insertion product, identified here as H-V-(eta(3)-allyl). Use of d(3)-propene (CD(3)-CH?CH(2)) demonstrates that the initial V-atom insertion occurs at the methyl group of the propene molecule, and DFT calculations have been used to support the identity of the initial product. Upon increasing the partial pressure of propene, additional features corresponding to propane (C(3)H(8)) are observed, with the hydrogen-atom source for the observed hydrogenation demonstrated to be additional propene units. Analysis of a systematic increase in the partial pressure of propene in the system demonstrates that the yield of propane correlates with the decrease of the allyl product, demonstrating the H-V(allyl) species as a reactive intermediate in the overall hydrogenation process. An overall mechanism is proposed to rationalize the formation of the insertion product and ultimately the products of hydrogenation, which agrees with previous gas-phase and matrix-isolation work involving propene and the related system, ethene. PMID- 21711000 TI - Carotenoid radical formation: dependence on conjugation length. AB - The relative energy of carotenoid neutral radicals formed by proton loss from the radical cations of linear carotenoids has been examined as a function of conjugation length from n = 15 to 9. For a maximum conjugation length of n = 15 (bisdehydrolycopene, a symmetrical compound), proton loss can occur from any of the 10 methyl groups, with proton loss from the methyl group at position C1 or C1' being the most favorable. In contrast, the most energetically favorable proton loss from the radical cations of lycopene, neurosporene, spheroidene, spheroidenone, spirilloxanthin, and anhydrorhodovibrin occurs from methylene groups that extend from the conjugated system. For example, decreasing the conjugation length to n = 11 (lycopene) by saturation of the double bonds C3-C4 and at C3'-C4' of bisdehydrolycopene favors proton loss at C4 or C4' methylene groups. Saturation at C7'-C8' in the case of neurosporene, spheroidene, and spheroidenone (n = 9, 10, 11) favors the formation of a neutral radical at the C8' methylene group. Saturation of C1-C2 by addition of a methoxy group to a bisdehydrolycopene-like structure with conjugation of n = 12 or 13 (anhydrorhodovibrin, spirilloxanthin) favors proton loss at the C2 methylene group. As a consequence of deprotonation of the radical cation, the unpaired electron spin distribution changes so that larger beta-methyl proton couplings occur for the neutral radicals (13-16 MHz) than for the radical cation (7-10 MHz), providing a means to identify possible carotenoid radicals in biological systems by Mims ENDOR. PMID- 21711002 TI - Coexistence of 1D and quasi-0D photoluminescence from single silicon nanowires. AB - Single silicon nanowires (Si-NWs) prepared by electron-beam lithography and reactive-ion etching are investigated by imaging optical spectroscopy under variable temperatures and laser pumping intensities. Spectral images of individual Si-NWs reveal a large variability of photoluminescence (PL) along a single Si-NW. The weaker broad emission band asymmetrically extended to the high energy side is interpreted to be due to recombination of quasi-free 1D excitons while the brighter localized emission features (with significantly variable peak position, width, and shape) are due to localization of electron-hole pairs in surface protrusions acting like quasi-0D centers or quantum dots (QDs). Correlated PL and scanning electron microscopy images indicate that the efficiently emitting QDs are located at the Si-NW interface with completely oxidized neck of the initial Si wall. Theoretical fitting of the delocalized PL emission band explains its broad asymmetrical band to be due to the Gaussian size distribution of the Si-NW diameter and reveals also the presence of recombination from the Si-NW excited state which can facilitate a fast capture of excitons into QD centers. PMID- 21711003 TI - Adsorption of trimethyl phosphate on maghemite, hematite, and goethite nanoparticles. AB - Adsorption of trimethyl phosphate (TMP) on well-characterized hematite, maghemite and goethite nanoparticles was studied by in situ DRIFT spectroscopy as a model system for adsorption of organophosphorous (OP) compounds on iron minerals. The iron minerals were characterized by X-ray diffraction (XRD), Raman spectroscopy, transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), specific surface area, and pore size distribution. The minerals were found to consist of stoichimetrically and morphologically well-defined maghemite, hematite, and goethite nanoparticles. Analysis of in situ diffuse reflectance Fourier transform (DRIFT) spectroscopy shows that TMP bonds mainly to Lewis acid Fe sites through the O phosphoryl atom (-P?O-Fe) on hematite and maghemite. On goethite most TMP molecules bond to Bronstedt acid surface OH groups and form hydrogen bonded surface complexes. The vibrational mode analysis and uptake kinetics suggest two main reasons for the observed trend of reactivity toward TMP (hematite > maghemite > goethite): (i) larger number of accessible Lewis acid adsorption sites on hematite; (ii) stronger interaction between the Lewis acid Fe sites and the phosphoryl O atom on TMP for hematite and maghemite compared to goethite with concomitant formation of surface coordinated TMP and dimethyl phosphate intermediates. As a result, on the oxides a surface oxidation pathway dominates during the initial adsorption, which results in the formation of surface methoxy and formate. In contrast, on goethite a slower hydrolysis pathway is identified, which eventually yields phosphoric acid. The observed trends of the reactivity and analysis of the corresponding surface structure and particle morphology suggest an intimate relation between the surface chemistry of exposed crystal facets on the iron minerals. These results are important to understand OP surface chemistry on iron minerals. PMID- 21711001 TI - Mechanism and substrate recognition of 2-hydroxyethylphosphonate dioxygenase. AB - HEPD belongs to the superfamily of 2-His-1-carboxylate non-heme iron-dependent dioxygenases. It converts 2-hydroxyethylphosphonate (2-HEP) to hydroxymethylphosphonate (HMP) and formate. Previously postulated mechanisms for the reaction catalyzed by HEPD cannot explain its conversion of 1-HEP to acetylphosphate. Alternative mechanisms that involve either phosphite or methylphosphonate as intermediates, which potentially explain all experimental studies including isotope labeling experiments and use of substrate analogues, were investigated. The results of these studies reveal that these alternative mechanisms are not correct. Site-directed mutagenesis studies of Lys16, Arg90, and Tyr98 support roles of these residues in binding of 2-HEP. Mutation of Lys16 to Ala resulted in an inactive enzyme, whereas mutation of Arg90 to Ala or Tyr98 to Phe greatly decreased k(cat)/K(m,2-HEP). Furthermore, the latter mutants could not be saturated in O(2). These results suggest that proper binding of 2-HEP is important for O(2) activation and that the enzyme uses a compulsory binding order with 2-HEP binding before O(2). The Y98F mutant produces methylphosphonate as a minor side product providing indirect support for the proposal that the last step during catalysis involves a ferric hydroxide reacting with a methylphosphonate radical. PMID- 21711004 TI - Soft embossing of nanoscale optical and plasmonic structures in glass. AB - We describe here soft nanofabrication methods using spin-on glass (SOG) materials for the fabrication of both bulk materials and replica masters. The precision of soft nanofabrication using SOG is tested using features on size scales ranging from 0.6 nm to 1.0 MUm. The performance of the embossed optics is tested quantitatively via replica patterning of new classes of plasmonic crystals formed by soft nanoimprinting of SOG. These crystals are found to offer significant improvements over previously reported plasmonic crystals fabricated using embossed polymeric substrate materials in several ways. The SOG structures are shown to be particularly robust, being stable in organic solvent environments and at high temperatures (~450 degrees C), thus extending the capacities and scope of plasmonic crystal applications to sensing in these environments. They also provide a stable, and particularly high-performance, platform for surface enhanced Raman scattering. We further illustrate that SOG embossed nanostructures can serve as regenerable masters for the fabrication of plasmonic crystals. Perhaps most significantly, we show how the design rules of plasmonic crystals replicated from a single master can be tuned during the embossing steps of the fabrication process to provide useful modifications of their optical responses. We illustrate how the strongest feature in the transmission spectrum of a plasmonic crystal formed using a single SOG master can be shifted precisely in a SOG replica between 700 and 900 nm for an exemplary design of a full 3D plasmonic crystal by careful manipulation of the process parameters used to fabricate the optical device. PMID- 21711005 TI - Regiodivergent reactions through catalytic enantioselective silylation of chiral diols. Synthesis of sapinofuranone A. AB - Through the use of an amino acid based imidazole catalyst, a regiodivergent silylation of chiral diols in cases where there is not a significant steric and electronic difference between the regioisotopic hydroxyl groups has been developed. This transformation allows for the conversion of racemic diols into regioisomeric, enantiomerically enriched, monosilylated products. The utility of this process is highlighted in the efficient enantioselective preparation of a useful synthetic intermediate and the natural product, sapinofuranone A. PMID- 21711006 TI - Glycomimetic building blocks: a divergent synthesis of epimers of shikimic acid. AB - A divergent synthesis of (-)-4-epi-shikimic acid was developed. This route features a one-pot zinc-mediated reductive ring opening of an arabinofuranose followed by a Barbier reaction and culminates in a ring-closing metathesis. Functionalization of (-)-4-epi-shikimic acid via conjugate addition of a thiol occurs in high diastereoselectivity to afford a product with the features of fucosylated glycans. PMID- 21711007 TI - [3]Rotaxane-based dinuclear palladium catalysts for ring-closure Mizoroki-Heck reaction. AB - [3]Rotaxane containing two Pd centers in the cyclic compounds catalyzes a Mizoroki-Heck reaction of substrates with two iodophenyl groups with bisacrylate. Formation of the cyclic products is enhanced by the rotaxane catalyst more smoothly than Pd(OAc)(2). PMID- 21711008 TI - Flexizymes: their evolutionary history and the origin of catalytic function. AB - Transfer RNA (tRNA) is an essential component of the cell's translation apparatus. These RNA strands contain the anticodon for a given amino acid, and when "charged" with that amino acid are termed aminoacyl-tRNA. Aminoacylation, which occurs exclusively at one of the 3'-terminal hydroxyl groups of tRNA, is catalyzed by a family of enzymes called aminoacyl-tRNA synthetases (ARSs). In a primitive translation system, before the advent of sophisticated protein-based enzymes, this chemical event could conceivably have been catalyzed solely by RNA enzymes. Given the evolutionary implications, our group attempted in vitro selection of artificial ARS-like ribozymes, successfully uncovering a functional ribozyme (r24) from an RNA pool of random sequences attached to the 5'-leader region of tRNA. This ribozyme preferentially charges aromatic amino acids (such as phenylalanine) activated with cyanomethyl ester (CME) onto specific kinds of tRNA. During the course of our studies, we became interested in developing a versatile, rather than a specific, aminoacylation catalyst. Such a ribozyme could facilitate the preparation of intentionally misacylated tRNAs and thus serve a convenient tool for manipulating the genetic code. On the basis of biochemical studies of r24, we constructed a truncated version of r24 (r24mini) that was 57 nucleotides long. This r24mini was then further shortened to 45 nucleotides. This ribozyme could charge various tRNAs through very simple three-base-pair interactions between the ribozyme's 3'-end and the tRNA's 3'-end. We termed this ribozyme a "flexizyme" (Fx3 for this particular construct) owing to its flexibility in addressing tRNAs. To devise an even more flexible tool for tRNA acylation, we attempted to eliminate the amino acid specificity from Fx3. This attempt yielded an Fx3 variant, termed dFx, which accepts amino acid substrates having 3,5-dinitrobenzyl ester instead of CME as a leaving group. Similar selection attempts with the original phenylalanine-CME and a substrate activated by (2-aminoethyl)amidocarboxybenzyl thioester yielded the variants eFx and aFx (e and a denote enhanced and amino, respectively). In this Account, we describe the history and development of these flexizymes and their appropriate substrates, which provide a versatile and easy-to-use tRNA acylation system. Their use permits the synthesis of a wide array of acyl-tRNAs charged with artificial amino and hydroxy acids. In parallel to these efforts, we initiated a crystallization study of Fx3 covalently conjugated to a microhelix RNA, which is an analogue of tRNA. The X-ray crystal structure, solved as a co-complex with phenylalanine ethyl ester and U1A-binding protein, revealed the structural basis of this enzyme. Most importantly, many biochemical observations were consistent with the crystal structure. Along with the predicted three regular-helix regions, however, the flexizyme has a unique irregular helix that was unexpected. This irregular helix constitutes a recognition pocket for the aromatic ring of the amino acid side chain and precisely brings the carbonyl group to the 3'-hydroxyl group of the tRNA 3'-end. This study has clearly defined the molecular interactions between Fx3, tRNA, and the amino acid substrate, revealing the fundamental basis of this unique catalytic system. PMID- 21711009 TI - Isolated and solvated thioxanthone: a photophysical study. AB - Quantum chemical methods have been employed to study the photophysics of thioxanthone in vacuum and various solvents. Structurally, the solvation leads to a lengthening of the carbonyl bond, whereas the benzene skeleton is mostly unaffected. This is mirrored by the larger blue shift of the (n(O)pi*) states as compared to the red shift which the (pipi*) states undergo. For a proper understanding of the radiative and radiationless processes occurring, the excitation energy profile along a linearly interpolated path has been determined in various cases. The interesting interplay of excited states thus revealed, has been investigated to qualitatively suggest the relaxation pathways available (or dominant) in the cases under study. Rates for these processes have also been computed wherever possible. PMID- 21711010 TI - Mean-field "temperature" in far from equilibrium systems. AB - We calculate the nonequilibrium mean-field "temperature" of a brownian system in contact with a heat bath. We consider two different cases: an equilibrium bath in the presence of strong external forces, and a nonequilibrium bath. By proving the existence of a generalized fluctuation-dissipation relation, this mean-field "temperature" can be used to describe a nonequilibrium system as is if it were in thermal equilibrium with a thermal bath at the mean-field "temperature" mentioned above. We apply our results to chemical reactions in the presence of external forces showing how chemical equilibrium and Kramers rate constants are modified by the presence of these forces. PMID- 21711011 TI - Effect of dissolved organic carbon on the transport and attachment behaviors of Cryptosporidium parvum oocysts and carboxylate-modified microspheres advected through temperate humic and tropical volcanic agricultural soil. AB - Transport of Cryptosporidium parvum oocysts and microspheres in two disparate (a clay- and Fe-rich, volcanic and a temperate, humic) agricultural soils were studied in the presence and absence of 100 mg L(-1) of sodium dodecyl benzene sulfonate (SDBS), and Suwannee River Humic Acid (SRHA) at pH 5.0-6.0. Transport of carboxylate-modified, 1.8 MUm microspheres in soil columns was highly sensitive to the nature of the dissolved organic carbon (DOC), whereas oocysts transport was more affected by soil mineralogy. SDBS increased transport of microspheres from 48% to 87% through the tropical soil and from 43% to 93% in temperate soil. In contrast, SRHA reduced transport of microspheres from 48% to 28% in tropical soil and from 43% to 16% in temperate soil. SDBS also increased oocysts transport through the temperate soil 5-fold, whereas no oocyst transport was detected in tropical soil. SRHA had only a nominal effect in increasing oocysts transport in tropical soil, but caused a 6-fold increase in transport through the temperate soil. Amendments of only 4 mg L(-1) SRHA and SDBS decreased oocyst hydrophobicity from 66% to 20% and from 66% to 5%, respectively. However, SDBS increased microsphere hydrophobicity from 16% to 33%. Soil fines, which includes clays, and SRHA, both caused the oocysts zeta potential (zeta) to become more negative, but caused the highly hydrophilic microspheres to become less negatively charged. The disparate behaviors of the two colloids in the presence of an ionic surfactant and natural organic matter suggest that microspheres may not be suitable surrogates for oocysts in certain types of soils. These results indicate that whether or not DOC inhibits or promotes transport of oocysts and microspheres in agricultural soils and by how much, depends not only on the surface characteristics of the colloid, but the nature of the DOC and the soil mineralogy. PMID- 21711012 TI - Prelithiated silicon nanowires as an anode for lithium ion batteries. AB - Silicon is one of the most promising anode materials for the next-generation high energy lithium ion battery (LIB), while sulfur and some other lithium-free materials have recently shown high promise as cathode materials. To make a full battery out of them, either the cathode or the anode needs to be prelithiated. Here, we present a method for prelithiating a silicon nanowire (SiNW) anode by a facile self-discharge mechanism. Through a time dependence study, we found that 20 min of prelithiation loads ~50% of the full capacity into the SiNWs. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) studies show that the nanostructure of SiNWs is maintained after prelithiation. We constructed a full battery using our prelithiated SiNW anode with a sulfur cathode. Our work provides a protocol for pairing lithium-free electrodes to make the next generation high-energy LIB. PMID- 21711013 TI - Effective work function modulation of graphene/carbon nanotube composite films as transparent cathodes for organic optoelectronics. AB - In this study, we found that the work functions (Phi(w)) of solution-processable, functional graphene/carbon nanotube-based transparent conductors were readily manipulated, varying between 5.1 and 3.4 eV, depending on the nature of the doping alkali carbonate salt. We used the graphene-based electrodes possessing lower values of Phi(w) as cathodes in inverted-architecture polymer photovoltaic devices to effectively collect electrons, giving rise to an optimal power conversion efficiency of 1.27%. PMID- 21711014 TI - Understanding the origins of time-dependent inhibition by polypeptide deformylase inhibitors. AB - The continual bacterial adaptation to antibiotics creates an ongoing medical need for the development of novel therapeutics. Polypeptide deformylase (PDF) is a highly conserved bacterial enzyme, which is essential for viability. It has previously been shown that PDF inhibitors represent a promising new area for the development of antimicrobial agents, and that many of the best PDF inhibitors demonstrate slow, time-dependent binding. To improve our understanding of the mechanistic origin of this time-dependent inhibition, we examined in detail the kinetics of PDF catalysis and inhibition by several different PDF inhibitors. Varying pH and solvent isotope led to clear changes in time-dependent inhibition parameters, as did inclusion of NaCl, which binds to the active site metal of PDF. Quantitative analysis of these results demonstrated that the observed time dependence arises from slow binding of the inhibitors to the active site metal. However, we also found several metal binding inhibitors that exhibited rapid, non time-dependent onset of inhibition. By a combination of structural and chemical modification studies, we show that metal binding is only slow when the rest of the inhibitor makes optimal hydrogen bonds within the subsites of PDF. Both of these interactions between the inhibitor and enzyme were found to be necessary to observe time-dependent inhibition, as elimination of either leads to its loss. PMID- 21711015 TI - Bicyclic conformationally restricted diamines. PMID- 21711016 TI - One-step production of a biologically active novel furan fatty acid from 7,10 dihydroxy-8(E)-octadecenoic acid. AB - Furan fatty acids (F-acids) gain special attention because they are known to play important roles in biological systems including humans. Specifically, F-acids are known to have strong antioxidant activitis such as radical scavenging activity. Although widely distributed in most biological systems, F-acids are trace components and their biosynthesis is complicated and quite different by sources. On the basis of biochemical study, they are considered to be an essential nutritional factor for mammals and should be provided through the diet. Hence, several studies reported the chemical synthesis of F-acids using chemical catalysts. However, chemical synthesis required complicated multiple steps. In this study was developed a simple one-step synthesis of a novel F-acid, 7,10 epoxyoctadeca-7,9-dienoic acid (EODA), from a dihydroxyl fatty acid, 7,10 dihydroxy-8(E)-octadecenoic acid (DOD), by heat treatment. The structure of EODA was confirmed by GC-MS, NMR, and FTIR analyses, and maximum production yield under the reaction conditions of 90 degrees C and 24 h reached 80%. PMID- 21711017 TI - Occurrence and mass balance of isoflavones on an experimental grassland field. AB - Isoflavones and coumestrol (COU) are estrogenic compounds that are naturally produced by plants (e.g., red clover, soybeans). Although these compounds have been extensively studied in food and feed, only little is known about their environmental fate. Therefore, we investigated the occurrence of isoflavones (formononetin, daidzein, equol, biochanin A, and genistein) and COU over 3.5 years in red clover, manure, and soil of a grassland field with and without manure application, as well as their emission via drainage water. Isoflavones were regularly quantified in plant (<= 15 * 10(6) ng/g(dry weight (dw))), manure (<= 230 * 10(3) ng/g(dw)), soil (<= 3.4 * 10(3) ng/g(dw)), and drainage water samples (<= 3.6 * 10(3) ng/L). In contrast, COU was observed only in manure and soil. Cumulative isoflavone loads emitted via drainage water were around 0.2 * 10(-3) kg/ha/y, which is very little compared to the amounts present in red clover (105-220 kg/ha/y), manure (0.5-1.0 kg/ha/y), and soil (0.1-5.1 kg/ha/y). Under good agricultural practice, no additional emission of isoflavones into drainage water was observed after manure application. With calculated 17beta estradiol equivalents up to 0.46 ng/L in drainage water, isoflavones can constitute a dominant and ecotoxicological relevant portion of the total estrogenicity in small rural river catchments. PMID- 21711018 TI - Prediction of the temperature dependence of the surface tension of SO2, N2, O2, and Ar by Monte Carlo molecular simulations. AB - We report Monte Carlo simulations of the liquid-vapor interface of SO(2), O(2), N(2), and Ar to reproduce the dependence of the surface tension with the temperature. Whereas the coexisting densities, critical temperature, density, and pressure are very well reproduced by the two-phase simulations showing the same accuracy as the calculations performed using the Gibbs ensemble Monte Carlo technique (GEMC), the performance of the prediction of the variation of the surface tension with the temperature depends on the magnitude of the electrostatic and repulsive-dispersive interactions. The surface tension of SO(2) is very well reproduced, whereas the prediction of this property is less satisfactory for O(2) and N(2), for which the average intermolecular electrostatic interactions are several orders smaller than the dispersion interactions. For argon, we observe significant deviations from experiments. The representation of the surface tension of argon in reduced units shows that our calculations are in line with the existing surface tensions of the Lennard-Jones fluid in the literature. This underlines the difficulty of reproducing the temperature dependence of the surface tension of argon with interactions only modeled by the Lennard-Jones pair potential. PMID- 21711019 TI - UV-switchable polyoxometalate sandwiched between TiO2 and metal nanoparticles for enhanced visible and solar light photococatalysis. AB - To improve the photocatalytic efficiency of TiO(2)-based nanomaterials, we demonstrate a facile, generalized, highly localized reduction approach to the decoration of TiO(2)-polyoxometalate composites with a range of metal nanoparticles including Cu, Ag, Pt, and Au. The synthesis of nanocomposite photococatalysts reported in this study has been achieved by utilizing the unique ability of the TiO(2)-bound PTA (phosphotungstic acid) molecules (a polyoxometalate, POM) to act as a highly localized UV-switchable reducing agent that specifically reduces metal ions to their nanoparticulate forms directly and only onto the TiO(2) surface. This leads to the metal contaminant-free synthesis of TiO(2)-PTA-metal nanocomposites, which is a significant advantage of the proposed approach. The study further demonstrates that polyoxometalates are regenerable photoactive molecules with outstanding electron-transfer ability and the deposition of metal nanoparticles on the TiO(2)-PTA cocatalytic surface can have a dramatic effect on increasing the overall photocatalytic performance of the composite system. Moreover, it is observed that the photococatalytic performance of the TiO(2)-PTA-metal nanoparticles can be fine tuned by choosing the composition of metal nanoparticles in the nanocomposite. Interestingly, the photococatalysts reported here are found to be active under visible and simulated solar-light conditions. The underlying reaction mechanism for enhanced solar light photococatalysis has been proposed. PMID- 21711020 TI - Hierarchically porous titania thin film prepared by controlled phase separation and surfactant templating. AB - Poly(propylene glycol) (PPG) of moderately high molecular weight (M(n) = 3500 Da) exhibits amphibious behavior in aqueous solution in that it is hydrophilic at low temperature but hydrophobic at high temperature. This property is utilized to generate porous titania thin films with a hierarchical structure consisting of macroporous voids/cracks in films with mesoporous walls. The smaller mesopores result from the self-assembly of the Pluronic block copolymer P123 to form micellar templates in well-ordered arrays with hexagonal symmetry. The larger pores are generated from the phase separation of PPG during aging of the films. The PPG acts to a limited degree as a swelling agent for the P123 micelles, but because the films are aged at a low temperature where PPG is hydrophilic, much of the PPG remains in the polar titania phase. Upon heating, the PPG phase separates to form randomly dispersed, large pores throughout the film while retaining the ordered mesoporous P123-templated structure in the matrix of the material. TEM and SEM imaging confirm that calcined titania thin films have interconnected hierarchical porous structures consisting of ordered mesopores 4-12 nm in diameter and macroporous voids >100 nm in size. The density and size of the voids increase as more PPG is added to the films. PMID- 21711021 TI - Characterization and inventory of PCDD/Fs and PBDD/Fs emissions from the incineration of waste printed circuit board. AB - Many developing countries have not significantly changed their course with regard to electronic waste contamination, and they are still facing the specter of mountains of hazardous electronic waste, with serious consequences for both the environment and public health. An efficient and stable analytical method was developed to determine the inventory and emission factors of polybrominated dibenzo-p-dioxin and dibenzofurans (PBDD/Fs) and polychlorinated dibenzo-p-dioxin and dibenzofurans (PCDD/Fs) formed from the incineration of scrap printed circuit boards (PCBs). Both PBDD/Fs and PCDD/Fs have been found in all experimental sections with a maximum formation rate at temperatures between 250 and 400 degrees C. The amounts tended first to increase and then began to decrease as the temperature rose. When subjected to a heating temperature of 325 degrees C, the total content of twelve 2,3,7,8-substituted PBDD/Fs congeners (tetra- through octabromo-) gathered from three outputs was the largest, at 19 000, 160 000, and 57 ng TEQ/kg in solid, liquid, and gaseous fractions, respectively; the total content of seventeen 2,3,7,8-substituted PCDD/Fs congeners (tetra- through octachloro-) was 820, 550, and 1.4 ng TEQ/kg. The formation of PCDD/Fs was remarkably less than that of PBDD/Fs because bromine concentrations considerably exceeded chlorine concentrations. The ingredients and conditions necessary to form PCDD/Fs or PBDD/Fs were definitely present, such as products of incomplete combustion, halogenides, an oxidizing atmosphere, and a catalyst-Cu salts being the most effective, significantly increasing the yields of PCDD/Fs and PBDD/Fs and decreasing the optimum temperature range. PMID- 21711022 TI - Wettability increase by "corona" ionization. AB - Experiments showing an increase in the wettability of a hydrophobic surface when using corona air ionization are shown. Photoluminiscence observations support the predictions of charge accumulation at the triple line and confirm previous experiments. In all of the experiments, the contact angle was in the saturation regime at a value smaller than that predicted by the condition of a zero value for the solid-liquid surface tension. The PDMS did not show any deterioration due to the corona exposure under the experimental conditions used. The contact angle is shown to increase with humidity. PMID- 21711023 TI - Use of a generalized fisher equation for global optimization in chemical kinetics. AB - A new approach for parameter estimation in chemical kinetics has been recently proposed (Ross et al. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 12777). It makes use of an optimization criterion based on a Generalized Fisher Equation (GFE). Its utility has been demonstrated with two reaction mechanisms, the chlorite iodide and Oregonator, which are computationally stiff systems. In this Article, the performance of the GFE-based algorithm is compared to that obtained from minimization of the squared distances between the observed and predicted concentrations obtained by solving the corresponding initial value problem (we call this latter approach "traditional" for simplicity). Comparison of the proposed GFE-based optimization method with the "traditional" one has revealed their differences in performance. This difference can be seen as a trade-off between speed (which favors GFE) and accuracy (which favors the traditional method). The chlorite-iodide and Oregonator systems are again chosen as case studies. An identifiability analysis is performed for both of them, followed by an optimal experimental design based on the Fisher Information Matrix (FIM). This allows to identify and overcome most of the previously encountered identifiability issues, improving the estimation accuracy. With the new data, obtained from optimally designed experiments, it is now possible to estimate effectively more parameters than with the previous data. This result, which holds for both GFE-based and traditional methods, stresses the importance of an appropriate experimental design. Finally, a new hybrid method that combines advantages from the GFE and traditional approaches is presented. PMID- 21711024 TI - Modeling the nonradiative decay rate of electronically excited thioflavin T. AB - A computational model of nonradiative decay is developed and applied to explain the time-dependent emission spectrum of thioflavin T (ThT). The computational model is based on a previous model developed by Glasbeek and co-workers (van der Meer, M. J.; Zhang, H.; Glasbeek, M. J. Chem. Phys. 2000, 112, 2878) for auramine O, a molecule that, like ThT, exhibits a high nonradiative rate. The nonradiative rates of both auramine O and ThT are inversely proportional to the solvent viscosity. The Glasbeek model assumes that the excited state consists of an adiabatic potential surface constructed by adiabatic coupling of emissive and dark states. For ThT, the twist angle between the benzothiazole and the aniline is responsible for the extensive mixing of the two excited states. At a twist angle of 90 degrees , the S(1) state assumes a charge-transfer-state character with very small oscillator strength, which causes the emission intensity to be very small as well. In the ground state, the twist angle of ThT is rather small. The photoexcitation leads first to a strongly emissive state (small twist angle). As time progresses, the twist angle increases and the oscillator strength decreases. The fit of the experimental results by the model calculations is good for times longer than 3 ps. When a two-coordinate model is invoked or a solvation spectral-shift component is added, the fit to the experimental results is good at all times. PMID- 21711026 TI - Free energy calculations on the two drug binding sites in the M2 proton channel. AB - Two alternative binding sites of adamantane-type drugs in the influenza A M2 channel have been suggested, one with the drug binding inside the channel pore and the other with four drug molecule S-binding to the C-terminal surface of the transmembrane domain. Recent computational and experimental studies have suggested that the pore binding site is more energetically favorable but the external surface binding site may also exist. Nonetheless, which drug binding site leads to channel inhibition in vivo and how drug-resistant mutations affect these sites are not completely understood. We applied molecular dynamics simulations and potential of mean force calculations to examine the structures and the free energies associated with these putative drug binding sites in an M2 lipid bilayer system. We found that, at biological pH (~7.4), the pore binding site is more thermodynamically favorable than the surface binding site by ~7 kcal/mol and, hence, would lead to more stable drug binding and channel inhibition. This result is in excellent agreement with several recent studies. More importantly, a novel finding of ours is that binding to the channel pore requires overcoming a much higher energy barrier of ~10 kcal/mol than binding to the C-terminal channel surface, indicating that the latter site is more kinetically favorable. Our study is the first computational work that provides both kinetic and thermodynamic energy information on these drug binding sites. Our results provide a theoretical framework to interpret and reconcile existing and often conflicting results regarding these two binding sites, thus helping to expand our understanding of M2-drug binding, and may help guide the design and screening of novel drugs to combat the virus. PMID- 21711025 TI - Etched glass microarrays with differential resonance for enhanced contrast and sensitivity of surface plasmon resonance imaging analysis. AB - We report the fabrication and characterization of gold-coated etched glass array substrates for surface plasmon resonance imaging (SPRi) analysis with significantly enhanced performance, in particular image contrast and sensitivity. The etching of the glass substrate induces a variation in the resonance condition and thus in the resonance angle between the etched wells and the surrounding area, leading to the isolation of the array spot resonance with a significant reduction of the background signal. FDTD simulations show arrays with large spots and minimal spot-to-spot spacing yield ideal differential resonance conditions, which are verified by experimental results. Simulations also indicate the etched well structure exhibits enhanced SPR electric field intensity by 3-fold as compared to standard planar gold chips. Changes in the bulk sensitivity of the etched arrays have been obtained at the 10(-4) RIU level based on image intensity difference. The strong image contrast allows for improved microarray imaging analysis with easily distinguished signals from background resonance. The etched array chips are demonstrated for SPRi detection of bacterial toxins through the coating of an ultrathin SiO(2) film for direct vesicle fusion that establishes a supported membrane-based biosensing interface. Protein detection with cholera toxin (CT) at 5 nM is obtained, making this chip one of the most sensitive SPR imaging substrates ever reported without a postbinding amplification scheme. Furthermore, the surface can be regenerated by Triton X-100 for repeated cycles of membrane formation, protein binding, and biomolecular removal. The reusability and enhanced performance of the etched glass array chips should find a broad range of applications, opening up new avenues for high-throughput SPR imaging detection with convenience and marked surface sensitivity. PMID- 21711027 TI - Mechanism of cobalt(II) porphyrin-catalyzed C-H amination with organic azides: radical nature and H-atom abstraction ability of the key cobalt(III)-nitrene intermediates. AB - The mechanism of cobalt(II) porphyrin-catalyzed benzylic C-H bond amination of ethylbenzene, toluene, and 1,2,3,4-tetrahydronaphthalene (tetralin) using a series of different organic azides [N(3)C(O)OMe, N(3)SO(2)Ph, N(3)C(O)Ph, and N(3)P(O)(OMe)(2)] as nitrene sources was studied by means of density functional theory (DFT) calculations and electron paramagnetic resonance (EPR) spectroscopy. The DFT computational study revealed a stepwise radical process involving coordination of the azide to the metal center followed by elimination of dinitrogen to produce unusual "nitrene radical" intermediates (por)Co(III)-N(*)Y (4) [Y = -C(O)OMe, -SO(2)Ph, -C(O)Ph, -P(O)(OMe)(2)]. Formation of these nitrene radical ligand complexes is exothermic, predicting that the nitrene radical ligand complexes should be detectable species in the absence of other reacting substrates. In good agreement with the DFT calculations, isotropic solution EPR signals with g values characteristic of ligand-based radicals were detected experimentally from (por)Co complexes in the presence of excess organic azide in benzene. They are best described as nitrene radical anion ligand complexes (por)Co(III)-N(*)Y, which have their unpaired spin density located almost entirely on the nitrogen atom of the nitrene moiety. These key cobalt(III) nitrene radical intermediates readily abstract a hydrogen atom from a benzylic position of the organic substrate to form the intermediate species 5, which are close-contact pairs of the thus-formed organic radicals R'(*) and the cobalt(III) amido complexes (por)Co(III)-NHY ({R'(*)...(por)Co(III)-NHY}). These close contact pairs readily collapse in a virtually barrierless fashion (via transition state TS3) to produce the cobalt(II)-amine complexes (por)Co(II)-NHYR', which dissociate to afford the desired amine products NHYR' (6) with regeneration of the (por)Co catalyst. Alternatively, the close-contact pairs {R'(*)...(por)Co(III)-NHY} 5 may undergo beta-hydrogen-atom abstraction from the benzylic radical R'(*) by (por)Co(III)-NHY (via TS4) to form the corresponding olefin and (por)Co(III)-NH(2)Y, which dissociates to give Y-NH(2). This process for the formation of olefin and Y-NH(2) byproducts is also essentially barrierless and should compete with the collapse of 5 via TS3 to form the desired amine product. Alternative processes leading to the formation of side products and the influence of different porphyrin ligands with varying electronic properties on the catalytic activity of the cobalt(II) complexes have also been investigated. PMID- 21711028 TI - Dual (C, H) isotope fractionation in anaerobic low molecular weight (poly)aromatic hydrocarbon (PAH) degradation: potential for field studies and mechanistic implications. AB - Anaerobic polycyclic aromatic hydrocarbon (PAH) degradation is a key process for natural attenuation of oil spills and contaminated aquifers. Assessments by stable isotope fractionation, however, have largely been limited to monoaromatic hydrocarbons. Here, we report on measured hydrogen isotope fractionation during strictly anaerobic degradation of the PAH naphthalene. Remarkable large hydrogen isotopic enrichment factors contrasted with much smaller values for carbon: epsilon(H) = -1000/00 +/- 150/00, epsilon(C) = -5.00/00 +/- 1.00/00 (enrichment culture N47); epsilon(H) = -730/00 +/- 110/00, epsilon(C) = -0.70/00 +/- 0.30/00 (pure culture NaphS2). This reveals a considerable potential of hydrogen isotope analysis to assess anaerobic degradation of PAHs. Furthermore, we investigated the conclusiveness of dual isotope fractionation to characterize anaerobic aromatics degradation. C and H isotope fractionation during benzene degradation (epsilon(C) = -2.50/00 +/- 0.20/00; epsilon(H) = -550/00 +/- 40/00 (sulfate reducing strain BPL); epsilon(C) = -3.00/00 +/- 0.50/00; epsilon(H) = -560/00 +/- 80/00 (iron-reducing strain BF)) resulted in dual isotope slopes (Lambda = 20 +/- 2; 17 +/- 1) similar to those reported for nitrate-reducers. This breaks apart the current picture that anaerobic benzene degradation by facultative anaerobes (denitrifiers) can be distinguished from that of strict anaerobes (sulfate reducers, fermenters) based on the stable isotope enrichment factors. PMID- 21711029 TI - Boron-boron sigma-bond formation by two-electron reduction of a H-bridged dimer of monoborane. AB - Diborane(6) as a H-bridged dimer of monoborane can be converted cleanly by two electron reduction into diborane(6) dianion, which is isoelectronic with ethane, through B-B sigma-bond formation when each boron atom has a bulky ligand on it. The existence of the B-B sigma bond is supported by the X-ray molecular structure [B-B bond length of 1.924(3) A], NMR studies, magnetic susceptibility measurements, and DFT calculations. Stepwise hydride abstraction reactions of the diborane(6) dianion produce the corresponding H-bridged diborane(5) anion and doubly H-bridged diborane(4) without B-B bond scission. PMID- 21711030 TI - Postsynthetic modification of a metal-organic framework for stabilization of a hemiaminal and ammonia uptake. AB - In our study, we show by solid-state (15)N NMR measurements that an important zirconium metal-organic framework (UiO-66) with amino-functionalized links is composed of a mixture of amino and -NH(3)(+)Cl(-) salt functionalities rather than all amino functionality to give a composition of Zr(6)O(4)(OH)(4)(BDC NH(2))(4)(BDC-NH(3)(+)Cl(-))(2) (UiO-66-A). UiO-66-A was postsynthetically modified to form a mixture of three functionalities, where the hemiaminal functionality is the majority species in UiO-66-B and aziridine is the majority functionality in UiO-66-C. UiO-66-A-C are all porous with surface areas ranging from 780 to 820 m(2)/g and have chemical stability, as evidenced by reversible ammonia uptake and release showing capacities ranging from 134 to 193 cm(3)/g. PMID- 21711031 TI - Reduced graphene oxide as a solid-state electron mediator in Z-scheme photocatalytic water splitting under visible light. AB - The effectiveness of reduced graphene oxide as a solid electron mediator for water splitting in the Z-scheme photocatalysis system is demonstrated. We show that a tailor-made, photoreduced graphene oxide can shuttle photogenerated electrons from an O(2)-evolving photocatalyst (BiVO(4)) to a H(2)-evolving photocatalyst (Ru/SrTiO(3):Rh), tripling the consumption of electron-hole pairs in the water splitting reaction under visible-light irradiation. PMID- 21711032 TI - Synthesis of the carboline disaccharide domain of shishijimicin A. AB - A synthetic route to the carboline disaccharide domain (2) of shishijimicin A (1) has been developed. The convergent synthesis relies on a novel application of the Reetz-Muller-Starke reaction to form the central, sulfur-bearing quaternary carbon center and addition of the carboline structural motif as a dianion to a disaccharide aldehyde fragment. PMID- 21711033 TI - Pseudocryptand-type [2]pseudorotaxanes based on bis(meta-phenylene)-32-crown-10 derivatives and paraquats with remarkably improved association constants. AB - The first dual component pseudocryptand-type [2]pseudorotaxanes were designed and prepared via the self-assembly of synthetically easily accessible bis(meta phenylene)-32-crown-10 pyridyl, quinolyl, and naphthyridyl derivatives with paraquat. The formation of the pseudocryptand structures in the complexes remarkably improved the association constant by forming the third pseudobridge via H-bonding with the guest and pi-stacking of the heterocyclic units. PMID- 21711034 TI - Palladium and platinum complexes of a benzannulated N-heterocyclic plumbylene with an unusual bonding mode. AB - Reaction of the N,N'-diisobutyl-substituted benzannulated N-heterocyclic plumbylene (NHPb) 1 with [Pd(PPh(3))(4)] and [Pt(PPh(3))(4)] gave the complexes [M(NHPb)(PPh(3))(3)] (M = Pd [2], Pt [3]). X-ray diffraction studies of both complexes showed an angle of ~125 degrees between the plumbylene plane and the transition-metal-Pb axis, indicating coordination of the transition metal to the empty pi orbital of the plumbylene Pb atom. The experimentally determined metric parameters of complexes [2] and [3] are discussed on the basis of DFT calculations. PMID- 21711035 TI - An examination of the ternary methane + carbon dioxide + water phase diagram using the SAFT-VR approach. AB - In this work, the molecular based Variable Range Statistical Associating Fluid Theory (SAFT-VR) has been used to estimate the global phase equilibria diagram of the ternary mixture water + carbon dioxide + methane, over a wide pressure and temperature range. An accurate determination of the phase equilibria of this mixture is relevant in Petrophysics, as, for instance, in enhanced natural gas recovery from low permeability reservoirs (the so-called tight gas reservoirs), or in geology, as it is the basic composition of many geological fluids. A previous study on the phase behavior of the binary mixtures involved is presented, using in a transferable manner the characteristic molecular parameters for the three molecules involved. The ternary mixture presents a very rich and complex phase behavior, with a wide region of the thermodynamic space of phases (at higher pressures) presenting a large gap of ternary liquid-liquid equilibria, that upon descending pressures leads to the transition to a three-phase liquid liquid-vapor equilibria region, and both regions are separated by a continuous critical end point line. The ability of the theory to describe this complex multicomponent mixture phase transition with a reduced and physically sound set of characteristic parameters must be underlined. PMID- 21711036 TI - Adsorption of fatty acids on iron (hydr)oxides from aqueous solutions. AB - The interaction of iron (hydr)oxides with fatty acids is related to many industrial and natural processes. To resolve current controversies about the adsorption configurations of fatty acids and the conditions of the maximum hydrophobicity of the minerals, we perform a detailed study of the adsorption of sodium laurate (dodecanoate) on 150 nm hematite (alpha-Fe(2)O(3)) particles as a model system. The methods used include in situ FTIR spectroscopy, ex situ X-ray photoelectron spectroscopy (XPS), measurements of the adsorption isotherm and contact angle, as well as the density functional theory (DFT) calculations. We found that the laurate adlayer is present as a mixture of inner-sphere monodentate mononuclear (ISMM) and outer-sphere (OS) hydration shared complexes independent of the solution pH. Protonation of the OS complexes does not influence the conformational order of the surfactant tails. One monolayer, which is filled through the growth of domains and is reached at the micellization/precipitation edge of laurate, makes the particles superhydrophobic. These results contradict previous models of the fatty acid adsorption and suggest new interpretation of literature data. Finally, we discovered that the fractions of both the OS laurate and its molecular form increase in D(2)O, which can be used for interpreting complex spectra. We discuss shortcomings of vibrational spectroscopy in determining the interfacial coordination of carboxylate groups. This work advances the current understanding of the oxide-carboxylate interactions and the research toward improving performance of fatty acids as surfactants, dispersants, lubricants, and anticorrosion reagents. PMID- 21711037 TI - Magnetic nanoparticle-enhanced biosensor based on grating-coupled surface plasmon resonance. AB - A highly sensitive surface plasmon resonance (SPR) biosensor employing magnetic nanoparticle (MNP) assays is presented. In the reported approach, MNPs simultaneously served as "vehicles" for rapid delivery of target analyte from a sample to the sensor surface and as labels increasing the measured refractive index changes that are associated with the binding of target analyte. An optical setup based on grating-coupled surface plasmon resonance (GC-SPR) was used with a magnetic field gradient applied through the sensor chip for manipulating with MNPs on its surface. Iron oxide MNPs and a sensor surface with metallic diffraction grating were modified with antibodies that specifically recognize different epitopes of the analyte of interest. The sensitivity of the biosensor was investigated as a function of mass transport of the analyte to the sensor surface driven by diffusion (free analyte) or by the magnetic field gradient (analyte bound to MNPs). Immunoassay-based detection of beta human chorionic gonadotropin (betahCG) was implemented to evaluate the sensitivity of the MNP enhanced GC-SPR biosensor scheme. The results reveal that the sensitivity of betahCG detection was improved by 4 orders of magnitude compared with the regular SPR sensor with direct detection format, and a limit of detection below pM was achieved. PMID- 21711038 TI - Correlation between atomic coordination structure and enhanced electrocatalytic activity for trimetallic alloy catalysts. AB - This Article describes findings of the correlation between the atomic scale structure and the electrocatalytic performance of nanoengineered PtNiFe/C catalysts treated at different temperatures for oxygen reduction reaction, aiming at providing a new fundamental insight into the role of the detailed atomic alloying and interaction structures of the catalysts in fuel cell reactions. Both mass and specific activities of the catalysts were determined using rotating disk electrode and proton exchange membrane fuel cell. The mass activities extracted from the kinetic regions in both measurements revealed a consistent trend of decreasing activity with increasing temperature. However, the specific activity data from RDE revealed an opposite trend, that is, increasing activity with increasing temperature. In addition to TEM, XRD, and XPS characterizations, a detailed XAFS analysis of the atomic scale coordination structures was carried out, revealing increased heteroatomic coordination with improved alloying structures for the catalyst treated at the elevated temperatures. XPS analysis has further revealed a reduced surface concentration of Pt for the catalyst for the high temperature treated catalyst. The higher mass activity for the lower temperature treated catalyst is due to Pt surface enrichment on the surface sites, whereas the higher specific activity for the higher temperature treated catalyst reflects an enhanced Pt-alloying surface sites. These findings have thus provided a new insight for assessing the structural correlation of the electrocatalytic activity with the fcc-type lattice change and the atomic scale alloying characteristics. Implications of these findings to the design of highly active alloy electrocatalysts are discussed, along with their enhanced electrocatalytic performance in the fuel cell. PMID- 21711039 TI - Highly photoluminescent nanocrystals based on a gold(I) complex and their electrophoretic patterning. AB - The fabrication of nanocrystals (NCs) composed of the cationic Au(I) complex was demonstrated by the reprecipitation method in which the colloidal solution of the NCs showed brilliant green phosphorescence with a quantum yield of 83% in n hexane. Characterization of the prepared NCs was performed by transmission electron microscopy observation and elemental analysis with energy-dispersive X ray spectroscopy. The obtained Au(I) NCs were particles of random shapes with a diameter of 200-400 nm. The selected-area electron diffraction and X-ray diffraction measurements showed the characteristic diffraction patterns attributable to the crystal structure of the bulk crystal of the Au(I) complex. A similar method was performed with a different counteranion, leading to a colloidal solution of the microcrystals (MCs) with brilliant yellow phosphorescence and a quantum yield of 26% in n-hexane. Luminescence patterning of the NCs and MCs was also achieved successfully by electrophoretic deposition onto an indium tin oxide (ITO)-coated glass substrate, resulting in characteristic luminescence patterns on the ITO substrates with relatively high photoluminescence quantum yields. PMID- 21711040 TI - Optimization of the coating procedure for a high-throughput 96-blade solid phase microextraction system coupled with LC-MS/MS for analysis of complex samples. AB - Biocompatible C18-polyacrylonitrile (PAN) coating was used as the extraction phase for an automated 96-blade solid phase microextraction (SPME) system with thin-film geometry. Three different methods of coating preparation (dipping, brush painting, and spraying) were evaluated; the spraying method was optimum in terms of its stability and reusability. The high-throughput sample preparation was achieved by using a robotic autosampler that enabled simultaneous preparation of 96 samples in 96-well-plate format. The increased volume of the extraction phase of the C18-PAN thin film coating resulted in significant enhancement in the extraction recovery when compared with that of the C18-PAN rod fibers. Various factors, such as reusability, reproducibility, pH stability, and reliability of the coating were evaluated. The results showed that the C18-PAN 96-blade SPME coating presented good extraction recovery, long-term reusability, good reproducibility, and biocompatibility. The limits of detection and quantitation were in the ranges of 0.1-0.3 and 0.5-1 ng/mL for all four analytes. PMID- 21711041 TI - Efficient wastewater treatment by membranes through constructing tunable antifouling membrane surfaces. AB - In the present study, a facile in situ approach for constructing tunable amphiphilic or hydrophilic antifouling membrane surfaces was demonstrated by exquisitely manipulating the microphase separation and surface segregation behavior of the tailor-made ternary amphiphilic block copolymers during the commonly utilized wet phase inversion membrane-formation process. Under dead-end filtration for oily wastewater treatment, the membrane with amphiphilic surface exhibited over 99.5% retention ratio of chemical oxygen demand (COD) without appreciable membrane fouling: the water permeation flux was slightly decreased during operation (total flux decline was 6.8%) and almost completely recovered to the initial value (flux recovery ratio was more than 99.0%) after simple hydraulic washing. While for the proteins-containing wastewater treatment, the membrane with hydrophilic surface exhibited about 52.6% COD retention ratio and superior antifouling performance: only 17.0% total flux decline and also more than 99.0% flux recovery ratio. Hopefully, the present approach can be developed as a competitive platform technology for the preparation of robust and versatile antifouling membrane, leading to the high process efficiency of wastewater treatments. PMID- 21711042 TI - Systematic investigation of the metal-structure-photophysics relationship of emissive d10-complexes of group 11 elements: the prospect of application in organic light emitting devices. AB - A series of new emissive group 11 transition metal d(10)-complexes 1-8 bearing functionalized 2-pyridyl pyrrolide together with phosphine ancillary such as bis[2-(diphenylphosphino)phenyl] ether (POP) or PPh(3) are reported. The titled complexes are categorized into three classes, i.e. Cu(I) complexes (1-3), Ag(I) complexes (4 and 5), and Au(I) metal complexes (6-8). Via combination of experimental and theoretical approaches, the group 11 d(10)-metal ions versus their structural variation, stability, and corresponding photophysical properties have been investigated in a systematic and comprehensive manner. The results conclude that, along the same family, how much a metal d-orbital is involved in the electronic transition plays a more important role than how heavy the metal atom is, i.e. the atomic number, in enhancing the spin-orbit coupling. The metal ions with and without involvement of a d orbital in the lowest lying electronic transition are thus classified into internal and external heavy atoms, respectively. Cu(I) complexes 1-3 show an appreciable metal d contribution (i.e., MLCT) in the lowest lying transition, so that Cu(I) acts as an internal heavy atom. Despite its smallest atomic number among group 11 elements, Cu(I) complexes 1-3 exhibit a substantially larger rate of intersystem crossing (ISC) and phosphorescence radiative decay rate constant (k(r)(p)) than those of Ag(I) (4 and 5) and Au(I) (6-8) complexes possessing pure pi -> pi* character in the lowest transition. Since Ag(I) and Au(I) act only as external heavy atoms in the titled complexes, the spin-orbit coupling is mainly governed by the atomic number, such that complexes associated with the heavier Au(I) (6-8) show faster ISC and larger k(r)(p) than the Ag(I) complexes (4 and 5). This trend of correlation should be universal and has been firmly supported by experimental data in combination with empirical derivation. Along this line, Cu(I) complex 1 exhibits intensive phosphorescence (Phi(p) = 0.35 in solid state) and has been successfully utilized for fabrication of OLEDs, attaining peak EL efficiencies of 6.6%, 20.0 cd/A, and 14.9 lm/W for the forward directions. PMID- 21711043 TI - On the cause of controlling affinity to small molecules of imprinted polymeric membranes prepared by noncovalent approach: a computational and experimental investigation. AB - Imprinting technique applied to membrane preparation via phase inversion methods yields membranes with enhanced affinity toward target molecules. In the imprinted membranes prepared by noncovalent approach hydrogen bond and electrostatic interactions can play a crucial role in determining the performance of these membranes. In this work, quantum mechanical calculations and experiments were performed to understand the physical-chemical causes of the affinity increase in imprinted polymeric membranes to 4,4'-methylendianiline (MDA), dissolved in an organic solvent. An ad hoc synthesized copolymer of acrylonitrile and acrylic acid was used to prepare the membranes. The calculated binding energies show that the hydrogen bonds and electrostatic interactions among polymeric chains are comparable to the strength of the same interactions occurring between polymer and MDA. Using this result and correlated experimental data, this work concluded that one of the causes responsible for the increased affinity of the imprinted membranes is the augmented availability of free carboxylic groups in the nanocavities of the membranes. However, along with this reason, the membrane pore sizes must evermore be taken into account. The knowledge acquired in this study helps us to better understand the mechanisms of molecular recognition and hence to optimize the design of new imprinted membranes. PMID- 21711044 TI - Scaffolding a cage-like 3D framework by coordination and constitutional dynamic chemistry. AB - By exploiting the supramolecular assistance of a sterically encumbered phenanthroline-Cu(+) motif, we report on the self-assembly of a trigonal nanoprism, its post-self-assembly functionalization, and transformation into a cage-like 3D framework with distinct compartments. PMID- 21711045 TI - Transformation of a close-packed Au nanoparticle/polymer monolayer into a large area array of oriented Au nanowires via E-beam promoted uniaxial deformation and room temperature sintering. AB - Transformation of 2D Au nanoparticle (NP) arrays into large scale, ordered, and oriented nanorod/nanowire arrays supported on a transferrable polymer film has been accomplished. E-beam irradiation followed by room temperature aging of a suspended Au NP/polymethylmethacrylate (PMMA) polymer close packed monolayer results in one-dimensional nanoparticle aggregation, reorientation, and sintering into a high density array of oriented Au nanowires with coherent single-crystal like interfaces. Molecular dynamics simulations of alkane-thiol capped Au NPs, interacting through the Vincent potential and undergoing 2D Poisson compression, account semiquantitatively for the qualitative features of the transformation. This fabrication approach should be extendable to directing 1D aggregation of highly anisotropic nanostructures in arbitrary NP systems. PMID- 21711046 TI - Quantification of a male sea lamprey pheromone in tributaries of Laurentian Great Lakes by liquid chromatography-tandem mass spectrometry. AB - We developed an assay for measuring 7alpha,12alpha,24-trihydroxy-5a-cholan-3-one 24-sulfate (3kPZS), a mating pheromone released by male sea lampreys (Petromyzon marinus), at low picomolar concentrations in natural waters to assess the presence of invasive populations. 3kPZS was extracted from streamwater at a rate of recovery up to 90% using a single cation-exchange and reversed-phase mixed mode cartridge, along with [(2)H(5)]3kPZS as an internal standard, and quantified using ultrahigh performance liquid chromatography-tandem mass spectrometry. The limit of detection was below 0.1 ng L(-1) (210 fM), which was the lowest concentration tested. Intra- and interday coefficients of variation were between 0.3-11.6% and 4.8-9.8%, respectively, at 1 ng 3kPZS L(-1) and 5 ng 3kPZS L(-1). This assay was validated by repeat measurements of water samples from a stream spiked with synthesized 3kPZS to reach 4.74 ng L(-1) or 0.24 ng L(-1). We further verified the utility of this assay to detect spawning populations of lampreys; in the seven tributaries to the Laurentian Great Lakes sampled, 3kPZS concentrations were found to range between 0.15 and 2.85 ng L(-1) during the spawning season in known sea lamprey infested segments and were not detectable in uninfested segments. The 3kPZS assay may be useful for the integrated management of sea lamprey, an invasive species in the Great Lakes where pheromone-based control and assessment techniques are desired. PMID- 21711047 TI - On the ground state of Pd13. AB - First-principles electronic structure calculations within a gradient corrected density functional formalism have been carried out to investigate the electronic structure and magnetic properties of Pd(13) clusters. It is shown that a bilayer ground-state structure that can be regarded as a relaxed bulk fragment is most compatible with the experimental results from Stern-Gerlach measurements. An icosahedral structure, considered to be the ground state in numerous previous studies, is shown to be around 0.14 eV above the ground state. A detailed analysis of the molecular orbitals reveals the near degeneracy of the bilayer or icosahedral structures is rooted in the stabilization by p- or d-like cluster orbitals. The importance of low-lying spin states in controlling the electronic and magnetic properties of the cluster is highlighted. PMID- 21711049 TI - Accounting legacy. PMID- 21711048 TI - Carboxybetaine methacrylate polymers offer robust, long-term protection against cell adhesion. AB - Films of poly(carboxybetaine methacrylate), poly(CBMA), grafted onto microetched gold slides are effective in preventing nonspecific adhesion of cells of different types. The degree of adhesion resistance is comparable to that achieved with the self-assembled monolayers, SAMs, of oligo(ethylene glycol) alkanethiolates. In sharp contrast to the SAMs, however, substrates protected with poly(CBMA) can be stored in dry state without losing their protective properties for periods up to 2 weeks. PMID- 21711050 TI - Agrowaste-based nanofibers as a probiotic encapsulant: fabrication and characterization. AB - This study explored the potential of soluble dietary fiber (SDF) from agrowastes, okara (soybean solid waste), oil palm trunk (OPT), and oil palm frond (OPF) obtained via alkali treatment, in the nanoencapsulation of Lactobacillus acidophilus . SDF solutions were amended with 8% poly(vinyl alcohol) to produce nanofibers using electrospinning technology. The spinning solution made from okara had a higher pH value at 5.39 +/- 0.01 and a higher viscosity at 578.00 +/- 11.02 mPa.s (P < 0.05), which resulted in finer fibers. FTIR spectra of nanofibers showed the presence of hemicellulose material in the SDF. Thermal behavior of nanofibers suggested possible thermal protection of probiotics in heat-processed foods. L. acidophilus was incorporated into the spinning solution to produce nanofiber-encapsulated probiotic, measuring 229-703 nm, visible under fluorescence microscopy. Viability studies showed good bacterial survivability of 78.6-90% under electrospinning conditions and retained viability at refrigeration temperature during the 21 day storage study. PMID- 21711051 TI - 3D micro-XRF for cultural heritage objects: new analysis strategies for the investigation of the Dead Sea Scrolls. AB - A combination of 3D micro X-ray fluorescence spectroscopy (3D micro-XRF) and micro-XRF was utilized for the investigation of a small collection of highly heterogeneous, partly degraded Dead Sea Scroll parchment samples from known excavation sites. The quantitative combination of the two techniques proves to be suitable for the identification of reliable marker elements which may be used for classification and provenance studies. With 3D micro-XRF, the three-dimensional nature, i.e. the depth-resolved elemental composition as well as density variations, of the samples was investigated and bromine could be identified as a suitable marker element. It is shown through a comparison of quantitative and semiquantitative values for the bromine content derived using both techniques that, for elements which are homogeneously distributed in the sample matrix, quantification with micro-XRF using a one-layer model is feasible. Thus, the possibility for routine provenance studies using portable micro-XRF instrumentation on a vast amount of samples, even on site, is obtained through this work. PMID- 21711052 TI - Determination of nickel species in stack emissions from eight residual oil-fired utility steam-generating units. AB - XAFS spectroscopy has been used to determine the Ni species in particulate matter collected on quartz thimble filters in the stacks of eight residual (No. 6 fuel) oil-burning electric utility steam-generating units. Proper speciation of nickel in emitted particulate matter is necessary to correctly anticipate potential health risks. Analysis of the spectroscopic data using least-squares linear combination methods and a newly developed method specific for small quantities of Ni sulfide compounds in such emissions show that potentially carcinogenic Ni sulfide compounds are absent within the detection limits of the method (<= 3% of the total Ni) in the particulate matter samples investigated. In addition to the major nickel sulfate phase (NiSO(4).6H(2)O), lesser amounts of (Ni,Mg)O and/or NiFe(2)O(4) were also identified in most emission samples. On the basis of the results from these emission characterization studies, the appropriateness of the U.S. Environmental Protection Agency's assumption that the Ni compound mixture emitted from residual oil-fired power plants is 50% as carcinogenic as nickel subsulfide (Ni(3)S(2)) should be re-evaluated. PMID- 21711053 TI - Structure-activity relationship studies on isoindoline inhibitors of dipeptidyl peptidases 8 and 9 (DPP8, DPP9): is DPP8-selectivity an attainable goal? AB - This work represents the first directed study to identify modification points in the topology of a representative DPP8/9-inhibitor, capable of rendering selectivity for DPP8 over DPP9. The availability of a DPP8-selective compound would be highly instrumental for studying and untwining the biological roles of DPP8 and DPP9 and for the disambiguation of biological effects of nonselective DPP-inhibitors that have mainly been ascribed to blocking of DPPIV's action. The cell-permeable DPP8/9-inhibitor 7 was selected as a lead and dissected into several substructures that were modified separately for evaluating their potential to contribute to selectivity. The obtained results, together with earlier work from our group, clearly narrow down the most probable DPP8 selectivity imparting modification points in DPP8/9 inhibitors to parts of space that are topologically equivalent to the piperazine ring system in 7. This information can be considered of high value for future design of compounds with maximal DPP8 selectivity. PMID- 21711054 TI - Synthesis and significant cytostatic activity of 7-hetaryl-7-deazaadenosines. AB - A series of 7-aryl- and 7-hetaryl-7-deazaadenosines was prepared by the cross coupling reactions of unprotected or protected 7-iodo-7-deazaadenosines with (het)arylboronic acids, stannanes, or zinc halides. Nucleosides bearing 5 membered heterocycles at the position 7 exerted potent in vitro antiproliferative effects against a broad panel of hematological and solid tumor cell lines. Cell cycle analysis indicated profound inhibition of RNA synthesis and induction of apoptosis in treated cells. Intracellular conversion to triphosphates has been detected with active compounds. The triphosphate metabolites showed only a weak inhibitory effect on human RNA polymerase II, suggesting potentially other mechanisms for the inhibition of RNA synthesis and quick onset of apoptosis. Initial in vivo evaluation demonstrated an effect of 7-(2-thienyl)-7-deazaadenine ribonucleoside on the survival rate in syngeneic P388D1 mouse leukemia model. PMID- 21711055 TI - High-throughput-screening-based identification and structure-activity relationship characterization defined (S)-2-(1-aminoisobutyl)-1-(3 chlorobenzyl)benzimidazole as a highly antimycotic agent nontoxic to cell lines. AB - Novel nontoxic (S)-2-aminoalkylbenzimidazole derivatives were found to be effective against Candida spp. at low micromolar concentrations using high throughput screening with infected HeLa cells. A collection of analogues defined the chemical groups relevant for activity. The most active compound was characterized by transcriptional analysis of the response of C. albicans Sc5314. (S)-2-(1-Aminoisobutyl)-1-(3-chlorobenzyl)benzimidazole had a strong impact on membrane biosynthesis. Testing different clinically relevant pathogenic fungi showed the selectivity of the antimycotic activity against Candida species. PMID- 21711057 TI - Smart polymer nanoparticles designed for environmentally compliant coatings. AB - We describe the synthesis, characterization, and film-forming properties of two component nanoparticles that undergo a reversible morphology transformation in water as a function of pH. The particles consist of a high molecular weight acrylate copolymer and an acid-rich oligomer designed to be miscible with the polymer when its -COOH groups are protonated. Attaching a fluorescence resonance energy transfer (FRET) pair to components inside the nanoparticles enabled us to assess morphology at the molecular level. By inspecting changes in the donor fluorescence decay profile at different pH values, we established miscibility of the components in acidic solution but with charge-induced phase separation when the oligomers were neutralized to their carboxylate form. Complementary titration experiments revealed that the nanoparticles adopt a core-shell structure when the acid groups are deprotonated. We studied the effect of the acid-rich oligomer on the diffusion rate of the high molecular weight polymers following film formation. Our results show that the carboxylated oligomer enhanced the rate of diffusive mixing between high molecular weight molecules by more than 2 orders of magnitude. FRET measurements carried out on partially dried films using a low resolution microscope showed that the carboxylate oligomer shell can delay coalescence for ca. 30 min after passage of the drying front. This delay is expected to help with increasing the 'open time' of latex paints, a desirable property of solvent-based paints that remains difficult to achieve with (environmentally compliant) waterborne paints. Use of ammonia as a volatile base resulted in synergistic effects: initial retardation of coalescence followed by acceleration of diffusive mixing as the ammonium salts dissociated and ammonia evaporated from the film. PMID- 21711056 TI - Anti-DNA:RNA antibodies and silicon photonic microring resonators: increased sensitivity for multiplexed microRNA detection. AB - In this paper, we present a method for the sensitive detection of microRNAs (miRNAs) utilizing an antibody that specifically recognizes DNA:RNA heteroduplexes and a silicon photonic microring resonator array transduction platform. Microring resonator arrays are covalently functionalized with DNA capture probes that are complementary to solution phase miRNA targets. Following hybridization on the sensor, the anti-DNA:RNA antibody is introduced and binds selectively to the heteroduplexes, giving a larger signal than the original miRNA hybridization due to the increased mass of the antibody, as compared to the 22 mer oligoribonucleotide. Furthermore, the secondary recognition step is performed in neat buffer solution and at relatively higher antibody concentrations, facilitating the detection of miRNAs of interest. The intrinsic sensitivity of the microring resonator platform coupled with the amplification provided by the anti-DNA:RNA antibodies allows for the detection of microRNAs at concentrations as low as 10 pM (350 amol). The simplicity and sequence generality of this amplification method position it as a promising tool for high-throughput, multiplexed miRNA analysis as well as a range of other RNA based detection applications. PMID- 21711058 TI - Use of nicorandil in cardiovascular disease and its optimization. AB - Nicorandil, a unique dual pharmacological mechanism anti-anginal agent with adenosine triphosphate sensitive potassium (K(ATP)) channel agonist and nitrate like properties, provides cardiologists with a means of managing angina pectoris patients effectively and provides long-term cardioprotection. The aim of this review is to provide an update on the efficacy of treatment with nicorandil, which counteracts cardiac damage in patients with acute or chronic ischaemic heart disease, congestive heart failure and arrhythmia, with particular emphasis on that induced by ischaemic preconditioning (in which strong protection against ischaemia-reperfusion injury is afforded by a brief preliminary ischaemic period). First, the rationale for nicorandil treatment and its pharmacological effects on the vasculature and cardiomyocytes are reviewed. The mechanisms underlying ischaemic preconditioning, with a focus on those that involve the K(ATP) channel pathway, such as mitochondrial permeability transition pores, sub lethal reactive oxygen species generation and nitric oxide production are then discussed. Next, clinical practice related to ischaemic preconditioning and pharmacological preconditioning with nicorandil as well as other favourable mechanisms of improvement of prognosis, in which it plays a role in improving endothelial function, modulating autonomic nervous system activity and stabilizing plaque are summarized. Finally, the tolerability of nicorandil is discussed. PMID- 21711059 TI - Role of spleen tyrosine kinase inhibitors in the management of rheumatoid arthritis. AB - Spleen tyrosine kinase (Syk) is a cytoplasmic tyrosine kinase involved in signalling in many of the cells that drive immune inflammation. The development of small molecules that inhibit Syk kinase may change the way we treat disorders such as rheumatoid arthritis (RA), as well as a range of other inflammatory diseases. Fostamatinib (R-788) is an orally bioavailable small molecule. It is the prodrug of R406, which is a potent Syk inhibitor. Fostamatinib was developed because it has more favourable physiochemical properties. It is rapidly converted to R406 by intestinal enterocytes. It has been evaluated in experimental models of RA, such as collagen-induced arthritis. In these models, fostamatinib suppressed clinical arthritis, bone erosions, pannus formation and synovitis. A phase II programme with fostamatinib has largely been completed. Three key trials have been published, lasting 12-26 weeks and each enrolling 189-457 patients (875 in total). All these trials involved placebo therapy and patients continued to receive methotrexate in addition to active treatment with fostamatinib. The first dose-ranging trial evaluated three treatment doses in RA patients who had not fully responded to methotrexate therapy. The second trial compared two treatment doses in patients who had not responded to methotrexate therapy. The third trial compared a single treatment dose with placebo in patients who had not responded to biological therapy. The primary outcome measure was the number of patients achieving American College of Rheumatology (ACR) 20% (ACR20) responses. Placebo ACR20 response rates in all three trials were similar (35-38%). All three trials involved one treatment arm receiving fostamatinib 100 mg twice daily; ACR20 responses with this active treatment ranged from 38% to 67%. A meta-analysis of ACR responses in these trials, using responses to the highest dose in each trial for comparisons with placebo therapy in a random effects model, showed a borderline benefit with ACR20 responses. There were more significant differences with ACR50 and ACR70 responses. The reason that this meta-analysis was not more strongly positive is that the third trial, which evaluated patients who had failed to respond to biological treatments, gave negative results. Individual ACR response components, such as changes in swollen joint counts, showed significant differences in the first two trials, but there were no definite treatment benefits in the third trial. Overall, the differences were significant in a meta analysis of all three trials. The most important adverse reactions were diarrhoea, neutropenia and raised ALT levels, which all showed significant excesses with active treatment compared with placebo. Too few patients have been studied for a definitive safety profile to be known. Overall, the results of the phase II trials were sufficiently encouraging for a phase III programme to be initiated. It will be some years before their definitive results are available. PMID- 21711060 TI - Tuberculosis and HIV co-infection: screening and treatment strategies. AB - Globally, tuberculosis (TB) and HIV interact in deadly synergy. The high burden of TB among HIV-infected individuals underlies the importance of TB diagnosis, treatment and prevention for clinicians involved in HIV care. Despite expanding access to antiretroviral therapy (ART) to treat HIV infection in resource-limited settings, many individuals in need of therapy initiate ART too late and have already developed clinically significant TB by the time they present for care. Many co-infected individuals are in need of concurrent ART and anti-TB therapy, which dramatically improves survival, but also raises several management challenges, including drug interactions, shared drug toxicities and TB immune reconstitution inflammatory syndrome (IRIS). Due to the survival benefits of promptly initiating ART among all HIV-infected individuals, including those with TB, it is recommended that co-infected individuals receive treatment for both diseases, regardless of CD4+ cell count. We review current screening and treatment strategies for TB and HIV co-infection. Recent findings and ongoing studies will assist clinicians in managing the prevention and treatment of TB and HIV co-infection, which remains a major global health challenge. PMID- 21711061 TI - Locally advanced rectal cancer: a comparison of management strategies. AB - Traditionally, there has been a high local recurrence rate in rectal cancer and 10-40% of patients require a permanent stoma. Both short-course preoperative radiotherapy (SCPRT) and long-course preoperative chemoradiation (CRT) are used to reduce the risk of local recurrence and enable a curative resection. Total mesorectal excision has reduced the rate of local recurrence (even without radiotherapy) to below 10%, but has highlighted a high risk of metastatic disease in 30-40% of patients. Current trials suggest that in resectable cancers, where the preoperative magnetic resonance imaging (MRI) suggests the circumferential resection margin (CRM) is not potentially involved, then SCPRT and CRT are equivalent in terms of outcomes such as local recurrence, disease-free survival (DFS) and overall survival (OS). For patients with more advanced disease, where the CRM is breached or threatened according to the MRI, the integration of more active chemotherapy and biological agents into chemoradiation is an attractive strategy because of the high risk of metastases. However, in none of the trials published in the last decade has chemoradiation impacted on DFS or OS. We examine the strategies of neoadjuvant, concurrent, consolidation (after chemoradiation and before surgery) and postoperative adjuvant chemotherapy with cytotoxic agents, and the integration of biological agents for future potential strategies of treatment. We also compare the trials and compare the different strategies of long-course preoperative radiotherapy and SCPRT; the intensification of preoperative radiation and chemoradiation with dose escalation of external beam radiotherapy, using brachytherapy, intra-operative radiotherapy, hyperfractionation, and various available techniques such as intensity-modulated radiotherapy. We recommend examining dose escalation of radiotherapy to the primary tumour where MRI predicts a threatened CRM. Of the potential treatment strategies involving cytotoxic agents, such as neoadjuvant, concurrent, consolidation and postoperative adjuvant chemotherapy, the most promising would appear to be consolidation chemotherapy following chemoradiation in locally advanced disease, and neoadjuvant chemotherapy in MRI-selected patients who do not require radiation. Improvement in the quality of surgery is also an important future goal. PMID- 21711062 TI - Vascular endothelial growth factor-targeted therapy for the treatment of renal cell carcinoma. AB - Vascular endothelial growth factor (VEGF)-targeted agents have rapidly been adopted into standard-of-care treatment for renal cell carcinoma (RCC). However, a substantial proportion of patients fail to respond to these agents or experience considerable toxicity. This article reviews the benefits and limitations of currently approved anti-VEGF agents in advanced and metastatic RCC, and the role for newly approved and developmental agents. Sunitinib and bevacizumab plus interferon (IFN)-alpha have demonstrated significant improvements in progression-free survival (PFS) compared with IFNalpha in treatment-naive patients. A PFS benefit has also been shown with sorafenib versus placebo second-line to cytokine therapy. However, no anti-VEGF agent has shown a significant overall survival benefit. Anti-VEGF therapy is generally well tolerated, but a number of key adverse events, including dermatological, mucosal and constitutional symptoms, may limit treatment compliance and success. Pazopanib is a recently approved, highly selective anti-VEGF agent that shows benefit in PFS over IFNalpha, with low rates of treatment-related adverse events and, therefore, may be better tolerated than other currently approved agents. The advent of VEGF-targeted therapy for RCC has greatly improved prospects for patients with advanced or metastatic disease, but more efficacious agents are required that demonstrate a clear survival advantage. Ongoing trials evaluating novel anti-VEGF therapies could establish whether the increased potency and selectivity of these agents results in improved efficacy and tolerability in RCC patients, further improving their prognosis. PMID- 21711065 TI - Racial variation in the cost-effectiveness of chemotherapy for prostate cancer. AB - OBJECTIVE: Heterogeneity of treatment effects and expenditures impacts the cost effectiveness of health interventions. This study investigates the variation in costs, effects, and incremental cost-effectiveness ratios (ICERs) associated with chemotherapy in elderly patients with metastatic (M1) prostate cancer (PC) across race/ethnicity subgroups (non-Hispanic whites, non-Hispanic blacks, and others). STUDY DESIGN: Retrospective observational analysis. METHODS: We examined patients 66 years or older, identified by using the linked Surveillance, Epidemiology, and End Results-Medicare data set, who were diagnosed with M1 PC between 2000 and 2005. Cost data on the basis of Medicare reimbursements were available for 36 months after diagnosis. Mean costs and effects (life-years gained [LYG]) were adjusted for censoring. The baseline scenario examined PC-specific medical costs at 24 months and required survival of at least 3 months. Sensitivity analysis considered sampling uncertainty, selection into treatment, and adjustments to initial model assumptions. RESULTS: We identified 3888 patients with M1 PC, of whom 24% (n = 930) received chemotherapy (primarily docetaxel and mitoxantrone). Twenty percent of observations were censored. The full sample ICER was $99,146 per LYG (95% confidence interval [CI], $75,042 to $130,195). Estimates for whites (ICER, $107,095; 95% CI, $78,391 to $148,272), blacks (ICER, $59,887; 95% CI, $22,860 to $121,509), and others (ICER, $123,909; 95% CI, $37,782 to $366,376) suggest considerable variation in the likelihood of chemotherapy being cost effective. Results were similar in sensitivity analysis. CONCLUSION: Chemotherapy use in elderly patients with M1 PC is associated with an ICER of $99,146 per LYG. Subgroup analysis revealed heterogeneity in point estimates and considerable statistical uncertainty. To generate a reliable evidence base, efforts to increase the representation of minorities in healthcare data sets need to continue. PMID- 21711063 TI - Current concepts in the pharmacotherapy of pseudobulbar affect. AB - Arising in settings of CNS insult, pseudobulbar affect (PBA) consists of uncontrollable episodes of crying or laughter incongruent to the patient's mood. The syndrome has been described by a plethora of names, including pathological laughing and crying, emotional lability, emotionalism and emotional incontinence, which hampers efforts to survey published assessments of pharmacological intervention. Still, until quite recently, all treatment has unavoidably been off label, chiefly involving antidepressants. Using PBA and other syndrome names as search terms, a PubMed search for English-language case reports and therapeutic trials involving at least five patients identified 22 such publications from 1980 through to 2010. Among the seven randomized, double-blind, antidepressant studies with placebo control, two trials assessed 106 and 123 subjects, respectively. However, the other five assessed only 12-28 subjects, and only one of these seven trials (with 28 subjects) measured change in syndrome severity using a validated scale. The three randomized, double-blind studies of dextromethorphan plus quinidine assessed 129, 150 and 326 subjects. Among these studies, two were placebo-controlled and all three used a validated severity scale. Across all placebo-controlled trials, response to active treatment - either an antidepressant or dextromethorphan/quinidine - has in general been significantly greater than response to placebo, but placebo response has sometimes been substantial, suggesting caution in interpreting uncontrolled findings. In October 2010, dextromethorphan/quinidine received approval from the US FDA as first-in class PBA pharmacotherapy. Advocates of a continuing role for antidepressants, notably selective serotonin reuptake inhibitors, can point to numerous positive case reports and trials, the potential benefit of attempting to treat PBA and concomitant depression without using multiple drugs, and the ever-present need to tailor treatment to the individual patient. PMID- 21711064 TI - Rivastigmine transdermal patch: a review of its use in the management of dementia of the Alzheimer's type. AB - Rivastigmine, a cholinesterase inhibitor, is available as a transdermal patch (Exelon((r)) patch, Rivastach((r)) patch, Prometax((r)) patch) for the treatment of mild to moderate Alzheimer's disease. Rivastigmine transdermal patch was effective, in terms of improving cognitive and global function, and generally well tolerated in patients with mild to moderate dementia of the Alzheimer's type in a large, well designed trial. Most adverse events associated with rivastigmine patch were mild to moderate in severity, with the patch generally better tolerated than oral rivastigmine, especially in terms of cholinergic gastrointestinal adverse events. The patch also had good skin adhesion and a favourable skin tolerability profile in this study, with most application-site reactions being mild in severity. Additionally, in a safety and tolerability study, rivastigmine patch, regardless of concomitant memantine therapy, was generally well tolerated in patients switching from oral donepezil therapy. Thus, current evidence suggests that rivastigmine transdermal patch is an effective treatment option for patients with Alzheimer's disease, with the potential for improving compliance and providing sustained clinical benefit because of its ease of use and generally favourable tolerability profile. PMID- 21711066 TI - Impact of new drugs and biologics on colorectal cancer treatment and costs. AB - OBJECTIVE: To compare medical expenditures of patients receiving old and new colorectal cancer (CRC) regimens. STUDY DESIGN: Using claims data, we identified 2 cohorts of privately insured patients diagnosed with CRC: first, those diagnosed before new treatment introduction (January 1, 2002, to December 31, 2002), and second, those diagnosed after new treatment introduction (June 1, 2004, to May 31, 2005). CRC diagnosis was identified using International Classification of Diseases-9 codes 153.xx, 154.xx, and 159.0. First- and second line chemotherapy regimens were identified. Treatments and expenditures were then observed for up to 2 years after initial diagnosis. METHODS: We estimated multivariate models to measure changes in cost with changes in treatment regimen. Approval dates of new regimens were used as natural experiments. RESULTS: New regimens, such as fluorouracil, leucovorin, and oxaliplatin (FOLFOX), have rapidly replaced the most prevalent preperiod product (ie, fluorouracil/leucovorin). Changes in treatment have caused large increases in total expenditure, primarily through increases in chemotherapy prices. FOLFOX alone has increased total average cost by 14%. New treatments have not substituted for other medical services; rather, they have indirectly raised costs through nonstandard regimen use and increases in second-line treatment use. We found no evidence that expenditure effects were driven by changes in follow-up duration. CONCLUSION: New CRC treatments have increased both regimen choice and expenditures. New regimens have primarily increased expenditures through direct treatment costs; we observed no offsetting expenditure reductions. PMID- 21711067 TI - Impact of clinical oral chemotherapy program on wastage and hospitalizations. AB - OBJECTIVE: The oral chemotherapy cycle management program (CMP) provides clinical management support to patients receiving certain oral chemotherapies. The CMP includes a dose-monitoring (ie, split-fill) plan for early identification and management of adverse effects. If serious adverse effects are identified mid cycle, the remainder of the monthly supply is withheld, thus avoiding potential waste associated with early therapy discontinuation. This study investigated medication wastage and estimated potential cost savings for patients who were enrolled in the CMP, as compared with those who were not enrolled in the program. STUDY DESIGN: Retrospective test-control study. PATIENTS AND METHODS: Patients whose oral chemotherapy was initiated between June 2008 and February 2010 and who were enrolled in the CMP were included as the test group. Patients whose oral chemotherapy was initiated between June 2007 and May 2008 and who were not part of the CMP were included as the control group. RESULTS: Medication wastage associated with early therapy discontinuation was found to be lower in the CMP group. Approximately 34% of patients in the CMP group could have avoided medication wastage if split-fill plans had been available, potentially realizing savings of approximately $934.20 per patient. Linear probability regression models showed that the CMP group had a 2.9% probability for reduction in hospital admissions (P <.05), resulting in additional savings of approximately $440.00 per patient. Combined savings resulting from reduced wastage and hospital admissions was approximately $1374 per patient. CONCLUSION: Dose-monitoring programs such as the CMP effectively reduce wastage and serious adverse effects associated with oral chemotherapeutic agents, realizing potential cost savings for both payers and patients. PMID- 21711068 TI - Genomic testing and therapies for breast cancer in clinical practice. AB - OBJECTIVE: Given the likely proliferation of targeted testing and treatment strategies for cancer, a better understanding of the utilization patterns of human epidermal growth factor receptor 2 (HER2) testing and trastuzumab and newer gene expression profiling (GEP) for risk stratification and chemotherapy decision making are important. STUDY DESIGN: Cross-sectional. METHODS: We performed a medical record review of women aged 35 to 65 years diagnosed between 2006 and 2007 with invasive localized breast cancer, identified using claims from a large national health plan (N = 775). RESULTS: Almost all women received HER2 testing (96.9%), and 24.9% of women with an accepted indication received GEP. Unexplained socioeconomic differences in GEP use were apparent after adjusting for age and clinical characteristics; specifically, GEP use increased with income. For example, those in the lowest income category (<$40,000) were less likely than those with an income of $125,000 or more to receive GEP (odds ratio, 0.34; 95% confidence interval, 0.16 to 0.73). A majority of women (57.7%) with HER2 positive disease received trastuzumab; among these women, differences in age and clinical characteristics were not apparent, although surprisingly, those in the lowest income category were more likely than those in the high-income category to receive trastuzumab (P = .02). Among women who did not have a positive HER2 test, 3.9% still received trastuzumab. Receipt of adjuvant chemotherapy increased as GEP score indicated greater risk of recurrence. CONCLUSION: Identifying and eliminating unnecessary variation in the use of these expensive tests and treatments should be part of quality improvement and efficiency programs. PMID- 21711069 TI - Oncology management programs for payers and physicians. PMID- 21711070 TI - Journey forward: the new face of cancer survivorship care. PMID- 21711071 TI - US insurance program's experience with a multigene assay for early-stage breast cancer. AB - OBJECTIVE: National guidelines recommend a 21-gene recurrence score (RS) to aid in adjuvant treatment decision in patients with estrogen receptor (ER)-positive, lymph node (LN)-negative early-stage breast cancer (ESBC). This study was performed to assess the economic implication of the assay in community practices from the perspective of a US payer. METHODS: The study analyzed 952 women with ESBC enrolled with Humana (Louisville, KY) who were tested with the 21-gene RS between June 2006 and June 2010. The proportions of women classified by the assay according to RS risk category, use, costs of chemotherapy regimens and supportive care, and costs of adverse events were obtained from Humana. We adopted a validated Markov model to compute the cost implications of RS for a representative patient. The probability of risk of recurrence, the chemotherapy benefit, and the decision impact of RS were derived from published studies. RESULTS: A total of 255 patients within the tested population received adjuvant chemotherapy. Adjuvant chemotherapy was administered to 10% of women at low risk, 36% of women at intermediate risk, and 72% of women at high risk of recurrence. On the basis of a meta-analysis in the reduction of chemotherapy after RS, the model estimated an average test saving of $1160 per patient. The immediate direct savings for chemotherapy drugs, supportive care, and management of adverse events were $1885, $2578, and $472, respectively. Prevention of recurrence through appropriate treatment of patients at high risk resulted in additional savings of $199. CONCLUSION: The adoption of the 21-gene RS led to targeted management of women with ER-positive, LN-negative ESBC and consequently directed savings to the payer. PMID- 21711072 TI - Effect of the pay-for-performance program for breast cancer care in Taiwan. AB - OBJECTIVE: To evaluate the impact of the nationwide pay-for-performance (P4P) program for breast cancer care (BC-P4P) in Taiwan on care quality, patient survival, and recurrence. STUDY DESIGN: A population-based observational study with cross-sectional design. METHODS: Retrospective analysis of population based cancer registration and claims data was used in this study. A total of 4528 patients with stage I or II breast cancer diagnosed in 2002 or 2003 who received curative surgery were observed until the end of 2008. This study applied multivariate linear regression to explore the association between BC-P4P enrollment and quality of care. Cox regression was applied to examine the effect of BC-P4P enrollment on 5-year recurrence and overall survival among patients with breast cancer. RESULTS: After controlling for age, stage, type of surgery, and other factors, BC-P4P enrollees were found to have received better quality care than nonenrollees (P = .001). Cox regression models also indicated that after controlling for patient characteristics, quality of care was related to better 5-year overall survival (odds ratio [OR], 0.212; P = .001) and recurrence (OR, 0.289; P <.001). Even when controlled by quality of care provided to patients and its interaction with status of BC-P4P enrollment, BC-P4P enrollment remained statistically significant regarding 5-year overall survival (OR, 0.167; P <.001) and recurrence (OR, 0.370; P = .002). CONCLUSION: Patients with breast cancer enrolled in the BC-P4P program received better quality care and had better outcome than nonenrolled patients. Evidence from this study indicates that financial incentives in the payment design had a positive impact on outcome of breast cancer care. PMID- 21711073 TI - Developing dialogue in healthcare. PMID- 21711075 TI - Advancing performance measurement in oncology. AB - The American healthcare system, including the cancer care system, is under pressure to improve patient outcomes and lower the cost of care. Government payers have articulated an interest in partnering with the private sector to create learning communities to measure quality and improve the value of healthcare. In 2006, the American Society of Clinical Oncology (ASCO) unveiled the Quality Oncology Practice Initiative (QOPI), which has become a key component of the measurement system to promote quality cancer care. QOPI is a physician led, voluntary, practice-based, quality-improvement program, using performance measurement and benchmarking among oncology practices across the United States. Since its inception, ASCO's QOPI has grown steadily to include 973 practices as of November 2010. One key area that QOPI has addressed is end-of-life care. During the most recent data collection cycle in the fall of 2010, those practices completing multiple data collection cycles had better performance on care of pain compared with sites participating for the first time (62.61% vs 46.89%). Similarly, repeat QOPI participants demonstrated meaningfully better performance than their peers in the rate of documenting discussions of hospice and palliative care (62.42% vs 54.65%) and higher rates of hospice enrollment. QOPI demonstrates how a strong performance measurement program can lead to improved quality and value of care for patients. PMID- 21711074 TI - Characterizing medical care by disease phase in metastatic colorectal cancer. AB - OBJECTIVE: To characterize patterns of medical care by disease phase in patients with newly diagnosed metastatic colorectal cancer (mCRC). METHODS: Patients with mCRC newly diagnosed between 2004 and 2008 were selected from a large US national commercially insured claims database and were observed from initial mCRC diagnosis to death, disenrollment, or end of study period (July 31, 2009), whichever occurred first. The observation period was divided into 3 distinct phases of disease: diagnostic, treatment, and death. Within each phase, patterns of medical care were examined by the mutually exclusive service categories of inpatient, emergency department (ED), outpatient office and facility, outpatient pharmacy, chemotherapy, and biologic therapy, as measured by estimation of aggregate and category costs per patient per month. RESULTS: A total of 6675 patients with newly diagnosed mCRC were analyzed. Mean age was 64.1 years; 55.5% were males. Mean costs per patient per month for diagnostic, treatment, and death phases were $16,895, $8891, and $27,554, respectively. Inpatient care was the primary driver of medical care for both the diagnostic (41.7% of costs) and death (71.4% of costs) phases. The largest category of medical care for the treatment phase was outpatient care (45.0% of costs). Chemotherapy and biologic therapy accounted for 15.6% and 17.6% of costs in the treatment phase, respectively. CONCLUSION: Substantial differences in patterns of medical care were found between mCRC disease phases. Inpatient care was the key driver of medical care in the diagnostic and death phases compared with outpatient care in the treatment phase. PMID- 21711076 TI - Patient and plan characteristics affecting abandonment of oral oncolytic prescriptions. AB - OBJECTIVE: To calculate the abandonment rate of oral oncolytic medications and identify factors that may affect likelihood of abandonment. STUDY DESIGN: Cross sectional cohort study using administrative claims data. METHODS: We analyzed a nationally representative pharmacy claims database and identified 10,508 patients with Medicare and commercial insurance for whom oral oncolytic therapy was initiated between 2007 and 2009. We calculated the abandonment rate for the initial claim, in which abandonment was defined as reversal of an adjudicated pharmacy claim without a subsequent paid claim for any oncolytic (oral or intravenous) within the ensuing 90 days. We assessed likelihood of abandonment using bivariate and multivariate logistic regression analyses including patient demographics, plan type, drug type, cost sharing, and concurrent prescription activity. RESULTS: The abandonment rate of newly initiated oral oncolytics was 10.0%. Unadjusted bivariate analyses found that high cost sharing, increased prescription activity, lower income, and Medicare coverage were associated with a higher abandonment rate (P <.05). In the logistic regression model, claims with cost sharing greater than $500 were 4 times more likely to be abandoned than claims with cost sharing of $100 or less (odds ratio [OR], 4.46; P <.001). Patients with 5 or more prescription claims processed within in the previous month had 50% higher likelihood of abandonment than patients with no other prescription activity (OR, 1.50; P <.001). CONCLUSION: Abandonment of newly prescribed oral oncolytic therapy is not uncommon, and the likelihood increases for patients enrolled in plans with pharmacy benefit designs that require high cost sharing. Increased concurrent prescription activity was also associated with a higher abandonment rate. These factors should be taken into account when considering likely adherence to cancer therapy. PMID- 21711077 TI - Pathways, outcomes, and costs in colon cancer: retrospective evaluations in 2 distinct databases. AB - OBJECTIVE: The goal of this study was to use 2 separate databases to evaluate the clinical outcomes and the economic impact of adherence to Level I Pathways, an evidence-based oncology treatment program in the treatment of colon cancer. PATIENTS AND METHODS: The first study used clinical records from an electronic health record (EHR) database to evaluate survival according to pathway status in patients with colon cancer. Disease-free survival in patients receiving adjuvant treatment and overall survival in patients receiving first-line therapy for metastatic disease was calculated. The second study used claims data from a national administrative claims database to examine direct medical costs and use, including the cost of chemotherapy and of chemotherapy-related hospitalizations according to pathway status. RESULTS: Overall costs from the national claims database-including total cost per case and chemotherapy costs-were lower for patients treated according to Level I Pathways (on- Pathway) compared with patients not treated according to Level I Pathways. Use of pathways was also associated with a shorter duration of therapy and lower rate of chemotherapy related hospital admissions. Survival for patients on- Pathways in the EHR database was comparable with that in the published literature. CONCLUSION: Results from 2 distinct databases suggest that treatment of patients with colon cancer on-Pathways costs less; use of these pathways demonstrates clinical outcomes consistent with published evidence. PMID- 21711078 TI - Health technology assessment and private payers's coverage of personalized medicine. AB - OBJECTIVE: Health technology assessment (HTA) plays an increasing role in translating emerging technologies into clinical practice and policy. Private payers are important users of HTA whose decisions impact adoption and use of new technologies. We examine the current use of HTA by private payers in coverage decisions for personalized medicine, a field that is increasingly impacting oncology practice. STUDY DESIGN: Literature review and semistructured interviews. METHODS: We reviewed 7 HTA organizations used by private payers in decision making and explored how HTA is used by major US private payers (n = 11) for coverage of personalized medicine. RESULTS: All payers used HTA in coverage decisions, but the number of HTA organizations used by an individual payer ranged from 1 (n = 1) to all 7 (n = 1), with the majority of payers (n = 8) using 3 or more. Payers relied more extensively on HTAs for reviews of personalized medicine (64%) than for other technologies. Most payers (82%) equally valued expertise of reviewers and rigor of evaluation as HTA strengths, whereas genomic-specific methodology was less important. Key reported shortcomings were limited availability of reviews (73%) and limited inclusion of nonclinical factors (91%), such as cost-effectiveness or adoption of technology in clinical practice. CONCLUSION: Payers use a range of HTAs in their coverage decisions related to personalized medicine, but the current state of HTA to comprehensively guide those decisions is limited. HTA organizations should address current gaps to improve their relevance to payers and clinicians. Current HTA shortcomings may also inform the national HTA agenda. PMID- 21711080 TI - Trying something new: episode payments for cancer therapy. PMID- 21711081 TI - Are we winning the war on cancer? PMID- 21711079 TI - Do economic evaluations of targeted therapy provide support for decision makers? AB - OBJECTIVE: Decision makers must make decisions without complete information. That uncertainty can be decreased when economic evaluations use local data and can be quantified by considering the variability of all model inputs concurrently per international evaluation guidelines. It is unclear how these recommendations have been implemented in evaluations of targeted cancer therapy. By using economic evaluations of adjuvant trastuzumab, we have assessed the extent to which decision support recommendations were adopted. STUDY DESIGN: Systematic review. METHODS: Published economic evaluations of adjuvant trastuzumab treatment in early-stage breast cancer were examined as an established example of targeted therapy. Canadian, United Kingdom, and US economic evaluation guidelines were reviewed to establish extraction criteria. Extraction characterized the use of effectiveness evidence and local data sources for model parameters, sensitivity analysis methods (scenario, univariate, multivariate, and probabilistic), and uncertainty representation (ie, cost-effectiveness plane, scatterplot, confidence ellipses, tornado diagrams, cost-effectiveness acceptability curve). RESULTS: Fifteen economic evaluations of adjuvant trastuzumab were identified in the literature. Local data were used to estimate costs (15 of 15) and utilities rarely (2 of 15) but not trastuzumab efficacy. Univariate sensitivity analysis was most common (12 of 15), whereas probabilistic analysis was less frequent (10 of 15). Two-thirds of all studies provided visual representation of results and decision uncertainty. CONCLUSION: Authors of adjuvant trastuzumab economic evaluations rarely use local data beyond costs. Quantification of uncertainty and its representation also fell short of guideline recommendations. This review demonstrates that economic evaluations of adjuvant trastuzumab, as an example of targeted cancer therapy, can be improved for decision-making support. PMID- 21711082 TI - Occurrence and functional significance of secondary carbohydrate binding sites in glycoside hydrolases. AB - Non-catalytic carbohydrate binding on independent carbohydrate-binding modules (CBMs) has been reported frequently for glycoside hydrolases (GHs) and reviewed thoroughly. However, various structural studies of GHs have revealed that non catalytic carbohydrate binding sites can also occur on the surface of the structural unit comprising the active site. Here, the discovery of these sites, referred to as secondary binding sites (SBSs), and their putative roles in different GHs is reviewed for the first time. The majority of the SBSs have been discovered in starch-active enzymes, but there are also many reports of SBSs in various other enzymes. A wide variety of functions has been ascribed to these sites, including (1) targeting of the enzyme towards its substrate, (2) guiding the substrate into the active site groove, (3) substrate disruption, (4) enhancing processivity, (5) allosteric regulation, (6) passing on reaction products, and (7) anchoring to the cell wall of the parent microorganism. A lot of these putative functions are in agreement with the functions ascribed to non catalytic binding in CBMs. Contrarily to CBMs, SBSs have a fixed position relative to the catalytic site, making them more or less suitable to take up specific functions. PMID- 21711083 TI - Analgesic and anti-inflammatory effects of ethyl acetate fraction of Polygonum cuspidatum in experimental animals. AB - Polygonum cuspidatum (PC) has been used for the treatment of arthritis and urinary diseases in traditional medicine. Despite recent evidence that PC has anti-oxidant, anti-tumoral, and anti-inflammatory effects, analgesic and anti inflammatory effects of PC have not been elucidated yet in vivo. Thus, in the present study, analgesic and anti-inflammatory effects of ethyl acetate extract of PC (EAPC) were investigated in vivo for the first time. Hot plate test and tail-flick test revealed that EAPC at 200 mg/kg exerts analgesic effect (p < 0.05). In contrast, EAPC did not show significant analgesic effect in acetic acid induced writhing test. Serotonin-induced paw edema model and Freund's complete adjuvant (FCA)-induced adjuvant arthritis model were used to examine anti inflammatory effect of EAPC in vivo. In serotonin-induced paw edema model, EAPC suppressed swelling inflammatory response within 12 min after serotonin injection, at both 100- and 200-mg/kg dose (p < 0.05). Consistently, in FCA induced adjuvant arthritis model, FCA at 200 mg/kg significantly suppressed FCA induced joint swelling within 3 days (p < 0.05), whereas FCA at 100 mg/kg showed the similar result within 5 days (p < 0.05). Furthermore, EAPC effectively inhibited positive responses of c-reactive protein and rheumatoid factor compared to untreated control. Taken together, our findings suggest that EAPC can be a potent candidate for rheumatoid arthritis treatment. PMID- 21711084 TI - A novel lipid nanocarrier for insulin delivery: production, characterization and toxicity testing. AB - A novel nanocarrier based on solid lipid nanoparticles (SLNs) was developed for insulin delivery using a novel double emulsion method. Physical stability of particles was assessed by size analysis using dynamic light scattering (DLS), matrix crystallinity by differential scanning calorimetry (DSC) and toxicity analysis by Drosophila melanogaster testing. Insulin-SLNs were composed of Softisan(r)100 1.25% wt, Lutrol(r)F68 1% wt, soybean lecithin 0.125% wt, and loaded with 0.73-0.58 mg/mL peptide. Placebo-SLNs (insulin-free) also contained 0.025% wt Tween(r)80. Mean particle sizes of placebo-SLN and insulin-SLN were 958 +/- 9.5 and 978 +/- 8.3 nm, respectively. The polydispersity index (PI) was 0.28 +/- 0.018 and 0.29 +/- 0.013, respectively. Polarized light microscopy analysis depicted no aggregation of developed particles. DSC analysis allowed characterizing SLN with 43-51% matrix crystallinity. Using Drosophila melanogaster test, no toxicity was reported for SLN and for the bulk lipid. This study shows that SLNs are promising and helpful to overcome conventional insulin therapy, in particular for their lack of toxicity for oral delivery. PMID- 21711085 TI - Nano-based theranostics for chronic obstructive lung diseases: challenges and therapeutic potential. AB - The major challenges in the delivery and therapeutic efficacy of nano-delivery systems in chronic obstructive airway conditions are airway defense, severe inflammation and mucous hypersecretion. Chronic airway inflammation and mucous hypersecretion are hallmarks of chronic obstructive airway diseases, including asthma, COPD (chronic obstructive pulmonary disease) and CF (cystic fibrosis). Distinct etiologies drive inflammation and mucous hypersecretion in these diseases, which are further induced by infection or components of cigarette smoke. Controlling chronic inflammation is at the root of treatments such as corticosteroids, antibiotics or other available drugs, which pose the challenge of sustained delivery of drugs to target cells or tissues. In spite of the wide application of nano-based drug delivery systems, very few are tested to date. Targeted nanoparticle-mediated sustained drug delivery is required to control inflammatory cell chemotaxis, fibrosis, protease-mediated chronic emphysema and/or chronic lung obstruction in COPD. Moreover, targeted epithelial delivery is indispensable for correcting the underlying defects in CF and targeted inflammatory cell delivery for controlling other chronic inflammatory lung diseases. We propose that the design and development of nano-based targeted theranostic vehicles with therapeutic, imaging and airway-defense penetrating capability, will be invaluable for treating chronic obstructive lung diseases. This paper discusses a novel nano-theranostic strategy that we are currently evaluating to treat the underlying cause of CF and COPD lung disease. PMID- 21711086 TI - Management strategies for autoimmune pancreatitis. AB - INTRODUCTION: Autoimmune pancreatitis (AIP) is a newly developed concept for a peculiar type of pancreatitis, and at present is recognized as a pancreatic lesion reflecting IgG4-related systemic disease. It is of utmost importance to differentiate AIP from pancreatic cancer to avoid unnecessary surgery. AREAS COVERED: The current management strategies for AIP, including its clinical features, diagnostic criteria, clinical subtypes, steroid therapy and prognosis are discussed, based on our 66 AIP cases and papers searched in PubMed from 1992 to March 2011, using the term 'autoimmune pancreatitis'. A new clinicopathological entity, an 'IgG4-related sclerosing disease' is also mentioned. EXPERT OPINION: AIP should be considered in the differential diagnosis in elderly male patients presented with obstructive jaundice and pancreatic mass. Steroids are a standard therapy for AIP, but their regimen including maintenance therapy should be evaluated in prospective trials. PMID- 21711087 TI - Recent progress in therapeutic applications of chalcones. AB - INTRODUCTION: Chalcones are a group of plant-derived polyphenolic compounds belonging to the flavonoids family that possess a wide variety of cytoprotective and modulatory functions, which may have therapeutic potential for multiple diseases. Their physicochemical properties seem to define the extent of their biological activity. AREAS COVERED: A comprehensive synopsis of recent patent literature (2005 - 2011) describing chalcones and their derivatives on selected activities (e.g., anti-inflammatory, antimitotic, cytotoxic, antioxidant, anti infection) is provided in this paper. Synthesis, combinatorial techniques, biological evaluation in vitro/in vivo, and new biological assays are discussed. In addition to selected biological data, a wide range of pharmaceutical applications and pharmaceutical compositions are also summarized. EXPERT OPINION: Several natural and synthetic chalcones and their derivatives appear as promising anti-inflammatory and anticancer activities. Their clinical evaluation will be critical to assess their therapeutic utility. Those for which the mechanism of action is well defined can serve as lead compounds for the design of new, more promising molecules. PMID- 21711088 TI - Aflatoxins and growth impairment: a review. AB - Aflatoxins, fungal toxins produced by Aspergillus flavus and Aspergillus parasiticus in a variety of food crops, are well known as potent human hepatocarcinogens. Relatively less highlighted in the literature is the association between aflatoxin and growth impairment in children. Foodborne aflatoxin exposure, especially through maize and groundnuts, is common in much of Africa and Asia--areas where childhood stunting and underweight are also common, due to a variety of possibly interacting factors such as enteric diseases, socioeconomic status, and suboptimal nutrition. The effects of aflatoxin on growth impairment in animals and human children are reviewed, including studies that assess aflatoxin exposure in utero and through breastfeeding. Childhood weaning diets in various regions of the world are briefly discussed. This review suggests that aflatoxin exposure and its association with growth impairment in children could contribute a significant public health burden in less developed countries. PMID- 21711089 TI - In vitro immunomodulatory effects of extracts from three plants of the Labiatae family and isolation of the active compound(s). AB - Plants may have the ability to modulate immune responses. In the present study, the effects of three plants belonging to Labiatae family, each traditionally used for the treatments of infections and inflammatory diseases, as well as the role of thymol (as one the major components of these plants), were investigated for their potential to affect the activation of lymphocytes. Four organic extracts of Thymus vulgaris and two other plants (i.e., T. daenensis and Zataria multiflora) were prepared. The effect of the extracts on mitogen (PHA)-stimulated peripheral blood lymphocytes was determined using a cell proliferation assay. The hexane extracts obtained from the three plants showed the strongest inhibitory effects on PHA-induced proliferation. Use of preparative thin layer and gas chromatographies in conjunction with the proliferation assay confirmed that thymol was the major component responsible for the observed effects from the three plants. Thymol inhibited inducible lymphocyte proliferation in a concentration-dependent manner, with reductions ranging from 62.8% at 50 ug/ml to 89.8% at 200 ug/ml (> 0.1 ug/ml (p < 0.01). Flow cytometric analysis using propidium iodide staining showed that the inhibitory effect of thymol at 200 ug/ml was due to a cytotoxic activity. In conclusion, the three Labiatae plants studied here each showed immunosuppressive effects against lymphocytes and it was most likely that thymol was the compound in these plants responsible for this effect. PMID- 21711091 TI - Interphase chromosome structures of human cells. AB - Major intermediates of chromosome condensation in erythroleukemia K562 cells are presented. Interphase chromatin structures became visible after reversal of permeabilization. Large-scale chromatin structures and the development of individual interphase chromosomes were observed by fluorescence microscopy. In the linear arrangement the following major intermediates of K562 chromatin condensation could be distinguished: (1) the most decondensed chromatin veil, (2) chromatin ribbon, (3) chromatin funnel, a new intermediate regarded as the earliest visible form of interphase chromosomes, (4) chromatin body, (5) 300 nm chromatin fiber, (6) u, v, or s forms of chromosomes, and (7) linear chromosomes. The observations made in nuclei of K562 cells conform to the model of helical coil chromosome condensation. PMID- 21711092 TI - GSTP1 I105V polymorphism and susceptibility to colorectal cancer in Kashmiri population. AB - The glutathione S-transferase (GST) enzyme encoded by the GSTP1 gene is one of the critical enzymes involved in detoxification of carcinogens. The substitution of isoleucine to valine residue at position 105 of the GSTP1 protein results in decreased enzyme activity and hence less capability of effective detoxification. Hence, we investigated the role of GSTP1 I105V polymorphism in modulating the risk of colorectal cancer (CRC) associated in a Kashmiri population. We designed a case-control study in which 86 CRC cases were studied for GSTP1 I105V polymorphism against 160 controls taken from the general population employing the polymerase chain reaction-restriction length fragment polymorphism technique. There was no significant association between GSTP1 I105V genotypes and the disease, but the Val/Val genotype was associated with an increased risk with some clinicopathological parameters (odds ratio=1.5; 95% confidence interval=0.55 4.57). This study suggests that the GSTP1 I105V polymorphism may modulate CRC risk in the Kashmiri population. PMID- 21711093 TI - Characterization of interferon-gamma-treated melanoma tumor cells for use in dendritic cell-based immunotherapy. AB - Efficient delivery of tumor-associated antigens to professional antigen presenting cells is important for inducing a response in patients receiving cancer immunotherapy. Interferon-gamma (IFN-gamma) is used by the immune system to combat viral and fungal infections by restricting cell proliferation and, in some cases, inducing apoptosis. Using IFN-gamma to activate target tumor cells prior to antigen loading of dendritic cells (DCs) may enhance the beneficial qualities of whole-cell tumor vaccines. The incubation of melanoma cell cultures with IFN-gamma resulted in an increase in the expression of major histocompatibility complex molecules and ICAM-1 but generally decreased the expression of melanoma-associated tumor antigens. Additionally, important immune stimulating molecules (heat-shock proteins, high-mobility group box-1 protein, and calreticulin) were also present but differentially regulated by IFN-gamma. Loading of DCs with IFN-gamma-treated tumor cells resulted in a small but significant increase in the expression of CD83-positive DCs, indicating the initiation of DC maturation (p=0.019). IFN-gamma treatment of melanoma cell lines prior to antigen loading of DCs may aid in antigen processing and presentation. PMID- 21711094 TI - Should high-dose interleukin-2 still be the preferred treatment for patients with metastatic renal cell cancer? AB - Interleukin-2 (IL-2) was the preferred treatment for medically fit patients with advanced kidney cancer, but recently, several targeted therapies have been approved for metastatic renal cell carcinoma. We wished to determine the long term survival rate for patients with kidney cancer treated with IL-2 and whether the use of intense inpatient IL-2 has declined since the introduction of targeted therapies. Patients who received IL-2 were identified from clinical trial enrollment, pharmacy logs, and financial billing records. Survival was determined from the earliest date of IL-2 therapy. There were 79 patients hospitalized for high-dose infusional IL-2 between March 1989 and March 2009. Median age was 58 years, and 27% were older than 65 years at the time of treatment. At the time of this analysis, 72 patients had deceased. Median survival was 9.9 months, but 5 year survival was 19.4%. The average number of patients with IL-2 increased from 2.2 per year during 1989-1992 to 5.6 during 1993-2001 after FDA approval, but dropped to 2.0 during 2002-2009. High-dose IL-2 is associated with a 5-year survival rate that is higher than objective response rates, suggesting a delayed immunotherapy benefit for some patients. The use of intensive IL-2 has declined dramatically in recent years, but unless a long-term survival benefit can be shown for these new targeted products, we feel that inpatient IL-2 remains the preferred initial treatment. PMID- 21711095 TI - Lymph node metastasis of squamous cell carcinoma from an unknown primary in the upper and middle neck: Impact of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography. AB - PURPOSE: The purpose of this study was to assess the potential of (18)F fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging for detection of the primary tumor and its impact on treatment planning in patients presenting with cancer of unknown primary and squamous cell carcinoma (SCC)-positive cervical lymph nodes of the upper and middle neck. METHODS: The study population consisted of 18 consecutive patients with biopsy-proven SCC involving lymph nodes of the upper and middle neck region and negative conventional diagnostic procedures with regard to the location of the primary. All patients underwent FDG-PET/CT according to a standard procedure in search for the primary, unidentified tumor. RESULTS: In none of the patients FDG-PET/CT was able to indicate a primary tumor localization. Although FDG-PET/CT did identify all sites of known lymph node involvement, neither additional sites of lymph node involvement nor sites of distant metastases were identified. Accordingly, FDG PET/CT did not impact patient treatment planning. CONCLUSIONS: In this series, including patients suffering from lymph node metastases by an SCC of unknown primary in the upper and middle neck, FDG-PET/CT was unable to identify a primary tumor. In addition, FDG-PET/CT did not modify the treatment planning in any of the patients studied. PMID- 21711096 TI - Preclinical evaluation of (177)lu-nimotuzumab: a potential tool for radioimmunotherapy of epidermal growth factor receptor-overexpressing tumors. AB - BACKGROUND: The humanized monoclonal antibody Nimotuzumab (h-R3) has demonstrated an exceptional and better clinical profile than other monoclonal antibodies for immunotherapy of epidermal growth factor receptor-overexpressing tumors. This work deals with the preparation and radiolabeling optimization of (177)Lu Nimotuzumab and their preclinical evaluation. METHODS: Nimotuzumab was conjugated with S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), testing different molar ratios. The immunoconjugates were characterized. The radiolabeling with (177)Lu was optimized. Radioimmunoconjugates stability was tested in 2-[bis[2 [bis(carboxymethyl)amino]ethyl]amino]acetic acid (DTPA) excess and human serum. In vitro studies were performed in tumor model cell lines. Receptor-specific binding was tested by competitive inhibition. (177)Lu-Nimotuzumab in vivo studies were conducted in healthy and xenograft animals. RESULTS: Nimotuzumab conjugates were obtained with high purity. Radiolabeling yield and specific activities ranged from 63.6% to 94.5% and from 748 to 1142 MBq/mg, respectively. The stability in DTPA excess and human serum was 95.9% and 93.2% after 10 days, respectively. The radioimmunoconjugate showed specific receptor binding in tumor cell lines. Biodistribution in healthy animals showed the typical behavior of the immunoconjugates based on monoclonal antibodies. The study in xenografts mice demonstrated uptake of (177)Lu-Nimotuzumab in the tumor and reticuloendothelial organs. CONCLUSIONS: (177)Lu-Nimotuzumab was obtained with high purity and specific activities under optimal conditions without significant loss in immunoreactivity and might be a potential radioimmunoconjugate for radioimmunotherapy of tumors with epidermal growth factor receptor overexpression. PMID- 21711097 TI - Developmental stages of Hepatozoon hemprichii sp. nov. infecting the skink Scincus hemprichii and the tick Hyalomma impeltatum from Saudi Arabia. AB - The life cycle of Hepatozoon hemprichi n. sp. is described; the vertebrate host is Scincus hemprichii and it is vectored by Hyalomma impeltatum. Erythrocytic stages of 18 +/- 1.8 * 4 +/- 0.8 um developed in the hemocoel of ticks to sporozoites within 16-18 days. Schizogony occurred in the liver parenchyma and the endothelial cells of blood capillaries in lung and spleen. Mature schizonts measuring 27 +/- 3.11 * 20.13 +/- 3.0 um produced 28 merozoites (on average). The merozoites were 13 +/- 1.21 * 1.21 +/- 0.72 um with nuclei 5 +/- 0.65 * 2.1 +/- 0.51 um. Syzygy and differentiation of gamonts took place in tick's hemocoel up to the third day post-infection (PI). The microgamont (16 +/- 0.31 * 18 +/- 0.42 um) produced 4, uniflagellated microgametes at 4-5 days PI. The microgamete measured 15.2 +/- 0.31 um while the flagellum was always at least 26 um. The macrogamete was very large in size (31 +/- 3.11 um) with a central nucleus. After fertilization, (5-6 days PI) zygotes developed into oocysts (55 +/- 3.41 * 52 +/- 4.11 um) in which repeated mitotic divisions with centripetal invaginations occurred; each contained 18 banana-shaped sporozoites, 13.61 +/- 0.8 * 1.2 +/- 0.31 um in size. Experimental transmission was successfully carried out by oral administration or by intra-peritoneal inoculation of the infective stages (sporozoites) to uninfected skinks and led to the appearance of blood stages after 5 wk and 4 wk, respectively. PMID- 21711098 TI - Internal movement of estuarine digenetic trematodes through their intermediate snail host Cerithidea californica. AB - The ability of free-swimming larval parasites to control emergence from their hosts can be critical in increasing the chances of successful infection transmission. For a group of estuarine trematodes, emergence of cercariae from their snail hosts is known to match favorable temperature, tidal activity, and light intensity. How the larvae time this behavior is not well understood, but the pathway that the larvae take through their host may play a role. Through video and histological analysis, we were able to identify the snail's anus as the emergence point and the peri-intestinal sinus dorsal to the intestines as the route by which they reach that point. By moving through this open sinus, the larvae have an energetically efficient pathway to reach their emergence point while minimizing damage to the host. Most importantly, it allows control over emergence to be maintained by the parasite, not the host, thus increasing the chances of the larva successfully reaching its intended destination. PMID- 21711099 TI - Morphological and molecular differentiation of Clinostomum complanatum and Clinostomum marginatum (Digenea: Clinostomidae) metacercariae and adults. AB - The separation of Clinostomum complanatum Rudolphi, 1814 and Clinostomum marginatum Rudolphi, 1819 has long been unclear. Recent data confirm the validity of the junior species, C. marginatum , by ~ 1% differences in its 18S rDNA sequences. We collected adults and metacercariae of C. complanatum and C. marginatum and found reliable morphological differences in the genital complex at both developmental stages. In addition, we identified basic morphometrics (distance between suckers, body width) in metacercariae that may be useful for discriminating the species. The morphological differences were supported by the comparison of sequences of internal transcribed spacers of ribosomal DNA and of the mitochondrial gene cytochrome c oxidase I (COI) from 39 specimens. In 36 specimens, the average divergence between the species was 7.3% in ITS and 19.4% in COI sequences. Two specimens from North America and 1 from Europe had sequences that did not allow them to be clearly allied with either species. PMID- 21711100 TI - Phase I clinical trial of the (131)I-labeled anticarcinoembryonic antigen CIGB-M3 multivalent antibody fragment. AB - Center for Genetic Engineering and Biotechnology (CIGB)-M3 is a trivalent recombinant single-chain Fv antibody fragment specific for carcinoembryonic antigen (CEA). Preclinical studies with radiolabeled CIGB-M3 have showed that the antibody fragment accumulates in human colon tumor xenografts growing in nude mice. A Phase I clinical trial was carried out to determine safety, biodistribution, and pharmacokinetics of the radiolabeled CIGB-M3 in two groups of patients with CEA+ colorectal cancers. Group I (10 patients) received a single intravenous injection of 0.3 mg of (131)I-CIGB-M3 (16.7-23.3 mCi/mg). Group II (7 patients) received 1 mg (5-7 mCi/mg). No adverse events related to the injected product were recorded, and no immunology response was detected up to 6 months after the injection. Tumors were detected in 15 of the 17 studied cases. The pharmacokinetic profile showed beta half-times of 14.1 and 6.3 hours for Groups I and II, respectively. Seventy-two (72) hours after the administration of the product, 85% of the total injected activity was excreted in urine in the form of free (131)I. The kidneys were identified as the organs that can limit the maximum tolerated dose. The (131)I-CIGB-M3 was safe in patients with colorectal cancer. The biodistribution and pharmacokinetic data suggest that the product can be further tested for molecular radiotherapy of CEA+tumors. PMID- 21711101 TI - A new Eimeria species parasitic in Isoodon obesulus (Marsupialia: Peramelidae) in Western Australia. AB - Feces from southern brown bandicoots, Isoodon obesulus, inhabiting the Perth metropolitan area were examined using fecal flotation and light microscopy, and were frequently found to contain oocysts (10/24; 42%). To enable formal description of the proposed new Eimeria species, i.e., Eimeria quenda n. sp., fecal oocysts from 1 juvenile male I. obesulus were allowed to sporulate in 2% potassium dichromate (K(2)Cr(2)O(7)) at room temperature. Sporulated oocysts are spheroidal to subspheroidal 24.5 * 23.6 (22.5-26.0 * 22.5-24.8) um, with L/W ratio of 1.04 (1.00-1.13), lack a micropyle and oocyst residuum, and are contained within a smooth trilaminate oocyst wall 1.8 (1.6-2.0) um thick. Sporocysts are ovoid, 12.6 * 9.2 (12.0-13.8 * 8.5-10.0) um, with L/W ratio of 1.37 (1.20-1.53), have a sporocyst residuum, and 2 comma-shaped sporozoites, each containing 2 spheroidal refractile bodies. Sporulation takes 1-3 days at room temperature. This is the second formal description of an Eimeria species parasitic in the order Peramelemorphia. PMID- 21711102 TI - Detection of Anaplasma bovis in an undescribed tick species collected from the eastern rock sengi Elephantulus myurus. AB - Ticks are important vectors of numerous pathogens causing illness, fatalities, and economic loss worldwide. Infectious disease episodes are increasing, and novel tick-borne pathogens are described frequently. Identification of novel reservoir hosts and vectors of tick-borne pathogens is essential if control measures are to be successful. In South Africa, the eastern rock sengi, Elephantulus myurus , hosts a number of tick species of veterinary importance. Despite this, there remains a paucity of information regarding the tick fauna of this species, the pathogen associations of ticks that it hosts, and its role as a reservoir host of tick-borne pathogens. The current study documents the tick fauna of E. myurus and sympatric small mammal species in Limpopo Province, South Africa. The pathogen associations of ticks hosted by elephant shrews were also investigated by PCR screening of engorged nymphs for a broad range of bacterial and protozoan tick-borne infections, including Borrelia burgdorferi sensu lato and members of Apicomplexa and the order Rickettsiales. There were marked differences in tick species and abundance among host species. Elephantulus myurus was heavily, and predominantly, parasitized by an as-yet undescribed tick species that we identify as Rhipicephalus sp. near warburtoni. PCR and sequence analysis revealed the presence of Anaplasma bovis in this tick species, which may have consequences for livestock production and conservation efforts in the area where this tick species occurs. PMID- 21711103 TI - Development and evaluation of real-time PCR assay for the detection of Babesia orientalis in water buffalo (Bubalus bubalis, Linnaeus, 1758). AB - Babesia orientalis is the causative agent of babesiosis in water buffalo (Bubalus babalis, Linnaeus, 1758). In this study, a TaqMan real-time PCR assay was developed for quantitative detection of B. orientalis in water buffalo. Hybridization probe and oligonucleotide primers were designed based on the v4 region of 18S rRNA gene. Detection limit was determined at 2 parasites. Blood samples were collected from experimentally infected water buffalo, as well as from 180 field samples, which were collected from 4 different geographical locations to the north and south of the Yangtse River. The parasite was detected by real-time PCR on day 2 until day 39 post-infection, while reverse line blot (RLB) was on day 6 until day 36 in experimentally infected water buffalo. For the results of 180 field samples, statistical analysis showed no significant difference in relative effectiveness of real-time PCR and RLB. The analysis also indicated that there was no difference in the prevalence of B. orientalis between the regions of south and north of the Yangtse River by both the real-time PCR assay and RLB detection. These results indicated that the parasite infection has spread to the north of the Yangtse River. PMID- 21711104 TI - Acceptance of the Clark P. Read Mentor Award: Mentoring the mentor. PMID- 21711106 TI - Surface ultrastructure of juvenile and adult Acanthoparyphium tyosenense (Digenea: Echinostomatidae). AB - The tegumental ultrastructure of juvenile and adult Acanthoparyphium tyosenense (Digenea: Echinostomatidae) was observed by scanning electron microscopy. One- to 3-day-old juveniles and 10-day-old adults were harvested from chicks experimentally fed metacercariae from a bivalve, Mactra veneriformis. The juvenile worms were minute, curved ventrally, and had 23 collar spines characteristically arranged in a single row. The lips of the oral sucker had 7 single aciliated sensory papillae and 4 grouped uniciliated sensory papillae. The ventral sucker had 25 aciliated round swellings on its lip. The anterolateral surface between the 2 suckers was densely packed with tongue-shaped tegumental spines, and the ventral surface just posterior to the ventral sucker was covered with peg-like spines. Retractile, peg-like spines were seen on the anterolateral surface, whereas scale-like spines with round tips and broad bases were sparsely distributed posterior to the ventral sucker. The cirrus was characteristically protruding and armed with minute spines. The surface ultrastructure of A. tyosenense was unique, especially in the number and arrangement of collar spines, shape, and distribution of tegumental spines and in distribution of sensory papillae. PMID- 21711105 TI - Cryptosporidium-malnutrition interactions: mucosal disruption, cytokines, and TLR signaling in a weaned murine model. AB - Cryptosporidiosis is a leading cause of persistent diarrhea in children in impoverished and developing countries and has both a short- and long-term impact on the growth and development of affected children. An animal model of cryptosporidial infection that mirrors closely the complex interaction between nutritional status and infection in children, particularly in vulnerable settings such as post-weaning and malnourishment, is needed to permit exploration of the pathogenic mechanisms involved. Weaned C57BL/6 mice received a protein-deficient (2%) diet for 3-12 days, then were infected with 5 * 10(7) excysted C. parvum oocyts, and followed for rate of growth, parasite stool shedding, and intestinal invasion/morphometry. Mice had about 20% reduction in weight gain over 12 days of malnutrition and an additional 20% weight loss after C. parvum challenge. Further, a significantly higher fecal C. parvum shedding was detected in malnourished infected mice compared to the nourished infected mice. Also, higher oocyst counts were found in ileum and colon tissue samples from malnourished infected mice, as well as a significant reduction in the villous height-crypt depth ratio in the ileum. Tissue Th1 cytokine concentrations in the ileum were significantly diminished by malnutrition and infection. mRNA for toll-like receptors 2 and 4 were diminished in malnourished infected mice. Treatment with nitazoxanide did not prevent weight loss or parasite stool shedding. These findings indicate that, in the weaned animal, malnutrition intensifies cryptosporidial infection, while cryptosporidial infection further impairs normal growth. Depressed TLR2 and 4 signaling and Th1 cytokine response may be important in the mechanisms underlying the vicious cycle of malnutrition and enteric infection. PMID- 21711107 TI - The radioprotective effect of Zataria multiflora against genotoxicity induced by gamma irradiation in human blood lymphocytes. AB - The radioprotective effect of hydroalcholic Zataria multiflora (Avishan-e shirazi) extract was investigated against genotoxicity induced by gamma irradiation in human lymphocytes. Peripheral blood samples were collected from human volunteers and incubated with Z. multiflora extract at different concentrations (5, 10, and 50 MUg/mL) for 1 hour. At each dose point, the whole blood was exposed in vitro to 150 cGy of cobalt-60 gamma irradiation, and then the lymphocytes were cultured with mitogenic stimulation to determine number of the micronuclei in cytokinesis-blocked binucleated cells. The treatment of lymphocytes with extract showed a significant decrease in the incidence of micronuclei binucleated cells, compared with similarly irradiated lymphocytes without extract against gamma irradiation. The maximum protection and decrease in frequency of micronuclei was observed at 50 MUg/mL of Zataria extract by 32% reduction. High-performance liquid chromatography analysis of extract showed that it contains high amounts of thymol. Zataria extract exhibited concentration dependent radical-scavenging activity on 1,1-diphenyl-2-picryl hydrazyl free radicals. These data have an important application for the protection of human lymphocyte from the genetic damage and side-effects induced by gamma irradiation in personnel exposed to radiation. PMID- 21711108 TI - Beclin1/PI3K-mediated autophagy prevents hypoxia-induced apoptosis in EAhy926 cell line. AB - Although hypoxia can induce cell death, the cancer cells and endothelial cells within a solid tumor that remain active in the hypoxia microenvironment often possess an enhanced survival potential. Developing approaches aimed at increasing the sensitivity of endothelial cells to hypoxia-induced cell death represents a potentially important avenue for antiangiogenesis treatment. This study investigated approaches to increase the sensitivity of endothelial cells to hypoxia-induced apoptosis. Autophagy and apoptosis of endothelial cells induced by hypoxia were investigated by transmission electron microscopy, confocallaser microscopy, and western blotting. Moreover, cell invasion was observed by a transwell assay and F-actin quantitative analysis. In this study, it was found that hypoxia could induce both autophagy and apoptosis in hypoxia-inducible factor-1- and Beclin1-dependent endothelial cells. Hypoxia-induced autophagy was prohibited by phosphatidylinositol 3-kinase/Akt inhibitor but not mitogen activated protein kinase inhibitor. Inhibition of autophagy promoted the rate of apoptosis. Further, the reversal of hypoxia-induced autophagy increased cell migration compared with the normoxia condition. This study concludes that hypoxia triggers a feedback mechanism that delays apoptosis of endothelial cells and that is driven by hypoxia-induced autophagy. Thus, approaches aimed at the disruption of this mechanism can be expected to enhance the susceptibility of endothelial cells to hypoxia-induced apoptosis. PMID- 21711110 TI - microRNA-143 protects cells from DNA damage-induced killing by downregulating FHIT expression. AB - MicroRNAs (miRNAs) are posttranscriptional modulators of gene expression and play an important role in many developmental processes. Recent studies suggest roles of miRNAs in carcinogenesis. Fragile histidine triad (FHIT) gene deletion, methylation, and reduced Fhit protein expression occur in about 70% of human epithelial tumors and are clearly associated with tumor progression. Although it has been previously reported that Fhit(-/-)cells exhibit more resistance to multi DNA damage inducers, including ionizing radiation, it remains unclear how miRNAs targeting FHIT in DNA damage response play the role. This study reports that miR 143 directly targets FHIT and that overexpression of miR-143 results in significant G2-phase arrest and protects cells from DNA damage-induced killing. These results indicate an association of FHIT gene inactivation with increased survival after DNA damage and also provide useful information for miRNA-based drug development in two directions: protect cells from DNA damage-induced killing and sensitize cells to radiation therapy. PMID- 21711111 TI - CK2 inhibitors enhance the radiosensitivity of human non-small cell lung cancer cells through inhibition of stat3 activation. AB - CK2 interacts and phosphorylates >300 proteins, including Stat3, and is linked to a number of human cancers. Constitutively activated Stat3 has been reported in 50% of human lung cancers. Inhibition of CK2 activity can induce apoptosis and suppression of Stat3 activation in cancer cells. This study examined the effects of CK2 inhibitors on growth inhibition of lung cancer cells and the therapeutic potential on lung cancer. The CK2 inhibitor and radiation both suppressed cancer cell growth in a dose-dependent manner. Besides, the cytotoxic effect of irradiation could be augmented by CK2 inhibitors (p<0.05, two-way analysis of variance and Tukey's Honestly Significant Difference). Moreover, the growth inhibition of CK2 inhibitor and irradiation was both associated with suppression of Stat3 activation. Taken together, inhibition of CK2 activity appears to be a promising treatment strategy for non-small cell lung cancer and CK2 inhibition results in reduced Stat3 activation. Our data warrant further effort to develop CK2-targeted radiosensitizer for lung cancer treatment. PMID- 21711112 TI - Molecular mechanism of silymarin-induced apoptosis in a highly metastatic lung cancer cell line anip973. AB - BACKGROUND: Silymarin, the main flavonoid constituent element extracted from Silybum marianum possessing antioxidant activity, is already known to be able to block the NF-kappaB activation process and result in cell apoptosis, implicating silymarin's potential to control cancer cell growth. MATERIALS AND METHODS: In this study, based upon the above assumption, silymarin was administered to a highly metastatic lung cancer cell line Anip973 to test silymarin's role in cancer cell proliferation. RESULTS: Silymarin had significant inhibitory effects on the proliferation of Anip973 cells in a dose-dependent and time-response manner within 48 hours. Silymarin can induce Anip973 apoptosis. CONCLUSIONS: Silymarin may in vitro inhibit the proliferation of the human lung adenocarcinoma cell line Anip973 and induce apoptosis via the mitochondria-dependent caspase cascade pathway. PMID- 21711114 TI - Polysaccharide protein complex isolated from mushroom Phellinus rimosus (berk.) Pilat alleviates gamma radiation-induced toxicity in mice. AB - Ionizing radiations generate reactive oxygen species in irradiated tissue that induces several pathophysiological changes in the body. Radiotherapy induced toxicity is a major dose-limiting factor in anticancer treatments. Radioprotective agents are of significant importance in medical, industrial, environmental, military, and space applications. Radioprotective effect of polysaccharide protein complex (PPC-Pr) isolated from mushroom, Phellinus rimosus, was evaluated in Swiss albino mice. PPC-Pr (5 and 10 mg/kg bwt, i.p.) significantly increased leukocyte count, bone marrow cellularity, glutathione content, and activities of antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase in blood as well as intestinal mucosa when compared with the irradiated control group. Histopathological observation of intestinal jejunal mucosa revealed the tissue protective effects of PPC-Pr. Further radioprotective activity of PPC-Pr was in a dose-dependent manner. The findings suggest potential radioprotective efficacy of PPC-Pr. PMID- 21711113 TI - Pharmacokinetics and dosimetry of (111)In/(188)Re-labeled PEGylated liposomal drugs in two colon carcinoma-bearing mouse models. AB - PEGylated liposomes are important drug carriers for nanomedicine cancer therapy. PEGylated liposomes can encapsulate radio- and chemo-drugs and passively target tumor sites via enhanced permeability and retention effect. This study estimated the pharmacokinetics and dosimetry after administration of radio chemotherapeutics ((111)In-labeled vinorelbine [VNB]-encapsulated liposomes, InVNBL, and (188)Re-labeled doxorubicin [DXR]-encapsulated liposomes, ReDXRL) for radionuclide therapy in two colon carcinoma-bearing mouse models. A C26 colon carcinoma tumor/ascites mouse model and a subcutaneous solid tumor-bearing mouse model were employed. Biodistribution studies of InVNBL and ReDXRL after intraperitoneal administration in tumor/ascites-bearing mice (protocol A) and intravenous administration in subcutaneous solid tumor-bearing mice (protocol B) were performed. The radiation dose to normal tissues and tumors were calculated based on the results of distribution studies in mice, using the OLINDA/EXM program. The cumulated activities in most organs after administration of InVNBL in either the tumor/ascites-bearing mice (protocol A) or the subcutaneous solid tumor-bearing mice (protocol B) were higher than those of ReDXRL. Higher tumor-to normal-tissues absorption dose ratios (T/NTs) were observed after administration of InVNBL than those of ReDXRL for protocol A. The T/NTs for the liver, spleen, and red marrow after injection of InVNBL for protocol B were similar to those of ReDXRL. The critical organ was found to be red marrow, and thus the red marrow absorption dose defined the recommended maximum administration activity of these liposomal drugs. Characterization of pharmacokinetics and dosimetry is needed to select the appropriate radiotherapeutics for specific tumor treatment applications. The results suggest that InVNBL is a promising therapeutic agent, which is as good as ReDXRL, in two mouse tumor models. PMID- 21711115 TI - Preclinical evaluation of a new bombesin analog for imaging of gastrin-releasing peptide receptors. AB - Bombesin (BBN) is a peptide showing high affinity for the gastrin-releasing peptide receptor. Tumors such as prostate, small cell lung cancer, breast, gastric, and colon cancer are known to over express receptors to BBN and gastrin releasing peptide (GRP). The goal of this study was to evaluate a new (67)Ga radiolabeled BBN analog based on the bifunctional chelating ligand DOTA (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid), which could be used as a tool for diagnosis of GRP receptor-positive tumors. DOTA-GABA-BBN (7-14) NH(2) was synthesized using a standard Fmoc strategy. Labeling with (67)Ga was performed at 95 degrees C for 30 minutes in ammonium acetate buffer (pH = 4.8). Radiochemical analysis involved ITLC and HPLC methods. The stability of radiopeptide was examined in the presence of human serum at 37 degrees C up to 24 hours. The receptor-bound internalization and externalization rates were studied in GRP receptor expressing PC-3 cells. Biodistribution of radiopeptide was studied in nude mice bearing PC-3 tumor. Labeling yield of >90% was obtained corresponding to a specific activity of approximatrly 2.6 MBq/nmol. Peptide conjugate showed good stability in the presence of human serum. The radioligand showed a good and specific internalization into PC-3 cells (16.13% +/- 0.71% at 4 hours). After 4 hours, a considerable amount of activity (52.42% +/- 1.86%) was externalized. In animal biodistribution studies, a receptor-specific uptake of radioactivity was observed in GRP-receptor-positive organs. After 4 hours, the uptake in mouse tumor and pancreas was 1.30% +/- 0.18% ID/g (percentage of injected dose per gram of tissue) and 1.21% +/- 0.13% ID/g, respectively. These data show that [(67)Ga]-DOTA-GABA-BBN (7-14) NH2 is a specific radioligand for GRP receptor positive tumors and is a suitable candidate for clinical studies. PMID- 21711116 TI - Cascading adoptive cell therapy for metastatic melanoma. AB - Adoptive tumor-infiltrating lymphocytes (TILs) therapy has demonstrated drastic effects on advanced malignant melanoma. Intensive pretreatment such as chemotherapy and/or total body irradiation has been used to eliminate immunosuppressive components and therefore enhances the antitumor effects of TILs. However, these pretreatments may cause severe side effects, especially for elderly patients. This case observes the complete response of how a patient with metastatic melanoma was treated sequentially with local tumor resection, postoperative adoptive cytokine-induced killer cells and TILs infusion. In addition, the cascading adoptive cell therapy was well-tolerated by the patient. Therefore, being pretreated with cytokine-induced killer cells could ameliorate the immunosuppressive condition in the patient and provide a favorable circumstance for subsequent TILs infusion. The further adoptive TILs therapy could exert the most powerful antitumor activity in such an amicable circumstance. PMID- 21711118 TI - Correlation of physical parameters during radiochemical synthesis of (18)F positron emission tomography radiopharmaceuticals. AB - Positron emission tomography is a highly specialized imaging technique using short-lived radiolabel substances to produce extremely high resolution images of the body's biological function. The (18)F(-) ion is produced via the (18)O(p,n)(18)F reaction using a silver target cell filled with 1.4 mL of enriched [(18)O] water. On a typical run, the target is irradiated for 45 minutes with 16.5 MeV protons (on target) and an average beam current of 5-45 mA. When the same reaction takes place with [(16)O] water [(13)N] Ammonia is produced as the primary product by the abstraction of hydrogen from water. This study investigated the physical parameters of medical cyclotron during the radiochemical process with induced radioactivity flux and mutual correlation of physical parameters for 16.5 MeV medical cyclotron at the INMAS Delhi, India. It is observed that by getting farther from the target, the relative number of low energy neutrons increases while the overall flux of neutrons decreases. This is due to multiple scattering of high-energy neutrons in the walls and eventually absorption of low-energy neutrons. The other parameters are also linked with each other which are correlatable. PMID- 21711117 TI - Effects of the proapoptotic regulator Bcl2/adenovirus EIB 19 kDa-interacting protein 3 on radiosensitivity of cervical cancer. AB - PURPOSE: Bcl2/adenovirus EIB 19 kDa-interacting protein 3 (BNIP3) is a proapoptotic member of the Bcl-2 family. To address its potential as a therapeutic target for radiosensitization, this study investigated the effect of Bnip3 expression on radiosensitivity of cervical cancer in vitro and in vivo. MATERIALS AND METHODS: In vitro: A plasmid expressing the BNIP3 gene was transfected into human cervical cancer HeLa cells using Lipofectamine(2000), and western blot and immunohistochemistry analysis were performed to evaluate the expression of BNIP3 in transfected cells. The effects on radiation-induced apoptosis were investigated using a clone formation assay and flow cytometry. In vivo: A total of 6 * 106 HeLa cells were subcutaneously inoculated into the dorsal flank of nude mice, and plasmids expressing the BNIP3 gene were injected into the mice via the tail vein. Tumor volume was calculated, and immunohistochemistry was used to detect the expression of BNIP3 in tumor cells. TUNEL assays were performed to determine the apoptosis rates in tumor tissues. RESULTS: Transfection with the recombinant BNIP3 plasmid increased expression of the Bnip3 protein in tumor cells. This apoptosis regulator significantly decreased the viability of cells (p < 0.01) and increased the apoptosis rates (p < 0.01) both in vitro and in vivo. The antitumor effect of radiotherapy was enhanced by overexpression of BNIP3, as revealed by tumor growth curve analysis. CONCLUSIONS: Radiosensitization in human cervical cancer cells was observed after treatment with the recombinant BNIP3 plasmid in vitro and in vivo. Results suggested that BNIP3 may play a role in enhancement of radiotherapy efficiency, and its expression may have a synergistic effect on radiation treatments. PMID- 21711119 TI - Impact of 5-HT(3) RA selection within triple antiemetic regimens on uncontrolled highly emetogenic chemotherapy-induced nausea/vomiting. AB - BACKGROUND: It is recommended that patients initiate triple antiemetic therapy with one of the 5-hydroxytryptamine receptor antagonists (5-HT(3) RAs), aprepitant (or its intravenous prodrug fosaprepitant) and dexamethasone prior to the start of highly emetogenic chemotherapy (HEC). However, the impact of 5-HT(3) RA selection within triple antiemetic regimens on the risk of uncontrolled chemotherapy-induced nausea and vomiting (CINV) with HEC has not been well studied. AIM: To assess the likelihood of an uncontrolled CINV event following antiemetic prophylaxis with the 5-HT(3) RA palonosetron + aprepitant/fosaprepitant + dexamethasone (palonosetron cohort) versus any of the other 5-HT(3) RAs + aprepitant/fosaprepitant + dexamethasone (other 5-HT(3) RA cohort) among single-day HEC cycles. METHODS: Single-day HEC cycles (a gap of at least 5 days between two administrations) among patients with a cancer diagnosis and receiving antiemetic prophylaxis with the aforementioned regimens between 1/1/2006 and 6/30/2010 were identified from the IMS LifeLink claims database. Uncontrolled CINV events were identified through ICD-9-CM codes (nausea and vomiting), Current Procedural Terminology codes (hydration), rescue medications and/or use of antiemetic therapy from days 2-5 following HEC administration. Risks for an uncontrolled CINV event among all patients, and within breast cancer and multiple cancer subpopulations, were analyzed at cycle level using logistic multivariate regression models. RESULTS: A total of 8018 cycles for the palonosetron cohort and 1926 cycles for the other 5-HT(3) RA cohort (3574 and 978 patients, respectively) were analyzed. Single-day HEC cycles received by the palonosetron cohort had a significantly lower unadjusted risk of an uncontrolled CINV event (17.5 vs 20.7% for the other 5-HT(3) RA cohort; p = 0.0010), with a 17% lower adjusted risk for palonosetron-administered cycles (odds ratio: 0.83; 95% CI: 0.73-0.94; p = 0.0042). Results in the breast cancer and multiple cancer subgroups were consistent with those for the overall population. CONCLUSION: In this retrospective claims data analysis, single-day HEC cycles administered with palonosetron + aprepitant/fosaprepitant + dexamethasone had a lower risk for an uncontrolled CINV event versus other 5-HT(3) RAs + aprepitant/fosaprepitant + dexamethasone. PMID- 21711120 TI - Combining basal insulin analogs with glucagon-like peptide-1 mimetics. AB - Basal insulin analogs are recognized as an effective method of achieving and maintaining glycemic control for patients with type 2 diabetes. However, the progressive nature of the disease means that some individuals may require additional ways to maintain their glycemic goals. Intensification in these circumstances has traditionally been achieved by the addition of short-acting insulin to cover postprandial glucose excursions that are not targeted by basal insulin. However, intensive insulin regimens are associated with a higher risk of hypoglycemia and weight gain, which can contribute to a greater burden on patients. The combination of basal insulin with a glucagon-like peptide-1 (GLP-1) mimetic is a potentially attractive solution to this problem for some patients with type 2 diabetes. GLP-1 mimetics target postprandial glucose and should complement the activity of basal insulins; they are also associated with a relatively low risk of associated hypoglycemia and moderate, but significant, weight loss. Although the combination has not been approved by regulatory authorities, preliminary evidence from mostly small-scale studies suggests that basal insulins in combination with GLP-1 mimetics do provide improvements in A1c and postprandial glucose with concomitant weight loss and no marked increase in the risk of hypoglycemia. These results are promising, but further studies are required, including comparisons with basal-bolus therapy, before the complex value of this association can be fully appreciated. PMID- 21711122 TI - One big happy family? Interdisciplinary variation in job satisfaction among hospice providers. AB - BACKGROUND: Job satisfaction is particularly important in the hospice industry, given the emotional and interpersonal challenges that hospice staff face in providing care to patients near the end of life and their families. However, little is known about the job satisfaction of hospice providers, or about variation in satisfaction among disciplines. METHODS: Staff at participating hospices completed the Survey of Team Attitudes and Relationships (STAR) using an online user interface. The STAR has 6 domains that comprise 45 items. RESULTS: Results were submitted for 8,495 staff from 177 hospices in 41 states. The mean total score was 28 on a 0-100 scale (range, 0-100; interquartile range, 8-45) and hospice-level scores ranged from 15 to 44. Nonclinical staff (n = 3260) and clinical staff (n = 5235) had similar total scores (28 for both). Among clinical staff, in a mixed effects model adjusting for individual and hospice characteristics, physicians had the highest total scores (adjusted mean 42; 95% confidence interval: 35-46) compared to chaplains (30; 28-33), bereavement coordinators (27; 24-30), nurses' aides (29; 27-33); nurses (26; 28-33), and social workers (25; 23-26). CONCLUSIONS: There is significant variation in job satisfaction both among hospices and disciplines. PMID- 21711121 TI - Metabolic syndrome, cardiovascular disease, and risk for chronic kidney disease in an Italian cohort: analysis of the INCIPE study. AB - BACKGROUND: Metabolic syndrome is a frequent condition that has been linked to cardiovascular disease (CVD) and mortality. Metabolic syndrome has been extensively shown to increase the risk of chronic nephropathies in Americans and Asians, but not in European populations. Renal disease increases the risk of CVD and mortality. However, the chronic nephropathy-CVD liaison has not been analyzed in the framework of the possible role of metabolic syndrome in both. METHODS: We analyzed data from 3,757 subjects participating in the INCIPE survey (Initiative on Nephropathy, of relevance to public health, which is Chronic, possibly in its Initial stages, and carries a Potential risk of major clinical End-points), a cross-sectional study enrolling subjects from the general population in the Veneto region in Italy, and calculated the odds ratio (OR) and 95% confidence interval (CI) of the association between metabolic syndrome, and/or chronic kidney disease (CKD) and albuminuria, and/or previous CVD after adjustment for confounding factors. RESULTS: Metabolic syndrome is associated with CKD (OR 2.17; P<0.001) and albuminuria (OR 2.28; P<0.001) and CVD (OR 1.58; P=0.002). There is a direct correlation between number of metabolic syndrome traits and nephropathy and CVD. CVD and nephropathies are associated even after adjustment for metabolic syndrome (OR 2.30; P<0.001). CONCLUSIONS: In a homogeneous Caucasian European population, metabolic syndrome is associated with CKD and albuminuria, and CVD. Although metabolic syndrome is a risk factor for both CVD and nephropathy, it does not entirely explain the dangerous CVD-nephropathy liaison. PMID- 21711123 TI - Asiasari sieboldii suppresses inflammatory mediators through the induction of hemeoxygenase-1 expression in RAW264.7 cells. AB - OBJECTIVE: Asiasari sieboldii is widely used in Korean traditional medicine. In this study, we examined the anti-inflammatory effects of A. sieboldii ethanolic extract (ASEE) in a lipopolysaccharide (LPS)-induced murine macrophage RAW264.7 cell, and then sought to understand the mechanism(s) underlying the observed effects. MATERIALS AND METHODS: The production levels of nitrite oxide (NO), prostaglandin E2 (PGE2) and cytokines were measured using the Griess reagent and enzyme-linked immunosorbent assays (ELISA), while the cell protein expression levels were monitored by Western blot analysis. RESULTS: Our results revealed that ASEE had prominent inhibitory effects on NO, PGE2, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha production, as well as the expression of inducible nitrite oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in LPS induced RAW264.7 cells. Mechanistically, ASEE upregulated the expression of hemeoxygenase-1 (HO-1), and inhibited the nuclear translocation of nuclear factor (NF)-kappaB by preventing degradation of inhibitor kappaB-alpha (IkappaB-alpha). CONCLUSION: These results indicate that the anti-inflammatory activity of ASEE occurs at least partially through the induction of HO-1 and subsequent suppression of the NF-kappaB pathway. PMID- 21711124 TI - Unsuitable for the intensive care unit: what happens next? AB - CONTEXT: In recent years numbers of referrals to intensive care units (ICU) throughout the United Kingdom has been increasing. A number of referrals to the ICU are considered to be inappropriate for a variety of reasons, including those patients who are felt to be either too well for admission, or have comorbidities making survival unlikely and aggressive interventions unsuitable. OBJECTIVES: This study aims to examine the outcomes and symptoms in those patients who are unsuitable for admission to ICU. By looking at this population we hope to ascertain if this is an at-risk group in terms of symptomatic or care needs at the end of life. METHODS: This was as an observational prospective study with the sample population identified via the ICU referrals process. All patients referred to the ICU for admission but deemed unsuitable were recorded and followed up by researchers on the wards. RESULTS: Fifty patients were identified between January and April 2009. Outcomes at one week were split between "death" (34%), "discharge" (24%), and ongoing illness/rehabilitation (40%). Levels of comorbidity were high, with a corresponding prevalence of severe breathlessness in all outcome groups. CONCLUSION: The results suggest there are small numbers of patients with uncontrolled symptoms who could benefit from specialist input from the palliative care team. The identification of the imminently dying should facilitate appropriate communication of this by clinical staff and allow the relevant social, psychological, and spiritual preparations for death that are the hallmark of good care of the dying. PMID- 21711125 TI - Quality of life trajectory in patients with advanced cancer during the last year of life. AB - INTRODUCTION: Due to the high mortality of cancer a large number of patients pass a preterminal phase of their illness. Within this phase medical care aims at maintaining patients' quality of life (QOL) and reducing symptom burden. Our study investigated the patient-reported severity of QOL impairments during the last year of life, with a special focus on their course at the end of life. METHODS: All patients with cancer receiving palliative care at Natters State Hospital (Austria) were considered as eligible for the study. QOL data were collected with the EORTC QLQ-C30 questionnaire as part of computerized patient reported outcome monitoring (ePROM) within clinical routine. QOL was investigated longitudinally in regard to its course toward death as well as to changes in determinants of global QOL. RESULTS: Eighty-five patients participated in the ePROM (255 assessments in total). Regarding trajectories, physical, role and cognitive functioning, fatigue and global QOL worsened sharply during the last 3 months of life. A steady decline was found for emotional functioning, pain, appetite loss and taste alterations. The impact of role functioning, sleep disturbances, and taste alterations on global QOL increased within the last 3 months of life. CONCLUSION: Our results indicate that most aspects of QOL are considerably impaired in patients with advanced cancer. Furthermore, they highlight the importance of assessing QOL in general and taste alterations in particular within palliative care. PMID- 21711126 TI - Posthumous reproduction and palliative care. AB - Posthumous reproduction is an issue fraught with legal, ethical, religious, and moral debate. The involvement of the hospice and palliative care community in this debate may be peripheral due to the fact that other health care professionals would be actually delivering the services. However, the hospice and palliative care community are more likely to treat patients considering posthumous reproduction as they near the end of their lives. This article provides the hospice and palliative care community with a review of the medical, ethical, and legal considerations associated with posthumous reproduction. Having knowledge of these issues, and a list of available resources, will be useful if hospice and palliative care staff find themselves facing a patient or family that is considering posthumous reproduction. PMID- 21711128 TI - ASP President 2010-2011, Janine Caira: this is your life! PMID- 21711127 TI - Epithelial-mesenchymal transition contributes to SWCNT-induced pulmonary fibrosis. AB - Previous studies suggest that single-walled carbon nanotube (SWCNT) exposure causes pulmonary fibrosis. We investigated the contribution of epithelial mesenchymal transition (EMT) during SWCNT-induced pulmonary fibrosis. C57BL6 female mice were intratracheally instilled with SWCNT at 80 MUg/mouse for up to 56 days. SWCNT exposure caused pulmonary epithelial and mesenchymal injury, followed by granulomatous and fibrotic changes. Immunofluorescence staining demonstrated the increasing occurrence of epithelial-derived fibroblasts up to 42 days post-exposure. Flow cytometry analysis revealed that 42.60% of N-cadherin (N cad)-positive fibroblasts were derived from pulmonary epithelial cells, and, in separate experiments, 30.68% of SPC positive cells were stained for N-cad at 42 days. These epithelial-derived fibroblasts were functional in collagen production. With the progression of fibrosis, there were increases in the number of hyperplastic epithelial cells stained positively for TGF-beta/p-Smad2 or beta catenin. Therefore, EMT contributes significantly to fibroblast expansion. Aberrant activations of TGF-beta/p-Smad2 and beta-catenin are postulated to induce EMT during SWCNT-induced pathogenic fibrosis. PMID- 21711129 TI - Confirmation of the three-factor model of problematic internet use on off-line adolescent and adult samples. AB - As the Internet became widely used, problems associated with its excessive use became increasingly apparent. Although for the assessment of these problems several models and related questionnaires have been elaborated, there has been little effort made to confirm them. The aim of the present study was to test the three-factor model of the previously created Problematic Internet Use Questionnaire (PIUQ) by data collection methods formerly not applied (off-line group and face-to-face settings), on the one hand, and by testing on different age groups (adolescent and adult representative samples), on the other hand. Data were collected from 438 high-school students (44.5 percent boys; mean age: 16.0 years; standard deviation=0.7 years) and also from 963 adults (49.9 percent males; mean age: 33.6 years; standard deviation=11.8 years). We applied confirmatory factor analysis to confirm the measurement model of problematic Internet use. The results of the analyses carried out inevitably support the original three-factor model over the possible one-factor solution. Using latent profile analysis, we identified 11 percent of adults and 18 percent of adolescent users characterized by problematic use. Based on exploratory factor analysis, we also suggest a short form of the PIUQ consisting of nine items. Both the original 18-item version of PIUQ and its short 9-item form have satisfactory reliability and validity characteristics, and thus, they are suitable for the assessment of problematic Internet use in future studies. PMID- 21711130 TI - Novel stone-magnetizing microparticles: in vitro toxicity and biologic functionality analysis. AB - BACKGROUND AND PURPOSE: We have developed novel iron-based microparticles (Fe-MP) that bind to calcium oxalate stone fragments, rendering them paramagnetic. Previously, we demonstrated enhanced efficiency of stone extraction in an inanimate model using magnetic instrumentation. Before in vivo stone extraction studies, we sought to further characterize Fe-MP with regard to cellular toxicity and to assess the influence of biologic fluids on binding performance. MATERIALS AND METHODS: TOXICITY: Monolayers of murine fibroblasts, human urothelium, and human transitional-cell carcinoma cells were exposed to 1 mg/mL of Fe-MP or saline via an agarose overlay. Cellular viability was assessed using neutral red staining and densitometry. Biologic functionality: Human calcium oxalate stone fragments were incubated with a solution of 1 mg/mL of Fe-MP containing varying concentrations of urine (10%-50%) or blood (0.5%-2%) for 10 minutes. Fragments were then extracted using an 8F magnetic tool. Assays of 10 stone fragments categorized as small (3-3.9 mg) or large (6-6.9 mg) were run in quadruplicate at each concentration. RESULTS: No toxicity was seen in any of the three cell lines after 48 hours of particle exposure, except in urothelial cells at the lowest cell concentration. Stone extraction success was 100% for all stones, regardless of concentration of urine or blood, and extractions were completed in less than 10 minutes. CONCLUSIONS: Preliminary toxicity testing revealed minimal to no cellular toxicity that was attributable to Fe-MP. The microparticles function well in the presence of clinically relevant concentrations of urine and blood that may be present during endoscopic stone surgery. Further toxicity and stone extraction testing in animal models is necessary. PMID- 21711131 TI - Laparoscopic extraperitoneal repair of symptomatic hydrocele in children: a single-center experience with 73 surgeries. AB - PURPOSE: To introduce a novel, two-port laparoscopic technique for treatment of hydrocele in children, which allows completely extraperitoneal closure of the patent processus vaginalis (PPV) and does not necessitate laparoscopic suturing skills. PATIENTS AND METHODS: We describe a consecutive series of 56 boys with a median age of 36 months (range 12-144 mos) who presented with a presumably communicating hydrocele. Laparoscopic repair of these hydroceles was performed between July 2009 and June 2010. During surgery, a 5-mm laparoscope and a 3-mm grasping forceps were inserted through an identical umbilical incision (10 mm). The hydrocele sac orifice was closed extraperitoneally by circuit suturing around the internal inguinal ring. RESULTS: All cases were preoperatively diagnosed to be unilaterally based on physical examination and ultrasonography. During surgery, 17 of the 56 (30%) patients presented a contralateral PPV. A total of 73 laparoscopic procedures were achieved, with a success rate of 100%. The mean operative time was 25+/-6 and 36+/-5 minutes for unilateral and bilateral operations, respectively. During a median follow-up period of 6 months (range 1 12 mos), neither recurrence nor other postoperative complication was encountered. CONCLUSIONS: Our limited experiences suggest that the two-port, totally extraperitoneal laparoscopic technique could be a safe, effective, and reliable alternative for management of pediatric hydrocele. PMID- 21711132 TI - Optimal laser fiber rotational movement during photoselective vaporization of the prostate in a bovine ex-vivo animal model. AB - BACKGROUND AND PURPOSE: Photoselective vaporization of the prostate (PVP) has emerged as an effective debulking procedure for prostatic urinary obstruction. Surgical technique for the most efficient vaporization has, however, received little scientific investigation. We used an ex-vivo bovine prostate model to investigate how variation in the angle of laser fiber rotational movement ("sweeping") affects prostate tissue vaporization efficiency. MATERIALS AND METHODS: Experiments were conducted using the GreenLightTM HPS 120W laser system. A single surgeon performed a clinical PVP video analysis, forming the basis of our study design. Sixty bovine prostate specimens were vaporized using an ex-vivo chamber equipped with computer-assisted axial movements. Specimens were vaporized at a fixed sweeping speed (0.5 sweeps/sec) and variable sweeping angles (0, 15, 30, 60, 90, and 120 degrees). The volume of tissue vaporized was calculated from cross sections and compared by a two-sample t test. RESULTS: Clinical PVP video analysis of a single experienced surgeon showed a mean angle of 47.7 degrees with 25% of vaporization between 0 and 30 degrees. Ex-vivo analysis showed larger sweeping angles generated wider but more superficial vaporization defects, leading to smaller vaporized volumes. Specifically, vaporization volumes with angles of 0, 15, or 30 degrees were significantly greater than those with rotational angles of 45, 60, and 90 degrees (1.5-3.0 X; P<0.05). The depth of tissue coagulation significantly increased with greater rotational angles. CONCLUSIONS: Optimal PVP occurred at narrower angles of laser fiber sweeping in our ex-vivo model. Our findings highlight that PVP laser fiber movement can be tested in a scientific manner, identifying parameters to maximize vaporization efficiency. PMID- 21711133 TI - Case presentation. PMID- 21711135 TI - Adjuvant effects of salidroside from Rhodiola rosea L. on the immune responses to ovalbumin in mice. AB - Salidroside, a major component of Rhodiola rosea L., was evaluated for its adjuvant effects on the immune responses in mice by ovalbumin (OVA) stimulation. BALB/c mice were immunized subcutaneously with OVA 100 MUg or OVA 100 MUg dissolved in saline containing alum (100 MUg) or salidroside (12.5, 25, or 50 MUg) on Days 1 and 15. Two weeks later (Day 28), blood samples were collected to analyze OVA-specific IgG, IgG1, and IgG2b antibodies. Meanwhile, splenocytes were harvested to assess lymphocyte proliferation, cytokines (IL-2, IL-4, and IFN gamma) production, and CD4(+), CD8(+) lymphocyte subsets. The results indicated that co-administration of salidroside with OVA significantly enhanced the ConA-, LPS-, and OVA-induced splenocyte proliferation, produced more IL-2, IL-4, IFN gamma, and IgG, IgG1, and IgG2b antibody levels, and increased the percentage of CD4(+), CD8(+) lymphocyte subsets than OVA alone. Thus, salidroside possess immunological adjuvant activity by regulating humoral and cellular immune responses in mice. PMID- 21711136 TI - Failure after laparoscopic pyeloplasty: prevention and management. AB - BACKGROUND AND PURPOSE: Because of the high success of laparoscopic pyeloplasty (LP) for ureteropelvic junction obstruction, strategies for managing failures are less well described. We report our experience with persistent or recurrent obstruction after LP. PATIENTS AND METHODS: We reviewed 128 patients who were treated with LP at our institution from 1996 through 2008. Success was defined as objective resolution of obstruction by renal scintigraphy, Whitaker testing, or direct visualization. We extracted data by chart review regarding patient demographics, medical history, operative technique, and salvage treatments. We then assessed for association between patient characteristics and treatment failure. RESULTS: Overall, 102 patients had sufficient follow-up, of which 84 (82%) were successes. Of 18 failures, median time to failure was 2.5 months (0.5 88 mos). Of 10 failures managed endoscopically, 7 were salvaged. One of two patients treated conservatively ultimately had resolution while six patients needed simple nephrectomy. Overall, 8 (44%) were salvageable with median follow up of 19 months (4-58 mos). Patients with failure were more likely to have diabetes mellitus, longer length of stay, higher American Society of Anesthesiologists (ASA) score, a stent placed at the time of pyeloplasty, or ureteral stent malfunction (P<0.05). Patients with failure despite salvage were more likely to have stent malfunction or body mass index >30 kg/m(2) (P<0.05). Adjusting for the above factors, stent placement at time of surgery and ASA score >2 were associated with failure (P<0.05) while periureteral fibrosis trended toward a significant association (P=0.061). CONCLUSION: Nearly half of failures after LP are salvageable, many with endoscopic management. PMID- 21711137 TI - The Canadian StoneBreaker trial: a randomized, multicenter trial comparing the LMA StoneBreakerTM and the Swiss LithoClast(r) during percutaneous nephrolithotripsy. AB - BACKGROUND AND PURPOSE: Percutaneous nephrolithotripsy (PCNL) is the treatment of choice for patients with large renal stones. The StoneBreakerTM (SB) is a novel handheld pneumatic lithotriptor, powered by a compressed carbon dioxide cartridge. The purpose of this study was to compare the efficiency of the SB to a standard pneumatic lithotriptor, the Swiss LithoClast((r)) (LC). PATIENTS AND METHODS: From January 2008 to December 2009, patients undergoing PCNL were randomized to either the SB or the Swiss LC. Primary outcomes included time to fragment the stone, retrieve the fragments, and remove debris using ultrasonic lithotripsy. Secondary end points were stone-free rate, lithotriptor setup time, ease of use, operator fatigue, endoscopic visualization, damage to mucosa, and device-related complications. RESULTS: Of the initial 115 patients recruited, 77 were enrolled and 38 were excluded. The SB had significantly faster stone fragmentation time, total lithotripsy time, and setup time than the Swiss LC (P <= 0.05). A significant difference was also noted in the ease of use and operator fatigue in favor of the SB. There were no device-related complications. CONCLUSION: The SB pneumatic lithotriptor is easier to set up and use, and it provides faster stone fragmentation than the Swiss LC. PMID- 21711138 TI - Ex-vivo ureteroscopy at the time of live donor nephrectomy. AB - BACKGROUND AND PURPOSE: Potential transplant renal allograft recipients exceed the number of donors. Our institution now considers patients with small, unilateral, nonobstructing, incidental renal calculi for possible renal donation. We adopted ex-vivo ureteroscopy (ExURS) to render these kidneys stone free at the time of renal transplantation. We examined the safety and efficacy of ExURS. PATIENTS AND METHODS: After confirming a lack of significant metabolic defects on 24-hour urinalysis, 23 patients with small nonobstructing unilateral nephrolithiasis detected on preoperative CT angiography underwent donor nephrectomy. Immediately after cold perfusion, ExURS was performed with ice cold saline irrigation. Retrospective review was performed. RESULTS: Pyeloscopy was successfully performed in all 23 patients. A total of 28 calculi, mean largest diameter 3.9 mm (range 3-6 mm), were visualized in 19 kidneys. Basket extraction and holmium laser lithotripsy was performed in 12 and 6 kidneys, respectively. Treatment rendered 17/19 stone-containing kidneys stone free with a mean treatment time of 6.2 minutes (3-10 min). There were no intraoperative complications. Median serum creatinine level of recipients at 1 month and 1 year were 1.4 +/- 1.8 mg/dL and 1.3 +/- 0.6 mg/dL, respectively. At a median follow-up of 63 +/- 47.2 months, there were no transplant urinary calculi among the recipients. CONCLUSIONS: ExURS safely renders live donor kidney allografts stone free with low risk of recurrence. When used appropriately, ExURS could safely increase the number of potential kidney donors and minimize the risk of adverse stone events. PMID- 21711139 TI - Outreach, care, and prevention to engage HIV seropositive young men of color who have sex with men: a special project of national significance program initiative. PMID- 21711140 TI - Age of MSM sexual debut and risk factors: results from a multisite study of racial/ethnic minority YMSM living with HIV. AB - The average reported age of sexual debut for youth in the United States is 14.4 years, with approximately 7% reporting their sexual debut prior to age 13. While the research literature on sexual debut for youth addresses gender and ethnic differences (with males and African-American youth experiencing earlier sexual debut), there is limited data regarding factors associated with sexual debut for young men who have sex with men (YMSM). Early sexual debut poses potential health risks, such as contracting HIV with an increased risk of unprotected intercourse. Given current high HIV infection rates for racial/ethnic minority YMSM, learning more about their sexual debuts and associated risk factors of this population is of great importance. This study investigated risk behaviors and emotional distress, and their association with MSM sexual debut for a multisite cohort of racial/ethnic minority YMSM living with HIV. We hypothesized that a MSM sexual debut younger than age 16 would be associated with engagement in more high-risk sexual behaviors (unprotected sex and exchange sex), substance use, and emotional distress than a MSM sexual debut at age 16 or older. Results indicated that participants having a MSM sexual debut before the age of 16 reported more exchange sex; drug use (specifically marijuana); emotional/psychological problems related to substance use; and a history of suicide attempts, compared to participants with later MSM sexual debuts. Comprehensive interventions that are racially/ethnically sensitive, inquire about initial sexual experiences, and focus on sexual health and healthy relationships are needed to improve health outcomes for this population. PMID- 21711141 TI - Early linkage and retention in care: findings from the outreach, linkage, and retention in care initiative among young men of color who have sex with men. AB - Early linkage and retention in HIV clinical care is essential for optimal disease management, promotion of health, and receipt of secondary prevention messages to decrease onward transmission of HIV. Youth, specifically racial/ethnic minority young men who have sex with men (YMSM), continue to acquire new HIV infections and have been shown to be less likely to engage in regular HIV care and adhere to scheduled medical visits. The goal of the current study was to evaluate the characteristics of participants and program delivery that were associated with early linkage and retention in HIV care among HIV-infected YMSM of color enrolled in an outreach, linkage, and retention study. Of the 334 patients included in the linkage analysis, 72% were linked to care within 30 days of diagnosis, 81% within 60 days, and 87% within 90 days. While no patient-level characteristics were associated with early linkage, having the person who provided the positive HIV test result refer the patient to HIV care (p=0.048), specifically calling to make the appointment (p=0.009), was associated with earlier linkage. Retention of Latino participants (96.2%) was significantly higher than for the African American (79.9%) youth (p=0.006). Overall, 221 participants had at least 1 year of possible follow-up and 82.8% of these participants were retained at 1 year. While unique challenges exist in the care of adolescents infected with HIV from identification to engagement and retention in clinical care, programs that are responsive and dedicated to the needs of these youth can be successful in retaining them in care. PMID- 21711142 TI - Atraumatic splenic rupture: an unusual manifestation of acute HIV infection. AB - A 27-year-old white male, who had sex with other men, presented to the emergency department with 3 days of left shoulder and abdominal pain. He reported no history of trauma to the abdomen. On abdominal imaging, he was found to have hemoperitoneum from a ruptured spleen; he underwent splenectomy. Causes of atraumatic splenic rupture can be divided into six main categories: infectious, neoplastic, inflammatory, congenital or structural, iatrogenic, and idiopathic. Work-up of the atraumatic splenic rupture revealed that his HIV antibody was newly positive. He had a documented negative HIV antibody 3 weeks prior to the current admission. CD4 cell count, obtained after splenectomy, was 904 cells per microliter and the HIV-1 plasma RNA level was 4657 copies per milliliter. Spleen pathology demonstrated an enlarged spleen with increase in the number of small to intermediate size lymphoid cells in the red pulp, and reactive follicular lymphoid hyperplasia, with numerous secondary lymphoid follicles and reactive germinal centers in the white pulp. T-cell receptor (TCR) gene rearrangement studies demonstrated a positive TCR beta gene rearrangement, without a TCR gamma gene rearrangement, consistent with a clonal CD8(+) T-cell population. The case gives rare insight into what happens in the spleen during acute HIV infection and encourages HIV testing in those presenting with atraumatic splenic rupture. Counseling patients with acute HIV to avoid potential trauma should also be considered. PMID- 21711143 TI - The impact of removing the immigration ban on HIV-infected persons. PMID- 21711144 TI - Roles and challenges of outreach workers in HIV clinical and support programs serving young racial/ethnic minority men who have sex with men. AB - The federal government has established rapid identification, linkage, and engagement in medical care of HIV-positive individuals as a high priority. Outreach workers and other linkage coordinators are identified as key personnel in implementing this policy. Young racial/ethnic minority men who have sex with men (MSM) have relatively high and growing rates of HIV infection and would benefit from the services of outreach workers. In this article, we describe the characteristics of outreach workers employed by eight demonstration sites participating in the federal Special Projects of National Significance (SPNS) Young MSM of Color Initiative, the linkage and retention models used by the sites, and the number of outreach/ linkage contacts and individuals referred to HIV care. We summarize rates of retention of outreach workers in employment, factors associated with worker turnover, and costs associated with their replacement. We also summarize the experiences of demonstration sites in employing and retaining outreach workers and improving their performance. The insights of outreach workers are reported regarding the challenges they experienced while conducting outreach. Recommendations from demonstration site project managers and outreach workers are offered to improve workplace performance and job retention. Outreach and retention strategies, as well as lessons learned in employing outreach workers, are useful to programs serving young racial/ethnic minority MSM and other HIV-positive groups. PMID- 21711145 TI - Baseline clinical characteristics, antiretroviral therapy use, and viral load suppression among HIV-positive young men of color who have sex with men. AB - Given the continued high incidence of HIV infection in the United States among racial/ethnic minority young men who have sex with men (YMSM), and an appreciation that antiretroviral therapy (ART) can provide personal and public health benefits, attention is needed to enhance the detection of HIV-infected youth and engage them in medical care and support services that encourage sustained HIV treatment and suppression of viremia. Poor retention in clinical care has been associated with higher mortality, an increase in HIV RNA, and decreased CD4 cell count. The goal of the current study was to evaluate the health care utilization and health outcomes of HIV-infected racial/ethnic minority YMSM enrolled in an outreach, linkage, and retention study funded by the Health Resources and Services Administration (HRSA) HIV/AIDS Bureau (HAB). We hypothesized that among racial/ethnic minority YMSM, baseline CD4 counts and usage of ART are influenced by age, race, drug and alcohol use, and mental health symptoms. Overall, 155 subjects had at least a baseline CD4 count recorded at study entry. There was a low rate of ART use in this population with only one half of the cohort with CD4 counts <= 350 cells/mm(3) being prescribed ART to treat their infection. However, of those youth who were started on ART, the majority (74%) did achieve undetectable viral loads (< 400 copies). Given the continued increase in cases of HIV infection among racial/ethnic minority YMSM, efforts to increase both the provision of ART and support services that encourage adherence in this population are warranted. PMID- 21711146 TI - Epidemiologic data on young men of color who have sex with men. AB - Young men of color who have sex with men (YMSM of color) have been disproportionately affected by the HIV/AIDS epidemic in the United States. Between 2001 and 2006, HIV/AIDS diagnoses increased 93.1% among African-American MSM aged 13-24 and 45.8% among Latino MSM aged 13-24. Many multisite studies have yielded valuable information on the behaviors associated with HIV infection in adolescents, MSM, African-Americans, and Latinos. Studies among adolescents found a high prevalence of risky sexual behaviors, including having multiple partners and unprotected intercourse and frequent substance use. Multisite studies of MSM also found frequent reports of alcohol and drug abuse, and one study found that nearly one-half (48%) of HIV-positive MSM were unaware of their infection. Similarly, two multisite studies of YMSM found high rates of unprotected sex, substance use, and HIV-infection among YMSM of color. Recognizing these challenges, the HIV/AIDS Bureau (HAB) of the Health Resources and Services Administration (HRSA) funded the first multisite study to improve engagement, linkage to HIV care, and retention in care for HIV-positive YMSM of color. The objective of this article is to review the epidemiologic data on HIV-positive YMSM of color from surveillance and multisite studies in order to identify the needs of this population and the gaps in the literature. PMID- 21711147 TI - Prevalence of plasmid-mediated quinolone resistance genes in uropathogenic Escherichia coli isolated in a teaching hospital of northern Italy. AB - A retrospective study was conducted to determine the prevalence of plasmid mediated quinolone resistance (PMQR) determinants in uropathogenic Escherichia coli isolated from inpatients and outpatients in a teaching hospital of northern Italy. The presence of qnrA, qnrB, qnrS, aac(6')-Ib-cr, and qepA was evaluated in 76 and 72 nalidixic acid-resistant E. coli, isolated in 2004 and 2006, respectively. Positivity for the aac(6')-Ib-cr gene was demonstrated in 3 of 76 (3.9%) and 8 of 72 (11%) isolates, respectively; no other PMQR determinant was found. All aac(6')-Ib-cr-positive strains also showed two point mutations in the gyrA and parC genes. Most aac(6')-Ib-cr-positive isolates demonstrated the contemporary presence of bla(CTX-M-15), bla(OXA-1/30), and bla(TEM-1) genes and 4/11 harbored a class 1 integron with a dfrA17-aadA5 gene cassette arrangement. Interestingly, all aac(6')-Ib-cr-positive isolates belonged to B2 phylogenetic group, O25b antigen type, multi locus sequence type 131, and to a cluster of approximately 70% similarity level by pulsed-field gel electrophoresis (PFGE). These findings suggest the circulation of the previously described intercontinentally spreading E. coli O25:H4-ST131 clone in our geographical area since 2004. Hybridization studies of the PFGE profiles showed the aac(6')-Ib-cr gene to be associated with different molecular weight bands (40-350 kb) and interestingly aac(6')-Ib-cr chromosomal integration was demonstrated in one strain by I-Ceu I method. This represents the first report to investigate the presence and diffusion of PMQR determinants in northern Italy and to describe aac(6')-Ib-cr chromosomal integration in E. coli. PMID- 21711148 TI - Carriage of antibiotic-resistant Escherichia coli among healthy children and home raised chickens: a household study in a resource-limited setting. AB - We have previously observed high rates of acquired antibiotic resistance in commensal Escherichia coli from healthy children living in urban areas of Bolivia and Peru, including resistance to tetracycline and quinolones, which are not routinely used in childhood. In this work we investigated acquired resistance in commensal E. coli from healthy children and home-raised chickens in 12 households from one of the previously surveyed urban area in Bolivia, to ascertain the possibility of human-animal exchange of resistant strains in similar settings. The resistance rates to ampicillin, tetracycline, chloramphenicol, streptomycin, and trimethoprim-sulphametoxazole were overall high (>=50%) and comparable between children and chickens, whereas those to quinolones were significantly higher in chickens (81% vs. 29% for nalidixic acid; 43% vs. 10% for ciprofloxacin). Molecular characterization of tetracycline- and quinolone resistant isolates (n = 66) from children and chickens of three selected households revealed a remarkable clonal diversity and, in some cases, the presence of the same resistant strains among children or among chickens living in the same household, but not between children and chickens. Several resistance plasmids were characterized, but inter-clonal plasmid dissemination was not detected. Overall, the results from the present study suggested that cross transmission between children and home-raised chickens could not represent a major spreading mechanism for resistant E. coli in households of resource-limited settings with high human-animal promiscuity. PMID- 21711149 TI - gyrA and gyrB gene mutation in ciprofloxacin-resistant Mycobacterium massiliense clinical isolates from Southern Brazil. AB - Fluoroquinolones (FQs) have been increasingly used for effective treatment of infections caused by rapidly growing mycobacteria, and resistance to this drug has been predominantly attributed to gyrA and gyrB mutations. Accordingly, this study investigated a total of 36 Mycobacterium massiliense clinical isolates for their susceptibility to ciprofloxacin and presence of gyrA and gyrB gene mutations. The minimal inhibitory concentration (MIC) values, determined by broth microdilution method, of 35 ciprofloxacin-resistant isolates ranged between 4 and 16 MUg/mL and a single susceptible isolate was obtained. A total of 31 of 35 (88.5%) ciprofloxacin-resistant isolates presented an amino acid substitution at codon 90 (Ala-90->Val) and no isolate presented mutation at position Asp-94. Moreover, 4 of 35 (11.4%) ciprofloxacin-resistant and one susceptible isolate had no mutation in Ala-90 and Asp-94. No gyrB mutation was observed in all tested M. massiliense isolates. In conclusion, our results have shown that mutations of gyrA codon 90 are frequent and may constitute an important mechanism of resistance to FQ in M. massiliense. PMID- 21711150 TI - Fitness and molecular mechanisms of resistance to rifaximin in in vitro selected Escherichia coli mutants. AB - AIMS: This study sought to analyze the molecular mechanisms contributing to the development of rifaximin (Rfx) resistance in vitro in Escherichia coli. Twenty eight Rfx-resistant mutants as well as four clinical isolates of E. coli were analyzed. The results obtained show that mutations in the rpoB gene and overexpression of Phe-Arg-beta-naphthylamide (PAbetaN)-inhibitible efflux pump were implicated in Rfx resistance. RESULTS: Amino acid substitutions at position 516 of the beta-subunit of RNA polymerases were the most frequently obtained (53.6% of the mutants). The efflux pump inhibitor decreased the minimal inhibitory concentration (MIC) of 71.43% (20/28) of the mutant strains. CONCLUSIONS: Mutations studied in the rpoB gene and overexpression of PAbetaN inhibitible efflux pumps contribute to Rfx resistance (together or not), whereas alterations in porin levels do not seem to have a relevant role in the acquisition of Rfx resistance. PMID- 21711151 TI - Description of primary multidrug-resistant tuberculous meningitis in an Italian child. AB - Tuberculous meningitis is the most severe form of tuberculosis and causes substantial morbidity and mortality in adults and children. The prevalence of multidrug-resistant (rifampin-isoniazid) strains requires the use of more toxic second-line drugs. We report a case of tuberculous meningitis in a 3-year-old Italian child. PMID- 21711152 TI - Symptoms of breast cancer in an age of technologic screening. PMID- 21711154 TI - The "bra sign" in breast cancer. PMID- 21711153 TI - Gestational weight gain and daughter's age at menarche. AB - BACKGROUND: Sexual development begins in utero and enters a dormant phase during infancy. The influence of maternal gestational weight gain (GWG) on daughter's age at menarche has not been explored. METHODS: We investigated the association between maternal GWG and age at menarche (<11 years, 11-15 years, >15 years of age) in a large cohort study of U.S. nurses, The Nurses' Health Study II (NHS II), and the Nurses' Mothers' Cohort Study. RESULTS: Among 32,218 respondents, 7% reported age at menarche age 15. Compared with women whose mothers gained 20-29 lbs during pregnancy, those whose mothers reported <10 lbs or >40 lbs of GWG were 30% more likely to report early onset menarche (<11 years of age) in logistic regression models adjusted for sociodemographic and maternal characteristics, and childhood body size and physical activity: adjusted odds ratio (OR) 1.31, 95% confidence interval (CI) 1.05-1.62, and 1.27, 95% CI 1.06-1.56. Maternal GWG was not associated with late menarche in the fully adjusted model (p(trend)=0.07). CONCLUSIONS: These results suggest that either extreme of maternal GWG may influence risk for early age at menarche in daughters. Maternal GWG may be a modifiable risk factor for early menarche. PMID- 21711156 TI - SPAG4L, a novel nuclear envelope protein involved in the meiotic stage of spermatogenesis. AB - SUN domain-containing proteins belong to a novel protein family. To date, several members--SUN1, SUN2, SUN3, and SPAG4--have been identified as nuclear envelope (NE) proteins. In this study, we sought to characterize and define the potential function of SPAG4L, a newly identified SUN protein. Using bioinformatic analysis, we found that SPAG4L contained a conserved SUN domain in the C-terminal. Subcellular localization analysis indicated that the expression of green fluorescent protein-labeled full-length SPAG4L was localized to the NE and the endoplasmic reticulum (ER). Deletion analysis revealed that the transmembrane region and the coiled-coil domain, but not the SUN domain, were required for localization of SPAG4L to the NE and ER. Subsequently, we confirmed that the human testes expressed endogenous SPAG4L as a 43-kDa protein. Further studies revealed that mouse Spag4L colocalized with the NE marker Lamin B1 and the ER marker PDI in isolated mouse spermatocytes. In addition, the expression of Spag4L was observed in meiosis I and II stages, suggesting that Spag4L may be involved in NE reconstitution and nuclear migration occurring during the process of spermatocyte division. Together, the findings indicate that SPAG4L, a new NE protein, may play an important role in the meiotic stage of spermatogenesis. PMID- 21711155 TI - Sequelae of breast cancer and the influence of menopausal status at diagnosis among rural breast cancer survivors. AB - BACKGROUND: Rural women are among the largest medically underserved groups in the nation, yet few studies have evaluated the sequelae of breast cancer in this population. The purpose of this study was to examine the physical and psychosocial effects of breast cancer experienced by rural survivors at the time of treatment and currently and to examine differences in these effects between younger and older rural survivors based on menopausal status at diagnosis. METHODS: Women treated for breast cancer within the past 6 years at one of three rural cancer centers were mailed a survey with a cover letter from their oncology provider. RESULTS: Survey respondents (n=918, 83% response rate) were 67+/-13 years old, on average 3.2 years from treatment, 22% were premenopausal at the time of breast cancer diagnosis, and 95% were postmenopausal at the time of the survey. Women who were premenopausal at diagnosis were significantly more likely to experience numerous symptoms at the time of treatment and currently, including higher rates of hot flashes, vaginal dryness, loss of sexual desire, and weight gain (p<=0.001). The most common psychosocial concerns were fear of recurrence and change in body image, and women premenopausal at diagnosis were significantly more likely than postmenopausal women to report experiencing these concerns (68% vs. 47%, and 43% vs. 27%, respectively, p<=0.001). CONCLUSIONS: Negative physical and psychosocial sequelae of breast cancer were common in this rural sample and were significantly worse for premenopausal women. Research and resources are needed for delivering targeted survivorship care to rural women, particularly younger rural women. PMID- 21711158 TI - Curcumin induces small cell lung cancer NCI-H446 cell apoptosis via the reactive oxygen species-mediated mitochondrial pathway and not the cell death receptor pathway. AB - Curcumin (diferuloylmethane), an active component of the spice turmeric, induces apoptosis in several types of malignancies. However, little is known about its anticancer activity in small cell lung cancer (SCLC). SCLC represents a highly malignant and particularly aggressive form of cancer, with early and widespread metastases and a poor prognosis. In this study, we found that curcumin does not activate caspase-8 cleavage or alter the expression of apoptotic receptors FAS and TRAIL in NCI-H446 cells, suggesting that curcumin-induced apoptosis is not associated with death receptor-mediated pathways in these cells. Instead, curcumin caused apoptosis by increasing Bax expression while decreasing the expression of Bcl-2 and Bcl-xL. Curcumin induced a rapid decrease in mitochondrial membrane potential and the release of cytochrome c into the cytosol, followed by activation of caspase-9 and caspase-3. In addition, curcumin induced apoptosis was accompanied by an increase of intracellular reactive oxygen species (ROS) level. These results indicated that a ROS-mediated mitochondrial pathway played an important role in the process of curcumin-induced apoptosis of human SCLC NCI-H446 cells. PMID- 21711157 TI - Favorable response of chronic refractory immune thrombocytopenic purpura to mesenchymal stem cells. AB - Seven patients with chronic refractory immune thrombocytopenic purpura (ITP) received adipose tissue-derived mesenchymal stem cells (AMSC) from haplo identical family donors. The AMSC dose was 2.0*10(6)/kg. No side effects were noted after the AMSC infusions. Overall responses were reached in all patients and sustained response rate was 57.1% (4/7). The serum levels of transforming growth factor beta1 (TGF-beta1), interleukin (IL)-4, and IL-10 were significantly elevated, whereas those of interferon-gamma (IFN-gamma) and IL-2 were significantly decreased after AMSC administration, compared with those in the patients with active ITP. During follow-up, the cytokine profiles in patients maintaining sustained response remained stable compared with the post-treatment level, but IFN-gamma and IL-2 levels were significantly increased, and those of TGF-beta1, IL-4, and IL-10 were significantly reduced again in relapsed patients. AMSC therapy seems to represent reasonable salvage treatment in severe, chronic refractory ITP by causing a shift in the Th1/Th2 cytokine balance to the same levels as normal controls. PMID- 21711159 TI - Antiproliferative activity of novel derivative of thiopyran on breast and colon cancer lines and DNA binding. AB - Dimethyl-5-acetyl-4-methyl-6-(4-methylphenylimino)-6H-thiopyran-2,3-dicarboxylate (4) has been synthesized and its antiproliferative activity is reported here. Compound 4 inhibited the growth of human colon cancer cell line HCT-15 with an IC(50) value of 3.5 MUM and of breast cancer cell line MCF-7 with an IC(50) value of 1.5 MUM in a dose/time-dependent manner using a sulforhodamine B assay. Moreover, suppression of clonogenic activity occurred after exposure to 4 at a concentration of 4 MUM for HCT-15 and 1.7 MUM for MCF-7. The results also showed tumor cell invasion through matrigel and cell adhesion. The effect of ligand complexation on DNA structure led to overall affinity constant of K(4 DNA)=9.8*10(4) M(-1). PMID- 21711160 TI - The role of p73 G4C14-to-A4T14 polymorphism in the susceptibility to cervical cancer. AB - Several reports have suggested the importance of p73 polymorphisms in tumor behavior. We investigated the role of a p73 gene polymorphism in the susceptibility to cervical lesions in a southwestern European population. Peripheral blood samples were obtained from Radiotherapy and Gynaecology Departments of Portuguese Institute of Oncology (Porto, Portugal), from 1998 to 2002. We analyzed the p73 cytosine thymine polymorphism in peripheral blood DNA of 176 healthy donors, 38 high-grade squamous intraepithelial lesions (HSIL), and 141 patients with primary untreated invasive cervical cancers (ICC), by polymerase chain reaction-restriction fragment length polymorphism. Our results demonstrate a twofold increased susceptibility to the development of HSIL in women carrying the p73 AT allele (OR=2.39; p=0.022). Further, this association seems to be more evident in women with high parity (OR=12.53; p=0.007). This is in agreement with the possible role of p73 in cervical carcinogenesis, namely, in human papillomavirus-infected transition zone subjected to the action of estrogens and in conjunction with disruption of differentiation program of this squamous epithelium that occurs in HSIL phase before the next step to invasiveness and squamous cervical cancer. PMID- 21711161 TI - Enhancer-blocking activity is associated with hypersensitive site V sequences in the human growth hormone locus control region. AB - Activation of the human growth hormone gene (hGH-N) is linked to a locus control region (LCR) containing four (I-III, V) hypersensitive sites (HS). Pit-1 binding to HS I/II is required for efficient pituitary expression. However, inclusion of HS III and V, located about 28 and 32 kb upstream of the hGH-N gene, respectively, is also required for consistent hGH-N expression levels in vivo. HS V is referred to as a boundary for the hGH LCR, but no specific enhancer blocking or barrier function is reported. We examined a 547 bp fragment containing HS V sequences (nucleotides -32,718/-32,172 relative to hGH-N) for enhancer-blocking activity using a well-established transient gene transfer system and assessed these sequences for CCCTC binding factor (CTCF), which is linked to enhancer blocking activity. The 547 bp HS V fragment decreased enhancer activity with a reverse-orientation preference when inserted between HS III enhancer sequences and a minimal thymidine kinase promoter (TKp). These sequences are associated with CTCF in human pituitary and nonpituitary chromatin. Enhancer-blocking activity with an orientation preference was further localized to a 45 bp sub fragment, with evidence of CTCF and upstream binding factor 1 (USF1) binding; USF1 is linked more closely with barrier function. The presence of yin and yang 1 (Yy1) that cooperates with CTCF in the regulation of X-chromosome inactivation was also seen. A decrease in CTCF and Yy1 RNA levels was associated with a significant reduction in enhancer-blocking activity. Assessment of CpG dinucleotides in the TKp indicates that the presence of HS V sequences are associated with an increased incidence of CpG-dinucleotide methylation of the GC box region. These data support association of CTCF and enhancer-blocking activity with HS V that is consistent with a role as a (LCR) boundary element and also implicates Yy1 in this process. PMID- 21711162 TI - A comparison of four sampling methods among men having sex with men in China: implications for HIV/STD surveillance and prevention. AB - Sample representativeness remains one of the challenges in effective HIV/STD surveillance and prevention targeting men who have sex with men (MSM) worldwide. Although convenience samples are widely used in studies of MSM, previous studies suggested that these samples might not be representative of the broader MSM population. This issue becomes even more critical in many developing countries where needed resources for conducting probability sampling are limited. We examined variations in HIV and Syphilis infections and sociodemographic and behavioral factors among 307 young migrant MSM recruited using four different convenience sampling methods (peer outreach, informal social network, Internet, and venue-based) in Beijing, China in 2009. The participants completed a self administered survey and provided blood specimens for HIV/STD testing. Among the four MSM samples using different recruitment methods, rates of HIV infections were 5.1%, 5.8%, 7.8%, and 3.4%; rates of Syphilis infection were 21.8%, 36.2%, 11.8%, and 13.8%; and rates of inconsistent condom use were 57%, 52%, 58%, and 38%. Significant differences were found in various sociodemographic characteristics (e.g., age, migration history, education, income, and places of employment) and risk behaviors (e.g., age at first sex, number of sex partners, involvement in commercial sex, and substance use) among samples recruited by different sampling methods. The results confirmed the challenges of obtaining representative MSM samples and underscored the importance of using multiple sampling methods to reach MSM from diverse backgrounds and in different social segments and to improve the representativeness of the MSM samples when the use of probability sampling approach is not feasible. PMID- 21711163 TI - Acceptability of neonatal male circumcision in Lusaka, Zambia. AB - Neonatal male circumcision (NMC) is being scaled up in Zambia and elsewhere in Southern Africa as a long-term HIV prevention strategy. We conducted 12 focus group discussions with 129 parents and grandparents in Lusaka, recruited from two sites providing free NMC services and information about NMC, to explore the acceptability of circumcising newborn boys. Most participants recognized the benefits of circumcision for HIV prevention, and the advantages of circumcising their children and grandchildren at a young age. Fear of negative outcomes, concerns about pain, and issues around cultural identity may challenge NMC uptake. To effectively promote the service, the upper age limit for NMC must be emphasized, and fathers must be targeted by messaging campaigns. PMID- 21711164 TI - A biomechanical analysis of finger joint forces and stresses developed during common daily activities. AB - The problem of modelling stresses incurred at the finger joints is critical to the design of durable joint replacements in the hand. The goal of this study was to characterise the forces and stresses at the finger and thumb joints occurring during activities such as typing at a keyboard, playing piano, gripping a pen, carrying a weight and opening a jar. The metacarpal and proximal phalanx were modelled using a COMSOL-based finite element analysis. Analysis of these activities indicates that joint forces in excess of 100 N may be common at the metacarpophalangeal joint (MCP) due to carrying objects such as groceries or while opening jars. The model predicted that stresses in excess of 2 MPa, similar to stresses at the hip, occur at the MCP with the properties of cancellous bone playing a significant role in the magnitude and distribution of stress. PMID- 21711165 TI - Problems taking pills: understanding HIV medication adherence from a new perspective. AB - HIV medication adherence remains a challenge for people taking antiretroviral therapy. In the last decade research in this area has proliferated, yet there is a need for novel research approaches that provide information on the development of successful medication adherence interventions. This study examined several key potential correlates of reasons for missed medication in a diverse sample of people living with HIV/AIDS (PLWHA) from nine cities in the US using an ordinal regression model. Examining the reasons for missed medication in relationship with regimen type, symptom experience, AIDS diagnosis, other health conditions, and social support offers a new approach. Problems taking pills (a factor of five reasons) was significantly associated (p=0.003) with use of a protease inhibitor (PI) regimen. A person taking a PI regimen has a 70% increase of having more problems taking pills versus a non-PI regimen. Symptom experience (odds ratio [OR]: 3.8; 95% confidence interval [CI]: 2.7, 5.2) and other health conditions (OR: 0.7; 95% CI: 0.45, 0.98) were found to be independently associated with problems taking pills. This new perspective may provide a framework for further conceptualizing new analyses that are related to enhancing adherence intervention research and development. PMID- 21711166 TI - Impact of personal and ambient-level exposures to nitrogen dioxide and particulate matter on cardiovascular function. AB - This work explored the association between nitrogen dioxide (NO(2)) and PM(2.5) components with changes in cardiovascular function in an adult non-smoking cohort. The cohort consisted of 65 volunteers participating in the US EPA's Detroit Exposure and Aerosol Research Study (DEARS) and a University of Michigan cardiovascular sub-study. Systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), brachial artery diameter (BAD), brachial artery flow-mediated dilatation (FMD) and nitroglycerin-mediated arterial dilatation (NMD) were collected by in-home examinations. A maximum of 336 daily environmental and health effect observations were obtained. Daily potassium air concentrations were associated with significant decreases in DBP (-0.0447 mmHg/ng/m(3) +/- 0.0132, p = 0.0016, lag day 0) among participants compliant with the personal monitoring protocol. Personal NO(2) exposures resulted in significant changes in BAD (e.g., 0.0041 mm/ppb +/- 0.0019, p = 0.0353, lag day 1) and FMD (0.0612 +/- 0.0235, p = 0.0103, lag day 0) among other findings. PMID- 21711167 TI - Transactional sex risk and STI among HIV-infected female sex workers and HIV infected male clients of FSWs in India. AB - To describe sex risk behaviors of HIV-infected female sex workers (FSWs) and HIV infected male clients of FSWs, to evaluate associations between risky transactional sex and number of unprotected transactional sex episodes, and to assess the association between unprotected transactional sex and self-reported sexually transmitted infection (STI). Adult HIV-infected FSWs (n = 211) and HIV infected male clients (n = 205) were surveyed in Mumbai about demographics, STI, and past 90-day and past year sex and substance use histories. Gender-stratified Poisson regression models were used to evaluate associations between four risky transactional sex behaviors (number of transactional sex partners; alcohol use before transactional sex; anal transactional sex; and transactional sex with a known HIV-infected partner) and number of unprotected transactional sex episodes; logistic regression was used to assess the association between unprotected transactional sex and self-reported STI. Twenty-nine percent of females and 7% of males reported any unprotected transactional sex episodes in the past 90 days. Thirty-nine percent of females and 12% of males reported past year STI. Among males, a greater number of transactional sex partners was associated with more unprotected transactional sex episodes (adjusted incidence rate ratio [IRR] = 8.2, 95% confidence interval [CI] = 1.8-38.4 highest vs. lowest tertile), and any unprotected transactional sex was associated with a higher odds of self-reported STI in the past year (adjusted odds ratio [AOR] = 5.6, 95% CI = 1.4-22.4). For women, risky transactional sex behaviors were not associated with condom non-use, and unprotected sex was negatively associated with STI (AOR = 0.4, 95% CI = 0.2 0.9). Reports of condom use during transactional sex were high for these samples. However, standard predictors of unprotected transactional sex (i.e., greater number of partners) and STI (i.e., unprotected sex) only held true for males. Further research is needed to guide an understanding of sex risk and STI among HIV-infected FSWs in India. PMID- 21711168 TI - Prevention messages and AIDS risk behavior in Kampala, Uganda. AB - Uganda was one of the first countries to substantially reduce HIV rates through behavior change, but these gains have not continued in recent years. Little is known about what messages Ugandans are currently hearing about AIDS prevention, what they themselves believe to be important prevention strategies, and how these beliefs are associated with behavior. We interviewed men and women aged between 20 and 39 in two poor peri-urban areas of Kampala, using a random sample, cross sectional household survey design. Respondents provided detailed reports of sexual behavior over the past six months, the main prevention message they are currently hearing about AIDS, and their own ranking of the importance of prevention strategies. Condom use was the main AIDS prevention message that respondents reported hearing, followed by getting tested. These were also what respondents themselves considered most important, followed closely by faithfulness. Abstinence was the lowest ranked strategy, but a higher ranking for this prevention strategy was the only one consistently associated with less risky behavior. A higher ranking for condoms was associated with higher levels of risk behavior, while the ranking of testing made no difference in any behavior. These results present challenges for AIDS prevention strategies that rely primarily on promoting condoms and testing. HIV prevention programs need to assess their impact on behavior. PMID- 21711170 TI - Urinary metabolites of cinobufagin in rats and their antiproliferative activities. AB - Cinobufagin was one of the important cardenolidal steroids and a major component of Chan'Su, a famous traditional Chinese medicine. The urinary metabolites of cinobufagin after single oral doses of 25 mg kg-1 in rats were investigated. Eleven metabolites were isolated and purified by liquid-liquid extraction, open column chromatography, medium-pressure liquid chromatography, as well as semi preparative high-performance liquid chromatography. Their structures were elucidated by chemical and various spectroscopic methods, which were identified as desacetylcinobufagin (M-1), 3-oxo-desacetylcinobufagin (M-2), 3-oxo cinobufagin (M-3), 3-epi-desacetylcinobufagin (M-4), 3-epi-12beta-hydroxyl desacetylcinobufagin (M-5), 5beta-hydroxyl cinobufagin (M-6), 5beta-hydroxyl desacetylcinobufagin (M-7), 12beta-hydroxyl cinobufagin (M-8), 1beta,12beta dihydroxyl cinobufagin (M-9), 12beta-hydroxyl desacetylcinobufagin (M-10) and 1beta,12beta-dihydroxyl desacetylcinobufagin (M-11), respectively. Among them, M 1 was the main urinary metabolite of cinobufagin with a yield of 17.7%. Most metabolites were hydroxylated products of cinobufagin at C-1beta, 5beta and 12beta positions, as well as deacetylated products at C-16. Except M-1, M-4 and M 7, the other eight metabolites were novel in vivo metabolites of cinobufagin. Some metabolites showed potential cytotoxicity against human hepatoma cells (HepG2) and human leukaemia (K562, HL-60) cells; however, their cytotoxicities generally decreased after metabolic conversion. PMID- 21711169 TI - Indian married men's interest in microbicide use. AB - Research suggests that the HIV/AIDS epidemic has spread to monogamous women in India. Gender inequalities prevent women from asserting control over the circumstances that increase their vulnerability to infection. Men control most of the sexual decision-making. The present study explores views on use of microbicides by men and circumstances in which they might find microbicide use with their wives acceptable. Progressive in-depth interviews were conducted among 15 consenting men from Pune, India. Men felt that women with identifiable HIV risk, such as being a sex worker, having an HIV infected husbands or being educated; were more likely to use microbicides. Most high-risk men would permit or force their wives to use microbicides and had a higher intention to use microbicides compared with low-risk men probably due to perceived susceptibility. The majority of men with previous experience of microbicide use mentioned that privacy was important for gel use. Most low-risk men believed that they would be angry with covert gel use by their wives. They felt that covert use was impossible since their wives were under their control and they would notice the gel due to a change in their sexual experience. Low-risk men also opined that husband's permission was not required if he was HIV-infected or having extra marital sex. Some men stressed the need for exercising sexual control while women inserted gel before sex. Men's risk-perception, knowledge about their safety concerns, as well as their behavior may affect acceptability of gel use, hence men's involvement and cooperation is imperative for microbicide gel use by women in India. PMID- 21711171 TI - The influence of orphan care and other household shocks on health status over time: a longitudinal study of children's caregivers in rural Malawi. AB - In the context of rising rates of orphanhood in AIDS-affected settings, very little is understood about implications for caregiver well-being given increasing and intensifying responsibilities for the care of orphaned children. Emotional distress and self-reported health status as well as shifts in household orphan care, wealth, food security and recent illness and death among household members were measured among a panel of 1219 caregivers in rural Malawi between 2007 and 2009. Logistic regression was used to identify predictors of improved and diminished caregiver health and emotional distress. Results suggest that becoming an orphan caregiver is associated with a shift from good to poor health status (adjusted odds ratio [AOR]=2.29, 95% confidence interval [CI]=1.16-4.54), and that elevated levels of distress and poor health both persist over time in comparison with care for non-orphans only. Once engaged in orphan care, taking on additional orphans is associated with increased emotional distress in relation to not caring for orphans (AOR=3.16, 95% CI=1.30-7.73) as well as in relation to maintaining the same number of orphans in care over time (AOR=2.84, 95% CI=1.04 7.70). In addition, findings illustrate the strong influence of household wealth and food security on caregiver well-being. Food insecurity and poverty that persist or develop over time are associated with increasing distress. Conversely, maintenance or improvement in food security and household wealth are associated with decreases in distress. Providing all aspects of household maintenance and care for children, primary caregivers are key to the extended family solution for orphaned and vulnerable children. Bolstering the foundation of rural African families to ensure care and protection of these children involves targeting support to orphan caregivers but must also include addressing the issues of poverty and food insecurity that pose a wider threat to caregiving capacity. PMID- 21711172 TI - Chemical composition and antioxidant activities of ansu apricot oil growing wild in north Xinjiang, China. AB - Ansu apricots growing wild in north Xinjiang are recognised as being one of the major wild-plant resources in China. In order to improve the level of comprehensive utilisation and the number of cultivated apricot varieties, the chemical composition of ansu apricot oil was analysed by capillary GC-MS and elucidated based on the standard mass spectral data; the antioxidant activities were also evaluated. Seven components of ansu apricots oil were identified, and the total unsaturated fatty acid (FA) (TUFA) and total essential FA (TEFA) contents of the ansu apricot oil were found to be 90.35 g/100 g and 48.93 g/100 g, respectively. The scavenging capacity of the ansu apricots oil in the superoxide anion radical system and the hydroxyl radical system performed better than in the DPPH radical system. The IC50 values of the ansu apricot oil for the superoxide anion radical system and the hydroxyl radical system were 0.15 mg mL-1 and 0.30 mg mL-1, respectively: stronger than that of the control (ascorbic acid). In the DPPH system, the IC50 value of the ansu apricot oil was 0.50 mg mL 1, and the IC50 value of ascorbic acid was 0.30 mg mL-1, but within the selected dosage, the highest scavenging capacity of ansu apricot oil was higher than the control. The results obtained in this study clearly suggest that ansu apricot oil is a natural source of antioxidants and could serve as a functional food ingredient with potential application in food products and thus provide related health benefits. PMID- 21711175 TI - Induction of apoptosis in human promyelocytic leukemia HL60 cells by an extract from Erythrina suberosa stem bark. AB - In this study, the apoptosis-inducing effect of an alcoholic extract from Erythrina suberosa stem bark (ESB) was investigated using human promyelocytic leukemia HL60 cells. Cell viability was estimated by MTT assay. We found that the ESB inhibited cell proliferation in a dose- and time-dependent manner. A series of well-documented morphological changes, such as cell shrinkage, condensation of nuclear chromatin, and nuclear fragmentation, were observed by fluorescence microscopy. The gold standard scanning electron micrographs showed apoptotic bodies and formation of blebs. Cell cycle analysis showed a significant increase in Sub G(0) population of cells above 50 MUg/ml. ESB treatment resulted in a dose dependent increase in annexin V positive cells. Increase in intracellular ROS production up to sixfold was detected in ESB-treated HL60 cells by DCFH-DA assay. Dissipation of mitochondrial membrane potential of intact cells accompanied by increase in cytosolic cytochrome c was observed, which was followed by activation of caspase-9 and -3 but not caspase-8. DNA fragmentation analysis revealed typical ladders as early as 18 h indicative of caspase-3 role in the apoptotic pathway. The overall results suggest that ESB induces mitochondria-mediated intrinsic apoptotic pathway in HL60 cells and might have therapeutic value against human leukemia. PMID- 21711174 TI - Serum IGF-1 concentrations change with soy and seaweed supplements in healthy postmenopausal American women. AB - Insulin-like growth factor 1 (IGF-1) is an anabolic hormone important for growth and development. However, high-circulating serum concentrations in adults are associated with increased risk of postmenopausal breast cancer. Nutritional status and specific foods influence serum IGF-1 concentrations. Breast cancer incidence is typically low in Asian countries where soy is commonly consumed. Paradoxically, soy supplement trials in American women have reported significant increases in IGF-1. Seaweed also is consumed regularly in Asian countries where breast cancer risk is low. We investigated the possibility that seaweed could modify soy-associated increases in IGF-1 in American women. Thirty healthy postmenopausal women (mean age 58 yr) participated in this 14-wk double-blinded, randomized, placebo-controlled crossover clinical trial. Participants consumed 5 g/day placebo or seaweed (Alaria esculenta) in capsules for 7 wk. During the 7th wk, a high-soy protein isolate powder was added (2 mg/kg body weight aglycone equivalent isoflavones). Overnight fasting blood samples were collected after each intervention period. Soy significantly increased serum IGF-1 concentrations compared to the placebo (21.2 nmol/L for soy vs. 16.9 nmol/L for placebo; P = 0.0001). The combination of seaweed and soy significantly reduced this increase by about 40% (21.2 nmol/L for soy alone vs. 19.4 nmol/L; P = 0.01). Concurrent seaweed and soy consumption may be important in modifying the effect of soy on IGF-1 serum concentrations. PMID- 21711176 TI - Clove (Syzygium aromaticum Linn) extract rich in eugenol and eugenol derivatives shows bone-preserving efficacy. AB - This study examined the efficacy of hydroalcoholic extract of dried clove buds, which is rich in phenolic compounds namely eugenol and eugenol derivatives (precursors of flavones, isoflavones and flavonoids), on different primary and secondary osteoporotic marker changes in an ovariectomised (OVX) rat model of osteoporosis. Female Wistar rats were randomly divided into three groups: sham operated control (A), OVX (B) and OVX plus 50% hydroalcoholic extract of dried clove buds for 4 weeks (C). Results indicated that, compared to control, serum alkaline phosphatase (AP; 48.25%, p < 0.01), serum tartrate-resistant acid phosphatase (TRAP; 63.48%, p < 0.01), urinary calcium (14.70%, p < 0.01), urinary phosphate (50.30%, p < 0.01) and urinary creatinine (122.44%, p < 0.01) were significantly altered in OVX rats. All these altered responses were significantly restored (AP: 27.53%, p < 0.01; TRAP: 33.51%, p < 0.01; calcium: 53.15%, p < 0.01; phosphate: 27.49%, p < 0.01; creatinine: 46.40%, p < 0.01) by supplementation with hydroalcoholic extract of dried clove buds. Results of bone density, bone mineral content, bone tensile strength and histological analysis also showed similar trend of results, which supported initial observations of this study. It is proposed that hydroalcoholic extract of dried clove buds has bone-preserving efficacy against hypogonadal osteoporosis. PMID- 21711177 TI - Volatile constituents of essential oil and rose water of damask rose (Rosa damascena Mill.) cultivars from North Indian hills. AB - Rosa damascena Mill. is an important aromatic plant for commercial production of rose oil, water, concrete and absolute. The rose water and rose oil produced under the mountainous conditions of Uttarakhand were investigated for their chemical composition. The major components of rose water volatiles obtained from the bud, half bloom and full bloom stages of cultivar 'Ranisahiba' were phenyl ethyl alcohol (66.2-79.0%), geraniol (3.3-6.6%) and citronellol (1.8-5.5%). The rose water volatiles of cultivar 'Noorjahan' and 'Kannouj' also possessed phenyl ethyl alcohol (80.7% and 76.7%, respectively) as a major component at full bloom stage. The essential oil of cultivar 'Noorjahan' obtained from two different growing sites was also compared. The major components of these oils were citronellol (15.9-35.3%), geraniol (8.3-30.2%), nerol (4.0-9.6%), nonadecane (4.5 16.0%), heneicosane (2.6-7.9%) and linalool (0.7-2.8%). This study clearly showed that the flower ontogeny and growing site affect the composition of rose volatiles. The rose oil produced in this region was comparable with ISO standards. Thus, it was concluded that the climatic conditions of Uttarakhand are suitable for the production of rose oil of international standards. PMID- 21711178 TI - Impact of maternal human immunodeficiency virus infection on pregnancy and birth outcomes in Pune, India. AB - Little is known about birth outcomes for HIV-infected women in India. We examine maternal and neonatal birth outcomes in HIV-infected women within the context of enhanced pre-natal care associated with a randomized clinical trial conducted in Pune, India. Birth outcomes of 212 HIV-infected pregnant women were compared with those of 130 HIV-uninfected pregnant women attending a government tertiary care hospital between 2002 and 2004. These women and children were participating in the Six Week Extended-Dose Nevirapine (SWEN) study. Birth outcomes and maternal morbidity data were collected at delivery. We found no differences between HIV infected and uninfected pregnant women with respect to the proportion with elevated intrapartum blood pressure, eclampsia, oligohydramnios, intrauterine growth restriction (IUGR), preterm delivery, or caesarean section (p>0.05). HIV infected women were more likely to have peri-partum fever (3% versus 0%, p=0.04). There were no differences in neonatal parameters such as low birth weight (LBW), infants who were small for gestational age, or those having congenital anomalies (p>0.05). Compared with infants of HIV-infected women enrolled antenatally, infants of HIV-infected women enrolled in the post-partum ward had a higher risk of pre-term delivery (20% versus 8%, p=0.02) and LBW (41% versus 22%, p=0.002). HIV-infected women in this cohort in India were not found to have significant negative birth outcomes. Antenatal care was important as those not having received any antenatal care prior to deliver were at increased risk of having a pre-term delivery or an infant with LBW. Based on these data, regular antenatal care provided to HIV-infected women can reduce risk of adverse birth outcomes for their infants. PMID- 21711179 TI - Disabled persons' knowledge of HIV prevention and access to health care prevention services in South Africa. AB - The main research question in this article is how access to information about HIV/AIDS and level of HIV/AIDS prevention related knowledge are distributed among disabled people, and whether level of knowledge predicts access to HIV/AIDS related services. A survey was carried out among a sample of 285 disabled people from three provinces in South Africa. Analyses of the data revealed that gender and level of education, together with geographical differences, are key predictors for access to information and knowledge about HIV/AIDS among disabled people. For male respondents number of information sources predicts access to voluntary counselling and testing services and HIV testing, while knowledge about prevention predicts access to Voluntary Counselling and Testing centres. Significant gender differences with regards to information, knowledge and access to services highlight the need for gender specific prevention strategies among disabled people. PMID- 21711180 TI - Gender, socio-economic status, migration origin and neighbourhood of residence are barriers to HIV testing in the Paris metropolitan area. AB - In France, numerous HIV patients still discover their HIV status as a result of AIDS-related symptoms. We investigated factors related to the absence of any HIV testing in men and women separately, using the data from the SIRS cohort, which includes 3023 households representative of the Paris metropolitan area in 2005. The failure to use HIV testing services was studied in relation to individual socio-economic and demographic factors as well as some psychosocial characteristics. The effect of the characteristics of the residential neighbourhood was also analysed using multilevel models. In multivariate analysis, the factors associated with no history of HIV testing in women were an age >44 years, the absence of any pregnancy during the previous 15 years, a low education level, unemployment, to have had no or only one steady relationship in one's lifetime, to have a religious affiliation and to live in a poor neighbourhood. In men, factors were age <30 or >44 years, to have had no or only one steady relationship during one's lifetime, to have a religious affiliation and to perceive oneself as being at low risk of HIV infection. An association according to the "migration origin" was observed among men: foreigners and French men born to (at least) one foreign parent were more likely not to have been tested than French men born to two French parents. We conclude that gender, social and territorial differences exist in HIV testing among people living in the Paris area. More systematic proposals of HIV test in primary care would be an effective policy to overcome these persistent social stratifications. PMID- 21711181 TI - Infectious bronchitis virus variants: a review of the history, current situation and control measures. AB - The history, current situation and control measures for infectious bronchitis virus (IBV) variants are reviewed. A large number of IBV variants exist worldwide; some being unique to a particular area, others having a more general distribution. The possible reasons why some strains spread readily over major parts of the world, whereas other strains stay more localized are discussed. The advantages and disadvantages of strain classification by protectotyping, serotyping and genotyping are discussed in relation to in vivo protection. The different vaccination strategies are also considered. PMID- 21711182 TI - Development of a SYBR Green quantitative polymerase chain reaction assay for rapid detection and quantification of infectious laryngotracheitis virus. AB - Infectious laryngotracheitis is an acute viral respiratory disease of chickens with a worldwide distribution. Sensitive detection of the causative herpesvirus is particularly important because it can persist in the host at a very low copy number and be transmitted to other birds. Quantification of viral genome copy number is also useful for clinical investigations and experimental studies. In the study presented here, a quantitative polymerase chain reaction (qPCR) assay was developed using SYBR Green chemistry and the viral gene UL15a to detect and quantify infectious laryngotracheitis virus (ILTV) in ILTV-inoculated chicken embryos or naturally infected birds. The specificity of the assay was confirmed using a panel of viral and bacterial pathogens of poultry. The sensitivity of the assay was compared with two conventional PCR assays, virus titration and an antigen-detecting enzyme-linked immunosorbent assay. The qPCR developed in this study was highly sensitive and specific, and has potential for quantification of ILTV in tissues from naturally and experimentally infected birds and embryos. PMID- 21711183 TI - The dynamics of Salmonella occurrence in commercial laying hen flocks throughout a laying period. AB - Contaminated eggs and egg products have been recognized for many years as an important source of Salmonella infections in humans in the European Union and in the United States. Longitudinal studies can help to increase our knowledge about the dynamics of the occurrence of Salmonella in the course of a laying period. The total of 41 laying hen flocks-18 in Belgium, six in Denmark and 17 in Germany were followed during an entire laying period. Samples taken from the empty cleaned and disinfected poultry houses were all negative for Salmonella. After hens arrived on the farms, five pooled faecal samples, one pooled dust sample and 40 cloacal swabs (Belgium and Germany) or 40 swabs from fresh droppings (Denmark) were taken four times from 18 flocks, three times from 21 flocks and two times from two flocks in the course of the laying period. Ten flocks (two Belgian and eight German flocks) tested up to three times positive for Salmonella. Forty three out of 50 positive samples contained Salmonella Enteritidis phage type 4 (29 isolates) or phage type 8 (14 isolates). The probability of subsequent Salmonella-positive findings increased significantly in Salmonella-positive flocks (P<0.05, odds ratio = 6.4). However, the probability of finding Salmonella did not depend on the time of sampling in the laying period or the season. PMID- 21711184 TI - Capsid protein sequence diversity of avian nephritis virus. AB - The capsid gene sequences of 25 avian nephritis viruses (ANVs), collected in the UK, Germany and Belgium from the 1980s to 2008, were determined and compared with those of serotype 1 (ANV-1) and serotype 2 (ANV-2) ANV isolates. Amino acid identities as low as 51% were determined. Pairwise comparisons supported by phylogenetic analysis identified six ANVs, including ANV-1 and ANV-2, which shared<80% amino acid identities with one another, and which were selected to be representative of six groups. The ANVs were not distributed according to geographical location or year of sampling, and the detection of ANVs from five different groups in 11 samples sourced from six flocks belonging to the same UK organization within a 4-month period indicated that sequence-diverse ANVs were co circulating. Amino acid alignments demonstrated the existence of variable regions throughout the capsid protein, nine of which were selected for detailed comparisons. With most ANVs, the variable region sequences were similar to those of one of the six representative ANVs, but some ANV capsids displayed novel variable region profiles, in which variable regions that were characteristic of more than one representative ANV were present. Phylogenetic analysis based on C terminal sequences of approximately 260 amino acids and SimPlot analysis provided evidence that RNA recombination events located in the 1250 to 1350 nucleotide region resulted in new combinations of the N-terminal and C-terminal capsid regions. The high level of capsid sequence diversity observed in the present study has important implications for both the control and diagnosis of ANV infections. PMID- 21711185 TI - An ALV-J isolate is responsible for spontaneous haemangiomas in layer chickens in China. AB - Subgroup J avian leukosis virus (ALV-J), first isolated in 1989, mainly induces tumours of myeloid leukosis (ML) in meat-type chickens. In 2006, ALV-J strain SCAU-HN06 was isolated from commercial layer hens with spontaneous haemangiomas in China. To confirm its role in the induction of haemangioma, we constructed a full-length copy of the proviral genome from SCAU-HN06, recovered virus from DF-1 cells detected by enzyme-linked immunosorbent assay, characterized its growth property and investigated its pathogenicity. The recovered virus appeared to be identical to SCAU-HN06 analysed by both blast gene sequences and indirect immunofluorescence assay. It also showed similarities in growth to the parental wild-type virus in vitro. The pathogenicity of the rescued and parental virus in specific-pathogen-free White Leghorn chickens was investigated. Both SCAU-HN06 and rSCAU-HN06 could induce haemangioma, with incidence of 52% and 42.8% respectively. Overall, our findings indicated that the ALV-J strain SCAU-HN06 was the causal agent inducing haemangiomas rather than ML in certain layer chickens. PMID- 21711186 TI - Detection and molecular characterization of recombinant avian leukosis viruses in commercial egg-type chickens in China. AB - Two natural recombinant avian leukosis viruses (ALVs) were isolated from Chinese commercial egg-type chickens in 2009, which suffered from haemangiomas and myelocytomas. Sequence analysis of the complete proviral genomes revealed several unique genetic characteristics of the present two isolates, demonstrating that the two viruses were derived from recombination between earlier Chinese ALV-J and endogenous virus sequences. The two recombinant viruses presented typical genetic organization of replication-competent genus Alpharetrovirus, and the gag and pol genes were well conserved with those of ALVs. The env genes of the two viruses were composed of the internal identical sequences (about 240 bp) of endogenous viruses, and the rest of the sequence belonged to subgroup J ALVs. The long terminal repeats of the two viruses were more closely related to HPRS-103 and earlier Chinese ALV-J than other subgroup ALVs, and multiple transcription regulatory elements of ALV-J were highly conserved. In addition, the two viruses shared an almost identical 3'-untranslated region (UTR) sequence with earlier Chinese ALV-J strains and the US strain 4817, containing a ~127 bp deletion in the E element region. However, further comparison with endogenous ALV indicated that the 3'-UTR sequences with ~127 bp deletion of ALV-J were most probably derived from endogenous viruses by recombination. These results suggested that the two isolates can be characterized as recombinant ALV-J with the internal env gene and 3'-UTR sequence of endogenous ALV. PMID- 21711187 TI - Pathobiology of Heterakis gallinarum mono-infection and co-infection with Histomonas meleagridis in layer chickens. AB - Little is known about the induction and modulation of gut-associated immune reactions after nematode infection in the chicken. The objective of the present study was to compare the pathogenesis, induction of immune reactions and electrophysiological changes of the gut after mono-infection with Heterakis gallinarum and after dual infection with H. gallinarum and Histomonas meleagridis in layer chickens. In two experiments 3-week-old chickens were inoculated with embryonated H. gallinarum eggs, which were positive for H. meleagridis. While birds of the first experiment were left untreated, those of the second experiment were treated with dimetridazol to prevent H. meleagridis co-infection. Mild to moderate histological lesions and local immune reactions with a significant increase in CD4(+), CD8alpha(+), TCRalphabeta(+) and TCRdeltagamma(+) cells in the lamina propria and induction of the T-helper type 2 (Th2) cytokine interleukin-13 dominated the H. gallinarum immune response at 2 weeks post infection. Co-infection with H. gallinarum and H. meleagridis induced an increase in mRNA expression of the T-helper type 1 (Th1) cytokine interferon-gamma, a decrease in splenic CD4(+) cells and severe destruction of the caecal mucosa in association with strong T-cell infiltration in the caecal lamina propria. There was no obvious effect on the chloride secretion of the caecal epithelium, which was investigated once the mucosa had almost recovered from the infection, in either experiment. These results suggest that the local T-cell reactions to nematode infections in chickens may be comparable with mammals and may be shifted from a Th2-dominated to a Th1-dominated response when accompanied by a protozoan infection. PMID- 21711188 TI - Protein tyrosine kinase and mitogen-activated protein kinase signalling pathways contribute to differences in heterophil-mediated innate immune responsiveness between two lines of broilers. AB - Protein tyrosine phosphorylation mediates signal transduction of cellular processes with protein tyrosine kinases (PTKs) regulating virtually all signalling events. The mitogen-activated protein kinase (MAPK) super-family consists of three conserved pathways that convert receptor activation into cellular functions: extracellular response kinases (ERK), c-Jun N-terminal kinases (JNK) and p38. Previously conducted studies using two chicken lines (A and B) show line A heterophils are functionally more responsive and produce a differential cytokine/chemokine profile compared with line B, which also translates to increased resistance to bacterial challenges. Therefore, we hypothesize the differences between the lines result from distinctive signalling cascades that mediate heterophil function. Heterophils from lines A and B were isolated from 1-day-old chickens and total phosphorylated PTK and p38, JNK, ERK, and transcription factor (activator protein 1 (AP-1) and nuclear factor kappa B (NF-kappaB)) protein levels quantified following interaction with Salmonella Enteritidis (SE). Control and SE-treated heterophils from line A had greater (P<=0.05) PTK phosphorylation compared to line B with increased (P<=0.05) activation of p38. Conversely, line B heterophils activated JNK (P<=0.05). There were no differences in ERK between control and activated heterophils for either line. Defined signalling inhibitors were used to show specificity. The AP-1 and NF-kappaB transcription factor families were also examined, and c-Jun and p50, respectively, were the only members different between the lines and both were up regulated in line A compared with line B. These data indicate that increased responsiveness of line A heterophils is mediated, largely, by an increased ability to activate PTKs, the p38 MAPK pathway and specific transcription factors, all of which directly affect the innate immune response. PMID- 21711189 TI - Neuraminidase of Mycoplasma synoviae desialylates heavy chain of the chicken immunoglobulin G and glycoproteins of chicken tracheal mucus. AB - Major poultry pathogens, Mycoplasma gallisepticum and Mycoplasma synoviae share several genes, including nanH that encodes their sialidases (neuraminidases). Previous studies have shown considerable differences in neuraminidase enzymatic activity (NEAC) in M. synoviae strains and NEAC absence in individual cultures of two strains, ULB 925 and ULB 9122. The present study shows that the cultures lacking NEAC did not express NanH neuraminidase detectable by specific antibodies. In cultures of M. synoviae ULB 925 and ULB 9122, which lacked NEAC and detectable NanH, deletions of a single adenine in different nanH regions of each strain created translational frameshifts resulting in TAA (UAA) stop codons and premature termination of translation. ULB 925 and ULB 9122 with such nanH mutations did not desialylate reference fetuin and transferrin or chicken glycoproteins that M. synoviae strains with NEAC efficiently desialylated. They desialylated several chicken serum glycoproteins with SAalpha(2-6)gal moieties, including the immunoglobulin G heavy chain. Neuraminidase inhibitor 2,3-didehydro 2-deoxy-N-acetylneuraminic acid inhibited such desialylation otherwise caused by M. synoviae WVU 1853 neuraminidase. WVU 1853 also cleaved sialic acid from SAalpha(2-3)gal moieties from glycoproteins of mucus from chicken tracheas. This is the first demonstration that M. synoviae desialylates glycoproteins of its host. PMID- 21711190 TI - Safety and efficacy of a virulence gene-deleted live vaccine candidate for fowl typhoid in young chickens. AB - The safety and efficacy of a live lon-and-cpxR-deleted Salmonella enterica serovar Gallinarum (SG) vaccine candidate (JOL916) was evaluated in young layer chickens. Vaccinated (n=25) and unvaccinated (n=25) groups were organized, respectively, at 1, 2, 3, and 4 weeks of age. One-week-old and 2-week-old chickens were orally inoculated with 2*10(7) colony-forming units of JOL916, and orally challenged with 2 x 10(6) colony-forming units of a wild-type SG strain at the third week post vaccination (w.p.v.). Doses of vaccination and challenge were increased 10-fold for 3-week-old and 4-week-old chickens. SG-antigen-specific peripheral lymphocyte proliferation response and concentrations of plasma IgG and secretary IgA in the intestine were examined at the second w.p.v. Gross lesions of the liver and spleen and recovery of the vaccine strain from the spleen were also examined at the second w.p.v. No evidence of side effects was detected by observation of general condition and body weight gain in all vaccinated groups. No, or very mild, gross lesions in the chickens were observed in the liver and/or spleen after vaccination. Significant cellular immune responses and systemic IgG responses were induced after vaccination in all age groups. Elevation of secretary IgA concentration was significant in the group, vaccinated at the age of 1 week. Depression scores after challenge were significantly lower in the vaccinated groups, as compared with the corresponding control groups. Significant reductions of death rates were observed in all vaccinated groups, as compared with the equivalent unvaccinated groups. Thus, the oral vaccination of young chickens with JOL916 was demonstrated to be safe. Moreover, it offered efficient protection against fowl typhoid. PMID- 21711192 TI - Experimental infection of domestic canaries (Serinus canaria domestica) with Mycoplasma gallisepticum: a new model system for a wildlife disease. AB - The ethical and logistical challenges inherent in experimental infections of wild caught animals present a key limitation to the study of wildlife diseases. Here we characterize a potentially useful domestic model for a wildlife disease that has been of particular interest in recent decades; that is, infection of North American house finches (Carpodacus mexicanus) with Mycoplasma gallisepticum, more commonly known as a worldwide poultry pathogen. Seven domestic canaries (Serinus canaria domestica) were infected experimentally with M. gallisepticum alongside two wild-caught house finches (C. mexicanus) and the resulting clinical disease, pathogen load, serology and pathology were compared. Although rates of morbidity were higher in domestic canaries in response to M. gallisepticum infection, no significant differences were detected between the two species in the four measures of infection and disease studied. Our results support previous field and experimental studies that have documented universal susceptibility to M. gallisepticum infection in the avian family Fringillidae, which includes domestic canaries. Our results also indicate that domestic canaries may serve as a potentially useful model system for the experimental study of M. gallisepticum infection in songbirds. PMID- 21711191 TI - Application of in-situ hybridization for the detection and identification of avian malaria parasites in paraffin wax-embedded tissues from captive penguins. AB - In captive penguins, avian malaria due to Plasmodium parasites is a well recognized disease problem as these protozoa may cause severe losses among valuable collections of zoo birds. In blood films from naturally infected birds, identification and differentiation of malaria parasites based on morphological criteria are difficult because parasitaemia is frequently light and blood stages, which are necessary for identification of parasites, are often absent. Post mortem diagnosis by histological examination of tissue samples is sometimes inconclusive due to the difficulties in differentiating protozoal tissue stages from fragmented nuclei in necrotic tissue. The diagnosis of avian malaria would be facilitated by a technique with the ability to specifically identify developmental stages of Plasmodium in tissue samples. Thus, a chromogenic in-situ hybridization (ISH) procedure with a digoxigenin-labelled probe, targeting a fragment of the 18S rRNA, was developed for the detection of Plasmodium parasites in paraffin wax-embedded tissues. This method was validated in comparison with traditional techniques (histology, polymerase chain reaction), on various tissues from 48 captive penguins that died at the zoological garden Schonbrunn, Vienna, Austria. Meronts of Plasmodium gave clear signals and were easily identified using ISH. Potential cross-reactivity of the probe was ruled out by the negative outcome of the ISH against a number of protozoa and fungi. Thus, ISH proved to be a powerful, specific and sensitive tool for unambiguous detection of Plasmodium parasites in paraffin wax-embedded tissue samples. PMID- 21711193 TI - Investigations into an outbreak of corvid respiratory disease associated with Pasteurella multocida. AB - The possible cause of disease and mortality in corvids on an outdoor pig unit in the north of England between August 2007 and March 2008 was investigated. Nine carrion crows (Corvus corone corone) and nine rooks (Corvus frugilegus), comprising five live-caught birds with clinical signs of respiratory disease, one live-caught bird without respiratory disease, and 12 birds submitted dead were examined. Clinical signs, gross and histopathological examination, microbiology and toxicology indicated that Pasteurella multocida infection was the cause of disease. Molecular and serotyping analyses showed that P. multocida isolates (obtained from live-caught birds with clinical respiratory disease) were all capsular type F with a mix of somatic serotypes 3, 4 and 7. Immunohistochemistry increased the diagnostic sensitivity of the analysis and detected P. multocida within the pulmonary lesions of all affected live-caught birds and 10 of 12 birds found dead. These findings suggest that wild corvids in the UK can suffer from lung pathology associated with P. multocida and, as potential vectors of P. multocida, may pose a risk to domestic poultry. PMID- 21711199 TI - Factors that influence risky sexual behaviors among men who have sex with men in Liaoning province, China: a structural equation model. AB - HIV prevalence among men who have sex with men (MSM) has increased rapidly in China. Behavioral and biologic interventions are the key to control the spreading of HIV in the MSM population and the primary strategy for reducing the spread of AIDS in China. The objective of this study is to explore the relationship among HIV-related knowledge, the basic information of respondents, service utilization and risky sexual behavior. Respondent-driven sampling was used to recruit 225 MSM in Fushun and Huludao in China. The results of univariate analysis showed that condom use in the past 6 months was associated with age, being more knowledgeable about HIV, accepting lubricant distribution, and peer education (p<0.05). The structural equation modeling (SEM) results was as following, chi(2)=863.45 (p<0.01); root mean square error of approximation (RMSEA)=0.04; goodness of fit (GFI)=0.94, which indicated the model fitted the data well. The factor loads of HIV-related knowledge, the basic information of respondents, service utilization and risky sexual behavior was -0.06, 0.07, -0.27, respectively, which indicated that service utilization was likely to be a major factor negatively impacting risky sexual behavior. For service utilization, the greatest item load was for distribution of lubricants and peer education, 0.69, 0.68, respectively. The factor load of HIV-related knowledge and service utilization was 0.15, which suggested that risky sexual behaviors might be indirectly reduced by improving HIV/AIDS knowledge to increase service utilization. Basic information (age, income, marital status, age at first sexual intercourse) had a greater impact on service utilization, with a load factor of 0.26. For basic information, the greatest item load was age (0.96). In terms of the intervention strategies, it is essential that public health education is provided for the young, to ultimately decrease risky behaviors in MSM. PMID- 21711201 TI - Shenmai injection for chronic pulmonary heart disease: a systematic review and meta-analysis. AB - OBJECTIVES: This study sought to evaluate the efficacy and safety of shenmai injection for chronic pulmonary heart disease (CPHD). METHODS: A systematic review was conducted of clinical trials that compared shenmai injection plus conventional medicine treatment versus conventional medicine treatment alone. Randomized controlled trials of clinical therapeutic studies on CPHD by shenmai injection were included. Searches were applied to the following electronic databases: the PubMed (1977-2008), the Cochrane Library, EMBASE, AMED, Chinese BioMedical Literature Database, and CBM. No blinding and language restriction was used. Data were extracted independently by 2 reviewers. All trials included were analyzed according to the criteria of the Cochrane Handbook. Review Manager 5.0 software was used for data analysis. RESULTS: Thirty-three (33) randomized clinical trials (2617 patients) with low methodological quality were included. Compared to conventional medicine treatment alone, shenmai plus conventional medicine treatment showed significant improvement in New York Heart Association classification of clinical status (odds ratio 0.24; 95% confidence interval 0.19 0.30), five studies had reported adverse events. No serious adverse effects were reported in any of the included trials. CONCLUSIONS: While there is some evidence that suggests potential effectiveness of shenmai plus conventional medical treatment for CPHD, the results of this study were limited by the methodological flaws, unknowns in concealment of allocation, number of dropouts, and blinding methods in the studies. Long-term and high-quality studies are needed to provide clear evidence for the future use of shenmai injection. PMID- 21711202 TI - Yoga therapy as an adjunctive treatment for schizophrenia: a randomized, controlled pilot study. AB - OBJECTIVES: There has been limited study of therapeutic yoga as a complementary treatment for schizophrenia. This study investigates the effects of a Yoga Therapy program on symptomatology and quality of life in adults with schizophrenia in a state psychiatric facility. METHODS: In a randomized, controlled pilot study, 18 clinically stable patients (12 men and 6 women) with schizophrenia (mean age=42+/-13.5) were randomized to an 8-week Yoga Therapy program (YT) and a Waitlist group (WL). YT intervention included yoga postures, breathing exercises, and relaxation. At baseline and at 8 weeks, symptomatology was measured using the Positive and Negative Syndrome Scale (PANSS). Secondary efficacy outcomes were measured with the World Health Organization Quality of Life BREF questionnaire (WHOQOL-BREF). RESULTS: The YT group obtained significant improvements in positive and negative symptoms of schizophrenia symptoms compared to WL, including PANSS scores on positive syndrome (t=-2.64, p=0.02), negative syndrome (t=-3.04, p<0.01), general psychopathology (t=-3.74, p<0.00), activation (t=-2.29, p<0.04), paranoia (t=-2.89, p<0.01), and depression subscales (t=-2.62, p<0.02). PANSS total scores also decreased for the YT group (t=-4.54, p<0.00). YT had improved perceived quality of life in physical (t=2.38, p<0.04) and psychologic domains (t=2.88, p<0.01). CONCLUSIONS: Adults with schizophrenia being treated in a state psychiatric facility who participated in an 8-week therapeutic yoga program showed significant improvements in psychopathology and quality of life compared with controls. The findings of this study need to be confirmed in larger, more sufficiently powered studies with active control groups. PMID- 21711203 TI - Mindfulness and psychologic well-being: are they related to type of meditation technique practiced? AB - OBJECTIVES: This study examined whether practitioners of two meditation types differ on self-reported mindfulness skills and psychologic well-being. DESIGN: This was a cross-sectional study comparing two convenience meditation groups drawn from local meditation centers, one group practicing mindfulness meditation (MM), and the other practicing transcendental meditation (TM). SETTINGS/LOCATION: The study was conducted at several meditation centers in southern Netherlands. SUBJECTS: Thirty-five (35) participants practiced MM (69% women) and 20 practiced TM (42% women). OUTCOME MEASURES: Participants completed questionnaires on mindfulness skills (Mindful Attention Awareness Scale and two subscales from Kentucky Inventory of Mindfulness Skills), psychologic well-being (perceived stress, global mood, and quality of life), and meditation duration and frequency. RESULTS: All self-reported mindfulness facets correlated with almost all measures of well-being across groups, but no differences were evident between meditation types regarding mindfulness or well-being. Days per week spent on meditation was the only multivariable predictor of both higher mindfulness and lower perceived stress. CONCLUSIONS: The results suggest that self-reported mindfulness and psychologic well-being may be associated with meditation frequency rather than any potential differences when comparing MM and TM in this study. Note that substantial differences between MM and TM groups were present on basic demographics, which were controlled statistically. PMID- 21711204 TI - Acute effects of an Avena sativa herb extract on responses to the Stroop Color Word test. AB - BACKGROUND AND AIMS: Extracts from oat (Avena sativa) herb may benefit cognitive performance. This study investigated whether Neuravena((r)), an oat herb extract, could acutely improve responses to the Stroop Color-Word test, a measure of attention and concentration and the ability to maintain task focus. SUBJECTS AND METHODS: Elderly volunteers with below-average cognitive performance consumed single doses (0, 1600, and 2400 mg) of oat herb extract at weekly intervals in a double-blind, randomized, crossover comparison. Resting blood pressure (BP) was assessed before and after supplementation, and a Stroop test was performed. RESULTS: Significantly fewer errors were made during the color-naming component of the Stroop test after consuming the 1600-mg dose than after the 0-mg or 2400 mg doses (F (1,36)=18.85, p<0.001). In 7 subjects with suspected cognitive impairment, Stroop interference score was also improved by the 1600-mg dose compared to 0- and 2400-mg doses (F (1, 34)=2.40, p<0.01). Resting BP was unaffected by supplementation. CONCLUSIONS: Taking 1600 mg of oat herb extract may acutely improve attention and concentration and the ability to maintain task focus in older adults with differing levels of cognitive status. PMID- 21711205 TI - Treatment of constipation in long-term care with Chinese herbal formula: a randomized, double-blind placebo-controlled trial. AB - OBJECTIVES: This study is aimed to evaluate the therapeutic efficacy and safety of CCH1, modified from an ancient herbal formula in Traditional Chinese Medicine, for the residents with constipation in long-term care. METHODS: In this randomized, double-blind, placebo-controlled trial, 90 residents from three long term care units were randomized to 8 weeks of treatment with CCH1 or placebo and then the subjects were followed up for an additional 4 weeks. RESULTS: The mean numbers of weekly spontaneous bowel movement in the CCH1 group were greater than in the placebo group during the treatment phase of 8 weeks (p < 0.05); the greatest difference was during weeks 1-4 (6.2 +/- 2.2 versus 3.4 +/- 2.1, p < 0.001). Smaller mean numbers of weekly rectal treatments were observed with CCH1 compared with placebo during weeks 1-8 (p < 0.05). The mean numbers of weekly rescue laxative tablets of magnesium oxide were significantly less in the CCH1 group than in the placebo group during the entire 12-week period (p < 0.01), with the greatest difference during weeks 5-8 (14.4 +/- 16.3 versus 33.4 +/- 23.5, p < 0.001). No significant safety concerns were noted. CONCLUSIONS: The six-herb formula (CCH1), compared with placebo, is effective on the treatment of constipation in long-term care. However, its maintenance effect needs further trial. Comparison of efficacy or cost-effectiveness with current laxatives is encouraged. PMID- 21711207 TI - A composite renal tumor: metanephric adenofibroma, Wilms tumor, and renal cell carcinoma: a missing link? AB - A coexistence of different renal tumors has rarely been reported. The most commonly described association is of Wilms tumor and renal cell carcinoma. Metanephric adenofibroma has also been associated with Wilms tumor or papillary renal cell carcinoma. Another reported association is metanephric adenoma and papillary renal cell carcinoma with sarcomatoid dedifferentiation. Herein we describe a complex renal tumor containing areas of metanephric adenofibroma, Wilms tumor, and undifferentiated renal cell carcinoma in a previously healthy 18 year-old boy. The tumor showed histologic and immunohistochemical features of these 3 different tumors, offering additional support to the view that these 3 tumors are related. PMID- 21711209 TI - Cervical ribs are more prevalent in stillborn fetuses than in live-born infants and are strongly associated with fetal aneuploidy. AB - This study was undertaken to determine the prevalence of cervical ribs in stillborn fetuses undergoing autopsy at our institution and to search for significant associations with cervical ribs. European studies have reported an increased prevalence of cervical ribs in patients with childhood cancer and in stillborn fetuses. We reviewed data from autopsies performed at Primary Children's Medical Center, Utah, between 2006 and 2009 on 225 stillborns (>=20 weeks) and 93 deceased live-born infants (<1 year). Digital fetal radiographs in anterior-posterior and lateral views had been taken of each subject. Chi-square analysis and general linear models were used for statistical analysis of the data. The overall prevalence of cervical ribs was higher in stillborns than in live-borns who died in the first year (43.1% vs 11.8%). Karyotypes were available for 93 (41.3%) of the stillborns. Of those, cervical ribs were present in 33 of 76 (43.4%) stillborns with normal karyotype and in 13 of 17 (76.4%) stillborns with aneuploidy. Females with unavailable karyotypes were more likely to have cervical ribs than those with normal karyotypes (P = 0.0002). This greater likelihood was not observed in males. Among the stillborns with normal karyotypes, we found no statistically significant association with gender or gestational age at fetal death. There was also no statistically significant association between congenital anomalies and the presence of cervical ribs. Our findings support the hypothesis that cervical ribs are markers for disadvantageous developmental events occurring during blastogenesis and have been subject to strong negative selection during evolution. PMID- 21711208 TI - Recurrent Johanson-Blizzard syndrome in a triplet pregnancy complicated by urethral obstruction sequence: a clinical, molecular, and immunohistochemical approach. AB - We report on a triplet pregnancy of consanguineous parents with one fetus being affected by recurrent Johanson-Blizzard syndrome (JBS). At autopsy in the 35th gestational week, the affected triplet presented with an especially severe and lethal manifestation of the disorder as compared to his elder affected brother and to cases in the literature, thus exemplifying great interfamilial and intrafamilial phenotypic variability. Arhinencephaly and cystic renal dysplasia associated with urethral obstruction sequence were features not described previously in the literature. In addition to the lack of exocrine acini as the characteristic feature of JBS, the pancreas revealed a resorptive inflammatory reaction with infiltration by eosinophilic granulocytes that focally dispersed onto islets of Langerhans, thus favoring a progressive destructive rather than primary dysplastic process and possibly explaining the occurrence of diabetes mellitus in later life. JBS maps to chromosome 15q15-q21.1 and is associated with mutations in the UBR1 gene. Testing the fetus and the affected sibling revealed a homozygous truncating mutation in UBR1. The resulting absence of the UBR1 protein was confirmed by Western blot. Immunohistochemical staining using a commercial anti-UBR1 antibody demonstrated staining, presumably artifactual. This finding suggests that, until an appropriately validated antibody has been identified, this modality should not be utilized for diagnosis or confirmation of this disorder. PMID- 21711210 TI - MUC1 peptide vaccine mediated antitumor activity in non-small cell lung cancer. AB - Lung cancer is the most common cause of cancer mortality worldwide for both men and women, causing approximately 1.2 million deaths per year. With the existing therapeutic efforts, the long-term survival for lung cancer patients remains low with only 15% surviving for 5 years following diagnosis. Therefore, new therapeutic strategies are needed. One such approach is the development of immune therapy for lung cancer. Immune approaches for lung cancer remain attractive because although surgery, chemotherapy and radiotherapy alone or in combination have response rates in all histological types of lung cancer, relapse is frequent. Immunologic targeting of lung cancer has the potential for nontoxic and specific therapy. Strategies that harness the immune system to react against tumors can be integrated with existing forms of therapy for optimal responses toward this devastating disease. PMID- 21711211 TI - Determinants of health-related quality of life in adults living with HIV in Vietnam. AB - Health-related quality of life (HRQL) is a good indicator to monitor and evaluate healthcare services for adults with HIV/AIDS. This study described HRQL of adults with HIV and its determinants, and compared it with HRQL for the general population. A cross-sectional study with a national multistage sampling of households with and without HIV-positive people was conducted in 2008. Six provinces were purposively selected to represent areas of the country and progressions of HIV epidemics. Households were sampled with probability proportional-to-size, following the selection of rural and urban districts. A total of 820 HIV-positive and HIV-negative adults (mean age: 32.5; 38.7% female) were interviewed. Among 400 HIV-positive people, 52.3% had a history of injecting drugs, and 56.3% were at AIDS stage and receiving antiretroviral treatment (ART). HRQL was measured using the EuroQOL five-dimension questionnaire (EQ-5D). Multiple regression models were purposefully constructed to examine the determinants of HRQL. The EQ-5D index and visual analog scale (VAS) score in less advanced HIV people (0.90, 69.3) and AIDS patients (0.88, 65.2) were significantly lower than those of the general population (0.96, 81.6) (p<0.001). The frequency of reported problems across EQ-5D dimensions in the HIV population (2.4-30.9%) was significantly higher than in the general population (0.7-12.1%). Compared to ART patients, those at earlier HIV stages reported having problems at similar proportions across four HRQL dimensions, except pain/discomfort, where ART patients had a significantly higher proportion. Injecting drug users taking ART perceived lower HRQL score than non-injecting drug users. Multiple regression determined that joblessness (p<0.01) and inaccessibility to health services (p<0.05) were associated with lower HRQL. In addition, involvements in self-help groups significantly improved HRQL among HIV-positive participants (p<0.05). The findings highlight the need to improve the health service referral system and enhance psychological and social supports for patients in early stages of HIV infection in Vietnam. PMID- 21711212 TI - Interventions supporting self and identity in people with dementia: A systematic review. AB - OBJECTIVES: Recently, researchers have started to focus on ways to support self and identity in people with dementia. The purpose of this review is to discuss the main features of existing interventions aiming to support self and identity in people with dementia, to draw conclusions regarding the effectiveness of these interventions and to highlight the implications for future research. METHOD: Systematic review of intervention studies aiming to support self and identity in people with dementia. RESULTS: Ten studies met the inclusion criteria. All reported some benefits to participants. There were significant methodological limitations and study quality was generally low. The interventions varied in terms of participant characteristics, content and outcome measures, making it difficult to draw overall conclusions about effectiveness. CONCLUSIONS: Interventions aiming to support self and identity in people with dementia are currently in the early stages of development. Firm recommendations cannot be made at this time. Further well-designed studies are required to provide more robust evidence. PMID- 21711213 TI - Response actions to difficulties in using everyday technology after acquired brain injury. AB - PURPOSE: People with acquired brain injury (ABI) have difficulties using everyday technology (ET) in daily tasks at home and in society. To support them in managing the demands imposed by using ET, knowledge is needed concerning their response actions to the difficulties. The aim of this study was to explore and describe what characterizes response actions to difficulties using ET, their conditions, and how they influence the experiences of tasks in daily life among people with ABI. METHODS: Interviews and observations were undertaken with 13 persons with an ABI. Data were analysed qualitatively using the constant comparative method. RESULTS: The participants' response actions were categorized as (i) deliberate and organized planning, (ii) random and inflexible repeating (iii), re-evaluating tasks, (iv) explaining difficulties related to others, and (iv) proving and protecting capability. Certain conditions were decisive for the different response actions to be applied and also for their effectiveness in enabling engagement in tasks in daily life. Each participant used several types of response actions and the same action could be applied in several situations. CONCLUSION: To support people with an ABI to manage the demands imposed by using ET, it is important to identify the uniqueness of each client and his or her response actions to difficulties using ET and thereafter adjust the interventions accordingly. PMID- 21711214 TI - Surgical management options and postoperative functional outcomes of petrous apex cholesteatoma. AB - CONCLUSION: In cases of petrous apex (PA) cholesteatoma, radical removal should be prioritized over an unreasonable sparing of hearing or facial symmetry. Nevertheless, for patients with serviceable hearing and spared inner ear structures, conservative approaches may be applicable. Restoration of facial nerve (FN) function is achievable by reanimation procedures. OBJECTIVES: To analyze clinical manifestations, surgical techniques, and postoperative functional results of PA cholesteatoma. METHODS: From 1987 to 2010, 13 cases of PA cholesteatoma underwent operations. Clinical, audiological, and radiological findings, surgical approach, and postoperative functional outcomes were analyzed retrospectively. RESULTS: The most common symptoms were hearing loss and FN paralysis. All PA cholesteatomas extended to the middle ear; 10 (76.9%) through the anterior-superior route, whereas the other 3 (23.1%) were through the posterior-superior route. In 10 patients, labyrinthectomy was inevitable because of inner ear invasion. However, three limited cholesteatomas were removable via the middle cranial fossa or transmastoid approach without changing the bone conduction threshold. Among six cases with FN paralysis, one underwent interposition graft, two FN decompression, and the others hypoglossal-FN anastomosis. One FN decompression case recovered to House-Brackmann grade I, and all other reanimation cases finally presented with grade IV. There were no major complications or recurrences during the follow-up period. PMID- 21711215 TI - Modified therapeutic community aftercare for clients triply diagnosed with HIV/AIDS and co-occurring mental and substance use disorders. AB - This clinical trial evaluated a modified therapeutic community aftercare (MTC-A) program for a population triply diagnosed with HIV/AIDS, a substance use disorder, and a mental disorder. After six months of MTC residential treatment (MTC-R), subjects were randomly assigned to MTC-A (n=42) or to standard aftercare (C; n=34). Follow-up interviews at six and 12 months assessed eight outcome domains and adherence to prescribed HIV medication. A propensity model was used to re-balance the retrieved sample. At the six-month follow-up, High stratum MTC A clients (those with greater psychological functioning and stable physical health at baseline) had greater improvement overall and for substance use and mental health than C clients in the same stratum. In contrast, C clients in the Low/Medium stratum (those with poorer psychological functioning and improved physical health) had more favorable outcomes overall and for substance use than their MTC-A counterparts; however, this stratum was not re-balanced effectively. Differences in HIV medication adherence were not detected. Clients with greater psychological functioning and stable health at treatment entry benefit more from the MTC-A program. In view of the potentially progressive nature of HIV, measuring physical and mental health during treatment and controlling for changes could be important in future research. PMID- 21711216 TI - Muscle-driven finite element simulation of human foot movements. AB - This paper describes a finite element scheme for realistic muscle-driven simulation of human foot movements. The scheme is used to simulate human ankle plantar flexion. A three-dimensional anatomically detailed finite element model of human foot and lower leg is developed and the idea of generating natural foot movement based entirely on the contraction of the plantar flexor muscles is used. The bones, ligaments, articular cartilage, muscles, tendons, as well as the rest soft tissues of human foot and lower leg are included in the model. A realistic three-dimensional continuum constitutive model that describes the biomechanical behaviour of muscles and tendons is used. Both the active and passive properties of muscle tissue are accounted for. The materials for bones and ligaments are considered as homogeneous, isotropic and linearly elastic, whereas the articular cartilage and the rest soft tissues (mainly fat) are defined as hyperelastic materials. The model is used to estimate muscle tissue deformations as well as stresses and strains that develop in the lower leg muscles during plantar flexion of the ankle. Stresses and strains that develop in Achilles tendon during such a movement are also investigated. PMID- 21711217 TI - Twelve tips for teaching expertise in clinical reasoning. AB - BACKGROUND: Clinical reasoning is one of the most critical skills to teach to medical learners, yet clinician educators rarely receive adequate training on how to teach this topic. AIMS: To enhance clinician educators' ability to teach clinical reasoning. METHODS: I conducted a review of cognitive, medical decision making, and expertise theory literature to develop practical tips that could be applied to typical teaching encounters. RESULTS: Through the literature review, twelve tips were designed to provide a blueprint for teaching clinical reasoning on the wards or in the clinics. CONCLUSIONS: Teaching clinical reasoning is important and feasible. Teachers who explicitly teach problem solving and decision making may help learners to improve their diagnostic accuracy and treatment choices. PMID- 21711218 TI - Problem-based learning in evidence-based medicine courses at Lanzhou University. PMID- 21711219 TI - The development of copper radiopharmaceuticals for imaging and therapy. AB - The increasing use of positron emission tomography in preclinical and clinical settings has widened the demand for radiopharmaceuticals with high specificity that can image biological phenomena in vivo. While many PET tracers have been developed from small organic molecules labeled with carbon-11 or fluorine-18, the short half-lives of these radionuclides preclude their incorporation into radiotracers, which can be used to image biological processes that are not induced immediately after system perturbation. Additionally, the continuing development of targeted agents, such as antibodies and nanoparticles, which undergo extended circulation, require that radionuclides with half-lives that are complimentary to the biological half-lives of these molecules be developed. Copper radionuclides have received considerable attention since they offer a variety of half-lives and decay energies and because the coordination chemistry of cooper and its role in biology is well understood. However, in addition to the radiometal chelate, a successful copper based radiopharmaceutical depends upon the chemical structure of the entire radiotracer, which may include a biologically important molecule and a chemical linker that can be used to deliver the copper radionuclide to a specific target and modulate its in vivo properties, respectively. This review discusses the development of copper radiopharmaceuticals and the importance of factors such as chemical structure on their pharmacokinetics in vivo. PMID- 21711220 TI - Radiopharmaceutical chemistry with iodine-124: a non-standard radiohalogen for positron emission tomography. AB - Positron emission tomography (PET) is a powerful molecular imaging technology with the ability to image and monitor molecular events in vivo and in real time. With the increased application of PET radiopharmaceuticals for imaging physiological and pathological processes in vivo, there is a demand for versatile positron emitters with longer physical and biological half-lives. Traditional PET radionuclides, such as carbon-11 ((11)C) and fluorine-18 ((18)F), have relatively short half-lives (20 min and 110 min, respectively). Among the currently available positron emitters, the non-standard radiohalogen iodine-124 ((124)I) has the longest physical half-life at 4.2 d. This, combined with the well characterized radiochemistry of radioiodine, is contributing to the increasing utility of (124)I in investigating slow and complex pharmacokinetic processes in clinical nuclear medicine and small animal PET imaging studies. This review will summarize the progress to date on the potential of (124)I as a positron emitting nuclide for molecular imaging purposes, beginning with the production of (124)I. Particular emphasis will be placed on the basic radiochemistry as it applies to the production of various (124)I-labeled compounds, from small molecules, to biomolecules such as peptides and proteins, and finally to macromolecules like nanoparticles. The review will conclude by highlighting promising future directions in using (124)I as a positron emitter in PET radiochemistry and molecular imaging. PMID- 21711221 TI - 89Zr radiochemistry for positron emission tomography. AB - The positron emitting isotope (89)Zr is an ideal radionuclide for use in positron emission tomography (PET) imaging with monoclonal antibodies (mAbs). This article reviews the cyclotron physics of (89)Zr production, and the chemical separation methods for isolating it from yttrium target material. (89)Zr coordination with the bifunctional chelate desferrioxamine B is discussed, along with the common procedures for attaching the chelate to mAbs. The review is intended to detail the procedure for creating (89)Zr labeled mAbs, going from cyclotron to PET. PMID- 21711223 TI - Positron emitting [68Ga]Ga-based imaging agents: chemistry and diversity. AB - Positron Emission Tomography (PET) field and, in particular utilization of (68)Ga radiometal is getting momentum. The development of new imaging agents for targeted, pre-targeted, non-targeted imaging and their clinical applications is accelerating worldwide. The pharmacopoeia monographs regarding generator produced (68)Ga radionuclide and (68)Ga-labeled somatostatin (SST) analogues are in progress. The number of commercial generators and automated synthesizers for (68)Ga-labeling chemistry is increasing constantly. Development of a molecular imaging agent is a complex process including identification of the biological target, respective lead compound, synthesis of the imaging agent, its chemical characterization, pre-clinical, and clinical evaluation. The introduction of new radiopharmaceuticals and their accessibility are important factors determining the expansion of clinical nuclear medicine for early disease detection and personalized medicine with higher therapeutic efficiency. Further, the availability of the technology for GMP compliant automated tracer production can facilitate the introduction of new radiopharmaceuticals due to the ability to conduct standardized and harmonized multi-center studies for regulatory approval. This review reflects on the current status of (68)Ga in PET field with the focus on the achievements in the chemistry as well as diversity and potential of the resulting tracers. PMID- 21711222 TI - 86Y based PET radiopharmaceuticals: radiochemistry and biological applications. AB - Development of targeted radionuclide therapy with (90)Y labeled antibodies and peptides has gained momentum in the past decade due to the successes of (90)Y ibritumomab tiuxetan and (90)Y-DOTA-Phe(1)-Tyr(3)-octreotide in treatment of cancer. (90)Y is a pure beta(-)-emitter and cannot be imaged for patient-specific dosimetry which is essential for pre-therapeutic treatment planning and accurate absorbed dose estimation in individual patients to mitigate radiation related risks. This review article describes the utility of (86)Y, a positron emitter (33%) with a 14.7-h half-life that can be imaged by positron emission tomography and used as an isotopically matched surrogate radionuclide for (90)Y radiation doses estimations. This review discusses various aspects involved in the development of (86)Y labeled radiopharmaceuticals with the specific emphasis on the radiochemistry and biological applications with antibodies and peptides. PMID- 21711225 TI - Radiochemistry for positron emission tomography. PMID- 21711224 TI - Labeling strategies with F-18 for positron emission tomography imaging. AB - The labeling of probes with fluorine-18 [(18)F, beta(+); 96.7%] continues to play a considerably important role in the development of positron emission tomography (PET) as a modality for both clinical research and clinical diagnoses. This review summarizes the strategies and recent developments in the fluorine-18 labeling of probes for PET imaging. Problems and issues relating to the practical production of fluorine-18 currently in widespread use are also discussed. PMID- 21711226 TI - Targeting the central nervous system with herpes simplex virus / Sleeping Beauty hybrid amplicon vectors. AB - The pursuits of sustainable treatments for diseases and disorders that afflict the central nervous system (CNS) have proven challenging for the field of viral vector-based gene therapy. However, recent advances in viral vector technology coupled with efficient delivery methods have opened up new avenues that show promise at the preclinical testing stage. The development of the Herpes Simplex Virus/Sleeping Beauty (HSV/SB) hybrid vector represents such an advance for devising treatments targeting the CNS with its potential for stably integrating large transgenomic segments of DNA within the genomes of transduced cells. In utero administration of this hybrid vector into the embryonic mouse brain has revealed the capacity for widespread transgene dissemination due to the targeting of a neuronal precursor cell population. This unique feature has provided the means to stably express a transgene throughout the brain for prolonged periods, which is a prerequisite for the treatment of progressive CNS disorders. In this review we provide a comprehensive breakdown of the characteristics of the HSV/SB vector system and how it can be efficiently employed in the derivation of CNS targeted gene therapeutic strategies. PMID- 21711227 TI - Local gene delivery for cancer therapy. AB - Gene therapy is an emerging technique with widespread applications in treatment of cardiovascular diseases, monogenic disorder, infectious diseases, and especially cancers. The major challenge for gene therapy is to deliver therapeutic genes to target tissues. Although various gene delivery vectors such as harmless viruses and micro/nano-particles have been developed (i.e. commonly system delivery), concerns remain for the transfection efficiency and stability of those working copies in these vectors. Local gene delivery such as intratumoral infusion, electroporation and implants offers significantly enhanced transfection efficiency with decreased toxicity compared to system delivery and has been broadly used in clinics. In this paper, we reviewed the local gene delivery methods and discussed their distinctive advantages and potential challenges in cancer treatment. PMID- 21711228 TI - Design and pre-clinical development of epitope-based DNA vaccines against B-cell lymphoma. AB - Optimally designed cancer vaccines should combine the best tumor antigens with the most effective immunotherapy agents and delivery strategies to achieve positive clinical results. The unique immunoglobulin (Ig) idiotype on the surface of each B-cell lymphoma represents an ideal tumor-specific antigen for use as a cancer vaccine. It has been theorized that effective cancer vaccines can be developed using the minimum essential subset of T cell and B cell epitopes that comprise the 'immunome', the universe of neoplasm-derived peptides that interface with B and T cells of the host immune system. Idiotypic antigenic determinants of a B-cell lymphoma lie within the hypervariable regions and mainly within the complementarity-determining regions (CDR)s 3. Thus, the CDR3s are considered a "hot spot" of particular interest for construction of subunit vaccines. DNA vaccines, whose safety and tolerability are substantiated in completed and ongoing clinical trials, have emerged as a novel lymphoma vaccine formulation for antigen-specific immunotherapy. The molecular precision tools offered by gene based vaccines allow to explore the use of CDR3 sequence as an anti-lymphoma vaccine. PMID- 21711229 TI - "Legal highs" - new players in the old drama. AB - Recently, a new class of "designer drugs" has emerged on the drug use market, known as "legal highs" or "herbal highs". They include a wide range of products, from natural plant-originated substances to synthetic compounds, that can be purchased both online and from high street retailers. "Legal highs" mimic psychoactive effects of illicit drugs of abuse. However, they are claimed to consist of compounds that are legal to sell, possess and use. Based on the spectrum of their actions on the cognitive processes, mood, and behavior "legal highs" can be classified into three basic categories: amphetamine- and ecstasy like psychostimulants, hallucinogens, and synthetic cannabinoids ("spice"). This review surveys the current state of knowledge regarding the pharmacological properties of "legal highs". It also addresses the negative consequences of using these products. PMID- 21711230 TI - The 2D:4D digit ratio: a biomarker of alcohol and drug abuse? PMID- 21711231 TI - The urokinase receptor system as strategic therapeutic target: challenges for the 21st century. AB - The story that led to the discovery of urokinase receptor (uPAR) system started in 1947 with the report of MacFarlane and Pilling who identified but did not named urokinase (uPA). Today, the uPAR system is recognized as one very important actor in tumourigenesis and is even considered as a valuable tumour marker. Its critical functions justify the important effort of translational research that has produced many inhibitors which unfortunately failed to be transferred in the clinic. However, the role of the uPAR system in cancer development should not shade the vital functions of this system in hematopoietic stem cells mobilization, cognitive functions including language development, inflammation, innate immunity, coagulation and fibrinolysis. All these topics are covered in this special theme issue of the journal Current Pharmaceutical Design that comprises 9 reviews written by leading scientists. Other aspects are also embraced by additional articles including the first attempt to depict the complete atlas of the uPAR interactome, and the regulation of the uPAR system by the LDL receptor-related protein-1 (LRP-1). PMID- 21711232 TI - Urokinase receptor (uPAR) ligand based recombinant toxins for human cancer therapy. AB - The urokinase receptor (uPAR) exerts essential functions in the pathophysiology of cancers and therefore constitutes an important drug target. In order to generate efficient drugs against uPAR, a new approach includes chimeric proteins associating one molecular address to specifically target uPAR and one bacterial or plant toxin that will eventually kill the tumoural cell. Using this frame, several recombinant toxins have been designed namely DTAT, DTAT13, EGFATFKDEL 7 mut, and ATF-SAP. As molecular address, all of these fusion proteins use the amino-terminal fragment of urokinase that binds with high affinity to uPAR through its growth factor domain (GFD). The various toxin moieties were derived from either diphtheria toxin, Pseudomonas exotoxin A (PE38), or saporin. In this review, we describe the rational, design, production and therapeutic anti-cancer potential of these chimeric toxins. PMID- 21711233 TI - The role of the urokinase receptor in epilepsy, in disorders of language, cognition, communication and behavior, and in the central nervous system. AB - As a key component of the plasminogen activation system, uPAR, the receptor for the plasminogen activator of the urokinase type, is involved in many physiological and pathological processes. Besides its classical roles, there has been increased evidence that uPAR or uPAR-associated pathways, participate in the development, in the functioning and in the pathology of the central nervous system. Qualitative and quantitative changes in the expressions of uPAR and of its canonical ligand uPA have been observed in a large variety of epileptic disorders, either in human or in animal models, as well as in other brain diseases (stroke and brain trauma, multiple sclerosis, Alzheimer's disease, cerebral malaria, HIV-associated leukoencephalopathy and encephalitis). The variety of such pathological conditions and the different brain areas and cell types involved, likely reflects the wide range and the complexity of the multiple and somehow intertwined pathophysiological mechanisms related with uPAR. In the mouse, the knock-out of the Upar-encoding gene (Plaur) leads to significant and nearly complete loss in parvalbumin-containing interneurons during brain development. This is associated with increased susceptibility to spontaneous and chemically-induced seizures and with increased anxiety and impaired social interactions. The recent identification of the novel uPAR ligand SRPX2 (Sushi repeat protein, X-linked 2) and the regulation of both the SRPX2 and PLAUR genes by transcription factor FOXP2 has shed novel and exciting insights into the role of uPAR-related molecular networks in rolandic epilepsy, in developmental verbal dyspraxia, in perisylvian polymicrogyria, and generally in disorders of the speech areas and circuits. uPAR, its regulators and partners, as well as other proteins containing Ly-6/uPAR/alpha-neurotoxin domains, represent key entry points for present and future studies not only on speech-related disorders but also on epilepsy and autism spectrum disorders. PMID- 21711235 TI - The urokinase-type plasminogen activator and the generation of inhibitors of urokinase activity and signaling. AB - Urokinase (uPA) was originally identified in human urine for its ability to catalyse the transformation of plasminogen into its active form, plasmin which degrades fibrin and extracellular matrix components. Two major, functionally independent regions have been identified in the uPA molecule: a non-catalytic N terminal region (residues 1-135) and a large catalytic region (residues 159-411) spaced by the "connecting peptide" (residues 136-158). Binding of uPA to its specific surface receptor (uPAR) amplifies cell surface plasminogen activation, thus enhancing pericellular proteolysis. The uPAR, linked to the lipid bilayer via a glycosylphosphatidylinositol anchor, mediates signaling through the assembly of a multiprotein complex with transmembrane receptors, like the integrins, EGFR, GPCRs. Receptor engagement with uPA results in a variety of cell responses, including increased proliferation, survival, migration and invasion. These responses may be enhanced by the concomitant binding of the uPA "connecting peptide" region to alphavbeta5 integrin, thus favoring uPAR-integrin association. Receptors engaged with uPA exhibit a high affinity for vitronectin, stimulating cell adhesion. The uPA/uPAR system is regarded as one of the key systems driving tumour invasion and metastases. Different strategies to prevent the activity of the protease, as well as the interactions of uPAR with integrins and GPCRs have been designed. Many preclinical studies are ongoing and, at least, two uPA related compounds have reached Phase II clinical trials. The aim of this review is to provide a comprehensive picture of the functionally relevant interactions, together with a description of the promising compounds and strategies to control uPA activity and signaling in human pathologies. PMID- 21711234 TI - Development of novel therapeutics targeting the urokinase plasminogen activator receptor (uPAR) and their translation toward the clinic. AB - The urokinase plasminogen activator receptor (uPAR) mediates cell motility and tissue remodeling. Although uPAR may be expressed transiently in many tissues during development and wound healing, its constitutive expression appears to be associated with several pathological conditions, including cancer. uPAR expression has been demonstrated in most solid tumors and several hematologic malignancies including multiple myeloma and acute leukemias.Unlike many tumor antigens, uPAR is present not only in tumor cells but also in a number of tumor associated cells including angiogenic endothelial cells and macrophages. The expression of uPAR has been shown to be fairly high in tumor compared to normal, quiescent tissues, which has led to uPAR being proposed as a therapeutic target, as well as a targeting agent, for the treatment of cancer. The majority of therapeutic approaches that have been investigated to date have focused on inhibiting the urokinase plasminogen activator (uPA)-uPAR interaction but these have not led to the development of a viable uPAR targeted clinical candidate. Genetic knockdown approaches e.g. siRNA, shRNA focused on decreasing uPAR expression have demonstrated robust antitumor activity in pre-clinical studies but have been hampered by the obstacles of stability and drug delivery that have limited the field of RNA nucleic acid based therapeutics. More recently, novel approaches that target interactions of uPAR that are downstream of uPA binding e.g. with integrins or that exploit observations describing the biology of uPAR such as mediating uPA internalization and signaling have generated novel uPAR targeted candidates that are now advancing towards clinic evaluation. This review will discuss some of the pitfalls that have delayed progress on uPAR-targeted interventions and will summarize recent progress in the development of uPAR targeted therapeutics. PMID- 21711236 TI - Regulation of the urokinase receptor (uPAR) by LDL receptor-related protein-1 (LRP1). AB - LDL receptor-related protein (LRP1) is an endocytic receptor for multiple ligands, including proteases, growth factors, apolipoproteins, and extracellular matrix proteins. In some cell types, including neurons, neuron-like cells, and Schwann cells, ligand-binding to LRP1 triggers robust cell-signaling. This "direct" pathway by which LRP1 regulates cell-signaling promotes cell survival and cell migration. LRP1 also regulates the composition of the plasma membrane proteome. Although multiple mechanisms are involved, LRP1 and receptors in the same gene family facilitate the endocytosis of other plasma membrane proteins. When LRP1 regulates the abundance or trafficking of another cell-signaling receptor in the plasma membrane, activation of important cell-signaling pathways may be controlled "indirectly" by LRP1. The urokinase receptor (uPAR) was the first cell-signaling receptor identified as a member of the LRP1-regulated plasma membrane proteome. Because LRP1 down-regulates cell-surface uPAR by facilitating its endocytosis, under some conditions, uPAR-initiated cell-signaling may be inhibited by LRP1. However, the relationship between LRP1 and uPAR is complicated because uPAR endocytosis may be necessary for sustained uPAR-initiated cell signaling. Certain cell-signaling factors, including ERK, phosphatidylinositol 3 kinase, and Rac1 are regulated by LRP1, directly, and indirectly through uPAR. Thus, the predominant effect of LRP1 on cell-signaling, in different cell types, may depend on the abundance of LRP1 and uPAR and on the availability of ligands for LRP1 and uPAR. Opportunities for targeting the uPAR-LRP1 system through drug discovery are discussed. PMID- 21711237 TI - The urokinase receptor interactome. AB - The urokinase receptor (uPAR) was originally identified as the membrane receptor of the serine protease urokinase (uPA), thereby implicated in the plasminogen activation cascade and regulation of pericellular proteolysis. Later on, vitronectin was showed to be another major ligand providing uPAR with a role in cell adhesion. Other unrelated ligands have been subsequently reported including for example factor XII and SRPX2 expanding the functions of uPAR to unexpected biological areas such as the initiation of the coagulation cascade or the regulation of language development. Due to its glycosylphosphatidylinositol (GPI) anchor, uPAR has no intracellular domain and thus exerts its signaling capacity through lateral interactions with other components of the plasma membrane that actually mediate uPAR-induced signals. As yet, a total 42 proteins interacting directly with uPAR can be numbered comprising 9 soluble ligands and 33 lateral partners. The fact that uPAR interacts with members of three major families of membrane receptors i.e. G protein-coupled receptors, receptor tyrosine kinases, and integrins implies that the actual number of components constituting the uPAR interacome is extremely high. For example, 156 factors belong to the integrin adhesome. Moreover, in the light of the wide diversity of the components of the uPAR interactome, uPAR appears to be an essential player of major biological systems including the blood coagulation, complement and plasma kallikrein-kinin cascades. This review describes the soluble ligands and lateral partners of the uPAR interactome, the mechanisms regulating uPAR interactions and their proved and/or potential biological functions. PMID- 21711238 TI - The urokinase receptor system, a key regulator at the intersection between inflammation, immunity, and coagulation. AB - The urokinase plasminogen activator (uPA) and its receptor (uPAR) provide a cell surface integrated multimolecular complex that exerts pleiotropic functions influencing the development of inflammatory, immune, coagulation and fibrinolytic responses. Here we review the evidences indicating a role of the uPA/uPAR system in the regulation of the innate immune system in the inflammation process, of the adaptive immune response, as well as the role of fibrin and fibrin degradation products at the cross-road between coagulation and inflammation. Comparative studies have clearly highlighted the notion that coagulation and immunity are co regulated and intertwined. The implication is that the vertebrate blood clotting system is evolutionarily by product of the innate immune system, where the blood clotting proteases have diverged from those comprising the complement system. Differences have emerged gradually, as shown by the acquisition of unique protein structures, such as kringle domains and gla (glutammic acid) domains, in order to comply with the increasingly complex vertebrate systems and to defend higher organisms against a range of infections and injuries. Plasminogen activation also controls the formation of complement anaphylotoxins (responsibe for vasodilatation, increase of venular permeability and leukocyte chemotaxis) and of bradykinin (which accounts for vasodilatation, increase of venular permeability and pain) by regulating the plasma contact system. The urokinase plasminogen activator and its cellular receptor, expressed on the surface of human leukocytes, provide a functional unit that, by regulating interaction of leukocytes with extracellular matrix, as well as its degradation, is critical for the migration of leukocytes and for their movement in the damaged tissues. PMID- 21711239 TI - Clinical applications of the urokinase receptor (uPAR) for cancer patients. AB - Since decades the urokinase plasminogen activator (uPA) system has been associated with the invasion of malignant cells. The receptor of urokinase (uPAR) is one of the key players in this proteolytic cascade, because it focuses uPA's proteolytic activity to the cell surface and in addition functions as a signaling receptor. uPAR is highly expressed in virtually all human cancers, suggesting possible clinical applications as diagnostic marker, predictive tool of survival or clinical response, and as a target for therapy and imaging. This review summarizes the possibilities of uPAR in clinical applications for cancer patients. PMID- 21711240 TI - The urokinase receptor in hematopoietic stem cells mobilization. AB - The receptor for urokinase plasminogen activator (uPAR) is required in hematopoietic stem/progenitor cells (HSC, HPC) mobilization in the mouse. Indeed, uPAR Ko mice are deficient both in retention and mobilization of HSC and HPC, because uPAR causes their retention in the BM through its interaction with the alpha4beta1 integrin and at the same time its removal promotes their migration. Normally, the membrane signal is cleaved by plasmin which on one side releases the cells from their osteoblasts interaction and on the other produces a cleaved soluble uPAR product that stimulates mobilization. Available data suggest that a similar mechanism may take place in humans. PMID- 21711242 TI - Inhomogeneous molecular distribution in self-spreading lipid bilayers at the solid/liquid interface. AB - Self-spreading lipid bilayers at the solid/liquid interface can be used as a molecular transport medium in targeting nano-devices such as drug delivery and micro-total analytical systems. To gain physico-chemical insight in the self spreading lipid bilayer, we have characterized the distribution of dye-labeled lipids in the upper and lower monolayers of a self-spreading lipid bilayer on a hydrophobic substrate by fluorescence quenching experiments using KI as a quencher. TR-DHPE, a molecule with a dye moiety at the head group, was found to be distributed primarily in the upper layer and accumulated especially at the spreading edge because of high steric repulsion. This resulted in an asymmetric distribution of TR-DHPE in the self-spreading bilayer in both the vertical and lateral directions. By contrast, NBD-PC, bearing a dye moiety at the alkyl chain, was distributed almost symmetrically both vertically and laterally. The observed difference is attributed to the difference in interactions between these molecules in the lower layer and the substrate surface. We have also found that the self-spreading velocity was decreased by the addition of KI. Since the spreading dynamics are determined by the interaction energy between the bilayer and solid substrate, a part of the observed velocity decrease could be explained by the change in the lipid density resulting from the adsorption of the I- anion on the lipid head group, thereby reducing the van der Waals interaction energy. PMID- 21711241 TI - Up-regulation of the cardiac lipid metabolism at the onset of heart failure. AB - Chronic pressure overload and atherosclerosis are primary etiologic factors for cardiac hypertrophy and failure. However, mechanisms underlying the transition from hypertrophy to heart failure are incompletely understood. We analyzed the development of heart failure in mice with chronic pressure overload induced by aortic constriction and compared the results with aged apolipoprotein E-deficient mice suffering from advanced atherosclerosis. We combined cardiac function analysis by echocardiography and invasive hemodynamics with a comprehensive microarray gene expression study (GSE25765-8). The microarray data showed that the onset of heart failure induced by pressure overload or advanced atherosclerosis was accompanied by a strong up-regulation of key lipid metabolizing enzymes involved in fat synthesis, storage and oxidation. Cardiac lipid overload may be involved in the progression of heart failure by enhancing cardiomyocyte death. Up-regulation of the cardiac lipid metabolism was related to oxygen and ATP depletion of failing hearts because anti-ischemic treatment with ranolazine normalized the cardiac lipid metabolism and improved cardiac function. Vice versa, inhibition of cellular respiration and ATP generation by mild thiol blocking with cystamine triggered the cardiac lipid metabolism and caused signs of heart failure. Cardiac tissue specimens of patients with heart failure also showed high protein levels of key fat metabolizing enzymes as well as lipid accumulation. Taken together, our data strongly indicate that up-regulation of the cardiac lipid metabolism and myocardial lipid overload are underlying the development of heart failure. PMID- 21711243 TI - Artificial chaperone polysaccharide nanogels for protein delivery: a thermodynamic study of protein-nanogel interactions using fluorescence correlation spectroscopy. AB - Molecular chaperones selectively trap heat-denatured proteins or their intermediates, primarily by hydrophobic interactions, to prevent irreversible aggregation resulting from macromolecular host (molecular chaperone)-guest (protein) interactions. The molecular chaperone function is an important concept that is expected to lead to breakthroughs in drug delivery systems, especially for protein or peptide delivery in regenerative medicine, such as bone regeneration. We have reported that polysaccharide nanogels act as artificial molecular chaperones. To further clarify the molecular chaperone function of nanogels as protein carriers, the elucidation of nanogel-protein interactions are especially important. Here, we investigated the interaction of a protein with a polysaccharide nanogel using fluorescence correlation spectroscopy at variable temperatures, using fluorescence-labeled bovine serum albumin (BSA) as a model protein. In particular, thermodynamic parameters of the heat-induced complexation of protein with CHP nanogels were evaluated using the van't Hoff plot. The plot shows that the CHP nanogels strongly complexed with heat-denatured BSA. The increased hydrophobicity of the denatured, unfolded protein may prefer complexation with amphiphilic hydrogel nanoparticles over complexation with the completely folded native protein. Thermodynamic parameters suggest that the complexation is entropically driven, rather than enthalpically, under the conditions studied. PMID- 21711244 TI - Characterization of the dehydratase WcbK and the reductase WcaG involved in GDP-6 deoxy-manno-heptose biosynthesis in Campylobacter jejuni. AB - The capsule of Campylobacter jejuni strain 81-176 comprises the unusual 6-deoxy alpha-D-altro-heptose, whose biosynthesis and function are not known. In the present study, we characterized enzymes of the capsular cluster, WcbK and WcaG, to determine their role in 6-deoxy-altro-heptose synthesis. These enzymes are similar to the Yersinia pseudotuberculosis GDP-manno-heptose dehydratase/reductase DmhA/DmhB that we characterized previously. Capillary electrophoresis and MS analyses showed that WcbK is a GDP-manno-heptose dehydratase whose product can be reduced by WcaG, and that WcbK/WcaG can use the substrate GDP-mannose, although with lower efficiency than heptose. Comparison of kinetic parameters for WcbK and DmhA indicated that the relaxed substrate specificity of WcbK comes at the expense of catalytic performance on GDP-manno heptose. Moreover, although WcbK/WcaG and DmhA/DmhB are involved in altro- versus manno-heptose synthesis respectively, the enzymes can be used interchangeably in mixed reactions. NMR spectroscopy analyses indicated conservation of the sugar manno configuration during catalysis by WcbK/WcaG. Therefore additional capsular enzymes may perform the C3 epimerization necessary to generate 6-deoxy-altro heptose. Finally, a conserved residue (Thr(187) in WcbK) potentially involved in substrate specificity was identified by structural modelling of mannose and heptose dehydratases. Site-directed mutagenesis and kinetic analyses demonstrated its importance for enzymatic activity on heptose and mannose substrates. PMID- 21711245 TI - Why does mitochondrial complex I have so many subunits? AB - The prokaryotic and eukaryotic homologues of complex I (proton-pumping NADH:quinone oxidoreductase) perform the same function in energy transduction, but the eukaryotic enzymes are twice as big as their prokaryotic cousins, and comprise three times as many subunits. Fourteen core subunits are conserved in all complexes I, and are sufficient for catalysis - so why are the eukaryotic enzymes embellished by so many supernumerary or accessory subunits? In this issue of the Biochemical Journal, Angerer et al. have provided new evidence to suggest that the supernumerary subunits are important for enzyme stability. This commentary aims to put this suggestion into context. PMID- 21711246 TI - Signal transduction by vascular endothelial growth factor receptors. AB - VEGFs (vascular endothelial growth factors) control vascular development during embryogenesis and the function of blood vessels and lymphatic vessels in the adult. There are five related mammalian ligands, which act through three receptor tyrosine kinases. Signalling is modulated through neuropilins, which act as VEGF co-receptors. Heparan sulfate and integrins are also important modulators of VEGF signalling. Therapeutic agents that interfere with VEGF signalling have been developed with the aim of decreasing angiogenesis in diseases that involve tissue growth and inflammation, such as cancer. The present review will outline the current understanding and consequent biology of VEGF receptor signalling. PMID- 21711248 TI - Fibroblast growth factors and their receptors in cancer. AB - FGFs (fibroblast growth factors) and their receptors (FGFRs) play essential roles in tightly regulating cell proliferation, survival, migration and differentiation during development and adult life. Deregulation of FGFR signalling, on the other hand, has been associated with many developmental syndromes, and with human cancer. In cancer, FGFRs have been found to become overactivated by several mechanisms, including gene amplification, chromosomal translocation and mutations. FGFR alterations are detected in a variety of human cancers, such as breast, bladder, prostate, endometrial and lung cancers, as well as haematological malignancies. Accumulating evidence indicates that FGFs and FGFRs may act in an oncogenic fashion to promote multiple steps of cancer progression by inducing mitogenic and survival signals, as well as promoting epithelial mesenchymal transition, invasion and tumour angiogenesis. Therapeutic strategies targeting FGFs and FGFRs in human cancer are therefore currently being explored. In the present review we will give an overview of FGF signalling, the main FGFR alterations found in human cancer to date, how they may contribute to specific cancer types and strategies for therapeutic intervention. PMID- 21711249 TI - Partnership and cooperation is necessary to improve and expand neurology. AB - BACKGROUND: Brain disorders have a large impact on society, representing one third of the total burden of disease. Neurology is more than before divided into fields of highly specialized branches. OBJECTIVE: To assess the need for co operation in neuromedicine to achieve optimal results for patient treatment, diagnosis and care. DISCUSSION: Co-operation regarding patients with disorders in the brain and nervous system should involve medical specialists, general practitioners, other professionals, patients and carers. Optimal co-operation represents both an institutional and personal challenge. The principle of joint action between several subspecialists should also have consequences for educational systems and requirements. Formalised co-operation is well established in medical research, and principles for good practice in neuroscience have relevance also for clinical medicine. How to organise the optimal treatment is therefore not only a challenge for neurologists, but also for the total health system within hospitals and in society. CONCLUSION: Open-handedness and a willingness to co-operate should be a hallmark for neurologists. PMID- 21711250 TI - Communication and neurology--bad news and how to break them. AB - How to deliver bad news to patients is a crucial part of medical practice. Many neurological diseases are incurable, progressive and result in physical or cognitive disabilities, which pose special challenges in the process of communication. Information about diagnosis, therapy and prognosis should be given in an appropriate setting and tailored to the patient's needs and cognitive level of functioning. Support and advice to the family and a team-oriented approach in the follow-up of neurological patients are of high importance. Patient autonomy, truth disclosure expectations and the access to other sources of information is important aspects that influence communication. There is a need for a special and continuous focus on communication in the education of neurologists with regard to the specific needs of this field. Attention should be given to the consequences of neurological disease as well as to therapy and prognosis. PMID- 21711247 TI - Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution. AB - Inflammation when unchecked is associated with many prevalent disorders such as the classic inflammatory diseases arthritis and periodontal disease, as well as the more recent additions that include diabetes and cardiovascular maladies. Hence mechanisms to curtail the inflammatory response and promote catabasis are of immense interest. In recent years, evidence has prompted a paradigm shift whereby the resolution of acute inflammation is a biochemically active process regulated in part by endogenous PUFA (polyunsaturated fatty acid)-derived autacoids. Among these are a novel genus of SPMs (specialized proresolving mediators) that comprise novel families of mediators including lipoxins, resolvins, protectins and maresins. SPMs have distinct structures and act via specific G-protein seven transmembrane receptors that signal intracellular events on selective cellular targets activating proresolving programmes while countering pro-inflammatory signals. An appreciation of these endogenous pathways and mediators that control timely resolution opened a new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation. In the present review, we provide an overview of the biosynthesis and actions of resolvin E1, underscoring its protective role in vascular systems and regulating platelet responses. We also give an overview of newly described resolution circuitry whereby resolvins govern miRNAs (microRNAs), and transcription factors that counter-regulate pro-inflammatory chemokines, cytokines and lipid mediators. PMID- 21711251 TI - Gender differences in risk-taking behaviour in youth with epilepsy: a Norwegian population-based study. AB - OBJECTIVES: It is well known that behavioural problems and psychiatric disorders occur with greater prevalence in children and adolescents with epilepsy. Youth with epilepsy (YWE) may also be more susceptible to risk-taking behaviour, but this has seldom been studied. The aim of this study was to explore risk-taking behaviour in YWE. MATERIAL AND METHODS: In this study, 19,995 young people (age range: 13-19 years) participated and completed an extensive questionnaire, including The Strengths and Difficulties Questionnaire self-report. A variable, risk-taking behaviour, was identified, including daily consumption of alcohol, substance abuse or having committed a criminal offence such as being in a fight with a weapon, committing a burglary or using threats to obtain money. RESULTS: Two hundred and forty-seven youths reported currently having, or having had, epilepsy (lifetime prevalence: 1.2%). Of these, 8.3% reported daily alcohol consumption (1.0% in controls; P<0.001), 12.4% had tried illegal substances (5.5% of controls; P<0.001), and 19.7% had committed criminal offences (8.5% in controls; P<0.001). A gender difference was found: girls with epilepsy did not exhibit risk-taking behaviour more frequently than controls, but having epilepsy was a risk factor for such behaviour in boys (OR: 3.2). CONCLUSION: Boys with epilepsy exhibit risk-taking behaviour more frequently than controls. Other risk factors for this behaviour were living with a single parent, low family income and psychiatric symptoms. This behavioural association should be addressed as it probably contributes to the negative social outcomes that frequently occur in the adult epilepsy population. PMID- 21711252 TI - Subclinical carotid atherosclerosis and cognitive function. AB - Carotid artery atherosclerosis is a major risk factor for stroke and subsequent cognitive impairment. Recent studies indicate that carotid atherosclerosis without clinical stroke may also be an independent risk factor for cognitive decline and dementia. Ultrasonography is an easily assessable and non-invasive method to measure different stages of the carotid artery atherosclerotic process and is widely used in clinical assessment as well as in epidemiological and clinical research. We give a brief review of studies that have investigated degrees of the subclinical atherosclerosis in the carotid arteries in relation to cognitive function and dementia, and we discuss several possible mechanisms that could explain the association between atherosclerosis and cognitive impairment. PMID- 21711253 TI - Haematological side effects of antiepileptic drug treatment in patients with epilepsy. AB - OBJECTIVES: Little is known about the haematological side effects of the newer antiepileptic drugs (AEDs), but recent case reports have raised concerns regarding the possibility of altered thrombocyte counts or function in some patients during levetiracetam (LEV) treatment. The aim of our study was to investigate haematological changes in patients treated with the newer AEDs, LEV and lamotrigine (LTG), compared with the older AEDs, valproate (VPA) and carbamazepine (CBZ). METHODS: This cross-sectional study included 251 patients with epilepsy of both genders, aged 18-45 years, using AED monotherapy: 52 patients on LEV (31 men, 21 women), 80 on LTG (37 men, 43 women), 90 on CBZ (61 men, 29 women), 29 on VPA (15 men, 14 women), and 79 healthy controls (36 men, 43 women). Haemoglobin (Hb), white blood cells (WBC) and platelet (thrombocyte) counts were estimated. The subjects were recruited from hospitals in south eastern Norway and Innsbruck, Austria. RESULTS: Significantly lower platelet counts were recorded in both men and women on LEV monotherapy. In the LEV group, platelets were 14% lower (40.68 * 10(9) /l lower) than in the control group. There was no difference according to sex or age of the patients. Only minor changes in haematological parameters were observed for the other drugs investigated. CONCLUSIONS: Both men and women treated with LEV monotherapy have lower blood platelet counts than healthy controls, with no difference in Hb or WBC. Haematological changes observed with the other AEDs were minor. PMID- 21711254 TI - Ischemic stroke--novel therapeutic strategies. AB - OBJECTIVES: Treatment of acute, ischemic stroke has changed markedly during the last two decades. We review existing data for optimizing modern stroke care. RESULTS: Implementation of stroke units, giving systematic treatment and observation to stroke patients, has lead to a significant reduction in death and dependency. Introduction of intravenous rt-PA (IVT) within 3 h for selected stroke patients and recent extension of the time window to 4.5 h improved the outcome even further. Still, one must consider that IVT has several limitations, such as a narrow time window and several contraindications, and the effect is modest, particularly in strokes with a large vessel occlusion. Recanalization of the occluded vessel is a major predictor for good outcome and should be set as a goal. Intra-arterial rt-PA (IAT) and the concept of bridging therapy (IVT prior to IAT or thrombectomy with a mechanical device) may improve recanalization rates and outcome. Randomized controlled trials (RCT) are available for IAT, but not for thrombectomy with devices, and we mostly have retrospective non-controlled data. The Merci- and Penumbra system are the most studied devices, for which recent studies report acceptable safety and efficacy. CONCLUSIONS: Sufficiently powered RCTs to evaluate the effect of thrombectomy with mechanical devices are warranted, but as the natural course of a large vessel stroke carries a devastating prognosis, a proactive recanalization approach is justified based on today's knowledge. PMID- 21711255 TI - A randomized controlled trial on medication-overuse headache: outcome after 1 and 4 years. AB - BACKGROUND: Different opinions exist regarding the optimal treatment of patients with medication-overuse headache (MOH). Few studies have evaluated the long-term prognosis among these patients, and there are no standard measures of outcome in such studies. AIM: To summarize the 1- and 4-year outcome of patients with MOH previously included in a randomized follow-up study. MATERIAL AND METHODS: Sixty one patients with MOH were randomly assigned to receive either preventive treatment from day 1 without detoxification, a standard out patient detoxification program without preventive treatment from day 1, or no specific treatment. Sixty patients still alive were invited to a 4-year follow-up, whereof 50 (83%) participated. RESULTS: Early introduction of preventive treatment effectively reduced headache days and in particular headache suffering both during the first months and at 12-month follow-up. At 4-year follow-up, 16 persons (32%) were considered as responders (i.e. >=50% reduction in headache frequency from baseline), whereas 17 persons (34%) met the criteria for MOH. None of the baseline characteristics consistently influenced all five outcome measures. DISCUSSION: Early introduction of prophylactic medication was an effective way to reduce headache days during the first 3 months, and the notion that patients with MOH need withdrawal of analgesics to respond to preventive medication seems to be incorrect. The long-term prognosis during the 4-year follow-up was relatively favorable as there was a steady decline in headache, one third of the patients with MOH having >=50% reduction in headache frequency from baseline and two-thirds being without medication overuse. PMID- 21711256 TI - Multiple sclerosis, a cause of secondary osteoporosis? What is the evidence and what are the clinical implications? AB - BACKGROUND: Both women and men with multiple sclerosis (MS) are at increased risk of developing osteoporosis. METHODS: A non-systematic review of the prevalence,pathogenesis and treatment of osteoporosis in patients with multiple sclerosis. RESULTS: MS and osteoporosis share aetiological risk factors such as smoking and hypovitaminosis D, as well as pathogenetic players such as osteopontin and osteoprotegerin. Recently, low bone mineral density (BMD) values have been measured shortly after diagnosis of clinically isolated syndrome and MS and in fully ambulatory persons with MS below 50 years of age. Studies consistently show that BMD at the femoral neck decreases with increasing MS related disability. Osteoporosis-related fractures cause increased morbidity and mortality and add to the burden of having MS. CONCLUSION: We argue that MS, like a number of other chronic diseases, is a cause of secondary osteoporosis. Therefore, bone health assessment should be a part of the integral management of persons with MS. We suggest that BMD be measured shortly after diagnosis, that BMD measurements be repeated depending on BMD values and individual osteoporosis risk profile, and that serum 25-hydroxyvitamin D be monitored. All persons with MS should receive bone health advice. PMID- 21711257 TI - Botulinum toxin treatment of secondary headaches and cranial neuralgias: a review of evidence. AB - BACKGROUND: Recent scientific data support an effect of botulinum neurotoxin (BoNT) on pain and headache. OBJECTIVE: We sought to conduct a systematic review of BoNT in the secondary headaches and cranial neuralgias. METHODS: MEDLINE, EMBASE, Cochrane, ClinicalTrials.gov and reference lists were searched up to December 2010 to identify all relevant publications. RESULTS: Only two papers were rated as highest evidence (Level 1). The absolute majority (30/38, 79%) of identified publications yield only low evidence (Level 4). DISCUSSION: No treatment recommendations of Grade A or Grade B can be made based on available research. Grade C treatment recommendations in support of BoNT can be made for chronic headache attributed to whiplash injury, cephalalgic alopecia areata, headache and facial pain in blepharospasm, trigeminal neuralgia, occipital neuralgia and nummular headache. As a result of studies being troublingly inconsistent or inconclusive, only the weakest rank of recommendations (Grade D) can be made for using BoNT in medication overuse headache, cervicogenic headache, headache attributed to craniocervical dystonia, pain in masticatory hyperactivity and headache or facial pain attributed to temporomandibular disorder. CONCLUSION: At present, BoNT cannot be firmly recommended as an evidence-based treatment in secondary headaches or cranial neuralgias. PMID- 21711258 TI - What initiates a migraine attack? Conclusions from four longitudinal studies of quantitative EEG and steady-state visual-evoked potentials in migraineurs. AB - OBJECTIVES: Quantitative electroencephalograpic (QEEG) frequency spectra and steady-state visual-evoked potentials (SSVEP) are indicators of corticothalamic excitability (e.g., arousal). Increased interictal excitability is suggested to be an important element in the migraine pathophysiology. In this paper, we summarize our results from four studies of QEEG and SSVEP recordings in migraineurs interictally and in the days before an attack with the intention to shed light on attack-initiating mechanisms. MATERIAL AND METHODS: Thirty-two healthy controls, 33 migraineurs without and eight with aura each had three EEGs with photic stimulation on different days. Using the patient headache diaries, we classified the recordings as interictal, preictal, ictal, or post-ictal retrospectively. Interictal recordings were compared pairwise with attack-related EEGs from the same patient as well as with control EEGs. We also correlated clinical variables with the QEEG and SSVEP data. RESULTS: Between attacks, we found increased relative theta activity and attenuated medium-frequency photic responses in migraineurs without aura compared with those in controls. Within 36 h before the attack, slow and asymmetric EEG activity developed. Increased trigger sensitivity and photophobia correlated with higher theta power and depressed photic responses. Attack duration, migraine history duration, and pain intensity were associated with EEG slowing. CONCLUSIONS: A general tendency toward EEG slowing and depression of photic responses characterized the migraine group. This pattern was also related to increased severity of symptoms. A change in cortical activity occurred within 36 h before attacks. Our results indicate that thalamocortical hypoexcitability is associated with attack initiation and sensory hypersensitivity in migraine. PMID- 21711259 TI - Nerve biopsy--some comments on procedures and indications. AB - Nerve biopsy is most often a final step in the evaluation of patients with peripheral neuropathy. The procedure should always be expected to result in varying degree of sensory loss within the innervation area of the biopsied nerve and chronic pain in the area may also occur. Therefore appropriate informed consent must be obtained and a weighing of such side effects and benefits for the patient, particularly therapeutical consequences, should be seriously considered before the procedure is performed. The surgical procedure and the processing in the laboratory of the nerve material must hold a high standard at all levels. Nerve biopsy should not be performed before adequate clinical, electrophysiological and laboratory investigations have been performed. The choice of nerve is important, but in most instances the sural nerve is biopsied, although the superficial peroneal nerve is also an option and allows an easy access to muscle biopsy in the same procedure. Laboratories performing nerve biopsies should have the facilities and expertise to prepare and evaluate fixed and frozen sections (paraffin, cryostat and epoxy-sections) and teased fibers, and also to perform light and electron microscopy and immunohistochemistry. Although not routinely used, the option of morphometry should be available as well. We recommend that properly trained technicians start the processing procedures in the operating room and, if feasible, even in hospitals outside that of the hospital with nerve laboratory. We also prefer routine use of teased fiber analysis as this visualizes in an excellent way pathological processes like axonal degeneration, demyelination and remyelination as well as other features. Evaluation of small fiber neuropathy is rarely an indication for nerve biopsy and should be investigated with skin biopsy and visualization and quantification of intraepidermal nerve fibers. Investigation of inflammatory neuropathy, particularly to demonstrate nerve vasculitis, is the main indication of nerve biopsy. PMID- 21711260 TI - Cardiovascular and urological dysfunction in spinal cord injury. AB - OBJECTIVE: A spinal cord injury (SCI) above the sixth thoracic vertebra interrupts the supraspinal control of the sympathetic nervous system causing an imbalance between the sympathetic and the parasympathetic nervous system. This article focuses on the symptoms, treatment and examination of autonomic disturbances of the cardiovascular and the urinary system after a SCI. METHODS: A non-systematic literature search in the PubMed database. RESULTS: Frequent complications in the acute phase of cervical and high thoracic SCI are bradyarrhythmias, hypotension, hypothermia/hyperthermia, increased neurogenic shock, vagovagal reflex, supraventricular/ventricular ectopic beats, vasodilatation and congestion. Serious complications in the chronic phase of SCI are orthostatic hypotension, impaired cardiovascular reflexes, autonomic dysreflexia (AD), reduced sensation of cardiac pain, loss of reflex cardiac acceleration, quadriplegic cardiac atrophy due to loss of left ventricular mass and pseudo-myocardial infarction. AD is associated with a sudden, uncontrolled sympathetic response, triggered by stimuli below the injury. It may cause mild symptoms like skin rash or slight headache, but also severe hypertension, cerebral haemorrhage and death. Early recognition and prompt treatment are important. Urinary autonomic dysfunctions include hyperreflexia or areflexia of detrusor and/or sphincter of the bladder. CONCLUSIONS: Patients with SCI have a high risk of cardiovascular complications, AD and urinary autonomic dysfunction both in the acute phase and later, affecting their prognosis and quality of life. Knowledge of cardiovascular and urological complications after SCI is important for proper diagnosis and treatment. PMID- 21711261 TI - Fractures and falls in patients with newly diagnosed clinically isolated syndrome and multiple sclerosis. AB - BACKGROUND: Increased risk of falls and reduced bone strength may both contribute to enhanced fracture risk in patients with multiple sclerosis (MS). Fall tendency and fractures have not been investigated in newly diagnosed patients. OBJECTIVES: The aim was to compare the fall tendency and fracture risk in a cohort of newly diagnosed clinically isolated syndrome (CIS) and MS patients with that in the general population. METHODS: We performed a population-based case-control study in Oslo of self-reported fall tendency and fracture history in consecutive patients diagnosed with either a CIS suggestive of demyelinating disease or MS between January 2005 and January 2008. Two age-, sex-, and ethnicity-matched control groups were included; one group from the population registry and one group recruited by the patients. RESULTS: Ninety-nine patients (mean time since the first symptom 1.6 +/- 1.3 years, mean expanded disability status scale [EDSS] score 1.4 +/- 1.1) and 159 controls were included. Whereas no difference in the number of fractures was reported, 20% of the patients and 3% of the controls reported a tendency to fall (P<0.001). Fall tendency was associated with degree of disability (mean EDSS score among patients with and without self-reported fall tendency was 2.4 +/- 1.4 and 1.1 +/- 0.9, respectively; P=0.001). Fall tendency was also reported in two of 22 patients with EDSS 0. CONCLUSIONS: Fall tendency may occur early in the disease course of MS, before impairment of locomotion and balance becomes evident on clinical examination. PMID- 21711262 TI - Onconeural antibodies in patients with neurological symptoms: detection and clinical significance. AB - BACKGROUND: Onconeural antibodies are strongly associated with cancer and paraneoplastic neurological syndromes (PNS). Most of these antibodies are well characterized (antibodies against Hu, Yo, Ri, CRMP5, amphiphysin, Ma2 and Tr) and are in common use for the diagnosis of definite PNS. MATERIALS AND METHODS: Literature on detection and clinical significance of onconeural antibodies were identified by using relevant search terms in PubMed and reviewed. CONCLUSIONS: The onconeural antibodies are directed against intracellular antigens and their pathogenic role is still largely unknown. They are highly specific markers of paraneoplastic aetiology in patients with neurological symptoms. Detection of an onconeural antibody in a patient with neurological symptoms should lead to prompt investigation for cancer. However, absence of detectable onconeural antibodies does not exclude the PNS diagnosis. In particular, failure to detect antibodies in patients without classical PNS symptoms may result in less vigorous cancer screening and diagnostic delay. Neuronal antibodies that are directed to synaptic proteins or proteins of the cell membrane are also associated with neurological symptoms, and probably have pathogenic effects. The association between these antibodies and cancer is less robust, and they are usually not included among the onconeural antibodies. PMID- 21711263 TI - Bone health in adults with epilepsy. AB - Patients with epilepsy have a 2-6 times greater risk of bone fractures compared with the general population. There are several potential explanations. Some fractures are caused by seizure-related injuries, or they may be associated with the osteopenic effect of reduced physical activity in patients with epilepsy. Antiepileptic drugs (AEDs), especially those that affect the liver enzymes, e.g., phenytoin, carbamazepine, phenobarbital, as well as valproate, are also associated with increased fracture rate and low bone mineral density. Many patients with epilepsy and general practitioners seem unaware of this problem. Measurements of bone density should be taken regularly in patients at risk of developing osteoporosis. Non-pharmaceutical initiatives, such as partaking in regular physical activity and eating a well-balanced diet, should be recommended. The risk of developing osteoporosis should be taken into consideration in the selection of an AED for treating a newly diagnosed patient with epilepsy. PMID- 21711264 TI - Oral topiramate as an add-on treatment for refractory status epilepticus. AB - OBJECTIVES: Oral anti-epileptic drugs (AED) represent possible add-on options in refractory status epilepticus (SE). We report our experience in using topiramate (TPM) to treat SE unresponsive to sequential trials of multiple agents. MATERIALS AND METHODS: Over 57 months, we identified 11 SE patients treated with TPM in our hospital, all of them suffered from SE refractory to at least two treatments, and six had generalized SE. Nine patients were managed in the ICU and required intubation. RESULTS: We found a definite electro-clinical response in 2/11 patients, already evident after 12-96 h after TPM introduction, and a possible response in 2/11 patients (concomitantly with other AEDs); 7/11 did not respond. Partial-complex SE appeared to better respond than generalized-convulsive SE. One patient developed a severe nephrolithiasis. CONCLUSIONS: As compared to previous small series describing only patients responding to TPM, this unselected observation underscores the difficulty of treating refractory SE, regardless of the agent. PMID- 21711265 TI - In this issue: Equine influenza in Australia in 2007--the definitive story. PMID- 21711266 TI - Special issue: Equine influenza in Australia in 2007. Foreword. PMID- 21711267 TI - Overview of the 2007 Australian outbreak of equine influenza. AB - In August 2007 equine influenza (EI) was diagnosed in Australia's horse population following the failure to contain infection in quarantine after the importation of one or more infected horses. The response had many unique features, and addressed financial, social, economic, human and animal health, trade and recovery issues. The outbreak and the associated control measures had a vast impact on individual horse owners, the horse industry and associated sectors in both infected and uninfected states. PMID- 21711268 TI - Diagnosis of equine influenza virus infections in quarantine stations in Australia, 2007. AB - In August 2007, several horses showed pyrexia and respiratory signs while in post arrival quarantine in Australia. Subsequent investigations diagnosed equine influenza by serology and PCR in two quarantine stations. A common origin in a shipment of horses from Japan was indicated. PMID- 21711269 TI - The first five days: field and laboratory investigations during the early stages of the equine influenza outbreak in Australia, 2007. AB - Until August 2007, Australia was one of only three countries internationally recognised to be free of equine influenza (EI). This report documents the diagnosis of the first cases of EI in Australian horses and summarises the investigations that took place over the next 5 days. During that time, a multifocal outbreak was identified across eastern New South Wales and south eastern Queensland. The use of an influenza type A pan-reactive real-time reverse transcription polymerase chain reaction allowed rapid confirmation of suspect cases of EI. PMID- 21711270 TI - Equine influenza in Australia: a clinical overview. AB - The clinical symptoms observed during the 2007 equine influenza outbreak are compared and contrasted with those observed in overseas outbreaks and described in the veterinary literature. PMID- 21711271 TI - Behaviour of equine influenza virus in a naive population: a practitioner's perspective. AB - We describe the behaviour of equine influenza (EI) virus infection in a naive population as observed by equine veterinary practitioners. The clinical signs displayed by infected horses and the highly contagious nature of the disease are discussed, as well as the treatment and management of infected horses. PMID- 21711272 TI - Equine influenza: a clinical perspective in Centennial Parklands Equestrian Centre. AB - The clinical signs of horses diagnosed with equine influenza (EI) at Centennial Parklands Equestrian Centre (CPEC) and the events surrounding their diagnosis are described. This was the site of the first case of EI diagnosed outside of the Eastern Creek Animal Quarantine Station. The clinical data demonstrate the rapid spread of the disease after a sufficient viral load had developed from the initial cases within CPEC. PMID- 21711273 TI - Clinical impression of equine influenza at Morgan Park and the western region of Brisbane, Queensland, Australia. AB - The clinical signs of horses infected with equine influenza in two Queensland locations, Morgan Park Recreational Grounds at Warwick, and the western region of Brisbane, are described and compared. Clinical signs were observed to be more severe, and treatment more intensive, in horses in stressful settings. PMID- 21711274 TI - Clinical signs of equine influenza in a closed population of horses at a 3-day event in southern Queensland, Australia. AB - This report describes the clinical signs of equine influenza (EI) during an epidemic in a closed, predominantly immunologically naive population of horses. It included 254 study horses, few of which exhibited all three signs of pyrexia, nasal discharge and cough simultaneously. We conclude that although the majority of affected horses exhibit temperature patterns resembling those most often described in the published literature, clinicians should be aware that other profiles are quite common. PMID- 21711275 TI - Pathological changes in horses dying with equine influenza in Australia, 2007. AB - Analysis of pathology results from the 2007 equine influenza (EI) outbreak in Australia indicate that young foals in naive horse populations are prone to developing broncho-interstitial pneumonia, and that this can be a rare manifestation of EI virus infection in mature horses. All horses may develop secondary bacterial bronchopneumonia, with mature horses more likely to die. EI outbreaks among heavily pregnant mares can result in increased neonatal losses because of premature placental separation and dystocia causing fetal hypoxia. PMID- 21711276 TI - Longitudinal study describing the clinical signs observed in horses naturally infected with equine influenza. AB - We describe the clinical signs and disease course during an outbreak of equine influenza (EI) in naive horses in a police stables in Sydney, New South Wales, Australia. PMID- 21711277 TI - Internet-based survey of horse owners for mortality and morbidity related to equine influenza in the 2007 Australian epidemic. AB - Anecdotally, some sections of the horse community were under the impression that there was a high mortality rate in horses in 2007 because of the EI epidemic. A survey of horse deaths in the Hunter Valley of New South Wales (NSW) in 2007 indicated that there were few infections and deaths attributable to equine influenza (EI) infections in foals, but other authors found a very high seroprevalence across all age classes. This study aimed to generate objective information on mortality and morbidity rates associated with EI in Australian horses during the 2007 epidemic. PMID- 21711278 TI - Determining the endpoint of an outbreak of equine influenza in a large population of racing Thoroughbreds. AB - Outbreaks of equine influenza (EI) cause major disruption to the racing industry, resulting in cessation of racing until affected horses have recovered from the disease. The introduction of EI to a large population of Thoroughbred horses stabled at a Sydney racecourse provided the opportunity to observe clinical signs and monitor the spread of EI in this predominantly naive population and to assist in determining an endpoint to infection spread to allow resumption of racing events. PMID- 21711279 TI - Infection of dogs with equine influenza virus: evidence for transmission from horses during the Australian outbreak. AB - During the equine influenza (EI) outbreak, respiratory disease was observed in dogs that were in close proximity to infected horses. Investigations were undertaken to exclude influenza virus infection. Of the 23 dogs that were seropositive in tests using the influenza A/Sydney/2007 virus as the test antigen, 10 showed clinical signs. EI virus appeared to be readily transmitted to dogs that were held in close proximity to infected horses, but there was no evidence of lateral transmission of the virus to other dogs that did not have contact with or were not held in close proximity to horses. PMID- 21711280 TI - Role of the diagnostic laboratories during the 2007 equine influenza outbreak in Australia. AB - During the 2007 equine influenza (EI) outbreak in Australia, diagnostic laboratories and the use of appropriate tests played a pivotal role in the response to the crisis. This role began with the detection of EI virus in New South Wales (NSW) on the evening of 24 August 2007 and culminated in providing the final 'proof of freedom' from EI in March 2008. The tests that were used during the EI response were able to provide results quickly, and with high sensitivity and specificity. This section of the supplement describes the roles and functions of the Australian laboratories; tests used and their performance characteristics; improvements made and methods used to validate assays; strategies that were followed during the response; the characterisation of viruses detected; and the resources that were available to laboratories. PMID- 21711281 TI - Responding to the equine influenza outbreak: challenges from a laboratory perspective. AB - The unique challenges that laboratories in Queensland and New South Wales faced during the response to the 2007 equine influenza outbreak and how these were managed are described. PMID- 21711282 TI - Isolation and characterisation of an H3N8 equine influenza virus in Australia, 2007. AB - Before 2007, equine influenza had never been diagnosed in Australia. On 22 August 2007, infection was confirmed in horses at Eastern Creek Animal Quarantine Station near Sydney. The virus subsequently isolated (A/equine/Sydney/2888 8/2007) was confirmed by sequence analysis of the haemagglutinin (HA) gene as an H3 virus of the variant American Florida lineage that is now referred to as Clade 1. The HA sequence of the virus was identical to that of a virus isolated from a contemporaneous outbreak in Japan and showed high homology to viruses circulating in North America. PMID- 21711283 TI - Real-time RT-PCR for detection of equine influenza and its evaluation using samples from horses infected with A/equine/Sydney/2007 (H3N8). PMID- 21711284 TI - Application of high-throughput systems for the rapid detection of DNA and RNA viruses during the Australian equine influenza outbreak. PMID- 21711285 TI - Validation of an influenza virus A 5'Taq nuclease assay for the detection of equine influenza virus A RNA in nasal swab samples. AB - OBJECTIVE: Describe the in-house validation of a previously reported influenza virus type A 5'Taq nuclease assay for detecting equine influenza virus A RNA in nasal swab material. METHODS: The validation compares the 5'Taq nuclease assay with a gel-based reverse transcription nested polymerase chain reaction (PCR) previously reported by the Irish Equine Centre for detection of H3N8 and H7N7 equine influenza viruses. This test was chosen because it targets a different region of the viral genome to the real-time test, so it is not merely a repeat of the same test in a different format. Moreover, nested PCRs are commonly considered to have similar sensitivity to real-time PCRs and are therefore ideal for evaluation comparisons. RESULTS: The sensitivity of the nested PCR was comparable to the 5'Taq nuclease test. Known positive samples and known negative samples reacted with both tests with 100% correlation. Parallel testing of 276 nasal swab samples showed 98% agreement. CONCLUSION: The specificity of the nested amplicons was confirmed by nucleotide sequencing and showed >99.5% identity with the same region of previously published equine influenza virus A sequences. The results of this work are appropriate validation for the acceptance of the real-time PCR for equine influenza A virus in equine nasal swabs. PMID- 21711286 TI - Application of real-time PCR and ELISA assays for equine influenza virus to determine the duration of viral RNA shedding and onset of antibody response in naturally infected horses. AB - During the equine influenza (EI) outbreak, two assays were used in parallel to diagnose the disease, to demonstrate freedom from infection in disease control zones and ultimately to demonstrate that EI virus had been eliminated from the Australian horse population. A longitudinal study of a population of naturally infected horses was established to determine the performance characteristics of these assays. PMID- 21711287 TI - Diagnostic specificity of an equine influenza blocking ELISA estimated from New South Wales field data from the Australian epidemic in 2007. AB - This observational study was undertaken in order to evaluate the diagnostic specificity of the blocking enzyme-linked immunosorbent assay (bELISA) for serum antibodies to influenza A virus nucleoprotein during the equine influenza (EI) outbreak response in New South Wales, Australia, in 2007. Using data collected during the outbreak response, bELISA testing data were collated for assumed uninfected horses from areas where EI infection was never recorded. Diagnostic specificity of the bELISA used during the EI response was high, but varied significantly between some regions, although the reason(s) for this variation could not be determined. PMID- 21711288 TI - Use of a blocking ELISA for antibodies to equine influenza virus as a test to distinguish between naturally infected and vaccinated horses: proof of concept studies. AB - An important consideration in the selection of a vaccine during the Australian equine influenza (EI) outbreak in 2007 was the ability to differentiate between infected and vaccinated animals (DIVA). A blocking enzyme-linked immunosorbent assay (bELISA) targeted for the nucleoprotein of influenza A viruses was developed to differentiate between naturally infected horses and horses vaccinated with the ProteqFlu(r) vaccine, which only induces a response to viral haemagglutinin. This bELISA assay met the DIVA requirements and was used extensively during the EI control and eradication programs and 'proof of freedom' testing. PMID- 21711289 TI - Role of the New South Wales Department of Primary Industries' Laboratory Information Management System (LIMS) in the 2007 equine influenza emergency animal disease response. AB - A Laboratory Information Management System (LIMS) was used to manage the laboratory data and support planning and field activities as part of the response to the equine influenza outbreak in Australia in 2007. The database structure of the LIMS and the system configurations that were made to best handle the laboratory implications of the disease response are discussed. The operational aspects of the LIMS and the related procedures used at the laboratory to process the increased sample throughput are reviewed, as is the interaction of the LIMS with other corporate systems used in the management of the response. Outcomes from this tailored configuration and operation of the LIMS resulted in effective provision and control of the laboratory and laboratory information aspects of the response. The extent and immediate availability of the information provided from the LIMS was critical to some of the activities of key operatives involved in controlling the response. PMID- 21711290 TI - Overview of the epidemiology of equine influenza in the Australian outbreak. AB - This overview of the equine influenza (EI) epidemic as it occurred in two Australian states, New South Wales and Queensland, in 2007 describes the functions and activities of the epidemiology teams that were engaged during the outbreak and also identifies key features of the epidemiology of EI during the outbreak. PMID- 21711291 TI - Significant features of the epidemiology of equine influenza in New South Wales, Australia, 2007. AB - Equine influenza (EI) was first diagnosed in the Australian horse population on 24 August 2007 at Centennial Park Equestrian Centre (CPEC) in Sydney, New South Wales (NSW), Australia. By then, the virus had already spread to many properties in NSW and southern Queensland. The outbreak in NSW affected approximately 6000 premises populated by approximately 47,000 horses. Analyses undertaken by the epidemiology section, a distinct unit within the planning section of the State Disease Control Headquarters, included the attack risk on affected properties, the level of under-reporting of affected properties and a risk assessment of the movement of horses out of the Special Restricted Area. We describe the epidemiological features and the lessons learned from the outbreak in NSW. PMID- 21711292 TI - Analysis of horse movements and events during the 2007 outbreak of equine influenza in New South Wales, Australia. AB - OBJECTIVE: To analyse horse event and horse movement registration data collected between September 2007 and December 2008 during the outbreak of equine influenza in New South Wales, Australia. RESULTS: A total of 9356 events were registered, involving 504,382 horses and 242,952 riders. Registered horse movements totalled 224,084, involving 349,327 horses (excluding mobs) travelling 34.4 million km with an average of 154 km per journey. The number of recorded events and movements were low while movement controls were most stringent, then increased from December 2007 as restrictions were eased, to peak in April 2008 with up to 290 events and 15,730 movements weekly, after which registrations declined as the disease was eradicated. The main types of events registered were pony clubs (38%), race meetings and trials (17%), competition (13%), and clinics and lessons (11%). CONCLUSIONS: Registration of horse events and movements allowed movement controls to be progressively eased while retaining the ability to trace the movements of large numbers of horses if needed. The number of recorded events, movements and distances travelled confirms the highly mobile nature of the recreational horse industries, helps to explain the rapid and widespread dispersal of the disease before movement restrictions were imposed, and also demonstrates the value of those restrictions as a control measure. The data provide a quantitative snap-shot of horse events and movements, albeit distorted by the prevailing movement restrictions as well as by limitations in the data recording that should be addressed when developing traceability systems for horses in future. PMID- 21711293 TI - Spatial association and clinical development of equine influenza in horses yarded overnight at an equestrian event at Maitland prior to propagating the 2007 epidemic in Australia. AB - The interaction and stabling of horses at equine events may have a substantial impact on the spread of a zoonotic disease. This study aimed to investigate the spread of equine influenza (EI) at an equestrian event at the start of the Australian outbreak. Around one-third of the competing horses were stabled overnight at the event and, of these, 70% developed symptoms of EI within 7 days. The index case was never positively identified, but stabling position and disease onset provided clues to its potential identity. PMID- 21711294 TI - Attack risk on infected properties during the 2007 equine influenza outbreak in New South Wales, Australia. AB - The aim of this preliminary study was to estimate the proportions of seropositive horses on infected premises (IPs) in order to assess the attack risk of the disease. Logistic regression analyses were conducted to evaluate the differences in attack risks between enterprise sizes and predefined spatial clusters/regions. The average attack risk experienced during the outbreak was 96.88% (median 100%), but it differed according to the size of the enterprise and other geographic and demographic conditions. The highest attack risks were observed in the Dubbo cluster/region and the lowest in the Narrabri-Northern cluster. Properties with fewer horses were generally more likely to have higher attack risks than larger enterprises, though this was not true for all cluster/regions. PMID- 21711295 TI - Assessment of the proportion of under-reporting during the 2007 equine influenza outbreak in New South Wales, Australia. AB - During the 2007 equine influenza (EI) outbreak in Australia, there was no objective information about the possible under-reporting of cases by horse owners either so that they would avoid movement restrictions or because of their inability to detect infection. This investigation aimed to estimate the proportion of under-reporting during the outbreak based on the results of surveillance undertaken in conjunction with vaccination. The results provided improved estimates of morbidity during the outbreak and indicated the level of under-reporting likely to occur in future outbreaks of other infectious diseases in horses in Australia. PMID- 21711296 TI - Risk of an equine influenza virus reservoir establishing in wild horses in New South Wales during the Australian epidemic. AB - Australia has the world's largest population of wild equids and equine influenza (EI) was confirmed on several properties in New South Wales (NSW) close to uncontrolled areas of land during the 2007 outbreak. Likelihood and risk management assessments were carried out to determine the risk of EI infection of the wild horse populations. The likelihood of spread to the wild horse population was determined to be extremely low, but the likelihood of spread from an established wild horse reservoir back to domestic horses was considered high. The most effective mechanism of control was determined to be prevention of the spread of EI into the wild horse population through a vaccination buffer zone between EI infection foci and known wild horse populations. PMID- 21711297 TI - Significant features of the epidemiology of equine influenza in Queensland, Australia, 2007. AB - An outbreak of equine influenza (EI) caused by influenza A H3N8 subtype virus occurred in the Australian states of Queensland and New South Wales in August 2007. Infection in the Australian horse population was associated with the introduction of infection by horses from overseas. The first case of EI in Queensland was detected on 25 August 2007 at an equestrian sporting event. Infection subsequently spread locally and to other clusters through horse movements prior to the implementation of an official standstill. There were five main clusters of infected properties during this outbreak and several outliers, which were investigated to find the potential mechanism of disease spread. To contain the outbreak, Queensland was divided into infection status zones, with different movement controls applied to each zone. Vaccination was implemented strategically in infected areas and within horse subpopulations. Control and eventual eradication of EI from Queensland was achieved through a combination of quarantine, biosecurity measures, movement control, rapid diagnostic testing and vaccination. PMID- 21711298 TI - Epidemic curve and hazard function for occurrence of clinical equine influenza in a closed population of horses at a 3-day event in southern Queensland, Australia, 2007. AB - The risk of individuals becoming infected during an epidemic of infectious disease can vary as the disease progresses. Monitoring this risk may provide information about the dynamics of transmission. This study describes the epidemic curve for an epidemic of equine influenza (EI) in a closed population of horses predominantly immunologically naive to EI at a 3-day event at Morgan Park in southern Queensland, Australia. The hazard function suggested that a subset of horses were at reduced risk of becoming infected. This highlights the importance, when modelling infectious disease in populations, of considering possible differences in the risk of infection among subgroups in the population. PMID- 21711299 TI - The role of land use patterns in limiting the spread of equine influenza in Queensland during the 2007 Australian epidemic. PMID- 21711300 TI - Surveillance and prevention in a non-affected state: Victoria. AB - The equine influenza outbreak detected in August 2007 in New South Wales and Queensland did not enter Victoria, which was, however, considered at risk because of its sizable border with New South Wales. Accordingly, Victoria implemented a response plan to prevent disease entry and enable early detection of any disease. Horse movement restrictions, surveillance strategies and public awareness formed a large part of this response. PMID- 21711301 TI - The August 2007 equine influenza response management framework. AB - This section outlines the most important issues addressed in the management of the response in the two infected states, New South Wales and Queensland. There were differences in the management of the response between the states for logistic, geographic and organisation structural reasons. Issues included the use of control centres, information centres, the problems associated with the lack of trained staff to undertake all the roles, legislative issues, controls of horse movements, the availability of resources for adequate surveillance, the challenges of communication between disparate groups and tracing the movements of both humans and horses. PMID- 21711302 TI - High-level coordination and strategy in the 2007 equine influenza outbreak response. AB - The equine influenza (EI) outbreak presented many challenges that required high level coordination and decision making, as well as the development of new approaches for satisfactory and consistent resolution. This paper outlines the elements of the national coordination arrangements, preparatory arrangements in place prior to the outbreak that facilitated national coordination, and some of the issues faced and resolved in the response. PMID- 21711303 TI - Industry liaison officers in the infected states of Australia during the 2007 equine influenza outbreak. AB - We describe the activities of persons who were formally employed as industry liaison officers (ILOs) in the infected states of Australia during the 2007 equine influenza outbreak. The knowledge and communication skills of ILOs allowed them to function very effectively, despite most of them having received no prior training. It is arguable, however, that if ILOs had received prior training, they would have performed more effectively sooner. We suggest that more individuals need ILO training in 'peacetime' and that 'just-in-time' training packages require preparation and trial prior to outbreaks to be effective. PMID- 21711304 TI - Quantitative analysis of the risk of spread of equine influenza associated with movements of vaccinated horses from infected areas during the Australian outbreak. AB - Simulation models were developed to quantify the likelihood of equine influenza virus infection entering pre-movement isolation, persisting through pre- and post movement isolation periods without being detected by scheduled laboratory testing, and escaping to infect susceptible horses at a destination. The mean probability of escape ranged from 1 in 1,200,000 to 1 in 600,000 depending on lot size. For 95% of iterations the probability of escape was less than 1 in 200,000, regardless of lot size. For a large group of 600 horses processed as multiple separate lots, the mean probability of escape ranged from 1 in 10,000 to 1 in 56,000 depending on lot size. As a result of this analysis, a modified protocol, with two tests during pre-movement isolation and an additional test during post movement isolation at the Chief Veterinary Officer's discretion, was implemented. PMID- 21711305 TI - Biosecurity and vaccination strategies to minimise the effect of an equine influenza outbreak on racing and breeding. AB - Three biosecurity and relief-and-recovery initiatives adopted by the NSW horse racing industries reduced the economic and social disruption caused by the disease and subsequent movement controls during the 2007 Australian equine influenza (EI) incursion. The first was the creation of biosecure horse training and racing precincts around the Sydney area to permit racing to continue with healthy horses. Infection was excluded for 3-5 weeks and race meetings were conducted safely during this period. The second was a vaccination program of racehorses at these and other precincts to maintain an ongoing healthy pool of racehorses. Vaccination commenced too late to enable viable racing to continue in Sydney in the short term, but assisted in managing an early return to racing throughout the state before EI-free status had been regained. The third was the establishment of approved quarantine stations to facilitate the movement of racing and breeding horses out of high-risk regions. The difficulties in establishing and managing these initiatives in the face of the EI incursion are discussed. PMID- 21711306 TI - Innovative zoning to support equine influenza eradication from New South Wales, Australia. AB - Following detection of equine influenza (EI) in New South Wales, a complete standstill was imposed the next morning on the movement of all horses and donkeys within the state. Premises' biosecurity guidelines became progressively more stringent with time in an effort to stop local spread. The standstill was highly effective as a primary response to stop EI becoming widespread across Australia, but did not prevent spread to properties contiguous to infected premises in areas of high horse density and small property size, nor transmission by fomites nor possible local airborne transmission. Within 2 weeks of the start of the outbreak, a zoning system of Purple (Special Restricted), Red (Restricted), Amber (Control), and Green (Protected) Zones was implemented, and progressively modified as disease distribution changed. The colour coding system proved to be an easy way to communicate zone changes, the approximate level of disease risk and the stringency of movement restrictions to the general public and should be adopted more generally in AUSVETPLAN. PMID- 21711307 TI - Equine influenza immunity in the Special Restricted Area (Purple Zone) of New South Wales, Australia. AB - The 2007 equine influenza (EI) outbreak in New South Wales (NSW) consisted of a central infected area that extended south from the lower New England Tableland, across the Hunter Valley, Central Coast and the Sydney basin, and a series of isolated clusters outside this area across rural NSW. The central area was assigned the status of a Purple Zone (Special Restricted Area, SRA) approximately 1 month after the outbreak commenced. Within this SRA, the eradication program's focus was to increase the proportion of horses immune to EI via vaccination, thus reducing the susceptible proportion to a level below the critical threshold for EI spread. An estimated 84-87% of all horse-owning premises achieved immunity to EI by the end of the outbreak. A high proportion (60-90%) of premises within most parts of the SRA became naturally infected with EI, and the rate of newly infected premises fell to low levels before EI vaccination commenced. Immunity to EI from very rapid natural spread appears to have been the most important factor in disease eradication within the SRA. PMID- 21711308 TI - Role of personal decontamination in preventing the spread of equine influenza. AB - BACKGROUND: During the 2007 equine influenza (EI) outbreak, infected horses were quarantined at Morgan Park Recreational Grounds (MPRG) near Warwick, Queensland. Some individuals caring for horses were reported to have made return journeys between MPRG and home properties containing other horses during the time there was active infection at MPRG. OBJECTIVE: A retrospective cohort study to assess the biosecurity and hygiene measures undertaken and their outcomes. METHODS: All individuals recorded as being responsible for caring for one or more horses at MPRG, and who were also recorded on entry and exit logs at the gate to MPRG during the period of interest, and kept horses at their home property were contacted for a telephone questionnaire. RESULTS: Of the 31 individuals identified, valid responses were obtained from 27 (87% response rate). Respondents had 2-25 horses at their home property, and 1-10 return trips were reported; 11 respondents reported contact with horses at home and provided information on biosecurity practices. CONCLUSION: Although horses at some home properties became infected with EI, it appears unlikely that this was the result of spread from MPRG via horse handlers. Simple preventive measures based on personal decontamination and other biosecurity measures are considered likely to have prevented spread of infection from MPRG to other properties. PMID- 21711309 TI - Hygiene practices to prevent the spread of equine influenza by humans. AB - This paper describes a protocol for hygiene practices that was devised by a practice in which all veterinarians were involved on a daily basis in visiting infected premises, including sampling, treatment of clinical cases and general veterinary work. This protocol was strictly followed when attending an infected or at risk property. PMID- 21711310 TI - Vaccination program in the response to the 2007 equine influenza outbreak in Australia. AB - At the time of the initial notification of the occurrence of equine influenza (EI) in Australia in August 2007, vaccination was restricted to horses for which it was an import requirement and only with the approval of the state or territory Chief Veterinary Officer. This paper describes the complexities involved in the selection of a vaccine and its distribution. A combination of ring, predictive and blanket vaccination was implemented during the response. The specific vaccination programs, including its use in buffer zones and for movement of horses, the performance of the vaccine, any adverse reactions and the effect on exposure of vaccinated horses to circulating virus, are also described. Vaccination is considered to have made a valuable contribution to the containment and subsequent eradication of EI from Australia and to risk management in the resumption of horse activities in affected areas from December 2007. Movement restrictions and other biosecurity measures were critically important in controlling the spread of EI and contributing to its eventual eradication, and vaccination was an aid to these measures. PMID- 21711311 TI - Equine influenza: patterns of disease and seroprevalence in Thoroughbred studs and implications for vaccination. AB - This study included 10 large Thoroughbred horse studs in the upper Hunter Valley of New South Wales and in southeast Queensland, Australia. The aims were to describe the EI epidemic in studs in the Special Restricted Area (Purple Zone) of NSW, to estimate seroprevalence among different groups of horses on these studs and to look for evidence of exposure to EI virus in horses on 'vaccinated' studs in southeast Queensland that were thought to have remained free of infection. As serology results from Queensland suggest that vaccination may have reduced the sensitivity of clinical surveillance to detect the presence of infection on 'vaccinated' premises, we conclude that vaccine efficacy must be considered in terms of reduction in clinical disease, as well as in terms of infection and infectiousness. PMID- 21711312 TI - Evaluation of the response to an accelerated immunisation schedule using a canarypox-vectored equine influenza vaccine, shortened interdose intervals and vaccination of young foals. AB - The results of an accelerated immunisation schedule for horses used as part of the emergency response plan to contain and eradicate equine influenza in Australia in 2007 is described. The horses studied were vaccinated with a recombinant canarypox-vectored vaccine (ProteqFlu(r), Merial) with a shorter interdose interval. Vaccinated horses included foals aged less than 4 months. PMID- 21711314 TI - Evaluating the effectiveness of the response to equine influenza in the Australian outbreak and the potential role of early vaccination. AB - OBJECTIVE: To use modelling and epidemiological analyses to assess the effectiveness of control strategies employed during the equine influenza outbreak and determine if early vaccination might have had a beneficial effect. METHODS: Transmission of infection was modelled using stochastic, spatial simulation, based on data from 16 regions in New South Wales and Queensland over the first month of the outbreak. RESULTS: The model accurately represented the spread of infection in both space and time and showed that vaccination strategies would have reduced new infections by ~60% and reduced the size of the infected area by 8-9%, compared to the non-vaccination baseline. CONCLUSION: When used in conjunction with biosecurity measures and movement controls, early vaccination could play an important role in the containment and eradication of equine influenza. PMID- 21711313 TI - Clinical outcomes and virology of equine influenza in a naive population and in horses infected soon after receiving one dose of vaccine. AB - As part of the control measures of the equine influenza (EI) outbreak, in addition to the strategic use of vaccination to provide buffer zones around infected populations, approval was obtained to vaccinate Thoroughbred racing horses. We review the clinical expression of the disease and virus excretion in a population of racehorses that were exposed to EI approximately 7 days after administration of a single dose of the canarypox-vectored recombinant compared with a similar unvaccinated population of horses at a nearby racetrack. Although this study was undertaken opportunistically and under the difficult field conditions that prevailed during the outbreak, our observations demonstrate that an appropriate vaccine can be effectively used as a disease control measure, even in the face of an outbreak, and therefore should be rapidly implemented as soon as there is evidence of infection in a naive population. PMID- 21711315 TI - Positive results in a real-time PCR for type A influenza associated with the use of an inactivated vaccine. AB - A real-time reverse transcription polymerase chain reaction (qRT-PCR) test for the matrix gene of type A influenza viruses was used during the 2007 Australian equine influenza (EI) outbreak in order to confirm diagnosis and, later, eradication of the virus. During the EI outbreak, horses being exported required vaccination and individual proof of freedom from EI. At the end of the outbreak, positive results were obtained from four horses destined for export, because of contamination of the samples with the vaccine. This report highlights the need for EI testing and vaccination to occur on separate days and with the collection of swabs for testing to precede vaccination. PMID- 21711316 TI - Overview of the industry and social impacts of the 2007 Australian equine influenza outbreak. AB - The equine influenza (EI) outbreak occurred at the worst time of the year as far as the horse industry was concerned. All horse sports and horse breeds had events planned in the spring, including those relating to qualification for the 2008 Beijing Olympic Games. These were all disrupted and many were cancelled. The social and industry impacts were extensive, and included difficulties related to communication, animal welfare, vaccination, movement restrictions, economics, as well as the psychological stresses experienced by those involved, especially those for whom their primary source of income was horse related. PMID- 21711317 TI - Insights into the economic consequences of the 2007 equine influenza outbreak in Australia. AB - We estimate and describe the financial costs of the equine influenza (EI) outbreak in Australia, including the costs of emergency response measures and lost income/assets to businesses, associations and private horse owners. Costs to associations, governments and industry are discussed. We identify a lack of reliable data about the financial costs of the EI outbreak to the non-racing sectors of the horse industry. PMID- 21711318 TI - Factors associated with high psychological distress in horse industry participants during the 2007 Australian equine influenza outbreak and evidence of recovery after 1 year. AB - This short report summarises data on the prevalence of high psychological distress in horse industry participants during the 2007 Australian equine influenza (EI) outbreak and the statistical analysis undertaken to identify the factors associated with this high psychological distress. In addition, follow-up data collected 1 year later are reported briefly. PMID- 21711319 TI - An insider's view of the lockdown at Moonbi during the Australian equine influenza outbreak. AB - Participants in the 1- and 2-day Tamworth Dressage Club (TDC) annual dressage championships arrived in Moonbi, New South Wales (NSW) as reports of the equine influenza outbreak surfaced on 25 August 2007. Three horses who had attended a competition in Maitland the weekend before had been showing flu-like symptoms and the next day the site was declared a suspect premise. On 27 August, infection was confirmed and the site was placed in total quarantine. Although most participants had travelled long distances to compete and did not have provisions for them or their horses, the quarantine was not lifted until 3 October, having a great social and personal impact on all those trapped in Moonbi. PMID- 21711320 TI - Impact of the Australian equine influenza outbreak on a small business that was not infected. AB - At the outbreak of equine influenza (EI) we chose to close our horse-based business, as we did not want to risk our horses contracting the disease and the demand for our services ceased. We report our experiences of the outbreak. PMID- 21711321 TI - Proof of freedom from equine influenza infection in Australia in 2007-08. AB - The challenges faced in demonstrating Australia's freedom from equine influenza following the outbreak in 2007-08 and the responding strategy developed by the Proof of Freedom Working Group are presented. PMID- 21711322 TI - Demonstrating freedom from equine influenza in New South Wales, Australia, following the 2007 outbreak. AB - OBJECTIVE: To quantify the probability of freedom from equine influenza (EI) in New South Wales (NSW), Australia, based on analysis of polymerase chain reaction (PCR) testing. METHODS: Testing in the infected areas of NSW during the period 1 January to 30 April 2008. RESULTS: Data from the random survey were collated and analysed to provide estimates of the probability of detecting EI if it was present at a prevalence ranging from 0.01% to 0.5%. The sensitivity estimates were then combined with a prior estimate of the probability of freedom in a simulation model, to estimate the posterior probability of freedom from EI (given the negative results of the random survey). CONCLUSIONS: The very large volume of PCR tests performed provided a very high level of confidence that EI had been successfully eradicated from NSW. PMID- 21711323 TI - Regaining Australia's equine influenza-free status: a national perspective. AB - The first cases of equine influenza (EI) in Australia were reported in late August 2007. By 14 March 2008, provisional freedom from EI was declared and in December 2008 Australia was officially declared EI-free, 12 months after the last reported clinical case. Containment, and ultimate eradication, of EI was achieved through a combination of movement restrictions, zoning, vaccination and enhanced biosecurity measures that drew on the resources and expertise of industry and state and federal governments. Through these measures, the EI outbreak, which peaked in October 2007, was contained to just 3% of Australia, with no new cases reported after 9 December 2007, just four months after the outbreak began. PMID- 21711324 TI - Interferon-alpha stimulates TRAIL expression in human keratinocytes and peripheral blood mononuclear cells: implications for the pathogenesis of cutaneous lupus erythematosus. AB - BACKGROUND: The tumour necrosis factor-related apoptosis-inducing ligand TRAIL has been shown to participate in the pathogenesis of systemic lupus erythematosus (SLE). The accumulation of apoptotic cell debris has been hypothesized to induce this autoimmune inflammation, and TRAIL may trigger this programmed cell death. Furthermore, TRAIL is among the interferon (IFN)-regulated genes which are typically expressed in the peripheral blood of patients with acute SLE. OBJECTIVES: As an inappropriate activation of the type I IFN system plays an important role in both SLE and cutaneous lupus erythematosus (CLE) subsets, we hypothesized that TRAIL might also participate in the pathogenesis of CLE. METHODS: Immunohistochemistry and immunofluorescence analyses were used to identify and localize TRAIL-expressing cells in CLE skin specimens. TRAIL expression in peripheral blood mononuclear cells (PBMC) isolated from patients with CLE was measured by flow cytometry. The impact of IFN-alpha treatment on TRAIL expression by keratinocytes and PBMC was evaluated by reverse transcription polymerase chain reaction and flow cytometry. RESULTS: Keratinocytes are beside CD11c+ and BDCA2+ dendritic cells the major TRAIL-expressing cells in CLE lesions. TRAIL is upregulated on the surface of circulating CD11c+ PBMC isolated from patients with CLE. Treatment of keratinocytes and PBMC with recombinant IFN alpha strongly enhances TRAIL expression by these cells. The proapoptotic TRAIL receptor R1 is expressed by keratinocytes in CLE skin lesions. CONCLUSIONS: TRAIL is strongly expressed in the skin and the blood of patients with CLE and may trigger the apoptotic death of kerationcytes in CLE via the TRAIL receptor R1. An IFN-alpha-induced TRAIL expression may in this way participate in the pathogenesis of CLE. PMID- 21711325 TI - Are we giving patients enough information on how to use topical treatments? Analysis of 767 prescriptions in psoriasis. AB - BACKGROUND: Unclear instructions probably contribute to the suboptimal efficacy and adherence to topical agents in psoriasis. OBJECTIVES: To analyse the quality of prescriptions for topical therapy in psoriasis and to determine factors associated with high-quality prescription writing. METHODS: We made a systematic analysis of 767 topical prescriptions written by dermatologists and general practitioners (GPs). The following parameters were recorded: writing mode (electronic vs. hand written), indication of formulation, frequency of administration, duration of treatment, indication of areas to be treated, and indication of amount of product to be used. We considered prescriptions of high quality to be those including at least four of the five prospectively defined quality parameters. RESULTS: Only 35.7% of prescriptions fulfilled the definition of a high-quality prescription. Quality of prescription writing was significantly influenced by two factors: electronic writing [odds ratio (OR) 3.04, 95% confidence interval (CI) 2.2-4.21; P < 10(-4) ] and specialty of the prescriber, dermatologists writing higher quality prescriptions compared with GPs (OR 1.61, 95% CI 1.54-2.14; P < 10(-4) ). CONCLUSIONS: Almost two-thirds of topical prescriptions are not adequately written and do not include the required information to help patients manage their topical treatment in psoriasis correctly. The quality of topical prescriptions could be improved by making the use of electronic prescriptions widespread and by the development of aids for easy evaluation of the right amount of topical treatment to be applied according to body surface area involved. PMID- 21711326 TI - Detection of linear IgE deposits in bullous pemphigoid and mucous membrane pemphigoid: a useful clue for diagnosis. AB - BACKGROUND: Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease of the skin associated with IgG autoantibodies to BP180 and BP230, while mucous membrane pemphigoid (MMP) comprises a heterogeneous group of autoimmune blistering diseases characterized by a predominant mucous membrane involvement and scarring tendency associated with an autoantibody response to various autoantigens, including BP180. While the pathogenicity of IgG autoantibodies to BP180 has been demonstrated in BP, the role of IgE autoantibodies in mediating tissue damage in BP and MMP is unclear. OBJECTIVES: To assess the presence of tissue-bound IgE in patients with BP and MMP, and their correlation with distinct clinical features. METHODS: In this retrospective study, we assessed the presence of IgE deposits as detected by direct immunofluorescence microscopy of skin biopsy specimens obtained from 44 and 13 patients with a new diagnosis of BP and MMP, respectively. Distinct clinical features at time of diagnosis, such as itch, urticarial papules and plaques and eczematous lesions, were noted. RESULTS: In 18 of 44 (41%) patients with BP linear deposits of IgE of variable intensity were detectable along the dermoepidermal junction. In 14 (32%) of the cases, IgE deposits were found concomitantly with IgG and C3. In two (5%) patients, diagnosis of BP was based on the isolated detection of IgE together with consistent clinicopathological features. Nine of 13 (69%) patients with MMP also exhibited linear IgE deposits, including one case with isolated linear IgE deposits. Patients with BP with tissue-bound IgE deposits had clinically significant urticarial papules and plaques when compared with patients with BP without IgE deposits. CONCLUSIONS: Our findings indicate that demonstration of tissue-bound IgE deposits provides an additional useful criterion for diagnosis of BP and MMP in some patients. Prospective studies are needed to better correlate the presence of tissue-bound and circulating IgE autoantibodies and their specificity with distinct clinical features and course of BP and MMP. PMID- 21711327 TI - Increased retinol-binding protein (RBP) 4 and anti-RBP4 antibody in alopecia areata. AB - BACKGROUND: Neither the underlying pathogenesis of alopecia areata (AA) nor the molecular mechanisms leading to hair loss have been fully elucidated. OBJECTIVES: To compare the protein profiles of sera obtained from patients with AA with those from healthy controls. METHODS: Protein profiles of sera obtained from subjects with AA and healthy controls were compared using proteomics techniques. Serum levels of the identified protein were quantified by specific enzyme-linked immunosorbent assay (ELISA). The relative serum reactivities of the recombinant human protein were compared between patients with AA and healthy controls using Western blots and double indirect immunofluorescence. RESULTS: The upregulated expression of retinol-binding protein (RBP) 4 was identified, and RBP4 ELISA demonstrated significantly increased serum levels of RBP4 among subjects with AA when compared with healthy controls. Western blots using recombinant human RBP4 and the sera from both groups presented serum reactivity of antihuman recombinant RBP4 IgG antibodies in 10/15 subjects with AA (67%) and 2/15 healthy controls (13%). Double indirect immunofluorescence demonstrated merged fluorescence signals of serum anti-RBP4 IgG antibodies and monoclonal antibodies to RBP4 in subjects with AA on the outer root sheath and companion layer. CONCLUSIONS: Our data demonstrate that AA is associated with increased serum levels of RBP4 and positive IgG immunoreactivity against recombinant human RBP4. These results suggest that the major components for the retinoic acid biosynthesis pathway may be crucially involved in the pathogenic process of AA. PMID- 21711328 TI - Complete skin examination is essential in the assessment of dermatology patients: findings from 483 patients. AB - BACKGROUND: Dermatological teaching has traditionally stressed that complete skin examination is essential in the assessment of patients with potential skin disease. OBJECTIVES: To determine whether complete skin examination results in increased diagnoses of skin malignancies that would not have been discovered otherwise. METHODS: New patients (n = 483) attending a dermatology clinic in a university teaching hospital and private dermatology practice had a complete skin examination, as is our normal practice. These patients were seen over a 9-month period (January-September 2009). All patients were examined by the same consultant dermatologist. Data were collected on patients' sex, age, presenting complaint and findings on complete skin examination. RESULTS: Two nodular malignant melanomas with mean Breslow thickness of 0.6 mm (0.4%) and one melanoma in situ were identified at sites distant from the patient's presenting complaint. Sixteen patients (3.3%) had a basal cell carcinoma that would not have been discovered if the presenting lesion alone had been examined. Thirty-three patients (6.8%) had actinic keratoses or squamous cell carcinoma in situ and nine (1.9%) had dysplastic naevi. A further 21 patients (4.3%) had a suspicious lesion biopsied or excised with subsequent benign histology. Seventy-three patients (15.1%) had other benign dermatological diagnoses requiring treatment or investigation. CONCLUSIONS: In a 9-month period, in a sample of 483 new patients, three patients (0.6%) had potentially lethal skin malignancies identified that would not have been diagnosed without a complete skin examination. Sixteen (3.3%) patients had basal cell carcinomas that would have been missed without complete skin examination. This study confirms the traditional teaching that complete skin examination has the potential to reduce morbidity and mortality from cutaneous malignancy. PMID- 21711329 TI - Why dermatologists shouldn't practise in red light districts. PMID- 21711330 TI - Deletion of LCE3C and LCE3B genes is associated with psoriasis in a northern Chinese population. AB - BACKGROUND: It has been shown that a deletion in the late cornified envelope (LCE) gene cluster (LCE3C_LCE3B-del) is associated with susceptibility to psoriasis in European populations. However, the relationship remains unclear in a northern Chinese population. OBJECTIVES: The aim of the present study was to clarify this association in this population. METHODS: In total, 970 patients with psoriasis and 1064 healthy controls were recruited and a polymerase chain reaction assay was used to determine the frequency of this deletion. The effect of this deletion on susceptibility to psoriasis was assessed using SPSS software and the PLINK software package. RESULTS: The frequency of the LCE3C_LCE3B-del differed significantly between patients and healthy controls. In subgroup analysis, the distribution was significantly different between patients with a positive family history of psoriasis and controls, as well as between patients with early-onset psoriasis and controls. CONCLUSIONS: The findings indicate that the LCE3C_LCE3B-del is an important risk factor in the pathogenesis of psoriasis and that the LCE3C_LCE3B-del does not show an epistatic effect with the HLA-Cw6 allele on susceptibility to psoriasis in the northern Chinese population. PMID- 21711331 TI - Factors in the surgical management of primary eccrine porocarcinoma: prognostic histological factors can guide the surgical procedure. AB - BACKGROUND: Primary eccrine porocarcinoma is a rare cutaneous neoplasm and there is no consensus concerning its surgical management. OBJECTIVES: To conduct a retrospective analysis of all the cases of eccrine porocarcinoma seen in our hospital in order to identify prognostic factors. METHODS: Clinical data were retrieved from the patients' files. Each histological sample was reviewed by the pathologist and classified into three eccrine porocarcinoma subtypes: 'infiltrative', 'pushing' and 'pagetoid' eccrine porocarcinoma, according to Robson's criteria. Statistical methods were used to estimate the recurrence risk. RESULTS: Twenty-four patients were included. The surgical margins realized were >= 2 cm or < 2 cm in six and 13 patients, respectively, and slow Mohs procedure was performed in two patients. Ten, seven and two patients presented with 'infiltrative', 'pushing' or 'pagetoid' eccrine porocarcinoma, respectively. Eight patients (of 23) experienced recurrences (35%). The recurrence risk was linked to the histological subtype: two out of two pagetoid eccrine porocarcinoma, four out of 10 'infiltrative' and none of seven 'pushing' eccrine porocarcinoma recurred (P=0.026). The recurrence risk was not associated with epidermal growth factor receptor status, nor the margin realized. CONCLUSIONS: The recurrence risk of 'pushing' eccrine porocarcinoma is significantly lower than for 'infiltrative' eccrine porocarcinoma. Based on these considerations, a decisional algorithm might be proposed: first step, excisional biopsy of the primary eccrine porocarcinoma and identification of the histological subtype; second step, infiltrative or pagetoid porocarcinoma should be excised with an additional modified micrographic Mohs procedure, while no additional surgery is needed for 'pushing' eccrine porocarcinoma if the first excisional biopsy is complete. Although demonstrated in a limited case series, the histological subtype might guide the surgical management of primary eccrine porocarcinoma. PMID- 21711332 TI - Ultraviolet B radiation and reactive oxygen species modulate interleukin-31 expression in T lymphocytes, monocytes and dendritic cells. AB - BACKGROUND: Interleukin (IL)-31 is a novel Th2 T-cell cytokine that induces pruritus and dermatitis in transgenic mice. While enhanced mRNA expression of this cytokine is detected in skin samples of inflammatory skin diseases, the regulation of IL-31 expression is poorly understood. OBJECTIVES: To assess the effects of ultraviolet (UV) B radiation and H2O2 on IL-31 mRNA and protein expression in skin and different peripheral blood mononuclear cells (PBMCs). METHODS: The effects of UVB radiation and H2O2, as a prototypic reactive oxygen species, on IL-31 mRNA and protein expression were analysed in various inflammation-related cells and murine skin tissue. RESULTSTreatment of cells with UVB radiation and H2 O2 strongly induced IL-31 mRNA and protein expression in human PBMCs and in the skin of SKH-1 mice. Following exposure to UVB or H2O2, we observed increased expression of IL-31 mRNA in T cells, monocytes, macrophages, and immature and especially mature dendritic cells. H2O2 treatment but not UVB radiation led to a moderate upregulation of IL-31 mRNA expression in epidermal keratinocytes and dermal fibroblasts. Pretreatment of T lymphocytes with the MAPK p38 inhibitor SB203580 or the MEK1 inhibitor U0126 reduced the stimulatory effect of H2O2. These experiments suggest that p38 is involved in the regulation of IL 31 expression in human skin. CONCLUSIONS: Our studies reveal that UVB and reactive oxygen species stimulate the expression of IL-31 in PBMCs and skin, especially in T cells, monocytes and monocyte-derived dendritic cells. PMID- 21711333 TI - Cumulative risks and rates of subsequent basal cell carcinomas in the Netherlands. AB - BACKGROUND: The incidence of multiple basal cell carcinomas (BCCs) is not well documented. OBJECTIVES: To calculate the cumulative risks, rates and risk factors for the development of subsequent histologically confirmed BCCs. METHODS: For this cohort study the Dutch nationwide network and registry of histopathology and cytopathology (PALGA) was used. The first 2483 patients diagnosed with a first histologically confirmed BCC in the year 2004 were followed for 5years. Multifailure survival models were used to study whether gender or age affected the risk of developing subsequent tumours. RESULTS: During our observational period, the 2483 patients developed a total of 3793 histologically confirmed BCCs. The 5-year cumulative risk of developing one or more subsequent BCCs was 29.2%. Incidence rates were 25,318 per 100,000person-years in the first 6months after first BCC diagnosis, decreasing to 6953 per 100,000person-years after 5years of follow-up. Males compared with females had a 30% [adjusted hazard ratio (HR) 1.30, 95% CI (confidence interval) 1.11-1.53] higher risk of developing multiple BCCs and those aged 65-79years had more than 80% (adjusted HR 1.81, 95% CI 1.37-2.41) higher risk of having subsequent tumours compared with patients younger than 50years. CONCLUSIONS: The high incidence rate of subsequent BCCs among patients with a first BCC is highest in the first months after diagnosis of the first BCC but persists long term, indicating that patients with BCC should undergo full-body skin examinations at first presentation and subsequent follow up visits. Special attention should be paid to males and persons of older age at index lesion. PMID- 21711334 TI - CXCR3 ligands promote expression of functional indoleamine 2,3-dioxygenase in basal cell carcinoma keratinocytes. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy in humans worldwide. Studies suggest that BCCs exhibit immunoprotection, similar to other keratinocyte carcinomas, although the mechanisms of defence have not been defined. OBJECTIVES: To examine if indoleamine 2,3-dioxygenase (IDO), an immune privilege-associated enzyme, would be expressed in BCC, regulated in part by CXCR3. METHODS: We analysed the expression and function of IDO in human BCC (hBCC) tissues using nonlesional skin epithelial (NL) tissues as a control. RESULTS: Quantitative real-time reverse transcription-polymerase chain reaction (qPCR) revealed significant upregulation of IDO1 and IDO2 (12.5- and 19.14-fold change, respectively) in nodular hBCCs as compared with NL tissues. Immunohistochemistry showed that IDO colocalized with keratin 17, a BCC keratinocyte marker, in hBCC tissues. Western blot identified a full-length IDO (42 kDa) product and a splice variant (~30 kDa) in BCC tissues. Kynurenine assays and qPCR were conducted to determine IDO enzymatic activity in hBCCs in vitro with CXCL11 supplementation, which has previously been shown to be required for the tumour cell growth. Addition of CXCL11 upregulated IDO2 and increased l kynurenine concentration in a dose-dependent manner in hBCCs while normal primary keratinocytes exhibited no response. CONCLUSIONS: The expression of IDO at both mRNA and protein levels in hBCC tissues, the upregulation of IDO2 and the IDO mediated l-kynurenine production in hBCCs with CXCL11 treatment suggest that functional IDO is synthesized by hBCC tumours and may be used as a method of immunoprotection during tumorigenesis. Also, IDO enzymatic activity may be modulated by CXCR3/CXCL11 signalling in BCCs. PMID- 21711336 TI - Differential expression of stem cell markers in lichen planopilaris and alopecia areata. PMID- 21711335 TI - Serotonin induces melanogenesis via serotonin receptor 2A. AB - BACKGROUND: Serotonin (5-hydroxytryptamine, 5-HT) levels are increased by light exposure but the role and mechanism of 5-HT in the pigmentation of skin cells are unclear. OBJECTIVES: To clarify the effect of 5-HT on melanogenesis and to determine the 5-HT receptor subtype involved. METHODS: B16F10, SK-MEL-2 and Melan A cells were cultured in Dulbecco's modified Eagle's medium with low fetal bovine serum. The three cell lines were treated with various concentrations of 5-HT, and 5-HT receptor agonists and antagonists. The involvement of the 5-HT receptor 2A (5-HTR2A) was examined by gene silencing and use of 5-HTR2A antagonists. RESULTS: 5-HT and the 5-HTR2A agonist, DOI, increased melanogenesis in the three cell lines. These increased events were suppressed by 5-HTR2A antagonists or gene silencing of the HTR2A gene. CONCLUSIONS: 5-HTR2A is involved in melanogenesis. These findings highlight the role of 5-HT and suggest new ways of controlling melanogenesis. PMID- 21711337 TI - Laser and intense pulsed light therapy for the treatment of hypertrophic scars: a systematic review. AB - Hypertrophic scars are difficult to improve and remain a therapeutic challenge. Several lasers and light sources have been evaluated in the past decades and have been shown to improve hypertrophic scars. However, a systematic review is not available. To assess current evidence of efficacy of all laser and intense pulsed light therapies used in the treatment of hypertrophic scars, we performed a systematic review searching electronic databases MEDLINE, EMBASE and CENTRAL. The quality of the controlled clinical trials was evaluated according to the Cochrane Collaboration's tool for assessing risk of bias. Thirteen articles involving seven different lasers met the inclusion criteria. Most evidence was found for the pulsed dye laser (PDL) 585 nm (eight studies), followed by the PDL 595 nm (two studies), whereas limited evidence (one trial per laser) was available for the fractional nonablative laser 1540 nm, CO2 laser 10,600 nm, low-level laser therapy, Nd:YAG laser 532 nm and Erbium:YAG laser 2940 nm. Treatment recommendations should be formulated with caution as current evidence is insufficient for comparing the efficacy of different laser therapies. The PDL 585 nm showed a low efficacy for the treatment of hypertrophic scars. With moderate efficacy, the PDL 595 nm is promising, although more research is necessary. Little evidence was found for the efficacy of other lasers. Future research, with a low risk of bias, well-defined scar characteristics, validated outcome measures, standardized measurement methods, follow-up periods of at least 6 months and well-defined laser settings, is needed. PMID- 21711338 TI - Merkel cell carcinoma in Western Australia: a population-based study of incidence and survival. AB - BACKGROUND: Merkel cell carcinoma (MCC) is an uncommon but aggressive cutaneous skin cancer. Even with the appropriate treatment, MCC is prone to recurrence, and metastases are common. Exposure to ultraviolet radiation has been suggested as contributing towards the development of MCC. MCC has not been extensively investigated in Australia, even though Australia has the highest incidence of sun related cancers in the world. OBJECTIVES: To describe the demographics and determine trends of incidence and survival of MCC cases in Western Australia (WA). METHODS: All reported invasive cases of MCC incident between 1 January 1993 and 31 December 2007 were extracted from the WA Cancer Registry. Age-adjusted incidence rates for MCC were calculated using direct standardization to the U.S. standard 2000 population. Cause-specific survival was investigated using Kaplan Meier and Cox proportional hazards analysis. results: Two hundred and fifteen cases were confirmed by pathological review as being definite cases of MCC. Patients were mainly males (65%) and elderly (median age 77 years). Standardized age-adjusted incidence rates were higher in men (1.0/100,000) than in women (0.63/100,000) and higher in older ages (15.5/100,000 in the 85+year age group) than younger ages (0.1/100,000 in the 30-34 year age group). Five-year cause specific survival was 64%. CONCLUSIONS: Incidence of MCC in WA is the highest reported in the literature. In addition, MCC has worse survival than melanoma. The high rates and demographic and anatomical distribution are consistent with sun exposure playing a causal role. PMID- 21711339 TI - Medical comorbidity associated with psoriasis in adults: a population-based study. AB - BACKGROUND: Most publications to date on comorbidities associated with psoriasis have focused on cardiovascular and metabolic diseases. Few comprehensive investigations of medical comorbidities in a cohort of patients with psoriasis appear in the literature. OBJECTIVES: To examine the prevalence of comorbidities in adult patients with psoriasis, including a comparison of comorbid prevalence vs. that in controls without psoriasis, in a nationally representative dataset in Taiwan. METHODS: There were 1685 adult patients with psoriasis in the study group and 5055 randomly selected subjects in the comparison group. We used conditional logistic regression analyses to examine the risk of 29 comorbidities for these two groups after adjusting for monthly income, geographical region of residence and the level of urbanization of each patient's community of residence. RESULTS: After adjusting for several potential confounders, patients with psoriasis had higher odds of comorbid congestive heart failure [odds ratio (OR) 1.63], ischaemic heart disease (OR 1.51), renal failure (OR 1.45), uncomplicated diabetes (OR 1.37), liver diseases (OR 1.34), hepatitis B or C (OR 1.34), complicated diabetes (OR 1.32), hyperlipidaemia (OR 1.28), hypertension (OR 1.24) and peptic ulcer (OR 1.22) than did patients without psoriasis. However, patients with mild psoriasis had higher odds of comorbidity only with uncomplicated diabetes (OR 1.55), asthma (OR 1.30), liver diseases (OR 1.30) and peptic ulcer (OR 1.26) than patients without psoriasis. CONCLUSIONS: We conclude that psoriasis is associated with a variety of medical comorbidities including cardiovascular diseases, metabolic diseases, renal failure, liver diseases, viral hepatitis B or C, asthma and peptic ulcers. PMID- 21711340 TI - Sweet syndrome associated with sporotrichosis. PMID- 21711341 TI - Nuclear localization of activated STAT6 and STAT3 in epidermis of prurigo nodularis. AB - BACKGROUND: Prurigo nodularis (PN) is a chronic dermatitis characterized by discrete, raised, and firm papulonodules with intense pruritus. The pathogenesis still remains to be elucidated. OBJECTIVES: To clarify the role of Th1 and Th2 cytokines in the pathogenesis of PN. METHODS: We examined the cytokine signatures, such as phosphorylation of STAT1, STAT3 and STAT6, HLA-DR and hyaluronan accumulation, to reveal the Th1 and Th2 cytokine influence on the lesional epidermis of PN. RESULTS: We first optimized antigen retrieval methods to detect these signatures with antibodies for phospho-STAT1 (pSTAT1), phospho STAT3 (pSTAT3), phospho-STAT6 (pSTAT6), HLA-DR and hyaluronic acid binding protein (HABP) on the formalin-fixed paraffin-embedded sections of psoriasis, lichen planus and atopic dermatitis biopsy samples. Activation of STAT1 and STAT6 in epidermis by Th1 and Th2 cytokines was further confirmed in a cultured skin equivalent model treated with interferon-gamma or interleukin (IL)-4/IL-13. With the relevant immunostaining methods, we examined the cytokine signatures in 22 cases of PN. The results revealed that (i) the entire epidermis of 19 cases was stained with anti-pSTAT6 antibody, (ii) 21 cases demonstrated nuclear staining with anti-pSTAT3 antibody, (iii) the entire epidermis of 21 cases was stained with HABP, (iv) the epidermis of eight cases showed scattered staining with anti pSTAT1 antibody, and (v) six cases were positive for HLA-DR membrane expression. CONCLUSIONS: These data indicated that Th2 cytokines related to STAT6 activation together with some unknown stimuli that activate STAT3 play a principal role in the pathogenesis of PN. PMID- 21711342 TI - microRNA-mediated keratinocyte hyperproliferation in psoriasis vulgaris. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by intense proliferation and abnormal differentiation of keratinocytes, although the pathogenesis is still not completely clarified. OBJECTIVES: We investigated the mechanism of keratinocyte proliferation seen in psoriasis, focusing on microRNA (miRNA). MATERIALS AND METHODS: miRNAs were extracted from tissues and sera of psoriasis, atopic dermatitis and healthy control. To determine pathogenic miRNAs, we performed miRNA polymerase chain reaction (PCR) array analysis. The results were confirmed with quantitative real-time PCR, in situ hybridization, immunohistochemistry, transient transfection of siRNA and inhibitor in cultured keratinocytes and Western blotting. RESULTS: PCR array analysis using tissue miRNA demonstrated miR-424 level was markedly decreased in psoriasis skin in vivo. Protein expression of mitogen-activated protein kinase kinase 1 (MEK1) or cyclin E1, predicted target genes of miR-424, was increased in psoriatic skin, although their mRNA levels were not. The transfection of specific inhibitor of miR-424 in normal human keratinocytes led to upregulation of MEK1 or cyclin E1 protein, and resulted in increased cell proliferation. On the other hand, cell number was significantly decreased when cells were transfected with siRNA for MEK1 or cyclin E1. Furthermore, we first investigated serum miRNA levels in psoriasis. Although not significant, serum miR-424 concentration tended to be decreased in patients with psoriasis compared with healthy controls. CONCLUSIONS: Decreased miR-424 expression and subsequently increased MEK1 or cyclin E1 may play a key role in the pathogenesis of psoriasis. Investigation of the regulatory mechanisms of keratinocyte proliferation by miRNA may lead to new treatments and a disease activity marker. PMID- 21711343 TI - Psoriasis, cardiovascular disease and flow-mediated dilatation. PMID- 21711344 TI - Treatment of notalgia paraesthetica with an 8% capsaicin patch. PMID- 21711345 TI - Nodular lesions arising in a large congenital melanocytic naevus in a newborn with eruptive disseminated Spitz naevi. AB - Congenital malignant melanoma within a pre-existing large congenital melanocytic naevus (CMN) is exceedingly rare. Its incidence is difficult to determine due to the small number of reported cases and because of problems associated with diagnosis. Some benign nodular proliferations (called proliferative nodules) arising in CMN, while rare, are significantly more common and can mimic malignant melanoma clinically or histologically. There are no reported cases of congenital melanoma or benign proliferative nodules in CMN in patients who also had eruptive disseminated Spitz naevi. We describe a girl who was noted to have a dark-brown plaque with several large erythematous nodules affecting the scalp at delivery, in addition to multiple erythematous dome-shaped papules that developed in a disseminated manner over several months, beginning at 10 days of age. It was difficult, not only clinically but also histologically, to determine the benign or malignant nature of all of these lesions. As primary cutaneous melanoma, atypical proliferative nodules in CMN, bland CMN or CMN with foci of increased cellularity and Spitz naevi show clear differences in the genetic aberration patterns, comparative genomic hybridization (CGH) could be a diagnostic help in ambiguous cases such as this. CGH performed on this patient showed multiple DNA copy number changes in the most atypical nodule, but such alterations could not be found in the remainder of the lesions. CGH showed differences between the nodular lesions that occurred in the CMN and helped us in supporting the diagnosis of this unique case of benign proliferative nodules and a possible congenital melanoma arising in a large CMN, associated with multiple widespread eruptive Spitz naevi. PMID- 21711346 TI - A note on the estimation of the Pareto efficient set for multiobjective matrix permutation problems. AB - There are a number of important problems in quantitative psychology that require the identification of a permutation of the n rows and columns of an n * n proximity matrix. These problems encompass applications such as unidimensional scaling, paired-comparison ranking, and anti-Robinson forms. The importance of simultaneously incorporating multiple objective criteria in matrix permutation applications is well recognized in the literature; however, to date, there has been a reliance on weighted-sum approaches that transform the multiobjective problem into a single-objective optimization problem. Although exact solutions to these single-objective problems produce supported Pareto efficient solutions to the multiobjective problem, many interesting unsupported Pareto efficient solutions may be missed. We illustrate the limitation of the weighted-sum approach with an example from the psychological literature and devise an effective heuristic algorithm for estimating both the supported and unsupported solutions of the Pareto efficient set. PMID- 21711347 TI - Human natural killer cells expressing the memory-associated marker CD45RO from tuberculous pleurisy respond more strongly and rapidly than CD45RO- natural killer cells following stimulation with interleukin-12. AB - Natural killer (NK) cells are known as innate immune lymphocytes that respond rapidly when challenged by pathogens but little is known about adaptive immune features including memory related to NK cells from human beings. In the present study, we demonstrate for the first time that human NK cells expressing the memory-associated marker CD45RO were persistent in pleural fluid cells (PFCs) from tuberculous patients. CD45RO(+) NK cells produced significantly more interferon-gamma and were more cytotoxic compared with CD45RO(-) NK cells from PFCs when stimulated with interleukin-12 (IL-12). Consistently, IL-12 enhanced the expression of granzyme B, CD69, CD25, NKG2D, IL-12 receptors beta1 and beta2 on CD45RO(+) NK cells from PFCs. Our experiments contribute to a better understanding of the NK cells from PFCs and indicate that human CD45RO(+) NK cells from PFCs expressing a 'memory-like' phenotype may have an important role in defending against infection by Mycobacterium tuberculosis. PMID- 21711348 TI - Enhancement of toll-like receptor 2-mediated immune responses by AIMP1, a novel cytokine, in mouse dendritic cells. AB - Aminoacyl tRNA synthetase-interacting protein 1 (AIMP1) is a novel pleiotropic cytokine that was identified initially from Meth A-induced fibrosarcoma. It is expressed in the salivary glands, small intestine and large intestine, and is associated with the innate immune system. Previously, we demonstrated that AIMP1 might function as a regulator of innate immune responses by inducing the maturation and activation of bone-marrow-derived dendritic cells (BM-DCs). Toll like receptors (TLRs) are major pathogen-recognition receptors that are constitutively expressed on DCs. In this study, we attempted to determine whether AIMP1 is capable of regulating the expression of TLRs, and also capable of affecting the TLR-mediated activation of DCs. Expression of TLR1, -2, -3 and -7 was highly induced by AIMP1 treatment in BM-DCs, whereas the expression of other TLRs was either down-regulated or remained unchanged. In particular, the expression of the TLR2 protein was up-regulated by AIMP1 in a time-dependent and dose-dependent manner, and was suppressed upon the addition of BAY11-7082, an inhibitor of nuclear factor-kappaB. AIMP1 was also shown to increase nuclear factor-kappaB binding activity. Importantly, AIMP1 enhanced the production of interleukin-6 and interleukin-12, and the expression of co-stimulatory molecules on BM-DCs when combined with lipoteichoic acid or Pam3Cys, two well-known TLR2 agonists. Collectively, these results demonstrate that the AIMP1 protein enhances TLR2-mediated immune responses via the up-regulation of TLR2 expression. PMID- 21711349 TI - Generation and function of immunosuppressive human and murine CD8+ T cells by transforming growth factor-beta and retinoic acid. AB - The intestinal immune system is constantly challenged by foreign antigens and commensal bacteria. Therefore, proper control of the intestinal microenvironment is required. One important arm of this regulatory network consists of regulatory T cells. In contrast to CD4(+) Foxp3(+) regulatory T cells, which have been well characterized, immunomodulatory CD8(+) T cells that express Foxp3 are less well defined in terms of their generation and function. Failures of these regulatory mechanisms contribute to the development of inflammatory bowel disease. In this study we demonstrate that the frequency of CD8(+) Foxp3(+) T cells is reduced in the peripheral blood of patients with ulcerative colitis. As these cells might play a currently underestimated role in the maintenance of intestinal homeostasis, we have investigated human and murine CD8(+) Foxp3(+) T cells generated by stimulating naive CD8(+) T cells in the presence of transforming growth factor-beta and retinoic acid, mediators that are abundantly produced in the intestinal mucosa. These CD8(+) Foxp3(+) fully competent regulatory T cells show strong expression of regulatory molecules CD25, Gpr83 and CTLA-4 and exhibit cell-cell contact-dependent immunosuppressive activity in vitro. Our study illustrates a previously unappreciated critical role of CD8(+) Foxp3(+) T cells in controlling potentially dangerous T cells and in the maintenance of intestinal homeostasis. PMID- 21711351 TI - High tryptophan diet reduces extracellular dopamine release via kynurenic acid production in rat striatum. AB - At endogenous brain concentrations, the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA) is a preferential antagonist of the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). In the present study, male Wistar rats were fed a high tryptophan diet (adding 0.1-1.5% tryptophan) for 24 h to examine (i) the effect of increased tryptophan on extracellular dopamine (DA) and KYNA levels and (ii) to determine any possible interactions between DA and KYNA. Brain KYNA levels were dose-dependently increased by tryptophan intake, and these increase were consistent with kynurenine (KYN), the precursor to KYNA, levels in the brain, plasma and liver. Administration of the 1.5% tryptophan added diet reduced the extracellular DA level to 60%, and increased the extracellular KYNA to 320% in the striatum. The DA reduction was attenuated through inhibiting KYNA synthesis with 2-aminoadipic acid. These results indicate that a high tryptophan diet can induce KYNA production and suppress DA release. One possible mechanism is that as more KYN is metabolized from the high doses of tryptophan in the liver and released into the blood stream, KYNA production in astrocytes is enhanced and the increased extracellular KYNA inhibits DA release by blocking alpha7nAChRs. Dietary manipulation of KYNA formation in astrocytes may offer a unique strategy to modulate DA. PMID- 21711354 TI - Age, sex and individual differences in punishment sensitivity: factors influencing the feedback-related negativity. AB - The anterior cingulate cortex (ACC) is central to evaluating performance outcomes and has been linked to individual differences in affective responses to feedback. We used electrophysiological source localization to examine the feedback-related negativity (FRN) and related ACC activity during a gambling task in relation to punishment and reward sensitivity among 16- to 17-year-old adolescents (n=20) and 18- to 29-year-old adults (n=30). The FRN was larger for monetary loss compared to win feedback and larger for high relative to low monetary value feedback, with no age differences in the FRN for win or loss feedback. Self-reported sensitivity to punishment accounted for unique variance (over sex and sensitivity to reward) in FRNs, with higher scores relating to larger FRNs and increased rostral ACC activity. These results support the ACC role in experiencing negative performance feedback, especially for individuals highly sensitive to punishment. PMID- 21711350 TI - CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease. AB - Chronic antigenic stimulation leads to gradual accumulation of late differentiated, antigen-specific, oligoclonal T cells, particularly within the CD8(+) T-cell compartment. They are characterized by critically shortened telomeres, loss of CD28 and/or gain of CD57 expression and are defined as either CD8(+) CD28(-) or CD8(+) CD57(+) T lymphocytes. There is growing evidence that the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population plays a significant role in various diseases or conditions, associated with chronic immune activation such as cancer, chronic intracellular infections, chronic alcoholism, some chronic pulmonary diseases, autoimmune diseases, allogeneic transplantation, as well as has a great influence on age-related changes in the immune system status. CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population is heterogeneous and composed of various functionally competing (cytotoxic and immunosuppressive) subsets thus the overall effect of CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell-mediated immunity depends on the predominance of a particular subset. Many articles claim that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells have lost their proliferative capacity during process of replicative senescence triggered by repeated antigenic stimulation. However recent data indicate that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells can transiently up-regulate telomerase activity and proliferate under certain stimulation conditions. Similarly, conflicting data is provided regarding CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell sensitivity to apoptosis, finally leading to the conclusion that this T-cell population is also heterogeneous in terms of its apoptotic potential. This review provides a comprehensive approach to the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population: we describe in detail its origins, molecular and functional characteristics, subsets, role in various diseases or conditions, associated with persistent antigenic stimulation. PMID- 21711355 TI - Allyl isothiocyanate (AITC) induces stomatal closure in Arabidopsis. AB - Isothiocyanates (ITCs) are degradation products of glucosinolates in crucifer plants and have repellent effect on insects, pathogens and herbivores. In this study, we report that exogenously applied allyl isothiocyanate (AITC) induced stomatal closure in Arabidopsis via production of reactive oxygen species (ROS) and nitric oxide (NO), and elevation of cytosolic Ca(2+) . AITC-induced stomatal closures were partially inhibited by an inhibitor of NADPH oxidase and completely inhibited by glutathione monoethyl ester (GSHmee). AITC-induced stomatal closure and ROS production were examined in abscisic acid (ABA) deficient mutant aba2-2 and methyl jasmonate (MeJA)-deficient mutant aos to elucidate involvement of endogenous ABA and MeJA. Genetic evidences have demonstrated that AITC-induced stomatal closure required MeJA priming but not ABA priming. These results raise the possibility that crucifer plants produce ITCs to induce stomatal closure, leading to suppression of water loss and invasion of fungi through stomata. PMID- 21711356 TI - Understanding the role of H(2)O(2) during pea seed germination: a combined proteomic and hormone profiling approach. AB - In a previous publication, we showed that the treatment of pea seeds in the presence of hydrogen peroxide (H(2)O(2)) increased germination performance as well as seedling growth. To gain insight into the mechanisms responsible for this behaviour, we have analysed the effect of treating mature pea seeds in the presence of 20 mm H(2)O(2) on several oxidative features such as protein carbonylation, endogenous H(2)O(2) and lipid peroxidation levels. We report that H(2)O(2) treatment of the pea seeds increased their endogenous H(2)O(2) content and caused carbonylation of storage proteins and of several metabolic enzymes. Under the same conditions, we also monitored the expression of two MAPK genes known to be activated by H(2)O(2) in adult pea plants. The expression of one of them, PsMAPK2, largely increased upon pea seed imbibition in H(2)O(2) , whereas no change could be observed in expression of the other, PsMAPK3. The levels of several phytohormones such as 1-aminocyclopropane carboxylic acid, indole-3 acetic acid and zeatin appeared to correlate with the measured oxidative indicators and with the expression of PsMAPK2. Globally, our results suggest a key role of H(2)O(2) in the coordination of pea seed germination, acting as a priming factor that involves specific changes at the proteome, transcriptome and hormonal levels. PMID- 21711357 TI - Redox regulation in plant programmed cell death. AB - Programmed cell death (PCD) is a genetically controlled process described both in eukaryotic and prokaryotic organisms. Even if it is clear that PCD occurs in plants, in response to various developmental and environmental stimuli, the signalling pathways involved in the triggering of this cell suicide remain to be characterized. In this review, the main similarities and differences in the players involved in plant and animal PCD are outlined. Particular attention is paid to the role of reactive oxygen species (ROS) as key inducers of PCD in plants. The involvement of different kinds of ROS, different sites of ROS production, as well as their interaction with other molecules, is crucial in activating PCD in response to specific stimuli. Moreover, the importance is stressed on the balance between ROS production and scavenging, in various cell compartments, for the activation of specific steps in the signalling pathways triggering this cell suicide process. The review focuses on the complexity of the interplay between ROS and antioxidant molecules and enzymes in determining the most suitable redox environment required for the occurrence of different forms of PCD. PMID- 21711358 TI - Glycinebetaine enhances the tolerance of tomato plants to high temperature during germination of seeds and growth of seedlings. AB - Tomato (Lycopersicon esculentum cv. 'Moneymaker') was transformed with a codA gene, from Arthrobacter globiformis, for choline oxidase that had been modified to allow targeting to both chloroplasts and the cytosol. Glycinebetaine (GB) accumulated in seeds of transformed plants up to 1 umol g(-1) dry weight (DW), while no detectable GB was found in wild-type (WT) seeds. The codA-transgenic seeds germinated faster and at higher frequency than WT seeds with high temperature treatment. After heat stress, levels of expression of a mitochondrial small heat-shock protein (MT-sHSP), heat-shock protein 70 (HSP70) and heat-shock cognate 70 (HSC70) were higher in transgenic seeds than in WT seeds during heat stress, and the accumulation of HSP70 was more prominent in codA-transgenic seeds than in WT seeds. Addition of GB to the germination medium or imbibition of seeds in a solution of GB enhanced the tolerance of WT seeds to high temperatures. WT seeds treated with exogenous GB also expressed heat-shock genes at elevated levels and accumulated more HSP70 than controls. Our results suggest that GB, either applied exogenously or accumulated in vivo in codA-transgenic seeds, enhanced the expression of heat-shock genes in and improved the tolerance to high temperature of tomato seeds during germination. PMID- 21711359 TI - An Arabidopsis (malectin-like) leucine-rich repeat receptor-like kinase contributes to downy mildew disease. AB - Biotrophic filamentous plant pathogens frequently establish intimate contact with host cells through intracellular feeding structures called haustoria. To form and maintain these structures, pathogens must avoid or suppress defence responses and reprogramme the host cell. We used Arabidopsis whole-genome microarrays to characterize genetic programmes that are deregulated during infection by the biotrophic' oomycete downy mildew pathogen, Hyaloperonospora arabidopsidis. Marked differences were observed between early and late stages of infection, but a gene encoding a putative leucine-rich repeat receptor-like kinase (LRR-RLK) was constantly up-regulated. We investigated the evolutionary history of this gene and noticed it being one of the first to have emerged from a common ancestral gene that gave rise to a cluster of 11 genes through duplications. The encoded LRR-RLKs harbour an extracellular malectin-like (ML) domain in addition to a short stretch of leucine-rich repeats, and are thus similar to proteins from the symbiosis receptor-like kinase family. Detailed expression analysis showed that the pathogen-responsive gene was locally expressed in cells surrounding the oomycete. A knockout mutant showed reduced downy mildew infection, but susceptibility was fully restored through complementation of the mutation, suggesting that the (ML-)LRR-RLK contributes to disease. According to the mutant phenotype, we denominated it Impaired Oomycete Susceptibility 1 (IOS1). PMID- 21711360 TI - Resistance to liver fluke infection in the natural sheep host is correlated with a type-1 cytokine response. AB - Indonesian thin-tail (ITT) sheep can resist infection with Fasciola gigantica but not F. hepatica and presents an ideal model to investigate the mechanisms of liver fluke resistance in a natural host. This study examines the local and systemic immune responses of sheep during Fasciola infection and demonstrates that different anatomical tissues display distinct cytokine profiles consistent with liver fluke migration. The study also reveals a significant difference in the cytokine and antibody profiles of ITT sheep infected with F. gigantica compared with F. hepatica, with a higher ratio of IL-4/IFN-gamma mRNA expression and specific IgG1/IgG2 antibodies strongly correlating with pathology. Interestingly, the significant type-1 cytokine profile occurred in the lymph node closest to the site of infection at a time when the effective immune response against F. gigantica liver flukes is thought to occur. When the same F. gigantica infection in the resistant ITT sheep was compared with the susceptible Merino breed, the resistant type-1 phenotype against liver fluke infection was only observed in the ITT sheep. These studies provide the first evidence to suggest that the induction of an early type-1 immune response in this natural sheep host may be responsible for the ability to resist liver fluke infection. PMID- 21711361 TI - Functional genomics approaches in parasitic helminths. AB - As research on parasitic helminths is moving into the post-genomic era, an enormous effort is directed towards deciphering gene function and to achieve gene annotation. The sequences that are available in public databases undoubtedly hold information that can be utilized for new interventions and control but the exploitation of these resources has until recently remained difficult. Only now, with the emergence of methods to genetically manipulate and transform parasitic worms will it be possible to gain a comprehensive understanding of the molecular mechanisms involved in nutrition, metabolism, developmental switches/maturation and interaction with the host immune system. This review focuses on functional genomics approaches in parasitic helminths that are currently used, to highlight potential applications of these technologies in the areas of cell biology, systems biology and immunobiology of parasitic helminths. PMID- 21711362 TI - Cytokine gene expression at the materno-foetal interface after experimental Neospora caninum infection of heifers at 110 days of gestation. AB - Neospora caninum is a major cause of abortion in cattle, but the reasons why only some animals abort remain unclear. The immunological control of the parasite in the placenta or by the foetus could be the key to determining the mechanism of abortion and/or transplacental transmission to the foetus. In this study, cytokine gene expression, analysed by real-time RT-PCR, at the maternal (caruncle) and foetal placenta (cotyledon) of heifers infected at 110 days of gestation by intravenous inoculation of N. caninum tachyzoites was compared with the responses in uninfected heifers. Animals were euthanized 3 weeks after infection. Upregulated Th1, Th2 and T-regulatory (Treg) cytokine gene expression was observed in both the maternal and the foetal placenta in the infected group. In the caruncle of infected animals, the main changes included upregulation of IFN-gamma, IL-12p40, IL-6 and IL-10. In the cotyledon, the main changes included upregulation of IFN-gamma and downregulation of TGF-beta, being the later the only cytokine downregulated in the infected group. The observed cytokine expression pattern was associated with alive but transplacentally infected foetuses, suggesting that such cytokine pattern is beneficial to foetal survival, but could have a role in the transplacental transmission of the parasite. PMID- 21711363 TI - Adoptive transfer of dendritic cells isolated from helminth-infected mice enhanced T regulatory cell responses in airway allergic inflammation. AB - Our and others' previous studies have shown that Schistosoma japonicum (SJ) infection can inhibit allergic reactions. Moreover, we found that adoptive transfer of dendritic cells (DCs) from inhibited mice showed a similar inhibitory effect on allergy, suggesting a critical role of DCs in SJ-infected mediated inhibition of allergy. In this study, we further examined the mechanism by which DCs contribute to inhibition of allergy. Our results showed that DCs from SJ infected mice (SJDCs) produced significantly higher levels of IL-10 compared to those from naive control mice (NDCs). Adoptive transfer of SJDCs, unlike NDCs, significantly increased CD4+CD25+Foxp3+ T cells and CD4+CD25+IL-10+ T cells regulatory T-cell responses in vivo. This was correlated with significantly reduced production of IL-4 and IL-5 by CD4+ T cells, eotaxin in lung tissues and reduced airway allergic inflammation in the SJDC recipients following allergen sensitization and challenge. These data suggest that helminth infection may induce tolerogenic DCs that can inhibit the development of airway allergic inflammation through enhancing T regulatory cell responses. PMID- 21711364 TI - Influence of beta-glucan on innate immunity and resistance of Lutjanus guttatus to an experimental infection of dactylogyrid monogeneans. AB - The present study investigated the effect of beta-1,3/1,6-glucan on growth, haematology, innate immunity and resistance against dactylogyrids on the spotted rose snapper (Lutjanus guttatus). Fish were fed during 5 weeks with commercial diet (control group) and same diet supplemented with three levels of beta-glucans (0.05%, 0.1% and 0.5%/kg feed). The results showed that at concentrations of 0.05% and 0.1%, fish growth was enhanced, and in weeks 2 and 4, an increase in cellular responses such as percentage of monocytes, neutrophils, respiratory burst activity and nitric oxide activity was observed. In diet with 0.5%beta glucans, changes were registered at the end of the experiment. At week 2, 0.05%beta-glucans showed the best response to most of the analysed parameters. In a second trial, diet with 0.05%beta-glucans was chosen to prove its effect on the resistance of infected fish with monogeneans. The results showed that fish reduce significantly the number of dactylogyrids, and parameters such as WBC, percentage of lymphocytes, neutrophils and eosinophils were increased. In addition, WBC and percentage of thrombocytes increased in the control (+). The beta-glucans have the potential to be use in diet formulations of the spotted rose snapper and to limit the adverse effects of dactylogyrids. PMID- 21711365 TI - Role of scuticociliate proteinases in infection success in turbot, Psetta maxima (L.). AB - Scuticociliatosis caused by Philasterides dicentrarchi is one of the most severe diseases of farmed turbot, Psetta maxima (L.). Immunized fish showed elevated levels of specific antibodies (Ab), which caused the destruction of parasites through the activation of complement by the alternative and classical pathways. By using affinity chromatography on bacitracin-sepharose columns, we demonstrated the existence of high levels of parasite proteinases in the serum and, to a lesser extent, in the ascitic fluid of experimentally infected fish, and the absence of such proteinases in the serum of uninfected fish. Serum from uninfected fish displayed haemolytic activity against sheep red blood cells. However, incubation of this serum with parasite proteinases led to a decrease in serum haemolytic activity, suggesting that proteinases are able to destroy fish complement. Proteinases isolated from serum or ascitic fluid of infected fish were also able to degrade turbot Ab. Preincubation of turbot serum containing specific Ab for P. dicentrarchi with the proteinases led to a significant decrease in the killing activity of the serum. The results confirm that P. dicentrarchi proteinases in serum from infected fish may provide a mechanism for circumventing normal host immunity by inactivating the Ab and complement factors required for complement activation. PMID- 21711366 TI - Identification of bacterial plasmids based on mobility and plasmid population biology. AB - Plasmids contain a backbone of core genes that remains relatively stable for long evolutionary periods, making sense to speak about plasmid species. The identification and characterization of the core genes of a plasmid species has a special relevance in the study of its epidemiology and modes of transmission. Besides, this knowledge will help to unveil the main routes that genes, for example antibiotic resistance (AbR) genes, use to travel from environmental reservoirs to human pathogens. Global dissemination of multiple antibiotic resistances and virulence traits by plasmids is an increasing threat for the treatment of many bacterial infectious diseases. To follow the dissemination of virulence and AbR genes, we need to identify the causative plasmids and follow their path from reservoirs to pathogens. In this review, we discuss how the existing diversity in plasmid genetic structures gives rise to a large diversity in propagation strategies. We would like to propose that, using an identification methodology based on plasmid mobility types, we can follow the propagation routes of most plasmids in Gammaproteobacteria, as well as their cargo genes, in complex ecosystems. Once the dissemination routes are known, designing antidissemination drugs and testing their efficacy will become feasible. We discuss in this review how the existing diversity in plasmid genetic structures gives rise to a large diversity in propagation strategies. We would like to propose that, by using an identification methodology based on plasmid mobility types, we can follow the propagation routes of most plasmids in ?-proteobacteria, as well as their cargo genes, in complex ecosystems. PMID- 21711367 TI - Origins of bacterial diversity through horizontal genetic transfer and adaptation to new ecological niches. AB - Horizontal genetic transfer (HGT) has played an important role in bacterial evolution at least since the origins of the bacterial divisions, and HGT still facilitates the origins of bacterial diversity, including diversity based on antibiotic resistance. Adaptive HGT is aided by unique features of genetic exchange in bacteria such as the promiscuity of genetic exchange and the shortness of segments transferred. Genetic exchange rates are limited by the genetic and ecological similarity of organisms. Adaptive transfer of genes is limited to those that can be transferred as a functional unit, provide a niche transcending adaptation, and are compatible with the architecture and physiology of other organisms. Horizontally transferred adaptations may bring about fitness costs, and natural selection may ameliorate these costs. The origins of ecological diversity can be analyzed by comparing the genomes of recently divergent, ecologically distinct populations, which can be discovered as sequence clusters. Such genome comparisons demonstrate the importance of HGT in ecological diversification. Newly divergent populations cannot be discovered as sequence clusters when their ecological differences are coded by plasmids, as is often the case for antibiotic resistance; the discovery of such populations requires a screen for plasmid-coded functions. This paper reviews the features of bacterial genetics that allow HGT, the similarities between organisms that foster HGT between them, the limits to the kinds of adaptations that can be transferred, and amelioration of fitness costs associated with HGT; the paper also reviews approaches to discover the origins of new, ecologically distinct bacterial populations and the role that HGT plays in their founding. PMID- 21711368 TI - Isolation of bacterial extrachromosomal DNA from human dental plaque associated with periodontal disease, using transposon-aided capture (TRACA). AB - The human oral cavity is host to a complex microbial community estimated to comprise >700 bacterial species, of which at least half are thought to be not yet cultivable in vitro. To investigate the plasmids present in this community, we used a transposon-aided capture system, which allowed the isolation of plasmids from human oral supra- and subgingival plaque samples. Thirty-two novel plasmids and a circular molecule that could be an integrase-generated circular intermediate were isolated. PMID- 21711369 TI - Metal-ion susceptibility of oral bacterial species. AB - AIMS: This study aimed to evaluate the effect of lead (Pb) on growth of bacterial species related to dental diseases in vitro. METHODS AND RESULTS: The effects of lead acetate on representative species of the oral flora were examined at 0.1-10 mmol l(-1) and compared with the effect of silver nitrate and ferrous sulfate. The minimal inhibitory concentration of lead acetate was between 0.15 and 5 mmol l(-1) for the bacterial strains tested. The minimal bactericidal concentration of lead acetate for most oral species was detected in the range of 5-10 mmol l(-1). Silver nitrate at a concentration of 1.25 mmol l(-1) was sufficient to exhibit antibacterial activity against almost all bacteria tested. Ferrous sulfate had the lowest effect. CONCLUSIONS: The study indicated a general antimicrobial effect of lead on oral bacterial species in the range of 0.15-10 mmol l(-1). The toxicity of silver nitrate was the highest, whereas that of ferrous sulfate was the lowest. Gram-positive species had a tendency to be less susceptible for metals than Gram-negatives. SIGNIFICANCE AND IMPACT OF THE STUDY: The study shows that it is possible that microbiological changes may occur in the dental plaque in children because of toxic exposure of environmental lead. PMID- 21711370 TI - CAC2634-disrupted mutant of Clostridium acetobutylicum can be electrotransformed in air. AB - AIMS: To simplify the electrotransformation process of Clostridium acetobutylicum, which currently needs to be performed in an anaerobic chamber, thus laborious and time-consuming. METHODS AND RESULTS: The CAC2634 gene encoding PerR is a known peroxide regulon repressor in Cl. acetobutylicum. CAC2634 in a previously constructed Restriction-Modification system deficient Cl. acetobutylicum mutant SMB009 was disrupted using ClosTron method. The resulted mutant SMB012 can be electrotransformed in air with an efficiency of 1.2-3.1 * 10(3) transformants MUg(-1) DNA. CONCLUSIONS: We demonstrated that the disruption of CAC2634 in Cl. acetobutylicum enables its electrotransformation in air. SIGNIFICANCE AND IMPACT OF THE STUDY: The electrotransformation process of Cl. acetobutylicum could be significantly simplified, especially when operating multiple electrotransformations. PMID- 21711371 TI - Comparison of two filtration-elution procedures to improve the standard methods ISO 10705-1 & 2 for bacteriophage detection in groundwater, surface water and finished water samples. AB - AIM: To select a reliable method for bacteriophage concentration prior detection by culture from surface water, groundwater and drinking water to enhance the sensitivity of the standard methods ISO 10705-1 & 2. METHODS AND RESULTS: Artificially contaminated (groundwater and drinking water) and naturally contaminated (surface water) 1-litre samples were processed for bacteriophages detection. The spiked samples were inoculated with about 150 PFU of F-specific RNA bacteriophages and somatic coliphages using wastewater. Bacteriophage detection in the water samples was achieved using the standard method without and with a concentration step (electropositive Anodisc membrane or a pretreated electronegative Micro Filtration membrane, MF). For artificially contaminated matrices (drinking and ground waters), recovery rates using the concentration step were superior to 70% whilst analyses without concentration step mainly led to false negative results. Besides, the MF membrane presented higher performances compared with the Anodisc membrane. CONCLUSION: The concentration of a large volume of water (up to one litre) on a filter membrane avoids false negative results obtained by direct analysis as it allows detecting low number of bacteriophages in water samples. SIGNIFICANCE AND IMPACT OF THE STUDY: The addition of concentration step before applying the standard method could be useful to enhance the reliability of bacteriophages monitoring in water samples as bio-indicators to highlight faecal pollution. PMID- 21711373 TI - Association of serum retinol-binding protein 4 with insulin resistance and metabolic parameters during olanzapine therapy. AB - OBJECTIVE: Retinol-binding protein 4 (RBP4) has been shown to be associated with insulin resistance (IR), metabolic indices and metabolic syndrome (MetS) in various patient populations and in obesity. We investigated the association between metabolic parameters, IR and RBP4 during olanzapine therapy. DESIGN: A prospective study. PATIENTS: Thirty-seven participants with psychiatric disorder who were atypical antipsychotic naive and newly initiated on olanzapine were assessed. MEASUREMENTS: Fasting RBP4, anthropometric and metabolic variables were measured before and after 3 months of olanzapine therapy. RESULTS: Participants who developed MetS showed higher RBP4 levels compared with those without MetS, although not significant (P = 0.053). The variation in RBP4 level was correlated with changes in systolic blood pressure (r = 0.423, P = 0.009), diastolic blood pressure (r = 0.390, P = 0.017), total cholesterol (r = 0.446, P = 0.006) and low density lipoprotein (LDL) (r = 0.407, P = 0.012). Multiple linear regression analysis illustrated that end-point log insulin level was the most significant independent predictor of final log RBP4 levels (standardized beta = 0.353, P = 0.024). CONCLUSIONS: Our results suggest that RBP4 levels might be associated with at least some olanzapine-induced metabolic abnormalities and cardiovascular disease risk factors. PMID- 21711372 TI - The relationship between fat depot-specific preadipocyte differentiation and metabolic syndrome in obese women. AB - OBJECTIVE: Obesity is strongly associated with metabolic syndrome, but not all obese individuals display a clustering of metabolic risk factors. Recent studies have shown that in vitro subcutaneous (SC)-preadipocyte differentiation is negatively associated with obesity. These results suggest that impaired adipogenesis is an important factor linking obesity to metabolic disorders. We examined whether in vitro preadipocyte differentiation is associated with metabolic syndrome, independent of obesity. DESIGN/PATIENTS/MEASUREMENTS: Paired adipose tissue samples were obtained from the 13 nonobese women and the 65 obese women. The CD34(+)/CD31(-) cells were isolated from the stromal-vascular fraction of both SC and omental (OM) fat depots by immune magnetic separation, and the subset was cultured with a differentiation cocktail. Then, we analysed the relationship between the degree of preadipocyte differentiation and metabolic factors. RESULTS: Obese women without metabolic syndrome (n = 37) had significantly higher SC-preadipocyte differentiation than equally obese women with metabolic syndrome (n = 28); however, OM-preadipocyte differentiation was similar in both groups. SC-preadipocyte differentiation was strongly correlated with triglycerides, HDL cholesterol, homoeostasis model assessment of insulin resistance and OM-adipocyte size. However, OM-preadipocyte differentiation was not correlated with any of these parameters. CONCLUSIONS: This study identified that SC-preadipocyte differentiation is associated with metabolic syndrome independent of obesity, whereas OM-preadipocyte differentiation is not. These findings suggest that, in the setting of obesity, an enhanced adipogenic capacity of SC depots could be protective for metabolic syndrome. Our data underscores an interaction between adipose tissue homoeostasis and metabolic disorder. PMID- 21711374 TI - Sex hormone-binding globulin at the crossroad of body composition, somatotropic axis and insulin/glucose homeostasis in young healthy men. AB - OBJECTIVES: Sex hormone-binding globulin (SHBG) modulates the bioavailability of sex steroids at tissue level. Genetic, hormonal and lifestyle-related factors determine the SHBG levels, and low SHBG levels are a known risk factor for the development of the metabolic syndrome, diabetes and cardiovascular diseases. We investigated to what extent different determinants contribute to the variation in SHBG levels in healthy young men. DESIGN AND PATIENTS: Healthy male siblings (n = 677) aged 25-45 year were recruited in a cross-sectional, population-based study. MEASUREMENTS: Lean and fat mass were measured using dual-energy X-ray absorptiometry (DXA), and immunoassays were used to determine the serum hormonal levels. Additional information about smoking and physical activity was obtained using questionnaires. Carriers of two SHBG polymorphisms, the Asp327Asn polymorphism and the (TAAAA)(n) repeat polymorphism, were identified. RESULTS: Weight, BMI, whole body fat mass and truncal fat mass were negatively associated with SHBG levels. Body composition characteristics did not differ between SHBG genotype groups, indicating that body composition controls SHBG levels rather than the other way around. The associations may be mediated by adipokines because leptin and adiponectin were, respectively, inversely and positively associated with SHBG levels. Insulin and glucose were negatively associated with SHBG levels, as well as IGF-1 and IGF-BP3, while no associations were found with free thyroid hormone status. CONCLUSIONS: In conclusion, we found that fat mass, insulin and IGF-1 levels are important negative determinants of SHBG levels in young healthy men. The association with fat mass could be mediated by the effects of adiponectin and/or leptin on SHBG synthesis. PMID- 21711375 TI - Germline RET sequence variation I852M and occult medullary thyroid cancer: harmless polymorphism or causative mutation? AB - OBJECTIVE: Rearranged during transfection (RET) gene analysis, widely used to identify carriers at risk of medullary thyroid cancer (MTC), occasionally uncovers novel sequence 'variants of unknown clinical significance' including RET I852M. This study aimed to clarify whether RET I852M represents a harmless polymorphism or a pathogenic mutation. DESIGN: Clinical investigation supported by functional characterization of I852M mutant cells in vitro. PATIENTS AND MEASUREMENTS: Genotype-phenotype correlation including five kindreds from a three generational Caucasian I852M RET family. RESULTS: A node-negative occult MTC was found in the 64-year-old index patient who had increased basal and stimulated peak calcitonin levels of 190 and 13 307 ng/l, respectively. Her 4-year-old grandson had no histopathological evidence of C-cell disease although his serum calcitonin levels had increased within 5 months from 3.2 to 6.3 ng/l basally and from 17.2 to 24.5 ng/l after pentagastrin stimulation. His mother and two 11- and 1.5-year-old siblings, also carrying the gene, had normal basal and stimulated calcitonin levels and hence did not undergo surgery. Functional characterization of transfected NIH3T3 cells in vitro (cell proliferation rate; cell viability; anchorage-independent cell growth; cell migration; and invasion) indicated that I852M mutant cells have transforming and migratory activities similar to American Thyroid Association (ATA) class A V804M mutants. I852M mutants demonstrated a weaker proliferative potential than fast-proliferating ATA class C C634R mutants and revealed a weaker migratory activity compared with aggressively growing ATA class D A883F mutants. CONCLUSIONS: I852M sequence variations represent genuine RET mutations, falling into ATA class A of weakly activating RET germline mutations. PMID- 21711376 TI - The impact of intensified exercise training on insulin resistance and fitness in overweight and obese women with and without polycystic ovary syndrome. AB - OBJECTIVE: To evaluate mechanisms of insulin resistance (IR) in overweight and obese women with and without polycystic ovary syndrome (PCOS) and explore relationships between IR, fitness and body mass index (BMI) at baseline and following exercise intervention. DESIGN: Prospective controlled intensified exercise intervention study. PATIENTS: A total of 20 overweight (BMI > 25 kg/m(2) ) and obese (>30 kg/m(2) ), reproductive-aged PCOS women and 13 non-PCOS overweight, healthy controls of comparable BMI and age were studied at baseline. Measures were repeated in 13 PCOS and eight control women following three 1-h exercise sessions per week over 12 weeks. MEASUREMENTS: Insulin resistance was measured by glucose infusion rate on euglycaemic hyperinsulinaemic clamp, and fitness was assessed by VO(2max) . RESULTS: At baseline, PCOS women were 46% more insulin resistant than controls (175.6 vs 257.2 mg/m(2) /min, P < 0.05) with IR independently associated with VO(2max) and BMI in the PCOS group only (P < 0.01). Postexercise IR improved across both groups (P < 0.01). In PCOS women, IR improved by 16% (P < 0.05) but was not restored to the same level as controls (P < 0.05). Improvement in IR and in VO(2max) was related to the PCOS group (r(2) = 0.85, P < 0.05), yet change in IR and in fitness was not related. No associations were found in controls. CONCLUSIONS: While intensified exercise improves IR in PCOS women, a higher IR persisted following exercise in PCOS women, and a clear relationship between improved IR and improved fitness was not found. Therefore, other mechanisms of, and therapies for, IR must be explored in PCOS as IR remains higher than observed in non-PCOS controls. PMID- 21711377 TI - Primary meningeal histiocytic sarcoma: a report of two unusual cases. PMID- 21711378 TI - Heme oxygenase-1 could mediate the protective effects of hyperbaric oxygen preconditioning against hepatic ischemia-reperfusion injury in rats. AB - 1. Heme oxygenase 1 (HO-1) has been shown to play a pivotal role in the maintenance of cellular homeostasis when the liver undergoes sublethal stress, such as ischaemia-reperfusion (I/R) injury. In the present study, we investigated the protective role of HO-1 in hyperbaric oxygen (HBO) preconditioning against liver injury after I/R. 2. A total hepatic ischaemia (30 min) and reperfusion (60 min) injury model in rats was used in the present study. Preconditioned groups were exposed to HBO 24 h prior to the induction of I/R injury. Other groups were injected with zinc protoporphyrin IX (ZnPP) intraperitoneally 1 h before I/R to inhibit HO-1 activity. At the end of the reperfusion period, blood and liver samples were collected for the analysis of liver injury markers, morphological changes, and HO-1 expression and activity in the liver. 3. In untreated rats, I/R induced an increase in hepatic injury markers, such as plasma transaminases, inflammatory cytokines (tumour necrosis factor-alpha and interleukin-1beta), and tissue malondialdehyde. However, HBO preconditioning attenuated the I/R-induced increases in these hepatic injury markers, and prevented both the necrosis and apoptosis of hepatocytes induced by I/R injury. Furthermore, HBO preconditioning significantly increased HO-1 mRNA and protein levels in the liver. In rats in which HO-1 activity had been inhibited with ZnPP pretreatment, the protective effects of HBO preconditioning against I/R injury were abolished. 4. In conclusion, HBO preconditioning can protect the liver against I/R injury and it appears that this effect might be mediated by the induction of HO-1. PMID- 21711379 TI - Rho kinase inhibition by fasudil exerts antioxidant effects in hypercholesterolemic rats. AB - 1. The inhibition of Rho kinase (ROCK) ameliorates many cardiovascular dysfunctions, but the role of ROCK in oxidative stress in hypercholesterolemic rats has not been explored. The aim of the current study was to investigate the antioxidant effects and the potential related mechanisms of fasudil, a selective ROCK inhibitor, in high-cholesterol diet (HCD)-induced hypercholesterolemic rats. 2. Hypercholesterolemia was induced in rats by feeding with a HCD for 4 weeks. Starting from day 15, physiological saline (1 mL/100 g) or ROCK inhibitor, fasudil (10 or 30 mg/kg), was injected intraperitoneally for another 14 days. 3. The results showed that fasudil significantly suppressed ROCK activity, potently elevated the activities of antioxidant enzymes and the expression of endothelial nitric oxide synthase, as well as the concentration of nitric oxide in the serum and cardiac tissue. In addition, fasudil notably suppressed the extent of lipid peroxidation and attenuated the histopathological changes in the heart and liver of hypercholesterolemic rats. 4. These antioxidant effects of fasudil suggest that ROCK activation is involved in oxidative stress in hypercholesterolemic rats. PMID- 21711380 TI - Multiple factors are required for the prediction of metabolic syndrome. PMID- 21711381 TI - Mechanisms of reduced contractility in an animal model of hypertensive heart failure. AB - 1. Alterations in intracellular Ca(2+) homeostasis have frequently been implicated as underlying the contractile dysfunction of failing hearts. Contraction in cardiac muscle is due to a balance between sarcolemmal (SL) and sarcoplasmic reticulum (SR) Ca(2+) transport, which has been studied in single cells and small tissue samples. However, many studies have not used physiological temperatures and pacing rates, and this could be problematic given different temperature dependencies and kinetics for transport processes. 2. Spontaneously hypertensive rats (SHR) and their age-matched Wistar Kyoto controls (WKY) provide an animal model of hypertensive failure with many features in common to heart failure in humans. Steady-state measurements of Ca(2+) and force showed that peak stress was reduced in trabeculae from failing SHR hearts in comparison to WKY, although the Ca(2+) transients were bigger and decayed more slowly. 3. Dynamic Ca(2+) cycling was investigated by determining the recirculation fraction (RF) of activator Ca(2+) through the SR between beats during recovery from experimental protocols that potentiated twitch force. No difference in RF between rat strains was found, although the RF was dependent on the potentiation protocol used. 4. Superfusion with 10 mmol/L caffeine and 0 mmol/L [Ca(2+)](o) was used to measure SL Ca(2+) extrusion. The caffeine-induced [Ca(2+)](i) transient decayed more slowly in SHR trabeculae, suggesting that SL Ca(2+) extrusion was slower in SHR. 5. An ultrastructural immunohistochemical analysis of left ventricular free wall sections using confocal microscopy showed that t-tubule organization was disrupted in myocytes from SHR, with reduced labelling of the SR Ca(2+) -ATPase and Na(+) -Ca(2+) exchanger in comparison to WKY, with the latter possibly related to a lower fraction of t-tubules per unit cell volume. 6. We suggest that although Ca(2+) transport is altered in the progression to heart failure, force development is not limited by the amplitude of the Ca(2+) transient. Despite slower SR Ca(2+) transport, the recirculation fraction and dynamic response to a change of inotropic state minimally altered changes in the SHR model because there was a similar slowing in Ca(2+) extrusion across the surface membrane. PMID- 21711382 TI - Are threshold levels of signal transduction required for the protective effect of cilostazol against cardiac ischaemia-reperfusion injury? PMID- 21711383 TI - Nitric oxide synthase activity in the abdominal aorta of rats is decreased after 4 weeks of simulated microgravity. AB - 1. The aim of the present study was to investigate the effects of simulated microgravity on the arterial dilatory responsiveness and L-arginine (L-Arg) nitric oxide (NO)-cGMP pathway in the abdominal aorta of rats. 2. Twenty healthy male Sprague-Dawley were randomly divided into control and simulated microgravity groups. Rats in the simulated microgravity group were subjected to hindlimb unweighting (HU). After 4 weeks, arterial dilatory responsiveness was examined in vitro in isolated abdominal aortic rings. Western blotting was used to measure endothelial (e) and inducible (i) NO synthase (NOS) protein content. Total concentrations of nitrate and nitrite (NO(x)), the stable metabolites of NO, were determined by the chemiluminescence method. Nitric oxide synthase activity in the abdominal aorta was determined through the conversion of [(3)H]-L-Arg to [(3)H]-L citrulline. 3. The data showed that the dilatory responses of the arterial rings to L-Arg and acetylcholine decreased in rats exposed to simulated microgravity, but the dilatory responses to sodium nitroprusside and 8-bromo-cGMP were similar in both simulated microgravity and control rats. The expression of eNOS and iNOS did not differ significantly between the two groups. The NO(x) concentration in the abdominal aorta of HU rats was significantly less than that in control rats. Nitric oxide synthase activity in the aorta decreased after 4 weeks of HU. 4. The data indicate that endothelium-dependent vasorelaxation in the abdominal aorta decreased due to 4 weeks of simulated microgravity in rats and that this impaired dilatory responsiveness may result from decreased NOS activity. PMID- 21711384 TI - Psychometric testing of the Spanish version of the practice environment scale of the nursing work index in a primary healthcare context. AB - AIM: This paper is a report of psychometric testing of the Spanish version of the Practice Environment Scale of the Nursing Work Index for use in a primary health care. BACKGROUND: The Practice Environment Scale of the Nursing Work Index has been widely used in different studies and contexts. However, there is no validated version for primary care nursing staff in Spain. METHODS: A descriptive, multicentre, cross-sectional study for transcultural adaptation and psychometric validation purposes. Data were collected from October 2009 to January 2010. To test the reliability of the factors in the measurement model, Cronbach's alpha was used. To study the measurement model, different structural models were tested, using exploratory and confirmatory factor analyses. 377 completed questionnaires were obtained from a total of 553 nurses working for the Public Health Service in the Balearic Islands (Spain). This represents a response rate of 68.2%. RESULTS: For overall reliability, a Cronbach alpha of 0.91 was obtained. The confirmatory analysis upholds the original five-factor structure. CONCLUSION: The excellent goodness of fit of the confirmatory analysis corroborates the validity of this adapted version in primary healthcare contexts. PMID- 21711385 TI - Moderators of access and utilization of clinical preventive services in older adults. AB - AIM: This paper reports a study exploring the relationships between potential moderators of access and utilization of clinical preventive services in a homogeneous sample of older adults with near universal health coverage. BACKGROUND: Advancements have occurred in eliminating financial and structural barriers to utilization of clinical preventive services (primary, secondary and tertiary prevention) in most developed countries, but variations in utilization continue. These variations may be attributed to non-social determinants of health moderators that impact utilization in older adults. METHODS: Theorized relationships were explored using questions from the United States Behavioral Risk Factor Surveillance System Survey and a homogenous convenience sample of 202 older adults (mean age 84; sd 5.23) with near universal health coverage. Data collected across a 2 year period (2007-2009) were analysed using Chi-square, Mann Whitney U and Hierarchical Logistic Regression. FINDINGS: Several logistic regression models of personal access (advised to lose weight, high blood pressure, high cholesterol); moderators (gender, perceived health status, BMI >= 30 kg/m(2)); and clinical preventive services utilization (check-up in last 12 months; ever had colonoscopy/sigmoidoscopy) showed statistically significant (P < 0.05) improvement in model fit by adding interaction terms (access X moderator). CONCLUSION: Exploring the impact of moderators on utilization may yield more insight into variations than could be explained by measurement of the direct affect of having near universal health coverage alone. PMID- 21711386 TI - Exploring the antipathy of nursing staff who work within secure healthcare facilities across the United Kingdom to young people who self-harm. AB - AIMS: This paper is a report of a study that compared relevant attitudinal dimensions of Registered Nurses and nursing aides working within a Young Offenders' Institute and two young people's forensic units in the United Kingdom towards young people in their care who self-harm. BACKGROUND: Nurses caring for young people within secure environments may engage at some point with patients who harm themselves. These staff often experience strong negative emotional reactions which can lead to antipathy and alienation. METHODS: Forty seven Registered Nurses and 22 nursing aides completed the Self-Harm Antipathy Scale, which consists of 30 attitudinal self-report items. The data were collected between June 2008 and December 2008, and analysed using spss version 17. RESULTS: Results displayed that age per se, length of service with self-harming clients, and whether the participant was a Registered Nurse or nursing aide, and number of self-harming clients worked with did not influence the Self-Harm Antipathy Scale score or any of its component sub-scores. However, field of nursing the nurse was registered under, previous study of self-harm, year first registered and gender showed significant effects. CONCLUSIONS: Given that responses reflect a degree of both empathy and apathy it seems that there is a need to promote greater therapeutic alliances and communication; for example, the use of positive regard to help reduce the incidence of labelling and the negative effects this has upon relationships. There is a significant need for nursing staff working with young people who self-harm to have access to relevant educational programmes. A focus on harm minimization could be key areas for further development. PMID- 21711387 TI - Diprosopia/dicephalia in calves in northern Italy: clinical and aetio pathological features. AB - Cephalic parapagia, a rare congenital anomaly caused by the fusion of two monozygotic embryos, is characterized by a single body and a spectrum of duplication of craniofacial structures. The authors describe the clinical and pathological aspects of the parapagus conjoined twin defect in nine calves referred to the Department of Animal Pathology, Turin, between 1999 and 2009. The majority of the calves (eight cases) presented two snouts that shared three or four eyes (diprosopia); one calf presented two separate skulls fused at the foramen magnum (dicephalia). Bilateral inferior brachygnathia was observed in four calves. Post-mortem examination of the skull revealed complete brain duplication with fusion at the caudal portion of the brainstem in all calves. Histological features of the cerebral hemispheres and brainstem were normal; moderate disorganization of the cerebellar cortex was noted in two cases. Cardiac malformations were observed in three calves. No aetiologic cause was determined. This article underscores the importance of diprosopia in cattle species and suggests the need for more detailed investigations to better understand its pathogenesis. PMID- 21711388 TI - Perceptions and preferences on denture marking in an Indian sample. AB - AIM: Denture marking is useful in institutional settings and post-mortem identification. Numerous markers have been developed, and their advantages and limitations assessed previously; however, patient perception to denture marking is paramount. We evaluated this in an Indian sample and also gauged their preference for different markers. MATERIALS AND METHODS: One-hundred and one edentulous patients seeking prosthodontic treatment in our institution were shown four denture markers (stainless steel matrix band, paper strip with name inscribed on it, patient photograph and optically readable laminated bar code) and asked whether they wanted similar markers in their dentures; patients were also asked to rank the markers based on preference and indicate their satisfaction with it. RESULTS: Approximately two-thirds of patients (65/101) were uninterested in getting their dentures marked; among the 36 who agreed, 10 preferred the stainless steel band followed by photographs (9), paper strip (6) and bar code (2); nine gave multiple responses and were excluded from analyses. Sixteen patients expressed dissatisfaction with the photographic marker and bar code, while this number reduced for the stainless steel band (13) and paper strip (10). CONCLUSIONS: The results are in contrast to European studies wherein the majority of patients agreed to denture marking, indicating patient background (e.g. education level) may affect perception to denture marking; amongst those who agreed to marking, most preferred, or were satisfied with, the stainless steel and paper strip markers over photographic marker and a complex method such as bar-coding, implying that simple methods harbouring basic patient information may suffice in the Indian context. PMID- 21711389 TI - New method for determining surface roughness of tongue. AB - OBJECTIVE: The degree of atrophy of the lingual papillae in elderly individuals was evaluated using a quantitative method. SUBJECTS AND METHODS: One hundred and eighty-two subjects living in nursing homes and 20 healthy adults as controls were studied. To express the degree of atrophy of the lingual papillae quantitatively, lingual surface roughness was determined by taking an impression with silicone dental material. Based on the impressions obtained from the elderly subjects, they were classified by three expert dentists into three groups: Normal, Smooth and Rough. The same determinations were also performed in the 20 healthy controls and compared with 38 of the elderly subjects who had agreement from all of the experts and without the presence of fissures (Normal, n = 6; Smooth, n = 12; Rough, n = 20). RESULTS: The roughness average value for the controls was 65.0 MUm, while that for the elderly subjects in the Normal, Smooth and Rough groups was 73.9 MUm, 42.2 MUm and 94.1 MUm, respectively, which were significantly different. CONCLUSION: The present results indicate that the present technique of obtaining an impression of the tongue surface is simple and reliable for routine evaluation and quantification of the degree of atrophy as well as morphology of the lingual papillae. PMID- 21711390 TI - Relationships between bone mass and micro-architecture at the mandible and iliac bone in edentulous subjects: a dual X-ray absorptiometry, computerised tomography and microcomputed tomography study. AB - OBJECTIVES: To compare bone volume, bone mineral density, cortical thickness and bone micro-architecture in a series of paired mandibular and iliac bone samples analysed by various imagery techniques to see whether relationships exist between the various techniques and between mandibular and iliac bone. MATERIALS AND METHODS: Bone samples from the mandible and ilium were harvested in 20 cadavers and analysed by dual energy X-ray absorptiometry (DXA), computerised tomography (CT) on a conventional hospital machine and microCT. RESULTS: Significant correlations were found between Hounsfield density obtained by CT, and bone mass determined by microCT but not with DXA values. Cortical thickness measurements were well correlated between CT and microCT. No relationships were found between mandibular and iliac bone, when considering mineral density, cortical thickness, bone volume or micro-architecture. CONCLUSION: In clinical practice, CT remains the most appropriate routine means for bone qualitative and quantitative evaluation at the mandible. In this ex vivo study, these results confirm that mandibular bone status does not reflect the axial skeletal one and assist in the placement of implants with dental prostheses in old or osteoporotic patients. PMID- 21711391 TI - Association and evolutionary studies of the melatonin receptor 1B gene (MTNR1B) in the self-contained population of Sorbs from Germany. AB - AIMS: Several polymorphisms of the melatonin receptor 1B gene (MTNR1B) have been shown to be associated with elevated fasting plasma glucose and impaired early insulin release. The aim of this study was to assess the effects of MTNR1B variants on traits related to the metabolic syndrome in the self-contained population of Sorbs from Germany. As comprehensive studies concerning the conservation of MTNR1B are lacking, we also evaluated natural selection in vertebrates and human populations at this locus. METHODS: Five single nucleotide polymorphisms representing all blocks of linkage disequilibrium within and surrounding the MTNR1B locus were genotyped in 937 Sorbs for association analyses on metabolic traits related to Type 2 diabetes. The associations were assessed by regression analyses, the conservation between species was investigated with phylogenetic analysis by maximum likelihood (PAML). In addition, various tests of population genetic measures (e.g. fixation index, Tajima's D) were performed. RESULTS: Previously reported association between MTNR1B variants (rs10830963, rs4753426) and oral glucose tolerance test-derived indices of beta-cell function (homeostasis model assessment-B, P = 3.7 * 10-6 and P = 0.004, respectively), as well as insulin (fasting insulin: P=2*10-3 and P=0.02; 30-min insulin: P = 2.1 * 10-4 and P=0.03, respectively) and fasting glucose (rs10830963, P=1.2*10-6) parameters could be replicated in the present study. Phylogenetic analysis by maximum likelihood analyses showed that the gene was strongly conserved between species (omega=0.2583). Structures important for the receptor function are also conserved. On the lineage leading to human adaptive selection was present (omega=1.1030). Population genetic measures further indicated natural selection. CONCLUSIONS: Our data support the physiologic importance of MTNR1B in the context of glucose homeostasis and suggest evidence of selection at this locus. PMID- 21711392 TI - Estimation of LDL cholesterol by the Friedewald formula during an oral glucose tolerance test. PMID- 21711393 TI - Continuous glucose monitoring system during physical exercise in adolescents with type 1 diabetes. AB - AIM: Continuous glucose monitoring system (CGMS) provides detailed information on glucose fluctuations. The aim was to establish whether CGMS could be used during physical exercise and whether it detects more episodes of hypoglycaemia and hyperglycaemia than frequent blood glucose measurements. METHODS: Adolescents with type 1 diabetes (12 girls and 47 boys) participated in three annual sports camps that lasted for 3-4 days and included different types of exercise: soccer, floorball + cross-country skiing and golf. During the study, blood glucose values, mean 8.7 +/- 3.3 per day, were obtained with Hemocue in parallel with the CGMS. RESULTS: Ninety-eight per cent of the participants used the sensor at all times during the camps. Eighty-seven per cent of the sensors gave adequate signals for 24 h and 66% for 48 h. Median durations of hypoglycaemia and hyperglycaemia were 1.7 h per day and 3.8 h per day, respectively. The CGMS identified significantly more episodes of hypoglycaemia (p < 0.005) and hyperglycaemia (p < 0.005) during the day and night than frequent blood glucose tests. CONCLUSION: We demonstrate that, even during days that included episodic strenuous physical exercise, CGMS could provide useful information on glucose fluctuations during day and night, albeit with significant failure rates. PMID- 21711394 TI - Imaging the urinary tract in children with urinary tract infection. AB - AIM: To evaluate whether ultrasonography (US) alone is sufficient in imaging the urinary tract in 1185 children with urinary tract infection (UTI). METHODS: The reports on US and voiding cystourethrography (VCUG) were reviewed. RESULTS: Initial US was normal in 861/1185 patients (73%). VCUG revealed abnormal findings in 285/861 (33%), of which grade III-V vesicoureteral reflux (VUR) comprised 97 cases (11%). During follow-up, VUR had resolved in 88/97 (91%) patients: in 50/57 (88%) patients without active treatment for VUR, in 27/29 (93%) with endoscopic and in 11/11 (100%) with open surgery for VUR. During follow-up, 11/97 patients (11%) had developed new renal scarring detectable in US, but no renal impairment occurred. Except for VUR, VCUG showed nonobstructive urethral valves in two infant boys with normal initial US. Thus, in 861 children with normal initial US, 40 patients with grade III-V VUR and two patients with significant nonreflux pathology may have benefited from surgical treatment, giving the total number of possibly missed pathological finding in 42/861 (4.9%) cases if VCUG had not been performed. CONCLUSION: We suggest that children with UTI could be examined using US alone and to use VCUG only after additional indications. PMID- 21711395 TI - Prognostic relevance of cytometric quantitative assessment in patients with myelodysplastic syndromes. AB - OBJECTIVES: Morphology and cytogenetics are currently used to define prognosis in myelodysplastic syndromes (MDS). However, these parameters have some limits. Flow cytometry has been recently included in the diagnostic panel for MDS, and its prognostic significance is under evaluation. METHODS: Marrow aspirates from 424 MDS patients were analyzed by flow cytometry to evaluate the impact of bone marrow cell immunophenotype on overall survival (OS) and leukemia-free survival (LFS). The immature compartment of myeloblasts was analyzed by the quantitative expression of CD34 (<3% vs. >=3%), CD117, and CD11b(-) /CD66b(-) (<5% vs. >=5%); myeloid maturation was analyzed by the expression of CD11b(+) /CD66b(++) (<15% vs. >=15%) and CD11b(+) /CD66b(+) (<25% vs. >=25%). RESULTS: In univariate analysis, the expression of immaturity markers (CD34(+) , CD117(+) , and CD11b(-) /CD66b(-) ) was associated with shorter LFS and OS (P < 0.0001); higher expression of differentiation markers (CD11b(+) /CD66b(++) and CD11b(+) /CD66b(+) ) was associated with longer LFS (P < 0.0001 and P = 0.0002, respectively) and OS (P < 0.0001). In multivariate analysis, expression of CD34(+) (P = 0.007), CD117(+) (P = 0.013), and CD11b(+) /CD66b(++) (P = 0.023) retained independent prognostic value for OS, while only the expression of CD34(+) was a prognostic factor for LFS (P = 0.0003). Two different risk groups were defined according to the presence of 0-1 or >=2 of these factors with significant different LFS and OS (P < 0.0001). This score showed prognostic value in predicting survival even in subanalysis according to IPSS and WHO subgroups. CONCLUSIONS: Flow cytometric analysis in MDS may provide meaningful prognostic information. Blast percentage expressed as CD117(+) or CD34(+) cells and the quantitative assessment of myeloid maturation showed prognostic value for survival. PMID- 21711396 TI - The c.273+11dup genetic change in the WAS gene is a functionally neutral polymorphism. AB - Several pediatric patients showing symptoms consistent with the Wiskott-Aldrich syndrome (WAS) were referred to us and turned out to display the c.273+11dup change in the WAS gene. It consisted of the insertion of one C in an unusual tract of 7C near the intron 2 donor splicing site of the WAS gene. In the patients, non-synonymous WAS mutations were found twice only and one mutation was elucidated in RUNX1. In the absence of a non-synonymous mutation in the WAS gene, the c.273+11dup change affected neither the levels nor the sequence of WAS mRNA. In the presence of a non-synonymous WAS mutation, the c.273+11dup alteration failed to worsen the expected phenotype. Minor splicing abnormalities concerning exon 10 were observed both in WAS patients, and in healthy individuals carrying or not carrying the c.273+11dup. The c.273+11dup change was encountered four times in 107 normal male and female controls (172 alleles tested: 2.3%), and eight times in a series of 248 male patients (248 alleles tested: 3.2%). We conclude that the presence of the additional C in the WAS gene is a functionally neutral polymorphism. PMID- 21711397 TI - Basic procedures in tension-free vaginal mesh operation for pelvic organ prolapse. AB - A variety of tension-free vaginal mesh (TVM) systems are available for surgical treatment of pelvic organ prolapse (POP). These include Prolift, Apogee/Perigee and Avaulta, all of which vary in terms of mesh size, shape and surgical technique to such an extent that they cannot truly be considered the same operation for the purpose of evaluating results. I began carrying out self-made mesh cut out from Gynemesh PS in 2005. This system has four main characteristics: (i) the mesh is intended as a replacement for defective visceral pelvic fascia; (ii) it bridges between the left and right arcus tendineus fascia pelvis (white line, or ATFP); (iii) large-size mesh is held in place by passing cannulas through the obturator fascia (anterior wall) or the sacrospinous ligament (SSL) to attach the arms of the mesh graft; and (iv) the bladder neck is preserved. The mesh that I have used since then has been essentially similar to the Prolift System, developed by a French TVM group, in terms of size and shape of its central portion. Mesh grafts used for the anterior wall are quite large, so skillful execution will provide sufficient room between the left and right ATFP in almost all cases. This video discusses the fundamental techniques necessary for skillful execution of the tension-free vaginal mesh (TVM) procedure using the Prolift System, focusing on the following points: (i) surgical separation of the correct layers of the vaginal wall, and the area separated, and effective hemostasis; (ii) precise puncture technique, especially the second puncture for the anterior TVM (TVM-A) procedure and the sacrospinous ligament (SSL) puncture in the posterior TVM (TVM-P) procedure; (iii) firmly securing the mesh to the vaginal wall or cervical canal; and (iv) careful mesh placement and formation of a bridge between the left and right arcus tendineus fascia pelvis (ATFP). Proper separation of the vaginal wall layers, in particular, is crucial for preventing unnecessary blood loss and mesh erosion. The second puncture in the TVM-A is the most important of the puncture maneuvers for the procedure. Penetrating the tough tissue near the ischial spine represents a significant challenge, and the SSL penetration in the TVM-P procedure is unexpectedly difficult for those without sufficient experience. In order to become proficient, the surgeon must have hands on experience under the supervision of experts. Finally, TVM is a relatively new procedure, so one must master the fundamentals before gaining true proficiency. The technique does not call for virtuosity on the part of the surgeon, but key points must be mastered to reduce the risk of complications and recurrences. With repeated hands-on training, surgical skills will gradually improve to the requisite level. This is a translated section of a video article originally published in Japanese as a DVD in the Audio-Visual Journal Vol.15 No.15. 2009 by The Japanese Urological Association. PMID- 21711398 TI - Toll-like receptor-2-activating bifidobacteria strains differentially regulate inflammatory cytokines in the porcine intestinal epithelial cell culture system: finding new anti-inflammatory immunobiotics. AB - A total of 23 strains of bifidobacteria taxonomically belonging to five species were tested for their potent immunomodulatory effect using a combination of two methods: the NF-kappaB-reporter assay using a toll-like receptor 2-expressing transfectant (HEK(pTLR2) system) and the mitogenic assay using porcine Peyer's patches immunocompetent cells. Among the four preselected strains from different immunomodulatory groups, Bifidobacterium breve MCC-117 was able to efficiently modulate the inflammatory response triggered by enterotoxigenic Escherichia coli (ETEC) in a porcine intestinal epithelial (PIE) cell line. Moreover, using PIE cells and swine Peyer's patches immunocompetent cell co-culture system, we demonstrated that the immunoregulatory effect of B. breve MCC-117 was related to the capacity of the strain to influence PIE and immune cell interactions, leading to the stimulation of regulatory T cells. The results suggested that bifidobacteria that express high activity in both the HEK(pTLR2) and the mitogenic assays may behave like potential anti-inflammatory strains. The combination of the HEK(pTLR2) system, the evaluation of mitogenic activity and PIE cells will be of value for the development of new immunologically functional foods and feeds that could prevent inflammatory intestinal disorders. Although our findings should be proven in appropriate experiments in vivo, the results of the present work provide a scientific rationale for the use of B. breve MCC-117 to prevent ETEC-induced intestinal inflammation. PMID- 21711399 TI - High-resolution live imaging of plant growth in near physiological bright conditions using light sheet fluorescence microscopy. AB - Most plant growth occurs post-embryonically and is characterized by the constant and iterative formation of new organs. Non-invasive time-resolved imaging of intact, fully functional organisms allows studies of the dynamics involved in shaping complex organisms. Conventional and confocal fluorescence microscopy suffer from limitations when whole living organisms are imaged at single-cell resolution. We applied light sheet-based fluorescence microscopy to overcome these limitations and study the dynamics of plant growth. We designed a special imaging chamber in which the plant is maintained vertically under controlled illumination with its leaves in the air and its root in the medium. We show that minimally invasive, multi-color, three-dimensional imaging of live Arabidopsis thaliana samples can be achieved at organ, cellular and subcellular scales over periods of time ranging from seconds to days with minimal damage to the sample. We illustrate the capabilities of the method by recording the growth of primary root tips and lateral root primordia over several hours. This allowed us to quantify the contribution of cell elongation to the early morphogenesis of lateral root primordia and uncover the diurnal growth rhythm of lateral roots. We demonstrate the applicability of our approach at varying spatial and temporal scales by following the division of plant cells as well as the movement of single endosomes in live growing root samples. This multi-dimensional approach will have an important impact on plant developmental and cell biology and paves the way to a truly quantitative description of growth processes at several scales. PMID- 21711400 TI - The APC/C subunit 10 plays an essential role in cell proliferation during leaf development. AB - The largest E3 ubiquitin-ligase complex, known as anaphase-promoting complex/cyclosome (APC/C), regulates the proteolysis of cell cycle regulators such as CYCLIN B and SECURIN that are essential for sister-chromatid separation and exit from mitosis. Despite its importance, the role of APC/C in plant cells and the regulation of its activity during cell division remain poorly understood. Here, the Arabidopsis thaliana APC/C subunit APC10 was characterized and shown to functionally complement an apc10 yeast mutant. The APC10 protein was located in specific nuclear bodies, most probably resulting from its association with the proteasome complex. An apc10 Arabidopsis knockout mutant strongly impaired female gametogenesis. Surprisingly, constitutive overexpression of APC10 enhanced leaf size. Through kinematic analysis, the increased leaf size was found to be due to enhanced rates of cell division during the early stages of leaf development and, at the molecular level, by increased APC/C activity as measured by an amplification of the proteolysis rate of the mitotic cyclin, CYCB1;1. PMID- 21711401 TI - Identification and characterization of the cysteine protease inhibitor gene MdCPI from Musca domestica. AB - Cysteine proteinase inhibitors (CPIs) are involved in many vital cellular processes such as signalling pathways, apoptosis, immune response and development; however, no CPIs have yet been reported from the housefly Musca domestica. Here we report the isolation and characterization of a housefly CPI gene designated MdCPI. The gene contains an open reading frame of 357 bp encoding a protein of 118 amino acid residues with a putative signal peptide of 17 amino acid residues. Protein alignment demonstrated a high homology to that of Sarcophaga crassipalpis (identity = 51%). Phylogenetic analysis suggested that all CPIs from dipterans, including the housefly, belong to the I25A family and may be descended from a single common ancestor. The gene was expressed in and purified from Escherichia coli. Biochemical studies showed that MdCPI exerts an inhibiting function on papain, which is a classical assay to confirm CPIs. Real time quantitative PCR and immunolocalization analysis revealed that MdCPI is specifically expressed in haemocytes and fat bodies. It is highly down-regulated in larvae and markedly up-regulated in the pupal stage, suggesting that it may be related to development. PMID- 21711402 TI - The pathway of triacylglycerol synthesis through phosphatidylcholine in Arabidopsis produces a bottleneck for the accumulation of unusual fatty acids in transgenic seeds. AB - Engineering of oilseed plants to accumulate unusual fatty acids (FAs) in seed triacylglycerol (TAG) requires not only the biosynthetic enzymes for unusual FAs but also efficient utilization of the unusual FAs by the host-plant TAG biosynthetic pathways. Competing pathways of diacylglycerol (DAG) and subsequent TAG synthesis ultimately affect TAG FA composition. The membrane lipid phosphatidylcholine (PC) is the substrate for many FA-modifying enzymes (desaturases, hydroxylases, etc.) and DAG can be derived from PC for TAG synthesis. The relative proportion of PC-derived DAG versus de novo synthesized DAG utilized for TAG synthesis, and the ability of each pathway to utilize unusual FA substrates, are unknown for most oilseed plants, including Arabidopsis thaliana. Through metabolic labeling experiments we demonstrate that the relative flux of de novo DAG into the PC-derived DAG pathway versus direct conversion to TAG is ~14/1 in wild-type Arabidopsis. Expression of the Ricinus communis FA hydroxylase reduced the flux of de novo DAG into PC by ~70%. Synthesis of TAG directly from de novo DAG did not increase, resulting in lower total synthesis of labeled lipids. Hydroxy-FA containing de novo DAG was rapidly synthesized, but it was not efficiently accumulated or converted to PC and TAG, and appeared to be in a futile cycle of synthesis and degradation. However, FA hydroxylation on PC and conversion to DAG allowed some hydroxy-FA to accumulate in sn-2 TAG. Therefore, the flux of DAG through PC represents a major bottleneck for the accumulation of unusual FAs in TAG of transgenic Arabidopsis seeds. PMID- 21711403 TI - Genetic impacts of Anacapa deer mice reintroductions following rat eradication. AB - The Anacapa deer mouse is an endemic subspecies that inhabits Anacapa Island, part of Channel Islands National Park, California. We used mitochondrial DNA cytochrome c oxidase subunit II gene (COII) and 10 microsatellite loci to evaluate the levels of genetic differentiation and variation in ~1400 Anacapa deer mice sampled before and for 4 years after a black rat (Rattus rattus) eradication campaign that included trapping, captive holding and reintroduction of deer mice. Both mitochondrial and microsatellite analyses indicated significant differentiation between Anacapa deer mice and mainland mice, and genetic variability of mainland mice was significantly higher than Anacapa mice even prior to reintroduction. Bayesian cluster analysis and Principal Coordinates Analysis indicated that East, Middle and West Anacapa mice were genetically differentiated from each other, but translocation of mice among islands resulted in the East population becoming less distinct as a result of management. Levels of heterozygosity were similar before and after management. However, numerous private alleles in the founder populations were not observed after reintroduction and shifts in allele frequencies occurred, indicating that the reintroduced populations experienced substantial genetic drift. Surprisingly, two mitochondrial haplotypes observed in an earlier study of Anacapa deer mice were lost in the 20 years prior to the rat eradication program, leaving only a single haplotype in Anacapa deer mice. This study demonstrates how genetic monitoring can help to understand the re-establishment of endemic species after the eradication of invasive species and to evaluate the effectiveness of the management strategies employed. PMID- 21711404 TI - Intoxicated workers: findings from a national Australian survey. AB - AIMS: To identify prevalence of alcohol and drug use and intoxication at work. PARTICIPANTS: A total of 9,828 Australian workers >=14 years old. SETTING: Australia 2007. MEASUREMENTS: Work-place alcohol use and drug use, intoxication at work, industry and occupation of employment. DESIGN: Secondary analysis of a large nationally representative survey involving descriptive and weighted multivariate logistic regressions. FINDINGS: Differential patterns were identified by drug type, worker characteristics and occupational setting, controlling for demographic variables. Nearly 9% of workers surveyed (8.7%) usually drank alcohol at work and 0.9% usually used drugs at work. Attending work under the influence of alcohol was more prevalent (5.6%) than attending work under the influence of drugs (2.0%), and significantly more likely among young, male, never married workers with no dependent children. Hospitality industry workers were 3.5 times more likely than other workers to drink alcohol and two to three times more likely to use drugs at work or attend work under the influence of alcohol or drugs. Other high-risk industries and occupations included construction, financial services, tradespersons and unskilled workers. CONCLUSION: More than one in 20 Australian workers admit to having worked under the influence of alcohol and almost one in 50 report attending work under the influence of psychoactive drugs. The rates are higher for some industries, such as the hospitality industry, than others. PMID- 21711405 TI - Commentary: Electrosurgery and implantable electronic devices. PMID- 21711406 TI - Commentary: long-term treatment of glabellar rhytides using onabotulinumtoxina. PMID- 21711407 TI - Commentary: Treatment of cutaneous lupus erythematosus using the pulsed dye laser. PMID- 21711408 TI - External nasal splint for nasal resurfacing. PMID- 21711409 TI - Efficacy and safety evaluation of a novel botulinum toxin topical gel for the treatment of moderate to severe lateral canthal lines. PMID- 21711410 TI - Granuloma faciale treated with 595-nm pulsed dye laser. PMID- 21711411 TI - Pigmented Bowen's disease: a report of two cases. PMID- 21711412 TI - Dermal curette-a useful cartilage sculpting tool. PMID- 21711413 TI - Yes, skin cancer consumer education is just a click away. PMID- 21711414 TI - A novel method to differentiate the epidermal side from the dermal side in suction-blistered epidermal grafting. PMID- 21711415 TI - Half-blade danger and limitation. PMID- 21711416 TI - The lower esophageal sphincter. AB - The lower esophageal sphincters (LES) together with the crural diaphragm are the major antireflux barriers protecting the esophagus from reflux of gastric content. However, reflux of gastric contents into the esophagus is a normal phenomenon in healthy individuals occurring primarily during episodes of transient lower esophageal sphincter relaxation (TLESR), defined as LES relaxation in the absence of a swallow. Transient lower esophageal sphincter relaxation is also the dominant mechanism of pathologic reflux in gastroesophageal reflux disorder (GERD) patients. Frequency of TLESR does not differ significantly between healthy individuals and those with GERD, but TLESRs are more likely to be associated with acid reflux in GERD patients. Understanding the mechanisms responsible for elicitation of a TLESR, using recently introduced novel technology is an area of intense interest. Pharmacologic and non pharmacologic manipulation of receptors involved in the control of TLESR has recently emerged as a potential target for GERD therapy. PMID- 21711417 TI - The usefulness of antiplatelet prescriptions for the identification of patients with atherothrombosis in primary care: a Dutch cross-sectional study. AB - RATIONALE, AIMS AND OBJECTIVES: Patients with atherothrombotic cardiovascular disease (ACD) should receive specific treatments, including lipid-lowering medication. In order to optimize treatment for patients with ACD in primary care, an efficient method to identify all these patients is needed. We aimed to assess which method serves best to identify all patients with ACD in Dutch primary care: morbidity records, antiplatelet prescribing records or a combination of these. METHODS: In a cross-sectional study in 45 Dutch general practices, computerized medical records of all patients with any cardiovascular disease, cardiovascular symptoms or cardiovascular medication were analysed. RESULTS: Of the 7280 patients with a recorded indisputable indication for antiplatelet therapy, 4715 (64.8%) could be identified by means of antiplatelet prescriptions. Of the patients with a recorded indisputable indication for antiplatelets but without any antiplatelet prescription, 28.9% received a vitamin K antagonist. Of the 8718 patients with antiplatelet therapy, 5697 (65.3%) could be identified by means of a recorded indisputable or possible indication for antiplatelet therapy. Female patients, patients younger than 60 years old and patients having a recorded diagnosis of angina pectoris or diabetes had a higher risk to be missed by antiplatelet prescribing records. CONCLUSION: Morbidity records and prescribing records should be used both in order to identify all patients with ACD in primary care. Patients who use antiplatelet prescriptions but do not have a recorded ACD deserve extra attention, because they are either treated without a good indication for antiplatelet therapy (overtreatment) or need a correction of their morbidity records. PMID- 21711418 TI - Use of a collaborative database for epidemiological analyses and professional practice evaluation. AB - RATIONALE: In nephrology, the NEOERICA project assessed the feasibility of the diagnosis scheme based on a general practice database. This approach opened a new area where routinely collected data could be used for purposes other than patient management, such as epidemiological analysis and professional practice evaluation. In Lyon, the TIRCEL network is made up of a coordination team and an online database. In 2008, a total of 468 professionals participated and 983 patients were in the database corresponding to 4114 consultations and 9250 biological assessments. OBJECTIVE: To investigate the impact of a quality control process on the data from operational databases. METHODS: We set up a quality control process and we described the impact of this process on data. We also specifically investigated the role of measurement scales in error frequency and we studied the impact of data quality on variables which could be used for professional practice evaluation. RESULTS: Quality control allowed us to detect as inconsistent data 7.5% of tested data. This rate is linked to the parameters and varied from less than 1% (weight, diastolic blood pressure and urinary sodium) to more than 30% (serum iron and ferritin). Quality control led mainly to the validation of the identified data for 80.4%, a direct correction was realized for 12.9%, 5.6% by the lab and only 1.2% were set to missing. Average proteinuria was modified with the quality control process (2.09 g per 24 hours vs. 0.82 g per 24 hours); however, the median remained stable (0.21 g per 24 hours). CONCLUSION: Specialty databases such as TIRCEL could not be used for epidemiological research or for the extraction of indicators for professional practice evaluation without strict quality control or the set-up of data-entering limits and alarms. PMID- 21711419 TI - Clinical applications of positron emission tomography in hepatic tumors. AB - Fluorodeoxyglucose (FDG), which allows the evaluation of glucose metabolism, is widely used for tumor diagnosis using positron emission tomography (PET). FDG PET, which is used for the diagnosis of intrahepatic tumor lesions, shows high FDG accumulation in cholangiocellular carcinoma (CCC) and metastatic liver cancer. FDG-PET shows high FDG accumulation in moderately or poorly differentiated hepatocellular carcinoma (HCC) and is useful for the diagnosis of extrahepatic HCC metastases and recurrences. However, because the imaging method frequently shows low FDG accumulation in well-differentiated HCC, it is not very useful for that diagnosis. For the diagnosis of well-differentiated HCC, F-18 fluorocholine for evaluation of phospholipid metabolism and C-11 acetate for evaluation of free fatty acid metabolism are useful in the diagnosis of that HCC. It is expected that the combination of these PET agents will enhance the diagnostic performance of FDG-PET for HCC in the future. The problem of a lack of anatomical information is being resolved with the development of the use of PET in combination with computed tomography or magnetic resonance imaging. For the problem of low resolution, PET devices using semiconductors have been developed. PMID- 21711420 TI - Systematic review with meta-analyses of studies on the association between cirrhosis and liver metastases. AB - The hemodynamic, cellular and metabolic changes seen in patients with cirrhosis may reduce the risk of liver metastases. The aim of this case-control is to compare the risk of liver metastases from extrahepatic malignant diseases among patients with or without cirrhosis. Electronic searches (Medline, Embase, and Web of Science) and manual searches were combined (October 2010) to identify observational studies on patients with malignant disease reporting the risk of liver metastases among cases (with cirrhosis) and controls (without liver disease). Meta-analysis was performed using random effects models due to an expected clinical heterogeneity. Sixteen studies were included. Evidence of liver metastases was diagnosed in 22% of cases and 38% of controls based on autopsies (n = 14 studies) or laparoscopy (n = 2 studies). Random effects meta-analysis suggested that patients with cirrhosis had a lower risk of liver metastases (relative risk = 0.53; 95% confidence interval = 0.42-0.66). The conclusions were confirmed in sensitivity and subgroup analyses accounting for the year of publication, matching for age, sex and location of tumors (within the portal vein). No statistical evidence of bias was identified and the analyses were confirmed when adjusting for multiple testing. The present review suggests that cirrhosis reduces the risk of liver metastases. However, additional evidence from prospective studies adjusting for confounding factors is still needed. PMID- 21711421 TI - Impact of ribavirin dose reduction on the efficacy of pegylated interferon plus ribavirin combination therapy for elderly patients infected with genotype 1b and high viral loads. AB - AIM: To examine the impact of ribavirin dose reduction on the efficacy of pegylated interferon (PEG IFN) plus ribavirin combination therapy for elderly patients infected with genotype 1b and high viral loads. METHODS: A total of 72 patients, over 65 years old, were recruited for this study. Patients were divided into groups receiving either 600-800 mg of ribavirin according to bodyweight (Group 1, n = 36) or 400 mg of ribavirin (Group 2, n = 36) plus 1.5 ug/kg (range: 1.3-2.0 ug/kg) of PEG IFN-alpha-2b for 48 weeks. RESULTS: Total ribavirin doses were administrated at 9.80 +/- 2.39 mg/kg per day (3.29 +/- 0.80 g/kg) for Group 1 and 5.87 +/- 1.82 mg/kg per day (1.97 +/- 0.61 g/kg) for Group 2 (P < 0.001). According to the total clearance (CL/F) of ribavirin, 34 of 36 patients in Group 1 received over-doses of ribavirin. In contrast, numbers of those receiving equivalent doses of ribavirin were two of 36 patients in Group 1 and 36 of 36 patients in Group 2, respectively (P < 0.001). End-of-treatment response (ETR) rates were observed in 23 of 36 patients (63.9%) in the standard ribavirin dose protocol and in 23 of 36 patients (63.9%) in the reduction ribavirin dose protocol (NS). Sustained virological response (SVR) rates were observed in 11 of 36 patients (30.6%) in the standard ribavirin dose protocol, and in 13 of 36 patients (36.1%) in the reduced ribavirin dose protocol (NS). CONCLUSION: Reduction of ribavirin doses for elderly patients did not affect the outcome for the 48-week combination therapy. PMID- 21711422 TI - Percutaneous radiofrequency ablation for liver tumors: Is it safer and more effective in low-risk areas than in high-risk areas? AB - AIM: To evaluate the feasibility and safety of ultrasound-guided radiofrequency ablation (RFA) of hepatic tumors in high-risk areas (in caudate lobe, adjacent to the hilum, capsular surface, gallbladder or diaphragm) in comparison with those in low-risk areas. METHODS: A total of 526 patients with hepatic tumor treated with ultrasound-guided cool-tip RFA between October 2001 and October 2008 were included. The patients were divided into two groups according to the tumor location: group I (high-risk areas, 163 patients); group II (low-risk areas, 363 patients). The two groups had similar baseline characteristics. Repeated RFA was adopted if complete ablation (CA) was not achieved. RESULTS: In group I, 20 cases had tumors close to the hilum, 11 in the caudate, 79 adjacent to the capsule, 24 near the gallbladder and 29 cases against the diaphragm. The percentage of patients with primary hepatic tumors in group I was higher than that in group 2 (80.4% vs 56.2%, P < 0.01). More patients in group I felt pain (61.3%, 100/163) than in group II (33.1%, 120/363) (P < 0.01). There was no mortality or major complications in either group. No significant differences were found in the CA rate and the minor complications between the two groups. CONCLUSION: RESULTS for RFA using cool-tip electrodes for liver tumors in high risk areas are comparable to those in low-risk areas in the aspects of CA, complications and mortality. PMID- 21711423 TI - Risk factors associated with relapse of type 1 autoimmune hepatitis in Japan. AB - AIM: Patients receiving corticosteroid therapy on a tapered schedule occasionally suffer autoimmune hepatitis (AIH) relapses. The aim of this study was to assess the frequency and features of relapses, explore risk factors associated with relapses, and evaluate the effectiveness of azathioprine (AZP) therapy against relapses in Japanese patients with type 1 AIH. METHODS: We assessed clinical characteristics and therapeutic processes in 67 patients diagnosed with AIH. RESULTS: Twenty patients (29.9%) suffered from relapses during tapering of corticosteroid therapy. The remaining 47 patients sustained their remission. At the onset of disease, risk factors associated with relapse were: age of 50 years or older; total bilirubin of 1.5 mg/dL or more; aspartate aminotransferase levels of 250 IU/L or more; alanine aminotransferase levels of 250 IU/L or more; prothrombin activity of 80% or more; gamma-globulin levels of 3.4 g/dL or more; and International Autoimmune Hepatitis Group (IAIHG) score of 17 or more in univariate analysis. Grading of histological interface hepatitis is not significantly associated with relapse. Multivariate analysis revealed that IAIHG scores of 17 or more were significantly associated with relapse (odds ratio = 6.57, 95% confidence interval = 1.19-36.33). Seven patients who relapsed were treated with AZP and prednisolone (PSL), and all sustained remission (100%). Of the remaining 13 relapse patients who received only PSL, eight (61.5%) suffered additional relapses. CONCLUSION: Our results demonstrate the risk factors associated with relapse of AIH. We also show that early administration of AZP after the first relapse may help to prevent additional relapses. PMID- 21711424 TI - Ursodeoxycholic acid dose-dependently improves liver injury in rats fed a methionine- and choline-deficient diet. AB - AIM: The data on the beneficial effect of ursodeoxycholic acid (UDCA) in non alcoholic steatohepatitis (NASH) are controversial. The difference of opinion is connected with UDCA dosage to be used. Therefore, we evaluated the dose-dependent efficacy of UDCA in experimental NASH. METHODS: Male Wistar rats were fed the methionine- and choline-deficient (MCD) diet for 10 weeks. Rats were administrated UDCA (10, 20, 40 and 80 mg/kg bodyweight intragastrically) after 6 weeks of the MCD diet. RESULTS: Animals fed the MCD diet developed severe steatohepatitis. Treatment with UDCA dose-dependently decreased liver damage, but only high-dose UDCA (80 mg/kg) significantly diminished ultrastructural changes in addition to preventing steatosis, ballooning and inflammatory changes in the liver. The activities of serum marker enzymes and the content of liver triglyceride and blood glucose were increased in MCD diet-fed rats, but decreased in all the UDCA-treated groups. Serum insulin concentration was decreased whereas the quantitative insulin sensitivity check index did not changed in MCD diet-fed groups. Serum tumor necrosis factor-alpha content was strongly increased after MCD diet and normalized in the UDCA-treated rats, with the most pronounced effect in the highest dose groups, 40 and 80 mg/kg. The contents of endogenous ethanol in blood and intestinal mucus were increased in MCD diet-fed rats which were significantly lowered by UDCA (40 and 80 mg/kg per day). CONCLUSION: The present data demonstrate a beneficial effect of UDCA that manifested by the decrease of liver steatosis, inflammatory signs and serum tumor necrosis factor alpha content especially of the highest 40 and 80 mg/kg day doses. PMID- 21711425 TI - Iron chelator deferasirox rescued mice from Fas-induced fulminant hepatitis. AB - AIM: Fulminant hepatitis is a disease characterized by development of hepatic failure due to severe liver cell injury. Orthotopic liver transplantation is the therapy proven to improve patient survival; however, less burdensome and safer strategies are required. In a previous study, we showed that iron was intimately involved in hepatocyte apoptosis by demonstrating that spontaneous development of fulminant hepatitis in Long-Evans cinnamon rats was prevented by feeding an iron deficient diet. Recently, a new iron chelator, deferasirox, has become widely available for the treatment of transfusional hemosiderosis. Deferasirox demonstrated good efficacy and improved compliance due to convenient, once-daily p.o. administration. Our aim was to investigate the efficacy of deferasirox as a therapeutic drug against fulminant hepatitis. METHODS: Human primary hepatocytes undergoing Fas-stimulated apoptosis were challenged with deferoxamine (DFO) in vitro. In further in vivo experiments, we tested DFO in a mice model of fulminant hepatitis induced by Fas-stimulation. RESULTS: The apoptosis-inducing activity of anti-Fas antibody on human primary hepatocytes was inhibited by the chelation of iron with DFO. DFO suppressed the Fas-induced production of reactive oxygen species (ROS) and the activation of caspase-3, both of which were also suppressed by antioxidant, N-acetyl-L-cystein. In the in vivo experiments, deferasirox effectively reduced hepatic iron concentrations and rescued mice from Fas-induced fulminant hepatitis. CONCLUSION: These findings indicated that the iron chelation exerted a hepatoprotective effect by scavenging ROS upstream of caspase-3 and that iron chelation with deferasirox is a potential treatment for patients with fulminant hepatitis. PMID- 21711426 TI - NASH: A global health problem. AB - Non-alcoholic fatty liver disease (NAFLD) is a major public health problem both in the Western world and in the East. This is mainly due to the high prevalence of the disease and its effects on the individual with NAFLD. In the USA, it is estimated that approximately a third of the general population has NAFLD. Increasing age, obesity and the presence of multiple features of metabolic syndrome, especially diabetes, are associated with a higher probability of having non-alcoholic steatohepatitis (NASH). In the individual with NAFLD, excess hepatic fat is associated with an increased risk of developing diabetes, hypertension, cardiovascular events, abnormal resting electrocardiography and endothelial dysfunction. These findings have been corroborated in studies in teenagers as well as adults. There is also an increase in cardiovascular mortality, especially in those with NASH. In addition, there is an increased risk of death from a variety of non-hepatocellular cancers. From a liver perspective, NAFLD is associated with a 15-20% risk of progression to cirrhosis. The disease progresses more rapidly in those with diabetes, increasing age and obesity. The PNPLA3 gene mutation at position 148 is associated with not only steatosis, but with the likelihood of having steatohepatitis and increased inflammation and fibrosis. Once cirrhosis develops, the liver disease decompensates at the rate of 3-4% per year. NASH-related cirrhosis is a risk factor for hepatocellular cancer. All of these factors indicate that NAFLD is a common condition that has significant adverse health consequences for those who are afflicted. It is therefore a major public health hazard throughout the world. PMID- 21711427 TI - Non-alcoholic steatohepatitis-induced fibrosis: Toll-like receptors, reactive oxygen species and Jun N-terminal kinase. AB - Non-alcoholic steatohepatitis (NASH) represents the progression of hepatic steatosis to streatohepatitis, fibrosis and cirrhosis. Three signaling pathways have been associated with this progression; Toll-like receptors, reactive oxygen species and Jun N-terminal kinase. This review will describe how activation of these three pathways is required for development of fibrosis in murine models of NASH. The three pathways are related and synergistic through intracellular cross talk. Disruption of any of these pathways may inhibit NASH-induced fibrosis and are potential targets for therapeutic intervention. PMID- 21711428 TI - Pharmacological therapy for non-alcoholic steatohepatitis: How efficient are thiazolidinediones? AB - Although diet and lifestyle changes are the first-line therapy in patients with non-alcoholic steatohepatitis (NASH), few patients are able to successfully implement these measures over the long run while others have an advanced disease requiring specific pharmacological therapy. Because insulin resistance is the underlying condition favoring the occurrence of NASH, insulin sensitizers have been tested in this condition although available trials are heterogenous in terms of choice of the drug, dosage, length of therapy and patient profile. Overall, thiazolidinediones reduce aminotransferase levels and induce a strong anti steatogenic response. Most studies have shown an improvement in inflammation and liver cell injury while none have convincingly demonstrated an effect on fibrosis regression. The optimal duration of therapy is unknown as prolonged therapy does not seem to induce additional histological benefit. Although some tolerance issues and safety concerns, in particular cardiovascular, have been raised, thiazolidinediones are the class of drugs with the largest body of evidence in the treatment of NASH so far and can be successfully used in some patients with this disease. PMID- 21711429 TI - Influence of CYP3A5 polymorphism on tacrolimus maintenance doses and serum levels after renal transplantation: age dependency and pharmacological interaction with steroids. AB - TAC, MMF and MP are used in pediatric kidney tx. The cytochrome P450 (CYP)3A5 enzyme appears to play a role in TAC metabolism. The aims of this study were to investigate CYP3A5 polymorphism's effect on TAC dosing and the age dependency of TAC dosing by testing blood concentrations, and the interaction between steroids and TAC during the first year after tx. Genomic DNA was extracted and amplified with specific primers. CYP3A5 alleles were confirmed by direct sequencing of PCR products on an automated AB13100 capillary sequencer. We studied 48 renal transplant patients (age at tx 12+/-0.5yr, 22 boys) receiving TAC, MMF, MP. Of these, 79% were CYP3A5*3/*3 (non-expressers homozygotes) and 21% were CYP3A5*1/*3 (expressers). TAC trough levels were 7.1+/-0.4ng/mL in CYP3A5*3/*3 patients and 6.5+/-0.7ng/mL in CYP3A5*1/*3 group (p=0.03). CYP3A5*1/*3 patients had lower levels of dose-adjusted TAC (36.7+/-5.8ng/mL/mg/kg/day) to achieve target blood concentration and required higher daily dose per weight (0.21+/-0.03mg/kg/day) than CYP3A5*3/*3 patients, 72.4+/-8.0ng/mL/mg/kg/day and 0.13+/-0.01mg/kg/day (p<0.001). Prepubertal patients with different CYP3A5 polymorphisms required significant higher TAC doses and achieved lower dose-normalized concentration compared with pubertal patients. Both TAC dose and adjusted-dose correlated with daily MP dose in CYP3A5*1*3 (r: 0.4, p<0.03 and r: 0.4, p<0.03) and in CYP3A5*3*3 (r: 0.6, p<0.01 and r: 0.47, p<0.001) patients. CYP3A5 polymorphism performed before tx could contribute to a better individualization of TAC therapy. The higher TAC dose in prepubertal patients and the pharmacological interactions between MP and TAC may not be fully explained by different CYP3A5 polymorphisms. PMID- 21711430 TI - CD39 reveals novel insights into the role of transmembrane domains in protein processing, apical targeting and activity. AB - Cargo proteins of the biosynthetic secretory pathway are folded in the endoplasmic reticulum (ER) and proceed to the trans Golgi network for sorting and targeting to the apical or basolateral sides of the membrane, where they exert their function. These processes depend on diverse protein domains. Here, we used CD39 (NTPdase1), a modulator of thrombosis and inflammation, which contains an extracellular and two transmembrane domains (TMDs), as a model protein to address comprehensively the role of native TMDs in folding, polarized transport and biological activity. In MDCK cells, CD39 exits Golgi dynamin-dependently and is targeted to the apical side of the membrane. Although the N-terminal TMD possesses an apical targeting signal, the N- and C-terminal TMDs are not required for apical targeting of CD39. Folding and transport to the plasma membrane relies only on the C-terminal TMD, while the N-terminal one is redundant. Nevertheless, both N- and C-terminal anchoring as well as genuine TMDs are critical for optimal enzymatic activity and activation by cholesterol. We conclude therefore that TMDs are not just mechanical linkers between proteins and membranes but are also able to control folding and sorting, as well as biological activity via sensing components of lipid bilayers. PMID- 21711431 TI - Prostate-specific antigen 1.5-4.0 ng/mL: a diagnostic challenge and danger zone. AB - What's known on the subject? and What does the study add? Large population screening trials like the ERSPC, PCPT and PLCO have noted that men with seemingly low PSA (even as low as 0.5 ng/dL) still can have prostate cancer. Despite these findings, PSA is still predominantly used as a current indicator for possible presence of prostate cancer rather than also serving as a prognostic marker. This study examines a larger number of men in a diverse US population to determine the prognostic value of a man's baseline or first PSA. OBJECTIVES: * To assess the value of a PSA threshold of 1.5 ng/mL as a predictor of increased prostate cancer risk over a four-year period based on a man's first PSA test, including racial differences. * To review the risk of progression of benign prostatic hyperplasia (BPH) based on a similar PSA threshold. PATIENTS AND METHODS: * A retrospective review involving 21,502 men from a large Midwestern health system was performed. * Men at least 40 years old with baseline PSA values between 0 and 4.0 ng/mL and at least four years of follow-up after initial PSA test were included. * Optimal PSA threshold and predictive value of PSA for development of prostate cancer were calculated. RESULTS: * Prostate cancer rates were 15-fold higher in patients with PSA >=1.5 ng/mL vs patients with PSA <1.5 ng/mL (7.85% vs 0.51%). * African American patients with baseline PSA <1.5 ng/mL faced prostate cancer rates similar to the whole study population (0.54% vs 0.51%, respectively), while African American patients with PSA 1.5-4.0 ng/mL faced a 19-fold increase in prostate cancer. CONCLUSION: * Both Caucasian and African American men with baseline PSA values between 1.5 and 4.0 ng/mL are at increased risk for future prostate cancer compared with those who have an initial PSA value below the 1.5 ng/mL threshold. * Based on a growing body of literature and this analysis, it is recommended that a first PSA test threshold of 1.5 ng/mL and above, or somewhere between 1.5 and 4.0 ng/mL, represent the Early-Warning PSA Zone (EWP Zone). * This should serve to inform patients and clinicians alike to future clinical activities with respect to prostate cancer and BPH. PMID- 21711432 TI - Location of residual cancer after transrectal high-intensity focused ultrasound ablation for clinically localized prostate cancer. AB - What's known on the subject ? and What does the study add? Transrectal High Intensity Focused Ultrasound (HIFU) ablation has been used as a minimally invasive treatment for localized prostate cancer for 15 years. Five-year disease free survival rates of 66-78% have been reported, challenging the results of external-beam radiation therapy. Usually, a 6-mm safety margin is used in the apex to preserve the urinary sphincter and potency. The influence of this 6-mm margin on the results of the treatment has never been assessed. This retrospective study of a cohort of 99 patients who underwent systematic biopsy 3 6 months after HIFU ablation for prostate cancer (with a 6-mm safety margin in the apex) shows that post-HIFU residual cancer is found more frequently in the apex. Therefore, new strategies improving the prostate destruction at the apex while preserving the urinary continence need to be found. OBJECTIVE: * To evaluate whether the location (apex/midgland/base) of prostate cancer influences the risk of incomplete transrectal high-intensity focused ultrasonography (HIFU) ablation. PATIENTS AND METHODS: * We retrospectively studied 99 patients who underwent prostate cancer HIFU ablation (Ablatherm; EDAP, Vaulx-en-Velin, France) with a 6-mm safety margin at the apex, and had systematic biopsies 3-6 months after treatment. * Locations of positive pre- and post-HIFU sextants were compared. * The present study included two analyses. First, sextants negative before and positive after treatment were recoded as positive/positive, hypothesizing that cancer had been missed at pretreatment biopsy. Second, patients with such sextants were excluded. RESULTS: * Pre-HIFU biopsies found cancer in all patients and in 215/594 sextants (36.2%); 55 (25.6%) positive sextants were in the apex, 86 (40%) in the midgland and 74 (34.4%) in the base. * After treatment, residual cancer was found in 36 patients (36.4%) and 50 sextants (8.4%); 30 (60%) positive sextants were in the apex, 12 (24%) in the midgland and eight (16%) in the base. * Both statistical analyses found that the locations of the positive sextants before and after HIFU ablation were significantly different (P < 0.001), with a higher proportion of positive apical sextants after treatment. * At the first analysis, the mean (95% confidence interval) probability for a sextant to remain positive after HIFU ablation was 8.8% (3.5 20.3%) in the base, 12.7% (5.8-25.9%) in the midgland and 41.7% (27.2-57.89%) in the apex. * At the second analysis, these same probabilities were 5.9% (1.9-17%), 9.9% (3.9-23.2%) and 27.3% (13.7-47%), respectively. CONCLUSION: * When a 6-mm apical safety margin is used, residual cancer after HIFU ablation is found significantly more frequently in the apex. PMID- 21711433 TI - Surgery for renal cell cancer extending into the inferior vena cava - evaluation of survival and perioperative complications using a standardized classification system. AB - OBJECTIVE: * To present a single-centre experience of surgery for kidney cancer involving vena cava thrombus with surgical technique, complications and outcome using a standardized classification system for perioperative complications. PATIENTS AND METHODS: * Sixty-eight consecutive cases were retrospectively analysed. Thrombus extension was at level I (but inside the vena cava) in 10 cases, level II in 28 cases, level III in 18 cases and level IV in 12 cases; 18 patients had distant metastases. * Radical tumour nephrectomy was performed in all cases. Complete liver mobilization was carried out in 23 cases and cardiovascular bypass with circulatory arrest was performed in five cases. * Follow-up was available for 66 patients. Median follow-up was 29 months (interquartile range 30.75). RESULTS: * The 28-day mortality was 0%. * According to the Clavien-Dindo classification there were two grade 1, 54 grade 2, two grade 3a, two grade 3b and two grade 4a perioperative complications. * The factors pN, grading and metastases at presentation predicted overall survival in univariate analyses. In a multivariate model none of the factors age, metastases at presentation, pN, WHO-grading, American Society of Anesthesiologists score, tumour size and thrombus level significantly predicted survival. * Immediate target therapy with neoadjuvant intention in three patients did not result in surgical therapy. CONCLUSIONS: * Aggressive surgical treatment causes no perioperative mortality and leads to a low rate of grade 3 and grade 4 complications (8.8%). * A median overall survival of 47 months shows that surgical treatment has favourable results in these patients. PMID- 21711434 TI - Penile revascularization in vasculogenic erectile dysfunction (ED): long-term follow-up. AB - OBJECTIVE: To determine the overall long-term success of penile revascularization surgery in the treatment of vasculogenic erectile dysfunction (ED) and also to investigate the effect of risk factors on the results of a modified Furlow-Fisher technique. PATIENTS AND METHODS: Between 1999 and 2010, 125 men with a mean (sd, range) age of 43.2 (11.3, 23-69) years underwent penile revascularization surgery. In all, 110 men completed the long-term follow-up with a mean follow-up of 73.2 months. Diagnostic evaluations, penile colour Doppler ultrasonography, corpus cavernosum electromyography, and cavernosometry, were performed in all the men before surgery. The efficacy of the surgery was assessed as improvement or failure according to the change in the five-item version of the International Index of Erectile Function (IIEF-5). A >=5 point increase in the IIEF-5 score during the latest patient visit after surgery compared with that before surgery was regarded as improvement (surgical success). RESULTS: The mean (SD) IIEF-5 score was 7.3 (3.2) before surgery and at the end of the follow-up period it was 16.8 (3.1). The success rates were 81.8% at 3 months, 77.2% at 1 year, 70% at 2 years, 66.3% at 3 years and 63.6% at 5 years after surgery in the men who achieved a no-ED threshold score of >26 in the IIEF-15. The success rate was the highest in the men with no risk factors (92.8%). Seven patients (6.36%) showed signs of glans hypervascularization as a major complication. CONCLUSIONS: Penile revascularization surgery has not been widely used by urologists probably due to the technical difficulties and the use of phosphodiesterase type 5 inhibitors. However, with reported high rates of noncompliance or failure of oral pharmacotherapy it seems likely that this surgery will become more popular in the near future. PMID- 21711435 TI - Establishing a reference range for penile length in Caucasian British men: a prospective study of 609 men. AB - OBJECTIVES: * To establish a reference range for adult male genital size in the UK using penile length measurements. * To compare the reference ranges for normal penile length reported from several different countries and the anthropometric differences noted between different nationalities and ethnic backgrounds. METHODS AND MATERIALS: * Over 20 months, genital measurements were taken from all men undergoing routine examination in clinics (n= 499) and in operating theatres during examination under anaesthetic (n= 110). * Using a rigid metric ruler three penile measurements were taken: flaccid pendulous penile length, flaccid penopubic penile length (to the pubic arch) and stretched flaccid penopubic length. In addition, testicular size was measured using an orchidometer. * The patient's age and the reason for referral were recorded. * Statistical analysis was carried out using Pearson correlation analysis. RESULTS: * Measurements from 610 patients aged 16-90 years were available for analysis. * The mean penile lengths were: pendulous length 8.7 cm (sd 1.6 cm), penopubic length 10.2 cm (sd 1.4 cm) and stretched length 14.3 cm (sd 1.7 cm). The mean testicular volume was 19.8 mL (sd 5.4 mL) for both left and right testicles. * Men with penile disease (including phimosis and Peyronie's disease) had slightly reduced penile length (pendulous -3.3 mm, P= 0.014; penopubic -2.3 mm, P= 0.029; stretched -5.1 mm, P < 0.001) compared with other referral groups (erectile dysfunction, testicular disease, prostate and bladder disease). * There was no significant correlation between penile length and age or testicular size CONCLUSION: * These data establish a reference range for adult male genital size in the UK, which should be helpful for urologists when counselling patients. PMID- 21711436 TI - The impact of nerve sparing on incidence and location of positive surgical margins in radical prostatectomy. AB - OBJECTIVE: * To examine whether nerve-sparing surgery (NSS) is a risk factor for positive surgical margins (PSMs) in patients with either organ-confined prostate cancer or extracapsular extension (ECE). PATIENTS AND METHODS: * Clinicopathological outcome data on 945 consecutive patients treated with radical prostatectomy (RP) were prospectively collected. * All patients underwent RP (bilateral, unilateral or non-NSS) by one surgeon between 2002 and 2007. * Risk of PSMs and their locations with respect to NSS was determined by multivariate logistic regression analysis adjusting for preoperative risk factors for PSMs within pT2, pT3a and pT3b tumours. RESULTS: * Overall a PSM was identified in 19.6% of patients in an unscreened population with mean prostate-specific antigen (PSA) level of 8.1 ng/mL. * There was no significant difference in rates of PSMs between NSS groups on multivariate analysis (P= 0.147). * There was no significant difference in pT2 (P= 0.880), pT3a (P= 0.175) or pT3b (P= 0.354) tumours. * The only significant predictor of PSMs was preoperative PSA level (risk ratio 1.289, P= 0.006). * There was no significant difference in the location of PSMs except for the pT3a group, where the patients that had bilateral NSS were at higher risk of a posterolateral PSM (P= 0.028). CONCLUSIONS: * With appropriate selection of patients, NSS does not increase the risk of PSMs, whether the cancer is organ confined or ECE is present. * The adverse impact of the NSS procedure in the hands of an experienced surgeon is minimal and is a realistic compromise to obtain the increase in health-related quality of life offered by NSS. PMID- 21711437 TI - Impact of renal vein invasion and fat invasion in pT3a renal cell carcinoma. AB - OBJECTIVE: * To evaluate the prognostic impact of tumor fat invasion (FI) and renal vein invasion (RVI) in patients with T3a renal cell carcinoma. PATIENTS AND METHODS: * In total, 220 consecutive patients treated for renal cell carcinoma between 1992 and 2009 were analyzed. T3a stage cases were selected. * A single pathologist reviewed all cases. RESULTS: * The present study cohort included 46 patients with mean follow-up of 28.6 months, of whom 17 (36.9%) died from disease. Patients were initially divided into three groups including 24 (52.1%) of FI only, 11 (23.9%) of RVI only and 11 (23.9%) of both FI and RVI. * In univariate analysis, no significant differences in disease-specific survival (DSS) were noted between FI only and RVI only groups (P= 0.91). DSS was significantly worse in the FI + RVI group compared to the other groups (P= 0.02). * When grouped into FI or RVI vs FI + RVI, DSS remained significantly lower in the group containing the parameters concurrently (P= 0.009). Progression-free survival also was significantly lower in FI + RVI group (P= 0.01). * Metastasis, positive lymph nodes and the presence of FI + RVI remained as isolated predictors of survival. * Patients with FI + RVI presented a 2.6-fold increase in risk of death from cancer and a 2.5-fold increase in risk of disease progression (P= 0.04) compared to those with either of them alone. CONCLUSION: * The isolated or concomitant presence of FI and RVI may be used as one of the criteria for staging in the next edition of the Tumour-Node-Metastasis classification because they have significantly different outcomes. PMID- 21711438 TI - Treatment changes and long-term recurrence rates after hexaminolevulinate (HAL) fluorescence cystoscopy: does it really make a difference in patients with non muscle-invasive bladder cancer (NMIBC)? AB - OBJECTIVES: * To evaluate in a prospective, randomized study the impact of hexaminolevulinate blue-light cystoscopy (HAL-BLC) on the diagnostic accuracy and treatment changes in cases of non-muscle invasive bladder cancer (NMIBC) compared with standard white-light cystoscopy (WLC). * To compare the long-term recurrence rates in the two study arms. PATIENTS AND METHODS: * In all, 362 patients suspected of NMIBC were included in the trial based on positive urinary cytology and/or ultrasonographic suspicion of bladder tumours and underwent transurethral resection of bladder tumours. * A single postoperative mytomicin-C instillation was performed in all cases, intravesical chemotherapy for intermediate-risk patients and BCG instillations for high-risk cases. * The follow-up protocol consisted of urinary cytology and WLC every 3 months for 2 years. * Only first-time recurrences after the initial diagnosis were considered. RESULTS: * In the 142 patients with NMIBC in the HAL-BLC series, tumour detection rates significantly improved for carcinoma in situ, pTa andoverall cases. * In 35.2% of the cases, additional malignant lesions were found by HAL-BLC and consequently, the recurrence- and progression-risk categories of patients and subsequent treatment improved in 19% of the cases due to fluorescence cystoscopy. * In all, 125 patients in the HAL-BLC group and 114 of the WLC group completed the follow-up. * The recurrence rate at 3 months was lower in the HAL-BLC series (7.2% vs 15.8%) due to fewer 'other site' recurrences when compared with the WLC series (0.8% vs 6.1%). * The 1 and 2 years recurrence rates were significantly decreased in the HAL-BLC group compared with the WLC group (21.6% vs 32.5% and 31.2% vs 45.6%, respectively). CONCLUSIONS: * HAL-BLC was better than WLC for detecting NMIBC cases and improved tumour detection rates. * HAL-BLC significantly modified the postoperative treatment of cases. * The 3 months, 1 and 2 years recurrence rates were significantly improved in the HAL-BLC arm. PMID- 21711439 TI - Exposed proliferation antigen 210 (XPA-210) in renal cell carcinoma (RCC) and oncocytoma: clinical utility and biological implications. AB - OBJECTIVE: * To determine the clinical role of the exposed proliferation antigen 210 (XPA-210) of the proliferation marker thymidine kinase 1 (TK1) in a large cohort of different renal cell carcinoma (RCC) types, oncocytomas and normal renal tissues samples, as TK1 is reported to be of clinical significance in several cancer entities and is suggested as a prognostic serum biomarker for RCC. PATIENTS AND METHODS: * Expressions of XPA-210 were determined immunohistochemically in 40 clear cell RCCs (ccRCC), 25 papillary RCCs (papRCC), 17 chromophobe RCC (chRCC), 27 oncocytomas and 64 normal renal parenchyma paraffin-embedded specimens. * Immunohistochemistry was performed with a monoclonal anti-XPA-210 antibody. Staining was measured by the percentage of positive cells. * Expression was compared between subgroups and correlated with respective clinical data using one-way analysis of variance with post hoc Tukey Kramer analyses. RESULTS: * XPA-210 staining in the RCC subgroup was significantly different from the oncocytomas (mean [sem] 4.1 [0.4] vs 2.2 [0.4]; P = 0.004) and from normal renal tissue (1.0 [0.1]; P < 0.001], whereas oncocytomas did not differ from normal renal parenchyma staining (P = 0.18). * Subdivided into RCC groups, only ccRCC (mean [sem] 5.1 [0.6]; P < 0.001) and papRCC (4.4 [0.6]; P < 0.001) varied from normal renal parenchyma, whereas chRCC (1.4 [0.3]; P = 0.99) did not. * RCC XPA-210 staining was significantly associated with higher tumour stage (T = 3, P = 0.002) and grade (G = 3, P = 0.001). CONCLUSIONS: * The malignant character of RCC is reflected by higher XPA 210 expression as compared with oncocytomas and normal kidney. * The ccRCC and papRCC subgroups had higher XPA-210 levels. * XPA-210 could be considered a potential marker for the assessment of the proliferative activity in primary RCC. PMID- 21711440 TI - TURP and sex: patient and partner prospective 12 years follow-up study. AB - OBJECTIVE: * To evaluate the effect of transurethral resection of the prostate (TURP) on sexual function in the short (6 months), medium (6 years) and long (12 years) term and assess the conformity between patient and partner regarding sexual function. PATIENTS AND METHODS: * A prospective cohort study set at the Aberdeen Royal Infirmary University Hospital. * A total of 280 men referred with lower urinary tract symptoms (LUTS) to a university hospital underwent TURP between January 1993 and September 1994; 145 of their partners (partner or spouse) participated. * Assessment included American Urological Association symptom score, flow rates and validated self-reported sexual questionnaires (SQ). * Data were collected at baseline, 3 months, 6 months, 6 years and 12 years of follow-up. RESULTS: * In all, 120 (43%) men were sexually active preoperatively. At 6 months, 73 (61%) of these 120 men completed the SQ and all were sexually active. * No sexually active patient became impotent after the procedure. Moreover, 27 (15%) with pre-existing erectile dysfunction reported improved sexual activity and erection quality. * At 6 years 101 men completed the SQ and 31 (30.7%) were sexually active. At 12 years, 36 (31.9%) of 113 who completed the SQ were sexually active. * Partners agreed with the men's self assessment at all visits. * Limitations include possible attrition bias and lack of information from non-responders. CONCLUSIONS: * Erectile dysfunction associated with LUTS frequently precedes TURP. * The TURP did not adversely affect sexual function. * Pre-operative erectile dysfunction can be improved by TURP and long-term sexual function is maintained after TURP. These findings, corroborated by the partners, were statistically significant. PMID- 21711442 TI - Thrombocytopenia associated with dialysis treatments. AB - We present a case of a 51-year-old woman who developed thrombocytopenia associated with dialysis treatments. Laboratory values revealed a platelet count of 50,000 or less postdialysis, with recovery of platelet count during her interdialytic period. An extensive work up including infectious serology and heparin-induced thrombocytopenia test was negative. Based on the pattern of thrombocytopenia and negative work-up, it is concluded that her thrombocytopenia was due to her dialysis treatments. We discuss the literature on thrombocytopenia and hemodialysis and postulate that our patient had a reaction to her dialyzer membrane or to the electron beam radiation method used to sterilize her dialyzer. PMID- 21711441 TI - Comparative kinetic analyses of gene profiles of naive CD4+ and CD8+ T cells from young and old animals reveal novel age-related alterations. AB - It is well established that immune responses are diminished in the old. However, we still do not have a clear understanding of what dictates the dysfunction of old T cells at the molecular level. Although microarray analysis has been used to compare young and old T cells, identifying hundreds of genes that are differentially expressed among these populations, it has been difficult to utilize this information to pinpoint which biological pathways truly affect the function of aged T cells. To better define differences between young and old naive CD4+ and CD8+ T cells, microarray analysis was performed pre- and post-TCR stimulation for 4, 12, 24 and 72 h. Our data indicate that many genes are differentially expressed in the old compared to the young at all five time points. These genes encode proteins involved in multiple cellular functions such as cell growth, cell cycle, cell death, inflammatory response, cell trafficking, etc. Additionally, the information from this microarray analysis allowed us to underline both intrinsic deficiencies and defects in signaling only seen after activation, such as pathways involving T-cell signaling, cytokine production, and Th2 differentiation in old T cells. With the knowledge gained, we can proceed to design strategies to restore the function of old T cells. Therefore, this microarray analysis approach is a powerful and sensitive tool that reveals the extensive changes seen between young and old CD4+ and CD8+ naive T cells. Evaluation of these differences provides in-depth insight into potential functional and phenotypical differences among these populations. PMID- 21711443 TI - Prevention of venous thromboembolism after major orthopedic surgery: indirect comparison of three new oral anticoagulants. PMID- 21711444 TI - Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. AB - BACKGROUND: Histones are basic proteins that contribute to cell injury and tissue damage when released into the extracellular space. They have been attributed a prothrombotic activity, because their injection into mice induces diffuse microvascular thrombosis. The protein C-thrombomodulin (TM) system is a fundamental regulator of coagulation, particularly in the microvasculature, and its activity can be differentially influenced by interaction with several cationic proteins. OBJECTIVE: To evaluate the effect of histones on the protein C TM system in a plasma thrombin generation assay and in purified systems. METHODS: The effect of histones on plasma thrombin generation in the presence or absence of TM was analyzed by calibrated automated thrombinography. Protein C activation in purified systems was evaluated by chromogenic substrate cleavage. The binding of TM and protein C to histones was evaluated by solid-phase binding assay. RESULTS: Histones dose-dependently increased plasma thrombin generation in the presence of TM, independently of its chondroitin sulfate moiety. This effect was not caused by inhibition of activated protein C activity, but by the impairment of TM-mediated protein C activation. Histones were able to bind to both protein C and TM, but the carboxyglutamic acid domain of protein C was required for their effect. Histones H4 and H3 displayed the highest activity. Importantly, unlike heparin, DNA did not inhibit the potentiating effect of histones on thrombin generation. CONCLUSIONS: Histones enhance plasma thrombin generation by reducing TM-dependent protein C activation. This mechanism might contribute to microvascular thrombosis induced by histones in vivo at sites of organ failure or severe inflammation. PMID- 21711445 TI - Expanded phenotype-genotype correlations in a pediatric population with type 1 von Willebrand disease. AB - BACKGROUND: Recent phenotype-genotype studies have provided valuable insights into the pathophysiology of type 1 von Willebrand disease (VWD); however, no study has examined an exclusively pediatric cohort. OBJECTIVES: To describe phenotype-genotype correlations in a selected pediatric cohort with a historical diagnosis of type 1 VWD, using first-degree family members as controls. METHODS: Comprehensive phenotypic assessment included standard assays of von Willebrand factor (VWF) level and function, bleeding score, desmopressin response, VWF propeptide (VWFpp) level, and platelet-derived VWF mRNA level. RESULTS: Fourteen VWF mutations were identified in 17 of 23 index cases (ICs) (aged 5-17 years), including four that were previously unreported (L60P, nt1658 insT, Q1388X, and C2237F). VWFpp levels were lower in ICs than in unaffected controls (median 49 vs. 86 U dL(-1) , P < 0.0001). A VWFpp/VWF antigen ratio of > 1.6 was observed in eight of nine ICs with a suboptimal response to desmopressin, including four of four with the R1205H (Vicenza) mutation (median 7.9), and three of four IC with the R1315C mutation (median 1.9). The R1315C mutation was also associated with a reduced absolute VWFpp level (median 32 U dL(-1) ), a previously unreported finding. The amount of platelet-derived VWF mRNA was significantly reduced in individuals with nonsense mutations. CONCLUSIONS: Increased VWF clearance and intracellular retention are important mechanisms underlying type 1 VWD in pediatric patients, concordant with the observations of larger, predominantly adult, cohort studies. Additionally, in some patients, nonsense-mediated decay of mutant mRNA transcripts may be contributory. Several mechanisms underlie the variable phenotype associated with the R1315C mutation. The potential utility of VWFpp as an independent marker of VWF biosynthesis and release warrants further research. PMID- 21711446 TI - Fibrinogen replacement therapy for congenital fibrinogen deficiency. AB - This review of published studies was conducted to derive data on patients with congenital fibrinogen deficiency (CFD), including dosing of fibrinogen replacement therapy, outcome, and adverse events, either temporally related or distant to fibrinogen replacement, in order to assist clinicians in developing treatment plans for patients with CFD. A systematic review was performed of case reports identified by a MEDLINE search between 1961 and 2010. Eligible studies included subjects with a diagnosis of CFD who received fibrinogen replacement. An attempt was made to extract dose, frequency, duration, hemostatic efficacy and adverse events such as thrombosis or allergic reactions. Reported thrombotic events distant from fibrinogen replacement were also recorded. From 104 papers reviewed, a total of 50 cases were identified: afibrinogenemia (35), hypofibrinogenemia (6), and dysfibrinogenemia (9). Fibrinogen replacement therapy was generally effective in preventing or treating bleeding in doses adequate to achieve and maintain fibrinogen activity above 50-100 mg dL(-1) (non-surgical and obstetric use) or 100-200 mg dL(-1) (surgical prophylaxis). Increased fibrinogen clearance was observed with massive hemorrhage, major surgery, and advanced pregnancy. Obstetric outcomes were optimized when fibrinogen replacement was initiated prior to conception. Uncontrolled hemorrhage, allergic reactions and antibody formation were rare events. However, thromboses, both related and unrelated to fibrinogen replacement, occurred in 15 of 50 (30%) patients overall, and in eight of 12 (67%) adult non-obstetric patients with afibrinogenemia. Published fibrinogen replacement regimens are presented for 50 CFD patients. Fibrinogen replacement therapy requires careful monitoring of fibrinogen levels. Afibrinogenemia is associated with thromboembolic complications with or without treatment. PMID- 21711447 TI - Transcriptional insights on the regenerative mechanics of axotomized neurons in vitro. AB - Axotomized neurons have the innate ability to undergo regenerative sprouting but this is often impeded by the inhibitory central nervous system environment. To gain mechanistic insights into the key molecular determinates that specifically underlie neuronal regeneration at a transcriptomic level, we have undertaken a DNA microarray study on mature cortical neuronal clusters maintained in vitro at 8, 15, 24 and 48 hrs following complete axonal severance. A total of 305 genes, each with a minimum fold change of +/- 1.5 for at least one out of the four time points and which achieved statistical significance (one-way ANOVA, P < 0.05), were identified by DAVID and classified into 14 different functional clusters according to Gene Ontology. From our data, we conclude that post-injury regenerative sprouting is an intricate process that requires two distinct pathways. Firstly, it involves restructuring of the neurite cytoskeleton, determined by compound actin and microtubule dynamics, protein trafficking and concomitant modulation of both guidance cues and neurotrophic factors. Secondly, it elicits a cell survival response whereby genes are regulated to protect against oxidative stress, inflammation and cellular ion imbalance. Our data reveal that neurons have the capability to fight insults by elevating biological antioxidants, regulating secondary messengers, suppressing apoptotic genes, controlling ion-associated processes and by expressing cell cycle proteins that, in the context of neuronal injury, could potentially have functions outside their normal role in cell division. Overall, vigilant control of cell survival responses against pernicious secondary processes is vital to avoid cell death and ensure successful neurite regeneration. PMID- 21711448 TI - Derivation of the uncontrolled donation after circulatory determination of death protocol for New York city. AB - Evidence from Europe suggests establishing out-of-hospital, uncontrolled donation after circulatory determination of death (UDCDD) protocols has potential to substantially increase organ availability. The study objective was to derive an out-of-hospital UDCDD protocol that would be acceptable to New York City (NYC) residents. Participatory action research and the SEED-SCALE process for social change guided protocol development in NYC from July 2007 to September 2010. A coalition of government officials, subject experts and communities necessary to achieve support was formed. Authorized NY State and NYC government officials and their legal representatives collaboratively investigated how the program could be implemented under current law and regulations. Community stakeholders (secular and religious organizations) were engaged in town hall style meetings. Ethnographic data (meeting minutes, field notes, quantitative surveys) were collected and posted in a collaborative internet environment. Data were analyzed using an iterative coding scheme to discern themes, theoretical constructs and a summary narrative to guide protocol development. A clinically appropriate, ethically sound UDCDD protocol for out-of-hospital settings has been derived. This program is likely to be accepted by NYC residents since the protocol was derived through partnership with government officials, subject experts and community participants. PMID- 21711449 TI - ALK, the key gene for gelatinization temperature, is a modifier gene for gel consistency in rice. AB - Gelatinization temperature (GT) is an important parameter in evaluating the cooking and eating quality of rice. Indeed, the phenotype, biochemistry and inheritance of GT have been widely studied in recent times. Previous map-based cloning revealed that GT was controlled by ALK gene, which encodes a putative soluble starch synthase II-3. Complementation vector and RNAi vector were constructed and transformed into Nipponbare mediated by Agrobacterium. Phenotypic and molecular analyses of transgenic lines provided direct evidence for ALK as a key gene for GT. Meanwhile, amylose content, gel consistency and pasting properties were also affected in transgenic lines. Two of four nonsynonymous single nucleotide polymorphisms in coding sequence of ALK were identified as essential for GT. Based on the single nucleotide polymorphisms (SNPs), two new sets of SNP markers combined with one cleaved amplified polymorphic sequence marker were developed for application in rice quality breeding. PMID- 21711451 TI - Effects of Doxorubicin and Fenofibrate on the activities of NADH oxidase and citrate synthase in mice. AB - Doxorubicin (Dox) has widely been used as an anticancer drug, but its use is limited by serious toxicity to the heart, kidney and liver. Mitochondrial dysfunction is one of the potential mechanisms of toxicity but not fully understood. Fenofibrate, one of the peroxisome proliferator-activated receptor alpha (PPARalpha) ligands, is involved in lipid metabolism which takes place primarily in the mitochondria, so mitochondrial function may be affected by fenofibrate. Therefore, we investigated the effects of DOX and fenofibrate on activities of both mitochondrial citrate synthase and NADH oxidase, which are marker enzymes in the tricarboxylic acid (TCA) cycle and a measure of the complex I-III-IV activity in electron transport chain, respectively. Dox (15 mg/kg) and/or fenofibrate (100 mg/kg/day) were administered to mice for 3 or 14 days, and the activities of citrate synthase and NADH oxidase were measured. Our study showed that Dox significantly inhibits the activity of citrate synthase while fenofibrate induces the activity. Similar to citrate synthase, NADH oxidase activity was also induced by fenofibrate except in spleen but inhibited by Dox except in the heart and liver. Furthermore, fenofibrate not only protects citrate synthase activity from Dox-induced toxicity in the ventricle but also significantly rescues NADH oxidase activity in the kidney. These results reveal the actions of fenofibrate and Dox on the mitochondria, and the underlying mechanism may be related to the toxicity of Dox, which has clinical implications in the side effects of Dox treatment by modulation of mitochondrial function. PMID- 21711450 TI - The KdpC subunit of the Escherichia coli K+-transporting KdpB P-type ATPase acts as a catalytic chaperone. AB - In Bacteria and Archaea, high-affinity potassium uptake is mediated by the ATP driven KdpFABC complex. On the basis of the biochemical properties of the ATP hydrolyzing subunit KdpB, the transport complex is classified as type IA P-type ATPase. However, the KdpA subunit, which promotes K(+) transport, clearly resembles a potassium channel, such that the KdpFABC complex represents a chimera of ion pumps and ion channels. In the present study, we demonstrate that the blending of these two groups of transporters in KdpFABC also entails a nucleotide binding mechanism in which the KdpC subunit acts as a catalytic chaperone. This mechanism is found neither in P-type ATPases nor in ion channels, although parallels are found in ABC transporters. In the latter, the ATP nucleotide is coordinated by the LSGGQ signature motif via double hydrogen bonds at a conserved glutamine residue, which is also present in KdpC. High-affinity nucleotide binding to the KdpFABC complex was dependent on the presence of this conserved glutamine residue in KdpC. In addition, both ATP binding to KdpC and ATP hydrolysis activity of KdpFABC were sensitive to the accessibility, presence or absence of the hydroxyl groups at the ribose moiety of the nucleotide. Furthermore, the KdpC subunit was shown to interact with the nucleotide-binding loop of KdpB in an ATP-dependent manner around the ATP-binding pocket, thereby increasing the ATP-binding affinity by the formation of a transient KdpB/KdpC/ATP ternary complex. PMID- 21711452 TI - How does social functioning in the early stages of psychosis relate to depression and social anxiety? AB - AIMS: The study aims to compare social functioning in young people considered to be at risk of psychosis with those meeting criteria for first episode psychosis (FEP) and controls, and to determine the association between social functioning and positive and negative symptoms, depressive symptoms, and social anxiety. METHODS: This study examined social functioning in 20 individuals at risk of psychosis, 20 FEP patients and 20 healthy controls. Social functioning was measured using the Social Functioning Scale and World Health Organization Disability Assessment Scale. Psychiatric variables were also measured using the Comprehensive Assessment of At-Risk Mental States, the Brief Psychiatric Rating Scale, the Brief Social Phobia Scale, and the Depression Anxiety and Stress Scale. RESULTS: At-risk individuals had comparable social deficits to the FEP group, and both patient groups had significantly poorer social functioning than controls. Importantly, social functioning was most strongly associated with depressive and social anxiety symptoms and to a lesser extent with positive symptoms. However, negative symptoms did not appear to relate to social functioning. CONCLUSION: Social functioning impairments precede the onset of full threshold psychosis and may therefore be a significant marker for the illness. Additionally, associated psychiatric symptoms such as depression and social anxiety may provide an avenue for early interventions of social functioning deficits in psychosis. PMID- 21711453 TI - Constitutive activation of the ETS-1-miR-222 circuitry in metastatic melanoma. AB - MicroRNAs-221 and -222 are highly upregulated in several solid tumors, including melanomas. We demonstrate that the proto-oncogene ETS-1, involved in the pathogenesis of cancers of different origin, is a transcriptional regulator of miR-222 by direct binding to its promoter region. Differently from 293FT cells or early stage melanomas, where unphosphorylated ETS-1 represses miR-222 transcription, in metastatic melanoma the constitutively Thr-38 phosphorylated fraction of ETS-1 induces miR-222. Despite its stepwise decreased expression along with melanoma progression, the oncogenic activity of ETS-1 relies on its RAS/RAF/ERK-dependent phosphorylation status more than on its total amount. To close the loop, we demonstrate ETS-1 as a direct target of miR-222, but not miR 221, showing the novel option of their uncoupled functions. In addition, a spatial redistribution of ETS-1 protein from the nucleus to the cytoplasm is also evidenced in advanced melanoma cells. Finally, in vivo studies confirmed the contribution of miR-222 to the increased invasive potential obtained by ETS- silencing. PMID- 21711455 TI - The influence of age at single-event multilevel surgery on outcome in children with cerebral palsy who walk with flexed knee gait. AB - AIM: Information on the timing and long-term outcome of single-event multilevel surgery in children with bilateral spastic cerebral palsy (CP) walking with flexed knee gait is limited. Based on our clinical experience, we hypothesized that older children with bilateral spastic CP would benefit more from single event multilevel surgery than younger children. Moreover, any improvement in older children could be maintained with fewer additional surgery events. METHOD: We performed a retrospective analysis of the long-term outcomes of single-event multilevel surgery. Thirty-two children (17 males, 15 females) who had received single-event multilevel surgery between 1995 and 2000 with a mean age at the time of surgery of 10 years 6 months (range 5y 8mo-15y 6mo; SD 3y 1mo) and in Gross Motor Function Classification System level II (n=12) or III (n=20) were included in the study. The inclusion criteria required that all children were ambulatory with spastic bilateral CP, had a flexed knee gait, had a full set of data for single-event multilevel surgery preoperatively and at 1 year and 10 years postoperatively, had not had previous surgery on their lower limbs, had not had any treatment with botulinum toxin A before gait assessment, and had not received intrathecal baclofen medication. The follow-up time lasted for over 10 years until the participants reached adulthood (mean age at the last follow-up 21 years 4 months, SD 3y 4mo). Data were collected on six separate occasions: preoperatively, at 1 year, at 2 to 3 years, at 5 years, at 7 to 8 years, and at 10 or more years postoperatively. The primary outcome was the Gait Deviation Index, and the secondary outcomes were the number and type of initial and additional surgeries. A linear mixed model and Spearman's rank correlation coefficient were used to prove the hypothesis. RESULTS: The older the child was at the time of the surgery, the better the long-term result ((Age,Time) =0.15; p=0.03). We did not find any correlation between age at the time of surgery and the number of bony or soft-tissue procedures performed initially as well as during the 10 years of follow-up. INTERPRETATION: Children with CP who require single-event multilevel surgery at an older age fare better in the long term than those who are younger at the time of surgery. The pubertal growth spurt is discussed as a contributing factor to gait deterioration. PMID- 21711454 TI - Beta-adrenergic signals regulate cardiac differentiation of mouse embryonic stem cells via mitogen-activated protein kinase pathways. AB - As embryonic stem cell-derived cardiomyocytes (ESC-CMs) have the potential to be used in cell replacement therapy, an understanding of the signaling mechanisms that regulate their terminal differentiation is imperative. In previous studies, we discovered the presence of adrenergic and muscarinic receptors in mouse embryonic stem cells (ESCs). However, little is known about the role of these receptors in cardiac differentiation and development, which is critically important in cardiac physiology and pharmacology. Here, we demonstrated that a beta-adrenergic receptor (beta-AR) agonist significantly enhanced cardiac differentiation as indicated by a higher percentage of beating embryoid bodies and a higher expression level of cardiac markers. Application of beta1-AR and beta2-AR antagonists partly abolished the effect of the beta-AR agonist. In addition, by administering selective inhibitors we found that the effect of beta AR was driven via p38 mitogen-activated protein kinase and extracellular-signal regulated kinase pathway. These findings suggest that ESCs are also a target for beta-adrenergic regulation and beta-adrenergic signaling plays a role in ESC cardiac differentiation. PMID- 21711456 TI - Programmed cell death of the ovarian nurse cells during oogenesis of the ladybird beetle Adalia bipunctata (Coleoptera: Coccinellidae). AB - Programmed cell death (PCD) is an evolutionary conserved and genetically regulated form of cell death, in which the cell plays an active role in its own demise. It is widely recognized that PCD can be morphologically classified into three major types: type I, known as apoptosis, type II, called autophagy, and type III, specified as cytoplasmic cell death. So far, PCD has been morphologically analyzed in certain model insect species of the meroistic polytrophic ovary-type, but has never been examined before in insects carrying meroistic telotrophic ovaries. In the present study, we attempted to thoroughly describe the three different types (I, II and III) of PCD occurring during oogenesis in the meroistic telotrophic ovary of the Coleoptera species Adalia bipunctata, at different developmental ages of the adult female insects. We reveal that in the ladybird beetle A. bipunctata, the ovarian tropharia undergo age-dependent forms of apoptotic, autophagic and cytoplasmic (paraptotic-like) cell death, which seem to operate in a rather synergistic fashion, in accordance with previous observations in Diptera and Lepidoptera species. Furthermore, we herein demonstrate the occurrence of morphogenetically abnormal ovarioles in A. bipunctata female insects. These atretic ovarioles collapse and die through a PCD mediated process that is characterized by the combined activation of all three types of PCD. Conclusively, the distinct cell death programs (I, II and III) specifically engaged during oogenesis of A. bipunctata provide strong evidence for the structural and functional conserved nature of PCD during insect evolution among meroistic telotrophic and meroistic polytrophic ovary-type insects. PMID- 21711457 TI - Assessment of specific characteristics of abnormal general movements: does it enhance the prediction of cerebral palsy? AB - AIM: Abnormal general movements at around 3 months corrected age indicate a high risk of cerebral palsy (CP). We aimed to determine whether specific movement characteristics can improve the predictive power of definitely abnormal general movements. METHOD: Video recordings of 46 infants with definitely abnormal general movements at 9 to 13 weeks corrected age (20 males; 26 females; median gestational age 30wks; median birthweight 1200g) were analysed for the following characteristics: presence of fidgety, cramped synchronized, stiff, or jerky movements and asymmetrical tonic neck reflex pattern. Neurological condition (presence or absence of CP), gross motor development (Alberta Infant Motor Scales), quality of motor behaviour (Infant Motor Profile), functional mobility (Pediatric Evaluation of Disability Inventory), and Mental Developmental Index (Bayley Scales) were assessed at 18 months corrected age. Infants were excluded from participating in the study if they had severe congenital anomalies or if their caregivers had an insufficient knowledge of the Dutch language. RESULTS: Of the 46 assessed infants, 10 developed spastic CP (Gross Motor Function Classification System levels I to V; eight bilateral spastic CP, two unilateral spastic CP). The absence of fidgety movements and the presence of predominantly stiff movements were associated with CP (Fisher's exact test, p=0.018 and p=0.007 respectively) and lower Infant Motor Profile scores (Mann-Whitney U test, p=0.015 and p=0.022 respectively); stiff and predominantly stiff movements were associated with lower Alberta Infant Motor Scales scores (Mann-Whitney U test, p=0.01 and p=0.004 respectively). Cramped synchronized movements and the asymmetrical tonic neck reflex pattern were not related to outcome. None of the movement characteristics were associated with Pediatric Evaluation of Disability Inventory scores or the Mental Developmental Index. INTERPRETATION: The assessment of fidgety movements and movement stiffness may improve the predictive power of definitely abnormal general movements for developmental outcome. However, the presence of fidgety movements does not preclude the development of CP. PMID- 21711458 TI - The use of cyanobacteria as filler in nitrocellulose capillaries improves ultrastructural preservation of immature barley pollen upon high pressure freezing. AB - The high pressure freezing (HPF) followed by freeze substitution technique has advantages over chemical fixation in the context of preserving sample ultrastructure. However, when HPF is applied to cultured pollen grains, the large intercellular spaces present lead to a poor level of ultrastructure preservation. We report here that the mixing of cyanobacteria with immature barley pollen grains succeeded in greatly reducing the volume of liquid present between the large pollen grains, and so improved the loading of the sample into a nitrocellulose capillary. The use of yeast or cyanobacteria paste to surround the filled capillaries was beneficial in speeding the transfer of heat during the freezing process. This modification of the HPF method resulted in a greatly improved level of ultrastructure preservation. PMID- 21711459 TI - Smad8 is expressed in the anterior necrotic zone: evidence for a role of bone morphogenetic proteins/SMAD signaling in the activation of a molecular cascade that culminates in cell death. AB - Bone morphogenetic proteins (BMPs) play a crucial role in programmed cell death (PCD), a biological process required for the sculpturing of the embryonic limbs. However, it is unknown if BMP signaling directly promotes cell death, or if it induces a molecular cascade that culminates in cell death. Given that Smad8, which encodes one component of BMP signaling, is expressed during the regression of interdigital tissue and responds to BMPs, we presumed that it may be expressed in other cell death areas during chick limb development such as the anterior and posterior necrotic zones (ANZ and PNZ). The present study found that the Smad8 expression pattern in the anterior mesoderm of the hindlimb is very similar to that observed in limbs stained to detect cell death. Also, BMPs and retinoic acid, which act as apoptosis-promoting factors, induced expression of Smad8 before the onset of cell death, while sonic hedgehog protein, acting as a survival factor, inhibited Smad8 expression in the ANZ. However, although there was correlation between Smad8 expression patterns and PCD in the ANZ, phosphorylated forms of SMAD1/5/8 and TUNEL staining did not co-localize in dying cells. Interestingly, a short pulse of BMP was sufficient to trigger cell death. On the other hand, most dying cells were located in the avascular region, while many cells expressing Smad8 were located in the vascular region of the ANZ. These results suggest that BMPs mediated by SMAD signaling activate a molecular cascade that culminates in PCD. PMID- 21711460 TI - Imaging of Bernal stacked and misoriented graphene and boron nitride: experiment and simulation. AB - Experimental atomic resolution bright and high angle dark field transmission electron microscopy images of mono- and few-layer graphene and boron nitride, as well as of turbostratic arrangements in both materials, are compared to their simulated counterparts. Changes in the images according to defocus, layer number and accelerating voltage are discussed. It emerges that simulations with realistic microscope parameters accurately depict experimental graphene and boron nitride images and present a reliable tool for their interpretation. PMID- 21711462 TI - Improvements for imaging ceramics sintering in situ in ESEM. AB - Sintering of green samples of alumina produced by ice-templating was followed in situ in an environmental scanning electron microscope (ESEM) up to temperatures as high as 1375 degrees C. These alumina samples with well-defined architectures are of great interest in the field of materials science due to their high specific strength (especially in compression), low density and adaptable porosity. For the present study, they also have the advantage to exhibit an important topography, inducing interesting contrast when imaged in an ESEM. Improvements of the imaging conditions in the ESEM were essential to really follow the sintering process involving formation of necks between grains or shift of the centre of grains. This paper describes the improvements made and the results observed on the sintering process of alumina green samples processed by ice-templating. PMID- 21711461 TI - Induction of self-antigen-specific Foxp3+ regulatory T cells in the periphery by lymphodepletion treatment with anti-mouse thymocyte globulin in mice. AB - Lymphodepletion therapies are increasingly tested for controlling immune damage. One appealing premise for such a therapy is that it may 'reboot' the immune system and restore immune tolerance. However, the tolerogenic potential of lymphodepletion therapies remains controversial. The debate is exemplified by conflicting evidence from the studies of anti-thymocyte globulin (ATG), a prototype of immunodepleting drugs, in particular on whether it induces CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells. To understand the impact of ATG on T cells at a clonal level in vivo, we studied the effect of anti-mouse thymocyte globulin (mATG) in a reductionist model in which the T-lymphocyte repertoire consists of a single clone of pathogenic T effector (Teff) cells specific to a physiological self-antigen. The mATG treatment led to peripheral induction of antigen-specific Treg cells from an otherwise monoclonal Teff repertoire, independent of thymic involvement. The de novo induction of Treg cells occurred consistently in local draining lymph nodes, and persistence of induced Treg cells in blood correlated with long-term protection from autoimmune destruction. This study provides in vivo evidence for clonal conversion from a pathogenic self antigen-specific Teff cell to a Treg cell in the setting of immunodepletion therapies. PMID- 21711463 TI - Surface rejuvenating effect of Achillea millefolium extract. AB - Proopiomelanocortin is a precursor peptide that gives rise to several neuropeptides including adrenocorticotrophic hormone (ACTH) and beta-endorphin. POMC-derived peptides have been shown to be synthesized in human epidermis where they modulate numerous skin functions. Because we previously observed that melanocortin receptor-2 and MU-opioid receptor 1, the respective receptors for ACTH and beta-endorphin decreased with ageing in human epidermis, we have selected an active ingredient (INCI name: Achillea millefolium extract) able to upregulate receptor expressions. The aim of the present work was first to evaluate the effect of A. millefolium extract on the expression pattern of various epidermal differentiation markers ex vivo in normal human skin biopsies using quantitative image analysis and second to evaluate its capacity to rejuvenate the appearance of skin surface in vivo. Results show an improved expression profile of cytokeratin 10, transglutaminase-1 and filaggrin in cultured skin biopsies as well as an increased epidermal thickness. In vivo, a 2 month treatment with A. millefolium extract at 2% significantly improved the appearance of wrinkles and pores compared with placebo. Results were also directionally better than those of glycolic acid that was chosen as reference resurfacing molecule. PMID- 21711464 TI - Learning to live well with chronic fatigue: the personal perspective. AB - BACKGROUND: Persistent fatigue is recognized as an integral and significantly disabling aspect of the experience of living with a long-term health condition. Acute medical care models have limited applicability when seeking to provide health care to meet the needs of those living with chronic fatigue. AIMS: This article is a report of a study that sought to understand how people can live well in spite of the presence of chronic fatigue. METHODS: A thematic analysis was conducted on 43 narratives provided by people living with chronic fatigue during 2007 as part of an internet-based study. FINDINGS: This report focuses on the two themes that appeared of most relevance to participants: managing energy and redefining self. Two particular approaches to energy management were noted. In the first, the focus is upon moderating and avoiding excess to manage energy. In the second approach, the body was conceptualized as a machine so that energy becomes a limited resource to be managed. Work to redefine the sense of self appeared to be focused upon the desire to seek normality, to see oneself as rational and come to terms with change. CONCLUSION: People can and do find ways to live well with chronic fatigue. Understanding how the person with chronic fatigue has come to conceptualize his/her experiences will be a more fruitful starting point than providing recipes for successful living if nurses are to work effectively with this group of people. PMID- 21711465 TI - Type 2 diabetes: how do Thai Buddhist people with diabetes practise self management? AB - AIMS: This paper is a report of a study of how Thai Buddhist people with type 2 diabetes practice self-management. BACKGROUND: The importance of diabetes self management is recognized in the literature. However, research on self-care management in Thailand, in particular concerning Buddhist people with type 2 diabetes, is scarce. METHODS: A descriptive qualitative study was conducted. Purposive convenience sampling was used, and thirty men and women with diabetes, aged 28-79 years, participated. Data were collected from June to August 2009 and analysed by use of manifest and latent content analysis. FINDINGS: Five themes of self-management among Thai Buddhist people with type 2 diabetes were identified: cultural influence on disease control, Buddhism and Thai culture, struggle for disease control, family support and economy a high priority. CONCLUSION: Even though the Buddhist people with diabetes had certain self-management capabilities, many had poor control of their blood sugar levels and needed assistance. Reference to Buddhist moderation can be an effective means of helping the people with diabetes better manage their disease and change their lifestyles. In addition to cultural and religious traditions, family, economy and social environment should be taken into account both in the care and in interventions aimed at helping people with diabetes cope and empowering them to control their disease. PMID- 21711466 TI - Sunbed use and campaign initiatives in the Danish population, 2007-2009: a cross sectional study. AB - BACKGROUND: Denmark has experienced an increase in melanoma incidence since the 1960s. In 2007, a skin cancer prevention campaign was launched, one of the targets being the widespread use of sunbeds in Denmark. The antisunbed campaign comprised public affairs initiatives and campaign activities, which included the social media, with young people as the main target. OBJECTIVE: The aim of this study was to describe the development in sunbed use after the start of the campaign in the period 2007-2009. METHODS: A population-based sample of 14,514 respondents aged 15-59 years completed four questionnaires in 2007-2009 on artificial exposure to ultraviolet radiation. We examined the relations between sunbed use, time and demographic factors using logistic regression analysis. RESULTS: The odds ratio (OR) for being a sunbed user in 2009 when compared with 2007 was 0.61 (0.54-0.69); in the age group of 15-19 years, the OR was 0.42 (0.30 0.69). In 2009, however, 23% of Danes (33% of 15-19-year-olds) still reported sunbed use within the past 12 months, and more than 50% had experienced sunburn caused by a sunbed. In 2009, the majority of the population, including the age group of 15-19 years, was in favour of restricting admission to sunbed parlours for children under 18 years. CONCLUSIONS: Sunbed use in Denmark decreased concurrently with the campaign activities, with the largest change in the youngest age group, which was a prioritized target of the campaign. Results suggest that a legislative solution should be found to avoid exposure of a large proportion of children to ultraviolet radiation and to reduce future melanoma incidence. PMID- 21711467 TI - A randomized comparison of excimer laser versus narrow-band ultraviolet B phototherapy after punch grafting in stable vitiligo patients. AB - Background Ultraviolet radiation following punch grafting may stimulate the migration of melanocytes from the grafts into the vitiliginous skin, thereby increasing the rate of repigmentation. We compared the effects of the 308-nm xenon chloride excimer laser (EL) vs. narrow-band ultraviolet B (NB-UVB) after punch grafting in patients with vitiligo. Objectives The aims of this study were to evaluate (i) repigmentation (%); (ii) treatment satisfaction; and (iii) patient preferences for EL vs. NB-UVB therapy after punch grafting in vitiligo. Methods Fourteen patients were treated with the punch-grafting technique on two symmetrical vitiligo patches. Starting 1 week after the punch grafting, the vitiligo patches were treated twice a week during 3 months, with EL on one side and with NB-UVB on the other side. Repigmentation (%) was measured by a digital image analysis system. Patients' satisfaction and preference for treatment were also assessed. Results Whereas both treatment modalities induced repigmentation, no statistically significant difference was found in grade of repigmentation after 3 months. With EL, 71.4% lower cumulative dose was reached. Patients were significantly more satisfied with NB-UVB and preferred it over EL. Conclusions The choice between EL and NB-UVB cannot solely be based on repigmentation, but rather on other factors, such as patients' preferences. However, given the lower UV dose of EL, we recommend its use in vulnerable populations, such as in small children and patients with sun-damaged skin with a history of long-term UVB treatment. PMID- 21711468 TI - Peeling skin diseases: 21 cases from Turkey and a review of the literature. AB - BACKGROUND: Peeling skin diseases (PSD) refer to a group of rare autosomal recessive dermatosis which are characterized by spontaneous, continual peeling of the skin. Three different clinical pictures can be distinguished: Inflammatory PSD also referred to as peeling skin syndrome (PSS) type B, non-inflammatory PSD also referred to as PSS type A, and localized forms i.e. acral type PSS. OBJECTIVE: To characterize the clinical and histopathological features of PSD in Turkey. METHODS: We retrospectively reviewed the medical records and clinical photographs of patients who were given diagnosis of PSD and conducted histopathological evaluation of skin biopsies to identify the site of cleavage. Also we evaluated the cases including age, gender, age onset, clinical and histological findings, family history, associated disorders and PSD type. RESULTS: Twenty-one patients with PSD were seen at Gulhane School of Medicine in Ankara between the years 1994 and 2010 in this retrospective study. All patients were men. Their ages were between 20 and 26 years (22.44+/-2.30, Mean age+/-SD). Of the patients, eight cases (40%) were type A, eight cases (40%) were type B, and five cases (20%) were acral type PSS. Eleven cases (52%) had parental consanguinity. Keratoderma, cheilitis, keratosis pilaris, melanonichia, clubbing, hyperhidrosis, onychodystrophy were observed in eight cases as an accompanying disorder. CONCLUSIONS: In this case series, PSD occurred rarely and also showed generally mild course of disease in Turkey and most likely related to consanguineous of marriages. Future investigations on PSD will contribute to our progressing alternative targets for pathogenesis-based therapy. PMID- 21711469 TI - Skin disorders and the role of dermatologists after the tsunami in Japan. PMID- 21711472 TI - Stepping forward or staying in our comfort zone. PMID- 21711471 TI - Developing a 'critical' approach to patient and public involvement in patient safety in the NHS: learning lessons from other parts of the public sector? AB - There has been considerable momentum within the NHS over the last 10 years to develop greater patient and public involvement (PPI). This commitment has been reflected in numerous policy initiatives. In patient safety, the drive to increase involvement has increasingly been seen as an important way of building a safety culture. Evidence suggests, however, that progress has been slow and even more variable than in health care generally. Given this context, the paper analyses some of the key underlying drivers for involvement in the wider context of health and social care and makes some suggestions on what lessons can be learned for developing the PPI agenda in patient safety. To develop PPI further, it is argued that a greater understanding is needed of the contested nature of involvement in patient safety and how this has similarities to the emergence of user involvement in other parts of the public services. This understanding has led to the development of a range of critical theories to guide involvement that also make more explicit the underlying factors that support and hinder involvement processes, often related to power inequities and control. Achieving greater PPI in patient safety is therefore seen to require a more critical framework for understanding processes of involvement that can also help guide and evaluate involvement practices. PMID- 21711473 TI - Sexual function: diagnosis and management of sexual dysfunction. PMID- 21711474 TI - Potential Risks for the Off-Label Use of SSRIs in Premature Ejaculation (CME). PMID- 21711470 TI - Molecular characterization of Der p 10: a diagnostic marker for broad sensitization in house dust mite allergy. AB - BACKGROUND: Tropomyosins represent clinically relevant seafood allergens but the role of mite tropomyosin, Der p 10, in house dust mite (HDM) allergy has not been studied in detail. OBJECTIVE: To express and purify a recombinant Der p 10 with equivalent IgE reactivity as natural Der p 10 and to evaluate its IgE reactivity and allergenic activity in HDM-allergic patients. METHODS: rDer p 10 was expressed in Escherichia coli, purified and characterized by mass spectrometry and circular dichroism. It was tested for IgE reactivity in 1322 HDM-allergic patients. Detailed IgE-reactivity profiles to six HDM allergens (Der p 1, 2, 5, 7, 10, 21) were established for subgroups of Der p 10-positive and -negative patients. The allergenic activity of rDer p 10 was evaluated in basophil degranulation experiments. RESULTS: rDer p 10 is an alpha-helical protein sharing IgE epitopes with nDer p 10. It is recognized by 15.2% of HDM-allergic patients. Der p 10-negative patients were primarily sensitized to Der p 1 and/or Der p 2, whereas Der p 10-positive patients reacted to several other HDM allergens besides the major allergens (Der p 1, Der p 2) or showed a rather selective Der p 10 reactivity. The allergenic activity of Der p 10 was generally low but patients could be identified who suffered from clinically relevant HDM allergy due to Der p 10 sensitization. CONCLUSION AND CLINICAL RELEVANCE: Der p 10 may be a diagnostic marker for HDM-allergic patients with additional sensitization to allergens other than Der p 1 and Der p 2. Such patients may require attention when allergen-specific immunotherapy is considered. PMID- 21711477 TI - Morokoff, P. J., & Heiman, J. R. (1980). Effects of erotic stimuli on sexually functional and dysfunctional women: multiple measures before and after sex therapy. PMID- 21711478 TI - Novel water-soluble curcumin derivative mediating erectile signaling. AB - INTRODUCTION: Curcumin is an inducer of heme oxygenase enzyme-1 (HO-1) that is involved in erectile signaling via elevating cyclic guanosine monophosphate (cGMP)levels. AIM: To assess the effect of oral administration of a water-soluble long-acting curcumin derivative on erectile signaling. METHODS: Two hundred and thirty six male white albino rats were divided into four groups; group 1 (N = 20) includes control. Group 2 (N = 72) was equally divided into four subgroups; subgroup 1 received pure curcumin (10 mg/kg), subgroup 2 received the long-acting curcumin derivative (2 mg/kg), subgroup 3 received the long-acting curcumin derivative (10 mg/kg), and subgroup 4 received sildenafil (4 mg/kg). Subgroups were sacrificed after the first, second, and third hour. Group 3 (N = 72) was equally divided into the same four subgroups already mentioned and were sacrificed after 24 hours, 48 hours, and 1 week. Group 4 (N = 72) was subjected to intracavernosal pressure (ICP) measurements 1 hour following oral administration of the same previous doses in the same rat subgroups. MAIN OUTCOME MEASURE: Cavernous tissue HO enzyme activity, cGMP, and ICP. RESULTS: In group 2, there was a significant progressive maintained elevation of HO activity and cGMP tissue levels starting from the first hour in subgroups 3 and 4, whereas, the rise in HO activity and cGMP started from second hour regarding the other rat subgroups. Sildenafil effect decreased after 3 hours. In group 3, there was a significant maintained elevation of HO activity and cGMP tissue levels extended to 1 week as compared to controls for all rat subgroups that received both forms of curcumin. In group 4, long-acting curcumin derivative exhibited more significant potentiation of intracavernosal pressure as compared to control and to the pure curcumin. CONCLUSION: Water-soluble long-acting curcumin derivative could mediate erectile function via upregulating cavernous tissue cGMP. PMID- 21711480 TI - Hypoactive sexual desire disorder: when is low sexual desire a sexual dysfunction? PMID- 21711479 TI - Efficacy and safety of tadalafil 20 mg on demand vs. tadalafil 5 mg once-a-day in the treatment of post-radiotherapy erectile dysfunction in prostate cancer men: a randomized phase II trial. AB - INTRODUCTION: The role of phosphodiesterase type 5 inhibitors in the treatment of post-radiotherapy erectile dysfunction (ED) has not been extensively investigated. AIM: To compare the efficacy and safety of on-demand 20-mg tadalafil (arm A) with the newly released tadalafil 5-mg once-a-day dosing (arm B) in patients with ED following radiotherapy for prostate cancer (PC). METHODS: Randomized study to receive on-demand 20-mg or once-a-day 5-mg tadalafil for 12 weeks. Main Outcome Measures. Changes in the International Index of Erectile Function (IIEF) domain scores and Sexual Encounter Profile (SEP) question 2 and 3 positive response rates. RESULTS: Fifty-two out of 86 screened patients were randomized. Forty-four patients were evaluable for efficacy. A significant improvement in all domains of the IIEF was observed in both arms (P = 0.0001) with mean erectile function domain scores values of 25 and 27.1 for the 20-mg and 5-mg tadalafil, respectively (P = 0.19). SEP 2 and 3 positive response rates increased from 0% in both arms at baseline to 81% and 70% in the 20-mg arm and 90% and 73% in the 5-mg arm, respectively, at the end of treatment (P = 0.27). End of treatment global efficacy question positive answers were 86% in the 20-mg arm and 95% in the 5-mg arm (P = 0.27). Higher treatment compliance was shown in arm B (100%) as compared with arm A (86%). There was a nonstatistically significant trend toward fewer side effects in favor of the 5-mg daily dose arm. CONCLUSIONS: In the study population, both tadalafil formulations generated significantly high response rates according to the outcome measures and were well tolerated. The once-a-day 5-mg dosing showed higher compliance and marginally reduced side effects, thus making it an attractive alternative to on-demand therapy for ED in post-radiotherapy PC patients. PMID- 21711481 TI - The passion of sexual medicine. PMID- 21711483 TI - Update in testosterone therapy for men. AB - INTRODUCTION: Male hypogonadism is a condition characterized by inadequate testicular production of sex steroids and sperms; however, the term is more commonly used to identify testosterone (T) deficiency. When fertility is not desired, T replacement therapy (TRT) is the gold standard. AIM: To review the pathogenesis of male hypogonadism and the available preparations for TRT, along with the main clinical outcomes. METHODS: A systematic search of published evidence was performed using Medline (1969 to September 2010). Data from a consecutive series of subjects attending our Andrology Unit were also provided to stress the clinical correlates of low T. Inventories available for detecting hypogonadism (including ANDROTEST) were overviewed. MAIN OUTCOME MEASURES: The most important studies regarding the pathogenesis of male hypogonadism and the preparations for its treatment were reviewed. To review TRT outcomes, only meta analytic studies were considered. RESULTS: The goals of TRT are to alleviate clinical symptoms and to restore serum T levels to the mid-normal range, without significant side effects or safety concerns. Different T formulations have been approved. TRT is associated with a reduction of fat mass, an increase of lean mass, and a possible positive effect on lipid profile and glycometabolic control. Bone density and depressive symptoms are improved by TRT, while effects on cardiovascular risk and frailty are more controversial. No increase of prostate cancer and prostate-related problems has been reported so far. TRT, alone or in combination with phosphodiesterase type 5 inhibitors, is considered the first line therapy in hypogonadal subjects with erectile dysfunction. CONCLUSIONS: T deficiency is highly prevalent in the aging male and represents a sign of physical and sexual frailty. The significance of low T in elderly men has yet to be completely clarified. Large, prospective intervention trials will help solve this dilemma. PMID- 21711485 TI - Traditional (retroperitoneal) and abdominal wall (ectopic) reservoir placement. PMID- 21711487 TI - Palladium nanoparticles on InP for hydrogen detection. AB - Layers of palladium (Pd) nanoparticles on indium phosphide (InP) were prepared by electrophoretic deposition from the colloid solution of Pd nanoparticles. Layers prepared by an opposite polarity of deposition showed different physical and morphological properties. Particles in solution are separated and, after deposition onto the InP surface, they form small aggregates. The size of the aggregates is dependent on the time of deposition. If the aggregates are small, the layer has no lateral conductance. Forward and reverse I-V characteristics showed a high rectification ratio with a high Schottky barrier height. The response of the structure on the presence of hydrogen was monitored. PMID- 21711488 TI - 17-DMAG diminishes hemorrhage-induced small intestine injury by elevating Bcl-2 protein and inhibiting iNOS pathway, TNF-alpha increase, and caspase-3 activation. AB - BACKGROUND: Hemorrhage increases inducible nitric oxide synthase (iNOS) and depletes ATP levels in various tissues. Previous studies have shown that geldanamycin, an inducer of heat shock protein 70kDa (HSP-70) and inhibitor of iNOS, limits both processes. Reduction in NO production limits lipid peroxidation, apoptosome formation, and caspase-3 activation, thereby increasing cellular survival and reducing the sequelae of hemorrhage. The poor solubility of geldanamycin in aqueous solutions, however, limits its effectiveness as a drug. 17-DMAG is a water-soluble analog of geldanamycin that might have greater therapeutic utility. This study investigated the effectiveness of 17-DMAG at reducing hemorrhagic injury in mouse small intestine. RESULTS: In mice, the hemorrhage-induced iNOS increase correlated with increases in Kruppel-like factor 6 (KLF6) and NF-kB and a decrease in KLF4. As a result, increases in NO production and lipid peroxidation occurred. Moreover, hemorrhage also resulted in decreased Bcl-2 and increased TNF-alpha, IL-6, and IL-10 concentrations, p53 protein, caspase-3 activation, and cellular ATP depletion. A shortening and widening of villi in the small intestine was also observed. Treatment with 17 DMAG significantly reduced the hemorrhage-induced increases in iNOS protein, jejunal alteration, and TNF-alpha and IL-10 concentrations, but 17-DMAG did not affect the hemorrhage-induced increases in p53 and IL-6 concentration. 17-DMAG treatment by itself upregulated HSP-70, Bcl-2, and p53. CONCLUSION: Since 17-DMAG is water soluble, bioactive, and not toxic, 17-DMAG may prove useful as a prophylactic drug for hemorrhage. PMID- 21711490 TI - Revelation of graphene-Au for direct write deposition and characterization. AB - Graphene nanosheets were prepared using a modified Hummer's method, and Au graphene nanocomposites were fabricated by in situ reduction of a gold salt. The as-produced graphene was characterized by X-ray photoelectron spectroscopy, ultraviolet-visible spectroscopy, scanning electron microscopy, and high resolution transmission electron microscopy (HR-TEM). In particular, the HR-TEM demonstrated the layered crystallites of graphene with fringe spacing of about 0.32 nm in individual sheets and the ultrafine facetted structure of about 20 to 50 nm of Au particles in graphene composite. Scanning helium ion microscopy (HIM) technique was employed to demonstrate direct write deposition on graphene by lettering with gaps down to 7 nm within the chamber of the microscope. Bare graphene and graphene-gold nanocomposites were further characterized in terms of their composition and optical and electrical properties. PMID- 21711491 TI - The role of particle size of particulate nano-zinc oxide wood preservatives on termite mortality and leach resistance. AB - Historically most residential wood preservatives were aqueous soluble metal formulations, but recently metals ground to submicron size and dispersed in water to give particulate formulations have gained importance. In this study, the specific role nano-zinc oxide (ZnO) particle size and leach resistance plays in termite mortality resulting from exposure to particulate ZnO-treated wood was investigated. Southern yellow pine (SYP) sapwood impregnated with three concentrations of two particle sizes (30 and 70 nm) of ZnO were compared to wood treated with soluble zinc sulphate (ZnSO4) preservative for leach resistance and termite resistance. Less than four percent leached from the particulate nano-ZnO treated specimens, while 13 to 25% of the zinc sulphate leached from the soluble treated wood. Nano-ZnO was essentially non-leachable from wood treated with 5% formulation for the 30-nm particle size. In a no-choice laboratory test, eastern subterranean termites (Reticulitermes flavipes) consumed less than 10% of the leached nano-ZnO-treated wood with 93 to 100% mortality in all treatment concentrations. In contrast, termites consumed 10 to 12% of the leached ZnSO4 treated wood, but with lower mortality: 29% in the 1% treatment group and less than 10% (5 and 8%, respectively) in the group of wood blocks treated with 2.5 and 5.0% ZnSO4. We conclude that termites were repelled from consuming wood treated with nano-ZnO, but when consumed it was more toxic to eastern subterranean termites than wood treated with the soluble metal oxide formulation. There were no differences in leaching or termite mortality between the two particle sizes of nano-ZnO. PMID- 21711489 TI - Environmental adaptability and stress tolerance of Laribacter hongkongensis: a genome-wide analysis. AB - BACKGROUND: Laribacter hongkongensis is associated with community-acquired gastroenteritis and traveler's diarrhea and it can reside in human, fish, frogs and water. In this study, we performed an in-depth annotation of the genes in its genome related to adaptation to the various environmental niches. RESULTS: L. hongkongensis possessed genes for DNA repair and recombination, basal transcription, alternative sigma-factors and 109 putative transcription factors, allowing DNA repair and global changes in gene expression in response to different environmental stresses. For acid stress, it possessed a urease gene cassette and two arc gene clusters. For alkaline stress, it possessed six CDSs for transporters of the monovalent cation/proton antiporter-2 and NhaC Na+:H+ antiporter families. For heavy metals acquisition and tolerance, it possessed CDSs for iron and nickel transport and efflux pumps for other metals. For temperature stress, it possessed genes related to chaperones and chaperonins, heat shock proteins and cold shock proteins. For osmotic stress, 25 CDSs were observed, mostly related to regulators for potassium ion, proline and glutamate transport. For oxidative and UV light stress, genes for oxidant-resistant dehydratase, superoxide scavenging, hydrogen peroxide scavenging, exclusion and export of redox-cycling antibiotics, redox balancing, DNA repair, reduction of disulfide bonds, limitation of iron availability and reduction of iron-sulfur clusters are present. For starvation, it possessed phosphorus and, despite being asaccharolytic, carbon starvation-related CDSs. CONCLUSIONS: The L. hongkongensis genome possessed a high variety of genes for adaptation to acid, alkaline, temperature, osmotic, oxidative, UV light and starvation stresses and acquisition of and tolerance to heavy metals. PMID- 21711492 TI - CdSe/TiO2 core-shell nanoparticles produced in AOT reverse micelles: applications in pollutant photodegradation using visible light. AB - CdSe quantum dots with a prominent band-edge photoluminescence were obtained by a soft AOT water-in-oil (w/o) microemulsion templating method with an estimated size of 2.7 nm. The CdSe particles were covered with a TiO2 layer using an intermediate SiO2 coupling reagent by a sol-gel process. The resulting CdSe/TiO2 core/shell nanoparticles showed appreciable photocatalytic activity at lambda = 405 nm which can only originate because of electron injection from the conduction band of CdSe to that of TiO2. PMID- 21711493 TI - Spontaneous confocal Raman microscopy--a tool to study the uptake of nanoparticles and carbon nanotubes into cells. AB - Confocal Raman microscopy as a label-free technique was applied to study the uptake and internalization of poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) and carbon nanotubes (CNTs) into hepatocarcinoma human HepG2 cells. Spontaneous confocal Raman spectra was recorded from the cells exposed to oxidized CNTs and to PLGA NPs. The Raman spectra showed bands arising from the cellular environment: lipids, proteins, nucleic acids, as well as bands characteristic for either PLGA NPs or CNTs. The simultaneous generation of Raman bands from the cell and nanomaterials from the same spot proves internalization, and also indicates the cellular region, where the nanomaterial is located. For PLGA NPs, it was found that they preferentially co-localized with lipid bodies, while the oxidized CNTs are located in the cytoplasm. PMID- 21711494 TI - Modeling of polyethylene, poly(l-lactide), and CNT composites: a dissipative particle dynamics study. AB - Dissipative particle dynamics (DPD), a mesoscopic simulation approach, is used to investigate the effect of volume fraction of polyethylene (PE) and poly(l lactide) (PLLA) on the structural property of the immiscible PE/PLLA/carbon nanotube in a system. In this work, the interaction parameter in DPD simulation, related to the Flory-Huggins interaction parameter chi, is estimated by the calculation of mixing energy for each pair of components in molecular dynamics simulation. Volume fraction and mixing methods clearly affect the equilibrated structure. Even if the volume fraction is different, micro-structures are similar when the equilibrated structures are different. Unlike the blend system, where no relationship exists between the micro-structure and the equilibrated structure, in the di-block copolymer system, the micro-structure and equilibrated structure have specific relationships. PMID- 21711495 TI - Dynamics of mechanical waves in periodic grapheme nanoribbon assemblies. AB - We simulate the natural frequencies and the acoustic wave propagation characteristics of graphene nanoribbons (GNRs) of the type (8,0) and (0,8) using an equivalent atomistic-continuum FE model previously developed by some of the authors, where the C-C bonds thickness and average equilibrium lengths during the dynamic loading are identified through the minimisation of the system Hamiltonian. A molecular mechanics model based on the UFF potential is used to benchmark the hybrid FE models developed. The acoustic wave dispersion characteristics of the GNRs are simulated using a Floquet-based wave technique used to predict the pass-stop bands of periodic mechanical structures. We show that the thickness and equilibrium lengths do depend on the specific vibration and dispersion mode considered, and that they are in general different from the classical constant values used in open literature (0.34 nm for thickness and 0.142 nm for equilibrium length). We also show the dependence of the wave dispersion characteristics versus the aspect ratio and edge configurations of the nanoribbons, with widening band-gaps that depend on the chirality of the configurations. The thickness, average equilibrium length and edge type have to be taken into account when nanoribbons are used to design nano-oscillators and novel types of mass sensors based on periodic arrangements of nanostructures.PACS 62.23.Kn . 62.25.Fg . 62.25.Jk. PMID- 21711496 TI - A facile synthesis of polypyrrole/carbon nanotube composites with ultrathin, uniform and thickness-tunable polypyrrole shells. AB - An improved approach to assemble ultrathin and thickness-tunable polypyrrole (PPy) films onto multiwall carbon nanotubes (MWCNTs) has been investigated. A facile procedure is demonstrated for controlling the morphology and thickness of PPy film by adding ethanol in the reaction system and a possible mechanism of the coating formation process is proposed. The coated PPy films can be easily tuned by adding ethanol and adjusting a mass ratio of pyrrole to MWCNTs. Moreover, the thickness of PPy significantly influences the electronic conductivity and capacitive behavior of the PPy/MWCNT composites. The method may provide a facile strategy for tailoring the polymer coating on carbon nanotubes (CNTs) for carbon based device applications. PMID- 21711497 TI - Self-organized chains of nanodots induced by an off-normal incident beam. AB - We propose a model to show that under off-normal bombardment of an incident ion beam, a solid surface may spontaneously form nanoscale dots lining up into chains perpendicular to the incident beam direction. These dots demonstrate a highly ordered hexagonal pattern. We attribute the self-organization behavior to surface instability under concurrent surface kinetics and to a shadow effect that causes the self-alignment of dots. The fundamental mechanism may be applicable to diverse systems, suggesting an effective approach for nanofabrication. PMID- 21711498 TI - Structural and thermal studies of silver nanoparticles and electrical transport study of their thin films. AB - This work reports the preparation and characterization of silver nanoparticles synthesized through wet chemical solution method and of silver films deposited by dip-coating method. X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), field emission transmission electron microscopy (FETEM), high resolution transmission electron microscopy (HRTEM), selected area electron diffraction (SAED), and energy dispersive spectroscopy (EDX) have been used to characterize the prepared silver nanoparticles and thin film. The morphology and crystal structure of silver nanoparticles have been determined by FESEM, HRTEM, and FETEM. The average grain size of silver nanoparticles is found to be 17.5 nm. The peaks in XRD pattern are in good agreement with that of face-centered-cubic form of metallic silver. TGA/DTA results confirmed the weight loss and the exothermic reaction due to desorption of chemisorbed water. The temperature dependence of resistivity of silver thin film, determined in the temperature range of 100-300 K, exhibit semiconducting behavior of the sample. The sample shows the activated variable range hopping in the localized states near the Fermi level. PMID- 21711499 TI - Gold nanoparticles supported on magnesium oxide for CO oxidation. AB - Au was loaded (1 wt%) on a commercial MgO support by three different methods: double impregnation, liquid-phase reductive deposition and ultrasonication. Samples were characterised by adsorption of N2 at -96 degrees C, temperature programmed reduction, high-resolution transmission electron microscopy, energy dispersive X-ray spectroscopy and X-ray diffraction. Upon loading with Au, MgO changed into Mg(OH)2 (the hydroxide was most likely formed by reaction with water, in which the gold precursor was dissolved). The size range for gold nanoparticles was 2-12 nm for the DIM method and 3-15 nm for LPRD and US. The average size of gold particles was 5.4 nm for DIM and larger than 6.5 for the other methods. CO oxidation was used as a test reaction to compare the catalytic activity. The best results were obtained with the DIM method, followed by LPRD and US. This can be explained in terms of the nanoparticle size, well known to determine the catalytic activity of gold catalysts. PMID- 21711500 TI - Efficient spin filter using multi-terminal quantum dot with spin-orbit interaction. AB - We propose a multi-terminal spin filter using a quantum dot with spin-orbit interaction. First, we formulate the spin Hall effect (SHE) in a quantum dot connected to three leads. We show that the SHE is significantly enhanced by the resonant tunneling if the level spacing in the quantum dot is smaller than the level broadening. We stress that the SHE is tunable by changing the tunnel coupling to the third lead. Next, we perform a numerical simulation for a multi terminal spin filter using a quantum dot fabricated on semiconductor heterostructures. The spin filter shows an efficiency of more than 50% when the conditions for the enhanced SHE are satisfied.PACS numbers: 72.25.Dc,71.70.Ej,73.63.Kv,85.75.-d. PMID- 21711501 TI - Catalytic growth of ZnO nanostructures by r.f. magnetron sputtering. AB - The catalytic effect of gold seed particles deposited on a substrate prior to zinc oxide (ZnO) thin film growth by magnetron sputtering was investigated. For this purpose, selected ultra thin gold layers, with thicknesses close to the percolation threshold, are deposited by thermal evaporation in ultra high vacuum (UHV) conditions and subsequently annealed to form gold nanodroplets. The ZnO structures are subsequently deposited by r.f. magnetron sputtering in a UHV chamber, and possible morphological differences between the ZnO grown on top of the substrate and on the gold are investigated. The results indicate a moderate catalytic effect for a deposited gold underlayer of 4 nm, quite close to the gold thin film percolation thickness. PMID- 21711502 TI - Photo-catalytic activity of Zn1-xMnxS nanocrystals synthesized by wet chemical technique. AB - Polyvinyl pyrrolidone capped Zn1-xMnxS (0 <= x <= 0.1) nanocrystals have been synthesized using wet chemical co-precipitation method. Crystallographic and morphological characterization of the synthesized materials have been done using X-ray diffraction and transmission electron microscope. Crystallographic studies show the zinc blende crystals having average crystallite size approx. 3 nm, which is almost similar to the average particle size calculated from electron micrographs. Atomic absorption spectrometer has been used for qualitative and quantitative analysis of synthesized nanomaterials. Photo-catalytic activity has been studied using methylene blue dye as a test contaminant. Energy resolved luminescence spectra have been recorded for the detailed description of radiative and non-radiative recombination mechanisms. Photo-catalytic activity dependence on dopant concentration and luminescence quantum yield has been studied in detail. PMID- 21711503 TI - TBP-related factors: a paradigm of diversity in transcription initiation. AB - TATA binding protein (TBP) is a key component of the eukaryotic transcription initiation machinery. It functions in several complexes involved in core promoter recognition and assembly of the pre-initiation complex. Through gene duplication eukaryotes have expanded their repertoire of TATA binding proteins, leading to a variable composition of the transcription machinery. In vertebrates this repertoire consists of TBP, TBP-like factor (TLF, also known as TBPL1, TRF2) and TBP2 (also known as TBPL2, TRF3). All three factors are essential, with TLF and TBP2 playing important roles in development and differentiation, in particular gametogenesis and early embryonic development, whereas TBP dominates somatic cell transcription. TBP-related factors may compete for promoters when co-expressed, but also show preferential interactions with subsets of promoters. Initiation factor switching occurs on account of differential expression of these proteins in gametes, embryos and somatic cells. Paralogs of TFIIA and TAF subunits account for additional variation in the transcription initiation complex. This variation in core promoter recognition accommodates the expanded regulatory capacity and specificity required for germ cells and embryonic development in higher eukaryotes. PMID- 21711504 TI - Sensors vs. experts - a performance comparison of sensor-based fall risk assessment vs. conventional assessment in a sample of geriatric patients. AB - BACKGROUND: Fall events contribute significantly to mortality, morbidity and costs in our ageing population. In order to identify persons at risk and to target preventive measures, many scores and assessment tools have been developed. These often require expertise and are costly to implement. Recent research investigates the use of wearable inertial sensors to provide objective data on motion features which can be used to assess individual fall risk automatically. So far it is unknown how well this new method performs in comparison with conventional fall risk assessment tools. The aim of our research is to compare the predictive performance of our new sensor-based method with conventional and established methods, based on prospective data. METHODS: In a first study phase, 119 inpatients of a geriatric clinic took part in motion measurements using a wireless triaxial accelerometer during a Timed Up&Go (TUG) test and a 20 m walk. Furthermore, the St. Thomas Risk Assessment Tool in Falling Elderly Inpatients (STRATIFY) was performed, and the multidisciplinary geriatric care team estimated the patients' fall risk. In a second follow-up phase of the study, 46 of the participants were interviewed after one year, including a fall and activity assessment. The predictive performances of the TUG, the STRATIFY and team scores are compared. Furthermore, two automatically induced logistic regression models based on conventional clinical and assessment data (CONV) as well as sensor data (SENSOR) are matched. RESULTS: Among the risk assessment scores, the geriatric team score (sensitivity 56%, specificity 80%) outperforms STRATIFY and TUG. The induced logistic regression models CONV and SENSOR achieve similar performance values (sensitivity 68%/58%, specificity 74%/78%, AUC 0.74/0.72, +LR 2.64/2.61). Both models are able to identify more persons at risk than the simple scores. CONCLUSIONS: Sensor-based objective measurements of motion parameters in geriatric patients can be used to assess individual fall risk, and our prediction model's performance matches that of a model based on conventional clinical and assessment data. Sensor-based measurements using a small wearable device may contribute significant information to conventional methods and are feasible in an unsupervised setting. More prospective research is needed to assess the cost benefit relation of our approach. PMID- 21711505 TI - Predictive value of obsessive-compulsive drinking scale (OCDS) for outcome in alcohol-dependent inpatients: results of a 24-month follow-up study. AB - BACKGROUND: The present study examined whether craving as measured by the obsessive-compulsive drinking scale (OCDS) predict long-term outcome in alcohol dependent inpatients. METHODS: This was a 24-month prospective, observational study in 198 alcohol-dependent inpatients treated under standardized conditions. The primary outcome criterion was abstinence, defined as no subjective report or objective indication of alcohol consumption since discharge from treatment. The patients self-rated their craving for alcohol at the 6- and 12-month follow-ups by using the German version of the OCDS, which measures obsessive and compulsive aspects of craving. Univariate and logistic regression analyses with covariates were performed. RESULTS: Of the 104 patients interviewed at the 24-month follow up, 60% (n = 62) were abstinent. We found significant associations between total OCDS scores at 6 months and outcome at 12 months and between total OCDS scores at 12 months and outcome at 24 months: the higher the OCDS total score at one follow up evaluation, the less likely patients were to be abstinent at the subsequent one. The same association was found for each of the two OCDS subscales, control and consequences and drinking obsessions. CONCLUSIONS: These results support earlier findings that OCDS scores can predict outcome in alcohol-dependent patients. This information can be used for the timely development of protective resources. Hence, decisions over the use of resources can be made on the basis of objectified parameters to develop a personalized treatment concept. Consequently, economic considerations can induce a reduction of high medical costs. PMID- 21711506 TI - A cross-sectional testing of The Iowa Personality Disorder Screen in a psychiatric outpatient setting. AB - BACKGROUND: Patients suspected of personality disorders (PDs) by general practitioners are frequently referred to psychiatric outpatient clinics (POCs). In that setting an effective screening instrument for PDs would be helpful due to resource constraints. This study evaluates the properties of The Iowa Personality Disorder Screen (IPDS) as a screening instrument for PDs at a POC. METHODS: In a cross-sectional design 145 patients filled in the IPDS and were examined with the SCID-II interview as reference. Various case-findings properties were tested, interference of socio-demographic and other psychopathology were investigated by logistic regression and relationships of the IPDS and the concept of PDs were studied by a latent variable path analysis. RESULTS: We found that socio demographic and psychopathological factors hardly disturbed the IPDS as screening instrument. With a cut-off >=4 the 11 items IPDS version had sensitivity 0.77 and specificity 0.71. A brief 5 items version showed sensitivity 0.82 and specificity 0.74 with cut-off >= 2. With exception for one item, the IPDS variables loaded adequately on their respective first order variables, and the five first order variables loaded in general adequately on their second order variable. CONCLUSION: Our results support the IPDS as a useful screening instrument for PDs present or absent in the POC setting. PMID- 21711507 TI - Teachers' ideas versus experts' descriptions of 'the good teacher' in postgraduate medical education: implications for implementation. A qualitative study. AB - BACKGROUND: When innovations are introduced in medical education, teachers often have to adapt to a new concept of what being a good teacher includes. These new concepts do not necessarily match medical teachers' own, often strong beliefs about what it means to be a good teacher.Recently, a new competency-based description of the good teacher was developed and introduced in all the Departments of Postgraduate Medical Education for Family Physicians in the Netherlands. We compared the views reflected in the new description with the views of teachers who were required to adopt the new framework. METHODS: Qualitative study. We interviewed teachers in two Departments of Postgraduate Medical Education for Family Physicians in the Netherlands. The transcripts of the interviews were analysed independently by two researchers, who coded and categorised relevant fragments until consensus was reached on six themes. We investigated to what extent these themes matched the new description. RESULTS: Comparing the teachers' views with the concepts described in the new competency based framework is like looking into two mirrors that reflect clearly dissimilar images. At least two of the themes we found are important in relation to the implementation of new educational methods: the teachers' identification and organisational culture. The latter plays an important role in the development of teachers' ideas about good teaching. CONCLUSIONS: The main finding of this study is the key role played by the teachers' feelings regarding their professional identity and by the local teaching culture in shaping teachers' views and expectations regarding their work. This suggests that in implementing a new teaching framework and in faculty development programmes, careful attention should be paid to teachers' existing identification model and the culture that fostered it. PMID- 21711508 TI - Postprandial lipid responses to an alpha-linolenic acid-rich oil, olive oil and butter in women: a randomized crossover trial. AB - BACKGROUND: Postprandial lipaemia varies with gender and the composition of dietary fat due to the partitioning of fatty acids between beta-oxidation and incorporation into triacylglycerols (TAGs). Increasing evidence highlights the importance of postprandial measurements to evaluate atherogenic risk. Postprandial effects of alpha-linolenic acid (ALA) in women are poorly characterized. We therefore studied the postprandial lipid response of women to an ALA-rich oil in comparison with olive oil and butter, and characterized the fatty acid composition of total lipids, TAGs, and non-esterified fatty acids (NEFAs) in plasma. METHODS: A randomized crossover design (n = 19) was used to compare the postprandial effects of 3 meals containing 35 g fat. Blood samples were collected at regular intervals for 7 h. Statistical analysis was carried out with ANOVA (significant difference = P < 0.05). RESULTS: No significant difference was seen in incremental area under the curve (iAUC) plasma-TAG between the meals. ALA and oleic acid levels were significantly increased in plasma after ALA-rich oil and olive oil meals, respectively. Palmitic acid was significantly increased in plasma-TAG after the butter meal. The ratios of 18:2 n-6 to18:3 n-3 in plasma-TAGs, three and seven hours after the ALA-rich oil meal, were 1.5 and 2.4, respectively. The corresponding values after the olive oil meal were: 13.8 and 16.9; and after the butter meal: 9.0 and 11.6. CONCLUSIONS: The postprandial p-TAG and NEFA response in healthy pre-menopausal women was not significantly different after the intake of an ALA-rich oil, olive oil and butter. The ALA-rich oil significantly affected different plasma lipid fractions and improved the ratio of n-6 to n-3 fatty acids several hours postprandially. PMID- 21711509 TI - Establishment of stable Huh-7 cell lines expressing various hepatitis C virus genotype 3a protein: an in-vitro testing system for novel anti-HCV drugs. AB - BACKGROUND: Hepatitis C virus (HCV) infection is the leading cause of chronic hepatitis which progresses to hepatocellular carcinoma (HCC) afflicting > 170 million people worldwide. HCV 3a is the most common genotype (about 70% of all genotypes) circulating in Pakistan. Expression of HCV individual gene of 3a would facilitate therapeutic and vaccines strategies against chronic HCV and liver Cirrhosis. The aim of the present study was the establishment of stable Huh-7 cell lines expressing structural and non structural proteins of HCV Genotype 3a Pakistani isolate obtained from chronic HCV patients. METHODS: Blood samples were obtained from chronic HCV-3a positive patients. HCV individual genes were amplified using PCR with gene specific primers having restriction sites. These gene amplicons were cloned in mammalian expression vector PcDNA3.1+. Huh-7 cell lines were transfected with these constructed plasmids having structural or non structural HCV genes in confluent cells with lipofectamine. Positive clones were selected with G418 and then confirmed by genome PCR. Subsequently, transcription and expression of the integrated genes were demonstrated by RT-PCR, sequencing and Western blot analysis. RESULTS: We successfully cloned and express five HCV 3a genes in PcDNA3.1+ mammalian expression vector. Results of western blot and sequencing PCR confirmed the stable expression of these five genes. CONCLUSION: The stable cell-lines expressing HCV-3a individual genes would be a useful tool to investigate the role of various HCV proteins on HCV disease outcome and testing of new therapeutic strategies against HCV. PMID- 21711510 TI - Co-cultivation of murine BMDCs with 67NR mouse mammary carcinoma cells give rise to highly drug resistant cells. AB - BACKGROUND: Tumor tissue resembles chronically inflamed tissue. Since chronic inflammatory conditions are a strong stimulus for bone marrow-derived cells (BMDCs) it can be assumed that recruitment of BMDCs into cancer tissue should be a common phenomenon. Several data have outlined that BMDC can influence tumor growth and metastasis, e.g., by inducing a paracrine acting feedback loop in tumor cells. Likewise, cell fusion and horizontal gene transfer are further mechanisms how BMDCs can trigger tumor progression. RESULTS: Hygromycin resistant murine 67NR-Hyg mammary carcinoma cells were co-cultivated with puromycin resistant murine BMDCs from Tg(GFPU)5Nagy/J mice. Isolation of hygromycin/puromycin resistant mBMDC/67NR-Hyg cell clones was performed by a dual drug selection procedure. PCR analysis revealed an overlap of parental markers in mBMDC/67NR-Hyg cell clones, suggesting that dual resistant cells originated by cell fusion. By contrast, both STR and SNP data analysis indicated that only parental 67NR-Hyg alleles were found in mBMDC/67NR-Hyg cell clones favoring horizontal gene transfer as the mode of origin. RealTime-PCR-array analysis showed a marked up-regulation of Abcb1a and Abcb1b ABC multidrug transporters in mBMDC/67NR-Hyg clones, which was verified by Western Blot analysis. Moreover, the markedly increased Abcb1a/Abcb1b expression was correlated to an efficient Rhodamine 123 efflux, which was completely inhibited by verapamil, a well-known Abcb1a/Abcb1b inhibitor. Likewise, mBMDCs/67NR-Hyg clones revealed a marked resistance towards chemotherapeutic drugs including 17-DMAG, doxorubicin, etoposide and paclitaxel. In accordance to Rhodamine 123 efflux data, chemotherapeutic drug resistance of mBMDC/67NR-Hyg cells was impaired by verapamil mediated blockage of Abc1a/Abcb1b multidrug transporter function. CONCLUSION: Co-cultivation of mBMDCs and mouse 67NR-Hyg mammary carcinoma cells gave rise to highly drug resistant cells. Even though it remains unknown whether mBMDC/67NR-Hyg clones originated by cell fusion or horizontal gene transfer, our data indicate that the exchange of genetic information between two cellular entities is crucial for the origin of highly drug resistant cancer (hybrid) cells, which might be capable to survive chemotherapy. PMID- 21711511 TI - High-density lipoprotein proteome dynamics in human endotoxemia. AB - BACKGROUND: A large variety of proteins involved in inflammation, coagulation, lipid-oxidation and lipid metabolism have been associated with high-density lipoprotein (HDL) and it is anticipated that changes in the HDL proteome have implications for the multiple functions of HDL. Here, SELDI-TOF mass spectrometry (MS) was used to study the dynamic changes of HDL protein composition in a human experimental low-dose endotoxemia model. Ten healthy men with low HDL cholesterol (0.7+/-0.1 mmol/L) and 10 men with high HDL cholesterol levels (1.9+/-0.4 mmol/L) were challenged with endotoxin (LPS) intravenously (1 ng/kg bodyweight). We previously showed that subjects with low HDL cholesterol are more susceptible to an inflammatory challenge. The current study tested the hypothesis that this discrepancy may be related to differences in the HDL proteome. RESULTS: Plasma drawn at 7 time-points over a 24 hour time period after LPS challenge was used for direct capture of HDL using antibodies against apolipoprotein A-I followed by subsequent SELDI-TOF MS profiling. Upon LPS administration, profound changes in 21 markers (adjusted p-value < 0.05) were observed in the proteome in both study groups. These changes were observed 1 hour after LPS infusion and sustained up to 24 hours, but unexpectedly were not different between the 2 study groups. Hierarchical clustering of the protein spectra at all time points of all individuals revealed 3 distinct clusters, which were largely independent of baseline HDL cholesterol levels but correlated with paraoxonase 1 activity. The acute phase protein serum amyloid A-1/2 (SAA-1/2) was clearly upregulated after LPS infusion in both groups and comprised both native and N-terminal truncated variants that were identified by two-dimensional gel electrophoresis and mass spectrometry. Individuals of one of the clusters were distinguished by a lower SAA-1/2 response after LPS challenge and a delayed time-response of the truncated variants. CONCLUSIONS: This study shows that the semi-quantitative differences in the HDL proteome as assessed by SELDI-TOF MS cannot explain why subjects with low HDL cholesterol are more susceptible to a challenge with LPS than those with high HDL cholesterol. Instead the results indicate that hierarchical clustering could be useful to predict HDL functionality in acute phase responses towards LPS. PMID- 21711512 TI - High prevalence of shoulder girdle muscles with myofascial trigger points in patients with shoulder pain. AB - BACKGROUND: Shoulder pain is reported to be highly prevalent and tends to be recurrent or persistent despite medical treatment. The pathophysiological mechanisms of shoulder pain are poorly understood. Furthermore, there is little evidence supporting the effectiveness of current treatment protocols. Although myofascial trigger points (MTrPs) are rarely mentioned in relation to shoulder pain, they may present an alternative underlying mechanism, which would provide new treatment targets through MTrP inactivation. While previous research has demonstrated that trained physiotherapists can reliably identify MTrPs in patients with shoulder pain, the percentage of patients who actually have MTrPs remains unclear. The aim of this observational study was to assess the prevalence of muscles with MTrPs and the association between MTrPs and the severity of pain and functioning in patients with chronic non-traumatic unilateral shoulder pain. METHODS: An observational study was conducted. Subjects were recruited from patients participating in a controlled trial studying the effectiveness of physical therapy on patients with unilateral non-traumatic shoulder pain. Sociodemographic and patient-reported symptom scores, including the Disabilities of the Arm, Shoulder, and Hand (DASH) Questionnaire, and Visual Analogue Scales for Pain were compared with other studies. To test for differences in age, gender distribution, and education level between the current study population and the populations from Dutch shoulder studies, the one sample T-test was used. One observer examined all subjects (n = 72) for the presence of MTrPs. Frequency distributions, means, medians, standard deviations, and 95% confidence intervals were calculated for descriptive purposes. The Spearman's rank-order correlation (rho) was used to test for association between variables. RESULTS: MTrPs were identified in all subjects. The median number of muscles with MTrPs per subject was 6 (active MTrPs) and 4 (latent MTrPs). Active MTrPs were most prevalent in the infraspinatus (77%) and the upper trapezius muscles (58%), whereas latent MTrPs were most prevalent in the teres major (49%) and anterior deltoid muscles (38%). The number of muscles with active MTrPs was only moderately correlated with the DASH score. CONCLUSION: The prevalence of muscles containing active and latent MTrPs in a sample of patients with chronic non-traumatic shoulder pain was high. PMID- 21711514 TI - Why some do but most don't. Barriers and enablers to engaging low-income groups in physical activity programmes: a mixed methods study. AB - BACKGROUND: The beneficial effect of physical activity for the prevention of a range of chronic diseases is widely acknowledged. These chronic conditions are most pronounced in economically disadvantaged groups where physical activity levels are consistently lower, yet this group is particularly difficult to recruit and retain in physical activity programmes. This study examined the perceptions of participants, non-participants, and exercise leaders in a low income area regarding barriers, motives, and enabling factors for organised physical activity with a view to improving recruitment and retention. METHODS: A mixed methods research approach was adopted to guide data collection and analysis. A survey, incorporating the Motivation for Physical Activity Measure - Revised (MPAM-R), was used to assess the motivations of 152 physical activity session participants in a highly deprived suburban neighbourhood. The MPAM-R data were analysed using t tests, analyses of variance to estimate age, body mass index, and activity mode differences and Pearson's correlation coefficient to address associations. Semi-structured interviews were also conducted with 33 local residents who did not participate in activity sessions and with 14 activity session leaders. All interviews were audio-taped, transcribed verbatim and analyzed using an inductive thematic approach. RESULTS: Participants reported cost, childcare, lack of time and low awareness as barriers to joining activity classes. The need for support, confidence and competence in order to take up activity was widely expressed, particularly among women. Once people are active, high levels of social interaction, interest and enjoyment are associated with improved levels of retention, with different types of physical activity scoring differently on these factors. CONCLUSIONS: This study suggests that some factors such as cost, the fear of 'walking in alone', accessibility of facilities, and appropriate communication strategies may be of particular importance to increasing recruitment of low income groups. Interventions targeting this group should consider low cost sessions and childcare; activities popular with the target group and associated with good recruitment and retention; sessions held at accessible times; a focus on fun and socialising; well-researched and designed communications strategies; targeting of friendship groups; clearly branded beginners' sessions, and the potential of social marketing as strategies. The evidence presented here suggests that the current UK government approach designed to 'enable and guide people's choices' may not be sufficient if low-income groups are to be effectively supported in changing their health behaviours. PMID- 21711513 TI - Systems analysis of multiple regulator perturbations allows discovery of virulence factors in Salmonella. AB - BACKGROUND: Systemic bacterial infections are highly regulated and complex processes that are orchestrated by numerous virulence factors. Genes that are coordinately controlled by the set of regulators required for systemic infection are potentially required for pathogenicity. RESULTS: In this study we present a systems biology approach in which sample-matched multi-omic measurements of fourteen virulence-essential regulator mutants were coupled with computational network analysis to efficiently identify Salmonella virulence factors. Immunoblot experiments verified network-predicted virulence factors and a subset was determined to be secreted into the host cytoplasm, suggesting that they are virulence factors directly interacting with host cellular components. Two of these, SrfN and PagK2, were required for full mouse virulence and were shown to be translocated independent of either of the type III secretion systems in Salmonella or the type III injectisome-related flagellar mechanism. CONCLUSIONS: Integrating multi-omic datasets from Salmonella mutants lacking virulence regulators not only identified novel virulence factors but also defined a new class of translocated effectors involved in pathogenesis. The success of this strategy at discovery of known and novel virulence factors suggests that the approach may have applicability for other bacterial pathogens. PMID- 21711515 TI - Inducible viral receptor, A possible concept to induce viral protection in primitive immune animals. AB - A pseudolysogen (PL) is derived from the lysogenic Vibrio harveyi (VH) which is infected with the VHS1 (Vibrio harveyi Siphoviridae-like 1) bacteriophage. The lysogenic Vibrio harveyi undergoes an unequivalent division of the extra chromosomal VHS1 phage genome and its VH host chromosome and produces a true lysogen (TL) and pseudolysogen (PL). The PL is tolerant to super-infection of VHS1, as is of the true lysogen (TL), but the PL does not contain the VHS1 phage genome while the TL does. However, the PL can become susceptible to VHS1 phage infection if the physiological state of the PL is changed. It is postulated that this is due to a phage receptor molecule which can be inducible to an on-and-off regulation influence by an alternating condition of the bacterial host cell. This characteristic of the PL leads to speculate that this phenomenon can also occur in high organisms with low immunity such as shrimp. This article proposes a hypothesis that the viral receptor molecule on the target cell can play a crucial role in which the invertebrate aquaculture animals can become tolerant to viral infection. A possible mechanism may be that the target cell disrupts the viral receptor molecule to prevent super infection. This concept can explain a mechanism for the prevention of viral infection in invertebrate animals which do not have acquired immunity in response to pathogens. It can guide us to develop a mechanism of immunity to viral infection in low-evolved-immune animals. Also, it can be an additional mechanism that exists in high immune organism, as in human for the prevention of viral infection. PMID- 21711516 TI - Dietary supplementation with phytosterol and ascorbic acid reduces body mass accumulation and alters food transit time in a diet-induced obesity mouse model. AB - Previous research indicates that animals fed a high fat (HF) diet supplemented with disodium ascorbyl phytostanyl phosphate (DAPP) exhibit reduced mass accumulation when compared to HF control. This compound is a water-soluble phytostanol ester and consists of a hydrophobic plant stanol covalently bonded to ascorbic acid (Vitamin C). To provide insight into the mechanism of this response, we examined the in vivo effects of a high fat diet supplemented with ascorbic acid (AA) in the presence and absence of unesterified phytosterols (PS), and set out to establish whether the supplements have a synergistic effect in a diet-induced obesity mouse model. Our data indicate that HF diet supplementation with a combination of 1% w/w phytosterol and 1% w/w ascorbic acid results in reduced mass accumulation, with mean differences in absolute mass between PSAA and HF control of 10.05%; and differences in mass accumulation of 21.6% (i.e. the PSAA group gained on average 21% less mass each week from weeks 7-12 than the HF control group). In our previous study, the absolute mass difference between the 2% DAPP and HF control was 41%, while the mean difference in mass accumulation between the two groups for weeks 7-12 was 67.9%. Mass loss was not observed in animals supplemented with PS or AA alone. These data suggest that the supplements are synergistic with respect to mass accumulation, and the esterification of the compounds further potentiates the response. Our data also indicate that chronic administration of PS, both in the presence and absence of AA, results in changes to fecal output and food transit time, providing insight into the possibility of long-term changes in intestinal function related to PS supplementation. PMID- 21711517 TI - Safety of phosphatidylserine containing omega-3 fatty acids in non-demented elderly: a double-blind placebo-controlled trial followed by an open-label extension. AB - BACKGROUND: Phosphatidylserine (PS) is a naturally occurring phospholipid present in the inner leaflet of mammalian plasma membranes. Administration of PS extracted from bovine cortex (BC-PS), which contains high levels of omega-3 long chain polyunsaturated fatty acid (LC-PUFA) attached to its backbone, resulted in positive effects on brain functions such as learning and memory. Recently, a novel marine-sourced PS with omega-3 LC-PUFA attached to its backbone was developed (PS-DHA). In the present study, we evaluated the safety profile of the novel PS preparation in non-demented elderly with memory complaints. The efficacy study of this novel formulation indicated that PS-DHA may ameliorate cognitive deficits in non-demented elderly population. METHODS: 157 non-demented elderly participants with memory complaints were randomized to receive either PS-DHA (300 mg PS/day) or placebo for 15 weeks. Standard biochemical and hematological safety parameters, blood pressure and heart rate were evaluated at baseline and endpoint. 122 participants continued into an open-label extension for additional 15 weeks, in which they all consumed PS-DHA (100 mg PS/day) and were evaluated for their blood pressure, heart rate and weight at endpoint. Adverse events were monitored throughout the double-blind and open-label phases. RESULTS: 131 participants completed the double-blind phase. No significant differences were found in any of the tested safety parameters between the study groups, or within each group. 121 participants completed the open-label phase. At the end of this phase, there was a reduction in resting diastolic blood pressure and a slight weight gain among participants who consumed PS-DHA for 30 weeks. CONCLUSIONS: The results of this study indicate that consumption of PS-DHA at a dosage of 300 mg PS/day for 15 weeks, or 100 mg PS/day for 30 weeks, is safe, well tolerated, and does not produce any negative effects in the tested parameters. TRIAL REGISTRATION: clinicaltrials. gov, identifier: NCT00437983. PMID- 21711519 TI - Genetic diversity and population structure of Glossina pallidipes in Uganda and western Kenya. AB - BACKGROUND: Glossina pallidipes has been implicated in the spread of sleeping sickness from southeastern Uganda into Kenya. Recent studies indicated resurgence of G. pallidipes in Lambwe Valley and southeastern Uganda after what were deemed to be effective control efforts. It is unknown whether the G. pallidipes belt in southeastern Uganda extends into western Kenya. We investigated the genetic diversity and population structure of G. pallidipes in Uganda and western Kenya. RESULTS: AMOVA indicated that differences among sampling sites explained a significant proportion of the genetic variation. Principal component analysis and Bayesian assignment of microsatellite genotypes identified three distinct clusters: western Uganda, southeastern Uganda/Lambwe Valley, and Nguruman in central-southern Kenya. Analyses of mtDNA confirmed the results of microsatellite analysis, except in western Uganda, where Kabunkanga and Murchison Falls populations exhibited haplotypes that differed despite homogeneous microsatellite signatures. To better understand possible causes of the contrast between mitochondrial and nuclear markers we tested for sex-biased dispersal. Mean pairwise relatedness was significantly higher in females than in males within populations, while mean genetic distance was lower and relatedness higher in males than females in between-population comparisons. Two populations sampled on the Kenya/Uganda border, exhibited the lowest levels of genetic diversity. Microsatellite alleles and mtDNA haplotypes in these two populations were a subset of those found in neighboring Lambwe Valley, suggesting that Lambwe was the source population for flies in southeastern Uganda. The relatively high genetic diversity of G. pallidipes in Lambwe Valley suggest large relict populations remained even after repeated control efforts. CONCLUSION: Our research demonstrated that G. pallidipes populations in Kenya and Uganda do not form a contiguous tsetse belt. While Lambwe Valley appears to be a source population for flies colonizing southeastern Uganda, this dispersal does not extend to western Uganda. The complicated phylogeography of G. pallidipes warrants further efforts to distinguish the role of historical and modern gene flow and possible sex-biased dispersal in structuring populations. PMID- 21711518 TI - Risk and protective genetic variants in suicidal behaviour: association with SLC1A2, SLC1A3, 5-HTR1B &NTRK2 polymorphisms. AB - BACKGROUND: Suicidal behaviour is known to aggregate in families. Patients with psychiatric disorders are at higher risk for suicide attempts (SA), however protective and risk genetic variants for suicide appear to be independent of underlying psychiatric disorders. Here we investigate genetic variants in genes important for neurobiological pathways linked to suicidal behaviour and/or associated endophenotypes, for association with SA among patients with co existing psychiatric illness. Selected gene-gene and gene-environment interactions were also tested. METHODS: DNA was obtained from bloods of 159 patients (76 suicide attempters and 83 non-attempters), who were profiled for DSM IV Axis I psychiatric diagnosis. Twenty-eight single nucleotide polymorphisms (SNPs) from 18 candidate genes (COMT, 5-HT2A, 5-HT1A, 5-HTR1B, TPH1, MAO-A, TPH2, DBH, CNR1, BDNF, ABCG1, GABRA5, GABRG2, GABRB2, SLC1A2, SLC1A3, NTRK2, CRHR1) were genotyped. Genotyping was performed by KBioscience. Tests of association between genetic variants and SA were conducted using Chi squared and Armitage Trend tests. Binary logistical regression analyses were performed to evaluate the contribution of individual genetic variants to the prediction of SA, and to examine SNPs for potential gene-gene and gene-environment interactions. RESULTS: Our analysis identified 4 SNPs (rs4755404, rs2269272, rs6296 and rs1659400), which showed evidence of association with SA compared to a non-attempter control group. We provide evidence of a 3-locus gene-gene interaction, and a putative gene-environment interaction, whereby genetic variation at the NTRK2 locus may moderate the risk associated with history of childhood abuse. CONCLUSION: Preliminary findings suggest that allelic variability in SLC1A2/3, 5-HTR1B and NTRK2 may be relevant to the underlying diathesis for suicidal acts. PMID- 21711520 TI - Demographics of cattle movements in the United Kingdom. AB - BACKGROUND: The United Kingdom (UK) government has been recording the births, deaths, and movements of cattle for the last decade. Despite reservations about the accuracy of these data, they represent a large and valuable body of information about the demographics of the UK cattle herd and its contact structure. In this article, a range of demographic data about UK cattle, and particularly their movements, are presented, as well as yearly trends in the patterns of movements. RESULTS: A clear seasonal pattern is evident in the number of movements of cattle, as are the reductions in movement volume due to foot and mouth disease outbreaks in 2001 and 2007. The distribution of ages of cattle at their time of death is multimodal, and the impact of the over thirty months rule is marked. Most movements occur between agricultural holdings, markets, and slaughterhouses, and there is a non-random pattern to the types of holdings movements occur between. Most animals move only a short distance and a few times in their life. Most movements between any given pair of holdings only occurred once in the last 10 years, but about a third occurred between 2 and 10 times in that period. There is no clear trend to movement patterns in the UK since 2002. CONCLUSIONS: Despite a substantial number of regulatory interventions during the last decade, movement patterns show no clear trend since 2002. The observed patterns in the repeatability of movements, the types of holdings involved in movements, the distances and frequencies of cattle movements, and the batch sizes involved give an insight into the structure of the UK cattle industry, and could act as the basis for a predictive model of livestock movements in the UK. PMID- 21711521 TI - Elevated transforming growth factor beta and mitogen-activated protein kinase pathways mediate fibrotic traits of Dupuytren's disease fibroblasts. AB - BACKGROUND: Dupuytren's disease is a fibroproliferative disorder of the palmar fascia. The treatment used to date has mostly been surgery, but there is a high recurrence rate. Transforming growth factor beta (TGF-beta) has been implicated as a key stimulator of myofibroblast activity and fascial contraction in Dupuytren's disease. RESULTS: We studied Dupuytren's fibroblasts in tissues ex vivo and in cells cultured in vitro and found increased TGF-beta expression compared to control fibroblasts. This correlated not only with elevated expression and activation of downstream Smad effectors but also with overactive extracellular signal-regulated kinase 1/2 (ERK1/2)/mitogen-activated protein (MAP) kinase signalling. Treatment with the TGF-beta type I receptor kinase inhibitor SB-431542 and bone morphogenetic protein 6 (BMP6) led to inhibition of elevated Smad and ERK1/2/MAP kinase signalling as well as to inhibition of the increased contractility of Dupuytren's fibroblasts. BMP6 attenuated TGF-beta expression in Dupuytren's fibroblasts, but not in control fibroblasts. Platelet derived growth factor (PDGF) expression was strongly promoted by TGF-beta in Dupuytren's fibroblasts and was curbed by SB-431542 or BMP6 treatment. High basal expression of phosphorylated ERK1/2 MAP kinase and fibroproliferative markers was attenuated in Dupuytren's fibroblasts by a selective PDGF receptor kinase inhibitor. Cotreatment of Dupuytren's fibroblasts with SB-431542 and the mitogen activated protein kinase kinase 1 inhibitor PD98059 was sufficient to abrogate proliferation and contraction of Dupuytren's fibroblasts. CONCLUSIONS: Both TGF beta and ERK1/2 MAP kinase pathways cooperated in mediating the enhanced proliferation and high spontaneous contraction of Dupuytren's fibroblasts. Our data indicate that both signalling pathways are prime targets for the development of nonsurgical intervention strategies to treat Dupuytren's disease. PMID- 21711522 TI - Centriole polarisation to the immunological synapse directs secretion from cytolytic cells of both the innate and adaptive immune systems. AB - BACKGROUND: Cytolytic cells of the immune system destroy pathogen-infected cells by polarised exocytosis of secretory lysosomes containing the pore-forming protein perforin. Precise delivery of this lethal hit is essential to ensuring that only the target cell is destroyed. In cytotoxic T lymphocytes (CTLs), this is accomplished by an unusual movement of the centrosome to contact the plasma membrane at the centre of the immunological synapse formed between killer and target cells. Secretory lysosomes are directed towards the centrosome along microtubules and delivered precisely to the point of target cell recognition within the immunological synapse, identified by the centrosome. We asked whether this mechanism of directing secretory lysosome release is unique to CTL or whether natural killer (NK) and invariant NKT (iNKT) cytolytic cells of the innate immune system use a similar mechanism to focus perforin-bearing lysosome release. RESULTS: NK cells were conjugated with B-cell targets lacking major histocompatibility complex class I 721.221 cells, and iNKT cells were conjugated with glycolipid-pulsed CD1-bearing targets, then prepared for thin-section electron microscopy. High-resolution electron micrographs of the immunological synapse formed between NK and iNKT cytolytic cells with their targets revealed that in both NK and iNKT cells, the centrioles could be found associated (or 'docked') with the plasma membrane within the immunological synapse. Secretory clefts were visible within the synapses formed by both NK and iNKT cells, and secretory lysosomes were polarised along microtubules leading towards the docked centrosome. The Golgi apparatus and recycling endosomes were also polarised towards the centrosome at the plasma membrane within the synapse. CONCLUSIONS: These results reveal that, like CTLs of the adaptive immune system, the centrosomes of NK and iNKT cells (cytolytic cells of the innate immune system) direct secretory lysosomes to the immunological synapse. Morphologically, the overall structure of the immunological synapses formed by NK and iNKT cells are very similar to those formed by CTLs, with both exocytic and endocytic organelles polarised towards the centrosome at the plasma membrane, which forms a focal point for exocytosis and endocytosis within the immunological synapse. We conclude that centrosomal polarisation provides a rapid, responsive and precise mechanism for secretory lysosome delivery to the immunological synapse in CTLs, NK cells and iNKT cells. PMID- 21711523 TI - Large cell non-Hodgkin's lymphoma masquerading as renal carcinoma with inferior vena cava thrombosis: a case report. AB - INTRODUCTION: Many cancers are associated with inferior vena cava (IVC) obstruction, but very few cancers have the ability to propagate within the lumen of the renal vein or the IVC. Renal cell carcinoma is the most common of these cancers. Renal cancer with IVC extension has a high rate of recurrence and a low five year survival rate. CASE PRESENTATION: A 62-year-old Caucasian woman previously in good health developed the sudden onset of severe reflux symptoms and right-sided abdominal pain that radiated around the right flank. A subsequent ultrasound and CT scan revealed a right upper pole renal mass with invasion of the right adrenal gland, liver, left renal vein and IVC. This appeared to be consistent with stage III renal cancer with IVC extension. Metastatic nodules were believed to be present in the right pericardial region; the superficial anterior abdominal wall; the left perirenal, abdominal and pelvic regions; and the left adrenal gland. The pattern of these metastases, as well as the invasion of the liver by the tumor, was thought to be atypical of renal cancer. A needle biopsy of a superficial abdominal wall mass revealed a surprising finding: The malignant cells were diagnostic of large-cell, B-cell non-Hodgkin's lymphoma. The lymphoma responded dramatically to systemic chemotherapy, which avoided the need for nephrectomy. CONCLUSION: Lymphomas only rarely progress via intraluminal vascular extension. We have been able to identify only one other case report of renal lymphoma with renal vein and IVC extension. While renal cancer would have been treated with radical nephrectomy and tumor embolectomy, large-cell B-cell lymphomas are treated primarily with chemotherapy, and nephrectomy would have been detrimental. It is important to remember that, rarely, other types of cancer arise from the kidney which are not derived from the renal tubular epithelium. These may be suspected if an atypical pattern of metastases or unusual invasion of surrounding organs is present. A preoperative or intraoperative biopsy may be helpful in these cases. PMID- 21711524 TI - Ectopic thymoma presenting as a giant intrathoracic tumor: a case report. AB - Ectopic thymoma rarely presents as an intrathoracic tumor. We report a case of ectopic thymoma presenting as a giant right intrathoracic tumor that was treated with resection. The patient was a 50-year-old Japanese woman who presented with the chief complaint of chest pain. Detailed examination revealed a solid tumor measuring 15 * 10 * 8 cm in diameter, with a clear border. The Imaging findings suggested a solitary fibrous tumor, and surgery was performed. At surgery, the tumor was found to be adherent to the diaphragm, mediastinal pleura, and lower lobe of the lung, although it could be dissected with relative ease and was removed. Pathological diagnosis indicated a type B1 tumor with no capsular invasion according to the World Health Organization classification, and a diagnosis of Masaoka stage I thymoma was made. No continuity with the normal thymus tissue was seen, and the thymoma was considered to be derived from ectopic thymic tissue in the pleura. PMID- 21711525 TI - Upper limb children action-observation training (UP-CAT): a randomised controlled trial in hemiplegic cerebral palsy. AB - BACKGROUND: Rehabilitation for children with hemiplegic cerebral palsy (HCP) aimed to improve function of the impaired upper limb (UL) uses a wide range of intervention programs. A new rehabilitative approach, called Action-Observation Therapy, based on the recent discovery of mirror neurons, has been used in adult stroke but not in children. The purpose of the present study is to design a randomised controlled trial (RCT) for evaluating the efficacy of Action Observation Therapy in improving UL activity in children with HCP. METHODS/DESIGN: The trial is designed according to CONSORT Statement. It is a randomised, evaluator-blinded, match-pair group trial. Children with HCP will be randomised within pairs to either experimental or control group. The experimental group will perform an Action-Observation Therapy, called UP-CAT (Upper Limb Children Action-Observation Training) in which they will watch video sequences showing goal-directed actions, chosen according to children UL functional level, combined with motor training with their hemiplegic UL. The control group will perform the same tailored actions after watching computer games. A careful revision of psychometric properties of UL outcome measures for children with hemiplegia was performed. Assisting Hand Assessment was chosen as primary measure and, based on its calculation power, a sample size of 12 matched pairs was established. Moreover, Melbourne and ABILHAND-Kids were included as secondary measures. The time line of assessments will be T0 (in the week preceding the onset of the treatment), T1 and T2 (in the week after the end of the treatment and 8 weeks later, respectively). A further assessment will be performed at T3 (24 weeks after T1), to evaluate the retention of effects. In a subgroup of children enrolled in both groups functional Magnetic Resonance Imaging, exploring the mirror system and sensory-motor function, will be performed at T0, T1 and T2. DISCUSSION: The paper aims to describe the methodology of a RCT for evaluating the efficacy of Action-Observation Therapy in improving UL activity in children with hemiplegia. This study will be the first to test this new type of treatment in childhood. The paper presents the theoretical background, study hypotheses, outcome measures and trial methodology. TRIAL REGISTRATION: NCT01016496. PMID- 21711526 TI - Ploidy influences cellular responses to gross chromosomal rearrangements in Saccharomyces cerevisiae. AB - BACKGROUND: Gross chromosomal rearrangements (GCRs) such as aneuploidy are key factors in genome evolution as well as being common features of human cancer. Their role in tumour initiation and progression has not yet been completely elucidated and the effects of additional chromosomes in cancer cells are still unknown. Most previous studies in which Saccharomyces cerevisiae has been used as a model for cancer cells have been carried out in the haploid context. To obtain new insights on the role of ploidy, the cellular effects of GCRs were compared between the haploid and diploid contexts. RESULTS: A total number of 21 haploid and diploid S. cerevisiae strains carrying various types of GCRs (aneuploidies, nonreciprocal translocations, segmental duplications and deletions) were studied with a view to determining the effects of ploidy on the cellular responses. Differences in colony and cell morphology as well as in the growth rates were observed between mutant and parental strains. These results suggest that cells are impaired physiologically in both contexts. We also investigated the variation in genomic expression in all the mutants. We observed that gene expression was significantly altered. The data obtained here clearly show that genes involved in energy metabolism, especially in the tricarboxylic acid cycle, are up-regulated in all these mutants. However, the genes involved in the composition of the ribosome or in RNA processing are down-regulated in diploids but up-regulated in haploids. Over-expression of genes involved in the regulation of the proteasome was found to occur only in haploid mutants. CONCLUSION: The present comparisons between the cellular responses of strains carrying GCRs in different ploidy contexts bring to light two main findings. First, GCRs induce a general stress response in all studied mutants, regardless of their ploidy. Secondly, the ploidy context plays a crucial role in maintaining the stoichiometric balance of the proteins: the translation rates decrease in diploid strains, whereas the excess protein synthesized is degraded in haploids by proteasome activity. PMID- 21711527 TI - Polymethylmethacrylate-assisted ventral discectomy: rate of pseudarthrosis and clinical outcome with a minimum follow-up of 5 years. AB - BACKGROUND: Polymethylmethacrylate (PMMA) assisted ventral discectomy has been criticized for high rates of graft migration and pseudarthrosis when compared with various other fusion procedures for the treatment of cervical degenerative disc disease (DDD), therefore rendering it not the preferred choice of treatment today. Recently however spine surgery has been developing towards preservation rather than restriction of motion, indicating that fusion might not be necessary for clinical success. This study presents a long term comparison of clinical and radiological data from patients with pseudarthrosis and solid arthrodesis after PMMA assisted ventral discectomy was performed. METHODS: From 1986 to 2004 416 patients underwent ventral discectomy and PMMA interposition for DDD. The clinical and radiological outcome was assessed for 50 of 127 eligible patients after a mean of 8.1 years. Based on postoperative radiographs the patients were dichotomized in those with a pseudarthrosis (group A) and those with solid arthrodesis (group B). RESULTS: Pseudarthrosis with movement of more than 2 of the operated segment was noted in 17 cases (group A). In 33 cases no movement of the vertebral segment could be detected (group B). The analysis of the clinical data assessed through the neck disability index (NDI), the visual analogue scale (VAS) of neck and arm pain and Odom's criteria did not show any significant differences between the groups.Patients from group B showed a trend to higher adjacent segment degeneration (ASD) than group A (p = 0.06). This correlated with the age of the patients. CONCLUSIONS: PMMA assisted discectomy shows a high rate of pseudarthrosis. But the clinical long-term success does not seem to be negatively affected by this. PMID- 21711528 TI - Analysis of EGFR signaling pathway in nasopharyngeal carcinoma cells by quantitative phosphoproteomics. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) is usually overexpressed in nasopharyngeal carcinoma (NPC) and is associated with pathogenesis of NPC. However, the downstream signaling proteins of EGFR in NPC have not yet been completely understood at the system level. The aim of this study was identify novel downstream proteins of EGFR signaling pathway in NPC cells. RESULTS: We analyzed EGFR-regulated phosphoproteome in NPC CNE2 cells using 2D-DIGE and mass spectrometry analysis after phosphoprotein enrichment. As a result, 33 nonredundant phosphoproteins including five known EGFR-regulated proteins and twenty-eight novel EGFR-regulated proteins in CNE2 were identified, three differential phosphoproteins were selectively validated, and two differential phosphoproteins (GSTP1 and GRB2) were showed interacted with phospho-EGFR. Bioinformatics analysis showed that 32 of 33 identified proteins contain phosphorylation modification sites, and 17 identified proteins are signaling proteins. GSTP1, one of the EGFR-regulated proteins, associated with chemoresistance was analyzed. The results showed that GSTP1 could contribute to paclitaxel resistance in EGF-stimulated CNE2 cells. Furthermore, an EGFR signaling network based on the identified EGFR-regulated phosphoproteins were constructed using Pathway Studio 5.0 software, which includes canonical and novel EGFR-regulated proteins and implicates the possible biological roles for those proteins. CONCLUSION: The data not only can extend our knowledge of canonical EGFR signaling, but also will be useful to understand the molecular mechanisms of EGFR in NPC pathogenesis and search therapeutic targets for NPC. PMID- 21711529 TI - Case report: BRCA in the Ashkenazi population: are current testing guidelines too exclusive? AB - The BRCA1/2 genes account for a significant portion of hereditary breast and ovarian cancers and they are especially prevalent in the Ashkenazi Jewish population. Women who have a mutation can prevent breast and ovarian cancer with surgical intervention. We describe an Ashkenazi Jewish patient who illustrates that current testing criteria are too restrictive, particularly for this population of patients. The patient's sister was diagnosed with breast cancer at age 33; however, she was not a mutation carrier. Based on practice guidelines, the patient was not recommended genetic testing. She subsequently underwent direct-to-consumer (DTC) testing and discovered that she was a mutation carrier. This case demonstrates the need for clinicians to be aware of the higher prevalence of BRCA mutations in the Ashkenazi population. It also exemplifies the need to involve medical professionals, including genetic counselors, in the dissemination of DNA test results. PMID- 21711530 TI - Development, design, and conceptual issues of project zero exposure: A program to protect young children from tobacco smoke exposure. AB - BACKGROUND: Tobacco smoke exposure (TSE) is a serious threat to child health. Roughly 40% of children worldwide are exposed to tobacco smoke, and the very young are often "captive smokers" in homes in which others smoke.The goal of this research project is to develop and evaluate an intervention to reduce young child tobacco smoke exposure. The objective of this paper is to document our approach to building the intervention, to describe the planned intervention, and to explore the conceptual issues regarding the intervention and its evaluation. METHODS/DESIGN: This project is being developed using an iterative approach. We are currently in the middle of Stage 1. In this first stage, Intervention Development, we have already conducted a comprehensive search of the professional literature and internet resources, consulted with experts in the field, and conducted several Design Workshops. The planned intervention consists of parental group support therapy, a website to allow use of an "online/offline" approach, involvement of pediatricians, use of a video simulation game ("Dr. Cruz") to teach parents about child TSE, and personalized biochemical feedback on exposure levels. As part of this stage we will draw on a social marketing approach. We plan to use in-depth interviews and focus groups in order to identify barriers for behavior change, and to test the acceptability of program components.In Stage II, we plan to pilot the planned intervention with 5-10 groups of 10 parents each.In Stage III, we plan to implement and evaluate the intervention using a cluster randomized controlled trial with an estimated 540 participants. DISCUSSION: The major challenges in this research are twofold: building an effective intervention and measuring the effects of the intervention. Creation of an effective intervention to protect children from TSE is a challenging but sorely needed public health endeavor. We hope that our approach will contribute to building a stronger evidence base for control of child exposure to tobacco smoke. PMID- 21711531 TI - Drug utilization patterns and reported health status in ethnic German migrants (Aussiedler) in Germany: a cross-sectional study. AB - BACKGROUND: Inadequate utilization of healthcare services by migrant populations is an important public health concern. Inadequate drug consumption and poor compliance to the therapeutic regimen are common manifestations of low health care seeking behavior present in migrants even in the countries with well established healthcare systems. There are few studies on the use of medicines among the different groups of migrants in Germany. The objective of this study is to investigate drug consumption patterns of ethnic German migrants (Aussiedler) and their current health status. METHODS: A cross-sectional study nested into a cohort of 18,621 individuals aged 20-70 years who migrated to Germany from the former Soviet Union between 1990 and 2005 was conducted. Data on consumption of drugs, drug handling, major health risk factors, and one-year disease prevalence were obtained for 114 individuals through a self-administered questionnaire and phone interviews. Results were compared to the data on the German population derived from the Disease Analyzer database and Robert Koch Institute (RKI) annual reports. Direct age standardization, test of differences, Chi-square test, and descriptive statistics were applied as appropriate. For drug classification the Anatomical Therapeutic Chemical (ATC) system was used. RESULTS: Of the respondents, 97% reported to have at least one disease within a 12-month period. The one-year prevalence of asthma (6.9%), hypertension (26.7%), chronic bronchitis (8.6%), and diabetes (4.9%) in migrants was similar to the general German population. 51% regularly took either over-the-counter (OTC) medication or prescription medicines. Six ATC groups were analyzed. The highest drug consumption was reported for the ATC cardiovascular (22%), nervous (9%), and muskulo-skeletal system (8%). 30% used OTC medicines obtained in the country of origin. Difficulties with drug handling were rare. Alcohol consumption did not differ from the German population (p = 0.19 males and 0.27 females), however smoking prevalence was lower (p < 0.01) in both sexes. CONCLUSION: Ethnic German migrants seem to differ only slightly from Germans in health status, drug utilization, and disease risk factors, and if so, not in an extreme way. Country of origin remains a source of medicines for a substantial part of migrants. The study is limited by a small sample size and low response rate. PMID- 21711532 TI - Genome-scale reconstruction and in silico analysis of the Ralstonia eutropha H16 for polyhydroxyalkanoate synthesis, lithoautotrophic growth, and 2-methyl citric acid production. AB - BACKGROUND: Ralstonia eutropha H16, found in both soil and water, is a Gram negative lithoautotrophic bacterium that can utillize CO2 and H2 as its sources of carbon and energy in the absence of organic substrates. R. eutropha H16 can reach high cell densities either under lithoautotrophic or heterotrophic conditions, which makes it suitable for a number of biotechnological applications. It is the best known and most promising producer of polyhydroxyalkanoates (PHAs) from various carbon substrates and is an environmentally important bacterium that can degrade aromatic compounds. In order to make R. eutropha H16 a more efficient and robust biofactory, system-wide metabolic engineering to improve its metabolic performance is essential. Thus, it is necessary to analyze its metabolic characteristics systematically and optimize the entire metabolic network at systems level. RESULTS: We present the lithoautotrophic genome-scale metabolic model of R. eutropha H16 based on the annotated genome with biochemical and physiological information. The stoichiometic model, RehMBEL1391, is composed of 1391 reactions including 229 transport reactions and 1171 metabolites. Constraints-based flux analyses were performed to refine and validate the genome-scale metabolic model under environmental and genetic perturbations. First, the lithoautotrophic growth characteristics of R. eutropha H16 were investigated under varying feeding ratios of gas mixture. Second, the genome-scale metabolic model was used to design the strategies for the production of poly[R-(-)-3hydroxybutyrate] (PHB) under different pH values and carbon/nitrogen source uptake ratios. It was also used to analyze the metabolic characteristics of R. eutropha when the phosphofructokinase gene was expressed. Finally, in silico gene knockout simulations were performed to identify targets for metabolic engineering essential for the production of 2 methylcitric acid in R. eutropha H16. CONCLUSION: The genome-scale metabolic model, RehMBEL1391, successfully represented metabolic characteristics of R. eutropha H16 at systems level. The reconstructed genome-scale metabolic model can be employed as an useful tool for understanding its metabolic capabilities, predicting its physiological consequences in response to various environmental and genetic changes, and developing strategies for systems metabolic engineering to improve its metabolic performance. PMID- 21711533 TI - MAVENs: motion analysis and visualization of elastic networks and structural ensembles. AB - BACKGROUND: The ability to generate, visualize, and analyze motions of biomolecules has made a significant impact upon modern biology. Molecular Dynamics has gained substantial use, but remains computationally demanding and difficult to setup for many biologists. Elastic network models (ENMs) are an alternative and have been shown to generate the dominant equilibrium motions of biomolecules quickly and efficiently. These dominant motions have been shown to be functionally relevant and also to indicate the likely direction of conformational changes. Most structures have a small number of dominant motions. Comparing computed motions to the structure's conformational ensemble derived from a collection of static structures or frames from an MD trajectory is an important way to understand functional motions as well as evaluate the models. Modes of motion computed from ENMs can be visualized to gain functional and mechanistic understanding and to compute useful quantities such as average positional fluctuations, internal distance changes, collectiveness of motions, and directional correlations within the structure. RESULTS: Our new software, MAVEN, aims to bring ENMs and their analysis to a broader audience by integrating methods for their generation and analysis into a user friendly environment that automates many of the steps. Models can be constructed from raw PDB files or density maps, using all available atomic coordinates or by employing various coarse-graining procedures. Visualization can be performed either with our software or exported to molecular viewers. Mixed resolution models allow one to study atomic effects on the system while retaining much of the computational speed of the coarse-grained ENMs. Analysis options are available to further aid the user in understanding the computed motions and their importance for its function. CONCLUSION: MAVEN has been developed to simplify ENM generation, allow for diverse models to be used, and facilitate useful analyses, all on the same platform. This represents an integrated approach that incorporates all four levels of the modeling process - generation, evaluation, analysis, visualization and also brings to bear multiple ENM types. The intension is to provide a versatile modular suite of programs to a broader audience. MAVEN is available for download at http://maven.sourceforge.net. PMID- 21711534 TI - Severe gastric variceal haemorrhage due to splenic artery thrombosis and consecutive arterial bypass. AB - BACKGROUND: Upper gastrointestinal haemorrhage is mainly caused by ulcers. Gastric varicosis due to portal hypertension can also be held responsible for upper gastrointestinal bleeding. Portal hypertension causes the development of a collateral circulation from the portal to the caval venous system resulting in development of oesophageal and gastric fundus varices. Those may also be held responsible for upper gastrointestinal haemorrhage. CASE PRESENTATION: In this study, we describe the case of a 69-year-old male with recurrent severe upper gastrointestinal bleeding caused by arterial submucosal collaterals due to idiopathic splenic artery thrombosis. The diagnosis was secured using endoscopic duplex ultrasound and angiography. The patient was successfully treated with a laparoscopic splenectomy and complete dissection of the short gastric arteries, resulting in the collapse of the submucosal arteries in the gastric wall. Follow up gastroscopy was performed on the 12th postoperative week and showed no signs of bleeding and a significant reduction in the arterial blood flow within the gastric wall. Subsequent follow-up after 6 months also showed no further gastrointestinal bleeding as well as subjective good quality of life for the patient. CONCLUSION: Submucosal arterial collaterals must be excluded by endosonography via endoscopy in case of recurrent upper gastrointestinal bleeding. Laparoscopic splenectomy provides adequate treatment in preventing any recurrent bleeding, if gastric arterial collaterals are caused by splenic artery thrombosis. PMID- 21711535 TI - Effect of osteopathic manipulative treatment on gastrointestinal function and length of stay of preterm infants: an exploratory study. AB - BACKGROUND: Organizational improvement of neonatal intensive care units requires strict monitoring of preterm infants, including routine assessment of physiological functions of the gastrointestinal system and optimized procedures for the definition of appropriate discharge timing. METHODS: We conducted a prospective study on the effect of osteopathic manipulative treatment in a cohort of N = 350 consecutive premature infants admitted to a neonatal intensive care unit without any major complication between 2005 and 2008. In addition to ordinary care, N = 162 subjects received osteopathic treatment. Endpoints of the study were differences between study and control groups in terms of excessive length of stay and gastrointestinal symptoms, defined as the upper quartiles in the distribution of the overall population. Statistical analysis was based on crude and adjusted odds ratios from multivariate logistic regression. RESULTS: Baseline characteristics were evenly distributed across treated/control groups, except for the rate of infants unable to be oral fed at admission, significantly higher among those undergoing osteopathic care (p = .03). Osteopathic treatment was significantly associated with a reduced risk of an average daily occurrence of gut symptoms per subject above .44 (OR = 0.45; 0.26-0.74). Gestational age lower or equal to 32 weeks, birth weight lower or equal to 1700 grams and no milk consumption at admission were associated with higher rates of length of stay in the unit of at least 28 days, while osteopathic treatment significantly reduced such risk (OR = 0.22;0.09-0.51). CONCLUSIONS: In a population of premature infants, osteopathic manipulative treatment showed to reduce a high occurrence of gastrointestinal symptoms and an excessive length of stay in the NICU. Randomized control studies are needed to generalize these results to a broad population of high risk newborns. PMID- 21711536 TI - The impact of tensioning device mal-positioning on strand tension during anterior cruciate ligament reconstruction. AB - BACKGROUND: In order to confer optimal strength and stiffness to the graft in Anterior Cruciate Ligament (ACL) reconstruction, the maintenance of equal strand tension prior to fixation, is desired; positioning of the tensioning device can significantly affect strand tension This study aimed to determine the effect of tensioning device mal-positioning on individual strand tension in simulated cadaveric ACL reconstructions. METHODS: Twenty cadaveric specimens, comprising bovine tibia and tendon harvested from sheep, were used to simulate ACL reconstruction with a looped four-strand tendon graft. A proprietary tensioning device was used to tension the graft during tibial component fixation with graft tension recorded using load cells. The effects of the tensioning device at extreme angles, and in various locking states, was evaluated. RESULTS: Strand tension varied significantly when the tensioning device was held at extreme angles (p < 0.001) or in 'locked' configurations of the tensioning device (p < 0.046). Tendon position also produced significant effects (p < 0.016) on the resultant strand tension. CONCLUSION: An even distribution of tension among individual graft strands is obtained by maintaining the tensioning device in an unlocked state, aligned with the longitudinal axis of the tibial tunnel. If the maintenance of equal strand tension during tibial fixation of grafts is important, close attention must be paid to positioning of the tensioning device in order to optimize the resultant graft tension and, by implication, the strength and stiffness of the graft and ultimately, surgical outcome. PMID- 21711537 TI - A biochemical hypothesis on the formation of fingerprints using a turing patterns approach. AB - BACKGROUND: Fingerprints represent a particular characteristic for each individual. Characteristic patterns are also formed on the palms of the hands and soles of the feet. Their origin and development is still unknown but it is believed to have a strong genetic component, although it is not the only thing determining its formation. Each fingerprint is a papillary drawing composed by papillae and rete ridges (crests). This paper proposes a phenomenological model describing fingerprint pattern formation using reaction diffusion equations with Turing space parameters. RESULTS: Several numerical examples were solved regarding simplified finger geometries to study pattern formation. The finite element method was used for numerical solution, in conjunction with the Newton Raphson method to approximate nonlinear partial differential equations. CONCLUSIONS: The numerical examples showed that the model could represent the formation of different types of fingerprint characteristics in each individual. PMID- 21711538 TI - Acute neurological signs as the predominant clinical manifestation in four dogs with Angiostrongylus vasorum infections in Denmark. AB - Four dogs with acute neurological signs caused by haemorrhages in the central nervous system were diagnosed with Angiostrongylus vasorum infection as the underlying aetiology. Two dogs presented with brain lesions, one dog with spinal cord lesions and one with lesions in both the brain and spinal cord. Only one dog presented with concurrent signs of classical pulmonary angiostrongylosis (respiratory distress, cough), and only two dogs displayed overt clinical signs of haemorrhages. Results of coagulation assays were inconsistent. Neurological signs reflected the site of pathology and included seizures, various cranial nerve deficits, vestibular signs, proprioceptive deficits, ataxia and paraplegia. One dog died and three were euthanised due to lack of improvement despite medical treatment. This emphasises canine angiostrongylosis as a potential cause of fatal lesions of the central nervous system and the importance of including A. vasorum as a differential diagnosis in young dogs with acute neurological signs in Denmark. PMID- 21711539 TI - Schistosoma-associated Salmonella resist antibiotics via specific fimbrial attachments to the flatworm. AB - BACKGROUND: Schistosomes are parasitic helminths that infect humans through dermo invasion while in contaminated water. Salmonella are also a common water-borne human pathogen that infects the gastrointestinal tract via the oral route. Both pathogens eventually enter the systemic circulation as part of their respective disease processes. Concurrent Schistosoma-Salmonella infections are common and are complicated by the bacteria adhering to adult schistosomes present in the mesenteric vasculature. This interaction provides a refuge in which the bacterium can putatively evade antibiotic therapy and anthelmintic monotherapy can lead to a massive release of occult Salmonella. RESULTS: Using a novel antibiotic protection assay, our results reveal that Schistosoma-associated Salmonella are refractory to eight different antibiotics commonly used to treat salmonellosis. The efficacy of these antibiotics was decreased by a factor of 4 to 16 due to this association. Salmonella binding to schistosomes occurs via a specific fimbrial protein (FimH) present on the surface on the bacterium. This same fimbrial protein confers the ability of Salmonella to bind to mammalian cells. CONCLUSIONS: Salmonella can evade certain antibiotics by binding to Schistosoma. As a result, effective bactericidal concentrations of antibiotics are unfortunately above the achievable therapeutic levels of the drugs in co-infected individuals. Salmonella-Schistosoma binding is analogous to the adherence of Salmonella to cells lining the mammalian intestine. Perturbing this binding is the key to eliminating Salmonella that complicate schistosomiasis. PMID- 21711540 TI - Identification of target antigens of anti-endothelial cell and anti-vascular smooth muscle cell antibodies in patients with giant cell arteritis: a proteomic approach. AB - INTRODUCTION: Immunological studies of giant cell arteritis (GCA) suggest that a triggering antigen of unknown nature could generate a specific immune response. We thus decided to detect autoantibodies directed against endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in the serum of GCA patients and to identify their target antigens. METHODS: Sera from 15 GCA patients were tested in 5 pools of 3 patients' sera and compared to a sera pool from 12 healthy controls (HCs). Serum immunoglobulin G (IgG) reactivity was analysed by 2-D electrophoresis and immunoblotting with antigens from human umbilical vein ECs (HUVECs) and mammary artery VSMCs. Target antigens were identified by mass spectrometry. RESULTS: Serum IgG from GCA patients recognised 162 +/- 3 (mean +/- SD) and 100 +/- 17 (mean +/- SD) protein spots from HUVECs and VSMCs, respectively, and that from HCs recognised 79 and 94 protein spots, respectively. In total, 30 spots from HUVECs and 19 from VSMCs were recognised by at least two thirds and three-fifths, respectively, of the pools of sera from GCA patients and not by sera from HCs. Among identified proteins, we found vinculin, lamin A/C, voltage-dependent anion-selective channel protein 2, annexin V and other proteins involved in cell energy metabolism and key cellular pathways. Ingenuity pathway analysis revealed that most identified target antigens interacted with growth factor receptor-bound protein 2. CONCLUSIONS: IgG antibodies to proteins in the proteome of ECs and VSMCs are present in the sera of GCA patients and recognise cellular targets that play key roles in cell biology and maintenance of homeostasis. Their potential pathogenic role remains to be determined. PMID- 21711541 TI - Active hepatitis C infection and HCV genotypes prevalent among the IDUs of Khyber Pakhtunkhwa. AB - Injection drug users (IDUs) are considered as a high risk group to develop hepatitis C due to needle sharing. In this study we have examined 200 injection drug users from various regions of the Khyber Pakhtunkhwa province for the prevalence of active HCV infection and HCV genotypes by Immunochromatographic assays, RT-PCR and Type-specific PCR. Our results indicated that 24% of the IDUs were actively infected with HCV while anti HCV was detected among 31.5% cases. Prevalent HCV genotypes were HCV 2a, 3a, 4 and 1a. Majority of the IDUs were married and had attained primary or middle school education. 95% of the IDUs had a previous history of needle sharing. Our study indicates that the rate of active HCV infection among the IDUs is higher with comparatively more prevalence of the rarely found HCV types in KPK. The predominant mode of HCV transmission turned out to be needle sharing among the IDUs. PMID- 21711542 TI - Spatial distribution and male mating success of Anopheles gambiae swarms. AB - BACKGROUND: Anopheles gambiae mates in flight at particular mating sites over specific landmarks known as swarm markers. The swarms are composed of males; females typically approach a swarm, and leave in copula. This mating aggregation looks like a lek, but appears to lack the component of female choice. To investigate the possible mechanisms promoting the evolution of swarming in this mosquito species, we looked at the variation in mating success between swarms and discussed the factors that structure it in light of the three major lekking models, known as the female preference model, the hotspot model, and the hotshot model. RESULTS: We found substantial variation in swarm size and in mating success between swarms. A strong correlation between swarm size and mating success was observed, and consistent with the hotspot model of lek formation, the per capita mating success of individual males did not increase with swarm size. For the spatial distribution of swarms, our results revealed that some display sites were more attractive to both males and females and that females were more attracted to large swarms. While the swarm markers we recognize help us in localizing swarms, they did not account for the variation in swarm size or in the swarm mating success, suggesting that mosquitoes probably are attracted to these markers, but also perceive and respond to other aspects of the swarming site. CONCLUSIONS: Characterizing the mating system of a species helps understand how this species has evolved and how selective pressures operate on male and female traits. The current study looked at male mating success of An. gambiae and discussed possible factors that account for its variation. We found that swarms of An. gambiae conform to the hotspot model of lek formation. But because swarms may lack the female choice component, we propose that the An. gambiae mating system is a lek-like system that incorporates characteristics pertaining to other mating systems such as scramble mating competition. PMID- 21711543 TI - Prediction of plant promoters based on hexamers and random triplet pair analysis. AB - BACKGROUND: With an increasing number of plant genome sequences, it has become important to develop a robust computational method for detecting plant promoters. Although a wide variety of programs are currently available, prediction accuracy of these still requires further improvement. The limitations of these methods can be addressed by selecting appropriate features for distinguishing promoters and non-promoters. METHODS: In this study, we proposed two feature selection approaches based on hexamer sequences: the Frequency Distribution Analyzed Feature Selection Algorithm (FDAFSA) and the Random Triplet Pair Feature Selecting Genetic Algorithm (RTPFSGA). In FDAFSA, adjacent triplet-pairs (hexamer sequences) were selected based on the difference in the frequency of hexamers between promoters and non-promoters. In RTPFSGA, random triplet-pairs (RTPs) were selected by exploiting a genetic algorithm that distinguishes frequencies of non adjacent triplet pairs between promoters and non-promoters. Then, a support vector machine (SVM), a nonlinear machine-learning algorithm, was used to classify promoters and non-promoters by combining these two feature selection approaches. We referred to this novel algorithm as PromoBot. RESULTS: Promoter sequences were collected from the PlantProm database. Non-promoter sequences were collected from plant mRNA, rRNA, and tRNA of PlantGDB and plant miRNA of miRBase. Then, in order to validate the proposed algorithm, we applied a 5-fold cross validation test. Training data sets were used to select features based on FDAFSA and RTPFSGA, and these features were used to train the SVM. We achieved 89% sensitivity and 86% specificity. CONCLUSIONS: We compared our PromoBot algorithm to five other algorithms. It was found that the sensitivity and specificity of PromoBot performed well (or even better) with the algorithms tested. These results show that the two proposed feature selection methods based on hexamer frequencies and random triplet-pair could be successfully incorporated into a supervised machine learning method in promoter classification problem. As such, we expect that PromoBot can be used to help identify new plant promoters. Source codes and analysis results of this work could be provided upon request. PMID- 21711544 TI - Salmonella Typhimurium invasion of HEp-2 epithelial cells in vitro is increased by N-acylhomoserine lactone quorum sensing signals. AB - BACKGROUND: In Gram-negative bacteria, the most commonly studied quorum sensing signals are the N-acylhomoserine lactones (AHLs). In Salmonella, AHLs are recognized by SdiA, which is believed to be a sensor of AHLs produced by other bacteria, since Salmonella does not produce AHLs itself. It has been speculated that AHLs produced by the gastrointestinal flora may influence the regulation of virulence traits in Salmonella. The aim of the present work was to study the effect of AHLs on epithelial cell invasion by Salmonella in vitro. METHODS: Invasion by Salmonella enterica subspecies enterica serovar Typhimurium (S. Typhimurium) strain and its isogenc sdiA mutant was studied using a conventional gentamycin invasion assay with HEp-2 cells at 37 degrees C. Gene expression was studied using a semi-quantitative PCR. RESULTS: The S. Typhimurium strain, but not its isogenic sdiA mutant, displayed increased in vitro invasion after addition of both N-hexanoyl-DL-homoserine lactone (C6-AHL) and N-octanoyl-DL homoserine lactone (C8-AHL). Increased expression of two of the genes in the SdiA regulon (rck and srgE) was observed in the wild type strain, but not in the sdiA mutant. CONCLUSIONS: The results from the present study show that S. Typhimurium can respond to two different AHL quorum sensing signals (C6-AHL and C8-AHL) with increased cell invasion at 37 degrees C in vitro, and that this response most likely is sdiA mediated. These results indicate that if AHLs are present in the intestinal environment, they may increase the invasiveness of Salmonella. PMID- 21711545 TI - Aging deteriorated perception of urge-to-cough without changing cough reflex threshold to citric acid in female never-smokers. AB - BACKGROUND: The effect of aging on the cognitive aspect of cough has not been studied yet. The purpose of this study is to investigate the aging effect on the perception of urge-to-cough in healthy individuals. METHODS: Fourteen young, female, healthy never-smokers were recruited via public postings. Twelve elderly female healthy never-smokers were recruited from a nursing home residence. The cough reflex threshold and the urge-to-cough were evaluated by inhalation of citric acid. The cough reflex sensitivities were defined as the lowest concentration of citric acid that elicited two or more coughs (C2) and five or more coughs (C5). The urge-to-cough was evaluated using a modified the Borg scale. RESULTS: There was no significant difference in the cough reflex threshold to citric acid between young and elderly subjects. The urge-to-cough scores at the concentration of C2 and C5 were significantly smaller in the elderly than young subjects. The urge-to-cough log-log slope in elderly subjects (0.73 +/- 0.71 point . L/g) was significantly gentler than those of young subjects (1.35 +/ 0.53 point . L/g, p < 0.01). There were no significant differences in the urge to-cough threshold estimated between young and elderly subjects. CONCLUSIONS: The cough reflex threshold did not differ between young and elderly subjects whereas cognition of urge-to-cough was significantly decreased in elderly subjects in female never-smokers. Objective monitoring of cough might be important in the elderly people. PMID- 21711546 TI - Equity in the delivery of community healthcare to older people: findings from 10/66 Dementia Research Group cross-sectional surveys in Latin America, China, India and Nigeria. AB - BACKGROUND: To describe patterns of recent health service utilisation, and consequent out-of-pocket expenses among older people in countries with low and middle incomes, and to assess the equity with which services are accessed and delivered. METHODS: 17,944 people aged 65 years and over were assessed in one phase population-based cross-sectional surveys in geographically-defined catchment areas in nine countries - urban and rural sites in China, India, Mexico and Peru, urban sites in Cuba, Dominican Republic, Puerto Rico and Venezuela, and a rural site in Nigeria. The main outcome was use of community health care services in the past 3 months. Independent associations were estimated with indicators of need (dementia, depression, physical impairments), predisposing factors (age, sex, and education), and enabling factors (household assets, pension receipt and health insurance) using Poisson regression to generate prevalence ratios and fixed effects meta-analysis to combine them. RESULTS: The proportion using healthcare services varied from 6% to 82% among sites. Number of physical impairments (pooled prevalence ratio 1.37, 95% CI 1.26-1.49) and ICD-10 depressive episode (pooled PR 1.21, 95% CI 1.07-1.38) were associated with service use, but dementia was inversely associated (pooled PR 0.93, 95% CI 0.90 0.97). Other correlates were female sex, higher education, more household assets, receiving a pension, and health insurance. Standardisation for age, sex, physical impairments, depression and dementia did not explain variation in service use. There was a strong borderline significant ecological correlation between the proportion of consultations requiring out-of-pocket costs and the prevalence of health service use (r = -0.50, p = 0.09). CONCLUSIONS: While there was little evidence of ageism, inequity was apparent in the independent enabling effects of education and health insurance cover, the latter particularly in sites where out of-pocket expenses were common, and private health insurance an important component of healthcare financing. Variation in service use among sites was most plausibly accounted for by stark differences in the extent of out-of-pocket expenses, and the ability of older people and their families to afford them. Health systems that finance medical services through out-of-pocket payments risk excluding the poorest older people, those without a secure regular income, and the uninsured. PMID- 21711549 TI - Detection of human cytomegalovirus in motile spermatozoa and spermatogenic cells in testis organotypic culture. AB - BACKGROUND: The presence of human cytomegalovirus (HCMV) in male genital tract suggests its vertical transmission with spermatozoa and the development of a potentially dangerous fetal infection. The objective of the present study was to evaluate the possibility of intracellular HCMV localization in male germ cells and to examine the effect of the virus on human spermatogenesis. METHODS: Semen samples from 91 infertile and 47 fertile men were analyzed. HCMV was detected by real time PCR, rapid culture method and PCR in situ. Human testis organotypic culture and quantitative karyological analysis were used to investigate viral effects on spermatogenesis. Localization of HCMV in immature germ cells and spermatozoa was studied by immunostaining with monoclonal antibodies and ultrastructural analysis of infected organotypic culture. RESULTS: Viral DNA was detected in 12.3% samples of motile spermatozoa, while infectious activity only in 2.9% infertile and fertile men without statistically significant intergroup difference. According to PCR in situ, the mean percentage of infected cell in both groups was 1.5% (0.25%-15%), which can serve as a criterion for evaluating the risk of HCMV transmission. In HCMV-infected organotypic culture viral antigens were identified in spermatides on day 4, in spermatogonia and spermatocytes on day 8, and in spermatozoa on day 14. Empty and full capsides and virions were visualized in germ cells by electron microscopy. The number of cells before introduction in culture was taken for 100%. On day 14 infected culture contained 36.8% spermatogonia, 18.7% spermatocytes, 27.6% round spermatides and 42.5% elongated spermatides; in comparison with 82.2%, 51.5%, 70.4% and 65.7% in uninfected culture, respectively (all p < 0.05). There were no changes in the number and viability of spermatozoa. CONCLUSIONS: HCMV was detected in male germ cells, both in sperm samples and in testis organotypic culture. The virus may infect immature germ cells which develop to mature HCMV-carrying spermatozoa. A considerable decrease in the number of immature germ cells indicates that HCMV produces a direct gametotoxic effect and can contribute to male infertility. PMID- 21711548 TI - Regulation of gene expression in ovarian cancer cells by luteinizing hormone receptor expression and activation. AB - BACKGROUND: Since a substantial percentage of ovarian cancers express gonadotropin receptors and are responsive to the relatively high concentrations of pituitary gonadotropins during the postmenopausal years, it has been suggested that receptor activation may contribute to the etiology and/or progression of the neoplasm. The goal of the present study was to develop a cell model to determine the impact of luteinizing hormone (LH) receptor (LHR) expression and LH-mediated LHR activation on gene expression and thus obtain insights into the mechanism of gonadotropin action on ovarian surface epithelial (OSE) carcinoma cells. METHODS: The human ovarian cancer cell line, SKOV-3, was stably transfected to express functional LHR and incubated with LH for various periods of time (0-20 hours). Transcriptomic profiling was performed on these cells to identify LHR expression/activation-dependent changes in gene expression levels and pathways by microarray and qRT-PCR analyses. RESULTS: Through comparative analysis on the LHR transfected SKOV-3 cells exposed to LH, we observed the differential expression of 1,783 genes in response to LH treatment, among which five significant families were enriched, including those of growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors. The most highly induced early and intermediate responses were found to occupy a network impacting transcriptional regulation, cell growth, apoptosis, and multiple signaling transductions, giving indications of LH-induced apoptosis and cell growth inhibition through the significant changes in, for example, tumor necrosis factor, Jun and many others, supportive of the observed cell growth reduction in in vitro assays. However, other observations, e.g. the substantial up-regulation of the genes encoding the endothelin-1 subtype A receptor, stromal cell-derived factor 1, and insulin-like growth factor II, all of which are potential therapeutic targets, may reflect a positive mediation of ovarian cancer growth. CONCLUSION: Overall, the present study elucidates the extensive transcriptomic changes of ovarian cancer cells in response to LH receptor activation, which provides a comprehensive and objective assessment for determining new cancer therapies and potential serum markers, of which over 100 are suggested. PMID- 21711550 TI - Effect of health insurance on delivery care utilization and perceived delays and barriers among southern Thai women. AB - BACKGROUND: Financial reform aims to overcome the problems of financial barriers and utilization of health services. However, it is unclear whether financial reforms or health insurance can reduce delays and/or barriers or if there are still other important obstacles for preventing pregnant women accessing delivery care. This study aimed to assess the effect of health insurance and other factors on delivery care utilization and the perception of delays and barriers to delivery care among women living in Songkhla province, Thailand. METHODS: A cross sectional study was conducted from November 2007 to December 2008. Women who delivered at hospital or home in the areas of participating hospitals in four districts were interviewed at 24- or 48-hours postpartum. The impact of health insurance and other factors on outcomes of interest was assessed using multivariate logistic regression. RESULTS: Of 2,847 women, 2,822 delivered at a hospital and 25 at home, of which 80% and 40% had health insurance for delivery care, respectively. Muslims, low educated women, those who thought they could not use health insurance for delivery care and those less willing to seek care at their delivery place were more likely to give birth at home. Perception of delays to seeking care, reaching a hospital and receiving care was reduced in women insured by civil servant medical benefit. Women insured by universal coverage and social security perceived a lower delay in reaching a hospital but a higher delay in receiving care. Low education, unwillingness to seek care, out-of-pocket payment, worry about cost of delivery care, transportation difficulties, low perception of receiving good care or a perception of being treated badly were also associated with delays and barriers to health care. Almost all (93%) agreed that health insurance could reduce financial barriers for accessing services. However, having health insurance influenced them to seek care, reach a hospital, and receive care quickly in 50%, 32%, and 23% of the women, respectively. CONCLUSIONS: Health insurance has a significant impact on perceived delays and barriers, but not place of delivery. Socio-economic determinants continue to play an important role for place of delivery and perceived delays and barriers. PMID- 21711551 TI - Physical exertion and working efficiency of reforestation workers. AB - BACKGROUND: The purpose of this study was to quantify the physical exertion during tree planting work and to examine the relationships between exertion, task efficiency, and productivity. METHODS: Heart rate (HR) was monitored on 34 tree planters while they worked. HR data was collected for a complete working day on 19 subjects and for shorter periods of time on 15 subjects. Video of work tasks was recorded on 22 subjects (video was recorded on 7 of the subjects for whom HR was monitored through a full working day) and analyzed for working pace and proportion of time spent on each task. RESULTS: HR during a full day (9.0 +/- 1.2 hours) of tree planting work was 115.2 +/- 8.8 beats.min-1, and working HR was 128.2 +/- 15.6 beats.min-1 for 82.5 +/- 6.8% of the work day. Mean work pace was 452 +/- 174 trees.h-1, and the proportion of time spent planting each tree was 53 +/- 8% of the working time. Significant (P < 0.05) positive correlations were found between work pace and experience level, and between work pace and working HR, and a significant (P < 0.05) negative correlation was found between experience level and HR for a given work pace. No significant relationships were found between experience level or work pace and the proportion of time spent planting each tree. CONCLUSIONS: Tree planters work at approximately 65% of age predicted HRmax, and maintain HR at approximately 59% of HRmax throughout the entire working day. Productivity in these workers appears to be related to effort rather than to experience or task efficiency per se. PMID- 21711552 TI - Post-operative infection and sepsis in humans is associated with deficient gene expression of gammac cytokines and their apoptosis mediators. AB - INTRODUCTION: Lymphocyte homeostasis is dependent on the gammac cytokines. We hypothesised that sepsis in humans is associated with differential gene expression of the gammac cytokines and their associated apoptosis mediators. METHODS: The study population consisted of a total of 60 patients with severe sepsis, 15 with gram negative bacteraemia, 10 healthy controls and 60 patients undergoing elective lung resection surgery. Pneumonia was diagnosed by CDC NNIC criteria. Gene expression in peripheral blood leukocytes (PBLs) of interleukin (IL)-2, 7, 15 and interferon (IFN)-gamma, Bax, Bim, Bcl-2 was determined by qRT PCR and IL-2 and IL-7 serum protein levels by ELISA. Gene expression of IL-2, 7 and IFN-gamma was measured in peripheral blood leukocytes (PBL), cultured in the presence of lipopolysaccharide (LPS) and CD3 binding antibody (CD3ab) RESULTS: IL 2 gene expression was lower in the bacteraemia group compared with controls, and lower still in the sepsis group (P < 0.0001). IL-7 gene expression was similar in controls and bacteraemia, but lower in sepsis (P < 0.0001). IL-15 gene expression was similar in the three groups. Bcl-2 gene expression was less (P < 0.0001) and Bim gene expression was greater (P = 0.0003) in severe sepsis compared to bacteraemic and healthy controls. Bax gene expression was similar in the three groups.In lung resection surgery patients, post-operative pneumonia was associated with a perioperative decrease in IL-2 mRNA (P < 0.0001) and IL-7 mRNA (P = 0.003). IL-2 protein levels were reduced in sepsis and bacteraemia compared to controls (P = 0.02) but similar in pneumonia and non-pneumonia groups. IL-7 protein levels were similar in all groups.In cultured PBLs, IFN-gamma gene expression was decreased in response to LPS and increased in response to CD3ab with sepsis: IL-7 gene expression increased in response to LPS in controls and to CD3ab with sepsis; Bcl-2 gene expression decreased in response to combined CD3ab and IL-2 with sepsis. CONCLUSIONS: Patients with infection and sepsis have deficient IL-2 and IL-7 gene expression in PBLs. Aberrant cytokine gene expression may precede the onset of infection. PMID- 21711553 TI - Host shifts and molecular evolution of H7 avian influenza virus hemagglutinin. AB - Evolutionary consequences of host shifts represent a challenge to identify the mechanisms involved in the emergence of influenza A (IA) viruses. In this study we focused on the evolutionary history of H7 IA virus in wild and domestic birds, with a particular emphasis on host shifts consequences on the molecular evolution of the hemagglutinin (HA) gene. Based on a dataset of 414 HA nucleotide sequences, we performed an extensive phylogeographic analysis in order to identify the overall genetic structure of H7 IA viruses. We then identified host shift events and investigated viral population dynamics in wild and domestic birds, independently. Finally, we estimated changes in nucleotide substitution rates and tested for positive selection in the HA gene. A strong association between the geographic origin and the genetic structure was observed, with four main clades including viruses isolated in North America, South America, Australia and Eurasia-Africa. We identified ten potential events of virus introduction from wild to domestic birds, but little evidence for spillover of viruses from poultry to wild waterbirds. Several sites involved in host specificity (addition of a glycosylation site in the receptor binding domain) and virulence (insertion of amino acids in the cleavage site) were found to be positively selected in HA nucleotide sequences, in genetically unrelated lineages, suggesting parallel evolution for the HA gene of IA viruses in domestic birds. These results highlight that evolutionary consequences of bird host shifts would need to be further studied to understand the ecological and molecular mechanisms involved in the emergence of domestic bird-adapted viruses. PMID- 21711554 TI - Quetiapine in refractory hyperactive and mixed intensive care delirium: a case series. AB - INTRODUCTION: Delirium affects up to 80% of patients admitted to intensive care units (ICUs) and contributes to increased morbidity and mortality. Haloperidol is the gold standard for treatment, although quetiapine has been successfully used in the management of delirium. METHODS: We conducted a retrospective study of patients admitted to the ICU between February 2008 and May 2010 who were prescribed quetiapine by the attending clinician. Data collected included demographics, history of drug and/or alcohol dependence, ICU and hospital length of stay, length of mechanical ventilation and the duration of treatment with sedatives and medications for delirium. The daily dose of quetiapine was recorded. Hyperactive or mixed delirium was identified by a validated chart review and a Richmond Agitation Sedation Scale (RASS) score persistently greater than 1 for 48 hours despite therapy. RESULTS: Seventeen patients were included. Delirium onset occurred after a median of five days. Patients were being given at least four agents for delirium prior to the introduction of quetiapine, and they had a median RASS score of 3. Quetiapine was initiated at a 25 mg daily dose and titrated to a median daily dose of 50 mg. The median duration of delirium prior to quetiapine therapy was 15 days. Quetiapine commencement was associated with a reduction in the need for other medications (within 0 to 6 days) and resolution of delirium within a median of four days. Adverse events included somnolence and transient hypotension. CONCLUSIONS: This case series provides an initial effort to explore a possible role for quetiapine in the management of refractory hyperactive and mixed ICU delirium. PMID- 21711555 TI - Development of a microplate coagulation assay for Factor V in human plasma. AB - BACKGROUND: Factor V (FV) in its activated form, FVa, is a critical regulator of thrombin generation during fibrin clot formation. There is a need of a simple, fast, and inexpensive microplate-based coagulation assay to measure the functional activity of FV in human plasma. The objective of this study was to develop a microplate-based assay that measures FV coagulation activity during clot formation in human plasma, which is currently not available. METHODS: The FV assay requires a kinetic microplate reader to measure the change in absorbance at 405nm during fibrin formation in human plasma. The FV assay accurately measures the time, initial rate, and extent of fibrin clot formation in human plasma. RESULTS: The FV microplate assay is simple, fast, economical, sensitive to approx 24-80pM, and multiple samples may be analyzed simultaneously. All the required materials are commercially available. Standard curves of time or initial rate of fibrin clot formation vs FV activity in the 1-stage assay (Without activation by thrombin) may be used to measure FV activity in samples of human plasma. The assay was used to demonstrate that in nine patients with disseminated intravascular coagulation (DIC), the FV 1-stage, 2-stage (With activation by thrombin), and total (2-stage activity - 1-stage activity) activities were decreased, on average, by approximately 54%, 44%, and 42%, respectively, from prolonged clot times when compared to normal pooled human reference plasma (NHP). The results indicate that the FV in the DIC patient plasmas supported both a delayed and slower rate of fibrin clot formation compared with NHP; however, the extent of fibrin clot formation in the DIC patients remained largely unchanged from that observed with NHP. CONCLUSIONS: The FV microplate assay may be easily adapted to measure the activity of any coagulation factor using the appropriate factor-deficient plasma and clot initiating reagent. The microplate assay will find use in both research and clinical laboratories to provide measurement of the functional coagulation activity of FV in human plasma. PMID- 21711556 TI - Discrimination of grade 2 and 3 cervical intraepithelial neoplasia by means of analysis of water soluble proteins recovered from cervical biopsies. AB - BACKGROUND: Cervical intraepithelial neoplasia (CIN) grades 2 and 3 are usually grouped and treated in the same way as "high grade", in spite of their different risk to cancer progression and spontaneous regression rates. CIN2-3 is usually diagnosed in formaldehyde-fixed paraffin embedded (FFPE) punch biopsies. This procedure virtually eliminates the availability of water-soluble proteins which could have diagnostic and prognostic value. AIM: To investigate whether a water soluble protein-saving biopsy processing method followed by a proteomic analysis of supernatant samples using LC-MS/MS (LTQ Orbitrap) can be used to distinguish between CIN2 and CIN3. METHODS: Fresh cervical punch biopsies from 20 women were incubated in RPMI1640 medium for 24 hours at 4 degrees C for protein extraction and subsequently subjected to standard FFPE processing. P16 and Ki67-supported histologic consensus review CIN grade (CIN2, n = 10, CIN3, n = 10) was assessed by independent gynecological pathologists. The biopsy supernatants were depleted of 7 high abundance proteins prior to uni-dimensional LC-MS/MS analysis for protein identifications. RESULTS: The age of the patients ranged from 25-40 years (median 29.7), and mean protein concentration was 0.81 mg/ml (range 0.55 - 1.14). After application of multistep identification criteria, 114 proteins were identified, including proteins like vimentin, actin, transthyretin, apolipoprotein A-1, Heat Shock protein beta 1, vitamin D binding protein and different cytokeratins. The identified proteins are annotated to metabolic processes (36%), signal transduction (27%), cell cycle processes (15%) and trafficking/transport (9%). Using binary logistic regression, Cytokeratin 2 was found to have the strongest independent discriminatory power resulting in 90% overall correct classification. CONCLUSIONS: 114 proteins were identified in supernatants from fresh cervical biopsies and many differed between CIN2 and 3. Cytokeratin 2 is the strongest discriminator with 90% overall correct classifications. PMID- 21711557 TI - Granulocyte colony stimulating factor attenuates inflammation in a mouse model of amyotrophic lateral sclerosis. AB - BACKGROUND: Granulocyte colony stimulating factor (GCSF) is protective in animal models of various neurodegenerative diseases. We investigated whether pegfilgrastim, GCSF with sustained action, is protective in a mouse model of amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease with manifestations of upper and lower motoneuron death and muscle atrophy accompanied by inflammation in the CNS and periphery. METHODS: Human mutant G93A superoxide dismutase (SOD1) ALS mice were treated with pegfilgrastim starting at the presymptomatic stage and continued until the end stage. After long-term pegfilgrastim treatment, the inflammation status was defined in the spinal cord and peripheral tissues including hematopoietic organs and muscle. The effect of GCSF on spinal cord neuron survival and microglia, bone marrow and spleen monocyte activation was assessed in vitro. RESULTS: Long-term pegfilgrastim treatment prolonged mutant SOD1 mice survival and attenuated both astro- and microgliosis in the spinal cord. Pegfilgrastim in SOD1 mice modulated the inflammatory cell populations in the bone marrow and spleen and reduced the production of pro-inflammatory cytokine in monocytes and microglia. The mobilization of hematopoietic stem cells into the circulation was restored back to basal level after long-term pegfilgrastim treatment in SOD1 mice while the storage of Ly6C expressing monocytes in the bone marrow and spleen remained elevated. After pegfilgrastim treatment, an increased proportion of these cells in the degenerative muscle was detected at the end stage of ALS. CONCLUSIONS: GCSF attenuated inflammation in the CNS and the periphery in a mouse model of ALS and thereby delayed the progression of the disease. This mechanism of action targeting inflammation provides a new perspective of the usage of GCSF in the treatment of ALS. PMID- 21711558 TI - Directional RNA deep sequencing sheds new light on the transcriptional response of Anabaena sp. strain PCC 7120 to combined-nitrogen deprivation. AB - BACKGROUND: Cyanobacteria are potential sources of renewable chemicals and biofuels and serve as model organisms for bacterial photosynthesis, nitrogen fixation, and responses to environmental changes. Anabaena (Nostoc) sp. strain PCC 7120 (hereafter Anabaena) is a multicellular filamentous cyanobacterium that can "fix" atmospheric nitrogen into ammonia when grown in the absence of a source of combined nitrogen. Because the nitrogenase enzyme is oxygen sensitive, Anabaena forms specialized cells called heterocysts that create a microoxic environment for nitrogen fixation. We have employed directional RNA-seq to map the Anabaena transcriptome during vegetative cell growth and in response to combined-nitrogen deprivation, which induces filaments to undergo heterocyst development. Our data provide an unprecedented view of transcriptional changes in Anabaena filaments during the induction of heterocyst development and transition to diazotrophic growth. RESULTS: Using the Illumina short read platform and a directional RNA-seq protocol, we obtained deep sequencing data for RNA extracted from filaments at 0, 6, 12, and 21 hours after the removal of combined nitrogen. The RNA-seq data provided information on transcript abundance and boundaries for the entire transcriptome. From these data, we detected novel antisense transcripts within the UTRs (untranslated regions) and coding regions of key genes involved in heterocyst development, suggesting that antisense RNAs may be important regulators of the nitrogen response. In addition, many 5' UTRs were longer than anticipated, sometimes extending into upstream open reading frames (ORFs), and operons often showed complex structure and regulation. Finally, many genes that had not been previously identified as being involved in heterocyst development showed regulation, providing new candidates for future studies in this model organism. CONCLUSIONS: Directional RNA-seq data were obtained that provide comprehensive mapping of transcript boundaries and abundance for all transcribed RNAs in Anabaena filaments during the response to nitrogen deprivation. We have identified genes and noncoding RNAs that are transcriptionally regulated during heterocyst development. These data provide detailed information on the Anabaena transcriptome as filaments undergo heterocyst development and begin nitrogen fixation. PMID- 21711559 TI - Inhibition of cyclophilins alters lipid trafficking and blocks hepatitis C virus secretion. AB - Host cyclophilin (cyp) inhibitors, such as NIM811, efficiently inhibit replication of hepatitis C virus (HCV) and have shown significant promise in recent clinical trials for the treatment of chronic HCV. It is therefore important to fully understand the mechanism of action of these therapeutic agents. Data obtained from comprehensive systems biology approaches have led to the hypothesis that the antiviral activity of cyclophilin inhibitors is mediated through impairing the cellular machinery on which HCV relies to traffic cofactors necessary for formation of the replication complex. Indeed, our results demonstrate when cyclophilins are inhibited by NIM811, lipid and protein trafficking within the VLDL pathway is impaired. Following treatment of replicon or HCV infected cells with NIM811, intracellular lipid droplets (LD) more than double in size and decrease in number. Changes in the LDs in response to cyclophilin inhibition are dependent upon expression of viral proteins. Additionally, in cells treated with NIM811, apoB accumulates in a crescent or ring shaped structure surrounding the enlarged LDs and is no longer secreted. Silencing of cypA or cyp40 using siRNA had a similar effect on LD size and apoB localization as compound treatment, suggesting these cyclophilins may play an important role in lipid and apoB trafficking. Interestingly, the decrease in apoB secretion correlates with a decrease in release of viral particles in HCV infected cells. Altogether, these results add a new level of complexity to the mechanism of action of cyclophilin inhibition, and suggest the role for cyclophilins in the virus life cycle extends beyond replication to virus release. PMID- 21711560 TI - Development and mechanical testing of a short intramedullary nail for fixation of femoral rotational osteotomy in cerebral palsy patients. AB - BACKGROUND: Rotational osteotomy is frequently indicated to correct excessive femoral anteversion in cerebral palsy patients. Angled blade plate is the standard fixation device used when performed in the proximal femur, but extensile exposure is required for plate accommodation. The authors developed a short locked intramedullary nail to be applied percutaneously in the fixation of femoral rotational osteotomies in children with cerebral palsy and evaluated its mechanical properties. METHODS: The study was divided into three stages. In the first part, a prototype was designed and made based on radiographic measurements of the femoral medullary canal of ten-year-old patients. In the second, synthetic femoral models based on rapid-prototyping of 3D reconstructed images of patients with cerebral palsy were obtained and were employed to adjust the nail prototype to the morphological changes observed in this disease. In the third, rotational osteotomies were simulated using synthetic femoral models stabilized by the nail and by the AO-ASIF fixed-angle blade plate. Mechanical testing was done comparing both devices in bending-compression and torsion. RESULTS: The authors observed proper adaptation of the nail to normal and morphologically altered femoral models, and during the simulated osteotomies. Stiffness in bending-compression was significantly higher in the group fixed by the plate (388.97 +/- 57.25 N/mm) than in that fixed by the nail (268.26 +/- 38.51 N/mm) as torsional relative stiffness was significantly higher in the group fixed by the plate (1.07 +/- 0.36 Nm/ degrees ) than by the nail (0.35 +/- 0.13 Nm/ degrees ). CONCLUSIONS: Although the device presented adequate design and dimension to fit into the pediatric femur, mechanical tests indicated that the nail was less stable than the blade plate in bending-compression and torsion. This may be a beneficial property, and it can be attributed to the more flexible fixation found in intramedullary devices. PMID- 21711561 TI - More resistant tendons obtained from the association of Heteropterys aphrodisiaca and endurance training. AB - BACKGROUND: Popular Brazilian medicine uses Heteropterys aphrodisiaca infusion as a tonic or stimulant, for the treatment of nervous debility and breakdown and for muscle and bone weakness. This study investigated the effects of Heteropterys aphrodisiaca infusion on the tendon properties and extracellular matrix of rats under endurance training. METHODS: Wistar rats were grouped as follows: CS- control sedentary, HS- H. aphrodisiaca sedentary, CT-control trained, HT- H. aphrodisiaca trained. The training protocol consisted in running on a motorized treadmill, five times a week, with weekly increase in treadmill speed and duration. Control groups received water while the HS and HT groups received H. aphrodisiaca infusion, daily, by gavage for the 8 weeks of training. Achilles tendons were frozen for biochemical and biomechanical analysis or preserved in Karnovsky's fixative, then processed for histomorphological analysis with light microscopy. RESULTS: Biomechanical analysis showed significant increase in maximum load, maximum stress, modulus of elasticity and stiffness of the HT animals' tendons. The metalloproteinase-2 activity was reduced in the HT group. The compression region of HT animals' tendons had a stronger and more intense metachromasy, which suggests an increase in glycosaminoglycan concentration in this region of the tendon. The most intense birefringence was observed in both compression and tension regions of HT animals' tendons, which may indicate a higher organizational level of collagen bundles. The hydroxyproline content increased in the HT group. CONCLUSIONS: The association of endurance training with H. aphrodisiaca resulted in more organized collagen bundles and more resistant tendons to support higher loads from intense muscle contraction. Despite the clear anabolic effects of Heteropterys aphrodisiaca and the endurance exercise association, no side effects were observed, such as those found for synthetic anabolic androgenic steroids. PMID- 21711562 TI - Providing medical care for undocumented migrants in Denmark: what are the challenges for health professionals? AB - BACKGROUND: The rights of undocumented migrants are frequently overlooked. Denmark has ratified several international conventions recognizing the right to health care for all human beings, but has very scanty legislation and no existing policies for providing health care to undocumented migrants. This study focuses on how health professionals navigate and how they experience providing treatment for undocumented migrants in the Danish health care system. METHODS: The study was carried out as part of an EU-project on European Best Practices in Access, Quality and Appropriateness of Health Services for Immigrants in Europe (EUGATE). This presentation is based on 12 semi-structured interviews with general practitioners (9) and emergency room physicians (3) in Denmark. RESULTS: The emergency room physicians express that treatment of undocumented migrants is no different from the treatment of any other person. However, care may become more complicated due to lack of previous medical records and contact persons. Contrary to this, general practitioners explain that undocumented migrants will encounter formal barriers when trying to obtain treatment. Additional problems in the treatment of undocumented migrants include language issues, financial aspects for general practitioners, concerns about how to handle the situation including possibilities of further referrals, and an uncertainty as to whether to involve the police. CONCLUSIONS: The health professionals in our study describe that undocumented migrants experience an unequal access to primary care facilities and that great uncertainties exist amongst health professionals as how to respond in such situations. The lack of official policies concerning the right to health care for undocumented migrants continue to pass on the responsibility to health professionals and, thereby, leaves it up to the individual to decide whether treatment can be obtained or not. PMID- 21711563 TI - Utility of certain nucleophilic aromatic substitution reactions for the assay of pregabalin in capsules. AB - BACKGROUND: Pregabalin (PG) is an anticonvulsant, analgesic and anxiolytic drug. A survey of the literature reveals that all the reported spectrophotometric methods are either don't offer high sensitivity, need tedious extraction procedures, recommend the measurement of absorbance in the near UV region where interference most probably occurs and/or use non specific reagent that don't offer suitable linearity range. RESULTS: Two new sensitive and simple spectrophotometric methods were developed for determination of pregabalin (PG) in capsules. Method (I) is based on the reaction of PG with 1,2-naphthoquinone-4 sulphonate sodium (NQS), yielding an orange colored product that was measured at 473 nm. Method (II) is based on the reaction of the drug with 2,4 dinitrofluorobenzene (DNFB) producing a yellow product measured at 373 nm. The different experimental parameters affecting the development and stability of the reaction product in methods (I) and (II) were carefully studied and optimized. The absorbance-concentration plots were rectilinear over the concentration ranges of 2-25 and 0.5-8 MUg mL-1 for methods (I) and (II) respectively. The lower detection limits (LOD) were 0.15 and 0.13 MUg mL-1 and the lower quantitation limits (LOQ) were 0.46 and 0.4 MUg mL-1 for methods (I) and (II) respectively. CONCLUSION: The developed methods were successfully applied to the analysis of the drug in its commercial capsules. The mean percentage recoveries of PG in its capsule were 99.11 +/- 0.98 and 100.11 +/- 1.2 (n = 3). Statistical analysis of the results revealed good agreement with those given by the comparison method. Proposals of the reaction pathways were postulated. PMID- 21711564 TI - On the alleged origin of geminiviruses from extrachromosomal DNAs of phytoplasmas. AB - BACKGROUND: Several phytoplasmas, wall-less phloem limited plant pathogenic bacteria, have been shown to contain extrachromosomal DNA (EcDNA) molecules encoding a replication associated protein (Rep) similar to that of geminiviruses, a major group of single stranded (ss) DNA plant viruses. On the basis of that observation and of structural similarities between the capsid proteins of geminiviruses and the Satellite tobacco necrosis virus, it has been recently proposed that geminiviruses evolved from phytoplasmal EcDNAs by acquiring a capsid protein coding gene from a co-invading plant RNA virus. RESULTS: Here we show that this hypothesis has to be rejected because (i) the EcDNA encoded Rep is not of phytoplasmal origin but has been acquired by phytoplasmas through horizontal transfer from a geminivirus or its ancestor; and (ii) the evolution of geminivirus capsid protein in land plants implies missing links, while the analysis of metagenomic data suggests an alternative scenario implying a more ancient evolution in marine environments. CONCLUSION: The hypothesis of geminiviruses evolving in plants from DNA molecules of phytoplasma origin contrasts with other findings. An alternative scenario concerning the origin and spread of Rep coding phytoplasmal EcDNA is presented and its implications on the epidemiology of phytoplasmas are discussed. PMID- 21711566 TI - Ethnobotany, diverse food uses, claimed health benefits and implications on conservation of barley landraces in North Eastern Ethiopia highlands. AB - BACKGROUND: Barley is the number one food crop in the highland parts of North Eastern Ethiopia produced by subsistence farmers grown as landraces. Information on the ethnobotany, food utilization and maintenance of barley landraces is valuable to design and plan germplasm conservation strategies as well as to improve food utilization of barley. METHODS: A study, involving field visits and household interviews, was conducted in three administrative zones. Eleven districts from the three zones, five kebeles in each district and five households from each kebele were visited to gather information on the ethnobotany, the utilization of barley and how barley end-uses influence the maintenance of landrace diversity. RESULTS: According to farmers, barley is the "king of crops" and it is put for diverse uses with more than 20 types of barley dishes and beverages reportedly prepared in the study area. The products are prepared from either boiled/roasted whole grain, raw- and roasted-milled grain, or cracked grain as main, side, ceremonial, and recuperating dishes. The various barley traditional foods have perceived qualities and health benefits by the farmers. Fifteen diverse barley landraces were reported by farmers, and the ethnobotany of the landraces reflects key quantitative and qualitative traits. Some landraces that are preferred for their culinary qualities are being marginalized due to moisture shortage and soil degradation. CONCLUSIONS: Farmers' preference of different landraces for various end-use qualities is one of the important factors that affect the decision process of landraces maintenance, which in turn affect genetic diversity. Further studies on improving maintenance of landraces, developing suitable varieties and improving the food utilization of barley including processing techniques could contribute to food security of the area. PMID- 21711565 TI - Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice. AB - BACKGROUND: Obesity and related metabolic abnormalities, including inflammation and lipid accumulation in the liver, play a role in liver carcinogenesis. Adipocytokine imbalances, such as decreased serum adiponectin levels, are also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of pitavastatin - a drug used for the treatment of hyperlipidemia - on the development of diethylnitrosamine (DEN)-induced liver preneoplastic lesions in C57BL/KsJ-db/db (db/db) obese mice. METHODS: Male db/db mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks. RESULTS: At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK alpha protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-alpha and the expression of TNF-alpha and interleukin-6 mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition. CONCLUSIONS: Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals. PMID- 21711568 TI - The effect of oxidized low-density lipoprotein combined with adriamycin on the proliferation of Eca-109 cell line. AB - BACKGROUND: The purpose of this study was to identify the affect on the proliferation Eca-109 cells treated with oxidized low-density lipoprotein (ox LDL) combined with adriamycin (ADM). METHODS: Eca-109 cell were cultured in the presence of oxLDL/ADM, and cell proliferation tested by MTT and cell apoptosis was monitored by the proportion of apoptosis and cell cycle by flow cytomester. We simultaneously evaluated the level of associated- apoptosis Bcl-2, Bax, and Caspase-3 gene mRNA and protein. RESULTS: OxLDL were cytotoxic and activate apoptosis. OxLDL combined with ADM significant enhanced the proportion rate of apoptosis on a time and dose dependency. The expressions of the inhibiting apoptosis Bcl-2 gene mRNA and protein were down regulated, whereas, the expressions of the promoting apoptosis Bax, and Caspase-3 genes mRNA and protein were up regulation. CONCLUSION: These results suggested that oxLDL have cytotoxicity and activate apoptosis on the Eca-109 cells. OxLDL combined with ADM have a synergistic effect on the apoptosis induced Eca-109 cells. Furthermore, oxLDL may contribute to the improvement of clinical chemotherapy of cancer need to make further investigation. PMID- 21711569 TI - Theory, simulation and experimental results of the acoustic detection of magnetization changes in superparamagnetic iron oxide. AB - BACKGROUND: Magnetic Particle Imaging is a novel method for medical imaging. It can be used to measure the local concentration of a tracer material based on iron oxide nanoparticles. While the resulting images show the distribution of the tracer material in phantoms or anatomic structures of subjects under examination, no information about the tissue is being acquired. To expand Magnetic Particle Imaging into the detection of soft tissue properties, a new method is proposed, which detects acoustic emissions caused by magnetization changes in superparamagnetic iron oxide. METHODS: Starting from an introduction to the theory of acoustically detected Magnetic Particle Imaging, a comparison to magnetically detected Magnetic Particle Imaging is presented. Furthermore, an experimental setup for the detection of acoustic emissions is described, which consists of the necessary field generating components, i.e. coils and permanent magnets, as well as a calibrated microphone to perform the detection. RESULTS: The estimated detection limit of acoustic Magnetic Particle Imaging is comparable to the detection limit of magnetic resonance imaging for iron oxide nanoparticles, whereas both are inferior to the theoretical detection limit for magnetically detected Magnetic Particle Imaging. Sufficient data was acquired to perform a comparison to the simulated data. The experimental results are in agreement with the simulations. The remaining differences can be well explained. CONCLUSIONS: It was possible to demonstrate the detection of acoustic emissions of magnetic tracer materials in Magnetic Particle Imaging. The processing of acoustic emission in addition to the tracer distribution acquired by magnetic detection might allow for the extraction of mechanical tissue parameters. Such parameters, like for example the velocity of sound and the attenuation caused by the tissue, might also be used to support and improve ultrasound imaging. However, the method can also be used to perform imaging on its own. PMID- 21711567 TI - In-vitro and in-vivo phenotype of type Asia 1 foot-and-mouth disease viruses utilizing two non-RGD receptor recognition sites. AB - BACKGROUND: Foot-and-mouth disease virus (FMDV) uses a highly conserved Arg-Gly Asp (RGD) triplet for attachment to host cells and this motif is believed to be essential for virus viability. Previous sequence analyses of the 1D-encoding region of an FMDV field isolate (Asia1/JS/CHA/05) and its two derivatives indicated that two viruses, which contained an Arg-Asp-Asp (RDD) or an Arg-Ser Asp (RSD) triplet instead of the RGD integrin recognition motif, were generated serendipitously upon short-term evolution of field isolate in different biological environments. To examine the influence of single amino acid substitutions in the receptor binding site of the RDD-containing FMD viral genome on virus viability and the ability of non-RGD FMDVs to cause disease in susceptible animals, we constructed an RDD-containing FMDV full-length cDNA clone and derived mutant molecules with RGD or RSD receptor recognition motifs. Following transfection of BSR cells with the full-length genome plasmids, the genetically engineered viruses were examined for their infectious potential in cell culture and susceptible animals. RESULTS: Amino acid sequence analysis of the 1D-coding region of different derivatives derived from the Asia1/JS/CHA/05 field isolate revealed that the RDD mutants became dominant or achieved population equilibrium with coexistence of the RGD and RSD subpopulations at an early phase of type Asia1 FMDV quasispecies evolution. Furthermore, the RDD and RSD sequences remained genetically stable for at least 20 passages. Using reverse genetics, the RDD-, RSD-, and RGD-containing FMD viruses were rescued from full length cDNA clones, and single amino acid substitution in RDD-containing FMD viral genome did not affect virus viability. The genetically engineered viruses replicated stably in BHK-21 cells and had similar growth properties to the parental virus. The RDD parental virus and two non-RGD recombinant viruses were virulent to pigs and bovines that developed typical clinical disease and viremia. CONCLUSIONS: FMDV quasispecies evolving in a different biological environment gained the capability of selecting different receptor recognition site. The RDD containing FMD viral genome can accommodate substitutions in the receptor binding site without additional changes in the capsid. The viruses expressing non-RGD receptor binding sites can replicate stably in vitro and produce typical FMD clinical disease in susceptible animals. PMID- 21711570 TI - Cinnamon extract inhibits alpha-glucosidase activity and dampens postprandial glucose excursion in diabetic rats. AB - BACKGROUND: alpha-glucosidase inhibitors regulate postprandial hyperglycemia (PPHG) by impeding the rate of carbohydrate digestion in the small intestine and thereby hampering the diet associated acute glucose excursion. PPHG is a major risk factor for diabetic vascular complications leading to disabilities and mortality in diabetics. Cinnamomum zeylanicum, a spice, has been used in traditional medicine for treating diabetes. In this study we have evaluated the alpha-glucosidase inhibitory potential of cinnamon extract to control postprandial blood glucose level in maltose, sucrose loaded STZ induced diabetic rats. METHODS: The methanol extract of cinnamon bark was prepared by Soxhlet extraction. Phytochemical analysis was performed to find the major class of compounds present in the extract. The inhibitory effect of cinnamon extract on yeast alpha-glucosidase and rat-intestinal alpha-glucosidase was determined in vitro and the kinetics of enzyme inhibition was studied. Dialysis experiment was performed to find the nature of the inhibition. Normal male Albino wistar rats and STZ induced diabetic rats were treated with cinnamon extract to find the effect of cinnamon on postprandial hyperglycemia after carbohydrate loading. RESULTS: Phytochemical analysis of the methanol extract displayed the presence of tannins, flavonoids, glycosides, terpenoids, coumarins and anthraquinones. In vitro studies had indicated dose-dependent inhibitory activity of cinnamon extract against yeast alpha-glucosidase with the IC 50 value of 5.83 MUg/ml and mammalian alpha-glucosidase with IC 50 value of 670 MUg/ml. Enzyme kinetics data fit to LB plot pointed out competitive mode of inhibition and the membrane dialysis experiment revealed reversible nature of inhibition. In vivo animal experiments are indicative of ameliorated postprandial hyperglycemia as the oral intake of the cinnamon extract (300 mg/kg body wt.) significantly dampened the postprandial hyperglycemia by 78.2% and 52.0% in maltose and sucrose loaded STZ induced diabetic rats respectively, compared to the control. On the other hand, in rats that received glucose and cinnamon extract, postprandial hyperglycemia was not effectively suppressed, which indicates that the observed postprandial glycemic amelioration is majorly due to alpha-glucosidase inhibition. CONCLUSIONS: The current study demonstrates one of the mechanisms in which cinnamon bark extract effectively inhibits alpha-glucosidase leading to suppression of postprandial hyperglycemia in STZ induced diabetic rats loaded with maltose, sucrose. This bark extract shows competitive, reversible inhibition on alpha-glucosidase enzyme. Cinnamon extract could be used as a potential nutraceutical agent for treating postprandial hyperglycemia. In future, specific inhibitor has to be isolated from the crude extract, characterized and therapeutically exploited. PMID- 21711571 TI - General and disease-specific quality of life in patients with chronic suppurative otitis media--a prospective study. AB - BACKGROUND: Chronic suppurative otitis media (CSOM) is frequently associated with symptoms of inflammation like discharge from the ear or pain. In many cases, patients suffer from hearing loss causing communication problems and social withdrawal. The objective of this work was to collect prospective audiological data and data on general and disease-specific quality of life with validated quality of life measurement instruments to assess the impact of the disease on health-related quality of life (HR-QOL). METHODS: 121 patients were included in the study. Patients were clinically examined in the hospital before and 6 months after surgery including audiological testing. They filled in the quality of life questionnaires SF-36 and Chronic Otitis Media Outcome Test 15 (COMOT-15) pre operatively and 6 and 12 months post-operatively, respectively. RESULTS: Complete data records from 90 patients were available for statistical analysis. Disease specific HR-QOL in patients with CSOM improved after tympanoplasty in all the scales of the COMOT-15. There was no difference in HR-QOL assessment between patients with mesotympanic respectively epitympanic CSOM. However, we did find the outcome to be worse in patients who received revision surgery compared with those receiving primary surgery. Audiometric findings correlated very well with the subscale hearing function from the COMOT-15 questionnaire. General HR-QOL measured with the SF-36 was not significantly changed by tympanoplasty. CONCLUSIONS: Tympanoplasty did lead to a significant improvement of disease specific HR-QOL in patients with CSOM while general HR-QOL did not change. Very well correlations were found between the subscale hearing function from the COMOT 15 questionnaire and audiological findings. Revision surgery seems to be a predictor for a worse outcome. PMID- 21711572 TI - Tinnitus in elderly patients and prognosis of mild-to-moderate congestive heart failure: a cross-sectional study with a long-term extension of the clinical follow-up. AB - BACKGROUND: The complex mechanism responsible for tinnitus, a symptom highly prevalent in elderly patients, could involve an impaired control of the microcirculation of the inner ear, particularly in patients with poor blood pressure control and impaired left ventricular (LV) function. METHODS: In order to define the relationship between the presence of tinnitus and the severity and clinical prognosis of mild-to-moderate chronic heart failure (CHF) in a large population of elderly patients (N = 958), a cross-sectional study was conducted with a long-term extension of the clinical follow-up. Blood pressure, echocardiographic parameters, brain natriuretic peptide (BNP), hospitalization, and mortality for CHF were measured. Multivariate logistic regression analysis was used to assess the association between the presence of tinnitus and some of the prognostic determinants of heart failure. RESULTS: The presence of tinnitus was ascertained in 233 patients (24.3%; mean age 74.9 +/- 6 years) and was associated with reduced systolic and diastolic blood pressure (123.1 +/- 16/67.8 +/- 9 vs 125.9 +/- 15/69.7 +/- 9; P = .027/P = .006), reduced LV ejection fraction (LVEF%; 43.6 +/- 15 vs 47.9 +/- 14%, P = .001), and increased BNP plasma levels (413.1 +/- 480 vs 286.2 +/- 357, P = .013) in comparison to patients without symptoms. The distribution of CHF functional class was shifted toward a greater severity of the disease in patients with tinnitus. Combined one-year mortality and hospitalization for CHF (events/year) was 1.43 +/- 0.2 in patients with tinnitus and 0.83 +/- 0.1 in patients without tinnitus, with an adjusted hazard ratio (HR) of 0.61 (95% confidence interval (CI): 0.37 to 0.93, P <.002). CONCLUSIONS: Our preliminary data indirectly support the hypothesis that tinnitus is associated with a worse CHF control in elderly patients and can have some important clinical implications for the early identification of patients who deserve a more aggressive management of CHF. PMID- 21711573 TI - Monodisperse alpha-Fe2O3 Mesoporous Microspheres: One-Step NaCl-Assisted Microwave-Solvothermal Preparation, Size Control and Photocatalytic Property. AB - A simple one-step NaCl-assisted microwave-solvothermal method has been developed for the preparation of monodisperse alpha-Fe2O3 mesoporous microspheres. In this approach, Fe(NO3)3 . 9H2O is used as the iron source, and polyvinylpyrrolidone (PVP) acts as a surfactant in the presence of NaCl in mixed solvents of H2O and ethanol. Under the present experimental conditions, monodisperse alpha-Fe2O3 mesoporous microspheres can form via oriented attachment of alpha-Fe2O3 nanocrystals. One of the advantages of this method is that the size of alpha Fe2O3 mesoporous microspheres can be adjusted in the range from ca. 170 to ca. 260 nm by changing the experimental parameters. High photocatalytic activities in the degradation of salicylic acid are observed for alpha-Fe2O3 mesoporous microspheres with different specific surface areas. PMID- 21711575 TI - Persistent deNOx Ability of CaAl2O4:(Eu, Nd)/TiO2-xNy Luminescent Photocatalyst. AB - CaAl2O4:(Eu, Nd)/TiO2-xNy composite luminescent photocatalyst was successfully synthesized by a simple planetary ball milling process. Improvement of photocatalytic deNOx ability of TiO2-xNy, together with the persistent photocatalytic activity for the decomposition of NO after turning off the light were realized, by coupling TiO2-xNy with long afterglow phosphor, CaAl2O4:(Eu, Nd). The novel persistent photocatalytic behavior was related to the overlap between the absorption wavelength of TiO2-xNy and the emission wavelength of the CaAl2O4:(Eu, Nd). It was found that CaAl2O4:(Eu, Nd)/TiO2-xNy composites provided the luminescence to persist photocatalytic reaction for more than 3 h after turning off the light. GRAPHICAL CaAl2O4:(Eu, Nd)/TiO2-xNy composite luminescent photocatalyst with persistent deNOx activity after turning off the light was successfully synthesized by a simple planetary ball milling process. The novel persistent photocatalytic behavior was related to the overlap between the absorption wavelength of TiO2-xNy and the emission wavelength of the CaAl2O4:(Eu, Nd). PMID- 21711574 TI - Hydroxyapatite Mineralization on the Calcium Chloride Blended Polyurethane Nanofiber via Biomimetic Method. AB - Polyurethane nanofibers containing calcium chloride (CaCl2) were prepared via an electrospinning technique for the biomedical applications. Polyurethane nanofibers with different concentration of CaCl2 were electrospun, and their bioactivity evaluation was conducted by incubating in biomimetic simulated body fluid (SBF) solution. The morphology, structure and thermal properties of the polyurethane/CaCl2 composite nanofibers were characterized by means of scanning electron microscopy (SEM), field-emission scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy and thermogravimetry. SEM images revealed that the CaCl2 salt incorporated homogeneously to form well-oriented nanofibers with smooth surface and uniform diameters along their lengths. The SBF incubation test confirmed the formation of apatite-like materials, exhibiting enhanced bioactive behavior of the polyurethane/CaCl2 composite nanofibers. This study demonstrated that the electrospun polyurethane containing CaCl2 composite nanofibers enhanced the in vitro bioactivity and supports the growth of apatite-like materials. PMID- 21711576 TI - Large-Scale Fabrication of Boron Nitride Nanotubes via a Facile Chemical Vapor Reaction Route and Their Cathodoluminescence Properties. AB - Cylinder- and bamboo-shaped boron nitride nanotubes (BNNTs) have been synthesized in large scale via a facile chemical vapor reaction route using ammonia borane as a precursor. The structure and chemical composition of the as synthesized BNNTs are extensively characterized by X-ray diffraction, scanning electron microscopy, high-resolution transmission electron microscopy, and selected-area electron diffraction. The cylinder-shaped BNNTs have an average diameter of about 100 nm and length of hundreds of microns, while the bamboo shaped BNNTs are 100-500 nm in diameter with length up to tens of microns. The formation mechanism of the BNNTs has been explored on the basis of our experimental observations and a growth model has been proposed accordingly. Ultraviolet-visible and cathodoluminescence spectroscopic analyses are performed on the BNNTs. Strong ultraviolet emissions are detected on both morphologies of BNNTs. The band gap of the BNNTs are around 5.82 eV and nearly unaffected by tube morphology. There exist two intermediate bands in the band gap of BNNTs, which could be distinguishably assigned to structural defects and chemical impurities. PMID- 21711577 TI - Discoid Bicelles as Efficient Templates for Pillared Lamellar Periodic Mesoporous Silicas at pH 7 and Ultrafast Reaction Times. AB - We report the first synthesis of periodic mesoporous silicas templated by bicelles. The obtained materials form novel pillared lamellar structures with a high degree of periodic order, narrow pore size distributions, and exceptionally high surface areas. PMID- 21711579 TI - Ultra-steep side facets in multi-faceted SiGe/Si(001) Stranski-Krastanow islands. AB - For the prototypical Ge/Si(001) system, we show that at high growth temperature a new type of Stranski-Krastanow islands is formed with side facets steeper than {111} and high aspect ratio. Nano-goniometric analysis of the island shapes reveals the presence of six new facet groups in addition to those previously found for dome or barn-shaped islands. Due to the highly multi-faceted island shape and high aspect ratio, the new island types are named "cupola" islands and their steepest {12 5 3} side facet is inclined by 68 degrees to the substrate surface. Assessing the relative stability of the new facets from surface area analysis, we find that their stability is similar to that of {113} and {15 3 23} facets of dome islands. The comparison of the different island shapes shows that they form a hierarchical class of geometrical structures, in which the lower aspect ratio islands of barns, domes and pyramids are directly derived from the cupola islands by successive truncation of the pedestal bases without facet rearrangements. The results underline the key role of surface faceting in the process of island formation, which is as crucial for understanding the island's growth evolution as it is important for device applications. PMID- 21711578 TI - Effect of surface properties of silica nanoparticles on their cytotoxicity and cellular distribution in murine macrophages. AB - Surface properties are often hypothesized to be important factors in the development of safer forms of nanomaterials (NMs). However, the results obtained from studying the cellular responses to NMs are often contradictory. Hence, the aim of this study was to investigate the relationship between the surface properties of silica nanoparticles and their cytotoxicity against a murine macrophage cell line (RAW264.7). The surface of the silica nanoparticles was either unmodified (nSP70) or modified with amine (nSP70-N) or carboxyl groups (nSP70-C). First, the properties of the silica nanoparticles were characterized. RAW264.7 cells were then exposed to nSP70, nSP70-N, or nSP70-C, and any cytotoxic effects were monitored by analyzing DNA synthesis. The results of this study show that nSP70-N and nSP70-C have a smaller effect on DNA synthesis activity by comparison to unmodified nSP70. Analysis of the intracellular localization of the silica nanoparticles revealed that nSP70 had penetrated into the nucleus, whereas nSP70-N and nSP70-C showed no nuclear localization. These results suggest that intracellular localization is a critical factor underlying the cytotoxicity of these silica nanoparticles. Thus, the surface properties of silica nanoparticles play an important role in determining their safety. Our results suggest that optimization of the surface characteristics of silica nanoparticles will contribute to the development of safer forms of NMs. PMID- 21711580 TI - A general strategy for synthesis of metal oxide nanoparticles attached on carbon nanomaterials. AB - We report a general strategy for synthesis of a large variety of metal oxide nanoparticles on different carbon nanomaterials (CNMs), including single-walled carbon nanotubes, multi-walled carbon nanotubes, and a few-layer graphene. The approach was based on the pi-pi interaction between CNMs and modified aromatic organic ligands, which acted as bridges connecting metal ions and CNMs. Our methods can be applicable for a large variety of metal ions, thus offering a great potential application. PMID- 21711581 TI - Phonon Raman spectra of colloidal CdTe nanocrystals: effect of size, non stoichiometry and ligand exchange. AB - Resonant Raman study reveals the noticeable effect of the ligand exchange on the nanocrystal (NC) surface onto the phonon spectra of colloidal CdTe NC of different size and composition. The oleic acid ligand exchange for pyridine ones was found to change noticeably the position and width of the longitudinal optical (LO) phonon mode, as well as its intensity ratio to overtones. The broad shoulder above the LO peak frequency was enhanced and sharpened after pyridine treatment, as well as with decreasing NC size. The low-frequency mode around 100 cm-1 which is commonly related with the disorder-activated acoustical phonons appears in smaller NCs but is not enhanced after pyridine treatment. Surprisingly, the feature at low-frequency shoulder of the LO peak, commonly assigned to the surface optical phonon mode, was not sensitive to ligand exchange and concomitant close packing of the NCs. An increased structural disorder on the NC surface, strain and modified electron-phonon coupling is discussed as the possible reason of the observed changes in the phonon spectrum of ligand-exchanged CdTe NCs.PACS: 63.20.-e, 78.30.-j, 78.67.-n, 78.67.Bf. PMID- 21711582 TI - Formation and reinforcement of clusters composed of C60 molecules. AB - We carry out two experiments: (1) the formation of clusters composed of C60 molecules via self-assembly and (2) the reinforcement of the clusters. Firstly, clusters such as fibres and helices composed of C60 molecules are produced via self-assembly in supercritical carbon dioxide. However, C60 molecules are so weakly bonded to each other in the clusters that the clusters are broken by the irradiation of electron beams during scanning electron microscope observation. Secondly, UV photons are irradiated inside a chamber in which air is filled at 1 atm and the above clusters are placed, and it was found that the clusters are reinforced; that is, they are not broken by electron beams any more. C60 molecules located at the surface of the clusters are oxidised, i.e. C60On molecules, where n = 1, 2, 3 and 4, are produced according to time-of-flight mass spectroscopy. It is supposed that oxidised C60 molecules at the surface of the clusters may have an important role for the reinforcement, but the actual mechanism of the reinforcement of the clusters has not yet been clearly understood and therefore is an open question. PMID- 21711583 TI - GaN nanorods grown on Si (111) substrates and exciton localization. AB - We have investigated exciton localization in binary GaN nanorods using micro- and time-resolved photoluminescence measurements. The temperature dependence of the photoluminescence has been measured, and several phonon replicas have been observed at the lower energy side of the exciton bound to basal stacking faults (I1). By analyzing the Huang-Rhys parameters as a function of temperature, deduced from the phonon replica intensities, we have found that the excitons are strongly localized in the lower energy tails. The lifetimes of the I1 and I2 transitions were measured to be < 100 ps due to enhanced surface recombination.PACS: 78.47.+p, 78.55.-m, 78.55.Cr, 78.66.-w, 78.66.Fd. PMID- 21711584 TI - Formation of Ge-Sn nanodots on Si(100) surfaces by molecular beam epitaxy. AB - The surface morphology of Ge0.96Sn0.04/Si(100) heterostructures grown at temperatures from 250 to 450 degrees C by atomic force microscopy (AFM) and scanning tunnel microscopy (STM) ex situ has been studied. The statistical data for the density of Ge0.96Sn0.04 nanodots (ND) depending on their lateral size have been obtained. Maximum density of ND (6 * 1011 cm-2) with the average lateral size of 7 nm can be obtained at 250 degrees C. Relying on the reflection of high energy electron diffraction, AFM, and STM, it is concluded that molecular beam growth of Ge1-xSnx heterostructures with the small concentrations of Sn in the range of substrate temperatures from 250 to 450 degrees C follows the Stranski-Krastanow mechanism. Based on the technique of recording diffractometry of high energy electrons during the process of epitaxy, the wetting layer thickness of Ge0.96Sn0.04 films is found to depend on the temperature of the substrate. PMID- 21711585 TI - Scalable synthesis of aligned carbon nanotubes bundles using green natural precursor: neem oil. AB - Practical application of aligned carbon nanotubes (ACNTs) would have to be determined by a matter of its economical and large-scale preparation. In this study, neem oil (also named Margoaa oil, extracted from the seeds of the neem- Azadirachta indica) was used as carbon source to fabricate the bundles of ACNTs. ACNTs have been synthesized by spray pyrolysis of neem oil and ferrocene mixture at 825 degrees C. The major components of neem oil are hydrocarbon with less amount of oxygen, which provided the precursor species in spray pyrolysis growth of CNTs. The bundles of ACNTs have been grown directly inside the quartz tube. The as-grown ACNTs have been characterized through Raman spectroscopy, scanning and transmission electron microscopic (SEM/TEM) techniques. SEM images reveal that the bundles of ACNTs are densely packed and are of several microns in length. High-resolution TEM analysis reveals these nanotubes to be multi-walled CNTs. These multi-walled CNTs were found to have inner diameter between 15 and 30 nm. It was found that present technique gives high yield with high density of bundles of ACNTs. PMID- 21711586 TI - The right journal for the right time - Cell & Bioscience. AB - Cell & Bioscience welcomes the submission of your best work for rapid open access publication. This is the official journal of the Society of Chinese Bioscientists in America (SCBA). PMID- 21711587 TI - Wnt/beta-catenin signaling activates microRNA-181 expression in hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant cancer with an observable heterogeneity and microRNAs are functionally associated with the tumorigenesis of HCC. We recently identified that EpCAM (CD326)-positive cells isolated from alpha-fetoprotein (AFP)-positive HCC samples are hepatic cancer stem cells (HepCSCs). EpCAM+AFP+ HepCSCs have an activated Wnt/beta-catenin signaling with a parallel increased expression of all four microRNA-181 family members. We hypothesized that Wnt/beta-catenin signaling transcriptionally activates microRNA-181s in HCC. RESULTS: Using both western blot and quantitative reverse transcriptase-PCR analyses, we found that the expression of all four microRNA-181 family members was positively correlated with beta-catenin expression in HCC cell lines. MicroRNA-181 expression could be directly induced upon an activation of Wnt/beta-catenin signaling, which includes Wnt10B overexpression, inhibition of GSK3beta signaling by LiCl, or forced expression of beta-catenin/Tcf4. Moreover, microRNA-181 expression was inhibited upon an inactivation of Wnt/beta-catenin signaling by an induction of adenomatosis polyposis coli (APC) expression or silencing beta-catenin via RNA interference. In addition, seven putative beta-catenin/Tcf4 binding sites were identified in the promoter region of the microRNA-181a-2 and microRNA-181b-2 transcripts. Consistently, we found that Tcf4 interacted with these regions in vivo using chromatin immunoprecipitation assay. CONCLUSIONS: Taken together, our results demonstrate that microRNA-181s are transcriptionally activated by the Wnt/beta catenin signaling pathway in HCC. PMID- 21711588 TI - If you organize, they will join. AB - This Editorial briefly introduces the Society of Chinese Bioscientists in America (SCBA) to readers of Cell & Bioscience. PMID- 21711589 TI - Combined plasma gas-phase synthesis and colloidal processing of InP/ZnS core/shell nanocrystals. AB - Indium phosphide nanocrystals (InP NCs) with diameters ranging from 2 to 5 nm were synthesized with a scalable, flow-through, nonthermal plasma process at a rate ranging from 10 to 40 mg/h. The NC size is controlled through the plasma operating parameters, with the residence time of the gas in the plasma region strongly influencing the NC size. The NC size distribution is narrow with the standard deviation being less than 20% of the mean NC size. Zinc sulfide (ZnS) shells were grown around the plasma-synthesized InP NCs in a liquid phase reaction. Photoluminescence with quantum yields as high as 15% were observed for the InP/ZnS core-shell NCs. PMID- 21711590 TI - Resonant frequency of gold/polycarbonate hybrid nano resonators fabricated on plastics via nano-transfer printing. AB - We report the fabrication of gold/polycarbonate (Au/PC) hybrid nano resonators on plastic substrates through a nano-transfer printing (nTP) technique, and the parametric studies of the resonant frequency of the resulting hybrid nano resonators. nTP is a nanofabrication technique that involves an assembly process by which a printable layer can be transferred from a transfer substrate to a device substrate. In this article, we applied nTP to fabricate Au/PC hybrid nano resonators on a PC substrate. When an AC voltage is applied, the nano resonator can be mechanically excited when the AC frequency reaches the resonant frequency of the nano resonator. We then performed systematic parametric studies to identify the parameters that govern the resonant frequency of the nano resonators, using finite element method. The quantitative results for a wide range of materials and geometries offer vital guidance to design hybrid nano resonators with a tunable resonant frequency in a range of more than three orders of magnitude (e.g., 10 KHz-100 MHz). Such nano resonators could find their potential applications in nano electromechanical devices. Fabricating hybrid nano resonators via nTP further demonstrates nTP as a potential fabrication technique to enable a low-cost and scalable roll-to-roll printing process of nanodevices. PMID- 21711591 TI - Preparation and characterization of spindle-like Fe3O4 mesoporous nanoparticles. AB - Magnetic spindle-like Fe3O4 mesoporous nanoparticles with a length of 200 nm and diameter of 60 nm were successfully synthesized by reducing the spindle-like alpha-Fe2O3 NPs which were prepared by forced hydrolysis method. The obtained samples were characterized by transmission electron microscopy, powder X-ray diffraction, attenuated total reflection fourier transform infrared spectroscopy, field emission scanning electron microscopy, vibrating sample magnetometer, and nitrogen adsorption-desorption analysis techniques. The results show that alpha Fe2O3 phase transformed into Fe3O4 phase after annealing in hydrogen atmosphere at 350 degrees C. The as-prepared spindle-like Fe3O4 mesoporous NPs possess high Brunauer-Emmett-Teller (BET) surface area up to ca. 7.9 m2 g-1. In addition, the Fe3O4 NPs present higher saturation magnetization (85.2 emu g-1) and excellent magnetic response behaviors, which have great potential applications in magnetic separation technology. PMID- 21711592 TI - The encapsulation effect of UV molecular absorbers into biocompatible lipid nanoparticles. AB - The efficiency of a cosmetic product depends not only on the active ingredients, but also on the carrier system devoted to improve its bioavailability. This article aims to encapsulate two couples of UV molecular absorbers, with a blocking action on both UV-A and UV-B domains, into efficient lipid nanoparticles. The effect of encapsulation on the specific properties such as sun protection factor and photostability behaviour has been demonstrated. The lipid nanoparticles with size range 30-350 nm and a polydispersity index between 0.217 and 0.244 are obtained using a modified high shear homogenisation method. The nanoparticles had spherical shapes with a single crystallisation form of lipid matrices characteristic for the least ordered crystal structure (alpha-form). The in vitro determination of photoprotection has led to high SPF ratings, with values of about 20, which assure a good photoprotection and filtering about 95% of UV radiation. The photoprotection effect after irradiation stage was observed to be increased more than twice compared to initial samples as a result of isomerisation phenomena. All the results have shown that good photoprotection effect and improved photostability could be obtained using such sunscreen couples, thus demonstrating that UV absorbers-solid lipid nanoparticles are promising carriers for cosmetic formulations. PMID- 21711593 TI - In vivo microRNA-155 expression influences antigen-specific T cell-mediated immune responses generated by DNA vaccination. AB - BACKGROUND: MicroRNA (miRNA) molecules are potent mediators of post transcriptional gene silencing that are emerging to be critical in the regulation of innate and adaptive immunity. RESULTS: Here we report that miR-155--an oncogenic miRNA with important function in the mammalian immune system--is induced in dendritic cells (DCs) upon maturation and potentially attenuates their ability to activate T cells. Biolistic epidermal transfection with DNA encoding miR-155 suppressed the induction of antigen-specific T cell-mediated immunity, whereas reduction of endogenous miR-155 by a partially complementary antisense sequence reversed this effect. Because DCs represent a significant component of epidermal tissue and are among the most potent of antigen-presenting cells, the inhibitory actions of miR-155 could be mediated through this subset of cells. CONCLUSIONS: These results suggest that miR-155 may repress the expression of key molecules involved in lymph node migration, antigen presentation, or T cell activation in DCs, and thus forms part of a negative regulatory pathway that dampens the generation of T cell-mediated immune responses. Modulation of miR-155 expression in epidermis therefore represents a potentially promising form of gene therapy for the control of diseases ranging from autoimmunity to cancer and viral infection. PMID- 21711595 TI - Characterization of MHz pulse repetition rate femtosecond laser-irradiated gold coated silicon surfaces. AB - In this study, MHz pulse repetition rate femtosecond laser-irradiated gold coated silicon surfaces under ambient condition were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction analysis (XRD), and X-ray photoelectron spectroscopy (XPS). The radiation fluence used was 0.5 J/cm2 at a pulse repetition rate of 25 MHz with 1 ms interaction time. SEM analysis of the irradiated surfaces showed self assembled intermingled weblike nanofibrous structure in and around the laser irradiated spots. Further TEM investigation on this nanostructure revealed that the nanofibrous structure is formed due to aggregation of Au-Si/Si nanoparticles. The XRD peaks at 32.2 degrees , 39.7 degrees , and 62.5 degrees were identified as (200), (211), and (321) reflections, respectively, corresponding to gold silicide. In addition, the observed chemical shift of Au 4f and Si 2p lines in XPS spectrum of the irradiated surface illustrated the presence of gold silicide at the irradiated surface. The generation of Si/Au-Si alloy fibrous nanoparticles aggregate is explained by the nucleation and subsequent condensation of vapor in the plasma plume during irradiation and expulsion of molten material due to high plasma pressure. PMID- 21711594 TI - Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine? AB - Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major forms of primary liver cancers (PLC), accounting for approximately 90% and 5% respectively. The incidence of each is increasing rapidly in the western world, however our knowledge of the underlying mechanisms remains limited and the outcome, dismal. The etiologies of each vary geographically; nevertheless, chronic inflammation has been identified in more than 80% of the cases and appears to be a key mediator in altering the liver microenvironment, increasing the risk of carcinogenesis. However, since not all HCC and especially ICC cases have a recognized risk factor, there are currently two proposed models for liver carcinogenesis. The clonal evolution model demonstrates a multi-step process of tumor development from precancerous lesions to metastatic carcinoma, arising from the accumulation of genetic and epigenetic changes in a cell in the setting of chronic inflammation. While the majority of cases do occur as a consequence of chronic inflammation, most individuals with chronic infection do not develop PLC, suggesting the involvement of individual genetic and environmental factors. Further, since hepatocytes and cholangiocytes both have regenerative potential and arise from the same bi-potential progenitor cell, the more recently proposed cancer stem cell model is gaining its due attention. The integration of these models and the constant improvement in molecular profiling platforms is enabling a broader understanding of the mechanisms underlying these two devastating malignancies, perhaps moving us closer to a new world of molecularly-informed personalized medicine. PMID- 21711596 TI - Effects of low-temperature capping on the optical properties of GaAs/AlGaAs quantum wells. AB - We study the effects of low-temperature capping (200-450 degrees C) on the optical properties of GaAs/AlGaAs quantum wells. Photoluminescence measurements clearly show the formation of abundant nonradiative recombination centers in an AlGaAs capping layer grown at 200 degrees C, while there is a slight degradation of the optical quality in AlGaAs capping layers grown at temperatures above 350 degrees C compared to that of a high-temperature capping layer. In addition, the optical quality can be restored by post-growth annealing without any structural change, except for the 200 degrees C-capped sample. PMID- 21711598 TI - A novel mechanical cleavage method for synthesizing few-layer graphenes. AB - A novel method to synthesize few layer graphene from bulk graphite by mechanical cleavage is presented here. The method involves the use of an ultrasharp single crystal diamond wedge to cleave a highly ordered pyrolytic graphite sample to generate the graphene layers. Cleaving is aided by the use of ultrasonic oscillations along the wedge. Characterization of the obtained layers shows that the process is able to synthesize graphene layers with an area of a few micrometers. Application of oscillation enhances the quality of the layers produced with the layers having a reduced crystallite size as determined from the Raman spectrum. Interesting edge structures are observed that needs further investigation. PMID- 21711597 TI - Properties of gold nanostructures sputtered on glass. AB - We studied the electrical and optical properties, density, and crystalline structure of Au nanostructures prepared by direct current sputtering on glass. We measured temperature dependence of sheet resistance and current-voltage characteristics and also performed scanning electron microscopy [SEM] analysis of gold nanolayers. It was shown that within the wide range of temperatures, gold nanolayers (<10 nm) exhibit both metal and semiconducting-like type of conductivity. UV/Vis analysis proved the semiconducting characteristic of intrinsic Au clusters. SEM analysis showed the initiatory stadium of gold layer formation to be running over isolated islands. Gold density calculated from the weight and effective thickness of the layers is an increasing function of the layer thickness up to approximately 100 nm. In thin layers deposited on solid surface, a lattice expansion is observed, which is manifested in the increase of the lattice parameter and the decrease of metal density. With increasing layer thickness, the lattice parameter and the density approach the bulk values. PMID- 21711599 TI - International Conference on Superlattices, Nanostructures and Nanodevices (ICSNN 2010). PMID- 21711600 TI - Size and temperature effects on the viscosity of water inside carbon nanotubes. AB - The influences of the diameter (size) of single-walled carbon nanotubes (SWCNTs) and the temperature on the viscosity of water confined in SWCNTs are investigated by an "Eyring-MD" (molecular dynamics) method. The results suggest that the relative viscosity of the confined water increases with increasing diameter and temperature, whereas the size-dependent trend of the relative viscosity is almost independent of the temperature. Based on the computational results, a fitting formula is proposed to calculate the size- and temperature- dependent water viscosity, which is useful for the computation on the nanoflow. To demonstrate the rationality of the calculated relative viscosity, the relative amount of the hydrogen bonds of water confined in SWCNTs is also computed. The results of the relative amount of the hydrogen bonds exhibit similar profiles with the curves of the relative viscosity. The present results should be instructive for understanding the coupling effect of the size and the temperature at the nanoscale. PMID- 21711601 TI - Investigation of cracks in GaN films grown by combined hydride and metal organic vapor-phase epitaxial method. AB - Cracks appeared in GaN epitaxial layers which were grown by a novel method combining metal organic vapor-phase epitaxy (MOCVD) and hydride vapor-phase epitaxy (HVPE) in one chamber. The origin of cracks in a 22-MUm thick GaN film was fully investigated by high-resolution X-ray diffraction (XRD), micro-Raman spectra, and scanning electron microscopy (SEM). Many cracks under the surface were first observed by SEM after etching for 10 min. By investigating the cross section of the sample with high-resolution micro-Raman spectra, the distribution of the stress along the depth was determined. From the interface of the film/substrate to the top surface of the film, several turnings were found. A large compressive stress existed at the interface. The stress went down as the detecting area was moved up from the interface to the overlayer, and it was maintained at a large value for a long depth area. Then it went down again, and it finally increased near the top surface. The cross-section of the film was observed after cleaving and etching for 2 min. It was found that the crystal quality of the healed part was nearly the same as the uncracked region. This indicated that cracking occurred in the growth, when the tensile stress accumulated and reached the critical value. Moreover, the cracks would heal because of high lateral growth rate. PMID- 21711602 TI - Silver nanowire-based transparent, flexible, and conductive thin film. AB - The fabrication of transparent, conductive, and uniform silver nanowire films using the scalable rod-coating technique is described in this study. Properties of the transparent conductive thin films are investigated, as well as the approaches to improve the performance of transparent silver nanowire electrodes. It is found that silver nanowires are oxidized during the coating process. Incubation in hydrogen chloride (HCl) vapor can eliminate oxidized surface, and consequently, reduce largely the resistivity of silver nanowire thin films. After HCl treatment, 175 Omega/sq and approximately 75% transmittance are achieved. The sheet resistivity drops remarkably with the rise of the film thickness or with the decrease of transparency. The thin film electrodes also demonstrated excellent flexible stability, showing < 2% resistance change after over 100 bending cycles. PMID- 21711603 TI - Europium-doped amorphous calcium phosphate porous nanospheres: preparation and application as luminescent drug carriers. AB - Calcium phosphate is the most important inorganic constituent of biological tissues, and synthetic calcium phosphate has been widely used as biomaterials. In this study, a facile method has been developed for the fabrication of amorphous calcium phosphate (ACP)/polylactide-block-monomethoxy(polyethyleneglycol) hybrid nanoparticles and ACP porous nanospheres. Europium-doping is performed to enable photoluminescence (PL) function of ACP porous nanospheres. A high specific surface area of the europium-doped ACP (Eu3+:ACP) porous nanospheres is achieved (126.7 m2/g). PL properties of Eu3+:ACP porous nanospheres are investigated, and the most intense peak at 612 nm is observed at 5 mol% Eu3+ doping. In vitro cytotoxicity experiments indicate that the as-prepared Eu3+:ACP porous nanospheres are biocompatible. In vitro drug release experiments indicate that the ibuprofen-loaded Eu3+:ACP porous nanospheres show a slow and sustained drug release in simulated body fluid. We have found that the cumulative amount of released drug has a linear relationship with the natural logarithm of release time (ln(t)). The Eu3+:ACP porous nanospheres are bioactive, and can transform to hydroxyapatite during drug release. The PL properties of drug-loaded nanocarriers before and after drug release are also investigated. PMID- 21711604 TI - Nanofluid bioconvection in water-based suspensions containing nanoparticles and oxytactic microorganisms: oscillatory instability. AB - The aim of this article is to propose a novel type of a nanofluid that contains both nanoparticles and motile (oxytactic) microorganisms. The benefits of adding motile microorganisms to the suspension include enhanced mass transfer, microscale mixing, and anticipated improved stability of the nanofluid. In order to understand the behavior of such a suspension at the fundamental level, this article investigates its stability when it occupies a shallow horizontal layer. The oscillatory mode of nanofluid bioconvection may be induced by the interaction of three competing agencies: oxytactic microorganisms, heating or cooling from the bottom, and top or bottom-heavy nanoparticle distribution. The model includes equations expressing conservation of total mass, momentum, thermal energy, nanoparticles, microorganisms, and oxygen. Physical mechanisms responsible for the slip velocity between the nanoparticles and the base fluid, such as Brownian motion and thermophoresis, are accounted for in the model. An approximate analytical solution of the eigenvalue problem is obtained using the Galerkin method. The obtained solution provides important physical insights into the behavior of this system; it also explains when the oscillatory mode of instability is possible in such system. PMID- 21711605 TI - Large-scale fabrication of ordered arrays of microcontainers and the restraint effect on growth of CuO nanowires. AB - Technique has been developed to fabricate ordered arrays of microcontainers. We report that ordered microcontainer arrays of Cu can be fabricated on glass substrate by thin film deposition and self-assembly technology. In addition, CuO nanowires are found to grow only in the inner sides of microcontainers, which verifies the stress growth mechanism of CuO nanowires. High-resolution transmission electron microscopy study reveals that CuO nanowires grow along the [110] direction. Such structure may have potential application in micro-electron sources, which have the self-focused function. PMID- 21711606 TI - Solvothermal synthesis of uniform bismuth nanospheres using poly(N-vinyl-2 pyrrolidone) as a reducing agent. AB - Uniform bismuth nanospheres were successfully prepared from bismuth nitrate in the presence of poly(N-vinyl-2-pyrrolidone) (PVP) by solvothermal process. The product was characterized by powder X-ray diffraction, scanning electron microscopy, transmission electron microscopy, selected area electron diffraction, and energy-dispersive X-ray. PVP plays a critical role both as a reducing agent and a capping agent in the formation of bismuth nanospheres. Shape and size of bismuth nanospheres could be tuned by changing the employed PVP/bismuth salt ratio. It was also found the solvent had an effect on the morphologies of bismuth nanomaterials. The possible formation and growth mechanism of bismuth nanospheres were also discussed and proposed to explain the reduction step. PMID- 21711607 TI - Two novel hierarchical homogeneous nanoarchitectures of TiO2 nanorods branched and P25-coated TiO2 nanotube arrays and their photocurrent performances. AB - We report here for the first time the synthesis of two novel hierarchical homogeneous nanoarchitectures of TiO2 nanorods branched TiO2 nanotube arrays (BTs) and P25-coated TiO2 nanotube arrays (PCTs) using two-step method including electrochemical anodization and hydrothermal modification process. Then the photocurrent densities versus applied potentials of BTs, PCTs, and pure TiO2 nanotube arrays (TNTAs) were investigated as well. Interestingly, at -0.11 V and under the same illumination condition, the photocurrent densities of BTs and PCTs show more than 1.5 and 1 times higher than that of pure TNTAs, respectively, which can be mainly attributed to significant improvement of the light-absorbing and charge-harvesting efficiency resulting from both larger and rougher surface areas of BTs and PCTs. Furthermore, these dramatic improvements suggest that BTs and PCTs will achieve better photoelectric conversion efficiency and become the promising candidates for applications in DSSCs, sensors, and photocatalysis. PMID- 21711608 TI - Electrical behavior of multi-walled carbon nanotube network embedded in amorphous silicon nitride. AB - The electrical behavior of multi-walled carbon nanotube network embedded in amorphous silicon nitride is studied by measuring the voltage and temperature dependences of the current. The microstructure of the network is investigated by cross-sectional transmission electron microscopy. The multi-walled carbon nanotube network has an uniform spatial extension in the silicon nitride matrix. The current-voltage and resistance-temperature characteristics are both linear, proving the metallic behavior of the network. The I-V curves present oscillations that are further analyzed by computing the conductance-voltage characteristics. The conductance presents minima and maxima that appear at the same voltage for both bias polarities, at both 20 and 298 K, and that are not periodic. These oscillations are interpreted as due to percolation processes. The voltage percolation thresholds are identified with the conductance minima. PMID- 21711609 TI - Morphology-dependent field emission properties and wetting behavior of ZnO nanowire arrays. AB - The fabrication of three kinds of ZnO nanowire arrays with different structural parameters over Au-coated silicon (100) by facile thermal evaporation of ZnS precursor is reported, and the growth mechanism are proposed based on structural analysis. Field emission (FE) properties and wetting behavior were revealed to be strongly morphology dependent. The nanowire arrays in small diameter and high aspect ratio exhibited the best FE performance showing a low turn-on field (4.1 V/MUm) and a high field-enhancement factor (1745.8). The result also confirmed that keeping large air within the films was an effective way to obtain super water-repellent properties. This study indicates that the preparation of ZnO nanowire arrays in an optimum structural model is crucial to FE efficiency and wetting behavior. PMID- 21711610 TI - Effect of sulfur on enhancing nitrogen-doping and magnetic properties of carbon nanotubes. AB - Sulfur (S) is introduced as an additive in the growth atmosphere of carbon nanotubes (CNTs) in the range of 940-1020 degrees C. CNT products with distorted sidewalls can be obtained by S-assisted growth. Moreover, many fascinating CNT structures can also be found in samples grown with S addition, such as bamboo like CNTs, twisted CNTs, arborization-like CNTs, and bead-like CNTs. Compared with CNTs grown without S, more nitrogen-doping content is achieved in CNTs with S addition, which is beneficial for the properties and applications of nitrogen doped CNTs. In addition, S can also enhance the encapsulation of ferromagnetic materials and thus improve the soft magnetic properties of CNTs, which is favorable to the applications of CNTs in the electromagnetic wave-absorbing and magnetic data storage areas. PMID- 21711611 TI - Temperature and electron density dependence of spin relaxation in GaAs/AlGaAs quantum well. AB - Temperature and carrier density-dependent spin dynamics for GaAs/AlGaAs quantum wells (QWs) with different structural symmetries have been studied by using time resolved Kerr rotation technique. The spin relaxation time is measured to be much longer for the symmetrically designed GaAs QW comparing with the asymmetrical one, indicating the strong influence of Rashba spin-orbit coupling on spin relaxation. D'yakonov-Perel' mechanism has been revealed to be the dominant contribution for spin relaxation in GaAs/AlGaAs QWs. The spin relaxation time exhibits non-monotonic-dependent behavior on both temperature and photo-excited carrier density, revealing the important role of non-monotonic temperature and density dependence of electron-electron Coulomb scattering. Our experimental observations demonstrate good agreement with recently developed spin relaxation theory based on microscopic kinetic spin Bloch equation approach. PMID- 21711612 TI - Core shell hybrids based on noble metal nanoparticles and conjugated polymers: synthesis and characterization. AB - Noble metal nanoparticles of different sizes and shapes combined with conjugated functional polymers give rise to advanced core shell hybrids with interesting physical characteristics and potential applications in sensors or cancer therapy. In this paper, a versatile and facile synthesis of core shell systems based on noble metal nanoparticles (AuNPs, AgNPs, PtNPs), coated by copolymers belonging to the class of substituted polyacetylenes has been developed. The polymeric shells containing functionalities such as phenyl, ammonium, or thiol pending groups have been chosen in order to tune hydrophilic and hydrophobic properties and solubility of the target core shell hybrids. The Au, Ag, or Pt nanoparticles coated by poly(dimethylpropargylamonium chloride), or poly(phenylacetylene-co allylmercaptan). The chemical structure of polymeric shell, size and size distribution and optical properties of hybrids have been assessed. The mean diameter of the metal core has been measured (about 10-30 nm) with polymeric shell of about 2 nm. PMID- 21711613 TI - Circular polarization in a non-magnetic resonant tunneling device. AB - We have investigated the polarization-resolved photoluminescence (PL) in an asymmetric n-type GaAs/AlAs/GaAlAs resonant tunneling diode under magnetic field parallel to the tunnel current. The quantum well (QW) PL presents strong circular polarization (values up to -70% at 19 T). The optical emission from GaAs contact layers shows evidence of highly spin-polarized two-dimensional electron and hole gases which affects the spin polarization of carriers in the QW. However, the circular polarization degree in the QW also depends on various other parameters, including the g-factors of the different layers, the density of carriers along the structure, and the Zeeman and Rashba effects. PMID- 21711614 TI - Metal-functionalized single-walled graphitic carbon nitride nanotubes: a first principles study on magnetic property. AB - The magnetic properties of metal-functionalized graphitic carbon nitride nanotubes were investigated based on first-principles calculations. The graphitic carbon nitride nanotube can be either ferromagnetic or antiferromagnetic by functionalizing with different metal atoms. The W- and Ti-functionalized nanotubes are ferromagnetic, which are attributed to carrier-mediated interactions because of the coupling between the spin-polarized d and p electrons and the formation of the impurity bands close to the band edges. However, Cr-, Mn , Co-, and Ni-functionalized nanotubes are antiferromagnetic because of the anti alignment of the magnetic moments between neighboring metal atoms. The functionalized nanotubes may be used in spintronics and hydrogen storage. PMID- 21711615 TI - Mono- and bi-functional arenethiols as surfactants for gold nanoparticles: synthesis and characterization. AB - Stable gold nanoparticles stabilized by different mono and bi-functional arenethiols, namely, benzylthiol and 1,4-benzenedimethanethiol, have been prepared by using a modified Brust's two-phase synthesis. The size, shape, and crystalline structure of the gold nanoparticles have been determined by high resolution electron microscopy and full-pattern X-ray powder diffraction analyses. Nanocrystals diameters have been tuned in the range 2 / 9 nm by a proper variation of Au/S molar ratio. The chemical composition of gold nanoparticles and their interaction with thiols have been investigated by X-ray photoelectron spectroscopy. In particular, the formation of networks has been observed with interconnected gold nanoparticles containing 1,4 benzenedimethanethiol as ligand. PMID- 21711616 TI - Preface to Symposium E: Nanoscaled Si, Ge based Materials. PMID- 21711617 TI - Polycrystallization effects on the nanoscale electrical properties of high-k dielectrics. AB - In this study, atomic force microscopy-related techniques have been used to investigate, at the nanoscale, how the polycrystallization of an Al2O3-based gate stack, after a thermal annealing process, affects the variability of its electrical properties. The impact of an electrical stress on the electrical conduction and the charge trapping of amorphous and polycrystalline Al2O3 layers have been also analyzed. PMID- 21711618 TI - Patterned growth of InGaN/GaN quantum wells on freestanding GaN grating by molecular beam epitaxy. AB - We report here the epitaxial growth of InGaN/GaN quantum wells on freestanding GaN gratings by molecular beam epitaxy (MBE). Various GaN gratings are defined by electron beam lithography and realized on GaN-on-silicon substrate by fast atom beam etching. Silicon substrate beneath GaN grating region is removed from the backside to form freestanding GaN gratings, and the patterned growth is subsequently performed on the prepared GaN template by MBE. The selective growth takes place with the assistance of nanoscale GaN gratings and depends on the grating period P and the grating width W. Importantly, coalescences between two side facets are realized to generate epitaxial gratings with triangular section. Thin epitaxial gratings produce the promising photoluminescence performance. This work provides a feasible way for further GaN-based integrated optics devices by a combination of GaN micromachining and epitaxial growth on a GaN-on-silicon substrate.PACS81.05.Ea; 81.65.Cf; 81.15.Hi. PMID- 21711619 TI - Nanoscale characterization of electrical transport at metal/3C-SiC interfaces. AB - In this work, the transport properties of metal/3C-SiC interfaces were monitored employing a nanoscale characterization approach in combination with conventional electrical measurements. In particular, using conductive atomic force microscopy allowed demonstrating that the stacking fault is the most pervasive, electrically active extended defect at 3C-SiC(111) surfaces, and it can be electrically passivated by an ultraviolet irradiation treatment. For the Au/3C-SiC Schottky interface, a contact area dependence of the Schottky barrier height (PhiB) was found even after this passivation, indicating that there are still some electrically active defects at the interface. Improved electrical properties were observed in the case of the Pt/3C-SiC system. In this case, annealing at 500 degrees C resulted in a reduction of the leakage current and an increase of the Schottky barrier height (from 0.77 to 1.12 eV). A structural analysis of the reaction zone carried out by transmission electron microscopy [TEM] and X-ray diffraction showed that the improved electrical properties can be attributed to a consumption of the surface layer of SiC due to silicide (Pt2Si) formation. The degradation of Schottky characteristics at higher temperatures (up to 900 degrees C) could be ascribed to the out-diffusion and aggregation of carbon into clusters, observed by TEM analysis. PMID- 21711620 TI - Synthesis of multi-walled carbon nanotube/polyhedral oligomeric silsesquioxane nanohybrid by utilizing click chemistry. AB - A new hybrid material consisting of a polyhedral oligomeric silsesquioxane (POSS) and carbon nanotube (CNT) was synthesized by a simple and versatile approach entailing click coupling between azide moiety-functionalized POSS and alkyne-functionalized multi-walled CNTs. This approach provides a simple and convenient route to efficiently functionalize a wide variety of nanoscale nanostructure materials on the surface of CNTs. PMID- 21711621 TI - Negative pressure characteristics of an evaporating meniscus at nanoscale. AB - This study aims at understanding the characteristics of negative liquid pressures at the nanoscale using molecular dynamics simulation. A nano-meniscus is formed by placing liquid argon on a platinum wall between two nano-channels filled with the same liquid. Evaporation is simulated in the meniscus by increasing the temperature of the platinum wall for two different cases. Non evaporating films are obtained at the center of the meniscus. The liquid film in the non-evaporating and adjacent regions is found to be under high absolute negative pressures. Cavitation cannot occur in these regions as the capillary height is smaller than the critical cavitation radius. Factors which determine the critical film thickness for rupture are discussed. Thus, high negative liquid pressures can be stable at the nanoscale, and utilized to create passive pumping devices as well as significantly enhance heat transfer rates. PMID- 21711622 TI - Advanced materials nanocharacterization. AB - This special issue of Nanoscale Research Letters contains scientific contributions presented at the Symposium D "Multidimensional Electrical and Chemical Characterization at the Nanometer-scale of Organic and Inorganic Semiconductors" of the E-MRS Fall Meeting 2010, which was held in Warsaw, Poland from 13th to 17th September, 2010. PMID- 21711623 TI - Conductive-probe atomic force microscopy characterization of silicon nanowire. AB - The electrical conduction properties of lateral and vertical silicon nanowires (SiNWs) were investigated using a conductive-probe atomic force microscopy (AFM). Horizontal SiNWs, which were synthesized by the in-plane solid-liquid-solid technique, are randomly deployed into an undoped hydrogenated amorphous silicon layer. Local current mapping shows that the wires have internal microstructures. The local current-voltage measurements on these horizontal wires reveal a power law behavior indicating several transport regimes based on space-charge limited conduction which can be assisted by traps in the high-bias regime (> 1 V). Vertical phosphorus-doped SiNWs were grown by chemical vapor deposition using a gold catalyst-driving vapor-liquid-solid process on higly n-type silicon substrates. The effect of phosphorus doping on the local contact resistance between the AFM tip and the SiNW was put in evidence, and the SiNWs resistivity was estimated. PMID- 21711625 TI - Rapid thermal annealing and crystallization mechanisms study of silicon nanocrystal in silicon carbide matrix. AB - In this paper, a positive effect of rapid thermal annealing (RTA) technique has been researched and compared with conventional furnace annealing for Si nanocrystalline in silicon carbide (SiC) matrix system. Amorphous Si-rich SiC layer has been deposited by co-sputtering in different Si concentrations (50 to approximately 80 v%). Si nanocrystals (Si-NC) containing different grain sizes have been fabricated within the SiC matrix under two different annealing conditions: furnace annealing and RTA both at 1,100 degrees C. HRTEM image clearly reveals both Si and SiC-NC formed in the films. Much better "degree of crystallization" of Si-NC can be achieved in RTA than furnace annealing from the research of GIXRD and Raman analysis, especially in high-Si-concentration situation. Differences from the two annealing procedures and the crystallization mechanism have been discussed based on the experimental results. PMID- 21711624 TI - Doping graphene films via chemically mediated charge transfer. AB - Transparent conductive films (TCFs) are critical components of a myriad of technologies including flat panel displays, light-emitting diodes, and solar cells. Graphene-based TCFs have attracted a lot of attention because of their high electrical conductivity, transparency, and low cost. Carrier doping of graphene would potentially improve the properties of graphene-based TCFs for practical industrial applications. However, controlling the carrier type and concentration of dopants in graphene films is challenging, especially for the synthesis of p-type films. In this article, a new method for doping graphene using the conjugated organic molecule, tetracyanoquinodimethane (TCNQ), is described. Notably, TCNQ is well known as a powerful electron accepter and is expected to favor electron transfer from graphene into TCNQ molecules, thereby leading to p-type doping of graphene films. Small amounts of TCNQ drastically improved the resistivity without degradation of optical transparency. Our carrier doping method based on charge transfer has a huge potential for graphene-based TCFs. PMID- 21711626 TI - Synthesis and magnetic properties of single-crystalline Na2-xMn8O16 nanorods. AB - The synthesis of single-crystalline hollandite-type manganese oxides Na2-xMn8O16 nanorods by a simple molten salt method is reported for the first time. The nanorods were characterized by powder X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and a superconducting quantum interference device magnetometer. The magnetic measurements indicated that the nanorods showed spin glass behavior and exchange bias effect at low temperatures. The low-temperature magnetic behaviors can be explained by the uncompensated spins on the surface of the nanorods. PMID- 21711627 TI - Coherent magnetic semiconductor nanodot arrays. AB - In searching appropriate candidates of magnetic semiconductors compatible with mainstream Si technology for future spintronic devices, extensive attention has been focused on Mn-doped Ge magnetic semiconductors. Up to now, lack of reliable methods to obtain high-quality MnGe nanostructures with a desired shape and a good controllability has been a barrier to make these materials practically applicable for spintronic devices. Here, we report, for the first time, an innovative growth approach to produce self-assembled and coherent magnetic MnGe nanodot arrays with an excellent reproducibility. Magnetotransport experiments reveal that the nanodot arrays possess giant magneto-resistance associated with geometrical effects. The discovery of the MnGe nanodot arrays paves the way towards next-generation high-density magnetic memories and spintronic devices with low-power dissipation. PMID- 21711628 TI - Improvement of performance of InAs quantum dot solar cell by inserting thin AlAs layers. AB - A new measure to enhance the performance of InAs quantum dot solar cell is proposed and measured. One monolayer AlAs is deposited on top of InAs quantum dots (QDs) in multistack solar cells. The devices were fabricated by molecular beam epitaxy. In situ annealing was intended to tune the QD density. A set of four samples were compared: InAs QDs without in situ annealing with and without AlAs cap layer and InAs QDs in situ annealed with and without AlAs cap layer. Atomic force microscopy measurements show that when in situ annealing of QDs without AlAs capping layers is investigated, holes and dashes are present on the device surface, while capping with one monolayer AlAs improves the device surface. On unannealed samples, capping the QDs with one monolayer of AlAs improves the spectral response, the open-circuit voltage and the fill factor. On annealed samples, capping has little effect on the spectral response but reduces the short-circuit current, while increasing the open-circuit voltage, the fill factor and power conversion efficiency. PMID- 21711629 TI - A cylindrical core-shell-like TiO2 nanotube array anode for flexible fiber-type dye-sensitized solar cells. AB - A versatile anodization method was reported to anodize Ti wires into cylindrical core-shell-like and thermally crystallized TiO2 nanotube (TNT) arrays that can be directly used as the photoanodes for semi- and all-solid fiber-type dye sensitized solar cells (F-DSSC). Both F-DSSCs showed higher power conversion efficiencies than or competitive to those of previously reported counterparts fabricated by depositing TiO2 particles onto flexible substrates. The substantial enhancement is presumably attributed to the reduction of grain boundaries and defects in the prepared TNT anodes, which may suppress the recombination of the generated electrons and holes, and accordingly lead to more efficient carrier transfer channels. PMID- 21711630 TI - GaInNAs-based Hellish-vertical cavity semiconductor optical amplifier for 1.3 MUm operation. AB - Hot electron light emission and lasing in semiconductor heterostructure (Hellish) devices are surface emitters the operation of which is based on the longitudinal injection of electrons and holes in the active region. These devices can be designed to be used as vertical cavity surface emitting laser or, as in this study, as a vertical cavity semiconductor optical amplifier (VCSOA). This study investigates the prospects for a Hellish VCSOA based on GaInNAs/GaAs material for operation in the 1.3-MUm wavelength range. Hellish VCSOAs have increased functionality, and use undoped distributed Bragg reflectors; and this coupled with direct injection into the active region is expected to yield improvements in the gain and bandwidth. The design of the Hellish VCSOA is based on the transfer matrix method and the optical field distribution within the structure, where the determination of the position of quantum wells is crucial. A full assessment of Hellish VCSOAs has been performed in a device with eleven layers of Ga0.35In0.65N0.02As0.08/GaAs quantum wells (QWs) in the active region. It was characterised through I-V, L-V and by spectral photoluminescence, electroluminescence and electro-photoluminescence as a function of temperature and applied bias. Cavity resonance and gain peak curves have been calculated at different temperatures. Good agreement between experimental and theoretical results has been obtained. PMID- 21711631 TI - Special issue on nanofluids. PMID- 21711632 TI - Properties of silicon dioxide layers with embedded metal nanocrystals produced by oxidation of Si:Me mixture. AB - A two-dimensional layers of metal (Me) nanocrystals embedded in SiO2 were produced by pulsed laser deposition of uniformly mixed Si:Me film followed by its furnace oxidation and rapid thermal annealing. The kinetics of the film oxidation and the structural properties of the prepared samples were investigated by Rutherford backscattering spectrometry, and transmission electron microscopy, respectively. The electrical properties of the selected SiO2:Me nanocomposite films were evaluated by measuring C-V and I-V characteristics on a metal-oxide semiconductor stack. It is found that Me segregation induced by Si:Me mixture oxidation results in the formation of a high density of Me and silicide nanocrystals in thin film SiO2 matrix. Strong evidence of oxidation temperature as well as impurity type effect on the charge storage in crystalline Me-nanodot layer is demonstrated by the hysteresis behavior of the high-frequency C-V curves. PMID- 21711633 TI - Inorganic nanotubes reinforced polyvinylidene fluoride composites as low-cost electromagnetic interference shielding materials. AB - Novel polymer nanocomposites comprising of MnO2 nanotubes (MNTs), functionalized multiwalled carbon nanotubes (f-MWCNTs), and polyvinylidene fluoride (PVDF) were synthesized. Homogeneous distribution of f-MWCNTs and MNTs in PVDF matrix were confirmed by field emission scanning electron microscopy. Electrical conductivity measurements were performed on these polymer composites using four probe technique. The addition of 2 wt.% of MNTs (2 wt.%, f-MWCNTs) to PVDF matrix results in an increase in the electrical conductivity from 10-16S/m to 4.5 * 10 5S/m (3.2 * 10-1S/m). Electromagnetic interference shielding effectiveness (EMI SE) was measured with vector network analyzer using waveguide sample holder in X band frequency range. EMI SE of approximately 20 dB has been obtained with the addition of 5 wt.% MNTs-1 wt.% f-MWCNTs to PVDF in comparison with EMI SE of approximately 18 dB for 7 wt.% of f-MWCNTs indicating the potential use of the present MNT/f-MWCNT/PVDF composite as low-cost EMI shielding materials in X-band region. PMID- 21711634 TI - Luminescence of colloidal CdSe/ZnS nanoparticles: high sensitivity to solvent phase transitions. AB - We investigate nanosecond photoluminescence processes in colloidal core/shell CdSe/ZnS nanoparticles dissolved in water and found strong sensitivity of luminescence to the solvent state. Several pronounced changes have been observed in the narrow temperature interval near the water melting point. First of all, the luminescence intensity substantially (approximately 50%) increases near the transition. In a large temperature scale, the energy peak of the photoluminescence decreases with temperature due to temperature dependence of the energy gap. Near the melting point, the peak shows N-type dependence with the maximal changes of approximately 30 meV. The line width increases with temperature and also shows N-type dependence near the melting point. The observed effects are associated with the reconstruction of ligands near the ice/water phase transition. PMID- 21711635 TI - Scanning tip measurement for identification of point defects. AB - Self-assembled iron-silicide nanostructures were prepared by reactive deposition epitaxy of Fe onto silicon. Capacitance-voltage, current-voltage, and deep level transient spectroscopy (DLTS) were used to measure the electrical properties of Au/silicon Schottky junctions. Spreading resistance and scanning probe capacitance microscopy (SCM) were applied to measure local electrical properties. Using a preamplifier the sensitivity of DLTS was increased satisfactorily to measure transients of the scanning tip semiconductor junction. In the Fe deposited area, Fe-related defects dominate the surface layer in about 0.5 MUm depth. These defects deteriorated the Schottky junction characteristic. Outside the Fe-deposited area, Fe-related defect concentration was identified in a thin layer near the surface. The defect transients in this area were measured both in macroscopic Schottky junctions and by scanning tip DLTS and were detected by bias modulation frequency dependence in SCM. PMID- 21711636 TI - Dispersion of single-walled carbon nanotubes modified with poly-l-tyrosine in water. AB - In this study, complexes composed of poly-l-tyrosine (pLT) and single-walled carbon nanotubes (SWCNTs) were produced and the dispersibility of the pLT/SWCNT complexes in water by measuring the zeta potential of the complexes and the turbidity of the solution were investigated. It is found that the absolute value of the zeta potential of the pLT/SWCNT complexes is as high as that of SWCNTs modified with double-stranded DNA (dsDNA) and that the complexes remain stably dispersed in the water at least for two weeks. Thermogravimetry analysis (TGA) and visualization of the surface structures of pLT/SWCNT complexes using an atomic force microscope (AFM) were also carried out. PMID- 21711637 TI - On the direct insulator-quantum Hall transition in two-dimensional electron systems in the vicinity of nanoscaled scatterers. AB - A direct insulator-quantum Hall (I-QH) transition corresponds to a crossover/transition from the insulating regime to a high Landau level filling factor nu > 2 QH state. Such a transition has been attracting a great deal of both experimental and theoretical interests. In this study, we present three different two-dimensional electron systems (2DESs) which are in the vicinity of nanoscaled scatterers. All these three devices exhibit a direct I-QH transition, and the transport properties under different nanaoscaled scatterers are discussed. PMID- 21711638 TI - Discussion on the thermal conductivity enhancement of nanofluids. AB - Increasing interests have been paid to nanofluids because of the intriguing heat transfer enhancement performances presented by this kind of promising heat transfer media. We produced a series of nanofluids and measured their thermal conductivities. In this article, we discussed the measurements and the enhancements of the thermal conductivity of a variety of nanofluids. The base fluids used included those that are most employed heat transfer fluids, such as deionized water (DW), ethylene glycol (EG), glycerol, silicone oil, and the binary mixture of DW and EG. Various nanoparticles (NPs) involving Al2O3 NPs with different sizes, SiC NPs with different shapes, MgO NPs, ZnO NPs, SiO2 NPs, Fe3O4 NPs, TiO2 NPs, diamond NPs, and carbon nanotubes with different pretreatments were used as additives. Our findings demonstrated that the thermal conductivity enhancements of nanofluids could be influenced by multi-faceted factors including the volume fraction of the dispersed NPs, the tested temperature, the thermal conductivity of the base fluid, the size of the dispersed NPs, the pretreatment process, and the additives of the fluids. The thermal transport mechanisms in nanofluids were further discussed, and the promising approaches for optimizing the thermal conductivity of nanofluids have been proposed. PMID- 21711639 TI - Ag nanoparticles/PPV composite nanofibers with high and sensitive opto-electronic response. AB - The novel Ag nanoparticles/poly(p-phenylene vinylene) [PPV] composite nanofibers were prepared by electrospinning. The transmission electron microscope image shows that the average diameter of composite fibers is about 500 nm and Ag nanoparticles are uniformly dispersed in the PPV matrix with an average diameter of about 25 nm. The Fourier transform infrared spectra suggest that there could be a coordination effect to a certain extent between the Ag atom and the pi system of PPV, which is significantly favorable for the dissociation of photoexcitons and the charge transfer at the interface between the Ag nanoparticle and the PPV. The Au top electrode device of the single Ag/PPV composite nanofiber exhibits high and sensitive opto-electronic responses. Under light illumination of 5.76 mW/cm2 and voltage of 20 V, the photocurrent is over three times larger than the dark current under same voltage, which indicates that this kind of composite fiber is an excellent opto-electronic nanomaterial. PMID- 21711640 TI - Supported quantum clusters of silver as enhanced catalysts for reduction. AB - Quantum clusters (QCs) of silver such as Ag7(H2MSA)7, Ag8(H2MSA)8 (H2MSA, mercaptosuccinic acid) were synthesized by the interfacial etching of Ag nanoparticle precursors and were loaded on metal oxide supports to prepare active catalysts. The supported clusters were characterized using high resolution transmission electron microscopy, scanning electron microscopy, X-ray photoelectron spectroscopy, and laser desorption ionization mass spectrometry. We used the conversion of nitro group to amino group as a model reaction to study the catalytic reduction activity of the QCs. Various aromatic nitro compounds, namely, 3-nitrophenol (3-np), 4-nitrophenol (4-np), 3-nitroaniline (3-na), and 4 nitroaniline (4-na) were used as substrates. Products were confirmed using UV visible spectroscopy and electrospray ionization mass spectrometry. The supported QCs remained active and were reused several times after separation. The rate constant suggested that the reaction followed pseudo-first-order kinetics. The turn-over frequency was 1.87 s-1 per cluster for the reduction of 4-np at 35 degrees C. Among the substrates investigated, the kinetics followed the order, SiO2 > TiO2 > Fe2O3 > Al2O3. PMID- 21711641 TI - Efficient manganese luminescence induced by Ce3+-Mn2+ energy transfer in rare earth fluoride and phosphate nanocrystals. AB - Manganese materials with attractive optical properties have been proposed for applications in such areas as photonics, light-emitting diodes, and bioimaging. In this paper, we have demonstrated multicolor Mn2+ luminescence in the visible region by controlling Ce3+-Mn2+ energy transfer in rare earth nanocrystals [NCs]. CeF3 and CePO4 NCs doped with Mn2+ have been prepared and can be well dispersed in aqueous solutions. Under ultraviolet light excitation, both the CeF3:Mn and CePO4:Mn NCs exhibit Mn2+ luminescence, yet their output colors are green and orange, respectively. By optimizing Mn2+ doping concentrations, Mn2+ luminescence quantum efficiency and Ce3+-Mn2+ energy transfer efficiency can respectively reach 14% and 60% in the CeF3:Mn NCs. PMID- 21711642 TI - On the nature of the stretched exponential photoluminescence decay for silicon nanocrystals. AB - The influence of hydrogen rate on optical properties of silicon nanocrystals deposited by sputtering method was studied by means of time-resolved photoluminescence spectroscopy as well as transmission and reflection measurements. It was found that photoluminescence decay is strongly non-single exponential and can be described by the stretched exponential function. It was also shown that effective decay rate probability density function may be recovered by means of Stehfest algorithm. Moreover, it was proposed that the observed broadening of obtained decay rate distributions reflects the disorder in the samples. PMID- 21711643 TI - Lateral homogeneity of the electronic properties in pristine and ion-irradiated graphene probed by scanning capacitance spectroscopy. AB - In this article, a scanning probe method based on nanoscale capacitance measurements was used to investigate the lateral homogeneity of the electron mean free path both in pristine and ion-irradiated graphene. The local variations in the electronic transport properties were explained taking into account the scattering of electrons by charged impurities and point defects (vacancies). Electron mean free path is mainly limited by charged impurities in unirradiated graphene, whereas an important role is played by lattice vacancies after irradiation. The local density of the charged impurities and vacancies were determined for different irradiated ion fluences. PMID- 21711644 TI - Aggregate of nanoparticles: rheological and mechanical properties. AB - The understanding of the rheological and mechanical properties of nanoparticle aggregates is important for the application of nanofillers in nanocompoistes. In this work, we report a rheological study on the rheological and mechanical properties of nano-silica agglomerates in the form of gel network mainly constructed by hydrogen bonds. The elastic model for rubber is modified to analyze the elastic behavior of the agglomerates. By this modified elastic model, the size of the network mesh can be estimated by the elastic modulus of the network which can be easily obtained by rheology. The stress to destroy the aggregates, i.e., the yield stress (sigmay), and the elastic modulus (G') of the network are found to be depended on the concentration of nano-silica (phi, wt.%) with the power of 4.02 and 3.83, respectively. Via this concentration dependent behavior, we can extrapolate two important mechanical parameters for the agglomerates in a dense packing state (phi = 1): the shear modulus and the yield stress. Under large deformation (continuous shear flow), the network structure of the aggregates will experience destruction and reconstruction, which gives rise to fluctuations in the viscosity and a shear-thinning behavior. PMID- 21711645 TI - Synthesis of long group IV semiconductor nanowires by molecular beam epitaxy. AB - We report the growth of Si and Ge nanowires (NWs) on a Si(111) surface by molecular beam epitaxy. While Si NWs grow perpendicular to the surface, two types of growth axes are found for the Ge NWs. Structural studies of both types of NWs performed with electron microscopies reveal a marked difference between the roughnesses of their respective sidewalls. As the investigation of their length dependence on their diameter indicates that the growth of the NWs predominantly proceeds through the diffusion of adatoms from the substrate up along the sidewalls, difference in the sidewall roughness qualitatively explains the length variation measured between both types of NWs. The formation of atomically flat {111} sidewalls on the <110>-oriented Ge NWs accounts for a larger diffusion length. PMID- 21711646 TI - Scanning Probe Microscopy on heterogeneous CaCu3Ti4O12 thin films. AB - The conductive atomic force microscopy provided a local characterization of the dielectric heterogeneities in CaCu3Ti4O12 (CCTO) thin films deposited by MOCVD on IrO2 bottom electrode. In particular, both techniques have been employed to clarify the role of the inter- and sub-granular features in terms of conductive and insulating regions. The microstructure and the dielectric properties of CCTO thin films have been studied and the evidence of internal barriers in CCTO thin films has been provided. The role of internal barriers and the possible explanation for the extrinsic origin of the giant dielectric response in CCTO has been evaluated. PMID- 21711647 TI - Spin effects in InAs self-assembled quantum dots. AB - We have studied the polarized resolved photoluminescence in an n-type resonant tunneling diode (RTD) of GaAs/AlGaAs which incorporates a layer of InAs self assembled quantum dots (QDs) in the center of a GaAs quantum well (QW). We have observed that the QD circular polarization degree depends on applied voltage and light intensity. Our results are explained in terms of the tunneling of minority carriers into the QW, carrier capture by InAs QDs and bias-controlled density of holes in the QW. PMID- 21711648 TI - The role of the surfaces in the photon absorption in Ge nanoclusters embedded in silica. AB - The usage of semiconductor nanostructures is highly promising for boosting the energy conversion efficiency in photovoltaics technology, but still some of the underlying mechanisms are not well understood at the nanoscale length. Ge quantum dots (QDs) should have a larger absorption and a more efficient quantum confinement effect than Si ones, thus they are good candidate for third generation solar cells. In this work, Ge QDs embedded in silica matrix have been synthesized through magnetron sputtering deposition and annealing up to 800 degrees C. The thermal evolution of the QD size (2 to 10 nm) has been followed by transmission electron microscopy and X-ray diffraction techniques, evidencing an Ostwald ripening mechanism with a concomitant amorphous-crystalline transition. The optical absorption of Ge nanoclusters has been measured by spectrophotometry analyses, evidencing an optical bandgap of 1.6 eV, unexpectedly independent of the QDs size or of the solid phase (amorphous or crystalline). A simple modeling, based on the Tauc law, shows that the photon absorption has a much larger extent in smaller Ge QDs, being related to the surface extent rather than to the volume. These data are presented and discussed also considering the outcomes for application of Ge nanostructures in photovoltaics.PACS: 81.07.Ta; 78.67.Hc; 68.65.-k. PMID- 21711649 TI - Crystal and electronic structure of PbTe/CdTe nanostructures. AB - In this article, the authors reported a theoretical study of structural and electronic properties of PbTe inclusions in CdTe matrix as well as CdTe nano clusters in PbTe matrix. The structural properties are studied by ab initio methods. A tight-binding model is constructed to calculate the electron density of states (DOS) of the systems. In contrast to the ab initio methods, the latter allows studying nanostructures with diameters comparable to the real ones. The calculations show that both kinds of inclusions lead to changes of the DOS of the carriers near the Fermi level, which may affect optical, electrical and thermoelectric properties of the material. These changes depend on the size, shape, and concentration of inclusions. PMID- 21711650 TI - Single-crystalline nanoporous Nb2O5 nanotubes. AB - Single-crystalline nanoporous Nb2O5 nanotubes were fabricated by a two-step solution route, the growth of uniform single-crystalline Nb2O5 nanorods and the following ion-assisted selective dissolution along the [001] direction. Nb2O5 tubular structure was created by preferentially etching (001) crystallographic planes, which has a nearly homogeneous diameter and length. Dense nanopores with the diameters of several nanometers were created on the shell of Nb2O5 tubular structures, which can also retain the crystallographic orientation of Nb2O5 precursor nanorods. The present chemical etching strategy is versatile and can be extended to different-sized nanorod precursors. Furthermore, these as-obtained nanorod precursors and nanotube products can also be used as template for the fabrication of 1 D nanostructured niobates, such as LiNbO3, NaNbO3, and KNbO3. PMID- 21711651 TI - Strain-induced high ferromagnetic transition temperature of MnAs epilayer grown on GaAs (110). AB - MnAs films are grown on GaAs surfaces by molecular beam epitaxy. Specular and grazing incidence X-ray diffractions are used to study the influence of different strain states of MnAs/GaAs (110) and MnAs/GaAs (001) on the first-order magnetostructural phase transition. It comes out that the first-order magnetostructural phase transition temperature Tt, at which the remnant magnetization becomes zero, is strongly affected by the strain constraint from different oriented GaAs substrates. Our results show an elevated Tt of 350 K for MnAs films grown on GaAs (110) surface, which is attributed to the effect of strain constraint from different directions.PACS: 68.35.Rh, 61.50.Ks, 81.15.Hi, 07.85.Qe. PMID- 21711652 TI - Prolate spheroidal hematite particles equatorially belt with drug-carrying layered double hydroxide disks: Ring Nebula-like nanocomposites. AB - A new nanocomposite architecture is reported which combines prolate spheroidal hematite nanoparticles with drug-carrying layered double hydroxide [LDH] disks in a single structure. Spindle-shaped hematite nanoparticles with average length of 225 nm and width of 75 nm were obtained by thermal decomposition of hydrothermally synthesized hematite. The particles were first coated with Mg-Al NO3-LDH shell and then subjected to anion exchange with salicylate ions. The resulting bio-nanohybrid displayed a close structural resemblance to that of the Ring Nebula. Scanning electron microscope and transmission electron microscopy images showed that the LDH disks are stacked around the equatorial part of the ellipsoid extending along the main axis. This geometry possesses great structural tunability as the composition of the LDH and the nature of the interlayer region can be tailored and lead to novel applications in areas ranging from functional materials to medicine by encapsulating various guest molecules. PMID- 21711653 TI - Superlattices: problems and new opportunities, nanosolids. AB - Superlattices were introduced 40 years ago as man-made solids to enrich the class of materials for electronic and optoelectronic applications. The field metamorphosed to quantum wells and quantum dots, with ever decreasing dimensions dictated by the technological advancements in nanometer regime. In recent years, the field has gone beyond semiconductors to metals and organic solids. Superlattice is simply a way of forming a uniform continuum for whatever purpose at hand. There are problems with doping, defect-induced random switching, and I/O involving quantum dots. However, new opportunities in component-based nanostructures may lead the field of endeavor to new heights. The all important translational symmetry of solids is relaxed and local symmetry is needed in nanosolids. PMID- 21711654 TI - Carbon nanotubes: are they dispersed or dissolved in liquids? AB - Carbon nanotubes (CNTs) constitute a novel class of nanomaterials with remarkable applications in diverse domains. However, the main intrincsic problem of CNTs is their insolubility or very poor solubility in most of the common solvents. The basic key question here is: are carbon nanotubes dissolved or dispersed in liquids, specifically in water? When analyzing the scientific research articles published in various leading journals, we found that many researchers confused between "dispersion" and "solubilization" and use the terms interchangeably, particularly when stating the interaction of CNTs with liquids. In this article, we address this fundamental issue to give basic insight specifically to the researchers who are working with CNTs as well asgenerally to scientists who deal with nano-related research domains. PMID- 21711655 TI - Near-surface processing on AlGaN/GaN heterostructures: a nanoscale electrical and structural characterization. AB - The effects of near-surface processing on the properties of AlGaN/GaN heterostructures were studied, combining conventional electrical characterization on high-electron mobility transistors (HEMTs), with advanced characterization techniques with nanometer scale resolution, i.e., transmission electron microscopy, atomic force microscopy (AFM) and conductive atomic force microscopy (C-AFM). In particular, a CHF3-based plasma process in the gate region resulted in a shift of the threshold voltage in HEMT devices towards less negative values. Two-dimensional current maps acquired by C-AFM on the sample surface allowed us to monitor the local electrical modifications induced by the plasma fluorine incorporated in the material.The results are compared with a recently introduced gate control processing: the local rapid thermal oxidation process of the AlGaN layer. By this process, a controlled thin oxide layer on surface of AlGaN can be reliably introduced while the resistance of the layer below increase locally. PMID- 21711656 TI - A delta-doped quantum well system with additional modulation doping. AB - A delta-doped quantum well with additional modulation doping may have potential applications. Utilizing such a hybrid system, it is possible to experimentally realize an extremely high two-dimensional electron gas (2DEG) density without suffering inter-electronic-subband scattering. In this article, the authors report on transport measurements on a delta-doped quantum well system with extra modulation doping. We have observed a 0-10 direct insulator-quantum Hall (I-QH) transition where the numbers 0 and 10 correspond to the insulator and Landau level filling factor nu = 10 QH state, respectively. In situ titled-magnetic field measurements reveal that the observed direct I-QH transition depends on the magnetic component perpendicular to the quantum well, and the electron system within this structure is 2D in nature. Furthermore, transport measurements on the 2DEG of this study show that carrier density, resistance and mobility are approximately temperature (T)-independent over a wide range of T. Such results could be an advantage for applications in T-insensitive devices. PMID- 21711657 TI - Facile purification of colloidal NIR-responsive gold nanorods using ions assisted self-assembly. AB - Anisotropic metal nanoparticles have been paid much attention because the broken symmetry of these nanoparticles often leads to novel properties. Anisotropic gold nanoparticles obtained by wet chemical methods inevitably accompany spherical ones due to the intrinsically high symmetry of face-centred cubic metal. Therefore, it is essential for the purification of anisotropic gold nanoparticles. This work presents a facile, low cost while effective solution to the challenging issue of high-purity separation of seed-mediated grown NIR responsive gold nanorods from co-produced spherical and cubic nanoparticles in solution. The key point of our strategy lies in different shape-dependent solution stability between anisotropic nanoparticles and symmetric ones and selective self-assembly and subsequent precipitation can be induced by introducing ions to the as-made nanorod solution. As a result, gold nanorods of excellent purity (97% in number density) have been obtained within a short time, which has been confirmed by SEM observation and UV-vis-NIR spectroscopy respectively. Based on the experimental facts, a possible shape separation mechanism was also proposed. PMID- 21711658 TI - Characterization of silicon heterojunctions for solar cells. AB - Conductive-probe atomic force microscopy (CP-AFM) measurements reveal the existence of a conductive channel at the interface between p-type hydrogenated amorphous silicon (a-Si:H) and n-type crystalline silicon (c-Si) as well as at the interface between n-type a-Si:H and p-type c-Si. This is in good agreement with planar conductance measurements that show a large interface conductance. It is demonstrated that these features are related to the existence of a strong inversion layer of holes at the c-Si surface of (p) a-Si:H/(n) c-Si structures, and to a strong inversion layer of electrons at the c-Si surface of (n) a Si:H/(p) c-Si heterojunctions. These are intimately related to the band offsets, which allows us to determine these parameters with good precision. PMID- 21711659 TI - Ion beam-induced shaping of Ni nanoparticles embedded in a silica matrix: from spherical to prolate shape. AB - Present work reports the elongation of spherical Ni nanoparticles (NPs) parallel to each other, due to bombardment with 120 MeV Au+9 ions at a fluence of 5 * 1013 ions/cm2. The Ni NPs embedded in silica matrix have been prepared by atom beam sputtering technique and subsequent annealing. The elongation of Ni NPs due to interaction with Au+9 ions as investigated by cross-sectional transmission electron microscopy (TEM) shows a strong dependence on initial Ni particle size and is explained on the basis of thermal spike model. Irradiation induces a change from single crystalline nature of spherical particles to polycrystalline nature of elongated particles. Magnetization measurements indicate that changes in coercivity (Hc) and remanence ratio (Mr/Ms) are stronger in the ion beam direction due to the preferential easy axis of elongated particles in the beam direction. PMID- 21711660 TI - Confined conversion of CuS nanowires to CuO nanotubes by annealing-induced diffusion in nanochannels. AB - Copper oxide (CuO) nanotubes were successfully converted from CuS nanowires embedded in anodic aluminum oxide (AAO) template by annealing-induced diffusion in a confined tube-type space. The spreading of CuO and formation of CuO layer on the nanochannel surface of AAO, and the confinement offered by AAO nanochannels play a key role in the formation of CuO nanotubes. PMID- 21711661 TI - New Si-based multilayers for solar cell applications. AB - In this article, we have fabricated and studied a new multilayer structure Si SiO2/SiNx by reactive magnetron sputtering. The comparison between SiO2 and SiNx host matrices in the optical properties of the multilayers is detailed. Structural analysis was made on the multilayer structures using Fourier transform infrared spectroscopy. The effect of specific annealing treatments on the optical properties is studied and we report a higher visible luminescence with a control over the thermal budget when SiO2 is replaced by the SiNx matrix. The latter seems to be a potential candidate to replace the most sought SiO2 host matrix. PMID- 21711662 TI - Room temperature spin diffusion in (110) GaAs/AlGaAs quantum wells. AB - Transient spin grating experiments are used to investigate the electron spin diffusion in intrinsic (110) GaAs/AlGaAs multiple quantum well at room temperature. The measured spin diffusion length of optically excited electrons is about 4 MUm at low spin density. Increasing the carrier density yields both a decrease of the spin relaxation time and the spin diffusion coefficient Ds. PMID- 21711663 TI - Ultraviolet photodetectors based on ZnO nanorods-seed layer effect and metal oxide modifying layer effect. AB - Pt/ZnO nanorod (NR) and Pt/modified ZnO NR Schottky barrier ultraviolet (UV) photodetectors (PDs) were prepared with different seed layers and metal oxide modifying layer materials. In this paper, we discussed the effect of metal oxide modifying layer on the performance of UV PDs pre- and post-deposition annealing at 300 degrees C, respectively. For Schottky barrier UV PDs with different seed layers, the MgZnO seed layer-PDs without metal oxide coating showed bigger responsivity and larger detectivity (Dlambda*) than those of PDs with ZnO seed layer, and the reason was illustrated through energy band theory and the electron transport mechanism. Also the ratio of D254* to D546* was calculated above 8 * 102 for all PDs, which demonstrated that our PDs showed high selectivity for detecting UV light with less influence of light with long wavelength. PMID- 21711664 TI - Impact of AFM-induced nano-pits in a-Si:H films on silicon crystal growth. AB - Conductive tips in atomic force microscopy (AFM) can be used to localize field enhanced metal-induced solid-phase crystallization (FE-MISPC) of amorphous silicon (a-Si:H) at room temperature down to nanoscale dimensions. In this article, the authors show that such local modifications can be used to selectively induce further localized growth of silicon nanocrystals. First, a Si:H films by plasma-enhanced chemical vapor deposition on nickel/glass substrates are prepared. After the FE-MISPC process, yielding both conductive and non-conductive nano-pits in the films, the second silicon layer at the boundary condition of amorphous and microcrystalline growth is deposited. Comparing AFM morphology and current-sensing AFM data on the first and second layers, it is observed that the second deposition changes the morphology and increases the local conductivity of FE-MISPC-induced pits by up to an order of magnitude irrespective of their prior conductivity. This is attributed to the silicon nanocrystals (<100 nm) that tend to nucleate and grow inside the pits. This is also supported by micro-Raman spectroscopy. PMID- 21711665 TI - Selective patterning of ZnO nanorods on silicon substrates using nanoimprint lithography. AB - In this research, nanoimprint lithography (NIL) was used for patterning crystalline zinc oxide (ZnO) nanorods on the silicon substrate. To fabricate nano patterned ZnO nanorods, patterning of an n-octadecyltrichlorosilane (OTS) self assembled monolayers (SAMs) on SiO2 substrate was prepared by the polymer mask using NI. The ZnO seed layer was selectively coated only on the hydrophilic SiO2 surface, not on the hydrophobic OTS SAMs surface. The substrate patterned with the ZnO seed layer was treated with the oxygen plasma to oxidize the silicon surface. It was found that the nucleation and initial growth of the crystalline ZnO were proceeded only on the ZnO seed layer, not on the silicon oxide surface. ZnO photoluminescence spectra showed that ZnO nanorods grown from the seed layer treated with plasma showed lower intensity than those untreated with plasma at 378 nm, but higher intensity at 605 nm. It is indicated that the seed layer treated with plasma produced ZnO nanorods that had a more oxygen vacancy than those grown from seed layer untreated with plasma. Since the oxygen vacancies on ZnO nanorods serve as strong binding sites for absorption of various organic and inorganic molecules. Consequently, a nano-patterning of the crystalline ZnO nanorods grown from the seed layer treated with plasma may give the versatile applications for the electronics devices. PMID- 21711666 TI - Atomic characterization of Si nanoclusters embedded in SiO2 by atom probe tomography. AB - Silicon nanoclusters are of prime interest for new generation of optoelectronic and microelectronics components. Physical properties (light emission, carrier storage...) of systems using such nanoclusters are strongly dependent on nanostructural characteristics. These characteristics (size, composition, distribution, and interface nature) are until now obtained using conventional high-resolution analytic methods, such as high-resolution transmission electron microscopy, EFTEM, or EELS. In this article, a complementary technique, the atom probe tomography, was used for studying a multilayer (ML) system containing silicon clusters. Such a technique and its analysis give information on the structure at the atomic level and allow obtaining complementary information with respect to other techniques. A description of the different steps for such analysis: sample preparation, atom probe analysis, and data treatment are detailed. An atomic scale description of the Si nanoclusters/SiO2 ML will be fully described. This system is composed of 3.8-nm-thick SiO layers and 4-nm thick SiO2 layers annealed 1 h at 900 degrees C. PMID- 21711667 TI - Nanoscale electro-structural characterisation of ohmic contacts formed on p-type implanted 4H-SiC. AB - This work reports a nanoscale electro-structural characterisation of Ti/Al ohmic contacts formed on p-type Al-implanted silicon carbide (4H-SiC). The morphological and the electrical properties of the Al-implanted layer, annealed at 1700 degrees C with or without a protective capping layer, and of the ohmic contacts were studied using atomic force microscopy [AFM], transmission line model measurements and local current measurements performed with conductive AFM.The characteristics of the contacts were significantly affected by the roughness of the underlying SiC. In particular, the surface roughness of the Al implanted SiC regions annealed at 1700 degrees C could be strongly reduced using a protective carbon capping layer during annealing. This latter resulted in an improved surface morphology and specific contact resistance of the Ti/Al ohmic contacts formed on these regions. The microstructure of the contacts was monitored by X-ray diffraction analysis and a cross-sectional transmission electron microscopy, and correlated with the electrical results. PMID- 21711668 TI - Study of the formation processes of gold droplet arrays on Si substrates by high temperature anneals. AB - In this study, the peculiarities of the transformations of gold films deposited on the Si wafer surfaces as a result of high temperature anneals are investigated experimentally depending on the conditions of wafer surface preparation and the annealing regimes. The morphology and the distribution functions of the crystallites of gold films as well as the gold droplets formed as a result of anneals are studied as functions of annealing temperature, type of annealing (rapid thermal or rapid furnace annealing), and the state of the surface of Si wafers. The results obtained can be used for the controlled preparation of the arrays of catalytic gold droplets for subsequent growth of Si wire-like crystals. PMID- 21711669 TI - Electronic and magnetic properties of SnO2/CrO2 thin superlattices. AB - In this article, using first-principles electronic structure calculations within the spin density functional theory, alternated magnetic and non-magnetic layers of rutile-CrO2 and rutile-SnO2 respectively, in a (CrO2)n(SnO2)n superlattice (SL) configuration, with n being the number of monolayers which are considered equal to 1, 2, ..., 10 are studied. A half-metallic behavior is observed for the (CrO2)n(SnO2)n SLs for all values of n. The ground state is found to be FM with a magnetic moment of 2 MUB per chromium atom, and this result does not depend on the number of monolayers n. As the FM rutile-CrO2 is unstable at ambient temperature, and known to be stabilized when on top of SnO2, the authors suggest that (CrO2)n(SnO2)n SLs may be applied to spintronic technologies since they provide efficient spin-polarized carriers. PMID- 21711670 TI - Multidimensional characterization, Landau levels and Density of States in epitaxial graphene grown on SiC substrates. AB - Using high-temperature annealing conditions with a graphite cap covering the C face of, both, on axis and 8 degrees off-axis 4H-SiC samples, large and homogeneous single epitaxial graphene layers have been grown. Raman spectroscopy shows evidence of the almost free-standing character of these monolayer graphene sheets, which was confirmed by magneto-transport measurements. On the best samples, we find a moderate p-type doping, a high-carrier mobility and resolve the half-integer quantum Hall effect typical of high-quality graphene samples. A rough estimation of the density of states is given from temperature measurements. PMID- 21711671 TI - The origin of the red emission in n-ZnO nanotubes/p-GaN white light emitting diodes. AB - In this article, the electroluminescence (EL) spectra of zinc oxide (ZnO) nanotubes/p-GaN light emitting diodes (LEDs) annealed in different ambients (argon, air, oxygen, and nitrogen) have been investigated. The ZnO nanotubes by aqueous chemical growth (ACG) technique on p-GaN substrates were obtained. The as grown ZnO nanotubes were annealed in different ambients at 600 degrees C for 30 min. The EL investigations showed that air, oxygen, and nitrogen annealing ambients have strongly affected the deep level emission bands in ZnO. It was concluded from the EL investigation that more than one deep level defect is involved in the red emission appearing between 620 and 750 nm and that the red emission in ZnO can be attributed to oxygen interstitials (Oi) appearing in the range from 620 nm (1.99 eV) to 690 nm (1.79 eV), and to oxygen vacancies (Vo) appearing in the range from 690 nm (1.79 eV) to 750 nm (1.65 eV). The annealing ambients, especially the nitrogen ambient, were also found to greatly influence the color-rendering properties and increase the CRI of the as - grown LEDs from 87 to 96. PMID- 21711672 TI - Quasi-radial growth of metal tube on si nanowires template. AB - It is reported in this article that Si nanowires can be employed as a positive template for the controllable electrochemical deposition of noble metal tube. The deposited tube exhibits good crystallinity. Scanning electron microscope and transmission electron microscope characterizations are conducted to reveal the growth process of metal tube, showing that the metal tube grows quasi-radially on the wall of Si nanowire. The quasi-radial growth of metal enables the fabrication of thickness-defined metal tube via changing deposition time. Inner-diameter defined metal tube is achieved by choosing Si nanowires with desired diameter as a template. Metal tubes with inner diameters ranging from 1 MUm to sub-50 nm are fabricated. PMID- 21711673 TI - Effect of the Nd content on the structural and photoluminescence properties of silicon-rich silicon dioxide thin films. AB - In this article, the microstructure and photoluminescence (PL) properties of Nd doped silicon-rich silicon oxide (SRSO) are reported as a function of the annealing temperature and the Nd concentration. The thin films, which were grown on Si substrates by reactive magnetron co-sputtering, contain the same Si excess as determined by Rutherford backscattering spectrometry. Fourier transform infrared (FTIR) spectra show that a phase separation occurs during the annealing because of the condensation of the Si excess resulting in the formation of silicon nanoparticles (Si-np) as detected by high-resolution transmission electron microscopy and X-ray diffraction (XRD) measurements. Under non-resonant excitation at 488 nm, our Nd-doped SRSO films simultaneously exhibited PL from Si np and Nd3+ demonstrating the efficient energy transfer between Si-np and Nd3+ and the sensitizing effect of Si-np. Upon increasing the Nd concentration from 0.08 to 4.9 at.%, our samples revealed a progressive quenching of the Nd3+ PL which can be correlated with the concomitant increase of disorder within the host matrix as shown by FTIR experiments. Moreover, the presence of Nd-oxide nanocrystals in the highest Nd-doped sample was established by XRD. It is, therefore, suggested that the Nd clustering, as well as disorder, are responsible for the concentration quenching of the PL of Nd3+. PMID- 21711674 TI - Memory effects in annealed hybrid gold nanoparticles/block copolymer bilayers. AB - We report on the use of the self-organization process of sputtered gold nanoparticles on a self-assembled block copolymer film deposited by horizontal precipitation Langmuir-Blodgett (HP-LB) method. The morphology and the phase separation of a film of poly-n-butylacrylate-block-polyacrylic acid (PnBuA-b-PAA) were studied at the nanometric scale by using atomic force microscopy (AFM) and Time of Flight Secondary Ion Mass Spectrometry (TOF-SIMS). The templating capability of the PnBuA-b-PAA phase-separated film was studied by sputtering gold nanoparticles (NPs), forming a film of nanometric thickness. The effect of the polymer chain mobility onto the organization of gold nanoparticle layer was assessed by heating the obtained hybrid PnBuA-b-PAA/Au NPs bilayer at T >Tg. The nanoparticles' distribution onto the different copolymer domains was found strongly affected by the annealing treatment, showing a peculiar memory effect, which modifies the AFM phase response of the Au NPs layer onto the polar domains, without affecting their surfacial composition. The effect is discussed in terms of the peculiar morphological features induced by enhanced mobility of polymer chains on the Au NPs layer. PMID- 21711676 TI - Hf-based high-k materials for Si nanocrystal floating gate memories. AB - Pure and Si-rich HfO2 layers fabricated by radio frequency sputtering were utilized as alternative tunnel oxide layers for high-k/Si-nanocrystals-SiO2/SiO2 memory structures. The effect of Si incorporation on the properties of Hf-based tunnel layer was investigated. The Si-rich SiO2 active layers were used as charge storage layers, and their properties were studied versus deposition conditions and annealing treatment. The capacitance-voltage measurements were performed to study the charge trapping characteristics of these structures. It was shown that with specific deposition conditions and annealing treatment, a large memory window of about 6.8 V is achievable at a sweeping voltage of +/- 6 V, indicating the utility of these stack structures for low-operating-voltage nonvolatile memory devices. PMID- 21711675 TI - CREB3 subfamily transcription factors are not created equal: Recent insights from global analyses and animal models. AB - The CREB3 subfamily of membrane-bound bZIP transcription factors has five members in mammals known as CREB3 and CREB3L1-L4. One current model suggests that CREB3 subfamily transcription factors are similar to ATF6 in regulated intramembrane proteolysis and transcriptional activation. Particularly, they were all thought to be proteolytically activated in response to endoplasmic reticulum (ER) stress to stimulate genes that are involved in unfolded protein response (UPR). Although the physiological inducers of their proteolytic activation remain to be identified, recent findings from microarray analyses, RNAi screens and gene knockouts not only demonstrated their critical roles in regulating development, metabolism, secretion, survival and tumorigenesis, but also revealed cell type specific patterns in the activation of their target genes. Members of the CREB3 subfamily show differential activity despite their structural similarity. The spectrum of their biological function expands beyond ER stress and UPR. Further analyses are required to elucidate the mechanism of their proteolytic activation and the molecular basis of their target recognition. PMID- 21711677 TI - Toward nanofluids of ultra-high thermal conductivity. AB - The assessment of proposed origins for thermal conductivity enhancement in nanofluids signifies the importance of particle morphology and coupled transport in determining nanofluid heat conduction and thermal conductivity. The success of developing nanofluids of superior conductivity depends thus very much on our understanding and manipulation of the morphology and the coupled transport. Nanofluids with conductivity of upper Hashin-Shtrikman (H-S) bound can be obtained by manipulating particles into an interconnected configuration that disperses the base fluid and thus significantly enhancing the particle-fluid interfacial energy transport. Nanofluids with conductivity higher than the upper H-S bound could also be developed by manipulating the coupled transport among various transport processes, and thus the nature of heat conduction in nanofluids. While the direct contributions of ordered liquid layer and particle Brownian motion to the nanofluid conductivity are negligible, their indirect effects can be significant via their influence on the particle morphology and/or the coupled transport. PMID- 21711678 TI - Formation of tungsten oxide nanostructures by laser pyrolysis: stars, fibres and spheres. AB - In this letter, the production of multi-phase WO3 and WO3-x (where x could vary between 0.1 and 0.3) nanostructures synthesized by CO2-laser pyrolysis technique at varying laser wavelengths (9.22-10.82 mm) and power densities (17-110 W/cm2) is reported. The average spherical particle sizes for the wavelength variation samples ranged between 113 and 560 nm, and the average spherical particle sizes for power density variation samples ranged between 108 and 205 nm. Synthesis of W18O49 (= WO2.72) stars by this method is reported for the first time at a power density and wavelength of 2.2 kW/cm2 and 10.6 MUm, respectively. It was found that more concentrated starting precursors result in the growth of hierarchical structures such as stars, whereas dilute starting precursors result in the growth of simpler structures such as wires. PMID- 21711679 TI - Guided assembly of nanoparticles on electrostatically charged nanocrystalline diamond thin films. AB - We apply atomic force microscope for local electrostatic charging of oxygen terminated nanocrystalline diamond (NCD) thin films deposited on silicon, to induce electrostatically driven self-assembly of colloidal alumina nanoparticles into micro-patterns. Considering possible capacitive, sp2 phase and spatial uniformity factors to charging, we employ films with sub-100 nm thickness and about 60% relative sp2 phase content, probe the spatial material uniformity by Raman and electron microscopy, and repeat experiments at various positions. We demonstrate that electrostatic potential contrast on the NCD films varies between 0.1 and 1.2 V and that the contrast of more than +/-1 V (as detected by Kelvin force microscopy) is able to induce self-assembly of the nanoparticles via coulombic and polarization forces. This opens prospects for applications of diamond and its unique set of properties in self-assembly of nano-devices and nano-systems. PMID- 21711680 TI - Effect of thermal treatment on the growth, structure and luminescence of nitride passivated silicon nanoclusters. AB - Silicon nanoclusters (Si-ncs) embedded in silicon nitride films have been studied to determine the effects that deposition and processing parameters have on their growth, luminescent properties, and electronic structure. Luminescence was observed from Si-ncs formed in silicon-rich silicon nitride films with a broad range of compositions and grown using three different types of chemical vapour deposition systems. Photoluminescence (PL) experiments revealed broad, tunable emissions with peaks ranging from the near-infrared across the full visible spectrum. The emission energy was highly dependent on the film composition and changed only slightly with annealing temperature and time, which primarily affected the emission intensity. The PL spectra from films annealed for duration of times ranging from 2 s to 2 h at 600 and 800 degrees C indicated a fast initial formation and growth of nanoclusters in the first few seconds of annealing followed by a slow, but steady growth as annealing time was further increased. X-ray absorption near edge structure at the Si K- and L3,2-edges exhibited composition-dependent phase separation and structural re-ordering of the Si-ncs and silicon nitride host matrix under different post-deposition annealing conditions and generally supported the trends observed in the PL spectra. PMID- 21711681 TI - Studying the local character of Raman features of single-walled carbon nanotubes along a bundle using TERS. AB - Here, we show that the Raman intensity of the G-mode in tip-enhanced Raman spectroscopy (TERS) is strongly dependent on the height of the bundle. Moreover, using TERS we are able to position different single-walled carbon nanotubes along a bundle, by correlating the observed radial breathing mode (RBM) with the AFM topography at the measuring point. The frequency of the G- mode behaves differently in TERS as compared to far-field Raman. Using the RBM frequency, the diameters of the tubes were calculated and a very good agreement with the G--mode frequency was observed. PMID- 21711682 TI - Tuning the electronic properties of boron nitride nanotube by mechanical uni axial deformation: a DFT study. AB - The effect of uni-axial strain on the electronic properties of (8,0) zigzag and (5,5) armchair boron nitride nanotubes (BNNT) is addressed by density functional theory calculation. The stress-strain profiles indicate that these two BNNTS of differing types display very similar mechanical properties, but there are variations in HOMO-LUMO gaps at different strains, indicating that the electronic properties of BNNTs not only depend on uni-axial strain, but on BNNT type. The variations in nanotube geometries, partial density of states of B and N atoms, B and N charges are also discussed for (8,0) and (5,5) BNNTs at different strains. PMID- 21711683 TI - Lattice Boltzmann simulation of alumina-water nanofluid in a square cavity. AB - A lattice Boltzmann model is developed by coupling the density (D2Q9) and the temperature distribution functions with 9-speed to simulate the convection heat transfer utilizing Al2O3-water nanofluids in a square cavity. This model is validated by comparing numerical simulation and experimental results over a wide range of Rayleigh numbers. Numerical results show a satisfactory agreement between them. The effects of Rayleigh number and nanoparticle volume fraction on natural convection heat transfer of nanofluid are investigated in this study. Numerical results indicate that the flow and heat transfer characteristics of Al2O3-water nanofluid in the square cavity are more sensitive to viscosity than to thermal conductivity. PMID- 21711684 TI - Field emission enhancement of Au-Si nano-particle-decorated silicon nanowires. AB - Au-Si nano-particle-decorated silicon nanowire arrays have been fabricated by Au film deposition on silicon nanowire array substrates and then post-thermal annealing under hydrogen atmosphere. Field emission measurements illustrated that the turn-on fields of the non-annealed Au-coated SiNWs were 6.02 to 7.51 V/MUm, higher than that of the as-grown silicon nanowires, which is about 5.01 V/MUm. Meanwhile, after being annealed above 650 degrees C, Au-Si nano-particles were synthesized on the top surface of the silicon nanowire arrays and the one dimensional Au-Si nano-particle-decorated SiNWs had a much lower turn-on field, 1.95 V/MUm. The results demonstrated that annealed composite silicon nanowire array-based electron field emitters may have great advantages over many other emitters. PMID- 21711685 TI - Enhanced functionalization of Mn2O3@SiO2 core-shell nanostructures. AB - Core-shell nanostructures of Mn2O3@SiO2, Mn2O3@amino-functionalized silica, Mn2O3@vinyl-functionalized silica, and Mn2O3@allyl-functionalized silica were synthesized using the hydrolysis of the respective organosilane precursor over Mn2O3 nanoparticles dispersed using colloidal solutions of Tergitol and cyclohexane. The synthetic methodology used is an improvement over the commonly used post-grafting or co-condensation method as it ensures a high density of functional groups over the core-shell nanostructures. The high density of functional groups can be useful in immobilization of biomolecules and drugs and thus can be used in targeted drug delivery. The high density of functional groups can be used for extraction of elements present in trace amounts. These functionalized core-shell nanostructures were characterized using TEM, IR, and zeta potential studies. The zeta potential study shows that the hydrolysis of organosilane to form the shell results in more number of functional groups on it as compared to the shell formed using post-grafting method. The amino functionalized core-shell nanostructures were used for the immobilization of glucose and L-methionine and were characterized by zeta potential studies. PMID- 21711686 TI - Numerical study of instability of nanofluids: the coagulation effect and sedimentation effect. AB - This study is a numerical study on the coagulation as well as the sedimentation effect of nanofluids using the Brownian dynamics method. Three cases are simulated, focusing on the effects of the sizes, volume fraction, and zeta potentials of nano-particles on the formation of coagulation and sedimentation of nanofluids. The rms fluctuation of the particle number concentration, as well as the flatness factor of it, is employed to study the formation and variation of the coagulation process. The results indicate a superposition of coagulation and sedimentation effect of small nano-particles. Moreover, it is stable of nanofluids with the volume fraction of particles below the limit of "resolution" of the fluids. In addition, the effect of zeta potentials is against the formation of coagulation and positive to the stability of nanofluids. PMID- 21711687 TI - Electrical characterisation of deep level defects in Be-doped AlGaAs grown on (100) and (311)A GaAs substrates by MBE. AB - The growth of high mobility two-dimensional hole gases (2DHGs) using GaAs-GaAlAs heterostructures has been the subject of many investigations. However, despite many efforts hole mobilities in Be-doped structures grown on (100) GaAs substrate remained considerably lower than those obtained by growing on (311)A oriented surface using silicon as p-type dopant. In this study we will report on the properties of hole traps in a set of p-type Be-doped Al0.29Ga0.71As samples grown by molecular beam epitaxy on (100) and (311)A GaAs substrates using deep level transient spectroscopy (DLTS) technique. In addition, the effect of the level of Be-doping concentration on the hole deep traps is investigated. It was observed that with increasing the Be-doping concentration from 1 * 1016 to 1 * 1017 cm-3 the number of detected electrically active defects decreases for samples grown on (311)A substrate, whereas, it increases for (100) orientated samples. The DLTS measurements also reveal that the activation energies of traps detected in (311)A are lower than those in (100). From these findings it is expected that mobilities of 2DHGs in Be-doped GaAs-GaAlAs devices grown on (311)A should be higher than those on (100). PMID- 21711688 TI - Microenvironment determinants of brain metastasis. AB - Metastasis accounts for 90% of cancer-related mortality. Brain metastases generally present during the late stages in the natural history of cancer progression. Recent advances in cancer treatment and management have resulted in better control of systemic disease metastatic to organs other than the brain and improved patient survival. However, patients who experience recurrent disease manifest an increasing number of brain metastases, which are usually refractory to therapies. To meet the new challenges of controlling brain metastasis, the research community has been tackling the problem with novel experimental models and research tools, which have led to an improved understanding of brain metastasis. The time-tested "seed-and-soil" hypothesis of metastasis indicates that successful outgrowth of deadly metastatic tumors depends on permissible interactions between the metastatic cancer cells and the site-specific microenvironment in the host organs. Consistently, recent studies indicate that the brain, the major component of the central nervous system, has unique physiological features that can determine the outcome of metastatic tumor growth. The current review summarizes recent discoveries on these tumor-brain interactions, and the potential clinical implications these novel findings could have for the better treatment of patients with brain metastasis. PMID- 21711689 TI - Extracellular domain of CD98hc is required for early murine development. AB - BACKGROUND: The multifunctional protein CD98 heavy chain (CD98hc, Slc3a2) associates with integrin beta1 through its cytoplasmic and transmembrane domains and the CD98hc-mediated integrin signaling is required for maintenance of ES cell proliferation. CD98hc-null mice exhibit early post-implantation lethality similar to integrin beta1-null mice, supporting the importance of its interaction with integrin beta1. On the other hand, the extracellular domain of CD98hc interacts with L-type amino acid transporters (LATs) and is essential for appropriate cell surface distribution of LATs. LATs mediate the transport of amino acids and other molecules such as thyroid hormone. In this respect, CD98hc may also affect development via these transporters. RESULTS: In this study, mice were generated from embryonic stem (ES) cell line (PST080) harboring a mutant CD98hc allele (CD98hcDelta/+). Expression of the CD98hc mutant allele results in DeltaCD98hc beta geo fusion protein where extracellular C-terminal 102 amino acids of CD98hc are replaced with beta geo. Analyses of PST080 ES cells as well as reconstituted frog oocytes demonstrated that DeltaCD98hc-beta geo fusion protein preserved its ability to interact with integrin beta1 although this mutant protein was hardly localized on the cell surface. These findings suggest that DeltaCD98hc-beta geo protein can mediate integrin signaling but cannot support amino acid transport through LATs. CD98hcDelta/+ mice were normal. Although some of the implantation sites lacked embryonic component at E9.5, all the implantation sites contained embryonic component at E7.5. Thus, CD98hcDelta/Delta embryos are likely to die between E7.5 and E9.5. CONCLUSIONS: Considering that CD98hc complete knockout (CD98hc-/-) embryos are reported to die shortly after implantation, our findings suggest potential stage-specific roles of CD98hc in murine embryonic development. CD98hc may be essential for early post-implantation development by regulating integrin-dependent signaling, while the other function of CD98hc as a component of amino acid transporters may be required for embryonic development at later stages. PMID- 21711690 TI - First-principles study of half-metallicity in semi-hydrogenated BC3, BC5, BC7, and B-doped graphone sheets. AB - Using first principles calculations, we investigate the electronic structures of semi-hydrogenated BC3, BC5, BC7, and B-doped graphone sheets. We find that all the semi-hydrogenated boron-carbon sheets exhibit half-metallic behaviors. The magnetism originates from the non-bonding pz orbitals of carbon atoms, which cause the flat bands to satisfy the Stoner criterion. On the other hand, boron atoms weaken the magnetic moments of nearby carbon atoms and act as holes doped in the sheets. It induces the down shift of the Fermi level and the half metallicity in semi-hydrogenated sheets. Our studies demonstrate that the semi hydrogenation is an effective route to achieve half-metallicity in the boron carbon systems. PMID- 21711691 TI - Multiple metallic-shell nanocylinders for surface-enhanced spectroscopes. AB - The optical properties of multiple dielectric-core-gold-shell nanocylinder pairs are investigated by two-dimensional finite difference time domain method. The core-shell cylinders are assumed to be of the same dimension and composition. For normal incidence, the diffraction spectra of multiple cylinder pairs contain the lightning-rod plasmon mode, and the electric field intensity is concentrated in the gap between the nanocylinder pairs in the infrared region. The resonance wavelength and local field enhancement of this plasmon mode can be tuned by varying the pair-distance between the pairs, the gap-distance between the pairs, and the optical constants of the dielectric-core and the surrounding medium. The results show that the multiple core-shell nanocylinder pair contains the plasmon mode same as that of the solid metallic cylinder pairs at the long wavelength part of the spectrum. The large electric field intensity in the infrared region at long wavelength makes multiple core-shell cylinders as ideal candidates for surface-enhanced spectroscopes. PMID- 21711692 TI - Memory properties and charge effect study in Si nanocrystals by scanning capacitance microscopy and spectroscopy. AB - In this letter, isolated Si nanocrystal has been formed by dewetting process with a thin silicon dioxide layer on top. Scanning capacitance microscopy and spectroscopy were used to study the memory properties and charge effect in the Si nanocrystal in ambient temperature. The retention time of trapped charges injected by different direct current (DC) bias were evaluated and compared. By ramp process, strong hysteresis window was observed. The DC spectra curve shift direction and distance was observed differently for quantitative measurements. Holes or electrons can be separately injected into these Si-ncs and the capacitance changes caused by these trapped charges can be easily detected by scanning capacitance microscopy/spectroscopy at the nanometer scale. This study is very useful for nanocrystal charge trap memory application. PMID- 21711693 TI - Preparation and thermal conductivity of CuO nanofluid via a wet chemical method. AB - In this article, a wet chemical method was developed to prepare stable CuO nanofluids. The influences of synthesis parameters, such as kinds and amounts of copper salts, reaction time, were studied. The thermal conductivities of CuO nanofluids were also investigated. The results showed that different copper salts resulted in different particle morphology. The concentration of copper acetate and reaction time affected the size and shape of clusters of primary nanoparticles. Nanofluids with different microstructures could be obtained by changing the synthesis parameters. The thermal conductivities of CuO nanofluids increased with the increase of particle loading. PMID- 21711694 TI - Numerical investigation of Al2O3/water nanofluid laminar convective heat transfer through triangular ducts. AB - In this article, laminar flow-forced convective heat transfer of Al2O3/water nanofluid in a triangular duct under constant wall temperature condition is investigated numerically. In this investigation, the effects of parameters, such as nanoparticles diameter, concentration, and Reynolds number on the enhancement of nanofluids heat transfer is studied. Besides, the comparison between nanofluid and pure fluid heat transfer is achieved in this article. Sometimes, because of pressure drop limitations, the need for non-circular ducts arises in many heat transfer applications. The low heat transfer rate of non-circular ducts is one the limitations of these systems, and utilization of nanofluid instead of pure fluid because of its potential to increase heat transfer of system can compensate this problem. In this article, for considering the presence of nanoparticl: es, the dispersion model is used. Numerical results represent an enhancement of heat transfer of fluid associated with changing to the suspension of nanometer-sized particles in the triangular duct. The results of the present model indicate that the nanofluid Nusselt number increases with increasing concentration of nanoparticles and decreasing diameter. Also, the enhancement of the fluid heat transfer becomes better at high Re in laminar flow with the addition of nanoparticles. PMID- 21711695 TI - Heat transfer augmentation in nanofluids via nanofins. AB - Theoretical results derived in this article are combined with experimental data to conclude that, while there is no improvement in the effective thermal conductivity of nanofluids beyond the Maxwell's effective medium theory (J.C. Maxwell, Treatise on Electricity and Magnetism, 1891), there is substantial heat transfer augmentation via nanofins. The latter are formed as attachments on the hot wire surface by yet an unknown mechanism, which could be related to electrophoresis, but there is no conclusive evidence yet to prove this proposed mechanism. PMID- 21711696 TI - Kinetics of Si and Ge nanowires growth through electron beam evaporation. AB - Si and Ge have the same crystalline structure, and although Si-Au and Ge-Au binary alloys are thermodynamically similar (same phase diagram, with the eutectic temperature of about 360 degrees C), in this study, it is proved that Si and Ge nanowires (NWs) growth by electron beam evaporation occurs in very different temperature ranges and fluence regimes. In particular, it is demonstrated that Ge growth occurs just above the eutectic temperature, while Si NWs growth occurs at temperature higher than the eutectic temperature, at about 450 degrees C. Moreover, Si NWs growth requires a higher evaporated fluence before the NWs become to be visible. These differences arise in the different kinetics behaviors of these systems. The authors investigate the microscopic growth mechanisms elucidating the contribution of the adatoms diffusion as a function of the evaporated atoms direct impingement, demonstrating that adatoms play a key role in physical vapor deposition (PVD) NWs growth. The concept of incubation fluence, which is necessary for an interpretation of NWs growth in PVD growth conditions, is highlighted. PMID- 21711697 TI - Relationship between structural changes, hydrogen content and annealing in stacks of ultrathin Si/Ge amorphous layers. AB - Hydrogenated multilayers (MLs) of a-Si/a-Ge have been analysed to establish the reasons of H release during annealing that has been seen to bring about structural modifications even up to well-detectable surface degradation. Analyses carried out on single layers of a-Si and a-Ge show that H is released from its bond to the host lattice atom and that it escapes from the layer much more efficiently in a-Ge than in a-Si because of the smaller binding energy of the H Ge bond and probably of a greater weakness of the Ge lattice. This should support the previous hypothesis that the structural degradation of a-Si/a-Ge MLs primary starts with the formation of H bubbles in the Ge layers. PMID- 21711698 TI - Electrical behavior of MIS devices based on Si nanoclusters embedded in SiOxNy and SiO2 films. AB - We examined and compared the electrical properties of silica (SiO2) and silicon oxynitride (SiOxNy) layers embedding silicon nanoclusters (Sinc) integrated in metal-insulator-semiconductor (MIS) devices. The technique used for the deposition of such layers is the reactive magnetron sputtering of a pure SiO2 target under a mixture of hydrogen/argon plasma in which nitrogen is incorporated in the case of SiOxNy layer. Al/SiOxNy-Sinc/p-Si and Al/SiO2-Sinc/p-Si devices were fabricated and electrically characterized. Results showed a high rectification ratio (>104) for the SiOxNy-based device and a resistive behavior when nitrogen was not incorporating (SiO2-based device). For rectifier devices, the ideality factor depends on the SiOxNy layer thickness. The conduction mechanisms of both MIS diode structures were studied by analyzing thermal and bias dependences of the carriers transport in relation with the nitrogen content. PMID- 21711699 TI - Study of the vertical transport in p-doped superlattices based on group III-V semiconductors. AB - The electrical conductivity sigma has been calculated for p-doped GaAs/Al0.3Ga0.7As and cubic GaN/Al0.3Ga0.7N thin superlattices (SLs). The calculations are done within a self-consistent approach to the k->?p-> theory by means of a full six-band Luttinger-Kohn Hamiltonian, together with the Poisson equation in a plane wave representation, including exchange correlation effects within the local density approximation. It was also assumed that transport in the SL occurs through extended minibands states for each carrier, and the conductivity is calculated at zero temperature and in low-field ohmic limits by the quasi-chemical Boltzmann kinetic equation. It was shown that the particular minibands structure of the p-doped SLs leads to a plateau-like behavior in the conductivity as a function of the donor concentration and/or the Fermi level energy. In addition, it is shown that the Coulomb and exchange-correlation effects play an important role in these systems, since they determine the bending potential. PMID- 21711700 TI - Nanofluids for heat transfer: an engineering approach. AB - An overview of systematic studies that address the complexity of nanofluid systems and advance the understanding of nanoscale contributions to viscosity, thermal conductivity, and cooling efficiency of nanofluids is presented. A nanoparticle suspension is considered as a three-phase system including the solid phase (nanoparticles), the liquid phase (fluid media), and the interfacial phase, which contributes significantly to the system properties because of its extremely high surface-to-volume ratio in nanofluids. The systems engineering approach was applied to nanofluid design resulting in a detailed assessment of various parameters in the multivariable nanofluid systems. The relative importance of nanofluid parameters for heat transfer evaluated in this article allows engineering nanofluids with desired set of properties. PMID- 21711701 TI - A proteomic study of TAR-RNA binding protein (TRBP)-associated factors. AB - BACKGROUND: The human TAR RNA-binding protein, TRBP, was first identified and cloned based on its high affinity binding to the small hairpin trans-activation responsive (TAR) RNA of HIV-1. TRBP has more recently been found to be a constituent of the RNA-induced silencing complex (RISC) serving as a Dicer co factor in the processing of the ~70 nucleotide pre-microRNAs(miRNAs) to 21-25 nucleotide mature miRNAs. FINDINGS: Using co-immunoprecipitation and protein identification by mass spectrometry, we characterized intracellular proteins that complex with TRBP. These interacting proteins include those that have been described to act in protein synthesis, RNA modifications and processing, DNA transcription, and cell proliferation. CONCLUSIONS: Our findings provide a proteome of factors that may cooperate with TRBP in activities such as miRNA processing and in RNA interference by the RISC complex. PMID- 21711702 TI - Multiscale investigation of graphene layers on 6H-SiC(000-1). AB - In this article, a multiscale investigation of few graphene layers grown on 6H SiC(000-1) under ultrahigh vacuum (UHV) conditions is presented. At 100-MUm scale, the authors show that the UHV growth yields few layer graphene (FLG) with an average thickness given by Auger spectroscopy between 1 and 2 graphene planes. At the same scale, electron diffraction reveals a significant rotational disorder between the first graphene layer and the SiC surface, although well-defined preferred orientations exist. This is confirmed at the nanometer scale by scanning tunneling microscopy (STM). Finally, STM (at the nm scale) and Raman spectroscopy (at the MUm scale) show that the FLG stacking is turbostratic, and that the domain size of the crystallites ranges from 10 to 100 nm. The most striking result is that the FLGs experience a strong compressive stress that is seldom observed for graphene grown on the C face of SiC substrates. PMID- 21711703 TI - AFM-assisted fabrication of thiol SAM pattern with alternating quantified surface potential. AB - Thiol self-assembled monolayers (SAMs) are widely used in many nano- and bio technology applications. We report a new approach to create and characterize a thiol SAMs micropattern with alternating charges on a flat gold-coated substrate using atomic force microscopy (AFM) and Kelvin probe force microscopy (KPFM). We produced SAMs-patterns made of alternating positively charged, negatively charged, and hydrophobic-terminated thiols by an automated AFM-assisted manipulation, or nanografting. We show that these thiol patterns possess only small topographical differences as revealed by AFM, and distinguished differences in surface potential (20-50 mV), revealed by KPFM. The pattern can be helpful in the development of biosensor technologies, specifically for selective binding of biomolecules based on charge and hydrophobicity, and serve as a model for creating surfaces with quantified alternating surface potential distribution. PMID- 21711704 TI - The rate sensitivity and plastic deformation of nanocrystalline tantalum films at nanoscale. AB - Nanoindentation creep and loading rate change tests were employed to examine the rate sensitivity (m) and hardness of nanocrystalline tetragonal Ta films. Experimental results suggested that the m increased with the decrease of feature scale, such as grain size and indent depth. The magnitude of m is much less than the corresponding grain boundary (GB) sliding deformation with m of 0.5. Hardness softening behavior was observed for smaller grain size, which supports the GB sliding mechanism. The rate-controlling deformation was interpreted by the GB mediated processes involving atomic diffusion and the generation of dislocation at GB. PMID- 21711705 TI - Promotion of allergic immune responses by intranasally-administrated nanosilica particles in mice. AB - With the increase in use of nanomaterials, there is growing concern regarding their potential health risks. However, few studies have assessed the role of the different physical characteristics of nanomaterials in allergic responses. Here, we examined whether intranasally administered silica particles of various sizes have the capacity to promote allergic immune responses in mice. We used nanosilica particles with diameters of 30 or 70 nm (nSP30 or nSP70, respectively), and conventional micro-sized silica particles with diameters of 300 or 1000 nm (nSP300 or mSP1000, respectively). Mice were intranasally exposed to ovalbumin (OVA) plus each silica particle, and the levels of OVA-specific antibodies (Abs) in the plasma were determined. Intranasal exposure to OVA plus smaller nanosilica particles tended to induce a higher level of OVA-specific immunoglobulin (Ig) E, IgG and IgG1 Abs than did exposure to OVA plus larger silica particles. Splenocytes from mice exposed to OVA plus nSP30 secreted higher levels of Th2-type cytokines than mice exposed to OVA alone. Taken together, these results indicate that nanosilica particles can induce allergen-specific Th2 type allergic immune responses in vivo. This study provides the foundations for the establishment of safe and effective forms of nanosilica particles. PMID- 21711706 TI - Fabrication of ordered nanoporous anodic alumina prepatterned by mold-assisted chemical etching. AB - In this article, a simple and cost-effective method to create patterned nanoindentations on Al surface via mold-assisted chemical etching process is demonstrated. This report shows the reaction-diffusion method which formed nanoscale shallow etch pits by the absorption/liberation behaviors of chemical etchant in poly(dimethylsiloxane) stamp. During subsequent anodization, it was possible to obtain the ordered nanopore arrays with 277 nm pitch that were guided by the prepatterned etch pits. The prepatterned etch pits obtained can guide the growth of AAO nanopores during anodization and facilitate the preparation of ordered nanopore arrays. PMID- 21711707 TI - Chemical characterization of extra layers at the interfaces in MOCVD InGaP/GaAs junctions by electron beam methods. AB - Electron beam methods, such as cathodoluminescence (CL) that is based on an electron-probe microanalyser, and (200) dark field and high angle annular dark field (HAADF) in a scanning transmission electron microscope, are used to study the deterioration of interfaces in InGaP/GaAs system with the GaAs QW on top of InGaP. A CL emission peak different from that of the QW was detected. By using HAADF, it is found that the GaAs QW does not exist any longer, being replaced by extra interlayer(s) that are different from GaAs and InGaP because of atomic rearrangements at the interface. The nature and composition of the interlayer(s) are determined by HAADF. Such changes of the nominal GaAs QW can account for the emission observed by CL. PMID- 21711708 TI - Effect of ion implantation energy for the synthesis of Ge nanocrystals in SiN films with HfO2/SiO2 stack tunnel dielectrics for memory application. AB - Ge nanocrystals (Ge-NCs) embedded in SiN dielectrics with HfO2/SiO2 stack tunnel dielectrics were synthesized by utilizing low-energy (<=5 keV) ion implantation method followed by conventional thermal annealing at 800 degrees C, the key variable being Ge+ ion implantation energy. Two different energies (3 and 5 keV) have been chosen for the evolution of Ge-NCs, which have been found to possess significant changes in structural and chemical properties of the Ge+-implanted dielectric films, and well reflected in the charge storage properties of the Al/SiN/Ge-NC + SiN/HfO2/SiO2/Si metal-insulator-semiconductor (MIS) memory structures. No Ge-NC was detected with a lower implantation energy of 3 keV at a dose of 1.5 * 1016 cm-2, whereas a well-defined 2D-array of nearly spherical and well-separated Ge-NCs within the SiN matrix was observed for the higher-energy implanted (5 keV) sample for the same implanted dose. The MIS memory structures implanted with 5 keV exhibits better charge storage and retention characteristics compared to the low-energy-implanted sample, indicating that the charge storage is predominantly in Ge-NCs in the memory capacitor. A significant memory window of 3.95 V has been observed under the low operating voltage of +/- 6 V with good retention properties, indicating the feasibility of these stack structures for low operating voltage, non-volatile memory devices. PMID- 21711709 TI - Growth and characterization of gold catalyzed SiGe nanowires and alternative metal-catalyzed Si nanowires. AB - The growth of semiconductor (SC) nanowires (NW) by CVD using Au-catalyzed VLS process has been widely studied over the past few years. Among others SC, it is possible to grow pure Si or SiGe NW thanks to these techniques. Nevertheless, Au could deteriorate the electric properties of SC and the use of other metal catalysts will be mandatory if NW are to be designed for innovating electronic. First, this article's focus will be on SiGe NW's growth using Au catalyst. The authors managed to grow SiGe NW between 350 and 400 degrees C. Ge concentration (x) in Si1-xGex NW has been successfully varied by modifying the gas flow ratio: R = GeH4/(SiH4 + GeH4). Characterization (by Raman spectroscopy and XRD) revealed concentrations varying from 0.2 to 0.46 on NW grown at 375 degrees C, with R varying from 0.05 to 0.15. Second, the results of Si NW growths by CVD using alternatives catalysts such as platinum-, palladium- and nickel-silicides are presented. This study, carried out on a LPCVD furnace, aimed at defining Si NW growth conditions when using such catalysts. Since the growth temperatures investigated are lower than the eutectic temperatures of these Si-metal alloys, VSS growth is expected and observed. Different temperatures and HCl flow rates have been tested with the aim of minimizing 2D growth which induces an important tapering of the NW. Finally, mechanical characterization of single NW has been carried out using an AFM method developed at the LTM. It consists in measuring the deflection of an AFM tip while performing approach-retract curves at various positions along the length of a cantilevered NW. This approach allows the measurement of as-grown single NW's Young modulus and spring constant, and alleviates uncertainties inherent in single point measurement. PMID- 21711710 TI - Ultrasonic-aided fabrication of gold nanofluids. AB - A novel ultrasonic-aided one-step method for the fabrication of gold nanofluids is proposed in this study. Both spherical- and plate-shaped gold nanoparticles (GNPs) in the size range of 10-300 nm are synthesized. Subsequent purification produces well-controlled nanofluids with known solid and liquid contents. The morphology and properties of the nanoparticle and nanofluids are characterized by transmission electron microscopy, scanning electron microscope, energy dispersive X-ray spectroscope, X-ray diffraction spectroscopy, and dynamic light scattering, as well as effective thermal conductivities. The ultrasonication technique is found to be a very powerful tool in engineering the size and shape of GNPs. Subsequent property measurement shows that both particle size and particle shape play significant roles in determining the effective thermal conductivity. A large increase in effective thermal conductivity can be achieved (approximately 65%) for gold nanofluids using plate-shaped particles under low particle concentrations (i.e.764 MUM/L). PMID- 21711712 TI - Effect of annealing treatments on photoluminescence and charge storage mechanism in silicon-rich SiNx:H films. AB - In this study, a wide range of a-SiNx:H films with an excess of silicon (20 to 50%) were prepared with an electron-cyclotron resonance plasma-enhanced chemical vapor deposition system under the flows of NH3 and SiH4. The silicon-rich a SiNx:H films (SRSN) were sandwiched between a bottom thermal SiO2 and a top Si3N4 layer, and subsequently annealed within the temperature range of 500-1100 degrees C in N2 to study the effect of annealing temperature on light-emitting and charge storage properties. A strong visible photoluminescence (PL) at room temperature has been observed for the as-deposited SRSN films as well as for films annealed up to 1100 degrees C. The possible origins of the PL are briefly discussed. The authors have succeeded in the formation of amorphous Si quantum dots with an average size of about 3 to 3.6 nm by varying excess amount of Si and annealing temperature. Electrical properties have been investigated on Al/Si3N4/SRSN/SiO2/Si structures by capacitance-voltage and conductance-voltage analysis techniques. A significant memory window of 4.45 V was obtained at a low operating voltage of +/- 8 V for the sample containing 25% excess silicon and annealed at 1000 degrees C, indicating its utility in low-power memory devices. PMID- 21711711 TI - Light-emitting diodes enhanced by localized surface plasmon resonance. AB - Light-emitting diodes [LEDs] are of particular interest recently as their performance is approaching fluorescent/incandescent tubes. Moreover, their energy saving property is attracting many researchers because of the huge energy crisis we are facing. Among all methods intending to enhance the efficiency and intensity of a conventional LED, localized surface plasmon resonance is a promising way. The mechanism is based on the energy coupling effect between the emitted photons from the semiconductor and metallic nanoparticles fabricated by nanotechnology. In this review, we describe the mechanism of this coupling effect and summarize the common fabrication techniques. The prospect, including the potential to replace fluorescent/incandescent lighting devices as well as applications to flat panel displays and optoelectronics, and future challenges with regard to the design of metallic nanostructures and fabrication techniques are discussed. PMID- 21711713 TI - Lithium ion storage between graphenes. AB - In this article, we investigate the storage of lithium ions between two parallel graphene sheets using the continuous approximation and the 6-12 Lennard-Jones potential. The continuous approximation assumes that the carbon atoms can be replaced by a uniform distribution across the surface of the graphene sheets so that the total interaction potential can be approximated by performing surface integrations. The number of ion layers determines the major storage characteristics of the battery, and our results show three distinct ionic configurations, namely single, double, and triple ion forming layers between graphenes. The number densities of lithium ions between the two graphenes are estimated from existing semi-empirical molecular orbital calculations, and the graphene sheets giving rise to the triple ion layers admit the largest storage capacity at all temperatures, followed by a marginal decrease of storage capacity for the case of double ion layers. These two configurations exceed the maximum theoretical storage capacity of graphite. Further, on taking into account the charge-discharge property, the double ion layers are the most preferable choice for enhanced lithium storage. Although the single ion layer provides the least charge storage, it turns out to be the most stable configuration at all temperatures. One application of the present study is for the design of future high energy density alkali batteries using graphene sheets as anodes for which an analytical formulation might greatly facilitate rapid computational results. PMID- 21711714 TI - Magnetotransport in quantum cascade detectors: analyzing the current under illumination. AB - Photocurrent measurements have been performed on a quantum cascade detector structure under strong magnetic field applied parallel to the growth axis. The photocurrent shows oscillations as a function of B. In order to describe that behavior, we have developed a rate equation model. The interpretation of the experimental data supports the idea that an elastic scattering contribution plays a central role in the behavior of those structures. We present a calculation of electron lifetime versus magnetic field which suggests that impurities scattering in the active region is the limiting factor. These experiments lead to a better understanding of these complex structures and give key parameters to optimize them further. PMID- 21711715 TI - Mixed convective boundary layer flow over a vertical wedge embedded in a porous medium saturated with a nanofluid: Natural Convection Dominated Regime. AB - A boundary layer analysis is presented for the mixed convection past a vertical wedge in a porous medium saturated with a nano fluid. The governing partial differential equations are transformed into a set of non-similar equations and solved numerically by an efficient, implicit, iterative, finite-difference method. A parametric study illustrating the influence of various physical parameters is performed. Numerical results for the velocity, temperature, and nanoparticles volume fraction profiles, as well as the friction factor, surface heat and mass transfer rates have been presented for parametric variations of the buoyancy ratio parameter Nr, Brownian motion parameter Nb, thermophoresis parameter Nt, and Lewis number Le. The dependency of the friction factor, surface heat transfer rate (Nusselt number), and mass transfer rate (Sherwood number) on these parameters has been discussed. PMID- 21711716 TI - Pumped double quantum dot with spin-orbit coupling. AB - We study driven by an external electric field quantum orbital and spin dynamics of electron in a one-dimensional double quantum dot with spin-orbit coupling. Two types of external perturbation are considered: a periodic field at the Zeeman frequency and a single half-period pulse. Spin-orbit coupling leads to a nontrivial evolution in the spin and orbital channels and to a strongly spin- dependent probability density distribution. Both the interdot tunneling and the driven motion contribute into the spin evolution. These results can be important for the design of the spin manipulation schemes in semiconductor nanostructures.PACS numbers: 73.63.Kv,72.25.Dc,72.25.Pn. PMID- 21711717 TI - Spin-orbit interaction induced anisotropic property in interacting quantum wires. AB - : We investigate theoretically the ground state and transport property of electrons in interacting quantum wires (QWs) oriented along different crystallographic directions in (001) and (110) planes in the presence of the Rashba spin-orbit interaction (RSOI) and Dresselhaus SOI (DSOI). The electron ground state can cross over different phases, e.g., spin density wave, charge density wave, singlet superconductivity, and metamagnetism, by changing the strengths of the SOIs and the crystallographic orientation of the QW. The interplay between the SOIs and Coulomb interaction leads to the anisotropic dc transport property of QW which provides us a possible way to detect the strengths of the RSOI and DSOI.PACS numbers: 73.63.Nm, 71.10.Pm, 73.23.-b, 71.70.Ej. PMID- 21711718 TI - Graphene on ferromagnetic surfaces and its functionalization with water and ammonia. AB - In this article, an angle-resolved photoelectron spectroscopy (ARPES), X-ray absorption spectroscopy (XAS), and density-functional theory (DFT) investigations of water and ammonia adsorption on graphene/Ni(111) are presented. The results of adsorption on graphene/Ni(111) obtained in this study reveal the existence of interface states, originating from the strong hybridization of the graphene pi and spin-polarized Ni 3d valence band states. ARPES and XAS data of the H2O (NH3)/graphene/Ni(111) system give an information regarding the kind of interaction between the adsorbed molecules and the graphene on Ni(111). The presented experimental data are compared with the results obtained in the framework of the DFT approach. PMID- 21711719 TI - Particle size effects in the thermal conductivity enhancement of copper-based nanofluids. AB - We present an analysis of the dispersion characteristics and thermal conductivity performance of copper-based nanofluids. The copper nanoparticles were prepared using a chemical reduction methodology in the presence of a stabilizing surfactant, oleic acid or cetyl trimethylammonium bromide (CTAB). Nanofluids were prepared using water as the base fluid with copper nanoparticle concentrations of 0.55 and 1.0 vol.%. A dispersing agent, sodium dodecylbenzene sulfonate (SDBS), and subsequent ultrasonication was used to ensure homogenous dispersion of the copper nanopowders in water. Particle size distribution of the copper nanoparticles in the base fluid was determined by dynamic light scattering. We found that the 0.55 vol.% Cu nanofluids exhibited excellent dispersion in the presence of SDBS. In addition, a dynamic thermal conductivity setup was developed and used to measure the thermal conductivity performance of the nanofluids. The 0.55 vol.% Cu nanofluids exhibited a thermal conductivity enhancement of approximately 22%. In the case of the nanofluids prepared from the powders synthesized in the presence of CTAB, the enhancement was approximately 48% over the base fluid for the 1.0 vol.% Cu nanofluids, which is higher than the enhancement values found in the literature. These results can be directly related to the particle/agglomerate size of the copper nanoparticles in water, as determined from dynamic light scattering. PMID- 21711720 TI - Electromodulated reflectance study of self-assembled Ge/Si quantum dots. AB - We perform an electroreflectance spectroscopy of Ge/Si self-assembled quantum dots in the near-infrared and in the mid-infrared spectral range. Up to three optical transitions are observed. The low-energy resonance is proposed to correspond to a band-to-continuum hole transition in the Ge valence band. The other two modulation signals are attributed to the spatially direct transitions between the electrons confined in the L and Delta(4) valleys of the Ge conduction band, and the localized hole states at the Gamma point. PMID- 21711721 TI - Growth of carbon nanowalls at atmospheric pressure for one-step gas sensor fabrication. AB - Carbon nanowalls (CNWs), two-dimensional "graphitic" platelets that are typically oriented vertically on a substrate, can exhibit similar properties as graphene. Growth of CNWs reported to date was exclusively carried out at a low pressure. Here, we report on the synthesis of CNWs at atmosphere pressure using "direct current plasma-enhanced chemical vapor deposition" by taking advantage of the high electric field generated in a pin-plate dc glow discharge. CNWs were grown on silicon, stainless steel, and copper substrates without deliberate introduction of catalysts. The as-grown CNW material was mainly mono- and few layer graphene having patches of O-containing functional groups. However, Raman and X-ray photoelectron spectroscopies confirmed that most of the oxygen groups could be removed by thermal annealing. A gas-sensing device based on such CNWs was fabricated on metal electrodes through direct growth. The sensor responded to relatively low concentrations of NO2 (g) and NH3 (g), thus suggesting high quality CNWs that are useful for room temperature gas sensors.PACS: Graphene (81.05.ue), Chemical vapor deposition (81.15.Gh), Gas sensors (07.07.Df), Atmospheric pressure (92.60.hv). PMID- 21711722 TI - Grain size-dependent magnetic and electric properties in nanosized YMnO3 multiferroic ceramics. AB - Magnetic and electric properties are investigated for the nanosized YMnO3 samples with different grain sizes (25 nm to 200 nm) synthesized by a modified Pechini method. It shows that magnetic and electric properties are strongly dependent on the grain size. The magnetic characterization indicates that with increasing grain size, the antiferromagnetic (AFM) transition temperature increases from 52 to 74 K. A corresponding shift of the dielectric anomaly is observed, indicating a strong correlation between the electric polarization and the magnetic ordering. Further analysis suggests that the rising of AFM transition temperature with increasing grain size should be from the structural origin, in which the strength of AFM interaction as well as the electrical polarization is dependent on the in-plane lattice parameters. Furthermore, among all samples, the sample with grain size of 95 nm is found to have the smallest leakage current density (< 1 MUA/cm2).PACS: 75.50.Tt, 75.50.Ee, 75.85.+t, 77.84. s. PMID- 21711723 TI - Micro-spectroscopy on silicon wafers and solar cells. AB - Micro-Raman (MURS) and micro-photoluminescence spectroscopy (MUPLS) are demonstrated as valuable characterization techniques for fundamental research on silicon as well as for technological issues in the photovoltaic production. We measure the quantitative carrier recombination lifetime and the doping density with submicron resolution by MUPLS and MURS. MUPLS utilizes the carrier diffusion from a point excitation source and MURS the hole density-dependent Fano resonances of the first order Raman peak. This is demonstrated on micro defects in multicrystalline silicon. In comparison with the stress measurement by MURS, these measurements reveal the influence of stress on the recombination activity of metal precipitates. This can be attributed to the strong stress dependence of the carrier mobility (piezoresistance) of silicon. With the aim of evaluating technological process steps, Fano resonances in MURS measurements are analyzed for the determination of the doping density and the carrier lifetime in selective emitters, laser fired doping structures, and back surface fields, while MUPLS can show the micron-sized damage induced by the respective processes. PMID- 21711724 TI - Structure-dependent growth control in nanowire synthesis via on-film formation of nanowires. AB - On-film formation of nanowires, termed OFF-ON, is a novel synthetic approach that produces high-quality, single-crystalline nanowires of interest. This versatile method utilizes stress-induced atomic mass flow along grain boundaries in the polycrystalline film to form nanowires. Consequently, controlling the magnitude of the stress induced in the films and the microstructure of the films is important in OFF-ON. In this study, we investigated various experimental growth parameters such as deposition rate, deposition area, and substrate structure which modulate the microstructure and the magnitude of stress in the films, and thus significantly affect the nanowire density. We found that Bi nanowire growth is favored in thermodynamically unstable films that facilitate atomic mass flow during annealing. A large film area and a large thermal expansion coefficient mismatch between the film and the substrate were found to be critical for inducing large compressive stress in a film, which promotes Bi nanowire growth. The OFF-ON method can be routinely used to grow nanowires from a variety of materials by tuning the material-dependent growth parameters. PMID- 21711725 TI - Ionic liquid-templated preparation of mesoporous silica embedded with nanocrystalline sulfated zirconia. AB - A series of mesoporous silicas impregnated with nanocrystalline sulphated zirconia was prepared by a sol-gel process using an ionic liquid-templated route. The physicochemical properties of the mesoporous sulphated zirconia materials were studied using characterisation techniques such as inductively coupled optical emission spectroscopy, X-ray diffraction, transmission electron microscopy, energy-dispersive X-ray microanalysis, elemental analysis and X-ray photoelectron spectroscopy. Analysis of the new silicas indicates isomorphous substitution of silicon with zirconium and reveals the presence of extremely small (< 10 nm) polydispersed zirconia nanoparticles in the materials with zirconium loadings from 27.77 to 41.4 wt.%. PMID- 21711726 TI - Chloroquine treatment of ARPE-19 cells leads to lysosome dilation and intracellular lipid accumulation: possible implications of lysosomal dysfunction in macular degeneration. AB - BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of vision loss in elderly people over 60. The pathogenesis is still unclear. It has been suggested that lysosomal stress may lead to drusen formation, a biomarker of AMD. In this study, ARPE-19 cells were treated with chloroquine to inhibit lysosomal function. RESULTS: Chloroquine-treated ARPE-19 cells demonstrate a marked increase in vacuolation and dense intracellular debris. These are identified as chloroquine-dilated lysosomes and lipid bodies with LAMP-2 and LipidTOX co localization, respectively. Dilation is an indicator of lysosomal dysfunction. Chloroquine disrupts uptake of exogenously applied rhodamine-labeled dextran by these cells. This suggests a disruption in the phagocytic pathway. The increase in LAMP protein levels, as assessed by Western blots, suggests the possible involvement in autophagy. Oxidative stress with H2O2 does not induce vacuolation or lipid accumulation. CONCLUSION: These findings suggest a possible role for lysosomes in AMD. Chloroquine treatment of RPE cells may provide insights into the cellular mechanisms underlying AMD. PMID- 21711727 TI - Microscopic study of electrical properties of CrSi2 nanocrystals in silicon. AB - Semiconducting CrSi2 nanocrystallites (NCs) were grown by reactive deposition epitaxy of Cr onto n-type silicon and covered with a 50-nm epitaxial silicon cap. Two types of samples were investigated: in one of them, the NCs were localized near the deposition depth, and in the other they migrated near the surface. The electrical characteristics were investigated in Schottky junctions by current voltage and capacitance-voltage measurements. Atomic force microscopy (AFM), conductive AFM and scanning probe capacitance microscopy (SCM) were applied to reveal morphology and local electrical properties. The scanning probe methods yielded specific information, and tapping-mode AFM has shown up to 13-nm-high large-area protrusions not seen in the contact-mode AFM. The electrical interaction of the vibrating scanning tip results in virtual deformation of the surface. SCM has revealed NCs deep below the surface not seen by AFM. The electrically active probe yielded significantly better spatial resolution than AFM. The conductive AFM measurements have shown that the Cr-related point defects near the surface are responsible for the leakage of the macroscopic Schottky junctions, and also that NCs near the surface are sensitive to the mechanical and electrical stress induced by the scanning probe. PMID- 21711728 TI - Observation of strong anisotropic forbidden transitions in (001) InGaAs/GaAs single-quantum well by reflectance-difference spectroscopy and its behavior under uniaxial strain. AB - The strong anisotropic forbidden transition has been observed in a series of InGaAs/GaAs single-quantum well with well width ranging between 3 nm and 7 nm at 80 K. Numerical calculations within the envelope function framework have been performed to analyze the origin of the optical anisotropic forbidden transition. It is found that the optical anisotropy of this transition can be mainly attributed to indium segregation effect. The effect of uniaxial strain on in plane optical anisotropy (IPOA) is also investigated. The IPOA of the forbidden transition changes little with strain, while that of the allowed transition shows a linear dependence on strain.PACS 78.66.Fd, 78.20.Bh, 78.20.Fm. PMID- 21711729 TI - Investigation of pre-structured GaAs surfaces for subsequent site-selective InAs quantum dot growth. AB - In this study, we investigated pre-structured (100) GaAs sample surfaces with respect to subsequent site-selective quantum dot growth. Defects occurring in the GaAs buffer layer grown after pre-structuring are attributed to insufficient cleaning of the samples prior to regrowth. Successive cleaning steps were analyzed and optimized. A UV-ozone cleaning is performed at the end of sample preparation in order to get rid of remaining organic contamination. PMID- 21711730 TI - Migration of carbon nanotubes from liquid phase to vapor phase in the refrigerant based nanofluid pool boiling. AB - The migration characteristics of carbon nanotubes from liquid phase to vapor phase in the refrigerant-based nanofluid pool boiling were investigated experimentally. Four types of carbon nanotubes with the outside diameters from 15 to 80 nm and the lengths from 1.5 to 10 MUm were used in the experiments. The refrigerants include R113, R141b and n-pentane. The oil concentration is from 0 to 10 wt.%, the heat flux is from 10 to 100 kW.m-2, and the initial liquid-level height is from 1.3 to 3.4 cm. The experimental results indicate that the migration ratio of carbon nanotube increases with the increase of the outside diameter or the length of carbon nanotube. For the fixed type of carbon nanotube, the migration ratio decreases with the increase of the oil concentration or the heat flux, and increases with the increase of the initial liquid-level height. The migration ratio of carbon nanotube increases with the decrease of dynamic viscosity of refrigerant or the increase of liquid phase density of refrigerant. A model for predicting the migration ratio of carbon nanotubes in the refrigerant based nanofluid pool boiling is proposed, and the predictions agree with 92% of the experimental data within a deviation of +/-20%. PMID- 21711731 TI - Valence band offset of wurtzite InN/SrTiO3 heterojunction measured by x-ray photoelectron spectroscopy. AB - The valence band offset (VBO) of wurtzite indium nitride/strontium titanate (InN/SrTiO3) heterojunction has been directly measured by x-ray photoelectron spectroscopy. The VBO is determined to be 1.26 +/- 0.23 eV and the conduction band offset is deduced to be 1.30 +/- 0.23 eV, indicating the heterojunction has a type-I band alignment. The accurate determination of the valence and conduction band offsets paves a way to the applications of integrating InN with the functional oxide SrTiO3. PMID- 21711732 TI - Ordered GeSi nanorings grown on patterned Si (001) substrates. AB - An easy approach to fabricate ordered pattern using nanosphere lithography and reactive iron etching technology was demonstrated. Long-range ordered GeSi nanorings with 430 nm period were grown on patterned Si (001) substrates by molecular beam epitaxy. The size and shape of rings were closely associated with the size of capped GeSi quantum dots and the Si capping processes. Statistical analysis on the lateral size distribution shows that the high growth temperature and the long-term annealing can improve the uniformity of nanorings.PACS code1.PACS code2.moreMathematics Subject Classification (2000) MSC code1.MSC code2.more. PMID- 21711733 TI - Phase transition on the Si(001) clean surface prepared in UHV MBE chamber: a study by high-resolution STM and in situ RHEED. AB - The Si(001) surface deoxidized by short annealing at T ~ 925 degrees C in the ultrahigh vacuum molecuar beam epitaxy chamber has been in situ investigated using high-resolution scanning tunneling microscopy (STM)and redegreesected high energy electron diffraction (RHEED. RHEED patterns corresponding to (2 * 1) and (4 * 4) structures were observed during sample treatment. The (4 * 4) reconstruction arose at T ? 600 degrees C after annealing. The reconstruction was observed to be reversible: the (4 * 4) structure turned into the (2 * 1) one at T ? 600 degrees C, the (4 * 4) structure appeared again at recurring cooling. The c(8 * 8) reconstruction was revealed by STM at room temperature on the same samples. A fraction of the surface area covered by the c(8 * 8) structure decreased, as the sample cooling rate was reduced. The (2 * 1) structure was observed on the surface free of the c(8 * 8) one. The c(8 * 8) structure has been evidenced to manifest itself as the (4 * 4) one in the RHEED patterns. A model of the c(8 * 8) structure formation has been built on the basis of the STM data. Origin of the high-order structure on the Si(001) surface and its connection with the epinucleation phenomenon are discussed.PACS 68.35.B .68.37.Ef.68.49.Jk.68.47.Fg. PMID- 21711734 TI - Defect induced changes on the excitation transfer dynamics in ZnS/Mn nanowires. AB - Transients of Mn internal 3d5 luminescence in ZnS/Mn nanowires are strongly non exponential. This non-exponential decay arises from an excitation transfer from the Mn ions to so-called killer centers, i.e., non-radiative defects in the nanostructures and is strongly related to the interplay of the characteristic length scales of the sample such as the spatial extensions, the distance between killer centers, and the distance between Mn ions. The transients of the Mn related luminescence can be quantitatively described on the basis of a modified Forster model accounting for reduced dimensionality. Here, we confirm this modified Forster model by varying the number of killer centers systematically. Additional defects were introduced into the ZnS/Mn nanowire samples by irradiation with neon ions and by varying the Mn implantation or the annealing temperature. The temporal behavior of the internal Mn2+ (3d5) luminescence is recorded on a time scale covering almost four orders of magnitude. A correlation between defect concentration and decay behavior of the internal Mn2+ (3d5) luminescence is established and the energy transfer processes in the system of localized Mn ions and the killer centers within ZnS/Mn nanostructures is confirmed. If the excitation transfer between Mn ions and killer centers as well as migration effects between Mn ions are accounted for, and the correct effective dimensionality of the system is used in the model, one is able to describe the decay curves of ZnS/Mn nanostructures in the entire time window. PMID- 21711736 TI - Lateral electrical transport, optical properties and photocurrent measurements in two-dimensional arrays of silicon nanocrystals embedded in SiO2. AB - In this study we investigate the electronic transport, the optical properties, and photocurrent in two-dimensional arrays of silicon nanocrystals (Si NCs) embedded in silicon dioxide, grown on quartz and having sizes in the range between less than 2 and 20 nm. Electronic transport is determined by the collective effect of Coulomb blockade gaps in the Si NCs. Absorption spectra show the well-known upshift of the energy bandgap with decreasing NC size. Photocurrent follows the absorption spectra confirming that it is composed of photo-generated carriers within the Si NCs. In films containing Si NCs with sizes less than 2 nm, strong quantum confinement and exciton localization are observed, resulting in light emission and absence of photocurrent. Our results show that Si NCs are useful building blocks of photovoltaic devices for use as better absorbers than bulk Si in the visible and ultraviolet spectral range. However, when strong quantum confinement effects come into play, carrier transport is significantly reduced due to strong exciton localization and Coulomb blockade effects, thus leading to limited photocurrent. PMID- 21711735 TI - The Role of XPG in Processing (CAG)n/(CTG)n DNA Hairpins. AB - BACKGROUND: During DNA replication or repair, disease-associated (CAG)n/(CTG)n expansion can result from formation of hairpin structures in the repeat tract of the newly synthesized or nicked DNA strand. Recent studies identified a nick directed (CAG)n/(CTG)n hairpin repair (HPR) system that removes (CAG)n/(CTG)n hairpins from human cells via endonucleolytic incisions. Because the process is highly similar to the mechanism by which XPG and XPF endonucleases remove bulky DNA lesions during nucleotide excision repair, we assessed the potential role of XPG in conducting (CAG)n/(CTG)n HPR. RESULTS: To determine if the XPG endonuclease is involved in (CAG)n/(CTG)n hairpin removal, two XPG-deficient cell lines (GM16024 and AG08802) were examined for their ability to process (CAG)n/(CTG)n hairpins in vitro. We demonstrated that the GM16024 cell line processes all hairpin substrates as efficiently as HeLa cells, and that the AG08802 cell line is partially defective in HPR. Analysis of repair intermediates revealed that nuclear extracts from both XPG-deficient lines remove CAG/CTG hairpins via incisions, but the incision products are distinct from those generated in HeLa extracts. We also show that purified recombinant XPG protein greatly stimulates HPR in XPG-deficient extracts by promoting an incision 5' to the hairpin. CONCLUSIONS: Our results strongly suggest that 1) human cells possess multiple pathways to remove (CAG)n/(CTG)n hairpins located in newly synthesized (or nicked) DNA strand; and 2) XPG, although not essential for (CAG)n/(CTG)n hairpin removal, stimulates HPR by facilitating a 5' incision to the hairpin. This study reveals a novel role for XPG in genome-maintenance and implicates XPG in diseases caused by trinucleotide repeat expansion. PMID- 21711737 TI - Thermal conductivity and viscosity measurements of ethylene glycol-based Al2O3 nanofluids. AB - The dispersion and stability of nanofluids obtained by dispersing Al2O3 nanoparticles in ethylene glycol have been analyzed at several concentrations up to 25% in mass fraction. The thermal conductivity and viscosity were experimentally determined at temperatures ranging from 283.15 K to 323.15 K using an apparatus based on the hot-wire method and a rotational viscometer, respectively. It has been found that both thermal conductivity and viscosity increase with the concentration of nanoparticles, whereas when the temperature increases the viscosity diminishes and the thermal conductivity rises. Measured enhancements on thermal conductivity (up to 19%) compare well with literature values when available. New viscosity experimental data yield values more than twice larger than the base fluid. The influence of particle size on viscosity has been also studied, finding large differences that must be taken into account for any practical application. These experimental results were compared with some theoretical models, as those of Maxwell-Hamilton and Crosser for thermal conductivity and Krieger and Dougherty for viscosity. PMID- 21711738 TI - Integrated sensitive on-chip ion field effect transistors based on wrinkled InGaAs nanomembranes. AB - Self-organized wrinkling of pre-strained nanomembranes into nanochannels is used to fabricate a fully integrated nanofluidic device for the development of ion field effect transistors (IFETs). Constrained by the structure and shape of the membrane, the deterministic wrinkling process leads to a versatile variation of channel types such as straight two-way channels, three-way branched channels, or even four-way intersection channels. The fabrication of straight channels is well controllable and offers the opportunity to integrate multiple IFET devices into a single chip. Thus, several IFETs are fabricated on a single chip using a III-V semiconductor substrate to control the ion separation and to measure the ion current of a diluted potassium chloride electrolyte solution. PMID- 21711739 TI - Experimental and theoretical studies of nanofluid thermal conductivity enhancement: a review. AB - Nanofluids, i.e., well-dispersed (metallic) nanoparticles at low- volume fractions in liquids, may enhance the mixture's thermal conductivity, knf, over the base-fluid values. Thus, they are potentially useful for advanced cooling of micro-systems. Focusing mainly on dilute suspensions of well-dispersed spherical nanoparticles in water or ethylene glycol, recent experimental observations, associated measurement techniques, and new theories as well as useful correlations have been reviewed.It is evident that key questions still linger concerning the best nanoparticle-and-liquid pairing and conditioning, reliable measurements of achievable knf values, and easy-to-use, physically sound computer models which fully describe the particle dynamics and heat transfer of nanofluids. At present, experimental data and measurement methods are lacking consistency. In fact, debates on whether the anomalous enhancement is real or not endure, as well as discussions on what are repeatable correlations between knf and temperature, nanoparticle size/shape, and aggregation state. Clearly, benchmark experiments are needed, using the same nanofluids subject to different measurement methods. Such outcomes would validate new, minimally intrusive techniques and verify the reproducibility of experimental results. Dynamic knf models, assuming non-interacting metallic nano-spheres, postulate an enhancement above the classical Maxwell theory and thereby provide potentially additional physical insight. Clearly, it will be necessary to consider not only one possible mechanism but combine several mechanisms and compare predictive results to new benchmark experimental data sets. PMID- 21711740 TI - Effect of phonons on the ac conductance of molecular junctions. AB - We theoretically examine the effect of a single phonon mode on the structure of the frequency dependence of the ac conductance of molecular junctions, in the linear response regime. The conductance is enhanced (suppressed) by the electron phonon interaction when the chemical potential is below (above) the energy of the electronic state on the molecule.PACS numbers: 71.38.-k, 73.21.La, 73.23.-b. PMID- 21711741 TI - Pool boiling of water-Al2O3 and water-Cu nanofluids on horizontal smooth tubes. AB - Experimental investigation of heat transfer during pool boiling of two nanofluids, i.e., water-Al2O3 and water-Cu has been carried out. Nanoparticles were tested at the concentration of 0.01%, 0.1%, and 1% by weight. The horizontal smooth copper and stainless steel tubes having 10 mm OD and 0.6 mm wall thickness formed test heater. The experiments have been performed to establish the influence of nanofluids concentration as well as tube surface material on heat transfer characteristics at atmospheric pressure. The results indicate that independent of concentration nanoparticle material (Al2O3 and Cu) has almost no influence on heat transfer coefficient while boiling of water-Al2O3 or water-Cu nanofluids on smooth copper tube. It seems that heater material did not affect the boiling heat transfer in 0.1 wt.% water-Cu nanofluid, nevertheless independent of concentration, distinctly higher heat transfer coefficient was recorded for stainless steel tube than for copper tube for the same heat flux density. PMID- 21711742 TI - Measurement of the extinction coefficients of magnetic fluids. AB - A novel spectral transmittance approach for measuring the extinction coefficient of magnetic fluids is proposed. The measuring principle and accuracy of the approach are analysed. Experiments are conducted to measure the extinction coefficient of magnetic fluids with different particle volume fractions. The relative uncertainty of experimental data is less than 1.8%. The experimental results indicate that the extinction coefficient of magnetic fluids increases with increase of the volume fraction of suspended magnetic nanoparticles and the optical properties of the particle material have a significant effect on the extinction coefficient of the magnetic fluids. PMID- 21711743 TI - Numerical study of a confined slot impinging jet with nanofluids. AB - BACKGROUND: Heat transfer enhancement technology concerns with the aim of developing more efficient systems to satisfy the increasing demands of many applications in the fields of automotive, aerospace, electronic and process industry. A solution for obtaining efficient cooling systems is represented by the use of confined or unconfined impinging jets. Moreover, the possibility of increasing the thermal performances of the working fluids can be taken into account, and the introduction of nanoparticles in a base fluid can be considered. RESULTS: In this article, a numerical investigation on confined impinging slot jet working with a mixture of water and Al2O3 nanoparticles is described. The flow is turbulent and a constant temperature is applied on the impinging. A single-phase model approach has been adopted. Different geometric ratios, particle volume concentrations and Reynolds number have been considered to study the behavior of the system in terms of average and local Nusselt number, convective heat transfer coefficient and required pumping power profiles, temperature fields and stream function contours. CONCLUSIONS: The dimensionless stream function contours show that the intensity and size of the vortex structures depend on the confining effects, given by H/W ratio, Reynolds number and particle concentrations. Furthermore, for increasing concentrations, nanofluids realize increasing fluid bulk temperature, as a result of the elevated thermal conductivity of mixtures. The local Nusselt number profiles show the highest values at the stagnation point, and the lowest at the end of the heated plate. The average Nusselt number increases for increasing particle concentrations and Reynolds numbers; moreover, the highest values are observed for H/W = 10, and a maximum increase of 18% is detected at a concentration equal to 6%. The required pumping power as well as Reynolds number increases and particle concentrations grow, which is almost 4.8 times greater than the values calculated in the case of base fluid.List of symbols. PMID- 21711744 TI - Anti-reflective nano- and micro-structures on 4H-SiC for photodiodes. AB - In this study, nano-scale honeycomb-shaped structures with anti-reflection properties were successfully formed on SiC. The surface of 4H-SiC wafer after a conventional photolithography process was etched by inductively coupled plasma. We demonstrate that the reflection characteristic of the fabricated photodiodes has significantly reduced by 55% compared with the reference devices. As a result, the optical response Iillumination/Idark of the 4H-SiC photodiodes were enhanced up to 178%, which can be ascribed primarily to the improved light trapping in the proposed nano-scale texturing. PMID- 21711745 TI - High-quality reduced graphene oxide-nanocrystalline platinum hybrid materials prepared by simultaneous co-reduction of graphene oxide and chloroplatinic acid. AB - Reduced graphene oxide-nanocrystalline platinum (RGO-Pt) hybrid materials were synthesized by simultaneous co-reduction of graphene oxide (GO) and chloroplatinic acid with sodium citrate in water at 80 degrees C, of pH 7 and 10. The resultant RGO-Pt hybrid materials were characterized using transmission electron microscopy (TEM), powder X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Fourier-transform infrared spectroscopy, and thermogravimetric analysis. Platinum (Pt) nanoparticles were anchored randomly onto the reduced GO (RGO) sheets with average mean diameters of 1.76 (pH 7) and 1.93 nm (pH 10). The significant Pt diffraction peaks and the decreased intensity of (002) peak in the XRD patterns of RGO-Pt hybrid materials confirmed that the Pt nanoparticles were anchored onto the RGO sheets and intercalated into the stacked RGO layers at these two pH values. The Pt loadings for the hybrid materials were determined as 36.83 (pH 7) and 49.18% (pH 10) by mass using XPS analysis. With the assistance of oleylamine, the resultant RGO-Pt hybrid materials were soluble in the nonpolar organic solvents, and the dispersion could remain stable for several months. PMID- 21711746 TI - Two-phase numerical model for thermal conductivity and convective heat transfer in nanofluids. AB - Due to the numerous applications of nanofluids, investigating and understanding of thermophysical properties of nanofluids has currently become one of the core issues. Although numerous theoretical and numerical models have been developed by previous researchers to understand the mechanism of enhanced heat transfer in nanofluids; to the best of our knowledge these models were limited to the study of either thermal conductivity or convective heat transfer of nanofluids. We have developed a numerical model which can estimate the enhancement in both the thermal conductivity and convective heat transfer in nanofluids. It also aids in understanding the mechanism of heat transfer enhancement. The study reveals that the nanoparticle dispersion in fluid medium and nanoparticle heat transport phenomenon are equally important in enhancement of thermal conductivity. However, the enhancement in convective heat transfer was caused mainly due to the nanoparticle heat transport mechanism. Ability of this model to be able to understand the mechanism of convective heat transfer enhancement distinguishes the model from rest of the available numerical models. PMID- 21711747 TI - Temperature- and thickness-dependent elastic moduli of polymer thin films. AB - The mechanical properties of polymer ultrathin films are usually different from those of their counterparts in bulk. Understanding the effect of thickness on the mechanical properties of these films is crucial for their applications. However, it is a great challenge to measure their elastic modulus experimentally with in situ heating. In this study, a thermodynamic model for temperature- (T) and thickness (h)-dependent elastic moduli of polymer thin films Ef(T,h) is developed with verification by the reported experimental data on polystyrene (PS) thin films. For the PS thin films on a passivated substrate, Ef(T,h) decreases with the decreasing film thickness, when h is less than 60 nm at ambient temperature. However, the onset thickness (h*), at which thickness Ef(T,h) deviates from the bulk value, can be modulated by T. h* becomes larger at higher T because of the depression of the quenching depth, which determines the thickness of the surface layer delta. PMID- 21711748 TI - Stability of nanofluids in quiescent and shear flow fields. AB - An experimental study was conducted to investigate the structural stability of ethylene glycol-based titanium dioxide nanoparticle suspensions (nanofluids) prepared by two-step method. The effects of particle concentration, fluid temperature, shear rate and shear duration were examined. Particle size and thermal conductivity measurements in quiescent state indicated the existence of aggregates and that they were stable in temperatures up to 60 degrees C. Shear stability tests suggested that the structure of nanoparticle aggregates was stable in a shear interval of 500-3000 s-1 measured over a temperature range of 20-60 degrees C. These findings show directions to resolve controversies surrounding the underlying mechanisms of thermal conduction and convective heat transfer of nanofluids. PMID- 21711749 TI - Structural and optical properties of germanium nanostructures on Si(100) and embedded in high-k oxides. AB - The structural and optical properties of Ge quantum dots (QDs) grown on Si(001) for mid-infrared photodetector and Ge nanocrystals embedded in oxide matrices for floating gate memory devices are presented. The infrared photoluminescence (PL) signal from Ge islands has been studied at a low temperature. The temperature- and bias-dependent photocurrent spectra of a capped Si/SiGe/Si(001) QDs infrared photodetector device are presented. The properties of Ge nanocrystals of different size and density embedded in high-k matrices grown using radio frequency magnetron sputtering have been studied. Transmission electron micrographs have revealed the formation of isolated spherical Ge nanocrystals in high-k oxide matrix of sizes ranging from 4 to 18 nm. Embedded nanocrystals in high band gap oxides have been found to act as discrete trapping sites for exchanging charge carriers with the conduction channel by direct tunneling that is desired for applications in floating gate memory devices. PMID- 21711750 TI - Nanofluid optical property characterization: towards efficient direct absorption solar collectors. AB - Suspensions of nanoparticles (i.e., particles with diameters < 100 nm) in liquids, termed nanofluids, show remarkable thermal and optical property changes from the base liquid at low particle loadings. Recent studies also indicate that selected nanofluids may improve the efficiency of direct absorption solar thermal collectors. To determine the effectiveness of nanofluids in solar applications, their ability to convert light energy to thermal energy must be known. That is, their absorption of the solar spectrum must be established. Accordingly, this study compares model predictions to spectroscopic measurements of extinction coefficients over wavelengths that are important for solar energy (0.25 to 2.5 MUm). A simple addition of the base fluid and nanoparticle extinction coefficients is applied as an approximation of the effective nanofluid extinction coefficient. Comparisons with measured extinction coefficients reveal that the approximation works well with water-based nanofluids containing graphite nanoparticles but less well with metallic nanoparticles and/or oil-based fluids. For the materials used in this study, over 95% of incoming sunlight can be absorbed (in a nanofluid thickness >=10 cm) with extremely low nanoparticle volume fractions - less than 1 * 10-5, or 10 parts per million. Thus, nanofluids could be used to absorb sunlight with a negligible amount of viscosity and/or density (read: pumping power) increase. PMID- 21711751 TI - Constructal blade shape in nanofluids. AB - Blade configuration of nanofluids has been proven to perform much better than dispersed configuration for some heat conduction systems. The analytical analysis and numerical calculation are made for the cylinder--shaped and regular rectangular-prism--shaped building blocks of the blade-configured heat conduction systems (using nanofluids as the heat conduction media) to find the optimal cross sectional shape for the nanoparticle blade under the same composing materials, composition ratio, volumetric heat generation rate, and total building block volume. The regular-triangular-prism--shaped blade has been proven to perform better than all the other three kinds of blades, namely, the regular-rectangular prism--shaped blade, the regular-hexagonal-prism--shaped blade, and the cylinder- shaped blade. Thus, the regular-triangular-prism--shaped blade is selected as the optimally shaped blade for the two kinds of building blocks that are considered in this study. It is also proven that the constructal cylinder--regular triangular-prism building block performs better than the constructal regular rectangular-prism--regular-triangular-prism building block. PMID- 21711752 TI - Crystallographic plane-orientation dependent atomic force microscopy-based local oxidation of silicon carbide. AB - The effect of crystalline plane orientations of Silicon carbide (SiC) (a-, m-, and c-planes) on the local oxidation on 4H-SiC using atomic force microscopy (AFM) was investigated. It has been found that the AFM-based local oxidation (AFM LO) rate on SiC is closely correlated to the atomic planar density values of different crystalline planes (a-plane, 7.45 cm-2; c-plane, 12.17 cm-2; and m plane, 6.44 cm-2). Specifically, at room temperature and under about 40% humidity with a scan speed of 0.5 MUm/s, the height of oxides on a- and m-planes 4H-SiC is 6.5 and 13 nm, respectively, whereas the height of oxides on the c-plane increased up to 30 nm. In addition, the results of AFM-LO with thermally grown oxides on the different plane orientations in SiC are compared. PMID- 21711753 TI - The molecular dynamic simulation on impact and friction characters of nanofluids with many nanoparticles system. AB - Impact and friction model of nanofluid for molecular dynamics simulation was built which consists of two Cu plates and Cu-Ar nanofluid. The Cu-Ar nanofluid model consisted of eight spherical copper nanoparticles with each particle diameter of 4 nm and argon atoms as base liquid. The Lennard-Jones potential function was adopted to deal with the interactions between atoms. Thus motion states and interaction of nanoparticles at different time through impact and friction process could be obtained and friction mechanism of nanofluids could be analyzed. In the friction process, nanoparticles showed motions of rotation and translation, but effected by the interactions of nanoparticles, the rotation of nanoparticles was trapped during the compression process. In this process, agglomeration of nanoparticles was very apparent, with the pressure increasing, the phenomenon became more prominent. The reunited nanoparticles would provide supporting efforts for the whole channel, and in the meantime reduced the contact between two friction surfaces, therefore, strengthened lubrication and decreased friction. In the condition of overlarge positive pressure, the nanoparticles would be crashed and formed particles on atomic level and strayed in base liquid. PMID- 21711754 TI - Infrared thermometry study of nanofluid pool boiling phenomena. AB - Infrared thermometry was used to obtain first-of-a-kind, time- and space resolved data for pool boiling phenomena in water-based nanofluids with diamond and silica nanoparticles at low concentration (<0.1 vol.%). In addition to macroscopic parameters like the average heat transfer coefficient and critical heat flux [CHF] value, more fundamental parameters such as the bubble departure diameter and frequency, growth and wait times, and nucleation site density [NSD] were directly measured for a thin, resistively heated, indium-tin-oxide surface deposited onto a sapphire substrate. Consistent with other nanofluid studies, the nanoparticles caused deterioration in the nucleate boiling heat transfer (by as much as 50%) and an increase in the CHF (by as much as 100%). The bubble departure frequency and NSD were found to be lower in nanofluids compared with water for the same wall superheat. Furthermore, it was found that a porous layer of nanoparticles built up on the heater surface during nucleate boiling, which improved surface wettability compared with the water-boiled surfaces. Using the prevalent nucleate boiling models, it was possible to correlate this improved surface wettability to the experimentally observed reductions in the bubble departure frequency, NSD, and ultimately to the deterioration in the nucleate boiling heat transfer and the CHF enhancement. PMID- 21711755 TI - Heterogeneous nanofluids: natural convection heat transfer enhancement. AB - Convective heat transfer using different nanofluid types is investigated. The domain is differentially heated and nanofluids are treated as heterogeneous mixtures with weak solutal diffusivity and possible Soret separation. Owing to the pronounced Soret effect of these materials in combination with a considerable solutal expansion, the resulting solutal buoyancy forces could be significant and interact with the initial thermal convection. A modified formulation taking into account the thermal conductivity, viscosity versus nanofluids type and concentration and the spatial heterogeneous concentration induced by the Soret effect is presented. The obtained results, by solving numerically the full governing equations, are found to be in good agreement with the developed solution based on the scale analysis approach. The resulting convective flows are found to be dependent on the local particle concentration phi and the corresponding solutal to thermal buoyancy ratio N. The induced nanofluid heterogeneity showed a significant heat transfer modification. The heat transfer in natural convection increases with nanoparticle concentration but remains less than the enhancement previously underlined in forced convection case. PMID- 21711756 TI - Theoretical study of the role of metallic contacts in probing transport features of pure and defected graphene nanoribbons. AB - Understanding the roles of disorder and metal/graphene interface on the electronic and transport properties of graphene-based systems is crucial for a consistent analysis of the data deriving from experimental measurements. The present work is devoted to the detailed study of graphene nanoribbon systems by means of self-consistent quantum transport calculations. The computational formalism is based on a coupled Schrodinger/Poisson approach that respects both chemistry and electrostatics, applied to pure/defected graphene nanoribbons (ideally or end-contacted by various fcc metals). We theoretically characterize the formation of metal-graphene junctions as well as the effects of backscattering due to the presence of vacancies and impurities. Our results evidence that disorder can infer significant alterations on the conduction process, giving rise to mobility gaps in the conductance distribution. Moreover, we show the importance of metal-graphene coupling that gives rise to doping related phenomena and a degradation of conductance quantization characteristics. PMID- 21711757 TI - Optimal synthesis and characterization of Ag nanofluids by electrical explosion of wires in liquids. AB - Silver nanoparticles were produced by electrical explosion of wires in liquids with no additive. In this study, we optimized the fabrication method and examined the effects of manufacturing process parameters. Morphology and size of the Ag nanoparticles were determined using transmission electron microscopy and field emission scanning electron microscopy. Size and zeta potential were analyzed using dynamic light scattering. A response optimization technique showed that optimal conditions were achieved when capacitance was 30 MUF, wire length was 38 mm, liquid volume was 500 mL, and the liquid type was deionized water. The average Ag nanoparticle size in water was 118.9 nm and the zeta potential was 42.5 mV. The critical heat flux of the 0.001-vol.% Ag nanofluid was higher than pure water. PMID- 21711758 TI - Controlling exchange bias in Fe3O4/FeO composite particles prepared by pulsed laser irradiation. AB - Spherical iron oxide nanocomposite particles composed of magnetite and wustite have been successfully synthesized using a novel method of pulsed laser irradiation in ethyl acetate. Both the size and the composition of nanocomposite particles are controlled by laser irradiation condition. Through tuning the laser fluence, the Fe3O4/FeO phase ratio can be precisely controlled, and the magnetic properties of final products can also be regulated. This work presents a successful example of the fabrication of ferro (ferri) (FM)/antiferromagnetic (AFM) systems with high chemical stability. The results show this novel simple method as widely extendable to various FM/AFM nanocomposite systems. PMID- 21711760 TI - Experimental study of combustion characteristics of nanoscale metal and metal oxide additives in biofuel (ethanol). AB - An experimental investigation of the combustion behavior of nano-aluminum (n-Al) and nano-aluminum oxide (n-Al2O3) particles stably suspended in biofuel (ethanol) as a secondary energy carrier was conducted. The heat of combustion (HoC) was studied using a modified static bomb calorimeter system. Combustion element composition and surface morphology were evaluated using a SEM/EDS system. N-Al and n-Al2O3 particles of 50- and 36-nm diameters, respectively, were utilized in this investigation. Combustion experiments were performed with volume fractions of 1, 3, 5, 7, and 10% for n-Al, and 0.5, 1, 3, and 5% for n-Al2O3. The results indicate that the amount of heat released from ethanol combustion increases almost linearly with n-Al concentration. N-Al volume fractions of 1 and 3% did not show enhancement in the average volumetric HoC, but higher volume fractions of 5, 7, and 10% increased the volumetric HoC by 5.82, 8.65, and 15.31%, respectively. N-Al2O3 and heavily passivated n-Al additives did not participate in combustion reactively, and there was no contribution from Al2O3 to the HoC in the tests. A combustion model that utilized Chemical Equilibrium with Applications was conducted as well and was shown to be in good agreement with the experimental results. PMID- 21711759 TI - Synthesis, structure, and opto-electronic properties of organic-based nanoscale heterojunctions. AB - Enormous research effort has been put into optimizing organic-based opto electronic systems for efficient generation of free charge carriers. This optimization is mainly due to typically high dissociation energy (0.1-1 eV) and short diffusion length (10 nm) of excitons in organic materials. Inherently, interplay of microscopic structural, chemical, and opto-electronic properties plays crucial role. We show that employing and combining advanced scanning probe techniques can provide us significant insight into the correlation of these properties. By adjusting parameters of contact- and tapping-mode atomic force microscopy (AFM), we perform morphologic and mechanical characterizations (nanoshaving) of organic layers, measure their electrical conductivity by current sensing AFM, and deduce work functions and surface photovoltage (SPV) effects by Kelvin force microscopy using high spatial resolution. These data are further correlated with local material composition detected using micro-Raman spectroscopy and with other electronic transport data. We demonstrate benefits of this multi-dimensional characterizations on (i) bulk heterojunction of fully organic composite films, indicating differences in blend quality and component segregation leading to local shunts of photovoltaic cell, and (ii) thin-film heterojunction of polypyrrole (PPy) electropolymerized on hydrogen-terminated diamond, indicating covalent bonding and transfer of charge carriers from PPy to diamond. PMID- 21711761 TI - Effect of particle size on the thermal conductivity of nanofluids containing metallic nanoparticles. AB - A one-parameter model is presented for the thermal conductivity of nanofluids containing dispersed metallic nanoparticles. The model takes into account the decrease in thermal conductivity of metal nanoparticles with decreasing size. Although literature data could be correlated well using the model, the effect of the size of the particles on the effective thermal conductivity of the nanofluid could not be elucidated from these data. Therefore, new thermal conductivity measurements are reported for six nanofluids containing silver nanoparticles of different sizes and volume fractions. The results provide strong evidence that the decrease in the thermal conductivity of the solid with particle size must be considered when developing models for the thermal conductivity of nanofluids. PMID- 21711762 TI - Viscosity affected by nanoparticle aggregation in Al2O3-water nanofluids. AB - An investigation on viscosity was conducted 2 weeks after the Al2O3-water nanofluids having dispersants were prepared at the volume concentration of 1-5%. The shear stress was observed with a non-Newtonian behavior. On further ultrasonic agitation treatment, the nanofluids resumed as a Newtonian fluids. The relative viscosity increases as the volume concentrations increases. At 5% volume concentration, an increment was about 60% in the re-ultrasonication nanofluids in comparison with the base fluid. The microstructure analysis indicates that a higher nanoparticle aggregation had been observed in the nanofluids before re ultrasonication. PMID- 21711763 TI - Electron cotunneling through doubly occupied quantum dots: effect of spin configuration. AB - A microscopic theory is presented for electron cotunneling through doubly occupied quantum dots in the Coulomb blockade regime. Beyond the semiclassic framework of phenomenological models, a fully quantum mechanical solution for cotunneling of electrons through a one-dimensional quantum dot is obtained using a quantum transmitting boundary method without any fitting parameters. It is revealed that the cotunneling conductance exhibits strong dependence on the spin configuration of the electrons confined inside the dot. Especially for the triplet configuration, the conductance shows an obvious deviation from the well known quadratic dependence on the applied bias voltage. Furthermore, it is found that the cotunneling conductance reveals more sensitive dependence on the barrier width than the height. PMID- 21711764 TI - Effect of Peierls transition in armchair carbon nanotube on dynamical behaviour of encapsulated fullerene. AB - The changes of dynamical behaviour of a single fullerene molecule inside an armchair carbon nanotube caused by the structural Peierls transition in the nanotube are considered. The structures of the smallest C20 and Fe@C20 fullerenes are computed using the spin-polarized density functional theory. Significant changes of the barriers for motion along the nanotube axis and rotation of these fullerenes inside the (8,8) nanotube are found at the Peierls transition. It is shown that the coefficients of translational and rotational diffusions of these fullerenes inside the nanotube change by several orders of magnitude. The possibility of inverse orientational melting, i.e. with a decrease of temperature, for the systems under consideration is predicted. PMID- 21711765 TI - Experimental study and analysis of lubricants dispersed with nano Cu and TiO2 in a four-stroke two wheeler. AB - The present investigation summarizes detailed experimental studies with standard lubricants of commercial quality known as Racer-4 of Hindustan Petroleum Corporation (India) dispersed with different mass concentrations of nanoparticles of Cu and TiO2. The test bench is fabricated with a four-stroke Hero-Honda motorbike hydraulically loaded at the rear wheel with proper instrumentation to record the fuel consumption, the load on the rear wheel, and the linear velocity. The whole range of data obtained on a stationery bike is subjected to regression analysis to arrive at various relationships between fuel consumption as a function of brake power, linear velocity, and percentage mass concentration of nanoparticles in the lubricant. The empirical relation correlates with the observed data with reasonable accuracy. Further, extension of the analysis by developing a mathematical model has revealed a definite improvement in brake thermal efficiency which ultimately affects the fuel economy by diminishing frictional power in the system with the introduction of nanoparticles into the lubricant. The performance of the engine seems to be better with nano Cu-Racer-4 combination than the one with nano TiO2. PMID- 21711766 TI - Nonlinear dynamics of non-equilibrium holes in p-type modulation-doped GaInNAs/GaAs quantum wells. AB - Nonlinear charge transport parallel to the layers of p-modulation-doped GaInNAs/GaAs quantum wells (QWs) is studied both theoretically and experimentally. Experimental results show that at low temperature, T = 13 K, the presence of an applied electric field of about 6 kV/cm leads to the heating of the high mobility holes in the GaInNAs QWs, and their real-space transfer (RST) into the low-mobility GaAs barriers. This results in a negative differential mobility and self-generated oscillatory instabilities in the RST regime. We developed an analytical model based upon the coupled nonlinear dynamics of the real-space hole transfer and of the interface potential barrier controlled by space-charge in the doped GaAs layer. Our simulation results predict dc bias dependent self-generated current oscillations with frequencies in the high microwave range. PMID- 21711767 TI - Defect-related hysteresis in nanotube-based nano-electromechanical systems. AB - The electronic properties of multi-walled carbon nanotubes (MWCNTs) depend on the positions of their walls with respect to neighboring shells. This fact can enable several applications of MWCNTs as nano-electromechanical systems (NEMS). In this article, we report the findings of a first-principles study on the stability and dynamics of point defects in double-walled carbon nanotubes (DWCNTs) and their role in the response of the host systems under inter-tube displacement. Key defect-related effects, namely, sudden energy changes and hysteresis, are identified, and their relevance to a host of MWCNT-based NEMS is highlighted. The results also demonstrate the dependence of these effects on defect clustering and chirality of DWCNT shells. PMID- 21711768 TI - Neuroprotective effects of alpha lipoic Acid on haloperidol-induced oxidative stress in the rat brain. AB - Haloperidol is an antipsychotic drug that exerts its' antipsychotic effects by inhibiting dopaminergic neurons. Although the exact pathophysiology of haloperidol extrapyramidal symptoms are not known, the role of reactive oxygen species in inducing oxidative stress has been proposed as one of the mechanisms of prolonged haloperidol-induced neurotoxicity. In the present study, we evaluate the protective effect of alpha lipoic acid against haloperidol-induced oxidative stress in the rat brain. Sprague Dawley rats were divided into control, alpha lipoic acid alone (100 mg/kg p.o for 21 days), haloperidol alone (2 mg/kg i.p for 21 days), and haloperidol with alpha lipoic acid groups (for 21 days). Haloperidol treatment significantly decreased levels of the brain antioxidant enzymes super oxide dismutase and glutathione peroxidase and concurrent treatment with alpha lipoic acid significantly reversed the oxidative effects of haloperidol. Histopathological changes revealed significant haloperidol-induced damage in the cerebral cortex, internal capsule, and substantia nigra. Alpha lipoic acid significantly reduced this damage and there were very little neuronal atrophy. Areas of angiogenesis were also seen in the alpha lipoic acid-treated group. In conclusion, the study proves that alpha lipoic acid treatment significantly reduces haloperidol-induced neuronal damage. PMID- 21711769 TI - Monodisperse upconversion GdF3:Yb, Er rhombi by microwave-assisted synthesis. AB - We have synthesized a variety of monodisperse colloidal GdF3:Yb, Er upconversion nanocrystals with different shape, size, and dopants by microwave-assisted synthesis. Typical upconversion emission from Er3+ was observed. In addition to highly monodisperse spherical particles, we were able to prepare monodispersed rhombic-shaped slices that showed a tendency for self-assembly into stacks. PMID- 21711770 TI - Nanostructured titania films sensitized by quantum dot chalcogenides. AB - The optical and structural properties of cadmium and lead sulfide nanocrystals deposited on mesoporous TiO2 substrates via the successive ionic layer adsorption and reaction method were comparatively investigated by reflectance, transmittance, micro-Raman and photoluminescence measurements. Enhanced interfacial electron transfer is evidenced upon direct growth of both CdS and PbS on TiO2 through the marked quenching of their excitonic emission. The optical absorbance of CdS/TiO2 can be tuned over a narrow spectral range. On the other side PbS/TiO2 exhibits a remarkable band gap tunability extending from the visible to the near infrared range, due to the distinct quantum size effects of PbS quantum dots. However, PbS/TiO2 suffers from severe degradation upon air exposure. Degradation effects are much less pronounced for CdS/TiO2 that is appreciably more stable, though it degrades readily upon visible light illumination. PMID- 21711771 TI - Preparation of stable magnetic nanofluids containing Fe3O4@PPy nanoparticles by a novel one-pot route. AB - Stable magnetic nanofluids containing Fe3O4@Polypyrrole (PPy) nanoparticles (NPs) were prepared by using a facile and novel method, in which one-pot route was used. FeCl3.6H2O was applied as the iron source, and the oxidizing agent to produce PPy. Trisodium citrate (Na3cit) was used as the reducing reagent to form Fe3O4 NPs. The as-prepared nanofluid can keep long-term stability. The Fe3O4@PPy NPs can still keep dispersing well after the nanofluid has been standing for 1 month and no sedimentation is found. The polymerization reaction of the pyrrole monomers took place with Fe3+ ions as the initiator, in which these Fe3+ ions remained in the solution adsorbed on the surface of the Fe3O4 NPs. Thus, the core shell NPs of Fe3O4@PPy were obtained. The particle size of the as-prepared Fe3O4@PPy can be easily controlled from 7 to 30 nm by the polymerization reaction of the pyrrole monomers. The steric stabilization and weight of the NPs affect the stability of the nanofluids. The as-prepared Fe3O4@PPy NPs exhibit superparamagnetic behavior. PMID- 21711772 TI - Fabrication and evolution of multilayer silver nanofilms for surface-enhanced Raman scattering sensing of arsenate. AB - Surface-enhanced Raman scattering (SERS) has recently been investigated extensively for chemical and biomolecular sensing. Multilayer silver (Ag) nanofilms deposited on glass slides by a simple electroless deposition process have been fabricated as active substrates (Ag/GL substrates) for arsenate SERS sensing. The nanostructures and layer characteristics of the multilayer Ag films could be tuned by varying the concentrations of reactants (AgNO3/BuNH2) and reaction time. A Ag nanoparticles (AgNPs) double-layer was formed by directly reducing Ag+ ions on the glass surfaces, while a top layer (3rd-layer) of Ag dendrites was deposited on the double-layer by self-assembling AgNPs or AgNPs aggregates which had already formed in the suspension. The SERS spectra of arsenate showed that characteristic SERS bands of arsenate appear at approximately 780 and 420 cm-1, and the former possesses higher SERS intensity. By comparing the peak heights of the approximately 780 cm-1 band of the SERS spectra, the optimal Ag/GL substrate has been obtained for the most sensitive SERS sensing of arsenate. Using this optimal substrate, the limit of detection (LOD) of arsenate was determined to be approximately 5 MUg.l-1. PMID- 21711773 TI - Correction: Biofabrication of anisotropic gold nanotriangles using extract of endophytic Aspergillus clavatus as a dual functional reductant and stabilizer. PMID- 21711774 TI - Novel docetaxel-loaded nanoparticles based on poly(lactide-co-caprolactone) and poly(lactide-co-glycolide-co-caprolactone) for prostate cancer treatment: formulation, characterization, and cytotoxicity studies. AB - Docetaxel (Dtx) chemotherapy is the optional treatment in patients with hormone refractory metastatic prostate cancer, and Dtx-loaded polymeric nanoparticles (NPs) have the potential to induce durable clinical responses. However, alternative formulations are needed to overcome the serious side effects, also due to the adjuvant used, and to improve the clinical efficacy of the drug.In the present study, two novel biodegradable block-copolymers, poly(lactide-co caprolactone) (PLA-PCL) and poly(lactide-co-caprolactone-co-glycolide) (PLGA PCL), were explored for the formulation of Dtx-loaded NPs and compared with PLA- and PLGA-NPs. The nanosystems were prepared by an original nanoprecipitation method, using Pluronic F-127 as surfactant agent, and were characterized in terms of morphology, size distribution, encapsulation efficiency, crystalline structure, and in vitro release. To evaluate the potential anticancer efficacy of a nanoparticulate system, in vitro cytotoxicity studies on human prostate cancer cell line (PC3) were carried out. NPs were found to be of spherical shape with an average diameter in the range of 100 to 200 nm and a unimodal particle size distribution. Dtx was incorporated into the PLGA-PCL NPs with higher (p < 0.05) encapsulation efficiency than that of other polymers. Differential scanning calorimetry suggested that Dtx was molecularly dispersed in the polymeric matrices. In vitro drug release study showed that release profiles of Dtx varied on the bases of characteristics of polymers used for formulation. PLA-PCL and PLGA-PCL drug loaded NPs shared an overlapping release profiles, and are able to release about 90% of drug within 6 h, when compared with PLA- and PLGA-NPs. Moreover, cytotoxicity studies demonstrated advantages of the Dtx-loaded PLGA-PCL NPs over pure Dtx in both time- and concentration-dependent manner. In particular, an increase of 20% of PC3 growth inhibition was determined by PLGA PCL NPs with respect to free drug after 72 h incubation and at all tested Dtx concentration. In summary, PLGA-PCL copolymer may be considered as an attractive and promising polymeric material for the formulation of Dtx NPs as delivery system for prostate cancer treatment, and can also be pursued as a validated system in a more large context. PMID- 21711775 TI - Nanomechanical properties of alpha-synuclein amyloid fibrils: a comparative study by nanoindentation, harmonic force microscopy, and Peakforce QNM. AB - We report on the use of three different atomic force spectroscopy modalities to determine the nanomechanical properties of amyloid fibrils of the human alpha synuclein protein. alpha-Synuclein forms fibrillar nanostructures of approximately 10 nm diameter and lengths ranging from 100 nm to several microns, which have been associated with Parkinson's disease. Atomic force microscopy (AFM) has been used to image the morphology of these protein fibrils deposited on a flat surface. For nanomechanical measurements, we used single-point nanoindentation, in which the AFM tip as the indenter is moved vertically to the fibril surface and back while the force is being recorded. We also used two recently developed AFM surface property mapping techniques: Harmonic force microscopy (HarmoniX) and Peakforce QNM. These modalities allow extraction of mechanical parameters of the surface with a lateral resolution and speed comparable to tapping-mode AFM imaging. Based on this phenomenological study, the elastic moduli of the alpha-synuclein fibrils determined using these three different modalities are within the range 1.3-2.1 GPa. We discuss the relative merits of these three methods for the determination of the elastic properties of protein fibrils, particularly considering the differences and difficulties of each method. PMID- 21711776 TI - Micro&Nano2010 - Special Symposium on Nanomaterials for sensing and energy harvesting devices. PMID- 21711778 TI - Thermal, dielectrical and mechanical response of alpha and beta-poly(vinilydene fluoride)/Co-MgO nanocomposites. AB - Nanocomposites of the self-forming core-shell Co-MgO nanoparticles, which were of approximately 100 nm in diameter, and poly(vinylidene fluoride) (PVDF) polymer have been prepared. When the polymer is crystallized in the alpha-phase, the introduction of the nanoparticles leads to nucleation of the gamma-phase of PVDF, increasing also the melting temperature of the polymer. With the introduction of the Co-MgO particles, the dielectric constant of the material slightly increases and the storage modulus decreases with respect to the values obtained for the pure polymer. PMID- 21711777 TI - Defect symmetry influence on electronic transport of zigzag nanoribbons. AB - The electronic transport of zigzag-edged graphene nanoribbon (ZGNR) with local Stone-Wales (SW) defects is systematically investigated by first principles calculations. While both symmetric and asymmetric SW defects give rise to complete electron backscattering region, the well-defined parity of the wave functions in symmetric SW defects configuration is preserved. Its signs are changed for the highest-occupied electronic states, leading to the absence of the first conducting plateau. The wave function of asymmetric SW configuration is very similar to that of the pristine GNR, except for the defective regions. Unexpectedly, calculations predict that the asymmetric SW defects are more favorable to electronic transport than the symmetric defects configuration. These distinct transport behaviors are caused by the different couplings between the conducting subbands influenced by wave function alterations around the charge neutrality point. PMID- 21711779 TI - Quantum interference effect in electron tunneling through a quantum-dot-ring spin valve. AB - Spin-dependent transport through a quantum-dot (QD) ring coupled to ferromagnetic leads with noncollinear magnetizations is studied theoretically. Tunneling current, current spin polarization and tunnel magnetoresistance (TMR) as functions of the bias voltage and the direct coupling strength between the two leads are analyzed by the nonequilibrium Green's function technique. It is shown that the magnitudes of these quantities are sensitive to the relative angle between the leads' magnetic moments and the quantum interference effect originated from the inter-lead coupling. We pay particular attention on the Coulomb blockade regime and find the relative current magnitudes of different magnetization angles can be reversed by tuning the inter-lead coupling strength, resulting in sign change of the TMR. For large enough inter-lead coupling strength, the current spin polarizations for parallel and antiparallel magnetic configurations will approach to unit and zero, respectively.PACS numbers: PMID- 21711780 TI - Enhancing surface heat transfer by carbon nanofins: towards an alternative to nanofluids? AB - BACKGROUND: Nanofluids are suspensions of nanoparticles and fibers which have recently attracted much attention because of their superior thermal properties. Nevertheless, it was proven that, due to modest dispersion of nanoparticles, such high expectations often remain unmet. In this article, by introducing the notion of nanofin, a possible solution is envisioned, where nanostructures with high aspect-ratio are sparsely attached to a solid surface (to avoid a significant disturbance on the fluid dynamic structures), and act as efficient thermal bridges within the boundary layer. As a result, particles are only needed in a small region of the fluid, while dispersion can be controlled in advance through design and manufacturing processes. RESULTS: Toward the end of implementing the above idea, we focus on single carbon nanotubes to enhance heat transfer between a surface and a fluid in contact with it. First, we investigate the thermal conductivity of the latter nanostructures by means of classical non-equilibrium molecular dynamics simulations. Next, thermal conductance at the interface between a single wall carbon nanotube (nanofin) and water molecules is assessed by means of both steady-state and transient numerical experiments. CONCLUSIONS: Numerical evidences suggest a pretty favorable thermal boundary conductance (order of 107 W.m-2.K-1) which makes carbon nanotubes potential candidates for constructing nanofinned surfaces. PMID- 21711781 TI - Transport through a strongly coupled graphene quantum dot in perpendicular magnetic field. AB - We present transport measurements on a strongly coupled graphene quantum dot in a perpendicular magnetic field. The device consists of an etched single-layer graphene flake with two narrow constrictions separating a 140 nm diameter island from source and drain graphene contacts. Lateral graphene gates are used to electrostatically tune the device. Measurements of Coulomb resonances, including constriction resonances and Coulomb diamonds prove the functionality of the graphene quantum dot with a charging energy of approximately 4.5 meV. We show the evolution of Coulomb resonances as a function of perpendicular magnetic field, which provides indications of the formation of the graphene specific 0th Landau level. Finally, we demonstrate that the complex pattern superimposing the quantum dot energy spectra is due to the formation of additional localized states with increasing magnetic field. PMID- 21711782 TI - ZnSe nanotrenches: formation mechanism and its role as a 1D template. AB - High-resolution transmission electron microscopy was used to characterize the microstructures of ZnSe nanotrenches induced by mobile Au-alloy droplets. The contact side interfaces between the AuZndelta alloy droplets and the ZnSe as well as the four side walls of the resulting <011>-oriented nanotrenches were found all belong to the {111} plane family, with the front and back walls being the {111}A planes while the other two side walls being the {111}B planes. These findings offer a deeper understanding on the formation mechanism of the nanotrenches. Pure Au nanodashes were formed upon further deposition of Au on the nanotrenches.PACS: 61.46.Df, Structure of nanocrystals and nanoparticles. 81.16.Rf, Micro and nanoscale pattern formation. 68.37.Og, High resolution transmission electron microscopy. PMID- 21711783 TI - Stability and rheology of dilute TiO2-water nanofluids. AB - The apparent wall slip (AWS) effect, accompanying the flow of colloidal dispersions in confined geometries, can be an important factor for the applications of nanofluids in heat transfer and microfluidics. In this study, a series of dilute TiO2 aqueous dispersions were prepared and tested for the possible presence of the AWS effect by means of a novel viscometric technique. The nanofluids, prepared from TiO2 rutile or anatase nanopowders by ultrasonic dispersing in water, were stabilized by adjusting the pH to the maximum zeta potential. The resulting stable nanofluid samples were dilute, below 0.7 vol.%. All the samples manifest Newtonian behavior with the fluidities almost unaffected by the presence of the dispersed phase. No case of important slip contribution was detected: the Navier slip coefficient of approximately 2 mm Pa-1 s-1 would affect the apparent fluidity data in a 100-MUm gap by less than 1%. PMID- 21711784 TI - Investigation of electrical and magnetic properties of ferro-nanofluid on transformers. AB - This study investigated a simple model of transformers that have liquid magnetic cores with different concentrations of ferro-nanofluids. The simple model was built on a capillary by enamel-insulated wires and with ferro-nanofluid loaded in the capillary. The ferro-nanofluid was fabricated by a chemical co-precipitation method. The performances of the transformers with either air core or ferro nanofluid at different concentrations of nanoparticles of 0.25, 0.5, 0.75, and 1 M were measured and simulated at frequencies ranging from 100 kHz to 100 MHz. The experimental results indicated that the inductance and coupling coefficient of coils grew with the increment of the ferro-nanofluid concentration. The presence of ferro-nanofluid increased resistance, yielding to the decrement of the quality factor, owing to the phase lag between the external magnetic field and the magnetization of the material. PMID- 21711785 TI - Enhancement of heat transfer and entropy generation analysis of nanofluids turbulent convection flow in square section tubes. AB - In this article, developing turbulent forced convection flow of a water-Al2O3 nanofluid in a square tube, subjected to constant and uniform wall heat flux, is numerically investigated. The mixture model is employed to simulate the nanofluid flow and the investigation is accomplished for particles size equal to 38 nm.An entropy generation analysis is also proposed in order to find the optimal working condition for the given geometry under given boundary conditions. A simple analytical procedure is proposed to evaluate the entropy generation and its results are compared with the numerical calculations, showing a very good agreement.A comparison of the resulting Nusselt numbers with experimental correlations available in literature is accomplished. To minimize entropy generation, the optimal Reynolds number is determined. PMID- 21711786 TI - Synthesis of freestanding HfO2 nanostructures. AB - Two new methods for synthesizing nanostructured HfO2 have been developed. The first method entails exposing HfTe2 powders to air. This simple process resulted in the formation of nanometer scale crystallites of HfO2. The second method involved a two-step heating process by which macroscopic, freestanding nanosheets of HfO2 were formed as a byproduct during the synthesis of HfTe2. These highly two-dimensional sheets had side lengths measuring up to several millimeters and were stable enough to be manipulated with tweezers and other instruments. The thickness of the sheets ranged from a few to a few hundred nanometers. The thinnest sheets appeared transparent when viewed in a scanning electron microscope. It was found that the presence of Mn enhanced the formation of HfO2 by exposure to ambient conditions and was necessary for the formation of the large scale nanosheets. These results present new routes to create freestanding nanostructured hafnium dioxide.PACS: 81.07.-b, 61.46.Hk, 68.37.Hk. PMID- 21711787 TI - Enhancements of thermal conductivities with Cu, CuO, and carbon nanotube nanofluids and application of MWNT/water nanofluid on a water chiller system. AB - In this study, enhancements of thermal conductivities of ethylene glycol, water, and synthetic engine oil in the presence of copper (Cu), copper oxide (CuO), and multi-walled carbon nanotube (MWNT) are investigated using both physical mixing method (two-step method) and chemical reduction method (one-step method). The chemical reduction method is, however, used only for nanofluid containing Cu nanoparticle in water. The thermal conductivities of the nanofluids are measured by a modified transient hot wire method. Experimental results show that nanofluids with low concentration of Cu, CuO, or carbon nanotube (CNT) have considerably higher thermal conductivity than identical base liquids. For CuO ethylene glycol suspensions at 5 vol.%, MWNT-ethylene glycol at 1 vol.%, MWNT water at 1.5 vol.%, and MWNT-synthetic engine oil at 2 vol.%, thermal conductivity is enhanced by 22.4, 12.4, 17, and 30%, respectively. For Cu-water at 0.1 vol.%, thermal conductivity is increased by 23.8%. The thermal conductivity improvement for CuO and CNT nanofluids is approximately linear with the volume fraction. On the other hand, a strong dependence of thermal conductivity on the measured time is observed for Cu-water nanofluid. The system performance of a 10-RT water chiller (air conditioner) subject to MWNT/water nanofluid is experimentally investigated. The system is tested at the standard water chiller rating condition in the range of the flow rate from 60 to 140 L/min. In spite of the static measurement of thermal conductivity of nanofluid shows only 1.3% increase at room temperature relative to the base fluid at volume fraction of 0.001 (0.1 vol.%), it is observed that a 4.2% increase of cooling capacity and a small decrease of power consumption about 0.8% occur for the nanofluid system at a flow rate of 100 L/min. This result clearly indicates that the enhancement of cooling capacity is not just related to thermal conductivity alone. Dynamic effect, such as nanoparticle dispersion may effectively augment the system performance. It is also found that the dynamic dispersion is comparatively effective at lower flow rate regime, e.g., transition or laminar flow and becomes less effective at higher flow rate regime. Test results show that the coefficient of performance of the water chiller is increased by 5.15% relative to that without nanofluid. PMID- 21711789 TI - Gold-ionic liquid nanofluids with preferably tribological properties and thermal conductivity. AB - Gold/1-butyl-3-methylimidazolium hexafluorophosphate (Au/[Bmim][PF6]) nanofluids containing different stabilizing agents were fabricated by a facile one-step chemical reduction method, of which the nanofluids stabilized by cetyltrimethylammonium bromide (CTABr) exhibited ultrahighly thermodynamic stability. The transmission electron microscopy, UV-visible absorption, Fourier transform infrared, and X-ray photoelectron characterizations were conducted to reveal the stable mechanism. Then, the tribological properties of these ionic liquid (IL)-based gold nanofluids were first investigated in more detail. In comparison with pure [Bmim][PF6] and the nanofluids possessing poor stability, the nanofluids with high stability exhibited much better friction-reduction and anti-wear properties. For instance, the friction coefficient and wear volume lubricated by the nanofluid with rather low volumetric concentration (1.02 * 10 3%) stabilized by CTABr under 800 N are 13.8 and 45.4% lower than that of pure [Bmim][PF6], confirming that soft Au nanoparticles (Au NPs) also can be excellent additives for high performance lubricants especially under high loads. Moreover, the thermal conductivity (TC) of the stable nanofluids with three volumetric fraction (2.55 * 10-4, 5.1 * 10-4, and 1.02 * 10-3%) was also measured by a transient hot wire method as a function of temperature (33 to 81 degrees C). The results indicate that the TC of the nanofluid (1.02 * 10-3%) is 13.1% higher than that of [Bmim][PF6] at 81 degrees C but no obvious variation at 33 degrees C. The conspicuously temperature-dependent and greatly enhanced TC of Au/[Bmim][PF6] nanofluids stabilized by CTABr could be attributed to micro-convection caused by the Brownian motion of Au NPs. Our results should open new avenues to utilize Au NPs and ILs in tribology and the high-temperature heat transfer field. PMID- 21711788 TI - Atomic scale investigation of silicon nanowires and nanoclusters. AB - In this study, we have performed nanoscale characterization of Si-clusters and Si-nanowires with a laser-assisted tomographic atom probe. Intrinsic and p-type silicon nanowires (SiNWs) are elaborated by chemical vapor deposition method using gold as catalyst, silane as silicon precursor, and diborane as dopant reactant. The concentration and distribution of impurity (gold) and dopant (boron) in SiNW are investigated and discussed. Silicon nanoclusters are produced by thermal annealing of silicon-rich silicon oxide and silica multilayers. In this process, atom probe tomography (APT) provides accurate information on the silicon nanoparticles and the chemistry of the nanolayers. PMID- 21711790 TI - Electrorheology of nanofiber suspensions. AB - Electrorheological (ER) fluid, which can be transformed rapidly from a fluid like state to a solid-like state under an external electric field, is considered to be one of the most important smart fluids. However, conventional ER fluids based on microparticles are subjected to challenges in practical applications due to the lack of versatile performances. Recent researches of using nanoparticles as the dispersal phase have led to new interest in the development of non conventional ER fluids with improved performances. In this review, we especially focus on the recent researches on electrorheology of various nanofiber-based suspensions, including inorganic, organic, and inorganic/organic composite nanofibers. Our goal is to highlight the advantages of using anisotropic nanostructured materials as dispersal phases to improve ER performances. PMID- 21711791 TI - Excitonic effects on the second-order nonlinear optical properties of semi spherical quantum dots. AB - We study the excitonic effects on the second-order nonlinear optical properties of semi-spherical quantum dots considering, on the same footing, the confinement potential of the electron-hole pair and the Coulomb interaction between them. The exciton is confined in a semi-spherical geometry by means of a three-dimensional semi-parabolic potential. We calculate the optical rectification and second harmonic generation coefficients for two different values of the confinement frequency based on the numerically computed energies and wavefunctions of the exciton. We present the results as a function of the incident photon energy for GaAs/AlGaAs quantum dots ranging from few nanometers to tens of nanometers. We find that the second-order nonlinear coefficients exhibit not only a blue-shift of the order of meV but also a change of intensity compared with the results obtained ignoring the Coulomb interaction in the so-called strong-confinement limit. PMID- 21711792 TI - Round-robin test on thermal conductivity measurement of ZnO nanofluids and comparison of experimental results with theoretical bounds. AB - Ethylene glycol (EG)-based zinc oxide (ZnO) nanofluids containing no surfactant have been manufactured by one-step pulsed wire evaporation (PWE) method. Round robin tests on thermal conductivity measurements of three samples of EG-based ZnO nanofluids have been conducted by five participating labs, four using accurate measurement apparatuses developed in house and one using a commercial device. The results have been compared with several theoretical bounds on the effective thermal conductivity of heterogeneous systems. This study convincingly demonstrates that the large enhancements in the thermal conductivities of EG based ZnO nanofluids tested are beyond the lower and upper bounds calculated using the models of the Maxwell and Nan et al. with and without the interfacial thermal resistance. PMID- 21711793 TI - Enhanced plasmonic behavior of bimetallic (Ag-Au) multilayered spheres. AB - In this article we study the plasmonic behavior of some stable, highly biocompatible bimetallic metal-dielectric-metal (MDM) and double concentric nanoshell (DCN) structures. By simply switching the material of the inner structure from Au to Ag, the intensity of their surface plasmon resonance could be increased in the optical transparency region of the human tissues up to 20 and 60 percent for the MDM and DCN, respectively, while the biocompatibility is retained. The obtained results indicate that these novel structures could be highly suitable for surface enhanced Raman scattering and photothermal cancer therapy. PMID- 21711794 TI - A review on boiling heat transfer enhancement with nanofluids. AB - There has been increasing interest of late in nanofluid boiling and its use in heat transfer enhancement. This article covers recent advances in the last decade by researchers in both pool boiling and convective boiling applications, with nanofluids as the working fluid. The available data in the literature is reviewed in terms of enhancements, and degradations in the nucleate boiling heat transfer and critical heat flux. Conflicting data have been presented in the literature on the effect that nanofluids have on the boiling heat-transfer coefficient; however, almost all researchers have noted an enhancement in the critical heat flux during nanofluid boiling. Several researchers have observed nanoparticle deposition at the heater surface, which they have related back to the critical heat flux enhancement. PMID- 21711796 TI - Efficient thermoelectric energy conversion on quasi-localized electron states in diameter modulated nanowires. AB - It is known that the thermoelectric efficiency of nanowires increases when their diameter decreases. Recently, we proposed that increase of the thermoelectric efficiency could be achieved by modulating the diameter of the nanowires. We showed that the electron thermoelectric properties depend strongly on the geometry of the diameter modulation. Moreover, it has been shown by another group that the phonon conductivity decreases in nanowires when they are modulated by dots. Here, the thermoelectric efficiency of diameter modulated nanowires is estimated, in the ballistic regime, by taking into account the electron and phonon transmission properties. It is demonstrated that quasi-localized states can be formed that are prosperous for efficient thermoelectric energy conversion. PMID- 21711795 TI - Absorption and scattering properties of carbon nanohorn-based nanofluids for direct sunlight absorbers. AB - In the present work, we investigated the scattering and spectrally resolved absorption properties of nanofluids consisting in aqueous and glycol suspensions of single-wall carbon nanohorns. The characteristics of these nanofluids were evaluated in view of their use as sunlight absorber fluids in a solar device. The observed nanoparticle-induced differences in optical properties appeared promising, leading to a considerably higher sunlight absorption with respect to the pure base fluids. Scattered light was found to be not more than about 5% with respect to the total attenuation of light. Both these effects, together with the possible chemical functionalization of carbon nanohorns, make this new kind of nanofluids very interesting for increasing the overall efficiency of the sunlight exploiting device. PACS: 78.40.Ri, 78.35.+c, 78.67.Bf, 88.40.fh, 88.40.fr, 81.05.U. PMID- 21711797 TI - Solution-processed germanium nanowire-positioned Schottky solar cells. AB - Germanium nanowire (GeNW)-positioned Schottky solar cell was fabricated by a solution process. A GeNW-containing solution was spread out onto asymmetric metal electrodes to produce a rectifying current flow. Under one-sun illumination, the GeNW-positioned Schottky solar cell yields an open-circuit voltage of 177 mV and a short-circuit current of 19.2 nA. Schottky and ohmic contacts between a single GeNW and different metal electrodes were systematically investigated. This solution process may provide a route to the cost-effective nanostructure solar architecture. PMID- 21711798 TI - Transmission electron microscopic observations of nanobubbles and their capture of impurities in wastewater. AB - Unique properties of micro- and nanobubbles (MNBs), such as a high adsorption of impurities on their surface, are difficult to verify because MNBs are too small to observe directly. We thus used a transmission electron microscope (TEM) with the freeze-fractured replica method to observe oxygen (O2) MNBs in solutions. MNBs in pure water and in 1% NaCl solutions were spherical or oval. Their size distribution estimated from TEM images close to that of the original solution is measured by light-scattered methods. When we applied this technique to the observation of O2 MNBs formed in the wastewater of a sewage plant, we found the characteristic features of spherical MNBs that adsorbed surrounding impurity particles on their surface.PACS: 68.03.-g, 81.07.-b, 92.40.qc. PMID- 21711799 TI - Systematic analysis of secreted proteins reveals synergism between IL6 and other proteins in soft agar growth of MCF10A cells. AB - INTRODUCTION: Breast cancer, the most common malignancy in women, still holds many secrets. The causes for non-hereditary breast cancer are still unknown. To elucidate any role for circulating naturally secreted proteins, a screen of secreted proteins' influence of MCF10A cell anchorage independent growth was set up. METHODS: To systematically screen secreted proteins for their capacity to transform mammalian breast epithelial cells, a soft agar screen of MCF10A cells was performed using a library of ~ 470 secreted proteins. A high concentration of infecting viral particles was used to obtain multiple infections in individual cells to specifically study the combined effect of multiple secreted proteins. RESULTS: Several known breast cancer factors, such as Wnt, FGF and IL were retained, as well as factors that were previously unknown to have a role in breast cancer, such as paraoxonase 1 and fibroblast growth factor binding protein 2. Additionally, a combinatory role of Interleukin 6 with other factors in MCF10A anchorage-independent growth is demonstrated. CONCLUSION: The transforming effect of combinations of IL6 with other secreted proteins allows studying the transformation of mammary epithelial cells in vitro, and may also have implications in in vivo studies where secreted proteins are upregulated or overexpressed. PMID- 21711800 TI - Production of nanoparticles from natural hydroxylapatite by laser ablation. AB - Laser ablation of solids in liquids technique has been used to obtain colloidal nanoparticles from biological hydroxylapatite using pulsed as well as a continuous wave (CW) laser. Transmission electron microscopy (TEM) measurements revealed the formation of spherical particles with size distribution ranging from few nanometers to hundred nanometers and irregular submicronic particles. High resolution TEM showed that particles obtained by the use of pulsed laser were crystalline, while those obtained by the use of CW laser were amorphous. The shape and size of particles are consistent with the explosive ejection as formation mechanism. PMID- 21711801 TI - Gallium hydride vapor phase epitaxy of GaN nanowires. AB - Straight GaN nanowires (NWs) with diameters of 50 nm, lengths up to 10 MUm and a hexagonal wurtzite crystal structure have been grown at 900 degrees C on 0.5 nm Au/Si(001) via the reaction of Ga with NH3 and N2:H2, where the H2 content was varied between 10 and 100%. The growth of high-quality GaN NWs depends critically on the thickness of Au and Ga vapor pressure while no deposition occurs on plain Si(001). Increasing the H2 content leads to an increase in the growth rate, a reduction in the areal density of the GaN NWs and a suppression of the underlying amorphous (alpha)-like GaN layer which occurs without H2. The increase in growth rate with H2 content is a direct consequence of the reaction of Ga with H2 which leads to the formation of Ga hydride that reacts efficiently with NH3 at the top of the GaN NWs. Moreover, the reduction in the areal density of the GaN NWs and suppression of the alpha-like GaN layer is attributed to the reaction of H2 with Ga in the immediate vicinity of the Au NPs. Finally, the incorporation of H2 leads to a significant improvement in the near band edge photoluminescence through a suppression of the non-radiative recombination via surface states which become passivated not only via H2, but also via a reduction of O2-related defects. PMID- 21711802 TI - Origins of 1/f noise in nanostructure inclusion polymorphous silicon films. AB - In this article, we report that the origins of 1/f noise in pm-Si:H film resistors are inhomogeneity and defective structure. The results obtained are consistent with Hooge's formula, where the noise parameter, alphaH, is independent of doping ratio. The 1/f noise power spectral density and noise parameter alphaH are proportional to the squared value of temperature coefficient of resistance (TCR). The resistivity and TCR of pm-Si:H film resistor were obtained through linear current-voltage measurement. The 1/f noise, measured by a custom-built noise spectroscopy system, shows that the power spectral density is a function of both doping ratio and temperature. PMID- 21711803 TI - Nanoscale structural characterization of epitaxial graphene grown on off-axis 4H SiC (0001). AB - In this work, we present a nanometer resolution structural characterization of epitaxial graphene (EG) layers grown on 4H-SiC (0001) 8 degrees off-axis, by annealing in inert gas ambient (Ar) in a wide temperature range (Tgr from 1600 to 2000 degrees C). For all the considered growth temperatures, few layers of graphene (FLG) conformally covering the 100 to 200-nm wide terraces of the SiC surface have been observed by high-resolution cross-sectional transmission electron microscopy (HR-XTEM). Tapping mode atomic force microscopy (t-AFM) showed the formation of wrinkles with approx. 1 to 2 nm height and 10 to 20 nm width in the FLG film, as a result of the release of the compressive strain, which builds up in FLG during the sample cooling due to the thermal expansion coefficients mismatch between graphene and SiC. While for EG grown on on-axis 4H SiC an isotropic mesh-like network of wrinkles interconnected into nodes is commonly reported, in the present case of a vicinal SiC surface, wrinkles are preferentially oriented in the direction perpendicular to the step edges of the SiC terraces. For each Tgr, the number of graphene layers was determined on very small sample areas by HR-XTEM and, with high statistics and on several sample positions, by measuring the depth of selectively etched trenches in FLG by t-AFM. Both the density of wrinkles and the number of graphene layers are found to increase almost linearly as a function of the growth temperature in the considered temperature range. PMID- 21711804 TI - Solar light-driven photocatalytic hydrogen evolution over ZnIn2S4 loaded with transition-metal sulfides. AB - A series of Pt-loaded MS/ZnIn2S4 (MS = transition-metal sulfide: Ag2S, SnS, CoS, CuS, NiS, and MnS) photocatalysts was investigated to show various photocatalytic activities depending on different transition-metal sulfides. Thereinto, CoS, NiS, or MnS-loading lowered down the photocatalytic activity of ZnIn2S4, while Ag2S, SnS, or CuS loading enhanced the photocatalytic activity. After loading 1.0 wt.% CuS together with 1.0 wt.% Pt on ZnIn2S4, the activity for H2 evolution was increased by up to 1.6 times, compared to the ZnIn2S4 only loaded with 1.0 wt.% Pt. Here, transition-metal sulfides such as CuS, together with Pt, acted as the dual co-catalysts for the improved photocatalytic performance. This study indicated that the application of transition-metal sulfides as effective co catalysts opened up a new way to design and prepare high-efficiency and low-cost photocatalysts for solar-hydrogen conversion. PMID- 21711805 TI - Thermal conductivity and thermal boundary resistance of nanostructures. AB - : We present a fabrication process of low-cost superlattices and simulations related with the heat dissipation on them. The influence of the interfacial roughness on the thermal conductivity of semiconductor/semiconductor superlattices was studied by equilibrium and non-equilibrium molecular dynamics and on the Kapitza resistance of superlattice's interfaces by equilibrium molecular dynamics. The non-equilibrium method was the tool used for the prediction of the Kapitza resistance for a binary semiconductor/metal system. Physical explanations are provided for rationalizing the simulation results. PACS: 68.65.Cd, 66.70.Df, 81.16.-c, 65.80.-g, 31.12.xv. PMID- 21711806 TI - Mechanical tuning of molecular machines for nucleotide recognition at the air water interface. AB - Molecular machines embedded in a Langmuir monolayer at the air-water interface can be operated by application of lateral pressure. As part of the challenge associated with versatile sensing of biologically important substances, we here demonstrate discrimination of nucleotides by applying a cholesterol-armed triazacyclononane host molecule. This molecular machine can discriminate ribonucleotides based on a twofold to tenfold difference in binding constants under optimized conditions including accompanying ions in the subphase and lateral surface pressures of its Langmuir monolayer. The concept of mechanical tuning of the host structure for optimization of molecular recognition should become a novel methodology in bio-related nanotechnology as an alternative to traditional strategies based on increasingly complex and inconvenient molecular design strategies. PMID- 21711807 TI - Thermal conductivity and viscosity of self-assembled alcohol/polyalphaolefin nanoemulsion fluids. AB - Very large thermal conductivity enhancement had been reported earlier in colloidal suspensions of solid nanoparticles (i.e., nanofluids) and more recently also in oil-in-water emulsions. In this study, nanoemulsions of alcohol and polyalphaolefin (PAO) are spontaneously generated by self-assembly, and their thermal conductivity and viscosity are investigated experimentally. Alcohol and PAO have similar thermal conductivity values, so that the abnormal effects, such as particle Brownian motion, on thermal transport could be deducted in these alcohol/PAO nanoemulsion fluids. Small angle neutron-scattering measurement shows that the alcohol droplets are spheres of 0.8-nm radius in these nanoemulsion fluids. Both thermal conductivity and dynamic viscosity of the fluids are found to increase with alcohol droplet loading, as expected from classical theories. However, the measured conductivity increase is very moderate, e.g., a 2.3% increase for 9 vol%, in these fluids. This suggests that no anomalous enhancement of thermal conductivity is observed in the alcohol/PAO nanoemulsion fluids tested in this study. PMID- 21711809 TI - Fabrication and magnetic properties of granular Co/porous InP nanocomposite materials. AB - A novel Co/InP magnetic semiconductor nanocomposite was fabricated by electrodeposition magnetic Co nanoparticles into n-type porous InP templates in ethanol solution of cobalt chloride. The content or particle size of Co particles embedded in porous InP increased with increasing deposition time. Co particles had uniform distribution over pore sidewall surface of InP template, which was different from that of ceramic template and may open up new branch of fabrication of nanocomposites. The magnetism of such Co/InP nanocomposites can be gradually tuned from diamagnetism to ferromagnetism by increasing the deposition time of Co. Magnetic anisotropy of this Co/InP nanocomposite with magnetization easy axis along the axis of InP square channel was well realized by the competition between shape anisotropy and magnetocrystalline anisotropy. Such Co/InP nanocomposites with adjustable magnetism may have potential applications in future in the field of spin electronics.PACS: 61.46. +w . 72.80.Tm . 81.05.Rm . 75.75. +a . 82.45.Aa. PMID- 21711808 TI - Preparation and evaluation of novel mixed micelles as nanocarriers for intravenous delivery of propofol. AB - Novel mixed polymeric micelles formed from biocompatible polymers, poly(ethylene glycol)-poly(lactide) (mPEG-PLA) and polyoxyethylene-660-12-hydroxy stearate (Solutol HS15), were fabricated and used as a nanocarrier for solubilizing poorly soluble anesthetic drug propofol. The solubilization of propofol by the mixed micelles was more efficient than those made of mPEG-PLA alone. Micelles with the optimized composition of mPEG-PLA/Solutol HS15/propofol = 10/1/5 by weight had particle size of about 101 nm with narrow distribution (polydispersity index of about 0.12). Stability analysis of the mixed micelles in bovine serum albumin (BSA) solution indicated that the diblock copolymer mPEG efficiently protected the BSA adsorption on the mixed micelles because the hydrophobic groups of the copolymer were efficiently screened by mPEG, and propofol-loaded mixed micelles were stable upon storage for at least 6 months. The content of free propofol in the aqueous phase for mixed micelles was lower by 74% than that for the commercial lipid emulsion. No significant differences in times to unconsciousness and recovery of righting reflex were observed between mixed micelles and commercial lipid formulation. The pharmacological effect may serve as pharmaceutical nanocarriers with improved solubilization capacity for poorly soluble drugs. PMID- 21711810 TI - Simple two-step fabrication method of Bi2Te3 nanowires. AB - Bismuth telluride (Bi2Te3) is an attractive material for both thermoelectric and topological insulator applications. Its performance is expected to be greatly improved when the material takes nanowire structures. However, it is very difficult to grow high-quality Bi2Te3 nanowires. In this study, a simple and reliable method for the growth of Bi2Te3 nanowires is reported, which uses post sputtering and annealing in combination with the conventional method involving on film formation of nanowires. Transmission electron microscopy study shows that Bi2Te3 nanowires grown by our technique are highly single-crystalline and oriented along [110] direction. PMID- 21711811 TI - Preparation of SnS2 colloidal quantum dots and their application in organic/inorganic hybrid solar cells. AB - Dispersive SnS2 colloidal quantum dots have been synthesized via hot-injection method. Hybrid photovoltaic devices based on blends of a conjugated polymer poly[2-methoxy-5-(3",7"dimethyloctyloxy)-1,4-phenylenevinylene] (MDMO-PPV) as electron donor and crystalline SnS2 quantum dots as electron acceptor have been studied. Photoluminescence measurement has been performed to study the surfactant effect on the excitons splitting process. The photocurrent of solar cells with the hybrid depends greatly on the ligands exchange as well as the device heat treatment. AFM characterization has demonstrated morphology changes happening upon surfactant replacement and annealing, which can explain the performance variation of hybrid solar cells. PMID- 21711812 TI - Synthesis of carbon nanotubes with and without catalyst particles. AB - The initial development of carbon nanotube synthesis revolved heavily around the use of 3d valence transition metals such as Fe, Ni, and Co. More recently, noble metals (e.g. Au) and poor metals (e.g. In, Pb) have been shown to also yield carbon nanotubes. In addition, various ceramics and semiconductors can serve as catalytic particles suitable for tube formation and in some cases hybrid metal/metal oxide systems are possible. All-carbon systems for carbon nanotube growth without any catalytic particles have also been demonstrated. These different growth systems are briefly examined in this article and serve to highlight the breadth of avenues available for carbon nanotube synthesis. PMID- 21711813 TI - Synthesis and characterization of VO2-based thermochromic thin films for energy efficient windows. AB - Thermochromic VO2 thin films have successfully been grown on SiO2-coated float glass by reactive DC and pulsed-DC magnetron sputtering. The influence of substitutional doping of V by higher valence cations, such as W, Mo, and Nb, and respective contents on the crystal structure of VO2 is evaluated. Moreover, the effectiveness of each dopant element on the reduction of the intrinsic transition temperature and infrared modulation efficiency of VO2 is discussed. In summary, all the dopant elements--regardless of the concentration, within the studied range-- formed a solid solution with VO2, which was the only compound observed by X-ray diffractometry. Nb showed a clear detrimental effect on the crystal structure of VO2. The undoped films presented a marked thermochromic behavior, specially the one prepared by pulsed-DC sputtering. The dopants effectively decreased the transition of VO2 to the proximity of room temperature. However, the IR modulation efficiency is markedly affected as a consequence of the increased metallic character of the semiconducting phase. Tungsten proved to be the most effective element on the reduction of the semiconducting-metal transition temperature, while Mo and Nb showed similar results with the latter being detrimental to the thermochromism. PMID- 21711814 TI - A promising routine to fabricate GeSi nanowires via self-assembly on miscut Si (001) substrates. AB - : Very small and compactly arranged GeSi nanowires could self-assembled on vicinal Si (001) substrates with ~8 degrees off toward ?110? during Ge deposition. The nanowires were all oriented along the miscut direction. The small ration of height over width of the nanowire indicated that the nanowires were bordered partly with {1 0 5} facets. These self-assembled small nanowires were remarkably influenced by the growth conditions and the miscut angle of substrates in comparison with large dome-like islands obtained after sufficient Ge deposition. These results proposed that the formation of the nanowire was energetically driven under growth kinetic assistance. Three-dimensionally self assembled GeSi nanowires were first realized via multilayer Ge growth separated with Si spacers. These GeSi nanowires were readily embedded in Si matrix and compatible with the sophisticated Si technology, which suggested a feasible strategy to fabricate nanowires for fundamental studies and a wide variety of applications.PACS: 81.07.Gf, 81.16.Dn, 68.65.-k, 68.37.Ps. PMID- 21711815 TI - Generating and measuring the anisotropic elastic behaviour of Co thin films with oriented surface nano-strings on micro-cantilevers. AB - In this research, the elastic behaviour of two Co thin films simultaneously deposited in an off-normal angle method was studied. Towards this end, two Si micro-cantilevers were simultaneously coated using pulsed laser deposition at an oblique angle, creating a Co nano-string surface morphology with a predetermined orientation. The selected position of each micro-cantilever during the coating process created longitudinal or transverse nano-strings. The anisotropic elastic behaviour of these Co films was determined by measuring the changes that took place in the resonant frequency of each micro-cantilever after this process of creating differently oriented plasma coatings had been completed. This differential procedure allowed us to determine the difference between the Young's modulus of the different films based on the different direction of the nano strings. This difference was determined to be, at least, the 20% of the Young's modulus of the bulk Co.PACS: 62.25.-g; 81.16.Rf; 68.60.Bs; 81.15.Fg; 68.37.Ef; 85.85.+j. PMID- 21711816 TI - Can graphene make better HgCdTe infrared detectors? AB - We develop a simple and low-cost technique based on chemical vapor deposition from which large-size graphene films with 5-10 graphene layers can be produced reliably and the graphene films can be transferred easily onto HgCdTe (MCT) thin wafers at room temperature. The proposed technique does not cause any thermal and mechanical damages to the MCT wafers. It is found that the averaged light transmittance of the graphene film on MCT thin wafer is about 80% in the mid infrared bandwidth at room temperature and 77 K. Moreover, we find that the electrical conductance of the graphene film on the MCT substrate is about 25 times larger than that of the MCT substrate at room temperature and 77 K. These experimental findings suggest that, from a physics point of view, graphene can be utilized as transparent electrodes as a replacement for metal electrodes while producing better and cheaper MCT infrared detectors. PMID- 21711817 TI - Experimental stability analysis of different water-based nanofluids. AB - In the recent years, great interest has been devoted to the unique properties of nanofluids. The dispersion process and the nanoparticle suspension stability have been found to be critical points in the development of these new fluids. For this reason, an experimental study on the stability of water-based dispersions containing different nanoparticles, i.e. single wall carbon nanohorns (SWCNHs), titanium dioxide (TiO2) and copper oxide (CuO), has been developed in this study. The aim of this study is to provide stable nanofluids for selecting suitable fluids with enhanced thermal characteristics. Different dispersion techniques were considered in this study, including sonication, ball milling and high pressure homogenization. Both the dispersion process and the use of some dispersants were investigated as a function of the nanoparticle concentration. The high-pressure homogenization was found to be the best method, and the addition of n-dodecyl sulphate and polyethylene glycol as dispersants, respectively in SWCNHs-water and TiO2-water nanofluids, improved the nanofluid stability. PMID- 21711818 TI - Cohesive strength of nanocrystalline ZnO:Ga thin films deposited at room temperature. AB - In this study, transparent conducting nanocrystalline ZnO:Ga (GZO) films were deposited by dc magnetron sputtering at room temperature on polymers (and glass for comparison). Electrical resistivities of 8.8 * 10-4 and 2.2 * 10-3 Omega cm were obtained for films deposited on glass and polymers, respectively. The crack onset strain (COS) and the cohesive strength of the coatings were investigated by means of tensile testing. The COS is similar for different GZO coatings and occurs for nominal strains approx. 1%. The cohesive strength of coatings, which was evaluated from the initial part of the crack density evolution, was found to be between 1.3 and 1.4 GPa. For these calculations, a Young's modulus of 112 GPa was used, evaluated by nanoindentation. PMID- 21711819 TI - Friction-induced nanofabrication method to produce protrusive nanostructures on quartz. AB - In this paper, a new friction-induced nanofabrication method is presented to fabricate protrusive nanostructures on quartz surfaces through scratching a diamond tip under given normal loads. The nanostructures, such as nanodots, nanolines, surface mesas and nanowords, can be produced on the target surface by programming the tip traces according to the demanded patterns. The height of these nanostructures increases with the increase of the number of scratching cycles or the normal load. Transmission electron microscope observations indicated that the lattice distortion and dislocations induced by the mechanical interaction may have played a dominating role in the formation of the protrusive nanostructures on quartz surfaces. Further analysis reveals that during scratching, a contact pressure ranged from 0.4Py to Py (Py is the critical yield pressure of quartz) is apt to produce protuberant nanostructures on quartz under the given experimental conditions. Finally, it is of great interest to find that the protrusive nanostructures can be selectively dissolved in 20% KOH solution. Since the nanowords can be easily 'written' by friction-induced fabrication and 'erased' through selective etching on a quartz surface, this friction-induced method opens up new opportunities for future nanofabrication. PMID- 21711820 TI - Optical identification of electronic state levels of an asymmetric InAs/InGaAs/GaAs dot-in-well structure. AB - We have studied the electronic state levels of an asymmetric InAs/InGaAs/GaAs dot-in-well structure, i.e., with an In0.15Ga0.85As quantum well (QW) as capping layer above InAs quantum dots (QDs), via temperature-dependent photoluminescence, photo-modulated reflectance, and rapid thermal annealing (RTA) treatments. It is shown that the carrier transfer via wetting layer (WL) is impeded according to the results of temperature dependent peak energy and line width variation of both the ground states (GS) and excited states (ES) of QDs. The quenching of integrated intensity is ascribed to the thermal escape of electron from the dots to the complex In0.15Ga0.85As QW + InAs WL structure. Additionally, as the RTA temperature increases, the peak of PL blue shifts and the full width at half maximum shrinks. Especially, the intensity ratio of GS to ES reaches the maximum when the energy difference approaches the energy of one or two LO phonon(s) of InAs bulk material, which could be explained by phonon-enhanced inter-sublevels carrier relaxation in such asymmetric dot-in-well structure.PACS: 73.63.Kv; 73.61.Ey; 78.67.Hc; 81.16.Dn. PMID- 21711821 TI - Organic nanofibers integrated by transfer technique in field-effect transistor devices. AB - The electrical properties of self-assembled organic crystalline nanofibers are studied by integrating these on field-effect transistor platforms using both top and bottom contact configurations. In the staggered geometries, where the nanofibers are sandwiched between the gate and the source-drain electrodes, a better electrical conduction is observed when compared to the coplanar geometry where the nanofibers are placed over the gate and the source-drain electrodes. Qualitatively different output characteristics were observed for top and bottom contact devices reflecting the significantly different contact resistances. Bottom contact devices are dominated by contact effects, while the top contact device characteristics are determined by the nanofiber bulk properties. It is found that the contact resistance is lower for crystalline nanofibers when compared to amorphous thin films. These results shed light on the charge injection and transport properties for such organic nanostructures and thus constitute a significant step forward toward a nanofiber-based light-emitting device. PMID- 21711822 TI - One-step synthesis of PbSe-ZnSe composite thin film. AB - This study investigates the preparation of PbSe-ZnSe composite thin films by simultaneous hot-wall deposition (HWD) from multiple resources. The XRD result reveals that the solubility limit of Pb in ZnSe is quite narrow, less than 1 mol%, with obvious phase-separation in the composite thin films. A nanoscale elemental mapping of the film containing 5 mol% PbSe indicates that isolated PbSe nanocrystals are dispersed in the ZnSe matrix. The optical absorption edge of the composite thin films shifts toward the low-photon-energy region as the PbSe content increases. The use of a phase-separating PbSe-ZnSe system and HWD techniques enables simple production of the composite package. PMID- 21711823 TI - Measurement of local two-phase flow parameters of nanofluids using conductivity double-sensor probe. AB - A two-phase flow experiment using air and water-based gamma-Al2O3 nanofluid was conducted to observe the basic hydraulic phenomenon of nanofluids. The local two phase flow parameters were measured with a conductivity double-sensor two-phase void meter. The void fraction, interfacial velocity, interfacial area concentration, and mean bubble diameter were evaluated, and all of those results using the nanofluid were compared with the corresponding results for pure water. The void fraction distribution was flattened in the nanofluid case more than it was in the pure water case. The higher interfacial area concentration resulted in a smaller mean bubble diameter in the case of the nanofluid. This was the first attempt to measure the local two-phase flow parameters of nanofluids using a conductivity double-sensor two-phase void meter. Throughout this experimental study, the differences in the internal two-phase flow structure of the nanofluid were identified. In addition, the heat transfer enhancement of the nanofluid can be resulted from the increase of the interfacial area concentration which means the available area of the heat and mass transfer. PMID- 21711824 TI - Enhanced convective heat transfer using graphene dispersed nanofluids. AB - Nanofluids are having wide area of application in electronic and cooling industry. In the present work, hydrogen exfoliated graphene (HEG) dispersed deionized (DI) water, and ethylene glycol (EG) based nanofluids were developed. Further, thermal conductivity and heat transfer properties of these nanofluids were systematically investigated. HEG was synthesized by exfoliating graphite oxide in H2 atmosphere at 200 degrees C. The nanofluids were prepared by dispersing functionalized HEG (f-HEG) in DI water and EG without the use of any surfactant. HEG and f-HEG were characterized by powder X-ray diffractometry, electron microscopy, Raman and FTIR spectroscopy. Thermal and electrical conductivities of f-HEG dispersed DI water and EG based nanofluids were measured for different volume fractions and at different temperatures. A 0.05% volume fraction of f-HEG dispersed DI water based nanofluid shows an enhancement in thermal conductivity of about 16% at 25 degrees C and 75% at 50 degrees C. The enhancement in Nusselts number for these nanofluids is more than that of thermal conductivity. PMID- 21711825 TI - An antibacterial coating based on a polymer/sol-gel hybrid matrix loaded with silver nanoparticles. AB - In this work a novel antibacterial surface composed of an organic-inorganic hybrid matrix of tetraorthosilicate and a polyelectrolyte is presented. A precursor solution of tetraethoxysilane (TEOS) and poly(acrylic acid sodium salt) (PAA) was prepared and subsequently thin films were fabricated by the dip-coating technique using glass slides as substrates. This hybrid matrix coating is further loaded with silver nanoparticles using an in situ synthesis route. The morphology and composition of the coatings have been studied using UV-VIS spectroscopy and atomic force microscopy (AFM). Energy dispersive X-ray (EDX) was also used to confirm the presence of the resulting silver nanoparticles within the thin films. Finally the coatings have been tested in bacterial cultures of genus Lactobacillus plantarum to observe their antibacterial properties. It has been experimentally demonstrated that these silver loaded organic-inorganic hybrid films have a very good antimicrobial behavior against this type of bacteria. PMID- 21711827 TI - Theory and simulation of photogeneration and transport in Si-SiOx superlattice absorbers. AB - Si-SiOx superlattices are among the candidates that have been proposed as high band gap absorber material in all-Si tandem solar cell devices. Owing to the large potential barriers for photoexited charge carriers, transport in these devices is restricted to quantum-confined superlattice states. As a consequence of the finite number of wells and large built-in fields, the electronic spectrum can deviate considerably from the minibands of a regular superlattice. In this article, a quantum-kinetic theory based on the non-equilibrium Green's function formalism for an effective mass Hamiltonian is used for investigating photogeneration and transport in such devices for arbitrary geometry and operating conditions. By including the coupling of electrons to both photons and phonons, the theory is able to provide a microscopic picture of indirect generation, carrier relaxation, and inter-well transport mechanisms beyond the ballistic regime. PMID- 21711826 TI - Tissue inhibitor of metalloproteinase 1 (TIMP-1) deficiency exacerbates carbon tetrachloride-induced liver injury and fibrosis in mice: involvement of hepatocyte STAT3 in TIMP-1 production. AB - BACKGROUND: Tissue inhibitor of metalloproteinase 1 (TIMP-1), which is thought to be produced mainly by activated hepatic stellate cells and Kupffer cells in the liver, plays a pivotal role in matrix remodeling during liver injury and repair; while the effect of TIMP-1 on hepatocellular damage remains obscure. RESULTS: Hepatic expression of TIMP-1 mRNA and protein was up-regulated both in acute and chronic liver injury induced by carbon tetrachloride (CCl4). Compared with wild type mice, TIMP-1 knockout mice were more susceptible to CCl4-induced acute and chronic liver injury, as shown by higher levels of serum alanine aminotransferase (ALT), greater number of apoptotic hepatocytes, and more extended necroinflammatory foci. TIMP-1 knockout mice also displayed greater degree of liver fibrosis after chronic CCl4 injection when compared with wild-type mice. In vitro treatment with TIMP-1 inhibited cycloheximide-induced cell death of primary mouse hepatocytes. Finally, up-regulation of TIMP-1 in the liver and serum after chronic CCl4 treatment was markedly diminished in hepatocyte-specific signal transducer and activator of transcription 3 (STAT3) knockout mice. In vitro treatment with interleukin-6 stimulated TIMP-1 production in primary mouse hepatocytes, but to a lesser extent in STAT3-deficient hepatocytes. CONCLUSIONS: TIMP-1 plays an important role in protecting against acute and chronic liver injury and subsequently inhibiting liver fibrosis induced by CCl4. In addition to activated stellate cells and Kupffer cells, hepatocytes are also responsible for TIMP-1 production during liver injury via a STAT3-dependent manner. PMID- 21711828 TI - Preparation and characterization of carbon nanofluid by a plasma arc nanoparticles synthesis system. AB - Heat dissipation from electrical appliances is a significant issue with contemporary electrical devices. One factor in the improvement of heat dissipation is the heat transfer performance of the working fluid. In this study, we used plasma arc technology to produce a nanofluid of carbon nanoparticles dispersed in distilled water. In a one-step synthesis, carbon was simultaneously heated and vaporized in the chamber, the carbon vapor and particles were then carried to a collector, where cooling furnished the desired carbon/water nanofluid. The particle size and shape were determined using the light-scattering size analyzer, SEM, and TEM. Crystal morphology was examined by XRD. Finally, the characterization include thermal conductivity, viscosity, density and electric conductivity were evaluated by suitable instruments under different temperatures. The thermal conductivity of carbon/water nanofluid increased by about 25% at 50 degrees C compared to distilled water. The experimental results demonstrated excellent thermal conductivity and feasibility for manufacturing of carbon/water nanofluids. PMID- 21711829 TI - Electromagnetic modeling of waveguide amplifier based on Nd3+ Si-rich SiO2 layers by means of the ADE-FDTD method. AB - By means of ADE-FDTD method, this paper investigates the electromagnetic modelling of a rib-loaded waveguide composed of a Nd3+ doped Silicon Rich Silicon Oxide active layer sandwiched between a SiO2 bottom cladding and a SiO2 rib. The Auxilliary Differential Equations are the rate equations which govern the levels populations. The Finite Difference Time Domain (FDTD) scheme is used to solve the space and time dependent Maxwell equations which describe the electromagnetic field in a copropagating scheme of both pumping (lambdapump = 488 nm) and signal (lambdasignal = 1064 nm) waves. Such systems are characterized by extremely different specific times such as the period of electromagnetic field ~ 10-15 s and the lifetimes of the electronic levels between ~ 10-10s and ~ 10-4 s. The time scaling method is used in addition to specific initial conditions in order to decrease the computational time. We show maps of the Poynting vector along the propagation direction as a function of the silicon nanograin (Si-ng) concentrations. A threshold value of 1024 Si-ng m-3 is extracted below which the pump wave can propagate so that a signal amplication is possible. PMID- 21711830 TI - Particle shape effect on heat transfer performance in an oscillating heat pipe. AB - The effect of alumina nanoparticles on the heat transfer performance of an oscillating heat pipe (OHP) was investigated experimentally. A binary mixture of ethylene glycol (EG) and deionized water (50/50 by volume) was used as the base fluid for the OHP. Four types of nanoparticles with shapes of platelet, blade, cylinder, and brick were studied, respectively. Experimental results show that the alumina nanoparticles added in the OHP significantly affect the heat transfer performance and it depends on the particle shape and volume fraction. When the OHP was charged with EG and cylinder-like alumina nanoparticles, the OHP can achieve the best heat transfer performance among four types of particles investigated herein. In addition, even though previous research found that these alumina nanofluids were not beneficial in laminar or turbulent flow mode, they can enhance the heat transfer performance of an OHP. PMID- 21711831 TI - Fabrication of functional micro- and nanoneedle electrodes using a carbon nanotube template and electrodeposition. AB - Carbon nanotube (CNT) is an attractive material for needle-like conducting electrodes because it has high electrical conductivity and mechanical strength. However, CNTs cannot provide the desired properties in certain applications. To obtain micro- and nanoneedles having the desired properties, it is necessary to fabricate functional needles using various other materials. In this study, functional micro- and nanoneedle electrodes were fabricated using a tungsten tip and an atomic force microscope probe with a CNT needle template and electrodeposition. To prepare the conductive needle templates, a single-wall nanotube nanoneedle was attached onto the conductive tip using dielectrophoresis and surface tension. Through electrodeposition, Au, Ni, and polypyrrole were each coated successfully onto CNT nanoneedle electrodes to obtain the desired properties. PMID- 21711832 TI - Effect of the carbon nanotube surface characteristics on the conductivity and dielectric constant of carbon nanotube/poly(vinylidene fluoride) composites. AB - Commercial multi-walled carbon nanotubes (CNT) were functionalized by oxidation with HNO3, to introduce oxygen-containing surface groups, and by thermal treatments at different temperatures for their selective removal. The obtained samples were characterized by adsorption of N2 at -196 degrees C, temperature programmed desorption and determination of pH at the point of zero charge. CNT/poly(vinylidene fluoride) composites were prepared using the above CNT samples, with different filler fractions up to 1 wt%. It was found that oxidation reduced composite conductivity for a given concentration, shifted the percolation threshold to higher concentrations, and had no significant effect in the dielectric response. PMID- 21711833 TI - Influence of electrolyte co-additives on the performance of dye-sensitized solar cells. AB - The presence of specific chemical additives in the redox electrolyte results in an efficient increase of the photovoltaic performance of dye-sensitized solar cells (DSCs). The most effective additives are 4-tert-butylpyridine (TBP), N methylbenzimidazole (NMBI) and guanidinium thiocyanate (GuNCS) that are adsorbed onto the photoelectrode/electrolyte interface, thus shifting the semiconductor's conduction band edge and preventing recombination with triiodides. In a comparative work, we investigated in detail the action of TBP and NMBI additives in ionic liquid-based redox electrolytes with varying iodine concentrations, in order to extract the optimum additive/I2 ratio for each system. Different optimum additive/I2 ratios were determined for TBP and NMBI, despite the fact that both generally work in a similar way. Further addition of GuNCS in the optimized electrolytic media causes significant synergistic effects, the action of GuNCS being strongly influenced by the nature of the corresponding co-additive. Under the best operation conditions, power conversion efficiencies as high as 8% were obtained. PMID- 21711834 TI - Porous silicon nanoparticles for cancer photothermotherapy. AB - The in vitro cell tests and in vivo animal tests were performed to investigate the feasibility of the photothermal therapy based on porous silicon (PSi) in combination with near-infrared (NIR) laser. According to the Annexin V- fluorescein isothiocyanate Apoptosis assay test results, the untreated cells and the cells exposed to NIR laser without PSi treatment had a cell viability of 95.6 and 91.3%, respectively. Likewise, the cells treated with PSi but not with NIR irradiation also had a cell viability of 74.4%. Combination of these two techniques, however, showed a cell viability of 6.7%. Also, the cell deaths were mostly due to necrosis but partly due to late apoptosis. The in vivo animal test results showed that the Murine colon carcinoma (CT-26) tumors were completely resorbed without nearly giving damage to surrounding healthy tissue within 5 days of PSi and NIR laser treatment. Tumors have not recurred at all in the PSi/NIR treatment groups thereafter. Both the in vitro cell test and in vivo animal test results suggest that thermotherapy based on PSi in combination with NIR laser irradiation is an efficient technique to selectively destroy cancer cells without damaging the surrounding healthy cells. PMID- 21711835 TI - Pt-decorated nanoporous gold for glucose electrooxidation in neutral and alkaline solutions. AB - Exploiting electrocatalysts with high activity for glucose oxidation is of central importance for practical applications such as glucose fuel cell. Pt decorated nanoporous gold (NPG-Pt), created by depositing a thin layer of Pt on NPG surface, was proposed as an active electrode for glucose electrooxidation in neutral and alkaline solutions. The structure and surface properties of NPG-Pt were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray powder diffraction (XRD), and cyclic voltammetry (CV). The electrocatalytic activity toward glucose oxidation in neutral and alkaline solutions was evaluated, which was found to depend strongly on the surface structure of NPG-Pt. A direct glucose fuel cell (DGFC) was performed based on the novel membrane electrode materials. With a low precious metal load of less than 0.3 mg cm-2 Au and 60 MUg cm-2 Pt in anode and commercial Pt/C in cathode, the performance of DGFC in alkaline is much better than that in neutral condition. PMID- 21711836 TI - An investigation into the conversion of In2O3 into InN nanowires. AB - Straight In2O3 nanowires (NWs) with diameters of 50 nm and lengths >=2 MUm have been grown on Si(001) via the wet oxidation of In at 850 degrees C using Au as a catalyst. These exhibited clear peaks in the X-ray diffraction corresponding to the body centred cubic crystal structure of In2O3 while the photoluminescence (PL) spectrum at 300 K consisted of two broad peaks, centred around 400 and 550 nm. The post-growth nitridation of In2O3 NWs was systematically investigated by varying the nitridation temperature between 500 and 900 degrees C, flow of NH3 and nitridation times between 1 and 6 h. The NWs are eliminated above 600 degrees C while long nitridation times at 500 and 600 degrees C did not result into the efficient conversion of In2O3 to InN. We find that the nitridation of In2O3 is effective by using NH3 and H2 or a two-step temperature nitridation process using just NH3 and slower ramp rates. We discuss the nitridation mechanism and its effect on the PL. PMID- 21711837 TI - Preparation of Aligned Ultra-long and Diameter-controlled Silicon Oxide Nanotubes by Plasma Enhanced Chemical Vapor Deposition Using Electrospun PVP Nanofiber Template. AB - Well-aligned and suspended polyvinyl pyrrolidone (PVP) nanofibers with 8 mm in length were obtained by electrospinning. Using the aligned suspended PVP nanofibers array as template, aligned ultra-long silicon oxide (SiOx) nanotubes with very high aspect ratios have been prepared by plasma-enhanced chemical vapor deposition (PECVD) process. The inner diameter (20-200 nm) and wall thickness (12 90 nm) of tubes were controlled, respectively, by baking the electrospun nanofibers and by coating time without sacrificing the orientation degree and the length of arrays. The micro-PL spectrum of SiOx nanotubes shows a strong blue green emission with a peak at about 514 nm accompanied by two shoulders around 415 and 624 nm. The blue-green emission is caused by the defects in the nanotubes. PMID- 21711838 TI - Wet chemical synthesis and magnetic properties of single crystal Co nanochains with surface amorphous passivation Co layers. AB - : In this study, for the first time, high-yield chain-like one-dimensional (1D) Co nanostructures without any impurity have been produced by means of a solution dispersion approach under permanent-magnet. Size, morphology, component, and structure of the as-made samples have been confirmed by several techniques, and nanochains (NCs) with diameter of approximately 60 nm consisting of single crystalline Co and amorphous Co-capped layer (about 3 nm) have been materialized. The as-synthesized Co samples do not include any other adulterants. The high quality NC growth mechanism is proposed to be driven by magnetostatic interaction because NC can be reorganized under a weak magnetic field. Room-temperature enhanced coercivity of NCs was observed, which is considered to have potential applications in spin filtering, high density magnetic recording, and nanosensors. PACS: 61.46.Df; 75.50; 81.07.Vb; 81.07. PMID- 21711839 TI - Copper nanofiber-networked cobalt oxide composites for high performance Li-ion batteries. AB - We prepared a composite electrode structure consisting of copper nanofiber networked cobalt oxide (CuNFs@CoOx). The copper nanofibers (CuNFs) were fabricated on a substrate with formation of a network structure, which may have potential for improving electron percolation and retarding film deformation during the discharging/charging process over the electroactive cobalt oxide. Compared to bare CoOxthin-film (CoOxTF) electrodes, the CuNFs@CoOxelectrodes exhibited a significant enhancement of rate performance by at least six-fold at an input current density of 3C-rate. Such enhanced Li-ion storage performance may be associated with modified electrode structure at the nanoscale, improved charge transfer, and facile stress relaxation from the embedded CuNF network. Consequently, the CuNFs@CoOxcomposite structure demonstrated here can be used as a promising high-performance electrode for Li-ion batteries. PMID- 21711840 TI - Sustained release of VEGF from PLGA nanoparticles embedded thermo-sensitive hydrogel in full-thickness porcine bladder acellular matrix. AB - We fabricated a novel vascular endothelial growth factor (VEGF)-loaded poly(lactic-co-glycolic acid) (PLGA)-nanoparticles (NPs)-embedded thermo sensitive hydrogel in porcine bladder acellular matrix allograft (BAMA) system, which is designed for achieving a sustained release of VEGF protein, and embedding the protein carrier into the BAMA. We identified and optimized various formulations and process parameters to get the preferred particle size, entrapment, and polydispersibility of the VEGF-NPs, and incorporated the VEGF-NPs into the (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (Pluronic(r)) F127 to achieve the preferred VEGF-NPs thermo-sensitive gel system. Then the thermal behavior of the system was proven by in vitro and in vivo study, and the kinetic-sustained release profile of the system embedded in porcine bladder acellular matrix was investigated. Results indicated that the bioactivity of the encapsulated VEGF released from the NPs was reserved, and the VEGF-NPs thermo-sensitive gel system can achieve sol-gel transmission successfully at appropriate temperature. Furthermore, the system can create a satisfactory tissue compatible environment and an effective VEGF-sustained release approach. In conclusion, a novel VEGF-loaded PLGA NPs-embedded thermo-sensitive hydrogel in porcine BAMA system is successfully prepared, to provide a promising way for deficient bladder reconstruction therapy. PMID- 21711841 TI - Boundary layer flow past a stretching/shrinking surface beneath an external uniform shear flow with a convective surface boundary condition in a nanofluid. AB - The problem of a steady boundary layer shear flow over a stretching/shrinking sheet in a nanofluid is studied numerically. The governing partial differential equations are transformed into ordinary differential equations using a similarity transformation, before being solved numerically by a Runge-Kutta-Fehlberg method with shooting technique. Two types of nanofluids, namely, Cu-water and Ag-water are used. The effects of nanoparticle volume fraction, the type of nanoparticles, the convective parameter, and the thermal conductivity on the heat transfer characteristics are discussed. It is found that the heat transfer rate at the surface increases with increasing nanoparticle volume fraction while it decreases with the convective parameter. Moreover, the heat transfer rate at the surface of Cu-water nanofluid is higher than that at the surface of Ag-water nanofluid even though the thermal conductivity of Ag is higher than that of Cu. PMID- 21711842 TI - Valence band offset of InN/BaTiO3 heterojunction measured by X-ray photoelectron spectroscopy. AB - X-ray photoelectron spectroscopy has been used to measure the valence band offset of the InN/BaTiO3 heterojunction. It is found that a type-I band alignment forms at the interface. The valence band offset (VBO) and conduction band offset (CBO) are determined to be 2.25 +/- 0.09 and 0.15 +/- 0.09 eV, respectively. The experimental VBO data is well consistent with the value that comes from transitivity rule. The accurate determination of VBO and CBO is important for use of semiconductor/ferrroelectric heterojunction multifunctional devices. PMID- 21711843 TI - A combination of hard and soft templating for the fabrication of silica hollow microcoils with nanostructured walls. AB - Hollow silica microcoils have been prepared by using functionalized carbon microcoils as hard templates and surfactant or amphiphilic dye aggregates as soft templates. The obtained materials have been characterized by electron and optical microscopy, nitrogen sorption and small angle X-ray scattering. The obtained hollow microcoils resemble the original hard templates in shape and size. Moreover, they have mesoporous walls (pore size ~ 3 nm) with some domains where pores are ordered in a hexagonal array, originated from surfactant micelles. The obtained silica microcoils also show preferential adsorption of cationic fluorescent dyes. A mechanism for the formation of silica microcoils is proposed. PMID- 21711844 TI - Fabrication of complete titania nanoporous structures via electrochemical anodization of Ti. AB - We present a novel method to fabricate complete and highly oriented anodic titanium oxide (ATO) nano-porous structures with uniform and parallel nanochannels. ATO nano-porous structures are fabricated by anodizing a Ti-foil in two different organic viscous electrolytes at room temperature using a two-step anodizing method. TiO2 nanotubes covered with a few nanometer thin nano-porous layer is produced when the first and the second anodization are carried out in the same electrolyte. However, a complete titania nano-porous (TNP) structures are obtained when the second anodization is conducted in a viscous electrolyte when compared to the first one. TNP structure was attributed to the suppression of F-rich layer dissolution between the cell boundaries in the viscous electrolyte. The structural morphologies were examined by field emission scanning electron microscope. The average pore diameter is approximately 70 nm, while the average inter-pore distance is approximately 130 nm. These TNP structures are useful to fabricate other nanostructure materials and nanodevices. PMID- 21711845 TI - Size-dependent visible absorption and fast photoluminescence decay dynamics from freestanding strained silicon nanocrystals. AB - In this article, we report on the visible absorption, photoluminescence (PL), and fast PL decay dynamics from freestanding Si nanocrystals (NCs) that are anisotropically strained. Direct evidence of strain-induced dislocations is shown from high-resolution transmission electron microscopy images. Si NCs with sizes in the range of approximately 5-40 nm show size-dependent visible absorption in the range of 575-722 nm, while NCs of average size <10 nm exhibit strong PL emission at 580-585 nm. The PL decay shows an exponential decay in the nanosecond time scale. The Raman scattering studies show non-monotonic shift of the TO phonon modes as a function of size because of competing effect of strain and phonon confinement. Our studies rule out the influence of defects in the PL emission, and we propose that owing to the combined effect of strain and quantum confinement, the strained Si NCs exhibit direct band gap-like behavior. PMID- 21711846 TI - bOptimizing atomic force microscopy for characterization of diamond-protein interfaces. AB - Atomic force microscopy (AFM) in contact mode and tapping mode is employed for high resolution studies of soft organic molecules (fetal bovine serum proteins) on hard inorganic diamond substrates in solution and air. Various effects in morphology and phase measurements related to the cantilever spring constant, amplitude of tip oscillations, surface approach, tip shape and condition are demonstrated and discussed based on the proposed schematic models. We show that both diamond and proteins can be mechanically modified by Si AFM cantilever. We propose how to choose suitable cantilever type, optimize scanning parameters, recognize and minimize various artifacts, and obtain reliable AFM data both in solution and in air to reveal microscopic characteristics of protein-diamond interfaces. We also suggest that monocrystalline diamond is well defined substrate that can be applicable for fundamental studies of molecules on surfaces in general. PMID- 21711847 TI - Advances in modelling of biomimetic fluid flow at different scales. AB - The biomimetic flow at different scales has been discussed at length. The need of looking into the biological surfaces and morphologies and both geometrical and physical similarities to imitate the technological products and processes has been emphasized. The complex fluid flow and heat transfer problems, the fluid interface and the physics involved at multiscale and macro-, meso-, micro- and nano-scales have been discussed. The flow and heat transfer simulation is done by various CFD solvers including Navier-Stokes and energy equations, lattice Boltzmann method and molecular dynamics method. Combined continuum-molecular dynamics method is also reviewed. PMID- 21711848 TI - Combining scanning probe microscopy and x-ray spectroscopy. AB - A new versatile tool, combining Shear Force Microscopy and X-Ray Spectroscopy was designed and constructed to obtain simultaneously surface topography and chemical mapping. Using a sharp optical fiber as microscope probe, it is possible to collect locally the visible luminescence of the sample. Results of tests on ZnO and on ZnWO4 thin layers are in perfect agreement with that obtained with other conventional techniques. Twin images obtained by simultaneous acquisition in near field of surface topography and of local visible light emitted by the sample under X-Ray irradiation in synchrotron environment are shown. Replacing the optical fibre by an X-ray capillary, it is possible to collect local X-ray fluorescence of the sample. Preliminary results on Co-Ti sample analysis are presented. PMID- 21711849 TI - Anisotropic TixSn1-xO2 nanostructures prepared by magnetron sputter deposition. AB - Regular arrays of TixSn1-xO2 nanoflakes were fabricated through glancing angle sputter deposition onto self-assembled close-packed arrays of 200-nm-diameter polystyrene spheres. The morphology of nanostructures could be controlled by simply adjusting the sputtering power of the Ti target. The reflectance measurements showed that the melon seed-shaped nanoflakes exhibited optimal properties of antireflection in the entire visible and ultraviolet region. In addition, we determined their anisotropic reflectance in the direction parallel to the surface of nanoflakes and perpendicular to it, arising from the anisotropic morphology. PMID- 21711850 TI - On the stability of the exact solutions of the dual-phase lagging model of heat conduction. AB - The dual-phase lagging (DPL) model has been considered as one of the most promising theoretical approaches to generalize the classical Fourier law for heat conduction involving short time and space scales. Its applicability, potential, equivalences, and possible drawbacks have been discussed in the current literature. In this study, the implications of solving the exact DPL model of heat conduction in a three-dimensional bounded domain solution are explored. Based on the principle of causality, it is shown that the temperature gradient must be always the cause and the heat flux must be the effect in the process of heat transfer under the dual-phase model. This fact establishes explicitly that the single- and DPL models with different physical origins are mathematically equivalent. In addition, taking into account the properties of the Lambert W function and by requiring that the temperature remains stable, in such a way that it does not go to infinity when the time increases, it is shown that the DPL model in its exact form cannot provide a general description of the heat conduction phenomena. PMID- 21711851 TI - Synthesis and optical property of one-dimensional spinel ZnMn2O4 nanorods. AB - Spinel zinc manganese oxide (ZnMn2O4) nanorods were successfully prepared using the previously synthesized alpha-MnO2 nanorods by a hydrothermal method as template. The nanorods were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, UV-Vis absorption, X-ray photoelectron spectroscopy, surface photovoltage spectroscopy, and Fourier transform infrared spectroscopy. The ZnMn2O4 nanorods in well-formed crystallinity and phase purity appeared with the width in 50-100 nm and the length in 1.5-2 MUm. They exhibited strong absorption below 500 nm with the threshold edges around 700 nm. A significant photovoltage response in the region below 400 nm could be observed for the nanorods calcined at 650 and 800 degrees C. PMID- 21711852 TI - Wettability of amorphous and nanocrystalline Fe78B13Si9 substrates by molten Sn and Bi. AB - The wettability of amorphous and annealing-induced nanocrystalline Fe78B13Si9 ribbons by molten Sn and Bi at 600 K was measured using an improved sessile drop method. The results demonstrate that the structural relaxation and crystallization in the amorphous substrates do not substantially change the wettability with molten Bi because of their invariable physical interaction, but remarkably deteriorate the wettability and interfacial bonding with molten Sn as a result of changing a chemical interaction to a physical one for the atoms at the interface. PMID- 21711853 TI - Solvothermal synthesis and thermoelectric properties of indium telluride nanostring-cluster hierarchical structures. AB - A simple solvothermal approach has been developed to successfully synthesize n type alpha-In2Te3 thermoelectric nanomaterials. The nanostring-cluster hierarchical structures were prepared using In(NO3)3 and Na2TeO3 as the reactants in a mixed solvent of ethylenediamine and ethylene glycol at 200 degrees C for 24 h. A diffusion-limited reaction mechanism was proposed to explain the formation of the hierarchical structures. The Seebeck coefficient of the bulk pellet pressed by the obtained samples exhibits 43% enhancement over that of the corresponding thin film at room temperature. The electrical conductivity of the bulk pellet is one to four orders of magnitude higher than that of the corresponding thin film or p-type bulk sample. The synthetic route can be applied to obtain other low-dimensional semiconducting telluride nanostructures.PACS: 65.80.-g, 68.35.bg, 68.35.bt. PMID- 21711854 TI - Shock-induced breaking of the nanowire with the dependence of crystallographic orientation and strain rate. AB - The failure of the metallic nanowire has raised concerns due to its applied reliability in nanoelectromechanical system. In this article, the breaking failure is studied for the [100], [110], and [111] single-crystal copper nanowires at different strain rates. The statistical breaking position distributions of the nanowires have been investigated to give the effects of strain rate and crystallographic orientation on micro-atomic fluctuation in the symmetric stretching of the nanowires. When the strain rate is less than 0.26% ps 1, macro-breaking position distributions exhibit the anisotropy of micro-atomic fluctuation. However, when the strain rate is larger than 3.54% ps-1, the anisotropy is not obvious because of strong symmetric shocks. PMID- 21711856 TI - Application of silver nanofluid containing oleic acid surfactant in a thermosyphon economizer. AB - This article reports a recent study on the application of a two-phase closed thermosyphon (TPCT) in a thermosyphon for economizer (TPEC). The TPEC had three sections of equal size; the evaporator, the adiabatic section, and the condenser, of 250 mm * 250 mm * 250 mm (W * L * H). The TPCT was a steel tube of 12.7-mm ID. The filling ratios chosen to study were 30, 50, and 80% with respect to the evaporator length. The volumetric flow rates for the coolant (in the condenser) were 1, 2.5, and 5 l/min. Five working fluids investigated were: water, water based silver nanofluid with silver concentration 0.5 w/v%, and the nanofluid (NF) mixed with 0.5, 1, and 1.5 w/v% of oleic acid (OA). The operating temperatures were 60, 70, and 80 degrees C. Experimental data showed that the TPEC gave the highest heat flux of about 25 kW/m2 and the highest effectiveness of about 0.3 at a filling ratio of 50%, with the nanofluid containing 1 w/v% of OA. It was further found that the effectiveness of nanofluid and the OA containing nanofluids were superior in effectiveness over water in all experimental conditions came under this study. Moreover, the presence of OA had clearly contributed to raise the effectiveness of the nanofluid. PMID- 21711855 TI - A comparative study of non-covalent encapsulation methods for organic dyes into silica nanoparticles. AB - Numerous luminophores may be encapsulated into silica nanoparticles (< 100 nm) using the reverse microemulsion process. Nevertheless, the behaviour and effect of such luminescent molecules appear to have been much less studied and may possibly prevent the encapsulation process from occurring. Such nanospheres represent attractive nanoplatforms for the development of biotargeted biocompatible luminescent tracers. Physical and chemical properties of the encapsulated molecules may be affected by the nanomatrix. This study examines the synthesis of different types of dispersed silica nanoparticles, the ability of the selected luminophores towards incorporation into the silica matrix of those nanoobjects as well as the photophysical properties of the produced dye-doped silica nanoparticles. The nanoparticles present mean diameters between 40 and 60 nm as shown by TEM analysis. Mainly, the photophysical characteristics of the dyes are retained upon their encapsulation into the silica matrix, leading to fluorescent silica nanoparticles. This feature article surveys recent research progress on the fabrication strategies of these dye-doped silica nanoparticles. PMID- 21711857 TI - Biocompatibility of hydrophilic silica-coated CdTe quantum dots and magnetic nanoparticles. AB - Fluorescent magnetic nanoparticles exhibit great application prospects in biomedical engineering. Herein, we reported the effects of hydrophilic silica coated CdTe quantum dots and magnetic nanoparticles (FMNPs) on human embryonic kidney 293 (HEK293) cells and mice with the aim of investigating their biocompatibility. FMNPs with 150 nm in diameter were prepared, and characterized by high-resolution transmission electron microscopy and photoluminescence (PL) spectra and magnetometer. HEK293 cells were cultured with different doses of FMNPs (20, 50, and 100MU g/ml) for 1-4 days. Cell viability and adhesion ability were analyzed by CCK8 method and Western blotting. 30 mice were randomly divided into three groups, and were, respectively, injected via tail vein with 20, 60, and 100 MUg FMNPs, and then were, respectively, raised for 1, 7, and 30 days, then their lifespan, important organs, and blood biochemical parameters were analyzed. Results show that the prepared water-soluble FMNPs had high fluorescent and magnetic properties, less than 50 MUg/ml of FMNPs exhibited good biocompatibility to HEK293 cells, the cell viability, and adhesion ability were similar to the control HEK293 cells. FMNPs primarily accumulated in those organs such as lung, liver, and spleen. Lung exposed to FMNPs displayed a dose-dependent inflammatory response, blood biochemical parameters such as white blood cell count (WBC), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), displayed significant increase when the FMNPs were injected into mice at dose of 100MUg. In conclusion, FMNPs exhibit good biocompatibility to cells under the dose of less than 50 MUg/ml, and to mice under the dose of less than 2mg/kg body weight. The FMNPs' biocompatibility must be considered when FMNPs are used for in vivo diagnosis and therapy. PMID- 21711858 TI - Low-temperature fabrication of layered self-organized Ge clusters by RF sputtering. AB - In this article, we present an investigation of (Ge + SiO2)/SiO2 multilayers deposited by magnetron sputtering and subsequently annealed at different temperatures. The structural properties were investigated by transmission electron microscopy, grazing incidence small angles X-ray scattering, Rutherford backscattering spectrometry, Raman, and X-ray photoelectron spectroscopies. We show a formation of self-assembled Ge clusters during the deposition at 250 degrees C. The clusters are ordered in a three-dimensional lattice, and they have very small sizes (about 3 nm) and narrow size distribution. The crystallization of the clusters was achieved at annealing temperature of 700 degrees C. PMID- 21711859 TI - Micro-nano hybrid structures with manipulated wettability using a two-step silicon etching on a large area. AB - Nanoscale surface manipulation technique to control the surface roughness and the wettability is a challenging field for performance enhancement in boiling heat transfer. In this study, micro-nano hybrid structures (MNHS) with hierarchical geometries that lead to maximizing of surface area, roughness, and wettability are developed for the boiling applications. MNHS structures consist of micropillars or microcavities along with nanowires having the length to diameter ratio of about 100:1. MNHS is fabricated by a two-step silicon etching process, which are dry etching for micropattern and electroless silicon wet etching for nanowire synthesis. The fabrication process is readily capable of producing MNHS covering a wafer-scale area. By controlling the removal of polymeric passivation layers deposited during silicon dry etching (Bosch process), we can control the geometries for the hierarchical structure with or without the thin hydrophobic barriers that affect surface wettability. MNHS without sidewalls exhibit superhydrophilic behavior with a contact angle under 10 degrees , whereas those with sidewalls preserved by the passivation layer display more hydrophobic characteristics with a contact angle near 60 degrees . PMID- 21711860 TI - Flame synthesis of carbon nanostructures on Ni-plated hardmetal substrates. AB - In this article, we demonstrate that carbon nanostructures could be synthesized on the Ni-plated YG6 (WC-6 wt% Co) hardmetal substrate by a simple ethanol diffusion flame method. The morphologies and microstructures of the Ni-plated layer and the carbon nanostructures were examined by various techniques including scanning electron microscopy, X-ray diffraction, and Raman spectroscopy. The growth mechanism of such carbon nanostructures is discussed. This work may provide a strategy to improve the performance of hardmetal products and thus to widen their potential applications. PMID- 21711861 TI - T cells enhance gold nanoparticle delivery to tumors in vivo. AB - Gold nanoparticle-mediated photothermal therapy (PTT) has shown great potential for the treatment of cancer in mouse studies and is now being evaluated in clinical trials. For this therapy, gold nanoparticles (AuNPs) are injected intravenously and are allowed to accumulate within the tumor via the enhanced permeability and retention (EPR) effect. The tumor is then irradiated with a near infrared laser, whose energy is absorbed by the AuNPs and translated into heat. While reliance on the EPR effect for tumor targeting has proven adequate for vascularized tumors in small animal models, the efficiency and specificity of tumor delivery in vivo, particularly in tumors with poor blood supply, has proven challenging. In this study, we examine whether human T cells can be used as cellular delivery vehicles for AuNP transport into tumors. We first demonstrate that T cells can be efficiently loaded with 45 nm gold colloid nanoparticles without affecting viability or function (e.g. migration and cytokine production). Using a human tumor xenograft mouse model, we next demonstrate that AuNP-loaded T cells retain their capacity to migrate to tumor sites in vivo. In addition, the efficiency of AuNP delivery to tumors in vivo is increased by more than four-fold compared to injection of free PEGylated AuNPs and the use of the T cell delivery system also dramatically alters the overall nanoparticle biodistribution. Thus, the use of T cell chaperones for AuNP delivery could enhance the efficacy of nanoparticle-based therapies and imaging applications by increasing AuNP tumor accumulation. PMID- 21711862 TI - Selective area epitaxy of ultra-high density InGaN quantum dots by diblock copolymer lithography. AB - Highly uniform InGaN-based quantum dots (QDs) grown on a nanopatterned dielectric layer defined by self-assembled diblock copolymer were performed by metal-organic chemical vapor deposition. The cylindrical-shaped nanopatterns were created on SiNx layers deposited on a GaN template, which provided the nanopatterning for the epitaxy of ultra-high density QD with uniform size and distribution. Scanning electron microscopy and atomic force microscopy measurements were conducted to investigate the QDs morphology. The InGaN/GaN QDs with density up to 8 * 1010 cm-2 are realized, which represents ultra-high dot density for highly uniform and well-controlled, nitride-based QDs, with QD diameter of approximately 22-25 nm. The photoluminescence (PL) studies indicated the importance of NH3 annealing and GaN spacer layer growth for improving the PL intensity of the SiNx-treated GaN surface, to achieve high optical-quality QDs applicable for photonics devices. PMID- 21711863 TI - Organic electrochemical transistors based on a dielectrophoretically aligned nanowire array. AB - In this study, we synthesized an organic electrochemical transistor (OECT) using dielectrophoresis of a carbon nanotube-Nafion (CNT-Nafion) suspension. Dielectrophoretically aligned nanowires formed a one-dimensional submicron bundle between triangular electrodes. The CNT-Nafion composite nanowire bundles showed p type semiconductor characteristics. The drain-source current decreased with increasing gate voltage. The nanowire bundles showed potential as pH sensor because the drain-source current ratio varied linearly according to the gate voltage in pH buffers. PMID- 21711864 TI - Great blue-shift of luminescence of ZnO nanoparticle array constructed from ZnO quantum dots. AB - ZnO nanoparticle array has been fabricated on the Si substrate by a simple thermal chemical vapor transport and condensation without any metal catalysts. This ZnO nanoparticles array is constructed from ZnO quantum dots (QDs), and half embedded in the amorphous silicon oxide layer on the surface of the Si substrate. The cathodoluminescence measurements showed that there is a pronounced blue-shift of luminescence comparable to those of the bulk counterpart, which is suggested to originate from ZnO QDs with small size where the quantum confinement effect can work well. The fabrication mechanism of the ZnO nanoparticle array constructed from ZnO QDs was proposed, in which the immiscible-like interaction between ZnO nuclei and Si surface play a key role in the ZnO QDs cluster formation. These investigations showed the fabricated nanostructure has potential applications in ultraviolet emitters. PMID- 21711865 TI - Facile solution growth of vertically aligned ZnO nanorods sensitized with aqueous CdS and CdSe quantum dots for photovoltaic applications. AB - Vertically aligned single crystalline ZnO nanorod arrays, approximately 3 MUm in length and 50-450 nm in diameter are grown by a simple solution approach on a Zn foil substrate. CdS and CdSe colloidal quantum dots are assembled onto ZnO nanorods array using water-soluble nanocrystals capped as-synthesized with a short-chain bifuncional linker thioglycolic acid. The solar cells co-sensitized with both CdS and CdSe quantum dots demonstrate superior efficiency compared with the cells using only one type of quantum dots. A thin Al2O3 layer deposited prior to quantum dot anchoring successfully acts as a barrier inhibiting electron recombination at the Zn/ZnO/electrolyte interface, resulting in power conversion efficiency of approximately 1% with an improved fill factor of 0.55. The in situ growth of ZnO nanorod arrays in a solution containing CdSe quantum dots provides better contact between two materials resulting in enhanced open circuit voltage. PMID- 21711866 TI - Subretinal gene delivery using helper-dependent adenoviral vectors. AB - This study describes the successful delivery of helper-dependent adenoviral vectors to the mouse retina with long term and robust levels of reporter expression in the retina without apparent adverse effects. Since these vectors have a large cloning capacity, they have great potential to extend the success of gene therapy achieved using the adeno-associated viral vector. PMID- 21711867 TI - Conjugate heat transfer of laminar mixed convection of a nanofluid through an inclined tube with circumferentially non-uniform heating. AB - Laminar mixed convection of a nanofluid consisting of water and Al2O3 in an inclined tube with heating at the top half surface of a copper tube has been studied numerically. The bottom half of the tube wall is assumed to be adiabatic (presenting a tube of a solar collector). Heat conduction mechanism through the tube wall is considered. Three-dimensional governing equations with using two phase mixture model have been solved to investigate hydrodynamic and thermal behaviours of the nanofluid over wide range of nanoparticle volume fractions. For a given nanoparticle mean diameter the effects of nanoparticle volume fractions on the hydrodynamics and thermal parameters are presented and discussed at different Richardson numbers and different tube inclinations. Significant augmentation on the heat transfer coefficient as well as on the wall shear stress is seen. PMID- 21711868 TI - A compact model for magnetic tunnel junction (MTJ) switched by thermally assisted Spin transfer torque (TAS + STT). AB - Thermally assisted spin transfer torque [TAS + STT] is a new switching approach for magnetic tunnel junction [MTJ] nanopillars that represents the best trade-off between data reliability, power efficiency and density. In this paper, we present a compact model for MTJ switched by this approach, which integrates a number of physical models such as temperature evaluation and STT dynamic switching models. Many experimental parameters are included directly to improve the simulation accuracy. It is programmed in the Verilog-A language and compatible with the standard IC CAD tools, providing an easy parameter configuration interface and allowing high-speed co-simulation of hybrid MTJ/CMOS circuits. PMID- 21711869 TI - Investigation of the electrical conductivity of propylene glycol-based ZnO nanofluids. AB - Electrical conductivity is an important property for technological applications of nanofluids that has not been widely studied. Conventional descriptions such as the Maxwell model do not account for surface charge effects that play an important role in electrical conductivity, particularly at higher nanoparticle volume fractions. Here, we perform electrical characterizations of propylene glycol-based ZnO nanofluids with volume fractions as high as 7%, measuring up to a 100-fold increase in electrical conductivity over the base fluid. We observe a large increase in electrical conductivity with increasing volume fraction and decreasing particle size as well as a leveling off of the increase at high volume fractions. These experimental trends are shown to be consistent with an electrical conductivity model previously developed for colloidal suspensions in salt-free media. In particular, the leveling off of electrical conductivity at high volume fractions, which we attribute to counter-ion condensation, represents a significant departure from the "linear fit" models previously used to describe the electrical conductivity of nanofluids. PMID- 21711870 TI - STM-induced light emission from thin films of perylene derivatives on the HOPG and Au substrates. AB - We have investigated the emission properties of N,N'-diheptyl-3,4,9,10 perylenetetracarboxylic diimide thin films by the tunneling-electron-induced light emission technique. A fluorescence peak with vibronic progressions with large Stokes shifts was observed on both highly ordered pyrolytic graphite (HOPG) and Au substrates, indicating that the emission was derived from the isolated molecule-like film condition with sufficient pi-pi interaction of the perylene rings of perylenetetracarboxylic diimide molecules. The upconversion emission mechanism of the tunneling-electron-induced emission was discussed in terms of inelastic tunneling including multiexcitation processes. The wavelength-selective enhanced emission due to a localized tip-induced surface plasmon on the Au substrate was also obtained. PMID- 21711871 TI - Electro-synthesis of novel nanostructured PEDOT films and their application as catalyst support. AB - Poly(3,4-ethylenedioxythiophene) (PEDOT) films doped with nitric and chlorine ions have been electrochemically deposited simply by a one-step electrochemical method in an aqueous media in the absence of any surfactant. The fabricated PEDOT films were characterized by scanning electron microscopy, transmission electron microscopy, and Raman spectroscopy. The results indicate that the hierarchical structured PEDOT film doped with nitric ions displays a 'lunar craters' porous morphology consisting of PEDOT nano-sheets with a thickness of less than 2 nm. The effect of counter ions on the electro-polymerization, the electrochemistry, and the morphology of the polymer film was studied. Compared with PEDOT film doped with nitric acid, PEDOT film deposited in the presence of chlorine ions shows irregular morphology and less electrochemical activity. The specific nanostructure of the polymer was further studied as catalyst support for platinum nanoparticles to methanol electro-oxidation. PMID- 21711872 TI - Hyperspectral optical imaging of two different species of lepidoptera. AB - In this article, we report a hyperspectral optical imaging application for measurement of the reflectance spectra of photonic structures that produce structural colors with high spatial resolution. The measurement of the spectral reflectance function is exemplified in the butterfly wings of two different species of Lepidoptera: the blue iridescence reflected by the nymphalid Morpho didius and the green iridescence of the papilionid Papilio palinurus. Color coordinates from reflectance spectra were calculated taking into account human spectral sensitivity. For each butterfly wing, the observed color is described by a characteristic color map in the chromaticity diagram and spreads over a limited volume in the color space. The results suggest that variability in the reflectance spectra is correlated with different random arrangements in the spatial distribution of the scales that cover the wing membranes. Hyperspectral optical imaging opens new ways for the non-invasive study and classification of different forms of irregularity in structural colors. PMID- 21711873 TI - The influence of the dispersion method on the electrical properties of vapor grown carbon nanofiber/epoxy composites. AB - The influence of the dispersion of vapor-grown carbon nanofibers (VGCNF) on the electrical properties of VGCNF/Epoxy composites has been studied. A homogenous dispersion of the VGCNF does not imply better electrical properties. In fact, it is demonstrated that the most simple of the tested dispersion methods results in higher conductivity, since the presence of well-distributed nanofiber clusters appears to be a key factor for increasing composite conductivity.PACS: 72.80.Tm; 73.63.Fg; 81.05.Qk. PMID- 21711874 TI - Structural and electronic properties of Eu- and Pd-doped ZnO. AB - Doping ZnO with rare earth and 4d transition elements is a popular technique to manipulate the optical properties of ZnO systems. These systems may also possess intrinsic ferromagnetism due to their magnetic moment borne on 4f and 4d electrons. In this work, the structural, electronic, and magnetic properties of Eu- and Pd-doped ZnO were investigated by the ab initio density functional theory methods based on generalized gradient approximation. The relative stability of incorporation sites of the doped elements in the ZnO host lattice was studied. The ground state properties, equilibrium bond lengths, and band structures of both the ZnO:Eu and ZnO:Pd systems were also investigated. The total and partial densities of electron states were also determined for both systems. It was found that in the ZnO:Eu system, ambient ferromagnetism can be induced by introducing Zn interstitial which leads to a carrier-mediated ferromagnetism while the ZnO:Pd system possesses no ferromagnetism.PACS 31.15.E-, 75.50.Pp, 75.30Hx. PMID- 21711875 TI - Designing novel Sn-Bi, Si-C and Ge-C nanostructures, using simple theoretical chemical similarities. AB - A framework of simple, transparent and powerful concepts is presented which is based on isoelectronic (or isovalent) principles, analogies, regularities and similarities. These analogies could be considered as conceptual extensions of the periodical table of the elements, assuming that two atoms or molecules having the same number of valence electrons would be expected to have similar or homologous properties. In addition, such similar moieties should be able, in principle, to replace each other in more complex structures and nanocomposites. This is only partly true and only occurs under certain conditions which are investigated and reviewed here. When successful, these concepts are very powerful and transparent, leading to a large variety of nanomaterials based on Si and other group 14 elements, similar to well known and well studied analogous materials based on boron and carbon. Such nanomaterias designed in silico include, among many others, Si-C, Sn-Bi, Si-C and Ge-C clusters, rings, nanowheels, nanorodes, nanocages and multidecker sandwiches, as well as silicon planar rings and fullerenes similar to the analogous sp2 bonding carbon structures. It is shown that this pedagogically simple and transparent framework can lead to an endless variety of novel and functional nanomaterials with important potential applications in nanotechnology, nanomedicine and nanobiology. Some of the so called predicted structures have been already synthesized, not necessarily with the same rational and motivation. Finally, it is anticipated that such powerful and transparent rules and analogies, in addition to their predictive power, could also lead to far-reaching interpretations and a deeper understanding of already known results and information. PMID- 21711876 TI - Structure-dependent mechanical properties of ultrathin zinc oxide nanowires. AB - Mechanical properties of ultrathin zinc oxide (ZnO) nanowires of about 0.7-1.1 nm width and in the unbuckled wurtzite (WZ) phase have been carried out by molecular dynamics simulation. As the width of the nanowire decreases, Young's modulus, stress-strain behavior, and yielding stress all increase. In addition, the yielding strength and Young's modulus of Type III are much lower than the other two types, because Type I and II have prominent edges on the cross-section of the nanowire. Due to the flexibility of the Zn-O bond, the phase transformation from an unbuckled WZ phase to a buckled WZ is observed under the tensile process, and this behavior is reversible. Moreover, one- and two-atom wide chains can be observed before the ZnO nanowires rupture. These results indicate that the ultrathin nanowire possesses very high malleability. PMID- 21711877 TI - Review of thermo-physical properties, wetting and heat transfer characteristics of nanofluids and their applicability in industrial quench heat treatment. AB - The success of quenching process during industrial heat treatment mainly depends on the heat transfer characteristics of the quenching medium. In the case of quenching, the scope for redesigning the system or operational parameters for enhancing the heat transfer is very much limited and the emphasis should be on designing quench media with enhanced heat transfer characteristics. Recent studies on nanofluids have shown that these fluids offer improved wetting and heat transfer characteristics. Further water-based nanofluids are environment friendly as compared to mineral oil quench media. These potential advantages have led to the development of nanofluid-based quench media for heat treatment practices. In this article, thermo-physical properties, wetting and boiling heat transfer characteristics of nanofluids are reviewed and discussed. The unique thermal and heat transfer characteristics of nanofluids would be extremely useful for exploiting them as quench media for industrial heat treatment. PMID- 21711879 TI - Intermatrix synthesis: easy technique permitting preparation of polymer stabilized nanoparticles with desired composition and structure. AB - The synthesis of polymer-stabilized nanoparticles (PSNPs) can be successfully carried out using intermatrix synthesis (IMS) technique, which consists in sequential loading of the functional groups of a polymer with the desired metal ions followed by nanoparticles (NPs) formation stage. After each metal-loading NPs-formation cycle, the functional groups of the polymer appear to be regenerated. This allows for repeating the cycles to increase the NPs content or to obtain NPs with different structures and compositions (e.g. core-shell or core sandwich). This article reports the results on the further development of the IMS technique. The formation of NPs has been shown to proceed by not only the metal reduction reaction (e.g. Cu0-NPs) but also by the precipitation reaction resulting in the IMS of PSNPs of metal salts (e.g. CuS-NPs). PMID- 21711878 TI - Sensitive and molecular size-selective detection of proteins using a chip-based and heteroliganded gold nanoisland by localized surface plasmon resonance spectroscopy. AB - A highly sensitive and molecular size-selective method for the detection of proteins using heteroliganded gold nanoislands and localized surface plasmon resonance (LSPR) is described. Two different heteroligands with different chain lengths (3-mercaptopionicacid and decanethiol) were used in fabricating nanoholes for the size-dependent separation of a protein in comparison with its aggregate. Their ratios on gold nanoisland were optimized for the sensitive detection of superoxide dismutase (SOD1). This protein has been implicated in the pathology of amyotrophic lateral sclerosis (ALS). Upon exposure of the optimized gold nanoisland to a solution of SOD1 and aggregates thereof, changes in the LSPR spectra were observed which are attributed to the size-selective and covalent chemical binding of SOD1 to the nanoholes. With a lower detection limit of 1.0 ng/ml, the method can be used to selectively detect SOD1 in the presence of aggregates at the molecular level. PMID- 21711881 TI - Preparation and surface functionalization of MWCNTs: study of the composite materials produced by the interaction with an iron phthalocyanine complex. AB - Carbon nanotubes [CNTs] were synthesized by the catalytic vapor decomposition method. Thereafter, they were functionalized in order to incorporate the oxygen groups (OCNT) and subsequently the amine groups (ACNT). All three CNTs (the as synthesized and functionalized) underwent reaction with an iron organometallic complex (FePcS), iron(III) phthalocyanine-4,4",4",4""-tetrasulfonic acid, in order to study the nature of the interaction between this complex and the CNTs and the potential formation of nanocomposite materials. Transmission electronic microscopy, N2 adsorption at 77 K, thermogravimetric analysis, temperature programmed desorption, and X-ray photoelectron spectroscopy were the characterization techniques employed to confirm the successful functionalization of CNTs as well as the type of interaction existing with the FePcS. All results obtained led to the same conclusion: There were no specific chemical interactions between CNTs and the fixed FePcS. PMID- 21711880 TI - Study on the visible-light-induced photokilling effect of nitrogen-doped TiO2 nanoparticles on cancer cells. AB - Nitrogen-doped TiO2 (N-TiO2) nanoparticles were prepared by calcining the anatase TiO2 nanoparticles under ammonia atmosphere. The N-TiO2 showed higher absorbance in the visible region than the pure TiO2. The cytotoxicity and visible light-induced phototoxicity of the pure- and N-TiO2 were examined for three types of cancer cell lines. No significant cytotoxicity was detected. However, the visible-light-induced photokilling effects on cells were observed. The survival fraction of the cells decreased with the increased incubation concentration of the nanoparticles. The cancer cells incubated with N-TiO2 were killed more effectively than that with the pure TiO2. The reactive oxygen species was found to play an important role on the photokilling effect for cells. Furthermore, the intracellular distributions of N-TiO2 nanoparticles were examined by laser scanning confocal microscopy. The co-localization of N-TiO2 nanoparticles with nuclei or Golgi complexes was observed. The aberrant nuclear morphologies such as micronuclei were detected after the N-TiO2-treated cells were irradiated by the visible light. PMID- 21711882 TI - Quantum-squeezing effects of strained multilayer graphene NEMS. AB - Quantum squeezing can improve the ultimate measurement precision by squeezing one desired fluctuation of the two physical quantities in Heisenberg relation. We propose a scheme to obtain squeezed states through graphene nanoelectromechanical system (NEMS) taking advantage of their thin thickness in principle. Two key criteria of achieving squeezing states, zero-point displacement uncertainty and squeezing factor of strained multilayer graphene NEMS, are studied. Our research promotes the measured precision limit of graphene-based nano-transducers by reducing quantum noises through squeezed states. PMID- 21711883 TI - Flat edge modes of graphene and of Z2 topological insulator. AB - A graphene nano-ribbon in the zigzag edge geometry exhibits a specific type of gapless edge modes with a partly flat band dispersion. We argue that the appearance of such edge modes are naturally understood by regarding graphene as the gapless limit of a Z2 topological insulator. To illustrate this idea, we consider both Kane-Mele (graphene-based) and Bernevig-Hughes-Zhang models: the latter is proposed for HgTe/CdTe 2D quantum well. Much focus is on the role of valley degrees of freedom, especially, on how they are projected onto and determine the 1D edge spectrum in different edge geometries. PMID- 21711884 TI - Novel hybrid organic/inorganic 2D quasiperiodic PC: from diffraction pattern to vertical light extraction. AB - Recently, important efforts have been dedicated to the realization of a fascinating class of new photonic materials or metamaterials, known as photonic quasicrystals (PQCs), in which the lack of the translational symmetry is compensated by rotational symmetries not achievable by the conventional periodic crystals. As ever, more advanced functionality is demanded and one strategy is the introduction of non-linear and/or active functionality in photonic materials. In this view, core/shell nanorods (NRs) are a promising active material for light emitting applications. In this article a two-dimensional (2D) hybrid a 2D octagonal PQC which consists of air rods in an organic/inorganic nanocomposite is proposed and experimentally demonstrated. The nanocomposite was prepared by incorporating CdSe/CdS core/shell NRs into a polymer matrix. The PQC was realized by electron beam lithography (EBL) technique. Scanning electron microscopy, far field diffraction and spectra measurements are used to characterize the experimental structure. The vertical extraction of the light, by the coupling of the modes guided by the PQC slab to the free radiation via Bragg scattering, consists of a narrow red emissions band at 690 nm with a full width at half maximum (FWHM) of 21.5 nm. The original characteristics of hybrid materials based on polymers and colloidal NRs, able to combine the unique optical properties of the inorganic moiety with the processability of the host matrix, are extremely appealing in view of their technological impact on the development of new high performing optical devices such as organic light-emitting diodes, ultra-low threshold lasers, and non-linear devices.PACS: 81.07.Pr Organic-inorganic hybrid nanostructures, 81.16.-c Methods of nanofabrication and processing, 42.70.Qs Photonic band-gap materials. PMID- 21711885 TI - Shrinking of Solid-state Nanopores by Direct Thermal Heating. AB - Solid-state nanopores have emerged as useful single-molecule sensors for DNA and proteins. A novel and simple technique for solid-state nanopore fabrication is reported here. The process involves direct thermal heating of 100 to 300 nm nanopores, made by focused ion beam (FIB) milling in free-standing membranes. Direct heating results in shrinking of the silicon dioxide nanopores. The free standing silicon dioxide membrane is softened and adatoms diffuse to a lower surface free energy. The model predicts the dynamics of the shrinking process as validated by experiments. The method described herein, can process many samples at one time. The inbuilt stress in the oxide film is also reduced due to annealing. The surface composition of the pore walls remains the same during the shrinking process. The linear shrinkage rate gives a reproducible way to control the diameter of a pore with nanometer precision. PMID- 21711886 TI - CMOS-compatible dense arrays of Ge quantum dots on the Si(001) surface: hut cluster nucleation, atomic structure and array life cycle during UHV MBE growth. AB - We report a direct observation of Ge hut nucleation on Si(001) during UHV molecular beam epitaxy at 360 degrees C. Nuclei of pyramids and wedges were observed on the wetting layer (WL) (M * N) patches starting from the coverage of 5.1 A and found to have different structures. Atomic models of nuclei of both hut species have been built as well as models of the growing clusters. The growth of huts of each species has been demonstrated to follow generic scenarios. The formation of the second atomic layer of a wedge results in rearrangement of its first layer. Its ridge structure does not repeat the nucleus. A pyramid grows without phase transitions. A structure of its vertex copies the nucleus. Transitions between hut species turned out to be impossible. The wedges contain point defects in the upper corners of the triangular faces and have preferential growth directions along the ridges. The derived structure of the {105} facet follows the paired dimer model. Further growth of hut arrays results in domination of wedges, and the density of pyramids exponentially drops. The second generation of huts arises at coverages >10 A; new huts occupy the whole WL at coverages ~14 A. Nanocrystalline Ge 2D layer begins forming at coverages >14 A. PMID- 21711887 TI - Single nanowire-based UV photodetectors for fast switching. AB - Relatively long (30 um) high quality ZnO nanowires (NWs) were grown by the vapor liquid-solid (VLS) technique. Schottky diodes of single NW were fabricated by putting single ZnO NW across Au and Pt electrodes. A device with ohmic contacts at both the sides was also fabricated for comparison. The current-voltage (I-V) measurements for the Schottky diode show clear rectifying behavior and no reverse breakdown was seen down to -5 V. High current was observed in the forward bias and the device was found to be stable up to 12 V applied bias. The Schottky barrier device shows more sensitivity, lower dark current, and much faster switching under pulsed UV illumination. Desorption and re-adsorption of much smaller number of oxygen ions at the Schottky junction effectively alters the barrier height resulting in a faster response even for very long NWs. The NW was treated with oxygen plasma to improve the switching. The photodetector shows high stability, reversibility, and sensitivity to UV light. The results imply that single ZnO NW Schottky diode is a promising candidate for fabricating UV photodetectors. PMID- 21711888 TI - Shape and phase control of CdS nanocrystals using cationic surfactant in noninjection synthesis. AB - Monodispersed CdS nanocrystals with controllable shape and phase have been successfully synthesized in this study by adding cationic surfactant in noninjection synthesis system. With the increase of the amount of cetyltrimethylammonium chloride (CTAC) added, the shape of the CdS nanocrystals changed from spherical to multi-armed, and the phase changed from zinc-blende to wurtzite. It was found that halide ion Cl- plays a key role in the transformation, and other halide ions such as Br- can also induce similar transformation. We proposed that the strong binding between Cd2+ and halide ions reduced the reactivity of the precursors, decreased the nuclei formed in the nucleation stage, and led to the high concentration of precursor in the growth stage, resulting in the increase of size and phase transformation of CdS nanocrystals. In addition, it was found that the multi-armed CdS nanocrystals lost quantum confinement effect because of the increase of the size with the increase of the concentration of CTAC. PMID- 21711889 TI - Development of Polysorbate 80/Phospholipid mixed micellar formation for docetaxel and assessment of its in vivo distribution in animal models. AB - Docetaxel (DTX) is a very important member of taxoid family. Despite several alternative delivery systems reported recently, DTX formulated by Polysorbate 80 and alcohol (Taxotere(r)) is still the most frequent administration in clinical practice. In this study, we incorporated DTX into Polysorbate 80/Phospholipid mixed micelles and compared its structural characteristics, pharmacokinetics, biodistribution, and blood compatibility with its conventional counterparts. Results showed that the mixed micelles loaded DTX possessed a mean size of approximately 13 nm with narrow size distribution and a rod-like micelle shape. In the pharmacokinetics assessment, there was no significant difference between the two preparations (P > 0.05), which demonstrated that the DTX in the two preparations may share a similar pharmacokinetic process. However, the Polysorbate 80/Phospholipid mixed micelles can increase the drug residence amount of DTX in kidney, spleen, ovary and uterus, heart, and liver. The blood compatibility assessment study revealed that the mixed micelles were safe for intravenous injection. In conclusion, Polysorbate 80/Phospholipid mixed micelle is safe, can improve the tumor therapeutic effects of DTX in the chosen organs, and may be a potential alternative dosage form for clinical intravenous administration of DTX. PMID- 21711890 TI - Synthesis of magnetic nanofibers using femtosecond laser material processing in air. AB - In this study, we report formation of weblike fibrous nanostructure and nanoparticles of magnetic neodymium-iron-boron (NdFeB) via femtosecond laser radiation at MHz pulse repetition frequency in air at atmospheric pressure. Scanning electron microscopy (SEM) analysis revealed that the nanostructure is formed due to aggregation of polycrystalline nanoparticles of the respective constituent materials. The nanofibers diameter varies between 30 and 70 nm and they are mixed with nanoparticles. The effect of pulse to pulse separation rate on the size of the magnetic fibrous structure and the magnetic strength was reported. X-ray diffraction (XRD) analysis revealed metallic and oxide phases in the nanostructure. The growth of magnetic nanostructure is highly recommended for the applications of magnetic devices like biosensors and the results suggest that the pulsed-laser method is a promising technique for growing nanocrystalline magnetic nanofibers and nanoparticles for biomedical applications. PMID- 21711891 TI - Efficient visible luminescence of nanocrystalline silicon prepared from amorphous silicon films by thermal annealing and stain etching. AB - Films of nanocrystalline silicon (nc-Si) were prepared from hydrogenated amorphous silicon (a-Si:H) by using rapid thermal annealing. The formed nc-Si films were subjected to stain etching in hydrofluoric acid solutions in order to passivate surfaces of nc-Si. The optical reflectance spectroscopy revealed the nc Si formation as well as the high optical quality of the formed films. The Raman scattering spectroscopy was used to estimate the mean size and volume fraction of nc-Si in the annealed films, which were about 4 to 8 nm and 44 to 90%, respectively, depending on the annealing regime. In contrast to as-deposited a Si:H films, the nc-Si films after stain etching exhibited efficient photoluminescence in the spectral range of 600 to 950 nm at room temperature. The photoluminescence intensity and lifetimes of the stain etched nc-Si films were similar to those for conventional porous Si formed by electrochemical etching. The obtained results indicate new possibilities to prepare luminescent thin films for Si-based optoelectronics. PMID- 21711892 TI - A new heat propagation velocity prevails over Brownian particle velocities in determining the thermal conductivities of nanofluids. AB - An alternative insight is presented concerning heat propagation velocity scales in predicting the effective thermal conductivities of nanofluids. The widely applied Brownian particle velocities in published literature are often found too slow to describe the relatively higher nanofluid conductivities. In contrast, the present model proposes a faster heat transfer velocity at the same order as the speed of sound, rooted in a modified kinetic principle. In addition, this model accounts for both nanoparticle heat dissipation as well as coagulation effects. This novel model of effective thermal conductivities of nanofluids agrees well with an extended range of experimental data. PMID- 21711893 TI - Polytetrafluorethylene-Au as a substrate for surface-enhanced Raman spectroscopy. AB - This study deals with preparation of substrates suitable for surface-enhanced Raman spectroscopy (SERS) applications by sputtering deposition of gold layer on the polytetrafluorethylene (PTFE) foil. Time of sputtering was investigated with respect to the surface properties. The ability of PTFE-Au substrates to enhance Raman signals was investigated by immobilization of biphenyl-4,4'-dithiol (BFD) from the solutions with various concentrations. BFD was also used for preparation of sandwich structures with Au or Ag nanoparticles by two different procedures. Results showed that PTFE can be used for fabrication of SERS active substrate with easy handle properties at low cost. This substrate was sufficient for the measurement of SERS spectrum of BFD even at 10-8 mol/l concentration. PMID- 21711894 TI - Magnetoluminescence from trion and biexciton in type-II quantum dot. AB - We theoretically investigate optical Aharonov-Bohm (AB) effects on trion and biexciton in the type-II semiconductor quantum dots, in which holes are localized near the center of the dot, and electrons are confined in a ring structure formed around the dot. Many-particle states are calculated numerically by the exact diagonalization method. Two electrons in trion and biexciton are strongly correlated to each other, forming a Wigner molecule. Since the relative motion of electrons are frozen, the Wigner molecule behaves as a composite particle whose mass and charges are twice those of an electron. As a result, the period of AB oscillation for trion and biexciton becomes h/2e as a function of magnetic flux penetrating the ring. We find that the magnetoluminescence spectra from trion and biexciton change discontinuously as the magnetic flux increases by h/2e.PACS: 71.35.Ji, 73.21.-b, 73.21.La, 78.67.Hc. PMID- 21711895 TI - Photoluminescence of spray pyrolysis deposited ZnO nanorods. AB - Photoluminescence of highly structured ZnO layers comprising well-shaped hexagonal rods is presented. The ZnO rods (length 500-1,000 nm, diameter 100-300 nm) were grown in air onto a preheated soda-lime glass (SGL) or ITO/SGL substrate by low-cost chemical spray pyrolysis method using zinc chloride precursor solutions and growth temperatures in the range of 450-550 degrees C. We report the effect of the variation in deposition parameters (substrate type, growth temperature, spray rate, solvent type) on the photoluminescence properties of the spray-deposited ZnO nanorods. A dominant near band edge (NBE) emission is observed at 300 K and at 10 K. High-resolution photoluminescence measurements at 10 K reveal fine structure of the NBE band with the dominant peaks related to the bound exciton transitions. It is found that all studied technological parameters affect the excitonic photoluminescence in ZnO nanorods.PACS: 78.55.Et, 81.15.Rs, 61.46.Km. PMID- 21711896 TI - Design process of the nanofluid injection mechanism in nuclear power plants. AB - Nanofluids, which are engineered suspensions of nanoparticles in a solvent such as water, have been found to show enhanced coolant properties such as higher critical heat flux and surface wettability at modest concentrations, which is a useful characteristic in nuclear power plants (NPPs). This study attempted to provide an example of engineering applications in NPPs using nanofluid technology. From these motivations, the conceptual designs of the emergency core cooling systems (ECCSs) assisted by nanofluid injection mechanism were proposed after following a design framework to develop complex engineering systems. We focused on the analysis of functional requirements for integrating the conventional ECCSs and nanofluid injection mechanism without loss of performance and reliability. Three candidates of nanofluid-engineered ECCS proposed in previous researches were investigated by applying axiomatic design (AD) in the manner of reverse engineering and it enabled to identify the compatibility of functional requirements and potential design vulnerabilities. The methods to enhance such vulnerabilities were referred from TRIZ and concretized for the ECCS of the Korean nuclear power plant. The results show a method to decouple the ECCS designs with the installation of a separate nanofluids injection tank adjacent to the safety injection tanks such that a low pH environment for nanofluids can be maintained at atmospheric pressure which is favorable for their injection in passive manner. PMID- 21711897 TI - Effect of Eu-implantation and annealing on the GaN quantum dots excitonic recombination. AB - Undoped self-assembled GaN quantum dots (QD) stacked in superlattices (SL) with AlN spacer layers were submitted to thermal annealing treatments. Changes in the balance between the quantum confinement, strain state of the stacked heterostructures and quantum confined Stark effect lead to the observation of GaN QD excitonic recombination above and below the bulk GaN bandgap. In Eu-implanted SL structures, the GaN QD recombination was found to be dependent on the implantation fluence. For samples implanted with high fluence, a broad emission band at 2.7 eV was tentatively assigned to the emission of large blurred GaN QD present in the damage region of the implanted SL. This emission band is absent in the SL structures implanted with lower fluence and hence lower defect level. In both cases, high energy emission bands at approx. 3.9 eV suggest the presence of smaller dots for which the photoluminescence intensity was seen to be constant with increasing temperatures. Despite the fact that different deexcitation processes occur in undoped and Eu-implanted SL structures, the excitation population mechanisms were seen to be sample-independent. Two main absorption bands with maxima at approx. 4.1 and 4.7 to 4.9 eV are responsible for the population of the optically active centres in the SL samples. PMID- 21711898 TI - Freestanding HfO2 grating fabricated by fast atom beam etching. AB - We report here the fabrication of freestanding HfO2 grating by combining fast atom beam etching (FAB) of HfO2 film with dry etching of silicon substrate. HfO2 film is deposited onto silicon substrate by electron beam evaporator. The grating patterns are then defined by electron beam lithography and transferred to HfO2 film by FAB etching. The silicon substrate beneath the HfO2 grating region is removed to make the HfO2 grating suspend in space. Period- and polarization dependent optical responses of fabricated HfO2 gratings are experimentally characterized in the reflectance measurements. The simple process is feasible for fabricating freestanding HfO2 grating that is a potential candidate for single layer dielectric reflector.PACS: 73.40.Ty; 42.70.Qs; 81.65.Cf. PMID- 21711899 TI - Scaling properties of ballistic nano-transistors. AB - Recently, we have suggested a scale-invariant model for a nano-transistor. In agreement with experiments a close-to-linear thresh-old trace was found in the calculated ID - VD-traces separating the regimes of classically allowed transport and tunneling transport. In this conference contribution, the relevant physical quantities in our model and its range of applicability are discussed in more detail. Extending the temperature range of our studies it is shown that a close to-linear thresh-old trace results at room temperatures as well. In qualitative agreement with the experiments the ID - VG-traces for small drain voltages show thermally activated transport below the threshold gate voltage. In contrast, at large drain voltages the gate-voltage dependence is weaker. As can be expected in our relatively simple model, the theoretical drain current is larger than the experimental one by a little less than a decade. PMID- 21711900 TI - Preparation and properties of copper-oil-based nanofluids. AB - In this study, the lipophilic Cu nanoparticles were synthesized by surface modification method to improve their dispersion stability in hydrophobic organic media. The oil-based nanofluids were prepared with the lipophilic Cu nanoparticles. The transport properties, viscosity, and thermal conductivity of the nanofluids have been measured. The viscosities and thermal conductivities of the nanofluids with the surface-modified nanoparticles have higher values than the base fluids do. The composition has more significant effects on the thermal conductivity than on the viscosity. It is valuable to prepare an appropriate oil based nanofluid for enhancing the heat-transfer capacity of a hydrophobic system. The effects of adding Cu nanoparticles on the thermal oxidation stability of the fluids were investigated by measuring the hydroperoxide concentration in the Cu/kerosene nanofluids. The hydroperoxide concentrations are observed to be clearly lower in the Cu nanofluids than in their base fluids. Appropriate amounts of metal nanoparticles added in a hydrocarbon fuel can enhance the thermal oxidation stability. PMID- 21711901 TI - Numerical evaluation of laminar heat transfer enhancement in nanofluid flow in coiled square tubes. AB - Convective heat transfer can be enhanced by changing flow geometry and/or by enhancing thermal conductivity of the fluid. This study proposes simultaneous passive heat transfer enhancement by combining the geometry effect utilizing nanofluids inflow in coils. The two nanofluid suspensions examined in this study are: water-Al2O3 and water-CuO. The flow behavior and heat transfer performance of these nanofluid suspensions in various configurations of coiled square tubes, e.g., conical spiral, in-plane spiral, and helical spiral, are investigated and compared with those for water flowing in a straight tube. Laminar flow of a Newtonian nanofluid in coils made of square cross section tubes is simulated using computational fluid dynamics (CFD)approach, where the nanofluid properties are treated as functions of particle volumetric concentration and temperature. The results indicate that addition of small amounts of nanoparticles up to 1% improves significantly the heat transfer performance; however, further addition tends to deteriorate heat transfer performance. PMID- 21711904 TI - Evaluation of the nanotube intrinsic resistance across the tip-carbon nanotube metal substrate junction by Atomic Force Microscopy. AB - Using an atomic force microscope (AFM) at a controlled contact force, we report the electrical signal response of multi-walled carbon nanotubes (MWCNTs) disposed on a golden thin film. In this investigation, we highlight first the theoretical calculation of the contact resistance between two types of conductive tips (metal coated and doped diamond-coated), individual MWCNTs and golden substrate. We also propose a circuit analysis model to schematize the "tip-CNT-substrate" junction by means of a series-parallel resistance network. We estimate the contact resistance R of each contribution of the junction such as Rtip-CNT, RCNT substrate and Rtip-substrate by using the Sharvin resistance model. Our final objective is thus to deduce the CNT intrinsic radial resistance taking into account the calculated electrical resistance values with the global resistance measured experimentally. An unwished electrochemical phenomenon at the tip apex has also been evidenced by performing measurements at different bias voltages with diamond tips. For negative tip-substrate bias, a systematic degradation in color and contrast of the electrical cartography occurs, consisting of an important and non-reversible increase of the measured resistance. This effect is attributed to the oxidation of some amorphous carbon areas scattered over the diamond layer covering the tip. For a direct polarization, the CNT and substrate surface can in turn be modified by an oxidation mechanism. PMID- 21711902 TI - Virulence determinants, drug resistance and mobile genetic elements of Laribacter hongkongensis: a genome-wide analysis. AB - BACKGROUND: Laribacter hongkongensis is associated with community-acquired gastroenteritis and traveler's diarrhea. In this study, we performed an in-depth annotation of the genes in its genome related to the various steps in the infective process, drug resistance and mobile genetic elements. RESULTS: For acid and bile resistance, L. hongkongensis possessed a urease gene cassette, two arc gene clusters and bile salt efflux systems. For intestinal colonization, it possessed a putative adhesin of the autotransporter family homologous to those of diffusely adherent Escherichia coli (E. coli) and enterotoxigenic E. coli. To evade from host defense, it possessed superoxide dismutase and catalases. For lipopolysaccharide biosynthesis, it possessed the same set of genes that encode enzymes for synthesizing lipid A, two Kdo units and heptose units as E. coli, but different genes for its symmetrical acylation pattern, and nine genes for polysaccharide side chains biosynthesis. It contained a number of CDSs that encode putative cell surface acting (RTX toxin and hemolysins) and intracellular cytotoxins (patatin-like proteins) and enzymes for invasion (outer membrane phospholipase A). It contained a broad variety of antibiotic resistance-related genes, including genes related to beta-lactam (n = 10) and multidrug efflux (n = 54). It also contained eight prophages, 17 other phage-related CDSs and 26 CDSs for transposases. CONCLUSIONS: The L. hongkongensis genome possessed genes for acid and bile resistance, intestinal mucosa colonization, evasion of host defense and cytotoxicity and invasion. A broad variety of antibiotic resistance or multidrug resistance genes, a high number of prophages, other phage-related CDSs and CDSs for transposases, were also identified. PMID- 21711903 TI - Lithium promotes neural precursor cell proliferation: evidence for the involvement of the non-canonical GSK-3beta-NF-AT signaling. AB - Lithium, a drug that has long been used to treat bipolar disorder and some other human pathogenesis, has recently been shown to stimulate neural precursor growth. However, the involved mechanism is not clear. Here, we show that lithium induces proliferation but not survival of neural precursor cells. Mechanistic studies suggest that the effect of lithium mainly involved activation of the transcription factor NF-AT and specific induction of a subset of proliferation related genes. While NF-AT inactivation by specific inhibition of its upstream activator calcineurin antagonized the effect of lithium on the proliferation of neural precursor cells, specific inhibition of the NF-AT inhibitor GSK-3beta, similar to lithium treatment, promoted neural precursor cell proliferation. One important function of lithium appeared to increase inhibitory phosphorylation of GSK-3beta, leading to GSK-3beta suppression and subsequent NF-AT activation. Moreover, lithium-induced proliferation of neural precursor cells was independent of its role in inositol depletion. These findings not only provide mechanistic insights into the clinical effects of lithium, but also suggest an alternative therapeutic strategy for bipolar disorder and other neural diseases by targeting the non-canonical GSK-3beta-NF-AT signaling. PMID- 21711905 TI - Analytical model for the photocurrent-voltage characteristics of bilayer MEH PPV/TiO2 photovoltaic devices. AB - The photocurrent in bilayer polymer photovoltaic cells is dominated by the exciton dissociation efficiency at donor/acceptor interface. An analytical model is developed for the photocurrent-voltage characteristics of the bilayer polymer/TiO2 photovoltaic cells. The model gives an analytical expression for the exciton dissociation efficiency at the interface, and explains the dependence of the photocurrent of the devices on the internal electric field, the polymer and TiO2 layer thicknesses. Bilayer polymer/TiO2 cells consisting of poly[2-methoxy-5 (2-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV) and TiO2, with different thicknesses of the polymer and TiO2 films, were prepared for experimental purposes. The experimental results for the prepared bilayer MEH-PPV/TiO2 cells under different conditions are satisfactorily fitted to the model. Results show that increasing TiO2 or the polymer layer in thickness will reduce the exciton dissociation efficiency in the device and further the photocurrent. It is found that the photocurrent is determined by the competition between the exciton dissociation and charge recombination at the donor/acceptor interface, and the increase in photocurrent under a higher incident light intensity is due to the increased exciton density rather than the increase in the exciton dissociation efficiency. PMID- 21711906 TI - New potential antitumoral fluorescent tetracyclic thieno[3,2-b]pyridine derivatives: interaction with DNA and nanosized liposomes. AB - Fluorescence properties of two new potential antitumoral tetracyclic thieno[3,2 b]pyridine derivatives were studied in solution and in liposomes of DPPC (dipalmitoyl phosphatidylcholine), egg lecithin (phosphatidylcholine from egg yolk; Egg-PC) and DODAB (dioctadecyldimethylammonium bromide). Compound 1, pyrido[2',3':3,2]thieno[4,5-d]pyrido[1,2-a]pyrimidin-6-one, exhibits reasonably high fluorescence quantum yields in all solvents studied (0.20 <= PhiF <= 0.30), while for compound 2, 3-[(p-methoxyphenyl)ethynyl]pyrido[2',3':3,2]thieno[4,5 d]pyrido[1,2-a]pyrimidin-6-one, the values are much lower (0.01 <= PhiF <= 0.05). The interaction of these compounds with salmon sperm DNA was studied using spectroscopic methods, allowing the determination of intrinsic binding constants, Ki = (8.7 +/- 0.9) * 103 M-1 for compound 1 and Ki = (5.9 +/- 0.6) * 103 M-1 for 2, and binding site sizes of n = 11 +/- 3 and n = 7 +/- 2 base pairs, respectively. Compound 2 is the most intercalative compound in salmon sperm DNA (35%), while for compound 1 only 11% of the molecules are intercalated. Studies of incorporation of both compounds in liposomes of DPPC, Egg-PC and DODAB revealed that compound 2 is mainly located in the hydrophobic region of the lipid bilayer, while compound 1 prefers a hydrated and fluid environment. PMID- 21711907 TI - Investigations on antibody binding to a micro-cantilever coated with a BAM pesticide residue. AB - The attachment of an antibody to an antigen-coated cantilever has been investigated by repeated experiments, using a cantilever-based detection system by Cantion A/S. The stress induced by the binding of a pesticide residue BAM (2,6 dichlorobenzamide) immobilized on a cantilever surface to anti-BAM antibody is measured using the CantiLab4(c) system from Cantion A/S with four gold-coated cantilevers and piezo resistive readout. The detection mechanism is in principle label-free, but fluorescent-marked antibodies have been used to subsequently verify the binding on the cantilever surface. The bending and increase in mass of each cantilever has also been investigated using a light interferometer and a Doppler Vibrometer. The system has been analyzed during repeated measurements to investigate whether the CantiLab4(c) system is a suited platform for a pesticide assay system. PMID- 21711908 TI - Long-term oxidization and phase transition of InN nanotextures. AB - The long-term (6 months) oxidization of hcp-InN (wurtzite, InN-w) nanostructures (crystalline/amorphous) synthesized on Si [100] substrates is analyzed. The densely packed layers of InN-w nanostructures (5-40 nm) are shown to be oxidized by atmospheric oxygen via the formation of an intermediate amorphous In-Ox-Ny (indium oxynitride) phase to a final bi-phase hcp-InN/bcc-In2O3 nanotexture. High resolution transmission electron microscopy, energy-dispersive X-ray spectroscopy, electron energy loss spectroscopy and selected area electron diffraction are used to identify amorphous In-Ox-Ny oxynitride phase. When the oxidized area exceeds the critical size of 5 nm, the amorphous In-Ox-Ny phase eventually undergoes phase transition via a slow chemical reaction of atomic oxygen with the indium atoms, forming a single bcc In2O3 phase. PMID- 21711909 TI - Nanostructured hybrid ZnO thin films for energy conversion. AB - We report on hybrid films based on ZnO/organic dye prepared by electrodeposition using tetrasulfonated copper phthalocyanines (TS-CuPc) and Eosin-Y (EoY). Both the morphology and porosity of hybrid ZnO films are highly dependent on the type of dyes used in the synthesis. High photosensitivity was observed for ZnO/EoY films, while a very weak photoresponse was obtained for ZnO/TS-CuPc films. Despite a higher absorption coefficient of TS-CuPc than EoY, in ZnO/EoY hybrid films, the excited photoelectrons between the EoY levels can be extracted through ZnO, and the porosity of ZnO/EoY can also be controlled. PMID- 21711910 TI - Carbon composite micro- and nano-tubes-based electrodes for detection of nucleic acids. AB - The first aim of this study was to fabricate vertically aligned multiwalled carbon nanotubes (MWCNTs). MWCNTs were successfully prepared by using plasma enhanced chemical vapour deposition. Further, three carbon composite electrodes with different content of carbon particles with various shapes and sizes were prepared and tested on measuring of nucleic acids. The dependences of adenine peak height on the concentration of nucleic acid sample were measured. Carbon composite electrode prepared from a mixture of glassy and spherical carbon powder and MWCNTs had the highest sensitivity to nucleic acids. Other interesting result is the fact that we were able to distinguish signals for all bases using this electrode. PMID- 21711911 TI - Reliable processing of graphene using metal etchmasks. AB - Graphene exhibits exciting properties which make it an appealing candidate for use in electronic devices. Reliable processes for device fabrication are crucial prerequisites for this. We developed a large area of CVD synthesis and transfer of graphene films. With patterning of these graphene layers using standard photoresist masks, we are able to produce arrays of gated graphene devices with four point contacts. The etching and lift off process poses problems because of delamination and contamination due to polymer residues when using standard resists. We introduce a metal etch mask which minimises these problems. The high quality of graphene is shown by Raman and XPS spectroscopy as well as electrical measurements. The process is of high value for applications, as it improves the processability of graphene using high-throughput lithography and etching techniques. PMID- 21711912 TI - Hydrogen sensors based on electrophoretically deposited Pd nanoparticles onto InP. AB - Electrophoretic deposition of palladium nanoparticles prepared by the reverse micelle technique onto InP substrates is addressed. We demonstrate that the substrate pre-deposition treatment and the deposition conditions can extensively influence the morphology of the deposited palladium nanoparticle films. Schottky diodes based on these films show notably high values of the barrier height and of the rectification ratio giving evidence of a small degree of the Fermi level pinning. Moreover, electrical characteristics of these diodes are exceptionally sensitive to the exposure to gas mixtures with small hydrogen content. PMID- 21711913 TI - Improved ground-state modulation characteristics in 1.3 MUm InAs/GaAs quantum dot lasers by rapid thermal annealing. AB - We investigated the ground-state (GS) modulation characteristics of 1.3 MUm InAs/GaAs quantum dot (QD) lasers that consist of either as-grown or annealed QDs. The choice of annealing conditions was determined from our recently reported results. With reference to the as-grown QD lasers, one obtains approximately 18% improvement in the modulation bandwidth from the annealed QD lasers. In addition, the modulation efficiency of the annealed QD lasers improves by approximately 45% as compared to the as-grown ones. The observed improvements are due to (1) the removal of defects which act as nonradiative recombination centers in the QD structure and (2) the reduction in the Auger-related recombination processes upon annealing. PMID- 21711914 TI - Direct growth of ultra-long platinum nanolawns on a semiconductor photocatalyst. AB - A template- and surfactant-free process, thermally assisted photoreduction, is developed to prepare vertically grown ultra-long Pt nanowires (NWs) (about 30-40 nm in diameter, 5-6 MUm in length, and up to 80 NWs/100 MUm2 in the wire density) on TiO2 coated substrates, including Si wafers and carbon fibers, with the assistance of the photocatalytic ability and semiconductor characteristics of TiO2. A remarkable aspect ratio of up to 200 can be achieved. TEM analytical results suggest that the Pt NWs are single-crystalline with a preferred <111> growth direction. The precursor adopted and the heat treatment conditions are crucial for the yield of NWs. The photoelectrons supplied by TiO2 gives rise to the formation of nano-sized Pt nuclei from salt melt or solution. The subsequent growth of NWs is supported by the thermal electrons which also generated from TiO2 during the post thermal treatment. The interactions between the ions and the electrons in the Pt/TiO2 junction are discussed in this study. PMID- 21711915 TI - The influence of colloidal parameters on the specific power absorption of PAA coated magnetite nanoparticles. AB - The suitability of magnetic nanoparticles (MNPs) to act as heat nano-sources by application of an alternating magnetic field has recently been studied due to their promising applications in biomedicine. The understanding of the magnetic relaxation mechanism in biocompatible nanoparticle systems is crucial in order to optimize the magnetic properties and maximize the specific absorption rate (SAR). With this aim, the SAR of magnetic dispersions containing superparamagnetic magnetite nanoparticles bio-coated with polyacrylic acid of an average particle size of ~10 nm has been evaluated separately by changing colloidal parameters such as the MNP concentration and the viscosity of the solvent. A remarkable decrease of the SAR values with increasing particle concentration and solvent viscosity was found. These behaviours have been discussed on the basis of the magnetic relaxation mechanisms involved.PACS: 80; 87; 87.85jf. PMID- 21711916 TI - Low-temperature synthesis of CuO-interlaced nanodiscs for lithium ion battery electrodes. AB - In this study, we report the high-yield synthesis of 2-dimensional cupric oxide (CuO) nanodiscs through dehydrogenation of 1-dimensional Cu(OH)2 nanowires at 60 degrees C. Most of the nanodiscs had a diameter of approximately 500 nm and a thickness of approximately 50 nm. After further prolonged reaction times, secondary irregular nanodiscs gradually grew vertically into regular nanodiscs. These CuO nanostructures were characterized using X-ray diffraction, transmission electron microscopy, and Brunauer-Emmett-Teller measurements. The possible growth mechanism of the interlaced disc CuO nanostructures is systematically discussed. The electrochemical performances of the CuO nanodisc electrodes were evaluated in detail using cyclic voltammetry and galvanostatic cycling. Furthermore, we demonstrate that the incorporation of multiwalled carbon nanotubes enables the enhanced reversible capacities and capacity retention of CuO nanodisc electrodes on cycling by offering more efficient electron transport paths. PMID- 21711917 TI - General metabolism of Laribacter hongkongensis: a genome-wide analysis. AB - BACKGROUND: Laribacter hongkongensis is associated with community-acquired gastroenteritis and traveler's diarrhea. In this study, we performed an in-depth annotation of the genes and pathways of the general metabolism of L. hongkongensis and correlated them with its phenotypic characteristics. RESULTS: The L. hongkongensis genome possesses the pentose phosphate and gluconeogenesis pathways and tricarboxylic acid and glyoxylate cycles, but incomplete Embden Meyerhof-Parnas and Entner-Doudoroff pathways, in agreement with its asaccharolytic phenotype. It contains enzymes for biosynthesis and beta-oxidation of saturated fatty acids, biosynthesis of all 20 universal amino acids and selenocysteine, the latter not observed in Neisseria gonorrhoeae, Neisseria meningitidis and Chromobacterium violaceum. The genome contains a variety of dehydrogenases, enabling it to utilize different substrates as electron donors. It encodes three terminal cytochrome oxidases for respiration using oxygen as the electron acceptor under aerobic and microaerophilic conditions and four reductases for respiration with alternative electron acceptors under anaerobic conditions. The presence of complete tetrathionate reductase operon may confer survival advantage in mammalian host in association with diarrhea. The genome contains CDSs for incorporating sulfur and nitrogen by sulfate assimilation, ammonia assimilation and nitrate reduction. The existence of both glutamate dehydrogenase and glutamine synthetase/glutamate synthase pathways suggests an importance of ammonia metabolism in the living environments that it may encounter. CONCLUSIONS: The L. hongkongensis genome possesses a variety of genes and pathways for carbohydrate, amino acid and lipid metabolism, respiratory chain and sulfur and nitrogen metabolism. These allow the bacterium to utilize various substrates for energy production and survive in different environmental niches. PMID- 21711918 TI - A review of experimental investigations on thermal phenomena in nanofluids. AB - Nanoparticle suspensions (nanofluids) have been recommended as a promising option for various engineering applications, due to the observed enhancement of thermophysical properties and improvement in the effectiveness of thermal phenomena. A number of investigations have been reported in the recent past, in order to quantify the thermo-fluidic behavior of nanofluids. This review is focused on examining and comparing the measurements of convective heat transfer and phase change in nanofluids, with an emphasis on the experimental techniques employed to measure the effective thermal conductivity, as well as to characterize the thermal performance of systems involving nanofluids. PMID- 21711919 TI - Facile template-free synthesis of pine needle-like Pd micro/nano-leaves and their associated electro-catalytic activities toward oxidation of formic acid. AB - Pine needle-like Pd micro/nano-leaves have been synthesized by a facile, template-free electrochemical method. As-synthesized Pd micro/nano-leaves were directly electrodeposited on an indium tin oxide substrate in the presence of 1.0 mM H2PdCl4 + 0.33 M H3PO4. The formation processes of Pd micro/nano-leaves were revealed by scanning electron microscope, and further characterized by X-ray diffraction and electrochemical analysis. Compared to conventional Pd nanoparticles, as-prepared Pd micro/nano-leaves exhibit superior electrocatalytic activities for the formic acid oxidation. PMID- 21711920 TI - Polymer-stabilized palladium nanoparticles for catalytic membranes: ad hoc polymer fabrication. AB - Metal nanoparticles are known as highly effective catalysts although their immobilization on solid supports is frequently required to prevent aggregation and to facilitate the catalyst application, recovery, and reuse. This paper reports the intermatrix synthesis of Pd0 nanoparticles in sulfonated polyethersulfone with Cardo group membranes and their use as nanocomposite catalytic membrane reactors. The synthesized polymer and the corresponding nanocomposite were characterized by spectroscopic and microscopic techniques. The catalytic efficiency of catalytic membranes was evaluated by following the reduction of p-nitrophenol in the presence of NaBH4. PMID- 21711921 TI - Plasmonic propagations distances for interferometric surface plasmon resonance biosensing. AB - A surface plasmon resonance (SPR) scheme is proposed in which the local phase modulations of the coupled plasmons can interfere and yield phase-sensitive intensity modulations in the measured signal. The result is an increased traceability of the SPR shifts for biosensing applications. The main system limitation is the propagation distance of the coupled plasmon modes. This aspect is therefore studied for thin film microstructures operating in the visible and near-infrared spectral regions. The surface roughness of the substrate layer is examined for different dielectrics and deposition methods. The Au layer, on which the plasmonic modes are propagating and the biosensing occurs, is also examined. The surface roughness and dielectric values for various deposition rates of very thin Au films are measured. We also investigate an interferometric SPR setup where, due to the power flux transfer between plasmon modes, the specific choice of grating coupler can either decrease or increase the plasmon propagation length. PMID- 21711922 TI - Microwave-assisted synthesis of water-dispersed CdTe/CdSe core/shell type II quantum dots. AB - A facile synthesis of mercaptanacid-capped CdTe/CdSe (core/shell) type II quantum dots in aqueous solution by means of a microwave-assisted approach is reported. The results of X-ray diffraction and high-resolution transmission electron microscopy revealed that the as-prepared CdTe/CdSe quantum dots had a core/shell structure with high crystallinity. The core/shell quantum dots exhibit tunable fluorescence emissions by controlling the thickness of the CdSe shell. The photoluminescent properties were dramatically improved through UV-illuminated treatment, and the time-resolved fluorescence spectra showed that there is a gradual increase of decay lifetime with the thickness of CdSe shell. PMID- 21711923 TI - Size-dependent catalytic and melting properties of platinum-palladium nanoparticles. AB - While nanocatalysis is a very active field, there have been very few studies in the size/shape-dependent catalytic properties of transition metals from a thermodynamical approach. Transition metal nanoparticles are very attractive due their high surface to volume ratio and their high surface energy. In particular, in this paper we focus on the Pt-Pd catalyst which is an important system in catalysis. The melting temperature, melting enthalpy, and catalytic activation energy were found to decrease with size. The face centered cubic crystal structure of platinum and palladium has been considered in the model. The shape stability has been discussed. The phase diagram of different polyhedral shapes has been plotted and the surface segregation has been considered. The model predicts a nanoparticle core rich in Pt surrounded by a layer enriched in Pd. The Pd segregation at the surface strongly modifies the catalytic activation energy compared to the non-segregated nanoparticle. The predictions were compared with the available experimental data in the literature. PACS: 65.80-g; 82.60.Qr; 64.75.Jk. PMID- 21711924 TI - Synthesis and highly visible-induced photocatalytic activity of CNT-CdSe composite for methylene blue solution. AB - Carbon nanotube-cadmium selenide (CNT-CdSe) composite was synthesized by a facile hydrothermal method derived from multi-walled carbon nanotubes as a stating material. The as-prepared products were characterized by X-ray diffraction, scanning electron microscopy with energy dispersive X-ray analysis, transmission electron microscopy (TEM), and UV-vis diffuse reflectance spectrophotometer. The as-synthesized CNT-CdSe composite efficiently catalyzed the photodegradation of methylene blue in aqueous solutions under visible-light irradiation, exhibiting higher photocatalytic activity. PMID- 21711925 TI - Tuning photoluminescence of organic rubrene nanoparticles through a hydrothermal process. AB - Light-emitting 5,6,11,12-tetraphenylnaphthacene (rubrene) nanoparticles (NPs) prepared by a reprecipitation method were treated hydrothermally. The diameters of hydrothermally treated rubrene NPs were changed from 100 nm to 2 MUm, depending on hydrothermal temperature. Photoluminescence (PL) characteristics of rubrene NPs varied with hydrothermal temperatures. Luminescence of pristine rubrene NPs was yellow-orange, and it changed to blue as the hydrothermal temperature increased to 180 degrees C. The light-emitting color distribution of the NPs was confirmed using confocal laser spectrum microscope. As the hydrothermal temperature increased from 110 degrees C to 160 degrees C, the blue light emission at 464 to approximately 516 nm from filtered-down NPs was enhanced by H-type aggregation. Filtered-up rubrene NPs treated at 170 degrees C and 180 degrees C exhibited blue luminescence due to the decrease of intermolecular excimer densities with the rapid increase in size. Variations in PL of hydrothermally treated rubrene NPs resulted from different size distributions of the NPs. PMID- 21711926 TI - Flow through a circular tube with a permeable Navier slip boundary. AB - For Newtonian fluid flow in a right circular tube, with a linear Navier slip boundary, we show that a second flow field arises which is different to conventional Poiseuille flow in the sense that the corresponding pressure is quadratic in its dependence on the length along the tube, rather than a linear dependence which applies for conventional Poiseuille flow. However, assuming that the quadratic pressure is determined, say from known experimental data, then the new solution only exists for a precisely prescribed permeability along the boundary. While this cannot occur for conventional pipe flow, for fluid flow through carbon nanotubes embedded in a porous matrix, it may well be an entirely realistic possibility, and could well explain some of the high flow rates which have been reported in the literature. Alternatively, if the radial boundary flow is prescribed, then the new flow field exists only for a given quadratic pressure. Our primary purpose here is to demonstrate the existence of a new pipe flow field for a permeable Navier slip boundary and to present a numerical solution and two approximate analytical solutions. The maximum flow rate possible for the new solution is precisely twice that for the conventional Poiseuille flow, which occurs for constant inward directed flow across the boundary. PMID- 21711927 TI - Metallic nano-structures for polarization-independent multi-spectral filters. AB - Cross-shaped-hole arrays (CSHAs) are selected for diminishing the polarization dependent transmission differences of incident plane waves. We investigate the light transmission spectrum of the CSHAs in a thin gold film over a wide range of features. It is observed that two well-separated and high transmission efficiency peaks could be obtained by designing the parameters in the CSHAs for both p polarized and s-polarized waves; and a nice transmission band-pass is also observed by specific parameters of a CSHA too. It implicates the possibility to obtain a desired polarization-independent transmission spectrum from the CSHAs by designing their parameters. These findings provide potential applications of the metallic nano-structures in optical filters, optical band-pass, optical imaging, optical sensing, and biosensors. PMID- 21711928 TI - Materialization of single multicomposite nanowire: entrapment of ZnO nanoparticles in polyaniline nanowire. AB - We present materialization of single multicomposite nanowire (SMNW)-entrapped ZnO nanoparticles (NPs) via an electrochemical growth method, which is a newly developed fabrication method to grow a single nanowire between a pair of pre patterned electrodes. Entrapment of ZnO NPs was controlled via different conditions of SMNW fabrication such as an applied potential and mixture ratio of NPs and aniline solution. The controlled concentration of ZnO NP results in changes in the physical properties of the SMNWs, as shown in transmission electron microscopy images. Furthermore, the electrical conductivity and elasticity of SMNWs show improvement over those of pure polyaniline nanowire. The new nano-multicomposite material showed synergistic effects on mechanical and electrical properties, with logarithmical change and saturation increasing ZnO NP concentration. PMID- 21711929 TI - Surface properties of glass micropipettes and their effect on biological studies. AB - In this paper, an investigation on surface properties of glass micropipettes and their effect on biological applications is reported. Pipettes were pulled under different pulling conditions and the effect of each pulling parameter was analyzed. SEM stereoscopic technique was used to reveal the surface roughness properties of pipette tip and pipette inner wall in 3D. More than 20 pipettes were reconstructed. Pipette heads were split open using focused ion beam (FIB) milling for access to the inner walls. It is found that surface roughness parameters are strongly related on the tip size. Bigger pipettes have higher average surface roughness and lower developed interfacial area ratio. Furthermore, the autocorrelation of roughness model of the inner surface shows that the inner surface does not have any tendency of orientation and is not affected by pulling direction. To investigate the effect of surface roughness properties on biological applications, patch-clamping tests were carried out by conventional and FIB-polished pipettes. The results of the experiments show that polished pipettes make significantly better seals. The results of this work are of important reference value for achieving pipettes with desired surface properties and can be used to explain biological phenomenon such as giga-seal formation. PMID- 21711930 TI - Thickness-dependent optimization of Er3+ light emission from silicon-rich silicon oxide thin films. AB - This study investigates the influence of the film thickness on the silicon excess-mediated sensitization of Erbium ions in Si-rich silica. The Er3+ photoluminescence at 1.5 MUm, normalized to the film thickness, was found five times larger for films 1 MUm-thick than that from 50-nm-thick films intended for electrically driven devices. The origin of this difference is shared by changes in the local density of optical states and depth-dependent interferences, and by limited formation of Si-based sensitizers in "thin" films, probably because of the prevailing high stress. More Si excess has significantly increased the emission from "thin" films, up to ten times. This paves the way to the realization of highly efficient electrically excited devices. PMID- 21711931 TI - Influence of surface properties on the electrical conductivity of silicon nanomembranes. AB - Because of the large surface-to-volume ratio, the conductivity of semiconductor nanostructures is very sensitive to surface chemical and structural conditions. Two surface modifications, vacuum hydrogenation (VH) and hydrofluoric acid (HF) cleaning, of silicon nanomembranes (SiNMs) that nominally have the same effect, the hydrogen termination of the surface, are compared. The sheet resistance of the SiNMs, measured by the van der Pauw method, shows that HF etching produces at least an order of magnitude larger drop in sheet resistance than that caused by VH treatment, relative to the very high sheet resistance of samples terminated with native oxide. Re-oxidation rates after these treatments also differ. X-ray photoelectron spectroscopy measurements are consistent with the electrical conductivity results. We pinpoint the likely cause of the differences.PACS: 73.63.-b, 62.23.Kn, 73.40.Ty. PMID- 21711932 TI - Anomalous heat transfer modes of nanofluids: a review based on statistical analysis. AB - This paper contains the results of a concise statistical review analysis of a large amount of publications regarding the anomalous heat transfer modes of nanofluids. The application of nanofluids as coolants is a novel practise with no established physical foundations explaining the observed anomalous heat transfer. As a consequence, traditional methods of performing a literature review may not be adequate in presenting objectively the results representing the bulk of the available literature. The current literature review analysis aims to resolve the problems faced by researchers in the past by employing an unbiased statistical analysis to present and reveal the current trends and general belief of the scientific community regarding the anomalous heat transfer modes of nanofluids. The thermal performance analysis indicated that statistically there exists a variable enhancement for conduction, convection/mixed heat transfer, pool boiling heat transfer and critical heat flux modes. The most popular proposed mechanisms in the literature to explain heat transfer in nanofluids are revealed, as well as possible trends between nanofluid properties and thermal performance. The review also suggests future experimentation to provide more conclusive answers to the control mechanisms and influential parameters of heat transfer in nanofluids. PMID- 21711934 TI - Formation of silicon nanodots via ion beam sputtering of ultrathin gold thin film coatings on Si. AB - Ion beam sputtering of ultrathin film Au coatings used as a physical catalyst for self-organization of Si nanostructures has been achieved by tuning the incident particle energy. This approach holds promise as a scalable nanomanufacturing parallel processing alternative to candidate nanolithography techniques. Structures of 11- to 14-nm Si nanodots are formed with normal incidence low-energy Ar ions of 200 eV and fluences above 2 * 1017 cm-2. In situ surface characterization during ion irradiation elucidates early stage ion mixing migration mechanism for nanodot self-organization. In particular, the evolution from gold film islands to the formation of ion-induced metastable gold silicide followed by pure Si nanodots formed with no need for impurity seeding. PMID- 21711935 TI - Hysteresis loops of individual Co nanostripes measured by magnetic force microscopy. AB - High-resolution magnetic imaging is of utmost importance to understand magnetism at the nanoscale. In the present work, we use a magnetic force microscope (MFM) operating under in-plane magnetic field in order to observe with high accuracy the domain configuration changes in Co nanowires as a function of the externally applied magnetic field. The main result is the quantitative evaluation of the coercive field of the individual nanostructures. Such characterization is performed by using an MFM-based technique in which a map of the magnetic signal is obtained as a function of both the lateral displacement and the magnetic field. PMID- 21711933 TI - Role of dendritic cells in the induction of regulatory T cells. AB - Dendritic cells (DCs) play a key role in initiating immune responses and maintaining immune tolerance. In addition to playing a role in thymic selection, DCs play an active role in tolerance under steady state conditions through several mechanisms which are dependent on IL-10, TGF-beta, retinoic acid, indoleamine-2,3,-dioxygenase along with vitamin D. Several of these mechanisms are employed by DCs in induction of regulatory T cells which are comprised of Tr1 regulatory T cells, natural and inducible foxp3+ regulatory T cells, Th3 regulatory T cells and double negative regulatory T cells. It appears that certain DC subsets are highly specialized in inducing regulatory T cell differentiation and in some tissues the local microenvironment plays a role in driving DCs towards a tolerogenic response. In this review we discuss the recent advances in our understanding of the mechanisms underlying DC driven regulatory T cell induction. PMID- 21711936 TI - Nanoscale surface modifications to control capillary flow characteristics in PMMA microfluidic devices. AB - Polymethylmethacrylate (PMMA) microfluidic devices have been fabricated using a hot embossing technique to incorporate micro-pillar features on the bottom wall of the device which when combined with either a plasma treatment or the coating of a diamond-like carbon (DLC) film presents a range of surface modification profiles. Experimental results presented in detail the surface modifications in the form of distinct changes in the static water contact angle across a range from 44.3 to 81.2 when compared to pristine PMMA surfaces. Additionally, capillary flow of water (dyed to aid visualization) through the microfluidic devices was recorded and analyzed to provide comparison data between filling time of a microfluidic chamber and surface modification characteristics, including the effects of surface energy and surface roughness on the microfluidic flow. We have experimentally demonstrated that fluid flow and thus filling time for the microfluidic device was significantly faster for the device with surface modifications that resulted in a lower static contact angle, and also that the incorporation of micro-pillars into a fluidic device increases the filling time when compared to comparative devices. PMID- 21711937 TI - Peptide immobilisation on porous silicon surface for metal ions detection. AB - In this work, a Glycyl-Histidyl-Glycyl-Histidine (GlyHisGlyHis) peptide is covalently anchored to the porous silicon PSi surface using a multi-step reaction scheme compatible with the mild conditions required for preserving the probe activity. In a first step, alkene precursors are grafted onto the hydrogenated PSi surface using the hydrosilylation route, allowing for the formation of a carboxyl-terminated monolayer which is activated by reaction with N hydroxysuccinimide in the presence of a peptide-coupling carbodiimide N-ethyl-N' (3-dimethylaminopropyl)-carbodiimide and subsequently reacted with the amino linker of the peptide to form a covalent amide bond. Infrared spectroscopy (FT IR) and X-ray photoelectron spectroscopy are used to investigate the different steps of functionalization.The property of peptides to form stable complexes with metal ions is exploited to achieve metal-ion recognition by the peptide-modified PSi-based biosensor. An electrochemical study of the GlyHisGlyHis-modified PSi electrode is achieved in the presence of copper ions. The recorded cyclic voltammograms show a quasi-irreversible process corresponding to the Cu(II)/Cu(I) couple. The kinetic factors (the heterogeneous rate constant and the transfer coefficient) and the stability constant of the complex formed on the porous silicon surface are determined. These results demonstrate the potential role of peptides grafted on porous silicon in developing strategies for simple and fast detection of metal ions in solution. PMID- 21711938 TI - Photoinduced oxygen release and persistent photoconductivity in ZnO nanowires. AB - Photoconductivity is studied in individual ZnO nanowires. Under ultraviolet (UV) illumination, the induced photocurrents are observed to persist both in air and in vacuum. Their dependence on UV intensity in air is explained by means of photoinduced surface depletion depth decrease caused by oxygen desorption induced by photogenerated holes. The observed photoresponse is much greater in vacuum and proceeds beyond the air photoresponse at a much slower rate of increase. After reaching a maximum, it typically persists indefinitely, as long as good vacuum is maintained. Once vacuum is broken and air is let in, the photocurrent quickly decays down to the typical air-photoresponse values. The extra photoconductivity in vacuum is explained by desorption of adsorbed surface oxygen which is readily pumped out, followed by a further slower desorption of lattice oxygen, resulting in a Zn-rich surface of increased conductivity. The adsorption-desorption balance is fully recovered after the ZnO surface is exposed to air, which suggests that under UV illumination, the ZnO surface is actively "breathing" oxygen, a process that is further enhanced in nanowires by their high surface to volume ratio. PMID- 21711939 TI - Unusual magneto-optical behavior induced by local dielectric variations under localized surface plasmon excitations. AB - We study the effect of global and local dielectric variations on the polarization conversion rps response of ordered nickel nanowires embedded in an alumina matrix. When considering local changes, we observe a non-monotonous behavior of the rps, its intensity unusually modified far beyond to what it is expected for a monotonous change of the whole refractive index of the embedding medium. This is related to the local redistribution of the electromagnetic field when a localized surface plasmon is excited. This finding may be employed to develop and improve new biosensing magnetoplasmonic devices. PMID- 21711940 TI - Distinct biological effects of different nanoparticles commonly used in cosmetics and medicine coatings. AB - BACKGROUND: Metal oxides in nanoparticle form such as zinc oxide and titanium dioxide now appear on the ingredient lists of household products as common and diverse as cosmetics, sunscreens, toothpaste, and medicine. Previous studies of zinc oxide and titanium dioxide in non-nanoparticle format using animals have found few adverse effects. This has led the FDA to classify zinc oxide as GRAS (generally recognized as safe) for use as a food additive. However, there is no regulation specific for the use of these chemicals in nanoparticle format. Recent studies, however, have begun to raise concerns over the pervasive use of these compounds in nanoparticle forms. Unfortunately, there is a lack of easily adaptable screening methods that would allow for the detection of their biological effects. RESULTS: We adapted two image-based assays, a fluorescence resonance energy transfer-based caspase activation assay and a green fluorescent protein coupled-LC3 assay, to test for the biological effects of different nanoparticles in a high-throughput format. We show that zinc oxide nanoparticles are cytotoxic. We also show that titanium dioxide nanoparticles are highly effective in inducing autophagy, a cellular disposal mechanism that is often activated when the cell is under stress. CONCLUSION: We suggest that these image based assays provide a method of screening for the biological effects of similar compounds that is both efficient and sensitive as well as do not involve the use of animals. PMID- 21711941 TI - Effects of crossed states on photoluminescence excitation spectroscopy of InAs quantum dots. AB - In this report, the influence of the intrinsic transitions between bound-to delocalized states (crossed states or quasicontinuous density of electron-hole states) on photoluminescence excitation (PLE) spectra of InAs quantum dots (QDs) was investigated. The InAs QDs were different in size, shape, and number of bound states. Results from the PLE spectroscopy at low temperature and under a high magnetic field (up to 14 T) were compared. Our findings show that the profile of the PLE resonances associated with the bound transitions disintegrated and broadened. This was attributed to the coupling of the localized QD excited states to the crossed states and scattering of longitudinal acoustical (LA) phonons. The degree of spectral linewidth broadening was larger for the excited state in smaller QDs because of the higher crossed joint density of states and scattering rate. PMID- 21711942 TI - Investigation of utilization of nanosuspension formulation to enhance exposure of 1,3-dicyclohexylurea in rats: Preparation for PK/PD study via subcutaneous route of nanosuspension drug delivery. AB - 1,3-Dicyclohexylurea (DCU), a potent soluble epoxide hydrolase (sEH) inhibitor has been reported to lower systemic blood pressure in spontaneously hypertensive rats. One limitation of continual administration of DCU for in vivo studies is the compound's poor oral bioavailability. This phenomenon is mainly attributed to its poor dissolution rate and low aqueous solubility. Previously, wet-milled DCU nanosuspension has been reported to enhance the bioavailability of DCU. However, the prosperities and limitations of wet-milled nanosuspension have not been fully evaluated. Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal. In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling. It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation. Based on the model and in vivo data, a subcutaneous route of delivery of nanosuspension of DCU was evaluated and demonstrated to be appropriate for future PK/PD studies. PMID- 21711943 TI - Improved infrared photoluminescence characteristics from circularly ordered self assembled Ge islands. AB - The formation of circularly ordered Ge-islands on Si(001) has been achieved because of nonuniform strain field around the periphery of the holes patterned by focused ion beam in combination with a self-assembled growth using molecular beam epitaxy. The photoluminescence (PL) spectra obtained from patterned areas (i.e., ordered islands) show a significant signal enhancement, which sustained till 200 K, without any vertical stacking of islands. The origin of two activation energies in temperature-dependent PL spectra of the ordered islands has been explained in detail. PMID- 21711944 TI - Cellulose fibres, nanofibrils and microfibrils: The morphological sequence of MFC components from a plant physiology and fibre technology point of view. AB - During the last decade, major efforts have been made to develop adequate and commercially viable processes for disintegrating cellulose fibres into their structural components. Homogenisation of cellulose fibres has been one of the principal applied procedures. Homogenisation has produced materials which may be inhomogeneous, containing fibres, fibres fragments, fibrillar fines and nanofibrils. The material has been denominated microfibrillated cellulose (MFC). In addition, terms relating to the nano-scale have been given to the MFC material. Several modern and high-tech nano-applications have been envisaged for MFC. However, is MFC a nano-structure? It is concluded that MFC materials may be composed of (1) nanofibrils, (2) fibrillar fines, (3) fibre fragments and (4) fibres. This implies that MFC is not necessarily synonymous with nanofibrils, microfibrils or any other cellulose nano-structure. However, properly produced MFC materials contain nano-structures as a main component, i.e. nanofibrils. PMID- 21711945 TI - Microstructure of non-polar GaN on LiGaO2 grown by plasma-assisted MBE. AB - We have investigated the structure of non-polar GaN, both on the M - and A plane, grown on LiGaO2 by plasma-assisted molecular beam epitaxy. The epitaxial relationship and the microstructure of the GaN films are investigated by transmission electron microscopy (TEM). The already reported epi-taxial relationship and for M -plane GaN is confirmed. The main defects are threading dislocations and stacking faults in both samples. For the M -plane sample, the density of threading dislocations is around 1 * 1011 cm-2 and the stacking fault density amounts to approximately 2 * 105 cm-1. In the A-plane sample, a threading dislocation density in the same order was found, while the stacking fault density is much lower than in the M -plane sample. PMID- 21711946 TI - Fabrication of HfO2 patterns by laser interference nanolithography and selective dry etching for III-V CMOS application. AB - Nanostructuring of ultrathin HfO2 films deposited on GaAs (001) substrates by high-resolution Lloyd's mirror laser interference nanolithography is described. Pattern transfer to the HfO2 film was carried out by reactive ion beam etching using CF4 and O2 plasmas. A combination of atomic force microscopy, high resolution scanning electron microscopy, high-resolution transmission electron microscopy, and energy-dispersive X-ray spectroscopy microanalysis was used to characterise the various etching steps of the process and the resulting HfO2/GaAs pattern morphology, structure, and chemical composition. We show that the patterning process can be applied to fabricate uniform arrays of HfO2 mesa stripes with tapered sidewalls and linewidths of 100 nm. The exposed GaAs trenches were found to be residue-free and atomically smooth with a root-mean square line roughness of 0.18 nm after plasma etching.PACS: Dielectric oxides 77.84.Bw, Nanoscale pattern formation 81.16.Rf, Plasma etching 52.77.Bn, Fabrication of III-V semiconductors 81.05.Ea. PMID- 21711947 TI - Morphological variations in cadmium sulfide nanocrystals without phase transformation. AB - A very novel phenomenon of morphological variations of cadmium sulfide (CdS) nanorods under the transmission electron microscopy (TEM) beam was observed without structural phase transformation. Environmentally stable and highly crystalline CdS nanorods have been obtained via a chemical bath method. The energy of the TEM beam is believed to have a significant influence on CdS nanorods and may melt and transform them into smaller nanowires. Morphological variations without structural phase transformation are confirmed by recording selected area electron diffraction at various stages. The prepared CdS nanorods have been characterized by X-ray powder diffraction, TEM, UV-Vis spectroscopy, and photoluminescence spectroscopy. The importance of this phenomenon is vital for the potential application for CdS such as smart materials. PMID- 21711948 TI - Porous anodic alumina on galvanically grown PtSi layer for application in template-assisted Si nanowire growth. AB - We report on the fabrication and morphology/structural characterization of a porous anodic alumina (PAA)/PtSi nano-template for use as matrix in template assisted Si nanowire growth on a Si substrate. The PtSi layer was formed by electroless deposition from an aqueous solution containing the metal salt and HF, while the PAA membrane by anodizing an Al film deposited on the PtSi layer. The morphology and structure of the PtSi layer and of the alumina membrane on top were studied by Scanning and High Resolution Transmission Electron Microscopies (SEM, HRTEM). Cross sectional HRTEM images combined with electron diffraction (ED) were used to characterize the different interfaces between Si, PtSi and porous anodic alumina. PMID- 21711949 TI - Enhancement of critical heat flux in nucleate boiling of nanofluids: a state-of art review. AB - Nanofluids (suspensions of nanometer-sized particles in base fluids) have recently been shown to have nucleate boiling critical heat flux (CHF) far superior to that of the pure base fluid. Over the past decade, numerous experimental and analytical studies on the nucleate boiling CHF of nanofluids have been conducted. The purpose of this article is to provide an exhaustive review of these studies. The characteristics of CHF enhancement in nanofluids are systemically presented according to the effects of the primary boiling parameters. Research efforts to identify the effects of nanoparticles underlying irregular enhancement phenomena of CHF in nanofluids are then presented. Also, attempts to explain the physical mechanism based on available CHF theories are described. Finally, future research needs are identified. PMID- 21711950 TI - Mechanics of lipid bilayer junctions affecting the size of a connecting lipid nanotube. AB - In this study we report a physical analysis of the membrane mechanics affecting the size of the highly curved region of a lipid nanotube (LNT) that is either connected between a lipid bilayer vesicle and the tip of a glass microinjection pipette (tube-only) or between a lipid bilayer vesicle and a vesicle that is attached to the tip of a glass microinjection pipette (two-vesicle). For the tube only configuration (TOC), a micropipette is used to pull a LNT into the interior of a surface-immobilized vesicle, where the length of the tube L is determined by the distance of the micropipette to the vesicle wall. For the two-vesicle configuration (TVC), a small vesicle is inflated at the tip of the micropipette tip and the length of the tube L is in this case determined by the distance between the two interconnected vesicles. An electrochemical method monitoring diffusion of electroactive molecules through the nanotube has been used to determine the radius of the nanotube R as a function of nanotube length L for the two configurations. The data show that the LNT connected in the TVC constricts to a smaller radius in comparison to the tube-only mode and that tube radius shrinks at shorter tube lengths. To explain these electrochemical data, we developed a theoretical model taking into account the free energy of the membrane regions of the vesicles, the LNT and the high curvature junctions. In particular, this model allows us to estimate the surface tension coefficients from R(L) measurements. PMID- 21711951 TI - CdTe quantum dots with daunorubicin induce apoptosis of multidrug-resistant human hepatoma HepG2/ADM cells: in vitro and in vivo evaluation. AB - Cadmium telluride quantum dots (Cdte QDs) have received significant attention in biomedical research because of their potential in disease diagnosis and drug delivery. In this study, we have investigated the interaction mechanism and synergistic effect of 3-mercaptopropionic acid-capped Cdte QDs with the anti cancer drug daunorubicin (DNR) on the induction of apoptosis using drug-resistant human hepatoma HepG2/ADM cells. Electrochemical assay revealed that Cdte QDs readily facilitated the uptake of the DNR into HepG2/ADM cells. Apoptotic staining, DNA fragmentation, and flow cytometry analysis further demonstrated that compared with Cdte QDs or DNR treatment alone, the apoptosis rate increased after the treatment of Cdte QDs together with DNR in HepG2/ADM cells. We observed that Cdte QDs treatment could reduce the effect of P-glycoprotein while the treatment of Cdte QDs together with DNR can clearly activate apoptosis-related caspases protein expression in HepG2/ADM cells. Moreover, our in vivo study indicated that the treatment of Cdte QDs together with DNR effectively inhibited the human hepatoma HepG2/ADM nude mice tumor growth. The increased cell apoptosis rate was closely correlated with the enhanced inhibition of tumor growth in the studied animals. Thus, Cdte QDs combined with DNR may serve as a possible alternative for targeted therapeutic approaches for some cancer treatments. PMID- 21711952 TI - Electrical resistance of CNT-PEEK composites under compression at different temperatures. AB - Electrically conductive polymers reinforced with carbon nanotubes (CNTs) have generated a great deal of scientific and industrial interest in the last few years. Advanced thermoplastic composites made of three different weight percentages (8%, 9%, and 10%) of multiwalled CNTs and polyether ether ketone (PEEK) were prepared by shear mixing process. The temperature- and pressure dependent electrical resistance of these CNT-PEEK composites have been studied and presented in this paper. It has been found that electrical resistance decreases significantly with the application of heat and pressure. PMID- 21711953 TI - Optimizing the design of nanostructures for improved thermal conduction within confined spaces. AB - Maintaining constant temperature is of particular importance to the normal operation of electronic devices. Aiming at the question, this paper proposes an optimum design of nanostructures made of high thermal conductive nanomaterials to provide outstanding heat dissipation from the confined interior (possibly nanosized) to the micro-spaces of electronic devices. The design incorporates a carbon nanocone for conducting heat from the interior to the exterior of a miniature electronic device, with the optimum diameter, D0, of the nanocone satisfying the relationship: D02(x) ? x1/2 where x is the position along the length direction of the carbon nanocone. Branched structure made of single-walled carbon nanotubes (CNTs) are shown to be particularly suitable for the purpose. It was found that the total thermal resistance of a branched structure reaches a minimum when the diameter ratio, beta* satisfies the relationship: beta* = gamma 0.25bN-1/k*, where gamma is ratio of length, b = 0.3 to approximately 0.4 on the single-walled CNTs, b = 0.6 to approximately 0.8 on the multiwalled CNTs, k* = 2 and N is the bifurcation number (N = 2, 3, 4 ...). The findings of this research provide a blueprint in designing miniaturized electronic devices with outstanding heat dissipation.PACS numbers: 44.10.+i, 44.05.+e, 66.70.-f, 61.48.De. PMID- 21711954 TI - Synthesis and characterisation of biologically compatible TiO2 nanoparticles. AB - We describe for the first time the synthesis of biocompatible TiO2 nanoparticles containing a functional NH2 group which are easily dispersible in water. The synthesis of water dispersible TiO2 nanoparticles coated with mercaptosuccinic acid is also reported. We show that it is possible to exchange the stearic acid from pre-synthesised fatty acid-coated anatase 5-nm nanoparticles with a range of organic ligands with no change in the size or morphology. With further organic functionalisation, these nanoparticles could be used for medical imaging or to carry cytotoxic radionuclides for radioimmunotherapy where ultrasmall nanoparticles will be essential for rapid renal clearance. PMID- 21711955 TI - Size-controlled synthesis of monodispersed gold nanoparticles via carbon monoxide gas reduction. AB - An in depth analysis of gold nanoparticle (AuNP) synthesis and size tuning, utilizing carbon monoxide (CO) gas as a reducing agent, is presented for the first time. The sizes of the AuNPs are tunable from ~4 to 100 nm by altering the concentration of HAuCl4 and inlet CO gas-injection flow rate. It is also found that speciation of aqueous HAuCl4, prior to reduction, influences the size, morphology, and properties of AuNPs when reduced with CO gas. Ensemble extinction spectra and TEM images provide clear evidence that CO reduction offers a high level of monodispersity with standard deviations as low as 3%. Upon synthesis, no excess reducing agent remains in solution eliminating the need for purification. The time necessary to synthesize AuNPs, using CO, is less than 2 min. PMID- 21711956 TI - Erectile dysfunction. AB - INTRODUCTION: Erectile dysfunction may affect 30% to 50% of men aged 40 to 70 years, with age, smoking, and obesity being the main risk factors, although 20% of cases have psychological causes. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of phosphodiesterase inhibitors in men with erectile dysfunction of any cause? What are the effects of phosphodiesterase inhibitors on erectile dysfunction in men with diabetes, with cardiovascular disease, with spinal cord injury, and with prostate cancer or undergoing prostatectomy? What are the effects of drug treatments other than phosphodiesterase inhibitors in men with erectile dysfunction of any cause? What are the effects of devices, psychological/behavioural treatments, and alternative treatments in men with erectile dysfunction of any cause? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 81 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: alprostadil (intracavernosal, intraurethral, topical), cognitive behavioural therapy, ginseng, papaverine, papaverine plus phentolamine (bimix), papaverine plus phentolamine plus alprostadil (trimix), penile prostheses, phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil), psychosexual counselling, vacuum devices, and yohimbine. PMID- 21711957 TI - Bronchitis (acute). AB - INTRODUCTION: Acute bronchitis affects over 40/1000 adults a year in the UK. The causes are usually considered to be infective, but only around half of people have identifiable pathogens. The role of smoking or of environmental tobacco smoke inhalation in predisposing to acute bronchitis is unclear. One third of people may have longer-term symptoms or recurrence. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute bronchitis in people without chronic respiratory disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: analgesics, antibiotics (macrolides, tetracyclines, cephalosporins, penicillins, or trimethoprim-sulfamethoxazole [co-trimoxazole]), antihistamines, antitussives, beta(2) agonists (inhaled or oral), and expectorants/mucolytics. PMID- 21711958 TI - Herniated lumbar disc. AB - INTRODUCTION: Herniated lumbar disc is a displacement of disc material (nucleus pulposus or annulus fibrosis) beyond the intervertebral disc space. The highest prevalence is among people aged 30 to 50 years, with a male to female ratio of 2:1. There is little evidence to suggest that drug treatments are effective in treating herniated disc. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments, non-drug treatments, and surgery for herniated lumbar disc? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 37 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acupuncture, advice to stay active, analgesics, antidepressants, bed rest, corticosteroids (epidural injections), cytokine inhibitors (infliximab), discectomy (automated percutaneous, laser, microdiscectomy, standard), exercise therapy, heat, ice, massage, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), percutaneous disc decompression, spinal manipulation, and traction. PMID- 21711959 TI - Use of montelukast alone or in combination with desloratadine or levocetirizine in patients with persistent allergic rhinitis. AB - BACKGROUND: We assessed the course of treatment in patients with persistent allergic rhinitis (AR) treated with montelukast, levocetirizine, or desloratadine alone or combinations of antihistamine and montelukast. METHODS: A 32-week randomized, double-blind, placebo-controlled, crossover, double-armed study in 40 adult patients with history of persistent AR, clinical allergy to house-dust mites, and a total nasal symptom score of at least 5 (congestion of at least 2) has been performed. Patients with asthma, chronic obstructive pulmonary disease, nonallergic rhinitis with clinical allergy associated with seasonal allergens, and other serious diseases were excluded. There were four 6-week treatment periods separated by 2-week washout periods. Twenty patients received either montelukast or antihistamine, a combination of montelukast and antihistamine, or placebo. The sequence of treatment was randomly assigned. Nasal symptoms were assessed using a 4-point scale at baseline, daily during the 1st week and on days 14, 21, 28, 35, and 42 of treatment. RESULTS: Montelukast alone, levocetirizine alone, desloratadine alone, and the montelukast/antihistamine combinations significantly improved nasal symptoms during the first 24 hours. Improvement gradually increased during the 6 weeks of treatment, especially in patients receiving montelukast alone or in combination therapy with the antihistamine in both arms. Improvement at 42 days of treatment was significantly greater than that achieved on the 1st day of therapy in patients treated with the combination of montelukast and levocetirizine. CONCLUSION: Montelukast alone or in combination with antihistamines gave a gradual increase in nasal symptom improvement within 6 weeks of treatment in patients with persistent AR. PMID- 21711960 TI - The expression of fibrinolytic components in chronic paranasal sinus disease. AB - BACKGROUND: Fibrinolytic components, their receptors, and inhibitors are considered to play an important role in inflammation and tissue remodeling including chronic rhinosinusitis (CRS). To clarify the relationship between these components and the pathology of CRS, we analyzed fibrinolytic components in sinonasal mucosa of CRS. METHODS: Sinonasal mucosa samples from 12 patients with CRS without nasal polyp (CRSsNP), 14 patients with CRS with nasal polyp (CRSwNP), and 12 control patients were prepared. By immunohistochemistry and ELISA, samples were studied with respect to urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1) and key mediators in sinus disease, TGF-beta1 and eosinophil cationic protein (ECP). RESULTS: uPA- or uPAR-positive inflammatory cells were increased in CRSwNP compared to controls and CRSsNP, whereas PAI-1-positive cells were increased in CRSsNP compared to CRSwNP and controls. ELISA measurements revealed that uPAR concentrations were increased in both CRSsNP (16.1 ng/mL; 10.4-22.9; p < 0.05) and CRSwNP (20.8 ng/mL; 9.62-25.9; p < 0.01) compared to controls (8.7 ng/mL; 7.9-12.9), and PAI-1 concentrations were increased in CRSsNP (198.8 ng/mL; 147.4-234.1) compared to controls (107.3 ng/mL; 92.6-175.3; p < 0.01) and CRSwNP (113.5 ng/mL; 105.1 193.5; p < 0.05). Moreover, the concentrations of TGF-beta1 correlated with PAI-1 in CRSsNP, and ECP correlated with uPAR protein in CRSwNP. CONCLUSION: Fibrinolytic components were highly expressed in CRSwNP compared to normal controls, whereas the inhibiting protein was up-regulated in CRSsNP. Furthermore, correlations between the expressions of fibrinolytic components and key mediators in CRS were found. PMID- 21711961 TI - Role of thrombin in chronic rhinosinusitis-associated tissue remodeling. AB - BACKGROUND: Thrombin, the effector enzyme of the coagulation system, has been reported to promote inflammatory responses in nasal diseases through its protease activated receptors (PARs). Chronic rhinosinusitis (CRS) is characterized by increased deposition of extracellular matrix proteins, tissue remodeling, and formation of nasal polyps. The role of thrombin in chronic nasal inflammation associated tissue remodeling still has not been appraised. This study was conducted to elucidate the role of thrombin in the pathogenesis of CRS. METHODS: Nasal secretion was collected from patients with CRS with nasal polyp (CRSwNP) with asthma (n = 9), CRSwNP without asthma (n = 10), allergic rhinitis (n = 7), and control patients (n = 3). The concentrations of thrombin, thrombin antithrombin (TAT) complex, and vascular endothelial growth factor (VEGF) were evaluated by enzyme immunoassays. The concentration of thrombin and TAT complex was measured in nasal secretion from each group of patients, and VEGF was measured in culture medium from airway epithelial cells treated with thrombin or thrombin receptor agonist peptide. RESULTS: Thrombin and TAT complex were significantly increased in nasal secretion of patients with CRSwNPs with asthma compared with the control group. Thrombin and PAR-1 agonist peptide significantly stimulated VEGF secretion from cultured human airway epithelial cells. CONCLUSION: The results of this study showed that there is increased activation of the coagulation system in the nasal mucosa of CRS patients and that thrombin may play a role in nasal polyp formation by stimulating VEGF production from airway epithelial cells. PMID- 21711962 TI - Nasal growth after pediatric septoplasty at long-term follow-up. AB - BACKGROUND: Septoplasty in children is still a matter of open discussion, because it is thought that a surgical procedure on a developing structure might produce some adverse effects on normal nasal growth. The goal of this retrospective study is to evaluate the effects of pediatric nasal septum surgery in a long-term follow-up by anthropometry. METHODS: Forty-four Italian patients, 25 male patients and 19 female patients, who had undergone septoplasty during childhood using the endonasal approach, were reassessed after a mean follow-up of 12.2 years. Anthropometric recordings were used to identify any growth retardation due to the operation by a comparison with previously published age-specific normative data of North American white subjects. Nasal measurements consisted of five linear parameters, three angular parameters, and three proportional index. RESULTS: There were no significant differences in any of the measures between the sample and controls (p > 0.1) with regard to gender, with the exception of the nasolabial angle measurement. Indeed, the nasolabial angle of the female patients was significantly reduced compared with controls (p = 0.04), whereas that of the male patients was reduced compared with controls (p = 0.08). This measurement seems to be influenced by the type of operation, because it has been noted that the nasolabial angle of patients treated surgically by extracorporeal septoplasty were significantly lower than those of patients treated surgically by conservative septoplasty. CONCLUSION: Pediatric septoplasty may be indicated in selected cases of obstructing nasal septum deformities. The operation, performed via endonasal approach, does not interfere with the normal growing nasal process. PMID- 21711963 TI - Chitinolytic activity in nasal polyps. AB - BACKGROUND: Chitin is a recognition element for tissue infiltration by innate cells implicated in allergy and immunity. This process can be negatively regulated by vertebrate chitinases. Both acidic mammalian chitinase (AMCase) and chitotriosidase (ChT) have chitinolytic activity. This study aimed to determine the activities of AMCase and ChT in nasal polyps (NPs), as well as their in situ localization in NP tissue. METHODS: AMCase and ChT activities in NPs were compared with those in inferior turbinate tissue samples. Tissue samples were measured for AMCase and ChT activities at a range of pHs using the fluorogenic substrate 4-methylumbelliferyl-beta-d-N,N',N''-triacetyl-chitotriose. Double immunofluorescent staining for the localization of both AMCase and ChT was performed using NP cryosections. RESULTS: Both AMCase and ChT displayed markedly increased chitinolytic activity in all NPs, compared with inferior turbinate tissues. Double immunofluorescent staining revealed that CD68 highlighted monocytes in the submucosa of NP and these cells disclosed coexpression of AMCase and ChT. CD31 detected capillary endothelial cells, but did not express any AMCase and ChT. CONCLUSION: The increased chitinolytic activities of AMCase and ChT in NPs may be important in NP pathogenesis, suggesting that inhibition of chitinolytic activity may be a novel therapeutic strategy for the treatment of NPs. PMID- 21711964 TI - High-definition imaging in endoscopic transsphenoidal pituitary surgery. AB - BACKGROUND: The transsphenoidal approach to sellar lesions has evolved enormously since its first description in the early 20th century. Endoscopic surgical strategies have become an integral part of the surgical armamentarium. More recently, high-definition (HD) digital cameras with better image resolution were introduced, although their value for the surgical procedure remains equivocal. The purpose of this study was to compare the image quality of a standard definition (SD) camera with a new HD camera. METHODS: A transsphenoidal pituitary adenomectomy was recorded simultaneously in HD and SD resolution. Eight experienced neurosurgeons were asked to identify predefined as well as not predefined anatomic structures in HD and SD. Additionally, the video quality of three complementary surgical sequences was rated with grades from 1 ("very good") to 6 ("poor"). RESULTS: An average of 23.6 +/- 2.7 predefined structures (84.38%) were identified in HD versus 17.6 +/- 4.4 predefined structures (62.95%) identified in SD. This profound difference in the recognition of anatomic structures reached statistical significance (p = 0.012). Subjective impression of video quality was rated 1.9, 1.9, and 1.4 for the videos in HD and 3.5, 3.3, and 3.5 for the complementary videos in SD. These differences also reached statistical significance (p <= 0.005). CONCLUSION: HD imaging in endoscopic transsphenoidal pituitary surgery accounts for significantly better identification of anatomic structures in comparison with SD images. Additionally, the subjective impression of video quality is significantly better in HD. This improved intraoperative orientation by better digital image quality might contribute to reduce the gap in intraoperative visual accuracy between microsurgery and endoscopy in pituitary surgery. PMID- 21711966 TI - Detection of bacteria in normal adult nasal cavity based on polymerase chain reaction-denaturing gradient gel electrophoresis. AB - BACKGROUND: This study investigated the bacterial diversity in a normal adult nasal cavity using polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) of 16S ribosomal RNA (rRNA) gene fragments and compared the results with those of a culture-based method. METHODS: We swabbed the inferior turbinate from 19 normal volunteers. The transport media was divided by two, one for bacterial culture and another direct extraction for bacterial DNA. PCR-DGGE was performed from the bacterial DNA and all of the sequences were compared with the reference organism by using the BLAST program (a genome database of GenBank in the National Center for Biotechnology Information, Bethesda, MD). RESULTS: All 224 colonies were obtained from 19 samples by using a culture-based method; however, only 9 kinds of bacteria were detected. Staphylococcus epidermidis was the most frequently detected bacteria, and Staphylococcus aureus was the second most. The detection rates of other bacteria were very low. On the other hand, the PCR-DGGE from direct DNA extraction revealed 34 different bands that corresponded to 23 different kinds of bacteria. There were nine genera, viz., Staphylococcus, Bacillus, Enterobacter, Corynebacterium, Actinobacterium, Hafnia, Moraxella, Dolosigranulum, and Clostridium. Among them, unspecific Staphylococcus species and Enterobacter aerogenes were detected most frequently. CONCLUSION: Compared with the previous culture-based method, PCR-DGGE can detect much more diversity of bacteria in the nasal cavity. PMID- 21711965 TI - Hypoxia induces cysteine-rich 61, vascular endothelial growth factor, and interleukin-8 expressions in human nasal polyp fibroblasts: An implication of neutrophils in the pathogenesis of nasal polyposis. AB - BACKGROUND: The purpose of this article was to elucidate the roles of neutrophils and angiogenesis factors in the pathogenesis of nasal polyposis. The effect of hypoxia on the expressions of angiogenesis factors as cysteine-rich 61 (Cyr61) and vascular endothelial growth factor (VEGF) and neutrophil chemoattractant as interleukin (IL)-8 in nasal polyp fibroblasts (NPFs), and the role of nuclear factor kappa B (NF-kappaB) in this reaction were investigated. The action of Cyr61 on the synthesis of VEGF and IL-8 in NPFs was also examined. METHODS: Primary cultures of NPFs were established from nasal polyps (NPs). Productions of Cyr61, VEGF, and IL-8 by NPFs under hypoxia were detected by Western blot (Cyr61 and VEGF) or enzyme-linked immunosorbent assay (ELISA; IL-8). Immunohistochemical staining was used to examine the relation between fibroblastic expression of Cyr61 and neovascularization/neutrophil infiltration in NPs. RESULTS: Western blot showed that the hypoxia inducer CoCl(2) stimulated Cyr61 synthesis in NPFs in a time-dependent manner, reaching a peak at 24 hours. Bay-117082 (a specific NF-kappaB inhibitor) attenuated the levels of Cyr61 stimulated by hypoxia. Cyr61 induced IL-8 secretion and VEGF synthesis by NPFs, as evidenced by Western blot and ELISA analysis. Bay-117082 abolished hypoxia-stimulated IL-8 and VEGF synthesis, whereas Cyr61 restored the stimulative effect of hypoxia readily. Immunohistochemical staining revealed the presence of Cyr61 and IL-8 in NPFs. Neutrophils and capillaries aggregating around these NPFs were frequently found. CONCLUSION: Under hypoxia, NPFs contribute to NP propagation by expressing Cyr61, which subsequently stimulates VEGF and IL-8 production, leading to angiogenesis and activating neutrophil infiltration in NPs. PMID- 21711967 TI - Association of T cells and eosinophils with Staphylococcus aureus exotoxin A and toxic shock syndrome toxin 1 in nasal polyps. AB - BACKGROUND: Staphylococcus aureus exotoxins (SEs) have been implicated in the pathogenesis of nasal polyps (NPs) in patients with chronic rhinosinusitis (CRS). The aim of this study was to identify the correlation between SEs and T cells in NPs. METHODS: After a nasal smear culture, the nasal lavage fluid and NP tissue were obtained from 30 CRS with NP (CRSwNP) patients. The control samples were taken from 10 normal individuals. The presence of S. aureus exotoxin A (SEA) and toxic shock syndrome toxin 1 (TSST-1) was verified through a polymerase chain reaction (PCR) analysis and immunohistochemical staining. Immunohistochemical staining for CD4(+) and CD8(+) T cells was performed, followed by hematoxylin and eosin (H&E) staining for eosinophils. RESULTS: The PCR analysis and immunohistochemical staining for SEA and TSST-1 showed a significantly higher expression in the NP group when compared with that in the control group. Furthermore, the number of T cells and eosinophils were notably increased in the NP group when compared with that in the control group. Significant correlation was observed between the results of the culture, PCR, and immunohistochemical staining in the NP group. Moreover, the number of T cells and eosinophils was significantly increased in the positive experimental groups, when compared with that in the control group. CONCLUSION: Our results indicate that there was, indeed, some correlation between the expression of SE in the nasal cavity and the increased number of T cells and eosinophils in NPs. PMID- 21711968 TI - Increased expression of angiogenin in nasal polyps. AB - BACKGROUND: The aim of this study was to determine the expression and distribution of angiogenin in nasal polyps and to evaluate the implication of such expression with respect to the development of nasal polyps. METHODS: Normal inferior turbinate mucosa was obtained from 20 patients undergoing surgery for augmentation rhinoplasty. Nasal polyp samples were obtained from 20 patients undergoing endoscopic sinus surgery for chronic polypoid rhinosinusitis. A semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was performed for angiogenin mRNA. Sections of nasal polyps were immunostained for localization of angiogenin and quantitatively analyzed using computer-based image analysis. Western blot analysis was performed. RESULTS: Semiquantitative RT-PCR and Western blot analysis showed that angiogenin expression in nasal polyps was increased compared with that in normal nasal mucosa. Using immunohistochemical staining, moderate-to-high levels of angiogenin were mainly localized in the infiltrating inflammatory cells of nasal polyps and faint staining was found in normal nasal mucosa. CONCLUSION: These results suggest that angiogenin may play a role in the pathophysiology of nasal polyps. PMID- 21711969 TI - Nonallergic rhinitis and its association with smoking and lower airway disease: A general population study. AB - BACKGROUND: The cause of nonallergic rhinitis (NAR) and its relation to lower airway disease remains unclear. The purpose of this study was to perform a descriptive analysis of the occurrence of rhinitis in a Danish general population with focus on NAR and its association with smoking and lower airway disease. METHODS: A population-based, cross-sectional study conducted in Copenhagen, Denmark was performed. A random sample from the general population (n = 7931; age, 18-69 years) was invited to a general health examination including measurements of serum-specific immunoglobulin E (IgE) to common aeroallergens; 3471 (44%) persons were accepted. For further analysis, we divided the population into the following groups: (I) negative specific IgE and no rhinitis (controls); (II) negative specific IgE and rhinitis (NAR); (III) positive specific IgE and rhinitis (allergic rhinitis [AR]); and (IV) positive specific IgE but no rhinitis (sensitized). RESULTS: We found that NAR was associated with asthma (odds ratio [OR] = 2.51 [1.87-3.37]); chronic bronchitis (OR = 2.27 [1.85-2.79]); current smoking (>15 g/day; OR = 1.57 [1.18-2.08]); lower forced expiratory volume in 1 second/forced vital capacity (FEV(1)/FVC) ratios and reduced FEV(1) values. The association with chronic bronchitis was stronger in NAR than in AR, whereas the opposite was true for asthma. FEV(1)/FVC of <70% was not significantly associated to any group. CONCLUSION: This epidemiological study indicates that both asthma and chronic bronchitis are important comorbidities in NAR confirming the "united airway" hypothesis, and that smoking might be a significant modulator of disease. Although NAR was significantly associated with poor lung function, no significant association with chronic obstructive pulmonary disease was shown. PMID- 21711970 TI - The effect of dilute baby shampoo on nasal mucociliary clearance in healthy subjects. AB - BACKGROUND: Biofilm formation has been implicated as an etiologic factor in the development of chronic rhinosinusitis (CRS). Nasal irrigation with surfactants including dilute baby shampoo have been proposed as an antibiofilm treatment for CRS patients. The effect of dilute baby shampoo on normal sinonasal mucosal function is unknown. METHODS: Mucociliary clearance time (MCT), as measured by the time in minutes for a subject to detect a sweet taste after the application of a saccharin granules at the anterior part of the inferior turbinate, was performed before and shortly after nasal irrigation with 50 ml of 1% baby shampoo (Johnson & Johnson, New Brunswick, NJ) in 27 healthy volunteers. RESULTS: Mean MCTs before and after irrigation were 12.09 (+/-4.83 minutes) and 15.45 (+/-7.71 minutes) minutes, respectively. The mean difference, 3.37 minutes, was statistically significant (p = 0.031). Pre- and post-MCTs for each subject were not correlated (r = 0.324; p = 0.100). CONCLUSION: Nasal irrigations with dilute baby shampoo increase MCTs in healthy subjects. The impact of such interventions in CRS patients warrants additional investigation. PMID- 21711971 TI - Early bronchial involvement in children with allergic rhinitis. AB - BACKGROUND: Allergic rhinitis (AR) may be frequently associated with asthma or precede it. Bronchial involvement in AR is usually detected by spirometry. Forced expiratory volume in 1 second (FEV(1)) is considered a reliable parameter for asthma diagnosis. However, forced expiratory flow at 25-75% (FEF(25-75)) could be considered a possible marker of early bronchial involvement in AR; indeed, it has been proposed that FEF(25-75) values <70% of predicted may predict this evolution. The aim of this study was to evaluate a large cohort of children with AR to define an FEV(1) value corresponding to impaired FEF(25-75) values. METHODS: Eight hundred fifty AR children (555 boys; median age, 10 years) were studied. Spirometry and skin-prick test were performed in all of them. Descriptive statistic and multivariate analysis were considered. RESULTS: Three hundred (35.3%) patients had FEF(25-75) values <70% of predicted. Still, normal FEV(1) values were associated with overt impaired FEF(25-75) values and the cutoff value was 83%. CONCLUSION: Spirometry should be adequately interpreted in AR patients; indeed, an FEV(1) cutoff value of 83% detects with good efficiency AR children with early bronchial impairment. PMID- 21711972 TI - Paranasal sinus development in children: A magnetic resonance imaging analysis. AB - BACKGROUND: The anatomy of the paranasal sinus is significantly different between adults and children, and surgeons must be aware of these differences to safely perform pediatric functional endoscopic sinus surgery. The purpose of this study was to determine the normal dimensions of the paranasal sinuses during development using magnetic resonance imaging (MRI) data compiled from the largest cohort to date. METHODS: The records of 2025 children, aged 0-18 years, who underwent cranial MRI, were examined retrospectively and 1452 patients with no history of sinus disease were included in the study. Coronal, axial, and sagittal images were used to measure the dimensions of the frontal, maxillary, ethmoid, and sphenoid sinuses, and the sinus volume index was measured. Patients were divided into 10 cohorts based on their age at the time of the scan. RESULTS: No difference between left and right one-dimensional measurements and volume indexes for the maxillary, sphenoid, ethmoid, and frontal sinuses was observed in any age group. Initial signs of pneumatization were observed at birth for the maxillary and ethmoid sinuses, at 9 months for sphenoid sinus, and after the age of 5 years for the frontal sinus. CONCLUSION: These results will help physicians correlate the clinical and radiographic findings of pediatric patients who are being evaluated for sinus disease and potential surgical intervention. Knowledge of the variations in the size of the paranasal sinuses is essential for determining the significance of incidental findings. PMID- 21711973 TI - Dolichandrone platycalyx: New entomophilous pollen--A report on pollen sensitization in allergic individuals. AB - BACKGROUND: Dolichandrone platycalyx, commonly known as Nile trumpet tree, is believed to have originated in East Africa. However, this and the variants of this tree are found in Europe, Asia, and America (California and Florida). The tree mostly grows in tropical climates, but temperate species are also found. This study was designed to evaluate the allergenicity of D. platycalyx, one of the most common entomophilous avenue trees in Karnataka state, and to determine the pollen production of D. platycalyx. METHODS: All of the patients with allergic rhinitis and asthma attending a tertiary care center in South India during August 2007 to March 2008 underwent a detailed clinical evaluation and skin-prick testing to common allergens along with D. platycalyx. Control subjects without any symptoms of respiratory allergy also underwent skin testing. The pollen counts were determined for a mature unopened flower of D. platycalyx. RESULTS: A total of 317 subjects with respiratory allergy and 30 controls were included in the study. A significant percentage (16.1%) of patients evaluated were observed to be sensitive to Dolichandrone pollen extract by skin-prick testing, whereas none of the control subjects were found to be sensitized. D. platycalyx was the fourth most common sensitizer after Parthenium hysterophorus, Prosopis juliflora, and Artemesia vulgaris. D. platycalyx was found to be a moderate pollen producer at 66,000 pollens/flower. CONCLUSION: Sensitization to D. platycalyx is common in subjects with respiratory allergies. The clinical relevance of this sensitization and other entomophilous plants needs additional study. PMID- 21711974 TI - Recombinant marker allergens in diagnosis of patients with allergic rhinoconjunctivitis to tree and grass pollens. AB - BACKGROUND: The aim of this study was to investigate recombinant marker allergens in patients with allergic rhinoconjunctivitis to tree and grass pollens. METHODS: Sera of 260 tree pollen- and 282 grass pollen-allergic patients were analyzed. Bet v 1 and Phl p 1/p 5 were used as marker allergens for allergies to pollen from birch and grasses. Profilin (Bet v 2 and Phl p 12) and calcium-binding protein (Bet v 4 and Phl p 7) were used as markers for polysensitization. RESULTS: Two hundred thirty-nine (92%) patients tested positive for IgE anti-Bet v 1. All of them were positive for IgE antibodies against natural birch extract (t3), hazel (t4), and alder (t2). Bet v 1 in combination with t3 identified allergies from related trees with a sensitivity of 99.2%. Two hundred fifty-six patients (91%) tested positive for IgE anti-Phl p 1 and/or anti-Phl p 5. All of them were positive for IgE antibodies against natural timothy (g6) and rye (g12) extract. Phl p 1/p 5 and natural timothy extract identified allergies from grasses and rye with a sensitivity of 99.3%. All Patients reacting to the cross reactive allergens Bet v 2, Phl p 12, Bet v 4, and Phl p 7 were polysensitized. CONCLUSION: Bet v 1 in combination with natural birch pollen extract identifies allergies from related trees with a sensitivity of 99.2%. Phl p 1, Phl p 5, and natural timothy extract identifies allergies from grasses and rye in 99.3%. Reactivity to the allergens Bet v 2, Phl p 12, Bet v 4, and Phl p 7 identifies polysensitization and cross-reactivity. PMID- 21711975 TI - Assessments of nasal bone fracture effects on nasal airflow: A computational fluid dynamics study. AB - BACKGROUND: The aim of this study was to evaluate effects of nasal bone fractures on nasal aerodynamic flow patterns using computational fluid dynamics (CFD) simulations. METHODS: A three-dimensional model of nasal cavity with a nasal bone fracture was constructed from computerized tomography (CT) scans of a patient with use of software Mimics 13.0 (The Materilize Group, Leuven, Belgium). CFD simulations were performed using Fluent 6.3 (ANSYS, Inc., Canonsburg, PA) with a turbulent flow model. Numerical results were presented with velocity, streamline, and pressure contour distributions in left and right nasal cavities and were compared with those of a healthy one. Possible outcomes on functional performances or patencies of the nose were also examined and discussed. RESULTS: For the nose with a nasal bone fracture, distributions of velocity contours showed there was more airflow in the right nasal cavity than in the left one, especially for inspiration status. In the left cavity, the airflow was redirected irregularly and there were also more circulations with larger sizes, higher pressure jumps, and greater wall shear stresses. Flow partitioning in the right and left cavities was noticeable with a larger nasal resistance compared with the healthy one. When the inspirational flow rate was increased, pressure jump from the nostril to the nasopharynx increased faster. CONCLUSION: The aerodynamic flow was redistributed greatly for the nose with a nasal bone fracture compared with the healthy one, which might affect local normal nasal functions. Such physical assessments of nasal airflow based on a model from the patients' CT scans may help clinicians determine the best treatment in advance. PMID- 21711976 TI - The effect of a low concentration of hypochlorous acid on rhinovirus infection of nasal epithelial cells. AB - BACKGROUND: Low concentrations of hypochlorous acid (HOCl) have been shown to exhibit both antibacterial and anti-influenza virus activity, but HOCl still has not been used to kill human rhinovirus (HRV). To model the antiviral effect of nasal irrigation with low-level HOCl in patients with the common cold, we tested the effects of a low concentration of HOCl on HRV infection of primary human nasal epithelial cells (HNEC). METHODS: Cells were infected with HRV for 24 hours and treated with HOCl three times, for 5 minutes each time, at 12 hour intervals. The effects of HOCl on rhinovirus-induced secretion of IL-6 and IL-8 were assessed by ELISA and HRV replication was determined by viral titration. RESULTS: HOCl treatment significantly inhibited HRV-induced secretion of IL-6 and IL-8 and significantly reduced viral titer. The effects of HOCl peaked at 1 minute after HOCl generation and decreased thereafter. CONCLUSION: These in vitro findings indicate that nasal irrigation with low-level HOCl solution may improve clinical symptoms in patients with the common cold. PMID- 21711977 TI - Alterations of vasoactive intestinal polypeptide receptors in allergic rhinitis. AB - BACKGROUND: Vasoactive intestinal peptide (VIP) is one of the parasympathetic neurotransmitters involved in the regulation of airway mucus secretion. The biological functions of VIP are mediated through two receptors (vasoactive intestinal peptide receptor type 1 [VPAC1R] and type 2 [VPAC2R]). The purpose of this study was to determine the distribution of VIP receptors and to compare the level of VIP receptor expression in the nasal mucosa of patients with allergic rhinitis and normal controls. METHODS: Inferior turbinate mucosal samples were obtained from 20 normal subjects and 20 patients with allergic rhinitis. VPAC1R and VPAC2R mRNA was extracted from the nasal mucosa, and then a reverse transcription-polymerase chain reaction was performed. Sections were immunostained using specific antibodies for VIP receptors. Western blot analysis was used to analyze differences in the level of expression of VPAC1R and VPAC2R protein between patients with allergic rhinitis and normal controls. RESULTS: The level of expression of VIP receptor mRNA and protein in patients with allergic rhinitis was significantly increased compared with normal nasal mucosa. VIP receptor immunoreactivity was detected on the nasal epithelium and submucosal glands in nasal specimens from both normal controls and patients with allergic rhinitis. In the epithelium from patients with allergic rhinitis, VIP receptor immunoreactivity was strong, whereas in the nasal epithelium from normal subjects it was faint. CONCLUSION: These results suggest that an increased expression level of VIP receptors is one possible explanation for nasal hyperresponsiveness in patients with allergic rhinitis. PMID- 21711978 TI - Critical appraisal and meta-analysis of nasal surgery for obstructive sleep apnea. AB - BACKGROUND: Nasal surgery is commonly involved in surgical treatment for obstructive sleep apnea (OSA). The aim of this study was to investigate the outcomes of nasal surgery for OSA using evidence-based methodology. METHODS: The MedLine database (1999~2009) was searched for original articles published in peer reviewed journals concerning nasal surgery for snoring/sleep apnea. Data extracted from these articles were reviewed and analyzed using meta-analysis technology. RESULTS: Thirteen articles were critically appraised. Two studies provided control groups and 11 articles (84.6%) consisted of prospective noncontrolled clinical trials (level II in evidence strength). The weighted mean apnea/hypopnea index measured by polysomnography in nine studies decreased from 35.2 +/- 22.6 to 33.5 +/- 23.8 event/hour after nasal surgery (overall, p = 0.69). The pooled success rate of nasal surgery in treating OSA was 16.7%. Epworth Sleepiness Scale scores in eight studies decreased from 10.6 +/- 3.9 to 7.1 +/- 3.7 (overall, p <0.001). Nasal surgery for snoring assessed by individual questionnaires and visual analog scale reported significant improvement (p < 0.05). CONCLUSION: The critical literature appraisal and meta-analyses show that nasal surgery can effectively reduce daytime sleepiness and snoring. However, the efficacy of nasal surgery in treating OSA is limited. PMID- 21711979 TI - A previously undescribed branch of the pterygopalatine ganglion. AB - BACKGROUND: Endonasal and infrazygomatic pterygopalatine ganglion (PPG) block for facial pain provides pain relief in a broader area than expected on anatomic grounds. The aim of this study was to search for neural structures in the pterygopalatine fossa (PPF) that could explain unexpected pain relief after PPG blockage. METHODS: The neural PPF content was explored through human cadaver study and nerve-specific staining. Five human PPF specimens were dissected as whole-mount preparations with the aid of an operation microscope and stained for acetylcholinesterase. One of these specimens was partially sectioned and analyzed through nitric oxide synthase (NOS) immunohistochemistry. RESULTS: A previously unknown nerve was identified. The nerve runs between the PPG and the ophthalmic nerve and was identified in all five specimens. NOS-containing nerve fibers were present but did not occupy the complete nerve area. CONCLUSION: Because it is likely that the nerve contains sensory fibers, our findings may provide an anatomic basis for unexplained pain relief in the ophthalmic area after PPG blockage. PMID- 21711980 TI - A novel use of a landmark to avoid injury of the anterior ethmoidal artery during endoscopic sinus surgery. AB - BACKGROUND: The aim of this study was to describe and correlate radiographically the anterior ethmoidal artery (AEA) to useful endoscopic surgical landmarks, such as the nasal beak (NB), nasal crest (NC), and axilla of the middle turbinate, because these are commonly encountered during endoscopic sinus surgery and skull base surgery. METHODS: A retrospective review and software analysis was performed by three independent observers. Measurements of distance and angulation from the AEA to the NC, NB, and axilla of the middle turbinate were performed. A total of 138 unique computed tomography (CT) scans performed at a university tertiary care center were evaluated. RESULTS: The average age of the patients whose scans were analyzed was 50.5 (range, 17-90 years) years of age. The gender distribution was 61 male and 89 female patients. After comparing the measurements to the three landmarks noted, it was determined that the NB had the most interpatient concordance and the least interobserver variability. The average distance between the NB and the AEA as it penetrates the lamina papyracea is 2.34 cm (variance, 0.07) at an angle of 45.21 degrees from the Frankfurt horizontal line. CONCLUSION: The real advantage of this novel use of the NB as a landmark to identify the AEA is that it is easy to use, unobtrusive, and is not time consuming. This relationship between the NB and the AEA is consistent across genders and ethnicities and is more valuable than others presented previously, which may be more variable. PMID- 21711981 TI - A theoretical cause of nasal obstruction in patients with repaired cleft palate. AB - BACKGROUND: During cleft palate repair, mucoperiosteal flaps are elevated from the palatal shelves and the nasal septum to accomplish tension-free closure of the nasal floor. This study was designed to geometrically describe how palate repair inherently limits airflow by decreasing nasal cavity cross-sectional area and increasing nasal airflow resistance. In addition, this study investigates whether the width of the repaired cleft palate directly affects the degree of postoperative airflow resistance. METHODS: A simplified geometric model of normal nasal cavity anatomy was compared with an equivalent schematic representing an individual with an unrepaired palatal cleft. Mathematical equations approximating the cross-sectional areas of normal and cleft nasal cavities were created. The theoretical postoperative loss of nasal cavity cross-sectional area was then considered for both unilateral and bilateral palatal clefts. RESULTS: According to this geometric model, the cross-sectional area of the nasal cavity is decreased in patients who undergo cleft repair. Repaired bilateral clefts experience a greater area loss than their unilateral counterparts. CONCLUSION: Nasal cavity resistance is higher in patients who have undergone cleft repair than in individuals who have not undergone cleft repair. because tension-free closure of the nasal floor inherently reduces cross-sectional breathing area. The wider the cleft, the higher the resistance to nasal airflow postoperatively. This iatrogenic source of nasal resistance is likely additive to other anatomic contributors to airflow resistance observed in individuals with cleft nasal deformities. PMID- 21711982 TI - Endoscopically guided chitosan nasal packing for intractable epistaxis. AB - BACKGROUND: The purpose of this study was to evaluate the effectiveness and safety of endoscopically guided chitosan packing in controlling intractable epistaxis. A prospective case series was performed. METHODS: This is a prospective clinical study conducted in a tertiary rhinology fellowship training hospital between January 2009 and November 2009. The study population consisted of patients with intractable epistaxis that failed to respond to traditional anterior-posterior nasal packing using either a 10-cm Pope PVA Merocel or a Rapid Rhino. The bleeding site was identified using a nasal endoscope and controlled using a pack made of a ChitoFlex chitosan dressing wrapped around a polyvinyl acetal nasal sponge. RESULTS: The intent-to-treat population consisted of 20 severe epistaxis subjects (8 men and 12 women) who continued to bleed despite traditional anterior-posterior nasal packing. The mean age was 67 years (+/-19 years). Sixteen subjects were on antiplatelets and/or anticoagulants. Eleven subjects (55%) presented with anterior epistaxis, and 7 subjects (35%) presented with posterior epistaxis. Chitosan nasal packing was performed on an outpatient basis and resulted in effective and immediate hemostasis in 19/20 subjects (95%). One subject had persistent bleeding after the first packing attempt and was successfully repacked within 30 minutes. Time to complete cessation of bleeding was 3.6 +/- 2.2 minutes in the 19 subjects; the pack was removed after 48 hours, without any evidence of rebleeding or any serious side effects. CONCLUSION: Endoscopically guided chitosan packing is a safe, effective, and well-tolerated outpatient treatment for the management of intractable epistaxis. PMID- 21711984 TI - Genes and gene therapy. PMID- 21711985 TI - Detection and characterization of intracranial aneurysms: magnetic resonance angiography versus digital subtraction angiography. AB - OBJECTIVE: To compare magnetic resonance angiography (MRA) with Intra-arterial digital subtraction angiography (IA-DSA) in detection and characterization of intracranial aneurysms. STUDY DESIGN: Comparative cross-sectional study. PLACE AND DURATION OF STUDY: Department of Diagnostic Imaging, Lahore General Hospital, Lahore, from January to June 2007. METHODOLOGY: Thirty patients presented with aneurysmal subarachnoid haemorrhage (SAH) and focal neurological signs were selected by convenience sampling. Three dimensional time of flight (3D TOF) MRA using maximum intensity projection (MIP) was performed on all patients along with DSA. Results of 3D TOF MRA were compared with those of IA-DSA taking IA-DSA as Gold standard. RESULTS: Out of 30 patients 14 (46.7%) were males and 16 (53.3%) were females with mean age of 41+/-14.1 years. MRA detected 29 out of 30 aneurysmal lesions with sensitivity of 96.7%. Regarding characterization of aneurysms results of MRA were comparable to those of IA-DSA. CONCLUSION: 3D TOF MRA technique showed a high sensitivity in this study. This technique can be used as a non-invasive screening test for intracranial aneurysms and as a suitable alternative primary examination to IA-DSA prior to aneurysmal surgery. PMID- 21711983 TI - A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health. AB - Mental illnesses, such as bipolar disorder, attention-deficit/hyperactivity disorder, depression and schizophrenia are a major public health concern worldwide. Several pharmacologic agents acting on monoamine neurotransmission are used for the management of these disorders. However, there is still little understanding of the ultimate molecular mechanisms responsible for the therapeutic effects of these drugs or their relations with disease etiology. Here I provide an overview of recent advances on the involvement of the signalling molecules Akt and glycogen synthase kinase-3 (GSK3) in the regulation of behaviour by the monoamine neurotransmitters dopamine (DA) and serotonin (5-HT). I examine the possible participation of these signalling molecules to the effects of antidepressants, lithium and antipsychotics, as well as their possible contribution to mental disorders. Regulation of Akt and GSK3 may constitute an important signalling hub in the subcellular integration of 5-HT and DA neurotransmission. It may also provide a link between the action of these neurotransmitters and gene products, like disrupted in schizophrenia 1 (DISC1) and neuregulin (NRG), that are associated with increased risk for mental disorders. However, changes in Akt and GSK3 signalling are not restricted to a single disorder, and their contribution to specific behavioural symptoms or therapeutic effects may be modulated by broader changes in biologic contexts or signalling landscapes. Understanding these interactions may provide a better understanding of mental illnesses, leading to better efficacy of new therapeutic approaches. PMID- 21711986 TI - Modified palatal stiffening procedure for snoring. AB - OBJECTIVE: To evaluate the efficacy of a modified procedure of palatal stiffening for the treatment of snoring. STUDY DESIGN: A quasi-experimental study. PLACE AND DURATION OF STUDY: ENT, and Head and Neck Surgery Departments of Pakistan Air Force (PAF) Hospital Masroor, Combined Military Hospital (CMH) Rawalpindi and PAF Hospital Sargodha, from January 2000 to January 2005. METHODOLOGY: Patients of either gender and above 20 years of age having snoring as their primary complaint were registered. Patients with an obvious cause of upper airway obstruction like oropharyngeal swelling, growths and obstructive sleep apnea were excluded. A grading system was designed to classify the patients according to severity and criteria for successful outcome defined; grades were equated with VAS. Palatal stiffening was achieved by using an insulated 22 gauge LP needle for infiltration cautery. Results were analyzed at 6 weeks post operatively on SPSS-16. Paired t test was applied to compare the improvement in snoring and significance was tested at p-value less than 0.05. RESULTS: Forty four (44) patients underwent the palatal stiffening procedure. Male to female ratio was 42:2. Twenty eight (28) patients (63%) had complete resolution of symptoms after first surgery. Out of the remaining, ten more patients (22.72%) became symptom free after 1st revision surgery while six patients (12.5%) needed 2nd revision. Pain in throat was the main post operative complaint which settled in 10 to 14 days. CONCLUSION: Palatal stiffening procedure causing relatively less morbidity, simple and minimally invasive, but effective at the same time. PMID- 21711987 TI - End treatment response with pegylated interferon among chronic hepatitis C non responders. AB - OBJECTIVE: To determine the frequency of end treatment virologic response (ETR) with pegylated interferon alpha and ribavirin in treatment of chronic hepatitis C patients who failed to respond to interferon plus ribavirin therapy given for at least 24 weeks. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Medical Unit-II, Benazir Bhutto Hospital, Shafi Clinic Rawalpindi and PAEC Hospital Islamabad, Pakistan, from July 2008 to June 2009. METHODOLOGY: Patients with hepatitis C who were non-responders to previous treatment with standard interferon and ribavirin, were given Pegylated Interferon alpha plus ribavirin. Total duration of treatment was 24 weeks for genotypes 2 and 3 and 48 weeks for genotypes 1 and 4. The primary end point was undetectable HCV RNA by polymerase chain reaction assay at the completion of therapy. RESULTS: Out of the 44 enrolled patients, 24 (54.5%) were males and 20 (45.5%) were females. Mean age of patients was 45.25+/-7.14 years. HCV genotypes were 3 in 64%, 2 in 30% and 7% each had genotypes 1 and 4. Both the early virological response and end of treatment response was seen in 75% patients. CONCLUSION: There was a high ETR rate of 75 in previous non-responders to conventional combination therapy. This high ETR as compared to international data is because of existence of favourable genotypes in our country which is encouraging in the treatment of non-responders. PMID- 21711988 TI - Postgraduate trainee performance with structured assessment techniques in competency-based model of training. AB - OBJECTIVE: To determine the effect of changes in curriculum and structured assessment on the performance of candidates at the end of the first phase of residency program by comparing pass percentages of candidates with older residency program. STUDY DESIGN: Interventional study. PLACE AND DURATION OF STUDY: From 2007 to 2009 at the College of Physicians and Surgeons Pakistan. METHODOLOGY: Results of midterm assessment (intermediate module, IMM) for the years 2006-2007 (Historical group) in 9 specialties were compared with those of years 2008-2009 (Interventional group) after implementation of curricular changes. The changes were evaluated with structured assessment technique. Results for the IMM exams for years 2006 to 2009 were included in the study. Percentage changes in results of both groups were subjected to statistical analysis. RESULTS: The average pass percentage for theory examination in the Historical group was 52.6% + 13.87, and 59.96 + 14.88 in Intervention group. The pass percentage in old-residency program for the clinical examination was 61.6% (ranging from 48.0% to 78.4%) which was less when compared with the new residency system that was 73.9% (ranging rom 61.5% to 82.45%). CONCLUSION: The curricular changes and structured assessment at set competency standard resulted in better performance and higher pass percentages of candidates at midterm assessment. PMID- 21711989 TI - Susceptibility pattern of extended spectrum beta-lactamase producing isolates in various clinical specimens. AB - OBJECTIVE: To determine the susceptibility pattern of extended spectrum beta lactamase (ESBL) producing Gram negative isolates from various clinical specimens. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Microbiology Department, Armed Forces Institue of Pathology, Rawalpindi, from January 2008 to January 2009. METHODOLOGY: A total of 308 ESBL producing isolates from various clinical specimens sent to AFIP for culture and sensitivity were identified using standard microbiological techniques and tested for antimicrobial susceptibility. At the same time screening for ESBL production was also done. ESBL production was confirmed by combination disc synergy method. The susceptibility pattern of isolates was then recorded in frequency percentages. RESULTS: Out of the 308 ESBL producing isolates more than 99% were susceptible to carbapenems, 84% to tazobactam/ piperacillin, 81% to sulbactam/cefoperazone, 12% to fluoroquinolones, 13% to cotrimoxazole, 59% to amikacin and 18% to gentamicin. Among the urinary isolates 49% were susceptible to Nitrofurontoin and only 5% to Pipemidic acid. CONCLUSION: Antibiotic choices in case of ESBL producing isolates are limited and at present only carbapenems can be regarded as treatment of choice. As empirical agents, beta-lactam/beta lactamase inhibitor combinations should be used cautiously for serious infections. Fluoroquinolones showed very poor efficacy. Amikacin can be used alternatively in such cases. Nitrofurantoin is still a good oral agent for treating UTI. PMID- 21711990 TI - Effect of phacoemulsification on intraocular pressure. AB - OBJECTIVE: To evaluate the effect of phacoemulsification on intraocular pressure in normal eyes and glaucomatous eyes. STUDY DESIGN: Quasi-experimental study. PLACE AND DURATION OF STUDY: Layton Rehmatulla Benevolent Trust, Eye and Cancer Hospital, Lahore, from September 2009 to August 2010. METHODOLOGY: The study subjects were adult patients with cataract and open or occludable angle, with or without raised intraocular pressure, who underwent phacoemulsification. Patients having any corneal pathology, synecheal angle closure more than 180 degrees, inflammatory eye disease, previous ocular surgery including YAG iridotomy and endothelial cell density less than 1500/mm2 were excluded from the study. They were followed-up for one year. Outcome measures included intraocular pressure, angle width, visual acuity and number of antiglaucoma medicines. Results were compared using chi-square test for proportions and t-test for mean values. RESULTS: There were 50 (41%) males and 72 (59%) females with 80 (65.6%) right and 42 (34.4%) left eyes. Mean age was 56.4+/-8.57 years. Pre-operatively 52 patients had open angles while 70 patients had occludable angles. Postoperatively 96 patients had open angles and 26 patients had occludable angles. Mean pre operative IOP was 25.70+/-7.79 mmHg, which was decreased to 17.44+/-2.8 mmHg (p < 0.001) at final follow-up visit. Number of mean antiglaucoma agents decreased from 1.12+/-1.30 pre-operatively to 0.62+/-0.92 at final follow-up visit. Mean pre-operative visual acuity was 0.4+/-0.19 that increased to 0.86+/-0.15. CONCLUSION: Phacoemulsification resulted in reduction in intraocular pressure in normal as well as glaucomatous eyes and it significantly reduced the need for anti-glaucoma medicines. PMID- 21711991 TI - Cognitive disturbance comparison among drug-naive depressed cases and healthy controls. AB - OBJECTIVE: To assess and compare cognitive disturbances among newly diagnosed depressed and healthy control cases on the McNair and Kahn auto-evaluation scale. STUDY DESIGN: Comparative, cross-sectional study. PLACE AND DURATION OF STUDY: Out-patients Department of Psychiatry, Jinnah Postgraduate Medical Centre, Karachi, Pakistan, from February to May, 2007. METHODOLOGY: All consecutive new cases reporting at the out patient department were screened for depressive illness. They were matched with healthy-controls aged between 18-40 years. Clinical assessment was carried out on the basis of detailed history, physical examination, mental state examination by psychiatrists. For diagnostic purpose, application of ICD-10 followed by administration of Scale for Cognitive Difficulties. RESULTS: Sixty subjects, 30 depressed patients (20 females and 10 males) and 30 healthy-controls (18 females and 12 males) were assessed. The age of cases with depressive disorder ranged 18-38 years. It was found that 63.3% (65% females and 60% males) depressed patients had cognitive difficulties compared to 3.3% of healthy-controls (p < 0.001). Proportions were compared using chi-square test with significance at p < 0.05. CONCLUSION: Depression is not merely an emotional (mood) disorder but has an impact on cognition domain as well. Attention/concentration was the most common domain of cognition affected, followed by memory disturbance among the drug-naive depressed patients. PMID- 21711992 TI - Pregnancy outcome among HIV positive women receiving antenatal HAART versus untreated maternal HIV infection. AB - OBJECTIVE: To evaluate adverse pregnancy outcome in HIV infected women who received highly active antiretroviral therapy (HAART) from early pregnancy compared with untreated-maternal HIV infection. STUDY DESIGN: A cohort study. PLACE AND DURATION OF STUDY: Antenatal clinic, University of Benin Teaching Hospital, Nigeria, from January 2008 to June 2009. METHODOLOGY: Two hundred and forty nine HIV infected women who had intrapartum care constituted the study population. Unbooked HIV positive pregnant women, who had not received antiretroviral drugs during the antenatal period but received nevirapine in labour, referred to as untreated-maternal HIV infection, were compared with women who received HAART early in pregnancy. Outcome measures of interest were obstetric complications and perinatal outcome proportion. RESULTS: Intrauterine growth restriction (IUGR) (20.5% vs. 6.3%, p = 0.003), pre-term birth (25.0% vs. 9.8%, p = 0.005) and caesarean delivery (45.5% vs. 29.8%, p = 0.04) were significantly higher among women with untreated-HIV infection in pregnancy compared with women who received HAART from early pregnancy. Untreated maternal HIV-infection was associated with higher frequency of birth weight less than 2500g, 5-minutes Apgar score less than 7 and admission into neonatal unit (p < 0.05). Women with primary education were significantly higher in the group with untreated maternal HIV infection (27.3% vs. 12.7%, p = 0.003). CONCLUSION: Untreated maternal HIV-infection in pregnancy may be associated with adverse pregnancy outcome. HIV positive women with low level of education utilise PMTCT services suboptimally. This information is important for programmes designed to increase access to PMTCT services including HAART from early pregnancy. PMID- 21711993 TI - Continuing medical education and pharmaceutical industry. AB - Continuing medical education providers' (academia) and industrial relationship is drawing attention all over the world. To date, there are no national commercial support guidelines available in Pakistan to properly regulate cooperation between the two distinct entities. However, the fact is that the future of all continuing medical education depends on pharmaceutical support and the providers are heavily dependent on the pharmaceutical industry to remain in action. It should always be remembered that medical education and profession is regarded as a moral of enterprise based on a blind faith between the physician and the patient. The funding support by the industry should not bind or influence physician's prescription for any reason. To be trusted, medicine must be free of all such dependency; it should be accountable only to the society it serves and to its own professional standards. PMID- 21711994 TI - Bronchial atresia with partial anomalous pulmonary venous return. AB - Bronchial atresia and anomalous superior pulmonary venous return into the left brachiocephalic vein are unusual anomalies. We present a young asymptomatic man in whom these two distinct anomalies were co-existingly found on routine medical examination. Patient was diagnosed as a case of congenital bronchial atresia with partial anomalous pulmonary venous return based on the evidence of special features on X-ray chest film, characteristic contrast enhanced 16-slice CT chest findings, lack of symptoms and no change on fallow-up X-ray chest films. PMID- 21711995 TI - Pneumatosis intestinalis successfully treated with oxygen inhalation. AB - Pneumatosis intestinalis is a rare disease with variable presentation. It is characterized by presence of gas in the gut wall. It may be primary (idiopathic) or secondary to other diseases. In the absence of signs and symptoms of perforation and peritonitis, pneumatosis intestinalis can be managed conservatively with inhaled oxygen and close monitoring of the patient. We present a case of 62 years old lady with this condition who was successfully treated with oxygen therapy. PMID- 21711996 TI - Bilobed gallbladder. AB - We report a rare case of duplication anomaly of gallbladder in a female aged 17 years, who presented with right hypochondrial pain for 3 months. Ultrasound findings suggested multiple stones in gallbladder and per-operatively she was found to have bilobed gallbladder. This case emphasizes the need for complete removal of both gallbladders during initial surgery, as a failure of this may result in recurrence of symptoms and stones and a need for re-exploration. PMID- 21711997 TI - Myeloid sarcoma in a child with acute myeloblastic leukaemia. AB - We report a rare occurrence of myeloid sarcoma in a 7 years old child with acute myeloblastic leukaemia (AML-FAB type M2). He presented with fever, generalized weakness, bilateral proptosis and left parotid swelling. CT scan revealed a mass in paranasal sinuses extending into brain and retro-orbital region. Diagnosis of AML M2 was made on bone marrow aspiration and special stains. Induction therapy for AML was given according to standard protocol. The extramedullary lesion as well as the acute leukaemia went into complete remission. PMID- 21711998 TI - Neuroendocrine carcinoma of breast. AB - Neuroendocrine tumours (NETS) are rare tumours. The commonest site of occurrence is the gastrointestinal tract. NETS in the breast are even rarer, accounting for less than 0.1% of all breast cancers and less than 1% of all NETS. We are reporting a case of primary neuroendocrine carcinoma of the breast in a 60 years old female. Investigations were done to rule out any other associated lesion. Patient was treated by modified radical mastectomy and adjuvant chemo and radiotherapy. PMID- 21711999 TI - Bilateral iridocorneal endothelial (ICE) syndrome with microspherophakia. AB - Iridocorneal endothelial syndrome is described to be a rare, usually unilateral ocular condition in young females. There are three known overlapping clinical variants of this condition namely, essential iris atrophy, Cogan-Reese and Chandler syndrome. We report a case of bilateral iridocorneal endothelial (ICE) syndrome with microspherophakia. A 25 years old female presented with microspherophakic lens dislocated into anterior chamber in right eye, and displaced inferiorly in left eye. She was also diagnosed with ICE syndrome and underwent lensectomies in both eyes. This unique combination has never been reported before. PMID- 21712000 TI - Popliteal artery entrapment syndrome. AB - Popliteal artery entrapment syndrome is an uncommon cause of intermittent claudication in young athletic persons. A 32 years old soldier presented with 14 months history of intermittent claudication. On the basis of history, physical examination and angiographic findings a diagnosis of popliteal artery entrapment was made. Exploration revealed a fibrous band tightly compressing popliteal artery and irreversibly damaged popliteal artery. Short saphenous vein graft was used to bypass the occluded segment of popliteal artery. This led to complete resolution of symptoms and continuation of active service. PMID- 21712001 TI - Frequency of Helicobacter pylori infection using 13C-UBT in asymptomatic individuals of Barakaho, Islamabad, Pakistan. AB - High frequency of Helicobacter (H.) pylori infection has been reported in Pakistan mainly for dyspeptic patients, while the published data is inadequate regarding asymptomatic population. The non-invasive 13C urea breath test (UBT) was used to determine the frequency of H. pylori infection in 516 asymptomatic individuals and to find out its association with gender and age. Overall prevalence was 74.4% (384/516) while 63.5% (113/178) children were positive for 13C-UBT and the percentage increased with age in both the genders with significantly higher prevalence in adolescents (p=0.003) and adults (p < 0.001). Moreover, there was non-significant difference between the prevalence of H. pylori infection in males and females in all age categories. The reported high frequency of H. pylori infection warrants further studies to identify epidemiological and environmental risk factors. PMID- 21712002 TI - Detection of filaggrin gene mutation (2282del4) in Pakistani Ichthyosis vulgaris families. AB - The aim of this study was to detect an 811 bp filaggrin (FLG) gene fragment known to carry a mutation 2282del4 which causes ichthyosis vulgaris. Seven clinically examined ichthyosis vulgaris families were included in this study. An 811 bp FLG gene fragment was targeted in the genomic DNA of all the members of the seven families by PCR amplification using known primers RPT1P7 and RPT2P1. Successful amplification of an 811 bp FLG gene fragment in all the families suggested the possible role of the 2282del4 mutation in causing ichthyosis vulgaris in Pakistani population. PMID- 21712003 TI - Epidemiology of non-disaster spinal injuries at a spine unit. PMID- 21712004 TI - Health locus of control among Pakistani university students. PMID- 21712005 TI - [The English disease--a disease which should be history!]. PMID- 21712006 TI - [Severe vitamin D deficiency in children born in Denmark of dark-skinned women]. AB - Rickets due to malnutrition is rare in Denmark. The Danish Board of Health recommend that: pregnant women are treated with a daily dose of vitamin D daily (10 micrograms); emigrants with coloured skin have their vitamin D level assessed during pregnancy; all children receive a daily dose of vitamin D (10 micrograms) until two years old. Despite of these recommendations two cases of severe nutritional rickets among children of emigrants were discovered upon hospital admission. The symptoms were heterogeneous: delayed walking skills and convulsions. We conclude that nutritional rickets is a tricky diagnosis, but is preventable. PMID- 21712008 TI - [Documented effect of extra corporeal photopheresis on T-cell mediated diseases]. AB - During extra corporeal photopheresis (ECP) 1.500 ml blood is extracted. Leucocytes are separated by centrifugation. Methoxsalen is added to the leucocytes and activated by UVA light. After treatment leucocytes are returned to the patient. ECP is a part of the treatment of acute and chronic graft-versus host disease (GVHD) in bone marrow transplant patients and severe cutaneous T cell lymphomas (CTLC). Studies have documented an effect of ECP in GVHD and CTLC. ECP has been used to treat other T-cell mediated diseases, the documentation however is sparse. The side effects of ECP are few and not serious. PMID- 21712007 TI - [Weight reducing and glucose reducing effects of liraglutide treatment for patients with type 2 diabetes]. AB - Treatment with glucagon-like peptide-1 analogues including liraglutide is a new treatment option for patients with type 2 diabetes. Treatment with liraglutide decreases HbA1c by 1-2%, and additionally liraglutide has a reducing effect on weight, lipids and blood pressure. Most adverse events are related to the gastrointestinal system and most often they disappear within a few weeks. The risk of major hypoglycaemic episodes is minimal. Long term data on treatment and adverse events with liraglutide are still lacking. PMID- 21712009 TI - [Diagnosis and treatment of oesophageal perforations]. AB - The treatment of oesophageal perforations (EP) has primarily been a surgical issue and despite significant advances in surgery and intensive care medicine EP is continuously associated with high morbidity and mortality. Implementation of an effective treatment algorithm which steps away from the traditional surgical approach is essential for achieving a better clinical outcome. A modern treatment algorithm includes contrast computed tomography and endoscopy diagnostics and use of non- or semi-invasive procedures like selfexpanding metal stents, selective digestive decontamination and the establishment of a controlled fistula. PMID- 21712010 TI - [Checklists have a potential in health care]. AB - A checklist is a cognitive tool specifying the actions necessary to complete a given task. It serves to improve the quality of care, support the memory of the user and it may serve to indicate the necessary communicative steps within a team. Checklists are used increasingly in health care. Preliminary results indicate a potential for patient safety. However, no evidence indicates that a checklist in itself is sufficient to obtain clinical results: training and motivating staff, supporting implementation, and conducting follow-up and evaluation are as important as the checklist itself to achieve results. PMID- 21712011 TI - [Infections related to central venous catheters in children affected from malignant diseases]. AB - Central venous catheters (CVC) are an essential part of the treatment of children with haematological and oncological diseases. Unfortunately, CVC also represent a major risk factor of bloodstream infections. Catheter-related bloodstream infections (CRBSI) in children are often diagnosed based on blood cultures from the CVC only. Most CRBSI can be treated without catheter removal. On suspicion of CRBSI empirical antibiotic treatment with piperacillin-tazobactam, meropenem or ampicillin in combination with gentamicin is recommended. The systemic treatment can be combined with catheter-lock therapy. PMID- 21712012 TI - [Amoxicillin-induced hepatitis]. AB - Amoxicillin with and without clavulanic acid is a widely used antibiotic in adults and children alike. The drug is used prophylactically as well as therapeutically. In Denmark, it has not been described that amoxicillin alone can lead to hepatitis. In literature often referenced by Danish physicians (medicin.dk and Laegemiddelkataloget), hepatotoxicity is not listed as a side effect. However, in the present case, a 61 year-old male who suffered a tick bite and was treated prophylactically with amoxicillin without clavulanic acid presented with pharmacologically induced hepatitis 20 days after treatment. PMID- 21712013 TI - [Picture of the month: dercum disease]. PMID- 21712014 TI - New insight into clinical development of nucleic acid aptamers. AB - Nucleic acid-based aptamers have been shown as high-affinity ligands and potential antagonists of disease-associated proteins. Aptamers, isolated from combinatorial libraries by an iterative in vitro selection process, discriminate between closely related targets and are characterized by high specificity and low toxicity thus representing a valid alternative to antibodies to target specific proteins of biomedical interest. Moreover, they are non-immunogenic and can be easily stabilized by chemical modifications thus expanding their therapeutic potential. Here, we will focus on the structural and functional features of aptamers that have entered the clinical development pipeline together with those aptamers holding great potential as therapeutics in preclinical studies. The future perspectives of aptamers as therapeutics will be discussed as well. PMID- 21712015 TI - Olfactory targeting through intranasal delivery of biopharmaceutical drugs to the brain: current development. AB - Many therapeutic drugs are difficult to reach the central nervous system (CNS) from the systemic blood circulation because the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) form a very effective barrier which prevents most molecules from passing through. To bypass BBB, drugs can be delivered through olfactory region for nose-to-brain targeting. Peptide and protein drugs have been developed for the treatment of various neurodegenerative diseases. Drug delivery of these therapeutic proteins is facing several challenges because of the instability, high enzymatic metabolism, low gastrointestinal absorption, rapid renal elimination, and potential immunogenicity. New genetically engineered biotechnology products, such as recombinant human nerve growth factor, human VEGF, and interferons, are now possible to be delivered into the brain from the non-invasive intranasal route. For gene therapy, intranasal route is also a promising alternative method to deliver plasmid DNA to the brain. This review provides an overview of strategies to improve the drug delivery to the brain and the latest development of protein, peptide, and gene intranasal delivery for brain targeting. PMID- 21712016 TI - External beam radiotherapy in the management of spinal metastases: review of current strategies and perspectives for highly conformal irradiation modalities. AB - Bone metastases are frequent in advanced metastatic solid tumors. These secondary lesions are responsible for significant impairment of quality of life of patients with onset of pain, which is frequently resistant to standard analgesics. The therapeutic challenge for a patient with spinal metastasis is to maintain a quality of life as good as possible, commensurate with its life expectancy. Radiotherapy can provide efficient pain relief, but it should be integrated into a multidisciplinary approach. In the case of epidural spinal cord compression, it should be performed whenever possible after surgery. New highly conformal irradiation modalities have emerged for treatment of spinal metastases with therapeutic perspectives. Stereotactic radiosurgery could be provided for patients with single lesions or oligometastatic disease, a good general condition, absence of cord compression, and a life expectancy greater than 6 months. It is particularly promising for the treatment of classically radioresistant tumors or relapsing disease. Intensity-modulated radiotherapy, including Helical Tomotherapy, is a new perspective for treatment of multiple metastases. However, if these new techniques can provide efficient pain sedation, hindsight is currently low to judge their therapeutic benefit and these techniques are hardly available in most centers. Here, we offer a quick review of current strategies and new modalities of radiotherapy to put into perspective the place of these techniques in therapy of spinal metastases. PMID- 21712017 TI - Innate immunity in type 1 diabetes. AB - Type 1 diabetes (T1D) is a complex autoimmune disease that is untimely caused by the destruction of insulin-producing pancreatic beta-cells by autoreactive T cells. The development of the pathology involved several cell types of both the innate and adaptive immune systems. This disease is under the control of several genetic loci of susceptibility but it is also influenced by environmental factors such as infectious agents. Studies in animal models, such as the non-obese diabetic (NOD) mouse, reveal that during the development of T1D multiple interactions occur between macrophages, dendritic cells (DC), natural killer (NK) cells, NKT cells, and lymphocytes. As a consequence, the various components of the immune system can be of peculiar interest as therapeutic targets for disease prevention or cure. This review focuses on the involvement of innate immune cells in the development and the prevention of T1D. PMID- 21712018 TI - Ghrelin biology and its role in weight-related disorders. AB - The discovery of ghrelin and its role in human metabolism has promoted significant research and advances in the study of obesity and other weight related disorders. Ghrelin is relevant to many disorders of metabolism and weight such as obesity, cachexia, Prader-Willi Syndrome (PWS), and Anorexia Nervosa (AN), and its role in the pathophysiology differs. The changes observed in ghrelin physiology in these disorders shed light on the overall role of ghrelin in human metabolism and growth. The purpose of this review is to summarize the existing literature on ghrelin and some disorders of metabolism and growth. The disorders that will be discussed include obesity, cachexia, PWS, and AN. Within each disorder we will review relevant ghrelin physiology, recent studies, and potential modes of intervention with ghrelin analogues. PMID- 21712019 TI - Stem cell-mediated gene therapies for malignant gliomas: a promising targeted therapeutic approach? AB - Glioblastomas are aggressive intrinsic brain tumors. The median overall survival does not exceed 15 months despite surgical resection, radiotherapy, and chemotherapy even in selected clinical trial populations. One reason for this poor outcome is the characteristic infiltrative growth pattern of glioblastomas with tumor cells deeply infiltrating into the normal brain parenchyma and thereby escaping surgical debulking and involved-field radiation therapy. Novel therapeutic strategies are urgently needed including those that target disseminated tumor cells, too. In this regard, the application of adult stem cells as cellular vehicles for the delivery of therapeutic molecules has emerged during the last decade as an experimental approach. Adult stem cells with a tropism for gliomas include neural stem and progenitor cells, mesenchymal stem cells, hematopoietic progenitor cells, and endothelial progenitor cells. Importantly, these candidate cellular carriers also localize to sites of hypoxia and invasive tumor borders which are usually not targeted by currently available therapeutic approaches. Stem cell-based therapeutic approaches could therefore help to overcome some of the current limitations of radio- and chemotherapy and may circumvent toxicity to normal resident cells of the central nervous system. The development of neural stem- and progenitor-based therapies is advanced with a currently ongoing phase I clinical study. We review rationale, achievements, and future challenges in this field. PMID- 21712020 TI - Aging, immunity, and cancer. AB - Age is the most important risk factor for tumorigenesis. More than 60% of new cancers and more than 70% of cancer deaths occur in elderly subjects >65 years. The immune system plays an important role in the battle of the host against cancer development. Deleterious alterations occur to the immune response with aging, termed immunosenescence. It is tempting to speculate that this waning immune response contributes to the higher incidence of cancer, but robust data on this important topic are few and far between. This review is devoted to discussing state of the art knowledge on the relationship between immunosenescence and cancer. Emerging understanding of the aging process at the molecular level is viewed from the perspective of this increased tumorigenesis. We also consider some of the most recent means to intervene in the modulation of immunosenescence to increase the ability of the immune system to fight against tumors. Future research will unravel new aspects of the immune response against tumors which will be modulable to decrease the burden of cancer in elderly individuals. PMID- 21712021 TI - Pharmacogenomics, personalized medicine, and heart failure. AB - Heart failure, a major clinical problem affecting millions of people, may be modified by the genetic diversity of the affected individuals. A novel medical approach, personalized medicine, seeks to use genetic information to "personalize" and improve diagnosis, prevention, and therapy. The personalized management of heart failure involves a large spectrum of potential applications, from diagnostics of monogenic disorders, to prevention and management strategies based on modifier genes, to pharmacogenomics. In rare monogenic disorders causing heart failure, recent guidelines now assist the clinician in molecular diagnostics, genetic counseling, and therapeutic choices. Several lines of evidence suggest that common polymorphic variants of modifier genes can influence the susceptibility to heart failure, and it is expected that more advanced high throughput technologies will allow the discovery of a number of novel modifier genes that could be used for prognostic profiling and development of novel therapeutics. Finally, using pharmacogenomic approaches to affect heart failure management appears very promising. Common genetic variants of beta-adrenergic receptors, alpha-adrenergic receptors, and endothelin receptors among others significantly alter the response to heart failure therapy. This knowledge could be used to personalize and optimize heart failure therapy based on the patient's genetic profile. While the advances in technologies will continue to transition personalized medicine from the research to the clinical setting, physicians and in particular cardiologists need to reshape clinical diagnostics paradigms, learn how to use new genomic information to change management decisions, and provide the patients with appropriate education and management recommendations. PMID- 21712023 TI - Transseptal puncture through atrial septal closure devices. PMID- 21712022 TI - Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-kappaB mediated inflammatory response in mice. AB - BACKGROUND & AIMS: Loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) in the biliary epithelium reduces bile flow and alkalinization in patients with cystic fibrosis (CF). Liver damage is believed to result from ductal cholestasis, but only 30% of patients with CF develop liver defects, indicating that another factor is involved. We studied the effects of CFTR deficiency on Toll-like receptor 4 (TLR4)-mediated responses of the biliary epithelium to endotoxins. METHODS: Dextran sodium sulfate (DSS) was used to induce colitis in C57BL/6J-Cftrtm1Unc (Cftr-KO) mice and their wild-type littermates. Ductular reaction and portal inflammation were quantified by keratin 19 and CD45 immunolabeling. Cholangiocytes isolated from wild-type and Cftr-KO mice were challenged with lipopolysaccharide (LPS); cytokine secretion was quantified. Activation of nuclear factor kappaB (NF-kappaB), phosphorylation of TLR4, and activity of Src were determined. HEK-293 that expressed the secreted alkaline phosphatase reporter and human TLR4 were transfected with CFTR complementary DNAs. RESULTS: DSS-induced colitis caused biliary damage and portal inflammation only in Cftr-KO mice. Biliary damage and inflammation were not attenuated by restoring biliary secretion with 24-nor-ursodeoxycholic acid but were significantly reduced by oral neomycin and polymyxin B, indicating a pathogenetic role of gut-derived bacterial products. Cftr-KO cholangiocytes incubated with LPS secreted significantly higher levels of cytokines regulated by TLR4 and NF-kappaB. LPS-mediated activation of NF-kappaB was blocked by the TLR4 inhibitor TAK-242. TLR4 phosphorylation by Src was significantly increased in Cftr-KO cholangiocytes. Expression of wild-type CFTR in the HEK293 cells stimulated with LPS reduced activation of NF-kappaB. CONCLUSIONS: CFTR deficiency alters the innate immunity of the biliary epithelium and reduces its tolerance to endotoxin, resulting in an Src-dependent inflammatory response mediated by TLR4 and NF-kappaB. These findings might be used to develop therapies for CF associated cholangiopathy. PMID- 21712025 TI - FcepsilonRI, but not FcgammaR, signals induce prostaglandin D2 and E2 production from basophils. AB - Prostaglandin (PG) D2 and PGE2 are arachidonic acid metabolites that are generated though an isomerization reaction catalyzed by PG synthases. PGs have been implicated in immunologic reactions in addition to a wide range of physiological functions. It has long been thought that basophils, in contrast to mast cells, do not synthesize PGs, although they do release leukotrienes and platelet-activating factor. Here, we show that basophils function as a source of PGD2 and PGE2. In vitro-cultured basophils from mouse bone marrow produced both PGD2 and PGE2 in response to IgE + antigen (Ag), but not to IgG + Ag. Release of PGs was almost completely abrogated in cultured basophils from FcRgamma-chain(-/ ) mice, indicating the involvement of FcepsilonRI. Basophils freshly isolated from bone marrow cells (primary basophils) were also capable of secreting PGD2 and PGE2. Although the amount of PGD2 released from primary basophils was lower than that from mast cells, the capability of primary basophils to generate PGE2 was more potent than that of mast cells. Transcripts and proteins for both hematopoietic-type PGD synthase and PGE synthase were detected in basophils. In addition, human basophils, like mouse basophils, also produced PGD2 through IgE mediated stimulation. Thus, basophils could be an important source of PGD2/PGE2 and may contribute to allergic inflammation and immune responses. PMID- 21712024 TI - Microglia/macrophages migrate through retinal epithelium barrier by a transcellular route in diabetic retinopathy: role of PKCzeta in the Goto Kakizaki rat model. AB - Diabetic retinopathy is associated with ocular inflammation, leading to retinal barrier breakdown, macular edema, and visual cell loss. We investigated the molecular mechanisms involved in microglia/macrophages trafficking in the retina and the role of protein kinase Czeta (PKCzeta) in this process. Goto Kakizaki (GK) rats, a model for spontaneous type 2 diabetes were studied until 12 months of hyperglycemia. Up to 5 months, sparse microglia/macrophages were detected in the subretinal space, together with numerous pores in retinal pigment epithelial (RPE) cells, allowing inflammatory cell traffic between the retina and choroid. Intercellular adhesion molecule-1 (ICAM-1), caveolin-1 (CAV-1), and PKCzeta were identified at the pore border. At 12 months of hyperglycemia, the significant reduction of pores density in RPE cell layer was associated with microglia/macrophages accumulation in the subretinal space together with vacuolization of RPE cells and disorganization of photoreceptors outer segments. The intraocular injection of a PKCzeta inhibitor at 12 months reduced iNOS expression in microglia/macrophages and inhibited their migration through the retina, preventing their subretinal accumulation. We show here that a physiological transcellular pathway takes place through RPE cells and contributes to microglia/macrophages retinal trafficking. Chronic hyperglycemia causes alteration of this pathway and subsequent subretinal accumulation of activated microglia/macrophages. PMID- 21712026 TI - Correlation of structural and functional thermal stability of the integral membrane protein Na,K-ATPase. AB - The membrane-bound cation-transporting P-type Na,K-ATPase isolated from pig kidney membranes is much more resistant towards thermal inactivation than the almost identical membrane-bound Na,K-ATPase isolated from shark rectal gland membranes. The loss of enzymatic activity is correlated well with changes in protein structure as determined using synchrotron radiation circular dichroism (SRCD) spectroscopy. The enzymatic activity is lost at a 12 degrees C higher temperature for pig enzyme than for shark enzyme, and the major changes in protein secondary structure also occur at T(m)'s that are ~10-15 degrees C higher for the pig than for the shark enzyme. The temperature optimum for the rate of hydrolysis of ATP is about 42 degrees C for shark and about 57 degrees C for pig, both of which are close to the temperatures for onset of thermal unfolding. These results suggest that the active site region may be amongst the earliest parts of the structure to unfold. Detergent-solubilized Na,K-ATPases from the two sources show the similar differences in thermal stability as the membrane-bound species, but inactivation occurs at a lower temperature for both, and may reflect the stabilizing effect of a bilayer versus a micellar environment. PMID- 21712027 TI - Cancer-associated adipocytes promotes breast tumor radioresistance. AB - Mature adipocytes are excellent candidates to influence tumor behavior through heterotypic signaling processes since these cells produce hormones, growth factors, cytokines and other molecules, a heterogeneous group of molecules named adipokines. Using a 2D coculture system, we demonstrate that breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance and an earlier and higher increase in the effector kinase Chk1, a phenotype that was associated with decreased cell death as compared to tumor cells grown alone. Interestingly, the adipocytes-induced tumor changes taking place during the coculture time preceding the exposure to IR were sufficient to confer the radioresistant effect. Notorious among the changes brought by adipocytes was the significant increase of IL-6 expression in tumor cells, whose activity may well account for the observed tumor cell protection from IR toxicity. Indeed, our data confirmed the protective role of this cytokine as tumor cells incubated after irradiation with recombinant IL-6 exhibit an increased in Chk1 phosphorylation and a radioresistant phenotype, thus far recapitulating the effects observed in the presence of adipocytes. Our current study sheds light on a new role of tumor surrounding adipocytes in fostering a radioresistant phenotype in breast tumors, a finding that might have important clinical implications in obese patients that frequently exhibit aggressive diseases. PMID- 21712028 TI - Perturbations of model membranes induced by pathogenic dynorphin A mutants causing neurodegeneration in human brain. AB - Several effects of the endogenous opioid peptide dynorphin A (Dyn A) are not mediated through the opioid receptors. These effects are generally excitatory, and result in cell loss and induction of chronic pain and paralysis. The mechanism(s) is not well defined but may involve formation of pores in cellular membranes. In the 17-amino acid peptide Dyn A we have recently identified L5S, R6W, and R9C mutations that cause the dominantly inherited neurodegenerative disorder Spinocerebellar ataxia type 23. To gain further insight into non-opioid neurodegenerative mechanism(s), we studied the perturbation effects on lipid bilayers of wild type Dyn A and its mutants in large unilamellar phospholipid vesicles encapsulating the fluorescent dye calcein. The peptides were found to induce calcein leakage from uncharged and negatively charged vesicles to different degrees, thus reflecting different membrane perturbation effects. The mutant Dyn A R6W was the most potent in producing leakage with negatively charged vesicles whereas Dyn A L5S was virtually inactive. The overall correlation between membrane perturbation and neurotoxic response [3] suggests that pathogenic Dyn A actions may be mediated through transient pore formation in lipid domains of the plasma membrane. PMID- 21712029 TI - N-terminal short fragment of TUP1 confers resistance to 5-bromodeoxyuridine in the yeast Saccharomyces cerevisiae. AB - Small molecules that exhibit biological activity have contributed to the understanding of the molecular mechanisms of various biological phenomena. 5 Bromodeoxyuridine (BrdU) is a thymidine analogue that modulates various biological phenomena such as cellular differentiation and cellular senescence in cultured mammalian cells. Although BrdU is thought to function through changing chromatin structure and gene expression, its precise molecular mechanisms are not understood. To study the molecular mechanism for the action of BrdU, we have employed the yeast Saccharomyces cerevisiae as a model system, and screened multi copy suppressor genes that confer resistance to BrdU. Our genetic screen has revealed that expression of the N-terminal short fragment of TUP1, and also disruption of HDA1 or HOS1, histone deacetylases that interact with TUP1, conferred resistance to BrdU. These results suggest the implication of the chromatin proteins in the function of BrdU, and would provide novel clues to answer the old question of how BrdU modulates various biological phenomena. PMID- 21712030 TI - Breast cancer subtypes express distinct receptor repertoires for tumor-associated macrophage derived cytokines. AB - Infiltration of the tumor microenvironment by macrophages is associated with poor outcomes in breast cancer and other solid tumors, however the identity and roles of many of the soluble factors these macrophages produce remains to be elucidated in detail. In addition to producing angiogenic factors (e.g. VEGF), proteases (e.g. MMP9) and immunomodulatory factors (e.g. IL10) which, by modifying the local microenvironment, likely contribute to progression in the majority of solid tumors, we have evaluated the extent to which macrophage cytokines may differentially affect distinct breast cancer subtypes. We identified 23 cytokines produced in a culture model of human tumor-associated macrophages and report that basal and luminal breast cancer cell lines express different repertoires of receptors for these cytokines. These data suggest that tumor-associated macrophages make specific contributions to different breast cancer subtypes and that understanding the importance of these interactions will be crucial to developing subtype-specific therapies targeting the macrophage component of the breast tumor microenvironment. PMID- 21712031 TI - Heat shock induces apoptosis through reactive oxygen species involving mitochondrial and death receptor pathways in corneal cells. AB - Although many studies have been performed to elucidate the molecular consequences of ultraviolet irradiation, little is known about the effect of infrared radiation on ocular disease. In addition to photons, heat is generated as a consequence of infrared irradiation, and heat shock is widely considered to be an environmental stressor. Here, we are the first to investigate the biological effect of heat shock on Statens Seruminstitut Rabbit Cornea (SIRC) cells. Our results indicate that heat shock exhibits effective cell proliferation inhibition by inducing apoptosis. Heat shock triggers the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in caspase-9 activity. In addition, heat shock triggered the death receptor apoptotic pathway indicated by a change in Fas ligand expression, resulting in caspase-8 activity. Furthermore, we also found that generation of reactive oxygen species (ROS) is a critical mediator in heat shock-induced apoptosis. In addition, the antioxidant vitamin C significantly decreased heat shock-mediated apoptosis. Taken together, these findings suggest a critical role for ROS involving mitochondrial and death receptor pathways in heat shock-mediated apoptosis of cornea cells. PMID- 21712032 TI - Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis. AB - Recent studies suggest that progressive motoneuron death in amyotrophic lateral sclerosis (ALS) is non-cell autonomous and may involve the participation of non neuronal cells such as glial cells and skeletal muscle. Therefore, a drug that targets motoneurons as well as neighboring non-neuronal cells might be a potential therapeutic strategy to delay disease progression in ALS. Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, has shown protective effects in multiple cell types implicated in ALS by resetting gene transcription profiles through increased histone acetylation. To test whether TSA could serve as a potential therapeutic agent, we intraperitoneally injected TSA from postnatal day 90 (P90), after disease symptoms appear, until P120 or the end-stage in SOD1-G93A mice. We found that TSA ameliorated motoneuron death and axonal degeneration in SOD1-G93A mice. Reduced gliosis and upregulation of the glutamate transporter (GLT-1) were also observed in the spinal cord of TSA-treated SOD1-G93A mice. In addition, TSA ameliorated muscle atrophy and neuromuscular junction (NMJ) denervation, which are the pathological characteristics of ALS found in skeletal muscle. Improved morphology in TSA-treated SOD1-G93A mice was accompanied by enhanced motor functions as assessed by rota-rod and grip strength analyses. Furthermore, TSA treatment significantly increased the mean survival duration after the treatment by 18% and prolonged lifespan by 7%. Our findings suggest that TSA may provide a potential therapy to slow disease progression as well as to enhance motor performance to improve the quality of life for ALS patients. PMID- 21712033 TI - Comparative genome-scale metabolic modeling of actinomycetes: the topology of essential core metabolism. AB - Actinomycetes are highly important bacteria. On one hand, some of them cause severe human and plant diseases, on the other hand, many species are known for their ability to produce antibiotics. Here we report the results of a comparative analysis of genome-scale metabolic models of 37 species of actinomycetes. Based on in silico knockouts we generated topological and genomic maps for each organism. Combining the collection of genome-wide models, we constructed a global enzyme association network to identify both a conserved "core network" and an "essential core network" of the entire group. As has been reported for low-degree metabolites in several organisms, low-degree enzymes (in linear pathways) turn out to be generally more essential than high-degree enzymes (in metabolic hubs). PMID- 21712034 TI - A rare cause of pneumoperitoneum. PMID- 21712035 TI - Unusual cause of upper gastrointestinal bleeding. PMID- 21712036 TI - Unexplained anemia and neutropenia. PMID- 21712037 TI - An unusual case of peritonitis in an intravenous drug user. PMID- 21712038 TI - A palpable mass and diarrhea. PMID- 21712039 TI - Proximity to a high traffic road: glucocorticoid and life history consequences for nestling white-crowned sparrows. AB - Roads have been associated with decreased reproductive success and biodiversity in avian communities and increased physiological stress in adult birds. Alternatively, roads may also increase food availability and reduce predator pressure. Previous studies have focused on adult birds, but nestlings may also be susceptible to the detrimental impacts of roads. We examined the effects of proximity to a road on nestling glucocorticoid activity and growth in the mountain white-crowned sparrow (Zonotrichia leucophrys oriantha). Additionally, we examined several possible indirect factors that may influence nestling corticosterone (CORT) activity secretion in relation to roads. These indirect effects include parental CORT activity, nest-site characteristics, and parental provisioning. And finally, we assessed possible fitness consequences of roads through measures of fledging success. Nestlings near roads had increased CORT activity, elevated at both baseline and stress-induced levels. Surprisingly, these nestlings were also bigger. Generally, greater corticosterone activity is associated with reduced growth. However, the hypothalamic-pituitary-adrenal axis matures through the nestling period (as nestlings get larger, HPA-activation is greater). Although much of the variance in CORT responses was explained by body size, nestling CORT responses were higher close to roads after controlling for developmental differences. Indirect effects of roads may be mediated through paternal care. Nestling CORT responses were correlated with paternal CORT responses and paternal provisioning increased near roads. Hence, nestlings near roads may be larger due to increased paternal attentiveness. And finally, nest predation was higher for nests close to the road. Roads have apparent costs for white-crowned sparrow nestlings--increased predation, and apparent benefits- increased size. The elevation in CORT activity seems to reflect both increased size (benefit) and elevation due to road proximity (cost). Whether or not roads are good or bad for nestlings remains equivocal. However, it is clear that roads affect nestlings; how or if these effects influence adult survival or reproduction remains to be elucidated. PMID- 21712040 TI - Species specificity in the magnitude and duration of the acute stress response in Mediterranean marine fish in culture. AB - The aim of the present study was to examine the species-specific stress response for seven Mediterranean fishes in culture. Also, to evaluate the method of measuring free cortisol concentration in the rearing water as a non-invasive and reliable indicator of stress in marine species, of aquaculture importance. Gilthead sea bream, Sparus aurata (Sparidae); common dentex, Dentex dentex (Sparidae); common Pandora, Pagellus erythrinus (Sparidae); sharpsnout sea bream, Diplodus puntazzo (Sparidae); dusky grouper, Epinephelus marginatus (Serranidae); meagre, Argyrosomus regius (Sciaenidae) and European sea bass, Dicentrarchus labrax (Moronidae) were subjected to identical acute stress (5-6 min chasing and 1-1.5 min air exposure) under the same environmental conditions and samples were analyzed by the same procedures. Results indicated that there was a clear species specificity in the magnitude, timing and duration of the stress response in terms of cortisol, glucose and lactate. European sea bass showed a very high response and dusky grouper and meagre a very low response, except plasma glucose concentrations of dusky grouper which was constantly high, while sharpsnout sea bream presented a protracted stress response, up to 8h. The present study confirmed that free cortisol release rate into the water can be used as a reliable stress indicator. PMID- 21712041 TI - Different doses of estradiol benzoate induce conditioned place preference after paced mating. AB - The ovarian hormones estrogen and progesterone are required for the complete display of sexual behavior in female rats. Paced mating produces a reward state in intact cycling and ovariectomized (OVX), hormonally primed females as evaluated by the conditioned place preference (CPP) paradigm. Most of the studies that have evaluated CPP induced by paced mating in OVX females have used relatively high doses of estradiol benzoate (EB). In the present study we determined if different doses of EB, combined with progesterone (P), could induce CPP after paced mating. For this purpose OVX female rats were divided in five groups that received one of different doses of estradiol benzoate (5, 2.5, 1.25 or 0.625 MUg estradiol+0.5mg of progesterone) before being allowed to pace the sexual interaction and conditioned in a CPP paradigm. We found that the lowest dose of EB used (0.625 MUg) significantly reduced the lordosis quotient and the lordosis coefficient. Even though these females paced the sexual interaction, they didn't change its original preference, suggesting that sexual interaction did not induce a positive affective, reward state. Females allowed to pace the sexual interaction with higher doses of EB developed CPP after paced mating. These results indicate that a threshold of estradiol is required for paced mating to induce CPP. PMID- 21712042 TI - Rapid colonisation of Lymnaea stagnalis by larval trematodes in eutrophic ponds in central Europe. AB - High recruitment rates of multiple species and hierarchical competition are the keys to a competitive exclusion model of community assembly in larval trematode communities in molluscs. Eutrophic environments provide conditions for accelerating trematode transmission and this would increase the strength of interspecific interactions. To test these predictions, we provide the first known assessment for a pulmonate snail host, and for highly productive aquatic environments, of the rates of colonisation and extinction at the level of individual snail host patches, of a large guild of trematode species. Using a uniquely large dataset from a relatively long-term mark-recapture study of Lymnaea stagnalis in six eutrophic fishponds in central Europe, we demonstrate extraordinarily rapid colonisation by trematodes of a snail host, thus meeting the assumptions of the competitive exclusion model. Overall annual colonisation rates ranged from 243% to 503% year(-1) so that the odds of trematode establishment in an individual snail in these ponds are two to five times per year. Extinction rates were substantially lower than colonisation rates and, therefore, would not result in turnover rates high enough to significantly affect prevalence patterns in the snail populations. At the species level, analyses of sample-based estimates of probabilities of colonisation revealed that shared species traits associated with transmission and competitive abilities determined the limits of colonisation abilities. Colonisation rates were exceedingly high for the species transmitted to the snails passively via eggs. There was a significant effect of species competitive abilities on colonisation rates due to subordinate species being substantially better colonisers than both strong and weak dominants, a pattern consistent with the predictions of the competition colonisation trade-off hypothesis. Our results suggest that, with the extraordinarily high trematode colonisation potential in the area studied, the spatial and temporal patterns of intraspecific heterogeneity in recruitment may provide conditions for intensification of interspecific interactions so that complex community assembly rules may be involved. PMID- 21712043 TI - Gene expression evidence for off-target effects caused by RNA interference mediated gene silencing of Ubiquitin-63E in the cattle tick Rhipicephalus microplus. AB - Knowledge of cattle tick (Rhipicephalus (Boophilus) microplus; Acari: Ixodidae) molecular and cellular pathways has been hampered by the lack of an annotated genome. In addition, most of the tick expressed sequence tags (ESTs) available to date consist of ~50% unassigned sequences without predicted functions. The most common approach to address this has been the application of RNA interference (RNAi) methods to investigate genes and their pathways. This approach has been widely adopted in tick research despite minimal knowledge of the tick RNAi pathway and double-stranded RNA (dsRNA) uptake mechanisms. A strong knockdown phenotype of adult female ticks had previously been observed using a 594 bp dsRNA targeting the cattle tick homologue for the Drosophila Ubiquitin-63E gene leading to nil or deformed eggs. A NimbleGen cattle tick custom microarray based on the BmiGI.V2 database of R. microplus ESTs was used to evaluate the expression of mRNAs harvested from ticks treated with the tick Ubiquitin-63E 594 bp dsRNA compared with controls. A total of 144 ESTs including TC6372 (Ubiquitin-63E) were down-regulated with 136 ESTs up-regulated following treatment. The results obtained substantiated the knockdown phenotype with ESTs identified as being associated with ubiquitin proteolysis as well as oogenesis, embryogenesis, fatty acid synthesis and stress responses. A bioinformatics analysis was undertaken to predict off-target effects (OTE) resulting from the in silico dicing of the 594 bp Ubiquitin-63E dsRNA which identified 10 down-regulated ESTs (including TC6372) within the list of differentially expressed probes on the microarrays. Subsequent knockdown experiments utilising 196 and 109 bp dsRNAs, and a cocktail of short hairpin RNAs (shRNA) targeting Ubiquitin-63E, demonstrated similar phenotypes for the dsRNAs but nil effect following shRNA treatment. Quantitative reverse transcriptase PCR analysis confirmed differential expression of TC6372 and selected ESTs. Our study demonstrated the minimisation of predicted OTEs in the shorter dsRNA treatments (~100-200 bp) and the usefulness of microarrays to study knockdown phenotypes. PMID- 21712044 TI - Mesenchymal stromal cells affect cardiomyocyte growth through juxtacrine Notch 1/Jagged-1 signaling and paracrine mechanisms: clues for cardiac regeneration. AB - The possibility to induce myocardial regeneration by the activation of resident cardiac stem cells (CSCs) has raised great interest. However, to propose endogenous CSCs as therapeutic options, a better understanding of the complex mechanisms controlling heart morphogenesis is needed, including the cellular and molecular interactions that cardiomyocyte precursors establish with cells of the stromal compartment. In the present study, we co-cultured immature cardiomyocytes from neonatal mouse hearts with mouse bone marrow-derived mesenchymal stromal cells (MSCs) to investigate whether these cells could influence cardiomyocyte growth in vitro. We found that cardiomyocyte proliferation was enhanced by direct co-culture with MSCs compared with the single cultures. We also showed that the proliferative response of the neonatal cardiomyocytes involved the activation of Notch-1 receptor by its ligand Jagged-1 expressed by the adjacent MSCs. In fact, the cardiomyocytes in contact with MSCs revealed a stronger immunoreactivity for the activated Notch-intracellular domain (Notch-ICD) as compared with those cultured alone and this response was significantly attenuated when MSCs were silenced for Jagged-1. The presence of various cardiotropic cytokines and growth factors in the conditioned medium of MSCs underscored the contribution of paracrine mechanisms to Notch-1 up-regulation by the cardiomyocytes. In conclusions these findings unveil a previously unrecognized function of MSCs in regulating cardiomyocyte proliferation through Notch-1/Jagged-1 pathway and suggest that stromal-myocardial cell juxtacrine and paracrine interactions may contribute to the development of new and more efficient cell-based myocardial repair strategies. PMID- 21712045 TI - Reorganized PKA-AKAP associations in the failing human heart. AB - Here we reveal that the characterization of large-scale re-arrangements of signaling scaffolds induced by heart failure can serve as a novel concept to identify more specific therapeutic targets. In the mammalian heart, the cAMP pathway, with the cAMP-dependent protein kinase (PKA) in a central role, acts directly downstream of adrenergic receptors to mediate cardiac contractility and rhythm. Heart failure, characterized by severe alterations in adrenergic stimulation is, amongst other interventions, often treated with beta-blockers. Contrasting results, however, have shown both beneficial and detrimental effects of decreased cAMP levels in failing hearts. We hypothesize that the origin of this behavior lies in the complex spatiotemporal organization of the regulatory subunit of PKA (PKA-R), which associates tightly with various A-kinase anchoring proteins (AKAPs) to specifically localize PKA's activity. Using chemical proteomics directly applied to human patient and control heart tissue we demonstrate that the association profile of PKA-R with several AKAPs is severely altered in the failing heart, for instance effecting the interaction between PKA and the novel AKAP SPHKAP was 6-fold upregulated upon failing heart conditions. Also a significant increase in captured cGMP-dependent protein kinase (PKG) and phosphodiesterase 2 (PDE2) was observed. The observed altered profiles can already explain many aspects of the aberrant cAMP-response in the failing human heart, validating that this dataset may provide a resource for several novel, more specific, treatment options. This article is part of a Special Issue entitled "Local Signaling in Myocytes". PMID- 21712046 TI - Coronary no reflow. AB - The no-reflow phenomenon has been studied extensively in the basic science laboratory and has entered the clinical arena. No-reflow, which develops largely within the first 2h of reperfusion, is primarily the result of ischemic endothelial cell injury that obstructs the capillary lumen. Additional contributing mechanisms in experimental models include neutrophil accumulation, reactive oxygen species, and the coagulation cascade. Atherosclerotic- and thromboembolism also contribute to no-reflow during percutaneous coronary intervention and clinical myocardial infarction. No-reflow is assessed using tracers, electrocardiography (ST segment resolution), angiography (thrombolysis in myocardial infarction [TIMI] flow grading and myocardial blush grading), Doppler guidewires, myocardial contrast echocardiography, and cardiac magnetic resonance imaging. No-reflow is a poor prognosticator for left ventricular remodeling and function, and acute and long-term clinical events and survival. No reflow benefits from therapies initiated during coronary occlusion or during early reperfusion. Potential therapies include vasodilators, statins, antiplatelet agents, thrombus aspiration, distal protection devices, ischemic preconditioning, remote ischemic preconditioning and postconditioning, pharmacologic preconditioning, and hypothermia. This comprehensive review will cover the underlying mechanisms, methods of assessment, prognostic implications, and potential therapies for the no-reflow phenomenon. This article is part of a Special Issue entitled "Coronary Blood Flow". PMID- 21712047 TI - Increased expression of the coxsackie and adenovirus receptor downregulates alphavbeta3 and alphavbeta5 integrin expression and reduces cell adhesion and migration. AB - AIMS: Coxsackie and adenovirus receptor (CAR) is a tumor suppressor and a primary receptor for adenovirus type 5 (Ad5). Our study aims to examine the influence of forced expression of CAR in rhabdomyosarcoma cells (RD) on expression levels of integrins implicated in Ad5 entry, and the effect of CAR on cell-extracellular matrix adhesion and migration. MAIN METHODS: CAR expressing clones were established from RD cells by stable transfection. Flow cytometry was used to evaluate the expression of CAR and integrins. Adhesion was measured in plates previously coated with vitronectin or fibronectin. Boyden chambers were used to investigate migration. Transfection of cells with siRNA was used to achieve integrin silencing. Ad5-mediated transgene expression was measured by beta-gal staining. KEY FINDINGS: Increased expression of CAR in RD cells reduces the expression of alphavbeta3 and alphavbeta5 integrins. Cells overexpressing CAR exhibit significantly reduced adhesion to vitronectin and fibronectin, and reduced cell migration. Specifically silencing alphavbeta3 integrin in RD cells reduced cell migration indicating that reduced migration could be the consequence of alphavbeta3 integrin downregulation. This study also demonstrates the negative effect of reduced levels of alphavbeta3 and alphavbeta5 integrins on Ad5-mediated transgene expression with Ad5 retargeted to alphav integrins. SIGNIFICANCE: The pharmacological upregulation of CAR aimed to increase Ad5-mediated transgene expression may actually downregulate alphavbeta3 and alphavbeta5 integrins and thus alter Ad5-mediated gene transfer. The mechanism of decreased cell migration, a prerequisite for metastasis and invasion, due to increased CAR expression may be explained by reduced alphavbeta3 integrin expression. PMID- 21712048 TI - Molecular and cellular sex differences at the intersection of stress and arousal. AB - Elucidating the mechanisms underlying sex biases in the prevalence and severity of diseases can advance our understanding of their pathophysiological basis and serve as a guide for developing treatments. A well-established sex difference in psychiatry is the higher incidence of mood and anxiety disorders in females. These disorders share stress as a potential etiological contributor and hyperarousal as a core symptom, suggesting that the distinction between sexes lies at the intersection of stress and arousal systems. This review focuses on the link between the stress axis and the brain norepinephrine arousal system as a key point at which sex differences occur and are translated to differences in the expression of mood disorders. Evidence for a circuit designed to relay emotion related information via the limbic corticotropin-releasing factor (CRF) system to the locus coeruleus (LC)-norepinephrine arousal system is reviewed. This is followed by recent novel findings of sex differences in CRF receptor signaling and trafficking that would result in an enhanced arousal response and a compromised ability to adapt to chronic stress in females. Finally, we discuss the evidence for sex differences in LC dendritic structure that allow for an increased receipt and processing of limbic information in females compared to males. Together these complementary sets of data suggest that in females, the LC arousal system is poised to process more limbic information and to respond to some of this information in an enhanced manner compared to males. The clinical and therapeutic considerations arising from this perspective are discussed. This article is part of a Special Issue entitled 'Anxiety and Depression'. PMID- 21712049 TI - Polymorphisms in TAS2R38 and the taste bud trophic factor, gustin gene co-operate in modulating PROP taste phenotype. AB - The PROP taste phenotype varies greatly among individuals, influencing eating behavior and therefore may play a role in body composition. This variation is associated with polymorphisms in the bitter receptor gene TAS2R38 and the taste bud trophic factor gustin gene. The aim of this study was to examine the relationship between TAS2R38 haplotypes and the gustin gene polymorphism rs2274333 in modulating PROP taste phenotype. PROP phenotype was determined in seventy-six volunteers (29 males, 47 females, age 25+/-3 y) by scaling methods and threshold measurements. TAS2R38 and gustin gene genotyping was performed using PCR techniques. The lowest responsiveness in PROP nontasters is strongly associated with the AVI nontasting TAS2R38 variant and the highest responsiveness in supertasters is strongly associated to allele A and genotype AA of the gustin gene. These data support the hypothesis that the greater sensitivity of supertasters could be mediated by a greater taste-bud density. Polymorphisms in TAS2R38 and gustin gene, together, accounted for up to 60% of the phenotypic variance in PROP bitterness and to 40% in threshold values. These data, suggest that other unidentified factors may be more relevant for detecting low concentrations of PROP. Moreover, the presence of the PAV variant receptor may be important for detecting high concentrations of PROP, whereas the presence of allele A in gustin polymorphism may be relevant for perceiving low concentrations. These data show how the combination of the TAS2R38 and gustin gene genotypes modulate PROP phenotype, providing an additional tool for the evaluation of human eating behavior and nutritional status. PMID- 21712051 TI - On the evolution of group-escape strategies of selfish prey. AB - The phenomenon of group escape cannot be explained by an argument of risk dilution, applied to gregarious behaviour of passive prey whose risk of predation is equally shared by all group members (Hamilton, 1971). Instead, individuals at the tail of an escaping group suffer the bulk of the group's predation risk, and thus have the highest incentive to desert it. Just because of this, desertion, in this case, may serve as a signal of vulnerability for the pursuing predator. Under wide conditions, it is therefore shown that the predator is always expected to prefer the chasing of a deserter, whenever it is observed. Consequently, an individual who finds himself at the tail of the herd must compare the risk of remaining there with that of deserting the herd and thereby becoming a likely target for predation. If the first risk is higher than the latter, the herd disperses; if the latter is higher, the herd cohesively follows the fastest individuals in its lead (we deal also with cases in which only part of the herd disperses). We see, however, that the question which risk is higher depends not only on the terrain, but also on the route of escape that is decided by the fastest members at the lead of the herd, those that are least likely to be caught. Concentrating on herds without family structure, we assume that the route of escape is selfishly chosen by these ad hoc leaders to minimize their own predation risk, regardless of the others' welfare. However, the predation risk of the leader depends very much on the willingness of other herd members to follow him, thus providing a buffer between him and the pursuing predator. Consequently, when choosing an escape route, the leader has also to consider the cohesion of the herd, i.e., the reaction of slower individuals to his choice. Under some plausible conditions, this choice may force the herd to follow, while other conditions may lead to its dispersal. In some cases the leader may choose a route that serves the needs of the entire group, and sometime only those of its more vulnerable members. In other cases the leader may choose a route that sacrifices the weakest members, thereby improving the survival probability of the others. We employ a model of a k+1 players game, a single predator, and k heterogeneous prey individuals. The predator aims to maximize the probability of a successful catch, and each individual aims to minimize his probability of being caught. PMID- 21712050 TI - Social isolation affects partner-directed social behavior and cortisol during pair formation in marmosets, Callithrix geoffroyi. AB - Pair-bonded relationships form during periods of close spatial proximity and high sociosexual contact. Like other monogamous species, marmosets form new social pairs after emigration or ejection from their natal group resulting in periods of social isolation. Thus, pair formation often occurs following a period of social instability and a concomitant elevation in stress physiology. Research is needed to assess the effects that prolonged social isolation has on the behavioral and cortisol response to the formation of a new social pair. We examined the sociosexual behavior and cortisol during the first 90-days of cohabitation in male and female Geoffroy's tufted-ear marmosets (Callithrix geoffroyi) paired either directly from their natal group (Natal-P) or after a prolonged period of social isolation (ISO-P). Social isolation prior to pairing seemed to influence cortisol levels, social contact, and grooming behavior; however, sexual behavior was not affected. Cortisol levels were transiently elevated in all paired marmosets compared to natal-housed marmosets. However, ISO-P marmosets had higher cortisol levels throughout the observed pairing period compared to Natal-P marmoset. This suggests that the social instability of pair formation may lead to a transient increase in hypothalamic-pituitary-adrenal (HPA) axis activity while isolation results in a prolonged HPA axis dysregulation. In addition, female social contact behavior was associated with higher cortisol levels at the onset of pairing; however, this was not observed in males. Thus, isolation-induced social contact with a new social partner may be enhanced by HPA axis activation, or a moderating factor. PMID- 21712052 TI - Breast cancer screening in developing countries. AB - The incidence of breast cancer in developing countries is rapidly on the rise, and cancers are generally detected at advanced stages when a cure is not possible. If advanced cancers could be down-staged by earlier detection, many lives can be saved. However, can a screening program be successfully implemented in these countries? A high level of compliance at every level of a screening program is essential for its success. In the absence of a high level of awareness, compounded by a fatalistic attitude to life, the necessary level compliance may not be achieved. Furthermore, in view of a relatively low incidence, many women will have to be screened to detect a breast cancer; and hence a screening program may not be cost effective. It is not clear which is the best screening test to be employed; although clinical breast examination would seem appropriate, there is currently no randomized evidence that it would lead to mortality reduction. The most reasonable approach to breast cancer control in developing countries would be to provide the minimal level of cancer care that will reduce mortality and suffering, as well as to enlighten the population about the benefits of early detection using innovative approaches. PMID- 21712053 TI - Protein kinase C alpha regulates nuclear pri-microRNA 15a release as part of endothelin signaling. AB - Endothelin-1 induced signaling is characterized by an early induction of a nuclear factor-kappa B p65/mitogen-activated phosphokinase p38 transcription complex via its A-receptor versus a late induction via diacylglycerol, and protein kinase C. A possible interaction between these two pathways and a potential function for protein kinase C in this context has not previously been elucidated. Here we report that in Caki-1 tumor cells, protein kinase C alpha is a part of the transcription complex. With importin alpha4 and alpha5 as chaperones, the transcription complex transmigrates into the nucleus. Protein kinase C alpha blocks the nuclear release of pri-microRNA 15a by direct binding shown by electrophoretic mobility shift assay and Duolink immune histology. The expression levels of miRNA 15a can be further manipulated by transfection of si protein kinase C alpha, or an expression vector containing protein kinase C alpha or miRNA 15. The miRNA 15a regulation by protein kinase C alpha is detectable in different malignant human tumor cell lines (renal cell carcinoma, breast carcinoma, and melanoma). Furthermore, all three cell lines harbor both endothelin receptors (ETAR/ETBR). Specific blockage of each receptor leads to major reduction of miRNA 15a expression due to increased nuclear protein kinase C alpha translocation. We conclude that the nuclear binding of pri-microRNA 15a is a novel function of protein kinase C alpha, which plays an important role in endothelin-1 mediated signaling. Since several endothelin-sensitive, malignant tumor cell lines harbor this regulation, it could indicate a more general role in tumor biology. PMID- 21712054 TI - The biological role of the glycinergic synapse in early zebrafish motility. AB - Glycine mediates fast inhibitory neurotransmission in the spinal cord, brainstem and retina. Loss of synaptic glycinergic transmission in vertebrates leads to a severe locomotion defect characterized by an exaggerated startle response accompanied by transient muscle rigidity in response to sudden acoustic or tactile stimuli. Several molecular components of the glycinergic synapse have been characterized as an outcome of genetic and physiological analyses of synaptogenesis in mammals. Recently, the glycinergic synapse has been studied using a forward genetic approach in zebrafish. This review aims to discuss molecular components of the glycinergic synapse, such as glycine receptor subunits, gephyrin, gephyrin-binding proteins and glycine transporters, as well as recent studies relevant to the genetic analysis of the glycinergic synapse in zebrafish. PMID- 21712056 TI - Bombesin receptor subtype-3 agonists stimulate the growth of lung cancer cells and increase EGF receptor tyrosine phosphorylation. AB - The effects of bombesin receptor subtype-3 (BRS-3) agonists were investigated on lung cancer cells. The BRS-3 agonist (DTyr(6), (Ala(11), Phe(13), Nle(14)) bombesin(6-14) (BA1), but not gastrin releasing peptide (GRP) or neuromedin B (NMB) increased significantly the clonal growth of NCI-H1299 cells stably transfected with BRS-3 (NCI-H1299-BRS-3). Also, BA1 addition to NCI-H727 or NCI H1299-BRS-3 cells caused Tyr(1068) phosphorylation of the epidermal growth factor receptor (EGFR). Similarly, (DTyr(6), R-Apa(11), Phe(13), Nle(14)) bombesin(6-14) (BA2) and (DTyr(6), R-Apa(11), 4-Cl,Phe(13), Nle(14)) bombesin(6-14) (BA3) but not gastrin releasing peptide (GRP) or neuromedin B (NMB) caused EGFR transactivation in NCI-H1299-BRS-3 cells. BA1-induced EGFR or ERK tyrosine phosphorylation was not inhibited by addition of BW2258U89 (BB(2)R antagonist) or PD168368 (BB(1)R antagonist) but was blocked by (DNal-Cys-Tyr-DTrp-Lys-Val-Cys Nal)NH(2) (BRS-3 ant.). The BRS-3 ant. reduced clonal growth of NCI-H1299-BRS-3 cells. BA1, BA2, BA3 and BRS-3 ant. inhibit specific (125)I-BA1 binding to NCI H1299-BRS-3 cells with an IC(50) values of 1.1, 21, 15 and 750nM, respectively. The ability of BRS-3 to regulate EGFR transactivation in NCI-H1299-BRS-3 cells was reduced by AG1478 or gefitinib (EGFR tyrosine kinase inhibitors), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), N-acetylcysteine (anti oxidant), Tiron (superoxide scavenger) and DPI (NADPH oxidase inhibitor). These results demonstrate that BRS-3 agonists may stimulate lung cancer growth as a result of EGFR transactivation and that the transactivation is regulated by BRS-3 in a Src-, reactive oxygen and matrix metalloprotease-dependent manner. PMID- 21712055 TI - Lymphatic drug delivery using engineered liposomes and solid lipid nanoparticles. AB - The lymphatic system plays a crucial role in the immune system's recognition and response to disease, and most solid cancers initially spread from the primary site via the tumor's surrounding lymphatics before hematological dissemination. Hence, the lymphatic system is an important target for developing new vaccines, cancer treatments, and diagnostic agents. Targeting the lymphatic system by subcutaneous, intestinal, and pulmonary routes has been evaluated and subsequently utilized to improve lymphatic penetration and retention of drug molecules, reduce drug-related systemic toxicities, and enhance bioavailability of poorly soluble and unstable drugs. Lymphatic imaging is an essential tool for the detection and staging of cancer. New nano-based technologies offer improved detection and characterization of the nodal diseases, while new delivery devices can better target and confine treatments to tumors within the nodal space while sparing healthy tissues. This manuscript reviews recent advances in the field of lymphatic drug delivery and imaging and focuses specifically on the development of liposomes and solid lipid nanoparticles for lymphatic introduction via the subcutaneous, intestinal, and pulmonary routes. PMID- 21712057 TI - Lymphocyte subset characterization associated with persistent hepatitis C virus infection and subsequent progression of liver fibrosis. AB - This study aims to deepen the understanding of lymphocyte phenotypes related to the course of hepatitis C virus (HCV) infection and progression of liver fibrosis in a cohort of atomic bomb survivors. The study subjects comprise 3 groups: 162 HCV persistently infected, 145 spontaneously cleared, and 3,511 uninfected individuals. We observed increased percentages of peripheral blood T(H)1 and total CD8 T cells and decreased percentages of natural killer (NK) cells in the HCV persistence group compared with the other 2 groups after adjustment for age, gender, and radiation exposure dose. Subsequently, we determined that increased T(H)1 cell percentages in the HCV persistence group were significantly associated with an accelerated time-course reduction in platelet counts-accelerated progression of liver fibrosis-whereas T(C)1 and NK cell percentages were inversely associated with progression. This study suggests that T(H)1 immunity is enhanced by persistent HCV infection and that percentages of peripheral T(H)1, T(C)1, and NK cells may help predict progression of liver fibrosis. PMID- 21712058 TI - Common and well-documented (CWD) alleles of human leukocyte antigen-A, -B, -C, DRB1, and -DQB1 loci for the Chinese Han population do not quite correlate with the ASHI CWD alleles. AB - Human leukocyte antigen (HLA), which is extremely polymorphic, plays an important role in stem cell transplantation. The Chinese Han comprise a large population of approximately 1.3 billion with diverse HLA alleles that need to be characterized. Data from 3,296 independent, unrelated Chinese Han individuals (1,457 recipients and 1,839 donors) were provided by the China Marrow Donor Program (CMDP) for donor-recipient confirmatory typing. Sequence-based typing, sequence-specific oligonucleotide probe (SSOP)/High Definition-SSOP, and sequence-specific primer methods were used to obtain 4-digit alleles. A total of 49, 86, 50, 63, and 24 HLA-A, -B, -C, -DRB1, and -DQB1 alleles were observed. Following American Society for Histocompatibility and Immunogenetics (ASHI) common and well-documented (CWD) criteria, CWD alleles for Chinese Han in our laboratory test and other laboratory reports do not quite correlate with the ASHI CWD alleles: A*11:53, A*02:34, A*02:53N, B*27:24, B*46:02, B*55:12, C*01:06, C*03:17, C*06:06, C*07:66, C*07:67, C*08:22, DRB1*12:10, DQB1*03:13, and DQB1*06:05 are CWD, but are not included in the ASHI CWD list. A series of alleles are well-documented alleles and are listed in the ASHI CWD list. Conversely, A*26:03, B*51:03, C*12:05, C*15:09, C*15:11, C*17:03, DRB1*11:07, DRB1*11:11, DRB1*13:05, DRB1*13:13, DRB1*14:06, DRB1*14:12, DRB1*14:22, DRB1*14:25, and DQB1*06:11 are rare alleles, but are included in the ASHI CWD list. HLA ethnic diversity is the main reason for the differences in HLA alleles worldwide. The ASHI HLA CWD alleles help reduce the workload and expenses in high-resolution donor registries and the HLA allele frequencies provide a basis from which to predict the chances of finding HLA matching donors. Our data will be meaningful for the CMDP, for other worldwide donor registries, and for an updated ASHI CWD allele list. PMID- 21712059 TI - Tolerance to incompatible ABO blood group antigens is not observed following homograft implantation. AB - Failure to develop antibodies to nonself A and B blood group antigens is well described after infant ABO-incompatible heart transplantation and suggests that exposure to incompatible ABO antigens early in life may lead to tolerance rather than immunogenicity. If this finding is also true following ABO-incompatible cryopreserved homograft implantation, then such patients who require transplantation may be able to accept certain ABO-incompatible organs. In this study, we measured anti-A and -B antibody titers (isohemagglutinins) and allosensitization to human leukocyte antigens (HLA) in 21 patients after homograft placement (12 of whom were <1 year of age at initial homograft exposure) in childhood. We also examined homograft explant specimens for endothelial preservation and expression of HLA and A and B blood group antigens. We observed no differences in isohemagglutinins between patients who received ABO incompatible versus ABO-compatible homografts. Allosensitization to HLA was present in 88% of patients (9 of 9 ABO-incompatible recipients and 5 of 7 ABO compatible recipients). In 7 homograft explant specimens (median implant duration 10.1 years), the vasa vasorum endothelium was intact with ABO blood group antigen expression on 3 of 5 non-O homografts. These data suggest that tolerance to incompatible A and B blood group antigens does not occur following placement of ABO-incompatible homografts in childhood. PMID- 21712060 TI - Efficacy of predictive modeling as a scientific criterion in dermal hazard identification for assignment of skin notations. AB - Skin notations (SNs) represent a hazard characterization tool for alerting workers of health hazards associated with dermal contact with chemicals. This study evaluated the efficacy of a predictive model utilized by the National Institute for Occupational Safety and Health to identify dermal hazards based on potential of systemic absorption compared to hazard assignments based on dermal lethal dose 50% or logarithm of octanol-water partition coefficient. A total of 480 chemicals assigned an SN from at least one of seven institutes were selected and partitioned into seven hazard categories by frequency of SN assignment to provide a basis of evaluation for the predictivity of the examined criteria. We find that all three properties serve as a qualitative indicator in support of a dichotomous decision on dermal hazard; the predictive modeling was identified from a multiple regression analysis as the most significant indicator. The model generated estimates that corresponded to anticipated hazard potentials, suggesting a role of the model to further serve as a hazard-ranking tool. The hazard-ranking capability of the model was consistent with the scheme of acute toxicity classification in the Globally Harmonized System of Classification and Labeling of Chemicals. PMID- 21712061 TI - Protective activity of the Uncaria tomentosa extracts on human erythrocytes in oxidative stress induced by 2,4-dichlorophenol (2,4-DCP) and catechol. AB - The purpose of this study was to evaluate the effect of the ethanolic and aqueous extracts of Uncaria tomentosa on human erythrocytes and additionally the assessment of protective effect of these extracts on hemolysis induction, hemoglobin oxidation, and changes in the level of reactive oxygen species (ROS) and lipid peroxidation, which were provoked by selected xenobiotics, i.e. 2,4 dichlorophenol (2,4-DCP) and catechol. All tested extracts, even at a very high concentration of 500 MUg/ml were not toxic to the erythrocytes because they did not cause lipid peroxidation, increase methemoglobin and ROS levels nor provoked hemolysis. The results of this study also revealed protective effect of extracts of U. tomentosa. The extracts studied depleted the extent of hemoglobin oxidation and lipid peroxidation as well as decreased the level of ROS and hemolysis, which was provoked by 2,4-DCP. No protective activity of the extracts against catechol action, which is a precursor of semiquinones in cell was found. A difference in the effect of the extracts studied was observed. Ethanol-based extracts revealed more pronounced ability to inhibit oxidation processes in human erythrocytes. PMID- 21712062 TI - In vitro effects of ethanol and mouthrinse on permeability in an oral buccal mucosal tissue construct. AB - The current study investigated the influence of ethanol and ethanol-containing mouthrinses on model chemical permeability in an in vitro oral buccal mucosal construct (EpiOral, ORL-200, MatTek). Innate ethanol transport and metabolism in the tissue construct was also studied. Caffeine flux in buccal tissue was measured after pre-treatment with < 26.9% ethanol or Listerine((r)) products under conditions modeling a typical mouthwash rinsing. Specifically, a 30s exposure to alcohol products followed by a 10h non-treatment phase and then a second 30s exposure prior to addition of caffeine. At 10min specific intervals, media was collected from the basal part of the tissue insert for HPLC analysis of caffeine. The results demonstrated no increase in caffeine flux due to prior exposure to either ethanol or Listerine((r)), and the flux and permeability constants were derived from the linear phase. No cytotoxicity or histopathological effects were observed in these tissues. We also studied the transepithelial transport and metabolism of ethanol in these tissues. Transport of ethanol was concentration-dependent with rate of diffusion proportional to the concentration gradient across the membrane. The potential metabolism of ethanol in the EpiOral construct was addressed by analyzing the remaining level of ethanol after incubation and de novo accumulation of acetaldehyde or acetic acid in culture media. Incubation for 30min incubation resulted in no change in ethanol level up to 2000mM, the highest concentration tested. No acetaldehyde or acetic acid was detected in culture media. In conclusion, ethanol and ethanol containing mouthrinse treatment modeled after a typical daily mouthrinse pattern had no apparent effect on the permeability of the standard model chemical, caffeine. This exposure also had no effect on the viability of the tissue construct or histopathology, and uptake of ethanol was rapid into the tissue construct. PMID- 21712063 TI - Comparative analysis of the antioxidant and DNA protection capacities of Anadenanthera colubrina, Libidibia ferrea and Pityrocarpa moniliformis fruits. AB - This study aimed to explore the antioxidant and DNA protection abilities of hydroalcoholic extracts from fruits of Anadenanthera colubrina (ACHE), Libidibia ferrea (LFHE) and Pityrocarpa moniliformis (PMHE). These extracts were tested by five antioxidant methods (phosphomolibdenium and reducing power assays; superoxide, hydrogen peroxide and nitric oxide scavenging) and DNA protection capacity. Total phenolic content was measured by Folin-Ciocalteu method. ACHE exhibited the highest phenolic content (578 mg/g GAE), followed by LFHE (460 mg/g GAE) and PMHE (448 mg/g GAE). In phosphomolibdenium assay, ACHE showed 24.81% of activity in relation to ascorbic acid, whereas LFHE and PMHE had 21.08% and 18.05%, respectively. These plants showed high ability to inhibit reactive species tested with IC50 values ranged from 10.66 to 14.37 MUg/mL for superoxide radical; 26.05 to 45.43 MUg/mL for hydrogen peroxide; 178.42 to 182.98 MUg/mL for reducing power; and 199.2 to 283 MUg/mL for nitric oxide. Furthermore, these extracts had capacity to break the DNA damage induced by hydroxyl radicals. The antioxidant activity of these plants is related with their higher phenolic content and show that they may be used as source of bioactive compounds, relevant to the maintenance of oxidative stability of the food matrix, cosmetics and/or pharmaceutical preparations. PMID- 21712064 TI - Comparative antioxidant capacities of quercetin and butylated hydroxyanisole in cholesterol-modified erythrocytes damaged by tert-butylhydroperoxide. AB - Phenolic compounds are potent antioxidants that scavenge reactive oxygen species (ROS), protecting the cells against oxidative damage. Their antioxidant capacities are governed by their structural features and the nature and physical state of the cell membrane. Our study compares the protective effects of butylated hydroxyanisole (BHA) and quercetin against the cellular injury induced by oxidative stress, and the influence of membrane cholesterol contents in their antioxidant capacities, analyzing the structural changes and cellular stability of native and cholesterol-modified erythrocytes exposed to tert butylhydroperoxide in presence of each antioxidant. The data provide clear evidence that BHA affords better protection than quercetin against ROS generation, lipid peroxidation and lipid and GSH losses in oxidized erythrocytes. However, cellular integrity and stability are better protected by quercetin owing to the hemolytic effect of BHA. Both antioxidants suppress the alterations in membrane fluidity with similar efficiency, reducing methemoglobin formation in all oxidized erythrocytes. Membrane cholesterol depletion decreases the protection against the oxidative damage provided by both antioxidants. This lower preservation may be due to low antioxidant contents, a lower antioxidant capacity, or even to an increased oxidative damage in this membrane type as a consequence of environment modifications after cholesterol depletion. PMID- 21712065 TI - Biomarkers and bioaccumulation of clam Ruditapes philippinarum in response to combined cadmium and benzo[alpha]pyrene exposure. AB - Biochemical and molecular biomarkers (the contents of metallothionein (MT), glutathione (GSH), the activities of aryl hydrocarbon hydroxylase (AHH), glutathione S-transferase (GST) and superoxide dismutase (SOD) and the mRNA expressions of GST-pi and Cu, Zn-SOD) were evaluated in clams Ruditapes philippinarum exposed to cadmium (Cd, 15 MUg/L) and benzo[alpha]pyrene (BaP, 0.01 MUg/L) individually and in combination (15 MUg/L Cd+0.01 MUg/L BaP) for 21 days. The accumulation of Cd, BaP and the biomarkers measured in the gills and digestive glands of the clam showed significant increase in combination treatment and it was significantly higher than the Cd or BaP treatment (P>0.05). The contents of MT increased in Cd and Cd+BaP treatment, while AHH activities were increased in Bap and Cd+BaP treatment (P>0.05). GSH levels enhanced in Cd group and declined significantly in Cd+BaP treatment (P>0.05). The activities of GST, SOD, and mRNA expressions of GST-pi, Cu, Zn-SOD increased remarkably in the clams exposed to combined pollutants. In this study, a significant interaction was observed for Cd and BaP accumulation in the clam and the current findings demonstrate the differences in antioxidant response of the biomarkers in clam to single contaminant and the mixtures. PMID- 21712067 TI - Calcium signalling in T-lymphocytes. AB - Calcium signalling is essential for most of the biological T-cell activities, including in Th2 lymphocytes, a T-cell subset that produce interleukin 4, 5 and 13 and which is involved in allergic diseases. T-cell receptor engagement induces the production of inositol trisphosphate that binds to its receptor, releasing intracellular Ca(2+) stores. STIM in the endo (sarco) plasmic reticulum (ER/SR) is a Ca(2+) sensor that perceives the depletion of intracellular Ca(2+) stores, localizes near the cell membrane and allows the activation of ORAI, the main calcium channels at the cell membrane. However, other calcium channels at the membrane of intracellular compartments and at the cell membrane can also contribute to the TCR-driven intracellular Ca(2+) rise. Among them, voltage dependent calcium (Ca(v)1) channels have been reported in several types of T lymphocytes, although how they are gated in these non-excitable cells remains unsolved. We have shown that Cav1 channel expression was selectively up regulated in Th2 lymphocytes. In this review, we will discuss about the diversity of the Ca(2+) channels responsible for Ca(2+) homeostasis in the different cell subsets and the interactions between these molecules, which can account for the variety of the calcium responses depending upon the functions of effector T-cells. PMID- 21712066 TI - Mirtrons: microRNA biogenesis via splicing. AB - A well-defined mechanism governs the maturation of most microRNAs (miRNAs) in animals, via stepwise cleavage of precursor hairpin transcripts by the Drosha and Dicer RNase III enzymes. Recently, several alternative miRNA biogenesis pathways were elucidated, the most prominent of which substitutes Drosha cleavage with splicing. Such short hairpin introns are known as mirtrons, and their study has uncovered related pathways that combine splicing with other ribonucleolytic machinery to yield Dicer substrates for miRNA biogenesis. In this review, we consider the mechanisms of splicing-mediated miRNA biogenesis, computational strategies for mirtron discovery, and the evolutionary implications of the existence of multiple miRNA biogenesis pathways. Altogether, the features of mirtron pathways illustrate unexpected flexibility in combining RNA processing pathways, and highlight how multiple functions can be encoded by individual transcripts. PMID- 21712068 TI - Orthologues of a plant-specific At-4/1 gene in the genus Nicotiana and the structural properties of bacterially expressed 4/1 protein. AB - Arabidopsis thaliana At-4/1 is the protein of unknown function capable of polar localization in plant cells and intercellular trafficking. In this work, we cloned cDNAs and chromosomal genes of At-4/1 orthologues from several Nicotiana species. Similarly to the 4/1 genes of A. thaliana and Oryza sativa, Nicotiana 4/1 genes have eight exons and seven introns but are considerably longer due to their larger introns. The allotetraploid genome of Nicotiana tabacum, which is known to consist of the 'S genome' originated from Nicotiana sylvestris and the 'T genome' derived from Nicotiana tomentosiformis, encodes two 4/1 genes. The T genome-encoded 4/1 gene, but not that of the S genome, contains a SINE-like transposable element in its intron 2. The 4/1 genes of Nicotiana hesperis and Nicotiana benthamiana lack such an element in the intron 2, but possess a related SINE-like sequence in their intron 4. Collectively, the sequence analysis data provide an insight into the organization of 4/1 genes in flowering plants and the patterns of evolution in the genus Nicotiana. The Nicotiana 4/1 proteins and those of other flowering plants show a significant level of sequence similarity. Computer-assisted analysis was further used to compare their predicted secondary structures. Several algorithms confidently predicted the presence of several coiled-coil domains occupying similar positions in different 4/1 proteins. Analysis of circular dichroism spectra carried out for bacterially expressed N. tabacum 4/1 protein (Nt-4/1) and its N- and C-terminally truncated mutants confirmed that the secondary structure of Nt-4/1 is generally alpha-helical. The C-terminal region of Nt-4/1 was found to undergo a partial proteolysis in Escherichia coli cells. Differential scanning calorimetry of Nt-4/1 protein and its mutants revealed three calorimetric domains most probably corresponding to the N-terminal, central, and C-terminal structural domains of the protein. PMID- 21712070 TI - The effect of low-energy laser irradiation on apoptotic factors following experimentally induced transient cerebral ischemia. AB - Apoptosis, or programmed cell death, resulting from cerebral ischemia may be related to decreased levels of anti-apoptotic factors, such as serine/threonine kinase (Akt), phosphorylated Akt (pAkt), pBAD, and Bcl-2, and increased levels of pro-apoptotic factors, such as BAD, caspase 9, and caspase 3 activities. In this study, we investigated the effects of low-energy laser (660 nm) irradiation (LLI) on the levels and activity of various anti- and pro-apoptotic factors following ischemia. Transient cerebral ischemia was induced in Sprague-Dawley rats by unilateral occlusion of the middle cerebral artery for 1 h, followed by reperfusion. LLI was then directed on the cerebrum for varying lengths of duration (1, 5, or 10 min at an energy density of 2.64 J/cm2, 13.2 J/cm2, and 24.6 J/cm2, respectively). The expression levels of Akt, pAkt, BAD, pBAD, Bcl-2, caspase 9, and caspase 3 activities were measured 4 days after injury. The levels of Akt, pAkt, Bcl-2, and pBAD were significantly increased following laser irradiation. In addition, LLI significantly decreased caspase 9 and caspase 3 activities caused by ischemia-reperfusion. LLI may protect the brain by upregulating Akt, pAkt, pBAD, and Bcl-2 expression and downregulating caspase 9 and caspase 3 expression following transient cerebral ischemia. This modality is a promising protective therapeutic intervention after strokes or other ischemic events. PMID- 21712069 TI - Proteinases as molecular adjuvants in allergic airway disease. AB - BACKGROUND: Asthma and related respiratory tract allergic diseases are among the most common chronic diseases of adults and children. Despite their importance, disease course cannot be predicted and treatment remains non-specific and potentially hazardous, with no means for cure. Improved clinical management of asthma will require an improved understanding of the fundamental factors that initiate allergic inflammation, especially T helper type 2 (T(H)2) cell induction. SCOPE OF REVIEW: In this review, we explore the Proteinase Hypothesis of allergic airway disease, considering specifically how organismal proteinases contribute to the expression of allergic disease and potentially important proteinase signaling pathways. MAJOR CONCLUSIONS: Proteinases from diverse sources (bacteria, fungi, plants) may cause occupational asthma by acting as immune adjuvant factors that specifically elicit T(H)2 cell-dependent allergic inflammation. However, more conventional allergic airway diseases (asthma, allergic sinusitis) are more likely to arise from contained fungal or viral infections of the airway in which proteinases are produced and serve as major virulence factors. Proteinases may elicit allergic disease by disrupting numerous cellular proteins, potentially including Toll like receptor (TLR) 4, but critical proteinase-activated signaling pathways remain largely unknown. GENERAL SIGNIFICANCE: Clarification of how proteinases cause allergic disease, specifically confirming an infectious basis for airway proteinase exposure, will likely radically advance how asthma and related respiratory tract disorders are diagnosed and treated. This article is part of a Special Issue entitled Biochemistry of Asthma. PMID- 21712071 TI - Expression of monocyte chemoattractant protein-1 and its induction by tumor necrosis factor receptor 1 in sensory neurons in the ventral rhizotomy model of neuropathic pain. AB - The expression and role of monocyte chemoattractant protein-1 (MCP-1) in the rat dorsal root ganglion (DRG) and spinal cord was evaluated in the lumbar 5 ventral rhizotomy (L5 VR) model of neuropathic pain. MCP-1 protein expression in the L4/L5 DRG neurons following L5 VR peaked after 3 days, and then declined. Immunohistochemistry showed that no MCP-1 immunoreactivity was observed in the spinal cord after L5 VR, while enzyme-linked immunosorbent assay (ELISA) revealed a small but significant increase in MCP-1 protein content. L5 VR resulted in robust and prolonged mechanical allodynia and thermal hyperalgesia. Administration of anti-MCP-1 neutralizing antibody before and at early time points after L5 VR resulted in a significant attenuation of mechanical allodynia and thermal hyperalgesia, while post-treatment had a weaker effect on established neuropathic pain. Extensive colocalization of tumor necrosis factor receptor 1 (TNFR1) and MCP-1 was observed in the L5 DRG following L5 VR, and treatment with TNFR1 antisense oligonucleotide reduced L5 VR-induced MCP-1 expression in L5 DRG neurons and neuropathic pain behaviors. MCP-1/chemokine (C-C motif) receptor 2 signaling has been proposed as a major regulator of macrophage trafficking. In contrast to the effect on pain behaviors, however, intrathecal administration of anti-MCP-1 neutralizing antibody had no effect on the L5 VR-induced increase in ED-1-immunoreactive macrophages in the L5 DRG and the distal stump of the transected L5 ventral root. These data indicate that increased MCP-1 in DRG neurons might participate in the initiation, rather than the maintenance, of neuropathic pain induced by L5 VR. Furthermore, increased MCP-1 in the DRG is induced by TNF-alpha/TNFR1 and has no effect on the infiltration of macrophages into the DRG following L5 VR. PMID- 21712072 TI - Molecular aspects involved in swimming exercise training reducing anhedonia in a rat model of depression. AB - Patients suffering from depression frequently display hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA) resulting in elevated cortisol levels. One main symptom of this condition is anhedonia. There is evidence that exercise training can be used as a rehabilitative intervention in the treatment of depressive disorders. In this scenario, the aim of the present study was to assess the effect of an aerobic exercise training protocol on the depressive-like behavior, anhedonia, induced by repeated dexamethasone administration. The study was carried out on adult male Wistar rats randomly divided into four groups: the "control group" (C), "exercise group" (E), "dexamethasone group" (D) and the "dexamethasone plus exercise group" (DE). The exercise training consisted of swimming (1 h/d, 5 d/wk) for 3 weeks, with an overload of 5% of the rat body weight. Every day rats were injected with either dexamethasone (D/DE) or saline solution (C/E). Proper positive controls, using fluoxetine, were run in parallel. Decreased blood corticosterone levels, reduced adrenal cholesterol synthesis and adrenal weight (HPA disruption), reduced preference for sucrose consumption and increased immobility time (depressive-like behavior), marked hippocampal DNA oxidation, increased IL-10 and total brain-derived neurotrophic factor (BDNF; pro plus mature-forms) and a severe loss of body mass characterized the dexamethasone treated animals. Besides increasing testosterone blood concentrations, the swim training protected depressive rats from the anhedonic state, following the same profile as fluoxetine, and also from the dexamethasone-induced impaired neurochemistry. The data indicate that physical exercise could be a useful tool in preventing and treating depressive disorders. PMID- 21712073 TI - Viral-mediated expression of a constitutively active form of cAMP response element binding protein in the dentate gyrus increases long term synaptic plasticity. AB - The transcription factor cAMP response element binding protein (CREB) is a key player in synaptic plasticity and learning. Phosphorylation of CREB induced by neuronal activity leads to gene transcription, a process thought to contribute to memory formation. We have previously reported that increasing CREB activity in glutamatergic CA1 pyramidal neurons or in dentate gyrus (DG) granule cells is sufficient to enhance hippocampal-dependent memory formation. This enhancement correlates with an increase in CA1 glutamatergic synaptic plasticity. However, the effects of increasing CREB activity on DG glutamatergic plasticity have not been investigated. To address this issue, we boosted CREB-dependent transcription in DG granule cells in vivo via viral mediated expression of a constitutively active form of CREB (CREBCA). Using in vitro extracellular field recordings of infected slices, we observed an increase in long-term potentiation (LTP) while short-term plasticity and basic synaptic transmission remained unaffected. These data demonstrate that boosting CREB activity in DG granule cells is sufficient to enhance LTP and suggest that this enhancement participates in the formation of better memories. PMID- 21712074 TI - Orexin neurons in hypothalamic slice cultures are vulnerable to endoplasmic reticulum stress. AB - Narcolepsy results from disruption of orexin neurons in the hypothalamus that play a key role in maintenance of the arousal state. Underlying mechanisms leading to selective loss of orexin neurons remain unknown. On the other hand, endoplasmic reticulum stress, namely, conditions associated with impairment of endoplasmic reticulum functions such as proper folding and sorting of newly synthesized proteins, is implicated in pathogenesis of several types of neurodegenerative disorders. Here we found that application of endoplasmic reticulum stress inducers such as tunicamycin (that prevents protein N glycosylation) and thapsigargin (that inhibits Ca2+-ATPase) to organotypic slice cultures of the hypothalamus caused preferential loss of orexin-immunoreactive neurons, as compared to melanin-concentrating hormone- or calcitonin gene-related peptide-immunoreactive neurons. The decrease in orexin-immunoreactive neurons at early time points (6-24 h) was not accompanied by induction of cell death as indicated by the absence of caspase-3 activation and no significant change in the number of NeuN-positive cells, whereas sustained treatment with tunicamycin for 72 h induced cell death. At 24-h treatment, tunicamycin and thapsigargin did not decrease expression of prepro-orexin mRNA, suggesting that post-transcriptional mechanisms were responsible for depletion of orexin peptides. In addition, inhibition of axonal transport by colchicine and inhibition of proteasomal activity by MG132 significantly prevented the decrease in orexin immunoreactivity by tunicamycin. Comparative examinations of expression of unfolded protein response-related proteins revealed that C/EBP-homologous protein (a transcription factor that promotes induction of apoptosis) as well as phosphorylated form of RNA-dependent protein kinase-like endoplasmic reticulum kinase (a protein kinase that mediates inhibition of protein translation) was expressed more prominently in orexin neurons than in melanin-concentrating hormone neurons, in response to tunicamycin. These results indicate that orexin neurons are particularly sensitive to endoplasmic reticulum stress, which may be relevant to pathogenic events in narcolepsy. PMID- 21712075 TI - RU486 (mifepristone) ameliorates cognitive dysfunction and reverses the down regulation of astrocytic N-myc downstream-regulated gene 2 in streptozotocin induced type-1 diabetic rats. AB - Diabetic cognitive dysfunction (DCD), usually accompanied with chronically elevated glucocorticoids and hippocampal astrocytic alterations, is one of the most serious complications in patients with type-1 diabetes. However, the role for chronically elevated glucocorticoids and hippocampal astrocytic activations in DCD remains to be elucidated, and it is not clear whether astrocytic N-myc downstream-regulated gene 2 (NDRG2, involved in cell differentiation and development) participated in DCD. In the present study, three months after streptozotocin (STZ)-induced type-1 diabetes onset, rats showed cognitive impairments in Morris water maze test as well as elevated corticosterone level. Diabetic rats also presented down-regulation of glial fibrillary acidic protein (GFAP, a key indicator of astrocytic reactivity) and NDRG2 in hippocampus revealed by immunohistochemistry staining, real-time PCR and Western blot. Moreover, the diabetic cognitive impairments were ameliorated by 9-day glucocorticoids receptor (GR) blockade with RU486, and the down-regulation of hippocampal NDRG2 and GFAP in diabetic animals was also attenuated by 9-day GR blockade. These results suggest that glucocorticoids-GR system is crucial for DCD, and that astrocytic reactivity and NDRG2 are involved in these processes. Thus, inhibiting GR activation in the hippocampus may be a novel therapeutic strategy for treating DCD. PMID- 21712076 TI - Identification and characterization of a novel mammalian isoform of the endocytic adaptor ITSN1. AB - Intersectin 1 (ITSN1) is an evolutionarily conserved adaptor protein engaged in clathrin-mediated endocytosis, cell signaling and actin cytoskeleton rearrangements. Two major ITSN1 isoforms were initially described, the ubiquitous short isoform (ITSN1-s) and the long isoform (ITSN1-l) expressed predominantly in neurons. Numerous alternative splicing events for ITSN1 pre-mRNA were later identified. Here we describe a novel isoform ITSN1-22a with an alternative C terminus encoded by exon 22a. This exon is only found in placental mammals. The transcript of ITSN1-22a is detected in a wide range of human and mouse tissues. We show here that two alternative splicing events affect the coding sequence of the ITSN1-22a isoform. Moreover, alternative polyadenylation of these transcripts was demonstrated in human tissues. The protein encoded by the ITSN1-22a transcript possesses two EH domains, a coiled-coil region, an SH3A domain and a specific C-terminal domain (CTD) but lacks four SH3 domains in comparison with ITSN1-s. The level of ITSN1-22a protein varies in different mouse tissues and human cell lines. The highest amounts of this isoform occur in mouse brain, spleen, lung and the human B cell line DG75. ITSN1-22a binds via its CTD to the SH3 domain of the endocytic protein amphiphysin 1 and the SH3A domain of ITSN1. Furthermore association in vivo and codistribution of ITSN1-22a and ITSN1-s were demonstrated suggesting that these isoforms could function in concert. We have revealed differential binding of ITSN1-s and ITSN1-22a to the ubiquitin ligase Cbl. Both isoforms possess the SH3A domain capable of binding to Cbl; however ITSN1-22a in contrast to ITSN1-s did not interact with Cbl in vivo. In vitro binding experiments demonstrated that the CTD of ITSN1-22a negatively regulated its binding to Cbl; at the same time interaction with another partner, dynamin 1 was not affected by the presence of the CTD. These data suggest that intramolecular interaction within ITSN1-22a could specifically regulate its binding to protein partners. Thus, this novel mammalian ITSN1 isoform possesses a significantly altered domain structure and performs specific protein-protein interactions. PMID- 21712077 TI - EST analysis on adipose tissue of rainbow trout Oncorhynchus mykiss and tissue distribution of adiponectin. AB - Although energy metabolism in mammals is critically regulated by adipokines from adipocytes, it is unclear whether this is the case in fish as well. In this study, over 30,000 expressed sequence tags (ESTs) were obtained from adipose tissue in rainbow trout Oncorhynchus mykiss peritoneal cavity and searched for genes possibly related to lipid metabolism. Large numbers of ESTs encoded digestive enzymes and hormones usually found in the pancreas in higher vertebrates, consistent with the fact that pancreatic cells are dispersed in the adipose tissue. Many ESTs encoded apolipoprotein C-I, fatty acid-binding proteins and lymphocyte G0/G1 switch protein 2, which function in lipid transport, fatty acid accumulation and adipocyte differentiation, respectively. None of the ESTs encoded adipokines. We therefore obtained a cDNA encoding adiponectin, an adipokine that regulates oxidation of glucose and lipids in peripheral tissues, using rainbow trout ESTs in the public database. Real-time RT-PCR analyses revealed that its transcript levels were high in muscle and quite low in adipose tissue. These results strongly suggest that adipocytes of rainbow trout and possibly other fish species, unlike those of mammals, are not involved in the production of adipokines. PMID- 21712078 TI - Characterization of a CENP-B homolog in the holocentric Lepidoptera Spodoptera frugiperda. AB - The discovery of an homolog of the human centromeric protein B, CENP-B, in an EST database of the holocentric insect species Spodoptera frugiperda prompted us to further characterize that gene because i) CENP-B has not been described in invertebrates yet ii) it should be a milestone in the molecular characterization of the holocentric centromere of Lepidoptera. Like its human counterpart, the Sf CENP-B protein is related to the transposase of the pogo transposable element (TE) of D. melanogaster. In this paper, we show evidences that the lepidopteran cenpB gene has evolved from domestication of a transposase. Furthermore, the Sf CENP-B nuclear location and its ability to bind to a retrotransposon derived sequence in vivo argue in favor of a functional homology to CENP-B proteins. PMID- 21712079 TI - RNA polymerase III transcription control elements: themes and variations. AB - Eukaryotic genomes are punctuated by a multitude of tiny genetic elements, that share the property of being recognized and transcribed by the RNA polymerase (Pol) III machinery to produce a variety of small, abundant non-protein-coding (nc) RNAs (tRNAs, 5S rRNA, U6 snRNA and many others). The highly selective, efficient and localized action of Pol III at its minute genomic targets is made possible by a handful of cis-acting regulatory elements, located within the transcribed region (where they are bound by the multisubunit assembly factor TFIIIC) and/or upstream of the transcription start site. Most of them participate directly or indirectly in the ultimate recruitment of TFIIIB, a key multiprotein initiation factor able to direct, once assembled, multiple transcription cycles by Pol III. But the peculiar efficiency and selectivity of Pol III transcription also depends on its ability to recognize very simple and precisely positioned termination signals. Studies in the last few years have significantly expanded the set of known Pol III-associated loci in genomes and, concomitantly, have revealed unexpected features of Pol III cis-regulatory elements in terms of variety, function, genomic location and potential contribution to transcriptome complexity. Here we review, in a historical perspective, well established and newly acquired knowledge about Pol III transcription control elements, with the aim of providing a useful reference for future studies of the Pol III system, which we anticipate will be numerous and intriguing for years to come. PMID- 21712080 TI - Novel genes specifically expressed during the development of the male thalli and antheridia in the dioecious liverwort Pellia endiviifolia. AB - In bryophytes (lower plants), sex determination is manifested in the gametophyte generation by the production of egg- and sperm-forming gametangia. We identified four genes specifically expressed in the male thalli of dioecious liverwort Pellia endiviifolia species B using RDA-cDNA method. These are: PenB_TUA1 coding for an alpha-tubulin family protein, PenB_Raba1/11 coding for a Rab family protein, PenB_HMG-box coding for an HMG-box family protein and PenB_MT coding for an unknown transcript that contains an ORF of 295 amino acid residues. The expression of identified genes shows developmental and environmental regulation. PenB_TUA1 and PenB_Raba1/11 are expressed in the male thalli, regardless of whether they develop antheridia. PenB_HMG-box and PenB_MT are exclusively expressed in the male thalli-producing antheridia while growing in the field. Moreover, two genes PenB_TUA1 and PenB_Raba1/11 are encoded only in the male genome of P. endiviifolia sp B. Our studies show for the first time the specific contribution of identified genes in the liverwort male gametophyte development. In higher plants, correct regulation of alpha-tubulin and Rab family genes activity is essential for tip-focused membrane trafficking and growth of the male gametophyte. Thus these genes are critical to the reproductive success of these plants. Plant HMG-box proteins bind DNA and may affect chromatin structure, promoting the assembly of nucleoprotein complexes that control DNA-dependent processes including transcription. Our results show that genes connected with the gametogenesis processes are evolutionarily conserved from the liverworts - the oldest living land plants, to higher plants. PMID- 21712081 TI - Sequence conservation among orthologous vomeronasal type 1 receptor-like (ora) genes does not support the differential tuning hypothesis in Salmonidae. AB - Salmon utilize olfactory cues to guide natal stream homing during spawning migrations. Both inorganic and biogenic chemicals have been proposed as odorants that might be used by salmon during homing. In this study, we used genomic DNA sequence data from nine salmonid species to compare nucleotide identities for orthologous main olfactory receptor (mOR) genes with nucleotide identities for orthologous vomeronasal type 1-like (ora) receptor genes. We found that orthologs for both classes of olfactory receptor genes (mORs and Oras) appear to be highly conserved among species. Our findings do not support the differential tuning hypothesis in Salmonidae, which predicts higher sequence conservation for mORs than ora. We did, however, find convincing evidence for site-specific positive selection acting on paralogous main olfactory receptor genes. PMID- 21712082 TI - Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on steroid concentrations in blood and gonads of chicken embryo. AB - The aim of the present study was to examine the effect of TCDD (2,3,7,8 tetrachlorodibenzo-p-dioxin) injected at the early stage of incubation on hormonal activity of the chicken ovary and testis during the second half of embryogenesis measured by steroid concentrations in blood plasma and gonads. The effect of TCDD on hatchability was also evaluated. In the first experiment TCDD was administrated to chicken eggs on day 7 of embryogenesis (E7) at doses of 0 (control), 2.5, 5 and 10ng/egg dissolved in 50MUl of peanut oil. Blood plasma for estradiol (E2) and testosterone (T) determination was collected from embryos at E14, E18, E20 and at hatching (D1). In the second experiment TCDD at doses of 0 (control), 2.5, 5 and 10ng/egg dissolved in 50MUl of DMSO was injected on E6. Blood plasma and gonads were collected on the day of hatching for progesterone (P4), T and E2 concentrations measured by means of the RIA method. It was found that TCDD injection: (1) increased the level of T and decreased the level of E2 in the plasma of female chicken embryos during the second half of embryogenesis, while on the other hand in male embryos the effect of TCDD was opposite, (2) increased T and E2 concentrations in plasma of newly hatched female chickens with a concomitant decrease of these hormones in the ovary; P4 in the ovary was elevated by TCDD, (3) decreased P4 and T in plasma and testes, whereas increased E2 concentration in the plasma of newly hatched male embryos (E2 concentration in the testes was below the sensitivity of the applied RIA method), and (4) decreased hatchability at all examined doses. The results obtained clearly demonstrate that exposure to TCDD at an early stage of embryogenesis affects steroid production and secretion by chicken gonads. The effect of TCDD depends on (1) the applied dose, (2) the day of embryogenesis, and (3) the sex. It is suggested that dioxins are potent modulators of the process of steroidogenesis in the chicken gonads. Moreover, the data obtained indicate that dioxins exert an effect on embryo development and the hatching process. PMID- 21712083 TI - Mainstream smoke of the waterpipe: does this environmental matrix reveal as significant source of toxic compounds? AB - In recent years the number of waterpipe smokers has increased substantially worldwide. Here we report on the concentrations of tobacco-specific nitrosamines (TSNAs) and polycyclic aromatic hydrocarbons (PAHs) in waterpipe smoke and the analysis of selected biomarkers indicative for the body burden in waterpipe users. We further identify high amounts of unburned humectants (glycerol and propylene glycol) in the waterpipe smoke as main part of the so-called "tar" fraction. These results give cause for serious concern. For standardization we applied a machine smoking protocol. Smoke was collected on glass fiber filters and analyzed for nicotine, water, humectants, TSNAs, and PAHs. In addition, we determined carbon monoxide and found high amounts in the smoke being causative for high levels of carboxyhemoglobin (COHb) in the blood of smokers. In comparison to the reference cigarette 3R4F, the nicotine contents were 10-times higher, but TSNA levels were found lower in waterpipe smoke. This finding explained the low levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol detected in the urine of waterpipe smokers. Finally, the levels of benzo[a]pyrene were three times higher in waterpipe smoke compared to the reference cigarette. Altogether, the data presented in this study point to the health hazards associated with the consumption of waterpipes. PMID- 21712084 TI - Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPARalpha. AB - Perfluorooctanoate, a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist, has the potential to lower testosterone levels as a result of testicular toxicity. To elucidate the mechanism and impact of PPARalpha on this reproductive toxicity, ammonium perfluorooctanoate (APFO) at doses of 0, 1.0 (low) mg/kg/day, or 5.0 (high) mg/kg/day was orally given daily to 129/sv wild type (mPPARalpha), Pparalpha-null and PPARalpha-humanized (hPPARalpha) mice for 6 weeks. Both low- and high-dose APFO significantly reduced plasma testosterone concentrations in mPPARalpha and hPPARalpha mice, respectively. These decreases may, in part, be associated with decreased expression of mitochondrial cytochrome P450 side-chain cleavage enzyme, steroidogenic acute regulatory protein or peripheral benzodiazepine receptor as well as microsomal cytochrome P450(17alpha) involved in the steroidogenesis. Additionally, both doses increased abnormalities in sperm morphology and vacuolated cells in the seminiferous tubules of both mouse lines. In contrast, APFO caused only a marginal effect either on the testosterone synthesis system or sperm and testis morphology in Pparalpha-null mice. These results suggest that APFO may disrupt testosterone biosynthesis by lowering the delivery of cholesterol into the mitochondria and decreasing the conversion of cholesterol to pregnenolone and androstandione in the testis of mPPARalpha and hPPARalpha mice, which may, in part, be related to APFO-induced mitochondrial damage. PMID- 21712085 TI - 2',5'-Dihydroxychalcone-induced glutathione is mediated by oxidative stress and kinase signaling pathways. AB - Hydroxychalcones are naturally occurring compounds that continue to attract considerable interest because of their anti-inflammatory and antiangiogenic properties. They have been reported to inhibit the synthesis of the inducible nitric oxide synthase and to induce the expression of heme oxygenase-1. This study examines the mechanisms by which 2',5'-dihydroxychalcone (2',5'-DHC) induces an increase in cellular glutathione (GSH) levels using a cell line stably expressing a luciferase reporter gene driven by antioxidant-response elements (MCF-7/AREc32). The 2',5'-DHC-induced increase in cellular GSH levels was partially inhibited by the catalytic antioxidant MnTDE-1,3-IP(5+), suggesting that reactive oxygen species (ROS) mediate the antioxidant adaptive response. 2',5'-DHC treatment induced phosphorylation of the c-Jun N-terminal kinase (JNK) pathway, which was also inhibited by MnTDE-1,3-IP(5+). These findings suggest a ROS-dependent activation of the AP-1 transcriptional response. However, whereas 2',5'-DHC triggered the NF-E2-related factor 2 (Nrf2) transcriptional response, cotreatment with MnTDE-1,3-IP(5+) did not decrease 2',5'-DHC-induced Nrf2/ARE activity, showing that this pathway is not dependent on ROS. Moreover, pharmacological inhibitors of mitogen-activated protein kinase (MAPK) pathways showed a role for JNK and p38MAPK in mediating the 2',5'-DHC-induced Nrf2 response. These findings suggest that the 2',5'-DHC-induced increase in GSH levels results from a combination of ROS-dependent and ROS-independent pathways. PMID- 21712087 TI - The role of free radical generation in increasing cerebrovascular permeability. AB - The brain endothelium constitutes a barrier to the passive movement of substances from the blood into the cerebral microenvironment, and disruption of this barrier after a stroke or trauma has potentially fatal consequences. Reactive oxygen species (ROS), which are formed during these cerebrovascular accidents, have a key role in this disruption. ROS are formed constitutively by mitochondria and also by the activation of cell receptors that transduce signals from inflammatory mediators, e.g., activated phospholipase A2 forms arachidonic acid that interacts with cyclooxygenase and lipoxygenase to generate ROS. Endothelial NADPH oxidase, activated by cytokines, also contributes to ROS. There is a surge in ROS following reperfusion after cerebral ischemia and the interaction of the signaling pathways plays a role in this. This review critically evaluates the literature and concludes that the ischemic penumbra is a consequence of the initial edema resulting from the ROS surge after reperfusion. PMID- 21712086 TI - NRF2 deficiency reduces life span of mice administered thoracic irradiation. AB - Subsets of cancer survivors who have been subjected to thoracic irradiation face the prospect of developing pulmonary injury. Radiation-induced pulmonary fibrosis is an insidious injury that presents 6 to 24 months after irradiation and continues to progress over a period of years. TGF-beta and reactive oxygen species contribute significantly to the pathogenesis of this injury. The transcription factor NRF2 controls antioxidant gene expression and therefore regulates the cellular oxidant burden. This work demonstrates an additional paradigm for NRF2: suppression of TGF-beta-mediated signaling, assessed by measuring expression of a surrogate TGF-beta1 target gene (PAI-1) in lung fibroblasts. Thoracic irradiation of Nfe2l2(-/-) mice resulted in rapid expression of PAI-1 and FSP-1 compared to irradiated wild-type mice. Examination of lung tissue 16 weeks after thoracic irradiation of Nfe2l2(-/-) mice revealed the presence of distended alveoli and decreased numbers of alveoli compared to wild-type mice. Suppression of NRF2 expression shortened life span in mice administered 16 Gy to the thorax. Nfe2l2(+/-) and Nfe2l2(-/-) mice exhibited a mean life span of 176 days compared to wild-type mice, which lived an average of 212 days. These novel results identify NRF2 as a susceptibility factor for the development of late tissue injury. PMID- 21712088 TI - Transactivation of epidermal growth factor receptor by enhanced levels of endogenous angiotensin II contributes to the overexpression of Gialpha proteins in vascular smooth muscle cells from SHR. AB - We earlier showed that the increased expression of Gi proteins exhibited by vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) was attributed to the enhanced levels of endogenous endothelin. Since the levels of angiotensin II (Ang II) are also enhanced in VSMC from SHR, the present study was undertaken to examine the role of enhanced levels of endogenous Ang II in the overexpression of Gialpha proteins in VSMC from SHR and to further explore the underlying mechanisms responsible for this increase. The enhanced expression of Gialpha-2 and Gialpha-3 proteins in VSMC from SHR compared to WKY was attenuated by the captopril, losartan and AG1478, inhibitors of angiotensin converting enzyme, AT(1) receptor and epidermal growth factor receptor (EGFR) respectively as well as by the siRNAs of AT1, cSrc and EGFR. The enhanced inhibition of forskolin-stimulated adenylyl cyclase activity by low concentrations of GTPgammaS (receptor-independent functions) and of inhibitory responses of hormones on adenylyl cyclase activity (receptor-dependent functions) in VSMC from SHR was also attenuated by losartan. Furthermore, the enhanced phosphorylation of EGFR in VSMC from SHR was also restored to control levels by captopril, losartan, PP2, a c-Src inhibitor and N-acetyl-L-cysteine (NAC), superoxide anion (O(2)(-)) scavenger, whereas enhanced ERK1/2 phosphorylation was attenuated by captopril and losartan. Furthermore, NAC also restored the enhanced phosphorylation of c Src in SHR to control levels. These results suggest that the enhanced levels of endogenous Ang II in VSMC from SHR, transactivate EGFR, which through MAP kinase signaling, enhance the expression of Gialpha proteins and associated adenylyl cyclase signaling. PMID- 21712089 TI - Immune modulation to prevent antibody-mediated rejection after allogeneic hematopoietic stem cell transplantation. AB - It has been shown that antibodies to donor CD34+/VEGFR-2+ stem cells or antibodies against mismatched HLA are associated with graft rejection after hematopoietic stem cell transplantation (HSCT). CD34/VEGFR-2 positive stem cells have been implicated to play a major role in engraftment after HSCT. In this study we treated four patients with an imminent risk of antibody-mediated rejection with immune modulation, i.e. plasma exchange, intravenous immunoglobulin (IVIG), and rituximab before HSCT. Three of the patients had been previously transplanted and rejected their initial grafts after 12 months, 1 month, and less than 1 month, respectively. The fourth patient was not transplanted previously but had HLA directed antibodies present against the graft. During the immune modulatory treatment we followed the pattern of antibodies in sera using FACS and microcytotoxicity assay. We could show that two patients had antibodies against donor CD34+/VEGFR-2+ cells while the other two had antibodies directed against HLA. All four patients tolerated the immune modulatory regimen without any side effects. In this preliminary study we show that immune modulatory treatment may be used to reduce antibody levels and to prevent rejection after HSCT. In two of the three patients which experienced previous rejections and had detectable anti-HLA or anti-CD34+/VEGFR-2+ antibodies, immune modulation resulted in engraftment. In the fourth patient with known anti-HLA-class I antibodies, the treatment also resulted in engraftment. Our results encourage further studies regarding this treatment regimen. PMID- 21712090 TI - Clinical applications of non-antibacterial tetracyclines. Part II. PMID- 21712091 TI - A general method of protein purification for recombinant unstructured non-acidic proteins. AB - Typical late embryogenesis abundant (LEA) proteins accumulate in response to water deficit imposed by the environment or by plant developmental programs. Because of their physicochemical properties, they can be considered as hydrophilins and as a paradigm of intrinsically unstructured proteins (IUPs) in plants. To study their biophysical and biochemical characteristics large quantities of highly purified protein are required. In this work, we report a fast and simple purification method for non-acidic recombinant LEA proteins that does not need the addition of tags and that preserves their in vitro protective activity. The method is based on the enrichment of the protein of interest by boiling the bacterial protein extract, followed by a differential precipitation with trichloroacetic acid (TCA). Using this procedure we have obtained highly pure recombinant LEA proteins of groups 1, 3, and 4 and one recombinant bacterial hydrophilin. This protocol will facilitate the purification of this type of IUPs, and could be particularly useful in proteomic projects/analyses. PMID- 21712092 TI - A simple approach for human recombinant apolipoprotein E4 expression and purification. AB - We report a simple expression and purification procedure for the production of recombinant apolipoprotein E4 (apoE4), an important protein for the lipid homeostasis in humans that plays critical roles in the pathogenesis of cardiovascular and neurodegenerative diseases. Our approach is based on the expression of a thioredoxin-apoE4 fusion construct in bacterial cells and subsequent removal of the fused thioredoxin using the highly specific 3C protease, avoiding costly and laborious lipidation-delipidation steps used before. Our approach results in rapid, high-yield production of structurally and functionally competent apoE4 as evidenced by secondary structure measurements, thermal and chemical melting profiles and the kinetic profile of solubilization of dimyristoyl-phosphatidylcholine (DMPC) vesicles. This protocol is appropriate for laboratories with little experience in apolipoprotein biochemistry and will facilitate future studies on the role of apoE4 in the pathogenesis of cardiovascular disease and neurodegenerative diseases, including Alzheimer's disease. PMID- 21712093 TI - Insight on cellular and humoral components of innate immunity in Squilla mantis (Crustacea, Stomatopoda). AB - For deeper insights into the function of crustacean haemocytes in immune responses, we studied the morphology and enzyme content of circulating cells of the mantis shrimp Squilla mantis from the North Adriatic Sea, together with their ability to phagocytose foreign cells. We also assayed the enzyme content and the agglutinating and haemolytic activities of cell-free haemolymph. Three haemocyte types, i.e., hyalinocytes, semigranulocytes and granulocytes, can be distinguished, according to cell and nuclear morphology and the presence of cytoplasmic granules. All of them share the same patterns of enzyme activities and are recognised by the same lectins. Spreading cells (hyalinocytes and semigranulocytes) can ingest foreign cells; granules of semigranular and granular cells have similar cytochemical properties. Injection of Micrococcus luteus into the heart sinus results in an increase in the frequency of hyaline cells and a decrease in the frequency of granulocytes. After 24 h from the injection, a decrease in the number of phagocytosing hyalinocytes, and a general decrease in the frequency of acid phosphatase-positive cells was reported. Our data match previous results and suggest the existence of a single differentiation pathway for Squilla haemocytes with the three haemocyte morphs as different stages of cell differentiation. Results also indicate that Squilla haemolymph performs immunosurveillance, through rapid changes in haemocyte distribution, increase of antimicrobial and antioxidant enzymes and secretion of lectins stimulating agglutination, phagocytosis and encapsulation. PMID- 21712094 TI - Selection for improved resistance to Aeromonas hydrophila in Indian major carp Labeo rohita: survival and innate immune responses in first generation of resistant and susceptible lines. AB - Selection for disease resistance in fish may be performed directly on basis of survival data obtained in controlled challenge trials, or indirectly using information from immunological or molecular markers linked to differential survival. In the present study, several key innate immune parameters were measured in aeromoniasis resistant and susceptible lines of rohu Labeo rohita to assess their suitability as immune markers for use in indirect selection for increased resistance. Experimental infection with Aeromonas hydrophila (9.55 * 10(6) cfu g(-1) fish) through the intraperitoneal route produced higher survival in the resistant line (73.33%) as compared to the susceptible line (16.67%). Blood and liver tissue samples from both lines were collected to study some of the innate immune parameters and immune-related gene expression. The respiratory burst activity of blood phagocytes, serum myeloperoxidase activity and ceruloplasmin level were significantly (p < 0.05) higher in the resistant line compared to the susceptible line. Lower level of blood glucose and serum natural haemolysin titre were marked in the resistant line as compared to the susceptible line. No significant difference was measured in total serum protein concentration, antiprotease activity and bacterial agglutinin level between two lines, while the expression of transferrin, complement factor C3 and TLR 22-like transcripts were significantly (P < 0.05) higher in liver samples of the susceptible line. However, no such difference was found in beta(2)-microglobulin and lysozyme gene expression between lines. The study demonstrated the possibility of using some of the investigated innate immune parameters as indirect marker traits for selection for improved resistance to aeromoniasis in rohu. PMID- 21712095 TI - Use of suppressive subtractive hybridization to identify differentially expressed genes in ayu (Plecoglossus altivelis) associated with Listonella anguillarum infection. AB - Suppressive subtractive hybridization (SSH) was employed to identify differentially expressed genes in ayu (Plecoglossus altivelis) associated with Listonella anguillarum infection. 800 random clones were selected from forward and reverse subtractive libraries and 787 were successfully sequenced. After assembling, 105 contigs and 414 singletons were finally obtained, some of which were immune-related genes. A real-time quantitative PCR (RT-qPCR) analysis of the expression patterns of 28 transcripts showed that the false-positive rate was approximately 7.1%. Furthermore, Wap65-2 was overexpressed in Escherichia coli, purified and used for antiserum preparation. Western blot analysis revealed that serum Wap65-2 of ayu significantly increased after bacterial infection, suggesting that it was a positive acute-phase protein (APP). PMID- 21712096 TI - Effect of oxybutynin and imidafenacin on central muscarinic receptor occupancy and cognitive function: a monkey PET study with [(11)C](+)3-MPB. AB - Although antimuscarinic agents are widely used to treat overactive bladder (OAB), they have been shown to induce side effects including dry mouth and cognitive impairment. The present study was aimed to investigate the effects of antimuscarinic agents, oxybutynin and imidafenacin, on temporal changes in cognitive function and central mAChR occupancy in conscious monkeys (Macaca mulatta). Three conscious monkeys underwent positron emission tomography (PET) scans with a mAChR radioligand N-[(11)C]methyl-3-piperidyl benzilate ([(11)C](+)3 MPB). The scan sequence was pre, and 1, 4, and 24h post oral administration of oxybutynin (0.1-1.0mg/kg) or imidafenacin (0.01-0.1mg/kg). Maximum cognitive impairment was observed 1h post-oxybutynin at oral doses of 0.3 and 1.0mg/kg, in a dose-dependent manner, and oxybutynin produced significant positive correlations between mAChR occupancy and cognitive impairment in the cortices, thalamus, brainstem, and striatum. The most significant correlation was observed in the brainstem, and then cortices. In contrast, imidafenacin did not induce discernible cognitive impairment, despite having obtained some lesser occupancy in cortices and brainstem. We propose that the thresholds of mAChR occupancy to produce cognitive impairment by antimuscarinic agents are ca. 30-40% in cortices and ca. 20-30% in brainstem, and a desirable drug for OAB treatment should not occupy central mAChR above these thresholds. PMID- 21712097 TI - Raw attitudes, wetland cultures, life-cycles: socio-cultural dynamics relating to Opisthorchis viverrini in the Mekong Basin. AB - Opisthorchis viverrini is one of the most common and medically important food borne parasites in the Lower Mekong area of Southeast Asia. As we learn more about its ecology, pathology and epidemiology we see the need to consider more deeply the socio-cultural dynamics with which food-borne species complexes are associated. This paper argues that the Mekong region is characterized by strong livelihoods and life-style associations within wetland ecosystems, which are inseparable from human eating habits ("raw attitudes"). Within the fish-rice economies of the region there are many long-cherished food cultures based on eating raw, semi-cooked and fermented fish dishes, which are known to lead to opisthorchiasis, and potentially cholangiocarcinoma. This paper examines evidence from northeast Thailand showing that dedicated health outreach campaigns do help to reduce prevalence of opisthorchiasis over time. For disease prevention and health education approaches to be most effective, they must be sensitive to culture, livelihood economics, gender, and age. Further integrative, inter disciplinary and international research must incorporate the complex dynamics of parasite ecology, human behavior, socio-economics, and public health awareness. PMID- 21712098 TI - Chiral lipidomics of E-series resolvins: aspirin and the biosynthesis of novel mediators. AB - Control of the inflammatory response is of wide interest given its important role in many diseases. In recent years we identified novel mechanisms and lipid mediators that play an active role in stimulating the resolution of self-limited acute inflammation. These novel pro-resolving mediators include the essential fatty acid-derived lipoxins, resolvins, protectins and maresins. Members of each possess a unique pro-resolving mechanism of action; each limits neutrophilic infiltration, regulates local mediators (chemokines, cytokines) as well as stimulates macrophage-enhanced clearance of apoptotic PMN, cellular debris and microbes. Given this unique mechanism of action, resolvins have already been shown to play pivotal roles in regulating key events in a wide range of experimental inflammatory diseases. These pro-resolving mediators also provide a molecular link between omega-3 essential fatty acids (e.g. EPA, DHA) and the resolution process of inflammation and tissue homeostasis. Here, we review recent evidence obtained using chiral LC-MS-MS-based lipidomics to identify a novel 18S series of resolvins derived from EPA. Resolvin E1 possesses potent actions in vivo and in vitro demonstrated now in many laboratories, and herein we review comparisons in E-series resolvin biosynthesis and action of 18S-resolvin E1 and 18S-resolvin E2. The biosynthesis and formation of both 18S and 18R-series are enhanced with aspirin treatment and involve the utilization of dietary EPA as well as recombinant human 5-lipoxygenase and LTA(4) hydrolase in their stereospecific biosynthesis. Herein we also demonstrate the utility of LC-MS-MS based lipidomics in identifying resolvins, protectins and related products in marine organisms such as Engraulis (Peruvian anchovy). These new findings emphasize the utility of chiral LC-MS-MS lipidomics and the potential for identifying new resolution circuits with chiral LC-MS-MS-based lipidomics and metabolomics. PMID- 21712099 TI - A clonal strain of Trichomonas gallinae is the aetiologic agent of an emerging avian epidemic disease. AB - Trichomonas gallinae is a protozoan parasite that is well characterised as a cause of trichomonosis in columbid and raptor species world-wide. The parasite emerged as a novel infection of British passerines in 2005, leading to epidemic mortality associated with significant declines of breeding populations of greenfinches (Carduelis chloris) and chaffinches (Fringilla coelebs). We characterised the extent of T. gallinae genotypic heterogeneity within the affected wild British avifauna by analysing individual isolates from 17 of the species affected. To do so, we employed improved platform-based multilocus typing tools as well as the hydrogenosomal Fe-hydrogenase gene as a single marker locus for fine-typing. We found no evidence of heterogeneity amongst the parasites infecting British passerines, indicating that a clonal strain of T. gallinae is the causative agent of this emerging infectious disease. PMID- 21712100 TI - Altered TNF-alpha and IFN-gamma levels associated with PD1 but not TNFA polymorphisms in patients with chronic HBV infection. AB - Production of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma, two important cytokines involved in the immune responses to hepatitis B virus (HBV) infection, may be influenced by gene polymorphisms of TNFA and PD1. This study determined the associations of serum TNF-alpha and IFN-gamma levels with TNFA promoter -308 G/A and -238 G/A and PD1 -606 G/A and +8669 G/A polymorphisms in chronic HBV patients and healthy controls. The results showed that TNFA polymorphisms had no association with TNF-alpha and IFN-gamma levels. However, patients with PD1 -606 AA genotype had lower TNF-alpha and IFN-gamma levels. HBV infection in patients with PD1 +8669 GG genotype altered TNF-alpha to higher levels compared with controls. HBV patients with PD1 -606A/+8669A or -606G/+8669A haplotype tended to have significantly lower or higher TNF-alpha and IFN-gamma levels, respectively. Combined with the lower frequency of PD1 +8669 GG genotype in HBV patients and the minor contribution of PD1 -606 G allele to the protective role of PD1 +8669 G allele, it is indicated that PD1 -606 G allele in a haplotype with PD1 +8669 G allele may have strong inhibitory effect on programmed cell death-1 (PD-1) function and thus reduce its negative impact on T-cell activation and function, leading to higher cytokines secretion and exhibiting a protective role, while the minor predisposing role of PD1 -606 AA genotype to chronic HBV infection may be incurred by decreasing the inhibitory effect on PD-1 function. PMID- 21712101 TI - Variation in European harbour seal immune response genes and susceptibility to phocine distemper virus (PDV). AB - Phocine distemper virus (PDV) has caused two mass mortalities of European harbour seals (Phoca vitulina) in recent decades. Levels of mortality varied considerably among European populations in both the 1988 and 2002 epidemics, with higher mortality in continental European populations in comparison to UK populations. High levels of genetic differentiation at neutral makers among seal populations allow for the possibility that there could be potential genetic differences at functional loci that may account for some of the variation in mortality. Recent genome sequencing of carnivore species and development of genomic tools have now made it possible to explore the possible contribution of variation in candidate genes from harbour seals in relation to the differential mortality patterns. We assessed variation in eight genes (CD46, IFNG, IL4, IL8, IL10, RARa, SLAM and TLR2) encoding key proteins involved in host cellular interactions with Morbilliviruses and the relationship of variants to disease status. This work constitutes the first genetic association study for Morbillivirus disease susceptibility in a non-model organism, and for a natural mortality event. We found no variation in harbour seals from across Europe in the protein coding domains of the viral receptors SLAM and CD46, but SNPs were present in SLAM intron 2. SNPs were also present in IL8 p2 and RARa exon 1. There was no significant association of SLAM or RARa polymorphisms with disease status implying no role of these genes in determining resistance to PDV induced mortality, that could be detected with the available samples and the small number of polymorphisms indentified. However there was significant differentiation of allele frequencies among populations. PDV and other morbilliviruses are important models for wildlife epidemiology, host switches and viral evolution. Despite a negative result in this case, full sequencing of pinniped and other 'non-model' carnivore genomes will help in refining understanding the role of host genetics in disease susceptibility for these viruses. PMID- 21712102 TI - Intra-genotypic diversity of archival G4P[8] human rotaviruses from Washington, DC. AB - Group A human rotaviruses (RVs) remain the most frequently detected viral agents associated with acute gastroenteritis in infants and young children. Despite their medical importance, relatively few complete genome sequences have been determined for commonly circulating G/P-type strains (i.e., G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8]). In the current study, we sequenced the genomes of 11 G4P[8] isolates from stool specimens that were collected in Washington, DC during the years of 1974-1991. We found that the VP7-VP4-VP6-VP1-VP2-VP3-NSP1-NSP2-NSP3 NSP4-NSP5/6-encoding genes of all 11 G4P[8] RVs have the genotypes of G4-P[8]-I1 R1-C1-M1-A1-N1-T1-E1-H1. By constructing phylogenetic trees for each gene, extensive intra-genotypic diversity was revealed among the G4P[8] RVs, and new sub-genotype gene alleles were identified. Several of these alleles are nearly identical to those of G3P[8] isolates previously sequenced from this same Washington, DC collection, strongly suggesting that the RVs underwent gene reassortment. On the other hand, we observed that some G4P[8] RVs exhibit completely different allele-based genome constellations, despite being collected during the same epidemic season; there was no evidence of gene reassortment between these strains. This observation extends our previous findings and supports the notion that stable, genetically-distinct clades of human RVs with the same G/P-type can co-circulate in a community. Interestingly, the sub genotype gene alleles found in some of the DC RVs share a close evolutionary relationship with genes of more contemporary human strains. Thus, archival human RVs sequenced in this study might represent evolutionary precursors to modern-day strains. PMID- 21712103 TI - Broad-coverage molecular epidemiology of Orientia tsutsugamushi in Thailand. AB - Orientia tsutsugamushi, an obligate intracellular bacterium closely related to the genus Rickettsia, is the causative agent of scrub typhus, a major cause of febrile illness in rural areas of Asia-Pacific region. Scrub typhus is transmitted by the bite of infected mites of the genus Leptotrombidium. The region of the 56-kDa TSA gene spanning from variable domain I (VDI) to variable domain IV (VDIV) was sequenced and used for genotyping 77 O. tsutsugamushi samples from human patients confirmed with scrub typhus from 2001 to 2003 and 2009 to 2010 in different regions of Thailand. These sequences were also compared to previously published 56-kDa TSA sequences. Only 4 genotypes out of 8 previously reported in Thailand were identified, i.e. Karp, JG-v, TA763 and Kato, respectively. Two strains were not associated with known genotypes but were closely related to Taiwanese strains. The Karp genotype was confirmed as the predominant clade. The JG-v and TA763 genotypes, in contrast to other studies, also were found. The genotype TA716 was not found, except for one strain previously described. PMID- 21712104 TI - Inflammation and cardio-respiratory control. Foreword. PMID- 21712105 TI - alpha-Tricalcium phosphate: synthesis, properties and biomedical applications. AB - Nowadays, alpha-tricalcium phosphate (alpha-TCP, alpha-Ca(3)(PO(4))(2)) is receiving growing attention as a raw material for several injectable hydraulic bone cements, biodegradable bioceramics and composites for bone repair. In the phase equilibrium diagram of the CaO-P(2)O(5) system, three polymorphs corresponding to the composition Ca(3)(PO(4))(2) are recognized: beta-TCP, alpha TCP and alpha'-TCP. alpha-TCP is formed by heating the low-temperature polymorph beta-TCP or by thermal crystallization of amorphous precursors with the proper composition above the transformation temperature. The alpha-TCP phase may be retained at room temperature in a metastable state, and its range of stability is strongly influenced by ionic substitutions. It is as biocompatible as beta-TCP, but more soluble, and hydrolyses rapidly to calcium-deficient hydroxyapatite, which makes alpha-TCP a useful component for preparing self-setting osteotransductive bone cements and biodegradable bioceramics and composites for bone repairing. The literature published on the synthesis and properties of alpha TCP is sometimes contradictory, and therefore this article focuses on reviewing and critically discussing the synthetic methods and physicochemical and biological properties of alpha-TCP-based biomaterials (excluding alpha-TCP-based bone cements). PMID- 21712107 TI - PAUL A. GRAYBURN, MD, on percutaneous mitral repair with the MitraClipTM device: a conversation with the editor. PMID- 21712106 TI - Management of non-ST-segment elevation acute myocardial infarction in patients with chronic kidney disease (from the Korea Acute Myocardial Infarction Registry). AB - The aim of this study was to compare clinical outcomes among early invasive (EI), deferred invasive (DI), and conservative strategies in patients with acute non-ST segment elevation myocardial infarction (NSTEMI) and chronic kidney disease (CKD). High-risk patients with NSTEMI are believed to fare better with an EI strategy, but the optimal treatment for patients with NSTEMI and CKD is not known. In total 5,185 patients with acute NSTEMI were enrolled from the Korea Acute Myocardial Infarction Registry and followed for 1 year. Patients were divided into EI, DI, and conservative treatment groups and classified into 4 stages using references from the National Kidney Foundation. The invasive EI and DI groups were compared to the conservative groups, and the EI and DI groups were compared according to each renal function stage. At 1-year follow-up, mortality rates in the conservative group were significantly higher than in the invasive groups except for the severe CKD group. The benefit of the EI over the DI strategy, although there were no significant differences between the 2 groups, tended to decrease as renal function decreased. In conclusion, in the management of NSTEMI, an invasive strategy decreased mortality compared to a conservative strategy except for severe CKD. In the timing of an invasive strategy, the EI strategy was observed to be superior to the DI strategy in patients with mild CKD; however, this tendency reversed as renal function decreased. When patients with NSTEMI have severe CKD, a conservative or DI strategy with prescription of cardioprotective medications and prevention of further deterioration in renal function should be considered. PMID- 21712108 TI - Dr. Thomas N. James, MD, MACP (1925-2010): in memoriam. PMID- 21712109 TI - Asymmetry in funnel plot. PMID- 21712110 TI - Comment. PMID- 21712112 TI - Editorial comment. PMID- 21712114 TI - Editorial comment. PMID- 21712115 TI - Editorial comment. PMID- 21712117 TI - Editorial comment. PMID- 21712119 TI - Editorial comment. PMID- 21712120 TI - Editorial. PMID- 21712121 TI - Editorial comment. PMID- 21712123 TI - Transvaginal bladder neck closure with posterior urethral flap for devastated urethra. AB - OBJECTIVES: To present a modified transvaginal bladder neck closure (TV BNC) technique using a posterior urethral flap to minimize the potential risk of ureteral injury and fistula formation. Urethral and bladder neck destruction owing to chronic indwelling urethral catheters in female neurogenic patients is a devastating complication. METHODS: A retrospective review was performed of all patients undergoing TV BNC at a single institution during a 3-year period. All patients had had a nonfunctional or destroyed urethra because of a long-term indwelling urethral catheter. In brief, the devastated outlet was closed using the dorsally bivalved urethra as a flap that was rotated cephalad onto the incised anterior bladder wall for closure, thereby rotating the suture line high into the retropubic space. A postoperative cystogram was obtained at 2-3 weeks. RESULTS: A total of 11 consecutive female patients with a devastated outlet underwent TV BNC, as described, with placement of a suprapubic tube. One patient experienced failure at 6 weeks postoperatively. The mean follow-up for the entire cohort was 9.6 months (range 1-36). Serial upper tract imaging at the last follow up visit revealed no new hydroureteronephrosis. CONCLUSIONS: The results of our study have shown that TV BNC with a posterior urethral flap provides satisfactory early results. This technique creates a suture line far removed from the ureteral orifices, minimizing the risk of upper tract injury during closure. Also, the rotation of the posterior urethra onto the anterior bladder wall secures the suture line high into the retropubic space, minimizing the risk of failure and postoperative fistula formation. PMID- 21712124 TI - Editorial comment. PMID- 21712127 TI - Re: Goel et al.: Mechanical suction: an effective and safe method to remove large and tenacious clots from the urinary bladder (Urology 2011;77:494-496). PMID- 21712129 TI - Re: Tanriverdi et al.: Emergent stenting after uncomplicated ureteroscopy: evaluation of 23 patients (Urology 2011;77:305-308). PMID- 21712131 TI - Re: Liu et al.: Association between manganese superoxide dismutase gene polymorphism and risk of prostate cancer: a meta-analysis (Urology 2009;74:884). PMID- 21712132 TI - Re: Gordetsky et al.: (Almost) painless surgery: a historical review of the evolution of intraurethral anesthesia in urology (Urology 2011;77:12-16). PMID- 21712134 TI - Re: Li et al.: XRCC3 T241M Polymorphism and bladder cancer risk: a meta-analysis (Urology 2011;77:e511-e515). PMID- 21712135 TI - Comparison of CTX-M-14- and CTX-M-15-producing Escherichia coli and Klebsiella pneumoniae isolates from patients with bacteremia. AB - OBJECTIVE: Recently, CTX-M-15-producing Enterobacteriaceae has disseminated worldwide. To better understand the success of CTX-M-15-type extended-spectrum beta-lactamase, we compared the CTX-M-15-producing Escherichia coli and Klebsiella pneumoniae isolates with CTX-M-14-producing E. coli and K. pneumoniae isolates that had been more prevalent before the recent increase of CTX-M-15 in Korea. METHODS: Eighty-nine CTX-M-producing E. coli bloodstream infection isolates and 33 K. pneumoniae bloodstream infection isolates were collected in 2008 from nine hospitals in Korea. In vitro susceptibility testing and multilocus sequence typing were performed for all isolates. Phylogenetic groupings and distribution of virulence determinants and addiction systems were examined for only E. coli isolates. RESULTS: Among the 89 CTX-M-producing E. coli isolates, 54 isolates (60.7%) contained bla(CTx-M-15) and bla(CTx-M-14) was identified in 31 isolates (34.8%). Among 33 CTX-M-producing K. pneumoniae isolates, bla(CTx-M-14) and bla(CTx-M-15) were identified in 18 (54.5%) and 15 (45.5%) isolates, respectively. While CTX-M-14- and CTX-M-15-producing E. coli isolates displayed similar antimicrobial resistance rates, CTX-M-15-producing K. pneumoniae isolates showed significantly higher resistance rates of ciprofloxacin and piperacillin tazobactam than CTX-M-14-producing isolates. ST131 and ST405 were the main clones in both CTX-M-14- and CTX-M-15-producing E. coli isolates. Although the frequency of virulence determinants was similar between two E. coli groups, ST131 and ST405 isolates producing CTX-M-15 showed higher frequency of determinants. In addition, CTX-M-15-producing E. coli isolates showed higher prevalence of addiction systems, particularly vagCD. ST405 showed the highest prevalence rates among main E. coli clones. In K. pneumoniae, ST15 and ST11, with high resistance rates, were the main clones of CTX-M-15-producing isolates, but no main clones was found among CTX-M-14-producing isolates because of extreme diversity. CONCLUSIONS: Rapid increase of CTX-M-15-producing E. coli isolates was due to certain clone with high frequency of virulence determinants and addiction systems. High antimicrobial resistance rates of CTX-M-15-producing K. pneumoniae isolates may contribute to their increase. PMID- 21712136 TI - Complications of low-profile dorsal versus volar locking plates in the distal radius: a comparative study. AB - PURPOSE: Dorsal plating of distal radius fractures with traditional 2.5-mm-thick plates is associated with extensor tendon complications. Consequently, volar locking plates have gained widespread acceptance. A new generation of 1.2- to 1.5 mm, low-profile dorsal plates was designed to minimize tendon irritation. This study examines the complication rates of low-profile dorsal plates compared with volar locking plates. METHODS: We identified patients with distal radius fractures treated between September 2002 and June 2006 by low-profile dorsal or volar locking plates. Information pertaining to 7 categories of complications (hardware discomfort and pain, tendon irritation/rupture, failure of reduction, infection, complex regional pain syndrome, stiffness, and neuropathy/hypersensitivity) was collected. Complications were defined as any postoperative plating complications requiring additional surgical intervention, whereas those that only caused patient discomfort were considered secondary problems. RESULTS: We included 100 patients, comprising 104 plating cases (57 dorsal, 47 volar), in this study. Overall length of follow-up was 44 +/- 21 months (range, 12-80 mo). A total of 18 patients (8 dorsal, 10 volar) experienced complications, whereas 47 (25 dorsal, 22 volar) had secondary reports. Three dorsal and 4 volar patients had complete plate removals. Three dorsal and no volar plates had screw removals only. One volar plate (no dorsal plates) had a major tendon rupture (flexor pollicis longus); 3 dorsal and 3 volar plates resulted in tendon irritation complications, and 4 dorsal and 3 volar plates had secondary problems from tendon irritation. None of the above measures approached statistical significance. Volar cases were associated with significantly more neuropathic complications than dorsal cases. CONCLUSIONS: Dorsal low-profile plates are not associated with significantly more tendon irritation or rupture complications. However, volar plating is associated with a higher rate of neuropathic complications. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 21712137 TI - Posttraumatic reconstruction of the hand--a retrospective review of 87 toe-to hand transfers compared with an earlier report. AB - PURPOSE: The purpose of this study was to retrospectively review the results of 87 toe-to-hand transfers performed in 73 procedures, compare them to the report published by the senior author in 1983, and confirm the hypothesis that results of toe-to-hand transfers at our center have improved over time. METHODS: The results of 87 toe-to-hand transfers performed between 1981 and 2001 were reviewed and compared with the results of 54 toe-to-hand transfers performed between 1974 and 1980. The measured parameters were type of reconstruction performed, anticoagulation therapy, vascular patency, frequency of secondary surgery, and strength of thumb reconstructions. RESULTS: In the recent time period, 11% of the procedures had complications with revascularization of the transferred digit, and long-term survival was seen in 98% of the toe-to-hand transfers. This is a significant improvement over earlier results, in which 33% of the cases had some microvascular compromise and the survival of grafts was lower (91%). Pinch strength for thumb reconstructions improved, and the number of secondary surgeries performed dropped, but neither of these parameters reached a significant level. Toes used for reconstruction changed, with an 18% decrease in use of big toe for thumb reconstruction and a similar increase in use of the second toe. For non-thumb digital reconstructions there was a 60% decrease in use of second and third toe combined, whereas use of the second toe alone increased similarly. CONCLUSIONS: This study showed reduction of the incidence of vascular compromise compared to the previous report. Improved strength of thumb reconstructions and reduced need for secondary surgery was also displayed. These findings are likely attributed to refinements in reconstructive procedures and operative techniques. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 21712138 TI - Semmes-weinstein monofilaments: influence of temperature, humidity, and age. AB - PURPOSE: To determine whether the buckling force of Semmes-Weinstein monofilaments is influenced by changes in temperature, humidity, and aging. METHODS: We tested 16 Semmes-Weinstein monofilaments from North Coast Medical, varying in age from new to 12 years old. From each kit, we used the 2.83/0.07 g, 3.61/0.4 g, 4.31/2g, and 4.56/4 g filaments. Four observers tested the filaments under temperature/humidity conditions of 26 degrees C/33%, 26 degrees C/80%, 37 degrees C/33%, and 37 degrees C/80%. RESULTS: Air temperature and humidity both significantly influence buckling force. At 26 degrees C/33% the buckling force varies by an average of 2% from the standard data supplied by the manufacturer, whereas in the other 3 conditions (26 degrees C/80%, 37 degrees C/33%, and 37 degrees C/80%), the buckling force can decrease by as much as 39%. Effect of age was small and not clinically relevant. CONCLUSIONS: The significant changes in buckling force of the Semmes-Weinstein monofilaments in different temperature and humidity conditions might lead to a potential misinterpretation by the examiner regarding the level of peripheral nerve function loss. This could lead to incorrect diagnosis and treatment. CLINICAL RELEVANCE: Examiners should be aware when using Semmes-Weinstein monofilaments that the environmental effects of temperature and humidity can affect the accuracy of measurement. PMID- 21712139 TI - Technique of olecranon bone grafting for surgical fixation of scaphoid fractures. AB - Currently described sources of bone graft, such as iliac crest and distal radius, for supplemental fixation of scaphoid fractures are suboptimal. In our experience, olecranon bone has the advantage of providing a convenient source of corticocancellous block graft that can be harvested within the same sterile operative field used for fixation of the scaphoid fracture, and it also causes less postoperative pain compared to that obtained from iliac crest. Here, we describe our surgical technique for harvest and use of olecranon bone graft for fixation of scaphoid fractures. PMID- 21712142 TI - Arthroscopic resection arthroplasty for treatment of combined carpometacarpal and scaphotrapeziotrapezoid (pantrapezial) arthritis. PMID- 21712143 TI - Abortion restrictions in the U.S. military: voices from women deployed overseas. AB - PURPOSE: U.S. military women and dependents have few options for abortion when facing an unintended pregnancy overseas. Federal law prohibits the use of Department of Defense facilities and funds for abortion except when the woman's life is at risk, and privately funded abortions are permitted at military facilities only if a pregnancy is the result of rape or incest. The purpose of this study was to explore military women's experiences seeking abortion care during overseas deployment. METHODS: We reviewed routine consultation data and user queries from an online service providing information about medication abortion. Information received between September 2005 and December 2009 from U.S. military women and dependents overseas was included. All women gave consent for anonymous use of their data, which were analyzed qualitatively for themes related to experiences seeking abortion. FINDINGS: Data were analyzed for 130 women, including 128 women in the U.S. military and 2 military dependents. Women reported facing numerous challenges accessing abortion overseas, including legal and logistical barriers to care in-country, and real or perceived difficulties accessing abortion elsewhere owing to confidentiality concerns, fear of military reprimand for the pregnancy, and the narrow timeframe for early abortion. With no perceived alternatives, some women considered unsafe methods to terminate the pregnancy themselves. CONCLUSION: U.S. servicewomen overseas lack access to safe abortion services, which may place their health and careers in jeopardy. These women should have the same rights to abortion care as women living in the United States. PMID- 21712144 TI - Perceptions of mental health services among low-income, perinatal African American women. AB - INTRODUCTION: The objective of this qualitative study was to explore perceptions of mental health services as a barrier to service use among low-income, urban, perinatal African-American clients of home visiting programs. METHODS: Inductive thematic analysis procedures were used to analyze data collected from focus groups conducted with clients (n = 38) and staff (n = 26) of two paraprofessional home visiting programs. FINDINGS: Four complementary themes were identified: Perceptions of mental health care providers, concerns about confidentiality, beliefs about the effectiveness of psychotherapy, and perceptions of psychotropic medication. Overall, perceptions of mental health services were largely negative. Many women equated seeing a mental health care provider with being prescribed psychotropic medication, and providers were commonly described as uncaring and emotionally detached. In general, psychotherapy was perceived as ineffective, and many women expressed strong negative views about psychotropic medication. CONCLUSION: Perceptions of mental health services were clearly an impediment to service use in this population of low-income, perinatal African-American women. Findings from this study can inform efforts to overcome barriers to mental health service use and develop effective perinatal mental health interventions. Implications of this work include use of the home visitation setting as a context for delivering knowledge and shaping positive attitudes and behaviors with respect to mental health practices. PMID- 21712145 TI - Synthesis and antimicrobial properties of some new thiazolyl coumarin derivatives. AB - Two novel series of hydrazinyl thiazolyl coumarin derivatives have been synthesized and fully characterized by IR, (1)H NMR, (13)C NMR, elemental analysis and mass spectral data. The structures of some compounds were further confirmed by X-ray crystallography. All of these derivatives, 10a-d and 15a-h, were screened in vitro for antimicrobial activity against various bacteria species including Mycobacterium tuberculosis and Candida albicans. The compounds 10c, 10d and 15e exhibited very good activities against all of the tested microbial strains. PMID- 21712146 TI - Synthesis and evaluation of aliphatic-chain hydroxamates capped with osthole derivatives as histone deacetylase inhibitors. AB - Our previous studies have demonstrated that osthole, a Chinese herbal compound, could be incorporated into the hydroxycinnamide scaffold of LBH-589, a potent HDAC inhibitor, as an effective hydrophobic cap; the resulting compounds showed significant potency against several HDAC isoforms. Here, we presented a series of osthole derivatives fused with the aliphatic-hydroxamate core of suberoylanilide hydroxamic acid (SAHA), a clinically-approved HDAC inhibitor. Several compounds showed potent activity against nuclear HDACs. Further assays against individual HDAC isoforms revealed that some compounds showed not only SAHA-like activity towards HDAC1, -4 and -6, they inhibited HDAC8 by log difference than SAHA and thus exhibited a broader HDAC inhibition spectrum. Among them, compound 6g showed potent antiproliferative effect on several human cancer cell lines. PMID- 21712147 TI - Does combining antiretroviral agents in a single dosage form enhance quality of life of HIV/AIDS patients? A cost-utility study. AB - BACKGROUND: Combining various antiretroviral agents into one single dosage form has been a strategy to reduce pill burden and enhance medication adherence among human immunodeficiency virus /AIDS (HIV/AIDS) patients. OBJECTIVES: This is a cost-utility study from a health care system's perspective comparing coformulated fixed dose (FXD) strategy versus multiple free dose combination (FRC) in antiretroviral therapy. METHOD: The Medical Expenditure Panel Survey (MEPS) was used to identify HIV/AIDS patients with >=2 active antiretroviral medications. Patients on FXD were matched in 1:1 ratio with the FRC group using propensity scores. All medical costs excluding those paid by patients and families were included. Utility was measured using SF-6D scores from the SF-12 questionnaire. Incremental cost-utility ratios (ICURs) were calculated using the mean annual estimates. A cost-effectiveness acceptability curve was determined using a Monte Carlo probabilistic simulation technique. RESULTS: Nine FXD antiretroviral formulations approved by the U.S. Food and Drug Administration by 2005 was included in this study. One hundred seventy HIV/AIDS patients with >=2 antiretroviral agents were identified from the MEPS database, of which 53% (n=92) were on FXD formulation. On matching, 70 patients from FXD had a match from the FRC group. No differences in sociodemographic and health status variables were observed between the matched groups. The mean annual cost was $15,766.15 for FXD patients and $11,875.21 for FRC patients. The mean utility gained by using FXD over FRC was 0.085; however, this difference was not statistically significant. The ICUR for the FXD treatment over FRC treatment was $45,540.49/quality-adjusted life years (QALYs). Probabilistic sensitivity analysis showed FXD to dominate FRC (>50% probability of being cost-effective) above the $40,000 threshold. CONCLUSION: Although the cost-effectiveness of a single-pill strategy was within the acceptable willingness-to-pay threshold, the QALY difference were minimal. Further research is recommended to explore the long-term impact of the strategy. PMID- 21712148 TI - The quality of online antidepressant drug information: an evaluation of English and Finnish language Web sites. AB - BACKGROUND: The Internet is a frequently used source of drug information, including among people with mental disorders. Online drug information may be narrow in scope, incomplete, and contain errors of omission. OBJECTIVE: To evaluate the quality of online antidepressant drug information in English and Finnish. METHODS: Forty Web sites were identified using the search terms antidepressants and masennuslaakkeet in English and Finnish, respectively. Included Web sites (14 English, 8 Finnish) were evaluated for aesthetics, interactivity, content coverage, and content correctness using published criteria. All Web sites were assessed using the Date, Author, References, Type, Sponsor (DARTS) and DISCERN quality assessment tools. RESULTS: English and Finnish Web sites had similar aesthetics, content coverage, and content correctness scores. English Web sites were more interactive than Finnish Web sites (P<.05). Overall, adverse drug reactions were covered on 21 of 22 Web sites; however, drug-alcohol interactions were addressed on only 9 of 22 Web sites, and dose was addressed on only 6 of 22 Web sites. Few (2/22 Web sites) provided incorrect information. The DISCERN score was significantly correlated with content coverage (r=0.670, P<.01), content correctness (r=0.663, P<.01), and the DARTS score (r=0.459, P<.05). CONCLUSIONS: No Web site provided information about all aspects of antidepressant treatment. Nevertheless, few Web sites provided incorrect information. Both English and Finnish Web sites were similar in terms of aesthetics, content coverage, and content correctness. PMID- 21712149 TI - Multiscale analysis of microvascular blood flow: a multiscale entropy study of laser Doppler flowmetry time series. AB - Processes regulating the cardiovascular system (CVS) are numerous. Each possesses several temporal scales. Their interactions lead to interdependences across multiple scales. For the CVS analysis, different multiscale studies have been proposed, mostly performed on heart rate variability signals (HRV) reflecting the central CVS; only few were dedicated to data from the peripheral CVS, such as laser Doppler flowmetry (LDF) signals. Very recently, a study implemented the first computation of multiscale entropy for LDF signals. A nonmonotonic evolution of multiscale entropy with two distinctive scales was reported, leading to a markedly different behavior from the one of HRV. Our goal herein is to confirm these results and to go forward in the investigations on origins of this behavior. For this purpose, 12 LDF signals recorded simultaneously on the two forearms of six healthy subjects are processed. This is performed before and after application of physiological scales-based filters aiming at isolating previously found frequency bands linked to physiological activities. The results obtained with signals recorded simultaneously on two different sites of each subject show a probable central origin for the nonmonotonic behavior. The filtering results lead to the suggestion that origins of the distinctive scales could be dominated by the cardiac activity. PMID- 21712150 TI - Identifying types of physical activity with a single accelerometer: evaluating laboratory-trained algorithms in daily life. AB - Accurate identification of physical activity types has been achieved in laboratory conditions using single-site accelerometers and classification algorithms. This methodology is then applied to free-living subjects to determine activity behavior. This study is aimed at analyzing the reproducibility of the accuracy of laboratory-trained classification algorithms in free-living subjects during daily life. A support vector machine (SVM), a feed-forward neural network (NN), and a decision tree (DT) were trained with data collected by a waist mounted accelerometer during a laboratory trial. The reproducibility of the classification performance was tested on data collected in daily life using a multiple-site accelerometer augmented with an activity diary for 20 healthy subjects (age: 30 +/- 9; BMI: 23.0 +/- 2.6 kg/m(2)). Leave-one-subject-out cross validation of the training data showed accuracies of 95.1 +/- 4.3%, 91.4 +/- 6.7%, and 92.2 +/- 6.6% for the SVM, NN, and DT, respectively. All algorithms showed a significantly decreased accuracy in daily life as compared to the reference truth represented by the IDEEA and diary classifications (75.6 +/- 10.4%, 74.8 +/- 9.7%, and 72.2 +/- 10.3%; p < 0.05). In conclusion, cross validation of training data overestimates the accuracy of the classification algorithms in daily life. PMID- 21712151 TI - Establishing multiscale models for simulating whole limb estimates of electric fields for osseointegrated implants. AB - Although the survival rates of warfighters in recent conflicts are among the highest in military history, those who have sustained proximal limb amputations may present additional rehabilitation challenges. In some of these cases, traditional prosthetic limbs may not provide adequate function for service members returning to an active lifestyle. Osseointegration has emerged as an acknowledged treatment for those with limited residual limb length and those with skin issues associated with a socket together. Using this technology, direct skeletal attachment occurs between a transcutaneous osseointegrated implant (TOI) and the host bone, thereby eliminating the need for a socket. While reports from the first 100 patients with a TOI have been promising, some rehabilitation regimens require 12-18 months of restricted weight bearing to prevent overloading at the bone-implant interface. Electrically induced osseointegration has been proposed as an option for expediting periprosthetic fixation and preliminary studies have demonstrated the feasibility of adapting the TOI into a functional cathode. To assure safe and effective electric fields that are conducive for osseoinduction and osseointegration, we have developed multiscale modeling approaches to simulate the expected electric metrics at the bone-implant interface. We have used computed tomography scans and volume segmentation tools to create anatomically accurate models that clearly distinguish tissue parameters and serve as the basis for finite element analysis. This translational computational biological process has supported biomedical electrode design, implant placement, and experiments to date have demonstrated the clinical feasibility of electrically induced osseointegration. PMID- 21712152 TI - Adventitious sounds identification and extraction using temporal-spectral dominance-based features. AB - Respiratory sound (RS) signals carry significant information about the underlying functioning of the pulmonary system by the presence of adventitious sounds (ASs). Although many studies have addressed the problem of pathological RS classification, only a limited number of scientific works have focused on the analysis of the evolution of symptom-related signal components in joint time frequency (TF) plane. This paper proposes a new signal identification and extraction method for various ASs based on instantaneous frequency (IF) analysis. The presented TF decomposition method produces a noise-resistant high definition TF representation of RS signals as compared to the conventional linear TF analysis methods, yet preserving the low computational complexity as compared to those quadratic TF analysis methods. The discarded phase information in conventional spectrogram has been adopted for the estimation of IF and group delay, and a temporal-spectral dominance spectrogram has subsequently been constructed by investigating the TF spreads of the computed time-corrected IF components. The proposed dominance measure enables the extraction of signal components correspond to ASs from noisy RS signal at high noise level. A new set of TF features has also been proposed to quantify the shapes of the obtained TF contours, and therefore strongly, enhances the identification of multicomponents signals such as polyphonic wheezes. An overall accuracy of 92.4+/-2.9% for the classification of real RS recordings shows the promising performance of the presented method. PMID- 21712153 TI - A time-variant processing approach for the analysis of alpha and gamma MEG oscillations during flicker stimulus generated entrainment. AB - Repetitive flicker stimulation (photic driving) offers the possibility to study the properties and coupling characteristics of stimulation-sensitive neuronal oscillators by means of the MEG/EEG analysis. With flicker frequencies in the region of the individual alpha band frequency, the dynamics of the entrainment process of the alpha oscillation, as well as the dynamics of the accompanying gamma oscillations and the coupling between the oscillations, are investigated by means of an appropriate combination of time-variant analysis methods. The Hilbert and the Gabor transformation reveal time-variant properties (frequency entrainment, phase locking, and n:m synchronization) of the entrainment process in the whole frequency range. Additionally, time-variant partial directed coherence is applied to identify ocular saccadic interferences and to study the directed information transfer between the recording sites of the simultaneously derived MEG/EEG data during the entrainment. The MEG data is the focus of this methodological study as the entrainment effects of the alpha oscillation are stronger in MEG than in the EEG. The occipital brain region (visual cortex) was mainly investigated and the dynamics of the alpha entrainment quantified. It can be shown that at the beginning of this entrainment, a transient, strongly phase locked "40-Hz" gamma oscillation occurs. PMID- 21712154 TI - A novel phase congruency based algorithm for online data reduction in ambulatory EEG systems. AB - Real signals are often corrupted by noise with a power spectrum variable over time. In applications involving these signals, it is expected that dynamically estimating and correcting for this noise would increase the amount of useful information extracted from the signal. One such application is scalp EEG monitoring in epilepsy, where electrical activity generated by cranio-facial muscles obscure the measured brainwaves. This paper presents a data-selection algorithm based on phase congruency to identify interictal spikes from background EEG; together with a novel statistical method that allows a more comprehensive trade-off based quantitative comparison of two algorithms which have been tested at a fixed threshold in the same database. Here, traditional phase congruency has been modified to incorporate a dynamic estimate of muscle activity present in the input scalp EEG signal. The proposed algorithm achieves 50% data reduction whilst detecting more than 80% of interictal spikes. This represents a significant improvement over the state-of-the-art denoising method for phase congruency. PMID- 21712155 TI - Multiscale modeling of intracranial aneurysms: cell signaling, hemodynamics, and remodeling. AB - The genesis, growth, and rupture of intracranial aneurysms (IAs) involve physics at the molecular, cellular, blood vessel, and organ levels that occur over time scales ranging from seconds to years. Comprehensive mathematical modeling of IAs, therefore, requires the description and integration of events across length and time scales that span many orders of magnitude. In this letter, we outline a strategy for mulstiscale modeling of IAs that involves the construction of individual models at each relevant scale and their subsequent combination into an integrative model that captures the overall complexity of IA development. An example of the approach is provided using three models operating at different length and time scales: 1) shear stress induced nitric oxide production; 2) smooth muscle cell apoptosis; and 3) fluid-structure-growth modeling. A computational framework for combining them is presented. We conclude with a discussion of the advantages and challenges of the approach. PMID- 21712156 TI - Adaptive phase extraction: incorporating the Gabor transform in the matching pursuit algorithm. AB - Short-time Fourier transform (STFT), Gabor transform (GT), wavelet transform (WT), and the Wigner-Ville distribution (WVD) are just some examples of time frequency analysis methods which are frequently applied in biomedical signal analysis. However, all of these methods have their individual drawbacks. The STFT, GT, and WT have a time-frequency resolution that is determined by algorithm parameters and the WVD is contaminated by cross terms. In 1993, Mallat and Zhang introduced the matching pursuit (MP) algorithm that decomposes a signal into a sum of atoms and uses a cross-term free pseudo-WVD to generate a data-adaptive power distribution in the time-frequency space. Thus, it solved some of the problems of the GT and WT but lacks phase information that is crucial e.g., for synchronization analysis. We introduce a new time-frequency analysis method that combines the MP with a pseudo-GT. Therefore, the signal is decomposed into a set of Gabor atoms. Afterward, each atom is analyzed with a Gabor analysis, where the time-domain gaussian window of the analysis matches that of the specific atom envelope. A superposition of the single time-frequency planes gives the final result. This is the first time that a complete analysis of the complex time frequency plane can be performed in a fully data-adaptive and frequency-selective manner. We demonstrate the capabilities of our approach on a simulation and on real-life magnetoencephalogram data. PMID- 21712157 TI - Maternal MCG interference cancellation using splined independent component subtraction. AB - Signal distortion is commonly observed when using independent component analysis (ICA) to remove maternal cardiac interference from the fetal magnetocardiogram. This can be seen even in the most conservative case where only the independent components dominated by maternal interference are subtracted from the raw signal, a procedure we refer to as independent component subtraction (ICS). Distortion occurs when the subspaces of the fetal and maternal signals have appreciable overlap. To overcome this problem, we employed splining to remove the fetal signal from the maternal source component. The maternal source components were downsampled and then interpolated to their original sampling rate using a cubic spline. A key aspect of the splining procedure is that the maternal QRS complexes are downsampled much less than the rest of the maternal signal so that they are not distorted, despite their higher bandwidth. The splined maternal source components were projected back onto the magnetic field measurement space and then subtracted from the raw signal. The method was evaluated using data from 24 subjects. We compared the results of conventional, i.e., unsplined, ICS with our method, splined ICS, using matched filtering as a reference. Correlation and subjective assessment of the P-wave and QRS complex were used to assess the performance. Using ICS, we found that the P-wave was adversely affected in 7 of 24 (29%) subjects, all having correlations less than 0.8. Splined ICS showed negligible distortion and improved the signal fidelity to some extent in all subjects. We also demonstrated that maternal T-wave interference could be problematic when the fetal and maternal heartbeats were synchronous. In these instances, splined ICS was more effective than matched filtering. PMID- 21712158 TI - Personalization of cardiac motion and contractility from images using variational data assimilation. AB - Personalization is a key aspect of biophysical models in order to impact clinical practice. In this paper, we propose a personalization method of electromechanical models of the heart from cine-MR images based on the adjoint method. After estimation of electrophysiological parameters, the cardiac motion is estimated based on a proactive electromechanical model. Then cardiac contractilities on two or three regions are estimated by minimizing the discrepancy between measured and simulation motion. Evaluation of the method on three patients with infarcted or dilated myocardium is provided. PMID- 21712159 TI - Quaternion-valued nonlinear adaptive filtering. AB - A class of nonlinear quaternion-valued adaptive filtering algorithms is proposed based on locally analytic nonlinear activation functions. To circumvent the stringent standard analyticity conditions which are prohibitive to the development of nonlinear adaptive quaternion-valued estimation models, we use the fact that stochastic gradient learning algorithms require only local analyticity at the operating point in the estimation space. It is shown that the quaternion valued exponential function is locally analytic, and, since local analyticity extends to polynomials, products, and ratios, we show that a class of transcendental nonlinear functions can serve as activation functions in nonlinear and neural adaptive models. This provides a unifying framework for the derivation of gradient-based learning algorithms in the quaternion domain, and the derived algorithms are shown to have the same generic form as their real- and complex valued counterparts. To make such models second-order optimal for the generality of quaternion signals (both circular and noncircular), we use recent developments in augmented quaternion statistics to introduce widely linear versions of the proposed nonlinear adaptive quaternion valued filters. This allows full exploitation of second-order information in the data, contained both in the covariance and pseudocovariances to cater rigorously for second-order noncircularity (improperness), and the corresponding power mismatch in the signal components. Simulations over a range of circular and noncircular synthetic processes and a real world 3-D noncircular wind signal support the approach. PMID- 21712160 TI - An algorithm for the contextual adaption of SURF octave selection with good matching performance: best octaves. AB - Speeded-Up Robust Features is a feature extraction algorithm designed for real time execution, although this is rarely achievable on low-power hardware such as that in mobile robots. One way to reduce the computation is to discard some of the scale-space octaves, and previous research has simply discarded the higher octaves. This paper shows that this approach is not always the most sensible and presents an algorithm for choosing which octaves to discard based on the properties of the imagery. Results obtained with this best octaves algorithm show that it is able to achieve a significant reduction in computation without compromising matching performance. PMID- 21712161 TI - A novel algorithm for view and illumination invariant image matching. AB - The challenges in local-feature-based image matching are variations of view and illumination. Many methods have been recently proposed to address these problems by using invariant feature detectors and distinctive descriptors. However, the matching performance is still unstable and inaccurate, particularly when large variation in view or illumination occurs. In this paper, we propose a view and illumination invariant image-matching method. We iteratively estimate the relationship of the relative view and illumination of the images, transform the view of one image to the other, and normalize their illumination for accurate matching. Our method does not aim to increase the invariance of the detector but to improve the accuracy, stability, and reliability of the matching results. The performance of matching is significantly improved and is not affected by the changes of view and illumination in a valid range. The proposed method would fail when the initial view and illumination method fails, which gives us a new sight to evaluate the traditional detectors. We propose two novel indicators for detector evaluation, namely, valid angle and valid illumination, which reflect the maximum allowable change in view and illumination, respectively. Extensive experimental results show that our method improves the traditional detector significantly, even in large variations, and the two indicators are much more distinctive. PMID- 21712162 TI - Cross-Domain Semi-Supervised Learning Using Feature Formulation. AB - Semi-Supervised Learning (SSL) traditionally makes use of unlabeled samples by including them into the training set through an automated labeling process. Such a primitive Semi-Supervised Learning (pSSL) approach suffers from a number of disadvantages including false labeling and incapable of utilizing out-of-domain samples. In this paper, we propose a formative Semi-Supervised Learning (fSSL) framework which explores hidden features between labeled and unlabeled samples to achieve semi-supervised learning. fSSL regards that both labeled and unlabeled samples are generated from some hidden concepts with labeling information partially observable for some samples. The key of the fSSL is to recover the hidden concepts, and take them as new features to link labeled and unlabeled samples for semi-supervised learning. Because unlabeled samples are only used to generate new features, but not to be explicitly included in the training set like pSSL does, fSSL overcomes the inherent disadvantages of the traditional pSSL methods, especially for samples not within the same domain as the labeled instances. Experimental results and comparisons demonstrate that fSSL significantly outperforms pSSL-based methods for both within-domain and cross domain semi-supervised learning. PMID- 21712163 TI - Does afferent heterogeneity matter in conveying tactile feedback through peripheral nerve stimulation? AB - One approach to conveying tactile feedback from sensorized neural prostheses is to characterize the neural signals that would normally be produced in an intact limb and reproduce them through electrical stimulation of the residual peripheral nerves. Toward this end, we have developed an integrate-and-fire model that predicts with millisecond accuracy the timing of responses of the mechanoreceptive afferents that innervate the glabrous skin of the hand. Individual afferents produce highly repeatable and stereotyped responses to a given stimulus. However, responses differ considerably across afferents, even across afferents of a given type. In the present study, we wish to assess the extent to which this within-type variability shapes the signal conveyed by the hand to the brain. Specifically, we wish to determine the extent to which a single canonical model can be used to mimic the responses of a population of afferents during a set of activities of daily living. We find that the spiking responses simulated using the canonical model does not match, in their fine temporal structure, those simulated using individually fit models. However, population firing rates simulated using a canonical model match those simulated using individual models. Our results suggest that afferent heterogeneity is important if the read-out of the response of afferent populations is sensitive to the precise temporal structure of the population response. To the extent that precise spike timing (at a resolution of milliseconds) is not essential, a canonical model can be used to simulate the responses of populations of afferents. PMID- 21712164 TI - Small universal spiking neural P systems working in exhaustive mode. AB - Spiking neural P systems are a class of distributed parallel computing devices inspired from the way neurons communicate by means of spikes. In this paper, the problem of looking for small universal computing devices is investigated in the framework of spiking neural P systems. A new approach is introduced to simulate register machines by spiking neural P systems, where only one neuron is used for all instructions of the simulated register machine; in this way, less neurons are used to construct universal spiking neural P systems working in exhaustive mode. Specifically, a universal spiking neural P system with 36 neurons is constructed, which works in exhaustive mode. This significantly improves the already known result, where 125 neurons are used. PMID- 21712165 TI - Low frequency dielectric properties of human blood. AB - Nano- and microparticles in human blood affect drastically the charge transfer CT through the viable fluid. Low-frequency dielectric properties of the blood, characterized by CT of beta - dispersion type, are widely investigated with special stress on physical mechanisms. However, no publication in the literature deals with the presence of alpha - dispersion in human blood. In the present study, a mechanism associated with alpha-, beta-, and gamma- dispersions is presented. The dielectric losses (electrical conduction) phenomenon is also discussed with special emphasis on the distribution of relaxation times. These losses cause problems with low-frequency dielectric measurements, thus, they are correlated with the famous empirical Col-Cole factor, (1-alpha). A Gaussian distribution of relaxation times is suggested and found to be exponentially related with (1-alpha). The results suggest new diagnostic and therapeutic methods for blood disorders. PMID- 21712166 TI - Nerve growth factor-immobilized electrically conducting fibrous scaffolds for potential use in neural engineering applications. AB - Engineered scaffolds simultaneously exhibiting multiple cues are highly desirable for neural tissue regeneration. To this end, we developed a neural tissue engineering scaffold that displays submicrometer-scale features, electrical conductivity, and neurotrophic activity. Specifically, electrospun poly(lactic acid-co-glycolic acid) (PLGA) nanofibers were layered with a nanometer thick coating of electrically conducting polypyrrole (PPy) presenting carboxylic groups. Then, nerve growth factor (NGF) was chemically immobilized onto the surface of the fibers. These NGF-immobilized PPy-coated PLGA (NGF-PPyPLGA) fibers supported PC12 neurite formation ( 28.0+/-3.0% of the cells) and neurite outgrowth (14.2 MUm median length), which were comparable to that observed with NGF (50 ng/mL) in culture medium ( 29.0+/-1.3%, 14.4 MUm). Electrical stimulation of PC12 cells on NGF-immobilized PPyPLGA fiber scaffolds was found to further improve neurite development and neurite length by 18% and 17%, respectively, compared to unstimulated cells on the NGF-immobilized fibers. Hence, submicrometer-scale fibrous scaffolds that incorporate neurotrophic and electroconducting activities may serve as promising neural tissue engineering scaffolds such as nerve guidance conduits. PMID- 21712167 TI - Cheatham-Platinum stent for native and recurrent aortic coarctation in children and adults: immediate and early follow-up results. AB - OBJECTIVE: To present our institutional experience of endovascular Cheatham Platinum stent implantation in children and adults with native and recurrent aortic coarctation. METHODS: Between August 2007 and November 2009, 45 patients had aortic coarctation treated with 47 stents implantation. We preferred primarily stent implantation in adult patient with coarctation, in children more than five years-old it is preferred in cases of aneurysm, subatretic or blind coarctation and coarctation with patent ductus arteriosus or in restenosis. Files of stent-implanted patients were retrospectively analyzed in terms of patients' demographic features, echocardiographic and angiographic findings both before and after procedure. Patients were grouped as Group 1: native coarctation and Group 2: recoarctation developed after either surgery or balloon angioplasty. Findings of the cases' were compared using paired and unpaired Student's t, Mann-Whitney U and Chi-square tests. RESULTS: Sixteen covered and 31 bare totally 47 balloon expandable stents were implanted in 45 patients. The mean follow up duration was 12.1 +/- 7.1, median 11 months (2-29 months). There was no procedure related death. In two patients two stents were implanted in tandem. While the coarctation of the aorta was native in 26 patients (functionally interrupted aortic arch in one), recoarctation was detected in 7 patients after surgery, in 8 patients after balloon angioplasty, in 4 patients both after surgery and balloon angioplasty. One patient had functionally interrupted aortic arch perforated with guide wire and then covered stent implanted. The mean age 12.2 +/- 5.9 years (5-33 years) and mean body mass index was 21 +/- 3.7 kg/m2 (14.8-31 kg/m2). Considering all cases, a statistically significant decrease in both the invasive and echocardiographic gradients (p<0.001 for both) and statistically significant increase in lesion diameter (p<0.001) were detected. The decrease in invasive and echocardiographic gradients and increase in lesion diameter is statistically significant in each group also (p<0.001, <0.001 and <0.001 for both groups, respectively). Before the procedure, the invasive gradient was significantly higher and the lesion diameter was significantly lower in group I than in group II (p=0.002 and p=0.005, respectively). Also the percentage of decrease in gradient and increase in diameter was statistically higher in group 1 than in group 2 (p=0.04 and p=0.04). CONCLUSION: Our early and short- term follow-up results indicate that stent implantation is safe and very effective in reducing coarctation gradient and increasing lesion diameter both in native coarctation and recoarctation. PMID- 21712168 TI - [The efficiency of cutting balloon angioplasty in the treatment of in-stent restenosis]. AB - OBJECTIVE: Although stents reduce the restenosis rate, stent restenosis continues to be a major problem and the optimal treatment of stent restenosis is still controversial. In this study, we aimed to investigate the angiographic recurrent stent restenosis rate at 6-12 months after successful cutting balloon angioplasty (CBA) for the bare metal stent restenosis. METHODS: Thirty patients (mean age: 57.9 +/- 11.6, 22 males) undergoing successful CBA for the treatment of in-stent restenosis at our hospital were prospectively included in this study. Control coronary angiography was performed at 6-12 months after CBA. Lesion length, minimal lumen diameter (MLD), and reference vessel diameter were analyzed by computerized digital angiographic analysis. Recurrent restenosis was defined as the lesions obstructing the lumen more than 50%. We described the lesions shorter than 10 mm as to be focal and those longer than 10 mm as to be diffuse. We used Student t, Chi-square, and Mann-Whitney U tests for statistical analysis. RESULTS: Two patients had two distinct lesions; therefore, 32 lesions were assessed. There were 9 (28.1%) recurrent restenosis on the control coronary angiography. Recurrent restenosis developed in 3/21 (14.3%) of focal type lesions and 6/11(54.5%) of diffuse type lesions (p=0.035). Pre-procedural MLD was lower in the restenotic group compared to non-restenotic group (0.41 +/- 0.29 vs. 0.64 +/- 0.17 mm, p=0.048) while percent of stenosis was higher in the restenotic group (76.8 +/- 12 vs. 69.6 +/- 5.37%, p=0.029). CONCLUSION: In the selected patients, CBA is an effective and a safe method for the treatment of bare metal stent restenosis. CBA might be considered as a first-line treatment method in patients with focal type lesions. PMID- 21712169 TI - Ivabradine, a novel heart rate slower: is it a sword of double blades in patients with idiopathic dilated cardiomyopathy? AB - OBJECTIVE: To prospectively assess the safety and efficacy of ivabradine in patients with idiopathic dilated cardiomyopathy. METHODS: We included 35 patients with idiopathic dilated cardiomyopathy with an ejection fraction (EF) <40% and heart rate >70 beats/min despite optimal medical therapy, according to the international guidelines in this prospective, non-randomized, single-arm, open label safety study. Ivabradine was used as an add-on therapy to the maximally tolerated b-blocker in an increasing titrated dose till a target dose of 15 mg/day or resting heart rate of 60 beats/min for 3 months. During follow-up period the safety, patient tolerance and efficacy of this drug were assessed. All patients underwent 12-lead resting electrocardiography and Holter monitoring at inclusion and after 3 months. Statistical analysis was accomplished using paired t-test and Pearson correlation analysis. RESULTS: We found a significant reduction in the resting heart rate by a mean of 25.9 +/- 9.4%, without a significant change of blood pressure. There was no prolongation of PR, QTc or QRS durations. Ventricular ectopic activity showed significant reduction (p<0.001). There was a significant correlation between the resting heart rate, NYHA and left ventricular ejection fraction (p<0.001 for both). One patient developed photopsia and decompensation was observed in another patient. CONCLUSION: Ivabradine is a safe and effective drug in reducing resting heart rate, improving NYHA functional class without undesirable effects on conduction parameters or ectopic activity. PMID- 21712170 TI - Ischemic stroke history predicts increased cardiovascular mortality in chronic heart failure. AB - OBJECTIVE: To investigate comorbidities that predict cardiac mortality and re hospitalization in chronic heart failure (CHF) patients. METHODS: Five hundred eighty patients (mean age 63 +/- 13 years, 373 male, 207 female, mean ejection fraction (EF) 26 +/- 9%) with mild, moderate or severe CHF [NYHA class II-IV] were included in this prospective observational study. We evaluated all comorbidities such as history of ischemic stroke, coronary artery disease, peripheral arterial disease, chronic obstructive lung disease, hypertension, diabetes mellitus and chronic kidney disease in CHF patients who were hospitalized due to decompensated heart failure in Kocaeli University, Faculty of Medicine's Hospital between January 2003 and July 2009. Cox regression and Kaplan Meier survival analyses were used to establish predictors of unfavorable outcomes. RESULTS: Of 580 patients 207 (36%) patients died due to cardiovascular reasons. In multivariable Cox regression analysis age (HR-1.06, 95% CI 1.04-1.08, p<0.001), NYHA functional class (HR-3.20 95% CI, 1.90-5.41, p<0.001), history of ischemic stroke (HR-2.48, 95% CI 1.14-5.37, p=0.022), high-sensitive C-reactive protein (HR-1.09, 95% CI, 1.04-1.15, p=0.001), brain natriuretic peptide (HR 1.00, 95% CI 1.00-1.00, p=0.01) and hemoglobin (HR-0.90, 95% CI 0.81-0.99, p=0.038) were independent predictors of cardiac death in the present study. History of ischemic stroke was demonstrated as an important comorbidity that predicts cardiovascular mortality beyond other co-morbidities in CHF patients. NYHA functional class (HR-2.85, 95% CI 1.80-4.65, p<0.001), left ventricular EF [(HR-0.98, 95% CI 0.95-0.99, p=0.039) and ischemic stroke history (HR-2.41, 95% CI 1.15-5.05, p=0.019) were independent predictors for recurrence hospitalization. The stroke history was only predictor showing recurrent hospitalization at least in one year among the other comorbid conditions, which were evaluated during study. CONCLUSION: History of ischemic stroke may be an important risk factor for increased cardiac mortality and recurrence hospitalization in CHF patients. PMID- 21712171 TI - [Evaluation of the relationship between serum high sensitive C-reactive protein and the elasticity properties of the aorta in patients with coronary artery ectasia]. AB - OBJECTIVE: Previous studies have shown an association between high sensitive C reactive protein (hsCRP) and arterial stiffness in most cardiovascular diseases. High sensitive C-reactive protein and arterial stiffness have been considered as independent predictors of cardiovascular mortality in cardiovascular disease. The aim of this study was to investigate the relationship between hsCRP, a marker of systemic inflammation and aortic stiffness in patients with coronary artery ectasia (CAE). METHODS: Our study was designed as cross-sectional study. Serum hsCRP levels and aortic stiffness parameters were measured in CAE patients (n=28) and age - and gender-matched control subjects (n=25). Serum hsCRP levels were determined by an immunonephelometry assay. Aortic strain (AS) and aortic distensibility (AD) were calculated from the aortic diameters measured using M mode echocardiography and blood pressure obtained by sphygmomanometry. Independent samples "t" test, Chi-square test and Spearman correlation test were used for statistical analysis. RESULTS: Serum levels of hsCRP in CAE group were higher than in the controls (p<0.001). AS and AD were significantly decreased in CAE patients compared to the controls (p<0.001 and p<0.001, respectively). There were negative correlations between hsCRP and AS (r=-0.862; p<0.001), and AD (r=0.852; p<0.001) and a positive correlation between hsCRP, and ASI (r=0.852; p<0.001). CONCLUSION: We have demonstrated that there is a significant correlation between serum hsCRP levels and aortic stiffness in patients with CAE. These findings may indicate an important role of hsCRP in the pathogenesis of impaired aortic stiffness in coronary ectasia. PMID- 21712172 TI - [Role of plasmapheresis in immunological kidney diseases. Experience from 1050 completed plasmapheresis treatment sessions]. AB - Plasmapheresis is an effective treatment modality in several immunological kidney diseases. It is also indicated in certain neurological and hematological abnormalities, and some other diseases. AIMS: In this study the indications and outcomes of the plasma exchange treatments performed in the Plasmapheresis Unit of the authors during the last 12 years are summarized, and the findings are compared to those published in the literature. The procedure, mechanisms of action and adverse effects are also briefly discussed. METHODS: Between 1999 and 2010 authors completed 1050 plasma exchanges in 195 patients with an average 5.4 (1-20) treatments/person. In the 78 males and 117 females (age 57+/-16 years) the indications were as follows: 47% anti-cytoplasmic antibody-associated vasculitis, 4% anti-glomerular basement membrane disease, 3% rapidly progressing immunocomplex glomerulonephritis, 11% severe complications of systemic lupus erythematosus, 1% treatment resistant focal segmental glomerular sclerosis, 5% hemolytic uremic syndrome, 13% complications of multiple myeloma, 4% HELLP syndrome, 10% neurological diseases, and 2% other abnormalities. RESULTS: Plasmapheresis, completed as part of combined immunosuppressive treatment, resulted in remarkable improvements in patients with anti-cytoplasmic antibody associated vasculitis. Out of the 91 patients, 54 needed urgent dialysis on admission, and renal replacement therapy could be discontinued in 44% of them. Renal functions in those patients who did not need dialysis also improved significantly, and pulmonary hemorrhage ceased in all affected subjects. Survival of the patients with anti-glomerular basement membrane diseases was 100%. The treatment significantly improved the renal function in rapidly progressive lupus nephritis, and all the 5 cases of lupus cerebritis were successfully cured. The results showed less effectiveness in therapy resistant focal segmental glomerular sclerosis and in rapidly progressing immunocomplex glomerulonephritis. Plasmapheresis proved to be very efficient in cases with the primary hemolytic uremic syndrome, and each patient with HELLP syndrome recovered completely. The outcome of those with multiple myeloma was less favorable, although hyperviscosity was rapidly and effectively decreased by the plasmapheresis. The treatment improved the conditions of almost all patients with neurological diseases. DISCUSSION: According to these findings plasmapheresis treatment, introduced by proper indications, effectively improves the outcomes of several diseases. Early diagnosis and immediate introduction of the plasmapheresis are very important - in conjunction with the appropriate therapy of the underlying diseases. PMID- 21712173 TI - [Therapy of radiation enteritis--current challenges]. AB - Radiation enteritis is one of the most feared complications after abdominal and pelvic radiation therapy. The incidence varies from 0.5 to 5%. It is not rare that the slowly progressing condition will be fatal. During a period of 13 years 24 patients were operated due to the complication of radiation enteritis. Despite different types of surgery repeated operation was required in 25% of cases and finally 4 patients died. Analyzing these cases predisposing factors and different therapeutic options of this condition are discussed. Treatment options of radiation induced enteritis are limited; however, targeted therapy significantly improves the outcome. Cooperation between oncologist, gastroenterologist and surgeon is required to establish adequate therapeutic plan. PMID- 21712174 TI - [Optical coherence tomography in otolaryngology]. AB - Optical coherence tomography is an imaging technique based on coherence interferometry. It is used in many medical fields due to its non-invasive imaging capabilities with micrometer resolution. The aim of the authors was to review the applicability of the optical coherence tomography in otolaryngology. Literature data and their own studies show that optical coherence tomography is a reliable method for identifying and targeted biopsy of inflammated, pre-malignant or cancer tissue in human laryngeal and pharyngeal mucosa. Another emerging field for optical coherence tomography is diagnosis of middle ear diseases, especially stapes ankylosis and cholesteatoma. PMID- 21712175 TI - [Art collector and connoiseur Hungarian physicians]. PMID- 21712176 TI - [A journey round my wife -- Mrs. Karinthy, Aranka Bohm, MD (1893-1944)]. PMID- 21712178 TI - [Editorial comment: Diabetes complications]. PMID- 21712179 TI - [Diabetes and cancer risk: oncologic considerations]. AB - Type 2 diabetes mellitus and malignant tumors are frequent diseases worldwide. The incidence of these two diseases is growing continuously and causes serious health care problem. Population based epidemiologic studies show that the coexistence of type 2 diabetes and malignant tumors is more frequent than expected by the age-corrected incidence and prevalence of each disease. Epidemiologic studies and meta-analyses show that type 2 diabetes increases the risk and tumor specific mortality of certain cancers. The overlapping risk factors of the diseases suggest a relationship between type 2 diabetes and malignant tumors, with a significant role of obesity as a major risk factor. In the pathophysiology of type 2 diabetes there are several biological processes, which may explain the higher cancer risk in type 2 diabetes. In vitro experiments, and in vivo animal studies show that the mitotic effect of hyperinsulinemia plays an important role in the relationship of cancer and type 2 diabetes mellitus. Recent studies show that the different treatment modalities, antidiabetic drugs and their combinations used for the treatment of type 2 diabetes can modify cancer risk. The majority of the data show that metformin therapy decreases, while insulin secretagog drugs slightly increase the risk of certain types of cancers in type 2 diabetes. Metformin can decrease cell proliferation and induce apoptosis in certain cancer cell lines. Endogenous and exogenous (therapy induced) hyperinsulinemia may be mitogenic and may increase the risk of cancer in type 2 diabetes. Human studies showed that the analogue insulin glargin increases the risk of certain cancers. As a result of conceptual weaknesses in study design, data collection, and statistical methods the results of these studies are questionable. According to present knowledge, obtaining and maintaining optimal metabolic target values with the appropriate choice of treatment modality is the aim of treatment in type 2 diabetes. Presently, study results showing elevated mitogenic potential with some antidiabetic treatment modalities are not taken into account, when considering the choice of antidiabetic treatment in type 2 diabetic patients. In the care of patients with increased cancer risk, oncologic considerations should be taken into account. Well designed, prospective, clinical studies would be necessary to demonstrate the possible correlation between treatment modalities of type 2 diabetes and change of cancer risk in type 2 diabetes mellitus. PMID- 21712180 TI - [Diabetes and bone metabolism]. AB - In the past decade several novel findings point to the critical role of the skeleton in several homeostatic processes, including energy balance. The connection begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Osteoblasts and adipocytes produce factors affecting insulin homeostasis. The hormonally active adipose tissue can regulate bone metabolism. In this review authors discuss targets taking critical part in the bone-fat network: leptin, osteocalcin, PPAR gamma2 and the Wnt/beta catenin pathway. Leptin regulates energy metabolism through controlling appetite. Mutation of the leptin gene resulting leptin resistance leads to high leptin levels, enormous appetite and pathologic obesity. Leptin also can influence the bone mass. The main effects of the thiazolidinedions - PPARgamma agonists - are mediated through receptors located in adipocytes. However, beside their positive effects, they also suppress osteoblastogenesis and increase the risk for pathologic fractures. Osteocalcin, a known marker of bone formation, produced by osteoblasts decreases fat mass, promotes adiponectin production and insulin sensitivity, increases the number of pancreatic beta-cells and increases insulin secretion. Thus, the skeletal system can regulate glucose metabolism and this substantially changed our view on this issue. Novel molecules can now be tested as targets in order to enhance bone formation and possibly prevent fractures. PMID- 21712181 TI - [Diabetes and osteoporosis]. AB - Over the last decades a considerable amount of data has accumulated to indicate that metabolic and endocrine alterations of diabetes affect bone quantity and quality. These skeletal changes may increase the risk of bone fracture. There is strong evidence that in type 1 diabetes the decreased bone mass, lack of insulin and insulin-like growth factor-1, dysregulation of adipokines, and increased levels of proinflammatory cytokines are in the background of fragility fractures. In type 2 diabetes hyperinsulinemia, insulin resistance and increased body weight may result in an increase of bone mass; however, accumulation of advanced glycation end products within the bone collagen driven by glucotoxicity may increase the cortical porosity. There is a higher incidence of falls resulting from diabetes-related co-morbidities such as diabetic retinopathy, peripheral neuropathy, hypoglycemic episodes and sometimes from the medications. Vitamin D deficiency has special impact on glucose metabolism and the prevalence of diabetes. Vitamin D supplementation in childhood can decrease incidence of type 1 diabetes by 80%. The effect of thiazolidinediones, glucagon-like peptide-1 agonists and metformin, agents for treatment of diabetes open a new connection between bone, carbohydrate and fat metabolism. PMID- 21712182 TI - [Diabetic neovascularisation and secondary glaucoma]. AB - Neovascular glaucoma develops from intraocular neovascularisation in diabetes mellitus. Neovascularisation is a consequence of hypoxia-induced production of vascular endothelial growth factor-A. Neovascular glaucoma is one of the most serious, sight-threatening late complications of diabetes. Several intraocular pressure lowering drugs, surgical and adjunctive laser treatments have been used to treat this disease, but the efficacy of the interventions is limited. The role of vascular endothelial growth factor-A blocking therapy in the treatment of neovascular glaucoma remains to be determined. Development of neovascularisation, however, can be prevented with adequate long-term glycemic and lipid control, effective treatment of arterial hypertension and optimal timing of adequate panretinal photocoagulation, in the majority of the cases. Unfortunately, in clinical practice diabetic neovascular glaucoma is more frequently experienced in Hungary than would be expected based on the variety of available therapeutic possibilities. In order to increase the success of prevention both cooperation of general practitioners, diabetologists, dietitians and ophthalmologists, and compliance of diabetic patients need to be improved. PMID- 21712183 TI - [Diabetic foot syndrome]. AB - Diabetes mellitus contributes to a number of disorders that can affect the quality of life. Amongst this diabetic foot syndrome and diabetic foot ulceration are serious secondary complications of diabetes mellitus. Persons with diabetic foot ulceration have an increased risk of amputation. In the first part of this review the author focuses on the pathophysiology of diabetic foot ulceration. The second part covers the topics of current and future therapies. The reader will understand the need and modes for preventive measures, the importance of multi level education in this topic, and the need for specialized wound care centers. As emphasized by the author, diabetic foot syndrome and ulceration are serious complications of diabetes mellitus, which can lead to devastating lower-extremity amputations and possible death. Specialized wound care centers, multi level education and proper adherence to standard treatment regimes can potentially prevent the need for amputation. PMID- 21712187 TI - Inter-chromosomal variation in the pattern of human population genetic structure. AB - Emerging technologies now make it possible to genotype hundreds of thousands of genetic variations in individuals, across the genome. The study of loci at finer scales will facilitate the understanding of genetic variation at genomic and geographic levels. We examined global and chromosomal variations across HapMap populations using 3.7 million single nucleotide polymorphisms to search for the most stratified genomic regions of human populations and linked these regions to ontological annotation and functional network analysis. To achieve this, we used five complementary statistical and genetic network procedures: principal component (PC), cluster, discriminant, fixation index (FST) and network/pathway analyses. At the global level, the first two PC scores were sufficient to account for major population structure; however, chromosomal level analysis detected subtle forms of population structure within continental populations, and as many as 31 PCs were required to classify individuals into homogeneous groups. Using recommended population ancestry differentiation measures, a total of 126 regions of the genome were catalogued. Gene ontology and networks analyses revealed that these regions included the genes encoding oculocutaneous albinism II (OCA2), hect domain and RLD 2 (HERC2), ectodysplasin A receptor (EDAR) and solute carrier family 45, member 2 (SLC45A2). These genes are associated with melanin production, which is involved in the development of skin and hair colour, skin cancer and eye pigmentation. We also identified the genes encoding interferon gamma (IFNG) and death-associated protein kinase 1 (DAPK1), which are associated with cell death, inflammatory and immunological diseases. An in-depth understanding of these genomic regions may help to explain variations in adaptation to different environments. Our approach offers a comprehensive strategy for analysing chromosome-based population structure and differentiation, and demonstrates the application of complementary statistical and functional network analysis in human genetic variation studies. PMID- 21712188 TI - A meta-analysis of single base-pair substitutions in translational termination codons ('nonstop' mutations) that cause human inherited disease. AB - 'Nonstop' mutations are single base-pair substitutions that occur within translational termination (stop) codons and which can lead to the continued and inappropriate translation of the mRNA into the 3'-untranslated region. We have performed a meta-analysis of the 119 nonstop mutations (in 87 different genes) known to cause human inherited disease, examining the sequence context of the mutated stop codons and the average distance to the next alternative in-frame stop codon downstream, in comparison with their counterparts from control (non mutated) gene sequences. A paucity of alternative in-frame stop codons was noted in the immediate vicinity (0-49 nucleotides downstream) of the mutated stop codons as compared with their control counterparts (p = 7.81 * 10-4). This implies that at least some nonstop mutations with alternative stop codons in close proximity will not have come to clinical attention, possibly because they will have given rise to stable mRNAs (not subject to nonstop mRNA decay) that are translatable into proteins of near-normal length and biological function. A significant excess of downstream in-frame stop codons was, however, noted in the range 150-199 nucleotides from the mutated stop codon (p = 8.55 * 10-4). We speculate that recruitment of an alternative stop codon at greater distance from the mutated stop codon may trigger nonstop mRNA decay, thereby decreasing the amount of protein product and yielding a readily discernible clinical phenotype. Confirmation or otherwise of this postulate must await the emergence of a clearer understanding of the mechanism of nonstop mRNA decay in mammalian cells. PMID- 21712189 TI - Analysis of pharmacogenetic traits in two distinct South African populations. AB - Our knowledge of pharmacogenetic variability in diverse populations is scarce, especially in sub-Saharan Africa. To bridge this gap in knowledge, we characterised population frequencies of clinically relevant pharmacogenetic traits in two distinct South African population groups. We genotyped 211 tagging single nucleotide polymorphisms (tagSNPs) in 12 genes that influence antiretroviral drug disposition, in 176 South African individuals belonging to two distinct population groups residing in the Western Cape: the Xhosa (n = 109) and Cape Mixed Ancestry (CMA) (n = 67) groups. The minor allele frequencies (MAFs) of eight tagSNPs in six genes (those encoding the ATP binding cassette sub family B, member 1 [ABCB1], four members of the cytochrome P450 family [CYP2A7P1, CYP2C18, CYP3A4, CYP3A5] and UDP-glucuronosyltransferase 1 [UGT1A1]) were significantly different between the Xhosa and CMA populations (Bonferroni p < 0.05). Twenty-seven haplotypes were inferred in four genes (CYP2C18, CYP3A4, the gene encoding solute carrier family 22 member 6 [SLC22A6] and UGT1A1) between the two South African populations. Characterising the Xhosa and CMA population frequencies of variant alleles important for drug transport and metabolism can help to establish the clinical relevance of pharmacogenetic testing in these populations. PMID- 21712190 TI - Update on the aldehyde dehydrogenase gene (ALDH) superfamily. AB - Members of the aldehyde dehydrogenase gene (ALDH) superfamily play an important role in the enzymic detoxification of endogenous and exogenous aldehydes and in the formation of molecules that are important in cellular processes, like retinoic acid, betaine and gamma-aminobutyric acid. ALDHs exhibit additional, non enzymic functions, including the capacity to bind to some hormones and other small molecules and to diminish the effects of ultraviolet irradiation in the cornea. Mutations in ALDH genes leading to defective aldehyde metabolism are the molecular basis of several diseases, including gamma-hydroxybutyric aciduria, pyridoxine-dependent seizures, Sjogren-Larsson syndrome and type II hyperprolinaemia. Interestingly, several ALDH enzymes appear to be markers for normal and cancer stem cells. The superfamily is evolutionarily ancient and is represented within Archaea, Eubacteria and Eukarya taxa. Recent improvements in DNA and protein sequencing have led to the identification of many new ALDH family members. To date, the human genome contains 19 known ALDH genes, as well as many pseudogenes. Whole-genome sequencing allows for comparison of the entire complement of ALDH family members among organisms. This paper provides an update of ALDH genes in several recently sequenced vertebrates and aims to clarify the associated records found in the National Center for Biotechnology Information (NCBI) gene database. It also highlights where and when likely gene-duplication and gene-loss events have occurred. This information should be useful to future studies that might wish to compare the role of ALDH members among species and how the gene superfamily as a whole has changed throughout evolution. PMID- 21712191 TI - A review of software for microarray genotyping. AB - The focus of this review is software for the genotyping of microarray single nucleotide polymorphisms, in particular software for Affymetrix and Illumina arrays. Different statistical principles and ideas have been applied to the construction of genotyping algorithms - for example, likelihood versus Bayesian modelling, and whether to genotype one or all arrays at a time. The release of new arrays is generally followed by new, or updated, algorithms. PMID- 21712192 TI - Pathway annotation and analysis with Reactome: the solute carrier class of membrane transporters. AB - Reactome is an expert-authored, peer-reviewed knowledge base of human reactions and pathways that functions as a data-mining resource and electronic textbook. Its current release covers approximately 23 per cent of the complete human proteome from UniProt. The pathway browser, search and data-mining tools facilitate searching and visualising pathway data and the analysis of user supplied high-throughput datasets. A catalogue of all the solute-carrier (SLC) class of transporters which have known ligands has been annotated in Reactome. Reactome provides a detailed and interactive view of this set of transport reactions. Using the example of the SLC class of transporters, we show how they can be overlaid with protein-protein interaction, protein-drug interaction and gene expression data and compared with equivalent pathways in other species, to facilitate over-representation, expression and other pathway analyses. PMID- 21712194 TI - Molecular genetics of growth and development in Populus (Salicaceae). v. mapping quantitative trait loci affecting leaf variation. AB - We examined the genetic variation of leaf morphology and development in the 2-yr old replicated plantation of an interspecific hybrid pedigree of Populus trichocarpa T. & G. and P. deltoides Marsh. via both molecular and quantitative genetic methods. Leaf traits chosen were those that show pronounced differences between the original parents, including leaf size, shape, orientation, color, structure, petiole size, and petiole cross section. Leaves were sampled from the current terminal, proleptic, and sylleptic branches. In the F2 generation, leaf traits were all significantly different among genotypes, but with significant effects due to genotype X crown-position interaction. Variation in leaf pigmentation, petiole length. And petiole length proportion appeared to be under the control of few quantitative trait loci (QTLs). More QTLs were associated with single leaf area, leaf shape, lamina angle, abaxial color, and petiole flatness, and in these traits the number of QTLs varied among crown positions. In general, the estimates of QTL numbers from Wright's biometric method were close to those derived from molecular markers. For those traits with few underlying QTLs, a single marker interval could explain from 30 to 60% of the observed phenotypic variance. For multigenic traits, certain markers contributed more substantially to the observed variation than others. Genetic cluster analysis showed developmentally related traits to be more strongly associated with each other than with unrelated traits. This finding was also supported by the QTL mapping. For example, the same chromosomal segment of linkage group L seemed to account for 20% of the phenotypic variation of all dimension-related traits, leaf size, petiole length. and midrib angle. In both traits. the P. deltoides alleles had positive effects and were dominant to the P. trichocarpa alleles. Similar relationships were also found for lamina angle. abaxial greenness, and petiole. PMID- 21712195 TI - Extreme preformation in alpine Polygonum viviparum: an architectural and developmental analysis. AB - Preformation, the initiation of organs one or more years prior to maturation and function, is reported to be common and crucial for plant survival in arctic and alpine environments, yet the phenomenon is remarkably little studied. In order to understand the role of preformation in the ecology and evolution of tundra species, this investigation takes a developmental and architectural approach to the analysis of plant growth and reproduction in the alpine perennial Polygonum viviparam L. Analyses show that the extent and duration of preformation in P. viviparam are extraordinary. Four years are required for each leaf and inflorescence to progress from initiation to functional and structural maturity. This single salient feature of development has profound consequences for basic architecture, dynamics of resource allocation, and the timing of plant responses to environmental variation. As a consequence of the protracted duration of leaf and inflorescence development, five cohorts of primordia, initiated in successive years, are borne simultaneously by an individual plant. In the year prior to maturation leaves reach 30% of their maximum size, and the maximum potential reproductive output of each inflorescence is determined. Thus, developmental processes that affect final morphology and resource allocation occur at least 1 yr before functional maturity. From the developmental and architectural models constructed for P. viviparum, a 1-yr delay in measurable plant responses to environmental variation is predicted. The models also apply generally to arctic and alpine species and provide a mechanistic explanation for observed patterns of productivity at the community and ecosystem scale. PMID- 21712196 TI - Perithecial ontogeny in erithecial ontogeny in the fungal genus Epichloe: An examination of the claviciptalean centrum. AB - The structure and development of perithecia in five collections of Epichloe from Europe and North America were studied. Perithecia in early stages of development are oblong to ovate in overall shape. Dichotomously branched paraphyses form on the bottom and sides of the inner walls of the perithecial primordium. As the ovate primordium expands, a mound of ascogenous mycelium develops in its base. As asci develop from the ascogenous mound, paraphyses proximal to asci evanesce and no paraphyses are observable within the cluster of asci. In E. amarillans and E. baconii paraphyses are converted into pseudoparenchyma-like tissues, while in E. typhina paraphyses remain filamentous until they evanesce. Ascospore development is seen to differ among all three species of Epichloe. The development and structure of the Epichloe centrum are compared to those of the Nectria and Xylaria types. It is apparent that a distinct type of centrum is present in Epichloe, and perhaps all of the Clavicipitaceae. It is proposed that the Epichloe type centrum may represent a key feature for distinguishing the Clavicipitaceae from the Hypocreaceae or other groups of pyrenomycetes. PMID- 21712197 TI - Demographic change and microhabitat variability in a grassland endemic, Silene douglasii var. oraria (Caryophyllaceae). AB - Variable spatial and temporal environments are known to affect the population dynamics of plants, but studies of local scale variability and its relationship to demographic change within a population remain limited. Using mapped plants, we examined the population dynamics of a coastal grassland endemic, Silene douglasii var. oraria, in two habitats over 10 yr. We hypothesized that ecological differences between rocky and grassy habitats might influence demographic parameters, including adult survival, growth, and density. Soil pH, soil moisture. and other abiotic variables differed little between habitats, but microsite differences in light, soil depth. and vegetation height were related to variation in Silene density and plant circumference. We also found significantly higher population densities, lower adult mortality, and more juvenile recruitment in rocky areas. Finite rates of population growth varied across years and habitats (lambda = 0.82-1.12). with different patterns evident in the two habitats. In both, observed population sizes in 1992 were similar to matrix projections using 1982-1985 data. Populations declined in size in some years despite high adult survivorship and variable recruitment. More intensive study of seedlings is needed, including experimental evaluation of the role of light and competition. However, the habitat-specific differences we observed imply that ecological studies and conservation plans developed for rare plants should consider the effect of local scale variability on demography. PMID- 21712198 TI - Quantitative analyses of the genetic structure of closely related conifers with disparate distributions and demographics: the Cupressus arizonica (Cupressaceae) complex. AB - Seedling populations of seven Cupressus taxa were compared in common gardens to assess relationships among taxa and to elucidate the genetic structure of three taxa with different distributions and demographics. Discriminant analyses of 15 quantitative traits separated C. sargentii and C. forbesii from taxa within the C. arizonica complex (C. arizonica, C. glabra, C. stephensonii, C. nevadensis, and C. montana); aligned a population of C. arizonica from Sierra de Arteaga, Mexico, with families of the same taxon from southwestern United States; and described a close relationship between C. nevadensis and C. glabra. but nevertheless separated taxa within the C. arizonica complex. Analyses of wind pollinated progenies of single trees showed the narrow endemic, C. glabra, to have a greater degree of population differentiation than the more broadly dispersed C. arizonica. In addition, genetic variances within the numerically small populations of C. arizonica were about the same as in the much larger populations of C. glabra. The results also suggested that genetic variability in C. stephensonii, a taxon occurring in a single population, may occur primarily among inbred lines. While the genetic structures of C. arizonica and C. glabra have counterparts among broadly dispersed conifers, that of C. stephensonii appears to be unique. Together, the results support the view that genetic structure primarily reflects the uncertain, chance events that are interspersed throughout evolutionary history. PMID- 21712199 TI - Evolutionary implications of meiotic chromosome behavior, reproductive biology, and hybridization in 6x and 9x cytotypes of Andropogon gerardii (Poaceae). AB - Andropogon gerardii, big bluestem, has 60 and 90 chromosome cytotypes. Meiosis in the hexaploid was shown to be regular, although some secondary associations of bivalents form. Meiosis in the enneaploid (2n = 9z = 90) is irregular, leading to most gametes having unbalanced chromosome complements. Both cytotypes show considerable self-incompatibility. Cytotypes crossed freely, forming a variety of fertile euploids and aneuploids. Indistinguishable exomorphology, intermixing in natural populations, and compatibility suggest that A. gerardii is best understood as a cytotypically complex single species. PMID- 21712200 TI - Cockroach pollination and breeding system of Uvaria elmeri (Annonaceae) in a lowland mixed-dipterocarp forest in Sarawak. AB - Tropical forest plants are known to be pollinated by a diverse array of animals. Here we report on the pollination of a woody climber species, Uvaria elmeri (Annonaceae), by cockroaches in a lowland mixed-dipterocarp forest in Sarawak, Malaysia. To the best of our knowledge, this is the first report of pollination by cockroaches. The cauliflorous flowers in the understory are protogynous and bloomed for 50 h. An odor similar to decayed wood or a mushroom was secreted by flowers and was stronger during the male stage. Pollinators were cockroaches (Blattellidae) and drosophilid flies (Drosophilidae). Cockroaches, the main pollinators, visited flowers during both female and male stages at night, feeding on stigmatic exudate and pollen. Drosophilids, the secondary pollinators. mainly visited female-stage flowers during daytime, fed on stigmatic exudate. and laid eggs on stigmas. Neither autogamy nor self-compatibility was observed. Fruit production appeared to be pollen-limited. The fruit set, which was 2% of flowers in natural condition, was significantly lower than the 30% fruit set obtained by artificial cross-pollination. We discuss the traits of cockroaches as pollinators and the breeding system of U. elmeri. PMID- 21712201 TI - Contrasted pollen capture mechanisms in Phyllocladaceae and certain Podocarpaceae (Coniferales). AB - Comparative study shows that Phyllocladus and representative Podocarpaceae differ in the mechanism by which pollen is introduced into the pollen chamber and onto the apex of the nucellus ("pollen capture"). Both types involve a pollination drop, but only in Podocarpaceae is it consistently inverted and in contact with adjacent surfaces. Phyllocladus has functionally nonsaccate pollen (although a vestigial saccus has been claimed); its pollen is wettable and sinks in water. Podocarpaceae (except Saxegorhaea) have saccate pollen, which is nonwettable and floats on water. In Phyllocladus the pollination drop receives the pollen directly and presence of pollen stimulates complete drop withdrawal, which may be a metabolic process. Once pollinated, an ovule does not resecrete a pollination drop. In Podocarpaceae the drop usually receives the pollen indirectly via pollen scavenging and saccate pollen is preferentially captured. The retraction of the drop appears to be the result of evaporation and is presumably nonmetabolic. Drop secretion can be repeated in the presence of pollen. A major consequence of these contrasted mechanisms is that in Phyllocladus the entire contents of the pollination drop are ingested, whereas in Podocarpaceae only that part of the drop that includes saccate pollen is ingested. Because of differences in repeatability of the secretion process, Podocarpaceae are likely to capture more pollen. In neither mechanism does the process favor 'own" pollen. but in Podocarpaceae all but saccate pollen is excluded. We thus have further evidence for differences in pollen capture mechanisms in conifers with a pollination drop, and differences in the behavior of the pollination drop itself. PMID- 21712202 TI - Genetic diversity in three colonizing orchids with contrasting mating systems. AB - Comparative studies on the genetic attributes of colonizing orchids with diverse mating systems are lacking in the literature. Eulophia sinensis, Spiranthes hongkongensis, and Zeuxine strateumatica are colonizing orchids that frequently occupy newly created habitats in Hong Kong. Mating system studies showed that E. sinensis is a self-compatible but pollinator-dependent outcrossing species, S. hongkongensis is a self-pollinating taxon, and Z srateumatica is apomictic. Population genetic attributes of these orchid species were investigated. Despite their contrasting mating systems, electrophoretic surveys revealed a striking lack of allozyme variation, both within and among populations, in all three species. However, gene duplications were evident in these species, due to their likely polyploid origins, The percentage of duplicate loci exhibiting "fixed heterozygosity" was 10, 21.4, and 20% in E. sinensis, S. hongkongensis, and Z. strateumatica, respectively. The genetic attributes of these orchids are compared to those found in other colonizing plant species. PMID- 21712203 TI - The effect of interplant distance on mating success in federally threatened, self incompatible Hymenoxys herbacea = H. acaulis var. glabra (Asteraceae). AB - We investigated large- and fine-scale effects of interplant distance on compatibility, seed set, and seed germination in a rare, self-incompatible perennial, Lakeside daisy (Hymenoxys herbacea = H. acaulis var. glabra). Plants were collected at the Marblehead Peninsula. Ohio, and transplanted to a greenhouse where they were hand-pollinated. For the large-scale analysis, 110 crosses were classified in three categories: Near crosses (0.75-6.70 m), Far crosses (17-72 m), and Very Far crosses (>900 ml. There was no significant effect of interplant distance on compatibility, seed set, or seed germination in these crosses. For the fine-scale analysis, we made 44 crosses with interplant distances ranging from 0.75 to 10 m. At this scale, interplant distance explained 10.9% of the variance of the seed/floret ratio, suggesting that local genetic structure may result in a modest amount of biparental inbreeding. We found no fine-scale effects of interplant distance on compatibility or percentage of seed germination, but it is possible that biparental inbreeding could affect later stages of the life cycle not included in this study. For all distance classes, >80% of the crosses were compatible, indicating that lack of compatibility between mates is not likely to limit seed production. Apparently, presumed population bottlenecks have not been severe enough for genetic drift to eliminate substantial numbers of self-incompatibility alleles. PMID- 21712204 TI - The flora of the early Miocene Brandon Lignite, Vermont, USA. VIII. Caldesia (Alismataceae). AB - Caldesia, a genus of aquatic monocotyledons, is represented by four living species, which are widely distributed in the temperate and tropical Old World. The genus has an extensive Oligocene through Pleistocene fossil record in Eurasia. We survey the morphology of the extant and fossil fruits of the Alismataceae, and provide a detailed review of the morphology and anatomy of living and fossil Caldesia fruits. The latter exhibit substantial similarity, making the recognition of separate species on the basis of fruit morphology difficult. We erect the new species Caldesia brandoniana from the Early Miocene Brandon Lignite of Vermont primarily on the basis of its geographic isolation; careful revision of all fossil fruiting material of Caldesia might require placement of the Brandon specimens in a more inclusive form species. Together with leaves of Caldesia from the Miocene Clarkia flora of Idaho, this occurrence indicates that Caldesia was in the New World as recently as the Early Miocene. PMID- 21712205 TI - Relationships in the Caryophyllales as suggested by phylogenetic analyses of partial chloroplast DNA ORF2280 homolog sequences. AB - Phylogenetic relationships within the angiosperm order Caryophyllales were investigated by comparative sequencing of two portions of the highly conserved inverted repeat (totaling some 1100 base pairs) coinciding with the region occupied by ORF2280 in Nicotiana, the largest gene in the plastid genomes of most land plants. Data were obtained for 33 species in 11 families within the order and for one species each of Plumbaginaceae, Polygonaceae, and Nepenthaceae. These data, when analyzed along with previously published ORF (open reading frame) sequences from Nicotiana. Spinacia. Epifagus, and Pelargonium using parsimony, neighbor-joining, and maximum likelihood methods, reveal that: (1) Amaranthus, Celosia, and Froelichia (all Amaranthaceae) do not comprise a monophyletic group; (2) Amaranthus may be nested within a paraphyletic Chenopodiaceae; (3) Sarcobatus (Chenopodiaceae) is allied with Nyctaginaceae + Phytolaccaceae (the latter family excluding Stegnosperma but including Petiveria); and (4) Caryophyllaceae (with Corrigiola basal within the clade) are sister group to Chenopodiaceae + Amaranthaceae. Basal relations within the order remain obscure. Sequence divergence values in pairwise comparisons across all Caryophyllales taxa ranged from 0.1 to 5% of nucleotides. However, despite these low values, 23 insertion and deletion events were apparent, of which five were informative phylogenetically and bolstered several of the relationships listed above. A polymerase chain reaction (PCR) survey for ORF homolog length variants in representatives from 70 additional angiosperm families revealed major deletions, of 100 to 1400 base pairs, in 19 of these families. Although the ORF is located within the mutationally retarded inverted repeat region of most angiosperm chloroplast DNAs, this gene appears particularly prone to length mutation. PMID- 21712206 TI - Effect of day length on germination of seeds collected in Alaska. AB - Day length control can effectively limit seed germination to favorable seasons, but this phenomenon has been studied in relatively few wild plants. I tested species from interior Alaska for day length control of germination under controlled conditions, and I also monitored germination phenology in natural habitats. Unstratified and cold-stratified seeds were germinated on short (13 h) and long (22 h) day length and in the dark at constant and alternating temperatures. On long day length, unstratified Ledum decumbens and Saxifraga tricuspidata seeds germinated from 5 C to 20 C, but on short day length few or no seeds germinated at 5 C and 10 C and germination was reduced at higher temperatures. Unstratified seeds of Diapensia lapponica and Chamaedaphne calyculata germinated only at 15 C and 20 C on long day length, and short day length completely inhibited germination. Cold stratification widened the temperature range for germination on both long and short day lengths, but germination was still lower on short than long day length. Germination phenology in natural habitats was consistent with germination in controlled conditions. In these species, short day length and low temperatures interact to inhibit germination in the fall. After overwintering, seeds germinate in the spring at low temperatures and on long day lengths. The inhibitory effect of short day length is not important in the spring because day length is already long at snowmelt. PMID- 21712207 TI - Effects of thermoperiod on recovery of seed germination of halophytes from saline conditions. AB - Recovery of seed germination from NaCl salinity of desert shrubs (Haloxylon recurvum and Suaeda fruticosa, and the herbs Zygophyllum simplex and Triglochin maritima was studied under various thermoperiods. The percentage of ungerminated seeds that recovered when they were transferred to distilled water varied significantly with variation in species and thermoperiods. Zygophyllum simplex had little recovery from all NaCl concentrations in all thermoperiods. Haloxylon recurvum, S. fruticosa, and T. maritima showed substantial recovery. Percentage recovery was highest in S. fruticosa, followed by T. maritima, and H. recurvum. Thermoperiodic effects varied with the species investigated. There was little thermoperodic effect on the percentage recovery of S. fruticosa, except in the higher salinity treatment at higher thermoperiods. Variation in thermoperiod appears to play an important role in recovery of germination of halophytes from salt stress when seeds are transferred to distilled water. PMID- 21712208 TI - Introduction: emergency medicine pharmacotherapy. PMID- 21712209 TI - Emergency medicine pharmacy practice. AB - Emergency medicine (EM) pharmacy practice has existed for over 30 years. In recent years, however, the specialty has grown significantly. A large number of health care systems have either a dedicated EM pharmacist or other clinical pharmacist presence in the Emergency department (ED). Over the past decade, the role of the EM pharmacist as a critical member of the health care team has expanded significantly and many innovative practices have evolved throughout the country. There is also some heterogeneity between different EM pharmacy practice sites. This article reviews the history and general concepts of EM pharmacy practice as well as illustrate some of the established benefits of an EM pharmacist. PMID- 21712210 TI - The role of the emergency pharmacist in trauma resuscitation. AB - The clinical pharmacist in the emergency department is now commonly incorporated as a member of the emergency department trauma team. As such, the emergency pharmacist needs to have detailed knowledge of the pharmacotherapy of resuscitation and be able to apply the skills needed to function as a valuable member of this team. In addition to the traditional skills of the discipline of clinical pharmacy, the emergency pharmacist must be familiar with the intricacies of treating life-threatening injuries in an emergent setting and be able to anticipate the direction of the patient's care. The ability to provide valuable pharmacological interventions throughout the resuscitation and stabilization process requires familiarity with the process of resuscitation, including rapid sequence induction, analgesia and sedation, seizure prophylaxis, appropriate antibiotic and tetanus prophylaxis, intracranial pressure control, hemodynamic stabilization, and any other specific drug therapy that the clinical situation demands. This article discusses the aforementioned pharmacotherapeutic topics and describes the role of the Emergency Pharmacist on the ED trauma team. PMID- 21712211 TI - Early management of stroke patients in the emergency department. AB - Stroke continues to be one of the leading causes of death and adult disability. Increasing public awareness of stroke has led to a rise in the number of patients presenting to emergency departments (EDs) who qualify for emergent and time sensitive treatments such as t-PA, clot extraction, and surgery. Timely treatment and supportive care of the stroke patient in the ED is crucial for patient outcomes. Emergency medicine (EM) pharmacists are the medication experts and can have a significant impact on the care of a stroke patient. Thus, it is essential for EM pharmacists to have a solid knowledge of the current guidelines and evidence-based literature or lack there of. In this article, we describe the epidemiology of stroke, review the classifications of stroke, and discuss the present treatment strategies for emergent and supportive care. PMID- 21712212 TI - Toxicology today: what you need to know now. AB - Clinicians are frequently confronted with toxicological emergencies and challenged with the task of correctly identifying the possible agents involved and providing appropriate treatments. In this review article, we describe the epidemiology of overdoses, provide a practical approach to the recognition and diagnosis of classic toxidromes, and discuss the initial management strategies that should be considered in all overdoses. In addition, we evaluate some of the most common agents involved in poisonings and present their respective treatments. Recognition of toxidromes with knowledge of indications for antidotes and their limitations for treating overdoses is crucial for the acute care of poisoned patients. PMID- 21712213 TI - Procedural sedation and analgesia in the emergency department. AB - Patients present to the emergency department (ED) for a variety of reasons and some require diagnostic and therapeutic procedures for their conditions. In order for some of these procedures to be carried out successfully, the patient must be at a suppressed level of consciousness in order to tolerate the associated pain and anxiety. Medications administered to achieve these goals include analgesics and sedatives as they decrease the patient's discomfort and awareness while allowing the patient to maintain their airway. However, medication selection and dosing is critical and should be tailored to each patient and procedure. Pharmacists have an opportunity to reduce medication errors during procedural sedation and analgesia (PSAA) as the majority of medication errors leading to adverse events occur during the ordering and administration steps of the medication use process. Common errors include drug-dosing, potential drug interactions, and administration of the wrong pharmacologic agent. Pharmacists in the ED can provide drug information and assist with drug selection and dosing; medication preparation; and monitoring of the patient and of the time intervals since medication administration relative to the duration of the procedure. Having a pharmacist present provides an extra layer of protection and reduces the likelihood for potential medication errors. PMID- 21712214 TI - Antimicrobial stewardship in the emergency department. AB - The practice of antimicrobial stewardship can be defined as optimizing clinical outcomes while minimizing the consequences of antimicrobial therapy such as resistance and superinfection. Antimicrobial stewardship can be difficult to transition to the emergency department (ED) since the traditional activities include the evaluation of broad-spectrum antimicrobial regimens at 72 and 96 hours and intravenous to oral medication conversion. The emergency medicine clinical pharmacist (EPh) has the knowledge and clinical assessment skills to manage an antimicrobial stewardship program focused on culture follow-up for patients discharged from the ED. This paper summarizes the experiences of developing an EPh-managed antimicrobial stewardship and culture follow-up program in the ED from 2 separate institutions. Specifically, the focus is on the steps for establishing an EPh-managed antimicrobial stewardship program, a description of the culture follow-up process, managing the culture data and cultures that require emergent notification and review, medical/legal concerns, and barriers to implementation. Outcomes data available from institutions with similar ED based antimicrobial stewardship programs are also discussed. PMID- 21712215 TI - Efficacy and safety of pegylated interferon in children and adolescents infected with chronic hepatitis C: a preliminary study. AB - This study researches the efficacy and safety of pegylated interferon alpha-2a (pegIFNalpha-2a) in Egyptian children and adolescents diagnosed with hepatitis C virus. Thirty patients were enrolled to receive pegIFN once a week with ribavirin twice daily for 12 weeks; viral load and experienced adverse effects were then assessed. Of the 30 patients, 16 (53.33%) were cleared from the virus, showing early virologic response (EVR). Three patients (10%) showed a 2-log reduction by week 12, with an overall early response rate of 63.33%. Three patients who showed EVR after 4 weeks relapsed by week 12. Levels of serum alanine aminotransferase (ALT) normalized at week 12. Adverse events included fever, myalgia, headache, flu-like symptoms, fatigue, anemia, and leucopenia; 63.33% of the patients showed significant reduction in their body weight. Although the patients showed a reduction in average body mass index, this reduction was not significant. Hemoglobin values decreased within the first 2 weeks and then stabilized but not back to baseline. A significant reduction in the level of absolute neutrophil count (ANC) was observed by the 4th week and started to improve by the 12th week. Of the recruited patients, 29.4% were subjected to IFN dose reduction. None of the patients with neutropenia developed serious infection or sepsis. The authors concluded that pegIFN plus ribavirin therapy is promising when tested on Egyptian children. PMID- 21712216 TI - Practices of Arab American patients with type 2 diabetes mellitus during Ramadan. AB - AIMS: To examine practices and complications among Arab Americans observing fasting during Ramadan. METHODS: Adults with type 2 diabetes mellitus, of native Arab ancestry, and observing fasting were invited to complete an interview. Changes made to behavioral characteristics or diabetes management during Ramadan and consequences of fasting were assessed. RESULTS: Twenty-seven patients (60.1 +/- 9.8 years, 51.9% male) participated. Majority reported exercising less frequently during Ramadan. Modifications in home blood glucose monitoring (HBGM) were observed in 48% of patients, of these 25% and 17% decreased frequency or had not tested at all, respectively. Consultation with providers prior to Ramadan was reported by 67%. Education regarding medications, risks of fasting, indications to break fasting, meal plans, and exercise were not provided in the majority. Therapeutic changes were made in 50% and 46% of insulin and oral medication users, respectively. Excessive thirst was the most commonly reported symptom. The overall frequency of hypoglycemia and hyperglycemia was low. One patient stopped fasting during Ramadan due to uncontrolled hyperglycemia. Hospitalization or emergency room visits were not reported. CONCLUSIONS: Lack of patient education prior to Ramadan may contribute to the suboptimal practices reported. Pharmacists may be able to ensure safe fasting practices among Arab Americans by providing patient-specific education. PMID- 21712217 TI - Within-patient atazanavir trough concentration monitoring in HIV-1-infected patients. AB - OBJECTIVE: Protease inhibitors (PIs) exhibit considerable interpatient pharmacokinetic variability in plasma trough concentrations. Therapeutic drug monitoring (TDM) is occasionally used to guide chronic dosing to achieve target trough concentrations, but its clinical success assumes minimal intrasubject variability. Therefore, our primary objective was to evaluate intrapatient variability in atazanavir (ATV) plasma trough concentrations in HIV-1-infected patients. DESIGN/METHODS: In a single-site, prospective, cohort study, patients on atazanavir with or without ritonavir (ATV/r or ATV) for 2 clinic visits were enrolled. Adherence and time since last dose (TSLD) were verified at each visit. ATV was assayed with high-performance liquid chromatography. Intra- and interpatient variation was evaluated using the median intraindividual percentage coefficient of variation (ICV). RESULTS: The mean 24-hour ATV trough concentrations for the first and second visit for the ATV/r group (n = 10) was 598 (CV 84%) and 525 ng/mL (CV 66%), respectively (P = .511), and 300 (CV 81%) and 434 ng/mL (CV 106%) for the ATV group (n = 4), respectively (P = .369). Median ICV was 43.1% for all patients (range: 0.6%-107.6%), 38.1% (0.6%-107.6%) for the ATV/r group, and 33.1% (2.3%-87.6%) for the ATV group. CONCLUSIONS: Potential intrapatient variability in ATV troughs suggests that repeated measurements may be required to ensure that target values are maintained. PMID- 21712218 TI - The knowledge levels and opinions of biomedical students regarding the human papillomavirus quadrivalent (types 6, 11, 16, and 18) recombinant vaccine. AB - The objective of this research was to assess the knowledge levels and attitudes of all students enrolled in 1 biomedical university regarding the human papillomavirus quadrivalent (types 6, 11, 16, and 18) recombinant vaccine (Gardasil-Merck; the HPV vaccine). A survey of students from all 7 programs at the University was conducted in January 2009. A total of 1120 useable questionnaires were obtained. These programs included pharmacy, osteopathic medicine, physician assistant, physical therapy, occupational therapy, doctor of psychology, and master of biomedical sciences. Mean percentage correct on the HPV vaccine knowledge test was 73. Subjects scored highest on the question that asks whether the vaccine helps prevent cervical cancer (97% correct) and lowest on the one asking whether it helps prevent genital warts (41% correct). Eighty-eight percent thought that patients 18 years and older should be able to receive the HPV vaccine without parental consent. Only about 5% think that the vaccine would cause patients to become sexually active, or that it would cause patients to have unprotected sex. The results suggest that these students have reasonable but limited knowledge of the vaccine. Their positive attitudes suggest that they will likely recommend or provide the vaccine to their patients. PMID- 21712219 TI - Building critical reflection skills for lifelong learning in the emergent landscape of a national registration and accreditation scheme. AB - In 2010 many of the health disciplines in Australia will be involved in national registration and accreditation, to ensure a more sustainable and flexible health workforce for the future. To this end, in each of the health professions, there is an increasing emphasis on reflective practice and lifelong learning to maintain practice competency. This research focuses on academic teaching and learning in the Pharmacy undergraduate curriculum to develop an indicator tool of graduate practice skills before the student enters the practice internship year. The Graduated Descriptors Competency Tool was developed by means of state, territory, and national stakeholder collaboration. The aim of the project was to assist the scaffolding processes around undergraduate practice teaching and learning. Students on experiential placements have used the tool to demonstrate their current practice skills and the learning required to attain competency during their internship year. Students are guided to develop critical reflection skills for deep understanding and insight into the continued learning and professional development required to maintain long-term health care expertise. PMID- 21712220 TI - The effect of vitamin C on the common cold. PMID- 21712224 TI - Serotonin influences locomotion in the nudibranch mollusc Melibe leonina. AB - Serotonin (5-HT) influences locomotion in many animals, from flatworms to mammals. This study examined the effects of 5-HT on locomotion in the nudibranch mollusc Melibe leonina (Gould, 1852). M. leonina exhibits two modes of locomotion, crawling and swimming. Animals were bath-immersed in a range of concentrations of 5-HT or injected with various 5-HT solutions into the hemolymph and then monitored for locomotor activity. In contrast to other gastropods studied, M. leonina showed no significant effect of 5-HT on the distance crawled or the speed of crawling. However, the highest concentration (10(-3) mol l(-1) for bath immersion and 10(-5) mol l(-1) for injection) significantly increased the time spent swimming and the swimming speed. The 5-HT receptor antagonist methysergide inhibited the influence of 5-HT on the overall amount of swimming but not on swimming speed. These results suggest that 5-HT influences locomotion at the behavioral level in M. leonina. In conjunction with previous studies on the neural basis of locomotion in M. leonina, these results also suggest that this species is an excellent model system for investigating the 5-HT modulation of locomotion. PMID- 21712225 TI - Effects of light dynamics on coral spawning synchrony. AB - Synchrony of spawning in many hermatypic corals, typically a few nights after the full moon, is putatively dependent on solar and lunar light cycles in conjunction with other possible cues such as tides and temperature. We analyze here the contributions of separate components of light dynamics, because the effects of twilight and lunar skylight on coral spawning synchrony have previously been conflated and the alternative hypothesis that these components have differential contributions as proximate cues has not been tested. Moonlight-dependent changes in spectra during twilight, rates of decreasing twilight intensities, and changes in lunar photoperiod were experimentally decoupled using programmed light emitting diodes and compared for their separate effects on spawning synchrony in Acropora humilis. Effects on synchrony under the control of synthetic lunar cues were greatest in response to changes in lunar photoperiod; changes in light intensities and spectra had lesser influence. No significant differences among treatment responses were found at the circa-diel time scale. We conclude that spawning synchrony on a particular lunar night and specific time of night is a threshold response to differential periods of darkness after twilight that is primarily influenced by lunar photoperiod and secondarily by discrete optical components of early nocturnal illumination. PMID- 21712226 TI - Swimming of Xenopus laevis sperm exhibits multiple gears and its duration is extended by egg jelly constituents. AB - The motility of Xenopus sperm is initiated by the osmotic shock experienced when these cells are ejaculated into low-salinity pond water. Motility is brief and is required for the sperm to penetrate the jelly layers and fertilize the egg. In this study we demonstrate that extracts of egg jelly contain factors that extend the period of sperm motility as well as providing a chemoattractant activity as previously reported. Both activities are partially dependent on extracellular calcium. Time-lapse and video microscopy show that after activation of motility the number of motile sperm decreases rapidly, with a half-time of about 2 min. Addition of 10% v/v egg jelly extract ("egg water") increased the number of motile sperm 2-fold over controls at 20 s and about 4- to 10-fold over controls at 10 min after initiation of motility. Extension of motility lifetime was not mediated by a nonspecific protein or by allurin, the egg-water protein that has chemoattractant activity. The helical path of Xenopus sperm exhibited tight coupling between rotational and forward velocities in egg jelly, but coupling changed rapidly from moment to moment in low-salinity buffer. Our observations suggest that jelly-derived factors regulate both the longevity and directionality of sperm propulsion. PMID- 21712227 TI - Opposed ciliary bands in the feeding larvae of sabellariid annelids. AB - The larvae of marine annelids capture food using an unusual diversity of suspension-feeding mechanisms. Many of the feeding mechanisms of larval annelids are poorly known despite the abundance and ecological significance of both larvae and adults of some annelid taxa. Here we show that larvae of two species of sabellariid annelids, Sabellaria cementarium and Phragmatopoma californica, bear prototrochal and metatrochal cilia that beat in opposition to each other. For larvae of S. cementarium, we provide evidence that these opposed bands of cilia are used to capture suspended particles. In video recordings, captured particles were overtaken by a prototrochal cilium and then moved with the cilium to the food groove, a band of cilia between the prototroch and metatroch. They were then transported by cilia of the food groove to the mouth. Lengths of the prototrochal cilia, lengths of the prototrochal ciliary band, size range of the particles captured, and estimated rates of clearance increased with larval age and body size. Confirmation of the presence of opposed bands in larvae of sabellariids extends their known occurrence in the annelids to members of 10 families. Opposed bands in these different taxa differ in the arrangements and spacing of prototrochal and metatrochal cilia, and in whether they are used in combination with other feeding mechanisms. Opposed bands appear to be particularly widespread among the larvae of sabellidan annelids (a clade that includes sabellariids, sabellids, and serpulids), even in some species whose larvae do not feed. A parsimony analysis suggests that opposed bands are ancestral in this clade of annelids. PMID- 21712228 TI - Populations of Symbiodinium muscatinei show strong biogeographic structuring in the intertidal anemone Anthopleura elegantissima. AB - Among temperate cnidarian symbioses, the partnership between the intertidal anemone Anthopleura elegantissima and its dinoflagellate and chlorophyte symbionts is one of the most well characterized. Biogeographic, reciprocal transplant, and physiological studies have convincingly demonstrated a relationship between environmental factors such as temperature and irradiance and the distribution of symbionts from both algal phyla. However, little is known about the fine-scale diversity or biogeographic distribution within symbiont lineages of this anemone. We used sequence information from the mitochondrial cytochrome b and chloroplast 23S ribosomal genes and restriction fragment length polymorphism data from the 18S nuclear ribosomal gene to characterize the Symbiodinium populations in tentacles clipped from 105 anemones at 14 sites along the entire California coast, spanning about 1200 km. Our results show the presence of at least three primary biogeographic regions with breaks around Cape Mendocino and Monterey Bay, each dominated by a different Symbiodinium muscatinei genotype. Sharp clines suggest limited gene flow between adjacent regions. Few sampling locations or individual anemones showed symbiont diversity at either organellar locus within the limits of our detection method, while sequence analysis of cloned nr18S polymerase chain reaction product suggests that nuclear pseudogenes may underlie intra-host diversity observed at that locus. PMID- 21712229 TI - Importance of behavior and morphological traits for controlling body temperature in littorinid snails. AB - For organisms living in the intertidal zone, temperature is an important selective agent that can shape species distributions and drive phenotypic variation among populations. Littorinid snails, which occupy the upper limits of rocky shores and estuaries worldwide, often experience extreme high temperatures and prolonged aerial emersion during low tides, yet their robust physiology- coupled with morphological and behavioral traits--permits these gastropods to persist and exert strong grazing control over algal communities. We use a mechanistic heat-budget model to compare the effects of behavioral and morphological traits on the body temperatures of five species of littorinid snails under natural weather conditions. Model predictions and field experiments indicate that, for all five species, the relative contribution of shell color or sculpturing to temperature regulation is small, on the order of 0.2-2 degrees C, while behavioral choices such as removing the foot from the substratum or reorienting the shell can lower body temperatures by 2-4 degrees C on average. Temperatures in central California rarely exceeded the thermal tolerance limits of the local littorinid species during the study period, but at sites where snails are regularly exposed to extreme high temperatures, the functional significance of the tested traits may be important. The mechanistic approach used here provides the ability to gauge the importance of behavioral and morphological traits for controlling body temperature as species approach their physiological thresholds. PMID- 21712230 TI - Quantifying complex shapes: elliptical fourier analysis of octocoral sclerites. AB - Species descriptions of most alcyonacean octocorals rely heavily on the morphology of sclerites, the calcium carbonate spicules embedded in the soft tissue. Sclerites provide taxonomic characters for species delineation but require qualitative descriptions, which introduce ambiguities in recognizing morphological features. Elliptical Fourier analysis of the outline of sclerites was used to quantify the morphology of eight species of gorgoniid octocoral in the genus Pseudopterogorgia. Sclerites from one to seven colonies of each species were compared. Scaphoids and spindles were examined separately; rods and octoradiates were excluded from the analyses because of their morphologic similarity across all species. Discriminant analysis of elliptical Fourier descriptors (EFDs) was used to determine whether the elliptical Fourier analysis could be used to identify the specimens. Sclerites were highly variable even within a single colony. Correct species assignments of individual sclerites were greater than 50% for both scaphoids and spindles. Species assignments based on averages of the EFDs for each colony approached 90%. Elliptical Fourier analysis quantifies morphological differences between species and measures colony variance in sclerite size and shape among colonies and species. Phylogenetic analysis based on EFDs did not capture monophyletic groups. The quantification of complex shapes such as sclerites provides an important tool in alpha taxonomy but may be less useful in phylogenetic analyses. PMID- 21712232 TI - Surgical ego, the good, the bad, and the ugly. PMID- 21712233 TI - Review: Minimally invasive versus conventional dynamic hip screw fixation in elderly patients with intertrochanteric fractures: a systematic review and meta analysis. AB - The classic dynamic hip screw fixation of intertrochanteric fractures may be associated with significant blood loss and soft tissue damage, which may worsen existing comorbidities of frail elderly patients. Recently, minimally invasive dynamic hip screw (MIDHS) technique was developed for osteosynthesis of intertrochanteric fractures. A highly sensitive search strategy was used to identify all published randomized or quasi-randomized controlled trials (RCTs/ qRCTs) and comparative observational studies comparing the MIDHS technique with the conventional dynamic hip screw (CDHS) technique in patients with intertrochanteric fractures. A pooled estimate of effect size was produced using both random and fixed effects models. Four RCTs/qRCTs and 2 retrospective comparative studies were identified. The MIDHS technique resulted in less blood loss, shorter hospitalization, lower pain level, faster fracture healing, and better hip function when compared with the CDHS technique. There was no significance difference between the 2 groups with regard to postoperative complications and implant position. The MIDHS technique may achieve perioperative benefits when compared with the CDHS technique. PMID- 21712234 TI - New technique for retraction of the strap muscles in endoscopic thyroidectomy. AB - OBJECTIVE: It is extremely important to establish sufficient exposure and room for manipulation during endoscopic thyroidectomy. To solve this problem, the authors have developed a new technique for retraction of the strap muscles perfected during 500 cases of breast-approach endoscopic thyroidectomy. METHODS: The new technique encompasses the use of 3 styles of retractor: the suture retractor, the button retractor, and the adjustable button retractor. These retractors are all easy to make and are all useful in different situations. CONCLUSIONS: The new technique is a safe and cost-effective method. It reduces the operation time required to obtain good exposure without transecting the strap muscles. In addition, it is minimally invasive and confers cosmetic benefits. PMID- 21712236 TI - Hydraulic adjustments underlying drought resistance of Pinus halepensis. AB - Drought-induced tree mortality has increased over the last decades in forests around the globe. Our objective was to investigate under controlled conditions the hydraulic adjustments underlying the observed ability of Pinus halepensis to survive seasonal drought under semi-arid conditions. One hundred 18-month saplings were exposed in the greenhouse to 10 different drought treatments, simulating combinations of intensities (fraction of water supply relative to control) and durations (period with no water supply) for 30 weeks. Stomata closed at a leaf water potential (Psi(l)) of -2.8 MPa, suggesting isohydric stomatal regulation. In trees under extreme drought treatments, stomatal closure reduced CO(2) uptake to -1 umol m(-2) s(-1), indicating the development of carbon starvation. A narrow hydraulic safety margin of 0.3 MPa (from stomatal closure to 50% loss of hydraulic conductivity) was observed, indicating a strategy of maximization of CO2 uptake in trees otherwise adapted to water stress. A differential effect of drought intensity and duration was observed, and was explained by a strong dependence of the water stress effect on the ratio of transpiration to evapotranspiration T/ET and the larger partitioning to transpiration associated with larger irrigation doses. Under intense or prolonged drought, the root system became the main target for biomass accumulation, taking up to 100% of the added biomass, while the stem tissue biomass decreased, associated with up to 60% reduction in xylem volume. PMID- 21712237 TI - Impact of variable [CO2] and temperature on water transport structure-function relationships in Eucalyptus. AB - Nearly 30 years ago, Whitehead and Jarvis and Whitehead et al. postulated an elegant mechanistic explanation for the observed relationship between tree hydraulic structure and function, hypothesizing that structural adjustments promote physiological homeostasis. To date, this framework has been nearly completely overlooked with regard to varying atmospheric carbon dioxide ([CO(2)]). Here, we evaluated Whitehead's hypothesis of leaf water potential (Psi(l)) homeostasis in faster-growing (Eucalyptus saligna) and slower-growing (Eucalyptus sideroxylon) tree saplings grown under three [CO(2)] (pre-industrial, current and future) and two temperature (ambient and ambient + 4 degrees C) treatments. We tested for relationships between physiological (stomatal conductance and Psi(l)) and structural (leaf and sapwood areas (A(l), A(s)), height (h), xylem conductivity (k(s))) plant variables as a function of the [CO(2)] and temperature treatments to assess whether structural variables adjusted to maintain physiological homeostasis. Structural components (A(l), A(s), h) generally increased with [CO(2)] or temperature, while g(s) was negatively correlated with [CO(2)]. Contrary to Whitehead's hypothesis, Psi(l) did not exhibit homeostasis in either species; elevated temperatures were associated with more negative Psi(l) in faster-growing E. saligna, and less negative Psi(l) in slower-growing E. sideroxylon. Moreover, individual structural variables were generally uncorrelated with Psi(l). However, across both species, the integrated hydraulic property of leaf specific hydraulic conductance (K(l)) was positively correlated with an independent calculation of K(l) determined exclusively from leaf physiological variables. These results suggest that physiological homeostasis may not apply to saplings exposed to global change drivers including [CO(2)] and temperature. Nevertheless, Whitehead et al.'s formulation identified K(l) as a sensitive measure of plant structural physiological co-variation across species. PMID- 21712238 TI - In vitro susceptibility of Actinobaculum schaalii to mecillinam. PMID- 21712239 TI - PCR ribotype prevalence and molecular basis of macrolide-lincosamide streptogramin B (MLSB) and fluoroquinolone resistance in Irish clinical Clostridium difficile isolates. AB - BACKGROUND: Antimicrobial use is recognized as a risk factor for Clostridium difficile infection (CDI) and outbreaks. We studied the relationship between PCR ribotype, antimicrobial susceptibility and the genetic basis of resistance in response to exposure to antimicrobial agents. METHODS: C. difficile isolates were cultured from 133 CDI patients for whom recent antimicrobial drug exposure had been recorded. Isolates were ribotyped by PCR and assessed for their susceptibility to the macrolide-lincosamide-streptogramin B (MLS(B)) group of compounds (erythromycin and clindamycin) and fluoroquinolone antimicrobials (ciprofloxacin, levofloxacin and moxifloxacin). Where relevant, the genetic basis of resistance was determined. RESULTS: Prevalent ribotypes (including 027, 001 and 106) exhibited significantly greater antimicrobial resistance compared with ribotypes 078 and 014, among others. Clindamycin-resistant ribotype 078 was detected for the first time. Ribotypes 027 and 001 were more likely to exhibit MLS(B) resistance, a feature that was associated with the erm(B) gene. Exposure to MLS(B) or fluoroquinolone antimicrobial compounds in the 8 weeks prior to the onset of infection was not associated with specific genetic markers of resistance. Single amino acid substitutions in the A and B subunits of DNA gyrase were noted and were ribotype specific and linked to resistance to moxifloxacin. CONCLUSIONS: Resistance to MLS(B) and fluoroquinolone antimicrobial compounds is common among prevalent ribotypes of C. difficile. The genetic basis for antimicrobial resistance appears to be ribotype specific and conserved in the absence of recent antimicrobial selection pressure. PMID- 21712240 TI - Comment on: The DART Trial: 'The Doctor's Dilemma' revisited. PMID- 21712242 TI - Determination of rifabutin dosing regimen when administered in combination with ritonavir-boosted atazanavir. AB - OBJECTIVES: Treatment of HIV/tuberculosis (TB) co-infected patients is complex due to drug-drug interactions for these chronic diseases. This study evaluates an intermittent dosing regimen for rifabutin when it is co-administered with ritonavir-boosted atazanavir. PATIENTS AND METHODS: A randomized, multiple-dose, parallel-group study was conducted in healthy subjects and these subjects received a daily dose of rifabutin 150 mg (n = 15, reference group) or a twice weekly dose with atazanavir 300 mg/ritonavir 100 mg once daily (n = 18, test group). Serial blood samples were collected at steady-state for pharmacokinetic analysis. Modelling and simulation techniques were utilized, integrating data across several healthy subject studies. This study is known as Study AI424-360 and is registered with ClinicalTrials.gov, number NCT00646776. RESULTS: The pharmacokinetic parameters (C(max), AUC(24avg) and C(min)) for rifabutin (149%, 48% and 40% increase, respectively) and 25-O-desacteyl rifabutin (6.77-, 9.90- and 10.45-fold increases, respectively) were both increased when rifabutin was co administered with atazanavir/ritonavir than rifabutin 150 mg once daily alone. The study was stopped because subjects experienced more severe declines in neutrophil counts when rifabutin was given with atazanavir/ritonavir than alone. A post-hoc simulation analysis showed that when rifabutin 150 mg was given three times weekly with atazanavir/ritonavir, the average daily exposure of rifabutin was comparable to rifabutin 300 mg once daily, a dose necessary for reducing rifamycin resistance in HIV/TB co-infected patients. CONCLUSIONS: The benefits to HIV/TB co-infected patients receiving rifabutin 150 mg three times weekly or every other day may outweigh the risks of neutropenia observed here in non-HIV infected subjects, provided that patients on combination therapy will be closely monitored for safety and tolerability. PMID- 21712243 TI - Diauxic shift-dependent relocalization of decapping activators Dhh1 and Pat1 to polysomal complexes. AB - Dhh1 and Pat1 in yeast are mRNA decapping activators/translational repressors thought to play key roles in the transition of mRNAs from translation to degradation. However, little is known about the physical and functional relationships between these proteins and the translation machinery. We describe a previously unknown type of diauxic shift-dependent modulation of the intracellular locations of Dhh1 and Pat1. Like the formation of P bodies, this phenomenon changes the spatial relationship between components involved in translation and mRNA degradation. We report significant spatial separation of Dhh1 and Pat1 from ribosomes in exponentially growing cells. Moreover, biochemical analyses reveal that these proteins are excluded from polysomal complexes in exponentially growing cells, indicating that they may not be associated with active states of the translation machinery. In contrast, under diauxic growth shift conditions, Dhh1 and Pat1 are found to co-localize with polysomal complexes. This work suggests that Dhh1 and Pat1 functions are modulated by a re-localization mechanism that involves eIF4A. Pull-down experiments reveal that the intracellular binding partners of Dhh1 and Pat1 change as cells undergo the diauxic growth shift. This reveals a new dimension to the relationship between translation activity and interactions between mRNA, the translation machinery and decapping activator proteins. PMID- 21712244 TI - Recycling of protein subunits during DNA translocation and cleavage by Type I restriction-modification enzymes. AB - The Type I restriction-modification enzymes comprise three protein subunits; HsdS and HsdM that form a methyltransferase (MTase) and HsdR that associates with the MTase and catalyses Adenosine-5'-triphosphate (ATP)-dependent DNA translocation and cleavage. Here, we examine whether the MTase and HsdR components can 'turnover' in vitro, i.e. whether they can catalyse translocation and cleavage events on one DNA molecule, dissociate and then re-bind a second DNA molecule. Translocation termination by both EcoKI and EcoR124I leads to HsdR dissociation from linear DNA but not from circular DNA. Following DNA cleavage, the HsdR subunits appear unable to dissociate even though the DNA is linear, suggesting a tight interaction with the cleaved product. The MTases of EcoKI and EcoAI can dissociate from DNA following either translocation or cleavage and can initiate reactions on new DNA molecules as long as free HsdR molecules are available. In contrast, the MTase of EcoR124I does not turnover and additional cleavage of circular DNA is not observed by inclusion of RecBCD, a helicase-nuclease that degrades the linear DNA product resulting from Type I cleavage. Roles for Type I restriction endonuclease subunit dynamics in restriction alleviation in the cell are discussed. PMID- 21712245 TI - In silico analysis of phytoene synthase and its promoter reveals hints for regulation mechanisms of carotenogenesis in Duanliella bardawil. AB - MOTIVATION: Previous researches showed that phytoene synthase (Psy) from Dunaliella bardawil is the first regulatory point in carotenogenesis. We hypothesize certain interactions between the environmental stress factors and the regulatory sequences of Psy in D.bardawil (DbPsy). Consequently, LA PCR-based genomic walking approach was performed for isolation of psy promoter and terminator, respectively. The obtained nucleic acid sequences and the corresponding protein structure of DbPsy were analyzed and predicted using various bioinformatics tools. Finally, we presented some hints for the regulation mechanisms of DbPsy at the molecular level according to the computed results. RESULTS: LA PCR-based genomic walking results showed that the isolated sequences are the promoter and terminator of psy, correspondingly. Computational analysis demonstrated several candidate motifs of the promoter exhibiting hypothetic UV-B , norglurzon- and salt-induced characteristics, as well as some typical domains universally discovered in promoter sequences, such as TATA-box, CCAAT-box and GATA-box, etc. Furthermore, the structure of Psy was also predicted and aligned along with many counterparts at the protein level. Low homology of N-terminus was found in D.bardawil, while a relatively conserved C-terminus was predicted to be involved in the catalytic activity and substrate recognization/binding. Phylogenic analysis classified the DbPsy into a cluster with other algae. These results implied that Psy may share similar regulation mechanisms among algae with respect to their C-termini; while the diversity in N-terminus among Psys, along with the predicted inducible motifs in psy promoter from D.bardawil, may confer the fine tuning differences between D.bardawil and other algae. CONCLUSION: By means of computer techniques, we found in D.barawali that two interesting conserved motifs of psy promoter may involve in UV-B, norglurzon and salt regulation correspondingly; and that the diversity of Psy protein mainly lies in the N-termini among algae. These results indicate some hints for regulation mechanisms of carotenogenesis in D.bradawil. CONTACT: jgjiang@scut.edu.cn. PMID- 21712241 TI - Efficacy and safety of raltegravir in treatment-experienced HIV-1-infected patients switching from enfuvirtide-based regimens: 48 week results of the randomized EASIER ANRS 138 trial. AB - OBJECTIVES: To assess the sustainable efficacy and safety of a switch from enfuvirtide to raltegravir in patients with multidrug-resistant HIV infection. METHODS: One hundred and seventy patients with multidrug-resistant HIV infection and suppressed plasma HIV RNA levels < 400 copies/mL under an enfuvirtide-based regimen were randomized to maintain their regimen or to switch to a raltegravir based regimen (immediate group) in a 48 week prospective, randomized, open-label trial. At week 24, patients in the maintenance arm also switched to raltegravir (deferred group). Baseline genotypic susceptibility scores (GSSs) were calculated using available historical resistance tests. Efficacy was assessed by the cumulative proportion of patients with virological failure, defined as a confirmed plasma HIV RNA >= 400 copies/mL up to week 48. The EASIER ANRS 138 trial is registered at ClinicalTrials.gov (NCT00454337). RESULTS: At baseline, 86% of patients had plasma HIV RNA levels <50 copies/mL and 86% had a GSS >= 1. Through to week 48, in the on-treatment analysis, only one patient in the immediate group, with a GSS of 0, developed virological failure. At week 48, 90% of patients in both the immediate and deferred groups had plasma HIV-1 RNA levels <50 copies/mL. Median CD4 cell counts remained stable during follow-up. Of note, 12 of 66 (18.2%) patients receiving a regimen combining raltegravir and ritonavir boosted tipranavir experienced alanine aminotransferase elevations, which led to a switch from tipranavir to darunavir in 8 cases, without discontinuation of raltegravir. CONCLUSIONS: In well-suppressed patients with multidrug-resistant HIV infection, a switch from enfuvirtide to raltegravir is generally well tolerated and has sustained antiviral efficacy when combined with a potent background regimen. PMID- 21712246 TI - CAMPAIGN: an open-source library of GPU-accelerated data clustering algorithms. AB - MOTIVATION: Data clustering techniques are an essential component of a good data analysis toolbox. Many current bioinformatics applications are inherently compute intense and work with very large datasets. Sequential algorithms are inadequate for providing the necessary performance. For this reason, we have created Clustering Algorithms for Massively Parallel Architectures, Including GPU Nodes (CAMPAIGN), a central resource for data clustering algorithms and tools that are implemented specifically for execution on massively parallel processing architectures. RESULTS: CAMPAIGN is a library of data clustering algorithms and tools, written in 'C for CUDA' for Nvidia GPUs. The library provides up to two orders of magnitude speed-up over respective CPU-based clustering algorithms and is intended as an open-source resource. New modules from the community will be accepted into the library and the layout of it is such that it can easily be extended to promising future platforms such as OpenCL. AVAILABILITY: Releases of the CAMPAIGN library are freely available for download under the LGPL from https://simtk.org/home/campaign. Source code can also be obtained through anonymous subversion access as described on https://simtk.org/scm/?group_id=453. CONTACT: kjk33@cantab.net. PMID- 21712247 TI - MetATT: a web-based metabolomics tool for analyzing time-series and two-factor datasets. AB - SUMMARY: Time-series and multifactor studies have become increasingly common in metabolomic studies. Common tasks for analyzing data from these relatively complex experiments include identification of major variations associated with each experimental factor, comparison of temporal profiles across different biological conditions, as well as detection and validation of the presence of interactions. Here we introduce MetATT, a web-based tool for time-series and two factor metabolomic data analysis. MetATT offers a number of complementary approaches including 3D interactive principal component analysis, two-way heatmap visualization, two-way ANOVA, ANOVA-simultaneous component analysis and multivariate empirical Bayes time-series analysis. These procedures are presented through an intuitive web interface. At the end of each session, a detailed analysis report is generated to facilitate understanding of the results. AVAILABILITY: Freely available at http://metatt.metabolomics.ca CONTACT: jianguox@ualberta.ca. PMID- 21712248 TI - BRISK--research-oriented storage kit for biology-related data. AB - MOTIVATION: In genetic science, large-scale international research collaborations represent a growing trend. These collaborations have demanding and challenging database, storage, retrieval and communication needs. These studies typically involve demographic and clinical data, in addition to the results from numerous genomic studies (omics studies) such as gene expression, eQTL, genome-wide association and methylation studies, which present numerous challenges, thus the need for data integration platforms that can handle these complex data structures. Inefficient methods of data transfer and access control still plague research collaboration. As science becomes more and more collaborative in nature, the need for a system that adequately manages data sharing becomes paramount. RESULTS: Biology-Related Information Storage Kit (BRISK) is a package of several web-based data management tools that provide a cohesive data integration and management platform. It was specifically designed to provide the architecture necessary to promote collaboration and expedite data sharing between scientists. AVAILABILITY AND IMPLEMENTATION: The software, documentation, Java source code and demo are available at http://genapha.icapture.ubc.ca/brisk/index.jsp. BRISK was developed in Java, and tested on an Apache Tomcat 6 server with a MySQL database. CONTACT: denise.daley@hli.ubc.ca. PMID- 21712249 TI - CytoscapeRPC: a plugin to create, modify and query Cytoscape networks from scripting languages. AB - SUMMARY: CytoscapeRPC is a plugin for Cytoscape which allows users to create, query and modify Cytoscape networks from any programming language which supports XML-RPC. This enables them to access Cytoscape functionality and visualize their data interactively without leaving the programming environment with which they are familiar. AVAILABILITY: Install through the Cytoscape plugin manager or visit the web page: http://wiki.nbic.nl/index.php/CytoscapeRPC for the user tutorial and download. CONTACT: j.j.bot@tudelft.nl; j.j.bot@tudelft.nl. PMID- 21712250 TI - Integration and visualization of host-pathogen data related to infectious diseases. AB - MOTIVATION: Infectious disease research is generating an increasing amount of disparate data on pathogenic systems. There is a growing need for resources that effectively integrate, analyze, deliver and visualize these data, both to improve our understanding of infectious diseases and to facilitate the development of strategies for disease control and prevention. RESULTS: We have developed Disease View, an online host-pathogen resource that enables infectious disease-centric access, analysis and visualization of host-pathogen interactions. In this resource, we associate infectious diseases with corresponding pathogens, provide information on pathogens, pathogen virulence genes and the genetic and chemical evidences for the human genes that are associated with the diseases. We also deliver the relationships between pathogens, genes and diseases in an interactive graph and provide the geolocation reports of associated diseases around the globe in real time. Unlike many other resources, we have applied an iterative, user centered design process to the entire resource development, including data acquisition, analysis and visualization. AVAILABILITY AND IMPLEMENTATION: Freely available at http://www.patricbrc.org; all major web browsers supported. CONTACT: cmao@vbi.vt.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21712251 TI - Paired-end RAD-seq for de novo assembly and marker design without available reference. AB - MOTIVATION: Next-generation sequencing technologies have facilitated the study of organisms on a genome-wide scale. A recent method called restriction site associated DNA sequencing (RAD-seq) allows to sample sequence information at reduced complexity across a target genome using the Illumina platform. Single-end RAD-seq has proven to provide a large number of informative genetic markers in reference as well as non-reference organisms. RESULTS: Here, we present a method for de novo assembly of paired-end RAD-seq data in order to produce extended contigs flanking a restriction site. We were able to reconstruct one-tenth of the guppy genome represented by 200-500 bp contigs associated to EcoRI recognition sites. In addition, these contigs were used as reference allowing the detection of thousands of new polymorphic markers that are informative for mapping and population genetic studies in the guppy. AVAILABILITY: A perl and C++ implementation of the method demonstrated in this article is available under http://guppy.weigelworld.org/weigeldatabases/radMarkers/ as package RApiD. CONTACT: christine.dreyer@tuebingen.mpg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21712252 TI - Introduction: maintenance of certification. PMID- 21712253 TI - Up-regulation of breast cancer resistance protein plays a role in HER2-mediated chemoresistance through PI3K/Akt and nuclear factor-kappa B signaling pathways in MCF7 breast cancer cells. AB - Human epidermal growth factor receptor 2 (HER2/neu, also known as ErbB2) overexpression is correlated with the poor prognosis and chemoresistance in cancer. Breast cancer resistance protein (BCRP and ABCG2) is a drug efflux pump responsible for multidrug resistance (MDR) in a variety of cancer cells. HER2 and BCRP are associated with poor treatment response in breast cancer patients, although the relationship between HER2 and BCRP expression is not clear. Here, we showed that transfection of HER2 into MCF7 breast cancer cells (MCF7/HER2) resulted in an up-regulation of BCRP via the phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B (NF-kappaB) signaling. Treatment of MCF/HER2 cells with the PI3K inhibitor LY294002, the IkappaB phosphorylation inhibitor Bay11-7082, and the dominant negative mutant of IkappaBalpha inhibited HER2-induced BCRP promoter activity. Furthermore, we found that HER2 overexpression led to an increased resistance of MCF7 cells to multiple antitumor drugs such as paclitaxel (Taxol), cisplatin (DDP), etoposide (VP-16), adriamycin (ADM), mitoxantrone (MX), and 5-fluorouracil (5-FU). Moreover, silencing the expression of BCRP or selectively inhibiting the activity of Akt or NF-kappaB sensitized the MCF7/HER2 cells to these chemotherapy agents at least in part. Taken together, up-regulation of BCRP through PI3K/AKT/NF-kappaB signaling pathway played an important role in HER2-mediated chemoresistance of MCF7 cells, and AKT, NF-kappaB, and BCRP pathways might serve as potential targets for therapeutic intervention. PMID- 21712254 TI - The hepatitis B virus-associated estrogen receptor alpha (ERalpha) was regulated by microRNA-130a in HepG2.2.15 human hepatocellular carcinoma cells. AB - The estrogen receptors (ERs) play important roles in hepatocarcinogenesis, which is always fostered by persistent hepatitis B virus (HBV) infection. Recent studies have linked microRNAs (miRNAs) to viral pathogenesis or oncogenesis. ERalpha could lead to cell cycle progression or inhibition of apoptosis, while ERbeta had opposite effects. Here we proposed that HBV affected ERs expression in viral oncogenesis, which might be triggered by miRNAs. The protein expression of ERalpha in HepG2.2.15 cells was much stronger than that in HepG2 cells, which was not consistent with its mRNA expression in these cells. MicroRNA-130a (miR-130a) was predicted to be a regulator of ERalpha by targeting its 3' untranslated region (3'-UTR). The enhanced green fluorescence protein (EGFP) reporter experiment confirmed the direct interaction of miR-130a and ERalpha. Moreover, ERalpha protein level was inversely correlated with the miR-130a level. Taken together, our studies supported that HBV infection might attenuate miR-130a expression and ERalpha was a direct target of miR-130a. Difference in miR-130a levels between HepG2 and HepG2.2.15 cells resulted in the difference in ERalpha expression, implying host-virus crosstalk in viral pathogenesis mediated by miRNAs. PMID- 21712255 TI - Outcomes of radical surgery for gallbladder cancer patients with lymphatic metastases. AB - OBJECTIVE: The objective of this study was to investigate whether radical surgical treatment can be associated with reasonable survival for patients with Stage IV gallbladder cancer with distant lymph node metastasis. METHODS: Fifty five patients (20 men and 35 women) with complete clinical and follow-up data for Japanese Society of Biliary Surgery TNM system Stage IV gallbladder cancer were included in our study. Patients were divided into three treatment groups for clinical analysis: Group A (radical resection, n = 24), Group B (chemotherapy, n = 8) and Group C (other palliative treatment, n = 23). RESULTS: The survival rate in Group A was significantly higher when compared with Groups B (P=0.008) and C (P=0.004). Moreover, the prognosis of patients with distant lymph node metastasis (Group A2, Japanese Society of Biliary Surgery N3; American Joint Committee on Cancer M1) was significantly worse versus those with local lymph node metastasis (Group A1, Japanese Society of Biliary Surgery N1-N2; American Joint Committee on Cancer N1) (P=0.007). Most importantly, no significant difference in the survival rate was observed between patients in Group A2 and Groups B (P = 0.47) or C (P = 0.74). CONCLUSIONS: Radical resection might result in a reasonable prognosis for gallbladder cancer patients with local metastasis of the lymph nodes (Japanese Society of Biliary Surgery N1-N2), but was not effective when distant lymph nodes (Japanese Society of Biliary Surgery N3) were involved. PMID- 21712256 TI - Exposure rate by the spectrum dose index method using plastic scintillator detectors. AB - The spectrum dose index (SDI) method was tested for use with data from plastic scintillator detectors by irradiating a typical portal detector system using different gamma sources and natural background. Measurements were compared with exposure rates simultaneously measured using a calibrated pressurised ion chamber. It was found that a modified SDI algorithm could be used to calculate exposure rates for these detectors despite the lack of photopeaks in plastic scintillator spectra. PMID- 21712257 TI - Potential dosemeter for quantifying biologically effective blue light exposures. AB - This paper reports on the development of a blue light (VIS(BL)) dosemeter. The VIS(BL) dosemeter is based on the combination of polysulfone and phenothiazine as a potential VIS(BL) dosemeter for population studies of exposures related to the blue light hazard. This research found that this combination of photosensitive chromophores reacts to both ultraviolet and visible wavelengths of the solar spectrum. Further to this, the majority of the ultraviolet wavelengths <380 nm can be filtered out with the use of a low-pass filter. It was found that a large change in optical absorbance at 437 nm occurred when the dosemeter was employed to quantify the solar blue light hazard exposures. Preliminary results indicate that this dosemeter saturates relatively slowly and is able to measure exposures equivalent to >1200 kJ m(-2) of blue light hazard weighted solar radiation. PMID- 21712258 TI - Factors associated with overweight and obesity among Kuwaiti men. AB - Obesity is a global epidemic and has become a critical issue in Gulf countries such as Kuwait. The objective of this study is to assess the factors that are associated with overweight and obesity among Kuwaiti adult men. Weights and heights of a random sample of 464 men and their companions were collected to obtain body mass index (BMI). The overall levels of overweight and obesity were 48.5% and 19.8%, respectively. Logistic regression analysis of significantly associated factors revealed that factors contributing to risk of overweight and obesity included increasing age, having an obese mother or brother(s) and/or other obese relatives, having a lower grade point average, not being physically active, and being in poor health. Having a higher income and feeling tired were risk factors for obesity only. Family history is an important predictor of overweight and obesity in Kuwaiti men; however, this study identified several modifiable factors. It is recommended that factors that contribute to the development of overweight and obesity in Kuwait be targeted with behavioral change and/or health education interventions. PMID- 21712259 TI - The relationship between complex fractionated electrograms and atrial low-voltage zones during atrial fibrillation and paced rhythm. AB - AIMS: Mapping of atrial fibrillation (AF) involves identification of low-voltage regions associated with complex fractionated electrograms (CFE) which theoretically represent abnormal substrate and targets for ablation. Whether low voltage CFE areas also identify abnormal substrate during paced rhythm is unknown. METHODS AND RESULTS: Twelve patients with persistent AF undergoing ablation of AF had high-density three-dimensional electroanatomic maps created during AF and paced rhythm (24 maps) and the mean voltage during AF and paced rhythm was compared for eight segments of the left atrium (LA). The following were correlated during AF and paced rhythm: regional mean voltage; %low voltage (defined as <0.5 mV); and extent of CFE. In addition, the relationship between the extent of CFE in AF: (i) %low voltage and (ii) conduction during paced rhythm were determined. Mean voltage was lower during AF than paced rhythm for all regions and globally (0.7 +/- 0.2 mV vs. 2.1 +/- 0.6 mV, P < 0.001). The regional and overall %low voltage of the LA was greater during AF than paced rhythm (53 +/ 19% vs. 9 +/- 2%, P < 0.001). There was no correlation between mean voltage or %low voltage during AF and paced rhythm. Complex fractionated electrograms were prevalent throughout all regions during AF, but did not correlate with %low voltage, fractionation, or slowed conduction during paced rhythm. CONCLUSION: Areas of CFE and low voltage recorded during AF frequently demonstrate normal atrial myocardial characteristics (normal conduction, electrograms, and voltage) during sinus rhythm. Therefore, AF CFE sites do not necessarily identify regions of an abnormal atrial substrate. However, this does not exclude the possibility that CFE might identify a focal driver or source occurring in a region of normal atrial myocardium. PMID- 21712260 TI - Feasibility of percutaneous implantation of transapical endocardial left ventricular pacing electrode for cardiac resynchronization therapy. AB - Failure of coronary sinus lead implantation for resynchronization therapy requires alternative approaches. For such events we have developed a transapical implantation technique as a feasible alternative. We report the outcome of this technique and its evolution from a minithoracotomy to a percutaneous approach. Twenty patients underwent alternative resynchronization therapy with transapical endocardial left ventricular (LV) pacing lead implantation in a multicentre, international study between October 2007 and March 2010. Eighteen patients underwent minithoracotomy and transapical puncture under direct observation. Two recent patients had transthoracic echocardiography-guided percutaneous apical puncture to enter the LV cavity. A 19 or 21 ga needle and two-stage Seldinger dilatation with 4 and 7 Fr sheaths were then used to introduce the lead. In the two patients with closed-chest insertion of the electrode there was no puncture related bleeding or lung damage. Lead dislocation occurred in two minithoracotomy patients. Repositioning was performed without re-opening the pleural cavity. One patient developed right-sided implanted cardiac defibrillator lead endocarditis requiring complete system removal. Twelve patients have >1 year follow-up; all have sustained and significant improvement in LV dimensions (diastolic Delta4.2 +/- 2.9, systolic Delta7.2 +/- 5.8 mm), ejection fraction (Delta9.5 +/- 9.6%), and functional status (Delta1.1 +/- 0.3). Transapical placement of LV endocardial pacing lead is an effective alternative strategy for cardiac resynchronization. A closed-chest, percutaneous approach is feasible and should offer even less invasive intervention. PMID- 21712261 TI - Right ventricular lead positioning does not influence the benefits of cardiac resynchronization therapy in patients with heart failure and atrial fibrillation. AB - AIMS: Little is known about the optimal right ventricular (RV) pacing site in cardiac resynchronization therapy (CRT). This study compares bi-ventricular pacing at the left ventricular (LV) free wall combined with two different RV stimulation sites: RV outflow tract (RVOT+LV) vs. RV-apex (RVA+LV). METHODS AND RESULTS: Thirty-three patients (32 males) with chronic heart failure, NYHA class III-IV, optimal drug therapy, QRS-duration >=150 ms, and chronic atrial fibrillation (AF) received CRT with two different RV leads, in the apex (RVA) or outflow tract (RVOT), together with an LV lead, all connected to a bi-ventricular pacemaker. Randomization to pacing in RVOT+LV or RVA+LV was made 1 month after implantation and cross-over to the alternate pacing configuration occurred after 3 months. The median age of patients was 69 +/- 10 years, the mean QRS was 179 +/ 23 ms, and 58% of patients had ischaemic heart disease. Seven patients had pacemaker rhythm at inclusion and 60% were treated with atrioventricular junctional ablation before randomization. In the RVA+LV and RVOT+LV pacing modes, 67 and 63% (nonsignificant) responded symptomatically with a decrease of at least 10 points in the Minnesota Living with Heart Failure score. The secondary end points (6-min walk test, peak oxygen uptake, N-Terminal fragment of B-type Natriuretic Peptide, and left ventricular ejection fraction) showed significant improvement between baseline and CRT, but not between RVOT+LV and RVA+LV. CONCLUSION: In this randomized controlled study, the exact RV pacing site, either apex or outflow tract, did not influence the benefits of CRT in a group of patients with chronic heart failure and AF. ClinicalTrials.gov ID: NCT00457834. PMID- 21712263 TI - Hospitalization: a relevant endpoint in atrial fibrillation management? PMID- 21712262 TI - LQT5 masquerading as LQT2: a dominant negative effect of KCNE1-D85N rare polymorphism on KCNH2 current. AB - AIMS: KCNE1 encodes an auxiliary subunit of cardiac potassium channels. Loss-of function variations in this gene have been associated with the LQT5 form of the long QT syndrome (LQTS), secondary to reduction of I(Ks) current. We present a case in which a D85N rare polymorphism in KCNE1 is associated with an LQT2 phenotype. METHODS AND RESULTS: An 11-year old competitive athlete presented with mild bradycardia and a QTc interval of 470 ms. An LQT2 phenotype, consisting of low-voltage bifid T waves, was evident in the right precordial electrocardiogram leads. During the tachycardia phase following adenosine, QTc increased to 620 ms. Genetic analysis revealed a rare heterozygous polymorphism in KCNE1 predicting the substitution of asparagine for aspartic acid at position 85 of minK (D85N). Patch clamp experiments showed that KCNE1-D85N, when co-expressed with KCNH2 in TSA201 cells, significantly reduced I(Kr). Homozygous co-expression of the mutant with KCNH2 reduced I(Kr) tail current by 85%, whereas heterozygous co-expression reduced the current by 52%, demonstrating for the first time a dominant-negative effect of D85N to reduce I(Kr). Co-expression of the mutant with KCNQ1, either homozygously or heterozygously, produced no change in I(Ks). CONCLUSIONS: Our results suggest that a rare polymorphism KCNE1-D85N underlies the development of an LQT2 phenotype in this young athlete by interacting with KCNH2 to cause a dominant-negative effect to reduce I(Kr). Our data provide further evidence in support of the promiscuity of potassium channel beta subunits in modulating the function of multiple potassium channels leading to a diversity of clinical phenotypes. PMID- 21712264 TI - Prognostic value of total atrial conduction time estimated with tissue Doppler imaging to predict the recurrence of atrial fibrillation after radiofrequency catheter ablation. AB - AIMS: Total atrial activation time has been identified as an independent predictor of new-onset atrial fibrillation (AF). Echocardiographic assessment of PA-TDI duration provides an estimation of total atrial conduction time. The aim of this study was to investigate the prognostic value of total atrial conduction time to predict AF recurrence after radiofrequency catheter ablation (RFCA). METHODS AND RESULTS: In 213 patients undergoing RFCA for symptomatic drug refractory paroxysmal AF, the total atrial conduction time was estimated by measuring the time delay between the onset of the P-wave in lead II of the surface electrocardiogram and the peak A'-wave on the tissue Doppler tracing of the left atrial (LA) lateral wall (PA-TDI duration). After RFCA, all patients were evaluated on a systematic basis at the outpatient clinic. After a mean follow-up of 13 +/- 3 months, 74 patients (35%) had recurrent AF whereas 139 patients (65%) maintained sinus rhythm. Left atrial maximum volume index and PA TDI duration were identified as independent predictors of AF recurrence after RFCA. However, receiver operator characteristics curve analyses demonstrated that PA-TDI duration had a superior accuracy to predict AF recurrence compared with LA maximum volume index (area under the curve 0.765 vs. 0.561, respectively). CONCLUSION: Assessment of total atrial conduction time using tissue Doppler imaging can be used to predict AF recurrence after RFCA. PMID- 21712265 TI - Extrasystolic stimulation with bi-ventricular pacing: an acute haemodynamic evaluation. AB - AIMS: Cardiac resynchronization therapy (CRT) by means of biventricular pacing (BiVP) is well established as a treatment for patients with heart failure (HF). Post-extrasystolic potentiation, (PESP) which involves a transient increase in myocardial contractility following a ventricular extrasystole, can be achieved using extrasystolic stimulation (ESS). On this basis, ESS has been proposed as a therapeutic. We assessed acute haemodynamic effects of ESS in the context of BiVP. METHODS AND RESULTS: Patients (n = 15, left ventricular ejection fraction < 40%, QRS >= 125 ms) with HF, received BiVP in combination with right ventricular (RV) ESS (single stimulus or pulse train). Left ventricular (LV) and peripheral arterial pressures were recorded and dP/dt was monitored. Addition of RV ESS to BiVP pacing led to a 21% increase in maximum (max) dP/dt (P < 0.001) and an 8.5 mm Hg increase in a systolic arterial pressure (P < 0.001). The modest fall in end-diastolic pressure (3.3 mmHg, P < 0.001) observed during ESS and BiVP was prevented by maintaining baseline sinus rate. Varying ESS modes or pacing outputs was not associated with differences in haemodynamic parameters. CONCLUSIONS: Biventricular pacing in combination with ESS, with maintenance of sinus rate, improves myocardial contractility in patients undergoing CRT. PMID- 21712267 TI - Where are the T-waves? PMID- 21712268 TI - Duration of head-up tilt test for patients with suspected vasovagal syncope: a not-so-'original article'. PMID- 21712269 TI - Beat-to-beat variability of T-wave amplitude for the risk assessment of ventricular tachyarrhythmia in patients without structural heart disease. AB - AIMS: Increased temporal repolarization lability, assessed by beat-to-beat variability of T-wave amplitude (TAV), has been shown to be associated with ventricular tachyarrhythmia in patients with a variety of clinical conditions. The aim of this study was to test the ability of TAV to identify patients presenting with malignant ventricular arrhythmia and to predict subsequent occurrences. METHODS AND RESULTS: We studied 20 consecutive patients (age 42 +/- 15 years, mean +/- standard deviation) presenting with ventricular tachyarrhythmia who did not have substantial underlying heart disease and compared them with 40 age- and sex-matched control subjects. The TAV was determined by Holter recording (Ela Medical). Patients with ventricular tachyarrhythmia had a higher maximum value of TAV (max TAV: 38 +/- 18 vs. 22 +/- 15 MUV, P < 0.001) than did the controls. The sensitivity and specificity of max TAV > 22.4 MUV for detecting the occurrence of ventricular tachyarrhythmia were 77 and 90%, respectively. During a mean follow-up period of 23 months, three patients had relapses of ventricular tachyarrhythmia. Patients with a recurrence of ventricular tachyarrhythmia had a trend towards a higher max TAV as compared with those who had ventricular tachyarrhythmia but did not relapse (56 +/- 23 vs. 36 +/- 16 MUV, P = 0.061). CONCLUSION: Our results suggest that Holter-derived TAV might be associated with the occurrence and recurrence of ventricular tachyarrhythmia in patients without structural heart disease. Prospective validation will be necessary to assess the potential diagnostic value of the TAV in a large general population. PMID- 21712270 TI - Do not always accuse the leads.... PMID- 21712271 TI - Three-dimensional look at internal cardiodefibrillator-leads and right atrial thrombus. PMID- 21712272 TI - Pseudo-T-wave alternans with atrio-ventricular nodal reentrant tachycardia and group beating: the proof is in the QRS complexes. PMID- 21712275 TI - Sustained ventricular tachycardia in renal cell carcinoma metastatic to anterior apical wall of the left ventricle. AB - A 50-year-old man with a history of renal cell carcinoma was admitted with ventricular tachycardia. Echocardiography showed a mass in the apex of the left ventricle. Cardiac magnetic resonance confirmed a mass infiltrating the anterior apical wall of the left ventricle. This is the first case describing an association between ventricular tachycardia and renal cell carcinoma metastatic to the left ventricle. PMID- 21712274 TI - The European cardiac resynchronization therapy survey: patient selection and implantation practice vary according to centre volume. AB - AIMS: The European cardiac resynchronization therapy (CRT) survey is a joint initiative taken by the Heart Failure Association and the European Heart Rhythm Association of the European Society of Cardiology with the primary objective of describing current European practice associated with CRT implantations. The results demonstrated that a substantial number of implantations took place in patients without conventional guideline indications. We investigated whether the volume of implants per centre was a determinant of the propensity to use devices for 'off-label' indications. METHODS AND RESULTS: One hundred and forty-one centres from 13 European countries contributed data from consecutive patients successfully implanted with a CRT-P or CRT-D device between November 2008 and June 2009. Centres were categorized into low volume (LVol; <= 120 implantations/year) and high volume (HVol; >120 implantations/year) based on median implantable cardioverter-defibrilator implantation the previous year. No differences were noted with regard to sex, age, or peri-procedural and device related complications. High-volume centres implanted CRT devices in significantly more patients with mild symptoms and a narrow QRS width. The procedure and fluoroscopy times were substantially longer at LVol centres and devices were more frequently implanted by surgeons and interventional cardiologists. Patients stayed longer in hospital in LVol centres with a median of 4 (2-9) vs. 2 (2-6) days. CONCLUSIONS: High-volume centres explore newer indications in their CRT practice and implant devices more frequently in patients with mild symptoms and narrow QRS durations. Electrophysiologists dominate implantation practice at HVol centres and duration of hospitalization is substantially shorter at these centres. PMID- 21712276 TI - Catheter ablation of severe neurally meditated reflex (neurocardiogenic or vasovagal) syncope: cardioneuroablation long-term results. AB - AIMS: Neurally meditated reflex or neurocardiogenic or vasovagal syncope (NMS) is usually mediated by a massive vagal reflex. This study reports the long-term outcome of NMS therapy based on endocardial radiofrequency (RF) catheter ablation of the cardiac vagal nervous system aiming permanent attenuation or elimination of the cardioinhibitory reflex (cardioneuroablation). METHODS AND RESULTS: A total of 43 patients (18F/25M, 32.9 +/- 15 years) without apparent cardiopathy (left ventricular ejection fraction=68.6 +/- 5%) were included. All had recurrent NMS (4.7 +/- 2 syncope/patient) with important cardioinhibition (pauses=13.5 +/- 13 s) at head-up tilt test (HUT), normal electrocardiogram (ECG), and normal atropine test (AT). The patients underwent atrial endocardial RF ablation using spectral mapping to track the neurocardiac interface (AF Nest Mapping). The follow-up (FU) consisted of clinical evaluation, ECG (1 month/every 6 months/or symptoms), Holter (every 6 months/or symptoms), HUT (>= 4 months/or symptoms), and AT (end of ablation and >= 6 months). A total of 44 ablations (48 +/- 9 points/patient) were performed. Merely three cases of spontaneous syncope occurred in 45.1 +/- 22 months (two vasodepressor, one undefined). Only four partial cardioinhibitory responses occurred in post-ablation HUT without pauses or asystole (sinus bradycardia). Long-term AT (21.7 +/- 11 months post) was negative in 33 (76.7%, P < 0.01), partially positive in 7(16.3%), and normal in three patients only (6.9%) reflecting long-term vagal denervation (AT-Delta%HR pre 79.4% * 23.2% post). The post-ablation stress test and Holter showed no abnormalities. No major complications occurred. CONCLUSION: Endocardial RF catheter ablation of severe neurally meditated reflex syncope prevented pacemaker implantation and showed excellent long-term results in well selected patients. Despite no action in vasodepression it seems to cause enough long-term vagal reflex attenuation, eliminating the cardioinhibition, and keeping most patients asymptomatic. Indication was based on clinical symptoms, reproduction of severe cardioinhibitory syncope, and normal atropine response. PMID- 21712277 TI - Inappropriate mode switch consecutive to P-wave double counting. AB - We report a case of multiple inappropriate mode switches in a patient with a dual chamber pacemaker, resulting from P-wave double counting due to a double potential on the atrial electrogram. The differential diagnosis of this rarely reported phenomenon is discussed. PMID- 21712278 TI - Spatiotemporal electrophysiological changes in a murine ablation model. AB - AIMS: High recurrence rates after complex radiofrequency ablation procedures, such as for atrial fibrillation, remain a major clinical problem. Local electrophysiological changes that occur following cardiac ablation therapy are incompletely described in the literature. The purpose of this study was to determine whether alterations in conduction velocity, action potential duration (APD), and effective refractory period resolve dynamically following cardiac ablation. METHODS AND RESULTS: Lesions were delivered to the right ventricle of mice using a subxiphoid approach. The sham-operated control group (SHAM) received the same procedure without energy delivery. Hearts were isolated at 0, 1, 7, 30, and 60 days following the procedure and electrophysiological parameters were obtained using high-resolution optical mapping with a voltage-sensitive dye. Conduction velocity was significantly decreased at the lesion border in the 0, 7, and 30 day groups compared to SHAM. APD(70) at the lesion border was significantly increased at all time points compared to SHAM. Effective refractory period was significantly increased at the lesion border at 0, 1, 7, and 30 days but not at 60 days post-ablation. This study demonstrated that post-ablation electrophysiological changes take place immediately following energy delivery and resolve within 60 days. CONCLUSIONS: Cardiac ablation causes significant electrophysiological changes both within the lesion and beyond the border zone. Late recovery of electrical conduction in individual lesions is consistent with clinical data demonstrating that arrhythmia recurrence is associated with failure to maintain bi-directional conduction block. PMID- 21712279 TI - Significant mitral regurgitation regression by slight modification of the right ventricular pacing site. AB - A dual-chamber pacemaker was implanted because of symptomatic bradycardia in a 60 year-old patient free from other heart disease. Then, the patient developed acute congestive heart failure due to pacing-induced mitral regurgitation (MR). Under echocardiographic guidance, modification of location of the right ventricular pacing lead led to a significant decrease in MR severity resulting in immediate clinical improvement. PMID- 21712281 TI - Management of atrial fibrillation around the world: a comparison of current ACCF/AHA/HRS, CCS, and ESC guidelines. AB - New guidelines for the management of atrial fibrillation (AF) have recently been published by the American College of Cardiology Foundation/American Heart Association, and Heart Rhythm Society (ACCF/AHA/HRS) task force on practice guidelines, the Canadian Cardiovascular Society (CCS), and the European Society of Cardiology (ESC). Although they all refer to the same scientific data and agree in the majority of AF management, interpretation, and weighing of study results are quite different in some aspects. While recommendations for stroke risk assessment and prophylaxis are rather conservative in the ESC guidelines, the CCS guideline recommendations are more conservative with regard to lenient rate control and the ACCF/AHA/HRS recommendations are rather strict with regard to rhythm management. PMID- 21712280 TI - Risk factors of self-terminating and perpetuating ventricular tachyarrhythmias in post-infarction patients with moderately depressed left ventricular function, a CARISMA sub-analysis. AB - AIMS: The present study aimed to assess whether there are differences in risk indicators for perpetuating ventricular tachyarrhythmias (pVT) and self terminating ventricular tachyarrhythmias (stVT). METHODS AND RESULTS: Patients with acute myocardial infarction (AMI) and baseline left ventricular ejection fraction <= 40% (n = 292) received an implantable electrocardiogram loop recorder from 5 to 21 days after AMI and were followed up for 24 months to document arrhythmic events in the Cardiac Arrhythmias and Risk Stratification after Acute Myocardial Infarction (CARISMA) study. Several risk markers, such as the inducibility to sustained ventricular tachycardia during programmed electrical stimulation (PES), the signal-averaged ECG QRS duration (SAECG-QRS), heart rate variability (HRV) and turbulence (HRT), T-wave alternans, and non-sustained ventricular tachycardia on Holter were analysed at 6 weeks after the AMI. During the follow-up, 26 patients (9%) experienced an stVT (>= 16 beats and < 30 s), and 21 patients (7%) a pVT. The occurrence of non-sustained ventricular tachycardia on Holter significantly predicted stVT [hazard ratio (HR) = 2.90, 1.26-6.67, 95% confidence interval (CI), P = 0.01], but not pVT during the follow-up. The inducibility during PES (HR = 5.02, 1.85-13.60, 95% CI, P = 0.001), SAECG-QRS >= 130 ms (HR = 8.73, 3.38-22.56, 95% CI, P < 0.001), the short-term scaling exponent HRV parameter <= 0.77 (HR = 5.65, 2.12-15.10, 95% CI, P = 0.001), and HRT slope <= 1.75 ms/NN (HR = 4.57, 1.80-11.59, 95% CI, P = 0.001) were significant predictors of pVT, even after adjustments with relevant clinical parameters (P from < 0.01 to < 0.001), but did not significantly predict the occurrence of stVT (P from 0.35 to 0.75). CONCLUSION: Self-terminating ventricular tachyarrhythmia and pVT have differences in electrophysiological substrate and arrhythmia modifiers in post-AMI patients with moderate left ventricular dysfunction. PMID- 21712282 TI - Regional fractionation and dominant frequency in persistent atrial fibrillation: effects of left atrial ablation and evidence of spatial relationship. AB - AIMS: The aim was to study regional fractionation and dominant frequency (DF) to determine if any relationship exists between the two parameters and also to assess the impact of limited left atrial ablation. METHODS AND RESULTS: Patients undergoing catheter ablation of persistent AF using three-dimensional navigation were studied. Regional left atrial electrograms were analysed in the frequency domain by assessing DF and organization index (OI), and for degree of fractionation [using complex fractionated electrograms (CFE)-mean] before and after circumferential pulmonary vein and left atrial roof ablation. Twenty-three patients with persistent AF were studied. After ablation, global CFE-mean increased [100 +/- 5 to 147 +/- 11 ms (P= 0.0003)], DF decreased [6.1 +/- 0.2 to 5.3 +/- 0.2 Hz (P= 0.0003)], and OI was unchanged [0.27 +/- 0.01 to 0.26 +/- 0.02, (P= 0.70)]. Comparing sites close to and distant from ablation lines, percentage change in CFE-mean was 94 +/- 10 vs. 37 +/- 6% (P< 0.0001), DF change was -13 +/- 3 vs.-12 +/- 2% (P= 0.98), and OI change was 3 +/- 6 vs. 10 +/- 5% (P= 0.75), respectively. There was modest correlation between CFE-mean and DF points prior to ablation (r = -0.33, P< 0.0001) which was reduced following left atrial ablation (r = -0.24, P= 0.005). CONCLUSIONS: Left atrial ablation reduces global left atrial DF and decreases the degree of fractionation. Complex fractionated electrograms-mean and DF appear to share only modest spatial correlation and are affected to different extents by ablation, suggesting that they are either separate entities or reflect different components of the same substrate. PMID- 21712283 TI - Pacemaker implantation in small hospitals: complication rates comparable to larger centres. AB - AIMS: Some countries have a demography that makes it necessary to maintain relatively small pacemaker centres. We wanted to assess the quality of pacemaker surgery in two such hospitals. METHODS AND RESULTS: Through patient records we gathered information on ~535 consecutive primary pacemaker implantations in two small pacemaker centres with 30 and 80 annual operations, respectively. All patients were followed for 3 years. All complications documented in the patient records were registered. Furthermore, we performed a non-systematic literature search comparing our data with reports from major centres published over the last 10 years.We found 72 complications in 64 (12.0%) of the patients, the most common being bleeding, lead failure, and pneumothorax. If minor bleedings without any consequences for the patients are excluded, the number of complications was 46 in 40 patients (7.5%). We had to reoperate on 5.2% of the patients. There was no statistically significant difference in complication rates between the two hospitals. Education candidates generated statistically significant more complications than experienced doctors (13.7 vs. 7.1%, P < 0.05). CONCLUSION: There are no generally accepted norms of complication rates in pacemaker surgery. However, we found no indications that our centres have a rate of complications that is unacceptably high. PMID- 21712284 TI - Impact of left ventricular ejection fraction on occurrence of ventricular events in defibrillator patients with coronary artery disease. AB - AIMS: Primary preventive implantable cardioverter defibrillator (ICD) therapy is indicated in patients with coronary artery disease (CAD) and left ventricular ejection fraction (LVEF) of <= 35%, but some patients in the major trials had LVEF in the range of 30-35%. We hypothesized that these patients constitute a lower-risk population and might derive less benefit from ICD therapy. METHODS AND RESULTS: In this retrospective study, patients with CAD in whom an ICD was implanted for primary prevention were studied. We determined the incidence of ICD therapies in two predefined LVEF cut-off groups (<=/>20%; <=/>30%), predictors of ICD therapies, and overall mortality. A total of 536 patients were included: 88% male, age 63 +/- 10 years, follow-up 30 +/- 25 months. In all, 115 patients (22%) experienced appropriate ICD interventions; in 36% of them, the arrhythmia was treated with shock. Inappropriate therapy was delivered in 8%. Cumulative mortality at 5 years was 20%. Using our two cut-off levels, more ICD-therapies occurred in patients with poorer LVEF, but the difference was significant only with the cut-off value of <=/>20%. Only 2 of 12 parameters were predictors of appropriate ICD therapy: age, odds ratio (OR) 1.047 (1.015-1.079) per year and QRS width, OR 1.014 per ms (1.004-1.024). CONCLUSION: Refined risk stratification using different LVEF cut-off levels is not helpful in patients with CAD and LVEF <= 35%. Mortality was lower than in randomized trials in this real-world setting, probably due to better drug treatment at implant. PMID- 21712285 TI - Pacemaker clinic: an opportunity to detect silent atrial fibrillation and improve antithrombotic treatment. AB - AIMS: The prevalence of atrial fibrillation (AF) in patients with pacemakers is high, and often passes unnoticed. Our aim was to assess the use of antithrombotic treatment in this group of patients. METHODS AND RESULTS: All patients who came to our institution to have their pacemakers checked during the year 2008 were included in this study. The atrial activity was assessed by slowing down the paced frequency if necessary, and by the analysis of atrial electrograms in atrial-based pacemakers. The appropriateness of the antithrombotic treatment was evaluated by a cardiologist. Out of 585 patients, 216 (36.9%) displayed AF at some point during the 5.5-year monitoring period (1.5-11), although only 58 (9.9%) displayed it at the time of the implant. Of these 216, 58% were men, with an average age of 80 years (76-86 years). The pacemaker was implanted in response to an atrioventricular block (AVB) in 46.3% of the cases, sinoatrial node disorder in 24.1% of the cases, and slow AF in 25.9% of the cases. The CHADS2 score was 0 points in 4.2% (9) of the cases, 1 point in 19% (41) of the cases, and >= 2 points in 77% (173) of the cases. Despite this, only 58.3% of the cases received anticoagulant treatment. The existence of arrhythmia at the time of implantation [odds ratio (OR) = 4.25; 95% confidence interval (95% CI), 1.72 10.51; P = 0.002] and the implantation of a pacemaker with atrioventricular synchronization (OR = 13.23; 95% CI, 2.89-60.56; P = 0.001) were associated with the use of anticoagulant treatment in those cases with CHADS2>2. CONCLUSION: Atrial fibrillation is common in patients fitted with pacemakers. Despite the high risk of embolism, an underuse of anticoagulant treatment was observed. PMID- 21712286 TI - Long-term outcome of cardiac contractility modulation in patients with severe congestive heart failure. AB - AIMS: Cardiac contractility modulation (CCM) is a new form of electrical therapy in patients with congestive heart failure. Recently published clinical studies provide evidence of safety and improvements of exercise tolerance and quality of life. In this study, we investigated the impact of CCM on cardiac and all-cause mortality. METHODS AND RESULTS: Fifty-four consecutive patients (age 63 +/- 10 years, 91% male, left ventricular ejection fraction 23 +/- 6%, baseline peak oxygen consumption 10.0 +/- 4.8 mL/min/kg, N-terminal pro-B-type natriuretic peptide 5194 pg/mL, New York Heart Association III/IV) who underwent implantation of an Optimizer system (IMPULSE Dynamics, Orangeburg, NY, USA) at our centre between June 2003 and June 2010 were analysed retrospectively. Patients were followed every 3 months at our outpatient clinic. This study determined long-term outcomes of patients receiving CCM therapy. Twenty-four (44%) patients died during the follow-up period, which included 19 cardiac deaths (3 sudden cardiac deaths and 16 terminal cardiac pump failure deaths). The Kaplan-Meier analysis calculated a median survival time of 992 days (33.1 months) and a mean death rate of 18.4% per year. All-cause mortality for these patients was precisely predicted by the Seattle Heart Failure Model. CONCLUSION: Cardiac contractility modulation appears to be a safe therapeutic option for advanced heart failure patients who have no other therapeutic options. Symptomatic improvement by CCM has been shown in earlier studies but our observational study suggests, for the first time, that there is no adverse effect of CCM on long-term survival. PMID- 21712287 TI - Quality of life is impaired similarly in heart failure patients with preserved and reduced ejection fraction. AB - AIMS: To compare quality of life (QoL) in heart failure (HF) patients with preserved ejection fraction (HF-PEF) and HF patients with reduced ejection fraction (HF-REF) in a well-defined HF population. METHODS AND RESULTS: Patients with HF-PEF [left ventricular ejection fraction (LVEF) >=40%] were matched by age and gender to patients with HF-REF (LVEF <40%). In the current study, we only included HF patients with a B-type natriuretic peptide level (BNP) >100 pg/mL. Quality of life was assessed by Cantril's Ladder of Life, RAND-36, and the Minnesota Living with Heart Failure questionnaire, and impairment of QoL was adjusted for by BNP as a marker for severity of HF. We examined a total of 290 HF patients, of whom 145 had HF-PEF (41% female; age 72 +/- 10; LVEF 51 +/- 8%) and 145 had HF-REF (41% female; age 73 +/- 10, LVEF 26 +/- 7%). All HF patients reported markedly low scores of QoL, both on the general and disease-specific QoL questionnaires. Quality of life between patients with HF-PEF and HF-REF did not differ significantly. When adjusting the QoL scores for BNP, an association between QoL and LVEF was not found, i.e. patients with HF-PEF and HF-REF with similar BNP levels had the same impairment in QoL. CONCLUSION: Quality of life is similarly impaired in patients with HF-PEF as in HF-REF. These findings further support the need for more pharmacological and non-pharmacological studies in patients with HF-PEF. TRIAL REGISTRATION NUMBER: NCT 98675639. PMID- 21712288 TI - Short-term opioids for breathlessness in stable chronic heart failure: a randomized controlled trial. AB - AIMS: To assess the effect of oral opioids vs. placebo on breathlessness in patients with chronic heart failure (CHF). METHODS AND RESULTS: Oral morphine (Oramorph), oral oxycodone (Oxynorm), and placebo were studied in an outpatient setting. Once randomized, participants received all three interventions in a controlled double-blind crossover trial for 4 days each, with a 3-day washout between interventions. Patients known to the Hull and East Yorkshire Academic Cardiology department with CHF (New York Heart Association Grade III-IV) were invited to participate. Participants were eligible if they were on standard medical therapy with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and diuretics. Participant-rated change in 11-point numerical rating scale (NRS) (average over previous 24 h) breathlessness severity score from baseline (Day 1) to Day 4 of treatment was the primary outcome measure. The study was powered to detect a one-point change in severity.Thirty-nine patients were randomized and 35 completed all three study arms. Breathlessness severity was reduced from baseline with all three interventions. There was no statistically significant difference between active intervention and placebo or between the two types of opioid for the primary endpoint [-1.37 in NRS score for placebo group vs. -0.41 in morphine group (P = 0.13) and -1.29 for oxycodone group (P = 0.90)]. The response to treatment was not affected by aetiology, severity of CHF, or concurrent drug therapy. Opioid administration did not cause detrimental changes in clinical observations and was well tolerated. CONCLUSION: We demonstrated no benefit over placebo for the relief of breathlessness with short-term low-dose oral opioids for CHF patients. Trial registered prior to the recruitment of the first participant with Current Controlled Trials (www.controlled-trials.com; Trial number ISRCTN 85268059). PMID- 21712289 TI - Characterization of heart failure patients with preserved ejection fraction: a comparison between ADHERE-US registry and ADHERE-International registry. AB - AIMS: To characterize geographic differences in clinical characteristics and care of patients hospitalized with heart failure and preserved ejection fraction (HF PEF). METHODS AND RESULTS: Using data on 61 182 admissions in 307 US hospitals from March 2004 to March 2006 from the Acute Decompensated Heart Failure National Registry (ADHERE)-United States (US) database and 10 904 admissions in 70 hospitals from 10 countries from March 2005 to January 2009 from the ADHERE International (I) database composed of countries in Asia-Pacific and Latin American regions, we compared characteristics, treatments, length of stay, and in hospital mortality between patients with PEF (left ventricular EF >= 40%). There were 26 258 (49.6%) admissions with HF-PEF in the ADHERE-US and 4206 (45.7%) in ADHERE-I. The USA cohort was older [median 77.2 years (25th, 75th, 66.5, and 84.4) vs. 71.0 (59.0, 79.0), P< 0.001] and more likely to be female (61.8 vs. 54.7%, P< 0.001). The international cohort had a longer length of stay [median 6.0 days (4.0, 10.0)] vs. 4.0 days [3.0, 7.0], P< 0.001) and higher use of inotropes (12.5 vs. 4.8%, P< 0.001). At discharge, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers, and diuretics were prescribed more in the USA (57.6 vs. 54.4%, P< 0.001; 63.0 vs. 35.5%, P< 0.001; 78.2 vs. 76.2%, P< 0.001); digoxin was prescribed more outside the USA (26.0 vs. 17.7%, P< 0.001). After adjusting for baseline characteristics, 7-day inpatient mortality was similar between the international and the USA cohorts [hazard ratio 0.80, 95% CI (0.61-1.05); P= 0.11]. CONCLUSIONS: Clinical characteristics, inpatient interventions, discharge therapies, and length of stay vary significantly for HF-PEF patients across geographic regions. This has important implications for global clinical trials and outcome studies in HF. PMID- 21712290 TI - Directions from Hecate: towards a multi-marker approach for heart failure assessment. PMID- 21712291 TI - Revascularization for patients with heart failure. Inconsistencies between theory and practice. PMID- 21712292 TI - Grading diastolic left ventricular function. PMID- 21712293 TI - Clinical trials update from the American College of Cardiology Meeting 2011: STICH, NorthStar, TARGET, and EVEREST II. AB - This article provides information and a commentary on key trials relevant to the pathophysiology, prevention, and treatment of heart failure (HF) presented at the annual American College of Cardiology meeting held in New Orleans in 2011. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. The STICH trial failed to show a benefit of revascularization on all-cause mortality in patients with HF and coronary artery disease; however, cardiovascular deaths were reduced compared with medical therapy alone. Results from the NorthStar study suggest that patients with clinically stable systolic HF, who are on optimal medical therapy, including those with elevated amino-terminal B-type natriuretic peptide levels, may not benefit from long-term follow-up in an HF clinic. Results from the TARGET study demonstrate that targeted left ventricular lead placement using speckle tracking echocardiography is feasible in patients undergoing implantation of a cardiac resynchronization therapy device and is associated with an enhanced response. Two year follow-up data from EVEREST II show that although a catheter-based mitral valve repair procedure using the MitraClip((r)) system was less effective at reducing mitral regurgitation than conventional surgery, similar improvements in clinical outcomes were observed with fewer short-term adverse events. PMID- 21712294 TI - Environmental regulation of sex determination in oil palm: current knowledge and insights from other species. AB - BACKGROUND: The African oil palm (Elaeis guineensis) is a monoecious species of the palm subfamily Arecoideae. It may be qualified as 'temporally dioecious' in that it produces functionally unisexual male and female inflorescences in an alternating cycle on the same plant, resulting in an allogamous mode of reproduction. The 'sex ratio' of an oil palm stand is influenced by both genetic and environmental factors. In particular, the enhancement of male inflorescence production in response to water stress has been well documented. SCOPE: This paper presents a review of our current understanding of the sex determination process in oil palm and discusses possible insights that can be gained from other species. Although some informative phenological studies have been carried out, nothing is as yet known about the genetic basis of sex determination in oil palm, nor the mechanisms by which this process is regulated. Nevertheless new genomics based techniques, when combined with field studies and biochemical and molecular cytological-based approaches, should provide a new understanding of the complex processes governing oil palm sex determination in the foreseeable future. Current hypotheses and strategies for future research are discussed. PMID- 21712295 TI - Lessons from Plectocephalus (Compositae, Cardueae-Centaureinae): ITS disorientation in annuals and Beringian dispersal as revealed by molecular analyses. AB - BACKGROUND AND AIMS: The geographic distribution of the genus Plectocephalus comprises a single species in Ethiopia, two in North America and possibly four more in South America, in a striking disjunction that is exceptional for genera of the tribe Cardueae. The enormity of this disjunction cast doubts on the precise taxonomic delineation of the genus, which is not unanimously recognized as a natural entity. The aims of this study were to define the generic boundaries of Plectocephalus and to formulate a hypothesis that would explain its natural range. METHODS: A combined molecular approach, using nuclear internal transcribed spacers (ITS) and external transcribed spacers (ETS), and plastid trnL-trnL-F, rpl32-trnL(UAG) and ndhF markers, was chosen for phylogenetic reconstruction by maximum parsimony and Bayesian inference. KEY RESULTS: Phylogenetic analysis shows that Plectocephalus is a natural genus that includes the African species P. varians, together with all the native South American species, currently classified as Centaurea, C. cachinalensis, C. floccosa and C. tweediei. The recognition of Centaurodendron as an independent genus, which we consider appropriate, would make Plectocephalus paraphyletic. Affinities of Plectocephalus should lie with eastern representatives of Centaureinae. Geographic disjunction is explained as a consequence of dispersal via the Bering Land Bridge during the Miocene--Pliocene. The phylogeny of the basal grade of Centaureinae differs from previous phylogenies, and artefacts resulting from differences in mutation rates of annual and perennial taxa are confirmed. Sensitivity of ITS to these differences was the highest observed for all DNA regions used in this study. CONCLUSIONS: The natural status of the genus Plectocephalus is confirmed and several nomenclatural combinations are proposed. New evidence contributes to the debate concerning problems posed by the use of ITS in the phylogenetic reconstruction of groups that differ in terms of their life cycles. Dispersal from Caucasus and Anatolia along the Siberian route and then across the Bering Land Bridge follows a route previously proposed for other taxonomic groups. PMID- 21712296 TI - A cell-type-specific defect in border cell formation in the Acacia mangium root cap developing an extraordinary sheath of sloughed-off cells. AB - BACKGROUND AND AIMS: Root caps release border cells, which play central roles in microbe interaction and root protection against soil stresses. However, the number and connectivity of border cells differ widely among plant species. Better understanding of key border-cell phenotype across species will help define the total function of border cells and associated genes. METHODS: The spatio-temporal detachment of border cells in the leguminous tree Acacia mangium was investigated by using light and fluorescent microscopy with fluorescein diacetate, and their number and structural connectivity compared with that in soybean (Glycine max). KEY RESULTS: Border-like cells with a sheet structure peeled bilaterally from the lateral root cap of A. mangium. Hydroponic root elongation partially facilitated acropetal peeling of border-like cells, which accumulate as a sheath that covers the 0- to 4-mm tip within 1 week. Although root elongation under friction caused basipetal peeling, lateral root caps were minimally trimmed as compared with hydroponic roots. In the meantime, A. mangium columella caps simultaneously released single border cells with a number similar to those in soybean. CONCLUSIONS: These results suggest that cell type-specific inhibitory factors induce a distinct defective phenotype in single border-cell formation in A. mangium lateral root caps. PMID- 21712297 TI - Geographical ecology of the palms (Arecaceae): determinants of diversity and distributions across spatial scales. AB - BACKGROUND: The palm family occurs in all tropical and sub-tropical regions of the world. Palms are of high ecological and economical importance, and display complex spatial patterns of species distributions and diversity. SCOPE: This review summarizes empirical evidence for factors that determine palm species distributions, community composition and species richness such as the abiotic environment (climate, soil chemistry, hydrology and topography), the biotic environment (vegetation structure and species interactions) and dispersal. The importance of contemporary vs. historical impacts of these factors and the scale at which they function is discussed. Finally a hierarchical scale framework is developed to guide predictor selection for future studies. CONCLUSIONS: Determinants of palm distributions, composition and richness vary with spatial scale. For species distributions, climate appears to be important at landscape and broader scales, soil, topography and vegetation at landscape and local scales, hydrology at local scales, and dispersal at all scales. For community composition, soil appears important at regional and finer scales, hydrology, topography and vegetation at landscape and local scales, and dispersal again at all scales. For species richness, climate and dispersal appear to be important at continental to global scales, soil at landscape and broader scales, and topography at landscape and finer scales. Some scale-predictor combinations have not been studied or deserve further attention, e.g. climate on regional to finer scales, and hydrology and topography on landscape and broader scales. The importance of biotic interactions - apart from general vegetation structure effects - for the geographic ecology of palms is generally underexplored. Future studies should target scale-predictor combinations and geographic domains not studied yet. To avoid biased inference, one should ideally include at least all predictors previously found important at the spatial scale of investigation. PMID- 21712299 TI - Optimizing reproductive phenology in a two-resource world: a dynamic allocation model of plant growth predicts later reproduction in phosphorus-limited plants. AB - BACKGROUND AND AIMS: Timing of reproduction is a key life-history trait that is regulated by resource availability. Delayed reproduction in soils with low phosphorus availability is common among annuals, in contrast to the accelerated reproduction typical of other low-nutrient environments. It is hypothesized that this anomalous response arises from the high marginal value of additional allocation to root growth caused by the low mobility of phosphorus in soils. METHODS: To better understand the benefits and costs of such delayed reproduction, a two-resource dynamic allocation model of plant growth and reproduction is presented. The model incorporates growth, respiration, and carbon and phosphorus acquisition of both root and shoot tissue, and considers the reallocation of resources from senescent leaves. The model is parameterized with data from Arabidopsis and the optimal reproductive phenology is explored in a range of environments. KEY RESULTS: The model predicts delayed reproduction in low-phosphorus environments. Reproductive timing in low-phosphorus environments is quite sensitive to phosphorus mobility, but is less sensitive to the temporal distribution of mortality risks. In low-phosphorus environments, the relative metabolic cost of roots was greater, and reproductive allocation reduced, compared with high-phosphorus conditions. The model suggests that delayed reproduction in response to low phosphorus availability may be reduced in plants adapted to environments where phosphorus mobility is greater. CONCLUSIONS: Delayed reproduction in low-phosphorus soils can be a beneficial response allowing for increased acquisition and utilization of phosphorus. This finding has implications both for efforts to breed crops for low-phosphorus soils, and for efforts to understand how climate change may impact plant growth and productivity in low-phosphorus environments. PMID- 21712298 TI - The importance of Anatolian mountains as the cradle of global diversity in Arabis alpina, a key arctic-alpine species. AB - BACKGROUND AND AIMS: Anatolia is a biologically diverse, but phylogeographically under-explored region. It is described as either a centre of origin and long-term Pleistocene refugium, or as a centre for genetic amalgamation, fed from distinct neighbouring refugia. These contrasting hypotheses are tested through a global phylogeographic analysis of the arctic-alpine herb, Arabis alpina. METHODS: Herbarium and field collections were used to sample comprehensively the entire global range, with special focus on Anatolia and Levant. Sequence variation in the chloroplast DNA trnL-trnF region was examined in 483 accessions. A haplotype genealogy was constructed and phylogeographic methods, demographic analysis and divergence time estimations were used to identify the centres of diversity and to infer colonization history. KEY RESULTS: Fifty-seven haplotypes were recovered, belonging to three haplogroups with non-overlapping distributions in (1) North America/Europe/northern Africa, (2) the Caucuses/Iranian Plateau/Arabian Peninsula and (3) Ethiopia-eastern Africa. All haplogroups occur within Anatolia, and all intermediate haplotypes linking the three haplogroups are endemic to central Anatolia and Levant, where haplotypic and nucleotide diversities exceeded all other regions. The local pattern of haplotype distribution strongly resembles the global pattern, and the haplotypes began to diverge approx. 2.7 Mya, coinciding with the climate cooling of the early Middle Pleistocene. CONCLUSIONS: The phylogeographic structure of Arabis alpina is consistent with Anatolia being the cradle of origin for global genetic diversification. The highly structured landscape in combination with the Pleistocene climate fluctuations has created a network of mountain refugia and the accumulation of spatially arranged genotypes. This local Pleistocene population history has subsequently left a genetic imprint at the global scale, through four range expansions from the Anatolian diversity centre into Europe, the Near East, Arabia and Africa. Hence this study also illustrates the importance of sampling and scaling effects when translating global from local diversity patterns during phylogeographic analyses. PMID- 21712300 TI - Ontogeny and structure of the acervulate partial inflorescence in Hyophorbe lagenicaulis (Arecaceae; Arecoideae). AB - BACKGROUND AND AIMS: The palm tribe Chamaedoreeae displays flowers arranged in a complex partial inflorescence called an acervulus. This type of partial inflorescence has so far not been reported elsewhere in the largest palm subfamily Arecoideae, which is traditionally characterized by flowers predominantly arranged in triads of one central female and two lateral male flowers. The ontogenetic basis of the acervulus is as yet unknown and its structural diversity throughout the genera of the Chamaedoreeae poorly recorded. This study aims to provide critical information on these aspects. METHODS: Developmental series and mature inflorescences were sampled from plants cultivated in international botanical gardens and wild populations. The main techniques employed included scanning electronic microscopy and serial anatomical sectioning of resin-embedded fragments of rachillae. KEY RESULTS: Inflorescence ontogeny in Hyophorbe lagenicaulis demonstrates that the acervulus and the inflorescence rachilla form a condensed and cymose branching system resembling a coenosome. Syndesmy results from a combined process of rapid development and adnation, without or with reduced axis elongation. Acervulus diversity in the ten taxa of the Chamaedoreeae studied is displayed at the level of their positioning within the inflorescence, their arrangement, the number of floral buds and their sexual expression. CONCLUSIONS: The results show that a more general definition of the type of partial inflorescence observed within the large subfamily Arecoideae would correspond to a cyme rather than to a floral triad. In spite of their common cymose architecture, the floral triad and the acervulus present differences with respect to the number and arrangement of floral buds, the superficial pattern of development and sexual expression. PMID- 21712301 TI - Effects of a psychiatric label on medical residents' attitudes. AB - BACKGROUND: Few data are available on the effects of a psychiatric label on medical residents' attitudes towards an individual. AIMS: To investigate the effect of a psychiatric label on the attitudes of medical residents towards an individual. METHODS: Medical residents were randomly assigned to one of two vignettes describing the same apparently healthy person, differing only in the presence of a psychiatric label for one of them. Participants (N = 322) reported their attitudes towards the described individual and their willingness to treat this person. RESULTS: Residents allocated to the psychiatric-diagnostic label group reported being less at ease with becoming the individual's nextdoor neighbour, working in the same place, sharing a house, having him look after their children, having a member of their family date him, having their finances run by the individual, less willing to become friends with the described individual and more uneasy having to examine him the next time he visits the emergency room. CONCLUSION: Implementing effective programmes to combat stigma in the curriculum of medical residents appears to be needed. PMID- 21712302 TI - Children with surgically corrected hand deformities and upper limb deficiencies: self-concept and psychological well-being. AB - We studied self-concept and psychological well-being in children with hand deformities and upper limb deficiencies. Ninety-two children, 53 boys, 39 girls, aged 9-11 years were included. The children were divided into two subgroups - one with milder (less visible) deformities and one with severe (more complex and visible) finger-hand-arm deformities. Of the 92 children, 79 had received reconstructive surgery, and 13 had been treated with prostheses. The Piers-Harris Children's Self-Concept Scale (PHCSCS) was used to measure self-esteem and well being. Overall PHCSCS scores showed that the whole hand deformity group had 'good' self-concept with mean scores in excess of 60 points, equal to a comparison group of healthy children. Within the hand deformity group, those with mild deformities had lower scores than those with severe deformities. This result was also found in the group of boys but not in the girls. The children with severe deformities had even higher scores than the comparison group regarding the subscale 'Intellectual and School Status'. The children with milder deformities had lower scores than the comparison group regarding the subscale 'Popularity'. PMID- 21712303 TI - Arthroscopic ligamentoplasty (bone-tendon-tenodesis). A new surgical technique for scapholunate instability: preliminary cadaver study. AB - We present an anatomical study and description of a new surgical technique for arthroscopic treatment of scapholunate ligament injuries. Five cadaver specimens were used to perform the technique. After arthroscopic surgery, anatomic dissection was performed to measure the distances to critical wrist structures such as the posterior interosseous nerve and the radial artery, and the size and position of the plasty. This arthroscopic technique offers three advantages: soft tissue damage is reduced (avoiding an extensive approach and injury to the secondary stabilizers and reducing scar tissue); injury to the posterior interosseous nerve is avoided (maintaining wrist proprioception and the role of the dynamic stabilizers); and a biotenodesis is made that ensures proper placement, tension and functionality of the flexor carpi radialis ligament reconstruction. PMID- 21712304 TI - The avidity of anti-beta2-glycoprotein I antibodies in patients with or without antiphospholipid syndrome: a collaborative study in the frame of the European forum on antiphospholipid antibodies. AB - OBJECTIVE: The objective of this study was to extend the findings of the preliminary study by measuring the avidity of IgG anti-beta2-glycoprotein I antibodies (anti-beta2-GPI) on a larger group of patients with primary or secondary antiphospholipid syndrome (APS) and anti-beta2-GPI positive patients without APS in the frame of the European Forum on antiphospholipid antibodies (aPL). METHODS: Serum from 137 patients with primary APS, APS associated with autoimmune diseases, and patients with autoimmune diseases other than APS from five EU rheumatology centres were tested for anti-beta2-GPI antibodies. The 109 patients who were sera positive for anti-beta2-GPI by the in-house anti-beta2-GPI enzyme-linked immunosorbent assay (ELISA) at the Immunology Laboratory, UMC Ljubljana were selected for further testing on avidity with chaotropic anti-beta2 GPI ELISA. RESULTS: High, low and heterogeneous avidity IgG anti-beta2-GPI was found in 32/109, 17/109 and 60/109 patients respectively. Significantly more patients with APS were in the high avidity than in the low avidity anti-beta2-GPI group, while the opposite was observed for non-APS (both p < 0.001). The most common clinical feature among patients with high avidity anti-beta2-GPI was thrombosis, mainly due to venous thrombosis (p < 0.01 and p < 0.001, versus low avidity anti-beta2-GPI group). CONCLUSION: Patients with or without APS had anti beta2-GPI of high, low or heterogeneous avidity. High avidity anti-beta2-GPI was associated with thrombosis and APS, while in the low avidity anti-beta2-GPI group non-APS (predominantly SLE) patients prevailed. Determination of anti-beta2-GPI avidity should be considered in the analytical strategies for further differentiation of patients with anti-beta2-GPI antibodies. PMID- 21712305 TI - Emergence of multi-drug resistant Salmonella enterica serotype Stanleyville infections among children in Yaounde, Cameroon. PMID- 21712306 TI - Adjuvant analgesics in cancer pain: a review. AB - Adjuvant analgesics (co-analgesics) are medications whose primary indication is the management of a medical condition with secondary effects of analgesia. Cancer pain is multifactorial and often involves inflammatory, nociceptive, and neuropathic pain subtypes. Adjuvant analgesics used in conjunction with opioids have been found to be beneficial in the management of many cancer pain syndromes; however, they are currently underutilized. Antidepressants, anticonvulsants, local anesthetics, topical agents, steroids, bisphosphonates, and calcitonin are all adjuvants which have been shown to be effective in the management of cancer pain syndromes. When utilizing analgesic adjuvants in the treatment of cancer pain, providers must take into account the particular side effect profile of the medication. Ideally, adjuvant analgesics will be initiated at lower dosages and escalated as tolerated until efficacy or adverse effects are encountered. PMID- 21712307 TI - Aesthetic engagements: "being" in everyday life with advanced cancer. AB - Living with advanced cancer can present an overwhelming challenge. It may impact the everyday life of the individual with respect to an array of psychological, physical, social, and existential issues. We focus on ways in which people with advanced cancer experience and use their engagement in daily activities when confronting nearing death. Through a phenomenological analysis based on Heidegger's thinking, we illuminate the complexities of "being toward death" and the human striving for authentic being through engagement in daily living. The main findings demonstrate how sensory experiences support being through an appreciation of everyday aesthetics. Furthermore, the making of material things was identified as a means to express the value of self and others in relation to the involved individual's past, present, and future. PMID- 21712308 TI - Barriers to hospice for children as perceived by hospice organizations in North Carolina. AB - Despite improving organization of hospice for children with life-limiting illnesses, services may be underutilized. We asked representatives of all 76 existing North Carolina hospice organizations about barriers to serving children. Representatives of 61 agencies responded (80%). Hospices serving children differed from hospices not serving children on perception of barriers: 1) Lack of pediatric trained staff (8% vs 42%, p = 0.01); 2) lack of pediatrician consultation (23% vs 50%, p = 0.03); 3) lack of pediatric pharmacy (4% vs 32%, p = 0.006), and inconsistent plan of care between pediatrician and hospice (12% vs 47%, p = 0.01). Lack of pediatric referrals (78%) and families wanting to continue curative therapies while receiving hospice care (77%) were felt to be the most important barriers overall. Enhanced training of pediatric providers and a model of care which blends disease-specific treatment with hospice may improve access to hospice services for children. PMID- 21712309 TI - Lymph-node metastases in invasive lobular carcinoma are different from those in ductal carcinoma of the breast. AB - AIM: Invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) of the breast are distinct morphological entities with different biological features and clinical behaviour. In the present study, the authors compare the axillary-lymph node (ALN) status of patients with grade-matched ILC (no=426) and IDC (no=820). The pattern of nodal metastatic deposits (nodular, sinusoidal and diffuse) and the proportion of involved nodes were also analysed in a selected group of 246 tumours, which were associated with a single positive ALN. RESULTS: Compared with grade-matched IDC, ILC was associated with a higher nodal stage (13.1% vs 4.5% of ILC and IDC were stage 3), higher absolute number of positive nodes and higher ratio of positive nodes (0.46+/-0.30 and 0.33+/-0.23 in ILC and IDC respectively). These differences were maintained in the different size subgroups. The most common metastatic morphological pattern was nodular in both types of carcinomas. A sinusoidal pattern was more frequent in IDC, and the diffuse pattern was more frequent in ILC. Despite these differences, ILC and grade matched IDC exhibited similar rates of regional recurrences (RR) and breast cancer survival. CONCLUSION: This study provides clinical evidence which further demonstrates that ILC and IDC are biologically distinct entities with different lymph-node involvement patterns and ILC having a tendency to metastasise to more nodes than IDC. However, this difference was not associated with a significant impact on patient outcome. PMID- 21712310 TI - Initiative in anaesthesia. PMID- 21712311 TI - Ethics should trump science in Fukushima. PMID- 21712312 TI - Has child protection become a form of madness? Yes and No. PMID- 21712313 TI - Good medical practice. PMID- 21712314 TI - Beyond the valley of the dolls? PMID- 21712315 TI - Kenneth Taylor responds to Des Spence. PMID- 21712316 TI - Let's look at system failure. PMID- 21712318 TI - Let's think operationally. PMID- 21712317 TI - Impact of contracting out care. PMID- 21712319 TI - What would the number needed to examine be? PMID- 21712320 TI - NHS rethink: charade or cause for new hope? PMID- 21712321 TI - Institute of Medicine responds. Fall prevention with vitamin D. PMID- 21712322 TI - Spain bans sale of unhealthy food in schools in bid to tackle obesity. PMID- 21712323 TI - Fat babies are not healthy, says new report on preventing obesity. PMID- 21712324 TI - Big Pharma would like to befriend you. PMID- 21712325 TI - BMA meeting: BMA urges no let up in fight against damaging changes. PMID- 21712326 TI - Seriously injured patients may suffer under new rules on litigation, MPs say. PMID- 21712327 TI - GMC guidance puts duty on doctors to try to prevent child abuse. PMID- 21712328 TI - Health department won't be able to show preference between NHS and private providers of health services. PMID- 21712329 TI - Commentary: Skilled forensic capacity needed to investigate allegations of research misconduct. PMID- 21712330 TI - The fraud squad. PMID- 21712331 TI - Anticholinergic effects of common drugs are associated with increased mortality in over 65s. PMID- 21712332 TI - Government cuts are jeopardising move to personal health budgets. PMID- 21712333 TI - High prevalence of HIV and hepatitis B and C is found among injecting drug users. PMID- 21712334 TI - Experiences of dying, death and bereavement in motor neurone disease: a qualitative study. AB - OBJECTIVES: to explore the experiences of people with Motor Neurone Disease (MND), current and bereaved carers in the final stages of the disease and bereavement period. METHODS: a qualitative study using narrative interviews was used to elicit accounts from 24 people with MND and 18 current family carers and 10 former family carers. RESULTS: the needs of patients and carers are not being adequately met in the final stages of MND and there appears a need for increased, co-ordinated support from palliative care services. The use of advance care planning tools is regarded as beneficial for patients and carers, but health professionals demonstrate a limited understanding of them. Anxiety and distress in patients, carers and bereaved carers is heightened during this period. Carer burden is excessive and may exacerbate patient distress and desire for hastening death. CONCLUSION: this study has identified a number of issues people with MND and their carers face in the final stages of the illness, indicating some ways in which health, social and palliative care services could be improved or co-operate more effectively in order to better meet their needs. PMID- 21712335 TI - What would happen to health inequalities if smoking were eliminated? PMID- 21712336 TI - Effect of financial incentives on incentivised and non-incentivised clinical activities: longitudinal analysis of data from the UK Quality and Outcomes Framework. AB - OBJECTIVE: To investigate whether the incentive scheme for UK general practitioners led them to neglect activities not included in the scheme. DESIGN: Longitudinal analysis of achievement rates for 42 activities (23 included in incentive scheme, 19 not included) selected from 428 identified indicators of quality of care. SETTING: 148 general practices in England (653 500 patients). MAIN OUTCOME MEASURES: Achievement rates projected from trends in the pre incentive period (2000-1 to 2002-3) and actual rates in the first three years of the scheme (2004-5 to 2006-7). RESULTS: Achievement rates improved for most indicators in the pre-incentive period. There were significant increases in the rate of improvement in the first year of the incentive scheme (2004-5) for 22 of the 23 incentivised indicators. Achievement for these indicators reached a plateau after 2004-5, but quality of care in 2006-7 remained higher than that predicted by pre-incentive trends for 14 incentivised indicators. There was no overall effect on the rate of improvement for non-incentivised indicators in the first year of the scheme, but by 2006-7 achievement rates were significantly below those predicted by pre-incentive trends. CONCLUSIONS: There were substantial improvements in quality for all indicators between 2001 and 2007. Improvements associated with financial incentives seem to have been achieved at the expense of small detrimental effects on aspects of care that were not incentivised. PMID- 21712337 TI - Cause specific mortality, social position, and obesity among women who had never smoked: 28 year cohort study. AB - OBJECTIVE: To investigate the relations between causes of death, social position, and obesity in women who had never smoked. DESIGN: Prospective cohort study. SETTING: Renfrew and Paisley, Scotland. PARTICIPANTS: 8353 women and 7049 men aged 45-64 were recruited to the Renfrew and Paisley Study in 1972-6. Of these, 3613 women had never smoked and were the focus of this study. They were categorised by occupational class (I and II, III non-manual, III manual, and IV and V) and body mass index groups (normal weight, overweight, moderately obese, and severely obese). MAIN OUTCOME MEASURES: All cause and cause specific mortality during 28 years of follow-up by occupational class and body mass index, using Cox proportional hazards models adjusted for age and other confounders. RESULTS: The women in lower occupational classes who had never smoked were on average shorter and had poorer lung function and higher systolic blood pressure than women in the higher occupational classes. Overall, 43% (n = 1555) were overweight, 14% (n = 515) moderately obese, and 5% (n = 194) severely obese. Obesity rates were higher in lower occupational classes and much higher in all occupational classes than in current smokers in the full cohort. Half the women died, 51% (n = 916) from cardiovascular disease and 27% (n = 487) from cancer. Relative to occupational class I and II, all cause mortality rates were more than a third higher in occupational classes III manual (relative rate 1.35, 95% confidence interval 1.16 to 1.57) and IV and V (1.34, 1.17 to 1.55) and largely explained by differences in obesity, systolic blood pressure, and lung function. Similar upward gradients were seen for cardiovascular disease and respiratory disease but not for cancer. Mortality rates were highest in severely obese women in the lowest occupational classes. CONCLUSIONS: Women who had never smoked and were not obese had the lowest mortality rates, regardless of their social position. Where obesity is socially patterned as in this cohort, it may contribute to health inequalities and increase pressure on health and social services serving more disadvantaged populations. PMID- 21712338 TI - Depression and chronic illness: a test of competing hypotheses. AB - No Indonesian studies have addressed the relationship between chronic illness and depression. Using simultaneous equation modeling, this study modeled the joint dependency of depression and chronic illness. The findings showed that the odds of having at least two chronic health conditions increase with the level of depression and individuals with at least two chronic health conditions have higher odds of being in a higher depression category. The health benefits of education are greater among Indonesian women after controlling for mobility, age, marital status, and smoking. Policies directed toward reducing gender differences in education are crucial to reduce persistent health inequalities. PMID- 21712339 TI - Safety and efficacy of femoral artery closure with the FemoSeal(R) device after coronary angiography using a 7 French sheath. AB - Post-cardiac catheterization femoral artery hemostasis can be accomplished with several mechanisms, including the FemoSeal(r) hemostasis device which has been designed and approved for closure of 6 French (F) arterial puncture sites. The aim of this study was to investigate whether the FemoSeal(r) vascular closure device can effectively and safely seal 7F arterial puncture sites after diagnostic and interventional cardiac catheterizations. Femoral artery puncture sites of 50 consecutive patients undergoing cardiac catheterization were closed with the FemoSeal(r) vascular closure device, according to the manufacturer's instructions. Efficacy endpoints were time to hemostasis and successful ambulation. Safety endpoints included bleeding complications, vessel occlusion and pseudoaneurysms. Mean time to hemostasis was 57.8+/-26.3 seconds (0-125 seconds). Hemostasis was achieved in 100 percent of the 50 patients. One patient suffered minor bleeding the next day, i.e. local hematoma. This clinical study demonstrates that the FemoSeal(r) vascular closure device, initially approved for closure of 6F arterial puncture sites, shows promising efficacy and safety to seal a larger (7F) femoral arterial puncture sites after diagnostic and interventional cardiac catheterizations. PMID- 21712340 TI - Optimal methods to screen men and women for intimate partner violence: results from an internal medicine residency continuity clinic. AB - Contradictory data exist regarding optimal methods and instruments for intimate partner violence (IPV) screening in primary care settings. The purpose of this study was to determine the optimal method and screening instrument for IPV among men and women in a primary-care resident clinic. We conducted a cross-sectional study at an urban, academic, internal medicine residency continuity clinic in Connecticut among English or Spanish speaking adult patients. One group of patients ( n = 340) received a self-administered questionnaire (SAQ) containing the partner violence screen (PVS) and the Hurt, Insulted, Threatened or Screamed at Questionnaire (HITS). A second group (n = 126) was screened with PVS and HITS by their primary care providers during face-to-face (FTF) clinical encounters. Multivariable logistic regression models were used to determine the association between IPV prevalence and screening method (SAQ or FTF) after adjusting for socio-demographic effects. The overall IPV prevalence was 17.3% using the SAQ and 9.0% with FTF screening (p = .008). Patients receiving the SAQ were more likely to report IPV than those who were screened FTF (adjusted odds ratio [AOR]: 2.6, 95% confidence interval [CI]: 1.2-5.6). This effect persisted for women, who had a higher odds of IPV when screened through a SAQ than when screened FTF (AOR: 3.5, 95% CI: 1.4-8.6). Men did not differ in reporting IPV between methods: 11% with SAQ versus 9.4% FTF (p = .69). In internal medicine residency continuity clinics, a SAQ for IPV may result in higher disclosure and completion rates among female patients compared to FTF screening. Unique screening instruments and methods may be needed for men. PMID- 21712341 TI - Comparative genomics approach to detecting split-coding regions in a low-coverage genome: lessons from the chimaera Callorhinchus milii (Holocephali, Chondrichthyes). AB - Recent development of deep sequencing technologies has facilitated de novo genome sequencing projects, now conducted even by individual laboratories. However, this will yield more and more genome sequences that are not well assembled, and will hinder thorough annotation when no closely related reference genome is available. One of the challenging issues is the identification of protein-coding sequences split into multiple unassembled genomic segments, which can confound orthology assignment and various laboratory experiments requiring the identification of individual genes. In this study, using the genome of a cartilaginous fish, Callorhinchus milii, as test case, we performed gene prediction using a model specifically trained for this genome. We implemented an algorithm, designated ESPRIT, to identify possible linkages between multiple protein-coding portions derived from a single genomic locus split into multiple unassembled genomic segments. We developed a validation framework based on an artificially fragmented human genome, improvements between early and recent mouse genome assemblies, comparison with experimentally validated sequences from GenBank, and phylogenetic analyses. Our strategy provided insights into practical solutions for efficient annotation of only partially sequenced (low-coverage) genomes. To our knowledge, our study is the first formulation of a method to link unassembled genomic segments based on proteomes of relatively distantly related species as references. PMID- 21712342 TI - Literature mining, ontologies and information visualization for drug repurposing. AB - The immense growth of MEDLINE coupled with the realization that a vast amount of biomedical knowledge is recorded in free-text format, has led to the appearance of a large number of literature mining techniques aiming to extract biomedical terms and their inter-relations from the scientific literature. Ontologies have been extensively utilized in the biomedical domain either as controlled vocabularies or to provide the framework for mapping relations between concepts in biology and medicine. Literature-based approaches and ontologies have been used in the past for the purpose of hypothesis generation in connection with drug discovery. Here, we review the application of literature mining and ontology modeling and traversal to the area of drug repurposing (DR). In recent years, DR has emerged as a noteworthy alternative to the traditional drug development process, in response to the decreased productivity of the biopharmaceutical industry. Thus, systematic approaches to DR have been developed, involving a variety of in silico, genomic and high-throughput screening technologies. Attempts to integrate literature mining with other types of data arising from the use of these technologies as well as visualization tools assisting in the discovery of novel associations between existing drugs and new indications will also be presented. PMID- 21712343 TI - Ortholog identification in the presence of domain architecture rearrangement. AB - Ortholog identification is used in gene functional annotation, species phylogeny estimation, phylogenetic profile construction and many other analyses. Bioinformatics methods for ortholog identification are commonly based on pairwise protein sequence comparisons between whole genomes. Phylogenetic methods of ortholog identification have also been developed; these methods can be applied to protein data sets sharing a common domain architecture or which share a single functional domain but differ outside this region of homology. While promiscuous domains represent a challenge to all orthology prediction methods, overall structural similarity is highly correlated with proximity in a phylogenetic tree, conferring a degree of robustness to phylogenetic methods. In this article, we review the issues involved in orthology prediction when data sets include sequences with structurally heterogeneous domain architectures, with particular attention to automated methods designed for high-throughput application, and present a case study to illustrate the challenges in this area. PMID- 21712344 TI - The role of FOXO3 in DNA damage response in thyrocytes. AB - Members of the forkhead box-O (FOXO) transcription factors family play an important role in stress defence. FOXO3 deregulation has recently been identified as a hallmark of thyroid carcinogenesis. In this study, we explore the role of FOXO3 in defence of oxidative stress in normal thyrocytes. Stable rat thyroid cell lines were generated expressing either the human wild-type FOXO3, a constitutively activating FOXO3 mutant, or the empty control vector. Cell clones were characterised for proliferation, function and morphology. Hydrogen peroxide and UV irradiation were used to induce oxidative stress. Changes in FOXO3 activity, induction of cell cycle arrest or apoptosis and kinetics of DNA damage repair were analysed. Upregulation of FOXO3 in thyrocytes resulted in decreased proliferation and changes in morphology, but did not affect differentiation. Hydrogen peroxide stimulated the expression of the FOXO3 target genes growth arrest and DNA damage-inducible protein 45 alpha (Gadd45alpha) and Bcl-2 interacting mediator of cell death (BIM) and induced programmed cell death in cells with overexpression of the human wild-type FOXO3. In contrast, UV irradiation resulted in a distinct cellular response with activation of FOXO3-c Jun-N-terminal kinase-Gadd45alpha signalling and induction of cell cycle arrest at the G(2)-M-checkpoint. This was accompanied by FOXO3-induced DNA damage repair as evidenced by lower DNA breaks over time in a comet assay in FOXO3 cell clones compared with control cells. In conclusion, FOXO3 is a pivotal relay in the coordination of the cellular response to genotoxic stress in the thyroid. Depending on the stimulus, FOXO3 induces either cell cycle arrest or apoptosis. Conversely, FOXO3 inactivation in thyroid cancers is consistent with genomic instability and loss of cell cycle control. PMID- 21712345 TI - Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy. AB - The majority of prostate cancers (PCa) express high levels of androgen receptor (AR) and are dependent for their growth on testosterone produced by the testes, which is reduced in the prostate to the higher affinity ligand 5alpha dihydrotestosterone (DHT). PCa growth can be suppressed by androgen deprivation therapy, which involves removal of testicular androgens (surgical or medical castration) or treatment with an AR antagonist (or a combination of both), but patients invariably relapse with tumors that have been termed castration recurrent/resistant PCa (CRPC). Importantly, AR transcriptional activity becomes reactivated at this CRPC stage of the disease and remains essential for tumor growth. The objective of this review is to outline one clinically important mechanism contributing to this AR reactivation, which is increased intratumoral synthesis of testosterone and DHT from weak androgens produced by the adrenal glands and possibly de novo from cholesterol. Early studies showed that a substantial fraction of CRPC patients responded to adrenalectomy or medical suppression of adrenal androgen synthesis using agents such as ketoconazole (CYP17A1 inhibitor), and a recent phase III study of a more potent and selective CYP17A1 inhibitor (abiraterone) has demonstrated an improvement in survival. With the pending FDA approval of abiraterone for CRPC, defining the molecular mechanisms contributing to CYP17A1 inhibitor resistance/relapse and AR reactivation is now critical to build on these advances. PMID- 21712346 TI - Src kinase activity coordinates cell adhesion and spreading with activation of mammalian target of rapamycin in pancreatic endocrine tumour cells. AB - Pancreatic endocrine tumours (PETs) are rare and heterogeneous neoplasms, often diagnosed at metastatic stage, for which no cure is currently available. Recently, activation of two pathways that support proliferation and invasiveness of cancer cells, the Src family kinase (SFK) and mammalian target of rapamycin (mTOR) pathways, was demonstrated in PETs. Since both pathways represent suitable targets for therapeutic intervention, we investigated their possible interaction in PETs. Western blot and immunofluorescence analyses indicated that SFK and mTOR activity correlate in PET cell lines. We also found that SFKs coordinate cell adhesion and spreading with activation of the mTOR pathway in PET cells. Live cell metabolic labelling and biochemical studies demonstrated that SFK activity enhance mTOR-dependent translation initiation. Furthermore, microarray analysis of the mRNAs associated with polyribosomes revealed that SFKs regulate mTOR dependent translation of specific transcripts, with an enrichment in mRNAs encoding cell cycle proteins. Importantly, a synergic inhibition of proliferation was observed in PET cells concomitantly treated with SFK and mTOR inhibitors, without activation of the phosphatidylinositol 3-kinase/AKT pro-survival pathway. Tissue microarray analysis revealed activation of Src and mTOR in some PET samples, and identified phosphorylation of 4E-BP1 as an independent marker of poor prognosis in PETs. Thus, our work highlights a novel link between the SFK and mTOR pathways, which regulate the translation of mRNAs for cell cycle regulators, and suggest that crosstalk between these pathways promotes PET cell proliferation. PMID- 21712347 TI - GDNF fails to exert neuroprotection in a rat alpha-synuclein model of Parkinson's disease. AB - The neuroprotective effect of the glial cell line-derived neurotrophic factor has been extensively studied in various toxic models of Parkinson's disease. However, it remains unclear whether this neurotrophic factor can protect against the toxicity induced by the aggregation-prone protein alpha-synuclein. Targeted overexpression of human wild-type alpha-synuclein in the nigrostriatal system, using adeno-associated viral vectors, causes a progressive degeneration of the nigral dopamine neurons and the development of axonal pathology in the striatum. In the present study, we investigated, using different paradigms of delivery, whether glial cell line-derived neurotrophic factor can protect against the neurodegenerative changes and the cellular stress induced by alpha-synuclein. We found that viral vector-mediated delivery of glial cell line-derived neurotrophic factor into substantia nigra and/or striatum, administered 2-3 weeks before alpha synuclein, was inefficient in preventing the wild-type alpha-synuclein-induced loss of dopamine neurons and terminals. In addition, glial cell line-derived neurotrophic factor overexpression did not ameliorate the behavioural deficit in this rat model of Parkinson's disease. Quantification of striatal alpha-synuclein positive aggregates revealed that glial cell line-derived neurotrophic factor had no effect on alpha-synuclein aggregation. These data provide the evidence for the lack of neuroprotective effect of glial cell line-derived neurotrophic factor against the toxicity of human wild-type alpha-synuclein in an in vivo model of Parkinson's disease. The difference in neuroprotective efficacy of glial cell line-derived neurotrophic factor seen in our model and the commonly used neurotoxin models of Parkinson's disease, raises important issues pertinent to the interpretation of the results obtained in preclinical models of Parkinson's disease, and their relevance for the therapeutic use glial cell line-derived neurotrophic factor in patients with Parkinson's disease. PMID- 21712348 TI - Causal chain mapping: a novel method to analyse treatment compliance decisions relating to lymphatic filariasis elimination in Alor, Indonesia. AB - Many public health programmes require individuals to comply with particular behaviours that are novel to them, for example, acquiring new eating habits, accepting immunizations or taking a new medication. In particular, mass drug administration programmes only work to reduce the prevalence of a disease if significant proportions of the target population take the drug in question. In such cases, knowledge of the factors most likely to lead to high levels of compliance is crucial to the programme's success. Existing models of compliance tend to either address interpersonal, organizational or psychological causes independently. Here, the authors present a formal method for analysing relevant factors in the situational context of the compliant behaviour, identifying how these factors may interact within the individual. This method was developed from semantic network analysis, augmented to include environmental and demographic variables to show causal linkages-hence the name 'causal chain mapping'. The ability of this method to provide significant insight into the actual behaviour of individuals is demonstrated with examples from a mass drug administration for lymphatic filariasis in Alor District, Indonesia. The use of this method is likely to help identify key components influencing compliance, and thus make any public health programme reliant on the adoption of novel behaviours more effective. PMID- 21712349 TI - Early stenotic prosthesis failure after implantation of a stentless porcine aortic valve prosthesis. AB - Stentless biological aortic prostheses are used routinely in aortic valve replacement surgery, offering beneficial hemodynamics compared to stented biological valves of similar size. We report here a rare case of early stenotic prosthesis failure of a RootElan stentless porcine aortic valve prosthesis due to swelling at the bottom of the right coronary cusp of the prosthesis. PMID- 21712350 TI - Leukocyte subsets dynamics following open pulmonary lobectomy for lung cancer: a prospective, observational study. AB - This study was planned to observe prospectively the effects of standard open pulmonary lobectomy on leukocyte subsets and their connection with oncological outcome. Leukocyte subsets from 200 patients undergoing pulmonary lobectomy were analyzed: 151 patients had non-small-cell lung cancer, and 49 had non-malignant diseases. Blood samples were taken for leukocyte flow cytometry before and five, 30 and 60 days after operation. The end points were: observation of postoperative leukocyte subsets that are dynamic in patients with lung cancer vs. patients without malignant disease; correlations between leukocyte subsets trend and disease-free interval or survival; and identification of prognostic factors related to preoperative leukocyte subsets. Lymphocyte counts significantly decreased at five days after lobectomy while monocyte counts increased, and complete recovery of the preoperative leukocyte setting was documented at 30 and 60 days. The patients with lung cancer showed a significant low percentage of human leukocyte antigens on their monocytes before surgery (P=0.0017), followed by a peculiar disarrangement of leukocytes subsets compared with patients without malignant disease at the five-day control point. There was no correlation between leukocyte subset dynamics and disease free interval or survival. This study proves reductions of T-, B and natural killer cells, and the expression of DR on T-lymphocyte after pulmonary lobectomy; oncological patients were significantly less affected by surgery than non-cancer patients. PMID- 21712351 TI - Do patients with haemophilia undergoing cardiac surgery have good surgical outcomes? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether patients with haemophilia undergoing cardiac surgery have good surgical outcomes. Haemophilia A and haemophilia B are sex-linked recessive inherited diseases affecting males only, with females acting as carriers. The conditions result in various degrees of factor VIII or factor IX deficiency, respectively. The life expectancy of haemophilia patients is increasing and now approaches that of the general male population, and they are confronted with age-related co-morbidity, including ischaemic cardiovascular disease. Replacement of the deficient factor (VIII for haemophilia A and IX for haemophilia B) is the cornerstone of treatment; other therapeutic options include tranexamic acid, desmopressin and aprotinin. Recently, the advent of recombinant factor VIII and IX has eliminated the infective risk of using factor concentrates, such as prothrombin complex concentrate or fresh frozen plasma. A total of 84 papers were found using the reported search criteria, and out of this 25 papers, selected with reference to a more modern date range, provided the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results were tabulated. We conclude that there is lack of good-quality evidence and that, in all probability, these papers are subject to publication bias as poor outcomes are unlikely to have been reported. However, all the reported series showed that good outcomes are possible in this specific subgroup of patients given the correct approach. The data accrued from these studies (a total of 30 adults and three children) suggest that routine cardiac surgery can be performed safely in patients with haemophilia, with minimal morbidity and mortality. We identified the following key points to achieve this result: a team approach, a factor replacement protocol and perioperative monitoring of factor levels. Intraoperative plasma factor levels can be easily measured before heparin and after protamine sulphate administration, whereas during cardiopulmonary bypass this will require a chromogenic method. Exposure to factor concentrates early in the life might predispose a patient with severe haemophilia to the development of inhibitors. Moreover, the absence of inhibitors should be confirmed before any surgical procedure. PMID- 21712352 TI - Triclosan-coated sutures for the reduction of sternal wound infections? A retrospective observational analysis. AB - OBJECTIVES: Sternal wound infections are an infrequent but serious complication of cardiac surgery, leading to a prolonged hospital stay, increased costs and greater morbidity. To prevent bacterial colonisation of the suture material, which disables local mechanisms of wound decontamination, sutures coated with triclosan were developed. The current study set out to evaluate the effectiveness of such sutures against the development of sternal wound infections after cardiac surgery. METHODS: Between October 2006 and October 2007, a total of 963 patients underwent cardiac surgery with a standard median sternotomy and cardiopulmonary bypass at the General Hospital of Vienna (AKH). A total of 198 patients had their wounds closed with normal sutures, and 765 with the new triclosan-coated sutures. Of these 765 patients, 678 received total closure (sternal fascia, subcutaneous tissue and skin) using the new sutures, whereas in 87 patients the new sutures were used only for the sternal fascia. The study was designed as not being double blinded, and evaluation was carried out retrospectively. RESULTS: The rate of sternal wound infection was 3.0% in the conventionally closed group, 2.3% in the group with only the sternal fascia closed using triclosan sutures, and 3.2% in the group with total triclosan suture closure (fascia, subcutaneous tissue and skin). CONCLUSIONS: Triclosan-coated sutures therefore showed no advantage in avoiding or reducing sternal wound infections. As the cost of these new materials is higher, the rationale for using these sutures remains to be determined. PMID- 21712353 TI - GULiVER--travelling into the heart of good doctor-patient communication from a patient perspective: study protocol of an international multicentre study. AB - BACKGROUND: The project GULiVer explores how lay people in Belgium (Gent), the Netherlands (Utrecht), the UK (Liverpool) and Italy (Verona) evaluate physicians' communicative skills. The aims are to present the study design and to assess the quality of collected data. METHODS: In each centre one out of two sets of four videotaped consultations involving medical students with varying communication skills were shown to eight lay panels of six to nine participants each (n = 259). The selection of lay participants was stratified by gender and age in order to obtain a heterogeneous sample. Background characteristics included socio demographics, participants' general physical (COOP-WONCA) and mental health (GHQ), communication preferences (QUOTE-com) and trust in doctors (TMP). Participants were asked to give quantitative and qualitative evaluations of the student doctors' performance in a mixed-methods design. Quality assessment of the collected data and protocol adherence of the four centres was carried out by Generalized Linear Model (GLM). RESULTS: The overall sample comprised 259 participants. Participants were equally distributed among the centres and balanced in terms of age, gender and OSCE scenario, confirming the quality of collected data. CONCLUSION: The study design and the applied procedures will ensure a great richness of data allowing a wider European perspective on lay persons' views, assessed both individually and through focus group discussion. PMID- 21712354 TI - Applying Semantic Web technologies to improve the retrieval, credibility and use of health-related web resources. AB - The number of health-related websites is increasing day-by-day; however, their quality is variable and difficult to assess. Various "trust marks" and filtering portals have been created in order to assist consumers in retrieving quality medical information. Consumers are using search engines as the main tool to get health information; however, the major problem is that the meaning of the web content is not machine-readable in the sense that computers cannot understand words and sentences as humans can. In addition, trust marks are invisible to search engines, thus limiting their usefulness in practice. During the last five years there have been different attempts to use Semantic Web tools to label health-related web resources to help internet users identify trustworthy resources. This paper discusses how Semantic Web technologies can be applied in practice to generate machine-readable labels and display their content, as well as to empower end-users by providing them with the infrastructure for expressing and sharing their opinions on the quality of health-related web resources. PMID- 21712355 TI - Enriching the trustworthiness of health-related web pages. AB - We present an experimental mechanism for enriching web content with quality metadata. This mechanism is based on a simple and well-known initiative in the field of the health-related web, the HONcode. The Resource Description Framework (RDF) format and the Dublin Core Metadata Element Set were used to formalize these metadata. The model of trust proposed is based on a quality model for health-related web pages that has been tested in practice over a period of thirteen years. Our model has been explored in the context of a project to develop a research tool that automatically detects the occurrence of quality criteria in health-related web pages. PMID- 21712356 TI - Developing tools and resources for the biomedical domain of the Greek language. AB - This paper presents the design and implementation of terminological and specialized textual resources that were produced in the framework of the Greek research project "IATROLEXI". The aim of the project was to create the critical infrastructure for the Greek language, i.e. linguistic resources and tools for use in high level Natural Language Processing (NLP) applications in the domain of biomedicine. The project was built upon existing resources developed by the project partners and further enhanced within its framework, i.e. a Greek morphological lexicon of about 100,000 words, and language processing tools such as a lemmatiser and a morphosyntactic tagger. Christos Tsalidis, Additionally, it developed new assets, such as a specialized corpus of biomedical texts and an ontology of medical terminology. PMID- 21712357 TI - A medical ontology for intelligent web-based skin lesions image retrieval. AB - Researchers have applied increasing efforts towards providing formal computational frameworks to consolidate the plethora of concepts and relations used in the medical domain. In the domain of skin related diseases, the variability of semantic features contained within digital skin images is a major barrier to the medical understanding of the symptoms and development of early skin cancers. The desideratum of making these standards machine-readable has led to their formalization in ontologies. In this work, in an attempt to enhance an existing Core Ontology for skin lesion images, hand-coded from image features, high quality images were analyzed by an autonomous ontology creation engine. We show that by exploiting agglomerative clustering methods with distance criteria upon the existing ontological structure, the original domain model could be enhanced with new instances, attributes and even relations, thus allowing for better classification and retrieval of skin lesion categories from the web. PMID- 21712358 TI - Is adult education associated with reduced coronary heart disease risk? AB - BACKGROUND: Although there is consistent evidence that higher levels of education are associated with better health and reduced disease risk, there is little evidence on whether this is true throughout the lifecourse. This study examines whether additional higher educational qualifications acquired later on in adulthood are associated with a reduction in coronary heart disease (CHD) risk over and above qualifications from earlier on in life. METHODS: The National Child Development Study 1958 British birth cohort was analysed, with data at birth, age 7 (1965), age 23 (1981), 42 (2000) and age 44 years (2002). The effect of highest academic and vocational qualifications obtained by the age of 23 years, and after the age of 23 years on 10-year risk of developing CHD was estimated. RESULTS: CHD risk among women who left school without any qualifications but went on to obtain some qualifications was lower (0.1% risk) compared with their peers who left school without any qualifications (0.14% risk). Among men, the effect of additional higher qualifications on CHD risk was also negative but restricted to those who left school without any qualifications. CONCLUSIONS: Men and women who leave school without any qualifications may be able to 'catch up' to some extent with more qualified people in terms of lowered CHD risk, if they obtain qualifications later on in life. However, there are important limitations to these observed associations which limit any causal interpretation of the results. PMID- 21712359 TI - Consensus statement on indications for anti-angiogenic therapy in the management of corneal diseases associated with neovascularisation: outcome of an expert roundtable. AB - The cornea is the clear window at the front of the eye and is the eye's main refractive medium. Its transparency is essential for vision. Corneal neovascularisation is a common clinical problem with serious consequences for vision; it can compromise corneal transparency and plays a major role in corneal graft rejection by breaching corneal immune privilege. In this review, we formulate a consensus on the unmet medical needs in the management of corneal neovascularisation and outline a framework for the clinical research that is needed to identify suitable agents to meet these needs. PMID- 21712360 TI - Comparing the astigmatic outcome after paediatric cataract surgery with different incisions. AB - AIMS: To compare astigmatism with clear corneal incision versus scleral tunnel incision following paediatric cataract surgery with primary intraocular lens implantation. METHODS: Retrospective, comparative case series of 218 eyes of 138 children <12 years of age undergoing cataract extraction with intraocular lens implantation. The study cohorts were grouped into two categories based on incision location: group 1 comprising 108 eyes from 65 children with scleral incision; group 2 comprising 110 eyes from 73 children with clear corneal incision. Cycloplegic refraction was performed at 1, 3 and 6 months postoperatively. RESULTS: The mean age in group 1 was 61 +/- 39 months and in group 2, 51 +/- 41 months. The mean postoperative astigmatism in group 1 was 1.28 +/- 0.97 D, 1.42 +/- 1.00 D and 1.38 +/- 0.98 D at 1, 3 and 6 months respectively. The change in astigmatism between 1 and 6 months was non significant (p=0.26). The mean astigmatism in group 2 was 1.34 +/- 1.20 D, 1.13 +/- 0.88 D and 1.03 +/- 0.89 D at 1, 3 and 6 months respectively. Astigmatism in group 2 decreased significantly with time (p<0.001). The amount of astigmatism was comparable between the two groups at 1 month postsurgery (p=0.90), while it was significantly lower in the corneal incision group at 3 (p=0.03) and 6 months (p=0.01). CONCLUSIONS: Postoperative astigmatism after paediatric cataract surgery by clear corneal incision was lower compared with scleral incision. However, the difference was small and clinically insignificant. PMID- 21712361 TI - Evidence coupling increased hexosamine biosynthesis pathway activity to membrane cholesterol toxicity and cortical filamentous actin derangement contributing to cellular insulin resistance. AB - Hyperinsulinemia is known to promote the progression/worsening of insulin resistance. Evidence reveals a hidden cost of hyperinsulinemia on plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate (PIP(2))-regulated filamentous actin (F-actin) structure, components critical to the normal operation of the insulin regulated glucose transport system. Here we delineated whether increased glucose flux through the hexosamine biosynthesis pathway (HBP) causes PIP(2)/F-actin dysregulation and subsequent insulin resistance. Increased glycosylation events were detected in 3T3-L1 adipocytes cultured under conditions closely resembling physiological hyperinsulinemia (5 nm insulin; 12 h) and in cells in which HBP activity was amplified by 2 mm glucosamine (GlcN). Both the physiological hyperinsulinemia and experimental GlcN challenge induced comparable losses of PIP(2) and F-actin. In addition to protecting against the insulin-induced membrane/cytoskeletal abnormality and insulin-resistant state, exogenous PIP(2) corrected the GlcN-induced insult on these parameters. Moreover, in accordance with HBP flux directly weakening PIP(2)/F-actin structure, pharmacological inhibition of the rate-limiting HBP enzyme [glutamine-fructose-6-phosphate amidotransferase (GFAT)] restored PIP(2)-regulated F-actin structure and insulin responsiveness. Conversely, overexpression of GFAT was associated with a loss of detectable PM PIP(2) and insulin sensitivity. Even less invasive challenges with glucose, in the absence of insulin, also led to PIP(2)/F-actin dysregulation. Mechanistically we found that increased HBP activity increased PM cholesterol, the removal of which normalized PIP(2)/F-actin levels. Accordingly, these data suggest that glucose transporter-4 functionality, dependent on PIP(2) and/or F actin status, can be critically compromised by inappropriate HBP activity. Furthermore, these data are consistent with the PM cholesterol accrual/toxicity as a mechanistic basis of the HBP-induced defects in PIP(2)/F-actin structure and impaired glucose transporter-4 regulation. PMID- 21712362 TI - Early metabolic programming of puberty onset: impact of changes in postnatal feeding and rearing conditions on the timing of puberty and development of the hypothalamic kisspeptin system. AB - Kiss1 neurons have recently emerged as a putative conduit for the metabolic gating of reproduction, with leptin being a regulator of hypothalamic Kiss1 expression. Early perturbations of the nutritional status are known to predispose to different metabolic disorders later in life and to alter the timing of puberty; however, the potential underlying mechanisms remain poorly defined. Here we report how changes in the pattern of postnatal feeding affect the onset of puberty and evaluate key hormonal and neuropeptide [Kiss1/kisspeptin (Kp)] alterations linked to these early nutritional manipulations. Female rats were raised in litters of different sizes: small (four pups per dam: overfeeding), normal (12 pups per dam), and large litters (20 pups per litter: underfeeding). Postnatal overfeeding resulted in persistently increased body weight and earlier age of vaginal opening, as an external sign of puberty, together with higher levels of leptin and hypothalamic Kiss1 mRNA. Conversely, postnatal underfeeding caused a persistent reduction in body weight, lower ovarian and uterus weights, and delayed vaginal opening, changes that were paralleled by a decrease in leptin and Kiss1 mRNA levels. Kisspeptin-52 immunoreactivity (Kp-IR) in the hypothalamus displayed similar patterns, with lower numbers of Kp-IR neurons in the arcuate nucleus of postnatally underfed animals, and a trend for increased Kp-positive fibers in the periventricular area of early overfed rats. Yet, gonadotropin responses to Kp at puberty were similar in all groups, except for enhanced responsiveness to low doses of Kp-10 in postnatally underfed rats. In conclusion, our data document that the timing of puberty is sensitive to both overfeeding and subnutrition during early (postnatal) periods and suggest that alterations in hypothalamic expression of Kiss1/kisspeptin may underlie at least part of such programming phenomenon. PMID- 21712363 TI - Minireview: cracking the metabolic code for thyroid hormone signaling. AB - Cells are not passive bystanders in the process of hormonal signaling and instead can actively customize hormonal action. Thyroid hormone gains access to the intracellular environment via membrane transporters, and while diffusing from the plasma membrane to the nucleus, thyroid hormone signaling is modified via the action of the deiodinases. Although the type 2 deiodinase (D2) converts the prohormone T(4) to the biologically active T(3), the type 3 deiodinase (D3) converts it to reverse T(3), an inactive metabolite. D3 also inactivates T(3) to T(2), terminating thyroid hormone action. Therefore, D2 confers cells with the capacity to produce extra amounts of T(3) and thus enhances thyroid hormone signaling. In contrast expression of D3 results in the opposite action. The Dio2 and Dio3 genes undergo transcriptional regulation throughout embryonic development, childhood, and adult life. In addition, the D2 protein is unique in that it can be switched off and on via an ubiquitin regulated mechanism, triggered by catalysis of T(4). Induction of D2 enhances local thyroid hormone signaling and energy expenditure during activation of brown adipose tissue by cold exposure or high-fat diet. On the other hand, induction of D3 in myocardium and brain during ischemia and hypoxia decreases energy expenditure as part of a homeostatic mechanism to slow down cell metabolism in the face of limited O(2) supply. PMID- 21712364 TI - Integrated regulation of hepatic metabolism by fibroblast growth factor 21 (FGF21) in vivo. AB - Fibroblast growth factor (FGF21) plays an important role in regulating hepatic oxidation of fatty acids and gluconeogenesis in response to fasting and during consumption of a ketogenic diet. However, the metabolic pathways through which FGF21 regulates hepatic function are not well defined. To identify the effects of FGF21 on the liver in vivo, we administered FGF21 to mice and analyzed acute effects on signaling and gene expression. We found that FGF21 acts directly on the liver to stimulate phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2. Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1alpha. In addition, injection of FGF21 was associated with decreased circulating insulin and free fatty acid levels. FGF21 treatment induced mRNA and protein expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha), suggesting that PGC-1alpha may play a role in regulating FGF21 action. However, studies using mice with liver-specific ablation of PGC-1alpha revealed the same regulation of gluconeogenic gene expression by FGF21 as seen in wild-type mice, indicating that PGC-1alpha is not necessary for the effect of FGF21 on glucose metabolism. These data demonstrate that FGF21 acts directly on the liver to modulate hepatic metabolism. The direct effects we examined are not dependent on PGC-1alpha. In addition, FGF21 treatment is associated with decreased serum insulin levels that my affect hepatic function. PMID- 21712365 TI - Paracrine-acting adiponectin promotes mammary epithelial differentiation and synergizes with genistein to enhance transcriptional response to estrogen receptor beta signaling. AB - Mammary stromal adipocytes constitute an active site for the synthesis of the adipokine, adiponectin (APN) that may influence the mammary epithelial microenvironment. The relationship between "local," mammary tissue-derived APN and breast cancer risk is poorly understood. Here, we identify a novel mechanism of APN-mediated signaling that influences mammary epithelial cell proliferation, differentiation, and apoptosis to modify breast cancer risk. We demonstrate that early dietary exposure to soy protein isolate induced mammary tissue APN production without corresponding effects on systemic APN levels. In estrogen receptor (ER)-negative MCF-10A cells, recombinant APN promoted lobuloalveolar differentiation by inhibiting oncogenic signal transducer and activator of transcription 3 activity. In ER-positive HC11 cells, recombinant APN increased ERbeta expression, inhibited cell proliferation, and induced apoptosis. Using the estrogen-responsive 4X-estrogen response element promoter-reporter construct to assess ER transactivation and small interfering RNA targeting of ERalpha and ERbeta, we show that APN synergized with the soy phytoestrogen genistein to promote ERbeta signaling in the presence of estrogen (17beta-estradiol) and ERbeta-specific agonist 2,3-bis(4-hydroxyphenyl)-propionitrile and to oppose ERalpha signaling in the presence of the ERalpha-specific agonist 4,4',4'-(4 propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol. The enhancement of ERbeta signaling with APN + genistein cotreatments was associated with induction of apoptosis, increased expression of proapoptotic/prodifferentiation genes (Bad, p53, and Pten), and decreased antiapoptotic (Bcl2 and survivin) transcript levels. Our results suggest that mammary-derived APN can influence adjacent epithelial function by ER-dependent and ER-independent mechanisms that are consistent with reduction of breast cancer risk and suggest local APN induction by dietary factors as a targeted approach for promotion of breast health. PMID- 21712366 TI - Cholesterol elevation impairs glucose-stimulated Ca(2+) signaling in mouse pancreatic beta-cells. AB - Recent studies have demonstrated that cholesterol elevation in pancreatic islets is associated with a reduction in glucose-stimulated insulin secretion, but the underlying cellular mechanisms remain elusive. Here, we show that cholesterol enrichment dramatically reduced the proportion of mouse beta-cells that exhibited a Ca(2+) signal when stimulated by high glucose. When cholesterol-enriched beta cells were challenged with tolbutamide, there was a decrease in the amplitude of the Ca(2+) signal, and it was associated with a reduction in the cell current density of voltage-gated Ca(2+) channels (VGCC). Although the cell current densities of the ATP-dependent K(+) channels and the delayed rectifier K(+) channels were also reduced in the cholesterol-enriched beta-cells, glucose evoked only a small depolarization in these cells. In cholesterol-enriched cells, the glucose-mediated increase in cellular ATP content was dramatically reduced, and this was related to a decrease in glucose uptake via glucose transporter 2 and an impairment of mitochondrial metabolism. Thus, cholesterol enrichment impaired glucose-stimulated Ca(2+) signaling in beta-cells via two mechanisms: a decrease in the current density of VGCC and a reduction in glucose-stimulated mitochondrial ATP production, which in turn led to a smaller glucose-evoked depolarization. The decrease in VGCC-mediated extracellular Ca(2+) influx in cholesterol-enriched beta-cells was associated with a reduction in the amount of exocytosis. Our findings suggest that defect in glucose-stimulated Ca(2+) signaling is an important mechanism underlying the impairment of glucose stimulated insulin secretion in islets with elevated cholesterol level. PMID- 21712367 TI - The metastasis promoting protein S100A4 is increased in idiopathic inflammatory myopathies. AB - OBJECTIVES: The S100A4 protein is known as a metastasis promoting factor; however, its involvement in non-malignant diseases such as RA and psoriasis has been recently described. The aim of this study was to investigate the expression and possible role of S100A4 in idiopathic inflammatory myopathies. METHODS: S100A4 protein expression was detected by immunohistochemistry in muscle tissue from control individuals (n = 11) and patients with PM and DM (n = 8/6). IF staining was used to co-localize S100A4 with selected cells. Cytokine expression and protein synthesis in S100A4-treated cells were analysed by RT-PCR and ELISA. RESULTS: S100A4 protein was significantly up-regulated in muscle tissue of patients with inflammatory myopathies compared with control individuals and was associated particularly with the presence of mononuclear infiltrates. Only few regenerating muscle fibres in PM/DM expressed S100A4. Then we analysed the effect of S100A4 on human myocytes and peripheral blood mononuclear cells (PBMCs). Although S100A4 did not affect myocytes, stimulation of PBMCs with S100A4 significantly induced the expression and synthesis of TNF-alpha, IL-1beta and IL 6, but not of IFN-alpha. We showed that S100A4 is not directly involved in perforin/granzyme B-induced apoptosis and that it does not modulate the expression of Bax and Bcl2 mRNA in myocytes and PBMCs. CONCLUSION: Increased expression of S100A4 in inflamed muscle tissue highlights its potential role in the pathogenesis of inflammatory myopathies. S100A4 may act as a cytokine-like factor indirectly promoting muscle fibre damage by stimulating mononuclear cells to increase the synthesis of pro-inflammatory cytokines. PMID- 21712368 TI - Complex regional pain syndrome in adults. AB - Complex regional pain syndrome (CRPS) is a highly painful, limb-confined condition, which arises usually after trauma. It is associated with a particularly poor quality of life, and large health-care and societal costs. The causes of CRPS remain unknown. The condition's distinct combination of abnormalities includes limb-confined inflammation and tissue hypoxia, sympathetic dysregulation, small fibre damage, serum autoantibodies, central sensitization and cortical reorganization. These features place CRPS at a crossroads of interests of several disciplines including rheumatology, pain medicine and neurology. Significant scientific and clinical advances over the past 10 years hold promise both for an improved understanding of the causes of CRPS, and for more effective treatments. This review summarizes current concepts of our understanding of CRPS in adults. Based on the results from systematic reviews, treatment approaches are discussed within the context of these concepts. The treatment of CRPS is multidisciplinary and aims to educate about the condition, sustain or restore limb function, reduce pain and provide psychological intervention. Results from recent randomized controlled trials suggest that it is possible that some patients whose condition was considered refractory in the past can now be effectively treated, but confirmatory trials are required. The review concludes with a discussion of the need for additional research. PMID- 21712370 TI - Prevalence of adverse events in the hospitals of five Latin American countries: results of the 'Iberoamerican Study of Adverse Events' (IBEAS). AB - BACKGROUND: Interest in patient safety (PS) is growing exponentially, fuelled by epidemiological research unveiling the extent of unsafe care. However, there is little information about the frequency of harm in developing and transitional countries. To address this issue, the authors performed a study known as the Iberoamerican Adverse Event Study, through a collaborative between the governments of Argentina, Colombia, Costa Rica, Mexico and Peru, the Spanish Ministry of Health, Social Policy and Equality, the Pan American Health Organization and the WHO Patient Safety. METHODS: The study used a cross sectional design, involving 58 hospitals in the five Latin American countries, to measure the point prevalence of patients presenting an adverse event (AE) on the day of observation. All inpatients at the time of the study were included. RESULTS: A total of 11 379 inpatients were surveyed. Of these, 1191 had at least one AE that the reviewer judged to be related to the care received rather than to the underlying conditions. The estimated point prevalence rate was 10.5% (95% CI 9.91 to 11.04), with more than 28% of AE causing disability and another 6% associated with the death of the patient. Almost 60% of AE were considered preventable. CONCLUSIONS: The high rate of prevalent AE found suggests that PS may represent an important public-health issue in the participating hospitals. While new studies may be needed to confirm these results, these may already be useful to inspire new PS-improvement policies in those settings. PMID- 21712371 TI - Safety hazards in cancer care: findings using three different methods. AB - BACKGROUND: Patients with cancer are at risk of injury during treatment. Some injuries are preventable, but prevention requires knowledge about the hazards. Aims To identify hazards and injuries relating to Danish patients with cancer (types and severity) and to test three different methods of identifying cancer specific hazards. METHODS: Adverse events in cancer care were identified through reports from healthcare staff to the Danish Patient Safety Database, a retrospective chart review using the Global Trigger Tool, and reports to the Danish Cancer Society from patients with cancer and their relatives. Events were typed using the draft International Classification for Patient Safety. Severity was assessed by Safety Assessment Coding, the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) and qualitative assessment. RESULTS: 2429 cancer-related adverse event reports were found on the Danish Patient Safety Database, 260 adverse events were identified using the Global Trigger Tool, and 151 safety events were reported by patients and their relatives. Cancer-specific adverse events and general safety problems were identified. In most cases injury to patients was temporary but severe and permanent injury occurred with a relatively high frequency. CONCLUSION: Patients with cancer are at risk of injury from cancer treatment procedures and as a consequence of problems related to administrative processes and communication. Types of identified events varied according to the methods used, and each method added new information. Further research on patient safety in cancer care and safety-enhancing activities is needed. PMID- 21712372 TI - Improving teamwork in healthcare: current approaches and the path forward. PMID- 21712373 TI - Myosin-1C associates with microtubules and stabilizes the mitotic spindle during cell division. AB - The mitotic spindle in eukaryotic cells is composed of a bipolar array of microtubules (MTs) and associated proteins that are required during mitosis for the correct partitioning of the two sets of chromosomes to the daughter cells. In addition to the well-established functions of MT-associated proteins (MAPs) and MT-based motors in cell division, there is increasing evidence that the F-actin based myosin motors are important mediators of F-actin-MT interactions during mitosis. Here, we report the functional characterization of the long-tailed class 1 myosin myosin-1C from Dictyostelium discoideum during mitosis. Our data reveal that myosin-1C binds to MTs and has a role in maintenance of spindle stability for accurate chromosome separation. Both myosin-1C motor function and tail-domain mediated MT-F-actin interactions are required for the cell-cycle-dependent relocalization of the protein from the cell periphery to the spindle. We show that the association of myosin-1C with MTs is mediated through the tail domain. The myosin-1C tail can inhibit kinesin motor activity, increase the stability of MTs, and form crosslinks between MTs and F-actin. These data illustrate that myosin-1C is involved in the regulation of MT function during mitosis in D. discoideum. PMID- 21712374 TI - The impact of the heparin-induced thrombocytopenia (HIT) computerized alert on provider behaviors and patient outcomes. AB - OBJECTIVE: The aim of this study was to measure the effect of an electronic heparin-induced thrombocytopenia (HIT) alert on provider ordering behaviors and on patient outcomes. MATERIALS AND METHODS: A pop-up alert was created for providers when an individual's platelet values had decreased by 50% or to <100,000/mm(3) in the setting of recent heparin exposure. The authors retrospectively compared inpatients admitted between January 24, 2008 and August 24, 2008 to a control group admitted 1 year prior to the HIT alert. The primary outcome was a change in HIT antibody testing. Secondary outcomes included an assessment of incidence of HIT antibody positivity, percentage of patients started on a direct thrombin inhibitor (DTI), length of stay and overall mortality. RESULTS: There were 1006 and 1081 patients in the control and intervention groups, respectively. There was a 33% relative increase in HIT antibody test orders (p=0.01), and 33% more of these tests were ordered the first day after the criteria were met when a pop-up alert was given (p=0.03). Heparin was discontinued in 25% more patients in the alerted group (p=0.01), and more direct thrombin inhibitors were ordered for them (p=0.03). The number who tested HIT antibody-positive did not differ, however, between the two groups (p=0.99). The length of stay and mortality were similar in both groups. CONCLUSIONS: The HIT alert significantly impacted provider behaviors. However, the alert did not result in more cases of HIT being detected or an improvement in overall mortality. Our findings do not support implementation of a computerized HIT alert. PMID- 21712375 TI - Adapting to blur produced by ocular high-order aberrations. AB - The perceived focus of an image can be strongly biased by prior adaptation to a blurred or sharpened image. We examined whether these adaptation effects can occur for the natural patterns of retinal image blur produced by high-order aberrations (HOAs) in the optics of the eye. Focus judgments were measured for 4 subjects to estimate in a forced choice procedure (sharp/blurred) their neutral point after adaptation to different levels of blur produced by scaled increases or decreases in their HOAs. The optical blur was simulated by convolution of the PSFs from the 4 different HOA patterns, with Zernike coefficients (excluding tilt, defocus, and astigmatism) multiplied by a factor between 0 (diffraction limited) and 2 (double amount of natural blur). Observers viewed the images through an Adaptive Optics system that corrected their aberrations and made settings under neutral adaptation to a gray field or after adapting to 5 different blur levels. All subjects adapted to changes in the level of blur imposed by HOA regardless of which observer's HOA was used to generate the stimuli, with the perceived neutral point proportional to the amount of blur in the adapting image. PMID- 21712376 TI - The role of shape-from-shading information in the perception of local and global form in Glass patterns. AB - Three-dimensional (3D) shape can be inferred from the surface shading gradient of objects. Using Glass patterns, we investigated the importance of shape-from shading information to the perception of global form. We examined whether different 3D shapes inferred from shading affect the extraction of local dipole orientations (local analysis) and the integration of dipoles in the perception of Glass structure (global analysis). In Experiment 1, we showed that incongruence in shading between partner dots prevents the recovery of the dipole orientation: partner dots with different 3D shapes are not paired to recover the dipole orientation. However, when incongruent "bipartite" partner dots (that have the same contrast polarity as shaded dots, but are two-dimensional) were used, the visual system was able to extract the local dipole orientation and detect the global pattern (Experiment 2). In Experiment 3, we showed that additional noise dipoles affect the detection of Glass structure regardless of the 3D shape difference between signal and additional noise dipoles. This demonstrates that the visual system combines different oriented 3D dipoles to detect Glass structure. Our findings show that shape-from-shading information impacts on the ability to detect form structure but in different ways at local and global stages of processing. PMID- 21712377 TI - Identification of plant-like galactolipids in Chromera velia, a photosynthetic relative of malaria parasites. AB - Apicomplexa are protist parasites that include Plasmodium spp., the causative agents of malaria, and Toxoplasma gondii, responsible for toxoplasmosis. Most Apicomplexa possess a relict plastid, the apicoplast, which was acquired by secondary endosymbiosis of a red alga. Despite being nonphotosynthetic, the apicoplast is otherwise metabolically similar to algal and plant plastids and is essential for parasite survival. Previous studies of Toxoplasma gondii identified membrane lipids with some structural features of plastid galactolipids, the major plastid lipid class. However, direct evidence for the plant-like enzymes responsible for galactolipid synthesis in Apicomplexan parasites has not been obtained. Chromera velia is an Apicomplexan relative recently discovered in Australian corals. C. velia retains a photosynthetic plastid, providing a unique model to study the evolution of the apicoplast. Here, we report the unambiguous presence of plant-like monogalactosyldiacylglycerol and digalactosyldiacylglycerol in C. velia and localize digalactosyldiacylglycerol to the plastid. We also provide evidence for a plant-like biosynthesis pathway and identify candidate galactosyltranferases responsible for galactolipid synthesis. Our study provides new insights in the evolution of these important enzymes in plastid-containing eukaryotes and will help reconstruct the evolution of glycerolipid metabolism in important parasites such as Plasmodium and Toxoplasma. PMID- 21712378 TI - Resveratrol induces p53-independent, X-linked inhibitor of apoptosis protein (XIAP)-mediated Bax protein oligomerization on mitochondria to initiate cytochrome c release and caspase activation. AB - Resveratrol, a naturally occurring phytoalexin, is known to induce apoptosis in multiple cancer cell types, but the underlying molecular mechanisms remain unclear. Here, we show that resveratrol induced p53-independent, X-linked inhibitor of apoptosis protein (XIAP)-mediated translocation of Bax to mitochondria where it underwent oligomerization to initiate apoptosis. Resveratrol treatment promoted interaction between Bax and XIAP in the cytosol and on mitochondria, suggesting that XIAP plays a critical role in the activation and translocation of Bax to mitochondria. This process did not involve p53 but required accumulation of Bim and t-Bid on mitochondria. Bax primarily underwent homo-oligomerization on mitochondria and played a major role in release of cytochrome c to the cytosol. Bak, another key protein that regulates the mitochondrial membrane permeabilization, did not interact with p53 but continued to associate with Bcl-xL. Thus, the proapoptotic function of Bak remained suppressed during resveratrol-induced apoptosis. Caspase-9 silencing inhibited resveratrol-induced caspase activation, whereas caspase-8 knockdown did not affect caspase activity, suggesting that resveratrol induces caspase-9-dependent apoptosis. Together, our findings characterize the molecular mechanisms of resveratrol-induced caspase activation and subsequent apoptosis in cancer cells. PMID- 21712379 TI - Implication of Ca2+ in the regulation of replicative life span of budding yeast. AB - In eukaryotic cells, Ca(2+)-triggered signaling pathways are used to regulate a wide variety of cellular processes. Calcineurin, a highly conserved Ca(2+)/calmodulin-dependent protein phosphatase, plays key roles in the regulation of diverse biological processes in organisms ranging from yeast to humans. We isolated a mutant of the SIR3 gene, implicated in the regulation of life span, as a suppressor of the Ca(2+) sensitivity of zds1Delta cells in the budding yeast Saccharomyces cerevisiae. Therefore, we investigated a relationship between Ca(2+) signaling and life span in yeast. Here we show that Ca(2+) affected the replicative life span (RLS) of yeast. Increased external and intracellular Ca(2+) levels caused a reduction in their RLS. Consistently, the increase in calcineurin activity by either the zds1 deletion or the constitutively activated calcineurin reduced RLS. Indeed, the shortened RLS of zds1Delta cells was suppressed by the calcineurin deletion. Further, the calcineurin deletion per se promoted aging without impairing the gene silencing typically observed in short-lived sir mutants, indicating that calcineurin plays an important role in a regulation of RLS even under normal growth condition. Thus, our results indicate that Ca(2+) homeostasis/Ca(2+) signaling are required to regulate longevity in budding yeast. PMID- 21712380 TI - An Atg13 protein-mediated self-association of the Atg1 protein kinase is important for the induction of autophagy. AB - Autophagy pathways in eukaryotic cells mediate the turnover of a diverse set of cytoplasmic components, including damaged organelles and abnormal protein aggregates. Autophagy-mediated degradation is highly regulated, and defects in these pathways have been linked to a number of human disorders. The Atg1 protein kinase appears to be a key site of this control and is targeted by multiple signaling pathways to ensure the appropriate autophagic response to changing environmental conditions. Despite the importance of this kinase, relatively little is known about the molecular details of Atg1 activation. In this study we show that Atg13, an evolutionarily conserved regulator of Atg1, promotes the formation of a specific Atg1 self-interaction in the budding yeast, Saccharomyces cerevisiae. The appearance of this Atg1-Atg1 complex is correlated with the induction of autophagy, and conditions that disrupt this complex result in diminished levels of both autophagy and Atg1 kinase activity. Moreover, the addition of a heterologous dimerization domain to Atg1 resulted in elevated kinase activity both in vivo and in vitro. The formation of this complex appears to be an important prerequisite for the subsequent autophosphorylation of Thr-226 in the Atg1 activation loop. Previous work indicates that this modification is necessary and perhaps sufficient for Atg1 kinase activity. Interestingly, this Atg1 self-association does not require Atg17, suggesting that this second conserved regulator might activate Atg1 in a manner mechanistically distinct from that of Atg13. In all, this work suggests a model whereby this self-association stimulates the autophosphorylation of Atg1 within its activation loop. PMID- 21712381 TI - Acireductone dioxygenase 1 (ARD1) is an effector of the heterotrimeric G protein beta subunit in Arabidopsis. AB - Heterotrimeric G protein complexes are conserved from plants to mammals, but the complexity of each system varies. Arabidopsis thaliana contains one Galpha, one Gbeta (AGB1), and at least three Ggamma subunits, allowing it to form three versions of the heterotrimer. This plant model is ideal for genetic studies because mammalian systems contain hundreds of unique heterotrimers. The activation of these complexes promotes interactions between both the Galpha subunit and the Gbetagamma dimer with enzymes and scaffolds to propagate signaling to the cytoplasm. However, although effectors of Galpha and Gbeta are known in mammals, no Gbeta effectors were previously known in plants. Toward identifying AGB1 effectors, we genetically screened for dominant mutations that suppress Gbeta-null mutant (agb1-2) phenotypes. We found that overexpression of acireductone dioxygenase 1 (ARD1) suppresses the 2-day-old etiolated phenotype of agb1-2. ARD1 is homologous to prokaryotic and eukaryotic ARD proteins; one function of ARDs is to operate in the methionine salvage pathway. We show here that ARD1 is an active metalloenzyme, and AGB1 and ARD1 both control embryonic hypocotyl length by modulating cell division; they also may contribute to the production of ethylene, a product of the methionine salvage pathway. ARD1 physically interacts with AGB1, and ARD enzymatic activity is stimulated by AGB1 in vitro. The binding interface on AGB1 was deduced using a comparative evolutionary approach and tested using recombinant AGB1 mutants. A possible mechanism for AGB1 activation of ARD1 activity was tested using directed mutations in a loop near the substrate-binding site. PMID- 21712383 TI - Spectrin-like repeats 11-15 of human dystrophin show adaptations to a lipidic environment. AB - Dystrophin is essential to skeletal muscle function and confers resistance to the sarcolemma by interacting with cytoskeleton and membrane. In the present work, we characterized the behavior of dystrophin 11-15 (DYS R11-15), five spectrin-like repeats from the central domain of human dystrophin, with lipids. DYS R11-15 displays an amphiphilic character at the liquid/air interface while maintaining its secondary alpha-helical structure. The interaction of DYS R11-15 with small unilamellar vesicles (SUVs) depends on the lipid nature, which is not the case with large unilamellar vesicles (LUVs). In addition, switching from anionic SUVs to anionic LUVs suggests the lipid packing as a crucial factor for the interaction of protein and lipid. The monolayer model and the modulation of surface pressure aim to mimic the muscle at work (i.e. dynamic changes of muscle membrane during contraction and relaxation) (high and low surface pressure). Strikingly, the lateral pressure modifies the protein organization. Increasing the lateral pressure leads the proteins to be organized in a regular network. Nevertheless, a different protein conformation after its binding to monolayer is revealed by trypsin proteolysis. Label-free quantification by nano-LC/MS/MS allowed identification of the helices in repeats 12 and 13 involved in the interaction with anionic SUVs. These results, combined with our previous studies, indicate that DYS R11-15 constitutes the only part of dystrophin that interacts with anionic as well as zwitterionic lipids and adapts its interaction and organization depending on lipid packing and lipid nature. We provide strong experimental evidence for a physiological role of the central domain of dystrophin in sarcolemma scaffolding through modulation of lipid-protein interactions. PMID- 21712382 TI - Transforming growth factor-beta1 (TGF-beta1) utilizes distinct pathways for the transcriptional activation of microRNA 143/145 in human coronary artery smooth muscle cells. AB - MicroRNA 143/145 (miR143/145) is restricted to adult smooth muscle cell (SMC) lineages and mediates, in part, the expression of several SMC contractile genes. Although the function of miR143/145 has begun to be elucidated, its transcriptional regulation in response to various signaling inputs is poorly understood. In an effort to define a miR signature for SMC differentiation, we screened human coronary artery SMCs for miRs modulated by TGF-beta1, a known stimulus for SMC differentiation. Array analysis revealed a number of TGF-beta1 induced miRs, including miR143/145. Validation studies showed that TGF-beta1 stimulated miR143/145 expression in a dose- and time-dependent manner. We utilized several chemical inhibitors and found that SB203580, a specific inhibitor of p38MAPK, significantly decreased TGF-beta1-induced miR143/145 expression. siRNA studies demonstrated that the effect of TGF-beta1 on miR143/145 was dependent upon the myocardin and serum response factor transcriptional switch as well as SMAD4. TGF-beta1 stimulated a 580-bp human miR143/145 enhancer, and mutagenesis studies revealed a critical role for both a known CArG box and an adjacent SMAD-binding element for full TGF-beta1-dependent activation of the enhancer. Chromatin immunoprecipitation assays documented TGF-beta1-mediated enrichment of SMAD3 and SMAD4 binding over the enhancer region containing the SMAD-binding element. Pre-miR145 strongly promoted SMC differentiation, whereas an anti-miR145 partially blocked TGF-beta1-induced SMC differentiation. These results demonstrate a dual pathway for TGF-beta1-induced transcription of miR143/145, thus revealing a novel mechanism underlying TGF-beta1-induced human vascular SMC differentiation. PMID- 21712384 TI - Silencer of death domains (SODD) inhibits skeletal muscle and kidney enriched inositol 5-phosphatase (SKIP) and regulates phosphoinositide 3-kinase (PI3K)/Akt signaling to the actin cytoskeleton. AB - Phosphoinositide 3-kinase (PI3K) regulates cell polarity and migration by generating phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P(3)) at the leading edge of migrating cells. The serine-threonine protein kinase Akt binds to PI(3,4,5)P(3), resulting in its activation. Active Akt promotes spatially regulated actin cytoskeletal remodeling and thereby directed cell migration. The inositol polyphosphate 5-phosphatases (5-ptases) degrade PI(3,4,5)P(3) to form PI(3,4)P(2), which leads to diminished Akt activation. Several 5-ptases, including SKIP and SHIP2, inhibit actin cytoskeletal reorganization by opposing PI3K/Akt signaling. In this current study, we identify a molecular co-chaperone termed silencer of death domains (SODD/BAG4) that forms a complex with several 5 ptase family members, including SKIP, SHIP1, and SHIP2. The interaction between SODD and SKIP exerts an inhibitory effect on SKIP PI(3,4,5)P(3) 5-ptase catalytic activity and consequently enhances the recruitment of PI(3,4,5)P(3)-effectors to the plasma membrane. In contrast, SODD(-/-) mouse embryonic fibroblasts exhibit reduced Akt-Ser(473) and -Thr(308) phosphorylation following EGF stimulation, associated with increased SKIP PI(3,4,5)P(3)-5-ptase activity. SODD(-/-) mouse embryonic fibroblasts exhibit decreased EGF-stimulated F-actin stress fibers, lamellipodia, and focal adhesion complexity, a phenotype that is rescued by the expression of constitutively active Akt1. Furthermore, reduced cell migration was observed in SODD(-/-) macrophages, which express the three 5-ptases shown to interact with SODD (SKIP, SHIP1, and SHIP2). Therefore, this study identifies SODD as a novel regulator of PI3K/Akt signaling to the actin cytoskeleton. PMID- 21712385 TI - The tumor suppressor hamartin enhances Dbl protein transforming activity through interaction with ezrin. AB - The Rho guanine nucleotide exchange factor (GEF) Dbl binds to the N-terminal region of ezrin, a member of the ERM (ezrin, radixin, moesin) proteins known to function as linkers between the plasma membrane and the actin cytoskeleton. Here we have characterized the interaction between ezrin and Dbl. We show that binding of Dbl with ezrin involves positively charged amino acids within the region of the pleckstrin homology (PH) domain comprised between beta1 and beta2 sheets. In addition, we show that Dbl forms a complex with the tuberous sclerosis-1 (TSC-1) gene product hamartin and with ezrin. We demonstrate that hamartin and ezrin are both required for activation of Dbl. In fact, the knock-down of ezrin and hamartin, as well as the expression of a mutant hamartin, unable to bind ezrin, inhibit Dbl transforming and exchange activity. These results suggest that Dbl is regulated by hamartin through association with ezrin. PMID- 21712386 TI - Activity-dependent phosphorylation of neuronal Kv2.1 potassium channels by CDK5. AB - Dynamic modulation of ion channel expression, localization, and/or function drives plasticity in intrinsic neuronal excitability. Voltage-gated Kv2.1 potassium channels are constitutively maintained in a highly phosphorylated state in neurons. Increased neuronal activity triggers rapid calcineurin-dependent dephosphorylation, loss of channel clustering, and hyperpolarizing shifts in voltage-dependent activation that homeostatically suppress neuronal excitability. These changes are reversible, such that rephosphorylation occurs after removal of excitatory stimuli. Here, we show that cyclin-dependent kinase 5 (CDK5), a Pro directed Ser/Thr protein kinase, directly phosphorylates Kv2.1, and determines the constitutive level of Kv2.1 phosphorylation, the rapid increase in Kv2.1 phosphorylation upon acute blockade of neuronal activity, and the recovery of Kv2.1 phosphorylation after stimulus-induced dephosphorylation. We also demonstrate that although the phosphorylation state of Kv2.1 is also shaped by the activity of the PP1 protein phosphatase, the regulation of Kv2.1 phosphorylation by CDK5 is not mediated through the previously described regulation of PP1 activity by CDK5. Together, these studies support a novel role for CDK5 in regulating Kv2.1 channels through direct phosphorylation. PMID- 21712387 TI - Interaction of transducin with uncoordinated 119 protein (UNC119): implications for the model of transducin trafficking in rod photoreceptors. AB - The key visual G protein, transducin undergoes bi-directional translocations between the outer segment (OS) and inner compartments of rod photoreceptors in a light-dependent manner thereby contributing to adaptation and neuroprotection of rods. A mammalian uncoordinated 119 protein (UNC119), also known as Retina Gene 4 protein (RG4), has been recently implicated in transducin transport to the OS in the dark through its interaction with the N-acylated GTP-bound transducin-alpha subunit (Galpha(t1)). Here, we demonstrate that the interaction of human UNC119 (HRG4) with transducin is dependent on the N-acylation, but does not require the GTP-bound form of Galpha(t1). The lipid specificity of UNC119 is unique: UNC119 bound the myristoylated N terminus of Galpha(t1) with much higher affinity than a prenylated substrate, whereas the homologous prenyl-binding protein PrBP/delta did not interact with the myristoylated peptide. UNC119 was capable of interacting with Galpha(t1)GDP as well as with heterotrimeric transducin (G(t)). This interaction of UNC119 with G(t) led to displacement of Gbeta(1)gamma(1) from the heterotrimer. Furthermore, UNC119 facilitated solubilization of G(t) from dark-adapted rod OS membranes. Consistent with these observations, UNC119 inhibited rhodopsin-dependent activation of G(t), but had no effect on the GTP hydrolysis by Galpha(t1). A model for the role of UNC119 in the IS->OS translocation of G(t) is proposed based on the UNC119 ability to dissociate G(t) subunits from each other and the membrane. We also found that UNC119 inhibited activation of G(o) by D2 dopamine receptor in cultured cells. Thus, UNC119 may play conserved inhibitory role in regulation of GPCR-G protein signaling in non visual tissues. PMID- 21712388 TI - Effect of Src kinase phosphorylation on disordered C-terminal domain of N-methyl D-aspartic acid (NMDA) receptor subunit GluN2B protein. AB - NMDA receptors are ligand-gated ion channels with a regulatory intracellular C terminal domain (CTD). In GluN2B, the CTD is the largest domain in the protein but is intrinsically disordered. The GluN2B subunit is the major tyrosine phosphorylated protein in synapses. Src kinase phosphorylates the GluN2B CTD, but it is unknown how this affects channel activity. In disordered proteins, phosphorylation can tip the balance between order and disorder. Transitions can occur in both directions, so it is not currently possible to predict the effects of phosphorylation. We used single molecule fluorescence to characterize the effects of Src phosphorylation on GluN2B. Scanning fluorescent labeling sites throughout the domain showed no positional dependence of the energy transfer. Instead, efficiency only scaled with the separation between labeling sites suggestive of a relatively featureless conformational energy landscape. Src phosphorylation led to a general expansion of the polypeptide, which would result in greater exposure of known protein-binding sites and increase the physical separation between contiguous sites. Phosphorylation makes the CTD more like a random coil leaving open the question of how Src exerts its effects on the NMDA receptor. PMID- 21712389 TI - Early growth response 1 (Egr1) regulates cholesterol biosynthetic gene expression. AB - The early growth response (EGR) family of transcription factors has been implicated in control of lipid biosynthetic genes. Egr1 is induced by insulin both in vitro and in vivo and is the most highly expressed family member in liver. In this study, we investigated whether Egr1 regulates cholesterol biosynthetic genes in liver. Using an insulin-sensitive liver cell line, we show that localization of Egr1 to cholesterol biosynthetic genes is induced by insulin treatment and that this localization precedes the induction of the genes. Reduction in Egr1 expression using targeted siRNA blunted the insulin-dependent induction of cholesterol genes. A similar reduction in squalene epoxidase expression was also observed in Egr1 null mice. In addition, application of chromatin immunoprecipitation (ChIP) samples to tiled gene microarrays revealed localization of Egr1 in promoter regions of many cholesterol gene loci. In vivo ChIP assays using liver tissue show that Egr1 localization to several cholesterol biosynthetic gene promoters is induced by feeding. Finally, analysis of plasma cholesterol in Egr1(-/-) mice indicated a significant decrease in serum cholesterol when compared with wild-type mice. Together these data point to Egr1 as a modulator of the cholesterol biosynthetic gene family in liver. PMID- 21712390 TI - Ornithine decarboxylase antizyme Oaz3 modulates protein phosphatase activity. AB - Ornithine decarboxylase antizyme 3 (Oaz3) is expressed in spermatids, makes up the antizyme family of Oaz genes with Oaz1 and Oaz2, and was proposed to encode a 22 kDa antizyme protein involved in polyamine regulation similar to the 22 kDa OAZ1 and OAZ2 proteins. Here we demonstrate however that the major product encoded by Oaz3 is a 12 kDa protein, p12, which lacks the antizyme domain that interacts with ornithine decarboxylase. We show that p12 does not affect ornithine decarboxylase levels, providing an explanation for the surprising observation made in Oaz3 knock-out male mice, which do not display altered testis polyamine metabolism. This suggested a novel activity for Oaz3 p12. Using immuno electron microscopy we localized p12 to two structures in the mammalian sperm tail, viz. the outer dense fibers and fibrous sheath, as well as to the connecting piece linking head and tail. We identified myosin phosphatase targeting subunit 3 (MYPT3), a regulator of protein phosphatase PP1beta, as a major p12-interacting protein, and show that MYPT3 is present in sperm tails and that its ankyrin repeat binds p12. We show that MYPT3 can also bind protein phosphatase PP1gamma2, the only protein phosphatase present in sperm tails, and that p12- MYPT3 interaction modulates the activity of both PP1beta and PP1gamma2. This is, to our knowledge, the first demonstration of a novel activity for an Oaz encoded protein. PMID- 21712391 TI - Autocatalytic cleavage of human gamma-glutamyl transpeptidase is highly dependent on N-glycosylation at asparagine 95. AB - gamma-Glutamyl transpeptidase (GGT) is a heterodimeric membrane enzyme that catalyzes the cleavage of extracellular glutathione and other gamma-glutamyl containing compounds. GGT is synthesized as a single polypeptide (propeptide) that undergoes autocatalytic cleavage, which results in the formation of the large and small subunits that compose the mature enzyme. GGT is extensively N glycosylated, yet the functional consequences of this modification are unclear. We investigated the effect of N-glycosylation on the kinetic behavior, stability, and functional maturation of GGT. Using site-directed mutagenesis, we confirmed that all seven N-glycosylation sites on human GGT are modified by N-glycans. Comparative enzyme kinetic analyses revealed that single substitutions are functionally tolerated, although the N95Q mutation resulted in a marked decrease in the cleavage efficiency of the propeptide. However, each of the single site mutants exhibited decreased thermal stability relative to wild-type GGT. Combined mutagenesis of all N-glycosylation sites resulted in the accumulation of the inactive propeptide form of the enzyme. Use of N-glycosylation inhibitors demonstrated that binding of the core N-glycans, not their subsequent processing, is the critical glycosylation event governing the autocleavage of GGT. Although N glycosylation is necessary for maturation of the propeptide, enzymatic deglycosylation of the mature wild-type GGT does not substantially impact either the kinetic behavior or thermal stability of the fully processed human enzyme. These findings are the first to establish that co-translational N-glycosylation of human GGT is required for the proper folding and subsequent cleavage of the nascent propeptide, although retention of these N-glycans is not necessary for maintaining either the function or structural stability of the mature enzyme. PMID- 21712392 TI - Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12-(S)-hydroxyeicosatetraenoic acid. AB - Hydroxy fatty acids are critical lipid mediators involved in various pathophysiologic functions. We cloned and identified GPR31, a plasma membrane orphan G protein-coupled receptor that displays high affinity for the human 12 lipoxygenase-derived product 12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (HETE). Thus, GPR31 is named 12-(S)-HETE receptor (12-HETER) in this study. The cloned 12-HETER demonstrated high affinity binding for 12-(S)-[(3)H]HETE (K(d) = 4.8 +/- 0.12 nm). Also, 12-(S)-HETE efficiently and selectively stimulated GTPgammaS coupling in the membranes of 12-HETER-transfected cells (EC(50) = 0.28 +/- 1.26 nm). Activating GTPgammaS coupling with 12-(S)-HETE proved to be both regio- and stereospecific. Also, 12-(S)-HETE/12-HETER interactions lead to activation of ERK1/2, MEK, and NFkappaB. Moreover, knocking down 12-HRTER specifically inhibited 12-(S)-HETE-stimulated cell invasion. Thus, 12-HETER represents the first identified high affinity receptor for the 12-(S)-HETE hydroxyl fatty acids. PMID- 21712393 TI - The assessment of tobacco dependence in young users of smokeless tobacco. AB - INTRODUCTION: As all published measures of dependence for users of smokeless tobacco (dippers) have poor reliability, in the present work the Hooked on Nicotine Checklist (HONC) and the Autonomy Over Smoking Scale (AUTOS) were evaluated for use with this population. Dippers and smokers were also compared in relation to dependence, the pleasure derived from using tobacco and the latency to the onset of withdrawal. METHODS: In 2010, an anonymous self-completed paper survey was administered to 1541 students of mixed race and ethnicity in grades 9 12 (mean age 15.9 years) in a Florida high school where students used cigarettes and smokeless tobacco. RESULTS: The reliability (Cronbach's alpha) for the HONC was 0.90 for smokers (n = 139) and 0.91 for dippers (n = 85), and for the AUTOS was 0.94 for smokers and dippers. Dippers and smokers did not differ significantly in relation to scores on the HONC, AUTOS, latency to withdrawal onset or pleasure derived from smoking. One or more symptoms on the HONC were reported by 56% of dippers and 57% of smokers with <100 lifetime uses of their favoured tobacco product, and by 91% of dippers and 91% of smokers with >= 100 lifetime uses (not significant). Greater lifetime use was associated with a significantly shorter latency to withdrawal for smokers and dippers. CONCLUSIONS: The HONC and AUTOS are highly reliable measures of dependence for adolescent users of cigarettes and smokeless tobacco. Using these measures and other indicators, no meaningful differences in dependence were found between dippers and smokers at comparable levels of lifetime use. PMID- 21712394 TI - Nuocytes: expanding the innate cell repertoire in type-2 immunity. AB - Activation and differentiation of the Th1 cell population lead to their production of the classical type-1 cytokines IFN-gamma, IL-2, and TNF-beta, thus promoting type-1 immunity. This is thought to occur via the ligation of TLRs by bacterial and viral products, which in turn, drive production of the essential Th1 cell differentiation factor, IL-12, by dendritic cells (DCs). Concurrent studies have been able to identify the effector cytokines produced by Th2 cells (IL-4, IL-5, IL-9, and IL-13) as being essential for parasitic immunity and also as essential factors in allergic asthma. However, the factors that are critical for initiation of the type-2 response remained obscure. Recently however, two critical observations have led to a more detailed understanding of the innate type-2 response. First, two novel, type-2-inducing cytokines-IL-25 and IL-33-were identified as being necessary for the up-regulation of the type-2 effector cytokines, mirroring the role of IL-12 in the type-1 response. Second, studies focused on target cell populations of IL-25 and IL-33 have identified novel, innate cell populations, which potentially bridge the gap between presentation of the type-2-inducing cytokine and the later adaptive Th2 cell response. In this review, we will discuss these new type-2 innate cell populations, in particular, the recently discovered nuocyte population, which are required for type-2 responses against helminthic parasites. PMID- 21712395 TI - Rac2 is required for the formation of neutrophil extracellular traps. AB - Neutrophils play a critical role as a first line of defense against invading pathogens. Recently, a new defense strategy of neutrophils was described, in which pathogens are trapped and killed by NETs. However, the exact underlying mechanisms leading to the formation of NETs remain elusive. Here, we explored the role of the Rac small GTPases in the formation of NETs using neutrophils that lack Rac1, Rac2, or both isoforms. Efficient NET formation was observed in WT and Rac1null neutrophils. In contrast, NET formation was markedly impaired in cells lacking Rac2 or both Rac2 and Rac1. The defect in NET formation in Rac2null cells was rescued by exogenous ROS sources, suggesting that Rac2-mediated ROS generation is required for NET formation. In addition, we assessed the role of NO in NET formation in mouse neutrophils. Blocking NO production with the NOS inhibitor L-NAME significantly reduced NET formation. Moreover, we show that Rac2null cells produce significantly less NO than Rac1null cells or their WT counterparts. Our data suggest that Rac2 is essential for NET formation via pathways involving ROS and NO. PMID- 21712396 TI - IFN-gamma production by lung NK cells is critical for the natural resistance to pulmonary metastasis of B16 melanoma in mice. AB - NK cells are effector lymphocytes playing a critical role in the natural resistance against tumors. However, the precise mechanisms underlying NK cell mediated natural resistance against tumor metastasis are still unrevealed. B16 cells, mouse melanoma cells, were resistant to freshly isolated NK cell-mediated killing; nevertheless, NK cells were critical for natural resistance against experimental lung metastasis of B16 cells. We found that lung metastasis was increased significantly in IFN-gamma(-/-) mice but not pfp(-/-), IFN-alphaR(-/-), or IL-12/IL-18(-/-) mice. Interestingly, freshly isolated lung NK cells, but not spleen or liver NK cells, displayed augmented IFN-gamma production after B16 inoculation. Adoptive transfer of pfp(-/-) NK cells, but not IFN-gamma(-/-) NK cells, significantly decreased B16 lung metastasis in IFN-gamma(-/-) and pfp/IFN gamma(-/-)mice. Lung metastases of IFN-gammaRDN B16 was also increased in NK cell depleted or IFN-gamma(-/-) mice, suggesting that the IFN-gamma response of host cells was required in the NK cell and IFN-gamma-mediated antimetastatic effect. Our results demonstrate that IFN-gamma production from lung resident NK cells is a key response in the natural resistance to the experimental lung metastasis of NK cell-resistant tumor cells. PMID- 21712397 TI - Structural aspects of binding of alpha-linked digalactosides to human galectin-1. AB - By definition, adhesion/growth-regulatory galectins are known for their ability to bind beta-galactosides such as Galbeta(1 -> 4)Glc (lactose). Indications for affinity of human galectin-1 to alpha-linked digalactosides pose questions on the interaction profile with such bound ligands and selection of the galactose moiety for CH-pi stacking. These issues are resolved by a combination of (15)N-(1)H heteronuclear single quantum coherence (HSQC) chemical shift and saturation transfer difference nuclear magnetic resonance (STD NMR) epitope mappings with docking analysis, using the alpha(1 -> 3/4)-linked digalactosides and also Galalpha(1 -> 6)Glc (melibiose) as test compounds. The experimental part revealed interaction with the canonical lectin site, and this preferentially via the non reducing-end galactose moiety. Low-energy conformers appear to be selected without notable distortion, as shown by molecular dynamics simulations. With the alpha(1 -> 4) disaccharide, however, the typical CH-pi interaction is significantly diminished, yet binding appears to be partially compensated for by hydrogen bonding. Overall, these findings reveal that the type of alpha-linkage in digalactosides has an impact on maintaining CH-pi interactions and the pattern of hydrogen bonding, explaining preference for the alpha(1 -> 3) linkage. Thus, this lectin is able to accommodate both alpha- and beta-linked galactosides at the same site, with major contacts to the non-reducing-end sugar unit. PMID- 21712398 TI - Alternative transcription exceeds alternative splicing in generating the transcriptome diversity of cerebellar development. AB - Despite our growing knowledge that many mammalian genes generate multiple transcript variants that may encode functionally distinct protein isoforms, the transcriptomes of various tissues and their developmental stages are poorly defined. Identifying the transcriptome and its regulation in a cell/tissue is the key to deciphering the cell/tissue-specific functions of a gene. We built a genome-wide inventory of noncoding and protein-coding transcripts (transcriptomes), their promoters (promoteromes) and histone modification states (epigenomes) for developing, and adult cerebella using integrative massive parallel sequencing and bioinformatics approach. The data consists of 61,525 (12,796 novel) distinct mRNAs transcribed by 29,589 (4792 novel) promoters corresponding to 15,669 protein-coding and 7624 noncoding genes. Importantly, our results show that the transcript variants from a gene are predominantly generated using alternative transcriptional rather than splicing mechanisms, highlighting alternative promoters and transcriptional terminations as major sources of transcriptome diversity. Moreover, H3K4me3, and not H3K27me3, defined the use of alternative promoters, and we identified a combinatorial role of H3K4me3 and H3K27me3 in regulating the expression of transcripts, including transcript variants of a gene during development. We observed a strong bias of both H3K4me3 and H3K27me3 for CpG-rich promoters and an exponential relationship between their enrichment and corresponding transcript expression. Furthermore, the majority of genes associated with neurological diseases expressed multiple transcripts through alternative promoters, and we demonstrated aberrant use of alternative promoters in medulloblastoma, cancer arising in the cerebellum. The transcriptomes of developing and adult cerebella presented in this study emphasize the importance of analyzing gene regulation and function at the isoform level. PMID- 21712399 TI - Dynamic mechanisms for pre-miRNA binding and export by Exportin-5. AB - The biogenesis and function of mature microRNAs (miRNAs) is dependent on the nuclear export of miRNA precursors (pre-miRNA) by Exportin-5 (Exp5). To characterize the molecular mechanisms of how pre-miRNA is recognized and transported by Exp5, we have performed 21 molecular dynamic (MD) simulations of RNA-bound Exp5 (Exp5-RanGTP-premiRNA, Exp5-RanGDP-premiRNA, Exp5-premiRNA), RNA unbound Exp5 (Exp5-RanGTP, Exp5-RanGDP, apo-Exp5), and pre-miRNA. Our simulations with standard MD, steered molecular dynamics (SMD), and energy analysis have shown that (1) Free Exp5 undergoes extensive opening motion, and in this way facilitates the RanGTP binding. (2) RanGTP efficiently regulates the association/dissociation of pre-miRNA to its complex by inducing conformational changes in the HEAT-repeat helix stacking of Exp5. (3) The GTP hydrolysis prevents Ran from rebinding to Exp5 by regulating the hydrophobic interfaces and salt bridges between Ran and Exp5. (4) The transition from the A'-form to the A form of the pre-miRNA modulates the structural complementarities between the protein and the pre-miRNA, thus promoting efficient assembly of the complex. (5) The base-flipping process (from the closed to the fully flipped state) of the 2 nt 3' overhang is a prerequisite for the pre-miRNA recognition by Exp5, which occurs in a sequence-independent manner as evidenced by the fact that different 2 nt 3' overhangs bind to Exp5 in essentially the same way. And finally, a plausible mechanism of the pre-miRNA export cycle has been proposed explaining how the protein-protein and protein-RNA interactions are coordinated in physiological conditions. PMID- 21712402 TI - Modelling the compression and reorganization of cell aggregates. AB - In this paper, we study the mechanical behaviour of multicellular aggregates using the notion of multiple natural configurations. In particular, we extend the elasto-visco-plastic model proposed in Preziosi et al. (2010, An elasto-visco plastic model of cell aggregates. J. Theor. Biol., 262, 35-47) taking into account the liquid constituent present in cellular spheroids. Aggregates are treated as porous materials, composed of cells and filled with water. The cellular constituent is responsible for the elastic and the plastic behaviour of the material. The plastic component is due to the rearrangement of adhesion bonds between cells and it is translated into the existence of a yield stress in the macroscopic constitutive equation. On the other hand, the liquid constituent is responsible for the viscous-like response during deformation. The general framework is then applied to describe uniaxial homogeneous compression both when a constant load is applied and when a fixed deformation is imposed and subsequently released. We compare the results of the model with the dynamics observed during the experiments in Forgacs et al. (1998, Viscoelastic properties of living embryonic tissues: a quantitative study. Biophys. J., 74, 2227-2234). PMID- 21712400 TI - RNA molecules with conserved catalytic cores but variable peripheries fold along unique energetically optimized pathways. AB - Functional and kinetic constraints must be efficiently balanced during the folding process of all biopolymers. To understand how homologous RNA molecules with different global architectures fold into a common core structure we determined, under identical conditions, the folding mechanisms of three phylogenetically divergent group I intron ribozymes. These ribozymes share a conserved functional core defined by topologically equivalent tertiary motifs but differ in their primary sequence, size, and structural complexity. Time-resolved hydroxyl radical probing of the backbone solvent accessible surface and catalytic activity measurements integrated with structural-kinetic modeling reveal that each ribozyme adopts a unique strategy to attain the conserved functional fold. The folding rates are not dictated by the size or the overall structural complexity, but rather by the strength of the constituent tertiary motifs which, in turn, govern the structure, stability, and lifetime of the folding intermediates. A fundamental general principle of RNA folding emerges from this study: The dominant folding flux always proceeds through an optimally structured kinetic intermediate that has sufficient stability to act as a nucleating scaffold while retaining enough conformational freedom to avoid kinetic trapping. Our results also suggest a potential role of naturally selected peripheral A minor interactions in balancing RNA structural stability with folding efficiency. PMID- 21712401 TI - A role for noncanonical microRNAs in the mammalian brain revealed by phenotypic differences in Dgcr8 versus Dicer1 knockouts and small RNA sequencing. AB - Noncanonical microRNAs (miRNAs) and endogenous small interfering RNAs (endo siRNAs) are distinct subclasses of small RNAs that bypass the DGCR8/DROSHA Microprocessor but still require DICER1 for their biogenesis. What role, if any, they have in mammals remains unknown. To identify potential functional properties for these subclasses, we compared the phenotypes resulting from conditional deletion of Dgcr8 versus Dicer1 in post-mitotic neurons. The loss of Dicer1 resulted in an earlier lethality, more severe structural abnormalities, and increased apoptosis relative to that from Dgcr8 loss. Deep sequencing of small RNAs from the hippocampus and cortex of the conditional knockouts and control littermates identified multiple noncanonical microRNAs that were expressed at high levels in the brain relative to other tissues, including mirtrons and H/ACA snoRNA-derived small RNAs. In contrast, we found no evidence for endo-siRNAs in the brain. Taken together, our findings provide evidence for a diverse population of highly expressed noncanonical miRNAs that together are likely to play important functional roles in post-mitotic neurons. PMID- 21712403 TI - Hypertensive crisis and end-organ damage induced by over-the-counter nasal decongestant abuse. PMID- 21712404 TI - ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). AB - Cardiovascular disease (CVD) due to atherosclerosis of the arterial vessel wall and to thrombosis is the foremost cause of premature mortality and of disability adjusted life years (DALYs) in Europe, and is also increasingly common in developing countries.1 In the European Union, the economic cost of CVD represents annually E192 billion1 in direct and indirect healthcare costs. The main clinical entities are coronary artery disease (CAD), ischaemic stroke, and peripheral arterial disease (PAD). The causes of these CVDs are multifactorial. Some of these factors relate to lifestyles, such as tobacco smoking, lack of physical activity, and dietary habits, and are thus modifiable. Other risk factors are also modifiable, such as elevated blood pressure, type 2 diabetes, and dyslipidaemias, or non-modifiable, such as age and male gender. These guidelines deal with the management of dyslipidaemias as an essential and integral part of CVD prevention. Prevention and treatment of dyslipidaemias should always be considered within the broader framework of CVD prevention, which is addressed in guidelines of the Joint European Societies' Task forces on CVD prevention in clinical practice.2 - 5 The latest version of these guidelines was published in 20075; an update will become available in 2012. These Joint ESC/European Atherosclerosis Society (EAS) guidelines on the management of dyslipidaemias are complementary to the guidelines on CVD prevention in clinical practice and address not only physicians [e.g. general practitioners (GPs) and cardiologists] interested in CVD prevention, but also specialists from lipid clinics or metabolic units who are dealing with dyslipidaemias that are more difficult to classify and treat. PMID- 21712405 TI - Sperm motility: things are moving in the lab! PMID- 21712406 TI - FoxM1: a master regulator of tumor metastasis. AB - The FoxM1 transcription factor gene is overexpressed in cancer. Its expression is stimulated by oncogenic signaling pathways and reactive oxygen species. It is also a target of regulation by the tumor suppressor genes. The transcriptional activity of FoxM1 depends upon activation by cyclin and cyclin-dependent kinases as well as Plk1. FoxM1 stimulates expression of several genes involved in the cell cycle progression. Moreover, it supports proliferation of tumor cells by stimulating expression of the antioxidant genes and reducing oxidative stress. A new study provides evidence that FoxM1, in the absence of its inhibitor, the tumor suppressor Arf, drives metastasis of hepatocellular carcinoma (HCC). It induces an epithelial-mesenchymal-like transition phenotype in HCC cells, increases cell migration, and induces premetastatic niche at the distal organ of metastasis. FoxM1 directly activates genes involved in multiple steps of metastasis. In this review, we discuss the evidence for a master regulatory role of FoxM1 in tumor metastasis. PMID- 21712408 TI - Analysis of mitosis and antimitotic drug responses in tumors by in vivo microscopy and single-cell pharmacodynamics. AB - Cancer relies upon frequent or abnormal cell division, but how the tumor microenvironment affects mitotic processes in vivo remains unclear, largely due to the technical challenges of optical access, spatial resolution, and motion. We developed high-resolution in vivo microscopy methods to visualize mitosis in a murine xenograft model of human cancer. Using these methods, we determined whether the single-cell response to the antimitotic drug paclitaxel (Ptx) was the same in tumors as in cell culture, observed the impact of Ptx on the tumor response as a whole, and evaluated the single-cell pharmacodynamics (PD) of Ptx (by in vivo PD microscopy). Mitotic initiation was generally less frequent in tumors than in cell culture, but subsequently it proceeded normally. Ptx treatment caused spindle assembly defects and mitotic arrest, followed by slippage from mitotic arrest, multinucleation, and apoptosis. Compared with cell culture, the peak mitotic index in tumors exposed to Ptx was lower and the tumor cells survived longer after mitotic arrest, becoming multinucleated rather than dying directly from mitotic arrest. Thus, the tumor microenvironment was much less proapoptotic than cell culture. The morphologies associated with mitotic arrest were dose and time dependent, thereby providing a semiquantitative, single cell measure of PD. Although many tumor cells did not progress through Ptx induced mitotic arrest, tumor significantly regressed in the model. Our findings show that in vivo microscopy offers a useful tool to visualize mitosis during tumor progression, drug responses, and cell fate at the single-cell level. PMID- 21712409 TI - Tumor immunology: basic and clinical advances. AB - The third in a series of AACR conferences, entitled "Tumor Immunology: Basic and Clinical Advances," was held in Miami Beach, Florida from November 30 to December 3, 2010. The overall objective of this meeting was to discuss rapid developments in the understanding of basic principles of antitumor immunity and strategies for increasing the success rate of cancer immunotherapy. The key findings that emerged from the meeting included (i) that integrated approaches are required for the development of effective cancer immunotherapies and (ii) attention should be on multiple cellular and molecular components and their broader networks rather than on a single pathway or cell type. PMID- 21712412 TI - The role of tenascin C in cardiovascular disease. AB - The extracellular matrix protein tenascin C (TnC) is expressed in a variety of embryonic tissues, but its expression in adult arteries is co-incident with sites of vascular disease. TnC expression has been linked to the development and complications of intimal hyperplasia, pulmonary artery hypertension, atherosclerosis, myocardial infarction, and heart failure. This review identifies the growing collection of evidence linking TnC with cardiovascular disease development. The transient upregulation of this extracellular matrix protein at sites of vascular disease could provide a means to target TnC in the development of diagnostics and new therapies. Studies in TnC-deficient mice have implicated this protein in the development of intimal hyperplasia. Further animal and human studies are required to thoroughly assess the role of TnC in some of the other pathologies it has been linked with, such as atherosclerosis and pulmonary hypertension. Large population studies are also warranted to clarify the diagnostic value of this extracellular matrix protein in cardiovascular disease, for example by targeting its expression using radiolabelled antibodies or measuring circulating concentrations of TnC. PMID- 21712413 TI - Introducing Richard H. Masland, the 2010 recipient of the Proctor medal. PMID- 21712410 TI - HIF induces human embryonic stem cell markers in cancer cells. AB - Low oxygen levels have been shown to promote self-renewal in many stem cells. In tumors, hypoxia is associated with aggressive disease course and poor clinical outcomes. Furthermore, many aggressive tumors have been shown to display gene expression signatures characteristic of human embryonic stem cells (hESC). We now tested whether hypoxia might be responsible for the hESC signature observed in aggressive tumors. We show that hypoxia, through hypoxia-inducible factor (HIF), can induce an hESC-like transcriptional program, including the induced pluripotent stem cell (iPSC) inducers, OCT4, NANOG, SOX2, KLF4, cMYC, and microRNA-302 in 11 cancer cell lines (from prostate, brain, kidney, cervix, lung, colon, liver, and breast tumors). Furthermore, nondegradable forms of HIFalpha, combined with the traditional iPSC inducers, are highly efficient in generating A549 iPSC-like colonies that have high tumorigenic capacity. To test potential correlation between iPSC inducers and HIF expression in primary tumors, we analyzed primary prostate tumors and found a significant correlation between NANOG-, OCT4-, and HIF1alpha-positive regions. Furthermore, NANOG and OCT4 expressions positively correlated with increased prostate tumor Gleason score. In primary glioma-derived CD133 negative cells, hypoxia was able to induce neurospheres and hESC markers. Together, these findings suggest that HIF targets may act as key inducers of a dynamic state of stemness in pathologic conditions. PMID- 21712414 TI - Cell populations of the retina: the Proctor lecture. PMID- 21712415 TI - Cytosolic gamma-glutamyl peptidases process glutathione conjugates in the biosynthesis of glucosinolates and camalexin in Arabidopsis. AB - The defense-related plant metabolites known as glucosinolates play important roles in agriculture, ecology, and human health. Despite an advanced biochemical understanding of the glucosinolate pathway, the source of the reduced sulfur atom in the core glucosinolate structure remains unknown. Recent evidence has pointed toward GSH, which would require further involvement of a GSH conjugate processing enzyme. In this article, we show that an Arabidopsis thaliana mutant impaired in the production of the gamma-glutamyl peptidases GGP1 and GGP3 has altered glucosinolate levels and accumulates up to 10 related GSH conjugates. We also show that the double mutant is impaired in the production of camalexin and accumulates high amounts of the camalexin intermediate GS-IAN upon induction. In addition, we demonstrate that the cellular and subcellular localization of GGP1 and GGP3 matches that of known glucosinolate and camalexin enzymes. Finally, we show that the purified recombinant GGPs can metabolize at least nine of the 10 glucosinolate-related GSH conjugates as well as GS-IAN. Our results demonstrate that GSH is the sulfur donor in the biosynthesis of glucosinolates and establish an in vivo function for the only known cytosolic plant gamma-glutamyl peptidases, namely, the processing of GSH conjugates in the glucosinolate and camalexin pathways. PMID- 21712417 TI - Long-distance dispersal and high genetic diversity are implicated in the invasive spread of the common reed, Phragmites australis (Poaceae), in northeastern North America. AB - PREMISE OF THE STUDY: The Eurasian subspecies of the common reed (Phragmites australis subsp. australis, hereafter abbreviated as P. a. australis) was introduced to North America in the late 18(th) century and rapidly expanded its range, posing an ecological threat to wetlands. In this study, we aimed to determine whether admixture among multiple lineages, dispersal mechanisms, and high genetic diversity have contributed to the invasion of P. a. australis in the northeastern part of its range. Understanding mechanisms of the P. a. australis invasion will 1) contribute to a broader understanding of the factors that facilitate plant invasion, and 2) help us to develop effective management strategies for wetlands threatened by P. a. australis invasion. METHODS: We used a population genetics approach incorporating nine microsatellite loci to study genetic diversity and population structure in relation to biogeography of introduced North American Phragmites a. australis stands in the northeastern continental region. KEY RESULTS: Phragmites a. australis is genetically diverse in the region studied here. Significant population structure exists, and population structure is likely influenced by both long-distance dispersal via major waterways, and short-distance dispersal overland. Different lineages sometimes colonize geographically proximate locations leading to opportunities for admixture. Clonal reproduction likely exaggerates geographical structure among some stands, although high genetic and clonal diversity within some stands implies that sexual reproduction occurs frequently in P. a. australis. CONCLUSIONS: A variety of factors, including admixture among multiple lineages, multiple modes of dispersal, and plasticity in reproductive strategy promote the invasion success of Phragmites a. australis. Wetland managers in the St. Lawrence River/Great Lakes region should focus monitoring efforts on the shores of conservation lands to prevent the establishment of propagules from novel lineages. PMID- 21712416 TI - Subunit stoichiometry, evolution, and functional implications of an asymmetric plant plastid ClpP/R protease complex in Arabidopsis. AB - The caseinolytic protease (Clp) protease system has been expanded in plant plastids compared with its prokaryotic progenitors. The plastid Clp core protease consists of five different proteolytic ClpP proteins and four different noncatalytic ClpR proteins, with each present in one or more copies and organized in two heptameric rings. We determined the exact subunit composition and stoichiometry for the intact core and each ring. The chloroplast ClpP/R protease was affinity purified from clpr4 and clpp3 Arabidopsis thaliana null mutants complemented with C-terminal StrepII-tagged versions of CLPR4 and CLPP3, respectively. The subunit stoichiometry was determined by mass spectrometry-based absolute quantification using stable isotope-labeled proteotypic peptides generated from a synthetic gene. One heptameric ring contained ClpP3,4,5,6 in a 1:2:3:1 ratio. The other ring contained ClpP1 and ClpR1,2,3,4 in a 3:1:1:1:1 ratio, resulting in only three catalytic sites. These ClpP1/R1-4 proteins are most closely related to the two subunits of the cyanobacterial P3/R complex and the identical P:R ratio suggests conserved adaptation. Furthermore, the plant specific C-terminal extensions of the ClpP/R subunits were not proteolytically removed upon assembly, suggesting a regulatory role in Clp chaperone interaction. These results will now allow testing ClpP/R structure-function relationships using rationale design. The quantification workflow we have designed is applicable to other protein complexes. PMID- 21712418 TI - Patterns of diversity in leaves from canopies of Ginkgo biloba are revealed using Specific Leaf Area as a morphological character. AB - PREMISE OF THE STUDY: The difference reported in the literature for the Specific Leaf Area (SLA, cm(2)/g) of leaves on short- and long-shoots of Acer rubrum could mean that SLA can serve as a quantitative morphological trait. Our survey of SLA in canopies of Ginkgo biloba sampled a different clade of seed plants to investigate this morphological phenomenon. Such a survey in this dioecious taxon, and one in which a single canopy may have juvenile and reproductive portions, as well as one where canopies bear leaves of several shapes, examine these additional morphological factors as well as any long-shoot short-shoot differences. METHODS: We measured SLA for a set of 642 dried leaves, a sampling across all morphological levels in canopies of large landscape specimens. The tabulated values were analyzed as distributions. KEY RESULTS: Populations of leaves of G. biloba, sorted by morphological features of canopy structure, differ between long- and short-shoots (175%), on the two genders of tree (131%), in the juvenile and reproductive portions of a canopy (183%), and with the presence or absence of seed on short-shoots in the reproductive portion of megasporangiate canopies (114%). Basipetal leaves of long-shoots and leaves of short-shoots have similar values of SLA. CONCLUSIONS: With the exception of the acropetal decrease in SLA along long-shoots, the differences among the several classes of leaf seem to reflect local sink strength, even though the sink itself develops after leaves mature. The large overall range in the values of SLA in Ginkgo underscores the relevance of the details of canopy structure to parsing ecological phenomena. PMID- 21712419 TI - Photosynthetic Mediterranean meadow orchids feature partial mycoheterotrophy and specific mycorrhizal associations. AB - PREMISE OF THE STUDY: We investigated whether four widespread, photosynthetic Mediterranean meadow orchids (Ophrys fuciflora, Anacamptis laxiflora, Orchis purpurea, and Serapias vomeracea) had either nutritional dependency on mycobionts or mycorrhizal fungal specificity. Nonphotosynthetic orchids generally engage in highly specific interactions with fungal symbionts that provide them with organic carbon. By contrast, fully photosynthetic orchids in sunny, meadow habitats have been considered to lack mycorrhizal specificity. METHODS: We performed both culture-dependent and culture-independent ITS sequence analysis to identify fungi from orchid roots. By analyzing stable isotope ((13)C and (15)N) natural abundances, we also determined the degree of autotrophy and mycoheterotrophy in the four orchid species. KEY RESULTS: Phylogenetic and multivariate comparisons indicated that Or. purpurea and Oph. fuciflora featured lower fungal diversity and more specific mycobiont spectra than A. laxiflora and S. vomeracea. All orchid species were significantly enriched in (15)N compared with neighboring non orchid plants. Orchis purpurea had the most pronounced N gain from fungi and differed from the other orchids in also obtaining C from fungi. CONCLUSIONS: These results indicated that even in sunny Mediterranean meadows, orchids may be mycoheterotrophic, with correlated mycorrhizal fungal specificity. PMID- 21712420 TI - Nile red detection of bacterial hydrocarbons and ketones in a high-throughput format. AB - A method for use in high-throughput screening of bacteria for the production of long-chain hydrocarbons and ketones by monitoring fluorescent light emission in the presence of Nile red is described. Nile red has previously been used to screen for polyhydroxybutyrate (PHB) and fatty acid esters, but this is the first report of screening for recombinant bacteria making hydrocarbons or ketones. The microtiter plate assay was evaluated using wild-type and recombinant strains of Shewanella oneidensis and Escherichia coli expressing the enzyme OleA, previously shown to initiate hydrocarbon biosynthesis. The strains expressing exogenous Stenotrophomonas maltophilia oleA, with increased levels of ketone production as determined by gas chromatography-mass spectrometry, were distinguished with Nile red fluorescence. Confocal microscopy images of S. oneidensis oleA-expressing strains stained with Nile red were consistent with a membrane localization of the ketones. This differed from Nile red staining of bacterial PHB or algal lipid droplets that showed intracellular inclusion bodies. These results demonstrated the applicability of Nile red in a high-throughput technique for the detection of bacterial hydrocarbons and ketones. PMID- 21712421 TI - Structure and function of the D-galactose network in enterobacteria. AB - Galactose is important for the survival and virulence of bacteria. In Escherichia coli, galactose is utilized by the Leloir pathway, which is controlled by a complex network. To shed light on the potential functions the galactose network could perform, we performed bioinformatical analysis of reference genome sequences belonging to the Enterobacteriaceae family. We found that several genomes have reduced numbers of components compared to the E. coli galactose system, suggesting that the network can be optimized for different environments. Typically, genes are removed by deletions; however, in Yersinia pestis, the galactose mutarotase (galM) gene is inactivated by a single-base-pair deletion. Lack of GalM activity indicates that the two anomers of D-galactose are used for different purposes, alpha-D-galactose as a carbon source and beta-D-galactose for induction of UDP-galactose synthesis for biosynthetic glycosylation. We demonstrate that activity of the galM gene can be restored by different single base-pair insertions. During the evolution of Y. pestis to become a vector transmitted systemic pathogen, many genes were converted to pseudogenes. It is not clear whether pseudogenes are present to maintain meiotrophism or are in the process of elimination. Our results suggest that the galM pseudogene has not been deleted because its reactivation may be beneficial in certain environments. PMID- 21712422 TI - Intracellular TLR4/MD-2 in macrophages senses Gram-negative bacteria and induces a unique set of LPS-dependent genes. AB - Toll-like receptor (TLR)4/MD-2, a sensor for LPS, delivers the MyD88-dependent signal from the cell surface, then traffics to endolysosomes and delivers the TRIF/TICAM-1-dependent signal. Both signals are thought to be dependent on cell surface TLR4/MD-2. Although TLR4/MD-2 is located also in recycling endosomes, the Golgi apparatus or the endoplasmic reticulum, little is known about a role for intracellular TLR4/MD-2 in LPS responses. We here studied intracellular LPS sensing in macrophages. PRAT4A (protein associated with TLR4 A) is a cochaperone for a general chaperone gp96 and required for cell surface expression of TLR4/MD 2. Cell surface TLR4/MD-2 was undetectable on PRAT4A(-/-) thioglycollate-elicited peritoneal macrophages (P-Macs) and bone marrow-derived macrophages (BM-Macs). LPS responses were all abolished in PRAT4A(-/-) P-Macs, whereas a part of LPS responses remained detectable in PRAT4A(-/-) BM-Macs. Of note, LPS responses in PRAT4A(-/-) BM-Macs were not necessarily dependent on TRIF/TICAM-1 signaling. PRAT4A(-/-) BM-Macs showed unimpaired production of both TRIF/TICAM-1-dependent chemokine RANTES (CCL5) and MyD88-dependent chemokine MCP-1 (CCL2). Moreover, up regulation of co-stimulatory molecules, CD40 and CD86 was not altered. In contrast, TRIF/TICAM-1-dependent production of type I IFN was profoundly impaired. In response to heat-killed bacteria Escherichia coli, BM-Macs also required PRAT4A-independent TLR4/MD-2 for production of MCP-1 (CCL2) and RANTES (CCL5) and for up-regulation of CD40 and CD86, indicating that intracellular TLR4/MD-2 is able to sense phagocytosed bacteria and activate immune responses. These results demonstrate that intracellular TLR4/MD-2 is responsible for unique set of LPS responses. PMID- 21712423 TI - Mucosal-associated invariant T cells regulate Th1 response in multiple sclerosis. AB - Mucosal-associated invariant T (MAIT) cells are innate T cells expressing an invariant Valpha7.2-Jalpha33 T-cell antigen receptor alpha chain and are enriched in mucosal-associated lymphoid tissues. Although the regulatory role of MAIT cells in experimental autoimmune encephalomyelitis has been determined, their role in multiple sclerosis (MS) has not been elucidated. In the present study, the character of MAIT cells in the peripheral blood of MS patients was analyzed. Compared with healthy controls, the frequency of MAIT cells in peripheral blood was significantly reduced in MS patients in remission and even more profoundly reduced in those with relapse. The frequency of MAIT cells reflected the disease activity, as they were reduced significantly in patients with active disease compared with stable patients, and when blood samples from patients undergoing attack were analyzed 2-3 months later, the frequency significantly increased in parallel with clinical recovery. The frequency of MAIT cells positively correlated with the frequency of CD4(+) invariant NKT cells and of CD56(bright) NK cells in healthy controls but not in MS patients. This suggests the existence of an immune-regulatory link between MAIT cells and these other cell populations with disruption of this cross talk in MS. Moreover, MAIT cells showed a suppressive activity against IFN-gamma production by T cells in vitro. This suppression required cell contact but was independent of IL-10, inducible co stimulator or the presence of B cells. Taken together, these results suggest an immune-regulatory role of MAIT cells in MS through suppression of pathogenic T(h)1 cells. PMID- 21712424 TI - Effect of lead on apoptosis in cultured rat primary osteoblasts. AB - To investigate the effect of lead exposure on apoptosis of cultured rat primary osteoblasts (ROBs), which were derived from newborn calvariae of Sprague Dawley rat. They were identified by the staining of alkaline phosphatase and mineralized matrix. The ROBs were received at 0, 20, 40 and 80 MUM Pb2+ of lead acetate solution for 24 h, respectively, before being doubly marked by Annexin V fluorescein isothiocyanate/propidium iodide. The intracellular concentration of calcium ([Ca2+](i)) was detected under the laser scan confocal microscope. The activities of phosphatidylcholine-specific phospholipase C (PC-PLC) were measured and the effect of lead exposure on the expression of PC-PLC was observed by immunoblotting assay. The results showed that when compared with that of the control group, lead exposure induced an increase of [Ca2+](i) of lead-treated ROBs, resulting in a significant development in apoptosis. In the meantime, a significant decline in protein level and enzymatic activities of PC-PLC were observed in a dose-dependent manner. It was concluded that lead can induce apoptosis in ROBs, and one of the mechanisms of lead-induced apoptosis may be that activating intracellular calcium stores by decreasing protein levels and enzymatic activities of PC-PLC can increase the [Ca2+](i), and consequently, the apoptotic signal pathway can be induced. PMID- 21712425 TI - Genetic variants in cytosolic 5'-nucleotidase II are associated with its expression and cytarabine sensitivity in HapMap cell lines and in patients with acute myeloid leukemia. AB - Cytosolic 5'-nucleotidase II (NT5C2) is involved in the development of 1-beta-d arabinofuranosylcytosine (ara-C) resistance and has been associated with clinical outcome in patients receiving ara-C-based chemotherapy. NT5C2 inactivates ara-C by dephosphorylating ara-C monophosphate to ara-C. In this study, we sequenced NT5C2 in genomic DNA samples from International HapMap project panels with European [Centre d'Etude du Polymorphisme Humain (CEU); n = 90] or African [Yoruba people in Ibadan, Nigeria (YRI); n = 90] ancestry. We identified 41 genetic variants [one insertion-deletion and 40 single nucleotide polymorphisms (SNPs)], including three nonsynonymous SNPs (Y3A, K47R, and Q136R). Twenty-five SNPs were novel and 16 overlapped with the HapMap data. Subjects with African ancestry had NT5C2 mRNA expression levels that was significantly higher than those with European ancestry (p = 0.005). Furthermore, there was a correlation between NT5C2 mRNA expression and ara-C sensitivity in CEU but not in YRI cell lines. None of the nonsynonymous SNPs demonstrated any effect on NT5C2 activity. The genotypes of several SNPs were significantly associated with NT5C2 mRNA expression and/or ara-C sensitivity in CEU cell lines, but very few were significant in YRI cell lines. Of most interest, SNPs (linkage disequilibrium group CEU.12) in the 5'-untranslated region were associated with NT5C2 expression and ara-C sensitivity in HapMap cell lines and with NT5C2 mRNA expression and ara C sensitivity in diagnostic leukemic blasts from pediatric patients with acute myeloid leukemia. Functional genomics analysis demonstrated that the promoter SNP rs11191612 was associated with altered luciferase activation in reporter assays and altered DNA-protein binding in gel shift assays. These results suggest that genetic variations in NT5C2 influence its expression and, potentially, cellular responses to nucleoside analogs. PMID- 21712426 TI - Regulation of ingestive behaviors in the rat by GSK1521498, a novel micro-opioid receptor-selective inverse agonist. AB - MU-Opioid receptor (MOR) agonism induces palatable food consumption principally through modulation of the rewarding properties of food. N-{[3,5-difluoro-3'-(1H 1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498) is a novel opioid receptor inverse agonist that, on the basis of in vitro affinity assays, is greater than 10- or 50-fold selective for human or rat MOR, respectively, compared with kappa-opioid receptors (KOR) and delta-opioid receptors (DOR). Likewise, preferential MOR occupancy versus KOR and DOR was observed by autoradiography in brain slices from Long Evans rats dosed orally with the drug. GSK1521498 suppressed nocturnal food consumption of standard or palatable chow in lean and diet-induced obese (DIO) Long Evans rats. Both the dose-response relationship and time course of efficacy in lean rats fed palatable chow correlated with MU receptor occupancy and the plasma concentration profile of the drug. Chronic oral administration of GSK1521498 induced body weight loss in DIO rats, which comprised fat mass reduction. The reduction in body weight was equivalent to the cumulative reduction in food consumption; thus, the effect of GSK1521498 on body weight is related to inhibition of food consumption. GSK1521498 suppressed the preference for sucrose-containing solutions in lean rats. In operant response models also using lean rats, GSK1521498 reduced the reinforcement efficacy of palatable food reward and enhanced satiety. In conclusion, GSK1521498 is a potent, MOR-selective inverse agonist that modulates the hedonic aspects of ingestion and, therefore, could represent a pharmacological treatment for obesity and binge-eating disorders. PMID- 21712427 TI - Detection of prostate cancer with three-dimensional transrectal ultrasound: correlation with biopsy results. AB - OBJECTIVES: The aim of this study was to evaluate the role of three-dimensional transrectal ultrasound in the diagnosis of prostate cancer. METHODS: A total of 112 patients with elevated serum prostate-specific antigen (PSA) or a positive digital rectal examination were evaluated using three-dimensional greyscale transrectal ultrasound (3D-GS TRUS) and three-dimensional power Doppler sonography (3D-PDS). Target biopsies were obtained together with 12 core systematic biopsies. Pathological results were correlated with the imaging data. RESULTS: Cancers were detected in 269 biopsy sites from 41 patients. 229 sites of cancer were depicted by 3D-GS TRUS and 213 sites were depicted by 3D-PDS. 30 sites were missed by both 3D-GS TRUS and 3D-PDS. Abnormal prostate images depicted by 3D-GS TRUS and 3D-PDS were associated with lesions with a Gleason score of 6.9 or higher. CONCLUSION: The detection rates of prostate cancer were significantly improved with 3D-GS TRUS and 3D-PDS on serum PSA levels >10 ng ml( 1) or 20 ng ml(-1). 3D-GS TRUS and 3D-PDS may improve the biopsy yield by determining appropriate sites for target and systematic biopsies. The abnormalities detected by 3D ultrasound were associated with moderate- and high grade prostate cancers. However, based on the number of false-negative TRUS results, the use of systematic prostate biopsies should not be eliminated. PMID- 21712428 TI - Single-arc volumetric-modulated arc therapy can provide dose distributions equivalent to fixed-beam intensity-modulated radiation therapy for prostatic irradiation with seminal vesicle and/or lymph node involvement. AB - OBJECTIVES: Volumetric-modulated arc therapy (VMAT) is becoming an increasingly utilised modality for treating a variety of anatomical sites. However, the efficacy of single-arc VMAT to treat prostate cancer suspicious for extraprostatic extension was heretofore unknown. In this work, we report our institutional experience with single-arc VMAT and fixed-beam intensity-modulated radiation therapy (IMRT) for prostate cancer patients treated for seminal vesicle and/or lymph node involvement. METHODS: Single-arc VMAT and 7- or 9-field IMRT treatment plans were compared for 10 prostate cancer patients treated for seminal vesicle involvement and/or lymph node involvement. All treatment plans were constructed using the Philips Pinnacle treatment planning system (v.9.0, Fitchburg, WI) and delivered on an Elekta Infinity radiotherapy accelerator (Crawley, UK). Resulting plans were compared using metrics that characterised dosimetry and delivery efficiency. RESULTS: No statistically significant differences in target coverage, target homogeneity or normal tissue doses were noted between the plans (p>0.05). For prostate patients treated for seminal vesicle involvement, VMAT plans were delivered in 1.4+/-0.1 min (vs 9.5+/-2.4 min for fixed-beam IMRT) (p<0.01) and required approximately 20% fewer monitor units (p=0.01). For prostate patients treated for lymph node involvement, VMAT plans were delivered in 1.4+/-0.1 min (vs 11.7+/-1.3 min for fixed-beam IMRT) (p<0.01) and required approximately 45% fewer monitor units (p<0.01). CONCLUSION: Single arc VMAT plans were dosimetrically equivalent to fixed-beam IMRT plans with significantly improved delivery efficiency. PMID- 21712429 TI - Breast-specific gamma imaging as an adjunct modality for the diagnosis of invasive breast cancer with correlation to tumour size and grade. AB - OBJECTIVES: The purpose of this study was to determine the sensitivity of breast specific gamma imaging (BSGI) in the detection of invasive breast cancers and to characterise the sensitivity of BSGI based on tumour size and pathological grade. METHODS: 139 females with invasive carcinoma who underwent BSGI were retrospectively reviewed. Patients were injected in the antecubital vein with 20 30 mCi (925-1110 MBq) of (99m)Tc-sestamibi. Images were obtained with a high resolution, breast-specific gamma camera (Dilon 6800; Dilon Technologies, Newport News, VA) and were categorised based on radiotracer uptake as normal, normal with heterogeneous uptake, probably abnormal and abnormal. For a positive examination, the region of the area of increased uptake had to correlate with the laterality and location of the biopsy-proven cancer. RESULTS: 149 invasive cancers in 139 patients with a mean size of 1.8 cm (0.2-8.5 cm) were included. 146 were identified with BSGI (98.0%). All cancers which measured >= 0.7 cm (n = 123) as well as all cancers grade 2 or higher (n = 102), regardless of tumour size, were identified with BSGI (100%). There were 6 cancers that were pathological grade 1 and measured <7 mm, of which 50% (3/6) were identified with BSGI. The overall sensitivity of BSGI for the detection of invasive breast cancer is 98.0%. The sensitivity for subcentimetre cancers is 88.5% (23/26). CONCLUSION: BSGI has a high sensitivity for the detection of invasive breast cancer. Our results demonstrate that BSGI detected all invasive breast cancers pathological grade 2 and higher regardless of size and all cancers which measured >= 7 mm regardless of grade. BSGI can reliably detect invasive breast cancers and is a useful adjunct imaging modality for the diagnosis of breast cancer. PMID- 21712430 TI - An evaluation of diaphragmatic movements in hemiplegic patients. AB - OBJECTIVE: The aim of this study was to evaluate the effect of hemiplegia on diaphragmatic movements using motion-mode ultrasonography. METHODS: 23 hemiplegic patients who were diagnosed with a single-hemisphere lesion (mean age 60.5 years; 13 males and 10 females) and a control group of 20 patients (13 males and 7 females) were all evaluated by ultrasonography. Ultrasonography recordings were made of the amplitude of diaphragmatic movement during spontaneous and deep breathing. The patients underwent lung function tests. RESULTS: When the hemiplegic and control groups were compared, the forced vital capacity, forced expired volume in 1 s, maximum inspiratory pressure and maximum expiratory pressure values were significantly lower in the groups with right and left hemiplegia (p<0.05). When a comparison was made between the right hemiplegic group and the control group and between the left hemiplegic group and the control group in terms of diaphragmatic excursions, for both groups, no significant difference was determined between the movements of the right hemidiaphragm during spontaneous and deep breathing and those of the left hemidiaphragm in spontaneous respiration. In contrast, for both hemiplegic groups, a significant decrease was noted in the movements of the left hemidiaphragm in deep respiration. CONCLUSION: The diaphragm is both contralaterally innervated and ipsilaterally innervated, and innervation exhibits marked variations from person to person. This provides an explanation for varying diaphragmatic movements in hemiplegic cases during deep respiration. PMID- 21712431 TI - The effect of low-dose exposure on germline microsatellite mutation rates in humans accidentally exposed to caesium-137 in Goiania. AB - A serious radiological accident occurred in 1987 in Goiania, Brazil, which lead to extensive human and environmental contamination as a result of ionising radiation (IR) from caesium-137. Among the exposed were those in direct contact with caesium-137, their relatives, neighbours, liquidators and health personnel involved in the handling of the radioactive material and the clean-up of the radioactive sites. The exposed group consisted of 10 two-generation families, totalling 34 people. For each exposed family, at least one of the progenitors was directly exposed to very low doses of gamma-IR. The control group consisted of 215 non-irradiated families, composed of a father, mother and child, all of them from Goiania, Brazil. Genomic DNA was purified using 100 MUl of whole blood. The amplification reactions were prepared according to PowerPlex(r) 16, following the manufacturer's instructions. Genetic profiles were obtained from a single polymerase chain reaction amplification. The exposed group had only one germline mutation of a paternal origin in the 'locus' D8S1179 and the observed mutation presented a gain of only one repeat unit. In the control group, 11 mutations were observed and the mutational events were distributed in five loci D16S539, D3S1358, FGA, Penta E and D21S11. The mutation rates for the exposed and control groups were 0.006 and 0.002, respectively. There was no statistically significant difference (P = 0.09) between the mutation rate of the exposed and control groups. In conclusion, the quantification of mutational events in short tandem repeats can provide a useful system for detecting induced mutations in a relatively small population. PMID- 21712432 TI - Evaluating phylogenetic congruence in the post-genomic era. AB - Congruence is a broadly applied notion in evolutionary biology used to justify multigene phylogeny or phylogenomics, as well as in studies of coevolution, lateral gene transfer, and as evidence for common descent. Existing methods for identifying incongruence or heterogeneity using character data were designed for data sets that are both small and expected to be rarely incongruent. At the same time, methods that assess incongruence using comparison of trees test a null hypothesis of uncorrelated tree structures, which may be inappropriate for phylogenomic studies. As such, they are ill-suited for the growing number of available genome sequences, most of which are from prokaryotes and viruses, either for phylogenomic analysis or for studies of the evolutionary forces and events that have shaped these genomes. Specifically, many existing methods scale poorly with large numbers of genes, cannot accommodate high levels of incongruence, and do not adequately model patterns of missing taxa for different markers. We propose the development of novel incongruence assessment methods suitable for the analysis of the molecular evolution of the vast majority of life and support the investigation of homogeneity of evolutionary process in cases where markers do not share identical tree structures. PMID- 21712433 TI - Distribution of KAI-9803, a novel delta-protein kinase C inhibitor, after intravenous administration to rats. AB - KAI-9803 is composed of a selective delta-protein kinase C (deltaPKC) inhibitor peptide derived from the deltaV1-1 portion of deltaPKC (termed "cargo peptide"), conjugated reversibly to the cell-penetrating peptide 11-amino acid, arginine rich sequence of the HIV type 1 transactivator protein (TAT47-57; termed "carrier peptide") via a disulfide bond. KAI-9803 administration at the end of ischemia has been found to reduce cardiac damage caused by ischemia-reperfusion in a rat model of acute myocardial infarction. In the study presented here, we examined the TAT47-57-mediated distribution of KAI-9803 in rats after a single intravenous bolus administration (1 mg/kg). 14C-KAI-9803 was rapidly delivered to many tissues, including the heart (1.21 MUg eq/g tissue), while being quickly cleared from the systemic circulation. The microautoradiography analysis showed that 14C KAI-9803 was effectively delivered into various cells, including cardiac myocytes and cardiac endothelial cells within 1 min after dosing. The tissue distribution of 125I-labeled KAI-9803 was compared to that of 125I-labeled cargo peptide; this comparison demonstrated that the distribution of KAI-9803 to tissues such as the liver, kidney, and heart was facilitated by the reversible conjugation to TAT47 57. In an in vitro cardiomyocyte study, the extent of 125I-KAI-9803 internalization was greater at 37 degrees C than that at 4 degrees C, whereas the internalization of the 125I-cargo peptide at 37 degrees C was not observed, indicating that the uptake of 125I-KAI-9803 into the cardiomyocytes was mediated by the TAT47-57 carrier. Our studies demonstrated that after a single intravenous administration, KAI-9803 can be delivered into the target cells in the liver, kidney, and heart by a TAT47-57-mediated mechanism. PMID- 21712434 TI - Pharmacokinetic and pharmacodynamic modeling of the effect of an sodium-glucose cotransporter inhibitor, phlorizin, on renal glucose transport in rats. AB - A pharmacokinetic and pharmacodynamic (PK-PD) model for the inhibitory effect of sodium-glucose cotransporter (SGLT) inhibitors on renal glucose reabsorption was developed to predict in vivo efficacy. First, using the relationship between renal glucose clearance and plasma glucose level in rats and both the glucose affinity and transport capacity obtained from in vitro vesicle experiments, a pharmacodynamic model analysis was performed based on a nonlinear parallel tube model to express the renal glucose transport mediated by SGLT1 and SGLT2. This model suitably expressed the relationship between plasma glucose level and renal glucose excretion. A PK-PD model was developed next to analyze the inhibitory effect of phlorizin on renal glucose reabsorption. The PK-PD model analysis was performed using averaged concentrations of both the drug and glucose in plasma and the corresponding renal glucose clearance. The model suitably expressed the concentration-dependent inhibitory effect of phlorizin on renal glucose reabsorption. The in vivo inhibition constants of phlorizin for SGLT in rats were estimated to be 67 nM for SGLT1 and 252 nM for SGLT2, which are similar to the in vitro data reported previously. This suggests that the in vivo efficacy of SGLT inhibitors could be predicted from an in vitro study based on the present PK-PD model. The present model is based on physiological and biochemical parameters and, therefore, would be helpful in understanding individual differences in the efficacy of an SGLT inhibitor. PMID- 21712435 TI - Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome. AB - BACKGROUND: A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in ~10-15% of cases of suspected Lynch syndrome, no disease-causing mechanism can be detected. METHODS: Oligo array analysis was performed to search for genomic imbalances in patients with suspected mutation-negative Lynch syndrome with MLH1 deficiency in their colorectal tumours. RESULTS AND CONCLUSION: A deletion in the LRRFIP2 (leucine rich repeat flightless-interacting protein 2) gene flanking the MLH1 gene was detected, which turned out to be a paracentric inversion on chromosome 3p22.2 creating two new stable fusion transcripts between MLH1 and LRRFIP2. A single nucleotide polymorphism in MLH1 exon 8 was expressed from both alleles, initially pointing to appropriate MLH1 function at least in peripheral cells. In a second case, an inherited duplication of the MLH1 gene region resulted in constitutional MLH1 promoter methylation. Constitutional MLH1 promoter methylation may therefore in rare cases be a heritable disease mechanism and should not be overlooked in seemingly sporadic patients. PMID- 21712436 TI - Transcriptional profiling and network analysis of the murine angiotensin II induced abdominal aortic aneurysm. AB - We sought to characterize temporal gene expression changes in the murine angiotensin II (ANG II)-ApoE-/- model of abdominal aortic aneurysm (AAA). Aortic ultrasound measurements were obtained over the 28-day time-course. Harvested suprarenal aortic segments were evaluated with whole genome expression profiling at 7, 14, and 28 days using the Agilent Whole Mouse Genome microarray platform and Statistical Analysis of Microarrays at a false discovery rate of <1%. A group of angiotensin-treated mice experienced contained rupture (CR) within 7 days and were analyzed separately. Progressive aortic dilatation occurred throughout the treatment period. However, the numerous early expression differences between ANG II-treated and control were not sustained over time. Ontologic analysis revealed widespread upregulation of inflammatory, immune, and matrix remodeling genes with ANG II treatment, among other pathways such as apoptosis, cell cycling, angiogenesis, and p53 signaling. CR aneurysms displayed significant decreases in TGF-beta/BMP-pathway signaling, MAPK signaling, and ErbB signaling genes vs. non CR/ANG II-treated samples. We also performed literature-based network analysis, extracting numerous highly interconnected genes associated with aneurysm development such as Spp1, Myd88, Adam17 and Lox. 1) ANG II treatment induces extensive early differential expression changes involving abundant signaling pathways in the suprarenal abdominal aorta, particularly wide-ranging increases in inflammatory genes with aneurysm development. 2) These gene expression changes appear to dissipate with time despite continued growth, suggesting that early changes in gene expression influence disease progression in this AAA model, and that the aortic tissue adapts to prolonged ANG II infusion. 3) Network analysis identified nexus genes that may constitute aneurysm biomarkers or therapeutic targets. PMID- 21712437 TI - Molecular in situ topology of Aczonin/Piccolo and associated proteins at the mammalian neurotransmitter release site. AB - The protein machinery of neurotransmitter exocytosis requires efficient orchestration in space and time, for speed and precision of neurotransmission and also for synaptic ontogeny and plasticity. However, its spatial organization in situ is virtually unknown. Aczonin/Piccolo is a putative organizer protein of mammalian active zones. We determined by immunogold electron microscopy (EM) (i) the spatial arrangement (i.e., topology) of 11 segments of the Aczonin polypeptide in situ, and correlated it to (ii) the positioning of Aczonin interacting domains of Bassoon, CAST/ELKS, Munc13, and RIM and (iii) the ultrastructurally defined presynaptic macromolecular aggregates known as dense projections and synaptic ribbons. At conventional synapses, Aczonin assumes a compact molecular topology within a layer 35 to 80 nm parallel to the plasma membrane (PM), with a "trunk" sitting on the dense projection top and a C terminal "arm" extending down toward the PM and sideward to the dense projection periphery. At ribbon synapses, Aczonin occupies the whole ribbon area. Bassoon colocalizes with Aczonin at conventional synapses but not at ribbon synapses. At both conventional and ribbon synapses, CAST, Munc13, and RIM are segregated from Aczonin, closer to the PM, and Aczonin is positioned such that it may control the access of neurotransmitter vesicles to the fusion site. PMID- 21712438 TI - Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-gamma1 to activation of the osmoprotective transcription factor NFAT5. AB - Separate reports that hypertonicity activates p38 via a Rac1-OSM-MEKK3-MKK3-p38 pathway and that p38alpha contributes to activation of TonEBP/OREBP led us to the hypothesis that Rac1 might activate TonEBP/OREBP via p38. The present studies examine that possibility. High NaCl is hypertonic. We find that siRNA knockdown of Rac1 reduces high NaCl-induced increase of TonEBP/OREBP transcriptional activity (by reducing its transactivating activity but not its nuclear localization). Similarly, siRNA knockdown of osmosensing scaffold for MEKK3 (OSM) also reduces high NaCl-dependent TonEBP/OREBP transcriptional and transactivating activities. Simultaneous siRNA knockdown of Rac1 and OSM is not additive in reduction of TonEBP/OREBP transcriptional activity, indicating a common pathway. However, siRNA knockdown of MKK3 does not reduce TonEBP/OREBP transcriptional activity, although siRNA knockdown of MKK6 does. Nevertheless, the effect of Rac1 on TonEBP/OREBP is also independent of MKK6 because it occurs in MKK6-null cells. Furthermore, we find that siRNA knockdown of Rac1 or OSM actually increases activity (phosphorylation) of p38, rather than decreasing it, as previously reported. Thus, the effect of Rac1 on TonEBP/OREBP is independent of p38. We find instead that phospholipase C-gamma1 (PLC-gamma1) is involved. When transfected into PLC-gamma1-null mouse embryonic fibroblast cells, catalytically active Rac1 does not increase TonEBP/OREBP transcriptional activity unless PLC-gamma1 is reconstituted. Similarly, dominant-negative Rac1 also does not inhibit TonEBP/OREBP in PLC-gamma1-null cells unless PLC-gamma1 is reconstituted. We conclude that Rac1/OSM supports TonEBP/OREBP activity and that this activity is mediated via PLC-gamma1, not p38. PMID- 21712439 TI - Functional synthetic Antennapedia genes and the dual roles of YPWM motif and linker size in transcriptional activation and repression. AB - Segmental identity along the anteroposterior axis of bilateral animals is specified by Hox genes. These genes encode transcription factors, harboring the conserved homeodomain and, generally, a YPWM motif, which binds Hox cofactors and increases Hox transcriptional specificity in vivo. Here we derive synthetic Drosophila Antennapedia genes, consisting only of the YPWM motif and homeodomain, and investigate their functional role throughout development. Synthetic peptides and full-length Antennapedia proteins cause head-to-thorax transformations in the embryo, as well as antenna-to-tarsus and eye-to-wing transformations in the adult, thus converting the entire head to a mesothorax. This conversion is achieved by repression of genes required for head and antennal development and ectopic activation of genes promoting thoracic and tarsal fates, respectively. Synthetic Antennapedia peptides bind DNA specifically and interact with Extradenticle and Bric-a-brac interacting protein 2 cofactors in vitro and ex vivo. Substitution of the YPWM motif by alanines abolishes Antennapedia homeotic function, whereas substitution of YPWM by the WRPW repressor motif, which binds the transcriptional corepressor Groucho, allows all proteins to act as repressors only. Finally, naturally occurring variations in the size of the linker between the homeodomain and YPWM motif enhance Antennapedia repressive or activating efficiency, emphasizing the importance of linker size, rather than sequence, for specificity. Our results clearly show that synthetic Antennapedia genes are functional in vivo and therefore provide powerful tools for synthetic biology. Moreover, the YPWM motif is necessary--whereas the entire N terminus of the protein is dispensable--for Antennapedia homeotic function, indicating its dual role in transcriptional activation and repression by recruiting either coactivators or corepressors. PMID- 21712440 TI - Site-specific characterization of threonine, serine, and tyrosine glycosylations of amyloid precursor protein/amyloid beta-peptides in human cerebrospinal fluid. AB - The proteolytic processing of human amyloid precursor protein (APP) into shorter aggregating amyloid beta (Abeta)-peptides, e.g., Abeta1-42, is considered a critical step in the pathogenesis of Alzheimer's disease (AD). Although APP is a well-known membrane glycoprotein carrying both N- and O-glycans, nothing is known about the occurrence of released APP/Abeta glycopeptides in cerebrospinal fluid (CSF). We used the 6E10 antibody and immunopurified Abeta peptides and glycopeptides from CSF samples and then liquid chromatography-tandem mass spectrometry for structural analysis using collision-induced dissociation and electron capture dissociation. In addition to 33 unglycosylated APP/Abeta peptides, we identified 37 APP/Abeta glycopeptides with sialylated core 1 like O glycans attached to Thr(-39, -21, -20, and -13), in a series of APP/AbetaX-15 glycopeptides, where X was -63, -57, -52, and -45, in relation to Asp1 of the Abeta sequence. Unexpectedly, we also identified a series of 27 glycopeptides, the Abeta1-X series, where X was 20 (DAEFRHDSGYEVHHQKLVFF), 19, 18, 17, 16, and 15, which were all uniquely glycosylated on Tyr10. The Tyr10 linked O-glycans were (Neu5Ac)(1-2)Hex(Neu5Ac)HexNAc-O- structures with the disialylated terminals occasionally O-acetylated or lactonized, indicating a terminal Neu5Acalpha2,8Neu5Ac linkage. We could not detect any glycosylation of the Abeta1 38/40/42 isoforms. We observed an increase of up to 2.5 times of Tyr10 glycosylated Abeta peptides in CSF in six AD patients compared to seven non-AD patients. APP/Abeta sialylated O-glycans, including that of a Tyr residue, the first in a mammalian protein, may modulate APP processing, inhibiting the amyloidogenic pathway associated with AD. PMID- 21712441 TI - Diverse two-cysteine photocycles in phytochromes and cyanobacteriochromes. AB - Phytochromes are well-known as photoactive red- and near IR-absorbing chromoproteins with cysteine-linked linear tetrapyrrole (bilin) prosthetic groups. Phytochrome photoswitching regulates adaptive responses to light in both photosynthetic and nonphotosynthetic organisms. Exclusively found in cyanobacteria, the related cyanobacteriochrome (CBCR) sensors extend the photosensory range of the phytochrome superfamily to shorter wavelengths of visible light. Blue/green light sensing by a well-studied subfamily of CBCRs proceeds via a photolabile thioether linkage to a second cysteine fully conserved in this subfamily. In the present study, we show that dual-cysteine photosensors have repeatedly evolved in cyanobacteria via insertion of a second cysteine at different positions within the bilin-binding GAF domain (cGMP-specific phosphodiesterases, cyanobacterial adenylate cyclases, and formate hydrogen lyase transcription activator FhlA) shared by CBCRs and phytochromes. Such sensors exhibit a diverse range of photocycles, yet all share ground-state absorbance of near-UV to blue light and a common mechanism of light perception: reversible photoisomerization of the bilin 15,16 double bond. Using site-directed mutagenesis, chemical modification and spectroscopy to characterize novel dual cysteine photosensors from the cyanobacterium Nostoc punctiforme ATCC 29133, we establish that this spectral diversity can be tuned by varying the light dependent stability of the second thioether linkage. We also show that such behavior can be engineered into the conventional phytochrome Cph1 from Synechocystis sp. PCC6803. Dual-cysteine photosensors thus allow the phytochrome superfamily in cyanobacteria to sense the full solar spectrum at the earth surface from near infrared to near ultraviolet. PMID- 21712442 TI - Macroevolutionary consequences of "spatial sorting". PMID- 21712443 TI - Can the functional MRI responses to physical pain really tell us why social rejection "hurts"? PMID- 21712444 TI - Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination. AB - PURPOSE: The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib. PATIENTS AND METHODS: Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines. RESULTS: Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-gamma/IL 2 production and increased IL-10 compared with healthy controls. CONCLUSION: We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib. PMID- 21712445 TI - Gene expression profiling of fixed tissues identified hypoxia-inducible factor 1alpha, VEGF, and matrix metalloproteinase-2 as biomarkers of lymph node metastasis in hepatocellular carcinoma. AB - PURPOSE: Hepatocellular carcinoma (HCC) most often develops in patients infected with hepatitis B or hepatitis C virus. Differential gene expression profiling is useful for investigating genes associated with lymph node metastasis (LNM). We screened genes to identify potential biomarkers for LNM in HCC. EXPERIMENTAL DESIGN: RNA was extracted from formalin-fixed specimens of paired intratumoral and peritumoral tissues of patients with lymph node-positive (n = 36) or negative (n = 36) HCC. A cDNA-mediated annealing, selection, extension, and ligation assay was done with an array of 502 known cancer-related genes to identify differentially expressed genes in 20 pairs of patients with or without LNM. Candidate biomarkers were evaluated by using immunohistochemistry and tissue microarrays in an independent cohort of 309 HCC patients who had undergone hepatectomy. Of the 309 patients, 235 (76.1%) patients were infected with hepatitis B. RESULTS: Compared with lymph node-negative patients, lymph node positive patients had 17 overexpressed genes and 19 underexpressed genes in intratumoral tissues, and 25 overexpressed genes and 22 underexpressed genes in peritumoral tissues. Hypoxia-inducible factor (HIF)-1alpha, VEGF, and matrix metalloproteinase (MMP)-2 were selected for analysis in the cohort of 309 HCC patients. We found that intratumoral protein levels of HIF-1alpha, VEGF, and MMP 2 were independent risk factors for developing LNM. CONCLUSION: We identified 83 cancer genes that were differentially expressed in lymph node-positive and lymph node-negative HCC. Our findings show that the combination of intratumoral HIF 1alpha, VEGF, and MMP-2 may be useful as a molecular prediction model for LNM. PMID- 21712446 TI - FGFR signaling promotes the growth of triple-negative and basal-like breast cancer cell lines both in vitro and in vivo. AB - PURPOSE: The oncogenic drivers of triple-negative (TN) and basal-like breast cancers are largely unknown. Substantial evidence now links aberrant signaling by the fibroblast growth factor receptors (FGFR) to the development of multiple cancer types. Here, we examined the role of FGFR signaling in TN breast cancer. EXPERIMENTAL DESIGN: We examined the sensitivity of a panel of 31 breast cancer cell lines to the selective FGFR inhibitor PD173074 and investigated the potential mechanisms underlying sensitivity. RESULTS: TN breast cancer cell lines were more sensitive to PD173074 than comparator cell lines (P = 0.011), with 47% (7/15) of TN cell lines showing significantly reduced growth. The majority of TN cell lines showed only modest sensitivity to FGFR inhibition in two-dimensional growth but were highly sensitive in anchorage-independent conditions. PD173074 inhibited downstream mitogen-activated protein kinase and PI3K-AKT signaling and induced cell-cycle arrest and apoptosis. Basal-like breast cancer cell lines were found to express FGF2 ligand (11/21 positive) and, similarly, 62% of basal-like breast cancers expressed FGF2, as assessed by immunohistochemistry compared with 5% of nonbasal breast cancers (P < 0.0001). RNA interference targeting of FGF2 in basal-like cell lines significantly reduced growth in vitro and reduced down stream signaling, suggesting an autocrine FGF2 signaling loop. Treatment with PD173074 significantly reduced the growth of CAL51 basal-like breast cancer cell line xenografts in vivo. CONCLUSIONS: Basal-like breast cancer cell lines, and breast cancers, express autocrine FGF2 and show sensitivity to FGFR inhibitors, identifying a potential novel therapeutic approach for these cancers. PMID- 21712447 TI - Novel functional germline variants in the VEGF receptor 2 gene and their effect on gene expression and microvessel density in lung cancer. AB - PURPOSE: VEGF receptor 2 (VEGFR-2) plays a crucial role in mediating angiogenic endothelial cell responses via the VEGF pathway, and angiogenesis inhibitors targeting VEGFR-2 are in clinical use. As angiogenesis is a host-driven process, functional heritable variation in KDR, the gene encoding VEGFR-2, may affect VEGFR-2 function and, ultimately, the extent of tumor angiogenesis. EXPERIMENTAL DESIGN: We resequenced KDR using 24 DNAs each from healthy Caucasian, African American, and Asian groups. Nonsynonymous genetic variants were assessed for function by phosphorylation assays. Luciferase reporter gene assays were used to examine effects of variants on gene expression. KDR mRNA and protein expression and microvessel density (MVD) were measured in non-small cell lung cancer (NSCLC) tumor samples, and matching patient DNA samples were genotyped to test for associations with variants of interest. RESULTS: KDR resequencing led to the discovery of 120 genetic variants, of which 25 had not been previously reported. Q472H had increased VEGFR-2 protein phosphorylation and associated with increased MVD in NSCLC tumor samples. -2854C and -2455A increased luciferase expression and associated with higher KDR mRNA levels in NSCLC samples. -271A reduced luciferase expression and associated with lower VEGFR-2 levels in NSCLC samples. -906C and 23408G associated with higher KDR mRNA levels in NSCLC samples. CONCLUSIONS: This study has defined KDR genetic variation in 3 populations and identified common variants that impact on tumoral KDR expression and vascularization. These findings may have important implications for understanding the molecular basis of genetic associations between KDR variation and clinical phenotypes related to VEGFR-2 function. PMID- 21712448 TI - Interleukin-7 inhibits tumor-induced CD27-CD28- suppressor T cells: implications for cancer immunotherapy. AB - PURPOSE: We have previously reported that many types of tumors can induce changes in human T cells that lead to the acquisition of suppressive function and phenotypic alterations resembling those found in senescent T cells. In the present study, we find a role for interleukin 7 (IL-7) in protecting T cells from these changes and further define involved signaling pathways. EXPERIMENTAL DESIGN: We evaluated the ability of IL-7 treatment to prevent the gain of suppressive function and phenotypic alterations in human T cells after a short coculture with tumor cells in vitro. We then used inhibitors of components of the phosphoinositide 3-kinase (PI3K)/AKT pathway and short interfering RNA knockdown of Mcl-1 and Bim to evaluate the role of these signaling pathways in IL-7 protection. RESULTS: We found that IL-7 inhibits CD27/CD28 loss and maintains proliferative capacity, IL-2 production, and reduced suppressive function. The protective ability of IL-7 depended on activation of the PI3K/AKT pathway, which inhibited activation of glycogen synthase kinase 3beta, which, in turn, prevented the phosphorylation and loss of Mcl-1. We further showed a key role for Mcl-1 in that its knockdown or inhibition abrogated the effects of IL-7. In addition, knockdown of the Mcl-1 binding partner and proapoptotic protein Bim protected T cells from these dysfunctional alterations. CONCLUSION: These observations confirm the role for Bcl-2 family members in cytokine signaling and suggest that IL-7 treatment in combination with other immunotherapies could lead to new clinical strategies to maintain normal T-cell function and reduce tumor-induced generation of dysfunctional and suppressor T cells. PMID- 21712449 TI - Lupeol, a novel androgen receptor inhibitor: implications in prostate cancer therapy. AB - PURPOSE: Conventional therapies to treat prostate cancer (CaP) of androgen dependent phenotype (ADPC) and castration-resistant phenotype (CRPC) are deficient in outcome which has necessitated a need to identify those agents that could target AR for both disease types. We provide mechanism-based evidence that lupeol (Lup-20(29)-en-3b-ol) is a potent inhibitor of androgen receptor (AR) in vitro and in vivo. EXPERIMENTAL DESIGN: Normal prostate epithelial cell (RWPE-1), LAPC4 (wild functional AR/ADPC), LNCaP (mutant functional/AR/ADPC), and C4-2b (mutant functional/AR/CRPC) cells were used to test the anti-AR activity of lupeol. Cells grown under androgen-rich environment and treated with lupeol were tested for proliferation, AR transcriptional activity, AR competitive ligand binding, AR-DNA binding, and AR-ARE/target gene binding. Furthermore, in silico molecular modeling for lupeol-AR binding was done. Athymic mice bearing C4-2b and LNCaP cell-originated tumors were treated intraperitoneally with lupeol (40 mg/kg; 3 times/wk) and tumor growth and surrogate biomarkers were evaluated. To assess bioavailability, lupeol serum levels were measured. RESULTS: Lupeol significantly inhibited R1881 (androgen analogue) induced (i) transcriptional activity of AR and (ii) expression of PSA. Lupeol (i) competed antagonistically with androgen for AR, (ii) blocked the binding of AR to AR-responsive genes including PSA, TIPARP, SGK, and IL-6, and (iii) inhibited the recruitment of RNA Pol II to target genes. Lupeol sensitized CRPC cells to antihormone therapy. High performance liquid chromatography analysis showed that lupeol is bioavailable to mice. Lupeol inhibited the tumorigenicity of both ADPC and CRPC cells in animals. Serum and tumor tissues exhibited reduced PSA levels. CONCLUSION: Lupeol, an effective AR inhibitor, could be developed as a potential agent to treat human CaP. PMID- 21712450 TI - A Phase II study of pazopanib in Asian patients with recurrent/metastatic nasopharyngeal carcinoma. AB - PURPOSE: Nasopharyngeal carcinoma is endemic in Asia and angiogenesis is important for growth and progression. We hypothesized that pazopanib would have antiangiogenic activity in nasopharyngeal carcinoma. EXPERIMENTAL DESIGN: A single arm monotherapy study of pazopanib in patients with WHO type II/III nasopharyngeal carcinoma who had metastatic/recurrent disease and failed at least one line of chemotherapy. A Simon's optimal 2-stage design was used. Patients with Eastern Cooperative Oncology Group (ECOG) 0-2 and adequate organ function were treated with pazopanib 800 mg daily on a 21-day cycle. The primary endpoint was clinical benefit rate (CR/PR/SD) achieved after 12 weeks of treatment. Secondary endpoints included toxicity and progression-free survival. Exploratory studies of dynamic-contrast enhanced computed tomography (DCE-CT) paired with pharmacokinetics (PK) of pazopanib was done. RESULTS: Thirty-three patients were accrued. Patients were ECOG 0-1 with median age of 50 years (range 36-68). There were 2 (6.1%) partial responses, 16 (48.5%) stable disease, 11 (33.3%) progressive disease, 4 (12.1%) were not evaluable for response. The clinical benefit rate was 54.5% (95% CI: 38.0-70.2). Ten patients (30.3%) received more than 6 cycles (4 months) of treatment and 7 (21.2%) had PR/SD that lasted at least 6 months. One patient each died from epistaxis and myocardial infarction. Common grade 3/4 toxicities included fatigue (15.2%), hand-foot syndrome (15.2%), anorexia (9.1%), diarrhea (6.1%), and vomiting (6.1%). Serial DCE-CT scans show significant reductions in tumor blood flow, permeability surface area product, and fractional intravascular blood volume. CONCLUSION: Pazopanib showed encouraging activity in heavily pretreated nasopharyngeal carcinoma with an acceptable toxicity profile. PMID- 21712451 TI - Gastric cancer growth control by BEZ235 in vivo does not correlate with PI3K/mTOR target inhibition but with [18F]FLT uptake. AB - PURPOSE: In this study, we tested the antitumor activity of the dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor BEZ235 against gastric cancer in vitro and in vivo. EXPERIMENTAL DESIGN: Gastric cancer cell lines (N87, MKN45, and MKN28) were incubated with BEZ235 and assessed for cell viability, cell cycle, and PI3K/mTOR target inhibition. In vivo, athymic nude mice were inoculated with N87, MKN28, or MKN45 cells and treated daily with BEZ235. 3' Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) uptake was measured via small animal positron emission tomography (PET). RESULTS: In vitro, BEZ235 dose dependently decreased the cell viability of gastric cancer cell lines. The antiproliferative activity of BEZ235 was linked to a G(1) cell-cycle arrest. In vivo, BEZ235 treatment resulted in PI3K/mTOR target inhibition as shown by dephosphorylation of AKT and S6 protein in all xenograft models. However, BEZ235 treatment only inhibited tumor growth of N87 xenografts, whereas no antitumor effect was observed in the MKN28 and MKN45 xenograft models. Sensitivity to BEZ235 in vivo correlated with downregulation of the proliferation marker thymidine kinase 1. Accordingly, [(18)F]FLT uptake was only significantly reduced in the BEZ235 sensitive N87 xenograft model as measured by PET. CONCLUSION: In conclusion, in vivo sensitivity of gastric cancer xenografts to BEZ235 did not correlate with in vitro antiproliferative activity or in vivo PI3K/mTOR target inhibition by BEZ235. In contrast, [(18)F]FLT uptake was linked to BEZ235 in vivo sensitivity. Noninvasive [(18)F]FLT PET imaging might qualify as a novel marker for optimizing future clinical testing of dual PI3K/mTOR inhibitors. PMID- 21712452 TI - Treatment-induced oxidative stress and cellular antioxidant capacity determine response to bortezomib in mantle cell lymphoma. AB - PURPOSE: Proteasome inhibition disrupts protein homeostasis and induces apoptosis. Up to 50% of patients with relapsed mantle cell lymphoma (MCL) respond to bortezomib. We used gene expression profiling to investigate the connection between proteasome inhibition, cellular response, and clinical efficacy. EXPERIMENTAL DESIGN: We assessed transcriptional changes in primary tumor cells from five patients during treatment with bortezomib in vivo, and in 10 MCL cell lines exposed to bortezomib in vitro, on Affymetrix microarrays. Key findings were confirmed by western blotting. RESULTS: MCL cell lines exposed to bortezomib in vitro showed upregulation of endoplasmic reticulum and oxidative stress response pathways. Gene expression changes were strongest in bortezomib-sensitive cells and these cells were also more sensitive to oxidative stress induced by H2O2. Purified tumor cells obtained at several timepoints during bortezomib treatment in 5 previously untreated patients with leukemic MCL showed strong activation of the antioxidant response controlled by NRF2. Unexpectedly, activation of this homeostatic program was significantly stronger in tumors with the best clinical response. Consistent with its proapoptotic function, we found upregulation of NOXA in circulating tumor cells of responding patients. In resistant cells, gene expression changes in response to bortezomib were limited and upregulation of NOXA was absent. Interestingly, at baseline, bortezomib resistant cells displayed a relatively higher expression of the NRF2 gene expression signature than sensitive cells (P < 0.001). CONCLUSION: Bortezomib triggers an oxidative stress response in vitro and in vivo. High cellular antioxidant capacity contributes to bortezomib resistance. PMID- 21712453 TI - Getting personal with melanoma. AB - Long-term follow-up of patients with metastatic melanoma who received adoptive immunotherapy with autologous tumor infiltrating lymphocytes shows that patients who attained complete remission had durable responses, with 19 of 20 such patients remaining in remission from 3 to 7 years or more. PMID- 21712456 TI - Gefitinib versus docetaxel for previously treated NSCLC--letter. PMID- 21712457 TI - Modeling the tumor growth profiles in xenograft experiments--letter. PMID- 21712458 TI - Clinical trial development as a predictor of accrual performance--letter. PMID- 21712460 TI - How market-oriented education policies might influence young people's health: development of a logic model from qualitative case studies in English secondary schools. AB - BACKGROUND: School systems are increasingly typified by diversity of provision, parental choice and publication of performance data. Schools shape their students' lifestyles and health, but the effects of 'marketisation' are under researched. The authors use qualitative data to develop a logic model regarding such effects. METHODS: Case studies in seven English secondary schools, interviews with 103 students and 39 staff. RESULTS: 'Parental choice' was associated with dispersal of students' friendship groups on transition to secondary school, reduced social support and emotional harms. 'Choice' meant some schools were regarded as 'dumping grounds' for socially disadvantaged students, creating potentially violent environments where students engaged in risk behaviours such as substance use to facilitate protective bonds with peers. Schools focused strongly on academic attainment, reflecting external pressures from the school inspectorate and performance league tables. Some schools sought to improve their league table position by targeting resources on 'key marginal' students on the threshold of passing five exams, the key metric. Less-academic students commonly became disengaged, engaging in various health risk behaviours as alternative status markers. The exam-focused environment aroused anxiety among high and low attainers, some using substances as self-medication. Schools also de prioritised health education and sport in this performance-driven context. CONCLUSION: Our logic model aims to guide further research on how marketisation might affect young people health behaviours. PMID- 21712461 TI - The relationship between income and health using longitudinal data from New Zealand. AB - BACKGROUND: Evidence for a cross-sectional relationship between income and health is strong but is probably biased by substantial confounding. Longitudinal data with repeated income and health measures on the same individuals can be analysed to control completely for time-invariant confounding, giving a more accurate estimate of the impact of short-term changes in income on health. METHODS: 4 years of annual data (2002--2005) from the New Zealand longitudinal Survey of Family, Income and Employment were used to investigate the relationship between annual household income and self-rated health (SRH) using a fixed-effects ordinal logistic regression model. Possible effect modification of the income--SRH relationship by poverty and baseline health was tested with interactions. RESULTS: An increase in income of $10 000 over the past year increased the odds of reporting better SRH by 1% (OR 1.01, 95% CI 1.00 to 1.02). Poor baseline health significantly modified the association between income and SRH. A $10 000 increase in income increased the odds of better SRH by 10% for those with two or more chronic conditions. Poverty or deprivation did not modify the income--health association. CONCLUSIONS: The overall small, positive, but statistically non significant, income--health effect size is consistent with similar analyses from other longitudinal studies. Despite the overwhelming consensus that income matters for health over the medium and long-term, evidence free of time-invariant confounding for the short-run association remains elusive. However, measurement error in income and health has probably biased estimates towards the null. PMID- 21712462 TI - Relative deprivation between neighbouring wards is predictive of coronary heart disease mortality after adjustment for absolute deprivation of wards. AB - BACKGROUND: The aims of this study were to assess whether deprivation inequality at small area level in England is associated with coronary heart disease (CHD) mortality rates and to assess whether this provides evidence of an association between area-level and individual-level risk. METHODS: Mortality rates for all wards in England were calculated using all CHD deaths between 2001 and 2006. Ward level deprivation was measured using the Carstairs Index. Deprivation inequality within local authorities (LAs) was measured by the IQR of deprivation for wards within the LA. Relative deprivation for wards was measured as the modulus of the difference between deprivation for the ward and average deprivation for all neighbouring wards. RESULTS: Deprivation inequality within LAs was positively associated with CHD mortality rates per 100000 (eg, all men beta; 95% CI=2.7; 1.1 to 4.3) after adjustment for absolute deprivation (p<0.001 for all models). Relative deprivation for wards was positively associated with CHD mortality rates per 100000 (eg, all men 1.4; 0.7 to 2.1) after adjustment for absolute deprivation (p<0.001 for all models). Subgroup analyses showed that relative deprivation was independently associated with CHD mortality rates in both affluent and deprived wards. CONCLUSIONS: Rich wards surrounded by poor areas have higher CHD mortality rates than rich wards surrounded by rich areas, and poor wards surrounded by rich areas have worse CHD mortality rates than poor wards surrounded by poor areas. Local deprivation inequality has a similar adverse impact on both rich and poor areas, supporting the hypothesis that income inequality of an area has an impact on individual-level health outcomes. PMID- 21712463 TI - Large-scale academic achievement testing of deaf and hard-of-hearing students: past, present, and future. AB - The first large-scale, nationwide academic achievement testing program using Stanford Achievement Test (Stanford) for deaf and hard-of-hearing children in the United States started in 1969. Over the past three decades, the Stanford has served as a benchmark in the field of deaf education for assessing student academic achievement. However, the validity and reliability of using the Stanford for this special student population still require extensive scrutiny. Recent shifts in educational policy environment, which require that schools enable all children to achieve proficiency through accountability testing, warrants a close examination of the adequacy and relevance of the current large-scale testing of deaf and hard-of-hearing students. This study has three objectives: (a) it will summarize the historical data over the last three decades to indicate trends in academic achievement for this special population, (b) it will analyze the current federal laws and regulations related to educational testing and special education, thereby identifying gaps between policy and practice in the field, especially identifying the limitations of current testing programs in assessing what deaf and hard-of-hearing students know, and (c) it will offer some insights and suggestions for future testing programs for deaf and hard-of-hearing students. PMID- 21712464 TI - Comparison of 18F-FDG PET/CT with bone scintigraphy for detection of bone metastasis: a meta-analysis. AB - BACKGROUND: The skeleton is one of the favorable sites for the metastasis of almost all human malignant neoplasms. An accurate diagnosis of bone metastasis is crucial for the patient's staging and management. PURPOSE: To investigate and compare diagnostic performance of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and bone scintigraphy (BS) for detection of bone metastasis in malignancies using meta-analysis. MATERIAL AND METHODS: PubMed (Medline included) was searched for relevant articles. We assessed the methodological quality with Quality Assessment of Diagnosis Accuracy Studies (QUADAS) score tool, and used statistical software to obtain pooled estimates of sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver-operating characteristic (SROC) curve. RESULTS: Six studies met inclusion criteria. For 18F-FDG PET/CT, the pooled sensitivity and specificity were 0.934 and 0.975, respectively. The pooled positive likelihood ratio (LR+), negative likelihood ratio (LR-) and diagnostic odds ratio (DOR) were 34.990, 0.068 and 559.02, respectively. The area under the SROC curve was 0.9854. For BS, the pooled sensitivity, specificity, LR + , LR- and DOR were 0.706 (0.642-0.764), 0.911 (0.896-0.926), 13.982 (2.419-80.817), 0.319 (0.143-0.712), and 60.420 (21.393-170.64), respectively. The area under the SROC curve was 0.9386. CONCLUSION: The results indicate that 18F-FDG PET/CT do have both higher sensitivity and specificity than bone scintigraphy for detecting metastatic bone tumor. However, further research is needed to evaluate the diagnostic performance of 18F-FDG PET/CT and BS in each common malignancy. PMID- 21712465 TI - New perspectives on old problems: health behavior change research in the 21st century. PMID- 21712467 TI - Opening up their doors: perspectives on the involvement of the African American faith community in HIV prevention in four communities. AB - In 1998, the U.S. government launched the Minority AIDS Initiative (MAI) to address growing ethnic and racial disparities in HIV/AIDS cases. The CDC performed an evaluation of its MAI-funded programs, including an assessment of community stakeholders' perspective on the involvement of the faith community in HIV prevention. Individual interviews (N = 113) were conducted annually over 3 years in four communities. The majority of participants described a change in faith community's attitudes toward HIV and a rise in HIV-related activities conducted by faith-based organizations. Participants attributed changes to faith based funding, acknowledgment by African American community leadership that HIV is a serious health issue, and faith leaders' desire to become more educated on HIV/AIDS. Participants reported conservative faith doctrine and stigma as barriers to faith community involvement. The findings suggest that although barriers remain, there is an increased willingness to address HIV/AIDS, and the faith community serves as a vital resource in HIV prevention. PMID- 21712468 TI - The 1.688 repetitive DNA of Drosophila: concerted evolution at different genomic scales and association with genes. AB - Concerted evolution leading to homogenization of tandemly repeated DNA arrays is widespread and important for genome evolution. We investigated the range and nature of the process at chromosomal and array levels using the 1.688 tandem repeats of Drosophila melanogaster where large arrays are present in the heterochromatin of chromosomes 2, 3, and X, and short arrays are found in the euchromatin of the same chromosomes. Analysis of 326 euchromatic and heterochromatic repeats from 52 arrays showed that the homogenization of 1.688 repeats occurred differentially for distinct genomic regions, from euchromatin to heterochromatin and from local arrays to chromosomes. We further found that most euchromatic arrays are either close to, or are within introns of, genes. The short size of euchromatic arrays (one to five repeats) could be selectively constrained by their role as gene regulators, a situation similar to the so called "tuning knobs." PMID- 21712469 TI - Gene duplication and loss in a MADS box gene transcription factor circuit. AB - Although many models have been proposed that could lead to the maintenance of gene duplicates, the ways in which interacting gene duplicates influence each other's evolution and function remain poorly understood. Here, we focus on duplication and loss of the B class MADS box transcription factor genes in the euasterids I and the ramifications of such changes on paralog evolution and their encoded functions. In core eudicots, the B class genes belong to two paralogous lineages whose products form obligate heterodimers. Based on comparative genomic and phylogenetic analyses, we show that five stepwise B class MADS box gene gain or loss events occurred during the radiation of the euasterids I within core eudicots. Gene loss in one sublineage was correlated with a deficit of other sublineage genes. We also show that the gain or loss of B class MADS box gene paralogs were associated with altered protein-protein interactions among the remaining copies. These altered protein interactions were correlated with asymmetric patterns of sequence diversification and selection, suggesting that compensatory changes were driving the evolution of such genes. Furthermore, these B class MADS box gene gain or loss events were associated with the evolutionary divergence of floral morphology in the euasterids I. Together, these observations point to a cooperative strategy by which gene networks evolve, with selection maintaining the overall logic of a network despite changes in individual components. PMID- 21712470 TI - Coronary atherosclerosis in African American and white patients with acute chest pain: characterization with coronary CT angiography. AB - PURPOSE: To use coronary computed tomographic (CT) angiography to compare the prevalence, extent, and composition of coronary atherosclerotic lesions in African American and white patients with acute chest pain. MATERIALS AND METHODS: The institutional review board waived the requirement for informed consent for this retrospective, HIPAA-compliant matched-cohort study. The authors analyzed the CT angiographic data of 301 patients (150 consecutive African American patients; 151 white control patients; mean age, 55 years +/- 11 [standard deviation]; 33% male) with acute chest pain. Each coronary artery segment was evaluated for presence of atherosclerotic plaque, plaque composition (calcified, noncalcified, or mixed), and stenosis. In addition, the noncalcified plaque volume was quantified by using a threshold-based automated algorithm. The presence and extent of atherosclerotic plaque were compared between the groups by using univariate and multivariate regression analyses. RESULTS: While there was no significant difference between the African American and white patients with respect to presence of any plaque (118 [79%] of 150 vs 112 [74%] of 151 patients, respectively; P = .36) or presence of stenosis (26 [17%] vs 37 [24%] patients, respectively; P = .13), the African American patients had a significantly higher prevalence (96 [64%] vs 62 [41%] patients, respectively; P < .001) and volume (median volume, 2.2 vs 1.4 mL, respectively; P < .001) of noncalcified plaque, independent of diabetes and other cardiovascular risk factors (odds ratio, 2.45; 95% confidence interval: 1.52, 4.04). In contrast, the African American patients had a lower prevalence of calcified plaque (39 [26%] vs 68 [45%] white patients, P = .001). CONCLUSION: Study results suggest that atherosclerotic plaque burden and composition, as measured by using coronary CT angiography, differ between African American and white patients, with relatively more noncalcified disease in African Americans and more calcified disease in white individuals. Further research is warranted to determine whether CT plaque characterization can improve cardiac risk prediction in African Americans. PMID- 21712471 TI - Is dynamic gadolinium enhancement needed in MR imaging for the preoperative assessment of scaphoidal viability in patients with scaphoid nonunion? AB - PURPOSE: To compare the accuracy of dynamic gadolinium-enhanced magnetic resonance (MR) imaging with that of standard MR imaging for assessing the viability of the proximal pole of the scaphoid in patients with nonunion. MATERIALS AND METHODS: The study protocol was submitted to the institutional review board, and the need to obtain additional approval was waived for this retrospective study. Twenty-eight patients (mean age +/- standard deviation, 24.3 years +/- 6.4) with nonunion of a scaphoid fracture underwent dynamic gadolinium enhanced MR imaging of the wrist 28 days +/- 19 before surgery. Dynamic gadolinium-enhanced MR imaging consisted of acquisition of 40 consecutive coronal T1-weighted images over 1 minute. Two readers retrospectively evaluated MR images obtained with a standard protocol and rated the viability of the proximal scaphoid pole. The steepest upslope of gadolinium uptake was calculated in a region of interest placed in the proximal scaphoid pole by a third reader. Receiver operating characteristic curves were calculated, and the areas under the receiver operating characteristic curve (A(z) values) were compared. Diagnostic performance in determining scaphoid viability was calculated for readers 1 and 2. Histologic findings in 11 patients and surgical findings in all patients served as the standard of reference. RESULTS: The sensitivity, specificity, and accuracy of standard MR imaging in the detection of scaphoid necrosis were 54%, 93%, and 75%, respectively, for reader 1 and 62%, 93%, and 78% for reader 2. Interreader reliability was excellent (kappa = 0.92). The A(z) was 0.82 for reader 1 and 0.87 for reader 2. The diagnostic performance of dynamic gadolinium-enhanced MR imaging, determined with the steepest upslope value, was inferior to that of standard MR imaging, with an A(z) of 0.57. Findings at histologic examination (viable bone, necrotic bone, callus formation) did not correlate with those at dynamic gadolinium-enhanced MR imaging. CONCLUSION: Because the diagnostic performance of dynamic gadolinium-enhanced MR imaging in the evaluation of scaphoid viability was inferior to that of a standard MR imaging protocol, dynamic acquisition may not be needed in patients with nonunion of scaphoid fractures. PMID- 21712472 TI - Quantitative evaluation of liver function with use of gadoxetate disodium enhanced MR imaging. AB - PURPOSE: To determine whether liver function correlating with indocyanine green (ICG) clearance could be estimated quantitatively from gadoxetate disodium enhanced magnetic resonance (MR) images. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and the requirement for informed consent was waived. Twenty-three consecutive patients who underwent an ICG clearance test and gadoxetate disodium-enhanced MR imaging with the same parameters as were used for a preoperative examination were chosen. The hepatocellular uptake index (HUI) from liver volume (V(L))and mean signal intensity of the liver on contrast-enhanced T1-weighted images with fat suppression (L(20)) and mean signal intensity of the spleen on contrast-enhanced T1-weighted images with fat suppression (S(20)) on 3D gradient-echo T1-weighted images with fat suppression obtained at 20 minutes after gadoxetate disodium (0.025 mmol per kilogram of body weight) administration was determined with the following equation: V(L)[(L(20)/S(20)) - 1]. The correlation of the plasma disappearance rate of ICG (ICG-PDR) and various factors derived from MR imaging, including HUI, iron and fat deposition in the liver and spleen, and spleen volume (V(S)), were evaluated with stepwise multiple regression analysis. The difference between the ratio of the remnant HUI to the HUI of the total liver (rHUI/HUI) and ratio of the liver remnant V(L) to the total V(L) (rV(L)/V(L)) was evaluated in four patients who had segmental heterogeneity of liver function. RESULTS: HUI and V(S) were the factors significantly correlated with ICG-PDR (R = 0.87). The mean value and its 95% confidence interval were 0.18 and 0.01 to 0.34, respectively, for the following calculation: (rHUI/HUI) - (rV(L)/V(L)). CONCLUSION: The liver function correlating with ICG-PDR can be estimated quantitatively from the signal intensities and the volumes of the liver and spleen on gadoxetate disodium enhanced MR images, which may improve the estimation of segmental liver function. PMID- 21712473 TI - A dual-targeting anticancer approach: soil and seed principle. AB - PURPOSE: To test the hypothesis that targeting the microenvironment (soil) may effectively kill cancer cells (seeds) through a small-molecular weight sequential dual-targeting theragnostic strategy, or dual-targeting approach. MATERIALS AND METHODS: With approval from the institutional animal care and use committee, 24 rats were implanted with 48 liver rhabdomyosarcomas (R1). First, the vascular disrupting agent combretastatin A4 phosphate (CA4P) was injected at a dose of 10 mg/kg to cause tumor necrosis, which became a secondary target. Then, the necrosis-avid agent hypericin was radiolabeled with iodine 131 to form (131)I hypericin, which was injected at 300 MBq/kg 24 hours after injection of CA4P. Both molecules have small molecular weight, are naturally or synthetically derivable, are intravenously injectable, and are of unique targetablities. The tumor response in the dual-targeting group was compared with that in vehicle control and single-targeting (CA4P or (131)I-hypericin) groups with in vivo magnetic resonance imaging and scintigrams and ex vivo gamma counting, autoradiography, and histologic analysis. Tumor volumes, tumor doubling time (TDT), and radiobiodistribution were analyzed with statistical software. P values below .05 were considered to indicate a significant difference. RESULTS: Eight days after treatment, the tumor volume of rhabdomyosarcoma in the vehicle-control group was double that in both single-targeting groups (P < .001) and was five times that in the dual-targeting group (P < .0001), without treatment-related animal death. The TDT was significantly longer in the dual-targeting group (P < .0001). Necrosis appeared as hot spots on scintigrams, corresponding to 3.13% of the injected dose of (131)I-hypericin per gram of tissue (interquartile range, 2.92%-3.97%) and a target-to-liver ratio of 20. The dose was estimated to be 100 times the cumulative dose of 50 Gy needed for radiotherapeutic response. Thus, accumulated (131)I-hypericin from CA4P-induced necrosis killed residual cancer cells with ionizing radiation and inhibited tumor regrowth. CONCLUSION: This dual targeting approach may be a simple and workable solution for cancer treatment and deserves further exploitation. PMID- 21712474 TI - Swedish two-county trial: impact of mammographic screening on breast cancer mortality during 3 decades. AB - PURPOSE: To estimate the long-term (29-year) effect of mammographic screening on breast cancer mortality in terms of both relative and absolute effects. MATERIALS AND METHODS: This study was carried out under the auspices of the Swedish National Board of Health and Welfare. The board determined that, because randomization was at a community level and was to invitation to screening, informed verbal consent could be given by the participants when they attended the screening examination. A total of 133 065 women aged 40-74 years residing in two Swedish counties were randomized into a group invited to mammographic screening and a control group receiving usual care. Case status and cause of death were determined by the local trial end point committees and, independently, by an external committee. Mortality analysis was performed by using negative binomial regression. RESULTS: There was a highly significant reduction in breast cancer mortality in women invited to screening according to both local end point committee data (relative risk [RR] = 0.69; 95% confidence interval: 0.56, 0.84; P < .0001) and consensus data (RR = 0.73; 95% confidence interval: 0.59, 0.89; P = .002). At 29 years of follow-up, the number of women needed to undergo screening for 7 years to prevent one breast cancer death was 414 according to local data and 519 according to consensus data. Most prevented breast cancer deaths would have occurred (in the absence of screening) after the first 10 years of follow up. CONCLUSION: Invitation to mammographic screening results in a highly significant decrease in breast cancer-specific mortality. Evaluation of the full impact of screening, in particular estimates of absolute benefit and number needed to screen, requires follow-up times exceeding 20 years because the observed number of breast cancer deaths prevented increases with increasing time of follow-up. PMID- 21712475 TI - Liposomal delivery of MicroRNA-7-expressing plasmid overcomes epidermal growth factor receptor tyrosine kinase inhibitor-resistance in lung cancer cells. AB - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been strikingly effective in lung cancers harboring activating EGFR mutations. Unfortunately, the cancer cells eventually acquire resistance to EGFR-TKI. Approximately 50% of the acquired resistance involves a secondary T790M mutation. To overcome the resistance, we focused on EGFR suppression using microRNA-7 (miR 7), targeting multiple sites in the 3'-untranslated region of EGFR mRNA. Two EGFR TKI-sensitive cell lines (PC-9 and H3255) and two EGFR-TKI-resistant cell lines harboring T790M (RPC-9 and H1975) were used. We constructed miR-7-2 containing miR-7-expressing plasmid. After transfection of the miR-7-expressing plasmid, using cationic liposomes, a quantitative PCR and dual luciferase assay were conducted to examine the efficacy. The antiproliferative effect was evaluated using a cell count assay and xenograft model. Protein expression was examined by Western blotting. The miR-7 expression level of the transfectants was approximately 30-fold higher, and the luciferase activity was ablated by 92%. miR 7 significantly inhibited cell growth not only in PC-9 and H3255 but also in RPC 9 and H1975. Expression of insulin receptor substrate-1 (IRS-1), RAF-1, and EGFR was suppressed in the four cell lines. Injection of the miR-7-expressing plasmid revealed marked tumor regression in a mouse xenograft model using RPC-9 and H1975. EGFR, RAF-1, and IRS-1 were suppressed in the residual tumors. These findings indicate promising therapeutic applications of miR-7-expressing plasmids against EGFR oncogene-addicted lung cancers including T790M resistance by liposomal delivery. PMID- 21712476 TI - Antitumor actions of ruthenium(III)-based nitric oxide scavengers and nitric oxide synthase inhibitors. AB - The role of endogenous nitric oxide (NO) in the growth and vascularization of a rat carcinosarcoma (P22) has been investigated. Tumor-bearing animals were treated with (i) nitric oxide synthase (NOS) inhibitors, administered via the drinking water, including N(G)-nitro-l-arginine methyl ester (L-NAME), a nonisoform-selective inhibitor, and 2 others that target the inducible (NOS II) enzyme preferentially, namely 1-amino-2-hydroxyguanidine or N-[3 (aminomethyl)benzyl]acetamidine hydrochloride; or (ii) daily injections (intraperitoneally) of 2 Ru(III) polyaminocarboxylates, AMD6221 and AMD6245, both of which are effective NO scavengers. L-NAME, AMD6221, and AMD6245 reduced tumor growth by approximately 60% to 75% of control rates. Tumor sections stained with abs to CD-31/platelet endothelial cell adhesion molecule-1 or NOS III showed that this was associated with a marked reduction (60%-77%) of tumor microvascular densitiy (MVD). Tumors resumed growing promptly when treatment was discontinued, accompanied by partial or complete restoration of MVDs. In contrast, NOS-II selective inhibitors had no effect on tumor growth or vascularization, indicating that both responses require complete blockade of NO production. The results corroborate the view that endogenous NO facilitates tumor development. We suggest that NO deprivation causes tumor feeder vessels to constrict, reducing tumor blood flow. The delivery of oxygen and essential nutrients to the developing tumor is impaired as a consequence, hampering further growth. Normalizing NO levels by withholding treatment causes tumor feeder vessels to dilate, increasing tumor perfusion and reestablishing conditions that allow tumors to begin growing again. PMID- 21712478 TI - Novel therapeutic options in anaplastic large cell lymphoma: molecular targets and immunological tools. AB - Anaplastic large cell lymphoma (ALCL) is a CD30-positive, aggressive T-cell lymphoma, and about half of the patients with this disease harbor the t(2;5)(p21;q35) translocation. This chromosomal aberration leads to fusion of the NPM gene with the ALK tyrosine kinase, leading to its constitutive activation. To date, treatment options include polychemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone), which is sometimes combined with radiation in the case of bulky disease, leading to remission rates of ~80%. However, the remaining patients do not respond to therapy, and some patients experience chemo-resistant relapses, making the identification of new and better treatments imperative. The recent discovery of deregulated ALK in common cancers such as non-small cell lung cancer and neuroblastoma has reinvigorated industry interest in the development of ALK inhibitors. Moreover, it has been shown that the ALK protein is an ideal antigen for vaccination strategies due to its low expression in normal tissue. The characterization of microRNAs that are deregulated in ALCL will yield new insights into the biology of ALCL and open new avenues for therapeutic approaches in the future. Also, CD30 antibodies that have been tested in ALCL for quite a while will probably find a place in forthcoming treatment strategies. PMID- 21712477 TI - Compensatory pathways induced by MEK inhibition are effective drug targets for combination therapy against castration-resistant prostate cancer. AB - Targeted therapies have often given disappointing results when used as single agents in solid tumors, suggesting the importance of devising rational combinations of targeted drugs. We hypothesized that construction of such combinations could be guided by identification of growth and survival pathways whose activity or expression become upregulated in response to single-agent drug treatment. We mapped alterations in signaling pathways assessed by gene array and protein phosphorylation to identify compensatory signal transduction pathways in prostate cancer xenografts treated with a MAP/ERK kinase (MEK) inhibitor PD325901. In addition to numerous components of the extracellular signal regulated kinase (ERK) signaling pathway, components of the IKK, hedgehog, and phosphoinositide 3-kinase/Akt/mTOR pathways were upregulated following treatment with PD325901. Combinations of PD325901 with inhibitors of any one of these upregulated pathways provided synergistically greater growth inhibition of in vitro cell growth and survival than the individual drugs alone. Thus, the identification of compensatory signal transduction pathways paves the way for rational combinatorial therapies for the effective treatment of prostate cancer. PMID- 21712479 TI - Long-term mobile phone use and the risk of vestibular schwannoma: a Danish nationwide cohort study. AB - Vestibular schwannomas grow in the region within the brain where most of the energy by radiofrequency electromagnetic fields from using mobile phones is absorbed. The authors used 2 Danish nationwide cohort studies, one a study of all adult Danes subscribing for a mobile phone in 1995 or earlier and one on sociodemographic factors and cancer risk, and followed subjects included in both cohorts for occurrence of vestibular schwannoma up to 2006 inclusively. In this study including 2.9 million subjects, a long-term mobile phone subscription of >=11 years was not related to an increased vestibular schwannoma risk in men (relative risk estimate = 0.87, 95% confidence interval: 0.52, 1.46), and no vestibular schwannoma cases among long-term subscribers occurred in women versus 1.6 expected. Vestibular schwannomas did not occur more often on the right side of the head, although the majority of Danes reported holding their mobile phone to the right ear. Vestibular schwannomas in long-term male subscribers were not of larger size than expected. Overall, no evidence was found that mobile phone use is related to the risk of vestibular schwannoma. Because of the usually slow growth of vestibular schwannoma and possible diagnostic delay, further surveillance is indicated. PMID- 21712480 TI - Nonrandom variation in within-species sample size and missing data in phylogenetic comparative studies. PMID- 21712481 TI - Dexamphetamine improves upper extremity outcome during rehabilitation after stroke: a pilot randomized controlled trial. AB - BACKGROUND: For early inpatient stroke rehabilitation, the effectiveness of amphetamine combined with physiotherapy varies across studies. OBJECTIVE: To investigate whether the recovery of activities of daily living (ADL, primary outcome) and motor function (secondary outcome) can be improved by dexamphetamine added to physiotherapy. METHODS: In a double-blind, placebo-controlled trial, 16 patients, from 918 who were screened, were randomized to the experimental group (EG, dexamphetamine + physiotherapy) or control group (CG, placebo + physiotherapy). Both groups received multidisciplinary inpatient rehabilitation. Dexamphetamine (10 mg oral) or placebo was administered 2 days per week before physiotherapy. ADL and motor function were measured using the Chedoke-McMaster Stroke Assessment (CMSA) twice during baseline, every week during the 5-week treatment period, and at follow-up 1 week, 6 months, and 12 months after intervention. RESULTS: The majority of ineligible patients had too little paresis, were on anticoagulants, or had a stroke >60 days prior to entry. Participants (EG, n = 7, age 70.3 +/- 10 years, 5 women, 37.9 +/- 9 days after stroke; CG, n = 9, age 65.2 +/- 17 years, 3 women, 40.3 +/- 9 days after stroke) did not differ at baseline except for the leg subscale. Analysis of variance from baseline to 1 week follow-up revealed significant improvements in favor of EG for subscales ADL (P = .023) and arm function (P = .020) at end of treatment. No adverse events were detected. CONCLUSION: In this small trial that was based on prior positive trials, significant gains in ADL and arm function suggest that the dose and timing of dexamphetamine can augment physiotherapy. Effect size calculation suggests inclusion of at least 25 patients per group in future studies. PMID- 21712482 TI - Which on-field signs/symptoms predict protracted recovery from sport-related concussion among high school football players? AB - BACKGROUND: There has been increasing attention and understanding of sport related concussions. Recent studies show that neurocognitive testing and symptom clusters may predict protracted recovery in concussed athletes. On-field signs and symptoms have not been examined empirically as possible predictors of protracted recovery. PURPOSE: This study was undertaken to determine which on field signs and symptoms were predictive of a protracted (>=21 days) versus rapid (<=7 days) recovery after a sports-related concussion. On-field signs and symptoms included confusion, loss of consciousness, posttraumatic amnesia, retrograde amnesia, imbalance, dizziness, visual problems, personality changes, fatigue, sensitivity to light/noise, numbness, and vomiting. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: The sample included 107 male high school football athletes who completed computerized neurocognitive testing within an average 2.4 days after injury, and who were followed until returned to play as determined by neuropsychologists using international clinical concussion management guidelines. Athletes were then grouped into rapid (<=7 days, n = 62) or protracted (>=21 days, n = 36) recovery time groups. The presence of on-field signs and symptoms was determined at the time of injury by trained sports medicine professionals (i.e., ATC [certified athletic trainer], team physician). A series of odds ratios with chi(2) analyses and subsequent logistic regression were used to determine which on-field signs and symptoms were associated with an increased risk for a protracted recovery. RESULTS: Dizziness at the time of injury was associated with a 6.34 odds ratio (95% confidence interval = 1.34 29.91, chi(2) = 5.44, P = .02) of a protracted recovery from concussion. Surprisingly, the remaining on-field signs and symptoms were not associated with an increased risk of protracted recovery in the current study. CONCLUSION: Assessment of on-field dizziness may help identify high school athletes at risk for a protracted recovery. Such information will improve prognostic information and allow clinicians to manage and treat concussion more effectively in these at risk athletes. PMID- 21712483 TI - Quality of life and clinical outcome comparison of semitendinosus and gracilis tendon versus patellar tendon autografts for anterior cruciate ligament reconstruction: an 11-year follow-up of a randomized controlled trial. AB - BACKGROUND: There are still controversies about graft selection for primary anterior cruciate ligament reconstruction. Prospective, randomized long-term studies are needed to determine the differences between the graft materials. HYPOTHESIS: Eleven years after anterior cruciate ligament reconstruction there is no difference in functional outcome and quality of life between patients with patellar tendon or hamstring tendon autografts; however, the patients with patellar tendon autograft would have a higher prevalence of osteoarthritis. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: From June 1999 to March 2000, 64 patients were included in this prospective study. A single surgeon performed primary arthroscopically assisted anterior cruciate ligament reconstruction in an alternating sequence. In 32 patients, anterior cruciate ligament reconstruction was performed with hamstring tendon autograft (semitendinosus and gracilis [STG] group) while in the other 32 patients the reconstruction was performed with patellar tendon autograft (PT group). RESULTS: At the 11-year follow-up, no statistically significant differences were seen with respect to the Lysholm score and Short Form-36, KT-1000 arthrometer laxity testing, anterior knee pain, single-legged hop test, or International Knee Documentation Committee (IKDC) classification results. Positive pivot-shift test (1+) was significantly more frequent in the PT group (P = .036). Twenty-two patients (81%) in the STG group and 18 patients (72%) in the PT group were still at their preinjury level of activity. Graft rupture occurred in 2 patients from the STG group (6%) and in 4 patients from the PT (12%). Grade B and C abnormal radiographic findings were seen in 84% (21 of 25) of patients in the PT group and in 63% (17 of 27) of patients in the STG group (P = .008). CONCLUSION: Both hamstring and patellar tendon autografts provided good subjective outcomes and objective stability at 11 years. Positive pivot-shift test (1+) was significantly more frequent in the PT group. No significant differences in the rate of graft failure were identified. Patients with patellar tendon graft had a greater prevalence of osteoarthritis at 11 years after surgery. PMID- 21712485 TI - Prognostic impact of phosphorylated HER-2 in HER-2+ primary breast cancer. AB - PURPOSE: Tyrosine 1248 is one of the autophosphorylation sites of human epidermal growth factor receptor (HER)-2. We determined the prognostic value of the expression level of tyrosine 1248-phosphorylated HER-2 (pHER-2) in patients with HER-2(+) primary breast cancer using a reverse-phase protein array. PATIENTS AND METHODS: The optimal cutoff value of pHER-2 for segregating disease-free survival (DFS) was determined by receiver operating characteristic (ROC) curve analysis. Five-year DFS for pHER-2 expression level was estimated with the Kaplan-Meier method using both derivation (n = 162) and validation (n = 227) cohorts. RESULTS: Of the 162 patients in the derivation cohort, 26 had high HER-2 expression levels. The area under the ROC curve for pHER-2 level and DFS was 0.662. Nineteen of the 162 patients (11.7%) had high pHER-2 expression levels (pHER-2(high)); 143 patients (88.3%) had low pHER-2 expression levels (pHER-2(low)). Among the 26 patients with high HER-2 expression levels, the 17 pHER-2(high) patients had a significantly lower 5-year DFS rate than the nine pHER-2(low) patients (23.5% versus 77.8%). On multivariate analysis, only pHER-2(high) independently predicted DFS in the Cox proportional hazards model. In the validation cohort, among 61 patients with high HER-2 expression, the difference in 5-year DFS rates between pHER-2(high) (n = 7) and pHER-2(low) (n = 54) patients was marginal (57.1% versus 81.5%). CONCLUSION: In patients with HER-2(+) primary breast cancer, pHER-2(high) patients had a lower 5-year DFS rate than pHER-2(low) patients. Quantification of pHER-2 expression level may provide prognostic information beyond the current standard HER-2 status. PMID- 21712486 TI - A prospective, controlled study of the botanical compound mixture LCS101 for chemotherapy-induced hematological complications in breast cancer. AB - BACKGROUND: This prospective, controlled study evaluated the safety, tolerability, and efficacy of the mixture of botanical compounds known as LCS101 in preventing chemotherapy-induced hematological toxicity in breast cancer patients. METHODS: Female patients diagnosed with localized breast cancer were randomly allocated to receive treatment with either LCS101 or placebo capsules, in addition to conventional chemotherapy. The study intervention was initiated 2 weeks prior to the initiation of chemotherapy and continued until chemotherapy was completed, with participants receiving 2 g of LCS101 capsules thrice daily. Subjects were assessed for the development of hematological and nonhematological toxicities, as well as the tolerability and safety of the study intervention. RESULTS: Sixty-five breast cancer patients were recruited, with 34 allocated to LCS101 and 31 allocated to placebo treatment. Patients in the treatment group developed significantly less severe (grades 2-4) anemia (p < .01) and leukopenia (p < .03) when comparing grades 0-1 with grades 2-4, with significantly less neutropenia (p < .04) when comparing grades 0-2 with grades 3-4. This effect was more significant among patients undergoing a dose-dense regimen. No statistically significant effect was found with respect to nonhematological toxicities, and side effect rates were not significantly different between the groups, with no severe or life-threatening events observed in either group. CONCLUSION: The addition of LCS101 to anthracycline- and taxane-based chemotherapy is safe and well tolerated, and may significantly prevent some chemotherapy-induced hematological toxicities in early breast cancer patients. These results should encourage further larger and more extensive clinical trials. PMID- 21712487 TI - Is laparoscopic donation safe for paediatric recipients?--a study of 85 paediatric recipients comparing open and laparoscopic donor nephrectomy. AB - INTRODUCTION: The safety of adult laparoscopic donor nephrectomy remains controversial with respect to paediatric recipients with few data existing about its efficacy. Small studies have shown no difference in graft survival when compared with open techniques, but previous data from United Network for Organ Sharing suggests a higher incidence of rejection in laparoscopically procured kidneys. METHODS: We examined the outcome in a total of 85 consecutive paediatric renal recipients, comparing 46 recipients of laparoscopically procured kidneys (performed over a 3-year period, 2004-07) to a historical control of 39 open donor recipients. Thirty-seven laparoscopic donors were by the hand-assisted technique. RESULTS: Mean recipient age was 9.8 (SD 5.04) years in the laparoscopic group and 10.4 (SD 4.67) years in the open group (P = 0.617). Two patients had delayed graft function in the laparoscopic group (4.3%) and one (2.5%) in the open group (P = 0.562). At 1 year follow-up, there was 100% graft survival in the laparoscopic group compared to 92% (P = 0.093) in the open group. Incidence of biopsy-proven acute rejection within 1 year of transplant was 26% (16 episodes in 12 patients) in the laparoscopic group compared to 41% (29 episodes in 16 patients) in the open group (P = 0.219). There were no deaths in the laparoscopic group but there were three deaths (7.6%) in the open group (P = 0.093). CONCLUSIONS: Our experience of laparoscopic kidney donation for paediatric recipients suggests excellent outcome with no difference in rejection rate or graft survival compared to open donation. Laparoscopic donation is the optimal method of kidney procurement for paediatric recipients. PMID- 21712488 TI - Left ventricular periostin gene expression is associated with fibrogenesis in experimental renal insufficiency. AB - BACKGROUND: Cardiovascular diseases are the most important cause of death in patients with impaired kidney function. Left ventricular hypertrophy (LVH), cardiac interstitial fibrosis and cardiovascular calcifications are characteristic of chronic renal insufficiency (CRI). Periostin is a fibrogenesis- and calcification-related matricellular protein re-expressed in adult tissues undergoing remodelling in response to pathological stimuli. The role of periostin in CRI-induced LVH is unknown. METHODS: Rats were 5/6-nephrectomized (NX), and after 15 weeks of disease progression high-calcium, high-phosphate or paricalcitol treatment was given for 12 weeks. Cardiac tissue and blood samples were taken to study periostin gene expression and to determine factors contributing to its reactivation, respectively. Left ventricular (LV) periostin expression was also examined in response to angiotensin II or arginine(8) vasopressin (AVP)-induced pressure overload and in spontaneously hypertensive rats. RESULTS: CRI resulted in a 6.5-fold increase in LV periostin messenger RNA (mRNA) levels. Positive extracellular immunostaining for periostin was detected in areas of infiltrated inflammatory cells and fibrotic lesions. There was a significant correlation between LV periostin mRNA levels and plasma biomarkers of impaired kidney function, LVH, fibrogenesis-related proteins osteopontin and osteoactivin, and anti-calcific matrix Gla protein. Moreover, LV periostin gene expression in CRI correlated positively with systolic blood pressure (BP) and was activated rapidly in response to angiotensin II or AVP infusions. CONCLUSIONS: Periostin is involved in fibrotic cardiac remodelling in CRI. The re-expression of periostin is localized to the fibrotic and inflammatory lesions and is most likely the consequence of elevated BP. PMID- 21712489 TI - Red blood cell distribution width is an independent predictor of mortality in acute kidney injury patients treated with continuous renal replacement therapy. AB - BACKGROUND: A potential independent association was recently demonstrated between high red blood cell distribution width (RDW) and the risk of all-cause mortality in patients with cardiovascular disease, although the mechanism remains unclear. However, there have been no reports on the relationship between RDW and mortality in acute kidney injury (AKI) patients treated with continuous renal replacement therapy (CRRT). In this study, we assessed whether RDW was associated with mortality in AKI patients on CRRT treatment in the intensive care unit (ICU). METHODS: We enrolled 470 patients with AKI who were treated with CRRT at the Yonsei University Medical Center ICU from August 2007 to September 2009 in this study. We performed a retrospective analysis of demographic, biochemical parameters and patient outcomes. Following CRRT treatment, 28-day all-cause mortality was evaluated. RESULTS: At the initiation of CRRT treatment, RDW level was significantly correlated with white blood cell count, hemoglobin (Hb) and total cholesterol. Patients with high RDW levels exhibited significantly higher 28-day mortality rates than patients with low RDW levels (P < 0.01). Baseline RDW level, Sequential Organ Failure Assessment (SOFA) score, low mean arterial pressure (MAP) and low cholesterol levels were independent risk factors for mortality. In multivariate Cox proportional hazard analyses, RDW at CRRT initiation was an independent predictor for 28-day all-cause mortality after adjusting for age, gender, MAP, Hb, albumin, total cholesterol, C-reactive protein and SOFA score. CONCLUSION: Our study demonstrates that RDW could be an additive predictor for all-cause mortality in AKI patients on CRRT treatment in the ICU. PMID- 21712490 TI - Impact of CMV infection on acute rejection and long-term renal allograft function: a systematic analysis in patients with protocol biopsies and indicated biopsies. AB - BACKGROUND: Higher rates of acute rejection (AR) and reduced graft survival have been reported in patients with cytomegalovirus (CMV) infection, but an association between these factors remains controversial. METHODS: In this study, serial protocol biopsies (PBs) and clinically indicated biopsies (IBs) from a large cohort of renal allograft recipients (n ¼ 594) were analyzed to examine the relation between CMV and AR. RESULTS: Patients with CMV were more likely to receive IB (85 of the 153 patients; 56%) compared to patients without CMV (138 of 441 patients; 32%; P = 0.003). However, this did not translate into a greater number of patients with episodes of acute cellular rejection on histopathology in IBs. Analysis of PBs revealed a significantly higher number of episodes of rejection per patient with CMV infection (P = 0.04), but only in a subgroup of patients with triple immunosuppression. Long-term graft function post transplantation was analyzed in four different subgroups according to CMV infection and/or AR. Differences in renal function were apparent within the first 6 weeks after transplantation and persisted during follow-up, with the best renal function in patients without AR or CMV, whereas patients with both AR and CMV had the worst (P < 0.012 at 1 year; P < 0.001 at 2 years). On average, the latter group had significantly older donors and more often delayed graft function. CONCLUSIONS: Our data suggests that the link between CMV and AR is far less significant than previously thought. Outcome in patients with CMV may be more determined by coexisting conditions like high donor age and delayed graft function. PMID- 21712491 TI - Tribulus terrestis-induced nephrotoxicity? PMID- 21712492 TI - Additional role of urine output criterion in defining acute kidney injury. AB - BACKGROUND: Diagnosis of acute kidney injury (AKI) has been a major concern due to its association with increased morbidity and mortality. However, the clinical implication of the urine output criterion (UOCr) in diagnosing AKI has not been fully established. METHODS: We assessed the incidence of AKI among 1625 critically ill patients and analysed the overall survival rates based on the serum creatinine criterion (CrCr) and UOCr, both of which have been defined by the AKI Network (AKIN). RESULTS: Within 7 days of admission, the risk rate of AKI was 57.0% and the rate determined by UOCr alone was 25.7%. AKI determined by the UOCr alone increased hazard ratios (HRs) for mortality; 1.81 (Stage 1), 2.96 (Stage 2) and 4.17 (Stage 3) compared to non-AKI. However, the difference in mortality between Stages 2 and 3 using the CrCr alone was not significant (P = 0.881). In patients with Stages 2 and 3 by the CrCr, the UOCr further separated the survival rates (P = 0.001 among the four UOCr stages). The diuretic dose did not alter the discriminative function of the UOCr for survival rates. However, 42.1% of non-AKI cases, as determined by the UOCr, were identified as AKI cases by the CrCr. CONCLUSION: Although some AKI cases were not identified by the UOCr alone, the UOCr has an additional role in AKI staging, regardless of diuretic use. PMID- 21712493 TI - Minimal modeling approaches to value of information analysis for health research. AB - Value of information (VOI) techniques can provide estimates of the expected benefits from clinical research studies that can inform decisions about the design and priority of those studies. Most VOI studies use decision-analytic models to characterize the uncertainty of the effects of interventions on health outcomes, but the complexity of constructing such models can pose barriers to some practical applications of VOI. However, because some clinical studies can directly characterize uncertainty in health outcomes, it may sometimes be possible to perform VOI analysis with only minimal modeling. This article 1) develops a framework to define and classify minimal modeling approaches to VOI, 2) reviews existing VOI studies that apply minimal modeling approaches, and 3) illustrates and discusses the application of the minimal modeling to 2 new clinical applications to which the approach appears well suited because clinical trials with comprehensive outcomes provide preliminary estimates of the uncertainty in outcomes. The authors conclude that minimal modeling approaches to VOI can be readily applied in some instances to estimate the expected benefits of clinical research. PMID- 21712495 TI - Toll-like receptor 3 C1234T may protect against geographic atrophy through decreased dsRNA binding capacity. AB - The genetic association between a variant in the Toll-like receptor 3 (TLR3) gene (C1234T in mRNA, L412F in protein, Reference SNP Cluster Report rs3775291) and geographic atrophy (GA; also called advanced "dry" age-related macular degeneration) was controversial in previous studies. We performed a meta-analysis by pooling the current evidence in literature and found that the T allele of the TLR3 C1234T variant showed a summary odds ratio of 0.753 (95% confidence interval: 0.612-0.927; P=0.007). Further experiments were performed to analyze how this mutant influences the function of TLR3. We found that this SNP did not affect mRNA, protein, or surface expression of TLR3. However, the binding capacity of L412F mutation of TLR3 for double-stranded RNA in the TLR3 protein was only 51.12 +/- 3.96% (P<0.001) of the wild-type level. There was a consistently reduced TLR3-mediated NF-kappaB activation. Therefore, TLR3 C1234T (L412F in the protein) may protect against GA by reduced binding capacity of TLR3 to dsRNA. This study may provide a better understanding of the genetic architecture underlying disease susceptibility and may advance the potential for preclinical prediction in future genetic testing. PMID- 21712496 TI - Scientific considerations for pharmacoenhancers in antiretroviral therapy. PMID- 21712494 TI - Role of sphingolipids in murine radiation-induced lung injury: protection by sphingosine 1-phosphate analogs. AB - Clinically significant radiation-induced lung injury (RILI) is a common toxicity in patients administered thoracic radiotherapy. Although the molecular etiology is poorly understood, we previously characterized a murine model of RILI in which alterations in lung barrier integrity surfaced as a potentially important pathobiological event and genome-wide lung gene mRNA levels identified dysregulation of sphingolipid metabolic pathway genes. We hypothesized that sphingolipid signaling components serve as modulators and novel therapeutic targets of RILI. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to sphingosine 1 phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage fluid, and lung tissue. Mice with a targeted deletion of SphK1 (SphK1(-/-)) or with reduced expression of S1P receptors (S1PR1(+/-), S1PR2(-/-), and S1PR3(-/-)) exhibited marked RILI susceptibility. Finally, studies of 3 potent vascular barrier-protective S1P analogs, FTY720, (S)-FTY720-phosphonate (fTyS), and SEW 2871, identified significant RILI attenuation and radiation-induced gene dysregulation by the phosphonate analog, fTyS (0.1 and 1 mg/kg i.p., 2*/wk) and to a lesser degree by SEW-2871 (1 mg/kg i.p., 2*/wk), compared with those in controls. These results support the targeting of S1P signaling as a novel therapeutic strategy in RILI. PMID- 21712497 TI - Effects of yogurt and applesauce on the oral bioavailability of nilotinib in healthy volunteers. AB - Nilotinib, a potent orally bioavailable BCR-ABL tyrosine kinase inhibitor, is currently available as a hard gelatin capsule that must be swallowed whole. For patients who may have difficulty swallowing the intact capsule, an alternative mode of administration is desirable. The authors compared the bioavailability of nilotinib from the following administrations in 48 healthy subjects: (1) 400 mg nilotinib given as two 200-mg nilotinib intact capsules; (2) contents of two 200 mg nilotinib capsules, each capsule dispersed in 1 teaspoon of nonfat plain yogurt; and (3) contents of two 200-mg nilotinib capsules, each capsule dispersed in 1 teaspoon of applesauce. Nilotinib absorption was modestly increased following the administration of nilotinib dispersed in yogurt. The geometric mean ratios (90% confidence intervals) for nilotinib C(max), AUC(0-tlast), and AUC(0 inf) were 1.31 (1.22-1.41), 1.11 (1.05-1.16), and 1.08 (1.02-1.15), respectively. Administration of nilotinib dispersed in applesauce showed equivalent bioavailability compared with administration of nilotinib as intact capsules. The geometric mean ratios (90% confidence intervals) for nilotinib C(max), AUC(0 tlast), and AUC(0-inf) were 0.95 (0.88-1.02), 0.99 (0.94-1.04), and 0.97 (0.90 1.03), respectively. Each treatment was well tolerated in the study subjects. The data support a feasible alternative method of nilotinib administration; each capsule's contents may be dispersed in 1 teaspoon of applesauce and taken immediately. PMID- 21712498 TI - Steady-state pharmacokinetic interactions of darunavir/ritonavir with lipid lowering agent rosuvastatin. AB - HIV-1 protease inhibitors often cause dyslipidemia, necessitating the use of lipid-lowering agents such as rosuvastatin. However, when given concomitantly, these therapeutic agents often exhibit adverse drug interactions. In this study (phase I open-label trial, n = 12 HIV-1 seronegative participants), the authors assessed the drug interactions between darunavir/ritonavir given in combination with rosuvastatin. Participants were randomized to receive rosuvastatin (10 mg/day) or darunavir/ritonavir (600/100 mg twice daily) alone for 7 days in a crossover design followed by combination therapy for 7 days with intervening 7 day washout periods. Intensive blood sampling for pharmacokinetics and fasting lipids was performed on days 7, 21, and 35. The geometric mean AUC(0-24 h) of rosuvastatin increased from 109 to 161 ng.h/mL (P < .005) and C(max) increased 6.7 to 16.3 ng/mL (P < .001) when coadministered with darunavir/ritonavir. In the presence of darunavir/ritonavir and rosuvastatin, total cholesterol and triglyceride levels increased by 10% (P = .007) and 56% (P = .011), whereas the high-density lipoprotein cholesterol levels decreased by 13% (P = .006) relative to rosuvastatin administration alone. There were no significant adverse events attributable to the coadministration of these drugs. Rosuvastatin levels increase in the presence of darunavir/ritonavir coadministration, whereas the lipid lowering benefits are blunted. The clinical significance of these changes requires further investigation. PMID- 21712499 TI - Using interviews and peer pairs to better understand how school environments affect young children's playground physical activity levels: a qualitative study. AB - School break times provide a daily opportunity for children to be active; however, research indicates this time is underutilized. Reasons for low children's playground activity levels have primarily focused on physical barriers. This research aimed to contribute to physical environmental findings affecting children's playground physical activity levels by identifying additional variables through the interview process. Thirteen public schools were included in the sample (total 2946 children). Physical activity and environmental data were collected over 3 days. Environmental variables were manually assessed at each of the 13 schools. Observational data were used to determine which three schools were the most and least active. The principal, three teachers and 20 students in Grades 4-6 from these six schools (four lower and two average socioeconomic status) were invited to participate in the interview process. Student interviews involved the paired interview technique. The main themes generated from the school interviews included the effect of non-fixed equipment (including balls), playground markings, playground aesthetics, activity preference, clothing, the amount of break time available for play, teacher playground involvement, gender, bullying, school policies, student confidence in break-time activity and fundamental movement skills. The effect of bullying on playground physical activity levels was concerning. PMID- 21712500 TI - Physical activity promotion in call centres: employers' perspectives. AB - This study followed a predominantly qualitative approach to explore the perspectives of employers in Sudbury, Ontario, Canada, call centres (CCs) regarding physical activity (PA) promotion in workplaces, by identifying current practices and employers' motivation to promote PA, as well as perceived facilitators and barriers. In-depth interviews were conducted with 15 managers in 10 of 12 local CCs and questionnaires were used to collect quantitative information about participants and their workplaces. Thematic analysis revealed that participants' responses to recommendations for PA promotion were generally positive and some CCs were engaged in some PA initiatives. Employers' motivations to promote PA included direct benefits to the employer, concern for employee well being and the greater good. Barriers to PA promotion within CCs included the nature of CC work, managers' concerns regarding participation, fairness and cost and special limitations of the workspace. Results indicate additional actions and supports are required to facilitate implementation of PA in CCs according to governmental recommendations. Efforts are required to increase awareness and use of existing resources. Smaller organizations may require more assistance to promote PA than those with a larger number of employees and may benefit from enhanced interaction with existing networks and public health programs and resources. PMID- 21712501 TI - Effect of a tailored behavior change program on a composite lifestyle change score: a randomized controlled trial. AB - To evaluate the effect of a tailored behavior change program on a composite lifestyle change score. A randomized controlled trial conducted in Belgium in 2007-08 with 314 participants allocated to a control and an intervention condition. The intervention was a tailored behavior change program (web-based and individual coaching). The dose of the coaching was chosen by the participants and registered. Outcome measures were weight, saturated fat intake, fruit and vegetable intake, physical activity, smoking status and a composite lifestyle change score. Mann-Whitney U-tests, Kruskal-Wallis tests, t-tests and one-way analyses of variance were used to compare the study conditions and three intervention dose groups (no/low, medium and high intervention dose). There were no significant differences between the study conditions or between the intervention dose groups for the individual lifestyle factors. The composite lifestyle change score was significantly higher in the high intervention dose group compared with the no/low intervention dose group (P = 0.009). The composite lifestyle change score was positively related to the intervention dose, while the individual lifestyle factors were not. Behavior change programs that target multiple lifestyle factors could be evaluated by using a composite lifestyle change score taking into account the intervention dose. PMID- 21712502 TI - Parental influences on adolescent fruit consumption: the role of adolescent self efficacy. AB - The aims of this study were to examine whether adolescent self-efficacy mediates the associations between parental control, perceptions of the importance of healthy nutrition for child health and barriers to buying fruits and vegetables and adolescent fruit consumption using a theoretically derived explanatory model. Data were drawn from a community-based sample of 1606 adolescents in Years 7 and 9 of secondary school and their parents, from Victoria, Australia. Adolescents completed a web-based survey assessing their fruit consumption and self-efficacy for increasing fruit consumption. Parents completed a survey delivered via mail assessing parental control, perceptions and barriers to buying fruit and vegetables. Adolescent self-efficacy for increasing fruit consumption mediated the positive associations between parental control and perceptions of the importance of healthy nutrition for child health and adolescent fruit consumption. Furthermore, adolescent self-efficacy mediated the negative association between parental barriers to buying fruits and vegetables and adolescent fruit consumption. The importance of explicating the mechanisms through which parental factors influence adolescent fruit consumption not only relates to the advancement of scientific knowledge but also offers potential avenues for intervention. Future research should assess the effectiveness of methods to increase adolescent fruit consumption by focussing on both improving adolescents' dietary self-efficacy and on targeting parental control, perceptions and barriers. PMID- 21712503 TI - The effects and costs of a group-based education programme for self-management of patients with Type 2 diabetes. A community-based study. AB - The worldwide epidemic of Type 2 diabetes necessitates evidence-based self management education programmes. The purpose of this study was to investigate the effects and costs of an empowerment-based structured diabetes self-management education programme in an unselected group of patients with Type 2 diabetes. Seven hundred and two patients undergoing treatment by general practitioners (GPs) were included. The education comprised three modules over a 12-month period. It was based on the empowerment philosophy. The education followed a written curriculum, and the educators were given special training in its use. Glycemic control (HbA1c) was found to improve from 7.34 +/- 1.34 to 6.88 +/- 1.09%, P < 0.001 and body weight decreased from 90.9 +/- 19.3 to 87.1 +/- 18.1 kg, P < 0.001, following the education programme. Moreover, significant improvements were found in terms of fasting blood glucose, blood pressure, female waist circumference, lipid profile, quality of life, physical activity and the patients' knowledge of diabetes whilst the number of visits to GPs declined. This study supports the use of an empowerment vision as a basis for an interdisciplinary group-based education programme with individuals with Type 2 diabetes. Moreover, the costs of implementing this education programme were found to be minimal. PMID- 21712504 TI - Investigation of the mode of action underlying the tumorigenic response induced in B6C3F1 mice exposed orally to hexavalent chromium. AB - Chronic ingestion of high concentrations of hexavalent chromium [Cr(VI)] in drinking water induces intestinal tumors in mice. To investigate the mode of action (MOA) underlying these tumors, a 90-day drinking water study was conducted using similar exposure conditions as in a previous cancer bioassay, as well as lower (heretofore unexamined) drinking water concentrations. Tissue samples were collected in mice exposed for 7 or 90 days and subjected to histopathological, biochemical, toxicogenomic, and toxicokinetic analyses. Described herein are the results of toxicokinetic, biochemical, and pathological findings. Following 90 days of exposure to 0.3-520 mg/l of sodium dichromate dihydrate (SDD), total chromium concentrations in the duodenum were significantly elevated at >= 14 mg/l. At these concentrations, significant decreases in the reduced-to-oxidized glutathione ratio (GSH/GSSG) were observed. Beginning at 60 mg/l, intestinal lesions were observed including villous cytoplasmic vacuolization. Atrophy, apoptosis, and crypt hyperplasia were evident at >= 170 mg/l. Protein carbonyls were elevated at concentrations >= 4 mg/l SDD, whereas oxidative DNA damage, as assessed by 8-hydroxydeoxyguanosine, was not increased in any treatment group. Significant decreases in the GSH/GSSG ratio and similar histopathological lesions as observed in the duodenum were also observed in the jejunum following 90 days of exposure. Cytokine levels (e.g., interleukin-1beta) were generally depressed or unaltered at the termination of the study. Overall, the data suggest that Cr(VI) in drinking water can induce oxidative stress, villous cytotoxicity, and crypt hyperplasia in the mouse intestine and may underlie the MOA of intestinal carcinogenesis in mice. PMID- 21712505 TI - Time crawls: the temporal resolution of infants' visual attention. AB - Conscious visual perception of the constantly changing environment is one of the brain's most critical functions. In virtually every moment of every daily activity, the visual system is confronted with the task of accurately representing and interpreting scenes that change rapidly over time. Adults can judge the identity and order of changing images presented at a rate of up to 10 Hz (~50 ms per image); this limit reflects a finite temporal resolution of attention. In the research reported here, although 6- to 15-month-old infants could detect the presence of rapid flicker without difficulty, their ability to segment individual alternating states within the flicker was severely limited: Fifteen-month-old infants had a temporal resolution of attention approximately one order of magnitude lower than that of adults (~1 Hz). Coarse temporal resolution constrains how infants perceive and utilize dynamic visual information and may play a role in the visual processing deficits found in individuals with neurodevelopmental disorders. PMID- 21712506 TI - Activated partial thromboplastin time versus antifactor Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion. AB - BACKGROUND: Unfractionated heparin (UFH) has been used clinically for 5 decades. Despite being a cornerstone of anticoagulation, UFH is limited by its unpredictable pharmacokinetic profile, which makes close laboratory monitoring necessary. The most common methods for monitoring UFH are the activated partial thromboplastin time (aPTT) and antifactor Xa heparin assay (anti-Xa HA), but both present challenges, and the optimal method to monitor UFH remains unclear. OBJECTIVE: To compare the performance of the aPTT with the anti-Xa HA for efficiency and safety of monitoring intravenous UFH infusions. METHODS: This was a single-center, retrospective, observational cohort study conducted in an 852 bed academic medical center. RESULTS: One hundred patients receiving intravenous UFH for a variety of indications were enrolled in the study; 50 were assigned to each group. The mean (SD) time to achieve therapeutic anticoagulation was significantly less in the anti-Xa HA group compared with the aPTT group (28 [16] vs 48 [26] hours, p < 0.001). In addition, a greater percentage of anti-Xa HA patients compared to aPTT patients achieved therapeutic anticoagulation at 24 hours (OR 3.5; 95% CI 1.5 to 8.7) and 48 hours (OR 10.9; 95% CI 3.3 to 44.2). Patients in the anti-Xa HA group also had more test values within the therapeutic range (66% vs 42%, p < 0.0001). A significant difference was seen between the 2 groups in the number of aPTT or anti-Xa HA tests performed per 24 hours (p < 0.0001) and number of infusion rate changes per 24 hours (p < 0.01), both favoring the anti-Xa HA group. CONCLUSIONS: Monitoring intravenous UFH infusions with the anti-Xa HA, compared to the aPTT, achieves therapeutic anticoagulation more rapidly, maintains the values within the goal range for a longer time, and requires fewer adjustments in dosage and repeated tests. PMID- 21712507 TI - Medication utilization and illness management study in Nigeria. AB - BACKGROUND: Little is known about rates of illness, illness management, or drug utilization in developing countries. OBJECTIVE: To determine patterns of illness and drug utilization in urban and rural households in Nigeria. METHODS: A survey was developed and validated for data collection. A random sample from some communities in Owan East Local Government Area (LGA) of Edo State, Nigeria, was selected, based on a national population survey, using both the supervisory and enumeration areas of the LGA. We determined the sample size using methods described by Cochran, including 5% precision, 5% alpha, and allowing for 5% data error. Respondents were queried in face-to-face interviews about illnesses in their households during the previous 2 weeks; demographic information; how they were treated; and where they sought treatment, advice, and medicines. As well, we determined how they kept families well. Descriptive statistics were used to summarize data. RESULTS: Out of 549 persons, 497 completed the questionnaires, giving a response rate of 90.5%. Of these respondents, 395 (79.5%) reported 517 illnesses during the previous 2 weeks. The average age of the ill person was 30.6 +/- 24.3 years (range 3 months to 95 years). Percentages by age were: infants younger than 1 year 1.0%, children aged 1-17 years 36.0%, and adults aged >=18 years 63.0%. Average monthly income per household was low (13,247 naira/88.31 US$). Malaria and its symptoms (fever, chills, joint pain, headache, gastrointestinal problems) and upper respiratory symptoms were most common. A majority (44.8%) of the ill persons self-treated, with 93.6% using antibiotic and antimalarial drugs. Among the households surveyed, 42.1% had drugs on hand (average 2.3 +/- 1.3, range 1-7, median 2) for disease prevention, and the most used drugs were analgesics (46.2%) and antimalarial drugs (37.3%). CONCLUSIONS: Illness is frequent in Nigeria and is usually self-treated with antibiotic and antimalarial drugs. Medications were reported to be the most frequently used measure to prevent household illness. The implications of these findings are discussed. PMID- 21712508 TI - Dofetilide dose calculation errors in elderly associated with use of the modification of diet in renal disease equation. AB - OBJECTIVE: To report 2 cases of drug dosage calculation errors that occurred when the Modification of Diet in Renal Disease (MDRD) equation was used for initiating drug therapy with dofetilide in elderly patients with chronic kidney disease. CASE SUMMARY: An 83-year-old woman and a 92-year-old man were admitted for dofetilide treatment initiation and cardioversion for atrial fibrillation. The estimated glomerular filtration rate (eGFR) determined with use of the MDRD equation was significantly higher than the estimated creatinine clearance (eCrCl) determined with use of the Cockcroft-Gault equation for both cases (85 vs 43 mL/min for the man and 40 vs 24 mL/min for the woman). Initial dofetilide dosages calculated by the MDRD equation were 2-fold higher than those calculated by eCrCl in both cases. Initiation of dose based on the MDRD in the first patient led to a 32% increase in the QTc interval from baseline. Dofetilide therapy was adjusted for QTc interval prolongation based on eCrCl and reinitiated at a lower dose, and the patient did not develop further significant increases in the QTc interval. In the second patient, the lower dose based on eCrCl was initiated and the QTc interval remained within an acceptable range. DISCUSSION: The initial dosing of dofetilide is based on eCrCl as specified by the drug manufacturer. Recent widespread use and automated reporting of the eGFR by clinical laboratories has tempted some clinicians to consider using eGFR for calculating drug doses. However, recent data suggest that the eGFR, calculated by the MDRD equation, consistently overestimates eCrCl, leading to dose discrepancies, particularly in the elderly. The cases reported here illustrate the drug dose calculation errors that may occur when using the MDRD equation for initiating doses of dofetilide. CONCLUSIONS: Use of the eGFR or MDRD equation for calculation of doses in renal dysfunction has not been validated, and significant drug dose errors have been reported. The use of eGFR to calculate doses of dofetilide should be avoided. PMID- 21712509 TI - Potential inaccuracy of point-of-care INR in dabigatran-treated patients. AB - OBJECTIVE: To report 2 cases in which point-of-care international normalized ratios (INRs) in dabigatran-treated patients were inaccurate. CASE SUMMARY: A 59 year-old woman with paroxysmal atrial fibrillation was started on warfarin. After 3 days, warfarin was discontinued, and the decision was made to switch to dabigatran 150 mg twice a day, which was started 2 days after the warfarin was discontinued. As treatment was being converted from warfarin to dabigatran therapy, the woman's primary care physician referred her to our anticoagulation clinic, where her point-of-care INR was 7.2. A laboratory INR performed approximately 30 minutes later was 1.7. Several repeat point-of-care INRs were elevated and discordant with the laboratory INRs. A second patient, a 52-year-old man, was started on dabigatran after an ablation procedure, as a bridge to warfarin. Approximately 16 hours after a single dose of dabigatran etexilate 150 mg, the point-of-care INR was 1.6. DISCUSSION: Dabigatran etexilate is an oral direct thrombin inhibitor that is approved for use in thromboprophylaxis of atrial fibrillation and deep vein thrombosis. Dabigatran's predictable pharmacokinetic profile allows for a fixed-dose regimen without the need for coagulation monitoring. In certain clinical situations (eg, switching treatment between dabigatran and warfarin), INR testing is performed as part of routine clinical care. During the development program for dabigatran, laboratory testing of INR was performed, with INRs at therapeutic concentrations of dabigatran ranging from 1.1 to 1.7. Supratherapeutic concentrations of dabigatran elevated the INR to slightly higher levels, between 1.7 and 2.4. Even at extremely high dabigatran concentrations, the INR was generally in the range of 2.3-3.5. CONCLUSIONS: We advocate laboratory INR testing with simultaneous assessment of the activated partial thromboplastin time in patients who are receiving or who have recently received dabigatran. A prospective evaluation assessing the accuracy of the commonly used point-of-care INR devices in patients receiving dabigatran would confirm our findings with respect to this device and determine whether our findings extend to other commonly used devices. PMID- 21712512 TI - Rapid onset of iatrogenic adrenal insufficiency in a patient with cystic fibrosis related liver disease treated with inhaled corticosteroids and a moderate CYP3A4 inhibitor. AB - OBJECTIVE: To report the rapid onset of adrenal insufficiency and subsequent development of Cushing syndrome precipitated by a CYP3A4-mediated drug-drug interaction that may have been enhanced by the presence of cystic fibrosis (CF) related liver disease. CASE SUMMARY: A 9-year-old girl with CF and cirrhosis experienced a decline in lung function that led to a diagnosis of asthma. After initiation of asthma therapy with inhaled fluticasone 110 MUg/actuation, the patient experienced improvement in lung function to baseline. Seven weeks after the initiation of inhaled fluticasone, she developed vaginal candidiasis and was prescribed fluconazole 100 mg/day, a CYP3A4 inhibitor. Three days after starting fluconazole, she developed polyuria and polydipsia and was found to have severe hyperglycemia, which led to the diagnosis of Cushing syndrome. Fluticasone was discontinued, and the patient's adrenal function normalized. DISCUSSION: Patients with CF are commonly prescribed complex medication regimens that may affect drug metabolism. CYP3A4 inhibitors may significantly decrease metabolic clearance in patients using chronic inhaled corticosteroids. Iatrogenic Cushing syndrome has been reported in patients with CF treated concomitantly, and for extended duration, with inhaled corticosteroids and CYP3A4 inhibitors. This case highlights rapid onset of adrenal insufficiency in a patient with CF-related liver disease treated briefly with a moderate CYP3A4 inhibitor. Use of the Horn drug interaction probability scale indicates that the interaction between fluticasone and fluconazole was probable. CONCLUSIONS: CYP3A4-mediated drug interactions represent a significant risk in patients treated with long-term inhaled corticosteroids. The presence of clinically significant CF-related liver disease may enhance this risk. PMID- 21712513 TI - Systematic review of the safety of regular preventive asthma medications during pregnancy. AB - OBJECTIVE: To review the safety of regular preventive asthma medications during pregnancy. DATA SOURCES: The following databases were searched from inception to February 2011: Ovid MEDLINE, PubMed, Cochrane Library, EMBASE and CINAHL Plus. STUDY SELECTION AND DATA EXTRACTION: The search was limited to human studies published in the English language. Titles of all articles were screened for relevance. Abstracts of relevant articles were scrutinized to confirm relevance before obtaining full text. DATA SYNTHESIS: Selected articles were read by 2 authors and the accuracy of the data extracted was confirmed. RESULTS: Thirty three articles were included in the final review. Small sample size, missing data, inadequate control for confounding factors, and poor documentation of dosage range were common limitations of the studies reviewed. The use of inhaled corticosteroids, cromolyns, and long-acting beta(2) agonists during pregnancy was not associated with any particular adverse event, although the fluticasone/salmeterol combination has been associated with poor outcomes in postmarketing studies. Congenital malformations have been reported with leukotriene receptor antagonist exposure during pregnancy, but those women also had exposure to other medications, including oral corticosteroids. CONCLUSIONS: Some negative outcomes of preventive asthma medications have been reported, although their direct link with medication use is inconclusive. Selection of preventive medications for asthma management during pregnancy should be based on an assessment of the risks and benefits of medication use versus the risks of poorly controlled asthma. PMID- 21712514 TI - Beta amyloid deposition and neurofibrillary tangles spontaneously occur in the brains of captive cheetahs (Acinonyx jubatus). AB - Alzheimer disease is a dementing disorder characterized pathologically by Abeta deposition, neurofibrillary tangles, and neuronal loss. Although aged animals of many species spontaneously develop Abeta deposits, only 2 species (chimpanzee and wolverine) have been reported to develop Abeta deposits and neurofibrillary tangles in the same individual. Here, the authors demonstrate the spontaneous occurrence of Abeta deposits and neurofibrillary tangles in captive cheetahs (Acinonyx jubatus). Among 22 cheetahs examined in this study, Abeta deposits were observed in 13. Immunostaining (AT8) revealed abnormal intracellular tau immunoreactivity in 10 of the cheetahs with Abeta deposits, and they were mainly distributed in the parahippocampal cortex and CA1 in a fashion similar to that in human patients with Alzheimer disease. Ultrastructurally, bundles of straight filaments filled the neuronal somata and axons, consistent with tangles. Interestingly, 2 of the cheetahs with the most severe abnormal tau immunoreactivity showed clinical cognitive dysfunction. The authors conclude that cheetahs spontaneously develop age-related neurodegenerative disease with pathologic changes similar to Alzheimer disease. PMID- 21712515 TI - Systemic Coxiella-like infection with myocarditis and hepatitis in an eclectus parrot (Eclectus roratus). AB - A multiorgan infection with a Coxiella-like organism was determined to be the cause of death of a female eclectus parrot (Eclectus roratus). The diagnosis was based on gross lesions, histopathology, Gimenez and Gram special stains, immunohistochemistry, electron microscopy, and polymerase chain reaction amplification and sequencing of a bacterial 16s rRNA gene fragment isolated from hepatic and cardiac tissue. Gross postmortem examination revealed multifocal to coalescing foci of hepatic necrosis. The most significant histologic lesions included multifocal lymphohistiocytic necrotizing hepatitis, locally extensive lymphoplasmacytic myocarditis, and myocardial degeneration and necrosis. Intralesional cytoplasmic organisms were identified in cardiomyocytes, biliary epithelium, and pancreatic exocrine cells. This is the first description of a Coxiella-like organism with wide-ranging cellular tropisms in a psittacine bird. In addition, lymphoplasmacytic neuritis, myositis, splenitis, airsacculitis, and enteritis were detected. It is also the first report of a Coxiella-like infection in an eclectus parrot. PMID- 21712516 TI - Mammary tumors with sebaceous differentiation in dogs. PMID- 21712517 TI - Localization of canine, feline, and mouse renal membrane proteins. AB - Immunohistochemistry allows the localization of proteins to specific regions of the nephron. This article reports the identification and localization of proteins in situ within normal canine, feline, and mouse kidney by immunohistochemistry; maps their distribution; and compares results to previously reported findings in other species. The proteins investigated are aquaporin 1, aquaporin 2, calbindin D-28k, glutathione S-transferase-alpha, and Tamm-Horsfall protein. Aquaporins are integral membrane proteins involved in water transport across cell membranes. Calbindin D-28k is involved in renal calcium metabolism. Glutathione S transferase-alpha is a protein that aids in detoxification and drug metabolism. The role of Tamm-Horsfall protein is not fully understood. Proposed functions include inhibition of calcium crystallization and reduction of bacterial urinary tract infection. The authors' findings in the dog are similar to those in other species: Specifically, the authors localize aquaporin 1 to the proximal convoluted tubule epithelium, vasa recta endothelium, and descending thin limbs; aquaporin 2 to collecting duct epithelium; and calbindin D-28k within distal convoluted tubule epithelium. Glutathione S-transferase-alpha has variable expression and is found in only the renal transitional epithelium in some individuals, in only the proximal straight tubules in others, or in both locations in others. Tamm-Horsfall protein localizes to thick ascending limb epithelium. These findings are similar in the cat, with the exception that aquaporin 1 is located in glomerular podocytes, in addition to proximal convoluted tubule epithelium, and glutathione S-transferase-alpha is found solely within the proximal convoluted tubule within all kidney samples examined. The mouse kidney is almost identical to the dog but expresses glutathione S transferase-alpha in the glomeruli only. PMID- 21712518 TI - Temporal trends in cardiogenic shock treatment and outcomes among ontario patients with myocardial infarction between 1992 and 2008. AB - BACKGROUND: Clinical trials have demonstrated that emergent revascularization improves survival of patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). However, rates of uptake and impact on outcomes remain uncertain. METHODS AND RESULTS: We identified 9750 patients (3.1%) with CS among 311 183 AMI patients in the Ontario Myocardial Infarction Database between 1992 and 2008 (55.8% men; mean age, 73 years). CS incidence, mortality, revascularization, and transfers from nonrevascularization sites were studied over 3 periods: period 1, before the 1999 American College of Cardiology/American Heart Association AMI guidelines recommending urgent revascularization for patients <75 years; period 2 (1999 to 2004); and period 3, after 2004 guideline revisions suggesting revascularization for patients >=75 years. Compared with period 1, period 3 was marked by significantly lower CS incidence (3.4% versus 2.6%), increase in transfers from nonrevascularization sites (10.6% versus 23.9%), and adjusted 1-year mortality rates (81.9% versus 71.5%; all comparisons statistically significant). Admission to nonrevascularization sites was associated with lower revascularization rates (8.6% versus 46.6%, P<0.001) and higher adjusted 1-year mortality rates (78.8% [95% confidence interval, 77.4 to 80.2] versus 71.9% [95% confidence interval, 69.8 to 74.1]). Patients >=75 years of age were less likely to be revascularized or transferred. The greatest increase in transfers from nonrevascularization sites occurred between periods 1 and 2 for patients <75 years (16.5% to 31.4%; P<0.001) and between periods 2 and 3 for patients >=75 years (6.7% to 12.8%; P<0.001). CONCLUSIONS: Publication of American College of Cardiology/American Heart Association guidelines was followed by increased revascularization and transfer rates, along with declining mortality rates among Ontario AMI patients with CS. These results highlight possibilities for further improvement, particularly among patients eligible for transfer from nonrevascularization sites. PMID- 21712519 TI - The risk of incident coronary heart disease among veterans with and without HIV and hepatitis C. AB - BACKGROUND: Whether hepatitis C virus (HCV) confers additional coronary heart disease (CHD) risk among human immunodeficiency virus (HIV) infected individuals is unclear. Without appropriate adjustment for antiretroviral therapy, CD4 count, and HIV-1 RNA and substantially different mortality rates among those with and without HIV and HCV infection, the association between HIV, HCV, and CHD may be obscured. METHODS AND RESULTS: We analyzed data on 8579 participants (28% HIV+, 9% HIV+HCV+) from the Veterans Aging Cohort Study Virtual Cohort who participated in the 1999 Large Health Study of Veteran Enrollees. We analyzed data collected on HIV and HCV status, risk factors for and the incidence of CHD, and mortality from January 2000 to July 2007. We compared models to assess CHD risk when death was treated as a censoring event and as a competing risk. During the median 7.3 years of follow-up, there were 194 CHD events and 1186 deaths. Compared with HIV HCV- Veterans, HIV+HCV+ Veterans had a significantly higher risk of CHD regardless of whether death was adjusted for as a censoring event (adjusted hazard ratio, 2.03; 95% confidence interval, 1.28 to 3.21) or a competing risk (adjusted HR, 2.45; 95% confidence interval, 1.83 to 3.27 respectively). Compared with HIV+HCV- Veterans, HIV+HCV+ Veterans also had a significantly higher adjusted risk of CHD regardless of whether death was treated as a censored event (adjusted hazard ratio, 1.93; 95% confidence interval, 1.02 to 3.62) or a competing risk (adjusted hazard ratio, 1.46; 95% confidence interval, 1.03 to 2.07). CONCLUSIONS: HIV+HCV+ Veterans have an increased risk of CHD compared with HIV+HCV- and HIV-HCV- Veterans. PMID- 21712520 TI - Effectiveness of preprocedural statin therapy on clinical outcomes for patients with stable coronary artery disease after percutaneous coronary interventions. AB - BACKGROUND: Data have shown that preprocedural statin therapy reduces periprocedural myocardial infarction after percutaneous coronary intervention (PCI). However, whether preprocedural statins improve clinical outcomes in patients with stable coronary artery disease (CAD) has not been established. We aimed to evaluate the clinical effectiveness of preprocedural statin therapy in patients with stable CAD undergoing PCI. METHODS AND RESULTS: We conducted an observational study of 12 980 patients, age >65 years with stable CAD, who underwent PCI from December 1, 2003, to March 31, 2008. Using propensity score matching analysis, 3098 unique matched pairs (6196 patients) who had similar likelihood of receiving preprocedural statins were identified. Additional analyses adjusting for postprocedural statins as a time-varying variable were performed. The main outcome measure was a composite of death or recurrent acute coronary syndrome. In the propensity-matched cohort, at 90 days, the primary outcome of death and acute coronary syndrome occurred in 5.6% in the preprocedural statin group as compared with 7.4% in the no-pretreatment group (P=0.005). Improved clinical outcomes associated with preprocedural statins were still observed at 2 years (16.7% versus 19.3%, P=0.007). The effectiveness of preprocedural statins was most pronounced at 90 days after PCI (adjusted hazard ratio, 0.80; 95% confidence interval, 0.65 to 0.98) but was no longer significant at 1 year (adjusted hazard ratio, 0.92; 95% confidence interval, 0.79 to 1.07) after accounting for postprocedural statin therapy. CONCLUSIONS: Preprocedural statin therapy was associated with significant reduction in the risk of death or recurrent acute coronary syndrome in stable CAD patients after PCI. These findings support the routine use of preprocedural statins for suitable candidates. PMID- 21712521 TI - The business case for quality improvement: oral anticoagulation for atrial fibrillation. AB - BACKGROUND: The potential to save money within a short time frame provides a more compelling "business case" for quality improvement than merely demonstrating cost effectiveness. Our objective was to demonstrate the potential for cost savings from improved control in patients anticoagulated for atrial fibrillation. METHODS AND RESULTS: Our population consisted of 67 077 Veterans Health Administration patients anticoagulated for atrial fibrillation between October 1, 2006, and September 30, 2008. We simulated the number of adverse events and their associated costs and utilities, both before and after various degrees of improvement in percent time in therapeutic range (TTR). The simulation had a 2 year time horizon, and costs were calculated from the perspective of the payer. In the base-case analysis, improving TTR by 5% prevented 1114 adverse events, including 662 deaths; it gained 863 quality-adjusted life-years and saved $15.9 million compared with the status quo, not accounting for the cost of the quality improvement program. Improving TTR by 10% prevented 2087 events, gained 1606 quality-adjusted life-years, and saved $29.7 million. In sensitivity analyses, costs were most sensitive to the estimated risk of stroke and the expected stroke reduction from improved TTR. Utilities were most sensitive to the estimated risk of death and the expected mortality benefit from improved TTR. CONCLUSIONS: A quality improvement program to improve anticoagulation control probably would be cost-saving for the payer, even if it were only modestly effective in improving control and even without considering the value of improved health. This study demonstrates how to make a business case for a quality improvement initiative. PMID- 21712523 TI - Care processes associated with quicker door-in-door-out times for patients with ST-elevation-myocardial infarction requiring transfer: results from a statewide regionalization program. AB - BACKGROUND: The ability to rapidly identify patients with ST-segment elevation myocardial infarction (STEMI) at hospitals without percutaneous coronary intervention (PCI) and transfer them to hospitals with PCI capability is critical to STEMI regionalization efforts. Our objective was to assess the association of prehospital, emergency department (ED), and hospital processes of care implemented as part of a statewide STEMI regionalization program with door-in door-out times at non-PCI hospitals. METHODS AND RESULTS: Door-in-door-out times for 436 STEMI patients at 55 non-PCI hospitals were determined before (July 2005 to September 2005) and after (January 2007 to March 2007) a year-long implementation of standardized protocols as part of a statewide regionalization program (Reperfusion of Acute Myocardial Infarction in North Carolina Emergency Departments, RACE). The association of 8 system care processes (encompassing emergency medical services [EMS], ED, and hospital settings) with door-in-door out times was determined using multivariable linear regression. Median door-in door-out times improved significantly with the intervention (before: 97.0 minutes, interquartile range, 56.0 to 160.0 minutes; after: 58.0 minutes, interquartile range, 35.0 to 90.0 minutes; P<0.0001). Hospital, ED, and EMS care processes were each independently associated with shorter door-in-door-out times (-17.7 [95% confidence interval, -27.5 to -7.9]; -10.1 [95% confidence interval, 19.0 to -1.1], and -7.3 [95% confidence interval, -13.0 to -1.5] minutes for each additional hospital, ED, and EMS process, respectively). Combined, adoption of EMS processes was associated with the shortest median treatment times (44 versus 138 minutes for hospitals that adopted all EMS processes versus none). CONCLUSIONS: Prehospital, ED, and hospital processes of care were independently associated with shorter door-in-door-out times for STEMI patients requiring transfer. Adoption of several EMS processes was associated with the largest reduction in treatment times. These findings highlight the need for an integrated, system-based approach to improving STEMI care. PMID- 21712522 TI - Upstream use of small-molecule glycoprotein iib/iiia inhibitors in patients with non-ST-segment elevation acute coronary syndromes: a systematic overview of randomized clinical trials. AB - BACKGROUND: The use of upstream small-molecule glycoprotein (GP) IIb/IIIa inhibitors in non-ST-segment elevation acute coronary syndromes (NSTE ACS) has been studied in multiple randomized clinical trials. We systematically reviewed the effect of upstream GP IIb/IIIa inhibitor use in NSTE ACS as reported in published clinical trials. METHODS AND RESULTS: Randomized clinical trials of upstream small-molecule GP IIb/IIIa inhibitors in NSTE ACS were identified through a PubMed and EMBASE search and were included if they contained 30-day outcome data. Odds ratios were generated from the published data and pooled by means of random effects modeling. The primary outcome measures were 30-day death and 30-day death or myocardial infarction. Primary safety measures were major bleeding and transfusion during the index hospitalization. Twelve clinical trials were included, evaluating tirofiban, eptifibatide, and lamifiban. Of these, 7 evaluated upstream GP IIb/IIIa inhibitors versus placebo (n=24 031) and 5 evaluated a strategy of upstream GP IIb/IIIa inhibitors versus upstream placebo with later provisional use at the time of percutaneous coronary intervention (n=19 643). Overall, upstream GP IIb/IIIa inhibitor use was associated with an 11% reduction in 30-day death/myocardial infarction (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.83 to 0.95) but no significant mortality effect (OR, 0.93; 95% CI, 0.83 to 1.05). The risk of major bleeding was 23% higher in patients treated with upstream GP IIb/IIIa inhibitors (OR, 1.23; 95% CI, 1.02 to 1.48). Results were similar when only trials comparing upstream GP IIb/IIIa inhibitors versus placebo were considered: 30-day death/myocardial infarction (OR, 0.88; 95% CI, 0.81 to 0.95); 30-day death (OR, 0.89; 95% CI, 0.76 to 1.03); and major bleeding (OR, 1.17; 95% CI, 0.88 to 1.54). Upstream versus selective use at percutaneous coronary intervention trended toward lower 30-day death/myocardial infarction (OR, 0.91; 95% CI, 0.82 to 1.01) but had no effect on mortality (OR, 1.00; 95% CI, 0.81 to 1.23) and increased major bleeding risk by 34% (OR, 1.34; 95% CI, 1.10 to 1.63). CONCLUSIONS: In NSTE ACS, treatment with upstream small-molecule GP IIb/IIIa inhibitors provides a significant but modest ischemic benefit when compared with initial placebo. Compared with delayed, selective use at percutaneous coronary intervention, early upstream use is associated with a trend toward fewer ischemic events. However, these modest benefits are associated with an increased risk of bleeding. PMID- 21712524 TI - Long-term follow-up of early versus delayed invasive approach after fibrinolysis in acute myocardial infarction. AB - BACKGROUND: Optimal reperfusion strategy in ST-elevation myocardial infarction is controversial. Failure of fibrinolytic therapy is related to limited efficacy, high reocclusion rates, reinfarction, and systemic bleeding complications. Data on the impact of percutaneous coronary intervention (PCI) after fibrinolysis are conflicting. The Southwest German Interventional Study in Acute Myocardial Infarction (SIAM III) evaluated the effects of transfer for early PCI in acute ST elevation-myocardial infarction compared with a delayed PCI strategy. METHODS AND RESULTS: SIAM III was a multicenter, randomized, prospective, controlled trial in patients with ST-elevation-myocardial infarction receiving fibrinolysis <12 hours after onset of symptoms. All patients received reteplase, aspirin in combination with ticlopidine, and heparin. Patients of the early PCI group were transferred within 6 hours after fibrinolysis for PCI. The delayed PCI group received elective PCI 2 weeks after fibrinolysis. In total, 197 patients were included; 163 were treated by PCI. The primary end point was the composite of death, reinfarction, target lesion revascularization, and ischemic events. During a mean follow-up time of 7.9+/-3.4 years (maximum, 11.2 years), early PCI was associated with a significant reduction of the primary end point (hazard ratio, 0.61 [95% confidence interval, 0.42 to 0.88]; P=0.008). Long-term survival was higher in the early PCI group (P=0.057). Ischemic events were significantly reduced after early PCI (P=0.003). CONCLUSIONS: Early PCI after fibrinolysis improves long-term event-free survival compared with a delayed PCI treatment strategy. PMID- 21712525 TI - Changes in left main bifurcation geometry after a single-stent crossover technique: an intravascular ultrasound study using direct imaging of both the left anterior descending and the left circumflex coronary arteries before and after intervention. AB - BACKGROUND: We assessed geometric changes responsible for acute lumen loss at the left circumflex coronary artery (LCX) ostium after crossover stenting from the left anterior descending coronary artery (LAD) to the left main artery. METHODS AND RESULTS: Twenty-three left main artery bifurcation lesions with a preprocedural angiographic diameter stenosis <50% at the LCX ostium were evaluated using prestenting and poststenting intravascular ultrasound pullbacks from both the LAD and the LCX. At the minimal lumen area (MLA) sites within the LCX ostium and at the LCX carina, the lumen, stent, plaque+media (P+M), and external elastic membrane (EEM) areas were measured; the EEM eccentricity was calculated at the LCX carina. The change in MLA within the LCX ostium (DeltaL), the change in EEM area at the MLA site (DeltaV), and the change in P+M area at the MLA site (DeltaP) were calculated. The MLA within the LCX ostium significantly decreased from 5.4 mm(2) (first and third quartiles, 4.3 mm(2), 7.2 mm(2)) prestenting to 4.0 mm(2) (3.0 mm(2), 4.8 mm(2)) poststenting (P<0.001). The percent change in MLA within the LCX ostium correlated with changes in EEM eccentricity (r=-0.414, P=0.049) and percent change in EEM area at the MLA site (r=0.626, P=0.001). A smaller distal carina angle between the LAD and the LCX before stenting was associated with a greater percent reduction in lumen (r=0.472, P=0.023) and EEM (r=0.402, P=0.048) after stenting. In 18 lesions with >10% reduction of MLA within the LCX ostium despite the lack of direct relationship between DeltaL and DeltaP at the MLA site, DeltaP closely correlated with the ratio of DeltaV to DeltaL (r=-0.953, P<0.001), suggesting that an increase in plaque at the LCX ostium contributed to the MLA loss relative to the decrease in EEM area. CONCLUSIONS: Lumen loss at the LCX ostium frequently occurred after crossover stenting from the distal LM to the LAD. The main mechanism was carina shift that was associated with a narrow angle between the LAD and LCX. PMID- 21712526 TI - Potent long-term cardioprotective effects of single low-dose insulin-like growth factor-1 treatment postmyocardial infarction. AB - BACKGROUND: Insulin-like growth factor-1 (IGF-1) is recognized as an important regulator of cardiac structure and cardiomyocyte homeostasis. The prosurvival and antiapoptotic effects of IGF-1 have been investigated in vitro and in rodent models of myocardial infarction (MI). However, the clinical application of IGF-1 has been hampered by dose-dependent side effects both acutely and during chronic administration. We hypothesized that single, low-dose IGF-1 (LD-IGF-1) administered locally and early in the reperfusion phase after acute MI in a large animal model would avoid significant side effects but would have prosurvival effects that would manifest in long-term structural and functional improvement after MI treatment. METHODS AND RESULTS: Forty-four female Landrace pigs underwent intracoronary administration of LD-IGF-1 or saline 2 hours into the reperfusion phase of acute left anterior descending artery occlusion MI. In the area of infarction, IGF-1 receptor and signaling responses were activated at 30 minutes and cardiomyocyte cell death attenuated at 24 hours after LD-IGF-1 but not saline treatment. Hemodynamic and structural studies using pressure-volume loop, CT, and triphenyltetrazolium chloride analysis 2 months post-MI confirmed a marked reduction in infarct size, attenuation of wall thinning, and augmentation of wall motion in the LD-IGF-1-treated but not in the saline-treated animals. These regional structural benefits were associated with global reductions in left ventricular volumes and significant improvement in left ventricular systolic and diastolic function. CONCLUSIONS: One-time LD-IGF-1 effects potent acute myocardial salvage in a preclinical model of left anterior descending artery occlusive MI, extending to long-term benefits in MI size, wall structure, and function and underscoring its potential as an adjunctive therapeutic agent. PMID- 21712528 TI - Prevention of melanoma with regular sunscreen use. PMID- 21712529 TI - Lipopolysaccharide-induced pulpitis up-regulates TRPV1 in trigeminal ganglia. AB - Tooth pain often accompanies pulpitis. Accumulation of lipopolysaccharides (LPS), a product of Gram-negative bacteria, is associated with painful clinical symptoms. However, the mechanisms underlying LPS-induced tooth pain are not clearly understood. TRPV1 is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and hyperalgesia under inflammation or injury. Although TRPV1 is expressed in pulpal afferents, it is not known whether the application of LPS to teeth modulates TRPV1 in trigeminal nociceptors. By assessing the levels of protein and transcript of TRPV1 in mouse trigeminal ganglia, we demonstrate that dentinal application of LPS increases the expression of TRPV1. Our results suggest that the up-regulation of TRPV1 in trigeminal nociceptors following bacterial infection could contribute to hyperalgesia under pulpitis conditions. PMID- 21712527 TI - Sirolimus-eluting stent implantation for ostial left anterior descending coronary artery lesions: three-year outcome from the j-Cypher Registry. AB - BACKGROUND: Ostial left anterior descending coronary artery (LAD) lesion has been regarded as a lesion subset unsuitable for coronary stenting. Long-term outcomes of sirolimus-eluting stent (SES) implantation for ostial LAD lesions have not been adequately evaluated. METHODS AND RESULTS: Among 12 824 patients enrolled in the j-Cypher Registry, 3-year outcomes were compared between 481 patients with SES-treated ostial LAD lesions and 5369 patients with SES-treated nonostial proximal LAD lesions. Patients with ostial LAD lesions had similar incidences of target lesion revascularization (TLR) as those with nonostial proximal LAD lesions (9.4% versus 9.7%; P=0.98; adjusted hazard ratio [HR], 0.99; 95% CI, 0.7 to 1.36; P=0.94) and death/myocardial infarction (MI) (10.7% versus 11.4%; P=0.82; adjusted HR, 1.05; 95% CI, 0.76 to 1.4; P=0.77). Among the patients with ostial LAD lesions, those undergoing both main and side branch stenting (n=62) compared to main branch stenting alone (n=419) had a higher risk for TLR (adjusted HR, 4.65; 95% CI, 2.32 to 9.25; P<0.0001) but similar risk for death/MI (adjusted HR, 1.15; 95% CI, 0.49 to 2.41; P=0.73). In patients with main branch stenting alone, outcomes after crossover stenting across the circumflex coronary artery (n=225) were not different from those after ostial stenting (n=194) for TLR (adjusted HR, 0.77; 95% CI, 0.33 to 1.82; P=0.55) and for death/MI (adjusted HR, 1.54; 95% CI, 0.78 to 3.2; P=0.22). CONCLUSIONS: In terms of both safety and efficacy, 3-year outcomes of percutaneous coronary intervention using SES for ostial LAD lesions were comparable to those for nonostial proximal LAD lesions. Crossover stenting with a 1-stent approach might be a reasonable option in treating ostial LAD lesions. PMID- 21712530 TI - Decreased plasma ghrelin contributes to anorexia following novelty stress. AB - We hypothesized that anorexia induced by novelty stress caused by exposure to a novel environment may be due to activation of corticotropin-releasing factor (CRF) and subsequently mediated by decreasing peripheral ghrelin concentration via serotonin (5-HT) and melanocortin-4 receptors (MC4R). Each mouse was transferred from group-housed cages to individual cages to establish the novelty stress. We observed the effect of changes in feeding behavior in a novel environment using the method of transferring group-housed mice to individual cages. We investigated the effect of an intracerebroventricular injection of antagonists/agonists of CRF1/2 receptors (CRF1/2Rs), 5-HT(1B)/(2C) receptors (5 HT(1B)/(2C)R), and MC4R to clarify the role of each receptor on the decrease in food intake. Plasma ghrelin levels were also measured. The novelty stress caused a reduction in food intake that was abolished by administering a CRF1R antagonist. Three hours after the novelty stress, appetite reduction was associated with reduced levels of neuropeptide Y/agouti-related peptide mRNA, increased levels of proopiomelanocortin mRNA in the hypothalamus, and a decrease in plasma ghrelin level. Administering a CRF1R antagonist, a 5-HT(1B)/(2C)R antagonist, an MC4R antagonist, exogenous ghrelin, and an enhancer of ghrelin secretion, rikkunshito, resolved the reduction in food intake 3 h after the novelty stress by enhancing circulating ghrelin concentrations. We showed that anorexia during a novelty stress is a process in which CRF1R is activated at the early stage of appetite loss and is subsequently activated by a 5-HT(1B)/(2C)R and MC4R stimulus, leading to decreased peripheral ghrelin concentrations. PMID- 21712531 TI - Increased adiposity in DNA binding-dependent androgen receptor knockout male mice associated with decreased voluntary activity and not insulin resistance. AB - In men, as testosterone levels decrease, fat mass increases and muscle mass decreases. Increased fat mass in men, in particular central obesity, is a major risk factor for type 2 diabetes, cardiovascular disease, and all-cause mortality. Testosterone treatment has been shown to decrease fat mass and increase fat-free mass. We hypothesize that androgens act directly via the DNA binding-dependent actions of the androgen receptor (AR) to regulate genes controlling fat mass and metabolism. The aim of this study was to determine the effect of a global DNA binding-dependent (DBD) AR knockout (DBD-ARKO) on the metabolic phenotype in male mice by measuring body mass, fat mass, food intake, voluntary physical activity, resting energy expenditure, substrate oxidation rates, serum glucose, insulin, lipid, and hormone levels, and metabolic gene expression levels and second messenger protein levels. DBD-ARKO males have increased adiposity despite a decreased total body mass compared with wild-type (WT) males. DBD-ARKO males showed reduced voluntary activity, decreased food intake, increased serum leptin and adiponectin levels, an altered lipid metabolism gene profile, and increased phosphorylated CREB levels compared with WT males. This study demonstrates that androgens acting via the DNA binding-dependent actions of the AR regulate fat mass and metabolism in males and that the increased adiposity in DBD-ARKO male mice is associated with decreased voluntary activity, hyperleptinemia and hyperadiponectinemia and not with insulin resistance, increased food intake, or decreased resting energy expenditure. PMID- 21712532 TI - O-linked beta-N-acetylglucosamine supports p38 MAPK activation by high glucose in glomerular mesangial cells. AB - Hyperglycemia augments flux through the hexosamine biosynthetic pathway and subsequent O-linkage of single beta-N-acetyl-d-glucosamine moieties to serine and threonine residues on cytoplasmic and nuclear proteins (O-GlcNAcylation). Perturbations in this posttranslational modification have been proposed to promote glomerular matrix accumulation in diabetic nephropathy, but clear evidence and mechanism are lacking. We tested the hypothesis that O-GlcNAcylation enhances profibrotic signaling in rat mesangial cells. An adenovirus expressing shRNA directed against O-GlcNAc transferase (OGT) markedly reduced basal and high glucose-stimulated O-GlcNAcylation. Interestingly, O-GlcNAc depletion prevented high-glucose-induced p38 mitogen-activated protein kinase (MAPK) and c-Jun NH(2) terminal kinase phosphorylation. Downstream of p38, O-GlcNAc controlled the expression of plasminogen activator inhibitor-1, fibronectin, and transforming growth factor-beta, important factors in matrix accumulation in diabetic nephropathy. Treating mesangial cells with thiamet-G, a highly selective inhibitor of O-GlcNAc-specific hexosaminidase (O-GlcNAcase), increased O GlcNAcylation and p38 phosphorylation. The high-glucose-stimulated kinase activity of apoptosis signal-regulating kinase 1 (ASK1), an upstream MAPK kinase kinase for p38 that is negatively regulated by Akt, was inhibited by OGT shRNA. Akt Thr(308) and Ser(473) phosphorylation were enhanced following OGT shRNA expression in high-glucose-exposed mesangial cells, but high-glucose-induced p38 phosphorylation was not attenuated by OGT shRNA in cells pretreated with the phosphatidylinositol 3-kinase inhibitor LY-294002. OGT shRNA also reduced high glucose-stimulated reactive oxygen species (ROS) formation. In contrast, diminished O-GlcNAcylation caused elevated ERK phosphorylation and PKCdelta membrane translocation. Thus, O-GlcNAcylation is coupled to profibrotic p38 MAPK signaling by high glucose in part through Akt and possibly through ROS. PMID- 21712533 TI - Intramyocellular lipid content and insulin sensitivity are increased following a short-term low-glycemic index diet and exercise intervention. AB - The relationship between intramyocellular (IMCL) and extramyocellular lipid (EMCL) accumulation and skeletal muscle insulin resistance is complex and dynamic. We examined the effect of a short-term (7-day) low-glycemic index (LGI) diet and aerobic exercise training intervention (EX) on IMCL and insulin sensitivity in older, insulin-resistant humans. Participants (66 +/- 1 yr, BMI 33 +/- 1 kg/m(2)) were randomly assigned to a parallel, controlled feeding trial [either an LGI (LGI/EX, n = 7) or high GI (HGI/EX, n = 8) eucaloric diet] combined with supervised exercise (60 min/day, 85% HR(max)). Insulin sensitivity was determined via 40 mU.m(-2).min(-1) hyperinsulinemic euglycemic clamp and soleus IMCL and EMCL content was assessed by (1)H-MR spectroscopy with correction for fiber orientation. BMI decreased (kg/m(2) -0.6 +/- 0.2, LGI/EX; -0.7 +/- 0.2, HGI/EX P < 0.0004) after both interventions with no interaction effect of diet composition. Clamp-derived insulin sensitivity increased by 0.91 +/- 0.21 (LGI/EX) and 0.17 +/- 0.55 mg.kg(-1).min(-1) (HGI/EX), P = 0.04 (effect of time). HOMA-IR was reduced by -1.1 +/- 0.4 (LGI/EX) and -0.1 +/- 0.2 (HGI/EX), P = 0.007 (effect of time), P = 0.02 (time * trial). Although both interventions increased IMCL content, (Delta: 2.3 +/- 1.3, LGI/EX; 1.4 +/- 0.9, HGI/EX, P = 0.03), diet composition did not significantly effect the increase. However, the LGI/EX group showed a robust increase in the [IMCL]/[EMCL] ratio compared with the HGI/EX group (Delta: 0.5 +/- 0.2 LGI/EX vs. 0.07 +/- 0.1, P = 0.03). The LGI/EX group also demonstrated greater reductions in [EMCL] than the HGI/EX group (Delta: -5.8 +/- 3.4, LGI/EX; 2.3 +/- 1.1, HGI/EX, P = 0.03). Changes in muscle lipids and insulin sensitivity were not correlated; however, the change in [IMCL]/[EMCL] was negatively associated with the change in FPI (r = -0.78, P = 0.002) and HOMA-IR (r = -0.61, P = 0.03). These data suggest that increases in the IMCL pool following a low glycemic diet and exercise intervention may represent lipid repartitioning from EMCL. The lower systemic glucose levels that prevail while eating a low glycemic diet may promote redistribution of lipid stores in the muscle. PMID- 21712534 TI - Maternal prenatal undernutrition programs adipose tissue gene expression in adult male rat offspring under high-fat diet. AB - Several studies have shown that maternal undernutrition leading to low birth weight predisposes offspring to the development of metabolic pathologies such as obesity. Using a model of prenatal maternal 70% food restriction diet (FR30) in rat, we evaluated whether postweaning high-fat (HF) diet would amplify the phenotype observed under standard diet. We investigated biological parameters as well as gene expression profile focusing on white adipose tissues (WAT) of adult offspring. FR30 procedure does not worsen the metabolic syndrome features induced by HF diet. However, FR30HF rats displayed catch-up growth to match the body weight of adult control HF animals, suggesting an increase of adiposity while showing hyperleptinemia and a blunted increase of corticosterone. Using quantitative RT-PCR array, we demonstrated that FR30HF rats exhibited leptin and Ob-Rb as well as many peptide precursor and receptor gene expression variations in WAT. We also showed that the expression of genes involved in adipogenesis was modified in FR30HF animals in a depot-specific manner. We observed an opposite variation of STAT3 phosphorylation levels, suggesting that leptin sensitivity is modified in WAT adult FR30 offspring. We demonstrated that 11beta-HSD1, 11beta HSD2, GR, and MR genes are coexpressed in WAT and that FR30 procedure modifies gene expression levels, especially under HF diet. In particular, level variation of 11beta-HSD2, whose protein expression was detected by Western blotting, may represent a novel mechanism that may affect WAT glucocorticoid sensitivity. Data suggest that maternal undernutrition differently programs the adult offspring WAT gene expression profile that may predispose for altered fat deposition. PMID- 21712536 TI - New gene targets for glucagon-like peptide-1 during embryonic development and in undifferentiated pluripotent cells. AB - In humans, glucagon-like peptide (GLP-1) functions during adult life as an incretin hormone with anorexigenic and antidiabetogenic properties. Also, the therapeutic potential of GLP-1 in preventing the adipocyte hyperplasia associated with obesity and in bolstering the maintenance of human mesenchymal stem cell (hMSC) stores by promoting the proliferation and cytoprotection of hMSC seems to be relevant. Since these observations suggest a role for GLP-1 during developmental processes, the aim of the present work was to characterize GLP-1 in early development as well as its gene targets in mouse embryonic stem (mES) cells. Mouse embryos E6, E8, and E10.5 and pluripotent mES were used for the inmunodetection of GLP-1 and GLP-1 receptor. Quantitative real-time PCR was used to determine the expression levels of GLP-1R in several tissues from E12.5 mouse embryos. Additionally, GLP-1 gene targets were studied in mES by multiple gene expression analyses. GLP-1 and its receptors were identified in mES and during embryonic development. In pluripotent mES, GLP-1 modified the expression of endodermal, ectodermal, and mesodermal gene markers as well as sonic hedgehog, noggin, members of the fibroblast and hepatic growth factor families, and others involved in pancreatic development. Additionally, GLP-1 promoted the expression of the antiapoptotic gene bcl2 and at the same time reduced proapoptotic caspase genes. Our results indicate that apart from the effects and therapeutic benefits of GLP-1 in adulthood, it may have additional gene targets in mES cells during embryonic life. Furthermore, the pathophysiological implications of GLP-1 imbalance in adulthood may have a counterpart during development. PMID- 21712535 TI - Absence of fatty acid transporter CD36 protects against Western-type diet-related cardiac dysfunction following pressure overload in mice. AB - Cardiac patients often are obese and have hypertension, but in most studies these conditions are investigated separately. Here, we aimed at 1) elucidating the interaction of metabolic and mechanophysical stress in the development of cardiac dysfunction in mice and 2) preventing this interaction by ablation of the fatty acid transporter CD36. Male wild-type (WT) C57Bl/6 mice and CD36(-/-) mice received chow or Western-type diet (WTD) for 10 wk and then underwent a sham surgery or transverse aortic constriction (TAC) under anesthesia. After a 6-wk continuation of the diet, cardiac function, morphology, lipid profiles, and molecular parameters were assessed. WTD administration affected body and organ weights of WT and CD36(-/-) mice, but it affected only plasma glucose and insulin concentrations in WT mice. Cardiac lipid concentrations increased in WT mice receiving WTD, decreased in CD36(-/-) on chow, and remained unchanged in CD36(-/ ) receiving WTD. TAC induced cardiac hypertrophy in WT mice on chow but did not affect cardiac function and cardiac lipid concentrations. WTD or CD36 ablation worsened the outcome of TAC. Ablation of CD36 protected against the WTD-related aggravation of cardiac functional and structural changes induced by TAC. In conclusion, cardiac dysfunction and remodeling worsen when the heart is exposed to two stresses, metabolic and mechanophysical, at the same time. CD36 ablation prevents the metabolic stress resulting from a WTD. Thus, metabolic conditions are a critical factor for the compromised heart and provide new targets for metabolic manipulation in cardioprotection. PMID- 21712537 TI - Residues Arg568 and Phe592 contribute to an antigenic surface for anti-ADAMTS13 antibodies in the spacer domain. AB - BACKGROUND: The majority of patients diagnosed with thrombotic thrombocytopenic purpura have autoantibodies directed towards the spacer domain of ADAMTS13. DESIGN AND METHODS: In this study we explored the epitope specificity and immunoglobulin class and immunoglobulin G subclass distribution of anti-ADAMTS13 antibodies. The epitope specificity of anti-spacer domain antibodies was examined using plasma from 48 patients with acute acquired thrombotic thrombocytopenic purpura by means of immunoprecipitation of ADAMTS13 variants containing single or multiple alanine substitutions. Using similar methods, we also determined the presence of anti-TSP2-8 and CUB1-2 domain antibodies in this cohort of patients. RESULTS: Antibody profiling revealed that anti-ADAMTS13 immunoglobulin G1 and immunoglobulin G4 predominate in plasma of patients with acquired thrombotic thrombocytopenic purpura. Analysis of anti-spacer domain antibodies revealed that Arg568 and Phe592, in addition to residues Arg660, Tyr661, and Tyr665, also contribute to an antigenic surface in the spacer domain. The majority of patients (90%) lost reactivity towards the spacer domain following introduction of multiple alanine substitutions at Arg568, Phe592, Arg660, Tyr661 and Tyr665. Anti TSP2-8 and anti-CUB1-2 domain-directed antibodies were present in, respectively, 17% and 35% of the patients' samples analyzed. CONCLUSIONS: Immunoglobulin G directed towards a single antigenic surface comprising residues Arg568, Phe592, Arg660, Tyr661 and Tyr665 predominates in the plasma of patients with acquired thrombotic thrombocytopenic purpura. PMID- 21712538 TI - Anti-tumor activity and signaling events triggered by the isothiocyanates, sulforaphane and phenethyl isothiocyanate, in multiple myeloma. AB - BACKGROUND: Isothiocyanates, a family of phytochemicals found in cruciferous vegetables, have cytotoxic effects against several types of tumor cells. Multiple myeloma is a fatal disease characterized by clonal proliferation of plasma cells in the bone marrow. The growing body of preclinical information on the anti cancer activity of isothiocyanates led us to investigate their anti-myeloma properties. DESIGN AND METHODS: We evaluated the anti-myeloma activity of the isothiocyanates, sulforaphane and phenethyl isothiocyanate, on a panel of human myeloma cell lines as well as primary myeloma tumor cells. Cell viability, apoptosis, cell cycle alterations and cell proliferation were then analyzed in vitro and in a xenograft mouse model in vivo. The molecular sequelae of isothiocyanate treatment in multiple myeloma cells were evaluated by multiplex analyses using bead arrays and western blotting. RESULTS: We observed that sulforaphane and phenylethyl isothiocyanate have activity against myeloma cell lines and patients' myeloma cells both in vitro and in vivo using a myeloma xenograft mouse model. Isothiocyanates induced apoptotic death of myeloma cells; depletion of mitochondrial membrane potential; cleavage of PARP and caspases-3 and -9; as well as down-regulation of anti-apoptotic proteins including Mcl-1, X IAP, c-IAP and survivin. Isothiocyanates induced G(2)/M cell cycle arrest accompanied by mitotic phosphorylation of histone H3. Multiplex analysis of phosphorylation of diverse components of signaling cascades revealed changes in MAPK activation; increased phosphorylation of c-jun and HSP27; as well as changes in the phosphorylation of Akt, and GSK3alpha/beta and p53. Isothiocyanates suppressed proliferation of myeloma cells alone and when co-cultured with HS-5 stromal cells. Sulforaphane and phenylethyl isothiocyanate enhanced the in vitro anti-myeloma activity of several conventional and novel therapies used in multiple myeloma. CONCLUSIONS: Our study shows that isothiocyanates have potent anti-myeloma activities and may enhance the activity of other anti-multiple myeloma agents. These results indicate that isothiocyanates may have therapeutic potential in multiple myeloma and provide the preclinical framework for future clinical studies of isothiocyanates in multiple myeloma. PMID- 21712539 TI - On the potential involvement of CD11d in co-stimulating the production of interferon-gamma by natural killer cells upon interaction with neutrophils via intercellular adhesion molecule-3. AB - Interaction between neutrophils and other leukocytes plays a variety of important roles in regulating innate and adaptive immune responses. Recently, we have shown that neu-trophils amplify NK cell/6-sulfo LacNAc(+) dendritic cells (slanDC) mediated cytokine production, by potentiating IL-12p70 release by slanDC via CD18/ICAM-1 and directly co-stimulating IFNgamma production by NK cells via ICAM 3. Herein, we have identified additional molecules involved in the interactions among neutrophils, NK cells and slanDC. More specifically, we provide evidence that: i) the cross-talk between neutrophils and NK cells is mediated by ICAM-3 and CD11d/CD18, respectively; ii) slanDC potentiate the production of IFNgamma by NK cells via CD11a/CD18. Altogether, our studies shed more light on the role that adhesion molecules play within the neutrophil/NK cell/slanDC network. Our data also have potential implications in the pathogenesis of diseases driven by hyperactivated leukocytes, such as Sweet's syndrome, in which a neutrophil/NK cell co-localization is frequently observed. PMID- 21712540 TI - Disruption of the ASXL1 gene is frequent in primary, post-essential thrombocytosis and post-polycythemia vera myelofibrosis, but not essential thrombocytosis or polycythemia vera: analysis of molecular genetics and clinical phenotypes. AB - BACKGROUND: The myeloproliferative neoplasms, essential thrombocytosis, polycythemia vera and primary myelofibrosis, share the same acquired genetic lesion, but the concept of JAK2 V617F serving as the sole lesion responsible for these neoplasms is under question, and there has been interest in identifying additional mutations that may contribute to disease pathogenesis. Because ASXL1 lesions have been increasingly identified in myeloid neoplasms, we examined the relationships of ASXL1 mutation or deletion to both clinical phenotype and associated molecular features in 166 patients with myeloproliferative neoplasms. DESIGN AND METHODS: Exon 12 of ASXL1 was amplified from neutrophil genomic DNA and bidirectionally sequenced in 77 patients with myelofibrosis (including patients with primary and post-essential thrombocytosis or post-polycythemia myelofibrosis), 42 patients with polycythemia vera, 41 with essential thrombocytosis and 6 with post-myelofibrosis acute myeloid leukemia. Pyrosequencing assays were designed to determine the allele percentages of JAK2 V617F (G5073770T), ASXL1 2475dupA, and ASXL1 2846_2847del in neutrophil genomic DNA samples. Clinical and laboratory characteristics of patients with wild-type and ASXL1 mutations were then compared. RESULTS: We identified nonsense mutations or hemizygous deletion of ASXL1 in 36% of the patients with myelofibrosis, but very rarely among those with polycythemia vera or essential thrombocytosis. Among the patients with myelofibrosis, those with ASXL1 lesions were not distinguished from their wild-type counterparts with regard to JAK2 V617F status, exposure to chemotherapy or evolution to leukemia. Myelofibrosis patients with ASXL1 lesions were more likely to have received anemia-directed therapy compared to those without lesions [15/26 (58%) versus 11/39 (23%); P=0.02]. Using serial banked samples and quantitative ASXL1 mutant allele burden assays, we observed the acquisition and accumulation of ASXL1 mutations over time in two patients with post-essential thrombocytosis myelofibrosis. CONCLUSIONS: ASXL1 haploinsufficiency is associated with a myelofibrosis phenotype in the context of other known and unknown lesions, and disruption of ASXL1 function may contribute to the disease pathogenesis of myelofibrosis. PMID- 21712542 TI - The European Medicines Agency review of eltrombopag (Revolade) for the treatment of adult chronic immune (idiopathic) thrombocytopenic purpura: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. AB - On 11(th) March 2010, the European Commission issued a marketing authorization valid throughout the European Union for Revolade for the treatment of adult chronic immune (idiopathic) thrombocytopenic purpura. Revolade is an orphan medicinal product indicated for splenectomized patients with immune (idiopathic) thrombocytopenic purpura who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) and as second-line treatment for non splenectomized patients where surgery is contraindicated. The active substance of Revolade is eltrombopag (ATC code B02BX05). Eltrombopag increases platelet production through activation of the thrombopoietin receptor. The recommended oral dose is 50 mg once daily to achieve and maintain a platelet count of the 50*10(9)/L or more necessary to reduce or prevent the risk of bleeding. The benefit of Revolade is a durable response in maintaining platelet levels. The most common side effects include headache, nausea, hepatobiliary toxicity, diarrhea, fatigue, paresthesia, constipation, rash, pruritus, cataract, arthralgia and myalgia. The decision to grant the marketing authorization was based on the favorable recommendation of the Committee for Medicinal Products for Human Use of the European Medicines Agency. The objective of this paper is to describe the data submitted to the European Medicines Agency and to summarize the scientific review of the application. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (www.ema.europa.eu). PMID- 21712541 TI - Over-expression of mitochondrial ferritin affects the JAK2/STAT5 pathway in K562 cells and causes mitochondrial iron accumulation. AB - BACKGROUND: Mitochondrial ferritin is a nuclear encoded iron-storage protein localized in mitochondria. It has anti-oxidant properties related to its ferroxidase activity, and it is able to sequester iron avidly into the organelle. The protein has a tissue-specific pattern of expression and is also highly expressed in sideroblasts of patients affected by hereditary sideroblastic anemia and by refractory anemia with ringed sideroblasts. The present study examined whether mitochondrial ferritin has a role in the pathogenesis of these diseases. DESIGN AND METHODS: We analyzed the effect of mitochondrial ferritin over expression on the JAK2/STAT5 pathway, on iron metabolism and on heme synthesis in erythroleukemic cell lines. Furthermore its effect on apoptosis was evaluated on human erythroid progenitors. RESULTS: Data revealed that a high level of mitochondrial ferritin reduced reactive oxygen species and Stat5 phosphorylation while promoting mitochondrial iron loading and cytosolic iron starvation. The decline of Stat5 phosphorylation induced a decrease of the level of anti apoptotic Bcl-xL transcript compared to that in control cells; however, transferrin receptor 1 transcript increased due to the activation of the iron responsive element/iron regulatory protein machinery. Also, high expression of mitochondrial ferritin increased apoptosis, limited heme synthesis and promoted the formation of Perls-positive granules, identified by electron microscopy as iron granules in mitochondria. CONCLUSIONS: Our results provide evidence suggesting that Stat5-dependent transcriptional regulation is displaced by strong cytosolic iron starvation status induced by mitochondrial ferritin. The protein interferes with JAK2/STAT5 pathways and with the mechanism of mitochondrial iron accumulation. PMID- 21712543 TI - Focus issue: choreographing the dance of the mitotic kinases. AB - Phosphoproteomic analysis of mammalian or yeast cells arrested in mitosis provides a comprehensive view of how phosphorylation contributes to this process, and the research highlighted in this issue implicates previously unrecognized players in this complex process of cell division. Analysis of substrate selectivity and the motifs targeted by specific kinases suggests that cells combine negative and positive site selection, along with spatial segregation, to ensure that the multiple kinases that participate in mitosis find their proper targets. Because alterations in the activities of these kinases can lead to uncontrolled cell proliferation and because of their essential roles in regulating cell division, these kinases are the targets of anticancer therapeutic agents. The research highlighted in this issue not only provides rich data sets for future investigation but also has the potential to lead to the development of new treatments aimed at reining in uncontrolled cell proliferation. PMID- 21712544 TI - Substrates of mitotic kinases. AB - Most signaling pathways in cells involve numerous phosphorylation reactions. Some of the rules for kinase-substrate specificity are known, but a complete description of all substrates is missing. Research published in Science Signaling addresses the process of mitosis and asks how the relevant kinases recognize substrate sequence motifs and, in the cellular context, what substrates are phosphorylated and where. The results increase our molecular understanding of how individual events are coordinated during the process of cell division and show the importance of both sequence epitopes for kinase specificity and the notion of a sense of place through localization in subcellular compartments. PMID- 21712546 TI - Quantitative phosphoproteomics identifies substrates and functional modules of Aurora and Polo-like kinase activities in mitotic cells. AB - Mitosis is a process involving a complex series of events that require careful coordination. Protein phosphorylation by a small number of kinases, in particular Aurora A, Aurora B, the cyclin-dependent kinase-cyclin complex Cdk1/cyclinB, and Polo-like kinase 1 (Plk1), orchestrates almost every step of cell division, from entry into mitosis to cytokinesis. To discover more about the functions of Aurora A, Aurora B, and kinases of the Plk family, we mapped mitotic phosphorylation sites to these kinases through the combined use of quantitative phosphoproteomics and selective targeting of kinase activities by small-molecule inhibitors. Using this integrated approach, we connected 778 phosphorylation sites on 562 proteins with these enzymes in cells arrested in mitosis. By connecting the kinases to protein complexes, we associated these kinases with functional modules. In addition to predicting previously unknown functions, this work establishes additional substrate-recognition motifs for these kinases and provides an analytical template for further use in dissecting kinase signaling events in other areas of cellular signaling and systems biology. PMID- 21712547 TI - Mitotic substrates of the kinase aurora with roles in chromatin regulation identified through quantitative phosphoproteomics of fission yeast. AB - Kinases of the Aurora family are essential for the proper execution of mitosis in eukaryotes, and Aurora inhibitors are in clinical trials as anticancer drugs. We applied site-specific quantitative phosphoproteomics in conjunction with chemical inhibition of Aurora to identify mitotic Aurora substrates in fission yeast on a proteome-wide scale. We detected 8000 phosphorylation events, of which we assigned almost 6000 to a specific residue; 220 were reduced in cells exposed to the Aurora inhibitor. After controlling for unspecific effects of the inhibitor, we classified 70 sites (on 42 proteins) as probable targets of Aurora, which enabled refinement of the consensus sequence for phosphorylation by Aurora. Several of the substrate candidates were known targets of Aurora, validating the approach, but most represented newly detected Aurora substrates. The involvement of these Aurora substrates in diverse aspects of chromatin dynamics suggests that in addition to its established role in controlling chromosome compaction and attachment to the mitotic spindle, Aurora influences other aspects of chromatin architecture and function during mitosis. PMID- 21712548 TI - Point-of-care assays for hemoglobin A(1c): is performance adequate? PMID- 21712545 TI - Spatial exclusivity combined with positive and negative selection of phosphorylation motifs is the basis for context-dependent mitotic signaling. AB - The timing and localization of events during mitosis are controlled by the regulated phosphorylation of proteins by the mitotic kinases, which include Aurora A, Aurora B, Nek2 (never in mitosis kinase 2), Plk1 (Polo-like kinase 1), and the cyclin-dependent kinase complex Cdk1/cyclin B. Although mitotic kinases can have overlapping subcellular localizations, each kinase appears to phosphorylate its substrates on distinct sites. To gain insight into the relative importance of local sequence context in kinase selectivity, identify previously unknown substrates of these five mitotic kinases, and explore potential mechanisms for substrate discrimination, we determined the optimal substrate motifs of these major mitotic kinases by positional scanning oriented peptide library screening (PS-OPLS). We verified individual motifs with in vitro peptide kinetic studies and used structural modeling to rationalize the kinase-specific selection of key motif-determining residues at the molecular level. Cross comparisons among the phosphorylation site selectivity motifs of these kinases revealed an evolutionarily conserved mutual exclusion mechanism in which the positively and negatively selected portions of the phosphorylation motifs of mitotic kinases, together with their subcellular localizations, result in proper substrate targeting in a coordinated manner during mitosis. PMID- 21712549 TI - Heritability, weak effects, and rare variants in genomewide association studies. PMID- 21712550 TI - Unusual increased beta-globulins in an elderly patient. PMID- 21712551 TI - Commentary. PMID- 21712552 TI - Commentary. PMID- 21712553 TI - What is your guess? Multiple cerebrospinal fluid bands: multiple sclerosis? PMID- 21712556 TI - Consumer e-health: an overview of research evidence and implications for future policy. AB - Consumer e-health is rapidly becoming a fundamental component of healthcare. However, to date only provisional steps have been taken to increase our understanding of how consumers engage with e-health. This study, an interpretive review, assessed the evidence about consumer use of e-health and identified five categories that encompass consumer e-health: (i) peer-to-peer online support groups; (ii) self-management/self-monitoring applications; (iii) decision aids; (iv) the personal health record; and (v) Internet use. Our findings reveal that e health offers consumers many possibilities and potential benefits, although there appears to be apprehension concerning the efficacy of some interventions and barriers relating to the trustworthiness of Internet-acquired information. It is imperative that policy initiatives address these issues to ensure that consumer e health services can be effectively, efficiently, and safely accessed. PMID- 21712557 TI - Developing policies for e-health: use of online health information by Australian health professionals and their patients. AB - An online survey (www.limesurvey.org) was used to identify patterns of usage of health information available on the Internet by five major Australian health professions (AHPs: general practice, social work, dietetics, physiotherapy and optometry. Survey questions were developed to explore participants' responses associated with their level of Internet usage. From the five AHPs (n=746), it was found that social workers and dietitians most frequently recommended health websites to their patients (11-20% of the time throughout a 12-month period [2009]). Health information topics most frequently recommended and brought to health professionals' attention by patients were concerned with "specific health conditions" and the main source professionals used to access health information was identified through the use of "search engines". This study further reports that Internet recommendations from health professionals (1-10%), Internet requests from patients (<1%) and Internet consultation processes (1%), do not mirror similar international research. It is recommended that development of policies that might influence e-health should not be based on a presumption that the use of the Internet for accessing health information is universal or that the Internet strongly influences Australian healthcare delivery. PMID- 21712558 TI - Does attitude matter in computer use in Australian general practice? A zero inflated Poisson regression analysis. AB - The purpose of this study was to explore factors that facilitate or hinder effective use of computers in Australian general medical practice. This study is based on data extracted from a national telephone survey of 480 general practitioners (GPs) across Australia. Clinical functions performed by GPs using computers were examined using a zero-inflated Poisson (ZIP) regression modelling. About 17% of GPs were not using computer for any clinical function, while 18% reported using computers for all clinical functions. The ZIP model showed that computer anxiety was negatively associated with effective computer use, while practitioners' belief about usefulness of computers was positively associated with effective computer use. Being a female GP or working in partnership or group practice increased the odds of effectively using computers for clinical functions. To fully capitalise on the benefits of computer technology, GPs need to be convinced that this technology is useful and can make a difference. PMID- 21712559 TI - Improving quality of service of home healthcare units with health information technologies. AB - Deployment of health information technologies (HITs) provides home care units with the means to generate improvements in accuracy and timeliness of information required to meet dynamic patient demands and provide high quality patient care. Increasing availability of information can also facilitate organisational learning, which leads to the invocation of processes that result in improved responses and decisions. This study examined crucial links between HITs and quality of service provided through an empirical investigation of 252 patients in a hospital-in-the-home unit (HHU) in a Spanish regional hospital. The study sought to test the relationship between HITs and the quality of service using factor analysis and structural equation modeling (SEM) to investigate how HITs mediate effects of organisational learning on quality of service. Findings support the notion that the relationship between organisational learning and quality of service can be mediated by HITs. This study provides HHU managers with guidelines for understanding the role of organisational learning processes with respect to HITs and quality of service. PMID- 21712560 TI - Teratogen information service for pharmacists: a pilot study. AB - We report on the first Helpline for pharmacists dealing with the safety of medications in pregnancy and during breastfeeding. Pharmacists from all parts of Canada participated in this pilot, receiving guidance in approximately 90% of cases. There were 472 inquiries relating to 598 products with regards to safety in pregnancy and 197 calls relating to 249 products regarding exposure in breastfeeding. All callers who were surveyed found the service helpful in counseling both patients and physicians. PMID- 21712561 TI - Language impairments in children with fetal alcohol spectrum disorders. AB - BACKGROUND: Fetal Alcohol Spectrum Disorder (FASD) is associated with a range of disabilities, including physical, behavioural, and cognitive deficits. One specific area of concern in children with FASD is the use and development of speech and language. Language deficits in FASD have been linked to learning problems and social difficulties. OBJECTIVES: The current study sought to examine the language difficulties of children with FASD, and to identify areas of deficit that may be particularly pronounced among these children. METHODS: Fifty children, aged 5 to 13, (27 with FASD, 23 control children) were tested on the CREVT-2, the TOLD-P:3, and the TOLD-I:3. RESULTS: Children with FASD had significantly lower scores than control children on both receptive and expressive subtests of the CREVT-2. Younger children scored significantly lower than controls on the Relational Vocabulary and Sentence Imitation subtests of the TOLD P:3, and older children were significantly delayed on the Word Ordering, Grammatic Comprehension, and Malapropisms subtests of the TOLD-I:3. CONCLUSIONS: This study identified several areas of marked difficulty in children with FASD, adding to the current understanding of language development in this population. The results have implications for tailoring early interventions, and for providing evidence-based support to children prenatally exposed to alcohol. PMID- 21712562 TI - Integrative data analysis in systems biology. PMID- 21712563 TI - Gene regulation in glioblastoma: a combinatorial analysis of microRNAs and transcription factors. AB - Glioblastoma is the most common and most lethal brain tumour in humans. Illustrating the functions being disturbed during carcinogenesis and how they are deregulated is very important for us to understand its underlying mechanism. Transcriptional aberrations may play a vital role in the etiology of glioblastoma, which might be caused by both genomic alterations and other regulation molecules. In this study, we investigated possible cooperative deregulation of microRNAs (miRNAs) and transcription factors (TFs) in glioblastoma, under the hypothesis that miRNAs and TFs might have a combinational regulatory effect on glioblastoma genes. We searched glioblastoma-specific regulatory networks by integrating glioblastoma related miRNAs, TFs and genes, and identified 54 feed-forward loops (FFLs). Follow up functional enrichment analysis of these FFLs uncovered some functions important to carcinogenesis but also some unique functions specific to the FFLs we identified. PMID- 21712564 TI - Integrative identification of core genetic regulatory modules via a structural model-based clustering method. AB - Regulatory modules play fundamental roles in processing and dispatching signals in cell life cycle. Although current clustering methods may reduce data complexity to lower dimension, they tend to neglect biological meanings within high-throughput data. We propose a module-detection algorithm through defining network activity measures and associating them through a weighted clustering approach. We verify our method on diverse models and it provides a unique perspective for analysing model dynamics and expression data, especially with consideration of inherent biological meanings. As it can detect core regulatory modules effectively, it facilitates pathway/network modelling in systems biology. PMID- 21712565 TI - Gene co-expression network and functional module analysis of ovarian cancer. AB - We constructed gene co-expression networks and identified the ovarian cancer related genes by network structure analysis in two independent ovarian cancer studies. To study the properties of networks, modules were identified and their functions and roles were investigated. Our results showed that the inferred networks were structurally conservative and the identified modules were highly overlapped between two data sets. We discovered 42 common hub genes and four common conserved modules, which were enriched with the genes in four cancer related pathways in two independent studies. In addition, we detected two ovarian cancer susceptibility genes: CCEN2 and BRIC5. PMID- 21712566 TI - Multiple genome sequences alignment algorithm based on coding regions. AB - Multiple Sequence Alignment (MSA) is the computational biology tool for facilitating the study of DNA homology, phylogeny determinations and conserved motifs. Many MSA methods have been presented to align protein, DNA, and RNA sequences successfully but not for coding region sequences. Therefore, we propose a heuristic alignment method, CORAL-M, for multiple genome sequences, especially for coding regions. CORAL-M adopts a codon-based probabilistic filtration model and the local optimal alignment solution to align multiple genome sequences in linear time. The experimental results presents that CORAL-M can find more potential function sites than that of other commonly used tools by aligning Enterovirus strains. PMID- 21712567 TI - Integration of clustering and biclustering procedures for analysis of large DNA microarray datasets. AB - In this paper, a new biclustering method is introduced based on a geometric method. The Hough Transform (HT) in column-pair space is used to find sub biclusters and the k-means method is used to optimise the combining process. The experiment results show that the K-means Based Geometric Biclustering (KGBC) algorithm proposed here reduces the computing time for combining sub-biclusters and provides considerably higher classification accuracy compared with existing methods. Experiments on both simulated and real microarray data demonstrate that our method can identify biclusters with different noise levels and overlapping degrees. PMID- 21712568 TI - Exploratory analysis of cell-based screening data for phenotype identification in drug-siRNA study. AB - Most phenotype-identification methods in cell-based screening assume prior knowledge about expected phenotypes or involve intricate parameter-setting. They are useful for analysis targeting known phenotype properties; but need exists to explore, with minimum presumptions, the potentially-interesting phenotypes derivable from data. We present a method for this exploration, using clustering to eliminate phenotype-labelling requirement and GUI visualisation to facilitate parameter-setting. The steps are: outlier-removal, cell clustering and interactive visualisation for phenotypes refinement. For drug-siRNA study, we introduce an auto-merging procedure to reduce phenotype redundancy. We validated the method on two Golgi apparatus screens and showcase its contribution for better understanding of screening-images. PMID- 21712569 TI - Offline comparison of spatial filters for two-dimensional movement control with noninvasive field potentials. AB - Paralyzed individuals can control the movement of an assistive device using changes in electroencephalographic (EEG) power resulting from attempted movements. Simultaneous, proportional control of two-dimensional (2D) device movements can be achieved with the concurrent modulation of brain activity that is associated with the attempted movement and rest of two independent body parts. Movement control may be improved by spatial filtering methods that recombine raw EEGs to form new signals with more focused information about the underlying brain activity. This study compared spatial filters offline for improving simultaneous proportional 2D movement commands from EEGs. Filtering options evaluated were common average referencing, Laplacian, independent component analysis, principle component analysis, and two novel ways of applying common spatial pattern (CSP) analysis. CSP analysis is a supervised algorithm that optimally recombines EEGs collected under two known conditions. Both CSP options resulted in more accurate movement prediction than the other filtering options. CSP was particularly advantageous when separating EEGs associated with neighboring or overlapping areas on the motor homunculus. Finally, CSP performed well using smaller subsets of filtered signals, thus making CSP practical and efficient for simultaneous 2D control. A 2D online cursor control example using CSP filtering is included to show CSP's utility. PMID- 21712570 TI - Common time-frequency analysis of local field potential and pyramidal cell activity in seizure-like events of the rat hippocampus. AB - To study cell-field dynamics, physiologists simultaneously record local field potentials and the activity of individual cells from animals performing cognitive tasks, during various brain states or under pathological conditions. However, apart from spike shape and spike timing analyses, few studies have focused on elucidating the common time-frequency structure of local field activity relative to surrounding cells across different periods of phenomena. We have used two algorithms, multi-window time frequency analysis and wavelet phase coherence (WPC), to study common intracellular-extracellular (I-E) spectral features in spontaneous seizure-like events (SLEs) from rat hippocampal slices in a low magnesium epilepsy model. Both algorithms were applied to 'pairs' of simultaneously observed I-E signals from slices in the CA1 hippocampal region. Analyses were performed over a frequency range of 1-100 Hz. I-E spectral commonality varied in frequency and time. Higher commonality was observed from 1 to 15 Hz, and lower commonality was observed in the 15-100 Hz frequency range. WPC was lower in the non-SLE region compared to SLE activity; however, there was no statistical difference in the 30-45 Hz band between SLE and non-SLE modes. This work provides evidence of strong commonality in various frequency bands of I E SLEs in the rat hippocampus, not only during SLEs but also immediately before and after. PMID- 21712571 TI - True associations between resting fMRI time series based on innovations. AB - We calculated voxel-by-voxel pairwise crosscorrelations between prewhitened resting-state BOLD fMRI time series recorded from 60 cortical areas (30 per hemisphere) in 18 human subjects (nine women and nine men). Altogether, more than a billion-and-a-quarter pairs of BOLD time series were analyzed. For each pair, a crosscorrelogram was computed by calculating 21 crosscorrelations, namely at zero lag +/- 10 lags of 2 s duration each. For each crosscorrelogram, in turn, the crosscorrelation with the highest absolute value was found and its sign, value, and lag were retained for further analysis. In addition, the crosscorrelations at zero lag (irrespective of the location of the peak) were also analyzed as a special case. Based on known varying density of anatomical connectivity, we distinguished four general brain groups for which we derived summary statistics of crosscorrelations between voxels within an area (group I), between voxels of paired homotopic areas across the two hemispheres (group II), between voxels of an area and all other voxels in the same (ipsilateral) hemisphere (group III), and voxels of an area and all voxels in the opposite (contralateral) hemisphere (except those in the homotopic area) (group IV). We found the following. (a) Most of the crosscorrelogram peaks occurred at zero lag, followed by +/- 1 lag; (b) over all groups, positive crosscorrelations were much more frequent than negative ones; (c) average crosscorrelation was highest for group I, and decreased progressively for groups II-IV; (d) the ratio of positive over negative crosscorrelations was highest for group I and progressively smaller for groups II IV; (e) the highest proportion of positive crosscorrelations (with respect to all positive ones) was observed at zero lag; and (f) the highest proportion of negative crosscorrelations (with respect to all negative ones) was observed at lag = 2. These findings reveal a systematic pattern of crosscorrelations with respect to their sign, magnitude, lag and brain group, as defined above. Given that these groups were defined along a qualitative gradient of known overall anatomical connectivity, our results suggest that functional interactions between two voxels may simply reflect the density of such anatomical connectivity between the areas to which the voxels belong. PMID- 21712572 TI - Neurite outgrowth is significantly increased by the simultaneous presentation of Schwann cells and moderate exogenous electric fields. AB - Axonal extension is influenced by a variety of external guidance cues; therefore, the development and optimization of a multi-faceted approach is probably necessary to address the intricacy of functional regeneration following nerve injury. In this study, primary dissociated neonatal rat dorsal root ganglia neurons and Schwann cells were examined in response to an 8 h dc electrical stimulation (0-100 mV mm(-1)). Stimulated samples were then fixed immediately, immunostained, imaged and analyzed to determine Schwann cell orientation and characterize neurite outgrowth relative to electric field strength and direction. Results indicate that Schwann cells are viable following electrical stimulation with 10-100 mV mm(-1), and retain a normal morphology relative to unstimulated cells; however, no directional bias is observed. Neurite outgrowth was significantly enhanced by twofold following exposure to either a 50 mV mm(-1) electric field (EF) or co-culture with unstimulated Schwann cells by comparison to neurons cultured alone. Neurite outgrowth was further increased in the presence of simultaneously applied cues (Schwann cells + 50 mV mm(-1) dc EF), exhibiting a 3.2-fold increase over unstimulated control neurons, and a 1.2-fold increase over either neurons cultured with unstimulated Schwann cells or the electrical stimulus alone. These results indicate that dc electric stimulation in combination with Schwann cells may provide synergistic guidance cues for improved axonal growth relevant to nerve injuries in the peripheral nervous system. PMID- 21712573 TI - Integrated soil-crop system management: reducing environmental risk while increasing crop productivity and improving nutrient use efficiency in China. AB - During the past 47 yr (1961-2007), Chinese cereal production has increased by 3.2 fold, successfully feeding 22% of the global human population with only 9% of the world's arable land, but at high environmental cost and resource consumption. Worse, crop production has been stagnant since 1996 while the population and demand for food continue to rise. New advances for sustainability of agriculture and ecosystem services will be needed during the coming 50 yr to reduce environmental risk while increasing crop productivity and improving nutrient use efficiency. Here, we advocate and develop integrated soil-crop system management (ISSM). In this approach, the key points are (i) to take all possible soil quality improvement measures into consideration, (ii) to integrate the utilization of various nutrient resources and match nutrient supply to crop requirements, and (iii) to integrate soil and nutrient management with high yielding cultivation systems. Recent field experiments have shed light on how ISSM can lead to significant increases in crop yields while increasing nutrient use efficiency and reducing environmental risk. PMID- 21712574 TI - Biofuel development, food security and the use of marginal land in China. AB - With concerns of energy shortages, China, like the United States, European Union, and other countries, is promoting the development of biofuels. However, China also faces high future demand for food and feed, and so its bioenergy program must try to strike a balance between food and fuel. The goals of this paper are to provide an overview of China's current bioethanol program, identify the potential for using marginal lands for feedstock production, and measure the likely impacts of China's bioethanol development on the nation's future food self sufficiency. Our results indicate that the potential to use marginal land for bioethanol feedstock production is limited. Applying a modeling approach based on highly disaggregated data by region, our analysis shows that the target of 10 million t of bioethanol by 2020 seems to be a prudent target, causing no major disturbances in China's food security. But the expansion of bioethanol may increase environmental pressures due to the higher levels of fertilizer use. This study shows also that if China were able to cultivate 45% of its required bioethanol feedstock on new marginal land, it would further limit negative effects of the bioethanol program on the domestic and international economy, but at the expense of having to apply another 750 thousand t of fertilizer. PMID- 21712575 TI - Pesticide risk mitigation by vegetated treatment systems: a meta-analysis. AB - Pesticides entering agricultural surface waters threaten water quality and aquatic communities. Recently, vegetated treatment systems (VTSs) (e.g., constructed wetlands and vegetated ditches) have been proposed as pesticide risk mitigation measures. However, little is known about the effectiveness of VTSs in controlling nonpoint source pesticide pollution and factors relevant for pesticide retention within these systems. Here, we conducted a meta-analysis on pesticide mitigation by VTSs using data from the scientific literature and the European LIFE ArtWET project. Overall, VTSs effectively reduced pesticide exposure levels (i.e., the majority of pesticide retention performances was >70%). A multiple linear regression analysis of 188 retention performance cases identified the two pesticide properties, organic carbon sorption coefficient value and water-phase 50% dissipation time, as well as the VTS characteristics overall plant coverage and hydraulic retention time for targeting high efficacy of pesticide retention. The application of a Tier I risk assessment (EU Uniform Principle) revealed a higher toxicity reduction for hydrophobic and nonpersistent insecticides compared with less sorptive and not readily degradable herbicides and fungicides. Overall, nearly half (48.5%) of all pesticide field concentrations ( = 130) failed Tier I standard risk assessment at the inlet of VTSs, and 29.2% of all outlet concentrations exceeded conservative acute threshold levels. We conclude that VTSs are a suitable and effective risk mitigation strategy for agricultural nonpoint source pesticide pollution of surface waters. Further research is needed to improve their overall efficacy in retaining pesticides. PMID- 21712576 TI - The phosphorus footprint of China's food chain: implications for food security, natural resource management, and environmental quality. AB - Efficient use of phosphorus (P) for producing food, preventing water pollution, and managing a dwindling rock P reserve are major challenges for China. We analyzed P stocks and flows in the Chinese food chain to identify where P use efficiency can be improved, where P leaks to the environment, and the research, technologies, and policies needed to improve P use. We found a high degree of inefficiency; of 6652 Gg P entering the food chain, only 1102 Gg P (18%) exit as food for humans. The greatest inefficiencies were a large build-up of soil P (3670 Gg P yr; 52% of P inputs) and high P losses to the environment from animal production (1582 Gg P yr; 60% of excreted P). Improving P use in China must focus on national-scale nutrient management strategies, better animal nutrition, and adoption of technologies and policies to reduce P discharges from the animal sector and recycle P as manures in agriculture. PMID- 21712577 TI - Daily, monthly, seasonal, and annual ammonia emissions from Southern High Plains cattle feedyards. AB - Ammonia emitted from beef cattle feedyards adds excess reactive N to the environment, contributes to degraded air quality as a precursor to secondary particulate matter, and represents a significant loss of N from beef cattle feedyards. We used open path laser spectroscopy and an inverse dispersion model to quantify daily, monthly, seasonal, and annual NH emissions during 2 yr from two commercial cattle feedyards in the Panhandle High Plains of Texas. Annual patterns of NH fluxes correlated with air temperature, with the greatest fluxes (>100 kg ha d) during the summer and the lowest fluxes (<15 kg ha d) during the winter. Mean monthly per capita emission rate (PCER) of NH-N at one feedyard ranged from 31 g NH-N head d (January) to 207 g NH-N head d (October), when increased dietary crude protein from wet distillers grains elevated emissions. Ammonia N emissions at the other feedyard ranged from 36 g NH-N head d (January) to 121 g NH-N head d (September). Monthly fractional NH-N loss ranged from a low of 19 to 24% to a high of 80 to 85% of fed N at the two feedyards. Seasonal PCER at the two feedyards averaged 60 to 71 g NH-N head d during winter and 103 to 158 g NH-N head d during summer. Annually, PCER was 115 and 80 g NH-N head d at the two feedyards, which represented 59 and 52% of N fed to the cattle. Detailed studies are needed to determine the effect of management and environmental variables such as diet, temperature, precipitation, and manure water content on NH emissions. PMID- 21712578 TI - Stability of odorants from pig production in sampling bags for olfactometry. AB - Odor from pig production facilities is typically measured with olfactometry, whereby odor samples are collected in sampling bags and assessed by human panelists within 30 h. In the present study, the storage stability of odorants in two types of sampling bags that are often used for olfactometry was investigated. The bags were made of Tedlar or Nalophan. In a field experiment, humid and dried air samples were collected from a pig production facility with growing-finishing pigs and analyzed with a gas chromatograph with an amperometric sulfur detector at 4, 8, 12, 28, 52, and 76 h after sampling. In a laboratory experiment, the bags were filled with a humid gas mixture containing carboxylic acids, phenols, indoles, and sulfur compounds and analyzed with proton-transfer-reaction mass spectrometry after 0, 4, 8, 12, and 24 h. The results demonstrated that the concentrations of carboxylic acids, phenols, and indoles decreased by 50 to >99% during the 24 h of storage in Tedlar and Nalophan bags. The concentration of hydrogen sulfide decreased by approximately 30% during the 24 h of storage in Nalophan bags, whereas in Tedlar bags the concentration of sulfur compounds decreased by <5%. In conclusion, the concentrations of odorants in air samples from pig production facilities significantly decrease during storage in Tedlar and Nalophan bags, and the composition changes toward a higher relative presence of sulfur compounds. This can result in underestimation of odor emissions from pig production facilities and of the effect of odor reduction technologies. PMID- 21712579 TI - Fertilizer management effects on nitrate leaching and indirect nitrous oxide emissions in irrigated potato production. AB - Potato ( L.) is a N-intensive crop, with high potential for nitrate (NO) leaching, which can contribute to both water contamination and indirect nitrous oxide (NO) emissions. Two approaches that have been considered for reducing N losses include conventional split application (CSA) of soluble fertilizers and single application of polymer-coated urea (PCU). The objectives of this study were to: (i) compare NO leaching using CSA and two PCUs (PCU-1 and PCU-2), which differed in their polymer formulations, and (ii) use measured NO leaching rates and published emissions factors to estimate indirect NO emissions. Averaged over three growing seasons (2007-2009), NO leaching rates were not significantly different among the three fertilizer treatments. Using previously reported direct NO emissions data from the same experiment, total direct plus indirect growing season NO emissions with PCU-1 were estimated to be 30 to 40% less than with CSA. However, PCU-1 also resulted in greater residual soil N after harvest in 2007 and greater soil-water NO in the spring following the 2008 growing season. These results provide evidence that single PCU applications for irrigated potato production do not increase growing season NO leaching compared with multiple split applications of soluble fertilizers, but have the potential to increase N losses after the growing season and into the following year. Estimates of indirect NO emissions ranged from 0.8 to 64% of direct emissions, depending on what value was assumed for the emission factor describing off-site conversion of NO to NO. Thus, our results also demonstrate how more robust models are needed to account for off-site conversion of NO to NO, since current emission factor models have an enormous degree of uncertainty. PMID- 21712580 TI - Stimulated rhizodegradation of atrazine by selected plant species. AB - The efficacy of vegetative buffer strips (VBS) in removing herbicides deposited from surface runoff is related to the ability of plant species to promote rapid herbicide degradation. A growth chamber study was conducted to compare C-atrazine (ATR) degradation profiles in soil rhizospheres from different forage grasses and correlate ATR degradation rates and profiles with microbial activity using three soil enzymes. The plant treatments included: (i) orchardgrass ( L.), (ii) smooth bromegrass ( Leyss.), (iii) tall fescue ( Schreb.), (iv) Illinois bundle flower (), (v) perennial ryegrass ( L.), (vi) switchgrass ( L.), and (vii) eastern gamagrass (). Soil without plants was used as the control. The results suggested that all plant species significantly enhanced ATR degradation by 84 to 260% compared with the control, but eastern gamagrass showed the highest capability for promoting biodegradation of ATR in the rhizosphere. More than 90% of ATR was degraded in the eastern gamagrass rhizosphere compared with 24% in the control. Dealkylation of atrazine strongly correlated with increased enzymatic activities of beta-glucosidase (GLU) ( = 0.96), dehydrogenase (DHG) ( = 0.842), and fluorescein diacetate (FDA) hydrolysis ( = 0.702). The incorporation of forage species, particularly eastern gamagrass, into VBS designs will significantly promote the degradation of ATR transported into the VBS by surface runoff. Microbial parameters widely used for assessment of soil quality, e.g., DHG and GLU activities, are promising tools for evaluating the overall degradation potential of various vegetative buffer designs for ATR remediation. PMID- 21712581 TI - Phosphogypsum capping depth affects revegetation and hydrology in Western Canada. AB - Phosphogypsum (PG), a byproduct of phosphate fertilizer manufacturing, is commonly stacked and capped with soil at decommissioning. Shallow (0, 8, 15, and 30 cm) and thick (46 and 91 cm) sandy loam caps on a PG stack near Fort Saskatchewan, Alberta, Canada, were studied in relation to vegetation establishment and hydrologic properties. Plant response was evaluated over two growing seasons for redtop ( L.), slender wheatgrass ( (Link) Malte ex H.F. Lewis), tufted hairgrass ( (L.) P. Beauv.), and sheep fescue ( L.) and for a mix of these grasses with alsike clover ( L.). Water content below the soil-PG interface was monitored with time-domain reflectometry probes, and leachate water quantity and quality at a depth of 30 cm was measured using lysimeters. Vegetation responded positively to all cap depths relative to bare PG, with few significant differences among cap depths. Slender wheatgrass performed best, and tufted hairgrass performed poorly. Soil caps <1 m required by regulation were sufficient for early revegetation. Soil water fluctuated more in shallow than in thick caps, and water content was generally between field capacity and wilting point regardless of cap depth. Water quality was not affected by cap depths <=30 cm. Leachate volumes at 30 cm from distinct rainfall events were independent of precipitation amount and cap depth. The study period had lower precipitation than normal, yet soil caps were hospitable for plant growth in the first 2 yr of establishment. PMID- 21712582 TI - Activated carbon immobilizes residual polychlorinated biphenyls in weathered contaminated soil. AB - Activated carbon (AC) has recently been shown to be effective in sequestering persistent organic pollutants (POPs) from aquatic sediments. Most studies have demonstrated significant reductions of POP concentrations in water and in aquatic organisms; however, limited data exist on the possibility of using AC to immobilize remaining POPs at terrestrial contaminated sites. Under greenhouse conditions, pumpkin ssp cv. Howden) were grown, and red wiggler worms () were exposed to an industrial contaminated soil containing a mixture of polychlorinated biphenyls (PCBs), i.e., Aroclors 1254 and 1260) treated with one of four concentrations of AC (0.2, 0.8, 3.1, and 12.5%) for 2 mo. The addition of AC to contaminated soils virtually eliminated the bioavailability of PCBs to the plant and invertebrate species. There were reductions in PCB concentrations of more than 67% in ssp and 95% in . These data suggest that AC could be included as part of comprehensive site closure strategy at PCB-contaminated sites. PMID- 21712583 TI - Potential adverse effects of applying phosphate amendments to immobilize soil contaminants. AB - Seven-day batch equilibrium experiments were conducted to measure the efficacy of four phosphate amendments (trisodium trimetaphosphate [TP3], dodecasodium phytate [Na-IP6], precipitated calcium phytate [Ca-IP6], and hydroxyapatite [HA]) for immobilizing Ni and U in organic-rich sediment. Using the eight-step modified Miller's sequential extraction procedure and the USEPA's Toxicity Characteristic Leaching Procedure, the effect of these amendments on the distribution of Ni and U was assessed. Relative to unamended controls, equilibrium aqueous-phase U concentrations were lower following HA and Ca-IP6 additions but higher following TP3 and Na-IP6 amendments, whereas aqueous Ni concentrations were not decreased only in the Na-IP6 amended treatment relative to the control. The poor rates of contaminant immobilization following TP3 and Na-IP6 amendments correlate with the dispersion of organic matter and organo-mineral colloids, which probably contain sorbed U and Ni. While all amendments shifted the U distribution toward more recalcitrant soil fractions, Ni was redistributed to more labile soil fractions. This study cautions that the addition of orthophosphates and organophosphates as contaminant immobilizing amendments may in fact have adverse effects, especially in high-organic soils. Particular attention is warranted at sites with mixed contaminants with varying geochemical behaviors. PMID- 21712584 TI - The desorption of antimony(V) from sediments, hydrous oxides, and clay minerals by carbonate, phosphate, sulfate, nitrate, and chloride. AB - The desorption of antimony, Sb(V), from two sediment samples by phosphate, carbonate, sulfate, chloride, and nitrate at pH 8 was examined. One highly contaminated sediment sample was taken from an Sb mine (Goesdorf, Luxembourg); the other sample was the certified reference material PACS-2 (marine sediment). Phosphate was found to have a strong mobilizing ability, whereas that of carbonate was in general weaker. For comparison, and to understand better the possible importance of individual components of the sediments, desorption experiments were performed on pure phases (i.e., hydrous oxides of Fe, Mn, and Al) and the clay minerals kaolinite and montmorillonite. In the cases of hydrous metal oxides, Sb(V) was most effectively desorbed by phosphate, followed by carbonate. Phosphate also desorbed Sb(V) from the clay minerals, whereas carbonate had no effect. The pH dependence of adsorption of Sb(V) in the absence and presence of carbonate revealed that adsorption densities were higher (except in the case of montmorillonite) in the absence of carbonate, suggesting a competition between carbonate and [Sb(OH)] for surface sites generally and a lowering of surface charge in the case of hydrous aluminum oxide. The observations are unlikely to be due to ionic strength effects because activity coefficients in the blank and spiked solutions differ by <4%. Desorption experiments on sediments with varying concentrations of phosphate and carbonate demonstrated that at environmentally relevant concentrations, desorption by phosphate is negligible, whereas the effect of carbonate is not. Sulfate, chloride, and nitrate generally had little effect. The proportion of Sb desorbed in blank experiments coincides with that mobilized in the first fraction of the Bureau Communautaire de Reference (BCR) sequential extraction (easily exchangeable and carbonate-bound fraction). PMID- 21712585 TI - Environmental impacts of asphalt mixes with electric arc furnace steel slag. AB - Electric arc furnace (EAF) steel slag can be used as an alternative high-quality material in road construction. Although asphalts with slag aggregates have been recognized as environmentally acceptable, there is a lack of data concerning the potential leaching of toxic Cr(VI) due to the highly alkaline media of EAF slag. Leaching of selected water extractable metals from slag indicated elevated concentrations of total chromium and Cr(VI). To estimate the environmental impacts of asphalt mixes with slag, leachability tests based on diffusion were performed using pure water and salt water as leaching agents. Compact and ground asphalt composites with natural aggregates, and asphalt composites in which the natural aggregates were completely replaced by slag were prepared. The concentrations of total chromium and Cr(VI) were determined in leachates over a time period of 6 mo. After 1 and 6 mo, the concentrations of some other metals were also determined in the leachates. The results indicated that chromium in leachates from asphalt composites with the addition of slag was present almost solely in its hexavalent form. However, the concentrations were very low (below 25 MUg L) and did not represent an environmental burden. The leaching of other metals from asphalt composites with the addition of slag was negligible. Therefore, the investigated EAF slag can be considered as environmentally safe substitute for natural aggregates in asphalt mixes. PMID- 21712586 TI - Effect of organic matter oxidation on the fractionation of copper, zinc, lead, and arsenic in sewage sludge and amended soils. AB - Long-term land application of sewage sludge (SS) has caused concern over the potential release of trace metals into the environment following the degradation of organic matter (OM). This study was performed to assess the impact of OM degradation on the relative distribution of Cu, Zn, Pb, and As in SS and SS amended soils. Three SSs of different ages and two soils treated with SS were subjected to incubation and direct chemical oxidation using diluted HO, followed by a sequential extraction. The majority of Cu, Pb, and As were bound to OM, whereas the majority of Zn was bound with Fe/Mn oxides for all three SSs. Incubation of SS for 6 mo did not result in a substantial decrease in OM content or a change in the relative distribution of Cu, Zn, Pb, and As. Direct OM oxidation to 30 and 70% by diluted HO resulted in a significant decrease in organically bound Cu but increased its exchangeable, carbonate-bound, and Fe/Mn bound fractions. Oxidation of OM slightly decreased organically bound Zn but significantly increased exchangeable Zn in all SSs. Oxide- and carbonate-bound Zn also decreased following OM oxidation. Exchangeable fractions of As and Pb were minute before and after OM degradation, indicating that release into the environment would be unlikely. The relative distribution of Cu, Zn, Pb, and As in SS-treated soils was similar to that of SS, suggesting a dominant role of SS properties in controlling metal distribution following OM oxidation. Overall, OM oxidation increased the mobility and bioavailability of Zn and Cu, whereas it had less impact on Pb and As. PMID- 21712587 TI - Chromated copper arsenate-treated fence posts in the agronomic landscape: soil properties controlling arsenic speciation and spatial distribution. AB - Soils adjacent to chromated copper arsenate (CCA)-treated fence posts along a fence line transecting different soil series, parent material, drainage classes, and slope were used to determine which soil properties had the most influence on As spatial distribution and speciation. Metal distribution was evaluated at macroscopic (total metal concentration contour maps) and microscopic scales (micro-synchrotron X-ray fluorescence maps), As speciation was determined using extended X-ray absorption fine structure spectroscopy, and redox status and a myriad of other basic soil properties were elucidated. All geochemical parameters measured point to a condition in which the mobilization of As becomes more favorable moving down the topographic gradient, likely resulting through competition (Meh-P, SOM), neutral or slightly basic pH, and redox conditions that are favorable for As mobilization (higher Fe(II) and total-Fe concentrations in water extracts). On the landscape scale, with hundreds of kilometers of fence, the arsenic loading into the soil can be substantial (~8-12 kg km). Although a significant amount of the As is stable, extended use of CCA-treated wood has resulted in elevated As concentrations in the local environment, increasing the risk of exposure and ecosystem perturbation. Therefore, a move toward arsenic free alternatives in agricultural applications for which it is currently permitted should be considered. PMID- 21712588 TI - Modeling sediment and nitrogen export from a rural watershed in eastern Canada using the soil and water assessment tool. AB - Watershed simulation models can be used to assess agricultural nonpoint-source pollution and for environmental planning and improvement projects. However, before application of any process-based watershed model, the model performance and reliability must be tested with measured data. The Soil and Water Assessment Tool version 2005 (SWAT2005) was used to model sediment and nitrogen loads from the Thomas Brook Watershed, which drains a 7.84 km rural landscape in the Annapolis Valley of Nova Scotia, Canada. The Thomas Brook SWAT model was comprised of 28 subbasins and 265 hydrologic response units, most of them containing agricultural land use, which is the main nonpoint nitrogen source in the watershed. Crop rotation schedules were incorporated into the model using field data collected within Agriculture and Agri-Food Canada's Watershed Evaluation of Beneficial Management Practices program. Model calibration (2004 2006) and validation (2007-2008) were performed on a monthly basis using continuous stream flow, sediment, and nitrogen export measurements. Model performance was evaluated using the coefficient of determination, Nash-Sutcliff efficiency (NSE), and percent bias (PBIAS) statistics. Study results show that the model performance was satisfactory (NSE > 0.4; > 0.5) for stream flow, sediment, nitrate-nitrogen, and total nitrogen simulations. Annual corn, barley, and wheat yields were also simulated well, with PBIAS values ranging from 0.3 to 7.2%. This evaluation of SWAT demonstrated that the model has the potential to be used as a decision support tool for agricultural watershed management in Nova Scotia. PMID- 21712589 TI - Field evaluation of a new plastic film (vapor safe) to reduce fumigant emissions and improve distribution in soil. AB - Preplant soil fumigation is an important pest management practice in coastal California strawberry production regions. Potential atmospheric emissions of fumigants from field treatment, however, have drawn intensive environmental and human health concerns; increasingly stringent regulations on fumigant use have spurred research on low-emission application techniques. The objectives of this research were to determine the effects of a new low-permeability film, commonly known as totally impermeable film (TIF), on fumigant emissions and on fumigant distribution in soil. A 50/50 mixture of 1,3-dichloropropene (1,3-D) and chloropicrin (CP) was shank-applied at 314 kg ha in two location-separate field plots (0.4 ha each) in Ventura County, California, in fall 2009. One plot was surface-covered with standard polyethylene (PE) film, and the other was covered with TIF immediately after fumigant application. Data collection included emissions, soil-gas phase concentration profile, air concentration under the film, and soil residuals of the applied fumigants. Peak emission flux of 1,3-D and CP from the TIF field was substantially lower than from the PE field. Total through-film emission loss was 2% for 1,3-D and <1% for CP from the TIF field during a 6-d film covering period, compared with 43% for 1,3-D and 12% for CP from the PE field. However, on film-cutting, greater retention of 1,3-D in the TIF field resulted in a much higher emission surge compared with the PE field, while CP emissions were fairly low in both fields. Higher concentrations and a more uniform distribution in the soil profile for 1,3-D and CP were observed under the TIF compared with the PE film, suggesting that the TIF may allow growers to achieve satisfactory pest control with lower fumigant rates. The surging 1,3-D emissions after film-cutting could result in high exposure risks to workers and bystanders and must be addressed with additional mitigation measures. PMID- 21712590 TI - Soil fate of agricultural fumigants in raised-bed, plasticulture systems in the southeastern United States. AB - Soil concentrations and degradation rates of methyl isothio-cyanate (MITC), chloropicrin (CP), 1,3-dichloropropene (1,3-D), and dimethyl disulfide (DMDS) were determined under fumigant application scenarios representative of commercial raised bed, plastic mulched vegetable production systems. Five days after application, 1,3-D, MITC, and CP were detected at concentrations up to 3.52, 0.72, and 2.45 MUg cm, respectively, in the soil atmosphere when applications were made in uniformly compacted soils with a water content >200% of field capacity and covered by a virtually impermeable or metalized film. By contrast, DMDS, MITC, and CP concentrations in the soil atmosphere were 0.81, 0.02, and 0.05 MUg cm, respectively, 5 d after application in soil containing undecomposed plant residue, numerous large (>3 mm) clods, and water content below field capacity and covered by low-density polyethylene. Ranked in order of impact on the persistence of fumigants in soil were soil water content (moisture), soil tilth (the physical condition of soil as related to its fitness as a planting bed), the type of plastic film used to cover fumigated beds, and soil texture. Fumigants were readily detected 13 d after application when applied in uniformly compacted soils with water contents >200% of capacity and covered by a virtually impermeable or metalized film. By contrast, 1,3-D and MITC had dissipated 5 d after application in soils with numerous large (>3 mm) clods and water contents below field capacity that were covered by low-density polyethylene. Soil degradation of CP, DMDS, and MITC were primarily attributed to biological mechanisms, whereas degradation of 1,3-D was attributed principally to abiotic factors. This study demonstrates improved soil retention of agricultural fumigants in application scenarios representative of good agricultural practices. PMID- 21712591 TI - Evaluating agricultural best management practices in tile-drained subwatersheds of the Mackinaw River, Illinois. AB - Best management practices (BMPs) are widely promoted in agricultural watersheds as a means of improving water quality and ameliorating altered hydrology. We used a paired watershed approach to evaluate whether focused outreach could increase BMP implementation rates and whether BMPs could induce watershed-scale (4000 ha) changes in nutrients, suspended sediment concentrations, or hydrology in an agricultural watershed in central Illinois. Land use was >90% row crop agriculture with extensive subsurface tile drainage. Outreach successfully increased BMP implementation rates for grassed waterways, stream buffers, and strip-tillage within the treatment watershed, which are designed to reduce surface runoff and soil erosion. No significant changes in nitrate-nitrogen (NO N), total phosphorus (TP), dissolved reactive phosphorus, total suspended sediment (TSS), or hydrology were observed after implementation of these BMPs over 7 yr of monitoring. Annual NO-N export (39-299 Mg) in the two watersheds was equally exported during baseflow and stormflow. Mean annual TP export was similar between the watersheds (3.8 Mg) and was greater for TSS in the treatment (1626 +/ 497 Mg) than in the reference (940 +/- 327 Mg) watershed. Export of TP and TSS was primarily due to stormflow (>85%). Results suggest that the BMPs established during this study were not adequate to override nutrient export from subsurface drainage tiles. Conservation planning in tile-drained agricultural watersheds will require a combination of surface-water BMPs and conservation practices that intercept and retain subsurface agricultural runoff. Our study emphasizes the need to measure conservation outcomes and not just implementation rates of conservation practices. PMID- 21712592 TI - Nitrate, phosphate, and ammonium loads at subsurface drains: agroecosystems and nitrogen management. AB - Artificial subsurface drainage in cropland creates pathways for nutrient movement into surface water; quantification of the relative impacts of common and theoretically improved management systems on these nutrient losses remains incomplete. This study was conducted to assess diverse management effects on long term patterns (1998-2006) of NO, NH, and PO loads (). We monitored water flow and nutrient concentrations at subsurface drains in lysimeter plots planted to continuous corn ( L.) (CC), both phases of corn-soybean [ (L.) Merr.] rotations (corn, CS; soybean, SC), and restored prairie grass (PG). Corn plots were fertilized with preplant or sidedress urea-NHNO (UAN) or liquid swine manure injected in the fall (FM) or spring (SM). Restored PG reduced NO eightfold compared with fields receiving UAN (2.5 vs. 19.9 kg N ha yr; < 0.001), yet varying UAN application rates and timings did not affect NO across all CCUANs and CSUANs. The NO from CCFM (33.3 kg N ha yr) were substantially higher than for all other cropped fields including CCSM (average 19.8 kg N ha yr, < 0.001). With respect to NH and PO, only manured soils recorded high but episodic losses in certain years. Compared with the average of all other treatments, CCSM increased NH in the spring of 1999 (217 vs. 680 g N ha yr), while CCFM raised PO in the winter of 2005 (23 vs. 441 g P ha yr). Our results demonstrate that fall manuring increased nutrient losses in subsurface-drained cropland, and hence this practice should be redesigned for improvement or discouraged. PMID- 21712593 TI - Losses of surface runoff, total solids, and nitrogen during bermudagrass establishment on levee embankments. AB - Nutrient and sediment runoff from newly constructed levee embankments pose a threat to water quality during soft armor vegetation establishment. Research was initiated in 2008 and 2009 to evaluate the effect of bermudagrass ( L.) coverage and N source on nutrient and sediment runoff from levee embankments during establishment. Bermudagrass plots were seeded at 195.3 kg pure live seed ha and fertilized at 50 kg N ha using a water-soluble N source, urea or NH-NO, or slow release N source, S-coated urea (SCU) or urea formaldehyde (UF), with controls unfertilized. Vegetative cover percentage, time until the onset of runoff, runoff volume, and total solids (TS), NO-N, and NH-N concentrations were measured from simulated and natural rainfall events for 70 d in 2008 and 56 d in 2009. Bermudagrass at 90% grass cover delayed the onset of runoff an additional 441 to 538 s and reduced runoff volumes 74 to 84% of that exhibited at 10% grass cover. Nitrogen fertilizers did not accelerate bermudagrass growth sufficiently, however, to reduce TS loading compared with unfertilized bermudagrass in either year of the study. The application of urea and SCU resulted in cumulative N losses of 2.45 and 3.13 kg ha compared with 1.59 kg ha from the unfertilized bermudagrass in 2008, and 1.73 kg ha from NH-NO vs. 0.24 kg ha from controls in 2009. Only UF increased bermudagrass establishment without increasing cumulative N losses compared with unfertilized bermudagrass. Therefore, the benefit of greater erosion and runoff resistance expected from N-accelerated vegetative growth did not occur but had the unintended consequence of higher N losses when water-soluble N and SCU fertilizers were applied. PMID- 21712594 TI - Change point analysis of phosphorus trends in the Illinois River (Oklahoma) demonstrates the effects of watershed management. AB - Detecting water quality improvements following watershed management changes is complicated by flow-dependent concentrations and nonlinear or threshold responses that are difficult to detect with traditional statistical techniques. In this study, we evaluated the long-term trends (1997-2009) in total P (TP) concentrations in the Illinois River of Oklahoma, and some of its major tributaries, using flow-adjusted TP concentrations and regression tree analysis to identify specific calendar dates in which change points in P trends may have occurred. Phosphorus concentrations at all locations were strongly correlated with stream flow. Flow-adjusted TP concentrations increased at all study locations in the late 1990s, but this trend was related to a change in monitoring practices where storm flow samples were specifically targeted after 1998. Flow adjusted TP concentrations decreased in the two Illinois River sites after 2003. This change coincided with a significant decrease in effluent TP concentrations originating with one of the largest municipal wastewater treatment facilities in the basin. Conversely, flow-adjusted TP concentrations in one tributary increased, but this stream received treated effluent from a wastewater facility where effluent TP did not decrease significantly over the study period. Results of this study demonstrate how long-term trends in stream TP concentrations are difficult to quantify without consistent long-term monitoring strategies and how flow adjustment is likely mandatory for examining these trends. Furthermore, the study demonstrates how detecting changes in long-term water quality data sets requires statistical methods capable of identifying change point and nonlinear responses. PMID- 21712595 TI - Nitrate loading and isotopic signatures in subsurface agricultural drainage systems. AB - Artificially draining soils using subsurface tiles is a common practice on many agricultural fields. High levels of nitrate-nitrogen (NO-N) are often released from these systems; therefore, knowledge on the sources and processes controlling NO-N in drainage systems is needed. A dual isotope study (deltaN and deltaO) was used to investigate three subsurface drainage systems (shallow, conventional, and controlled) in Onslow, Nova Scotia, Canada. The objectives of this study were (i) to identify which drainage system more effectively reduced the NO-N loading, (ii) to examine differences in isotopic signatures under identical nutrient and cropping regimes for a fixed soil type, and (iii) to identify the utility of different drainage systems in controlling nutrient flows. Nitrate concentrations measured ranged from 0.92 to 11.8, from 2.3 to 17.3, and from 2.1 to 19.8 mg L for the shallow, conventional, and controlled drains, respectively. Total NO-N loading from shallow and controlled drains were 20 and 5.6 kg ha, respectively, lower than conventional (39.1 kg ha). The isotopic composition of NO-N for all drainage types appeared to be a mixture of two organic sources (manure and soil organic matter) via the process of nitrification. There was no evidence that denitrification played a significant role in removing NO-N during transport. Overall, shallow drainage reduced NO-N loading but offered no water conservation benefits. Combining the benefits of decreased NO-N loading from shallow systems with water control capability may offer the best solution to reducing nutrient loadings into water systems, achieving optimal crop yield, and decreasing drainage installation costs. PMID- 21712596 TI - Influence of irrigated paddy fields on the fluorescence properties of fluvial dissolved organic matter. AB - This study investigated seasonal and geographical variation in the fluorescence properties of dissolved organic matter (DOM) in a river system that includes rice paddy fields in its watershed. The river system covers a northern area of the main island of Japan, and between 6 and 45% the watershed area of the tributaries is paddy fields. Water samples were collected monthly from eight tributaries for 1 yr, and the fluorescence properties of DOM were monitored by combined excitation-emission matrix (EEM) and parallel factor analysis. The EEM was statistically decomposed into six fluorescence components with different environmental dynamics. The relative proportion of these components varied with season and geographic location, the former having a greater effect than the latter. Seasonal variation is largely attributed to changes in the source of DOM associated with irrigated rice cultivation practice. The fluorescence component composition showed a stronger autochthonous signature, which varied over a wider range during off-cropping period (October-April) than cropping period (May September). During the cropping period, a large amount of allochthonous DOM with relatively similar quality was transported into river water from flooded paddy fields and masked the variability in the quality of DOM among tributaries. Therefore, irrigated rice cropping practices are considered to be one of major factors that influence seasonal and geographical variation of fluvial DOM composition. PMID- 21712598 TI - Comparative losses of glyphosate and selected residual herbicides in surface runoff from conservation-tilled watersheds planted with corn or soybean. AB - Residual herbicides regularly used in conjunction with conservation tillage to produce corn ( L.) and soybean [ (L.) Merr] are often detected in surface water at concentrations that exceed their U.S. maximum contaminant levels (MCL) and ecological standards. These risks might be reduced by planting glyphosate tolerant varieties of these crops and totally or partially replacing the residual herbicides alachlor, atrazine, linuron, and metribuzin with glyphosate, a contact herbicide that has a short half-life and is strongly sorbed to soil. Therefore, we applied both herbicide types at typical rates and times to two chisel-plowed and two no-till watersheds in a 2-yr corn/soybean rotation and at half rates to three disked watersheds in a 3-yr corn/soybean/wheat-red clover ( L.- L.) rotation and monitored herbicide losses in surface runoff for three crop years. Average dissolved glyphosate loss for all tillage practices, as a percentage of the amount applied, was significantly less ( <= 0.05) than the losses of atrazine (21.4x), alachlor (3.5x), and linuron (8.7x) in corn-crop years. Annual, flow weighted, concentration of atrazine was as high as 41.3 MUg L, much greater than its 3 MUg L MCL. Likewise, annual, flow-weighted alachlor concentration (MCL = 2 MUg L) was as high as 11.2 and 4.9 MUg L in corn- and soybean-crop years, respectively. In only one runoff event during the 18 watershed-years it was applied did glyphosate concentration exceed its 700 MUg L MCL and the highest, annual, flow-weighted concentration was 3.9 MUg L. Planting glyphosate-tolerant corn and soybean and using glyphosate in lieu of some residual herbicides should reduce the impact of the production of these crops on surface water quality. PMID- 21712597 TI - Use of industrial byproducts to filter phosphorus and pesticides in golf green drainage water. AB - Golf courses are vulnerable to phosphate (PO) and pesticide loss by infiltration of the sandy, porous grass rooting media used and through subsurface tile drainage. In this study, an effort was made to remove PO, chlorothalonil, mefenoxam, and propiconazole in a golf green's drainage water with a filter blend comprised of industrial byproducts, including granulated blast furnace slag, cement kiln dust, silica sand, coconut shell-activated carbon, and zeolite. To test this filter media, two 6-h storm events were simulated by repeat irrigation of the golf green after PO and pesticide application. Drainage flows ranged from 0.0034 to 0.6433 L s throughout the course of the simulations. A significant decrease in the chlorothalonil load for the experimental run (with filter media) was observed compared with the control (without filter media) ( < 0.05). In general, percent reductions in chlorothalonil were very high (>80%) near peak flows. In contrast, filter media was not effective in removing PO, mefenoxam, or propiconazole ( > 0.05). Instead, it appears that the filter blend added PO to the effluent above flow rates of 0.037 L s. Overall, flow rate, the amount of filter media used, and contaminant properties may have influenced the filter media's ability to remove contaminants. More research is needed to determine the optimal blend and configuration for the filter media to remove significant amounts of all contaminants investigated. PMID- 21712599 TI - Linking dissolved and particulate phosphorus export in rivers draining California's Central Valley with anthropogenic sources at the regional scale. AB - Pollution of water resources by phosphorus (P) is a critical issue in regions with agricultural and urban development. In this study, we estimated P inputs from agricultural and urban sources in 24 catchments draining to the Central Valley in California and compared them with measured river P export to investigate hydrologic and anthropogenic factors affecting regional P retention and export. Using spatially explicit information on fertilizer use, livestock population, agricultural production, and human population, we calculated that net surface balances for anthropogenic P ranged from -12 to 648 kg P km yr in the early 2000s. Inorganic P fertilizer and manure P comprised the largest fraction of total input for all but two catchments. From 2000 to 2003, a median of 7% (range, -287 to 88%) of net annual anthropogenic P input was exported as total P (TP). Yields (kg P km yr) of dissolved inorganic P (DIP), dissolved organic P, particulate P, and TP were not significantly related to catchment-level, per area anthropogenic P input. However, there were significant relationships between mean annual P concentrations and P input from inorganic fertilizers and manure due to the concentration of agricultural land near catchment mouths and regional variation in runoff. Catchment-level P fertilizer and manure inputs explained 4 to 23% more variance in mean annual DIP and TP concentrations than percent of catchment area in agriculture. This study suggests that spatially explicit estimates of anthropogenic P input can help identify sources of multiple forms of P exported in rivers at management-relevant spatial scales. PMID- 21712600 TI - Grazing management effects on sediment, phosphorus, and pathogen loading of streams in cool-season grass pastures. AB - Erosion and runoff from pastures may lead to degradation of surface water. A 2-yr grazing study was conducted to quantify the effects of grazing management on sediment, phosphorus (P), and pathogen loading of streams in cool-season grass pastures. Six adjoining 12.1-ha pastures bisected by a stream in central Iowa were divided into three treatments: continuous stocking with unrestricted stream access (CSU), continuous stocking with restricted stream access (CSR), and rotational stocking (RS). Rainfall simulations on stream banks resulted in greater ( < 0.10) proportions of applied precipitation and amounts of sediment and P transported in runoff from bare sites than from vegetated sites across grazing treatments. Similar differences were observed comparing vegetated sites in CSU and RS pastures with vegetated sites in CSR pastures. Bovine enterovirus was shed by an average of 24.3% of cows during the study period and was collected in the runoff of 8.3 and 16.7% of runoff simulations on bare sites in CSU pastures in June and October of 2008, respectively, and from 8.3% of runoff simulations on vegetated sites in CSU pastures in April 2009. Fecal pathogens (bovine coronavirus [BCV], bovine rotavirus group A, and O157:H7) shed or detected in runoff were almost nonexistent; only BCV was detected in feces of one cow in August of 2008. Erosion of cut-banks was the greatest contributor of sediment and P loading to the stream; contributions from surface runoff and grazing animals were considerably less and were minimized by grazing management practices that reduced congregation of cattle by pasture streams. PMID- 21712601 TI - Salinity management using an anionic polymer in a pecan field with calcareous sodic soil. AB - Soil salinity and sodicity have long been recognized as the major concerns for irrigated agriculture in the Trans-Pecos Basin, where fields are being flood irrigated with Rio Grande River water that has elevated salinity. Reclamation of these salt-affected lands is difficult due to fine-texture, high shrink-swell soils with low permeability. Conventional practice of subsoiling to improve soil permeability is expensive and has had limited success on the irrigated soils that have appreciable amounts of readily weatherable Ca minerals. If these native Ca sources can be effectively used to counter sodicity, it can improve soil permeability and reduce amelioration costs. This study evaluated the effects of 3 yr of polyacrylamide (PAM) application at 10 mg L concentration during the first irrigation of the season to evaluate soil permeability, in situ Ca mineral dissolution, and leaching of salts from the effective root zone in a pecan field of El Paso County, TX. Results indicated that PAM application improved water movement throughout the effective root zone that resulted in Na leaching. Polymer application significantly decreased CaCO (estimated based on inorganic C analysis) concentrations in the top 45 cm compared with baseline levels, indicating solubilization and redistribution of calcite. The PAM application also reduced soil electrical conductivity (EC) in the top 60 cm (4.64-2.76 dS m) and sodium adsorption ratio (SAR) from 13.1 to 5.7 mmol L in the top 75-cm depths. As evidence of improved soil conditions, pecan nut yields increased by 34% in PAM treated fields over the control. Results suggested that PAM application helped in effective use of native Ca sources present in soils of the study site and reduced Na by improving soil permeability. PMID- 21712602 TI - Nutrients and bacteria in common contiguous Mississippi soils with and without broiler litter fertilization. AB - In Mississippi, spent poultry litter is used as fertilizer. Nutrient and bacterial levels in litter and nutrient levels in litter-fertilized (L+) soil are known, but less is known of bacterial levels in L+ soil. This study compared contiguous L+ and non-litter-fertilized (L-) soils comprising 15 soil types on five farms in April through May 2009. Levels of pH; NO-N; and Mehlich-3 extractable (M3) and water-extractable (WE) P, Ca, K, and Cu were higher in L+ than in L- soil. Total C; total N; NH-N; and M3 and WE Na, Fe, and Zn did not differ in L+ and L- soil. Bacterial levels were higher in 0- to 5-cm than in 5- to 10-cm cores. Levels were higher in L+ than in L- soil for culturally determined heterotrophic plate counts and staphylococci and were lower for total bacteria estimated by quantitative polymerase chain reaction (qPCR) of 16S rRNA, but cultural levels of thermotolerant coliforms, , , and enterococci were not different. Cultural presence/absence (CPA) tests and qPCR for spp., spp., and spp. detected only spp., which did not differ in L+ (CPA = 77% positive samples; mean qPCR = 0.65 log genomic units [gu] g) and L- (CPA = 70% positive samples; mean qPCR = 0 log gu g) soils. Litter applications were associated with higher levels of pH, P, Cu, heterotrophic plate counts, and staphylococci. Fecal indicator and enteric pathogen levels were not affected. We conclude that, although some litter-derived nutrients and bacteria persisted between growing seasons in L+ soils, enteric pathogens did not. PMID- 21712603 TI - Electrocoagulation of palm oil mill effluent as wastewater treatment and hydrogen production using electrode aluminum. AB - Palm oil mill effluent (POME) is highly polluting wastewater generated from the palm oil milling process. Palm oil mill effluent was used as an electrolyte without any additive or pretreatment to perform electrocoagulation (EC) using electricity (direct current) ranging from 2 to 4 volts in the presence of aluminum electrodes with a reactor volume of 20 L. The production of hydrogen gas, removal of chemical oxygen demand (COD), and turbidity as a result of electrocoagulation of POME were determined. The results show that EC can reduce the COD and turbidity of POME by 57 and 62%, respectively, in addition to the 42% hydrogen production. Hydrogen production was also helpful to remove the lighter suspended solids toward the surface. The production of Al(OH)XHO at the aluminum electrode (anode) was responsible for the flocculation-coagulation process of suspended solids followed by sedimentation under gravity. The production of hydrogen gas from POME during EC was also compared with hydrogen gas production by electrolysis of tap water at pH 4 and tap water without pH adjustment under the same conditions. The main advantage of this study is to produce hydrogen gas while treating POME with EC to reduce COD and turbidity effectively. PMID- 21712604 TI - Land application of hydrofracturing fluids damages a deciduous forest stand in West Virginia. AB - In June 2008, 303,000 L of hydrofracturing fluid from a natural gas well were applied to a 0.20-ha area of mixed hardwood forest on the Fernow Experimental Forest, West Virginia. During application, severe damage and mortality of ground vegetation was observed, followed about 10 d later by premature leaf drop by the overstory trees. Two years after fluid application, 56% of the trees within the fluid application area were dead. Ehrh. was the tree species with the highest mortality, and L. was the least affected, although all tree species present on the site showed damage symptoms and mortality. Surface soils (0-10 cm) were sampled in July and October 2008, June and October 2009, and May 2010 on the fluid application area and an adjacent reference area to evaluate the effects of the hydrofracturing fluid on soil chemistry and to attempt to identify the main chemical constituents of the hydrofracturing fluid. Surface soil concentrations of sodium and chloride increased 50-fold as a result of the land application of hydrofracturing fluids and declined over time. Soil acidity in the fluid application area declined with time, perhaps from altered organic matter cycling. This case study identifies the need for further research to help understand the nature and the environmental impacts of hydrofracturing fluids to devise optimal, safe disposal strategies. PMID- 21712606 TI - Residual platelet reactivity after clopidogrel loading in patients with ST elevation myocardial infarction undergoing an unexpectedly delayed primary percutaneous coronary intervention. - Impact on intracoronary thrombus burden and myocardial perfusion-. AB - BACKGROUND: Residual platelet reactivity (RPR) after clopidogrel loading, measured by the VerifyNow assay, has been shown to predict 12-month clinical events in patients with acute coronary syndromes. However, links between coronary angiographic findings and outcome in patients with ST-elevation myocardial infarction (STEMI), with RPR have not been reported. We investigated whether RPR is associated with the amount of intracoronary thrombus burden (TB) in patients with STEMI undergoing unexpectedly-delayed primary percutaneous coronary intervention (pPCI). Moreover, we evaluated whether RPR might influence coronary flow and myocardial perfusion immediately post-pPCI. METHODS AND RESULTS: The VerifyNow assay was used to determine RPR after clopidogrel loading, expressed in P2Y12-Reaction-Units (PRU). Intracoronary-TB was angiographically estimated and stratified as TB-Grade-A, -B and -C. Thrombolysis In Myocardial Infarction (TIMI) flow and Myocardial Blush (MB) were also estimated post-PCI. A total of 74 consecutive patients who presented with STEMI were enrolled in the study. Patients with greater TB presented significantly higher PRU-levels (174.1 +/- 91.5, 196.23 +/- 113.4 and 252.8 +/- 107.8 for TB-Grade A, B and C, respectively; P=0.044). PRU-levels >251.5 were shown to predict Large-TB (LTB; TB-Grade-C) (sensitivity=57.9%; specificity=77.8%; P=0.014). Impaired TIMI-flow and MB after PCI were significantly associated with higher PRU-levels (P < 0.001). CONCLUSIONS: Among the studied patients, those with a higher RPR after clopidogrel loading presented larger intracoronary TB, worse post-PCI myocardial flow and perfusion. PMID- 21712607 TI - Evaluation of patient compliance, quality of life impact and cost-effectiveness of a "test in-train out" exercise-based rehabilitation program for patients with intermittent claudication. AB - BACKGROUND: Patients with intermittent claudication (IC) could benefit from low cost, effective rehabilitative programs. This retrospective study evaluates compliance, impact on Quality of Life (QoL) and cost-effectiveness of a hospital prescribed, at-home performed (Test-in/Train-out) rehabilitative program for patients with IC. METHODS AND RESULTS: Two-hundred and eighty-nine patients with IC (71 +/- 10.1 years, M = 210) were enrolled for a 2-year period. Two daily 10 min home walking sessions at maximal asymptomatic speed were prescribed, with serial check-ups at the hospital. Compliance with the program was assessed by assigning a score of 1 (lowest compliance) to 4 (highest compliance). The SF-36 questionnaire and a constant-load treadmill test were used to evaluate QoL and Initial/Absolute Claudication Distance, respectively. Both direct and indirect costs of the program were considered for cost-effectiveness analysis. Two-hundred and fifty patients (70.5 +/- 9.2 years, M = 191), at Fontaine's II-B stage (86%), were included in the study. No adverse events were reported. The average compliance score was 3.1. At discharge, both SF-36 domains and walking performance significantly increased (P < 0.0001). A total of 1,839 in-hospital check-ups (7.36 /patient) were performed. Direct and indirect costs represented 93% and 7% of the total costs, respectively. The average costs of a visit and of a therapy cycle were C68.93 and C507.20, respectively. The cost to walk an additional meter before stopping was C9.22. CONCLUSIONS: A Test-in/Train-out program provided favourable patient compliance, QoL impact and cost-effectiveness in patients with IC. PMID- 21712608 TI - Early- and long-term outcomes after surgery for acute type a aortic dissection in patients aged 45 years and younger. AB - BACKGROUND: Acute type A aortic dissection (AAAD) is rare in young people. The early- and long-term outcomes after surgery for AAAD in patients aged <= 45 years was investigated. METHODS AND RESULTS: Subjects were 355 patients who had undergone emergency surgery for AAAD. The patients were grouped as those aged <= 45 years (n=30; mean age, 38.3 years; younger group) and those aged > 45 years (n = 325; mean age, 65.3 years; older group). Clinical and prognostic variables were compared between the groups. Male sex, Marfan syndrome, and severe aortic regurgitation were more prevalent in the younger group. In-hospital mortality (16.7% vs. 8.6%, P = 0.15) and postoperative patency of the distal aorta (90.8% vs. 59.1%, P < 0.01) were more frequent in the younger group. The leading causes of late death were aortic rupture in the younger group (75.0%) and malignancy in the older group (27.5%). Although actuarial survival at 10 years was similar (64.5% vs. 62.5%), freedom from aortic reoperation at 10 years was decreased in the younger group (49.4% vs. 85.0%, P = 0.012). A distal aorta > 45 mm (P<0.001), Marfan syndrome (P < 0.01), and age <= 45 years (P = 0.045) were shown to be independent risk factors for reoperation. CONCLUSIONS: Early- and long-term surgical outcomes are not better for patients <= 45 years, and the risk for reoperation is high in this group. Careful follow up is important in young patients with AAAD. PMID- 21712609 TI - Molecular and functional changes in voltage-gated Na+ channels in cardiomyocytes during mouse embryogenesis. AB - BACKGROUND: Embryonic cardiomyocytes undergo profound changes in their electrophysiological properties during development. However, the molecular and functional changes in Na+ channel during cardiogenesis are not yet fully explained. METHODS AND RESULTS: To study the functional changes in the Na+ channel during cardiogenesis, Na+ currents were recorded in the early (EDS) and late (LDS) developmental stages of cardiomyocytes in embryonic mice. Compared with EDS myocytes, LDS myocytes exhibited a larger peak current density, a more negative shift in the voltage of half inactivation, a larger fast inactivation component and a smaller slow inactivation component, and smaller time constants for recovery from inactivation. Additionally, multiple Na+ channel alpha-subunits (Nav 1.1-1.6) and beta-subunits (Nav beta1-beta3) of mouse embryos were investigated. Transcripts of Nav 1.1-1.3 were absent or present at very low levels in embryonic hearts. Transcripts encoding Nav 1.4-1.6 and Nav beta1-beta3 increased during embryogenesis. Data on the sensitivity of total Na+ currents to tetrodotoxin (TTX) showed that TTX-resistant Nav 1.5 is the predominant isoform expressed in the heart of the mouse embryo. CONCLUSIONS: The results indicate that significant changes in the functional properties of Na+ channels develop in the cardiomyocytes of the mouse embryo, and that different Na+ channel subunit genes are strongly regulated during embryogenesis, which further support a physiological role for voltage-gated Na+ channels during heart development. PMID- 21712610 TI - Cost effectiveness of radiofrequency catheter ablation vs. medical treatment for atrial fibrillation in Japan. -Cost performance for atrial fibrillation-. AB - BACKGROUND: Radiofrequency catheter ablation (RF) has recently become widely available for the treatment of atrial fibrillation (AF) and has broadened treatment options while confusing the selection of medication therapy or RF. METHODS AND RESULTS: Two drugs for the maintenance of sinus rhythm (Ry) and 2 drugs for control of the pulse rate (Ra) were selected and the costs of medication therapy were calculated. RF procedures were grouped into 2 groups each for persistent or paroxysmal AF (RF) and for chronic AF (RFChr), according to the cost of the devices used. The calculated cost of medication therapy was 5,270 23,560 yen per month. The calculated cost of RF procedures was 1,063,200 2,029,640 yen. The costs of RF corresponded to those of Ry for 3.8-14.3 years. The costs of RFChr corresponded to those of Ra for 16.6-63.9 years. The treatment of complications ranged from 360,000 to 1,241,500 yen. CONCLUSIONS: From the aspect of medical costs and complications, RF should be considered for the treatment of patients with AF detected early or early-stage AF, whereas treatment for its complications should be given priority in patients with chronic AF associated with reduced cardiac function. PMID- 21712611 TI - Megalin/cubilin-mediated uptake of FITC-labeled IgG by OK kidney epithelial cells. AB - In this paper, we characterize the uptake mechanism of fluorescein isothiocyanate labeled human immunoglobulin G (FITC-hIgG) in opossum kidney (OK) epithelial cells, which have been shown to express megalin and cubilin. Confocal immunofluorescence microscopy showed the punctate expression of the neonatal Fc receptor FcRn in the cytoplasm, but not on the cell surface membrane. Temperature and energy-dependent uptake of FITC-hIgG was observed at pH 7.4 but not at pH 6.0, indicating that the internalization of FITC-hIgG might not be due to FcRn, which has a binding affinity for IgG under acidic conditions. Under physiological pH conditions, human and bovine serum gamma-globulin decreased FITC-hIgG uptake in a concentration-dependent manner. In addition, FITC-hIgG uptake was inhibited by various megalin and/or cubilin ligands including albumin, cytochrome c, transferrin and gentamicin. Endosomal acidification inhibitors (bafilomycin A(1) and chloroquine) significantly decreased the uptake of FITC-hIgG. Clathrin dependent endocytosis inhibitors (phenylarsine oxide and chlorpromazine) decreased FITC-hIgG uptake. Potassium depletion and hypertonicity, conditions known to inhibit clathrin-dependent endocytosis, also decreased FITC-hIgG uptake. In contrast, caveolin-dependent endocytosis inhibitors (nystatin and methyl-beta cyclodextrin) did not decrease, but rather increased the uptake of FITC-hIgG. These observations suggest that the internalization of FITC-hIgG in OK cells might be, at least in part, due to megalin/cubilin-mediated, clathrin-dependent endocytosis. PMID- 21712612 TI - Inhibitory effect of zinc on the absorption of JBP485 via the gastrointestinal oligopeptide transporter (PEPT1) in rats. AB - The aim of this study was to investigate the pharmacokinetic mechanism of interaction between JBP485 and zinc. The plasma concentration of JBP485 after oral administration in vivo, the plasma concentration of JBP485 from the portal vein after jejunal perfusions in situ, the serosal fluid concentration of JBP485 in everted small intestine preparations and the uptake of JBP485 by HeLa-hPEPT1 cells in vitro were determined by LC-MS/MS. RT-PCR and Western blotting were used to determine the mRNA and protein levels of Pept1 in the intestinal mucosa. The AUCs of JBP485 in in vivo, in vitro and in situ studies were significantly decreased after zinc pre-administration. Kinetic analysis showed that zinc inhibits the uptake of JBP485 by decreasing the affinity of JBP485 for PEPT1 in HeLa-hPEPT1 cells. RT-PCR and Western blotting indicated that zinc had no effect on basal intestinal Pept1 expression. Our results are novel in demonstrating for the first time that zinc ions, but not zinc gluconate, can inhibit the transport activity of PEPT1. In addition, the uptake of JBP485 was not affected by changes in pH values after zinc treatment. Zinc decreases the absorption of JBP485 by inhibiting the transport activity of PEPT1; however, basal intestinal Pept1 expression does not change. PMID- 21712613 TI - Chronopharmacological assessment identified GLUT4 as a factor responsible for the circadian variation of the hypoglycemic effect of tolbutamide in rats. AB - The circadian relationship between the pharmacokinetics and pharmacodynamics of tolbutamide in rats was analyzed using a compartment model. The basal concentration of plasma glucose had a circadian rhythm with the acrophase at 15:19 h. After intravenous administration of tolbutamide at 06:00, 14:00, or 18:00 h, the hypoglycemic effect showed a circadian variation, with the greatest effect at 18:00 h and the lowest effect at 06:00 h. The time courses of unbound tolbutamide concentration in plasma after intravenous administration were predicted using the model-estimated total concentration of tolbutamide and the albumin concentration and resulted in profiles that did not vary with the time of administration. Significant low insulin resistance was observed at 18:00 h to i.v. glucose and insulin loads. There was no obvious time dependency in the expression of glucose transporter 4 (GLUT4) in epididymal adipocytes. The hypoglycemic rate estimated from the plasma glucose concentration was described by the conventional pharmacokinetic-pharmacodynamic model with an effect compartment. The time courses of theoretical signals in the effect compartment described the observed circadian changes in the increased expression profile of GLUT4 normalized by the increased plasma insulin (IRI) concentration (DeltaGLUT4/DeltaIRI) after dosing. Thus, the time dependency in glucose uptake is responsible for the circadian variation of the hypoglycemic effect of tolbutamide. PMID- 21712614 TI - Serotonin levels in platelet-poor plasma and whole blood from healthy subjects: relationship with lipid markers and coronary heart disease risk score. AB - AIM: The serotonin level in platelet-poor plasma (PPP) is an important clinical marker for monitoring platelet activation accompanying vascular endothelial injury. We previously developed an HPLC method that combines column-switching with a post-column reaction to measure serotonin in PPP. This study determined serotonin levels in healthy volunteers and evaluated the possible relationship of serotonin levels with lipid markers and Framingham 10-year risk scores (FRS) for coronary heart disease. METHODS: Serotonin was isolated from samples using our HPLC method and converted into a fluorescent derivative with benzylamine for specific and sensitive detection. Lipid fractionation was also performed by HPLC. FRS was calculated using the following: age, sex, LDL cholesterol, HDL cholesterol, blood pressure, and smoking and diabetes status. RESULTS: The PPP serotonin to whole blood serotonin ratio (PPP/WB) and the PPP serotonin level correlated significantly with HDL cholesterol levels: r= 0.187, p< 0.05 and r= 0.184, p< 0.05, respectively. The PPP/WB ratio also correlated significantly with FRS (r= 0.176, p< 0.05). The reference range (95% confidence interval) of PPP and WB serotonin levels in healthy subjects were 0.86-16.96 and 385-1319 nmol/L, respectively. CONCLUSIONS: Significant positive correlations between the serotonin PPP/WB ratio and FRS suggest that the PPP/WB ratio can serve as a biomarker for estimating atherosclerotic cardiovascular risk. PMID- 21712615 TI - Characterization of monocyte chemoattractant proteins and CC chemokine receptor 2 expression during atherogenesis in apolipoprotein E-null mice. AB - AIM: We aimed to investigate the expression of monocyte chemoattractant proteins (MCPs) and their cognate receptor CC chemokine receptor 2 (CCR2) in aortas of apolipoprotein E-null (apoE(-/-)) mice during atherogenesis as well as the possible transcription pathway involved in the early induction of MCP-1 in vascular smooth muscle cells (VSMCs) in vivo. METHODS: Atherosclerotic lesion development, aortic MCPs and CCR2 mRNA expression as well as the cellular localization of MCP-1, CCR2 and MCP-1 related transcription factors in atherosclerotic lesions were analyzed in apoE(-/-) mice fed a high fat and cholesterol diet. RESULTS: MCP-1 and CCR2 mRNA expression was significantly induced during early atherogenesis and peaked after 10 and 12 weeks of diet, respectively, whereas MCP-2 and MCP-3 mRNA expression elevated in the late phases of lesion development. Immunostaining revealed that early MCP-1 expression was localized to VSMCs and that, in advanced lesions, both neointimal VSMCs and intimal macrophages expressed high levels of MCP-1. During the early (0 and 4 weeks of diet) induction of MCP-1 in VSMCs, the regulatory activator protein-1 (AP-1) proteins c-Jun and c-Fos were highly expressed and observed within the VSMCs nuclei, whereas nuclear factor-kappaB (NF-kappaB) protein p65 was only observed within the nuclei of VSMCs after 4 weeks of diet. CCR2 was also identified on intimal macrophages, endothelial cells and VSMCs in advanced lesions. CONCLUSION: This study provides fundamental information on the expression kinetics of MCPs and CCR2 during atherogenesis and indicates that the earliest induction of MCP-1 in VSMCs of apoE(-/-)mice appears to correlate with AP-1 but not NF-kappaB regulatory pathways. PMID- 21712616 TI - Elastography: the next step. AB - In the past few decades, various tools have emerged that claim to enhance detection of oral cancer. The most important prognostic factor in patients with oral cancer is lymph node status: the presence of nodal spread decreases the 5 year survival rate by approximately 50%. Differentiation between reactive and metastatic lymphadenopathy is thus vital, and one differentiating criterion is hardness (elasticity) of the lymph node. The purpose of this review is to highlight a promising new ultrasound technique, known as elastography, which measures the characteristics of tissue compliance. The principles underlying elastography are that tissue compression produces strain (displacement) within the tissue - which is lower in harder tissues than in softer tissues - and that malignant tissues are generally harder than normal surrounding tissue. Therefore, elastography might yield clinical information useful in diagnosing cervical metastasis and improving prognosis in oral cancer. It has long been used for cancers of the breast, pancreas, and thyroid, and its use in cervical lymphadenopathy is now being explored, which could lead to great advancements in the diagnosis and prognosis of oral cancer. PMID- 21712617 TI - The history and importance of aeronautic dentistry. AB - Current projected missions to Mars will require 18 to 24 months of exposure to microgravity conditions, which might have serious effects on human physiology, including that of the oral cavity. Very few studies have been published on the effect of microgravity on the oral cavity, although it has been reported that microgravity increases the prevalence of periodontitis, dental caries, bone loss and fracture in the jaw bone, pain and numbness in teeth and oral cavity tissue, salivary duct stones, and oral cancer. Aeronautic dentistry is a new field, so further study of the effects of microgravity are required. In this article, we review the role of aeronautic dentistry in space missions and offer our recommendations for the future growth of this field. PMID- 21712618 TI - Polymeric immunoglobulin receptor. AB - The surface of mucosal sites, such as the intestinal tract, are covered by epithelial cells. To protect the intestinal environment from invading pathogens and maintain homeostasis, the human body developed an exquisite acquired immune system, referred to as the mucosal immune system, in which epithelial cells and lymphocytes function cooperatively. The main player in this immune system is the polymeric immunoglobulins (pIgs), in particular dimeric IgA (dIgA). To exert its protective effect, dIgA produced in the lamina propria must be transported to the intestinal lumen across epithelial cells. This process is called transcytosis and is mediated by polymeric immunoglobulin receptor (pIgR), which is exclusively produced by intestinal epithelial cells (IECs). DIgA is captured by pIgR on the basolateral surface of IECs and transcytosed to the opposite side of IECs. The dIgA-pIgR complex is expressed on the apical surface of IECs and proteolytically cleaved to generate secretory IgA (SIgA). This review describes the current understanding and recent progress in this research field. PMID- 21712619 TI - Effectiveness of tenoxicam and ibuprofen for pain prevention following endodontic therapy in comparison to placebo: a randomized double-blind clinical trial. AB - Tenoxicam is an effective analgesic and anti-inflammatory agent for symptomatic treatment of various conditions. The purpose of this study was to evaluate clinically the effectiveness of prophylactic tenoxicam and prophylactic ibuprofen in reducing post-endodontic pain compared with placebo. A total of 48 patients consented to a double-blind, single dose, prophylactic oral administration of 20 mg of tenoxicam, 200 mg of ibuprofen, or a placebo before root canal treatment. The root canal treatment was performed in one visit. The patients registered their degree of discomfort on a 100-mm visual analog scale, immediately postoperative, and 6, 12, 24, 48 and 72 h after initiation of root canal treatment. The two-way ANOVA test and Tukey HSD post hoc test showed that in the 6-h period, both 20 mg of tenoxicam and 200 mg of ibuprofen provided significantly better pain relief than the placebo. Prophylactic administration of a single dose of 20 mg tenoxicam or 200 mg ibuprofen before RCT provides an effective reduction at 6 h (P < 0.05). Because of the advantages of tenoxicam, it may be useful as a prophylactic analgesic when post-endodontic pain is anticipated. PMID- 21712620 TI - Effect of experimental xylitol and fluoride-containing dentifrices on enamel erosion with or without abrasion in vitro. AB - This in vitro study aimed to analyze the effect of including xylitol into a fluoridated dentifrice to provide protection against enamel erosion with or without abrasion. Bovine enamel specimens were subjected to erosion or erosion plus abrasion (7 days) and the treatment with the following dentifrices: 10% xylitol; 10% xylitol plus 1,030 ppm F (NaF); 1,030 ppm F; and placebo. The erosive challenges were performed 4 times a day (2 min at a time). The specimens were exposed to the slurries of the dentifrices 2 times daily (15 s at a time). Half of the specimens per group were additionally abraded using an electrical toothbrush (F = 1.5 N). Between the challenges, the specimens were remineralized by artificial saliva. Enamel loss was measured profilometrically (um). The data were statistically analyzed by two-way ANOVA and Bonferroni's post-hoc test (P < 0.05). Ten percent xylitol plus F and F dentifrices significantly reduced enamel erosion compared to placebo and xylitol dentifrices. On the other hand, all dentifrices presented a significant potential to protect against enamel erosion plus abrasion compared to placebo, with 10% xylitol plus F showing the best results. Based on this result, the inclusion of 10% xylitol increased the effect of the fluoridated dentifrice against enamel erosion plus abrasion in vitro. In situ or clinical studies are needed to confirm the data. PMID- 21712621 TI - CD47 regulates the TGF-beta signaling pathway in osteoblasts and is distributed in Meckel's cartilage. AB - Previously, CD47 gene expression has been shown to increase during mandible development using a micro array technique. To determine the function of CD47 in osteoblasts, CD47 was silenced using siRNA in vitro. The TGF-beta1 and phosphorylated-Smad2 levels and transcription factor genes related to bone metabolism increased dose-dependently with CD47 silencing. Furthermore, we determined the distribution of CD47 in mouse embryonic E13 and E15 in vivo. The CD47-positive cells were localized in Meckel's cartilage and antenatal mandibular bone. These results suggest that TGF-beta1 signaling and mandible development might be regulated by CD47. PMID- 21712622 TI - Major differences in oral health knowledge and behavior in a group of Iranian pre university students: a cross-sectional study. AB - To establish efficient methods for self-prevention of oral diseases, assessment of dental health behavior and knowledge in various social classes is necessary. The main purpose of this study was to determine the major differences in oral health knowledge and behavior in a group of Iranian pre-university students. In this cross-sectional study, 591 pre-university students from different regions of Mashhad, Iran were randomly selected to complete a questionnaire consisting of two parts including dental health behavior and knowledge. Scores were recorded and statistical analyses performed to determine the correlation between dental health behavior and knowledge. Data was analyzed with Student's t-test, one-way analysis of variance and Pearson correlation. The mean score of dental health knowledge was significantly lower than the dental health behavior (2.95 +/- 0.02 vs. 3.31 +/- 0.05, P < 0.001). This difference was observed with gender, birth location and major subject of study. The dental health behavior of Iranian pre university students was inadequate and their dental health knowledge was at a lower level compared to their behavior. Experimental science students had better oral health behavior compared to other students. PMID- 21712623 TI - Feasibility of including APF gel application in a school oral health promotion program as a caries-preventive agent: a community intervention trial. AB - A community intervention trial was conducted to assess the feasibility of APF gel as a caries-preventive agent in a high-risk group of school children in Bangalore City. The study was conducted in two schools, randomly selected from a list of schools catering to underprivileged children. These schools were randomly allocated into experimental and control groups. Children aged 9-16 years having three or more incipient or cavitated primary or secondary carious lesions were enrolled in the study. In the experimental group, APF gel was applied and oral health education was provided to both groups at baseline and 6 months. Follow-up examination was performed at 6 and 12 months and the caries status was recorded by an investigator who was blinded to the allocation of intervention. There was no statistically significant difference in DMFT and DMFS values, but a significant difference was seen in incipient carious lesions between the experimental and control groups at 6 and 12 months. These results suggest that biannual APF gel application is an effective preventive measure in reversing incipient carious lesions. PMID- 21712624 TI - Association of interleukin-1 polymorphisms with periodontitis in Down syndrome. AB - This study examined the association of IL1 genetic polymorphisms (IL-1A +4845, IL 1B +3954 & IL-1RN +2018) with periodontal disease status of Down syndrome (DS) individuals. Fifty-four DS patients (18-56 yr, 48.15% male, 77.78% Caucasians) were recruited from the Georgia Regional Hospital (GRH) health care system. Two comparable groups (71 mentally retarded patients and 87 control subjects) were also recruited. All subjects were nonsmokers. Periodontal evaluations (plaque index, gingival index, bleeding-on probing and clinical attachment levels (AL)), personal and professional dental care habits were recorded. Blood was collected by a venipuncture. The IL-1A +4845, IL-1B +3954 & IL-1RN +2018 loci were genotyped by the TaqMan assay. No statistically significant differences were noted in the distribution of IL-1 gene polymorphisms between the three groups. The IL-1 variant genotypes varied by race; for both IL-1A and IL-1RN, the variant gene was significantly more prevalent among whites than non-whites (ps > 0.1). ANCOVA, which also adjusted for age, showed a 3-way interaction among dental visits, gene variation and Down status [(F(1, 179) = 3.96, P = 0.048 in White subjects and F(1, 241) = 2.96, P = 0.087 in all subjects). Post-hoc t-tests confirmed lower levels of AL in IL-1RN-variant Down subjects receiving more frequent dental visits (P < 0.05). ANCOVA, which also adjusted for age, showed an interaction between IL-1A/B gene variation and Down status (F(1, 174) = 3.04, P = 0.083 in White subjects and F(1, 235) = 3.72, P = 0.055 in all subjects). Post hoc t-tests confirmed lower levels of AL in IL-1A/B-variant Down subjects (P < 0.05). The distribution of variant IL-1 genes in DS subjects was not different from the general population. However the association between the carriage of the IL-1 rare alleles and periodontitis differed between the Down and non-Down subjects. The carriage of the IL-1 rare alleles in the Down subjects tended to confer a protective effect against loss of periodontal attachment. PMID- 21712625 TI - Oral manifestations of HIV infection and their correlation with CD4 count. AB - Human Immunodeficiency Virus (HIV)-related oral lesions can be used as markers of the immune status. The present cross-sectional study was conducted to identify the oral manifestations in HIV-infected individuals and their association with reduced Cluster of Differentiation 4 (CD4) count. The study population included known HIV-positive patients. A detailed case history of 399 HIV-positive patients was obtained and general examination was carried out. Diagnosis of oral lesions was done based on presumptive criteria of EEC Clearinghouse, 1993. The CD4 count was determined in 369 patients and correlated with oral manifestations. The prevalence of oral lesions was found to be 76.70% (n = 306). Oral candidiasis (157 (39.3%)) was the most common oral lesion associated with HIV infection. Amongst various forms of oral candidiasis, erythematous candidiasis (122 (39.3%)) outnumbered the other forms. The mean CD4 count of patients with oral lesions (207 cells/mm(3)) was less than in patients without oral lesions (291 cells/mm(3)) (P = 0.002). Oral candidiasis was found to be significantly correlated to a reduced CD4 cell count below 200 cells/mm(3) (P = 0.000; Odds ratio = 3.1; 95% Confidence interval 1.9-4.9) with good sensitivity, best specificity and positive predictive value. Oral manifestations may be used as an alternative to CD4 count at field-based settings to diagnose the immune compromised status of HIV-infected individuals. PMID- 21712626 TI - Immunohistochemical detection of p53 and PCNA in ameloblastoma and adenomatoid odontogenic tumor. AB - Although ameloblastoma and adenomatoid odontogenic tumor (AOT) belong to the same group according to the World Health Organization, they show different biologic behaviors. PCNA, an amplifier of cell proliferation, and p53, a tumor suppressor protein, are overexpressed in some odontogenic lesions. The purpose of this study was to immunohistochemically evaluate the expression of p53 and PCNA to clarify the possible role of these proteins in different behaviors of ameloblastoma and AOT. The immunohistochemical expression of PCNA and p53 was determined in 30 solid ameloblastomas and 12 AOTs. Statistical tests including one-way ANOVA, t test, chi-square, Mann-Whitney U and Kendall were used to analyze the data. All tissue sections (except one specimen of plexiform ameloblastoma) exhibited immunoexpression for p53. PCNA was expressed in all specimens. There was no significant difference in PCNA expression between ameloblastomas and AOTs (P > 0.05). For p53, there was no statistical difference between subtypes of ameloblastomas (P > 0.05), whereas statistical differences were observed between ameloblastomas and AOTs (P < 0.001). There was no statistical difference in PCNA intensity of staining between ameloblastomas and AOTs (P > 0.05), whereas the p53 intensity in ameloblastomas was stronger than AOTs (P < 0.05). Positive correlation between PCNA and p53 was observed. We concluded that PCNA overexpression is not responsible for the difference in clinical behavior of these two lesions, whereas the expression of p53 in ameloblastoma may explain the more aggressive nature of this tumor compared with AOT. PMID- 21712627 TI - Effect of canal taper and plugger size on warm gutta-percha obturation of lateral depressions. AB - This study used transparent epoxy-resin root canal models to evaluate different main root canal tapers and various methods of vertical compaction for warm gutta percha obturation of lateral depressions. The root canal models had straight main root canals with three tapers and four lateral depressions at right angles to the main root canal, 1.0 mm and 3.0 mm from the apex. Three types of experimental stainless steel pluggers with different flat-tip diameters and tapers were used to compact the warm gutta-percha. The Obtura II was used for obturation. After obturation, the depth of penetration into lateral depressions was measured under a stereoscopic microscope, and the effects of root canal taper and plugger size were analyzed by using two-way analysis of variance. The penetration of warm gutta-percha into lateral depressions using the smallest-diameter plugger decreased with increasing main root canal taper. Penetration into lateral depressions increased with the use of pluggers of the correct size. There was a close relationship between plugger size and canal taper. The results suggest that main root canal taper and plugger size should be closely matched so as to promote gutta-percha obturation of lateral depressions. PMID- 21712628 TI - Use of aminoguanidine, a selective inducible nitric oxide synthase inhibitor, to evaluate the role of nitric oxide in periapical inflammation. AB - The purpose of this study was to evaluate the effects of aminoguanidine (AG) as a selective inhibitor of inducible nitric oxide synthase (iNOS) on the degree of inflammatory response in periapical lesions in the canine teeth of cats. Root canals from 52 cat canine teeth were exposed to the oral cavity and sealed after 7 days. One day before pulp exposure, cats were administered either AG (experimental group) or normal saline (control group), which was continued on a daily basis until the day of sacrifice. Animals were sacrificed at 28 days after pulp exposure. Inflammatory response in the periapical zones was analyzed histologically. The degree of periapical inflammation in the AG group was significantly lower than that in the control group (P < 0.05). Selective iNOS inhibitors such as AG thus reduce the intensity of inflammatory responses in periapical lesions. PMID- 21712629 TI - Prevalence and distribution of selected developmental dental anomalies in an Indian population. AB - The purpose of this study was to determine the prevalence of developmental dental anomalies in an Indian population and to statistically analyze the distribution of these anomalies. The study was based on clinical examination, evaluation of dental casts, and panoramic radiographs of 1123 Indian subjects (572 males, 551 females), who visited the outpatient clinic at Government Dental College, Indore between November 2009 and September 2010, after obtaining their informed consent. These patients were examined for the following developmental dental anomalies: shape anomalies (microdontia, talon cusp, dens evaginatus, fusion, taurodontism), number anomalies (hypodontia, oligodontia, anodontia), structural anomalies (amelogenesis imperfecta, dentinogenesis imperfecta) and positional anomalies (ectopic eruption, rotation, impaction). The percentages of these anomalies were assessed for the whole group and compared using statistical analysis. Among the 1123 subjects, a total of 385 individuals (34.28%) presented with the selected developmental dental anomalies. The distribution by sex was 197 males (34.44%), and 188 females (34.06%). Out of the total 1123 individuals, 351 (31.26%) exhibited at least one anomaly, 28 (2.49 %) showed two anomalies and 6 (0.53%) displayed more than two anomalies. P values indicated that the dental anomalies were statistically independent of sex. On intergroup comparison, positional anomalies were significantly most prevalent (P < 0.05) in the Indian population. The most common developmental dental anomaly was rotation (10.24%), followed by ectopic eruption (7.93%). The next common group was number anomalies. The most common number anomaly was hypodontia (4.19%), which had a higher frequency than hyperdontia (2.40%). Analyzing the next prevalent group of shape anomalies, microdontia (2.58%) was found to be the most common, followed by taurodontism (2.49%), dens evaginatus (2.40%) and talon cusp (0.97%). Dentinogenesis imperfecta (0.09%) was the rarest, followed by amelogenesis imperfecta (0.27%) and fusion (0.27%). PMID- 21712630 TI - Malignant melanoma of the oral cavity showing satellitism. AB - Oral malignant melanoma is a rare aggressive neoplasm of melanocytic origin, usually found on the hard palate and gingiva, and representing 0.2-8% of all melanomas. Unfortunately, oral mucosal melanomas have by far the worst prognosis, and therefore early detection is indispensable for improving their prognosis. Histopathological examination of any pigmented lesion is essential to rule out this lethal entity. Computed tomography is of help for assessing both the extent of the lesion and the presence of regional metastasis to the lymph nodes. Malignant melanoma cells stain positively with antibodies against HMB-45, S-100 protein and vimentin, and so immuno-histochemistry can play a crucial role in evaluating the depth of invasion and location of metastasis. The presence of satellite/in transit lesions is an important factor affecting prognosis. Here we report a 30-year-old female patient with malignant melanoma of the gingiva and hard palate with a satellite lesion, highlighting the role of various diagnostic tools in its detection, and the prognosis associated with satellitism. PMID- 21712631 TI - Mesenchymal chondrosarcoma in the mandible: report of a case with cytological findings. AB - Mesenchymal chondrosarcoma is an infrequent malignancy of bone and soft tissue, characterized by its peculiar bimorphic histological pattern. The use of fine needle aspiration (FNA) in the diagnosis of bone tumors is controversial. A 31 year-old woman presented with a mandibular lesion detected on routine examination for orthodontic treatment. Radiography revealed an ill-defined mixed radiolucency in the premolar region of the right mandible with invasive characteristics such as root resorption and widening of the periodontal ligament space of neighboring teeth. Blood clots obtained at FNA were fixed in formalin and exhibited spindle cells surrounding islands of pleomorphic chondroblasts against a bloody background. Histopathologically, clusters of spindle cells juxtaposed with mesenchymal tissue were detected, with a large hemangiopericytomatous component. In the present case, cytological findings combined with clinical and radiological data provided valuable information in establishing the diagnosis of malignancy and in planning further procedures and treatment. PMID- 21712632 TI - Submandibular ectopic thyroid tissue diagnosed by ultrasound-guided fine needle biopsy. AB - Ectopic thyroid gland is rarely seen in the submandibular region, thereby posing difficult diagnostic and management problems. Two Caucasian women presented with painful swelling in the submandibular region, which increased in size considerably during the preceding months. Ultrasound-guided fine needle biopsy (Ug-FNB) revealed ectopic thyroid tissue. In conclusion, ectopic thyroid gland with or without pathology should be included in the differential diagnosis of submandibular swelling and Ug-FNB should be one of the first diagnostic tools utilized for this rare clinical entity. PMID- 21712633 TI - Situs inversus in a patient with nevoid basal cell carcinoma syndrome: a histogenetic relationship? AB - Nevoid basal cell carcinoma syndrome (NBCCS) is an uncommon autosomal dominant inherited disorder with high penetrance and variable expressivity. It affects multiple organ systems, including the stomatological, skeletal, skin, eye, reproductive, and central nervous systems. It is caused by mutations in the patched tumor suppressor gene, PTCHI, located in the 9q22.3-q31 chromosome. To our knowledge, this is the first report of a patient with unusual radiological features, i. e. dextrocardia and situs inversus totalis, in conjunction with common features including multiple keratocystic odontogenic tumors, bifid ribs, palmar and plantar pits, bridging of the sella turcica and calcification of the falx cerebri. We examined whether these genetic conditions were associated, as both involve ciliary dysfunction. PMID- 21712634 TI - The usefulness of three-dimensional imaging in the diagnosis and treatment of clinically ambiguous gingival swelling. AB - We evaluated and treated a 54-year-old woman with gingival swelling. Conventional intraoral and panoramic radiography did not provide sufficient information for either determining the cause of gingival swelling or planning treatment of clinical symptoms. The 3D Accuitomo XYZ Slice View Tomograph (3DX) is a compact dental computed tomography device that allowed for accurate identification and optimal treatment of the causes of gingival swelling. At four years after treatment, 3DX radiographs showed no abnormalities in treated teeth or healing of surrounding structures. We conclude that high-resolution 3D images obtained with 3DX promise to be very effective for diagnosing oral diseases and determining effective treatment. PMID- 21712636 TI - Ganglioneuroma in the small intestine of a juvenile pig. AB - A mass was located in the small intestine of a slaughtered 6-month-old male Landrace-cross pig that had no clinical abnormalities. This egg-shaped well circumscribed mass was situated in the submucosal and muscular tissue layers and protruded into the lumen. Histopathologically, the tumor comprised discrete or aggregated ganglion and schwannian cells in neuropil-like tissue. Some ganglion cells contained Nissl substance in their cytoplasm. The ganglion cells stained positive for neuron-specific enolase, class III beta-tubulin, neurofilament, and synaptophysin; the schwannian cells stained positive for vimentin, S-100 protein, and glial fibrillary acidic protein. The tumor was diagnosed as a ganglioneuroma in accordance with these findings. Here, we have reported detailed immunohistochemical findings in addition to the histopathological features of a swine ganglioneuroma. PMID- 21712637 TI - An evaluation of acute toxicity of colloidal silver nanoparticles. AB - Tests for acute oral toxicity, eye irritation, corrosion and dermal toxicity of colloidal silver nanoparticles (AgNPs) were conducted in laboratory animals following OECD guidelines. Oral administration of AgNPs at a limited dose of 5,000 mg/kg produced neither mortality nor acute toxic signs throughout the observation period. Percentage of body weight gain of the mice showed no significant difference between control and treatment groups. In the hematological analysis, there was no significant difference between mice treated with AgNPs and controls. Blood chemistry analysis also showed no differences in any of the parameter examined. There was neither any gross lesion nor histopathological change observed in various organs. The results indicated that the LD(50) of colloidal AgNPs is greater than 5,000 mg/kg body weight. In acute eye irritation and corrosion study, no mortality and toxic signs were observed when various doses of colloidal AgNPs were instilled in guinea pig eyes during 72 hr observation period. However, the instillation of AgNPs at 5,000 ppm produced transient eye irritation during early 24 hr observation time. No any gross abnormality was noted in the skins of the guinea pigs exposed to various doses of colloidal AgNPs. In addition, no significant AgNPs exposure relating to dermal tissue changes was observed microscopically. In summary, these findings of all toxicity tests in this study suggest that colloidal AgNPs could be relatively safe when administered to oral, eye and skin of the animal models for short periods of time. PMID- 21712638 TI - Relationship between indocyanine green clearance test and feed intake and impaired hepatic function in dairy cows. AB - The purposes of this study were 1) to examine changes in the indocyanine green (ICG) clearance by feeding and 4-day fasting in dry cows, and (2) to investigate the relationship between ICG clearance and blood chemistry profile in postpartum cows. In 3 dry cows, post-feeding ICG half-life (T(1/2)) was shorter than the pre feeding value, and post-fasting T(1/2) was longer than pre-feeding and post feeding values. In 16 lactating cows, T(1/2) value at 2 weeks postpartum showed positive correlations with AST, T-Bil and gamma-GTP. These results suggested that ICG clearance correlated with T-Bil and liver enzymes can be sensitive and accurate diagnostic marker for impaired liver function in dairy cows. In addition, ICG clearance is greatly affected by feeding and fasting. PMID- 21712639 TI - Surveillance of Jaagsiekte sheep retrovirus in sheep in Hokkaido, the northern island of Japan. AB - Surveillance of jaagsiekte sheep retrovirus (JSRV) infection was performed by polymerase chain reaction (PCR) of blood DNA samples collected from 40 sheep and goats in 10 different flocks in Hokkaido, the northern island of Japan. No exogenous (oncogenic) JSRV sequence was detected by PCR in these samples, while the ovine endogenous retrovirus sequence was successfully amplified in all samples. Our paper is the first demonstration of JSRV surveillance in Japan and shows no evidence of oncogenic JSRV infection in sheep and goats in Hokkaido. PMID- 21712640 TI - N-acetylserotonin increases cell proliferation and differentiating neuroblasts with tertiary dendrites through upregulation of brain-derived neurotrophic factor in the mouse dentate gyrus. AB - In this study, we investigated the effects of N-acetylserotonin (NAS) on cell proliferation and neuroblast differentiation in the mouse dentate gyrus using anti-Ki67 and anti-doublecortin (DCX) antibodies. Ki67 is expressed in the nucleus or on the surface of chromosomes during all of the active phases of the cell cycle, and DCX is expressed in neuronal precursor cells as well as in immature neurons. At 17 weeks of age, 20 mg/kg of NAS or the same volume of vehicle was intraperitoneally administered once a day for 3 weeks. The animals were sacrificed 2 hr after the last vehicle or NAS treatment. NAS treatment significantly increased the number of Ki67-positive nuclei and DCX-immunoreactive neuroblasts with well-developed dendrites (tertiary dendrites) compared to the vehicle-treated group. However, the number of DCX-immunoreactive neuroblasts without tertiary dendrites was not changed. The administration of NAS also significantly increased the protein levels of brain-derived neurotrophic factor (BDNF) in the dentate gyrus. This result suggests that NAS significantly promotes cell proliferation and the number of differentiating neuroblasts with tertiary dendrites through an increase in BDNF levels in the mouse dentate gyrus. PMID- 21712641 TI - Expression of two novel cytochrome P450 3A131 and 3A132 in liver and small intestine of domestic cats. AB - Cytochrome P450 3A (CYP3A) is the major subfamily of CYP, one of the most important metabolizing enzymes for drugs in humans and other mammals. We found two novel CYP3A genes, CYP3A131 and CYP3A132 in domestic cats (Felis catus). Both feline CYP3A proteins consist of 504 deduced amino acids and show high identity with canine CYP3A homologues and those of some artiodactyls. CYP3A131 transcripts were expressed predominantly in liver and small intestine, and to a negligible extent in other tissues, including brain, heart, kidney and lung. CYP3A132 expression was only detected in liver with much lesser amount. These results suggest the possible major role of CYP3A131 in xenobiotic metabolism including first-pass effects in domestic cats. PMID- 21712642 TI - Detection of the new Ehrlichia species closely related to Ehrlichia ewingii from Haemaphysalis longicornis in Yonaguni Island, Okinawa, Japan. AB - We collected a total of 206 Haemaphysalis longicornis ticks by flagging in pastures in Yonaguni Island, Okinawa, Japan, in April 2008. Four of the 206 tick DNA samples tested were positive in a polymerase chain reaction (PCR) screening for the 16SrRNA gene of Anaplasmataceae. Partial sequences of 4 PCR products were identical to each other. Longer sequences of the 16SrRNA gene were successfully determined in 2 of the 4 tick samples, and the obtained 1,392 bp and 1,300 bp sequences revealed high similarity to the 16SrRNA gene sequences of the validated Ehrlichia species, including Ehrlichia ewingii, E. chaffeensis, and E. canis (98.3-98.6%). We also sequenced 1,304 bp of the groEL gene from the 2 tick samples, and found that these had the highest similarity to sequences of E. ewingii (94.0-94.4%) in the validated ehrlichial species. Based on the 16SrRNA and groEL gene sequences, the ehrlichial agents detected in this study were similar to the Ehrlichia species detected in Asia and may compose a new Ehrlichia species with other Ehrlichia species detected in Asia. PMID- 21712643 TI - Swine herds achieve high performance by culling low lifetime efficiency sows in early parity. AB - Sow lifetime performance and by-parity performance were analyzed using a 3 by 3 factorial design, comprising 3 herd productivity groups and 3 sow efficiency groups. Data was obtained from 101 Japanese herds, totaling 173,526 parity records of 34,929 sows, for the years 2001 to 2006. Sows were categorized into 3 groups based on the lower and upper 25th percentiles of the annualized lifetime pigs born alive: low lifetime efficiency sows (LE sows), intermediate lifetime efficiency sows or high lifetime efficiency sows. Herds were grouped on the basis of the upper and lower 25th percentiles of pigs weaned per mated female per year, averaged over 6 years: high-, intermediate- or low-performing herds. Mixed effects models were used for comparisons. LE sows in high-performing herds had 57.8 fewer lifetime nonproductive days and 0.5 earlier parity at removal than those in low-performing herds (P<0.05). The number of pigs born alive of LE sows continuously decreased from parity 1 to 5, whereas those of high lifetime efficiency sows gradually increased from parity 1 to 4 before decreasing up to parity >= 6 (P<0.05). In conclusion, the LE sows have a performance pattern of decreasing number of pigs born alive across parity. The present study also indicates that high-performing herds culled potential LE sows earlier than the other herds. PMID- 21712644 TI - Changes in acute-phase proteins and cytokines in serum and milk whey from dairy cows with naturally occurring peracute mastitis caused by Klebsiella pneumoniae and the relationship to clinical outcome. AB - This study was conducted to evaluate the changes in acute-phase proteins and cytokine concentrations in dairy cows with naturally occurring peracute Klebsiella pneumoniae (K. pneumoniae) mastitis and their association with the outcome of the disease. Seventeen Holstein cows with K. pneumoniae mastitis from 8 dairy farms were divided on the basis of outcome after local and systemic therapy into 2 groups comprising 8 euthanized cows and 9 that recovered. Changes in acute-phase proteins and cytokine concentrations in cows with K. pneumoniae mastitis were evaluated at the onset of the disease (day 0) and at days 3, 7 and 14 after therapy and compared with those of 13 healthy dairy cows. The concentrations of haptoglobin (Hp) and interleukin (IL)-6 in serum and alpha(1) acid glycoprotein and IL-1beta in serum and whey on day 0 were significantly (P<0.05) higher in the euthanized cows than in those that recovered and the healthy cows. A correlation (r=0.90, P<0.01, n=17) was found between IL-6 and Hp concentrations in sera from recovered and euthanized cows at day 0. This indicated that serum concentrations of Hp and IL-6 at the initial examination were prognostic factors for survival, and the cutoff values were 2,020 ug/ml and 32 ng/ml, respectively. These results suggest that IL-6 and Hp concentrations are involved in the manifestation of K. pneumoniae mastitis and may be possible indicators of the prognosis of peracute K. pneumoniae mastitis. PMID- 21712646 TI - Pre-deployment vaccinations and perception of risk among US military personnel. AB - BACKGROUND: Vaccination programs have significantly reduced the incidence of numerous infectious diseases; however, public attitudes toward immunization oftentimes remain contentious. Concerns over vaccine safety and effectiveness, compounded with reduced perceived risk of disease, influence decision making and frequently override public health recommendations. Although vaccinations are compulsory for US military personnel, their concerns mirror the general population, resulting in sub-optimal coverage. RESULTS: Demographics of the 1,757 respondents: 83.3% male, 71.1% Army, 87.5% enlisted, mean age of 29.2 years (standard deviation: 8.3). The majority (89.3%) reported receiving all pre deployment vaccines; 17.1% stated they would decline if given the opportunity. Factors associated with an increased likelihood of declining vaccines included a perception that the vaccines were not safe (odds ratio [OR]: 3.7; p < 0.001) and rarely/never believing information from the military command (OR: 2.2; p < 0.001). Those with a perceived risk for the diseases targeted by the vaccines were less likely to decline (OR: 0.6; p < 0.001). DISCUSSION: In US military personnel, negative perceptions of pre-deployment vaccines exist. These attitudes appear to be associated with negative perceptions of vaccine safety and low perceived disease risk. Targeted interventions, focusing on the drivers of negative perceptions toward vaccines, and accounting for the source of the educational material, may influence attitudes and improve vaccination perceptions. METHODS: A self-administered questionnaire was completed by a convenience sample of US military personnel deployed to Iraq, Afghanistan and surrounding regions. Questions solicited demographic information and assessed agreement with statements in an attempt to identify factors associated with declining pre-deployment vaccines. PMID- 21712645 TI - Safety and reactogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 viral-like-particle vaccine in older adolescents and young adults. AB - BACKGROUND: Prophylactic vaccination with a quadrivalent HPV (types 6, 11, 16, 18) vaccine (qHPV) has been shown to prevent infection with HPV 6/11/16/18 and associated disease in women and more recently, in men. Here we report on the safety and reactogenicity of the qHPV vaccine in males. A total of 4,065 healthy males aged 16-26 years were enrolled into a randomized, placebo-controlled, double-blind trial. Subjects were randomized 1:1 to receive qHPV vaccine or placebo at day 1, month 2, and month 6. Safety and tolerability were assessed via the collection of reported adverse experiences (AEs). All serious AEs (vaccine- or procedure-related or not) and all deaths occurring during the study were recorded. Safety analyses were conducted in all subjects who received at least one dose of vaccine or placebo. The proportion of subjects who reported at least one injection-site AE was higher in the qHPV vaccine group versus the placebo group (60.1% vs 53.7%, respectively), however most of these AEs were mild/moderate in intensity. The incidence of at least one systemic AE was comparable between the vaccine and placebo groups (31.7% vs 31.4%, respectively). There were no vaccine-related serious AEs or deaths. The occurrence of AEs did not increase with each successive injection, and among trial participants who were seropositive for at least one vaccine HPV type at enrollment, the profile of adverse events was similar to that of the entire study cohort. The qHPV vaccine was generally well tolerated in males aged 16-26 years and had a favorable safety profile. PMID- 21712647 TI - Molecular architecture of Ca2+ signaling control in muscle and heart cells. AB - Ca2+ signaling in skeletal and cardiac muscles is a bi-directional process that involves cross-talk between signaling molecules in the sarcolemmal membrane and Ca2+ release machinery in the intracellular organelles. Maintenance of a junctional membrane structure between the sarcolemmal membrane and the sarcoplasmic reticulum (SR) provides a framework for the conversion of action potential arrived at the sarcolemma into release of Ca2+ from the SR, leading to activation of a variety of physiological processes. Activity-dependent changes in Ca2+ storage inside the SR provides a retrograde signal for the activation of store-operated Ca2+ channel (SOC) on the sarcolemmal membrane, which plays important roles in the maintenance of Ca2+ homeostasis in physiology and pathophysiology. Research progress during the last 30 years had advanced our understanding of the cellular and molecular mechanisms for the control of Ca2+ signaling in muscle and cardiovascular physiology. Here we summarize the functions of three key molecules that are located in the junctional membrane complex of skeletal and cardiac muscle cells: junctophilin as a "glue" that physiologically links the SR membrane to the sarcolemmal membrane for formation of the junctional membrane framework, mitsugumin29 as a muscle-specific synaptophysin family protein that contributes to maintain the coordinated Ca2+ signaling in skeletal muscle, and TRIC as a novel cation-selective channel located on the SR membrane that provides counter-ion current during the rapid process of Ca2+ release from the SR. PMID- 21712648 TI - The SK channel as a novel target for treating alcohol use disorders. AB - We recently described the SK-type potassium channel as a novel target for treatment of excessive alcohol intake.1 SK channel function is reduced in the nucleus accumbens (NAcb) core in rats consuming alcohol under intermittent (IAA) but not continuous (CAA) access, and the FDA-approved SK activator chlorzoxazone reduces the excessive alcohol intake in IAA rats but not the more moderate intake in CAA rats. Here, we discuss the implications of these and related findings for SK as a treatment for alcohol use disorders. In addition, we report that many NAcb core electrophysiological parameters related to action potential waveform or basal parameters were not altered in alcohol-drinking rats. These results are in strong contrast to those reported for cocaine, where several NAcb ion channels show adaptations after cocaine exposure. These results suggest that alcohol intake is associated with only limited ion channel neuro-adaptations in the NAcb relative to cocaine, and support the hypothesis that SK represents a selective and potent intervention to reduce excessive alcohol intake. PMID- 21712649 TI - Bioinformatic prediction and experimental verification of sRNAs in the haloarchaeon Haloferax volcanii. AB - Recently a small-scale RNomics study led to the experimental identification of 21 intergenic and 18 antisense sRNA genes in the haloarchaeon Haloferax volcanii. To broaden the knowledge about sRNAs in haloarchaea, two bioinformatic approaches were used to predict sRNA genes in the genome of H. volcanii. More than 120 putative intergenic sRNA genes were identified by these comparative genomic approaches. The expression of 61 of the predicted genes was analyzed using DNA microarrays, and 37 were found to be expressed under at least one of three conditions tested. Using the results of Northern blot analyses and of a high throughput sequencing study the number of expressed genes was raised to 54 and the small size was verified for 26 predicted sRNAs. An analysis of the coding capacity revealed that the set of predicted sRNAs most likely does not encode proteins or peptides. In two cases it turned out that the predictions had not identified bona fide sRNAs but conserved regions in UTRs of large protein encoding transcripts. Taken together, the combination of bioinformatic prediction and experimental verification has more than tripled the number of known haloarchaeal sRNAs, underscoring the importance of regulatory RNAs in the third domain of life, the archaea. Further analyses of the biological functions of selected sRNAs, including the construction of deletion mutants, are currently under way. PMID- 21712650 TI - The emerging role of pre-messenger RNA splicing in stress responses: sending alternative messages and silent messengers. AB - Alternative splicing (AS) of pre-messenger RNAs is a major process contributing to both transcriptome and proteome diversity in various physiological and pathological situations. There is also accumulating evidence that various stresses impact on AS. In particular, recent analyses of the transcriptome reveal large numbers of AS events that are regulated by genotoxic stress inducers like radiations and chemotherapeutic agents. Many AS events have the potential to affect the relative production of protein isoforms with different activities, as shown in the case of several genes involved in apoptosis. There is also increasing evidence that stresses induce "non-productive" splice variants, leading to a decrease in gene expression levels or preventing increases in protein levels despite transcriptional stimulation. This is typically achieved by the production of splice variants that are subject to nonsense-mediated decay. In addition, recent studies suggest that pre-mRNA splicing efficiency or fidelity may be altered by stresses. For example, various genotoxic agents induce multiple exon skipping in MDM2 transcripts, thereby preventing the production of the main p53-ubiquitin ligase and favoring p53 activity in response to genotoxic agents. In terms of mechanisms, stresses can impact on pre-mRNA splicing by inducing post translational modifications and subcellular redistribution of splicing factors, or by targeting the communication between the splicing and transcription machineries. Altogether, these data suggest that splicing regulatory networks play a key role in the cellular responses triggered by stresses. PMID- 21712651 TI - Conformational heterogeneity and the determinants of tertiary stabilization in the hammerhead ribozyme from Dolichopoda cave crickets. AB - Repetitive DNA elements in Dolichopoda cave cricket genomes contain extended hammerhead ribozymes that are functional in adult crickets, but that exhibit very low self-cleavage activity in vitro relative to other extended hammerhead ribozymes. We find that the parental ribozyme tends to misfold into alternate secondary structures in vitro, complicating analysis of contributions by specific nucleotides to activity under biologically relevant magnesium concentrations. However, minor sequence alterations that stabilize the active secondary structure, without altering candidate tertiary interacting nucleotides, boosted observed rates more than 50-fold (4.4 +/- 1.7 min(-1)) and doubled the cleavage extent (>60%) in submillimolar magnesium. Productive alterations included flipping two base pairs in stem I, lengthening stem I and opening stem III to generate a trans-cleaving ribozyme. Specific peripheral nucleotides involved in tertiary stabilization were then identified through kinetic analysis for a series of sequence variants and by correlating plateau cleavage values with band intensity in native gel electrophoresis. These results demonstrate that conformational heterogeneity governs self-cleavage by the wild-type Dolichopoda hammerhead ribozyme in vitro, and they suggest a strategy for improving activity and enhancing the suitability of HHRz for intracellular and biotechnology applications. PMID- 21712652 TI - Developmental functions of piRNAs and transposable elements: a Drosophila point of-view. AB - The primary function of the piRNA pathway is to repress the expression and transposition of transposable elements. However, the piRNA pathway has additional biological and developmental functions. These functions are either a consequence of transposon regulation, or they result from direct roles of transposable elements in chromosome structure and gene regulation through piRNAs. Recent data have extended the functions of transposable elements in gene regulation, revealing a trans-acting role of transposable element piRNAs in the control of gene expression. Over the last few years, extensive studies on the piRNA pathway have rapidly increased our understanding of the relationships between transposable elements and the host genome, and of the essential role of transposable elements in biological and developmental processes. PMID- 21712653 TI - Calmodulin overexpression does not alter Cav1.2 function or oligomerization state. AB - Interactions between calmodulin (CaM) and voltage-gated calcium channels (Ca(v)s) are crucial for Ca(v) activity-dependent feedback modulation. We recently reported an X-ray structure that shows two Ca(2+)/CaM molecules bound to the Ca(v)1.2 C terminal tail, one at the PreIQ region and one at the IQ domain. Surprisingly, the asymmetric unit of the crystal showed a dimer in which Ca(2+)/CaM bridged two PreIQ helixes to form a 4:2 Ca(2+)/CaM:Ca(v) C-terminal tail assembly. Contrary to previous proposals based on a similar crystallographic dimer, extensive biochemical analysis together with subunit counting experiments of full-length channels in live cell membranes failed to find evidence for multimers that would be compatible with the 4:2 crossbridged complex. Here, we examine this possibility further. We find that CaM over-expression has no functional effect on Ca(v)1.2 inactivation or on the stoichiometry of full-length Ca(v)1.2. These data provide further support for the monomeric Ca(v)1.2 stoichiometry. Analysis of the electrostatic surfaces of the 2:1 Ca(2+)/CaM:Ca(V) C-terminal tail assembly reveals notable patches of electronegativity. These could influence various forms of channel modulation by interacting with positively charged elements from other intracellular channel domains. PMID- 21712655 TI - Treatment-centred prevention: an integrated biomedical and social approach to HIV prevention. PMID- 21712657 TI - Tenofovir and emtricitabine cerebrospinal fluid-to-plasma ratios correlate to the extent of blood-brainbarrier damage. PMID- 21712654 TI - Regulation and function of miRNA-21 in health and disease. AB - The small regulatory RNA microRNA-21 (miR-21) plays a crucial role in a plethora of biological functions and diseases including development, cancer, cardiovascular diseases and inflammation. The gene coding for pri-miR-21 (primary transcript containing miR-21) is located within the intronic region of the TMEM49 gene. Despite pri-miR-21 and TMEM49 are overlapping genes in the same direction of transcription, pri-miR-21 is independently transcribed by its own promoter regions and terminated with its own poly(A) tail. After transcription, primiR- 21 is finally processed into mature miR-21. Expression of miR-21 has been found to be deregulated in almost all types of cancers and therefore was classified as an oncomiR. During recent years, additional roles of miR-21 in cardiovascular and pulmonary diseases, including cardiac and pulmonary fibrosis as well as myocardial infarction have been described. MiR-21 additionally regulates various immunological and developmental processes. Due to the critical functions of its target proteins in various signaling pathways, miR-21 has become an attractive target for genetic and pharmacological modulation in various disease conditions. PMID- 21712658 TI - Bacterial translocation: a useful biomarker for immune activation and disease progression. PMID- 21712660 TI - Bibliography. Infections of the immunocompromised host. Current world literature. PMID- 21712661 TI - Human factors and systems in emergency departments. PMID- 21712662 TI - Prehospital resuscitative hysterotomy. PMID- 21712664 TI - Recent developments in imaging of multiple sclerosis. AB - BACKGROUND: Magnetic resonance imaging (MRI) has revolutionized the diagnosis and management of patients with multiple sclerosis (MS). Metrics derived from conventional MRI are now routinely used to detect therapeutic effects and extend clinical observations. Conventional MRI measures have insufficient sensitivity and specificity to reveal the true degree of pathologic changes occurring in MS. T2-weighted and T1-weighted imaging cannot distinguish between inflammation, edema, demyelination, Wallerian degeneration, and axonal loss. Nonconventional MRI techniques are now emerging and proving to be more related with the most disabling features of MS. REVIEW SUMMARY: The large variety of MRI metrics presently available are summarized, including measurement of T1-weighted hypointense lesions, central nervous system atrophy, magnetization transfer imaging, myelin water fraction, diffusion tensor imaging, magnetic resonance spectroscopy, and susceptibility-weighted imaging. The most up-to-date MRI techniques and their relationship with central nervous system pathology are described, and a comprehensive overview of the use of MRI in patients with MS is offered. CONCLUSIONS: Advanced MRI techniques provide a better understanding of the pathologic processes that most likely are related to disease activity and clinical progression. Such metrics are able to reveal a range of tissue changes that include demyelination, axonal loss, iron deposition, and neurodegeneration and they provide the evidence that important occult pathology is occurring in the normal appearing white and gray matter. Despite these promising results none of these techniques have been adopted in the MRI consensus guidelines for imaging of the brain and spinal cord in patients with MS due to lack of standardization. PMID- 21712663 TI - Presentation, diagnosis, pathophysiology, and treatment of the neurological features of Sturge-Weber syndrome. AB - BACKGROUND: Sturge-Weber syndrome (SWS) is a neurovascular disorder with a capillary malformation of the face (port-wine birthmark), a capillary-venous malformation in the eye, and a capillary-venous malformation in the brain (leptomeningeal angioma). Although SWS is a congenital disorder usually presenting in infancy, occasionally neurological symptoms first present in adulthood and most affected individuals do survive into adulthood with varying degrees of neurological impairment including epilepsy, hemiparesis, visual field deficits, and cognitive impairments ranging from mild learning disabilities to severe deficits. SWS is a multisystem disorder that requires the neurologist to be aware of the possible endocrine, psychiatric, ophthalmologic, and other medical issues that can arise and impact the neurological status of these patients. Some of these clinical features have only recently been described. REVIEW SUMMARY: This review summarizes the neurological manifestations of SWS, discusses issues related to the diagnosis of brain involvement, relates major neuroimaging findings, briefly describes the current understanding of pathogenesis, and provides an overview of neurological treatment strategies. CONCLUSIONS: Recent clinical research has highlighted several novel and lesser known aspects of this clinical syndrome including endocrine disorders. Functional imaging studies and clinical experience suggests that neurological progression results primarily from impaired blood flow and that prolonged seizures may contribute to this process. Treatment is largely symptomatic although aggressive efforts to prevent seizures and strokes, in young children especially, may impact outcome. PMID- 21712665 TI - Successful intravenous thrombolysis in a stroke patient with hemiballism. AB - INTRODUCTION: Hemiballism (HB) is a relatively rare hyperkinetic disorder commonly caused by an acute stroke. Such patients usually receive symptomatic therapy with limited effect. We report the case of an acute stroke patient with HB who was successfully treated with intravenous recombinant tissue plasminogen activator (rtPA). CASE REPORT: A 67-year-old man with a history of hypertension and ischemic coronary heart disease presented in the emergency room 85 minutes after sudden onset of involuntary coarse flinging movements of the left arm and leg. Neurological investigation revealed oromandibular dyskinesia; left blepharospasm; dyskinetic movements of the head and neck; dysarthria; and forceful, jerky, irregular, flinging, large-amplitude involuntary movements involving his left arm and left leg. Initial brain computed tomography showed only mild confluent periventricular hypodensities in the vicinity of the frontal horns. The calculated National Institutes of Health Stroke Scale score was 1, for dysarthria. The sudden onset of HB, however, suggested an acute stroke and we decided to treat the patient with intravenous rtPA. Thrombolytic therapy with rtPA began 200 minutes after symptom onset, and after the patient's increased arterial blood pressure was resolved. Follow-up examination performed 12 hours after therapy revealed only mild dysarthria; mild ataxia of the left arm, and ataxic gait. Delayed brain computed tomography did not indicate recent ischemia, although a fluid attenuated inversion recovery magnetic resonance imaging sequence revealed high signal intensity lesions in the vicinity of the right putamen and left cerebellar hemisphere. After 1 month, a follow-up examination revealed only mild dysarthria and mild ataxia of the left arm. CONCLUSIONS: Acute stroke patients with low National Institutes of Health Stroke Scale score, including patients with HB, should be considered as candidates for thrombolytic treatment. PMID- 21712666 TI - Cerebral venous sinus thrombosis associated with cerebral hemorrhage: is anticoagulant treatment safe? AB - The current recommended treatment for cerebral venous sinus thrombosis (CVST) is anticoagulation, and the presence of intracranial hemorrhage (ICH) is not a contraindication. We present a case of ICH associated with CVST in which heparin treatment was associated with rebleeding, and we review current evidence of anticoagulation safety in patients with ICH associated with CVST. A 65-year-old man presented with right hemiparesis and loss of consciousness. Brain computed tomography showed a left frontoparietal hemorrhage. Angiographic studies with magnetic resonance imaging showed the presence of a partial superior saggital sinus thrombosis. With a diagnosis of CVST, intravenous heparin was administered. After 24 hours the patient had a symptomatic increase in ICH size, and 2 days later the patient developed a status epilepticus with new evidence of rebleeding. Anticoagulant treatment was stopped and the patient experienced neurological improvement, with no new episodes of rebleeding. Evidence for the safety of anticoagulants in CVST comes from 2 small trials involving a total of 79 patients, but only 18 had some degree of bleeding in baseline computed tomography. A meta-analysis suggested that in CVST patients who are treated with anticoagulants, the risk of ICH is low, but acknowledged that an impact of up to 9% of new ICH cannot be ruled out. As there is not enough evidence for the safety of anticoagulant therapy in patients with early ICH associated with CVST, the therapeutic decision must be individualized and the rebleeding risk should be weighed in those patients. PMID- 21712667 TI - Co-segregation of Huntington disease and hereditary spastic paraplegia in 4 generations. AB - INTRODUCTION: Huntington disease (HD) is an autosomal dominant neurodegenerative disease characterized by choreic hyperkinesias, cognitive decline, and psychiatric manifestations, caused by an increased number of CAG repeats in the IT15 gene on chromosome 4p16.3. Silver syndrome is a rare autosomal dominant form of complicated hereditary spastic paraplegia, characterized by lower limb spasticity in addition to amyotrophy of the small muscles of the hands. In addition to the previously identified locus SPG17 on chromosome 11q12-q14, a new locus (SPG38) on chromosome 4p16-p15 has been recently identified, a region that includes the HD gene. REPORT OF THE CASES: We present a Greek family with 5 members diagnosed with HD in 4 generations. All affected members also presented with clinical features of Silver syndrome showing severe spastic paraplegia and prominent atrophy of all small hand muscles bilaterally. None of the other family members showed features of either HD or spastic paraplegia. CONCLUSIONS: The reported coexistence of Silver syndrome with HD in 4 generations is not fortuitous, suggesting that these 2 distinct genetic disorders are in linkage disequilibrium. Although rare, it is reasonable to expect additional similar cases. Clinical neurologists should perhaps investigate this possibility in cases combining features of HD and involvement of the upper and lower motor neurons. PMID- 21712668 TI - Acute Marchiafava-Bignami disease with selective involvement of the precentral cortex and splenium: a serial magnetic resonance imaging study. AB - INTRODUCTION: Marchiafava-Bignami disease (MBD) is defined pathologically as callosal degeneration associated with chronic alcoholism. We report a patient with MBD with acute lesions confined in the precentral cortex and splenium. Various magnetic resonance imaging (MRI) modalities were performed sequentially to elucidate the pathophysiology. CASE REPORT: A 52-year-old man with chronic alcoholism developed acute confusion and dysarthria. He improved incompletely with nutritional supplementation. Diffusion-weighted imaging MRI disclosed the presence of reversible lesions with low apparent diffusion coefficient values in the precentral cortex and splenium. Perfusion-weighted imaging revealed that the cerebral blood volume and flow decreased and subsequently increased, and the mean transit time and time to peak were persistently prolonged. On magnetic resonance spectroscopy, choline was initially normal and became elevated during the recovery period, whereas N-acetylaspartate was low initially and after the resolution of the lesion on conventional MRI. CONCLUSIONS: The precentral cortex and splenium are the most vulnerable areas in acute MBD. The lesions have reversible restricted diffusivity and hypoperfusion. The magnetic resonance spectroscopy findings correlate well with the clinical status. PMID- 21712669 TI - Spontaneous regression of an intracerebral lymphoma (ghost tumor) in a liver engrafted patient. AB - Posttransplantation lymphoproliferative disorder involving the central nervous system is a rare and serious complication associated with solid organ transplantation. We report a liver transplant recipient who noticed unbalance, dizziness, and headache 30 months after transplantation. Magnetic resonance imaging (MRI) showed a space-occupying lesion in the corpus callosum and adjacent parenchyma of the left hemisphere. In the following month, the neurological symptoms and the MRI findings regressed without any treatment. Four months later the patient developed a left-sided hemiparesis. MRI now revealed a considerable increase of the known lesion and new lesions in other locations. Stereotactic biopsy showed a B-cell non-Hodgkin lymphoma of high malignancy. A spontaneous regression of cerebral lymphoma is possible, even in immunosuppressed patients. Hence, this diagnosis must not be dismissed if there is spontaneous regression of a lesion in the MRI or an amelioration of the clinical symptoms. Owing to the high mortality rate associated with this disease, prompt pathologic diagnosis is required to initiate appropriate therapy. PMID- 21712670 TI - Adult Leigh disease without failure to thrive. AB - INTRODUCTION: Most Leigh disease (LD) patients die before reaching adulthood, but there are reports of "adult LD." The clinical features of adult LD were quite different from those in infant or childhood cases. Here, we describe a normally developed patient with adult LD, who presented with spastic paraplegia that was followed several years later by acute encephalopathy. We also conducted a systemic literature search on adult LD and integrated its various manifestations to arrive at a diagnostic procedure for adult LD. CASE REPORT: A 26-year-old woman presented with acute encephalopathy after spastic paraplegia. On her first admission, she exhibited bilateral basal ganglia lesion on magnetic resonance images and normal serum lactate levels. On second admission, she had acute encephalopathy with lactic acidosis and bilateral basal ganglia and brainstem lesions. A muscle biopsy revealed cytochrome c oxidase deficiency, and a diagnosis of adult LD was made. Despite treatment in the intensive care unit, she died 9 days after admission. CONCLUSIONS: A review of the literature describing adult LD revealed that developmental delay, COX deficiency, serum lactate elevation, and basal ganglia lesions occurred less frequently than they did in children with LD. Cranial nerve disturbance, pyramidal signs, and cerebellar dysfunction were the primary symptoms in adult LD. Thus, the many differences between childhood and adult LD may be helpful for diagnosing adult LD. PMID- 21712671 TI - Clinical and radiologic manifestations of H1N1 virus infection associated with neurological complications: a case report. AB - Encephalitis complicating novel influenza A (H1N1) viral infection is rare and has only been reported in children. We present cerebral magnetic resonance imaging findings from a confirmed adult case with H1N1 infection who presented with acute encephalitis and subsequent respiratory failure. Cerebral magnetic resonance imaging showed hyperintense abnormalities in the bilateral globus pallidus in T1-weighted images, and multiple hyperintense abnormalities in the right insular cortex, right parahippocampus, and the pontine tegmentum in fluid attenuated inversion recovery images. PMID- 21712672 TI - What is the effect of low-molecular weight heparin for venous thromboembolism prophylaxis compared with mechanical methods, on the occurrence of hemorrhagic and venous thromboembolic complications in patients with intracerebral hemorrhage? A critically appraised topic. AB - BACKGROUND: Patients with intracerebral hemorrhage (ICH) are at risk for venous thromboembolic (VTE) complications after stroke. The dilemma remains on whether it is safe to initiate low-dose low-molecular weight heparin (LMWH) in patients with ICH without risking expansion of the initial bleed. OBJECTIVE: To critically assess current evidence regarding the safety of low-dose LMWH in the prevention of VTE complications in patients with acute ICH. METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of vascular and hospital neurology. RESULTS: A recent quasi-randomized controlled trial was selected for critical appraisal. This trial assigned 75 ICH patients to subcutaneous LMWH or long compression stockings for deep venous thrombosis and pulmonary embolism prophylaxis. In patients who received low-dose LMWH, there was no hematoma enlargement at 72 hours, day 7, or day 21 compared with the compression stocking group. There was hematoma enlargement in 9 patients at 24 hours, 6 of which were in the LMWH group, but this was before the initiation of the LMWH, which occurred at 48 hours. Adverse events were VTE complications in 4 of 39 patients in the LMWH group and in 3 of 36 patients in the long compression stocking group. CONCLUSIONS: Initiation of low-dose LMWH in spontaneous ICH patients for the purpose of VTE prophylaxis is likely safe. However, a clinical decision based solely on the results of this study cannot be made due to numerous methodological and design shortcomings. A well-designed randomized controlled trial is still needed to answer this clinical question. PMID- 21712674 TI - Evidentialism: a borrowed approach to EBP. PMID- 21712675 TI - Transform into a culture of safety. PMID- 21712676 TI - Investing in the future nursing workforce. PMID- 21712677 TI - Education matters: does higher learning yield higher income? PMID- 21712679 TI - Transformation through IT. PMID- 21712680 TI - The Magnetic Pull: leading the change reaction. PMID- 21712681 TI - Need to improve patient satisfaction? Consider a staffing matrix. PMID- 21712682 TI - Help! Strategies for preventing information overload. PMID- 21712685 TI - Signet ring cell perianal paget disease: loss of MUC2 expression and loss of signet ring cell morphology associated with invasive disease. AB - Perianal Paget disease (PPD) is a rare and heterogeneous neoplasm in which underlying associated adenocarcinoma is a frequent comorbidity. Previous attempts have been made to define the cells of origin of this neoplasm and delineate the discriminating immunohistochemical (IHC) signature of primary versus secondary disease. We report a case of PPD in a 32-year-old male, that displays an unusual multiclonal immunostaining pattern with focal loss of MUC2 expression and simultaneous phenotypic loss of signet ring cell morphology associated with invasive disease. We postulate that our case captures the transition from PPD to invasive carcinoma. The loss of MUC2 positivity seen in this case could be relevant to biopsies of PPD in which no areas of invasion are initially found, and consequently a more thorough pathologic evaluation for invasive disease should be undertaken in cases with MUC2 negativity. Despite promising IHC staining patterns in individual case reports, PPD remains a heterogeneous entity. The specific IHC signature of primary versus secondary disease remains difficult to define due to the small number of cases reported in the literature and additional studies are needed. Therefore, in addition to a case's microscopic findings including IHC studies, distinguishing individual cases of primary from secondary PPD requires clinical correlation. PMID- 21712684 TI - Hemangiopericytoma-like dermatofibroma with mast cells. AB - We report an unusual case of hemangiopericytoma-like dermatofibroma in the right shoulder of an 82-year-old patient with a well-defined nodular growth located in the dermis. Microscopic study revealed a band of haphazardly arranged cells with a vascular component of gaping, simple, endothelial-lined vascular structures with intervening postcapillary venules and capillary-sized slit-like "staghorn" vascular channels filled with erythrocytes; abundant mast cells were also observed. The neoplasm cells were positive for CD68 and Factor XIIIA and negative for CD34. Few data have been published on the presence of abundant mast cells (tryptase and CD117 positive) in these neoplasm. The differential diagnosis of this entity should consider other spindle cell neoplasm, including hemangiopericytoma/solitary fibrous tumor, dermatofibrosarcoma protuberans, myopericytoma, angioleiomyoma, amelanotic melanoma, pecoma, and benign and malignant peripheral nerve tumors. We present an infrequent case of dermatofibroma with a vascular pattern resembling hemangiopericytoma and the presence of abundant mast cells, which may be responsible for this vascular component. PMID- 21712686 TI - Cutaneous mycobacterial spindle cell pseudotumor: a potential mimic of soft tissue neoplasms. AB - A 55-year-old man with scleroderma treated with prednisone and etanercept presented with enlarging sporotrichoid nodules on the forearm. Microscopically, there were large circumscribed dermal and subcutaneous nodules of spindled and epithelioid cells, resembling a spindle cell neoplasm. Small foci of neutrophils were also present, and a subsequent Ziehl-Neelsen stain highlighted beaded acid fast bacilli in the interstitium. Tissue culture demonstrated Mycobacterium chelonae. Cutaneous mycobacterial spindle cell pseudotumor is an exceedingly rare lesion, with only 6 previously reported cases. Although these included patients with autoimmune disease receiving immunosuppressive therapy, this is the first case reported in association with a tumor necrosis factor alpha inhibitor, etanercept. Furthermore, this represents the first mycobacterial spindle cell pseudotumor described in association with M. chelonae. Mycobacterial spindle cell pseudotumor should be considered in the differential diagnosis of cutaneous spindle cell proliferations, especially in immunocompromised patients. PMID- 21712687 TI - Recurrent CYLD nonsense mutation associated with a severe, disfiguring phenotype in an African American family with multiple familial trichoepithelioma. PMID- 21712688 TI - Dermatoscopy of an angiomatoid spitz nevus. AB - To date, only 12 cases of angiomatoid Spitz nevus have been characterized in the literature. We present the first case of angiomatoid Spitz nevus in which dermatoscopic findings are described. PMID- 21712689 TI - Molluscum contagiosum in an epidermoid cyst. PMID- 21712690 TI - Intratarsal keratinous cysts of the meibomian gland (a sebaceous duct cyst): report of 2 cases. AB - Intratarsal keratinous cyst of the meibomian gland is a recently described entity that recurs if not completely excised. Herein, we report 2 cases and discuss their diagnosis and management: (1) A 57-year-old man with a recurrent mass of the upper eyelid treated with incision and drainage as a chalazion for more than 5 years and (2) An 85-year-old man presented with a slow growing nodule of the upper eyelid. Exploration via the eyelid crease approach revealed cysts fixed to the tarsus that were completely excised with a portion of the anterior tarsus. Histologically, these cysts exhibited a keratinizing squamous epithelium without a granular layer (trichilemmal keratinization), were lined by an eosinophilic undulating cuticle, contain string-like keratin debris, and had a fibrous wall without sebaceous lobules. All epithelial components strongly expressed high molecular weight keratins, whereas the lining, cuticle, and keratin contents strongly expressed carcinoembryonic antigen. No recurrence has occurred 7 and 12 months postoperatively. The location and clinicopathologic findings of intratarsal keratinous cysts distinguish it from sebaceous tumors, steatocystoma simplex, epidermoid cyst, and dermoid cyst. However, like steatocystomas, intratarsal keratinous cysts exhibit a sebaceous duct phenotype. The anterior lid crease approach with partial tarsectomy seems to be an effective treatment. PMID- 21712691 TI - Follicular porokeratosis on the face. PMID- 21712692 TI - Routine use of immunohisto-chemistry may increase the frequency of hybrid peripheral nerve sheath tumors. PMID- 21712693 TI - Retrospective study of intraepidermal nerve fiber distribution in biopsies of patients with nummular eczema. AB - BACKGROUND: Nummular eczema is a chronic inflammatory condition characterized by pruritus and histologically characterized by spongiosis. The etiology is unknown, and the lesions frequently arise spontaneously. Neuropeptides contribute to mediating and maintaining eczematous conditions. Previous research indicates that the number of immunoreactive nerve fibers is increased in pruritic skin lesions. OBJECTIVE: We sought to determine if the number of immunoreactive nerve fibers is increased in nummular eczema, as in other inflammatory pruritic conditions. METHODS: Protein gene product 9.5 (PGP 9.5) was assessed by immunohistochemistry in 22 biopsies of nummular eczema and was compared with immunohistochemical expression of 8 skin biopsies uninvolved by nummular eczema. RESULTS: Nerve fiber distribution using PGP 9.5 stain showed that there was significantly reduced PGP9.5 stain amount in the epidermis of patients with nummular eczema compared with their respective healthy control (P = 0.0054). However, no statistical difference was seen in the papillary dermis. CONCLUSION: Pruritus of nummular eczema is not associated with an increase of epidermal nerve fiber density and sprouting. PMID- 21712694 TI - Anterior branch of the obturator nerve: a novel motor autograft for complex peripheral nerve reconstruction. AB - BACKGROUND: Autografting is the optimal reconstruction for many nerve gaps, because the retained nerve architecture serves as a regenerative scaffold. Experimental evidence suggests that motor regeneration is favored with the use of a motor nerve graft as compared with sensory nerve autografts, but clinical descriptions are lacking in the literature. As a novel solution, we report our use of the anterior branch of the obturator nerve as a large segment motor nerve graft with minimal functional morbidity. CASE: A 17-year-old boy reported progressive weakness and atrophy of the right thigh due to a multifascicular femoral nerve tumor. Motor branch defects of 7 and 4 cm were reconstructed using autografts from the motor nerve to the gracilis (MNG). The patient noted gradual clinical improvement in quadriceps strength, and repeat electromyography at 8- and 13-month follow-ups demonstrated improving motor unit action potentials and quadriceps muscle recruitment. DISCUSSION: The MNG is readily available, with an average total donor length of 11.4 cm. The use of motor nerve grafts is supported by experimental models demonstrating superior nerve regeneration. The MNG is a compelling choice for clinical use because donor-site morbidity is minimized by redundancy of the thigh adductors and a favorable incision location. CONCLUSION: This is the first published description of successful use of the anterior branch of the obturator nerve as a robust donor motor nerve graft. Clinical use of this graft may maximize functional outcomes and minimizes donor-site morbidity compared with traditional sensory nerve grafts. PMID- 21712695 TI - The course and variation of the facial artery and vein: implications for facial transplantation and facial surgery. AB - The main arterial supply of the facial skin envelope is the facial artery which serves as the main pedicle for a number of facial flaps, including a facial transplant graft. This study explored the course of the facial artery and vein, branching patterns, terminations, and anomalous variants. Cadaveric dissections of 201 facial arteries and 198 facial veins were performed. All branches originated from a single facial arterial trunk in 86% of specimens and branching patterns were symmetrical in 53%. The facial artery predominantly terminated as a lateral nasal artery (49%). In 5 cases, the facial artery was undetectable with transverse facial arterial dominance (1 case bilateral). The facial vein was predictable in position except for 2 instances, being replaced by a transverse facial vein (unilateral). Facial arterial dominance in facial blood supply is common but unpredictable. Careful vascular workup prior to facial transplantation and unipedicled flap procedures is therefore essential. PMID- 21712696 TI - Spatially controlled delivery of neurotrophic factors in silk fibroin-based nerve conduits for peripheral nerve repair. AB - Restoration with sufficient functional recovery after long-gap peripheral nerve damage remains a clinical challenge. Silk has shown clinical promise for numerous tissue engineering applications due to its biocompatibility, impressive mechanical properties, and Food and Drug Administration approval. The aim of this study was to evaluate the efficacy of silk fibroin--based nerve guides containing glial cell line-derived neurotrophic factor (GDNF) in a long-gap sized (15 mm) rat sciatic nerve defect model. Four groups of nerve conduits were prepared: (1) silk conduits with empty silk microspheres, (2) silk conduits with GDNF-loaded silk microspheres uniformly distributed in the conduit wall, (3) silk conduits with GDNF-loaded silk microspheres in a controlled manner with the highest GDNF concentration at the distal end, and (4) isograft. After 6 weeks, the nerve grafts were explanted, harvested, and fixed for histologic analysis. Nerve tissue stained with the S-100, and neuroendocrine marker PGP 9.5 antibodies demonstrated a significantly increased density of nerve tissue in the GDNF-treated groups compared with the empty microsphere (control) group (P < 0.05). GDNF-treated animals with a higher concentration of GDNF in the distal portion possessed a significantly higher density of PGP 9.5 protein middle conduit part than comparison to GDNF uniform-treated animals (P < 0.05). Silk-based nerve conduits possess optimal mechanical and degradative properties, rendering them potentially useful in peripheral nerve repair. This study demonstrates that novel, porous silk fibroin--based nerve conduits, infused with GDNF in a controlled manner, represent a potentially viable conduit for Schwann cell migration and proliferation in the regeneration of peripheral nerves. PMID- 21712697 TI - Complete excision of nonmelanotic skin cancer: a matter of surgical experience. AB - Nonmelanotic skin cancer is the most common human neoplasia and its incidence is rising. The completeness of resection is the most important quality feature of surgical treatment of nonmelanotic skin cancer, as a complete resection distinctly reduces local recurrence. In this trial, we analyze the incomplete resection rate of nonmelanotic skin cancer (N = 524) through plastic surgery assistant doctors in the first 3 years of surgical training. We find that the incomplete resection rate of nonmelanotic skin cancer decreases significantly (P = 0.026) from mean 12.1% in the first year of training to mean 5.7% in the third year of training, despite a gain in difficulty level concerning tumor localization. Moreover, we identify the following tumor features as a risk factor for incomplete resection: facial tumors (P = 0.034), recurrent lesions (P = 0.032), and the tumor class of the superficial basal cell carcinoma (P = 0.010). We prove that complete excision of nonmelanotic skin cancer distinctly depends on the surgeon's experience level. PMID- 21712698 TI - Facial self-perception, well-being, and aesthetic surgery. AB - BACKGROUND: It is controversial whether impaired well-being is associated with (a) an increased likelihood of having a negative body/facial image; or (b) dissatisfaction with the postoperative result following aesthetic surgery. We set out to improve current knowledge in this matter. METHODS: A total of 324 subjects (n = 162 females, n = 162 males, 18-30 years) were photographed, asked to complete the adjective mood scale and to rate 46 statements regarding their own appearance, and its impact on social functioning as well as their willingness to undergo aesthetic surgery on a visual analog scale. The photographs of these subjects were also assessed by 50 independent judges. RESULTS: Average self awarded ratings of appearance were significantly more positive in subjects with normal as compared to those with impaired well-being (P = 0.014). Items regarding the impact of appearance on social functioning were answered significantly more negatively by subjects with impaired well-being as compared with those with the normal well-being (P = 0.001). Subjects with impaired well-being did not declare an increased willingness to undergo aesthetic surgery (P > 0.197). Assessment by the independent judges did not reveal differences in the average level of attractiveness of subjects with impaired well-being and those with normal well being (P = 0.666). CONCLUSIONS: Impaired well-being is associated with impaired facial selfperception, independent of attractiveness. Willingness to undergo aesthetic surgery seems not to be affected by one's sense of well-being. In the subjects with impaired well-being who undergo aesthetic surgery, facial self perception seems unlikely to be improved. PMID- 21712699 TI - Demographic factors, outcomes, and complications in abdominal contouring surgery after massive weight loss in a developing country. AB - Few reports about body contouring surgery after massive weight loss (MWL) have been produced in the developing countries. As Mexico is considered a developing country, we performed a retrospective analysis of medical records of patients who underwent this type of surgery to evaluate their demographic characteristics as well as their outcomes and complications. Results from 684 patients with MWL, 69 (10%) had abdominoplasty; the type of abdominoplasty influenced the operative time, bleeding, and complications (P < 0.05); the body mass index influenced the weight of resected tissue (P < 0.000) and hospital stay (P < 0.020), but did not affect the type of abdominoplasty performed, surgical time, complications, reoperation, or transfusion rates. In contrast with the developed countries, in these procedures, operating time was higher and the patients had more surgical bleeding with higher rates of transfusion and a longer hospital stay, but with the same clinical results and percentage of complications. PMID- 21712700 TI - Controlled clinical trial with pirfenidone in the treatment of breast capsular contracture: association of TGF-beta polymorphisms. AB - BACKGROUND: Breast capsular contracture (BCC) is a commonly adverse event postmammoplastly characterized by an immune response mediated by cytokines and transforming growth factor (TGF)-beta1 resulting in excessive synthesis and deposit of extracellular matrix around the breast implant. Presence of TGF-beta1 polymorphisms has been associated as a risk factor to develop fibroproliferative diseases. METHODS: This open, controlled, prospective, and pilot clinical trial with 6 months duration was carried out to evaluate the efficacy of 1800 mg a day, of oral Pirfenidone (PFD) in the treatment of BCC (Baker Score III/IV) postmammoplasty. Twenty BCC cases received PFD and 14 BCC control cases underwent capsulectomy after 6 months of enrollment. Both groups were followed up for 6 more months up to 12 months to determine the relapse in the absence of PFD. Determination of TGF-beta1 polymorphisms was performed to establish a correlation with capsular contracture. RESULTS: PFD group experienced BCC-reduction in all breasts 6 months after enrollment. Only 1 of 20 cases relapsed after follow-up. In capsulectomy group, 2 of 14 cases presented progression to grade IV during presurgical period. All capsulectomy cases relapsed at end of follow-up. Nearly hundred percent of all patients studied in this protocol had a profibrogenic homozygous TGF-beta1 polymorphism (codon 25; genotype Arg25Arg). CONCLUSIONS: PFD is useful to improve BCC (Baker Score III/IV) postmammoplasty with no relapse after drug administration. There is also an association between capsular contracture and the presence of homozygous G/G TGF-beta1 genotype. PMID- 21712701 TI - Reconstruction of large defects of the lips and commissure using a composite radial forearm palmaris longus free flap associated with a lengthening temporalis myoplasty. AB - We performed a single-stage operation to reconstruct a large defect of the lips and commissure using a composite radial forearm-palmaris longus free flap. To obtain cranial traction and a voluntary smile, independently from any jaw movement, traction was achieved by using a lengthening temporalis myoplasty. The tendon attached to the coronoid process was fixed to the palmaris longus tendon, recreating a new commissure and a "neo-modiolus." Physical therapy was started on the 21st postoperative day to facilitate progress from a "mandibular smile," to ideally a spontaneous and symmetric smile after 3 months of therapy. This procedure was able to obtain good oral continence and a good commissural movement during smile which has not previously been mentioned in the published literature. PMID- 21712702 TI - Surgical treatment of gynecomastia: complications and outcomes. AB - Gynecomastia is defined as the benign enlargement of the male breast. Multiple surgical options have been used to improve outcomes. The aim of this study was to analyze the surgical approaches to the treatment of gynecomastia and their outcomes over a 10-year period. All patients undergoing surgical correction of gynecomastia in our department between 2000 and 2010 were included for retrospective evaluation. The data were analyzed for etiology, stage of gynecomastia, surgical technique, complications, risk factors, and revision rate. The surgical result was evaluated with self-assessment questionnaires. A total of 41 patients with 75 operations were included. Techniques included subcutaneous mastectomy alone or with additional ultrasound-assisted liposuction (UAL) and isolated UAL. The surgical revision rate for all patients was 4.8%. The skin sparing procedure gave good surgical results in grade IIb and grade III gynecomastia with low revision and complication rates. The self-assessment report revealed a good level of overall satisfaction and improvement in self-confidence (average scores 9.4 and 9.2, respectively, on a 10-point scale). The treatment of gynecomastia requires an individualized approach. Subcutaneous mastectomy combined with UAL could be used as the first choice for surgical treatment of grade II and III gynecomastia. PMID- 21712703 TI - Fetal mouse skin heals scarlessly in a chick chorioallantoic membrane model system. AB - In mammals, the early-gestation fetus has the regenerative ability to heal skin wounds without scar formation. This observation was first reported more than 3 decades ago, and has been confirmed in a number of in vivo animal models. Although an intensive research effort has focused on unraveling the mechanisms underlying scarless fetal wound repair, no suitable model of in vitro fetal skin healing has been developed. In this article, we report a novel model for the study of fetal wound healing. Fetal skin from gestational day 16.5 Balb/c mice (total gestation, 20 days) was grafted onto the chorioallantoic membrane of 12 day-old chicken embryos and cultured for up to 7 days. At 48 hours postengraftment, circular wounds (diameter = 1 mm) were made in the fetal skin using a rotating titanium sapphire laser (N = 45). The tissue was examined daily by visual inspection to look for signs of infection and ischemia. The grafts and the surrounding host tissue were examined histologically. In all fetal skin grafts, the wounds completely reepithelialized by postinjury day 7, with regeneration of the dermis. Fetal mouse skin xenografts transplanted onto the chorioallantoic membrane of fertilized chicken eggs provides a useful model for the study of fetal wound healing. This model can be used as an adjunct to traditional in vivo mammalian models of fetal repair. PMID- 21712704 TI - A prospective randomized trial comparing subatmospheric wound therapy with a sealed gauze dressing and the standard vacuum-assisted closure device. AB - OBJECTIVE: Two methods of subatmospheric pressure wound therapy--wall suction applied to a sealed gauze dressing (GSUC) and the vacuum-assisted closure device (VAC)--were compared in hospitalized patients at University of Chicago Medical Center. SUMMARY OF BACKGROUND DATA: VAC therapy is widely used, but can be expensive and difficult to apply; it also fails in some patients. METHODS: A randomized prospective study of 87 patients (N = 45 in the GSUC arm and N = 42 in the VAC arm) was undertaken between October 2006 and May 2008. The study comprised patients with acute wounds resulting from trauma, dehiscence, or surgery. RESULTS: Demographics and wound characteristics were similar in both groups. There were significant reductions in wound surface area and volume in each group. In the GSUC group, the reductions in wound surface area and volume were 4.5%/day and 8.4%/day, respectively (P < 0.001 for both), and in the VAC group, this was 4.9%/day and 9.8%/day, respectively (P < 0.001 for both). The reductions in wound surface area and volume were similar in both groups (P = 0.60 and 0.19, respectively, for the group-by-time interaction). The estimated difference (VAC - GSUC) was 0.4% (95% confidence interval: -1.0, 1.7) for wound surface area and 1.4% (95% confidence interval: -0.7, 3.5) for volume. The mean cost per day for GSUC therapy was $4.22 versus $96.51 for VAC therapy (P < 0.01) and the average time required for a GSUC dressing change was 19 minutes versus 31 minutes for a VAC dressing change (P < 0.01). The sum of pain intensity differences was 0.50 in the GSUC group compared with 1.73 for the VAC group (P = 0.02). CONCLUSIONS: GSUC is noninferior to VAC with respect to changes in wound volume and surface area in an acute care setting. In addition, GSUC dressings were easier to apply, less expensive, and less painful. PMID- 21712705 TI - Can a true perforator flap survive on venous blood? A case report of anterolateral thigh true perforator flap supplied by antegrade venous inflow. AB - In some cases of degloving injury, as a result of multiple venous anastomoses formed on the peripheral and proximal sides, the detached flap skin did survive, though with patchy necrosis. On the basis of this experience, the skin and soft tissue defects after removing skin cancer were closed with an anterolateral thigh true perforator flap, measuring 4 * 5 cm in size, which is nourished by venous blood. The subcutaneous vein on the peripheral side of the defect was anastomosed to the perforator artery, and the veins on the proximal side of the defects were anastomosed to the concomitant veins of the perforator. After surgery, to ensure a sufficient blood flow to the flap, the affected limb was positioned lower than the heart for 1 week. To prevent microthrombus in the perforator branch and the flap, preventive anticoagulant therapy was performed. The transplanted flap had marked cyanosis for a few days, but turned pinkish on the sixth day after surgery. The flap survived completely. As opposed to venous flaps reported in the past, the physiologic direction of blood flow of the flap is from arteries to veins, and it is nourished exclusively by venous blood. If a flap is small, and there are no appropriate recipient vessels nearby, this method could serve as a favorable alternative. PMID- 21712706 TI - Fractionated administration of carboplatin/paclitaxel reduces neurotoxicity in patients with advanced non-small cell lung cancer. AB - The combination of carboplatin/paclitaxel is commonly used as chemotherapy for advanced non-small cell lung cancer. However, the relatively high incidence of neurotoxicity remains a problem. This study was undertaken to determine whether the fractionated administration regimen can reduce the neurotoxicity. Patients with stage III or IV non-small cell lung cancer were randomized to the nonfractionated (NF) dose group, which received paclitaxel (200 mg/m(2)) and carboplatin (area under the concentration-time curve=6) on day 1, or the fractionated dose (F) group, which received paclitaxel (100 mg/m(2)) and carboplatin (area under the concentration-time curve=3) on days 1 and 8. The cycle was repeated every 3 weeks. Peripheral neuropathy was objectively evaluated by measuring the current perception threshold (CPT) in the median nerve using a neurometer. Fourteen and 13 patients were assigned to the NF and F groups, respectively. The incidence of subjective numbness was significantly lower in the F group (15.4%) than in the NF group (57.1%). The CPT value determined at 2000 Hz showed significant increases in the NF group compared with the pretreatment baseline, but no significant changes were observed in the F group. The response rate was comparable in both groups. The fractionated administration of carboplatin/paclitaxel combination therapy showed a significant reduction in neurotoxicity. Measurement of CPT by a neurometer is a useful tool to evaluate the neurotoxicity of anticancer drugs objectively. PMID- 21712707 TI - Translocation t(12;13)(p13;q14) in a patient with imatinib-sensitive MDS/MPD associated with resistance to treatment: review of the literature. AB - The category of myelodysplastic syndromes/myeloproliferative diseases (MDS/MPD) is a relatively new group of malignant hematologic diseases developed by the World Health Organization. These hematologic disorders lack the BCR/ABL fusion gene, although they can be associated with chromosomal translocations that involve genes encoding other protein kinases. Imatinib mesylate was recognized as a potent inhibitor of some of those kinases. We present a patient with a previously treated acute myeloid leukemia, who, after a 9-year-long remission, developed an MDS/MPD with normal karyotype, which initially responded to imatinib mesylate. Translocation t(12;13)(p12;q14) was detected after loss of response to imatinib treatment. Translocation t(12;13) is rare. It has been described in several hematologic malignancies including chronic myelomonocytic leukemia but not in MDS/MPD, previously described as Philadelphia-negative chronic myelogenous leukemia. Moreover, the correlation of this molecular abnormality with loss of efficacy of imatinib is unique in the literature. PMID- 21712708 TI - Opioid antinociception, tolerance and dependence: interactions with the N-methyl D-aspartate system in mice. AB - This study explored the involvement of N-methyl-D-aspartate (NMDA) in the effects of MU-opioid agonists. A hot-plate procedure was used to assess antinociception and tolerance in mice in which the NR1 subunit of the NMDA receptor was reduced [knockdown (KD)] to approximately 10%, and in mice treated with the NMDA antagonist, (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959). The MU opioid agonists, morphine, l-methadone and fentanyl, were approximately three-fold less potent in the NR1 KD mice than in wild-type (WT) controls; however, the development of morphine tolerance and dependence did not differ markedly in the NR1 KD and the WT mice. Acute administration of the NMDA antagonist, LY235959, produced dose-dependent, leftward shifts in the morphine dose-effect curve in the WT mice, but not in the NR1 KD mice. Chronic administration of LY235959 during the morphine tolerance regimen did not attenuate the development of tolerance in the NR1 KD or the WT mice. These results indicate that the NR1 subunit of the NMDA receptor does not play a prominent role in MU opioid tolerance. PMID- 21712709 TI - Dissimilar cannabinoid substitution patterns in mice trained to discriminate Delta(9)-tetrahydrocannabinol or methanandamide from vehicle. AB - Delta(9)-Tetrahydrocannabinol (THC) discrimination in rodents is a behavioral assay that has been used to probe differences among classes of cannabinoids in rats. The purpose of this study was to determine whether traditional and anandamide-like cannabinoids were distinguishable in cannabinoid discrimination procedures in mice. Male mice were trained to discriminate 30 mg/kg THC or 70 mg/kg methanandamide from vehicle in a two-lever milk-reinforced drug discrimination procedure. After acquisition, agonist tests with THC, methanandamide, CP 55940, and anandamide were conducted, as were antagonism tests with rimonabant. Substitution (agonism) and antagonism tests were also carried out in female mice trained to discriminate THC. THC and CP 55940 fully substituted in THC-trained mice of both sexes. Further, THC substitution was rimonabant reversible. In contrast, mice injected with methanandamide or anandamide failed to respond substantially on the THC lever, even up to doses that decreased overall responding. In methanandamide-trained mice, methanandamide fully generalized to the methanandamide training dose. Rimonabant did not reverse this generalization. Although THC, CP 55940, and anandamide also increased responding on the methanandamide lever, the magnitude of substitution was less than for methanandamide. These results suggest incomplete overlap in the underlying mechanisms mediating endocannabinoid pharmacology and marijuana intoxication. Further, they suggest that methanandamide discrimination may involve a non-CB(1) receptor mechanism that is particularly prominent at higher doses. PMID- 21712710 TI - For the love of paradox: from neurobiology to pharmacology. AB - The acute and chronic effects of certain drugs can often be opposite. For example, in congestive heart failure acute administration of beta-adrenoceptor agonists results in beneficial improvement in symptoms of the disease, but their chronic use increases mortality. Conversely, certain beta-adrenoceptor antagonists/inverse agonists (beta-blockers) initially cause a detrimental response by decreasing cardiac contractility in congestive heart failure, whereas chronic treatment with the same beta-blockers improves contractility and survival. Furthermore, this time-dependent reversal of outcomes occurs in nonpharmacological interventions, such as exercise, and can even be observed in the response of plants to pruning or other stressors, with the results being a different short-term versus long-term effect. Here, we review some of these phenomena with a special emphasis on the temporal dissociation of pharmacological effects. Although Francis Colpaert used this knowledge to lead a drug discovery project for an analgesic compound that initially produced hyperalgesia, we focused on examples outside the central nervous system. PMID- 21712711 TI - The metabolites N-desmethylclozapine and N-desmethylolanzapine produce cross tolerance to the discriminative stimulus of the atypical antipsychotic clozapine in C57BL/6 mice. AB - It has been previously shown that cross-tolerance to the discriminative stimulus properties of clozapine can be demonstrated with the drug discrimination paradigm. This study examined the ability of N-desmethylclozapine and N desmethylolanzapine (metabolites of the atypical antipsychotic drugs clozapine and olanzapine, respectively) to induce cross-tolerance to the discriminative stimulus effects of clozapine. After C57BL/6 mice were trained to reliably discriminate 2.5 mg/kg clozapine from vehicle, a clozapine generalization curve was generated. Next, training was suspended and the mice received a maintenance dosing regimen in which they were injected twice daily with 10 mg/kg N desmethylclozapine for 10 days. Then a second clozapine generalization curve was generated. This was followed by a 10-day washout period during which the mice did not receive drug injections or discrimination training. Finally, a third clozapine generalization curve was generated. These same procedures were followed for N-desmethylolanzapine (10 mg/kg twice daily during maintenance dosing). Both N-desmethylclozapine and N-desmethylolanzapine produced significant rightward shifts in the clozapine generalization curve indicating cross-tolerance between N desmethylclozapine and clozapine and between N-desmethylolanzapine and clozapine. After a washout period with no training or drug administration this cross tolerance effect was lost for both metabolites. This cross-tolerance drug discrimination procedure demonstrated in-vivo similarities between these two metabolites and clozapine and suggests that common underlying pharmacological mechanisms were responsible for the cross-tolerance that was observed. These findings also demonstrated that this procedure may be useful for identifying drugs with therapeutic efficacy similar to the atypical antipsychotic clozapine under repeated dosing conditions. PMID- 21712712 TI - Sensitization to MDMA locomotor effects and changes in the functionality of 5 HT(2A) and D2 receptors in mice. AB - The behavioral and neurochemical adaptations related to chronic 3,4 methylenedioxymethamphetamine (MDMA) treatment are largely unknown. In this study, we assessed whether repeated administration of MDMA would induce (a) context-dependent locomotor sensitization in mice and (b) changes in serotonin 5 HT(2A) and dopamine D2 receptor functionality as measured by [35S]GTPgammaS binding. Mice were treated with MDMA (10 mg/kg, intraperitoneally) or saline every other day for 11 days either in their home cages or in the environment where locomotor activity was measured. After a 10-day withdrawal period, mice were challenged with MDMA (5 and 10 mg/kg) and saline before locomotor activity measurements. During repeated MDMA treatment, locomotion was progressively enhanced, indicating the development of behavioral sensitization. The MDMA challenge at a dose of 5 mg/kg increased locomotor activity to a greater extent in mice pretreated with MDMA in the testing apparatus than in mice pretreated in the home cages, revealing that contextual cues paired with repeated drug exposure can enhance the expression of behavioral sensitization to MDMA. In contrast, a challenge administration of MDMA at 10 mg/kg induced similar locomotor sensitization in mice pretreated in both environments. An increase in the functionality of cortical 5-HT(2A) receptors was observed in mice pretreated with MDMA compared with mice pretreated with saline, but this activation was significantly greater in mice pretreated in the locomotor environment. In contrast, the functional activity of striatal D2 receptors was significantly decreased only in mice pretreated with MDMA in the testing apparatus. These results reveal neuroadaptations in cortical 5-HT(2A) and striatal D2 receptors after MDMA-induced behavioral sensitization in mice. PMID- 21712713 TI - Rapid local anesthesia in humans using minimally invasive microneedles. AB - OBJECTIVE: This study tested the hypothesis that minimally invasive microneedles cause less pain during injection of lidocaine, but induce local anesthesia in humans with the same rapid onset and efficacy as intradermal lidocaine injection using hypodermic needles. METHODS: This study was a randomized, single-blinded, within participants, controlled design. Hollow, 500-MUm long microneedles were used to inject lidocaine to the forearm of 15 human participants. The associated pain was recorded using a visual analog (VAS) scale. The area and depth of numbness were determined at 0, 7.5, and 15 minutes after injection. Lidocaine was also injected to the dorsum of the hand near a vein, followed by placement of an intravenous catheter and measurement of associated pain. A 26-gauge intradermal bevel hypodermic needle similarly administered lidocaine on the opposite forearm/hand to serve as the positive control. RESULTS: VAS pain scores revealed that injection using microneedles was significantly less painful than hypodermic needles for both the forearm and dorsum of the hand injections. However, there was no significant difference in the area or depth of the resulting numbness between the 2 treatment methods at any time point (0, 7.5, and 15 min) indicating that microneedles had immediate onset and were as effective as hypodermic needles in inducing dermal anesthesia. Moreover, insertion of an intravenous catheter immediately after lidocaine injection on the dorsum of the hand led to comparable pain scores for the microneedle and hypodermic needle treated sites, further confirming efficacy of microneedles in inducing rapid local anesthesia. Lastly, 77% of the participants preferred microneedles and 80% indicated that they did not consider microneedles to be painful. DISCUSSION: This study demonstrates for the first time that microneedle-based lidocaine injection is as rapid and as effective as hypodermic injection in inducing local anesthesia while resulting in significantly less pain during injection. PMID- 21712714 TI - Nociception affects motor output: a review on sensory-motor interaction with focus on clinical implications. AB - OBJECTIVES: Research has provided us with an increased understanding of nociception-motor interaction. Nociception-motor interaction is most often processed without conscious thoughts. Hence, in many cases neither patients nor clinicians are aware of the interaction. It is aimed at reviewing the scientific literature on nociception-motor interaction, with emphasis on clinical implications. METHODS: Narrative review. RESULTS: Chronic nociceptive stimuli result in cortical relay of the motor output in humans, and a reduced activity of the painful muscle. Nociception-induced motor inhibition might prevent effective motor retraining. In addition, the sympathetic nervous system responds to chronic nociception with enhanced sympathetic activation. Not only motor and sympathetic output pathways are affected by nociceptive input, afferent pathways (proprioception, somatosensory processing) are influenced by tonic muscle nociception as well. DISCUSSION: The clinical consequence of the shift in thinking is to stop trying to restore normal motor control in case of chronic nociception. Activation of central nociceptive inhibitory mechanisms, by decreasing nociceptive input, might address nociception-motor interactions. PMID- 21712715 TI - Acute cardiac syndromes without significant coronary stenosis: differential features between myocardial infarction and apical-ballooning syndrome. AB - OBJECTIVE: Among patients with acute cardiac syndromes without coronary stenosis, the clinical, electrocardiographic, echocardiographic, and angiographic features of those with a first acute myocardial infarction (AMI) were compared with those with apical-ballooning syndrome (ABS). METHODS: Data of consecutive patients admitted with a first AMI (n=30) or ABS (n=45) were reviewed. RESULTS: Patients with ABS were older (72 vs. 56 years; P=0.001) and presented a higher frequency of female sex (91 vs. 43%; P=0.001), triggering emotional or physical stress (47 vs. 17%; P=0.003) and a lower rate of tobacco smoking (27 vs. 50%; P=0.051) than those with the first AMI. They also presented a greater number of leads (5.5 vs. 3.6; P=0.01) and more anterior or anterior+inferior involvement (96 vs. 40%; P<0.001), more depressed ejection fraction (45 vs. 57%; P=0.001), more proportion of akinesia or diskinesia (89 vs. 27%; P=0.001) that extended beyond the boundaries of a single-vessel territory, and a greater rate of left ventricular outflow obstruction (29 vs. 0%; P=0.001) and heart failure (38 vs. 10%; P=0.015). Frequency of nonsignificant coronary stenosis or smooth vessels, however, was similar in both groups. CONCLUSION: Patients with ABS were older and more frequently were women than those with first AMI without significant coronary stenosis and had larger hypocontractile areas. The preponderance of tobacco smoking, pain without triggers, and hypocontractility limited to one-vessel territory in the latter, however, may suggest a transient thrombotic/vasospastic event as their underlying mechanism as opposed to patients with ABS. PMID- 21712716 TI - Perioperative fasting in adults and children: guidelines from the European Society of Anaesthesiology. AB - This guideline aims to provide an overview of the present knowledge on aspects of perioperative fasting with assessment of the quality of the evidence. A systematic search was conducted in electronic databases to identify trials published between 1950 and late 2009 concerned with preoperative fasting, early resumption of oral intake and the effects of oral carbohydrate mixtures on gastric emptying and postoperative recovery. One study on preoperative fasting which had not been included in previous reviews and a further 13 studies published since the most recent review were identified. The searches also identified 20 potentially relevant studies of oral carbohydrates and 53 on early resumption of oral intake. Publications were classified in terms of their evidence level, scientific validity and clinical relevance. The Scottish Intercollegiate Guidelines Network scoring system for assessing level of evidence and grade of recommendations was used. The key recommendations are that adults and children should be encouraged to drink clear fluids up to 2 h before elective surgery (including caesarean section) and all but one member of the guidelines group consider that tea or coffee with milk added (up to about one fifth of the total volume) are still clear fluids. Solid food should be prohibited for 6 h before elective surgery in adults and children, although patients should not have their operation cancelled or delayed just because they are chewing gum, sucking a boiled sweet or smoking immediately prior to induction of anaesthesia. These recommendations also apply to patients with obesity, gastro-oesophageal reflux and diabetes and pregnant women not in labour. There is insufficient evidence to recommend the routine use of antacids, metoclopramide or H2-receptor antagonists before elective surgery in non-obstetric patients, but an H2-receptor antagonist should be given before elective caesarean section, with an intravenous H2 receptor antagonist given prior to emergency caesarean section, supplemented with 30 ml of 0.3 mol l(-1) sodium citrate if general anaesthesia is planned. Infants should be fed before elective surgery. Breast milk is safe up to 4 h and other milks up to 6 h. Thereafter, clear fluids should be given as in adults. The guidelines also consider the safety and possible benefits of preoperative carbohydrates and offer advice on the postoperative resumption of oral intake. PMID- 21712717 TI - Perineal talc use and ovarian cancer risk: a case study of scientific standards in environmental epidemiology. AB - A number of observational studies (largely case-control) conducted over the last two decades suggest an association between use of talc powders on the female perineum and increased risk of ovarian cancer. A subset of these reports shows a roughly 30-60% increased risk of ovarian cancer associated with perineal talc exposure. A number of researchers partly base their conclusions of an association on the '...chemical relationship between talc and asbestos', the latter substance being a known human carcinogen. Although separating causal from noncausal explanations for an observed statistical association is a difficult process, there currently exist commonly accepted guidelines by which such inferences can be made. These scientific approaches include consideration of the strength of the association, the consistency of the finding across studies, and existence of a biological explanation of the observed phenomenon, among others. When applied to the context of a proposed talc/ovarian cancer association, we conclude that the weak statistical associations observed in a number of epidemiological studies do not support a causal association. PMID- 21712718 TI - Management of concurrent cholelithiasis in gastric banding for morbid obesity. AB - BACKGROUND: Both morbid obesity and gallstones can be treated using laparoscopic methods. In this study, we share our clinical experience about indications and timing for cholecystectomy in morbid obesity cases that had undergone laparoscopic gastric banding procedure. MATERIALS AND METHODS: In our clinic, 151 cases had undergone laparoscopic adjustable gastric banding procedure between September 2006 and May 2009. Eight cases that were diagnosed with symptomatic cholelithiasis in the preoperative period underwent cholecystectomy in the same session and from the same port of entry. Numerical variables were checked using Mann-Whitney U-test. P value less than 0.05 was considered to be significant. RESULTS: There were eight adults (six female and two male) with preoperative symptomatic cholelithiasis. Mean age was 28.2 +/- 5.8 years, mean preoperative BMI was 44.1 +/- 6.8 kg/m2, mean operative time was 94.0 +/- 18.6 min, and mean duration of hospital stay was 1.5 +/- 0.7 days. The same parameters for the group that did not undergo cholecystectomy were mean age=29.6 +/- 6.1 years, mean preoperative BMI=46.8 +/- 6.6 kg/m2, mean operative time=68.2.2 +/- 12.9 min, and mean duration of hospital stay=1.2 +/- 0.5 days, respectively. In the cholecystectomy group, the mean operative time was 25.8 +/- 6.9 min and mean hospital stay was 0.3 +/- 0.2 days longer than the laparoscopic adjustable gastric banding group (P=0.003 and 0.159, respectively). In the postoperative period, seven cases (4.8%) developed symptomatic cholelithiasis. The overall average follow-up period was 23.8 +/- 8.7 months. CONCLUSION: Cholecystectomy performed in the same session as laparoscopic gastric banding procedure on patients with asymptomatic cholelithiasis is a technically feasible approach with low complication rates. However, we do not recommend prophylactic cholecystectomy in patients without gallstones because of longer operative time and hospitalization and increased risk of complications. PMID- 21712719 TI - Entrepreneurship, culture, knowledge, and learning: a multispective view of patient safety improvement. PMID- 21712720 TI - To make or buy patient safety solutions: a resource dependence and transaction cost economics perspective. AB - BACKGROUND: For almost a decade, public and private organizations have pressured hospitals to improve their patient safety records. Since 2008, the Centers for Medicare & Medicaid Services has no longer been reimbursing hospitals for secondary diagnoses not reported during the point of admission. This ruling has motivated some hospitals to engage in safety-oriented programs to decrease adverse events. PURPOSE: This study examined which hospitals may engage in patient safety solutions and whether they create these patient safety solutions within their structures or use suppliers in the market. METHODOLOGY: We used a theoretical model that incorporates the key constructs of resource dependence theory and transaction cost economics theory to predict a hospital's reaction to Centers for Medicare & Medicaid Services "never event" regulations. We present propositions that speculate on how forces conceptualized from the resource dependence theory may affect adoption of patient safety innovations and, when they do, whether the adopting hospitals will do so internally or externally according to the transaction cost economics theory. FINDINGS: On the basis of forces identified by the resource dependence theory, we predict that larger, teaching, safety net, horizontally integrated, highly interdependent, and public hospitals in concentrated, high public payer presence, competitive, and resource rich environments will be more likely to engage in patient safety innovations. Following the logic of the transaction cost economics theory, we predict that of the hospitals that react positively to the never event regulation, most will internalize their innovations in patient safety solutions rather than approach the market, a choice that helps hospitals economize on transaction costs. PRACTICE IMPLICATIONS: This study helps hospital managers in their strategic thinking and planning in relation to current and future regulations related to patient safety. For researchers and policy analysts, our propositions provide the basis for empirical testing. PMID- 21712721 TI - Director of nursing current job tenure and past experience and quality of care in nursing homes. AB - BACKGROUND: Directors of nursing (DONs) are central to quality of care in nursing homes (NHs) because of their role in coordinating and overseeing nursing care. Research is needed to test the association between DON characteristics and quality using large, representative samples of NHs and global measures of quality. One such measure is the quality measure (QM) rating from the Centers for Medicare & Medicaid Services' Five-Star Quality Rating, which aggregates 10 individual QMs into a single rating. PURPOSE: This study examined whether DON current job tenure or past experience (a) differed across levels of the QM rating, (b) was associated with QM ratings, and (c) was associated with any of the individual 10 QM scores that comprise QM ratings. METHODOLOGY: Data for a nationally representative sample of 1,174 NHs were obtained from the 2004 National Nursing Home Survey, publicly reported QMs, and an Area Resource File. Wald tests were used to test differences in mean DON current job tenure and past experience across levels of the QM rating. Multinomial logistic and Poisson regression analyses were used to examine the association between DON current job tenure and past experience and QM ratings and QM scores, respectively, controlling for selected market and organizational characteristics. FINDINGS: Nursing homes with longer DON current job tenure tended to have higher QM ratings. Longer DON current job tenure was associated with higher QM ratings and lower QM scores for several individual QMs, suggesting higher quality. The past experience of the DON did not differ across levels of the QM rating and was not associated with QM ratings or QM scores. PRACTICE IMPLICATIONS: This study highlights the need for owners and administrators to support DONs as they either the transition into the role of the DON for the first time or learn to effectively fulfill their role in a new NH. PMID- 21712722 TI - Enhancing board oversight on quality of hospital care: an agency theory perspective. AB - BACKGROUND: Community hospitals in the United States are almost all governed by a governing board that is legally accountable for the quality of care provided. Increasing pressures for better quality and safety are prompting boards to strengthen their oversight function on quality. PURPOSE: In this study, we aimed to provide an update to prior research by exploring the role and practices of governing boards in quality oversight through the lens of agency theory and comparing hospital quality performance in relation to the adoption of those practices. METHODOLOGY: Data on board practices from a survey conducted by The Governance Institute in 2007 were merged with data on hospital quality drawn from two federal sources that measured processes of care and mortality. The study sample includes 445 public and private not-for-profit hospitals. We used factor analysis to explore the underlying dimensions of board practices. We further compared hospital quality performance by the adoption of each individual board practice. FINDINGS: Consistent with the agency theory, the 13 board practices included in the survey appear to center around enhancing accountability of the board, management, and the medical staff. Reviewing the hospital's quality performance on a regular basis was the most common practice. A number of board practices, not examined in prior research, showed significant association with better performance on process of care and/or risk-adjusted mortality: requiring major new clinical programs to meet quality-related criteria, setting some quality goals at the "theoretical ideal" level, requiring both the board and the medical staff to be as involved as management in setting the agenda for discussion on quality, and requiring the hospital to report its quality/safety performance to the general public. PRACTICE IMPLICATIONS: Hospital governing boards should examine their current practices and consider adopting those that would enhance the accountability of the board itself, management, and the medical staff. PMID- 21712723 TI - General practitioners' adherence to evidence-based guidelines: a multilevel analysis. AB - BACKGROUND: The growing burden of chronic diseases encourages health care systems to shift services and resources toward primary care. In this sector, general practitioners (GPs) play a key role, and several collaborative organizational models have been implemented in the attempt to improve the clinical effectiveness of GPs, their adherence to evidence-based guidelines, and their capacity to work in multiprofessional teams. However, evidence of the impact of different organizational models is sparse, and little is known about the contribution of these models to the good management of chronic diseases. PURPOSE: The aim of this study was to examine the relationship of individual sociodemographic characteristics of GPs and collaborative organizational models with the adherence of physicians to evidence-based guidelines for four major chronic diseases (diabetes, heart failure, stroke, and post-acute myocardial infarction). METHODOLOGY: Evidence-based indicators for the management of the selected chronic diseases were identified on the basis of the most recent international guidelines. Multilevel logistic regression models were used to identify the correlates of adherence to guidelines, taking into account patient characteristics and comorbidities. FINDINGS: Participation in group practice was associated with different indicators of adherence to guidelines for the management of diabetes and one indicator of post-acute myocardial infarction, whereas other organizational arrangements were linked to GPs' clinical behavior to a lesser degree. Female gender and younger age of GPs were associated with good management of diabetes. PRACTICE IMPLICATIONS: The relative impact of efforts at organizational design in primary care should be evaluated in more detail before further investments are made in this direction. Our findings suggest that the professional attitude of GPs (of which gender and age can be considered proxies) is equally, if not more, important than their organizational arrangement. Hence, attention should be paid to how organizations and managerial tools can support the consolidation and spread of this attitude. PMID- 21712724 TI - The importance of working capital management for hospital profitability: evidence from bond-issuing, not-for-profit U.S. hospitals. AB - BACKGROUND: Increased financial pressures on hospitals have elevated the importance of working capital management, that is, the management of current assets and current liabilities, for hospitals' profitability. Efficient working capital management allows hospitals to reduce their holdings of current assets, such as inventory and accounts receivable, which earn no interest income and require financing with short-term debt. The resulting cash inflows can be reinvested in interest-bearing financial instruments or used to reduce short-term borrowing, thus improving the profitability of the organization. PURPOSE: This study examines the relationship between hospitals' profitability and their performance at managing two components of working capital: accounts receivable, measured in terms of hospitals' average collection periods, and accounts payable, measured in terms of hospitals' average payment periods. METHODOLOGY/APPROACH: Panel data derived from audited financial statements for 1,397 bond-issuing, not for-profit U.S. hospitals for 2000-2007 were analyzed using hospital-level fixed effects regression analysis. FINDINGS: The results show a negative relationship between hospitals' average collection period and profitability. That is, hospitals that collected on their patient revenue faster reported higher profit margins than did hospitals that have larger balances of accounts receivable outstanding. We also found a negative relationship between hospitals' average payment period and their profitability. Hospital managers did not appear to delay paying their vendors. Rather, the findings indicated that more profitable hospitals paid their suppliers faster, possibly to avoid high effective interest rates on outstanding accounts payable, whereas less profitable hospitals waited longer to pay their bills. PRACTICE IMPLICATIONS: The findings of this study suggest that working capital management indeed matters for hospitals' profitability. Efforts aimed at reducing large balances in both accounts receivable and accounts payable may frequently be worthwhile investments that have the potential to reduce the costs associated with working capital management and thus improve the profitability of an organization. PMID- 21712725 TI - Network formation, governance, and evolution in public health: the North American Quitline Consortium case. AB - BACKGROUND: Collaborative networks of health organizations have received a great deal of attention in recent years as a way of enhancing the flow of information and coordination of services. However, relatively little is known about how such networks are formed and evolve, especially outside a local, community-based setting. This article is an in-depth discussion of the evolution of the North American Quitline Consortium (NAQC). The NAQC is a network of U.S. and Canadian organizations that provide telephone-based counseling and related services to people trying to quit smoking. METHODOLOGY: The research draws on data from interviews, documents, and a survey of NAQC members to assess how the network emerged, became formalized, and effectively governed. FINDINGS: The findings provide an understanding of how multiregional public health networks evolve, while building on and extending the broader literature on organizational networks in other sectors and settings. Specifically, we found that the network form that ultimately emerged was a product of the back-and-forth interplay between the internal needs and goals of those organizations that would ultimately become network members, in this case, state-, and provincial-level tobacco quitline organizations. We also found that network formation, and then governance through a network administrative organization, was driven by important events and shifts in the external environment, including the impact and influence of major national organizations. PRACTICE IMPLICATIONS: The results of the study provide health care leaders and policy officials an understanding of how the activities of a large number of organizations having a common health goal, but spanning multiple states and countries, might be coordinated and integrated through the establishment of a formal network. PMID- 21712726 TI - Relationship between clinicopathologic variables and serum and tissue levels of dickkopf-1 in patients with rectal cancer. AB - The major biomarker for rectal cancer is the pathologic development of the tumor. In our study, we identified Dikkopf-1 (DKK1) as a novel biomarker and a therapeutic target for rectal cancer. To emphasize the biological and clinicopathologic significance, we performed tumor tissue and serum analysis of 150 rectal cancer samples with enzyme-linked immunosorbent assay. Serum DKK-1 levels are found significantly higher in controls, in poor differentiation, and depth of invasion (in pT3 and pT4), present lymph node metastasis, and TNM stage (in pT3 and pT4) according to good differentiation, depth of invasion (in pT1 and pT2), absent lymph node metastasis, and TNM stage (in pT1 and pT2; P < 0.001 and P < 0.0001, respectively). Tissue DKK-1 levels are found in patients with rectal cancer than in control tissues (P < 0.0001). Dikkopf-1 correlated significantly with depth of invasion (P = 0.009), lymph node metastasis (P = 0.028), venous involvement (P = 0.019), and advanced pTNM stage (P = 0.001). There was no correlation between DKK-1 and age or sex (P > 0.05). This marker is also a potential candidate for development of rectal cancer cells and cancer progression. PMID- 21712727 TI - Computational approaches for translational clinical research in disease progression. AB - Today, there is an ever-increasing amount of biological and clinical data available that could be used to enhance a systems-based understanding of disease progression through innovative computational analysis. In this article, we review a selection of published research regarding computational methods, primarily from systems biology, which support translational research from the molecular level to the bedside, with a focus on applications in trauma and critical care. Trauma is the leading cause of mortality in Americans younger than 45 years, and its rapid progression offers both opportunities and challenges for computational analysis of trends in molecular patterns associated with outcomes and therapeutic interventions.This review presents methods and domain-specific examples that may inspire the development of new algorithms and computational methods that use both molecular and clinical data for diagnosis, prognosis, and therapy in disease progression. PMID- 21712728 TI - Health coverage and its relation to the prevalence and intensity of symptomatic knee osteoarthritis. AB - OBJECTIVE: This study aimed to determine whether health coverage among older adults is associated with (1) the prevalence of symptomatic knee osteoarthritis (OA) and (2) disablement in those with symptomatic knee OA. METHODS: Data were collected from the Osteoarthritis Initiative data set 5.2.1, a cohort study of subjects with or at risk for knee OA. Prevalence of symptomatic knee OA (knee symptoms on most of the last 30 days and Kellgren-Lawrence grade >2 on knee radiograph) was compared between those with and without health coverage among subjects aged 45 to 65 years, adjusted for age and body mass index. For those with symptomatic knee OA, Physical Activity for the Elderly scores and Knee Osteoarthritis Outcomes Survey function, pain, and quality-of-life scores were compared between those with and without health coverage before and after adjustment for age and body mass index. RESULTS: Among subjects with health coverage, 27.8% had symptomatic knee OA compared with 36.1% of those without health coverage (P = 0.0204 before and P > 0.24 after adjustment). Among subjects with symptomatic knee OA with and without health coverage physical activity differed significantly (P = 0.048), as did pain (P < 0.0001), function (P = 0.0001), and quality of life (P < 0.0001). CONCLUSIONS: Lack of health coverage was not associated with the prevalence of symptomatic knee OA after adjustment. However, those with symptomatic knee OA without health coverage reported reduced physical activity, greater pain, worse functional limitations, and decreased quality of life. PMID- 21712729 TI - APOA4 polymorphism as a risk factor for unfavorable lipid serum profile and depression: a cross-sectional study. AB - INTRODUCTION: APOA1/C3/A4/A5 gene cluster is closely involved in lipid metabolism, and its polymorphisms have been associated with coronary heart disease and lipid plasma levels. Here, we aimed to investigate associations of APOC3 (3238C>G, -482C>T, 1100C>T) and APOA4 (Gln360His, Thr347Ser) polymorphisms in 382 individuals from a cohort of a Longitudinal Brazilian Elderly Study with major age-related morbidities and with lipid and protein serum levels. MATERIALS AND METHODS: The whole sample was genotyped by polymerase chain reaction restriction fragment length polymorphism. Descriptive statistics, logistic regression analysis, Student t test, deviation from Hardy-Weinberg, Bonferroni correction for multiple testing, and haplotype analyses were performed. RESULTS: Although APOC3 1100T allele carriers presented lower triglyceride and very low density lipoprotein levels than non-T carriers, these associations disappeared after Bonferroni correction (P > 0.05). Moreover, APOA4 360His allele was associated with depression (P = 0.03), increased triglyceride (P = 0.035) and very low density lipoprotein (P = 0.035) levels, and reduced HDL levels (P = 0.0005). Haplotype analyses found an association between His/C/C haplotype (Gln360His/-482C>T/1100C>T) with depression, but this result was due to Gln360His polymorphism. CONCLUSIONS: Our data suggest that 360His allele might be a risk factor for depression and unfavorable lipid profile and depression for elderly people in the Brazilian population. PMID- 21712730 TI - Utility of routine hematological and inflammation parameters for the diagnosis of cancer in involuntary weight loss. AB - INTRODUCTION: A quarter of patients with involuntary weight loss (IWL) have cancer. Inflammation and anemia are associated with cancer, and recent studies showed that red blood cell distribution width (RDW) is a predictor of mortality, including cancer-related death. The aim of this study was to assess the ability of routine hematological and inflammation parameters to diagnose cancer in patients with IWL. MATERIALS AND METHODS: A total of 253 consecutive patients with IWL admitted in a secondary care university hospital were included. Routine hematological and inflammatory parameters (hemoglobin level, mean corpuscular volume, RDW, serum iron level, erythrocyte sedimentation rate, C-reactive protein level, and ferritin level) were recorded for all patients. The investigative workup was not standardized, but the patients were followed up for 6 months to avoid misclassification concerning the final diagnosis. RESULTS: All parameters, excepting mean cellular volume, were statistically associated with cancer. The areas under the curve were 0.708 (95% confidence interval [CI], 0.627-0.790) for C-reactive protein level, 0.690 (95% CI: 0.620-0.760) for erythrocyte sedimentation rate, 0.651 (95% CI, 0.566-0.735) for serum iron level, 0.607 (95% CI, 0.526-0.687) for hemoglobin level, 0.598 (95% CI, 0.518-0.679) for ferritin level, 0.594 (95% CI, 0.517-0.671) for RDW, and 0.561 (95% CI, 0.474-0.649) for mean cellular volume. In the multivariable analysis, only erythrocyte sedimentation rate remained associated with cancer. CONCLUSIONS: In patients with IWL, the hematological and inflammation parameters were statistically different in patients with cancer and in those without cancer. However, in clinical practice, they were modest diagnostic tests for cancer. PMID- 21712731 TI - Lifestyle intervention in postmenopausal women: winning the game against diabetes. PMID- 21712732 TI - Elevated serum visfatin/nicotinamide phosphoribosyl-transferase levels are associated with risk of postmenopausal breast cancer independently from adiponectin, leptin, and anthropometric and metabolic parameters. AB - OBJECTIVE: Obesity has been implicated in the etiology of postmenopausal breast cancer (PBC). We hypothesized that altered secretion of visfatin may underlie this association. We thus investigated the association of serum visfatin with PBC risk, taking into account known risk factors including adipokines and anthropometric and metabolic parameters. METHODS: In a case-control study, we studied 102 postmenopausal women with pathologically confirmed, incident invasive breast cancer and 102 control women matched on age and time of diagnosis between 2003 and 2010 at Army Share Fund Hospital, Veterans' Hospital (NIMTS). Levels of serum visfatin, adiponectin, leptin, metabolic parameters, carcinoembryonic antigen, and CA 15-3 were determined. RESULTS: The mean serum visfatin level was significantly higher in case than in control participants (P < 0.001). Women in the highest quartile of visfatin concentration presented significantly higher odds for PBC, adjusting for age, date of diagnosis, education, body mass index, waist circumference, years with menstruation, parity/age at first full-term pregnancy, breast-feeding, family history of cancer, use of exogenous hormones, alcohol consumption, smoking status, homeostasis model assessment score, and serum leptin and adiponectin concentrations (odds ratio, 7.93; 95% CI, 2.52 24.9). In case participants, the visfatin level correlated significantly with the tumor marker CA 15-3 (P = 0.03) but not with metabolic and anthropometric variables (P > 0.05). CONCLUSIONS: Further prospective studies are needed to determine whether an elevated serum visfatin level is implicated in the etiopathogenesis of PBC or reflects changes during PBC progression and could therefore be used as a biomarker for PBC. PMID- 21712733 TI - Effect of soy isoflavones on circulating C-reactive protein in postmenopausal women: meta-analysis of randomized controlled trials. AB - Strong evidence suggests that C-reactive protein (CRP) is a novel risk factor for cardiovascular disease. We aimed to examine the effect of soy isoflavones on circulating CRP concentrations in postmenopausal women by conducting a meta analysis of randomized controlled trials. We performed a literature search using PubMed, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases in December 2010 for randomized controlled trials conducted in postmenopausal women, using soy foods with isoflavones or isoflavone extracts as treatment, and with a report of CRP change. A meta-analysis was performed using a fixed-effects model or a random-effects model to calculate the combined effect size. In addition, subgroup and metaregression analyses were carried out to examine the influences of study designs and participant characteristics on the effect estimates. A pooled analysis of 14 trials showed a slight, but not significant, reduction of 0.17 mg/L (95% CI, -0.38 to 0.04; P = 0.12) in CRP concentrations among postmenopausal women with soy isoflavone intervention compared with controls. No substantial heterogeneity was observed. Subgroup analyses showed that soy isoflavones significantly lowered CRP by 0.70 mg/L (95% CI, -1.17 to -0.23; P = 0.003) among women with baseline CRP concentrations greater than 2.2 mg/L. No significant changes in CRP were observed in the other subgroups. Metaregression analysis further revealed that baseline CRP was a potential effect modifier of isoflavone treatment in lowering CRP. The present meta-analysis found insufficient evidence that soy isoflavones significantly reduce CRP concentrations in postmenopausal women. However, soy isoflavones may produce a significant reduction in CRP among postmenopausal women with elevated CRP. PMID- 21712734 TI - Severity of coronary artery disease in postmenopausal women: association with the androgen receptor gene (CAG)n repeat polymorphism. AB - OBJECTIVE: Androgen may adversely affect vascular health in women. We investigated the associations between the androgen receptor gene (CAG)n repeat polymorphism, which affects androgen receptor transcriptional activity, and the severity of coronary artery disease (CAD) in women undergoing coronary angiography. METHODS: We examined 131 postmenopausal women (46-82 y). CAD severity was assessed by the number of vessels with greater than 50% stenosis. The history of angina, myocardial infarctions, and biochemical parameters were recorded. CAG repeats ranged between 13 and 24 in the shorter allele and 16 and 28 in the longer allele. The mean lowest quartile corresponded to 19, and the highest, to 22 repeats. RESULTS: Carriers of 19 repeats or less in their shorter allele had severe disease (>=2 vessels affected) and a history of angina more frequently than those carrying 22 or more (39.2% vs 9.5%, P = 0.009 and 80.8% vs 55%, P = 0.037, respectively, using the Fisher exact test). A higher percentage of women carrying 19 repeats or less had one and two myocardial infarctions (28.6% and 10.7%, respectively) compared with women with more than 19 repeats (18.2% and 1.45%, respectively, P = 0.019). Women homozygous for two longer alleles (>=22 repeats) had less severe CAD, significantly higher sex hormone binding globulin levels, and less frequent antilipid drug therapy compared with those homozygous for shorter alleles (P < 0.05). Total cholesterol and low density lipoprotein cholesterol levels were negatively correlated with the number of repeats in the shorter allele (P < 0.04). CONCLUSIONS: Shorter polyglutamine stretch in the androgen receptor correlates with more severe CAD and worse predisposing factors in postmenopausal women undergoing coronary angiography. This association may support the adverse cardiovascular effect of lifelong androgenic exposure in this selected group of women. PMID- 21712735 TI - Effects of body composition and menopause characteristics on maximal oxygen uptake of postmenopausal women. AB - OBJECTIVE: The aim of this study was to identify the effects of body composition and menopause characteristics on maximal oxygen uptake (VO2max) variation in postmenopausal women. METHODS: The study was conducted on 208 healthy women aged 49 to 79 years. Data related to menopause were obtained through medical history. Measurements of fat mass, visceral fat area, skeletal muscle mass (SM), fat-free mass, and basal metabolic rate were assessed by octopolar bioimpedance. SM index was calculated using the formula SM index = SM/weight, and VO2max was assessed through a modified Bruce protocol. RESULTS: Cardiorespiratory fitness was negatively associated with age, percent fat mass, visceral fat area, body fat muscular condition, and central adiposity-muscular condition. Only time elapsed since menopause revealed a statistically significant correlation with VO2max. Age and time of menopause aside, body fat-muscular condition was related to the VO2max variation, presenting an interactive effect with basal metabolic rate. Central adiposity-muscular condition also affects VO2max; however, the association of all interactions, age, basal metabolic rate, and time elapsed since menopause was not significant. CONCLUSIONS: Our data suggest an impairment of cardiorespiratory fitness with increasing age and time elapsed since menopause, but especially in the presence of increased total and central adiposity or reduced SM index. Body fat-muscular condition was significantly related to the VO2max variation, regardless of age and time elapsed since menopause, but not of basal metabolic rate. Central adiposity-muscular condition was a significant and independent factor of the VO2max exercise-related variations. PMID- 21712736 TI - Effect of hormone therapy and calcitriol on serum lipid profile in postmenopausal older women: association with estrogen receptor-alpha genotypes. AB - OBJECTIVE: The aim of this study was to examine the effect of conjugated equine estrogens alone (ET), conjugated equine estrogens + medroxyprogesterone (EPT), calcitriol alone, calcitriol + EPT/ET, or placebo on serum lipid profile and analyze the interaction with estrogen receptor-alpha gene single nucleotide polymorphisms (ESR-alpha SNPs) on the response to therapy. METHODS: A total of 489 postmenopausal women older than 65 years were enrolled into a 3-year double blind, placebo-controlled clinical trial. RESULTS: In both intent-to-treat and complier (>80% adherent) analysis, there was a significant increase in serum high density lipoproteins and a significant decrease in serum low-density lipoproteins (LDLs) and the LDL/high-density lipoprotein ratio in all hormone treatment groups compared with placebo (P < 0.05). However, serum triglycerides and very low density lipoproteins increased in the EPT and ET + calcitriol groups versus placebo (P < 0.05). ESR-alpha SNPs PvuII and XbaI seemed to have a significant effect on the response to treatment. Genotypes containing the p allele showed a significantly greater decrease in serum cholesterol and very low-density lipoprotein than those having the P allele in the ET + calcitriol group (P < 0.05), and those with the x allele had a significantly greater decrease in serum cholesterol in the hormone therapy + calcitriol group at the end of 3 years versus the X allele, and a greater decrease in serum LDL in alleles x versus the X in the ET + calcitriol group (P < 0.05). CONCLUSIONS: ET with or without progesterone had a favorable effect on lipid profile in postmenopausal older women, and this was dependent on estrogen receptor SNPs--PvuII and XbaI. However, this interaction with ESR-alpha SNPs needs to be confirmed in larger studies. PMID- 21712738 TI - Neurological recovery across a 12-cm-long ulnar nerve gap repaired 3.25 years post trauma: case report. AB - BACKGROUND AND IMPORTANCE: The standard clinical technique for repairing peripheral nerve gaps is the use of autologous sensory nerve grafts. The present study tested whether a collagen tube filled with autologous platelet-rich fibrin could induce sensory and motor recovery across a 12-cm nerve gap repaired 3.25 years post trauma, and reduce or eliminate neuropathic pain. CLINICAL PRESENTATION: Two years postrepair, good ring and small finger motor function had developed that could generate 1 kg of force, and topographically correct 2-point discrimination and sensitivity to vibration in the small and ring finger and proximal but not distal wrist had developed. The patient's excruciating neuropathic pain was reduced to tolerable, and he avoided the indicated extremity amputation. The 12-cm-long nerve gap was bridged with a collagen tube filled with autologous platelet-rich fibrin. CONCLUSION: We demonstrate that a conduit filled with platelet-rich fibrin can induce limited, but appropriate, sensory and motor recovery across a 12-cm nerve gap repaired 3.25 years post trauma, without sacrificing a sensory nerve, can reduce existing excruciating neuropathic pain to tolerable, and allow avoidance of an indicated upper-extremity amputation. We believe the technique can be improved to induce more extensive and reliable neurological recovery. PMID- 21712737 TI - Enhanced hypothalamic-pituitary sensitivity to estrogen in premenopausal women with diminished ovarian reserve compared with older perimenopausal controls. AB - OBJECTIVE: We have previously characterized the reproductive hormone profile in infertile women with diminished ovarian reserve (DOR) as being distinct from that seen in age-comparable healthy controls. Hypothesizing that DOR reflects accelerated reproductive aging, we herein compare urinary reproductive hormone dynamics between young women with DOR and a population of chronologically older perimenopausal controls. METHODS: In this prospective observational study, urinary levels of pituitary gonadotropins (follicle-stimulating hormone and luteinizing hormone) and metabolites of estrogen (estrone conjugate) and progesterone were assessed in daily morning urine samples collected in a spontaneous menstrual cycle in 8 infertile premenopausal women with DOR and in 11 perimenopausal controls. Areas under the curves were calculated for the respective measured hormones, and comparisons were made using the Mann-Whitney U test. RESULTS: Urinary estrone conjugate levels were significantly attenuated in premenopausal women with DOR compared with the older perimenopausal cohort. Despite the relatively lower estrogen, a significantly more pronounced luteinizing hormone surge was evident in the younger population. Early follicle stimulating hormone was lower in women with DOR, but luteal urinary progesterone excretion was comparable in the two groups. CONCLUSIONS: Our data suggest distinctions in functioning of the central (hypothalamic-pituitary) and peripheral (ovarian) components of the hypothalamic-pituitary-ovarian axis in premenopausal women with DOR compared with chronologically older perimenopausal controls. Increased hypothalamic-pituitary sensitivity to estrogen positive feedback is suggested in premenopausal women with DOR. Our observations identify DOR as a distinct entity in the paradigm of reproductive senescence. PMID- 21712739 TI - Prevalence, severity, and impact of foraminal and canal stenosis among adults with degenerative scoliosis. AB - BACKGROUND: Management approaches for adult scoliosis are primarily based on adults with idiopathic scoliosis and extrapolated to adults with degenerative scoliosis. However, the often substantially, but poorly defined, greater degenerative changes present in degenerative scoliosis impact the management of these patients. OBJECTIVE: To assess the prevalence, severity, and impact of canal and foraminal stenosis in adults with degenerative scoliosis seeking operative treatment. METHODS: A prospectively collected database of adult patients with deformity was reviewed for consecutive patients with degenerative scoliosis seeking surgical treatment, without prior corrective surgery. Patients completed the Oswestry Disability Index, SF-12, Scoliosis Research Society 22 questionnaire, and a pain numeric rating scale (0-10). Based on MRI or CT myelogram, the central canal and foraminae from T6 to S1 were graded for stenosis (normal or minimal/mild/moderate/severe). RESULTS: Thirty-six patients were included (mean age, 68.9 years; range, 51-85). The mean leg pain numeric rating scale was 6.5, and the mean Oswestry Disability Index score was 53.2. At least 1 level of severe foraminal stenosis was identified in 97% of patients; 83% had maximum foraminal stenosis in the curve concavity. All but 1 patient reported significant radicular pain, including 78% with discrete and 19% with multiple radiculopathies. Of those with discrete radiculopathies, 76% had pain corresponding to areas of the most severe foraminal stenosis, and 24% had pain corresponding to areas of moderate stenosis. CONCLUSION: Significant foraminal stenosis was prevalent in patients with degenerative scoliosis, and the distribution of leg pain corresponded to levels of moderate or severe foraminal stenosis. Failure to address symptomatic foraminal stenosis when surgically treating adult degenerative scoliosis may negatively impact clinical outcomes. PMID- 21712740 TI - Meige syndrome relieved by bilateral pallidal stimulation with cycling mode: case report. AB - BACKGROUND AND IMPORTANCE: Deep brain stimulation (DBS) of the bilateral globus pallidus internus (GPi) has been used effectively to treat dystonia. We report a patient with severe Meige syndrome who received bilateral GPi DBS with good improvement in symptoms during the first 24-month stimulation therapy. To decrease energy consumption and to prolong battery life, the stimulation parameters of the replaced programmable pulse generator were adjusted to the cyclic mode and the stimulator was turned off during nighttime sleep. The patient achieved similar good treatment effect with extended battery life in the following years. CLINICAL PRESENTATION: A 66-year-old woman with a 3-year history of severe cranial-cervical dystonia received stereotaxic surgery for bilateral GPi DBS therapy. The Burke-Fahn-Marsden dystonia score improved from 32 to 7.5. The effect lasted up to 24 months after therapy when the battery ran out of life. After careful evaluation, we adjusted the stimulation parameters of the second implantable pulse generator to the cyclic stimulation mode and programmed the stimulator to turn off automatically during nighttime sleep. The patient showed persistent good effect 36 months after starting use of the second implantable pulse generator. CONCLUSION: To treat dystonic symptoms effectively, stimulation parameters with higher energy consumption are usually required. For reducing the discomfort of repeated battery replacement within a short time and decreasing energy consumption in implantable pulse generator, cyclic mode stimulation could be considered in dystonic patients receiving bilateral GPi DBS. PMID- 21712741 TI - Aplasia of the anterior arch of atlas associated with multiple congenital disorders: case report. AB - BACKGROUND AND IMPORTANCE: Congenital clefts and aplasias of the atlas vertebra are rare. A nonfused posterior arch occurs in 4% of the population; in contrast, a nonfused anterior arch occurs in only 0.1%. To the best of our knowledge, this is the first description of the combination of anterior arch aplasia and a cleft of the posterior arch of the atlas associated with Klippel-Feil and Treacher Collins syndromes and Sprengel deformity. CLINICAL PRESENTATION: An 11-year-old girl presented with neck pain and symptoms of myelopathy, including upper- and lower-extremity paresthesia. Computed tomography revealed significant congenital bony anomalies of the cervical spine, with congenital fusion of C2 through C5. There was aplasia of the anterior ring of C1 (A 2.3-cm gap was present within the anterior aspect of the lateral masses). The posterior elements of C3 and C4 were fused, and signs of Sprengel deformity were present. Magnetic resonance imaging revealed effacement of the ventral cerebrospinal fluid space at the craniocervical junction and mild mass effect at the cervicomedullary junction. Flexion and extension views showed abnormal motion at the craniocervical junction. There was no evidence of atlantoaxial instability, basilar invagination, or Chiari malformation. Occipito-C4-scapular fusion was performed to prevent spinal cord injury and further neurological symptoms. Postoperatively, the patient did extremely well, and her preoperative symptoms resolved. CONCLUSION: We describe a rare case of aplasia of the anterior arch of the atlas and posterior arch midline cleft in association with Treacher-Collins syndrome, Klippel-Feil syndrome, and Sprengel deformity. The patient's atlantoaxial instability was managed surgically with a unique construct that provided occipito C4-scapular fusion. PMID- 21712742 TI - Multicentric chordoma: a case report and review of the literature. AB - BACKGROUND AND IMPORTANCE: Chordomas are relatively rare tumors that arise from the neuraxis. Most often, chordomas are single lesions that metastasize late. There have been very few cases of chordomas arising from multiple foci along the neuraxis. Here, we present a case of a multicentric chordoma. CLINICAL PRESENTATION: The patient presented with pain in her right neck and soreness in her right shoulder that she had experienced for about 2.5 years that she attributed to a muscle strain. She experienced worsening of her symptoms, which prompted her to seek medical care. The patient underwent an occiput-to-C6 posterolateral fusion with autograft and an occiput-to-C6 posterior segmental instrumentation, along with decompression of the spinal cord. One month after the initial surgery, the patient underwent a second surgery. The C2 and C3 vertebral bodies were completely resected, and a C1-C4 anterior fusion was then carried out. A C5 vertebrectomy and C4-C6 fusion were also performed at this time. The patient then received proton beam radiation to the entire affected area. CONCLUSION: Recent studies have suggested that chordomas arise from benign notochordal tumors. We suggest that our patient suffered from multicentric chordomas with possible benign notochordal tumors. Although benign notochordal tumors do not require surgical resection, the possibility of transformation to a malignant lesion requires close follow-up. PMID- 21712743 TI - Comparison between angioplasty using compliant and noncompliant balloons for treatment of cerebral vasospasm associated with subarachnoid hemorrhage. AB - BACKGROUND: Considerable controversy exists regarding the choice of balloon used for performing angioplasty as treatment of cerebral vasospasm associated with subarachnoid hemorrhage. OBJECTIVE: To determine the impact of compliant and noncompliant balloons on angiographic and clinical outcomes among patients with subarachnoid hemorrhage-related cerebral vasospasm. METHODS: Consecutive patients with cerebral vasospasm who underwent balloon angioplasty were included. Patient characteristics, rate of angiographic recurrence, and occurrence of cerebral infarcts in the affected vessel distribution were compared between arteries treated using different balloons. RESULTS: A total of 30 patients underwent a first-time angioplasty using compliant (n = 34) or noncompliant (n = 51) balloons. At admission, patients were classified Hunt and Hess grade I to III (n = 20) and Hunt and Hess grade IV to V (n = 10). Fisher grades in patients were I (n = 1), II (n = 3), III (n = 20), and IV (n = 6). No significant differences in the rate of angiographic recurrence (32% vs 53%; P = .14), need for repeat angioplasty (21% vs 20%; P = .97), and occurrence of cerebral infarcts in the affected arterial distribution (21% vs 10% P = .39) were observed with compliant and noncompliant balloons, respectively. Independent of the balloon type, a significant reduction in the need for repeat angioplasty was observed when the initial angioplasty resulted in a normal or supranormal diameter compared with a subnormal diameter (63.5% vs 36.5%; P = .01). CONCLUSION: No clear difference was observed between compliant and noncompliant balloons for therapeutic angioplasty in preventing angiographic recurrence or the need for repeat angioplasty in patients with subarachnoid hemorrhage-related cerebral vasospasm. An immediate normal or supranormal vessel diameter after the first-time angioplasty resulted in a significant reduction in the need for repeat angioplasty. PMID- 21712744 TI - Utilization of emergency ultrasound in pediatric emergency departments. AB - OBJECTIVES: This study aimed to determine the utilization of emergency ultrasound (EUS) in pediatric emergency departments (EDs) and in pediatric emergency medicine (PEM) fellowship training programs and to assess if PEM fellowship programs provided formal training in EUS. METHODS: A Web-based survey was administered to pediatric emergency medical directors, fellowship directors, and graduating fellows. RESULTS: A response was received from 60% of individuals and 68% of institutions. Of the responders, 27% reported that their institution had a EUS program. Also, 96% of the responders reported having a dedicated US machine in the ED, but only 61% reported using EUS for managing ED patients. Responders reported using EUS for the focused assessment by sonography for trauma examination (93%), abscess management (82%), vascular access (78%), bladder scanning (70%), cardiac activity confirmation (59%), and pericardial effusion detection (59%). For pediatric emergency staff physicians, 63% of the responders reported obtaining EUS training from general emergency physicians and 59% from a commercial ultrasound course and from pediatric emergency physicians. For PEM fellows, 34% reported having a standardized EUS training program. Of the responders, 69% reported receiving training from general emergency physicians during adult ED rotations and 38% reported receiving training from pediatric emergency physicians. Only 28% of programs reported using criteria established by the American College of Emergency Physicians for the number of scans performed to attain competence. CONCLUSIONS: In our study sample, there is wide variation in the uses of EUS and the training pediatric emergency physicians receive in its use. PMID- 21712745 TI - Universally poor outcomes of pediatric traumatic arrest: a prospective case series and review of the literature. AB - OBJECTIVE: Few data are available on traumatic cardiopulmonary arrest in children. Efforts at resuscitation typically result in heavy utilization of finite resources with little understanding of which characteristics, if any, may be associated with success. The objectives of this study were to describe the outcome of children in traumatic cardiac arrest and to identify patients for whom aggressive resuscitation may or may not be warranted. METHODS: Data were analyzed from a previous study of prehospital pediatric airway management in Los Angeles and Orange Counties, Calif, over a 33-month period. Patients included in this secondary analysis were younger than 13 years and found pulseless and apneic after having had an injury. Data sources included prospective, phone interviews with paramedics after transfer of care to the receiving facility, and chart review to determine outcome. Two main outcomes were assessed: survival and neurological function as measured by the Pediatric Cerebral Performance Category. RESULTS: The emergency medical services responded to 118 traumatic arrests during the study period. Of these victims, only 6 (5%) survived. Median Injury Severity Score was 25 with an interquartile range of 16 to 75. The survivors all were neurologically impaired with a median Pediatric Cerebral Performance Category of 5 (interquartile range, 4-5). CONCLUSIONS: Children who had trauma resulting in cardiac arrest have universally poor outcomes, and survivors have severe neurological compromise. We are unable to identify a subset of patients for whom aggressive resuscitation is indicated. This is the largest prospective study of pediatric traumatic arrest to date. PMID- 21712746 TI - Procedural restraint use in preverbal and early-verbal children. AB - BACKGROUND: Children frequently undergo diagnostic and therapeutic procedures while in hospital. To conduct these procedures safely, preverbal and early-verbal children in particular are often restrained. However, the literature on procedural restraint use is very limited. We set out to describe the extent of restraint use in 4 common procedures. METHODS: In this prospective observational study at an urban tertiary children's hospital emergency department, children aged 6 to 42 months undergoing 4 commonly performed procedures (intravenous insertion [IV], nasogastric tube [NGT] insertion, metered-dose inhaler [MDI] use, and oxygen saturation [O2 sat] measurement) were recruited. An independent observer assessed the extent and forcefulness of restraint use. Results were analyzed descriptively by age and procedure. RESULTS: One hundred twenty-four patients were recruited. All successful procedures (n = 123) were completed in 3 or fewer attempts, with 102 (82%) successful on the first attempt. Physical restraint was used in 89 (72%) of 124 patients overall. All patients undergoing IV (n = 33) and NGT insertion (n = 30), 64% of children requiring MDI (21/33), and only 18% of children requiring O2 sat measurements (5/28) were restrained. Twenty-three (79%) of the NGT insertions and 16 (48%) of IV insertions required moderate or forceful restraint. No or gentle restraint was used for 24 (73%) of MDI use and 100% of saturation measurements. Overall, 41 (87%) of 47 children 6 to 18 months old required restraint use as compared with 28 (68%) of 41 of 18- to 30-month-olds and 20 (57%) of 35 of 30- to 42-month-olds. CONCLUSIONS: Procedural restraint use in preverbal and early-verbal children is extensive, and significant amounts of force are used, which vary by procedure. Restraint use diminishes with age. A scoring system for restraint use is suggested based on the number of body parts restrained. PMID- 21712747 TI - Teaching physicians to assess suicidal youth presenting to the emergency department. AB - OBJECTIVES: The objective of this study was to determine whether a 5-module self paced computerized educational program improves residents' skills in assessing and managing youth presenting to the emergency department in acute psychiatric distress. METHODS: The evaluation used a quasi-experimental posttest-only design assessing both knowledge of the educational context of the program and self-rated pretest knowledge of program content with 32 residents recruited from 1 medical center in Cleveland, Ohio. RESULTS: About half of the respondents were female (48%); almost two thirds were white (65%), and few were trained in psychiatric assessment of children/adolescents. On average, residents had significantly higher scores on the posttest compared with the self-rated pretest (6.4 +/- 1.1 vs 3.8 +/- 2.3; P < 0.001), an effect size of 1.32. Residents responded positively to the modules and rated them highly on educational content (4.2 +/- 0.5 on a 5-point scale) and satisfaction with clinical applicability (8.2 +/- 1.2 on a 10-point scale) and found the program easy to navigate (8.5 +/- 1.9 on a 10 point scale). CONCLUSIONS: A brief, self-administered, Web-based training program shows promise for improving residents' knowledge about suicidal behaviors in youth. PMID- 21712748 TI - Variation in the use of chest radiography for pneumonia in pediatric emergency departments. AB - OBJECTIVES: We sought to examine the utilization of chest radiography among children with pneumonia and other respiratory illnesses and to investigate interinstitution chest radiograph (CXR) utilization to identify if there is a relationship between CXR utilization and rate of pneumonia. METHODS: This is a retrospective study of children evaluated in an emergency department at 25 institutions contributing information to the Pediatric Health Information System database from 2003 to 2008. The use of chest radiographs was determined for patients with a diagnosis of pneumonia, upper respiratory tract illness, wheeze, and fever. RESULTS: Over a 6-year period, pneumonia accounted for 2.1% of all visits to an emergency department. Comparing institutions, the proportion of children with a diagnosis of pneumonia who had a CXR obtained ranged from 38% to 88%. There was no observed association between CXR utilization rate and the proportion of patients with a diagnosis of pneumonia between institutions. There was also a wide variation in the use of CXR for other diagnoses (upper respiratory tract infection [range, 9%-36%], wheeze [14%-56%], fever [7%-41%]). Eighty-percent of children hospitalized with pneumonia had a radiograph obtained, compared with 76% of children with pneumonia discharged from the ED (P = 0.28). However, the rate of utilization of CXR for patients hospitalized with other diagnoses was higher than respective rates of CXR use for discharged patients (upper respiratory tract infection, 68% vs 16% [P < 0.001]; wheeze, 57% vs 23% [P < 0.001]; and fever, 45% vs 18% [P < 0.001]). CONCLUSIONS: The use of CXR varies widely among pediatric emergency departments but does not appear to influence the institution-specific rate of pneumonia. PMID- 21712749 TI - Mortality and child abuse in children presenting with apparent life-threatening events. AB - BACKGROUND: Children who present to the emergency department following an apparent life-threatening event (ALTE) often appear well, have a normal physical examination, and usually do well. The incidence of mortality following an event appears to occur infrequently, but has not been well described. However, it has been our experience that children who are victims of occult child abuse have a high mortality rate. METHODS: Children younger than 24 months who presented to the emergency department following an ALTE were prospectively enrolled and followed up for a period of 12 months. Mortality rate was recorded. RESULTS: During the study period of 9 years, 563 patients were enrolled. The mean age of the patients was 2.6 months. Eleven patients (2%) were diagnosed with child abuse. Those diagnosed with child abuse were more likely to have focal findings on physical examination (54% vs 17%, P < 0.01). Three children died; the overall mortality rate was 0.5% (3/563). One of the 3 deaths was secondary to child abuse. The other 2 deaths were reported at autopsy to be secondary to sudden infant death syndrome. One of the 11 cases of child abuse ended in a death, which is a 9% mortality rate of child abuse victims who present with an ALTE. CONCLUSIONS: Although the subsequent mortality rate for children who present with an ALTE is low, child abuse was one of the identifiable causes of death and should be considered during evaluation of all children who present with an ALTE. PMID- 21712750 TI - The acceptability of mental health screening in a pediatric emergency department. AB - OBJECTIVES: The purposes of the study were (1) to assess the acceptability of mental health screening in the pediatric emergency department (ED) for children and their parents; (2) to measure providers' perceptions on whether screening has an impact on patient care; and (3) to determine the impact of screening status on acceptability. METHODS: A validated pediatric mental health screening instrument was administered to 384 parent-child dyads. A 6-item satisfaction questionnaire was administered by a trained research coordinator to assess parent-child reactions to the screen. Emergency department providers rated how difficult the screening made it for them to care for the patient. Research staff reported the difficulty of conducting screening during the ED visit and the amount of time parents/children spent completing the screen. RESULTS: Most parents (82%) and children (75%) felt the screening was acceptable. Parent reports of pediatric mental health problems were not associated with lower acceptability scores. The number of mental health problems reported by a child was associated with an increased likelihood that the screening made the child upset (P = 0.02). Parents who reported pediatric mental health problems were more likely to find the screening helpful (odds ratio,1.84 [95% confidence interval, 1.15-2.93]), with black parents more likely to report that the screen was helpful (odds ratio, 2.5 [95% confidence interval, 1.43-4.33]). Nearly all doctors (99%) and nurses (97%) reported that the screening did not make it difficult for them to care for the patient. CONCLUSIONS: Overall, mental health screening appears to be acceptable in the pediatric ED. PMID- 21712751 TI - The predictive value of a normal radiographic anterior fat pad sign following elbow trauma in children. AB - OBJECTIVE: The purposes of this study were to describe the characteristics of a normal anterior fat pad (AFP) and to determine the association between a normal AFP and the absence of fracture. METHODS: A prospective cohort of children aged 1 to 18 years with elbow trauma underwent radiographic examination. All patients received standard orthopedic management and follow-up 7 to 14 days after injury. A pediatric radiologist evaluated all radiographs for the presence or absence of fracture and documented whether the AFP was normal or abnormal on the lateral view. The radiologist also recorded specific measurements of the AFP including the apical angle, which is formed by the intersection of the humerus and the superior aspect of the AFP. The interpretation of the AFP on the initial lateral radiograph was compared with the final patient outcome (fracture/no fracture). RESULTS: Two hundred thirty-one patients had elbow radiographs; 34 patients (15%) were lost to follow-up. A total of 56 fractures were identified: 49 (87%) on the initial radiograph and an additional 7 (13%) on follow-up radiographs. This latter group was defined as occult fractures. Among the 197 patients available for analysis, 113 (57%) had a normal AFP on the initial radiograph. Of these, 2 children had a final diagnosis of fracture. The sensitivity of a normal AFP was 96.4% (95% confidence interval, 86.6%-99.4%), and the negative predictive value was 98.2% (95% confidence interval, 93.1%-99.7%). There was a significant difference in mean AFP angle when the AFP was read as normal (14.7 [SD, 3.3] degrees) compared with when it was read as abnormal (27.0 [SD, 6.8] degrees) (P < 0.01). CONCLUSIONS: Our data suggest that a normal AFP is highly associated with absence of elbow fracture and that the determination of a normal AFP can be aided by measuring the apical angle of the AFP. PMID- 21712752 TI - What do pediatric residents know about malpractice? AB - OBJECTIVE: The objective was to assess pediatric residents' attitudes toward and knowledge about medical malpractice before and after an educational intervention. METHODS: A survey of pediatric residents at our academic tertiary-care center was conducted before and 6 months after an educational workshop. RESULTS: Of 71 eligible residents, 46 (65%) completed surveys. Thirty-nine (85%) of the 46 original participants completed the follow-up survey. At baseline, 86% thought medical malpractice should be taught during residency. This proportion increased to 95% at follow-up. At baseline, 43% reported that fear of a malpractice claim affected their practice. At follow-up, 69% indicated that fear of malpractice affected their practice (P = 0.01), and 69% of these reported improved documentation. At baseline, 30% of participants correctly thought that a resident's level of training was not a factor in determining if standard of care was provided. This increased to 56% at follow-up (P = 0.01). The majority (91%) of baseline participants thought a physician would be notified of a claim within less than 2 years of the occurrence. The actual mean delay is 25 months. At follow-up, 71% thought a physician would be notified 2 years later or more. CONCLUSIONS: Pediatric residents are uncomfortable with their knowledge of medical malpractice and think it should be taught during residency. Confusion regarding responsibility to provide standard of care and underestimates of the likelihood of being sued and the time to notification of a suit support the need for malpractice education. An educational intervention improves background knowledge and self-reported documentation. PMID- 21712753 TI - Children presenting with acute pericarditis to the emergency department. AB - OBJECTIVE: The objective of the study was to evaluate the clinical features and the outcome of children who presented to the emergency department and were ultimately diagnosed with pericarditis. METHODS: A retrospective chart review of all children diagnosed with acute pericarditis from January 2000 through March 2007 was conducted. RESULTS: There were 94 children with pericarditis as the sole or one of the discharge diagnoses: 34 with postsurgical pericarditis and 38 with pericarditis as a component of a generalized illness were not examined further. Of the 22 children included in the study, the mean age was 12.3 (SD, 2.7) years, and 80% were males. Chest pain was present in 96%, and fever was present in 56%. All children had electrocardiographic changes comprising ST and T-wave abnormalities. Initial chest radiographs were reported as normal in 40%; although 82% (n = 18) had a pericardial effusion on echocardiography, 7 (32%) required pericardiocentesis. The etiology was considered idiopathic in 68% (n = 15). All children improved on treatment with nonsteroidal anti-inflammatory drugs. Eight children (36%) had recurrent pericarditis, of whom 2 had multiple recurrences. CONCLUSIONS: Children presenting with chest pain require further investigation if electrocardiographs show any abnormalities. Children presenting with pericarditis require follow-up and caution about recurrence. PMID- 21712754 TI - Impact of very advanced donor age on hepatic artery thrombosis after liver transplantation. AB - BACKGROUND: The impact of advanced donor age on hepatic artery thrombosis (HAT) after liver transplantation (LT) is controversial. METHODS: We analyzed the incidence of and risk factors for HAT in LT with donors aged 70 years or older. Eighty patients were transplanted between 1998 and 2002 (group A) and 132 between 2003 and 2008 (group B). RESULTS: In the more recent approach to hepatic artery (HA) reconstruction, the donor HA was systematically preferred to the Carrel patch/celiac trunk, the reconstruction of donor accessory right HA on the donor gastroduodenal artery significantly increased, and the use of interposition grafts was minimized. Group B showed higher Model for End-stage Liver Disease score, lower ischemia time, and lower use of the folding technique/mesenteric conduits. There were 10 cases of HAT (4.7%): 8 (10%) in group A and 2 (1.5%) in group B (P=0.007). Early HAT occurred in 7 (8.8%) patients in group A and in 2 (1.5%) in group B (P=0.02). Group A (P=0.01), anatomical variations of HA (P=0.005), and the use of interposition grafts (P=0.004) were all factors independently affecting HAT. CONCLUSIONS: A low incidence of late HAT was observed in single-center LTs with very old donors. Early HAT decreased over time to largely acceptable rates because of more appropriate technical management. PMID- 21712755 TI - Monoclonal gammopathy of undetermined significance does not affect outcomes in patients undergoing solid organ transplants. AB - BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic plasma cell proliferative disorder with a lifelong risk of progression to multiple myeloma or another plasma cell dyscrasia. Despite a high incidence in the general population and an increased relative risk for later malignancy, there are few reports about the clinical course of MGUS or risk profile in long-term immunosuppressed patients. METHODS: We reviewed 1593 solid organ transplant patients and reported the frequency and outcomes of patients with MGUS identified pretransplant. RESULTS: Polyclonal gammopathy pretransplant is common with 17% of all patients and as many as 75% of liver transplant candidates having increased globulins.However, a monoclonal immunoglobulin was identified in only 3% of all solid organ transplant patients pretransplant (n=34). Importantly, in these 34 patients, no cases of progression to multiple myeloma, amyloid, or lymphoma were observed during immune suppression, and there was no association between posttransplant lymphoproliferative disorders and pretransplant MGUS. Death in MGUS patients was not associated with progression of the monoclonal clone or development of posttransplant lymphoproliferative disorders or other malignancy. CONCLUSION: In conclusion, routine testing for MGUS before transplantation is not prognostic nor a contraindication to transplant, and therefore, it is not recommended. PMID- 21712756 TI - Graft-protective effects of the HMG-CoA reductase inhibitor pravastatin after lung transplantation--a propensity score analysis with 23 years of follow-up. AB - BACKGROUND: To determine whether the hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin has a graft-protective effect, we retrospectively analyzed 502 patients who had undergone lung transplantation in Hannover. METHODS: Propensity scores have been calculated for each patient and compared between two groups. Cox Hazard analyses were performed for different parameters (e.g., basic parameters of patients, underlying diagnoses, different operations, and important organ functions after lung transplantation). Lung function after transplantation was monitored using repeated measurement analyses. Additionally, conditional Kaplan-Meier survival analyses were used to explore the impact of different diagnoses, the severity of bronchiolitis obliterans, the type of transplantation, and different immunosuppressant regimes on patient survival. RESULTS: The results indicate a strong association between the postoperative administration of statins and the improvement of survival, maintenance of graft (lung) function, and slowing of the onset of bronchiolitis obliterans. CONCLUSION: These findings suggest a new postoperative therapeutic focus for maintaining graft function. PMID- 21712757 TI - Progress in the field of probiotics: year 2011. AB - PURPOSE OF REVIEW: The interest and scope for research in the field of probiotics has significantly widened in recent years. This brief review covers the significant advances in the field of probiotics. RECENT FINDINGS: These include conclusive evidence for the benefits of probiotics in preventing all cause mortality and necrotizing enterocolitis (NEC) in preterm very low birth weight (VLBW) neonates, understanding the role of probiotics as vaccine adjuvants, and in modulating inflammatory bowel diseases, bowel cancer, type 1 diabetes mellitus, obesity, high cholesterol levels, and bacterial resistance. Other areas of progress include understanding the role of probiotics in oral health and ageing. SUMMARY: Current evidence will lead to routine probiotic supplementation to prevent all cause mortality and NEC in preterm VLBW neonates. Probiotics may also become novel agents as vaccine adjuvants, and in dealing with major public health issues such as obesity, type I diabetes mellitus, and poor oral health. Research in applications of probiotics in food products will rationalize product development, and health claims. As new frontiers continue to be explored the challenges to the basis of the hygiene hypothesis will influence further developments in the field of probiotics. PMID- 21712758 TI - Lack of association between two dopamine D2 receptor gene polymorphisms and schizophrenia. PMID- 21712759 TI - In vitro activity of plant extracts and alkaloids against clinical isolates of extended-spectrum beta-lactamase (ESBL)-producing strains. AB - The antibacterial activity of 80% ethanol extracts of 10 medicinal plants collected in Yunnan (Southwest China), was tested against clinical isolates of extended-spectrum beta-lactamase (ESBL)-producing strains. Their MIC values ranged between 1.56-12.50 mg/mL. The most active plant extract was Chelidonium majus L. (MIC = 1.56 mg/mL). Two potent isoquinoline alkaloids, 8 hydroxydihydrosanguinarine and 8-hydroxydihydrochelerythrine, were identified as the major active principles through bioassay-guided fractionation and identification of the active ethyl acetate fraction from C. majus, with minimum MIC/MBC values of 15.63/62.50 mg/mL. PMID- 21712760 TI - Opportunities offered by chiral eta6-arene/N-arylsulfonyl-diamine-RuII catalysts in the asymmetric transfer hydrogenation of ketones and imines. AB - Methods for the asymmetric transfer hydrogenation (ATH) of ketones and imines are still being intensively studied and developed. Of foremost interest is the use of Noyori's [RuCl(eta6-arene)(N-TsDPEN)] complexes in the presence of a hydrogen donor (i-PrOH, formic acid). These complexes have found numerous practical applications and have been extensively modified. The resulting derivatives have been heterogenized, used in ATH in water or ionic liquids and even some attempts have been made to approach the properties of biocatalysts. Therefore, an appropriate modification of the catalyst that suits the specific requirements for the reaction conditions is very often readily available. The mechanism of the reaction has also been explored to a great extent. Model substrates, acetophenone (a ketone) and 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline (an imine), are both reduced by this Ru catalytic system with almost perfect selectivity. However, in each case the major product is a different enantiomer (S- for an alcohol, R- for an amine when the S,S-catalyst is used), which demanded an in depth mechanistic investigation. Full-scale molecular modelling of this system enabled us to visualize the plausible 3D structures of the transition states, allowing the proposition of a viable explanation of previous experimental findings. PMID- 21712761 TI - Synthesis and antibacterial activities of novel imidazo[2,1-b]-1,3,4 thiadiazoles. AB - 2-Amino-5-(2-aryl-2H-1,2,3-triazol-4-yl)-1,3,4-thiadiazoles 2-4 have been synthesized by the reaction of 2-aryl-2H-1,2,3-triazole-4-carboxylic acids 1 with thiosemicarbazide. Their reaction with phenacyl (p-substituted phenacyl) bromides led to formation of the respective 6-aryl-2-(2-aryl-2H-1,2,3-triazol-4 yl)imidazo[2,1-b]-1,3,4-thiadiazoles 5. Reactivity of the latter fused ring towards reaction with different electrophilic reagents afforded the corresponding 5-substituted derivatives 6-8. The structure of the above compounds was confirmed from their spectral characteristics. Some of these compounds were found to possess slight to moderate activity against the microorganisms Staphylococcus aureus, Candida albicans, Pseudomonas aeruginosa, and Escherichia coli. PMID- 21712762 TI - Rare complication after mitral valve replacement due to infective endocarditis (Part 2). AB - A 27-year-old woman who had undergone mitral valve replacement for infective endocarditis developed a significant paravalvular leak. Percutaneous transcatheter obliteration of the defect using an Amplatzer Vascular Plug III was undertaken, with an excellent clinical outcome. PMID- 21712763 TI - Biventricular decompression by trans-septal positioning of venous ECMO cannula through patent foramen ovale. PMID- 21712764 TI - Use of modified Sandwich-graft technique to preserve hypogastric artery in EVAR treatment of complex aortic aneurysm anatomy. AB - AIM: Since the introduction of the first endoprosthetic devices, continuous development in techniques and implants has occurred, such as the introduction of a stent graft with branches designed to preserve antegrade flow in the hypogastric artery, a stent-graft designed to treat extreme neck angulation and iliac tortuosity, as well as "Sandwich" and "Chimney" techniques used to maintain perfusion in branch vessels originating in the region to be treated. This paper describes how the Sandwich-Graft technique was adapted, as described by Lobato et al., employing the AorfixTM system (Lombard Medical) and the ViabahnTM (W.L.Gore) to preserve hypogastric flow in cases with extreme neck angulation and iliac tortuosity. METHODS: The study included four patients treated from April 2010 until November 2010 with the modified Sandwich technique. All patients eligible for this approach were considered unfit for open repair and were not suitable for an iliac branch graft (Z-BIS ZenithTM Cook Medical). RESULTS: A bifurcated endograft was implanted with specific, in-situ, branching to the target hypogastric artery and achieved clinical and technical success, in all the patients. After a 11-month follow-up in two cases and a six-month follow-up in the other two, clinical results were successful. All patients were endoleak-free, had patent hypogastric branches and had shrinking or stable aneurysms. CONCLUSION: The initial experience shows that the Sandwich technique with the AorfixTM stent-graft demonstrated to be effective in endovascular repair of abdominal aortic aneurysms in patients with aortoiliac anatomy hostile to preserving hypogastric artery patency. This graft allows a broader group of patients to be treated with endovascular repair without potential complications of hypogastric artery occlusion; however, further studies are needed to evaluate long-term results in larger numbers of patients. PMID- 21712766 TI - The combined treatment of aortic stenosis and abdominal aortic aneurysm using transcatheter techniques: a case report. AB - We describe the case of an 85 year old lady with symptomatic aortic stenosis (AS) with a history of previous coronary artery bypass grafting (CABG), who was referred for consideration of aortic valve replacement (AVR). Echocardiography revealed severe AS with peak gradient of 92 mmHg, orifice area of 0.6 cm2 and preserved left ventricular function. Computed tomography (CT) aortogram revealed a diffusely calcified aorta and an infrarenal abdominal aortic aneurysm (AAA) measuring 6.5 cm. For symptomatic and prognostic reasons she needed treatment of both the AAA and AS. Her calculated logistic EuroSCORE for AVR was 39%. Following discussion at a multidisciplinary forum, it was agreed that the best way to offer her treatment with the lowest risk was by using transcatheter techniques for both pathologies. She subsequently underwent transcatheter aortic valve implantation (TAVI) via the transapical approach to treat her AS, and 3 months later, endovascular stenting of her infrarenal AAA. She recovered well from both procedures. At 6 week follow up, her cardiac symptoms had improved considerably, and echocardiography revealed a mean AV gradient of 7 mmHg with good left ventricular function. Ultrasound of her abdomen revealed exclusion of the aneurysm sac with no endoleak. This is the first described case of TAVI and endovascular treatment of an AAA as a staged procedure. PMID- 21712767 TI - Conditions associated with placental dysfunction. AB - Placental dysfunction is a term to describe suboptimal placental function leading to variations in the fetal supply of all its necessary required nutrients as well as the disruption in the cleansing of fetal catabolic products. The dysfunctional placenta may interrupt the manufacturing of other essential factors involved in pregnancy conservation, can compromise the fetal appropriate, atraumatic and sterile medium to grow, the immunologic shield from maternal antibodies and the normal amniotic fluid levels. Placental dysfunction can lead to a group of disorders representing a diverse and important category of pathological processes conducting to fetal and neonatal morbidity and mortality. The mechanisms by which these inflammatory processes cause death and disability are diverse and can be separated into four distinct classes: first, placental damage with loss of function; second, induction of premature labor; third, release of inflammatory mediators; fourth, transplacental infection. Several conditions have been associated with placental dysfunction: IUGR, hypertension, hypoxic-ischemic injury, preterm labor, and fetal death. PMID- 21712768 TI - Asystole on anesthesia induction in adults: don't blame the Succinylcholine alone. PMID- 21712769 TI - Target fraction of inspired oxygen during open lung strategy in neonatal high frequency oscillatory ventilation: a retrospective study. AB - BACKGROUND: There is no agreement to define the target FiO2 to adopt in the lung recruitment phase during HFOV in preterm infants. We report our experience of an optimal lung volume strategy (OLVS), defined as FiO2<=0.25 during the recruitment phase, in a cohort of neonates with gestational age (GA) <=27 weeks treated with elective HFOV for respiratory distress syndrome (RDS) between July 2006 and September 2008. METHODS: FiO2 used during the recruitment phase was different according to physician' evaluation. 51 newborns were then divided into two groups: patients reaching FiO2<=0.25 (OLVS Group, N.=28), and patients reaching FiO2>0.25 (No-OLVS Group, N.=23). RESULTS: Prior to surfactant administration OLVS Group, respect to No-OLVS Group, received a significantly higher continuous distending pressure (CDP): 12.8+/-1.1 cmH2O vs 11.2+/-1.3 cmH2O (P<0.0001) and a significantly lower FiO2: 0.25+/-0.01 vs 0.35+/-0.06 (P<0.0001). A multivariate modeling approach confirmed that OLVS was significantly associated to the need for less surfactant doses (OR 0.19[95% CI 0.05-0.84]), a decreased risk of ductus arteriosus surgically ligated (OR 0.13[95% CI 0.02-0.86]) and to a lower number of ventilation hours before extubation: -152 (95% CI -284- -20). CONCLUSION: OLVS to fully recruit the lungs achieving FiO2<=0.25 during elective HFOV is associated with better short-term pulmonary outcomes respect to a strategy where the patients received a FiO2>0.25 during the recruitment phase. Utilizing HFOV in this way provides a more effective means to recruit and protect acutely injured lungs. PMID- 21712771 TI - Vesicular monoamine transporter-1 (VMAT-1) mRNA and immunoreactive proteins in mouse brain. AB - OBJECTIVE: Vesicular monoamine transporter 1 (VMAT-1) mRNA and protein were examined (1) to determine whether adult mouse brain expresses full-length VMAT-1 mRNA that can be translated to functional transporter protein and (2) to compare immunoreactive VMAT-1 proteins in brain and adrenal. METHODS: VMAT-1 mRNA was detected in mouse brain with RT-PCR. The cDNA was sequenced, cloned into an expression vector, transfected into COS-1 cells, and cell protein was assayed for VMAT-1 activity. Immunoreactive proteins were examined on western blots probed with four different antibodies to VMAT-1. RESULTS: Sequencing confirmed identity of the entire coding sequences of VMAT-1 cDNA from mouse medulla oblongata/pons and adrenal to a Gen-Bank reference sequence. Transfection of the brain cDNA into COS-1 cells resulted in transporter activity that was blocked by the VMAT inhibitor reserpine and a proton ionophore, but not by tetrabenazine, which has a high affinity for VMAT-2. Antibodies to either the C- or N- terminus of VMAT-1 detected two proteins (73 and 55 kD) in transfected COS-1 cells. The C-terminal antibodies detected both proteins in extracts of mouse medulla/pons, cortex, hypothalamus, and cerebellum but only the 73 kD protein and higher molecular weight immunoreactive proteins in mouse adrenal and rat PC12 cells, which are positive controls for rodent VMAT-1. CONCLUSIONS: These findings demonstrate that a functional VMAT-1 mRNA coding sequence is expressed in mouse brain and suggest processing of VMAT-1 protein differs in mouse adrenal and brain. PMID- 21712772 TI - Thyroid stimulating hormone and cognition during severe, transient hypothyroidism. AB - OBJECTIVE: The purpose of our pilot study was to explore the relationship between serum thyroid stimulating hormone (TSH) levels during overt hypothyroidism (OH) and hypothyroid-related neuropsychological symptoms. We hypothesized that TSH level may reflect the degree of 'brain hypothyroidism' such that an inverse correlation may exist between serum TSH and cognitive function in patients experiencing overt hypothyroidism (OH), and sought to explore this hypothesis. METHODS: Eleven thyroidectomized patients underwent neuropsychological and thyroid function testing while overtly hypothyroid, and again following thyroid hormone replacement. Their test performance was compared with that of eleven healthy controls at a similarly separated two points in time, and the change over time for the patient group and the controls was likewise assessed and compared. The patients' neuropsychological test scores were then correlated with their serum TSH levels while hypothyroid. RESULTS: The patients' performance while hypothyroid was worse than that of the controls in only one neurocognitive measure--Working Memory Index. The subjects improved similarly or to a greater degree than the controls, when the subjects were thyroid hormone replaced, on all but one neurocognitive measure - Thurstone Word Fluency. TSH level during hypothyroidism was inversely proportional to the patients' performance on these same two measures, but no others. CONCLUSION: Serum TSH level during hypothyroidism was inversely proportional to performance on the only two neurocognitive measures evidencing an adverse effect from hypothyroidism in our cohort. This suggests that serum TSH level may reflect the severity of 'brain hypothyroidism' during the overt stage of this condition. PMID- 21712773 TI - The effects of siRNA-mediated RGS4 gene silencing on the whole genome transcription profile: implications for schizophrenia. AB - OBJECTIVE: The regulator of G-protein signaling (RGS) molecules represent a class of proteins that modulate the signaling activity of G-protein coupled receptors. Regulator of G-protein signaling 4 (RGS4) is of particular interest in schizophrenia due to reported downregulation of RGS4 transcripts in schizophrenia as well as a connection between RGS4 and a number of receptors implicated in schizophrenia. The mechanism of RGS4 involvement in the pathophysiology of this illness is not clear. METHODS: To elucidate thise role of RGS4 in pathophysiology of schizophrenia, we silenced RGS4 using siRNAs in human neuroblastoma cell lines and we studied the effects of differential RGS4 expression by microarray. RESULTS AND CONCLUSION: The cell lines with downregulated expression of RGS4 showed 67 genes with changed expression (30 underexpressed and 37 overexpressed). We have detected three subgroups of genes which might be implicated in schizophrenia pathophysiology: histone genes, which suggest epigenetic mechanisms of the disease; genes for transcription factors associated with other genes relevant to schizophrenia pathology (BDNF and DISCI1) and a heterogeneous group containing genes for G-proteins (GPR50 and GPR64) and calcium binding proteins. PMID- 21712774 TI - SUMO negatively regulates BACE expression. AB - OBJECTIVE: The effect of SUMO on the promoter activity and mRNA expression of BACE gene was investigated to find the connection between sumoylation and APP processing. METHODS: The BACE promoter activity was measured by reporter gene analysis and BACE mRNA level was investigated using real-time RT-PCR method. RESULTS: BACE gene promoter activity was inhibited by the over-expression of SUMO proteins and was blocked by disrupting the SP1 site. Endogenous BACE mRNA level was also negatively regulated by the induction of SUMO proteins. Using a specific inhitor of SP1, BACE promoter activity was coordinately inhibited. CONCLUSIONS: SUMO negatively regulates the BACE expression and SP1 is involved in the process. PMID- 21712775 TI - Rare complications of pregnancy: aortic cystic medionecrosis, gallbladder carcinoma, Hodgkin lymphoma. AB - The authors present cases on rare but serious complications in pregnancy and puerperium concerning women with cystic aorta medionecrosis, gallbladder carcinoma and Hodgkin lymphoma. They describe the prognosis of pregnant women and their newborns with oncological and non-oncological malignancies while stressing an individual approach. PMID- 21712776 TI - Somatization, but not depression, is characterized by disorders in the tryptophan catabolite (TRYCAT) pathway, indicating increased indoleamine 2,3-dioxygenase and lowered kynurenine aminotransferase activity. AB - BACKGROUND: Reduced plasma tryptophan occurs in depression and somatization. Induction of indoleamine 2,3-dioxygenase (IDO) with consequent synthesis of tryptophan catabolites (TRYCATs) and lowered tryptophan are associated with the onset of depression in the puerperium and during interferon-alpha treatment. Depression is accompanied by lowered kynurenic acid, a neuroprotectant, or increased kynurenine, a neurotoxic TRYCAT. AIMS AND METHODS: To examine plasma tryptophan; kynurenine; kynurenic acid; the kynurenine / tryptophan (KY/TRP) ratio, indicating IDO activity; and the kynurenine / kynurenic acid (KY/KA) ratio, indicating kynurenine aminotransferase (KAT) activity, in somatization; depression; somatization + depression; and controls. Illness severity is measured by the Somatic Symptom Index (SSI), the Screening for Somatoform Symptoms (SOMS), and the Beck Depression Inventory (BDI). RESULTS: Tryptophan is significantly lower in patients than in controls and lower in somatization than in depression. KY/TRP is significantly increased in somatization. Kynurenic acid is significantly lower in patients than in controls, and lower in somatization than in depression. KY/KA is significantly higher in somatization and somatization + depression than in depression and controls. There are significant correlations between the severity of somatization, but not depression, and KY/TRP and KY/KA (positive) and tryptophan (negative). Kynurenine and kynurenic acid are significantly correlated in controls, somatization + depression, and depression, but not in somatization. CONCLUSIONS: Somatization is characterized by increased IDO activity and disorders in KAT activity and an increased neurotoxic potential. The TRYCAT pathway may play a role in the pathophysiology of somatizing and "psychosomatic" symptoms through effects on pain, gut motility, the autonomic nervous system, peripheral NMDA receptors, etc. Even more, biological disorders, such as aberrations in the TRYCAT pathway, which are considered to be a hallmark for depression, are in fact attributable to somatization rather than to depression per se. Future research in depression on the TRYCAT pathway should always control for the possible effects of somatization. PMID- 21712777 TI - Serum resistin concentrations are associated with HbA1c in obese non-diabetics, but not in obese diabetics: a cross-sectional human study. AB - OBJECTIVE: Glycosylated hemoglobin (HbA1c) and resistin may be influenced by diabetes, but their associations remain unclear. We hypothesized that serum resistin might be parallel to Hb1c. DESIGN AND SETTING: We measured serum resistin in 134 obese non-diabetic (73 women and 61 men), and 65 obese diabetic (33 women and 32 men) humans, and examined their relationships with HbA1c. The presence of diabetes was the only differentiating factor between the groups. RESULTS: Resistin, non-diabetic vs. diabetic, median and interquartile range, respectively: resistin (ng/mL) 26.08, 16.09 and 22.14,14.54, p>0.5. To investigate the influence of HbA1c on resistin, both groups were divided into tertiles based on HbA1c. In diabetics, resistin was similar in high, intermediate, and low HbA1c subgroups, p>0.05, and resistin was not influenced by HbA1c: r=-0.1785; p=0.15. In non-diabetics, resistin differed between HbA1c tertiles, p<0.001, and was influenced by HbA1c, r = -0.3599; p=0.0003. CONCLUSIONS: Resistin concentrations are similar in diabetic and non-diabetic humans with the same range of obesity. However, resistin is associated with HbA1c only in non-diabetic obese individuals which may point to the fact that resistin is a marker of glycaemic balance in obesity but not in diabetes. PMID- 21712778 TI - Relationship between unconjugated hyperbilirubinemia and lipoprotein spectrum. AB - OBJECTIVES: The aim of this study was to analyze the serum bilirubin level, lipid and lipoprotein parameters with the emphasis on the presence of atherogenic small dense LDL in patients with Gilbert's syndrome and to compare these results with probands in the control group. We used a new electrophoretic method, which enables to analyze up to 12 lipoprotein subpopulations. Atherogenic lipoprotein profile is characterized by the presence of very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL) and the presence of small dense LDL lipoproteins. The presence of LDL1 and LDL2 subpopulations, as well as HDL lipoproteins is considered as protective factor. METHODS: Molecular - genetic examination of Gilbert?'s syndrome using fragment analysis method was carried out in collaboration with the Centre for Medical Genetics, University Hospital in Bratislava. Total cholesterol and triglycerides in plasma were analyzed from lipid parameters by means of enzymatic CHOD-PAP method, Roche Diagnostics, Germany. Biochemical parameters - bilirubin (total, conjugated and unconjugated), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GMT), (Roche Diagnostics, Germany), TSH, FT3, fT4 (Siemens) were also examined. Serum lipoproteins and their subfractions were examined using Lipoprint LDL System Quantimetrix, CA, USA (12). RESULTS: We found significantly higher levels of total bilirubin and unconjugated bilirubin in patients with Gilbert's syndrome. In the control group, probands had significantly higher triglycerides levels, VLDL cholesterol levels, IDL cholesterol level, and small dense LDL levels compared to the group with Gilbert?'s syndrome. Probands with Gilbert's syndrome had significantly lower presence of atherogenic lipoprotein spectrum than probands in control group (5% vs. 18%). We found significantly negative correlation between serum unconjugated bilirubin levels and LDL 3-7 (r = - 0.594, p <0.01), as well as between bilirubin and triglycerides (r = -0.540, p<0.01). Serum bilirubin concentration and LDL 1-2 concentration correlated significantly positively (r = 0.451, p <0.05). CONCLUSION: The presence of atherogenic lipoprotein spectrum is determined by the particular representation of small dense LDL. Atherogenic spectrum was presented significantly less in patients with Gilbert?'s syndrome compared with the control group (5% vs. 18%). In our study, we have not followed the risk of coronary heart disease or other manifestations of atherosclerotic arteries disability. However, we found the inverse relationship of serum bilirubin levels and atherogenic small dense LDL. We found out that the protective antiatherogenic effect of hyperbilirubinemia is potentiated by low occurence of strongly atherogenic small dense LDL and persons with byperbilirubionemia (in our case represented Gilbert's syndrome), could be protected against the development of atheroscleosis. PMID- 21712779 TI - Peripheral nerve stimulation in intractable neuropathic pain. AB - Peripheral nerve stimulation (PNS) is a neurostimulation analgesic technique. PNS is utilized to treat peripheral neuropathic pain. It is highly sophisticated and a specialized technique used where other forms of treatment have failed. This paper describes the PNS procedure, its therapeutic principles, indications, and the comprehensive care for patients after the PNS implant. First, we summarize our experience using this type of invasive treatment. In the second part, a case of intractable neuropathic pain following repeated surgery to the ulnar nerve is reported. Prior to PNS, the patient underwent multiple types of antineuralgic treatment with no significant result. Only after the PNS application, was a significant analgesic effect achieved. PMID- 21712780 TI - Monitoring of selenium in oral cavity argyria - a clinical and microscopic study. AB - OBJECTIVE: Argyria is generally classified as localized or generalized condition. Distinct pigmentation of the oral mucosa in the vicinity of amalgam fillings is often referred to as amalgam tattoos. Pigmented areas can also be associated with silver-containing corrosion products of dental alloys used for prosthetic restorations. Silver-containing electron dense particles (Ag-EDPs) are frequently found in pigmented areas. We attempted to correlate results of the elemental composition of Ag-EDPs with excerpts from health profiles of our study paticipants. DESIGN/SETTING: Eight patients with diagnosed signs of localized argyria were investigated in this study. Biopsies from distinctly pigmented gingival areas were subjected to histological examination, electron microscopy and x-ray microanalysis. RESULTS: Elemental composition of Ag-EDPs determined by x-ray microanalysis showed mainly silver in combination with sulfur or selenium or a combination of both chalcogens. Elemental analyzes results of Ag-EDPs were analyzed along with excerpts from the patient's clinical records. Two patients with low or undetectable selenium in the Ag-EDPs suffered from autoimmune thyroiditis, Parkinson's disease, bronchial asthma, and allergies to molds, pollen and dust. CONCLUSIONS: We suggest that selenium in Ag-EDPs is a product of the detoxification process for Ag(+) ions in gingival tissue and that it may reflect the availability of endogenous selenium for physiological processes in the human body. Its presence or absence might thus be used as another marker of a patient's health status. PMID- 21712781 TI - Melatonin enhances the in vitro action of cytochalasin B on globular resistance and osmotic fragility of erythrocytes. AB - BACKGROUND: Some researches have shown that melatonin (MLT) has effects on the erythrocyte deformability and on the osmotic fragility which, currently, seem to be heterogeneous and fragmentary. OBJECTIVE: This work wished to evaluate in vitro the possible modifying action of MLT at pharmaceutical doses on the osmotic fragility of rat blood samples treated with cytochalasin B (CB). The variation of the lactate dehydrogenase (LDH) levels have been measured because LDH is an enzyme which is considered an important marker of hemolysis. Working in a strongly reducing environment has been necessary in order to avoid possible antioxidant actions of MLT, measuring the plasma levels of malondialdehyde and total phospholipids in order to highlight possible MLT actions which are not related to its recognized antioxidant properties. RESULTS: The data show a possible MLT action which strengthens the CB action on the osmotic fragility and on the membrane deformability of the erythrocytes. CONCLUSIONS: Under the adopted working conditions, a direct relation of MLT with the biochemical dynamics of the cytoskeleton-mediated processes can be suggested. Further studies will be needed to clarify the mechanisms and the extent of the observed phenomena. PMID- 21712783 TI - Identification of pregnant women at risk of Streptococcus group B colonisation. AB - OBJECTIVES: The aims of the study were: 1) to evaluate the prevalence of recto vaginal group B streptococci (GBS) colonisation using Todd Hewitt Broth - recommended by the Centers for Disease Control (CDC) - and Granada medium; 2) to establish the sensitivity and specificity of Granada medium for the detection of GBS colonisation; 3) to evaluate each vaginal Gram stained swab for bacterial vaginosis (BV) using Nugent criteria and for determining the amount of polymorphonuclear (PMN) leucocytes. METHODS: Eighty pregnant women between 35 and 40 gestation weeks hospitalised in the Department of Gynecology and Obstetrics, Medical University of Silesia, Poland, were included in the study. Two specimens were collected from each patient: one from the posterior vaginal fornix (Gram stain) and one from both vagina and anus to detect GBS colonisation. Each vaginal Gram stained swab was evaluated for BV using Nugent criteria as well as for PMN leucocyte count. To detect GBS colonisation, the liquid Todd Hewitt Broth, subsequently subcultured to blood agar and direct inoculation onto Granada medium, were used. Isolated GBS were identified by morphological features and by serological (Slidex Strepto-Kit, bioMerieux) and biochemical (rapid ID 32 Strep, bioMerieux) testing. RESULTS: GBS colonisation was observed in 22 (27.8%) patients in both used media. Only in one case were GBS detected in Todd Hewitt Broth and not detected in Granada medium. The sensitivity and specificity of Granada medium were established as: 95.65% and 100%, respectively, compared with Todd Hewitt Broth recommended by CDC. Nugent criteria demonstrated 6.25% of cases of BV; in one case both BV and GBS colonisation were detected. CONCLUSIONS: The selective Granada medium may be used concurrently with liquid Todd Hewitt Broth as a screening tool for prenatal group B streptococcal colonisation in pregnant women. PMID- 21712782 TI - In vitro effects of acetylcholinesterase inhibitors and reactivators on Complex I of electron transport chain. AB - OBJECTIVES: Inhibition of the enzyme acetylcholinesterase (AChE) is the main mechanism both of therapeutic action of drugs for the treatment of Alzheimer's disease and toxic action of organophosphorus compounds. Various types of oximes reactivate AChE and are commonly used as antidotes against organophosphates (pesticides, nerve agents). METHODS: Effects both of AChE inhibitors (tacrine, 7 methoxytacrine) and oximes (pralidoxime, trimedoxime, obidoxime, methoxime, HI-6) on Complex I of electron transport chain (ETC) were examined. The enzyme activity was measured spectrophotometrically in crude mitochondrial fraction isolated from pig brain. RESULTS: Our results showed statistically significant Complex I inhibition by tacrine, other drugs did not affect the enzyme activity significantly. CONCLUSIONS: These observations suggest the possibility of tacrine induced side effects related to disturbance in ETC. On the contrary, it seems that oximes do not affect cellular energetic metabolism. PMID- 21712784 TI - Hyper-betalipoproteinemia LDL 1,2: a newly identified nonatherogenic hypercholesterolemia in a group of hypercholesterolemic subjects. AB - OBJECTIVE: The identification of a non-atherogenic and an atherogenic lipoprotein profile, non-athero phenotype A vs. athero phenotype B, in a group of hypercholesterolemic subjects reveals newly discovered non-atherogenic hypercholesterolemia. Individuals with this type of hypercholesterolemia, or hyper-betalipoproteinemia LDL1,2, are probably not at increased risk to develop a premature atherothrombosis or a sudden cardiovascular event. Examined individuals with hyper-betalipoproteinemia LDL1,2 were divided into two subgroups: individuals under 40 years of age, and older individuals between 46 and 71 years of age. Subjects in the under 40 years of age group did not have any apparent clinical or laboratory-proven impairment of the cardiovascular system. The older subjects with hyper-betalipoproteinemia and a non-atherogenic lipoprotein profile had only mild signs of clinically irrelevant aortic valve sclerosis. METHODS: A quantitative analysis of the lipoprotein spectrum in plasma in a group of hypercholesterolemic subjects was performed. An innovative electrophoresis method on polyacrylamide gel (PAG) was used for the analysis of plasma lipoproteins and for the identification of atherogenic vs. non-atherogenic lipoproteins in plasma. With regard to lipids, total cholesterol and triglycerides in plasma were analyzed with an enzymatic CHOD PAP method (Roche Diagnostics, FRG). A new parameter, the score for anti-atherogenic Risk (SAAR), was calculated as the ratio between non-atherogenic to atherogenic plasma lipoproteins in the examined subjects. RESULTS: There was a high concentration of LDL1, and LDL2 subfractions (p<0.0001), and an extremely low concentration of LDL3-7 (p<0.0001) in the non atherogenic lipoprotein profile of hyper-betalipoproteinemia LDL1,2 compared to the control group. Higher concentrations (p<0.0001) of lipids and lipoproteins in the non-atherogenic hypercholesterolemia, compared to the control group, were also found. The hyper-betalipoproteinemia LDL1,2 was also characterized by high SAAR values. There was found a higher concentration of HDL large and HDL intermediate subfractions in hypercholesterolemic subjects. CONCLUSIONS: The advantages of this new diagnostic method include: (i) identification of the existence of a non-atherogenic hyper-betalipoproteinemia LDL1,2 in examined hypercholesterolemic subjects with untreated hypercholesterolemia (ii) introduction of a new risk measure, the score for anti-atherogenic risk (SAAR), for the estimation of atherogenic/anti-atherogenic risk. (iii) the presence of small dense LDL in plasma is decisive for the declaration of an atherogenic lipoprotein profile. It is valid for hyperlipidemia and for normolipidemia as well. PMID- 21712785 TI - Granulocytic sarcoma, an undiagnosed leukemia, initially manifested as paralysis. AB - Granulocytic sarcoma (GS) may be a presenting sign of myelogenous leukemia. Occasionally, an extramedullary neoplasm composed from myelocytic precursor cells occurs in patients without evidence of leukemia. Rarely, undiagnosed leukemia occurs initially manifesting with paralysis to spinal cord GS. We present a case report of 20-year-old girl with an undiagnosed leukemia, initially manifesting as paralysis. En bloc spondylectomy with chemotherapy postoperatively constituted the treatment of choice for this tumor. After two courses of chemotherapy, the patient made a good postoperative recovery with notable bilateral lower extremity improvement. PMID- 21712786 TI - Fatal course of cyclic Cushing's disease - lessons from a case. AB - We present a 56-year-old patient with cyclic Cushing's disease (CCD) observed for 28 months, who presented clinically and biochemically with alternating episodes of hyper-, normo- and hypocortisolemia. The course of the disease was fatal, the patient died due to severe hypokalemia. PMID- 21712787 TI - Effect of fluoxetine or adenosine receptor NECA agonist on G-proteins of C6 glioma cells or NK immunocytes. AB - OBJECTIVE: Neurochemical approaches to antidepressant effects and depressive disorder are also focusing on G-protein coupled receptors (GPCR) and subsequent signalling. Trimeric G-proteins play a crucial role in transmembrane signalling, its amplification and processing. It is evident that immune system participates in antidepressant mode of action by neurotransmitter GPCR. METHODS: We studied the effect of acute administration of fluoxetine or NECA agonist of adenosine receptor (GPCR) on C6 glioma cells and natural killer (NK) cell line, innate immunity. We used immunochemical estimation (ELISA) of the main types of G protein alpha subunits from isolated membranes of tested cells. RESULTS: Significant reduction of G alpha q/11 subunits after acute administration of fluoxetine or NECA agonist was found. In contrast, no significant influence of G alpha s or G alpha i1,2 subunit levels of C6 glioma cells were observed. Lowered Gq/11 signalling was in accordance with decreased 2nd messenger 1,4,5 IP3 formation by PLC. Acute effect of fluoxetine or NECA agonist on NK cell line resulted in significantly reduced G alpha q/11 levels without changes in G alpha s and G alpha i1,2. Furthermore, we determined that NECA agonist was able to abolish fluoxetine-evoked G alpha q/11 levels of NK cell line. CONCLUSIONS: Results show involvement of fluoxetine in the C6 glioma signal transduction and were comparable with NK cells. Similar inhibiton of G alpha q/11 by NECA agonist in both C6 glioma cells and NK cell line was determined. Furthermore NECA induced attenuation of fluoxetine evoked Galpha q/11 signalling can indicate parallel interference between GPCR and final response. Finally, we determined similarity in both interleukin 2, IL2 immunostimulator and fluoxetine evoked G q/11 levels in NK cell line and thus fluoxetine action could be related to signalling aspects of neuroimmunomodulatory activity. PMID- 21712788 TI - Cognitive changes in spinocerebellar ataxia type 2. AB - OBJECTIVES: Cognitive disorders and dementia occur in 19 to 42% of patients with spinocerebellar ataxia type 2 (SCA2). Neuropsychological tests can reveal executive dysfunction, impaired visual and verbal memory, tongue and speech impairment, attention disorders and impaired verbal fluency. METHODS: We performed psychiatric and neuropsychological examinations in 12 patients diagnosed with genetically confirmed SCA2 and 12 healthy volunteers matching the patients in age, gender, and length of education. The level of motor impairment was determined using the brief ataxia rating scale (BARS). The neuropsychological examination focused on testing executive functions, short-term visual and verbal memory, attention, psychomotor tempo, visual motor coordination, learning ability and comprehension ability. The tests were divided into two subgroups according to the difficulty of motor tasks. The cognitive abilities composite score (CACS) was determined by calculating the arithmetic mean of T scores of the respective tests. RESULTS: Patients with SCA2 had significantly lower CACSs (p=0.00005) compared to the healthy volunteers. Patients exhibited impaired performance in both difficult and simple motor tests. The severity of cognitive impairment was related to the age at the onset of the disease (p=0.002) but not to the duration or to the overall BARS score. CONCLUSIONS: Compared to healthy volunteers, patients with SCA2 exhibited significantly worse cognitive performance in all areas tested, including the tests of simple motor tasks. Moreover, the cognitive performance of patients worsened as the difficulty of the motor tasks increased. PMID- 21712789 TI - Changes of poststimulatory plasma renin activity in women with hyperthyroidism or hypothyroidism in relation to therapy. AB - OBJECTIVE: The influence of thyroid hormones upon renin-angiotensin-aldosterone system is poorly understood. Under basal conditions, individuals belong to normal, low or high plasma renin activity (PRA) subjects. The study was designed to evaluate basal and poststimulatory PRA and serum aldosterone (Aldo) level in patients with hyperthyroidism or hypothyroidism during therapy. MATERIAL AND METHODS: We examined 73 women with hyperthyroidism, 27 women with hypothyroidism and 36 healthy controls. The patients were investigated before initiation of therapy and after attainment of euthyroid state. All subjects were investigated under basal conditions (normal-sodium diet) and after application of a low-sodium diet for three days and upright position for 3 hr. PRA, serum Aldo level, blood pressure, serum sodium, potassium and thyroid hormone levels were determined in all subjects. The subjects were classified as low PRA (<1.0 ng/ml/h), normal PRA (1.0-4.0 ng/ml/h) and high PRA (>4.0 ng/ml/h) individuals according to results obtained under basal conditions. RESULTS: Relatively higher poststimulatory enhancement in PRA was found in patients with hyperthyroidism, especially those with low basal PRA, than in those with hypothyroidism. In women with thyroid dysfunctions poststimulatory increase in Aldo were relative lower than poststimulatory enhancement of PRA. After therapy these difference disappeared. The poststimulatory changes in PRA depended on the basal PRA. CONCLUSIONS: Poststimulatory PRA is higher in hyperthyroid women, especially those with low basal PRA. In women with hypothyroidism, basal and poststimulatory PRA is low. Blood pressure and severity of thyroid dysfunction was found to be similar in the patients with low, normal or high basic PRA. In women with thyroid dysfunctions, serum Aldo level and its relative poststimulatory increments are inadequate to changes of PRA; it is suggested that the dissociation in the renin-angiotensin aldosterone system occurs in hyperthyroid and hypothyroid women. PMID- 21712790 TI - Atherogenic normolipidemia - a new phenomenon in the lipoprotein profile of clinically healthy subjects. AB - OBJECTIVE: The identification of an atherogenic and a non-atherogenic lipoprotein profile, athero phenotype B vs. non-athero phenotype A, in a group of healthy normolipidemic subjects reveals a new clinical phenomenon in lipoprotein profiles, an atherogenic normolipidemia. Individuals with atherogenic normolipidemia are at increased risk to develop premature atherothrombosis and experience a sudden cardiovascular event. METHODS: A quantitative analysis of non atherogenic and atherogenic lipoproteins in plasma in a group of healthy normolipidemic volunteers who had no clinical signs of cardiovascular system impairment was performed. An innovative electrophoresis method on polyacrylamide gel (PAG) (Lipoprint LDL System, USA) was used for the analysis of plasma lipoproteins. With regard to lipids, total cholesterol and triglycerides in plasma were analyzed with an enzymatic method, CHOD PAP (Roche Diagnostics, FRG). Prostacyclin and thromboxane A2 were analyzed with an ELISA analysis (DRG USA). A new parameter, the score for anti-atherogenic risk (SAAR), was calculated as the ratio between non-atherogenic to atherogenic plasma lipoproteins in examined subjects. RESULTS: There was a high concentration of LDL3-7 subfraction (p<0.0001) and a slowly increasing triglyceride concentration (p<0.05) in the atherogenic subgroup. The non-atherogenic subgroup of healthy subjects was characterized by high SAAR scores, as well as a low concentration of LDL3-7 subfractions (p<0.0001). Other statistically significant differences between the atherogenic and non-atherogenic subgroup, including total cholesterol, prostanoid parameters (prostacyklin, thromboxane A2), and lipoproteins values, were not confirmed. CONCLUSIONS: The advantages of this new method include: (i) identification of an atherogenic and a nonatherogenic lipoprotein profile in an individual's plasma (ii) identification of an atherogenic normolipidemic lipoprotein profile in plasma (iii) introduction of a new risk measure, the score for anti-atherogenic risk (SAAR), for an estimation of a patient's atherogenic risk of atherothrombosis development. (iv) the presence of small dense LDL in plasma is decisive for declaration of an atherogenic lipoprotein profile. It is valid for hyperlipidemia and for normolipidemia as well. PMID- 21712791 TI - A positive fluid balance does not deteriorate tissue metabolism during fluid resuscitation of sepsis. AB - OBJECTIVE: Hypovolemia has occurs frequently in sepsis. Due to pathologically increased permeability of the capillaries, the fluid leaks to the interstitium. An adequate fluid therapy is the corner stone to achieve circulatory stabilization and sufficient tissue perfusion; on the other hand, according to the data from the literature a tissue swelling is associated with a risk of deteriorated function of the tissues. The study aimed to examine the effect of a positive fluid balance on muscular metabolism. METHODS: The experimental study employed the model of sepsis in the domestical pig. Ten animals were randomly distributed into a control and a septic group. Sepsis was induced by intravenous administration of E. coli, followed by fluid resuscitation by crystaloids. Microdialysis samples were withdrawn at one-hour intervals for a period of 24 hours and values of lactate, pyruvate, glycerol, and glucose. RESULTS: Pearson's method revealed positive correlations between the lactate/pyruvate ratio and cumulative fluid balance in the septic group (R=0.292, p<0.001) and negative correlations in the control group (R=-0.279, p<0.05). In both groups, however, there was a gradual significant decrease in glycerol values. CONCLUSION: Fluid resuscitation results in positive fluid balance in both septic and control animals. This leads to circulatory stabilization of septic animals, but not a decrease in the anaerobic share of glycolysis. A positive fluid balance in control animals does not result in alteration of muscular aerobic glycolysis. Decreasing glycerol levels in both groups give evidence that a positive fluid balance does not exert a negative impact on cell metabolism. PMID- 21712792 TI - A neuroeconomic theory of rational addiction and nonlinear time-perception. AB - Neuroeconomic conditions for "rational addiction" (Becker & Murphy 1988) have been unknown. This paper derived the conditions for "rational addiction" by utilizing a nonlinear time-perception theory of "hyperbolic" discounting, which is mathematically equivalent to the q-exponential intertemporal choice model based on Tsallis' statistics. It is shown that (i) Arrow-Pratt measure for temporal cognition corresponds to the degree of irrationality (i.e., Prelec's "decreasing impatience" parameter of temporal discounting) and (ii) rationality in addicts is controlled by a nondimensionalization parameter of the logarithmic time-perception function. Furthermore, the present theory illustrates the possibility that addictive drugs increase impulsivity via dopaminergic neuroadaptation without increasing irrationality. Future directions in the application of the model to studies in neuroeconomics are discussed. PMID- 21712793 TI - A strategy to identify de novo mutations in common disorders such as autism and schizophrenia. AB - There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, the de novo mutation rate in humans is relatively high, so new mutations are generated at a high frequency in the population. However, de novo mutations have not been reported in most common diseases. Mutations in genes leading to severe diseases where there is a strong negative selection against the phenotype, such as lethality in embryonic stages or reduced reproductive fitness, will not be transmitted to multiple family members, and therefore will not be detected by linkage gene mapping or association studies. The observation of very high concordance in monozygotic twins and very low concordance in dizygotic twins also strongly supports the hypothesis that a significant fraction of cases may result from new mutations. Such is the case for diseases such as autism and schizophrenia. Second, despite reduced reproductive fitness(1) and extremely variable environmental factors, the incidence of some diseases is maintained worldwide at a relatively high and constant rate. This is the case for autism and schizophrenia, with an incidence of approximately 1% worldwide. Mutational load can be thought of as a balance between selection for or against a deleterious mutation and its production by de novo mutation. Lower rates of reproduction constitute a negative selection factor that should reduce the number of mutant alleles in the population, ultimately leading to decreased disease prevalence. These selective pressures tend to be of different intensity in different environments. Nonetheless, these severe mental disorders have been maintained at a constant relatively high prevalence in the worldwide population across a wide range of cultures and countries despite a strong negative selection against them(2). This is not what one would predict in diseases with reduced reproductive fitness, unless there was a high new mutation rate. Finally, the effects of paternal age: there is a significantly increased risk of the disease with increasing paternal age, which could result from the age related increase in paternal de novo mutations. This is the case for autism and schizophrenia(3). The male-to-female ratio of mutation rate is estimated at about 4-6:1, presumably due to a higher number of germ-cell divisions with age in males. Therefore, one would predict that de novo mutations would more frequently come from males, particularly older males(4). A high rate of new mutations may in part explain why genetic studies have so far failed to identify many genes predisposing to complexes diseases genes, such as autism and schizophrenia, and why diseases have been identified for a mere 3% of genes in the human genome. Identification for de novo mutations as a cause of a disease requires a targeted molecular approach, which includes studying parents and affected subjects. The process for determining if the genetic basis of a disease may result in part from de novo mutations and the molecular approach to establish this link will be illustrated, using autism and schizophrenia as examples. PMID- 21712794 TI - Mouse complete stasis model of inferior vena cava thrombosis. AB - Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). In the United States (U.S.), the high morbidity and mortality rates make VTE a serious health concern (1-2). After heart disease and stroke, VTE is the third most common vascular disease (3). In the U.S. alone, there is an estimated 900,000 people affected each year, with 300,000 deaths occurring annually (3). A reliable in vivo animal model to study the mechanisms of this disease is necessary. The advantages of using the mouse complete stasis model of inferior vena cava thrombosis are several. The mouse model allows for the administration of very small volumes of limited availability test agents, reducing costs dramatically. Most promising is the potential for mice with gene knockouts that allow specific inflammatory and coagulation factor functions to be delineated. Current molecular assays allow for the quantitation of vein wall, thrombus, whole blood, and plasma for assays. However, a major concern involving this model is the operative size constraints and the friability of the vessels. Also, due to the small IVC sample weight (mean 0.005 grams) it is necessary to increase animal numbers for accurate statistical analysis for tissue, thrombus, and blood assays such as real-time polymerase chain reaction (RT-PCR), western blot, enzyme-linked immunosorbent (ELISA), zymography, vein wall and thrombus cellular analysis, and whole blood and plasma assays (4-8). The major disadvantage with the stasis model is that the lack of blood flow inhibits the maximal effect of administered systemic therapeutic agents on the thrombus and vein wall. PMID- 21712795 TI - Methods to assess beta cell death mediated by cytotoxic T lymphocytes. AB - Type 1 diabetes (T1D) is a T cell mediated autoimmune disease. During the pathogenesis, patients become progressively more insulinopenic as insulin production is lost, presumably this results from the destruction of pancreatic beta cells by T cells. Understanding the mechanisms of beta cell death during the development of T1D will provide insights to generate an effective cure for this disease. Cell-mediated lymphocytotoxicity (CML) assays have historically used the radionuclide Chromium 51 ((51)Cr) to label target cells. These targets are then exposed to effector cells and the release of (51)Cr from target cells is read as an indication of lymphocyte-mediated cell death. Inhibitors of cell death result in decreased release of (51)Cr. As effector cells, we used an activated autoreactive clonal population of CD8(+) Cytotoxic T lymphocytes (CTL) isolated from a mouse stock transgenic for both the alpha and beta chains of the AI4 T cell receptor (TCR). Activated AI4 T cells were co-cultured with (51)Cr labeled target NIT cells for 16 hours, release of (51)Cr was recorded to calculate specific lysis Mitochondria participate in many important physiological events, such as energy production, regulation of signaling transduction, and apoptosis. The study of beta cell mitochondrial functional changes during the development of T1D is a novel area of research. Using the mitochondrial membrane potential dye Tetramethyl Rhodamine Methyl Ester (TMRM) and confocal microscopic live cell imaging, we monitored mitochondrial membrane potential over time in the beta cell line NIT-1. For imaging studies, effector AI4 T cells were labeled with the fluorescent nuclear staining dye Picogreen. NIT-1 cells and T cells were co cultured in chambered coverglass and mounted on the microscope stage equipped with a live cell chamber, controlled at 37 degrees C, with 5% CO(2;), and humidified. During these experiments images were taken of each cluster every 3 minutes for 400 minutes. Over a course of 400 minutes, we observed the dissipation of mitochondrial membrane potential in NIT-1 cell clusters where AI4 T cells were attached. In the simultaneous control experiment where NIT-1 cells were co-cultured with MHC mis-matched human lymphocyte Jurkat cells, mitochondrial membrane potential remained intact. This technique can be used to observe real-time changes in mitochondrial membrane potential in cells under attack of cytotoxic lymphocytes, cytokines, or other cytotoxic reagents. PMID- 21712796 TI - Isolation of fidelity variants of RNA viruses and characterization of virus mutation frequency. AB - RNA viruses use RNA dependent RNA polymerases to replicate their genomes. The intrinsically high error rate of these enzymes is a large contributor to the generation of extreme population diversity that facilitates virus adaptation and evolution. Increasing evidence shows that the intrinsic error rates, and the resulting mutation frequencies, of RNA viruses can be modulated by subtle amino acid changes to the viral polymerase. Although biochemical assays exist for some viral RNA polymerases that permit quantitative measure of incorporation fidelity, here we describe a simple method of measuring mutation frequencies of RNA viruses that has proven to be as accurate as biochemical approaches in identifying fidelity altering mutations. The approach uses conventional virological and sequencing techniques that can be performed in most biology laboratories. Based on our experience with a number of different viruses, we have identified the key steps that must be optimized to increase the likelihood of isolating fidelity variants and generating data of statistical significance. The isolation and characterization of fidelity altering mutations can provide new insights into polymerase structure and function(1-3). Furthermore, these fidelity variants can be useful tools in characterizing mechanisms of virus adaptation and evolution(4 7). PMID- 21712797 TI - Neuromodulation and mitochondrial transport: live imaging in hippocampal neurons over long durations. AB - To understand the relationship between mitochondrial transport and neuronal function, it is critical to observe mitochondrial behavior in live cultured neurons for extended durations(1-3). This is now possible through the use of vital dyes and fluorescent proteins with which cytoskeletal components, organelles, and other structures in living cells can be labeled and then visualized via dynamic fluorescence microscopy. For example, in embryonic chicken sympathetic neurons, mitochondrial movement was characterized using the vital dye rhodamine 123(4). In another study, mitochondria were visualized in rat forebrain neurons by transfection of mitochondrially targeted eYFP(5). However, imaging of primary neurons over minutes, hours, or even days presents a number of issues. Foremost among these are: 1) maintenance of culture conditions such as temperature, humidity, and pH during long imaging sessions; 2) a strong, stable fluorescent signal to assure both the quality of acquired images and accurate measurement of signal intensity during image analysis; and 3) limiting exposure times during image acquisition to minimize photobleaching and avoid phototoxicity. Here, we describe a protocol that permits the observation, visualization, and analysis of mitochondrial movement in cultured hippocampal neurons with high temporal resolution and under optimal life support conditions. We have constructed an affordable stage-top incubator that provides good temperature regulation and atmospheric gas flow, and also limits the degree of media evaporation, assuring stable pH and osmolarity. This incubator is connected, via inlet and outlet hoses, to a standard tissue culture incubator, which provides constant humidity levels and an atmosphere of 5-10% CO(2;)/air. This design offers a cost-effective alternative to significantly more expensive microscope incubators that don't necessarily assure the viability of cells over many hours or even days. To visualize mitochondria, we infect cells with a lentivirus encoding a red fluorescent protein that is targeted to the mitochondrion. This assures a strong and persistent signal, which, in conjunction with the use of a stable xenon light source, allows us to limit exposure times during image acquisition and all but precludes photobleaching and phototoxicity. Two injection ports on the top of the stage-top incubator allow the acute administration of neurotransmitters and other reagents intended to modulate mitochondrial movement. In sum, lentivirus-mediated expression of an organelle targeted red fluorescent protein and the combination of our stage-top incubator, a conventional inverted fluorescence microscope, CCD camera, and xenon light source allow us to acquire time-lapse images of mitochondrial transport in living neurons over longer durations than those possible in studies deploying conventional vital dyes and off-the-shelf life support systems. PMID- 21712798 TI - Vibratome sectioning for enhanced preservation of the cytoarchitecture of the mammalian organ of Corti. AB - The mammalian organ of Corti is a highly ordered cellular mosaic of mechanosensory hair and nonsensory supporting cells (reviewed in (1,2)).Visualization of this cellular mosaic often requires that the organ of Corti is cross-sectioned. In particular, the nonsensory pillar and Deiters' cells, whose nuclei are located basally with respect to the hair cells, cannot be visualized without cross-sectioning the organ of Corti. However, the delicate cytoarchitecture of the mammalian organ of Corti, including the fine cytoplasmic processes of the pillar and Deiters' cells, is difficult to preserve by routine histological procedures such as paraffin and cryo-sectioning, which are compatible with standard immunohistochemical staining techniques. Here I describe a simple and robust procedure consisting of vibratome sectioning of the cochlea, immunohistochemical staining of these vibratome sections in whole mount, followed by confocal microscopy. This procedure has been used widely for immunhistochemical analysis of multiple organs, including the mouse limb bud, zebrafish gut, liver, pancreas, and heart (see (3-6) for selected examples). In addition, this procedure was sucessful for both imaging and quantitificaton of pillar cell number in mutant and control organs of Corti in both embryos and adult mice (7). This method, however, is currently not widely used to examine the mammalian organ of Corti. The potential for this procedure to both provide enhanced preservation of the fine cytoarchitecture of the adult organ of Corti and allow for quantification of various cell types is described. PMID- 21712799 TI - Rat mesentery angiogenesis assay. AB - The adult rat mesentery window angiogenesis assay is biologically appropriate and is exceptionally well suited to the study of sprouting angiogenesis in vivo [see review papers], which is the dominating form of angiogenesis in human tumors and non-tumor tissues, as discussed in invited review papers(1,2). Angiogenesis induced in the membranous mesenteric parts by intraperitoneal (i.p.) injection of a pro-angiogenic factor can be modulated by subcutaneous (s.c.), intravenous (i.v.) or oral (p.o.) treatment with modifying agents of choice. Each membranous part of the mesentery is translucent and framed by fatty tissue, giving it a window-like appearance. The assay has the following advantageous features: (i) the test tissue is natively vascularized, albeit sparsely, and since it is extremely thin, the microvessel network is virtually two-dimensional, which allows the entire network to be assessed microscopically in situ; (ii) in adult rats the test tissue lacks significant physiologic angiogenesis, which characterizes most normal adult mammalian tissues; the degree of native vascularization is, however, correlated with age, as discussed in(1); (iii) the negligible level of trauma-induced angiogenesis ensures high sensitivity; (iv) the assay replicates the clinical situation, as the angiogenesis-modulating test drugs are administered systemically and the responses observed reflect the net effect of all the metabolic, cellular, and molecular alterations induced by the treatment; (v) the assay allows assessments of objective, quantitative, unbiased variables of microvascular spatial extension, density, and network pattern formation, as well as of capillary sprouting, thereby enabling robust statistical analyses of the dose-effect and molecular structure-activity relationships; and (vi) the assay reveals with high sensitivity the toxic or harmful effects of treatments in terms of decreased rate of physiologic body-weight gain, as adult rats grow robustly. Mast-cell-mediated angiogenesis was first demonstrated using this assay(3,4). The model demonstrates a high level of discrimination regarding dosage-effect relationships and the measured effects of systemically administered chemically or functionally closely related drugs and proteins, including: (i) low dosage, metronomically administered standard chemotherapeutics that yield diverse, drug-specific effects (i.e., angiogenesis-suppressive, neutral or angiogenesis-stimulating activities(5)); (ii) natural iron-unsaturated human lactoferrin, which stimulates VEGF-A-mediated angiogenesis(6), and natural iron unsaturated bovine lactoferrin, which inhibits VEGF-A-mediated angiogenesis(7); and (iii) low-molecular-weight heparin fractions produced by various means(8,9). Moreover, the assay is highly suited to studies of the combined effects on angiogenesis of agents that are administered systemically in a concurrent or sequential fashion. The idea of making this video originated from the late Dr. Judah Folkman when he visited our laboratory and witnessed the methodology being demonstrated. Review papers (invited) discussing and appraising the assay Norrby, K. In vivo models of angiogenesis. J. Cell. Mol. Med. 10, 588-612 (2006). Norrby, K. Drug testing with angiogenesis models. Expert Opin. Drug. Discov. 3, 533-549 (2008). PMID- 21712800 TI - Characterizing herbivore resistance mechanisms: spittlebugs on Brachiaria spp. as an example. AB - Plants can resist herbivore damage through three broad mechanisms: antixenosis, antibiosis and tolerance(1). Antixenosis is the degree to which the plant is avoided when the herbivore is able to select other plants(2). Antibiosis is the degree to which the plant affects the fitness of the herbivore feeding on it(1).Tolerance is the degree to which the plant can withstand or repair damage caused by the herbivore, without compromising the herbivore's growth and reproduction(1). The durability of herbivore resistance in an agricultural setting depends to a great extent on the resistance mechanism favored during crop breeding efforts(3). We demonstrate a no-choice experiment designed to estimate the relative contributions of antibiosis and tolerance to spittlebug resistance in Brachiaria spp. Several species of African grasses of the genus Brachiaria are valuable forage and pasture plants in the Neotropics, but they can be severely challenged by several native species of spittlebugs (Hemiptera: Cercopidae)(4).To assess their resistance to spittlebugs, plants are vegetatively-propagated by stem cuttings and allowed to grow for approximately one month, allowing the growth of superficial roots on which spittlebugs can feed. At that point, each test plant is individually challenged with six spittlebug eggs near hatching. Infestations are allowed to progress for one month before evaluating plant damage and insect survival. Scoring plant damage provides an estimate of tolerance while scoring insect survival provides an estimate of antibiosis. This protocol has facilitated our plant breeding objective to enhance spittlebug resistance in commercial brachiariagrases(5). PMID- 21712802 TI - Optimized PCR-based detection of mycoplasma. AB - The maintenance of contamination-free cell lines is essential to cell-based research. Among the biggest contaminant concerns are mycoplasma contamination. Although mycoplasma do not usually kill contaminated cells, they are difficult to detect and can cause a variety of effects on cultured cells, including altered metabolism, slowed proliferation and chromosomal aberrations. In short, mycoplasma contamination compromises the value of those cell lines in providing accurate data for life science research. The sources of mycoplasma contamination in the laboratory are very challenging to completely control. As certain mycoplasma species are found on human skin, they can be introduced through poor aseptic technique. Additionally, they can come from contaminated supplements such as fetal bovine serum, and most importantly from other contaminated cell cultures. Once mycoplasma contaminates a culture, it can quickly spread to contaminate other areas of the lab. Strict adherence to good laboratory practices such as good aseptic technique are key, and routine testing for mycoplasma is highly recommended for successful control of mycoplasma contamination. PCR-based detection of mycoplasma has become a very popular method for routine cell line maintenance. PCR-based detection methods are highly sensitive and can provide rapid results, which allows researchers to respond quickly to isolate and eliminate contamination once it is detected in comparison to the time required using microbiological techniques. The LookOut Mycoplasma PCR Detection Kit is highly sensitive, with a detection limit of only 2 genomes per MUl. Taking advantage of the highly specific JumpStart Taq DNA Polymerase and a proprietary primer design, false positives are greatly reduced. The convenient 8-tube format, strips pre-coated with dNTPs, and associated primers helps increase the throughput to meet the needs of customers with larger collections of cell lines. Given the extreme sensitivity of the kit, great care must be taken to prevent inadvertent contamination of samples and reagents. The step-by-step protocol we demonstrate highlights the precautions and practices required for reliable mycoplasma detection. We also show and discuss typical results and their interpretation. Our goal is to ensure the success of researchers using the LookOut Mycoplasma PCR Detection Kit. PMID- 21712801 TI - Alginate hydrogels for three-dimensional organ culture of ovaries and oviducts. AB - Ovarian cancer is the fifth leading cause of cancer deaths in women and has a 63% mortality rate in the United States(1). The cell type of origin for ovarian cancers is still in question and might be either the ovarian surface epithelium (OSE) or the distal epithelium of the fallopian tube fimbriae(2,3). Culturing the normal cells as a primary culture in vitro will enable scientists to model specific changes that might lead to ovarian cancer in the distinct epithelium, thereby definitively determining the cell type of origin. This will allow development of more accurate biomarkers, animal models with tissue-specific gene changes, and better prevention strategies targeted to this disease. Maintaining normal cells in alginate hydrogels promotes short term in vitro culture of cells in their three-dimensional context and permits introduction of plasmid DNA, siRNA, and small molecules. By culturing organs in pieces that are derived from strategic cuts using a scalpel, several cultures from a single organ can be generated, increasing the number of experiments from a single animal. These cuts model aspects of ovulation leading to proliferation of the OSE, which is associated with ovarian cancer formation. Cell types such as the OSE that do not grow well on plastic surfaces can be cultured using this method and facilitate investigation into normal cellular processes or the earliest events in cancer formation(4). Alginate hydrogels can be used to support the growth of many types of tissues(5). Alginate is a linear polysaccharide composed of repeating units of beta-D-mannuronic acid and alpha-L-guluronic acid that can be crosslinked with calcium ions, resulting in a gentle gelling action that does not damage tissues(6,7). Like other three-dimensional cell culture matrices such as Matrigel, alginate provides mechanical support for tissues; however, proteins are not reactive with the alginate matrix, and therefore alginate functions as a synthetic extracellular matrix that does not initiate cell signaling(5). The alginate hydrogel floats in standard cell culture medium and supports the architecture of the tissue growth in vitro. A method is presented for the preparation, separation, and embedding of ovarian and oviductal organ pieces into alginate hydrogels, which can be maintained in culture for up to two weeks. The enzymatic release of cells for analysis of proteins and RNA samples from the organ culture is also described. Finally, the growth of primary cell types is possible without genetic immortalization from mice and permits investigators to use knockout and transgenic mice. PMID- 21712803 TI - High resolution 3D imaging of ex-vivo biological samples by micro CT. AB - Non-destructive volume visualization can be achieved only by tomographic techniques, of which the most efficient is the x-ray micro computerized tomography (MUCT). High resolution MUCT is a very versatile yet accurate (1-2 microns of resolution) technique for 3D examination of ex-vivo biological samples(1, 2). As opposed to electron tomography, the MUCT allows the examination of up to 4 cm thick samples. This technique requires only few hours of measurement as compared to weeks in histology. In addition, MUCT does not rely on 2D stereologic models, thus it may complement and in some cases can even replace histological methods(3, 4), which are both time consuming and destructive. Sample conditioning and positioning in MUCT is straightforward and does not require high vacuum or low temperatures, which may adversely affect the structure. The sample is positioned and rotated 180 degrees or 360 degrees between a microfocused x ray source and a detector, which includes a scintillator and an accurate CCD camera, For each angle a 2D image is taken, and then the entire volume is reconstructed using one of the different available algorithms(5-7). The 3D resolution increases with the decrease of the rotation step. The present video protocol shows the main steps in preparation, immobilization and positioning of the sample followed by imaging at high resolution. PMID- 21712804 TI - Neural correlates of the volitional regulation of the desire for food. AB - OBJECTIVE: In this study, we investigate the brain mechanisms of the conscious regulation of the desire for food using functional magnetic resonance imaging. Further, we examine associations between hemodynamic responses and participants' cognitive restraint of eating (CRE), as well as their susceptibility to uncontrolled eating. SUBJECTS: Seventeen non-vegetarian, right-handed, female Caucasian participants (age: 20-30 years, mean 25.3 years+/-3.1 s.d.; BMI: 20.2 31.2 kg m(-2), mean 25.1+/-3.5 s.d.). MEASUREMENTS: During scanning, our participants viewed pictures of food items they had pre-rated according to tastiness and healthiness. Participants were either allowed to admit to the desire for the food (ADMIT) or they were instructed to downregulate their desire using a cognitive reappraisal strategy, that is, thinking of negative long-term health-related and social consequences (REGULATE). RESULTS: Comparing the hemodynamic responses of the REGULATE with the ADMIT condition, we observed robust activation in the dorsolateral prefrontal cortex (DLPFC), the pre supplementary motor area, the inferior frontal gyrus (IFG), the dorsal striatum (DS), the bilateral orbitofrontal cortex (OFC), the anterior insula and the temporo-parietal junction (TPJ). Activation in the DLPFC and the DS strongly correlated with the degree of dietary restraint under both conditions. CONCLUSION: Cortical activation in the DLPFC, the pre-supplementary motor area and the inferior frontal gyrus (IFG) are known to underpin top-down control, inhibition of learned associations and pre-potent responses. The observed hemodynamic responses in the lateral OFC, the DS, the anterior insula and the TPJ support the notion of reward valuation and integration, interoceptive awareness, and self-reflection as key processes during active regulation of desire for food. In conclusion, an active reappraisal of unhealthy food recruits the brain's valuation system in combination with prefrontal cognitive control areas associated with response inhibition. The correlations between brain responses and CRE suggest that individuals with increased cognitive restraint show an automatic predisposition to regulate the hedonic aspects of food stimuli. This cognitive control might be necessary to counterbalance a lack of homeostatic mechanisms. PMID- 21712805 TI - Fast food, other food choices and body mass index in teenagers in the United Kingdom (ALSPAC): a structural equation modelling approach. AB - OBJECTIVE: To assess the association between the consumption of fast food (FF) and body mass index (BMI) of teenagers in a large UK birth cohort. METHODS: A structural equation modelling (SEM) approach was chosen to allow direct statistical testing of a theoretical model. SEM is a combination of confirmatory factor and path analysis, which allows for the inclusion of latent (unmeasured) variables. This approach was used to build two models: the effect of FF outlet visits and food choices and the effect of FF exposure on consumption and BMI. RESULTS: A total of 3620 participants had data for height and weight from the age 13 clinic and the frequency of FF outlet visits, and so were included in these analyses. This SEM model of food choices showed that increased frequency of eating at FF outlets is positively associated with higher consumption of unhealthy foods (beta=0.29, P<0.001) and negatively associated with the consumption of healthy foods (beta=-1.02, P<0.001). The SEM model of FF exposure and BMI showed that higher exposure to FF increases the frequency of visits to FF outlets (beta=0.61, P<0.001), which is associated with higher body mass index standard deviation score (BMISDS; beta=0.08, P<0.001). Deprivation was the largest contributing variable to the exposure (beta=9.2, P<0.001). CONCLUSIONS: The teenagers who ate at FF restaurants consumed more unhealthy foods and were more likely to have higher BMISDS than those teenagers who did not eat frequently at FF restaurants. Teenagers who were exposed to more takeaway foods at home ate more frequently at FF restaurants and eating at FF restaurants was also associated with lower intakes of vegetables and raw fruit in this cohort. PMID- 21712806 TI - Impaired insulin sensitivity is accompanied by disturbances in skeletal muscle fatty acid handling in subjects with impaired glucose metabolism. AB - OBJECTIVE: To determine insulin sensitivity and skeletal muscle fatty acid (FA) handling at baseline and after a high-fat mixed meal in impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG/IGT and normal glucose tolerance (NGT) subjects. DESIGN: In this multi-center study, insulin sensitivity and beta cell function were assessed (n=102), using a euglycemic-hyperinsulinemic and hyperglycemic clamp with additional arginine stimulation and a 75 g oral glucose tolerance test. Fasting and postprandial skeletal muscle FA handling was examined in a substudy using the forearm balance technique (n=35). SUBJECTS: A total of 102 subjects with IFG (n=48), IGT (n=12), IFG/IGT (n=26) and NGT (n=16). RESULTS: IFG, IGT and IFG/IGT subjects had lower insulin sensitivity with no differences between groups, and lower impaired beta-cell function compared with NGT controls. The early postprandial increase in triacylglycerol (TAG) concentration was higher (iAUC(0-2 h) IFG: 238.4+/-26.5, IGT: 234.0+/-41.0 and NGT: 82.6+/-13.8 MUmol l( 1) min(-1), both P<0.05) and early TAG extraction was increased (AUC(0-2 h) IFG: 56.8+/-9.0, IGT: 52.2+/-12.0 and NGT: 3.8+/-15.4 nmol.100 ml(-1) min(-1), P<0.05 and P=0.057, respectively) in both IFG and IGT subjects. CONCLUSION: IFG, IGT and IFG/IGT subjects have lower insulin sensitivity and impaired beta-cell function compared with age- and BMI-matched NGT controls. The increased postprandial TAG response and higher muscle TAG extraction in both IFG and IGT compared with NGT may lead to ectopic fat accumulation in the skeletal muscle, thereby contributing to insulin resistance. PMID- 21712807 TI - Trends in the prevalence of morbid obesity in Australian children and adolescents from 1985 to 2008: what do we know about? PMID- 21712809 TI - Bone morphogenetic protein-3b (BMP-3b) is expressed in adipocytes and inhibits adipogenesis as a unique complex. AB - BACKGROUND: Bone morphogenetic protein-3b (BMP-3b) is a member of the transforming growth factor-beta (TGF-beta) superfamily. BMP-3b regulates osteogenesis and has critical roles in developing embryos. BMP-3b is expressed not only in the bone and developing embryos but also in adipose tissues. However, the functions of BMP-3b in adipose tissue are still unknown. METHODS: BMP-3b expression was quantified in various adipose tissues and in the adipose-derived stromal-vascular fraction (SVF) and mature adipocyte fraction (AD.F) of mice. We also used 3T3-L1 preadipocytes to analyze the expression, function and molecular forms of BMP-3b. In order to determine the effects of BMP-3b on the adipogenesis of 3T3-L1 cells, BMP-3b siRNA-mediated knockdown and gene overexpression studies were performed, and a conditioned medium (CM) containing the BMP-3b protein was added to 3T3-L1 cell cultures. Adipocyte differentiation was evaluated by measuring the expression of adipogenic markers or by Oil Red O staining. The molecular form of BMP-3b that was secreted from the 3T3-L1 cells was analyzed by western blotting. RESULTS: BMP-3b is expressed in all adipose tissues and is expressed at higher levels in preadipocytes than in mature adipocytes. In mesenteric adipose tissue, BMP-3b expression was increased in diet-induced obesity (DIO) mice as compared with that in control mice. BMP-3b was also expressed highly in 3T3-L1 cells. We showed that siRNA-mediated knockdown of endogenous BMP-3b expression in 3T3-L1 cells enhanced adipogenesis. Conversely, overexpressing BMP-3b inhibited adipocyte differentiation. We also showed that addition of CM containing the BMP-3b protein inhibited the differentiation of 3T3 L1 cells, and that this inhibitory effect was abolished by removing BMP-3b with an anti-BMP-3b antibody. Furthermore, BMP-3b was secreted from adipocytes as a unique non-covalent complex. CONCLUSION: These data suggest that BMP-3b is secreted from adipocytes and is involved in adipocyte differentiation. PMID- 21712810 TI - The risk of general and abdominal adiposity in the occurrence of new vascular events and mortality in patients with various manifestations of vascular disease. AB - AIMS: Adiposity is associated with an increased but also with a decreased risk for successive vascular events or mortality in patients with different manifestations of vascular disease. In this study we directly compare the risk of general adiposity or abdominal obesity on the occurrence of new vascular events or mortality in these patients. METHODS: Patients with cerebrovascular disease (CVD; n=973), coronary artery disease (CAD; n=2339) or peripheral arterial disease (PAD; n=894) were prospectively followed for the occurrence of a vascular event or death. The median follow-up was 4.5 years. Adiposity was assessed with body mass index (BMI), waist circumference (WC) and determination of intra abdominal fat through ultrasound. Cox proportional hazards models were used to evaluate the risk for new vascular events, vascular mortality and all-cause mortality. RESULTS: CAD patients had a 12% increased risk for vascular mortality with 1 BMI unit increase (hazard ratio (HR) 1.12; 95% confidence interval (CI) 1.05-1.20) and a 25% increased risk with 1cm increase in intra-abdominal adipose tissue (HR 1.25; 95% CI 1.12-1.39). The risk for all-cause mortality was increased by 3% (HR 1.03; 95% CI 1.01-1.05) with 1 cm increase in WC and was increased by 15% (HR 1.15; 95% CI 1.06-1.25) with 1 cm increase in intra abdominal adipose tissue. In PAD patients there was an inverse relationship between BMI and vascular mortality (HR 0.93; 95% CI 0.87-0.98) and all-cause mortality (HR 0.90; 95% CI 0.86-0.94). In CVD patients there was no relation between obesity and vascular events or mortality. CONCLUSION: General adiposity is associated with an increased risk for vascular mortality in CAD patients and a decreased risk for (vascular) mortality in PAD patients. PMID- 21712811 TI - Low risk HLA-DQ and increased body mass index in newly diagnosed type 1 diabetes children in the Better Diabetes Diagnosis study in Sweden. AB - OBJECTIVE: Type 1 diabetes and obesity has increased in childhood. We therefore tested the hypothesis that type 1 diabetes human leukocyte antigen DQ (HLA-DQ) risk genotypes may be associated with increased body mass index (BMI). DESIGN: The type 1 diabetes high-risk HLA-DQ A1*05:01-B1*02:01/A1*03:01-B1*03:02 genotype along with lower risk DQ genotypes were determined at the time of clinical onset by PCR and hybridization with allele-specific probes. BMI was determined after diabetes was stabilized. SUBJECTS: A total of 2403 incident type 1 diabetes children below 18 years of age were ascertained in the Swedish national Better Diabetes Diagnosis (BDD) study between May 2005 to September 2009. All children classified with type 1 diabetes, including positivity for at least one islet autoantibody, were investigated. RESULTS: Overall, type 1 diabetes HLA-DQ risk was negatively associated with BMI (P<0.0008). The proportion of the highest risk A1*05:01-B1*02:01/A1*03:01-B1)03:02 genotype decreased with increasing BMI (P<0.0004). However, lower risk type 1 diabetes DQ genotypes were associated with an increased proportion of patients who were overweight or obese (P<0.0001). Indeed, the proportion of patients with the low-risk A1*05:01-B1*02:01/A1*05:01 B1*02:01 genotype increased with increasing BMI (P<0.003). The magnitude of association on the multiplicative scale between the A1*05:01-B1*02:01/A1*05:01 B1*02:01 genotype and increased BMI was significant (P<0.006). The odds ratio in patients with this genotype of being obese was 1.80 (95% confidence interval 1.21 2.61; P<0.006). The increased proportion of overweight type 1 diabetes children with the A1*05:01-B1*02:01 haplotype was most pronounced in children diagnosed between 5 and 9 years of age. CONCLUSIONS: Susceptibility for childhood type 1 diabetes was unexpectedly found to be associated with the A1*05:01 B1*02:01/A1*05:01-B1*02:01 genotype and an increased BMI. These results support the hypothesis that overweight may contribute to the risk of type 1 diabetes in children positive for HLA-DQ A1*05:01-B1*02:01. PMID- 21712812 TI - A novel strategy for evasion of NK cell immunity by tumours expressing core2 O glycans. AB - The O-glycan branching enzyme, core2 beta-1,6-N-acetylglucosaminyltransferase (C2GnT), forms O-glycans containing an N-acetylglucosamine branch connected to N acetylgalactosamine (core2 O-glycans) on cell-surface glycoproteins. Here, we report that upregulation of C2GnT is closely correlated with progression of bladder tumours and that C2GnT-expressing bladder tumours use a novel strategy to increase their metastatic potential. Our results showed that C2GnT-expressing bladder tumour cells are highly metastatic due to their high ability to evade NK cell immunity and revealed the molecular mechanism of the immune evasion by C2GnT expression. Engagement of an NK-activating receptor, NKG2D, by its tumour associated ligand, Major histocompatibility complex class I-related chain A (MICA), is critical to tumour rejection by NK cells. In C2GnT-expressing bladder tumour cells, poly-N-acetyllactosamine was present on core2 O-glycans on MICA, and galectin-3 bound the NKG2D-binding site of MICA through this poly-N acetyllactosamine. Galectin-3 reduced the affinity of MICA for NKG2D, thereby severely impairing NK cell activation and silencing the NK cells. This new mode of NK cell silencing promotes immune evasion of C2GnT-expressing bladder tumour cells, resulting in tumour metastasis. PMID- 21712813 TI - Linking the branchpoint helix to a newly found receptor allows lariat formation by a group II intron. AB - Like spliceosomal introns, the ribozyme-containing group II introns are excised as branched, lariat structures: a 2'-5' bond is created between the first nucleotide of the intron and an adenosine in domain VI, a component which is missing from available crystal structures of the ribozyme. Comparative sequence analysis, modelling and nucleotide substitutions point to the existence, and probable location, of a specific RNA receptor for the section of domain VI that lies just distal to the branchpoint adenosine. By designing oligonucleotides that tether domain VI to this novel binding site, we have been able to specifically activate lariat formation in an engineered, defective group II ribozyme. The location of the newly identified receptor implies that prior to exon ligation, the distal part of domain VI undergoes a major translocation, which can now be brought under control by the system of anchoring oligonucleotides we have developed. Interestingly, these oligonucleotides, which link the branchpoint helix and the binding site for intron nucleotides 3-4, may be viewed as counterparts of U2-U6 helix III in the spliceosome. PMID- 21712814 TI - Systemic administration of AAV8-alpha-galactosidase A induces humoral tolerance in nonhuman primates despite low hepatic expression. AB - In mice, liver-restricted expression of lysosomal enzymes from adeno-associated viral serotype 8 (AAV8) vectors results in reduced antibodies to the expressed proteins. To ask whether this result might translate to patients, nonhuman primates (NHPs) were injected systemically with AAV8 encoding alpha-galactosidase A (alpha-gal). As in mice, sustained expression in monkeys attenuated antibody responses to alpha-gal. However, this effect was not robust, and sustained alpha gal levels were 1-2 logs lower than those achieved in male mice at the same vector dose. Because our mouse studies had shown that antibody levels were directly related to expression levels, several strategies were evaluated to increase expression in monkeys. Unlike mice, expression in monkeys did not respond to androgens. Local delivery to the liver, immune suppression, a self complementary vector and pharmacologic approaches similarly failed to increase expression. While equivalent vector copies reached mouse and primate liver and there were no apparent differences in vector form, methylation or deamination, transgene expression was limited at the mRNA level in monkeys. These results suggest that compared to mice, transcription from an AAV8 vector in monkeys can be significantly reduced. They also suggest some current limits on achieving clinically useful antibody reduction and therapeutic benefit for lysosomal storage diseases using a systemic AAV8-based approach. PMID- 21712815 TI - Oncolytic adenovirus expressing soluble TGFbeta receptor II-Fc-mediated inhibition of established bone metastases: a safe and effective systemic therapeutic approach for breast cancer. AB - In recent years, oncolytic adenoviruses have shown some promise as a novel class of antitumor agents. However, their utility in targeting bone metastases is relatively less studied. We have examined whether the systemic therapy of oncolytic adenoviruses expressing the soluble form of transforming growth factor beta (TGFbeta) receptor II fused with human immunoglobulin G1 can be developed for the treatment of established breast cancer bone metastases. MDA-MB-231-luc2 human breast cancer cells were injected in the left heart ventricle of nude mice to establish bone metastasis. Mice with hind limb tumors were administered (on days 8 and 11) oncolytic adenoviruses-Ad.sTbetaRFc or mhTERTAd.sTbetaRFc. Skeletal tumor growth was monitored weekly by bioluminescence imaging (BLI) and radiography. At the termination time on day 28, hind limb bones were analyzed for tumor burden, synchrotron micro-computed tomography, and osteoclast activation. Intravenous delivery of Ad.sTbetaRFc and mhTERTAd.sTbetaRFc induced significant inhibition of tumor growth, reduction of tumor burden, osteoclast activation, and increased animals' survival. Oncolytic adenoviruses were safer than dl309, a wild type virus. A slight elevation of liver enzyme activity was observed after Ad.sTbetaRFc administration; this subsided with time. Based on these studies, we believe that Ad.sTbetaRFc and mhTERTAd.sTbetaRFc can be developed as a safe and effective approach for the treatment of established bone metastasis. PMID- 21712816 TI - Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome. AB - Defects in DNA replication are associated with genetic instability and cancer development, as illustrated in Bloom syndrome. Features of this syndrome include a slowdown in replication speed, defective fork reactivation and high rates of sister chromatid exchange, with a general predisposition to cancer. Bloom syndrome is caused by mutations in the BLM gene encoding a RecQ helicase. Here we report that BLM deficiency is associated with a strong cytidine deaminase defect, leading to pyrimidine pool disequilibrium. In BLM-deficient cells, pyrimidine pool normalization leads to reduction of sister chromatid exchange frequency and is sufficient for full restoration of replication fork velocity but not the fork restart defect, thus identifying the part of the Bloom syndrome phenotype because of pyrimidine pool imbalance. This study provides new insights into the molecular basis of control of replication speed and the genetic instability associated with Bloom syndrome. Nucleotide pool disequilibrium could be a general phenomenon in a large spectrum of precancerous and cancer cells. PMID- 21712817 TI - TRPV3 regulates nitric oxide synthase-independent nitric oxide synthesis in the skin. AB - Nitric oxide (NO) is an unstable signalling molecule synthesized de novo mainly from L-arginine by NO synthase (NOS) enzymes. Nitrite reduction can also produce NO, predominantly within body fluids (for example, saliva, sweat and blood plasma) and under extreme hypoxic and acidic conditions. It remains unknown if intracellular canonical signalling pathways regulate nitrite-dependent NO production. Here we examine NO production in the skin, a hypoxic tissue enriched in nitrites wherein NO has important roles in wound healing and other biological processes. We show that activation of TRPV3, a heat-activated transient receptor potential ion channel expressed in keratinocytes, induces NO production via a nitrite-dependent pathway. TRPV3 and nitrite are involved in keratinocyte migration in vitro and in wound healing and thermosensory behaviours in vivo. Our study demonstrates that activation of an ion channel can induce NOS-independent NO production in keratinocytes. PMID- 21712818 TI - Mediatorless high-power glucose biofuel cells based on compressed carbon nanotube enzyme electrodes. AB - Enzymatic fuel cells use enzymes to produce energy from bioavailable substrates. However, such biofuel cells are limited by the difficult electrical wiring of enzymes to the electrode. Here we show the efficient wiring of enzymes in a conductive pure carbon nanotube matrix for the fabrication of a glucose biofuel cell (GBFC). Glucose oxidase and laccase were respectively incorporated in carbon nanotube disks by mechanical compression. The characterization of each bioelectrode shows an open circuit potential corresponding to the redox potential of the respective enzymes, and high current densities for glucose oxidation and oxygen reduction. The mediatorless GBFC delivers a high power density up to 1.3 mW cm(-2) and an open circuit voltage of 0.95 V. Moreover, the GBFC remains stable for 1 month and delivers 1 mW cm(-2) power density under physiological conditions (5*10(-3) mol l(-1) glucose, pH 7). To date, these values are the best performances obtained for a GBFC. PMID- 21712819 TI - Cyclin B-dependent kinase 1 regulates human TRF1 to modulate the resolution of sister telomeres. AB - Cyclin B-Cdk1 is a key mediator of mitotic entry; however, little is known about its role in the separation of sister chromatids. Here we report that upon mitotic entry, Cdk1 specifically phosphorylates threonine 371 of TRF1, a telomere binding protein implicated in the regulation of sister telomere cohesion. Such phosphorylation is removed in late mitosis when Cdk1 activity is inhibited, indicative of a tight regulation of T371 phosphorylation. We show that T371 phosphorylation by Cdk1 keeps TRF1 free of chromatin and this phosphorylation is associated with loss of telomere-bound TRF1 and TIN2, and a reduction in telomere heterochromatin. We find that a phosphomimic mutation at T371 of TRF1 induces telomere deprotection, resulting in telomere loss and the formation of telomere fusions, whereas a non-phosphorylatable substitution of T371 blocks sister telomere resolution, promotes micronuclei formation and impairs cell proliferation. Our work suggests that Cdk1 controls TRF1 association with telomeres to facilitate temporal telomere de-protection, which is essential for sister telomere resolution. PMID- 21712820 TI - Imaging local electronic corrugations and doped regions in graphene. AB - Electronic structure heterogeneities are ubiquitous in two-dimensional graphene and profoundly impact the transport properties of this material. Here we show the mapping of discrete electronic domains within a single graphene sheet using scanning transmission X-ray microscopy in conjunction with ab initio density functional theory calculations. Scanning transmission X-ray microscopy imaging provides a wealth of detail regarding the extent to which the unoccupied levels of graphene are modified by corrugation, doping and adventitious impurities, as a result of synthesis and processing. Local electronic corrugations, visualized as distortions of the pi*cloud, have been imaged alongside inhomogeneously doped regions characterized by distinctive spectral signatures of altered unoccupied density of states. The combination of density functional theory calculations, scanning transmission X-ray microscopy imaging, and in situ near-edge X-ray absorption fine structure spectroscopy experiments also provide resolution of a longstanding debate in the literature regarding the spectral assignments of pre edge and interlayer states. PMID- 21712821 TI - Identification of vertebra-like elements and their possible differentiation from sclerotomes in the hagfish. AB - The hagfish, a group of extant jawless fish, are known to lack true vertebrae and, for this reason, have often been excluded from the group Vertebrata. However, it has yet to be conclusively shown whether hagfish lack all vertebra like structures, and whether their somites follow developmental processes and patterning distinct from those in lampreys and gnathostomes. Here we report the presence of vertebra-like cartilages in the in-shore hagfish, Eptatretus burgeri. These elements arise as small nodules occupying anatomical positions comparable to those of gnathostome vertebrae. Examination of hagfish embryos suggests that the ventromedial portion of a somite transforms into mesenchymal cells that express cognates of Pax1/9 and Twist, strikingly similar to the pattern of sclerotome development in gnathostomes. We conclude that the vertebra-like elements in the hagfish are homologous to gnathostome vertebrae, implying that this animal underwent secondary reduction of vertebrae in most of the trunk. PMID- 21712822 TI - Designing phase II trials in cancer: a systematic review and guidance. AB - BACKGROUND: Literature reviews of cancer trials have highlighted the need for better understanding of phase II statistical designs. Understanding the key elements associated with phase II design and knowledge of available statistical designs is necessary to enable appropriate phase II trial design. METHODS: A systematic literature review was performed to identify phase II trial designs applicable to oncology trials. The results of the review were used to create a library of currently available designs, and to develop a structured approach to phase II trial design outlining key points for consideration. RESULTS: A total of 122 papers describing new or adapted phase II trial designs were obtained. These were categorised into nine levels, reflecting the practicalities of implementation, and form a library of phase II designs. Key design elements were identified by data extraction. Along with detailed description of the key elements and the library of designs, a structured thought process was developed to form a guidance document for choice of phase II oncology trial design. CONCLUSION: The guidance offers researchers a structured and systematic approach to identifying phase II trial designs, highlighting key issues to be considered by both clinicians and statisticians and encouraging an interactive approach to more informed trial design. PMID- 21712823 TI - Circulating tumour markers can define patients with normal colons, benign polyps, and cancers. AB - BACKGROUND: Early diagnosis represents the best opportunity for cure of colorectal cancer. Current screening programmes use faecal occult blood testing for screening, which has limited sensitivity and poor specificity. METHODS: In this study we looked at a series of previously described diagnostic markers utilising circulating free DNA (cfDNA), with a preparation method allowing small DNA fragments to be isolated. The Circulating free DNA was isolated from samples obtained from 85 patients, including 35 patients without endoscopic abnormality, a group of 26 patients with benign colorectal adenomas, and 24 patients with colorectal carcinomas. In each case, polymerase chain reaction (PCR) was performed for Line1 79 bp, Line1 300 bp, Alu 115 bp, Alu 247 bp, and mitochondrial primers. In addition, carcinoembryonic antigen (CEA) was measured by ELISA. Each marker was analysed between normal, polyp, and cancer populations, and the best performing analysed in combination by logistic regression. RESULTS: The best model was able to discriminate normal from populations with adenoma or carcinoma using three DNA markers and CEA, showing an area under the receiver operator characteristic (ROC) curve of 0.855 with a positive predictive value of 81.1% for polyps and cancer diagnosis. CONCLUSION: These circulating markers in combination with other markers offer the prospect of a simple blood test as a possible secondary screen for colorectal cancers and polyps in patients with positive faecal occult blood tests. PMID- 21712825 TI - Mitochondrial recoupling: a novel therapeutic strategy for cancer? AB - Recent findings link metabolic transformation of cancer cells to aberrant functions of mitochondrial uncoupling proteins (UCPs). By inducing proton leak, UCPs interfere with mitochondrial synthesis of adenosine 5'-triphosphate, which is also a key determinant of glycolytic pathways. In addition, UCP suppress the generation of superoxide, a byproduct of mitochondrial electron transport and a major source of oxidative stress. The near ubiquitous UCP2 becomes highly abundant in some cancers and may advance metabolic reprogramming, further disrupt tumour suppression, and promote chemoresistance. Here we review current evidence to suggest that inhibition of mitochondrial uncoupling may eliminate these responses and reveal novel anti-cancer strategies. PMID- 21712824 TI - Methylator phenotype of malignant germ cell tumours in children identifies strong candidates for chemotherapy resistance. AB - BACKGROUND: Yolk sac tumours (YSTs) and germinomas are the two major pure histological subtypes of germ cell tumours. To date, the role of DNA methylation in the aetiology of this class of tumour has only been analysed in adult testicular forms and with respect to only a few genes. METHODS: A bank of paediatric tumours was analysed for global methylation of LINE-1 repeat elements and global methylation of regulatory elements using GoldenGate methylation arrays. RESULTS: Both germinomas and YSTs exhibited significant global hypomethylation of LINE-1 elements. However, in germinomas, methylation of gene regulatory regions differed little from control samples, whereas YSTs exhibited increased methylation at a large proportion of the loci tested, showing a 'methylator' phenotype, including silencing of genes associated with Caspase-8 dependent apoptosis. Furthermore, we found that the methylator phenotype of YSTs was coincident with higher levels of expression of the DNA methyltransferase, DNA (cytosine-5)-methyltransferase 3B, suggesting a mechanism underlying the phenotype. CONCLUSION: Epigenetic silencing of a large number of potential tumour suppressor genes in YSTs might explain why they exhibit a more aggressive natural history than germinomas and silencing of genes associated with Caspase-8 dependent cell death might explain the relative resistance of YSTs to conventional therapy. PMID- 21712826 TI - Prediction of outcome of early ER+ breast cancer is improved using a biomarker panel, which includes Ki-67 and p53. AB - BACKGROUND: The aim of this study is to determine whether immunohistochemical (IHC) assessment of Ki67 and p53 improves prognostication of oestrogen receptor positive (ER+) breast cancer after breast-conserving therapy (BCT). In all, 498 patients with invasive breast cancer from a randomised trial of BCT with or without tumour bed radiation boost were assessed using IHC. METHODS: The ER+ tumours were classified as 'luminal A' (LA): ER+ and/or PR+, Ki-67 low, p53-, HER2- or 'luminal B' (LB): ER+ and/or PR+and/or Ki-67 high and/or p53+ and/or HER2+. Kaplan-Meier and Cox proportional hazards methodology were used to ascertain relationships to ispilateral breast tumour recurrence (IBTR), locoregional recurrence (LRR), distant metastasis-free survival (DMFS) and breast cancer-specific survival (BCSS). RESULTS: In all, 73 patients previously LA were re-classified as LB: a greater than four-fold increase (4.6-19.3%) compared with ER, PR, HER2 alone. In multivariate analysis, the LB signature independently predicted LRR (hazard ratio (HR) 3.612, 95% CI 1.555-8.340, P=0.003), DMFS (HR 3.023, 95% CI 1.501-6.087, P=0.002) and BCSS (HR 3.617, 95% CI 1.629-8.031, P=0.002) but not IBTR. CONCLUSION: The prognostic evaluation of ER+ breast cancer is improved using a marker panel, which includes Ki-67 and p53. This may help better define a group of poor prognosis ER+ patients with a greater probability of failure with endocrine therapy. PMID- 21712827 TI - Expression of HOXC8 is inversely related to the progression and metastasis of pancreatic ductal adenocarcinoma. AB - BACKGROUND: The transcription factor HOXC8 regulates many genes involved in tumour progression. This study was to investigate the role of HOXC8 in pancreatic ductal adenocarcinoma (PDAC) growth and metastasis. METHODS: The Hoxc8 expression was determined in 15 PDAC cell lines and human specimens by RT-polymerase chain reaction and/or immunohistochemistry. The effects of HOXC8 silencing by RNA interference were investigated by functional tests. RESULTS: The Hoxc8 mRNA expression in PDAC cell lines was negatively related to their growth in vivo. Except for Suit2-007 cells, only those with low Hoxc8 mRNA expression grew in nude rats. Successful down-regulation of HOXC8 expression caused increased proliferation, migration (P <= 0.05) and colony formation (P <= 0.05) in Suit2 007, Panc-1 and MIA PaCa-2 PDAC cells, respectively. The Hoxc8 mRNA levels in diseased human pancreas tissues were significantly increased over normal in PDAC and autoimmune chronic pancreatitis specimens (P<0.01, respectively), but negatively related to tumour stage (P=0.09). In primary and metastatic tumour samples, immunohistochemical staining for HOXC8 was stronger in surrounding than in neoplastic tissues. Furthermore, grading of primary carcinomas was negatively associated with HOXC8 staining (P=0.03). Liver metastases showed the lowest HOXC8 expression of all neoplastic lesions. CONCLUSION: These data indicate that HOXC8 expression is inversely related to PDAC progression and metastasis. PMID- 21712830 TI - Cystic fibrosis in premature infants. AB - There are few reports of cystic fibrosis (CF) diagnosed in premature infants. We describe the clinical course of three patients, from our neonatal intensive care units, who were diagnosed with CF, and discuss the existing literature and treatment considerations. PMID- 21712828 TI - Pyrosequencing-based methods reveal marked inter-individual differences in oncogene mutation burden in human colorectal tumours. AB - BACKGROUND: The epidermal growth factor receptor-targeted monoclonal antibody cetuximab (Erbitux) was recently introduced for the treatment of metastatic colorectal cancer. Treatment response is dependent on Kirsten-Ras (K-Ras) mutation status, in which the majority of patients with tumour-specific K-Ras mutations fail to respond to treatment. Mutations in the oncogenes B-Raf and PIK3CA (phosphoinositide-3-kinase) may also influence cetuximab response, highlighting the need for a sensitive, accurate and quantitative assessment of tumour mutation burden. METHODS: Mutations in K-Ras, B-Raf and PIK3CA were identified by both dideoxy and quantitative pyrosequencing-based methods in a cohort of unselected colorectal tumours (n=102), and pyrosequencing-based mutation calls correlated with various clinico-pathological parameters. RESULTS: The use of quantitative pyrosequencing-based methods allowed us to report a 13.7% increase in mutation burden, and to identify low-frequency (<30% mutation burden) mutations not routinely detected by dideoxy sequencing. K-Ras and B-Raf mutations were mutually exclusive and independently associated with a more advanced tumour phenotype. CONCLUSION: Pyrosequencing-based methods facilitate the identification of low-frequency tumour mutations and allow more accurate assessment of tumour mutation burden. Quantitative assessment of mutation burden may permit a more detailed evaluation of the role of specific tumour mutations in the pathogenesis and progression of colorectal cancer and may improve future patient selection for targeted drug therapies. PMID- 21712831 TI - Extremely high phenylalanine levels in a newborn on parenteral nutrition: phenylketonuria in the neonatal intensive care unit. AB - A 1890-g newborn on total parenteral nutrition (TPN) had phenylalanine levels reaching 4164 MUM indicating phenylketonuria (PKU). Review of 64 PKU cases from the California Newborn Screening Program disclosed another newborn diagnosed while on TPN. Phenylalanine levels rose five times faster with TPN, as estimated from rates in these infants. Thus, TPN use is associated with very high phenylalanine levels in newborns with PKU. When starting TPN soon after birth (for example, on day 1), early detection of PKU-by newborn screening 12 to 24 h after infusions are begun-should be helpful in limiting exposures to toxic levels of phenylalanine. PMID- 21712832 TI - Effect of manganese chloride on the neurochemical profile of the rat hypothalamus. AB - Manganese (Mn(2+))-enhanced magnetic resonance imaging studies of the neuronal pathways of the hypothalamus showed that information about the regulation of food intake and energy balance circulate through specific hypothalamic nuclei. The dehydration-induced anorexia (DIA) model demonstrated to be appropriate for studying the hypothalamus with Mn(2+)-enhanced magnetic resonance imaging. Manganese is involved in the normal functioning of a variety of physiological processes and is associated with enzymes contributing to neurotransmitter synthesis and metabolism. It also induces psychiatric and motor disturbances. The molecular mechanisms by which Mn(2+) produces alterations of the hypothalamic physiological processes are not well understood. (1)H-magnetic resonance spectroscopy measurements of the rodent hypothalamus are challenging due to the distant location of the hypothalamus resulting in limited measurement sensitivity. The present study proposed to investigate the effects of Mn(2+) on the neurochemical profile of the hypothalamus in normal, DIA, and overnight fasted female rats at 14.1 T. Results provide evidence that gamma-aminobutyric acid has an essential role in the maintenance of energy homeostasis in the hypothalamus but is not condition specific. On the contrary, glutamine, glutamate, and taurine appear to respond more accurately to Mn(2+) exposure. An increase in glutamine levels could also be a characteristic response of the hypothalamus to DIA. PMID- 21712834 TI - Occlusion of cortical ascending venules causes blood flow decreases, reversals in flow direction, and vessel dilation in upstream capillaries. AB - The accumulation of small strokes has been linked to cognitive dysfunction. Although most animal models have focused on the impact of arteriole occlusions, clinical evidence indicates that venule occlusions may also be important. We used two-photon excited fluorescence microscopy to quantify changes in blood flow and vessel diameter in capillaries after occlusion of single ascending or surface cortical venules as a function of the connectivity between the measured capillary and the occluded venule. Clotting was induced by injuring the target vessel wall with femtosecond laser pulses. After an ascending venule (AV) occlusion, upstream capillaries showed decreases in blood flow speed, high rates of reversal in flow direction, and increases in vessel diameter. Surface venule occlusions produced similar effects, unless a collateral venule provided a new drain. Finally, we showed that AVs and penetrating arterioles have different nearest-neighbor spacing but capillaries branching from them have similar topology, which together predicted the severity and spatial extent of blood flow reduction after occlusion of either one. These results provide detailed insights into the widespread hemodynamic changes produced by cortical venule occlusions and may help elucidate the role of venule occlusions in the development of cognitive disorders and other brain diseases. PMID- 21712833 TI - SK2 channels are neuroprotective for ischemia-induced neuronal cell death. AB - In mouse hippocampal CA1 pyramidal neurons, the activity of synaptic small conductance Ca(2+)-activated K(+) channels type 2 (SK2 channels) provides a negative feedback on N-methyl-D-aspartate receptors (NMDARs), reestablishing Mg(2+) block that reduces Ca(2+) influx. The well-established role of NMDARs in ischemia-induced excitotoxicity led us to test the neuroprotective effect of modulating SK2 channel activity following cerebral ischemia induced by cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Administration of the SK channel positive modulator, 1-ethyl-benzimidazolinone (1-EBIO), significantly reduced CA1 neuron cell death and improved CA/CPR-induced cognitive outcome. Electrophysiological recordings showed that CA/CPR-induced ischemia caused delayed and sustained reduction of synaptic SK channel activity, and immunoelectron microscopy showed that this is associated with internalization of synaptic SK2 channels, which was prevented by 1-EBIO treatment. These results suggest that increasing SK2 channel activity, or preventing ischemia-induced loss of synaptic SK2 channels, are promising and novel approaches to neuroprotection following cerebral ischemia. PMID- 21712836 TI - Vitamin D and parathyroid hormone in insulin resistance of abdominal obesity: cause or effect? AB - The objective was to examine whether there were causal links between vitamin D status, parathyroid hormone, insulin resistance (IR)/insulin sensitivity (IS) and the metabolic syndrome (MS). A total of 72 Caucasian men and women, aged 55.7 +/- 7.57 years, with body mass index 33.4 +/- 4.02 kg/m(2) and abdominal obesity, were assessed for IR/IS based on three commonly used indices before and after 12 weeks of supervised weight loss. During weight stability, though both lower intact parathyroid hormone (iPTH) and higher vitamin D were independently associated with greater IS/lower IR, this was consistent for iPTH across the surrogate measures tested. Higher iPTH, but not lower vitamin D, increased the risk of MS after adjustment for IR/IS. Weight loss resulted in significant reductions in percent fat (-2.83 +/- 2.20%), waist (-9.26 +/- 5.11 cm), improvements in all IS indices, reductions in MS and iPTH (-0.28 +/- 1.17 pmol/l), but no increase in vitamin D (+2.19 +/- 12.17 nmol/l). Following weight loss, DeltaiPTH either predicted change in IR/IS or contributed to their variance by 4.1-8.9%. On adjustment for IR/IS, higher DeltaiPTH did not significantly predict MS after weight loss, though the odds ratios for the effect were sizeable. The data are suggestive of an intrinsic inverse relationship between iPTH and IS in abdominally obese individuals, independent of vitamin D. There remains the possibility of a direct relationship between iPTH and MS. PMID- 21712835 TI - Inulin increases short-term markers for colonic fermentation similarly in healthy and hyperinsulinaemic humans. AB - BACKGROUND/OBJECTIVES: Colonic fermentation of dietary fibre produces short-chain fatty acids (SCFAs), acetate, propionate and butyrate, which may protect against type 2 diabetes by reducing serum free-fatty acids (FFAs). Since hyperinsulinaemia is associated with insulin resistance and increased diabetes risk, the main objective was to compare markers of colonic fermentation after acute inulin ingestion in subjects with normal (<40 pmol/l, NI) and high (>=40 pmol/l, HI) plasma insulin. SUBJECTS/METHODS: Overnight fasted NI (n=9) and HI (n=9) subjects were studied for 4 h on two separate days after consuming 300 ml drinks containing 75 g glucose (Glucose) or 75 g glucose plus 24 g inulin (Inulin) using a randomized, single-blind, crossover design. RESULTS: Inulin elicited a higher breath hydrogen and methane areas under the curve (AUC), but the increases in SCFA responses were not statistically significant. Mean serum acetate concentration over the 4-h study period was higher in NI than in HI subjects (44.3 +/- 6.9 vs 22.5 +/- 3.7 MUmol/l, P=0.001). The rate of rebound of FFA was reduced by Inulin, with FFA at 4 h being less after Inulin than Glucose, regardless of insulin status (0.310 +/- 0.028 vs 0.432 +/- 0.042 mEq/l, P=0.008). CONCLUSIONS: This suggests that inulin increases short-term markers for colonic fermentation, but a longer study period may be necessary to observe differences in SCFA production. The reason for the lower serum acetate in HI is unclear but may be due to reduced absorption, increased clearance or decreased endogenous production. This suggests the need to compare acetate kinetics in normal and hyperinsulinaemic subjects. PMID- 21712837 TI - Breastfeeding initiation in immigrant and non-immigrant women in Spain. AB - Research about inequities between native and immigrant women regarding the quality of health care is still scarce. Initiation of breastfeeding in hospital is considered a quality care indicator. In this study, we explore the association between the geographical origin of the women and the establishment of breastfeeding in Spanish hospitals. Prevalence of breastfeeding initiation is higher for women from Latin America, Eastern Europe, Maghreb or sub-Saharan Africa than for Spanish women, and lower for Chinese women. Compared with Spanish women the odds of not breastfeeding in hospital were lower in all these immigrant groups but more than five times higher for Chinese immigrants. Culturally adapted health services are necessary to maintain breastfeeding rates in most immigrant groups. Moreover, it seems urgent to identify the factors influencing patterns of breastfeeding in Chinese immigrants and to develop innovative strategies to encourage breastfeeding initiation in hospital. PMID- 21712838 TI - Effect of three consecutive meals on the physicochemical properties of HDL and LDL in individuals with the metabolic syndrome and patients with type 2 diabetes. AB - BACKGROUND/OBJECTIVES: Postprandial hyperlipidemia, which is exaggerated and prolonged in insulin-resistant individuals, has been associated with cardiovascular disease. The objective of this study was to investigate whether and how the composition, size and function of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles are affected in the postprandial state among males with the metabolic syndrome (MetS) or type 2 diabetes (T2DM), compared with controls. SUBJECTS/METHODS: A total of 14 males with T2DM, 14 with the MetS and 14 age-matched controls were given three standardized high-fat mixed meals (900 kcal; 50-g fat, 75-g carbohydrate and 35-g protein) as breakfast, lunch and dinner. Blood sampling was performed just before each meal, and 4 and 8 h after the last meal. HDL and LDL were isolated by ultracentrifugation and analyzed for their composition, particle diameter and functional properties. RESULTS: Postprandial triglycerides levels in plasma, HDL and LDL particles increased significantly in all groups (P<0.01). Compared with the control subjects, patients with T2DM had smaller LDL particles, and in agreement, a lower cholesterol-to-protein content in both fasting and postprandial samples. A prolonged increase in susceptibility of LDL to oxidation was found in all subjects, but was most evident in T2DM. The postprandial effect on LDL oxidation was associated with an increase in LDL triglyceride (r=0.29, P<0.05). In T2DM the anti-oxidative capacity of HDL trended to impairment after the third meal. CONCLUSIONS: Postprandial increases in triglycerides, especially in T2DM, are accompanied by pro-atherosclerotic functional changes in HDL and LDL particles. PMID- 21712839 TI - Diet quality scores and oxidative stress in Korean adults. AB - BACKGROUND/OBJECTIVES: The purpose of diet-quality indices is to assess and guide individual dietary intake for the promotion of health and prevention of disease, and food based dietary-quality indices need to be applied by using each country's own unique diet. We assessed the relationships between relatively simple dietary quality scores modified for a Korean diet, such as the Recommended Food Score (RFS) and alternate Mediterranean Diet Score (aMDS), and oxidative stress biomarkers in Korean adults. SUBJECTS/METHODS: A total of 976 adults were recruited for the Biomarker Monitoring for Environmental Health Study between April and December 2005 in Seoul and Incheon, Korea. RFS and aMDS were calculated by using a food-frequency questionnaire. We used regression analyses to assess the associations between diet quality scores and urinary malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). RESULTS: RFS and aMDS were negatively associated with urinary MDA concentrations (P=0.032 for RFS, P=0.043 for aMDS), but not with 8-OHdG after adjusted for potential covariates. After stratified analyses by sex, negative associations between the both scores and urinary MDA concentrations were not significant in both men and women. There were no significant associations of RFS and aMDS with urinary 8-OHdG concentrations. CONCLUSIONS: Higher RFS and aMDS scores were related to lower oxidative stress. Therefore, good quality of diet may be useful in reducing oxidative stress. PMID- 21712840 TI - Learning and memory: Flies know their way. PMID- 21712841 TI - Circadian rhythms: Calcium sets the tempo. PMID- 21712842 TI - To Cut or NoCut in mitosis. PMID- 21712843 TI - Sizing up Arabidopsis genome evolution. PMID- 21712844 TI - Increased inbreeding and strong kinship structure in Taxus baccata estimated from both AFLP and SSR data. AB - Habitat fragmentation can have severe genetic consequences for trees, such as increased inbreeding and decreased effective population size. In effect, local populations suffer from reduction of genetic variation, and thus loss of adaptive capacity, which consequently increases their risk of extinction. In Europe, Taxus baccata is among a number of tree species experiencing strong habitat fragmentation. However, there is little empirical data on the population genetic consequences of fragmentation for this species. This study aimed to characterize local genetic structure in two natural remnants of English yew in Poland based on both amplified fragment length polymorphism (AFLP) and microsatellite (SSR) markers. We introduced a Bayesian approach that estimates the average inbreeding coefficient using AFLP (dominant) markers. Results showed that, in spite of high dispersal potential (bird-mediated seed dispersal and wind-mediated pollen dispersal), English yew populations show strong kinship structure, with a spatial extent of 50-100 m, depending on the population. The estimated inbreeding levels ranged from 0.016 to 0.063, depending on the population and marker used. Several patterns were evident: (1) AFLP markers showed stronger kinship structure than SSRs; (2) AFLP markers provided higher inbreeding estimates than SSRs; and (3) kinship structure and inbreeding were more pronounced in denser populations regardless of the marker used. Our results suggest that, because both kinship structure and (bi-parental) inbreeding exist in populations of English yew, gene dispersal can be fairly limited in this species. Furthermore, at a local scale, gene dispersal intensity can be more limited in a dense population. PMID- 21712845 TI - AFLPs support deep relationships among darters (Percidae: Etheostomatinae) consistent with morphological hypotheses. AB - Recent attention has focused on the efficacy of amplified fragment length polymorphisms (AFLPs) for resolving deep evolutionary relationships. Here we show that AFLPs provide resolution of deep relationships within the family Percidae that are more consistent with previous morphological hypotheses than are relationships proposed by previous molecular analyses. Despite in silico predictions, we were able to resolve relatively ancient divergences, estimated at >25 MA. We show that the most distantly related species share the fewest fragments, but suggest that large data sets and extensive taxon sampling are sufficient to overcome this obstacle of the AFLP technique for deep divergences. We compare genetic distances estimated from mitochondrial DNA with those from AFLPs and contrast traditional PAUP(*) Nei-Li AFLP genetic distances with a recently proposed method utilizing the Dice equation with constraining nucleotides. PMID- 21712846 TI - Bayesian shrinkage analysis of QTLs under shape-adaptive shrinkage priors, and accurate re-estimation of genetic effects. AB - The successful implementation of Bayesian shrinkage analysis of high-dimensional regression models, as often encountered in quantitative trait locus (QTL) mapping, is contingent upon the choice of suitable sparsity-inducing priors. In practice, the shape (that is, the rate of tail decay) of such priors is typically preset, with no regard for the range of plausible alternatives and the fact that the most appropriate shape may depend on the data at hand. This study is presumably the first attempt to tackle this oversight through the shape-adaptive shrinkage prior (SASP) approach, with a focus on the mapping of QTLs in experimental crosses. Simulation results showed that the separation between genuine QTL effects and spurious ones can be made clearer using the SASP-based approach as compared with existing competitors. This feature makes our new method a promising approach to QTL mapping, where good separation is the ultimate goal. We also discuss a re-estimation procedure intended to improve the accuracy of the estimated genetic effects of detected QTLs with regard to shrinkage-induced bias, which may be particularly important in large-scale models with collinear predictors. The re-estimation procedure is relevant to any shrinkage method, and is potentially valuable for many scientific disciplines such as bioinformatics and quantitative genetics, where oversaturated models are booming. PMID- 21712847 TI - The performance of the risk of ovarian malignancy algorithm. PMID- 21712850 TI - Chronic kidney disease: Levels of phosphorus and patient outcomes. PMID- 21712849 TI - The genetics of common kidney disease: a pathway toward clinical relevance. AB - Genome-wide association studies (GWASs) have advanced our understanding of the genetic basis for common renal diseases, including chronic kidney disease (CKD) and related traits such as hypertension. The 'common variant, common disease' hypothesis-the theoretical basis for gene mapping by GWASs-has, however, underestimated the complexity of the genetic architecture underlying these diseases. The disease-specific variants identified by GWASs, despite being supported by statistically robust associations, often fail to illuminate the biology underlying the association and explain only a small portion of the estimated heritability of these diseases, even in aggregate. Although these variants have highlighted novel pathways that can be targeted therapeutically, their small effect sizes have minimal effects on diagnosis, prognosis, and management of individual patients. At present, therefore, the data do not support the routine use of genetic testing in the management of patients with CKD. Advances in technology, such as massively parallel gene sequencing, and characterization of alternative modes of inheritance should further elucidate the genetic architecture of CKD and provide tools to improve patient care. PMID- 21712851 TI - Azathioprine-related myelosuppression in a patient homozygous for TPMT*3A. AB - BACKGROUND: A 50-year-old man who had received a simultaneous pancreas and kidney transplant 9 years earlier developed pancytopenia 3 weeks after starting azathioprine therapy to treat worsening proteinuria suspected to be caused by sirolimus. INVESTIGATIONS: Laboratory tests, including complete blood counts, measurement of serum levels of vitamin B(12) and folate, liver function tests, virological assays, and thiopurine S-methyltransferase (TPMT) genotyping. DIAGNOSIS: Severe myelosuppression as a consequence of azathioprine therapy in a patient homozygous for the TPMT*3A allele. MANAGEMENT: Discontinuation of azathioprine, treatment with an erythropoiesis-stimulating agent, red blood cell transfusions, filgrastim (a granulocyte colony-stimulating factor analogue) and folic acid. PMID- 21712852 TI - Early detection of CKD: the benefits, limitations and effects on prognosis. AB - The past decade has seen an increasing focus on chronic kidney disease (CKD) and its attendant complications, which has resulted in improved understanding of their impact on health-care resources. The early detection of CKD has been facilitated by the implementation of routine reporting of estimated glomerular filtration rates (eGFRs) and by education of primary care physicians on the implications of detecting a decreased eGFR with respect to patient safety as well as to cardiovascular and renal outcomes. The goals of early CKD detection are to prevent CKD progression and associated complications, thus improving patient outcomes and reducing the impact of CKD on health-care resources. This Review examines the benefits of the early detection of CKD, and describes the limitations of current knowledge with respect to screening, early detection and treatment, as well as the unintended consequences of detection. In addition, this article highlights what is currently known about cardiovascular and renal outcomes and the effects of intervention in patients with CKD. PMID- 21712853 TI - Balanced into array: genome-wide array analysis in 54 patients with an apparently balanced de novo chromosome rearrangement and a meta-analysis. AB - High-resolution genome-wide array analysis enables detailed screening for cryptic and submicroscopic imbalances of microscopically balanced de novo rearrangements in patients with developmental delay and/or congenital abnormalities. In this report, we added the results of genome-wide array analysis in 54 patients to data on 117 patients from seven other studies. A chromosome imbalance was detected in 37% of all patients with two-breakpoint rearrangements. In 49% of these patients, the imbalances were located in one or both breakpoint regions. Imbalances were more frequently (90%) found in complex rearrangements, with the majority (81%) having deletions in the breakpoint regions. The size of our own cohort enabled us to relate the presence of an imbalance to the clinical features of the patients by using a scoring system, the De Vries criteria, that indicates the complexity of the phenotype. The median De Vries score was significantly higher (P=0.002) in those patients with an imbalance (5, range 1-9) than in patients with a normal array result (3, range 0-7). This study provides accurate percentages of cryptic imbalances that can be detected by genome-wide array analysis in simple and complex de novo microscopically balanced chromosome rearrangements and confirms that these imbalances are more likely to occur in patients with a complex phenotype. PMID- 21712854 TI - Maternally inherited mitochondrial DNA disease in consanguineous families. AB - Mitochondrial respiratory chain disease represents one of the most common inborn errors of metabolism and is genetically heterogeneous, with biochemical defects arising from mutations in the mitochondrial genome (mtDNA) or the nuclear genome. As such, inheritance of mitochondrial respiratory chain disease can either follow dominant or recessive autosomal (Mendelian) inheritance patterns, the strictly matrilineal inheritance observed with mtDNA point mutations or X-linked inheritance. Parental consanguinity in respiratory chain disease is often assumed to infer an autosomal recessive inheritance pattern, and the analysis of mtDNA may be overlooked in the pursuit of a presumed nuclear genetic defect. We report the histochemical, biochemical and molecular genetic investigations of two patients with suspected mitochondrial disease who, despite being born to consanguineous first-cousin parents, were found to harbour well-characterised pathogenic mtDNA mutations, both of which were maternally transmitted. Our findings highlight that any diagnostic algorithm for the investigation of mitochondrial respiratory chain disease must include a full and complete analysis of the entire coding sequence of the mitochondrial genome in a clinically relevant tissue. An autosomal basis for respiratory chain disease should not be assumed in consanguineous families and that 'maternally inherited consanguineous' mitochondrial disease may thus be going undiagnosed. PMID- 21712855 TI - A mild form of Mucopolysaccharidosis IIIB diagnosed with targeted next-generation sequencing of linked genomic regions. AB - Next-generation sequencing (NGS) techniques have already shown their potential in the identification of mutations underlying rare inherited disorders. We report here the application of linkage analysis in combination with targeted DNA capture and NGS to a Norwegian family affected by an undiagnosed mental retardation disorder with an autosomal recessive inheritance pattern. Linkage analysis identified two loci on chromosomes 9 and 17 which were subject to target enrichment by hybridization to a custom microarray. NGS achieved 20-fold or greater sequence coverage of 83% of all protein-coding exons in the target regions. This led to the identification of compound heterozygous mutations in NAGLU, compatible with the diagnosis of Mucopolysaccharidosis IIIB (MPS IIIB or Sanfilippo Syndrome type B). This diagnosis was confirmed by demonstrating elevated levels of heparan sulphate in urine and low activity of alpha-N-acetyl glucosaminidase in cultured fibroblasts. Our findings describe a mild form of MPS IIIB and illustrate the diagnostic potential of targeted NGS in Mendelian disease with unknown aetiology. PMID- 21712856 TI - Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome. AB - Serpentine fibula polycystic kidney syndrome (SFPKS; MIM600330) is a rare skeletal dysplasia that has polycystic kidneys and dysmorphic facies as additional defining phenotypic components. The nosological classification of this disease has been debated as the condition shares features common to other skeletal dysplasias such as Melnick Needles syndrome (MNS; MIM309350) and Hajdu Cheney Syndrome (HCS; MIM102500). Here, two previously reported cases of SFPKS are presented with emphasis on their phenotypic evolution. With the recent discovery that HCS is caused by mutations in NOTCH2, DNA from the both cases was examined and both were found to have truncating mutations in exon 34 of NOTCH2. The phenotypic evolution of SFPKS and this molecular analysis strongly suggest that SFPKS is part of the phenotypic spectrum of HCS and should no longer be classified as a distinct disease entity. PMID- 21712857 TI - Identification of a Gypsy SHOX mutation (p.A170P) in Leri-Weill dyschondrosteosis and Langer mesomelic dysplasia. AB - We report the clinical and molecular characteristics of 12 Spanish families with multiple members affected with Leri-Weill dyschondrosteosis (LWD) or Langer mesomelic dysplasia (LMD), who present the SHOX (short stature homeobox gene) mutation p.A170P (c.508G>C) in heterozygosity or homozygosity, respectively. In all studied families, the A170P mutation co-segregated with the fully penetrant phenotype of mesomelic limb shortening and Madelung deformity. A shared haplotype around SHOX was observed by microsatellite analysis, confirming the presence of a common ancestor, probably of Gypsy origin, as 11 of the families were of this ethnic group. Mutation screening in 359 Eastern-European Gypsies failed to identify any carriers. For the first time, we have shown SHOX expression in the human growth plate of a 22-week LMD fetus, homozygous for the A170P mutation. Although the mutant SHOX protein was expressed in all zones of the growth plate, the chondrocyte columns in the proliferative zone were disorganized with the chondrocytes occurring in smaller columnal clusters. We have also identified a novel mutation at the same residue, c. 509C>A (p.A170D), in two unrelated Spanish LWD families, which similar to A170P mutation impedes nuclear localization of SHOX. In conclusion, we have identified A170P as the first frequent SHOX mutation in Gypsy LWD and LMD individuals. PMID- 21712860 TI - Extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS) in fulminant blastomycosis in Germany. AB - In fulminant blastomycosis with multiorgan failure, the earliest diagnosis possible is crucial for successful treatment. If severe acute respiratory distress syndrome (ARDS) develops, miniaturised veno-venous extracorporeal membrane oxygenation (ECMO) might provide a unique and efficacious possibility to prolong the time frame for diagnosis and the beginning of treatment. This is the first report on a case of fatal blastomycosis in Germany. It reminds us to add exotic infections to the differential diagnosis in patients with refractory pneumonia in the era of worldwide tourism. PMID- 21712861 TI - Endometriosis of the appendix presenting as acute appendicitis. AB - As with other types of endometriosis in the intestinal tract, endometriosis of the appendix is generally asymptomatic and is usually discovered incidentally during laparotomy in patients with pelvic endometriosis. When it presents with symptoms they are difficult to differentiate from acute appendicitis. Appendiceal endometriosis may not only cause symptoms of acute appendicitis, but may also present as cyclic and chronic right lower quadrant pain, melena, lower intestinal haemorrhage and caecal intussusception. We report a case of appendiceal endometriosis clinically presenting as acute appendicitis, where the definitive diagnosis was established by histopathological examination of the appendix. PMID- 21712862 TI - Emerging concepts in post-operative pain management. PMID- 21712863 TI - Ropivacaine: A review of its pharmacology and clinical use. AB - Ropivacaine is a long-acting amide local anaesthetic agent and first produced as a pure enantiomer. It produces effects similar to other local anaesthetics via reversible inhibition of sodium ion influx in nerve fibres. Ropivacaine is less lipophilic than bupivacaine and is less likely to penetrate large myelinated motor fibres, resulting in a relatively reduced motor blockade. Thus, ropivacaine has a greater degree of motor sensory differentiation, which could be useful when motor blockade is undesirable. The reduced lipophilicity is also associated with decreased potential for central nervous system toxicity and cardiotoxicity. The drug displays linear and dose proportional pharmacokinetics (up to 80 mg administered intravenously). It is metabolised extensively in the liver and excreted in urine. The present article details the clinical applications of ropivacaine and its current place as a local anaesthetic in the group. PMID- 21712864 TI - American Society of Anaesthesiologists physical status classification. AB - Although the American Society of Anaesthesiologists' (ASA) classification of Physical Health is a widely used grading system for preoperative health of the surgical patients, multiple variations were observed between individual anaesthetist's assessments when describing common clinical problems. This article reviews the current knowledge and evaluation regarding ASA Classification of Physical Health as well as trials for possible modification. PMID- 21712866 TI - Erratum: ERRATUM. AB - [This corrects the article on p. 478 in vol. 54, PMID: 21189893.][This corrects the article on p. 52 in vol. 54, PMID: 20532074.]. PMID- 21712865 TI - Dexmedetomidine and clonidine in epidural anaesthesia: A comparative evaluation. AB - Efforts to find a better adjuvant in regional anaesthesia are underway since long. Aims and objectives are to compare the efficacy and clinical profile of two alpha-2 adrenergic agonists, dexmedetomidine and clonidine, in epidural anaesthesia with special emphasis on their sedative properties and an ability to provide smooth intra-operative and post-operative analgesia. A prospective randomized study was carried out which included 50 adult female patients between the ages of 44 and 65 years of (American Society of Anaesthesiologists) ASAI/II grade who underwent vaginal hysterectomies. The patients were randomly allocated into two groups; ropivacaine + dexmedetomidine (RD) and ropivacaine + clonidine (RC), comprising of 25 patients each. Group RD was administered 17 ml of 0.75% epidural ropivacaine and 1.5 MUg/kg of dexmedetomidine, while group RC received admixture of 17 ml of 0.75% ropivacaine and 2 MUg/kg of clonidine. Onset of analgesia, sensory and motor block levels, sedation, duration of analgesia and side effects were observed. The data obtained was subjected to statistical computation with analysis of variance and chi-square test using statistical package for social science (SPSS) version 10.0 for windows and value of P < 0.05 was considered significant and P < 0.0001 as highly significant. The demographic profile, initial and post-operative block characteristics and cardio-respiratory parameters were comparable and statistically non-significant in both the groups. However, sedation scores with dexmedetomidine were better than clonidine and turned out to be statistically significant (P < 0.05). The side effect profile was also comparable with a little higher incidence of nausea and dry mouth in both the groups which was again a non-significant entity (P > 0.05). Dexmedetomidine is a better neuraxial adjuvant compared to clonidine for providing early onset of sensory analgesia, adequate sedation and a prolonged post-operative analgesia. PMID- 21712868 TI - The comparison of Proseal laryngeal mask airway and endotracheal tube in patients undergoing laparoscopic surgeries under general anaesthesia. AB - Aims to compare the efficacy of Proseal laryngeal mask airway(PLMA) and endotracheal tube (ETT) in patients undergoing laparoscopic surgeries under general anaesthesia. This prospective randomised study was conducted on 60 adult patients, 30 each in two groups, of ASA I-II who were posted for laparoscopic procedures under general anaesthesia. After preoxygenation, anaesthesia was induced with propofol, fentanyl and vecuronium. PLMA or ETT was inserted and cuff inflated. Nasogastric tube (NGT) was passed in all patients. Anaesthesia was maintained with N(2) O, O(2), halothane and vecuronium. Ventilation was set at 8 ml/kg and respiratory rate of 12/min. The attempts and time taken for insertion of devices, haemodynamic changes, oxygenation, ventilation and intraoperative and postoperative laryngopharyngeal morbidity (LPM) were noted. There was no failed insertion of devices. Time taken for successful passage of NGT was 9.77 s (6-16 s) and 11.5 s (8-17 s) for groups P and E, respectively. There were no statistically significant differences in oxygen saturation (SpO(2)) or end-tidal carbon dioxide (EtCO(2)) between the two groups before or during peritoneal insufflation. Median (range) airway pressure at which oropharyngeal leak occurred during the leak test with PLMA was 35 (24-40) cm of H(2)O. There was no case of inadequate ventilation, regurgitation, or aspiration recorded. No significant difference in laryngopharyngeal morbidity was noted. A properly positionedPLMA proved to be a suitable and safe alternative to ETT for airway management in elective fasted, adult patients undergoing laparoscopic surgeries. It provided equally effective pulmonary ventilation despite high airway pressures without gastric distention, regurgitation, and aspiration. PMID- 21712867 TI - Prevention and management of ventilator-associated pneumonia: A survey on current practices by intensivists practicing in the Indian subcontinent. AB - Implementation of evidence-based guidelines to prevent and manage ventilator associated pneumonia (VAP) in the clinical setting may not be adequate. We aimed to assess the implementation of selected VAP prevention strategies, and to learn how VAP is managed by the intensivists practicing in the Indian Subcontinent. Three hundred 10-point questionnaires were distributed during an International Critical Care Conferenceheld at New Delhi in 2009. A total of 126 (42%) questionnaires distributed among delegates from India, Nepal and Sri Lanka were analyzed. Majority (96.8%) reported using VAP bundles with a high proportion including head elevation (98.4%), chlorhexidine mouthcare (83.3%), stress ulcer prophylaxis (96.8%), heat and moisture exchangers (HME, 92.9%), early weaning (94.4%), and hand washing (97.6%) as part of their VAP bundle. Use of subglottic secretion drainage (SSD, 45.2%) and closed suction systems (CSS, 74.6%) was also reported by many intensivists, whereas use of selective gut decontamination was reported by only 22.2%. Commonest method for sampling was endotracheal suction by 68.3%. Gram negative organisms were reported to be the most commonly isolated. Majority (39.7%) reported using proton pump inhibitors for stress ulcer prophylaxis and 84.1% believed that VAP contributed to increased mortality. De escalating therapy was considered in patients responding to treatment by 57.9% and 65.9% considered adding empirical methicillin resistant Staphylococcus aureus (MRSA)coverage, while 63.5% considered adding nebulized antibiotics in certain high-risk patients. There was good concordance regarding VAP prophylaxis among the intensivists with a majority adhering to evidence-based guidelines. We could identify certain issues like the choice of agent for stress ulcer prophylaxis, use of HME filters, SSD and CSS, where there still exists some practice variability and opportunities for improvement. PMID- 21712869 TI - Comparative evaluation of atenolol and clonidine premedication on cardiovascular response to nasal speculum insertion during trans-sphenoid surgery for resection of pituitary adenoma: A prospective, randomised, double-blind, controlled study. AB - Severe cardiovascular responses in the form of tachycardia and hypertension following nasal speculum insertion occur during sublabial rhinoseptal trans sphenoid approach for resection of small pituitary tumours. We compare the effects of preoperative administration of clonidine (alpha-2 agonist) and atenolol (alpha-blocker) over haemodynamic response, caused by speculum insertion during trans-sphenoid pituitary resection. We enrolled 66 patients in age range 18-65 years, of ASA I-II, and of either sex undergoing elective sublabial rhinoseptal trans-sphenoidal hypophysectomy. Group I (control) received placebo, group II (clonidine) received tablet clonidine 5 ug/kg, and group III (atenolol) received tablet atenolol 0.5 mg/kg. The heart rate increased on speculum insertion and 5 and 10 minutes following speculum insertion as compared to the pre-speculum values in the control group, while no change in the heart rate was observed in other groups (P<0.05). There was a rise in the mean arterial pressure during and 5, 10, and 15 minutes after nasal speculum insertion in the control group, whereas it was not seen in other groups (P<0.05). We therefore suggest that oral clonidine and oral atenolol (given 2 hours prior to surgery) is an equally effective and safe method of attenuating haemodynamic response caused by nasal speculum insertion during trans-sphenoid pituitary resection. PMID- 21712870 TI - Role of epidural ketamine for postoperative analgesia after upper abdominal surgery. AB - Ketamine, a N-methyl-D-aspartate receptor antagonist inhibits central sensitization due to peripheral nociception thus potentiating the analgesic effect of morphine. The purpose of our study was to evaluate the effect of adding small-dose ketamine in a multimodal regimen of postoperative patient-controlled epidural analgesia (PCEA). One hundred patients of American Society of Anesthesiologists physical status I-II, undergoing major upper abdominal surgery were randomly allocated to two groups. Group I received PCEA device containing bupivacaine hydrochloride 0.0625% and morphine sulphate (preservative free) 0.05mg/ml. Group II received PCEA device containing bupivacaine hydrochloride 0.0625%, morphine sulphate (preservative free) 0.05 mg/ml and ketamine hydrochloride (preservative free) 0.2 mg/ml. The mean morphine consumption in group I after 1(st)and 2(nd)postoperative day was 8.38+/-2.85 and 7.64+/-1.95 mg, respectively, compared to 6.81+/-1.35 and 6.25+/-1.22 mg (P<0.05) in group II. Although group II consumed significantly less morphine, pain relief at rest and at movement after 6, 12, 24 and 48 hours, postoperatively was significantly better in group II (P<0.05) than in group I. These findings suggest that adding small-dose ketamine to a multimodal PCEA regimen provides better postoperative analgesia and reduces morphine consumption. PMID- 21712871 TI - Obstetric critical care: A prospective analysis of clinical characteristics, predictability, and fetomaternal outcome in a new dedicated obstetric intensive care unit. AB - A 1 year prospective analysis of all critically ill obstetric patients admitted to a newly developed dedicated obstetric intensive care unit (ICU) was done in order to characterize causes of admissions, interventions required, course and foetal maternal outcome. Utilization of mortality probability model II (MPM II) at admission for predicting maternal mortality was also assessed. During this period there were 16,756 deliveries with 79 maternal deaths (maternal mortality rate 4.7/1000 deliveries). There were 24 ICU admissions (ICU utilization ratio 0.14%) with mean age of 25.21+/-4.075 years and mean gestational age of 36.04+/ 3.862 weeks. Postpartum admissions were significantly higher (83.33% n=20, P<0.05) with more patients presenting with obstetric complications (91.66%, n=22, P<0.01) as compared to medical complications (8.32% n=2). Obstetric haemorrhage (n=15, 62.5%) and haemodynamic instability (n=20, 83.33%) were considered to be significant risk factors for ICU admission (P=0.000). Inotropic support was required in 22 patients (91.66%) while 17 patients (70.83%) required ventilatory support but they did not contribute to risk factors for poor outcome. The mean duration of ventilation (30.17+/-21.65 h) and ICU stay (39.42+/-33.70 h) were of significantly longer duration in survivors (P=0.01, P=0.00 respectively) versus non-survivors. The observed mortality (n=10, 41.67%) was significantly higher than MPM II predicted death rate (26.43%, P=0.002). We conclude that obstetric haemorrhage leading to haemodynamic instability remains the leading cause of ICU admission and MPM II scores at admission under predict the maternal mortality. PMID- 21712872 TI - Jaw lift causes less laryngeal interference during lightwand-guided intubation than combined jaw and tongue traction applied by single operator. AB - Lightwand-guided intubation is a semi-blind technique that takes advantage of the anterior location of the trachea in relation to the oesophagus. Fibreoptic evaluation of lightwand-guided intubation has revealed a possibility of laryngeal interference and epiglottic distortion. Jaw lift, tongue traction or a combination of both have been used to assist in lightwand-guided intubation. This study fibreoptically evaluates lightwand-guided intubation using jaw lift and combined jaw and tongue traction. Eighty four patients with normal airway undergoing general anaesthesia were studied. This randomised, double blinded, cross over study was done in two phases. First phase - after achieving adequate depth of anaesthesia, a fibrescope was advanced nasally, and lightwand-guided intubation was carried out under direct fibreoptic visualisation with the aid of either jaw lift or combined jaw and tongue traction. Second phase - Extubation followed by reintubation using the other manoeuvre. Interference with laryngeal structures during intubation and position of the epiglottis at the end of intubation were noted. Epiglottic distortion (deviated to one side/infolded into trachea) was observed in 6 patients with jaw lift and 17 patients with combined jaw and tongue traction (P=0.003). Laryngeal interference was significantly higher (P=0.012) with combined manoeuvre (30/78) than with jaw lift alone (9/81). Although lightwand-guided intubation can be performed quickly and easily, interference with laryngeal structures and distortion of the epiglottis can occur. Jaw lift manoeuvre causes less laryngeal interference than combined jaw and tongue traction applied by a single operator. PMID- 21712873 TI - Axillary brachial plexus blockade in moyamoya disease? AB - Moyamoya disease is characterized by steno-occlusive changes of the intracranial internal carotid arteries. Cerebral blood flow and metabolism are strictly impaired. The goal in perioperative anaesthetic management is to preserve the stability between oxygen supply and demand in the brain. Peripheral nerve blockade allows excellent neurological status monitoring and maintains haemodynamic stability which is very important in this patient group. Herein, we present an axillary brachial plexus blockade in a moyamoya patient operated for radius fracture. PMID- 21712874 TI - Pleural puncture with thoracic epidural: A rare complication? AB - Freedom from pain has almost developed to be a fundamental human right. Providing pain relief via epidural catheters in thoracic and upper abdominal surgeries is widely accepted. Pain relief through this technique not only provides continuous analgesia but also reduces post-operative pulmonary complications and also hastens recovery. But being a blind procedure it is accompanied by certain complications. Hypotension, dura puncture, high epidural, total spinal, epidural haematoma, spinal cord injury and infection are some of the documented side effects of epidural block. There are case reports eliciting neurological complications, catheter site infections, paresthesias, radicular symptoms and worsening of previous neurological conditions. Few technical problems related to breakage of epidural catheter are also mentioned in the literature. The patient had no sequelae on long term follow up even when a portion of catheter was retained. We present a case report where epidural catheter punctured pleura in a patient undergoing thoracotomy for carcinoma oesophagus. PMID- 21712876 TI - Hydatidiform mole: A sour encounter with a grapy case. AB - Hydatidiform mole cases are usually uncomplicated. However, few cases can be associated with perioperative complications of a critical nature, which can lead to substantial mortality and morbidity. Here is a report of one such case, which, in spite of extensive perioperative management, led to mortality. PMID- 21712875 TI - Patient with Wolff-Parkinson-White syndrome with intermittent pre-excitation under subarachnoid block for urological surgery. AB - Wolff-Parkinson-White (WPW) syndrome is one of the pre-excitation syndromes in which activation of an accessory atrioventricular (AV) conduction pathway leads to bypass the AV node and cause earlier ventricular activation than the normal pathway. We report a patient with intermittent WPW syndrome who repeatedly manifested pre-excitation after subarachnoid block. PMID- 21712877 TI - Nonconvulsive status epilepticus: An unusual cause of postoperative unresponsiveness following general anaesthesia. AB - Any altered behaviour or sensorium following general anaesthesia is of concern to the anaesthesiologist, as it could be attributed to the anaesthetic itself or to a hypoxic insult, both of which can have medicolegal implications. It is important to be aware of a relatively unfamiliar entity known as nonconvulsive status epilepticus in this context. We report two cases to highlight this condition. PMID- 21712878 TI - Anaesthesia for the separation of conjoined twins. AB - Thoraco-omphalopagus is one of the most common type of conjoint twins accounting for 74% cases of conjoint twins. We report the anaesthetic management for successful separation of thoraco-omphalopagus conjoint twins, both of them surviving till date. We highlight the responsibility of anaesthesia team in anaesthetising the two individual patients simultaneously, need of careful monitoring and anticipation of complications like massive blood loss, hypotension, hypokalemia, hypoxia and hypercabia. Detailed description of successful management is reported. PMID- 21712879 TI - Differential blockade to assess surgical repair by intraoperative active mobilization in knee injuries-Beyond labour analgesia. AB - Motor-sparing selective epidural analgesia has long been practised in the field of labour analgesia. However, the utility of such techniques in other fields remain limited. We present the successful use of a similar technique of differential blockade in a case of quadriceps plasty with realignment of patella for recurrent dislocation of patella. A very low concentration of bupivacaine and fentanyl was used through continous epidural. The adequacy of repair was assessed intraoperatively by active movement of operated limb by patient himself. PMID- 21712880 TI - Catatonia and jaw dislocation in the postoperative period with epidural morphine. AB - We report a case of temporomandibular joint dislocation occurring in the postoperative period in a patient, who developed catatonia following administration of a single dose of epidural morphine. The catatonic response to epidural morphine was delayed by several hours in the postoperative period, and might have resulted from intrathecal migration of the drug, through an initial dural puncture while locating the epidural space. The temporomandibular joint dislocation was diagnosed only after reversal of the effects of morphine with naloxone, when the patient complained of inability to fully close her mouth. PMID- 21712881 TI - Anaesthetic management of a patient with Eisenmenger syndrome and beta thalassemia major for splenectomy. AB - We describe for the first time, the perioperative care of a patient with a rare combination of Eisenmenger syndrome with beta-thalassemia major presenting for splenectomy. Patients with Eisenmenger syndrome have polycythemia because of chronic hypoxia but our patient was anaemic and had thrombocytopenia because of thalassemia major. The management of such a case can be challenging for any anaesthesiologist because of severe V/Q mismatch (high shunt fraction and restrictive lung disease because of hypersplenism), decreased oxygen carrying capacity (anaemia) and increased risk of haemorrhage (thrombocytopenia), along with the potential increase in intracardiac shunt during anaesthesia. PMID- 21712882 TI - Metformin poisoning: A complex presentation. AB - The objective of this case report is to highlight presentation, complications and treatment of metformin poisoning. Patient after ingestion of 45gms of metformin developed colicky abdominal pain, severe tachypnea and vomiting. He developed severe lactic acidosis, cardiac arrest, pancreatitis and hemolytic anemia which was treated with charcoal, sodium bicarbonate, early initiation of high volume continuous veno-venous hemofiltration and supportive therapy. Metformin poisoning is a rare presentation and we discuss course of events in the management of metformin poisoning and its associated complications. PMID- 21712883 TI - Comparison of oscillometric blood pressure measurement by two clinical monitors: Datex Ohmeda GE S/5 and Criticare 8100E nGenuity. PMID- 21712884 TI - Indigenous coated needle for nerve block. PMID- 21712885 TI - Fibreoptic aided retrograde intubation in an oral cancer patient. PMID- 21712886 TI - Paediatric face mask for adult ventilation in presence of nasal tumours. PMID- 21712887 TI - Life-threatening haemolysis in a patient with acute copper sulphate poisoning. PMID- 21712888 TI - Tri-colour concept with the use of LMA CTrach. PMID- 21712889 TI - Ramp position for intubating morbidly obese parturient: What's new? PMID- 21712890 TI - Use of LMA as ventilatory device for PCT: Our experience. PMID- 21712891 TI - Patient with post infective demyelinating disease for dynamic hip screw repair under epidural anaesthesia. PMID- 21712892 TI - Femoral sciatic block: A safe alternative in von Recklinghausen's disease. PMID- 21712893 TI - Fracture of first rib after sternotomy. PMID- 21712894 TI - Role of amino acid infusion in delayed recovery from neuromuscular blockers. PMID- 21712895 TI - Guidewire impaction during percutaneous dilatational tracheostomy. PMID- 21712896 TI - The Role of Liquid-crystalline Structures in the Morphogenesis of Animal Fibers. AB - The role of liquid-crystalline (mesophase) structures in extra-cellular morphogenesis is widely recognized. This paper summarizes a model for the more unusual case of intra-cellular mesophases. In the nascent mammalian hair cortex, cell differentiation is correlated with different mesophase textures within tactoids that are composed of intermediate filaments (IFs), and which form by a concerted process of unit-length-filament (ULF) polymerization and phase separation. Nematic and double-twist textures arise from differences in mesogen orientation and length in apposed tactoids. The model explains features of mature structures such as the fibril-matrix ratios in different cell types. The rapidity of IF formation suggests that a sudden-transition equilibrium polymerization, involving a high-energy initiating species, obeying the same statistical model as several other biological transitions, may be involved. This leads to an appealing symmetry, with the key factor in both polymerization and mesophase stability being the retention of protein head-group entropy. PMID- 21712897 TI - Emerging issues with the current keratin-associated protein nomenclature. AB - Keratin associated proteins (KAPs) are a class of proteins that associate with keratin intermediate filament proteins through disulphide linkages to give fibres such as hair and wool their unique properties. Up to 90 proteins from some 25 families have been identified and this does not include polymorphic variants of individual proteins within these families. The existence of this diverse group of proteins has been known for some 75 years but, despite this, there is still no universally accepted nomenclature for them. This paper sets out the case for revising the current system to deal with this nomenclature issue. PMID- 21712898 TI - Turban PUVASOL: An Effective Treatment in Alopecia Totalis. AB - Alopecia areata is characterized by patchy hair loss involving the scalp, eyelashes, and beard. The disease may at times lead to complete baldness of the scalp (alopecia totalis) or of the entire body (alopecia universalis). Alopecia totalis is usually resistant to therapy. We report two cases of alopecia totalis treated with turban psoralen with sunlight exposure (PUVASOL). PMID- 21712899 TI - An extraordinary colocalization of alopecia areata and vitiligo. AB - Although the association of alopecia areata (AA) and vitiligo occurring in the same patient has been frequently reported in the literature, the colocalization of AA and vitiligo is very rare. We report for the first time an adult patient with anatomic concurrence of AA and vitiligo on the scalp. Even though both AA and vitiligo are thought to have the same underlying pathophysiologic mechanisms, the striking rarity of their colocalization challenges this postulated common pathogenesis, and raises the question if autoimmunity is responsible for only a fraction of AA or vitiligo. PMID- 21712900 TI - Plica Neuropathica (Plica polonica) Following Azathioprine-induced Pancytopenia. AB - A 54-yr-old woman, on azathioprine for interstitial lung disease, developed pancytopenia and presented with sudden onset of extensive hair loss from the scalp followed overnight by appearance of elongated broad mass of uncombable matted hair which had the typical appearance of Plica neuropathica. Microscopic examination of hair clipped from the matted mass revealed irregular, nodal, superficial fractures of the hair shaft resembling Trichorrhexis nodosa and irregular ruffling of the cuticles. The areas of cuticular damage appeared dark under polarized light. Plica neuropathica following pancytopenia is unusual and the findings of hair shaft cuticular damage suggests that changes in surface characteristics of hair shafts may have led to the irreversible matting leading to development of plica along with extensive hair loss due to anagen effluvium. PMID- 21712901 TI - Pityriasis amiantacea-like eruptions in scalp: a novel manifestation of pityriasis rosea in a child. AB - Unusual clinical features are known in pityriasis rosea (PR). We report a case of a child who presented with onset of PR in scalp, clinically mimicking pityriasis amiantacea. Careful clinical observations and follow-up led us to appropriate diagnosis. PMID- 21712902 TI - Intermammary pilonidal sinus. PMID- 21712903 TI - Radiation-induced Alopecia. PMID- 21712904 TI - Hair Growth-Combing through the Various Determinants. PMID- 21712905 TI - Hair specialist, trichologist or dermato-trichologist? PMID- 21712906 TI - Hair India 2010. PMID- 21712907 TI - Invitation to the 15 annual meeting of the European hair research society, jerusalem, Israel, july 6-9, 2011. PMID- 21712908 TI - Androgenetic Alopecia: Quality-of-life and Associated Lifestyle Patterns. AB - BACKGROUND: Androgenetic alopecia (AGA) is a condition, which is an important psychosocial problem. The hormonal variations causing AGA are known, but whether behavioral patterns and lifestyle influence the condition and which age groups they influence is uncertain and such factors have not been studied in detail. OBJECTIVES: To compare association of lifestyle patterns with androgenetic alopecia, prevalence of psychiatric symptoms and resulting quality-of-life (QoL) between two age groups of males with AGA. MATERIALS AND METHODS: Male subjects in each of the two age groups attending the hair clinic diagnosed with AGA were administered a questionnaire on lifestyle patterns. HAIRDEX and symptom checklist 90 (SCL-90) to study the presence of psychosocial problems and QoL were used. The stress experienced by such patients was studied by a stressful life events scale. RESULTS: Of the 37 patients studied, 23 were in younger age group (average age) and 14 were in the older age group (average age). No significant difference was found in lifestyle, as far as eating habits, physical activity, occupational activity and leisure time were concerned. However, the younger age group had a significantly better psychological health. (P=0.013). On assessing the QoL, self assurance seemed better in younger age group (P=0.014), reflecting changing societal trends, causing better acceptance of hair loss. On the other subscales, emotions seemed to be more affected in the younger age group, while older patients had worse functioning, more symptoms and more sense of stigmatization. On assessing SCL-90, no significant psychopathological difference was found between both the groups; however the older patients appeared to have more psychological symptoms on almost all scales scoring highly on obsessive compulsive, interpersonal sensitivity and depression subscales. No significant difference in stressful life events at the time of onset of alopecia was noticed although older patients scored higher on this scale. Family history was found to be significantly associated with the onset of alopecia (P=0.0448). CONCLUSIONS: We concluded that lifestyle factors and stressful life events are not significantly affected by the onset of AGA. Only heredity seems to be associated with hair loss. Quality-of-life is affected in both the age groups but younger patients seem to have better self-assurance as well as better psychological health. PMID- 21712909 TI - Bimatoprost in the treatment of eyelash universalis alopecia areata. AB - OBJECTIVES: To evaluate topical bimatoprost for eyelash growth in patients with alopecia areata (AA). DESIGN: A 1-year retrospective study, bilateral eyelash alopecia. MATERIALS AND METHODS: Forty-one subjects with AA universalis without ocular disease applied 0.03% bimatoprost to the eyelid margin once a day over the course of 1 year. RESULTS: Thirty-seven subjects completed the study, one patient was eliminated due to conjunctivitis at the beginning of treatment, two patients developed conjunctivitis after 6 months of treatment, and a fourth did not follow directions. Researchers evaluated patients' eyelash growth every 4 months. We observed complete growth in 24.32%, moderate growth in 18.91%, slight growth in 27.02% and without response in 29.72%. CONCLUSION: Bimatoprost may be effective and safe in the treatment of eyelash AA. 43.24% of the patients had an acceptable cosmetic response (total and moderate growth). LIMITATIONS: Design without control. PMID- 21712910 TI - Location of Keratin-associated Proteins in Developing Fiber Cuticle Cells using Immunoelectron Microscopy. AB - AIMS: To investigate the location of keratin-associated proteins (KAPs) in developing hair fiber cuticle cells using transmission electron microscopy with immunogold techniques and specific antibodies. Other studies were aimed at detecting the presence of cornified envelope proteins including involucrin and loricrin. MATEIALS AND METHODS: Polyclonal antibodies were produced in rabbits against peptides from KAPS 5.1, KAPS 10.1 ultra high-sulfur proteins. RESULTS: The KAP proteins were found to form part of the developing exocuticle and a- layer. Cornified envelope proteins (involucrin and loricrin) were absent consistent with recent findings. CONCLUSIONS: The results have been discussed in terms of a revised model for fiber cuticle surface barriers including their role in fiber cuticle surface function. PMID- 21712912 TI - Nuclear medicine in sports. PMID- 21712911 TI - Loose anagen hair syndrome. AB - Loose anagen syndrome (LAS) is a benign, self-limiting condition where anagen hairs are easily and painlessly extracted. It is mainly reported in childhood; however, it may variably present in adulthood as well. The presence of anagen hair devoid of its sheath and with 'floppy sock appearance' is a characteristic feature of loose anagen hair (LAH) on trichogram. LAH can be seen in normal population and in alopecia areata. The percentage of LAH in LAS is more than 50%. The histopathological findings show clefting between the layers of hair and are very useful in differentiating LAS from alopecia areata. Here, a review on the diagnostic criteria and practical guidelines are discussed so as to enable the trichologist in managing this benign, self-limiting condition and differentiating it from the other causes of non-scarring alopecias. PMID- 21712913 TI - Metastasis of follicular thyroid carcinoma to the maxillary sinus. AB - Thyroid carcinoma metastatic to the paranasal sinuses is extremely rare. We report a case of follicular thyroid carcinoma metastatic to the right maxillary sinus, with extension into the right side of the hard palate in a young lady. A radioactive iodine-131 (I-131) scan post total thyroidectomy revealed 0.8% uptake in the neck; the whole body scan revealed a functioning metastasis in the region of the right maxillary antrum. Pathological confirmation of metastasis was done by correlating the fine needle aspirate cytology with the thyroidectomy histology. The patient initially received 40 Gy of external beam radiotherapy, subsequently, she received 110 millicuries of I-131, followed by 50 millicuries 6 months later. She continues to be on follow-up on EltroxinTM suppression and has remained disease free for the past 4 1/2 years. PMID- 21712914 TI - Metastatic involvement of the spleen in differentiated carcinoma of thyroid. AB - Splenic metastasis in differentiated thyroid carcinoma is rare occurrence. We describe an unusual case of diffuse metastatic splenic involvement with normal hematological indices in differentiated thyroid carcinoma demonstrated by post therapy whole body radioiodine scan. PMID- 21712915 TI - New Intraspinal cause of physiological FDG uptake. AB - We present a paediatric case of Papillary Ca thyroid under evaluation for elevated Thyroglobulin (Tg) level with negative (131)I wholebody scintigraphy. Differentiated thyroid cancer (DTC) arises from follicular epithelium and retains basic biological features like expression of sodium iodide symporter (NIS), which is the cellular basis of radio iodine ((131)I) concentration during thyroid ablation. Once dedifferentiation of thyroid cells occurs, cells fail to concentrate (131)I, posing both diagnostic and therapeutic problems in DTC and one may have to resort to other imaging techniques for disease localization. As DTC progression is slow, patients have a relatively good prognosis. However children with thyroid malignancies need aggressive management, as initial presentation itself maybe with nodal metastases. It is well known that FDG PET CT apart from its oncological applications, is also used in the evaluation of vascular inflammation especially Takayasu's arteritis. It is also reported in literature, that (18)F-FDG uptake can be seen relatively frequently in the arterial tree of cancer patients. Dunphy et al reported the association of vascular FDG uptake in inflammation as well as in normal arteries. This study typically describes FDG uptake in a patchwork of normal vessel, focal inflammation and or calcification of vessels. The other plausible reasons for significant vascular (18)F-FDG uptake are drugs such as potent non steroidal anti inflammatory agents, dexamethasone, prednisone and tacrolimus. Our patient showed false positive (18)F Fluorodeoxyglucose (FDG) uptake in spinal cord at D11/12 and D12/L1 vertebral levels in FDG PET CT imaging performed as part of raised Thyroglobulin workup. This intra spinal FDG uptake is attributed to physiological uptake and inadequate FDG clearance from artery of Adamkiewicz, which can be added as a new physiological cause of FDG uptake unreported in literature as yet. PMID- 21712916 TI - Cervical extension of the thymus mimicking metastatic recurrence of Ewing sarcoma on PET/CT. AB - Occasionally the thymus may extend in the neck, from its normal location in the anterior mediastinum. The cervical extension, especially when the native thymus is hyperplastic, can mimic a mass. We describe the detection of cervical extension of the hyperplastic thymus, presenting as a suspicious recurrent soft tissue mass in the neck in a patient with Ewing's sarcoma. PMID- 21712917 TI - Increased renal corticomedullary FDG activity in a patient of NHL-malignant or benign? AB - Authors describe diagnostic dilemma of differentiating pyelonephritis with lymphomatous involvement of kidney in a known case of lymphoma. FDG uptake pattern was non-discriminatory and pyelonephritis diagnosed retrospectively on follow up study. Authors emphasize the importance of recognition of features and subtle clues of infection evident on CT component of PET-CT. PMID- 21712918 TI - Role of percutaneous closed needle pleural biopsy among patients of undiagnosed exudative pleural effusion. AB - BACKGROUND: Sometimes etiological diagnosis of pleural effusion is difficult despite cytological, biochemical and microbiological tests and labeled as undiagnosed exudative pleural effusions.Aim of present study was to make an etiological diagnosis of pleural effusion. MATERIALS AND METHODS: Study group included patients of exudative pleural effusion where etiological diagnosis could not be yielded by conventional cytological, biochemical and microbiological investigations. Pleural tissue was obtained by Cope's pleural biopsy needle and or thoracoscopy. Pleural biopsy was subjected to histopathology, ZN staining and culture to find the mycobacterium tuberculosis. RESULTS: Out of 25 patients, 17 (68%) and 8 (32%) were male and female, respectively. Age ranged from 15 to 65 years (mean 31.72). Mean value of serum and pleural fluid LDH was 170.56 U/L and 1080.28 U/L, respectively. Histopathology of 9 (36%) showed epitheloid granuloma with caseation necrosis. In other 9 (36%) patients, epitheloid granulomas (with or without giant cells) was reported. In 5 (20%) patients, histopathology report was of nonspecific chronic inflammation. Histopathology was reported as normal in one case; it turned out to be a case of malignancy. In two (8%) patients, pleural tissue obtained was inadequate for opinions; however, other tests revealed malignancy in one and tuberculosis in other. Ziehl-Neelsen (ZN) stain was positive for AFB in two patients and culture of pleural tissue showed presence of Mycobacterium tuberculosis in three patients. CONCLUSIONS: The role of percutaneous closed needle biopsy of pleura among patients of undiagnosed exudative pleural effusion is still accepted as a diagnostic tool, as this may lead to a specific diagnosis among 76% of cases. This is of particular importance in a developing country like India where the facilities of thoracoscopy and imaging guided cutting needle biopsies are not easily available. PMID- 21712919 TI - Echocardiographic evaluation of heart in chronic obstructive pulmonary disease patient and its co-relation with the severity of disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) has considerable effects on cardiac functions, including those of the right ventricle, left ventricle, and pulmonary blood vessels. Most of the increased mortality associated with COPD is due to cardiac involvement. Echocardiography provides a rapid, noninvasive, portable, and accurate method to evaluate the cardiac changes. AIMS: To assess the cardiac changes secondary to COPD by echocardiography and to find out the correlation between echocardiographic findings and severity of COPD, if there is any. MATERIALS AND METHODS: A total 40 of patients of COPD were selected and staged by pulmonary function test (PFT) and evaluated byechocardiography. RESULTS: On echocardiographic evaluation of COPD, 50% cases had normal echocardiographic parameters. Measurable tricuspid regurgitation (TR) was observed in 27/40 cases (67.5%). Pulmonary hypertension (PH), which is defined as systolic pulmonary arterial pressure (sPAP)> 30 mmHg was observed in 17/27 (63%) cases in which prevalence of mild, moderate, and severe PH were 10/17 (58.82%), 4/17 (23.53%), and 3/17 (17.65%), respectively. The frequencies of PH in mild, moderate, severe, and very severe COPD were 16.67%, 54.55%, 60.00%, and 83.33%, respectively. Right atrial pressure was 10 mmHg in 82.5% cases and 15 mmHg in 17.5% cases. Cor pulmonale was observed in 7/17 (41.17%) cases; 7.50% cases had left ventricle (LV) systolic dysfunction and 47.5% cases had evidence of LV diastolic dysfunction defined as A >= E (peak mitral flow velocity of the early rapid filling wave (E), peak velocity of the late filling wave caused by atrial contraction (A) on mitral valve tracing) Left ventricle hypertrophy was found in 22.5% cases. CONCLUSION: Prevalence of PH has a linear relationship with severity of COPD and severe PH is almost associated with cor pulmonale. Echocardiography helps in early detection of cardiac complications in COPD cases giving time for early interventions. PMID- 21712920 TI - Can bronchial asthma be classified based on the immunological status? AB - BACKGROUND: Bronchial asthma is a chronic disorder of the airways. Bronchial asthma can be broadly categorized into atopic and nonatopic based on the immunological status, which may be helpful to plan appropriate treatment. In this study, the cytokine profile of the blood was estimated to evaluate the difference between the atopic and the nonatopic asthmatics. AIM: The aim was to document the differences in cytokine (IL-6, TNF-alpha, and IFN-gamma) imbalance in asthmatics with high serum immunoglobulin E (IgE) levels compared to those with normal serum IgE. MATERIALS AND METHODS: Thirty confirmed bronchial asthmatics (17 men, 13 women) were included in this study. The serum levels of IgE, IFN-gamma TNF-alpha, and IL-6 were measured using the enzyme-linked immunosorbent assay technique. They were divided into two groups based on serum IgE: asthmatics with normal serum IgE levels as group A (n = 7) and high IgE levels as group B (n = 23). RESULTS: : The differences in the mean values of IgE, TNF-alpha, and IFN-gamma were statistically significant between the groups. These values were significantly higher in group B compared to group A. IL-6 was not significantly different between the groups. In group A, IL-6 was negatively correlated with IgE and IFN-gamma. IgE and IFN-gamma were positively correlated. In group B, IFN gamma and TNF-alpha showed a high correlation of +0.93. CONCLUSION: Two groups of asthmatics stratified according to their serum IgE levels were immunologically different showing different profiles of serum cytokine levels and the relationship between the cytokines. PMID- 21712921 TI - Corticosteroids and ARDS: A review of treatment and prevention evidence. AB - To systematically review the role of corticosteroids in prevention of acute respiratory distress syndrome (ARDS) in high-risk patients, and in treatment of established ARDS. Primary articles were identified by English-language Pubmed/MEDLINE, Cochrane central register of controlled trials, and Cochrane systemic review database search (1960-June 2009) using the MeSH headings: ARDS, adult respiratory distress syndrome, ARDS, corticosteroids, and methylprednisolone (MP). The identified studies were reviewed and information regarding role of corticosteroids in prevention and treatment of ARDS was evaluated. Nine trials have evaluated the role of corticosteroid drugs in management of ARDS at various stages. Of the 9, 4 trials evaluated role of corticosteroids in prevention of ARDS, while other 5 trials were focused on treatment after variable periods of onset of ARDS. Trials with preventive corticosteroids, mostly using high doses of MP, showed negative results with patients in treatment arm, showing higher mortality and rate of ARDS development. While trials of corticosteroids in early ARDS showed variable results, somewhat, favoring use of these agents to reduce associated morbidities. In late stage of ARDS, these drugs have no benefits and are associated with adverse outcome. Use of corticosteroids in patients with early ARDS showed equivocal results in decreasing mortality; however, there is evidence that these drugs reduce organ dysfunction score, lung injury score, ventilator requirement, and intensive care unit stay. However, most of these trials are small, having a significant heterogeneity regarding study design, etiology of ARDS, and dosage of corticosteroids. Further research involving large-scale trials on relatively homogeneous cohort is necessary to establish the role of corticosteroids for this condition. PMID- 21712922 TI - Strengthening TB surveillance system in India: Way forward for improving estimates of TB incidence. AB - One of the key indicators used under India's TB control program is the DOTS case detection rate of new sputum smear positive TB whose estimates in India are based on incidence estimates derived from Styblo's rule. Styblo's rule was formulated in an era without well-established tuberculosis control program, effective tuberculosis drugs, and emergence of TB-HIV coinfection, so today it does not reflect the true incidence of TB. Considering various loopholes in different methods of measurement of incidence (prevalence surveys of disease/ infection, vital registration system and Styblo's rule), strengthening of existing surveillance system is the best tool to obtain correct estimates of tuberculosis incidence in India. PMID- 21712923 TI - First report on isolation of Mycobacterium monacense from sputum specimen in India. AB - We report a case of Mycobacterium monacense (M. monacense) isolated from sputum of a female patient for the first time in India. The chest radiograph and symptoms were suggestive of pulmonary tuberculosis. M. monacense was isolated from the sputum specimen at the end of 11 days of incubation. The identification was confirmed by conventional biochemical tests and polymerase chain reaction (PCR) -based Restriction Fragment Length Polymorphism (RFLP) and DNA sequencing targeting Internal Transcribed Spacer (ITS) region and hsp65 gene. The patient was treated with conventional anti-tuberculous drugs. PMID- 21712924 TI - Lung and lupus vulgaris. AB - Lupus vulgaris is chronic, postprimary, paucibacillary cutaneous tuberculosis found in individuals with moderate immunity and high degree of tuberculin sensitivity. Eighty percent of the lesions are on the head and neck. We present the case of a 38 year old lady who was admitted with complaints of worsening breathlessness and low grade fever of one month duration. Examination showed multiple, nontender skin ulcers on bilateral lumbar areas, two oozing serosanguinous discharge and others scarred in the centre. Respiratory system examination and chest X-ray revealed right sided pleural effusion. On investigation, pleural fluid was tuberculous in nature. Skin biopsy from the edge of ulcer was also suggestive of tuberculosis. Patient is doing well on antituberculous drugs. This case highlights the importance of cutaneous manifestations of systemic disease and is an example of the unusual presentation of lupus vulgaris in a case of pleural effusion. PMID- 21712925 TI - Bilateral hemorrhagic pleural effusion due to kerosene aspiration. AB - Kerosene ingested, intentionally or accidentally, is toxic. Data is scarce on complications and outcomes of hydrocarbon poisoning following kerosene aspiration in adults and there has been no known case of bilateral hemorrhagic effusion occurring due to it in literature. We, hereby, report a case of a bilateral hemorrhagic pleural effusion secondary to hydrocarbon aspiration in a 40-year old adult. PMID- 21712926 TI - Bilateral chylothorax, chylopericardium and chylous ascitis. AB - Non-Hodgkin's lymphoma (NHL) can commonly present as chylothorax and rarely as chylopericardium. Here we are presenting a case of a 21-years-old female with bilateral chylothorax, chylopericardium and chylous ascites all together finally diagnosed to have NHL as the etiology. To the best of our knowledge, it has been reported very infrequently. PMID- 21712927 TI - Multiple myeloma with lung plasmacytoma. AB - Malignant myeloma (MM) is a clonal proliferation of plasma cells with multiple osteolytic lesions. Extramedullary dissemination of multiple myeloma in lung is relatively uncommon. Hereby, we present a case of multiple myeloma with lung plasmacytoma of lung in a 45-years-old, non-smoker, female. PMID- 21712928 TI - Pulmonary alveolar microlithiasis. AB - Pulmonary alveolar microlithiasis is a rare disease of unknown cause. We report a case in a young boy who presented with history of failure to thrive and chest X ray finding suggestive of miliary mottling. Open lung biopsy revealed pulmonary alveolar microlithiasis. PMID- 21712929 TI - Video-assisted thoracoscopy in trauma: Case report and review of literature. AB - Video Assisted Thoracoscopy (VATS) like any other minimal access surgery has the obvious advantage of less surgical insult, enabling quicker recovery with its attendant reduced hospital costs and earlier return to work. The benefit of earlier return to work is much more important in developing countries. Unfortunately minimal access surgery is yet to gain popularity in trauma surgery, especially in the developing countries due to various reasons. We describe one case report where VATS was used successfully to remove an intrapleural foreign body. PMID- 21712930 TI - Rare vascular anomaly mimicking bronchogenic carcinoma. AB - We report a case of anomalous left pulmonary artery (pulmonary artery sling) detected incidentally on computed tomography thorax. This was carried out to rule out bronchogenic carcinoma in a patient of chronic obstructive pulmonary disease who presented with streaking. He was a chronic smoker having bilateral hilar prominence on chest radiograph. PMID- 21712931 TI - Ethics in writing: Learning to stay away from plagiarism and scientific misconduct. AB - Fraudulent data and plagiarized text may corrupt scientific medical literature and ultimately harm patients. By prescribing erroneous treatment to an individual, only single patient is affected; but by presenting incorrect data or transcripts, the whole scientific medical universe is affected. Although both scenarios are highly undesirable, one can assume the magnitude of the effect of latter. Writers of scientific medical literature have been found to be involved in plagiarism and other publication misconducts from time to time irrespective of social, economic and geographic structure. The reason of such behavior is not usually obvious. Easy availability of personal computers has led to widespread dissemination of medical literature. As a result, young scientists are now publishing their research more frequently and efficiently. At the same time, this has increased the tendency to submit hurriedly prepared, poorly drafted and even illegitimate publications. Use of some amount of copy-paste followed by modifications during preparation of a manuscript seems to be common. Therefore, the researchers, especially postgraduate students, should be educated continuously about ethical medical writing. PMID- 21712932 TI - Noninvasive ventilation in acute respiratory failure due to H1N1 influenza: A word of caution. PMID- 21712933 TI - Authors' reply. PMID- 21712934 TI - Adverse drug reaction and causality assessment scales. PMID- 21712935 TI - Sputum AFB in tuberculous pleural effusion. PMID- 21712936 TI - Authors' reply. PMID- 21712937 TI - Thoracoscopy for trauma. PMID- 21712938 TI - Pulmonary functions in patients with diabetes mellitus. AB - BACKGROUND: A reduction in lung capacity has been reported previously among diabetics. According to WHO estimates, Pakistan is currently eighth in the prevalence of diabetes mellitus (DM) and will become fourth by the year 2025 with over 15 million individuals. This study was designed to see the impairment of lung functions on spirometry in DM patients. OBJECTIVE: Our aim was to investigate the pulmonary functions tests of Pakistani patients with DM. MATERIALS AND METHODS: Between January to July 2004, 128 subjects who were never smokers and had no acute or chronic pulmonary disease were recruited. Sixty-four of these subjects had DM and 64 were healthy matched controls. All underwent screening with detailed history, anthropometry, lipid profile, and spirometric measurements at the Aga Khan University Hospital, Karachi, Pakistan. RESULTS: The mean age of diabetics and matched control were 54.3+/-9 and 54.0+/-8 (P<0.87) years, respectively. Diabetes patients showed a significant reduction in the forced vital capacity (FVC) [mean difference (95% CI) - 0.36 (-0.64, -0.07) P<0.01], forced expiratory volume in one second (FEV(1)) [- 0.25(-0.50, -0.003) P<0.04], and slow vital capacity (SVC) [- 0.28(-0.54, -0.01) P<0.04], relative to nondiabetic controls. There was no significant difference noted in the forced expiratory ratio and maximum mid-expiratory flow between the groups. There was also a significant higher level of triglycerides noted among diabetics (P<0.001). CONCLUSION: Diabetic patients showed impaired lung function independent of smoking. This reduced lung function is likely to be a chronic complication of diabetes mellitus. PMID- 21712939 TI - Clinical and laboratory profile of patients with TB/HIV coinfection: A case series of 50 patients. AB - BACKGROUND: Tuberculosis (TB) is said to be one of the commonest opportunistic infection in patients with HIV/AIDS. OBJECTIVE: To study the clinical and laboratory profile of patients with HIV/TB coinfection. MATERIALS AND METHODS: Fifty adult TB patients having confirmed HIV seropositivity were included in randomized manner. A detailed history and thorough physical examination was done. Laboratory and radiological investigations were carried out as appropriately warranted. RESULTS: Most of the patients were farm workers (30%) followed by manual laborers (22%) and transport drivers (16%). Heterosexual route was found in 86% of patients. Cough was present in 94% while fever and weight loss in 86% and 78% of patients, respectively. Out of 50 patients, 40% had only pulmonary TB (PTB), 46% had pulmonary and extra-pulmonary TB (EPTB), 10% had only EPTB and 4% had multisystemic EPTB. Mediastinal lymphadenopathy was present in 34% while pleural effusion and extra-thoracic lymph nodes was present in 20% and 18% of patients, respectively. Positive smear for acid-fast bacilli (AFB) was found in 25.58% while positive Mantoux test was found in 32.14% of patients. CONCLUSION: HIV/TB coinfection is more common in sexually active age group and commonest mode of HIV infection is heterosexual transfer. Sputum smear AFB and Mantoux test positivity is low in TB patients having HIV. Disseminated TB is common in HIV. Mediastinal lymphadenopathy is common site among extra-pulmonary tuberculosis. PMID- 21712940 TI - Clinical profile, diagnostic delay, and genetic make-up of cystic fibrosis in Kashmir, India. AB - OBJECTIVES: This observational study was done to describe the clinical profile, and delays in diagnosing cystic fibrosis (CF) disease in Kashmir, India. MATERIALS AND METHODS: A total of 6758 patients between the ages of 0 and 19 years were registered over a period of 1 year. Out of these, 150 patients suspected of having CF, on clinical grounds, were subjected to pilocarpine iontophoresis, and later on genetic evaluation. Apart from these specific tests, these patients were subjected to laboratory tests like blood counts, blood sugar, KFT, LFT, pancreatic function test, serum electrolytes, and chloride, urine, throat swab, blood culture, ABG analysis, chest and paranasal X-rays. In addition, sonographic evaluation of abdominal organs was carried out to know the status of internal organs. A polymerase chain reaction (PCR)-based test was used for the identification of CF mutation. RESULTS: CF was diagnosed in three (0.8%) patients. Median age of presentation of CF was 78 months. Family history suggestive of CF was present in one (33.3%) and consanguinity in three (100%) patients. Common clinical manifestations at the time of presentation included recurrent pneumonia in three (100%), failure to thrive in three (100%), recurrent diarrhea in one (33.3%) patients. General physical examination showed pallor in three (100%), malnutrition in three (100%), and clubbing in two (66.7%) patients. Examination of respiratory tract revealed hyperinflation in two (66.7%), rhinitis in two (66.7%), and creptations in two (66.7%) patients. Sonography of abdominal organs revealed pancreatic cysts in one (33.3%), hyperechoeic and increased liver span in two (66.7%), and small gallbladder in one (33.3%). Staphylococcus aureus was cultured from sputum in one (33.3%), pseudomonas aeruginosa in one (33.3%) patients. Delta F508 mutation was present in one (33.3%) patient. CONCLUSION: CF may be more common in Kashmir and other parts of Asia, than indicated by our study; diagnosis is often considerably delayed when the disease is identified solely on clinical grounds. It would be advisable to raise the index of suspicion about CF. PMID- 21712941 TI - The riddell ripkord system for shoulder pad removal in a cervical spine injured athlete: a paradigm shift. AB - Since the inception of the term Sports Medicine Athletic Trainers, Sports Physical Therapists, Paramedics, and Emergency Room Physicians have faced a number of challenges when it comes to providing care to an equipment laden athlete suspected of having a cervical spine or serious head injury. The same equipment that is designed to protect the player may significantly impede the medical team when it comes to diagnosing and treating cervical spine and head injuries. Incorrectly removing the helmet and shoulder pads from a football player with a cervical spine injury, may lead to unwanted motion of the cervical spine during removal. It is the purpose of this article to review the current concepts relating to equipment removal and to introduce a novel system for quick and easy removal of football shoulder pads called the RiddellTMRipKord system. PMID- 21712942 TI - Can upper extremity functional tests predict the softball throw for distance: a predictive validity investigation. AB - INTRODUCTION: Understanding the relationships between performance tests and sport activity is important to the rehabilitation specialist. The purpose of this study was two- fold: 1) To identify if relationships exist between tests of upper body strength and power (Single Arm Seated Shot Put, Timed Push-Up, Timed Modified Pull-Up, and The Davies Closed Kinetic Chain Upper Extremity Stability Test, and the softball throw for distance), 2) To determine which variable or group of variables best predicts the performance of a sport specific task (the softball throw for distance). METHODS: One hundred eighty subjects (111 females and 69 males, aged 18-45 years) performed the 5 upper extremity tests. The Pearson product moment correlation and a stepwise regression were used to determine whether relationships existed between performance on the tests and which upper extremity test result best explained the performance on the softball throw for distance. RESULTS: There were significant correlations (r=.33 to r=.70, p=0.001) between performance on all of the tests. The modified pull-up test was the best predictor of the performance on the softball throw for distance (r(2)= 48.7), explaining 48.7% of variation in performance. When weight, height, and age were added to the regression equation the r(2) values increased to 64.5, 66.2, and 67.5 respectively. CONCLUSION: The results of this study indicate that several upper extremity tests demonstrate significant relationships with one another and with the softball throw for distance. The modified pull up test was the best predictor of performance on the softball throw for distance. PMID- 21712943 TI - Nitrous Oxide Emissions from Ephemeral Wetland Soils are Correlated with Microbial Community Composition. AB - Nitrous oxide (N(2)O) is a greenhouse gas with a global warming potential far exceeding that of CO(2). Soil N(2)O emissions are a product of two microbially mediated processes: nitrification and denitrification. Understanding the effects of landscape on microbial communities, and the subsequent influences of microbial abundance and composition on the processes of nitrification and denitrification are key to predicting future N(2)O emissions. The objective of this study was to examine microbial abundance and community composition in relation to N(2)O associated with nitrification and denitrification processes over the course of a growing season in soils from cultivated and uncultivated wetlands. The denitrifying enzyme assay and [Formula: see text] pool dilution methods were used to compare the rates of denitrification and nitrification and their associated N(2)O emissions. Functional gene composition was measured with restriction fragment length polymorphism profiles and abundance was measured with quantitative polymerase chain reaction. The change in denitrifier nitrous oxide reductase gene (nosZ) abundance and community composition was a good predictor of net soil N(2)O emission. However, neither ammonia oxidizing bacteria ammonia monooxygenase (bacterial amoA) gene abundance nor composition predicted nitrification-associated-N(2)O emissions. Alternative strategies might be necessary if bacterial amoA are to be used as predictive in situ indicators of nitrification rate and nitrification-associated-N(2)O emission. PMID- 21712944 TI - Synchronous carcinoma of the ampulla of vater and colon cancer. AB - Carcinoma of the papilla of Vater is a relatively rare tumor and its coexistence with other primary sporadic cancers is very exceptional. Here we report the case of a 76-year-old man who presented with painless obstructive jaundice, pathologically elevated liver function tests and increased serum levels of carbohydrate antigen 19-9 and carcinoembryonic antigen. Endoscopic retrograde cholangiography revealed a large polypoid mass in the ampulla of Vater. A large tumor in the ascending colon was also incidentally detected by abdominal computed tomography. Endoscopic biopsies from both lesions showed adenocarcinomas. Metastases to the liver and to the hepatoduodenal ligament and hepatic artery lymph nodes were found during surgery. Right colectomy and a biliary bypass were performed. Histological analysis showed an ampullary adenocarcinoma with metastases to regional lymph nodes and the liver and a colonic adenocarcinoma with local invasion into the pericolic fat. Treatment with gemcitabine plus cisplatin was suggested postoperatively. The association of sporadic ampullary and colonic adenocarcinomas and the mutually increased risk of developing either a synchronous or a metachronous tumor following each other should be considered in patients with primary ampullary or colorectal cancer during the preoperative evaluation and postoperative follow-up of these patients. PMID- 21712945 TI - Use of balloon enteroscopy in preoperative diagnosis of neurofibromatosis associated gastrointestinal stromal tumours of the small bowel: a case report. AB - Neurofibromatosis type I (NF1) is one of the most common inheritable disorders and is associated with an increased risk of gastrointestinal stromal tumours (GISTs). However, the predominant location of these lesions in the small bowel makes them difficult to diagnose. We report the successful use of balloon enteroscopy in conjunction with conventional methods for clinical diagnosis of jejunal GISTs in a 70-year-old man with NF1 who presented with melaena. The importance of screening NF1 patients for GISTs and the complementary role of balloon enteroscopy with capsule endoscopy in such diagnoses is discussed. PMID- 21712946 TI - Extraluminal amyloidoma of the pelvic cavity causing large bowel obstruction. AB - AMYLOIDOSIS IS A GROUP OF DIVERSE DISORDERS THAT FALL INTO SEVERAL MAJOR CATEGORIES: primary, secondary, dialysis-associated, and hereditary forms. Clinically, amyloidosis may be categorized as localized or systemic. The gastrointestinal tract is among the most common places for deposition of amyloid, but large, localized amyloid deposits are an uncommon occurrence and rarely cause extraluminal bowel compression resulting in obstruction as was seen in the case presented in this clinical scenario. PMID- 21712947 TI - Adult intussusception caused by an inverted meckel diverticulum. AB - Adult intussusception caused by an inverted Meckel diverticulum is rare. We report a 55-year-old Japanese man with intussusception. He was admitted to our hospital with vomiting and abdominal pain. The abdomen was hard with tenderness and muscle guarding. Computed tomography scanning demonstrated a typical inhomogeneous target-shaped mass in the right abdomen. We diagnosed intussusception and performed emergency surgery. At laparotomy, ileocolic intussusception was observed and the ileocecal segment was resected. The surgical specimen comprised an 84 cm segment of resected ileocecum with an elongated polypoid lesion measuring 11 * 2 cm within the ileal lumen. Histopathological examination demonstrated that the polypoid lesion was an inverted Meckel diverticulum. Postoperatively, the patient made an uneventful recovery. PMID- 21712948 TI - Signet Ring Cell Gastric Cancer Occurring after Radiation Therapy for Helicobacter pylori-Uninfected Mucosa-Associated Lymphoid Tissue Lymphoma. AB - Helicobacter pylori infection is the major cause for mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancers. On the other hand, gastric cancers are known to arise from gastric mucosal atrophy. We here report a case of signet ring cell gastric cancer that developed after radiation therapy for MALT lymphoma in H. pylori-uninfected patient whose stomach did not show gastric mucosal atrophy. A 58-year-old female was referred to our hospital for treatment of gastric MALT lymphoma. This patient was not infected with H. pylori, and upper gastrointestinal endoscopy revealed that she did not have gastric mucosal atrophy but had submucosal tumor-like MALT lymphoma lesion in the anterior wall of the upper gastric body. Since conventional eradication therapy was ineffective, her whole stomach was irradiated as a second-line therapy. The MALT lymphoma lesion turned into complete remission state after the therapy. The patient was followed every 6 months by upper gastrointestinal endoscopy for 4 years as complete remission until a newly developed decolorized depressed lesion was detected in the greater curvature of the proximal antrum, a completely different location from the MALT lymphoma lesion. A biopsy specimen from the lesion contained signet ring cell carcinoma, and she was successfully treated by endoscopic submucosal dissection. No signs of recurrence have been detected so far. The radiation therapy for MALT lymphoma might be associated with the occurrence of this signet ring cell gastric cancer, and since MALT lymphoma is indolent in nature, this case suggests that careful consideration is required when choosing the second line therapy for MALT lymphoma patients. PMID- 21712949 TI - A rare cause for acute cor pulmonale. AB - A number of diseases may cause right atrial mass. Primary cardiac tumors range from 0.002 to 0.25%. Intracardiac manifestation and pulmonary embolism of hepatocellular carcinoma (HCC) is a very rare finding and uncommon even at autopsy. Here we describe the case of a 32-year-old Asian man who was referred for shortness of breath lasting for a month, along with unproductive cough. He was a manual laborer with a history of diabetes, alcoholism, and smoking. Clinically he was diagnosed as having pulmonary embolism. Echocardiogram showed a mass in the right atrium. Magnetic resonance imaging showed that he had a large mass in the right atrium extending down into the inferior vena cava. Further evaluation showed that he had chronic liver disease with portal hypertension and was hepatitis B surface antigen-positive, indicating hepatitis B infection. He underwent excision of the mass, and the pathological report showed metastasis of HCC with multiple vascular emboli in the lungs. As this is the second reported case of this kind in the literature, we highlight the need of screening at least 6-monthly all patients with chronic liver disease, hepatitis B and C virus infection for the early detection of HCC. PMID- 21712950 TI - Effective therapy using voglibose for nonalcoholic steatohepatitis in a patient with insufficient dietary and exercise therapy: exploring other treatment possibilities. AB - A 56-year-old Japanese female with a 10-year history of thyroiditis presented to our institution. The laboratory data and clinical findings suggested that the patient had complicated nonalcoholic fatty liver disease or nonalcoholic steatohepatitis (NASH) with autoimmune hepatitis according to the criteria by the application of the International Autoimmune Hepatitis score. The patient could not manage by herself so dietary- and exercise-based treatment was difficult. Accordingly, ursodeoxycholic acid and ezetimibe therapy was started and continued until the performance of a liver needle biopsy to define the diagnosis. However, no improvement in liver function was observed. In addition, pathological findings indicated that the patient had NASH. The patient was finally diagnosed as having NASH. Therefore, voglibose was added to the ursodeoxycholic acid and ezetimibe therapy, and this addition of voglibose actually took effect. The patient's serum aspartate transaminase and alanine aminotransferase levels decreased dramatically. This report is the first to document other treatment possibilities of NASH in a case when dietary therapy is difficult. PMID- 21712951 TI - Cambogin is preferentially cytotoxic to cells expressing PDGFR. AB - Platelet-derived growth factor receptors (PDGFRs) have been implicated in a wide array of human malignancies, including medulloblastoma (MB), the most common brain tumor of childhood. Although significant progress in MB biology and therapeutics has been achieved during the past decades, MB remains a horrible challenge to the physicians and researchers. Therefore, novel inhibitors targeting PDGFR signaling pathway may offer great promise for the treatment of MB. In the present study, we investigated the cytotoxicity and mechanisms of cambogin in Daoy MB cells. Our results show that cambogin triggers significant S phase cell cycle arrest and apoptosis via down regulation of cyclin A and E, and activation of caspases. More importantly, further mechanistic studies demonstrated that cambogin inhibits PDGFR signaling in Daoy and genetically defined mouse embryo fibroblast (MEF) cell lines. These results suggest that cambogin is preferentially cytotoxic to cells expressing PDGFR. Our findings may provide a novel approach by targeting PDGFR signaling against MB. PMID- 21712952 TI - The adiponectin receptor homologs in C. elegans promote energy utilization and homeostasis. AB - Adiponectin is an adipokine with insulin-sensitising actions in vertebrates. Its receptors, AdipoR1 and AdipoR2, are PAQR-type proteins with 7-transmembrane domains and topologies reversed that of GPCR's, i.e. their C-termini are extracellular. We identified three adiponectin receptor homologs in the nematode C. elegans, named paqr-1, paqr-2 and paqr-3. These are differently expressed in the intestine (the main fat-storing tissue), hypodermis, muscles, neurons and secretory tissues, from which they could exert systemic effects. Analysis of mutants revealed that paqr-1 and -2 are novel metabolic regulators in C. elegans and that they act redundantly but independently from paqr-3. paqr-2 is the most important of the three paqr genes: mutants grow poorly, fail to adapt to growth at low temperature, and have a very high fat content with an abnormal enrichment in long (C20) poly-unsaturated fatty acids when combined with the paqr-1 mutation. paqr-2 mutants are also synthetic lethal with mutations in nhr-49, sbp 1 and fat-6, which are C. elegans homologs of nuclear hormone receptors, SREBP and FAT-6 (a Delta9 desaturase), respectively. Like paqr-2, paqr-1 is also synthetic lethal with sbp-1. Mutations in aak-2, the C. elegans homolog of AMPK, or nhr-80, another nuclear hormone receptor gene, suppress the growth phenotype of paqr-2 mutants, probably because they restore the balance between energy expenditure and storage. We conclude that paqr-1 and paqr-2 are receptors that regulate fatty acid metabolism and cold adaptation in C. elegans, that their main function is to promote energy utilization rather than storage, and that PAQR class proteins have regulated metabolism in metazoans for at least 700 million years. PMID- 21712953 TI - Immune responses to the enduring hypoxic response antigen Rv0188 are preferentially detected in Mycobacterium bovis infected cattle with low pathology. AB - The DosR regulon and the Enduring Hypoxic Response (EHR) define a group of M. tuberculosis genes that are specifically induced in bacilli exposed in vitro to conditions thought to mimic the environment encountered by Mycobacteria during latent infection. Although well described in humans, latent mycobacterial infection in cattle remains poorly understood. Thus, the aim of this study was to identify antigens that may potentially disclose cattle with latent M. bovis infection. To this end, we initially screened 57 pools of overlapping peptides representing 4 DosR regulon and 29 EHR antigens for their ability to stimulate an immune response in whole blood from TB-reactor cattle using IFN-gamma and IL-2 as readouts. All 4 DosR regulon proteins were poorly recognized (maximum responder frequency of 10%). For the EHR antigens, both IFN-gamma and IL-2 revealed similar response hierarchies, with responder frequencies ranging from 54% down to 3% depending on the given EHR antigen. Furthermore, these results demonstrated that responses in the infected cattle were largely IFN-gamma biased. To support the concept for their role in latency, we evaluated if EHR antigen responses were associated with lower pathology. The EHR antigen Rv0188 was recognised predominantly in animals presenting with low pathology scores, whereas responses to ESAT-6/CFP-10 or the other EHR antigens tested were prevalent across the pathology spectrum. However, when we determined the production of additional cytokines induced by the M. bovis antigens PPD-B or ESAT-6/CFP-10, we detected significantly greater PPD-B-induced production of the pro-inflammatory cytokine IL-1beta in animals recognizing Rv0188 (i.e. those with limited or no pathology). Thus, these results are consistent with the idea that responses to Rv0188 may identify a subset of animals at early stages of infection or in which disease progression may be limited. PMID- 21712954 TI - Wnt/beta-catenin signaling induces the aging of mesenchymal stem cells through the DNA damage response and the p53/p21 pathway. AB - Recent studies have demonstrated the importance of cellular extrinsic factors in the aging of adult stem cells. However, the effects of an aged cell-extrinsic environment on mesenchymal stem cell (MSC) aging and the factors involved remain unclear. In the current study, we examine the effects of old rat serum (ORS) on the aging of MSCs, and explore the effects and mechanisms of Wnt/beta-catenin signaling on MSC aging induced by ORS treatment. Senescence-associated changes in the cells are examined with SA-beta-galactosidase staining and ROS staining. The proliferation ability is detected by MTT assay. The surviving and apoptotic cells are determined using AO/EB staining. The results suggest that ORS promotes MSC senescence and reduces the proliferation and survival of cells. The immunofluorescence staining shows that the expression of beta-catenin increases in MSCs of old rats. To identify the effects of Wnt/beta-catenin signaling on MSC aging induced with ORS, the expression of beta-catenin, GSK-3beta, and c-myc are detected. The results show that the Wnt/beta-catenin signaling in the cells is activated after ORS treatment. Then we examine the aging, proliferation, and survival of MSCs after modulating Wnt/beta-catenin signaling. The results indicate that the senescence and dysfunction of MSCs in the medium containing ORS is reversed by the Wnt/beta-catenin signaling inhibitor DKK1 or by beta-catenin siRNA. Moreover, the expression of gamma-H2A.X, a molecular marker of DNA damage response, p16(INK4a), p53, and p21 is increased in senescent MSCs induced with ORS, and is also reversed by DKK1 or by beta-catenin siRNA. In summary, our study indicates the Wnt/beta-catenin signaling may play a critical role in MSC aging induced by the serum of aged animals and suggests that the DNA damage response and p53/p21 pathway may be the main mediators of MSC aging induced by excessive activation of Wnt/beta-catenin signaling. PMID- 21712955 TI - Efficient allele-specific targeting of LRRK2 R1441 mutations mediated by RNAi. AB - Since RNA interference (RNAi) has the potential to discriminate between single nucleotide changes, there is growing interest in the use of RNAi as a promising therapeutical approach to target dominant disease-associated alleles. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been linked to dominantly inherited Parkinson's disease (PD). We focused on three LRRK2 mutations (R1441G/C and the more prevalent G2109S) hoping to identify shRNAs that would both recognize and efficiently silence the mutated alleles preferentially over the wild-type alleles. Using a luciferase-based reporter system, we identified shRNAs that were able to specifically target the R1441G and R1441C alleles with 80% silencing efficiency. The same shRNAs were able to silence specifically mRNAs encoding either partial or full-length mutant LRRK2 fusion proteins, while having a minimal effect on endogenous wild-type LRRK2 expression when transfected in 293FT cells. Shifting of the mutant recognition site (MRS) from position 11 to other sites (4 and 16, within the 19-mer window of our shRNA design) reduced specificity and overall silencing efficiency. Developing an allele-specific RNAi of G2019S was problematic. Placement of the MRS at position 10 resulted in efficient silencing of reporters (75-80%), but failed to discriminate between mutant and wild-type alleles. Shifting of the MRS to positions 4, 5, 15, 16 increased the specificity of the shRNAs, but reduced the overall silencing efficiency. Consistent with previous reports, these data confirm that MRS placement influences both allele-specificity and silencing strength of shRNAs, while further modification to hairpin design or MRS position may lead to the development of effective G2019S shRNAs. In summary, the effective shRNA against LRRK2 R1441 alleles described herein suggests that RNAi-based therapy of inherited Parkinson's disease is a viable approach towards developing effective therapeutic interventions for this serious neurodegenerative disease. PMID- 21712956 TI - Endobronchial ultrasound-guided transbronchial needle aspiration biopsy is useful evaluating mediastinal lymphadenopathy in a cancer center. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy is used to stage mediastinal lymph nodes in cancer patients to optimize treatment strategies. In this retrospective study, the authors determined the utility of EBUS-TBNA biopsy in the evaluation of mediastinal lymphadenopathy at a high-volume cancer center. MATERIALS AND METHODS: The pathology database was searched for all patients who had undergone EBUS-TBNA biopsy of mediastinal lymph nodes over a one-year period. Cytologic diagnoses were correlated with clinical histories, subsequent resection, and clinical follow-up data. RESULTS: Of 928 lymph node samples, 226 (24%) were diagnosed as malignant, 4 (0.4%) were suspicious for malignancy, 9 (1%) were atypical, 640 (69%) were benign, and 47 (5%) were insufficient for evaluation. In 89 (9.6%) cases, the patients had surgical resection. There was one false positive, in which the primary tumor contained infiltrating lymphocytes, had been sampled. There were five false-negative cases, which resulted from sampling errors, including two with micrometastases. The sensitivity, specificity, and positive and negative predictive value rates for EBUS-TBNA biopsy in the evaluation of mediastinal lymph nodes were 68.7% and 98.6% and 91.6% and 93.5%, respectively on a per lymph node basis. The overall clinical sensitivity, specificity, and positive and negative predictive value rates after one year clinical/radiological and histologic follow-up were 97%, 99.3%, 96.7% and 99.4%, respectively. CONCLUSIONS: EBUS-TBNA biopsy is a sensitive and specific method for evaluating mediastinal lymphadenopathy in patients with lung and other primary tumors. PMID- 21712957 TI - Defining the role of polyamines in colon carcinogenesis using mouse models. AB - Genetics and diet are both considered important risk determinants for colorectal cancer, a leading cause of death in the US and worldwide. Genetically engineered mouse (GEM) models have made a significant contribution to the characterization of colorectal cancer risk factors. Reliable, reproducible, and clinically relevant animal models help in the identification of the molecular events associated with disease progression and in the development of effictive treatment strategies. This review is focused on the use of mouse models for studying the role of polyamines in colon carcinogenesis. We describe how the available mouse models of colon cancer such as the multiple intestinal neoplasia (Min) mice and knockout genetic models facilitate understanding of the role of polyamines in colon carcinogenesis and help in the development of a rational strategy for colon cancer chemoprevention. PMID- 21712958 TI - Statistical methods for assays with limits of detection: Serum bile acid as a differentiator between patients with normal colons, adenomas, and colorectal cancer. AB - In analytic chemistry a detection limit (DL) is the lowest measurable amount of an analyte that can be distinguished from a blank; many biomedical measurement technologies exhibit this property. From a statistical perspective, these data present inferential challenges because instead of precise measures, one only has information that the value is somewhere between 0 and the DL (below detection limit, BDL). Substitution of BDL values, with 0 or the DL can lead to biased parameter estimates and a loss of statistical power. Statistical methods that make adjustments when dealing with these types of data, often called left censored data, are available in many commercial statistical packages. Despite this availability, the use of these methods is still not widespread in biomedical literature. We have reviewed the statistical approaches of dealing with BDL values, and used simulations to examine the performance of the commonly used substitution methods and the most widely available statistical methods. We have illustrated these methods using a study undertaken at the Vanderbilt-Ingram Cancer Center, to examine the serum bile acid levels in patients with colorectal cancer and adenoma. We have found that the modern methods for BDL values identify disease-related differences that are often missed, with statistically naive approaches. PMID- 21712959 TI - Perspective: Chemoprevention of colorectal neoplasia: Translating scientific promise into clinical practice. PMID- 21712960 TI - Therapeutic prevention of colorectal carcinogenesis. PMID- 21712961 TI - Elevated levels of urinary 8-hydroxy-2'-deoxyguanosine and 8-isoprostane in esophageal squamous cell carcinoma. AB - AIMS: To measure oxidative DNA and lipid damages, urinary levels of 8-hydroxy-2' deoxyguanosine (8-OHdG), and 8-isoprostane in esophageal squamous cell carcinoma (SCC) patients and compare the values with that in controls. MATERIALS AND METHODS: The urinary concentrations of 8-OHdG and 8-isoprostane were measured in 32 SCC patients (13 female/19 male; mean age: 61.4 +/- 10.5 years) and 45 controls (22 female/23 male; mean age: 58.1 +/- 8.3 years). RESULTS: Squamous cell carcinoma patients showed significantly higher levels of urinary 8-OHdG (15.6 +/- 5.1 ng/mg creatinine) than controls (5.8 +/- 2.1 ng/mg creatinine) (P<.001). Increased urinary concentrations of 8-isoprostane were also detected in SCC patients (35.4 +/- 6.5 ng/mmol creatinine) as compared to the controls (16.9 +/- 4.0 ng/mmol creatinine) (P<.001). CONCLUSIONS: Our results show the presence of oxidative DNA and lipid damage in the SCC patients. This may have a connection to carcinogenesis in the esophagus. PMID- 21712962 TI - Increasing Disparity in Colorectal Cancer Incidence and Mortality Among African Americans and Whites: A State's Experience. PMID- 21712963 TI - Exploring Parent-Adolescent Communication About Gender: Results from Adolescent and Emerging Adult Samples. AB - Although parents are assumed to be children's primary models of socialization when it comes to gender, little is known about direct communication of gendered values in the family. Accordingly, this study assessed the amount and content of recalled parental gender socialization messages using data from 291 U.S. college undergraduates attending a large Midwestern university and 259 U.S. adolescents enrolled in public high schools in the Midwest. The study examined the amount and content of parental communications of five gendered discourses and then tested for connections to current gender beliefs. Findings indicate that gender socialization may be quite similar for sons and daughters, with some evidence of gender typing in patterns of communication. No significant age differences emerged in the patterns of socialization, although high school students reported receiving greater amounts of communication than college students on two of the five discourses. In general, receiving messages promoting traditional gender roles was associated with more traditional gender beliefs (and vice versa), although interpretation of some messages appeared to vary by gender. PMID- 21712964 TI - Single Lipid Bilayers Constructed on Polymer Cushion Studied by Sum Frequency Generation Vibrational Spectroscopy. AB - Planar solid supported single lipid bilayers on mica, glass, or other inorganic surfaces have been widely used as models for cell membranes. To more closely mimic the cell membrane environment, soft hydrophilic polymer cushions were introduced between the hard inorganic substrate and the lipid bilayer to completely avoid the possible substrate-lipid interactions. In this article, sum frequency generation (SFG) vibrational spectroscopy was used to examine and compare single lipid bilayers assembled on the CaF(2) prism surface and on poly (L-lactic acid) (PLLA) cushion. By using asymmetric lipid bilayers composed of a hydrogenated 1,2-dipalmitoyl-sn-glycerol-3-phosphoglycerol (DPPG) leaflet and a deuterated 1,2-dipalmitoyl-(d62)-sn-glycerol-3-phosphoglycerol (d-DPPG) leaflet, it was shown that the DPPG lipid bilayers deposited on the CaF(2) and PLLA surfaces have similar structures. SFG has also been applied to investigate molecular interactions between an antimicrobial peptide Cecropin P(1) (CP1) and the lipid bilayers on the above two different surfaces. Similar results were again obtained. This research demonstrated that the hydrophilic PLLA cushion can serve as an excellent substrate to support single lipid bilayers. We believe that it can be an important cell membrane model for future studies on transmembrane proteins, for which the possible inorganic substrate-bilayer interactions may affect the protein structure or function. PMID- 21712965 TI - Methodological advances in drug discovery for Chagas disease. AB - INTRODUCTION: Chagas disease is the highest impact human infectious disease in Latin America, and the leading worldwide cause of myocarditis. Despite the availability of several compounds that have demonstrated efficacy in limiting the effects of T. cruzi, these compounds are rarely used due to their variable efficacy, substantial side effects and the lack of methodologies for confirming their effectiveness. Furthermore, the development of more efficacious compounds is challenged by limitations of systems for assessing drug efficacy in vitro and in vivo. AREAS COVERED: Herein, the authors review the development of Chagas disease drug discovery methodology, focusing on recent developments in high throughput screening, in vivo testing methods and assessments of efficacy in humans. Particularly, this review documents the significant progress that has taken place over the last 5 years that have paved the way for both target-focused and high-throughput screens of compound libraries. EXPERT OPINION: The tools for in vitro and in vivo screening of anti-T. cruzi compounds have improved dramatically in the last few years and there are now a number of excellent in vivo testing models available; this somewhat alleviates the bottleneck issue of quickly and definitively demonstrating in vivo efficacy in a relevant host animal system. These advances emphasize the potential for additional progress resulting in new treatments for Chagas disease in the coming years. That being said, national and international agencies must improve the coordination of research and development efforts in addition to cultivating the funding sources for the development of these new treatments. PMID- 21712966 TI - Facile Access to Sterically Hindered Aryl Ketones via Carbonylative Cross Coupling: Application to the Total Synthesis of Luteolin. AB - A general and mild protocol for achieving the carbonylative cross-coupling of sterically-hindered, ortho-disubstituted aryl ketones is reported. The commercially available PEPPSI-IPr catalyst is shown to efficiently promote the carbonylative cross-coupling of hindered ortho-disubstituted aryl iodides to give diaryl ketones; traditional phosphine catalysts are less effective. Carbonylative Suzuki-Miyaura cross-couplings provide a diverse array of biaryl ketones in good to excellent yields. The same catalyst is also shown to catalyze a carbonylative Negishi cross-coupling reaction, utilizing a variety of alkynyl zinc reagents to give the corresponding alkynyl aryl ketones. Application of this new methodology to the synthesis of the natural product luteolin is reported. PMID- 21712967 TI - DIFFERENTIAL GEOMETRIC APPROXIMATION OF THE GRADIENT AND HESSIAN ON A TRIANGULATED MANIFOLD. AB - In a number of medical imaging modalities, including measurements or estimates of electrical activity on cortical or cardiac surfaces, it is often useful to estimate spatial derivatives of data on curved anatomical surfaces represented by triangulated meshes. Assuming the triangle vertices are points on a smooth manifold, we derive a method for estimating gradients and Hessians on locally 2D surfaces embedded in 3D directly in the global coordinate system. Accuracy of the method is validated through simulations on both smooth and corrugated surfaces. PMID- 21712968 TI - Genetic divergence and geographic variation in the deep-water Conus orbignyi complex (Mollusca: Conoidea). AB - Puillandre, N. et al. (2010) Genetic divergence and geographic variation in a deep-water cone lineage: molecular and morphological analyses of the Conus orbignyi complex (Mollusca: Conoidea).The cone snails (family Conidae) are a hyperdiverse lineage of venomous gastropods. Two standard markers, COI and ITS2, were used to define six genetically-divergent groups within a subclade of Conidae that includes Conus orbignyi; each of these was then evaluated based on their shell morphology. We conclude that three forms, previously regarded as subspecies of Conus orbignyi are distinct species, now recognized as Conus orbignyi, Conus elokismenos and Conus coriolisi. In addition, three additional species (Conus pseudorbignyi, Conus joliveti and Conus comatosa) belong to this clade. Some of the proposed species (e.g., Conus elokismenos) are possibly in turn complexes comprising multiple species. Groups such as Conidae illustrate the challenges generally faced in species delimitation in biodiverse lineages. In the case of the Conus orbignyi complex, not only are there definable, genetically divergent lineages, but also considerable geographic variation within each group. Our study suggests that an intensive analysis of multiple specimens within a single locality helps to minimize the confounding effects of geographic variation and can be a useful starting point for circumscribing different species within such a confusing complex. PMID- 21712970 TI - Automatic Indexing of Documents from Journal Descriptors: A Preliminary Investigation. AB - A new, fully automated approach for indexing documents is presented based on associating textwords in a training set of bibliographic citations with the indexing of journals. This journal-level indexing is in the form of a consistent, timely set of journal descriptors (JDs) indexing the individual journals themselves. This indexing is maintained in journal records in a serials authority database. The advantage of this novel approach is that the training set does not depend on previous manual indexing of hundreds of thousands of documents (i.e., any such indexing already in the training set is not used), but rather the relatively small intellectual effort of indexing at the journal level, usually a matter of a few thousand unique journals for which retrospective indexing to maintain consistency and currency may be feasible. If successful, JD indexing would provide topical categorization of documents outside the training set, i.e., journal articles, monographs, WEB documents, reports from the grey literature, etc., and therefore be applied in searching. Because JDs are quite general, corresponding to subject domains, their most probable use would be for improving or refining search results. PMID- 21712969 TI - 2020 Foresight: Envisioning Therapeutic Innovations for Pain. PMID- 21712971 TI - Negative-pressure wound therapy: systematic review of randomized controlled trials. AB - BACKGROUND: In negative-pressure wound therapy (NPWT), a wound is covered with an airtight dressing, and negative pressure is applied. This is thought to promote healing. We evaluated NPWT with an updated, systematic review of the literature. METHODS: We systematically searched the PubMed and Cochrane Library databases for randomized, controlled trials (RCTs) of NPWT for the treatment of acute or chronic wounds. The primary outcome was complete wound closure. RESULTS: We found reports of 9 RCTs in addition to the 12 covered by earlier IQWiG reviews of this topic. Five of the 9 new trials involved NPWT systems that are not on the market. The frequency of complete wound closure is stated in only 5 of the 9 new reports; a statistically significant effect in favor of NPWT was found in only two trials.The results of 8 of the 9 new trials are hard to interpret, both because of apparent bias and because diverse types of wounds were treated. CONCLUSION: Although there may be a positive effect of NPWT, we did not find clear evidence that wounds heal any better or worse with NPWT than with conventional treatment. Good RCTs are still needed to evaluate NPWT. PMID- 21712972 TI - Tumors of the central nervous system in children and adolescents. AB - BACKGROUND: Multimodal treatment approaches for children with tumors of the central nervous system (CNS) have markedly contributed to improved survival. Before 1970, the survival rate among children with medulloblastoma, the most common malignant CNS tumor in children, was about 20%. At present, in contrast, cure can be achieved in more than 75% of children with a favorable constellation of risk factors. In this review article for clinicians, we give an overview of the current understanding of the pathology, presenting manifestations, early diagnosis, and treatment of CNS tumors in children and adolescents. METHODS: We report the research findings of the German Treatment Network "HIT" and selectively review the pertinent literature. RESULTS: Treatment-optimizing clinical trials have improved survival from all types of CNS tumors in children and adolescents. Biological features of the tumors now serve as the basis for improved stratification for multimodal, risk-adapted treatment. Targeted biological strategies are being developed. Difficulties remain, however, in the care of infants with CNS tumors and in the treatment of metastatic disease, tumors of certain histological types, and tumors in certain anatomical sites. Many of the affected children suffer from late effects of their disease and its treatment that can irreversibly impair their development. CONCLUSION: Children with a suspected or confirmed diagnosis of brain tumor should be referred early to a center with the relevant experience. Standardized diagnostic and therapeutic methods have markedly improved the chance of cure. Current research on molecular signaling pathways seems likely to lead to the development of new treatments, particularly for tumors currently associated with lower rates of survival. The long-term side effects of treatment must be systematically monitored so that they can be avoided in future, and so that appropriate support measures can be provided to the affected children. PMID- 21712973 TI - Downbeat and upbeat nystagmus. PMID- 21712976 TI - Early detection of growth disorders with the CrescNet system at the Leipzig Treatment Center. Cooperation should not be stopped. PMID- 21712975 TI - The diagnosis and treatment of autoimmune blistering skin diseases. AB - BACKGROUND: Autoimmune blistering skin diseases are a heterogeneous group of disorders associated with autoantibodies that are directed against desmosomal structural proteins (in pemphigus diseases) or hemidesmosomal ones (in pemphigoid diseases and epidermolysis bullosa acquisita), or else against epidermal/ tissue transglutaminases (in dermatitis herpetiformis). Knowledge of the clinical presentation of these disorders and of the relevant diagnostic procedures is important not just for dermatologists, but also for general practitioners, ophthalmologists, ENT specialists, dentists, gynecologists, and pediatricians. METHODS: The literature on the subject was selectively reviewed. There are no existing guidelines available in Germany. RESULTS: The recently developed sensitive and specific assays for circulating autoantibodies in these diseases now enable a serological diagnosis in about 90% of cases. The incidence of autoimmune blistering skin diseases in Germany has doubled in the last 10 years, to a current figure of about 25 new cases per million persons per year, because of improved diagnostic techniques as well as the aging of the population. Accurate and specific diagnosis is the prerequisite for reliable prognostication and appropriate treatment. For severe and intractable cases, more effective treatments have recently become available, including immunoadsorption, high-dose intravenous immunoglobulin, the anti-CD20 antibody rituximab, and combinations of the above. CONCLUSION: The diagnostic assessment of autoimmune blistering skin diseases can be expected to improve in the near future as new serological testing systems are developed that employ recombinant forms of the target antigens. The treatments currently in use still need to be validated by prospective, controlled trials. PMID- 21712978 TI - Is nasobiliary tube really safe? A case report. AB - A case of esophageal ulcer caused by nasobiliary tube is described. This tool is not routinely considered to be a cause of major complications in the literature and to our knowledge, this is the first report of this kind of complication in nasobiliary tube placement. A 72-year-old patient presented with Charcot's triad and was demonstrated to have cholangitis with multiple biliary stones in the common bile duct. Biliary drainage was achieved through endoscopic retrograde cholangiography, endoscopic sphincterotomy, biliary tree drainage and nasobiliary tube with double pigtail. The patient presented odynophagia, dysphagia and retrosternal pain 12 h after the procedure and upper endoscopy revealed a long esophageal ulcer, which was treated conservatively. This report provides corroboration of evidence that nasobiliary tube placement has potential complications related to pressure sores. In our opinion this is a possibility to consider in informed consent forms. PMID- 21712979 TI - Cystic lymphangioma of the pancreas with spontaneous rupture: report of a case. AB - Lymphangioma is a benign and congenital malformation of the lymphatic system. Most lymphangiomas are preferentially located in the head and neck region. The abdominal organs are uncommon sites of origin. Several cases of lymphangioma in abdominal organs were reported, however, the pancreas is one of the rarest origins. Generally, intra-abdominal lymphangioma is asymptomatic and found incidentally, but in some cases, the patient complains of abdominal distension or a palpable mass. We describe the case of a 38-year-old male who presented with sudden-onset upper abdominal pain. Rupture of a cystic tumor of the pancreatic head was suspected, based on the findings of computed tomography, magnetic resonance imaging and endoscopic ultrasonography. Subtotal stomach-preserving pancreaticoduodenectomy was undertaken. The tumor, which was 4 * 4.5 * 8 cm in size, was pathologically diagnosed as a cystic lymphangioma. In conclusion, pancreatic lymphangioma is mostly asymptomatic, a ruptured case causing 'acute abdomen' has never been reported. Since lymphangioma is benign, it could be observed with accurate diagnosis. The surgical indication would be limited to cases of symptomatic lymphangiomas. PMID- 21712980 TI - Drain Tube-Induced Jejunal Penetration Masquerading as Bile Leak following Whipple's Operation. AB - A 70-year-old man had undergone pancreaticoduodenectomy due to a distal common bile duct malignancy. After the operation, serous fluid discharge decreased from two drain tubes in the retroperitoneum. Over four weeks, the appearance of the serous fluid changed to a greenish bile color and the patient persistently drained over 300 ml/day. Viewed as bile leak at the choledochojejunostomy, treatment called for endoscopic diagnosis and therapy. Cap-fitted forward-viewing endoscopy demonstrated that the distal tip of a pancreatic drain catheter inserted at the pancreaticojejunostomy site had penetrated the opposite jejunum wall. One of the drain tubes primarily placed in the retroperitoneum had also penetrated the jejunum wall, with the distal tip positioned near the choledochojejunostomy site. No leak of contrast appeared beyond the jejunum or anastomosis site. Following repositioning of a penetrating catheter of the pancreaticojejunostomy, four days later, the patient underwent removal of two drain tubes without additional complications. In conclusion, the distal tip of the catheter, placed to drain pancreatic juice, penetrated the jejunum wall and may have caused localized perijejunal inflammation. The other drain tube, placed in the retroperitoneal space, might then have penetrated the inflamed wall of the jejunum, allowing persistent bile drainage via the drain tube. The results masqueraded as bile leakage following pancreaticoduodenectomy. PMID- 21712981 TI - MultiMSOAR 2.0: an accurate tool to identify ortholog groups among multiple genomes. AB - The identification of orthologous genes shared by multiple genomes plays an important role in evolutionary studies and gene functional analyses. Based on a recently developed accurate tool, called MSOAR 2.0, for ortholog assignment between a pair of closely related genomes based on genome rearrangement, we present a new system MultiMSOAR 2.0, to identify ortholog groups among multiple genomes in this paper. In the system, we construct gene families for all the genomes using sequence similarity search and clustering, run MSOAR 2.0 for all pairs of genomes to obtain the pairwise orthology relationship, and partition each gene family into a set of disjoint sets of orthologous genes (called super ortholog groups or SOGs) such that each SOG contains at most one gene from each genome. For each such SOG, we label the leaves of the species tree using 1 or 0 to indicate if the SOG contains a gene from the corresponding species or not. The resulting tree is called a tree of ortholog groups (or TOGs). We then label the internal nodes of each TOG based on the parsimony principle and some biological constraints. Ortholog groups are finally identified from each fully labeled TOG. In comparison with a popular tool MultiParanoid on simulated data, MultiMSOAR 2.0 shows significantly higher prediction accuracy. It also outperforms MultiParanoid, the Roundup multi-ortholog repository and the Ensembl ortholog database in real data experiments using gene symbols as a validation tool. In addition to ortholog group identification, MultiMSOAR 2.0 also provides information about gene births, duplications and losses in evolution, which may be of independent biological interest. Our experiments on simulated data demonstrate that MultiMSOAR 2.0 is able to infer these evolutionary events much more accurately than a well-known software tool Notung. The software MultiMSOAR 2.0 is available to the public for free. PMID- 21712982 TI - Modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in the rat. AB - BACKGROUND: We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoK(ATP) channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival. METHODOLOGY/PRINCIPAL FINDINGS: Male Sprague-Dawley rats (350-400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 umoles) in the presence/absence of 5HD (100 umoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (-40%) and at 6 hr post sepsis (-20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5+/-2.5 in sepsis and 69.2+/-1.2 at 24 hr in sepsis+5HD vs. 79.9+/-1.5 basal group) and cardiac output (63.3+/-1.2 mL/min sepsis and 79.3+/-3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8+/-1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C. CONCLUSION: The data suggest that Bax activation is an upstream event that may precede the opening of the mitoK(ATP) channels in sepsis. We concluded that mitoK(ATP) channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial contractile dysfunction. PMID- 21712983 TI - Human herpesvirus 8 seropositivity among sexually active adults in Uganda. AB - INTRODUCTION: Sexual transmission of human herpesvirus 8 (HHV8) has been implicated among homosexual men, but the evidence for sexual transmission among heterosexual individuals is controversial. We investigated the role of sexual transmission of HHV8 in a nationally representative sample in Uganda, where HHV8 infection is endemic and transmitted mostly during childhood. MATERIALS AND METHODS: The study population was a subset of participants (n = 2681) from a population-based HIV/AIDS serobehavioral survey of adults aged 15-59 years conducted in 2004/2005. High risk for sexual transmission was assessed by questionnaire and serological testing for HIV and herpes simplex virus 2. Anti HHV8 antibodies were measured using two enzyme immunoassays targeting synthetic peptides from the K8.1 and orf65 viral genes. The current study was restricted to 2288 sexually active adults. ORs and 95% CIs for HHV8 seropositivity were estimated by fitting logistic regression models with a random intercept using MPLUS and SAS software. RESULTS: The weighted prevalence of HHV8 seropositivity was 56.2%, based on 1302 seropositive individuals, and it increased significantly with age (P(trend)<0.0001). In analyses adjusting for age, sex, geography, education, and HIV status, HHV8 seropositivity was positively associated with reporting two versus one marital union (OR:1.52, 95% CI: 1.17-1.97) and each unit increase in the number of children born (OR: 1.04, 95% CI: 1.00-1.08), and was inversely associated with ever having used a condom (OR: 0.64, 95% CI: 0.45 0.89). HHV8 seropositivity was not associated with HIV (P = 0.660) or with herpes simplex virus 2 (P = 0.732) seropositivity. Other sexual variables, including lifetime number of sexual partners or having had at least one sexually transmitted disease, and socioeconomic variables were unrelated to HHV8 seropositivity. CONCLUSION: Our findings are compatible with the conclusion that sexual transmission of HHV8 in Uganda, if it occurs, is weak. PMID- 21712984 TI - Spatial and temporal characteristics of the 2009 A/H1N1 influenza pandemic in Peru. AB - BACKGROUND: Highly refined surveillance data on the 2009 A/H1N1 influenza pandemic are crucial to quantify the spatial and temporal characteristics of the pandemic. There is little information about the spatial-temporal dynamics of pandemic influenza in South America. Here we provide a quantitative description of the age-specific morbidity pandemic patterns across administrative areas of Peru. METHODS: We used daily cases of influenza-like-illness, tests for A/H1N1 influenza virus infections, and laboratory-confirmed A/H1N1 influenza cases reported to the epidemiological surveillance system of Peru's Ministry of Health from May 1 to December 31, 2009. We analyzed the geographic spread of the pandemic waves and their association with the winter school vacation period, demographic factors, and absolute humidity. We also estimated the reproduction number and quantified the association between the winter school vacation period and the age distribution of cases. RESULTS: The national pandemic curve revealed a bimodal winter pandemic wave, with the first peak limited to school age children in the Lima metropolitan area, and the second peak more geographically widespread. The reproduction number was estimated at 1.6-2.2 for the Lima metropolitan area and 1.3-1.5 in the rest of Peru. We found a significant association between the timing of the school vacation period and changes in the age distribution of cases, while earlier pandemic onset was correlated with large population size. By contrast there was no association between pandemic dynamics and absolute humidity. CONCLUSIONS: Our results indicate substantial spatial variation in pandemic patterns across Peru, with two pandemic waves of varying timing and impact by age and region. Moreover, the Peru data suggest a hierarchical transmission pattern of pandemic influenza A/H1N1 driven by large population centers. The higher reproduction number of the first pandemic wave could be explained by high contact rates among school-age children, the age group most affected during this early wave. PMID- 21712985 TI - A micro RNA processing defect in rapidly progressing idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF. METHODOLOGY AND PRINCIPAL FINDINGS: miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR 210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts. CONCLUSION: These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing. PMID- 21712986 TI - Mannose-binding lectin deficiency is associated with smaller infarction size and favorable outcome in ischemic stroke patients. AB - BACKGROUND: The Mannose-binding lectin (MBL) pathway of complement plays a pivotal role in the pathogenesis of ischemia/reperfusion (I/R) injury after experimental ischemic stroke. As comparable data in human ischemic stroke are limited, we investigated in more detail the association of MBL deficiency with infarction volume and functional outcome in a large cohort of patients receiving intravenous thrombolysis or conservative treatment. METHODOLOGY/PRINCIPAL FINDINGS: In a post hoc analysis of a prospective cohort study, admission MBL concentrations were determined in 353 consecutive patients with an acute ischemic stroke of whom 287 and 66 patients received conservative and thrombolytic treatment, respectively. Stroke severity, infarction volume, and functional outcome were studied in relation to MBL concentrations at presentation to the emergency department. MBL levels on admission were not influenced by the time from symptom onset to presentation (p = 0.53). In the conservative treatment group patients with mild strokes at presentation, small infarction volumes or favorable outcomes after three months demonstrated 1.5 to 2.6-fold lower median MBL levels (p = 0.025, p = 0.0027 and p = 0.046, respectively) compared to patients with more severe strokes. Moreover, MBL deficient patients (<100 ng/ml) were subject to a considerably decreased risk of an unfavorable outcome three months after ischemic stroke (adjusted odds ratio 0.38, p<0.05) and showed smaller lesion volumes (mean size 0.6 vs. 18.4 ml, p = 0.0025). In contrast, no association of MBL concentration with infarction volume or functional outcome was found in the thrombolysis group. However, the small sample size limits the significance of this observation. CONCLUSIONS: MBL deficiency is associated with smaller cerebral infarcts and favorable outcome in patients receiving conservative treatment. Our data suggest an important role of the lectin pathway in the pathophysiology of cerebral I/R injury and might pave the way for new therapeutic interventions. PMID- 21712987 TI - Classification of first-episode schizophrenia patients and healthy subjects by automated MRI measures of regional brain volume and cortical thickness. AB - BACKGROUND: Although structural magnetic resonance imaging (MRI) studies have repeatedly demonstrated regional brain structural abnormalities in patients with schizophrenia, relatively few MRI-based studies have attempted to distinguish between patients with first-episode schizophrenia and healthy controls. METHOD: Three-dimensional MR images were acquired from 52 (29 males, 23 females) first episode schizophrenia patients and 40 (22 males, 18 females) healthy subjects. Multiple brain measures (regional brain volume and cortical thickness) were calculated by a fully automated procedure and were used for group comparison and classification by linear discriminant function analysis. RESULTS: Schizophrenia patients showed gray matter volume reductions and cortical thinning in various brain regions predominantly in prefrontal and temporal cortices compared with controls. The classifiers obtained from 66 subjects of the first group successfully assigned 26 subjects of the second group with accuracy above 80%. CONCLUSION: Our results showed that combinations of automated brain measures successfully differentiated first-episode schizophrenia patients from healthy controls. Such neuroimaging approaches may provide objective biological information adjunct to clinical diagnosis of early schizophrenia. PMID- 21712988 TI - Absence of birth-weight lowering effect of ADCY5 and near CCNL, but association of impaired glucose-insulin homeostasis with ADCY5 in Asian Indians. AB - BACKGROUND: A feature of the Asian Indian phenotype is low birth weight with increased adult type 2 diabetes risk. Most populations show consistent associations between low birth weight and adult type 2 diabetes. Recently, two birth weight-lowering loci on chromosome 3 (near CCNL1 and ADCY5) were identified in a genome-wide association study, the latter of which is also a type 2 diabetes locus. We therefore tested the impact of these genetic variants on birth weight and adult glucose/insulin homeostasis in a large Indian birth cohort. METHODOLOGY/PRINCIPAL FINDINGS: Adults (n = 2,151) enrolled in a birth cohort (established 1969-73) were genotyped for rs900400 (near CCNL1) and rs9883204 (ADCY5). Associations were tested for birth weight, anthropometry from infancy to adulthood, and type 2 diabetes related glycemic traits. The average birth weight in this population was 2.79+/-0.47 kg and was not associated with genetic variation in CCNL1 (p = 0.87) or ADCY5 (p = 0.54). Allele frequencies for the 'birth weight-lowering' variants were similar compared with Western populations. There were no significant associations with growth or adult weight. However, the 'birth weight-lowering' variant of ADCY5 was associated with modest increase in fasting glucose (beta 0.041, p = 0.027), 2-hours glucose (beta 0.127, p = 0.019), and reduced insulinogenic index (beta -0.106, p = 0.050) and 2-hour insulin (beta -0.058, p = 0.010). CONCLUSIONS: The low birth weight in Asian Indians is not even partly explained by genetic variants near CCNL1 and ADCY5 which implies that non-genetic factors may predominate. However, the 'birth-weight-lowering' variant of ADCY5 was associated with elevated glucose and decreased insulin response in early adulthood which argues for a common genetic cause of low birth weight and risk of type 2 diabetes. PMID- 21712990 TI - Human trafficking: the shameful face of migration. PMID- 21712989 TI - Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease. AB - BACKGROUND: Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases. METHODS AND FINDINGS: In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid beta deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model. CONCLUSIONS: Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases. PMID- 21712991 TI - Serum soluble HLA-E in melanoma: a new potential immune-related marker in cancer. AB - BACKGROUND: Tumor-derived soluble factors, including soluble HLA molecules, can contribute to cancer immune escape and therefore impact on clinical course of malignant diseases. We previously reported that melanoma cells produce, in vitro, soluble forms of the non-classical MHC class I molecule HLA-E (sHLA-E). In order to investigate sHLA-E production by various tumors and to address its potential value as a tumor-associated marker, we developed a specific ELISA for the quantification of sHLA-E in biological fluids. METHODOLOGY/PRINCIPAL FINDINGS: We developed a sHLA-E specific and sensitive ELISA and we showed that serum sHLA-E levels were significantly elevated (P<0.01) in melanoma patients (n = 127), compared with healthy donors (n = 94). sHLA-E was also detected in the culture supernatants of a wide variety of tumor cell lines (n = 98) including melanomas, kidney, colorectal and breast cancers. Cytokines regulation of sHLA-E production by tumor cells was also carried out. IFN-gamma, IFN-alpha and TNF-alpha were found to upregulate sHLA-E production by tumor cells. CONCLUSIONS/SIGNIFICANCE: In view of the broad tumor tissue release of HLA-E and its up-regulation by inflammatory cytokines, sHLA-E should be studied for its involvement in immune responses against tumors. Interestingly, our results demonstrated a positive association between the presence of serum sHLA-E and melanoma. Therefore, the determination of sHLA-E levels, using ELISA approach, may be investigated as a clinical marker in cancer patients. PMID- 21712992 TI - Nutrition, diabetes and tuberculosis in the epidemiological transition. AB - BACKGROUND: Diabetes prevalence and body mass index reflect the nutritional profile of populations but have opposing effects on tuberculosis risk. Interactions between diabetes and BMI could help or hinder TB control in growing, aging, urbanizing populations. METHODS AND FINDINGS: We compiled data describing temporal changes in BMI, diabetes prevalence and population age structure in rural and urban areas for men and women in countries with high (India) and low (Rep. Korea) TB burdens. Using published data on the risks of TB associated with these factors, we calculated expected changes in TB incidence between 1998 and 2008. In India, TB incidence cases would have increased (28% from 1.7 m to 2.1 m) faster than population size (22%) because of adverse effects of aging, urbanization, changing BMI and rising diabetes prevalence, generating an increase in TB incidence per capita of 5.5% in 10 years. In India, general nutritional improvements were offset by a fall in BMI among the majority of men who live in rural areas. The growing prevalence of diabetes in India increased the annual number of TB cases in people with diabetes by 46% between 1998 and 2008. In Korea, by contrast, the number of TB cases increased more slowly (6.1% from 40,200 to 42,800) than population size (14%) because of positive effects of urbanization, increasing BMI and falling diabetes prevalence. Consequently, TB incidence per capita fell by 7.8% in 10 years. Rapid population aging was the most significant adverse effect in Korea. CONCLUSIONS: Nutritional and demographic changes had stronger adverse effects on TB in high-incidence India than in lower-incidence Korea. The unfavourable effects in both countries can be overcome by early drug treatment but, if left unchecked, could lead to an accelerating rise in TB incidence. The prevention and management of risk factors for TB would reinforce TB control by chemotherapy. PMID- 21712993 TI - Gene expression changes in GABA(A) receptors and cognition following chronic ketamine administration in mice. AB - Ketamine is a well-known anesthetic agent and a drug of abuse. Despite its widespread use and abuse, little is known about its long-term effects on the central nervous system. The present study was designed to evaluate the effect of long-term (1- and 3-month) ketamine administration on learning and memory and associated gene expression levels in the brain. The Morris water maze was used to assess spatial memory and gene expression changes were assayed using Affymetrix Genechips; a focus on the expression of GABA(A) receptors that mediate a tonic inhibition in the brain, was confirmed by quantitative real-time PCR and western blot. Compared with saline controls, there was a decline in learning and memory performance in the ketamine-treated mice. Genechip results showed that 110 genes were up-regulated and 136 genes were down-regulated. An ontology analysis revealed the most significant effects of ketamine were on GABA(A) receptors. In particular, there was a significant up-regulation of both mRNA and protein levels of the alpha 5 subunit (Gabra5) of the GABA(A) receptors in the prefrontal cortex. In conclusion, chronic exposure to ketamine impairs working memory in mice, which may be explained at least partly by up-regulation of Gabra5 subunits in the prefrontal cortex. PMID- 21712994 TI - Rickettsia 'in' and 'out': two different localization patterns of a bacterial symbiont in the same insect species. AB - Intracellular symbionts of arthropods have diverse influences on their hosts, and their functions generally appear to be associated with their localization within the host. The effect of localization pattern on the role of a particular symbiont cannot normally be tested since the localization pattern within hosts is generally invariant. However, in Israel, the secondary symbiont Rickettsia is unusual in that it presents two distinct localization patterns throughout development and adulthood in its whitefly host, Bemisia tabaci (B biotype). In the "scattered" pattern, Rickettsia is localized throughout the whitefly hemocoel, excluding the bacteriocytes, where the obligate symbiont Portiera aleyrodidarum and some other secondary symbionts are housed. In the "confined" pattern, Rickettsia is restricted to the bacteriocytes. We examined the effects of these patterns on Rickettsia densities, association with other symbionts (Portiera and Hamiltonella defensa inside the bacteriocytes) and on the potential for horizontal transmission to the parasitoid wasp, Eretmocerus mundus, while the wasp larvae are developing within the whitefly nymph. Sequences of four Rickettsia genes were found to be identical for both localization patterns, suggesting that they are closely related strains. However, real-time PCR analysis showed very different dynamics for the two localization types. On the first day post-adult emergence, Rickettsia densities were 21 times higher in the "confined" pattern vs. "scattered" pattern whiteflies. During adulthood, Rickettsia increased in density in the "scattered" pattern whiteflies until it reached the "confined" pattern Rickettsia density on day 21. No correlation between Rickettsia densities and Hamiltonella or Portiera densities were found for either localization pattern. Using FISH technique, we found Rickettsia in the gut of the parasitoid wasps only when they developed on whiteflies with the "scattered" pattern. The results suggest that the localization pattern of a symbiont may influence its dynamics within the host. PMID- 21712995 TI - HIV-1 gp120 induces expression of IL-6 through a nuclear factor-kappa B-dependent mechanism: suppression by gp120 specific small interfering RNA. AB - In addition to its role in virus entry, HIV-1 gp120 has also been implicated in HIV-associated neurocognitive disorders. However, the mechanism(s) responsible for gp120-mediated neuroinflammation remain undefined. In view of increased levels of IL-6 in HIV-positive individuals with neurological manifestations, we sought to address whether gp120 is involved in IL-6 over-expression in astrocytes. Transfection of a human astrocyte cell line with a plasmid encoding gp120 resulted in increased expression of IL-6 at the levels of mRNA and protein by 51.3+/-2.1 and 11.6+/-2.2 fold respectively; this effect of gp120 on IL-6 expression was also demonstrated using primary human fetal astrocytes. A similar effect on IL-6 expression was observed when primary astrocytes were treated with gp120 protein derived from different strains of X4 and R5 tropic HIV-1. The induction of IL-6 could be abrogated by use of gp120-specific siRNA. Furthermore, this study showed that the NF-kappaB pathway is involved in gp120-mediated IL-6 over-expression, as IKK-2 and IKKbeta inhibitors inhibited IL-6 expression by 56.5% and 60.8%, respectively. These results were also confirmed through the use of NF-kappaB specific siRNA. We also showed that gp120 could increase the phosphorylation of IkappaBalpha. Furthermore, gp120 transfection in the SVGA cells increased translocation of NF-kappaB from cytoplasm to nucleus. These results demonstrate that HIV-1 gp120-mediated over-expression of IL-6 in astrocytes is one mechanism responsible for neuroinflammation in HIV-infected individuals and this is mediated by the NF-kappaB pathway. PMID- 21712996 TI - Copy number variants in candidate genes are genetic modifiers of Hirschsprung disease. AB - Hirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract. The HSCR phenotype is highly variable with respect to gender, length of aganglionosis, familiality and the presence of additional anomalies. By molecular genetic analysis, a minimum of 11 neuro-developmental genes (RET, GDNF, NRTN, SOX10, EDNRB, EDN3, ECE1, ZFHX1B, PHOX2B, KIAA1279, TCF4) are known to harbor rare, high-penetrance mutations that confer a large risk to the bearer. In addition, two other genes (RET, NRG1) harbor common, low-penetrance polymorphisms that contribute only partially to risk and can act as genetic modifiers. To broaden this search, we examined whether a set of 67 proven and candidate HSCR genes harbored additional modifier alleles. In this pilot study, we utilized a custom-designed array CGH with ~33,000 test probes at an average resolution of ~185 bp to detect gene-sized or smaller copy number variants (CNVs) within these 67 genes in 18 heterogeneous HSCR patients. Using stringent criteria, we identified CNVs at three loci (MAPK10, ZFHX1B, SOX2) that are novel, involve regulatory and coding sequences of neuro-developmental genes, and show association with HSCR in combination with other congenital anomalies. Additional CNVs are observed under relaxed criteria. Our research suggests a role for CNVs in HSCR and, importantly, emphasizes the role of variation in regulatory sequences. A much larger study will be necessary both for replication and for identifying the full spectrum of small CNV effects. PMID- 21712997 TI - Protein phosphatase 1 (PP1) is a post-translational regulator of the mammalian circadian clock. AB - Circadian clocks coordinate the timing of important biological processes. Interconnected transcriptional and post-translational feedback loops based on a set of clock genes generate and maintain these rhythms with a period of about 24 hours. Many clock proteins undergo circadian cycles of post-translational modifications. Among these modifications, protein phosphorylation plays an important role in regulating activity, stability and intracellular localization of clock components. Several protein kinases were characterized as regulators of the circadian clock. However, the function of protein phosphatases, which balance phosphorylation events, in the mammalian clock mechanism is less well understood. Here, we identify protein phosphatase 1 (PP1) as regulator of period and light induced resetting of the mammalian circadian clock. Down-regulation of PP1 activity in cells by RNA interference and in vivo by expression of a specific inhibitor in the brain of mice tended to lengthen circadian period. Moreover, reduction of PP1 activity in the brain altered light-mediated clock resetting behavior in mice, enhancing the phase shifts in either direction. At the molecular level, diminished PP1 activity increased nuclear accumulation of the clock component PER2 in neurons. Hence, PP1, may reduce PER2 phosphorylation thereby influencing nuclear localization of this protein. This may at least partially influence period and phase shifting properties of the mammalian circadian clock. PMID- 21712998 TI - Self-guided psychological treatment for depressive symptoms: a meta-analysis. AB - BACKGROUND: A number of trials have examined the effects of self-guided psychological intervention, without any contact between the participants and a therapist or coach. The results and sizes of these trials have been mixed. This is the first quantitative meta-analysis, aimed at organizing and evaluating the literature, and estimating effect size. METHOD: We conducted systematic literature searches in PubMed, PsycINFO and Embase up to January 2010, and identified additional studies through earlier meta-analyses, and the references of included studies. We identified seven randomized controlled trials that met our inclusion criteria, with a total of 1,362 respondents. The overall quality of the studies was high. A post-hoc power calculation showed that the studies had sufficient statistical power to detect an effect size of d = 0.19. RESULTS: The overall mean effect size indicating the difference between self-guided psychological treatment and control groups at post-test was d = 0.28 (p<0.001), which corresponds to a NNT of 6.41. At 4 to 12 months follow-up the effect size was d = 0.23. There was no indication for significant publication bias. CONCLUSIONS: We found evidence that self-guided psychological treatment has a small but significant effect on participants with increased levels of depressive symptomatology. PMID- 21712999 TI - Reconstruction of endometrium from human endometrial side population cell lines. AB - Endometrial regeneration is mediated, at least in part, by the existence of a specialized somatic stem cell (SSC) population recently identified by several groups using the side population (SP) technique. We previously demonstrated that endometrial SP displays genotypic, phenotypic and the functional capability to develop human endometrium after subcutaneous injection in NOD-SCID mice. We have now established seven human endometrial SP (hESP) cell lines (ICE 1-7): four from the epithelial and three from the stromal fraction, respectively. SP cell lines were generated under hypoxic conditions based on their cloning efficiency ability, cultured for 12-15 passages (20 weeks) and cryopreserved. Cell lines displayed normal 46XX karyotype, intermediate telomerase activity pattern and expressed mRNAs encoding proteins that are considered characteristic of undifferentiated cells (Oct-4, GDF3, DNMT3B, Nanog, GABR3) and those of mesodermal origin (WT1, Cardiac Actin, Enolase, Globin, REN). Phenotype analysis corroborated their epithelial (CD9+) or stromal (vimentin+) cell origin and mesenchymal (CD90+, CD73+ and CD45-) attributes. Markers considered characteristic of ectoderm or endoderm were not detected. Cells did not express either estrogen receptor alpha (ERalpha) or progesterone receptor (PR). The hESP cell lines were able to differentiate in vitro into adipocytes and osteocytes, which confirmed their mesenchymal origin. Finally, we demonstrated their ability to generate human endometrium when transplanted beneath the renal capsule of NOD SCID mice. These findings confirm that SP cells exhibit key features of human endometrial SSC and open up new possibilities for the understanding of gynecological disorders such as endometriosis or Asherman syndrome. Our cell lines can be a valuable model to investigate new targets for endometrium proliferation in endometriosis. PMID- 21713000 TI - Epidemiological characteristics of 2009 (H1N1) pandemic influenza based on paired sera from a longitudinal community cohort study. AB - BACKGROUND: While patterns of incidence of clinical influenza have been well described, much uncertainty remains over patterns of incidence of infection. The 2009 pandemic provided both the motivation and opportunity to investigate patterns of mild and asymptomatic infection using serological techniques. However, to date, only broad epidemiological patterns have been defined, based on largely cross-sectional study designs with convenience sampling frameworks. METHODS AND FINDINGS: We conducted a paired serological survey of a cohort of households in Hong Kong, recruited using random digit dialing, and gathered data on severe confirmed cases from the public hospital system (>90% inpatient days). Paired sera were obtained from 770 individuals, aged 3 to 103, along with detailed individual-level and household-level risk factors for infection. Also, we extrapolated beyond the period of our study using time series of severe cases and we simulated alternate study designs using epidemiological parameters obtained from our data. Rates of infection during the period of our study decreased substantially with age: for 3-19 years, the attack rate was 39% (31% 49%); 20-39 years, 8.9% (5.3%-14.7%); 40-59 years, 5.3% (3.5%-8.0%); and 60 years or older, 0.77% (0.18%-4.2%). We estimated parameters for a parsimonious model of infection in which a linear age term and the presence of a child in the household were used to predict the log odds of infection. Patterns of symptom reporting suggested that children experienced symptoms more often than adults. The overall rate of confirmed pandemic (H1N1) 2009 influenza (H1N1pdm) deaths was 7.6 (6.2 9.5) per 100,000 infections. However, there was substantial and progressive increase in deaths per 100,000 infections with increasing age from 0.66 (0.65 0.86) for 3-19 years up to 220 (50-4,000) for 60 years and older. Extrapolating beyond the period of our study using rates of severe disease, we estimated that 56% (43%-69%) of 3-19 year olds and 16% (13%-18%) of people overall were infected by the pandemic strain up to the end of January 2010. Using simulation, we found that, during 2009, larger cohorts with shorter follow-up times could have rapidly provided similar data to those presented here. CONCLUSIONS: Should H1N1pdm evolve to be more infectious in older adults, average rates of severe disease per infection could be higher in future waves: measuring such changes in severity requires studies similar to that described here. The benefit of effective vaccination against H1N1pdm infection is likely to be substantial for older individuals. Revised pandemic influenza preparedness plans should include prospective serological cohort studies. Many individuals, of all ages, remained susceptible to H1N1pdm after the main 2009 wave in Hong Kong. Please see later in the article for the Editors' Summary. PMID- 21713001 TI - Col V siRNA engineered tenocytes for tendon tissue engineering. AB - The presence of uniformly small collagen fibrils in tendon repair is believed to play a major role in suboptimal tendon healing. Collagen V is significantly elevated in healing tendons and plays an important role in fibrillogenesis. The objective of this study was to investigate the effect of a particular chain of collagen V on the fibrillogenesis of Sprague-Dawley rat tenocytes, as well as the efficacy of Col V siRNA engineered tenocytes for tendon tissue engineering. RNA interference gene therapy and a scaffold free tissue engineered tendon model were employed. The results showed that scaffold free tissue engineered tendon had tissue-specific tendon structure. Down regulation of collagen V alpha1 or alpha2 chains by siRNAs (Col5alpha1 siRNA, Col5alpha2 siRNA) had different effects on collagen I and decorin gene expressions. Col5alpha1 siRNA treated tenocytes had smaller collagen fibrils with abnormal morphology; while those Col5alpha2 siRNA treated tenocytes had the same morphology as normal tenocytes. Furthermore, it was found that tendons formed by coculture of Col5alpha1 siRNA treated tenocytes with normal tenocytes at a proper ratio had larger collagen fibrils and relative normal contour. Conclusively, it was demonstrated that Col V siRNA engineered tenocytes improved tendon tissue regeneration. And an optimal level of collagen V is vital in regulating collagen fibrillogenesis. This may provide a basis for future development of novel cellular- and molecular biology-based therapeutics for tendon diseases. PMID- 21713002 TI - Pre-absorbed immunoproteomics: a novel method for the detection of Streptococcus suis surface proteins. AB - Streptococcus suis serotype 2 (SS2) is a zoonotic pathogen that can cause infections in pigs and humans. Bacterial surface proteins are often investigated as potential vaccine candidates and biomarkers of virulence. In this study, a novel method for identifying bacterial surface proteins is presented, which combines immunoproteomic and immunoserologic techniques. Critical to the success of this new method is an improved procedure for generating two-dimensional electrophoresis gel profiles of S. suis proteins. The S. suis surface proteins identified in this study include muramidase-released protein precursor (MRP) and an ABC transporter protein, while MRP is thought to be one of the main virulence factors in SS2 located on the bacterial surface. Herein, we demonstrate that the ABC transporter protein can bind to HEp-2 cells, which strongly suggests that this protein is located on the bacterial cell surface and may be involved in pathogenesis. An immunofluorescence assay confirmed that the ABC transporter is localized to the bacterial outer surface. This new method may prove to be a useful tool for identifying surface proteins, and aid in the development of new vaccine subunits and disease diagnostics. PMID- 21713003 TI - Genome-wide distribution and organization of microsatellites in plants: an insight into marker development in Brachypodium. AB - Plant genomes are complex and contain large amounts of repetitive DNA including microsatellites that are distributed across entire genomes. Whole genome sequences of several monocot and dicot plants that are available in the public domain provide an opportunity to study the origin, distribution and evolution of microsatellites, and also facilitate the development of new molecular markers. In the present investigation, a genome-wide analysis of microsatellite distribution in monocots (Brachypodium, sorghum and rice) and dicots (Arabidopsis, Medicago and Populus) was performed. A total of 797,863 simple sequence repeats (SSRs) were identified in the whole genome sequences of six plant species. Characterization of these SSRs revealed that mono-nucleotide repeats were the most abundant repeats, and that the frequency of repeats decreased with increase in motif length both in monocots and dicots. However, the frequency of SSRs was higher in dicots than in monocots both for nuclear and chloroplast genomes. Interestingly, GC-rich repeats were the dominant repeats only in monocots, with the majority of them being present in the coding region. These coding GC-rich repeats were found to be involved in different biological processes, predominantly binding activities. In addition, a set of 22,879 SSR markers that were validated by e-PCR were developed and mapped on different chromosomes in Brachypodium for the first time, with a frequency of 101 SSR markers per Mb. Experimental validation of 55 markers showed successful amplification of 80% SSR markers in 16 Brachypodium accessions. An online database 'BraMi' (Brachypodium microsatellite markers) of these genome-wide SSR markers was developed and made available in the public domain. The observed differential patterns of SSR marker distribution would be useful for studying microsatellite evolution in a monocot dicot system. SSR markers developed in this study would be helpful for genomic studies in Brachypodium and related grass species, especially for the map based cloning of the candidate gene(s). PMID- 21713004 TI - Vancomycin heteroresistance is associated with reduced mortality in ST239 methicillin-resistant Staphylococcus aureus blood stream infections. AB - BACKGROUND: Despite hVISA infections being associated with vancomycin treatment failure, no previous study has been able to detect a mortality difference between heteroresistant vancomycin intermediate Staphylococcus aureus (hVISA) and vancomycin susceptible Staphylococcus aureus (VSSA) bloodstream infections (BSI). METHODOLOGY: Consecutive methicillin-resistant S. aureus (MRSA) BSI episodes between 1996 and 2008 were reviewed. Patient demographics, clinical presentation, treatment and overall mortality at 30 days were extracted from the medical records. All isolates underwent vancomycin minimum inhibitory concentration (VMIC) testing by broth microdilution and Etest. hVISA was confirmed by population analysis profiling using the area under the curve method (PAP-AUC). PRINCIPAL FINDINGS: 401 evaluable MRSA BSI episodes were identified over the 12 years. Of these, 46 (11.5%) and 2 (0.5%) were confirmed as hVISA and VISA by PAP AUC respectively. hVISA predominantly occurred in ST239-like MRSA isolates with high VMIC (2 mg/L). Compared to VSSA, hVISA was associated with chronic renal failure (p<0.001), device related infections (haemodialysis access) (p<0.001) and previous vancomycin usage (p = 0.004). On multivariate analysis, independent predictors of mortality included age, presence of multiple co-morbidities, principal diagnosis, transit to ICU and severity of illness while infection related surgery and hVISA phenotype were associated with increased survival. CONCLUSIONS/SIGNIFICANCE: The presence of hVISA is dependent on the appropriate interplay between host and pathogen factors. hVISA in ST239 MRSA is an independent predictor of survival. Whether these findings would be replicated across all MRSA clones is unknown and warrants further study. PMID- 21713005 TI - Rhinovirus genome variation during chronic upper and lower respiratory tract infections. AB - Routine screening of lung transplant recipients and hospital patients for respiratory virus infections allowed to identify human rhinovirus (HRV) in the upper and lower respiratory tracts, including immunocompromised hosts chronically infected with the same strain over weeks or months. Phylogenetic analysis of 144 HRV-positive samples showed no apparent correlation between a given viral genotype or species and their ability to invade the lower respiratory tract or lead to protracted infection. By contrast, protracted infections were found almost exclusively in immunocompromised patients, thus suggesting that host factors rather than the virus genotype modulate disease outcome, in particular the immune response. Complete genome sequencing of five chronic cases to study rhinovirus genome adaptation showed that the calculated mutation frequency was in the range observed during acute human infections. Analysis of mutation hot spot regions between specimens collected at different times or in different body sites revealed that non-synonymous changes were mostly concentrated in the viral capsid genes VP1, VP2 and VP3, independent of the HRV type. In an immunosuppressed lung transplant recipient infected with the same HRV strain for more than two years, both classical and ultra-deep sequencing of samples collected at different time points in the upper and lower respiratory tracts showed that these virus populations were phylogenetically indistinguishable over the course of infection, except for the last month. Specific signatures were found in the last two lower respiratory tract populations, including changes in the 5'UTR polypyrimidine tract and the VP2 immunogenic site 2. These results highlight for the first time the ability of a given rhinovirus to evolve in the course of a natural infection in immunocompromised patients and complement data obtained from previous experimental inoculation studies in immunocompetent volunteers. PMID- 21713007 TI - Perceptual grouping of object contours survives saccades. AB - Human observers explore scenes by shifting their gaze from object to object. Before each eye movement, a peripheral glimpse of the next object to be fixated has however already been caught. Here we investigate whether the perceptual organization extracted from such a preview could guide the perceptual analysis of the same object during the next fixation. We observed that participants were indeed significantly faster at grouping together spatially separate elements into an object contour, when the same contour elements had also been grouped together in the peripheral preview display. Importantly, this facilitation occurred despite a change in the grouping cue defining the object contour (similarity versus collinearity). We conclude that an intermediate-level description of object shape persists in the visual system across gaze shifts, providing it with a robust basis for balancing efficiency and continuity during scene exploration. PMID- 21713006 TI - Identification of a highly antigenic linear B cell epitope within Plasmodium vivax apical membrane antigen 1 (AMA-1). AB - Apical membrane antigen 1 (AMA-1) is considered to be a major candidate antigen for a malaria vaccine. Previous immunoepidemiological studies of naturally acquired immunity to Plasmodium vivax AMA-1 (PvAMA-1) have shown a higher prevalence of specific antibodies to domain II (DII) of AMA-1. In the present study, we confirmed that specific antibody responses from naturally infected individuals were highly reactive to both full-length AMA-1 and DII. Also, we demonstrated a strong association between AMA-1 and DII IgG and IgG subclass responses. We analyzed the primary sequence of PvAMA-1 for B cell linear epitopes co-occurring with intrinsically unstructured/disordered regions (IURs). The B cell epitope comprising the amino acid sequence 290-307 of PvAMA-1 (SASDQPTQYEEEMTDYQK), with the highest prediction scores, was identified in domain II and further selected for chemical synthesis and immunological testing. The antigenicity of the synthetic peptide was identified by serological analysis using sera from P. vivax-infected individuals who were knowingly reactive to the PvAMA-1 ectodomain only, domain II only, or reactive to both antigens. Although the synthetic peptide was recognized by all serum samples specific to domain II, serum with reactivity only to the full-length protein presented 58.3% positivity. Moreover, IgG reactivity against PvAMA-1 and domain II after depletion of specific synthetic peptide antibodies was reduced by 18% and 33% (P = 0.0001 for both), respectively. These results suggest that the linear epitope SASDQPTQYEEEMTDYQK is highly antigenic during natural human infections and is an important antigenic region of the domain II of PvAMA-1, suggesting its possible future use in pre-clinical studies. PMID- 21713008 TI - Genus-wide physicochemical evidence of extracellular crystalline silver nanoparticles biosynthesis by Morganella spp. AB - This study was performed to determine whether extracellular silver nanoparticles (AgNPs) production is a genus-wide phenotype associated with all the members of genus Morganella, or only Morganella morganii RP-42 isolate is able to synthesize extracellular Ag nanoparticles. To undertake this study, all the available Morganella isolates were exposed to Ag+ ions, and the obtained nanoproducts were thoroughly analyzed using physico-chemical characterization tools such as transmission electron microscopy (TEM), UV-visible spectrophotometry (UV-vis), and X-ray diffraction (XRD) analysis. It was identified that extracellular biosynthesis of crystalline silver nanoparticles is a unique biochemical character of all the members of genus Morganella, which was found independent of environmental changes. Significantly, the inability of other closely related members of the family Enterobacteriaceae towards AgNPs synthesis strongly suggests that AgNPs synthesis in the presence of Ag+ ions is a phenotypic character that is uniquely associated with genus Morganella. PMID- 21713009 TI - Vernalization-repression of Arabidopsis FLC requires promoter sequences but not antisense transcripts. AB - The repression of Arabidopsis FLC expression by vernalization (extended cold) has become a model for understanding polycomb-associated epigenetic regulation in plants. Antisense and sense non-coding RNAs have been respectively implicated in initiation and maintenance of FLC repression by vernalization. We show that the promoter and first exon of the FLC gene are sufficient to initiate repression during vernalization; this initial repression of FLC does not require antisense transcription. Long-term maintenance of FLC repression requires additional regions of the gene body, including those encoding sense non-coding transcripts. PMID- 21713010 TI - Characterizing the role of cell-wall beta-1,3-exoglucanase Xog1p in Candida albicans adhesion by the human antimicrobial peptide LL-37. AB - Candida albicans is the major fungal pathogen of humans. Its adhesion to host cell surfaces is the first critical step during mucosal infection. Antimicrobial peptides play important roles in the first line of mucosal immunity against C. albicans infection. LL-37 is the only member of the human cathelicidin antimicrobial peptide family and is commonly expressed in various tissues, including epithelium. We previously showed that LL-37 significantly reduced C. albicans adhesion to plastic, oral epidermoid OECM-1 cells, and urinary bladders of female BALB/c mice. The inhibitory effect of LL-37 on cell adhesion occurred via the binding of LL-37 to cell-wall carbohydrates. Here we showed that formation of LL-37-cell-wall protein complexes potentially inhibits C. albicans adhesion to polystyrene. Using phage display and ELISA, we identified 10 peptide sequences that could bind LL-37. A BLAST search revealed that four sequences in the major C. albicans cell-wall beta-1,3-exoglucanase, Xog1p, were highly similar to the consensus sequence derived from the 10 biopanned peptides. One Xog1p derived peptide, Xog1p(90-115), and recombinant Xog1p associated with LL-37, thereby reversing the inhibitory effect of LL-37 on C. albicans adhesion. LL-37 reduced Xog1p activity and thus interrupted cell-wall remodeling. Moreover, deletion of XOG1 or another beta-1,3-exoglucanase-encoding gene EXG2 showed that only when XOG1 was deleted did cellular exoglucanase activity, cell adhesion and LL-37 binding decrease. Antibodies against Xog1p also decreased cell adhesion. These data reveal that Xog1p, originally identified from LL-37 binding, has a role in C. albicans adhesion to polystyrene and, by inference, attach to host cells via direct or indirect manners. Compounds that target Xog1p might find use as drugs that prevent C. albicans infection. Additionally, LL-37 could potentially be used to screen for other cell-wall components involved in fungal cell adhesion. PMID- 21713011 TI - The efficiency of attentional networks in early and late bilinguals: the role of age of acquisition. AB - Previous studies have demonstrated a bilingual advantage in the efficiency of executive attention. A question remains, however, about the impact of the age of L2 acquisition and relative balance of the two languages on the enhancement of executive functions in bilinguals, and whether this is modulated by the similarity of the bilingual's two languages. The present study explores these issues by comparing the efficiency of attentional networks amongst three groups of young adults living in Australia: English monolinguals and early and late Chinese-English bilinguals. We also address the impact of bilingualism on hemispheric lateralization of cognitive functions, which is of interest since a recent study on early bilinguals revealed reduced hemispheric asymmetry in attentional functioning. In the present study, participants performed a modified version of the lateralized attention network test. Both early and late bilinguals were found to have more efficient executive network than monolinguals. The late bilinguals, who were also reported to be more balanced in the proficiency and usage of their two languages, showed the greatest advantage in conflict resolution, whereas early bilinguals seemed to show enhanced monitoring processes. These group differences were observed when controlling for non-verbal intelligence and socioeconomic status. Such results suggest that specific factors of language experience may differentially influence the mechanisms of cognitive control. Since the bilinguals had distinct language sets, it seems that the influence of bilingualism on executive functions is present regardless of the similarity between the two languages. As for hemispheric lateralization, although the results were not clear-cut, they suggest the reduced lateralization in early bilinguals. PMID- 21713012 TI - Increased Alpha-Band Power during the Retention of Shapes and Shape-Location Associations in Visual Short-Term Memory. AB - Studies exploring the role of neural oscillations in cognition have revealed sustained increases in alpha-band (~8-14 Hz) power during the delay period of delayed-recognition short-term memory tasks. These increases have been proposed to reflect the inhibition, for example, of cortical areas representing task irrelevant information, or of potentially interfering representations from previous trials. Another possibility, however, is that elevated delay-period alpha-band power (DPABP) reflects the selection and maintenance of information, rather than, or in addition to, the inhibition of task-irrelevant information. In the present study, we explored these possibilities using a delayed-recognition paradigm in which the presence and task relevance of shape information was systematically manipulated across trial blocks and electroencephalographic was used to measure alpha-band power. In the first trial block, participants remembered locations marked by identical black circles. The second block featured the same instructions, but locations were marked by unique shapes. The third block featured the same stimulus presentation as the second, but with pretrial instructions indicating, on a trial-by-trial basis, whether memory for shape or location was required, the other dimension being irrelevant. In the final block, participants remembered the unique pairing of shape and location for each stimulus. Results revealed minimal DPABP in each of the location-memory conditions, whether locations were marked with identical circles or with unique task-irrelevant shapes. In contrast, alpha-band power increases were observed in both the shape-memory condition, in which location was task irrelevant, and in the critical final condition, in which both shape and location were task relevant. These results provide support for the proposal that alpha-band oscillations reflect the retention of shape information and/or shape-location associations in short-term memory. PMID- 21713013 TI - A crabbing misadventure. PMID- 21713014 TI - Teenage cervical screening in a high risk American population. AB - BACKGROUND: The new 2009 ACOG guideline for cervical cytology screening changed the starting age to 21 years regardless of the age of onset of sexual intercourse. However, many recent studies have shown a dramatic increase in the incidence of cervical epithelial abnormalities among adolescents within the past two decades. MATERIALS AND METHODS: For this study, the reports of 156,342 cervical cytology were available of which 12,226 (7.8%) were from teenagers. A total of 192 teenagers with high grade intraepithelial lesion (HSIL) cervical cytology were identified. The ages ranged from 13 to 19 years with a mean of 17.7 years and a median of 18 years. Among them, 31.3% were pregnant, 12.0% were postpartum, and 13.5% were on oral contraceptive. Ninety-eight had prior cervical cytology. RESULTS: The teenagers had statistically significant higher detection rates of overall abnormal cervical cytology (23.6% vs. 6.6%, P = 0), with 15.4% vs. 3.2% (P = 0) of low grade intraepithelial lesion (LSIL) and 1.8% vs. 1.0% (P = 2.56 * 10(-13) ) of HSIL compared to women >=20 years. The teenage group had the highest abnormal cytology among all age groups. The LSIL/HSIL ratio was 8.5:1 for teenagers and 3.1:1 for women >=20 years. A total of 131 teenagers had cervical biopsies within 12 months of the HSIL cytology, with diagnoses of 39 CIN 3, 1 VAIN 3, 15 CIN 2, 62 CIN 1, and 14 had a negative histology (CIN 0). Only in 19 of these 39 women, the CIN 2/3 lesion proved to be persistent. CONCLUSION: We conclude that cytology screening of high risk teenagers is effective in detecting CIN 2/3 lesions. Moreover, treatment and careful follow-up can be realized. PMID- 21713015 TI - Pattern of epithelial cell abnormality in Pap smear: A clinicopathological and demographic correlation. AB - BACKGROUND: In the low resource settings of a developing country, a conventional Papanicolaou (Pap) test is the mainstay screening system for cervical cancer. In order to counsel women and to organize a public health system for cervical cancer screening by Pap smear examination, it is imperative to know the pattern of premalignant and malignant lesions. This study was undertaken to find out the prevalence of an abnormal Pap smear, in a tertiary hospital of a developing country, and to carry out a clinicopathological and demographical analysis for establishing the pattern of epithelial cell abnormality in a Pap smear. MATERIALS AND METHODS: A cross-sectional descriptive study was carried out in a total of 1699 patients who underwent Pap smear examination. The prevalence of epithelial cell abnormality in the Pap smear was calculated in proportions / percentages. Specimen adequacy and reporting was assessed according to the revised Bethesda system. RESULTS: Among the total of 1699 patients who had their Pap smear done, 139 (8.18%) revealed epithelial cell abnormality. Altogether 26 smears revealed high-grade lesions and malignancy, most of which were found to be in women belonging to the 30 - 39 and >= 45 age group. A total of 75 (53.96%) women were in the 20 - 44 age group and 64 (46.04%) were in the >= 45 age group. A bimodal age distribution was detected in the epithelial cell abnormality, with the bulk being diagnosed in patients aged 45 or above. Overall one-third of the patients with an abnormal Pap smear result showed healthy cervix in per vaginal examination. CONCLUSIONS: A raised prevalence of epithelial cell abnormality reflects the lack of awareness about cervical cancer screening. Women aged 45 or above harbor the bulk of premalignant and malignant lesions in the Pap smear, signifying that these women are among the under users of cytological screening. PMID- 21713016 TI - Endoscopic ultrasound-guided fine-needle aspiration of metastases to the pancreas: A study of 25 cases. AB - BACKGROUND: Metastases to the pancreas are an uncommon cause of pancreatic masses seen on endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA). The purpose of this study is to retrospectively review the cytomorphology, clinical findings, and results of ancillary studies in a large series of these unusual cases. MATERIALS AND METHODS: We searched our institution's pathology database for EUS-guided FNAs of the pancreas that were diagnostic of metastatic tumor over a 5-year period. The final cytologic diagnosis, results of ancillary studies, corresponding histological material, and clinical follow-up data were reviewed in these cases. RESULTS: A total of 1172 pancreatic EUS-guided FNAs were identified, of which 25 cases (2.1%) had a confirmed diagnosis of a pancreatic metastasis. This included 12 (48%) cases of renal cell carcinoma, 3 (12%) melanomas, 3 (12%) small cell carcinomas, and 7 (28%) other malignancies. In these metastatic tumors involving the pancreas, 20 (80%) of the lesions were solitary. Four (16%) cases had no prior history of malignancy. The average time to diagnosis of pancreatic metastasis was 5.3 years. Immunohistochemistry and special stains were performed in 22 (88%) and 9 (36%) cases, respectively. CONCLUSIONS: Our data shows that although metastases to the pancreas are rare, they can present as a solitary mass many years after the primary malignancy is diagnosed and can even be the first manifestation of an extrapancreatic primary in a small number of cases. It is important to consider the possibility of a metastatic lesion in the pancreas because this may require a different management than a primary pancreatic tumor. PMID- 21713017 TI - Pyrethroid resistance reduces the efficacy of space sprays for dengue control on the island of Martinique (Caribbean). AB - BACKGROUND: Dengue fever is reemerging on the island of Martinique and is a serious threat for the human population. During dengue epidemics, adult Aedes aegypti control with pyrethroid space sprays is implemented in order to rapidly reduce transmission. Unfortunately, vector control programs are facing operational challenges with the emergence of pyrethroid resistant Ae. aegypti populations. METHODOLOGY/PRINCIPAL FINDINGS: To assess the impact of pyrethroid resistance on the efficacy of treatments, applications of deltamethrin and natural pyrethrins were performed with vehicle-mounted thermal foggers in 9 localities of Martinique, where Ae. aegypti populations are strongly resistant to pyrethroids. Efficacy was assessed by monitoring mortality rates of naturally resistant and laboratory susceptible mosquitoes placed in sentinel cages. Before, during and after spraying, larval and adult densities were estimated. Results showed high mortality rates of susceptible sentinel mosquitoes treated with deltamethrin while resistant mosquitoes exhibited very low mortality. There was no reduction of either larval or adult Ae. aegypti population densities after treatments. CONCLUSIONS/SIGNIFICANCE: This is the first documented evidence that pyrethroid resistance impedes dengue vector control using pyrethroid-based treatments. These results emphasize the need for alternative tools and strategies for dengue control programs. PMID- 21713018 TI - Age-specificity of clinical dengue during primary and secondary infections. AB - BACKGROUND: This study aims to estimate the age-specific risks of clinical dengue attack (i.e., the risk of symptomatic dengue among the total number of dengue virus (DENV) infections) during primary and secondary infections. METHODS: We analyzed two pieces of epidemiological information in Binh Thuan province, southern Vietnam, i.e., age-specific seroprevalence and a community-wide longitudinal study of clinical dengue attack. The latter data set stratified febrile patients with DENV infection by age as well as infection parity. A simple modeling approach was employed to estimate the age-specific risks of clinical dengue attack during primary and secondary infections. RESULTS: Using the seroprevalence data, the force of infection was estimated to be 11.7% (95% confidence intervals (CI): 10.8-12.7) per year. Median age (and the 25-75 percentiles) of dengue fever patients during primary and secondary infections were 12 (9-20) and 20 (14-31) years, respectively. The estimated age-specific risk of clinical dengue increases as a function of age for both primary and secondary infections; the estimated proportion of symptomatic patients among the total number of infected individuals was estimated to be <7% for those aged <10 years for both primary and secondary infections, but increased as patients become older, reaching to 8-11% by the age of 20 years. CONCLUSIONS/SIGNIFICANCE: For both primary and secondary infections, higher age at DENV infection was shown to result in higher risk of clinical attack. Age as an important modulator of clinical dengue explains recent increase in dengue notifications in ageing countries in Southeast Asia, and moreover, poses a paradoxical problem of an increase in adult patients resulting from a decline in the force of infection, which may be caused by various factors including time-dependent variations in epidemiological, ecological and demographic dynamics. PMID- 21713019 TI - Characterisation of the wildlife reservoir community for human and animal trypanosomiasis in the Luangwa Valley, Zambia. AB - BACKGROUND: Animal and human trypanosomiasis are constraints to both animal and human health in Sub-Saharan Africa, but there is little recent evidence as to how these parasites circulate in wild hosts in natural ecosystems. The Luangwa Valley in Zambia supports high densities of tsetse flies (Glossina species) and is recognised as an historical sleeping sickness focus. The objective of this study was to characterise the nature of the reservoir community for trypanosomiasis in the absence of influence from domesticated hosts. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional survey of trypanosome prevalence in wildlife hosts was conducted in the Luangwa Valley from 2005 to 2007. Samples were collected from 418 animals and were examined for the presence of Trypanosoma brucei s.l., T. b. rhodesiense, Trypanosoma congolense and Trypanosoma vivax using molecular diagnostic techniques. The overall prevalence of infection in all species was 13.9% (95% confidence interval [CI]: 10.71-17.57%). Infection was significantly more likely to be detected in waterbuck (Kobus ellipsiprymnus) (Odds ratio [OR]=10.5, 95% CI: 2.36-46.71), lion (Panthera leo) (OR=5.3, 95% CI: 1.40-19.69), greater kudu (Tragelaphus strepsiceros) (OR=4.7, 95% CI: 1.41-15.41) and bushbuck (Tragelaphus scriptus) (OR=4.5, 95% CI: 1.51-13.56). Bushbucks are important hosts for T. brucei s.l. while the Bovidae appear the most important for T. congolense. The epidemiology of T. vivax was less clear, but parasites were detected most frequently in waterbuck. Human infective T. b. rhodesiense were identified for the first time in African buffalo (Syncerus caffer) and T. brucei s.l. in leopard (Panthera pardus). Variation in infection rates was demonstrated at species level rather than at family or sub-family level. A number of significant risk factors interact to influence infection rates in wildlife including taxonomy, habitat and blood meal preference. CONCLUSION AND SIGNIFICANCE: Trypanosoma parasites circulate within a wide and diverse host community in this bio-diverse ecosystem. Consistent land use patterns over the last century have resulted in epidemiological stability, but this may be threatened by the recent influx of people and domesticated livestock into the mid Luangwa Valley. PMID- 21713020 TI - In-depth analysis of the antibody response of individuals exposed to primary dengue virus infection. AB - Humans who experience a primary dengue virus (DENV) infection develop antibodies that preferentially neutralize the homologous serotype responsible for infection. Affected individuals also generate cross-reactive antibodies against heterologous DENV serotypes, which are non-neutralizing. Dengue cross-reactive, non neutralizing antibodies can enhance infection of Fc receptor bearing cells and, potentially, exacerbate disease. The actual binding sites of human antibody on the DENV particle are not well defined. We characterized the specificity and neutralization potency of polyclonal serum antibodies and memory B-cell derived monoclonal antibodies (hMAbs) from 2 individuals exposed to primary DENV infections. Most DENV-specific hMAbs were serotype cross-reactive and weakly neutralizing. Moreover, many hMAbs bound to the viral pre-membrane protein and other sites on the virus that were not preserved when the viral envelope protein was produced as a soluble, recombinant antigen (rE protein). Nonetheless, by modifying the screening procedure to detect rare antibodies that bound to rE, we were able to isolate and map human antibodies that strongly neutralized the homologous serotype of DENV. Our MAbs results indicate that, in these two individuals exposed to primary DENV infections, a small fraction of the total antibody response was responsible for virus neutralization. PMID- 21713021 TI - Health services for Buruli ulcer control: lessons from a field study in Ghana. AB - BACKGROUND: Buruli ulcer (BU), caused by Mycobacterium ulcerans infection, is a debilitating disease of the skin and underlying tissue. The first phase of a BU prevention and treatment programme (BUPaT) was initiated from 2005-2008, in the Ga-West and Ga-South municipalities in Ghana to increase access to BU treatment and to improve early case detection and case management. This paper assesses achievements of the BUPaT programme and lessons learnt. It also considers the impact of the programme on broader interests of the health system. METHODS: A mixed-methods approach included patients' records review, review of programme reports, a stakeholder forum, key informant interviews, focus group discussions, clinic visits and observations. PRINCIPAL FINDINGS: Extensive collaboration existed across all levels, (national, municipality, and community), thus strengthening the health system. The programme enhanced capacities of all stakeholders in various aspects of health services delivery and demonstrated the importance of health education and community-based surveillance to create awareness and encourage early treatment. A patient database was also created using recommended World Health Organisation (WHO) forms which showed that 297 patients were treated from 2005-2008. The proportion of patients requiring only antibiotic treatment, introduced in the course of the programme, was highest in the last year (35.4% in the first, 23.5% in the second and 42.5% in the third year). Early antibiotic treatment prevented recurrences which was consistent with programme aims. CONCLUSIONS: To improve early case management of BU, strengthening existing clinics to increase access to antibiotic therapy is critical. Intensifying health education and surveillance would ultimately increase early reporting and treatment for all cases. Further research is needed to explain the role of environmental factors for BU contagion. Programme strategies reported in our study: collaboration among stakeholders, health education, community surveillance and regular antibiotic treatment can be adopted for any BU-endemic area in Ghana. PMID- 21713023 TI - The diagnostic sensitivity of dengue rapid test assays is significantly enhanced by using a combined antigen and antibody testing approach. AB - BACKGROUND: Serological tests for IgM and IgG are routinely used in clinical laboratories for the rapid diagnosis of dengue and can differentiate between primary and secondary infections. Dengue virus non-structural protein 1 (NS1) has been identified as an early marker for acute dengue, and is typically present between days 1-9 post-onset of illness but following seroconversion it can be difficult to detect in serum. AIMS: To evaluate the performance of a newly developed Panbio(r) Dengue Early Rapid test for NS1 and determine if it can improve diagnostic sensitivity when used in combination with a commercial IgM/IgG rapid test. METHODOLOGY: The clinical performance of the Dengue Early Rapid was evaluated in a retrospective study in Vietnam with 198 acute laboratory-confirmed positive and 100 negative samples. The performance of the Dengue Early Rapid in combination with the IgM/IgG Rapid test was also evaluated in Malaysia with 263 laboratory-confirmed positive and 30 negative samples. KEY RESULTS: In Vietnam the sensitivity and specificity of the test was 69.2% (95% CI: 62.8% to 75.6%) and 96% (95% CI: 92.2% to 99.8) respectively. In Malaysia the performance was similar with 68.9% sensitivity (95% CI: 61.8% to 76.1%) and 96.7% specificity (95% CI: 82.8% to 99.9%) compared to RT-PCR. Importantly, when the Dengue Early Rapid test was used in combination with the IgM/IgG test the sensitivity increased to 93.0%. When the two tests were compared at each day post-onset of illness there was clear differentiation between the antigen and antibody markers. CONCLUSIONS: This study highlights that using dengue NS1 antigen detection in combination with anti-glycoprotein E IgM and IgG serology can significantly increase the sensitivity of acute dengue diagnosis and extends the possible window of detection to include very early acute samples and enhances the clinical utility of rapid immunochromatographic testing for dengue. PMID- 21713022 TI - Community participation in Chagas disease vector surveillance: systematic review. AB - BACKGROUND: Vector control has substantially reduced Chagas disease (ChD) incidence. However, transmission by household-reinfesting triatomines persists, suggesting that entomological surveillance should play a crucial role in the long term interruption of transmission. Yet, infestation foci become smaller and harder to detect as vector control proceeds, and highly sensitive surveillance methods are needed. Community participation (CP) and vector-detection devices (VDDs) are both thought to enhance surveillance, but this remains to be thoroughly assessed. METHODOLOGY/PRINCIPAL FINDINGS: We searched Medline, Web of Knowledge, Scopus, LILACS, SciELO, the bibliographies of retrieved studies, and our own records. Data from studies describing vector control and/or surveillance interventions were extracted by two reviewers. Outcomes of primary interest included changes in infestation rates and the detection of infestation/reinfestation foci. Most results likely depended on study- and site specific conditions, precluding meta-analysis, but we re-analysed data from studies comparing vector control and detection methods whenever possible. Results confirm that professional, insecticide-based vector control is highly effective, but also show that reinfestation by native triatomines is common and widespread across Latin America. Bug notification by householders (the simplest CP-based strategy) significantly boosts vector detection probabilities; in comparison, both active searches and VDDs perform poorly, although they might in some cases complement each other. CONCLUSIONS/SIGNIFICANCE: CP should become a strategic component of ChD surveillance, but only professional insecticide spraying seems consistently effective at eliminating infestation foci. Involvement of stakeholders at all process stages, from planning to evaluation, would probably enhance such CP-based strategies. PMID- 21713024 TI - Duffy negative antigen is no longer a barrier to Plasmodium vivax--molecular evidences from the African West Coast (Angola and Equatorial Guinea). AB - BACKGROUND: Plasmodium vivax shows a small prevalence in West and Central Africa due to the high prevalence of Duffy negative people. However, Duffy negative individuals infected with P. vivax have been reported in areas of high prevalence of Duffy positive people who may serve as supply of P. vivax strains able to invade Duffy negative erythrocytes. We investigated the presence of P. vivax in two West African countries, using blood samples and mosquitoes collected during two on-going studies. METHODOLOGY/FINDINGS: Blood samples from a total of 995 individuals were collected in seven villages in Angola and Equatorial Guinea, and 820 Anopheles mosquitoes were collected in Equatorial Guinea. Identification of the Plasmodium species was achieved by nested PCR amplification of the small subunit rRNA genes; P. vivax was further characterized by csp gene analysis. Positive P. vivax-human isolates were genotyped for the Duffy blood group through the analysis of the DARC gene. Fifteen Duffy-negative individuals, 8 from Equatorial Guinea (out of 97) and 7 from Angola (out of 898), were infected with two different strains of P. vivax (VK210 and VK247). CONCLUSIONS: In this study we demonstrated that P. vivax infections were found both in humans and mosquitoes, which means that active transmission is occurring. Given the high prevalence of infection in mosquitoes, we may speculate that this hypnozoite forming species at liver may not be detected by the peripheral blood samples analysis. Also, this is the first report of Duffy negative individuals infected with two different strains of P. vivax (VK247 and classic strains) in Angola and Equatorial Guinea. This finding reinforces the idea that this parasite is able to use receptors other than Duffy to invade erythrocytes, which may have an enormous impact in P. vivax current distribution. PMID- 21713025 TI - The influence of reduced susceptibility to fluoroquinolones in Salmonella enterica serovar Typhi on the clinical response to ofloxacin therapy. AB - BACKGROUND: Infection with Salmonella enterica serovar Typhi (S. Typhi) with reduced susceptibility to fluoroquinolones has been associated with fluoroquinolone treatment failure. We studied the relationship between ofloxacin treatment response and the ofloxacin minimum inhibitory concentration (MIC) of the infecting isolate. Individual patient data from seven randomised controlled trials of antimicrobial treatment in enteric fever conducted in Vietnam in which ofloxacin was used in at least one of the treatment arms was studied. Data from 540 patients randomised to ofloxacin treatment was analysed to identify an MIC of the infecting organism associated with treatment failure. PRINCIPAL FINDINGS: The proportion of patients failing ofloxacin treatment was significantly higher in patients infected with S. Typhi isolates with an MIC>=0.25 ug/mL compared with those infections with an MIC of <=0.125 ug/mL (p<0.001). Treatment success was 96% when the ofloxacin MIC was <=0.125 ug/mL, 73% when the MIC was between 0.25 and 0.50 ug/mL and 53% when the MIC was 1.00 ug/mL. This was despite a longer duration of treatment at a higher dosage in patients infected with isolates with an MIC>=0.25 ug/mL compared with those infections with an MIC of <=0.125 ug/mL. SIGNIFICANCE: There is a clear relationship between ofloxacin susceptibility and clinical outcome in ofloxacin treated patients with enteric fever. An ofloxacin MIC of >=0.25 ug/mL, or the presence of nalidixic acid resistance, can be used to define S. Typhi infections in which the response to ofloxacin may be impaired. PMID- 21713026 TI - Multilocus sequence typing (MLST) for lineage assignment and high resolution diversity studies in Trypanosoma cruzi. AB - BACKGROUND: Multilocus sequence typing (MLST) is a powerful and highly discriminatory method for analysing pathogen population structure and epidemiology. Trypanosoma cruzi, the protozoan agent of American trypanosomiasis (Chagas disease), has remarkable genetic and ecological diversity. A standardised MLST protocol that is suitable for assignment of T. cruzi isolates to genetic lineage and for higher resolution diversity studies has not been developed. METHODOLOGY/PRINCIPAL FINDINGS: We have sequenced and diplotyped nine single copy housekeeping genes and assessed their value as part of a systematic MLST scheme for T. cruzi. A minimum panel of four MLST targets (Met-III, RB19, TcGPXII, and DHFR-TS) was shown to provide unambiguous assignment of isolates to the six known T. cruzi lineages (Discrete Typing Units, DTUs TcI-TcVI). In addition, we recommend six MLST targets (Met-II, Met-III, RB19, TcMPX, DHFR-TS, and TR) for more in depth diversity studies on the basis that diploid sequence typing (DST) with this expanded panel distinguished 38 out of 39 reference isolates. Phylogenetic analysis implies a subdivision between North and South American TcIV isolates. Single Nucleotide Polymorphism (SNP) data revealed high levels of heterozygosity among DTUs TcI, TcIII, TcIV and, for three targets, putative corresponding homozygous and heterozygous loci within DTUs TcI and TcIII. Furthermore, individual gene trees gave incongruent topologies at inter- and intra-DTU levels, inconsistent with a model of strict clonality. CONCLUSIONS/SIGNIFICANCE: We demonstrate the value of systematic MLST diplotyping for describing inter-DTU relationships and for higher resolution diversity studies of T. cruzi, including presence of recombination events. The high levels of heterozygosity will facilitate future population genetics analysis based on MLST haplotypes. PMID- 21713027 TI - The neural basis of following advice. AB - Learning by following explicit advice is fundamental for human cultural evolution, yet the neurobiology of adaptive social learning is largely unknown. Here, we used simulations to analyze the adaptive value of social learning mechanisms, computational modeling of behavioral data to describe cognitive mechanisms involved in social learning, and model-based functional magnetic resonance imaging (fMRI) to identify the neurobiological basis of following advice. One-time advice received before learning had a sustained influence on people's learning processes. This was best explained by social learning mechanisms implementing a more positive evaluation of the outcomes from recommended options. Computer simulations showed that this "outcome-bonus" accumulates more rewards than an alternative mechanism implementing higher initial reward expectation for recommended options. fMRI results revealed a neural outcome-bonus signal in the septal area and the left caudate. This neural signal coded rewards in the absence of advice, and crucially, it signaled greater positive rewards for positive and negative feedback after recommended rather than after non-recommended choices. Hence, our results indicate that following advice is intrinsically rewarding. A positive correlation between the model's outcome bonus parameter and amygdala activity after positive feedback directly relates the computational model to brain activity. These results advance the understanding of social learning by providing a neurobiological account for adaptive learning from advice. PMID- 21713028 TI - A voltage-gated H+ channel underlying pH homeostasis in calcifying coccolithophores. AB - Marine coccolithophorid phytoplankton are major producers of biogenic calcite, playing a significant role in the global carbon cycle. Predicting the impacts of ocean acidification on coccolithophore calcification has received much recent attention and requires improved knowledge of cellular calcification mechanisms. Uniquely amongst calcifying organisms, coccolithophores produce calcified scales (coccoliths) in an intracellular compartment and secrete them to the cell surface, requiring large transcellular ionic fluxes to support calcification. In particular, intracellular calcite precipitation using HCO3- as the substrate generates equimolar quantities of H+ that must be rapidly removed to prevent cytoplasmic acidification. We have used electrophysiological approaches to identify a plasma membrane voltage-gated H+ conductance in Coccolithus pelagicus ssp braarudii with remarkably similar biophysical and functional properties to those found in metazoans. We show that both C. pelagicus and Emiliania huxleyi possess homologues of metazoan H(v)1 H+ channels, which function as voltage-gated H+ channels when expressed in heterologous systems. Homologues of the coccolithophore H+ channels were also identified in a diversity of eukaryotes, suggesting a wide range of cellular roles for the H(v)1 class of proteins. Using single cell imaging, we demonstrate that the coccolithophore H+ conductance mediates rapid H+ efflux and plays an important role in pH homeostasis in calcifying cells. The results demonstrate a novel cellular role for voltage gated H+ channels and provide mechanistic insight into biomineralisation by establishing a direct link between pH homeostasis and calcification. As the coccolithophore H+ conductance is dependent on the trans-membrane H+ electrochemical gradient, this mechanism will be directly impacted by, and may underlie adaptation to, ocean acidification. The presence of this H+ efflux pathway suggests that there is no obligate use of H+ derived from calcification for intracellular CO2 generation. Furthermore, the presence of H(v)1 class ion channels in a wide range of extant eukaryote groups indicates they evolved in an early common ancestor. PMID- 21713029 TI - Will ion channels help coccolithophores adapt to ocean acidification? PMID- 21713030 TI - The Genomic Standards Consortium. AB - A vast and rich body of information has grown up as a result of the world's enthusiasm for 'omics technologies. Finding ways to describe and make available this information that maximise its usefulness has become a major effort across the 'omics world. At the heart of this effort is the Genomic Standards Consortium (GSC), an open-membership organization that drives community-based standardization activities, Here we provide a short history of the GSC, provide an overview of its range of current activities, and make a call for the scientific community to join forces to improve the quality and quantity of contextual information about our public collections of genomes, metagenomes, and marker gene sequences. PMID- 21713031 TI - The homeobox protein CEH-23 mediates prolonged longevity in response to impaired mitochondrial electron transport chain in C. elegans. AB - Recent findings indicate that perturbations of the mitochondrial electron transport chain (METC) can cause extended longevity in evolutionarily diverse organisms. To uncover the molecular basis of how altered METC increases lifespan in C. elegans, we performed an RNAi screen and revealed that three predicted transcription factors are specifically required for the extended longevity of mitochondrial mutants. In particular, we demonstrated that the nuclear homeobox protein CEH-23 uniquely mediates the longevity but not the slow development, reduced brood size, or resistance to oxidative stress associated with mitochondrial mutations. Furthermore, we showed that ceh-23 expression levels are responsive to altered METC, and enforced overexpression of ceh-23 is sufficient to extend lifespan in wild-type background. Our data point to mitochondria-to nucleus communications to be key for longevity determination and highlight CEH-23 as a novel longevity factor capable of responding to mitochondrial perturbations. These findings provide a new paradigm for how mitochondria impact aging and age dependent diseases. PMID- 21713034 TI - Concurrent outbreak of norovirus genotype I and enterotoxigenic Escherichia coli on a U.S. Navy ship following a visit to Lima, Peru. AB - An outbreak of norovirus (NoV) genotype I and Enterotoxigenic Escherichia coli (ETEC) occurred among US Navy Ship personnel following a visit to Lima, Peru, in June 2008. Visiting a specific area in Lima was significantly associated with illness. While ETEC and NoV are commonly recognized as causative agents of outbreaks, co-circulation of both pathogens has been rarely observed in shipboard outbreaks. PMID- 21713032 TI - The naturally processed CD95L elicits a c-yes/calcium/PI3K-driven cell migration pathway. AB - Patients affected by chronic inflammatory disorders display high amounts of soluble CD95L. This homotrimeric ligand arises from the cleavage by metalloproteases of its membrane-bound counterpart, a strong apoptotic inducer. In contrast, the naturally processed CD95L is viewed as an apoptotic antagonist competing with its membrane counterpart for binding to CD95. Recent reports pinpointed that activation of CD95 may attract myeloid and tumoral cells, which display resistance to the CD95-mediated apoptotic signal. However, all these studies were performed using chimeric CD95Ls (oligomerized forms), which behave as the membrane-bound ligand and not as the naturally processed CD95L. Herein, we examine the biological effects of the metalloprotease-cleaved CD95L on CD95 sensitive activated T-lymphocytes. We demonstrate that cleaved CD95L (cl-CD95L), found increased in sera of systemic lupus erythematosus (SLE) patients as compared to that of healthy individuals, promotes the formation of migrating pseudopods at the leading edge of which the death receptor CD95 is capped (confocal microscopy). Using different migration assays (wound healing/Boyden Chamber/endothelial transmigration), we uncover that cl-CD95L promotes cell migration through a c-yes/Ca2+/PI3K-driven signaling pathway, which relies on the formation of a CD95-containing complex designated the MISC for Motility-Inducing Signaling Complex. These findings revisit the role of the metalloprotease-cleaved CD95L and emphasize that the increase in cl-CD95L observed in patients affected by chronic inflammatory disorders may fuel the local or systemic tissue damage by promoting tissue-filtration of immune cells. PMID- 21713033 TI - Ligand activation of the prokaryotic pentameric ligand-gated ion channel ELIC. AB - While the pentameric ligand-gated ion channel ELIC has recently provided first insight into the architecture of the family at high resolution, its detailed investigation was so far prevented by the fact that activating ligands were unknown. Here we describe a study on the functional characterization of ELIC by electrophysiology and X-ray crystallography. ELIC is activated by a class of primary amines that include the neurotransmitter GABA at high micro- to millimolar concentrations. The ligands bind to a conserved site and evoke currents that slowly desensitize over time. The protein forms cation selective channels with properties that resemble the nicotinic acetylcholine receptor. The high single channel conductance and the comparably simple functional behavior make ELIC an attractive model system to study general mechanisms of ion conduction and gating in this important family of neurotransmitter receptors. PMID- 21713035 TI - Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells. AB - We propose the hypothesis that loss of estrogen receptor function which leads to endocrine resistance in breast cancer, also results in trans-differentiation from an epithelial to a mesenchymal phenotype that is responsible for increased aggressiveness and metastatic propensity. siRNA mediated silencing of the estrogen receptor in MCF7 breast cancer cells resulted in estrogen/tamoxifen resistant cells (pII) with altered morphology, increased motility with rearrangement and switch from a keratin/actin to a vimentin based cytoskeleton, and ability to invade simulated components of the extracellular matrix. Phenotypic profiling using an Affymetrix Human Genome U133 plus 2.0 GeneChip indicated geometric fold changes >= 3 in approximately 2500 identifiable unique sequences, with about 1270 of these being up-regulated in pII cells. Changes were associated with genes whose products are involved in cell motility, loss of cellular adhesion and interaction with the extracellular matrix. Selective analysis of the data also showed a shift from luminal to basal cell markers and increased expression of a wide spectrum of genes normally associated with mesenchymal characteristics, with consequent loss of epithelial specific markers. Over-expression of several peptide growth factors and their receptors are indicative of an increased contribution to the higher proliferative rates of pII cells as well as aiding their potential for metastatic activity. Signalling molecules that have been identified as key transcriptional drivers of epithelial to mesenchymal transition were also found to be elevated in pII cells. These data support our hypothesis that induced loss of estrogen receptor in previously estrogen/antiestrogen sensitive cells is a trigger for the concomitant loss of endocrine dependence and onset of a series of possibly parallel events that changes the cell from an epithelial to a mesenchymal type. Inhibition of this transition through targeting of specific mediators may offer a useful supplementary strategy to circumvent the effects of loss of endocrine sensitivity. PMID- 21713036 TI - Less work, less respect: authors' perceived importance of research contributions and their declared contributions to research articles. AB - BACKGROUND: Attitudes towards authorship are connected with authors' research experience and with knowledge of authorship criteria of International Committee of Medical Journal Editors (ICMJE). The objective of this study was to assess association between authors' perceived importance of contributions for authorship qualification and their participation in manuscripts submitted to a journal. METHODS: Authors (n = 1181) of 265 manuscripts submitted to the Croatian Medical Journal were asked to identify and rate their contribution in the preparation of the submitted manuscript (0-none to 4-full for 11 listed contributions) and the importance of these contributions as authorship qualifications (0-none to 4 full). They were randomly allocated into 3 groups: the first (n = 90 manuscripts, n = 404 authors) first received the contribution disclosure form and then contribution importance-rating questionnaire; the second (n = 88 manuscripts, n = 382 authors) first received the rating questionnaire and then the contribution disclosure form, and the third group (n = 87 manuscripts, n = 395 authors) received both questionnaires at the same time. We compared authors' perception of importance of contribution categories. RESULTS: 1014 (85.9%) authors of 235 manuscripts responded. Authors who declared contribution to a specific category rated it as more important for authorship than those authors who did not contribute to the same category (P>0.005 for all contribution categories, Mann Withney test). Authors qualifying for ICMJE authorship rated all contribution categories higher than non-qualifying authors. For all contributions, associations between perceived importance of contribution and actual author's contribution were statistically significant. CONCLUSIONS: Authorship seems to be not a normative issue subjective to categorization into criteria, but also a very personal view of the importance and value of one's contributions. PMID- 21713037 TI - Critical transition in tissue homeostasis accompanies murine lung senescence. AB - BACKGROUND: Respiratory dysfunction is a major contributor to morbidity and mortality in aged populations. The susceptibility to pulmonary insults is attributed to "low pulmonary reserve", ostensibly reflecting a combination of age related musculoskeletal, immunologic and intrinsic pulmonary dysfunction. METHODS/PRINCIPAL FINDINGS: Using a murine model of the aging lung, senescent DBA/2 mice, we correlated a longitudinal survey of airspace size and injury measures with a transcriptome from the aging lung at 2, 4, 8, 12, 16 and 20 months of age. Morphometric analysis demonstrated a nonlinear pattern of airspace caliber enlargement with a critical transition occurring between 8 and 12 months of age marked by an initial increase in oxidative stress, cell death and elastase activation which is soon followed by inflammatory cell infiltration, immune complex deposition and the onset of airspace enlargement. The temporally correlative transcriptome showed exuberant induction of immunoglobulin genes coincident with airspace enlargement. Immunohistochemistry, ELISA analysis and flow cytometry demonstrated increased immunoglobulin deposition in the lung associated with a contemporaneous increase in activated B-cells expressing high levels of TLR4 (toll receptor 4) and CD86 and macrophages during midlife. These midlife changes culminate in progressive airspace enlargement during late life stages. CONCLUSION/SIGNIFICANCE: Our findings establish that a tissue-specific aging program is evident during a presenescent interval which involves early oxidative stress, cell death and elastase activation, followed by B lymphocyte and macrophage expansion/activation. This sequence heralds the progression to overt airspace enlargement in the aged lung. These signature events, during middle age, indicate that early stages of the aging immune system may have important correlates in the maintenance of tissue morphology. We further show that time-course analyses of aging models, when informed by structural surveys, can reveal nonintuitive signatures of organ-specific aging pathology. PMID- 21713038 TI - Population-based biochemistry, immunologic and hematological reference values for adolescents and young adults in a rural population in Western Kenya. AB - BACKGROUND: There is need for locally-derived age-specific clinical laboratory reference ranges of healthy Africans in sub-Saharan Africa. Reference values from North American and European populations are being used for African subjects despite previous studies showing significant differences. Our aim was to establish clinical laboratory reference values for African adolescents and young adults that can be used in clinical trials and for patient management. METHODS AND FINDINGS: A panel of 298, HIV-seronegative individuals aged 13-34 years was randomly selected from participants in two population-based cross-sectional surveys assessing HIV prevalence and other sexually transmitted infections in western Kenya. The adolescent (<18 years)-to-adults (>= 18 years) ratio and the male-to-female ratio was 1?1. Median and 95% reference ranges were calculated for immunohematological and biochemistry values. Compared with U.S-derived reference ranges, we detected lower hemoglobin (HB), hematocrit (HCT), red blood cells (RBC), mean corpuscular volume (MCV), neutrophil, glucose, and blood urea nitrogen values but elevated eosinophil and total bilirubin values. Significant gender variation was observed in hematological parameters in addition to T bilirubin and creatinine indices in all age groups, AST in the younger and neutrophil, platelet and CD4 indices among the older age group. Age variation was also observed, mainly in hematological parameters among males. Applying U.S. NIH Division of AIDS (DAIDS) toxicity grading to our results, 40% of otherwise healthy study participants were classified as having an abnormal laboratory parameter (grade 1-4) which would exclude them from participating in clinical trials. CONCLUSION: Hematological and biochemistry reference values from African population differ from those derived from a North American population, showing the need to develop region-specific reference values. Our data also show variations in hematological indices between adolescent and adult males which should be considered when developing reference ranges. This study provides the first locally-derived clinical laboratory reference ranges for adolescents and young adults in western Kenya. PMID- 21713039 TI - A new drug design targeting the adenosinergic system for Huntington's disease. AB - BACKGROUND: Huntington's disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The expanded CAG repeats are translated into polyglutamine (polyQ), causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report a novel dual function compound, N(6)-(4-hydroxybenzyl)adenine riboside (designated T1-11) which activates the A(2A)R and a major adenosine transporter (ENT1). T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A(2A)R and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A(2A)R knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A(2A)R in vivo. Most importantly, addition of T1-11 (0.05 mg/ml) to the drinking water of a transgenic mouse model of HD (R6/2) ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor) in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD. CONCLUSIONS/SIGNIFICANCE: The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor/serotonin transporter) and may facilitate the development of new drugs for other neurodegenerative diseases. PMID- 21713040 TI - Excess mortality associated with influenza epidemics in Portugal, 1980 to 2004. AB - BACKGROUND: Influenza epidemics have a substantial impact on human health, by increasing the mortality from pneumonia and influenza, respiratory and circulatory diseases, and all causes. This paper provides estimates of excess mortality rates associated with influenza virus circulation for 7 causes of death and 8 age groups in Portugal during the period of 1980-2004. METHODOLOGY/PRINCIPAL FINDINGS: We compiled monthly mortality time series data by age for all-cause mortality, cerebrovascular diseases, ischemic heart diseases, diseases of the respiratory system, chronic respiratory diseases, pneumonia and influenza. We also used a control outcome, deaths from injuries. Age- and cause specific baseline mortality was modelled by the ARIMA approach; excess deaths attributable to influenza were calculated by subtracting expected deaths from observed deaths during influenza epidemic periods. Influenza was associated with a seasonal average of 24.7 all-cause excess deaths per 100,000 inhabitants, approximately 90% of which were among seniors over 65 yrs. Excess mortality was 3 6 fold higher during seasons dominated by the A(H3N2) subtype than seasons dominated by A(H1N1)/B. High excess mortality impact was also seen in children under the age of four years. Seasonal excess mortality rates from all the studied causes of death were highly correlated with each other (Pearson correlation range, 0.65 to 0.95, P<0.001) and with seasonal rates of influenza-like-illness (ILI) among seniors over 65 years (Pearson correlation rho>0.64, P<0.05). By contrast, there was no correlation with excess mortality from injuries. CONCLUSIONS/SIGNIFICANCE: Our excess mortality approach is specific to influenza virus activity and produces influenza-related mortality rates for Portugal that are similar to those published for other countries. Our results indicate that all cause excess mortality is a robust indicator of influenza burden in Portugal, and could be used to monitor the impact of influenza epidemics in this country. Additional studies are warranted to confirm these findings in other settings. PMID- 21713041 TI - Nitric oxide modulation in protective role of antidepressants against chronic fatigue syndrome in mice. AB - BACKGROUND AND OBJECTIVE: The present study was designed to elucidate the possible nitric oxide (NO) mechanism in the protective effect of antidepressants using mice model of chronic fatigue syndrome (CFS). MATERIALS AND METHODS: Male albino laca mice were forced to swim for each 6 min session for 7 days and immobility period was measured on every alternate day (1(st), 3(rd), 5(th), 7(th)). After 7 days various behavioral tests (locomotor, mirror chamber, and plus maze tests for anxiety) were performed and biochemical estimations (lipid peroxidation, nitrite levels, GSH (reduced glutathione), and catalase activity) in mice brain were performed. Animals were pretreated with citalopram (5 and 10 mg/kg) and imipramine (10 and 20 mg/kg) daily for 7 days. RESULTS: The present study showed that continued forced swimming for 7 days caused chronic fatigue induced anxiety-like behavior as assessed in mirror chamber, plus maze tests, and impairment in locomotor activity followed by oxidative damage (as evidenced by increased lipid peroxidation, nitrite levels, depleted reduced glutathione, and catalase activity) in animals. Seven days pretreatment with citalopram (5 and 10 mg/kg) and imipramine (10 and 20 mg/kg) significantly improved behavioral and biochemical alterations. Further, L-nitro-arginine methyl ester (L-NAME,5 mg/kg) and methylene blue (MB, 10 mg/kg) pretreatment with citalopram (5 mg/kg) or imipramine (10 mg/kg) potentiated their protective effect. However, l-arginine (100 mg/kg) pretreatment with citalopram (5 mg/kg) or imipramine (10 mg/kg) reversed their protective effect as compared with their effect per se (P < 0.05). CONCLUSION: The present study suggests that protective effect of citalopram and imipramine might be due to its NO modulation against chronic fatigue induced behavioral and biochemical alterations. PMID- 21713042 TI - Effect of alcohol on blood glucose and antioxidant enzymes in the liver and kidney of diabetic rats. AB - OBJECTIVE: Diabetes mellitus affects every organ in the man including eyes, kidney, heart, and nervous system. Alcohol consumption is a widespread practice. As the effects of chronic alcohol consumption on diabetic state have been little studied, this study was conducted with the objective of evaluating the effect of alcohol in diabetic rats. MATERIALS AND METHODS: For this study, the rats were divided into five groups (n = 6 in each group): normal control (NC), alcohol treatment (At), diabetic control (DC), diabetic plus alcohol treatment (D + At), diabetic plus glibenclamide treatment (D + Gli). Alcohol treatment was given to the diabetic rats for 30 days. During the period the blood glucose levels, and body weight changes were observed at regular intervals. The antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) levels were assayed in the liver and kidney tissues. RESULTS: The blood glucose levels were significantly (P < 0.001) elevated and body weight significantly (P < 0.001) decreased in alcohol-treated diabetic rats. SOD and CAT activities were decreased and the MDA level increased significantly (P < 0.001) in alcohol-treated diabetic rats. Histopathological studies showed that alcohol damages the liver and kidney tissues in diabetic rats. CONCLUSION: These finddings concluded that the consumption of alcohol in diabetic rats worsens the condition. So the consumption of alcohol by diabetic subjects may be potentially harmful. PMID- 21713043 TI - Antiulcer and antioxidant activity of ethanolic extract of Passiflora foetida L. AB - Passiflora foetida L. (Passifloraceae), a widely growing perennial climber, has been used in traditional medicine for treating many ailments. The objective of the present study was to evaluate the effects of ethanolic extract of P. foetida (EEPF) whole plant on gastric ulcer. The antiulcer effects of EEPF at 100 and 200 mg/kg doses were evaluated on ethanol and aspirin-induced gastric ulcer models. The antioxidant parameters and histological changes in gastric tissue of ulcer rats were also determined in both the models. P. foetida treatment significantly (P < 0.01) reduced the ulcer index and significantly (P < 0.01) increased the gastric pH of both ethanol and aspirin-induced ulcer rats. P. foetida showed significant (P < 0.01) reduction in lipid peroxidation and increase in reduced glutathione levels. The observations confirm that EEPF whole plant has antiulcer and antioxidant activities. PMID- 21713044 TI - Studies on the activity of Cyperus rotundus Linn. tubers against infectious diarrhea. AB - To study the antidiarrheal activity of the decoction of Cyperus rotundus Linn. tubers using representative assays of diarrheal pathogenesis and understand its mechanism of action.Antibacterial, antigiardial and antirotaviral activities were studied. Effect on adherence of enteropathogenic Escherichia coli (EPEC) and invasion of enteroinvasive E. coli (EIEC) and Shigella flexneri to HEp-2 cells was evaluated as a measure of effect on colonization. Effect on enterotoxins such as enterotoxigenic E. coli (ETEC) heat labile toxin (LT), heat stable toxin (ST) and cholera toxin (CT) was also assessed. The decoction showed antigiardial activity, reduced bacterial adherence to and invasion of HEp-2 cells and affected production of CT and action of LT. The decoction of C. rotundus does not have marked antimicrobial activity and exerts its antidiarrheal action by mechanisms other than direct killing of the pathogen. PMID- 21713045 TI - Drug use in pregnancy: Knowledge of drug dispensers and pregnant women in Dar es Salaam, Tanzania. AB - More than 90% of pregnant women take prescription or non-prescription drugs at some time during pregnancy. In general, unless absolutely necessary, drugs should not be used during pregnancy because many of them are harmful to the fetus. Appropriate dispensing is one of the steps for rational drug use; so, it is necessary that drug dispensers should have relevant and updated knowledge and skills regarding drug use in pregnancy. To assess the knowledge of drug dispensers and pregnant women regarding drug use in pregnancy, focusing on four commonly used drugs that are teratogenic or cause unwanted effects to the fetus and babies. The study was conducted in two parts: consumers' perception and providers' practice. It was a cross-sectional study involving visits to 200 private retail community pharmacies (as simulated client) within Temeke, Ilala and Kinondoni municipals in Dar es Salaam, Tanzania. The second part of the study was conducted at the antenatal clinics of the three municipal hospitals in Dar es Salaam. A semi-structured questionnaire was used to gather information from pregnant women. In total, 200 pregnant women were interviewed. Out of 200 drug dispensers, 86 (43%) were willing to dispense artemether-lumefantrine (regardless of the age of pregnancy), 56 (29%) were willing to dispense sodium valproate, 104 (52%) were willing to dispense captopril and 50 (25%) were willing to dispense tetracycline. One hundred and thirty-three (66.5%) pregnant women reported that they hesitated to take medications without consulting their physicians, 47 (23.5%) indicated that it was safe to take medications during pregnancy, while 123 (61.5%) mentioned that it was best to consult a doctor, while 30 (15%) did not have any preference. Sixty-three (31.5%) women reported that they were aware of certain drugs that are contraindicated during pregnancy. It is evident that most drug dispensers have low knowledge regarding the harmful effects of drugs during pregnancy. Drug dispensing personnel should be considered part of the therapeutic chain and, if appropriately trained, they will play a very important role in promoting rational use of medicines. PMID- 21713046 TI - Ageusia as a side effect of clopidogrel treatment. AB - Clopidogrel is prescribed in cardiac and extracardiac vascular diseases. It is generally well tolerated; however, few cases of taste disorders have been reported. We present a case of clopidogrel-induced ageusia notified in Sfax pharmacovigilance center on March 13, 2009. A 46-year-old patient developed ageusia with decreased appetite five weeks after starting clopidogrel. Other etiologies including ear nose throat (ENT) examination were ruled out. Five months after reduction of clopidogrel dose, ageusia partially decreased. Clopidogrel was strongly suspected as a causal drug. According to the French imputation method, score of imputability was considered as plausible (C2S2) I2. Physiopathology of this side effect is not yet understood. However, it seems to be a reversible and dose-related event. Although it is not life-threatening, loss of taste can have significant effect on the quality of life of patients. PMID- 21713047 TI - Immune reconstitution and inflammatory syndrome due to disseminated tuberculosis in a case of human immunodeficiency virus 2 infection. AB - We present a case of human immunodeficiency virus 2 (HIV- 2) infection with acquired immune deficiency syndrome with immune reconstitution and inflammatory syndrome due to disseminated tuberculosis. We address here the drug interactions between antiretroviral therapy and antituberculous treatment (ATT), choice of ATT, and duration of ATT when rifampicin is omitted as in our case. Though this problem is encountered rarely, we felt that it is important to report the issue to counter drug resistance in tuberculosis and HIV. PMID- 21713048 TI - Acute hepatic failure due to yellow phosphorus ingestion. AB - We report a case of three year old girl, who was brought to hospital for accidental consumption of rat-poison (3% phosphorus). The patient was asymptomatic for first 48 hours. Later on she developed the symptoms of hepatic failure. She was managed conservatively and was discharged after 14 days. PMID- 21713049 TI - Effect of potassium channel openers on intraocular pressure in rabbits. PMID- 21713050 TI - Are drugs prescribed rationally and according to standard guidelines in India? PMID- 21713051 TI - Authors' reply. PMID- 21713052 TI - Comparison of the efficacy and tolerability of telmisartan and enalapril in patients of mild to moderate essential hypertension. PMID- 21713053 TI - Authors' reply. PMID- 21713054 TI - Polypill-friend or foe? PMID- 21713055 TI - Biogenerics: Are we ready to take safety challenges in India? PMID- 21713056 TI - Empirical use of antituberculosis drugs should not be equated to their inappropriate and indiscriminate use. PMID- 21713057 TI - Changing trend in the use of antimicrobials over ten years in a tertiary care hospital. PMID- 21713058 TI - The inflammasome. PMID- 21713059 TI - Alpha 2 Delta (alpha(2)delta) Ligands, Gabapentin and Pregabalin: What is the Evidence for Potential Use of These Ligands in Irritable Bowel Syndrome. AB - Irritable bowel syndrome (IBS) is a complex disorder that is characterized by abdominal pain and altered bowel habit, and often associates with other gastrointestinal symptoms such as feelings of incomplete bowel movement and abdominal bloating, and extra-intestinal symptoms such as headache, dyspareunia, heartburn, muscle pain, and back pain. It also frequently coexists with conditions that may also involve central sensitization processes, such as fibromyalgia, irritable bladder disorder, and chronic cough. This review examines the evidence to date on gabapentin and pregabalin which may support further and continued research and development of the alpha(2)delta ligands in disorders characterized by visceral hypersensitivity, such as IBS. The distribution of the alpha(2)delta subunit of the voltage-gated calcium channel, possible mechanisms of action, pre-clinical data which supports an effect on motor-sensory mechanisms and clinical evidence that points to potential benefits in patients with IBS will be discussed. PMID- 21713061 TI - Numbers in Space: Differences between Concrete and Abstract Situations. AB - Numbers might be understood by grounding in spatial orientation, where small numbers are represented as low or to the left and large numbers are represented as high or to the right. We presented numbers in concrete (seven shoes in a shoe shop) or abstract (29 - 7) contexts and asked participants to make relative magnitude judgments. Following the judgment a target letter was presented at the top or bottom (Experiments 1-3) or left or right (Experiment 4) of the visual field. Participants were better at identifying letters at congruent than incongruent locations, but this effect was obtained only when numbers were presented in concrete contexts. We conclude that spatial grounding might have a smaller role for numbers in abstract than in concrete context. PMID- 21713062 TI - The role of lexical-semantic neighborhood in object naming: implications for models of lexical access. AB - The role of lexical-semantic neighborhood is relevant to models of lexical access. Recently it has been claimed that the size of the cohort of activated competitors affects ease of lexical selection in word production as well as the effect of semantically related distractors in picture-word interference tasks. Three experiments are reported in which subjects had to name pictures from large and small semantic categories (cf. "lion," "hammer" versus "funnel," "cage"). In Experiment 1, naming-impaired subjects exhibited semantic errors for targets from large categories. No semantic but many omission errors occurred for targets from small categories suggesting that few competitors were available for these "low competition targets." In contrast in two experiments with unimpaired subjects, targets were named equally fast. These experiments were sensitive enough to yield a highly significant repetition effect in Experiment 2. Contrary to the explicit predictions of a recent proposal, semantically related distractors caused interference for both groups of words in Experiment 3. The results suggest no role of neighborhood size in the naming of unimpaired individuals. Implications for models of lexical selection are discussed. PMID- 21713064 TI - The Fourth Major Restriction Factor Against HIV/SIV. PMID- 21713063 TI - Combined norepinephrine/serotonergic reuptake inhibition: effects on maternal behavior, aggression, and oxytocin in the rat. AB - BACKGROUND: Few systematic studies exist on the effects of chronic reuptake of monoamine neurotransmitter systems during pregnancy on the regulation of maternal behavior (MB), although many drugs act primarily through one or more of these systems. Previous studies examining fluoxetine and amfonelic acid treatment during gestation on subsequent MB in rodents indicated significant alterations in postpartum maternal care, aggression, and oxytocin levels. In this study, we extended our studies to include chronic gestational treatment with desipramine or amitriptyline to examine differential effects of reuptake inhibition of norepinephrine and combined noradrenergic and serotonergic systems on MB, aggression, and oxytocin system changes. METHODS: Pregnant Sprague-Dawley rats were treated throughout gestation with saline or one of three doses of either desipramine, which has a high affinity for the norepinephrine monoamine transporter, or amitriptyline, an agent with high affinity for both the norepinephrine and serotonin monoamine transporters. MB and postpartum aggression were assessed on postpartum days 1 and 6 respectively. Oxytocin levels were measured in relevant brain regions on postpartum day 7. Predictions were that amitriptyline would decrease MB and increase aggression relative to desipramine, particularly at higher doses. Amygdaloidal oxytocin was expected to decrease with increased aggression. RESULTS: Amitriptyline and desipramine differentially reduced MB, and at higher doses reduced aggressive behavior. Hippocampal oxytocin levels were lower after treatment with either drug but were not correlated with specific behavioral effects. These results, in combination with previous findings following gestational treatment with other selective neurotransmitter reuptake inhibitors, highlight the diverse effects of multiple monoamine systems thought to be involved in maternal care. PMID- 21713060 TI - Toward a neural basis of music perception - a review and updated model. AB - Music perception involves acoustic analysis, auditory memory, auditory scene analysis, processing of interval relations, of musical syntax and semantics, and activation of (pre)motor representations of actions. Moreover, music perception potentially elicits emotions, thus giving rise to the modulation of emotional effector systems such as the subjective feeling system, the autonomic nervous system, the hormonal, and the immune system. Building on a previous article (Koelsch and Siebel, 2005), this review presents an updated model of music perception and its neural correlates. The article describes processes involved in music perception, and reports EEG and fMRI studies that inform about the time course of these processes, as well as about where in the brain these processes might be located. PMID- 21713065 TI - Higher Order Spike Synchrony in Prefrontal Cortex during Visual Memory. AB - Precise temporal synchrony of spike firing has been postulated as an important neuronal mechanism for signal integration and the induction of plasticity in neocortex. As prefrontal cortex plays an important role in organizing memory and executive functions, the convergence of multiple visual pathways onto PFC predicts that neurons should preferentially synchronize their spiking when stimulus information is processed. Furthermore, synchronous spike firing should intensify if memory processes require the induction of neuronal plasticity, even if this is only for short-term. Here we show with multiple simultaneously recorded units in ventral prefrontal cortex that neurons participate in 3 ms precise synchronous discharges distributed across multiple sites separated by at least 500 MUm. The frequency of synchronous firing is modulated by behavioral performance and is specific for the memorized visual stimuli. In particular, during the memory period in which activity is not stimulus driven, larger groups of up to seven sites exhibit performance dependent modulation of their spike synchronization. PMID- 21713066 TI - The Legionella pneumophila Chaperonin - An Unusual Multifunctional Protein in Unusual Locations. AB - The Legionella pneumophila chaperonin, high temperature protein B (HtpB), was discovered as a highly immunogenic antigen, only a few years after the identification of L. pneumophila as the causative agent of Legionnaires' disease. As its counterparts in other bacterial pathogens, HtpB did not initially receive further attention, particularly because research was focused on a few model chaperonins that were used to demonstrate that chaperonins are essential stress proteins, present in all cellular forms of life and involved in helping other proteins to fold. However, chaperonins have recently attracted increasing interest, particularly after several reports confirmed their multifunctional nature and the presence of multiple chaperonin genes in numerous bacterial species. It is now accepted that bacterial chaperonins are capable of playing a variety of protein folding-independent roles. HtpB is clearly a multifunctional chaperonin that according to its location in the bacterial cell, or in the L. pneumophila-infected cell, plays different roles. HtpB exposed on the bacterial cell surface can act as an invasion factor for non-phagocytic cells, whereas the HtpB released in the host cell can act as an effector capable of altering organelle trafficking, the organization of actin microfilaments and cell signaling pathways. The road to discover the multifunctional nature of HtpB has been exciting and here we provide a historical perspective of the key findings linked to such discovery, as well as a summary of the experimental work (old and new) performed in our laboratory. Our current understanding has led us to propose that HtpB is an ancient protein that L. pneumophila uses as a key molecular tool important to the intracellular establishment of this fascinating pathogen. PMID- 21713067 TI - Obesity-Related Differences between Women and Men in Brain Structure and Goal Directed Behavior. AB - Gender differences in the regulation of body-weight are well documented. Here, we assessed obesity-related influences of gender on brain structure as well as performance in the Iowa Gambling Task. This task requires evaluation of both immediate rewards and long-term outcomes and thus mirrors the trade-off between immediate reward from eating and the long-term effect of overeating on body weight. In women, but not in men, we show that the preference for salient immediate rewards in the face of negative long-term consequences is higher in obese than in lean subjects. In addition, we report structural differences in the left dorsal striatum (i.e., putamen) and right dorsolateral prefrontal cortex for women only. Functionally, both regions are known to play complimentary roles in habitual and goal-directed control of behavior in motivational contexts. For women as well as men, gray matter volume correlates positively with measures of obesity in regions coding the value and saliency of food (i.e., nucleus accumbens, orbitofrontal cortex) as well as in the hypothalamus (i.e., the brain's central homeostatic center). These differences between lean and obese subjects in hedonic and homeostatic control systems may reflect a bias in eating behavior toward energy-intake exceeding the actual homeostatic demand. Although we cannot infer from our results the etiology of the observed structural differences, our results resemble neural and behavioral differences well known from other forms of addiction, however, with marked differences between women and men. These findings are important for designing gender-appropriate treatments of obesity and possibly its recognition as a form of addiction. PMID- 21713068 TI - Nitric Oxide Synthase Inhibitor Improves De Novo and Long-Term l-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats. AB - Inhibitors of neuronal and endothelial nitric oxide synthase decrease l-3,4 dihidroxifenilalanine (l-DOPA)-induced dyskinesias in rodents. The mechanism of nitric oxide inhibitor action is unknown. The aims of the present study were to investigate the decrease of l-DOPA-induced abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA)-lesioned rats by nitric oxide inhibitors following either acute or chronic treatment. The primary findings of this study were that NG-nitro-l-Arginine, an inhibitor of endothelial and neuronal nitric oxide synthase, attenuated AIMs induced by chronic and acute l-DOPA. In contrast, rotational behavior was attenuated only after chronic l-DOPA. The 6-OHDA lesion and the l-DOPA treatment induced a bilateral increase (1.5 times) in the neuronal nitric oxide synthase (nNOS) protein and nNOS mRNA in the striatum and in the frontal cortex. There was a parallel increase, bilaterally, of the FosB/DeltaFosB, primarily in the ipsilateral striatum. The exception was in the contralateral striatum and the ipsilateral frontal cortex, where chronic l-DOPA treatment induced an increase of approximately 10 times the nNOS mRNA. Our results provided further evidence of an anti-dyskinetic effect of NOS inhibitor. The effect appeared under l-DOPA acute and chronic treatment. The l-DOPA treatment also revealed an over-expression of the neuronal NOS in the frontal cortex and striatum. Our results corroborated findings that l-DOPA-induced rotation differs between acute and chronic treatment. The effect of the NOS inhibitor conceivably relied on the l-DOPA structural modifications in the Parkinsonian brain. Taken together, these data provided a rationale for further evaluation of NOS inhibitors in the treatment of l-DOPA-induced dyskinesia. PMID- 21713069 TI - Extraordinary claims require extraordinary evidence: the case of non-local perception, a classical and bayesian review of evidences. AB - Starting from the famous phrase "extraordinary claims require extraordinary evidence," we will present the evidence supporting the concept that human visual perception may have non-local properties, in other words, that it may operate beyond the space and time constraints of sensory organs, in order to discuss which criteria can be used to define evidence as extraordinary. This evidence has been obtained from seven databases which are related to six different protocols used to test the reality and the functioning of non-local perception, analyzed using both a frequentist and a new Bayesian meta-analysis statistical procedure. According to a frequentist meta-analysis, the null hypothesis can be rejected for all six protocols even if the effect sizes range from 0.007 to 0.28. According to Bayesian meta-analysis, the Bayes factors provides strong evidence to support the alternative hypothesis (H1) over the null hypothesis (H0), but only for three out of the six protocols. We will discuss whether quantitative psychology can contribute to defining the criteria for the acceptance of new scientific ideas in order to avoid the inconclusive controversies between supporters and opponents. PMID- 21713070 TI - Pupillometric assessment of sleepiness in narcolepsy. AB - PURPOSE: Excessive daytime sleepiness is highly prevalent in the general population, is the hallmark of narcolepsy, and is linked to significant morbidity. Clinical assessment of sleepiness remains challenging and the common objective multiple sleep latency test (MSLT) and subjective Epworth sleepiness scale (ESS) methods correlate poorly. We examined the relative utility of pupillary unrest index (PUI) as an objective measure of sleepiness in a group of unmedicated narcoleptics and healthy controls in a prospective, observational pilot study. METHODS: Narcolepsy (n = 20; untreated for >2 weeks) and control (n = 56) participants were tested under the same experimental conditions; overnight polysomnography was performed on all participants, followed by a daytime testing protocol including: MSLT, PUI, sleepiness visual analog scale (VAS), ESS, and the psychomotor vigilance test (PVT). RESULTS: The narcolepsy and control groups differed significantly on psychomotor performance and each measure of objective and subjective sleepiness, including PUI. Across the entire sample, PUI correlated significantly with objective (mean sleep latency, SL) and subjective (ESS and VAS) sleepiness, but none of the sleepiness measures correlated with performance (PVT). Among narcoleptics, VAS correlated with PVT measures. Within the control group, mean PUI was the only objective sleepiness measure that correlated with subjective sleepiness. Finally, in an ANCOVA model, SL and ESS were significantly predictive of PUI as measure of sleepiness. CONCLUSION: The role of PUI in quantifying and distinguishing sleepiness of narcolepsy from sleep satiated healthy controls merits further investigation as it is a portable, brief, and objective test. PMID- 21713071 TI - Numerical rule-learning in ring-tailed lemurs (lemur catta). AB - We investigated numerical discrimination and numerical rule-learning in ring tailed lemurs (Lemur catta). Two ring-tailed lemurs were trained to respond to two visual arrays, each of which contained between one and four elements, in numerically ascending order. In Experiment 1, lemurs were trained with 36 exemplars of each of the numerosities 1-4 and then showed positive transfer to trial-unique novel exemplars of the values 1-4. In Experiments 2A and 2B, lemurs were tested on their ability to transfer an ascending numerical rule from the values 1-4 to novel values 5-9. Both lemurs successfully ordered the novel values with above chance accuracy. Accuracy was modulated by the ratio between the two numerical values suggesting that lemurs accessed the approximate number system when performing the task. PMID- 21713072 TI - Methodological consequences of situation specificity: biases in assessments. AB - Social research is plagued by many biases. Most of them are due to situation specificity of social behavior and can be explained using a theory of situation specificity. The historical background of situation specificity in personality social psychology research is briefly sketched, then a theory of situation specificity is presented in detail, with as centerpiece the relationship between the behavior and its outcome which can be described as either "the more, the better" or "not too much and not too little." This theory is applied to reliability and validity of assessments in social research. The distinction between "maximum performance" and "typical performance" is shown to correspond to the two behavior-outcome relations. For maximum performance, issues of reliability and validity are much easier to be solved, whereas typical performance is sensitive to biases, as predicted by the theory. Finally, it is suggested that biases in social research are not just systematic error, but represent relevant features to be explained just as other behavior, and that the respective theories should be integrated into a theory system. PMID- 21713073 TI - Genetic pathways leading to therapy-related myeloid neoplasms. AB - Therapy-related myeloid neoplasm (t-MN) is a distinctive clinical syndrome occurring after exposure to chemotherapy or radiotherapy. t-MN arises in most cases from a multipotential hematopoietic stem cell or, less commonly, in a lineage committed progenitor cell. The prognosis for patients with t-MN is poor, as current forms of therapy are largely ineffective. Cytogenetic analysis, molecular analysis and gene expression profiling analysis of t-MN has revealed that there are distinct subtypes of the disease; however, our understanding of the genetic basis of t-MN is incomplete. Elucidating the genetic pathways and molecular networks that are perturbed in t-MNs, may facilitate the identification of therapeutic targets that can be exploited for the development of urgently needed targeted therapies. PMID- 21713074 TI - Antithrombotic prophylaxis in the middle East. AB - Several factors have been proposed to explain the persistence of a high incidence of venous thromboembolism worldwide with its associated morbidity and mortality. Underutilization of anticoagulants and failure of adherence to thromboprophylaxis guidelines are emerging global health concerns. We herein review this alarming observation with special emphasis on the Middle East region. We also discuss strategies that could help control this increasingly reported problem. PMID- 21713075 TI - Sickle cell disease and venous thromboembolism. AB - Hemoglobin S in homozygous state or in combination with one of the structural variants of Hb D-Punjab, Hb O-Arab, Hb C or beta-thalassemia mutation results in sickle cell disease (SCD) that is characterized by chronic hemolytic anemia and tissue injury secondary to vasooclusion. A chronic hypercoagulable state in SCD has been established with the increased risk of thromboembolic complications in these patients. The goal of present review is to survey of the literature related to thromboembolic events and genetic risk factors involved in the manifestation of these events in SCD patients with focus on studies from Mediterranean countries. Also, this review covers the pathogenesis of hypercoagulability and alteration in the components of hemostasis system. PMID- 21713076 TI - Low incidence rate of opportunistic and viral infections during imatinib treatment in chronic myeloid leukemia patients in early and late chronic phase. AB - BACKGROUND: Imatinib has become first line therapy in chronic myeloid leukemia patients. Little is known about the infective consequences during the treatment with this drug in large series of chronic phase patients. MATERIAL AND METHODS: From January 2001 to September 2006 we treated with imatinib 250 patients in first line (early CP) or after interferon failure (late CP), out of clinical trials and recorded all the bacterial and viral infections occurred. RESULTS: We recorded a similar incidence of bacterial and viral infections both in first line and late CP patients (respectively, 16% and 13%) during 3.5 years of follow-up. Analysis of presenting features predisposing to infections revealed differences only in late CP patients, with elevated percentage of high Sokal risk patients and a more longer median time from diagnosis to start of imatinib. CONCLUSIONS: Opportunistic infections and reactivation of Herpes Zoster are observed during imatinib therapy at very low incidence. PMID- 21713077 TI - Familial mediterranean Fever and hypercoagulability. AB - Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease which is characterized by recurrent attacks of fever and peritonitis, pleuritis, arthritis, or erysipelas-like skin disease. As such, FMF is a prototype of autoinflammatory diseases where genetic changes lead to acute inflammatory episodes. Systemic inflammation - in general - may increase procoagulant factors, and decrease natural anticoagulants and fibrinolytic activity. Therefore, it is anticipated to see more thrombotic events among FMF patients compared with healthy subjects. However, reviewing the current available literature and based upon our personal experience, thrombotic events related purely to FMF are very rare. Possible explanation for this discrepancy is that along with the procoagulant activity during FMF acute attacks, anticoagulant and fibrinolytic changes are also taking place. Colchicine which is the treatment of choice in FMF may also play a role in reducing inflammation thereby decreasing hypercoagulability. PMID- 21713078 TI - Epidemiology of therapy-related myeloid neoplasms after treatment for pediatric acute lymphoblastic leukemia in the nordic countries. AB - Of 1614 Nordic children with ALL that were treated according to the NOPHO ALL92 protocol, 20 developed an SMN (cumulative risk at 12 years: 1.6%). Sixteen of the twenty SMNs were acute myeloid leukemias or myelodysplasias, and 9 of these had either monosomy 7 (n=7) or 7q deletions (n=2). In Cox multivariate analysis longer duration of oral MTX/6MP maintenance therapy (p=0.02; being longest for standard risk patients) and presence of high-hyperdiploidy (p=0.07) were related to an increased risk of SMN. In 524 patients we determined the erythrocyte activity of thiopurine methyltransferase (TPMT), which methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. The TPMT activity was significantly lower in those that did compared to those that did not develop an SMN (Median: 12.1 vs 18.1 IU/ml; p=0.02). Among 427 TPMT wild type patients, those who developed SMN received higher 6MP doses than the remaining (69.7 vs 60.4 mg/m(2), p=0.03), which may reflect increased levels of methylated metabolites that inhibit purine de novo synthesis and thus enhance incorporation of 6-thioguanine nucleotides into DNA. In conclusion, the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMN. PMID- 21713080 TI - Hand knitting induced thrombosis of the subclavian vein in a young woman: an unusual cause of paget-schroetter syndrome. PMID- 21713079 TI - Thalassemia and venous thromboembolism. AB - Although the life expectancy of thalassemia patients has markedly improved over the last few decades, patients still suffer from many complications of this congenital disease. The presence of a high incidence of thromboembolic events, mainly in thalassemia intermedia, has led to the identification of a hypercoagulable state in these patients. In this review, the molecular and cellular mechanisms leading to hypercoagulability in thalassemia are highlighted, with a special focus on thalassemia intermedia being the group with the highest incidence of thrombotic events as compared to other types of thalassemia. Clinical experience and available clues on optimal management are also discussed. PMID- 21713081 TI - High serum erythropoietin and ferritin levels in conjunction with anemia response in malignant lymphoma. AB - Anemia is a common finding in lymphoma. There are few data available regarding the erythropoietin (EPO) levels in conjunction with ferritin in lymphoma patients. We prospectively evaluated 55 patients diagnosed with malignant lymphoma during the period between November 2006 and March 2008 at the King Abdullah University Teaching Hospital, Jordan. Our data showed that 74.4% of lymphoma patients were anemic. Furthermore, serum EPO and ferritin levels were higher in lymphoma patients compared with the healthy controls (P=0.001). The observed versus predicted EPO ratio showed also significantly higher levels in anemic lymphoma patients compared to healthy controls (p=0.03). There was an improvement in the Hb level in lymphoma patients who were treated with at least 3 cycles of chemotherapy as compared with newly-diagnosed patients. An adequate increase of EPO levels was observed in anemic lymphoma patients and notably associated with higher ferritin levels and improvement of Hb (p<0.001).Our findings suggest that ferritin estimation in lymphoma patients may predict the level of erythropoiesis and possibly the degree of anemia. Further studies to confirm these findings are warranted. PMID- 21713082 TI - The temporal and challenging faces of integration in medical education: The fate of pharmacology. PMID- 21713083 TI - Role of zinc in pediatric diarrhea. AB - Zinc supplementation is a critical new intervention for treating diarrheal episodes in children. Recent studies suggest that administration of zinc along with new low osmolarity oral rehydration solutions / salts (ORS), can reduce the duration and severity of diarrheal episodes for up to three months. The World Health Organization (WHO) and UNICEF recommend daily 20 mg zinc supplements for 10 - 14 days for children with acute diarrhea, and 10 mg per day for infants under six months old, to curtail the severity of the episode and prevent further occurrences in the ensuing -two to three months, thereby decreasing the morbidity considerably. This article reviews the available evidence on the efficacy and safety of zinc supplementation in pediatric diarrhea and convincingly concludes that zinc supplementation has a beneficial impact on the disease outcome. PMID- 21713084 TI - Promising molecular targeted therapies in breast cancer. AB - In recent years, there has been a significant improvement in the understanding of molecular events and critical pathways involved in breast cancer. This has led to the identification of novel targets and development of anticancer therapies referred to as targeted therapy. Targeted therapy has high specificity for the molecules involved in key molecular events that are responsible for cancer phenotype such as cell growth, survival, migration, invasion, metastasis, apoptosis, cell-cycle progression, and angiogenesis. Targeted agents that have been approved for breast cancer include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Several other targeted agents currently under evaluation in preclinical and clinical trials include inhibitors of epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, VEGF/VEGFR inhibitors, and agents that interfere with crucial signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK; agents against other tyrosine kinases such as Src, insulin-like growth factor (IGF)/IGF-receptor (IGFR); agents that promote apoptosis such as Poly ADP ribose polymerase inhibitors; agents that target invasion and metastasis such as matrix metalloproteinases inhibitors and others. In this review, we highlight the most promising targeted agents and their combination with mainstream chemotherapeutic drugs in clinical trials. PMID- 21713086 TI - Hepatoprotective activity of Leptadenia reticulata stems against carbon tetrachloride-induced hepatotoxicity in rats. AB - OBJECTIVE: To evaluate the hepatoprotective activity of ethanolic and aqueous extract of stems of Leptadenia reticulata (Retz.) Wight. and Arn. in carbon tetrachloride (CCl(4))-induced hepatotoxicity in rats. MATERIALS AND METHODS: The toxicant CCl(4) was used to induce hepatotoxicity at a dose of 1.25 ml/kg as 1 : 1 mixture with olive oil. Ethanolic and aqueous extracts of L. reticulata stems were administered in the doses of 250 and 500 mg/kg/day orally for 7 days. Silymarin (50 mg/kg) was used as standard drug. The hepatoprotective effect of these extracts was evaluated by the assessment of biochemical parameters such as serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, total bilirubin, serum protein, and histopathological studies of the liver. RESULTS: Treatment of animals with ethanolic and aqueous extracts significantly reduced the liver damage and the symptoms of liver injury by restoration of architecture of liver as indicated by lower levels of serum bilirubin and protein as compared with the normal and silymarin-treated groups. Histology of the liver sections confirmed that the extracts prevented hepatic damage induced by CCl(4) showing the presence of normal hepatic cords, absence of necrosis, and fatty infiltration. CONCLUSION: The ethanolic and aqueous extracts of stems of L. reticulata showed significant hepatoprotective activity. The ethanolic extract is more potent in hepatoprotection in CCl(4)-indiced liver injury model as compared with aqueous extract. PMID- 21713085 TI - Heavy metals and living systems: An overview. AB - Heavy metals are natural constituents of the earth's crust, but indiscriminate human activities have drastically altered their geochemical cycles and biochemical balance. This results in accumulation of metals in plant parts having secondary metabolites, which is responsible for a particular pharmacological activity. Prolonged exposure to heavy metals such as cadmium, copper, lead, nickel, and zinc can cause deleterious health effects in humans. Molecular understanding of plant metal accumulation has numerous biotechnological implications also, the long term effects of which might not be yet known. PMID- 21713087 TI - Adverse drug reaction profile of oseltamivir in Indian population: A prospective observational study. AB - OBJECTIVES: To analyze the pattern of adverse drug reactions (ADRs) of oseltamivir and its comparison with available data. MATERIALS AND METHODS: Suspected or confirmed cases of H1N1 influenza A on therapeutic regimen and close contacts of cases H1N1 influenza A on prophylactic regimen of oseltamivir were included. Data were collected by personal interview after obtaining written informed consent. Causality, severity, and preventability assessments were done by using Naranjo's scale, modified Hartwig and Siegel's scale, and modified Schumock and Thornton Scale, respectively. Data were expressed in proportions. Frequency of ADRs in therapeutic and prophylactic groups were compared with phase III trial of oseltamivir by using Chi-square test. RESULTS: Total 294 patients were interviewed. In prophylactic group, 107 of 257 (41.63%) and in therapeutic, group 23 of 37 (62.16%) developed ADRs. ADRs reported in therapeutic group was significantly (P = 0.029) higher as compared with prophylactic group. Frequently observed ADRs in both the groups were gastritis, nausea, vomiting, diarrhea weakness, sedation, loneliness, sadness, headache, and abdominal pain. Naranjo's algorithm showed all ADRs in probable category in prophylactic group, 27.78% probable and 72.22% possible reactions in therapeutic group. Severity assessment showed 76% mild and 24% moderate reactions in therapeutic group, 89% mild and 11% moderate reactions in prophylactic group. Severity of ADRs was significantly higher in therapeutic group. Most of ADRs were in nonpreventable category, except gastritis, nausea and vomiting were in definitely preventable category. CONCLUSION: Oseltamivir is well tolerated in Indian population. Gastrointestinal side effects are most common and preventable. PMID- 21713088 TI - A comparative study of the pharmacokinetics of traditional and automated dosing/blood sampling systems using gabapentin. AB - OBJECTIVE: The present study was undertaken to investigate the pharmacokinetics (PKs) of gabapentin as determined by traditional manual blood sampling and by using an automated dosing/blood sampling technique in awake and freely moving rats using combined liquid chromatography tandem mass-spectrometry (LC-MS/MS). MATERIALS AND METHODS: PK comparisons were conducted by allocating rats into two groups; an automated dosing/blood sampling (ADI/ABS) group (IV study, n = 6 and intragastric study, n = 6) and a manual group (IV study, n = 6 and oral study, n = 6). A series of blood samples from carotid artery were taken at specified times and analyzed using a validated LC-MS/MS method. Various PK parameters like area under curve (AUC(inf)), maximum concentration, time to reach maximum concentration, terminal half life, distribution volume at the steady state, and total clearance were calculated and the two study groups were compared with respect to these parameters. RESULTS: Significant differences in PK parameters were observed between the manual group and the ADI/ABS group and respective bioavailability were measured (46.82 +/- 19.45% and 61.54 +/- 21.23%, respectively) which is 1.31-fold difference (P = 0.0051, P<0.05). CONCLUSION: The described ADI/ABS method was found to be a useful drug development tool for accelerating the pace of preclinical in vivo studies and for obtaining reliable and accurate PK parameters even from single animals as it minimized interanimal and physiological variations. PMID- 21713089 TI - Pharmacodynamic interaction study of Allium sativum (garlic) with cilostazol in patients with type II diabetes mellitus. AB - AIM: Garlic is available as an over-the-counter herbal supplement and is known to have antiplatelet properties. Because of scarcity of clinical data regarding the safety of concomitant use of garlic supplements and anticoagulants, we tried to evaluate the effects of coadministration of single and multiple doses of garlic and cilostazol on platelet aggregation. MATERIALS AND METHODS: The study was a randomized, open label, placebo-controlled, crossover study of type II diabetic patients, where 14 patients were enrolled and 10 completed the study. The patients were administered 600 mg aged garlic extract, 100 mg cilostazol, 600 mg aged garlic extract, and cilostazol or placebo for seven days as per prior randomization schedule. Blood samples for platelet aggregation and bleeding time and clotting time were collected before and 2, 4, and 6 hours after single-dose drug administration and after seven days of treatment. RESULTS: After single- and multiple-dose administration of garlic, there was a significant inhibition of platelet aggregation at 2 hours, whereas with cilostazol, the inhibition was significant at all the three time points tested, with 4 hours showing maximum inhibition. Coadministration of garlic and cilostazol in single and multiple doses for seven days did not produce any significant change in the antiplatelet activity of the individual drugs. CONCLUSIONS: Coadministration of aged garlic extract and cilostazol did not enhance the antiplatelet activity compared with individual drugs. Large randomized trials are needed to further evaluate the possible interaction of garlic in higher doses and in combination with other antiplatelet activity drugs. PMID- 21713090 TI - Pre and post-interventional pattern of self medication in three common illnesses in staff of a tertiary hospital. AB - OBJECTIVE: To find the pattern of self medication in three common illnesses (diarrhea, sore throat, common cold) in nonmedical staff of a tertiary care teaching hospital and to study the effect of IEC. MATERIALS AND METHODS: This was a cross sectional study carried out in 100 randomly selected nonmedical staff members. Participants were interviewed by a semi structured questionnaire to obtain information about practice of self medication in the three illnesses. In the second phase participants were educated about proper self medication using Information, Education, and Communication (IEC) intervention. In post test the same information was obtained from the participants using the same questionnaire. Pre and post intervention data was compared to see whether intervention has resulted in any change in the pattern of self medication. RESULTS: For all the three diseases the use of medicines including anti microbials did not decrease significantly after intervention. During post test significantly more number of participants were aware about warning symptoms of the disease and precautions to be taken in children and pregnant women. Even during pre intervention many participants were aware about non-pharmacological measures to be adopted in the treatment of these diseases which increased after intervention, though not significantly. CONCLUSION: It is possible to improve self medication practices for the treatment of common illnesses if appropriate IEC intervention is adopted. This requires that all related stakeholders should intensify efforts to educate the general public and ensure appropriate use of OTC medicines. PMID- 21713091 TI - In vitro and in vivo antioxidant activities of the aqueous extract of Celosia argentea leaves. AB - OBJECTIVE: The aqueous extract of Celosia argentea var. cristata L. leaves at 100, 200, and 400 mg/kg body weight (b.w.) was investigated against cadmium (Cd) induced oxidative stress in Wistar rats. The in vitro antioxidant of the extract was evaluated using ammonium thiocyanate, reducing power, and membrane stabilizing models. MATERIALS AND METHODS: For the in vivo study, 30 male rats (Rattus norvegicus) weighing 138.02 +/- 7.02 g were completely randomized into 6 groups (A-F) of 5 animals each. Animals in groups A and B received 0.5 ml of distilled water and the same volume containing 8 mg/kg b.w. of Cd, respectively, for 7 days orally. Animals in groups C, D, E, and F were treated like those in group B except that they received 100 mg/kg b.w. of ascorbic acid, and 100, 200, and 400 mg/kg b.w. of the extract, respectively, in addition to Cd. RESULTS: Phytochemical screening revealed the presence of alkaloids (0.61%), saponins (2.93%), cardiac glycosides (0.21%), cardenolides (0.20%), phenolics (3.26%), and flavonoids (2.38%). A total of 10 mg/ml of the extract inhibited linoleic acid oxidation by 67.57%. The highest reducing power was 100 mg/ml as against 10 mg/ml for ascorbic acid. In addition, 2 mg/ml of the extract produced a membrane stabilizing activity of 63.49% as against 77.46% for indomethacin. Compared with the distilled water control group, the administration of Cd alone significantly (P < 0.05) decreased the alkaline phosphatase activity of the rat liver and brain. This decrease was accompanied by a corresponding increase in the serum enzyme. The simultaneous administration of the extract and Cd produced an enzyme activity that compared favorably (P > 0.05) with the animals that received Cd and ascorbic acid. In addition, the reduction in the superoxide dismutase and catalase activity of the liver and brain of the animals, serum uric acid, albumin and bilirubin, and also the increase in the serum malondialdehyde content in animals treated with Cd alone was attenuated by the extract; the values compared well (P > 0.05) with those simultaneously administered with Cd and ascorbic acid. CONCLUSION: Overall, the results indicated that the aqueous extract of C. argentea leaves attenuated Cd-induced oxidative stress in the animals, with the best result at 400 mg/kg b.w. The antioxidant activity of the extract may be attributed to the phenolic and flavonoid components of the extract. The induction of antioxidant enzymes and scavenging of free radicals may account for the mechanism of action of the extract as an antioxidant. PMID- 21713092 TI - Alcoholic leaf extract of Plectranthus amboinicus regulates carbohydrate metabolism in alloxan-induced diabetic rats. AB - OBJECTIVE: The present investigation was undertaken to explore the possible mechanisms of Plectranthus amboinicus leaf extract in alloxan-induced diabetic rats. MATERIALS AND METHODS: Control and alloxan-induced diabetic albino rats received different treatments; orally control (vehicle), 200 mg/kg and 400 mg/kg of ethanol extract of Plectranthus amboinicus (PAEE) and 600 MUg/kg of glibenclamide (standard) for 15 days. At the end of the experiment, the animals were sacrificed and enzyme activities of carbohydrate metabolism were measured in the liver. RESULTS: Diabetic control rats showed a significant elevation (P < 0.001) in fasting blood glucose on successive days of the experiment as compared with their basal values, which was maintained over a period of 2 weeks. Daily oral treatment with PAEE showed a significant reduction (P < 0.001) in the blood glucose levels on successive days of the experiment as compared with their basal values. The most pronounced antihyperglycemic effect was obtained with the dose of 400 mg/kg. PAEE shows a dose-dependent reduction in gluconeogenic enzymes like glucose-6-phosphatase and fructose-1,6-disphosphatase. After 15 days of treatment with PAEE, glycolytic enzymes like phosphoglucoisomerase resulted in a significant increase with a concomitant significant decrease in the activities of aldolase. On the other hand, glucose-6-phosphate dehydrogenase was significantly improved in diabetic rats on administration of PAEE; the 400 mg/kg dose of PAEE elicited a more potent effect compared with the 200 mg/kg dose. CONCLUSION: The results obtained in this study provide evidence of the antidiabetic activity of PAEE, mediated through the regulation of carbohydrate metabolic enzyme activities. PMID- 21713093 TI - Protective effect of ethyl acetate fraction of Rhododendron arboreum flowers against carbon tetrachloride-induced hepatotoxicity in experimental models. AB - OBJECTIVE: To evaluate the hepatoprotective potential of ethyl acetate fraction of Rhododendron arboreum (Family: Ericaceae) in Wistar rats against carbon tetrachloride (CCl(4))-induced liver damage in preventive and curative models. MATERIALS AND METHODS: Fraction at a dose of 100, 200, and 400 mg/kg was administered orally once daily for 14 days in CCl(4)-treated groups (II, III, IV, V and VI). The serum levels of glutamic oxaloacetic transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase (SALP), gamma glutamyltransferase (gamma -GT), and bilirubin were estimated along with activities of glutathione S-transferase (GST), glutathione reductase, hepatic malondialdehyde formation, and glutathione content. RESULT AND DISCUSSION: The substantially elevated serum enzymatic activities of SGOT, SGPT, SALP, gamma-GT, and bilirubin due to CCl(4) treatment were restored toward normal in a dose dependent manner. Meanwhile, the decreased activities of GST and glutathione reductase were also restored toward normal. In addition, ethyl acetate fraction also significantly prevented the elevation of hepatic malondialdehyde formation and depletion of reduced glutathione content in the liver of CCl(4)-intoxicated rats in a dose-dependent manner. Silymarin used as standard reference also exhibited significant hepatoprotective activity on post-treatment against CCl(4) induced hepatotoxicity in rats. The biochemical observations were supplemented with histopathological examination of rat liver sections. The results of this study strongly indicate that ethyl acetate fraction has a potent hepatoprotective action against CCl(4)-induced hepatic damage in rats. PMID- 21713094 TI - Effect of piperine in the regulation of obesity-induced dyslipidemia in high-fat diet rats. AB - OBJECTIVE: The present study was undertaken to explore the effect of piperine in obesity-induced dyslipidemia. MATERIALS AND METHODS: Male Sprague Dawley rats were fed high-fat diet (HFD) for the first eight weeks, to develop obesity induced dyslipidemia. Later on piperine (40 mg / kg) and sibutramine (5 mg / kg) were administered for three weeks along with the continuation of HFD to two separate groups, which served as the test and standard groups, respectively. Body weight, food intake, serum triglyceride, total cholesterol, LDL, VLDL, and HDL were measured at the end of the fourth, eighth (before treatment), and eleventh (after treatment) week, while the fat mass was measured at the end of the eleventh week in the normal, HFD-control, test, and standard groups. RESULTS: Supplementing piperine with HFD significantly reduced not only body weight, triglyceride, total cholesterol, LDL, VLDL, and fat mass, but also increased the HDL levels, with no change in food intake. CONCLUSION: The above results suggest that piperine possesses potential fat reducing and lipid lowering effects, without any change in food appetite, at a small dose of 40 mg / kg. The mechanism of action for such an activity needs to be determined. However, looking to structural similarity with the presently known Melanocortin-4 (MC-4) agonists, involvement of MC-4 receptors in its activity can be guessed. PMID- 21713095 TI - Effects of citral, a naturally occurring antiadipogenic molecule, on an energy intense diet model of obesity. AB - OBJECTIVES: Retinaldehyde inhibits adipogenesis, increases metabolic rate, reduces weight gain, and improves tolerance to a glucose load. We assessed the effects of citral - an inhibitor of retinaldehyde dehydrogenase (the primary enzyme metabolizing retinaldehyde), on body weight, glucose tolerance, fasting plasma glucose and insulin levels, metabolic rate, adipocyte size, and morphology in a diet-induced model of obesity. MATERIALS AND METHODS: Out of the 5 groups of 6-week-old male Sprague-Dawley rats, 4 were maintained on an energy-intense, palatable, diet for a period of - 42 days, while 1 served as the control. After obesity had been induced, 3 groups were treated with daily doses of citral (10, 15, and 20 mg/kg body weight) for a period of 28 days. They were then subjected to metabolic experiments. Body weight, fasting plasma glucose, glucose tolerance to an intraperitoneal glucose load, metabolic rate, and adipocyte size were assessed. RESULTS: Citral-treated groups showed a dose-dependent reduction in body weight gain. They significantly had lower fasting glucose levels, improved glucose tolerance, lower fasting plasma glucose, higher metabolic rate, and smaller adipocytes after drug administration. CONCLUSION: The findings suggest that citral increased energy dissipation (and also reduced lipid accumulation) consequently preventing and ameliorating diet-induced obesity. In addition it improved insulin sensitivity and glucose tolerance. In the current scenario of increasing prevalence of obesity and diabetes, citral may prove as novel agent in its management. PMID- 21713096 TI - Acceptability and safety profile of oral and sublingual misoprostol for uterine evacuation following early fetal demise. AB - BACKGROUND: It has been established that sublingual (SL) route of misoprostol has a great potential to be developed for medical abortion, but there is dearth of evidence to reveal satisfaction rate and safety profile among patients of oral and SL routes. Thus, this study was conducted to provide an insight into the acceptability and safety profile of the same. MATERIALS AND METHODS: A randomized controlled trial was carried out by giving 200 mg mifepristone orally, followed by administration of 600 MUg misoprostol orally to 50 women and sublingually to 50 women. The primary endpoints of study were measurements of acceptability and safety profile parameters (average blood loss, nausea, vomiting, diarrhea, hot flushes, fever) of both the groups. The secondary endpoints of the study were number of doses required for complete abortion, success rate and the induction to evacuation interval in both the groups. RESULTS: SL route of administration was more acceptable than the oral route (P = 0.009). Average blood loss was higher in the oral group than in the SL group (P = 0.001). Amongst the side effects, 34% in the SL group and 52% in the oral group had nausea (P = 0.264), 22% in the SL group and 44% in the oral group had vomiting (P = 0.031), 48% in the SL group and 86% in the oral group had diarrhea (P < 0.05), hot flushes were presented by 24% in the SL group and 50% in the oral group (P < 0.05), fever was presented by 20% in the SL group and 44% in the oral group (P < 0.05), and the number of cases aborted with only one dose was higher (86%) in the SL group as compared to 63% in the oral group (P = 0.004). The evacuation (success) rates were 92% in the SL group and 84% in the oral group (P = 0.218) and the mean +/- SD induction to evacuation intervals in the SL and oral groups were 5.6 +/- 4.54 hours and 9.44 +/- 5.61 hours, respectively (P = 0.0002). CONCLUSION: The SL route had fewer undesirable effects, was more satisfactory, required less number of doses and was more acceptable to the patient compared to the oral route. PMID- 21713097 TI - Improvement in endothelial dysfunction in patients with systemic lupus erythematosus with N-acetylcysteine and atorvastatin. AB - OBJECTIVE: To study the effects of N-acetylcysteine (NAC) and atorvastatin on endothelial dysfunction in patients with systemic lupus erythematosus (SLE). MATERIALS AND METHODS: Thirty-two SLE patients and age, sex-matched 10 healthy control subjects were studied. The patients were between 17 and 65 years of age and positive for diagnostic tests, such as antinuclear antibodies (ANA). Photoplethysmogram (PPG) detects the changes in the amount of light absorbed by hemoglobin, which reflects changes in the blood volume. Pulse wave analysis was performed at rest, 30 s, 90 s after shear stress, and 10 min after 300 MUm of salbutamol inhalation. RESULTS: Stiffness index (SI) of patients before the treatment was 8.46+/-2.78 cm/s and of controls was 6.07+/-1.4 cm/s (P = 0.002) and that of reflection index (RI) was 73+/-13 for patients and 65+/-7 for controls (P = 0.001). The percentage change in RI after salbutamol inhalation for controls and patients were -16+/-6 and -7+/-4 (P = 0.001), respectively, indicating the presence of endothelial dysfunction. The percentage decrease in RI after salbutamol inhalation was from -2.36+/-0.76 to ?7.92+/-1.46 in patients treated with N-acetylcysteine (NAC, P = 0.007). The percentage decrease in RI after salbutamol inhalation was from ?6.36?1.21 to -9.92+/-1.21 in patients treated with atorvastatin (P = 0.05). This indicated the improvement in endothelial function. There was decrease in C-reactive protein (CRP) from 1.03+/ 0.72 mg/dL to 0.52+/-0.22 mg/dL and that of malondialdehyde (MDA) from 11.20+/ 4.07 nmol/mL to 8.81+/-2.79 nmol/mL with N-acetylcysteine treatment (P < 0.05). The CRP was decreased from 1.11+/-0.92 mg/dL to 0.440.16 mg/dL (P = 0.05) and that of MDA was decreased from 9.37+/-3.29 nmol/mL to 8.51+/-3.27 nmol/mL after treatment with atorvastatin. It showed improvement in oxidative stress with these treatments. CONCLUSION: The presence of arterial stiffness indicated endothelial dysfunction. There was reduction in RI and SI with treatment of N-acetylcysteine and atorvastatin suggesting improvement in endothelial dysfunction. There was decrease in CRP (a marker of inflammation) and MDA after treatment with N acetylcysteine suggesting improvement in endothelial dysfunction. There was reduction in CRP after treatment with atorvastatin, suggesting improvement in endothelial function. Improvement in endothelial dysfunction is associated with decreased incidence of cardiovascular and cerebrovascular accidents. PMID- 21713098 TI - Role of the Rosa canina L. leaf extract as an antidiarrheal drug in rodents. AB - OBJECTIVES: The objective of the study was to investigate the effect of the leaf extract of Rosa canina L. against experimental diarrhea induced by castor oil in rodents. MATERIALS AND METHODS: The methanol extract of Rosa canina L. (30 and 60 mg/kg body weight) was administered orally to two groups of mice (five animals per group) in order to evaluate the activity of the extract against the castor oil-induced diarrhea model in mice. Two other groups received normal saline and diphenoxylate (5 mg/kg) as positive control. The effect of the extract on intestinal transit and castor oil-induced intestinal fluid accumulation (enteropooling) was assessed. The effects of the extract on the isolated rabbit jejunum and on the isolated rat ileum were studied. RESULTS: The preliminary phytochemical screening of the leaf extract of Rosa Canina L. revealed the presence of alkaloids, flavonoids, glycosides, saponins, and volatile oil. Intraperitoneal LD50 of the extract was found to be 455.19 +/- 23 mg/kg in mice. The antidiarrheal effect of the methanolic extract exhibited a concentration dependent inhibition of the spontaneous pendular movement of the isolated rabbit jejunum and inhibited acetylcholine-induced contraction of the rat ileum. A dose dependent decrease in gastrointestinal transit was observed with extracts (30 and 60 mg/kg), which also protected mice against castor oil-induced diarrhea and castor oil-induced fluid accumulation, respectively. CONCLUSIONS: The presence of some of the phytochemicals in the leaf extract may be responsible for the observed effects, and also the basis for its use in traditional medicine as an antidiarrheal drug. PMID- 21713099 TI - In vitro evaluation on the antioxidant capacity of triethylchebulate, an aglycone from Terminalia chebula Retz fruit. AB - OBJECTIVES: To evaluate the antioxidant and free-radical scavenging activities of triethylchebulate (TCL), an aglycone isolated from the fruit of Terminalia chebula Retz. MATERIALS AND METHODS: Microsomes, mitochondria and red blood cells (RBCs) were isolated from rat liver. The antioxidant capacities were evaluated by determining the inhibitory effects of TCL on lipid peroxidation, hydrogen peroxide (H(2)O(2))-induced RBCs hemolysis and RBCs autoxidative hemolysis. The free-radical scavenging activities were evaluated by 1,1-diphenyl-2 picrylhydrazyl (DPPH) method and 2',7'-dichlorodihydrofluorescin diacetate (DCFH(2)-DA) assay. RESULT: TCL significantly inhibited FeSO(4)/Cys-induced microsomes lipid peroxidation and protected both H(2)O(2-)-induced RBCs hemolysis and RBCs auto-hemolysis in a dose-dependent manner. Furthermore, TCL demonstrated potent DPPH free-radical scavenging ability with IC(50) at 2.4*10(-5) M. In addition, TCL also moderately suppressed azide-induced mitochondria ROS formation. CONCLUSION: These results demonstrated that TCL was a strong antioxidant and free-radical scavenger, which might contribute to the anti oxidative ability of Terminalia chebula Retz. PMID- 21713100 TI - Primary neuroendocrine carcinoma of breast. PMID- 21713101 TI - The Murine Angiotensin II-Induced Abdominal Aortic Aneurysm Model: Rupture Risk and Inflammatory Progression Patterns. AB - An abdominal aortic aneurysm (AAA) is an enlargement of the greatest artery in the body defined as an increase in diameter of 1.5-fold. AAAs are common in the elderly population and thousands die each year from their complications. The most commonly used mouse model to study the pathogenesis of AAA is the angiotensin II (Ang II) infusion method delivered via osmotic mini-pump for 28 days. Here, we studied the site-specificity and onset of aortic rupture, characterized three dimensional (3D) images and flow patterns in developing AAAs by ultrasound imaging, and examined macrophage infiltration in the Ang II model using 65 apolipoprotein E-deficient mice. Aortic rupture occurred in 16 mice (25%) and was nearly as prevalent at the aortic arch (44%) as it was in the suprarenal region (56%) and was most common within the first 7 days after Ang II infusion (12 of 16; 75%). Longitudinal ultrasound screening was found to correlate nicely with histological analysis and AAA volume renderings showed a significant relationship with AAA severity index. Aortic dissection preceded altered flow patterns and macrophage infiltration was a prominent characteristic of developing AAAs. Targeting the inflammatory component of AAA disease with novel therapeutics will hopefully lead to new strategies to attenuate aneurysm growth and aortic rupture. PMID- 21713102 TI - In vitro Toxicity Testing in the Twenty-First Century. AB - The National Research Council (NRC) article "Toxicity Testing in the 21st Century: A vision and A Strategy" (National Research Council, 2007) was written to bring attention to the application of scientific advances for use in toxicity tests so that chemicals can be tested in a more time and cost efficient manner while providing a more relevant and mechanistic insight into the toxic potential of a compound. Development of tools for in vitro toxicity testing constitutes an important activity of this vision and contributes to the provision of test systems as well as data that are essential for the development of computer modeling tools for, e.g., system biology, physiologically based modeling. This article intends to highlight some of the issues that have to be addressed in order to make in vitro toxicity testing a reality in the twenty-first century. PMID- 21713103 TI - Ethnopharmacology in the 21st century - grand challenges. PMID- 21713104 TI - Grand challenges in pharmacoeconomics and health outcomes. PMID- 21713105 TI - Blood pressure reduction combining baroreflex restoration for stroke prevention in hypertension in rats. AB - Blood pressure reduction is an important and effective strategy in stroke prevention in hypertensives. Recently, we found that baroreflex restoration was also crucial in stroke prevention. The present work was designed to test the hypothesis that a combination of blood pressure reduction and baroreflex restoration may be a new strategy for stroke prevention. In Experiment 1, the effects of ketanserin (0.3, 1, 3, 10 mg/kg), amlodipine (0.3, 1, 2, 3 mg/kg) and their combination (1 + 0.3, 1 + 1, 1 + 2, 1 + 3 mg/kg) on blood pressure and baroreflex sensitivity (BRS) of stroke-prone spontaneously hypertensive rats (SHR SP) were determined under conscious state. It was found that both amlodipine and ketanserin decreased blood pressure dose-dependently. Ketanserin enfanced BRS from a very small dose but amlodipine enfanced BRS only at largest dose used. At the dose of 1 + 2 mg/kg (ketanserin + amlodipine), the combination possessed the largest synergism on blood pressure reduction. In Experiments 2 and 3, SHR-SP and two-kidney, two-clip (2K2C) renovascular hypertensive rats received life-long treatments with ketanserin (1 mg/kg) and amlodipine (2 mg/kg) or their combination (0.5 + 1, 1 + 2, 2 + 4 mg/kg). The survival time was recorded and the brain lesion was examined. It was found that all kinds of treatments prolonged the survival time of SHR-SP and 2K2C rats. The combination possessed a significantly better effect on stroke prevention than mono-therapies. In conclusion, combination of blood pressure reduction and baroreflex restoration may be a new strategy for the prevention of stroke in hypertension. PMID- 21713107 TI - Dissecting the immune component of neurologic disorders: a grand challenge for the 21st century. PMID- 21713108 TI - The need for a proper definition of a "treatment refractoriness" in tourette syndrome. PMID- 21713106 TI - Understanding the molecular diversity of GABAergic synapses. AB - GABAergic synapses exhibit a high degree of subcellular and molecular specialization, which contrasts with their apparent simplicity in ultrastructural appearance. Indeed, when observed in the electron microscope, GABAergic synapses fit in the symmetric, or Gray's type II category, being characterized by a relatively simple postsynaptic specialization. The inhibitory postsynaptic density cannot be readily isolated, and progress in understanding its molecular composition has lagged behind that of excitatory synapses. However, recent studies have brought significant progress in the identification of new synaptic proteins, revealing an unexpected complexity in the molecular machinery that regulates GABAergic synaptogenesis. In this article, we provide an overview of the molecular diversity of GABAergic synapses, and we consider how synapse specificity may be encoded by selective trans-synaptic interactions between pre- and postsynaptic adhesion molecules and secreted factors that reside in the synaptic cleft. We also discuss the importance of developing cataloguing tools that could be used to decipher the molecular diversity of synapses and to predict alterations of inhibitory transmission in the course of neurological diseases. PMID- 21713109 TI - Acamprosate and Baclofen were Not Effective in the Treatment of Pathological Gambling: Preliminary Blind Rater Comparison Study. AB - OBJECTIVES: Pathological gambling (PG) is a highly prevalent and disabling impulse control disorder. A range of psychopharmacological options are available for the treatment of PG, including selective serotonin reuptake inhibitors, opioid receptor antagonists, anti-addiction drugs, and mood stabilizers. In our preliminary study, we examined the efficacy of two anti-addiction drugs, baclofen and acamprosate, in the treatment of PG. MATERIALS AND METHODS: Seventeen male gamblers were randomly divided into two groups. Each group received one of the two drugs without being blind to treatment. All patients underwent a comprehensive psychiatric diagnostic evaluation and completed a series of semi structured interviews. During the 6-months of study, monthly evaluations were carried out to assess improvement and relapses. Relapse was defined as recurrent gambling behavior. RESULTS: None of the 17 patients reached the 6-months abstinence. One patient receiving baclofen sustained abstinence for 4 months. Fourteen patients succeeded in sustaining abstinence for 1-3 months. Two patients stopped attending monthly evaluations. CONCLUSION: Baclofen and acamprosate did not prove efficient in treating pathological gamblers. PMID- 21713110 TI - The connectome viewer toolkit: an open source framework to manage, analyze, and visualize connectomes. AB - Advanced neuroinformatics tools are required for methods of connectome mapping, analysis, and visualization. The inherent multi-modality of connectome datasets poses new challenges for data organization, integration, and sharing. We have designed and implemented the Connectome Viewer Toolkit - a set of free and extensible open source neuroimaging tools written in Python. The key components of the toolkit are as follows: (1) The Connectome File Format is an XML-based container format to standardize multi-modal data integration and structured metadata annotation. (2) The Connectome File Format Library enables management and sharing of connectome files. (3) The Connectome Viewer is an integrated research and development environment for visualization and analysis of multi modal connectome data. The Connectome Viewer's plugin architecture supports extensions with network analysis packages and an interactive scripting shell, to enable easy development and community contributions. Integration with tools from the scientific Python community allows the leveraging of numerous existing libraries for powerful connectome data mining, exploration, and comparison. We demonstrate the applicability of the Connectome Viewer Toolkit using Diffusion MRI datasets processed by the Connectome Mapper. The Connectome Viewer Toolkit is available from http://www.cmtk.org/ PMID- 21713111 TI - Hyperbolic discounting emerges from the scalar property of interval timing. PMID- 21713112 TI - Distribution of tyrosine hydroxylase-expressing interneurons with respect to anatomical organization of the neostriatum. AB - We have recently shown in vitro that striatal tyrosine hydroxylase-expressing interneurons identified in transgenic mice by expression of enhanced green fluorescent protein (TH-eGFP) display electrophysiological profiles that are distinct from those of other striatal interneurons. Furthermore, striatal TH-eGFP interneurons show marked diversity in their electrophysiological properties and have been divided into four distinct subtypes. One question that arises from these observations is whether striatal TH-eGFP interneurons are distributed randomly, or obey some sort of organizational plan as has been shown to be the case with other striatal interneurons. An understanding of the striatal TH-eGFP interneuronal patterning is a vital step in understanding the role of these neurons in striatal functioning. Therefore, in the present set of studies the location of electrophysiologically identified striatal TH-eGFP interneurons was mapped. In addition, the distribution of TH-eGFP interneurons with respect to the striatal striosome-matrix compartmental organization was determined using MU opioid receptor (MOR) immunofluorescence or intrinsic TH-eGFP fluorescence to delineate striosome and matrix compartments. Overall, the distribution of the different TH-eGFP interneuronal subtypes did not differ in dorsal versus ventral striatum. However, striatal TH-eGFP interneurons were found to be mostly in the matrix in the dorsal striatum whereas a significantly higher proportion of these neurons was located in MOR-enriched domains of the ventral striatum. Further, the majority of striatal TH-eGFP interneurons was found to be located within 100 MUm of a striosome-matrix boundary. Taken together, the current results suggest that TH-eGFP interneurons obey different organizational principles in dorsal versus ventral striatum, and may play a role in communication between striatal striosome and matrix compartments. PMID- 21713113 TI - Adolescent opiate exposure in the female rat induces subtle alterations in maternal care and transgenerational effects on play behavior. AB - The non-medical use of prescription opiates, such as Vicodin((r)) and MSContin((r)), has increased dramatically over the past decade. Of particular concern is the rising popularity of these drugs in adolescent female populations. Use during this critical developmental period could have significant long-term consequences for both the female user as well as potential effects on her future offspring. To address this issue, we have begun modeling adolescent opiate exposure in female rats and have observed significant transgenerational effects despite the fact that all drugs are withdrawn several weeks prior to pregnancy. The purpose of the current set of studies was to determine whether adolescent morphine exposure modifies postpartum care. In addition, we also examined juvenile play behavior in both male and female offspring. The choice of the social play paradigm was based on previous findings demonstrating effects of both postpartum care and opioid activity on play behavior. The findings revealed subtle modifications in the maternal behavior of adolescent morphine-exposed females, primarily related to the amount of time females' spend nursing and in non-nursing contact with their young. In addition, male offspring of adolescent morphine-exposed mothers (MOR-F1) demonstrate decreased rough and tumble play behaviors, with no significant differences in general social behaviors (i.e., social grooming and social exploration). Moreover, there was a tendency toward increased rough and tumble play in MOR-F1 females, demonstrating the sex-specific nature of these effects. Given the importance of the postpartum environment on neurodevelopment, it is possible that modifications in maternal-offspring interactions, related to a history of adolescent opiate exposure, plays a role in the observed transgenerational effects. Overall, these studies indicate that the long-term consequences of adolescent opiate exposure can impact both the female and her future offspring. PMID- 21713114 TI - Compartmentalized Cerebral Metabolism of [1,6-(13)C]Glucose Determined by in vivo (13)C NMR Spectroscopy at 14.1 T. AB - Cerebral metabolism is compartmentalized between neurons and glia. Although glial glycolysis is thought to largely sustain the energetic requirements of neurotransmission while oxidative metabolism takes place mainly in neurons, this hypothesis is matter of debate. The compartmentalization of cerebral metabolic fluxes can be determined by (13)C nuclear magnetic resonance (NMR) spectroscopy upon infusion of (13)C-enriched compounds, especially glucose. Rats under light alpha-chloralose anesthesia were infused with [1,6-(13)C]glucose and (13)C enrichment in the brain metabolites was measured by (13)C NMR spectroscopy with high sensitivity and spectral resolution at 14.1 T. This allowed determining (13)C enrichment curves of amino acid carbons with high reproducibility and to reliably estimate cerebral metabolic fluxes (mean error of 8%). We further found that TCA cycle intermediates are not required for flux determination in mathematical models of brain metabolism. Neuronal tricarboxylic acid cycle rate (V(TCA)) and neurotransmission rate (V(NT)) were 0.45 +/- 0.01 and 0.11 +/- 0.01 MUmol/g/min, respectively. Glial V(TCA) was found to be 38 +/- 3% of total cerebral oxidative metabolism, accounting for more than half of neuronal oxidative metabolism. Furthermore, glial anaplerotic pyruvate carboxylation rate (V(PC)) was 0.069 +/- 0.004 MUmol/g/min, i.e., 25 +/- 1% of the glial TCA cycle rate. These results support a role of glial cells as active partners of neurons during synaptic transmission beyond glycolytic metabolism. PMID- 21713115 TI - Asc-dependent and independent mechanisms contribute to restriction of legionella pneumophila infection in murine macrophages. AB - The apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) is an adaptor molecule that mediates inflammatory and apoptotic signals. Legionella pneumophila is an intracellular bacterium and the causative agent of Legionnaire's pneumonia. L. pneumophila is able to cause pneumonia in immuno-compromised humans but not in most inbred mice. Murine macrophages that lack the ability to activate caspase-1, such as caspase(-1-/-) and Nlrc4(-/-) allow L. pneumophila infection. This permissiveness is attributed mainly to the lack of active caspase-1 and the absence of its down stream substrates such as caspase-7. However, the role of Asc in control of L. pneumophila infection in mice is unclear. Here we show that caspase-1 is moderately activated in Asc(-/-) macrophages and that this limited activation is required and sufficient to restrict L. pneumophila growth. Moreover, Asc-independent activation of caspase-1 requires bacterial flagellin and is mainly detected in cellular extracts but not in culture supernatants. We also demonstrate that the depletion of Asc from permissive macrophages enhances bacterial growth by promoting L. pneumophila mediated activation of the NF-kappaB pathway and decreasing caspase-3 activation. Taken together, our data demonstrate that L. pneumophila infection in murine macrophages is controlled by several mechanisms: Asc-independent activation of caspase-1 and Asc-dependent regulation of NF-kappaB and caspase-3 activation. PMID- 21713116 TI - Grand challenges in pharmacotherapy of inflammation for the first decades of the 21st century. PMID- 21713117 TI - Estimating neural signal dynamics in the human brain. AB - Although brain imaging methods are highly effective for localizing the effects of neural activation throughout the human brain in terms of the blood oxygenation level dependent (BOLD) response, there is currently no way to estimate the underlying neural signal dynamics in generating the BOLD response in each local activation region (except for processes slower than the BOLD time course). Knowledge of the neural signal is critical if spatial mapping is to progress to the analysis of dynamic information flow through the cortical networks as the brain performs its tasks. We introduce an analytic approach that provides a new level of conceptualization and specificity in the study of brain processing by non-invasive methods. This technique allows us to use brain imaging methods to determine the dynamics of local neural population responses to their native temporal resolution throughout the human brain, with relatively narrow confidence intervals on many response properties. The ability to characterize local neural dynamics in the human brain represents a significant enhancement of brain imaging capabilities, with potential applications ranging from general cognitive studies to assessment of neuropathologies. PMID- 21713118 TI - Towards a neuroscience of mind-wandering. AB - Mind-wandering (MW) is among the most robust and permanent expressions of human conscious awareness, classically regarded by philosophers, clinicians, and scientists as a core element of an intact sense of self. Nevertheless, the scientific exploration of MW poses unique challenges; MW is by nature a spontaneous, off task, internal mental process which is often unaware and usually difficult to control, document or replicate. Consequently, there is a lack of accepted modus operandi for exploring MW in a laboratory setup, leading to a relatively small amount of studies regarding the neural basis of MW. In order to facilitate scientific examination of MW the current review categorizes recent literature into five suggested strategies. Each strategy represents a different methodology of MW research within functional neuroimaging paradigms. Particular attention is paid to resting-state brain activity and to the "default-mode" network. Since the default network is known to exert high activity levels during off-task conditions, it stands out as a compelling candidate for a neuro biological account of mind-wandering, in itself a rest-based phenomenon. By summarizing the results within and across strategies we suggest further insights into the neural basis and adaptive value of MW, a truly intriguing and unique human experience. PMID- 21713120 TI - Predictive toxicity: grand challenges. PMID- 21713119 TI - Characterization of natural killer cells in tamarins: a technical basis for studies of innate immunity. AB - Natural killer (NK) cells are capable of regulating viral infection without major histocompatibility complex restriction. Hepatitis C is caused by chronic infection with hepatitis C virus (HCV), and impaired activity of NK cells may contribute to the control of the disease progression, although the involvement of NK cells in vivo remains to be proven. GB virus B (GBV-B), which is genetically most closely related to HCV, induces acute and chronic hepatitis upon experimental infection of tamarins. This non-human primate model seems likely to be useful for unveiling the roles of NK cells in vivo. Here we characterized the biological phenotypes of NK cells in tamarins and found that depletion of the CD16+ subset in vivo by administration of a monoclonal antibody significantly reduced the number and activity of NK cells. PMID- 21713121 TI - Perception of 3D Slant Out of the Box. AB - Evidence for contextual effects is widespread in visual perception. Although this suggests that contextual effects are the result of a generic property of the visual system, current explanations are limited to the domain in which they occur. In this paper we propose a more general mechanism of global influences on the perception of slant. We review empirical data and evaluate proposed explanations of contextual biases. By assessing not only a model about three dimensional slant perception but also evaluating more generic mechanisms of contextual modulation, we show that surround suppression of neural responses explains the major phenomena in the empirical data on contextual biases. Moreover, contextual biases may be part of a mechanism of grouping and segmentation. PMID- 21713122 TI - The influence of task-irrelevant music on language processing: syntactic and semantic structures. AB - Recent research has suggested that music and language processing share neural resources, leading to new hypotheses about interference in the simultaneous processing of these two structures. The present study investigated the effect of a musical chord's tonal function on syntactic processing (Experiment 1) and semantic processing (Experiment 2) using a cross-modal paradigm and controlling for acoustic differences. Participants read sentences and performed a lexical decision task on the last word, which was, syntactically or semantically, expected or unexpected. The simultaneously presented (task-irrelevant) musical sequences ended on either an expected tonic or a less-expected subdominant chord. Experiment 1 revealed interactive effects between music-syntactic and linguistic syntactic processing. Experiment 2 showed only main effects of both music syntactic and linguistic-semantic expectations. An additional analysis over the two experiments revealed that linguistic violations interacted with musical violations, though not differently as a function of the type of linguistic violations. The present findings were discussed in light of currently available data on the processing of music as well as of syntax and semantics in language, leading to the hypothesis that resources might be shared for structural integration processes and sequencing. PMID- 21713123 TI - An Improved BAC Transgenic Fluorescent Reporter Line for Sensitive and Specific Identification of Striatonigral Medium Spiny Neurons. AB - The development of BAC transgenic mice expressing promoter-specific fluorescent reporter proteins has been a great asset for neuroscience by enabling detection of neuronal subsets in live tissue. For the study of basal ganglia physiology, reporters driven by type 1 and 2 dopamine receptors have been particularly useful for distinguishing the two classes of striatal projection neurons - striatonigral and striatopallidal. However, emerging evidence suggests that some of the transgenic reporter lines may have suboptimal features. The ideal transgenic reporter line should (1) express a reporter with high sensitivity and specificity for detecting the cellular subset of interest and that does not otherwise alter the biology of the cells in which it is expressed, and (2) involve a genetic manipulation that does not cause any additional genetic effects other than expression of the reporter. Here we introduce a new BAC transgenic reporter line, Drd1a-tdTomato line 6, with features that approximate these ideals, offering substantial benefits over existing lines. In this study, we investigate the integrity of dopamine-sensitive behaviors and test the sensitivity and specificity of tdTomato fluorescence for identifying striatonigral projection neurons in mice. Behaviorally, hemizygous Drd1a-tdTomato line 6 mice are similar to littermate controls; while hemizygous Drd2-EGFP mice are not. In characterizing the sensitivity and specificity of line 6 mice, we find that both are high. The results of this characterization indicate that line 6 Drd1a tdTomato+/- mice offer a useful alternative approach to identify both striatonigral and striatopallidal neurons in a single transgenic line with a high degree of accuracy.